CN116284407A - 一种抗gucy2c抗体或其抗原结合片段及其用途 - Google Patents
一种抗gucy2c抗体或其抗原结合片段及其用途 Download PDFInfo
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Abstract
本发明提供了一种抗GUCY2C的抗体或其抗原结合片段,包含重链互补决定区HCDR1‑3和轻链互补决定区LCDR1‑3。本发明的抗GUCY2C的抗体或其抗原结合片段对靶分子GUCY2C亲和力高、特异性强,且能有效识别肿瘤细胞表面的GUCY2C蛋白,对于肿瘤的治疗具有重要的临床意义。
Description
技术领域
本申请涉及抗体药物领域,具体地,本申请涉及一种抗GUCY2C抗体或其抗原结合片段及其用途。
背景技术
胃肠道恶性肿瘤,包括结直肠癌(CRC)、胃癌和食管癌,根据2020年的《全球癌症统计报告》显示,全球结直肠癌致死人数占所有癌症致死总数的9.4%,胃癌占7.7%;而在中国,胃癌致死人数占所有癌症致死人数的12.4%,食管癌占10%,结直肠癌占9.5%,可见胃肠道恶性肿瘤是中国乃至全球临床上远未被满足的治疗领域。GUCY2C或GCC,即鸟苷酸环化酶2C,属于鸟苷酸环化酶受体家族。研究表明,GUCY2C在多种胃肠道癌症中过表达,包括各恶性阶段90%以上的结直肠癌和50%以上的胃或胃-食管交界处癌。生理状态下,GUCY2C的表达局限于健康肠道管腔紧密连接的上皮细胞表面,以维持肠道内的稳态。但在病理状态下,肿瘤的发生会破坏肠管腔表面的紧密连接结构,导致GUCY2C的暴露,从而可能成为靶向药物结合的靶标。
因此,开发靶向GUCY2C的抗体药物,可为胃肠道肿瘤的靶向治疗提供新的选择。
发明内容
本发明的目的在于提供一种新的抗GUCY2C的抗体或其抗原结合片段及其医药用途。
在本发明的第一方面,提供了一种抗GUCY2C的抗体或其抗原结合片段,所述抗体或其抗原结合片段包含重链互补决定区HCDR1-3和轻链互补决定区LCDR1-3。
在另一优选例中,所述重链互补决定区HCDR1-3和轻链互补决定区LCDR1-3选自以下组:
a)所述HCDR-1氨基酸序列如SEQ ID NO:3所示,所述HCDR-2氨基酸序列如SEQ IDNO:4所示,所述HCDR-3氨基酸序列如SEQ ID NO:5所示;所述LCDR-1氨基酸序列如SEQ IDNO:8所示,所述LCDR-2氨基酸序列如SEQ ID NO:9所示,所述LCDR-3氨基酸序列如SEQ IDNO:10所示;或,
b)所述HCDR-1氨基酸序列如SEQ ID NO:13所示,所述HCDR-2氨基酸序列如SEQ IDNO:14所示,所述HCDR-3氨基酸序列如SEQ ID NO:15所示;所述LCDR-1氨基酸序列如SEQ IDNO:18所示,所述LCDR-2氨基酸序列如SEQ ID NO:19所示,所述LCDR-3氨基酸序列如SEQ IDNO:20所示;或,
c)所述HCDR-1氨基酸序列如SEQ ID NO:23所示,所述HCDR-2氨基酸序列如SEQ IDNO:24所示,所述HCDR-3氨基酸序列如SEQ ID NO:25所示;所述LCDR-1氨基酸序列如SEQ IDNO:28所示,所述LCDR-2氨基酸序列如SEQ ID NO:29所示,所述LCDR-3氨基酸序列如SEQ IDNO:30所示;或,
d)所述HCDR-1氨基酸序列如SEQ ID NO:33所示,所述HCDR-2氨基酸序列如SEQ IDNO:34所示,所述HCDR-3氨基酸序列如SEQ ID NO:35所示;所述LCDR-1氨基酸序列如SEQ IDNO:38所示,所述LCDR-2氨基酸序列如SEQ ID NO:39所示,所述LCDR-3氨基酸序列如SEQ IDNO:40所示;或,
e)所述HCDR-1氨基酸序列如SEQ ID NO:43所示,所述HCDR-2氨基酸序列如SEQ IDNO:44所示,所述HCDR-3氨基酸序列如SEQ ID NO:45所示;所述LCDR-1氨基酸序列如SEQ IDNO:48所示,所述LCDR-2氨基酸序列如SEQ ID NO:49所示,所述LCDR-3氨基酸序列如SEQ IDNO:50所示。
在另一优选例中,所述的抗GUCY2C的抗体或其抗原结合片段包含重链可变区VH和轻链可变区VL,其中:
a)VH的氨基酸序列如SEQ ID NO:2所示,VL的氨基酸序列如SEQ ID NO:7所示;或,
b)VH的氨基酸序列如SEQ ID NO:12所示,VL的氨基酸序列如SEQ ID NO:17所示;或,
c)VH的氨基酸序列如SEQ ID NO:22所示,VL的氨基酸序列如SEQ ID NO:27所示,或,
d)VH的氨基酸序列如SEQ ID NO:32所示,VL的氨基酸序列如SEQ ID NO:37所示;或,
e)VH的氨基酸序列如SEQ ID NO:42所示,VL的氨基酸序列如SEQ ID NO:47所示。
在另一优选例中,所述的抗GUCY2C的抗体或其抗原结合片段包含重链可变区VH或其变体和轻链可变区VL或其变体,其中:
a)VH的氨基酸序列如SEQ ID NO:51所示,VL的氨基酸序列如SEQ ID NO:55所示;或,
b)VH的氨基酸序列如SEQ ID NO:51所示,VL的氨基酸序列如SEQ ID NO:57所示;或,
c)VH的氨基酸序列如SEQ ID NO:53所示,VL的氨基酸序列如SEQ ID NO:55所示;或,
d)VH的氨基酸序列如SEQ ID NO:53所示,VL的氨基酸序列如SEQ ID NO:57所示;或,
e)VH的氨基酸序列如SEQ ID NO:59所示,VL的氨基酸序列如SEQ ID NO:63所示;或,
f)VH的氨基酸序列如SEQ ID NO:61所示,VL的氨基酸序列如SEQ ID NO:63所示;或,
g)VH的氨基酸序列如SEQ ID NO:61所示,VL的氨基酸序列如SEQ ID NO:65所示,或,
h)VH的氨基酸序列如SEQ ID NO:59所示,VL的氨基酸序列如SEQ ID NO:65所示。
在另一优选例中,所述VH区变体是指与SEQ ID NO:51、SEQ ID NO:53、SEQ ID NO:59、SEQ ID NO:61具有至少90%、95%、98%、或99%的氨基酸序列同源性的变体;所述VL区变体是指与SEQ ID NO:55、SEQ ID NO:57、SEQ ID NO:63、SEQ ID NO:65具有至少90%、95%、98%、或99%的氨基酸序列同源性的变体。
在另一优选例中,所述VH区或VL区包括1-10个氨基酸突变;更优选的,所述突变是取代突变。
在另一优选例中,所述的抗GUCY2C的抗体或其抗原结合片段包含重链恒定区和轻链恒定区;优选的,所述重链恒定区选自人IgG1、人IgG2、人IgG3或人IgG4,所述轻链恒定区选自人κ(Kappa)或人λ(Lambda)。
在另一优选例中,所述人IgG1重链恒定区包含如SEQ ID NO:67所示的氨基酸序列,所述人κ轻链恒定区包含如SEQ ID NO:68所示的氨基序列。
在另一优选例中,所述重链恒定区和/或轻链恒定区包含突变的氨基酸;更优选的,所述人IgG4重链恒定区包含S228P突变。
在另一优选例中,所述抗体或其抗原结合片段为嵌合抗体或其抗原结合片段,或人源化抗体或其抗原结合片段。
在另一优选例中,所述抗体或其抗原结合片段选自全长抗体、scFv、Fv、Fab、F(ab')、F(ab')2、Fv、Fd。
在另一优选例中,所述抗体是单克隆抗体。
在本发明的第二方面,提供了一种多核苷酸分子,所述多核苷酸分子编码根据在本发明的第一方面所述的抗体或其抗原结合片段。
在本发明的第三方面,提供了一种表达载体,所述表达载体含有根据本发明的第二方面所述的多核苷酸分子。
在另一优选例中,所述表达载体为病毒或质粒。
在另一优选例中,所述表达载体选自下组:pcDNA3.4,pDR1,pcDNA3.1(+),pcDNA3.1/ZEO(+),pDHFR,pTT5,pDHFF,pGM-CSF或pCHO 1.0。
在本发明的第四方面,提供了一种宿主细胞,所述宿主细胞含有根据本发明的第三方面所述的表达载体。
在另一优选例中,所述宿主细胞选自下组:COS、CHO、NS0、sf9、sf21、DH5α、BL21(DE3)、TG1、BL21(DE3)、293F或293E细胞。
在本发明的第五方面,提供了一种根据本发明的第一方面所述的抗体或其抗原结合片段的制备方法,其特征在于,所述制备方法包括以下步骤:
a)在表达条件下,培养根据本发明的第四方面所述的宿主细胞,从而表达抗体或其抗原结合片段;
b)分离并纯化步骤a)所述的抗体或其抗原结合片段。
在本发明的第六方面,提供了一种药物组合物,其特征在于,所述药物组合物包含有效量的根据本发明的第一方面所述的抗体或其抗原结合片段和一种或多种药学上可接受的载体。
在另一优选例中,所述药物组合物为单元剂型。
在另一优选例中,所述药物组合物的剂型包括胃肠给药剂型或胃肠外给药剂型。
在另一优选例中,所述的胃肠外给药剂型包括玻璃体注射、静脉注射、静脉滴注、皮下注射、局部注射、肌肉注射、瘤内注射、腹腔内注射、颅内注射、或腔内注射。
在本发明的第七方面,提供了一种根据本发明的第一方面所述的抗体或其抗原结合片段、或根据本发明的第六方面所述的药物组合物在制备治疗癌症的药物中的用途。
在另一优选例中,所述癌症为GUCY2C相关癌症;更优选的,所述癌症GUCY2C异常表达。
在另一优选例中,所述癌症为胃肠道肿瘤或胰腺癌;更优选的,所述胃肠道肿瘤选自直肠癌、结肠癌、小肠癌、胃癌、食管癌和胃-食管交界部癌;进一步更优选的,所述胃肠道肿瘤为恶性肿瘤。
在本发明的第八方面,提供了一种治疗癌症的方法,所述方法包括向有需要的受试者施用根据本发明的第一方面所述的抗体或其抗原结合片段、或根据本发明的第六方面所述的药物组合物。
在另一优选例中,所述癌症为GUCY2C相关癌症;更优选的,所述癌症GUCY2C异常表达。
在另一优选例中,所述癌症为胃肠道肿瘤或胰腺癌;更优选的,所述胃肠道肿瘤选自直肠癌、结肠癌、小肠癌、胃癌、食管癌和胃-食管交界部癌;进一步更优选的,所述胃肠道肿瘤为恶性肿瘤。
在本发明的第九方面,提供了一种免疫偶联物,所述免疫偶联物包括:
a)如本发明的第一方面所述的抗GUCY2C的抗体或其抗原结合片段;和b)选自下组的偶联部分:可检测标记物、药物、毒素、细胞因子、放射性核素、或酶。
在另一优选例中,所述偶联物部分选自:荧光或发光标记物、放射性标记物、MRI(磁共振成像)或CT(电子计算机X射线断层扫描技术)造影剂、或能够产生可检测产物的酶、放射性核素、生物毒素、细胞因子。
在另一优选例中,所述免疫偶联物包括抗体-药物偶联物(ADC)。
