CN110357958A - 抗糖皮质激素诱导的肿瘤坏死因子受体(gitr)的小型化抗体、其聚合物及应用 - Google Patents
抗糖皮质激素诱导的肿瘤坏死因子受体(gitr)的小型化抗体、其聚合物及应用 Download PDFInfo
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- CN110357958A CN110357958A CN201810255332.2A CN201810255332A CN110357958A CN 110357958 A CN110357958 A CN 110357958A CN 201810255332 A CN201810255332 A CN 201810255332A CN 110357958 A CN110357958 A CN 110357958A
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Abstract
本发明提供特异性结合糖皮质激素诱导的肿瘤坏死因子受体(GITR)的抗体、抗体片段及其聚合物,以及含有该抗体或抗体片段的缀合物和融合物。本发明还提供编码这些抗体、抗体片段、聚合物、缀合物和融合物的核酸;载体和表达该核酸的宿主细胞。此外,本发明还提供一种包含这些抗体及其抗体片段、聚合物、缀合物或融合物的组合物,及其在治疗和诊断中的用途。
Description
技术领域
本发明涉及抗体领域。本发明尤其涉及特异性结合糖皮质激素诱导的肿瘤坏死因子受体(GITR)的抗体(包括小型化抗体)、抗体片段及其聚合物,以及含有该抗体或抗体片段的缀合物和融合物。本发明还涉及编码这些抗体、抗体片段、聚合物、缀合物和融合物的核酸;载体和表达该核酸的宿主细胞。此外,本发明也涉及包含这些抗体及其抗体片段、聚合物、免疫缀合物或融合物的产品,及在治疗和诊断中的应用。
背景技术
糖皮质激素诱导的肿瘤坏死因子受体(glucocorticoid induced tumornecrosis factor receptor,GITR,亦称作TNFRSF18、活化诱导型肿瘤坏死因子受体(TNFR)家族成员(AITR)、CD357及GITR-D),是肿瘤坏死因子受体(tumor necrosis factorreceptor,TNFR)超家族的第18个成员。GITR由其同源配体,GITR配体(GITRL)活化,可结合NFkB二聚体,激活下游的NFkB信号通路。
GITR在应答静息T细胞中低水平表达;当T细胞活化后,其表达水平显著上调。GITR在调节性T细胞(Treg,如CD4+CD25+或CD8+CD25+细胞)中高水平组成型表达,并且当这些细胞被活化时,表达水平进一步上调(Nocentini和Riccardi(2005)E.J.Immunol.35:1016-1022)。GITR表达不限于T细胞,已报道,GITR在NK细胞、巨噬细胞、B细胞、树突状细胞、肥大细胞及单核细胞上也表达(Nocentini和Riccardi(2005)E.J.Immunol.35:1016-1022)。
GITR配体(GITRL)主要在抗原递呈细胞(APC,包括巨噬细胞、B细胞、树突状细胞及内皮细胞)上表达。APC上的GITRL与应答T细胞上GITR的结合触发GITR信号传导,共刺激应答T细胞并抑制Treg细胞的抑制活性。由此,GITR对效应T细胞和调节性T细胞具有若干作用,包括:共刺激和活化效应T细胞,使T细胞对抑制更具抗性、抑制调节性T细胞、降低效应T细胞对由调节性T细胞引起的抑制的敏感性等(Nocentini等(2007)Eur.J.Immunol.37:1165-1169)。
这些作用意味着GITR活化可以导致免疫应答的增强,增加对肿瘤和病毒感染等的抗性。因此,能够活化GITR的物质可以增强需要的免疫反应(例如,抗肿瘤、治疗病毒感染),诱导或增强个体中的免疫应答,治疗免疫障碍和增生性障碍(例如肿瘤和癌症)等。
目前,现有技术中能够活化GITR的物质主要是标准结构的抗GITR抗体(参见CN103951753A、CN105829343A、CN106459203A、WO2016196792A1、WO2017068186A9等)。这样的抗体是GITR的激动剂(即,是激活型抗体),可诱导或增强GITR信号传导,在治疗需要增强免疫应答的多种GITR相关疾病或病症中是有效的。由于这样的抗GITR抗体是激活型抗体,故相对于其与抗原的结合亲和力,其激活活性的高低是其发挥活性(例如。免疫增强活性)更为关键的指标。
但是,上述标准结构的抗GITR抗体具有标准结构抗体的一些固有缺陷:生产成本高、制备周期长、制备工序复杂、体积大(组织渗透性差)、稳定性差、不同批次之间差异较大等,大大限制了其应用范围。
同时,包括单链抗体(single-chain variable fragment,scFv)、单域抗体(single-domain antibody,sdAd)、重链抗体(heavy-chain antibody,hcAb)、纳米抗体(nanobody,Nb或variable domain of heavy chain of heavy-chain antibody,VHH)、小型的类抗体支架蛋白(如Affibody、DARPins等)等小型化抗体由于克服了标准结构抗体的一些固有缺陷,其研发已引起生物技术应用领域的广泛关注,近年得以快速发展。
这类小型化抗体中的单域抗体和重链抗体没有轻链,具有的单一重链可变区保留了完整的抗原结合活性,具有分子小、稳定性高、体内组织渗透性好、可溶性好、熔解温度高、易表达等的特性。
例如,这类小型化抗体中的纳米抗体具有如下优点:
1.由于具有独特的结构,由此具有有益的抗原结合特性:纳米抗体较长的CDR3(互补决定区3),可形成稳定暴露的凸环结构(凸环中具有稳定结构的二硫键),能够深入抗原内部,从而更好地结合抗原,提高其抗原特异性和亲和力。而传统抗体Fab片段及单链抗体scFv的抗原结合表面常形成凹形拓扑结构,通常只能识别位于抗原表面的位点。因此,纳米抗体具有更有益的抗原结合性能,甚至当抗原蛋白紧密包裹,隐藏了普通抗体无法识别的表位时,纳米抗体也可以识别这样的表位。
2.当单独表达标准结构抗体的VH结构域时,表达出的VH结构域通常形成包涵体,或者暴露的疏水域相互黏附。而纳米抗体由于其FR2区域中的疏水残基被亲水残基所取代,使得纳米抗体的可溶性非常好,聚合性减少,在普通缓冲液中可轻易被浓缩到10mg/mL而不出现积聚。并且由于纳米抗体具有可逆重折叠性质,在高温(80~92℃)和高浓度变性剂作用下仍保持抗原结合活性,即使以包涵体形式表达,也很容易复性,使纳米抗体在层析或无菌处理时的短暂变性中,或在污染或有机溶剂等不良环境中,仍能出色地长期维持生物学活性,大大提高纳米抗体作为药物的利用率。
3.因为分子量小、结构简单,且由单一的基因编码,纳米抗体很容易在微生物中合成,能在价格低廉的噬菌体、酵母等微生物中大量表达,进行大规模生产。据报道,可通过酵母反应器将纳米抗体的产量提高至1克/升的产量。
同时,由于纳米抗体仅仅具有一个重链可变区,不存在配对问题,由此其筛选过程更为简便,常常仅仅需要文库即可。
4.纳米抗体由于分子很小,组织渗透性强,可以穿透或转移进入血脑屏障,也可以快速经肾脏滤过(肾脏截留值约60kDa),血液中半寿期约2小时,表位靶向唯一,是优异的治疗载体。
5.与sdAb、scFv等相比,纳米抗体具有如下突出优点:结构更简单,易与受体结合、可以识别嵌入配体沟槽或夹在两个亚基之间的隐藏抗原表位,而且相对分子量更小,免疫原性更低、积聚沉淀趋势更低、生物分散性更好,更易表达(原核或真核系统中高表达)、可溶性更好、稳定性更强,在极端pH、高浓度变性剂或高温等不利理化环境条件下更稳定,保质期长,可以口服或呼吸道给药等;同时不易如单链抗体(scFv)那样容易相互沾粘,甚至聚集成块,故已成为目前研究的热点。
由纳米抗体制成的检测试剂盒甚至可以直接储存在室温下,不用冷藏保存,减少巨大的冷藏费用。
结合上述能够活化GITR的物质的诸多作用和优点,本领域存在制备能够活化GITR的小型化抗体的需要,例如能够活化GITR的纳米抗体的需要,以便更好地诱导或增强个体中的免疫应答,治疗免疫障碍和增生性障碍(例如肿瘤和癌症)。
发明内容
如上所述,标准结构的抗GITR抗体具有如筛选流程复杂、组织渗透性差、生产成本高等不足之处,故开发抗GITR的小型化抗体可以很好地弥补这些不足,具有诸多其他优点,同时还能实现抗GITR抗体的性能。
然而,并不是简单地将已知标准结构抗体的重链可变区分离,就可以获得相应的VHH。因为如上所述,VHH中CDR1-3的氨基酸序列和长度,特别是CDR3的氨基酸选择和长度与标准结构抗体中对应的HCDR1-3(例如HCDR3不同,结构也不同,需要进行精心的设计和大量的筛选工作才能获得。
本发明的目的是提供一种分离的特异性结合糖皮质激素诱导的肿瘤坏死因子受体(GITR)的抗体或其抗原结合片段(简称“本发明的抗体或其抗原结合片段”),其具有以下一种或多种特性:
(i)以高亲和力与人GITR(如SEQ ID NO:123或127的多肽)结合;
(ii)以低解离常数与人GITR(如SEQ ID NO:123或127的多肽)结合;
(iii)与细胞表面的抗原高亲和力结合;
(iv)高效激活GITR下游的NFkB信号通路;
(v)与GITRL交叉竞争结合至GITR;
(vi)可以内化到人CD4细胞中
(vii)抑制调节性T细胞的抑制作用;
(viii)活化效应T细胞;
(ix)减少循环调节性T细胞;
(x)能够结合Fcγ受体(FcγR);和
(xi)在人血清中具有至少6、7、9或12天的半衰期。
本发明的另一目的是提供一种纳米抗体(简称“本发明的纳米抗体”),其中的HCDR3(重链互补决定区3)包含本发明的抗体或其抗原结合片段的HCDR3。
在一些实施方案中,本发明的纳米抗体的HCDR1(重链互补决定区1)和HCDR2(重链互补决定区2)分别包含本发明的抗体或其抗原结合片段的HCDR1和HCDR2。
在一些实施方案中,本发明的纳米抗体的HCDR1、HCDR2和HCDR3分别包含本发明的抗体或其抗原结合片段的HCDR1、HCDR2和HCDR3。
在一些实施方案中,本发明的纳米抗体仅包含如SEQ ID NO:64-85中任一序列所示的重链可变区序列或其变体,或本发明的纳米抗体仅由SEQ ID NO:64-85中任一序列所示的重链可变区序列或其变体组成。
本发明的另一目的是提供一种重链抗体(简称“本发明的重链抗体”),包含本发明的纳米抗体和IgG抗体的Fc片段。
本发明的另一目的是提供一种人源化重链抗体(简称“本发明的人源化重链抗体”),其改造自本发明的重链抗体。
在一些实施方案中,本发明的人源化重链抗体是全人源重链抗体。
本发明的另一目的是提供一种多聚物形式的抗体(简称“本发明的多聚物形式的抗体”),是本发明的纳米抗体、本发明的重链抗体的重链可变区或本发明的人源化重链抗体的重链可变区的多聚物形式。
在一些实施方案中,本发明的多聚物形式的抗体是本发明的纳米抗体、本发明的重链抗体的重链可变区或本发明的人源化重链抗体的重链可变区的四聚化形式或六聚化形式,优选是本发明的纳米抗体、本发明的重链抗体的重链可变区或本发明的人源化重链抗体的重链可变区的四聚化形式。
在一些实施方案中,本发明的多聚物形式的抗体由本发明的纳米抗体、本发明的重链抗体的重链可变区或本发明的人源化重链抗体的重链可变区连接到本发明的重链抗体(优选连接到本发明的人源化重链抗体)形成的新的结构聚合而成。
在一些实施方案中,本发明的多聚物形式的抗体由本发明的纳米抗体、本发明的重链抗体的重链可变区或本发明的人源化重链抗体的重链可变区连接到本发明的重链抗体的C末端形成的新的结构聚合而成;或者由本发明的纳米抗体、本发明的重链抗体的重链可变区或本发明的人源化重链抗体的重链可变区连接到本发明的重链抗体(优选连接到本发明的人源化重链抗体)的N末端形成的新的结构聚合而成。
在一些实施方案中,本发明的多聚物形式的抗体中,本发明纳米抗体、本发明的重链抗体的重链可变区或本发明的人源化重链抗体的重链可变区通过连接肽连接到本发明的重链抗体(优选连接到本发明的人源化重链抗体)。
本发明的另一目的是提供一种包含本发明的抗体的融合蛋白、免疫缀合物、组合物或试剂盒。
本发明的另一目的是提供一种编码本发明的抗体的分离的核酸;包含该核酸的载体;包含该载体的宿主细胞;包含这些核酸、载体或宿主细胞中的一个或多个的药物组合物。
本发明的另一目的是提供一种制备本发明的抗体或其抗原结合片段、本发明的融合蛋白、本发明的免疫缀合物或组合物(包括药物组合物)的方法。
本发明的另一目的是提供一种检测样品中GITR的存在的方法,包括使用本发明的抗体或其抗原结合片段。
本发明的另一目的是提供一种治疗癌症、诱导或增强个体中的免疫应答,和/或刺激抗原特异性T细胞应答的方法,其特征在于包括向所需个体施用有效量的本发明的抗体或其抗原结合片段、本发明的融合蛋白或本发明的免疫缀合物。
与现有技术中已有的标准结构抗GITR抗体相比,本发明的抗体不但具有筛选流程简便、组织渗透性好、生产成本低等优点;且相对于直接获自标准结构抗GITR抗体的单链抗体、单域抗体、重链抗体等,不再具有容易形成包涵体或者容易相互黏附的缺点。进一步,本发明的发明人令人惊讶地发现,本发明的抗体对GITR是高度特异性的,且不会干扰其他受体的活性,能够以相对低剂量刺激GITR信号传递;同时,本发明的抗体能够高效激活GITR下游的NFkB信号通路,产生有益的抗免疫疾病/障碍和抗增生性疾病/障碍的效果。
在下面的附图和具体实施方案中进一步说明本发明。然而,这些附图和具体实施方案不应被认为限制本发明的范围,并且本领域技术人员容易想到的改变将包括在本发明的精神和所附权利要求的保护范围内。
附图说明
图1.纳米抗体噬菌体文库构建流程示意图。
图2.SEC检测纯化后的hcIgG的纯度结果图。
图3.hcIgG和细胞表面GITR蛋白的结合情况检测结果图。
图4.hcIgG引起的ADCC作用图。
图5.HzhcIgG和细胞表面GITR蛋白的结合情况检测结果图。
图6.人源化后的hcIgG对GITR下游的NFkB信号通路的激活作用图。
图7.4xNb-IgG的结构示意图。
图8.SEC检测纯化后的4xNb-IgG的纯度结果图。
图9.4xNb-IgG对GITR下游的NFkB信号通路的激活作用图。
图10.抗GITR抗体(4xNb-IgG)本身,或与抗PD-1抗体联合使用在MC38移植瘤模型中对肿瘤的抑制作用图。
具体实施方式
以下结合实施例对本发明进行详细描述。所用的所有实验试剂和仪器设备,如无特别说明均为普通市售试剂和设备。
1.定义
除非本文中另外定义,否则本文中所用的所有术语均具有本领域普通技术人员通常理解的含义。此外,除非上下文另外要求,否则单数术语将包括复数术语且复数术语将包括单数术语。为了更好地解释和理解本发明,下面具体定义一些本文中使用的术语。
如本文所用,术语“约”在与数字数值联合使用时,意为涵盖比指定数字数值小5%的下限和比指定数字数值大5%的上限的范围内的数字数值。
如本文所用,术语“和/或”意指可选项中的任一项或可选项的两项。
如本文所用,术语“包含”或“包括”意指包括所述的要素、整数或步骤,但是不排除任意其他要素、整数或步骤。在本文中,当使用术语“包含”或“包括”时,除非另有指明,否则也涵盖由所述及的要素、整数或步骤组合的情形。例如,当提及“包含”某个具体序列的抗体可变区时,也旨在涵盖由该具体序列组成的抗体可变区。
如本文所用,术语“GITR”是指“糖皮质激素诱导的TNF相关基因和/或多肽”,在本领域中也称为TNF受体超家族18(TNFRSF18)。人和鼠形式的GITR的氨基酸和核酸序列描述于WO98/06842中,其以引用的方式并入本文。也参见GenBank登记号Q9Y5U5(人氨基酸序列)和AF109216(鼠核酸和氨基酸序列)。一个特定成熟人GITR多肽的的氨基酸序列陈述于SEQID NO:123中。如本文所用的术语GITR也包括其天然存在的等位基因或变体。
如本文所用,术语“抗原结合分子”、“抗原结合蛋白”与“抗体”在本文中可以互换使用,均指包含能够与靶抗原结合的抗原结合区或抗原结合部分的分子,例如蛋白质或多肽。在本发明中,当靶抗原是糖皮质激素诱导的肿瘤坏死因子受体(GITR)时,结合GITR的抗原结合分子也称作GITR结合分子、GITR抗体或抗GITR抗体。抗原结合分子包括例如抗体及其抗原结合片段、单链抗体(scFv)、单域抗体(sdAd)、重链抗体(hcAb)、纳米抗体(Nb或VHH);或这些抗体的多聚物形式、基于这些抗体的各种融合物和缀合物、免疫缀合物、抗体药物偶联物(ADC)、多/双特异性抗体、嵌合抗原受体(CAR)等。如本领域技术人员所知,抗体的抗原结合部分通常包含来自“互补决定区”或“CDR”的氨基酸残基。因此,在本发明中术语“GITR结合分子”与“本发明的抗体”、“GITR抗体”或“抗GITR抗体”中的任一个可以互换使用。
如本文所用,术语“抗体”是指至少包含轻链或重链免疫球蛋白可变区的多肽(免疫球蛋白),其特异性识别并结合抗原。该术语涵盖各种抗体结构,包括但不限于单克隆抗体;多特异性抗体;Fab片段、Fab’片段、F(ab’)2片段或Fv片段;双抗体、单链抗体(scFv)、单域抗体(sdAd)、重链抗体(hcAb)、纳米抗体(Nb或VHH)或这些抗体的多聚物形式;人抗体、人源化抗体或嵌合抗体;或经标记的抗体,只要它们呈现期望的抗原结合活性即可。
如本文所用,术语“全抗体”、“全长抗体”、“完全抗体”和“完整抗体”在本文中可互换使用,均指具有基本上与天然抗体结构相似的结构,包含至少两条重链(H)和两条轻链(L)。每条重链由重链可变区(本文中缩写为VH)和重链恒定区(本文中缩写为CH)组成。重链恒定区由3个结构域CH1、CH2和CH3组成。每条轻链由轻链可变区(本文中缩写为VL)和轻链恒定区(本文中缩写为CL)组成。轻链恒定区由一个结构域CL组成。恒定区不直接参与抗体与抗原的结合,但是显示出多种效应子功能。
如本文所用,术语“可变区(V区,Fv)”和“可变结构域”在本文中可以互换使用,均指参与抗体与抗原结合的抗体重链或轻链的结构域。天然抗体的重链可变结构域(VH)和轻链可变结构域(VL)通常具有相似的结构,其中每个结构域包含四个保守的框架区(FR)和三个互补决定区(CDR,参见,例如,Kindt等Kuby Immunology,第六版,W.H.Freeman and Co.,91页(2007))。单个VH或VL结构域可足以给予抗原结合特异性。轻链可变区和重链可变区从N-末端到C-末端通常包含结构域FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。
在一个给定的VH或VL氨基酸序列中,各CDR的精确氨基酸序列边界可以使用许多公知的抗体CDR指派系统的任一种或其组合确定,所述指派系统包括例如:基于抗体的三维结构和CDR环的拓扑学的Chothia(Chothia等人.(1989)Nature 342:877-883,Al-Lazikani等人,“Standard conformations for the canonical structures ofimmunoglobulins”,Journal of Molecular Biology,273,927-948(1997))基于抗体序列可变性的Kabat(Kabat等人,Sequences of Proteins of Immunological Interest,第4版,U.S.Department of Health and Human Services,National Institutes of Health(1987)),AbM(University of Bath),Contact(University College London),国际ImMunoGeneTics database(IMGT)(在万维网上imgt.cines.fr/上),以及基于利用大量晶体结构的近邻传播聚类(affinity propagation clustering)的North CDR定义。本发明抗体的CDR可以根据本领域的任何方案或其组合及人为评估确定边界。
抗体的轻链可以基于其恒定结构域的氨基酸序列分为两种类型kappa(κ)和lambda(λ)。抗体的重链可以取决于其重链恒定区的氨基酸序列而分为主要5种不同的类型:IgA、IgD、IgE、IgG和IgM,并且这些类型中的几种可以进一步划分成亚类,如,IgG1、IgG2、IgG3和IgG4、IgA1以及IgA2。对应于不同抗体类型的重链恒定区分别称作α、δ、ε、γ和μ。参见例如Fundamental Immunology,Ch.7(Paul,W.编辑,第二版,Raven Press,N.Y.(1989))(其为所有目的以其整体在此引作参考)。
如本文所用,术语“抗体片段”和“(抗体的)抗原结合片段”在本文中可互换使用,均指并非完整抗体的分子,其包含完整抗体中用于结合该完整抗体所结合的抗原的部分,能结合抗原或与完整抗体(即与抗原结合片段所来源的完整抗体)竞争结合抗原。可以通过重组DNA技术、或通过酶或化学切割完整的抗体,来制备抗原结合片段。抗原结合片段包括但不限于Fab、scFab、Fab’、F(ab’)2、Fab’-SH、可变区抗体片段(Fragment of variable,Fv)、单链Fv、双链抗体(diabody)、三链抗体(triabody)、四链抗体(tetrabody)、微抗体(minibody)、单结构域抗体(单域抗体,sdAb);以及从抗体片段形成的多特异性抗体。Fab片段是一种由VL、VH、CL和CH1结构域组成的单价片段,例如,通过木瓜蛋白酶消化完全抗体能够获得Fab片段。可以借助接头将Fab的轻链(L链)和重链(H链)融合构建成单一多肽链,即单链Fab(scFab)(参见例如US20070274985A1)。此外,通过胃蛋白酶在铰链区的二硫键下面消化完全抗体可以产生F(ab’)2,其为Fab’的二聚体,是二价的抗体片段。F(ab’)2可以在中性条件下通过破坏铰链区中的二硫键而被还原,从F(ab’)2二聚体转化为Fab’单体。Fab’单体基本上是具有铰链区的Fab片段。Fv片段由抗体单臂的VL和VH结构域组成。
如本文所用,术语“双链抗体”是具有两个抗原结合位点的抗体片段,该片段在同一多肽链中包含通过短接头连接的VL和VH。在双链抗体中,由于接头过短,同一链上的VH和VL两个结构域之间无法配对,而被迫与另一链上的互补结构域配对并且产生两个抗原结合位点。双链抗体可以是二价的或双特异性的。双链抗体的更详细描可以参见例如,EP 404,097;WO 1993/01161;Hudson等,Nat.Med.9:129-134(2003);以及Hollinger等,PNAS USA90:6444-6448(1993)。
三链抗体和四链抗体和微抗体也描述于Hudson等,Nat.Med.9:129-134(2003),和邵荣光等(编辑),抗体药物研究与应用,人民卫生出版社(2013)。
如本文所用,术语“单链抗体(single-chain variable fragment,scFv)”又称为“单链可变区抗体片段”,是指其中重链和轻链可变区通过(柔性)接头或(柔性)连接肽连接形成的单多肽链。例如,通过使用重组方法,将独立编码Fv片段的两个结构域VL和VH的基因,通过编码连接肽(接头)的核酸序列连接在一起,重组表达而形成。该单多肽链形成抗原结合区。单链抗体详述于国际专利申请公布号WO88/01649及美国专利号4,946,778和5,260,203中。
术语“(柔性)接头”和术语“(柔性)连接肽”在本文中可以互换使用,是指由氨基酸组成的短肽(肽接头)。通过这样的肽接头可以连接本发明的抗体中的各个可变结构域,例如VH和VL区。肽接头通常富含表现柔性的甘氨酸以及表现溶解性的丝氨酸或苏氨酸。例如可以单独或组合使用甘氨酸和/或丝氨酸残基。柔性连接肽或肽接头的非限定性例子公开于Shen等,Anal.Chem.80(6):1910-1917(2008)、WO2012/138475和WO2014/087010,将其内容全文并入作为参考。如本领域已知的,在scFv的构建中,接头将利于促使VH和VL配对,且不干扰VH和VL对形成功能有效的抗原结合位点。
如本文所用,术语“单域抗体(single-domain antibody,sdAb)”是指仅包含单个可变结构域(例如,重链可变结构域(VH)或轻链可变结构域(VL),就可以结合抗原的抗体,即其不需要与另一可变结构域相互作用即以识别靶抗原。单域抗体可以衍生自骆驼科重链抗体的重链可变结构域、衍生自鱼类IgNAR的VH样单结构域(v-NAR)等。
如本文所用,术语“纳米抗体(nanobody,Nb或variable domain of heavy chainof heavy-chain antibody,VHH)”是指仅由一个重链可变区组成,具有与抗原结合的活性的抗体,即从C端到N端仅包含一条链:FR4-VCDR3-FR3-VCDR2-FR2-VCDR1-FR1的抗体,可由骆驼天然产生或由基因工程技术产生。纳米抗体是目前已知的可结合目标抗原的最小单位。
如本文所用,术语“重链抗体(heavy-chain antibody,hcAb)”是指不具有轻链的抗体,从N段到C段可以包含VH-CH2-CH3,或包含VH-CH1-CH2-CH3;可以构成同型二聚体,例如不具有轻链的重链二聚体抗体。本发明的重链抗体中可以包含来自标准抗体的VH或者来自小型化抗体的VH。例如,本发明的重链抗体中的VH可以就是纳米抗体。
如本文所用,术语“单克隆抗体”表示得自基本上同质的抗体群体的抗体,即,除了通常以很少量存在的可能变体抗体(例如,含有天然突变或在单克隆抗体制品的生产过程中产生的变体抗体)以外,构成所述群体的各个抗体是相同的和/或结合相同表位。单克隆抗体可以通过多种技术来制备,该技术包括、但不限于杂交瘤方法、重组DNA方法、酵母展示方法,和使用包含人免疫球蛋白基因座的全部或部分的转基因动物的方法。
如本文所用,术语“人抗体”或“全人源抗体”在本文中可以互换使用,指包括其中构架区和CDR区二者均源自人种系免疫球蛋白序列的可变区的抗体。而且,如果抗体含有恒定区,恒定区也源自人种系免疫球蛋白序列。本发明的人抗体可包括不由人种系免疫球蛋白序列编码的氨基酸序列(例如,包含通过体外随机或点特异诱变或体内体细胞突变引入的突变),例如在CDR──尤其在CDR3中。然而,术语“人抗体”不意欲包括其中的CDR序列衍生自其他哺乳动物物种(如,小鼠)的种系而移植入人构架序列的抗体。
如本文所用,术语“人源化抗体”是指将源自其他哺乳动物物种例如小鼠种系的CDR序列接到人构架序列上的抗体。可以在人构架序列内进行额外的构架区修饰。
如本文所用,术语“嵌合抗体”是指可变区序列源自一物种、恒定区序列源自另一物种的抗体,例如,其中可变区序列源自小鼠抗体、恒定区序列源自人抗体的抗体。
如本文所用,术语“分离的”抗体是这样的抗体,其已经与其天然环境的组分分离。在一些实施方案中,将抗体纯化至超过95%或99%纯度,如通过例如电泳(例如,SDS-PAGE,等电聚焦(IEF),毛细管电泳)或层析(例如,离子交换或反相HPLC)确定的纯度。对于用于评估抗体纯度的方法的综述参见,例如,Flatman等,J.Chromatogr.B848:79-87(2007)。
如本文所用,术语“表位”是指抗体所结合的抗原区域。表位可以由连续的氨基酸形成或者通过蛋白的三级折叠而由非连续氨基酸形成。
如本文所用,术语“特异性结合”表示抗体选择性地或优先结合抗原。当GITR抗体基本不结合非GITR分子时,认为该抗体“特异性地结合”GITR。然而,特异性结合GITR的抗体可与来自不同物种的GITR多肽交叉反应。如果在生物光干涉测量中,抗体以约5×10-7M或更低、约1×10-7M或更低、约5×10-8M或更低、约1×10-8M或更低、约5×10-9M或更低的KD与人GITR结合,则该抗体是“与人GITR特异性结合”的抗体。
如本文所用,“亲和力”或“结合亲和力”指反映结合的成员之间相互作用的固有结合力。分子X对其配偶物Y的亲和力可以通常由平衡解离常数(KD)代表,平衡解离常数是解离速率常数和结合速率常数(分别是kdis和kon)的比值。亲和力可以由本领域已知的常见方法测量。用于测量亲和力的一个具体方法是本文中的ForteBio动力学结合测定法。
与结合例如GITR抗原的参考抗体“竞争结合的抗体”是指在竞争检验中阻断参考抗体与抗原(例如GITR)结合50%或更多的抗体。示例性竞争检验描述于:“Antibodies”,Harlow and Lane(Cold Spring Harbor Press,Cold Spring Harbor,NY)。竞争结合的抗体可以与参考抗体结合相同的表位区,例如相同表位、相邻表位或重叠表位。
