CN112955220A - 生物样品中的抗体定量 - Google Patents
生物样品中的抗体定量 Download PDFInfo
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- CN112955220A CN112955220A CN201980069152.8A CN201980069152A CN112955220A CN 112955220 A CN112955220 A CN 112955220A CN 201980069152 A CN201980069152 A CN 201980069152A CN 112955220 A CN112955220 A CN 112955220A
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Abstract
本发明涉及一种用于通过使用质谱法定量生物样品中的双特异性抗体,具体地说,双特异性抗体治疗剂,的独特特征肽来定量所述抗体的方法。本发明还涉及一种包括所述独特特征肽的试剂盒。
Description
技术领域
本发明涉及一种用于通过使用质谱法定量生物样品中的双特异性抗体(具体地说,双特异性抗体治疗剂)的独特特征肽来定量所述抗体的方法。本发明还涉及一种包括所述独特特征肽的试剂盒。
背景技术
随着药物开发中治疗性单克隆抗体(mAb)的快速增长,mAb治疗剂的定量生物分析已成为支持临床前和临床研究的必要条件。传统上,药代动力学分析方法采用基于免疫学的测定法对生物基质中的蛋白质进行定量分析。基于免疫学的方法可以检测低pg/ml浓度的复杂基质(如血清)中的蛋白质。然而,免疫测定法需要开发合适的捕获和检测试剂,这需要时间和资源,并且在药物发现和早期开发中可能无法承受。
由于其潜在的优势(例如,宽动态范围、快速的方法开发、对特定试剂的需求减少以及同时定量多种蛋白质的能力),基于质谱(MS)的测定法近年来引起了人们对mAb定量的兴趣。对于待通过MS定量的mAb,首先需要将其与非常相似的血清中内源性人免疫球蛋白(Ig)>1g/dL的多克隆本底区分开。大多数质谱分析方法依赖于目标mAb的蛋白水解消化和对至少一种独特特征肽的定量(其等同于整个蛋白质的水平)。用于人血清中治疗性mAb定量的独特特征肽来自免疫球蛋白可变区,所述免疫球蛋白可变区涉及鉴定和随后使用每种治疗性mAb的新特征肽。
液相色谱-串联质谱(LC-MS/MS)与免疫亲和样品富集相结合是实现针对血清中治疗性(人)mAb定量最灵敏的LC-MS测定法的当前选择方法,其达到了定量下限(LLOQ),所述定量下限在非灵长类哺乳动物的血清中为低ng/水平(在大鼠血清中为5ng/ml),而在人血清中则高于100ng/ml。对于人类或非人类临床前物种的药代动力学研究,这种灵敏度水平是不够的,特别是对于以低剂量施用的mAb(如抗CD3双特异性抗体)而言。
因此,需要更灵敏的基于LC-MS/MS的测定法来定量人类和非人灵长类动物血清中的治疗性mAb。最需要一种高度灵敏的基于LC-MS/MS的测定法,所述测定法将使用相同的试剂(特征肽)来定量各种mAb。
发明内容
发明人已经鉴定了一种用于通过质谱法进行双特异性抗体定量的独特特征肽,其允许在人血清中进行高度灵敏的抗体检测(LLOQ为50pg/ml并且检测/定量范围为50pg/ml到5000pg/ml)。用特征肽获得的灵敏度适合于以低剂量施用的治疗性双特异性抗体(如抗CD3双特异性抗体)的临床前和临床药代动力学研究。未使用用于选择特征肽的标准预测规则鉴定的特征肽位于包括工程化的人IgG CH3异二聚体的双特异性抗体的CH3结构域中。因此,所述独特特征肽可以有利地用于包括所述工程化的CH3异二聚体的所有双特异性抗体的高度灵敏和特定的定量,而与其特异性无关。高度灵敏和特定的抗体检测与多功能性相结合,使得这种新的特征肽成为用于临床前和临床研究中治疗性双特异性抗体定量的非常有用的工具。
因此,本发明提供了一种用于定量生物样品中的双特异性抗体的方法,其中所述抗体包括工程化的人IgG CH3异二聚体,所述异二聚体包括CH3结构域中的多个取代,包含第一CH3结构域的位置80到88处的至少两个取代,其中所述方法包括通过质谱法定量所述抗体的特征肽,其中所述特征肽是对应于所述第一CH3结构域的位置80到88的胰蛋白酶肽,并且其中所述氨基酸位置根据编号指示。
在根据本发明的方法的一些实施例中,所述特征肽由以下序列组成:
TX1PPX2LX3SX4GSFX5LX6SX7(SEQ ID NO:1)
其中X1代表T或D,X2代表V、L、P或M,X3代表D、Q或E,X4代表D或Q,X5代表F、A或W,X6代表S、W或H,并且X7代表K或R,前提是当X1为T时,X2、X3、X4、X5和X7中的至少一个使得X2为L、P或M;X3为Q或E;X4为Q;X5为A或W;并且X7为R。
在一些优选的实施例中,所述特征肽选自由以下组成的组:TTPPVLDSDGSFALSSK(SEQ ID NO:3)、TDPPLLESDGSFALSSR(SEQ ID NO:4)、TDPPLLESQGSFALSSR(SEQ ID NO:5)、TTPPPLQSDGSFWLWSK(SEQ ID NO:6)和TTPPMLESDGSFFLHSK(SEQ ID NO:7),优选地,SEQ IDNO:4或SEQ ID NO:5。
在一些实施例中,所述双特异性抗体包括使用基于T细胞受体的免疫球蛋白结构域界面工程化的人IgG CH3结构域异二聚体,其中所述第一CH3结构域来自人IgG1并且至少包括取代F85.1A和Y86S,而所述第二CH3结构域来自人IgG1或IgG3并且至少包括取代S20K、T22V、K26T、K79Y、K88W和T90N,并且其中所述位置根据编号指示。
在一些优选的实施例中:
-所述第一CH3结构域进一步包括以下取代中的一个或多个:Q3E、Y5A、L7F、S20T、T22V、K26T、T81D、V84L、D84.2E、K88R和T90R;优选地,Q3E、Y5A、L7F、S20T、T22V、K26T、T81D、V84L、D84.2E、K88R和T90R或Q3E、Y5A、L7F、S20T、T22V、K26T、T81D、V84L、D84.2E和K88R;并且
-所述第二CH3结构域进一步包括以下取代中的一个或多个:Q3A、D12E、L14M、N44S、V84M、F85.1S、Y86V、V101I、H115R和Y116F;优选地,F85.1S和Y86V;或对于来自人IgG1的CH3结构域,F85.1S、Y86V和Q3A,而对于来自人IgG3的CH3结构域,D12E、L14M、N44S、V84M、F85.1S、Y86V、V101I、H115R和Y116F。根据这些实施例的双特异性抗体包括SEQ ID NO:3、4、5的特征肽。优选地,所述双特异性抗体包括SEQ ID NO:4或5的特征肽。
在一些其它实施例中,所述双特异性抗体包括使用人IgG和IgD CH3结构域之间的免疫球蛋白结构域界面交换工程化的人IgG CH3结构域异二聚体,其中所述第一CH3结构域包括以下取代:Q3V、Y5L、K26S、V84P、D84.2Q、F85.1W和Y86W,并且所述第二CH3结构域包括以下取代:S20W、K79A、T81A、K88V和T90R。根据这些实施例的双特异性抗体包括SEQ ID NO:6的特征肽。
在一些其它实施例中,所述双特异性抗体包括使用人IgG和IgM CH3结构域之间的免疫球蛋白结构域界面交换工程化的人IgG CH3结构域异二聚体,其中所述第一CH3结构域包括以下取代:Q3D、K26T、V84M、D84.2E和Y86H,并且所述第二CH3结构域包括以下取代:S20T、K79V、T81S和K88I。根据这些实施例的双特异性抗体包括SEQ ID NO:7的特征肽。
在一些实施例中,所述双特异性抗体包括来自人免疫球蛋白(优选地,人IgG,更优选地,人IgG1或IgG3)的Fc、Fab和scFv。
在一些实施例中,所述双特异性抗体是治疗性抗体,优选地,双特异性抗CD3抗体,更优选地,抗CD3和抗Her2双特异性抗体、抗CD3和抗CD38双特异性抗体或抗CD3和抗EGFR双特异性抗体。
在一些实施例中,根据本发明的方法包括以下步骤:
a)通过免疫捕获从所述生物样品中纯化所述双特异性抗体,
b)用胰蛋白酶或胰蛋白酶/Lys C消化在步骤a)中获得的所述双特异性抗体,以产生包括所述特征肽的肽,以及
c)对步骤b)中获得的所述肽进行质谱分析,以通过与内标品或标准品曲线比较来确定所述生物样品中的特征肽的量。
在一些优选的实施例中,用对所述双特异性抗体具有特异性的抗原或抗体进行所述免疫捕获;优选地,抗独特型抗体、针对所述特征肽的抗体或其组合;优选地,在固体支持物上或使用免疫磁分离进行所述免疫捕获;更优选地,使用生物素化抗体和抗生蛋白链菌素包被的磁珠。
在一些实施例中,所述质谱法包括二维纳米液相色谱法,其与电喷雾电离轨道离子阱(Orbitrap)质谱法偶联。
在其它实施例中,使用了不同的质谱技术。
在一些实施例中,所述生物样品是人类生物样品,优选地,人体液,更优选地,人血清。
在一些实施例中,所述双特异性抗体的定量下限(LLOQ)为50pg/ml,并且在人血清中,所述双特异性抗体的检测范围为50pg/ml到5000pg/ml。
本发明还提供了一种试剂盒,其用于执行根据本发明的用于定量生物样品中的双特异性抗体的方法,所述试剂盒至少包括根据本发明的所述特征肽;优选地,所述试剂盒进一步包括对上述双特异性抗体具有特异性的抗体。
具体地说,所述试剂盒包含稳定同位素标记的内标品,所述内标品具有与所述特征肽相同的序列或扩展的序列
具体实施方式
本发明提供了一种高度灵敏和特定的方法,其用于在生物样品中定量包括工程化的人IgG CH3异二聚体的双特异性抗体。所述方法包括通过质谱法定量所述抗体的独特特征肽,其中所述特征肽是对应于一个CH3结构域的位置80到88的胰蛋白酶肽,其中所述氨基酸位置根据编号指示。
定义
如本文所使用的,“双特异性抗体”是指包括连接至两个不同的抗原结合结构域(或抗原结合臂)的免疫球蛋白Fc异二聚体的抗体,所述两个不同的抗原结合结构域结合至两个不同的表位。两个不同的抗原结合结构域是两个不同的免疫球蛋白重链(Hc)的一部分,所述两个不同的免疫球蛋白重链通过形成工程化的CH3异源二聚体的一对工程化的CH3结构域进行异源二聚化,而不是形成同二聚体。