在另一优选例中,所述免疫偶联物用于制备治疗癌症的药物组合物。
在本发明的第十方面,提供了一种治疗癌症的方法,所述方法包括向有需要的受试者施用如本发明的第九方面所述的免疫偶联物。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1鼠源抗体对人GUCY2C-Fc蛋白的结合能力检测
图2鼠源抗体对人结肠癌细胞CW2的结合能力检测
图3鼠源抗体对人GUCY2C-His蛋白的结合活性检测
图4鼠源抗体对人GUCY2C-His蛋白的结合活性检测
图5嵌合抗体对人GUCY2C-His蛋白的结合活性检测
图6人源化抗体对人GUCY2C-His蛋白的结合活性检测
图7人源化抗体对人GUCY2C-Fc蛋白的结合活性检测
图8人源化抗体对人GUCY2C过表达肿瘤细胞的结合活性检测
具体实施方式
本发明人经过广泛而深入地研究,经多重筛选获得了新的抗GUCY2C抗体。实验结果表明,本发明的抗GUCY2C抗体可有效的与人GUCY2C过表达肿瘤细胞结合,在此基础上完成了本发明。
术语
抗体
本发明中,术语“抗体”是指全长抗体,术语“抗原结合片段”是指来源于抗体且能结合抗原表位的片段,包括但不限于scFv、Fv、Fd、Fab、F(ab')2或F(ab')。
本发明中,术语“全长抗体”是指有相同结构特征的约150000道尔顿的异四聚糖蛋白,包含可变区和恒定区,其由两条相同的重链(HC)和两条相同的轻链(LC)组成。每条重链的一端有重链可变区(VH),其后是重链恒定区,重链恒定区由三个结构域CH1、CH2、以及CH3构成。每条轻链的一端有轻链可变区(VL),另一端有轻链恒定区,轻链恒定区包括一个结构域CL;轻链恒定区与重链恒定区的CH1结构域配对,轻链可变区与重链可变区配对。恒定区不直接参与抗体与抗原的结合,但是它们表现出不同的效应功能,例如参与抗体依赖的细胞介导的细胞毒性作用(ADCC,antibody-dependent cell-mediated cytotoxicity)等。重链恒定区包括IgG1、IgG2、IgG3、IgG4亚型;轻链恒定区包括κ(Kappa)或λ(Lambda)。抗体的重链和轻链通过重链的CH1结构域和轻链的CL结构域之间的二硫键共价连接在一起,抗体的两条重链通过铰链区之间形成的多肽间二硫键共价连接在一起。
本发明中,术语“可变”表示抗体中可变区的某些部分在序列上有所不同,它形成各种特定抗体对其特定抗原的结合和特异性。然而,可变性并不均匀地分布在整个抗体可变区中。它集中于重链可变区和轻链可变区中称为互补决定区(complementarity-determining region,CDR)或超变区中的三个片段中。可变区中较保守的部分称为框架区(frame region,FR)。天然重链和轻链的可变区中各自包含四个FR区,它们大致上呈β-折叠构型,由形成连接环的三个CDR相连,在某些情况下可形成部分β折叠结构。每条链中的CDR通过FR区紧密地靠在一起并与另一链的CDR一起形成了抗体的抗原结合部位(参见Kabat等,NIH Publ.No.91-3242,卷I,647-669页(1991))。重链可变区(VH)和轻链可变区(VL)的CDR分别称为HCDR和LCDR。
本发明中,术语“人源化抗体”是指抗体互补决定区(CDR)来源于非人物种(例如啮齿动物),抗体分子中残余的部分(包括框架区FR和恒定区)来源于人的抗体。其中,框架区FR残基可被改变以维持结合亲和性。本发明中,术语“嵌合抗体”是指可变区来源于非人物种(例如啮齿动物),恒定区来源于人的抗体。
本发明中,术语“框架区“(FR)”指抗体可变区内超变区之外的氨基酸组成和排列顺序变化相对较小的部分。抗体的轻链和重链各具有四个FR,分别称为FR1-L、FR2-L、FR3-L、FR4-L和FR1-H、FR2-H、FR3-H、FR4-H。优选地,本发明的FR是人抗体FR或其衍生物,所述人抗体FR的衍生物与天然存在的人抗体FR基本相同,即序列同源性达到至少85%、90%、95%、96%、97%、98%或99%。本领域的技术人员在获知CDR的氨基酸序列后,可确定框架区FR1-L、FR2-L、FR3-L、FR4-L和/或FR1-H、FR2-H、FR3-H、FR4-H序列。
本发明中,术语“单克隆抗体(单抗)”指从一类基本均一的群体中获得的抗体,除少数可能存在的天然突变外,该群体中包含的单个抗体是相同的。单克隆抗体针对抗原上的单个决定簇,对单个抗原位点高特异。单克隆抗体可以通过杂交瘤培养来合成,不会被其它免疫球蛋白污染。
本发明中,术语“抗”和“结合”是指两分子间的非随机的结合反应,如抗体和其所针对的抗原之间的反应。通常,抗体以小于大约10-7M,例如小于大约10-8M、10-9M、10-10M、10-11M或更小的平衡解离常数(KD)结合该抗原。术语“KD”是指特定抗体-抗原相互作用的平衡解离常数,其用于描述抗体与抗原之间的结合亲和力。平衡解离常数越小,抗体-抗原结合越紧密,抗体与抗原之间的亲和力越高。例如,使用表面等离子体共振术(Surface PlasmonResonance,缩写SPR)在BIACORE仪中测定抗体与抗原的结合亲和力或使用ELISA测定抗体与抗原结合的相对亲和力。
本领域技术人员可以通过本领域熟知的技术对本发明的抗体或其抗原结合片段进行修饰,例如添加、缺失和/或取代一个或几个氨基酸残基,从而进一步改善或优化抗体或其抗原结合片段的性能(例如亲和力),并通过常规的测定方法获得修饰后的结果。
在本发明中,本发明的抗体或其抗原结合片段还包括其保守性变异体,指与本发明的抗体或其抗原结合片段氨基酸序列相比,有至多10个,较佳地至多7个,更佳地至多5个,最佳地至多3个氨基酸被性质相似或相近的氨基酸所替换而形成多肽。这些保守性变异多肽最好根据表A进行氨基酸替换而产生。
表A
最初的残基 | 代表性的取代 | 优选的取代 |
Ala(A) | Val;Leu;Ile | Val |
Arg(R) | Lys;Gln;Asn | Lys |
Asn(N) | Gln;His;Lys;Arg | Gln |
Asp(D) | Glu | Glu |
Cys(C) | Ser | Ser |
Gln(Q) | Asn | Asn |
Glu(E) | Asp | Asp |
Gly(G) | Pro;Ala | Ala |
His(H) | Asn;Gln;Lys;Arg | Arg |
Ile(I) | Leu;Val;Met;Ala;Phe | Leu |
Leu(L) | Ile;Val;Met;Ala;Phe | Ile |
Lys(K) | Arg;Gln;Asn | Arg |
Met(M) | Leu;Phe;Ile | Leu |
Phe(F) | Leu;Val;Ile;Ala;Tyr | Leu |
Pro(P) | Ala | Ala |
Ser(S) | Thr | Thr |
Thr(T) | Ser | Ser |
Trp(W) | Tyr;Phe | Tyr |
Tyr(Y) | Trp;Phe;Thr;Ser | Phe |
Val(V) | Ile;Leu;Met;Phe;Ala | Leu |
本发明的抗体或其抗原结合片段可以单独使用,也可与可检测标记物(为诊断目的)、治疗剂、或任何以上这些物质的组合结合或偶联。
本发明中的氨基酸序列或蛋白(多肽)结构均按从氨基端到羧基端的顺序给出。
本发明中,蛋白(多肽)结构中的“-”代表肽键。
编码核酸和表达载体
本发明还提供了编码上述抗体或其抗原结合片段的多核苷酸分子。本发明的多核苷酸可以是DNA形式或RNA形式。DNA形式包括cDNA、基因组DNA或人工合成的DNA。DNA可以是单链的或是双链的。DNA可以是编码链或非编码链。
本发明中,术语“表达载体”是指携带表达盒用于表达特定目的蛋白或其他物质的载体,如质粒、病毒载体(如腺病毒、逆转录病毒)、噬菌体、酵母质粒或其他载体。例如包含适当的调控序列,例如启动子、终止子、增强子等的本领域的常规表达载体,所述表达载体包括但并不限于:病毒载体(如腺病毒、逆转录病毒)、质粒、噬菌体、酵母质粒或其他载体。所述表达载体较佳地包括pDR1、pcDNA3.4(+)、pDHFR或pTT5。一旦获得了有关的序列,就可以用重组法来大批量地获得有关序列。这通常是将其克隆入载体,再转入细胞,然后通过常规方法从增殖后的宿主细胞中分离得到有关序列。本发明还涉及包含上述的适当DNA序列以及适当启动子或者控制序列的载体。这些载体可以用于转化适当的宿主细胞,以使其能够表达蛋白质。
本发明中,术语“宿主细胞”为本领域常规的各种宿主细胞,只要能使载体稳定地自行复制,且所携带的多核苷酸分子可被有效表达即可。其中所述宿主细胞包括原核表达细胞和真核表达细胞,所述宿主细胞较佳地包括:COS、CHO、NS0、sf9、sf21、DH5α、BL21(DE3)、TG1、BL21(DE3)、293F或293E细胞。
药物组合物和应用
本发明还提供了一种组合物。优选地,所述的组合物是药物组合物,它含有上述的抗体或其抗原结合片段,以及药学上可接受的载体。通常,可将这些物质配制于无毒的、惰性的和药学上可接受的水性载体介质中,其中pH通常约为4-8,较佳地pH约为5-8,5-7,或6-8,尽管pH值可随被配制物质的性质以及待治疗的病症而有所变化。配制好的药物组合物可以通过常规途径进行给药,其中包括(但并不限于):静脉注射、静脉滴注、皮下注射、局部注射、肌肉注射、瘤内注射、腹腔内注射(如腹膜内)、颅内注射、或腔内注射。
本发明中,术语“药物组合物”是指本发明的抗体或其抗原结合片段可以和药学上可以接受的载体一起组成药物制剂组合物,从而更稳定地发挥疗效。这些制剂可以保证本发明公开的蛋白质的氨基酸核心序列的构象完整性,同时还保护蛋白质的多官能团防止其降解(包括但不限于凝聚、脱氨或氧化)。
本发明的药物组合物含有安全有效量(如0.001-99wt%,较佳地0.01-90wt%,更佳地0.1-80wt%)的本发明上述的抗体或其抗原结合片段以及药学上可接受的载体。这类载体包括(但并不限于):盐水、缓冲液、葡萄糖、水、甘油、乙醇、及其组合。药物制剂应与给药方式相匹配。本发明的药物组合物可以被制成针剂形式,例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。药物组合物如针剂、溶液宜在无菌条件下制造。活性成分的给药量是治疗有效量,例如每天约10微克/千克体重-约50毫克/千克体重。此外,本发明的抗体或其抗原结合片段还可与其他治疗剂一起使用。
