CN110256560A - 通过糖工程的位点特异性抗体-药物偶联 - Google Patents
通过糖工程的位点特异性抗体-药物偶联 Download PDFInfo
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Abstract
本公开提供结合多肽(例如抗体)和其效应部分偶联物(例如抗体药物偶联物或ADC),其包含在所述结合多肽的天然或工程化聚糖内的位点特异性工程化的药物‑聚糖连接基。本公开还提供编码抗原结合多肽的核酸、重组表达载体和用于制备这种抗原结合多肽的宿主细胞。还提供了使用本文公开的抗原结合多肽治疗疾病的方法。
Description
本申请是申请日为:2014年3月10日、申请号为:201480014338.0、题目为“通过糖工程的位点特异性抗体-药物偶联”的申请的分案申请。
相关申请
本申请要求保护2013年3月11日提交的名称为“通过糖工程的位点特异性抗体药物偶联”的美国临时申请61/776,724,2013年3月11日提交的名称为“高度糖基化的结合多肽”的美国临时申请61/776,710,和2013年3月11日提交的名称为“包含Fc的具有改变的糖基化和降低的效应功能的多肽”的美国临时申请61/776,715。上述申请的内容此处以其全文通过提述并入本文。
发明背景
癌症的治疗对于人类来说仍具有极大的挑战性。尽管目前标准的疗法包括手术、放疗和化疗已拯救了许多病人的生命,但对于更加有效的疗法仍存在巨大需求,特别是具有较高效力和更佳治疗窗口的靶向特异性疗法。这些靶向特异性治疗采用抗体-药物偶联物(ADC),其中抗原特异性抗体使非特异性化疗药物靶向肿瘤位点。这些分子在临床环境已显示具有效力和良好的安全性概貌。然而,由于包括抗体本身和连接基的稳定性在内的许多因素可能对肿瘤特异性具有显著影响,进而降低效力,因此这些疗法的建立可能具有挑战性。ADC在循环中具有高度非特异性结合和低稳定性,其在达到肿瘤前会通过正常组织清除。此外,具有高药物载荷的显著亚群的ADC可生成聚集体,其将由巨噬细胞消除,导致较短的半衰期。因此,对关键流程的控制和改进以及并发症的预防如产物聚集和来自IgG的非特异性毒性存在增加的需求。
尽管根据目前的方法生成的ADC是有效的,但由于使用的偶联化学方法通常导致异质混合物,因此这种疗法的建立具有挑战性。举例来说,由于可用于偶联的抗体中存在许多赖氨酸残基(~30)这一事实,因此将药物偶联至抗体的赖氨酸残基十分复杂。由于最佳数目的抗体对药物比率(DAR)低得多(例如大致4:1),赖氨酸偶联通常生成非常异质的分布。此外,许多赖氨酸位于CDR区的重要抗原结合位点且药物偶联可能导致抗体亲和力的降低。其他方面,尽管巯基介导的偶联主要靶向参与铰链二硫键的八个半胱氨酸,但是预测和鉴别八个半胱氨酸中的哪四个在不同的制备物中始终偶联仍十分困难。最近,游离半胱氨酸残基的基因工程已允许使用基于巯基的化学方法进行的位点特异性偶联,但这种连接基经常展示高度变化的稳定性,伴随药物接头经历的与白蛋白和其他含巯基的血清分子的交换反应。因此,生成具有限定的偶联位点和稳定连接基的ADC的位点特异性偶联策略在保证药物偶联并同时最小化对抗体结构或功能的不良影响方面将十分有用。
发明概述
本公开提供结合多肽(例如抗体)及其效应部分偶联物(例如药物偶联物)。在一些实施方案中,所述偶联物包含在所述结合多肽的天然或工程化聚糖内的位点特异性工程化的药物-聚糖连接基。本公开还提供编码抗原结合多肽的核酸、重组表达载体和用于制备这种抗原-结合多肽的宿主细胞。还提供了使用本文公开的抗原-结合多肽治疗疾病的方法。
在一些实施方案中,本发明的结合多肽可由通过稳定(例如肟)连接基偶联效应部分(例如药物部分)获得。该策略提供具有增强的体内稳定性和降低的聚集的高度限定的产物。在其他实施方案中,为提供进一步的位点选择性和均匀性,所述效应部分偶联物(例如药物偶联物)可通过偶联至IgG聚糖的末端糖残基(例如末端唾液酸或半乳糖残基)形成。末端糖残基可容易地通过温和氧化(例如用高碘酸钠)转换成具有反应性的醛形式。其后氧化糖残基可与醛反应性氨氧基药物接头偶联以提供稳定且均质的蛋白-药物偶联物群体(例如ADC)。
相应地,一方面,本发明提供包含至少一种修饰聚糖的结合多肽,所述修饰聚糖含有至少一个式(IV)的部分:
-Gal-Sia-C(H)=N-Q-CON-X
式(IV)
其中:
A)Q是NH或O;
B)CON是连接体部分;且
C)X是效应部分(例如,药物部分或靶向部分);
D)Gal是源自半乳糖的组件;
E)Sia是源自唾液酸的组件;且
其中Sia存在或不存在。
在一个实施方案中,所述修饰聚糖是双触角聚糖。在另一个实施方案中,所述双触角聚糖是岩藻糖化或非岩藻糖化的。在另一实施方案中,所述修饰聚糖包含至少两个式(IV)的部分,其中Sia仅在所述两个部分中的一个部分中存在。在另一实施方案中,所述修饰聚糖包含至少两个式(IV)的部分,其中Sia在两个部分中都存在。在另一实施方案中,所述修饰聚糖N-连接至所述结合多肽。
在另一实施方案中,所述结合多肽包含Fc结构域。在另一实施方案中,所述修饰聚糖经由在Fc结构域的氨基酸位置297处(根据EU编号)的天冬酰胺残基N-连接至所述结合多肽。在另一实施方案中,所述修饰聚糖经由在Fc结构域的氨基酸位置298处(根据EU编号)的天冬酰胺残基N-连接至所述结合多肽。在另一实施方案中,所述Fc结构域是人的。
在另一实施方案中,所述结合多肽包含CH1结构域。在一个实施方案中,所述修饰聚糖经由在CH1结构域的氨基酸位置114处(根据Kabat编号)的天冬酰胺残基N-连接至所述结合多肽。在一个实施方案中,所述结合多肽是抗体或免疫粘附素。
在一个实施方案中,所述效应部分是细胞毒素。在另一实施方案中,所述细胞毒素选自表1列举的细胞毒素的集合。在另一实施方案中,所述效应部分是检测剂。在一些实施方案中,所述效应部分是靶向部分。在一个实施方案中,所述靶向部分是糖或糖肽。在另一实施方案中,所述靶向部分是聚糖。
在另一实施方案中,连接体部分包含pH-敏感接头、二硫化物接头、酶敏感接头或其他可裂解的接头部分。在另一实施方案中,所述连接体部分包含选自表2或14描述的接头部分的集合的接头部分。
其他方面,本发明提供包含本发明的结合多肽和可药用的载剂或赋形剂的组合物。在一个实施方案中,所述治疗或诊断效应部分与结合多肽的比率小于4。在另一实施方案中,所述治疗或诊断效应部分与结合多肽的比率约为2。
其他方面,本发明提供治疗患者的方法,其中包括施用有效的量的本发明的组合物。
其他方面,本发明提供编码本发明的结合多肽的分离的多核苷酸。其他方面,本发明提供包含所述多核苷酸的载体。其他方面,本发明提供包含所述多核苷酸或载体的宿主细胞。
而在其他方面,本发明提供制备本发明的结合多肽的方法,所述方法包括使式(I)的效应部分与改变的包含氧化聚糖的结合多肽发生反应,所述式(I)为:
NH2-Q-CON-X
式(I),
其中:
A)Q是NH或O;
B)CON是连接体部分;且
C)X是效应部分。
在一个实施方案中,所述改变的包含氧化聚糖的结合多肽通过使包含聚糖的结合多肽与温和氧化剂发生反应生成。在一些实施方案中,所述温和氧化剂是高碘酸钠。在一些实施方案中,采用少于1mM的高碘酸钠。在一个实施方案中,所述氧化剂是半乳糖氧化酶。在另一实施方案中,所述包含聚糖的结合多肽含有一个或两个末端唾液酸残基。在另一实施方案中,所述末端唾液酸残基通过用唾液酸转移酶或唾液酸转移酶和半乳糖基转移酶的组合处理所述结合多肽引入。
附图简述
图1是抗体药物偶联物合成的示意图,其中毒素部分与氧化的抗体聚糖的唾液酸残基使用肟连接基连接。
图2是考马斯蓝染色的凝胶,其显示糖基化突变体的表达和纯化。
图3描述使用表面等离子体共振实验评估αβTCR HEBE1 IgG抗体突变体与重组人FcγRIIIa结合(V158&F158)的结果。
图4描述使用表面等离子体共振实验评估αβTCR HEBE1 IgG抗体突变体与重组人FcγRI结合的结果。
图5描述在突变的抗αβTCR抗体存在时PBMC对于TNFa、GM-CSF、IFNy和IL10的细胞因子释放概貌(第2天)。
图6描述在突变的抗αβTCR抗体存在时PBMC对于IL6、IL4和IL2的细胞因子释放概貌(第2天)。
图7描述在突变的抗αβTCR抗体存在时PBMC对于TNFa、GM-CSF、IFNy和IL10的细胞因子释放概貌(第4天)。
图8描述在突变的抗αβTCR抗体存在时PBMC对于IL6、IL4和IL2的细胞因子释放概貌(第4天)。
图9描述通过蛋白免疫印迹和表面等离子体共振研究2C3突变体表达水平的实验结果。
图10描述研究PNGase F处理前和处理后2C3突变体糖基化的实验结果。
图11描述研究从细胞培养分离的2C3突变体上糖基化位点的SDS-PAGE实验结果。
图12描述使用表面等离子体共振实验以评估修饰的抗CD52与重组人FcγRIIIa(V158)结合的结果。使用在Fc结构域中包含S298N/Y300S突变的抗CD52以评估修饰的分子与CD52肽(A)结合、与FcγRIIIa(V158,B)结合和与小鼠FcRn(C)对照结合的效应功能。
图13描述研究2C3突变体的Fc结合性质的表面等离子体共振实验结果。
图14描述研究修饰的抗CD52与FcγRIIIa(Val158)(如上)和FcγRIIIa(Phe158)两者结合的表面等离子体共振实验结果。使用在Fc结构域中包含S298N/Y300S突变的抗CD52抗体以评估修饰的分子与FcγRIIIa(Val158,图14A)和FcγRIIIa(Phe58,图14B)结合的效应功能。
图15描述S298N/Y300S突变体和WT 2C3对照(A)中C1q结合的分析和确认孔的等同包被的Eliza分析结果。
图16描述测量2C3突变体与CD-52肽741结合动力学的等离子体共振实验的实验结果。
图17描述包括WT抗CD-52 2C3和A114N高度糖基化突变体的抗原结合亲和力的等离子体共振实验的实验结果。
图18描述等电聚焦和质谱电荷表征实验以测定2C3突变体的聚糖含量的结果。
图19描述浓缩(Octet)和等离子体共振实验比较WT抗CD52 2C3和突变体的抗原结合亲和力的结果。
图20描述SDS-PAGE实验以证明抗TEM1 A114N突变体的额外糖基化的结果。
图21描述A114N抗Her2突变体的SDS-PAGE和疏水相互作用色谱分析的结果。
图22描述SDS-PAGE实验以证明PEG与2C3 A114N突变体通过氨氧基连接基偶联的结果。
图23描述LC-MS实验以测定抗TEM1 A114N高度糖基化突变体的聚糖含量的结果。
图24描述LC-MS实验以测定野生型HER2抗体和A114N抗Her2高度糖基化突变体的聚糖含量的结果。
图25描述用于实施根据本发明方法的抗体的位点特异性偶联的典型方法。
图26描述本发明典型效应部分的合成:氨氧基-Cys-MC-VC-PABC-MMAE和氨氧基-Cys-MC-VC-PABC-PEG8-Dol10。
图27描述针对唾液酸化的HER2抗体的表征信息。
图28描述针对氧化的唾液酸化的抗HER2抗体的表征信息。
图29描述用三种不同的唾液酸化的抗体与两种不同的氨氧基基团制备的糖偶联物的疏水相互作用色谱。
图30显示使用GAM(+)化学方法制备的抗Her2 A114糖基化突变体与AO-MMAE的偶联物的HIC色谱。
图31描述抗HER2糖偶联物与巯基偶联物的体外效力的比较。
图32描述抗FAP B11糖偶联物和巯基偶联物的体外效力的比较。
图33描述抗HER2糖偶联物和巯基偶联物在Her2+肿瘤细胞异种移植物模型中体内效力的比较。
图34描述LC-MS实验以测定包含S298N/Y300S突变的突变抗αβTCR抗体的聚糖含量的结果。
图35描述圆二色谱实验以测定野生型抗αβTCR抗体与包含S298N/Y300S突变的突变抗αβTCR抗体相对热稳定性的结果。
图36描述针对用带有A114N高度糖基化突变的抗HER抗体和AO-MMAE制备的ADC的细胞增殖试验的结果。
发明详述
本公开提供结合多肽(例如抗体),和其效应部分偶联物(例如药物偶联物)。在一些实施方案中,所述偶联物包含在抗原结合多肽如IgG分子的天然或工程化的聚糖内的位点特异性工程化的药物-聚糖连接基。本公开还提供编码所述抗原-结合多肽的核酸、重组表达载体和用于制备这种抗原结合多肽的宿主细胞。还提供了使用本文公开的抗原结合多肽治疗疾病的方法。
I.定义
如本文使用的术语"结合多肽"或“结合多肽”将指代包含至少一个负责选择性地与感兴趣的靶抗原(例如人抗原)结合的结合位点的多肽(例如抗体)。典型的结合位点包括抗体的可变结构域、受体的配体结合位点或配体的受体结合位点。一些方面,本发明的结合多肽包含多重(例如二、三、四或更多个)结合位点。
如本文使用的术语"天然的残基"将指代在结合多肽(例如抗体或其片段)的特定氨基酸位置天然存在且未经人为修饰、引入或改变的氨基酸残基。如本文使用的术语"改变的结合多肽"或“改变的结合多肽”包括含有至少一个非天然的突变的氨基酸残基的结合多肽(例如抗体或其片段)。
如本文使用的术语"特异性结合"指代抗体或其抗原结合片段以最多如下的解离常数(Kd)与抗原结合的能力:约1x10-6M、1x10-7M、1x10-8M、1x10-9M、1x10-10M、1x10-11M、1x10-12M或更低,和/或抗体或其抗原结合片段以相比其针对非特异性抗原至少高两倍的亲和力与抗原结合的能力。
如本文使用的术语"抗体"指代与感兴趣的抗原(例如肿瘤相关抗原)具有显著已知的特异性的免疫反应活性的这种装配体(例如完整的抗体分子、抗体片段或其变体)。抗体和免疫球蛋白包含轻链和重链,两者间可具有或不具有链间共价连接基。在脊椎动物体系中基本的免疫球蛋白结构已得到相对充分的认识。
如将在下文详细讨论的是,通用术语"抗体"包含五种不同的抗体种类,其可在生化水平进行区分。尽管全部五种抗体都明确属于本公开的保护范围内,但下列讨论将主要针对免疫球蛋白分子的IgG类。对于IgG,免疫球蛋白包含两条分子重量大致为23,000道尔顿的相同轻链和两条分子量为53,000-70,000的相同重链。所述四条链以"Y"构型通过二硫键结合,其中所述轻链在"Y"的开口处开始托架所述重链且持续贯穿可变区。
免疫球蛋白的轻链分为κ或λ(κ,λ)。每种重链可与κ或λ轻链结合。一般而言,所述轻链和重链共价地彼此结合,且当所述免疫球蛋白通过杂交瘤、B细胞或基因工程化的宿主细胞生成时,所述两种重链的"尾"部彼此通过共价二硫化物连接基或非共价连接基键合。在所述重链中,氨基酸序列从Y构型分叉末端处的N-末端持续至每条链底部处的C-末端。本领域的技术人员将理解重链分为γ、μ、α、δ或ε(γ、μ、α、δ、ε),且这些类别中还具有一些亚类(例如γl-γ4)。该链的性质决定了抗体分别为IgG、IgM、IgA、IgG或IgE的"种类"。免疫球蛋白同型亚类(例如IgG1、IgG2、IgG3、IgG4、IgA1等)已详细表征且已知赋予功能上的特质。在本发明的基础上本领域的技术人员可轻易辨别这些类别和同型中的每一种的修饰版本且相应地,其也在本公开的保护范围内。
轻链和重链都分为具有结构和功能同源性的区。术语"区"指代免疫球蛋白或抗体链的部分或组分且包括恒定区或可变区以及所述区更分散的部分或组分。举例来说,轻链可变区包括穿插在如本文定义的"框架区"或"FR"中的"互补决定区"或"CDR"。
在"恒定区"的情况中基于多种类别成员在所述区中序列变化的相对缺乏,或在"可变区"的情况中基于多种类别成员在所述区中的显著变化,免疫球蛋白重链或轻链的区可以定义为"恒定"(C)区或"可变"(V)区。术语"恒定区"和"可变区"还可在功能上使用。在这方面,可以理解的是免疫球蛋白或抗体的可变区决定抗原识别和特异性。相反地,免疫球蛋白或抗体的恒定区赋予重要的效应功能如分泌、经胎盘的移动性、Fc受体结合、补体结合等等。已知许多免疫球蛋白种类的恒定区的亚单元结构和三维构型。
免疫球蛋白重链和轻链的恒定和可变区折叠成为结构域。术语"结构域"指代重链或轻链的球状区,其包含通过举例来说β-折叠片层和/或链间二硫键稳定的肽环(例如包含3到4个肽环)。免疫球蛋白轻链上的恒定区结构域可互换地称为"轻链恒定区结构域"、"CL区"或"CL结构域"。重链上的恒定结构域(例如铰链、CH1、CH2或CH3结构域)可互换地称为"重链恒定区结构域"、"CH"区结构域或"CH结构域"。轻链上的可变结构域可互换地称为"轻链可变区结构域"、"VL区结构域或"VL结构域"。重链上的可变结构域可互换地称为"重链可变区结构域"、"VH区结构域"或“VH结构域"。
按照惯例,可变恒定区结构域的标号随其距离免疫球蛋白或抗体的抗原结合位点或氨基末端变远而增加。每条重或轻免疫球蛋白链的N-末端是可变区且C-末端是恒定区;CH3和CL结构域实际上分别包含重链或轻链的羧基-末端。相应地,轻链免疫球蛋白的结构域以VL-CL方向排列,而重链的结构域以VH-CH1-铰链-CH2-CH3的方向排列。
氨基酸在重链恒定区中的位置,包括氨基酸在CH1、铰链、CH2、CH3和CL结构域中的位置可根据Kabat索引编号系统进行编号(参见Kabat et al,in"Sequences of proteinsof Immunological Interest",U.S.Dept.Health and Human Services,5th edition,1991)。可替换地,抗体的氨基酸位置可根据EU索引编号系统进行编号(参见Kabat et al,ibid)。
如本文使用的术语"VH结构域"包括免疫球蛋白重链的氨基末端可变结构域,而术语"VL结构域"包括免疫球蛋白轻链的氨基末端可变结构域。
