CN117177997A - 新型抗-hvegfr2抗体 - Google Patents
新型抗-hvegfr2抗体 Download PDFInfo
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- CN117177997A CN117177997A CN202280028642.5A CN202280028642A CN117177997A CN 117177997 A CN117177997 A CN 117177997A CN 202280028642 A CN202280028642 A CN 202280028642A CN 117177997 A CN117177997 A CN 117177997A
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C07K—PEPTIDES
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- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
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- C07—ORGANIC CHEMISTRY
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- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
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- C07K—PEPTIDES
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- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
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Landscapes
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Abstract
本公开在本文中提供了抗‑hVEGFR2抗体或其抗原结合片段、编码该抗‑hVEGFR2抗体或其抗原结合片段的分离的多核苷酸、包括该抗‑hVEGFR2抗体或其抗原结合片段的药物组合物以及它们的用途。
Description
发明领域
本公开总体上涉及特异性结合人VEGFR2(hVEGFR2)的新型抗-hVEGFR2抗体。
背景技术
血管内皮生长因子受体2(VEGFR2)是可被血管内皮生长因子(VEGF)(例如VEGF-A、VEGF-C和VEGF-D)刺激的III型酪氨酸激酶。在与VEGF-A结合后,VEGFR2增加其表达并变成二聚体形式。VEGFR2的二聚化诱导VEGFR2的酪氨酸磷酸化,随后激活参与增殖、迁移、分化、管形成、维持血管完整性和增加内皮细胞血管通透性的下游通路。VEGFR2的异常高表达和/或活性破坏了血管生成的稳态并导致各种癌症和/或血管生成疾病。
因此,对于可用于治疗对hVEGFR2表达呈阳性的疾病如癌症以及其他血管生成疾病的新型抗-hVEGFR2抗体存在重大需求。
发明内容
在整个本公开中,冠词“一(a/an)”和“所述”在本文中用于指一个(种)或多于一个(种)(即,至少一个(种))所述冠词的语法对象。举例来说,“一抗体”意指一种抗体或多于一种抗体。
除其他外,本公开提供新型单克隆抗-hVEGFR2抗体、编码该抗体的核苷酸序列及其用途。
在一方面,本公开提供了一种抗-hVEGFR抗体或其抗原结合片段,其包括重链HCDR1、HCDR2和HCDR3和/或轻链LCDR1、LCDR2和LCDR3序列,其中:
HCDR1序列包括SSWMN(SEQ ID NO:1)、DYYMS(SEQ ID NO:19)、X1YGMS(SEQ ID NO:41)、X4YWIM(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(SEQID NO:20)、SISX2GGSYTYYADSVX19G(SEQ ID NO:42)、DIYPGX5GSTNYNEKFKS(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)、EX3DGNYDY(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)、RASESVX6NSGISFMX7(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(SEQID NO:29)、AASX8QX9S(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X1是I或M,X2是V或I,X3是L或M,X4是T或S,X5是T或S,X6是D或E,X7是T或H,X8是T或Y,X9是G或R和X19是E或K。
在某些实施例中,HCDR1包括SEQ ID NO:41的氨基酸序列,HCDR2包括SEQ ID NO:42的氨基酸序列,HCDR3包括SEQ ID NO:43的氨基酸序列,LCDR1包括SEQ ID NO:28的序列,LCDR2包括SEQ ID NO:29的序列,并且LCDR3包括SEQ ID NO:30的序列。
在某些实施例中,在本文提供的抗体或其抗原结合片段中,其中
a)HCDR1包括SEQ ID NO:25的序列,HCDR2包括SEQ ID NO:26的序列,HCDR3包括SEQ ID NO:27的序列;LCDR1包括SEQ ID NO:28的序列,LCDR2包括SEQ ID NO:29的序列,并且LCDR3包括SEQ ID NO:30的序列;或者
b)HCDR1包括SEQ ID NO:31的序列,HCDR2包括SEQ ID NO:32或SEQ ID NO:37的序列,并且HCDR3包括SEQ ID NO:33的序列,LCDR1包括SEQ ID NO:28的序列,LCDR2包括SEQID NO:29的序列,并且LCDR3包括SEQ ID NO:30的序列;或者
c)HCDR1包括SEQ ID NO:34的序列,HCDR2包括SEQ ID NO:35或SEQ ID NO:37的序列,并且HCDR3包括SEQ ID NO:36的序列,LCDR1包括SEQ ID NO:28的序列,LCDR2包括SEQID NO:29的序列,并且LCDR3包括SEQ ID NO:30的序列。
在某些实施例中,在本文提供的抗-hVEGFR抗体或其抗原结合片段中,其中HCDR1包括SEQ ID NO:44的氨基酸序列,HCDR2包括SEQ ID NO:45的氨基酸序列,HCDR3包括SEQID NO:46的氨基酸序列,LCDR1包括SEQ ID NO:47的序列,LCDR2包括SEQ ID NO:48的序列,并且LCDR3包括SEQ ID NO:49的序列。
在某些实施例中,在本文提供的抗体或其抗原结合片段中,其中
a)HCDR1包括SEQ ID NO:7的序列,HCDR2包括SEQ ID NO:8的序列,HCDR3包括SEQID NO:9的序列;LCDR1包括SEQ ID NO:10的序列,LCDR2包括SEQ ID NO:11的序列,并且LCDR3包括SEQ ID NO:12的序列;或者
b)HCDR1包括SEQ ID NO:13的序列,HCDR2包括SEQ ID NO:14的序列,并且HCDR3包括SEQ ID NO:15的序列,LCDR1包括SEQ ID NO:16的序列,LCDR2包括SEQ ID NO:17的序列,并且LCDR3包括SEQ ID NO:18的序列。
在某些实施例中,在本文提供的抗体或其抗原结合片段中,其中
a)HCDR1包括SEQ ID NO:1的序列,HCDR2包括SEQ ID NO:2的序列,并且HCDR3包括SEQ ID NO:3的序列,LCDR1包括SEQ ID NO:4的序列,LCDR2包括SEQ ID NO:5的序列,并且LCDR3包括SEQ ID NO:6的序列;或者
b)HCDR1包括SEQ ID NO:19的序列,HCDR2包括SEQ ID NO:20的序列,并且HCDR3包括SEQ ID NO:21的序列,LCDR1包括SEQ ID NO:22的序列,LCDR2包括SEQ ID NO:23的序列,并且LCDR3包括SEQ ID NO:24的序列。
在某些实施例中,本文提供的抗体或其抗原结合片段进一步包括重链HFR1、HFR2、HFR3和HFR4中的一种或多种,和/或轻链LFR1、LFR2、LFR3和LFR4中的一种或多种,其中:
HFR1包括EVQLVESGGGLVKPGGSLX10LSCAASGFTFS(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WVRQX11PGKRLEWVA(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RFTISRDNAKNTLYLQMNSLX12AEDTAVYYCAR(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WGX13GTTLTVSS(SEQ ID NO:87)或其至少80%序列同一性的同源序列,
LFR1包括DIVITQX14X15LSLPVTX16GESVSISC(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GVX17DRFSGSGSGTDFTLKISRVEAEDVGX18YYC(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,和
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X10是R或K,X11是A或T,X12是R或K,X13是Q或H,X14是D或T,X15是E或P,X16是F或P,X17是S或P,X18是V或I。
在某些实施例中,在本文提供的抗体或其抗原结合片段中,其中:
HFR1包括选自由SEQ ID NO:64、68和72组成的群组的序列,
HFR2包括选自由SEQ ID NO:65、69和73组成的群组的序列,
HFR3包括选自由SEQ ID NO:66、70和74组成的群组的序列,
HFR4包括选自由SEQ ID NO:67、71和75组成的群组的序列,
LFR1包括选自由SEQ ID NO:76和80组成的群组的序列,
LFR2包括选自由SEQ ID NO:77和81组成的群组的序列,
LFR3包括选自由SEQ ID NO:78和82组成的群组的序列,和
LFR4包括选自由SEQ ID NO:79和83组成的群组的序列。
在某些实施例中,在本文提供的抗体或其抗原结合片段中,其中重链可变区包括选自由以下组成的群组的序列: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 IDNO:98,及其具有至少80%序列同一性但仍保留对hVEGFR2的特异性结合亲和力的同源序列。
在某些实施例中,在本文提供的抗体或其抗原结合片段中,其中轻链可变区包括选自由以下组成的群组的序列: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对hVEGFR2的特异性结合亲和力的同源序列。
在某些实施例中,在本文提供的抗体或其抗原结合片段中,其中:
a)重链可变区包括SEQ ID NO:50的序列和轻链可变区包括SEQ ID NO:51的序列;
b)重链可变区包括SEQ ID NO:52的序列和轻链可变区包括SEQ ID NO:53的序列;
c)重链可变区包括SEQ ID NO:54的序列和轻链可变区包括SEQ ID NO:55的序列;
d)重链可变区包括SEQ ID NO:56的序列和轻链可变区包括SEQ ID NO:57的序列;
e)重链可变区包括SEQ ID NO:58的序列和轻链可变区包括SEQ ID NO:59的序列;
f)重链可变区包括SEQ ID NO:60的序列和轻链可变区包括SEQ ID NO:61的序列;
g)重链可变区包括SEQ ID NO:62的序列和轻链可变区包括SEQ ID NO:63的序列;或者
h)重链可变区包括SEQ ID NO:93或SEQ ID NO:94或SEQ ID NO:98的序列和轻链可变区包括SEQ ID NO:96或SEQ ID NO:97的序列。
在某些实施例中,本文提供的抗体或其抗原结合片段进一步包括一个或多个氨基酸残基取代或修饰,但仍保留对hVEGFR2的特异性结合亲和力。
在某些实施例中,取代或修饰中的至少一个在一个或多个CDR序列中,和/或在VH或VL序列的一个或多个非CDR区中。
在某些实施例中,本文提供的抗体或其抗原结合片段还包括免疫球蛋白恒定区,任选地人Ig的恒定区,或任选地人IgG的恒定区。
在某些实施例中,恒定区包括人IgG1、IgG2、IgG3或IgG4的恒定区。
在某些实施例中,人IgG1的恒定区包括SEQ ID NO:38,或其具有至少80%序列同一性的同源序列。
在某些实施例中,本文提供的抗体或其抗原结合片段是人源化的。
在某些实施例中,本文提供的抗体或其抗原结合片段是双功能抗体、Fab、Fab'、F(ab')2、Fd、Fv片段、二硫键稳定化Fv片段(dsFv)、(dsFv)2、双特异性dsFv(dsFv-dsFv')、二硫键稳定化双功能抗体(ds双功能抗体)、单链抗体分子(scFv)、scFv二聚体(二价双功能抗体)、多特异性抗体、骆驼化单结构域抗体、纳米抗体、结构域抗体或二价结构域抗体。
在某些实施例中,本文提供的抗体或其抗原结合片段是双特异性的。
在某些实施例中,本文提供的抗体或其抗原结合片段能够特异性结合hVEGFR2的第一和第二表位,或能够特异性结合hVEGFR2和第二抗原。
在某些实施例中,第二抗原是免疫相关靶标,任选地选自由以下组成的群组:PD-L1、PD-L2、PD-1、CLTA-4、TIM-3、LAG3、CD160、2B4、TGFβ、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和CD83。
在某些实施例中,第二抗原包括肿瘤抗原。
在某些实施例中,肿瘤抗原存在于表达VEGFR2的细胞中。
在某些实施例中,肿瘤抗原包括密蛋白18.2、CA-125、神经节苷脂G(D2)、G(M2)和G(D3)、CD20、CD52、CD33、Ep-CAM、CEA、铃蟾肽样肽、PSA、HER2/neu、表皮生长因子受体(EGFR)、erbB2、erbB3/HER3、erbB4、CD44v6、Ki-67、癌症相关粘蛋白、VEGF、VEGFR(例如VEGFR3)、雌激素受体、Lewis-Y抗原、TGFβ1、IGF-1受体、EGFα、c-Kit受体、转铁蛋白受体、IL-2R或CO17-1A。
在某些实施例中,本文提供的抗体或其抗原结合片段与一个或多个缀合物部分连接。
在某些实施例中,缀合物部分包括清除调节剂、化学治疗剂、毒素、放射性同位素、镧系元素、发光标记、荧光标记、酶-底物标记、DNA烷化剂、拓扑异构酶抑制剂、微管蛋白结合剂或其他抗癌药物。
在另一方面,本公开还提供与本文提供的抗体或抗原结合片段竞争结合hVEGFR2的抗体或其抗原结合片段。
在一方面,本公开提供一种药物组合物,其包括本文提供的抗体或抗原结合片段,以及一种或多种药学上可接受的载剂。
在某些实施例中,本文提供的药物组合物进一步包括第二治疗剂。
在某些实施例中,第二治疗剂包括抗癌疗法,任选地,抗癌疗法选自化学治疗剂、放射疗法、免疫治疗剂、抗血管生成剂(例如VEGFR(如VEGFR-1和VEGFR-3)的拮抗剂)、EGFR拮抗剂、PDGFR拮抗剂、IGFR拮抗剂、NGFR拮抗剂、FGFR拮抗剂、靶向治疗剂(例如HER2抗体、密蛋白18.2抗体)、细胞治疗剂、基因治疗剂、激素治疗剂、细胞因子、姑息治疗、治疗癌症的手术(例如肿瘤切除术)、一种或多种止吐药、化学疗法引起的并发症的治疗或癌症患者的膳食补充剂(例如吲哚-3-甲醇)。
在一方面,本公开提供一种分离的多核苷酸,其编码本文提供的抗体或其抗原结合片段。
在一方面,本公开提供一种载体,其包括本文提供的分离的多核苷酸。
在一方面,本公开提供一种宿主细胞,其包括本文提供的载体。
在一方面,本公开提供一种表达本文提供的抗体或其抗原结合片段的方法,包括在表达本文提供的载体的条件下培养本文提供的宿主细胞。
在一方面,本公开提供一种在受试者中治疗VEGFR2相关疾病或病症、降低VEGFR2相关疾病或病症的严重性和/或减缓VEGFR2相关疾病或病症的进展的方法,包括向受试者施用治疗有效量的本文提供的抗体或其抗原结合片段,或本文提供的药物组合物。
在某些实施例中,VEGFR2相关疾病或病症是肿瘤或血管生成疾病。
在某些实施例中,肿瘤产生VEGF(例如,VEGF-A)和/或对其微环境中存在的VEGF(例如,VEGF-A)敏感。
在某些实施例中,肿瘤是实体瘤或非实体瘤。
在某些实施例中,实体瘤选自由以下组成的群组:乳腺癌、肺癌、结直肠癌、胰腺癌、胶质瘤和淋巴瘤、头颈肿瘤、神经内分泌肿瘤、结直肠肿瘤、前列腺肿瘤、乳腺肿瘤、肺肿瘤(如小细胞和非小细胞肺肿瘤)、胰腺肿瘤、甲状腺肿瘤、卵巢肿瘤、宫颈肿瘤、肾肿瘤、脑肿瘤、肝肿瘤、卡波西肉瘤、CNS肿瘤、神经母细胞瘤、毛细血管母细胞瘤、脑膜瘤、脑转移、黑色素瘤、胃肠道和肾癌和肉瘤(例如胃癌)、横纹肌肉瘤、胶质母细胞瘤(优选多形性胶质母细胞瘤)、平滑肌肉瘤、鳞状细胞癌、基底细胞癌和可通过抑制恶性角化细胞(如人恶性角化细胞)的生长来治疗的皮肤癌。
在某些实施例中,肿瘤选自由以下组成的群组:胃癌、非小细胞肺癌如大细胞肺癌。
在某些实施例中,非实体瘤选自由以下组成的群组:白血病、多发性骨髓瘤和淋巴瘤,例如急性髓性白血病(AML)、慢性髓性白血病(CML)、急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、红细胞白血病或单核细胞白血病、霍奇金和非霍奇金淋巴瘤。
在某些实施例中,血管生成疾病选自由以下组成的群组:动脉粥样硬化、类风湿性关节炎(RA)、新生血管性青光眼、包含增殖性糖尿病视网膜病变在内的增殖性视网膜病变、黄斑变性、血管瘤、血管纤维瘤、牛皮癣、早产儿视网膜病变(例如,晶状体后纤维增生)、角膜移植排斥、胰岛素依赖型糖尿病、多发性硬化、重症肌无力、克罗恩病、自身免疫性肾炎、原发性胆汁性肝硬化、急性胰腺炎、同种异体移植排斥、过敏性炎症、接触性皮炎和迟发性超敏反应、炎性肠病、感染性休克、骨质疏松症、骨关节炎、由神经元炎症引起的认知缺陷、奥斯勒-韦伯综合征、再狭窄以及真菌、寄生虫和病毒感染如巨细胞病毒感染。
在某些实施例中,受试者是人。
在某些实施例中,施用通过口服、鼻、静脉内、皮下、舌下、瘤内或肌肉内施用进行。
在某些实施例中,本文提供的方法进一步包括施用治疗有效量的第二治疗剂。
在某些实施例中,第二治疗剂包括抗癌疗法,任选地,抗癌疗法选自化学治疗剂、放射疗法、免疫治疗剂、抗血管生成剂(例如VEGFR(如VEGFR-1、VEGFR-2和VEGFR-3)的拮抗剂)、EGFR拮抗剂、PDGFR拮抗剂、IGFR拮抗剂、NGFR拮抗剂、FGFR拮抗剂、靶向治疗剂、细胞治疗剂、基因治疗剂、激素治疗剂、细胞因子、姑息治疗、治疗癌症的手术(例如肿瘤切除术)、一种或多种止吐药、化学疗法引起的并发症的治疗或癌症患者的膳食补充剂(例如吲哚-3-甲醇)。
在一方面,本公开提供一种试剂盒,其包括本文提供的抗体或其抗原结合片段。
在一方面,本公开提供一种检测样品中VEGFR2的存在或量的方法,包括使样品与本文提供的抗体或其抗原结合片段接触,和确定样品中VEGFR2的存在或量。
在一方面,本公开提供本文提供的抗体或其抗原结合片段在制备用于在受试者中治疗VEGFR2相关疾病或病症、降低VEGFR2相关疾病或病症的严重性和/或减缓VEGFR2相关疾病或病症的进展的药物中的用途。
在某些实施例中,VEGFR2相关疾病或病症是肿瘤或血管生成疾病。
在某些实施例中,肿瘤产生VEGF(例如,VEGF-A)和/或对其微环境中存在的VEGF(例如,VEGF-A)敏感。
在某些实施例中,肿瘤是实体瘤或非实体瘤。
在某些实施例中,血管生成疾病选自由以下组成的群组:动脉粥样硬化、类风湿性关节炎(RA)、新生血管性青光眼、包含增殖性糖尿病视网膜病变在内的增殖性视网膜病变、黄斑变性、血管瘤、血管纤维瘤、牛皮癣、早产儿视网膜病变(例如,晶状体后纤维增生)、角膜移植排斥、胰岛素依赖型糖尿病、多发性硬化、重症肌无力、克罗恩病、自身免疫性肾炎、原发性胆汁性肝硬化、急性胰腺炎、同种异体移植排斥、过敏性炎症、接触性皮炎和迟发性超敏反应、炎性肠病、感染性休克、骨质疏松症、骨关节炎、由神经元炎症引起的认知缺陷、奥斯勒-韦伯综合征、再狭窄以及真菌、寄生虫和病毒感染如巨细胞病毒感染。
附图说明
图1A和图1B显示纯化的杂交瘤抗体#002、#003、#006、#018、#042、#048和#054与人VEGFR2(hVEGFR2)的剂量依赖性结合。
图2显示纯化的杂交瘤抗体对人VEGF-A(hVEGF-A)与hVEGFR2结合的剂量依赖性阻断活性。
图3显示杂交瘤抗体与HUVEC细胞的结合。
图4A和图4B显示结合hVEGFR2和恒河猴VEGFR2的嵌合抗体。
图5显示嵌合抗体阻断VEGF-A/VEGFR2相互作用。
图6显示嵌合抗体与HUVEC细胞的结合。
图7A和图7B显示通过竞争测定使用生物素-mAB002的表位组合。
图8A、图8B和图8C显示剂量依赖性竞争测定结果。
图9A、图9B和图9C显示嵌合抗体抑制由VEGF-A诱导的VEGFR2磷酸化。
图10A和图10B显示通过ELISA得到的在293T细胞中产生的人源化抗体与人VEGFR2-his的结合。
图11A和图11B显示通过ELISA得到的在CHO细胞中产生的人源化抗体与人VEGFR2-his和恒河猴VEGFR2-his的结合。
图12显示特异性结合VEGFR2的人源化抗体。
图13A和图13B显示阻断VEGF-A与人VEGFR2或恒河猴VEGFR2结合的人源化抗体。
图14A、图14B和图14C显示阻断VEGF-A、C或D与VEGFR2结合的人源化抗体。
图15显示与HUVEC细胞结合的人源化抗体。
图16显示人源化抗体054抑制VEGF-A诱导的VEGFR2磷酸化。
图17显示阻断VEGF-A介导的细胞增殖的人源化抗体。
图18显示用基准抗体1121B、嵌合054(54-C)、嵌合002(2-C)或盐水处理的NOD/SCID小鼠上的HL-60移植存活曲线。
图19显示嵌合-DC101与小鼠VEGFR2的ELISA结合。
图20显示嵌合-DC101阻断小鼠VEGFR2与人VEGF165(VEGF-A的剪接变体)的结合。
图21显示MKN45异种移植肿瘤在裸鼠上的肿瘤生长曲线(平均值±S.E.M.,n=10)。
图22显示H460异种移植肿瘤在裸鼠上的肿瘤生长曲线(平均值±S.E.M.,n=10)
图23显示H1975异种移植肿瘤在裸鼠上的肿瘤生长曲线(平均值±S.E.M.,n=10)
具体实施方式
以下对本公开的描述仅打算说明本公开的各种实施例。因此,所论述的具体修改不应被解释为对本公开范围的限制。对本领域的技术人员将显而易见的是,可以在不脱离本公开范围的情况下作出各种等效物、变化和修改,并且应理解,这些等效实施例将包含在本文中。本文引用的所有参考文献,包含出版物、专利和专利申请,均以全文引用的方式并入本文中。
定义
如本文所用,除非本文另有说明或与上下文明显矛盾,否则在本发明的上下文中(尤其是在权利要求的上下文中)使用的术语“一(a)”、“一个(an)”、“该(the)”和类似术语将被解释为涵盖单数和复数。
如本文所用,术语“抗体”包含与特异性抗原结合的任何免疫球蛋白、单克隆抗体、多克隆抗体、多价抗体、二价抗体、单价抗体、多特异性抗体或双特异性抗体。天然完整抗体包含两条重(H)链和两条轻(L)链。哺乳动物重链分为α、δ、ε、γ和μ,每条重链由可变区(VH)和第一、第二和第三恒定区(分别为CH1、CH2、CH3)组成;哺乳动物轻链分为λ或κ,而每条轻链由可变区(VL)和恒定区组成。抗体呈“Y”形,其中Y的主干由通过二硫键结合在一起的两条重链的第二和第三恒定区组成。Y的每个臂包含与单条轻链的可变区和恒定区结合的单条重链的可变区和第一恒定区。轻链和重链的可变区负责抗原结合。两条链的可变区一般含有三个高度可变的环,称为互补决定区(CDR)(轻链CDR包含LCDR1、LCDR2和LCDR3,重链CDR包含HCDR1、HCDR2、HCDR3)。本文公开的抗体和抗原结合结构域的CDR边界可以通过Kabat、IMGT、AbM、Chothia或Al-Lazikani的惯例(Al-Lazikani,B.、Chothia,C.、Lesk,A.M.的《分子生物学杂志(J.Mol.Biol.)》,273(4),927(1997);Chothia,C.等人,《分子生物学杂志》,12月5日;186(3):651-63(1985);Chothia,C.和Lesk,A.M.的《分子生物学杂志》,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,美国国立卫生研究院(National Institutes of Health),Bethesda,Md.(1991);Marie-Paule Lefranc等人,《发育和比较免疫学(Developmental andComparative Immunology)》,27:55-77(2003);Marie-Paule Lefranc等人,《免疫组学研究(Immunome Research)》,1(3),(2005);Marie-Paule Lefranc,《B细胞的分子生物学(Molecular Biology of B cells)》(第二版),第26章,481-514,(2015))来定义或识别。三个CDR插入于称为框架区(FR)的侧翼片段之间,框架区比CDR更高度保守,并形成支撑高变环的支架。重链和轻链的恒定区不参与抗原结合,但表现出各种效应物功能。基于抗体重链恒定区的氨基酸序列,将抗体分类。抗体的五种主要类别或同种型是IgA、IgD、IgE、IgG和IgM,其特征在于分别存在α、δ、ε、γ和μ重链。将若干主要抗体类别划分为子类,如IgG1(γ1重链)、IgG2(γ2重链)、IgG3(γ3重链)、IgG4(γ4重链)、IgA1(α1重链)或IgA2(α2重链)。在某些实施例中,本文提供的抗体涵盖任何其抗原结合片段。
