CN114599394A - 用于在低蛋白浓度下使蛋白损失最小化的组合物和方法 - Google Patents

用于在低蛋白浓度下使蛋白损失最小化的组合物和方法 Download PDF

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CN114599394A
CN114599394A CN202080074309.9A CN202080074309A CN114599394A CN 114599394 A CN114599394 A CN 114599394A CN 202080074309 A CN202080074309 A CN 202080074309A CN 114599394 A CN114599394 A CN 114599394A
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C·朱
D·G·格林尼
Q·郝
S·肯纳普拉姆
M·J·特雷乌海特
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Abstract

本发明涉及用于在低蛋白浓度下使蛋白损失(例如，由于吸附到固体表面)最小化的组合物和方法。本文披露的发明总体上涉及包含蛋白的组合物、特别是包含低蛋白浓度的治疗性蛋白的药物组合物的领域。本文披露的发明还涉及向有需要的受试者施用该组合物的方法。

Description

用于在低蛋白浓度下使蛋白损失最小化的组合物和方法
相关申请的交叉引用
本申请要求2019年10月25日提交的美国临时申请号62/926,089的权益，该临时申请通过援引以其全文并入本文。
以ASCII文本文件提交序列表
以下以ASCII文本文件提交的内容通过援引以其全文并入本文：序列表的计算机可读形式(CRF)(文件名：A-2429-WO-PCT_ST25，创建日期：2020年10月23日，大小：451,608字节)。
技术领域
本文披露的发明总体上涉及包含蛋白的组合物、特别是包含低蛋白浓度的治疗性蛋白的药物组合物的领域。本文披露的发明还涉及向有需要的受试者施用该组合物的方法。
背景技术
治疗性蛋白是用于治疗患者的一类重要疗法。蛋白分子具有表面活性，可能会吸附到固体表面。药物组合物中的治疗性蛋白可被吸附到蛋白所接触的固体表面(例如，容纳药物组合物的容器的表面)，这可能导致在储存和使用期间蛋白损失。通常，这些组合物中治疗性蛋白的浓度较高(例如，1mg/mL或更高)，以使蛋白吸附到固体表面不会导致可用于向患者施用的药物量不足。然而，当组合物中蛋白的浓度较低时(例如，低于0.1mg/mL，诸如当在向患者施用之前稀释组合物时)，蛋白损失的风险可能更明显，这可能导致可用于患者施用的药物量不足。
表面活性剂通常用于包含治疗性蛋白的药物组合物中，例如以防止蛋白聚集和稳定蛋白。尚不清楚当蛋白在药物组合物中以低浓度(例如，0.1mg/mL或更低)存在时，表面活性剂是否可以用于有效防止由于表面吸附而引起的蛋白损失。
需要最小化由于吸附到固体表面而引起的蛋白损失的蛋白组合物和方法，特别是当组合物包含低蛋白浓度的蛋白时。
发明内容
本文披露了包含低蛋白浓度的蛋白的组合物以及向有需要的受试者施用这些组合物的方法。本文披露的组合物和方法具有最小化或消除由于蛋白吸附到固体表面而引起的蛋白损失的优点，并确保向患者准确给药治疗性蛋白。
在某些实施例中，本文披露了一种包含蛋白和表面活性剂的水性组合物，其中蛋白以介于约0.001μg/ml与约100μg/ml之间的浓度存在于组合物中，并且表面活性剂以表面活性剂的临界胶束浓度(CMC)的至少约0.25倍的浓度存在于组合物中。
在某些实施例中，蛋白是双特异性抗体构建体，该双特异性抗体构建体包含与靶细胞表面抗原结合的第一结合结构域、与T细胞表面上的人CD3结合的第二结合结构域，以及任选地按氨基到羧基的顺序包含铰链-CH2结构域-CH3结构域-接头-铰链-CH2结构域-CH3结构域的第三结构域。在某些实施例中，第二结合结构域包含具有SEQ ID NO:201的序列的多肽。在某些实施例中，双特异性抗体构建体以介于约0.001μg/ml与约50μg/ml之间、或介于约0.01μg/ml至约50μg/ml、或0.1μg/ml至约50μg/ml、或0.1μg/ml至约10μg/ml、或1μg/ml至约10μg/ml之间的浓度存在。
在某些实施例中，表面活性剂是聚山梨醇酯、泊洛沙姆或曲拉通(triton)x-100。在某些实施例中，表面活性剂是聚山梨醇酯80、聚山梨醇酯60、聚山梨醇酯40、聚山梨醇酯20或曲拉通X-100。在某些实施例中，表面活性剂是泊洛沙姆188或泊洛沙姆407。在某些实施例中，表面活性剂以介于表面活性剂的CMC的约0.25倍与约20倍之间、或介于CMC的约0.25倍与约10倍之间的浓度存在。
在某些实施例中，其中组合物进一步包含盐、氨基酸、糖类或糖类衍生物或它们的组合。在某些实施例中，盐是NaCl。在某些实施例中，糖类或糖类衍生物是单糖、二糖、环状多糖或糖醇。在某些实施例中，糖类是蔗糖、海藻糖、甘露糖醇或山梨糖醇。在某些实施例中，氨基酸是赖氨酸。
在某些实施例中，其中组合物的pH介于约3.5与约7.5之间。在某些实施例中，组合物的pH介于约4.2与约7.0之间。
在某些实施例中，组合物进一步包含缓冲剂或防腐剂。在某些实施例中，缓冲剂是乙酸盐缓冲剂、谷氨酸盐缓冲剂、柠檬酸盐缓冲剂、琥珀酸盐缓冲剂、酒石酸盐缓冲剂、富马酸盐缓冲剂、马来酸盐缓冲剂、组氨酸缓冲剂或磷酸盐缓冲剂。
在某些实施例中，双特异性抗体构建体的第一结合结构域和第二结合结构域中的每一者包含VH区和VL区。在某些实施例中，双特异性抗体构建体是单链抗体构建体。在某些实施例中，双特异性抗体构建体包含具有选自SEQ ID NO:11、SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:66、SEQ IDNO:67、SEQ ID NO:76、SEQ ID NO:78、SEQ ID NO:87、SEQ ID NO:88、SEQ ID NO:108、SEQID NO:109、SEQ ID NO:110、SEQ ID NO:165、SEQ ID NO:166、SEQ ID NO:167、SEQ ID NO:176、SEQ ID NO:178和SEQ ID NO:192的氨基酸序列的多肽。在某些实施例中，双特异性抗体构建体包含具有SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:25、SEQ ID NO:48、SEQ IDNO:67、SEQ ID NO:78、SEQ ID NO:88、SEQ ID NO:109、SEQ ID NO:110、SEQ ID NO:165、SEQID NO:166、SEQ ID NO:167、SEQ ID NO:178或SEQ ID NO:192的氨基酸序列的多肽。
在某些实施例中，组合物容纳在塑料容器诸如IV袋或IV管中。在某些实施例中，容器由包含聚烯烃、聚氯乙烯(PVC)、乙酸乙烯乙酯(EVA)或聚氨酯的材料制成。在某些实施例中，容器由包含PVC的材料制成，并且其中PVC基本上不含邻苯二甲酸二-2-乙基己酯(DEHP)或偏苯三酸三-2-乙基己酯(TOTM)。
在某些实施例中，本文披露了一种包含容纳在容器内的水性药物组合物的药物制剂，其中水性药物组合物包含：浓度介于约0.001μg/ml与约100μg/ml之间的双特异性抗体构建体，以及浓度为表面活性剂的CMC的至少约0.25倍的表面活性剂，其中表面活性剂具有至少20的HLB值。在某些实施例中，表面活性剂是泊洛沙姆188或泊洛沙姆407。在某些实施例中，水性药物组合物包含浓度介于约0.001μg/ml与约50μg/ml之间的双特异性抗体构建体。在某些实施例中，水性药物组合物包含浓度介于表面活性剂的CMC的约0.25倍与约20倍之间、或介于CMC的约0.25倍与约10倍之间的表面活性剂。
在某些实施例中，水性药物组合物进一步包含盐、缓冲剂、氨基酸、糖类或糖类衍生物或它们的组合。在某些实施例中，水性药物组合物具有介于约4.2与约7.0之间的pH。
在某些实施例中，容器由包含聚烯烃、PVC、EVA或聚氨酯(例如，聚酯和聚醚)的材料制成。
在某些实施例中，双特异性抗体构建体包含具有选自SEQ ID NO:11、SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:47、SEQ ID NO:48、SEQ IDNO:66、SEQ ID NO:67、SEQ ID NO:76、SEQ ID NO:78、SEQ ID NO:87、SEQ ID NO:88、SEQ IDNO:108、SEQ ID NO:109、SEQ ID NO:110、SEQ ID NO:165、SEQ ID NO:166、SEQ ID NO:167、SEQ ID NO:176、SEQ ID NO:178和SEQ ID NO:192的氨基酸序列的多肽。在某些实施例中，双特异性抗体构建体包含具有SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:25、SEQ ID NO:48、SEQ ID NO:67、SEQ ID NO:78、SEQ ID NO:88、SEQ ID NO:109、SEQ ID NO:110、SEQ IDNO:165、SEQ ID NO:166、SEQ ID NO:167、SEQ ID NO:178或SEQ ID NO:192的氨基酸序列的多肽。
本文还披露了一种向患者施用双特异性抗体构建体的方法，该方法包括：在容器中制备水性药物组合物，其中水性药物组合物包含浓度介于约0.001μg/ml与约100μg/ml之间的双特异性抗体构建体以及浓度为表面活性剂的CMC的至少约0.25倍的表面活性剂，以及向患者施用水性药物组合物，其中双特异性抗体构建体包含具有选自SEQ ID NO:11、SEQID NO:13、SEQ ID NO:15、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:47、SEQ ID NO:48、SEQID NO:66、SEQ ID NO:67、SEQ ID NO:76、SEQ ID NO:78、SEQ ID NO:87、SEQ ID NO:88、SEQID NO:108、SEQ ID NO:109、SEQ ID NO:110、SEQ ID NO:165、SEQ ID NO:166、SEQ ID NO:167、SEQ ID NO:176、SEQ ID NO:178和SEQ ID NO:192的氨基酸序列的多肽。在某些实施例中，双特异性抗体构建体包含具有SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:25、SEQ IDNO:48、SEQ ID NO:67、SEQ ID NO:78、SEQ ID NO:88、SEQ ID NO:109、SEQ ID NO:110、SEQID NO:165、SEQ ID NO:166、SEQ ID NO:167、SEQ ID NO:178或SEQ ID NO:192的氨基酸序列的多肽。在某些实施例中，水性药物组合物包含浓度介于约0.001μg/ml与约50μg/ml之间的双特异性抗体构建体。
在某些实施例中，水性药物组合物包含浓度介于表面活性剂的CMC的约0.25倍与约20倍之间、或介于CMC的约0.25倍与约10倍之间的表面活性剂。在某些实施例中，表面活性剂是聚山梨醇酯80、聚山梨醇酯60、聚山梨醇酯40、聚山梨醇酯20、泊洛沙姆188、泊洛沙姆407或曲拉通X-100。
在某些实施例中，水性药物组合物进一步包含选自盐、缓冲剂、氨基酸、糖类或糖类衍生物和防腐剂中的一种或多种。在某些实施例中，水性药物组合物具有介于约4.2与约7.0之间的pH。
在某些实施例中，容器由包含聚烯烃、PVC、EVA、聚氨酯的材料制成。在某些实施例中，表面活性剂是聚山梨醇酯80、聚山梨醇酯60、聚山梨醇酯40或聚山梨醇酯20，并且其中容器由包含基本上不含DEHP或TOTM的PVC的材料制成。
在某些实施例中，水性药物组合物通过用合适的水性溶液稀释包含双特异性抗体构建体的第一组合物来制备。在某些实施例中，第一组合物是包含双特异性抗体构建体的液体组合物。在某些实施例中，第一组合物是由包含双特异性抗体构建体的冻干组合物重构的液体组合物。在某些实施例中，合适的溶液包含浓度为表面活性剂的CMC的至少约0.25倍的表面活性剂。在某些实施例中，水性药物组合物通过将合适的水性溶液添加到容器中，然后将适当量的第一组合物添加到容器中来制备。
在某些实施例中，患者是癌症患者。在某些实施例中，施用是IV施用。
附图说明
图1示出了用于测量与固体表面结合的蛋白的测定的示意图。
图2示出了在不存在表面活性剂的情况下蛋白与固体表面的结合。
图3示出了不同地添加各种表面活性剂防止蛋白与固体表面结合。
图4示出了在添加蛋白之前向固体表面添加表面活性剂更有效地防止蛋白与表面结合。
图5示出了相同浓度的不同表面活性剂对邻苯二甲酸二-2-乙基己酯(DEHP)从含DEHP的PVC中浸出的影响。
图6示出了在相同CMC倍数的不同表面活性剂对DEHP从含DEHP的PVC中浸出的影响。
具体实施方式
本文披露的发明基于以下令人惊讶的发现：当表面活性剂以低于其临界胶束浓度的浓度使用时，可以稳定液体组合物中低浓度的蛋白，并有效地防止由于吸附到固体表面而引起的蛋白损失。
在一些实施例中，本文披露了一种包含蛋白和表面活性剂的水性组合物，其中蛋白以介于约0.001μg/ml与约100μg/ml之间的浓度存在于组合物中，并且表面活性剂以表面活性剂的临界胶束浓度(CMC)的至少约0.25倍的浓度存在于组合物中。
可以用于组合物中的表面活性剂可以是通常用于药物组合物中的任何表面活性剂。在一些实施例中，表面活性剂是非离子表面活性剂。在一些实施例中，表面活性剂是聚山梨醇酯，诸如聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯65、聚山梨醇酯80或聚山梨醇酯85。在一些实施例中，表面活性剂是聚山梨醇酯20，在其他实施例中，表面活性剂是聚山梨醇酯80。在一些实施例中，表面活性剂是泊洛沙姆，诸如泊洛沙姆124、泊洛沙姆188、泊洛沙姆237、泊洛沙姆338和泊洛沙姆407。在一些实施例中，表面活性剂是曲拉通X-100。各种表面活性剂可商购获得(例如，吐温20、吐温80、普朗尼克F68和普朗尼克F127等)。
表面活性剂可以以该表面活性剂的临界胶束浓度(CMC)的至少约0.25倍(0.25x)的浓度存在于组合物中。在一些实施例中，表面活性剂以介于表面活性剂的CMC的约0.25倍与约20倍之间的浓度存在于组合物中。在一些实施例中，表面活性剂以介于表面活性剂的CMC的约0.25倍与约15倍之间、或介于约0.25倍与约10倍之间、或介于约0.25倍与约8倍之间、或介于约0.25倍与约6倍之间、或介于约0.25倍与约4之间、或介于约0.25倍与约2倍之间、或介于约0.25倍与约1倍之间的浓度存在于组合物中。
在一些实施例中，表面活性剂以介于表面活性剂的CMC的约0.5倍与约20倍之间的浓度存在于组合物中。在一些实施例中，表面活性剂以介于表面活性剂的CMC的约0.5倍与约15倍之间、或介于约0.5倍与约10倍之间、或介于约0.5倍与约8倍之间、或介于约0.5倍与约6倍之间、或介于约0.5倍与约4之间、或介于约0.5倍与约2倍之间、或介于约0.5倍与约1倍之间的浓度存在于组合物中。
在一些实施例中，表面活性剂以表面活性剂的CMC的约0.25倍、约0.5倍、约1倍、约2倍、约3倍、约4倍、约5倍、约6倍、约7倍、约8倍、约9倍、约10倍、约12倍、约14倍、约16倍、约18倍或约20倍的浓度存在于组合物中。在一些实施例中，表面活性剂以表面活性剂的CMC的约1.25倍、约2.5倍、约3.5倍、约4.5倍、约5.5倍、约6.5倍、约7.5倍、约8.5或约9.5倍的浓度存在于组合物中。
如本文所用，术语“约”在用于修饰特定值或范围时，应理解为是指给定值或范围内可以存在变化，包括规定值或范围的20％以内(例如，10％、5％、4％、3％、2％或1％以内)。
临界胶束浓度是指表面活性剂的浓度，高于该浓度时会形成胶束，它是表面活性剂的一种性质。表面活性剂的CMC值可以通过本领域公知的实验方法(诸如荧光测定法、表面张力、电导测定法和动态光散射)来测量。参见例如Norman Scholz,Thomas Behnke,UteResch-Genger.Journal of Fluorescence[荧光杂志]28:465-476(2018)以及
Figure BDA0003609980980000071
Topel,
Figure BDA0003609980980000072
Acar
Figure BDA0003609980980000073
Leyla Budama,Numan Hoda.Journal of Molecular Liquids[分子液体杂志]177 40-43(2013)。表面活性剂的CMC值也可以使用诸如
Figure BDA0003609980980000074
Sigma 700或701的装置来自动测量。
在一些实施例中，每种表面活性剂的CMC值在下表1中列出。
表1.常用表面活性剂的CMC
表面活性剂 CMC*(w/v％)
聚山梨醇酯20 0.007
聚山梨醇酯80 0.002
泊洛沙姆188 0.4
泊洛沙姆407 0.004
曲拉通X-100 0.014
*对于表中列出的CMC值，参见例如le Maire M,Champeil P,MollerJV.2000.Interaction of membrane proteins and lipids with solubilizingdetergents[膜蛋白和脂质与增溶洗涤剂的相互作用].Biochim Biophys Acta[生物化学生物物理学报]1508:86-111；Suksiriworapong J,Rungvimolsin T,A-gomol A,Junyaprasert VB,Chantasart D.Development and characterization of lyophilizeddiazepam-loaded polymeric micelles[载有地西泮的冻干聚合物胶束的开发和表征].2014.AAPS PharmSciTech[AAPS药学科技].15(1):52-64；https://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/Sigma/Product_Information_Sheet/1/t8532pis.pdf
蛋白可以以介于约0.001μg/ml与约100μg/ml之间的浓度存在于组合物中。在一些实施例中，蛋白以介于约0.001μg/ml与约90μg/ml、或介于约0.001μg/ml与约80μg/ml之间、或介于约0.001μg/ml与约70μg/ml之间、或介于约0.001μg/ml与约60μg/ml之间、或介于约0.001μg/ml与约50μg/ml之间、或介于约0.001μg/ml与约40μg/ml之间、介于约0.001μg/ml与约30μg/ml之间、或介于约0.001μg/ml与约20μg/ml之间、或介于约0.001μg/ml与约10μg/ml之间、或介于约0.001μg/ml与约5μg/ml之间、或介于约0.001μg/ml与约1μg/ml之间、或介于约0.001μg/ml与约0.01μg/ml之间的浓度存在于组合物中。
在一些实施例中，蛋白以介于约0.01μg/ml与约100μg/ml、或介于约0.01μg/ml与约80μg/ml之间、或介于约0.01μg/ml与约70μg/ml之间、或介于约0.01μg/ml与约60μg/ml之间、或介于约0.01μg/ml与约50μg/ml之间、或介于约0.01μg/ml与约40μg/ml之间、介于约0.01μg/ml与约30μg/ml之间、或介于约0.01μg/ml与约20μg/ml之间、或介于约0.01μg/ml与约10μg/ml之间、或介于约0.01μg/ml与约5μg/ml之间、或介于约0.01μg/ml与约1μg/ml之间、或介于约0.01μg/ml与约0.1μg/ml之间、或介于约0.1μg/ml与约1μg/ml之间、或介于约0.1μg/ml与约5 1μg/ml之间的浓度存在于组合物中。
在一些实施例中，蛋白以约0.001μg/ml、约0.005μg/ml、约0.01μg/ml、约0.05μg/ml、约0.1μg/ml、约1μg/ml、约4μg/ml、约8μg/ml、约10μg/ml、约15μg/ml、约20μg/ml、约25μg/ml、约30μg/ml、约35μg/ml、约40μg/ml、约45μg/ml、约50μg/ml、约55μg/ml、约60μg/ml、约65μg/ml、约70μg/ml、约75μg/ml、约80μg/ml、约85μg/ml、约90μg/ml、约95μg/ml或约100μg/ml的浓度存在于组合物中。
在本文披露的组合物中，可以将蛋白的任何浓度或浓度范围与表面活性剂的任何浓度或浓度范围组合。
任何蛋白可以是组合物中的蛋白。在一些实施例中，组合物中的蛋白是治疗性蛋白，诸如抗原结合蛋白或融合蛋白。
如本文所用，术语“抗原结合蛋白”是指特异性结合一种或多种靶抗原的蛋白。抗原结合蛋白包括但不限于抗体(例如，单克隆抗体)。抗原结合蛋白典型地包含特异性结合至抗原的抗原结合片段，且任选地包含使该抗原结合片段呈现促进该抗原结合蛋白结合至抗原的构型的支架或构架部分。“抗原结合片段”是指抗体中缺少全长重链和/或轻链中存在的至少一些氨基酸但仍能够特异性结合抗原的部分。抗原结合片段包括但不限于单链可变片段(scFv)、纳米抗体(例如，骆驼科重链抗体的VH结构域；VHH片段，参见Cortez-Retamozo等人,Cancer Research[癌症研究],第64卷：2853-57,2004)、Fab片段、Fab'片段、F(ab')2片段、Fv片段、Fd片段和互补决定区(CDR)片段，并且可以衍生自任何哺乳动物来源，诸如人、小鼠、大鼠、兔或骆驼科动物。抗原结合片段可与完整抗体竞争结合靶抗原，并且这些片段可通过修饰完整抗体(例如，酶促或化学裂解)或者使用本领域已知的重组DNA技术或肽合成从头合成来产生。
在一些实施例中，蛋白是双特异性的抗原结合蛋白。如本文所用，术语“双特异性”是指能够与两种不同抗原或靶标或表位特异性结合的抗原结合蛋白。如本文所用，“表位”是指能够被抗原结合蛋白诸如抗体或其片段特异性结合的任何决定簇。在一些实施例中，双特异性抗原结合蛋白包含与一种抗原或靶标特异性结合的第一结构域以及与另一种抗原或靶标特异性结合的第二结构域。在一些实施例中，双特异性抗原结合蛋白的第一结构域与靶细胞表面抗原特异性结合，并且双特异性抗原结合蛋白的第二结合结构域与人CD3(T细胞上的T细胞受体复合物的亚基)特异性结合。在一些优选的实施例中，双特异性抗原结合蛋白是如例如WO 2008119567和WO2017134140中所述的双特异性T细胞衔接
Figure BDA0003609980980000091
抗体构建体。
如本文所用，术语“抗体构建体”是指其中结构和/或功能基于抗体(例如，全长或完整免疫球蛋白分子)的结构和/或功能并且/或者从抗体或其片段的可变重链(VH)和/或可变轻链(VL)结构域中提取的分子。因此，抗体构建体能够与其特异性靶标或抗原结合。抗体构建体还包括修饰的抗体片段，诸如scFv、二scFv或双(s)-scFv、scFv-Fc、scFv-拉链、scFab、Fab2、Fab3、双抗体、单链双抗体、串联双抗体(Tandab)、串联二scFv、串联三scFv、“多抗体”(诸如三抗体或四抗体)和单结构域抗体(诸如仅包含一个可变结构域(它可能是独立于其他V区或结构域特异性结合抗原或表位的VHH、VH或VL)的纳米抗体或单可变结构域抗体)。
在一些实施例中，双特异性抗体构建体包含第一结合结构域和第二结合结构域，其中第一结合结构域与第一细胞表面抗原特异性结合，并且第二结合结构域与人CD3特异性结合。在一些实施例中，双特异性抗体构建体的第一结构域和第二结构域是“双特异性单链抗体构建体”、更优选双特异性“单链Fv”(scFv)。在scFv中，抗体的VL和VH例如通过合成接头连接为其中VL和VH区配对形成单价分子的单条蛋白链；参见例如Huston等人(1988)Proc.Natl.Acad.Sci USA[美国国家科学院院刊]85:5879-5883。接头可以是约10至约25个氨基酸、优选约15至20个氨基酸的短肽。接头通常富含甘氨酸以获得柔韧性，以及丝氨酸或苏氨酸以获得溶解性，并且可以将VH的N-末端与VL的C-末端连接起来，反之亦然。尽管去除了恒定区并引入了接头，但scFv保留了原始免疫球蛋白的特异性。VH和VL区以VH-VL或VL-VH的顺序排列。优选的是，VH区位于接头序列的N末端，并且VL区位于接头序列的C末端。在某些实施例中，双特异性抗体构建体的第一结构域和第二结构域是选自(scFv)2、scFv单结构域mAb、双抗体的形式以及这些形式中任一种的低聚体。
在一些实施例中，双特异性抗体构建体进一步包含第三结构域。在一些实施例中，第三结构域是单链Fc(scFc)结构域。在一些实施例中，scFc结构域是scFc半衰期延长(HLE)结构域。在一些优选的实施例中，双特异性抗体构建体的第三结构域是氨基至羧基顺序如下的HLE结构域：铰链-CH2-CH3-接头-铰链-CH2-CH3。
在一些实施例中，双特异性抗体构建体的第一结合结构域与第一细胞表面抗原结合。在一些实施例中，第一细胞表面抗原是CD70。CD70(也称为CD27L或TNFSF7)是一种II型整合膜蛋白，其正常表达限于活化的T细胞和B细胞、成熟的树突细胞和胸腺髓样上皮细胞的亚群。
在一些实施例中，第一细胞表面抗原是肿瘤抗原。如本文所用的术语“肿瘤抗原”应理解为是指呈递在肿瘤细胞上的那些抗原。这些抗原可以呈递在具有细胞外部分的细胞表面上，该细胞外部分通常与分子的跨膜和细胞质部分结合。这些抗原有时只能由肿瘤细胞呈递，而不能由正常细胞呈递。与正常细胞相比，肿瘤抗原可以只在肿瘤细胞上表达或者可能代表肿瘤特异性突变。在这种情况下，它们被称为肿瘤特异性抗原。更常见的是由肿瘤细胞和正常细胞呈递的抗原，并且它们被称为肿瘤相关抗原。与正常细胞相比，这些肿瘤相关抗原可以过表达，或者由于肿瘤组织的结构与正常组织相比不太紧密，因此是肿瘤细胞中的抗体结合可接近的。在一些实施例中，第一结合结构域与选自以下项的肿瘤抗原结合：CD19、CD33、表皮生长因子受体变体iii(EGFRvIII)、间皮素(MSLN)、钙粘素19(CDH19)、FMS样酪氨酸激酶3(FLT3)、δ样配体3(DLL3)、胎盘钙粘素(CDH3)、B细胞成熟抗原(BCMA)、前列腺特异性膜抗原(PSMA)、人粘蛋白17(MUC17)和闭合蛋白(claudin)-18同种型2(CLDN18.2)。在一些实施例中，肿瘤抗原是人肿瘤抗原。
在一些优选的实施例中，双特异性抗体构建体包含第一结构域、第二结构域和任选的第三结构域，其中第一结构域与CD70结合，并且第二结构域与人CD3结合，并且第三结构域(如果存在)是氨基至羧基顺序如下的HLE结构域：铰链-CH2-CH3-接头-铰链-CH2-CH3。在其他优选的实施例中，双特异性抗体构建体包含第一结构域、第二结构域和任选的第三结构域，其中第一结构域与选自以下项的肿瘤抗原结合：CD19、CD33、EGFRvIII、MSLN、CDH19、FLT3、DLL3、CDH3、BCMA、PSMA、MUC17和C:DN18.2，并且第二结构域与人CD3结合，并且第三结构域(如果存在)是氨基至羧基顺序如下的HLE结构域：铰链-CH2-CH3-接头-铰链-CH2-CH3。在优选的实施例中，第一结构域和第二结构域经由肽接头连接在一起，并经由肽接头连接到第三结构域(如果存在)。优选的肽接头已经在上文描述并且其特征在于具有氨基酸序列Gly-Gly-Gly-Gly-Ser(即Gly4Ser)或其聚合物(即(Gly4Ser)x)，其中x为1或更大的整数(例如，2、3、4、5、6或7)。在一些优选的实施例中，第二结合结构域包含具有SEQ IDNO:201的氨基酸序列的多肽。
在一些实施例中，第一结合结构域与CD33特异性结合。在一些实施例中，第一结合结构域包含具有SEQ ID NO:1-15中任一个的氨基酸序列的多肽。
在一些实施例中，第一结合结构域与EGFRvIII特异性结合。在一些实施例中，第一结合结构域包含具有SEQ ID NO:16-26中任一个的氨基酸序列的多肽。
在一些实施例中，第一结合结构域与MSLN特异性结合。在一些实施例中，第一结合结构域包含具有SEQ ID NO:27-38和165中任一个的氨基酸序列的多肽。
在一些实施例中，第一结合结构域与CDH19特异性结合。在一些实施例中，第一结合结构域包含具有SEQ ID NO:39-56中任一个的氨基酸序列的多肽。
在一些实施例中，第一结合结构域与DLL3特异性结合。在一些实施例中，第一结合结构域包含具有SEQ ID NO:68-78的氨基酸序列的多肽。
在一些实施例中，第一结合结构域与CD19特异性结合。在一些实施例中，第一结合结构域包含具有SEQ ID NO:79-88中任一个的氨基酸序列的多肽。
在一些实施例中，第一结合结构域与FLT3特异性结合。在一些实施例中，第一结合结构域包含具有SEQ ID NO:57-67中任一个的氨基酸序列的多肽。
在一些实施例中，第一结合结构域与CDH3特异性结合。在一些实施例中，第一结合结构域包含具有SEQ ID NO:89-99中任一个的氨基酸序列的多肽。
在一些实施例中，第一结合结构域与BCMA特异性结合。在一些实施例中，第一结合结构域包含具有SEQ ID NO:100-110中任一个的氨基酸序列的多肽。
在一些实施例中，第一结合结构域与PSMA特异性结合。在一些实施例中，第一结合结构域包含具有SEQ ID NO:111-155、166和167中任一个的氨基酸序列的多肽。
在一些实施例中，第一结合结构域与CD70特异性结合。在一些实施例中，第一结合结构域包含具有SEQ ID NO:156-164中任一个的氨基酸序列的多肽。
在一些实施例中，双特异性抗体构建体的第二结合结构域与T细胞表面上的人CD3ε特异性结合。在一些实施例中，双特异性抗体构建体的第二结构域与人CD3ε链的细胞外表位特异性结合。在一些实施例中，与人CD3特异性结合的双特异性抗体构建体的第二结构域包含VL区和VH区，该VL区包含具有SEQ ID NO:193的氨基酸序列的CDR-L1、具有SEQ ID NO:194的氨基酸序列的CDR-L2和具有SEQ ID NO:195的氨基酸序列的CDR-L3，该VH区包含具有SEQ ID NO:196的氨基酸序列的CDR-H1、具有SEQ ID NO:197的氨基酸序列的CDR-H2和具有SEQ ID NO:198的氨基酸序列的CDR-H3。
在一些实施例中，双特异性抗体构建体的第二结构域包含具有SEQ ID NO:199的氨基酸序列的VH和具有SEQ ID NO:200的氨基酸的VL。在一些实施例中，双特异性抗体构建体的第二结构域包含具有SEQ ID NO:201的氨基酸序列的多肽。
在一些实施例中，蛋白是CD70xCD3双特异性抗体构建体，其包含与CD70特异性结合的第一结构域和与CD3特异性结合的第二结构域。在一个实施例中，第一结构域与CD70特异性结合并且包含如SEQ ID NO:156-161所示的CDR，第二结构域与CD3特异性结合并且具有如SEQ ID NO:193-198所示的CDR。在一些实施例中，双特异性抗体构建体进一步包含HLE结构域(第三结构域)。在一个实施例中，双特异性抗体构建体包含VH和VL，其中该VH包含含有SEQ ID NO:162的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽，并且该VL包含含有SEQ ID NO:163的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，CD70xCD3双特异性抗体构建体包含含有SEQID NO:164的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。
在一些实施例中，蛋白是BCMAxCD3双特异性抗体构建体，其包含与BCMA特异性结合的第一结构域和与CD3特异性结合的第二结构域。在一些实施例中，双特异性抗体进一步包含HLE结构域(第三结构域)。在一个实施例中，第一结构域与BCMA特异性结合并且具有如SEQ ID NO:100-105所示的CDR，第二结构域与CD3特异性结合并且具有如SEQ ID NO:193-198所示的CDR。在一个实施例中，BCMAxCD3双特异性抗体构建体包含VH和VL，其中该VH包含含有SEQ ID NO:106的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽，并且该VL包含含有SEQ ID NO:107的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，BCMAxCD3双特异性抗体构建体包含含有SEQ ID NO:108的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，BCMAxCD3双特异性抗体构建体包含含有SEQ ID NO:109的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在另一个实施例中，BCMAxCD3双特异性抗体构建体包含含有SEQ ID NO:110的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。
在一些实施例中，双特异性抗体是CD33xCD3双特异性抗体构建体，其包含与CD33特异性结合的第一结构域和与CD3特异性结合的第二结构域。在一些实施例中，双特异性抗体构建体进一步包含HLE结构域(第三结构域)。在一个实施例中，第一结构域与CD33特异性结合并且具有如SEQ ID NO:3-5和8-10所示的CDR，第二结构域与CD3特异性结合并且具有如SEQ ID NO:193-198所示的CDR。在一个实施例中，CD33xCD3双特异性抗体构建体包含VH和VL，其中该VH包含含有SEQ ID NO:1或2的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽，并且该VL包含含有SEQ ID NO:6或7的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在另一个实施例中，CD33xCD3双特异性抗体构建体包含含有SEQ ID NO:11或12中任一个的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在另一个实施例中，BCMAxCD3双特异性抗体构建体包含含有SEQ ID NO:13或15的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。
在一些实施例中，蛋白是EGFRvIIIxCD3双特异性抗体构建体，其包含与EGFRvIII特异性结合的第一结构域和与CD3特异性结合的第二结构域。在一些实施例中，双特异性抗体进一步包含HLE结构域(第三结构域)。在一个实施例中，第一结构域与EGFRvIII特异性结合并且具有如SEQ ID NO:16-21所示的CDR，第二结构域与CD3特异性结合并且具有如SEQID NO:193-198所示的CDR。在一个实施例中，EGFRvIIIxCD3双特异性抗体构建体包含VH和VL，其中该VH包含含有SEQ ID NO:22的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽，并且该VL包含含有SEQ ID NO:23的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，EGFRvIIIxCD3双特异性抗体构建体包含含有SEQ ID NO:24或25的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，EGFRvIIIxCD3双特异性抗体构建体包含含有SEQ ID NO:24或26的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。
在一些实施例中，蛋白是MSLNxCD3双特异性抗体构建体，其包含与MSLN特异性结合的第一结构域和与CD3特异性结合的第二结构域。在一些实施例中，双特异性抗体构建体进一步包含HLE结构域(第三结构域)。在一个实施例中，第一结构域与MSLN特异性结合并且具有如SEQ ID NO:27-32所示的CDR，第二结构域与CD3特异性结合并且具有如SEQ ID NO:193-198所示的CDR。在一个实施例中，MSLNxCD3双特异性抗体构建体包含VH和VL，其中该VH包含含有SEQ ID NO:33的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽，并且该VL包含含有SEQ ID NO:34的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，MSLNxCD3双特异性抗体构建体包含含有SEQ ID NO:35-38中任一个的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，MSLNxCD3双特异性抗体构建体包含含有SEQ ID NO:165的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。