如本文使用的术语"CH1结构域"包括免疫球蛋白重链的第一(氨基最末端)恒定区结构域,其例如在Kabat编号系统中延伸自约位置114-223(EU位置118-215)。CH1结构域与VH结构域毗邻并且位于免疫球蛋白重链分子的铰链区的氨基末端,且不形成免疫球蛋白重链Fc区的一部分。
如本文使用的术语"铰链区"包括将CH1结构域结合至CH2结构域的重链分子部分。该铰链区包含大致25个残基且是柔性的,因此允许两个N-末端抗原结合区独立运动。铰链区可细分为三个不同的结构域:上、中和下铰链结构域(Roux et al.J.Immunol.1998,161:4083)。
如本文使用的术语"CH2结构域"包括重链免疫球蛋白分子的如下部分,其延伸自例如约Kabat编号系统(EU位置231-340)的位置244-360。CH2结构域是独特的,这在于其并不与另一结构域紧密配对。相反,两条N连接的分支糖插入完整的天然IgG分子的两个CH2结构域之间。在一个实施方案中,本公开的结合多肽包含源自IgG1分子的CH2结构域(例如人IgG1分子)。
如本文使用的术语"CH3结构域"包括重链免疫球蛋白分子的如下部分,其从CH2结构域的N-末端(例如从约Kabat编号系统的位置361-476(EU位置341-445))延伸大致110残基。CH3结构域通常形成抗体的C-末端部分。然而在一些免疫球蛋白中,额外的结构域可从CH3结构域延伸以形成分子的C-末端部分(例如IgM的μ链和IgE的e链中的CH4结构域)。在一个实施方案中,本公开的结合多肽包含源自IgG1分子(例如人IgG1分子)的CH3结构域。
如本文使用的术语"CL结构域"包括免疫球蛋白轻链的恒定区结构域,其例如延伸自约Kabat位置107A-216。CL结构域与VL结构域毗邻。在一个实施方案中,本公开的结合多肽包含源自κ轻链(例如人κ轻链)的CL结构域。
如本文使用的术语"Fc区"定义为重链恒定区的部分,其开始于铰链区中木瓜蛋白酶裂解位点的正好上游(just upstream)(将重链恒定区的第一残基视为114的话,即IgG中的残基216),并止于抗体的C-末端。相应地,完整的Fc区至少包含铰链结构域、CH2结构域和CH3结构域。
如本文使用的术语"天然Fc"指代包含非抗原结合片段的序列,无论是单体或多聚体形式,其可从抗体的消化或由其他方式产生获得,且可包含铰链区。天然Fc的初始的免疫球蛋白来源优选是人来源且可以是任何免疫球蛋白,尽管IgG1和IgG2是优选的。天然Fc分子由可通过共价(即二硫键)和非共价缔合连接成为二聚体或多聚体形式的单体多肽组成。天然Fc分子单体亚单位间的分子间二硫键的数目可为1-4,取决于种类(例如IgG、IgA和IgE)或亚类(例如IgG1、IgG2、IgG3、IgA1和IgGA2)。天然Fc的一个实例是从IgG的木瓜蛋白酶消化产生的二硫键键合的二聚体。如本文使用的术语"天然Fc"为单聚、二聚和多聚形式的上位术语。
如本文使用的术语"Fc变体"指代从天然Fc修饰而来但仍包含用于补救受体(salvage receptor)、FcRn(新生儿Fc受体)的结合位点的分子或序列。典型的Fc变体和其与补救受体的相互作用为本领域已知。因此,术语"Fc变体"可包含从非人天然Fc人源化的分子或序列。此外,天然的Fc包含由于提供并非为本发明的抗体样结合多肽所需的结构特征或生物活性而可去除的区。因此,术语"Fc变体"包含缺乏一个或多个天然Fc位点或残基的分子或序列,或其中一个或多个Fc位点或残基已修饰,所述位点或残基影响或参与:(1)二硫键形成,(2)与选择的宿主细胞的不兼容性,(3)在选择的宿主细胞中表达时N-末端的异质性,(4)糖基化,(5)与补体的相互作用,(6)与Fc受体而非补救受体的结合,或(7)抗体依赖的细胞的细胞毒性(ADCC)。
如本文使用的术语"Fc结构域"涵盖天然Fc和如上文定义的Fc变体和序列。与Fc变体和天然Fc分子相同的是,术语"Fc结构域"包括单聚或多聚形式的分子,无论是从完整抗体消化或通过其他方式产生。
如上文所示,抗体的可变区允许其选择性地识别和特异性地结合抗原上的表位。也就是说,抗体的VL结构域和VH结构域组合以形成界定三维抗原结合位点的可变区(Fv)。这种四元抗体结构形成存在于Y的每个臂的末端的抗原结合位点。更具体地,所述抗原结合位点通过在每条重链和轻链可变区上的三个互补决定区(CDR)界定。如本文使用的术语"抗原结合位点"包括特异性结合(与其发生免疫反应)抗原(例如细胞表面或可溶抗原)的位点。抗原结合位点包括免疫球蛋白重链和轻链可变区且通过这些可变区形成的结合位点决定抗体的特异性。抗原结合位点通过一个抗体与另一抗体间不同的可变区形成。本公开的改变的抗体包含至少一个抗原结合位点。
在一些实施方案中,本公开的结合多肽包含至少两个提供用于结合多肽与选择的抗原缔合的抗原结合结构域。所述抗原结合结构域无需源自相同的免疫球蛋白分子。在这方面,可变区可以或为源自可对其进行诱导以装载体液应答和生成抗预期抗原的免疫球蛋白的任何类型的动物。由此,所述结合多肽的可变区可以是举例来说哺乳动物来源的,例如可以是人、鼠类、大鼠、山羊、绵羊、非人灵长类动物(如食蟹猴、猕猴等)、狼或驼类(camelid)(例如来自骆驼、美洲驼和相关品种)。
在天然存在的抗体中,当抗体在水性环境中呈现其三维构型,每个单聚抗体上的CDR为特异性定位以形成抗原结合位点的氨基酸的短的、非连续序列。重链和轻链可变结构域的剩余部分显示氨基酸序列中较少的分子间可变性且称为框架区。所述框架区大量采取β-片层构象,并且CDR形成连接所述β-片层结构(在一些情况中,形成β-片层结构的一部分)的环。因此,这些框架区发挥作用以形成通过链间非共价相互作用用以使六个CDR在正确方向定位的支架。通过定位的CDR形成的抗原结合结构域界定与免疫反应性抗原的表位互补的表面。该互补表面促进抗体与免疫反应性抗原表位的非共价结合。
本发明的典型结合多肽包括抗体变体。如本文使用的术语“抗体变体”包括合成的和工程化形式的抗体,其经过改变因此其并非天然存在的,例如包含至少两个重链部分但不包含两个完整重链的抗体(如结构域缺失的抗体或微型抗体);改变以结合至两种或多种不同抗原或至单一抗原上的不同表位的多重特异性(例如双特异性、三特异性等)抗体形式;与scFv分子结合的重链分子等等。此外,术语“抗体变体”包括多价形式的抗体(例如三价、四价等,与相同抗原的三个、四个或多个拷贝结合的抗体。
如本文使用的术语“价”指代在多肽中潜在的靶结合位点的数目。每个靶结合位点特异性结合一个靶分子或在靶分子上的特异性位点。当多肽包含多于一个靶结合位点时,每个靶结合位点可特异性结合相同或不同分子(例如可与不同配体或不同抗原或相同抗原上的不同表位结合)。主题结合多肽优选具有至少一个特异性针对人抗原分子的结合位点。
术语“特异性”指代特异性结合给定靶抗原(例如人靶抗原)(例如与其发生免疫反应)的能力。结合多肽可以是单特异性或包含一个或多个特异性结合靶的结合位点或多肽可以是多重特异性的且包含两个或多个特异性结合相同或不同靶的结合位点。在一些实施方案中,本发明的结合多肽特异性针对相同靶的两个不同(例如非重叠的)部分。在一些实施方案中,本发明的结合多肽特异性针对多于一个靶。包含与表达在肿瘤细胞上的抗原结合的抗原结合位点的典型结合多肽(例如抗体)为本领域已知且来自这种抗体的一个或多个CDR可包括在本发明的抗体中。
术语"连接部分"包括能够将效应部分与本文公开的结合多肽连接的部分。可根据其可裂解(例如可酶裂解或pH-敏感)或非-可裂解对连接部分进行选择。典型的连接部分阐述于本文的表2中。
如本文使用的术语"效应部分"包含具有生物学或其他功能活性的作用剂(例如蛋白、核酸、脂质、糖、糖肽、药物部分和其片段)。举例来说,包含与结合多肽偶联的效应部分的修饰的结合多肽与未偶联的抗体相比具有至少一种额外的功能或特性。举例来说,毒性药物(例如效应部分)与结合多肽的偶联导致具有作为第二功能(即抗原结合以外)的药物毒性的结合多肽的形成。在另一实例中,第二结合多肽与结合多肽的偶联可赋予额外的结合性质。在一些实施方案中,其中效应部分是基因编码的治疗或诊断蛋白或核酸,所述效应部分可通过肽合成或本领域已知的重组DNA的方法而合成或表达。另一方面,其中所述效应部分是非基因编码的肽或药物部分,所述效应部分可人工合成或从天然来源纯化。如本文使用的术语"药物部分"包括抗炎、抗癌、抗感染(例如抗真菌、抗细菌、抗寄生物、抗病毒等)和麻醉治疗剂。在进一步的实施方案中,药物部分是抗癌或细胞毒性剂。相容的药物部分还可包含前体药物。典型的效应部分阐述于本文的表1中。
在一些实施方案中,“效应部分”包含“靶向部分”。如本文使用的术语"靶向部分"指代与靶分子结合的效应部分。靶向部分可以包括但不限于蛋白、核酸、脂质、糖(例如聚糖)及其组合(例如糖蛋白、糖肽和糖脂)。
如本文使用的术语"前体药物"指代与母体药物相比不那么活跃、具有反应性或容易产生副作用的药物活性剂的前体或衍生形式,且其能够在体内酶激活或以其他方式转变成更活跃的形式。与本公开的组合物相容的前体药物包括但不限于含磷酸盐的前体药物、含氨基酸的前体药物、含硫代磷酸盐的前体药物、含硫酸盐的前体药物、含肽的前体药物、含β-内酰胺的前体药物,含有任选的取代的苯氧酰胺前体药物或含有任选的取代的苯乙酰胺的前体药物、5-氟胞嘧啶和其他可转变为更活跃的细胞毒性游离药物的5-氟尿嘧啶的前体药物。本领域的技术人员可对预期的药物部分或其前体药物制备化学修饰进而就制备本公开的修饰的结合多肽而言使该化合物的反应更加便利。药物部分还包括本文描述的药物部分的衍生物、可药用的盐、酯、酰胺和醚。衍生物包括对本文鉴别的药物的修饰,其可以改进或不显著降低特定药物的预期治疗活性。
如本文使用的术语"抗癌剂"包括对赘生性或肿瘤细胞的生长和/或增殖不利且可发挥作用以降低、抑制或摧毁恶性肿瘤的作用剂。这种作用剂的实例包括但不限于细胞抑制剂、烷化剂、抗生素、细胞毒核苷、微管蛋白结合剂、激素、激素拮抗剂、细胞毒性剂等等。细胞毒性剂包括茅屋霉素衍生物、美登素衍生物、cryptophycine衍生物、蒽环类衍生物,二膦酸衍生物、来普霉素衍生物、链黑菌素衍生物、奥瑞他汀衍生物和duocarmycin衍生物。任何延迟或减缓免疫反应细胞或恶性细胞生长的作用剂都在本公开的保护范围之内。
如本文使用的术语"抗原"或"靶抗原"指代能够通过结合多肽的结合位点结合的分子或分子的部分。靶抗原可以具有一个或多个表位。
II.结合多肽
一方面,本公开提供包含糖基化的结构域例如糖基化的恒定结构域的结合多肽(例如抗体、抗体片段、抗体变体和融合蛋白)。本文公开的结合多肽涵盖任何包含具有N-连接糖基化位点的结构域的结合多肽。在一些实施方案中,所述结合多肽是抗体或其片段或衍生物。可将来自任何来源或物种的任何抗体应用于本文公开的结合多肽中。合适的抗体包括但不限于人抗体、人源化的抗体或嵌合抗体。
在一些实施方案中,所述的糖基化结构域是Fc结构域。在一些实施方案中,所述糖基化结构域是在N297处的天然糖基化结构域。
在其他实施方案中,所述糖基化结构域是工程化的糖基化结构域。在Fc结构域中典型的工程化的糖基化结构域包含在氨基酸位置298处(根据EU编号)的天冬酰胺残基;和在氨基酸位置300处的丝氨酸或苏氨酸残基(根据EU编号)。
来自任何免疫球蛋白种类(例如IgM、IgG、IgD、IgA和IgE)和物种的Fc结构域可用于本文公开的结合多肽。也可采用包含来自不同物种或Ig种类的Fc结构域部分的嵌合Fc结构域。在一些实施方案中,所述Fc结构域是人IgG1Fc结构域。在人IgG1Fc结构域的情况中,在Kabat位置298处的野生型氨基酸突变成天冬酰胺并且在Kabat位置300处的野生型氨基酸突变成丝氨酸或苏氨酸导致N-连接糖基化共有位点的形成(即N-X-T/S序列子,其中X是除脯氨酸外的任何氨基酸)。然而,在其他物种和/或Ig种类或同型的Fc结构域的情况中,本领域的技术人员会理解如果脯氨酸残基存在,有必要将Fc结构域的Kabat位置229突变以产生N-X-T/S序列子。
在其他实施方案中,本公开提供包含至少一个具有N-连接糖基化位点的CH1结构域的结合多肽(例如抗体、抗体片段、抗体变体和融合蛋白)。这种典型的结合多肽可包括举例来说在位置114处(Kabat编号)的工程化的糖基化位点。
来自任何免疫球蛋白类型(例如IgM、IgG、IgD、IgA和IgE)和种类的CH1结构域可用于本文公开的结合多肽。也可采用包含来自不同种类或Ig类型的CH1结构域的部分的嵌合CH1结构域。在一些实施方案中,所述CH1结构域是人IgG1CH1结构域。在人IgG1结构域的情况中,在位置114处的野生型氨基酸突变成天冬酰胺导致N连接糖基化共有位点(即N-X-T/S序列子,其中X是除脯氨酸外的任何氨基酸)的形成。然而,在其他种类和/或Ig类型或同型的其他CH1结构域的情况中,本领域的技术人员将理解有必要将CH1结构域位置115和/或116突变以生成N-X-T/S序列子。
在一些实施方案中,本公开的结合多肽可包含抗体的抗原结合片段。术语"抗原结合片段"指代结合抗原或与完整抗体竞争(即与其所来自的完整抗体竞争)抗原结合(即特异性结合)的免疫球蛋白或抗体的多肽片段。抗原结合片段可通过本领域熟知的重组或生化方法产生。典型的抗原结合片段包括Fv、Fab、Fab'和(Fab')2。在优选的实施方案中,本公开的抗原结合片段是包含至少一个工程化的糖基化位点的改变的抗原结合片段。在一个典型的实施方案中,本公开的改变的抗原结合片段包含前文所述的改变的VH结构域。在另一个典型的实施方案中,本公开的改变的抗原结合片段包含前文所述的改变的CH1结构域。
在典型的实施方案中,所述结合多肽包含单链可变区序列(ScFv)。单链可变区序列包含具有至少一个或多个抗原结合位点的单多肽,例如通过柔性接头与VH结构域连接的VL结构域。ScFv分子可以VH-接头-VL的方向或VL-接头-VH的方向构建。连接组成抗原结合位点的VL和VH结构域的柔性铰链优选包含约10至约50氨基酸残基。连接肽为本领域已知。本发明的结合多肽可包含至少一个scFv和/或至少一个恒定区。在一个实施方案中,本公开的结合多肽可包含至少一个与包含CH1结构域(例如在Kabat位置114处包含天冬酰胺残基的CH1结构域)和/或CH2结构域(例如在EU位置298处包含天冬酰胺残基和在EU位置300处包含丝氨酸或苏氨酸的CH2结构域)的抗体或片段连接或融合的scFv。
在一些典型的实施方案中,本公开的结合多肽是通过将编码抗体的DNA序列与ScFv分子(例如改变的ScFv分子)融合产生的多价(例如四价)抗体。举例来说,在一个实施方案中,组合这些序列进而ScFv分子(例如改变的ScFv分子)在其N-末端或C-末端与抗体的Fc片段经由柔性接头(例如gly/ser接头)连接。在另一实施方案中,本公开的四价抗体可通过将ScFv分子与连接肽融合制备,其与CH1结构域(例如在Kabat位置114处包含天冬酰胺残基的CH1结构域)融合以构建ScFv-Fab四价分子。
在另一实施方案中,本公开的结合多肽是改变的微型抗体。本公开的改变的微型抗体是各自包含ScFv分子(例如包含前文所述的改变的VH结构域的改变的ScFv分子)的两条多肽链组成的二聚分子,其与CH3结构域或其部分经由连接肽融合。微型抗体可通过构建ScFv组件和连接肽-CH3组件使用本领域描述的方法制备(参见例如US专利5,837,821或WO94/09817Al)。在另一实施方案中,可构建四价微型抗体。四价微型抗体可以与微型抗体相同的方式构建,除了两个ScFv分子使用柔性接头连接以外。连接的scFv-scFv构建体随后与CH3结构域结合。
在另一实施方案中,本公开的结合多肽包含双抗体。双抗体是各具有与scFv分子相似的多肽的二聚、四价分子,但其通常具有连接两个可变结构域的短(小于10且优选地为1-5)氨基酸残基接头进而使在相同多肽链上的VL和VH结构域不能相互作用。反而,一条多肽链的VL和VH结构域与在第二条多肽链上的VH和VL结构域(分别)相互作用(参见举例来说WO 02/02781)。本公开的双抗体包含与CH3结构域融合的scFv分子。
在其他实施方案中,本发明的结合多肽包含在相同多肽链上含有一个或多个系列可变结构域的多重特异性或多价抗体,例如串联结构域(TVD)多肽。典型的TVD多肽"双头"或"双-Fv"构型,描述于美国专利号5,989,830中。在双-Fv构型中,两种不同抗体的可变结构域在两条分离的链(一条重链和一条轻链)上以串联方向表达,其中一条多肽链具有通过肽接头分离的两个系列VH结构域(VH1-接头-VH2)且另一多肽链由通过肽接头系列连接的互补VL结构域组成(VL1-接头-VL2)。在交叉双头构型中,两种不同抗体的可变结构域在两条分离的多肽链上(一条重链和一条轻链)以串联方向表达,其中一条多肽链具有两个通过肽接头分离的两个系列VH结构域(VH1-接头-VH2)且另一多肽链由在相反方向的通过肽接头系列连接的互补VL结构域组成(VL2-接头-VL1)。基于"双-Fv"形式的额外抗体变体包括双可变结构域IgG(DVD-IgG)双特异性抗体(参见美国专利号7,612,181和TBTI形式(参见US2010/0226923 A1)。恒定结构域向双Fv的各条链的添加(CH1-Fc向重链和κ或λ恒定结构域向轻链)导致功能双特异性抗体而无需任何额外修饰(即恒定结构域的明显添加以增强稳定性)。
