CN112399975A - 与Tie2结合的抗体及其用途 - Google Patents
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- CN112399975A CN112399975A CN201980038199.8A CN201980038199A CN112399975A CN 112399975 A CN112399975 A CN 112399975A CN 201980038199 A CN201980038199 A CN 201980038199A CN 112399975 A CN112399975 A CN 112399975A
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Abstract
本发明涉及针对Tie‑2的抗体或其抗原结合片段、编码所述抗体或其抗原结合片段的核酸、包括所述核酸的载体、经所述载体转化的细胞、所述抗体或其抗原结合片段的产生方法、以及包含所述抗体或其抗原结合片段的用于预防或治疗血管生成疾病的组合物。
Description
技术领域
本发明涉及一种针对Tie-2的抗体或其抗原结合片段、编码所述抗体或其抗原结合片段的核酸、含有所述核酸的载体、经所述载体转化的细胞、用于制备所述抗体或其抗原结合片段的方法、以及用于预防或治疗血管生成疾病的药物组合物。
背景技术
在生物体的发育、生长、维持和体内平衡过程中,血管生成是通过多种调节因子动态发生的。在此过程中新形成的血管充当各种生物材料(诸如周围细胞中的营养素、氧气和激素)的运输通道。功能和结构异常的血管是各种疾病的发生和发展的直接或间接原因。肿瘤血管由于其有缺陷的功能和结构而加重了缺氧,从而导致肿瘤进展和转移至其他组织,并且还导致抗癌药物向肿瘤块核心的递送不良。除了癌症之外,在其他各种疾病和病症中也发现了有缺陷的血管。其例子包括各种眼病(例如,糖尿病性黄斑水肿、湿性年龄相关性黄斑变性)、病毒感染和急性炎症反应(诸如败血症)。因此,如果可获得能够使病理血管正常化的治疗剂,则可以将其应用于治疗患有血管异常的各种患者。
血管生成素家族在血管的形成和维持中起着重要作用,并且由四种血管生成素(Ang1、Ang2、Ang3和Ang4)组成。血管生成素-1(Ang1)与存在于血管内皮细胞表面上的Tie2受体结合,以磷酸化并激活Tie2受体,从而导致血管稳定。另一方面,血管生成素-2(Ang2)与Tie2受体结合,但充当拮抗剂以诱导Tie2受体的失活,从而导致血管不稳定和血管渗漏。据报道,在癌症患者、眼病、病毒和细菌感染以及炎性疾病的血液中,Ang2的表达水平大大提高(Saharinen P等人,2017,Nature Review Drug Discovery)。然而,还已知Ang2在若干个过程(包括淋巴管形成和维持)中充当激动剂以诱导Tie2受体的激活,并且因此认为Ang2根据情境执行多种功能。
到目前为止,各种抗Ang2抗体的开发和临床测试一直是许多生物制药公司关注的焦点(例如,US 7,658,924和US 8,987,420)。这些Ang2抗体显示抑制Ang2与Tie2的结合,并且这些Ang2中和作用最终显示出阻碍新血管的形成。这些抗Ang2抗体的抗血管生成和抗癌活性已在许多临床前模型中得到证实,并且正在各种癌症患者中对不同抗Ang2抗体进行临床测试。然而,已证明它们的抗癌功效不足。例如,由Amgen进行的3期临床试验显示,所述Ang2抗体在卵巢癌患者中的抗癌功效是不显著的(Marth C等人,2017,Eur.J.Cancer)。除了癌症模型之外,还在眼科患者中测试了Ang2中和抗体耐斯伐库单抗(Nesvacumab),但在临床2期联合研究中未能改善阿柏西普(抗VEGF)的功效。
与上述Ang2中和方法相反,直接Tie2激活也被认为是抑制血管生成和压制血管通透性的替代方法。直接与所述Tie2受体结合并诱导Tie2磷酸化和激活的重组蛋白已经在许多临床前癌症和眼科模型中得到开发和测试。其例子包括COMP-Angl(Cho等人,2004,PNAS)和血管肽(David S等人,2011,Am J Physiol Lung Cell Mol Physiol)。尽管这些试剂显示出抗血管生成和抗通透活性,但是它们具有非常短的半衰期和不稳定的物理化学特性。此外,还开发了一种小分子化合物(AKB-9778)作为磷酸酶VE-PTP的抑制剂,其可通过从磷酸化的Tie2中去除磷酸基团来灭活Tie2(Goel S,2013,J Natl Cancer Inst)。尽管该化合物具有也激活其他受体的缺点,但该化合物通过抑制VE-PTP间接增加Tie2活性(Frye M,2015,J Exp.Med,Hayashi M,2013,Nature Communication,Mellberg S等人,2009,FASEBJ.)。此外,已经开发了激动性Tie2抗体(US6365154B1、US20170174789A1)。这些抗体增加了内皮细胞的存活并抑制了血管渗漏。有趣的是,草药提取物显示出激活Tie2活性,并被声称可用作护肤化妆品(例如,JP2011102273A、JP2018043949A、JP2015168656A)。
在该技术背景下,本申请的发明人努力开发特异性结合Tie2的抗体。结果,诸位发明人开发了以亲和力结合的Tie2抗体,并证实这些Tie2抗体可通过诱导Tie2受体的磷酸化和活化而充当血管生成疾病的治疗剂,从而完成了本发明。
发明内容
本发明的目的是提供一种新的抗Tie2抗体或其抗原结合片段。
本发明的另一个目的是提供一种编码所述抗体或其抗原结合片段的核酸。
本发明的另一个目的是提供一种包含所述核酸的载体、一种用所述载体转化的细胞及其产生方法。
本发明的另一个目的是提供一种组合物,所述组合物包含用于预防或治疗血管生成疾病的所述抗体或其抗原结合片段。
本发明的另一个目的是提供一种组合物,所述组合物包含所述抗体或其抗原结合片段,并且与用于血管生成疾病的其他治疗剂共同给予。
为了实现上述目的,本发明提供了与包括SEQ ID NO:2的序列的Ig3-FNIII(1-3)结构域结合的抗Tie2抗体或其抗原结合片段。
具体地,本发明还提供了抗-Tie2抗体或其抗原结合片段,所述抗-Tie2抗体或其抗原结合片段包括在重链CDR内具有SEQ ID:3至5的氨基酸序列的重链可变区,在轻链CDR内具有氨基酸序列SEQ ID:6至8的轻链可变区;在重链CDR内具有SEQ ID:13至15的氨基酸序列的重链可变区,在轻链CDR内具有氨基酸序列SEQ ID:16至18的轻链可变区;在重链CDR内具有SEQ ID:23至25的氨基酸序列的重链可变区,在轻链CDR内具有氨基酸序列SEQ ID:26至28的轻链可变区;在重链CDR内具有SEQ ID:33至35的氨基酸序列的重链可变区,在轻链CDR内具有氨基酸序列SEQ ID:36至38的轻链可变区;或在重链CDR内具有SEQ ID:43至45的氨基酸序列的重链可变区,在轻链CDR内具有氨基酸序列SEQ ID:46至48的轻链可变区。
本发明还提供了一种编码所述抗体或其抗原结合片段的核酸。
本发明还提供了一种编码所述核酸的载体。
本发明还提供了一种用所述载体转化的细胞。
本发明还提供了所述抗体或其抗原结合片段的制造方法,所述制造方法包括以下步骤:(a)培养其细胞的步骤;以及(b)从所述细胞中回收所述抗体或其抗原结合片段的步骤。
本发明还提供了一种用于预防或治疗与血管生成有关的疾病的组合物,所述组合物包含作为活性成分的抗体或其抗原结合片段。
本发明还提供了一种组合物,所述组合物用于与包含所述抗体或其抗原结合片段的其他血管生成疾病治疗剂共同给予。
附图说明
图1是抗Tie2抗体诱导的Akt磷酸化的分析结果。将HUVEC进行血清饥饿6hr,并且将其与COMP-Ang1(CA1,0.5μg/ml)或抗Tie2抗体(11C4、4A4、3B2、3E12和3H7)孵育30min。对细胞裂解物进行SDS-PAGE/蛋白质印迹,并用抗磷酸化Akt(S473)或抗Akt抗体探测印迹。
图2是抗Tie2抗体3H7触发的剂量依赖性Tie2磷酸化(pTie2)的分析结果。通过免疫沉淀和蛋白质印迹分析研究了3H7抗体诱导Tie2磷酸化的能力。将血清饥饿的HUVEC与各种浓度的3H7抗体孵育30min。作为对照,将HUVEC与Ang2/对照Ab混合物孵育。用抗Tie2抗体对细胞裂解物进行免疫沉淀,随后进行SDS-PAGE/蛋白质印迹分析。用小鼠抗磷酸化酪氨酸(pY)抗体4G10探测Tie2磷酸化。
图3是抗Tie2抗体3H7触发的Tie2内吞作用和FOXO1易位的结果。将HUVEC进行血清饥饿6hr,并且将其与3H7或Ang2(A2)以及对照抗Ang2抗体(对照Ab,1ug/ml)孵育30min。固定后,将HUVEC用DAPI(蓝色)、抗Tie2抗体(绿色)和抗FOXO1抗体(红色)染色,以研究簇状Tie2受体和FOXO1的定位。箭头指示被3H7内吞的Tie2受体。
图4是3H7抑制VEGF或TNF-α诱导的血管通透性的结果。将HUVEC接种在transwell小室上并生长3天。在100%汇合度时,将HUVEC用Ang2(A2,1ug/ml)、Ang2和对照Ab(A2+对照Ab,1ug/ml)或3H7(1ug/ml)预处理30min并用VEGF(500ng/ml)处理45min(A)或用TNF-a(100ng/ml)处理22hr(B)进入上室。在上室中加入FITC-葡聚糖20min后,通过测量下室中的FITC荧光来评估血管通透性。值是平均值±SD。通过单因素方差分析,*p<0.05,**p<0.01,***p<0.001。
图5是热图的结果,所述热图代表当在氢/氘(H/D)交换-质谱分析中测试单独的Tie2或Tie2/3H7复合物时,氘吸收的显著差异区域。使用H/D交换-质谱的数据,在不存在或存在抗Tie2抗体3H7的情况下,生成了hTie2抗原在0.333、10、60和240min时每个残基的氘吸收的热图。色标指示在每个单独的时间单独的Tie2和Tie2/3H7混合物之间每个残基的H/D交换的百分比。红色指示氘交换增加的区域,蓝色指示没有吸收。
图6是显示Tie2上的3H7结合表位的示意图。通过H/D交换-质谱分析的hTie2抗原上的抗Tie2抗体3H7结合表位(红色)使用PyMol软件在hTie2FNIII(1-3)晶体结构(PDB:5UTK)的图像中可视化。
图7是人源化抗Tie2抗体诱导的Akt磷酸化(pAkt)的结果。将血清饥饿的HUVEC与人源化抗Tie2抗体孵育30min。此后,对细胞裂解物进行SDS-PAGE/蛋白质印迹,并用抗磷酸化Akt(S473)或抗Akt抗体探测印迹。
图8是在原发性开角型青光眼小鼠模型中人源化Tie2抗体3H7H12G4引起的SC面积增加和IOP降低的结果。在8周龄的A1:A2iΔ/Δ小鼠中进行他莫西芬的给予,以诱导血管生成素-1和-2的缺失。在12周龄时进行3H7H12G4(一只眼,5mg/ml溶液的1μl注射液)和Fc(对侧眼,5mg/ml溶液的1μl注射液)眼内给予。在12、13和14周龄时进行眼内压(IOP)的定期测量。在给予3H7H12G4后2周,测量CD144+SC面积以及CD144+SC中的Prox1和Tie2免疫染色的强度。比例尺,100μm。每组n=5。值是平均值±SD。通过Kruskal-Wallis检验,随后是Tukey’s HSD等级检验,*p<0.05。
图9是在激光诱导的CNV模型中玻璃体内注射3H7H12G4压制CNV(脉络膜新血管化)和血管渗漏的结果。激光光凝后7天进行抗体(5mg/ml溶液的1μl注射液)玻璃体内给予。在激光光凝后6天和/或14天,测量CD31+CNV体积,并将CNV周围的泄露面积计算为FA图像中测得的总超荧光面积除以ICGA图像中测得的CNV总面积。每组n=11。值是平均值±SD。通过单因素方差分析,随后是Student-Newman-Keuls事后检验,*p<0.05,***p<0.001;通过配对的学生氏t检验,##p<0.01,###p<0.001。
图10是3H7H12G4和CD31在CNV区域的内皮细胞中共定位的结果。激光光凝后1天进行3H7H12G4皮下给予。3H7H12G4和CD31在CNV内皮细胞中的共定位是在激光光凝后2、4和8天通过抗人IgG二抗直接检测的。
图11是通过皮下注射3H7H12G4压制的结果。激光光凝后1天进行3H7H12G4皮下给予。激光光凝后8天测量CD31+CNV体积。比例尺,100μm。每组n=10。值是平均值±SD。通过未配对的学生氏t检验,***p<0.001。
具体实施方式
除非另有定义,否则本文中所用的所有技术和科学术语都具有与本公开文本所属领域技术人员所理解的相同的含义。
本申请的发明人通过与包含SEQ ID NO:2的序列的Tie2Ig3-FNIII(1-3)结构域结合,证实了Tie2抗体是Tie2活性的增加剂。
Tie2是一种受体蛋白,其促进了血管的分化和稳定化,在血管中高度表达,并且如果被激活,所述Tie2受体可使癌血管稳定,并有可能聚集周围的支持细胞。通过根据本发明的抗体或其抗原结合片段,癌血管中的激活的Tie2使癌血管正常化,消除了肿瘤内增加的缺氧,通过增加进入肿瘤的血流量来提供足够的氧气,并增加了其他抗癌药物的递送和免疫细胞的渗透。
就此而言,本发明涉及与包括SEQ ID NO:2的序列的Tie2Ig3-FNIII(1-3)结构域结合的Tie2抗体或其抗原结合片段。
如本文所用,术语“抗体”意指与Tie2特异性结合的抗体。在本发明的范围内,除了与Tie2特异性结合的完全抗体之外,还包括抗体分子的抗原结合片段。
完全抗体具有两个全长轻链和两个全长重链的结构,并且每个轻链通过二硫键连接至重链。重链恒定区具有伽马(γ)、缪(μ)、阿尔法(α)、德耳塔(δ)和伊普西隆(ε)型,具有以下亚类:伽马1(γ1)、伽马2(γ2)、伽马3(γ3)、伽马4(γ4)、阿尔法1(α1)和阿尔法2(α2)。轻链恒定区具有卡帕(κ)和兰布达(λ)型。
抗体的抗原结合片段或抗体片段意指可以与抗原结合的片段,并且包括Fab、F(ab')、F(ab')2和Fv。在抗体片段中,Fab具有一个抗原结合位点,其具有轻链和重链的可变区、轻链的恒定区和重链的第一CH1的结构。
Fab'与Fab的不同之处在于它具有在CH1结构域的C末端包括一个或多个半胱氨酸残基的铰链区。F(ab')2抗体是通过在Fab’的铰链区的半胱氨酸残基之间形成二硫键而产生的。Fv是最小的抗体片段,其仅具有重链的可变区和轻链的可变区。双链Fv(两条链Fv)由重链可变区和轻链可变区之间的非共价键形成,并且单链Fv(scFv)通常通过重链的可变区或轻链的可变区之间的肽接头共价形成,或通过形成类似于双链Fv的二聚体状结构直接连接在C末端。该片段可以通过蛋白质水解酶获得(例如,您可以通过使用木瓜蛋白酶对全抗体进行限制性酶切消化来获得Fab,可以通过用胃蛋白酶切割来获得F(ab')2片段),也通过基因操作技术制备。