在一些实施例中，蛋白是CDH19xCD3双特异性抗体构建体，其包含与CDH19特异性结合的第一结构域和与CD3特异性结合的第二结构域。在一些实施例中，双特异性抗体进一步包含HLE结构域(第三结构域)。在一个实施例中，第一结构域与CDH19特异性结合并且具有如SEQ ID NO:39-44所示的CDR，第二结构域与CD3特异性结合并且具有如SEQ ID NO:193-198所示的CDR。在一个实施例中，CDH19xCD3双特异性抗体构建体包含VH和VL，其中该VH包含含有SEQ ID NO:45或51的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽，并且该VL包含含有SEQ ID NO:46或52的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，CDH19xCD3双特异性抗体构建体包含含有SEQ ID NO:47、48-50和53-56中任一个的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，CDH19xCD3双特异性抗体构建体包含含有SEQ ID NO:48的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。
在一些实施例中，蛋白是DLL3xCD3双特异性抗体，其包含与DLL3特异性结合的第一结构域和与CD3特异性结合的第二结构域。在一些实施例中，双特异性抗体进一步包含HLE结构域(第三结构域)。在一个实施例中，第一结构域与DLL3特异性结合并且具有如SEQID NO:68-73所示的CDR，第二结构域与CD3特异性结合并且具有如SEQ ID NO:193-198所示的CDR。在一个实施例中，DLL3xCD3双特异性抗体构建体包含VH和VL，其中该VH包含含有SEQID NO:74的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽，并且该VL包含含有SEQ ID NO:75的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，DLL3xCD3双特异性抗体构建体包含含有SEQ ID NO:76-78的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，DLL3xCD3双特异性抗体构建体包含含有SEQ ID NO:78的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。
在一些实施例中，蛋白是FLT3xCD3双特异性抗体构建体，其包含与FLT3特异性结合的第一结构域和与CD3特异性结合的第二结构域。在一些实施例中，双特异性抗体进一步包含HLE结构域(第三结构域)。在一个实施例中，第一结构域与FLT3特异性结合并且具有如SEQ ID NO:57-62所示的CDR，第二结构域与CD3特异性结合并且具有如SEQ ID NO:193-198所示的CDR。在一个实施例中，FLT3xCD3双特异性抗体构建体包含VH和VL，其中该VH包含含有SEQ ID NO:63的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽，并且该VL包含含有SEQ ID NO:64的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，FTL3xCD3双特异性抗体构建体包含含有SEQID NO:65-67中任一个的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，FTL3xCD3双特异性抗体构建体包含含有SEQ ID NO:67的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。
在一些实施例中，蛋白是CDH3xCD3双特异性抗体构建体，其包含与CDH3特异性结合的第一结构域和与CD3特异性结合的第二结构域。在一些实施例中，双特异性抗体构建体进一步包含HLE结构域(第三结构域)。在一个实施例中，第一结构域与CDH3特异性结合并且具有如SEQ ID NO:89-94所示的CDR，第二结构域与CD3特异性结合并且具有如SEQ ID NO:193-198所示的CDR。在一个实施例中，CDH3xCD3双特异性抗体构建体包含VH和VL，其中该VH包含含有SEQ ID NO:95的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽，并且该VL包含含有SEQ ID NO:96的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，CDH3xCD3双特异性抗体构建体包含含有SEQ ID NO:97-99中任一个的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，CDH3xCD3双特异性抗体构建体包含含有SEQ ID NO:99的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。
在一些实施例中，蛋白是PSMAxCD3双特异性抗体构建体，其包含与PSMA特异性结合的第一结构域和与CD3特异性结合的第二结构域。在一些实施例中，双特异性抗体构建体进一步包含HLE结构域(第三结构域)。在一个实施例中，第一结构域与PSMA特异性结合并且具有如SEQ ID NO:111-116中任一个所示的CDR，第二结构域与CD3特异性结合并且具有如SEQ ID NO:193-198所示的CDR。在一个实施例中，第一结构域与PSMA结合并且具有如SEQID NO:126-131和141-146中任一个所示的CDR，第二结构域与CD3结合并且具有SEQ ID NO:193-198所示的CDR。在一个实施例中，PSMAxCD3双特异性抗体包含VH和VL，其中该VH包含含有SEQ ID NO:117、132或147的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽，并且该VL包含含有SEQ ID NO:118、133或148的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，PSMAxCD3双特异性抗体构建体包含含有SEQ ID NO:119-125、134-140和149-155中任一个的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，PSMAxCD3双特异性抗体构建体包含含有SEQ ID NO:121、122、124、125、136、137、139、140、151、152、154和155中任一个的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，PSMAxCD3双特异性抗体构建体包含含有SEQ ID NO:166或167的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。
在一些实施例中，蛋白是Cldn18.2xCD3双特异性抗体构建体，其包含与Cldn18.2特异性结合的第一结构域和与CD3特异性结合的第二结构域。在一些实施例中，双特异性抗体进一步包含HLE结构域(第三结构域)。在一个实施例中，第一结构域与Cldn18.2特异性结合并且具有如SEQ ID NO:168-173所示的CDR，第二结构域与CD3特异性结合并且具有如SEQID NO:193-198所示的CDR。在一个实施例中，Cldn18.2xCD3双特异性抗体构建体包含VH和VL，其中该VH包含含有SEQ ID NO:174的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽，并且该VL包含含有SEQ ID NO:175的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，Cldn18.2xCD3双特异性抗体构建体包含含有SEQ ID NO:176或178的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，Cldn18.2xCD3双特异性抗体构建体包含含有SEQ ID NO:178的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。
在一些实施例中，蛋白是MUC17xCD3双特异性抗体构建体，其包含与MUC17特异性结合的第一结构域和与CD3特异性结合的第二结构域。在一些实施例中，双特异性抗体进一步包含HLE结构域(第三结构域)。在一个实施例中，第一结构域与MUC17特异性结合并且具有如SEQ ID NO:184-189所示的CDR，第二结构域与CD3特异性结合并且具有如SEQ ID NO:193-198所示的CDR。在一个实施例中，MUC17xCD3双特异性抗体构建体包含VH和VL，其中该VH包含含有SEQ ID NO:190的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽，并且该VL包含含有SEQ ID NO:191的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。在一个实施例中，MUC17xCD3双特异性抗体构建体包含含有SEQ ID NO:192的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。
在某些实施例中，双特异性抗体构建体包含含有SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:25、SEQ ID NO:48、SEQ ID NO:67、SEQ ID NO:78、SEQ ID NO:88、SEQ ID NO:109、SEQ ID NO:110、SEQ ID NO:165、SEQ ID NO:166、SEQ ID NO:167、SEQ ID NO:178或SEQ ID NO:192的氨基酸序列或者基本上由该氨基酸序列组成或由该氨基酸序列组成的多肽。
本文披露的双特异性抗体可以通过本领域已知的方法制备。例如，双特异性抗体可以通过WO 2008/119657和WO 2017/134140中披露的方法制备。
可用于组合物中的附加赋形剂
在一些实施例中，组合物进一步包含一种或多种适用于药物组合物的赋形剂。在一些实施例中，组合物进一步包含盐、缓冲剂、糖类或糖类衍生物、氨基酸或防腐剂或者两种或更多种前述物质的组合。在一些实施例中，组合物进一步包含盐、糖类或糖类衍生物、氨基酸和任选的防腐剂。在一些实施例中，组合物进一步包含盐、缓冲剂、糖类或糖类衍生物和氨基酸。在一些实施例中，组合物进一步包含盐、缓冲剂、糖类或糖类衍生物、氨基酸和防腐剂。
可用于组合物中的示例性盐包括适合用于药物组合物中的盐(例如，NaCl)。可用于组合物中的示例性缓冲剂包括乙酸盐缓冲剂、谷氨酸盐缓冲剂、柠檬酸盐缓冲剂、琥珀酸盐缓冲剂、酒石酸盐缓冲剂、富马酸盐缓冲剂、马来酸盐缓冲剂、组氨酸缓冲剂和磷酸盐缓冲剂。示例性糖类或糖类衍生物包括单糖、二糖、环状多糖和糖醇，诸如糖(例如，蔗糖和海藻糖)和糖醇(例如，甘露糖醇或山梨糖醇)。示例性氨基酸包括赖氨酸、组氨酸、精氨酸、甘氨酸、甲硫氨酸和丙氨酸。示例性防腐剂包括苯甲酸盐(例如，苯甲醇和苯甲酸钠)和山梨酸盐(例如，山梨酸钾)。
组合物的pH可以在约3.5至7.5的范围内。在一些实施例中，组合物具有约4.0至约7.0的pH。在一些实施例中，组合物具有约4.2至约7.0、或约5.0至约7.0、或约5.5至约7.0、或约6.0至约7.0、或约6.5至约7.0、或约4.2至约6.5、或约4.2至约6.0、或约4.2至约5.5、或约4.2至约5.0、或约5.0至约6.0、或约5.0至约6.5、或约5.0至约6.0、或约5.0至约5.5、或约5.5至约6.0、或约5.5至约6.5、或约5.5至约6.0、或约6.0至约6.5的pH。在一些实施例中，组合物的pH为约3.5、约4.0、约4.5、约5.0、约5.5、约6.0、约6.5、约7.0或约7.5。
组合物的pH可通过使用上文列出的一种或多种缓冲剂来实现。在一些实施例中，组合物包含选自乙酸盐缓冲剂、谷氨酸盐缓冲剂、柠檬酸盐缓冲剂、琥珀酸盐缓冲剂、酒石酸盐缓冲剂、富马酸盐缓冲剂、马来酸盐缓冲剂、组氨酸缓冲剂和磷酸盐缓冲剂的缓冲剂。在一些实施例中，组合物包含选自上述缓冲剂列表的两种缓冲剂(例如，谷氨酸盐缓冲剂和柠檬酸盐缓冲剂)的组合。
在一些实施例中，组合物基本上不包含附加缓冲剂。如本文所用，短语“基本上不包含附加缓冲剂”是指组合物中不含为了调节和/或维持组合物的pH而添加的缓冲剂。例如，盐水溶液(0.9％NaCl溶液)不含附加缓冲剂并且具有约5.5的pH。据信盐水溶液的pH部分地通过溶解在水中的大气CO2来实现和维持。参见例如Reddi,B.AJ Int.J.Med.Sci[国际医学科学杂志].10:747-750(2013)。这种组合物可含有对组合物的缓冲能力没有贡献的残余缓冲剂。
在一些实施例中，组合物包含上文披露的任何浓度的蛋白、上文披露的任何浓度的表面活性剂，并且进一步包含盐(例如，NaCl)、糖(例如，蔗糖)、氨基酸(例如，赖氨酸)和任选的防腐剂(例如，苯甲醇)。在一些实施例中，组合物包含上文披露的任何浓度的蛋白、上文披露的任何浓度的表面活性剂，并且进一步包含盐(例如，NaCl)、糖(例如，蔗糖)、氨基酸(例如，赖氨酸)、缓冲剂(例如，谷氨酸盐和/或柠檬酸盐缓冲剂)和任选的防腐剂(例如，苯甲醇)。组合物的pH可以是上文披露的任何pH值。在一些实施例中，组合物的pH为约5.5。
在一些实施例中，本文披露的组合物是药物组合物。如本文所用，术语“药物组合物”应理解为是指包含适合注射和/或施用到有需要的患者(例如，人)体内的蛋白(例如，双特异性抗体构建体)的配制品。更具体地，药物组合物是基本上无菌的并且不含对接受者具有过度毒性或感染性的任何药剂。
用于组合物的容器
在一些实施例中，本文披露的组合物容纳在容器中。可用于本文的容器包括适用于药物用途的那些，例如由无毒且保持物理完整性的材料制成的容器。在一些实施例中，容器是用于静脉内(IV)施用的部件。如本文所用，短语“用于IV施用的部件”应理解为是指在IV施用期间可接触组合物的容器或系统的一部分。在一些实施例中，容器是IV袋或IV管。
可用于制造容器的材料包括通常用于制造药物容器的那些，诸如玻璃和塑料。
在一些实施例中，容器是塑料容器。在一些实施例中，容器由包含聚烯烃(例如，聚丙烯(PP)和聚乙烯(PE))、聚氯乙烯(PVC)、乙酸乙烯乙酯(EVA)或聚氨酯(例如，聚酯和聚醚)的材料制成。在一些实施例中，容器由包含PVC的材料制成。在一些实施例中，PVC基本上不含邻苯二甲酸二-2-乙基己酯(DEHP)或偏苯三酸三-2-乙基己酯(TOTM)。如本文所用，术语“基本上不含”应理解为是指其中未使用和/或未检测到DEHP或TOTM的PVC。DEHP和TOTM是可用于使PVC更软因此可以制成不同的形状的增塑剂。在一些实施例中，容器由不包含PVC的材料制成。
在一些实施例中，容器由包含聚烯烃、EVA或聚氨酯(例如，聚酯和聚醚)的材料制成。在一些实施例中，容器由包含PP和/或PE的材料制成。
在某些条件下，某些类型的PVC塑料中含有的DEHP或TOTM可以在某些浓度的某些表面活性剂(例如，聚山梨醇酯，参见实例3)存在下从塑料中浸出。不希望受任何特定理论的束缚，据信表面活性剂的亲脂性越高，DEHP或TOTM在表面活性剂存在下就可以更容易地浸出。表面活性剂的亲水-亲脂平衡(HLB)是其亲水或亲脂程度的量度，并且可以通过本领域已知的方法来计算。参见例如Griffin,William C.Calculation of HLB Values ofNon-Ionic Surfactants[非离子表面活性剂的HLB值的计算],Journal of the Societyof Cosmetic Chemists[化妆品化学家协会志],5(4):249-56(1954)。HLB值可以用于预测表面活性剂的性质，例如，HLB>10表示表面活性剂更易溶于水(不溶于脂质)，而HLB<10表示表面活性剂更易溶于脂质(不溶于水)。可以用于本文披露的组合物中的示例性表面活性剂的HLB值包括17(聚山梨醇酯20)、15(聚山梨醇酯80)(https://pharmlabs.unc.edu/labs/ emulsions/hlb.htm)和29(泊洛沙姆188)(http://www.rumapel.com.ar/cosmetica_ miscelaneos/ficha_tecnica/Pluracare％20L-％20F％20Grades.pdf)。在容器由包含DEHP或TOTM的PVC塑料制成的实施例中，组合物中的表面活性剂优选地具有至少20的HLB值(例如，泊洛沙姆，参见实例3)、更优选介于20与30之间的HLB值。
由上文列出的材料制成的容器诸如IV部件(例如，用于IV施用的IV袋和管)可商购获得。例如，各种合适的容器可从诸如百特医疗用品公司(Baxter HealthcareCorporation)和布劳恩医疗公司(B.Braun Medical Inc.)的制造商获得。
药物制剂
本文还披露了包含上文披露的水性组合物的药物制剂。如本文所用，术语“药物制剂”应理解为是指在向患者(例如，人)施用之前在合适的药物容器中包含本文披露的水性组合物的制剂。在一些实施例中，本文披露了一种在容器中包含水性药物组合物的药物制剂，其中水性药物组合物包含：a)浓度介于约0.001μg/ml与约100μg/ml之间的蛋白，以及b)浓度为表面活性剂的CMC的至少约0.25倍的表面活性剂，并且其中蛋白不是博纳吐单抗(blinatumomab)。
在一些实施例中，包含在组合物中的表面活性剂是聚山梨醇酯。在一些实施例中，表面活性剂是选自聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯65、聚山梨醇酯80和聚山梨醇酯85的聚山梨醇酯。在一些实施例中，表面活性剂是聚山梨醇酯20或聚山梨醇酯80。在一些实施例中，表面活性剂是泊洛沙姆。在一些实施例中，表面活性剂是泊洛沙姆188或泊洛沙姆407。在一些实施例中，表面活性剂是曲拉通X-100。
在一些实施例中，本文披露了一种在容器中包含水性药物组合物的药物制剂，其中水性药物组合物包含：a)浓度介于约0.001μg/ml与约100μg/ml之间的双特异性抗体构建体，以及b)浓度为表面活性剂的CMC的至少约0.25倍的表面活性剂，其中表面活性剂是泊洛沙姆。在一些实施例中，泊洛沙姆是泊洛沙姆188或泊洛沙姆407。
在一些实施例中，表面活性剂以介于表面活性剂的CMC的约0.25倍与约20倍之间的浓度存在于组合物中。在一些实施例中，表面活性剂以介于表面活性剂的CMC的约0.25倍与约10倍之间的浓度存在于组合物中。在一些实施例中，表面活性剂以在上文披露的任何浓度范围内的浓度存在于组合物中。在一些实施例中，表面活性剂以作为上文披露的任何浓度的浓度存在于组合物中。表面活性剂的CMC值可以通过上文披露的方法测定。在一些实施例中，某些常用表面活性剂的CMC值在表1中列出。
在一些实施例中，水性药物组合物包含浓度介于约0.001μg/ml与约50μg/ml之间的蛋白。在一些实施例中，组合物包含浓度在上文披露的任何范围内的蛋白(例如，双特异性抗体构建体)。在一些实施例中，蛋白(例如，双特异性抗体构建体)以上文披露的任何浓度存在于组合物中。可以将上文披露的蛋白的任何浓度或浓度范围与上文披露的表面活性剂的任何浓度或浓度范围组合。
如上所披露，蛋白可以是治疗性蛋白，诸如抗原结合蛋白和融合蛋白。在一些实施例中，蛋白是双特异性抗原结合蛋白。在一些实施例中，蛋白是上文披露的双特异性抗体构建体。在一些实施例中，蛋白是CD70xCD3双特异性抗体构建体。在一些实施例中，蛋白是BCMAxCD3双特异性抗体构建体。在一些实施例中，蛋白是CD33xCD3双特异性抗体构建体。在一些实施例中，蛋白是EGFRvIIIxCD3双特异性抗体构建体。在一些实施例中，蛋白是MSLNxCD3双特异性抗体构建体。在一些实施例中，蛋白是CDH19xCD3双特异性抗体构建体。在一些实施例中，蛋白是DLL3xCD3双特异性抗体构建体。在一些实施例中，蛋白是FLT3xCD3双特异性抗体构建体。在一些实施例中，蛋白是CDH3xCD3双特异性抗体构建体。在一些实施例中，蛋白是PSMAxCD3双特异性抗体构建体。在一些实施例中，蛋白是Cldn18.2xCD3双特异性抗体构建体。在一些实施例中，蛋白是MUC17xCD3双特异性抗体构建体。这些双特异性抗体构建体中的每一种在上文披露。在某些实施例中，蛋白包含SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:25、SEQ ID NO:48、SEQ ID NO:67、SEQ ID NO:78、SEQ ID NO:88、SEQ IDNO:109、SEQ ID NO:110、SEQ ID NO:165、SEQ ID NO:166、SEQ ID NO:167、SEQ ID NO:178或SEQ ID NO:192的氨基酸序列，基本上由这些氨基酸序列组成或由这些氨基酸序列组成。
组合物的pH可以在上文披露的任何pH范围内。在一些实施例中，组合物的pH可以是上文披露的任何pH。
在一些实施例中，水性药物组合物进一步包含一种或多种适用于药物组合物的赋形剂。在一些实施例中，水性药物组合物进一步包含盐、缓冲剂、氨基酸、糖类或糖类衍生物、防腐剂或它们的组合。在一些实施例中，水性药物组合物进一步包含盐、氨基酸、糖类或糖类衍生物、防腐剂或它们的组合。可用于组合物中的示例性盐、缓冲剂、氨基酸、糖类或其衍生物和防腐剂在上文披露。
在一些实施例中，容器是塑料容器。在一些实施例中，容器由包含聚烯烃(例如，PP和PE)、PVC、EVA或聚氨酯(例如，聚酯和聚醚)的材料制成。在一些实施例中，容器由包含PVC的材料制成。在一些实施例中，PVC基本上不含DEHP或TOTM。在一些实施例中，容器由不包含PVC的材料制成。
在一些实施例中，包含在组合物中的表面活性剂是泊洛沙姆，并且容器可以由包含聚烯烃、PVC、EVA或聚氨酯(例如，聚酯和聚醚)的材料制成。在一些实施例中，包含在组合物中的表面活性剂是聚山梨醇酯或曲拉通X-100，并且容器可以由包含聚烯烃、基本上不含DEHP或TOTM的PVC、EVA或聚氨酯(例如，聚酯和聚醚)的材料制成。
在一些实施例中，容器是用于静脉内(IV)施用的部件。在一些实施例中，容器是IV袋或IV管。
在一些实施例中，药物制剂包含容器中的水性药物组合物，其中水性药物组合物包含双特异性抗体构建体(例如，本文披露的任何双特异性抗体构建体)、表面活性剂(例如，本文披露的任何表面活性剂)，并且进一步包含盐(例如，NaCl)、氨基酸(例如，赖氨酸)、糖类或糖类衍生物(例如，蔗糖或甘露醇)、任选的防腐剂(例如，苯甲醇)，并且其中容器由包含聚烯烃、PVC、EVA或聚氨酯(例如，聚酯和聚醚)的材料制成。在一些实施例中，药物制剂包含容器中的水性药物组合物，其中水性药物组合物包含双特异性抗体构建体(例如，本文披露的任何双特异性抗体构建体)、表面活性剂(例如，本文披露的任何表面活性剂)，并且进一步包含盐(例如，NaCl)、缓冲剂(例如，谷氨酸盐缓冲剂和/或柠檬酸盐缓冲剂)、氨基酸(例如，赖氨酸)、糖类或糖类衍生物(例如，蔗糖或甘露醇)、任选的防腐剂(例如，苯甲醇)，并且其中容器由包含聚烯烃、PVC、EVA或聚氨酯(例如，聚酯和聚醚)的材料制成。双特异性抗体构建体的浓度可以是上文针对蛋白披露的任何浓度。表面活性剂的浓度可以是上文披露的任何浓度。组合物的pH在介于约3.5与约7.0之间的范围内。在一些实施例中，组合物的pH为约5.5。在一些实施例中，容器是IV袋。
施用组合物的方法
本文还披露了向患者施用本文披露的组合物的方法。在一些实施例中，本文披露了一种向患者施用蛋白的方法，该方法包括a)在容器中制备水性药物组合物，其中该水性药物组合物包含浓度介于约0.001μg/ml与约100μg/ml之间的蛋白(例如，本文披露的双特异性抗体构建体)以及浓度为表面活性剂的CMC的至少约0.25倍的表面活性剂，以及b)向患者施用该水性药物组合物，其中蛋白不是博纳吐单抗。
在一些实施例中，水性药物组合物通过用合适的水性溶液稀释包含蛋白(例如，双特异性抗体构建体)的第一组合物来制备。在一些实施例中，水性药物组合物通过将合适的溶液添加到容器中，然后将适当量的第一组合物添加到容器中，从而稀释包含蛋白的第一组合物来制备。
在一些实施例中，第一组合物是包含蛋白的液体组合物。在一些实施例中，第一组合物是由包含蛋白的冻干组合物重构的液体组合物。在一些实施例中，第一组合物是使用无菌水由包含蛋白的冻干组合物重构的液体组合物。
在一些实施例中，用于稀释第一组合物的合适水性溶液包含浓度为表面活性剂的CMC的至少约0.25倍的表面活性剂。在一些实施例中，用于稀释第一组合物的合适水性溶液包含浓度介于表面活性剂的CMC的约0.25倍与20倍之间、或介于约0.25倍与约10倍之间的表面活性剂。在一些实施例中，用于稀释第一组合物的合适水性溶液包含浓度为表面活性剂的CMC的0.25倍、约0.5倍、约1倍、约2倍、约3倍、约4倍、约5倍、约6倍、约7倍、约8倍、约9倍、约10倍、约15倍或约20倍的表面活性剂。在一些实施例中，用于稀释第一组合物的合适水性溶液进一步包含NaCl。在一些实施例中，用于稀释第一组合物的合适水性溶液具有介于约3.5与约7.0之间、或介于约4.0与约6.5之间的pH。在一些实施例中，用于稀释第一组合物的合适水性溶液具有约5.5的pH。在一些实施例中，该方法进一步包括在制备步骤之前用用于稀释第一组合物的合适水性溶液冲洗容器。
在一些实施例中，水性药物组合物中的表面活性剂是聚山梨醇酯。在一些实施例中，表面活性剂是选自聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯65、聚山梨醇酯80和聚山梨醇酯85的聚山梨醇酯。在一些实施例中，表面活性剂是聚山梨醇酯20或聚山梨醇酯80。在一些实施例中，表面活性剂是泊洛沙姆。在一些实施例中，表面活性剂是泊洛沙姆188或泊洛沙姆407。在一些实施例中，表面活性剂是曲拉通X-100。
在一些实施例中，水性药物组合物中的表面活性剂以介于表面活性剂的CMC的约0.25倍与约20倍之间的浓度存在于组合物中。在一些实施例中，表面活性剂以介于表面活性剂的CMC的约0.25倍与约10倍之间的浓度存在于水性药物组合物中。在一些实施例中，表面活性剂以在上文披露的任何浓度范围内的浓度存在于水性药物组合物中。在一些实施例中，表面活性剂以作为上文披露的任何浓度的浓度存在于水性药物组合物中。表面活性剂的CMC值可以通过上文披露的方法测定。在一些实施例中，某些常用表面活性剂的CMC值在表1中列出。
在一些实施例中，水性药物组合物包含浓度介于约0.001μg/ml与约50μg/ml之间的蛋白。在一些实施例中，水性药物组合物包含浓度在上文披露的任何范围内的蛋白。在一些实施例中，蛋白以上文披露的任何浓度存在于组合物中。
如上所披露，蛋白可以是治疗性蛋白，诸如抗原结合蛋白、mAb或融合蛋白。在一些实施例中，蛋白是双特异性抗原结合蛋白。在一些实施例中，蛋白是上文披露的双特异性抗体构建体。在一些实施例中，蛋白是CD70xCD3双特异性抗体构建体。在一些实施例中，蛋白是BCMAxCD3双特异性抗体构建体。在一些实施例中，蛋白是CD33xCD3双特异性抗体构建体。在一些实施例中，蛋白是EGFRvIIIxCD3双特异性抗体构建体。在一些实施例中，蛋白是MSLNxCD3双特异性抗体构建体。在一些实施例中，蛋白是CDH19xCD3双特异性抗体构建体。在一些实施例中，蛋白是DLL3xCD3双特异性抗体构建体。在一些实施例中，蛋白是FLT3xCD3双特异性抗体构建体。在一些实施例中，蛋白是CDH3xCD3双特异性抗体构建体。在一些实施例中，蛋白是PSMAxCD3双特异性抗体构建体。在一些实施例中，蛋白是Cldn18.2xCD3双特异性抗体构建体。在一些实施例中，蛋白是MUC17xCD3双特异性抗体构建体。这些双特异性抗体构建体中的每一种在上文披露。在某些实施例中，蛋白包含SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:25、SEQ ID NO:48、SEQ ID NO:67、SEQ ID NO:78、SEQ ID NO:88、SEQ IDNO:109、SEQ ID NO:110、SEQ ID NO:165、SEQ ID NO:166、SEQ ID NO:167、SEQ ID NO:178或SEQ ID NO:192的氨基酸序列，基本上由这些氨基酸序列组成或由这些氨基酸序列组成。
组合物的pH可以在上文披露的任何pH范围内。在一些实施例中，组合物的pH可以是上文披露的任何pH。
在一些实施例中，水性药物组合物进一步包含一种或多种适用于药物组合物的赋形剂。在一些实施例中，水性药物组合物进一步包含盐、缓冲剂、氨基酸、糖类或糖类衍生物、任选的防腐剂或者两种或更多种前述物质的组合。在一些实施例中，水性药物组合物进一步包含盐、氨基酸、糖类或糖类衍生物、任选的防腐剂或者两种或更多种前述物质的组合。可用于组合物中的示例性盐、缓冲剂、氨基酸、糖类或其衍生物和防腐剂在上文披露。
在一些实施例中，容器是塑料容器或部件。在一些实施例中，容器由包含聚烯烃(例如，PP和PE)、PVC、EVA或聚氨酯(例如，聚酯和聚醚)的材料制成。在一些实施例中，容器由包含PVC的材料制成。在一些实施例中，PVC基本上不含DEHP或TOTM。在一些实施例中，容器由不包含PVC的材料制成。在一些实施例中，容器是IV袋或IV管。
在一些实施例中，水性药物组合物经由IV施用向患者施用。在一些实施例中，患者是癌症患者。在一些实施例中，患者是人。
使蛋白与固体表面结合的方法
本文还披露开了一种使蛋白与固体表面结合的方法。在一些实施例中，本文披露了使蛋白与固体表面结合的方法，该方法包括：a)将包含蛋白的水性溶液与固体表面一起孵育，其中将蛋白用荧光团标记，b)从固体表面除去水性溶液并冲洗表面，以及c)使用共聚焦显微镜对固体表面进行成像。
下表2列出了本文披露的序列。
Figure BDA0003609980980000271
Figure BDA0003609980980000281
Figure BDA0003609980980000291
Figure BDA0003609980980000301
Figure BDA0003609980980000311
Figure BDA0003609980980000321
Figure BDA0003609980980000331
Figure BDA0003609980980000341
Figure BDA0003609980980000351
Figure BDA0003609980980000361
Figure BDA0003609980980000371
Figure BDA0003609980980000381
Figure BDA0003609980980000391
Figure BDA0003609980980000401
Figure BDA0003609980980000411
Figure BDA0003609980980000421
Figure BDA0003609980980000431
Figure BDA0003609980980000441
Figure BDA0003609980980000451
Figure BDA0003609980980000461
Figure BDA0003609980980000471
Figure BDA0003609980980000481
Figure BDA0003609980980000491
Figure BDA0003609980980000501
Figure BDA0003609980980000511
Figure BDA0003609980980000521
Figure BDA0003609980980000531
Figure BDA0003609980980000541
Figure BDA0003609980980000551
Figure BDA0003609980980000561
Figure BDA0003609980980000571
Figure BDA0003609980980000581
Figure BDA0003609980980000591
Figure BDA0003609980980000601
Figure BDA0003609980980000611
Figure BDA0003609980980000621
Figure BDA0003609980980000631
Figure BDA0003609980980000641
Figure BDA0003609980980000651
Figure BDA0003609980980000661
Figure BDA0003609980980000671
Figure BDA0003609980980000681
Figure BDA0003609980980000691
Figure BDA0003609980980000701
Figure BDA0003609980980000711
Figure BDA0003609980980000721
Figure BDA0003609980980000731
Figure BDA0003609980980000741
Figure BDA0003609980980000751
Figure BDA0003609980980000761
Figure BDA0003609980980000771
Figure BDA0003609980980000781
通过参考以下实例将更充分地理解本发明。然而，这些实例不应被解释为限制本发明的范围。
实例
实例1.测量蛋白与固体表面结合的方法
双特异性抗体构建体是内部来源的。将它们用荧光团标记并在标记程序后纯化。
每个测量室包含塑料盖片。为了测量蛋白与固体表面的结合，首先将底部具有塑料盖片的测量室与含有荧光团-蛋白(例如，荧光团标记的抗体构建体)的溶液一起孵育。然后吸出样品溶液，冲洗盖片并用缓冲剂填充，以稍后在共聚焦显微镜上成像。通过共聚焦显微镜测量的荧光强度显示双特异性抗体构建体与盖片结合。图1示出了实验装置的图。
图2示出了在不存在表面活性剂的情况下分别与固体表面(例如，盖片)结合的两种荧光团标记的抗体构建体的滴定。通过对表面进行共聚焦xy扫描来测量结合的荧光团标记的抗体构建体的荧光强度。
实例2.用表面活性剂处理固体表面防止蛋白与表面结合
几种表面活性剂以其各自CMC的不同倍数使用，以确定每种表面活性剂防止双特异性抗体构建体与固体表面结合的有效性。在该研究中，首先将含有表面活性剂的溶液与表面一起孵育，然后添加荧光团标记的抗体构建体并孵育。之后，吸出溶液，冲洗表面并用缓冲剂填充，以在共聚焦显微镜上成像。结果在图3中示出。在该图中，第一组条是没有任何表面活性剂的情况下与表面结合的双特异性抗体。这些用作基准，并将所有以下数据组与这些数据进行比较。从第2组到最后一组是与用不同CMC的不同倍数的不同表面活性剂预处理的表面结合的蛋白的相对百分比。插入部分是该图的下部区域的放大。研究了PS 80、PS20、P188、P407和曲拉通X-100。
测试了向表面添加表面活性剂和抗体的顺序。对于双特异性抗体1和2，测试了两种顺序：在第一种顺序中，在将抗体添加到表面之前，将含表面活性剂的溶液添加到表面；而另一种顺序反过来。结果在图4中示出(左边是抗体1，右边是抗体2)。对于这两个图，第一组条是没有任何表面活性剂的情况下与表面结合的双特异性抗体。这些用作基准，并将所有以下数据组与这些数据进行比较。从第2组到最后一组是与用其CMC的不同倍数的PS 80预处理的表面结合的抗体的相对百分比。表面活性剂有效地防止蛋白与表面结合。
实例3.某些表面活性剂与塑料IV部件中使用的增塑剂的不相容性
将用盐水稀释剂预填充的Baxter Viaflex PVC-DEHP IV袋用于本研究。在研究中使用表面活性剂聚山梨醇酯80(PS80)、聚山梨醇酯20(PS20)、泊洛沙姆188(P188)、泊洛沙姆407(P407)和曲拉通X-100。将不同量的不同表面活性剂与袋在25℃下孵育24小时或48小时。然后对袋进行取样，并通过反相超高压液相色谱(RP-UHPLC)分析，并通过UV检测器检测。流动相A和B是0.1％三氟乙酸(TFA)的DI水溶液和0.1％TFA的乙腈溶液。梯度在下表3中列出。流速为0.6ml/min。为了定量，在相同条件下建立DEHP的标准曲线。