如本文所用,术语“Fc区”用于定义含有至少一部分的恒定区的免疫球蛋白重链的C-末端区域。该术语包括天然序列Fc-区和变体Fc-区。在一个实施方案中,人IgG重链Fc-区从重链的Cys226或从Pro230延伸至羧基端。然而,Fc-区的C-端赖氨酸(Lys447)可以存在或可以不存在。除非本文中另外指出,Fc-区或恒定区中的氨基酸残基的编号根据EU编号系统,也称为EU索引,如Kabat,E.A.等,Sequences of Proteins of ImmunologicalInterest,第5版,Public Health Service,National Institutes of Health,Bethesda,MD(1991),NIH Publication91-3242中所述。
与抗体相关的术语“变体”在本文中是指包含已经通过至少1个,例如1-30,或1-20或1-10个,例如1或2或3或4或5个氨基酸取代、缺失和/或插入而具有氨基酸改变的目标抗体区域(例如重链可变区或轻链可变区或重链CDR区或轻链CDR区)的抗体,其中变体基本上保持改变之前的抗体分子的生物学特性。
在本文中,“序列同一性”是指在比较窗中以逐个核苷酸或逐个氨基酸为基础的序列相同的程度。可以通过以下方式计算“序列同一性百分比”:将两条最佳比对的序列在比较窗中进行比较,确定两条序列中存在相同核酸碱基(例如,A、T、C、G、I)或相同氨基酸残基(例如,Ala、Pro、Ser、Thr、Gly、Val、Leu、Ile、Phe、Tyr、Trp、Lys、Arg、His、Asp、Glu、Asn、Gln、Cys和Met)的位置的数目以得到匹配位置的数目,将匹配位置的数目除以比较窗中的总位置数(即,窗大小),并且将结果乘以100,以产生序列同一性百分比。为了确定序列同一性百分数而进行的最佳比对,可以按本领域已知的多种方式实现,例如,使用可公开获得的计算机软件如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员可以确定用于比对序列的适宜参数,包括为实现正在比较的全长序列范围内或目标序列区域内最大比对所需要的任何算法。
在本发明中,就抗体序列而言,氨基酸序列同一性百分数通过将候选抗体序列与参考抗体序列最佳比对后,在一个优选方案中按照Kabat编号规则进行最佳比对后,予以确定。比对后,将目标抗体区域(例如,重链或轻链的整个可变区、或其部分例如一个或多个CDR区)与参考抗体的相同区域进行比较。目标抗体区域和参考抗体区域之间的序列同一性百分数为:在目标和参考抗体区域两者中被相同氨基酸占据的位置的数目除以两个区域的比对位置总数(空位不计入)并乘以100得到的百分数。在本文中,在不指定目标抗体区域的情况下,将适用于在参考抗体序列的全长上进行比对。在一些实施方案中,就抗体而言,序列同一性可以分布在整个重链可变区和/或整个轻链可变区上,或序列百分数同一性可以仅限定于构架区,而对应CDR区的序列保持100%相同。
在本文中,“保守性取代”是指导致某个氨基酸置换为化学上相似的氨基酸的氨基酸改变。提供功能上相似氨基酸的保守取代表是本领域熟知的。在本发明任一实施方案中,在一个优选的方面,保守取代残基来自以下的保守替代表A,优选地为表A中所示的优选取代残基。
表A
在本文中,术语“个体”或“受试者”可互换使用,是指哺乳动物。哺乳动物包括但不限于驯化动物(例如,奶牛、绵羊、猫、犬和马)、灵长类(例如,人和非人灵长类如猴)、兔和啮齿类(例如,小鼠和大鼠)。特别地,受试者是人。
在本文中,术语“治疗”指意欲改变正在接受治疗的个体中疾病的天然过程的临床介入。想要的治疗效果包括但不限于防止疾病出现或复发、减轻症状、减小疾病的任何直接或间接病理学后果、防止转移、降低病情进展速率、改善或缓和疾病状态,以及缓解或改善预后。
在本文中,术语“癌症”、“肿瘤”、“癌性的”和“恶性的”是指或描述哺乳动物中特征通常为细胞生长不受调节的生理状况。癌症的实例包括但不限于:癌,包括腺癌、淋巴瘤、母细胞瘤、黑素瘤、肉瘤和白血病。此类癌症的更具体实例包括:鳞状细胞癌、小细胞肺癌、非小细胞肺癌、胃肠癌、何杰金氏和非何杰金氏淋巴瘤、胰腺癌、胶质母细胞瘤、神经胶质瘤、宫颈癌、卵巢癌、肝癌诸如肝的癌和肝细胞瘤、膀胱癌、乳癌、结肠癌、结肠直肠癌、子宫内膜癌、骨髓瘤(诸如多发性骨髓瘤)、唾液腺癌、肾癌诸如肾细胞癌和威尔曼瘤、基底细胞癌、黑素瘤、前列腺癌、外阴癌、甲状腺癌、睾丸癌、食管癌、及各种类型的头颈癌。
随着癌性细胞生长和倍增,它们形成癌性组织块,这就是肿瘤,其侵入和破坏正常的邻近组织。恶性肿瘤是癌症。恶性肿瘤经常可以切除,但是它们可能再生。来自恶性肿瘤的细胞可以侵入和破坏附近的组织和器官。另外,癌细胞可以脱离恶性肿瘤,并进入血流或淋巴系统,这是癌细胞从原发肿瘤(即,最初的癌)扩散以在其他器官中形成新肿瘤的途径。癌症在体内的扩散被称作转移(What You Need to Know About Cancer-an Overview,NIH公开号00-1566;2000年9月26日公布,2002年9月16日更新(2002))。
2.详细描述
除非明确指明相反,否则本发明的实施将采用本领域内的常规化学、生物化学、有机化学、分子生物学、微生物学、重组DNA技术、遗传学、免疫学和细胞生物学的方法。这些方法的描述可以参见,例如,Sambrook等,Molecular Cloning:A Laboratory Manual(第3版,2001);Sambrook等,Molecular Cloning:A Laboratory Manual(第2版,1989);Maniatis等,Molecular Cloning:A Laboratory Manual(1982);Ausubel等,Current Protocols inMolecular Biology(John Wiley和Sons,2008年7月更新);Short Protocols inMolecular Biology:A Compendium of Methods from Current Protocols in MolecularBiology,Greene Pub.Associates和Wiley-Interscience;Glover,DNA Cloning:APractical Approach,vol.I&II(IRL Press,Oxford,1985);Anand,Techniques for theAnalysis of Complex Genomes,(Academic Press,New York,1992);Transcription andTranslation(B.Hames&S.Higgins编著,1984);Perbal,A Practical Guide to MolecularCloning(1984);Harlow和Lane,Antibodies,(Cold Spring Harbor Laboratory Press,Cold Spring Harbor,,N.Y.,1998)Current Protocols in Immunology Q.E.Coligan,A.M.Kruisbeek,D.H.Margulies,E.M.Shevach和W.Strober编著,1991);Annual Review ofImmunology;以及期刊专著如Advances in Immunology。
一方面,本发明提供了一种可以高效激活GITR下游的NFkB信号通路的抗体或其抗原结合片段(即,本发明的抗体或其抗原结合片段),其特异性结合糖皮质激素诱导的肿瘤坏死因子受体(GITR)。
在一些实施方案中,本发明的抗体是单克隆抗体或多特异性抗体(包括双抗体);和/或是IgG1、IgG2、IgG3或IgG4型;和/或是抗原结合片段,例如是Fab片段、Fab’片段、F(ab’)2片段或Fv片段;和/或是人抗体、人源化抗体或嵌合抗体;和/或是经标记的抗体。
在一些实施方案中,本发明的抗体是特异性结合GITR的小型化抗体,例如特异性结合GITR的单链抗体(scFv)、单域抗体(sdAd)、重链抗体(hcAb)、纳米抗体(Nb或VHH);或这些抗体的多聚物形式。这些小型化抗体优选包含本发明抗体重链可变区的HCDR3(重链互补决定区3);更优选还包含本发明抗体重链可变区的HCDR1(重链互补决定区1)和HCDR2(重链互补决定区2)。
本发明涵盖在本文中所述及的任何抗体的变体。在一个实施方案中,抗体变体保持改变前抗体的至少60%、70%、80%、90%或100%的生物学活性(例如抗原结合能力)。在一些实施方案中,该改变不导致抗体变体丧失对抗原的结合,但任选地可以赋予诸如提高的抗原亲和力和不同的效应子功能等性质。可以理解的,抗体的重链可变区或轻链可变区,或各CDR区可以单独改变或组合改变。在一些实施方案中,在一个或多个或全部三个重链CDR中的氨基酸改变不超过1个、2个、3个、4个、5个、6个、7个、8个、9个或10个。优选地,所述氨基酸改变为氨基酸取代,优选保守取代。在一些实施方案中,在一个或多个或全部三个重链CDR中的氨基酸改变不超过1个、2个、3个、4个、5个、6个、7个、8个、9个或10个。优选地,所述氨基酸改变为氨基酸取代,优选保守取代。在一些实施方案中,抗体变体与亲本抗体在目的抗体序列区域上具有至少80%、85%、90%或95%或99%或更高的氨基酸同一性。在一个实施方案中,本发明抗体与表B所列任一抗体相比,在重链可变区上具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%或更高的序列同一性。
例如,本发明的抗体包含与表B所列任一抗体的对应CDR相同的至少一个、两个、三个、四个、五个或六个CDR,或其变体。在一些实施方案中,本发明的抗体包含与表B所列任一抗体的对应重链CDR相同的至少一个、两个、或三个HCDR,或其变体。在本文中,“对应CDR”是指在可变区氨基酸序列中位于基本相似位置上的CDR。在本文中,CDR变体是已经通过至少一个,例如1或2或3个氨基酸取代、缺失和/或插入而修饰的CDR,其中包含CDR变体的抗体分子基本上保持包含未修饰CDR的抗体分子的生物学特性,例如,保持至少60%、70%、80%、90%或100%的生物学活性(例如抗原结合能力)。可以理解,各CDR可以单独修饰或组合修饰。优选地,氨基酸修饰为氨基酸取代,尤其是保守氨基酸取代,例如表A中列出的优选保守氨基酸置换。
在一些实施方案中,本发明的抗体或其抗原结合片段以高特异性和高亲合性结合GITR。
在一些实施方案中,本发明的抗体或其抗原结合片段以高亲和力与人GITR(如SEQID NO:123或127的多肽)结合,例如以小于约50nM、小于约30nM、小于约10-25nM或小于约20nM的高亲和力,优选以小于约10nM的亲和力与人GITR(如SEQ ID NO:123或127的多肽)结合。
例如,本发明的抗体或其抗原结合片段以约1-50nM、约5-50nM、约10-50nM、约1-30nM、约5-30nM、约10-30nM、约1-25nM、约5-25nM、约10-25nM、约1-20nM、约5-20nM、约10-20nM、约0.1-10nM、约1-10nM、约5-10nM、约10nM的亲和力与人GITR(如SEQ ID NO:123或127的多肽)结合。
在一些实施方案中,本发明的抗体或其抗原结合片段以高亲和力与人GITR(如SEQID NO:123或127的多肽)结合,例如以大于约0.01×104/Ms、大于约0.1×104/Ms、大于约1×104/Ms或大于约3×104/Ms的结合常数,优选以大于约5x 104/Ms的结合常数与人GITR(如SEQ ID NO:123或127的多肽)结合。
在一些实施方案中,本发明的抗体或其抗原结合片段以低解离常数与人GITR(如SEQ ID NO:123或127的多肽)结合,例如与人GITR(如SEQ ID NO:123或127的多肽)结合的解离常数(Kd)小于约2×10-2s-1、小于约1.5×10-2s-1、小于约8×10-3s-1或小于约5×10-3s-1;优选与人GITR(如SEQ ID NO:123或127的多肽)结合的解离常数为约1-3×10-3s-1。
例如,本发明的抗体或其抗原结合片段与人GITR(如SEQ ID NO:123或127的多肽)结合的解离常数(Kd)为约1×10-4s-1至2×10-2s-1、约1×10-3s-1至2×10-2s-1、约3×10-3s-1至2×10-2s-1、约1×10-4s-1至1.5×10-2s-1、约1×10-3s-1至1.5×10-2s-1、约3×10-3s-1至1.5×10-2s-1、约1×10-4s-1至8×10-2s-1、约1×10-3s-1至8×10-2s-1、约3×10-3s-1至1.5×10-2s-1、约1×10-4s-1至5×10-2s-1、约1×10-3s-1至5×10-2s-1、约3×10-3s-1至1.5×10-2s-1、1×10-3s-1至2×10-250nM、约3×10-3s-1至1.5×10-2s-1。
在一些实施方案中,本发明的抗体或其抗原结合片段与细胞表面的抗原高亲和力结合,例如以小于约50nM、小于约30nM、小于约25nM或小于约20nM的亲和力,优选以小于约10nM的亲和力与人GITR(如SEQ ID NO:123或127的多肽)结合。
例如,本发明的抗体或其抗原结合片段以约1nM-50nM、约5nM-50nM、约10nM-50nM、约1nM-30nM、约5nM-30nM、约10nM-30nM、约1nM-25nM、约5nM-25nM、约10nM-25nM、约1nM-20nM、约5nM-20nM、约10nM-20nM、约0.1-10nM、约1-10nM、约5-10nM、约10nM的亲和力与细胞表面的抗原。
在一些实施方案中,本发明的抗体或其抗原结合片段高效激活GITR下游的NFkB信号通路,例如激活NFkB信号通路的EC50值小于约50nM、小于约30nM、小于约25nM或小于约5nM,优选小于约1nM。
例如,本发明的抗体或其抗原结合片段激活NFkB信号通路的EC50值为约1nM-50nM、约5nM-50nM、约10nM-50nM、约1nM-30nM、约5nM-30nM、约10nM-30nM、约1nM-25nM、约5nM-25nM、约10nM-25nM、约1nM-20nM、约5nM-20nM、约10nM-20nM、约0.1-10nM、约1-10nM、约5-10nM或约10nM。
在一些实施方案中,本发明的抗体或其抗原结合片段与GITRL交叉竞争结合至GITR,优选与GITRL交叉竞争结合至人GITR(如SEQ ID NO:123或127的多肽)。
在一些实施方案中,本发明的抗体或其抗原结合片段可以内化到人CD4细胞中。
在一些实施方案中,本发明的抗体或其抗原结合片段抑制调节性T细胞的抑制作用。
在一些实施方案中,本发明的抗体或其抗原结合片段活化效应T细胞。
在一些实施方案中,本发明的抗体或其抗原结合片段减少循环调节性T细胞。
在一些实施方案中,本发明的抗体或其抗原结合片段能够结合Fcγ受体(FcγR)。
在一些实施方案中,本发明的抗体或其抗原结合片段在人血清中具有至少约6、约7、约9或约12天的半衰期。
另一方面,本发明提供了一种特异性结合GITR,并高效激活GITR下游的NFkB信号通路的纳米抗体(即,本发明的纳米抗体),该纳米抗体的HCDR3包含本发明抗体或抗原结合片段的HCDR3。
在一些实施方案中,本发明的纳米抗体的HCDR3包含SEQ ID NO:64-85中任一序列所示的重链可变区序列所含的HCDR3,或本发明的纳米抗体的HCDR3由SEQ ID NO:64-85中任一序列所示的重链可变区序列所含的HCDR3组成。
在一些实施方案中,本发明的纳米抗体的HCDR3包含与如SEQ ID NO:64-85中任一序列所示的重链可变区序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的重链可变区序列所含的HCDR3,其中优选序列差异不存在于CDR区域中,或本发明的纳米抗体的HCDR3由这样的重链可变区序列中所含的HCDR3组成。
在一些实施方案中,本发明的纳米抗体的HCDR3包含在如SEQ ID NO:64-85中任一序列所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列中所含的HCDR3,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的纳米抗体的HCDR3由这样的重链可变区序列中所含的HCDR3组成。
在一些实施方案中,本发明的纳米抗体的HCDR3包含如SEQ ID NO:45-63中任一序列所示的HCDR3,或本发明的纳米抗体的HCDR3由如SEQ ID NO:45-63中任一序列所示的HCDR3组成。
在一些实施方案中,本发明的纳米抗体的HCDR3包含在如SEQ ID NO:45-63中任一序列所示的HCDR3中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的HCDR3,或本发明的纳米抗体的HCDR3由这样的HCDR3组成。
在一些实施方案中,本发明的纳米抗体的HCDR1(重链互补决定区1)和HCDR2(重链互补决定区2)包含如SEQ ID NO:64-85中任一序列所示的重链可变区序列所含的HCDR1和HCDR2,或本发明的纳米抗体的HCDR1和HCDR2由如SEQ ID NO:64-85中任一序列所示的重链可变区序列所含的HCDR1和HCDR2组成。
在一些实施方案中,本发明的纳米抗体的HCDR1和HCDR2包含在如SEQ ID NO:64-85中任一序列所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列中所含的HCDR1和HCDR2,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的纳米抗体的HCDR1和HCDR2由这样的重链可变区序列中所含的HCDR1和HCDR2组成。
在一些实施方案中,本发明的纳米抗体的HCDR1包含如SEQ ID NO:1-22中任一序列所示的HCDR1,或本发明的纳米抗体的HCDR1由如SEQ ID NO:1-22中任一序列所示的HCDR1组成。
在一些实施方案中,本发明的纳米抗体的HCDR1包含在如SEQ ID NO:1-22中任一序列所示的HCDR1中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的HCDR1,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的纳米抗体的HCDR1由这样的HCDR1组成。
在一些实施方案中,本发明的纳米抗体的HCDR2包含如SEQ ID NO:23-44中任一序列所示的HCDR2,或本发明的纳米抗体的HCDR2由如SEQ ID NO:23-44中任一序列所示的HCDR2组成。
在一些实施方案中,本发明的纳米抗体的HCDR2包含在如SEQ ID NO:23-44中任一序列所示的HCDR2中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的HCDR2,或本发明的纳米抗体的HCDR2由这样的HCDR2组成。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:1所示的HCDR1、如SEQID NO:23所示的HCDR2和如SEQ ID NO:45所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:2所示的HCDR1、如SEQID NO:24所示的HCDR2和如SEQ ID NO:46所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:3所示的HCDR1、如SEQID NO:25所示的HCDR2和如SEQ ID NO:47所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:4所示的HCDR1、如SEQID NO:26所示的HCDR2和如SEQ ID NO:48所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:5所示的HCDR1、如SEQID NO:27所示的HCDR2和如SEQ ID NO:49所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:6所示的HCDR1、如SEQID NO:28所示的HCDR2和如SEQ ID NO:50所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:7所示的HCDR1、如SEQID NO:29所示的HCDR2和如SEQ ID NO:51所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:8所示的HCDR1、如SEQID NO:30所示的HCDR2和如SEQ ID NO:52所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:9所示的HCDR1、如SEQID NO:31所示的HCDR2和如SEQ ID NO:53所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:10所示的HCDR1、如SEQID NO:32所示的HCDR2和如SEQ ID NO:51所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:11所示的HCDR1、如SEQID NO:33所示的HCDR2和如SEQ ID NO:48所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:12所示的HCDR1、如SEQID NO:34所示的HCDR2和如SEQ ID NO:46所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:13所示的HCDR1、如SEQID NO:35所示的HCDR2和如SEQ ID NO:54所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:14所示的HCDR1、如SEQID NO:36所示的HCDR2和如SEQ ID NO:55所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:15所示的HCDR1、如SEQID NO:37所示的HCDR2和如SEQ ID NO:56所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:16所示的HCDR1、如SEQID NO:38所示的HCDR2和如SEQ ID NO:57所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:17所示的HCDR1、如SEQID NO:39所示的HCDR2和如SEQ ID NO:58所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:18所示的HCDR1、如SEQID NO:40所示的HCDR2和如SEQ ID NO:59所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:19所示的HCDR1、如SEQID NO:41所示的HCDR2和如SEQ ID NO:60所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:20所示的HCDR1、如SEQID NO:42所示的HCDR2和如SEQ ID NO:61所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:21所示的HCDR1、如SEQID NO:43所示的HCDR2和如SEQ ID NO:62所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:22所示的HCDR1、如SEQID NO:44所示的HCDR2和如SEQ ID NO:63所示的HCDR3的组合。
在一些实施方案中,本发明的纳米抗体包含如SEQ ID NO:64-85中任一序列所示的重链可变区序列,或由如SEQ ID NO:64-85中任一序列所示的重链可变区序列组成,优选仅由一条这样的重链可变区序列组成。
在一些实施方案中,本发明的纳米抗体包含与如SEQ ID NO:64-85中任一序列所示的重链可变区序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的重链可变区序列,其中优选序列差异不存在于CDR区域中,或本发明的纳米抗体由这样的重链可变区序列组成,优选仅由一条这样的重链可变区序列组成。
在一些实施方案中,本发明的纳米抗体包含在如SEQ ID NO:64-85中任一序列所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的纳米抗体由这样的重链可变区序列组成,优选仅由一条这样的重链可变区序列组成。
另一方面,本发明提供了一种特异性结合GITR,并高效激活GITR下游的NFkB信号通路的重链抗体(即,本发明的重链抗体),该重链抗体的HCDR3包含本发明抗体或抗原结合片段的HCDR3,或由本发明抗体或抗原结合片段的HCDR3组成;该重链抗体的HCDR3优选包含上述本发明纳米抗体的HCDR3或由上述本发明纳米抗体的HCDR3组成;更优选该重链抗体的HCDR1-2优选分别包含上述本发明纳米抗体的HCDR1-2或分别由上述本发明纳米抗体的HCDR1-2组成。
在一些实施方案中,本发明的重链抗体是人源化重链抗体,优选是全人源重链抗体(人抗体)。
在一些实施方案中,本发明的重链抗体的HCDR3包含如SEQ ID NO:65、66、67、70、72、73、79和83中任一序列所示的重链可变区序列所含的HCDR3,或本发明的重链抗体的HCDR3由如SEQ ID NO:65、66、67、70、72、73、79和83中任一序列所示的重链可变区序列所含的HCDR3组成。
在一些实施方案中,本发明的重链抗体的HCDR3包含与如SEQ ID NO:65、66、67、70、72、73、79和83中任一序列所示的重链可变区序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的重链可变区序列所含的HCDR3,其中优选序列差异不存在于CDR区域中,或本发明的重链抗体的HCDR3由这样的重链可变区序列所含的HCDR3组成。
在一些实施方案中,本发明的重链抗体的HCDR3包含在如SEQ ID NO:65、66、67、70、72、73、79和83中任一序列所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列中所含的HCDR3,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的重链抗体的HCDR3由这样的重链可变区序列所含的HCDR3组成。
在一些实施方案中,本发明的重链抗体的HCDR3包含如SEQ ID NO:46、47、48、51、53、57和61中任一序列所示的HCDR3,或本发明的重链抗体的HCDR3由如SEQ ID NO:46、47、48、51、53、57和61中任一序列所示的HCDR3组成。
在一些实施方案中,本发明的重链抗体的HCDR3包含在如SEQ ID NO:46、47、48、51、53、57和61中任一序列所示的HCDR3中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的HCDR3,或本发明的重链抗体的HCDR3由这样的HCDR3组成。
在一些实施方案中,本发明的重链抗体的HCDR1和HCDR2包含如SEQ ID NO:65、66、67、70、72、73、79和83中任一序列所示的重链可变区序列所含的HCDR1和HCDR2,或本发明的重链抗体的HCDR1和HCDR2由这样的重链可变区序列所含的HCDR1和HCDR2组成。
在一些实施方案中,本发明的重链抗体的HCDR1和HCDR2包含与如SEQ ID NO:65、66、67、70、72、73、79和83中任一序列所示的重链可变区序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的重链可变区序列所含的HCDR1和HCDR2,其中优选序列差异不存在于CDR区域中,或本发明的重链抗体的HCDR1和HCDR2由这样的重链可变区序列所含的HCDR1和HCDR2组成。
在一些实施方案中,本发明的重链抗体的HCDR1和HCDR2包含在如SEQ ID NO:65、66、67、70、72、73、79和83中任一序列所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列中所含的HCDR1和HCDR2,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的重链抗体的HCDR1和HCDR2由这样的重链可变区序列所含的HCDR1和HCDR2组成。
