CN116964100A - Gucy2c结合多肽及其用途 - Google Patents
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- Gastroenterology & Hepatology (AREA)
Abstract
本公开涉及一种GUCY2C结合多肽及其用途,并且具体而言涉及一种GUCY2C结合多肽、包含所述GUCY2C结合多肽的融合蛋白、嵌合抗原受体、表达所述嵌合抗原受体的免疫细胞及其用于治疗和/或诊断癌症的用途。
Description
技术领域
与相关申请的交叉引用
本申请要求基于2021年4月7日提交的韩国专利申请号10-2021-0045510的优先权利益,并且在相应的韩国专利申请的文件中公开的内容作为一部分并入本说明书。
本申请涉及一种GUVY2C结合多肽及其用途,并且具体而言,涉及一种GUCY2C结合多肽、包含所述多肽的融合蛋白、嵌合抗原受体、表达嵌合抗原受体的免疫细胞及其治疗和/或诊断癌症的用途。
背景技术
GUCY2C(鸟苷酸环化酶2C;鸟苷酰基环化酶C;GC-C或GCC)是一种跨膜细胞表面受体,其作用于肠液、电解质稳态和细胞增殖的维持等。在正常成年哺乳动物中,GUCY2C在覆盖小肠、大肠和直肠内壁的黏膜细胞中表达。这些细胞经历增殖、迁移、分化和凋亡的循环,并且增殖与凋亡之间的失衡可能在胃肠道中诱导肿瘤的形成。
发明内容
技术问题
因此,在本说明书中,提供了一种新的GUCY2C结合多肽、包含所述多肽的融合蛋白及其治疗和/或诊断癌症的用途。
一个实施方式提供了一种与GUCY2C结合的GUCY2C结合多肽。
所述GUCY2C结合多肽可以包含
重链可变区,其包含由选自SEQ ID NO:38至44的氨基酸序列表示的重链CDR1(后文中的CDR-H1)、由选自SEQ ID NO:45至53的氨基酸序列表示的CDR-H2和由选自SEQ IDNO:54至65的氨基酸序列表示的CDR-H3;
轻链可变区,其包含由选自SEQ ID NO:66至78的氨基酸序列表示的轻链CDR1(后文中的CDR-L1)、由选自SEQ ID NO:79至88的氨基酸序列表示的CDR-L2和由选自SEQ IDNO:89至106的氨基酸序列表示的CDR-L3;
或其组合。
在一个实施方式中,所述GUCY2C结合多肽可以是以不论何种顺序包含所述重链可变区和轻链可变区的单链可变片段(scFv)。所述scFv可以在从N-端至C-端的方向上以重链可变区和轻链可变区的顺序或轻链可变区和重链可变区的顺序包含所述重链可变区和轻链可变区,例如它可以在从N-端至C-端的方向上以重链可变区和轻链可变区的顺序包含它们。然后,所述重链可变区和轻链可变区可以通过肽接头相连或不使用接头直接连接。在一个特定实施方式中,所述多肽可以是由选自SEQ ID NO:1至18的氨基酸序列表示的scFv。
另一个实施方式提供了一种与GUCY2C特异性结合的抗体或其抗原结合片段,其包含所述重链可变区和轻链可变区。
另一个实施方式提供了一种包含所述GUCY2C结合多肽和免疫球蛋白的Fc结构域的融合蛋白。
另一个实施方式提供了一种包含所述GUCY2C结合多肽、抗体或其抗原结合片段或融合蛋白和药物的偶联物。所述药物可以是选自抗癌药剂、造影剂等的一者或多者。
另一个实施方式提供了一种包含所述GUCY2C结合多肽的嵌合抗原受体。所述嵌合抗原受体可以对GUCY2C特异。
另一个实施方式提供了一种包含所述嵌合抗原受体的免疫细胞。所述免疫细胞可以是在细胞表面上表达所述嵌合抗原受体的免疫细胞。所述免疫细胞可以是GUCY2C特异性免疫细胞。
另一个实施方式提供了一种多核苷酸,其编码所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白或嵌合抗原受体。另一个实施方式提供了一种包含所述多核苷酸的重组载体。另一个实施方式提供了一种包含所述多核苷酸或重组载体的重组细胞。
另一个实施方式提供了一种用于预防和/或治疗癌症的药物组合物,其包含选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、偶联物、嵌合抗原受体、编码它们的多核苷酸、包含所述多核苷酸的重组载体、包含所述重组载体的重组细胞和表达所述嵌合抗原受体的免疫细胞的一者或多者作为活性成分。
另一个实施方式提供了一种预防和/或治疗癌症的方法,所述方法包括在需要预防和/或治疗癌症的受试者中给药药物有效剂量的选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、偶联物、嵌合抗原受体、编码它们的多核苷酸、包含所述多核苷酸的重组载体、包含所述重组载体的重组细胞和表达所述嵌合抗原受体的免疫细胞的一者或多者。
另一个实施方式提供了选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、偶联物、嵌合抗原受体、编码它们的多核苷酸、包含所述多核苷酸的重组载体、包含所述重组载体的重组细胞和表达所述嵌合抗原受体的免疫细胞的一者或多者的用途,其用于预防和/或治疗癌症或用于制备预防和/或治疗癌症的药物组合物。
另一个实施方式提供了一种用于诊断癌症的组合物,其包含选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、偶联物、嵌合抗原受体、编码它们的多核苷酸、包含所述多核苷酸的重组载体、包含所述重组载体的重组细胞和表达所述嵌合抗原受体的免疫细胞的一者或多者作为活性成分。
另一个实施方式提供了一种诊断癌症的方法或为癌症诊断提供信息的方法,所述方法包括将选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、偶联物、嵌合抗原受体、编码它们的多核苷酸、包含所述多核苷酸的重组载体、包含所述重组载体的重组细胞和表达所述嵌合抗原受体的免疫细胞的一者或多者与从受试者获得的生物样品接触。所述受试者可以是需要诊断癌症的患者,并且所述生物样品可以是选自细胞、组织、体液及其培养物的一者或多者。
另一个实施方式提供了选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、偶联物、嵌合抗原受体、编码它们的多核苷酸、包含所述多核苷酸的重组载体、包含所述重组载体的重组细胞和表达所述嵌合抗原受体的免疫细胞的一者或多者的用途,其用于诊断癌症或用于制备诊断癌症的组合物。
另一个实施方式提供了一种用于检测GUCY2C的组合物,其包含选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、偶联物、嵌合抗原受体、编码它们的多核苷酸、包含所述多核苷酸的重组载体、包含所述重组载体的重组细胞和表达所述嵌合抗原受体的免疫细胞的一者或多者作为活性成分。
另一个实施方式提供了一种检测GUCY2C的方法,所述方法包括将选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、偶联物、嵌合抗原受体、编码它们的多核苷酸、包含所述多核苷酸的重组载体、包含所述重组载体的重组细胞和表达所述嵌合抗原受体的免疫细胞的一者或多者与生物样品接触。所述生物样品可以是选自分离的细胞、组织、体液及其培养物的一者或多者。
另一个实施方式提供了选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、偶联物、嵌合抗原受体、编码它们的多核苷酸、包含所述多核苷酸的重组载体、包含所述重组载体的重组细胞和表达所述嵌合抗原受体的免疫细胞的一者或多者的用途,其用于检测GUCY2C。
技术解决方案
术语定义
在本说明书中,GUCY2C(鸟苷酸环化酶2C;鸟苷酰基环化酶C;GC-C或GCC)、肠道鸟苷酸环化酶、鸟苷酸环化酶-C受体或热稳定肠毒素受体(hSTAR)是一种跨膜细胞表面受体,其作用于肠液、电解质稳态和细胞增殖的维持等。在一个实施方式中,GUCY2C可以是源自于哺乳动物的GUCY2C,例如,它可以是人GUCY2C(蛋白质:GenBank登记号NP_004954.2等;基因:GenBank登记号NM_004963.4等)、小鼠GUCY2C(蛋白质:GenBank登记号NP_001120790.1、NP_659504.2等;基因:GenBank登记号NM_001127318.1、NM_145067.3等),但不限于此。在一个实施方式中,GUCY2C可以在哺乳动物(例如灵长类动物如人类、猴子等,啮齿动物如小鼠、大鼠等)的结肠直肠癌中特异性表达,但是它甚至可以在肠系膜等例如大肠和食道、胃、胰腺等中表达,但没有特别限制。
在本说明书中,多核苷酸(可以与“基因”互换使用)或多肽(可以与“蛋白质”互换使用)“包含特定核酸序列或氨基酸序列”或“由特定核酸序列或氨基酸序列组成或表示”可以意味着所述多核苷酸或多肽基本上包含所述特定核酸序列或氨基酸序列,并且它可以被解释为包括“基本上等同的序列”,其中在维持所述多核苷酸或多肽的原始功能和/或所需功能的范围内向所述特定核酸序列或氨基酸序列添加了突变(缺失、替换、修饰和/或添加)(或者不排除所述突变)。
在一个实施方式中,多核苷酸或多肽“包含特定核酸序列或氨基酸序列”或“由特定核酸序列或氨基酸序列组成或表示”可以意味着所述多核苷酸或多肽(i)可能基本上包含所述特定核酸序列或氨基酸序列,或(ii)可能由与所述特定核酸序列或氨基酸序列具有70%或更高、75%或更高、80%或更高、85%或更高、90%或更高、91%或更高、92%或更高、93%或更高、94%或更高、95%或更高、96%或更高、97%或更高、98%或更高、99%或更高、99.5%或更高或99.9%或更高同一性的核酸序列或氨基酸序列组成或基本上包含所述序列,并维持原始功能和/或所需功能。在本说明书中,多肽、抗体或其抗原结合片段(例如CDR、可变区或重链/轻链)、融合蛋白和嵌合抗原受体“包含特定氨基酸序列或由特定氨基酸序列表示或组成”可以意味着下述所有情况:基本上包含所述氨基酸序列的情况,和在所述氨基酸序列中引入不影响原始活性和/或所需活性(例如GUCY2C结合活性等)的不重要突变(例如氨基酸残基的替换、缺失和/或添加)的情况。
在本说明书中,术语“同一性”意味着与给定核酸序列或氨基酸序列的对应程度,并且可以用百分率(%)表示。与核酸序列的同一性可以使用文献的BLAST算法(参见Karlin和Altschul,Pro.Natl.Acad.Sci.USA,90,5873,1993)或Pearson的FAST算法(参见MethodsEnzymol.,183,63,1990)来确定。基于这种BLAST算法,已开发了被称为BLASTN或BLASTX的程序(参见http://www.ncbi.nlm.nih.gov)。
在本文中,术语“抗体”以最广泛的意义用作描述与特定抗原特异性结合的蛋白质的通用术语,并且可以是在免疫系统中通过抗原的刺激而制备的蛋白质或通过化学合成或重组方法产生的蛋白质,其类型没有特别限制。具体而言,涵盖了单克隆抗体(包括全长单克隆抗体)、多克隆抗体、多特异性抗体(例如双特异性抗体)、合成抗体(或者也被称为抗体模拟物)、嵌合抗体、人源化抗体、人类抗体或抗体融合蛋白(或者也被称为抗体偶联物),只要表现出所需生物活性即可。
完整抗体(例如IgG型)的结构具有2条全长轻链和2条全长重链,并且每条轻链通过二硫键与重链相连。抗体的恒定区分为重链恒定区和轻链恒定区,并且重链恒定区具有gamma(γ)、mu(μ)、alpha(α)、delta(δ)或epsilon(ε)型,并具有gamma 1(γ1)、gamma 2(γ2)、gamma 3(γ3)、gamma 4(γ4)、alpha 1(α1)或alpha 2(α2)亚类。轻链的恒定区具有kappa(κ)和lambda(λ)型。
术语“抗原结合片段”是指抗体的一部分,其缺少全长链中存在的至少某些氨基酸,但仍然能够与抗原特异性结合。此类片段具有生物活性,因为它与靶抗原结合,并且能够与包括完整抗体在内的其他抗原结合分子竞争与给定表位的结合。抗原结合片段可以不包含完整抗体的Fc区的重链恒定结构域(即取决于抗体同型,它们是CH2、CH3和CH4)。抗原结合片段的实例包括scFv(单链可变片段)(例如scFv、(scFv)2等)、Fab(抗原结合片段)(例如Fab、Fab'、F(ab')2等)、结构域抗体、肽类抗体(peptibody)、微抗体、胞内抗体、双体抗体、三体抗体或单链抗体等,但不限于此。此外,所述抗原结合片段可以是scFv、scFv与免疫球蛋白(例如IgA、IgD、IgE、IgG(IgG1、IgG2、IgG3、IgG4)、IgM等)的Fc区融合的融合多肽(scFv-Fc)或scFv与轻链(例如κ或λ)的恒定区融合的融合多肽(scFv-Cκ(κ恒定区)或scFv-Cλ(λ恒定区)),但不限于此。
术语“重链”被解释为包括所有全长重链及其片段,所述全长重链包含可变结构域VH(其包含具有足以提供对抗原的特异性的可变区的氨基酸序列)和3个恒定区结构域CH1、CH2和CH3以及铰链。此外,术语“轻链”被解释为包括所有全长轻链及其片段的含义,所述全长轻链包含可变区结构域VL(其包含具有足以提供对抗原的特异性的可变区序列的氨基酸序列)和恒定区结构域CL。