使用药物组合物时,是将安全有效量的抗体或其抗原结合片段施用于哺乳动物,其中该安全有效量通常至少约10微克/千克体重,而且在大多数情况下不超过约50毫克/千克体重,较佳地该剂量是约10微克/千克体重-约10毫克/千克体重。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明中,术语“有效量”是指本发明的药物组合物施用受试者后,在治疗的个体中产生预期效果的量或剂量,该预期效果包括个体病症的改善。术语“受试者”包括但不限于哺乳动物,例如人、非人灵长类动物、大鼠和小鼠等。
本发明的主要优点体现在:本发明的抗GUCY2C的单克隆抗体亲和力高、特异性强,特别是能有效识别肿瘤细胞表面的GUCY2C蛋白。从而有利于降低毒副反应,提高量效比,具有肿瘤靶向治疗的临床前景。
下面结合具体实施例,进一步陈述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明详细条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。
以下实施例涉及的序列信息总结在序列表表B中。
表B
本发明序列均采用Kabat系统编号规则。
实验材料
小鼠骨髓瘤细胞SP2/0:购自ATCC,货号CRL-1581。
Balb/c小鼠:购自上海灵畅生物科技有限公司。
HRP-羊抗鼠二抗:购自博奥龙免疫技术有限公司,货号BF03001-1ML。
驴抗鼠PE荧光二抗:购自Jackson,货号715-116-150。
羊抗人PE荧光二抗:购自Jackson,货号109-115-098。
HRP-山羊抗人IgG Fab二抗:购自Sigma,货号A0293-1ML。
HRP-山羊抗人IgG Fc二抗:购自Sigma,货号A0170-1ML。
96孔板(酶标板不可拆):购自costar,货号9018。
PBS缓冲液:购自上海源培生物科技有限公司,货号B320KJ。
TMB:购自KPL公司,货号52-00-03。
牛血清白蛋白(BSA):购自生工,货号A600332-0100。
RPMI 1640Medium:购自Gibco公司,货号61870127。
青霉素-链霉素(Penicillin-streptomycin):购自Gibco公司,货号15140122。
胎牛血清(FBS):购自Gibco公司,货号10091-148。
polyethylene glycol solution:购自sigma公司,货号P7181。
Hybridoma-SFM:购自life technologies,货号12045-076。
HAT:购自Gibco,货号21060017。
pcDNA 3.4:购自ThermoFisher,货号A14697。
HEK-293F:购自Thermo Fisher,货号A14527。
实施例1抗原免疫动物以及杂交瘤的制备和筛选
1.1抗原表达
通过常规的基因合成和分子克隆的方法将GUCY2C的胞外区基因(序列来自UniProt,登记号为P25092)构建到pcDNA 3.4表达载体中,并在其N端加上信号肽序列,C末端加上6×His标签,转染HEK-293F细胞,表达5d后,收集细胞培养上清并纯化获得GUCY2C-His蛋白。同样,将上述6×His标签换成人IgG1的Fc序列后转染HEK-293F细胞,表达纯化后获得GUCY2C-Fc蛋白。
1.2抗原免疫小鼠
用GUCY2C-His蛋白常规免疫Balb/c小鼠。第1天,可溶性人GUCY2C-His蛋白与弗氏完全佐剂乳化后,对Balb/c小鼠进行皮下多点注射(GUCY2C-His蛋白,100μg/鼠/0.5mL),第14天,可溶性人GUCY2C-His蛋白与弗氏不完全佐剂乳化后,对Balb/c小鼠进行皮下注射(GUCY2C-His蛋白,50μg/鼠/0.5mL),在第28天,可溶性人GUCY2C-His蛋白与弗氏不完全佐剂乳化后,对Balb/c小鼠进行皮下注射(GUCY2C-His蛋白,50μg/小鼠/0.5mL),三周后用可溶性人GUCY2C-His蛋白,按照50μg/小鼠/0.2mL,腹腔内注射激发,3-4天后,取小鼠脾脏进行融合实验。
1.3杂交瘤的制备和筛选
在小鼠末次免疫后3-4天,使用常规的杂交瘤技术方案,将小鼠脾细胞与小鼠骨髓瘤细胞SP2/0进行PEG融合。融合后的细胞在完全培养基中悬浮均匀,完全培养基为将RPMI1640-GLUMAX加入1%Penicillin-streptomycin和20%FBS,1*HAT组成的培养基。融合后的细胞按3×104个细胞/200μL/孔,共铺60块96孔培养板,于37℃,CO2培养箱中培养。在7-12天后,收获上清液,通过ELISA方法筛选人GUCY2C结合活性阳性的杂交瘤孔。
其中,ELISA方法筛选人GUCY2C结合活性阳性的杂交瘤孔的方法如下:将GUCY2C-Fc以PBS缓冲液稀释至1μg/mL,100μL/孔加入ELISA板中,4℃培养过夜。次日甩掉上清,然后加入用PBS配制的5%脱脂奶粉37℃封闭2h,PBST洗板3次待用。将收取的杂交瘤上清液依次加入封闭后的板中,100μL/孔,37℃放置1h。PBST洗板3次,加入HRP标记的羊抗鼠IgG二抗,37℃放置30min;PBST洗板3次后,在吸水纸上尽量拍干残留液滴,每孔加入100μL的TMB,室温避光显色5min;每孔加入50μL2M H2SO4终止液终止底物反应,于多功能酶标仪450nm处读取OD值,分析待测抗体与靶抗原GUCY2C结合能力。通过融合筛选共计拿到18株杂交瘤细胞株。将上述在含血清完全培养基中扩增筛选获得的18株杂交瘤细胞株,离心换液至无血清培养液Hybridoma-SFM培养基,使细胞密度为1~2×107/mL,在8%CO2、37℃条件下培养1周,离心获取培养上清,通过Protein G亲和层析进行纯化,得到抗人GUCY2C单克隆抗体蛋白。
实施例2鼠源抗体对人GUCY2C-Fc蛋白的结合能力
间接酶联免疫吸附测定法(ELISA)测定实施例1获得的鼠源抗体对人GUCY2C-Fc蛋白的结合能力。具体方法如下:
GUCY2C-Fc蛋白以包被液(50mM的碳酸盐包被缓冲液,pH 9.6)稀释至1μg/mL包被ELISA板,4℃,过夜;然后用PBS配制5%的脱脂奶粉封闭,37℃孵育2h;PBST洗板3次后,将上述制备的抗人GUCY2C抗体蛋白以PBS配制的1%BSA缓冲液从10μg/mL,按照3倍梯度稀释11个梯度,随后100μL/孔加入预包被的GUCY2C-Fc的ELSIA板子中,37℃孵育1h;PBST洗板3次,加入HRP标记的羊抗鼠IgG二抗,37℃放置30min;PBST洗板3次后,在吸水纸上尽量拍干残留液滴,每孔加入100μL的TMB,室温避光显色5min,每孔加入50μL 2M H2SO4终止液终止底物反应,于多功能酶标仪450nm处读取OD值,分析待测抗体与靶抗原人GUCY2C-Fc的结合能力,结果如图1所示。各杂交瘤抗体与GUCY2C-Fc结合的EC50如表1所示。可见,32H2G1A1对GUCY2C-Fc的亲和力最强。
表1:各杂交瘤抗体与GUCY2C-Fc结合的EC50
样品 | EC50(ng/mL) | 样品 | EC50(ng/mL) |
45E8F6B11 | 1.659 | 37A11E5 | 31.97 |
31C62F11 | 8.469 | 48H7F8 | 76.4 |
55G7A7H2 | 21.55 | 50C9F2B8 | 198.1 |
60C8D2C1 | 28.88 | 19D9B9H3 | 899.3 |
43D11B1D2 | 18.03 | 32H2G1A1 | 7.089 |
4G12A4G6 | 13.37 | 49F2B8B8 | 63.05 |
8C7A4 | 2837 | 206E8E6 | 14.03 |
10D7A7 | 30.72 | 208D1B7 | 11.85 |
19B2F2H4 | 7833988 | 21E12B4 | 62.03 |
实施例3鼠源抗体对人结肠癌细胞CW2的结合能力
采用流式细胞术检测鼠源抗体对人结肠癌细胞CW2的结合活性,具体方法如下:
收集CW2细胞,离心去除细胞培养液,用PBS缓冲液洗2遍;计数并用含1%BSA的FACS缓冲液稀释至2×106细胞/mL,铺细胞至96孔圆底板中待用,100μL/孔;待测抗体以PBS配制的1%BSA缓冲液从10μg/mL,按照3倍稀释11个梯度加入到上述细胞圆底板中,4℃孵育1h;离心后,甩掉上清,用1%BSA的FACS缓冲液洗涤3遍,按1:500比例(详见荧光二抗说明书)每孔加入100μL的驴抗鼠PE荧光二抗,4℃,孵育1h;1%BSA的FACS缓冲液洗涤3遍,再用1%BSA的FACS缓冲液重悬,200μL/孔,使用BD FACSCelesta来测定分析样品,所示抗体结合细胞结果见图2。各样品对CW2细胞结合的EC50见表2。可见,10D7A7对CW2细胞的结合活性稍强。
表2:各杂交瘤抗体与CW2结合的EC50
样品 | EC50(ng/mL) | 样品 | EC50(ng/mL) |
45E8F6B11 | 574.2 | 37A11E5 | 8089 |
31C62F11 | 417.3 | 48H7F8 | 3985 |
55G7A7H2 | 6273 | 50C9F2B8 | 77.95 |
60C8D2C1 | 945.5 | 19D9B9H3 | 1127 |
43D11B1D2 | 364.7 | 32H2G1A1 | 9604 |
4G12A4G6 | 123 | 49F2B8B8 | 11656 |
8C7A4 | 7469 | 206E8E6 | 680.3 |
10D7A7 | 137.2 | 208D1B7 | 635.2 |
19B2F2H4 | 1490 | 21E12B4 | 3421 |
实施例4鼠源抗体对人GUCY2C-His蛋白的结合活性
用ELISA包被液将GUCY2C-His蛋白稀释至0.1μg/mL,包被ELISA板,100μL/孔,置于4℃,包被过夜。用PBST洗涤ELISA板三次,去除未结合抗原,并将ELISA板于吸水纸上拍干,除去多余的液体,然后用PBS配制2%BSA,200μL/孔,于室温封闭2h。用PBST洗涤三次,洗除多余的封闭液,并将ELISA板拍干,除去多余的液体,用PBST配制的1%BSA按3倍梯度分别稀释各单克隆抗体,最高浓度为200nM,稀释12个梯度,加入ELISA孔,100μL/孔,室温孵育1h,每个样品平行做2个复孔。洗除未结合的或非特异性结合的一抗,用抗体稀释液将HRP标记的抗鼠的二抗稀释至合适浓度(1:3000稀释),加入ELISA板,100μL/孔,室温孵育1h。用PBST洗涤三次,并将ELISA板于吸水纸上拍干,除去多余的液体,加入TMB显色液,100μL/孔,显色5min,每孔加入2M H2SO4,50μL/孔,以终止显色,并于多功能酶标仪中在450nm波长处测定其吸光度,分析数据。