在另一典型的实施方案中,所述结合多肽包含基于"双头"构型的交叉双可变结构域IgG(CODV-IgG)双特异性抗体(参见US20120251541 A1,其在本文通过提述以其全文并入)。CODV-IgG抗体变体具有其中VL结构域与CL结构域系列连接(VL1-L1-VL2-L2-CL)的一条多肽链和其中互补VH结构域以相反的方向与CH1结构域系列连接的第二多肽链(VH2-L3-VH1-L4-CH1),其中所述多肽链形成交叉的轻链-重链配对。在一些实施方案中,所述第二多肽可进一步与Fc结构域连接(VH2-L3-VH1-L4-CH1-Fc)。在一些实施方案中,接头L3是接头L1长度的至少两倍且/或接头L4是接头L2长度的至少两倍。举例来说,L1和L2长度上可以是1-3个氨基酸残基,L3在长度上可以是2至6个氨基酸残基,且L4在长度上可以是4至7个氨基酸残基。合适的接头的实例包括单甘氨酸(Gly)残基;二甘氨酸肽(Gly-Gly);三肽(Gly-Gly-Gly);具有四个甘氨酸残基的肽(Gly-Gly-Gly-Gly);具有五个甘氨酸残基的肽(Gly-Gly-Gly-Gly-Gly);具有六个甘氨酸残基的肽(Gly-Gly-Gly-Gly-Gly-Gly);具有七个甘氨酸残基的肽(Gly-Gly-Gly-Gly-Gly-Gly-Gly);具有八个甘氨酸残基的肽(Gly-Gly-Gly-Gly-Gly-Gly-Gly-Gly)。也可使用其他氨基酸残基的组合如肽Gly-Gly-Gly-Gly-Ser和肽Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser。
在一些实施方案中,所述结合多肽包含免疫粘附素分子,所述免疫粘附素分子包含与抗体恒定区融合的非抗体结合区(例如受体、配体或细胞粘附分子)(参见例如Ashkenazi et al.,Methods,1995 8(2),104–115,将其通过提述整体并入本文)。
在一些实施方案中,所述结合多肽包含免疫球蛋白-样结构域。合适的免疫球蛋白-样结构域包括但不限于纤维连接蛋白结构域(参见举例来说,Koide et al.(2007),Methods Mol.Biol.352:95–109,其在本文通过提述以其全文并入)、DARPin(参见举例来说,Stumpp et al.(2008)Drug Discov.Today 13(15–16):695–701,其在本文通过提述以其全文并入)、蛋白A的Z结构域(参见Nygren et al.(2008)FEBS J.275(11):2668–76,其在本文通过提述以其全文并入)、Lipocalins(参见举例来说,Skerra et al.(2008)FEBSJ.275(11):2677–83其在本文通过提述以其全文并入)、Affilins(参见举例来说,Ebersbach et al.(2007)J.Mol.Biol.372(1):172–85,其在本文通过提述以其全文并入)、Affitins(参见举例来说,Krehenbrink et al.(2008)。J.Mol.Biol.383(5):1058–68,其在本文通过提述以其全文并入)、Avimers(参见举例来说,Silverman et al.(2005)Nat.Biotechnol.23(12):1556–61,其在本文通过提述以其全文并入)、Fynomers(参见举例来说,Grabulovski et al.(2007)J Biol Chem 282(5):3196–3204,其在本文通过提述以其全文并入)和Kunitz结构域肽(参见举例来说,Nixon et al.(2006)Curr Opin DrugDiscov Devel 9(2):261–8,其在本文通过提述以其全文并入)。
III.N-连接聚糖
在一些实施方案中,本发明的结合多肽采用经由天冬酰胺残基“N-连接”至结合多肽的多肽骨架中的糖基化位点的N-连接聚糖。所述糖基化位点可以是天然的或工程化的糖基化位点。额外的或可替换地,聚糖可以是天然聚糖或包含非天然连接基的工程化聚糖。
在一些典型的实施方案中,本发明的结合多肽包含抗体Fc结构域的天然糖基化位点。这种天然糖基化位点包含在Fc结构域位置297处(N297)(根据EU编号)的野生型天冬酰胺残基。存在于该位置的天然的N-连接聚糖通常通过β-糖基酰胺连接基与N297侧链的氮基团连接。然而,也可采用其他合适的本领域认可的连接基。在其他典型的实施方案中,本发明的结合多肽包含一个或多个工程化的糖基化位点。这种工程化的糖基化位点包含将结合多肽的多肽骨架中一个或多个野生型氨基酸用能够由细胞的糖基化酶进行N-糖基化的天冬酰胺残基取代。本发明典型的工程化糖基化位点包括在Fc结构域的氨基酸位置298处(298N)或CH1结构域的氨基酸位置114处的天冬酰胺突变的引入。
任何类型的天然存在或合成的(即非天然)N-连接聚糖可与本发明结合多肽的糖基化位点连接。在一些实施方案中,所述聚糖包含可氧化(例如通过高碘酸盐处理或半乳糖氧化酶)的糖(例如位于寡糖末端的糖残基)以生成适于与效应部分(例如具有反应性的醛基基团)偶联的基团。合适的可氧化糖包括但不限于半乳糖和唾液酸(例如N-乙酰神经氨酸)。在一些实施方案中,所述聚糖是双触角聚糖(biantennary glygan)。在一些实施方案中,所述聚糖是天然存在的哺乳动物糖形。
糖基化可通过任何本领域已知的方式实现。在一些实施方案中,所述糖基化通过能够在细胞中N-连接糖基化的结合多肽的表达实现。可采用任何天然或工程化的细胞(例如原核或真核)。一般而言,采用哺乳动物细胞以实现糖基化。在哺乳动物细胞中产生的N-聚糖通常指代为复杂的、高甘露糖、混合型N-聚糖(参见例如Drickamer K,Taylor ME(2006).Introduction to Glycobiology,2nd ed.,其在本文通过提述以其全文并入)。这些复杂的N-聚糖具有的结构通常有二至六个外部分支,所述外部分支具有与内部核心结构Man3GlcNAc2连接的唾液酸乳糖胺序列。复杂的N-聚糖具有终止于寡糖的交替的GlcNAc和半乳糖(Gal)残基的至少一个分支,且优选至少两个,如举例来说:NeuNAc-;NeuAcα2,6GalNAcα1-;NeuAcα2,3Galβ1,3GalNAcα1-和NeuAcα2,3/6Galβ1,4GlcNAcβ1.;此外,硫酸酯可存在于半乳糖、GalNAc和GlcNAc残基上。NeuAc可以是O-乙酰化的或由NeuGl(N-羟乙酰神经氨酸)替代。复杂的N-聚糖还可以具有双开叉(bisecting)的GlcNAc和核心岩藻糖(Fuc)的链间取代。
此外或可替换地,糖基化可在体外通过酶的方式获得或修饰。举例来说,可采用一种或多种糖基转移酶添加特定的糖残基至结合多肽的天然或工程化的N-聚糖,且可采用一种或多种糖苷酶以从N-连接聚糖去除不想要的糖。这种酶的方式为本领域已知(参见例如WO2007/005786,其在本文通过提述以其全文并入)。
IV.免疫效应功能和Fc修饰
在一些实施方案中,本发明的结合多肽可包含介导一种或多种效应功能的抗体恒定区(例如IgG恒定区,例如人IgG恒定区,例如人IgG1或IgG4恒定区)。举例来说,C1-复合体与抗体恒定区的结合可激活补体系统。补体系统的激活在细胞病原体的调理作用和裂解中至关重要。补体系统的激活还刺激炎性响应且还可以参与自身免疫超敏反应。此外,抗体与在多种细胞上的受体经由Fc区结合(在抗体Fc区的Fc受体结合位点与细胞上的Fc受体(FcRs)结合)。存在多种特异性针对不同种类的抗体的Fc受体,包括IgG(γ受体)、IgE(ε受体)、IgA(α受体)和IgM(μ受体)。抗体与细胞表面上的Fc受体的结合激发多种重要且多样的生物响应,包括抗体包被的微粒的吞噬和破坏、免疫复合体的清除、抗体包被的靶细胞由杀伤细胞裂解(称为抗体依赖的细胞介导毒性或ADCC)、炎性调节子的释放、胎盘转移和免疫球蛋白产生的控制。在优选的实施方案中,本发明的结合多肽(例如抗体或其抗原结合片段)与Fc-γ受体结合。在可替换的实施方案中,本发明的结合多肽可包含缺乏一种或多种效应功能(例如ADCC活性)且/或不能与Fcγ受体结合的恒定区。
本发明的一些实施方案包括抗体,其中缺失或以其他方式改变了在一个或多个恒定区结构域中的至少一个氨基酸进而提供预期的生化特性,如与具有大致相同的免疫原性的完整或未改变的抗体相比时降低或增强的效应功能、非共价二聚化的能力、增加的在肿瘤位点定位的能力、降低的血清半衰期或增加的血清半衰期。举例来说,本文描述的用于在诊断和治疗方法中使用的一些抗体是结构域缺失的抗体,其包含与免疫球蛋白重链相似的多肽链,但缺少至少一个或多个重链结构域的一部分。举例来说,在一些抗体中,会缺失修饰的抗体恒定区的一个完整的结构域,举例来说,缺失CH2结构域的全部或部分。
在一些其他实施方案中,结合多肽包含源自不同抗体同型的恒定区(例如来自两个或多个人IgG1、IgG2、IgG3或IgG4的恒定区)。在其他实施方案中,结合多肽包含嵌合铰链(即包含源自不同抗体同型的铰链结构域(例如来自IgG4分子的上铰链结构域和IgG1中铰链结构域)的铰链区的铰链)。在一个实施方案中,结合多肽包含来自人IgG4分子的Fc区或其部分和在分子的核心铰链区中的Ser228Pro突变(EU编号)。
在一些实施方案中,可使用本领域已知的技术突变Fc部分以增加或减少效应功能。举例来说,恒定区结构域的缺失或失活(通过点突变或其他方式)可降低循环的修饰抗体的Fc受体结合,由此增加肿瘤定位。在其他情况中,与本发明相符的恒定区修饰可缓和补体结合且因此降低血清半衰期和偶联的细胞毒素的非特异性缔合。而恒定区的其他修饰可用于修饰由于增加的抗原特异性或柔性而允许增强的定位的二硫化物连接基或寡糖部分。可使用本领域已知的免疫技术而无需过度实验来轻易测量和量化所得修饰的生理概貌、生物利用度和其他生化效果,如肿瘤定位、生物分布和血清半衰期。
在一些实施方案中,在本发明的抗体中采用的Fc结构域是Fc变体。如本文使用的术语"Fc变体"指代相对于所述Fc结构域所来源的野生型Fc结构域具有至少一个氨基酸取代的Fc结构域。举例来说,其中所述Fc结构域源自人IgG1抗体、所述人IgG1Fc结构域的Fc变体相对于所述Fc结构域包含至少一个氨基酸取代。
Fc变体的氨基酸取代可以位于Fc结构域内的任何位置(即任何EU惯例的氨基酸位置)。在一个实施方案中,所述Fc变体包含位于铰链结构域或其部分中的氨基酸位置处的取代。在另一实施方案中,所述Fc变体包含位于CH2结构域或其部分中的氨基酸位置处的取代。在另一实施方案中,所述Fc变体包含位于CH3结构域或其部分中的氨基酸位置处的取代。在另一实施方案中,所述Fc变体包含位于CH4结构域或其部分中的氨基酸位置处的取代。
本发明的结合多肽可采用任何本领域认可的已知在效应功能和/或FcR结合中赋予改进(例如,降低或增强)的Fc变体。所述Fc变体可包括举例来说下列中公开的任何氨基酸取代:国际PCT公开WO88/07089A1、WO96/14339A1、WO98/05787A1、WO98/23289A1、WO99/51642A1、WO99/58572A1、WO00/09560A2、WO00/32767A1、WO00/42072A2、WO02/44215A2、WO02/060919A2、WO03/074569A2、WO04/016750A2、WO04/029207A2、WO04/035752A2、WO04/063351A2、WO04/074455A2、WO04/099249A2、WO05/040217A2、WO05/070963A1、WO05/077981A2、WO05/092925A2、WO05/123780A2、WO06/019447A1、WO06/047350A2和WO06/085967A2或美国专利号5,648,260;5,739,277;5,834,250;5,869,046;6,096,871;6,121,022;6,194,551;6,242,195;6,277,375;6,528,624;6,538,124;6,737,056;6,821,505;6,998,253;和7,083,784,其每一项在本文通过提述以其全文并入。在一个典型的实施方案中,本发明的结合多肽可包含在EU位置268处含有氨基酸取代的Fc变体(例如H268D或H268E)。在另一典型的实施方案中,本发明的结合多肽可在EU位置239处(例如S239D或S239E)和/或EU位置332处(例如I332D或I332Q)包含氨基酸取代。
在一些实施方案中,本发明的结合多肽可包含含有改变抗体的抗原依赖效应功能特别是结合多肽的循环半衰期的氨基酸取代的Fc变体。当与缺乏这些取代的结合多肽比较时,这种结合多肽展示与FcRn增加的或降低的结合,因此在血清中分别具有增加的或减少的半衰期。具有针对FcRn改进的亲和力的Fc变体预期具有较长的血清半衰期,且当期望施用的抗体具有较长半衰期时,这种分子在治疗哺乳动物的方法中具有有效应用,例如治疗慢性疾病或病症。相反,具有降低的FcRn结合亲和力的Fc变体预期具有较短半衰期且这种分子同样有效,举例来说,当缩短的循环时间可能有利时用于哺乳动物的施用,例如用于体内诊断成像或在当存在于用于时期延长的循环中时初始抗体具有毒副作用的情况中。具有降低的FcRn结合亲和力的Fc变体也不大可能穿过胎盘,且因此可在怀孕妇女中有效治疗疾病或病症。此外,其中可能期望降低的FcRn结合亲和力的其他应用包括定位在脑、肾和/或肝的应用。在一个典型的实施方案中,本发明改变的结合多肽(例如抗体或其抗原结合片段)展示降低的从血管穿过肾小球表皮的运输。在另一实施方案中,本发明改变的结合多肽(例如抗体或其抗原结合片段)展示从脑穿过血脑屏障(BBB)进入血管间隙的降低的运输。在一个实施方案中,具有改变的FcRn结合的抗体包含在Fc结构域的"FcRn结合环"内具有一个或多个氨基酸取代的Fc结构域。所述FcRn结合环由氨基酸残基280-299(根据EU编号)组成。改变FcRn结合活性的典型氨基酸取代公开于国际PCT公开No.WO05/047327,其在本文通过提述以其全文并入。在一些典型的实施方案中,本发明的结合多肽(例如抗体或其抗原结合片段)包含具有一个或多个下列取代的Fc结构域:V284E、H285E、N286D、K290E和S304D(EU编号)。而在其他典型的实施方案中,本发明的招标分子包含具有双突变H433K/N434F的人Fc结构域(参见例如美国专利号8,163,881)。
在其他实施方案中,用于本文描述的诊断和治疗方法中使用的结合多肽具有恒定区,例如IgG1或IgG4重链恒定区,对其改变以降低或消除糖基化。举例来说,本发明的结合多肽(例如抗体或其抗原结合片段)还可包含含有改变抗体Fc糖基化的氨基酸取代的Fc变体。举例来说,所述Fc变体可具有降低的糖基化(例如N-或O-连接糖基化)。在典型的实施方案中,所述Fc变体包含通常发现于氨基酸位置297(EU编号)处的N-连接聚糖降低的糖基化。在另一实施方案中,所述抗体在糖基化基序附近或之内具有氨基酸取代,举例来说,包含氨基酸序列NXT或NXS的N连接糖基化基序。在具体的实施方案中,所述抗体包含在氨基酸位置228或299(EU编号)处具有氨基酸取代的Fc变体。在更具体的实施方案中,所述抗体包含含有S228P和T299A突变(EU编号)的IgG1或IgG4恒定区。
赋予降低或改变的糖基化的典型氨基酸取代公开于国际PCT公开No.WO05/018572中,其在本文通过提述以其全文并入。在优选的实施方案中,修饰本发明的结合多肽以消除糖基化。可将这种结合多肽称作"agly"结合多肽(例如"agly"抗体)。不受理论限制,相信"agly"结合多肽在体内可具有改进的安全性和稳定性。Agly结合多肽可以是任何同型或其亚类,例如IgG1、IgG2、IgG3或IgG4。在一些实施方案中,agly结合多肽包含IgG4抗体的无糖基化Fc区,其缺乏Fc-效应功能,由此消除了潜在的对表达IL-6的正常生命器官的Fc介导的毒性。而在其他实施方案中,本发明的结合多肽包含改变的聚糖。举例来说,所述抗体可在Fc区Asn297处的N-聚糖上具有降低数目的岩藻糖残基(即为无岩藻糖化)。无岩藻糖化增加NK细胞上的FcγRII结合并有力地增加ADCC。已显示包含抗IL-6 scFv和抗CD3 scFv的双抗体通过ADCC诱导对表达IL-6的细胞的杀伤。相应地,在一个实施方案中,将无岩藻糖化的抗IL-6抗体用于靶向和杀伤IL-6表达细胞。在另一实施方案中,所述结合多肽可在Fc区Asn297处的N-聚糖上具有改变数目的唾液酸残基。多种本领域认可的方法可用于制备"agly"抗体或具有改变的聚糖的抗体。举例来说,基因工程化的具有修饰的糖基化途径(例如糖基转移酶缺失)的宿主细胞(例如修饰的酵母,例如毕赤酵母(Pichia)或CHO细胞)可用于产生这种抗体。
V.效应部分
在一些实施方案中,本公开的结合多肽包含效应部分(例如药物部分和靶向部分)。一般而言这些效应部分与结合多肽上的N-连接聚糖偶联(直接或通过接头部分),(例如与CH2结构域的N298(EU编号)和/或CH1结构域的N114(Kabat编号)连接的N-连接聚糖)。在一些实施方案中,所述结合多肽是包含两个在Kabat位置114处具有聚糖的CH1结构域的全长抗体,其中所述两聚糖都与一个或多个效应部分偶联。
可将任何效应部分添加至本文公开的结合多肽。所述效应部分优选地将非天然功能添加至改变的抗体或其片段而不显著改变结合多肽的内在活性。所述效应部分可以是举例来说但不限于治疗或诊断剂。本发明修饰的结合多肽(例如抗体)可包含一个或多个效应部分,其可相同或不同。
在一个实施方案中,所述效应部分可以是式(I):
H2N-Q-CON-X
式(I),
其中:
A)Q是NH或O;且
B)CON是连接体部分;且
C)X是效应部分(例如如本文定义的治疗诊断剂)。
连接体部分将治疗剂与H2N-Q-连接。所述连接体部分可包括本领域的技术人员已知的任何合适的组件(component)的至少一种,包括举例来说,亚烷基组件、聚乙二醇组件、多聚(甘氨酸)组件、多聚(噁唑啉)组件、羰基组件、源自半胱氨的组件、源自与瓜氨酸偶联的缬氨酸的组件和源自4-氨基苄基氨基甲酸的组件或其任何组合。
