CN107849148A - 三特异性结合蛋白质及使用方法 - Google Patents
三特异性结合蛋白质及使用方法 Download PDFInfo
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Abstract
本文提供了包含与CD3结合的结构域、半衰期延长结构域和与靶抗原结合的结构域的三特异性抗原结合蛋白质。还提供了其药物组合物,以及用于制备这类三特异性抗原结合蛋白质的核酸、重组表达载体和宿主细胞。还公开了在预防和/或治疗疾病、病况和病症中使用所公开的三特异性抗原结合蛋白质的方法。
Description
交叉引用
本申请要求2016年3月8日提交的美国临时申请号62/305,088、2015年5月22日提交的美国临时申请号62/165,833和2015年5月21日提交的美国临时申请号62/165,153的权益,全部这些申请均通过引用以其全文并入本文。
序列表
本申请包含以ASCII格式电子提交的序列表,并且其通过引用以其全文并入本文。在2016年5月17日创建的所述ASCII副本被命名为47517_701_601_SL.txt,并且大小为128,516字节。
发明背景
在多种临床环境中常常需要选择性破坏单个细胞或特定的细胞类型。例如,癌症疗法的首要目标是特定地破坏肿瘤细胞,同时使健康细胞和组织保持完整且不受损伤。一种这样的方法是诱导针对肿瘤的免疫应答,使得免疫效应细胞如自然杀伤(NK)细胞或细胞毒性T淋巴细胞(CTL)攻击并破坏肿瘤细胞。
发明内容
本文提供了三特异性抗原结合蛋白质,其药物组合物,用于制备这类三特异性抗原结合蛋白质的核酸、重组表达载体和宿主细胞,以及用于治疗疾病、病症或病况的方法。在一方面,本文描述了三特异性抗原结合蛋白质,其中所述蛋白质包含(a)与人CD3特异性结合的第一结构域(A);(b)第二结构域(B),其为半衰期延长结构域;和(c)与靶抗原特异性结合的第三结构域(C),其中所述结构域以H2N-(A)-(B)-(C)-COOH、H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(B)-(C)-(A)-COOH、H2N-(C)-(B)-(A)-COOH或H2N-(C)-(A)-(B)-COOH的顺序通过连接体L1和L2连接。
在某些方面,本文还提供了三特异性抗原结合蛋白质,其中所述蛋白质包含(a)与人CD3特异性结合的第一结构域(A);(b)第二结构域(B),其为半衰期延长结构域;和(c)与靶抗原特异性结合的第三结构域(C),其中所述结构域以H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(C)-(B)-(A)-COOH的顺序或通过连接体L1和L2连接。
在某些方面,本文还提供了三特异性抗原结合蛋白质,其中所述蛋白质包含(a)与人CD3特异性结合的第一结构域(A);(b)第二结构域(B),其为半衰期延长结构域;和(c)与靶抗原特异性结合的第三结构域(C),其中所述结构域以H2N-(A)-(B)-(C)-COOH、H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(B)-(C)-(A)-COOH、H2N-(C)-(B)-(A)-COOH或H2N-(C)-(A)-(B)-COOH的顺序通过连接体L1和L2连接,并且其中所述第一结构域以大于100nM的KD与人CD3结合。
在某些方面,本文还提供了三特异性抗原结合蛋白质,其中所述蛋白质包含(a)与人CD3特异性结合的第一结构域(A);(b)第二结构域(B),其为半衰期延长结构域;和(c)与靶抗原特异性结合的第三结构域(C),其中所述结构域以H2N-(A)-(B)-(C)-COOH、H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(B)-(C)-(A)-COOH、H2N-(C)-(B)-(A)-COOH或H2N-(C)-(A)-(B)-COOH的顺序通过连接体L1和L2连接,并且其中所述蛋白质具有小于55kDa的分子量。
本文还提供了三特异性抗原结合蛋白质,其中所述蛋白质包含(a)与人CD3特异性结合的第一结构域(A);(b)第二结构域(B),其为半衰期延长结构域;和(c)与靶抗原特异性结合的第三结构域(C),其中所述结构域以H2N-(A)-(B)-(C)-COOH、H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(B)-(C)-(A)-COOH、H2N-(C)-(B)-(A)-COOH或H2N-(C)-(A)-(B)-COOH的顺序通过连接体L1和L2连接,并且其中B包含与血清白蛋白结合的单结构域抗体。
本文还单独或组合地提供了三特异性抗原结合蛋白质的多个实施方案,涉及本文的任何方面。在一些实施方案中,第一结构域包含各自能够与人CD3特异性结合的可变轻链和可变重链。在一些实施方案中,该可变轻链为λ(lamda)轻链。在一些实施方案中,该可变轻链为κ(kappa)轻链。在一些实施方案中,第一结构域包含对于人CD3具特异性的单链可变片段(scFv)。在一些实施方案中,第一结构域对于CD3ε(epsilon)具特异性。在一些实施方案中,第一结构域对于CD3δ(delta)具特异性。在一些实施方案中,第一结构域对于CD3γ(gamma)具特异性。在一些实施方案中,第一结构域包含选自莫罗单抗(muromonab)-CD3(OKT3)、奥昔珠单抗(otelixizumab)(TRX4),替利珠单抗(teplizumab)(MGA031),维西珠单抗(visilizumab)(Nuvion)、SP34、X35、VIT3、BMA030(BW264/56)、CLB-T3/3、CRIS7、YTH12.5、F111-409、CLB-T3.4.2、TR-66、WT32、SPv-T3b、11D8、XIII-141、XIII-46、XIII-87、12F6、T3/RW2-8C8、T3/RW2-4B6、OKT3D、M-T301、SMC2、F101.01、UCHT-1和WT-31的互补决定区(CDR)。在一些实施方案中,第一结构域是人源化的或人的。在一些实施方案中,第一结构域与表达CD3的细胞上的CD3结合的KD为1000nM或更低。在一些实施方案中,第一结构域与表达CD3的细胞上的CD3结合的KD为100nM或更低。在一些实施方案中,第一结构域与表达CD3的细胞上的CD3结合的KD为10nM或更低。在一些实施方案中,第一结构域与食蟹猴CD3具有交叉反应性。在一些实施方案中,第一结构域包含本文提供的氨基酸序列。
在一些实施方案中,第二结构域结合人血清白蛋白。在一些实施方案中,第二结构域包含scFv、可变重链(VH)结构域、可变轻链(VL)结构域、单结构域抗体、肽、配体或小分子。在一些实施方案中,第二结构域包含scFv。在一些实施方案中,第二结构域包含VH结构域。在一些实施方案中,第二结构域包含VL结构域。在一些实施方案中,第二结构域包含单结构域抗体。在一些实施方案中,第二结构域包含肽。在一些实施方案中,第二结构域包含配体。在一些实施方案中,第二结构域包含小分子实体。
在一些实施方案中,第三结构域包含与靶抗原特异性结合的scFv、VH结构域、VL结构域、非Ig结构域、配体、knottin或小分子实体。在一些实施方案中,第三结构域对于细胞表面分子具特异性。在一些实施方案中,第三结构域对于肿瘤抗原具特异性。
在一些实施方案中,连接体L1和L2是肽连接体。在一些实施方案中,连接体L1和L2独立地由约20个或更少的氨基酸残基组成。在一些实施方案中,连接体L1和L2各自独立地选自(GS)n(SEQ ID NO:49)、(GGS)n(SEQ ID NO:50)、(GGGS)n(SEQ ID NO:51)、(GGSG)n(SEQ ID NO:52)、(GGSGG)n(SEQ ID NO:53)或(GGGGS)n(SEQ ID NO:54),其中n为1、2、3、4、5、6、7、8、9或10。在一些实施方案中,连接体L1和L2各自独立地为(GGGGS)4(SEQ ID NO:55)或(GGGGS)3(SEQ ID NO:56)。在一些实施方案中,连接体L1和L2是化学连接体。
在一些实施方案中,第一结构域在蛋白质的N-末端。在一些实施方案中,第二结构域在蛋白质的N-末端。在一些实施方案中,第三结构域在蛋白质的N-末端。在一些实施方案中,第一结构域在蛋白质的C-末端。在一些实施方案中,第二结构域在蛋白质的C-末端。在一些实施方案中,第三结构域在蛋白质的C-末端。
在一些实施方案中,所述蛋白质小于约80kDa。在一些实施方案中,该蛋白质为约50kDa至约75kDa。在一些实施方案中,该蛋白质小于约50kDa。在一些实施方案中,该蛋白质小于约40kDa。在一些实施方案中,该蛋白质为约20kDa至约40kDa。在一些实施方案中,该蛋白质具有至少约50小时的消除半衰期。在一些实施方案中,该蛋白质具有至少约100小时的消除半衰期。在一些实施方案中,与IgG相比,该蛋白质对于同一靶抗原具有增加的组织穿透。
在另一方面,本文还提供了编码根据任意一个上述实施方案的三特异性抗原结合蛋白质的多核苷酸。在另一方面,本文提供了包含所述多核苷酸的载体。在另一方面,本文提供了用所述载体转化的宿主细胞。
在另一方面,本文提供了药物组合物,其包含任意一个上述实施方案的三特异性抗原结合蛋白质、编码任意一个上述实施方案的三特异性抗原结合蛋白质的多核苷酸、包含所述多核苷酸的载体或用任意一个上述实施方案的载体转化的宿主细胞,以及药学上可接受的载剂(carrier)。
本文还提供了用于产生根据本文任意一个方面和实施方案的三特异性抗原结合蛋白质的方法,所述方法包括在允许该蛋白质表达的条件下培养用包含编码本文任何三特异性抗原结合蛋白质的核酸序列的载体转化或转染的宿主,以及从培养物中回收和纯化所产生的蛋白质。
本文还提供了用于治疗、改善增生性疾病、肿瘤疾病、炎性疾病、免疫性病症、自身免疫病、传染性疾病、病毒性疾病、变态反应、寄生虫反应、移植物抗宿主病或宿主抗移植物病的方法,其包括向需要这种治疗或改善的受试者施用任意一个上述实施方案的三特异性抗原结合蛋白质。在一些实施方案中,该受试者是人。在一些实施方案中,该方法进一步包括将药剂与本文所述的三特异性抗原结合蛋白质联合施用。
援引并入
本说明书中提及的所有出版物、专利和专利申请通过引用并入本文,其程度如同每个单独的出版物、专利或专利申请被特别地且单独地指出以引用的方式并入。
附图说明
本发明的新颖特征在所附权利要求中具体阐述。通过参考以下对利用了本发明原理的说明性实施方案加以阐述的详细描述及其附图,将会获得对本发明的特征和优点的更好的理解,在附图中:
图1是示例性三特异性抗原结合蛋白质的示意图,其中该蛋白质具有包含抗-CD3ε单链可变片段(scFv)和抗-HSA可变重链区的恒定核心元件;以及可变靶结合域,它可以是VH、scFv、非Ig结合物或配体。
图2是针对最佳组织穿透而构建的附加示例性三特异性抗原结合蛋白质的示意图。图2,左侧,对于其全部结构域均包含单结构域抗体片段的示例性三特异性抗原结合蛋白质。图2,中间,包含与靶抗原结合的knottin的示例性三特异性抗原结合蛋白质。图2,右侧,包含与靶抗原结合的天然配体的示例性三特异性抗原结合蛋白质。
图3是将小分子实体结合物附接至三特异性抗原结合蛋白质的示意图。该三特异性抗原结合蛋白质包含分选酶识别序列作为其靶抗原结合域。在将该蛋白质与分选酶和甘氨酸附接的小分子结合物一起温育后,分选酶将小分子结合物连接或缀合至识别位点上。图中公开了作为SEQ ID NO:60的“LPETGG”和作为SEQ ID NO:57的“LPETG”。
图4是可以排列这些三特异性抗原结合分子的三个结构域的六种不同方式的示意图。
图5比较了BiTE分子(来自Lutterbuese等人2007.PNAS 107:12605–12610的EGFR靶向BiTE,和PSMA靶向BiTE pasotuxizumab)与含有EGFR和PSMA靶向VH结构域的三特异性分子诱导原代人T细胞杀死肿瘤细胞的能力。
图6显示含有EGFR靶向VH结构域的三特异性分子的全部六种可能的构型均可诱导T细胞杀死人肿瘤细胞系NCI-1563。采用EGFR靶向BiTE作为阳性对照,在不存在(左侧)和存在(右侧)人血清白蛋白的情况下进行实验。
图7评估了含有PSMA靶向VH结构域的三特异性分子的五种可能的构型诱导T细胞杀死人肿瘤细胞系22Rv1的能力。采用PSMA靶向BiTE作为阳性对照,在不存在(左侧)和存在(右侧)人血清白蛋白的情况下进行实验。还显示了具有PSMA靶向scFv的PSMA靶向三特异性分子的活性。
图8显示三特异性分子可由包含抗-CD3ε单链可变片段(scFv)和抗-HSA可变重链区的恒定核心元件以及可变靶结合域组成,该可变靶结合域可以是scFv。
图9表明,使用fynomer而不是抗体衍生的结构域进行肿瘤靶向的三特异性分子可诱导T细胞杀死肿瘤细胞。
图10显示当EGFR靶向三特异性分子重新引导T细胞杀死人CaPan2肿瘤细胞时(小图A),T细胞被激活并以依赖于三特异性分子剂量的方式产生细胞因子TNF-α(小图B)和IFNγ(小图C)。
图11显示当PSMA靶向三特异性分子重新引导T细胞杀死人22Rv1肿瘤细胞时(小图A),T细胞被激活并以依赖于三特异性分子剂量的方式产生细胞因子TNF-α(小图B)和IFNγ(小图C)。
图12显示MSLN靶向三特异性分子可比常规抗体更快地迁移通过基质胶(matrigel)。
图13显示在生物素-CD3ε和生物素-HSA上的噬菌体滴定。
发明详述
本文描述了三特异性抗原结合蛋白质,其药物组合物,以及用于制备这类三特异性抗原结合蛋白质的核酸、重组表达载体和宿主细胞。还提供了在预防和/或治疗疾病、病况和病症中使用所公开的三特异性抗原结合蛋白质的方法。所述三特异性抗原结合蛋白质能够特异性结合靶抗原以及CD3和半衰期延长结构域如结合人血清白蛋白(HSA)的结构域。图1描绘了三特异性抗原结合蛋白质的一种非限制性实例。
在一方面,所述三特异性抗原结合蛋白质包含与CD3特异性结合的结构域(A)、与人血清白蛋白(HSA)特异性结合的结构域(B)以及与靶抗原特异性结合的结构域(C)。三特异性抗原结合蛋白质中的这三个结构域以任意顺序排列。因此,考虑到该三特异性抗原结合蛋白质的结构域顺序为:
H2N-(A)-(B)-(C)-COOH、
H2N-(A)-(C)-(B)-COOH、
H2N-(B)-(A)-(C)-COOH、
H2N-(B)-(C)-(A)-COOH、
H2N-(C)-(B)-(A)-COOH或
H2N-(C)-(A)-(B)-COOH。
在一些实施方案中,所述三特异性抗原结合蛋白质具有H2N-(A)-(B)-(C)-COOH的结构域顺序。在一些实施方案中,该三特异性抗原结合蛋白质具有H2N-(A)-(C)-(B)-COOH的结构域顺序。在一些实施方案中,该三特异性抗原结合蛋白质具有H2N-(B)-(A)-(C)-COOH的结构域顺序。在一些实施方案中,该三特异性抗原结合蛋白质具有H2N-(B)-(C)-(A)-COOH的结构域顺序。在一些实施方案中,该三特异性抗原结合蛋白质具有H2N-(C)-(B)-(A)-COOH的结构域顺序。在一些实施方案中,该三特异性抗原结合蛋白质具有H2N-(C)-(A)-(B)-COOH的结构域顺序。
本文所述的三特异性抗原结合蛋白质任选地包含具有表6或表7中所述序列(SEQID NO:1-48)及其子序列的多肽。在一些实施方案中,该三特异性抗原结合蛋白质包含与表6或表7中所述序列(SEQ ID NO:1-48)具有至少70%-95%或更高同源性的多肽。在一些实施方案中,该三特异性抗原结合蛋白质包含与表6或表7中所述序列(SEQ ID NO:1-48)具有至少70%、75%、80%、85%、90%、95%或更高同源性的多肽。在一些实施方案中,该三特异性抗原结合蛋白质具有包含表6或表7中所述序列(SEQ ID NO:1-48)的至少一部分的序列。在一些实施方案中,该三特异性抗原结合蛋白质包含含有表6或表7中所述序列(SEQ IDNO:1-48)中的一个或多个的多肽。
本文所述的三特异性抗原结合蛋白质被设计为允许通过募集细胞毒性T细胞来特异性靶向表达靶抗原的细胞。这与ADCC(抗体依赖性细胞介导的细胞毒性)相比提高了功效,ADCC是利用针对唯一抗原的全长抗体并且不能直接募集细胞毒性T细胞。相反,通过接合在这些细胞上特异性表达的CD3分子,所述三特异性抗原结合蛋白质可使细胞毒性T细胞与表达靶抗原的细胞以高度特异性的方式交联,从而将T细胞的细胞毒性潜能引导至靶细胞。本文所述的三特异性抗原结合蛋白质经由与表面表达的CD3蛋白质结合而接合细胞毒性T细胞,这形成TCR的一部分。几种三特异性抗原结合蛋白质与CD3和特定细胞表面上表达的靶抗原的同时结合引起T细胞活化,并介导特定靶抗原表达细胞的后续裂解。因此,预期三特异性抗原结合蛋白质显示强烈的、特异的和有效的靶细胞杀伤。在一些实施方案中,本文所述的三特异性抗原结合蛋白质刺激细胞毒性T细胞杀死靶细胞以消除致病细胞(例如肿瘤细胞、病毒或细菌感染的细胞、自身反应性T细胞等)。在一些这样的实施方案中,细胞被选择性地消除,从而减小毒副作用的可能性。在其他实施方案中,相同的多肽可以用于增强内源性细胞的消除以达成治疗效果,例如自身免疫病中的B或T淋巴细胞或用于干细胞移植的造血干细胞(HSC)。
本文所述的三特异性抗原结合蛋白质与传统单克隆抗体和其他较小的双特异性分子相比提供进一步的治疗优点。通常,重组蛋白质药物的有效性在很大程度上取决于蛋白质本身的内在药代动力学。一种这样的益处在于,本文所述的三特异性抗原结合蛋白质由于具有半衰期延长结构域,如对于HSA具特异性的结构域,而具有延长的药代动力学消除半衰期。就此而言,在一些实施方案中,本文所述的三特异性抗原结合蛋白质具有约两天、三天、约五天、约七天、约10天、约12天或约14天的延长的血清消除半衰期。这与具有相对短得多的消除半衰期的其他结合蛋白质如BiTE或DART分子形成对照。例如,BiTE CD19×CD3双特异性scFv-scFv融合分子由于其消除半衰期短而需要连续的静脉内输注(i.v.)药物递送。所述三特异性抗原结合蛋白质的较长的内在半衰期解决了这个问题,从而允许增加的治疗潜力,如低剂量药物制剂、减少的定期给药和/或新的药物组合物。
本文所述的三特异性抗原结合蛋白质还具有针对增强的组织穿透和组织分布的最优大小。较大的大小限制或阻止蛋白质在靶组织中的穿透或分布。本文所述的三特异性抗原结合蛋白质通过具有允许增强的组织穿透和分布的小尺寸而避免了这一问题。因此,在一些实施方案中,本文所述的三特异性抗原结合蛋白质具有约50kD至约80kD、约50kD至约75kD、约50kD至约70kD或约50kD至约65kD的大小。因此,所述三特异性抗原结合蛋白质的大小优于约150kD的IgG抗体以及约55kD但半衰期没有延长并因此很快通过肾脏清除的BiTE和DART双抗体(diabody)分子。