在一些实施方案中,本发明的重链抗体的HCDR1包含如SEQ ID NO:2、3、4、7、9、10、16、20中任一序列所示的HCDR1,或本发明的重链抗体的HCDR1由如SEQ ID NO:2、3、4、7、9、10、16、20中任一序列所示的HCDR1组成。
在一些实施方案中,本发明的重链抗体的HCDR1包含在如SEQ ID NO:2、3、4、7、9、10、16、20中任一序列所示的HCDR1中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的HCDR1,或本发明的重链抗体的HCDR1由这样的HCDR1组成。
在一些实施方案中,本发明的重链抗体的HCDR2包含如SEQ ID NO:24、25、26、29、31、32、38、42中任一序列所示的HCDR2,或本发明的重链抗体的HCDR2由如SEQ ID NO:24、25、26、29、31、32、38、42中任一序列所示的HCDR2组成。
在一些实施方案中,本发明的重链抗体的HCDR2包含在如SEQ ID NO:24、25、26、29、31、32、38、42中任一序列所示的HCDR2中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的HCDR2,或本发明的重链抗体的HCDR2由这样的HCDR2组成。
在一些实施方案中,本发明的重链抗体包含如SEQ ID NO:2所示的HCDR1、如SEQID NO:24所示的HCDR2和如SEQ ID NO:46所示的HCDR3的组合。
在一些实施方案中,本发明的重链抗体包含如SEQ ID NO:3所示的HCDR1、如SEQID NO:25所示的HCDR2和如SEQ ID NO:47所示的HCDR3的组合。
在一些实施方案中,本发明的重链抗体包含如SEQ ID NO:4所示的HCDR1、如SEQID NO:26所示的HCDR2和如SEQ ID NO:48所示的HCDR3的组合。
在一些实施方案中,本发明的重链抗体包含如SEQ ID NO:7所示的HCDR1、如SEQID NO:29所示的HCDR2和如SEQ ID NO:51所示的HCDR3。
在一些实施方案中,本发明的重链抗体包含如SEQ ID NO:9所示的HCDR1、如SEQID NO:31所示的HCDR2和如SEQ ID NO:53所示的HCDR3。
在一些实施方案中,本发明的重链抗体包含如SEQ ID NO:10所示的HCDR1、如SEQID NO:32所示的HCDR2和如SEQ ID NO:51所示的HCDR3。
在一些实施方案中,本发明的重链抗体包含如SEQ ID NO:16所示的HCDR1、如SEQID NO:38所示的HCDR2和如SEQ ID NO:57所示的HCDR3。
在一些实施方案中,本发明的重链抗体包含如SEQ ID NO:20所示的HCDR1、如SEQID NO:42所示的HCDR2和如SEQ ID NO:61所示的HCDR3。
在一些实施方案中,本发明的重链抗体的重链可变区序列包含如SEQ ID NO:65、66、67、70、72、73、79和83中任一序列所示的重链可变区序列,或本发明的重链抗体的重链可变区序列由如SEQ ID NO:65、66、67、70、72、73、79和83中任一序列所示的重链可变区序列组成。
在一些实施方案中,本发明的重链抗体的重链可变区序列包含与如SEQ ID NO:65、66、67、70、72、73、79和83中任一序列所示的重链可变区序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的重链可变区序列,其中优选序列差异不存在于CDR区域中,或本发明的重链抗体的重链可变区序列由这样的重链可变区序列组成。
在一些实施方案中,本发明的重链抗体的重链可变区序列包含在如SEQ ID NO:65、66、67、70、72、73、79和83中任一序列所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的重链抗体的重链可变区序列由这样的重链可变区序列组成。
在一些实施方案中,本发明的重链抗体包含如SEQ ID NO:108-115中任一序列所示的重链抗体序列,或本发明的重链抗体由一条、两条或多条如SEQ ID NO:108-115中任一序列所示的重链抗体序列组成。
在一些实施方案中,本发明的重链抗体包含与如SEQ ID NO:108-115中任一序列所示的重链抗体序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的重链抗体序列,其中优选序列差异不存在于CDR区域中,或本发明的重链抗体由一条、两条或多条这样的重链抗体序列组成。
在一些实施方案中,本发明的重链抗体包含在如SEQ ID NO:108-115中任一序列所示的重链抗体序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链抗体序列,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的重链抗体由一条、两条或多条这样的重链抗体序列组成。
另一方面,本发明提供了一种特异性结合GITR,并高效激活GITR下游的NFkB信号通路的人源化重链抗体(即,本发明的人源化重链抗体),该人源化重链抗体的HCDR3包含本发明抗体或抗原结合片段的HCDR3,或由本发明抗体或抗原结合片段的HCDR3组成。
在一些实施方案中,本发明的人源化重链抗体的HCDR3包含上述本发明纳米抗体或重链抗体的HCDR3,或由上述本发明纳米抗体或重链抗体的HCDR3组成;更优选本发明人源化重链抗体的HCDR1-2优选分别包含上述本发明纳米抗体或重链抗体的HCDR1-2,或分别由上述本发明纳米抗体或重链抗体的HCDR1-2组成。
在一些实施方案中,本发明的人源化重链抗体中的HCDR3包含如SEQ ID NO:124或125所示的重链可变区序列所含的HCDR3,或本发明的人源化重链抗体中的HCDR3由如SEQID NO:124或125所示的重链可变区序列所含的HCDR3组成。
在一些实施方案中,本发明的人源化重链抗体中的HCDR3包含与如SEQ ID NO:124或125所示的重链可变区序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的重链可变区序列所含的HCDR3,其中优选序列差异不存在于CDR区域中,或本发明的人源化重链抗体中的HCDR3由这样的重链可变区序列所含的HCDR3组成。
在一些实施方案中,本发明的人源化重链抗体中的HCDR3包含在如SEQ ID NO:124或125所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列中所含的HCDR3,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的人源化重链抗体中的HCDR3由这样的重链可变区序列所含的HCDR3组成。
在一些实施方案中,本发明的人源化重链抗体中的HCDR3包含选自SEQ ID NO:51或61的HCDR3,或本发明的人源化重链抗体中的HCDR3由选自SEQ ID NO:51或61的HCDR3组成。
在一些实施方案中,本发明的人源化重链抗体中的HCDR3包含在选自SEQ ID NO:51或61的HCDR3中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的HCDR3,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的人源化重链抗体中的HCDR3由这样的HCDR3组成。
在一些实施方案中,本发明的人源化重链抗体中的HCDR1和HCDR2包含选自SEQ IDNO:124或125的重链可变区序列所含的HCDR1和HCDR2,或本发明的人源化重链抗体中的HCDR1和HCDR2由选自SEQ ID NO:124或125的重链可变区序列所含的HCDR1和HCDR2组成。
在一些实施方案中,本发明的人源化重链抗体中的HCDR1和HCDR2包含与如SEQ IDNO:124或125所示的重链可变区序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的重链可变区序列所含的HCDR1和HCDR2,其中优选序列差异不存在于CDR区域中,或本发明的人源化重链抗体中的HCDR1和HCDR2由这样的重链可变区序列所含的HCDR1和HCDR2组成。
在一些实施方案中,本发明的人源化重链抗体中的HCDR1和HCDR2包含在如SEQ IDNO:124或125所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列中所含的HCDR1和HCDR2,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的人源化重链抗体中的HCDR1和HCDR2由这样的重链可变区序列所含的HCDR1和HCDR2组成。
在一些实施方案中,本发明的人源化重链抗体中的HCDR1包含如SEQ ID NO:7或20所示的HCDR1,或本发明的人源化重链抗体中的HCDR1由如SEQ ID NO:7或20所示的HCDR1组成。
在一些实施方案中,本发明的人源化重链抗体中的HCDR1包含在如SEQ ID NO:7或20所示的HCDR1中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的HCDR1,或本发明的人源化重链抗体中的HCDR1由这样的HCDR1组成。
在一些实施方案中,本发明的人源化重链抗体中的HCDR2包含如SEQ ID NO:29或42所示的HCDR2,或本发明的人源化重链抗体中的HCDR2由如SEQ ID NO:29或42所示的HCDR2组成。
在一些实施方案中,本发明的人源化重链抗体中的HCDR2包含在如SEQ ID NO:29或42所示的HCDR2中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的HCDR2,或本发明的人源化重链抗体中的HCDR2由这样的HCDR2组成。
在一些实施方案中,本发明的人源化重链抗体包含如SEQ ID NO:7所示的HCDR1、如SEQ ID NO:29所示的HCDR2和如SEQ ID NO:51所示的HCDR3的组合。
在一些实施方案中,本发明的人源化重链抗体包含如SEQ ID NO:20所示的HCDR1、如SEQ ID NO:42所示的HCDR2和如SEQ ID NO:61所示的HCDR3的组合。
在一些实施方案中,本发明的人源化重链抗体的重链可变区序列包含如SEQ IDNO:124或125所示的重链可变区序列,或本发明的人源化重链抗体的重链可变区序列由如SEQ ID NO:124或125所示的重链可变区序列组成。
在一些实施方案中,本发明的人源化重链抗体的重链可变区序列包含与如SEQ IDNO:124或125所示的重链可变区序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的重链可变区序列,其中优选序列差异不存在于CDR区域中,或本发明的人源化重链抗体的重链可变区序列由这样的重链可变区序列组成。
在一些实施方案中,本发明的人源化重链抗体的重链可变区序列包含在如SEQ IDNO:124或125所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的人源化重链抗体的重链可变区序列由这样的重链可变区序列组成。
在一些实施方案中,本发明的人源化重链抗体包含如SEQ ID NO:116或117所示的人源化重链抗体序列,或本发明的人源化重链抗体由一条、两条或多条如SEQ ID NO:116或117所示的人源化重链抗体序列组成。
在一些实施方案中,本发明的人源化重链抗体包含与如SEQ ID NO:116或117所示的人源化重链抗体序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的人源化重链抗体序列,其中优选序列差异不存在于CDR区域中,或本发明的人源化重链抗体由一条、两条或多条这样的人源化重链抗体序列组成。
在一些实施方案中,本发明的人源化重链抗体包含在如SEQ ID NO:116或117所示的人源化重链抗体序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的人源化重链抗体序列,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的人源化重链抗体由一条、两条或多条这样的人源化重链抗体序列组成。
在一些实施方案中,本发明的重链抗体或人源化重链抗体包含上述任一种重链可变区和Fc片段,优选该Fc片段包含下述序列(a)-(d)之一或由下述序列(a)-(d)之一组成:
(a)人IgG1的Fc片段;
(b)如SEQ ID NO:121所示的Fc片段;或
(c)与如SEQ ID NO:121所示的Fc片段具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的Fc片段;或
(d)在如SEQ ID NO:121所示的Fc片段中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的Fc片段。
在优选的实施方案中,本发明的重链抗体或人源化重链抗体包含两条选自上述序列(a)-(d)中的Fc序列。
在更优选的实施方案中,同一个本发明的重链抗体或人源化重链抗体的两条Fc序列(a)-(d)之间存在链间二硫键。
最优选的实施方案中,同一个本发明的重链抗体或人源化重链抗体的两条Fc序列(a)-(d)之间存在两个链间二硫键,该链间二硫键是本发明的重链抗体或人源化重链抗体中包含的CPPC序列中,氨基酸残基C之间形成的两个链间二硫键,该CPPC序列是本发明的重链抗体或人源化重链抗体中的纳米抗体与Fc之间连接的序列。
另一方面,本发明提供了一种特异性结合GITR,并高效激活GITR下游的NFkB信号通路的多聚物形式的抗体(即,本发明的多聚物形式的抗体),该多聚物形式的抗体的HCDR3包含本发明抗体或抗原结合片段的HCDR3,或由本发明抗体或抗原结合片段的HCDR3组成。
在一些实施方案中,本发明的多聚物形式的抗体的HCDR3包含上述本发明纳米抗体、重链抗体或人源化重链抗体的HCDR3,或由上述本发明纳米抗体、重链抗体或人源化重链抗体的HCDR3组成;更优选本发明多聚物形式的抗体的HCDR1-2优选分别包含上述本发明纳米抗体、重链抗体或人源化重链抗体的HCDR1-2,或分别由上述本发明纳米抗体、重链抗体或人源化重链抗体的HCDR1-2组成。
在优选的实施方案中,本发明的多聚物形式的抗体是本发明的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区的多聚物形式,优选是本发明的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区的四聚化形式或六聚化形式,最优选是本发明的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区的四聚化形式。
通过形成将本发明的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区形成多聚物形式的抗体,可以更有效地激活GITR下游的NFkB信号通路,同时可以适当延长本发明的纳米抗体、重链抗体、人源化重链抗体在活体内的半衰期。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区中的HCDR3包含如SEQ ID NO:125所示的重链可变区序列所含的HCDR3序列,或本发明的多聚物形式的抗体的重链可变区中的HCDR3由如SEQ ID NO:125所示的重链可变区序列所含的HCDR3组成。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区中的HCDR3包含与如SEQ ID NO:125所示的重链可变区序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的重链可变区序列所含的HCDR3序列,其中优选序列差异不存在于CDR区域中,或本发明的多聚物形式的抗体的重链可变区中的HCDR3由这样的HCDR3序列组成。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区中的HCDR3包含在如SEQ ID NO:125所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列中所含的HCDR3,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的多聚物形式的抗体的重链可变区中的HCDR3由这样的HCDR3序列组成。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区中的HCDR3包含所示SEQ ID NO:61所示的HCDR3序列,或本发明的多聚物形式的抗体的重链可变区中的HCDR3由所示SEQ ID NO:61所示的HCDR3序列组成。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区中的HCDR3包含在SEQ ID NO:61的HCDR3中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的HCDR3序列,或本发明的多聚物形式的抗体的重链可变区中的HCDR3由这样的HCDR3序列组成。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区中的HCDR1和HCDR2包含如SEQ ID NO:125所示的重链可变区序列所含的HCDR1和HCDR2序列,或本发明的多聚物形式的抗体的重链可变区中的HCDR1和HCDR2由如SEQ ID NO:125所示的重链可变区序列所含的HCDR1和HCDR2序列组成。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区中的HCDR1和HCDR2包含与如SEQ ID NO:125所示的重链可变区序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的重链可变区序列所含的HCDR1和HCDR2,其中优选序列差异不存在于CDR区域中,或本发明的多聚物形式的抗体的重链可变区中的HCDR1和HCDR2由这样的HCDR1和HCDR2序列组成。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区中的HCDR1和HCDR2包含在如SEQ ID NO:125所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列中所含的HCDR1和HCDR2,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的多聚物形式的抗体的重链可变区中的HCDR1和HCDR2由这样的HCDR1和HCDR2序列组成。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区中的HCDR1包含如SEQ ID NO:20所示的HCDR1序列,或本发明的多聚物形式的抗体的重链可变区中的HCDR1由如SEQ ID NO:20所示的HCDR1序列组成。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区中的HCDR1包含在SEQ ID NO:20的HCDR1中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的HCDR1序列,或本发明的多聚物形式的抗体的重链可变区中的HCDR1由这样的HCDR1序列组成。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区中的HCDR2包含如SEQ ID NO:42所示的HCDR2序列,或本发明的多聚物形式的抗体的重链可变区中的HCDR2由如SEQ ID NO:42所示的HCDR2序列组成。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区中的HCDR2包含在SEQ ID NO:42的HCDR2中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的HCDR2序列,或本发明的多聚物形式的抗体的重链可变区中的HCDR2由这样的HCDR2序列组成。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区包含如SEQ ID NO:20所示的HCDR1、如SEQ ID NO:42所示的HCDR2和如SEQ ID NO:61所示的HCDR3的组合。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区包含如SEQ ID NO:125所示的重链可变区序列,或本发明的多聚物形式的抗体的重链可变区由如SEQ ID NO:125所示的重链可变区序列组成。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区包含与如SEQ IDNO:125所示的重链可变区序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的重链可变区序列,其中优选序列差异不存在于CDR区域中,或本发明的多聚物形式的抗体的重链可变区由这样的重链可变区序列组成。
在一些实施方案中,本发明的多聚物形式的抗体的重链可变区包含在如SEQ IDNO:125所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的多聚物形式的抗体的重链可变区由这样的重链可变区序列组成。
在一些实施方案中,本发明的多聚物形式的抗体包含选自SEQ ID NO:118-120的任一序列,或本发明的多聚物形式的抗体由相同的两条、三条或多条选自SEQ ID NO:118-120的序列组成。
在一些实施方案中,本发明的多聚物形式的抗体包含与如SEQ ID NO:118-120中任一序列所示的序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更多序列同一性的序列,其中优选序列差异不存在于CDR区域中,或本发明的多聚物形式的抗体由相同的两条、三条或多条这样的序列组成。
在一些实施方案中,本发明的多聚物形式的抗体包含在如SEQ ID NO:118-120中任一序列所示的序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的序列,其中优选所述氨基酸改变不发生在CDR区域中,或本发明的多聚物形式的抗体由相同的两条、三条或多条这样的序列组成。
在一些实施方案中,本发明的多聚物形式的抗体中的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区(简称“本发明的抗体的重链可变区”)连接到本发明的人源化重链抗体。
在优选的实施方案中,本发明的多聚物形式的抗体中的本发明的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区连接到本发明的人源化重链抗体的C末端;或者本发明的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区连接到本发明的人源化重链抗体的N末端。
在更优选的实施方案中,本发明的多聚物形式的抗体包含两条相同的本发明的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区,该两条相同的本发明的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区分别连接到两条相同的本发明的人源化重链抗体的C末端;或者该两条相同的本发明的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区分别连接到两条相同的本发明的人源化重链抗体的N末端。
在最优选的实施方案中,本发明的多聚物形式的抗体是四聚体(包含四个相同的本发明的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区),其包含两条相同的链,每条链包含一个纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区,和一个本发明的人源化重链抗体。即,本发明的多聚物形式的抗体包含两条完全相同的链(完全相同的第一链和第二链),每条链均只包含一个额外的本发明的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区和一个本发明的人源化重链抗体,其中第一链包含的本发明的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区和第二链包含的本发明的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区相同;第一链包含的人源化重链抗体和第二链包含的人源化重链抗体相同。这两条相同的链之间还可以存在链间二硫键,该链间二硫键是每条链的人源化重链抗体中连接其中的重链可变区与Fc的序列(例如,CPPC序列)中,氨基酸残基C之间形成的两个链间二硫键。即,第一链的人源化重链抗体中的重链可变区与Fc之间的序列中的氨基酸残基C和第二链的人源化重链抗体中的重链可变区与Fc之间的序列中的氨基酸残基C之间形成链间二硫键。
在一些实施方案中,本发明的多聚物形式的抗体中的本发明的纳米抗体、重链抗体的重链可变区、人源化重链抗体的重链可变区通过连接肽连接到本发明的人源化重链抗体,该连接肽优选是柔性连接肽,更优选是氨基酸序列为(G4S)n(n为0-7整数)的连接肽。
本发明提供了如实施例中分离并表征的特异性结合GITR(例如人GITR)的纳米抗体、重链抗体、人源化重链抗体和四聚体形式的抗体。下表B中列出了本发明这些示例性抗体的氨基酸序列和核苷酸序列。其中,抗体的氨基酸序列中,从N端至C端以加粗斜体示出的序列分别是示例性CDR序列(通过本领域已知的各种确定CDR的精确氨基酸序列边界的方法中的任一种或其组合确定,例如可以按照本文上述介绍的方法,并参考其他因素,例如保守性,确定如下示例性CDR序列)。
表B.本发明示例性纳米抗体的氨基酸序列和核苷酸序列、重链抗体的氨基酸序列、人源化重链抗体的氨基酸序列和四聚体形式的抗体的氨基酸序列,及其SEQ ID NO编号。
下表C中给出本发明示例的序列对应的SEQ ID NO序号。
表C本发明示例的序列的SEQ ID NO序号
另一方面,本发明提供了一种融合蛋白或免疫缀合物(简称本发明的融合蛋白或免疫缀合物),其中本发明的抗体与一个或多个异源分子(第二分子)融合或缀合,其中该异源分子包括但不限于蛋白/多肽、标记物、药物或细胞毒性剂。
蛋白质、多肽或肽与抗体融合或缀合的方法是本领域已知的。参见,例如,美国专利号5,336,603、5,622,929和EP 367,166。
在一些实施方案中,本发明的融合蛋白或免疫缀合物中药物是抗肿瘤药物。
另一方面,本发明提供了一种组合物或试剂盒(简称本发明的组合物或试剂盒),其包含本发明的抗体。
在一些实施方案中,本发明的组合物或试剂盒包括载体和/或说明书。
在一些实施方案中,本发明的组合物或试剂盒中的抗体与诊断剂或可检测试剂缀合。
另一方面,本发明提供了一种分离的核酸(简称本发明的分离的核酸或本发明的核酸(分子)),其编码本发明的抗体或其片段(包括抗原结合片段)、本发明的融合蛋白或本发明的免疫缀合物。
在一些实施方案中,本发明的核酸分子是基本上纯化的核酸分子。
在一些实施方案中,本发明的核酸分子包含编码表B所示任一抗体的重链可变区或其变体的核苷酸序列。在一个具体实施方案中,核酸分子是表B中列出的纳米抗体的核苷酸序列。本发明的核酸分子包含编码表B所示任一抗体的重链至少一个CDR区和通常全部三个CDR区,或其变体的核苷酸序列。
本发明的一些其他核酸分子与表B中所示的氨基酸序列的编码核酸分子的核苷酸序列基本上相同(例如,至少65%、80%、95%、或99%同一性)。在适宜的表达载体表达时,由这些多核苷酸编码的多肽能够显示GITR抗原结合能力。
如本领域技术人员所知的,因为密码子简并性,每一个抗体或多肽氨基酸序列可以由多种核酸序列编码。