在另一实施方案中,式(I)的效应部分可以是式(Ia):
H2N-Q-CH2-C(O)-Z-X
式(Ia),
其中:
A)Q是NH或O;且
B)Z是-Cys-(MC)a-(VC)b-(PABC)c-(C16H32O8C2H4)f,
其中:
i.Cys是源自半胱氨酰胺的组件;
ii.MC是源自马来酰亚胺的组件;
iii.VC是源自与瓜氨酸偶联的缬氨酸的组件;
iv.PABC是源自4-氨基苄基氨基甲酸的组件;
v.X是效应部分(例如如本文定义的治疗或诊断剂);
vi.a是0或1;
vii.b是0或1;
viii.c是0或1;且
ix.f是0或1。
所述“源自半胱氨酰胺的组件”是与H2N-Q-CH2-C(O)-附着的点。在一个实施方案中,所述“源自半胱氨酰胺的组件”可指代具有下列结构的效应部分的一个或多个部分:
在一个实施方案中,所述效应部分的“Cys”组件可包括一个这样的部分。举例来说,下列结构显示具有一个这样的部分的效应部分(其中所述“Cys”组件用虚线框表示):
在另一实施方案中,所述效应部分的“Cys”组件可包括两个或多个这样的部分。举例来说,下列部分包含两个这样的部分:
如从所述结构可见,每个“Cys”组件带有-(MC)a-(VC)b-(PABC)c-(C16H32O8C2H4)f-X基团。
在一个实施方案中,所述短语“源自马来酰亚胺的组件”可指代任何具有下列结构的效应部分的任何部分:
其中d是2至5的整数。在效应部分中的任何Cys-(MC)a-(VC)b-(PABC)c-(C16H32O8C2H4)f-X基团中包括的MC组件的数目由下标“a”表示且可以是0或1。在一个实施方案中,a是1。在另一实施方案中,b是0。
在一个实施方案中,所述“Cys”组件可与“MC”组件经由“Cys”组件中的硫原子连接,如下列结构中的虚线框所示:
在一个实施方案中,短语“与瓜氨酸偶联的缬氨酸的组件”可指代具有下列结构的效应部分的任何部分:
包括在效应部分中任何Cys-(MC)a-(VC)b-(PABC)c-(C16H32O8C2H4)f-X基团中的VC组件的数目由下标“b”表示且可以是0或1。在一个实施方案中,b是1。在另一实施方案中,b是0。
在一个实施方案中,术语“源自4-氨基苄基氨基甲酸的组件”可指代具有下列结构的效应部分的任何部分:
包括在效应部分中的任何Cys-(MC)a-(VC)b-(PABC)c-(C16H32O8C2H4)f–X基团中的PABC组件的数目由下标“c”表示且可以是0或1。在一个实施方案中,c是1。在另一实施方案中,c是0。
在一个实施方案中,“C16H32O8C2H4”指代下列结构:
包括在效应部分中任何Cys-(MC)a-(VC)b-(PABC)c-(C16H32O8C2H4)f–X基团中的C16H32O8单元数目由下标“f”表示,在一个实施方案中,f是1。在另一实施方案中,f是0。
在一个实施方案中,a是1,b是1,c是1且f是0。
a)治疗性效应部分
在一些实施方案中,本公开的结合多肽与包含治疗剂的效应部分例如药物部分(或其前体药物)或放射性标记的化合物偶联。在一个实施方案中,所述治疗剂是细胞毒素。典型的细胞毒性治疗剂阐述于本文的表1中。
表1.典型的细胞毒性治疗剂
进一步的典型药物部分包括抗炎、抗癌、抗感染(例如抗真菌、抗细菌、抗寄生物、抗病毒等)和麻醉治疗剂。在进一步的实施方案中,所述药物部分是抗癌剂。典型的抗癌剂包括但不限于细胞抑制剂、酶抑制剂、基因调节剂、细胞毒性核苷、微管蛋白结合剂或微管蛋白抑制剂、蛋白酶体抑制剂、激素和激素拮抗剂、抗血管生成剂等等。典型的抑制细胞生长的抗癌剂(cytostatic anti-cancer agent)包括烷化剂如蒽环类家族药物(例如阿霉素、洋红霉素、环孢菌素A、氯喹、甲氨喋呤、光辉霉素(mithramycin)、甲基丝裂霉素(porfiromycin)、链黑菌素、甲基丝裂霉素、蒽二酮类(anthracenediones)和环乙亚胺类(aziridines))。其他抑制细胞生长的抗癌剂包括DNA合成抑制剂(例如甲氨蝶呤和二氯甲胺蝶呤、3-氨基-1,2,4-苯并三嗪-1,4-二氧化物、氨基蝶呤、胞嘧啶β-D-阿拉伯呋喃糖苷、5-氟-5'-脱氧尿苷、5-氟尿嘧啶、更昔洛韦、羟基脲、放线菌素-D和丝裂霉素C)、DNA-嵌入剂或交联剂(例如博来霉素、卡铂、卡莫司汀、苯丁酸氮芥、环磷酰胺、顺-二氨基铂(II)二氯化物(顺铂)、美法仑、米托蒽醌和奥沙利铂)和DNA-RNA转录调节剂(例如放线菌素D、柔红霉素、阿霉素、高三尖杉酯和伊达比星)。其他与本公开相容的典型的抑制细胞生长剂包括安沙霉素苯醌类、醌类衍生物(quinonoid derivatives)(例如喹诺酮类药物、染料木素、bactacyclin)、白消安、异环磷酰胺、二氯甲基二乙胺、三乙撑亚胺苯醌、地吖醌、卡巴醌、吲哚醌EO9、二乙烯亚氨基苯醌甲基DZQ、三亚乙基磷酰胺和亚硝脲化合物(例如卡莫司汀、洛莫司汀、司莫司汀)。
典型的细胞毒性核苷抗癌剂包括但不限于:阿糖腺苷、阿糖胞苷(cytarabine)、阿糖胞苷(cytosine arabinoside)、5-氟尿嘧啶、氟达拉滨、氟尿苷、替加氟和6-巯基嘌呤。典型的抗癌微管蛋白结合剂包括但不限于紫杉烷类(例如紫杉醇、多西紫杉醇、紫杉烷)、诺考达唑、根霉素、多拉司他汀(例如多拉司他汀-10、-11或-15),秋水仙素和类秋水仙素(colchicinoids)(例如ZD6126)、考布他汀(例如考布他汀A-4、AVE-6032)和长春花生物碱类(例如长春碱、长春新碱、长春地辛和长春瑞滨(诺维本))。典型的抗癌激素和激素拮抗剂包括但不限于:皮质类固醇(例如强的松)、孕激素(例如羟孕酮或Medroprogesterone)、雌激素(例如己烯雌酚)、抗雌激素(例如他莫昔芬)、雄激素(例如睾酮)、芳香酶抑制剂(例如氨鲁米特)、17-(烯丙基氨基)-17-去甲氧基格尔德霉素、4-氨基-1,8-萘二甲酰亚胺、芹菜素、布雷菲德菌素A、西咪替丁、二氯亚甲基二膦酸、亮脯利特(亮丙瑞林)、促黄体生成激素释放激素、皮斐松-a、雷帕霉素、性激素结合球蛋白和毒胡萝卜素。典型的抗癌、抗血管生成化合物包括但不限于:血管抑素KI-3、DL-a-二氟甲基鸟氨酸、内皮抑素、烟曲霉素、染料木素、米诺环素、星形孢菌素和(±)-沙利度胺。
典型的抗癌酶抑制剂包括但不限于:S(+)-喜树碱、姜黄素、(-)-鱼藤素、5,6-二氯苯咪唑1-β-D-呋喃核糖苷、依托泊苷、福美坦、福司曲星、Hispidin、2-亚氨基-1-咪唑烷乙酸(环肌酸(cyclocreatine))、麦维诺素(mevinolin)、曲古抑菌素A、酪氨酸磷酸化抑制剂AG34和酪氨酸磷酸化抑制剂AG879。
典型的抗癌基因调节剂包括但不限于:5-氮杂-2'-脱氧胞苷、5-氮杂胞苷、胆钙化固醇(维生素D3)、4-羟基他莫昔芬、褪黑激素、米非司酮、雷洛昔芬、反式-视黄醛(维生素A醛)、视黄酸、维生素A酸、9-顺式-视黄酸、13-顺式-视黄酸、视黄醇(维生素A)、他莫昔芬和曲格列酮。
其他优选的抗癌剂的种类包括但不限于:蝶啶家族药物、烯二炔类(diynenes)和鬼臼毒素类。这些种类特别有效的成员包括举例来说甲氨喋呤、鬼臼毒素或鬼臼毒素衍生物如依托泊苷或磷酸依托泊苷、异长春碱、长春地辛、环氧长春碱等等。
还有其他与本文教导相容的抗癌剂包括奥瑞他汀类(例如奥瑞他汀E和单甲基奥瑞他汀E)、格尔德霉素、卡奇霉素、短杆菌肽D、美登木素生物碱(maytansanoid)(例如美登木素)、新制癌菌素、托泊替康、紫杉烷类、细胞松弛素B、溴化乙锭、吐根碱、替尼泊苷、秋水仙碱、二羟基蒽二酮(dihydroxy anthracindione)、米托蒽醌、普鲁卡因、丁卡因、利多卡因、普萘洛尔、嘌呤霉素和其类似物或其同系物。
还有其他与本文教导相容的抗癌剂包括茅屋霉素衍生物、美登木素衍生物、cryptophycine衍生物、蒽环类衍生物、双膦酸盐衍生物、细霉素衍生物(leptomycinderivative)、链黑菌素衍生物、奥瑞他汀衍生物(auristatine derivative)和倍癌霉素衍生物(duocarmycin derivative)。
另一种可用作药物部分的相容抗癌剂是放射增敏药物,其有效针对肿瘤或免疫反应性细胞。这种药物部分增强对电离辐射的敏感性,由此增加放疗的效力。不受理论限制,但用放射增敏药物部分修饰并通过肿瘤细胞内化的抗体将更靠近核递送放射增敏剂,此处放射增敏将最大化。失去放射增敏剂部分的抗体将迅速从血液中清除,将剩余的放射增敏剂定位在靶向的肿瘤中并提供在正常组织中的最小吸收。从血液清除后,辅助的放疗可通过特异性针对肿瘤的体外射线照射、直接植入肿瘤的放射性或用相同修饰抗体的全身放射免疫治疗施用。
在一个实施方案中,所述治疗剂包含具有能够引起核DNA中多重链断裂的高能电离辐射的放射性核素或放射性标记,其导致细胞死亡。典型的高能放射性核素包括:90Y、125I、131I、123I、111In、105Rh、153Sm、67Cu、67Ga、166Ho、177Lu、186Re和188Re。这些同位素通常产生具有短路径长度的高能的α-或β微粒。这种放射性核素杀伤其邻近距离的细胞,举例来说偶联物附着或进入的肿瘤细胞。其对未定位的细胞具有很小作用或无作用且基本上是非免疫原性的。可替换地,高能同位素可通过同位素的热辐射(否则该同位素是稳定的)生成,举例来说如在硼中子-捕获疗法中(Guan et al.,PNAS,95:13206-10,1998)。
在一个实施方案中,所述治疗剂选自MMAE、MMAF和PEG8-Do110。
典型的治疗效应部分包括以下结构:
在一个实施方案中,所述效应部分选自:
在一些实施方案中,所述效应部分包含多于一种治疗剂。这些多重治疗剂可以相同或不同。
b)诊断效应部分
在一些实施方案中,本公开的结合多肽与包含诊断剂的效应部分偶联。在一个实施方案中,所述诊断剂是可检测的小分子标记例如生物素、荧光团、发色团、自旋共振探针或放射性标记。典型的荧光团包含荧光染料(例如荧光素、罗丹明等等)和其他发光分子(例如鲁米诺)。荧光团可以是环境敏感的,因此如果其位于在结合底物时经历结构变化的经修饰的结合多肽中的一个或多个残基附近,则其荧光发生变化(例如丹酰基探针)。典型的放射标记包括含有原子的小分子,所述原子带有一个或多个低灵敏度的核(13C、15N、2H、125I、124I、123I、99Tc、43K、52Fe、64Cu、68Ga、111In等等)。优选地,所述放射性核素是在施用和定位至成像位点间经过的时间后具有适于允许活性或检测的半衰期的γ、光子或发射正电子的放射性核素。
在一个实施方案中,所述诊断剂是多肽。典型的诊断多肽包括具有发荧光或显色活性(例如裂解形成荧光团或发色团作为产物的底物的能力)的酶,(即报告蛋白如萤光素酶)。其他诊断蛋白可具有固有荧光或显色活性(例如来自生物发光的海洋生物的绿色、红色和黄色荧光生物发光的水母发光蛋白)或其可包含含有一个或多个低能放射性原子核(13C、15N、2H、125I、124I、123I、99Tc、43K、52Fe、64Cu、68Ga、111In等等)的蛋白。
对于放射性标记的偶联物在与本公开相关联时的用途,本公开的结合多肽可直接标记(如通过碘化)或可通过螯合剂的使用间接标记。如本文使用,短语"间接标记"和"间接标记的方式"都意为螯合剂与结合多肽共价附着且至少一种放射性核素与螯合剂缔合。由于其与多肽和放射性同位素都结合,因此这种螯合剂通常被称为双功能螯合剂。典型的螯合剂包含1-异硫氰基苄基-3-甲基二亚乙基三胺五乙酸(1-isothiocycmatobenzyl-3-methyldiothelene triaminepentaacetic acid)("MX-DTPA")和环己基二亚乙基三胺五乙酸("CHX-DTPA")衍生物。其他螯合剂包含P-DOTA和EDTA衍生物。特别优选的用于间接标记的放射性核素包括111In和90Y。大多数的成像研究采用5mCi 111In-标记的抗体,由于该剂量既安全并且与低剂量相比又具有增加的成像效力,在抗体施用后的三至六天发生最佳成像。参见举例来说Murray,(1985),J.Nuc.Med.26:3328and Carraguillo et al,(1985),J.Nuc.Med.26:67。用于直接标记的特别优选的放射性核素为131I。本领域的技术人员将理解非放射性偶联物还可依赖于所选的待偶联作用剂装配。
在一些实施方案中,所述诊断效应部分是FRET(荧光共振能量转移)探针。FRET已用于多种诊断应用包括癌症诊断。FRET探针可包括连接FRET探针供体和受体部分的可裂解接头(酶敏感性或pH接头),其中裂解导致增强的荧光(包括近红外)(参见例如A.Cobos-Correa et.al.Membrane-bound FRET probe visualizes MMP12 activity in pulmonaryinflammation,Nature Chemical Biology(2009),5(9),628-63;S.Gehriget.al.Spatially Resolved Monitoring of Neutrophil Elastase Activity withRatiometric Fluorescent Reporters(2012)Angew.Chem.Int.Ed.,51,6258–6261)。
在一个实施方案中,所述效应部分选自:
c)功能化的效应部分
在一些实施方案中,可将本发明的效应部分功能化以在效应部分本身以外包含额外的基团。举例来说,所述效应部分可包含可裂解接头,其在特定条件下从结合多肽释放效应部分。在典型的实施方案中,所述效应部分可包含可由细胞酶裂解的接头且/或是pH敏感的接头。此外或可替换地,所述效应部分可包含二硫键,当吸收入细胞时其可通过细胞内谷胱甘肽裂解。典型的二硫化物和pH敏感接头提供如下:
而在其他实施方案中,所述效应部分可包含亲水性和生物相容性部分如多聚(甘氨酸)、多聚(噁唑啉)或PEG部分。典型的结构(“Y”)提供如下:
R=H,未取代的或含有烷基基团的功能性基团
P和Q=相同或不同的功能性基团,用于连接药物、报道分子和蛋白
在一些实施方案中,所述效应部分包含氨氧基基团,其经由稳定的肟连接基促进与结合多肽的偶联。典型的包含氨氧基基团的效应部分阐述于本文表2中。
表2.典型的氨氧基效应部分(其中X可以是任何接头,Y是任何间隔区,且其中X和/或Y是任选的)
在其他实施方案中,所述效应部分包含酰肼和/或N-烷基化的肼基团以经由稳定的腙连接基促进与结合多肽的偶联。典型的包含氨氧基基团的效应部分阐述于本文表14中。
表14.典型的肼和/或酰肼效应部分
d)靶向部分
在一些实施方案中,效应部分包含特异性地与一个或多个靶分子结合的靶向部分。可采用任何类型的靶向部分包括但不限于蛋白、核酸、脂质、糖(例如聚糖)和其组合(例如糖蛋白、糖肽和糖脂)。在一些实施方案中,所述靶向部分是糖或糖肽。在一些实施方案中,所述靶向部分是聚糖。靶向部分可以是天然或非天然存在的分子。
VI.效应部分与结合多肽的偶联
在一些实施方案中,效应部分与改变的结合多肽的氧化聚糖(例如氧化的N-连接聚糖)(例如在抗体CH1结构域N114处工程化的聚糖或在抗体F结构域的N297处天然的聚糖)偶联(直接或通过接头部分)。术语“氧化聚糖”意为已氧化的聚糖上的醇取代基,其提供羰基取代基。羰基取代基可与合适的氮亲核试剂发生发应以形成碳-氮双键。举例来说,羰基基团与氨氧基团或肼基基团的反应将分别形成肟或肼。在一个实施方案中,所述羰基取代基是醛。合适的氧化聚糖包括氧化半乳糖和氧化唾液酸。
在一个实施方案中,式(II)的修饰的多肽可以为式(II):
Ab(Gal-C(O)H)x(Gal-Sia-C(O)H)y
式(II),
其中
A)Ab是如本文定义的抗体或其他结合多肽;
B)Gal是源自半乳糖的组件;
C)Sia是源自唾液酸的组件;
D)x是0至5;且
E)y是0至5,
其中x和y中至少一个不为0。
可采用任何本领域认可的化学方法来将效应部分(例如包含接头部分的效应部分)与聚糖偶联(参见例如Hermanson,G.T.,Bioconjugate Techniques.Academic Press(1996),其在本文通过提述以其全文并入)。在一些实施方案中,聚糖的糖残基(例如唾液酸或半乳糖残基)首先氧化(例如使用高碘酸钠处理唾液酸或使用半乳糖氧化酶处理半乳糖)以生成具有反应性的醛基基团。该醛基基团与效应部分的氨氧基基团或肼基基团发生发应以分别形成肟或腙接头。采用这种通用反应方案的典型方法阐述于实施例10至15中。
在一些实施方案中,结合多肽的天然或工程化的聚糖首先在体外用糖基转移酶预处理以提供具有合适的反应性的末端糖残基。举例来说,唾液酸化可以首先使用半乳糖基转移酶(Gal T)和唾液酸转移酶(Sial T)的组合实现。在一些实施方案中,缺乏半乳糖(G0F或G0)或仅包含一个半乳糖(G1F或G1)的双触角聚糖可转换成适于偶联的高阶半乳糖基化或唾液酸化结构(G1F、G1、G2F、G2、G1S1F、G1S1、G2S1F、G2S1、G2S2F或G2S2)。
用于产生唾液酸化的糖偶联物的典型偶联方案示于图25C。唾液酸残基通过酶的方式且位点特异性地使用半乳糖基转移酶(Gal T)和唾液酸转移酶(Sial T)的组合引入抗体的聚糖(例如在Asn-297处的天然聚糖)。引入的唾液酸残基随后用低浓度的高碘酸钠氧化以获得可与药物接头(例如氨氧基药物接头)适当发生反应的具有反应性的唾液酸醛基以生成抗体药物偶联物(ADC)(例如肟连接ADC)。通过使用体外重塑控制聚糖数目和唾液酸残基数目,本领域的技术人员可具有对于ADC的抗体-药物比率(DAR)的精确控制。举例来说,如果将~1唾液酸添加至每条重链中的单个双触角聚糖(A1F)上,那么可以均匀地获得DAR为2的抗体或结合多肽。