如本文所使用的,“工程化的CH3异二聚体”是指包括CH3结构域的界面处的突变的CH3异二聚体,所述突变促进异二聚体的装配并阻碍同二聚体的形成。可以使用本领域中众所周知的各种技术来对CH3异二聚体进行工程化,如“旋钮入孔”(KiH)、“链交换工程化结构域”(SEED)和“免疫球蛋白结构域界面交换”。具体地说,免疫球蛋白结构域界面交换包含将免疫球蛋白的同二聚体蛋白质-蛋白质界面(例如,IgG CH3,如IgG1 CH3或IgG3 CH3)与完整的异二聚体界面(T细胞受体(TCR)α/β或TCRγ/δ恒定结构域对)进行交换,或与同二聚体界面的一半(例如,IgA CH3、IgD CH3、IgGM CH4)进行交换。免疫球蛋白结构域界面交换公开于以下文献中:WO 2012/131555;和Skegro等人,《生物化学杂志(JBC)》,2017,292,9745-9759。使用基于TCR的免疫球蛋白结构域界面交换技术工程化的双特异性抗体被指定为抗体,用于通过基于T细胞受体的抗体进行双特异性结合。CH3异二聚体的两个CH3结构域形成至少60%(优选地,至少70%、80%或90%)的异二聚体。异二聚体的形成可以通过本领域已知的标准测定法来测量(参见例如,Skegro等人,《生物化学杂志》,2017,292,9745-9759)。
如本文所使用的,“特征肽”是指双特异性抗体特有的肽,这意味着在生物样品的其它蛋白质中未发现所述肽。
如本文所使用的,“生物样品”是指包括蛋白质混合物的复杂基质。
包括特征肽的CH3结构域在本文中被指定为第一CH3结构域。
双特异性抗体和特征肽
根据本发明的方法定量的双特异性抗体包括独特特征肽,所述独特特征肽是源自人IgG CH3结构域的位置80到88的氨基酸序列的胰蛋白酶肽:
TTPPZ1LDSDGSFFLYSZ2(SEQ ID NO:2),
其中Z1为V或M并且Z2为K或R,并且
其中与SEQ ID NO:2相比,所述特征肽包括至少两个氨基酸取代。
特征肽可以包括SEQ ID NO:2中的2个、3个、4个、5个、6个、7个或更多个氨基酸取代,优选地,6个、7个或更多个氨基酸取代。
由于特征肽是胰蛋白酶肽,因此相对于特征肽序列,抗体序列在位置-1处包括赖氨酸(K)或精氨酸(R)。
仅在第一CH3结构域中发现特征肽,所述特征肽是独特的肽(即在第二CH3结构域中未发现特征肽)。
在一些优选的实施例中,特征肽由以下序列组成:
TX1PPX2LX3SX4GSFX5LX6SX7(SEQ ID NO:1),
其中:X1代表T或D,
X2代表V、L、P或M,
X3代表D、Q或E,
X4代表D或Q,
X5代表F、A或W,
X6代表S、W或H,并且
X7代表K或R,
前提是当X1为T时,X2、X3、X4、X5和X7中的至少一个使得X2为L、P或M;X3为Q或E;X4为Q;X5为A或W;并且X7为R。优选地,X2、X3、X4、X5和X7中的至少两个、三个、四个或全部使得X2为L、P或M;X3为Q或E;X4为Q;X5为A或W;并且X7为R;更优选地,X2、X3、X4、X5和X7中四个或全部使得X2为L、P或M;X3为Q或E;X4为Q;X5为A或W;并且X7为R。
在一些更优选的实施例中,所述特征肽选自由以下组成的组:TTPPVLDSDGSFALSSK(SEQ ID NO:3)、TDPPLLESDGSFALSSR(SEQ ID NO:4)、TDPPLLESQGSFALSSR(SEQ ID NO:5)、TTPPPLQSDGSFWLWSK(SEQ ID NO:6)和TTPPMLESDGSFFLHSK(SEQ ID NO:7);优选地,SEQ IDNO:4或SEQ ID NO:5。
根据本发明的方法定量的双特异性抗体包括免疫球蛋白Fc异二聚体,其包括工程化的人IgG CH3异二聚体,其中CH3异二聚体包括CH3结构域中的多个取代,包含第一CH3结构域的位置80到88处的至少两个取代。
在所述方法的各个实施例中,工程化的CH3异二聚体来自人IgG1、IgG2、IgG3、IgG4或其组合。第一CH3结构域优选地来自人IgG1、IgG2或IgG4,更优选地来自人IgG1。第二CH3结构域来自任何人IgG。在一些优选的实施例中,第一CH3结构域来自人IgG1,并且第二CH3结构域来自人IgG1或IgG3。
在所述方法的各个实施例中,工程化的CH3异二聚体包括第一CH3结构域的位置80到88处的2个、3个、4个、5个、6个、7个或更多个取代,优选地,6个、7个或更多个取代。
在一些实施例中,工程化的CH3异二聚体的第一CH3结构域来自人IgG1,而第二CH3结构域来自人IgG1或IgG3,并且第一CH3结构域包括位置80到88处的6个、7个或更多个取代。
在一些优选的实施例中,所述双特异性抗体包括使用基于TCR的免疫球蛋白结构域界面交换技术工程化的人IgG CH3结构域异二聚体,其中所述第一CH3结构域来自人IgG1并且至少包括取代F85.1A和Y86S,而所述第二CH3结构域来自人IgG1或IgG3并且至少包括取代S20K、T22V、K26T、K79Y、K88W和T90N。
在一些更优选的实施例中:
-所述第一CH3结构域进一步包括以下取代中的一个或多个:Q3E、Y5A、L7F、S20T、T22V、K26T、T81D、V84L、D84.2E、K88R和T90R;优选地,Q3E、Y5A、L7F、S20T、T22V、K26T、T81D、V84L、D84.2E、K88R和T90R或Q3E、Y5A、L7F、S20T、T22V、K26T、T81D、V84L、D84.2E和K88R;并且
-所述第二CH3结构域进一步包括以下取代中的一个或多个:Q3A、D12E、L14M、N44S、V84M、F85.1S、Y86V、V101I、H115R和Y116F;优选地,F85.1S和Y86V;或对于源自人IgG1的CH3结构域,F85.1S、Y86V和Q3A;而对于源自人IgG3的CH3结构域,D12E、L14M、N44S、V84M、F85.1S、Y86V、V101I、H115R和Y116F。
根据第一个优选的实施例的双特异性抗体包括SEQ ID NO:3、4、5的特征肽。优选地,所述双特异性抗体包括SEQ ID NO:4或5的特征肽。
在一些其它优选的实施例中,所述双特异性抗体包括使用人IgG和IgD CH3结构域之间的免疫球蛋白结构域界面交换工程化的人IgG1 CH3结构域异二聚体,其中所述第一CH3结构域包括以下取代:Q3V、Y5L、K26S、V84P、D84.2Q、F85.1W和Y86W,并且所述第二CH3结构域包括以下取代:S20W、K79A、T81A、K88V和T90R。根据这些实施例的双特异性抗体包括SEQ ID NO:6的特征肽。
在又一些其它实施例中,所述双特异性抗体包括使用人IgG和IgM CH3结构域之间的免疫球蛋白界面交换工程化的人IgG1 CH3结构域异二聚体,其中所述第一CH3结构域包括以下取代:Q3D、K26T、V84M、D84.2E和Y86H,并且所述第二CH3结构域包括以下取代:S20T、K79V、T81S和K88I。根据这些实施例的双特异性抗体包括SEQ ID NO:7的特征肽。
根据本发明的方法定量的双特异性抗体包括连接至两个不同的抗原结合结构域(或抗原结合臂)的免疫球蛋白Fc异二聚体的抗体,所述两个不同的抗原结合结构域结合至两个不同的表位。
Fc异二聚体至少包括工程化的人IgG CH3异二聚体。其通常进一步包括至少一对CH2同二聚体,优选地来自IgG,更优选地来自人IgG,还更优选地来自人IgG1。
Fc异二聚体有利地通过两个免疫球蛋白铰链(优选地,IgG铰链,更优选地,人IgG铰链,还更优选地,人IgG1铰链)连接至抗原结合臂。
抗原结合臂可以是免疫球蛋白Fab或scFv片段,优选地,人或人源化Fab或scFv片段。双特异性抗体可以包括两个Fab片段、两个scFv片段或一个Fab片段和一个scFv片段。
在一些实施例中,双特异性抗体包括来自人免疫球蛋白的Fc异二聚体、Fab和scFv。Fc异二聚体优选地来自人IgG1。Fc异二聚体优选地通过IgG1铰链(优选地,人IgG1铰链)连接至Fab和scFv中的每一个。
在一些实施例中,双特异性抗体是治疗性抗体。双特异性抗体针对两个治疗靶标。双特异性抗体的治疗靶标的非限制性实例包含:CD3、CD38、Her-2、EGFR、CD20、TNFα、VEGF、CEA、IL-12、IL-23、PD-L1、PD-1、补体C5和其它。单克隆抗体的许多治疗靶标是本领域众所周知的,并且针对各种靶标的众多单克隆抗体可用于治疗多种疾病,如癌症、自身免疫、炎性疾病、感染性疾病和其它疾病。双特异性抗体可以针对任何这些治疗靶标,或者可以源自任何这些治疗性单克隆抗体。
在一些优选的实施例中,治疗性双特异性抗体是双特异性抗CD3抗体,优选地,抗CD3和抗Her2双特异性抗体、抗CD3和抗CD38双特异性抗体或抗CD3和抗EGFR双特异性抗体。
生物样品制备
生物样品优选地来自已经用双特异性抗体治疗的人或动物来源,更优选地,人或猿猴受试者,还更优选地,人受试者。样品是生物组织或液体,优选地,生物流体,如但不限于:全血、血清、血浆、尿液、组织活检或粘膜分泌物(唾液、泪液、支气管肺泡灌洗液等),更优选地,血浆或血清。
可以使用常规技术处理样品,以提取抗体和/或去除干扰组分。例如,可以对固体和/或组织样品进行均质化和离心、过滤和/或色谱技术,以去除细胞或组织片段。在其它情况下,可以添加已知会沉淀或结合干扰组分的试剂。例如,可以使用常规的凝血技术处理全血,以去除红细胞和白细胞以及血小板。
可以使用本领域中已知的用于单克隆抗体的标准方法将双特异性抗体从样品中分离或富集(即浓缩)在样品中。这种方法包含去除来自样品的一种或多种非特异性抗体污染物。可以使用离心、过滤、超滤、透析、离子交换色谱、尺寸排阻色谱、蛋白A/G亲和色谱、亲和纯化、沉淀、凝胶电泳、毛细管电泳和化学分级分离来富集或纯化样品。在一些实施例中,双特异性抗体或其重链和/或轻链是基本上分离的,这意味着双特异性抗体与提供所述抗体的样品至少部分地或基本上分离。按双特异性抗体或其重链和/或轻链的重量计,基本上分离可以包含含有样品的至少约10%、至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%、至少约95%、至少约97%或至少约99%。用于分离单克隆抗体的方法,如上文描述的方法,是本领域的常规方法。