如本文所用,术语“抗原结合片段”是指由包括一个或多个CDR的抗体片段,或任何其他与抗原结合但不包括完整的原生抗体结构的抗体部分形成的抗体片段。抗原结合片段的实例包含但不限于双功能抗体、Fab、Fab'、F(ab')2、Fd、Fv片段、二硫键稳定化Fv片段(dsFv)、(dsFv)2、双特异性dsFv(dsFv-dsFv')、二硫键稳定化双功能抗体(ds双功能抗体)、单链抗体分子(scFv)、scFv二聚体(二价双功能抗体)、多特异性抗体、骆驼化单结构域抗体、纳米抗体、结构域抗体和二价结构域抗体。抗原结合片段能够与亲本抗体所结合的相同抗原结合。在某些实施例中,抗原结合片段可以包括来自特定人抗体的一个或多个CDR。
关于抗体的“Fab”是指抗体的单价抗原结合片段,其由单条轻链(可变区和恒定区)通过二硫键与单条重链的可变区和第一恒定区结合而成。Fab可以通过在接近铰链区的重链之间二硫键的N端的残基处木瓜蛋白酶消化抗体来获得。
“Fab'”是指包含铰链区的一部分的Fab片段,其可以通过胃蛋白酶消化在铰链区重链之间的二硫键的C末端附近的残基处的抗体获得,并且因此在铰链区的少量残基(包含一个或多个半胱氨酸)上与Fab不同。
“F(ab')2”是指Fab'的二聚体,其包括两条轻链和两条重链的一部分。
关于抗体的“Fc”是指由通过二硫键与第二重链的第二和第三恒定区结合的第一重链的第二和第三恒定区组成的抗体部分。IgG和IgM Fc区含有三个重链恒定区(每条链中的第二、第三和第四重链恒定区)。其可以通过木瓜蛋白酶消化抗体获得。抗体的Fc部分负责各种效应物功能,如ADCC、ADCP和CDC,但不在抗原结合中起作用。
关于抗体的“Fv”是指最小的带有完整抗原结合位点的抗体片段。Fv片段由结合于单条重链的可变区的单条轻链的可变区组成。“dsFv”是指二硫键稳定化Fv片段,其中在单条轻链的可变区与单条重链的可变区之间的连接是二硫键。
“单链Fv抗体”或“scFv”是指由轻链可变区和重链可变区直接或通过肽连接子序列相互连接组成的工程化抗体(Huston JS等人,《美国国家科学院院刊》,85:5879(1988))。“scFv二聚体”是指包括具有连接子的两个重链可变区和两个轻链可变区的单链。在某些实施例中,“scFv二聚体”是包括与另一个VH-VL部分二聚化的VH-VL(通过肽连接子连接)的二价双功能抗体或二价ScFv(BsFv),使得一个部分的VH与另一个部分的VL配位并形成可以靶向相同的抗原(或表位)或不同的抗原(或表位)的两个结合位点。在其他实施例中,“scFv二聚体”是双特异性双功能抗体,其包含VH1-VL2(由肽连接子连接)与VL1-VH2(也由肽连接子连接)结合,使得VH1与VL1配位且VH2与VL2配位并且每个配位对具有不同的抗原特异性。
“单链Fv-Fc抗体”或“scFv-Fc”是指由连接至抗体Fc区的scFv组成的工程化抗体。
“骆驼化单结构域抗体”、“重链抗体”、“纳米抗体”或“HCAb”是指含有两个VH结构域且不含轻链的抗体(Riechmann L.和Muyldermans S.,《免疫方法杂志(J ImmunolMethods.)》,12月10日;231(1-2):25-38(1999);Muyldermans S.,《生物技术杂志(JBiotechnol.)》,6月;74(4):277-302(2001);WO94/04678;WO94/25591;美国专利号6,005,079)。重链抗体最初是从骆驼科(Camelidae)(骆驼、单峰驼和美洲驼)获得的。尽管没有轻链,但骆驼化抗体具有真正的抗原结合库(Hamers-Casterman C.等人,《自然》,6月3日;363(6428):446-8(1993);Nguyen VK.等人,“骆驼科的重链抗体;进化创新案例(Heavychain antibodies in Camelidae;a case of evolutionary innovation)”,《免疫遗传学(Immunogenetics)》,4月;54(1):39-47(2002);Nguyen VK.等人,《免疫学(Immunology)》,5月;109(1):93-101(2003))。重链抗体的可变结构域(VHH结构域)代表由适应性免疫反应产生的已知最小的抗原结合单位(Koch-Nolte F.等人,《FASEB杂志(FASEBJ)》,11月;21(13):3490-8.Epub 2007Jun 15(2007))。“双功能抗体”包含具有两个抗原结合位点的小抗体片段,其中片段包括单条多肽链中与VL结构域连接的VH结构域(VH-VL或VL-VH)(参见例如Holliger P.等人,《美国国家科学院院刊》,7月15日;90(14):6444-8(1993);EP404097;WO93/11161)。因为连接子太短,所以同一条链上的两个结构域无法配对,因此,迫使结构域与另一条链的互补结构域配对,从而产生两个抗原结合位点。抗原结合位点可以靶向相同或不同抗原(或表位)。
“结构域抗体”是指仅含重链的可变区或轻链的可变区的抗体片段。在某些实施例中,两个或更多个VH结构域通过肽连接子共价接合以形成二价或多价结构域抗体。二价结构域抗体的两个VH结构域可靶向相同或不同的抗原。
在某些实施例中,“(dsFv)2”包括三个肽链:两个VH部分通过肽连接子连接并且通过二硫桥结合到两个VL部分。
在某些实施例中,“双特异性ds双功能抗体”包括VH1-VL2(由肽连接子连接)与VL1-VH2(也由肽连接子连接)通过VH1与VL1之间的二硫桥结合。
在某些实施例中,“双特异性dsFv”或“dsFv-dsFv'”包括三个肽链:VH1-VH2部分,其中重链通过肽连接子(例如,长的柔性连接子)结合并通过二硫桥分别与VL1和VL2部分配对。每个二硫键配对的重链和轻链具有不同的抗原特异性。
如本文所用,术语“人源化”意指抗体或抗原结合片段包括来源于非人类动物的CDR、来源于人类的FR区,和当适用时,来源于人类的恒定区。在某些实施例中,人源化hVEGFR2抗体的可变区框架的氨基酸残基被替换以进行序列优化。在某些实施例中,人源化hVEGFR2抗体链的可变区框架序列与相应的人可变区框架序列具有至少65%、70%、75%、80%、85%、90%、95%或100%同一性。
如本文所用,术语“嵌合”是指重链和/或轻链的一部分来源于一个物种,而重链和/或轻链的其余部分来源于不同的物种的抗体或抗原结合片段。在一说明性实例中,嵌合抗体可以包括来源于人类的恒定区和来源于非人类物种(如小鼠)的可变区。
术语“生殖系序列”是指编码可变区氨基酸序列或子序列的核酸序列,与所有其他已知的由生殖系免疫球蛋白可变区序列编码的可变区氨基酸序列相比,所述序列与参考可变区氨基酸序列或子序列具有最高的确定氨基酸序列同一性。生殖系序列也可以指与所有其他评估的可变区氨基酸序列相比,与参考可变区氨基酸序列或子序列具有最高氨基酸序列同一性的可变区氨基酸序列或子序列。生殖系序列可以是仅框架区、仅互补决定区、框架和互补决定区、可变区段(如上文所定义)或包括可变区的序列或子序列的其他组合。序列同一性可以使用本文所述的方法确定,例如,使用BLAST、ALIGN或本领域中已知的另一种比对算法比对两个序列。生殖系核酸或氨基酸序列可以与参考可变区核酸或氨基酸序列具有至少约90%、91、92%、93%、94%、95%、96%、97%、98%、99%或100%的序列同一性。例如,可以通过可公开获得的国际ImMunoGeneTics数据库(IMGT)和V-base确定生殖系序列。
如本文所用,“抗-hVEGFR2抗体”或“抗hVEGFR2抗体”是指能够以足够的亲和力特异性结合人VEGFR2例如以提供诊断和/或治疗用途的抗体。
如本文所用,术语“亲和力”是指免疫球蛋白分子(即抗体)或其片段与抗原之间的非共价相互作用的强度。
如本文所用,术语“特异性结合(specific binding/specifically binds)”是指两个分子之间,如例如抗体与抗原之间的非随机结合反应。在某些实施例中,本文提供的抗体或抗原结合片段以≤10-6M(例如,≤5x10-7M、≤2x10-7M、≤10-7M、≤5x10-8M、≤2x10-8M、≤10-8M、≤5x10-9M、≤4x10-9M、≤3x10-9M、≤2x10-9M或≤10-9M)的结合亲和力(KD)特异性结合hVEGFR2。本文使用的KD是指解离速率相对于缔合速率的比率(koff/kon),其可通过使用所属领域中已知的任何常规方法来确定,方法包含但不限于表面等离激元共振方法、微尺度热泳方法、HPLC-MS方法和流式细胞测量术(如FACS)方法。在某些实施例中,KD值可以通过使用流式细胞术法适当地确定。可以使用各种免疫测定格式来选择与特定蛋白特异性免疫反应的抗体。例如,固相ELISA免疫测定常规地用于选择与蛋白特异性免疫反应的抗体(关于可用于确定特异性免疫反应的免疫测定格式和条件的描述,参见例如Harlow和Lane,《使用抗体,实验室手册(Using Antibodies,A LaboratoryManual)》,(1998))。通常,特异性或选择性结合反应将产生至少两倍于背景信号,更通常是至少10至100倍于背景信号的信号。
关于氨基酸序列(或核酸序列)的“序列同一性百分比(%)”定义为在比对序列并在必要时引入空位以实现最大对应性之后,与参考序列中的氨基酸(或核酸)残基相同的候选序列中的氨基酸(或核酸)残基的百分比。可以例如使用公开可用的工具如BLASTN、BLASTp(可在美国国家生物技术信息中心(NCBI)的网站上获得,还参见Altschul S.F.等人,《分子生物学杂志》,215:403-410(1990);Stephen F.等人,《核酸研究(Nucleic AcidsRes.)》,25:3389–3402(1997))、ClustalW2(可在可在欧洲生物信息学研究所网站上获得,还参见Higgins D.G.等人,《酶学方法(Methods in Enzymology)》,266:383-402(1996);Larkin M.A.等人,《生物信息学(Bioinformatics)》,(Oxford,England),23(21):2947-8(2007)),和ALIGN或Megalign(DNASTAR)软件来实现用于确定氨基酸(或核酸)序列同一性百分比的比对。本领域的技术人员可使用工具提供的默认参数,或可自定义适于比对的参数,如例如通过选择合适算法进行。在某些实施例中,不相同的残基位置可以通过保守氨基酸取代而不同。“保守氨基酸取代”是其中一个氨基酸残基被具有化学特性(例如,电荷或疏水性)类似的侧链(R基团)的另一个氨基酸残基取代的氨基酸取代。通常,保守氨基酸取代不会基本上改变蛋白的功能特性。在两个或更多个氨基酸序列因保守取代而彼此不同的情况下,百分比或类似性程度可以向上调整以校正取代的保守性质。用于进行这种调整的装置对于本领域技术人员来说是众所周知的。参见例如,Pearson(1994),《分子生物学方法(MethodsMol.Biol.)》,24:307-331,其通过引用并入本文。
如本文所用,“同源序列(homologue sequence/homologous sequence)”可互换使用并且是指任选比对时与其他序列具有至少80%(例如至少85%、88%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%)的序列同一性的多核苷酸序列(或其互补链)或氨基酸序列。
“分离”的物质已通过人工方式自天然状态改变。如果“分离”的组合物或物质存在于自然界中,则组合物或物质已经从其原始环境改变或从其原始环境移出,或这两种情况都有。例如,天然地存在于活动物体内的多核苷酸或多肽不是“分离”的,但如果相同多核苷酸或多肽与其天然状态的共存材料充分地分离,由此以基本上纯的状态存在,那么多核苷酸或多肽是“分离”的。经分离“核酸”或“多核苷酸”可互换使用,且是指经分离核酸分子的序列。在某些实施例中,“分离的抗体或其抗原结合片段”是指具有至少60%、70%、75%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%的纯度的抗体或抗原结合片段,如通过电泳方法(如SDS-PAGE、等电聚焦、毛细管电泳)或色谱方法(如离子交换色谱法或反相HPLC)所确定的。
如本文所用,“阻断结合”的能力是指抗体或抗原结合片段将两个分子(例如VEGR-A和hVEGFR2)之间的结合相互作用抑制到任何可检测程度的能力。在某些实施例中,阻断两个分子(例如VEGR-A和hVEGFR2)之间结合的抗体或抗原结合片段将两个分子之间的结合相互作用抑制至少50%。在某些实施例中,这种抑制可以大于60%、大于70%、大于80%或大于90%。
如本文所用,术语“抗体药物缀合物”是指抗体或其抗原结合片段与另一种药剂如化学治疗剂、毒素、免疫治疗剂、成像探针等的连接。该连接可以是共价键,或非共价相互作用,如通过静电力产生的非共价相互作用。可以使用本领域已知的各种连接子以形成抗体药物缀合物。此外,抗体药物缀合物可以以融合蛋白的形式提供,该融合蛋白可以由编码缀合物的多核苷酸表达。如本文所用,“融合蛋白”是指通过连接两个或更多个基因或基因片段产生的蛋白,该基因或基因片段最初编码不同的蛋白(包含肽和多肽)。融合基因的翻译产生具有源自每种原始蛋白的功能特性的单一蛋白。
术语“受试者”包含人类和非人类动物。非人类动物包含所有脊椎动物,例如哺乳动物和非哺乳动物,如非人类灵长类动物、小鼠、大鼠、猫、兔、羊、狗、牛、鸡、两栖动物和爬行动物。除非另有说明,否则术语“患者”或“受试者”在本文中可互换使用。
如本文所用,“效应物功能”或“抗体效应物功能”是指可归因于抗体的Fc区与其效应物如C1复合物和Fc受体的结合的生物活性。示例性效应物功能包含:由抗体和C1q对C1复合物的相互作用诱导的补体依赖性细胞毒性(CDC);由抗体的Fc区与效应细胞上的Fc受体结合诱导的抗体依赖性细胞介导的细胞毒性(ADCC);和抗体依赖性细胞介导的吞噬作用(ADCP),其中表达FcγR的非特异性细胞毒性细胞识别靶细胞上的结合抗体并随后引起靶细胞的吞噬作用。效应物功能包含在抗原结合之后起作用的功能和独立于抗原结合起作用的功能。
如本文所用,病症的“治疗(treating/treatment)”包含预防或减轻病症,减缓病症的发作或发展速率,降低罹患病症的风险,预防或延迟与病症相关的症状的发展,减少或结束与病症相关的症状,产生病症的完全或部分消退,治愈病症或其某一组合。
如本文所用,术语“载体”是指一种媒剂,可将基因元件可操作地插入其中,以实现该基因元件的表达,从而产生由该基因元件编码的蛋白、RNA或DNA,或复制该基因元件。载体可用于转化、转导或转染宿主细胞,以使其携带的基因元件在宿主细胞内表达。载体的实例包含质粒;噬菌粒;粘粒;人工染色体,如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1衍生的人工染色体(PAC);噬菌体,如λ噬菌体或M13噬菌体;和动物病毒。载体可以含有多种用于控制表达的元件,包含启动子序列、转录起始序列、增强子序列、可选择元件和报告基因。另外,载体可以含有复制起点。载体还可以包含有助于其进入细胞的材料,包含但不限于病毒粒子、脂质体或蛋白包衣。载体可以是表达载体或克隆载体。本公开提供了载体(例如表达载体),其含有本文提供的编码抗体或其抗原结合片段的核酸序列、至少一个可操作地连接至该核酸序列的启动子(例如SV40、CMV、EF-1α),和至少一个选择标记物。
如本文所用,“宿主细胞”是指已将外源多核苷酸和/或载体引入其中的细胞。
可与术语“VEGF受体2”、“含有激酶插入结构域的受体(KDR)”、“CD309”或“胎肝激酶1(FLK1)”互换使用的术语“VEGFR2”是VEGF受体(VEGFR)的一种类型,其是III型受体酪氨酸激酶,特征在于其氨基末端胞外受体配体结合结构域中通常具有5或7个免疫球蛋白样环,以及跨膜区和羧基末端胞内催化结构域被称为激酶插入结构域的可变长度的亲水激酶间序列的插入中断(Kaipainen等人,《实验医学杂志(J.Exp.Med.)》,178:2077-88(1993);Terman等人,《癌基因(Oncogene)》,6:1677-83(1991))。其他类型的VEGFR包含fins样酪氨酸激酶受体(fit-1)或VEGFR1,以及VEGFR3(fit-4)(Shibuya等人,《癌基因》,5:519-24(1990))。氨基末端胞外受体配体结合结构域负责配体(例如,血管内皮生长因子A(VEGF-A))和结构域之间的亲和力。羧基末端胞内催化结构域负责启动参与例如细胞生长的信号传导通路。在例如胚胎发生和肿瘤形成期间,可以在内皮细胞上发现VEGFR的表达(Millauer,B.等人,《细胞(Cell)》,72:835-46(1993);Plate,K.等人,(1993))。VEGFR的表达也可以在非内皮细胞上发现,如肿瘤细胞,尤其是产生VEGF的肿瘤细胞,例如白血病细胞(Fielder等人,《血液(Blood)》,89:1870-5(1997)和Bellamy等人,《癌症研究(CancerRes.)》,59728-33(1999))。本文使用的人VEGFR2(hVEGFR2)包括可通过NCBI数据库中的登录号AAI31823.1访问的氨基酸序列或SEQ ID NO:39的氨基酸序列(MQSKVLLAVALWLCVETRAASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCR GQRDLDWLWPNNQSGSEQRVEVTECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQDYRSPFIASVSDQHGVVYITENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWDSKKGFTIPSYMISYAGMVFCEAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGITRSDQGLYTCAASSGLMTKKNSTFVRVHEKPFVAFGSGMESLVEATVGERVRIPAKYLGYPPPEIKWYKNGIPLESNHTIKAGHVLTIMEVSERDTGNYTVILTNPISKEKQSHVVSLVVYVPPQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECANEPSHAVSVTNPYPCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGERVISFHVTRGPEITLQPDMQPTEQESVSLWCTADRSTFENLTWYKLGPQPLPIHVGELPTPVCKNLDTLWKLNATMFSNSTNDILIMELKNASLQDQGDYVCLAQDRKTKKRHCVVRQLTVLERVAPTITGNLENQTTSIGESIEVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNRNLTIRRVRKEDEGLYTCQACSVLGCAKVEAFFIIEGAQEKTNLEIIILVGTAVIAMFFWLLLVIILRTVKRANGGELKTGYLSIVMDPDELPLDEHCERLPYDASKWEFPRDRLKLGKPLGRGAFGQVIEADAFGIDKTATCRTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNVVNLLGACTKPGGPLMVIVEFCKFGNLSTYLRSKRNEFVPYKTKGARFRQGKDYVGAIPVDLKRRLDSITSSQSSASSGFVEEKSLSDVEEEEAPEDLYKDFLTLEHLICYSFQVAKGMEFLASRKCIHRDLAARNILLSEKNVVKICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDRVYTIQSDVWSFGVLLWEIFSLGASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTMLDCWHGEPSQRPTFSELVEHLGNLLQANAQQDGKDYIVLPISETLSMEEDSGLSLPTSPVSCMEEEEVCDPKFHYDNTAGISQYLQNSKRKSRPVSVKTFEDIPLEEPEVKVIPDDNQTDSGMVLASEELKTLEDRTKLSPSFGGMVPSKSRESVASEGSNQTSGYQSGYHSDDTDTTVYSSEEAELLKLIEIGVQTGSTAQILQPDSGTTLSSPPV)。本文使用的小鼠VEGFR2包括可通过NCBI数据库中的登录号P35918.1访问的氨基酸序列或SEQ ID NO:100的氨基酸序列(MESKALLAVALWFCVETRAASVGLPGDFLHPPKLSTQKDILTILANTTLQITCRGQRDLDWLWP NAQRDSEERVLVTECGGGDSIFCKTLTIPRVVGNDTGAYKCSYRDVDIASTVYVYVRDYRSPFIASVSDQHGIVYITENKNKTVVIPCRGSISNLNVSLCARYPEKRFVPDGNRISWDSEIGFTLPSYMISYAGMVFCEAKINDETYQSIMYIVVVVGYRIYDVILSPPHEIELSAGEKLVLNCTARTELNVGLDFTWHSPPSKSHHKKIVNRDVKPFPGTVAKMFLSTLTIESVTKSDQGEYTCVASSGRMIKRNRTFVRVHTKPFIAFGSGMKSLVEATVGSQVRIPVKYLSYPAPDIKWYRNGRPIESNYTMIVGDELTIMEVTERDAGNYTVILTNPISMEKQSHMVSLVVNVPPQIGEKALISPMDSYQYGTMQTLTCTVYANPPLHHIQWYWQLEEACSYRPGQTSPYACKEWRHVEDFQGGNKIEVTKNQYALIEGKNKTVSTLVIQAANVSALYKCEAINKAGRGERVISFHVIRGPEITVQPAAQPTEQESVSLLCTADRNTFENLTWYKLGSQATSVHMGESLTPVCKNLDALWKLNGTMFSNSTNDILIVAFQNASLQDQGDYVCSAQDKKTKKRHCLVKQLIILERMAPMITGNLENQTTTIGETIEVTCPASGNPTPHITWFKDNETLVEDSGIVLRDGNRNLTIRRVRKEDGGLYTCQACNVLGCARAETLFIIEGAQEKTNLEVIILVGTAVIAMFFWLLLVILVRTVKRANEGELKTGYLSIVMDPDELPLDERCERLPYDASKWEFPRDRLKLGKPLGRGAFGQVIEADAFGIDKTATCKTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNVVNLLGACTKPGGPLMVIVEFSKFGNLSTYLRGKRNEFVPYKSKGARFRQGKDYVGELSVDLKRRLDSITSSQSSASSGFVEEKSLSDVEEEEASEELYKDFLTLEHLICYSFQVAKGMEFLASRKCIHRDLAARNILLSEKNVVKICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDRVYTIQSDVWSFGVLLWEIFSLGASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTMLDCWHEDPNQRPSFSELVEHLGNLLQANAQQDGKDYIVLPMSETLSMEEDSGLSLPTSPVSCMEEEEVCDPKFHYDNTAGISHYLQNSKRKSRPVSVKTFEDIPLEEPEVKVIPDDSQTDSGMVLASEELKTLEDRNKLSPSFGGMMPSKSRESVASEGSNQTSGYQSGYHSDDTDTTVYSSDEAGLLKMVDAAVHADSGTTLQLTSCLNGSGPVPAPPPTPGNHERGAA)。本文使用的恒河猴VEGFR2包括可通过NCBI数据库中的登录号XP_014994176.1访问的氨基酸序列或SEQ ID NO:101的氨基酸序列(MASKVLLAVALWLCVETRAASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCRGQRDLDWLWP NNQSGSEQRVEVTECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQDYRSPFIASVSDQHGVVYITENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWDSKKGFTIPSYMISYAGMVFCEAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGVELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKPFVAFGSGMESLVEATVGERVRIPVKYLGYPPPEIKWYKNGIPLESNHTVKVGHVLTIMEVSERDTGNYTVILTNPISKEKQSHVVSLVVYVPPQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECPNEPSQAVSVTNPYPCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGERVISFHVTRGPEITLQPDLQPTEQESVSLWCTADKSTFENLTWYKLGPQPLPVHVGELPTPVCKNLDTLWKLNATIFSNSTNDILIMELKNASLQDQGDYVCVAQDRKTKKRHCVVRQLTVLERVAPMITGNLENQTTSIGETIEVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNRNLTIRRVRKEDEGLYTCQACSVLGCAKVEAFFIIEGAQEKTNLEIIILVGTAVIAMFFWLLLVIILRTVKRANGGELKTGYLSIVMDPDELPLDEHCERLPYDASKWEFPRDRLKLGKPLGRGAFGQVIEADAFGIDKTATCRTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNVVNLLGACTKPGGPLMVIVEFCKFGNLSTYLRSKRNEFVPYKTKGARFRQGKDYVGAIPVDLKRRLDSITSSQSSASSGFVEEKSLSDVEEEEAPEDLYKDFLTLEHLICYSFQVAKGMEFLASRKCIHRDLAARNILLSEKNVVKICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDRVYTIQSDVWSFGVLLWEIFSLGASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTMLDCWHGEPSQRPTFSELVEHLGNLLQANAQQDGKDYIVLPISETLSMEEDSGLSLPTSPVSCMEEEEVCDPKFHYDNTAGISQYLQNSKRKSRPVSVKTFEDIPLEEPEVKVIPDDNQTDSGMVLASEELKTLEDRTKLAPSFSGMVSSKSRESVASEGSNQTSGYQSGYHSDDTDTTVYSSEEAELLKLIEIGVQTGSTAQILQPDSGTTLSSPPV)。
