CN114805576A - 抗vista抗体和片段 - Google Patents
抗vista抗体和片段 Download PDFInfo
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- CN114805576A CN114805576A CN202210281921.4A CN202210281921A CN114805576A CN 114805576 A CN114805576 A CN 114805576A CN 202210281921 A CN202210281921 A CN 202210281921A CN 114805576 A CN114805576 A CN 114805576A
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Abstract
本发明涉及抗VISTA抗体和片段,这些抗体和片段与T细胞活化的V结构域Ig抑制剂(VISTA)结合,并涉及检测VISTA的方法。
Description
本申请是分案申请,其原申请的国际申请号是PCT/IB2016/000886,国际申请日是2016年06月23日,中国国家申请号为201680048121.0,进入中国的日期为2018年02月13日,发明名称为“抗VISTA抗体和片段”。
技术领域
本发明涉及抗VISTA抗体和片段,这些抗体和片段与T细胞活化的V结构域Ig抑制剂(VISTA)结合,并涉及检测VISTA的方法。
相关申请的交叉引用
本申请要求于2015年6月24日提交的美国临时申请号62/184,108,以及于2015年7月1日提交的美国临时申请号62/187,659的权益。上述申请的全部教示内容通过引用结合在此。
ASCII文本文件中的材料通过引用结合在此。
本申请将包含在以下ASCII文本文件中的序列表通过引用结合,该序列表在此同时提交:
a)文件名:01481142017SEQUENCELISTING.txt;2016年6月22日产生,87KB大小。
背景技术
癌细胞或免疫细胞在肿瘤微环境中的负性免疫检查点调节物的表达可抑制宿主对肿瘤的免疫应答。为了有效对抗癌症,需要阻断肿瘤介导的宿主免疫应答抑制。因此,需要对肿瘤微环境中阻抑抗肿瘤免疫应答的负性免疫检查点调节剂进行抑制的新的有效治疗剂。
发明内容
在一个实施例中,本发明提供包含与哺乳动物T细胞活化蛋白质的V结构域Ig抑制剂(VISTA)结合的抗原结合区域的分离的抗体(例如,嵌合抗体)、或其抗原结合片段。该抗体包含抗体VH结构域,该抗体VH结构域包含具有SEQ ID NO:31的氨基酸序列的VH CDR1、具有SEQ ID NO:32的氨基酸序列的VH CDR2、和具有SEQ ID NO:33的氨基酸序列的VH CDR3。该抗体进一步包含抗体VL结构域,该抗体VL结构域包含具有SEQ ID NO:34的氨基酸序列的VL CDR1、具有SEQ ID NO:35的氨基酸序列的VL CDR2、和具有SEQ ID NO:36的氨基酸序列的VL CDR3。此外,该抗体包含非人类抗体重链恒定区和非人类抗体轻链恒定区。
在一个实施例中,抗体VH结构域包含SEQ ID NO:64。在另一个实施例中,抗体VL结构域包含SEQ ID NO:45。
在一些实施例中,该抗体包含作为鼠抗体重链恒定区的非人类抗体重链恒定区。在特定的实施例中,该鼠抗体重链恒定区是鼠IgG1重链恒定区。在具体的实施例中,该鼠IgG1重链恒定区包含SEQ ID NO:76中的重链恒定区。在另一个实施例中,该鼠抗体重链恒定区是鼠IgG2a重链恒定区。
在其他实施例中,该抗体包含作为鼠抗体轻链恒定区的非人类抗体轻链恒定区。在特定的实施例中,该鼠抗体轻链恒定区是鼠IgG1轻链恒定区。在具体的实施例中,该鼠IgG1轻链恒定区包含SEQ ID NO:77中的轻链恒定区。在另一个实施例中,该鼠抗体轻链恒定区是鼠IgG2a轻链恒定区。
在某些实施例中,该抗体或抗原结合片段与人类VISTA蛋白质结合。在特定的实施例中,该抗体或抗原结合片段与存在于具有以下显示的氨基酸序列的人类VISTA蛋白质中的表位结合:
MGVPTALEAGSWRWGSLLFALFLAASLGPVAAFKVATPYSLYVCPEGQNVTLTCRLLGPVDKGHDVTFYKTWYRSSRGEVQTCSERRPIRNLTFQDLHLHHGGHQAANTSHDLAQRHGLESASDHHGNFSITMRNLTLLDSGLYCCLVVEIRHHHSEHRVHGAMELQVQTGKDAPSNCVVYPSSSQESENITAAALATGACIVGILCLPLILLLVYKQRQAASNRRAQELVRMDSNIQGIENPGFEASPPAQGIPEAKVRHPLSYVAQRQPSESGRHLLSEPSTPLSPPGPGDVF(SEQ ID NO:46)。
在一个实施例中,该抗体或抗原结合片段是完整抗体。
在另一个实施例中,本发明提供包含抗体重链(包含SEQ ID NO:77)和抗体轻链(包含SEQ ID NO:68)的分离的抗体、或其抗原结合片段。
在还另一个实施例中,本发明提供包含本发明的抗体或抗原结合片段的组合物。
在另外的实施例中,本发明提供用于检测样品中哺乳动物VISTA蛋白质的方法。该方法包括在本发明的抗体或抗原结合片段与样品中的VISTA蛋白质结合的条件下,使样品与该抗体或抗原结合片段接触,并且检测与样品中的VISTA蛋白质结合的抗体或抗原结合片段。
在一个实施例中,该样品包含细胞。这些细胞除了其他之外可以包括免疫细胞(例如,髓样细胞)、基质细胞(例如,成纤维细胞、内皮细胞)、和/或癌症(例如,恶性的)细胞,如肺癌细胞、前列腺癌细胞、急性髓性白血病(AML)细胞、黑色素瘤细胞、卵巢癌细胞或结肠癌细胞,或其任何组合。在特定的实施例中,该样品包含组织或生物学流体。
在一个实施例中,在本方法中使用的该抗体或抗原结合片段包含可检测标记。