实验结果如图3和图4所示,55G7A7H2和32H2G1A1对GUCY2C-His的亲和力较高,43D11B1D2、10D7A7和37A11E5次之,各样品对GUCY2C-His结合的EC50值如表3和表4所示。
表3:各杂交瘤抗体与GUCY2C-His结合的EC50
样品 | EC50(nM) |
43D11B1D2 | 0.99 |
45E8F6B11 | 17.89 |
31C6-2F11 | 9.07 |
4G12A4G6 | 5.83 |
60C8D2C1 | \ |
55G7A7H2 | 0.12 |
表4:各杂交瘤抗体与GUCY2C-His结合的EC50
样品 | EC50(nM) |
208D1B7 | \ |
206E8E6 | \ |
4G12A4G6 | 13.56 |
32H2G1A1 | 0.26 |
37A11E5 | 0.81 |
10D7A7 | 0.80 |
实施例5杂交瘤抗体可变区基因获取及嵌合抗体的制备
本实施例通过分子生物学的相关方法获取杂交瘤55G7A7H2、32H2G1A1、43D11B1D2、10D7A7、37A11E5的重链可变区和轻链可变区,并进一步构建嵌合抗体。
通过Trizol提取55G7A7H2、32H2G1A1、43D11B1D2、10D7A7、37A11E5五个杂交瘤细胞的RNA并进行mRNA反转录获取cDNA,随后以cDNA为模板,分别用鼠源抗体的重链和轻链简并引物(参见《Antibody Engineering》Volume 1,Edited by Roland Kontermann andStefan Dübel,组合引物的序列来自第323页)进行PCR,对所获得的PCR产物进行测序并通过IMGT数据库分析,确定所获得的序列为鼠源抗体的可变区序列。相关序列信息总结在序列表中。
对所得的各杂交瘤重链可变区序列与人的IgG1恒定区拼接,轻链可变区序列与人的kappa链恒定区拼接,分别构建各嵌合抗体的重链和轻链至pcDNA3.4表达载体,转染HEK-293F细胞表达并纯化获得各嵌合抗体,分别命名为55G7-ch、32H2-ch、43D11-ch、10D7-ch、37A11-ch。
实施例6嵌合抗体对人GUCY2C-His蛋白的结合活性
参照实施例4方法测定嵌合抗体对GUCY2C-His的结合能力,其中二抗使用HRP标记抗人IgG Fc的二抗,实验结果如图5所示,32H2-ch、10D7-ch和43D11-ch均能与GUCY2C-His结合,说明我们钓取到正确的可变区基因,并且32H2-ch和10D7-ch对GUCY2C-His的亲和力明显优于43D11-ch,EC50分别为0.141nM、0.113nM和5.187nM。
实施例7人源化抗体的构建和制备
对各候选鼠源抗体轻链可变区和重链可变区的氨基酸序列进行分析,依据Kabat规则确定鼠源抗体的32H2G1A1和10D7A7的抗原互补决定区(CDR)和4个框架区(FR)。
在Germline数据库中选取与上述各鼠源抗体可变区匹配最好的人源化模板。然后将鼠源抗体的CDR区移植到所选择的人源化模板上,替换人源模板的CDR区,重链可变区再与人IgG1恒定区重组,轻链可变区与人的kappa链恒定区重组,同时以该抗体的三维结构为基础,对包埋残基、与CDR区有直接相互作用的残基,以及对各抗体的VL和VH的构象有重要影响的残基进行回复突变,最终获得多个人源化抗体,分别构建各人源化抗体的重链和轻链至pcDNA3.4表达载体,转染HEK-293F细胞表达并纯化获得各人源化抗体。
表5:各人源化抗体可变区序列表
实施例8人源化抗体对人GUCY2C-His蛋白的结合活性
参照实施例6方法测定各人源化抗体对GUCY2C-His的结合能力,实验结果如图6所示,人源化抗体32H2-Hu和32H2-HuG对GUCY2C-His有较高的亲和力,10D7-Hu和10D7-HuG次之,其各自的EC50值详见表6。
表6:各人源化抗体对GUCY2C-His结合的EC50
样品 | EC50(nM) |
10D7-Hu | 2.051 |
10D7-HuG | 1.483 |
32H2-Hu | 0.468 |
32H2-HuG | 0.746 |
实施例9人源化抗体对人GUCY2C-Fc蛋白的结合活性
参照实施例2方法测定各人源化抗体对GUCY2C-Fc的结合能力,其中二抗使用HRP标记抗人IgG Fab的二抗,实验结果如图7所示,人源化抗体32H2-Hu和10D7-HuG对GUCY2C-Fc有较高的亲和力,32H2-HuG和10D7-Hu稍弱,其各自的EC50值详见表7。
表7:各人源化抗体对GUCY2C-Fc结合的EC50
实施例10.人源化抗体对人GUCY2C过表达肿瘤细胞的结合活性
参照实施例3测定人源化抗体对人GUCY2C过表达肿瘤细胞CW2-GCC#1(通过表达GUCY2C基因的慢病毒感染CW2细胞和单克隆化筛选法获得的GUCY2C高度表达的细胞株)的结合亲和力,实验结果如图8所示,32H2-Hu和32H2-HuG可有效的与CW2-GCC#1细胞结合,其EC50分别为96.32nM和80.47nM,明显优于10D7-Hu和10D7-HuG。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 丹生医药技术(上海)有限公司
<120> 一种抗GUCY2C抗体或其抗原结合片段及其用途
<160> 68
<170> SIPOSequenceListing 1.0
<210> 1
<211> 348
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 1
caggtccagc tgcagcagtc tggggctgac ctggcaagac ctggggcctc agtgaagatg 60
tcctgcaagg cttctggcta cacctttact agctacacga tgcactgggt aaaacagagg 120
cctggacagg gtctggaatg gattggatac attaatccta gcagtggtta tactaattac 180
aatcagaagt tccaggacaa ggccacattg actgcagaca aatcctccag cacagcctac 240
atgcaactga gcagcctgac atctgaggac tctgcagtct attactgtgc aagattggga 300
aggatcggcg tgtactgggg ccaaggcacc actcttacag tctcctcc 348
<210> 2
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Gln Val Gln Leu Gln Gln Ser Gly Ala Asp Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Gln Asp 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 Tyr Cys
85 90 95
Ala Arg Leu Gly Arg Ile Gly Val Tyr Trp Gly Gln Gly Thr Thr Leu
100 105 110
Thr Val Ser Ser
115
<210> 3
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Ser Tyr Thr Met His
1 5
<210> 4
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Gln
1 5 10 15
Asp
<210> 5
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Leu Gly Arg Ile Gly Val Tyr
1 5
<210> 6
<211> 318
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
caaattgttc tctcccagtc tccagcaatc ctgtctgcat ttccagggga aaaggtcaca 60
ctgacttgca gggccagctc aagtgtaagt ttcatacact ggtaccagca gaagccagga 120
tcctccccca aaccctggat ttatgccaca tccaacctgg cttctggagt ccctgatcgc 180
ttcagtggca gtgggtctgg gacctctttc tctttcacaa tcagcagagt ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg agtagtaacc cgtggacgtt cggtggaggc 300
accaagctgg aaatcaag 318
<210> 7
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Phe Pro Gly
1 5 10 15
Glu Lys Val Thr Leu Thr Cys Arg Ala Ser Ser Ser Val Ser Phe Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Phe Ser Phe Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 8
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Arg Ala Ser Ser Ser Val Ser Phe Ile His
1 5 10
<210> 9
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Ala Thr Ser Asn Leu Ala Ser
1 5
<210> 10
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Gln Gln Trp Ser Ser Asn Pro Trp Thr
1 5
<210> 11
<211> 351
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
gaagtgatgc tggtggagtc tgggggagac ttggtgaagc ctggagggtc cctgaaactc 60