在进一步的实施方案中,本文所述的三特异性抗原结合蛋白质具有针对增强的组织穿透和分布的最优大小。在这些实施方案中,三特异性抗原结合蛋白质被构建为尽可能小,同时保留对其靶标的特异性。因此,在这些实施方案中,本文所述的三特异性抗原结合蛋白质具有约20kD至约40kD,或约25kD至约35kD至约40kD、至约45kD、至约50kD、至约55kD、至约60kD、至约65kD的大小。在一些实施方案中,本文所述的三特异性抗原结合蛋白质具有约50kD、49kD、48kD、47kD、46kD、45kD、44kD、43kD、42kD、41kD、40kD、约39kD、约38kD、约37kD、约36kD、约35kD、约34kD、约33kD、约32kD、约31kD、约30kD、约29kD、约28kD、约27kD、约26kD、约25kD、约24kD、约23kD、约22kD、约21kD或约20kD的大小。获得小尺寸的示例性方法是对于每个结构域都利用单结构域抗体(sdAb)片段。例如,特定的三特异性抗原结合蛋白质具有抗-CD3sdAb、抗-HSA sdAb和针对靶抗原的sdAb。这使得示例性三特异性抗原结合蛋白质的大小减小至40kD以下。因此,在一些实施方案中,该三特异性抗原结合蛋白质的结构域都是单结构域抗体(sdAb)片段。在其他实施方案中,本文所述的三特异性抗原结合蛋白质包含针对HSA和/或靶抗原的小分子实体(SME)结合物。SME结合物是大小平均为约500Da至2000Da的小分子,并且通过已知方法如分选酶连接或缀合而附接至三特异性抗原结合蛋白质。在这些实例中,三特异性抗原结合蛋白质的结构域之一为分选酶识别序列,例如,LPETG(SEQ ID NO:57)。为了将SME结合物附接至具有分选酶识别序列的三特异性抗原结合蛋白质,将该蛋白质与分选酶和SME结合物一起温育,从而分选酶将SME结合物附接至该识别序列。已知的SME结合物包括与前列腺特异性膜抗原(PSMA)结合的MIP-1072和MIP-1095。在其他实施方案中,本文所述三特异性抗原结合蛋白质的与靶抗原结合的结构域包含用于结合靶抗原的knottin肽。Knottin为具有半胱氨酸结支架(knot scaffold)的二硫键稳定化的肽,并且具有约3.5kD的平均大小。已预期Knottin与某些肿瘤分子如纤连蛋白和VEGF受体结合。在进一步的实施方案中,本文所述三特异性抗原结合蛋白质的与靶抗原结合的结构域包含天然受体配体,如B细胞活化因子(BAFF/BLyS)。
本文所述的三特异性抗原结合蛋白质的另一个特征是它们为具有其结构域的柔性连接的单多肽设计。这允许容易地生产和制备三特异性抗原结合蛋白质,因为它们可以由易于引入载体中的单个cDNA分子编码。另外,由于本文所述的三特异性抗原结合蛋白质为单体单多肽链,因此不存在链配对问题或不需要二聚化。考虑到本文所述的三特异性抗原结合蛋白质聚集的趋势减小,不同于其他报道的分子,如具有Fc-γ免疫球蛋白结构域的双特异性蛋白质。
在本文所述的三特异性抗原结合蛋白质中,结构域通过内部连接体L1和L2连接,其中L1连接该三特异性抗原结合蛋白质的第一和第二结构域,并且L2连接该三特异性抗原结合蛋白质的第二和第三结构域。连接体L1和L2具有优化的长度和/或氨基酸组成。在一些实施方案中,连接体L1和L2具有相同的长度和氨基酸组成。在其他实施方案中,L1和L2不同。在某些实施方案中,内部连接体L1和/或L2是“短的”,即,由0、1、2、3、4、5、6、7、8、9、10、11个或12个氨基残基组成。因此,在某些实例中,内部连接体由约12个或更少的氨基酸残基组成。在0个氨基酸残基的情况下,内部连接体为肽键。在某些实施方案中,内部连接体L1和/或L2是“长的”,即,由15、20个或25个氨基残基组成。在一些实施方案中,这些内部连接体由约3个至约15个,例如8、9或10个连续氨基酸残基组成。关于内部连接体L1和L2的氨基酸组成,选择具有以下性质的肽,即,能赋予该三特异性抗原结合蛋白质柔性,不干扰结合域,以及抵抗蛋白酶切割。例如,甘氨酸和丝氨酸残基通常提供蛋白酶抗性。适合于连接三特异性抗原结合蛋白质中的结构域的内部连接体的实例包括但不限于(GS)n(SEQ ID NO:49)、(GGS)n(SEQ ID NO:50)、(GGGS)n(SEQ ID NO:51)、(GGSG)n(SEQ ID NO:52)、(GGSGG)n(SEQ ID NO:53)或(GGGGS)n(SEQ ID NO:54),其中n为1、2、3、4、5、6、7、8、9或10。在一个实施方案中,内部连接体L1和/或L2为(GGGGS)4(SEQ ID NO:55)或(GGGGS)3(SEQ ID NO:56)。CD3结合域
T细胞反应的特异性由TCR对抗原(在主要组织相容性复合物MHC的背景下展示)的识别来介导。作为TCR的一部分,CD3是包含CD3γ(gamma)链、CD3δ(delta)链和存在于细胞表面的两条CD3ε(epsilon)链的蛋白质复合物。CD3与TCR的α(alpha)和β(beta)链以及CD3ζ(zeta)缔合在一起,以包含完整的TCR。T细胞上CD3如通过固定化抗-CD3抗体进行的簇集,导致与T细胞受体的接合类似但与其克隆典型的特异性无关的T细胞活化。
在一方面,本文所述的三特异性抗原结合蛋白质包含与CD3特异性结合的结构域。在一方面,本文所述的三特异性抗原结合蛋白质包含与人CD3特异性结合的结构域。在一些实施方案中,本文所述的三特异性抗原结合蛋白质包含与CD3γ特异性结合的结构域。在一些实施方案中,本文所述的三特异性抗原结合蛋白质包含与CD3δ特异性结合的结构域。在一些实施方案中,本文所述的三特异性抗原结合蛋白质包含与CD3ε特异性结合的结构域。
在进一步的实施方案中,本文所述的三特异性抗原结合蛋白质包含与TCR特异性结合的结构域。在某些实例中,本文所述的三特异性抗原结合蛋白质包含特异性结合TCR的α链的结构域。在某些实例中,本文所述的三特异性抗原结合蛋白质包含特异性结合TCR的β链的结构域。
在某些实施方案中,本文所述的三特异性抗原结合蛋白质的CD3结合域不仅表现出对于人CD3的有效的CD3结合亲和力,而且还显示出与各自的食蟹猴CD3蛋白质的优异的交叉反应性。在一些实例中,三特异性抗原结合蛋白质的CD3结合域与来自食蟹猴的CD3交叉反应。在某些实例中,CD3的人:食蟹猴KD比例为5至0.2。
在一些实施方案中,三特异性抗原结合蛋白质的CD3结合域可以是与CD3结合的任何结构域,其包括但不限于来自单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体的结构域。在一些实例中,CD3结合域来源于最终该三特异性抗原结合蛋白质所用于的相同物种是有益的。例如,对于用于人类来说,三特异性抗原结合蛋白质的CD3结合域包含来自抗体或抗体片段的抗原结合域的人或人源化残基可能是有益的。
因此,在一方面,抗原结合域包含人源化或人抗体或抗体片段或鼠抗体或抗体片段。在一个实施方案中,人源化或人抗-CD3结合域包含本文所述的人源化或人抗-CD3结合域的轻链互补决定区1(LC CDR1)、轻链互补决定区2(LC CDR2)和轻链互补决定区3(LCCDR3)中的一个或多个(例如,全部三个),和/或本文所述的人源化或人抗-CD3结合域的重链互补决定区1(HC CDR1)、重链互补决定区2(HC CDR2)和重链互补决定区3(HC CDR3)中的一个或多个(例如,全部三个),例如,人源化或人抗-CD3结合域包含一个或多个,例如,全部三个LC CDR,以及一个或多个,例如,全部三个HC CDR。
在一些实施方案中,人源化或人抗-CD3结合域包含对于CD3具特异性的人源化或人轻链可变区,其中对于CD3具特异性的轻链可变区包含人轻链框架区中的人或非人轻链CDR。在某些实例中,该轻链框架区为λ(lamda)轻链框架。在其他实例中,该轻链框架区为κ(kappa)轻链框架。
在一些实施方案中,人源化或人抗-CD3结合域包含对于CD3具特异性的人源化或人重链可变区,其中对于CD3具特异性的重链可变区包含人重链框架区中的人或非人重链CDR。
在某些实例中,重链和/或轻链的互补决定区来源于已知的抗-CD3抗体,例如,莫罗单抗-CD3(OKT3)、奥昔珠单抗(TRX4)、替利珠单抗(MGA031)、维西珠单抗(Nuvion)、SP34、TR-66或X35-3、VIT3、BMA030(BW264/56)、CLB-T3/3、CRIS7、YTH12.5、F111-409、CLB-T3.4.2、TR-66、WT32、SPv-T3b、11D8、XIII-141、XIII-46、XIII-87、12F6、T3/RW2-8C8、T3/RW2-4B6、OKT3D、M-T301、SMC2、F101.01、UCHT-1和WT-31。
在一个实施方案中,抗-CD3结合域为包含本文提供的氨基酸序列的轻链和重链的单链可变片段(scFv)。如本文所用,“单链可变片段”或“scFv”是指包含轻链可变区的抗体片段和至少一个包含重链可变区的抗体片段,其中轻链和重链可变区经由短的柔性多肽连接体连续连接,并且能够表达为单多肽链,并且其中该scFv保留作为其来源的完整抗体的特异性。在一个实施方案中,抗-CD3结合域包含:轻链可变区,其包含具有本文提供的轻链可变区的氨基酸序列的至少一个、两个或三个修饰(例如,置换)但不超过30、20或10个修饰(例如,置换)的氨基酸序列,或与本文提供的氨基酸序列具有95%-99%同一性的序列;和/或重链可变区,其包含具有本文提供的重链可变区的氨基酸序列的至少一个、两个或三个修饰(例如,置换)但不超过30、20或10个修饰(例如,置换)的氨基酸序列,或与本文提供的氨基酸序列具有95%-99%同一性的序列。在一个实施方案中,人源化或人抗-CD3结合域为scFv,并且包含本文所述氨基酸序列的轻链可变区经由scFv连接体附接至包含本文所述氨基酸序列的重链可变区。scFv的轻链可变区和重链可变区可以是例如以下取向中的任何一种:轻链可变区-scFv连接体-重链可变区或重链可变区-scFv连接体-轻链可变区。
在一些实例中,根据已知方法制备与CD3结合的scFv。例如,可通过利用柔性多肽连接体使VH和VL区连接在一起来产生scFv分子。scFv分子包含具有优化长度和/或氨基酸组成的scFv连接体(例如,Ser-Gly连接体)。因此,在一些实施方案中,scFv连接体的长度使得VH或VL结构域可以与其他可变结构域进行分子间缔合,从而形成CD3结合位点。在某些实施方案中,这样的scFv连接体是“短的”,即,由0、1、2、3、4、5、6、7、8、9、10、11个或12个氨基残基组成。因此,在某些实例中,scFv连接体由约12个或更少的氨基酸残基组成。在0个氨基酸残基的情况下,scFv连接体为肽键。在一些实施方案中,这些scFv连接体由约3个至约15个,例如8、9或10个连续氨基酸残基组成。关于scFv连接体的氨基酸组成,选择能赋予柔性,不干扰可变结构域以及允许链间折叠以使两个可变结构域一起形成功能性CD3结合位点的肽。例如,包含甘氨酸和丝氨酸残基的scFv连接体通常提供蛋白酶抗性。在一些实施方案中,scFv中的连接体包含甘氨酸和丝氨酸残基。scFv连接体的氨基酸序列可通过例如噬菌体展示法进行优化,以提高scFv的CD3结合和产率。适合于连接scFv中可变轻链结构域和可变重链结构域的肽scFv连接体的实例包括但不限于(GS)n(SEQ ID NO:49)、(GGS)n(SEQ IDNO:50)、(GGGS)n(SEQ ID NO:51)、(GGSG)n(SEQ ID NO:52)、(GGSGG)n(SEQ ID NO:53)或(GGGGS)n(SEQ ID NO:54),其中n为1、2、3、4、5、6、7、8、9或10。在一个实施方案中,scFv连接体可以为(GGGGS)4(SEQ ID NO:55)或(GGGGS)3(SEQ ID NO:56)。连接体长度的变化可以保持或增强活性,从而在活性研究中产生优异的功效。
在一些实施方案中,三特异性抗原结合蛋白质的CD3结合域对表达CD3的细胞上的CD3具有亲和力,其KD为1000nM或更低、500nM或更低、200nM或更低、100nM或更低、80nM或更低、50nM或更低、20nM或更低、10nM或更低、5nM或更低、1nM或更低或0.5nM或更低。在一些实施方案中,三特异性抗原结合蛋白质的CD3结合域对CD3ε、γ或δ具KD为1000nM或更低、500nM或更低、200nM或更低、100nM或更低、80nM或更低、50nM或更低、20nM或更低、10nM或更低、5nM或更低、1nM或更低或0.5nM或更低的亲和力。在进一步的实施方案中,三特异性抗原结合蛋白质的CD3结合域对CD3具有低亲和力,即,约100nM或更高。
与CD3结合的亲和力可通过例如三特异性抗原结合蛋白质自身或其CD3结合域与测定板上涂覆的、微生物细胞表面上展示的、溶液中的、或其它的CD3结合的能力来测定。本公开内容的三特异性抗原结合蛋白质自身或其CD3结构域与CD3的结合活性可如下测定:将配体(例如,CD3)或三特异性抗原结合蛋白质自身或其CD3结合域固定至珠子、基底、细胞等。可将试剂加入合适的缓冲液中并将结合配偶体在给定的温度下温育一段时间。洗涤以去除未结合的物质后,可采用例如SDS、高pH缓冲液等释放结合的蛋白质,并通过例如表面等离子体共振(SPR)进行分析。
半衰期延长结构域
本文考虑到延长抗原结合域的半衰期的结构域。预期这样的结构域包括但不限于HSA结合域、Fc结构域、小分子和本领域已知的其他半衰期延长结构域。
人血清白蛋白(HSA)(分子量为约67kDa)是血浆中最丰富的蛋白质,以约50mg/ml(600μM)存在,并且在人体中具有大约20天的半衰期。HSA用来维持血浆pH,促成胶体血压,用作许多代谢物和脂肪酸的载剂,并且充当血浆中主要的药物转运蛋白质。
与白蛋白的非共价缔合延长短寿命蛋白质的消除半衰期。例如,与仅施用Fab片段相比,当分别静脉内施用于小鼠和兔时,白蛋白结合域与Fab片段的重组融合导致25倍至58倍的体内清除和26倍至37倍的半衰期延长。在另一个实例中,当胰岛素被脂肪酸酰化以促进与白蛋白的缔合时,在兔或猪中皮下注射时观察到长效作用。总之,这些研究证明了白蛋白结合与延长的作用之间的联系。
在一方面,本文所述的三特异性抗原结合蛋白质包含半衰期延长结构域,例如与HSA特异性结合的结构域。在一些实施方案中,三特异性抗原结合蛋白质的HSA结合域可以是与HSA结合的任何结构域,其包括但不限于来自单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体的结构域。在一些实施方案中,该HSA结合域为对于HSA具特异性的单链可变片段(scFv),单结构域抗体如重链可变结构域(VH)、轻链可变结构域(VL)和骆驼科衍生的单结构域抗体的可变结构域(VHH),肽、配体或小分子实体。在某些实施方案中,该HSA结合域为单结构域抗体。在其他实施方案中,该HSA结合域为肽。在进一步的实施方案中,该HSA结合域为小分子。在一些实施方案中,考虑到三特异性抗原结合蛋白质的HSA结合域相当小并且不大于25kD、不大于20kD、不大于15kD或不大于10kD。在某些实例中,该HSA结合域如果是肽或小分子实体,则为5kD或更小。
三特异性抗原结合蛋白质的半衰期延长结构域提供三特异性抗原结合蛋白质自身的改变的药效学和药代动力学。如上所述,半衰期延长结构域延长消除半衰期。半衰期延长结构域还改变药效学性质,包括三特异性抗原结合蛋白质的组织分布、穿透和扩散的改变。在一些实施方案中,半衰期延长结构域提供了与不具有半衰期延长结构域的蛋白质相比改善的组织(包括肿瘤)靶向、组织分布、组织穿透、组织内扩散以及增强的功效。在一个实施方案中,治疗方法有效且高效地利用减少量的三特异性抗原结合蛋白质,从而导致副作用减小,如非肿瘤细胞毒性减小。
此外,可选择半衰期延长结构域的结合亲和力,以便针对特定三特异性抗原结合蛋白质中的特定消除半衰期。因此,在一些实施方案中,半衰期延长结构域具有高结合亲和力。在其他实施方案中,半衰期延长结构域具有中等结合亲和力。在其他实施方案中,半衰期延长结构域具有低或微小的结合亲和力。示例性结合亲和力包括10nM或更低(高)、10nM至100nM(中等)和大于100nM(低)的KD浓度。如上所述,通过已知方法如表面等离子体共振(SPR)测定与HSA的结合亲和力。
靶抗原结合域
除了所述CD3以及半衰期延长结构域之外,本文所述的三特异性抗原结合蛋白质还包含与靶抗原结合的结构域。靶抗原参与和/或与疾病、病症或病况有关。特别地,靶抗原与增生性疾病、肿瘤疾病、炎性疾病、免疫性病症、自身免疫病、传染性疾病、病毒性疾病、变态反应、寄生虫反应、移植物抗宿主病或宿主抗移植物病有关。在一些实施方案中,靶抗原是肿瘤细胞上表达的肿瘤抗原。或者,在一些实施方案中,靶抗原与病原体如病毒或细菌有关。
在一些实施方案中,靶抗原是细胞表面分子,如蛋白质、脂质或多糖。在一些实施方案中,靶抗原在肿瘤细胞、病毒感染的细胞、细菌感染的细胞、受损红细胞、动脉斑块细胞或纤维化组织细胞上。
本文所述的三特异性抗原结合蛋白质的设计允许靶抗原的结合域具有灵活性,因为靶抗原的结合域可以是任何类型的结合域,其包括但不限于来自单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体的结构域。在一些实施方案中,靶抗原的结合域为单链可变片段(scFv)、单结构域抗体如重链可变结构域(VH)、轻链可变结构域(VL)和骆驼科衍生的单结构域抗体的可变结构域(VHH)。在其他实施方案中,靶抗原的结合域为非Ig结合域,即,抗体模拟物,如anticalins、affilins、affibody分子、affimers、affitins、alphabodies、avimers、DARPins、fynomers、kunitz结构域肽和单抗体(monobodies)。在进一步的实施方案中,靶抗原的结合域为与靶抗原结合或缔合的配体或肽。在进一步的实施方案中,靶抗原的结合域为knottin。在进一步的实施方案中,靶抗原的结合域为小分子实体。
三特异性蛋白质修饰
本文所述的三特异性抗原结合蛋白质包括衍生物或类似物,其中(i)氨基酸被不是由遗传密码编码的氨基酸残基置换,(ii)成熟多肽与另一化合物如聚乙二醇融合,或(iii)附加的氨基酸与该蛋白质融合,如前导序列或分泌序列或用于纯化蛋白质的序列。
典型的修饰包括但不限于乙酰化、酰化、ADP-核糖基化、酰胺化、黄素的共价附接、血红素部分的共价附接、核苷酸或核苷酸衍生物的共价附接、脂质或脂质衍生物的共价附接、磷脂酰肌醇的共价附接、交联、环化、二硫键形成、脱甲基化、共价交联的形成、胱氨酸的形成、焦谷氨酸的形成、甲酰化、γ羧化、糖基化、GPI锚形成、羟基化、碘化、甲基化、肉豆蔻酰化、氧化、蛋白水解加工、磷酸化、异戊二烯化、外消旋化、硒化、硫酸化、转移RNA介导的氨基酸向蛋白质的添加,如精氨酰化和泛素化。
在本文所述的三特异性抗原结合蛋白质中的任何位置进行修饰,所述位置包括肽骨架、氨基酸侧链和氨基或羧基末端。可用于修饰三特异性抗原结合蛋白质的某些常见肽修饰包括糖基化、脂质附接、硫酸化、谷氨酸残基的γ-羧化、羟基化、多肽中的氨基或羧基或两者被共价修饰的阻断,以及ADP-核糖基化。
编码三特异性抗原结合蛋白质的多核苷酸
在一些实施方案中,还提供了编码本文所述三特异性抗原结合蛋白质的多核苷酸分子。在一些实施方案中,该多核苷酸分子以DNA构建体的形式提供。在其他实施方案中,该多核苷酸分子以信使RNA转录物的形式提供。
通过已知方法构建多核苷酸分子,例如通过将编码由肽连接体隔开,或在其他实施方案中通过肽键直接连接的三个结合域的基因合并为单个基因构建体,该单个基因构建体与合适的启动子以及任选合适的转录终止子可操作地连接,并且将其在细菌或其他合适的表达系统例如CHO细胞中表达。在靶抗原结合域为小分子的实施方案中,多核苷酸含有编码CD3结合域和半衰期延长结构域的基因。在半衰期延长结构域为小分子的实施方案中,多核苷酸含有编码与CD3和靶抗原结合的结构域的基因。根据所利用的载体系统和宿主,可使用任何数目的合适的转录和翻译元件,包括组成型和诱导型启动子。选择启动子使得其驱动多核苷酸在相应宿主细胞中的表达。
在一些实施方案中,将多核苷酸插入载体中,优选表达载体中,这代表进一步的实施方案。该重组载体可根据已知方法来构建。特别感兴趣的载体包括质粒、噬菌粒、噬菌体衍生物、病毒(virii)(例如,逆转录病毒、腺病毒、腺伴随病毒、疱疹病毒、慢病毒等)和粘粒。
可利用多种表达载体/宿主系统,以包含并表达编码所述三特异性抗原结合蛋白质的多肽的多核苷酸。用于在大肠杆菌(E.coli)中表达的表达载体的实例为pSKK(Le Gall等人,J Immunol Methods.(2004)285(1):111-27),或pcDNA5(Invitrogen)用于在哺乳动物细胞中表达。
因此,在一些实施方案中,如本文所述的三特异性抗原结合蛋白质通过以下步骤产生,将编码如上所述蛋白质的载体引入宿主细胞中,并在允许蛋白质结构域表达的条件下培养所述宿主细胞,可将其分离并任选地进一步纯化。