表3.RP-UPLC梯度
Figure BDA0003609980980000791
比较25℃下、24小时和48小时、PVC-DEHP IV袋中0.3重量％的盐水溶液中的PS80、PS 20和P188。结果在图5中示出。PS80和PS20导致DEHP从PVC-DEHP IV袋中大量浸出，而P188没有引起任何浸出(图5)。使用仅盐水，作为对照。
通过在25℃下在PVC-DEHP IV袋中的盐水中孵育24小时，比较各自CMC的不同倍数的PS 80、PS 20、P188、P407和曲拉通X-100。将浸出的DEHP的量在图6中根据CMC的倍数绘图。显然，聚山梨醇酯提取了一定量的DEHP，而泊洛沙姆则没有。浸出的DEHP量与所使用的表面活性剂的量相关。
序列表
<110> 安进公司
<120> 用于在低蛋白浓度下使蛋白损失最小化的组合物和方法
<130> A-2429-WO-PCT
<150> 62/926,089
<151> 2019-10-25
<160> 201
<170> PatentIn 3.5版
<210> 1
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> CD33 ccVH E11
<400> 1
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 2
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> CD33 VH E11
<400> 2
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 3
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> CD33 HCDR1 E11
<400> 3
Asn Tyr Gly Met Asn
1 5
<210> 4
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD33 HCDR2 E11
<400> 4
Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe Gln
1 5 10 15
Gly
<210> 5
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CD33 HCDR3 E11
<400> 5
Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr
1 5 10
<210> 6
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> CD33 CC VL E11
<400> 6
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Thr Val Ser Leu Gly
1 5 10 15
Glu Arg Thr Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asp Ser
20 25 30
Ser Thr Asn Lys Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Leu Ser Trp Ala Ser Thr Arg Glu Ser Gly Ile
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Asp Ser Pro Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Ser Ala His Phe Pro Ile Thr Phe Gly Cys Gly Thr Arg Leu Glu Ile
100 105 110
Lys
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<211> 113
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<400> 7
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Thr Val Ser Leu Gly
1 5 10 15
Glu Arg Thr Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asp Ser
20 25 30
Ser Thr Asn Lys Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Leu Ser Trp Ala Ser Thr Arg Glu Ser Gly Ile
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Asp Ser Pro Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Ser Ala His Phe Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile
100 105 110
Lys
<210> 8
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD33 LCDR1 E11
<400> 8
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
1 5 10 15
Ala
<210> 9
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CD33 LCDR2 E11
<400> 9
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 10
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CD33 LCDR3 E11
<400> 10
Gln Gln Ser Ala His Phe Pro Ile Thr
1 5
<210> 11
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> CD33 HL CC E11
<400> 11
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys
145 150 155 160
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser
180 185 190
Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu
210 215 220
Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr
225 230 235 240
Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys
245 250
<210> 12
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> CD33 HL E11
<400> 12
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys
145 150 155 160
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser
180 185 190
Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu
210 215 220
Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr
225 230 235 240
Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
245 250
<210> 13
<211> 505
<212> PRT
<213> 人工序列
<220>
<223> CD33 CC E11 HL x I2C HL双特异性分子
<400> 13
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys
145 150 155 160
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser
180 185 190
Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu
210 215 220
Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr
225 230 235 240
Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser
245 250 255
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
260 265 270
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
275 280 285
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
290 295 300
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
305 310 315 320
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
325 330 335
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
355 360 365
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
385 390 395 400
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
405 410 415
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
420 425 430
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
435 440 445
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
450 455 460
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
465 470 475 480
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
485 490 495
Gly Gly Gly Thr Lys Leu Thr Val Leu
500 505
<210> 14
<211> 530
<212> PRT
<213> 人工序列
<220>
<223> CD33 E11 HL x I2C HL
<400> 14
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala
65 70 75 80
Asp Lys Phe Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe
115 120 125
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met
145 150 155 160
Thr Gln Ser Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr
165 170 175
Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys
180 185 190
Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu
195 200 205
Leu Leu Ser Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe
210 215 220
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro
225 230 235 240
Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe
245 250 255
Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly
260 265 270
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
275 280 285
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
290 295 300
Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
305 310 315 320
Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr
325 330 335
Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser
340 345 350
Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr
355 360 365
Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile
370 375 380
Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
385 390 395 400
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
405 410 415
Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr
420 425 430
Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn
435 440 445
Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu
450 455 460
Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser
465 470 475 480
Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln
485 490 495
Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg
500 505 510
Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His
515 520 525
His His
530
<210> 15
<211> 993
<212> PRT
<213> 人工序列
<220>
<223> CD33 CC x I2C-scFc双特异性HLE分子
<400> 15
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys
145 150 155 160
Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser
180 185 190
Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu
210 215 220
Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr
225 230 235 240
Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser
245 250 255
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
260 265 270
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
275 280 285
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
290 295 300
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
305 310 315 320
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
325 330 335
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
355 360 365
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
385 390 395 400
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
405 410 415
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
420 425 430
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
435 440 445
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
450 455 460
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
465 470 475 480
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
485 490 495
Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr
500 505 510
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
515 520 525
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
530 535 540
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
545 550 555 560
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
565 570 575
Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val
580 585 590
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
595 600 605
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
610 615 620
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
625 630 635 640
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
645 650 655
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
660 665 670
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
675 680 685
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
690 695 700
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
705 710 715 720
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
725 730 735
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
740 745 750
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys
755 760 765
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
770 775 780
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
785 790 795 800
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
805 810 815
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
820 825 830
Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys
835 840 845
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
850 855 860
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
865 870 875 880
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
885 890 895
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
900 905 910
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
915 920 925
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
930 935 940
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
945 950 955 960
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
965 970 975
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
980 985 990
Lys
<210> 16
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> EGFRvIIIxCD3-scFc VH CDR1
<400> 16
Asn Tyr Gly Met His
1 5
<210> 17
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> EGFRvIIIxCD3-scFc VH CDR2
<400> 17
Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val Arg
1 5 10 15
Gly
<210> 18
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> EGFRvIIIxCD3-scFc VH CDR3
<400> 18
Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp Tyr
1 5 10 15
<210> 19
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> EGFRvIIIxCD3-scFc VL CDR1
<400> 19
Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr Leu Ser
1 5 10 15
<210> 20
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> EGFRvIIIxCD3-scFc VL CDR2
<400> 20
Arg Ile Ser Arg Arg Phe Ser
1 5
<210> 21
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> EGFRvIIIxCD3-scFc VL CDR3
<400> 21
Met Gln Ser Thr His Val Pro Arg Thr
1 5
<210> 22
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> EGFRvIII_CCxCD3-scFc VH
<400> 22
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 23
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> EGFRvIII_CCxCD3-scFc VL
<400> 23
Asp Thr Val Met Thr Gln Thr Pro Leu Ser Ser His Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro
35 40 45
Pro Arg Leu Leu Ile Tyr Arg Ile Ser Arg Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Glu Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser
85 90 95
Thr His Val Pro Arg Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 24
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> EGFRvIII_CCxCD3-scFc scFv
<400> 24
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Thr Val Met Thr
130 135 140
Gln Thr Pro Leu Ser Ser His Val Thr Leu Gly Gln Pro Ala Ser Ile
145 150 155 160
Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr
165 170 175
Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro Pro Arg Leu Leu Ile
180 185 190
Tyr Arg Ile Ser Arg Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ala Gly Thr Asp Phe Thr Leu Glu Ile Ser Arg Val Glu Ala
210 215 220
Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser Thr His Val Pro Arg
225 230 235 240
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys
245 250
<210> 25
<211> 506
<212> PRT
<213> 人工序列
<220>
<223> EGFRvIII_CCxCD3-scFc双特异性分子
<400> 25
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Thr Val Met Thr
130 135 140
Gln Thr Pro Leu Ser Ser His Val Thr Leu Gly Gln Pro Ala Ser Ile
145 150 155 160
Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr
165 170 175
Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro Pro Arg Leu Leu Ile
180 185 190
Tyr Arg Ile Ser Arg Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ala Gly Thr Asp Phe Thr Leu Glu Ile Ser Arg Val Glu Ala
210 215 220
Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser Thr His Val Pro Arg
225 230 235 240
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Ser Gly Gly Gly Gly
245 250 255
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
260 265 270
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys
275 280 285
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
290 295 300
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
305 310 315 320
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
325 330 335
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
340 345 350
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr
355 360 365
Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val
385 390 395 400
Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr
405 410 415
Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro
420 425 430
Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly
435 440 445
Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser
450 455 460
Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu
465 470 475 480
Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val
485 490 495
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
500 505
<210> 26
<211> 994
<212> PRT
<213> 人工序列
<220>
<223> EGFRvIII_CCxCD3-scFc双特异性HLE分子
<400> 26
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Thr Val Met Thr
130 135 140
Gln Thr Pro Leu Ser Ser His Val Thr Leu Gly Gln Pro Ala Ser Ile
145 150 155 160
Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr
165 170 175
Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro Pro Arg Leu Leu Ile
180 185 190
Tyr Arg Ile Ser Arg Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ala Gly Thr Asp Phe Thr Leu Glu Ile Ser Arg Val Glu Ala
210 215 220
Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser Thr His Val Pro Arg
225 230 235 240
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Ser Gly Gly Gly Gly
245 250 255
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
260 265 270
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys
275 280 285
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
290 295 300
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
305 310 315 320
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
325 330 335
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
340 345 350
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr
355 360 365
Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val
385 390 395 400
Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr
405 410 415
Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro
420 425 430
Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly
435 440 445
Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser
450 455 460
Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu
465 470 475 480
Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val
485 490 495
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys
500 505 510
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
515 520 525
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
530 535 540