tcctgtgcag cctctggatt cagtttcagg acctatgcca tgtcttgggt tcgccagagt 120
ccggagaaga gtctggagtg ggtcgcaacc attagtagtg gtagtagtta catttactat 180
ccagacagtg tgaaggggcg attcaccgtt ttcagagaca atgccaagaa taccctgtac 240
ctgcaaatga gcagtctgag gtctgaggac tcggccattt attactgtac atgttataga 300
atggaaactt ttgagtactg gggccaaggc accactctca cagtctcctc a 351
<210> 12
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Glu Val Met 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 Ser Phe Arg Thr Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ser Pro Glu Lys Ser Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Ser Ser Tyr Ile Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Val Phe Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Thr Cys Tyr Arg Met Glu Thr Phe Glu Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 13
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Thr Tyr Ala Met Ser
1 5
<210> 14
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Thr Ile Ser Ser Gly Ser Ser Tyr Ile Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 15
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Tyr Arg Met Glu Thr Phe Glu Tyr
1 5
<210> 16
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 16
gatgttgtga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tgaagcctcc 60
atctcttgta gatctagtca gagccttgta tacaataatg gaaacaccta tttacattgg 120
tacctgcaga agccaggcca gtctccaaag ctcctaatct acaaagtttc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt gggtcaggga cagatttcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tatttctgct ctcaaagtac acatgttccg 300
ctcacgttcg gtgctgggac caagctggaa ctgaaa 336
<210> 17
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Glu Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Asn
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 18
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Arg Ser Ser Gln Ser Leu Val Tyr Asn Asn Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 19
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 20
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Ser Gln Ser Thr His Val Pro Leu Thr
1 5
<210> 21
<211> 357
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 21
gacgtgaaac tcgtggagtc tgggggagtc ttagtgaagc ttggagggtc cctgaaactc 60
tcctgtgcag cctctggatt cactttcagt ggctatttca tgtcttgggt tcgccagact 120
ccagagaaga ggctggagtt ggtcgcagcc attaatagtg atggtggtag cacctactat 180
ccagacactg tgaagggccg attcaccatc tccagagaca atgccaaaaa caccctctac 240
ctgcaaatga gcagtctgaa gtctgaggac acggccttat attactgtgc aagacttgca 300
aggtacctct atgctatgga ctactggggt caaggaacct cagtcaccgt ctcctca 357
<210> 22
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Asp Val Lys Leu Val Glu Ser Gly Gly Val Leu Val Lys Leu Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr
20 25 30
Phe Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Leu Val
35 40 45
Ala Ala Ile Asn Ser Asp Gly Gly Ser Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Leu Ala Arg Tyr Leu Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 23
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Gly Tyr Phe Met Ser
1 5
<210> 24
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Ala Ile Asn Ser Asp Gly Gly Ser Thr Tyr Tyr Pro Asp Thr Val Lys
1 5 10 15
Gly
<210> 25
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Leu Ala Arg Tyr Leu Tyr Ala Met Asp Tyr
1 5 10
<210> 26
<211> 318
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 26
caaattgttc tcacccagtc tccagcaatc atgtctgcat ctccagggga gaaggtcacc 60
atgacctgca gtgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccagga 120
tcctccccca gactcctgat ttatgacaca tccaacctgg cttctggagt ccctgttcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagccgaat ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg actagttctt catggacgtt cggtggaggc 300
accaagctgg aaatcaaa 318
<210> 27
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Ser Ser Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 28
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Ser Ala Ser Ser Ser Val Ser Tyr Met Tyr
1 5 10
<210> 29
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Asp Thr Ser Asn Leu Ala Ser
1 5
<210> 30
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Gln Gln Trp Thr Ser Ser Ser Trp Thr
1 5
<210> 31
<211> 357
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 31
caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60
acctgcacag tctctggttt ctcattaact aactatggtg tacactgggt tcgccagtct 120
ccaggaaagg gtctggagtg gctgggagtg atatggagtg gtggaaggaa agactataat 180
gcagctttca tatccagact gaacatcacc aaggacaatt ccaagagtca agttttcttt 240