药物组合物
在一些实施方案中,还提供了药物组合物,其包含本文所述的三特异性抗原结合蛋白质、包含编码三特异性抗原结合蛋白质的多肽的多核苷酸的载体或被该载体转化的宿主细胞,以及至少一种药学上可接受的载剂。术语“药学上可接受的载剂”包括但不限于不干扰成分的生物活性的有效性且对施用的患者无毒的任何载剂。合适的药物载剂的实例是本领域公知的,且包括磷酸盐缓冲盐水溶液、水、乳液如油/水乳液、各种类型的润湿剂、无菌溶液等。这样的载剂可以通过常规方法配制,并且可以以合适的剂量施用于受试者。优选地,该组合物是无菌的。这些组合物还可以含有佐剂如防腐剂、乳化剂和分散剂。可通过包含多种抗细菌剂和抗真菌剂来确保阻止微生物的作用。
在药物组合物的一些实施方案中,本文所述的三特异性抗原结合蛋白质被包封在纳米颗粒中。在一些实施方案中,该纳米颗粒是富勒烯、液晶、脂质体、量子点、超顺磁纳米颗粒、树状聚体或纳米棒。在药物组合物的其他实施方案中,将三特异性抗原结合蛋白质附接至脂质体。在一些实例中,三特异性抗原结合蛋白质与脂质体表面缀合。在一些实例中,三特异性抗原结合蛋白质被包封在脂质体的壳内。在一些实例中,该脂质体为阳离子脂质体。
本文所述的三特异性抗原结合蛋白质被考虑用作药物。施用通过不同方式实现,例如,通过静脉内、腹膜内、皮下、肌肉内、局部或真皮内施用。在一些实施方案中,施用途径取决于疗法的种类和药物组合物中包含的化合物的种类。给药方案将由主治医师并根据其他临床因素来确定。对于任何一名患者的剂量依赖于许多因素,包括患者体型、体表面积、年龄、性别、待施用的具体化合物、施用的时间和途径、疗法的种类、总体健康和其他同时施用的药物。“有效剂量”是指活性成分的量,该量足以影响疾病的过程和严重程度,从而导致这种病理学的减轻或缓解,并且可利用已知方法来确定。
治疗方法
在一些实施方案中,本文还提供了用于刺激有需要的个体的免疫系统的方法和用途,其包括施用本文所述的三特异性抗原结合蛋白质。在一些实例中,本文所述三特异性抗原结合蛋白质的施用诱导和/或保持对表达靶抗原的细胞的细胞毒性。在一些实例中,表达靶抗原的细胞是癌细胞或肿瘤细胞、病毒感染的细胞、细菌感染的细胞、自身反应性T或B细胞、受损红细胞、动脉斑块或纤维化组织。
本文还提供了用于治疗与靶抗原有关的疾病、病症或病况的方法和用途,其包括向有需要的个体施用本文所述的三特异性抗原结合蛋白质。与靶抗原有关的疾病、病症或病况包括但不限于病毒感染、细菌感染、自身免疫病、移植排斥、动脉粥样硬化或纤维化。在其他实施方案中,与靶抗原有关的疾病、病症或病况为增生性疾病、肿瘤疾病、炎性疾病、免疫性病症、自身免疫病、传染性疾病、病毒性疾病、变态反应、寄生虫反应、移植物抗宿主病或宿主抗移植物病。在一个实施方案中,与靶抗原有关的疾病、病症或病况为癌症。在一个实例中,该癌症为血液系统癌症。在另一个实例中,该癌症为实体瘤癌症。
在一些实施方案中,如本文所用,“治疗”或“处理”是指治疗性处理,其中目的是减缓(减轻)不期望的生理病况、病症或疾病,或是获得有益或期望的临床结果。为了本文所述的目的,有益或期望的临床结果包括但不限于症状的减轻;病况、病症或疾病程度的减小;病况、病症或疾病状态的稳定(即不恶化);病况、病症或疾病的延迟发作或进展减缓;病况、病症或疾病状态的改善;以及缓解(无论是部分还是全部),无论是可检测的还是不可检测的,或者病况、病症或疾病的增强或改善。治疗包括引发临床上显著的反应,而没有过多的副作用。治疗还包括与不接受治疗的情况下预期的生存期相比延长生存期。在其他实施方案中,“治疗”或“处理”是指预防性措施,其中目的是例如在易患疾病的人(例如,携带疾病如乳腺癌的遗传标志物的个体)中,延迟不期望的生理病况、病症或疾病的发作或减小其严重程度。
在本文所述的方法的一些实施方案中,三特异性抗原结合蛋白质与用于治疗特定疾病、病症或病况的药剂联合施用。药剂包括但不限于涉及抗体、小分子(例如,化疗药物)、激素(甾体、肽等)的疗法、放射疗法(γ射线、X射线和/或放射性同位素的定向递送、微波、UV辐射等)、基因疗法(例如,反义,逆转录病毒疗法等)和其他免疫疗法。在一些实施方案中,三特异性抗原结合蛋白质与止泻剂、止吐剂、镇痛药、阿片类药物和/或非甾体抗炎剂联合施用。在一些实施方案中,三特异性抗原结合蛋白质在手术之前、期间或之后施用。
某些定义
如本文所用,“消除半衰期”以其普通含义使用,如Goodman和Gillman的ThePharmaceutical Basis of Therapeutics 21-25(Alfred Goodman Gilman,LouisS.Goodman,and Alfred Gilman,编著,第6版1980)中所述。简而言之,该术语意在包括药物消除的时间过程的定量量度。大多数药物的消除是指数式的(即,遵循一级动力学),因为药物浓度通常不接近消除过程的饱和所需的药物浓度。指数过程的速率可以用其速率常数k来表示,速率常数k表示每单位时间内的分数变化,或者用其半衰期t1/2来表示,半衰期t1/2是完成过程的50%所需的时间。这两个常量的单位分别是时间-1和时间。该反应的一阶速率常数和半衰期是简单相关的(k×t1/2=0.693),并且可以相应地互换。由于一级消除动力学规定每单位时间内损失恒定分数的药物,因此在初始分配阶段后(即在药物吸收和分配完成之后),药物浓度对数对时间的曲线在任何时候都是线性的。从这样的曲线图可以准确地确定药物消除的半衰期。
实施例
实施例1:针对CD20的示例性三特异性抗原结合蛋白质的构建
scFv CD3结合域的生成
人CD3ε链规范序列是Uniprot登录号P07766。人CD3γ链规范序列是Uniprot登录号P09693。人CD3δ链规范序列是Uniprot登录号043234。抗CD3ε、CD3γ或CD3δ的抗体通过已知技术如亲和力成熟来产生。当使用鼠抗-CD3抗体作为起始材料时,对于临床环境来说需要鼠抗-CD3抗体的人源化,其中小鼠特异性残基可以在接受本文所述的三特异性抗原结合蛋白质治疗的受试者中诱导人抗小鼠抗原(HAMA)反应。通过将来自鼠抗-CD3抗体的CDR区移植到合适的人种系受体框架上,任选包括对CDR和/或框架区的其他修饰来完成人源化。如本文所提供的,抗体和抗体片段残基编号遵循Kabat(Kabat E.A.等人,1991;Chothia等人,1987)。
因此,人或人源化的抗-CD3抗体用于产生针对三特异性抗原结合蛋白质的CD3结合域的scFv序列。获得编码人或人源化VL和VH结构域的DNA序列,并且任选地优化构建体的密码子以供在来自智人(Homo sapiens)的细胞中表达。VL和VH结构域在scFv中出现的顺序是不同的(即,VL-VH或VH-VL取向),并且“G4S”(SEQ ID NO:58)或“G4S”(SEQ ID NO:58)亚单位(G4S)3(SEQ ID NO:56)的三个拷贝连接可变结构域以产生scFv结构域。抗-CD3scFv质粒构建体可具有可选的Flag、His或其他亲和标签,并且电穿孔到HEK293或其他合适的人或哺乳动物细胞系中并纯化。验证测定包括通过FACS的结合分析、使用Proteon的动力学分析和表达CD3的细胞的染色。
scFv CD20结合域的产生
CD20是存在于B淋巴细胞上的细胞表面蛋白质之一。CD20抗原发现于正常和恶性前B和成熟B淋巴细胞中,包括超过90%的B细胞非霍奇金淋巴瘤(NHL)中的那些。在造血干细胞、活化的B淋巴细胞(浆细胞)和正常组织中不存在该抗原。因此,已经描述了几种主要来自鼠源的抗体:1F5、2B8/C2B8、2H7和1H4。
与上述产生针对CD3的scFv结合域的方法类似地产生针对CD20的scFv结合域。
编码三特异性抗原结合蛋白质的DNA表达构建体的克隆
所述抗-CD3scFv结构域用于与抗-CD20scFv结构域和HSA结合域(例如肽或VH结构域)组合构建三特异性抗原结合蛋白质,这些结构域如图1所示布置(organize)。为了在CHO细胞中表达三特异性抗原结合蛋白质,将所有蛋白质结构域的编码序列克隆到哺乳动物表达载体系统中。简而言之,分别合成并亚克隆编码CD3结合域、HSA结合域和CD20结合域以及肽连接体L1和L2的基因序列。然后将得到的构建体以“CD20结合域-L1-CD3结合域-L2-HSA结合域”的顺序连接在一起以产生最终构建体。所有表达构建体都被设计成含有N-末端信号肽和C-末端六组氨酸(6xHis)标签(SEQ ID NO:59)的编码序列,以分别促进蛋白质分泌和纯化。
三特异性抗原结合蛋白质在稳定转染的CHO细胞中的表达
使用CHO细胞表达系统(Life Technologies),即CHO-K1中国仓鼠卵巢细胞(ATCC,CCL-61)的衍生物(Kao和Puck,Proc.Natl.Acad Sci USA 1968;60(4):1275-81)。根据Life Technologies提供的标准细胞培养方案对粘附细胞进行传代培养。
为了适应悬浮生长,使细胞从组织培养瓶上脱壁并置于无血清培养基中。将适应悬浮的细胞在含有10%DMSO的培养基中冷冻保存。
通过转染适应悬浮的细胞,产生稳定表达分泌的三特异性抗原结合蛋白质的重组CHO细胞系。在使用抗生素潮霉素B进行选择期间,每周两次测量活细胞密度,并将细胞离心并以0.1x106个活细胞/mL的最大密度重悬于新鲜的选择培养基中。在选择2-3周后回收稳定表达三特异性抗原结合蛋白质的细胞池,此时将细胞转移到摇瓶中的标准培养基中。通过进行蛋白质凝胶电泳或流式细胞术来确认重组分泌蛋白质的表达。将稳定的细胞池在含有DMSO的培养基中冷冻保存。
在稳定转染的CHO细胞系的10天补料分批培养中,通过分泌到细胞培养上清液中产生三特异性抗原结合蛋白质。在10天后培养物活力通常>75%时收获细胞培养上清液。每隔一天从生产培养物中收集样品,并评估细胞密度和活力。在收获当天,细胞培养上清液在进一步使用前通过离心和真空过滤进行澄清。
通过SDS-PAGE分析细胞培养上清液中的蛋白质表达效价和产物完整性。
三特异性抗原结合蛋白质的纯化
三特异性抗原结合蛋白质以两步程序从CHO细胞培养上清液中纯化。在第一步中对构建体进行亲和色谱法,随后在第二步中在Superdex200上进行制备型大小排阻色谱法(SEC)。对样品进行缓冲液更换并通过超滤浓缩至>1mg/mL的典型浓度。最终样品的纯度和均一性(通常>90%)通过还原和非还原条件下的SDS PAGE进行评估,然后分别进行使用抗-HSA或抗独特型抗体的免疫印迹法以及分析型SEC。将纯化的蛋白质以等分试样在-80℃下储存直至使用。
实施例2:通过流式细胞术对抗原亲和力的测定
测定实施例1的三特异性抗原结合蛋白质对人CD3+和CD20+细胞以及食蟹猴CD3+和CD20+细胞的结合亲和力。
将CD3+和CD20+细胞与100μL连续稀释的实施例1三特异性抗原结合蛋白质一起温育。用FACS缓冲液洗涤三次后,将细胞与0.1mL的10μg/mL小鼠单克隆抗独特型抗体在相同缓冲液中在冰上一起温育45分钟。在第二次洗涤循环之后,在与之前相同的条件下,将细胞与0.1mL的15μg/mL FITC缀合的山羊抗小鼠IgG抗体一起温育。作为对照,将细胞与抗-HisIgG一起温育,继以不含所述三特异性抗原结合蛋白质的FITC缀合的山羊抗小鼠IgG抗体。然后再次洗涤细胞并将其重悬于含有2μg/mL碘化丙锭(PI)的0.2mL FACS缓冲液中以排除死细胞。使用采用MXP软件的Beckman-Coulter FC500MPL流式细胞仪(Beckman-Coulter,Krefeld,德国)或使用采用Incyte软件的Millipore Guava EasyCyte流式细胞仪(MerckMillipore,Schwalbach,德国)测量1x104个活细胞的荧光。使用CXP软件(Beckman-Coulter,Krefeld,德国)或Incyte软件(Merck Millipore,Schwalbach,德国)计算细胞样品的平均荧光强度。在减去单独使用第二和第三试剂染色的细胞的荧光强度值之后,所述值用于利用GraphPad Prism(用于Windows的6.00版本,GraphPad Software,La JollaCalifornia USA)的单点结合(双曲线)方程计算KD值。
在滴定和流式细胞术实验中,对CD3+Jurkat细胞和食蟹猴CD3+HSC-F细胞系(JCRB,目录号:JCB1164)评估CD3结合亲和力和交叉反应性。对人CD20+肿瘤细胞系评估CD20结合和交叉反应性。使用针对表达重组人抗原或重组食蟹猴抗原的CHO细胞系测定的KD值计算交叉反应性的KD比例。
实施例3:细胞毒性测定
在体外评估实施例1的三特异性抗原结合蛋白质对CD20+靶细胞的T细胞依赖性细胞毒性的介导。
在实施例1的三特异性抗原结合蛋白质的存在下,将荧光标记的CD20+REC-1细胞(套细胞淋巴瘤细胞系,ATCC CRL-3004)与作为效应细胞的从随机供体分离的PBMC或CB15T-细胞(标准化的T细胞系)一起温育。在潮湿的培养箱中于37℃下温育4h后,在分光荧光计中测定荧光染料从靶细胞向上清液中的释放。没有与实施例1的三特异性抗原结合蛋白质一起温育的靶细胞和在温育结束时通过加入皂苷而完全裂解的靶细胞分别作为阴性和阳性对照。
基于所测定的剩余活靶细胞,根据下式计算特定细胞裂解的百分比:[1-(活靶标数(样品)/活靶标数(自发的))]×100%。使用GraphPad软件通过非线性回归/4-参数逻辑拟合计算S形剂量响应曲线和EC50值。利用Prism软件通过4参数逻辑拟合分析,使用针对给定抗体浓度获得的裂解值计算S形剂量-响应曲线。
实施例4:三特异性抗原结合蛋白质的药代动力学
在动物研究中评价了实施例1的三特异性抗原结合蛋白质的半衰期消除。
将所述三特异性抗原结合蛋白质以0.5mg/kg团注(bolus injection)肌肉内施用于食蟹猴。另一个食蟹猴组接受在大小上与CD3和CD20结合域相当但缺乏HSA结合域的蛋白质。第三组和第四组分别接受具有CD3和HSA结合域的蛋白质和具有CD20和HSA结合域的蛋白质,并且两者的大小都与三特异性抗原结合蛋白质相当。每个测试组由5只猴子组成。在指定的时间点采取血清样品,连续稀释,并且使用与CD3和/或CD20的结合ELISA来确定蛋白质的浓度。
使用试验样品血浆浓度进行药代动力学分析。当针对给药后时间绘图时,每个试验样品的组平均血浆数据符合多指数曲线。通过标准的二室模型利用团注和分配和消除阶段的一级速率常数拟合这些数据。对于静脉内给药的数据的最佳拟合的一般方程是:c(t)=Ae-αt+Be-βt,其中c(t)是在时间t的血浆浓度,A和B是Y轴上的截距,而α和β分别是分配和消除阶段的表观一级速率常数。α阶段是清除的初始阶段,并且反映蛋白质向动物的所有细胞外液中的分配,而衰变曲线的第二或β阶段部分代表真实的血浆清除。拟合这种方程的方法是本领域公知的。例如,A=D/V(α-k21)/(α-β)、B=D/V(β-k21)/(α-β),并且α和β(对于α>β)是该二次方程的根:r2+(k12+k21+k10)r+k21k10=0,使用估计的参数V=分配体积,k10=消除速率,k12=从隔室1到隔室2的转移速率,且k21=从隔室2到隔室1的转移速率,并且D=施用剂量。
数据分析:使用KaleidaGraph(KaleidaGraphTM V.3.09 Copyright 1986-1997.Synergy Software.Reading,Pa.)制作浓度相对于时间的曲线图。报告为小于可报告值(LTR)的值不包括在PK分析中,并且不在图中示出。使用WinNonlin软件(Professional V.3.1 WinNonlinTM Copyright 1998-1999.PharsightCorporation.Mountain View,Calif.)通过隔室分析确定药代动力学参数。如在RitschelW A和Kearns G L,1999,IN:Handbook Of Basic Pharmacokinetics Including ClinicalApplications,第5版,American Pharmaceutical Assoc.,Washington,D.C.中所述计算药代动力学参数。
与缺乏HSA结合域的蛋白质相比,预期实施例1的三特异性抗原结合蛋白质具有改善的药代动力学参数,如消除半衰期增加。
实施例5:异种移植瘤模型
在异种移植模型中评价实施例1的三特异性抗原结合蛋白质。
对雌性免疫缺陷的NOD/scid小鼠进行亚致死照射(2Gy),并将4x106个Ramos RA1细胞皮下接种到它们的右背侧。当肿瘤达到100至200mm3时,将动物分成3个治疗组。第2组和第3组(每组8只动物)腹膜内注射1.5×107个活化的人T细胞。三天后,随后用总共9个静脉内剂量的50μg实施例1的三特异性抗原结合蛋白质(qdx9d)治疗第3组的动物。第1组和第2组仅用媒介物处理。测量体重和肿瘤体积30天。
与相应媒介物处理的对照组相比,预期用实施例1的三特异性抗原结合蛋白质治疗的动物具有统计学上显著的肿瘤生长延迟。
实施例6:关于将实施例1的三特异性抗原结合蛋白质施用于B细胞淋巴瘤患者的概念
验证临床试验方案
这是用于研究实施例1的三特异性抗原结合蛋白质作为B细胞淋巴瘤治疗方法的I/II期临床试验。
研究结果:
主要的:实施例1的三特异性抗原结合蛋白质的最大耐受剂量。
次要的:确定实施例1的三特异性抗原结合蛋白质的体外反应是否与临床反应有关。
I期
最大耐受剂量(MTD)将在该试验的I期部分确定。
1.1最大耐受剂量(MTD)将在该试验的I期部分确定。
1.2满足资格标准的患者将参加使用实施例1的三特异性抗原结合蛋白质的试验。
1.3目标是确定实施例1的三特异性抗原结合蛋白质的最高剂量,该最高剂量可以在参与者中安全施用而没有严重的或难以处理的副作用。给定的剂量将取决于之前已经参加该项研究的参与者的数目以及耐受剂量的程度。并非所有参与者都会接受相同的剂量。
II期
2.1随后的II期部分将以MTD进行治疗,目的是确定采用实施例1的三特异性抗原结合蛋白质的疗法是否会导致至少20%的反应率。
II期的主要结果---确定采用实施例1的三特异性抗原结合蛋白质的疗法是否会导致至少20%的患者获得临床反应(急变反应(blast response)、轻微反应、部分反应或完全反应)。
资格:
从2001年至2007年,根据当前的世界卫生组织分类,经组织学证实的新诊断的侵袭性B-细胞淋巴瘤
疾病的任何阶段。
用R-CHOP或R-CHOP类方案治疗(+/-移植)。
年龄≥18岁
Karnofsky体力状态≥50%或ECOG体力状态为0-2
平均寿命≥6周
实施例7:评估三特异性抗原结合分子的结合和细胞毒活性的方法
蛋白质产生
将三特异性分子的序列克隆到哺乳动物表达载体pCDNA 3.4(Invitrogen)中,其之前为前导序列,之后是6x组氨酸标签(SEQ ID NO:59)。将Expi293F细胞(LifeTechnologies A14527)以0.2-8×1e6个细胞/ml悬浮维持在最佳生长瓶(Optimum GrowthFlasks)(Thomson)中的Expi293培养基中。根据Expi293表达系统试剂盒(Expi293Expression System Kit)(Life Technologies,A14635)方案将纯化的质粒DNA转染到Expi293细胞中,并在转染后维持4-6天。通过亲和色谱法和脱盐色谱法对条件培养基进行部分纯化。三特异性蛋白质随后通过离子交换精制,或者用Amicon Ultra离心过滤单元(EMD Millipore)浓缩,施加于Superdex 200大小排阻培养基(GE Healthcare),并在含有赋形剂的中性缓冲液中解析。通过SDS-PAGE和分析SEC评估级分合并和最终纯度。
亲和力测量
使用Octet仪器通过生物层干涉法测量所有结合域分子的亲和力。