在某些实施例中,该方法包括免疫组织化学(IHC)染色测定。在另一个实施例中,该方法包括流式细胞术测定。
本发明提供用于检测生物学材料中的一种或多种VISTA蛋白质的改进的试剂和方法。此类试剂和方法典型地具有增强的敏感性和/或特异性。
附图说明
图1A-1C:图表,显示了在TF-1AML细胞系中通过流式细胞术在VISTA蛋白质的TF1AML细胞表达方面的VISTA表达。
图2A-2E:图表,显示了用于鉴定人类骨髓和淋巴子集的染色和门控策略。
图3A-3G:图表,显示了在来自一个健康正常供体的人类骨髓和淋巴子集上的VISTA表达。
图4:图表,显示了在多个健康正常供体中的人类骨髓和淋巴子集上的VISTA表达。
图5A-5B:图表,显示了用于鉴定在人类单核细胞和巨噬细胞上的VISTA表达的染色和门控策略。
图6A-6C:图表,显示了在人类单核细胞和巨噬细胞上的VISTA表达。
图7A-7E:图表,显示了用于鉴定人类T细胞和NK细胞子集上的VISTA表达的染色和门控策略。
图8A-8G:图表,显示了在来自一个健康正常供体的人类T细胞和NK细胞子集上的VISTA表达。
图9:图表,显示了多个健康正常供体中的人类T细胞和NK细胞子集上的VISTA表达。
图10A-10D:图表,显示了用于鉴定人类树突细胞子集上的VISTA表达的染色和门控策略。
图11A-11C:图表,显示了在来自一个健康正常供体的人类树突细胞子集和嗜碱粒细胞上的VISTA表达。
图12:图表,显示了多个健康正常供体的人类树突细胞子集和嗜碱粒细胞上的VISTA表达。
图13A-13D:健康人类外周血细胞上的VISTA在表达的分析。使用多色流式细胞术分析的健康人类外周血细胞上VISTA表达的谱图:将来自2个不同个体的全血样品分析VISTA在单核细胞(SSClo,CD11bhiCD14hiCD16-veCD33+veHLA-DR+veCD19-ve)(图13A)、中性粒细胞(SSChiCD177+CD11bhiCD14loCD16+veCD33+veHLA-DR-veCD19-ve)(图13B)上的表达。使用菲柯尔(Ficoll)梯度将外周血单核细胞分离用于分析CD4+T细胞(CD3+veCD4+ve)(图13C)、和CD8+T细胞(CD3+veCD8+ve)(图13D)。
图14A-14C;来自肺癌患者和健康对照供体的外周血细胞上的VISTA表达的分析。使用多色流式细胞术分析肺癌患者外周血细胞上VISTA表达的图谱:显示了来自一个个体的代表性的FACS图(图14A)。通过菲柯尔(Ficoll)分离外周血单核细胞并分析VISTA在单核细胞(CD14+CD11b+CD33+HLADR+CD15-)和(图14B)髓源性抑制细胞(CD14-CD11b+CD33-HLADR-CD15+CD16+)(图14C)上的表达。
图15A-15C:使用多色流式细胞术分析VISTA在来自患有结肠癌的患者的外周血细胞中的表达谱图:显示了来自一个个体的代表性FACS图(图15A)。通过菲柯尔(Ficoll)分离外周血单核细胞并分析VISTA在单核细胞(CD14+CD11b+CD33+HLADR+CD15-)和(图15B)髓源性抑制细胞(CD14-CD11b+CD33-HLADR-CD15+CD16+)(图15C)上的表达。
图16A-16D:使用多色流式细胞术分析VISTA在猕猴外周血细胞上的表达谱图:将来自4种不同的猴的全血分析VISTA在单核细胞(SSCloCD11bhiCD14hiHLA-DRhiCD16-veCD19-ve(图16A)和中性粒细胞CD11bhiCD14loHLA-DR-veCD16-veCD19-ve(图16B)上的表达。使用菲柯尔(Ficoll)梯度将来自三个猴的外周血单核细胞分离用于分析CD4+T细胞(TCRα/β+veCD4+ve)(图16C)和CD8+T细胞(TCRα/β+veCD8+ve)(图16D)。
图17:图表,显示了VISTA RNA在血红素细胞系中绝对表达值。
图18:用GFP或人类VISTA稳定地转化小鼠A20细胞。将它们与ova肽并与DO11.10 T细胞一起孵育。在孵育开始之后24小时测量T细胞的CD25表达。A20-huVISTA细胞抑制T细胞CD25的表达,但是通过与VSTB95一起孵育,该读数显著恢复。
图19A-19F:图表,显示了人类VISTAELISA结果。
图20A-20F:人类VISTA FACS结果,显示抗VISTA抗体与表达人类VISTA的细胞结合。
图21A-21D:对混合的淋巴细胞反应中6种抗VISTA抗体候选物从30μg/ml至0.0μg/ml的稀释研究。
图22A-22B:对SEB测定中(个体CPM计数和IFN-g浓度)6种抗VISTA抗体候选物从30μg/ml至0.0μg/ml的稀释研究。
图23:传感图,使用在Proteon SPR芯片上涂覆的抗VISTA抗体VSTB85和VISTA蛋白连同在芯片上运行的所示的竞争者(表16中列出的竞争者)。
图24::MB49鼠膀胱肿瘤模型的实验设计。
图25A-25B:在雌性C57Bl/6小鼠中的MB49肿瘤生长。图表显示用抗小鼠VISTA抗体(图25B)或对照IgG(图25A)处理的个体小鼠中的肿瘤生长。
图26:人类VISTA的氨基酸序列(SEQ ID NO:46)。
图27:VISTA直向同源物的多个序列比对。
图28:通过HDX确定的与VSTB50和VSTB60抗体(上)或VSTB95和VSTB112抗体(下)结合的人类VISTA区域。
图29:与VSTB112结合的VISTA表位。(上)VISTA以草图用线标记显示。在复合物中具有至少一个在VSTB112的内的原子的残基被染成蓝色。蓝色和橙色球体突出显示链断裂,青色和绿色球体分别标记VISTA结构的N-末端和C-末端。(下图)用于结构确定的VISTA构建体的序列。序列下面的圆圈用于指示仅与VSTB112进行主链接触的残基,并且三角形指示侧链接触,并且方形指示侧链接触导致由PISA计算的氢键或盐桥相互作用。形状被着色以指示具有与给定残基接触的最大原子数量的CDR,该给定残基具有图29中定义的CDR颜色。二级结构元件如在程序MOE中定义,用黄色箭头代表β-链并且红色矩形指α-螺旋。