acaatgaaca gtctgcattc tgatgacaca gccatatact actgtgccag acatggcacc 300
tacccttact ggtacttcgc tctctggggc gcagggacct cggtcaccat ctcctca 357
<210> 32
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Arg Lys Asp Tyr Asn Ala Ala Phe Ile
50 55 60
Ser Arg Leu Asn Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Thr Met Asn Ser Leu His Ser Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg His Gly Thr Tyr Pro Tyr Trp Tyr Phe Ala Leu Trp Gly Ala Gly
100 105 110
Thr Ser Val Thr Ile Ser Ser
115
<210> 33
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Asn Tyr Gly Val His
1 5
<210> 34
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Val Ile Trp Ser Gly Gly Arg Lys Asp Tyr Asn Ala Ala Phe Ile Ser
1 5 10 15
<210> 35
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
His Gly Thr Tyr Pro Tyr Trp Tyr Phe Ala Leu
1 5 10
<210> 36
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 36
gatatccaaa tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcacc 60
atcagttgca gggcaagtca ggacatcagt aattatttaa actggtatca gcagaaacca 120
gatggaactt ttaaactcct ggtctactac acatcaagat tacagtcagg ggtcccatca 180
aggttcagtg gcagtgggtc tggaacactt tattctctca ccattagcac cctggagcaa 240
gaggatgttg ccacttactt ttgccaacag ggtaaaacgc ttccgttttc gttcggtgga 300
ggcaccaggc tggaaatcaa a 321
<210> 37
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe Lys Leu Leu Val
35 40 45
Tyr Tyr Thr Ser Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Leu Tyr Ser Leu Thr Ile Ser Thr Leu Glu Gln
65 70 75 80
Glu Asp Val Ala Thr Tyr Phe Cys Gln Gln Gly Lys Thr Leu Pro Phe
85 90 95
Ser Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 38
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 39
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
Tyr Thr Ser Arg Leu Gln Ser
1 5
<210> 40
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
Gln Gln Gly Lys Thr Leu Pro Phe Ser
1 5
<210> 41
<211> 360
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 41
caggttcagg tgcagcagtc tggagttgaa ctgatgaagc ctggggcctc agtgaagata 60
tcctgcaagg ctactggcta ctcattcagt tcttactgga tagagtgggt aaagcagagg 120
cctggacatg gccttgagtg gattggagag atttttcctg gaagtgggac tactacctac 180
aatgagaagt tcaaggacaa ggccacattc actgcagaca catcctccaa cacagcctac 240
atgcaactca gcagcctgac atctgaggac tctgccgtct attattgtgc aaagggtaaa 300
attacgacat actgggtctt cgatgtctgg ggcgcaggga ccacggtcac cgtctcctca 360
<210> 42
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
Gln Val Gln Val Gln Gln Ser Gly Val Glu Leu Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Thr Gly Tyr Ser Phe Ser Ser Tyr
20 25 30
Trp Ile Glu Trp Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Phe Pro Gly Ser Gly Thr Thr Thr Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Lys Ala Thr Phe Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Lys Ile Thr Thr Tyr Trp Val Phe Asp Val Trp Gly Ala
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 43
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 43
Ser Tyr Trp Ile Glu
1 5
<210> 44
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 44
Glu Ile Phe Pro Gly Ser Gly Thr Thr Thr Tyr Asn Glu Lys Phe Lys
1 5 10 15
Asp
<210> 45
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 45
Gly Lys Ile Thr Thr Tyr Trp Val Phe Asp Val
1 5 10
<210> 46
<211> 318
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 46
caaattgttc tctcccagtc tccagcaatc ctgtctgcat ctccagggga gaaggtcaca 60
atgacttgca gggccagctc aagtgtaagt tacatgcact ggtaccagca gaagccagga 120
tcctccccca aaccctggat ttatgccaca tccaacctgg cttctggagt ccctgctcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagagt ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg agtagtaacc cacggacgtt cggtggaggc 300
accaagctgg aaatcaaa 318
<210> 47
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 47
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Arg Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 48
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 48
Arg Ala Ser Ser Ser Val Ser Tyr Met His
1 5 10
<210> 49
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 49
Ala Thr Ser Asn Leu Ala Ser
1 5
<210> 50
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 50
Gln Gln Trp Ser Ser Asn Pro Arg Thr
1 5
<210> 51
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 51
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 Thr Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Ser Gly Ser Ser Tyr Ile Tyr Tyr Pro 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 Tyr Arg Met Glu Thr Phe Glu Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 52
<211> 351
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 52