PSMA亲和力如下测量:将人PSMA-Fc蛋白质(100nM)加载到抗人IgG Fc生物传感器上120秒,随后是60秒基线,之后通过在三特异性分子的稀释系列中温育该传感器尖端180秒,然后解离50秒来测量缔合。EGFR和CD3亲和力如下测量:分别将人EGFR-Fc蛋白质或人CD3-Flag-Fc蛋白质(100nM)加载到抗人IgG Fc生物传感器上120秒,随后是60秒基线,之后通过在三特异性分子稀释系列中温育该传感器尖端180秒,然后解离300秒来测量缔合。通过将生物素化的白蛋白加载到链霉亲和素生物传感器上,然后按照与CD3亲和力测量相同的动力学参数,测量对人血清白蛋白(HSA)的亲和力。所有步骤均在30℃下在含0.25%酪蛋白的磷酸盐缓冲盐水中进行。
细胞毒性测定
使用人T-细胞依赖性细胞毒性(TDCC)测定来测量T细胞接合物(包括三特异性分子)引导T细胞杀死肿瘤细胞的能力(Nazarian等人,2015.J Biomol Screen.20:519-27)。在该测定中,将T细胞和靶癌细胞系细胞在384孔板中以10:1的比例混合在一起,并加入不同量的T细胞接合物。48小时后,将T细胞洗掉,留下未被T细胞杀死的靶细胞附着在板上。为了定量剩余的活细胞,使用发光细胞活力测定(Promega)。
细胞因子测定
使用针对TNFα和干扰素γ的αLISA测定(Perkin Elmer)获得T细胞在靶细胞的存在下被三特异性分子激活的证据。对于该测定,如细胞毒性测定中所述,将原代人T细胞和人肿瘤细胞在测试分子的存在下温育。温育48小时后,根据制造商的说明书分析2微升等分试样的测定上清液。
扩散测定
将一层基质胶(75μL)加入到24孔Transwell嵌入物(insert)(0.4μm)中,然后将PBS加入上室和下室(分别为100μL和1025μL)并在4℃下平衡过夜。将100pmol的IgG或Fab(山羊抗人Fc,JacksonImmunoResearch)或三特异性分子加入上室中,并且通过对每种分子具特异性的ELISA随时间推移对每种分子向下室中的扩散进行定量。通过固定在ELISA板上的驴抗山羊IgG(Jackson ImmunoResearch)捕获IgG和Fab,并用辣根过氧化物酶缀合的驴抗山羊IgG(Jackson ImmunoResearch)和TMB显影进行检测。通过固定在ELISA板上的人血清白蛋白(Athens Research&Technology)捕获三特异性分子,并用辣根过氧化物酶缀合的抗-His抗体(Genscript)和TMB显影进行检测。
在每个时间点的相对扩散计算为:(时间=t时下室中的浓度)/(时间=t时上室中的浓度)。
使用非配对t-检验来鉴定IgG分子与Fab或三特异性分子之间扩散的统计学显著差异。
实施例8:EGFR靶向三特异性分子的亲和力测量
EGFR靶向分子中三个结合域的亲和力使用Octet仪器通过生物层干涉法来测量,并总结在表1中。
与在中心或C-末端位置含有EGFR结合域的三特异性分子相比,其中EGFR结合域位于分子N-末端的三特异性分子显示出明显更高的对EGFR的亲和力。类似地,在N-末端含有白蛋白结合域的三特异性分子也表现出比在中间或C-末端位置含有白蛋白的三特异性分子更高的HSA亲和力。相反,所有三特异性分子均表现出非常相似的对人CD3的亲和力,而与三特异性分子内的结合域的位置无关。
实施例9:PSMA靶向三特异性分子的亲和力测量
PSMA靶向分子中三个结合域的亲和力使用Octet仪器通过生物层干涉法来测量,并总结在表2中。
在N-末端含有白蛋白结合域的三特异性分子比在中间或C-末端位置含有白蛋白结合域的三特异性分子具有更高的HSA亲和力。相反,CD3结合域的位置不影响对其靶标的亲和力。同样,PSMA结合域的位置对亲和力几乎没有影响,所有三特异性分子对人PSMA的亲和力彼此在3倍之内。
b施例10:用三特异性分子进行的细胞毒性测定
在T细胞依赖性细胞毒性(TDCC)测定中测试了三特异性分子诱导原代人T细胞以肿瘤靶标依赖性方式杀死人肿瘤细胞的能力。
参见图5,含有单结构域抗体衍生的针对EGFR或PSMA的肿瘤靶向结构域的三特异性分子可以以与双特异性T细胞接合物(BiTE)相当的方式诱导有效的细胞杀伤。
在使用NCI-1563人肺腺癌细胞系的TDCC测定中测试6种具有单结构域抗-EGFR抗体的EGFR靶向三特异性分子(见图4)和含有抗-EGFR scFv的三特异性分子。为了比较,每个测定中均包括EGFR BiTE(Lutterbuese等人2007.PNAS 107:12605-12610)。所有7种EFGR靶向三特异性分子构型均被证明能有效地杀死靶细胞(参见表3和表4以及图6和图8中的代表性数据),具有与EGFR BiTE相似的效力。还通过加入15mg/ml人血清白蛋白来进行TDCC测定,以评估白蛋白结合对三特异性分子的TDCC活性的影响。正如所料,缺乏白蛋白结合域的EGFR BiTE的效力在不存在或存在白蛋白的情况下是相似的。在白蛋白的存在下三特异性分子的效力降低,而降低的量取决于分子的构型。在白蛋白的存在下效力降低最小的构型为EGFR-scFv:C:A和E:A:C(抗-EGFR-scFv:抗-CD3E-scFv:抗-ALB-sdAb和抗-EGFR-sdAb:抗-ALB-sdAb:抗-CD3E-scFv)。
为了证明EGFR靶向三特异性分子的结果可以适用于所有三特异性分子,在使用22Rv1人前列腺癌上皮细胞系的TDCC测定中测试了5种具有单结构域抗-PSMA抗体的PSMA靶向三特异性分子和含有抗-PSMA scFv的三特异性分子。为了比较,该测定中包括PSMA BiTE(pasotuxizumab)。代表性结果见表5和图7。除了具有A:C:P构型(抗-PSMA-sdAb:抗-CD3E-scFv:抗-ALB-sdAb)的三特异性分子外,大多数PSMA靶向三特异性分子在TDCC测定中具有与PSMA BiTE类似的活性。还在含有15mg/ml人血清白蛋白的TDCC测定中测试了这些三特异性分子,以评估白蛋白结合对三特异性分子的TDCC活性的影响。正如所料,缺乏白蛋白结合域的PSMA BiTE的效力在存在或存在白蛋白的情况下是相似的。在白蛋白的存在下三特异性分子的效力降低,而降低的量取决于分子的构型。在白蛋白的存在下效力降低最小的构型为P:A:C(抗-PSMA-sdAb:抗-ALB-sdAb:抗-CD3E-scFv)。
本文所述的三特异性分子可以利用各种形态来靶向肿瘤细胞。图5、图6和图7显示了具有sdAb衍生的肿瘤靶向结构域的三特异性分子,而图7和8显示具有scFv衍生的肿瘤结合域的三特异性分子可以同样良好地起作用。图9表明肿瘤靶向结构域不限于衍生自抗体的构建体如sdAb和scFv,而非免疫球蛋白结构域也可以起作用。在该实施例中,对于Her2具特异性的7kDa fynomer用于重新引导静息的人T细胞杀死人卵巢癌细胞。
实施例11:用三特异性分子进行的细胞因子产生测定
为了显示此处测试的三特异性分子确实激活了T细胞并重新引导这些T细胞杀死肿瘤细胞,细胞因子TNFα和IFNγ的产生的测定与T细胞的细胞杀伤活性的测定同步进行,因为T细胞在被激活时产生这些细胞因子。
如图10和图11所示,四种测试的EGFR和PSMA靶向三特异性分子以与其细胞杀伤活性相似的效力刺激TNFα和干扰素γ产生。这些数据与三特异性分子在接合靶细胞时激活T细胞的陈述一致。
实施例12:扩散测定
此处分析的三特异性分子比常规的IgG分子更小,因此预期比单克隆抗体扩散更快并更好地穿透组织。开发了通过基质胶的扩散/迁移测定以评估该性质。为此,用基质胶涂覆transwell测定板,基质胶是一种类似于在许多组织中发现的复杂细胞外环境的凝胶状蛋白质混合物。将三特异性分子、全长IgG或Fab片段加入到上室中。8小时和12小时后,评估下室中能够迁移通过基质的大分子的量。如图12所示,三特异性分子在两个时间点以比全长IgG分子快得多的速率迁移。
实施例13:对人CD3ε具有不同亲和力的抗-CD3scFv变体的鉴定亲本抗-CD3ε噬菌体的表征
亲本抗-CD3ε显示出与生物素-CD3ε的良好结合以及与生物素-HSA的弱结合(图13)。
抗-CD3εscFv噬菌体文库
为重链CDR1、重链CDR2、重链CDR3、轻链CDR1、轻链CDR2和轻链CDR3结构域提供单个替代文库。通过诱变一次改变一个残基。克隆的选择和结合亲和力的测定
将单个替代文库与生物素化的hu-CD3ε结合,洗涤,洗脱,并计数。使用生物素化的食蟹猴CD3作为第1轮选择靶标,并在组合噬菌体从两个独立的文库中结合后洗涤4小时(约2次选择)。使用生物素化的hu-CD3作为第2轮选择靶标,并在两个文库结合后洗涤3小时(<2次选择)。将来自第二轮选择的PCR产生的插入片段亚克隆到pcDNA3.4His6表达载体中。挑选180个克隆,并将DNA纯化,测序,并转染到Expi293中。选择对人CD3ε具有一定亲和力的一组16个克隆进行更精确的Kd测定(表6)。
表1总结了含有EGFR靶向单结构域抗体的三特异性分子对于三种靶抗原的亲和力。表中缩写的说明:E=抗-EGFR单结构域抗体,C=抗-CD3E scFv,A=抗白蛋白单结构域抗体。
亲和力
表2总结了含有PSMA靶向单结构域抗体的三特异性分子对于三种靶抗原的亲和力。表中缩写的说明:P=抗-PSMA单结构域抗体,C=抗-CD3E scFv,A=抗白蛋白单结构域抗体。
亲和力
huPSMA | HuCD3 | HSA | |
三特异性构型 | KD(nM) | KD(nM) | KD(nM) |
P:C:A | 16.7 | 3.6 | 24.0 |
P:A:C | 31.6 | 4.1 | 21.0 |
C:A:P | 51.0 | 4.2 | 21.7 |
A:P:C | 25.0 | 2.1 | 3.5 |
A:C:P | 39.7 | 2.7 | 3.5 |
表3总结了含有EGFR靶向单结构域抗体的三特异性分子在细胞杀伤测定中的效力。EC50值以摩尔浓度表示。表中缩写的说明:E=抗-EGFR单结构域抗体,C=抗-CD3EscFv,A=抗白蛋白单结构域抗体。
表4总结了含有EGFR靶向scFv抗体的三特异性分子和BiTE分子在细胞杀伤测定中的效力。EC50值以摩尔浓度表示。表中缩写的说明:E=抗-EGFR单结构域抗体,C=抗-CD3EscFv,A=抗白蛋白单结构域抗体。
表5总结了含有PSMA靶向单结构域抗体的三特异性分子在细胞杀伤测定中的效力。EC50值以摩尔浓度表示。表中缩写的说明:P=抗-PSMA单结构域抗体,C=抗-CD3EscFv,A=抗白蛋白单结构域抗体。
表6总结了CD3e scFv噬菌体文库的结合亲和力。
表7:序列
表8:序列
尽管本文已经示出并描述了本发明的优选实施方案,但对本领域技术人员而言显而易见的是:这些实施方案仅以示例的方式提供。在不背离本发明的情况下,本领域技术人员现将想到大量变化、更改和替换。应当理解,本文中描述的本发明实施方案的各种替代方案可用于实施本发明。其意图在于,下列权利要求限定本发明的范围,从而涵盖这些权利要求范围内的方法和结构及其等同物。
序列表
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<120> 三特异性结合蛋白质及使用方法
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<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 3
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 Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala
260 265 270
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser
275 280 285
Ser Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu
290 295 300
Phe Val Val Ala Ile Asn Trp Ser Ser Gly Ser Thr Tyr Tyr Ala Asp
305 310 315 320
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr
325 330 335
Met Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Ala Ala Gly Tyr Gln Ile Asn Ser Gly Asn Tyr Asn Phe Lys
355 360 365
Asp Tyr Glu Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
370 375 380
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu
385 390 395 400
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
405 410 415
Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg
420 425 430
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
435 440 445
Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
450 455 460
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
465 470 475 480
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
485 490 495
Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His His
500 505 510
His His His
515
<210> 4
<211> 515
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 4
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 Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
260 265 270
Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
275 280 285
Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
290 295 300
Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp
305 310 315 320
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr
325 330 335
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
370 375 380
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu
385 390 395 400
Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr Ala Met
405 410 415
Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Val Ala
420 425 430
Ile Asn Trp Ser Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly
435 440 445
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu Gln
450 455 460
Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala
465 470 475 480
Gly Tyr Gln Ile Asn Ser Gly Asn Tyr Asn Phe Lys Asp Tyr Glu Tyr
485 490 495
Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser His His His
500 505 510
His His His
515
<210> 5
<211> 515
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 5
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr Ala Met Gly Trp
145 150 155 160
Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Val Ala Ile Asn
165 170 175
Trp Ser Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe
180 185 190
Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu Gln Met Asn
195 200 205
Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Tyr
210 215 220
Gln Ile Asn Ser Gly Asn Tyr Asn Phe Lys Asp Tyr Glu Tyr Asp Tyr
225 230 235 240
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
260 265 270
Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr
275 280 285
Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
290 295 300
Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
305 310 315 320
Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
325 330 335
Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp
340 345 350
Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr
355 360 365
Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
370 375 380
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
385 390 395 400
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
405 410 415
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
420 425 430
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
435 440 445
Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe
450 455 460