术语“互补决定区(CDR)”是指在抗体的可变区中提供对抗原的结合特异性或结合亲和性的区域。通常,在重链可变区中存在3个CDR(CDR-H1、CDR-H2、CDR-H3),并且在轻链可变区中存在3个CDR(CDR-L1、CDR-L2、CDR-L3)。CDR可以提供关键的接触残基,用于抗体或其片段与抗原或表位的结合。“构架区(FR)”是指直链和轻链的可变区的非CDR部分,并且通常在重链可变区中存在4个FR(FR-H1、FR-H2、FR-H3和FR-H4),并且在轻链可变区中存在4个FR(FR-L1、FR-L2、FR-L3和FR-L4)。给定CDR或FR的准确氨基酸序列边界可以通过使用多种公知的系统例如Kabat编号系统、Chothia编号系统、Contact编号系统、IMGT编号系统、Abo编号系统、AbM编号系统等中的任一者容易地确定。
术语“可变区”是指抗体的重链或轻链的参与抗体与抗原的结合的结构域。重链可变(VH)区和轻链可变(VL)区总体具有相似的结构,并且每个结构域包括4个保守的构架区(FR)和3个CDR。
GUCY2C结合多肽、抗体或其抗原结合片段、融合蛋白
本说明书中提供的GUCY2C结合多肽、抗体或其抗原结合片段可以包含:
重链可变区,其包含由选自SEQ ID NO:38至44的氨基酸序列表示的重链CDR1(或简称为CDR-H1)、由选自SEQ ID NO:45至53的氨基酸序列表示的CDR-H2和由选自SEQ IDNO:54至65的氨基酸序列表示的CDR-H3;
轻链可变区,其包含由选自SEQ ID NO:66至78的氨基酸序列表示的轻链CDR1(或简称为CDR-L1)、由选自SEQ ID NO:79至88的氨基酸序列表示的CDR-L2和由选自SEQ IDNO:89至106的氨基酸序列表示的CDR-L3;
或所述重链可变区和轻链可变区的组合。
包含在本说明书中提供的GUCY2C结合多肽、抗体或其抗原结合片段中的每个CDR的氨基酸序列和组合示例在下面的表1和表2中:表1示出了重链可变区的每个CDR的氨基酸序列,表2示出了轻链可变区的每个CDR的氨基酸序列。
[表1]
[表2]
在一个实施方式中,所述GUCY2C结合多肽可以包含含有上述重链CDR的重链可变区和含有所述轻链CDR的轻链可变区。所述重链可变区可以包含重链CDR和上述免疫球蛋白(例如IgA、IgD、IgE、IgG(IgG1、IgG2、IgG3、IgG4)、IgM等)的构架(例如FR1-(CDR-H1)-FR2-(CDR-H2)-FR3-(CDR-H3)-FR4的结构)。所述轻链可变区可以包含上述轻链CDRλ或κ亚型的构架(例如FR1-(CDR-L1)-FR2-(CDR-L2)-FR3-(CDR-L3)-FR4的结构)。
在一个特定实施方式中,所述GUCY2C结合多肽可以是scFv(单链可变片段),其是其中上述重链可变区和轻链可变区通过或不通过肽接头相连的单链多肽。
所述肽接头可以是由1至100个或2至50个任何氨基酸组成的多肽,并且包含的氨基酸的类型没有限制。例如,所述肽接头可以包含Gly、Asn和/或Ser残基,并且可以包含中性氨基酸例如Thr和/或Ala。适用于肽接头的氨基酸序列在本领域中是已知的。另一方面,对于接头来说,它的长度可以在不影响所述scFv的GUCY2C结合功能的限度内以各种方式确定。例如,所述肽接头可以由包含总共1至200个、2至50个或5至25个选自Gly、Asn、Ser、Thr和Ala的一种或多种氨基酸组成。在一个实施方式中,所述肽接头是(G4S)n(n是(G4S)的重复数,并且可以由1至10的整数例如2至5的整数表示)。
在一个特定实施方式中,采取scFv形式的GUCY2C结合多肽可以由选自SEQ ID NO:1至18的氨基酸序列表示,并且这些氨基酸序列示出在下面的表3中:
[表3]
(在表3中,粗体和下划线的区域依次表示CDR-H1、CDR-H2和CDR-H3、CDR-L1、CDR-L2和CDR-L3)
在另一个特定实施方式中,所述抗体或其抗原结合片段可以包含上述6个CDR,并且是基于免疫球蛋白(例如IgA、IgD、IgE、IgG(IgG1、IgG2、IgG3、IgG4)、IgM等)和λ或κ型。所述抗体可以是单克隆抗体,并且可以是动物(例如小鼠、兔等)来源的抗体、嵌合抗体、人源化抗体或人类抗体。
另一个实施方式提供了一种融合蛋白,其包含所述GUCY2C结合多肽和免疫球蛋白的Fc结构域。
所述GUCY2C结合多肽如上所述。所述免疫球蛋白的Fc结构域可以是哺乳动物(例如灵长类动物如人、猴、啮齿动物如小鼠、大鼠等)的免疫球蛋白(例如IgA、IgD、IgE、IgG(IgG1、IgG2、IgG3、IgG4)、IgM等)的Fc结构域。所述Fc结构域可以包含或不包含铰链区,并且可以包含CH2、CH3或它们两者。在本说明书中提供的融合蛋白中,所述GUCY2C结合多肽和免疫球蛋白的Fc结构域可以以任何顺序相连,例如所述GUCY2C结合多肽可以连接到免疫球蛋白的Fc结构域的C-端或N-端,或者两个或更多个GUCY2C结合多肽可以连接到免疫球蛋白的Fc结构域的C-端或N-端中的一者或多者。所述GUCY2C结合多肽和免疫球蛋白的Fc结构域多肽可以通过接头相连,或者不使用接头直接相连。
本说明书中提供的GUCY2C结合多肽、抗GUCY2C抗体或其抗原结合片段可能对GUCY2C(例如人GUCY2C)具有10mM或更低、5mM或更低、1mM或更低、0.5mM或更低、0.2mM或更低或0.15mM或更低的结合亲和性(KD),例如基于通过表面等离子体共振(SPR)测量到的情况,例如,它可以是0.001nM至10mM、0.005nM至10mM、0.01nM至10mM、0.05nM至10mM、0.1nM至10mM、0.5nM至10mM、1nM至10mM、0.001nM至5mM、0.005nM至5mM、0.01nM至5mM、0.05nM至5mM、0.1nM至5mM、0.5nM至5mM、1nM至5mM、0.001nM至1mM、0.005nM至1mM、0.01nM至1mM、0.05nM至1mM、0.1nM至1mM、0.5nM至1mM、1nM至1mM、0.001nM至0.5mM、0.005nM至0.5mM、0.01nM至0.5mM、0.05nM至0.5mM、0.1nM至0.5mM、0.5nM至0.5mM、1nM至0.5mM、0.001nM至0.2mM、0.005nM至0.2mM、0.01nM至0.2mM、0.05nM至0.2mM、0.1nM至0.2mM、0.5nM至0.2mM、1nM至0.2mM、0.001nM至0.15mM、0.005nM至0.15mM、0.01nM至0.15mM、0.05nM至0.15mM、0.1nM至0.15mM、0.5nM至0.15mM或1nM至0.15mM。
另一个实施方式提供了一种上述抗体或其抗原结合片段或融合蛋白与药物的偶联物。所述药物可以是选自抗癌药剂、造影剂等的一者或多者。
所述抗癌药剂可以是选自美登素、基于瑞奥西汀的药物、基于刺孢霉素的药物、基于吡咯并苯并二氮杂环庚三烯的药物、倍癌霉素(duocarmycin)、多西他赛、多柔比星、卡铂(paraplatin)、顺铂、环磷酰胺、异环磷酰胺、宁得朗、氮芥、盐酸氮芥、博来霉素、丝裂霉素C、阿糖胞苷、氟尿嘧啶、吉西他滨、三甲曲沙、甲氨蝶呤、依托泊苷、长春碱、长春瑞滨、爱宁达、六甲蜜胺、丙卡巴肼、紫杉醇(泰素)、多西紫杉醇、拓扑替康、伊立替康等的一者或多者,但不限于此。所述造影剂可以是选自MRI(磁共振成像)造影剂例如氧化铁、钆、放射性同位素(例如碘化物、金、铊、钯、铯、钇、镓、铜、镝、铷、钌、镭、氟、铋等)等以及PET(正电子发射断层扫描)造影剂等的一者或多者,但不限于此。
嵌合抗原受体(CAR)、表达嵌合抗原受体的细胞
另一个实施方式提供了一种包含所述GUCY2C结合多肽的嵌合抗原受体(CAR)。所述GUCY2C结合多肽可能适合用于嵌合抗原受体中,因为它可以被操作以作为单链的一部分与其他CAR组分一起表达。所述嵌合抗原受体可以是GUCY2C特异的。
所述嵌合抗原受体通常可以包含:包含所述GUCY2C结合多肽的胞外结构域(胞外域);跨膜结构域;和细胞内信号传导结构域(或T细胞活化结构域;胞内域)。此外,所述胞外结构域还可以在所述多肽与跨膜结构域之间包含间隔区(或铰链区)。此外,所述嵌合抗原受体还可以包含一个或多个共刺激结构域,并且优选地,所述共刺激结构域可以位于所述跨膜结构域与细胞内信号传导结构域之间。
因此,作为一个优选实施方式,所述嵌合抗原受体可以包含:包含所述GUCY2C结合多肽的胞外结构域;跨膜结构域;一个或多个共刺激结构域;和细胞内信号传导结构域。每个结构域可以是异源的。换句话说,它可以由源自于不同蛋白链的序列组成。每个结构域可以通过短的寡肽或多肽接头,例如长度为2至10个氨基酸的接头相连。此外,所述嵌合抗原受体可以由其中将每个结构域相连的一条多肽链组成。
所述胞外结构域包含上述GUCY2C结合多肽,并且它识别在癌细胞表面上表达的GUCY2C。
所述胞外结构域可以进一步包含间隔区(或铰链区)。所述间隔区可以位于所述GUCY2C结合多肽与跨膜结构域之间。所述间隔区允许所述GUCY2C结合多肽更灵活地识别靶抗原,与表达嵌合抗原受体的免疫细胞(在后文中也被称为“表达CAR的免疫细胞”;例如包括CAR-NK、CAR-T细胞等)的细胞膜隔开一定距离。所述间隔区通常可以是多肽,并且它可以具有10或更大的氨基酸长度,例如10至300的氨基酸长度、10至250的氨基酸长度、10至200的氨基酸长度、10至150的氨基酸长度、10至100的氨基酸长度或10至50的氨基酸长度,但不限于此。
作为所述间隔区,可以示例的是CD8α或CD28的铰链区或免疫球蛋白(IgG)的恒定区等,并且为了由此消除脱靶效应,可以引入突变。例如,所述免疫球蛋白恒定区可以源自于单独的IgG铰链或CH2和/或CH3结构域的全部或一部分,例如它可以是Fc区。所述IgG(IgG1、IgG2、IgG3、IgG4等)可以是IgG2或IgG4。在某些实施方式中,所述间隔物可以是含有源自于IgG2、IgG4和/或IgG2和IgG4的铰链和CH2和CH3序列中的一者或多者的嵌合多肽。
所述跨膜结构域发挥连接细胞膜结构域和细胞膜内的信号传导结构域的作用,并且可以源自于天然或合成来源。当所述来源是天然的时,所述结构域可以是任何膜结合或膜穿越蛋白。例如,所述跨膜结构域可以是T细胞受体的α、β或ζ链、CD3ε、CD4、CD5、CD8、CD9、CD16、CD22、CD28、CD33、CD37、CD45、CD64、CD80、CD86、CD134、CD137或CD154的跨膜结构域,但不限于此。作为一个优选实施方式,所述跨膜结构域可以是CD28或CD8的跨膜结构域,但不限于此。当所述来源是合成的时,所述合成跨膜结构域可以包含疏水残基例如亮氨酸和缬氨酸,并且可以在每个末端包含苯丙氨酸、色氨酸和缬氨酸等,但不限于此。
所述共刺激结构域是共刺激信号被传输到的位点,并且是用于传输信号以使表达CAR的免疫细胞产生免疫应答并自我增殖的位点。它可以被选择性引入以改善表达CAR的免疫细胞的增殖、细胞毒性、持续应答、寿命延长。所述共刺激结构域可以是选自CD28、OX-40(CD134)、4-1BB(CD137)、CD2、CD7、CD27、CD30、CD40、PD-1、ICOS、LFA-1(CD11a/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7-H3)、LIGHT(TNFSF14)、NKG2C、Igα(CD79a)、DAP-10、Fcγ受体、1类MHC分子、TNF受体蛋白、免疫球蛋白、细胞因子受体、整合蛋白、SLAM(信号传导淋巴细胞活化分子)、活化的NK细胞受体、BTLA、toll配体受体、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2Rβ、IL-2Rγ、IL-7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD11a、LFA-1、ITGAM、CD11b、ITGAX、CD11c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRTAM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A、Ly108)、SLAMF1(CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp或CD19a的信号传导位点中的一种或多种,例如1种或2种或3种,但不限于此。作为优选实施方式,它可以是选自CD28、OX-40(CD134)、4-1BB(CD137)、CD27或ICOS的信号传导位点中的一种或多种,例如1种或2种或3种,但不限于此。
所述细胞内信号传导结构域是激活免疫细胞对与所述GUCY2C结合多肽结合的抗原的免疫应答的位点。所述信号传导结构域可以含有已知作为免疫细胞受体(例如T细胞受体(TCR)等)的组分的信号传导基序或基于酪氨酸的活化基序(免疫受体基于酪氨酸的活化基序,ITAM)。作为实施方式,所述信号传导结构域可以是源自于TCR或CD3ζ、FcRγ、CD3γ、CD3δ和CD3ε的信号传导结构域,但不限于此。作为优选实施方式,它可以是CD3ζ的信号传导结构域,但不限于此。当胞外结构域的GUCY2C结合多肽位点与靶结合时,所述细胞内信号传导结构域可以激活表达CAR的免疫细胞。例如,所述CAR可以刺激免疫细胞(例如NK细胞、T细胞等)的功能例如细胞裂解活性或T-辅助细胞活性,并诱导细胞因子或其他因子的分泌。
在某些实施方式中,所述CAR可以以包含信号序列的形式表达。此外,所述CAR可以被表达成带有对监测有用的额外序列,例如核糖体跳跃序列如2A肽或截短的细胞表面多肽(tHER2或tEGFR或截短的PSMA等)。