在一些优选的实施例中,通过免疫捕获从生物样品中纯化双特异性抗体。用对所述双特异性抗体具有特异性的抗原或抗体进行所述免疫捕获;优选地,抗独特型抗体、针对特征肽的抗体或其组合,其中相继使用抗独特型抗体和抗肽抗体。当双特异性抗体是抗CD3抗体时,使用抗CD3独特型抗体(例如抗OKT3抗体)来进行免疫捕获。优选地,在固体支持物上或通过使用免疫磁分离进行免疫捕获;更优选地,使用生物素化抗体和抗生蛋白链菌素包被的磁珠。使用本领域已知的用于单克隆抗体的标准方法进行免疫捕获。
纯化后,优选地通过免疫捕获,将双特异性抗体用胰蛋白酶或胰蛋白酶/LysC消化,以产生包括特征肽的(胰蛋白酶)肽。使用本领域众所周知的标准方法进行胰蛋白酶或胰蛋白酶/LysC消化。优化消化条件(培育时间、温度、胰蛋白酶与双特异性抗体的比率),以确保充分且一致的消化。有利地使用固定化的胰蛋白酶或胰蛋白酶/lysC。
通过展开双特异性抗体、减少重链和轻链之间的二硫键并防止其重整,可以有利地进行预处理以提高消化效率和完整性。这可以通过用还原剂(如DTT和DTE(2,3二羟基丁烷-1,4-二硫醇)、巯基乙酸盐、半胱氨酸亚硫酸盐、亚硫酸氢盐、硫化物、二硫化物、TCEP(三(2-羧乙基)膦)和2-巯基乙醇)以及烷基化剂(如碘乙酰胺)处理双特异性抗体来实现。在用还原剂处理之前,可以用变性剂(如尿素)进行另外的处理。可替代地,可以通过提高消化温度、添加有机溶剂、微波辅助消化或沉淀消化方法来加速胰蛋白酶消化过程。例如,可以用TCEP和碘乙酰胺处理双特异性抗体。
质谱法
样品制备后,对双特异性抗体的胰蛋白酶肽进行串联质谱(MS)技术(LC-MS/MS),该技术将液相色谱法的物理分离能力与质谱法的质谱分析能力相结合。质谱分析依赖于根据带电物质的质量对其进行分离。可以使用任何LC-MS仪器。使用高效液相色谱柱进行LC。使用二维高效液相色谱法(2-D-HPLC)(如二维纳米液相色谱法)有利地进行LC。例如,可以使用2D Trap-Nano LC配置。捕集柱有利地是反相C18液相色谱HPLC柱。
可以使用与四极质谱仪(ESI Triple Quad MS)耦合的电喷雾电离进行质谱检测。四极杆质量分析器(Q)由四个平行设置的圆柱杆组成。Q也可以由其它多边形杆组成,如六角形和八角形以及稍微不平行的装配。在四极质谱仪中,四极杆是仪器的组件,其负责根据质荷比(m/z)过滤样品离子。可以使用任何ESI Triple Quad质谱仪。通过使用高分辨率精确质谱法(HRMS),可以提高灵敏度和特异性。HRMS仪器的实例是轨道离子阱(Orbitrap)和飞行时间(TOF)质谱仪。
在一些实施例中,所述质谱法包括二维纳米液相色谱法,其与电喷雾电离轨道离子阱质谱法偶联。
通过与内标品(IS)比较,确定生物样品中的特征肽的含量。内标品可以是双特异性抗体的稳定同位素标记的(SIL)类似物、稳定同位素标记的(SIL)特征肽或类似的双特异性抗体(如包括相同特征肽的双特异性抗体)。所述方法可以在人血清中达到50pg/ml的较低定量水平(LLOQ),并且检测范围为50pg/ml到5000pg/ml双特异性抗体。
试剂盒
本发明还涉及一种用于使用根据本发明的方法定量生物样品中的双特异性抗体的试剂盒,所述试剂盒至少包括根据本发明的特征肽。优选地,试剂盒进一步包括对双特异性抗体具有特异性的抗体和/或根据本发明的内标品。
方法的用途
本发明还涉及本发明的方法用于进行治疗性双特异性抗体的药代动力学研究(具体地说,治疗性双特异性抗体的临床前或临床研究)以及用于监测受试者中用治疗性双特异性抗体对疾病进行的治疗的用途。
本发明涉及用于治疗HER2阳性实体癌的T细胞重定向抗体,如双特异性抗体。
本公开还提供了一种用于通过向患者施用治疗有效量的所公开的抗体来治疗HER2阳性实体癌的方法。
根据本发明的一方面,通过技术(WO2012131555)产生T细胞重定向抗体。在本发明的更具体的方面,T细胞重定向抗体是HER2xCD3双特异性抗体(被称为GBR1302),其重定向细胞毒性T细胞以杀死过表达HER2的癌细胞。更具体地说,本发明的抗体包括SEQID NO:11到13的氨基酸序列。在另一个具体方面,T细胞重定向抗体是CD38xCD3双特异性抗体,其被称为GBR1342(SEQ ID NO:14到16)。
根据本发明的优选的方面,使用以下参数来执行所述方法:
在本发明的一个实施例中,所公开的T细胞重定向抗体用于治疗HER2阳性实体瘤。
在本发明的一个具体实施例中,在为期28天的治疗周期中,在第1天和第15天按1ng/kg和750ng/kg之间的剂量静脉内施用所公开的抗体。
在一个更具体的实施例中,治疗剂量选自包括以下的组:约1ng/kg、约3ng/kg、约10ng/kg、约30ng/kg、约60ng/kg、约100ng/kg、约200ng/kg、约300ng/kg、约500ng/kg和约750ng/kg。
为了将所公开的抗体用作治疗剂,有必要研究药物吸收、分布、代谢和排泄的时间过程,以增强药物的功效并降低其毒性。为了进行这些研究(统称为药代动力学研究),需要研究某些参数,包含:最大观察血清浓度(Cmax)、从时间0到最后可测量浓度时间的血清浓度时间曲线下的面积(AUClast)、最大观察血清浓度的时间(Tmax)、最后观察血清浓度的时间(Tlast)、血清消除半衰期(t1/2),最后可测量血浆浓度(Clast)。
根据本发明的一方面,所公开的抗体按以下剂量施用:
(a)约30ng/kg,Cmax等于或大于约0.25ng/mL且等于或小于约0.45ng/mL,AUClast等于或大于约10hr*ng/mL且等于或小于约25hr*ng/mL,Tmax等于或大于约1小时且等于或小于约4小时,Tlast等于或大于约40小时且等于或小于约160小时,t1/2约为70小时,并且Clast等于或大于约0.05ng/mL且等于或小于约0.15ng/mL;
(b)约60ng/kg,Cmax等于或大于约0.3ng/mL且等于或小于约0.9ng/mL,AUClast等于或大于约1.3hr*ng/mL且等于或小于约90hr*ng/mL,Tmax等于或大于约1小时且等于或小于约4小时,Tlast等于或大于约4小时且等于或小于约350小时,t1/2等于或大于约90小时且等于或小于约130小时,并且Clast等于或大于约0.05ng/mL且等于或小于约0.65ng/mL;
(c)约100ng/kg,Cmax等于或大于约0.5ng/mL且等于或小于约3ng/mL,AUClast等于或大于约25hr*ng/mL且等于或小于约210hr*ng/mL,Tmax等于或大于约1小时且等于或小于约5小时,Tlast等于或大于约110小时且等于或小于约360小时,t1/2等于或大于约80小时且等于或小于约130小时,并且Clast等于或大于约0.05ng/mL且等于或小于约0.2ng/mL;
(d)约200ng/kg,Cmax等于或大于约0.9ng/mL且等于或小于约2.5ng/mL,AUClast等于或大于约74hr*ng/mL且等于或小于约230hr*ng/mL,Tmax等于或大于约1小时且等于或小于约7小时,Tlast等于或大于约140小时且等于或小于约340小时,t1/2等于或大于约80小时且等于或小于约130小时,并且Clast等于或大于约0.05ng/mL且等于或小于约0.3ng/mL;
(e)约300ng/kg,Cmax等于或大于约2ng/mL且等于或小于约4.5ng/mL,AUClast等于或大于约9hr*ng/mL且等于或小于约330hr*ng/mL,Tmax等于或大于约1小时且等于或小于约6小时,Tlast等于或大于约4小时且等于或小于约540小时,t1/2等于或大于约80小时且等于或小于约120小时,并且Clast等于或大于约0.08ng/mL且等于或小于约2.4ng/mL;
(f)约500ng/kg,Cmax等于或大于约2,5ng/mL且等于或小于约8ng/mL,AUClast等于或大于约160hr*ng/mL且等于或小于约760hr*ng/mL,Tmax等于或大于约1小时且等于或小于约11小时,Tlast等于或大于约48小时且等于或小于约500小时,t1/2等于或大于约100小时且等于或小于约150小时,并且Clast等于或大于约0.1ng/mL且等于或小于约2ng/mL;
(g)约7,5ng/kg,Cmax等于或大于约7.5ng/mL且等于或小于约17ng/mL,AUClast等于或大于约240hr*ng/mL且等于或小于约1100hr*ng/mL,Tmax等于或大于约1小时且等于或小于约6小时,Tlast等于或大于约40小时且等于或小于约340小时,t1/2等于或大于约100小时且等于或小于约160小时,并且Clast等于或大于约0.35ng/mL且等于或小于约3.5ng/mL。
根据本发明的一方面,T细胞重定向抗体适合于治疗以HER2过表达为特征的癌症,并且具体地说,选自乳腺癌、卵巢癌、膀胱癌、唾液腺癌、子宫内膜癌、胰腺癌和非小细胞肺癌(NSCLC)。在本发明的最有利的方面,HER2阳性癌症是乳腺癌。
附图说明
-图1表示GBR 1302胰蛋白酶消化物的LC-HRMS/MS谱图。
A.GBR 1302胰蛋白酶消化物,其示出了具有m/z 896.44(M+2H)2+的肽TDPPLLESDGSFALSSR(SEQ ID NO:4),B.GBR 1302胰蛋白酶消化物,其示出了具有m/z615.31(M+2H)2+的肽EPEVATFPPSR(SEQ ID NO:10)。C.人血清空白。
-图2表示通过LC-HRMS/MS在人血清中进行的GBR 1302定量。
-图3表示通过LC-HRMS/MS在猴血清中进行的GBR 1342定量。
-图4:GBR1302的几何平均血清谱图。
实例
材料和方法
1.材料
-双特异性抗体
-内标品
-GBR 1302IS:稳定同位素标记的(SIL)特征肽SEQ ID NO:4(m/z 901.44(M+2H)2+)。工作溶液100pg/mL,于30:70ACN:水中
-GBR 1342IS:稳定同位素标记的(SIL)特征肽SEQ ID NO:5(m/z 907.96(M+2H)2+);工作溶液100pg/mL,于30:70ACN:水中
-试剂
-生物基质:人或猴血清
-抗生蛋白链菌素珠粒(DynaBeads抗生蛋白链菌素T1,p/n 650-02,英杰(Invitrogen))
-生物素化的OKT3抗体(Abpro和inhouse)