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
465 470 475 480
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn
485 490 495
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His
500 505 510
His His His
515
<210> 6
<211> 515
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 6
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
165 170 175
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
180 185 190
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
195 200 205
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
210 215 220
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
260 265 270
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
275 280 285
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
290 295 300
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
305 310 315 320
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
325 330 335
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
340 345 350
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
355 360 365
Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
370 375 380
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu
385 390 395 400
Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser Tyr Ala Met
405 410 415
Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val Val Ala
420 425 430
Ile Asn Trp Ser Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly
435 440 445
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Met Tyr Leu Gln
450 455 460
Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala
465 470 475 480
Gly Tyr Gln Ile Asn Ser Gly Asn Tyr Asn Phe Lys Asp Tyr Glu Tyr
485 490 495
Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser His His His
500 505 510
His His His
515
<210> 7
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 7
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Lys Gln
115 120 125
Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys
130 135 140
Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg
145 150 155 160
Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly
165 170 175
Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn
180 185 190
Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu Gln
195 200 205
Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr
210 215 220
Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ala 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
His His His His His His
500
<210> 8
<211> 626
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 8
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Lys Gln
115 120 125
Ser Gly Pro Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys
130 135 140
Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg
145 150 155 160
Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly
165 170 175
Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn
180 185 190
Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu Gln
195 200 205
Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr
210 215 220
Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ala 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 Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
500 505 510
Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala
515 520 525
Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln
530 535 540
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly
545 550 555 560
Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
565 570 575
Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
580 585 590
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser
595 600 605
Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His His His
610 615 620
His His
625
<210> 9
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 9
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Gly Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala
130 135 140
Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala
145 150 155 160
Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn
165 170 175
Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu
195 200 205
Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe
210 215 220
Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu
225 230 235 240
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val
260 265 270
Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala
275 280 285
Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln
290 295 300
Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr
305 310 315 320
Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr
325 330 335
Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu
340 345 350
Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
355 360 365
Leu Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu
370 375 380
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
385 390 395 400
Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg
405 410 415
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
420 425 430
Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
435 440 445
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
450 455 460
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
465 470 475 480
Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His His
485 490 495
His His His
<210> 10
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 10
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp
85 90 95
Gly Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala
145 150 155 160
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser
165 170 175
Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg
210 215 220
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
245 250 255
Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr
260 265 270
Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
275 280 285
Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
290 295 300
Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
305 310 315 320
Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr
340 345 350
Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
385 390 395 400
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
405 410 415
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
420 425 430
Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe
435 440 445
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
450 455 460
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn
465 470 475 480
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His
485 490 495
His His His
<210> 11
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 11
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 Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
260 265 270
Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
275 280 285
Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
290 295 300
Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp
305 310 315 320
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr
325 330 335
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
370 375 380
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
385 390 395 400
Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr Ser Met
405 410 415
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr
420 425 430
Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys Gly Arg
435 440 445
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met
450 455 460
Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp Gly Tyr
465 470 475 480
Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser His His His
485 490 495
His His His
<210> 12
<211> 495
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 12
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Thr Leu
130 135 140
Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr Ser Met His Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Asn
165 170 175
Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr
180 185 190
Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
195 200 205
Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp Gly Tyr Gly Tyr
210 215 220
Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
225 230 235 240
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
245 250 255
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
260 265 270
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
275 280 285
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
290 295 300
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
305 310 315 320
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
325 330 335
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
340 345 350
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