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
545 550 555 560
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
565 570 575
Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys
580 585 590
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
595 600 605
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
610 615 620
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
625 630 635 640
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
645 650 655
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
660 665 670
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
675 680 685
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
690 695 700
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
705 710 715 720
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
725 730 735
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
755 760 765
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
770 775 780
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
785 790 795 800
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
805 810 815
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
820 825 830
Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg
835 840 845
Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
850 855 860
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
865 870 875 880
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
885 890 895
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
900 905 910
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
915 920 925
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
930 935 940
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
945 950 955 960
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
965 970 975
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
980 985 990
Gly Lys
<210> 27
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> MSLN_5 VH CDR1
<400> 27
Asp Tyr Tyr Met Thr
1 5
<210> 28
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> MSLN_5 VH CDR2
<400> 28
Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 29
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> MSLN_5 VH CDR3
<400> 29
Asp Arg Asn Ser His Phe Asp Tyr Asp Arg Asn Ser His Phe Asp Tyr
1 5 10 15
<210> 30
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> MSLN_5 VL CDR1
<400> 30
Arg Ala Ser Gln Gly Ile Asn Thr Trp Leu Ala
1 5 10
<210> 31
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> MSLN_5 VL CDR2
<400> 31
Gly Ala Ser Gly Leu Gln Ser
1 5
<210> 32
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> MSLN_5 VL CDR3
<400> 32
Gln Gln Ala Lys Ser Phe Pro Arg Thr
1 5
<210> 33
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> MSLN _5 VH
<400> 33
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 Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 34
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> MSLN_5 VL
<400> 34
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Thr Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys Ser Phe Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 35
<211> 239
<212> PRT
<213> 人工序列
<220>
<223> MSLN_5 scFv
<400> 35
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 Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
145 150 155 160
Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys
210 215 220
Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
225 230 235
<210> 36
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> MSLN_5xI2C0双特异性分子
<400> 36
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 Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
145 150 155 160
Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys
210 215 220
Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser
225 230 235 240
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
245 250 255
Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
260 265 270
Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys
275 280 285
Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala
290 295 300
Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp
305 310 315 320
Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu
325 330 335
Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser
340 345 350
Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
355 360 365
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly
385 390 395 400
Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser
405 410 415
Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg
420 425 430
Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg
435 440 445
Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly
450 455 460
Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser
465 470 475 480
Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490
<210> 37
<211> 982
<212> PRT
<213> 人工序列
<220>
<223> MSLN_5xCD3-scFc双特异性HLE分子
<400> 37
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 Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly
145 150 155 160
Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys
210 215 220
Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser
225 230 235 240
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
245 250 255
Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
260 265 270
Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys
275 280 285
Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala
290 295 300
Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp
305 310 315 320
Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu
325 330 335
Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser
340 345 350
Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
355 360 365
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly
385 390 395 400
Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser
405 410 415
Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg
420 425 430
Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg
435 440 445
Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly
450 455 460
Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser
465 470 475 480
Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly
485 490 495
Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
500 505 510
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
515 520 525
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
530 535 540
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
545 550 555 560
Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser
565 570 575
Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
580 585 590
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
595 600 605
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
610 615 620
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
625 630 635 640
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
645 650 655
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
660 665 670
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
675 680 685
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
690 695 700
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
705 710 715 720
Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
755 760 765
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
770 775 780
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
785 790 795 800
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
805 810 815
Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly
820 825 830
Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp
835 840 845
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
850 855 860
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
865 870 875 880
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
885 890 895
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
900 905 910
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
915 920 925
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
930 935 940
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
945 950 955 960
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
965 970 975
Ser Leu Ser Pro Gly Lys
980
<210> 38
<211> 982
<212> PRT
<213> 人工序列
<220>
<223> MSLN_5_CCxCD3-scFc双特异性HLE分子
<400> 38
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 Asp His
20 25 30
Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Phe
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Gly Ile Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Gly Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp
145 150 155 160
Ile Ser Arg Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Leu Leu Ile Ser Ala Ala Ser Arg Leu Gln Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Ile Tyr Tyr Cys Gln Gln Ala Lys
210 215 220
Ser Phe Pro Arg Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Ser
225 230 235 240
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
245 250 255
Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe
260 265 270
Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys
275 280 285
Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala
290 295 300
Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp
305 310 315 320
Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu
325 330 335
Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser
340 345 350
Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
355 360 365
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly
385 390 395 400
Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser
405 410 415
Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg
420 425 430
Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg
435 440 445
Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly
450 455 460
Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser
465 470 475 480
Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly
485 490 495
Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
500 505 510
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
515 520 525
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
530 535 540
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
545 550 555 560
Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser
565 570 575
Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
580 585 590
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
595 600 605
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
610 615 620
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
625 630 635 640
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
645 650 655
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
660 665 670
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
675 680 685
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
690 695 700
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
705 710 715 720
Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
755 760 765
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
770 775 780
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
785 790 795 800
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
805 810 815
Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly
820 825 830
Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp
835 840 845
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
850 855 860
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
865 870 875 880
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
885 890 895
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
900 905 910
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
915 920 925
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
930 935 940
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
945 950 955 960
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
965 970 975
Ser Leu Ser Pro Gly Lys
980
<210> 39
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> CDR-H1 CDH19 65254.007
<400> 39
Ser Tyr Gly Met His
1 5
<210> 40
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDR-H2 CDH19 65254.007
<400> 40
Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val Lys
1 5 10 15
Asp
<210> 41
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> CDR-H3 CDH19 65254.007
<400> 41
Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 42
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CDR-L1 CDH19 65254.007
<400> 42
Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser
1 5 10
<210> 43
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR-L2 CDH19 65254.007
<400> 43
Gln Asp Thr Lys Arg Pro Ser
1 5
<210> 44
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDR-L3 CDH19 65254.007
<400> 44
Gln Ala Trp Glu Ser Ser Thr Val Val
1 5
<210> 45
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> VH CDH19 65254.007
<400> 45
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln 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
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 46
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> VL CDH19 65254.007
<400> 46
Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr
20 25 30
Ser Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr
35 40 45
Gln Asp Thr Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val
85 90 95
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Ser
100 105
<210> 47
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> VH-VL CDH19 65254.007
<400> 47
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln 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
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser
245
<210> 48
<211> 507
<212> PRT
<213> 人工序列
<220>
<223> CDH19 65254.007 x I2C
<400> 48
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln 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
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu His His His His His His
500 505
<210> 49
<211> 989
<212> PRT
<213> 人工序列
<220>
<223> CDH19 65254.007 x I2C -scFc双特异性HLE分子
<400> 49
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln 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
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys
755 760 765
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
770 775 780
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
785 790 795 800
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
805 810 815
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
820 825 830
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
835 840 845
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
850 855 860
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
865 870 875 880
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
885 890 895
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
900 905 910
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
915 920 925
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
930 935 940
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
945 950 955 960
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
965 970 975
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 50
<211> 987
<212> PRT
<213> 人工序列
<220>
<223> CDH19 65254.007 x I2C -scFc_delGK双特异性HLE分子
<400> 50
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln 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
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro
755 760 765
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
770 775 780
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
785 790 795 800
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
805 810 815
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys
820 825 830
Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val
835 840 845
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
850 855 860
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
865 870 875 880
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
885 890 895
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
900 905 910
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
915 920 925
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
930 935 940
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
945 950 955 960
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
965 970 975
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 51