图30:VSTB112互补位.(上)VISTA抗原以示例显示,并且在VISTA的5埃内的VSTB112在表面上显示,其颜色用于表示CDR同一性,如以下序列所示。与CDR相邻的接触性框架残基的颜色类似于VSTB112 Fv区域的相应CDR(底部)序列。根据Kabat定义,彩色背景指定CDR。序列下面的圆圈用于指示仅与VISTA进行主链接触的残基,并且三角形指示侧链接触,并且方形指示侧链接触导致由PISA计算的氢键或盐桥相互作用。
图31:通过晶体学和氢氘交换(HDX)鉴定的表位区域的比较。用于结构确定的VISTA构建体的序列。序列下面的圆圈用于指示仅与VSTB112进行主链接触的残基,并且三角形指示侧链接触,并且方形指示侧链接触导致由PISA计算的氢键或盐桥相互作用。
图32:通过VSTB174(源自VSTB112)在全部PBMC中激活CD14+单核细胞。在实验的每个部分中,将细胞与PBS、IgG1对照抗体或与1ug/ml、0.1ug/ml或0.01ug/ml的VSTB174孵育。左图显示CD80 MFI;右图显示HLA-DR MFI(测试两个供体,显示具有代表性的结果)。
图33:图表,显示了针对K562-VISTA细胞的VSTB174的ADCC活性。
图34:图表,显示了针对K562-VISTA细胞的VSTB174的ADCP活性。所描述的两种抗体具有相同的Fab,但是VSTB174具有IgG1Fc并且VSTB140具有Fc沉默IgG2。
图35:图表,显示了通过VSTB174、VSTB149或VSTB140 mAbs介导的针对K562-VISTA的吞噬作用。每种mAb用7个半对数剂量(范围从0.0008μg/ml至0.56ug/ml)进行测试。
图36:图表,显示了由VSTB174、VSTB149或VSTB140 mAbs介导的针对骨髓瘤细胞系K562细胞的吞噬作用。每种mAb用7个半对数剂量(范围从0.0008μg/ml至0.56ug/ml)进行测试。
图37:评估1mg/kg、5mg/kg、7.5mg/kg和10mg/kg的VSTB123在雌性VISTA-KI小鼠中的MB49肿瘤功效研究。当在移植后第6天开始给药时,肿瘤体积大约是50mm3。VSTB123是嫁接到小鼠Fc骨架上的VSTB112 Fab,并与VISTA-KI小鼠中的人类VISTA结合。
图38:图表显示在13/13肺癌样品中,以及在患者的远端肺组织和外周血中发现表达高/中水平VISTA的CD14+细胞。
图39:使用GG8在肺癌中的VISTA的IHC染色。
图40是结合率比抗体浓度的图表。
图41:使用VSTB175(图41A-41C)或阴性对照血清(图41D)在已经福尔马林固定并石蜡包埋的肺癌样品中的VISTA染色的代表性图像。图41A:小细胞肺癌;图41B:小细胞肺癌;图41C:肺鳞状细胞癌;图41D:小细胞肺癌。
图42:人类扁桃体中VISTA(VSTB175)染色。显示的是用VISTA(VSTB175)抗体染色的两个区域扁桃体组织块(左图和右图)。
图43:人类肺癌组织中的VISTA(VSTB175)染色实例。三个组织样品的代表性区域以20X放大显示,并在整个研究群组中观察到展示VISTA染色。
图44:细胞系、VISTA-K562。抗体VSTB175在VISTA-K562细胞中显示频繁的强染色。40X放大。
图45:细胞系、Raji。抗体VSTB175在阴性对照Raji细胞中是阴性。40X放大。
图46:肺呼吸道上皮细胞(左图)、肺泡(右图)。此正常肺样品是在外科手术中从43岁的女性获得。抗体VSTB175显示血管内白细胞(主要是中性粒细胞)的和呼吸道上皮内的少数上皮内中性粒细胞的染色。上皮细胞其自身和和剩余的细胞类型(包括巨噬细胞)是阴性的。40X放大。
图47:淋巴结。此正常淋巴结样品从37岁的男性获得。抗体VSTB175在窦的淋巴结组织中是阴性的。40X放大。
图48:胎盘绒毛。此正常胎盘样品在外科手术中从20岁女性获得。抗体VSTB175在滋养层中显示膜染色。40X放大。
图49:脾脏。此正常脾脏样品在尸体解剖中从患有阿尔茨海默症的73岁男性中获得。抗体VSTB175在红髓中在单核细胞、中性粒细胞和窦状内皮细胞中显示局灶性染色。白髓淋巴细胞大多为阴性。40X放大。
图50:扁桃体。此正常扁桃体样品从11岁女性获得。抗体VSTB175在与表面鳞状上皮相关的单核细胞中显示局灶性染色,但是大多数淋巴细胞是阴性的。40X放大。
图51:结肠、上皮癌。此结肠样品在外科手术中从57岁的女性获得。抗体VSTB175在此样品(包括恶性肿瘤细胞和炎性细胞(中性粒细胞))中是阴性的。40X放大。
图52:黑色素瘤。此黑色素瘤样品在外科手术中从54岁女性获得。抗体VSTB175在良性巨噬细胞中显示局灶性染色,但是在恶性肿瘤细胞中是阴性的。40X放大。
图53:卵巢、上皮癌。此卵巢样品从53岁女性中获得。抗体VSTB175在血管内白细胞(包括单核细胞和多形核中性白细胞两者)中显示胞质染色。恶性肿瘤细胞是阴性的,很少发现的散在炎性细胞亦如此。40X放大。
具体实施方式
本发明的示例实施例的描述如下。