VII.修饰的结合多肽
在一些实施方案中,本发明提供修饰多肽,其为偶联效应部分与改变的结合多肽的氧化聚糖(例如氧化的N-连接聚糖)(例如在抗体CH1结构域的N114处的工程化聚糖或抗体F结构域的N297处的天然聚糖)偶联(直接或通过接头部分)的产物。
在一个实施方案中,所述结合多肽可以为式(III):
Ab(Gal-C(H)=N-Q-CON-X)x(Gal-Sia-C(H)=N-Q-CON-X)y
式(III),
其中:
A)Ab是如本文定义的抗体;
B)Q是NH或O;
C)CON是如本文定义的连接体部分;且
D)X是如本文定义的治疗或诊断剂;
E)Gal是源自半乳糖的组件;
F)Sia是源自唾液酸的组件;
G)x是0至5;且
H)y是0至5,
其中x和y中至少一个不为0。
在一个实施方案中,所述结合多肽可以为式(III)可以为式(IIIa):
Ab(Gal-C(H)=N-Q-CH2-C(O)-Z-X)x(Gal-Sia-C(H)=N-Q-CH2-C(O)-Z-X)y
式(IIIa),
其中:
A)Ab是抗体;
B)Q是NH或O;
C)Z是Cys-(MC)a-(VC)b-(PABC)c-(C16H32O8C2H4)f-,其中
i.Cys是源自半胱氨酰胺的组件;
ii.MC是源自马来酰亚胺的组件;
iii.VC是源自与瓜氨酸偶联的缬氨酸的组件;
iv.PABC是源自4-氨基苄基氨基甲酸酯的组件;
v.X是效应部分(例如如本文定义的治疗或诊断剂);
vi.a是0或1;
vii.b是0或1;
viii.c是0或1;且
ix.f是0或1;
D)X是如本文定义的治疗剂;
E)Gal是源自半乳糖的组件;
F)Sia是源自唾液酸的组件;
G)x是0至5;且
H)y是0至5,
其中x和y中至少一个不为0。
可以理解的是式(III)并非意在暗示抗体、Gal取代基和Gal-Sia取代基以链样的方式连接。而是说当这种取代基存在时,所述抗体直接与每个取代基连接。举例来说,式(III)的结合多肽(其中x是1且y是2)可具有下列所示的排列:
式(III)中的CON取代基和其中的组件如参考式(I)关于效应部分所述。
在一个实施方案中,Q是NH。在另一实施方案中,Q是O。
在一个实施方案中,x是0。
式(III)的抗体Ab可以是如本文所述的任何合适的抗体。
在一个实施方案中,提供用于制备式(III)的结合多肽的方法,所述方法包括使式(I)的效应部分与式(II)的修饰抗体反应:
NH2-Q-CON-X
式(I),
其中:
A)Q是NH或O;
B)CON是连接体部分;且
C)X是效应部分(例如如本文定义的治疗或诊断剂),
Ab(OXG)r
式(II)
其中
A)OXG是氧化聚糖;且
B)r选自0至4;
在一个实施方案中,提供用于制备式(III)的结合多肽的方法,所述方法包括使式(I)的效应部分与式(IIa)的修饰抗体反应:
NH2-Q-CON-X
式(I),
其中:
A)Q是NH或O;
B)CON是连接体部分;且
C)X是效应部分(例如如本文定义的治疗或诊断剂),
Ab(Gal-C(O)H)x(Gal-Sia-C(O)H)y
式(IIa),
其中
A)Ab是如本文定义的抗体;
B)Gal是源自半乳糖的组件;
C)Sia是源自唾液酸的组件;
D)x是0至5;且
E)y是0至5,
其中x和y中至少一个不为0。
VII.用修饰抗体处理的方法
一方面,本发明提供治疗或诊断患者的方法,其中包括施用有效的量的本文公开的结合多肽。本公开的优选实施方案提供在需要这种治疗的哺乳动物受试者中用于诊断和/或治疗病症(例如肿瘤病症)的试剂盒和方法。优选地,受试者是人。
本公开的结合多肽在多种不同应用中都有效。举例来说,在一个实施方案中,主题的结合多肽对于降低或消除带有由结合多肽的结合结构域识别的表位的细胞。在另一实施方案中,所述主题结合多肽在降低循环中可溶抗原的浓度或消除循环中可溶抗原有效。在一个实施方案中,所述结合多肽可降低肿瘤大小、抑制肿瘤生长和/或延长带有肿瘤的动物的生存时间。相应地,该公开还涉及在人或其他动物中通过将有效的非毒性的量的修饰抗体施用至这些人或动物来治疗肿瘤的方法。本领域的技术人员将能够通过常规实验来确定就治疗恶性肿瘤而言修饰的结合多肽的有效、非毒性的量为多少。举例来说,修饰的抗体或其片段的治疗上具有活性的量可根据以下因素变化,所述因素如受试者的疾病阶段(例如阶段I对阶段IV)、年龄、性别、医学并发症(例如免疫抑制病况或疾病)和体重,以及在受试者中引起预期响应的修饰抗体的能力。给药方案可进行调整以提供最佳治疗响应。举例来说,每日可施用数次分开的剂量,或由治疗状况的紧急程度所指示的按比例减少。
一般而言,本公开提供的组合物可用于预防性或治疗性处理任何包含抗原标记的肿瘤(neoplasm),所述标记允许修饰抗体靶向癌细胞。
VIII.施用修饰抗体或其片段的方法
制备和施用本公开的结合多肽至受试者的方法已知或由本领域的技术人员很容易地确定。本公开的结合多肽的施用途径可以是口服、肠胃外、通过吸入或局部。如本文使用的术语肠胃外包括静脉内、动脉内、腹膜内、肌内、皮下、直肠或阴道施用。静脉内、动脉内、皮下和肌内形式的肠胃外施用通常是优选的。尽管所有这些施用形式很明显应考虑在本公开的保护范围之内,用于施用的形式可以是用于注射的溶液,特别是用于静脉内或动脉内注射或滴注。通常,合适的用于注射的药物组合物可包含缓冲液(例如醋酸、磷酸或柠檬酸缓冲液)、表面活性剂(例如聚山梨酯)、任选地稳定剂(例如人白蛋白)等。然而,在其他与本文的教导相容的方法中,修饰抗体可直接递送至不良细胞群体的位点,由此增加疾病组织对治疗剂的暴露。
在一个实施方案中,施用的结合多肽是式(III)的结合多肽:
Ab(Gal-C(H)=N-Q-CON-X)x(Gal-Sia-C(H)=N-Q-CON-X)y
式(III),
其中:
A)Ab是如本文定义的抗体;
B)Q是NH或O;
C)CON是如本文定义的连接体部分;且
D)X是效应部分(例如如本文定义的治疗或诊断剂);
E)Gal是源自半乳糖的组件;
F)Sia是源自唾液酸的组件;
G)x是0至5;且
H)y是0至5,
其中x和y中至少一个不为0。
用于肠胃外施用的制剂包括无菌水性或非水性溶液、悬浮液和乳液。非水性溶剂的实例为丙二醇、聚乙二醇、植物油如橄榄油和可注射的有机酯如油酸乙酯。水性载剂包括水、醇/水溶液、乳液或悬浮液,包括盐水和缓冲介质。在本公开的组合物和方法中,可药用的载剂包括但不限于0.01-0.1M且优选为0.05M磷酸缓冲液或0.8%盐水。其他常用的肠胃外媒介包括磷酸钠溶液、林格氏(Ringer’s)葡萄糖、葡萄糖和氯化钠,乳酸林格氏或不挥发油。静脉媒介包括液体和营养补充剂、电解质补充剂如基于林格氏葡萄糖的那些等等。防腐剂和其他添加剂也可存在,如举例来说抗微生物剂、抗氧化剂、螯合剂和惰性气体等等。更具体地,适于注射用途的药物组合物为包括无菌水性溶液(在水可溶性的情况下)或分散剂,和用于无菌可注射溶液或分散剂临场制备的无菌粉末。在这样的情况中,所述组合物必须为无菌且应以能够轻松注射的程度流动。其在制造和保存条件下应稳定且优选将防止微生物如细菌和真菌的污染作用。载剂可以是溶剂或分散剂介质,其包含举例来说水、醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等等)及其合适的混合物。可保持适当的流动性,举例来说,通过包衣如卵磷脂的使用、在分散剂的情况中通过保持所需的微粒尺寸和通过表面活性剂的使用。
微生物作用的预防可通过多种抗细菌和抗真菌剂实现,举例来说,羟基苯甲酸酯,氯丁醇,苯酚,抗坏血酸,硫柳汞等等。在很多情况中,组合物中优选包括等渗剂,举例来说糖、多元醇如甘露醇、山梨醇或氯化钠。可注射组合物的延长吸收可通过在组合物中包括延迟吸收的作用剂带来,举例来说单硬脂酸铝和明胶。
在任何情况中,无菌可注射溶液可通过以所需的量并入在适当的溶剂中与一种本文枚举的成分之一或成分的组合混合的具有活性的化合物(例如修饰的结合多肽本身或与其他活性剂的组合)制备,如果需要的话,随后可进行过滤除菌。一般而言,分散剂通过将具有活性的化合物并入包含基本的分散介质和来自那些上文枚举的所需的其他成分的无菌媒介制备。在用于无菌可注射溶液制备的无菌粉末情况中,优选的制备方法是真空干燥和冷冻干燥,其从之前过滤除菌的溶液收获活性成分的粉末加任何其他预期成分。加工用于注射的制剂,将其填入容器如安瓿瓶、袋、瓶、注射器或小瓶中,并根据本领域已知的方法在无菌条件下密封。此外,可将所述制剂包装并以试剂盒的形式出售,如那些在共同待审的U.S.S.N.09/259,337和U.S.S.N.09/259,338中所述,其每一篇在本文通过提述并入。这些制品优选将具有表明相关组合物可用于治疗患有自身免疫或肿瘤病症或对自身免疫或肿瘤病症易感的受试者的标签或说明书。
本发明的组合物用于治疗上述病况的有效剂量取决于多种不同的因素,包括施用方式、靶位点、患者的生理状态、患者为人还是动物、施用的其他药物和治疗为预防性还是治疗性。通常患者是人,但非人哺乳动物包括转基因哺乳动物也可接受治疗。治疗剂量可使用本领域技术人员已知的方法滴定测量以优化安全性和效力。
对于用结合多肽的被动免疫,剂量范围可以是,例如宿主体重的约0.0001至100mg/kg和更经常的0.01至5mg/kg(例如0.02mg/kg、0.25mg/kg、0.5mg/kg、0.75mg/kg、lmg/kg、2mg/kg等)。举例来说剂量可以是1mg/kg体重或10mg/kg体重或为1-10mg/kg的范围内,优选为至少1mg/kg。上述范围中间的剂量也意在本公开的保护范围之内。受试者可以每日、每隔一日、每周或根据由经验分析确定的任何其他日程施用这样的剂量。典型的治疗需要在延长的期限举例来说至少六个月施用多重剂量。其他典型的治疗方案需要每两周一次或一个月一次或每3至6个月一次施用。典型的给药日程包括连续多日1-10mg/kg或15mg/kg、隔日30mg/kg或每周60mg/kg。在一些方法中,同时施用具有不同结合特异性的两种或多种单克隆抗体,其中每种抗体的施用剂量落入所示范围。
本公开的结合多肽可在多重时机施用。两次单独给药的间隔可以为每周、每月或每年。间隔还可以无规律,按照通过测量患者中修饰的结合多肽或抗原的血液水平所示进行。在一些方法中,剂量调整至获得修饰的结合多肽的血浆浓度为1-1000μg/ml,而在一些方法中为25-300μg/ml。可替换地,结合多肽可作为持续释放的制备物施用,其中需要的施用频率较低。对于抗体,剂量和频率取决于抗体在患者中的半衰期而变化。一般而言人源化的抗体显示最长的半衰期,随后是嵌合抗体和非人抗体。
施用剂量和频率可取决于治疗是预防性还是治疗性而变化。在预防性应用中,将包含本发明抗体或其鸡尾酒混合(cocktail)的组合物施用至未在疾病状态中的患者以增强患者的抗性。这样的量定义为“预防上有效的量”。在这种用途中,精确的量也取决于患者的健康和整体免疫的状态,但通常为0.1至25mg每剂量,特别是0.5至2.5mg每剂量。相对低剂量以相对不频繁的间隔在较长的时期进行施用。一些患者在其余生持续接受治疗。在治疗性应用中,有时需要相对高的剂量(例如约1至400mg/kg的抗体每剂量,其中5至25mg的剂量更常用于放射性免疫偶联物且更高剂量用于细胞毒素-药物修饰的抗体)以相对较短的间隔直至疾病进展降低或终止,且优选直至患者表现疾病症状的部分或完全改善。此后,可对患者施用预防性的方案。
本公开的结合多肽可任选地与其他在需要治疗的病症或病况的治疗中(例如预防性或治疗性)有效的作用剂组合施用。本公开的90Y-标记的修饰抗体的有效的单治疗剂量(即治疗上有效的量)为约5-约75mCi,更优选地为约10-约40mCi。131I-修饰抗体的有效的单治疗非骨髓消融剂量为约5-约70mCi,更优选的为约5-约40mCi。131I-标记抗体的有效的单治疗消融剂量(即可能需要自体骨髓移植)为约30至约600mCi,更优选地为约50至约小于500mCi。与嵌合抗体一起时,由于vis-a-vis鼠类抗体较长的循环半衰期,碘-131标记嵌合抗体有效的单治疗非骨髓消融剂量为约5-约40mCi,更优选地为少于约30mCi。对于例如111In标记的成像标准通常少于约5mCi。
尽管所述结合多肽可如上文所述立即施用,但是必须强调的是其他实施方案中结合可作为一线治疗施用至健康患者。在这些实施方案中,所述结合多肽可施用至具有正常或普通红骨髓储备的患者和/或还未经历的患者。如本文使用,修饰的抗体或其片段与辅助疗法一起或组合施用意为所述疗法和公开的抗体的顺序、同步、共延、同时、伴随的或同期施用或应用。本领域的技术人员将理解组合治疗方案的多种组件的施用或应用可定时以增强治疗的整体有效性。举例来说,化疗剂可以标准、已知的治疗过程施用,随后数周内为本公开的放射性免疫偶联物。相反地,与结合多肽缔合的细胞毒素可静脉内施用,随后为肿瘤局部的外部射线照射。而在其他实施方案中,修饰的结合多肽可与一种或多种选择的化疗剂在单一就诊时同时施用。基于选择的辅助疗法和本说明书的教导,本领域的技术人员(例如有经验的肿瘤学家)将能够很容易地辨别有效的组合治疗方案而无需过度实验。
在这方面,可以理解的是结合多肽和化疗剂的组合可以任何顺序且在任何为患者提供疗效的时间框架内施用。也就是说,化疗剂和结合多肽可以任何顺序或同时施用。在所选的实施方案中,本公开的结合多肽将施用至之前经历了化疗的患者。而在其他其他实施方案中,所述结合多肽和化疗治疗将基本上同时或同时施用。举例来说,可在经历化疗过程时将所述结合多肽给予所述患者。在优选的实施方案中,修饰抗体将在任何化疗剂或治疗的一年内施用。在其他优选的实施方案中,所述结合多肽将在任何化疗剂或治疗的10、8、6、4或2个月内施用。在仍优选的其他实施方案中,所述结合多肽将在任何化疗剂或治疗的4、3、2或1周内施用。而在其他实施方案中,所述结合多肽将在所选的化疗剂或治疗的5、4、3、2或1天内施用。应该进一步理解的是两种作用剂或治疗可在数小时或分钟(即基本上同时)内施用至患者。
应该进一步理解的是本公开的结合多肽可用于与任何消除、降低、抑制或控制体内肿瘤细胞生长的化疗剂或作用剂联合或组合(例如以提供组合治疗方案)。与本公开相容的典型化疗剂包括烷化剂、长春花生物碱(例如长春新碱和长春碱)、甲基苄肼、甲氨蝶呤和强的松。四种药物的组合MOPP(mechlethamine(氮芥)、长春新碱(Oncovin)、甲基苄肼和强的松)在治疗多种类型的淋巴瘤中非常有效且包含本公开的优选的实施方案。在抗MOPP的患者中,可使用ABVD(例如阿霉素、博来霉素、长春碱和达卡巴嗪)、ChIVPP(苯丁酸氮芥、长春碱、丙卡巴肼和强的松)、CABS(洛莫司汀、阿霉素、博来霉素和链脲佐菌素)、MOPP加ABVD、MOPP加ABV(多柔比星、博来霉素和长春花碱)或BCVPP(卡莫司汀、环磷酰胺、长春碱、丙卡巴肼和强的松)的组合。Arnold S.Freedman和Lee M.Nadler,Malignant Lymphomas在HARRISON'S PRINCIPLES OF INTERNAL MEDICINE 1774-1788(Kurt J.Isselbacher etal,eds.,13th ed.1994)中以及V.T.DeVita et al,(1997)以及其中引用的参考文献可用于标准剂量和时间安排。这些疗法可无变化地使用,或对于特定患者根据所需进行改变,与一种或多种如本文描述的本公开的结合多肽组合。
其他在本公开的背景中有效的方案包括单一烷化剂如环磷酰胺或苯丁酸氮芥的使用,或如CVP(环磷酰胺、长春新碱和强的松)、CHOP(CVP和阿霉素)、C-MOPP(环磷酰胺、长春新碱、强的松和甲基苄肼)、CAP-BOP(CHOP加甲基苄肼和博来霉素)、m-BACOD(CHOP加甲氨蝶呤、博莱霉素和甲酰四氢叶酸)、ProMACE-MOPP(强的松、甲氨蝶呤、阿霉素、环磷酰胺、依托泊苷和甲酰四氢叶酸加标准MOPP)、ProMACE-CytaBOM(强的松、阿霉素、环磷酰胺、依托泊苷、阿糖胞苷、博来霉素、长春新碱、甲氨蝶呤和甲酰四氢叶酸)和MACOP-B(甲氨蝶呤、阿霉素、环磷酰胺、长春新碱、固定剂量强的松、博来霉素和亚叶酸)的组合。本领域的技术人员将能够很容易地确定对于这些方案中的每一种的标准剂量和日程安排。CHOP还已与博来霉素、氨甲蝶呤、甲基苄肼、氮芥、阿糖胞苷和依托泊苷组合。其他相容的化疗剂包括但不限于2-氯脱氧腺苷(2-CDA)、2'-脱氧柯福霉素和氟达拉滨。
对于具有中级和高级NHL的患者,其不能实现缓解或复发,可使用抢救疗法。抢救疗法采用药物如阿糖胞苷、卡铂、顺铂、依托泊苷和异环磷酰胺,所述药物单独或组合给予。在复发或侵袭形式的一些肿瘤病症中,使用下列方案:IMVP-16(异环磷酰胺、甲氨蝶呤和依托泊苷)、MIME(甲基-gag、异环磷酰胺、甲氨蝶呤和依托泊苷)、DHAP(地塞米松、高剂量的阿糖胞苷和顺铂)、ESHAP(依托泊苷、甲泼尼龙、HD阿糖胞苷、顺铂)、CEPP(B)(环磷酰胺、依托泊苷、丙卡巴肼、强的松和博来霉素)和CAMP(洛莫司汀、米托蒽醌、阿糖胞苷和强的松),其每一种以已知的给药速率和日程安排施用。
与本公开的修饰抗体组合使用的化疗剂的量可因受试者发生变化或可根据本领域已知进行施用。参见举例来说Bruce A Chabner et al,Antineoplastic Agents,inGOODMAN&GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS 1233-1287((JoelG.Hardman et al,eds.,9th ed.1996).