-生物素化的9G7抗体(Abpro和inhouse)
-生物素化的SP34抗体(Bio-rad和inhouse)
-TCEP还原溶液(75mM TCEP,于水中,新鲜制备)
-碘乙酰胺烷基化(IAA)溶液(150mM IAA,于水中,新鲜制备)
-胰蛋白酶溶液(胰蛋白酶金(PROMEGA)50μg/mL,于水中;新鲜制备)
-乙腈(ACN)溶液:30:70ACN:水
-PBS/BSA:0.1%BSA,于10mM PBS中
-TrisHCl,1M,pH 8.3
-HCl 30mM
-校准标准品和质量控制(QC)样品
-QC样品:生物基质中的50、150、300、750、4000pg/mL双特异性抗体
-标准品:STD1到STD8:生物基质中的50、75、100、250、500、1000、3000和5000pg/mL双特异性抗体
2.方法
2.1样品制备
将PBS-BSA中的样品、质量控制、标准品、零样品和空白分布在A板的孔中,然后添加生物素化抗体(2μg),并将A板在4℃下振荡培育过夜。然后将抗生蛋白链菌素T1珠粒添加到孔中,并将板A在室温下培育1小时,以结合生物素化抗体捕获的分析物。然后将珠粒转移到放置在磁力架上的收集板(板B)中,并用CHAP缓冲液洗涤两次,并用PBS缓冲液洗涤两次。通过以下进行抗体洗脱:向板B中添加30mM HCl,混合3分钟,并将洗脱液转移至含有1MTris pH 8.3的板C中;并重复洗脱步骤。
将内标品添加到板C的样品、质量控制、标准品和零样品中。将30:70ACN:水添加到板C的空白对照中。将75mM TCEP添加到每个孔中,混合1分钟后,将板在56℃下培育45分钟。将板在室温下冷却10分钟。向每个孔中添加150mM IAA,混合1分钟后,将板在室温下在黑暗中培育35分钟。将胰蛋白酶(50μg/mL)添加到每个孔中,混合1分钟后,将板在37℃下振荡培育过夜。
2.3色谱法
保留时间:GBR 1302 4.40±1.0分钟
GBR 1302-IS 4.40±1.0分钟
GBR 1342 4.10±1.0分钟
GBR 1342-IS 4.10±1.0分钟
该方法使用2D Trap-Nano LC配置执行,其中Thermo QE和Dionex Ultimate3000RSLC纳米LC与Thermo Easy-Spray源耦合。通过将泵加载到捕集柱上,然后切换到以600标准升/分钟的流速运行的nanoLC分析柱上,首先将样品上样。盘绕成环的分析柱与线性限流器发射器紧密耦合。将捕集柱和分析柱均用高有机溶剂洗涤,以通过纳米泵和微型泵洗脱高度保留的内源性组分。
2.4质谱法
MS采集时间:GRB1302和GRB1302 IS:4.1分钟到5.1分钟
GRB1342和GRB1342 IS:4分钟到5分钟
实例1:鉴定用于人类或非人灵长类动物血清中双特异性抗体定量的独特特征肽
在第一种方法中,使用标准选择规则来选择用于定量人血清中的双特异性抗体的潜在特征肽:6-15aa;没有化学反应性残基(色氨酸(W)、蛋氨酸(M)、半胱氨酸(C));不包含2R、2K和RK;没有潜在的PTM(酪氨酸(Y)、苏氨酸(T)、丝氨酸(S)、赖氨酸(K));优选地含有脯氨酸(P);R在P附近(可能错过了胰蛋白酶裂解)。基于这些规则,在外加有GBR 1302的人血清中选择了15种特征肽(SP)。基于质量响应强度,选择两种肽LYSGVPSR(SEQ ID NO:8)和FTISADTSK(SEQ ID NO:9)进行优化。观察到,空白人血清以及外加有GBR 1302的人血清样品中均存在所选的特征肽,这表明所述特征肽并非对GBR 1302具有特异性。
在第二种方法中,使用Expasy肽切割软件(http://web.expasy.org/peptide_ cutter/)来预测GBR 1302、GBR 1342和GBR 1372双特异性抗体的胰蛋白酶消化所产生的肽。然后将所得的胰蛋白酶肽序列与人血浆蛋白质组(NCBI BLAST)进行比较,以排除对于双特异性抗体来说并非独特的肽(存在于血浆蛋白质组中)。
在GBR 1302胰蛋白酶消化物的LC-HRMS/MS谱图中发现了两种独特特征肽:具有m/z 896.44(M+2H)2+的TDPPLLESDGSFALSSR(SEQ ID NO:4)以及具有m/z 615.31(M+2H)2+的EPEVATFPPSR(SEQ ID NO:10)(图1A和1B)。观察到二者是GBR 1302特有的,并且在空白的人血清和曲妥珠单抗中不存在(图1C)。
还观察到两种肽均位于工程化的CH3异二聚体中,所述异二聚体存在于通过免疫球蛋白结构域界面交换技术产生的所有双特异性抗体中。根据IGMT编号,SEQ ID NO:4的SP位于IgG CH3结构域的位置80到88。根据IGMT编号,SEQ ID NO:10的SP位于IgG CH3结构域的位置1到11。
基于质量响应强度,选择特征肽TDPPLLESDGSFALSSR(SEQ ID NO:4)用于双特异性抗体定量。
GBR 1372包括与GBR 1302相同的Fc异二聚体。在GBR 1372胰蛋白酶消化物的LC-HRMS/MS图谱中发现了相同的独特特征肽(SEQ ID NO:4)。
GBR 1342包括一个Fc异二聚体,其与GBR 1302和GBR 1372的Fc异二聚体的区别在于D84.4Q取代。在GBR 1342胰蛋白酶消化物的LC-HRMS/MS谱图中发现了具有m/z 902.96(M+2H)2+的相应特征肽TDPPLLESQGSFALSSR(SEQ ID NO:5)。
这些结果表明,来自工程化的人IgG CH3异二聚体的一个CH3结构域的位置80到88的特征肽是独特的特征肽,其可用于定量人血清中具有工程化的人IgG CH3异二聚体的所有双特异性抗体。
实例2:用于人或猴血清中的双特异性抗体定量的高灵敏度LC-HRMS/MS分析法
针对人类或非人灵长类动物血清中的双特异性抗体定量,开发了一种基于检测实例1中鉴定的独特特征肽的LC-HRMS/MS分析法。基于特征肽SEQ ID NO:4的MS分析,在人血清中对GBR 1302进行定量。基于特征肽SEQ ID NO:5的MS分析,在猴血清中对GBR 1342进行定量。所述分析法的步骤在材料和方法部分中详细公开。简单来说,使用生物素化的抗独特型抗体和抗生蛋白链菌素包被的免疫磁珠对外加有人或猴血清中的双特异性抗体进行免疫纯化。在用TCEP和碘乙酰胺和胰蛋白酶消化进行预处理之前,将双特异性抗体内标品(IS;稳定同位素标记的(SIL)特征肽)添加到免疫纯化的双特异性抗体中。然后使用ThermoQ-Exactive轨道离子阱质谱仪对胰蛋白酶消化物进行2D Trap-Nano LC-Nano ESI MS/MS分析。
人血清中的GBR 1302定量
使用8个标准品(STD1到STD8:50、75、100、250、500、1000、3000和5000pg/mL)建立平均校准系数R2=(0.9978)的线性校准曲线。校准曲线在2个数量级上呈线性,并且LLOQ为50pg/mL(图2)。使用这些实验中生成的线性回归曲线得出的GBR 1302浓度的准确度为(97.8-100.9%)并且CV%(不精确度)<9.4,图2和表1。
表1:人血清中的GBR 1302定量:准确度和精确度
标准品1 | 标准品2 | 标准品3 | 标准品4 | 标准品5 | 标准品6 | 标准品7 | 标准品8 | |
理论浓度 | 50 | 75 | 100 | 250 | 500 | 1000 | 3000 | 5000 |
发现浓度pg/mL | ||||||||
#1 | 48.46 | 76.14 | 98.42 | 269.95 | 480.97 | 986.58 | 3108.91 | 4890.80 |
#2 | 51.89 | 74.45 | 99.29 | 236.42 | 494.30 | 970.26 | 3060.55 | 5202.19 |
平均值 | 50.18 | 75.30 | 98.86 | 253.19 | 487.63 | 978.42 | 3084.73 | 5046.50 |
标准偏差 | 2.42 | 1.19 | 0.62 | 23.71 | 9.43 | 11.54 | 34.20 | 220.19 |
CV百分比 | 4.8 | 1.6 | 0.6 | 9.4 | 1.9 | 1.2 | 1.1 | 4.4 |
理论值百分比 | 100.4 | 100.4 | 98.9 | 101.3 | 97.5 | 97.8 | 102.8 | 100.9 |
偏差百分比 | 0.4 | 0.4 | -1.1 | 1.3 | -2.5 | -2.2 | 2.8 | 0.9 |
n | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 |
猴血清中的GBR 1342定量
使用8个标准品(STD1到STD8:50、75、100、250、500、1000、3000和5000pg/mL)建立平均校准系数R2=(0.9966)的线性校准曲线。校准曲线在2个数量级上呈线性,并且LLOQ为50pg/mL(图3)。使用这些实验中生成的线性回归曲线得出的GBR 1342浓度的准确度为(94.3-101.8%),CV百分比(不精确度)<5.7,图3和表2。
表2:猴血清中的GBR 1342定量:准确度和精确度
标准品1 | 标准品2 | 标准品3 | 标准品4 | 标准品5 | 标准品6 | 标准品7 | 标准品8 | |
理论浓度 | 50 | 75 | 100 | 250 | 500 | 1000 | 3000 | 5000 |
发现浓度 | ||||||||
#1 | 53.66 | 75.20 | 97.11 | 255.77 | 529.56 | 915.63 | 3103.21 | 5144.84 |
#2 | 46.56 | 75.18 | 102.49 | 238.59 | 486.42 | 969.49 | 3087.14 | 5038.80 |
平均值 | 50.11 | 75.19 | 99.80 | 247.18 | 507.99 | 942.56 | 3095.18 | 5091.82 |
标准偏差 | 5.02 | 0.02 | 3.81 | 12.15 | 30.50 | 38.08 | 11.36 | 74.98 |