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> CDH19 65254.007_CC x I2C -scFc VH
<400> 51
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln 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
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 52
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> CDH19 65254.007_CC x I2C -scFc VL
<400> 52
Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr
20 25 30
Ser Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr
35 40 45
Gln Asp Thr Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val
85 90 95
Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105
<210> 53
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> CDH19 65254.007_CC x I2C -scFc scFv
<400> 53
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln 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
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Cys Gly
225 230 235 240
Thr Lys Leu Thr Val Leu
245
<210> 54
<211> 501
<212> PRT
<213> 人工序列
<220>
<223> CDH19 65254.007_CC x I2C -scFc双特异性分子
<400> 54
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln 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
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Cys Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu
500
<210> 55
<211> 989
<212> PRT
<213> 人工序列
<220>
<223> CDH19 65254.007_CC x I2C -scFc双特异性HLE分子
<400> 55
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln 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
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Cys Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys
755 760 765
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
770 775 780
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
785 790 795 800
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
805 810 815
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
820 825 830
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
835 840 845
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
850 855 860
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
865 870 875 880
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
885 890 895
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
900 905 910
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
915 920 925
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
930 935 940
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
945 950 955 960
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
965 970 975
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 56
<211> 987
<212> PRT
<213> 人工序列
<220>
<223> CDH19 65254.007_CC x I2C -scFc_delGK双特异性HLE分子
<400> 56
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln 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
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu
130 135 140
Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile
145 150 155 160
Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln
165 170 175
Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys
180 185 190
Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn
195 200 205
Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp
210 215 220
Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Cys Gly
225 230 235 240
Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro
755 760 765
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
770 775 780
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
785 790 795 800
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
805 810 815
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys
820 825 830
Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val
835 840 845
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
850 855 860
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
865 870 875 880
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
885 890 895
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
900 905 910
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
915 920 925
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
930 935 940
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
945 950 955 960
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
965 970 975
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 57
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> FLT3_7 A8xCD3-scFc VH CDR1
<400> 57
Asn Ala Arg Met Gly Val Ser
1 5
<210> 58
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> FLT3_7 A8xCD3-scFc VH CDR2
<400> 58
His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Asn
1 5 10 15
His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Asn
20 25 30
<210> 59
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> FLT3_7 A8xCD3-scFc VH CDR3
<400> 59
Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp Tyr Ile Val
1 5 10 15
Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp Tyr
20 25
<210> 60
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> FLT3_7 A8xCD3-scFc VL CDR1
<400> 60
Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly
1 5 10
<210> 61
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> FLT3_7 A8xCD3-scFc VL CDR2
<400> 61
Ala Ala Ser Thr Leu Gln Ser
1 5
<210> 62
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> FLT3_7 A8xCD3-scFc VL CDR3
<400> 62
Leu Gln His Asn Ser Tyr Pro Leu Thr
1 5
<210> 63
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> FLT3_7 A8xCD3-scFc VH
<400> 63
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala
20 25 30
Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu
35 40 45
Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 64
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> FLT3_ A8-scFc VL
<400> 64
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys
100 105
<210> 65
<211> 246
<212> PRT
<213> 人工序列
<220>
<223> FLT3_7 A8xCD3- scFv
<400> 65
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala
20 25 30
Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu
35 40 45
Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr
180 185 190
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
210 215 220
Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu Thr Phe Gly Cys Gly
225 230 235 240
Thr Lys Val Glu Ile Lys
245
<210> 66
<211> 501
<212> PRT
<213> 人工序列
<220>
<223> FLT3_7 A8xCD3双特异性分子
<400> 66
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala
20 25 30
Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu
35 40 45
Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr
180 185 190
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
210 215 220
Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu Thr Phe Gly Cys Gly
225 230 235 240
Thr Lys Val Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu
500
<210> 67
<211> 989
<212> PRT
<213> 人工序列
<220>
<223> FLT3_7 A8xCD3-scFc双特异性HLE分子
<400> 67
Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala
20 25 30
Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu
35 40 45
Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
130 135 140
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
145 150 155 160
Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln
165 170 175
Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr
180 185 190
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
195 200 205
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
210 215 220
Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu Thr Phe Gly Cys Gly
225 230 235 240
Thr Lys Val Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro
500 505 510
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
515 520 525
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
530 535 540
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
545 550 555 560
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
565 570 575
Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr
580 585 590
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
595 600 605
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
610 615 620
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
625 630 635 640
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
645 650 655
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
660 665 670
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
675 680 685
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
690 695 700
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
705 710 715 720
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys
755 760 765
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
770 775 780
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
785 790 795 800
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
805 810 815
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
820 825 830
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
835 840 845
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
850 855 860
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
865 870 875 880
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
885 890 895
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
900 905 910
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
915 920 925
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
930 935 940
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
945 950 955 960
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
965 970 975
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 68
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> VH CDR1 DLL3_1_CC_delGK
<400> 68
Ser Tyr Tyr Trp Ser
1 5
<210> 69
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> VH CDR2 DLL3_1_CC_delGK
<400> 69
Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 70
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3 DLL3_1_CC_delGK
<400> 70
Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr
1 5 10
<210> 71
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1 DLL3_1_CC_delGK
<400> 71
Arg Ala Ser Gln Arg Val Asn Asn Asn Tyr Leu Ala
1 5 10
<210> 72
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2 DLL3_1_CC_delGK
<400> 72
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 73
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3 DLL3_1_CC_delGK
<400> 73
Gln Gln Tyr Asp Arg Ser Pro Leu Thr
1 5
<210> 74
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> VH DLL3_1_CC_delGK
<400> 74
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 75
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> VL DLL3_1_CC_delGK
<400> 75
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Asn Asn Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Arg Ser Pro
85 90 95
Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 76
<211> 241
<212> PRT
<213> 人工序列
<220>
<223> DLL3_1_CC_delGK
<400> 76
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln 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 Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys
<210> 77
<211> 496
<212> PRT
<213> 人工序列
<220>
<223> DLL3_1_CCxCD3_delGK双特异性分子
<400> 77
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln 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 Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
<210> 78
<211> 982
<212> PRT
<213> 人工序列
<220>
<223> DLL3_1_CCxCD3-scFc_delGK双特异性HLE分子
<400> 78
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln 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 Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
210 215 220
Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile
225 230 235 240
Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
500 505 510
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
515 520 525
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
530 535 540
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
545 550 555 560
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr
565 570 575
Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp
580 585 590
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
595 600 605
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
610 615 620
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
625 630 635 640
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
645 650 655
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
660 665 670
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
675 680 685
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
690 695 700
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
705 710 715 720
Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
725 730 735
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
740 745 750
Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
755 760 765
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
770 775 780
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
785 790 795 800
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
805 810 815
Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly
820 825 830
Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp
835 840 845
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
850 855 860
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
865 870 875 880
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
885 890 895
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
900 905 910
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
915 920 925
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
930 935 940
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
945 950 955 960
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
965 970 975
Ser Leu Ser Pro Gly Lys
980
<210> 79
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> VH CDR1 CD19 97-G1RE-C2
<400> 79
Ser Tyr Gly Met His
1 5
<210> 80
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> VH CDR2 CD19 97-G1RE-C2
<400> 80
Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val Lys
1 5 10 15
Gly
<210> 81
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3 CD19 97-G1RE-C2
<400> 81
Asp Arg Gly Thr Ile Phe Gly Asn Tyr Gly Leu Glu Val
1 5 10
<210> 82
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> VH CD19 97-G1RE-C2 CC
<400> 82
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Gly Thr Ile Phe Gly Asn Tyr Gly Leu Glu Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 83
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1 CD19 97-G1RE-C2
<400> 83
Arg Ser Ser Gln Ser Leu Leu His Lys Asn Ala Phe Asn Tyr Leu Asp
1 5 10 15
<210> 84
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2 CD19 97-G1RE-C2
<400> 84
Leu Gly Ser Asn Arg Ala Ser
1 5
<210> 85
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3 CD19 97-G1RE-C2
<400> 85
Met Gln Ala Leu Gln Thr Pro Phe Thr
1 5
<210> 86
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> VL CD19 97-G1RE-C2 CC
<400> 86
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ile Ser Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Lys
20 25 30
Asn Ala Phe Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Phe Thr Phe Gly Cys Gly Thr Lys Val Asp Ile Lys
100 105 110
<210> 87
<211> 525
<212> PRT
<213> 人工序列
<220>
<223> CD19 97-G1RE-C2 CC x I2C0
<400> 87
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Val Met Thr Gln Ser Pro Leu Ser
20 25 30
Leu Pro Val Ile Ser Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Leu Leu His Lys Asn Ala Phe Asn Tyr Leu Asp Trp Tyr Leu
50 55 60
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn
65 70 75 80
Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
Tyr Tyr Cys Met Gln Ala Leu Gln Thr Pro Phe Thr Phe Gly Cys Gly
115 120 125
Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
145 150 155 160
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
165 170 175
Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys
180 185 190
Cys Leu Glu Trp Val Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr
195 200 205
Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
210 215 220
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr
225 230 235 240
Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly Thr Ile Phe Gly Asn Tyr
245 250 255
Gly Leu Glu Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
260 265 270
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
275 280 285
Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr
290 295 300
Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
305 310 315 320
Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
325 330 335
Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
340 345 350
Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp
355 360 365
Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr
370 375 380
Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
385 390 395 400
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
405 410 415
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
420 425 430
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
435 440 445
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
450 455 460
Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe
465 470 475 480
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
485 490 495
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn
500 505 510
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
515 520 525
<210> 88
<211> 1013
<212> PRT
<213> 人工序列
<220>
<223> CD19 97-G1RE-C2 CC x I2C0-scFc
<400> 88
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Val Met Thr Gln Ser Pro Leu Ser
20 25 30
Leu Pro Val Ile Ser Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Leu Leu His Lys Asn Ala Phe Asn Tyr Leu Asp Trp Tyr Leu
50 55 60
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn
65 70 75 80
Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
Tyr Tyr Cys Met Gln Ala Leu Gln Thr Pro Phe Thr Phe Gly Cys Gly
115 120 125
Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val
145 150 155 160
Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
165 170 175
Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys
180 185 190
Cys Leu Glu Trp Val Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr
195 200 205
Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
210 215 220
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr
225 230 235 240
Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly Thr Ile Phe Gly Asn Tyr
245 250 255
Gly Leu Glu Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
260 265 270
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
275 280 285
Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr
290 295 300
Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
305 310 315 320
Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
325 330 335
Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
340 345 350
Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp
355 360 365
Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr
370 375 380
Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
385 390 395 400
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
405 410 415
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
420 425 430
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
435 440 445
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
450 455 460
Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe
465 470 475 480
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
485 490 495
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn
500 505 510
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly
515 520 525
Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
530 535 540
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
545 550 555 560
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
565 570 575
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
580 585 590
Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr
595 600 605
Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
610 615 620
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
625 630 635 640
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
645 650 655
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
660 665 670
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
675 680 685
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
690 695 700
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
705 710 715 720
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
725 730 735
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
740 745 750
Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
755 760 765
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
770 775 780
Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
785 790 795 800
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
805 810 815
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
820 825 830
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
835 840 845
Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser
850 855 860
Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
865 870 875 880
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
885 890 895
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
900 905 910
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
915 920 925
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
930 935 940
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
945 950 955 960
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
965 970 975
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
980 985 990
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
995 1000 1005
Leu Ser Pro Gly Lys
1010
<210> 89
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> VH CDR1 CDH3 G8A 6-B12
<400> 89
Ser Tyr Pro Ile Asn
1 5
<210> 90
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> VH CDR2 CDH3 G8A 6-B12
<400> 90
Val Ile Trp Thr Gly Gly Gly Thr Asn Tyr Ala Ser Ser Val Lys Gly
1 5 10 15
<210> 91
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> VH CDR3 CDH3 G8A 6-B12
<400> 91
Ser Arg Gly Val Tyr Asp Phe Asp Gly Arg Gly Ala Met Asp Tyr
1 5 10 15
<210> 92
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> VL CDR1 CDH3 G8A 6-B12
<400> 92
Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Phe
1 5 10 15
Ala
<210> 93
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> VL CDR2 CDH3 G8A 6-B12
<400> 93
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 94
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> VL CDR3 CDH3 G8A 6-B12
<400> 94
Gln Gln Tyr Tyr Ser Tyr Pro Tyr Thr
1 5
<210> 95
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> VH CDH3 G8A 6-B12
<400> 95
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr
20 25 30
Pro Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Val Ile Trp Thr Gly Gly Gly Thr Asn Tyr Ala Ser Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Ser Arg Gly Val Tyr Asp Phe Asp Gly Arg Gly Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 96
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> VL CDH3 G8A 6-B12
<400> 96
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 97
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> CDH3 G8A 6-B12 scFv
<400> 97
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr
20 25 30
Pro Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Val Ile Trp Thr Gly Gly Gly Thr Asn Tyr Ala Ser Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Ser Arg Gly Val Tyr Asp Phe Asp Gly Arg Gly Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr
165 170 175
Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
180 185 190
Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
210 215 220
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Ser Tyr Pro Tyr
225 230 235 240
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
245 250
<210> 98
<211> 506
<212> PRT
<213> 人工序列
<220>
<223> CDH3 G8A 6-B12 x I2C0双特异性分子
<400> 98
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr
20 25 30
Pro Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Val Ile Trp Thr Gly Gly Gly Thr Asn Tyr Ala Ser Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Ser Arg Gly Val Tyr Asp Phe Asp Gly Arg Gly Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr
165 170 175
Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
180 185 190
Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
210 215 220
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Ser Tyr Pro Tyr
225 230 235 240
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Ser Gly Gly Gly Gly
245 250 255
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
260 265 270
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys
275 280 285
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
290 295 300
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
305 310 315 320
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
325 330 335
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
340 345 350
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr
355 360 365
Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val
385 390 395 400
Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr
405 410 415
Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro
420 425 430
Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly
435 440 445
Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser
450 455 460
Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu
465 470 475 480
Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val
485 490 495
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
500 505
<210> 99
<211> 994
<212> PRT
<213> 人工序列
<220>
<223> CDH3 G8A 6-B12 x I2C0双特异性分子HLE
<400> 99
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr
20 25 30
Pro Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Val Ile Trp Thr Gly Gly Gly Thr Asn Tyr Ala Ser Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Ser Arg Gly Val Tyr Asp Phe Asp Gly Arg Gly Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln
130 135 140
Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn
145 150 155 160
Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr
165 170 175
Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
180 185 190
Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
210 215 220
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Ser Tyr Pro Tyr
225 230 235 240
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Ser Gly Gly Gly Gly
245 250 255
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
260 265 270
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys
275 280 285
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
290 295 300
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
305 310 315 320
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
325 330 335
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
340 345 350
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr
355 360 365
Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val
385 390 395 400
Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr
405 410 415
Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro
420 425 430
Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly
435 440 445
Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser
450 455 460
Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu
465 470 475 480
Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val
485 490 495
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys
500 505 510
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
515 520 525
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
530 535 540
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
545 550 555 560
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
565 570 575
Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys
580 585 590
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
595 600 605
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
610 615 620
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
625 630 635 640
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
645 650 655
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
660 665 670
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
675 680 685
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
690 695 700
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
705 710 715 720
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
725 730 735
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
755 760 765
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
770 775 780
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
785 790 795 800
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
805 810 815
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
820 825 830
Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg
835 840 845
Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
850 855 860
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
865 870 875 880
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
885 890 895
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
900 905 910
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
915 920 925
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
930 935 940
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
945 950 955 960
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
965 970 975
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
980 985 990
Gly Lys
<210> 100
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> BCMA A7 27-C4-G7 CDR1 VH
<400> 100
Asn His Ile Ile His
1 5
<210> 101
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> BCMA A7 27-C4-G7 CDR2 VH
<400> 101
Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe Gln
1 5 10 15
Gly
<210> 102
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> BCMA A7 27-C4-G7 CDR3 VH
<400> 102
Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr
1 5 10
<210> 103
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> BCMA A7 27-C4-G7 CDR1 VL
<400> 103
Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 104
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> BCMA A7 27-C4-G7 CDR2 VL
<400> 104
Tyr Thr Ser Arg Leu His Thr
1 5
<210> 105
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> BCMA A7 27-C4-G7 CDR3 VL
<400> 105
Gln Gln Gly Asn Thr Leu Pro Trp Thr
1 5
<210> 106
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> BCMA A7 27-C4-G7 CC (44/100) VH
<400> 106
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 107
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> BCMA A7 27-C4-G7 CC (44/100) VL
<400> 107
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 108
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> BCMA A7 27-C4-G7 CC (44/100) scFv
<400> 108
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln
145 150 155 160
Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 109
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> BCMA A7 27-C4-G7 CC (44/100) x I2C0双特异性分子
<400> 109
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln
145 150 155 160
Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu
<210> 110
<211> 986
<212> PRT
<213> 人工序列
<220>
<223> BCMA A7 27-C4-G7 CC (44/100) x I2C0-scFc双特异性分子HLE
<400> 110
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His
20 25 30
Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe
50 55 60
Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln
145 150 155 160
Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr
180 185 190
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 111
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC VH CDR1
<400> 111
Asp Tyr Tyr Met Tyr
1 5
<210> 112
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC VH CDR2
<400> 112
Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile Lys
1 5 10 15
Gly
<210> 113
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC VH CDR3
<400> 113
Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr
1 5 10
<210> 114
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC VL CDR1
<400> 114
Lys Ala Ser Gln Asn Val Asp Ala Asn Val Ala
1 5 10
<210> 115
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC VL CDR2
<400> 115
Ser Ala Ser Tyr Val Tyr Trp
1 5
<210> 116
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC VL CDR3
<400> 116
Gln Gln Tyr Asp Gln Gln Leu Ile Thr
1 5
<210> 117
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC VH
<400> 117
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 118
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC VL
<400> 118