在所述嵌合抗原受体中,外部结构域(抗原结合结构域和间隔结构域)、跨膜结构域和内部结构域(两个辅助刺激因子中的任一辅助刺激因子或至少一个或多个辅助刺激因子,和信号传导结构域)可以是以N-端至C-端的方向或以C-端至N-端的方向依次连接的单链多肽。
另一个实施方式提供了一种包含上述嵌合抗原受体的免疫细胞。所述免疫细胞可以是对GUCY2C特异的免疫细胞,在细胞表面上表达所述GUCY2C特异性嵌合抗原受体。在一个实施方式中,所述免疫细胞可以是被遗传工程改造以表达所述嵌合抗原受体的细胞,例如在其中引入了编码所述嵌合抗原受体的多核苷酸或包含所述多核苷酸的重组载体(表达载体)的免疫细胞。
所述免疫细胞包括T细胞、肿瘤浸润性淋巴细胞(TIL)、NK(自然杀伤)细胞、表达TCR(T细胞抗原受体)的细胞、树突状细胞或NK-T细胞,但不限于此。此外,所述免疫细胞可以源自于人诱导多能干细胞(iPSC)。所述免疫细胞可以源自于任何已知来源。例如,所述免疫细胞可以在体外从造血干细胞组分化,或者从患者获得。所述免疫细胞可以从例如外周血单核细胞(PBMC)、骨髓、淋巴腺组织、脐带血、胸腺组织、来自于感染部位的组织、腹水、胸腔积液、脾脏组织和肿瘤获得。此外,所述免疫细胞可以源自于本领域中可用的一种或多种免疫细胞系。所述免疫细胞可以是源自于哺乳动物(例如灵长类动物如人、猴,啮齿动物如小鼠、大鼠等)的细胞。
所述免疫细胞可以是自体或同种异体的。自体的是指源自于待治疗的患者。同种异体的是指源自于与待治疗的患者相同的物种的另一个个体。
此外,所述免疫细胞可以源自于人诱导多能干细胞(iPSC)。与自体或同种异体免疫细胞相比,源自于iPSC的免疫细胞的优点在于自我增殖是可能的,大规模增殖容易,并且可以制备适用于所有人的通用细胞治疗剂。
所述免疫细胞可以使用显微注射、电穿孔、超声处理、生物弹道学(例如基因枪)、脂质转染、聚合物转染、磷酸钙沉淀、原生质体融合、脂质体介导的转染、纳米颗粒或polyplexes等的方法用载体转染或转导,但方法不限于此。
在本说明书中,术语“自然杀伤细胞”或“NK细胞”是构成先天性免疫系统的主要组分的细胞毒性淋巴细胞,并被定义为大颗粒淋巴细胞(LGL),并且由从产生B和T淋巴细胞的共同淋巴系祖细胞(CLP)分化的第三种细胞组成。“自然杀伤细胞”或“NK细胞”可以包括源自于任何组织来源的没有额外修饰的自然杀伤细胞,并且不仅包括成熟的自然杀伤细胞,而且还包括自然杀伤前体。自然杀伤细胞被干扰素或巨噬细胞衍生细胞因子的反应激活,并且自然杀伤细胞包括控制细胞的细胞毒性活性的两种类型的表面受体,被标记为“活化受体”和“抑制性受体”。自然杀伤细胞可以由造血细胞,例如来自于任何来源例如胎盘组织、胎盘灌注液、脐带血、胎盘血、外周血、脾脏、肝脏等的造血干细胞或前体产生。
术语“受体”是指与特定物质结合以修饰NK细胞的活性的所有分子。所述特定物质可以包括化学组合物、身体来源的或人造特定蛋白、肽、胆固醇和糖蛋白,并包括由其他免疫细胞或NK细胞本身产生的细胞因子或趋化因子或靶细胞或NK细胞本身的特定受体或膜蛋白。例如,受体不仅包括定位于NK细胞的细胞表面上并与特定物质结合以将信号发送到细胞内并引起NK细胞活性的情况,而且包括作为通过细胞膜并存在于细胞膜的内表面或细胞质中,并且可以与外部特定刺激物质结合引起信号传导作用的受体的所有受体。受体的实例可以包括CD16、CD25、CD69、CD117、NKG2D、CD94/NKG2A、2B4(CD244)、DNAM-1(CD226)、CD2、CXCR3、NKp30、NKp44、NKp46和NKp80,但不限于此。在所述受体中,当CD117表达低并且CD94/NKG2D表达高时,可以确定NK细胞表现出成熟表型。对于“受体”来说,也包括“细胞因子相关受体”、“细胞因子受体”,并且对于细胞因子受体来说,包括IL-15Ra、IL-18Ra、CD122、PD-1(CD279)和ICAM-1(CD54),但不限于此。
NK细胞可以通过分泌细胞因子例如穿孔素(Prf1)、颗粒酶B(GzmB)、干扰素-γ(IFN-γ)、肿瘤坏死因子-α(TNF-α)等,通过直接介导靶癌细胞凋亡而杀伤癌细胞。因此,通过确认包括凋亡过程中的主要因子、IFN-γ、颗粒酶B和穿孔素在内的效应分子的分泌程度,可以确认NK细胞的杀伤能力。
多核苷酸、重组载体、重组细胞
在本说明书中,上述GUCY2C结合多肽、与GUCY2特异性结合的抗体或其抗原结合片段、融合蛋白和嵌合抗原受体以及编码它们的多核苷酸,可以重组或合成产生。
另一个实施方式提供了一种多核苷酸,其编码所述GUCY2C结合多肽、与GUCY2特异性结合的抗体或其抗原结合片段、融合蛋白或嵌合抗原受体。在一个特定实施方式中,所述多核苷酸可以被密码子优化以用于在人类中表达。
在一个实施方式中,编码由SEQ ID NO:1至18的氨基酸序列表示的GUCY2C结合多肽的多核苷酸,可以由SEQ ID NO:20至37的核酸序列表示。
另一个实施方式提供了一种包含所述多核苷酸的重组载体。所述重组载体可以是用于在宿主细胞中表达所述多核苷酸的表达载体。另一个实施方式提供了一种包含所述多核苷酸或重组载体的重组细胞。所述重组细胞可以是在宿主细胞中引入了所述多核苷酸或重组载体的细胞。
另一个实施方式提供了一种制备GUCY2C结合多肽、与GUCY2特异性结合的抗体或其抗原结合片段、融合蛋白或嵌合抗原受体的方法,所述方法包括在适合的宿主细胞中表达所述多核苷酸。所述表达可以包括培养包含所述多核苷酸的重组细胞。
术语“载体”意指一种用于在宿主细胞中表达靶基因(DNA或RNA)的手段。例如,可以示例的是质粒载体、黏粒载体和噬菌体载体、病毒载体等。在一个特定实施方式中,所述载体可以是选自慢病毒载体、腺病毒载体、反转录病毒载体、腺相关病毒载体(AAV)、鼠类白血病病毒载体、SFG载体、杆状病毒载体、Epstein Barr病毒载体、乳头瘤病毒载体、痘苗病毒载体、单纯性疱疹病毒载体等的病毒载体,但不限于此。在一个特定实施方式中,所述重组载体可以通过对本领域中常用的质粒(例如pSC101、pGV1106、pACYC177、ColE1、pKT230、pME290、pBR322、pUC8/9、pUC6、pBD9、pHC79、pIJ61、pLAFR1、pHV14、pGEX系列、pET系列和pUC19等)、噬菌体(例如λgt4λB、λ-Charon、λΔz1和M13等)或病毒(例如SV40等)进行工程改造来产生。
在所述重组载体中,所述核酸分子可以被可操作连接到启动子。术语“可操作连接”意味着核苷酸表达调控序列(例如启动子序列)与其他核苷酸序列之间的功能性结合。所述调控序列可以调控“可操作连接”的其他核苷酸序列的转录和/或翻译。
所述重组载体通常可以被构建成用于克隆的载体或用于表达的载体。作为用于表达的载体,可以使用本领域中常用于在植物、动物或微生物中表达外来蛋白的载体。所述重组载体可以通过本领域中已知的各种方法来构建。
所述重组载体可以通过使用原核细胞或真核细胞作为宿主来构建。例如,当所使用的载体是表达载体并使用原核细胞作为宿主时,它通常包含能够进行转录的强启动子(例如pLλ启动子、CMV启动子、trp启动子、lac启动子、tac启动子、T7启动子等)、用于翻译起始的核糖体结合位点和转录/翻译终止序列。当使用真核细胞作为宿主时,载体中包含的在真核细胞中起作用的复制原点包括f1复制原点、SV40复制原点、pMB1复制原点、腺病毒复制原点、AAV复制原点和BBV复制原点等,但不限于此。此外,可以使用源自于哺乳动物细胞的基因组的启动子(例如金属硫蛋白启动子)或源自于哺乳动物病毒的启动子(例如腺病毒晚期启动子、痘苗病毒7.5K启动子、SV40启动子、巨细胞病毒启动子、HSV的tk启动子等),并且作为转录终止序列,它通常具有多腺苷酸化序列。
所述重组细胞可以通过将所述重组载体引入到适合的宿主细胞中来获得。作为宿主细胞,可以使用本领域中已知的任何宿主细胞作为能够克隆或稳定且连续地表达所述重组载体的细胞,并且原核细胞包括例如大肠杆菌如大肠杆菌JM109、大肠杆菌BL21、大肠杆菌RR1、大肠杆菌LE392、大肠杆菌B、大肠杆菌X 1776、大肠杆菌W3110等、芽孢杆菌属菌株例如枯草芽孢杆菌(Bacillus subtilis)和苏云金芽孢杆菌(Bacillus thuringiensis)、肠杆菌科菌株例如鼠伤寒沙门氏菌(Salmonella typhimurium)、粘质沙雷氏菌(Serratiamarcescens)和各种假单胞菌属菌种等,并且当在真核细胞中转化时,作为宿主细胞可以使用酵母(酿酒酵母(Saccharomyces cerevisiae))、昆虫细胞、植物细胞和动物细胞,例如Sp2/0、CHO(中华仓鼠卵巢)K1、CHO DG44、CHO S、CHO DXB11、CHO GS-KO、PER.C6、W138、BHK、COS-7、293、HepG2、Huh7、3T3、RIN、MDCK细胞系等,但不限于此。
所述核酸分子和包含它的重组载体在宿主细胞中的递送(引入)可以使用本领域中广泛已知的递送方法。例如,所述递送方法当宿主细胞是原核细胞时可以使用CaCl2法或电穿孔法等,并且当宿主细胞是真核细胞时可以使用显微注射、磷酸钙沉淀、电穿孔、脂质体介导的转染和基因轰击等,但不限于此。
用于选择转化的宿主细胞的方法可以按照本领域中广泛使用的方法,通过使用由选择性标记物表达的表型容易地进行。例如,当所述选择性标记物是特定抗生素抗性基因时,可以通过将转化体在含有所述抗生素的培养基中培养来容易地选择转化体。
另一个实施方式提供了一种制备抗GUCY2C抗体或其抗原结合片段的方法,所述方法包括在宿主细胞中表达所述核酸分子或包含它的重组载体。所述表达可以通过将包含所述核酸分子(例如包含在重组载体中)的重组体在允许所述核酸分子表达的条件下培养来进行。所述制备方法可以包括在表达或培养后,从培养基分离和/或纯化抗体或抗原结合片段。
医学用途
另一个实施方式提供了一种用于检测GUCY2C的组合物,其包含选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、嵌合抗原受体、编码它们的多核苷酸和免疫细胞的一者或多者作为活性成分。
另一个实施方式提供了一种用于检测GUCY2C的方法,所述方法包括将选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、嵌合抗原受体、编码它们的多核苷酸和免疫细胞的一者或多者与生物样品接触。所述生物样品可以是选自分离的细胞、组织、体液及其培养物的一者或多者。在所述方法中,样品中的GUCY2C检测可以通过确认所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、嵌合抗原受体、编码它们的多核苷酸和免疫细胞与GUCY2C的反应(例如确认复合物形成)来进行。
另一个实施方式提供了选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、嵌合抗原受体、编码它们的多核苷酸和免疫细胞的一者或多者的用途,其用于检测GUCY2C。
另一个实施方式提供了一种用于诊断癌症的组合物,其包含选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、嵌合抗原受体、编码它们的多核苷酸和免疫细胞的一者或多者作为活性成分。
另一个实施方式提供了一种用于诊断癌症的方法或用于为癌症诊断提供信息的方法,所述方法包括将选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、嵌合抗原受体、编码它们的多核苷酸和免疫细胞的一者或多者与从受试者获得的生物样品接触。所述受试者可以是需要诊断癌症的患者,并且所述生物样品可以是选自细胞、组织、体液及其培养物的一者或多者。在所述方法中,当检测到GUCY2C时,更具体而言当检测到所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、嵌合抗原受体、编码它们的多核苷酸和免疫细胞与GUCY2C的复合物时,可以确认(决定、确定)所述生物样品包含癌细胞或获得所述生物样品的患者是癌症患者。
另一个实施方式提供了选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、嵌合抗原受体、编码它们的多核苷酸和免疫细胞的一者或多者的用途,其用于诊断癌症或用于制备诊断癌症的组合物。
GUCY2C检测和/或复合物形成的确认可以通过确认蛋白质-蛋白质相互作用或蛋白质-蛋白质之间的复合物形成的常见手段来进行,并且例如它可以通过选自免疫层析、免疫组织化学染色、酶联免疫吸附测定(ELISA)、放射免疫测定(RIA)、酶免疫测定(EIA)、荧光免疫测定(FIA)、发光免疫测定(LIA)、western印迹、微阵列等的方法来测量,但方法不限于此。
所述生物样品可以是受试者(例如哺乳动物,包括灵长类动物例如人、猴,啮齿动物如小鼠、大鼠等)或从所述受试者分离或人工培养的细胞、组织、体液(例如血液、血清、尿液、唾液等)等。
另一个实施方式提供了一种用于预防和/或治疗癌症的药物组合物,其包含选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、偶联物、嵌合抗原受体、编码它们的多核苷酸、包含所述多核苷酸的重组载体、包含所述重组载体的重组细胞和表达所述嵌合抗原受体的免疫细胞的一者或多者作为活性成分。
另一个实施方式提供了一种用于预防和/或治疗癌症的方法,所述方法包括将药物有效剂量的选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、偶联物、嵌合抗原受体、编码它们的多核苷酸、包含所述多核苷酸的重组载体、包含所述重组载体的重组细胞和表达所述嵌合抗原受体的免疫细胞的一者或多者给药到需要预防和/或治疗癌症的受试者中。