CV百分比 | 10 | 0 | 3.8 | 4.9 | 6 | 4 | 0.4 | 1.5 |
理论值百分比 | 100.2 | 100.3 | 99.8 | 98.9 | 101.6 | 94.3 | 103.2 | 101.8 |
偏差百分比 | 0.2 | 0.3 | -0.2 | -1.1 | 1.6 | -5.7 | 3.2 | 1.8 |
n | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 |
这些结果表明,根据本发明的LC-HRMS/MS测定法可以以高灵敏度(LLOQ为100pg/mL)、宽范围的检测(两个数量级,50pg/mL到5000pg/mL)和良好的精确度和准确度实现人类和非人灵长类动物血清中的双特异性抗体定量。因此,根据本发明的LC-HRMS/MS测定法是用于双特异性抗体治疗剂的临床前和临床研究的非常有效的测定法。
实例3:GBR1302在患有进行性HER2阳性实体瘤的患者中的药代动力学研究
材料和方法
为了评估GBR1302在患有进行性HER2阳性实体瘤(目前尚无标准或治愈性治疗方法)的成人中的药代动力学,进行了一项1期,首次在人类,开放标签,多中心,剂量递增的研究。受试者在为期28天的治疗周期的第1天和第15天以递增剂量水平(从1ng/kg开始)接受静脉内GBR 1302。前4个队列由单个受试者组成;随后的队列使用3+3设计进行招募。收集血液样品进行药代动力学(PK)和抗药物抗体(ADA)分析(次要终点)。分别使用经过验证的LC/MS/MS方法和ELISA方法进行GBR 1302血清浓度的定量(用于PK)和抗GBR 1302抗体的检测/确认(用于免疫原性)。使用标准的非房室方法评估PK参数。
估计以下PK参数:
-最大观察血清浓度(Cmax)
-从时间0到最后可测量浓度时间的血清浓度-时间曲线下面积(AUClast)
-最大观察血清浓度的时间(Tmax)
-最后观察血清浓度的时间(Tlast)
-血清消除半衰期(t1/2)
-最后可测量血浆浓度(Clast)
为了评估免疫原性,测量了抗药物抗体(ADA)的反应。
结果:
如表3和4以及图4所示,在31位受试者中研究了GBR1302的药代动力学,剂量范围为1ng/kg到750ng/kg。
表3:单个受试者的PK。使用Phoenix WinNonlin 8.0版线性梯形方法和静脉输注给药进行NCA分析。为了进行PK分析,使用了实际输注的开始和结束时间以及直到队列8的实际经过的PK采样时间点。对于队列9,实际的PK采样时间不可用,因此将计划的采样时间用于PK计算。b:标记为是因为调整后的R2<0.8,和/或外推的AUC%>20%,和/或Kel估计的持续时间小于所得t1/2的1.5倍。
b:标记为是因为调整后的R2<0.8,和/或外推的AUC%>20%,和/或Kel估计的持续时间小于所得t1/2的1.5倍
表4:GBR 1302的摘要PK参数[平均值(SD)]NC:无法计算;#:中值(最小-最大);a:N=2;b:N=3;c:N=1;d:N=6;e:N=7;f:N=4。
在第一剂量(1ng/kg)时,血清浓度低于50pg/mL的定量下限,并且在3ng/kg和10ng/kg剂量水平下仅观察到瞬时浓度。从30ng/kg起观察到可评估的PK曲线。GBR 1302在输注结束时显示出最大血浆浓度(Cmax),此后血清浓度呈双指数下降,平均终末半衰期约为4天到7天。Cmax和曲线下面积(AUC0-t)均显示接近剂量成比例的增加,最高可达750ng/kg(最大评估剂量)。从直到队列5的受试者收集的样品均未显示出ADA阳性反应。这些结果显示出良好的线性PK,到目前为止,所评估的受试者均未显示出ADA阳性反应。
序列表
<110> 伊克诺斯科学公司
<120> 生物样品中的抗体定量
<130> GBT4001
<160> 10
<170> PatentIn 3.5版
<210> 1
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 特征肽1
<220>
<221> 尚未归类的特征
<222> (2)..(2)
<223> T D
<220>
<221> 尚未归类的特征
<222> (5)..(5)
<223> V、L、P或M
<220>
<221> 尚未归类的特征
<222> (7)..(7)
<223> D、Q或E
<220>
<221> 尚未归类的特征
<222> (9)..(9)
<223> D或Q
<220>
<221> 尚未归类的特征
<222> (13)..(13)
<223> F、A或W
<220>
<221> 尚未归类的特征
<222> (15)..(15)
<223> S、W或H
<220>
<221> 尚未归类的特征
<222> (17)..(17)
<223> K或R
<400> 1
Thr Xaa Pro Pro Xaa Leu Xaa Ser Xaa Gly Ser Phe Xaa Leu Xaa Ser
1 5 10 15
Xaa
<210> 2
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<212> PRT
<213> 人工序列
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<223> 特征肽2
<220>
<221> 尚未归类的特征
<222> (5)..(5)
<223> V或M
<220>
<221> 尚未归类的特征
<222> (17)..(17)
<223> K或R
<400> 2
Thr Thr Pro Pro Xaa Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
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Xaa
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<211> 17
<212> PRT
<213> 人工序列
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Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Ala Leu Ser Ser
1 5 10 15
Lys
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<212> PRT
<213> 人工序列
<220>
<223> 特征肽4
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Thr Asp Pro Pro Leu Leu Glu Ser Asp Gly Ser Phe Ala Leu Ser Ser
1 5 10 15
Arg
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Thr Asp Pro Pro Leu Leu Glu Ser Gln Gly Ser Phe Ala Leu Ser Ser
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Arg
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Thr Thr Pro Pro Pro Leu Gln Ser Asp Gly Ser Phe Trp Leu Trp Ser
1 5 10 15
Lys
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<212> PRT
<213> 人工序列
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Thr Thr Pro Pro Met Leu Glu Ser Asp Gly Ser Phe Phe Leu His Ser
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Lys
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<212> PRT
<213> 人工序列
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<223> 特征肽8
<400> 8
Leu Tyr Ser Gly Val Pro Ser Arg
1 5
<210> 9
<211> 9
<212> PRT
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<220>
<223> 特征肽9
<400> 9
Phe Thr Ile Ser Ala Asp Thr Ser Lys
1 5
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<220>
<223> 特征肽10
<400> 10
Glu Pro Glu Val Ala Thr Phe Pro Pro Ser Arg
1 5 10
<210> 11
<211> 495
<212> PRT
<213> 人工序列
<220>
<223> 赫赛汀(Herceptin)ScFv LALA BTB Fc_蛋白
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Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
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Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
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Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn
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Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly
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Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr
65 70 75 80
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys
85 90 95
Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
100 105 110
Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp
115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
145 150 155 160
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
165 170 175
Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln
180 185 190
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe
195 200 205
Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr
210 215 220
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
225 230 235 240
Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly
245 250 255
Thr Lys Val Glu Ile Lys Arg Gly Gly Gly Gly Thr Asp Lys Thr His
260 265 270
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
275 280 285
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
290 295 300
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
305 310 315 320
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
325 330 335
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
340 345 350
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
355 360 365
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
370 375 380
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Glu Val Ala Thr Phe Pro
385 390 395 400
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Thr Leu Val Cys Leu
405 410 415
Val Thr Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
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Gly Gln Pro Glu Asn Asn Tyr Lys Thr Asp Pro Pro Leu Leu Glu Ser
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Asp Gly Ser Phe Ala Leu Ser Ser Arg Leu Arg Val Asp Lys Ser Arg
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Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
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His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
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<210> 12
<211> 469
<212> PRT
<213> 人工序列
<220>
<223> OKT3 H11 1133 LALA BTA蛋白
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Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
20 25 30
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr
35 40 45
Phe Thr Arg Tyr Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly
50 55 60
Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Tyr Tyr
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Ala Asp Ser Val Lys Gly Arg Phe Thr Leu Ser Thr Asp Lys Ser Lys
85 90 95
Asn Thr Ala Tyr Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala
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Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr
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Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
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Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
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Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
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Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
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Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
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Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
225 230 235 240
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
245 250 255
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
260 265 270
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
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Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr Val Asp Gly Val
290 295 300
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
305 310 315 320
Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
325 330 335
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
340 345 350
Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro
355 360 365
Ala Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
370 375 380
Val Lys Leu Val Cys Leu Val Thr Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn Asn Tyr Tyr Thr Thr
405 410 415
Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Ser Leu Val Ser Trp Leu
420 425 430
Asn Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly Lys