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Ala Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Val Tyr Trp Asp Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Ala Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ser
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Gln Gln Leu Ile
85 90 95
Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 119
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC scFv
<400> 119
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 120
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC x I2C0双特异性分子
<400> 120
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu
<210> 121
<211> 986
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC x I2C0-scFc双特异性HLE分子
<400> 121
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 122
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC x I2C0-scFc_delGK双特异性HLE分子
<400> 122
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 123
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC x I2C0 CC (103/43)-scFc双特异性分子
<400> 123
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu
<210> 124
<211> 986
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC x I2C0 CC (103/43)-scFc双特异性HLE分子
<400> 124
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 125
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.17 CC x I2C0 CC (103/43)-scFc_delGK双特异性HLE
分子
<400> 125
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 126
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC VH CDR1
<400> 126
Asp Tyr Tyr Met Tyr
1 5
<210> 127
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC VH CDR2
<400> 127
Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile Lys
1 5 10 15
Gly
<210> 128
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC VH CDR3
<400> 128
Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr
1 5 10
<210> 129
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC VL CDR1
<400> 129
Lys Ala Ser Gln Asn Val Asp Thr Asn Val Ala
1 5 10
<210> 130
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC VL CDR2
<400> 130
Ser Ala Ser Tyr Val Tyr Trp
1 5
<210> 131
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC VL CDR3
<400> 131
Gln Gln Tyr Asp Gln Gln Leu Ile Thr
1 5
<210> 132
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC VH
<400> 132
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 133
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC VL
<400> 133
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Val Tyr Trp Asp Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Ala Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ser
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Gln Gln Leu Ile
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 134
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC scFv
<400> 134
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 135
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0双特异性分子
<400> 135
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu
<210> 136
<211> 986
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0-scFc双特异性HLE分子
<400> 136
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 137
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0-scFc_delGK双特异性HLE分子
<400> 137
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 138
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0 CC (103/43)-scFc双特异性分子
<400> 138
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu
<210> 139
<211> 986
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0 CC (103/43)-scFc双特异性HLE分子
<400> 139
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 140
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0 CC (103/43)-scFc_delGK双特异性HLE
分子
<400> 140
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 141
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0-scFc VH CDR1
<400> 141
Asp Tyr Tyr Met Tyr
1 5
<210> 142
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0-scFc VH CDR2
<400> 142
Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile Lys
1 5 10 15
Gly
<210> 143
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0-scFc VH CDR3
<400> 143
Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr
1 5 10
<210> 144
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0-scFc VL CDR1
<400> 144
Lys Ala Ser Gln Asn Val Asp Thr Asn Val Ala
1 5 10
<210> 145
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0-scFc VL CDR2
<400> 145
Ser Ala Ser Tyr Val Tyr Trp
1 5
<210> 146
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0-scFc VL CDR3
<400> 146
Gln Gln Tyr Asp Gln Gln Leu Ile Thr
1 5
<210> 147
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0-scFc VH
<400> 147
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 148
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0-scFc VL
<400> 148
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Val Tyr Trp Asp Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Ala Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ser
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Gln Gln Leu Ile
85 90 95
Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 149
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0-scFc scFv
<400> 149
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys
<210> 150
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0-scFc双特异性分子
<400> 150
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu
<210> 151
<211> 986
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0-scFc双特异性HLE分子
<400> 151
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 152
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0-scFc_delGK双特异性HLE分子
<400> 152
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 153
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0 CC (103/43)-scFc双特异性分子
<400> 153
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu
<210> 154
<211> 986
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0 CC (103/43)-scFc双特异性HLE分子
<400> 154
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 155
<211> 984
<212> PRT
<213> 人工序列
<220>
<223> PM 76-B10.11 CC x I2C0 CC (103/43)-scFc_delGK双特异性HLE
分子
<400> 155
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 156
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> CD70_21D_CC VH CDR1
<400> 156
Thr Tyr Ala Met Ser
1 5
<210> 157
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CD70_21D_CC VH CDR2
<400> 157
Ala Ile Ser Gly Ser Gly Gly Arg Thr Phe Tyr Ala Glu Ser Val Glu
1 5 10 15
Gly
<210> 158
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> CD70_21D_CC VH CDR3
<400> 158
His Asp Tyr Ser Asn Tyr Pro Tyr Phe Asp Tyr
1 5 10
<210> 159
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CD70_21D_CC VL CDR1
<400> 159
Arg Ala Ser Gln Ser Val Arg Ser Thr Tyr Leu Ala
1 5 10
<210> 160
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CD70_21D_CC VL CDR2
<400> 160
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 161
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CD70_21D_CC VL CDR3
<400> 161
Gln Gln Tyr Gly Asp Leu Pro Phe Thr
1 5
<210> 162
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> CD70_21D_CC VH
<400> 162
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Met Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Arg Thr Phe Tyr Ala Glu Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys His Asp Tyr Ser Asn Tyr Pro Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 163
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> CD70_21D_CC VL
<400> 163
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Thr
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Ser Cys Gln Gln Tyr Gly Asp Leu Pro
85 90 95
Phe Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 164
<211> 986
<212> PRT
<213> 人工序列
<220>
<223> CD70_21D_CCx12C scFc
<400> 164
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Met Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Arg Thr Phe Tyr Ala Glu Ser Val
50 55 60
Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys His Asp Tyr Ser Asn Tyr Pro Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly
130 135 140
Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala
145 150 155 160
Ser Gln Ser Val Arg Ser Thr Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr
180 185 190
Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Ser Cys
210 215 220
Gln Gln Tyr Gly Asp Leu Pro Phe Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 165
<211> 1001
<212> PRT
<213> 人工序列
<220>
<223> MSLN_5_CCxCD3-scFc双特异性HLE分子
<400> 165
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Ser Asp Tyr Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Leu Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
85 90 95
Ser Leu Phe Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln
115 120 125
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser
145 150 155 160
Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
165 170 175
Ser Gln Gly Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly
180 185 190
Lys Ala Pro Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly
195 200 205
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
210 215 220
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
225 230 235 240
Gln Ala Lys Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu
245 250 255
Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
260 265 270
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala
275 280 285
Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala
290 295 300
Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn
305 310 315 320
Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile
325 330 335
Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu
340 345 350
Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe
355 360 365
Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu
370 375 380
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
385 390 395 400
Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val
405 410 415
Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala
420 425 430
Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln
435 440 445
Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr
450 455 460
Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr
465 470 475 480
Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu
485 490 495
Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
500 505 510
Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
515 520 525
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
530 535 540
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
545 550 555 560
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
565 570 575
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
580 585 590
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
595 600 605
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
610 615 620
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
625 630 635 640
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
645 650 655
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
660 665 670
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
675 680 685
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
690 695 700
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
705 710 715 720
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
725 730 735
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
755 760 765
Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
770 775 780
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
785 790 795 800
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
805 810 815
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
820 825 830
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
835 840 845
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
850 855 860
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
865 870 875 880
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
885 890 895
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
900 905 910
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
915 920 925
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
930 935 940
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
945 950 955 960
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
965 970 975
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
980 985 990
Lys Ser Leu Ser Leu Ser Pro Gly Lys
995 1000
<210> 166
<211> 986
<212> PRT
<213> 人工序列
<220>
<223> 具有cys钳的抗PSMA xI2C0，scFc双特异性分子HLE
PM76-B10.11
<400> 166
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro
500 505 510
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
515 520 525
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
530 535 540
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
545 550 555 560
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu
565 570 575
Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His
580 585 590
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
595 600 605
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
610 615 620
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
625 630 635 640
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
645 650 655
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
660 665 670
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
675 680 685
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
690 695 700
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
705 710 715 720
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly
725 730 735
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
740 745 750
Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys
755 760 765
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
770 775 780
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
785 790 795 800
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
805 810 815
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu
820 825 830
Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu
835 840 845
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
850 855 860
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
865 870 875 880
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
885 890 895
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
900 905 910
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
915 920 925
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
930 935 940
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
945 950 955 960
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
965 970 975
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985
<210> 167
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> 抗PSMA IC20双特异性分子PM76-B10.17
<400> 167
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 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 Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
130 135 140
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
145 150 155 160
Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser
180 185 190
Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr
195 200 205
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu
<210> 168
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn 18.2 VH CDR1 CL-1和CL-2
<400> 168
Gly Tyr Tyr Met His
1 5
<210> 169
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn18.2 VH CDR2
<400> 169
Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 170
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn18.2 VH CDR3
<400> 170
Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met Asp Val
1 5 10 15
<210> 171
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn18.2 VL CDR1
<400> 171
Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala
1 5 10
<210> 172
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn18.2 VL CDR2
<400> 172
Thr Ala Ser Ser Leu Gln Ser
1 5
<210> 173
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn18.2 VL CDR3
<400> 173
Gln Gln Ala Asn Ser Phe Pro Ile Thr
1 5
<210> 174
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn18.2 VH 抗CL-1
<400> 174
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 175
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn18.2 VL CL-1
<400> 175
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile
85 90 95