另一个实施方式提供了选自所述GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、偶联物、嵌合抗原受体、编码它们的多核苷酸、包含所述多核苷酸的重组载体、包含所述重组载体的重组细胞和表达所述嵌合抗原受体的免疫细胞的一者或多者的用途,其用于预防和/或治疗癌症或用于制备预防和/或治疗癌症的药物组合物。
除了活性成分(GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、嵌合抗原受体、编码它们的多核苷酸、包含所述多核苷酸的重组载体、包含所述重组载体的重组细胞和表达所述嵌合抗原受体的免疫细胞)之外,本说明书中提供的药物组合物还可以包含药学上可接受的载体。所述药学上可接受的载体是在药物的制备中常用的载体,并且可以是选自乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、矿物油等的一者或多者,但不限于此。所述药物组合物还可以包含选自药物组合物的制备中常用的稀释剂、赋形剂、润滑剂、润湿剂、甜味剂、调味剂、乳化剂、悬浮剂、防腐剂等的一者或多者。
所述药物组合物或抗体或其抗原结合片段的有效剂量可以被口服或肠胃外给药。在肠胃外给药的情况下,它可以通过静脉内注射、皮下注射、肌肉内注射、腹膜内注射、内皮给药、肺内给药、直肠内给药或病变部位局部给药等来给药。在口服给药的情况下,当摄入蛋白质或肽时,可以配制口服组合物以包被活性药物或保护它免于在胃中降解。此外,所述组合物可以通过可以将活性物质移动到靶细胞(例如癌细胞)的任何装置来给药。
所述抗GUCY2C抗体或其抗原结合片段可以以药物有效剂量包含在所述药物组合物中或给药到患者中。在本说明书中,“药物有效剂量”可以是指活性成分的能够表现出所述活性成分(GUCY2C结合多肽、与GUCY2C特异性结合的抗体或其抗原结合片段、融合蛋白、嵌合抗原受体和/或免疫细胞)的所需效果(例如抗癌效果)的量。所述药物有效剂量可以根据患者的年龄、体重、性别、病情、食物、排泄率、反应敏感性、制备方法、给药时间、给药间隔、给药途径、给药方法等因素进行不同的处方。例如,所述活性成分的每日剂量可以在0.005ug/kg至1000mg/kg、0.005ug/kg至500mg/kg、0.005ug/kg至250mg/kg、0.005ug/kg至100mg/kg、0.005ug/kg至75mg/kg、0.005ug/kg至50mg/kg、0.01ug/kg至1000mg/kg、0.01ug/kg至500mg/kg、0.01ug/kg至250mg/kg、0.01ug/kg至100mg/kg、0.01ug/kg至75mg/kg、0.01ug/kg至50mg/kg、0.05ug/kg至1000mg/kg、0.05ug/kg至500mg/kg、0.05ug/kg至250mg/kg、0.05ug/kg至100mg/kg、0.05ug/kg至75mg/kg或0.05ug/kg至50mg/kg的范围内,但不限于此。所述每日剂量可以通过以单剂形式配制在一个制剂中、通过适当分配进行配制或内化在多剂容器中来制备。
所述药物组合物可以被配制成在油或水性介质中的溶液、悬液、糖浆或乳液的形式,或者提取物、粉剂、粉剂、颗粒剂、片剂或胶囊等的形式,并且可以另外包含分散剂或稳定剂用于制剂。
本发明的应用对象患者可以是哺乳动物,包括灵长类动物例如人、猴,啮齿动物例如小鼠、大鼠等。
本说明书中提供的诊断和/或治疗的组合物和/或方法的对象癌症可以是实体癌或血癌,并且不限于此,但是它可以是结肠直肠癌、结肠癌、结肠直肠癌、直肠癌、乳腺癌、肺癌、前列腺癌、卵巢癌、脑癌、肝癌、宫颈癌、子宫内膜癌、子宫癌、肾癌、肾母细胞瘤、皮肤癌、口腔鳞癌、表皮癌、鼻咽癌、头颈癌、骨癌、食管癌、膀胱癌、淋巴癌(例如霍奇金淋巴瘤)、胃癌、胰腺癌、睾丸癌、甲状腺癌、甲状腺滤泡性癌、黑素瘤、骨髓瘤、多发性骨髓瘤、间皮瘤、骨肉瘤、骨髓增生异常综合征、间充质起源的肿瘤、软组织肉瘤、脂肪肉瘤、胃肠道间质肉瘤、恶性周围神经鞘瘤(MPNST)、尤因肉瘤、平滑肌肉瘤、间充质软骨肉瘤、淋巴肉瘤、纤维肉瘤、横纹肌肉瘤、畸胎癌、神经母细胞瘤、髓母细胞瘤、神经胶质瘤、皮肤良性肿瘤或白血病。所述肺癌可以是例如小细胞肺癌(SCLC)或非小细胞肺癌(NSCLC)。所述白血病可以是例如急性髓系白血病(AML)、慢性髓系白血病(CML)、急性淋巴细胞性白血病(ALL)或慢性淋巴细胞性白血病(CLL)。所述癌症可以是原发癌或转移癌。所述癌症可以是表达或过表达GUCY2C的癌症,例如表达或过表达GUCY2C的结肠直肠癌或结肠直肠癌来源的转移癌,但不限于此。
本说明书中的癌症治疗可以意指预防或减轻或改善癌症症状恶化或部分或全部摧毁癌症,例如癌细胞增殖的抑制、癌细胞死亡、转移抑制等的所有抗癌行动。
在一个特定实施方式中,治疗的对象患者可以是接受二次抗过度增殖疗法的患者。例如,所述二次抗过度增殖疗法可以是化疗、放疗、免疫疗法、光疗、冷冻疗法、毒素疗法、激素疗法或外科手术。
在一个实施方式中,使用本申请的包含含有GUCY2C结合多肽的嵌合抗原受体的免疫细胞的抗癌治疗可以通过一系列过程来实现:提取健康人或待治疗患者的血液中的免疫细胞(例如NK细胞、T细胞等),然后进行遗传工程改造以表达本申请的包含GUCY2C结合多肽的嵌合抗原受体,扩增和培养工程改造的免疫细胞,并将所培养的工程改造的免疫细胞给药到患者中。
作为优选实施方式,提取健康人或待治疗患者的血液中的免疫细胞,可以例如通过使用白细胞单采术(或血液成分单采术)分离白细胞,然后浓缩免疫细胞的过程来提取免疫细胞。免疫细胞可以使用特异性抗体珠结合物或标志物,在CD4/CD8配置的水平上分离。或者,可以通过从干细胞分化稳定地获得大量免疫细胞。
进行遗传工程改造以使所述提取的免疫细胞表达本申请中提供的嵌合抗原受体,可以例如通过使用载体例如病毒载体(慢病毒载体或反转录病毒载体等)来注入被设计用于表达嵌合抗原受体(CAR)的核酸分子。所述CAR可以以DNA形式引入,并且可以在以RNA形式引入然后使用反转录酶反转录成DNA后整合到免疫细胞的基因组中。
扩增和培养所述工程改造的免疫细胞可以按照本领域中已知的培养技术培养、增殖和扩增(扩大)免疫细胞。然后,需要针对病毒使用安全性和用于选择生产良好的表达CAR的免疫细胞的技术。
最后,将工程改造的免疫细胞再次给药到患者中,可以例如通过输注来实现。作为一个实施方式,在输注表达CAR的免疫细胞之前,为了降低白细胞计数,患者可以接受化疗,以使用环磷酰胺或氟达拉滨等控制白细胞去除。此外,为了提高表达CAR的免疫细胞的持久性,可以一起给药细胞因子例如IL-2等。
给药到患者中的工程改造的免疫细胞可以介导针对肿瘤的免疫应答。这种免疫应答包括免疫细胞的活化,免疫细胞的细胞因子例如IL-2和IFN-γ的分泌,识别肿瘤抗原的免疫细胞的增殖和扩增,以及靶阳性细胞的免疫细胞介导的特异性死亡(肿瘤去除)。例如,当在表达CAR的免疫细胞中CAR与GUCY2C特异性结合时,所述免疫细胞可以通过CD3ζ的基于酪氨酸的活化基序(免疫受体基于酪氨酸的活化基序,ITAM)的磷酸化而被激活,然后可以诱导所述免疫细胞的增殖、细胞毒性和/或细胞因子的分泌。
正如上文详述的,使用表达CAR的免疫细胞的抗癌疗法从根本上激活患者的免疫系统以表现出持续的抗癌效果,并因此它具有不需连续给药并且能够使用患者自己的免疫细胞进行个性化治疗的优点。
本说明书中提供的组合物的给药可以抑制或停止或延迟病情的出现或进展,或者引起或诱导或促进保护性免疫应答。
有利效果
本说明书中提供的表达以高亲和性与GUCY2C结合的结合片段(抗体、scFv)和在表面上包含所述结合片段的嵌合抗原受体(CAR)的免疫细胞,可以被有用地用作对癌症、特别是表达GUCY2C的癌症具有出色的抗癌效果的抗癌药剂。
附图说明
图1a是示意图,示意显示了使用ELISA测量scFv与GUCY2C的结合亲和性的过程。
图1b是示出了通过ELISA测量的scFv与3种GUCY2C(人GUCY2C、猴GUCY2C和小鼠GUCY2C)的结合亲和性的图。
图2a是示意图,示意显示了使用ELISA测量scFv与GUCY2C的亲和性排序的过程。
图2b和2c示出了通过ELISA测量的scFv与GUCY2C的亲和性排序的测量结果,并且2b示出了scFv 5nM的结果,2c示出了scFv 50nM的结果。
图3a示出了scFv与GUCY2C细胞的细胞结合测定的结果。
图3b是示出了作为scFv与GUCY2C细胞的细胞结合测定的结果而获得的MFI(荧光强度平均值)的图。
图4a是示出了通过流式细胞术确认在iPSC中分化的幼稚NK细胞的NK细胞表面标志物的表达的结果的图。
图4b是示出了确认在iPSC中分化的幼稚NK细胞的NK细胞表面标志物的表达的结果的图。
图4c是示出了确认在iPSC中分化的幼稚NK细胞的NK细胞凋亡过程的效应分子的表达的结果的图。
图5是示出了在引入抗GUCY2C CAR的NK细胞中抗GUCY2C CAR的表达水平的图。
图6a是示出了表达抗GUCY2C-CAR的NK细胞对不表达GUCY2C的靶细胞的细胞毒性的图。
图6b是示出了表达抗GUCY2C-CAR的NK细胞对表达GUCY2C的靶细胞的细胞毒性的图。
图7是示出了表达抗GUCY2C-CAR的NK细胞在体外对不表达GUCY2C的靶细胞和表达GUCY2C的靶细胞的CAR依赖性杀伤能力的图。
图8是示出了表达抗GUCY2C-CAR的NK细胞和靶向CD19的CAR-NK细胞在体内的CAR依赖性杀伤能力的图。
图9a是证实了当将表达抗GUCY2C-CAR的NK细胞与表达GUCY2C的靶细胞共培养时分泌的IFN-γ的量显著提高的图。在所述图中,“无NK”是未用NK细胞处理的实验组,并且对应于值0。
图9b是证实了当将包含GUCY2C结合性scFv(5F9、D08、G07)的CAR-NK细胞与作为GUCY2C阳性癌细胞的T84细胞共培养时分泌的IFN-γ的量显著提高的图。在所述图中,“无NK”是未用NK细胞处理的实验组,并且对应于值0。
图10是将给药表达抗GUCY2C-CAR的NK细胞时的存活率与对照组(载体给药组)的存活率进行比较的图。
具体实施方式
在下文中,将通过实施例更详细描述本发明,但所述实施例仅仅是说明性的,并不意图限制本发明的范围。对于本领域技术人员来说显而易见的是,在不违背本发明的基本要旨的情况下,下面描述的实施例可以在一定范围内修改。
实施例1:GUCY2C结合性scFv的产生
通过将人GUCY2C(R&D Systems,目录号2157-GC;SEQ ID NO:112)与CD4(SEQ IDNO:115)偶联制备了重组抗原,并筛选分泌特异性针对所述抗原的scFv的克隆,以获得18种与GCUCY2C特异性结合的scFv。
如上所述获得的scFv和编码它们的核酸分子分别示出在下面的表4和表5中:
[表4]
scFv氨基酸序列
(在表4中,粗体和下划线的区域依次表示CDR-H1、CDR-H2和CDR-H3、CDR-L1、CDR-L2和CDR-L3)
[表5]
编码scFv的核酸分子
实施例2:所选scFv与GUCY2C的结合亲和性
通过ELISA测量了实施例1中产生的scFv与抗原GUCY2C的结合亲和性。作为用于测量结合亲和性的抗原,与实施例1中制备的人GUCY2C重组抗原一起使用了通过相同方法制备的猴GUCY2C重组抗原和鼠类GUCY2C重组抗原,测量了与每种抗原的亲和性(参见图1a)。
更具体而言,将其中分别融合了所制备的人GUCY2C(SEQ ID NO:112)、猴GUCY2C(SEQ ID NO:114)和小鼠GUCY2C(SEQ ID NO:113)的GUCY2C-rCD4融合蛋白结合到NuncMaxisorpTM 96孔板中用链霉亲和素包被的地方。在用清洗缓冲液除去所有未结合的合成蛋白后,将在培养溶液中获得的抗GUCY2C scFV在每个孔中温育。然后,通过使用Eu-抗标签Ab读取DELFIA增强的信号来测量亲和性。
所使用的抗原的信息如下:
此外,以两种浓度(5nM、50nM)制备了实施例1中产生的18种scFv,并将它们分别用作ELISA的第一抗体以检测GUCY2C抗原,从而测量每个克隆之间的结合亲和性强度,并使用其获得排序。更具体而言,在MaxiSorb板中包被抗FLAG抗体并通过添加以前获得的scFv进行结合后,通过清洗过程除去剩余的scFv。此时,将生物素化的人GUCY2C-rCD4蛋白温育并合并,然后通过经由链霉亲和素-铕显色DELFIA增强法读取信号,来测量与抗原的亲和性。
此外,通过SPR(表面等离子体共振)分析测量了实施例1中产生的18种scFv对GUCY2C抗原的亲和性。更具体而言,将蛋白G以150ug/ml的浓度附连到HCA芯片,然后将5mMscFv和从800nM至12.5nM不同浓度的抗原以40ul/sec的速率流过。SPR测定使用2min结合时间和10min解离时间,在25摄氏度条件下使用MASS2(Sierra SPR-32;Bruker)进行。使用R3软件分析数据。
如上所述测量的18种scFv(SEQ ID NO:1至18)和阳性对照组scFv(5F9 scFv-Fc;SEQ ID NO:19)与3种抗原(人GUCY2C、猴GUCY2C和小鼠GUCY2C)的结合亲和性和亲和性排序结果,示出在表6以及图1b(结合亲和性,ELISA)、2b(亲和性排序,5nM)和2c(亲和性排序,50nM)中:
[表6]
(n.d.:未检测到)
正如表6和图1b中所示,显示了所有18种scFv与人GUCY2C的结合亲和性明显高于与猴GUCY2C和小鼠GUCY2C的结合亲和性,并且确认了它与人GUCY2C特异性结合。此外,正如在表6和图2b和2c中所示,确认了在与人GUCY2C具有相对高亲和性的scFv中存在与猴GUCY2C的亲和性。当对SPR结果进行总体测定时,证实了A10的scFV对人和猴GUCY2C具有相对高的结合能力和亲和性。
实施例3:细胞结合测定
使用天然表达GUCY2C的细胞,确认了实施例1中产生的18种scFv是否能够实际检测细胞表面上的GUCY2C表达。为此,使用了GUCY2C阳性癌细胞T84结肠癌细胞(CCL-248TM)。作为对照组,使用了GUCY2C阴性乳腺癌细胞T-47D(HTB-133TM)。
在使用胰蛋白酶-EDTA分离所述两种细胞系后,将它们置于FACS缓冲液(1x PBS+2%BSA)中。将10ug/mL的18种scFv和阳性对照组5F9 scFv中的每一者与T84和T-47D细胞在冰上培养1小时。使用5ug/mL IgG-Fc-PE Ab(BioLegend;409304)检测与细胞结合的scFv。将细胞与3(活/死染色剂)培养,然后使用流式细胞仪读数。使用FlowJo 10.5软件(FlowJo LLC)分析得到的数据。
得到的结果示出在图3a中。
此外,通过流式细胞术获得的MFI(荧光强度平均值)示出在图3b中。
如图3a和3b中所示,确认了A10 scFv(SEQ ID NO:9)以与阳性对照组5F9相等的水平结合到表达GUCY2C的T84细胞,并且B01scFv(SEQ ID NO:11)、B11 scFv(SEQ ID NO:15)和B12 scFv(SEQ ID NO:16)也显示出结合可能性。
实施例4:表达抗GUCY2C-CAR的免疫细胞(NK细胞)的制备
4.1.慢病毒产生
CAR-NK细胞是其中嵌合抗原受体(CAR)在NK细胞表面上表达的形式,并且在本实施例中使用的嵌合抗原受体由包含与GUCY2C结合的scFv多肽(参见实施例1和表4)的胞外结构域、跨膜结构域(CD28;由GenBank登记号NM_006139.4编码)和细胞内信号传导结构域(CD3ζ;由GenBank登记号NM_001378516.1编码)组成(抗GUCY2C-CAR)。通过慢病毒将CAR基因导入NK中。
为了产生表达CAR的慢病毒,通过用Lipofectamine 3000转染试剂盒(#L3000015,Invitrogen)和表达抗GUCY2C CAR(GUCY2C结合性scFv-CD28-CD3ζ)的质粒处理LentiX-293T(#632180Clonthech)进行病毒质粒转染,并在转染后次日起2天内,获得上清液。使用Lenti-X浓缩器(#631232,Clonetech)浓缩病毒。将得到的沉淀物溶解在CTS-PBS中并储存在-80℃下。
在使用病毒RNA分离试剂盒(#740956,Macherey-Nagel)从病毒提取RNA后,使用Lenti-X qRT-PCR滴定试剂盒(#631235,Takara)测量病毒滴度。
实施例4.2.NK细胞的制备
将iPSC(CMC-hiPSC-003,Korea Centers for Disease Control andPrevention)在mTeSRTM Plus(STEMCELL Technoology,100-0276)中培养2~3天,并且在形成直径为约500μm的聚集体时,将培养溶液改变成STEMdiffTM造血试剂盒(STEMCELLTechnoology,05310)的培养基A,由此进行造血干细胞(HSC)分化。在培养基A中培养3天后,将它们另外在同一试剂盒的培养基B中培养9天,以获得HSC。然后,每2~3天除去一半的培养溶液,并添加相同量的新培养溶液以代替所述培养溶液。
将HSC转移到用StemSpanTM NK细胞生成试剂盒(STEMCELL Technoology,09960)中包含的淋巴系分化包被材料表面处理的板,并在同一试剂盒中包含的淋巴系祖细胞扩增培养基中培养14天,并且每3~4天更换一半的培养溶液。然后,在通过在NK细胞分化培养基中每3~4天更换一半的培养溶液进行培养后14天内,获得NK细胞。
实施例4.3.在iPSC中分化的幼稚NK细胞的表面类型特征的证实
为了证实在实施例4.2中获得的在iPSC中分化的幼稚NK细胞的分化是否正常进行以及它们是否具有表面类型特性和NK细胞固有功能(穿孔素、颗粒酶B、IFN),通过流式细胞术证实了NK细胞表面标志物的表达,并证实了NK细胞的凋亡过程效应分子的表达。
具体而言,将实施例4.2中获得的在iPSC中分化的幼稚NK细胞与图4a至图4b中表示的每种抗体在4℃下温育1小时,然后使用流式细胞仪(FACS)证实它们。此外,为了证实细胞内的细胞因子表达,使用通透化试剂盒在细胞表面中开孔并使用固定溶液进行固定,然后使用图4c中表示的抗体(TNF-α、IFN-γ、穿孔素、颗粒酶B)对它们进行染色,并使用流式细胞仪对它们进行分析。
得到的结果示出在图4a至4c中,如图4a和4b中所示,表达抗GUCY2C CAR的NK细胞显示出低CD117表达和高CD94/NKG2D表达,并显示出NK细胞的成熟表型,并且已证实NK活化受体的表达高并且细胞因子受体正常表达。此外,如图4c中所示,证实了作为NK细胞凋亡过程中的主要因子的IFN-γ、颗粒酶B和穿孔素在表达抗GUCY2C CAR的NK细胞中的高表达。
实施例4.4.表达抗GUCY2C CAR的NK细胞的产生
在如上所述从iPSc获得NK细胞的过程中,在中间的HSC步骤中,将其中装载有实施例4.1中制备的抗GUCY2C CAR(GUCY2C结合性scFv-CD28-CD3ζ)的慢病毒以MOI 3000用lentiboost(Sirion)处理,并在第二天使用NK细胞,通过所描述的方法进行分化。
为了证实包含克隆ID A12(SEQ ID NO:3)、D08(SEQ ID NO:9)、H07(SEQ ID NO:11)、G07(SEQ ID NO:15)或5F9(SEQ ID NO:19;阳性对照)作为GUCY2C结合性scFv的CAR在分化的NK细胞中的表达,使用了1:100稀释的偶联有FITC的山羊抗人Fab抗体(#31628,Invitrogn),并将其在4摄氏度下温育20分钟。然后,将它用FACS缓冲液(2% FBS/PBS)清洗,并通过FACS分析(LSR fortessa,BD)确认表达水平。
得到的结果示出在图5中。如图5中所示,证实了所有分化的NK细胞均表达GUCY2C结合性scFv(D08、G07、A12、H07)。
实施例4.5.表达抗GUCY2C-CAR的NK细胞的体外细胞毒性测试
将GUCY2C基因(NM_004963.4)亚克隆在pLV-EF1α-puroR质粒中,并通过参考实施例4.1中描述的方法产生慢病毒。将制备的慢病毒转导到HT29细胞(ATCC HTB38TM)中以在细胞表面上表达它,并在2天后通过以2.5ug/ml的浓度用嘌呤霉素处理仅选择表达GUCY2C的细胞。在如此选择2周后,最终获得表达GUCY2C的HT29细胞系。使用CFSE增殖试剂盒(Thermo Fisher,C34554)标记如此制备的靶细胞(HT29(ATCC HTB38TM)或HT29-GUCY2C)。
在用PBS清洗后,将每种比率的效应细胞(表达抗GUCY2C-CAR的NK细胞)等分在96孔板中使得成为100ul/孔。将每种靶细胞固定,并根据E(效应细胞):T(靶细胞)比例调整NK细胞的数量,由此制备使得E:T比例为10:1、3:1、1:1、0.5:1。然后制备仅具有靶细胞的样品和仅具有效应细胞的孔用于阴性对照。将这些混合细胞在37℃温箱中培养4小时,然后用FACS清洗缓冲液(10% FBS/PBS)清洗,并最后用70ul/孔的DAPI-FACS缓冲液(DAPI最终工作浓度5ug/ml)制备样品,然后在10分钟内通过FACS(iQue Screener PLUS)进行分析。使用所述分析值,通过下述等式转换裂解活性。
得到的结果示出在图6a(靶细胞是HT29细胞的情况下的结果)和6b(靶细胞是表达GUCY2C的HT29细胞的情况下的结果)中。如图6a和6b中所示,表达包括4种GUCY2C结合性scFv(D08、G07、A12、H07)的CAR的NK细胞(CAR-NK)的细胞毒性得以确认。证实了当靶细胞是不表达GUCY2C的结肠直肠癌细胞系HT29时,CAR-NK显示出约20%或更低的细胞毒性,而它在过表达GUCY2C的HT29-GUCY2C靶细胞系中显示出最大60%或更大的细胞毒性。证实了取决于scFv的类型,细胞毒性值存在差异,但所有使用的克隆均显示出针对GUCY2C的剂量依赖性细胞毒性。
4.6表达抗GUCY2C-CAR的NK细胞在体外的CAR依赖性杀伤效果和NK固有杀伤(CAR不依赖性)效果的证实
为了证实表达抗GUCY2C-CAR的NK细胞的体外CAR依赖性杀伤效果,使用表达包含GUCY2C结合性scFv(D08)的CAR的NK细胞进行了下述实验。
具体而言,通过与实施例4.4中描述的方法相同的方法固定靶细胞细胞(HT29(ATCC HTB38TM)或HT29-GUCY2C),并通过FACS(iQue Screener PLUS)分析它们。使用所述分析值,通过下述等式转换裂解活性。
分化如下进行:制造聚集体并接种一定的量,然后通过造血干细胞分化培养基固定造血干细胞,并将它们分化成淋巴系祖细胞。再次通过分化成NK细胞的过程来获得细胞。
得到的结果示出在图7中(靶向GUCY2C的CAR-NK细胞的克隆号为D08)。如图7中所示,当将表达包含GUCY2C结合性scFv(D08)的CAR的NK细胞(靶向GUCY2C的CAR-NK细胞)与靶细胞系在体外共培养时,证实了CAR依赖性杀伤效果和NK固有杀伤效果(CAR不依赖性)。换句话说,通过图7的GUCY2C-HT29细胞中细胞毒性随着E:T比例的增加(效应细胞增加)而增加的结果,证实了它们具有CAR浓度依赖性而不是随机的杀伤效果,并且通过即使在模拟HT29细胞中也显示出细胞毒性,证实了也存在NK固有杀伤效果(CAR不依赖性)。
实施例4.7.表达抗GUCY2C-CAR的NK细胞在体内的CAR依赖性杀伤效果和NK固有杀伤(CAR不依赖性)的证实
为了证实表达抗GUCY2C-CAR的NK的体内CAR依赖性杀伤效果和NK固有杀伤(CAR不依赖性)效果,使用表达包含GUCY2C结合性scFv(D08)的CAR的NK细胞进行了下述实验。
具体而言,在将CFSE染色的靶细胞系(HT29-GUCY2细胞)腹膜内注射到小鼠中之后1小时内,将表达包含GUCY2C结合性scFv(D08)的CAR的NK细胞与IL-2/15一起腹膜内注射,以证实在小鼠体内靶细胞的减少程度。为观察此情况,通过等待4小时,将PBS注射到腹腔中并再次回收它的方法获得腹腔中的剩余细胞,并通过经流式细胞术测量CFSE染料的方法来观察靶细胞的死亡。
结果,如图8中所示,证实了表达包含GUCY2C结合性scFv(D08)的CAR的NK细胞在体内的CAR依赖性杀伤效果和NK固有杀伤效果(CAR不依赖性)。
实施例4.8.表达抗GUCY2C-CAR的NK细胞的IFN-γ分泌能力的证实
为了证实表达抗GUCY2C-CAR的NK细胞的IFN-γ分泌能力影响杀伤能力,使用表达包含GUCY2C结合性scFv(5F9、D08、G07)的CAR的NK细胞进行了下述实验。
具体而言,使用ELISA方法测量IFN-γ分泌能力,并在将靶细胞和每种NK细胞共培养24小时后,回收上清液。将回收的上清液在包被有识别IFN-γ的抗体的板中温育,并通过清洗操作除去剩余的溶液。为此,通过再次识别能够显色的IFN-γ抗体,测量显色程度以证实所分泌的IFN-γ。
结果,如图9a中所示,证实了当将表达抗GUCY2C-CAR的NK细胞与过表达GUCY2C的HT29-GUCY2C靶向细胞系(HT29 GCC细胞)共培养时,分泌的IFN-γ的量显著增加。如图9b中所示,通过在不包含CAR的幼稚NK(幼稚NK)细胞中与HT29-GUCY2C细胞共培养,IFN-γ的量没有增加,并且通过与GUCY2C阳性癌细胞T84细胞共培养证实了相对少量的IFN-γ增加。另一方面,证实了当将表达包含GUCY2C结合性scFv(5F9、D08、G07)的CAR的NK细胞与GUCY2C阳性癌细胞T84细胞共培养时,与不表达GUCY2C的模拟HT29细胞相比IFN-γ量显著增加。
实施例4.9.当在动物模型中给药表达抗GUCY2C-CAR的NK细胞时存活率的证实
为了证实当在动物模型中给药表达抗GUCY2C-CAR的NK细胞时的存活率,进行了下述实验。
具体而言,在将HT29-GUCY2C-Luc细胞i.p.(2.5x106个细胞)移植到NOG小鼠(DO)中之后,在第3天,将表现出相同量的HT29细胞(IVIS总通量)的小鼠分组,并一起给药CARNK和细胞因子。GUCY2C-CAR NK细胞以1x107个细胞的量腹膜内给药,并且给药的细胞因子的浓度为hIL-2(Novartis Proleukin)/10ug(ip,4次/周)、hIL-15(Peprotech)/3ug(ip,qd)。然后证实每个实验组的存活率和存活天数。
[表7]
结果,如表7和图10中所示,证实了与对照组相比,在CAR-NK细胞给药组中存活率明显较高,并且CAR-NK细胞给药组的存活天数长于对照组,因为对照组的平均存活天数为66天,而CAR-NK细胞给药组为82.5天。
<110> 株式会社LG化学(LG CHEM, LTD.)