在一个实施方案中,根据本发明的抗体是Fv形式(例如,scFv)或完全抗体形式。另外,重链的恒定区可以选自伽马(γ)、缪(μ)、阿尔法(α)、德耳塔(δ)或伊普西隆(ε)的任何同种型。例如,恒定区是伽马1(IgG1)、伽马3(IgG3)或伽马4(IgG4)。轻链恒定区可以是卡帕或兰布达类型。
本发明中的术语“重链”意指全长重链或其片段,包括可变区结构域VH和三个恒定区结构域CH1、CH2和CH3,氨基酸序列具有足够的可变区以提供抗原特异性。另外,本发明中的术语“轻链”意指全长轻链或其片段,包括可变区结构域VL和恒定区结构域CL,氨基酸序列具有足够的可变区以提供抗原特异性。
本发明的抗体是单克隆抗体、多特异性抗体、人抗体、人源化抗体、嵌合抗体、单链Fv(scFV)、单链抗体、Fab片段、F(ab')片段、二硫化物结合Fv(sdFV)和抗独特型(抗Id)抗体,或上述抗体的表位结合片段等包括在内,但不限于此。
所述单克隆抗体是从基本上均质的抗体群体(除了可能的自然突变外)中获得的抗体,即是指所述群体中相同的单个抗体,可能以痕量存在。单克隆抗体具有高度特异性且是针对单一抗原位点所诱导。与通常包括由不同表位指示的不同抗体的常规(多克隆)抗体相反,每种单克隆抗体由单个确定因子指示。
“表位”意指抗体可特异性结合的蛋白质决定簇。表位通常是一组化学活性表面分子,例如它由氨基酸或糖侧链组成,并且通常具有特定的电荷特征以及特定的三维结构特征。在存在变性溶剂的情况下,立体表位和非立体表位会失去与前者的键,但不会失去与后者的键。
当通过氢/氘交换鉴定表位时,根据本发明的Tie2抗体或其抗原结合片段与包括SEQ ID NO:1TLSDILPPQPEN的序列的Tie2的633至644氨基酸和/或氨基酸713至726FAENNIGSSNPAFS结合。
非人(例如鼠)抗体的“人源化”形式是包括来自非人抗体(供体抗体或源抗体)的一个或多个氨基酸序列(例如CDR序列)的嵌合抗体,其具有最小的源自非人免疫球蛋白的序列。在大多数情况下,所述人源化抗体是人免疫球蛋白(受体抗体),其高变区被来自非人灵长类动物、小鼠、大鼠、兔或非人灵长类动物(受体抗体)高变区的残基替代,具有期望的特异性、亲和力和来自受体高变区的残基的能力。为了人源化,构架域(FR)中的残基内的受体人抗体的一个或多个可变区可以被非人物种供体抗体替代为相应的残基。通过这种方式,它有助于维持一个或多个移植的CDR的适当的三维构型,从而改善亲和力和抗体稳定性。人源化抗体,例如,可以包括在其他受体抗体或供体抗体中不出现的新残基,以进一步改善抗体的其他性能。
作为源自人免疫球蛋白的分子,所述“人源化抗体”意指构成所述抗体的所有氨基酸序列(包括互补决定区和结构区)由人免疫球蛋白组成。
表现出所需生物学活性的任何“嵌合”抗体(免疫球蛋白)以及上述抗体的片段均包括在内,其中部分重链和/或轻链源自特定物种,或与属于所述亚类的抗体中的相应序列相同或同源,而其余的一条或多条链则源自另一物种,或属于其他抗体类别或与属于所述亚类的抗体中的相应序列相同。
根据本申请的具体例子,产生了源自小鼠的11C4、4A4、3B2、3E12和3H7抗体,并且将作为供体抗体的3H7抗体的CDR进行移植,产生了人源化3H7H11G4、3H7H12G4、3H7H21G4或3H7H22G4抗体。
如本文所用,“抗体可变结构域”是指互补决定区(CDR;即CDR1、CDR2和CDR3),以及抗体的包括框架区(FR)的氨基酸序列的轻链和重链部分。VH是指重链的可变结构域。VL是指轻链的可变结构域。
“互补决定区”(CDR;即CDR1、CDR2和CDR3)是指抗体可变结构域的抗原结合所必需的氨基酸残基。每个可变结构域通常包括三个CDR区,鉴定为CDR1、CDR2和CDR3。
在一个实施方案中,所述Tie2抗体或其抗原结合片段可包括重链可变区,所述重链可变区包括具有SEQ ID NO:3-5的氨基酸序列的重链CDR;轻链可变区,所述轻链可变区包括具有SEQ ID NO:6至8的氨基酸序列的轻链CDR;
重链可变区,所述重链可变区包括具有SEQ ID NO:13-15的氨基酸序列的重链CDR;轻链可变区,所述轻链可变区包括具有SEQ ID NO:16至18的氨基酸序列的轻链CDR;
重链可变区,所述重链可变区包括具有SEQ ID NO:23-25的氨基酸序列的重链CDR;轻链可变区,所述轻链可变区包括具有SEQ ID NO:26至28的氨基酸序列的轻链CDR;
重链可变区,所述重链可变区包括具有SEQ ID NO:33-35的氨基酸序列的重链CDR;轻链可变区,所述轻链可变区包括具有SEQ ID NO:36至38的氨基酸序列的轻链CDR;
重链可变区,所述重链可变区包括具有SEQ ID NO:43-45的氨基酸序列的重链CDR;轻链可变区,所述轻链可变区包括具有SEQ ID NO:46至48的氨基酸序列的轻链CDR。
“框架区”(FR)是除了CDR残基以外的可变结构域残基。每个可变结构域通常具有4个FR,鉴定为FR1、FR2、FR3和FR4。
Tie2抗体为单价或二价,并且包含单链或双链。在功能上,所述Tie2抗体的结合亲和力在10-5M至10-12M的范围内。
例如,所述Tie2抗体的结合亲和力为10-6M至10-12M、10-7M至10-12M、10-8M至10-12M、10-9M至10-12M、10-5M至10-11M、10-6M至10-11M、10-7M至10-11M、10-8M至10-11M、10-9M至10-11M、10-10M至10-11M、10-5M至10-10M、10-6M至10-10M、10-7M至10-10M、10-8M至10-10M、10-9M至10-10M、10-5M至10-9M、10-6M至10-9M、10-7M至10-9M、10-8M至10-9M、10-5M至10-8M、10-6M至10-8M、10-7M至10-8M、10-5M至10-7M、10-6M至10-7M或10-5M至10-6M。
所述Tie2抗体或其抗原结合片段可包括重链可变区,所述重链可变区包括SEQ IDNO:9的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:11的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:19的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:21的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:29的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:31的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:39的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:41的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:49的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:51的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:53的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:54的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:57的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:58的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:61的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:62的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:19的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:21的氨基酸序列。
本发明的抗体或抗体片段可以在可特异性识别Tie2的范围内包括其生物等效物。例如,它可以对氨基酸序列引入改变以进一步改善抗体的结合亲和力和/或其其他生物学特性。所述修饰可以包括例如所述抗体氨基酸序列残基的缺失、插入和/或取代。这些氨基酸变异是基于所述氨基酸取代的相对相似性,诸如所述氨基酸侧链的疏水性、亲水性、电荷、大小等。通过分析氨基酸侧链取代基的大小、形状和类型,可以知道精氨酸、赖氨酸和组氨酸都是带正电荷的残基;丙氨酸、甘氨酸和丝氨酸的大小相似;苯丙氨酸、色氨酸和酪氨酸具有相似的形状。因此,基于这些考虑,我们可以说精氨酸、赖氨酸和组氨酸;丙氨酸、甘氨酸和丝氨酸;以及苯丙氨酸、色氨酸和酪氨酸是生物学上的功能等同物。
考虑到具有生物学等效活性的上述变异,可以解释为本发明的抗体的氨基酸序列或编码相同抗体的核酸分子包括SEQ ID NO中的序列和表现出实质同一性的任何序列。实质同一性意指当本发明中描述的序列和任何其他序列尽可能地比对并通过本领域中使用的常用算法进行分析时,至少90%同源性、最优选至少95%同源性、96%或以上、97%或以上、98%或以上、99%或以上的序列同源性。用于序列比较的比对方法是本领域中已知的。NCBI基础局部比对搜索工具(BLAST)可从NBCI等获得,并且可与互联网上的序列分析程序诸如blastp、blasm、blastx、tblastn和tblastx联合使用。BLSAT可在www.ncbi.nlm.nih.gov/BLAST/获得。使用此程序的序列同源性比较方法可在www.ncbi.nlm.nih.gov/BLAST/blast_help.html找到。
基于此,当与说明书中所述的特定或全部序列相比时,本发明的抗体或其抗原结合片段可具有90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或以上的同源性。该同源性可以通过使用本领域中已知的方法进行序列比较和/或比对来确定。例如,序列比较算法(即BLAST或BLAST 2.0)、手动比对或视觉检查可用于确定本发明的核酸或蛋白质的序列同源性百分数。
在另一方面中,本发明涉及编码所述抗体或其抗原结合片段的核酸。
所述核酸可包括SEQ ID NO:10、12、20、22、30、32、40、42、50、52、55、56、59、60、63、64、67或68的序列。
可以通过分离编码本发明的抗体或其抗原结合片段的核酸来重组产生抗体或其抗原结合片段。可以通过分离核酸进一步克隆(DNA扩增),并将其插入可复制的载体中,或者可以进行进一步表达。基于此,本发明涉及另一方面的含有核酸的载体。
“核酸”是指包括DNA(gDNA和cDNA)和RNA分子在内,而核苷酸是核酸的基本结构单元,其本质上包括核苷酸,以及具有修饰的糖或碱基部分的类似物。编码本发明的重链可变区和轻链可变区的核酸的序列可以是修饰的。所述修饰包含核苷酸的添加、缺失、或非保守性或保守性取代。
使用常规方法(例如,使用能够与编码重链和轻链的DNA特异性结合的寡核苷酸探针)可以轻松地分离或合成编码所述抗体的DNA。许多载体是可用的。载体组分通常包括以下中一项或多项,但不限于:信号序列、复制起点、一种或多种标记基因、增强子元件、启动子和转录终止序列。
如本文所用,术语“载体”作为在宿主细胞中表达感兴趣的基因的手段,包括质粒载体、粘粒载体、噬菌体载体、腺病毒载体、逆转录病毒载体和病毒载体诸如腺相关病毒载体。载体中编码所述抗体的核酸与启动子可操作连接。
“可操作地连接”意指核酸表达控制序列(例如,启动子、信号序列或转录调节子结合位点阵列)与不同核酸序列之间的功能性连接,从而,控制序列控制转录和/或其他核酸序列的翻译。
在原核细胞作为宿主的情况下,通常包括可以进行转录的强启动子(例如,tac启动子、lac启动子、lacUV5启动子、lpp启动子、pLλ启动子、pRλ启动子、rac5启动子、amp启动子、recA启动子、SP6启动子、trp启动子和T7启动子等)、翻译起始和转录/翻译终止序列的核糖体结合位点。另外,例如,在将真核细胞作为宿主的情况下,可以使用源自哺乳动物细胞基因组的启动子(例如:金属硫氨酸启动子、β-肌动蛋白启动子、人血红蛋白启动子和人肌肉肌酸启动子)或源自哺乳动物病毒的启动子(例如:腺病毒晚期启动子、牛痘病毒7.5K启动子、SV40启动子、巨细胞病毒(CMV)启动子、HSV的tk启动子、小鼠乳腺肿瘤病毒(MMTV)启动子、HIV的LTR启动子、莫洛尼病毒启动子、EB病毒(EBV)启动子和劳斯肉瘤病毒(RSV)启动子),并且通常可以包括聚腺苷酸化序列作为转录终止序列。
在一些情况下,可以将所述载体与其他序列融合以促进表达抗体的纯化。待融合的序列是例如谷胱甘肽S-转移酶(Pharmacia,美国)、麦芽糖结合蛋白(NEB,美国)、FLAG(IBI,美国)和6x His(六组氨酸;Qiagen,美国)。
所述载体包含本领域通常用作选择标记的抗生素抗性基因,例如氨苄西林、庆大霉素、羧苄青霉素、氯霉素、链霉素、卡那霉素、遗传霉素、新霉素和四环素的抗性基因。
在另一方面,本发明涉及一种经上文所提及的载体转化的细胞。用于产生本发明的抗体的细胞可为原核生物、酵母或高等真核细胞,但不限于此。
可以使用原核生物宿主细胞,诸如大肠杆菌(Escherichia coli)、芽孢杆菌属菌株诸如枯草芽孢杆菌(Bacillus subtilis)和苏云金芽孢杆菌(Bacillusthuringiensis)、链霉菌属、假单胞菌属(例如,恶臭假单胞菌(Pseudomonas putida))、奇异变形杆菌(Proteus mirabilis)和葡萄球菌属(例如,肉葡萄球菌(Staphylocuscarnosus))。
然而,对动物细胞的兴趣最大,有用的宿主细胞系的例子是COS-7、BHK、CHO、CHOK1、DXB-11、DG-44、CHO/-DHFR、CV1、COS-7、HEK293、BHK、TM4、VERO、HELA、MDCK、BRL 3A、W138、Hep G2、SK-Hep、MMT、TRI、MRC 5、FS4、3T3、RIN、A549、PC12、K562、PER.C6、SP2/0、NS-0、U20S或HT1080,但不限于此。
在另一方面,本发明涉及(a)细胞培养步骤;以及(b)所述抗体及其抗原结合片段的制造方法,包括从培养细胞回收所述抗体或其抗原结合片段的步骤。
可以在各种培养基中培养细胞。可以无限制地使用任何商业培养基。可以以适当浓度包括本领域技术人员已知的所有其他必需补充物。已经使用了培养条件诸如温度、pH等以及选择的宿主细胞,并且这对于本领域技术人员将是显而易见的。
所述抗体或其抗原结合片段的回收可以通过例如使用离心或超滤以及例如使用亲和层析去除杂质来实现。可以使用另外的额外的纯化技术,诸如阴离子或阳离子交换层析、疏水相互作用层析、羟基磷灰石层析等。