在一些实施方案中,本发明的核酸序列编码本发明的上述任何纳米抗体。在一些实施方案中,编码纳米抗体的本发明核酸序列包含SEQ ID NO:86-107的核苷酸序列或与其基本相同的序列。在一些实施方案中,编码纳米抗体的本发明核酸序列由SEQ ID NO:86-107的核苷酸序列或与其基本相同的序列组成。
“基本相同”的核苷酸序列是指与参考核苷酸序列在序列上具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%,、98%或99%或更高同一性的序列。核苷酸序列的同一性可以使用本领域公知的各种序列比对方法确定。例如可以从NCBI(NationalCenter for Biotechnology Information,Bethesda,MD)的网站上获得BLAST序列比对检索工具。一般而言,百分比同一性采用NCBI Blast的默认参数进行。
可以通过从头固相DNA合成或通过PCR诱变编码GITR抗体或其结合片段的现有序列(例如,表B和2中所示的序列),产生GITR抗体或其结合片段的多核苷酸序列。核酸的直接化学合成可以通过本领域已知的方法完成,如Narang等,1979,Meth.Enzymol.68:90的磷酸三酯法;Brown等,Meth.Enzymol.68:109,1979的磷酸二酯法;Beaucage等,Tetra.Lett.,22:1859,1981的二乙基磷酰亚胺法;和美国专利号4,458,066的固相支持法。通过PCR向多核苷酸序列引入突变可以如同例如PCR Technology:Principles and Applications forDNA Amplification,H.A.Erlich(编著),Freeman Press,NY,NY,1992;PCR Protocols:AGuide to Methods and Applications,Innis等(编著),Academic Press,San Diego,CA,1990;Mattila等,Nucleic Acids Res.19:967,1991;and Eckert等,PCR Methods andApplications 1:17,1991中所述那样进行。
另一方面,本发明提供包含本发明的核酸的载体(简称本发明的载体)。
在一些实施方案中,本发明的载体是表达载体,即可以用来表达编码结合GITR的抗体链(例如本发明的任何抗体)或多肽(例如本发明的任何融合物和缀合物)的多核苷酸。
基于病毒的表达载体和非病毒表达载体都可用于在哺乳动物宿主细胞中产生抗体。非病毒载体和系统包含质粒、游离型载体和人工染色体,一般含有用于表达蛋白质或RNA的表达盒(参见,例如,Harrington等,Nat Genet 15:345,1997)。有用的病毒载体包括基于逆转录病毒、腺病毒、腺伴随病毒、疱疹病毒的载体,基于SV40、乳头瘤病毒、HBP EB病毒、痘苗病毒载体和Semliki Forest病毒(SFV)的载体。参见,Smith,Annu.Rev.Microbiol.49:807,1995;和Rosenfeld等,Cell 68:143,1992。
另一方面,本发明提供包含本发明的载体的宿主细胞(简称本发明的宿主细胞)。
在一些实施方案中,本发明的宿主细胞是适合本发明载体的克隆或表达的任何宿主细胞,包括原核或真核细胞。
在一些实施方案中,本发明的宿主细胞是细菌、酵母细胞、哺乳动物细胞或免疫效应细胞(如T细胞)。
例如,当不需要糖基化和Fc效应子功能时,抗体可以在细菌中生产。对于抗体片段和多肽在细菌中的表达,参见例如US 5,648,237、US 5,789,199和US 5,840,523。除了原核生物外,真核微生物例如丝状真菌或酵母是用于抗体编码载体的合适克隆或表达宿主,包括糖基化途径已被“人源化”的真菌和酵母菌株,这导致具有部分或完全人糖基化模式的抗体的生产。参见Gerngross,Nat.Biotech.22(2004)1409-1414;和Li,H.等,Nat.Biotech(2006)24:210-215。用于糖基化抗体表达的合适宿主细胞也可以源自多细胞生物(无脊椎动物和脊椎动物)。无脊椎动物细胞的实例包括植物和昆虫细胞。已经鉴定了众多杆状病毒株,其可以与昆虫细胞结合使用,特别用于草地贪夜蛾(Spodoptera frugiperda)细胞的转染。植物细胞培养物也可以用作宿主。参见,例如,US 5,959,177、US 6,040,498、US 6,420,548、US 7,125,978和US 6,417,429(描述用于在转基因植物中生产抗体的PLANTIBODIESTM技术)。可以用作宿主的脊椎动物细胞包括,例如,悬浮生长适应化的哺乳动物细胞系可以是有用的。有用的哺乳动物宿主细胞系的其他实例是SV40转化的猴肾CV1系(COS-7);人胚肾系(HEK293或例如Graham,F.L.等,J.Gen Virol.36(1997)59中描述的HEK293细胞);幼仓鼠肾细胞(BHK);小鼠塞尔托利细胞(例如Mather,J.P.,Biol.Reprod.23(1980)243-251中描述的TM4细胞);猴肾细胞(CV1);非洲绿猴肾细胞(VERO-76);人宫颈癌细胞(HELA);犬肾细胞(MDCK);Buffalo大鼠肝细胞(BRL 3A);人肺细胞(W138);人肝细胞(Hep G2);小鼠乳房肿瘤(MMT060562);TRI细胞,例如Mather,J.P.等,Annals N.Y.Acad.Sci.383(1982)44-68中描述的;MRC 5细胞;FS4细胞。其他有用的哺乳动物宿主细胞系包括中国仓鼠卵巢(CHO)细胞,包括DHFR-CHO细胞(Urlaub,G.等,Proc.Natl.Acad.Sci.USA 77(1980)4216-4220);和骨髓瘤细胞系,如Y0、NS0和Sp2/0。对于适合于抗体生产的一些哺乳动物宿主细胞系的综述,参见,例如,Yazaki,P.和Wu,A.M.,Methods in Molecular Biology,Vol.248,Lo.B.K.C.(编辑),Humana Press,Totowa,NJ(2004)pp.255-268。
在一些优选的实施方案中,大肠杆菌细胞(TG1细胞)、人胚肾系(293细胞)或人宫颈癌细胞(HELA)可以用来表达并产生结合GITR的本发明抗体。
另一方面,本发明提供一种包含制备本发明的抗体或其抗原结合片段、本发明的融合蛋白或本发明的免疫缀合物的方法(简称本发明的制备方法或本发明的方法),包括:在适于表达本发明的抗体或其抗原结合片段、融合蛋白或免疫缀合物的条件下,培养本发明的宿主细胞。
在一些实施方案中,本发明的方法中还包括采用有利于本发明的抗体或其抗原结合片段、融合蛋白或免疫缀合物表达和纯化的任何表达手段,例如采用分泌信号序列、表达增强元件、高效的启动子等本领域技术人员已知的任何表达、调节元件。
另一方面,本发明提供一种药物组合物(简称本发明的药物组合物),其包含本发明的抗体或其抗原结合片段、本发明的融合蛋白或本发明的免疫缀合物,以及任选地药用载体。
在一些实施方案中,本发明的药物组合物进一步包含其他成分,例如免疫治疗剂、抗血管生成剂及化疗剂。
在一些实施方案中,本发明的药物组合物中的免疫治疗剂可以诱导或增强免疫应答,包括例如:1)树突细胞活化剂;2)疫苗佐剂;3)T细胞刺激物;4)免疫检查点抑制剂,以及5)抑制性细胞、细胞因子和/或酶的抑制剂。
在一些实施方案中,本发明的药物组合物可包括用于治疗癌症的其他化合物、药物及/或药剂,包括但不限于刺激针对给定癌症的免疫应答的化学疗法药物、小分子药物或抗体。在一些情况下,治疗组合物可包括:抗CTLA-4抗体、抗PD-1抗体、抗PDL-1抗体、抗OX40(亦称作CD134、TNFRSF4、ACT35及/或TXGP1L)抗体、抗CD137抗体或抗LAG-3抗体。
另一方面,本发明提供本发明GITR结合分子(抗体)在诊断和/或检测中的用途(简称本发明的用途,或本发明的诊断和/或检测用途)及其中使用的组合物。本文中提供的任何抗GITR抗体均可以用于检测(定量或定性检测)生物样品中GITR的存在。例如通过免疫组织化学、免疫细胞化学、流式细胞术(例如,FACS)、抗体分子复合的磁珠、ELISA测定法、PCR-技术(例如,RT-PCR)等检测生物样品中GITR的存在。在一些实施方案中,生物样品包括体液、细胞或组织。在某些实施方案中,生物样品是血、血清或生物来源的其他液体样品。
在一个实施方案中,提供了抗GITR抗体用于诊断或检测方法。在进一步的方面中,提供了检测生物样品中GITR存在的方法。在一些实施方案中,该方法包括将生物样品在允许抗GITR抗体与GITR结合的条件下接触本文中所述的抗GITR抗体,并且检测抗GITR抗体和GITR之间是否形成了复合物。这样的方法可以是体外或体内方法。
在一个实施方案中,将抗GITR抗体用于选择适宜使用抗GITR抗体治疗的受试者,例如,当GITR是用于患者选择的生物标志物时。可以使用本发明的抗体诊断的示例性病症包括免疫障碍或再生性障碍。在一些实施方案中,提供了用本发明的抗体对免疫障碍或再生性障碍患者进行分层的方法。在一些实施方案中,抗GITR抗体是与诊断剂或可检测剂缀合的前述本发明任何免疫缀合物。在一些实施方案中,本发明提供用于诊断或检测的试剂盒,其包含本发明的GITR结合分子,例如本发明的任何抗GITR抗体。
在一个实施方案中,本发明提供一种检测样品中GITR的存在的方法,包括:
(a)将所述样品与本发明的分离的抗体或其抗原结合片段、本发明的融合蛋白或本发明的免疫缀合物接触;和
(b)检测所述抗体或其抗原结合片段、或融合蛋白或免疫缀合物和GITR蛋白之间复合物的形成。
另一方面,本发明提供本发明抗体的筛选、鉴定和表征方法。可以通过本领域已知的各种试验,针对其物理/化学特性和/或生物活性,筛选、鉴定、或表征本文中提供的抗GITR抗体。
可以从噬菌体/噬菌粒展示纳米抗体文库中选择与所关注的目标抗原以高亲合力结合的噬菌体/噬菌粒。已有多种在噬菌体/噬菌粒表面呈递或展示抗体或抗体片段以及筛选文库的方法。
对于抗体的鉴定,可以就其抗原结合活性,例如通过已知方法,如ELISA、αLISA、蛋白质印迹、抗体或反相阵列等、以及实施例中所述的方法,鉴定或表征本发明的抗体。
例如,可以采用ForteBio测定法检测抗体。ForteBio亲和力测定可以按照现有的方法(Estep,P等,High throughput solution Based measurement of antibody-antigenaffinity and epitope binning.MAbs,2013.5(2):第270-8页)进行。例如,可以将AHQ传感器在分析缓冲液中线下平衡30分钟,然后线上检测60秒建立基线。之后,将在线加载了经纯化的抗体的AHQ传感器,暴露于100nM抗原作用5分钟,将传感器转移至分析缓冲液进行5分钟的线下测量。使用1:1结合模型进行动力学分析。
另一方面,本发明提供一种治疗癌性病症、诱导或增强个体中的免疫应答,和/或刺激抗原特异性T细胞应答的方法,其特征在于包括向所述个体施用有效量的本发明的分离的抗体或其抗原结合片段、本发明的融合蛋白或本发明的免疫缀合物。
在一些实施方案中,免疫应答针对肿瘤抗原产生或针对感染性因子产生。
在一些实施方案中,本发明的上述方法可以治疗或预防“免疫病症”,例如包括病理性炎症、炎性病症和自身免疫性病症或疾病,也包括感染、持续感染和增生性病症,例如癌症、肿瘤和血管发生,包括抗免疫系统根除的感染、肿瘤和癌症。
在一些实施方案中,本发明的上述方法可以治疗或预防“免疫障碍”,其中免疫障碍指哺乳动物中由哺乳动物免疫系统成分引起、介导、或以其他方式促成发病的疾病;或刺激或干预免疫应答对疾病发展具有改善作用的疾病。“免疫障碍”包括自身免疫病、免疫介导的炎性疾病、非免疫介导的炎性疾病、传染病和免疫缺陷病。
可使用本发明抗体治疗的这些免疫相关疾病和炎性疾病的实例(其中有些是免疫或T细胞介导的)包括:系统性红斑狼疮、类风湿性关节炎、幼年型慢性关节炎、脊椎关节病、系统性硬化病(硬皮病)、特发性炎性肌病(皮肌炎、多肌炎)、干燥综合征、系统性血管炎、结节病、自身免疫性溶血性贫血(免疫性全血细胞减少症、阵发性夜间血红蛋白尿)、自身免疫性血小板减少症(特发性血小板减少性紫癜、免疫介导的血小板减少症)、甲状腺炎(格雷夫斯氏病、桥本甲状腺炎、幼年型淋巴细胞性甲状腺炎、萎缩性甲状腺炎)、糖尿病、免疫介导的肾病(肾小球肾炎、肾小管间质性肾炎)、中枢和周围神经系统的脱髓鞘病诸如多发性硬化病、特发性脱髓鞘多神经病或格-巴二氏(Guillain-Barre)综合征、和慢性炎性脱髓鞘多神经病、肝胆病诸如传染性肝炎(甲型、乙型、丙型、丁型、戊型和其他非嗜肝病毒肝炎)、自身免疫性慢性活动性肝炎、原发性胆汁性肝硬化、肉芽肿性肝炎、和硬化性胆管炎、炎性和纤维化肺病诸如炎性肠病(溃疡性结肠炎:克罗恩病)、麸胶敏感性肠病、和惠普尔氏(Whipple)病、自身免疫性或免疫介导的皮肤病包括大疱性皮肤病、多形红斑和接触性皮炎、银屑病、变应性疾病诸如哮喘、变应性鼻炎、特应性皮炎、食物超敏反应和荨麻疹、肺的免疫学疾病诸如嗜曙红细胞性肺炎、特发性肺纤维化和超敏感性肺炎、移植相关疾病包括移植物排斥和移植物抗宿主疾病。传染病包括AIDS(HIV感染)、甲型、乙型、丙型、丁型和戊型肝炎、细菌感染、真菌感染、原生动物感染和寄生虫感染。
在一些实施方案中,本发明的上述方法可以治疗或预防“癌性病症”,包括例如癌症、癌细胞、肿瘤、血管发生和癌变前病症,例如发育异常。
在一些实施方案中,癌症是转移性癌症、难治性癌症或复发性癌症,更优选是实体癌或血液癌;最优选是黑色素瘤、肺癌、头颈癌、结肠直肠癌、非小细胞肺癌、头颈部的鳞状细胞癌、膀胱癌、乳腺癌、子宫/子宫颈癌、卵巢癌、前列腺癌、睾丸癌、食道癌、胃肠癌、胰腺癌、结肠癌、肾癌、胃癌、生殖细胞癌、骨癌、肝癌、甲状腺癌、皮肤癌、中枢神经系统的新生物、淋巴瘤、白血病、骨髓瘤、肉瘤或病毒相关癌症。
在一些实施方案中,本发明抗体的有效量是在个体中实现以下一项或多项的量:a)减轻效应T细胞活性的调节性T细胞抑制;b)降低循环调节性T细胞的水平;c)活化效应T细胞;d)诱导或增强效应T细胞增殖;e)抑制肿瘤生长;f)诱导肿瘤消退;以及g)增加表达GITR的T细胞中的IL-2及/或IFN-γ产生、增加T细胞增殖。
在一些实施方案中,本发明的上述方法进一步包括以:a)施用化疗;b)施用放射疗法;和/或c)施用一种或多种另外的治疗剂,优选是免疫刺激剂。
在一些实施方案中,本发明的上述方法中的免疫刺激剂选自T-VEC、PD1拮抗剂、PDL1拮抗剂、CTLA-4拮抗剂及BiTE。
在一些实施方案中,本发明的上述方法中的化疗、放射疗法或治疗剂是在所述抗体或其抗原结合片段之前、同时或之后施用。
描述以下实施例以辅助对本发明的理解。不意在且不应当以任何方式将实施例解释成限制本发明的保护范围。
实施例
实施例1.抗GITR纳米抗体的筛选
1.骆驼免疫
将1mg抗原GITR-His(Acro biosystems)与弗氏佐剂(Sigma)等体积混合后平分于两个管子中,免疫两只新疆双峰驼。如此每周免疫一次,共免疫7次,刺激B淋巴细胞表达抗原特异性的纳米抗体。免疫七次之后,新疆双峰驼中产生的GITR-His纳米抗体的血清滴度可达到1:1000以上,由此确定骆驼中产生期望的纳米抗体。
2.噬菌体展示纳米抗体文库的构建
(1)7次免疫结束后,提取100ml骆驼血液,分离外周血淋巴细胞,提取总RNA;
(2)利用RT-PCR将步骤(1)中得到的总RNA反转录为cDNA,然后利用巢式PCR(两次PCR)扩增得到VHH,其扩增原理如图1所示;
(3)按照制造商的使用说明书,利用限制性内切酶PstI(NEB)及NotI(NEB)酶切20μg噬菌体展示载体及10μg VHH片段,然后利用T4连接酶(NEB)连接双酶切得到的两个片段;
(4)将连接产物电转化至感受态大肠杆菌细胞TG1中,构建纳米抗体文库。
3.抗GITR纳米抗体的筛选
(1)将溶解在100mM NaHCO3(pH8.2)中的抗原蛋白GITR-His(Acro biosystems)偶联在酶标板(Nunc)上,4℃放置过夜;
(2)第二天加入100μl封闭液(5%BSA(Jackson)),室温封闭2小时;
(3)2小时后,加入100μl噬菌体(5×1011PFU(plaque forming unit,噬菌体形成单位)上述构建的噬菌体展示纳米抗体文库),室温下作用1小时;
(4)用PBST(PBS+0.05%Tween-20(Bio Basic Inc.,BBI))洗涤5次,以洗掉非结合的噬菌体;
(5)用100mM TEA(Sigma)洗脱液将与抗原蛋白GITR-His特异性结合的噬菌体解离下来,之后感染处于对数期生长的大肠杆菌TG1细胞。37℃培养1小时,扩大培养噬菌体用于下一轮的筛选;
(6)步骤(1)至(5)的筛选过程重复3轮,得到富集的与抗原蛋白GITR-His特异性结合的噬菌体。
4.PE-ELISA鉴定阳性克隆
(1)从含有上述3轮筛选后得到的噬菌体的细胞培养皿中,随机挑选1000个单菌落并接种于含有氨苄青霉属(Amresco)的TB培养基(2%胰蛋白胨、2.4%酵母提取物、72mMK2HPO4、17mM KH2PO4、0.4%甘油)中。菌落生长至对数期后,加入IPTG(Sigma)至终浓度为1mM,28℃培养过夜;
(2)利用常规渗透冲击法获得粗提抗体,并将粗提抗体转移到已过夜包被抗原GITR-His的酶标板(Nunc)中,在室温下孵育1小时;
(3)用PBST洗去未结合的抗体,加入小鼠抗-HA tag抗体(SinoBiological),在室温下放置1小时;
(4)用PBST洗去未结合的抗体,加入山羊抗小鼠碱性磷酸酶标记抗体(Millipore),在室温下放置1小时;
(5)用PBST洗去未结合的抗体,加入碱性磷酸酶显色液(新赛美M30100),于ELISA仪(Thermo(MULTISCAN FC))上,在405nm波长读取吸收值;当样品孔OD值大于对照孔OD值(Ratio:+/-)3倍以上时,判为阳性克隆孔;
(6)PE-ELISA(Post-Enrichment Enzyme-linked Immunosorbent Assay,富集后)结果共出现486颗阳性克隆,其比值(Ratio:+/-)在3-30之间,随后,将所有阳性克隆转至LB培养基中培养过夜,提取质粒并进行测序。
5.测序结果分析
根据序列比对软件Vector NTI分析各个克隆株的基因序列,将CDR1、CDR2、CDR3序列相同的株视为同一克隆株,而其序列不同的株视为不同克隆株。最终获得22株序列不同的纳米抗体,其ELISA结果如表1所示。
表1.纳米抗体Nb-01至Nb-22的ELISA结果
抗体编号 | 氨基酸SEQ ID NO | 样品OD值(+) | 对照OD值(-) | 比率(+/-) |
Nb-01 | 64 | 0.467 | 0.075 | 6.227 |
Nb-02 | 65 | 1.425 | 0.069 | 20.652 |
Nb-03 | 66 | 0.786 | 0.067 | 11.728 |
Nb-04 | 67 | 1.628 | 0.074 | 22.000 |
Nb-05 | 68 | 1.412 | 0.066 | 21.518 |
Nb-06 | 69 | 0.314 | 0.095 | 3.305 |
Nb-07 | 70 | 2.346 | 0.072 | 32.583 |
Nb-08 | 71 | 1.705 | 0.074 | 23.041 |
Nb-09 | 72 | 1.449 | 0.063 | 23.107 |
Nb-10 | 73 | 2.269 | 0.076 | 29.855 |
Nb-11 | 74 | 0.552 | 0.071 | 7.775 |
Nb-12 | 75 | 0.444 | 0.098 | 4.531 |
Nb-13 | 76 | 0.263 | 0.080 | 3.288 |
Nb-14 | 77 | 0.460 | 0.115 | 4.000 |
Nb-15 | 78 | 1.254 | 0.249 | 5.036 |
Nb-16 | 79 | 1.674 | 0.081 | 20.667 |
Nb-17 | 80 | 1.037 | 0.069 | 15.112 |
Nb-18 | 81 | 1.010 | 0.103 | 9.800 |
Nb-19 | 82 | 1.324 | 0.072 | 18.469 |
Nb-20 | 83 | 1.414 | 0.116 | 12.212 |
Nb-21 | 84 | 0.522 | 0.069 | 7.548 |
Nb-22 | 85 | 0.606 | 0.060 | 10.031 |
实施例2.重链抗体的构建及表达、纯化
1.构建重链抗体(hcIgG):
(1)PCR扩增纳米抗体Nb-02、Nb-03、Nb-04、Nb-07、Nb-09、Nb-10、Nb-16、Nb-20的cDNA。
(2)胶回收获得各条PCR片段,通过同源重组的方法(Vazyme,C112-01/02)构建入HEK293表达载体pTT5(Biotechnology Research Institute;Montreal,Canada)中,其中已包含DNA序列如下的IgG1Fc片段:
GACAAAACCCACACCTGTCCCCCTTGTCCTGCTCCCGAGCTCCTGGGAGGACCTTCCGTGTTCCTCTTCCCTCCCAAACCCAAGGACACCCTGATGATTAGCAGGACACCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCATGAGGACCCCGAGGTGAAGTTTAACTGGTACGTGGACGGCGTCGAGGTGCACAACGCTAAGACCAAACCCAGGGAGGAGCAGTACAACTCCACATACCGGGTCGTGAGCGTGCTGACCGTCCTGCACCAGGATTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTGAGCAACAAGGCCCTGCCCGCCCCCATCGAGAAGACCATCAGCAAGGCCAAAGGACAGCCTCGGGAGCCCCAGGTTTATACTCTCCCCCCCAGCCGGGACGAACTGACCAAGAATCAGGTGTCCCTCACCTGCCTCGTGAAGGGCTTTTACCCCAGCGACATTGCCGTGGAGTGGGAGAGCAATGGACAGCCCGAAAACAACTACAAGACCACACCCCCCGTCCTGGACTCCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGGTGGCAGCAGGGCAACGTGTTTAGCTGCAGCGTCATGCACGAGGCTCTCCACAACCACTACACCCAGAAGTCCCTGAGCCTGAGCCCCGGAAAGTGA(SEQ IDNO:126)。
(3)通过测序(金唯智公司)验证载体构建的正确性。
2.hcIgG蛋白的表达
(1)根据所需转染体积传代HEK293细胞(Invitrogen),转染前一天将细胞密度调整至1×106/ml。转染当天细胞密度约为2×106/ml;
(2)取终体积1/10的F17(Gibco,A13835-01)培养基作为转染缓冲液,每毫升转染缓冲液加入10ug构建的HEK293表达载体pTT5,混匀;
(3)每毫升转染缓冲液加入30ug PEI(聚乙烯亚胺,Polysciences,23966)到质粒中,混匀后室温孵育10分钟。将混合物轻柔倒入HEK293细胞,36.5℃,8%CO2培养;
(4)过夜后各补加转染体积1/50的200g/L的FEED(Sigma,H6784-100G)和200g/L的葡萄糖母溶液,20小时后加VPA(丙戊酸Gibco,11140-050)至2mM/L;
(5)连续培养至第7天时,离心收集细胞上清用以纯化。
3.hcIgG蛋白纯化
通过HiTrapTM MabSelect SuReTM 5ml(GE Healthcare)纯化目的hcIgG蛋白。具体过程如下:
(1)用0.1M NaOH将AKTA蛋白纯化系统除去内毒(过夜)。收样当天将上述细胞上清7500转/分钟离心30分钟,使用SARTOPORE(Sartorius,5441307H4)过滤。纯化前用5倍柱体积的结合缓冲液(Tris 20mM,NaCl 150mM,pH 7.2)清洗系统以及平衡柱子。将上述离心后得到的细胞上清通过柱子。用5~10倍柱体积结合缓冲液再平衡,至基线平衡。用洗脱缓冲液(柠檬酸+柠檬酸钠100mM,pH 3.5)洗脱抗体,根据紫外吸收值来收集样品。每1ml的收集液加80μl的中和缓冲液(Tris-HCl 2M)中和备用。
(2)纯化后的蛋白利用SECC-HPLC(分子排阻高效液相色谱法)检测纯度,结果如图2所示,所有hcIgG经一步亲和纯化后纯度均>97%。
得到重链抗体hcIgG-02、hcIgG-03、hcIgG-04、hcIgG-07、hcIgG-09、hcIgG-10、hcIgG-16和hcIgG-20,其具体序列示于表B中。
实施例3.重链抗体的性质鉴定
1.FortiBio KD测定
本实验使用Fortebio方法(Estep,P等,High throughput solution Basedmeasurement of antibody-antigen affinity and epitope binning.MAbs,2013.5(2):第270-278页)测定抗原-抗体结合动力学及亲和力,GITR Inc.的抗GITR抗体作为阳性对照(在本申请中称为TRX518,根据US20130183321A1提供的序列进行克隆,轻链和重链的序列分别为US20130183321A1中的SEQ ID NO:44,和SEQ ID NO:54,瞬时转染HEK293细胞进行表达获得)。具体测定方法如下:
(1)准备传感器:实验开始前半个小时,将AHQ传感器(Pall,1506091)浸泡于SD缓冲液(PBS 1×,BSA 0.1%,Tween-20 0.05%)中;
(2)实验过程:取100μl的SD buffer、抗体(hcIgG-02、hcIgG-03、hcIgG-04、hcIgG-07、hcIgG-09、hcIgG-10、hcIgG-16和hcIgG-20,对照抗体)、GITR-His(Acro biosystems)分别加入到96孔黑色聚苯乙烯半量微孔板中。根据样品位置布板,选择传感器位置,设置运行步骤及时间:Baseline、Loading~1nm、Baseline、Association和Dissociation时间取决于样品结合、解离速度,转速为400转/分钟,温度为30℃。
(3)使用1:1结合模型进行动力学分析,发现本发明抗体(hcIgG-02、hcIgG-03、hcIgG-04、hcIgG-07、hcIgG-09、hcIgG-10、hcIgG-16和hcIgG-20)均具有比对照抗体TRX518更高的亲和力,结果如表2所示。
表2.hcIgG亲和力测定结果
2.检测hcIgG和细胞表面的抗原结合情况
(1)细胞准备:将携带克隆至多克隆位点MCS的人GITR cDNA的pCHO1.0载体(Invitrogen)转染至中国仓鼠卵巢癌细胞(CHO)(Invitrogen),产生过量表达人GITR的CHO细胞(CHO-GITR),将由此构建的表面过表达人GITR的CHO细胞(CHO-GITR)计数,并稀释至1×106个细胞/ml,向U型底96孔板中加入100μl/孔;
(1)检测步骤:400g离心5分钟,去除细胞培养基。将梯度稀释的样品加入U型板并重悬细胞,每孔加100μl,冰上静置30分钟。400g 5分钟去除上清,PBS洗细胞1遍。400g离心5分钟,去除PBS,每孔加入100μl 1:200稀释的PE-抗人Fc抗体(Jackson Immuno Research)。冰上避光孵育30分钟。400g离心5分钟去除上清,PBS洗细胞1遍。用100μl PBS重悬细胞。
(3)FACS检测。检测结果如图3所示,所有测定的hcIgG(hcIgG-02、hcIgG-03、hcIgG-04、hcIgG-07、hcIgG-09、hcIgG-10、hcIgG-16和hcIgG-20)均可以和细胞表面表达的抗原相结合。
3.差示扫描荧光检测抗体Tm
差示扫描荧光法(DSF)可根据图谱中的荧光变化过程提供有关结构稳定性的信息,检测蛋白的构型变化。荧光曲线绝对值最大时对应的温度为该蛋白的Tm。本研究利用DSF法,测定了抗GITR hcIgG的Tm值,用PBS稀释抗体(hcIgG-02、hcIgG-03、hcIgG-04、hcIgG-07、hcIgG-09、hcIgG-10、hcIgG-16和hcIgG-20)样品至1mg/ml。用PBS将SYPROOrange protein gel stain(GIBCO)稀释50倍,即4μl SYPRO Orange protein gel stain母液加196μl PBS。在96孔PCR板中加样,50μl稀释后抗体样品+10μl SYPRO Orangeprotein gel stain稀释液+40μl水。置于7500real time PCR system进行检测,结果如表3所示。