本发明涉及新颖的免疫球蛋白家族配体(命名为T细胞激活的V结构域免疫球蛋白抑制剂(VISTA)(Genbank:JN602184))的抗体(Wang等人,2010,2011)。VISTA与PD-L1具有同源性,但展现限于造血隔区的独特表达模式。具体地说,VISTA在CD11b高髓样细胞上组成性地并且高度地表达,并且在CD4+和CD8+T细胞上以低水平表达。人类同源物与鼠VISTA共享大约85%同源性,并具有相似的表达模式(Lines等人,Cancer Research[癌症研究]74:1924,2014)。在抗原呈递细胞(APC)上表达的VISTA通过独立于PD-1的同源受体抑制CD4+和CD8+T细胞增殖和细胞因子产生。在被动EAE(实验性自身免疫性脑脊髓炎)疾病模型中,VISTA特异性单克隆抗体增强T细胞依赖的免疫应答并加重疾病。VISTA在肿瘤细胞上的过度表达损害了荷肿瘤宿主中的保护性抗肿瘤免疫。人类VISTA的研究证实了其对人类T细胞的抑制功能(Lines等人,Cancer Research[癌症研究]74:1924,2014)。Flies等人的研究也鉴定VISTA(命名为PD-1H)为有效的免疫抑制分子(Flies等人,2011)。VISTA在美国公开申请US20130177557 A1和美国专利号7,919,585和8,236,304中进一步详细描述,所有这些通过引用以其整体结合在此。
如在本文实施例12中描述,在鼠肿瘤模型中用VISTA-特异性单克隆抗体治疗已经显示反转肿瘤免疫微环境的的抑制特征并增强保护性抗肿瘤免疫,因此,表明VISTA单克隆抗体作为新颖的治疗剂用于癌症免疫疗法的可能性。
本发明的抗体和片段
术语“抗体”意指包括通过任何已知的技术(如但不限于酶促裂解、肽合成或重组技术)提供的多克隆抗体、单克隆抗体(mAbs)、嵌合抗体、人源化抗体、人类抗体和抗独特型(抗Id)抗体,连同其片段、区域或衍生物。本发明的抗VISTA抗体能够与调整、调节、或增强免疫应答的VISTA的部分相结合。在一些实施例中,抗体竞争性抑制本文描述的抗VISTA抗体中的一种或多种。用于确定两种或更多种抗体是否竞争结合相同靶标的方法是本领域已知的。例如,可以使用竞争性结合测定来确定一种抗体是否阻断另一种抗体与靶标的结合。典型地,竞争性结合测定涉及使用与固体底物或细胞结合的纯化的靶抗原(例如PD-1)、未标记的测试结合分子和标记的参考性结合分子。竞争性抑制是通过在测试结合分子的存在下确定结合到固体表面或细胞的标记的量来测量。通常,该测试结合分子以过量存在。典型地,当竞争性结合抗体以过量存在时,它会将参考性结合分子与共同抗原特异性结合抑制至少50%-55%、55%-60%、60%-65%、65%-70%、70%-75%或更多。在一些实施例中,使用竞争性抑制ELISA测定确定竞争性抑制。
多克隆抗体是源自用抗原免疫的动物的血清的抗体分子的异质群体。单克隆抗体含有对抗原特异性的基本上同质的抗体群体,该群体含有基本相似的表位结合位点。单克隆抗体可以通过本领域技术人员已知的方法获得。参见,例如Kohler和Milstein,Nature[自然],256:495-497(1975);美国专利号4,376,110;Ausubel等人编,Current Protocolsin Molecular Biology[现行分子生物学方案],格林出版协会和威利国际科学出版公司(Greene Publishing Assoc.and Wiley Interscience),纽约,(1987,1992);以及Harlow和Lane ANTIBODIES:A Laboratory Manual[抗体:实验室手册],冷泉港实验室(ColdSpring Harbor Laboratory)(1988);Colligan等人编,Current Protocols inImmunology[现行分子生物学方案],格林出版协会和威利国际科学出版公司(GreenePublishing Assoc.and Wiley Interscience),纽约,(1992,1993),所有这些的内容通过引用以其整体结合在此。此类抗体可以是包括IgG、IgM、IgE、IgA、GILD的任何免疫球蛋白类别及其任何亚类。产生本发明的单克隆抗体的杂交瘤可以在体外、原位或体内培养。
本发明还涵盖消化片段、特异性部分及其变体,这些消化片段、特异性部分及其变体包括抗体模拟物或包含模拟抗体或其特异性片段或部分(包括单链抗体及其片段)的结构和/或功能的抗体部分。功能片断包括与哺乳动物VISTA蛋白质结合的抗原结合片段。例如,能够与VISTA或其部分(包括但不限于Fab(例如,通过木瓜蛋白酶消化)、Fab′(例如,通过胃蛋白酶消化和部分还原)和F(ab′)2(例如,通过胃蛋白酶消化)、facb(例如,通过纤溶酶消化)、pFc′(例如,通过胃蛋白酶或纤溶酶消化)、Fd(例如,通过胃蛋白酶消化、部分还原和再聚集)、Fv或scFv(例如,通过通过分子生物学技术)片段)结合的抗体片段由本发明涵盖(参见,例如Colligan,Immunology[免疫学],同上)。本发明的抗体片段也包括在AaronL.Nelson,mAbs 2:1,77-83(2010年1月/2月)中讨论并描述的那些,将其内容通过引用以其整体结合在此。
可以通过例如本领域已知的和/或如本文描述的酶促裂解、合成或重组技术产生此类片段。还可以使用抗体基因以各种截短形式产生抗体,其中一个或多个终止密码子已经被引入天然终止位点的上游。例如,可以将编码F(ab′)2重链部分的组合基因设计为包括编码重链CH1结构域和/或铰链区的DNA序列。抗体的各个部分可以通过常规技术化学连接在一起,或者可以使用遗传工程技术制备成连续蛋白质。
在一个实施例中,免疫球蛋白链、或其部分(例如,可变区,CDR)的氨基酸序列与本文描述的相应的可变序列链的氨基酸序列具有约70%-100%同一性(例如,70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100或其中的任何范围或值)。优选地,使用如本领域已知的合适的计算机程序确定70%-100%氨基酸同一性(例如,85、89、90、91、92、93、94、95、96、97、98、99、100或其中的任何范围或值)。
重链和轻链可变区序列的实例在本文中提供。
本发明的抗体、或其特异的变体可以包含来自本发明的抗体的任何数量的连续氨基酸残基,其中该数量选自下组整数,该组由以下各项组成:在抗TNF抗体中从10%-100%数量的连续残基。任选地,连续氨基酸的此子序列在长度上至少约10、20、30、40、50、60、70、80、90、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250或更多个氨基酸、或其中的任何范围或值。此外,此类子序列的数量可以是选自下组的任何整数,该组由以下各项组成:从1至20,如至少2、3、4、或5。