如之前所述,本公开的结合多肽、免疫反应片段或其组合可以对体内治疗哺乳动物病症有效的量进行施用。在这方面,可以理解的是可配制公开的结合多肽以促进施用并增进活性剂的稳定性。
优选地,与本公开对应的药物组合物包含可药用、无毒、无菌的载剂如生理盐水、无毒缓冲液、防腐剂等等。就本申请而言,与治疗剂偶联或非偶联的修饰结合多肽、免疫反应片段或其组合的药物上有效的量应保持足以实现与抗原的有效结合且实现益处例如改善疾病或病症或可检测物质或细胞的量的含义。在肿瘤细胞的情况中,修饰的结合多肽优选能够与肿瘤或免疫反应性细胞上的所选具有免疫反应性的抗原相互作用并用以增加那些细胞的死亡。当然,本公开的药物组合物可以单一或多重剂量施用以提供修饰结合多肽的药物上有效的量。
符合本公开的保护范围的是,本公开的结合多肽可以足以产生治疗或预防效果的量对应前文所述的治疗方施用至人或其他动物。本公开的结合多肽可通过根据已知技术组合本公开的抗体与常规的可药用载剂或稀释剂制备的常规剂型施用至这些人或其他动物。本领域的技术人员将认可的是可药用载剂或稀释剂的形式和特征通过将与其混合的活性成分的量、施用途径和其他已知变量决定。本领域的技术人员将进一步理解包含一种或多种本公开所述的结合多肽的鸡尾酒混合可能被证明特别有效。
IX.结合多肽的表达
一方面,本发明提供编码本文公开的结合多肽的多核苷酸。还提供了制备结合多肽的方法,包括表达这些多核苷酸。
编码本文公开的结合多肽的多核苷酸通常插入用于引入宿主细胞的表达载体,所述宿主细胞可用于产生预期质量的要求保护的抗体或其片段。相应地,一些方面,本发明提供包含本文公开的多核苷酸的表达载体和包含这些载体和多核苷酸的宿主细胞。
本文使用术语"载体"或"表达载体"是出于描述和要求保护的目的,意为与本发明对应使用的载体作为用于将预期基因引入细胞并表达的媒介。本领域的技术人员已知,这种载体可很容易地从下组选择:质粒、噬菌体、病毒和逆转录病毒。一般而言,与本发明相容的载体将包含选择标记、合适的限制性酶切位点以促进预期基因的克隆和进入真核或原核细胞和/或复制的能力。
可采用多种表达载体系统用于本发明的目的。举例来说,一类载体应用源自动物病毒的DNA元件,如源自牛乳头状瘤病毒、多瘤病毒、腺病毒、牛痘病毒,杆状病毒,逆转录病毒(RSV、MMTV或MoMLV)或SV40病毒的元件。其他包括具有内部核糖体结合位点的多顺反子系统的使用。此外,具有整合入其染色体的DNA的细胞可通过引入一种或多种允许转染宿主细胞选择的标记进行选择。标记可用于向营养缺陷型宿主提供原养型、杀菌抗性(例如抗生素)或重金属如铜抗性。可选择的标记基因可直接与将表达的DNA序列连接,或通过共转化引入相同细胞。其他元件对于优化mRNA的合成也可能是需要的。这些元件可包括信号序列、剪接信号以及转录启动子、增强子和终止信号。在具体的优选实施方案中,克隆的可变区基因与如上文讨论的合成的重链和轻链恒定区基因(优选是人的)共同插入表达载体。
在其他优选的实施方案中,本发明的结合多肽可使用多顺反子构建体表达。在这种表达系统中,感兴趣的多重基因产物如抗体的重链和轻链可从单一多顺反子构建体产生。这些系统有利地使用内部核糖体进入位点(IRES)以在真核宿主细胞中提供相对高水平的本发明的多肽。相容的IRES序列公开于美国专利号6,193,980,其在本文通过提述并入。本领域的技术人员将理解这种表达系统可用以有效产生全范围的本申请的多肽。
更普遍地,一旦编码抗体或其片段的载体或DNA序列已制备,所述表达载体可引入合适的宿主细胞。也就是说,可转化所述宿主细胞。质粒向宿主细胞的引入可通过多种本领域的技术人员熟知的技术完成。这些包括但不限于转染(包括电泳和电穿孔)、原生质体融合、磷酸钙沉淀、用包膜DNA的细胞融合、显微注射和用完整病毒的感染。参见Ridgway,A.A.G."Mammalian expression vectors"Chapter 24.2,pp.470-472vectors,Rodriguezand Denhardt,Eds.(Butterworths,Boston,Mass.1988)。最优选地,质粒经由电穿孔引入宿主。转化的细胞在适于产生轻链和重链的条件下生长,并对重链和/或轻链蛋白的合成进行测定。典型的测定技术包括酶联免疫吸附试验(ELISA)、放射免疫试验(RIA)或荧光激活细胞分选仪分析(FACS)、免疫组化等等。
如本文使用的术语"转化"应在广义上用于指代DNA向受体宿主细胞的引入,其改变基因型并从而导致受体细胞中的变化。
本着同样的含义,"宿主细胞"指代以使用重组DNA技术构建并编码至少一种异源基因的载体转化的细胞。对于从重组宿主分离多肽的工艺说明中,术语"细胞"和"细胞培养"可互换使用以指代抗体来源,除非另有清楚指明。也就是说,多肽从"细胞"的回收可意为从离心的完整细胞或从包含培养基和悬浮细胞的细胞培养物。
在一个实施方案中,用于抗体表达的宿主细胞系是哺乳动物来源;本领域的技术人员可判断哪些特定的宿主细胞系最适于预期的基因产物在其中表达。典型的宿主细胞系包括但不限于DG44和DUXB11(中国仓鼠卵巢细胞系,DHFR减)、HELA(人宫颈癌)、CVI(猴肾细胞系)、COS(具有SV40T抗原的CVI的衍生物)、R1610(中国仓鼠成纤维细胞)、BALBC/3T3(小鼠成纤维细胞)、HAK(仓鼠肾细胞系)、SP2/O(小鼠骨髓瘤),BFA-1c1BPT(牛内皮细胞)、RAJI(人淋巴细胞)、293(人肾)。在一个实施方案中,细胞系用于提供在其中表达的抗体的改变的糖基化,例如无岩藻糖基化(例如PER.C6.RTM.(Crucell)或FUT8敲除CHO细胞系(Potelligent.RTM.Cells)(Biowa,Princeton,N.J.))。在一个实施方案中,可使用NS0细胞。CHO细胞是特别优选的。宿主细胞系通常可从商业服务、American Tissue CultureCollection或从公开的文献获得。
体外制备允许扩大规模以提供较大的量的预期多肽。在组织培养条件下用于哺乳动物细胞培养的技术为本领域已知且包括均匀悬浮培养,例如在气升式反应器中或在连续搅拌反应器中,或固定化或包埋的细胞培养物,例如在空心纤维、微胶囊中,在琼脂糖微珠或陶瓷筒上。如果有必要和/或符合预期,多肽溶液可通过常规的色谱方法纯化,举例来说凝胶过滤、离子交换色谱、DEAE-纤维素上的色谱和/或(免疫)亲和力色谱。
编码本发明的结合多肽的基因还可在非哺乳动物细胞如细菌或酵母或植物细胞中表达。这方面,将理解的是也可转化多种单细胞非哺乳动物微生物如细菌;即能够在培养物或发酵中生长的那些。对转化易感的细菌包括肠杆菌科的成员,如大肠杆菌(Escherichia coli)或沙门氏菌(Salmonella);芽孢杆菌科(Bacillaceae)如枯草芽孢杆菌(Bacillus subtilis);肺炎球菌(Pneumococcus);链球菌(Streptococcus)和流感嗜血杆菌(Haemophilus influenzae)的菌株。将进一步理解的是当在细菌中表达时,多肽可以是包涵体的一部分。必须将所述多肽分离、纯化并随后装配成功能分子。
原核细胞外,也可以使用真核微生物。酿酒酵母(Saccharomyces cerevisiae),或常用的面包酵母是真核微生物中最常使用的微生物,尽管多种其他菌株也通常是可以获得的。对于在酿酒酵母中的表达,通常使用举例来说质粒YRp7(Stinchcomb et al.,Nature,282:39(1979);Kingsman et al.,Gene,7:141(1979);Tschemper et al.,Gene,10:157(1980))。该质粒已包含为缺乏在色氨酸中生长的能力的酵母突变株提供选择性标记的TRP1基因,举例来说ATCC No.44076或PEP4-1(Jones,Genetics,85:12(1977))。trpl病变作为酵母宿主细胞基因组的特征的存在随后为通过在不存在色氨酸的条件下的生长来检测转化提供了有效环境。
实施例
本发明通过下列实施例进一步阐述,其不应理解为进一步的限制。序列表的内容、附图和贯穿本申请引用的全部参考文献、专利和公开的专利申请通过提述明确并入本文。
实施例1. 2C3抗CD-52高度糖基化抗体突变体的设计、制备和表征
为达到添加大基团至相互作用界面的目的(例如FcRn结合位点以调节抗体药物动力学),用于通过改变其与FcγRs的相互作用来调节抗体的效应功能,或为引入新型交联位点亚序列化学修饰用于效应部分(包括但不限于药物、毒素、细胞毒性剂和放射性核素)的偶联,在抗CD-52抗体2C3的重链中设计了多重高度糖基化突变。高度糖基化的2C3突变体阐述于表3中。
表3.高度糖基化的2C3抗CD-52突变体
1A.2C3抗CD-52抗体高度糖基化突变体的产生
将基于Kabat编号系统指代的A114N突变通过诱变PCR引入2C3的CH1结构域。为产生全长抗体,VH结构域加突变的A114N残基通过连接非依赖克隆(LIC)插入编码抗体CH结构域1-3的pENTR-LIC-IgG1载体。所有其他突变通过定点诱变使用QuikChange定点诱变试剂盒(Agilent Technologies,Inc.,Santa Clara,CA,USA)引入pENTR-LIC-IgG1。将WT 2C3VH通过LIC克隆入突变载体。将全长的突变体通过Gateway克隆克隆入pCEP4(-E+I)Dest表达载体。基于EU编号系统指定Fc突变。通过DNA测序确认突变。WT 2C3重链和轻链和突变的2C3重链的氨基酸序列阐述于表4。突变的氨基酸以灰色标注且通过突变产生的共有糖基化靶位点为下划线部分。
表4. 2C3抗CD-52抗体的氨基酸序列
突变体和WT对照转染入在6孔板形式中的HEK293-EBNA细胞中。如图9所示,如通过SDS-PAGE和蛋白免疫印迹分析,发现表达水平为~0.1μg/ml。在条件培养基中突变体的表达也通过Biacore上蛋白A的捕获测量。浓度使用注射入固定的蛋白A6分钟后的解离响应测定。将在培养基中从90μg/mL至1.5ng/mL系列稀释的CHO-产生的WT 2C3用作标准曲线。通过使用4参数拟合的校准曲线计算浓度,最低至~0.2μg/mL。如图9所示,相对表达水平较低且大体上与蛋白免疫印迹的结果对应。
1B.高度糖基化的验证
为测定是否额外的糖基化位点可通过突变引入,2C3突变体和野生型蛋白使用通用的去糖基化酶PNGase F处理,且蛋白样品通过SDS-PAGE和蛋白免疫印迹分析。如图10所示,仅A114N突变体具有增加的表观分子量,表明额外的N连接糖的存在。
生产小规模的抗体制备以纯化2C3突变体用于进一步验证糖基化位点的引入。如图11所示,通过SDS-PAGE确认了仅A114N突变体具有额外引入的糖基化位点。
1C.2C3抗CD-52突变体的结合性质
使用Biacore以比较纯化蛋白的结合性质。小鼠和SEC-纯化的人FcRn-HPC4经由胺偶联固定在CM5芯片上。将每种抗体稀释至200、50和10nM并注射在固定的Fc受体上。Campath、CHO-产生的WT 2C3和DEPC-处理的Campath作为阳性和阴性对照包括在内。如图13所示,Y436S突变体展示出与人FcRn的结合中约2倍的降低。有趣的是,该突变体与小鼠FcRn的结合并未受到影响。其他2C3突变都未对人或小鼠FcRn结合具有任何显著影响。
使用Biacore并使用CD-52肽741Biacore结合试验来比较纯化蛋白的抗原结合性质。将CD-52肽741和对照肽777固定至CM5芯片。将抗体从60nM在HBS-EP中2倍系列稀释至0.2nM并一式两份注射持续3分钟,随后是在缓冲液中以50μL/min流速的5分钟的解离。GLD52批次17200-084作为对照包括在内。用1脉冲的40mM HCl使表面再生。使用1:1结合模型来拟合7.5至0.2nM曲线。如图16所示,相比该试验中的其他突变体,A114N突变体具有稍微较低的CD-52结合亲和力而NGT突变体具有稍微较高的亲和力。CD-52肽741Biacore结合试验用从大规模制备纯化的蛋白进行了重复。如图17所示,A114N突变体展示与WT 2C3可比较的CD-52肽结合。
1D.A114N突变体的电荷表征
实施等点聚焦(IEF)以表征2C3突变体的电荷。使纯化的蛋白在固定的pH梯度(pH3-10)丙烯酰胺(IPG)凝胶上运行。如图18A所示,可能由于唾液酸残基,发现A114N具有更多的负电荷。完整的MS数据确认了在A114N突变体上具有唾液酸的复杂结构。相反地,WT2C3显示具有G0F和G1F作为主要的糖基化种类(分别在图18C和18D中)。
实施例2.数种抗体骨架中高度糖基化的突变体的制备
2C3抗CD-52抗体外,在数种其他抗体骨架中工程化了A114N突变以确认独特的高度糖基化位点可引入不相关的重链可变结构域序列中。高度糖基化的抗TEM1、抗FAP和抗Her2突变体阐述于表5中。
表5.数种不相关的抗体骨架中设计的A114N和/或S298N突变体
2A.抗TEM1和抗FAP抗体高度糖基化突变体的产生
将基于Kabat编号系统设计的A114N突变通过诱变PCR引入抗TEM1和抗FAP的CH1结构域。为产生全长抗体,突变的VH加残基114通过连接非依赖克隆(LIC)插入编码抗体CH结构域1-3的pENTR-LIC-IgG1载体。全长的突变体随后通过Gateway克隆克隆入pCEP4(-E+I)Dest表达载体。突变通过DNA测序确认。抗TEM1野生型和突变的重链和轻链的氨基酸序列阐述于表6中。突变的氨基酸以灰色标注且通过突变产生的共有糖基化靶位点为下划线部分。
表6.抗TEM1和抗FAP抗体的氨基酸序列
突变体和野生型对照转染入在三烧瓶形式(triple flask format)中的HEK293-EBNA细胞并在HiTrap蛋白A柱(GE Healthcare Biosciences,Pittsburgh,PA,USA)上纯化。如通过NanoDrop分光光度计上A280分析,抗FAP A114N和抗FAP A114C的表达分别为约3μg/ml和约1μg/ml。抗TEM1 A114N的表达为约0.04μg/ml。
2B.高度糖基化的验证
为确认额外的糖基化位点引入了A114N突变体,从A114N突变体纯化的蛋白与野生型对照蛋白在还原SDS-PAGE上分析。一种额外的糖基化位点将添加2000-3000道尔顿至重链分子量。如图20所示,SDS-PAGE表明抗FAP和抗TEM1 A114N突变体重链条带具有增加的表观分子量,与额外的糖基化位点向两抗体的成功引入相符。
2C.抗Her2抗体高度糖基化突变体的产生
Her-2 A114N、Her-2 A114N/NNAS和WT Her-2抗体通过连接非依赖克隆产生。合成并用LIC-相容的引物集合PCR扩增野生型或带有A114N突变的赫赛汀(Herceptin)的VH结构域。为获得全长抗体,将扩增的VH插入片段(WT或A114N)克隆入编码CH 1-3结构域的两pENTR载体,pENTR-LIC-IgG1 WT和pENTR-LIC-IgG1 NNAS,获得三种全长的突变体(A114N、NNAS、A114N/NNAS)和作为pENTR上的入门克隆的WT对照。将这些突变体通过Gateway克隆克隆入pCEP4(-E+I)Dest表达载体。通过DNA测序确认突变。抗Her-2野生型和突变的重链和轻链的氨基酸序列阐述于表7。突变的氨基酸以灰色标注且通过突变产生的共有糖基化靶位点为下划线部分。
表7.抗Her-2抗体的氨基酸序列
2D.A114N抗Her2抗体高度糖基化突变体的表达
A114N抗Her2和野生型构建体用Lipofectamine-2000(试剂对DNA的比率为2.5:1)和XtremeGene HP(试剂对DNA的比率为3:1)转染入在12份三烧瓶(12triple flasks)中的HEK293-EBNA细胞中。从第3天的条件培养基(CM)的等分试样获得的Octet测量结果显示蛋白表达对于Lipofectamine-2000和XtremeGene HP两者在6个烧瓶之间是一致的。如表8所示,整体转染效率用XtremeGene HP高约30%。在第3天收集的条件培养基汇集在一起用于两种转染条件并通过蛋白A柱纯化。Octet测量显示了在包含血清的模拟培养基中的1.8ug/ml抗体对比在无血清模拟培养基中的0ug/ml。
表8.A114N抗Her2高度糖基化突变体的表达
收集来自第6天的条件培养基并对于每种转染条件分别纯化。将两种洗脱物分别缓冲交换入pH 7.2的PBS并使用Amicon-4(50kD截留)柱浓缩~15倍。第6天的CM与第3天的CM相比显示更高的表达水平。如表8所示,从第六天的条件培养基产生共3mg 15.59mg/ml的赫赛汀A114N(来自Lipofectamine转染)和6mg 16.86mg/ml的赫赛汀A114N(来自XtremeGene HP转染)用于其他下游应用,如抗体药物偶联。
2E.A114N抗Her2突变体的SDS-PAGE和HIC分析
偶联前,纯化的A114N赫赛汀通过SDS-PAGE和HIC(疏水相互作用色谱)表征。如图21所示,确定纯化的A114N赫赛汀的质量适于进一步的下游应用。
2F.工程化的糖基化的偶联
已证明了:a)糖基化位点在抗TEM1上的Kabat位置114处引入;b)通过还原SDS-PAGE该A114N突变体在重链上具有高度糖基化;且c)通过完整的LC/MS,该A114N高度糖基化变体具有复杂糖结构,包括末端唾液酸和半乳糖,其对于SAM和GAM偶联是理想的。为确认工程化的糖基化位点适于偶联,抗TEM1A114N与5kDa PEG经由氨氧基化学方法偶联。如图22所示,PEG通过氨氧基连接基成功与抗TEM1偶联。该突变体也成功在抗FAP和抗CD-522C3骨架(未显示)上制备。这些数据证明N114处的糖基化位点可用于效应部分的偶联。
实施例3:S298N/Y300S Fc突变体的生成
设计并生成了工程化的Fc变体,其中在EU位置Ser 298处引入新的糖基化位点,毗邻天然存在的Asn297位点。保持或通过突变消除Asn297处的糖基化。突变和预期的糖基化结果阐述于表9中。
表9:多种抗体变体的糖基化状态
3A.H66αβ-TCR抗体改变的糖基化变体的生成
在αβT-细胞受体抗体克隆#66的重链上通过Quikchange使用pENTR_LIC_IgG1模板进行突变。用LIC引物扩增HEBE1 Δab IgG1#66的VH结构域,之后通过LIC克隆入突变或野生型pENTR_LIC_IgG1以生成全长的突变或野生型抗体。用DraIII/XhoI双消化确认亚克隆,在成功的克隆中产生大致1250bp-大小的插入片段。将那些全长的突变体随后经由Gateway克隆克隆入表达载体pCEP4(-E+I)Dest。通过DNA测序确认突变。WT H66抗αβTCR重链和轻链的氨基酸序列和突变的H66重链阐述于表10中。突变的氨基酸以灰色标注且通过突变产生的共有糖基化靶位点为下划线部分。
表10:H66抗αβTCR抗体的氨基酸序列
将突变体、野生型和两种无糖基化对照的(pCEP4中的HEBE1 Agly IgG4和HEBE1Δab IgG1)构建体转染入在三烧瓶中的HEK293-EBNA细胞用于表达。从160ml的条件培养基(CM)用1ml HiTrap蛋白A柱(GE)使用多通道蠕动泵纯化蛋白。五微克的每种所得上清在4-20%Tris-甘氨酸还原和非还原SDS-PAGE凝胶上分析(参见图2)。无糖基化的突变体的重链(N297Q、T299A和Agly对照)具有进一步迁移(箭头),与在这些抗体中聚糖的损失一致。然而,工程化的糖基化抗体的重链(NSY、STY、SY、Δab和wt对照,箭头)与野生型对照迁移相似。该结果与在EU位置298处工程化的糖基化位点的存在一致。SEC-HPLC分析表明所有突变体都作为单体表达。
3B.通过LC-MS的糖基化分析
工程化的H66 IgG1 Fc变体用20mM DTT在37℃部分还原30min。样品随后通过毛细管LC/MS在与QSTAR qq TOF混合系统(QSTAR qq TOF hybrid system)(AppliedBiosystems)偶联的Agilent 1100毛细管HPLC系统上分析。使用Bayesian蛋白的重建和基线纠正以及Analyst QS 1.1(Applied Bisoystem)中的计算机建模用于数据分析。S298N/T299A/Y300S H66抗体突变体中,在氨基酸位点298处观察到一个糖基化位点,其中双触角和三触角复合型聚糖作为主要品种与G0F、G1F和G2F一起检出(参见图34)。这种改变的糖基化概貌与在N298处的迁移糖基化而非在N297处的野生型糖基化一致。
3C.使用Biacore的αβTCR抗体突变体与人FcγRIIIa和FcγRI的结合性质
使用Biacore评估与重组人FcγRIIIa(V158&F158)和FcγRI的结合。CM5芯片的全部四个流动池用抗HPC4抗体经由Biacore提供的标准胺偶联步骤固定。所述抗HPC4抗体在pH 5.0的10mM醋酸钠中稀释至50μg/mL用于偶联反应并以5μL/min注射25min。将大致12,000RU的抗体固定至芯片表面。将重组人FcγRIIIa-V158和FcγRIIIa-F158在结合缓冲液(具有1mM CaCl2的HBS-P)中稀释至0.6μg/mL并分别以5μL/min持续3min注射至流动池2和4以在抗HPC4芯片上捕获300–400RU受体。为在低结合者间进行区分,在抗HPC4表面捕获了比在该试验中通常使用的多达三倍的rhFcγRIIIa。将流动池1和3用作参照。每种抗体在结合缓冲液中稀释至200nM并持续4min注射至四个流动池中,随后在缓冲液中解离5分钟。表面用HBS-EP缓冲液中的10mM EDTA以20μL/min持续3min重生。这些实验的结果示于图3。
Biacore也用于比较FcγRI结合。将抗四His抗体使用Zeba Desalting柱缓冲交换入pH 4.0的10mM醋酸钠中,并在醋酸缓冲液中稀释至25μg/mL用于胺偶联。CM5芯片的两个流动池用~9000RU抗四His抗体以5μL/min注射20min后固定。如之前的实验中,捕获多达十倍的FcγRI至抗四-His表面以比较具有弱结合的样品。将重组人FcγRI在HBS-EP结合缓冲液中稀释为10μg/mL并以5μL/min持续1min注射至流动池以捕获~1000RU受体至抗四-His芯片。100nM单一浓度的抗体以30μL/min持续3min注射至捕获受体和对照的表面。随后,监测解离三分钟。所述表面随后用pH 2.5的10mM甘氨酸以20μL/min的两次30秒的注射重生。这些实验的结果如图4所示。
这些结果证明糖工程化的突变体与FcγRIIIa或FcγR结合中的显著降低。特别是H66 S298N/T299A/Y300S与两种受体都具有几乎完全消除的结合。选择该突变体用于更详细的分析。
3D.使用圆二色谱(CD)的稳定性表征
S298N/T299A/Y300S抗体突变体的稳定性通过Far-UV CD热熔实验监测,其中由于增加的温度导致抗体的去折叠(变性),因此监测了216nm和222nm处的CD信号。
温度通过热电珀耳帖(Jasco模型AWC100)控制并以1℃/min的速率从25℃增加至89℃。CD谱在Jasco 815分光光度计上以PBS缓冲液中大致0.5mg/mL的蛋白浓度于石英比色杯(Hellma,Inc)中用10mm的路径长度收集。扫描速度为50nm/min且数据间距为0.5nm。使用2.5nm的带宽伴随培养基的灵敏度设置。从210-260nm使用0.5nm的数据间隔和1℃的温度间隔收集CD信号和HT电压且对于每个样品实施四次重复扫描。结果证明δAB H66和S298N/T299A/Y300S H66突变体两者都显示相似的热行为且具有大致相同的针对降解的起始温度(大约63℃)(图35),进一步表明其具有可比较的稳定性。
实施例4:Fc-工程化突变体的功能分析
通过PBMC增殖试验和细胞因子释放试验评估Fc-工程化的突变体。在PBMC增殖试验中,人PBMC用浓度逐渐增加的治疗性抗体培养72小时,添加3H-胸腺嘧啶并在18小时后收获细胞。对于T细胞消耗/细胞因子释放试验,用浓度逐渐增加的治疗性抗体培养人PBMC并对细胞计数和生存力进行每日分析(Vi-Cell,Beckman Coulter)至第7天(out to day 7)。收获细胞上清,在-20℃保存并在8-丛细胞因子面板(8-plex cytokine panel)(Bio-Rad)上分析。
融化正常的供体PBMC并在下列条件下处理(都在包含补体的培养基中):未处理;BMA031、moIgG2b 10ug/ml;OKT3、moIgG2a 10ug/ml;H66、huIgG1δAB 10ug/ml、1ug/ml和0.1ug/ml;H66、huIgG1S298N/T299A/Y300S 10ug/ml、1ug/ml和0.1ug/ml。
在第2天(D2)和第4天(D4)收获细胞因子用于Bioplex分析(IL2、IL4、IL6、IL8、IL10、GM-CSF、IFNg、TNFa)。细胞在D4针对CD4、CD8、CD25和abTCR表达进行染色。
在图5-8中显示的结果证明H66S298N/T299A/Y300S与H66δAB在全部实施的基于细胞的试验中表现相似,表明通过CD25表达的最小T-细胞激活、与abTCR的结合(具有与δAB稍微不同的动力学)和在D2和D4两个时间点的最小细胞因子释放。因此S298N/T299A/Y300S突变体与δAB突变同样有效地消除了效应功能。
实施例5:抗CD52抗体骨架中工程化Fc变体的制备和表征
H66抗αβTCR抗体外,S298N/Y300S突变也在抗CD52抗体骨架(克隆2C3)中工程化。随后检测该突变体进而确定在S298N/Y300S H66抗αTCR抗体中观察到的效应功能调节是否与另一抗体骨架一致。
5A.2C3抗CD52抗体改变的糖基化变体的生成
首先,通过快速变化诱变(quick change mutagenesis)使用pENTR_LIC_IgG1制备了S298N/Y300S 2C3变体DNA,并将WT 2C3VH通过LIC克隆入突变的载体。将全长突变体使用Gateway技术克隆入pCEP4(-E+I)Dest表达载体。随后通过DNA测序确认突变且序列阐述于表11中。随后将突变体转染入在6孔板形式中的HEK293-EBNA细胞并从条件培养基纯化蛋白。抗CD52 2C3野生型抗体作为对照平行产生。使用SD-PAGE和蛋白免疫印迹分析发现表达水平为0.1μg/mL(图9A)。还通过在Biacore上蛋白A的捕获测量了在纯条件培养基(neatconditioned medium)中突变体的表达。向固定的蛋白A注射6分钟后使用解离响应测定浓度。将在培养基中从90μg/mL系列稀释至1.5ng/mL的CHO-产生的WT 2C3用作标准曲线。通过校准曲线使用4参数拟合在大致0.2μg/mL内计算浓度。相对表达水平较低且与蛋白免疫印迹数据基本一致(图9B)。