如本文所用,“hVEGFR2相关”疾病或病症是指由hVEGFR2表达或活性的增加或减少引起、恶化或以其他方式相关的任何疾病或病症。在一些实施例中,hVEGFR2相关病症是例如癌症或血管生成疾病。
可与术语“血管内皮生长因子A”互换使用的“VEGF-A”是指高度保守的二聚体糖蛋白或其转录物剪接变体,如分别含有206、189、165和121个氨基酸的VEGFA206、VEGFA189、VEGFA165和VEGFA121。VEGF-A是VEGF家族的成员,该家族还包含其他成员,如VEGF-B、VEGF-C和VEGF-D。
如本文所用,“癌症”是指以恶性细胞生长或肿瘤、异常增殖、浸润或转移为特征的任何医学病症,并且包含实体瘤和非实体癌(例如恶性血液病)如白血病。如本文所用,“实体肿瘤”是指赘生性和/或恶性细胞的实体块。
如本文所用,“血管生成疾病”是指与血管生成过程中的异常相关的任何医学病症,血管生成是新血管生长的过程。此类异常包含但不限于过度血管生成、血管生成不足、血管生成不当和破坏性血管生成。以例如过度或破坏性血管生成为特征的此类医学病症包含但不限于癌症、糖尿病性视网膜病变、年龄相关性黄斑变性和动脉粥样硬化、中风和心肌梗塞、类风湿性关节炎。
术语“药学上可接受的”表示指定的载剂、媒剂、稀释剂、赋形剂和/或盐通常与构成制剂的其他成分在化学上和/或物理上相容,并与接受者在生理上相容。
本文提及“约”值或参数包含(并描述)针对该值或参数本身的实施例。例如,提及“约X”的描述包含“X”的描述。数字范围包含定义该范围的数字。一般而言,术语“约”是指变量的指示值以及在指示值的实验误差内(例如,在平均值的95%置信区间内)或在指示值的10%内(以较大者为准)的变量的所有值。如果在时间段(年、月、周、天等)的上下文中使用术语“约”,则术语“约”是指该时间段加上或减去下一个从属时间段的一个量(例如约1年意味着11-13个月;约6个月意味着6个月加上或减去1周;约1周意味着6-8天;等等),或在指示值的10%内,以较大者为准。
抗-hVEGFR2抗体
本公开提供抗-hVEGFR2抗体及其抗原结合片段。本文提供的抗-hVEGFR2抗体和抗原结合片段能够特异性结合hVEGFR2或表达hVEGFR2的细胞。如本文所用,“特异性结合”是指结合亲和力(例如KD)≤10-6M(例如,≤5x10-7M、≤2x10-7M、≤10-7M、≤5x10-8M、≤2x10-8M、≤10-8M、≤5x10-9M、≤4x10-9M、≤3x10-9M、≤2x10-9M或≤10-9M)。
i.结合亲和力
本文提供的抗-hVEGFR2抗体和抗原结合片段的结合亲和力可以用KD值表示,KD值代表抗原与抗原结合分子之间的结合达到平衡时的解离速率与缔合速率的比率(koff/kon)。低亲和力抗体通常缓慢地结合抗原并且倾向于容易解离,而高亲和力抗体通常更快地结合抗原并且倾向于保持更长时间的结合。可以使用本领域已知的任何合适方法适当地确定抗原结合亲和力(例如KD),包含例如动力学排除测定(KinExA)、Biacore、Fortebio或流式细胞术。
在某些实施例中,根据本公开的“KD”或“KD值”在一个实施例中通过使用抗-hVEGFR2抗体和hVEGFR2进行的Biacore测定测量,如通过测量抗-hVEGFR2抗体的溶液结合亲和力的以下测定所描述的。一般来说,Biacore的工作原理是将恒定量的一种结合伴侣(CBP)与不同浓度的另一种结合伴侣(滴定剂)进行平衡,然后在较短的接触时间内通过荧光标记的二抗捕获一部分游离CBP,接触时间小于预先形成的CBP-滴定剂复合物解离所需的时间。捕获的CBP产生的荧光信号与平衡样品中游离CBP的浓度成正比,并用于在系列测量时生成结合曲线(游离CBP百分比与总滴定剂浓度)。更多详细信息可从Schreiber,G.、Fersht,A.R.,《自然结构生物学(Nature Structural Biology)》,1996,3(5),427-431获得。当抗-hVEGFR2抗体以恒定量用作CBP时,则hVEGFR2蛋白可用作滴定剂,反之亦然。在某些实施例中,抗-hVEGFR2抗体或其抗原结合片段的KD根据本公开实例16所述的方法确定。
在适用的情况下也可以使用适合测量Kd的其他方法,例如,放射性标记的抗原结合测定(参见例如Chen等人(1999),《分子生物学杂志》293:865-881)。
在某些实施例中,抗-hVEGFR2抗体的结合亲和力通过流式细胞术测量。一般而言,表达hVEGFR2的细胞(例如,HUVEC)与一系列浓度的抗-hVEGFR2抗体一起孵育,然后与荧光标记的二抗一起孵育,然后分析荧光信号强度。在某些实施例中,抗-hVEGFR2抗体或其抗原结合片段的结合亲和力根据本公开实例6中描述的方法确定。
在某些实施例中,本文提供的抗-hVEGFR2抗体及其抗原结合片段以由Biacore测定测量的不超过6nM、5nM、4nM、3nM、2nM、1nM或0.5nM的KD值特异性结合hVEGFR2(或表达hVEGFR2的细胞)。在某些实施例中,本文提供的抗-hVEGFR2抗体及其抗原结合片段以由Biacore测定测量的不超过0.089nM(或不超过0.001nM)的KD值特异性结合hVEGFR2(或表达hVEGFR2的细胞)。
或者,本文提供的抗-hVEGFR2抗体和抗原结合片段对hVEGFR2的结合亲和力也可以用“半最大有效浓度”(EC50)值表示,其是指其中观察到其最大作用(例如,结合)的50%的抗体浓度。EC50值可以通过所属领域中已知的方法,例如夹心测定,如ELISA、蛋白印迹、流式细胞测量测定和其他结合测定来测量。在某些实施例中,本文提供的抗-hVEGFR2抗体及其片段以由ELISA测量的不超过80ng/ml(或不超过70ng/ml、65ng/ml、60ng/ml、55ng/ml、50ng/ml、45ng/ml、40ng/ml、35ng/ml、30ng/ml、25ng/ml、20ng/ml、15ng/ml、12ng/ml或10ng/ml、9ng/ml或8ng/ml)的EC50值特异性结合重组hVEGFR2。在某些实施例中,本文提供的抗-hVEGFR2抗体及其片段以由ELISA测量的不超过35ng/ml、24ng/ml、15ng/ml、10ng/ml、9ng/ml、8ng/ml、7ng/ml或6ng/ml的EC50值特异性结合重组hVEGFR2。在某些实施例中,本文提供的抗-hVEGFR2抗体及其片段与小鼠VEGFR2交叉反应,通过ELISA测量的EC50值不超过35ng/ml。在某些实施例中,本文提供的抗-hVEGFR2抗体及其片段以不超过1121B的EC50值的60%的EC50值结合hVEGFR2,该EC50值由ELISA测量。在此类实施例中,抗-hVEGFR2抗体及其片段包括包括有SEQ ID NO:31的序列的HCDR1、包括有SEQ ID NO:32或SEQ ID NO:37序列的HCDR2、包括有SEQ ID NO:33的序列的HCDR3、包括有SEQ ID NO:28的序列的LCDR1、包括有SEQ ID NO:29的序列的LCDR2和包括有SEQ ID NO:30的序列的LCDR3。在某些实施例中,本文提供的抗-hVEGFR2抗体及其片段与恒河猴VEGFR2交叉反应,通过ELISA测量的EC50值不超过30ng/ml、25ng/ml、20ng/ml、15ng/ml、10ng/ml或9ng/ml。
在某些实施例中,本文提供的抗-hVEGFR2抗体及其片段以由流式细胞术测量的不超过160ng/ml(或不超过150ng/ml、140ng/ml、130ng/ml、120ng/ml、110ng/ml、100ng/ml、90ng/ml、80ng/ml、70ng/ml、65ng/ml、55ng/ml、50ng/ml、45ng/ml、40ng/ml、35ng/ml、30ng/ml或25ng/ml)的EC50值特异性结合表达hVEGFR2(例如,HUVEC)的细胞。
在某些实施例中,本文提供的抗体及其抗原结合片段表现出有效阻断VEGFR2与VEGF-A结合的竞争性VEGFR2结合特性。本文提供的抗体及其抗原结合片段的阻断作用可以使用例如本公开的实例5中描述的ELISA来测量。在某些实施例中,本文提供的抗体及其抗原结合片段的阻断作用可以以IC50表示,IC50表示在本公开的抗体及其抗原结合片段的存在下VEGFR2与VEGF-A的结合降低50%时的本文提供的抗体及其抗原结合片段的浓度。在某些实施例中,本文提供的抗体及其抗原结合片段的IC50的范围为0.001μg/ml至2.5μg/ml、0.005μg/ml至0.5μg/ml、0.05μg/ml至0.4μg/ml或0.1μg/ml至0.2μg/ml。在某些实施例中,本文提供的抗体及其抗原结合片段以不超过1121B的IC50值的82%的IC50值阻断VEGF-A诱导的表达hVEGFR2的细胞的增殖,该IC50值通过细胞活力测定测量。在此类实施例中,本文提供的抗体及其抗原结合片段包括包括有SEQ ID NO:31的序列的HCDR1、包括有SEQ IDNO:37的序列的HCDR2以及包括有SEQ ID NO:33的序列的HCDR3、包括有SEQ ID NO:28的序列的LCDR1、包括有SEQ ID NO:29的序列的LCDR2以及包括有SEQ ID NO:30的序列的LCDR3,优选在CHO中表达。
表位
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段结合包括至少一个或多个(例如,一个、两个、三个或更多个)在具有SEQ ID NO:103的氨基酸序列的hVEGFR2的位置Y137A、R164A、Y165A、V218A、Y221A、R222A、E251A、L252A、N253A、G255A、D257A、K286A、G312A、L313A、M314A、T315A和K316A处的氨基酸残基的表位。
如本文所用,术语“表位”是指抗体所结合的抗原上特定的一组原子或氨基酸。表位可以包含直接接触抗体的特定氨基酸、糖侧链、磷酰基或磺酰基。本领域技术人员将认识到,无需过多实验即可通过确定抗体是否与本公开的抗体(例如杂交瘤/嵌合或人源化抗体002、003、006、018、042、048和054和本文提供的任何嵌合和其人源化变体)竞争结合hVEGFR2抗原多肽来确定两者是否结合相同或重叠或相邻的表位。
如本文所用,关于两种抗原结合蛋白(例如抗体)的术语“竞争结合”是指由竞争性结合测定确定的一种抗原结合蛋白阻断或减少另一种与抗原(例如人/小鼠/恒河猴VEGFR2)的结合。竞争性结合测定在所属领域中众所周知,包含例如直接或间接放射免疫测定(RIA)、直接或间接酶免疫测定(EIA)和夹心竞争测定(参见例如Stahli等人1983,《酶学方法》9:242-253)。通常,此类测定涉及使用与固体表面结合的纯化抗原或带有抗原的细胞、未标记的测试抗体和标记的参考抗体。竞争性抑制通过测定在测试抗体存在下结合于固体表面或细胞的标记的量来测量。通常测试抗体过量存在。如果两种抗体竞争结合hVEGFR2,则两种抗体结合相同或重叠的表位,或与由另一抗体结合的表位足够临近的相邻表位以发生空间位阻。通常,当竞争性抗体过量存在时,它将测试抗体与共同抗原的特异性结合抑制(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。
在某些实施例中,表位或抗体结合的表位中的氨基酸残基可以通过突变抗原(即hVEGFR2)中的特定残基来确定。如果抗体以相对于其与野生型hVEGFR2的结合显著降低的水平结合具有突变的氨基酸残基(例如突变为丙氨酸)的突变hVEGFR2,则这将表明突变残基直接参与抗体与hVEGFR2抗原的结合,或者当它与抗原结合时与抗体非常接近。此类突变残基被认为在表位内,并且抗体被认为与包括该残基的表位特异性结合。如本文所用,显著降低的结合水平是指抗体与突变hVEGFR2之间的结合亲和力(例如EC50、KD或结合能力)相对于抗体与野生型hVEGFR2之间的结合降低超过10%、20%、30%、40%、50%、60%、70%、80%、90%或更多。此类结合测量可以使用本领域已知和本文公开的任何合适方法进行,例如但不限于KinExA测定、ELISA、Biacore、Fortebio和流式细胞术。
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段显示出由ELISA测量的与突变hVEGFR2的结合降低(例如降低至少30%,降低50%),其中野生型hVEGFR2中的残基被丙氨酸取代,并且残基选自由以下组成的群组:Y137A、R164A、Y165A、V218A、Y221A、R222A、E251A、L252A、N253A、G255A、D257A、K286A、G312A、L313A、M314A、T315A和K316A(相对于SEQ ID NO:103)。
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段结合hVEGFR2上的表位,其中该表位包括一个或多个选自由以下组成的群组的氨基酸残基:SEQ ID NO:103的Y137、R164、Y165、V218、Y221、R222、E251、L252、N253、G255、D257、K286、G312、L313、M314、T315和K316。
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段结合包括SEQ IDNO:103的Y165和/或L313但不包括R222、G255、D257和T315中任一个的表位。
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段结合包括SEQIDNO:103的Y137、V218、Y221、R222、E251、L252、N253、G255、D257、K286、L313、M314、T315、K316或其任何组合的表位。
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段结合包括SEQ IDNO:103的R164、Y165、D257或其任何组合的表位。
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段结合包括SEQ IDNO:103的Y165、Y221、R222、E251、G255、D257、G312、L313、M314、T315、K316或其任何组合的表位。
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段结合包括SEQ IDNO:103的Y165但不包括R222、G255、D257、L313和T315的表位。
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段结合包括SEQ IDNO:103的Y165、Y221、R222、E251、N253、G255、D257、G312、L313、M314、T315、K316或其任何组合的表位。
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段结合包括SEQ IDNO:103的R164、Y165、D257或其任何组合的表位。
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段结合包括SEQ IDNO:103的Y165、Y221、R222、E251、N253、G255、D257、G312、L313、M314、T315、K316或其任何组合的表位。
抗体序列
在另一方面,本发明提供了一种抗-hVEGFR2抗体或其抗原结合片段,其包括重链HCDR1、HCDR2和HCDR3和/或轻链LCDR1、LCDR2和LCDR3序列,其中
HCDR1序列包括SSWMN(SEQ ID NO:1)、DYYMS(SEQ ID NO:19)、X1YGMS(SEQ ID NO:41)、X4YWIM(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(SEQID NO:20)、SISX2GGSYTYYADSVX19G(SEQ ID NO:42)、DIYPGX5GSTNYNEKFKS(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)、EX3DGNYDY(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)、RASESVX6NSGISFMX7(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(SEQID NO:29)、AASX8QX9S(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X1是I或M,X2是V或I,X3是L或M,X4是T或S,X5是T或S,X6是D或E,X7是T或H,X8是T或Y,X9是G或R和X19是E或K。
在一方面,本公开提供了本文提供的抗-hVEGFR2抗体或其抗原结合片段,其中HCDR1包括SEQ ID NO:41的氨基酸序列,HCDR2包括SEQ ID NO:42的氨基酸序列,HCDR3包括SEQ ID NO:43的氨基酸序列,LCDR1包括SEQ ID NO:28的序列,LCDR2包括SEQ ID NO:29的序列,并且LCDR3包括SEQ ID NO:30的序列。
在一方面,本公开提供了本文提供的抗-hVEGFR2抗体或其抗原结合片段,其中
a)HCDR1包括SEQ ID NO:25的序列,HCDR2包括SEQ ID NO:26的序列,HCDR3包括SEQ ID NO:27的序列;LCDR1包括SEQ ID NO:28的序列,LCDR2包括SEQ ID NO:29的序列,并且LCDR3包括SEQ ID NO:30的序列;或者
b)HCDR1包括SEQ ID NO:31的序列,HCDR2包括SEQ ID NO:32或SEQ ID NO:37的序列,并且HCDR3包括SEQ ID NO:33的序列,LCDR1包括SEQ ID NO:28的序列,LCDR2包括SEQID NO:29的序列,并且LCDR3包括SEQ ID NO:30的序列;或者
c)HCDR1包括SEQ ID NO:34的序列,HCDR2包括SEQ ID NO:35或SEQ ID NO:37的序列,并且HCDR3包括SEQ ID NO:36的序列,LCDR1包括SEQ ID NO:28的序列,LCDR2包括SEQID NO:29的序列,并且LCDR3包括SEQ ID NO:30的序列。
在一方面,本公开提供了本文提供的抗-hVEGFR2抗体或其抗原结合片段,其中HCDR1包括SEQ ID NO:44的氨基酸序列,HCDR2包括SEQ ID NO:45的氨基酸序列,HCDR3包括SEQ ID NO:46的氨基酸序列,LCDR1包括SEQ ID NO:47的序列,LCDR2包括SEQ ID NO:48的序列,并且LCDR3包括SEQ ID NO:49的序列。
在一方面,本公开提供了本文提供的抗-hVEGFR2抗体或其抗原结合片段,其中
a)HCDR1包括SEQ ID NO:7的序列,HCDR2包括SEQ ID NO:8的序列,HCDR3包括SEQID NO:9的序列;LCDR1包括SEQ ID NO:10的序列,LCDR2包括SEQ ID NO:11的序列,并且LCDR3包括SEQ ID NO:12的序列;或者
b)HCDR1包括SEQ ID NO:13的序列,HCDR2包括SEQ ID NO:14的序列,并且HCDR3包括SEQ ID NO:15的序列,LCDR1包括SEQ ID NO:16的序列,LCDR2包括SEQ ID NO:17的序列,并且LCDR3包括SEQ ID NO:18的序列。
在一方面,本公开提供了本文提供的抗-hVEGFR2抗体或其抗原结合片段,其中
a)HCDR1包括SEQ ID NO:1的序列,HCDR2包括SEQ ID NO:2的序列,并且HCDR3包括SEQ ID NO:3的序列,LCDR1包括SEQ ID NO:4的序列,LCDR2包括SEQ ID NO:5的序列,并且LCDR3包括SEQ ID NO:6的序列;或者
b)HCDR1包括SEQ ID NO:19的序列,HCDR2包括SEQ ID NO:20的序列,并且HCDR3包括SEQ ID NO:21的序列,LCDR1包括SEQ ID NO:22的序列,LCDR2包括SEQ ID NO:23的序列,并且LCDR3包括SEQ ID NO:24的序列。
在某些实施例中,本文提供的抗体包括hVEGFR2抗体002、003、006、018、042、048和054的一个或多个(例如1、2、3、4、5或6个)CDR序列。
如本文所用,关于抗体的“002”或“2”是指具有SEQ ID NO:50的重链可变区和SEQID NO:51的轻链可变区的小鼠抗体。
如本文所用,关于抗体的“003”或“3”是指具有SEQ ID NO:52的重链可变区和SEQID NO:53的轻链可变区的小鼠抗体。
如本文所用,关于抗体的“006”或“6”是指具有SEQ ID NO:54的重链可变区和SEQID NO:55的轻链可变区的小鼠抗体。
如本文所用,关于抗体的“018”或“18”是指具有SEQ ID NO:56的重链可变区和SEQID NO:57的轻链可变区的小鼠抗体。
如本文所用,关于抗体的“042”或“42”是指具有SEQ ID NO:58的重链可变区和SEQID NO:59的轻链可变区的小鼠抗体。
如本文所用,关于抗体的“048”或“48”是指具有SEQ ID NO:60的重链可变区和SEQID NO:61的轻链可变区的小鼠抗体。
如本文所用,关于抗体的“054”或“45”是指具有SEQ ID NO:62的重链可变区和SEQID NO:63的轻链可变区的小鼠抗体。
表1显示了这些hVEGFR2抗体的CDR序列。重链和轻链可变区序列还提供于下表2中。
表1.hVEGFR2抗体的CDR区序列
其中X1是I或M,X2是V或I,X3是L或M,X4是T或S,X5是T或S,X6是D或E,X7是T或H,X8是T或Y,X9是G或R和X19是E或K。
表2.小鼠/嵌合抗体VH/VL的序列
其中CDR区加粗。
本文提供的抗-hVEGFR2抗体或其抗原结合片段可以是单克隆抗体、多克隆抗体、人源化抗体、嵌合抗体、重组抗体、双特异性抗体、标记抗体、二价抗体或抗独特型抗体。重组抗体为使用重组方法在体外而非在动物体内制备的抗体。
已知CDR负责抗原结合,然而,已发现并非所有6个CDR都一定是必不可少的或不可改变的。换句话说,有可能替换或改变或修饰在本文提供的抗-hVEGFR2抗体中的1、2或3个CDR,但仍基本上保留对hVEGFR2的特异性结合亲和力。
在某些实施例中,本文提供的抗-hVEGFR2抗体和抗原结合片段包括抗-hVEGFR2抗体002、003、006、018、042、048和054中一个的重链CDR3序列。重链CDR3区位于抗原结合位点的中心,并且因此被认为与抗原接触最多,并且为抗体与抗原的亲和力提供最多的自由能。还认为到目前为止重链CDR3是抗原结合位点中在长度、氨基酸组成和构象方面通过多种多样化机制变化最多的CDR(Tonegawa S.,《自然》,302:575-81)。重链CDR3的多样性足以产生大多数的抗体特异性(Xu JL、DavisMM.,《免疫(Immunity)》,13:37-45)以及理想的抗原结合亲和力(Schier R等人,《分子生物学杂志》,263:551-67)。
在一些实施例中,本文提供的抗-hVEGFR2抗体和抗原结合片段包括全部或部分的重链可变结构域和/或全部或部分的轻链可变结构域。在一个实施例中,本文提供的抗-hVEGFR2抗体和抗原结合片段是单结构域抗体,其由本文提供的全部或部分重链可变结构域组成。此类单结构域抗体的更多信息可在本领域获得(参见例如美国专利号6,248,516)。
在某些实施例中,本文提供的抗体和其抗原结合片段包括合适的框架区(FR)序列,只要该抗体和其抗原结合片段能特异性地与hVEGFR2结合。表1中提供的CDR序列获自小鼠抗体,但它们可以使用本领域已知的合适方法如重组技术移植到任何合适的物种如小鼠、人、大鼠、兔等的任何合适的FR序列上。
在某些实施例中,本文提供的抗体和其抗原结合片段是人源化的。人源化抗体或抗原结合片段的可取之处在于其对人类的免疫原性降低。人源化抗体在其可变区中是嵌合的,因为非人CDR序列被移植到人或基本上人FR序列。抗体或抗原结合片段的人源化实质上可以通过将非人(如鼠)CDR基因替换为人免疫球蛋白基因中相应的人CDR基因来进行(参见例如,Jones等人(1986),《自然》321:522-525;Riechmann等人(1988),《自然》332:323-327;Verhoeyen等人(1988),《科学(Science)》,239:1534-1536)。
可使用本领域中已知的方法选择合适的人重链和轻链可变结构域以实现此目的。在一个说明性的实例中,可以使用“最佳匹配”方法,其中筛选非人(例如啮齿动物)抗体可变结构域序列或针对已知的人可变结构域生殖系序列数据库进行BLAST比对,并且最接近非人查询序列的人序列被识别并用作用于移植非人CDR序列的人类支架(参见例如,Sims等人(1993),《免疫学杂志(J.Immunol.)》,151:2296;Chothia等人(1987),《分子生物学杂志》,196:901)。或者,源自所有人抗体的共有序列的框架可用于移植非人CDR(参见例如,Carter等人(1992),《美国国家科学院院刊》,89:4285;Presta等人(1993),《免疫学杂志》,151:2623)。
在某些实施例中,本文提供的人源化抗体或抗原结合片段由基本上所有人序列构成,非人CDR序列除外。在一些实施例中,可变区FR和恒定区如果存在则完全或基本上来自人免疫球蛋白序列。人类FR序列和人类恒定区序列可以来源于不同的人类免疫球蛋白基因,例如FR序列来源于一种人类抗体,且恒定区来源于另一人类抗体。在一些实施例中,人源化抗体或抗原结合片段包括人重/轻链FR1-4。