355 360 365
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
370 375 380
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
385 390 395 400
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
405 410 415
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
420 425 430
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
435 440 445
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
450 455 460
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
465 470 475 480
Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His His His
485 490 495
<210> 13
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 13
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
165 170 175
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
180 185 190
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
195 200 205
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
210 215 220
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
260 265 270
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
275 280 285
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
290 295 300
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
305 310 315 320
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
325 330 335
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
340 345 350
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
355 360 365
Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
370 375 380
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
385 390 395 400
Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu Tyr Ser Met
405 410 415
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr
420 425 430
Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val Lys Gly Arg
435 440 445
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met
450 455 460
Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asp Gly Tyr
465 470 475 480
Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser His His His
485 490 495
His His His
<210> 14
<211> 628
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 14
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 Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val
500 505 510
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
515 520 525
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val
530 535 540
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
545 550 555 560
Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
565 570 575
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
580 585 590
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
595 600 605
Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His
610 615 620
His His His His
625
<210> 15
<211> 504
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 15
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 His His His His His His
500
<210> 16
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 16
Gly Val Thr Leu Phe Val Ala Leu Tyr Asp Tyr Thr Ser Tyr Asn Thr
1 5 10 15
Arg Asp Leu Ser Phe His Lys Gly Glu Lys Phe Gln Ile Leu Arg Met
20 25 30
Glu Asp Gly Val Trp Trp Glu Ala Arg Ser Leu Thr Thr Gly Glu Thr
35 40 45
Gly Tyr Ile Pro Ser Asn Tyr Val Ala Pro Val Asp Ser Ile Gln Gly
50 55 60
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
65 70 75 80
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala
85 90 95
Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala
100 105 110
Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn
115 120 125
Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile
130 135 140
Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu
145 150 155 160
Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe
165 170 175
Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu
180 185 190
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
195 200 205
Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val
210 215 220
Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala
225 230 235 240
Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln
245 250 255
Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr
260 265 270
Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr
275 280 285
Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu
290 295 300
Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
305 310 315 320
Leu Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu
325 330 335
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
340 345 350
Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg
355 360 365
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
370 375 380
Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
385 390 395 400
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
405 410 415
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
420 425 430
Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His His
435 440 445
His His His
450
<210> 17
<211> 500
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 17
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 Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
260 265 270
Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
275 280 285
Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
290 295 300
Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp
305 310 315 320
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr
325 330 335
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gln Val
370 375 380
Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
385 390 395 400
Arg Leu Ser Cys Ala Ala Ser Asp Phe Asp Phe Ala Ala Tyr Asp Met
405 410 415
Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val Ala Ile
420 425 430
Ile Ser His Asp Gly Ile Asp Lys Tyr Tyr Asp Asp Ser Val Lys Gly
435 440 445
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
450 455 460
Met Asn Thr Leu Arg Ala Glu Asp Thr Ala Thr Tyr Gln Cys Leu Arg
465 470 475 480
Leu Gly Ala Val Gly Gln Gly Thr Leu Val Thr Val Ser Ser His His
485 490 495
His His His His
500
<210> 18
<211> 500
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 18
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gln Val Gln Leu
115 120 125
Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Asp Phe Asp Phe Ala Ala Tyr Asp Met Ser Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val Ala Ile Ile Ser
165 170 175
His Asp Gly Ile Asp Lys Tyr Tyr Asp Asp Ser Val Lys Gly Arg Phe
180 185 190
Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn
195 200 205
Thr Leu Arg Ala Glu Asp Thr Ala Thr Tyr Gln Cys Leu Arg Leu Gly
210 215 220
Ala Val Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
225 230 235 240
Ser 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 His His
485 490 495
His His His His
500
<210> 19
<211> 500
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 19
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
165 170 175
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
180 185 190
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
195 200 205
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
210 215 220
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
225 230 235 240
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
260 265 270
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
275 280 285
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
290 295 300
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
305 310 315 320
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
325 330 335
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
340 345 350
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
355 360 365
Lys Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Ser Gln Val
370 375 380
Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu
385 390 395 400
Arg Leu Ser Cys Ala Ala Ser Asp Phe Asp Phe Ala Ala Tyr Asp Met
405 410 415
Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val Ala Ile
420 425 430
Ile Ser His Asp Gly Ile Asp Lys Tyr Tyr Asp Asp Ser Val Lys Gly
435 440 445
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
450 455 460
Met Asn Thr Leu Arg Ala Glu Asp Thr Ala Thr Tyr Gln Cys Leu Arg
465 470 475 480
Leu Gly Ala Val Gly Gln Gly Thr Leu Val Thr Val Ser Ser His His
485 490 495
His His His His
500
<210> 20
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 20
Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser Val Glu Gly Gly Ser Gly Gly Ser Gly
115 120 125
Gly Ser Gly Gly Ser Gly Gly Val Asp Asp Ile Gln Leu Thr Gln Ser
130 135 140
Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys
145 150 155 160
Arg Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser
165 170 175
Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser
180 185 190
Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
195 200 205
Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu
225 230 235 240
Glu Leu Lys
<210> 21
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 21
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 Lys Phe Ser Gly Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Val Asp 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 Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Met Gly Tyr Trp His Phe Asp Leu Trp Gly Arg Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 22
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 22
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 23
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 23
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 Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp 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 Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 24
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 24
Asp Ile Gln Leu Thr Gln Pro Asn Ser Val Ser Thr Ser Leu Gly Ser
1 5 10 15
Thr Val Lys Leu Ser Cys Thr Leu Ser Ser Gly Asn Ile Glu Asn Asn
20 25 30
Tyr Val His Trp Tyr Gln Leu Tyr Glu Gly Arg Ser Pro Thr Thr Met
35 40 45
Ile Tyr Asp Asp Asp Lys Arg Pro Asp Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Arg Ser Ser Asn Ser Ala Phe Leu Thr Ile His Asn
65 70 75 80
Val Ala Ile Glu Asp Glu Ala Ile Tyr Phe Cys His Ser Tyr Val Ser
85 90 95
Ser Phe Asn Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg
100 105 110
<210> 25
<211> 243
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 25
Asp 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 Arg Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Thr Thr Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Gly Glu Gly Thr Ser Thr Gly Ser Gly
115 120 125
Gly Ser Gly Gly Ser Gly Gly Ala Asp Asp Ile Val Leu Thr Gln Ser
130 135 140
Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
145 150 155 160
Arg Ala Ser Gln Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
165 170 175
Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser
180 185 190
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser
195 200 205
Leu Thr Ile Asn Ser Leu Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Gly Gly Thr Lys Val
225 230 235 240
Glu Ile Lys
<210> 26
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 26
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Pro Val Thr Val Ser Ser
115
<210> 27
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 27
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 Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr
85 90 95
Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg
100 105
<210> 28
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 28
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 Thr Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 29
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 29
Gln Ala 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 Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Gly Gln Ala Phe Arg Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg 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 Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 30
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 30
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Asp Asn Ser Gly Tyr Gly His Tyr Tyr Tyr Gly Met Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ala Ser
115 120
<210> 31
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 31
Ala Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro
1 5 10 15
Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser
20 25 30
Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Ile Asn Trp Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 32
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 32
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Ser
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Ser Ala Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Arg Gln Val His Tyr Asp Tyr Asn Gly Phe Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 33
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 33
Gln Val Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Phe Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Ser Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Thr Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Arg Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Gln Ile Thr Arg
100 105
<210> 34
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 34
Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr 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 Gln Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120 125
<210> 35
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 35
Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly
35 40 45
Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala
65 70 75 80
Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
<210> 36
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 36
Glu Val Gln Leu Val 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 Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe
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 Ala 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 Thr Ser Asn Tyr Ala Asn
165 170 175
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
180 185 190
Thr Asn Lys Arg Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser Leu
195 200 205
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp
210 215 220
Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Thr Val Leu
245
<210> 37
<211> 245
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 37
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Ser Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Asp Ile Val Leu
115 120 125
Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr
130 135 140
Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln
145 150 155 160
Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys
165 170 175
Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr
180 185 190
Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu Asp Ala Ala Thr
195 200 205
Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly
210 215 220
Thr Lys Leu Glu Ile Asn Arg Ala Asp Thr Ala Ala Ala Gly Ser His
225 230 235 240
His His His His His
245
<210> 38
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 38
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 Thr Phe Ser Lys Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asp Phe Met Gly Pro His Thr Tyr Tyr Ala Asp 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 Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Arg Thr Ser Met Leu Pro Met Lys Gly Lys Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 39
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 39
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 Thr Ala Ser Gly Phe Thr Phe Asp Glu Tyr
20 25 30
Asn Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Leu Pro His Gly Asp Arg Thr Tyr Tyr Ala Asp 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 Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gln Asp Pro Leu Tyr Arg Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 40
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 40
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 Lys Ile Ala Thr Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ser Ser Ser Leu Gln Ser Ala Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Val Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Tyr Ala Val Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 41
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 41
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 Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Asn Ser Pro 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 Thr Tyr Arg Val Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 42
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 42
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Arg Phe
20 25 30
Gly Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Val Glu Trp Val
35 40 45
Ser Gly Ile Ser Ser Leu Gly Asp Ser Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Asn Pro Gly Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 43
<211> 45
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 43
Leu Lys Glu Ala Lys Glu Lys Ala Ile Glu Glu Leu Lys Lys Ala Gly
1 5 10 15
Ile Thr Ser Asp Tyr Tyr Phe Asp Leu Ile Asn Lys Ala Lys Thr Val
20 25 30
Glu Gly Val Asn Ala Leu Lys Asp Glu Ile Leu Lys Ala
35 40 45