gaggtgcagc tggtggagag cggcggcggt ctggtgaagc ctggaggctc tctgagactg 60
tcttgtgctg cctctggctt tacctttagc acctatgcca tgagctgggt gcggcaggcc 120
cccggcaagg gcctggagtg ggtgagcacc atctcttctg gttcttctta tatctattat 180
cctgattctg tgaagggaag attcaccatc tctagagata atgctaagaa tagtctgtat 240
ctgcagatga atagtctgag agctgaggat acagccgtgt attattgtgc tagatataga 300
atggagacct ttgagtattg gggccagggc accctggtga ccgtgagtag t 351
<210> 53
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 53
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 Ser Phe Arg Thr Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Ser Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Ser Ser Tyr Ile Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Val 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
Thr Cys Tyr Arg Met Glu Thr Phe Glu Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 54
<211> 351
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 54
gaggtgcagc tggtggaatc cggcggaggc ctggtgaaac caggcggcag cctgagactg 60
tcctgtgctg ctagcggttt ttcctttaga acttacgcta tgagctgggt gagacaggcc 120
ccaggaaagt ctctcgaatg ggtggccaca attagtagcg gcagtagcta catctactac 180
cctgactccg tgaagggccg gtttaccgtg agccgcgata acgccaagaa ctccctgtac 240
ctgcagatga acagcctgcg cgccgaggac accgccgtgt actactgcac ctgctaccga 300
atggagacct tcgagtactg gggccagggc accctggtga ccgtgagcag c 351
<210> 55
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 55
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Asn
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 56
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 56
gatgtggtca tgacccagtc tccactgtcc ctgcctgtga ccctgggcca gcccgcttct 60
atctcttgta gatcttctca gtctctggtg tataataatg gaaataccta tctgcattgg 120
ttccagcaga gacctggaca gtctcctaga aggctgatct ataaggtgtc taacaggttt 180
tctggcgtgc ctgatagatt ttctggctct ggatctggca cagattttac cctgaagatc 240
tctagagtgg aggctgagga tgtgggcgtg tattattgtt ctcagagcac acacgtgcca 300
ctgacatttg gccagggcac aaaggtggaa attaag 336
<210> 57
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 57
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Asn
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 58
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 58
gacgttgtga tgacacagtc tcctctgtcc ctgccagtga ccctgggaca gcctgcttct 60
atctcttgta gatcttctca gtctctggtg tacaataatg gaaacacata cctgcactgg 120
taccagcaga gacctggaca gtcccctaga ctgctgatct acaaggtgag taatagattt 180
tctggagtgc ctgatcggtt tagcggctct ggctctggca ccgattttac actgaagatc 240
tctagagtgg aggccgagga tgtgggcgtg tacttttgct cccagagcac acacgtgcct 300
ctgacctttg gacagggaac caaggtggag attaag 336
<210> 59
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 59
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Ser Gly Gly Arg Lys Asp Tyr Asn Ala Ala Phe Ile
50 55 60
Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg His Gly Thr Tyr Pro Tyr Trp Tyr Phe Ala Leu Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 60
<211> 357
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 60
caggtgcagc tggtggagtc tggcggcggc gtggtgcagc ctggaaggag tctgagactg 60
agttgtgccg ccagcggatt caccttctct aactatggag tgcattgggt gaggcaggct 120
cctggaaagg gcctggagtg ggtggccgtg atttggtctg gcggaagaaa ggattataat 180
gccgccttta tttcaagatt caccatcagc cgcgataaca gcaagaacac cctgtacctg 240
cagatgaaca gcctgagggc tgaggacacc gccgtgtatt actgcgccag gcacgggacc 300
tacccttact ggtacttcgc cctgtggggc cagggcaccc tggtgaccgt gtctagc 357
<210> 61
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 61
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Arg Lys Asp Tyr Asn Ala Ala Phe Ile
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Ser Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg His Gly Thr Tyr Pro Tyr Trp Tyr Phe Ala Leu Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 62
<211> 357
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 62
caggtgcagc tggtggagtc cggcggcggc gtggtgcagc ctggcagatc tctgaggctg 60
agttgtgctg tgagtggctt cacattttct aactatggcg tgcactgggt gagacaggcc 120
cctggaaagg gactggagtg gctgggagtg atctggtccg gaggaagaaa agattataat 180
gctgccttta tttctaggct gacaattagt aaggataatt ctaagtctac cgtgtatctg 240
cagatgaata gtctgagggc tgaggacaca gccgtgtatt actgcgctag acatggaaca 300
tatccttatt ggtattttgc cctgtgggga cagggcaccc ttgtgaccgt gagctct 357
<210> 63
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 63
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Lys Thr Leu Pro Phe
85 90 95
Ser Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 64
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 64
gatatccaga tgacccagtc tcctagctct ctgtctgctt ctgtgggaga tagagtgacc 60