本领域技术人员将理解,本发明包括本发明的至少一种生物活性抗体。生物活性抗体具有天然的(非合成的)、内源的或相关的以及已知的抗体的至少20%、30%、或40%,并且优选地至少50%、60%、或70%,并且最优选地至少80%、90%、或95%-100%的比活性。测定和定量测量酶活性和底物特异性的方法是本领域技术人员熟知的。
基本上相似地是指化合物与天然的(非合成的)、内源的或相关的和已知的抗体具有至少85%(例如,至少95%)同一性并且其至少85%(例如,至少95%)的活性。
如本文所使用的,术语“人类抗体”是指其中该蛋白质的每个部分(例如,CDR、框架、CL、CH结构域(例如CH1、CH2、CH3),铰链,(VL、VH))在人类中基本上都是实质上非免疫原性的抗体,只有很小的序列变化或变异。类似地,指定为灵长类动物(猴、狒狒、黑猩猩等)、啮齿动物(小鼠、大鼠等)和其它哺乳动物的抗体指定这样的物种、亚属、属、亚家族、家族的特异性抗体。此外,嵌合抗体可以包括上述的任何组合。此类改变或变化相对于未经修饰的抗体任选地并且优选地保留或减少人类或其他物种的免疫原性。因此,人类抗体不同于嵌合抗体或人源化抗体。要指出的是可以通过能够功能性地表达重排的人免疫球蛋白(例如,重链和/或轻链)基因的非人类动物或原核或真核细胞产生人类抗体。此外,当人类抗体是单链抗体时,其可以包含没有在天然人类抗体中发现的接头肽。例如,Fv可以包含接头肽,如两个至约八个甘氨酸或其他氨基酸残基,该接头肽连接重链的可变区和轻链的可变区。这种接头肽被认为是人类来源的。
还可以使用双特异性的、异种特异的、异源缀合的或相似的抗体,其是对至少两种不同抗原具有结合特异性的单克隆抗体,优选人类抗体或人源化抗体。在目前情况下,这些结合特异性中的一种是针对至少一种VISTA蛋白质,另一种针对任何其他抗原。用于产生双特异性抗体的方法是本领域已知的。双特异性抗体的重组生产可以基于两个免疫球蛋白重链-轻链对的共表达,其中这两条重链具有不同的特异性(Milstein和Cuello等人,Nature[自然]305:537,(1983))。还参见WO 93/08829,美国专利号6,210,668、6,193,967、6,132,992、6,106,833、6,060,285、6,037,453、6,010,902、5,989,530、5,959,084、5,959,083、5,932,448、5,833,985、5,821,333、5,807,706、5,643,759、5,601,819、5,582,996、5,496,549、4,676,980、WO 91/00360、WO 92/00373、EP 03089、Traunecker等人,EMBO J.[欧洲分子生物学学会杂志]10:3655(1991),Suresh等人,Methods in Enzymology[酶学方法]121:210(1986),每个通过引用整体结合在此。
在一个实施例中,本发明涉及靶向VISTA和第二靶蛋白(例如,免疫检查点蛋白质)的双特异性抗体。示例性双特异性抗体包括靶向VISTA和PD-L1的双特异性抗体以及靶向VISTA和PD-L2双特异性抗体。
可以针对适当的免疫原性抗原(例如VISTA蛋白质或其部分(包括合成分子,如合成肽))产生对人类VISTA蛋白或其片段特异的人类抗体。
其他特异性或一般性哺乳动物抗体可以类似地产生。可以使用任何合适的技术进行免疫原性抗原制备和单克隆抗体产生。
例如,通过将合适的永生细胞系(例如,骨髓瘤细胞系,如但不限于Sp2/0、Sp2/0-AG14、NSO、NS1、NS2、AE-1、L.5、>243、P3X63Ag8.653、Sp2 SA3、Sp2MAI、Sp2 SS1、Sp2 SA5、U937、MLA 144、ACT IV、MOLT4、DA-1、JURKAT、WEHI、K-562、COS、RAJI、NIH 3T3、HL-60、MLA144、NAMAIWA、NEURO 2A等、或杂合骨髓瘤、其融合产物、或源自于其的任何细胞或融合细胞、或本领域已知的任何其他合适的细胞系,(参见,例如www.atcc.org))与抗体生成细胞融合产生杂交瘤。抗体生成细胞可以包括分离的或克隆的脾脏、外周血、淋巴、扁桃体、或其他免疫细胞(例如,B细胞)、或者表达重链或轻链恒定区或可变区或框架或互补决定区(CDR)序列的任何其他细胞。此类抗体生成细胞可以是重组或内源的细胞,并且也可以是原核的或真核的(例如,哺乳动物,如啮齿动物、马、绵羊、山羊、绵羊、灵长类动物)。参见,例如Ausubel,同上,以及Colligan,Immunology[免疫学],同上,第2章,通过引用整体结合。
也可以从已经用目的抗原免疫的人类或其他合适的动物的外周血,或优选得脾脏或淋巴结获得抗体生成细胞。任何其他合适的宿主细胞也可以用于表达编码本发明抗体、其特异性片段或变体的异源或内源核酸。可以使用选择性培养条件或其他合适的已知方法分离融合的细胞(杂交瘤)或重组细胞,并通过有限稀释或细胞分选或其它已知方法进行克隆。产生具有所希望的特异性的抗体的细胞可以通过合适的测定(如酶联免疫吸附测定(ELISA))来选择。