在一些实施例中,来源于人的FR区可以包括与其来源于的人免疫球蛋白相同的氨基酸序列。在一些实施例中,人FR的一个或多个氨基酸残基经来自亲本非人抗体的相应残基取代。在某些实施例中,这可能是合乎需要的,以使人源化抗体或其片段紧密地接近非人亲本抗体结构,以减少或避免免疫原性和/或改善或保留结合活性或结合亲和力。
在某些实施例中,本文所提供的人源化抗体或抗原结合片段在每个人FR序列中包括不超过10、9、8、7、6、5、4、3、2或1个氨基酸残基取代,或者在重链或轻链可变结构域的所有FR中包括不超过10、9、8、7、6、5、4、3、2或1个氨基酸残基取代。在一些实施例中,此类氨基酸残基的变化可以仅存在于重链FR区,仅存在于轻链FR区,或存在于两条链中。在某些实施例中,一个或多个氨基酸残基突变,例如,回复突变为在衍生CDR序列的非人亲本抗体(例如在小鼠框架区)中发现的相应残基。合适的突变位置可由技术人员按照本领域中已知的原则选择。例如,在以下情况下可以选择突变位置:1)人生殖系序列框架中的残基是罕见的(例如在人可变区序列中少于20%或少于10%);2)该位置紧邻人生殖系链主序列中3个CDR中的一个或多个,因为它可能与CDR中的残基相互作用;或3)该位置在3维模型中接近CDR,并且因此可以与CDR中的氨基酸相互作用的概率大。所选位置的残基可以突变回亲本抗体中的相应残基,或者突变为以下残基,其既不是人生殖系序列中的相应残基也不是亲本抗体中的相应残基,而是人序列的典型残基,即在属于与人生殖系序列相同的亚组的已知人序列中更频繁地出现在该位置的残基(参见美国专利号5,693,762)。
在某些实施例中,本公开的人源化轻链和重链在人类中基本上没有免疫原性,并保持与hVEGFR2的亲本抗体基本相同的亲和力或甚至更高的亲和力。
在某些实施例中,本文提供的人源化抗体及其抗原结合片段包括人生殖系框架序列VK/2D-40的一个或多个轻链FR序列,和/或人生殖系框架序列VH/3-21的一个或多个重链FR序列,其中有或没有回复突变。如果需要的话,可以将回复突变引入人生殖系框架序列中。在某些实施例中,人源化抗体054可以含有一个或多个选自由以下组成的群组的回复突变:相对于重链框架序列VH/3-21的SEQ ID NO:92(EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSV KGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARELDGNYDYWGQGTTLTVSS)中的框架序列的R19K、A40T、G44R、S49A、S78T和R87K。人源化抗体048可以含有一个或多个选自由以下组成的群组的回复突变:相对于重链框架序列VH/3-21的SEQ IDNO:92(EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSYIYYADSVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCARELDGNYDYWGQGTTLTVSS)中的框架序列的G44R、S49A和S78T。在某些实施例中,人源化抗体054/048可以含有一个或多个选自由以下组成的群组的回复突变:相对于轻链框架序列VK/2D-40的SEQ ID NO:95(DIVMTQTPLSLPVTPGEPASISCRSSQSLLDSDDGNTYLDWYLQKPGQSPQLLIYTLSYRASGV PDRFSGSGTDFTLKISRVEAEDVGVYYCMQRIEFP)中的框架序列的M4T、T7D、P8E、P15F、P18S、A19V、Y42F、K45R、P65S和V91I。
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段包括重链可变区,其包括选自由SEQ ID NO:93、SEQ ID NO:94和SEQ ID NO:98组成的群组的序列,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对hVEGFR2、特别是人hVEGFR2的特异性结合亲和力的同源序列。
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段包括轻链可变区,其包括选自由SEQ ID NO:96和SEQ ID NO:97组成的群组的序列,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对hVEGFR2、特别是人hVEGFR2的特异性结合亲和力的同源序列。
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段包括:重链可变区和轻链可变区,该重链可变区包括选自由SEQ ID NO:93、SEQ ID NO:94和SEQ ID NO:98组成的群组的序列,该轻链可变区包括SEQ ID NO:96或SEQ ID NO:97的序列。
在某些实施例中,本文提供的抗-hVEGFR2抗体或其抗原结合片段进一步包括重链HFR1、HFR2、HFR3和HFR4中的一个或多个,和/或轻链LFR1、LFR2、LFR3和LFR4中的一个或多个,其中:
HFR1包括EVQLVESGGGLVKPGGSLX10LSCAASGFTFS(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WVRQX11PGKRLEWVA(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RFTISRDNAKNTLYLQMNSLX12AEDTAVYYCAR(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WGX13GTTLTVSS(SEQ ID NO:87)或其至少80%序列同一性的同源序列,
LFR1包括DIVITQX14X15LSLPVTX16GESVSISC(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GVX17DRFSGSGSGTDFTLKISRVEAEDVGX18YYC(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,和
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X10是R或K,X11是A或T,X12是R或K,X13是Q或H,X14是D或T,X15是E或P,X16是F或P,X17是S或P,X18是V或I。
在某些实施例中,HFR1包括选自由SEQ ID NO:64、68和72组成的群组的序列,HFR2包括选自由SEQ ID NO:65、69和73组成的群组的序列,HFR3包括选自由SEQ ID NO:66、70和74组成的群组的序列,HFR4包括选自由SEQ ID NO:67、71和75组成的群组的序列,LFR1包括选自由SEQ ID NO:76和80组成的群组的序列,LFR2包括选自由SEQ ID NO:77和81组成的群组的序列,LFR3包括选自由SEQ ID NO:78和82组成的群组的序列,以及LFR4包括选自由SEQID NO:79和83组成的群组的序列。
表3.人源化hVEGFR2抗体054和048的框架(FR)序列
表4和表5说明了人源化054和048抗体的可变区的序列。
表4.人源化054的序列
表5.人源化048的序列
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人源化048的轻链可变区与人源化054的轻链可变区相同。
本文提供的人源化抗-hVEGFR2抗体保留了与表达hVEGFR2的细胞的特异性结合亲和力,并且在该方面与亲本抗体至少相当,或甚至更优。本文提供的人源化抗体还可以保留其与表达VEGFR2的细胞如HUVEC细胞的功能相互作用,因为所有抗体均可以抑制VEGF-A诱导的VEGFR2磷酸化、HUVEC增殖和管形成。在某些实施例中,本文提供的抗-hVEGFR2抗体及其片段进一步包括免疫球蛋白恒定区,任选人Ig的恒定区,或任选人IgG的恒定区。在一些实施例中,免疫球蛋白恒定区包括重链和/或轻链恒定区。重链恒定区包括CH1、铰链和/或CH2-CH3区。在某些实施例中,重链恒定区包括Fc区。在某些实施例中,轻链恒定区包括Cκ或Cλ。
在某些实施例中,本文提供的抗-hVEGFR2抗体及其片段进一步包括人IgG1、IgG2、IgG3或IgG4的恒定区。在某些实施例中,本文提供的抗-hVEGFR2抗体及其抗原结合片段包括IgG1同种型的恒定区。在某些实施例中,人IgG1的恒定区包括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同种型的恒定区可以诱导效应物功能,如ADCC或CDC。本文提供的抗-hVEGFR2抗体及其抗原结合片段的效应物功能可导致对表达hVEGFR2的细胞的细胞毒性。效应物功能可以用各种测定评价,如Fc受体结合测定、C1q结合测定和细胞裂解测定,以及上述用于确定ADCC或CDC的任何测定。
抗体变体
本文提供的抗-hVEGFR2抗体及其抗原结合片段还涵盖本文提供的抗体序列的各种类型的变体。
在某些实施例中,变体包括表1中提供的1、2或3个CDR序列、一个或多个FR序列、本文提供的重链或轻链可变区序列和/或恒定区(例如Fc区)中的一个或多个修饰或取代。此类抗体变体保留了其亲本抗体对hVEGFR2的特异性结合亲和力,但具有一个或多个由修饰或取代所赋予的理想特性。例如,仅举几例,抗体变体可能具有改善的抗原结合亲和力、改善的糖基化模式、减少的糖基化风险、减少的脱氨、减少或增加的效应物功能、改善的FcRn受体结合、增加的药代动力学半衰期、pH敏感性和/或对缀合的兼容性(例如,一个或多个引入的半胱氨酸残基)。
可以使用本领域已知的方法,例如“丙氨酸扫描诱变”(参见例如Cunningham和Wells(1989),《科学》,244:1081-1085)筛选亲本抗体序列,以确定合适的或优选的残基进行修饰或取代。简言之,靶残基(例如带电残基,如Arg、Asp、His、Lys和Glu)可以被识别并被中性或带负电的氨基酸(例如丙氨酸或多丙氨酸)替换,和产生经修饰的抗体并筛选感兴趣的特性。如果在特定氨基酸位置的取代显示出感兴趣的功能变化,则该位置可以被识别为进行修饰或取代的潜在残基。可以通过用不同类型的残基(例如半胱氨酸残基、带正电的残基等)替代来进一步评估潜在的残基。
1.亲和力变体
亲和力变体保留了亲本抗体对hVEGFR2的特异性结合亲和力,或者甚至具有比亲本抗体更好的hVEGFR2特异性结合亲和力。所属领域中已知的各种方法可用于实现此目的。例如,可以用噬菌体展示技术产生和表达抗体变体库(如Fab或scFv变体),然后筛选出与hVEGFR2的结合亲和力。另一个实例是,可以用计算机软件来虚拟模拟抗体与hVEGFR2的结合,并识别抗体上形成结合界面的氨基酸残基。此类残基可避免进行取代以便防止结合亲和力的降低,或作为取代的目标以实现较强结合。
在某些实施例中,CDR序列、FR序列或可变区序列中的取代中的至少一个(或全部)包括保守取代。关于氨基酸序列的“保守取代”是指用具有类似生理化学特性的侧链的不同氨基酸残基置换氨基酸残基。例如,可以在具有疏水侧链的氨基酸残基(如Met、Ala、Val、Leu和Ile)中,在具有中性亲水侧链的残基(如Cys、Ser、Thr、Asn和Gln)中,在具有酸性侧链的残基(如Asp、Glu)中,在具有碱性侧链的氨基酸(如His、Lys和Arg)中,或在具有芳族侧链的残基(如Trp、Tyr和Phe)中进行保守取代。如本领域中已知,保守取代通常不会引起蛋白构象结构的显著变化,并且因此可保留蛋白的生物活性。
在某些实施例中,本文所提供的人源化抗体或抗原结合片段包括一或多个CDR序列和/或一或多个FR序列中的一或多个氨基酸残基取代。在某些实施例中,亲和力变体包括在一个或多个CDR序列和/或FR序列中总共不超过10、9、8、7、6、5、4、3、2或1个取代。
在某些实施例中,抗-hVEGFR2抗体及其抗原结合片段包括1、2或3个CDR序列,其与表1中所列的一个(或多个)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,并且同时将对hVEGFR2的结合亲和力保持在类似于或甚至高于其亲本抗体的水平。
在某些实施例中,抗-hVEGFR2抗体及其抗原结合片段包括一个或多个可变区序列,其与SEQ ID NO:50-63、93-94和96-98中的一个(或多个)具有至少80%(例如,至少85%、88%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%)的序列同一性,并且同时将对hVEGFR2的结合亲和力保持在类似于或甚至高于其亲本抗体的水平。在一些实施例中,在选自SEQ ID NO:50-63、93-94和96-98的序列中取代、插入或删除总计1至10个氨基酸。在一些实施例中,取代、插入或删除发生在CDR之外的区域(即在FR中)。
2.糖基化变体
本文提供的抗-hVEGFR2抗体和抗原结合片段还涵盖糖基化变体,可以获得该糖基化变体以增加或减少抗体或抗原结合片段的糖基化程度。如本文所用,术语“糖基化”是指将聚糖如岩藻糖、木糖、甘露糖或GlcNAc磷酸丝氨酸聚糖连接到蛋白、脂质或其他有机分子上的酶促过程。根据与聚糖相连的碳,糖基化可分为五类,包含:N-连接的糖基化、O-连接的糖基化、磷-糖基化、C-连接的糖基化和糖基磷脂酰肌醇化。
抗体的糖基化通常是N-连接或O-连接的。N-连接的是指碳水化合物部分与天冬酰胺残基(例如三肽序列,如天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸中的天冬酰胺残基,其中X是除脯氨酸外的任何氨基酸)的侧链的连接。O-连接的糖基化是指糖N-乙酰基半乳糖胺、半乳糖或木糖中的一种与羟基氨基酸的连接,最常见地与丝氨酸或苏氨酸的连接。
在某些实施例中,本文提供的抗体或其抗原结合片段是无岩藻糖基化的。术语“无岩藻糖基化”或“无岩藻糖基化的”是指附着在抗体上的N-聚糖上的核心岩藻糖减少或消失。人IgG抗体的大多数聚糖被称为G0、G1和G2,它们是复合的双天线分子,其中核心岩藻糖残基携带零、一或两个末端半乳糖。
可以使用本领域已知的方法制备无岩藻糖基化的抗体变体,该方法例如描述于US2003/0157108;WO 2000/61739;WO 2001/29246;US 2003/0115614;US 2002/0164328;US2004/0093621;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,《分子生物学杂志》,336:1239-1249(2004);Yamane-Ohnuki等人,《生物技术与生物工程(Biotech.Bioeng.)》87:614(2004)。
在某些实施例中,抗体糖基化变体可以通过例如去除天然糖基化位点(例如通过N297A取代)来获得,使得N-连接糖基化位点的三肽序列或O-连接糖基化位点的丝氨酸或苏氨酸残基不再存在于抗体或Fc序列中。或者,在某些实施例中,抗体糖基化变体可通过在宿主细胞系中产生抗体获得,该宿主细胞系在将所选糖基团添加至抗体中成熟核心碳水化合物结构方面存在缺陷。
3.半胱氨酸工程化变体
本文提供的抗-hVEGFR2抗体和抗原结合片段还涵盖半胱氨酸工程化变体,其包括一个或多个引入的游离半胱氨酸氨基酸残基。
游离半胱氨酸残基为不是二硫桥的一部分的半胱氨酸残基。半胱氨酸工程化变体可用于通过例如马来酰亚胺或卤代乙酰基在工程化半胱氨酸的位点处与例如细胞毒性和/或成像化合物、标记或放射性同位素等缀合。工程化抗体或抗原结合片段以引入游离半胱氨酸残基的方法是本领域已知的,参见例如WO2006/034488。
抗原结合片段
本文还提供了抗-hVEGFR2抗原结合片段。各种类型的抗原结合片段是本领域已知的并且可以基于本文提供的抗-hVEGFR2抗体开发,包含例如其CDR序列显示在表1中的示例性抗体,以及它们的不同变体(如亲和力变体、糖基化变体、Fc变体、半胱氨酸工程化变体等)。
在某些实施例中,本文提供的抗-hVEGFR2抗原结合片段是双功能抗体、Fab、Fab'、F(ab')2、Fd、Fv片段、二硫键稳定化Fv片段(dsFv)、(dsFv)2、双特异性dsFv(dsFv-dsFv')、二硫键稳定化双功能抗体(ds双功能抗体)、单链抗体分子(scFv)、scFv二聚体(二价双功能抗体)、多特异性抗体、骆驼化单结构域抗体、纳米抗体、结构域抗体或二价结构域抗体。
各种技术可用于产生此类抗原结合片段。说明性方法包含完整抗体的酶促消化(参见例如,Morimoto等人,《生物化学与生物物理方法杂志(Journal of Biochemical andBiophysicalMethods)》,24:107-117(1992);和Brennan等人,《科学》,229:81(1985)),通过宿主细胞如大肠杆菌进行重组表达(例如,对于Fab、Fv和ScFv抗体片段),从如上所讨论的噬菌体展示文库中筛选(例如,对于ScFv),以及将两个Fab'-SH片段化学偶联以形成F(ab')2片段(Carter等人,《生物技术(Bio/Technology)》,10:163-167(1992))。生产抗体片段的其他技术对熟练的从业者来说将是显而易见的。
在某些实施例中,抗原结合片段是scFv。scFv的产生描述于例如WO 93/16185;美国专利号5,571,894;和5,587,458。scFv可以在氨基或羧基末端与效应蛋白融合以提供融合蛋白(参见例如,《抗体工程化(Antibody Engineering)》,编辑Borrebaeck)。
在某些实施例中,本文提供的抗-hVEGFR2抗体及其抗原结合片段是二价的、四价的、六价的或多价的。如本文所用,术语“价”是指在给定分子中存在指定数量的抗原结合位点。因此,术语“二价”、“四价”和“六价”分别表示在抗原结合分子中存在两个结合位点、四个结合位点和六个结合位点。任何大于二价的分子被视为多价的,涵盖例如三价、四价、六价等。
如果两个结合位点都对与相同抗原或相同表位的结合具有特异性,则二价分子可以是单特异性的。在某些实施例中,这提供了比单价对应物更强的与抗原或表位的结合。类似地,多价分子也可以是单特异性的。在某些实施例中,在二价或多价抗原结合部分中,第一价结合位点和第二价结合位点在结构上相同(即具有相同的序列),或在结构上不同(即尽管具有相同的特异性但具有不同的序列)。
如果两个结合位点对不同的抗原或表位具有特异性,则二价也可以是双特异性的。这也适用于多价分子。例如,当两个结合位点对第一抗原(或表位)是单特异性的,而第三结合位点对第二抗原(或表位)具有特异性时,则三价分子可以是双特异性的。
双特异性抗体
在某些实施例中,本文提供的抗体及其抗原结合片段是双特异性的。如本文所用,术语“双特异性”涵盖具有两种特异性的分子和具有多于两种特异性的分子,即多特异性。在某些实施例中,本文提供的双特异性抗体及其抗原结合片段能够特异性结合hVEGFR2的第一和第二表位,或能够特异性结合hVEGFR2和第二抗原。在某些实施例中,hVEGFR2的第一表位和第二表位彼此不同或不重叠。在某些实施例中,双特异性抗体及其抗原结合片段可以同时与第一表位和第二表位结合。
在某些实施例中,双特异性抗体包括第一结合结构域和第二结合结构域,其中第一结合结构域包括包括有选自由SEQ ID NO:25、31、34和1组成的群组的序列的HCDR1、包括有选自由SEQ ID NO:26、32、35和2组成的群组的序列的HCDR2、包括有选自由SEQ ID NO:27、33、36和3组成的群组的序列的HCDR3、包括有选自由SEQ ID NO:28和4组成的群组的序列的LCDR1、包括有选自由SEQ ID NO:29和5组成的群组的序列的LCDR2和包括有选自由SEQID NO:30和6组成的群组的序列的LCDR3;并且其中第二结合结构域包括包括有选自由SEQID NO:7、13和19组成的群组的序列的HCDR1、包括有选自由SEQ ID NO:8、14和20组成的群组的序列的HCDR2、包括有选自由SEQ ID NO:9、15和21组成的群组的序列的HCDR3、包括有选自由SEQ ID NO:10、16和22组成的群组的序列的LCDR1、包括有选自由SEQ ID NO:11、17和23组成的群组的序列的LCDR2和包括有选自由SEQ ID NO:12、18和24组成的群组的序列的LCDR3。
在某些实施例中,双特异性抗体包括第一结合结构域和第二结合结构域,
其中第一结合结构域包括:
a)包括SEQ ID NO:25的序列的HCDR1、包括SEQ ID NO:26的序列的HCDR2、包括SEQID NO:27的序列的HCDR3;包括SEQ ID NO:28的序列的LCDR1、包括SEQ ID NO:29的序列的LCDR2和包括SEQ ID NO:30的序列的LCDR3;或
b)包括SEQ ID NO:31的序列的HCDR1、包括SEQ ID NO:32或SEQ ID NO:37的序列的HCDR2、包括SEQ ID NO:33的序列的HCDR3、包括SEQ ID NO:28的序列的LCDR1、包括SEQID NO:29的序列的LCDR2和包括SEQ ID NO:30的序列的LCDR3;或
c)包括SEQ ID NO:34的序列的HCDR1、包括SEQ ID NO:35或SEQ ID NO:37的序列的HCDR2、包括SEQ ID NO:36的序列的HCDR3、包括SEQ ID NO:28的序列的LCDR1、包括SEQID NO:29的序列的LCDR2和包括SEQ ID NO:30的序列的LCDR3;或
d)包括SEQ ID NO:1的序列的HCDR1、包括SEQ ID NO:2的序列的HCDR2、包括SEQID NO:3的序列的HCDR3、包括SEQ ID NO:4的序列的LCDR1、包括SEQ ID NO:5的序列的LCDR2和包括SEQ ID NO:6的序列的LCDR3;和
其中第二结合结构域包括:
e)包括SEQ ID NO:7的序列的HCDR1、包括SEQ ID NO:8的序列的HCDR2、包括SEQID NO:9的序列的HCDR3;包括SEQ ID NO:10的序列的LCDR1、包括SEQ ID NO:11的序列的LCDR2和包括SEQ ID NO:12的序列的LCDR3;或
f)包括SEQ ID NO:13的序列的HCDR1、包括SEQ ID NO:14的序列的HCDR2、包括SEQID NO:15的序列的HCDR3、包括SEQ ID NO:16的序列的LCDR1、包括SEQ ID NO:17的序列的LCDR2和包括SEQ ID NO:18的序列的LCDR3;或
g)包括SEQ ID NO:19的序列的HCDR1、包括SEQ ID NO:20的序列的HCDR2、包括SEQID NO:21的序列的HCDR3、包括SEQ ID NO:22的序列的LCDR1、包括SEQ ID NO:23的序列的LCDR2和包括SEQ ID NO:24的序列的LCDR3。
在某些实施例中,第二抗原不同于hVEGFR2。
在某些实施例中,第二抗原是免疫相关靶标。在一些实施例中,双特异性抗体及其抗原结合片段特异性结合hVEGFR2和免疫相关靶标,并且能够使免疫细胞靶向表达hVEGFR2的细胞(例如表达hVEGFR2的肿瘤细胞),和/或激活对表达hVEGFR2的靶细胞的hVEGFR2特异性免疫反应。如本文所用,免疫相关靶标涵盖参与免疫反应、任选地细胞免疫反应的产生或调节的生物分子。免疫相关靶标的实例是免疫检查点分子,以及细胞溶解性免疫细胞如T细胞或自然杀伤(NK)细胞的表面分子。
免疫检查点分子可以介导共刺激信号以增强免疫反应,或者可以介导共抑制信号以抑制免疫反应。免疫检查点分子的实例包含例如PD-L1、PD-L2、PD-1、CLTA-4、TIM-3、LAG3、A2AR、CD160、2B4、TGFβ、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和CD83。
细胞溶解性免疫细胞可以由其表面分子触发以攻击和介导靶细胞如肿瘤细胞的裂解。在某些实施例中,第二抗原是T细胞表面抗原。T细胞表面抗原的实例包含但不限于选自由CD3、CD2、CD4、CD5、CD6、CD8、CD28、CD40L和/或CD44组成的群组的抗原,优选CD3。在某些实施例中,所述第二抗原是CD3的ε链。在某些实施例中,所述双特异性抗体与T细胞上的CD3的结合导致所述T细胞增殖和/或活化,这诱导细胞毒性因子的释放,例如穿孔素和颗粒酶,以及靶细胞的细胞溶解和凋亡。在某些实施例中,第二抗原是NK细胞表面抗原,如CD16(FcγRIII)或CD56。在某些实施例中,双特异性抗体与NK细胞上的CD16的结合导致NK细胞脱粒和靶细胞的穿孔素依赖性靶细胞裂解(ADCC)。
在某些实施例中,第二抗原包括肿瘤抗原。如本文所用,“肿瘤抗原”是指肿瘤特异性抗原(例如,肿瘤细胞特有的且通常不在非肿瘤细胞上发现的那些)、肿瘤相关抗原(例如在肿瘤和非肿瘤细胞中均发现但在肿瘤细胞中表达不同)和肿瘤新抗原(例如,由于改变蛋白序列或在两个不相关序列之间产生融合蛋白的体细胞突变而在癌细胞中表达)。
肿瘤抗原的实例包含但不限于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、神经节苷脂GM1、GM2、GM3、GD1a、GD1b、GD2、GD3、GT1b、GT3、GQ1、NY-ESO-1、NFX2、SSX2、SSX4、Trp2、gp100(Pmel 17)、酪氨酸酶、Muc-1、端粒酶、生存素、G250、p53、CA125 MUC、Wue抗原、Lewis Y抗原、HSP-27、HSP-70、HSP-72、HSP-90、Pgp、MCSP、EpHA2和细胞表面靶标GC1 82、GT468或GT512、PD-L1、虫媒病毒E蛋白表位、胶质瘤相关抗原、癌胚抗原(CEA)、β-人绒毛膜促性腺激素、甲胎蛋白(AFP)、凝集素反应性AFP、甲状腺球蛋白、RAGE-1、MN-CA IX、人端粒酶逆转录酶、RU1、RU2(AS)、肠羧基酯酶、muthsp70-2、M-CSF、前列腺酶、前列腺特异性抗原(PSA)、PAP、NY-ESO-1、LAGE-la、p53、prostein、PSMA、生存素和端粒酶、前列腺癌肿瘤抗原-1(PCTA-1)、MAGE、ELF2M、嗜中性粒细胞弹性蛋白酶、ephrinB2、CD22、胰岛素生长因子(IGF)-I、IGF-II、IGF-I受体和间皮素、ART-1/MelanA(MART-1)、酪氨酸酶、TRP-1、TRP-2和肿瘤特异性多系抗原如MAGE-1、MAGE-3、BAGE、GAGE-1、GAGE-2、pi 5;Ras,由染色体易位产生的独特肿瘤抗原;如BCR-ABL、E2A-PRL、H4-RET、1GH-IGK、MYL-RAR;和病毒抗原,如爱泼斯坦-巴尔病毒抗原EBVA和人乳头瘤病毒(HPV)抗原E6和E7;基于蛋白的抗原包含TSP-180、MAGE-4、MAGE-5、MAGE-6、RAGE、NY-ESO、pl85erbB2、pl 80erbB-3、c-met、nm-23H l、PSA、TAG-72、CA19-9、CA72-4、CAM 17.1、NuMa、K-ras、β-连环蛋白、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、RCAS1、SDCCAG16、TA-90\Mac-2结合蛋白、亲环素C相关蛋白、TAAL6、TAG72、TLP和TPS。