attacatgta gagcttctca ggatatctcc aattatctga attggtatca gcagaaacca 120
ggcaaggccc caaagctgct gatctactat acatctagac tgcagagcgg cgtgccatcc 180
aggttttctg gctccggatc tggaacagat tttaccttta ccattagctc tctgcagcct 240
gaggatatcg ctacatatta ttgtcagcag ggcaagacac tgcctttttc ttttggccag 300
ggcaccaaag tggagatcaa g 321
<210> 65
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 65
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Thr Phe Lys Leu Leu Val
35 40 45
Tyr Tyr Thr Ser Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Lys Thr Leu Pro Phe
85 90 95
Ser Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 66
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 66
gatatccaga tgacacagtc tccttcctct ctgtctgcct ctgtgggcga tagggtgaca 60
atcacatgta gagcttctca ggatatctcc aattatctga attggtacca gcagaaacct 120
ggcaagacct ttaagctgct ggtgtactat acctccagac tgcagtctgg agtgccatct 180
agattttctg gctctggctc tggaaccgac tacaccttta ccatctctag cctgcagcct 240
gaagatatcg ctacctattt ttgtcagcag ggcaagactc tgccttttag cttcggccag 300
ggaaccaagg tggagatcaa g 321
<210> 67
<211> 330
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 67
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 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 68
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 68
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
Claims (17)
1.一种抗GUCY2C的抗体或其抗原结合片段,包含重链互补决定区HCDR1-3和轻链互补决定区LCDR1-3。
2.如权利要求1所述的抗GUCY2C的抗体或其抗原结合片段,其特征在于:
a)所述HCDR-1氨基酸序列如SEQ ID NO:3所示,所述HCDR-2氨基酸序列如SEQ ID NO:4所示,所述HCDR-3氨基酸序列如SEQ ID NO:5所示;所述LCDR-1氨基酸序列如SEQ ID NO:8所示,所述LCDR-2氨基酸序列如SEQ ID NO:9所示,所述LCDR-3氨基酸序列如SEQ ID NO:10所示;或,
b)所述HCDR-1氨基酸序列如SEQ ID NO:13所示,所述HCDR-2氨基酸序列如SEQ ID NO:14所示,所述HCDR-3氨基酸序列如SEQ ID NO:15所示;所述LCDR-1氨基酸序列如SEQ IDNO:18所示,所述LCDR-2氨基酸序列如SEQ ID NO:19所示,所述LCDR-3氨基酸序列如SEQ IDNO:20所示;或,
c)所述HCDR-1氨基酸序列如SEQ ID NO:23所示,所述HCDR-2氨基酸序列如SEQ ID NO:24所示,所述HCDR-3氨基酸序列如SEQ ID NO:25所示;所述LCDR-1氨基酸序列如SEQ IDNO:28所示,所述LCDR-2氨基酸序列如SEQ ID NO:29所示,所述LCDR-3氨基酸序列如SEQ IDNO:30所示;或,
d)所述HCDR-1氨基酸序列如SEQ ID NO:33所示,所述HCDR-2氨基酸序列如SEQ ID NO:34所示,所述HCDR-3氨基酸序列如SEQ ID NO:35所示;所述LCDR-1氨基酸序列如SEQ IDNO:38所示,所述LCDR-2氨基酸序列如SEQ ID NO:39所示,所述LCDR-3氨基酸序列如SEQ IDNO:40所示;或,
e)所述HCDR-1氨基酸序列如SEQ ID NO:43所示,所述HCDR-2氨基酸序列如SEQ ID NO:44所示,所述HCDR-3氨基酸序列如SEQ ID NO:45所示;所述LCDR-1氨基酸序列如SEQ IDNO:48所示,所述LCDR-2氨基酸序列如SEQ ID NO:49所示,所述LCDR-3氨基酸序列如SEQ IDNO:50所示。
3.如权利要求1或2所述的抗GUCY2C的抗体或其抗原结合片段,其特征在于,包含重链可变区VH和轻链可变区VL,其中:
a)VH的氨基酸序列如SEQ ID NO:2所示,VL的氨基酸序列如SEQ ID NO:7所示;或,
b)VH的氨基酸序列如SEQ ID NO:12所示,VL的氨基酸序列如SEQ ID NO:17所示;或,
c)VH的氨基酸序列如SEQ ID NO:22所示,VL的氨基酸序列如SEQ ID NO:27所示,或,
d)VH的氨基酸序列如SEQ ID NO:32所示,VL的氨基酸序列如SEQ ID NO:37所示;或,
e)VH的氨基酸序列如SEQ ID NO:42所示,VL的氨基酸序列如SEQ ID NO:47所示。
4.如权利要求1或2所述的抗GUCY2C的抗体或其抗原结合片段,其特征在于,包含重链可变区VH或其变体和轻链可变区VL或其变体,其中:
a)VH的氨基酸序列如SEQ ID NO:51所示,VL的氨基酸序列如SEQ ID NO:55所示;或,
b)VH的氨基酸序列如SEQ ID NO:51所示,VL的氨基酸序列如SEQ ID NO:57所示;或,
c)VH的氨基酸序列如SEQ ID NO:53所示,VL的氨基酸序列如SEQ ID NO:55所示;或,
d)VH的氨基酸序列如SEQ ID NO:53所示,VL的氨基酸序列如SEQ ID NO:57所示;或,
e)VH的氨基酸序列如SEQ ID NO:59所示,VL的氨基酸序列如SEQ ID NO:63所示;或,
f)VH的氨基酸序列如SEQ ID NO:61所示,VL的氨基酸序列如SEQ ID NO:63所示;或,
g)VH的氨基酸序列如SEQ ID NO:61所示,VL的氨基酸序列如SEQ ID NO:65所示,或,
h)VH的氨基酸序列如SEQ ID NO:59所示,VL的氨基酸序列如SEQ ID NO:65所示。
5.如权利要求4所述的抗GUCY2C的抗体或其抗原结合片段,其特征在于,
所述VH区变体是指与SEQ ID NO:51、SEQ ID NO:53、SEQ ID NO:59、SEQ ID NO:61具有至少90%、95%、98%、或99%的氨基酸序列同源性的变体;所述VL区变体是指与SEQ IDNO:55、SEQ ID NO:57、SEQ ID NO:63、SEQ ID NO:65具有至少90%、95%、98%、或99%的氨基酸序列同源性的变体。
6.如权利要求4所述的抗GUCY2C的抗体或其抗原结合片段,其特征在于,所述VH区或VL区包括1-10个氨基酸突变;优选的,所述突变是取代突变。
7.如权利要求1所述的抗GUCY2C的抗体或其抗原结合片段,其特征在于,包含重链恒定区和轻链恒定区;优选的,所述重链恒定区选自人IgG1、人IgG2、人IgG3或人IgG4,所述轻链恒定区选自人κ(Kappa)或人λ(Lambda)。
8.如权利要求7所述的抗GUCY2C的抗体,其特征在于,所述人IgG1重链恒定区包含如SEQ ID NO:67所示的氨基酸序列,所述人κ轻链恒定区包含如SEQ ID NO:68所示的氨基酸序列。
9.一种多核苷酸分子,其特征在于,所述多核苷酸分子编码如权利要求1-8任一项所述的抗GUCY2C的抗体或其抗原结合片段。
10.一种表达载体,其特征在于,所述表达载体含有如权利要求9所述的多核苷酸分子。
11.一种宿主细胞,其特征在于,所述宿主细胞含有如权利要求10所述的表达载体。
12.一种如权利要求1-8任一项所述的抗GUCY2C的抗体或其抗原结合片段的制备方法,其特征在于,所述制备方法包括以下步骤:
a)在表达条件下,培养如权利要求11所述的宿主细胞,从而表达抗GUCY2C的抗体或其抗原结合片段;
b)分离并纯化步骤a)所述的抗GUCY2C的抗体或其抗原结合片段。
13.一种药物组合物,其特征在于,所述药物组合物包含有效量的如权利要求1-8任一项所述的抗GUCY2C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体。
14.如权利要求1-8任一项所述的抗GUCY2C的抗体或其抗原结合片段,或如权利要求13所述的药物组合物在制备治疗癌症的药物中的用途。
15.如权利要求14所述的用途,其特征在于,所述癌症为GUCY2C相关癌症;优选的,所述癌症GUCY2C异常表达。
16.如权利要求14或15所述的用途,其特征在于,所述癌症为胃肠道肿瘤或胰腺癌;优选的,所述胃肠道肿瘤选自直肠癌、结肠癌、小肠癌、胃癌、食管癌和胃-食管交界部癌;更优选的,所述胃肠道肿瘤为恶性肿瘤。
17.一种免疫偶联物,其特征在于,所述免疫偶联物包括:
a)如权利要求1-8任一项所述的抗GUCY2C的抗体或其抗原结合片段;和b)选自下组的偶联部分:可检测标记物、药物、毒素、细胞因子、放射性核素、或酶。
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CN116574187B (zh) * | 2023-07-07 | 2024-03-08 | 浙江时迈药业有限公司 | 针对gucy2c的抗体及其用途 |
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