可以使用的产生或分离必需特异性的抗体的其它合适的方法,包括但不限于从肽或蛋白质文库(例如,但不限于噬菌体、核糖体、寡核苷酸、RNA、cDNA等,展示文库;例如,从剑桥抗体技术公司(Cambridge antibody Technologies)可得,剑桥郡,英国;莫弗西斯(MorphoSys),Martinsreid/Planegg,DE;Biovation,亚伯丁(Aberdeen),苏格兰,英国;Bioinvent,隆德(Lund),瑞典;Dyax Corp.,Enzon,Affymax/博识公司(Biosite);Xoma,伯克利(Berkeley),加利福尼亚;Ixsys.,参见,例如PCT/GB91/01134;PCT/GB92/01755;PCT/GB92/002240;PCT/GB92/00883;PCT/GB93/00605;PCT/GB94/01422;PCT/GB94/02662;PCT/GB97/01835;;WO90/14443;WO90/14424;WO90/14430;PCT/U594/1234;WO92/18619;WO96/07754;EP 614 989;WO95/16027;WO88/06630;WO90/3809;美国专利号4,704,692;PCT/US91/02989;WO89/06283;EP 371 998;EP 550 400;EP 229 046;PCT/US91/07149;会随机得产生的肽或蛋白质--美国专利号5,723,323;5,763,192;5,814,476;5,817,483;5,824,514;5,976,862;WO 86/05803、EP 590 689,每个通过引用以其整体结合在此)选择重组抗体的方法,或者依靠能够产生全套人类抗体的免疫转基因动物的方法(例如SCID小鼠,Nguyen等人,Microbiol.Immunol.[微生物免疫]41:901-907(1997);Sandhu等人,Crit.Rev.Biotechnol.[生物技术评论]16:95-118(1996);Eren等人,Immunol.[免疫学]93:154-161(1998),每个通过引用连同相关的专利和申请以其整体结合在此),如本领域技术人员已知的和/或如本文描述的。此类技术,包括但不限于核糖体展示(Hanes等人,Proc.Natl.Acad.Sci.USA[美国国家科学院院刊],94:4937-4942(May 1997);Hanes等人,Proc.Natl.Acad.Sci.USA[美国国家科学院院刊],95:14130-14135(1998年11月));单一细胞抗体产生技术(美国专利号5,627,052,Wen等人,J.Immunol.[免疫学杂志]17:887-892(1987);Babcook等人,Proc.Natl.Acad.Sci.USA[美国国家科学院院刊]93:7843-7848(1996));凝胶微滴和流式细胞术(Powell等人,Biotechnol.[生物技术]8:333-337(1990);One Cell Systems[一个细胞系统],剑桥,麻萨诸塞州(Mass.);Gray等人,J.Imm.Meth.[免疫方法杂志]182:155-163(1995);Kenny等人,Bio/Technol.[生物技术]13:787-790(1995));B细胞选择(Steenbakkers等人,Molec.Biol.Reports[分子生物学报道]19:125-134(1994);Jonak等人,Progress Biotech[生物技术进展],第5卷,In VitroImmunization in Hybridoma Technology[杂交技术的体外免疫],Borrebaeck编,爱思唯尔科学出版社(Elsevier Science Publishers B.V.),阿姆斯特丹(Amsterdam),荷兰(1988))。
也可以使用工程化或人源化非人类或人类抗体的方法,并且是本领域公知的。通常,人源化或工程化抗体具有来自非人类来源(例如但不限于小鼠、大鼠、兔、非人类灵长类动物或其他哺乳动物)的一个或多个氨基酸残基。这些人类氨基酸残基通常被称为“输入”残基,其典型地取自已知人类序列的“输入”可变区、恒定区或其他结构域。披露了已知的人类Ig序列,例如www.ncbi.nlm.nih.gov/entrez/query.fcgi;www.atcc.org/phage/hdb.html,每个通过引用以其整体结合在此。
如本领域已知的,此类输入序列可以用于降低免疫原性或降低、增强或改变结合、亲合性、亲合力、特异性、半衰期或任何其他合适的特征。通常保留非人类或人类CDR序列的部分或全部,而框架和/或恒定区的部分或全部非人类序列被人类或其他氨基酸替换。还可以任选使用本领域技术人员已知的三维免疫球蛋白模型将抗体人源化,同时保留对抗原的高亲和力和其他有利的生物学特性。可以得到说明并且显示所选候选免疫球蛋白序列的可能的三维构象结构的计算机程序。这些展示的检查允许对残基在候选免疫球蛋白序列的功能方面的可能作用进行分析,即对影响候选免疫球蛋白结合其抗原的能力的残基进行分析。按照此方式,可以从一致的并且输入的序列中选择并且组合框架(FR)残基,这样使得所希望的抗体特征,例如增加一种或多种靶抗原的亲和性得以实现。总体上,CDR残基直接地并且在多数情况下实质上涉及影响抗原结合。本发明的抗体的人源化或工程化可以使用任何已知的方法进行,这些方法如但不限于描述在以下的那些:例如,Winter(Jones等人,Nature[自然]321:522(1986);Riechmann等人,Nature[自然]332:323(1988);Verhoeyen等人,Science[科学]239:1534(1988),Sims等人,J.Immunol.[免疫学杂志]151:2296(1993);Chothia和Lesk,J.Mol.Biol.[分子生物学杂志]196:901(1987),Carter等人,Proc.Natl.Acad.Sci.U.S.A.[美国国家科学院院刊]89:4285(1992);Presta等人,J.Immunol.[免疫学杂志]151:2623(1993),美国专利号5,723,323、5,976862、5,824514、5,817483、5,814476、5,763,192、5,723,323、5,766,886、5,714,352、6,204,023、6,180,370、5,693,762、5,530,101、5,585,089、5,225,539;4,816,567,每个通过引用以其整体结合在此,包括其中引用的参考文献。