本文提供的双特异性抗体及其抗原结合片段可以是本领域中已知的合适格式。例如,示例性双特异性格式可以是双特异性双功能抗体、基于scFv的双特异性格式、IgG-scFv融合体、双可变结构域(DVD)-Ig、四价体瘤、杵-臼、共同轻链(例如,带杵-臼的共同轻链等)、BiTE、CrossMab、CrossFab、Duobody、SEEDbody、亮氨酸拉链、双作用Fab(DAF)-IgG和Mab2双特异性格式(参见例如,Brinkmann等人2017,《单克隆抗体(Mabs)》,9(2):182-212)。双特异性分子可以是对称或不对称的架构。
本文提供的双特异性抗体和抗原结合片段可以用本领域中已知的任何合适的方法制备。
在一个实施例中,具有不同抗原特异性的两个免疫球蛋白重链-轻链对在宿主细胞中共表达来以重组方式产生双特异性抗体(参见例如,Milstein和Cuello,《自然》,305:537(1983)),然后通过亲和色谱法纯化。
在另一个实施例中,将编码两种特异性的抗体重链可变结构域的序列分别融合至免疫球蛋白恒定结构域序列,随后插入一个或多个表达载体,该表达载体与轻链序列的表达载体共转染到合适的宿主细胞中以用于双特异性抗体的重组表达(参见例如,WO 94/04690;Suresh等人,《酶学方法》,121:210(1986))。类似地,scFv二聚体也可以从宿主细胞重组构建和表达(参见例如,Gruber等人,《免疫学杂志》,152:5368(1994))。
在另一种方法中,来自Fos和Jun蛋白的亮氨酸拉链肽可以通过基因融合与两种不同抗体的Fab'部分连接。连接的抗体在铰链区被还原为四个半抗体(即单体),然后再氧化形成异二聚体(Kostelny等人,《免疫学杂志》,148(5):1547-1553(1992))。
两个抗原结合结构域也可以缀合或交联以形成双特异性抗体或抗原结合片段。例如,一种抗体可以与生物素偶联,而另一种抗体与抗生物素蛋白偶联,并且生物素和抗生物素蛋白之间的强缔合将使两种抗体复合在一起形成双特异性抗体(参见例如,美国专利号4,676,980;WO 91/00360、WO 92/00373和EP 03089)。对于另一个实例,两种抗体或抗原结合片段可以通过本领域已知的常规方法交联,例如如美国专利号4,676,980中公开的。
双特异性抗原结合片段可由双特异性抗体产生,例如通过蛋白水解切割或通过化学连接产生。例如,可以制备抗体的抗原结合片段(例如,Fab')并将其转化为Fab'-硫醇衍生物,然后与另一种具有不同抗原特异性的转化的Fab'衍生物混合并反应以形成双特异性抗原结合片段(参见例如,Brennan等人,《科学》,229:81(1985))。
在某些实施例中,本文提供的双特异性抗体或其抗原结合片段可以在界面处工程化,使得可以形成杵-臼缔合以促进两个不同抗原结合位点的异二聚化。这可以最大化从重组细胞培养物中回收的异二聚体的百分比。如本文所用,“杵-臼”是指两个多肽(如Fc)之间的相互作用,其中一个多肽由于存在具有庞大侧链的氨基酸残基(例如酪氨酸或色氨酸)而具有突起(即“杵”),并且另一多肽具有腔(即“臼”),其中存在小的侧链氨基酸残基(例如丙氨酸或苏氨酸),并且突起可定位在腔中以促进两个多肽相互作用以形成异二聚体或复合物。产生具有杵-臼的多肽的方法在本领域中是已知的,例如如美国专利号5,731,168所述。
缀合物
在一些实施例中,抗-hVEGFR2抗体及其抗原结合片段与一个或多个缀合物部分连接。缀合物是可与抗体或其抗原结合片段连接的部分。预期多种缀合物可与本文提供的抗体或抗原结合片段连接(参见例如,“缀合物疫苗(Conjugate Vaccines)”,《对微生物学和免疫学的贡献(Contributions to Microbiology and Immunology)》,J.M.Cruse和R.E.Lewis,Jr.(编辑),Carger Press,New York,(1989))。这些缀合物可以通过共价结合、亲和力结合、嵌入、配位结合、复合、缔合、掺合或添加等方法与抗体或抗原结合片段连接。在某些实施例中,抗体或其抗原结合片段通过连接子与一个或多个缀合物连接。在某些实施例中,连接子是腙连接子、二硫连接子、双官能连接子、二肽连接子、葡萄糖苷酸连接子、硫醚连接子。
在某些实施例中,本文公开的抗-hVEGFR2抗体和抗原结合片段可被工程化以含有可用于结合一种或多种缀合物的表位结合部分之外的特定位点。例如,此类位点可以包含一个或多个反应性氨基酸残基,如例如半胱氨酸或组氨酸残基,以促进与缀合物的共价连接。
缀合物可以是清除调节剂、治疗剂(例如化疗剂)、毒素、放射性同位素、可检测标记(例如镧系元素、发光标记、荧光标记或酶-底物标记)、药代动力学修饰部分、DNA-烷化剂、拓扑异构酶抑制剂、微管蛋白结合剂、其他抗癌药物或纯化部分(如磁珠或纳米颗粒)。
可检测标记的实例可包含荧光标记(例如,荧光素、罗丹明、丹磺酰、藻红蛋白或德克萨斯红)、酶-底物标记(例如,辣根过氧化物酶、碱性磷酸酶、荧光素酶、葡糖淀粉酶、溶菌酶、糖氧化酶或β-D-半乳糖苷酶)、放射性同位素、其他镧系元素、发光标记、发色部分、地高辛、生物素/抗生物素蛋白、DNA分子或用于检测的金。
放射性同位素的实例可以包含123I、124I、125I、131I、35S、3H、111In、112In、14C、64Cu、67Cu、86Y、88Y、90Y、177Lu、211At、186Re、188Re、153Sm、212Bi和32P。放射性同位素标记的抗体可用于受体靶向成像实验。
在某些实施例中,缀合物可以是药代动力学调节部分,如PEG,其有助于增加抗体的半衰期。其他合适的聚合物包含如羧甲基纤维素、葡聚糖、聚乙烯醇、聚乙烯吡咯烷酮、乙二醇/丙二醇的共聚物等。
在某些实施例中,缀合物可以是纯化部分,如磁珠或纳米颗粒。
抗体-药物缀合物
在某些实施例中,本公开提供了抗体-药物缀合物(ADC),其包括与细胞毒剂缀合的任何上述抗-hVEGFR2抗体或抗原结合片段。
ADC可用于局部递送细胞毒剂,例如用于治疗癌症。这允许将细胞毒剂靶向递送至肿瘤并在其中进行细胞内积聚,这在这些未缀合的细胞毒剂的全身施用可能导致对正常细胞以及寻求消除的肿瘤细胞的毒性水平不可接受的情况下特别有用(Baldwin等人(1986),《柳叶刀(Lancet)》,(1986年3月15日)pp.:603-05;Thorpe(1985),“癌症疗法中细胞毒剂的抗体载剂:综述(Antibody Carriers Of Cytotoxic Agents In Cancer Therapy:AReview)”,《单克隆抗体'84:生物和临床应用(Monoclonal Antibodies'84:BiologicalAnd Clinical Applications)》,A.Pinchera等人(编辑),pp.475-506;Syrigos和Epenetos(1999),《抗癌研究(Anticancer Research)》,19:605-614;Niculescu-Duvaz和Springer(1997),《高等药物递送综述(Adv.Drg Del.Rev.)》,26:151-172;美国专利号4,975,278)。
在某些实施例中,细胞毒剂可为对细胞有害或可损害或杀灭细胞的任何药剂。在某些实施例中,细胞毒剂任选地是毒素、化学治疗剂(如DNA烷基化剂、拓扑异构酶抑制剂、微管蛋白结合剂、生长抑制剂或其他抗癌药物)或放射性同位素。
毒素的实例包含细菌毒素和植物毒素,如例如白喉毒素、外毒素A链(来自铜绿假单胞菌)、蓖麻毒素、相思豆毒蛋白、蒴莲根毒素、α-帚曲霉素、油桐蛋白、石竹素蛋白、美洲商陆蛋白(PARI、PAPII和PAP-S)、苦瓜抑制剂、泻果素、巴豆素、石碱花抑制剂、白树毒素、局限曲菌素、酚霉素、依诺霉素和单端孢霉烯(参见例如WO93/21232)。此类大分子毒素可以使用本领域已知的方法与本文提供的抗体或抗原结合片段缀合,例如如Vitetta等人(1987),《科学》,238:1098所述。
细胞毒剂也可以是小分子毒素和化学治疗剂,如格尔德霉素(Mandler等人(2000),《美国国立癌症研究杂志(Jour.of the Nat.Cancer Inst.)》,92(19):1573-1581;Mandler等人(2002),《生物缀合物化学(Bioconjugate Chem.)》,13:786-791)、美登素和美登木素(EP 1391213;Liu等人(1996),《美国国家科学院院刊》,93:8618-8623;美国专利号5,208,020)、卡奇霉素(Lode等人(1998),《癌症研究》,58:2928;Hinman等人(1993),《癌症研究》,53:3336-3342)、紫杉醇、细胞松弛素B、短杆菌肽D、溴化乙锭、依米汀、丝裂霉素、依托泊苷、替尼泊苷、长春新碱、长春碱、长春地辛、秋水仙素、多柔比星、柔红霉素、二羟基炭疽菌素二酮、米托蒽醌、光神霉素、放线菌素D、1-脱氢睾酮、糖皮质激素、普鲁卡因、丁卡因、利多卡因、普萘洛尔、嘌呤霉素及其类似物、抗代谢物(例如甲氨蝶呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、5-氟尿嘧啶达卡巴嗪)、烷化剂(例如氮芥、噻替派苯丁酸氮芥、美法仑、卡莫司汀(BSNU)和洛莫司汀(CCNU)、环磷酰胺、白消安、二溴甘露醇、链脲佐菌素、丝裂霉素C和顺式二氯二胺铂(II)(DDP)顺铂)、蒽环类(例如柔红霉素(原道诺霉素)和多柔比星)、抗生素(例如更生霉素(原放线菌素)、博来霉素、光神霉素和安曲霉素(AMC))和抗有丝分裂剂(例如长春新碱和长春碱)、卡奇霉素、美登木素、尾海兔素、澳瑞他汀(如MMAE和MMAF(美国专利号5,635,483;5,780,588))、多拉司他汀、单端孢霉烯和CC1065,及其具有细胞毒活性的衍生物。
细胞毒剂还可以是高放射性同位素。实例包含At211、I131、I125、Y90、Re186、Sm153、Bi212、P32、Pb212和Lu的放射性同位素。放射性同位素与抗体缀合的方法是本领域已知的,例如,通过合适的配体试剂(参见例如,WO94/11026;《免疫学当前方案(Current Protocolsin Immunology)》,第1卷和第2卷,Coligen等人编辑,Wiley-Interscience New York,N.Y.,Pubs.(1991))。配体试剂具有能与放射性同位素金属结合、螯合或以其他方式络合的螯合配体,并且还具有与抗体或抗原结合片段中半胱氨酸的硫醇具有反应性的官能团。例示性螯合配体包含DOTA、DOTP、DOTMA、DTPA和TETA(Macrocyclics,Dallas,Tex.)。
细胞毒剂可以通过本领域已知的任何合适的连接子连接至抗体或抗原结合片段,参见例如美国专利号5,208,020、6,441,163或EP专利0 425 235B1,Chari等人,《癌症研究》,52:127-131(1992)和US2005/0169933 A1,其公开内容通过引用明确并入本文。
在某些实施例中,连接子在特定生理环境下是可切割的,从而促进细胞毒性药物在细胞中的释放。例如,连接子可以是酸不稳定连接子、肽酶敏感连接子、光不稳定连接子、二甲基连接子或含二硫键的连接子、硫醚连接子和酯酶不稳定连接子(Chari等人,《癌症研究》,52:127-131(1992);美国专利号5,208,020)。在一些实施例中,连接子可包括氨基酸残基,如二肽、三肽、四肽或五肽。连接子中的氨基酸残基可以是天然或非天然存在的氨基酸残基。此类连接子的实例包含:缬氨酸-瓜氨酸(ve或val-cit)、丙氨酸-苯丙氨酸(af或ala-phe)、甘氨酸-缬氨酸-瓜氨酸(gly-yal-cit)、甘氨酸-甘氨酸-甘氨酸(gly-gly-gly)、缬氨酸-瓜氨酸-对氨基苄氧基羰基(“vc-PAB”)。可以设计氨基酸连接子组分并在其对特定酶例如肿瘤相关蛋白酶、组织蛋白酶B、C和D或纤溶酶蛋白酶的酶促切割的选择性方面优化。
在某些实施例中,细胞毒剂可以通过双官能连接子试剂连接至本文提供的抗体或其抗原结合片段,包含如N-琥珀酰亚胺基-3-(2-吡啶基二硫基)丙酸酯(SPDP)、琥珀酰亚胺基-4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯(SMCC)、N-琥珀酰亚胺基-4-(2-吡啶基硫基)戊酸酯(SPP)、亚氨基硫杂环戊烷(IT)、亚氨基酯的双官能衍生物(如二甲基己二亚酰胺HCl)、活性酯(如辛二酸二琥珀酰亚胺酯)、醛(如戊二醛)、双叠氮化合物(如双(对叠氮基苯甲酰基)己二胺)、双重氮衍生物(如双(对重氮苯甲酰基)-乙二胺)、二异氰酸酯(如甲苯2,6-二异氰酸酯)、双活性氟化合物(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和磺基-SMPB和SVSG(琥珀酰亚胺基-(4-乙烯基砜)苯甲酸酯)。那些连接子试剂是可商购的(例如,来自Pierce Biotechnology,Inc.,Rockford,Ill.,U.S.A,参见《应用手册和目录(Applications Handbook and Catalog)》第467页-第498页,2003-2004)。
在某些实施例中,在本文提供的ADC中,抗体(或其抗原结合片段)以约1至约20、约1至约6、约2至约6、约3至约6、约2至约5、约2至约4或约3至约4的抗体:药剂比率与一种或多种细胞毒剂缀合。
本文所提供的ADC可通过本领域中已知的任何合适的方法制备。在某些实施例中,抗体(或其抗原结合片段)的亲核基团首先与双官能连接子试剂反应,然后与细胞毒剂连接,或反过来,即首先使细胞毒剂的亲核基团与双官能连接子反应,然后连接到抗体。
在某些实施例中,细胞毒剂可含有(或修饰为含有)硫醇反应性官能团,其可与本文提供的抗体或抗原结合片段的游离半胱氨酸的半胱氨酸硫醇反应。示例性的硫醇反应性官能团包含例如马来酰亚胺、碘乙酰胺、吡啶基二硫化物、卤代乙酰基、琥珀酰亚胺酯(例如NHS、N-羟基琥珀酰亚胺)、异硫氰酸酯、磺酰氯、2,6-二氯三嗪基、五氟苯基酯或亚磷酰胺(Haugland 2003,《荧光探针和研究化学品的分子探针手册(Molecular Probes Handbookof Fluorescent Probes and Research Chemicals)》,Molecular Probes,Inc.;Brinkley1992,《生物缀合物化学》,3:2;Garman 1997,《非放射性标记:一种实用的方法(Non-Radioactive Labelling:A Practical Approach)》,Academic Press,London;Means(1990),《生物缀合物化学》,1:2;Hermanson,G.,《生物缀合物技术(BioconjugateTechniques)》,(1996)Academic Press,San Diego,pp.40-55,643-671)。
细胞毒剂或抗体可与连接试剂反应,随后缀合形成ADC。例如,细胞毒剂的N-羟基琥珀酰亚胺基酯(NHS)可执行、分离、纯化和/或表征,或其可原位形成并与抗体的亲核性基团反应。通常,缀合物的羧基形式通过与以下物质的某些组合反应而活化:碳二亚胺试剂(例如二环己基碳二亚胺;二异丙基碳二亚胺)或脲鎓试剂(例如TsTu(O--(N-琥珀酰亚胺基)-N,N,N',N'-四甲基脲鎓四氟硼酸盐)、HBTU((O-苯并三唑-1-基)-N,N,N'N'-四甲基脲鎓六氟磷酸盐)或HATU(O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐));活化剂(如1-羟基苯并三唑(HOBt)和N-羟基琥珀酰亚胺)以得到NHS酯。在一些情况下,细胞毒剂和抗体可以通过原位活化和反应连接以一步形成ADC。其他活化和连接试剂包含TBTU(2-(1H-苯并三唑-1-基)-1-1,3,3-四甲基脲鎓六氟磷酸盐)、TFFH(N,N',N”,N”'-四甲基脲鎓2-氟-六氟磷酸盐)、PyBOP(苯并三唑-1-基-氧基-三-吡咯烷子基-膦鎓六氟磷酸盐)、EEDQ(2-乙氧基-1-乙氧基羰基-1,2-二氢-喹啉)、DCC(二环己基碳二亚胺);DIPCDI(二异丙基碳二亚胺)、MSNT(1-(均三甲基苯-2-磺酰基)-3-硝基-1H-1,2,4-三唑)和芳基磺酰卤,例如三异丙基苯磺酰氯。在另一个实例中,抗体或抗原结合片段可以与生物素缀合,然后间接缀合至与抗生物素蛋白缀合的第二缀合物。
多核苷酸和重组方法
本公开提供了编码抗-hVEGFR2抗体及其抗原结合片段的分离的多核苷酸。如本文所用,术语“核酸”或“多核苷酸”是指单链或双链形式的脱氧核糖核酸(DNA)或核糖核酸(RNA)和其聚合物。除非另有说明,否则特定的多核苷酸序列还隐含地涵盖其保守修饰的变体(例如简并密码子取代)、等位基因、直向同源物、SNP和互补序列以及明确指出的序列。具体而言,简并密码子取代可通过产生其中一个或多个选定(或所有)密码子的第三位被混合碱基和/或脱氧肌苷残基取代的序列来实现(参见Batzer等人,《核酸研究》,19:5081(1991);Ohtsuka等人,《生物化学杂志(J.Biol.Chem.)》,260:2605-2608(1985);和Rossolini等人,《分子细胞探针(Mol.Cell.Probes)》,8:91-98(1994))。
使用常规程序(例如,通过使用能够特异性结合编码抗体重链和轻链的基因的寡核苷酸探针)容易地分离和测序编码单克隆抗体的DNA。编码DNA还可以通过合成方法获得。
本公开提供了包括本文提供的分离的多核苷酸的载体(例如表达载体)。在某些实施例中,本文提供的表达载体包括编码本文提供的抗体或其抗原结合片段的多核苷酸、可操作地连接至多核苷酸序列的至少一种启动子(例如SV40、CMV、EF-1α)和至少一种选择标记物。载体的实例包含但不限于逆转录病毒(包含慢病毒)、腺病毒、腺相关病毒、疱疹病毒(例如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳多空病毒(例如SV40)、λ噬菌体和M13噬菌体、质粒如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。
包括编码抗体或其抗原结合片段的多核苷酸序列的载体可以被引入宿主细胞中进行克隆或基因表达。用于克隆或表达本文载体中的DNA的合适宿主细胞是上述原核生物、酵母或更高等真核生物细胞。用于此目的的合适的原核生物包含真细菌,如革兰氏阴性或革兰氏阳性生物体,例如肠杆菌科,如埃希氏杆菌属例如大肠杆菌、肠杆菌属、欧文氏菌属、克雷伯氏菌属、变形杆菌属、沙门氏菌属例如鼠伤寒沙门氏菌、沙雷氏菌属例如粘质沙雷氏菌和志贺氏菌属,以及杆菌纲如枯草芽孢杆菌和地衣芽孢杆菌、假单胞菌属如铜绿假单胞菌和链霉菌属。
除原核生物外,真核微生物如丝状真菌或酵母也是抗-hVEGFR2抗体编码载体的合适克隆或表达宿主。酿酒酵母或普通面包酵母是低等真核宿主微生物中最常用的。然而,许多其他属、种和株在本文中通常是可用的和有用的,如粟酒裂殖酵母;克鲁维酵母菌属宿主,如例如乳酸克鲁维酵母、脆壁克鲁维酵母(ATCC 12,424)、保加利亚克鲁维酵母(ATCC16,045)、威克克鲁维酵母(ATCC 24,178)、克鲁雄酵母(ATCC 56,500)、果蝇克鲁维酵母(ATCC 36,906)、耐热克鲁维酵母和马克斯克鲁维酵母;耶氏酵母属(EP 402,226);毕赤酵母(EP 183,070);念珠菌属;里氏木霉(EP 244,234);粗糙脉孢菌;许旺酵母属,如许旺酵母;和丝状真菌,如例如,脉孢菌属、青霉菌属、弯颈霉属和曲霉属宿主,如构巢曲霉和黑曲霉。
用于表达本文提供的糖基化抗体或抗原片段的合适的宿主细胞来源于多细胞生物体,如无脊椎动物细胞,例如植物和昆虫细胞。已经鉴定出多种杆状病毒株和变体以及来自如下宿主的相应容许的昆虫宿主细胞:草地贪夜蛾(毛虫)、埃及伊蚊(蚊子)、白纹伊蚊(蚊子)、黑腹果蝇(果蝇)和家蚕。用于转染的多种病毒株是公开可用的,例如苜蓿银纹夜蛾NPV的L-1变体和家蚕NPV的Bm-5株,并且此类病毒可以用作根据本发明的本文的病毒,特别是用于草地贪夜蛾细胞的转染。棉花、玉米、马铃薯、大豆、矮牵牛、番茄和烟草的植物细胞培养物也可以用作宿主。
然而,人们对脊椎动物细胞的兴趣最大,脊椎动物细胞的培养繁殖(组织培养)已成为常规程序。有用的哺乳动物宿主细胞系的实例是由SV40转化的猴肾CV1系(COS-7,ATCCCRL 1651);人胚胎肾系(亚克隆以在悬浮培养物中生长的293或293细胞,Graham等人,《基因病毒杂志(J.Gen Virol.)》,36:59(1977));乳仓鼠肾细胞(BHK,ATCC CCL 10);中国仓鼠卵巢细胞/-DHFR(CHO,Urlaub等人,《美国国家科学院院刊》,77:4216(1980));小鼠支持细胞(TM4,Mather,《生殖生物学(Biol.Reprod.)》,23:243-251(1980));猴肾细胞(CV1 ATCCCCL 70);非洲绿猴肾细胞(VERO-76,ATCC CRL-1587);人宫颈癌细胞(HELA,ATCC CCL 2);犬肾细胞(MDCK,ATCC CCL 34);水牛大鼠肝细胞(BRL 3A,ATCC CRL 1442);人肺细胞(W138,ATCC CCL 75);人肝细胞(Hep G2,HB 8065);小鼠乳腺肿瘤(MMT 060562,ATCCCCL51);TRI细胞(Mather等人,《纽约科学院年报(Annals N.Y.Acad.Sci.)》,383:44-68(1982));MRC5细胞;FS4细胞;和人肝癌系(Hep G2)。在一些优选实施例中,宿主细胞是哺乳动物培养细胞系,如CHO、BHK、NS0、293和其衍生物。在一些优选实施例中,宿主细胞是CHO及其衍生物。
宿主细胞用上述表达或克隆载体转化以产生抗-hVEGFR2抗体,并在常规营养培养基中培养,该培养基经适当修饰以诱导启动子、选择转化子或扩增编码所需序列的基因。在另一实施例中,抗体可通过所属领域中已知的同源重组产生。
用于产生本文提供的抗体或抗原结合片段的宿主细胞可以在多种培养基中培养。市售培养基如Ham's F10(Sigma)、最小必需培养基(MEM)(Sigma)、RPMI-1640(Sigma)和达尔伯克改良伊格尔培养基(DMEM)(Sigma)适用于培养宿主细胞。此外,描述于Ham等人,《酶学方法》,58:44(1979),Barnes等人,《分析生物化学(Anal.Biochem.)》,102:255(1980),美国专利号4,767,704;4,657,866;4,927,762;4,560,655;或5,122,469;WO 90/03430;WO87/00195;或美国专利RE.30,985中的任何培养基可用作宿主细胞的培养基。这些培养基中的任一种都可以视需要补充激素和/或其他生长因子(如胰岛素、转铁蛋白或表皮生长因子)、盐(如氯化钠、钙盐、镁盐和磷酸盐)、缓冲剂(如HEPES)、核苷酸(如腺苷和胸苷)、抗生素(如GENTAMYCINTM药物)、微量元素(定义为通常以微摩尔范围内的最终浓度存在的无机化合物)和葡萄糖或等效能量源。也可以按照本领域技术人员已知的适当浓度包含其他必要的补充剂。培养条件(如温度、pH等)是先前与所选的用于表达的宿主细胞一起使用的那些条件,并且对于普通技术人员而言将是显而易见的。
当使用重组技术时,抗体可以在细胞内、在周质空间中产生,或直接分泌至培养基中。如果在细胞内产生抗体,那么作为第一步骤,例如通过离心或超滤去除宿主细胞或裂解片段的微粒碎片。Carter等人,《生物技术》,10:163-167(1992)描述了一种用于分离分泌到大肠杆菌的周质空间的抗体的程序。简单来说,将细胞糊状物在乙酸钠(pH 3.5)、EDTA和苯甲基磺酰氟(PMSF)的存在下经约30分钟解冻。细胞碎片可通过离心去除。在抗体分泌到培养基中的情况下,来自此类表达系统的上清液一般首先使用市售的蛋白浓缩过滤器,例如Amicon或Millipore Pellicon超滤装置进行浓缩。蛋白酶抑制剂如PMSF可以包含在任何前述步骤中,以抑制蛋白水解,并且可以包含抗生素以防止外来污染物的生长。
可以使用例如羟基磷灰石色谱法、凝胶电泳、透析、DEAE-纤维素离子交换色谱法、硫酸铵沉淀、盐析和亲和色谱法纯化从细胞制备的抗-hVEGFR2抗体及其抗原结合片段,亲和色谱法是优选的纯化技术。
在某些实施例中,固定在固相上的蛋白A用于进行抗体和其抗原结合片段的免疫亲和纯化。蛋白A作为亲和配体的适合性取决于抗体中存在的任何免疫球蛋白Fc结构域的种类和同种型。蛋白A可用于纯化基于人γ1、γ2或γ4重链的抗体(Lindmark等人,《免疫方法杂志》,62:1-13(1983))。建议将蛋白G用于所有小鼠同种型和人γ3(Guss等人,《EMBO杂志(EMBO J.)》,5:1567 1575(1986))。亲和配体所连接的基质最通常是琼脂糖,但也可以使用其他基质。机械稳定性基质(如受控孔玻璃或聚(苯乙烯二乙烯基)苯)比琼脂糖具有更快的流速和更短的处理时间。当抗体包括CH3结构域时,Bakerbond ABX.TM.树脂(J.T.Baker,Phillipsburg,N.J.)可用于纯化。用于蛋白纯化的其他技术,如离子交换柱上分级分离、乙醇沉淀、反相HPLC、二氧化硅上的色谱、肝素SEPHAROSETM上的色谱、阴离子或阳离子交换树脂(如聚天冬氨酸柱)上的色谱、色谱聚焦、SDS-PAGE以及硫酸铵沉淀也是可用的,取决于待回收的抗体。
在任何初步纯化步骤之后,可以使用pH在约2.5-4.5的洗脱缓冲液对包括感兴趣的抗体和污染物的混合物进行低pH疏水相互作用色谱法,优选在低盐浓度(例如,约0-0.25M盐)下进行。
药物组合物
本公开进一步提供了包括抗-hVEGFR2抗体或其抗原结合片段和一种或多种药学上可接受的载剂的药物组合物。