<120> GUCY2C结合多肽及其用途
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Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
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Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Glu Phe
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Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
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Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Asp Gly Gln Trp Leu Gln Phe Asp Tyr Trp Gly Gln Gly Thr
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Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
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Gly Gly Gly Ala Ser Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu
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Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln
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Ser Leu Leu Lys Lys Ser Asp Gly Asn Thr Tyr Leu Ser Trp Tyr His
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Gln Arg Pro Gly Gln Ser Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn
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Arg Asp Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Asp Thr
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Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Thr Glu Asp Val Gly Ile
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Tyr Tyr Cys Met Gln Gly Ser His Trp Pro Pro Thr Phe Gly Gln Gly
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Thr Lys Val Glu Ile Lys
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Leu Ser Ser Tyr
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Gly Arg Ile Ile Pro Ile Leu Gly Ile Thr Asn Tyr Ala Gln Lys Phe
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Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
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Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Leu Ser Ser Tyr
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Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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Gly Arg Ile Ile Pro Ile Leu Gly Ile Thr Asn Tyr Ala Gln Lys Phe
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Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
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Thr Val Leu
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Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
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Gly Arg Ile Ile Pro Val Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
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Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
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Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Gly Ser Tyr
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Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
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Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
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Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
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Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
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Ser Arg Val Thr Ile Ser Arg Asp Lys Ser Lys Asn Gln Leu Phe Leu
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Leu Thr Val Leu
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<223> 合成的GUCY2C结合性scFv
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
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Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val
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Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
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Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
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Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
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Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln
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<223> 合成的GUCY2C结合性scFv
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Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
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Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
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Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
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Tyr Tyr Cys Gln Gln Ser Ile Ser Leu Pro Tyr Thr Phe Gly Gln Gly
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Thr Lys Val Glu Ile Lys
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<210> 10
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv
<400> 10
Glu Val Gln Leu Val Gln Pro Gly Ala Glu Val Lys Lys Pro Gly Ser
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Leu Ser Ser Tyr
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Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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Gly Arg Ile Ile Pro Ile Leu Gly Ile Thr Asn Tyr Ala Gln Lys Phe
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Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
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Ala Arg Asp Gln Arg Pro Ala Ser Met Asp Val Trp Gly Gln Gly Thr
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Gly Gly Gly Ala Ser Gln Ser Glu Leu Thr Gln Pro Ala Ser Val Ser
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Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser
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Asp Val Gly Gly Tyr Ile Tyr Val Ser Trp Tyr Gln Gln His Pro Gly
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Lys Val Pro Lys Leu Met Ile His Asp Val Ser His Arg Pro Ser Gly
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Val Ser Asn Arg Phe Ser Gly Ser Arg Ser Gly Asn Thr Ala Ser Leu
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Ser Tyr Thr Ser Ser Asn Asn Tyr Val Phe Gly Thr Gly Thr Lys Val
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Thr Val Leu
<210> 11
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv
<400> 11
Glu Val Gln Leu Val Gln Pro Gly Ala Glu Val Lys Lys Pro Gly Ser
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Leu Ser Ser Tyr
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Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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Gly Arg Ile Ile Pro Ile Leu Gly Ile Thr Asn Tyr Ala Gln Lys Phe
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Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
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Ala Arg Asp Gln Arg Pro Ala Ser Met Asp Val Trp Gly Gln Gly Thr
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Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
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Thr Val Leu
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<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv
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Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Arg Pro Gly Ser
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
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Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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50 55 60
Gln Gly 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
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100 105 110
Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Ala Ser Asp Ile Val Met Thr Gln Ser Pro Leu
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Ser Leu Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser
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Ser Gln Ser Leu Val Tyr Thr Asp Gly Asn Thr Tyr Leu Asn Trp Phe
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Gln Gln Arg Pro Gly Gln Ser Pro Arg Arg Leu Ile Tyr Lys Val Ser
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Asn Arg Asp Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
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Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly
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Ile Tyr Tyr Cys Met His Ser Lys Gln Trp Pro Pro Thr Phe Gly Gly
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Gly Thr Lys Val Glu Ile Lys
245
<210> 13
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv
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Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly His Tyr Tyr Tyr Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Ala Ser Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser
130 135 140
Val Ser Pro Gly Glu Gly Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
145 150 155 160
Val Ser Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro
165 170 175
Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn
210 215 220
Asn Trp Pro Ser Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
225 230 235
<210> 14
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv
<400> 14
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly His Tyr Tyr Tyr Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Ala Ser Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser
130 135 140
Val Ser Pro Gly Glu Gly Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
145 150 155 160
Val Ser Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro
165 170 175
Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn
210 215 220
Asn Trp Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
225 230 235
<210> 15
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv
<400> 15
Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Gly Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ile Gln Pro Leu Arg Tyr Tyr Gly Met Asp Val Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Ala Ser Gln Ser Ala Leu Thr Gln Pro Pro
130 135 140
Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly
145 150 155 160
Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr Trp Tyr Gln Gln Leu
165 170 175
Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Arg Asn Asn Gln Arg Pro
180 185 190
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala
195 200 205
Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr
210 215 220
Cys Ala Ala Trp Asp Asp Ser Leu Ser Gly Arg Gly Val Phe Gly Gly
225 230 235 240
Gly Thr Gln Leu Thr Val Leu
245
<210> 16
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv
<400> 16
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Ser Gly Gly Ser Thr His Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg His 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 Gly Ala Gly Thr Leu Asn Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Ala Ser Gln Ser Gly Leu Thr Gln Pro Pro Ser Thr Ser
130 135 140
Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser
145 150 155 160
Asp Val Gly Ala Tyr Ser Tyr Val Ser Trp Tyr Gln Gln His Pro Gly
165 170 175
Lys Ala Pro Lys Leu Leu Ile Tyr Ala Val Thr Lys Arg Pro Ser Gly
180 185 190
Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu
195 200 205
Thr Val Ser Gly Leu Gln Asp Glu Asp Glu Ala Asp Tyr Tyr Cys Ser
210 215 220
Ser Phe Ala Gly Gly Ser Thr Leu Val Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Thr Val Leu
<210> 17
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv
<400> 17
Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Gly Tyr Ser Ser Ile Tyr Tyr Tyr Tyr Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Ala Ser Gln Ser Gly Leu Thr Gln Pro
130 135 140
Arg Ser Val Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr
145 150 155 160
Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln
165 170 175
Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Ser Lys
180 185 190
Arg Pro Ser Gly Val Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn
195 200 205
Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gly Ser Tyr Thr Ser Asp Gly Thr Leu Val Phe Gly Gly
225 230 235 240
Gly Thr Lys Leu Thr Val Leu
245
<210> 18
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv
<400> 18
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Thr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ser Tyr Asn Trp Leu Asp Pro Trp Gly Arg Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Ala Ser Gln Ser Ala Leu Thr Gln Pro Val Ser Val Ser
130 135 140
Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ile Ser
145 150 155 160
Asp Val Gly Asp Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly
165 170 175
Lys Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly
180 185 190
Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu
195 200 205
Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser
210 215 220
Ser Tyr Thr Ser Ser Ser Thr Leu Val Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Thr Val Leu
<210> 19
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv
<400> 19
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Gly Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Lys Thr Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Asn Val Glu Ile Lys Ala Ser Gly Gly Gly
100 105 110
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Glu Leu Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys
130 135 140
Pro Ser Glu Thr Leu Ser Leu Thr Cys Ala Val Phe Gly Gly Ser Phe
145 150 155 160
Ser Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu
165 170 175
Glu Trp Ile Gly Glu Ile Asn His Arg Gly Asn Thr Asn Asp Asn Pro
180 185 190
Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln
195 200 205
Phe Ala Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr
210 215 220
Tyr Cys Ala Arg Glu Arg Gly Tyr Thr Tyr Gly Asn Phe Asp His Trp
225 230 235 240
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250
<210> 20
<211> 738
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 20
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60
tcctgcaagg catctggata caccttcacc agctactata tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaata atcaacccta gtggtggtag cacaagctac 180
gcacaggagt tccagggcag agtcaccatg accagggaca cgtccacgag cacagtctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagatggg 300
cagtggcttc aatttgacta ctggggccaa ggaaccctgg tcaccgtctc gagtggtgga 360
ggcggttcag gcggaggtgg ctctggcggt ggcgctagcg atattgtgat gacacagtct 420
ccactctccc tgcccgtcac ccttgggcag ccggcctcca tctcctgcag gtctagtcaa 480
agcctcctaa aaaagagtga tgggaacacc tacttgagtt ggtatcacca gaggccaggc 540
caatctccac ggcgcctaat ttataaggtt tctaatcggg actctggggt cccagacaga 600
ttcagcggca gtgggtcaga cactgatttc actctgaaaa tcagcagagt ggagactgag 660
gatgttggaa tttattactg catgcaaggt tcacactggc ctccgacgtt cggccaaggg 720
accaaggtgg aaatcaaa 738
<210> 21
<211> 729
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 21
gaggtgcagc tggtgcagcc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccctcagc agctatgcta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat aacaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt atttctgtgc gagagatcag 300
cggccggcga gcatggacgt ctggggccag ggcaccctgg tcaccgtctc gagtggtgga 360
ggcggttcag gcggaggtgg ctctggcggt ggcgctagcc agtctgagct gactcagcct 420
gcctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccagcagt 480
gacgttggtg gttatatcta tgtctcctgg taccaacagc acccaggcaa agtccccaaa 540
ctcatgattc atgatgtcag tcatcggccc tcaggggttt ctaatcgctt ctctggctcc 600
aggtctggca acacggcctc cctgaccatc tctgggctcc aggctgagga cgaggctgac 660
tatttctgca gctcatatgc aggcagcaac aattatgtct tcggaactgg gaccaaggtc 720
accgtccta 729
<210> 22
<211> 735
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 22
caggtccagc tggtgcaatc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccttcagc agctatacta tcagctgggt gcgacaggcc 120
cctggacaag agcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattat 300
agcagcagct ggaactctat ggacgtctgg ggccagggaa ccctggtcac cgtctcgagt 360
ggtggaggcg gttcaggcgg aggtggctct ggcggtggcg ctagccagtc tgggctgact 420
cagcctccct ccgcgtccgg gtctcctgga cagtcagtca ccatctcctg cactggaacc 480
agcagtgaca ttggttatta tcactatgtc tcctggtacc aacaacaccc gggcaaagcc 540
cccaaactca tgatttatga ggacagtaag aggccctcag ggatttctaa tcgtttctct 600
ggctccaagt ctggcaccac ggcctccctg accgtctctg ggctccaggc tgaggacgag 660
gctcattatt actgcagttc ttttacaagt agaagtactt gggtgttcgg cggagggacc 720
cagctcaccg tccta 735
<210> 23
<211> 729
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 23
gaggtgcagc tggtgcagcc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccctcagc agctatgcta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat aacaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt atttctgtgc gagagatcag 300
cggccggcga gcatggacgt ctggggccag ggcaccctgg tcaccgtctc gagtggtgga 360
ggcggttcag gcggaggtgg ctctggcggt ggcgctagcc agtctgagct gactcagcct 420
gcctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccagcagt 480
gacgttggtg gttatatcta tgtctcctgg taccaacagc acccaggcaa agtccccaaa 540
ctcatgattc atgatgtcag tcatcggccc tcaggggttt ctaatcgctt ctctggctcc 600
aggtctggca acacggcctc cctgaccatc tctgggctcc aggctgagga cgaggctgac 660
tatttctgca gctcatatac aagcagcaac aattattact tcggaactgg gaccaaggtc 720
accgtccta 729
<210> 24
<211> 735
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 24
caggtccagc tggtgcaatc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccttcagc agctatacta tcacctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaagg atcatccctg tccttggtat agcaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattat 300
agcagcagct ggaactctat ggacgtctgg ggccagggaa ccctggtcac cgtctcgagt 360
ggtggaggcg gttcaggcgg aggtggctct ggcggtggcg ctagccagtc tgggctgact 420
cagcctcgct cagtgtccgg gtctcctgga cagtcagtca ccatctcctg cactggaacc 480
agcagtgatg ttggtggtta taactatgtc tcctggtacc aacagcaccc aggcaaagcc 540
cccaaactca tgatttatga tgtcagtaag cggccctcag gggtccctga tcgcttctcc 600
ggctccaagt ctgggaacac ggcctccctg accgtctctg ggctccacgc tgaggatgag 660
gctgattatt actgcagctc atatgcaggc agcaacaatt ttgtcttcgg aactgggacc 720
aaggtcaccg tccta 735
<210> 25
<211> 735
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 25
caggtgcagc tggtgcaatc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccttcggc agctatacta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattat 300
agcagcagct ggaactctat ggacgtctgg ggccaaggaa ccctggtcac cgtctcgagt 360
ggtggaggcg gttcaggcgg aggtggctct ggcggtggcg ctagccagtc tgggctgact 420
cagcctcgct cagtgtccgg gtctcctgga cagtcagtca ccatctcctg cactggaacc 480
agcagtgatg ttggtgctta taactatgtc tcctggtacc aacagcaccc aggcaaagcc 540
cccaaactca tgatttatga ggtcagtaag cggccctcag gggtccctga tcgcttctct 600
gcctccaagt ctggcaacac ggcctccctg accgtctctg ggctccaggc tgaggatgag 660
gctgattatt actgcagctc atatgcaggc agcaacaatt gggtgttcgg cggagggacc 720
aagctgaccg tccta 735
<210> 26
<211> 732
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 26
caggtgcagc tgcaggagtc gggcccaggg cttgtgaagc cttcggagac cctgtccctc 60
acttgcactg tctctggtgg ctccatcagt agttactact ggagctggat ccggcagccc 120
ccagggaagg gactggagtg gattgggtct atctattaca gtgggagcac caactacaac 180
ccctccctca agagtcgagt caccatctca agagacaagt cgaagaacca gttgtttctg 240
aagttgaatt ctatgaccgc cgcggacacg gccgtctatt attgtgcgag agatgtttgg 300
ggcagtggcc agtcatttga cagttggggc cagggcaccc tggtcaccgt ctcgagtggt 360
ggaggcggtt caggcggagg tggctctggc ggtggcgcta gcaattttat gctgactcag 420
ccccactctg tgtcggagtc tccggggaag acggtaacca tctcctgcac ccgcagcagt 480
ggcagcattg ccagcaacta tgtgcagtgg taccagcagc gcttgggcag ttcccccacc 540
actgtgatct atgaacatag ccgaagaccc tctggggtcc ctgatcggtt ctctgcctcc 600
atcgacagct cctccaactc tgcctccctc accatctctg gactgaagac tgaggacgag 660
gctgactact actgtcagtc ttatgatgtc agcaatcgag tgttcggcgg agggaccaag 720
ctgaccgtcc ta 732
<210> 27
<211> 738
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 27
gaggtgcagc tgttggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agctattgga tgagctgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gaaatactat 180
gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attattgtgc gaaagccccg 300
tggtatagca gctcgccgac accctacggt atggacgtct ggggccaggg caccctggtc 360
accgtctcga gtggtggagg cggttcaggc ggaggtggct ctggcggtgg cgctagcgac 420
atccagatga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 480
acttgccagg cgagtcagga cattagcaac tatttaaatt ggtatcagca gaaaccaggg 540
aaagccccta ggcgcctgat ctatggtgca tccactttga tgagtggggt cccatcaagg 600
ttcagcggca gtggatctgg gacagatttc actctcacca tcagcagtct gcaacctgaa 660
gattttgcaa cttactactg tcaacagagt tacagtacac ctctcacttt cggcggaggg 720
accaaggtgg aaatcaaa 738
<210> 28
<211> 738
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 28
gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaacacgt 300
tacatttggg ggagttatcg ggcatacggt atggacgtct ggggccaagg gacaatggtc 360
accgtctcga gtggtggagg cggttcaggc ggaggtggct ctggcggtgg cgctagcgac 420
atccagatga cccagtctcc atcctccatg tctgcatctg taggagacag agtcaccatc 480
acttgccgcg cgagtcagag cattagcagt catttaaatt ggtatcagca gctgccaggc 540
aatgccccta ctctcctgat ctattatgct tccaatttac aaagtggggt cccatctagg 600
ttcagtggca gtggatctgg gacagatttc actctcacca tcagcagtct gcagcctgat 660
gattttgcaa cttactactg tcaacagagt atcagtctcc cgtacacttt tggccagggg 720
accaaggtgg agatcaaa 738
<210> 29
<211> 729
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 29
gaggtgcagc tggtgcagcc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccctcagc agctatgcta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat aacaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt atttctgtgc gagagatcag 300
cggccggcga gcatggacgt ctggggccag ggcaccctgg tcaccgtctc gagtggtgga 360
ggcggttcag gcggaggtgg ctctggcggt ggcgctagcc agtctgagct gactcagcct 420
gcctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccagcagt 480
gacgttggtg gttatatcta tgtctcctgg taccaacagc acccaggcaa agtccccaaa 540
ctcatgattc atgatgtcag tcatcggccc tcaggggttt ctaatcgctt ctctggctcc 600
aggtctggca acacggcctc cctgaccatc tctgggctcc aggctgagga cgaggctgac 660
tatttctgca gctcatatac aagcagcaac aattatgtct tcggaactgg gaccaaggtc 720
accgtccta 729
<210> 30
<211> 729
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 30
gaggtgcagc tggtgcagcc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccctcagc agctatgcta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat aacaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt atttctgtgc gagagatcag 300
cggccggcga gcatggacgt ctggggccag ggcaccctgg tcaccgtctc gagtggtgga 360
ggcggttcag gcggaggtgg ctctggcggt ggcgctagcc agtctgggct gactcagcct 420
gcctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccagcagt 480
gatgttggtg gttataacta tgtctcctgg taccaacagc acccaggcaa agcccccaaa 540
ctcatgattt atgaggtcag taatcggccc tcaggggttt ctaatcgctt ctctggctcc 600
aagtctggca acacggcctc cctgaccatc tctgggctcc aggctgagga cgaggctgat 660
tactactgca gcacagttac aagcctcagc acttatgtct tcggaactgg gaccaagctg 720
accgtccta 729
<210> 31
<211> 741
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 31
gaggtgcagc tggtgcagtc tggggctgag gtgaagaggc ctgggtcctc ggtgaaggtc 60
tcctgcaagg catctggata caccttcacc agctactata tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaata atcaacccta gtggtggtag cacaagctac 180
gcacagaagt tccagggcag agtcaccatg accagggaca cgtccacgag cacagtctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc ggcaggaacg 300
tatagcagtg gctggacgat tgactactgg gggcaaggga ccacggtcac cgtctcgagt 360
ggtggaggcg gttcaggcgg aggtggctct ggcggtggcg ctagcgatat tgtgatgacg 420
cagtctccac tctccctgcc cgtcaccctt ggacagccgg cctccatctc ctgcaggtct 480
agtcaaagcc tcgtatacac tgatggaaac acctacttga attggtttca gcagaggcca 540
ggccaatctc caaggcgcct aatttataag gtttctaacc gggactctgg ggtcccagac 600
agattcagcg gcagtgggtc aggcactgat ttcacactga aaatcagcag ggtggaggct 660
gaggatgttg ggatttatta ctgcatgcat agtaaacagt ggcctcccac tttcggcgga 720
gggaccaagg tggaaatcaa a 741
<210> 32
<211> 714
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 32
gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaggacac 300
tactactaca tggacgtctg ggggcaaggg accacggtca ccgtctcgag tggtggaggc 360
ggttcaggcg gaggtggctc tggcggtggc gctagcgata ttgtgatgac tcagtctcca 420
gccaccctgt ctgtgtctcc aggggaagga gccaccctct cctgcagggc cagtcagagt 480
gttagcagca acttagcctg gtatcagcag aaacctggcc gggctcccag gctcctcatc 540
tatggtgcat ccaccagggc cactggtatc ccagccaggt tcagtggcag tgggtctggg 600
acagagttca ctctcaccat cagcagcctg cagtctgaag attttgcagt ttattactgt 660
cagcagtata ataactggcc cagtttcggc ggagggacca agctggagat caaa 714
<210> 33
<211> 714
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 33
gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaggacac 300
tactactaca tggacgtctg ggggcaaggg accacggtca ccgtctcgag tggtggaggc 360
ggttcaggcg gaggtggctc tggcggtggc gctagcgata ttgtgatgac tcagtctcca 420
gccaccctgt ctgtgtctcc aggggaagga gccaccctct cctgcagggc cagtcagagt 480
gttagcagca acttagcctg gtatcagcag aaacctggcc gggctcccag gctcctcatc 540
tatggtgcat ccaccagggc cactggtatc ccagccaggt tcagtggcag tgggtctggg 600
acagagttca ctctcaccat cagcagcctg cagtctgaag attttgcagt ttattactgt 660
cagcagtata ataactggcc cactttcggc ggagggacca agctggagat caaa 714
<210> 34
<211> 741
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 34
caggtgcagc tggtggagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120
cctggacaag gacttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240
atggagctga gcggcctgag atctgaggac acggccgtgt attactgtgc gagaggtata 300
cagcctcttc gctactacgg tatggacgtc tggggccaag gaaccctggt caccgtctcg 360
agtggtggag gcggttcagg cggaggtggc tctggcggtg gcgctagcca gtctgcgctg 420
actcagccac cctcagcgtc tgggaccccc gggcagaggg tcaccatctc ttgttctgga 480
agcagctcca acatcggaag taattatgta tactggtacc agcagctccc aggaacggcc 540
cccaaactcc tcatctatag gaataatcag cggccctcag gggtccctga ccgattctct 600
ggctccaagt ctggcacctc agcctccctg gccatcagtg ggctccggtc cgaggatgag 660
gctgattatt actgtgcagc atgggatgac agcctgagtg gtcggggagt gttcggcgga 720
gggacccagc tcaccgtcct a 741
<210> 35
<211> 729
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 35
caggtgcagc tggtggagtc tgggggaggc ctggtcaagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatagca tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac acactacgca 180
gactccgtga agggccgatt caccatctcc agacacaatt ccaagaacac gctgtatctt 240
caaatgaaca gcctgagagc tgaggacacg gccgtgtatt actgtgcgag gggggctggt 300
accttaaatg cttttgatat ctgggggcaa gggaccacgg tcaccgtctc gagtggtgga 360
ggcggttcag gcggaggtgg ctctggcggt ggcgctagcc agtctgggct gactcagcct 420
ccctccacgt ccgggtctcc tggacagtca gtcaccatct cctgcactgg aaccagcagt 480
gacgttggtg cttatagcta tgtctcctgg tatcaacaac acccaggcaa agcccccaaa 540
cttctcattt atgcggtcac taagaggccc tcgggggtcc ctgatcgctt ctctggctcc 600
aagtctggca acacggcctc cctgaccgtc tctggactcc aggatgagga tgaggctgat 660
tattactgca gctcttttgc aggcggcagc actctggtgt tcggcggagg gaccaagctg 720
accgtccta 729
<210> 36
<211> 741
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 36
caaatgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccttcagc agctatgcta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactat 180
gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgt gagaggatac 300
agttcaatat actactacta cggtatggac gtctggggcc aagggacaat ggtcaccgtc 360
tcgagtggtg gaggcggttc aggcggaggt ggctctggcg gtggcgctag ccagtctggg 420
ctgactcagc ctcgctcagt gtccgggtct cctggacagt cagtcaccat ctcctgcact 480
ggaaccagca gtgatgttgg tggttataac tatgtctcct ggtaccaaca gcacccaggc 540
aaagccccca aactcatgat ttatgatgtc agtaagcggc cctcaggggt ttctgatcgc 600
ttctctggct ccaagtctgg caacacggcc tccctgacca tctctgggct ccaggctgag 660
gacgaggctg attattactg cggctcatat acaagcgacg ggactctagt attcggcgga 720
gggaccaagc tgaccgtcct a 741
<210> 37
<211> 729
<212> DNA
<213> 人工序列
<220>
<223> 合成的GUCY2C结合性scFv编码序列
<400> 37
caggtgcagc tggtgcaatc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccttcagc agctatacta tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaagg atcatcccta tccttggtat agcaaactac 180
gcacagaagt tccagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagatagg 300
tcttacaact ggctcgaccc ctggggccgt ggcaccctgg tcaccgtctc gagtggtgga 360
ggcggttcag gcggaggtgg ctctggcggt ggcgctagcc agtctgcgct gactcagcct 420
gtctccgtgt ctgggtctcc tggacagtcg atcaccatct cctgcactgg aaccatcagt 480
gacgttggtg attataacta tgtctcctgg taccaacagc acccaggcaa agcccccaaa 540
ctcatgattt atgacgtcaa taatcggccc tcaggggttt ctaatcgctt ctctggctcc 600
aagtctggca acacggcctc cctgaccatc tctgggctcc aggctgagga cgaggctgat 660
tattactgca gctcatatac aagcagcagc actctggtat tcggcggagg gaccaagctg 720
accgtccta 729
<210> 38
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H1
<400> 38
Gly Tyr Thr Phe Thr Ser Tyr Tyr
1 5
<210> 39
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H1
<400> 39
Gly Gly Thr Leu Ser Ser Tyr Ala
1 5
<210> 40
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H1
<400> 40
Gly Gly Thr Phe Ser Ser Tyr Thr
1 5
<210> 41
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H1
<400> 41
Gly Gly Thr Phe Gly Ser Tyr Thr
1 5
<210> 42
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H1
<400> 42
Gly Gly Ser Ile Ser Ser Tyr Tyr
1 5
<210> 43
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H1
<400> 43
Gly Phe Thr Phe Ser Ser Tyr Trp
1 5
<210> 44
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H1
<400> 44
Gly Gly Thr Phe Ser Ser Tyr Ala
1 5
<210> 45
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H1
<400> 45
Gly Phe Thr Phe Ser Ser Tyr Ser
1 5
<210> 46
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H2
<400> 46
Ile Asn Pro Ser Gly Gly Ser Thr
1 5
<210> 47
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H2
<400> 47
Ile Ile Pro Ile Leu Gly Ile Thr
1 5
<210> 48
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H2
<400> 48
Ile Ile Pro Ile Leu Gly Ile Ala
1 5
<210> 49
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H2
<400> 49
Ile Ile Pro Val Leu Gly Ile Ala
1 5
<210> 50
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H2
<400> 50
Ile Tyr Tyr Ser Gly Ser Thr
1 5
<210> 51
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H2
<400> 51
Ile Lys Gln Asp Gly Ser Glu Lys
1 5
<210> 52
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H2
<400> 52
Ile Ile Pro Ile Phe Gly Thr Ala
1 5
<210> 53
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H2
<400> 53
Ile Tyr Ser Gly Gly Ser Thr
1 5
<210> 54
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H3
<400> 54
Asp Gly Gln Trp Leu Gln Phe Asp Tyr
1 5
<210> 55
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H3
<400> 55
Asp Gln Arg Pro Ala Ser Met Asp Val
1 5
<210> 56
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H3
<400> 56
Asp Tyr Ser Ser Ser Trp Asn Ser Met Asp Val