在另一方面,本发明涉及用于预防或治疗血管生成疾病的包含抗体或其抗原结合片段的活性成分的组合物。
血管生成意指从先前存在的血管中形成或生长新血管,“血管生成相关疾病”是指发生血管生成或与进展相关的疾病。如果可以用所述抗体治疗,则所述疾病可以不受限制地包括在血管生成相关疾病的范围内。血管生成相关疾病的例子选自癌症、转移、糖尿病性视网膜病变、早产儿视网膜病变、角膜移植排斥、黄斑变性、新生血管性青光眼、全身性皮肤变红、增殖性视网膜病变、银屑病、血友病性关节炎、动脉粥样硬化斑块中的毛细血管形成、瘢痕疙瘩、伤口肉芽形成、血管粘连、类风湿性关节炎、退行性骨关节炎、自身免疫疾病、克罗恩病、再狭窄、动脉粥样硬化、肠粘连、猫抓病、溃疡、肝硬化、肾炎、糖尿病性肾病、糖尿病、炎症性疾病和神经退行性疾病,但不限于此。此外,所述癌症选自食道癌、胃癌、大肠癌、直肠癌、口腔癌、咽癌、喉癌、肺癌、结肠癌、乳腺癌、子宫颈癌、子宫内膜癌、卵巢癌、前列腺癌、睾丸癌、膀胱癌、肾癌、肝癌、胰腺癌、骨癌、结缔组织癌、皮肤癌、脑癌、甲状腺癌、白血病、霍奇金淋巴瘤、淋巴瘤和多发性骨髓血癌,但不限于此。
如本文所用,术语“预防”是指通过给予本发明的抗体或组合物来抑制或延迟感兴趣的疾病的发作的任何作用。术语“治疗或疗法”指示通过给予本发明的抗体或组合物来改善感兴趣的疾病的症状或使感兴趣的疾病的症状变得更好的任何作用。
包含本发明的抗体的组合物优选是药物组合物,并且可以包括通常在本领域中使用的合适的媒介物、赋形剂或稀释剂。
具有药学上可接受的媒介物的药物组合物可以是各种口服或肠胃外剂型,诸如片剂、丸剂、粉剂、颗粒剂、胶囊剂、悬浮剂、口服溶液剂、乳剂、糖浆剂、无菌水溶液、非水溶液、悬浮剂、冻干剂和栓剂。与本发明的药物组合物相关的可以是可组合配制的稀释剂或赋形剂,诸如填充剂、增稠剂、粘合剂、湿润剂、崩解剂、表面活性剂等。用于口服给予的固体制剂可以是以下形式:片剂、丸剂、粉剂、颗粒剂、胶囊剂等。关于团结性(solidarity),本发明的化合物可以通过将一种或多种赋形剂诸如淀粉、碳酸钙、蔗糖、乳糖或明胶组合而配制。可以另外使用简单的赋形剂和润滑剂,诸如硬脂酸镁、滑石粉等。
用于口服给予的液体制剂可以是悬浮剂、口服溶液剂、乳剂、糖浆剂等。诸如水的赋形剂或像湿石蜡这样的简单稀释剂、各种润湿剂、甜味剂、芳香剂、防腐剂等都可以包括在液体配制品中。此外,本发明中的药物组合物可以是肠胃外剂型诸如无菌水溶液、非水溶剂、悬浮液、乳剂、冻干剂、栓剂等。可注射的丙二醇、聚乙二醇、植物油诸如橄榄油和酯诸如油酸乙酯可适用于不溶性溶剂和悬浮液。所述栓剂的基础物质包括Witepsol、聚乙二醇、吐温61、可可脂、月桂脂和甘油明胶。
本发明的组合物是以药学有效量给予。此处使用的术语“药学有效量”是指用于疾病治疗的药物组合物的足够量,具有可适用于所有医学治疗的适当的受益/风险比。有效量可能会有所不同,具体取决于各种因素,包括疾病的严重程度、患者的年龄和性别、疾病的类型、药物活性、药物敏感性、给予时间、给予途径、分泌率、治疗持续时间、药物的共同给予和本领域已知的其他因素。本发明的组合物可以单独或与其他治疗组合给予。在这种情况下,它可与常规疗法相继或同时给予。同样,上述组合物可以以单剂量给予或分成多剂量。当充分考虑这些因素时,重要的是给予足以获得最大效果而无副作用的最小量,并且专家可以容易地确定该剂量。本发明的药物组合物的剂量不受特别限制,但是它取决于各种因素而变化,包括患者的健康状况和体重、疾病的严重程度、药物类型、给予途径和给予时间。
所述组合物可以一天一次或多次通过通常接受的途径,例如口服、直肠、静脉内、皮下、子宫内或脑血管内给予于哺乳动物,包括大鼠、小鼠、家畜、人等。
本发明的另一个方面涉及血管生成疾病的预防或治疗方法以及抗血管生成方法,包括用于向需要所述抗体或上述组合物的个体给予的步骤。
本发明的方法包括对需要抑制血管生成的个体给予药学有效剂量的药物组合物的程序。对象是哺乳动物,诸如狗、牛、马、兔、小鼠、大鼠、鸡和人,但不限于此。所述药物组合物可以通过合适的方式给予,包括肠胃外、皮下、腹膜内、肺内或鼻内,并且如果需要,病灶内给予以进行局部治疗。本发明的药物组合物的优选剂量根据各种因素而变化,包括个体的健康状况和体重、疾病的严重程度、药物的类型、给予的途径和时间,并且其可以被本领域的技术人员容易地确定。
在另一方面,本发明涉及癌症预防或治疗的方法,包括将所述组合物或所述抗体给予于需要所述抗体以及包括所述抗体的用于癌症预防或治疗的组合物或药物组合物的个体的程序。
癌症不受限制,只要它可用本发明的抗体治疗即可。详细地,本发明的抗体可以通过抑制血管生成来预防癌症的发生或进展。所述癌症的例子包括食道癌、胃癌、大肠癌、直肠癌、口腔癌、咽癌、喉癌、肺癌、结肠癌、乳腺癌、子宫颈癌、子宫内膜癌、卵巢癌、前列腺癌、睾丸癌、膀胱癌、肾癌、肝癌、胰腺癌、骨癌、结缔组织癌、皮肤癌、脑癌、甲状腺癌、白血病、霍奇金淋巴瘤、淋巴瘤和多发性骨髓血癌,但不限于此。
此外,本发明的抗体可出于各种目的与其他抗体或生物活性剂或材料组合使用。在这一方面,本发明涉及用于与血管生成疾病的其他治疗剂(包括所述抗体或其抗原结合片段)组合给予的组合物。
用于血管生成疾病的其他治疗剂包括抗血管生成药、抗炎药和/或抗癌药。通过这种方式,我们可以克服彼此的抗性并改善疗效。
在根据本发明的组合物中,当与其他用于血管生成疾病的治疗剂组合给予时,可以相继或同时给予所述Tie2抗体和其他用于血管生成疾病的治疗剂。例如,在将抗血管生成药、抗炎药和/或抗癌药给予于目标个体后,可以给予以Tie2抗体或其抗原结合片段为活性成分的组合物,或者在给予上述组合物之后,可以给予抗血管生成药、抗炎药和/或抗癌药。根据情况,可以将上述组合物和抗血管生成药、抗炎药和/或抗癌药同时给予于目标个体。
实施例
在下文中,将通过实施例详细描述本发明。以下实施例仅用于说明本发明,并不构成对本发明的限制。
实施例1.小鼠单克隆抗Tie2抗体的制备
1.1用人Tie2进行的小鼠免疫
作为免疫原,将人Tie2(hTie2-Ig3-FNIII(1-3),SEQ ID NO:2)的Ig3-FNIII(1-3)结构域克隆到含有CMV启动子的载体中,并通过转染到HEK293F细胞系中来瞬时表达。孵育5天后,使用蛋白A通过亲和柱纯化表达的重组hTie2-Ig3-FNIII(1-3)蛋白。将五周大的BALB/c小鼠用混有佐剂的纯化的hTie2-Ig3-FNIII(1-3)(100μg/注射)每周免疫两次,持续6周。通过人Tie2(hTie2)ELISA试剂盒(R&D)检查了免疫小鼠血清中的抗Tie2抗体滴度。当抗体滴度(1:5,000稀释度)适当增加(OD>1.0)时,从免疫小鼠中提取脾脏,并从中分离出B淋巴细胞,并与培养的骨髓瘤细胞(SP2/0)融合。在含有次黄嘌呤、氨基蝶呤和胸苷的HAT培养基中培养融合细胞,并从中选择仅由骨髓瘤细胞和B淋巴细胞的融合组成的杂交瘤细胞,并进行培养。将存活的杂交瘤细胞接种在96孔板中,并通过hTie2 ELISA测试培养上清液。通过有限稀释选择显示阳性信号的杂交瘤群用于克隆选择。最后,建立了37个单克隆杂交瘤系。其中,几种结合Tie2的抗体显示出Tie2激活活性。基于Tie2激活水平和对人Tie2的高亲和力选择候选抗体,然后对其进行人源化处理。
表1.人Tie2全长(hTie2)和Ig3-FNIII(1-3)序列
1.2小鼠单克隆抗Tie2抗体的产生和纯化
为了产生基于ELISA阳性信号选择的抗Tie2抗体,将杂交瘤细胞培养在T75(75cm2面积)烧瓶中的含10%FBS的DMEM(达尔伯克改良伊格尔培养基)中。当细胞汇合度达到约90%时,将细胞用PBS洗涤,与50ml无血清培养基(SFM,Gibco)一起孵育并在37℃下培养3天。然后,收集其中从各单克隆杂交瘤分泌抗体的培养基,离心以去除细胞,并收集培养上清液并过滤。然后使用配备有蛋白质G亲和柱(GE Healthcare)的AKTA纯化设备(GE Healthcare)纯化抗体。通过使用离心过滤器单元(Amicon)用PBS替代上清液来浓缩纯化的抗体。
1.3.激动性Tie2抗体的鉴定和筛选
为了研究小鼠抗Tie2抗体是否诱导内皮细胞中Tie2受体的下游信号传导,用抗Tie2抗体对HUVEC(Lonza)进行处理,然后通过免疫印迹分析Tie2受体的主要下游信号传导蛋白的Akt磷酸化水平。作为阳性对照,将COMP-Ang1(CA1)处理入细胞。
具体地,将HUVEC(1×105个细胞/ml)在EGM-2培养基(Lonza)中在37℃下于60mm培养皿中培养。将90%汇合度的细胞与无血清EBM-2培养基孵育6hr,以使血清饥饿。用抗Tie2抗体处理血清饥饿的HUVEC,并进一步孵育30min。用冷PBS洗涤细胞,用裂解缓冲液处理,并在4℃下裂解20min。然后,通过以13000rpm离心15min来制备细胞裂解物。通过添加5x SDS样品缓冲液,制备了细胞裂解物,并对细胞裂解物进行SDS PAGE,并将蛋白质转移到硝酸纤维素膜(GE)上。
为研究Akt磷酸化,在室温(RT)下用含5%脱脂牛奶的TBS-T封闭印迹1hr,并在4℃下与抗磷酸Akt抗体(S473)孵育约8hr。磷酸化Akt的信号通过增强的化学发光(ECL)可视化。然后,将膜在剥离缓冲液(Thermo)中孵育15min,然后用抗Akt抗体再次探测以确定总Akt的量。
在用抗Tie2抗体(诸如11C4、4A4、3B2、3E12和3H7)处理的几个组中,强烈诱导了S473的Akt磷酸化(图1)。
1.4.通过Octet分析测量抗Tie2抗体对hTie2的亲和力
使用Octet系统(ForteBio)测量小鼠单克隆抗体对hTie2的亲和力,其中使用了黑色96孔板(96孔F型黑色板,Greiner)。将用于亲和力测量的生物传感器水合10min,然后用AR2G尖端(ForteBio Octet)测量。水合后,将hTie2稀释在10mM乙酸钠,pH 6.0缓冲液中,浓度为10μg/ml,固定在AR2G生物传感器上,并用1M乙醇胺封闭。将所述小鼠单克隆抗Tie2抗体用1×动力学缓冲液稀释至50、25、12.5、6.25、3.125和0nM,并进行300秒结合和900秒解离。对于亲和力测量(KD),通过结合曲线(全局)分析结合速率(K-on)和解离速率(K-off),并使用Octet数据分析v9.0.0.10程序将其拟合到1:1结合模型。小鼠抗Tie2抗体的亲和力示于表2中。
表2.小鼠抗Tie2抗体对hTie2的亲和力
1.5.小鼠Tie2抗体3H7诱导Tie2磷酸化
显示本发明中开发的抗Tie2抗体结合并诱导Tie2簇集,最终触发Tie2激活。进行实验以使用HUVEC分析抗Tie2抗体对Tie2磷酸化的作用。
具体地,将HUVEC(Lonza)在EGM-2(Lonza)中于37℃和5%CO2浓度在100mm培养皿中培养。在80%-90%汇合度时,将细胞更换为EBM-2(Lonza)培养基6hr以进行血清饥饿。在培养的细胞上处理各种浓度(0.02μg/ml至50μg/ml)的抗Tie2抗体,并进一步孵育30min。用冷PBS洗涤细胞两次,在1000μl裂解缓冲液(10mM Tris-Cl pH 7.4,150mM NaCl,5mM EDTA,10%甘油,1%Triton X-100,蛋白酶抑制剂,磷酸酶抑制剂)中裂解然后在4℃下孵育60min。制备细胞提取物,并以12,000rpm离心10min。通过BCA测定定量上清液中的蛋白质浓度。
对于Tie2免疫沉淀,将1μg Tie2抗体(R&D系统,AF313)添加到0.5mg裂解物中,并在4℃振动下孵育过夜。然后,添加DynabeadsTM蛋白G(Life technologies)以反应2hr。用磁铁把珠固定在试管的一侧,用裂解缓冲液洗涤3次,然后在70℃下与含还原剂的2x SDS样品缓冲液孵育10min。从所述样品中去除珠子,并在4%-15%SDS蛋白凝胶(Bio-Rad)上电泳,然后转移到0.45μm PVDF膜上。
在室温下,用混有5%(v/v)BSA的TBS-T与将膜封闭1hr,然后在4℃与抗磷酸酪氨酸抗体(4G10,Millipore)孵育8hr,随后是HRP缀合的抗小鼠抗体的孵育和随后的蛋白质印迹分析。为了测量免疫沉淀的Tie2的量,将所述膜在剥离缓冲液(Thermo)中反应15min,然后再次封闭,并用抗Tie2抗体(R&D系统,AF313)重新探测。如图2所示,当将所述抗Tie2抗体3H7添加至HUVEC细胞时,以剂量依赖性方式强烈诱导Tie2的磷酸化。这些数据表明所述抗Tie2抗体3H7直接诱导人内皮细胞中Tie2受体的激活。
1.6.通过Tie2抗体(3H7)在HUVEC中的簇状Tie2内吞作用和FOXO1易位
在HUVEC中通过免疫荧光检测了3H7对Tie2定位和FOXO1从细胞核到细胞质易位的作用。具体地,将HUVEC接种在8孔玻片室(Lab-TekII)上,并在EGM-2培养基中保持2-3天。在100%汇合度时,将细胞用EBM-2培养基进行血清饥饿4hr,然后用1μg/ml的抗Tie2抗体3H7处理30min。此后,将细胞在室温(RT)下用PBS中的4%甲醛固定10min,用PBS中的0.1%Triton X-100进行透化,在RT下用PBS中的1%BSA封闭60min,并用一抗在RT下孵育1hr。使用了hTie2和FOXO1的一抗。然后将细胞与二抗(Invitrogen)在黑暗中在RT下孵育1hr,并用带有DAPI的Vectashield固定培养基(Vector Labs)固定。用激光扫描共聚焦显微镜(LSM880,Carl Zeiss)拍摄图像。
如图3所示,3H7的处理明显诱导了Tie2内吞作用,就像对照Ang2抗体一样,已知它可以诱导Tie2簇集和激活(Han等人,2016,Science Translation Medicine)。与先前的报道表明FOXO1于磷酸化后在细胞质中的定位(Zhang等人,JBC 2002,277,45276–45284)一致,而在基础血清饥饿条件下,它位于细胞核中,与血清饥饿的对照(红色)相比,在用3H7处理的细胞核中FOXO1明显消失。
1.7.当在HUVEC中处理抗Tie2抗体3H7时,抑制VEGF或TNF-a诱导的血管通透性。
根据制造商的说明,使用体外血管通透性测定试剂盒(Millipore)在HUVEC中进行了血管渗漏测定。将HUVEC接种到跨孔板的插入物中,并培养3天以达到100%汇合度。将HUVEC与Ang2(1μg/ml)、Ang2(1μg/ml)以及对照抗体(1μg/ml)一起或与单独3H7抗体(1μg/ml)预孵育30min,然后添加VEGF(500ng/ml)或TNF-α(100ng/ml),并将细胞在37℃下分别孵育45min或22hr。将FITC-葡聚糖添加到上室中并孵育20min。FITC-右旋糖酐通过HUVEC单层的通道是通过荧光读取器在激发和发射波长分别为485和535nm处测量的。如图4所示,抗Tie2抗体3H7的预处理显著抑制了由血管渗漏促进因子VEGF或TNF-α诱导的血管渗漏。
实施例2.小鼠抗Tie2抗体的DNA基因序列分析