表11:抗CD52克隆2C3抗体序列
5B.使用PNGaseF的糖基化分析
为评估通过突变引入的额外的糖基化位点,富集的S298N/Y300S突变体用PNGaseF去糖基化。在分子量中未表明任何表观变化,这说明不存在额外的糖(图10)。实施了小规模制备以纯化这些突变体用于进一步表征,且结果再次确认在S298N/Y300S突变体上不存在额外的糖(图11)。
5C.使用Biacore的2C3抗CD52抗体突变体与人FcγRIIIa1的结合性质
还使用了Biacore来表征抗原结合、FcγRIII和纯化的抗体的结合性质(参见图12、13和14)。S298N/Y300S 2C3变体与CD52肽紧密结合且结合传感图与野生型对照无法区分,表明该突变并不影响其抗原结合(图12A)。
为测定Fc效应功能,在结合研究中使用了FcγRIII受体(Val158)。突变体和野生型对照抗体稀释至200nM并注射至HPC4-标签捕获的FcγRIIIa。FcγRIII结合对于S298N/Y300S突变体几乎不可检测,这表明该变体效应功能的损失(图12B和图14A)。为进一步测定Fc效应功能,还在结合研究中使用了FcγRIII受体(Phe158)。突变体和野生型对照抗体稀释至200nM并注射至HPC4-标签捕获的FcγRIIIa。FcγRIII结合对于S298N/Y300S突变体几乎不可检测,这表明使用Phe158变体的效应功能损失(图14B)。最后,使用Biacore比较纯化蛋白的FcRn结合性质。小鼠和SEC-纯化的人FcRn-HPC4经由胺偶联固定至CM5芯片。将每种抗体稀释至200、50和10nM并注射至受体上。Campath、CHO-产生的WT 2C3和DEPC-处理的Campath包括在内作为阳性和阴性对照。这些数据显示突变体与人和鼠类FcRn受体以与野生型抗体对照相同的亲和力结合且其在循环半衰期或其他药代动力学性质中可能不具有改变(参见图12C、图13A和B)。相应地,S298N/Y300S突变大体上可应用于抗体以降低或消除不想要的Fc效应功能,举例来说通过人Fcγ受体的参与。
实施例6:S298N/Y300S突变体中循环免疫复合体的检测
对于S298N/Y300S突变体和WT对照,循环的免疫复合体的检测使用C1q结合试验研究。高度结合Costar 96-孔板在4℃用100μl在包被缓冲液中(0.1M NaCHO3pH 9.2)浓度范围从10至0.001μg/ml的2倍系列稀释的2C3Ab包被。ELISA分析显示对于S298N/Y300S突变体,与WT比较C1q结合降低(图15A)。抗Fab Ab与包被的2C3Ab的结合证实孔的等同包被(图15B)。
实施例7:使用等点聚焦的S298N/Y300S突变体的分离和分析
运行pH3-10的等电聚焦(IEF)凝胶以表征S298N/Y300S突变体。发现S298/Y300S具有更多个负电荷,且因此可能具有更多的唾液酸分子(图18A)。S298N/Y300S突变体和WT2C3两者都通过完整的MS显示具有G0F和G1F作为主要的糖基化种类(分别在图18B和D中)。
实施例8:S298N/Y300S的抗原结合亲和力
使用Biacore比较从较小规模(图16)和较大规模(图17)表达制备和纯化的WT抗CD52 2C3 Ab和S298N/Y300S突变体的抗原结合亲和力。获得了用CD52肽741和对照肽777固定的CM5芯片。抗体在HBS-EP中从60nM 2倍系列稀释至0.2nM且随后持续3min注射至芯片表面,随后是以50μl/min的流动速率在缓冲液中5min的解离。表面随后用40mM HCl的脉冲再生。这些分析实施两次并证明S298N/Y300S突变体和WT 2C3抗体显示可比较的CD52肽结合。
设计了培养基筛选平台以在纯化前测试功能性结合性质进而在小规模转染过程中筛选生成的抗体。使用Octet实施这些测试(图19A)以测定浓度并使用了蛋白A生物传感器和GLD52标准曲线。将样品在HBS-Ep稀释至7.5和2nM用于使用Biacore的CD52结合比较(图19B)。肽结合试验的结果显示S298N/Y300S突变体和WT 2C3抗体都具有可比较的CD52肽结合。此外,这些分析表明Octet和Biacore在预测由来自小规模转染的抗体的抗原结合中表现良好。
实施例9:S298N/Y300S、S298N/T299A/Y300S和N297Q/S298N/Y300S改变的糖基化突变体在额外的抗体骨架中的制备
在抗αβ-TCR抗体和2C3抗CD-52抗体外,S298/Y300S、S298N/T299A/Y300S和N297Q/S298N/Y300S突变在其他抗体骨架中工程化以确认额外的串联糖基化位点可引入不相关的重链可变结构域序列。以不同方式的糖基化(alternatively glycosylated)抗CD-52 12G6和抗Her2突变体阐述于表12和13中。
表12:抗CD52克隆12G6抗体序列
表13:抗Her2抗体序列
实施例10.包含具有反应性的聚糖部分的改变的抗体的生成
为生成包含能够与衍生的效应部分反应的聚糖部分的抗体,首先使用糖基化转移酶和相关的糖核苷酸供体在体外对抗HER抗体糖基化。举例来说,为引入唾液酸残基,首先用β-半乳糖基转移酶将供体抗体糖基化,随后根据Kaneko et al.(Kaneko,Y.,Nimmerjahn,F.,and Ravetch,J.V.(2006)anti-inflammatory activity ofimmunoglobulin G resulting from Fc sialylation.Science 313,670-3)的方法用α2,6-唾液酸转移酶唾液酸化。反应在一锅合成步骤(one-pot synthesis step)中使用β-半乳糖基转移酶(50mU/mg,Sigma)和α2,6-唾液酸转移酶(5ug/mg,R&D系统)与供体糖核苷酸底物(包含5mM MnCl2的50mM MES缓冲液中(pH 6.5)的UDP-半乳糖(10mM)和CMP-唾液酸(10mM))进行。包含5mg/ml抗HER2抗体的反应混合物在37℃温育48小时。唾液酸化的验证使用由PNGase F从抗体释放的全甲基化的聚糖的MALDI-TOFMS分析,使用Dionex HPLC和使用SNA(一种特异性针对α2,6-唾液酸的凝集素)的凝集素印迹的唾液酸含量分析。
通过唾液酸化的抗HER2抗体的PNGase F处理释放的聚糖的MALDI-TOF分析表明天然聚糖已用主要为单唾液酸化的双触角结构A1F与少量的双唾液酸化种类共同完全重塑(图27A)。用较高的量的α2,6-唾液酸转移酶处理抗体产生了更均质的A1F糖形的群体,表明酶活性或聚糖定位可能阻止了完全唾液酸化。唾液酸含量测定为~2mol每mol抗体,这与A1F聚糖作为主要糖形种类一致(图27B)。用特异性针对α2,6-连接唾液酸的SAN凝集素(黑色接骨木凝集素(Sambucus nigra agglutinin))进行的凝集素印迹证实了在α2,6-连接基构型中存在的唾液酸(图27C)。
总之,尽管天然蛋白聚糖在某种程度上是异质的,但通过半乳糖和唾液酸转移酶的重塑获得几乎均匀的具有单唾液酸化但完全半乳糖基化的双触角聚糖(A1F)的抗体。在每个分支聚糖上的两个半乳糖受体上仅~1个唾液酸的引入可能是由于经常埋藏在抗体中的聚糖的半乳糖之一有限的可到达性或聚糖与蛋白表面非共价的相互作用。
实施例11.包含具有反应性的聚糖部分的改变的抗体的氧化
一旦验证了唾液酸化,用多种浓度的高碘酸盐(0.25至2mM)研究了唾液酸化的抗HER2抗体的过程中氧化。首先将唾液酸化的抗体缓冲交换入包含5mM EDTA的25mM Tris-HCl(pH 7.5),随后用PBS缓冲液进行缓冲交换。缓冲的抗体混合物随后应用至用PBS缓冲液预先平衡的蛋白A琼脂糖柱。用15柱体积的PBS、15柱体积的包含5mM EDTA的PBS和30柱体积的PBS洗涤柱后,随后用25mM柠檬酸盐磷酸盐缓冲液(pH 2.9)洗脱。洗脱物立即用磷酸氢二钠缓冲液中和并使用来自Millipore的Amicon ultra浓缩抗体。纯化后,再用在100mM醋酸钠缓冲液中(pH 5.6)的高碘酸钠(Sigma)在暗处冰上持续30分钟氧化唾液酸化的抗HER2抗体,且反应用3%甘油在冰上持续15分钟淬灭。产物通过5轮在50kDa Amicon上的超滤脱盐并交换入100mM醋酸钠(pH 5.6)中。图28A显示用多种高碘酸的量滴定的唾液酸化的抗体的唾液酸含量分析。唾液酸残基的完全氧化在大于0.5mM的高碘酸盐浓度获得。事实上,低如0.5mM的高碘酸浓度足以完全氧化引入的唾液酸。相应地,选择1mM浓度的高碘酸盐用于氧化用于药物偶联的唾液酸化的抗体。
氧化可对抗体的整体性具有不良作用。举例来说,接近FcRn结合位点的甲硫氨酸残基的氧化,包括位于Fc CH3区的Met-252和Met-428,已知影响对延长抗体血清半衰期至关重要的FcRn结合(Wang,W.,et al.(2011)Impact of methionine oxidation in humanIgG1 Fc on serum half-life of monoclonal antibodies.Mol Immunol 48,860-6)。相应地,为检测高碘酸盐氧化作用于对FcRn相互作用至关重要的甲硫氨酸残基(例如Met-252)的潜在副作用,唾液酸化的抗体的氧化状态通过胰蛋白酶肽消化的LC/MS分析测定。该分析揭示唾液酸化的曲妥珠单抗用1mM高碘酸盐处理后,~30%的Met-252氧化和<10%的Met-428氧化。为测定这种程度的甲硫氨酸氧化对FcRn结合的影响,使用表面等离子体共振(BIACORE)评估FcRn对于每种抗体的结合动力学。该分析揭示了氧化状态与FcRn结合的少量损失相关(对于小鼠和人FcRn的12%和26%降低,分别参见图28B和28C)。值得注意的是,已报道对于人FcRn的Ka中~25%的降低对人FcRn转基因小鼠中的血清半衰期无作用,这是由于单个完整的FcRn位点对每种抗体都足以提供功能性和PK优势(Wang et al.,Id)。
总之,这些数据表明通过唾液酸转移酶处理的高碘酸盐-敏感性唾液酸残基的引入允许浓度低得多的高碘酸的使用,获得对抗体-FcRn相互作用和对通过聚集体评估的抗体完整性的最小副作用(≤1%)。因此,使用根据本发明的方法的唾液酸化的抗体为可应用的氧化条件提供了更宽窗口,允许可再现地生成具有活性的糖偶联物而不存在对血清半衰期的影响。
高度糖基化的抗体突变体中的半乳糖也可使用半乳糖氧化酶特异性地氧化以生成用于偶联的醛基团。为证实该方法,将A114N抗TEM1抗体浓缩至13-20mg/ml且随后用在PBS中的20mU/mg唾液酸酶在37℃处理6小时。去唾液酸产物随后用半乳糖氧化酶(“GAO”)氧化,首先用5ug GAO/mg蛋白在37℃过夜,随后添加2ug GAO/mg蛋白并温育额外5小时。添加醋酸钠以调整pH至5.6(0.1v/v,pH5.6),并在偶联前添加DMSO以获得16%的最终反应浓度。高度糖基化突变体A114N抗HER抗体(15mg/ml)相似地用唾液酸酶(20mU/mg)去唾液酸化,并在单反应中用5ug GAO每mg蛋白在37℃过夜氧化。
实施例12.具有反应性的效应部分的合成
为促进本发明的与醛衍生的抗体糖形的偶联,候选的药物效应部分(例如单甲基奥瑞他汀E(MMAE)和多拉司他汀10(Dol10))用氨氧基-cystamide衍生以包含特异性与醛反应的功能性基团(例如氨氧基-cys)。
简要地,为生成氨氧基-cystamide作为初始材料,将S-三苯甲基-L-半胱氨酰胺(362mg,1mmol)添加至3mL t-BOC-氨氧酸醋酸N-羟基琥珀酰亚胺酯的DMF溶液中(289mg,1mmol)。如从HPLC分析显而易见的是反应在3h后完成。反应混合物随后用30ml二氯甲烷稀释并用0.1M碳酸氢钠溶液(2x20mL)、水(2x20mL)和盐水(2x20mL)洗涤。所述溶液在无水硫酸钠上干燥、过滤并浓缩至干燥。向该干燥残余物添加3mL的TFA,随后是150μL的三乙基硅烷。获得的溶液从叔丁基甲基醚沉淀并重复该过程三次。过滤后,将所述残余物在降低的压力下干燥,获得205mg灰白色固体(67%收率)。将该化合物用于下一步而无需进一步纯化。
为生成氨氧基衍生的MMAE(氨氧基-Cys-MC-VC-PABC-MMAE),将30.1mg的氨氧基-cystamide(0.098mmol,2当量)与64.6mg的MC-VC-PABC-MMAE(0.049mmol)和100μL的在3mLDMF中的三乙胺组合。获得的反应混合物在室温搅拌15分钟,根据HPLC分析通过这段时间完成了反应。该化合物通过制备型HPLC纯化,获得45mg(62%)为灰白色固体的期望产物。反相HPLC分析表明化合物的纯度为>96%。ESI计算值对于C73H116N14O18S(MH)+为1509.8501;实测值m/z 1509.8469。
为生成氨氧基衍生的Dol10(氨氧基-Cys-MC-VC-PABC-PEG8-Dol10),7.4mg(0.024mmol,3当量)的氨氧基-cystamide、12mg(0.008mmol)的MC-VC-PABC-PEG8-Dol10和30μL三乙胺在3mL的DMF中组合。根据HPLC分析该反应在15分钟内完成。制备型HPLC纯化获得了6.2mg(46%)为灰白色固体的预期产物。反相HPLC分析表明化合物的纯度为>96%。ESI计算值对于C80H124N16O19S2(MH)+为1678.0664,实测值m/z 1678.0613。
实施例13.唾液酸-介导(SAM)的具有反应性的效应部分的偶联
脱盐后,将实施例11的药物接头与实施例10的氧化、唾液酸化的抗体用75%DMSO(0.167v/v)以25mM的浓度组合以获得24:1的药物接头比抗体摩尔比率和5mg/ml的抗体终浓度。该混合物在室温温育过夜。未并入的药物接头和任何游离的药物使用BioBeads清除。产物使用PD-10柱缓冲交换入组氨酸-吐温缓冲液并过滤除菌。测定内毒素水平且对于体内研究获得了少于0.1EU/mg的ADC。
图29A-C显示与AO-MMAE糖偶联的不同唾液酸化的抗体(抗FAP B11和G11和实施例11的抗HER2抗体)的疏水相互作用色谱(HIC)。唾液酸化的HER2抗体也与药物接头AO-Cys-MC-VC-PABC-PEG8-Dol10偶联(图29D)。该分析揭示了每抗体主要存在一个或两个药物偶联物,具有范围在1.3-1.9的药物比抗体比率(DAR)。与MMAE糖偶联物(图29C)相比Dol10糖偶联物(图29D)增加的保留时间可能是由于Dol10更强的疏水性所致。
还用与两种不同药物接头(AO-MMAE或AO-PEG8-Dol10)偶联的抗HER抗体以30mg的规模实施了LC-MS分析。该分析显示1.7和1.5(偶联后)的相似DAR值,其与HIC分析具有可比性。尺寸排阻色谱(SEC)显示在这些偶联物中非常低的聚集物水平(1%)。
实施例14.半乳糖-介导(GAM)的具有反应性的效应部分的偶联
如实施例11所述用半乳糖氧化酶在A114N抗TEM1高度糖基化突变体抗体上生成的半乳糖醛基与24摩尔过量的抗体上的氨氧基-MC-VC-PABC-MMAE药物接头通过25℃过夜温育偶联,获得具有1.72DAR的ADC偶联物。
向如实施例11所述制备的半乳糖氧化酶-处理的抗HER抗体添加十分之一反应体积的pH5.6的1M醋酸钠以调整pH至5.6,并添加DMSO以生成14%的终浓度,之后添加24当量(eq.)氨氧基MC-VC-PABC-MMAE药物接头。反应在室温温育过夜。游离的药物和药物接头用Biobead清除且产物由SEC缓冲交换(65%收率)。产物偶联物通过HPLC分析。如图30所示,AO-MMAE已与~60%的分子偶联。
实施例15.体外ADC细胞增殖试验
本发明抗HER和抗FAP糖偶联物分子的体外活性也与相应的包含相同药物部分经由巯基连接基与相同供体抗体的铰链区半胱氨酸连接的巯基偶联物进行了比较。相比糖偶联物,所述巯基偶联物包含大致两倍数目的药物每抗体(DAR)。基于巯基的偶联如Stefanoet al(Methods in Molecular Biology 2013,出版中)所述实施。随后采用Her2+SK-BR-3和Her2-MDA-MB-231细胞系评估每种ADC的相对效力。该分析的结果示于下列表15中。
表15.糖偶联物和巯基偶联物EC50的比较
注意:*DAR由LC-MS测定;**DAR由HIC测定
图31显示抗HER糖偶联物和其对应的巯基偶联物体外效力的比较。细胞生存力在将偶联物暴露于Her2抗原表达(SK-BR-3)细胞(图30A和C)或非表达(MDA-MB-231)细胞(图31B和D)72hr后测定。ADC包含与聚糖(“糖”)或通过常规化学与铰链区的半胱氨酸(“巯基”)连接的MMAE或PEG8-Dol10。如图31A和C所示,与糖偶联物相比,对于巯基偶联物观察到~2倍更低的EC50,这与前者与后者相比2倍更高的DAR一致。Her2细胞系与任何多至100ug/ml的抗体未观察到毒性。
对于用针对肿瘤抗原(FAP)(其在包括结肠、胰腺和乳腺癌的上皮癌中通过具有反应性的间质成纤维细胞高度表达)的抗体制备的ADC,在细胞增殖中观察到相似的趋势(Teicher,B.A.(2009)antibody-drug conjugate targets.Curr Cancer Drug Targets9,982-1004)。这些偶联物再次通过将氨氧基MMAE药物接头或马来酰亚胺MMAE药物接头与聚糖或巯基基团偶联制备。这些偶联物的细胞增殖试验显示巯基偶联物的EC50对于用人FAP转染的CHO细胞与缺乏FAP表达的相同细胞相比具有~100倍更高的效力,如图32所示,其表明抗FAP B11糖偶联物与巯基偶联物体外效力的比较。将偶联物暴露于用或不用FAP抗原转染的CHO细胞后对细胞生存力进行了测定。ADC包含与聚糖(“糖”)或通过常规化学与铰链区的半胱氨酸(“巯基”)连接的MMAE。注意假定对于靶结合和抗原表达CHO细胞中内化的效力相似,与糖偶联物相比对于巯基~2倍更低的EC50与每抗体递送药物的相对量一致。平行测定了如之前所述的具有1.5DAR的抗FAP(B11)ADC糖偶联物且显示相比对应的巯基偶联物~2倍更高的EC50(DAR 3.3)。
如图36所示,对于如实施例14所述用带有A114N高度糖基化突变的抗HER抗体和AO-MMAE制备的ADC,当在SK-BR-3表达细胞或MDA-MB-231上试验时,在细胞增殖试验中观察到了相似的趋势。A114N糖偶联物清楚表明了针对Her2表达细胞系相比非表达细胞系增强的细胞毒性。与用相同抗体制备的SialT糖偶联物相比的相对毒性与该制剂较低的药物载荷一致。
如实施例14所述,对于用带有A114N高度糖基化突变的抗TEM1抗体和制备的AO-MMAE制备的ADC,也实施了细胞增殖试验。与非表达MDA-MB-231细胞系相比用TEM1-表达细胞系SJSA-1和A673观察到了较高的毒性。与用相同抗体的常规巯基偶联物相比,毒性水平与该制剂的药物载荷(DAR)保持一致。
总之,通过聚糖与裂解接头的位点特异性偶联产生的ADC具有与常规基于巯基的偶联物等同的毒性和体外效力,如使用不同抗体和不同药物接头所证明。此外2mM以下的高碘酸盐,药物偶联水平与唾液酸的还原相关。增加高碘酸盐至2mM以上产生小到几乎没有的益处,如根据唾液酸变成氧化形式的完全转换所预期的。然而,在所有条件下,药物每抗体的数目相比唾液酸含量稍低,表明氧化的唾液酸中的一些可能相似地不可用于偶联,这是由于其被埋藏或是另外由于因药物接头的大体积所引起的空间位阻所致。
实施例16.抗体药物偶联物的体内表征
抗HER糖偶联物的效力还在Her2+肿瘤细胞异种移植模型中进行了评估并与具有约2倍更高DAR的巯基偶联对应物进行了比较。为Beige/SCID小鼠植入SK-OV-3 Her2+肿瘤细胞,使其能够在治疗开始前建立~150mm3的肿瘤。3或10mg/kg剂量的ADC在第38、45、52和59天通过尾部静脉注射。~10只小鼠每组。测量了不同组中小鼠的肿瘤体积并记录了其生存率。基于Kaplan-Meier方法绘制了生存曲线。
图33显示抗HER糖偶联物和巯基偶联物在Her2+肿瘤细胞异种移植模型中体内效力的比较。植入SK-OV-3 Her2+肿瘤细胞的Beige/SCID小鼠用包含糖偶联物或~2倍更高DAR的巯基偶联物对应物的MMAE(图33A和B)和PEG8-Dol10(图33C和D)给药。MMAE偶联物的肿瘤生长动力学示于图33A。该情况中,糖偶联物显示相比裸抗体本身(黑色)显著更高但相比具有~2倍更高DAR的巯基偶联物对应物(绿色)低的效力。MMAE糖偶联物显示显著的肿瘤消退和肿瘤生长~20天的延迟(图33A)和从第一次给药起在生存时间上的~2倍增加(图33B)。巯基MMAE偶联物在相同的ADC剂量(10mg/kg)显示出近乎完全的肿瘤抑制。
PEG8-Dol10糖偶联物(“糖Dol10’)和具有~2倍更高DAR的巯基偶联对应物(“巯基Dol10”)的体内效力在相同的Her2+肿瘤细胞异种移植模型中进行了测定。两种偶联物都显示了相比如前文所述的MMAE偶联物低的效力。然而,10mg/kg的氨氧基-PEG8-Dol10糖偶联物(“糖Dol10”)显示肿瘤生长中15-天的延迟(图33C)和第一次施用后生存时间的~20天(1.7-倍)的增加(图33D)。巯基偶联物在相同剂量更加有效,展示生存率的2-倍增加。在较低的剂量(3mg/kg),巯基偶联物展示相比10mg/kg糖偶联物低的效力。相比对于糖偶联物110umol PEG8-Dol10药物每kg剂量,该剂量与80umol PEG8-Dol10药物每kg剂量对应。
这些数据证明药物向抗体聚糖的唾液酸上的位点特异性偶联获得具有与经由基于巯基化学生成的ADC相比可比较的效力的分子。在某种程度上较低的体内效力可能源于由每个抗体携载通过每个抗体结合抗原内化入肿瘤细胞中的药物数量较少。尽管我们尚未比较这些糖偶联物与具有相同DAR的巯基偶联物,但是在代表施用药物可比较水平的两种ADC的不同剂量观察到的效力显示糖偶联物具有与其巯基对应物相比可比较的固有效力,表明在该位点的偶联无有害影响。此外,仅引入28%更多药物的Dol10糖偶联物的10mg/kg剂量在生存率上提供超过巯基偶联物(以3mg/kg)的2-倍增加,表明这些偶联物在相同的DAR甚至提供具有优势的效力。鉴于唾液酸在天然聚糖上并入的明显限制,较高的药物载荷可通过多种不同策略实现,包括支链药物接头的使用或额外糖基化位点的引入和使用相同方法。
序列表
<110> 建新公司
<120> 通过糖工程的位点特异性抗体-药物偶联
<130> 554313 SA9-105PC
<140> PCT/US2014/022728
<141> 2014-03-10
<150> 61/776,724
<151> 2013-03-11
<150> 61/776,710
<151> 2013-03-11
<150> 61/776,715
<151> 2013-03-11
<160> 40
<170> PatentIn version 3.5
<210> 1
<211> 218
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 1
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Asn Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Val Gln Gly
85 90 95
Thr His Leu His Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 2
<211> 443
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 2
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
1 5 10 15
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr Trp
20 25 30
Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly
35 40 45
Gln Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu Ser
50 55 60
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser Leu
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Thr Pro Val Asp Phe Trp Gly Gln Gly Thr Thr Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
115 120 125
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
180 185 190
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
340 345 350
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 3
<211> 444
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明: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 Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Gln Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Pro Val Asp Phe Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Asn Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 4
<211> 444