用于本文所公开的药物组合物的药学上可接受的载剂可包含例如药学上可接受的液体、凝胶或固体载剂、水性媒剂、非水性媒剂、抗微生物剂、等渗剂、缓冲剂、抗氧化剂、麻醉剂、悬浮/分散剂、掩蔽剂或螯合剂、稀释剂、佐剂、赋形剂或无毒辅助物质、本领域中已知的其他组分或其各种组合。
合适的组分可包含例如抗氧化剂、填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、润滑剂、调味剂、增稠剂、着色剂、乳化剂或稳定剂,如糖和环糊精。合适抗氧化剂可包含例如甲硫氨酸、抗坏血酸、EDTA、硫代硫酸钠、铂、过氧化氢酶、柠檬酸、半胱氨酸、硫代甘油、硫代乙醇酸、硫代山梨糖醇、丁基化羟基苯甲醚、丁基化羟基甲苯和/或没食子酸丙酯。如本文所公开,在包括如本文所提供的抗体或抗原结合片段和缀合物的组合物中包含一种或多种抗氧化剂如甲硫氨酸,降低抗体或抗原结合片段的氧化。此氧化减少将防止或减少结合亲和力的损失,由此提高抗体稳定性并使储存寿命最大化。因此,在某些实施例中,提供了包括一种或多种本文公开的抗体或抗原结合片段和一种或多种抗氧化剂如甲硫氨酸的组合物。进一步提供了通过将抗体或抗原结合片段与一种或多种抗氧化剂如甲硫氨酸混合来防止本文提供的抗体或抗原结合片段氧化、延长本文提供的抗体或抗原结合片段的储存寿命和/或提高本文提供的抗体或抗原结合片段的功效的方法。
为了进一步说明,药学上可接受的载剂可以包含例如水性媒剂,如氯化钠注射液、林格注射液、等渗右旋糖注射液、无菌水注射液或右旋糖和乳酸林格注射液,非水性媒剂,如植物来源的不挥发油、棉籽油、玉米油、芝麻油或花生油,抑细菌或抑真菌浓度的抗微生物剂,等渗剂如氯化钠或右旋糖,缓冲剂如磷酸盐或柠檬酸盐缓冲剂,抗氧化剂如硫酸氢钠,局部麻醉剂如盐酸普鲁卡因,悬浮剂和分散剂如羧甲基纤维素钠、羟丙基甲基纤维素或聚乙烯吡咯烷酮,乳化剂如聚山梨醇酯80(TWEEN-80),掩蔽剂或螯合剂如EDTA(乙二胺四乙酸)或EGTA(乙二醇四乙酸)、乙醇、聚乙二醇、丙二醇、氢氧化钠、盐酸、柠檬酸或乳酸。用作载剂的抗微生物剂可添加到多剂量容器中的药物组合物中,抗微生物剂包含苯酚或甲酚、汞剂、苯甲醇、氯丁醇、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、硫柳汞、苯扎氯铵和苄索氯铵。合适的赋形剂可包含例如水、生理盐水、右旋糖、甘油或乙醇。合适的无毒辅助物质可包含例如润湿剂或乳化剂、pH缓冲剂、稳定剂、溶解性增强剂或如乙酸钠、脱水山梨糖醇单月桂酸酯、三乙醇胺油酸酯或环糊精的药剂。
药物组合物可为液体溶液、悬浮液、乳液、丸剂、胶囊、片剂、持续释放制剂或散剂。口服制剂可包含标准载剂,如药用级甘露糖醇、乳糖、淀粉、硬脂酸镁、聚乙烯吡咯烷酮、糖精钠、纤维素、碳酸镁等。
在某些实施例中,药物组合物被配制成可注射组合物。可注射的药物组合物可以任何常规形式制备,如例如液体溶液、悬浮液、乳液或适合产生液体溶液、悬浮液或乳液的固体形式。注射用制剂可包含准备好用于注射的无菌和/或无热原质溶液;准备好临在使用之前与溶剂组合的无菌干燥可溶性产品,如冻干粉末,包含皮下片剂;准备好用于注射的无菌悬浮液;准备好临在使用之前与媒剂组合的无菌干燥不溶性产品;和无菌和/或无热原质乳液。溶液可以是水性或非水性的。
在某些实施例中,单位剂量的肠胃外制剂被包装在安瓿、小瓶或带针头的注射器中。所有用于肠胃外施用的制剂都应该是无菌且无热原质的,正如本领域中已知和实践的那样。
在某些实施例中,通过将本文公开的抗体或抗原结合片段溶解在合适的溶剂中来制备无菌的冻干粉末。溶剂可含有提高粉末或由粉末制备的复原溶液的稳定性或其他药理学组分的赋形剂。可使用的赋形剂包含但不限于水、右旋糖、山梨糖醇、果糖、玉米糖浆、木糖醇、甘油、葡萄糖、蔗糖或其他合适的药剂。溶剂可含有缓冲剂,如柠檬酸盐、磷酸钠或磷酸钾或本领域技术人员已知的其他此类缓冲剂,在一个实施例中,pH值约为中性。随后无菌过滤溶液,接着在本领域技术人员已知的标准条件下冻干,得到所需制剂。在一个实施例中,将所得溶液分配到小瓶中以冻干。每个小瓶可以含有单剂量或多剂量的抗-hVEGFR2抗体或其抗原结合片段或其组合物。可以接受过量填充小瓶,少量超过一剂或一组剂量所需的量(例如,约10%),以促进准确的样品取出和准确的给药。冻干粉末可以在适当的条件下储存,如在约4℃至室温。
用注射用水重构冻干粉末提供了用于肠胃外施用的制剂。在一个实施例中,为了重构,将无菌和/或无热原质水或其他合适的液体载剂添加到冻干粉末中。精确量取决于给定的所选疗法,并且可以凭经验确定。
使用方法
本公开还提供了治疗方法,包括:向有此需要的受试者施用治疗有效量的本文提供的抗体或抗原结合片段和/或本文提供的药物组合物,从而在受试者中治疗VEGFR2相关疾病或病症、降低VEGFR2相关疾病或病症的严重性和/或减缓VEGFR2相关疾病或病症的进展。
在一些实施例中,VEGFR2相关疾病或病症是肿瘤或血管生成疾病。
肿瘤
在某些实施例中,VEGFR2相关疾病或病症是肿瘤,如实体瘤或非实体瘤。在一些实施例中,肿瘤产生VEGF(例如,VEGF-A)和/或对其微环境中存在的VEGF(例如,VEGF-A)敏感。研究已观察到实体瘤或非实体瘤如人白血病中的VEGF产生和VEGFR2表达(Sato,K.等人,《东北实验医学杂志(Tohoku J.Exp.Med.)》,185:173-84(1998);Ishii,Y.,《日本妇科学会杂志(Nippon Sanka Fujinka Gakkai Zasshi)》:4′I:133-40(1995);和Ferrer,F.A.等人,《泌尿学(Urology)》,54:567-72(1999);Fielder等人,《血液》,89:1870-5(1997)和Bellamy等人,《癌症研究》,59728-33(1999))。不希望受理论束缚,VEGF/hVEGFR2自分泌环在体内调节肿瘤细胞存活和迁移,并且已经进一步证明VEGFR1单克隆抗体抑制某些实体瘤细胞例如乳腺癌细胞中的自分泌VEGF/VEGFR1环,并抑制VEGF刺激的人白血病细胞迁移(参见例如,US7498414(B2))。
在某些实施例中,实体瘤选自由以下组成的群组:乳腺癌、肺癌、结直肠癌、胰腺癌、胶质瘤和淋巴瘤(例如头颈肿瘤)、结直肠肿瘤、前列腺肿瘤、乳腺肿瘤、肺肿瘤(如小细胞和非小细胞肺肿瘤)、胰腺肿瘤、甲状腺肿瘤、卵巢肿瘤、宫颈肿瘤、肾肿瘤、脑肿瘤和肝肿瘤、卡波西肉瘤、CNS肿瘤、神经母细胞瘤、毛细血管母细胞瘤、脑膜瘤、脑转移、黑色素瘤、胃肠道和肾癌和肉瘤(例如胃癌)、横纹肌肉瘤、胶质母细胞瘤(优选多形性胶质母细胞瘤)、平滑肌肉瘤、鳞状细胞癌、基底细胞癌和可通过抑制恶性角化细胞(如人恶性角化细胞)的生长来治疗的皮肤癌。在某些实施例中,实体瘤选自由以下组成的群组:胃癌、非小细胞肺癌如大细胞肺癌。
在某些实施例中,非实体瘤选自由以下组成的群组:白血病、多发性骨髓瘤和淋巴瘤,例如急性髓性白血病(AML)、慢性髓性白血病(CML)、急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、红细胞白血病或单核细胞白血病、霍奇金和非霍奇金淋巴瘤。
血管生成疾病
在某些实施例中,VEGFR2相关疾病或病症是血管生成疾病。血管生成疾病与不受控制的血管生成有关,血管生成可由VEGF例如VEGF-A调节。在伤口愈合过程中,可以在胚胎组织、巨噬细胞和增殖性表皮角化细胞中发现VEGF的表达(Breier等人,《发育(Development)》,114:521-32(1992);Brown等人,《实验医学杂志》,176:1375-9(1992);和Ferrara等人,《内分泌评论(Endocr.Rev)》,13:18-32(1992))。VEGF高表达也可见于肿瘤,如多形性胶质母细胞瘤、血管母细胞瘤、中枢神经系统肿瘤和AIDS相关卡波西肉瘤;见于动脉粥样硬化病变、斑块和炎性细胞(Nakamura,S.等人,《AIDS周刊(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);和Berkman,R.等人,《临床研究杂志(J.Clin.Invest.)》,91:153-9(1993))。不希望受理论束缚,与表达VEGF的肿瘤细胞相邻的内皮细胞通常表现出VEGF受体例如VEGFR2的上调表达。肿瘤释放VEGF导致刺激相邻内皮细胞中的血管生成,从而导致增殖、迁移、分化、管形成、维持血管完整性和增加内皮细胞的血管通透性。因此,本公开提供的抗-VEGFR2抗体或其抗原结合片段可以治疗血管生成疾病中涉及的VEGF/VEGFR2信号传导异常。
在一些实施例中,血管生成疾病是动脉粥样硬化、类风湿性关节炎(RA)、新生血管性青光眼、包含增殖性糖尿病视网膜病变在内的增殖性视网膜病变、黄斑变性、血管瘤、血管纤维瘤、牛皮癣、早产儿视网膜病变(例如,晶状体后纤维增生)、角膜移植排斥、胰岛素依赖型糖尿病、多发性硬化、重症肌无力、克罗恩病、自身免疫性肾炎、原发性胆汁性肝硬化、急性胰腺炎、同种异体移植排斥、过敏性炎症、接触性皮炎和迟发性超敏反应、炎性肠病、感染性休克、骨质疏松症、骨关节炎、由神经元炎症引起的认知缺陷、奥斯勒-韦伯综合征、再狭窄以及真菌、寄生虫和病毒感染如巨细胞病毒感染。
在一些实施例中,受试者是人。
本文提供的抗体或抗原结合片段和/或本文提供的药物组合物可以通过口服、鼻、静脉内、皮下、舌下、瘤内或肌肉内施用来施用。
在一些实施例中,本文提供的方法进一步包括施用治疗有效量的第二治疗剂,例如抗癌疗法,任选地,所述抗癌疗法选自化学治疗剂、放射疗法、免疫治疗剂、抗血管生成剂(例如VEGFR(如VEGFR-1、VEGFR-2和VEGFR-3)的拮抗剂)、EGFR拮抗剂、PDGFR拮抗剂、IGFR拮抗剂、NGFR拮抗剂、FGFR拮抗剂、靶向治疗剂、细胞治疗剂、基因治疗剂、激素治疗剂、细胞因子、姑息治疗、治疗癌症的手术(例如肿瘤切除术)、一种或多种止吐药、化学疗法引起的并发症的治疗或癌症患者的膳食补充剂(例如吲哚-3-甲醇)。
在一些实施例中,本公开提供了包括任选地与可检测部分缀合的本文提供的抗体或其抗原结合片段的试剂盒。该试剂盒可用于检测生物样品中hVEGFR2的存在或量,或可用于本文提供的诊断方法。
在一些实施例中,本公开提供了包括本文提供的抗体或其抗原结合片段和第二治疗剂的试剂盒。该试剂盒可用于治疗、预防和/或改善VEGFR2相关疾病或病症。
本公开还提供了检测样品中VEGFR2的存在或量的方法,包括使样品与本文提供的抗体或其抗原结合片段接触,并确定样品中VEGFR2的存在或量。
在一些实施例中,本公开还提供了本文提供的抗体或其抗原结合片段在制备用于在受试者中治疗VEGFR2相关疾病或病症、降低VEGFR2相关疾病或病症的严重性和/或减缓VEGFR2相关疾病或病症的进展的药物中的用途。
实例
实例1:VEGFR2蛋白的制备和表征
人VEGFR2/KDR-His:重组人VEGFR/KDR蛋白(hVEGFR2-his,登录号AAI31823.1)在人293细胞(HEK293)中表达。简言之,将来自Ala20-Glu764的在C末端具有6×his标签的人VEGFR2基因的编码区用于转染。使用His-标签亲和柱纯化上清液。使用SDS PAGE凝胶表征所得纯化蛋白。该蛋白购自ACRO Biosystems(Cat#KDR-H5227)。
具有His标签的恒河猴VEGFR2/KDR:使重组恒河猴VEGFR2/KDR蛋白胞外结构域Ala20至Glu764(登录号XP_014994176.1)在C末端与多组氨酸标签融合,并在人293细胞(HEK293)中产生。使用His-标签亲和柱纯化来自HEK293细胞的转染上清液。使用SDS PAGE凝胶表征所得纯化蛋白。该蛋白购自ACRO Biosystems(Cat#VE2-C52H3)。
上述VEGFR2蛋白用于以下实验。
实例2:抗体产生
1.抗原缀合和免疫
对于免疫,重组hVEGFR2-his蛋白与各种MabSpace免疫增强肽缀合。简言之,将2-8倍摩尔过量的肽与磺基-SMCC(4-[N-马来酰亚胺甲基]环己烷-1-羧酸磺基琥珀酰亚胺酯,Peirce#22322)激活的hVEGFR2蛋白混合,并在室温下孵育一小时。停止反应并使用SDS-PAGE凝胶分析和QC缀合的蛋白。
分别使用完全弗氏佐剂(Pierce)将上述缀合的hVEGFR2-his蛋白以1:1的比例乳化,然后皮下和腹膜内免疫C57B/L6小鼠。使用CpG和明矾进行额外的免疫以保持蛋白的天然构象。至少每2周进行一次免疫,并在第1次免疫后从小鼠中取出抗血清以通过ELISA测定进行抗-hVEGFR2滴度分析。
为了测定血清滴度,从每只免疫小鼠制备20μl小鼠血清。高结合透明聚苯乙烯96孔板(Nunc)包被有100μl/孔的1μg/ml溶液,该溶液由在高pH包被缓冲液(0.16% Na2CO3,0.3% NaHCO3,pH 9.8)中的人VEGFR2-his组成。将板在4℃下孵育过夜,然后在自动洗板机上使用洗涤缓冲液PBS+0.1% Tween 20(Sigma)洗涤一次。向每个孔中添加200μl封闭缓冲液(PBS+1% BSA +1%山羊血清+0.05% Tween 20)并在室温下孵育2小时。然后吸出封闭缓冲液,并将稀释缓冲液(PBS+1% BSA +1%山羊血清+0.01% Tween 20)中的100μl连续稀释血清转移到ELISA板的每个孔中,并使其在室温下孵育60min。然后使用上述方法将板洗涤3次。然后将100μl/孔的在稀释缓冲液中稀释的HRP缀合山羊抗小鼠Fc抗体溶液(Abcam,Cat#Ab98808)添加到板的每个孔中。之后,使ELISA板在室温下孵育60min,用250μl/孔洗涤缓冲液洗涤板3次。最后,向每个孔中添加100μl/孔的TMB,并使用0.64M H2SO4终止反应。在Thermo Multiscan FC上在450nM读取板。
2.融合
融合四天前,每只小鼠用在PBS中的未缀合的hVEGFR2蛋白腹膜内加强。在融合日,无菌取出脾脏,并且将器官加工成单细胞悬浮液。裂解红细胞并用DMEM(Gibco)洗涤脾细胞。将活的、对数期生长的骨髓瘤细胞(SP2/0)与鼠脾细胞以1:4的比例混合。然后在与PEG融合之前将细胞洗涤2次。融合后的细胞用DMEM洗涤并悬浮在补充有10% FBS+HFCS+OPI+1X HAT的细胞生长培养基中。将每孔200μl这种细胞悬浮液铺板于96孔细胞培养板中,并在37℃加湿的10% CO2培养箱中孵育过夜。将培养物孵育7天,然后将生长培养基从孔中吸出并更换为新鲜的生长培养基。更换培养基2-3天后开始筛选杂交瘤上清液。
3.由ELISA测定进行的抗体筛选
与上述测定血清滴度的方案相同。简言之,在4℃下包被0.5μg/ml hVEGFR2-his过夜。洗涤后,添加100μl杂交瘤上清液并使其完全结合。然后添加HRP缀合的山羊抗小鼠Fc抗体以检测结合的VEGFR2抗体。最后,在TMB反应和H2SO4终止后,在Thermo Multiscan FC上在450nM读取板。随后将来自ELISA阳性杂交瘤孔的细胞在细胞培养物中扩增,以进行进一步的表征研究。
实例3:阳性杂交瘤克隆的亚克隆和小规模抗体生产
1.阳性杂交瘤克隆的亚克隆
选择来自ELISA阳性杂交瘤孔的具有所需结合概况和阻断活性的细胞,并使用有限稀释将每个细胞铺板在96孔板中。使这些细胞生长7天。一旦达到足够的细胞质量,就收集来自每个孔的上清液并重新筛选抗原结合能力(参见实例2中的筛选)。
从每个96孔板中,识别出具有最高抗原结合活性的克隆,并在有限稀释下进一步扩增到96孔板中,其中每孔200μl杂交瘤生长培养基。7天后,对来自96孔板的细胞进行抗原结合测试。亚克隆进行了超过2次。当超过90个孔显示阳性结合信号时,识别出具有最高抗原结合活性的两个克隆并将其转移到具有培养基的24孔板中,并使其再生长2天。一旦24孔板汇合,就将细胞转移至6孔板。孵育5天后,将一部分细胞冻结。将剩余的细胞转移到烧瓶中并使其扩增。一旦烧瓶汇合,就将一半的细胞冻结(每个克隆3个小瓶)以用于额外的备份。使另一半在具有培养基的烧瓶中进一步扩增以用于抗体生产。使用标准方法确定同种型。
2.小规模抗体生产
将杂交瘤细胞接种到滚瓶中并用200-300ml杂交瘤培养基(Invitrogen)培养14天。如下从杂交瘤细胞培养物中纯化VEGFR2单克隆抗体(mAb)。所有纯化过程均在室温下进行。一种纯化方案用于纯化各种mAb并使用亲和色谱法。
将宿主细胞培养液(CCF)离心以去除细胞碎片。然后将CCF上清液过滤、稀释,然后以柱(蛋白G高性能(Bio-Rad))的形式加载到蛋白G色谱介质上并平衡。
加载后,洗涤蛋白G柱,直到流穿液的280nm处的吸光度恢复到基线。然后使用pH2.5的甘氨酸从柱中洗脱VEGFR2 mAb,并立即通过每mL洗脱体积添加50μL的1M TrisBase储备溶液中和。监测洗脱液在280nm处的吸光度并收集含有蛋白的级分以制备蛋白A池。
纯化后,通过使用10,000MWCO膜(Pierce Slide-A-Lyzer或透析管)透析在PBS中配制VEGFR2 mAb。配制后,过滤VEGFR2 mAb。
实例4:纯化的VEGFR2抗体的结合分析
与实例2通过ELISA测定筛选抗体的方案相同。简言之,包被0.5μg/ml hVEGFR2-his,并且连续稀释的纯化抗体将与包被抗原结合。使用HRP缀合的山羊抗小鼠Fc抗体可以检测各抗体的结合信号。
数据通过Graphpad Prism软件计算和拟合,并且抗体的EC50总结在图1A-1B和表6中。杂交瘤抗体对人具有相似的亲和力。
表6
实例5:评价纯化抗体抑制hVEGF-A与hVEGFR2结合的阻断活性
高结合透明聚苯乙烯96孔板用100μl/孔的1μg/ml hVEGFR2-his在4℃包被过夜。洗涤和阻断后,添加连续稀释的抗体(从10μg/ml到0.0006μg/ml)并在室温下孵育1小时。添加0.3μg/ml hVEGF-A(Acrobiosystem,Cat#VE5-H4210)并在室温下孵育2小时。然后添加100μl/孔的0.25μg/ml生物素化兔抗人VEGF-A(Peprotech,Cat#400-P10Bt)以检测结合的VEGF-A。然后依次添加100μl/孔的HRP缀合中性抗生物素蛋白抗体(Pierce,Cat#31001)和TMB溶液。最后,使用0.64M H2SO4终止反应,并在450nM处读取板。1121B是美国专利号:US7498414中公开的基准抗体(雷莫芦单抗)。
如图2所示,002、048、054和1121B具有相似的阻断活性和相当的IC50,表明前3种抗体也可通过阻断VEGF-A/VEGFR2相互作用来抑制VEGF-A的活性,如1121B。
实例6:通过FACS测量的纯化VEGFR2抗体与HUVEC结合的剂量依赖性反应
将对数期HUVEC细胞收集、计数并重悬于FACS缓冲液(5% BSA+PBS)中。将2×10^5个细胞添加至每个管中,然后用PBS洗涤一次(1500rpm,5min,室温)。然后将在FACS缓冲液中从杂交瘤上清液中纯化的100μl/管连续稀释的VEGFR2抗体添加到相应的管中,并在4℃下孵育1小时。然后用1ml PBS洗涤细胞两次,随后添加在FACS缓冲液中的100μl/管的2抗(1:400抗-mIgG(H+L)-PE,Cell signaling#8887)。将细胞在4℃下孵育0.5小时,然后用PBS洗涤两次,随后对于每个样品将细胞重悬于600μl PBS中。然后将细胞转移到FACS管中,并使用流式细胞术(BD Accuri C6)检测抗体与细胞的结合(见图3)。
通过Graphpad Prism软件计算和拟合阳性结合细胞的百分比。如图3所示,这些杂交瘤抗体可以与HUVEC细胞结合,这就是众所周知的VEGFR2在细胞表面的表达。
实例7:杂交瘤抗体的基因克隆和测序
小鼠抗人VEGFR2抗体轻链和重链可变区的序列通过称为5'RACE(cDNA末端快速扩增)的聚合酶链式反应(PCR)扩增技术获得。使用Trizol(Invitrogen)分离来自11B8(002)/21B4(003)/5G4(048)/10D11(054)抗体产生杂交瘤细胞的总RNA,并使用Superscript第一链合成系统(Invitrogen)利用寡核苷酸(DT)12-18引物(Invitrogen)合成cDNA。通过PCR克隆小鼠IgG基因的可变区,其中MuIgG VH3'-2和MuIg VH5'前导引物用于重链可变区,MuIgKVL3'-1和MuIgK VL5'前导引物用于轻链可变区(NOVAGEN)。将每种抗体的所得条带克隆到18-T克隆载体中,并使用ABIDNA测序仪器(Perkin Elmer)对来自20个克隆的DNA进行测序和确定。使用Vector NTI Advance10软件(Invitrogen)确定共有序列。
嵌合抗体的产生:在测序分析和确认后,将上述各基因的可变区克隆到重组表达载体pCP-Hck/Hcg1中。简言之,pCP-Hck/Hcg1载体首先通过两步限制酶消化。然后将轻链可变区(VL)和重链可变区(VH)的基因与消化的载体同源重组。在转化、克隆PCR和序列确认后,生成嵌合抗体的表达载体。
实例8:重组嵌合抗体表达与纯化
上述产生的重组嵌合抗体蛋白的表达和纯化通过以下方法进行:用终浓度为0.5μg/ml的DNA载体和1.0μg/ml的PEI(聚乙烯亚胺-线性,Polyscience)转染在含有10%Pluronic F-68的Freestyle 293表达培养基中以1x106个细胞/ml培养的HEK293E细胞。DNA与PEI的比例为1:2。与Optimal MEM形成DNA和PEI复合物的时段应为室温下15分钟。将转染细胞在5% CO2、37℃和125rpm振荡速度下于烧瓶中培养。在转染22至26小时后添加1%蛋白胨培养基。在第6天收获条件培养基并将上清液以3,000rpm离心30分钟。然后将澄清的条件培养基加载到预平衡的0.5ml蛋白A柱上,用5个柱体积的1XPBS洗涤,并且最后用3mL pH3.0 0.1M甘氨酸-HCL缓冲液洗脱结合的IgG。将洗脱的抗体蛋白透析至PBS并储存在-80℃。为了去除内毒素,使纯化的蛋白通过Hitrap DEAE琼脂糖F.F.柱进一步加工,并使用尺寸排阻色谱法(Superdex 200 5/150GL,G.E.Healthcare)分析所得抗体以确定纯度水平。
实例9:纯化的抗-VEGFR2嵌合抗体与人和恒河猴VEGFR2蛋白的结合
与实例4相同的方案,不同之处在于使用HRP缀合的山羊抗人Fc抗体作为二抗。还对与hVEGFR2-his和恒河猴VEGFR2-his(Acrobiosystems,Cat#VE2-C52H3)的结合进行头对头分析。
如图4A和4B所示,4个嵌合抗体可与人和恒河猴VEGFR2以相似的亲和力结合,如1121B,表明在恒河猴中评价安全性问题以进行进一步研究的可能性。
实例10:嵌合抗-VEGFR2抗体抑制VEGF-A与hVEGFR2结合的能力的表征
对于该测定,在添加嵌合抗体和VEGFR2的混合物之前,将0.25μg/ml VEGF-A包被在ELISA板上。为了检测游离的VEGF-A(不与VEGFR2结合),添加1:1000稀释的小鼠血清(先前用人VEGFR2免疫的小鼠),并使用HRP缀合的山羊抗小鼠Fc抗体作为二抗。
如图5所示,3种抗体(042C、048C和054C)对VEGF-A与VEGFR2结合的抑制效果与1121B一样好,甚至更好。002C显示出弱得多的中和活性。
实例11:选择纯化的嵌合抗体与HUVEC结合的基于FACS的分析
与实例6的方案相同,不同之处在于使用1:400兔抗-hIgG(H+L)-PE(Cellsignaling#8887)作为二抗。如图6所示,002C和054C与HUVEC细胞结合的EC50与1121B几乎相同。因此,这些VEGFR2抗体可以通过与在细胞表面表达的人VEGFR2结合而发挥作用。
实例12:通过竞争测定进行的表位分箱
与上述ELISA结合测定的方案类似。简言之,将0.5μg/ml hVEGFR2-his包被到板上。同时添加20μg/ml竞争者抗体和1.25μg/ml生物素化的其他抗体。孵育3小时后,添加中性抗生物素蛋白缀合的HRP以检测结合的生物素化抗体。如果竞争者抗体竞争相同的表位,则结合的生物素化抗体的信号会降低,但如果竞争不同的表位,则不会产生影响。
如图7所示,生物素-mA002与002、042、048和054竞争,说明它们可能属于同一表位组。并且后来发现该组具有最佳阻断活性和与1121B相同的表位(数据未显示)。
然后按照上述相同方案添加稀释的竞争者杂交瘤抗体(002、042、048和054)和较低浓度(100ng/ml)的嵌合抗体(002C、042C、054C)以进行替换。抗-hIgG Fc-HRP用作检测抗体。
如图8A-8C所示,随着杂交瘤抗体浓度的增加,嵌合抗体不能很好地结合或根本不能结合。与图7A和7B相同,杂交瘤002、042、048和054可以与嵌合抗体竞争,这可能是由于相同的表位。
实例13:剖析纯化嵌合抗体在HUVEC细胞中阻断VEGF-A诱导的pVEGFR2的活性
表达VEGFR2的细胞如HUVEC细胞将在VEGF-A刺激后上调VEGFR2的表达水平。然后增加的VEGFR2可以与VEGF-A结合并变成二聚体形式。二聚化将诱导VEGFR2的Tyr磷酸化,随后激活下游途径,如MAPK/ERK和PI3K。
简言之,将HUVEC细胞以1.5x105个细胞/孔的密度接种到12孔板中的含10% FBS的培养基中,并在37℃、5% CO2培养箱中孵育16小时,然后用无血清培养基将细胞饥饿4小时。每孔添加不同的嵌合抗体孵育30min,随后添加20ng/ml或40ng/ml VEGF-A孵育15min。最后,通过添加100μl含有完整蛋白酶抑制剂(Roche#04693132001)和磷酸酶抑制剂(Pierce#1862495)的RIPA缓冲液(Thermo ScientificTM,Cat#89900)制备细胞裂解物,在冰上孵育15分钟并离心以收集上清液。通过8% SDS-PAGE拆分等量的细胞裂解物。将蛋白转移到含有冰的罐上的PVDF膜(Millipore),在400amp下运行150min。然后将膜与含有5%BSA +TBST的溶液在室温下孵育2小时。然后将膜与含有1%BSA+TBST和兔抗磷酸化VEGFR2(Tyr1175)mAB(CST,Cat#3770)/小鼠抗-β-肌动蛋白抗体(Abbkine,Cat#A0101502)的溶液在4℃孵育过夜;然后在轻轻旋转下用TBST洗涤膜3次,每次10min;然后将膜与在1% BSA+TBST中以1:1000稀释的HRP缀合的山羊抗兔IgG Fc pAB(Abcam,Cat#Ab97080)/HRP缀合的山羊抗小鼠IgG pAb(Abcam,Cat#ab97040)孵育2小时。然后在轻轻旋转下用TBST洗涤膜3次,每次10min;最后,将1ml ECL混合物(Pierce)添加到PVDF膜上以用于信号暴露。