分析了实施例1.3中选择的抗体(源自杂交瘤细胞)的DNA核苷酸序列。具体地,将杂交瘤细胞(2×106个细胞/ml)培养在含10%FBS的DMEM中,然后使用RNeasy小型试剂盒(Qiagen)获得总RNA。接下来,测量RNA浓度,并通过逆转录(RT)反应合成cDNA。为了扩增所述重链和轻链可变区基因序列,使用小鼠Ig-引物组(Novagen)在以下条件下以上述cDNA为模板,在94℃下进行PCR 5min;[94℃下1min,50℃下1min,72℃下2min]×35个循环;在72℃下6min;冷却至4℃。将从每个反应获得的PCR产物克隆到TA载体中,并进行DNA测序,从而获得编码每种抗体的CDR、重链可变区和轻链可变区的核苷酸序列(表3至12)。
表3.小鼠抗Tie2抗体3B2的CDR序列
表4.小鼠抗Tie2抗体3B2的可变区序列
表5.小鼠抗Tie2抗体3E12的CDR序列
表6.小鼠抗Tie2抗体3E12的可变区序列
表7.小鼠抗Tie2抗体3H7的CDR序列
表8.小鼠抗Tie2抗体3H7的可变区序列
表9.小鼠抗Tie2抗体4A4的CDR序列
表10.小鼠抗Tie2抗体4A4的可变区序列
表11.小鼠抗Tie2抗体11C4的CDR序列
表12.小鼠抗Tie2抗体11C4的可变区序列
实施例3.小鼠抗Tie2抗体对hTie2的表位作图
通过HDX-MS(氢/氘交换-质谱)技术分析了小鼠单克隆抗体3H7识别的hTie2的抗原决定簇(表位)。在以下文章中描述了HDX-MS分析方法;Houde D,Engen JR(2013)MethodsMol.Biol.988:269-89和Houde等人(2011)J.Pharm.Sci.100(6),2071。
重组hTie2-Ig3-FNIII(1-3)蛋白用于分析抗体3H7的结合表位。在氘标记反应之前,将hTie2-Ig3-FNIII(1-3)/抗体混合物孵育3hr以上,以在15×稀释的氘标记缓冲液(KD=25nM)下保持最大结合(100%)。将制备的hTie2-Ig3-FNIII(1-3)/抗体复合物用氘标记缓冲液稀释15倍,在不同时间标记,然后用相同体积的淬灭缓冲液淬灭。所述标记反应时间为0min(氘)、0.33min、10min、60min和240min。但是,在非氘条件下,将氘标记缓冲液替换为平衡缓冲液,并立即用淬灭缓冲液终止反应。为了进行质谱法,将氘标记的hTie2-Ig3-FNIII(1-3)/抗体样品上样到胃蛋白酶柱上,并进行肽消化。质谱分析表明,从总共50种消化性肽中获得了82.6%的覆盖率数据。
比较分析了单独hTie2-Ig3-FNIII(1-3)和hTie2-Ig3-FNIII(1-3)/抗体复合物条件之间的氘吸收差异,显示出氘吸收明显降低的区域是抗体直接结合的肽或结构改变的区域。当单独hTie2-Ig3-FNIII(1-3)与hTie2-Ig3-FNIII(1-3)/抗体复合物之间的氘吸收差异为0.5-1Da或更高时,认为是显著的,在表13中以粗体表示。
使用H/D交换-质谱的数据,在不存在或存在抗Tie2抗体3H7的情况下,生成了hTie2抗原在0.333、10、60和240min时每个残基的氘吸收的热图(图5)。色标指示在每个单独的时间单独的抗原和抗原/mAb混合物之间每个残基的H/D交换的百分比。红色指示氘交换增加的区域,蓝色指示没有吸收。所述氘吸收差异的热图分析表明,抗体3H7结合的表位是hTie2的残基633至644(SEQ ID NO:1,TLSDILPPQPEN)和713-726(SEQ ID NO:1,FAENNIGSSNPAFS)(表13)。所述表位在hTie2-FNIII的3D结构上显示为红色,这使用PyMol软件生成(图6)。
表13.通过HDX-MS对3H7与hTie2结合的表位作图分析
实施例4.小鼠抗Tie2抗体的人源化和全长IgG转化
为消除当给予于人时的小鼠抗-Tie2抗体3H7的免疫原性,将所述抗体如下人源化。
4.1.重链人源化
人抗体重链可变基因IGHV1-46-01与抗体3H7的重链序列显示66%同源性。基于这些分析,将3H7抗体的3个CDR区移植到人抗体重链可变基因IGHV1-46-01中。在此过程中,设计了2个人源化重链抗体基因(表14)。移植的CDR在蛋白序列上加下划线。在人源化3H7的重链基因中引入了小鼠序列的反向突变,在表14的蛋白序列中以粗体表示。
4.2轻链人源化
人抗体轻链可变基因IGKV1-17-01与抗体3H7的轻链序列显示68%同源性。基于这些分析,将3H7抗体的3个CDR区移植到人抗体轻链可变基因IGKV1-17-01中。在此过程中,设计了2个人源化轻链抗体基因(表14)。移植的CDR在蛋白序列上加下划线。在人源化3H7轻链基因中引入了小鼠序列的反向突变,在表14的蛋白序列中以粗体表示。
4.3.人源化基因合成及至人全长IgG抗体的克隆
将表14中的抗体的人源化可变区克隆到人IgG4同种型骨架载体的重链和轻链载体中。将所述抗体的人源化重链可变区(VH)的DNA片段(Bioneer,Inc.)合成为“EcoRI-信号序列-VH-NheI-CH-XhoI”的序列。也将所述抗体的人源化轻链可变区(VL)的DNA片段合成为“EcoRI-信号序列-VL-BsiWI-CL-XhoI”的序列。分别将编码重链和轻链的DNA片段克隆到pOptiVECTM或pcDNATM3.3载体中。
表14.源于小鼠3H7抗体的人源化抗Tie2抗体
4.4.人源化抗Tie2抗体的产生和纯化
为了产生人源化抗Tie2抗体,使用了能够高效产生重组蛋白的Expi293F(Gibco)细胞。在锥形瓶中培养Expi293F细胞(2×106个细胞/ml),并使用ExpiFectamine 293转染试剂盒将编码重链和轻链的质粒共转染到Expi293F细胞中。将细胞在37℃,8%CO2下在振荡培养箱(定轨摇床,125rpm)中培养5天。收集所得的培养基并离心以去除细胞。分离包含分泌的抗体的培养物上清液,并在4℃下保存,或立即使用配备有亲和柱(蛋白A琼脂糖柱,GE Healthcare)的AKTA纯化系统(GE Healthcare)进行纯化。将纯化的抗体通过蛋白离心过滤器(Amicon)进行浓缩,同时用PBS代替溶液。
实施例5.人源化抗Tie2抗体对hTie2的亲和力的测量
使用Octet系统(ForteBio)测量人源化抗Tie2抗体对hTie2的亲和力,其中使用了黑色96孔板(96孔F型黑色板,Greiner)。将用于亲和力测量的生物传感器水合10min,然后用AR2G尖端(ForteBio Octet)测量。水合后,将人源化抗-Tie2抗体稀释在10mM乙酸钠,pH6.0缓冲液中,浓度为10μg/ml,固定在AR2G生物传感器上,并用1M乙醇胺封闭。用1×动力学缓冲液将重组hTie2稀释至50、25、12.5、6.25、3.125和0nM,并结合300秒和解离900秒。对于亲和力测量(KD),通过结合曲线(全局)分析结合速率(K-on)和解离速率(K-off),并使用Octet数据分析v9.0.0.10程序将其拟合到1:1结合模型。下表15中显示了KD值。
表15.人源化3H7抗体对hTie2-Ig3-FNIII(1-3)的亲和力
抗体 | Kon(1/Ms) | Koff(1/s) | K<sub>D</sub>(M) |
3H7 | 5.58E+05 | 1.05E-05 | 2.69E-11 |
3H7H11G4 | 6.26E+04 | 4.67E-04 | 7.47E-09 |
3H7H12G4 | 1.04E+04 | 9.99E-04 | 9.65E-08 |
3H7H21G4 | 7.85E+04 | 5.17E-04 | 6.59E-09 |
3H7H22G4 | 1.65E+04 | 6.56E-04 | 3.97E-08 |
实施例6.所选人源化抗Tie2抗体的体外生物学特性分析
6.1.Akt磷酸化
为了研究所述人源化抗Tie2抗体是否诱导内皮细胞中Tie2受体的下游信号传导,用人源化抗Tie2抗体处理HUVEC(Lonza)。然后,通过免疫印迹测量Tie2受体的主要下游信号传导蛋白Akt磷酸化水平。为了比较Akt激活的程度,在实验中以COMP-Ang1(CA1)作为阳性对照处理细胞。具体地,将HUVEC细胞(1×105个细胞/ml)在EGM-2(Lonza)中在37℃下于60mm培养皿中培养。将90%汇合度的细胞用EBM-2(Lonza)孵育4hr。用抗Tie2抗体处理血清饥饿的HUVEC,并进一步孵育30min。用冷PBS洗涤细胞,用裂解缓冲液处理,并在4℃下裂解20min。然后,通过以13000rpm离心15min来制备细胞裂解物。向所述细胞裂解物添加5x SDS样品缓冲液,并将所述混合物在95℃下煮沸5min。然后,将所述混合物进行SDS-PAGE和随后的蛋白质印迹。
为了研究Akt磷酸化,在RT下用含5%脱脂牛奶的TBST封闭膜1hr,并在4℃下与抗磷酸Akt抗体(S473)孵育约8hr。磷酸化Akt的量通过增强的化学发光(ECL)可视化。然后,将膜在剥离缓冲液(Thermo)中孵育15min,然后用抗Akt抗体再次探测以确定总Akt的量。
如图7所示,通过人源化3H7抗体的处理,Akt磷酸化显著增加。这些数据表明所述人源化抗Tie2抗体能够强烈诱导内皮细胞中Tie2受体的主要下游信号传导分子Akt的激活。
实施例7.3H7H12G4在原发性开角型青光眼小鼠模型中的作用。
为了测试3H7H12G4激活Tie2是否可以挽救退化的SC(施累姆氏管)和降低IOP(眼压),我们使用了原发性开角型青光眼的小鼠模型。通过将他莫昔芬给予于8周大的双重血管生成素-1/血管生成素-2缺陷(A1:A2iΔ/Δ)小鼠中以诱导血管生成素-1和-2基因的缺失而产生模型(图8A)。在12周龄时进行3H7H12G4(约5μg,一只眼睛)和Fc(约5μg,对侧眼睛)的眼内给予(图8A)。为了玻璃体内给予指示的试剂,使用装有玻璃毛细管的Nanoliter2000微型注射器(World Precision Instruments)将含有5μg的每种试剂的约1μl(5mg/ml)注入玻璃体腔。在12、13和14周龄时使用回弹眼压计(TonoLab)进行IOP测量(图8A)。通过在麻醉小鼠后立即将压力传感器的尖端放置在距中央角膜大约1/8英寸处来测量IOP。从所述眼压计获取5次连续IOP测量的数字读数。在野生型小鼠中,经3H7H12G4处理的眼睛和经过Fc处理的眼睛之间的IOP没有差异(图8C)。另一方面,与Fc处理的眼睛相比,A1:A2iΔ/Δ小鼠在3H7H12G4处理的眼睛中显示出IOP显著降低25.6%(图8D)。在给予3H7H12G4后2周,测量CD144+SC面积以及CD144+SC中的Prox1和Tie2免疫染色的强度。使用了抗CD144抗体(1:200,BD Biosciences)、抗Prox1抗体(1:200,ReliaTech)和抗Tie2抗体(1:200,R&D systems)。整个安装的角膜的CD144+SC面积计算为CD144+面积除以其对照面积的百分比。与Fc处理的眼睛相比,A1:A2iΔ/Δ小鼠在3H7H12G4处理的眼睛中显示出SC面积显著增加114.8%(图8B,E)。为了量化Prox1的相对表达,在CD144+SC的细胞核区域测量了强度。与Fc处理的眼睛相比,A1:A2iΔ/Δ小鼠在3H7H12G4处理的眼睛中显示出Prox1强度显著增加88.4%(图8B,F)。为了量化Tie2的表达,测量了CD144+SC面积的强度。与Fc处理的眼睛相比,A1:A2iΔ/Δ小鼠在3H7H12G4处理的眼睛中显示出Tie2强度显著增加63.0%(图8B,F)。总体而言,这些发现表明3H7H12G4激活Tie2可以挽救A1:A2iΔ/Δ小鼠受损的SC。
实施例8.在激光诱导的CNV模型中玻璃体内注射3H7H12G4消退CNV并压制血管渗漏。
使用激光诱导的CNV模型测试了3H7H12G4抑制脉络膜新生血管(CNV)的能力,脉络膜新生血管是湿性年龄相关性黄斑变性(AMD)的标志。用5mg/ml苯肾上腺素和5mg/ml托吡卡胺滴眼液(Santen Pharmaceutical)散瞳瞳孔并滴入0.5%盐酸普罗卡因盐酸盐滴眼液(Alcon)进行局部麻醉后,用带有裂隙灯递送系统的激光光凝器(Lumenis Inc.)与玻璃盖玻片一起用作接触镜来可视化视网膜。在每只眼睛的4个位置(后极的3、6、9和12点钟位置)递送了足够的激光能量(532nm波长,250mW功率,100ms持续时间,50μm光斑大小)。本研究仅包括在激光光凝时产生气泡(表明布鲁赫膜破裂)的灼伤。分析中排除了激光部位出血的斑点。为了概括临床情况,在激光光凝后7天向小鼠玻璃体内给予3H7H12G4(5μg)(图9A)。作为对照或用于比较,以相同方式向小鼠给予Fc或VEGF-Trap(各5μg)。为了玻璃体内给予指示的试剂,使用装有玻璃毛细管的Nanoliter 2000微型注射器(World PrecisionInstruments)将含有5μg的每种试剂的约1μl(5mg/ml)注入玻璃体腔。激光光凝后14天,使用MATLAB图像处理工具箱(MathWorks)计算视网膜色素上皮(RPE)–脉络膜-巩膜铺片的CD31+CNV体积。抗CD31抗体(1:200,Millipore)被用于检测CNV的内皮细胞。与Fc相比,VEGF-Trap有效诱导CNV消退64.4%,而3H7H12G4同样诱导CNV消退(65.7%)(图9B)。荧光素血管造影(FA)和吲哚菁绿血管造影(ICGA)的组合使我们能够测量激光损伤部位周围新血管的血管渗漏。488nm和785nm的连续波激光模块分别用作荧光素和ICG的激发源。通过由旋转多面镜(MC-5;Lincoln Laser)和基于检流计的扫描镜(6230H;Cambridge technology)组成的扫描仪系统获得激发激光器的光栅扫描图案,并将其递送到成像透镜的后孔。使用高数值孔径(NA)物镜(PlanApoλ,NA 0.75;Nikon)作为成像透镜,以提供广角眼底荧光图像。由光电倍增管(R9110;Hamamatsu Photonics)检测到的荧光信号由图像采集卡数字化,并实时重建为每帧512×512像素大小的图像。为了使用血管造影系统可视化晚期(6min)FA和ICGA图像,分别腹膜内和静脉内给予10mg荧光素钠(Alcon)和0.15mg ICG(DaiichiPharmaceutical)。成像过程在全身麻醉和瞳孔扩大下进行,以改善图像质量。使用基于Java的成像软件(ImajeJ;National Institutes of Health),将CNV的泄漏面积计算为FA图像中测得的总超荧光面积除以ICGA图像中测得的总CNV面积。与Fc相比,VEGF-Trap(37.0%)和3H7H12G4(24.6%)均相似地压制了血管渗漏(图9C)。值得注意的是,所述Fc处理组在激光光凝后6到14天之间未显示出明显的血管渗漏差异,但VEGF-Trap和3H7H12G4显著减少了血管渗漏(分别为45.6%和42.5%)(图9C)。因此,在激光诱导的CNV小鼠模型中,VEGF-Trap和3H7H12G4之间CNV和血管渗漏的压制程度在定量上是无法区分的。