如本文描述的和/或如本领域已知的,还可以任选地通过转基因动物(例如,小鼠、大鼠、兔、仓鼠、非人灵长类动物等)的免疫获得抗VISTA抗体,这些转基因动物能够产生人类抗体的所有组成成分。可以从此类动物中分离并使用合适的方法(如本文描述的的方法)永生化产生人类抗VISTA抗体的细胞。
可以产生人类抗体(与人类抗原结合)的所有组成成分的转基因动物可以通过已知的方法产生(例如,但不限于美国专利号5,770,428、5,569,825、5,545,806、5,625,126、5,625,825、5,633,425、5,661,016和5,789,650颁予Lonberg等人;Jakobovits等人WO 98/50433,Jakobovits等人WO 98/24893,Lonberg等人WO 98/24884,Lonberg等人WO 97/13852,Lonberg等人WO 94/25585,Kucherlapate等人WO 96/34096,Kucherlapate等人EP0463 151B1,Kucherlapate等人EP 0710 719A1,Surani等人美国专利号5,545,807,Bruggemann等人WO 90/04036,Bruggemann等人EP 0438 474B1,Lonberg等人EP 0814259A2,Lonberg等人GB 2 272 440A,Lonberg等人Nature[自然]368:856-859(1994),Taylor等人,Int.Immunol.[国际免疫学]6(4)579-591(1994),Green等人,NatureGenetics[自然遗传]7:13-21(1994),Mendez等人,Nature Genetics[自然遗传]15:146-156(1997),Taylor等人,Nucleic Acids Research[核酸研究]20(23):6287-6295(1992),Tuaillon等人,Proc Natl Acad Sci USA[美国国家科学院院刊]90(8)3720-3724(1993),Lonberg等人,Int Rev Immunol[国际免疫学评论]13(1):65-93(1995)和Fishwald等人,Nat Biotechnol[自然生物技术]14(7):845-851(1996),每个通过引用以其整体结合)。通常,这些小鼠包含至少一个转基因,该转基因包含来自至少一个功能性重排的人类免疫球蛋白基因座的DNA,或者该DNA可以经受功能性重排。在此类小鼠中的内源性免疫球蛋白基因座可以被破坏或缺失以消除动物产生抗体(由内源基因编码)的能力。
使用肽展示文库可方便地实现筛选与相似蛋白或片段特异性结合的抗体。此方法涉及筛选具有所希望的功能或结构的单个成员的大量肽集合。肽展示文库的抗体筛选在本领域是熟知的。展示的肽序列的长度可以是从3个至5000个或更多个氨基酸,经常地从5-100个氨基酸,并且通常长约8个至25个氨基酸长。除了用于产生肽文库的直接化学合成方法之外,还描述了若干种重组DNA方法。一种类型涉及在噬菌体或细胞表面展示肽序列。每种噬菌体或细胞含有编码特定展示的肽序列的核苷酸序列。在PCT专利公开号91/17271、91/18980、91/19818、和93/08278中描述了此类方法。用于产生肽文库的其他系统具有体外化学合成和重组方法的方面。参见,PCT专利公开号92/05258、92/14843、和96/19256。还参见,美国专利号5,658,754;以及5,643,768。肽展示文库、载体、和筛选试剂盒是从如英杰公司(Invitrogen)(卡尔斯巴德(Carlsbad),加利福尼亚)和剑桥抗体技术公司(Cambridgeantibody Technologies)(剑桥郡,英国)的此类供应商可商购的。参见,例如美国专利号4,704,692、4,939,666、4,946,778、5,260,203、5,455,030、5,518,889、5,534,621、5,656,730、5,763,733、5,767,260、5,856,456;5,223,409、5,403,484、5,571,698、5,837,500,转让给Dyax,5,427,908、5,580,717;5,885,793,转让给剑桥抗体技术公司(Cambridgeantibody Technologies);5,750,373,转让给基因泰克公司(Genentech),5,618,920、5,595,898、5,576,195、5,698,435、5,693,493、和5,698,417。
还可以使用编码至少一种抗VISTA抗体的核酸来制备本发明的抗体,以提供在奶中产生此类抗体的转基因动物(如山羊、牛、绵羊等)。可以使用已知的方法提供此类动物。参见,例如但不限于,美国专利号5,827,690;5,849,992;4,873,316;5,849,992;5,994,616;5,565,362;5,304,489等,每个通过引用以其整体结合在此。
根据已知的方法,也可以使用转基因植物产生本发明的抗VISTA抗体。还参见,例如Fischer等人,Biotechnol.Appl.Biochem.[应用生物化学和生物技术]30:99-108(1999年10月),Cramer等人,Curr.Top.Microbol.Immunol.[当前微生物学和免疫学课题]240:95-118(1999)及其中引用的参考文献;Ma等人,Trends Biotechnol.[生物技术趋势]13:522-7(1995);Ma等人,Plant Physiol.[植物生理学]109:341-6(1995);Whitelam等人,Biochem.Soc.Trans.[生物化学学会汇报]22:940-944(1994);及其中引用的参考文献。上述参考文献中的每个都通过引用以其整体结合在此。