如图9A、9B和9C所示,20ng/ml和40ng/ml的VEGF-A均能快速诱导VEGFR2磷酸化。并且054C、048C、042C和002C以及雷莫芦单抗可以以剂量依赖的方式逆转这种刺激。
实例14:人源化抗体的产生和表征
1.人源化抗体的产生、表达和纯化
小鼠抗体054和048的可变结构域序列用于识别与鼠框架同源性最高的生殖系序列。计算机建模用于设计具有CDR移植和回复突变的人源化变体。
Ab-54
用于轻链的人生殖系框架序列VK/2D-40和用于重链的VH/3-21分别用于CDR移植。
Mab54 HC的生殖系序列:
VH/3-21(Mab54-生殖系,SEQ ID NO:92):
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYA
DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARELDGNYDYWGQGTTLTVSS
VH/3-21变体1(Mab54-Hzd-HC-V1,SEQ ID NO:93):
EVQLVESGGGLVKPGGSLKLSCAASGFTFSMYGMSWVRQTPGKRLEWVASISIGGSYTYYA
DSVKGRFTISRDNAKNTLYLQMNSLKAEDTAVYYCARELDGNYDYWGQGTTLTVSS
VH/3-21变体2(Mab54-HC-V2,SEQ ID NO:94):
EVQLVESGGGLVKPGGSLRLSCAASGFTFSMYGMSWVRQAPGKRLEWVASISIGGSYTYYA
DSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCARELDGNYDYWGQGTTLTVSS
Mab54 LC的生殖系序列:
VK/2D-40(Mab54 LC生殖系,SEQ ID NO:95):
DIVMTQTPLSLPVTPGEPASISCRSSQSLLDSDDGNTYLDWYLQKPGQSPQLLIYTLSYRA
SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQRIEFP
VK/2D-40变体3(Mab54-Hzd-LC-V1,SEQ ID NO:96):
DIVITQDELSLPVTFGESVSISCRSSKSLLYKDGKTYLNWFLQRPGQSPQLLIYLMSTRAS
GVSDRFSGSGSGTDFTLKISRVEAEDVGIYYCQQLVEYPFTFGSGTKLEIK
VK/2D-40变体4(Mab54-Hzd-LC-V2,SEQ ID NO:97):
DIVITQTPLSLPVTPGESVSISCRSSKSLLYKDGKTYLNWFLQRPGQSPQLLIYLMSTRAS
GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQLVEYPFTFGSGTKLEIK
Ab-48
用于轻链的人生殖系框架序列VK/2D-40和用于重链的VH/3-21分别用于CDR移植。
Mab48 HC的生殖系序列:
VH/3-21(Mab48-HC生殖系,SEQ ID NO:102):
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYA
DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR
VH/3-21变体5(Mab48-Hzd-HC-V3,SEQ ID NO:98):
EVQLVESGGGLVKPGGSLRLSCAASGFTFSMYGMSWVRQAPGKRLEWVASISIGGSYTYYA
DSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCAREMDGNYDYWGHGTTLTVSS
Mab48的生殖系和轻链序列与Mab54相同。
因此,人源化Mab54有4种变体,简称为54-H1L1、54-H2L1、54-H1L2、54-H2L2,并且人源化Mab48有2种变体,简称为48-H3L1、48-H3L2。事实上,VH/3-21变体5与VH/3-21变体2几乎相同,HCDR3中的一个氨基酸除外。这也与本专利中显示的两种抗体的相似生物活性一致。
合成上述重链和轻链cDNA,并与Fc区的人IgG1恒定区融合(本文所述的重链残基编号依据Kabat的EU索引(参见Kabat等人,“免疫感兴趣的蛋白(Proteins ofImmunological Interest)”,美国卫生与人类服务部(1983)))。合成所选抗体基因的重链和轻链的可变区并克隆到表达载体中,并使用来自Promega的PureYieldTM质粒大提系统制备大规模DNA。根据制造商的方案,使用来自Invitrogen的ExpiFectamineTM 293试剂进行转染。当细胞活力约为50%时收获上清液。将蛋白A珠子和干净的上清液于4℃摇动下孵育2小时,然后通过柱。用PBS洗涤柱内的蛋白A珠子,并使用100mM甘氨酸缓冲液(pH 3.0)洗脱抗体,将其针对PBS缓冲液(137mM NaCl,2.7mM KCl 10mM Na2HPO4,2mM KH2PO4,pH7.4)在4℃下透析过夜。最后,使用Pierce高容量内毒素去除树脂(Invitrogen,目录号:88271)去除内毒素。纯化的抗体通过SDS-PAGE和SEC-HPLC表征。
2.ELISA中人源化抗体与hVEGFR2和恒河猴VEGFR2的结合
与实例9相同的方案。首先测试由293T细胞表达的人源化054和048抗体(参见图10A和10B)。
然后由CHO细胞表达两种人源化抗体54-H2L1和48-H3L1以用于进一步评估,分别标记为54-H2L1(CHO)和48-H3L1(CHO)。维持与恒河猴VEGFR2-his的跨物种结合,这是治疗性抗体开发的一个非常重要的特征(参见图11A和11B)。
3.人源化VEGFR2抗体的结合特异性
简言之,将1μg/ml人VEGFR1(Sino Biological,cat#10136-H08H)、VEGFR2(Acrobiosystem,cat#KDR-H5227)和VEGFR3(Sino Biological,cat#10806-H08H)蛋白在4℃包被过夜。添加1μg/ml人源化抗体(在CHO细胞中产生的48-H3L1和54-H2L1,或来自EliLilly Germany,批次#20150819的雷莫芦单抗)以用于结合包被抗原。添加二抗HRP缀合的山羊抗人Fc抗体用于检测结合信号。
如图12所示,VEGFR2抗体48-H3L1、54-H2L1和雷莫芦单抗仅与VEGFR2结合,而不与VEGFR1或VEGFR3结合,表明这些抗体具有高特异性。
4.ELISA中hVEGF-A与hVEGFR2和恒河猴VEGFR2的结合的阻断
与实例10相同的方案。简言之,将0.25μg/ml VEGF-A在4℃下包被过夜。阻断后,同时添加连续稀释的54-H2L1、48-H3L1、雷莫芦单抗和1μg/ml人VEGFR2或恒河猴VEGFR2,孵育2小时。洗涤后,添加含有多克隆VEGFR2抗体和HRP缀合的山羊抗小鼠Fc抗体的小鼠血清以用于检测包被在板上的游离VEGF-A(参见图13A和13B)。
如图13A和13B所示,两种人源化抗体可以阻断VEGF-A与人VEGFR2或恒河猴VEGFR2相互作用。48-H3L1和54-H2L1的中和活性与雷莫芦单抗相似或者甚至可能更好。
5.人源化抗体阻断VEGF-C和VEGF-D与VEGFR2的结合
与实例10类似的方案。简言之,包被0.5μg/ml VEGF-A或VEGF-C或VEGF-D,同时添加30μg/ml VEGFR2抗体和2.5μg/ml人VEGFR2,孵育2小时。使用与实例10相同的检测方法,可以测量包被在板上的游离VEGF-A或VEGF-C或VEGF-D(参见图14A、14B和14C)。
如图14A、14B和14C所示,包含1121B在内的VEGFR2抗体完全阻断VEGF-A与VEGFR2的结合,但不阻断VEGF-C或VEGF-D与VEGFR2的结合。虽然观察到VEGF-C结合略有下降,但窗口太有限以致无法得出结论。
6.FACS中人源化抗体与HUVEC上hVEGFR2的结合
与实例11相同的方法。简言之,收集对数期HUVEC细胞并将其添加到每个管中。然后添加在FACS缓冲液中的100μl/管连续稀释的人源化抗体,并在4℃下保持1小时。抗体与HUVEC的结合通过在1抗之后添加的2抗(抗-hIgG(H+L)-PE)的PE信号检测(参见图15)。
7.HUVEC中hVEGF-A诱导的hVEGFR2磷酸化的阻断
与实例13相同的方法。简言之,将HUVEC细胞接种到12孔板中含有10% FBS的培养基中并孵育16小时,然后在没有血清的情况下饥饿4小时。将稀释的人源化抗体添加至每个孔中,孵育30min,随后添加40ng/ml VEGF-A,孵育15min。最后,制备细胞裂解物并通过实例13中描述的蛋白印迹检测磷酸化-VEGFR2和β-肌动蛋白(参见图16)。
如图16所示,人源化54的两个变体可以降低VEGF-A诱导的磷酸化VEGFR2的量。54-H2L1的抑制作用比54-H1L1强。
实例15:纯化的人源化抗体抑制HUVEC增殖和管形成的能力的评价
将对数期HUVEC细胞以5x103个细胞/孔的密度接种到96孔板中的含10% FBS的培养基中,并在37℃、5% CO2培养箱中孵育过夜,然后用50μl/孔无血清培养基饥饿细胞4小时。以50μl/孔添加连续稀释的人源化抗体并孵育30min,随后添加50μl/孔的VEGF-A(终浓度:20ng/ml)并孵育72小时。细胞培养结束时,添加20μl/孔的Cell发光试剂盒,并将上清液转移到新的白板上以用于读取发光信号。
受VEGF家族刺激的HUVEC细胞将被激活并增殖。阻断VEGFR2和VEGF可以逆转刺激作用。如图17所示,人源化54和48抗体对增殖的抑制作用可与雷莫芦单抗相同,呈剂量依赖性方式,表明它们阻断了HUVEC细胞的VEGF/VEGFR2信号通路。
实施例16:通过Biacore评价选择小鼠杂交瘤或人源化抗-VEGFR2抗体的结合亲和力
通过7-min注射(10μl/min)新鲜制备的1:1 50mM N-羟基琥珀酰亚胺(NHS):200mM1-乙基-3-(3-二甲基氨基丙基)-碳二亚胺(EDC)在每个流动池中激活CM5传感器芯片。然后将在10mM醋酸钠缓冲液PH 5.0中浓度为10μg/ml的抗人Fc抗体(GE Healthcare)以10μl/min注射到激活的芯片上(HBS-EP运行缓冲液:10mM HEPES,150mM NaCl,3.4mM EDTA,0.005%表面活性剂P20,pH 7.4)。剩余的活性偶联位点通过以10μl/min注射1M乙醇胺7min封闭。每个流动池的固定水平约为9000RU。通过抗人Fc IgG或抗小鼠Fc(GE Healthcare)在FC2中捕获抗体至200-300RU。FC1用作参考池。在捕获抗体后,以不同浓度(2.5nM、5nM、10nM、20nM、40nM和80nM)注射抗原。抗体结合抗原的缔合时间为180s。在Gly pH 1.5中,表面再生条件为120s,速度为10μl/min。使用Biacore X100评价软件2.0版(Biacore)计算从没有捕获抗体的信号中减去捕获抗体的信号。
表7.与抗原结合的抗体的亲和力参数
抗体 | 克隆 | 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VEGF-A和VEGFR2-Fc之间的相互作用具有约89pM的KD(doi:10.1007/s10456-011-9249-6)。
实例17:通过丙氨酸扫描进行的选择抗VEGFR2的表位作图
1.突变人VEGFR2重组蛋白的产生
在体外合成编码胞外人VEGFR2(氨基酸1-1356)和人IgG1的Fc片段的cDNA(SEQ IDNO:103是氨基酸序列)。通过如下所述的重叠PCR并使用如(表8)中所示的引物(Dr.OligoBLP-192,Biolytic)扩增在如下所列指定位置具有单个氨基酸变化的人VEGFR2变体。所得片段分别在5'和3'末端用Hind III和BamH I的限制酶消化。然后按照制造商的说明,使用Syno组装混合试剂(Synbio)通过同源重组方法将PCR产物克隆到pcDNA3.1(+)载体中。质粒是纯化的QIAGEN质粒大提试剂盒(QIAGEN)。
氨基酸序列(SEQ ID NO:103):
MQSKVLLAVALWLCVETRAASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCRGQRDLDWLWPNNQSGSEQRVEVTECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQDYRSPFIASVSDQHGVVYITENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWDSKKGFTIPSYMISYAGMVFCEAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKPFVAFGSGMESLVEATVGERVRIPAKYLGYPPPEIKWYKNGIPLESNHTIKAGHVLTIMEVSERDTGNYTVILTNPISKEKQSHVVSLVVYVPPQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECANEPSQAVSVTNPYPCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGERVISFHVTRGPEITLQPDMQPTEQESVSLWCTADRSTFENLTWYKLGPQPLPIHVGELPTPVCKNLDTLWKLNATMFSNSTNDILIMELKNASLQDQGDYVCLAQDRKTKKRHCVVRQLTVLERVAPTITGNLENQTTSIGESIEVSCTASGNPPPQIMWFKDNETLVEDSE
使用上述产生的野生型VEGFR2质粒(SEQ ID NO:103和104)作为模板,用大引物(表8)产生整合序列的两个片段,并通过同源重组完成连接。然后将产物克隆到pcDNA3.1(+)载体中,通过测序筛选出单个阳性菌落以识别变体后,证明VEGFR2突变体产生成功。PCR程序和条件如下:
表8.变体突变引物序列
步骤 1:生成两个大变体片段
初始变性:98℃1min
变性:98℃15s
退火:58℃30s
延伸:72℃30s/Kb
最终延伸:72℃3min 30个循环
第2步:将两个部分连接在一起
在冰上建立以下反应(同源重组):
其他20个变体由另一家公司Genewiz(中国苏州)制备。执行利用Synbio Tech的类似方法来合成VEGFR2变体。
随后,将这些突变体和野生型VEGFR2的质粒转染到293T(CRL3216)细胞系中。首先,将5×106个293T细胞接种到60mm培养皿中,确保初级比例在60%-80%以用于转染。然后在400μl 1×HBS中稀释10μg DNA,孵育约5min。向上述混合物中添加10μl 25kDa线性PEI转染试剂(溶于1×HBS,1mg/ml储备溶液),确保DNA/PEI比例为1:2.5。然后将混合物逐滴添加到293T培养皿中。大约6-8小时后更换培养基并替换为完整的DMEM。72小时后,分别用0.22μm过滤器收集细胞培养上清液,然后在-80℃保存备用。
2.ELISA中VEGFR2抗体与hVEGFR2突变体的结合
如下所述,使用上清液以通过ELISA检测VEGFR2抗体的结合。
2.1对于小鼠Ab:
将0.5μg/ml抗人Fc抗体(Abcam)在室温下包被一小时。将在DMEM中含有各种突变人VEGFR2-Fc蛋白或500ng/ml野生型人VEGFR2-Fc蛋白的160μl DMEM上清液添加到每个孔中,并在室温下孵育1小时。添加0.5μg/ml的小鼠抗-VEGFR2抗体并在室温下孵育1小时。然后依次添加HRP缀合的山羊抗小鼠IgG Fc抗体和TMB,并使用0.64MH2SO4终止反应。在ThermoMultiscan FC上在450nM读取板。
2.2对于具有人Fc的Ab(嵌合或人源化抗体):
与2.1类似的方案,不同之处在于添加嵌合或人源化抗体以结合突变VEGFR2-Fc和HRP缀合的抗hIgG Fc作为二抗。
表9总结了hVEGFR2上的关键残基,该残基是ELISA测定中针对人VEGFR2测试每个单独抗体所需的。标记导致结合信号相对于野生型蛋白显著降低的人VEGFR2蛋白上的氨基酸残基突变。
表9.每种抗体在hVEGFR2上的关键残基汇总
实例18:大规模生产用于体内研究的抗-VEGFR2抗体
使用在CHO-K1细胞中的瞬时表达产生抗体。使用蛋白-A亲和柱纯化产生的抗体,并在脱盐后,将抗体以5mg/ml配制入PBS,内毒素水平<3单位/mg。使用SDS-PAGE凝胶和SEC-HPLC表征所得抗体的纯度。
使用CHO-K1细胞瞬时表达和纯化重组抗体
重链和轻链的可变区选择的抗体基因被合成并克隆到表达载体中。产生的表达对比用于转染适合在无血清培养基中生长的CHO-K1细胞。在10L Applikon生物反应器中生长10天后,收获培养基并使用超滤器去除细胞和细胞碎片。然后通过超滤浓缩澄清的上清液并上样到制备的蛋白A(人IgG)或G-琼脂糖(小鼠IgG)柱上。在用平衡缓冲液在UV监测器的监测下洗涤至基线后,然后用0.1M柠檬酸,pH 3.5洗脱柱,并立即用1.0MTris-HCl缓冲液,pH 8.0中和洗脱的抗体,并针对PBS,pH7.2(Invitrogen)在2-8℃下透析过夜,其中更换2次缓冲液。纯化的抗体通过0.22μm无菌注射器过滤器过滤,并在-80℃或更低温度下以等分试样储存。
实例19:嵌合抗人VEGFR2抗体在HL-60肿瘤模型中的体内评价
为了评价VEGFR2候选抗体的抗肿瘤功效,建立了HL-60小鼠模型并评估了对于许多症状的功效。简言之,将4-6周的雌性NOD/SCID小鼠随机分为4组。CTX(150mpk,i.p.)治疗后,在次日静脉内注射1.5×10^7个细胞/小鼠。并且在HL-60细胞注射3天后,用下表(表10)中列出的不同抗体治疗小鼠。
表10.分组和治疗时间表(n=6)
如图18和表11所示,与其他组相比,54-C的存活百分比和状况最好。54-C治疗无动物死亡,阴性对照组和2-C治疗组均死亡2只。正如我们所知,VEGFR2的激活是通过与其配体VEGF-A结合而发生的,VEGF-A通过自分泌信号传导介导HL-60细胞增殖。这可以解释VEGFR2中和抗体54-C和1121B的肿瘤抑制作用。
表11.每个治疗组的症状和死亡
实例20:抗小鼠VEGFR2抗体DC101的评价
1.抗小鼠VEGFR2抗体DC101的体外评价
我们根据下表12所列的其Fab区序列重组和表达抗小鼠VEGFR2抗体DC101。对于DC101的Fc区,将大鼠IgG1 Fc替换为人IgG1 Fc并命名为嵌合-DC101。然后通过体外测定评价嵌合-DC101以确认其生物活性。
表12.DC101的可变链序列
表12中加粗序列分别代表VH和VL的信号肽。
进行ELISA结合测定以确认其结合亲和力。简言之,用在包被缓冲液(0.16%Na2CO3,0.3% NaHCO3)中的500ng/mL小鼠VEGFR2包被ELISA板,并在4℃孵育过夜。洗涤两次后,添加封闭缓冲液(1% BSA、1%山羊血清、0.05% Tween 20,于PBS中)并将板在室温下孵育2小时。洗涤三次后,将连续稀释的嵌合-DC101添加至稀释缓冲液(1% BSA、1%山羊血清、0.01% Tween 20,于PBS中)中,并将板在室温下孵育3小时。洗涤三次后,添加山羊抗人HRP(1:5000稀释),并在室温下孵育板1小时。最后,洗涤三次后,添加TMB,并在4min后添加0.16mol/L硫酸以终止反应。读取并记录OD450 nm。
如图19所示,三批嵌合-DC101具有非常一致的结合曲线和EC50(约为0.06μg/mL),这也与人源化54抗体和48抗体的EC50非常相似。
进行ELISA阻断测定以确认其VEGF阻断活性。简言之,用在包被缓冲液中的250ng/mL重组人VEGF165包被ELISA板,并在4℃孵育过夜。洗涤两次后,添加封闭缓冲液,并将板在室温下孵育2小时。洗涤三次后,在稀释缓冲液中添加连续稀释的嵌合-DC101,然后添加1000ng/mL小鼠VEGFR2。将板在室温下孵育3小时。洗涤三次后,添加具有小鼠Fc的多克隆抗小鼠VEGFR2(1:1000),并在室温下孵育板1小时。洗涤三次后,添加山羊抗小鼠HRP(1:5000稀释),并在室温下孵育板1小时。最后,洗涤三次后,添加TMB,并在4min后添加0.16mol/L硫酸以终止反应。读取并记录OD450 nm。
如图20所示,三批嵌合-DC101具有一致的阻断曲线和IC50值,与人源化抗人VEGFR2抗体054和048非常相似。嵌合-DC101显示出与人源化054和048抗体具有相似的结合亲和力和阻断活性,表明它可以用作054和048抗体的替代抗体。
2.使用MKN45胃肿瘤模型在体内评价抗小鼠VEGFR2抗体DC101
于37℃在空气中含有5% CO2的大气中在补充有10%热灭活胎牛血清(ExCellBiology)、100U/ml青霉素和100ug/ml链霉素(Hyclone)的RPMI1640培养基(ThermoFisher)中将MKN45细胞作为单层培养物在体外维持。通过胰蛋白酶-EDTA处理(Hyclone)每周两次对肿瘤细胞进行常规传代培养。收获在指数生长阶段中生长的细胞并且对其计数以用于肿瘤接种。用与50%基质胶混合的5*10^6个MKN45细胞接种雌性SPF级裸鼠。当肿瘤大小在100mm^3左右时,选择荷瘤小鼠并随机分为5组(n=10)。用30mg/kg同种型对照、3mg/kg嵌合-DC101、10mg/kg嵌合-DC101、30mg/kg嵌合-DC101和5mg/kg多西他赛作为阳性对照治疗动物,同种型对照和嵌合-DC101每周两次通过腹膜内注射施用,持续3周,而多西他赛每周一次通过静脉内注射施用,持续3周。每周两次使用卡尺(INSIZE)在二维上测量肿瘤大小,并使用下式:V=0.5a*b^2以mm^3表示体积,其中a和b分别是肿瘤的长径和短径。使用Prism GraphPad分析结果并表示为平均值±S.E.M.。两组之间的比较通过T检验进行,并且如果p为*<0.05和**<0.01,则认为差异显著。
如表12和图21所示,与同种型对照组相比,3mg/kg嵌合-DC101显著抑制MKN45肿瘤生长。随着剂量的增加,抑瘤率也有所增加,从54%增加到77%,说明嵌合-DC101以剂量依赖性诱导肿瘤生长抑制。
表12.第22天嵌合DC101对MKN45异种移植肿瘤模型的肿瘤生长抑制
3.使用H460肺肿瘤模型在体内评价抗小鼠VEGFR2抗体DC101
于37℃在空气中含有5% CO2的大气中在补充有10%热灭活胎牛血清(ExCellBiology)、100U/ml青霉素和100ug/ml链霉素(Hyclone)的RPMI1640培养基(ThermoFisher)中将H460细胞作为单层培养物在体外维持。通过胰蛋白酶-EDTA处理(Hyclone)每周两次对肿瘤细胞进行常规传代培养。收获在指数生长阶段中生长的细胞并且对其计数以用于肿瘤接种。用与50%基质胶混合的5*10^6个H460细胞接种雌性SPF级裸鼠。当肿瘤大小在150mm^3左右时,选择荷瘤小鼠并随机分为5组(n=10)。用30mg/kg同种型对照、3mg/kg嵌合-DC101、10mg/kg嵌合-DC101、30mg/kg嵌合-DC101和5mg/kg多西他赛作为阳性对照治疗动物,同种型对照和嵌合-DC101每周两次通过腹膜内注射施用,持续2周,而多西他赛每5天一次通过静脉内注射施用,共3剂。每周两次使用卡尺(INSIZE)在二维上测量肿瘤大小,并使用下式:V=0.5a*b^2以mm^3表示体积,其中a和b分别是肿瘤的长径和短径。使用PrismGraphPad分析结果并表示为平均值±S.E.M.。两组之间的比较通过T检验进行,并且如果p为*<0.05和**<0.01,则认为差异显著。
如表13和图22所示,作为最低剂量的3mg/kg嵌合-DC101似乎不足以抑制H460肿瘤生长。当剂量达到10mg/kg和30mg/kg时,H460生长受到显著影响。剂量依赖性功效明显,表明它是由嵌合-DC101引起的。
表13.在第15天嵌合DC101在H460异种移植肿瘤模型上的肿瘤生长抑制
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4.使用H1975 NSCLC肿瘤模型在体内评价抗小鼠VEGFR2抗体DC101
于37℃在空气中含有5% CO2的大气中在补充有10%热灭活胎牛血清(ExCellBiology)、100U/ml青霉素和100ug/ml链霉素(Hyclone)的RPMI1640培养基(ThermoFisher)中将H1975细胞作为单层培养物在体外维持。通过胰蛋白酶-EDTA处理(Hyclone)每周两次对肿瘤细胞进行常规传代培养。收获在指数生长阶段中生长的细胞并且对其计数以用于肿瘤接种。用与50%基质胶混合的5*10^6个H1975细胞接种雌性SPF级裸鼠。当肿瘤大小在100mm^3左右时,选择荷瘤小鼠并随机分为5组(n=10)。用30mg/kg同种型对照、3mg/kg嵌合-DC101、10mg/kg嵌合-DC101、30mg/kg嵌合-DC101和5mg/kg多西他赛作为阳性对照治疗动物,同种型对照和嵌合-DC101每周两次通过腹膜内注射施用,持续2周,而多西他赛每周一次通过静脉内注射施用,持续2周。每周两次使用卡尺(INSIZE)在二维上测量肿瘤大小,并使用下式:V=0.5a*b^2以mm^3表示体积,其中a和b分别是肿瘤的长径和短径。使用Prism GraphPad分析结果并表示为平均值±S.E.M.。两组之间的比较通过T检验进行,并且如果p为*<0.05和**<0.01,则认为差异显著。
如表14和图23所示,嵌合-DC101对属于NSCLC腺癌的H1975异种移植肿瘤模型具有显著的肿瘤抑制作用。随着剂量的增加,由3mg/kg增至30mg/kg,肿瘤抑制作用越来越显著,由40%增至80%。剂量依赖性效应表明抑制是由嵌合-DC101引起的。
表14.在第15天嵌合DC101对H1975异种移植肿瘤模型的肿瘤生长抑制
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序列表
<110> 苏州创胜医药集团有限公司(SUZHOU TRANSCENTA THERAPEUTICS CO., LTD.)