实施例9.3H7H12G4和CD31在CNV内皮细胞中的共定位。
为了研究皮下注射3H7H12G4是否也能对CNV发挥治疗作用,我们首先评估了3H7H12G4和CD31在CNV内皮细胞中的共定位。激光光凝后1天进行3H7H12G4(25mg/kg)皮下给予。作为对照,以相同方式向小鼠给予Fc(25mg/kg)。3H7H12G4和抗CD31抗体(1:200,Millipore)在CNV内皮细胞中的共定位是在激光光凝后2、4和8天通过抗人IgG抗体(1:1000,Jackson ImmunoResearch Laboratories)直接检测的(图10A)。所给予的3H7H12G4在CD31+内皮细胞CNV中高度可检测(图10B-D)。
实施例10.皮下注射3H7H12G4抗体的CNV抑制作用。
为了确定皮下注射3H7H12G4对CNV抑制的作用,在激光光凝后1天进行3H7H12G4(25mg/kg)皮下给予。作为对照,以相同方式向小鼠给予Fc(25mg/kg)。使用抗CD31抗体(1:200,Millipore)检测CNV的内皮细胞,并在激光光凝后8天使用MATLAB图像处理工具箱(MathWorks)计算RPE-脉络膜-巩膜铺片的CD31+CNV体积(图11A)。与Fc相比,3H7H12G4将CNV形成有效抑制69.9%(图11B,C),表明不仅玻璃体内注射,而且皮下注射3H7H12G4对CNV都有抑制作用。
工业实用性
根据本发明的与Tie2结合的抗体或其抗原结合片段以高亲和力与Tie2结合,维持与人和小鼠的交叉反应性,并显示出所需的抗原反应性。另外,通过诱导Tie2磷酸化和Tie2受体的激活,它可以有效地用于预防或治疗感兴趣的血管生成疾病。
到现在为止,已经详细描述了本发明的内容的特定部分,并且对于本领域的普通技术人员显而易见的是,这些特定技术仅仅是优选的实施方案,因此本发明的范围不限于所述实施方案。
序列表自由文本
随附电子文件。
<110> 基础科学研究院
韩国科学技术院
<120> 与Tie2结合的抗体及其用途
<130> PP-B2229
<150> US 62/682,042
<151> 2018-06-07
<160> 68
<170> PatentIn 3.5版
<210> 1
<211> 1124
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 1
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450 455 460
Ile Ser Ser Glu Pro Tyr Phe Gly Asp Gly Pro Ile Lys Ser Lys Lys
465 470 475 480
Leu Leu Tyr Lys Pro Val Asn His Tyr Glu Ala Trp Gln His Ile Gln
485 490 495
Val Thr Asn Glu Ile Val Thr Leu Asn Tyr Leu Glu Pro Arg Thr Glu
500 505 510
Tyr Glu Leu Cys Val Gln Leu Val Arg Arg Gly Glu Gly Gly Glu Gly
515 520 525
His Pro Gly Pro Val Arg Arg Phe Thr Thr Ala Ser Ile Gly Leu Pro
530 535 540
Pro Pro Arg Gly Leu Asn Leu Leu Pro Lys Ser Gln Thr Thr Leu Asn
545 550 555 560
Leu Thr Trp Gln Pro Ile Phe Pro Ser Ser Glu Asp Asp Phe Tyr Val
565 570 575
Glu Val Glu Arg Arg Ser Val Gln Lys Ser Asp Gln Gln Asn Ile Lys
580 585 590
Val Pro Gly Asn Leu Thr Ser Val Leu Leu Asn Asn Leu His Pro Arg
595 600 605
Glu Gln Tyr Val Val Arg Ala Arg Val Asn Thr Lys Ala Gln Gly Glu
610 615 620
Trp Ser Glu Asp Leu Thr Ala Trp Thr Leu Ser Asp Ile Leu Pro Pro
625 630 635 640
Gln Pro Glu Asn Ile Lys Ile Ser Asn Ile Thr His Ser Ser Ala Val
645 650 655
Ile Ser Trp Thr Ile Leu Asp Gly Tyr Ser Ile Ser Ser Ile Thr Ile
660 665 670
Arg Tyr Lys Val Gln Gly Lys Asn Glu Asp Gln His Val Asp Val Lys
675 680 685
Ile Lys Asn Ala Thr Ile Thr Gln Tyr Gln Leu Lys Gly Leu Glu Pro
690 695 700
Glu Thr Ala Tyr Gln Val Asp Ile Phe Ala Glu Asn Asn Ile Gly Ser
705 710 715 720
Ser Asn Pro Ala Phe Ser His Glu Leu Val Thr Leu Pro Glu Ser Gln
725 730 735
Ala Pro Ala Asp Leu Gly Gly Gly Lys Met Leu Leu Ile Ala Ile Leu
740 745 750
Gly Ser Ala Gly Met Thr Cys Leu Thr Val Leu Leu Ala Phe Leu Ile
755 760 765
Ile Leu Gln Leu Lys Arg Ala Asn Val Gln Arg Arg Met Ala Gln Ala
770 775 780
Phe Gln Asn Val Arg Glu Glu Pro Ala Val Gln Phe Asn Ser Gly Thr
785 790 795 800
Leu Ala Leu Asn Arg Lys Val Lys Asn Asn Pro Asp Pro Thr Ile Tyr
805 810 815
Pro Val Leu Asp Trp Asn Asp Ile Lys Phe Gln Asp Val Ile Gly Glu
820 825 830
Gly Asn Phe Gly Gln Val Leu Lys Ala Arg Ile Lys Lys Asp Gly Leu
835 840 845
Arg Met Asp Ala Ala Ile Lys Arg Met Lys Glu Tyr Ala Ser Lys Asp
850 855 860
Asp His Arg Asp Phe Ala Gly Glu Leu Glu Val Leu Cys Lys Leu Gly
865 870 875 880
His His Pro Asn Ile Ile Asn Leu Leu Gly Ala Cys Glu His Arg Gly
885 890 895
Tyr Leu Tyr Leu Ala Ile Glu Tyr Ala Pro His Gly Asn Leu Leu Asp
900 905 910
Phe Leu Arg Lys Ser Arg Val Leu Glu Thr Asp Pro Ala Phe Ala Ile
915 920 925
Ala Asn Ser Thr Ala Ser Thr Leu Ser Ser Gln Gln Leu Leu His Phe
930 935 940
Ala Ala Asp Val Ala Arg Gly Met Asp Tyr Leu Ser Gln Lys Gln Phe
945 950 955 960
Ile His Arg Asp Leu Ala Ala Arg Asn Ile Leu Val Gly Glu Asn Tyr
965 970 975
Val Ala Lys Ile Ala Asp Phe Gly Leu Ser Arg Gly Gln Glu Val Tyr
980 985 990
Val Lys Lys Thr Met Gly Arg Leu Pro Val Arg Trp Met Ala Ile Glu
995 1000 1005
Ser Leu Asn Tyr Ser Val Tyr Thr Thr Asn Ser Asp Val Trp Ser Tyr
1010 1015 1020
Gly Val Leu Leu Trp Glu Ile Val Ser Leu Gly Gly Thr Pro Tyr Cys
1025 1030 1035 1040
Gly Met Thr Cys Ala Glu Leu Tyr Glu Lys Leu Pro Gln Gly Tyr Arg
1045 1050 1055
Leu Glu Lys Pro Leu Asn Cys Asp Asp Glu Val Tyr Asp Leu Met Arg
1060 1065 1070
Gln Cys Trp Arg Glu Lys Pro Tyr Glu Arg Pro Ser Phe Ala Gln Ile
1075 1080 1085
Leu Val Ser Leu Asn Arg Met Leu Glu Glu Arg Lys Thr Tyr Val Asn
1090 1095 1100
Thr Thr Leu Tyr Glu Lys Phe Thr Tyr Ala Gly Ile Asp Cys Ser Ala
1105 1110 1115 1120
Glu Glu Ala Ala
<210> 2
<211> 390
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 2
Thr Pro Lys Ile Val Asp Leu Pro Asp His Ile Glu Val Asn Ser Gly
1 5 10 15
Lys Phe Asn Pro Ile Cys Lys Ala Ser Gly Trp Pro Leu Pro Thr Asn
20 25 30
Glu Glu Met Thr Leu Val Lys Pro Asp Gly Thr Val Leu His Pro Lys
35 40 45
Asp Phe Asn His Thr Asp His Phe Ser Val Ala Ile Phe Thr Ile His
50 55 60
Arg Ile Leu Pro Pro Asp Ser Gly Val Trp Val Cys Ser Val Asn Thr
65 70 75 80
Val Ala Gly Met Val Glu Lys Pro Phe Asn Ile Ser Val Lys Val Leu
85 90 95
Pro Lys Pro Leu Asn Ala Pro Asn Val Ile Asp Thr Gly His Asn Phe
100 105 110
Ala Val Ile Asn Ile Ser Ser Glu Pro Tyr Phe Gly Asp Gly Pro Ile
115 120 125
Lys Ser Lys Lys Leu Leu Tyr Lys Pro Val Asn His Tyr Glu Ala Trp
130 135 140
Gln His Ile Gln Val Thr Asn Glu Ile Val Thr Leu Asn Tyr Leu Glu
145 150 155 160
Pro Arg Thr Glu Tyr Glu Leu Cys Val Gln Leu Val Arg Arg Gly Glu
165 170 175
Gly Gly Glu Gly His Pro Gly Pro Val Arg Arg Phe Thr Thr Ala Ser
180 185 190
Ile Gly Leu Pro Pro Pro Arg Gly Leu Asn Leu Leu Pro Lys Ser Gln
195 200 205
Thr Thr Leu Asn Leu Thr Trp Gln Pro Ile Phe Pro Ser Ser Glu Asp
210 215 220
Asp Phe Tyr Val Glu Val Glu Arg Arg Ser Val Gln Lys Ser Asp Gln
225 230 235 240
Gln Asn Ile Lys Val Pro Gly Asn Leu Thr Ser Val Leu Leu Asn Asn
245 250 255
Leu His Pro Arg Glu Gln Tyr Val Val Arg Ala Arg Val Asn Thr Lys
260 265 270
Ala Gln Gly Glu Trp Ser Glu Asp Leu Thr Ala Trp Thr Leu Ser Asp
275 280 285
Ile Leu Pro Pro Gln Pro Glu Asn Ile Lys Ile Ser Asn Ile Thr His
290 295 300
Ser Ser Ala Val Ile Ser Trp Thr Ile Leu Asp Gly Tyr Ser Ile Ser
305 310 315 320
Ser Ile Thr Ile Arg Tyr Lys Val Gln Gly Lys Asn Glu Asp Gln His
325 330 335
Val Asp Val Lys Ile Lys Asn Ala Thr Ile Thr Gln Tyr Gln Leu Lys
340 345 350
Gly Leu Glu Pro Glu Thr Ala Tyr Gln Val Asp Ile Phe Ala Glu Asn
355 360 365
Asn Ile Gly Ser Ser Asn Pro Ala Phe Ser His Glu Leu Val Thr Leu
370 375 380
Pro Glu Ser Gln Ala Pro
385 390
<210> 3
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 3
Ser Tyr Trp Met Asn
1 5
<210> 4
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 4
Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe Lys
1 5 10 15
Asp
<210> 5
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 5
Gly Asn Tyr Phe Asp Cys
1 5
<210> 6
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 6
Arg Ala Ser Gln Asp Ile Gly Ile Ser Leu Asn
1 5 10
<210> 7
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 7
Ala Thr Ser Ile Leu Asp Ser
1 5
<210> 8
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 8
Leu Gln Tyr Ala Ser Ser Pro Trp Thr
1 5
<210> 9
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 9
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Leu Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asn Tyr Phe Asp Cys Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser
115
<210> 10
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 10
caggtccaac tgcagcagcc tggggctgag ctggtgaggc ctggagcttc agtgaagctg 60
tcctgcaagg cttctggcta ctccttcacc agctactgga tgaactgggt gaagcagagg 120
cctggacaag gccttgagtg gattggcatg attcatcctt ccgatagtga aactaggtta 180
aatcagaagt tcaaggacaa ggccacattg actgtagaca aatcctccag cacagcctac 240
ttgcaactca gcagcccgac atctgaggac tctgcggtct attactgtgc aagggggaac 300
tactttgact gctggggcca aggcaccact ctcacagtct cctca 345
<210> 11
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 11
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Gly Ile Ser
20 25 30
Leu Asn Trp Leu Gln Gln Glu Pro Asp Gly Thr Ile Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ile Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Val Asp Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 12
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 12
gacatccaga tgacccagtc tccatcctcc ttatctgcct ctctgggaga aagggtcagt 60
ctcacttgtc gggcaagtca ggacattggt attagcttaa actggcttca gcaggaacca 120
gatggaacta ttaaacgcct gatctacgcc acatccattt tagattctgg tgtccccaaa 180
aggttcagtg gcagtaggtc tgggtcagat tattctctca ccatcagcag ccttgagtct 240
gaagattttg tagactatta ctgtctacaa tatgctagtt ctccgtggac gttcggtgga 300
ggcaccaagc tggaaatcaa a 321
<210> 13
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 13
Ser Tyr Trp Met Asn
1 5
<210> 14
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 14
Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe Lys
1 5 10 15
Asp
<210> 15
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 15
Gly Tyr Tyr Phe Gly Tyr
1 5
<210> 16
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 16
Arg Ala Ser Gln Asp Ile Gly Ile Ser Leu Asn
1 5 10
<210> 17
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 17
Ala Thr Ser Asn Leu Asp Ser
1 5
<210> 18
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 18
Leu Gln Tyr Ala Ser Ser Pro Pro Thr
1 5
<210> 19
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 19
Gln Val Gln Leu Gln Gln Pro Gly Ala Asp Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Tyr Tyr Phe Gly Tyr Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser
115
<210> 20
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 20
caggtccaac tgcagcagcc tggggctgac ctggtgaggc ctggagcttc agtgaagctg 60
tcctgcaagg cttctggcta ctccttcacc agctactgga tgaactgggt gaagcagagg 120
cctggacaag gccttgagtg gattggcatg attcatcctt ccgatagtga aactaggtta 180
aatcagaagt tcaaggacaa ggccacattg actgtagaca aatcctccag cacagcctac 240
atgcaactca gcagcccgac atctgaggac tctgcggtct attactgtgc aaaggggtac 300
tactttggct actggggcca aggcaccact ctcacagtct cctca 345
<210> 21
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 21
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Gly Ile Ser
20 25 30
Leu Asn Trp Leu Gln Gln Glu Pro Asp Gly Thr Ile Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Asn Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Val Asp Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 22
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 22
gacatccaga tgacccagtc tccatcctcc ttatctgcct ctctgggaga aagagtcagt 60
ctcacttgtc gggcaagtca ggacattggt attagtttaa actggcttca gcaggaacca 120
gatggaacta ttaaacgcct gatctacgcc acatccaatt tagattctgg tgtccccaaa 180
aggttcagtg gcagtaggtc tgggtcagat tattctctca ccatcagcag ccttgagtct 240
gaagattttg tagactatta ctgtctacaa tatgctagtt ctcctccgac gttcggtgga 300
ggcaccaagc tggaaatcaa a 321
<210> 23
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 23
Ser Tyr Trp Met Asn
1 5
<210> 24
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 24
Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe Met
1 5 10 15
Asp
<210> 25
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 25
Gly Leu Tyr Gly Asn Ser
1 5
<210> 26
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 26
Arg Ala Ser Gln Asp Ile Gly Ile Ser Leu Asn
1 5 10
<210> 27
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 27
Ala Thr Ser Ser Leu Asp Ser
1 5
<210> 28
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 28
Leu Gln Tyr Ala Ser Ser Pro Tyr Thr
1 5
<210> 29
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 29
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe
50 55 60
Met Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Tyr Gly Asn Ser Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala
115
<210> 30
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 30
caggtccaac tgcagcagcc tggggctgag ctggtgaggc ctggagcttc agtgaagctg 60
tcctgcaagg cttctggcta ctccttcacc agctactgga tgaactgggt gaagcagagg 120
cctggacaag gccttgagtg gattggcatg attcatcctt ccgatagtga aactaggtta 180
aatcagaagt tcatggacaa ggccacattg actgtagaca aatcctccag cacagcctac 240
atgcagctca gcagcccgac atctgaggac tctgcggtct attactgtgc tcgtggcctc 300
tatggtaact cttggggcca agggactctg gtcactgtct ctgca 345
<210> 31
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 31
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Gly Ile Ser
20 25 30
Leu Asn Trp Leu Gln Gln Glu Pro Asp Gly Thr Ile Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Val Asp Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 32
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 32
gacatccaga tgacccagtc tccatcctcc ttatctgcct ctctgggaga aagagtcagt 60
ctcacttgtc gggcaagtca ggacattggt attagcttaa actggcttca gcaggaacca 120
gatggaacta ttaaacgcct gatctacgcc acatccagtt tagattctgg tgtccccaaa 180
aggttcagtg gcagtaggtc tgggtcagat tattctctca ccatcagcag ccttgagtct 240
gaagattttg tagactatta ctgtctacaa tatgctagtt ctccgtacac gttcggaggg 300
gggaccaagc tggaaataaa a 321
<210> 33
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 33
Ser Tyr Trp Met Asn
1 5
<210> 34
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 34
Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe Lys