表3.hcIgG Tm值测定结果
检测hcIgG介导的ADCC作用
本实验利用Promega公司的ADCC Report Bioassay试剂盒对hcIgG介导的抗体依赖的(细胞介导的)细胞毒性作用(ADCC)作用进行了检测。所用的效应细胞为稳定转染NFAT-Luciferase报告基因的Jurkat细胞,靶细胞为过表达GITR的CHO细胞(CHO-GITR)。具体实验过程如下:
用ADCC Assay Buffer将靶细胞稀释至2.5×105个/ml,每孔加入50μl靶细胞;
加入25μl梯度稀释的抗体hcIgG-02、hcIgG-03、hcIgG-04、hcIgG-07、hcIgG-09、hcIgG-10、hcIgG-16和hcIgG-20(每种抗体的终浓度为3.33μg/ml、1.11μg/ml、0.37μg/ml、0.12μg/ml、0.041μg/ml、0.013μg/ml、0.0046μg/ml、0.0015μg/ml);
用ADCC Assay Buffer将效应细胞稀释至1.5×106个/ml,每孔加入25μl;
37℃反应6小时;之后每孔加入等体积的室温Bio-Glo Luciferase Reagent(Promega),室温孵育10分钟。
GloMax Multi+Plate Reader读数。结果如图4所示。从图中曲线趋势可以看出,本发明的hcIgG(hcIgG-02、hcIgG-03、hcIgG-04、hcIgG-07、hcIgG-09、hcIgG-10、hcIgG-16和hcIgG-20)均能够引起ADCC作用。
实施例4.抗GITR的重链抗体的人源化
1.hcIgG人源化改造
选择hcIgG-07和hcIgG-20进行人源化改造,人源化过程按照已有方法(Ce′cileVincke等,General Strategy to Humanize a Camelid Single-domain Antibody andIdentification of a Universal Humanized Nanobody Scaffold.JOURNAL OFBIOLOGICAL CHEMISTRY,2009.5(284):第3273-3284页)进行,得到人源化抗体HzhcIgG-07和HzhcIgG-20(具体序列参见表B)。
2.FortiBio KD测定
本实验使用Fortebio方法测定人源化之前的抗体hcIgG-20和人源化之后的抗体HzhcIgG-20的结合动力学及亲和力,方法同实施例3。ForteBio结果如表4。hcIgG-20和HzhcIgG-20维持了和GITR的结合能力,且亲和力高于对照抗体TRX518。
表4.hcIgG-20和HzhcIgG亲和力测定结果
3.检测hcIgG和细胞表面的抗原结合情况
检测方法同实施例4。流式细胞仪检测细胞结合结果如图5。hcIgG-20和HzhcIgG-20均保持了细胞结合活性(EC50从1.631nM到1.873nM)。
4.检测hcIgG对GITR介导的信号通路的激活作用
野生型Hela细胞通过工程改造后,表面过表达GITR蛋白。同时将表达NFkB结合位点和荧光报告素酶(Luciferase)表达基因的质粒转入Hela-GITR细胞中获得稳定的、同时表达GITR及NFkB荧光报告素酶基因的检测用细胞株Hela-GITR-NFkB-Luc-Rep。本实验利用该细胞检测了hcIgG-20和HzhcIgG-20对GITR下游的NFkB信号通路的激活作用。具体实验过程如下:
将表面过表达Hela-GITR-NFkB-Luc-Rep细胞调节细胞密度至1×106个/ml,第一孔加入150μl细胞悬液,其他孔100μl,第一孔加入抗体,终浓度500nM,吸取50μl细胞悬液入下一孔,混匀,以此类推(抗体稀释终浓度为500nM、166.67nM、55.56nM、18.52nM、6.17nM、2.06nM、0.69nM、0.23nM、0.08nM、0.025nM),置于二氧化碳培养箱,过夜孵育。
室温放置10分钟后,每孔加入80μl的室温Bio-Glo Luciferase Reagent(Promega),室温孵育5分钟。
GloMax Multi+Plate Reader读数。流式细胞仪检测细胞结合结果如图6。HzhcIgG-20对NFkB信号通路有激活作用,hcIgG-20、HzhcIgG-20及对照抗体TRX518的激活EC50分别为0.6894nM、0.6632nM和2.097nM,hcIgG-20、HzhcIgG-20均具有比对照抗体更优的NFkB通路激活能力。
实施例5.抗GITR 4xNb-IgG的构建及活性检测
1.构建4xNb-IgG分子
天然存在的单克隆抗体可以作为多聚体结构如IgM存在,其增加对固定表面上的其靶抗原的亲合性。因为TNFR的激动作用需要受体聚集,所以四价或六价单克隆抗体可以提供增加的聚集和受体激动作用。本发明的多聚物形式的抗体包含四个相同的纳米抗体区域,其具体构建方法如下:
4xNb-IgG-I:HzhcIgG-20的VHH部分(即HzhcIgG-20中的重链可变区VH)通过GGGGS的柔性连接肽连接到HzhcIgG-20的C末端(如图7A);
4xNb-IgG-II:HzhcIgG-20的VHH部分通过GGGGS的柔性连接肽连接到HzhcIgG-20的N末端(如图7B);
4xNb-IgG-III:HzhcIgG-20的VHH部分直接连接到HzhcIgG-20的N末端(如图7C)。
其中4xNb-IgG-I、4xNb-IgG-II和4xNb-IgG-III的具体序列参见表B。
将构建体通过常规方法克隆到HEK293细胞的表达载体pTT5.1的XhoI/NotI多克隆位点中。将构建好的质粒转染HEK293细胞,筛选表达和分泌的4xNb-IgG分子,并选择正确的分子用于进一步的实验。
2.4xNb-IgG蛋白的表达及纯化
4xNb-IgG的表达及纯化方法同实施例2。纯化后的蛋白利用SEC检测纯度,结果如图8所示,4xNb-IgG-I、4xNb-IgG-II和4xNb-IgG-III经一步亲和纯化后纯度分别为97.5%、96.86%和97.21%。
3.FortiBio KD测定
本实验使用Fortebio方法测定抗原-抗体结合动力学及亲和力,方法同实施例4。ForteBio结果如表5所示。
表5.4xNb-IgG的亲和力检测
4.检测4xNb-IgG对GITR介导的信号通路的激活作用
检测方法和实施例4基本类似,但是进行了优化,将抗体浓度降低,增加检测的灵敏度。
实验过程如下:
将表面过表达Hela-GITR-NFkB-Luc-Rep细胞调节细胞密度至5×105个/ml,第一孔加入200μl细胞悬液,其他孔100μl,第一孔加入抗体,终浓度10nM,吸取100μl细胞悬液入下一孔,以此类推(抗体稀释终浓度为10nM、5.00nM、2.50nM、1.25nM、0.63nM、0.31nM、0.16nM、0.08nM、0.04nM、0.02nM、0.01nM),置于二氧化碳培养箱,孵育7h。
室温放置10分钟,每孔加入80μl的室温Bio-Glo Luciferase Reagent(Promega),室温孵育5分钟。
GloMax Multi+Plate Reader读数。结果如图9所示,4xNb-IgG-I、4xNb-IgG-II和4xNb-IgG-III均显示出比阳性对照更强的激活活性。
5.本发明抗GITR抗体的抗肿瘤活性
利用MC38移植瘤小鼠模型研究了抗人GITR抗体4xNb-IgG-III单独使用,或与抗鼠PD-1抗体“Antibody C”(WO2017/133540)联合使用的抗肿瘤活性。
小鼠:雄性人GITR转基因小鼠(约8周大)购自百奥赛图基因生物技术有限公司。小鼠在到达后驯化7天,随后开始研究。
细胞:小鼠结肠癌细胞MC38(ATCC)购自ATCC,并严格按照ATCC要求进行常规传代培养用于后续体内实验。离心收集细胞,在无菌PBS中重悬细胞并调整细胞密度为5×106个/ml。在第0天取0.2ml细胞悬液皮下接种至人GITR转基因小鼠右侧腹部区域中来建立荷瘤小鼠模型。
给药:将小鼠分为四组(每组8只小鼠),每组皮下注射如下剂量的抗体:
(1)小鼠IgG对照(equitech-Bio),10mg/kg;
(2)PD-1(Antibody C),1mg/kg;
(3)4xNb-IgG-III,10mg/kg;
(4)4xNb-IgG-III,10mg/kg PBS+PD-1(Antibody C),1mg/kg。
试剂注射:接种后第8天,将符合实验要求的小鼠随机分组,每组6只。分别用如上四组试剂在第8天、第11天、第14天和第17天为每组小鼠按如上剂量给药。
分析:在整个研究期间每周测量两次肿瘤和体重,当肿瘤达到端点时或当小鼠具有>20%体重减轻时,使小鼠安乐死。采用游标卡尺测定肿瘤的最大长轴(L)和最大宽轴(W),肿瘤体积按如下公式计算:V=L×W2/2。将来自每组的小鼠的肿瘤尺寸与时间作图。使用方差分析(ANOVA)来确定统计显著性。P<0.05的值被视为在所有分析中具有统计显著性。
实验结果见图10,可见:
-本发明的抗GITR抗体4xNb-IgG-III与IgG对照(equitech-Bio)相比,能显著抑制肿瘤的生长;
-本发明的抗GITR抗体4xNb-IgG-III和抗PD-1单克隆抗体“Antibody C”联合使用与IgG及这两个抗体分别使用相比,能显著抑制肿瘤的生长。
SEQUENCE LISTING
<110> 信达生物制药(苏州)有限公司
<120> 抗糖皮质激素诱导的肿瘤坏死因子受体(GITR)的小型化抗体、其聚合物及应
用
<130> PF180017CNI
<140> 201810255332.2
<141> 2018-03-26
<160> 127
<170> PatentIn version 3.3
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<400> 69
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ala Tyr Thr Arg Asn
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Glu Val
35 40 45
Ala Thr Ile Asn Leu Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ala Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Ile Ala Gln Tyr Gly Gly Ser Leu Cys Ser Asn Phe Gly Trp
100 105 110
Tyr Asn Leu Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 70
<211> 116
<212> PRT
<213> 人工序列
<400> 70
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Thr Val Ser Gly Phe Ala Phe Gly Ser Ser
20 25 30
His Met Ser Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile His Ser Gly Gly Gly Phe Gly Asp Tyr Ala Asn Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Val Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Leu Ala Thr Asp Trp Arg Lys Pro Pro Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 71
<211> 125
<212> PRT
<213> 人工序列
<400> 71
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Ser Ser Arg Lys
20 25 30
Tyr Ile Gly Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val
35 40 45
Ala Gly Ile Asp Thr Gly Ala Gly Gly Thr Cys Thr Ile Ala Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Gln Asp Val Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Ile Asp Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Trp Val Arg Gly Gly Phe Cys Ser Gly Asp Ala Asp Phe
100 105 110
Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 72
<211> 122
<212> PRT
<213> 人工序列
<400> 72
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Gly Ala Ser Gly Phe Thr Phe Ser Ser Thr
20 25 30
Ala Met Trp Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Thr Ser Asp Val Ser Gly Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Gly Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Thr Ser Cys Gly Phe Ser Gly Gly Thr Trp Ser Cys Lys Tyr Arg
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 73
<211> 116
<212> PRT
<213> 人工序列
<400> 73
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Gly Ser Ser
20 25 30
His Met Ser Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile His Ser Gly Gly Gly Phe Gly Asp Tyr Ala Asn Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Val Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Leu Ala Thr Asp Trp Arg Lys Pro Pro Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 74
<211> 125
<212> PRT
<213> 人工序列
<400> 74
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Ala Ala
20 25 30
Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Asn Glu Cys Glu Leu Val
35 40 45
Ser Ile Ile Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ala Pro Arg Val Gly Val Gly Trp Val Arg Pro Cys Asp Tyr Glu Tyr
100 105 110
Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 75
<211> 125
<212> PRT
<213> 人工序列
<400> 75
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Asp Thr Tyr Thr Arg Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Thr Pro Gly Lys Glu Pro Glu Gly Val
35 40 45
Ala Val Leu Leu Pro Gly Gly Ala Tyr Thr Phe Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Thr Gln Asp Ser Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Asp Val Thr Val Gly Ser Arg Trp Ser Gln Ala Ser Asn Tyr
100 105 110
Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 76
<211> 121
<212> PRT
<213> 人工序列
<400> 76
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Ser Asn Thr Gly Arg Met Gly
20 25 30
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Thr Ala Val
35 40 45
Asp Asn Phe Gly Arg Thr Asn Tyr Ala Lys Tyr Val Lys Gly Arg Phe
50 55 60
Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn
65 70 75 80
Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Asp Pro
85 90 95
Trp Gly Arg Gly Ala Ala Leu Thr Pro Asn Glu Tyr Ile Tyr Trp Gly
100 105 110
Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 77
<211> 124
<212> PRT
<213> 人工序列
<400> 77
Gln Val Gln Leu Gln Glu Phe Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Cys Met Gly Trp Phe Arg Gln Asp Pro Gly Lys Glu Arg Glu Ala Val
35 40 45
Ala Arg Ile Phe Val Asp Gly Ser Thr Arg Tyr Ala Asp Ala Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Val
65 70 75 80
Gln Ile Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Thr
85 90 95
Thr Pro Phe Pro Trp Thr Leu Cys Val Asp Gly Pro Gly Ala Tyr Lys
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 78
<211> 129
<212> PRT
<213> 人工序列
<400> 78
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Val Phe Gly Asn Ile Phe Arg Asn Tyr
20 25 30
Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Val Val Ile Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys His Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Asp Gln Thr Thr Arg Tyr Ser Ser Asp Tyr Val Asn Val Gly
100 105 110
Pro Cys Asp Met Asp Ser Trp Gly Lys Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 79
<211> 128
<212> PRT
<213> 人工序列
<400> 79
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Asn Lys Tyr
20 25 30
Ser Trp Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Gly Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Ala Ser Asp Trp Val Ser Ala Ile Gln Ala Leu Gly Val Leu Ala Val
100 105 110
Arg Pro Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 80
<211> 125
<212> PRT
<213> 人工序列
<400> 80
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Ala Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Tyr Thr Ser Ser Ser Asn
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val
35 40 45
Ala Gly Ser Asp Thr Gly Ala Gly Ile Thr Cys Asn Ala Ala Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Asp Val Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Asp Trp Phe Arg Gly Ala Phe Cys Ser Gly Asp Ala Asp Phe
100 105 110
Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 81
<211> 125
<212> PRT
<213> 人工序列
<400> 81
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Ser Thr Thr Lys
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Gly Ile Tyr Ile Ser Ser Gly Ala Thr Tyr Tyr Asp Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu His Ile Asn Ser Leu Glu Pro Asp Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Ser Val Leu Ser Val Phe Arg Pro Leu Ser Ser Asn Gln Tyr
100 105 110
His Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 82
<211> 126
<212> PRT
<213> 人工序列
<400> 82
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr Ser Asn Tyr
20 25 30
Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Ala Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Ala Gly Asn Lys Lys Pro Tyr Gln Leu Cys Asn Thr Asp Ser Arg Arg
100 105 110
Tyr Tyr His Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 83
<211> 124
<212> PRT
<213> 人工序列
<400> 83
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Tyr Ser Arg Thr Ser Arg
20 25 30
Trp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Ala Ile Tyr Thr Gly Gly Ser Ser Thr Leu Tyr Ala Asn Ser Met
50 55 60
Ala Asp Arg Val Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Arg Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Asp Lys Leu Ala Gly Asp Phe Trp Leu Val Asp Arg Trp Arg
100 105 110
Ala Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 84
<211> 129
<212> PRT
<213> 人工序列
<400> 84
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Arg Thr Ser Gly Tyr Thr Asn Asn Leu Lys
20 25 30
Ser Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val
35 40 45
Ala Ser Ile His Asn Asn Gly Gly Pro Thr Tyr Asp Tyr Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Ala Ile Ser Gln Asp Asn Ala Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Ser Ser Ala Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ala Asp Asn Arg Phe Leu Gly Ser Gly Ser Trp Arg Leu
100 105 110
Pro Ser Leu Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
115 120 125
Ser
<210> 85
<211> 128
<212> PRT
<213> 人工序列
<400> 85
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Thr Ala
20 25 30
Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Ala Ile Asp Ser Asp Gly Arg Thr Glu Tyr Ala Asp Ala Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Ala Asp Lys Asp Asp Trp Leu Leu Leu His Gly Arg Ser Leu Phe Pro
100 105 110
Ser Ala Phe Ala Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
<210> 86
<211> 393
<212> DNA
<213> 人工序列
<400> 86
caggtgcagc tgcaggagtc tggaggaggc ttggtgcagc cgggggggtc tctgagactc 60