<120> 新型抗-HVEGFR2抗体
<130> 063694-8009CN01
<150> PCT/CN2021/087278
<151> 2021-04-14
<160> 103
<170> PatentIn版本3.5
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<223> 合成
<400> 24
Gln His Thr Trp Glu Ile Pro Leu Thr
1 5
<210> 25
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 25
Ile Tyr Gly Met Ser
1 5
<210> 26
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 26
Ser Ile Ser Val Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Glu
1 5 10 15
Gly
<210> 27
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 27
Glu Leu Asp Gly Asn Tyr Asp Tyr
1 5
<210> 28
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 28
Arg Ser Ser Lys Ser Leu Leu Tyr Lys Asp Gly Lys Thr Tyr Leu Asn
1 5 10 15
<210> 29
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 29
Leu Met Ser Thr Arg Ala Ser
1 5
<210> 30
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 30
Gln Gln Leu Val Glu Tyr Pro Phe Thr
1 5
<210> 31
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 31
Met Tyr Gly Met Ser
1 5
<210> 32
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 32
Ser Ile Ser Ile Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Glu
1 5 10 15
Gly
<210> 33
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 33
Glu Met Asp Gly Asn Tyr Asp Tyr
1 5
<210> 34
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 34
Met Tyr Gly Met Ser
1 5
<210> 35
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 35
Ser Ile Ser Ile Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Glu
1 5 10 15
Gly
<210> 36
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 36
Glu Leu Asp Gly Asn Tyr Asp Tyr
1 5
<210> 37
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 37
Ser Ile Ser Ile Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 38
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 39
<211> 1356
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 40
<211> 470
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 40
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
<210> 41
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<220>
<221> X
<222> (1)..(1)
<223> I或M
<400> 41
Xaa Tyr Gly Met Ser
1 5
<210> 42
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<220>
<221> X
<222> (4)..(4)
<223> V或I
<220>
<221> X
<222> (16)..(16)
<223> E或K
<400> 42
Ser Ile Ser Xaa Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Xaa
1 5 10 15
Gly
<210> 43
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<220>
<221> X
<222> (2)..(2)
<223> L或M
<400> 43
Glu Xaa Asp Gly Asn Tyr Asp Tyr
1 5
<210> 44
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<220>
<221> X
<222> (1)..(1)
<223> T或S
<400> 44
Xaa Tyr Trp Ile Met
1 5
<210> 45
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<220>
<221> X
<222> (6)..(6)
<223> T或S
<400> 45
Asp Ile Tyr Pro Gly Xaa Gly Ser Thr Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Ser
<210> 46
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 46
Asp Ser Asn Pro Asp Tyr
1 5
<210> 47
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成
<220>
<221> X
<222> (7)..(7)
<223> D或E
<220>
<221> X
<222> (15)..(15)
<223> T或H
<400> 47
Arg Ala Ser Glu Ser Val Xaa Asn Ser Gly Ile Ser Phe Met Xaa
1 5 10 15
<210> 48
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<220>
<221> X
<222> (4)..(4)
<223> T或Y
<220>
<221> X
<222> (6)..(6)
<223> G或R
<400> 48
Ala Ala Ser Xaa Gln Xaa Ser
1 5
<210> 49
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 49
Gln Gln Ser Lys Glu Val Pro Tyr Thr
1 5
<210> 50
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 51
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 52
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 53
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 54
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 55
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 56
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 57
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 58
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 59
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 60
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 61
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 62
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 63
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 64
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 65
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 65
Trp Val Arg Gln Thr Pro Gly Lys Arg Leu Glu Trp Val Ala
1 5 10
<210> 66
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 67
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 67
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
1 5 10
<210> 68
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 69
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 69
Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val Ala
1 5 10
<210> 70
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 71
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 71
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
1 5 10
<210> 72
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 73
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 73
Trp Val Arg Gln Ala Pro Gly Lys Arg Leu Glu Trp Val Ala
1 5 10
<210> 74
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 75
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 75
Trp Gly His Gly Thr Thr Leu Thr Val Ser Ser
1 5 10
<210> 76
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 77
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 77
Trp Phe Leu Gln Arg Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr
1 5 10 15
<210> 78
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 79
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 79
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 80
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 81
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 81
Trp Phe Leu Gln Arg Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr
1 5 10 15
<210> 82
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 83
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 83
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 84
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 合成
<220>
<221> X
<222> (19)..(19)
<223> R或K
<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
<210> 85
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成
<220>
<221> X
<222> (5)..(5)
<223> A或T
<400> 85
Trp Val Arg Gln Xaa Pro Gly Lys Arg Leu Glu Trp Val Ala
1 5 10
<210> 86
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成
<220>
<221> X
<222> (21)..(21)
<223> R或K
<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
<210> 87
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<220>
<221> X
<222> (3)..(3)
<223> Q或H
<400> 87
Trp Gly Xaa Gly Thr Thr Leu Thr Val Ser Ser
1 5 10
<210> 88
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> 合成
<220>
<221> X
<222> (7)..(7)
<223> D或T
<220>
<221> X
<222> (8)..(8)
<223> E或P
<220>
<221> X
<222> (15)..(15)
<223> F或P
<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
<210> 89
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 89
Trp Phe Leu Gln Arg Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr
1 5 10 15
<210> 90
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 合成
<220>
<221> X
<222> (3)..(3)
<223> S或P
<220>
<221> X
<222> (29)..(29)
<223> V或I
<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
<210> 91
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 91
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 92
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 93
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 94
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 95
<211> 101
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 96
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 97
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 98
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 99
<211> 239
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 100
<211> 1367
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 101
<211> 1356
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 102
<211> 98
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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
<210> 103
<211> 712
<212> PRT
<213> 人工序列
<220>
<223> 合成
<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)
1.一种抗-hVEGFR抗体或其抗原结合片段,其包括重链HCDR1、HCDR2和HCDR3和/或轻链LCDR1、LCDR2和LCDR3序列,其中:
所述HCDR1序列包括SSWMN(SEQ ID NO:1)、DYYMS(SEQ ID NO:19)、X1YGMS(SEQ ID NO:41)、X4YWIM(SEQ ID NO:44),或其至少80%序列同一性的同源序列;
所述HCDR2序列包括RIFPGDGDTYYNGKFQV(SEQ ID NO:2)、FIRNKANGYTTEYSASVKG(SEQID NO:20)、SISX2GGSYTYYADSVX19G(SEQID NO:42)、DIYPGX5GSTNYNEKFKS(SEQ ID NO:45),或其至少80%序列同一性的同源序列;
所述HCDR3序列包括FLDTSGRYVDY(SEQ ID NO:3)、FDYYGSTYCFDY(SEQ ID NO:21)、EX3DGNYDY(SEQ ID NO:43)、DSNPDY(SEQ ID NO:46),或其至少80%序列同一性的同源序列;
所述LCDR1序列包括KASQDVNTAVA(SEQ ID NO:4)、RASQSVSTSSSSFMH(SEQ ID NO:22)、RSSKSLLYKDGKTYLN(SEQ ID NO:28)、RASESVX6NSGISFMX7(SEQ ID NO:47),或其至少80%序列同一性的同源序列;
所述LCDR2序列包括SASYRYI(SEQ ID NO:5)、YASNLES(SEQ ID NO:23)、LMSTRAS(SEQID NO:29)、AASX8QX9S(SEQ ID NO:48),或其至少80%序列同一性的同源序列;
所述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X1是I或M,X2是V或I,X3是L或M,X4是T或S,X5是T或S,X6是D或E,X7是T或H,X8是T或Y,X9是G或R和X19是E或K。
2.根据权利要求1所述的抗-hVEGFR抗体或其抗原结合片段,其中所述HCDR1包括SEQID NO:41的氨基酸序列,所述HCDR2包括SEQ ID NO:42的氨基酸序列,所述HCDR3包括SEQID NO:43的氨基酸序列,所述LCDR1包括SEQ ID NO:28的序列,所述LCDR2包括SEQ ID NO:29的序列,并且所述LCDR3包括SEQ ID NO:30的序列。
3.根据权利要求2所述的抗体或其抗原结合片段,其中
a)所述HCDR1包括SEQ ID NO:25的序列,HCDR2包括SEQ ID NO:26的序列,所述HCDR3包括SEQ ID NO:27的序列;所述LCDR1包括SEQ ID NO:28的序列,所述LCDR2包括SEQ ID NO:29的序列,并且所述LCDR3包括SEQ ID NO:30的序列;或者
b)所述HCDR1包括SEQ ID NO:31的序列,所述HCDR2包括SEQ ID NO:32或SEQ ID NO:37的序列,并且所述HCDR3包括SEQ ID NO:33的序列,所述LCDR1包括SEQ ID NO:28的序列,所述LCDR2包括SEQ ID NO:29的序列,并且所述LCDR3包括SEQ ID NO:30的序列;或者
c)所述HCDR1包括SEQ ID NO:34的序列,所述HCDR2包括SEQ ID NO:35或SEQ ID NO:37的序列,并且所述HCDR3包括SEQ ID NO:36的序列,所述LCDR1包括SEQ ID NO:28的序列,所述LCDR2包括SEQ ID NO:29的序列,并且所述LCDR3包括SEQ ID NO:30的序列。
4.根据权利要求1所述的抗-hVEGFR抗体或其抗原结合片段,其中所述HCDR1包括SEQID NO:44的氨基酸序列,所述HCDR2包括SEQ ID NO:45的氨基酸序列,所述HCDR3包括SEQID NO:46的氨基酸序列,所述LCDR1包括SEQ ID NO:47的序列,所述LCDR2包括SEQ ID NO:48的序列,并且所述LCDR3包括SEQ ID NO:49的序列。
5.根据权利要求4所述的抗体或其抗原结合片段,其中
a)所述HCDR1包括SEQ ID NO:7的序列,所述HCDR2包括SEQ ID NO:8的序列,所述HCDR3包括SEQ ID NO:9的序列;所述LCDR1包括SEQ ID NO:10的序列,所述LCDR2包括SEQ ID NO:11的序列,并且所述LCDR3包括SEQ ID NO:12的序列;或者
b)所述HCDR1包括SEQ ID NO:13的序列,所述HCDR2包括SEQ ID NO:14的序列,并且所述HCDR3包括SEQ ID NO:15的序列,所述LCDR1包括SEQ ID NO:16的序列,所述LCDR2包括SEQ ID NO:17的序列,并且所述LCDR3包括SEQ ID NO:18的序列。
6.根据权利要求1所述的抗体或其抗原结合片段,其中
a)所述HCDR1包括SEQ ID NO:1的序列,所述HCDR2包括SEQ ID NO:2的序列,并且所述HCDR3包括SEQ ID NO:3的序列,所述LCDR1包括SEQ ID NO:4的序列,所述LCDR2包括SEQ IDNO:5的序列,并且所述LCDR3包括SEQ ID NO:6的序列;或者
b)所述HCDR1包括SEQ ID NO:19的序列,所述HCDR2包括SEQ ID NO:20的序列,并且所述HCDR3包括SEQ ID NO:21的序列,所述LCDR1包括SEQ ID NO:22的序列,所述LCDR2包括SEQ ID NO:23的序列,并且所述LCDR3包括SEQ ID NO:24的序列。
7.根据前述权利要求中任一项所述的抗体或其抗原结合片段,其进一步包括重链HFR1、HFR2、HFR3和HFR4中的一种或多种,和/或轻链LFR1、LFR2、LFR3和LFR4中的一种或多种,其中:
所述HFR1包括EVQLVESGGGLVKPGGSLX10LSCAASGFTFS(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,
所述HFR2包括WVRQX11PGKRLEWVA(SEQ ID NO:85)或其至少80%(或至少90%)序列同一性的同源序列,
所述HFR3包括RFTISRDNAKNTLYLQMNSLX12AEDTAVYYCAR(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,
所述HFR4包括WGX13GTTLTVSS(SEQ ID NO:87)或其至少80%序列同一性的同源序列,
所述LFR1包括DIVITQX14X15LSLPVTX16GESVSISC(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,
所述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,
所述LFR3包括GVX17DRFSGSGSGTDFTLKISRVEAEDVGX18YYC(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,和所述LFR4包括FGSGTKLEIK(SEQ IDNO:91)或其至少80%(或至少90%)序列同一性的同源序列,
其中X10是R或K,X11是A或T,X12是R或K,X13是Q或H,X14是D或T,X15是E或P,X16是F或P,X17是S或P,X18是V或I。
8.根据权利要求7所述的抗体或其抗原结合片段,其中:
所述HFR1包括选自由SEQ ID NO:64、68和72组成的群组的序列,
所述HFR2包括选自由SEQ ID NO:65、69和73组成的群组的序列,
所述HFR3包括选自由SEQ ID NO:66、70和74组成的群组的序列,
所述HFR4包括选自由SEQ ID NO:67、71和75组成的群组的序列,
所述LFR1包括选自由SEQ ID NO:76和80组成的群组的序列,
所述LFR2包括选自由SEQ ID NO:77和81组成的群组的序列,
所述LFR3包括选自由SEQ ID NO:78和82组成的群组的序列,和
所述LFR4包括选自由SEQ ID NO:79和83组成的群组的序列。
9.根据前述权利要求中任一项所述的抗体或其抗原结合片段,其中所述重链可变区包括选自由以下组成的群组的序列:SEQ ID NO:50、SEQ ID NO:52、SEQ ID NO:54、SEQ IDNO:56、SEQ ID NO:58、SEQ ID NO:60、SEQ ID NO:62、SEQ ID NO:93、SEQ ID NO:94、SEQ IDNO:98,及其具有至少80%序列同一性但仍保留对hVEGFR2的特异性结合亲和力的同源序列。
10.根据前述权利要求中任一项所述的抗体或其抗原结合片段,其中所述轻链可变区包括选自由以下组成的群组的序列:SEQ ID NO:51、SEQ ID NO:53、SEQ ID NO:55、SEQ IDNO: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对hVEGFR2的特异性结合亲和力的同源序列。
11.根据前述权利要求中任一项所述的抗体或其抗原结合片段,其中:
i)所述重链可变区包括SEQ ID NO:50的序列和所述轻链可变区包括SEQ ID NO:51的序列;
j)所述重链可变区包括SEQ ID NO:52的序列和所述轻链可变区包括SEQ ID NO:53的序列;
k)所述重链可变区包括SEQ ID NO:54的序列和所述轻链可变区包括SEQ ID NO:55的序列;
l)所述重链可变区包括SEQ ID NO:56的序列和所述轻链可变区包括SEQ ID NO:57的序列;
m)所述重链可变区包括SEQ ID NO:58的序列和所述轻链可变区包括SEQ ID NO:59的序列;
n)所述重链可变区包括SEQ ID NO:60的序列和所述轻链可变区包括SEQ ID NO:61的序列;
o)所述重链可变区包括SEQ ID NO:62的序列和所述轻链可变区包括SEQ ID NO:63的序列;或者
p)所述重链可变区包括SEQ ID NO:93或SEQ ID NO:94或SEQ ID NO:98的序列和所述轻链可变区包括SEQ ID NO:96或SEQ ID NO:97的序列。
12.根据前述权利要求中任一项所述的抗体或其抗原结合片段,其进一步包括一个或多个氨基酸残基取代或修饰,但仍保留对hVEGFR2的特异性结合亲和力。
13.根据权利要求12所述的抗体或其抗原结合片段,其中所述取代或修饰中的至少一个在一个或多个CDR序列中,和/或在VH或VL序列的一个或多个非CDR区中。
14.根据前述权利要求中任一项所述的抗体或其抗原结合片段,其还包括免疫球蛋白恒定区,任选地人Ig的恒定区,或任选地人IgG的恒定区。
15.根据权利要求14所述的抗体或其抗原结合片段,其中所述恒定区包括人IgG1、IgG2、IgG3或IgG4的恒定区。
16.根据权利要求15所述的抗体或其抗原结合片段,其中所述人IgG1的恒定区包括SEQID NO:38,或其具有至少80%序列同一性的同源序列。
17.根据前述权利要求中任一项所述的抗体或其抗原结合片段,其是人源化的。
18.根据前述权利要求中任一项所述的抗体或其抗原结合片段,其是双功能抗体、Fab、Fab'、F(ab')2、Fd、Fv片段、二硫键稳定化Fv片段(dsFv)、(dsFv)2、双特异性dsFv(dsFv-dsFv')、二硫键稳定化双功能抗体(ds双功能抗体)、单链抗体分子(scFv)、scFv二聚体(二价双功能抗体)、多特异性抗体、骆驼化单结构域抗体、纳米抗体、结构域抗体或二价结构域抗体。
19.根据前述权利要求中任一项所述的抗体或其抗原结合片段,其是双特异性的。
20.根据前述权利要求中任一项所述的抗体或其抗原结合片段,其能够特异性结合hVEGFR2的第一和第二表位,或能够特异性结合hVEGFR2和第二抗原。
21.根据权利要求20所述的抗体或其抗原结合片段,其中所述第二抗原是免疫相关靶标,任选地选自由以下组成的群组:PD-L1、PD-L2、PD-1、CLTA-4、TIM-3、LAG3、CD160、2B4、TGFβ、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和CD83。
22.根据权利要求20所述的抗体或其抗原结合片段,其中所述第二抗原包括肿瘤抗原。
23.根据权利要求22所述的抗体或其抗原结合片段,其中所述肿瘤抗原存在于表达VEGFR2的细胞中。
24.根据权利要求22所述的抗体或其抗原结合片段,其中所述肿瘤抗原包括密蛋白18.2、CA-125、神经节苷脂G(D2)、G(M2)和G(D3)、CD20、CD52、CD33、Ep-CAM、CEA、铃蟾肽样肽、PSA、HER2/neu、表皮生长因子受体(EGFR)、erbB2、erbB3/HER3、erbB4、CD44v6、Ki-67、癌症相关粘蛋白、VEGF、VEGFR(例如VEGFR3)、雌激素受体、Lewis-Y抗原、TGFβ1、IGF-1受体、EGFα、c-Kit受体、转铁蛋白受体、IL-2R或CO17-1A。
25.根据前述权利要求中任一项所述的抗体或其抗原结合片段,其与一个或多个缀合物部分连接。
26.根据权利要求25所述的抗体或其抗原结合片段,其中所述缀合物部分包括清除调节剂、化学治疗剂、毒素、放射性同位素、镧系元素、发光标记、荧光标记、酶-底物标记、DNA烷化剂、拓扑异构酶抑制剂、微管蛋白结合剂或其他抗癌药物。
27.一种抗体或其抗原结合片段,其与根据前述权利要求中任一项所述的抗体或其抗原结合片段竞争结合hVEGFR2。
28.一种药物组合物,其包括根据前述权利要求中任一项所述的抗体或其抗原结合片段,以及一种或多种药学上可接受的载剂。
29.根据权利要求28所述的药物组合物,其进一步包括第二治疗剂。
30.根据权利要求29所述的药物组合物,其中所述第二治疗剂包括抗癌疗法,任选地,所述抗癌疗法选自化学治疗剂、放射疗法、免疫治疗剂、抗血管生成剂(例如VEGFR(如VEGFR-1和VEGFR-3)的拮抗剂)、EGFR拮抗剂、PDGFR拮抗剂、IGFR拮抗剂、NGFR拮抗剂、FGFR拮抗剂、靶向治疗剂(例如HER2抗体、密蛋白18.2抗体)、细胞治疗剂、基因治疗剂、激素治疗剂、细胞因子、姑息治疗、治疗癌症的手术(例如肿瘤切除术)、一种或多种止吐药、化学疗法引起的并发症的治疗或癌症患者的膳食补充剂(例如吲哚-3-甲醇)。
31.一种分离的多核苷酸,其编码根据前述权利要求所述的抗体或其抗原结合片段。
32.一种载体,其包括根据权利要求31所述的分离的多核苷酸。
33.一种宿主细胞,其包括根据权利要求32所述的载体。
34.一种表达根据权利要求1至27中任一项所述的抗体或其抗原结合片段的方法,包括在表达根据权利要求31所述的载体的条件下培养根据权利要求33所述的宿主细胞。
35.一种在受试者中治疗VEGFR2相关疾病或病症、降低VEGFR2相关疾病或病症的严重性和/或减缓VEGFR2相关疾病或病症的进展的方法,包括向所述受试者施用治疗有效量的根据权利要求1至26中任一项所述的抗体或其抗原结合片段,或根据权利要求28至30中任一项所述的药物组合物。
36.根据权利要求35所述的方法,其中所述VEGFR2相关疾病或病症是肿瘤或血管生成疾病。
37.根据权利要求36所述的方法,其中所述肿瘤产生VEGF(例如,VEGF-A)和/或对其微环境中存在的VEGF(例如,VEGF-A)敏感。
38.根据权利要求36或37所述的方法,其中所述肿瘤是实体瘤或非实体瘤。
39.根据权利要求38所述的方法,其中所述实体瘤选自由以下组成的群组:乳腺癌、肺癌、结直肠癌、胰腺癌、胶质瘤和淋巴瘤、头颈肿瘤、神经内分泌肿瘤、结直肠肿瘤、前列腺肿瘤、乳腺肿瘤、肺肿瘤(如小细胞和非小细胞肺肿瘤)、胰腺肿瘤、甲状腺肿瘤、卵巢肿瘤、肝肿瘤、卡波西肉瘤、CNS肿瘤、神经母细胞瘤、毛细血管母细胞瘤、脑膜瘤、脑转移、黑色素瘤、胃肠道和肾癌和肉瘤(例如胃癌)、横纹肌肉瘤、胶质母细胞瘤(优选多形性胶质母细胞瘤)、平滑肌肉瘤、鳞状细胞癌、基底细胞癌和可通过抑制恶性角化细胞(如人恶性角化细胞)的生长来治疗的皮肤癌。
40.根据权利要求39所述的方法,其中所述肿瘤选自由以下组成的群组:胃癌、非小细胞肺癌如大细胞肺癌。
41.根据权利要求38所述的方法,其中所述非实体瘤选自由以下组成的群组:白血病、多发性骨髓瘤和淋巴瘤,例如急性髓性白血病(AML)、慢性髓性白血病(CML)、急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、红细胞白血病或单核细胞白血病、霍奇金和非霍奇金淋巴瘤。
42.根据权利要求36所述的方法,其中所述血管生成疾病选自由以下组成的群组:动脉粥样硬化、类风湿性关节炎(RA)、新生血管性青光眼、包含增殖性糖尿病视网膜病变在内的增殖性视网膜病变、黄斑变性、血管瘤、血管纤维瘤、牛皮癣、早产儿视网膜病变(例如,晶状体后纤维增生)、角膜移植排斥、胰岛素依赖型糖尿病、多发性硬化、重症肌无力、克罗恩病、自身免疫性肾炎、原发性胆汁性肝硬化、急性胰腺炎、同种异体移植排斥、过敏性炎症、接触性皮炎和迟发性超敏反应、炎性肠病、感染性休克、骨质疏松症、骨关节炎、由神经元炎症引起的认知缺陷、奥斯勒-韦伯综合征、再狭窄以及真菌、寄生虫和病毒感染如巨细胞病毒感染。
43.根据权利要求34至42中任一项所述的方法,其中所述受试者是人。
44.根据权利要求34至42中任一项所述的方法,其中所述施用通过口服、鼻、静脉内、皮下、舌下、瘤内或肌肉内施用进行。
45.根据权利要求34至42中任一项所述的方法,其进一步包括施用治疗有效量的第二治疗剂。
46.根据权利要求45所述的方法,其中所述第二治疗剂包括抗癌疗法,任选地,所述抗癌疗法选自化学治疗剂、放射疗法、免疫治疗剂、抗血管生成剂(例如VEGFR(如VEGFR-1、VEGFR-2和VEGFR-3)的拮抗剂)、EGFR拮抗剂、PDGFR拮抗剂、IGFR拮抗剂、NGFR拮抗剂、FGFR拮抗剂、靶向治疗剂、细胞治疗剂、基因治疗剂、激素治疗剂、细胞因子、姑息治疗、治疗癌症的手术(例如肿瘤切除术)、一种或多种止吐药、化学疗法引起的并发症的治疗或癌症患者的膳食补充剂(例如吲哚-3-甲醇)。
47.一种试剂盒,其包括根据权利要求1至27中任一项所述的抗体或其抗原结合片段。
48.一种检测样品中VEGFR2的存在或量的方法,包括使所述样品与根据权利要求1至27中任一项所述的抗体或其抗原结合片段接触,和确定所述样品中VEGFR2的存在或量。
49.根据权利要求1至27中任一项所述的抗体或其抗原结合片段在制备用于在受试者中治疗VEGFR2相关疾病或病症、降低VEGFR2相关疾病或病症的严重性和/或减缓VEGFR2相关疾病或病症的进展的药物中的用途。
50.根据权利要求49所述的用途,其中所述VEGFR2相关疾病或病症是肿瘤或血管生成疾病。
51.根据权利要求50所述的用途,其中所述肿瘤产生VEGF(例如,VEGF-A)和/或对其微环境中存在的VEGF(例如,VEGF-A)敏感。
52.根据权利要求50或51所述的用途,其中所述肿瘤是实体瘤或非实体瘤。
53.根据权利要求50中任一项所述的用途,其中所述血管生成疾病选自由以下组成的群组:动脉粥样硬化、类风湿性关节炎(RA)、新生血管性青光眼、包含增殖性糖尿病视网膜病变在内的增殖性视网膜病变、黄斑变性、血管瘤、血管纤维瘤、牛皮癣、早产儿视网膜病变(例如,晶状体后纤维增生)、角膜移植排斥、胰岛素依赖型糖尿病、多发性硬化、重症肌无力、克罗恩病、自身免疫性肾炎、原发性胆汁性肝硬化、急性胰腺炎、同种异体移植排斥、过敏性炎症、接触性皮炎和迟发性超敏反应、炎性肠病、感染性休克、骨质疏松症、骨关节炎、由神经元炎症引起的认知缺陷、奥斯勒-韦伯综合征、再狭窄以及真菌、寄生虫和病毒感染如巨细胞病毒感染。
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