1 5 10 15
Asp
<210> 35
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 35
Gly Tyr Tyr Phe Asp Tyr
1 5
<210> 36
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 36
Arg Ala Ser Gln Asp Ile Gly Ile Ser Leu Asn
1 5 10
<210> 37
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 37
Ala Thr Ser Ser Leu Asp Ser
1 5
<210> 38
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 38
Leu Gln Tyr Val Ser Ser Pro Trp Thr
1 5
<210> 39
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 39
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser
115
<210> 40
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 40
caggtccaac tgcagcagcc tggggctgag ctggtgaggc ctggagcttc agtgaagctg 60
tcctgcaagg cttctggcta ctccttcacc agctactgga tgaactgggt gaagcagagg 120
cctggacaag gccttgagtg gattggcatg attcatcctt ccgatagtga aactaggtta 180
aatcagaagt tcaaggacaa ggccacattg actgtagaca aatcctccag cacagcctac 240
atgcaactca gcagcccgac atctgaggac tctgcggtct attactgtgc aagaggctac 300
tactttgact actggggcca aggcaccact ctcacagtct cctca 345
<210> 41
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 41
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Gly Ile Ser
20 25 30
Leu Asn Trp Leu Gln Gln Glu Pro Asp Gly Thr Ile Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Lys Arg Phe Thr Gly
50 55 60
Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Val Asp Tyr Tyr Cys Leu Gln Tyr Val Ser Ser Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 42
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 42
gacatccaga tgacccagtc tccatcctcc ttatctgcct ctctgggaga aagagtcagt 60
ctcacttgtc gggcaagtca ggacattggt attagcttaa actggcttca gcaggaacca 120
gatggaacta ttaaacgcct gatctacgcc acatccagtt tagattctgg tgtccccaag 180
aggttcactg gcagtaggtc tgggtcagat tattctctca ccatcagcag ccttgagtct 240
gaagattttg tagactatta ctgtctacaa tatgttagtt ctccgtggac gttcggtgga 300
ggcaccaagc tggaaatcaa a 321
<210> 43
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 43
Ser Tyr Trp Met Asn
1 5
<210> 44
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 44
Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe Lys
1 5 10 15
Asp
<210> 45
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 45
Leu Thr Ile Tyr Phe Asp Tyr
1 5
<210> 46
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 46
Arg Ala Ser Gln Asp Ile Gly Ile Ser Leu Asn
1 5 10
<210> 47
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 47
Ala Thr Ser Ser Leu Asp Ser
1 5
<210> 48
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 48
Leu Gln Tyr Ala Ser Ser Pro Tyr Thr
1 5
<210> 49
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 49
Gln Val Gln Leu Gln Gln Pro Gly Ala Asp Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Arg Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Gly Leu Thr Ile Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu
100 105 110
Thr Val Ser Ser
115
<210> 50
<211> 348
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 50
caggtccaac tacagcagcc tggggctgac ctggtgaggc ctggagcttc agtgacgctg 60
tcctgcaagg cttctggcta ctccttcacc agctactgga tgaactgggt gaagcagagg 120
cctggacaag gcctggagtg gattggcatg attcatcctt ccgatagtga aactaggtta 180
aatcagaagt tcaaggacaa ggccacattg actgtagaca aatcctccag cacagcctac 240
atgcaactcc gcagcccgac atctgaggac tctgcggtct attactgtgc aggcctaact 300
atttactttg actattgggg ccaaggcacc actctcacag tctcctca 348
<210> 51
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 51
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Gly Ile Ser
20 25 30
Leu Asn Trp Leu Gln Gln Glu Pro Asp Gly Thr Ile Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Val Asp Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 52
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 52
gacatccaga tgacccagtc tccatcctcc ttatctgcct ctctgggaga aagagtcagt 60
ctcacttgtc gggcaagtca ggacattggt attagcttaa actggcttca gcaggaacca 120
gatggaacta ttaaacgcct gatctacgcc acatccagtt tagattctgg tgtccccaaa 180
aggttcagtg gcagtaggtc tgggtcagat tattctctca ccatcagcag ccttgagtct 240
gaagattttg tagactatta ctgtctacaa tatgctagtt ctccgtacac gttcggaggg 300
gggaccaagc tggaaataaa a 321
<210> 53
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 53
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe
50 55 60
Met Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Tyr Gly Asn Ser Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 54
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 54
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Gly Ile Ser
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 55
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 55
caggtgcagc tggtccaatc cggggctgag gtgaagaagc ctggagcatc agtgaaagtt 60
tcatgcaaag ctagtggtta caccttcacc agctattgga tgaactgggt gcggcaggcc 120
cccggtcagg ggcttgagtg gatgggcatg atccacccat ccgactctga gactaggctg 180
aaccagaagt ttatggatag agtgaccatg acaagagata cgtccacttc tactgtctat 240
atggaactga gcagtctgag atctgaagac acagccgttt actactgtgc tcgcggactc 300
tatggcaata gctggggcca aggaacattg gtaaccgtct cttct 345
<210> 56
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 56
gacatccaga tgacccaatc tccctcctcc ctgagcgcat ccgtggggga tagagtgacc 60
ataacctgcc gggcctctca ggacatcggt atttctttga attggtatca gcagaagccc 120
gggaaggccc ctaaacgcct gatctatgct acttccagtc tggacagcgg ggtcccgtca 180
aggttttcag gcagtggatc aggcacagag tttacactca caatttcgag cctgcagcct 240
gaagatttcg ccacttatta ctgtcttcaa tacgctagct ctccatacac gttcggccag 300
ggaaccaagg ttgagattaa a 321
<210> 57
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 57
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe
50 55 60
Met Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Tyr Gly Asn Ser Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 58
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 58
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Gly Ile Ser
20 25 30
Leu Asn Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 59
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 59
caggtgcagc tggtccaatc cggggctgag gtgaagaagc ctggagcatc agtgaaagtt 60
tcatgcaaag ctagtggtta caccttcacc agctattgga tgaactgggt gcggcaggcc 120
cccggtcagg ggcttgagtg gatgggcatg atccacccat ccgactctga gactaggctg 180
aaccagaagt ttatggatag agtgaccatg acaagagata cgtccacttc tactgtctat 240
atggaactga gcagtctgag atctgaagac acagccgttt actactgtgc tcgcggactc 300
tatggcaata gctggggcca aggaacattg gtaaccgtct cttct 345
<210> 60
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 60