tcctgtacag cctctggatt gacttttgat gattatgcca tgggctggtt ccgccaggct 120
ccagggaagg ggcgcgaggg tgtctcactt attacctgga gtggtagtag cacatactat 180
gcggactccg tgaagggccg attcaccgtc tccagagaca ccgccacgaa tacgctggtt 240
ctacaaatga acagcctgaa accagaggat acggccatgt attactgtgc ggcagatcca 300
cgtagtggtg gttactactc cagcccccct ccccccgctg tgtacaggta tctccgattt 360
tggggccagg gcacccaggt caccgtctcc tca 393
<210> 87
<211> 375
<212> DNA
<213> 人工序列
<400> 87
caggtgcagc tgcaggagtc tggaggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgcag cctctagaga cacctacacg cgctacttta tgggctggtt ccgccagact 120
ccagggaagg agggcgaggg ggtcgcagtc cttctacctg gcggtgatta tacattctat 180
gccgactccg tgaagggccg gttcaccatc acccaagaca gcgccaagaa cacggtgtat 240
ctgcaaatga acagcctgaa acctgaggac actgccatgt actactgtgc ggcagatgta 300
acggtcggta gtaggtggtc tcaagcttcg aattataact actggggcca ggggacccag 360
gtcaccgtct cctca 375
<210> 88
<211> 378
<212> DNA
<213> 人工序列
<400> 88
caggtgcagc tgcaggagtc tggaggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgcag cctctggata cacctacagt ggctactgta tgggctggtt ccgccaggct 120
ccagggaagg agcacgaggg ggtcgcaagt attgtttctg gtcttggtag accatactat 180
gccgattccg tgaagggccg attcaccatc tcccaagaca acgccaagaa cacggtgtat 240
ctgcaaatga acagcctgaa acctgaggac actgccatgt actactgtgc ggcagaatgg 300
gcgacgaaac tctgttctga gatacctgcc accgagtggg actactgggg ccaggggacc 360
caggtcaccg tctcctca 378
<210> 89
<211> 375
<212> DNA
<213> 人工序列
<400> 89
caggtgcagc tgcaggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtacag cctctggatt cactgttgac gattctggca tgggctggta ccgccaggct 120
ccagggaatg agtgcgagtt ggtctcaact attagtagtg atggtagcac atactatgca 180
gactccgtga agggccgatt caccatctcc caagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtgtatt actgtgcggc accccgggtc 300
ggtgtgggtt gggtacgtcc ctgtgattat gagtataact actggggcca ggggacccag 360
gtcaccgtct cctca 375
<210> 90
<211> 348
<212> DNA
<213> 人工序列
<400> 90
caggtgcagc tgcaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggatt caccttcagt aacaaagtca tgagctgggt ccgccaggct 120
ccagggaagg gattcgagtg ggtctcaagt attgcgagag gtggtgactg gacaacctat 180
gcagactccg tggagggccg attcaccatc tccagagaca acgccaagaa cactctgtat 240
ctgcaattga acagcctgaa aactgaggac acggccatgt attactgtgc ccaagctgag 300
aattggaaaa ccccgccggg ccaggggacc caggtcaccg tctcctca 348
<210> 91
<211> 378
<212> DNA
<213> 人工序列
<400> 91
caggtgcagc tgcaggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgcag cctctggata cgcctacact cgcaactgca tgggctggtt ccgccaggct 120
ccagggaagg agcgcgagga agtcgcaact attaatcttg gtggtggtag cacatactat 180
gccgactccg tgaagggccg attcgccatc tcccaagaca acgccaagaa cacggtgtat 240
ctgcaaatga acaacctgaa acctgaggac actgccatgt actactgtgc ggcgatcgct 300
cagtacggtg gtagcttgtg cagcaatttc ggatggtata acttgtgggg ccaggggacc 360
caggtcaccg tctcctca 378
<210> 92
<211> 348
<212> DNA
<213> 人工序列
<400> 92
caggtgcagc tgcaggagtc tggaggaggc ttggtgcagg caggggggtc tctgaagctc 60
tcctgtacag tctctggatt cgcattcggt tcctcccaca tgagctgggt ccgccgggct 120
ccagggaagg ggctcgagtg ggtctcaact attcatagcg gtggtggctt tggcgactat 180
gcgaactccg tgcagggccg attcaccatc tccagagacg tcgccaagaa cacgctgtat 240
ctgcaaatga acagcctgaa acctgaagac acggccatat attactgtgc gctcgcgacg 300
gattggagaa agccccccgg ccaggggacc caggtcaccg tctcctca 348
<210> 93
<211> 375
<212> DNA
<213> 人工序列
<400> 93
caggtgcagc tgcaggagtc tgggggaggg tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgcag cctctggata cacctccagt aggaaataca taggatggtt ccgacaggct 120
ccagggaagc agcgcgagtg ggtcgcaggt attgatactg gtgctggtgg cacatgcacg 180
atcgcctcag tgcagggccg gttcaccatc tcccaagacg tcgccaagaa cacgttgtat 240
ctccaaatag acagcctgaa acctgaagac actgccgtat actactgtgc ggcagattgg 300
gtccggggtg gtttttgctc aggcgatgct gactttcgtt attggggcca ggggacccag 360
gtcaccgtct cctca 375
<210> 94
<211> 366
<212> DNA
<213> 人工序列
<400> 94
caggtgcagc tgcaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtggag cctctggatt caccttcagt agcaccgcca tgtggtggtt ccgccaggct 120
ccagggaagg ggctggagtg ggtgtccagt attaccagtg atgttagtgg cacgtactat 180
gcagactccg tccagggccg attcaccatc tccagagaca acggcaagaa cacggtgtat 240
ctgcaaatga acagcctgag atctgaggac acggccctgt attattgtgc cacctcgtgt 300
gggtttagtg gtggtacgtg gtcttgtaaa tacaggggcc aggggaccca ggtcaccgtc 360
tcctca 366
<210> 95
<211> 348
<212> DNA
<213> 人工序列
<400> 95
caggtgcagc tgcaggagtc tgggggaggc ttggtgcagc ctggggggtc tctgagactc 60
tcctgtgcag cctctggatt cgcattcggt tcctcccaca tgagctgggt ccgccgggct 120
ccagggaagg ggctcgagtg ggtctcaact attcatagcg gtggtggctt tggcgactat 180
gcgaactccg tgcagggccg attcaccatc tccagagacg tcgccaagaa cacgctgtat 240
ctgcaaatga acagcctgaa acctgaagac acggccatat attactgtgc gctcgcgacg 300
gattggagaa agccccccgg ccaggggacc caggtcaccg tctcctca 348
<210> 96
<211> 375
<212> DNA
<213> 人工序列
<400> 96
caggtgcagc tgcaggagtc tggaggaggc tcggtgcaga ctggagggtc tctgagactc 60
tcctgtacag cctctggatt cacttttgat gcggctgaca tgggctggta ccgccaggct 120
ccagggaatg agtgcgagtt ggtctcaatt attagtagtg atggtagtac atactatgcc 180
gactccgtga agggccgatt caccatctcc caagacaacg ccaagaacac ggtgtatctg 240
caaatgaaca gcctgaaacc tgaggacacg gccgtgtatt actgtgcggc accccgggtc 300
ggtgtgggtt gggtacgtcc ctgtgactat gagtataact actggggcca ggggacccag 360
gtcaccgtct cctca 375
<210> 97
<211> 375
<212> DNA
<213> 人工序列
<400> 97
caggtgcagc tgcaggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgcag cctctagaga cacctacacg cgctacttta tgggctggtt ccgccagact 120
ccagggaagg agcccgaggg ggtcgcagtc cttctacctg gcggtgctta cacattctat 180
gccgactccg tgaagggccg gttcaccatc acccaagaca gcgccaagaa cacggtgtat 240
ctgcaaatga acagcctgaa acctgaggac actgccatgt actactgtgc ggcagatgtc 300
acggtcggta gtaggtggtc tcaagcttcg aactataact actggggcca ggggacccag 360
gtcaccgtct cctca 375
<210> 98
<211> 363
<212> DNA
<213> 人工序列
<400> 98
caggtgcagc tgcaggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtacag cctctagcaa caccggcagg atgggctggt tccgccaggc tccagggaaa 120
gagcgcgagg gggtcacagc ggttgataat tttggtagga caaactacgc gaagtacgtg 180
aagggccgat tcaccatctc caaagacaac gccaagaaca ctctgtatct gcaaatgaac 240
agcctgaaac ctgaggacac tgccatgtac tactgtgcgg cggatccctg gggacgtggt 300
gcggccctca ccccaaatga gtatatctac tggggccagg ggacccaggt caccgtctcc 360
tca 363
<210> 99
<211> 372
<212> DNA
<213> 人工序列
<400> 99
caggtgcagc tgcaggagtt tggaggaggc tcggtgcagg ctggagggtc tttgagactc 60
tcctgtgtag cctctggatt caccttcagt aactactgca tgggctggtt ccgccaggat 120
ccagggaagg agcgcgaggc ggtcgcacgt atttttgttg atggcagcac aaggtacgca 180
gacgccgtga agggccgatt caccatctcc aaggacaacg ccaagaacac tctgtatgtg 240
caaatcaaca gcctgaaacc tgaggacact gccatgtact actgtacgac accgtttccc 300
tggacattgt gtgttgatgg ccccggcgcg tataaatact ggggccaggg gacccaggtc 360
accgtctcct ca 372
<210> 100
<211> 387
<212> DNA
<213> 人工序列
<400> 100
caggtgcagc tgcaggagtc tgggggaggc tcagtgcagg ctggagggtc tctgagactc 60
tcctgtgtag tttttggaaa cattttcagg aactactgca tggcctggtt ccgccaggct 120
ccaggaaaag agcgcgaggg ggtggtagtt atttatactg gtggtggtag cacatactat 180
gccgactccg tgaagggccg attcaccatc tcccaagaca acgccaagaa cacggtgtat 240
ttgcaaatga acagcctgaa acatgaggac actgccatgt actactgtgc ggcagaccaa 300
accaccagat actcgagcga ctatgtaaat gtcggcccgt gcgacatgga cagctggggc 360
aaaggaaccc aggtcaccgt ctcctca 387
<210> 101
<211> 384
<212> DNA
<213> 人工序列
<400> 101
caggtgcagc tgcaggagtc tggaggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgcag cctctggata cacctacaat aaatactcct ggggctggtt ccgccaggct 120
ccagggaagg agcgcgaggg ggtcgcagga attgacagtg atggtagcac aagctacgca 180
gactccgtga agggccgatt caccatctcc aaagacaaca ccaagaacac tctgtatctg 240
caaatgaaca gcctgaaacc tgaggacact gccatgtact actgtgcggc atctgattgg 300
gtgtctgcta ttcaggctct tggtgttctg gcggtgaggc cgtatgagta ctggggccag 360
gggacccagg tcaccgtctc ctca 384
<210> 102
<211> 375
<212> DNA
<213> 人工序列
<400> 102
caggtgcagc tgcaggagtc tggaggaggt tcggcgcagg ctggagggtc tctgagactc 60
tcctgtgcag cctctagata cacctccagt agcaacgcga tgggatggtt ccgacaggct 120
ccagggaagc agcgcgagtg ggtcgcaggt agtgatactg gtgctggtat cacatgcaat 180
gccgcctcag tgaagggccg gttcaccatc tcccaagacg tcgccaagaa cacggtgtat 240
ctccaaatga acagcctgaa acctgaggac actgccgtat actactgtgc ggcagattgg 300
ttccggggtg ctttttgctc aggcgatgct gactttcgtt attggggcca ggggacccag 360
gtcaccgtct cctca 375
<210> 103
<211> 375
<212> DNA
<213> 人工序列
<400> 103
caggtgcagc tgcaggagtc tgggggaggc tcggtgcaga ctggagggtc tctgagactc 60
tcttgtgcag cttctggatt gaccagtact actaagtaca tgggctggtt ccgccaggct 120
ccagggaagg agcgcgaggg ggtcgcaggt atctatatta gtagtggtgc cacatactat 180
gacgactctg tgaagggccg attcaccatc tcccaagaca acgccaagaa cacggtatat 240
ttgcacatca acagcctgga acctgatgac accgcgatgt actactgtgc ggcttcagta 300
ttaagtgttt tccggcccct atctagcaac caatatcact actggggtca ggggacccag 360
gtcaccgtct cctca 375
<210> 104
<211> 378
<212> DNA
<213> 人工序列
<400> 104
caggtgcagc tgcaggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgcag cctctggatt tacctacagt aactactgca tggcctggtt ccgccaggct 120
ccagggaagg agcgcgaggg ggtcgcagct attgatagtg atggtagcac aagctacgca 180
gactccgtga agggccgatt caccatctcc caagacaacg ccaagaacac tctgtatctg 240
caaatgaaca gcctgaaacc tgaggacaca gccatgtact actgtgcggc agggaacaaa 300
aagccgtacc aactgtgtaa tactgactcc cgccgatatt accactgggg ccaggggacc 360
caggtcaccg tctcctca 378
<210> 105
<211> 372
<212> DNA
<213> 人工序列
<400> 105
caggtgcagc tgcaggagtc tggaggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgcgt cctctggata cagccgaact agtcgctgga tggcctggtt ccgccaggct 120
ccagggaagg agcgcgaggg ggtcgcagct atttatactg gtggtagtag tacattgtat 180
gccaactcca tggcggaccg agtcaccatc tcccaagaca acgccaagaa cacggtgtat 240
ctgcgaatga acaacctgaa acccgaggac actgccatgt actactgtgc ggcagataaa 300
ttggccggtg atttttggtt ggtagatcgg tggcgtgcct ggggccaggg gacccaggtc 360
accgtctcct ca 372
<210> 106
<211> 387
<212> DNA
<213> 人工序列
<400> 106
caggtgcagc tgcaggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtagaa cctctggata caccaacaat ctgaagtcca tggcctggtt ccgccaggct 120
ccagggaagg agcgcgaggc cgtcgcaagt atccataata acggaggacc cacatacgat 180
tactatgccg aatccgtgaa gggccgattc gccatctccc aagacaacgc caagaacacg 240
ctgtatctgc aaatgagcag cgcgaaacct gaggacactg ccgtgtatta ctgtgcggca 300
gataaccggt ttctggggtc gggttcgtgg cggttaccca gcctctataa ttactggggc 360
caggggaccc aggtcaccgt ctcctca 387
<210> 107
<211> 384
<212> DNA
<213> 人工序列
<400> 107
caggtgcagc tgcaggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60
tcctgtgcag cctctggata caccttcaca actgcctaca tgggctggtt ccgccaggct 120
ccagggaagg agcgcgaggg ggtcgcagca attgacagtg acggtcgaac ggaatacgca 180
gacgccgtga agggccgatt caccatctct aaagacaacg ccaagaatac tctgtatctg 240
caaatgaaca gcctgaaacc tgaggacact gccatgtact actgtgcggc agacaaggat 300
gactggttac tgctacacgg cagatcttta ttcccttcgg cctttgctta ctggggccag 360
gggacccagg tcaccgtctc ctca 384
<210> 108
<211> 352
<212> PRT
<213> 人工序列
<400> 108
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Asp Thr Tyr Thr Arg Tyr
20 25 30
Phe Met Gly Trp Phe Arg Gln Thr Pro Gly Lys Glu Gly Glu Gly Val
35 40 45
Ala Val Leu Leu Pro Gly Gly Asp Tyr Thr Phe Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Thr Gln Asp Ser Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Asp Val Thr Val Gly Ser Arg Trp Ser Gln Ala Ser Asn Tyr
100 105 110
Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Asp Lys Thr
115 120 125
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
130 135 140
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
145 150 155 160
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
165 170 175
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
180 185 190
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
195 200 205
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
210 215 220
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
225 230 235 240
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
245 250 255
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
260 265 270
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
275 280 285
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
290 295 300
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
305 310 315 320
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
325 330 335
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345 350
<210> 109
<211> 353
<212> PRT
<213> 人工序列
<400> 109
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Ser Gly Tyr
20 25 30
Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu His Glu Gly Val
35 40 45
Ala Ser Ile Val Ser Gly Leu Gly Arg Pro Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Glu Trp Ala Thr Lys Leu Cys Ser Glu Ile Pro Ala Thr Glu
100 105 110
Trp Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Asp Lys