Thr Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 176
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn18.2 scFv CL-1
<400> 176
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys
245
<210> 177
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn 18.2xCD3双特异性分子CL-1 xI2C
<400> 177
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu
500
<210> 178
<211> 990
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn 18.2xCD3双特异性scFc分子CL-1 xI2C-scFc
<400> 178
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys
500 505 510
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
515 520 525
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
530 535 540
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
545 550 555 560
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
565 570 575
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
580 585 590
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
595 600 605
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
610 615 620
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
625 630 635 640
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
645 650 655
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
660 665 670
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
675 680 685
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
690 695 700
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
705 710 715 720
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly
725 730 735
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
740 745 750
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr
755 760 765
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
770 775 780
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
785 790 795 800
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
805 810 815
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
820 825 830
Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val
835 840 845
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
850 855 860
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
865 870 875 880
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
885 890 895
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
900 905 910
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
915 920 925
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
930 935 940
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
945 950 955 960
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
965 970 975
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985 990
<210> 179
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn18.2 VH CL-2
<400> 179
Gln Val Gln Met Val Gln Ser Gly Ala Glu Val Lys Lys His Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 180
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn18.2 VL CL-2
<400> 180
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile
85 90 95
Thr Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 181
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn18.2 scFv CL-2
<400> 181
Gln Val Gln Met Val Gln Ser Gly Ala Glu Val Lys Lys His Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys
245
<210> 182
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn18.2xCD3双特异性分子CL-2xI2C
<400> 182
Gln Val Gln Met Val Gln Ser Gly Ala Glu Val Lys Lys His Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu
500
<210> 183
<211> 990
<212> PRT
<213> 人工序列
<220>
<223> 抗Cldn18.2xCD3双特异性scFc分子CL-2xI2C-scFc
<400> 183
Gln Val Gln Met Val Gln Ser Gly Ala Glu Val Lys Lys His Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Ile Thr Val Ala Gly Thr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Trp Leu Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser
180 185 190
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile Thr Phe Gly Cys
225 230 235 240
Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys
500 505 510
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
515 520 525
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
530 535 540
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
545 550 555 560
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
565 570 575
Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu
580 585 590
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
595 600 605
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
610 615 620
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
625 630 635 640
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
645 650 655
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
660 665 670
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
675 680 685
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
690 695 700
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
705 710 715 720
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly
725 730 735
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
740 745 750
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr
755 760 765
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
770 775 780
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
785 790 795 800
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
805 810 815
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
820 825 830
Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val
835 840 845
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
850 855 860
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
865 870 875 880
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
885 890 895
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
900 905 910
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
915 920 925
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
930 935 940
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
945 950 955 960
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
965 970 975
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
980 985 990
<210> 184
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 抗MUC17 VH CDR1 MU 8-B7
<400> 184
Gly Tyr Tyr Trp Ser
1 5
<210> 185
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 抗MUC17 VH CDR2 MU 8-B7
<400> 185
Asp Ile Asp Ala Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 186
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 抗MUC17 VH CDR3 MU 8-B7
<400> 186
Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Asn
1 5 10
<210> 187
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 抗MUC17 VL CDR1 MU 8-B7
<400> 187
Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala Ser
1 5 10
<210> 188
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 抗MUC17 VL CDR2 MU 8-B7
<400> 188
Gln Asp Arg Lys Arg Pro Ser
1 5
<210> 189
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 抗MUC17 VL CDR3 MU 8-B7
<400> 189
Gln Ala Trp Gly Ser Ser Thr Ala Val
1 5
<210> 190
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 抗MUC17 VH MU 8-B7
<400> 190
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asp Ala Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Asn Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 191
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 抗MUC17 VL MU 8-B7
<400> 191
Ser Tyr Glu Leu Thr Gln Pro Ser Ser Val Ser Val Pro Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Asp Lys Leu Gly Asp Lys Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr
35 40 45
Gln Asp Arg Lys Arg Pro Ser Gly Val Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Gly Ser Ser Thr Ala Val
85 90 95
Phe Gly Cys Gly Thr Lys Leu Thr Val Leu
100 105
<210> 192
<211> 984
<212> PRT
<213> 人工序列
<220>
<223>双特异性分子MU 8-B7 x I2C0scFc
<400> 192
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asp Ala Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Leu Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Lys Lys Tyr Ser Thr Val Trp Ser Tyr Phe Asp Asn Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu Thr Gln Pro Ser Ser
130 135 140
Val Ser Val Pro Pro Gly Gln Thr Ala Ser Ile Thr Cys Ser Gly Asp
145 150 155 160
Lys Leu Gly Asp Lys Tyr Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln
165 170 175
Ser Pro Val Leu Val Ile Tyr Gln Asp Arg Lys Arg Pro Ser Gly Val
180 185 190
Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr
195 200 205
Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp Tyr Tyr Cys Gln Ala
210 215 220
Trp Gly Ser Ser Thr Ala Val Phe Gly Cys Gly Thr Lys Leu Thr Val
225 230 235 240
Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
500 505 510
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
515 520 525
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
530 535 540
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
545 550 555 560
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr
565 570 575
Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp
580 585 590
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
595 600 605
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
610 615 620
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
625 630 635 640
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
645 650 655
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
660 665 670
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
675 680 685
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
690 695 700
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
705 710 715 720
Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
740 745 750
Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
755 760 765
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
770 775 780
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
785 790 795 800
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
805 810 815
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln
820 825 830
Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln
835 840 845
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
850 855 860
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
865 870 875 880
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
885 890 895
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
900 905 910
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
915 920 925
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
930 935 940
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
945 950 955 960
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
965 970 975
Ser Leu Ser Leu Ser Pro Gly Lys
980
<210> 193
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> I2C的CDR-L1
<400> 193
Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
1 5 10
<210> 194
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> I2C的CDR-L2
<400> 194
Gly Thr Lys Phe Leu Ala Pro
1 5
<210> 195
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> I2C的CDR-L3
<400> 195
Val Leu Trp Tyr Ser Asn Arg Trp Val
1 5
<210> 196
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> I2C的CDR-H1
<400> 196
Lys Tyr Ala Met Asn
1 5
<210> 197
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> I2C的CDR-H2
<400> 197
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Asp
<210> 198
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> I2C的CDR-H3
<400> 198
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 199
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> I2C的VH
<400> 199
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 200
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> I2C的VL
<400> 200
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
20 25 30
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn
85 90 95
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 201
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> I2C的VH-VL
<400> 201
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
130 135 140
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
145 150 155 160
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245

Claims (48)

1.一种水性组合物，该水性组合物包含浓度介于约0.001μg/ml与约100μg/ml之间的双特异性抗体构建体以及浓度为表面活性剂的临界胶束浓度(CMC)的至少约0.25倍的该表面活性剂，其中该双特异性抗体构建体包含与靶细胞表面抗原结合的第一结合结构域、与T细胞表面上的人CD3结合的第二结合结构域，以及任选地按氨基到羧基的顺序包含铰链-CH2结构域-CH3结构域-接头-铰链-CH2结构域-CH3结构域的第三结构域，其中该第二结合结构域包含具有SEQ ID NO:201的序列的多肽。
2.如权利要求1所述的组合物，其中该双特异性抗体构建体以介于约0.001μg/ml与约50μg/ml之间的浓度存在。
3.如权利要求1或2所述的组合物，其中该双特异性抗体构建体以介于约0.01μg/ml至约50μg/ml之间、或介于0.1μg/ml至约50μg/ml、或0.1μg/ml至约10μg/ml、或1μg/ml至约10μg/ml之间的浓度存在。
4.如权利要求1-3中任一项所述的组合物，其中该表面活性剂是聚山梨醇酯、泊洛沙姆或曲拉通x-100。
5.如权利要求1-4中任一项所述的组合物，其中该表面活性剂是聚山梨醇酯80、聚山梨醇酯60、聚山梨醇酯40、聚山梨醇酯20或曲拉通X-100。
6.如权利要求1-4中任一项所述的组合物，其中该表面活性剂是泊洛沙姆188或泊洛沙姆407。
7.如权利要求1-6中任一项所述的组合物，其中该表面活性剂以介于该表面活性剂的该CMC的约0.25倍与约20倍之间、或介于该CMC的约0.25倍与约10倍之间的浓度存在。
8.如权利要求1-7中任一项所述的组合物，其中该组合物进一步包含盐、氨基酸、糖类或糖类衍生物或它们的组合。
9.如权利要求8所述的组合物，其中该组合物进一步包含缓冲剂或防腐剂。
10.如权利要求8或9所述的组合物，其中该组合物的pH介于约3.5与约7.5之间。
11.如权利要求10所述的组合物，其中该组合物的pH介于约4.2与约7.0之间。
12.如权利要求8-11中任一项所述的组合物，其中该盐是NaCl。
13.如权利要求8-12中任一项所述的组合物，其中该糖类或糖类衍生物是单糖、二糖、环状多糖或糖醇。
14.如权利要求8-13所述的组合物，其中该糖类是蔗糖、海藻糖、甘露糖醇或山梨糖醇。
15.如权利要求8-14中任一项所述的组合物，其中该氨基酸是赖氨酸。
16.如权利要求9-15中任一项所述的组合物，其中该缓冲剂是乙酸盐缓冲剂、谷氨酸盐缓冲剂、柠檬酸盐缓冲剂、琥珀酸盐缓冲剂、酒石酸盐缓冲剂、富马酸盐缓冲剂、马来酸盐缓冲剂、组氨酸缓冲剂或磷酸盐缓冲剂。
17.如权利要求1-16中任一项所述的组合物，其中该双特异性抗体构建体的该第一结合结构域和该第二结合结构域中的每一者包含VH区和VL区。
18.如权利要求1-17中任一项所述的组合物，其中该双特异性抗体构建体是单链抗体构建体。
19.如权利要求1-18中任一项所述的组合物，其中该双特异性抗体构建体包含具有选自SEQ ID NO:11、SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:76、SEQ ID NO:78、SEQ IDNO:87、SEQ ID NO:88、SEQ ID NO:108、SEQ ID NO:109、SEQ ID NO:110、SEQ ID NO:165、SEQ ID NO:166、SEQ ID NO:167、SEQ ID NO:176、SEQ ID NO:178和SEQ ID NO:192的氨基酸序列的多肽。
20.如权利要求1-19中任一项所述的组合物，其中该组合物是药物组合物。
21.如权利要求1-20中任一项所述的组合物，其中该组合物容纳在塑料容器中。
22.如权利要求21所述的组合物，其中该容器由包含聚烯烃、PVC、EVA或聚氨酯的材料制成。
23.如权利要求22所述的组合物，其中该容器由包含PVC的材料制成，并且其中该PVC基本上不含DEHP或TOTM。
24.如权利要求21-23中任一项所述的组合物，其中该容器是IV袋或IV管。
25.一种包含容纳在容器内的水性药物组合物的药物制剂，其中该水性药物组合物包含：
a)浓度介于约0.001μg/ml与约100μg/ml之间的双特异性抗体构建体，以及
b)浓度为表面活性剂的CMC的至少约0.25倍的该表面活性剂，其中该表面活性剂具有至少20的HLB值。
26.如权利要求25所述的药物制剂，其中该水性药物组合物包含浓度介于约0.001μg/ml与约50μg/ml之间的该双特异性抗体构建体。
27.如权利要求25或26所述的药物制剂，其中该水性药物组合物包含浓度介于该表面活性剂的该CMC的约0.25倍与约20倍之间、或介于该CMC的约0.25倍与约10倍之间的该表面活性剂。
28.如权利要求25-27中任一项所述的药物制剂，其中该水性药物组合物进一步包含盐、缓冲剂、氨基酸、糖类或糖类衍生物或它们的组合。
29.如权利要求25-28中任一项所述的药物制剂，其中该水性药物组合物具有介于约4.2与约7.0之间的pH。
30.如权利要求25-29中任一项所述的药物制剂，其中该容器由包含聚烯烃、PVC、EVA或聚氨酯的材料制成。
31.如权利要求25-30中任一项所述的药物制剂，其中该双特异性抗体构建体包含具有选自SEQ ID NO:11、SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:24、SEQ ID NO:25、SEQ IDNO:47、SEQ ID NO:48、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:76、SEQ ID NO:78、SEQ IDNO:87、SEQ ID NO:88、SEQ ID NO:108、SEQ ID NO:109、SEQ ID NO:110、SEQ ID NO:165、SEQ ID NO:166、SEQ ID NO:167、SEQ ID NO:176、SEQ ID NO:178和SEQ ID NO:192的氨基酸序列的多肽。
32.一种向患者施用双特异性抗体构建体的方法，该方法包括：
a)在容器中制备水性药物组合物，其中该水性药物组合物包含浓度介于约0.001μg/ml与约100μg/ml之间的该双特异性抗体构建体以及浓度为表面活性剂的CMC的至少约0.25倍的该表面活性剂，以及
b)向该患者施用该水性药物组合物，
其中该双特异性抗体构建体包含具有选自SEQ ID NO:11、SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:66、SEQ IDNO:67、SEQ ID NO:76、SEQ ID NO:78、SEQ ID NO:87、SEQ ID NO:88、SEQ ID NO:108、SEQID NO:109、SEQ ID NO:110、SEQ ID NO:165、SEQ ID NO:166、SEQ ID NO:167、SEQ ID NO:176、SEQ ID NO:178和SEQ ID NO:192的氨基酸序列的多肽。
33.如权利要求32所述的方法，其中该水性药物组合物包含浓度介于约0.001μg/ml与约50μg/ml之间的该双特异性抗体构建体。
34.如权利要求32或33所述的方法，其中该水性药物组合物包含浓度介于该表面活性剂的该CMC的约0.25倍与约20倍之间、或介于该CMC的约0.25倍与约10倍之间的该表面活性剂。
35.如权利要求32-34中任一项所述的方法，其中该表面活性剂是聚山梨醇酯80、聚山梨醇酯60、聚山梨醇酯40、聚山梨醇酯20、泊洛沙姆188、泊洛沙姆407或曲拉通X-100。
36.如权利要求32-35中任一项所述的方法，其中该水性药物组合物进一步包含选自盐、缓冲剂、氨基酸、糖类和防腐剂中的一种或多种。
37.如权利要求32-36中任一项所述的方法，其中该水性药物组合物具有介于约4.2与约7.0之间的pH。
38.如权利要求32-37中任一项所述的方法，其中该容器由包含聚烯烃、PVC、EVA或聚氨酯的材料制成。
39.如权利要求32-38中任一项所述的方法，其中该表面活性剂是聚山梨醇酯80、聚山梨醇酯60、聚山梨醇酯40或聚山梨醇酯20，并且其中该容器由包含基本上不含DEHP或TOTM的PVC的材料制成。
40.如权利要求32-39中任一项所述的方法，其中该水性药物组合物通过用合适的水性溶液稀释包含该双特异性抗体构建体的第一组合物来制备。
41.如权利要求40所述的方法，其中该第一组合物是包含该双特异性抗体构建体的液体组合物。
42.如权利要求40所述的方法，其中该第一组合物是由包含该双特异性抗体构建体的冻干组合物重构的液体组合物。
43.如权利要求41-42中任一项所述的方法，其中该合适的溶液包含浓度为该表面活性剂的CMC的至少约0.25倍的该表面活性剂。
44.如权利要求40-43中任一项所述的方法，其中该水性药物组合物通过将该合适的水性溶液添加到该容器中，然后将适当量的该第一组合物添加到该容器中来制备。
45.如权利要求32-44中任一项所述的方法，其中该患者是癌症患者。
46.如权利要求32-45中任一项所述的方法，其中该施用是IV施用。
47.如权利要求25-31中任一项所述的药物制剂，其中该表面活性剂是泊洛沙姆188或泊洛沙姆407。
48.如权利要求19所述的组合物、如权利要求31所述的药物制剂或如权利要求32所述的方法，其中该双特异性抗体构建体包含具有SEQ ID NO:13、SEQ ID NO:15、SEQ ID NO:25、SEQ ID NO:48、SEQ ID NO:67、SEQ ID NO:78、SEQ ID NO:88、SEQ ID NO:109、SEQ IDNO:110、SEQ ID NO:165、SEQ ID NO:166、SEQ ID NO:167、SEQ ID NO:178或SEQ ID NO:192的氨基酸序列的多肽。
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