gacatccaga tgactcagtc cccctcgagc ctctcagctt ctgttggaga cagagtgaca 60
attacatgcc gggcctcaca ggatattggg atctccctga actggctgca acaggaacca 120
ggaaaggccc ctaagcgcct gatatatgcc acatcctctc ttgactcagg ggtcccaaag 180
aggtttagcg gcagtggatc aggtactgag ttcactctca ccatctctag cctgcagcct 240
gaggattttg caacctacta ttgtttgcaa tacgctagtt ccccctacac gttcggccag 300
ggcaccaaag tggaaatcaa a 321
<210> 61
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 61
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe
50 55 60
Met Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Tyr Gly Asn Ser Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 62
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 62
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Gly Ile Ser
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 63
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 63
caagtccagc tcgtgcagtc tggcgctgag gtgaaaaagc ccggggcctc agtgaaggtt 60
tcttgcaagg caagcggcta cacctttacc tcctattgga tgaattgggt gcgacagcgg 120
ccaggccagg ggttggagtg gatcggaatg attcacccta gtgactcaga aactaggctg 180
aaccagaaat tcatggacag agtcacaatg acgcgcgata caagcactag tacagtttac 240
atggagctga gcagcctgag atcggaagat actgccgtgt attactgtgc taggggactg 300
tatggaaact cttggggtca aggcaccctt gtaaccgtct cctcc 345
<210> 64
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 64
gacatccaga tgacccaatc tccctcctcc ctgagcgcat ccgtggggga tagagtgacc 60
ataacctgcc gggcctctca ggacatcggt atttctttga attggtatca gcagaagccc 120
gggaaggccc ctaaacgcct gatctatgct acttccagtc tggacagcgg ggtcccgtca 180
aggttttcag gcagtggatc aggcacagag tttacactca caatttcgag cctgcagcct 240
gaagatttcg ccacttatta ctgtcttcaa tacgctagct ctccatacac gttcggccag 300
ggaaccaagg ttgagattaa a 321
<210> 65
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 65
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe
50 55 60
Met Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Tyr Gly Asn Ser Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 66
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 66
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Gly Ile Ser
20 25 30
Leu Asn Trp Leu Gln Gln Glu Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 67
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 67
caagtccagc tcgtgcagtc tggcgctgag gtgaaaaagc ccggggcctc agtgaaggtt 60
tcttgcaagg caagcggcta cacctttacc tcctattgga tgaattgggt gcgacagcgg 120
ccaggccagg ggttggagtg gatcggaatg attcacccta gtgactcaga aactaggctg 180
aaccagaaat tcatggacag agtcacaatg acgcgcgata caagcactag tacagtttac 240
atggagctga gcagcctgag atcggaagat actgccgtgt attactgtgc taggggactg 300
tatggaaact cttggggtca aggcaccctt gtaaccgtct cctcc 345
<210> 68
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成序列
<400> 68
gacatccaga tgactcagtc cccctcgagc ctctcagctt ctgttggaga cagagtgaca 60
attacatgcc gggcctcaca ggatattggg atctccctga actggctgca acaggaacca 120
ggaaaggccc ctaagcgcct gatatatgcc acatcctctc ttgactcagg ggtcccaaag 180
aggtttagcg gcagtggatc aggtactgag ttcactctca ccatctctag cctgcagcct 240
gaggattttg caacctacta ttgtttgcaa tacgctagtt ccccctacac gttcggccag 300
ggcaccaaag tggaaatcaa a 321
Claims (13)
1.一种结合包括SEQ ID NO:2的Tie2 Ig3-FNIII(1-3)结构域的抗Tie2抗体或其抗原结合片段。
2.根据权利要求1所述的方法,其中所述抗体或其抗原结合片段结合包括SEQ ID NO:1的序列的Tie2的氨基酸633-644和/或氨基酸713-726。
3.根据权利要求1所述的方法,其中所述抗体或其抗原结合片段包括重链可变区,所述重链可变区包含包括SEQ ID NO:3-5的氨基酸序列的重链CDR;和轻链可变区,所述轻链可变区包含包括SEQ ID NO:6-8的氨基酸序列的轻链CDR;
重链可变区,所述重链可变区包含包括SEQ ID NO:13-15的氨基酸序列的重链CDR;和轻链可变区,所述轻链可变区包含包括SEQ ID NO:16-18的氨基酸序列的轻链CDR;
重链可变区,所述重链可变区包含包括SEQ ID NO:23-25的氨基酸序列的重链CDR;和轻链可变区,所述轻链可变区包含包括SEQ ID NO:26-28的氨基酸序列的轻链CDR;
重链可变区,所述重链可变区包含包括SEQ ID NO:33-35的氨基酸序列的重链CDR;和轻链可变区,所述轻链可变区包含包括SEQ ID NO:36-38的氨基酸序列的轻链CDR;或者
重链可变区,所述重链可变区包含包括SEQ ID NO:43-45的氨基酸序列的重链CDR;和轻链可变区,所述轻链可变区包含包括SEQ ID NO:46-48的氨基酸序列的轻链CDR。
4.根据权利要求1所述的方法,其中所述抗体或其抗原结合片段包括重链可变区,所述重链可变区包括SEQ ID NO:9的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ IDNO:11的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:19的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:21的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:29的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:31的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:39的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:41的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:49的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:51的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:53的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:54的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:57的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:58的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:61的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:62的氨基酸序列;
重链可变区,所述重链可变区包括SEQ ID NO:65的氨基酸序列;和轻链可变区,所述轻链可变区包括SEQ ID NO:66的氨基酸序列。
5.一种核酸,所述核酸编码根据权利要求1至4中任一项所述的抗体或其抗原结合片段。
6.根据权利要求5所述的方法,其中所述核酸的特征在于包括SEQ ID NO:10、12、20、22、30、32、40、42、50、52、55、56、59、60、63、64、67或68。
7.一种表达载体,所述表达载体包括根据权利要求5所述的核酸。
8.一种用根据权利要求7所述的表达载体转化的细胞。
9.一种制造结合Tie2的抗体或抗原结合片段的方法,所述方法包括以下步骤:
(a)培养根据权利要求8所述的细胞的过程;以及
(b)从所培养的细胞中回收抗体或其抗原结合片段的过程。
10.一种用于预防或治疗血管生成疾病的组合物,所述组合物包含作为有效成分的根据权利要求1至4中任一项所述的抗体或其抗原结合片段。
11.根据权利要求10所述的方法,其中组合物的特征在于,其中血管生成疾病选自癌症、转移、糖尿病性视网膜病变、早产儿视网膜病变、角膜移植排斥、黄斑变性、新生血管性青光眼、全身性皮肤变红、增殖性视网膜病变、银屑病、血友病性关节炎、联合硬化症、动脉粥样硬化斑块中的毛细血管形成、瘢痕疙瘩、伤口肉芽形成、血管粘连、类风湿性关节炎、骨关节炎、自身免疫疾病、克罗恩病、再狭窄、动脉粥样硬化、肠粘连、猫抓病、溃疡、肝硬化、肾炎、糖尿病性肾病、糖尿病、炎症性疾病和神经退行性疾病。
12.根据权利要求11所述的方法,其中组合物的特征在于,其中癌症选自食道癌、胃癌、大肠癌、直肠癌、口腔癌、咽癌、喉癌、肺癌、结肠癌、乳腺癌、子宫颈癌、子宫内膜癌、卵巢癌、前列腺癌、睾丸癌、膀胱癌、肾癌、肝癌、胰腺癌、骨癌、结缔组织癌、皮肤癌、脑癌、甲状腺癌、白血病、霍奇金淋巴瘤、淋巴瘤和多发性骨髓血癌。
13.一种用于与血管生成疾病的其他治疗剂进行组合治疗的组合物,所述组合物包含根据权利要求1至4中任一项所述的抗体或其抗原结合片段。
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KR20220059924A (ko) * | 2020-11-03 | 2022-05-10 | 한국생명공학연구원 | 신규 항-Tie2 항체 또는 이의 항원 결합 단편, 및 이의 용도 |
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- 2019-06-05 KR KR1020190066622A patent/KR20190139148A/ko unknown
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2020
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CN113993897B (zh) * | 2019-08-14 | 2024-06-07 | 药物抗体公司 | 抗tie2抗体及其用途 |
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JP2023175830A (ja) | 2023-12-12 |
US12024562B2 (en) | 2024-07-02 |
US20210179719A1 (en) | 2021-06-17 |
CA3101506A1 (en) | 2019-12-12 |
JP7390317B2 (ja) | 2023-12-01 |
CN112399975B (zh) | 2024-05-17 |
KR20190139148A (ko) | 2019-12-17 |
EP3805265A1 (en) | 2021-04-14 |
JP2021526801A (ja) | 2021-10-11 |
AU2019283520A1 (en) | 2021-01-07 |
EP3805265A4 (en) | 2022-07-06 |
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