115 120 125
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
130 135 140
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
145 150 155 160
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
165 170 175
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
180 185 190
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
195 200 205
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
210 215 220
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
225 230 235 240
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
245 250 255
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
260 265 270
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
275 280 285
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
290 295 300
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
305 310 315 320
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
325 330 335
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
340 345 350
Lys
<210> 110
<211> 352
<212> PRT
<213> 人工序列
<400> 110
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Val Asp Asp Ser
20 25 30
Gly Met Gly Trp Tyr Arg Gln Ala Pro Gly Asn Glu Cys Glu Leu Val
35 40 45
Ser Thr Ile Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ala Pro Arg Val Gly Val Gly Trp Val Arg Pro Cys Asp Tyr Glu Tyr
100 105 110
Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Asp Lys Thr
115 120 125
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
130 135 140
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
145 150 155 160
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
165 170 175
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
180 185 190
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
195 200 205
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
210 215 220
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
225 230 235 240
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
245 250 255
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
260 265 270
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
275 280 285
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
290 295 300
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
305 310 315 320
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
325 330 335
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345 350
<210> 111
<211> 343
<212> PRT
<213> 人工序列
<400> 111
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Thr Val Ser Gly Phe Ala Phe Gly Ser Ser
20 25 30
His Met Ser Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile His Ser Gly Gly Gly Phe Gly Asp Tyr Ala Asn Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Val Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Leu Ala Thr Asp Trp Arg Lys Pro Pro Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
115 120 125
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
130 135 140
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
145 150 155 160
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
165 170 175
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
180 185 190
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
195 200 205
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
210 215 220
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
225 230 235 240
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
245 250 255
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
260 265 270
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
275 280 285
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
290 295 300
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
305 310 315 320
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
325 330 335
Leu Ser Leu Ser Pro Gly Lys
340
<210> 112
<211> 349
<212> PRT
<213> 人工序列
<400> 112
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Gly Ala Ser Gly Phe Thr Phe Ser Ser Thr
20 25 30
Ala Met Trp Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Thr Ser Asp Val Ser Gly Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Asn Gly Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Thr Ser Cys Gly Phe Ser Gly Gly Thr Trp Ser Cys Lys Tyr Arg
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Asp Lys Thr His Thr Cys
115 120 125
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
130 135 140
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
145 150 155 160
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
165 170 175
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
180 185 190
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
195 200 205
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
210 215 220
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
225 230 235 240
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
245 250 255
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
260 265 270
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
275 280 285
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
290 295 300
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
305 310 315 320
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
325 330 335
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345
<210> 113
<211> 343
<212> PRT
<213> 人工序列
<400> 113
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Gly Ser Ser
20 25 30
His Met Ser Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile His Ser Gly Gly Gly Phe Gly Asp Tyr Ala Asn Ser Val
50 55 60
Gln Gly Arg Phe Thr Ile Ser Arg Asp Val Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Leu Ala Thr Asp Trp Arg Lys Pro Pro Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
115 120 125
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
130 135 140
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
145 150 155 160
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
165 170 175
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
180 185 190
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
195 200 205
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
210 215 220
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
225 230 235 240
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
245 250 255
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
260 265 270
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
275 280 285
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
290 295 300
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
305 310 315 320
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
325 330 335
Leu Ser Leu Ser Pro Gly Lys
340
<210> 114
<211> 355
<212> PRT
<213> 人工序列
<400> 114
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Asn Lys Tyr
20 25 30
Ser Trp Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Gly Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Asp Asn Thr Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Ala Ser Asp Trp Val Ser Ala Ile Gln Ala Leu Gly Val Leu Ala Val
100 105 110
Arg Pro Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120 125
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
130 135 140
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
145 150 155 160
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
165 170 175
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
180 185 190
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
195 200 205
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
210 215 220
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
225 230 235 240
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
245 250 255
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
260 265 270
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
275 280 285
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
290 295 300
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
305 310 315 320
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
325 330 335
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
340 345 350
Pro Gly Lys
355
<210> 115
<211> 351
<212> PRT
<213> 人工序列
<400> 115
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Tyr Ser Arg Thr Ser Arg
20 25 30
Trp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Ala Ile Tyr Thr Gly Gly Ser Ser Thr Leu Tyr Ala Asn Ser Met
50 55 60
Ala Asp Arg Val Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Arg Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ala Asp Lys Leu Ala Gly Asp Phe Trp Leu Val Asp Arg Trp Arg
100 105 110
Ala Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Asp Lys Thr His
115 120 125
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
130 135 140
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
145 150 155 160
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
165 170 175
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
180 185 190
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
195 200 205
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
210 215 220
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
225 230 235 240
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
245 250 255
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
260 265 270
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
275 280 285
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
290 295 300
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
305 310 315 320
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
325 330 335
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345 350
<210> 116
<211> 343
<212> PRT
<213> 人工序列
<400> 116
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Gly Ser Ser
20 25 30
His Met Ser Trp Phe Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile His Ser Gly Gly Gly Phe Gly Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Ala Thr Asp Trp Arg Lys Pro Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
115 120 125
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
130 135 140
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
145 150 155 160
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
165 170 175
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
180 185 190
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
195 200 205
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
210 215 220
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
225 230 235 240
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
245 250 255
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
260 265 270
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
275 280 285
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
290 295 300
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
305 310 315 320
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
325 330 335
Leu Ser Leu Ser Pro Gly Lys
340
<210> 117
<211> 351
<212> PRT
<213> 人工序列
<400> 117
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Arg Thr Ser Arg
20 25 30
Trp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ala Ala Ile Tyr Thr Gly Gly Ser Ser Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Val 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 Ala Asp Lys Leu Ala Gly Asp Phe Trp Leu Val Asp Arg Trp Arg
100 105 110
Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Asp Lys Thr His
115 120 125
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
130 135 140
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
145 150 155 160
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
165 170 175
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
180 185 190
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
195 200 205
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
210 215 220
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
225 230 235 240
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
245 250 255
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
260 265 270
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
275 280 285
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
290 295 300
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
305 310 315 320
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
325 330 335
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
340 345 350
<210> 118
<211> 480
<212> PRT
<213> 人工序列
<400> 118
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Arg Thr Ser Arg
20 25 30
Trp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ala Ala Ile Tyr Thr Gly Gly Ser Ser Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Val 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 Ala Asp Lys Leu Ala Gly Asp Phe Trp Leu Val Asp Arg Trp Arg
100 105 110
Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Asp Lys Thr His
115 120 125
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
130 135 140
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
145 150 155 160
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
165 170 175
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
180 185 190
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
195 200 205
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
210 215 220
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
225 230 235 240
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
245 250 255
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
260 265 270
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
275 280 285
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
290 295 300
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
305 310 315 320
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
325 330 335
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly
340 345 350
Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val
355 360 365
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser
370 375 380
Arg Thr Ser Arg Trp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly
385 390 395 400
Leu Glu Gly Val Ala Ala Ile Tyr Thr Gly Gly Ser Ser Thr Leu Tyr
405 410 415
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
420 425 430
Asn Ser Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
435 440 445
Val Tyr Tyr Cys Ala Ala Asp Lys Leu Ala Gly Asp Phe Trp Leu Val
450 455 460
Asp Arg Trp Arg Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
465 470 475 480
<210> 119
<211> 480
<212> PRT
<213> 人工序列
<400> 119
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Arg Thr Ser Arg
20 25 30
Trp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ala Ala Ile Tyr Thr Gly Gly Ser Ser Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Val 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 Ala Asp Lys Leu Ala Gly Asp Phe Trp Leu Val Asp Arg Trp Arg
100 105 110
Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Arg Thr Ser
145 150 155 160
Arg Trp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly
165 170 175
Val Ala Ala Ile Tyr Thr Gly Gly Ser Ser Thr Leu Tyr Ala Asp Ser
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Val
195 200 205
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Ala Ala Asp Lys Leu Ala Gly Asp Phe Trp Leu Val Asp Arg Trp
225 230 235 240
Arg Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Asp Lys Thr
245 250 255
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
260 265 270
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
275 280 285
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
290 295 300
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
305 310 315 320
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
325 330 335
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
340 345 350
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
355 360 365
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
370 375 380
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
385 390 395 400
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
405 410 415
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
420 425 430
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
435 440 445
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
450 455 460
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475 480
<210> 120
<211> 475
<212> PRT
<213> 人工序列
<400> 120
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Arg Thr Ser Arg
20 25 30
Trp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ala Ala Ile Tyr Thr Gly Gly Ser Ser Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Val 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 Ala Asp Lys Leu Ala Gly Asp Phe Trp Leu Val Asp Arg Trp Arg
100 105 110
Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gln Val Gln Leu
115 120 125
Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Tyr Ser Arg Thr Ser Arg Trp Met Ala Trp
145 150 155 160
Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val Ala Ala Ile Tyr
165 170 175
Thr Gly Gly Ser Ser Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe
180 185 190
Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Val Tyr Leu Gln Met Asn
195 200 205
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Asp Lys
210 215 220
Leu Ala Gly Asp Phe Trp Leu Val Asp Arg Trp Arg Ala Trp Gly Gln
225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser Asp Lys Thr His Thr Cys Pro Pro
245 250 255
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
260 265 270
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
275 280 285
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
290 295 300
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
305 310 315 320
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
325 330 335
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
340 345 350
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
355 360 365
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp
370 375 380
Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
385 390 395 400
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
405 410 415
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
420 425 430
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
435 440 445
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
450 455 460
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 121
<211> 227
<212> PRT
<213> 人工序列
<400> 121
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 122
<211> 5
<212> PRT
<213> 人工序列
<400> 122
Gly Gly Gly Gly Ser
1 5
<210> 123
<211> 136
<212> PRT
<213> 人工序列
<400> 123
Gln Arg Pro Thr Gly Gly Pro Gly Cys Gly Pro Gly Arg Leu Leu Leu
1 5 10 15
Gly Thr Gly Thr Asp Ala Arg Cys Cys Arg Val His Thr Thr Arg Cys
20 25 30
Cys Arg Asp Tyr Pro Gly Glu Glu Cys Cys Ser Glu Trp Asp Cys Met
35 40 45
Cys Val Gln Pro Glu Phe His Cys Gly Asp Pro Cys Cys Thr Thr Cys
50 55 60
Arg His His Pro Cys Pro Pro Gly Gln Gly Val Gln Ser Gln Gly Lys
65 70 75 80
Phe Ser Phe Gly Phe Gln Cys Ile Asp Cys Ala Ser Gly Thr Phe Ser
85 90 95
Gly Gly His Glu Gly His Cys Lys Pro Trp Thr Asp Cys Thr Gln Phe
100 105 110
Gly Phe Leu Thr Val Phe Pro Gly Asn Lys Thr His Asn Ala Val Cys
115 120 125
Val Pro Gly Ser Pro Pro Ala Glu
130 135
<210> 124
<211> 116
<212> PRT
<213> 人工序列
<400> 124
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Gly Ser Ser
20 25 30
His Met Ser Trp Phe Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile His Ser Gly Gly Gly Phe Gly Asp Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Leu Ala Thr Asp Trp Arg Lys Pro Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 125
<211> 124
<212> PRT
<213> 人工序列
<400> 125
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Arg Thr Ser Arg
20 25 30
Trp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ala Ala Ile Tyr Thr Gly Gly Ser Ser Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Val 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 Ala Asp Lys Leu Ala Gly Asp Phe Trp Leu Val Asp Arg Trp Arg
100 105 110
Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 126
<211> 684
<212> DNA
<213> 人工序列
<400> 126
gacaaaaccc acacctgtcc cccttgtcct gctcccgagc tcctgggagg accttccgtg 60
ttcctcttcc ctcccaaacc caaggacacc ctgatgatta gcaggacacc cgaggtgacc 120
tgtgtggtgg tggatgtgag ccatgaggac cccgaggtga agtttaactg gtacgtggac 180
ggcgtcgagg tgcacaacgc taagaccaaa cccagggagg agcagtacaa ctccacatac 240
cgggtcgtga gcgtgctgac cgtcctgcac caggattggc tgaatggcaa ggagtacaag 300
tgcaaggtga gcaacaaggc cctgcccgcc cccatcgaga agaccatcag caaggccaaa 360
ggacagcctc gggagcccca ggtttatact ctccccccca gccgggacga actgaccaag 420
aatcaggtgt ccctcacctg cctcgtgaag ggcttttacc ccagcgacat tgccgtggag 480
tgggagagca atggacagcc cgaaaacaac tacaagacca caccccccgt cctggactcc 540
gatggcagct tcttcctgta cagcaagctg accgtggaca agagcaggtg gcagcagggc 600
aacgtgttta gctgcagcgt catgcacgag gctctccaca accactacac ccagaagtcc 660
ctgagcctga gccccggaaa gtga 684
<210> 127
<211> 142
<212> PRT
<213> 人工序列
<400> 127
Gln Arg Pro Thr Gly Gly Pro Gly Cys Gly Pro Gly Arg Leu Leu Leu
1 5 10 15
Gly Thr Gly Thr Asp Ala Arg Cys Cys Arg Val His Thr Thr Arg Cys
20 25 30
Cys Arg Asp Tyr Pro Gly Glu Glu Cys Cys Ser Glu Trp Asp Cys Met
35 40 45
Cys Val Gln Pro Glu Phe His Cys Gly Asp Pro Cys Cys Thr Thr Cys
50 55 60
Arg His His Pro Cys Pro Pro Gly Gln Gly Val Gln Ser Gln Gly Lys
65 70 75 80
Phe Ser Phe Gly Phe Gln Cys Ile Asp Cys Ala Ser Gly Thr Phe Ser
85 90 95
Gly Gly His Glu Gly His Cys Lys Pro Trp Thr Asp Cys Thr Gln Phe
100 105 110
Gly Phe Leu Thr Val Phe Pro Gly Asn Lys Thr His Asn Ala Val Cys
115 120 125
Val Pro Gly Ser Pro Pro Ala Glu His His His His His His
130 135 140
Claims (16)
1.一种特异性结合糖皮质激素诱导的肿瘤坏死因子受体(GITR)的纳米抗体,其特征在于其中的HCDR3包含下述序列(a)-(c)之一或由下述序列(a)-(c)之一组成:
(a)如SEQ ID NO:64-85中任一序列所示的重链可变区序列所含的HCDR3序列;或
(b)与如SEQ ID NO:64-85中任一序列所示的重链可变区序列具有至少90%序列同一性的重链可变区序列所含的HCDR3序列,其中优选序列差异不存在于CDR区域中;或
(c)在如SEQ ID NO:64-85中任一序列所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列中所含的HCDR3序列,其中优选所述氨基酸改变不发生在CDR区域中。
2.权利要求1的纳米抗体,其特征在于所述HCDR3包含下述序列(a)-(c)之一或由下述序列(a)-(c)之一组成:
(a)如SEQ ID NO:45-63中任一序列所示的HCDR3序列;或
(b)在如SEQ ID NO:45-63中任一序列所示的HCDR3中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的HCDR3序列。
3.一种特异性结合糖皮质激素诱导的肿瘤坏死因子受体(GITR)的重链抗体,其特征在于所述重链抗体中的HCDR3包含下述序列(a)-(c)之一或由下述序列(a)-(c)之一组成:
(a)如SEQ ID NO:65、66、67、70、72、73、79和83中任一序列所示的重链可变区序列所含的HCDR3;或
(b)与如SEQ ID NO:65、66、67、70、72、73、79和83中任一序列所示的重链可变区序列具有至少90%序列同一性的重链可变区序列所含的HCDR3,其中优选序列差异不存在于CDR区域中;或
(c)在如SEQ ID NO:65、66、67、70、72、73、79和83中任一序列所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列中所含的HCDR3,其中优选所述氨基酸改变不发生在CDR区域中。
优选所述抗体是人源化重链抗体,更优选是全人源重链抗体。
4.权利要求3的重链抗体,其特征在于所述重链抗体是人源化重链抗体,其中所述人源化重链抗体中的HCDR3包含下述序列(a)-(c)之一或由下述序列(a)-(c)之一组成:
(a)如SEQ ID NO:124或125所示的重链可变区序列所含的HCDR3序列;或
(b)与如SEQ ID NO:124或125所示的重链可变区序列具有至少90%序列同一性的重链可变区序列所含的HCDR3序列,其中优选序列差异不存在于CDR区域中;或
(c)在如SEQ ID NO:124或125所示的重链可变区序列中的一处或多处(优选1-10个,更优选1-5个,最优选1-3个)具有氨基酸改变(优选取代、更优选保守取代)的重链可变区序列中所含的HCDR3序列,其中优选所述氨基酸改变不发生在CDR区域中。
5.权利要求1的抗体或其抗原结合片段,其特征在于所述抗体是多聚物形式的抗体,优选是权利要求4的人源化重链抗体的重链可变区的多聚物形式,更优选是权利要求4的人源化重链抗体的重链可变区的四聚化形式或六聚化形式,最优选是权利要求4的人源化重链抗体的重链可变区的四聚化形式。
6.一种融合蛋白,其包含权利要求1-5任一项的抗体或其抗原结合片段,和第二分子。
7.一种免疫缀合物、组合物或试剂盒,其包含权利要求1-5中任一项的抗体或其抗原结合片段,任选包括载体和/或说明书。
8.分离的核酸,其编码权利要求1-5中任一项的分离的抗体或其抗原结合片段、权利要求6的融合蛋白或权利要求7的免疫缀合物。
9.包含权利要求8的核酸的载体,优选所述载体是表达载体。
10.包含权利要求9的载体的宿主细胞,优选地,所述宿主细胞选自酵母细胞、哺乳动物细胞、免疫效应细胞(如T细胞)。
11.制备权利要求1至5中任一项的分离的抗体或其抗原结合片段、权利要求6的融合蛋白或权利要求7的免疫缀合物的方法,包括在适于表达所述抗体或其抗原结合片段、融合蛋白或免疫缀合物的条件下,培养权利要求10的宿主细胞。
12.药物组合物,其包含权利要求1至5中任一项的分离的抗体或其抗原结合片段、权利要求6的融合蛋白或权利要求7的免疫缀合物,以及任选的药用载体。
13.一种检测样品中GITR的存在的方法,包括:
(a)将所述样品与权利要求1至5中任一项的分离的抗体或其抗原结合片段、权利要求6的融合蛋白或权利要求7的免疫缀合物接触;和
(b)检测所述抗体或其抗原结合片段、或融合蛋白或免疫缀合物和GITR蛋白之间复合物的形成。
14.一种治疗癌症、诱导或增强个体中的免疫应答,和/或刺激抗原特异性T细胞应答的方法,其特征在于包括向所述个体施用有效量的权利要求1-5中任一项的分离的抗体或其抗原结合片段、权利要求6的融合蛋白或权利要求7的免疫缀合物。
15.一种分离的特异性结合糖皮质激素诱导的肿瘤坏死因子受体(GITR)的抗体或其抗原结合片段,其特征在于所述抗体或其抗原结合片段具有以下一种或多种特性:
(i)以高亲和力与人GITR(如SEQ ID NO:123或127的多肽)结合,例如以小于50nM、小于30nM、小于25nM或小于20nM的亲和力,优选以小于10nM的亲和力与人GITR(如SEQ ID NO:123或127的多肽)结合;
(ii)以高亲和力与人GITR(如SEQ ID NO:123或127的多肽)结合,例如以大于0.01x104/Ms、大于0.1x104/Ms、大于1x104/Ms或大于3x104/Ms的结合常数,优选以大于5x104/Ms的结合常数与人GITR(如SEQ ID NO:123或127的多肽)结合;
(iii)以低解离常数与人GITR(如SEQ ID NO:123或127的多肽)结合,例如与人GITR(如SEQ ID NO:123或127的多肽)结合的解离常数(Kd)小于2×10-2s-1、小于1.5×10-2s-1、小于8×10-3s-1或小于5×10-3s-1;优选与人GITR(如SEQ ID NO:123或127的多肽)结合的解离常数为约1-3×10-3s-1;
(iv)与细胞表面的抗原高亲和力结合,例如以小于50nM、小于30nM、小于25nM或小于20nM的亲和力,优选以小于10nM的高亲和力与人GITR(如SEQ ID NO:123或127的多肽)结合;
(v)高效激活GITR下游的NFkB信号通路,例如激活NFkB信号通路的EC50值小于50nM、小于30nM、小于10-25nM或小于5nM,优选小于1nM。
16.权利要求15的抗体或其抗原结合片段,其特征在于所述抗体是
(a)是双抗体、单链抗体(scFv)、单域抗体(sdAd)、重链抗体(hcAb)、纳米抗体(Nb或VHH);或这些抗体的多聚物形式;和/或
(b)是人抗体、人源化抗体或嵌合抗体,
其中所述Fab、单链抗体、单域抗体、重链抗体、纳米抗体;或这些抗体的人源化形式、全人源形式或多聚物形式包含权利要求1-5或15中任一项的抗体的HCDR3,优选还包含权利要求1-5或15中任一项的抗体的HCDR1和HCDR2。
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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CN201810255332.2A CN110357958A (zh) | 2018-03-26 | 2018-03-26 | 抗糖皮质激素诱导的肿瘤坏死因子受体(gitr)的小型化抗体、其聚合物及应用 |
US16/771,777 US11708417B2 (en) | 2018-03-26 | 2019-03-26 | Miniaturized antibody of anti-glucocorticoid-induced tumor necrosis factor receptor (GITR), and polymer and use thereof |
TW108110498A TWI724393B (zh) | 2018-03-26 | 2019-03-26 | 抗糖皮質激素誘導的腫瘤壞死因子受體(gitr)的小型化抗體、其聚合物及應用 |
CN201980006241.8A CN111448214B (zh) | 2018-03-26 | 2019-03-26 | 抗糖皮质激素诱导的肿瘤坏死因子受体(gitr)的小型化抗体、其聚合物及应用 |
PCT/CN2019/079625 WO2019184898A1 (zh) | 2018-03-26 | 2019-03-26 | 抗糖皮质激素诱导的肿瘤坏死因子受体(gitr)的小型化抗体、其聚合物及应用 |
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