1 5 10
<210> 57
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H3
<400> 57
Asp Val Trp Gly Ser Gly Gln Ser Phe Asp Ser
1 5 10
<210> 58
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H3
<400> 58
Ala Pro Trp Tyr Ser Ser Ser Pro Thr Pro Tyr Gly Met Asp Val
1 5 10 15
<210> 59
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H3
<400> 59
Thr Arg Tyr Ile Trp Gly Ser Tyr Arg Ala Tyr Gly Met Asp Val
1 5 10 15
<210> 60
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H3
<400> 60
Gly Thr Tyr Ser Ser Gly Trp Thr Ile Asp Tyr
1 5 10
<210> 61
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H3
<400> 61
Gly His Tyr Tyr Tyr Met Asp Val
1 5
<210> 62
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H3
<400> 62
Gly Ile Gln Pro Leu Arg Tyr Tyr Gly Met Asp Val
1 5 10
<210> 63
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H3
<400> 63
Gly Ala Gly Thr Leu Asn Ala Phe Asp Ile
1 5 10
<210> 64
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H3
<400> 64
Gly Tyr Ser Ser Ile Tyr Tyr Tyr Tyr Gly Met Asp Val
1 5 10
<210> 65
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H3
<400> 65
Asp Arg Ser Tyr Asn Trp Leu Asp Pro
1 5
<210> 66
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L1
<400> 66
Gln Ser Leu Leu Lys Lys Ser Asp Gly Asn Thr Tyr
1 5 10
<210> 67
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L1
<400> 67
Ser Ser Asp Val Gly Gly Tyr Ile Tyr
1 5
<210> 68
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L1
<400> 68
Ser Ser Asp Ile Gly Tyr Tyr His Tyr
1 5
<210> 69
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L1
<400> 69
Ser Ser Asp Val Gly Gly Tyr Asn Tyr
1 5
<210> 70
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L1
<400> 70
Ser Ser Asp Val Gly Ala Tyr Asn Tyr
1 5
<210> 71
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L1
<400> 71
Ser Gly Ser Ile Ala Ser Asn Tyr
1 5
<210> 72
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L1
<400> 72
Gln Asp Ile Ser Asn Tyr
1 5
<210> 73
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L1
<400> 73
Gln Ser Ile Ser Ser His
1 5
<210> 74
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L1
<400> 74
Gln Ser Leu Val Tyr Thr Asp Gly Asn Thr Tyr
1 5 10
<210> 75
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L1
<400> 75
Gln Ser Val Ser Ser Asn
1 5
<210> 76
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L1
<400> 76
Ser Ser Asn Ile Gly Ser Asn Tyr
1 5
<210> 77
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L1
<400> 77
Ser Ser Asp Val Gly Ala Tyr Ser Tyr
1 5
<210> 78
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L1
<400> 78
Ile Ser Asp Val Gly Asp Tyr Asn Tyr
1 5
<210> 79
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L2
<400> 79
Lys Val Ser
1
<210> 80
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L2
<400> 80
Asp Val Ser
1
<210> 81
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L2
<400> 81
Glu Asp Ser
1
<210> 82
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L2
<400> 82
Glu Val Ser
1
<210> 83
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L2
<400> 83
Glu His Ser
1
<210> 84
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L2
<400> 84
Gly Ala Ser
1
<210> 85
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L2
<400> 85
Tyr Ala Ser
1
<210> 86
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L2
<400> 86
Arg Asn Asn
1
<210> 87
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L2
<400> 87
Ala Val Thr
1
<210> 88
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L2
<400> 88
Asp Val Asn
1
<210> 89
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 89
Met Gln Gly Ser His Trp Pro Pro Thr
1 5
<210> 90
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 90
Ser Ser Tyr Ala Gly Ser Asn Asn Tyr Val
1 5 10
<210> 91
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 91
Ser Ser Phe Thr Ser Arg Ser Thr Trp Val
1 5 10
<210> 92
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 92
Ser Ser Tyr Thr Ser Ser Asn Asn Tyr Tyr
1 5 10
<210> 93
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 93
Ser Ser Tyr Ala Gly Ser Asn Asn Phe Val
1 5 10
<210> 94
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 94
Ser Ser Tyr Ala Gly Ser Asn Asn Trp Val
1 5 10
<210> 95
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 95
Gln Ser Tyr Asp Val Ser Asn Arg Val
1 5
<210> 96
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 96
Gln Gln Ser Tyr Ser Thr Pro Leu Thr
1 5
<210> 97
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 97
Gln Gln Ser Ile Ser Leu Pro Tyr Thr
1 5
<210> 98
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 98
Ser Ser Tyr Thr Ser Ser Asn Asn Tyr Val
1 5 10
<210> 99
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 99
Ser Thr Val Thr Ser Leu Ser Thr Tyr Val
1 5 10
<210> 100
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 100
Met His Ser Lys Gln Trp Pro Pro Thr
1 5
<210> 101
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 101
Gln Gln Tyr Asn Asn Trp Pro Ser
1 5
<210> 102
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 102
Gln Gln Tyr Asn Asn Trp Pro Thr
1 5
<210> 103
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 103
Ala Ala Trp Asp Asp Ser Leu Ser Gly Arg Gly Val
1 5 10
<210> 104
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 104
Ser Ser Phe Ala Gly Gly Ser Thr Leu Val
1 5 10
<210> 105
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 105
Gly Ser Tyr Thr Ser Asp Gly Thr Leu Val
1 5 10
<210> 106
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 106
Ser Ser Tyr Thr Ser Ser Ser Thr Leu Val
1 5 10
<210> 107
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H1
<400> 107
Gly Gly Ser Phe Ser Gly Tyr Tyr
1 5
<210> 108
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H2
<400> 108
Ile Asn His Arg Gly Asn Thr
1 5
<210> 109
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-H3
<400> 109
Glu Arg Gly Tyr Thr Tyr Gly Asn Phe Asp His
1 5 10
<210> 110
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L1
<400> 110
Gln Ser Val Ser Arg Asn
1 5
<210> 111
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的CDR-L3
<400> 111
Gln Gln Tyr Lys Thr Trp Pro Arg Thr
1 5
<210> 112
<211> 430
<212> PRT
<213> 人工序列
<220>
<223> 合成的Hu-GUCY2C
<400> 112
Met Lys Thr Leu Leu Leu Asp Leu Ala Leu Trp Ser Leu Leu Phe Gln
1 5 10 15
Pro Gly Trp Leu Ser Phe Ser Ser Gln Val Ser Gln Asn Cys His Asn
20 25 30
Gly Ser Tyr Glu Ile Ser Val Leu Met Met Gly Asn Ser Ala Phe Ala
35 40 45
Glu Pro Leu Lys Asn Leu Glu Asp Ala Val Asn Glu Gly Leu Glu Ile
50 55 60
Val Arg Gly Arg Leu Gln Asn Ala Gly Leu Asn Val Thr Val Asn Ala
65 70 75 80
Thr Phe Met Tyr Ser Asp Gly Leu Ile His Asn Ser Gly Asp Cys Arg
85 90 95
Ser Ser Thr Cys Glu Gly Leu Asp Leu Leu Arg Lys Ile Ser Asn Ala
100 105 110
Gln Arg Met Gly Cys Val Leu Ile Gly Pro Ser Cys Thr Tyr Ser Thr
115 120 125
Phe Gln Met Tyr Leu Asp Thr Glu Leu Ser Tyr Pro Met Ile Ser Ala
130 135 140
Gly Ser Phe Gly Leu Ser Cys Asp Tyr Lys Glu Thr Leu Thr Arg Leu
145 150 155 160
Met Ser Pro Ala Arg Lys Leu Met Tyr Phe Leu Val Asn Phe Trp Lys
165 170 175
Thr Asn Asp Leu Pro Phe Lys Thr Tyr Ser Trp Ser Thr Ser Tyr Val
180 185 190
Tyr Lys Asn Gly Thr Glu Thr Glu Asp Cys Phe Trp Tyr Leu Asn Ala
195 200 205
Leu Glu Ala Ser Val Ser Tyr Phe Ser His Glu Leu Gly Phe Lys Val
210 215 220
Val Leu Arg Gln Asp Lys Glu Phe Gln Asp Ile Leu Met Asp His Asn
225 230 235 240
Arg Lys Ser Asn Val Ile Ile Met Cys Gly Gly Pro Glu Phe Leu Tyr
245 250 255
Lys Leu Lys Gly Asp Arg Ala Val Ala Glu Asp Ile Val Ile Ile Leu
260 265 270
Val Asp Leu Phe Asn Asp Gln Tyr Phe Glu Asp Asn Val Thr Ala Pro
275 280 285
Asp Tyr Met Lys Asn Val Leu Val Leu Thr Leu Ser Pro Gly Asn Ser
290 295 300
Leu Leu Asn Ser Ser Phe Ser Arg Asn Leu Ser Pro Thr Lys Arg Asp
305 310 315 320
Phe Ala Leu Ala Tyr Leu Asn Gly Ile Leu Leu Phe Gly His Met Leu
325 330 335
Lys Ile Phe Leu Glu Asn Gly Glu Asn Ile Thr Thr Pro Lys Phe Ala
340 345 350
His Ala Phe Arg Asn Leu Thr Phe Glu Gly Tyr Asp Gly Pro Val Thr
355 360 365
Leu Asp Asp Trp Gly Asp Val Asp Ser Thr Met Val Leu Leu Tyr Thr
370 375 380
Ser Val Asp Thr Lys Lys Tyr Lys Val Leu Leu Thr Tyr Asp Thr His
385 390 395 400
Val Asn Lys Thr Tyr Pro Val Asp Met Ser Pro Thr Phe Thr Trp Lys
405 410 415
Asn Ser Lys Leu Pro Asn Asp Ile Thr Gly Arg Gly Pro Gln
420 425 430
<210> 113
<211> 430
<212> PRT
<213> 人工序列
<220>
<223> 合成的Mu-GUCY2C
<400> 113
Met Thr Ser Leu Leu Gly Leu Ala Val Arg Leu Leu Leu Phe Gln Pro
1 5 10 15
Ala Leu Met Val Phe Trp Ala Ser Gln Val Arg Gln Asn Cys Arg Asn
20 25 30
Gly Ser Tyr Glu Ile Ser Val Leu Met Met Asp Asn Ser Ala Tyr Lys
35 40 45
Glu Pro Met Gln Asn Leu Arg Glu Ala Val Glu Glu Gly Leu Asp Ile
50 55 60
Val Arg Lys Arg Leu Arg Glu Ala Asp Leu Asn Val Thr Val Asn Ala
65 70 75 80
Thr Phe Ile Tyr Ser Asp Gly Leu Ile His Lys Ser Gly Asp Cys Arg
85 90 95
Ser Ser Thr Cys Glu Gly Leu Asp Leu Leu Arg Glu Ile Thr Arg Asp
100 105 110
His Lys Met Gly Cys Ala Leu Met Gly Pro Ser Cys Thr Tyr Ser Thr
115 120 125
Phe Gln Met Tyr Leu Asp Thr Glu Leu Asn Tyr Pro Met Ile Ser Ala
130 135 140
Gly Ser Tyr Gly Leu Ser Cys Asp Tyr Lys Glu Thr Leu Thr Arg Ile
145 150 155 160
Leu Pro Pro Ala Arg Lys Leu Met Tyr Phe Leu Val Asp Phe Trp Lys
165 170 175
Val Asn Asn Ala Ser Phe Lys Pro Phe Ser Trp Asn Ser Ser Tyr Val
180 185 190
Tyr Lys Asn Gly Ser Glu Pro Glu Asp Cys Phe Trp Tyr Leu Asn Ala
195 200 205
Leu Glu Ala Gly Val Ser Tyr Phe Ser Glu Val Leu Asn Phe Lys Asp
210 215 220
Val Leu Arg Arg Ser Glu Gln Phe Gln Glu Ile Leu Thr Gly His Asn
225 230 235 240
Arg Lys Ser Asn Val Ile Val Met Cys Gly Thr Pro Glu Ser Phe Tyr
245 250 255
Asp Val Lys Gly Asp Leu Gln Val Ala Glu Asp Thr Val Val Ile Leu
260 265 270
Val Asp Leu Phe Ser Asn His Tyr Phe Glu Glu Asn Thr Thr Ala Pro
275 280 285
Glu Tyr Met Asp Asn Val Leu Val Leu Thr Leu Pro Ser Glu Gln Ser
290 295 300
Thr Ser Asn Thr Ser Val Ala Glu Arg Phe Ser Ser Gly Arg Ser Asp
305 310 315 320
Phe Ser Leu Ala Tyr Leu Glu Gly Thr Leu Leu Phe Gly His Met Leu
325 330 335
Gln Thr Phe Leu Glu Asn Gly Glu Asn Val Thr Gly Pro Lys Phe Ala
340 345 350
Arg Ala Phe Arg Asn Leu Thr Phe Gln Gly Phe Ala Gly Pro Val Thr
355 360 365
Leu Asp Asp Ser Gly Asp Ile Asp Asn Ile Met Ser Leu Leu Tyr Val
370 375 380
Ser Leu Asp Thr Arg Lys Tyr Lys Val Leu Met Lys Tyr Asp Thr His
385 390 395 400
Lys Asn Lys Thr Ile Pro Val Ala Glu Asn Pro Asn Phe Ile Trp Lys
405 410 415
Asn His Lys Leu Pro Asn Asp Val Pro Gly Leu Gly Pro Gln
420 425 430
<210> 114
<211> 430
<212> PRT
<213> 人工序列
<220>
<223> 合成的Cy-GUCY2C
<400> 114
Met Lys Thr Leu Leu Leu Asp Leu Val Leu Trp Ser Leu Leu Phe Gln
1 5 10 15
Pro Glu Trp Leu Tyr Leu Thr Ser Gln Val Ser Gln Asn Cys His Asn
20 25 30
Gly Ser Tyr Glu Ile Ser Val Leu Met Met Asp Asn Ser Ala Phe Ala
35 40 45
Glu Pro Leu Glu Asn Val Glu Asp Ala Val Asn Glu Gly Leu Glu Ile
50 55 60
Val Arg Gly Arg Leu Gln Asn Ala Gly Leu Asn Val Thr Val Asn Ala
65 70 75 80
Ser Phe Met Tyr Ser Asp Gly Leu Ile His Asn Ser Gly Asp Cys Arg
85 90 95
Ser Ser Thr Cys Glu Gly Leu Asp Leu Leu Arg Lys Ile Ser Asn Ala
100 105 110
Lys Arg Met Gly Cys Val Leu Met Gly Pro Ser Cys Thr Tyr Ser Thr
115 120 125
Phe Gln Met Tyr Leu Asp Thr Glu Leu Ser Tyr Pro Met Ile Ser Ala
130 135 140
Gly Ser Phe Gly Leu Ser Cys Asp Tyr Lys Glu Thr Leu Thr Arg Leu
145 150 155 160
Met Ser Pro Ala Arg Lys Leu Thr Tyr Phe Leu Val Asn Phe Trp Lys
165 170 175
Thr Asn Asp Leu Pro Phe Lys Thr Tyr Ser Trp Ser Thr Ser Tyr Val
180 185 190
Tyr Lys Asn Gly Thr Glu Ser Glu Asp Cys Phe Trp Tyr Leu Asn Ala
195 200 205
Leu Glu Ala Ser Val Ser Tyr Phe Ser His Glu Leu Ser Phe Lys Leu
210 215 220
Val Leu Arg Gln Asp Lys Glu Phe Gln Asp Ile Leu Met Asp His Asn
225 230 235 240
Arg Lys Ser Asn Val Ile Val Met Cys Gly Asp Pro Gln Phe Leu Tyr
245 250 255
Lys Leu Lys Gly Asp Arg Ala Val Ala Glu Asp Ile Val Ile Ile Leu
260 265 270
Val Asp Leu Phe Asn Asp Gln Tyr Phe Glu Asp Asn Val Thr Ala Pro
275 280 285
Asp Tyr Met Lys Asn Val Leu Val Leu Thr Gln Ser Pro Gly Asn Ser
290 295 300
Leu Leu Asn Ser Ser Phe Ser Arg Asn Leu Ser Pro Thr Lys Arg Asp
305 310 315 320
Phe Ala Leu Ala Tyr Leu Asn Gly Ile Leu Leu Phe Gly His Met Leu
325 330 335
Lys Thr Phe Leu Glu Asn Gly Glu Asn Ile Thr Thr Pro Lys Phe Ala
340 345 350
His Ala Phe Arg Asn Leu Thr Phe Glu Gly Tyr Asp Gly Pro Val Thr
355 360 365
Leu Asp Asp Trp Gly Asp Val Asp Ser Thr Met Val Leu Leu Tyr Thr
370 375 380
Ser Val Asp Thr Lys Lys Tyr Lys Val Leu Leu Thr Tyr Asp Thr His
385 390 395 400
Val Asn Gln Thr Asn Pro Val Asp Met Ser Pro Thr Phe Thr Trp Lys
405 410 415
Asn Ser Lys Leu Pro Asn Asp Ile Thr Asp Arg Gly Pro Gln
420 425 430
<210> 115
<211> 182
<212> PRT
<213> 人工序列
<220>
<223> 合成的rCD4
<400> 115
Thr Ser Ile Thr Ala Tyr Lys Ser Glu Gly Glu Ser Ala Glu Phe Ser
1 5 10 15
Phe Pro Leu Asn Leu Gly Glu Glu Ser Leu Gln Gly Glu Leu Arg Trp
20 25 30
Lys Ala Glu Lys Ala Pro Ser Ser Gln Ser Trp Ile Thr Phe Ser Leu
35 40 45
Lys Asn Gln Lys Val Ser Val Gln Lys Ser Thr Ser Asn Pro Lys Phe
50 55 60
Gln Leu Ser Glu Thr Leu Pro Leu Thr Leu Gln Ile Pro Gln Val Ser
65 70 75 80
Leu Gln Phe Ala Gly Ser Gly Asn Leu Thr Leu Thr Leu Asp Arg Gly
85 90 95
Ile Leu Tyr Gln Glu Val Asn Leu Val Val Met Lys Val Thr Gln Pro
100 105 110
Asp Ser Asn Thr Leu Thr Cys Glu Val Met Gly Pro Thr Ser Pro Lys
115 120 125
Met Arg Leu Ile Leu Lys Gln Glu Asn Gln Glu Ala Arg Val Ser Arg
130 135 140
Gln Glu Lys Val Ile Gln Val Gln Ala Pro Glu Ala Gly Val Trp Gln
145 150 155 160
Cys Leu Leu Ser Glu Gly Glu Glu Val Lys Met Asp Ser Lys Ile Gln
165 170 175
Val Leu Ser Lys Gly Leu
180
Claims (17)
1.一种GUCY2C结合多肽,其包含:
重链可变区,其包含由选自SEQ ID NO:38至44的氨基酸序列表示的重链CDR1(后文中的CDR-H1)、由选自SEQ ID NO:45至53的氨基酸序列表示的CDR-H2和由选自SEQ ID NO:54至65的氨基酸序列表示的CDR-H3;
轻链可变区,其包含由选自SEQ ID NO:66至78的氨基酸序列表示的轻链CDR1(后文中的CDR-L1)、由选自SEQ ID NO:79至88的氨基酸序列表示的CDR-L2和由选自SEQ ID NO:89至106的氨基酸序列表示的CDR-L3;
或所述重链可变区和轻链可变区的组合。
2.根据权利要求1所述的GUCY2C结合多肽,其中所述GUCY2C结合多肽是scFv(单链可变片段)。
3.根据权利要求2所述的GUCY2C结合多肽,其由选自SEQ ID NO:1至18的氨基酸序列表示。
4.一种GUCY2C结合抗体,其包含根据权利要求1所述的GUCY2C结合多肽或其抗原结合片段。
5.一种融合蛋白,其包含根据权利要求1所述的GUCY2C结合多肽和免疫球蛋白的Fc结构域。
6.根据权利要求5所述的融合蛋白,其中所述GUCY2C结合多肽由选自SEQ ID NO:1至18的氨基酸序列表示。
7.一种嵌合抗原受体,其是包含胞外结构域、跨膜结构域和细胞内信号传导结构域的嵌合抗原受体,其中所述胞外结构域包含根据权利要求2所述的GUCY2C结合性scFv。
8.根据权利要求7所述的嵌合抗原受体,其中所述GUCY2C结合性scFv由选自SEQ IDNO:1至18的氨基酸序列表示。
9.一种免疫细胞,其表达根据权利要求7或权利要求8所述的嵌合抗原受体。
10.根据权利要求9所述的免疫细胞,其中所述免疫细胞是T细胞、肿瘤浸润性淋巴细胞、NK(自然杀伤)细胞、TCR表达细胞、树突状细胞或NK-T细胞。
11.一种多核苷酸,其编码根据权利要求1至权利要求3中的任一权利要求所述的多肽、包含所述多肽的融合蛋白或包含所述多肽的嵌合抗原受体。
12.根据权利要求11所述的多核苷酸,其由选自SEQ ID NO:20至37的核酸序列表示。
13.一种用于检测GUCY2C的组合物,其包含根据权利要求1至权利要求3中的任一权利要求所述的多肽、包含所述多肽的融合蛋白或包含所述多肽的嵌合抗原受体。
14.一种用于诊断癌症的组合物,其包含根据权利要求1至权利要求3中的任一权利要求所述的多肽、包含所述多肽的融合蛋白或包含所述多肽的嵌合抗原受体。
15.根据权利要求14所述的用于诊断癌症的组合物,其中所述癌症表达GUCY2C。
16.一种用于预防或治疗癌症的药物组合物,其包含:
根据权利要求1至权利要求3中的任一权利要求所述的GUCY2C结合多肽;
编码所述GUCY2C结合多肽的多核苷酸;
包含编码所述GUCY2C结合多肽的多核苷酸的重组载体;
包含所述GUCY2C结合多肽的嵌合抗原受体;
编码所述嵌合抗原受体的多核苷酸;
包含编码所述嵌合抗原受体的多核苷酸的重组载体;和
包含编码所述嵌合抗原受体的多核苷酸或表达所述嵌合抗原受体的免疫细胞。
17.根据权利要求16所述的用于预防或治疗癌症的药物组合物,其中所述癌症表达GUCY2C。
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PCT/KR2022/005030 WO2022216079A1 (ko) | 2021-04-07 | 2022-04-07 | Gucy2c 결합 폴리펩타이드 및 그의 용도 |
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BR112023020802A2 (pt) | 2023-12-12 |
WO2022216079A1 (ko) | 2022-10-13 |
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IL307367A (en) | 2023-11-01 |
EP4299594A1 (en) | 2024-01-03 |
CL2023003005A1 (es) | 2024-03-15 |
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