<210> 44
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 44
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 Val Ser Gly Ile Asp Leu Ser Asn Tyr
20 25 30
Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Ile
35 40 45
Gly Ile Ile Trp Ala Ser Gly Thr Thr Phe Tyr Ala Thr Trp Ala 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
Arg Thr Val Pro Gly Tyr Ser Thr Ala Pro Tyr Phe Asp Leu Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 45
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 45
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 Gln Ser Ser Pro Ser Val Trp Ser Asn
20 25 30
Phe Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Glu Ala Ser Lys Leu Thr Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gly Gly Gly Tyr Ser Ser Ile
85 90 95
Ser Asp Thr Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Arg Thr
100 105 110
<210> 46
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 46
Ala Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Pro Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 47
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 47
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 48
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<400> 48
Ala Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Gly Gly Gly
1 5 10 15
Ser Leu Arg Leu Ala Cys Ala Ala Ser Glu Arg Ile Phe Asp Leu Asn
20 25 30
Leu Met Gly Trp Tyr Arg Gln Gly Pro Gly Asn Glu Arg Glu Leu Val
35 40 45
Ala Thr Cys Ile Thr Val Gly Asp Ser Thr Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Met Asp Tyr Thr Lys Gln Thr Val Tyr
65 70 75 80
Leu His Met Asn Ser Leu Arg Pro Glu Asp Thr Gly Leu Tyr Tyr Cys
85 90 95
Lys Ile Arg Arg Thr Trp His Ser Glu Leu Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser
115
<210> 49
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<220>
<221> MISC_FEATURE
<222> (1)..(20)
<223> 该序列可包含1-10个"Gly Ser"重复单元,其中一些位置可以不存在
<400> 49
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
1 5 10 15
Gly Ser Gly Ser
20
<210> 50
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(30)
<223> 该序列可包含1-10个"Gly Gly Ser"重复单元,其中一些位置可以不存在
<400> 50
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly
1 5 10 15
Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
20 25 30
<210> 51
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(40)
<223> 该序列可包含1-10个"Gly Gly Gly Ser"重复单元,其中一些位置可以不存在
<400> 51
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
20 25 30
Gly Gly Gly Ser Gly Gly Gly Ser
35 40
<210> 52
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(40)
<223> 该序列可包含1-10个"Gly Gly Ser Gly"重复单元,其中一些位置可以不存在
<400> 52
Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly
20 25 30
Gly Gly Ser Gly Gly Gly Ser Gly
35 40
<210> 53
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(50)
<223> 该序列可包含1-10个"Gly Gly Ser Gly Gly"重复单元,其中一些位置可以不存在
<400> 53
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
1 5 10 15
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
20 25 30
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
Gly Gly
50
<210> 54
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(50)
<223> 该序列可包含1-10个"Gly Gly Gly Gly Ser"重复单元,其中一些位置可以不存在
<400> 54
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25 30
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
35 40 45
Gly Ser
50
<210> 55
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 55
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 56
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 56
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 57
<211> 5
<212> PRT
<213> 未知
<220>
<223> “未知"的描述:分选酶识别序列
<400> 57
Leu Pro Glu Thr Gly
1 5
<210> 58
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
肽
<400> 58
Gly Gly Gly Gly Ser
1 5
<210> 59
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成
6xHis标签
<400> 59
His His His His His His
1 5
<210> 60
<211> 6
<212> PRT
<213> 未知
<220>
<223> "未知"的描述:分选酶识别序列
<400> 60
Leu Pro Glu Thr Gly Gly
1 5
Claims (57)
1.一种三特异性抗原结合蛋白质,其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A);
(b)第二结构域(B),其为半衰期延长结构域;和
(c)与靶抗原特异性结合的第三结构域(C),
其中所述结构域以H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(C)-(B)-(A)-COOH的顺序或通过连接体L1和L2连接。
2.如权利要求1所述的三特异性抗原结合蛋白质,其中所述第一结构域包含各自能够与人CD3特异性结合的可变轻链和可变重链。
3.如权利要求2所述的三特异性抗原结合蛋白质,其中所述可变轻链为λ(lamda)轻链。
4.如权利要求2所述的三特异性抗原结合蛋白质,其中所述可变轻链为κ(kappa)轻链。
5.如权利要求1-4中任一项所述的三特异性抗原结合蛋白质,其中所述第一结构域包含对于人CD3为特异性的单链可变片段(scFv)。
6.如权利要求1-5中任一项所述的三特异性抗原结合蛋白质,其中所述第一结构域对于CD3ε(epsilon)具特异性。
7.如权利要求1-5中任一项所述的三特异性抗原结合蛋白质,其中所述第一结构域对于CD3δ(delta)具特异性。
8.如权利要求1-5中任一项所述的三特异性抗原结合蛋白质,其中所述第一结构域对于CD3γ(gamma)具特异性。
9.如权利要求1-8中任一项所述的三特异性抗原结合蛋白质,其中所述第一结构域包含选自莫罗单抗-CD3(OKT3)、奥昔珠单抗(TRX4)、替利珠单抗(MGA031)、维西珠单抗(Nuvion)、SP34、X35、VIT3、BMA030(BW264/56)、CLB-T3/3、CRIS7、YTH12.5、F111-409、CLB-T3.4.2、TR-66、WT32、SPv-T3b、11D8、XIII-141、XIII-46、XIII-87、12F6、T3/RW2-8C8、T3/RW2-4B6、OKT3D、M-T301、SMC2、F101.01、UCHT-1和WT-31的互补决定区(CDR)。
10.如权利要求1-8中任一项所述的三特异性抗原结合蛋白质,其中所述第一结构域是人源化的或人的。
11.如权利要求1-10中任一项所述的三特异性抗原结合蛋白质,其中所述第一结构域与表达CD3的细胞上的CD3结合的KD为1000nM或更低。
12.如权利要求1-11中任一项所述的三特异性抗原结合蛋白质,其中所述第一结构域与表达CD3的细胞上的CD3结合的KD为100nM或更低。
13.如权利要求1-12中任一项所述的三特异性抗原结合蛋白质,其中所述第一结构域与表达CD3的细胞上的CD3结合的KD为10nM或更低。
14.如权利要求1-13中任一项所述的三特异性抗原结合蛋白质,其中所述第一结构域与食蟹猴CD3具有交叉反应性。
15.如权利要求1-14中任一项所述的三特异性抗原结合蛋白质,其中所述第一结构域包含本文提供的氨基酸序列。
16.如权利要求1-15中任一项所述的三特异性抗原结合蛋白质,其中所述第二结构域与人血清白蛋白结合。
17.如权利要求1-16中任一项所述的三特异性抗原结合蛋白质,其中所述第二结构域包含scFv、可变重链结构域(VH)、可变轻链结构域(VL)、单结构域抗体、肽、配体或小分子。
18.如权利要求1-17中任一项所述的三特异性抗原结合蛋白质,其中所述第二结构域包含scFv。
19.如权利要求1-17中任一项所述的三特异性抗原结合蛋白质,其中所述第二结构域包含VH结构域。
20.如权利要求1-17中任一项所述的三特异性抗原结合蛋白质,其中所述第二结构域包含VL结构域。
21.如权利要求1-17中任一项所述的三特异性抗原结合蛋白质,其中所述第二结构域包含单结构域抗体。
22.如权利要求1-17中任一项所述的三特异性抗原结合蛋白质,其中所述第二结构域包含肽。
23.如权利要求1-17中任一项所述的三特异性抗原结合蛋白质,其中所述第二结构域包含配体。
24.如权利要求1-17中任一项所述的三特异性抗原结合蛋白质,其中所述第二结构域包含小分子实体。
25.如权利要求1-24中任一项所述的三特异性抗原结合蛋白质,其中所述第三结构域包含与靶抗原特异性结合的scFv、VH结构域、VL结构域、非Ig结构域、配体、knottin或小分子实体。
26.如权利要求1-25中任一项所述的三特异性抗原结合蛋白质,其中所述第三结构域对于细胞表面分子具特异性。
27.如权利要求1-26中任一项所述的三特异性抗原结合蛋白质,其中所述第三结构域对于肿瘤抗原具特异性。
28.如权利要求1-27中任一项所述的三特异性抗原结合蛋白质,其中连接体L1和L2是肽连接体。
29.如权利要求28所述的三特异性抗原结合蛋白质,其中连接体L1和L2独立地由约20个或更少的氨基酸残基组成。
30.如权利要求29所述的三特异性抗原结合蛋白质,其中连接体L1和L2各自独立地选自(GS)n(SEQ ID NO:49)、(GGS)n(SEQ ID NO:50)、(GGGS)n(SEQ ID NO:51)、(GGSG)n(SEQID NO:52)、(GGSGG)n(SEQ ID NO:53)或(GGGGS)n(SEQ ID NO:54),其中n为1、2、3、4、5、6、7、8、9或10。
31.如权利要求28所述的三特异性抗原结合蛋白质,其中连接体L1和L2各自独立地为(GGGGS)4(SEQ ID NO:55)或(GGGGS)3(SEQ ID NO:56)。
32.如权利要求1-27中任一项所述的三特异性抗原结合蛋白质,其中连接体L1和L2是化学连接体。
33.如权利要求1-32中任一项所述的三特异性抗原结合蛋白质,其中所述第一结构域在所述蛋白质的N-末端。
34.如权利要求1-32中任一项所述的三特异性抗原结合蛋白质,其中所述第二结构域在所述蛋白质的N-末端。
35.如权利要求1-32中任一项所述的三特异性抗原结合蛋白质,其中所述第三结构域在所述蛋白质的N-末端。
36.如权利要求1-32、34和35中任一项所述的三特异性抗原结合蛋白质,其中所述第一结构域在所述蛋白质的C-末端。
37.如权利要求1-33和35中任一项所述的三特异性抗原结合蛋白质,其中所述第二结构域在所述蛋白质的C-末端。
38.如权利要求1-34中任一项所述的三特异性抗原结合蛋白质,其中所述第三结构域在所述蛋白质的C-末端。
39.如权利要求1-38中任一项所述的三特异性抗原结合蛋白质,其中所述蛋白质小于约80kD。
40.如权利要求1-39中任一项所述的三特异性抗原结合蛋白质,其中所述蛋白质为约50kDa至约75kDa。
41.如权利要求1-40中任一项所述的三特异性抗原结合蛋白质,其中所述蛋白质小于约50kDa。
42.如权利要求1-41中任一项所述的三特异性抗原结合蛋白质,其中所述蛋白质小于约40kDa。
43.如权利要求1-42中任一项所述的三特异性抗原结合蛋白质,其中所述蛋白质为约20kDa至约40kDa。
44.如权利要求1-43中任一项所述的三特异性抗原结合蛋白质,其中所述蛋白质具有至少约50小时的消除半衰期。
45.如权利要求1-44中任一项所述的三特异性抗原结合蛋白质,其中所述蛋白质具有至少约100小时的消除半衰期。
46.如权利要求1-45中任一项所述的三特异性抗原结合蛋白质,其中与IgG相比,所述蛋白质对于同一靶抗原具有增加的组织穿透。
47.一种三特异性抗原结合蛋白质,其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A);
(b)第二结构域(B),其为半衰期延长结构域;和
(c)与靶抗原特异性结合的第三结构域(C),
其中所述结构域以H2N-(A)-(B)-(C)-COOH、H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(B)-(C)-(A)-COOH、H2N-(C)-(B)-(A)-COOH或H2N-(C)-(A)-(B)-COOH的顺序通过连接体L1和L2连接,并且
其中所述第一结构域以大于100nM的KD与人CD3结合。
48.一种三特异性抗原结合蛋白质,其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A);
(b)第二结构域(B),其为半衰期延长结构域;和
(c)与靶抗原特异性结合的第三结构域(C),
其中所述结构域以H2N-(A)-(B)-(C)-COOH、H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(B)-(C)-(A)-COOH、H2N-(C)-(B)-(A)-COOH或H2N-(C)-(A)-(B)-COOH的顺序通过连接体L1和L2连接,并且
其中所述蛋白质具有小于55kDa的分子量。
49.一种三特异性抗原结合蛋白质,其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A);
(b)第二结构域(B),其为半衰期延长结构域;和
(c)与靶抗原特异性结合的第三结构域(C),
其中所述结构域以H2N-(A)-(B)-(C)-COOH、H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(B)-(C)-(A)-COOH、H2N-(C)-(B)-(A)-COOH或H2N-(C)-(A)-(B)-COOH的顺序通过连接体L1和L2连接,并且
其中B包含与血清白蛋白结合的单结构域抗体。
50.编码根据权利要求1-49中任一项所述的三特异性抗原结合蛋白质双抗体的多核苷酸。
51.包含如权利要求50所述的多核苷酸的载体。
52.用根据权利要求51所述的载体转化的宿主细胞。
53.一种药物组合物,其包含(i)根据权利要求1-49中任一项所述的三特异性抗原结合蛋白质、根据权利要求50所述的多核苷酸、根据权利要求51所述的载体或根据权利要求52所述的宿主细胞,和(ii)药学上可接受的载剂。
54.一种产生如权利要求1所述的三特异性抗原结合蛋白质的方法,所述方法包括在允许所述蛋白质表达的条件下培养用包含编码如权利要求1所述的三特异性抗原结合蛋白质的核酸序列的载体转化或转染的宿主,以及从培养物中回收和纯化所产生的蛋白质。
55.一种治疗或改善增生性疾病、肿瘤疾病、炎性疾病、免疫性病症、自身免疫病、传染性疾病、病毒性疾病、变态反应、寄生虫反应、移植物抗宿主病或宿主抗移植物病的方法,其包括向需要这种治疗或改善的受试者施用如权利要求1所述的三特异性抗原结合蛋白质。
56.根据权利要求55所述的方法,其中所述受试者是人。
57.根据权利要求55所述的方法,其中所述方法进一步包括将药剂与如权利要求1所述的三特异性抗原结合蛋白质联合施用。
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