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明: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 Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Gln Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Pro Val Asp Phe Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Ser Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 5
<211> 444
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 5
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
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Gln Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Pro Val Asp Phe Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Asn Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 6
<211> 444
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 6
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
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Gln Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Pro Val Asp Phe Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Asn Leu Ser Pro Gly Lys
435 440
<210> 7
<211> 447
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 7
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
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Gln Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Pro Val Asp Phe Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Asn Gly Thr
435 440 445
<210> 8
<211> 444
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 8
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
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Gln Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Pro Val Asp Phe Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Asn Thr Ser Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 9
<211> 215
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 9
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 10
<211> 454
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 10
Gln Val Gln Leu Gln Glu Ser Ala Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Arg Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Tyr Ile
35 40 45
Gly Tyr Ile Tyr Tyr Thr Gly Ser Ala Ile Tyr Asn Pro Ser Leu Gln
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Glu Gly Val Arg Gly Ala Ser Gly Tyr Tyr Tyr Tyr Gly Met Asp
100 105 110
Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
355 360 365
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Lys
450
<210> 11
<211> 454
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 11
Gln Val Gln Leu Gln Glu Ser Ala Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Arg Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Tyr Ile
35 40 45
Gly Tyr Ile Tyr Tyr Thr Gly Ser Ala Ile Tyr Asn Pro Ser Leu Gln
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Glu Gly Val Arg Gly Ala Ser Gly Tyr Tyr Tyr Tyr Gly Met Asp
100 105 110
Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Asn Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
355 360 365
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Lys
450
<210> 12
<211> 214
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 12
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg 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 His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 13
<211> 450
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 13
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 14
<211> 450
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 14
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Asn Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 15
<211> 450
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 15
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Asn Ala Ser Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 16
<211> 450
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 16
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Asn Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Asn Ala Ser Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 17
<211> 4
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 17
Gly Gly Gly Gly
1
<210> 18
<211> 5
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽
peptide"
<400> 18
Gly Gly Gly Gly Gly
1 5
<210> 19
<211> 6
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 19
Gly Gly Gly Gly Gly Gly
1 5
<210> 20
<211> 7
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽
peptide"
<400> 20
Gly Gly Gly Gly Gly Gly Gly
1 5
<210> 21
<211> 8
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 21
Gly Gly Gly Gly Gly Gly Gly Gly
1 5
<210> 22
<211> 5
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 22
Gly Gly Gly Gly Ser
1 5
<210> 23
<211> 213
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 23
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 Ser Ala Thr Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Arg Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 24
<211> 450
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 24
Glu Val Gln Leu Leu Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Lys Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Phe Thr Leu 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 Gly Ser Tyr Tyr Asp Tyr Asp Gly Phe Val Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 25
<211> 450
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 25
Glu Val Gln Leu Leu Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Lys Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Phe Thr Leu 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 Gly Ser Tyr Tyr Asp Tyr Asp Gly Phe Val Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Asn Thr Ser Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 26
<211> 450
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 26
Glu Val Gln Leu Leu Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Lys Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Phe Thr Leu 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 Gly Ser Tyr Tyr Asp Tyr Asp Gly Phe Val Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Asn Ala Ser Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 27
<211> 450
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 27
Glu Val Gln Leu Leu Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Lys Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Val Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Phe Thr Leu 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 Gly Ser Tyr Tyr Asp Tyr Asp Gly Phe Val Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gln Asn Thr Ser Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 28
<211> 218
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 28
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Asn Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Val Gln Gly
85 90 95
Thr His Leu His Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 29
<211> 444
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 29
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
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Gln Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Pro Val Asp Phe Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 30
<211> 444
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 30
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
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Gln Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Pro Val Asp Phe Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Asn Thr Ser Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 31
<211> 218
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 31
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Asn Gly Lys Thr Tyr Leu Asn Trp Val Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Val Gln Gly
85 90 95
Ser His Phe His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 32
<211> 444
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 32
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 Pro Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Gln Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Pro Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 33
<211> 444
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 33
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 Pro Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Gln Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Pro Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Asn Thr Ser Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 34
<211> 444
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 34
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 Pro Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Gln Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Pro Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Asn Ala Ser Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 35
<211> 444
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 35
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 Pro Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Gln Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Pro Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Gln Asn Thr Ser Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 36
<211> 214
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 36
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg 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 His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 37
<211> 450
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 37
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 38
<211> 450
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 38
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Asn Ala Ser Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 39
<211> 10
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽"
<400> 39
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 40
<211> 4
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的说明:合成多肽 4xHis标签"
<400> 40
His His His His
1
1
Claims (35)
1.一种结合多肽,其包含至少一种修饰聚糖,所述聚糖含有至少一个式(IV)的部分:
-Gal-Sia-C(H)=N-Q-CON-X
式(IV),
其中:
A)Q是NH或O;
B)CON是连接体部分;且
C)X是效应部分;
D)Gal是源自半乳糖的组件;
E)Sia是源自唾液酸的组件;且
其中Sia存在或不存在。
2.权利要求1的结合多肽,其中所述修饰聚糖是双触角聚糖。
3.权利要求1或2的结合多肽,其中所述双触角聚糖是岩藻糖化或非岩藻糖化的。
4.上述权利要求任一项的结合多肽,所述修饰聚糖包含至少两个式(IV)的部分,其中Sia仅在所述两个部分中的一个部分中存在。
5.权利要求1-3任一项的结合多肽,所述修饰聚糖包含至少两个式(IV)的部分,其中Sia在两个部分中都存在。
6.上述权利要求任一项的结合多肽,其中所述修饰聚糖N-连接至所述结合多肽。
7.上述权利要求任一项的结合多肽,其中所述结合多肽包含Fc结构域。
8.权利要求7的结合多肽,其中所述修饰聚糖经由根据EU编号在Fc结构域的氨基酸位置297处的天冬酰胺残基N-连接至所述结合多肽。
9.权利要求8的结合多肽,其中所述修饰聚糖经由根据EU编号在Fc结构域的氨基酸位置298处的天冬酰胺残基N-连接至所述结合多肽。
10.上述权利要求任一项的结合多肽,其中所述Fc结构域是人的。
11.上述权利要求任一项的结合多肽,其中所述结合多肽包含CH1结构域。
12.权利要求11的结合多肽,其中所述修饰聚糖经由根据Kabat编号在CH1结构域的氨基酸位置114处的天冬酰胺残基N-连接至所述结合多肽。
13.上述权利要求任一项的结合多肽,其中所述效应部分是细胞毒素。
14.权利要求13的结合多肽,其中所述细胞毒素选自表1列举的细胞毒素的集合。
15.权利要求1-13任一项的结合多肽,其中所述效应部分是检测剂。
16.权利要求1-13任一项的结合多肽,其中所述效应部分是靶向部分。
17.权利要求16的结合多肽,其中所述靶向部分是糖或糖肽。
18.权利要求16的结合多肽,其中所述靶向部分是聚糖。
19.上述权利要求任一项的结合多肽,其中所述连接体部分包含pH-敏感接头、二硫化物接头、酶敏感接头或其他可裂解的接头部分。
20.上述权利要求任一项的结合多肽,其中所述连接体部分包含选自表2或14描述的接头部分的集合的接头部分。
21.上述权利要求任一项的结合多肽,其为抗体或免疫粘附素。
22.一种组合物,其包含上述权利要求任一项的结合多肽和可药用的载剂或赋形剂。
23.权利要求22的组合物,其中所述治疗或诊断效应部分与结合多肽的比率小于4。
24.权利要求23的组合物,其中所述治疗或诊断效应部分与结合多肽的比率约为约2。
25.一种治疗患者的方法,其中包括施用有效的量的权利要求24的组合物。
26.一种分离的多核苷酸,其编码权利要求1-21任一项的结合多肽。
27.一种包含权利要求26的多核苷酸的载体。
28.一种包含权利要求26的多核苷酸或权利要求27的载体的宿主细胞。
29.一种制备上述权利要求任一项的结合多肽的方法,所述方法包括使式(I)的效应部分与改变的包含氧化聚糖的结合多肽发生反应,所述式(I)为:
NH2-Q-CON-X
式(I),
其中:
A)Q是NH或O;
B)CON是连接体部分;且
C)X是效应部分。
30.权利要求29的方法,其中所述改变的包含氧化聚糖的结合多肽通过使包含聚糖的结合多肽与温和氧化剂发生反应生成。
31.权利要求30的方法,其中所述温和氧化剂是高碘酸钠。
32.权利要求31的方法,其中采用少于1mM的高碘酸钠。
33.权利要求30的方法,其中所述氧化剂是半乳糖氧化酶。
34.权利要求29-33任一项的方法,其中所述包含聚糖的结合多肽含有一个或两个末端唾液酸残基。
35.权利要求34的方法,其中所述末端唾液酸残基通过用唾液酸转移酶或唾液酸转移酶和半乳糖基转移酶的组合处理所述结合多肽引入。
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