465
<210> 13
<211> 233
<212> PRT
<213> 人工序列
<220>
<223> OKT3 L8 LC_蛋白
<400> 13
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser
35 40 45
Val Ser Tyr Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
50 55 60
Arg Trp Ile Tyr Asp Thr Ser Lys Leu Tyr Ser Gly Val Pro Ser Arg
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Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser
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Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser
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Asn Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr
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Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
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Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
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Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
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Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
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Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
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Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
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Thr Lys Ser Phe Asn Arg Gly Glu Cys
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<210> 14
<211> 234
<212> PRT
<213> 人工序列
<220>
<223> GBR1342轻链序列 (hum9G7_VL_cK)
<400> 14
Met Arg Ser Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Ile Pro
1 5 10 15
Gly Thr Asn Ala Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp
35 40 45
Val Ile Thr Ser Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
50 55 60
Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser
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Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln His Tyr
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Thr Ile Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
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Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
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Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
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Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 15
<211> 470
<212> PRT
<213> 人工序列
<220>
<223> GBR1342重链序列(h9G7 1133 BTA LALA FTO (dA))
<400> 15
Met Arg Ser Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Ile Pro
1 5 10 15
Gly Thr Asn Ala Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val
20 25 30
Lys Pro Thr Gln Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Leu Ser
35 40 45
Leu Ser Thr Ser Gly Lys Gly Val Gly Trp Ile Arg Gln Pro Pro Gly
50 55 60
Lys Ala Leu Glu Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Arg
65 70 75 80
Tyr Asn Pro Ala Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser
85 90 95
Lys Asn Gln Val Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr
100 105 110
Ala Thr Tyr Tyr Cys Ala Arg Ile Glu Leu Gly Arg Ser Tyr Val Met
115 120 125
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
145 150 155 160
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
210 215 220
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu
225 230 235 240
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
245 250 255
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
260 265 270
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
275 280 285
Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr Val Asp
290 295 300
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
305 310 315 320
Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
325 330 335
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
340 345 350
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg
355 360 365
Glu Pro Ala Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
370 375 380
Asn Gln Val Lys Leu Val Cys Leu Val Thr Gly Phe Tyr Pro Ser Asp
385 390 395 400
Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn Asn Tyr Tyr
405 410 415
Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Ser Leu Val Ser
420 425 430
Trp Leu Asn Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile Phe Ser
435 440 445
Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser
450 455 460
Leu Ser Leu Ser Pro Gly
465 470
<210> 16
<211> 501
<212> PRT
<213> 人工序列
<220>
<223> GBR1342 scFv-Fc序列:hSP34_H3K21_W100eY/T29E-W91F-L95T
(hSP34v.3) scFv_11_BTB_D401Q_LALA
<400> 16
Met Arg Ser Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Ile Pro
1 5 10 15
Gly Thr Asn Ala Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
20 25 30
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
35 40 45
Phe Asn Thr Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
50 55 60
Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
65 70 75 80
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp
85 90 95
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr
115 120 125
Val Ser Tyr Phe Ala Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
130 135 140
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
145 150 155 160
Glu Ile Val Val Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
165 170 175
Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Thr Gly Ala Val Thr Glu
180 185 190
Ser Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Gly Gln Ala Phe Arg
195 200 205
Gly Leu Ile Gly Gly Ala Asn Lys Arg Ala Pro Gly Val Pro Ala Arg
210 215 220
Phe Ser Gly Ser Leu Ser Gly Asp Glu Ala Thr Leu Thr Ile Ser Ser
225 230 235 240
Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Ala Leu Phe Tyr Ser
245 250 255
Asn Thr Trp Val Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Gly Gly
260 265 270
Gly Gly Thr Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
275 280 285
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
290 295 300
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
305 310 315 320
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
325 330 335
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
340 345 350
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
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Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
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Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
385 390 395 400
Pro Glu Val Ala Thr Phe Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
405 410 415
Gln Val Thr Leu Val Cys Leu Val Thr Gly Phe Tyr Pro Ser Asp Ile
420 425 430
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
435 440 445
Asp Pro Pro Leu Leu Glu Ser Gln Gly Ser Phe Ala Leu Ser Ser Arg
450 455 460
Leu Arg Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
465 470 475 480
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
485 490 495
Ser Leu Ser Pro Gly
500
Claims (16)
2.根据权利要求1所述的方法,其中所述特征肽由以下序列组成:
TX1PPX2LX3SX4GSFX5LX6SX7(SEQ ID NO:1)
其中X1代表T或D,X2代表V、L、P或M,X3代表D、Q或E,X4代表D或Q,
X5代表F、A或W,X6代表S、W或H,并且X7代表K或R,前提是当X1为T时,X2、X3、X4、X5和X7中的至少一个使得X2为L、P或M;X3为Q或E;X4为Q;X5为A或W;并且X7为R。
3.根据权利要求2所述的方法,其中所述特征肽选自由以下组成的组:TTPPVLDSDGSFALSSK(SEQ ID NO:3)、TDPPLLESDGSFALSSR(SEQ ID NO:4)、TDPPLLESQGSFALSSR(SEQ ID NO:5)、TTPPPLQSDGSFWLWSK(SEQ ID NO:6)和TTPPMLESDGSFFLHSK(SEQ ID NO:7),优选地,SEQ ID NO:4或SEQ ID NO:5。
5.根据权利要求4所述的方法,其中:
-所述第一CH3结构域进一步包括以下取代中的一个或多个:Q3E、Y5A、L7F、S20T、T22V、K26T、T81D、V84L、D84.2E、K88R和T90R;优选地,Q3E、Y5A、L7F、S20T、T22V、K26T、T81D、V84L、D84.2E、K88R和T90R或Q3E、Y5A、L7F、S20T、T22V、K26T、T81D、V84L、D84.2E和K88R;并且
-所述第二CH3结构域进一步包括以下取代中的一个或多个:Q3A、D12E、L14M、N44S、V84M、F85.1S、Y86V、V101I、H115R和Y116F;优选地,F85.1S和Y86V;对于来自人IgG1的CH3结构域,F85.1S、Y86V和Q3A,而对于来自人IgG3的CH3结构域,D12E、L14M、N44S、V84M、F85.1S、Y86V、V101I、H115R和Y116F。
6.根据前述权利要求中任一项所述的方法,其中所述抗体包括使用人IgG和IgD CH3结构域之间的免疫球蛋白结构域界面交换工程化的人IgG CH3结构域异二聚体,其中所述第一CH3结构域包括以下取代:Q3V、Y5L、K26S、V84P、D84.2Q、F85.1W和Y86W,并且所述第二CH3结构域包括以下取代:S20W、K79A、T81A、K88V和T90R。
7.根据前述权利要求中任一项所述的方法,其中所述抗体包括使用人IgG和IgM CH3结构域之间的免疫球蛋白结构域界面交换工程化的人IgG CH3结构域异二聚体,其中所述第一CH3结构域包括以下取代:Q3D、K26T、V84M、D84.2E和Y86H,并且所述第二CH3结构域包括以下取代:S20T、K79V、T81S和K88I。
8.根据前述权利要求中任一项所述的方法,其中所述双特异性抗体包括来自人免疫球蛋白的Fc、Fab和scFv。
9.根据前述权利要求中任一项所述的方法,其中所述双特异性抗体是治疗性抗体。
10.根据前述权利要求中任一项所述的方法,其中所述双特异性抗体是双特异性抗CD3抗体,优选地,抗CD3和抗Her2双特异性抗体、抗CD3和抗CD38双特异性抗体或抗CD3和抗EGFR双特异性抗体。
11.根据前述权利要求中任一项所述的方法,其包括以下步骤:
a)通过免疫捕获从所述生物样品中纯化所述双特异性抗体,
b)用胰蛋白酶或胰蛋白酶/Lys C消化在步骤a)中获得的所述双特异性抗体,以产生包括所述特征肽的肽,以及
c)对步骤b)中获得的所述肽进行质谱分析,以通过与内标品比较或使用校准标准品来确定所述生物样品中的特征肽的量。
12.根据权利要求11所述的方法,其中用对所述双特异性抗体具有特异性的抗体进行所述免疫捕获;优选地,抗独特型抗体、针对所述特征肽的抗体或其组合;优选地,在固体支持物上或使用免疫磁分离进行所述免疫捕获;更优选地,使用生物素化抗体和抗生蛋白链菌素包被的磁珠。
13.根据前述权利要求中任一项所述的方法,其中所述质谱法包括与电喷雾电离轨道离子阱质谱法偶联的二维纳米液相色谱法。
14.根据前述权利要求中任一项所述的方法,其中所述生物样品是人类生物样品,优选地,人体液,更优选地,人血清。
15.根据前述权利要求中任一项所述的方法,其中所述双特异性抗体的定量下限为50pg/ml,并且在人血清中,所述双特异性抗体的检测范围为50pg/ml到5000pg/ml。
16.一种用于使用根据前述权利要求中任一项所述的方法定量生物样品中的双特异性抗体的试剂盒,所述试剂盒至少包括根据权利要求1到3中任一项所述的特征肽;优选地,所述试剂盒进一步包括如权利要求12中所定义的对所述双特异性抗体具有特异性的抗体。
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