本发明的抗体能以广泛的亲和力(KD)于人类VISTA结合。在优选的实施例中,本发明的至少一个人类单克隆抗体能以高亲和力与人类VISTA任选地结合。例如,人类单克隆抗体能以等于或小于约10-7M(如但不限于0.1-9.9(或其中的任何范围或值)x 10-7、10-8、10-9、10-10、10-11、10-12、10-13或其中的任何范围或值)的KD与人类VISTA结合。在一些实施例中,抗体或抗体片段能以至少1x10-7升/摩尔(例如,至少1x10-8升/摩尔,例如,至少1x10-9升/摩尔)的亲和力与人类VISTA结合。
抗体对抗原的亲和力或亲合力可以使用任何适合的方法进行实验性地确定;参见例如,Berzofsky等人类,“Antibody-Antigen Interactions[抗体-抗原相互作用]”;在基础免疫学中,Paul,W.E.编,纽约瑞文出版社(Raven Press New York),纽约(N.Y.)(1984);Kuby,Janis,Immunology[免疫学];W.H.Freeman和Company纽约,纽约(1992),以及本文所述的方法。如果在不同条件(例如盐浓度、pH)下测量,测量的特定抗体-抗原相互作用的亲和力可以变化。因此,亲和力和其他抗原结合参数(例如KD、Ka、Kd)的测量优选地用抗体和抗原的标准化溶液和标准化缓冲液进行。
核酸分子
使用本文提供的信息(如对具体片段、变体或其共同序列中的至少一个的至少70%-100%的连续氨基酸编码的核苷酸序列,或者包含这些序列的至少一个的保藏的载体),使用本文描述的或如本领域技术人员已知的方法,可以获得对包含SEQ ID NOS:1、2和3的所有重链可变CDR区和/或SEQ ID NOS:4、5和6的所有轻链可变CDR区的至少一个抗VISTA抗体编码的本发明的核酸分子。
本发明的核酸分子可以处于RNA(如mRNA、hnRNA、tRNA或任何其他形式)形式,或者处于DNA(包括但不限于cDNA和通过克隆或合成产生获得的基因组DNA)形式,或其任何组合。DNA可以是三链的、双链的或单链的或其任何组合。DNA或RNA的至少一条链的任何部分可以是编码链(也称为有义链),或者可以是非编码链(也称为反义链)。
本发明的分离的核酸分子可以包括核酸分子,该核酸分子包含开放阅读框(ORF),例如但不限于至少一个重链或轻链的至少一个CDR(如CDR1、CDR2和/或CDR3)的至少一个具体部分;核酸分子,该核酸分子包含抗VISTA抗体或片段(例如包含可变区的片段)的编码序列;以及核酸分子,该核酸分子包含与上文描述的那些不同的核苷酸序列,但是由于遗传密码的简并,该核酸分子仍然编码本文描述的和/或本领域已知的至少一个抗VISTA抗体。产生编码本发明的特异性抗VISTA抗体的此类简并核酸变体对于本领域技术人员而言是常规的。参见,例如Ausubel等人,同上,并且此类核酸变体包括在本发明中。
如本文所示,包含编码抗VISTA抗体的核酸的本发明的核酸分子可以包括但不限于编码抗体片段的氨基酸序列的那些;整个抗体或其部分的编码序列;抗体、片段或部分的编码序列,以及另外的序列,如至少一个信号前导肽或融合肽的编码序列,具有或不具有上述的另外的编码序列(如至少一个内含子),连同另外的非编码序列(包括但不限于非编码5’和3'序列),如转在转录中起作用的转录的非翻译序列、mRNA加工(包括剪接)和聚腺苷酸化信号(例如--mRNA的核糖体结合和稳定);编码另外的氨基酸(如提供另外的功能的那些)的另外的编码序列。因此,编码抗体的序列可以与标记序列融合,例如对有助于包含抗体片段或部分的融合抗体的纯化的肽进行编码的序列。
编码本发明抗体的恒定(C)区、片段和区域的人类基因可以通过已知方法源自人类胎儿肝脏文库。人类C区基因可以源自任何人类细胞(包括表达和产生人免疫球蛋白的那些)。人类CH区可以源自人类H链的任何已知类型或同种型,包括括γ、μ、α、δ或ε及其亚型,如G1、G2、G3和G4。由于H链同种型负责抗体的各种效应子功能,所以CH区的选择将由所希望的效应子功能(如补体结合或抗体依赖性细胞毒性(ADCC)中的活性)来指导。
组合物
本文披露的药物组合物根据标准程序制备并以选择的治疗(例如减少、预防、或消除)或减缓或停止被治疗的病症的进展的剂量给药(参见,例如Remington’sPharmaceutical Sciences[雷明顿药物科学],麦克出版公司(Mack PublishingCompany),伊斯顿(Easton),巴拿马(PA),以及Goodman and Gilman’s ThePharmaceutical Basis of Therapeutics[Goodman和Gilman的治疗药学基础],麦格劳希尔集团(McGraw-Hill),纽约,纽约,这些的内容通过引用结合在此,用于对用于人类治疗的各种试剂的给药的方法的一般描述)。包含披露的抗体和试剂的组合物可使用受控或缓释递送系统(例如胶囊、生物可降解基质)递送。适用于给予披露的化合物的组合物的药物递送的缓释递送系统的实例描述于例如美国专利号US 5,990,092;5,039,660;4,452,775;和3,854,480中,这些的全部教导通过引用结合在此。
为了从本发明的抗VISTA抗体和/或片段制备药物组合物,药学上可接受的载体可以是固体或液体。固体形式的制剂包括粉末、片剂、丸剂、胶囊剂、扁囊剂、栓剂和可分散颗粒剂。例如,本发明的化合物能以粉末形式用于在递送时复水。固体载体可以是也可用作稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂或包封材料的一种或多种物质。在粉末中,载体是精细分散的固体,其是呈与精细分散的活性成分的混合物。
粉末和片剂优选含有约百分之一至约百分之七十的活性成分。合适的载体是碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。片剂、粉剂、扁囊剂、锭剂、速溶条、胶囊和丸剂可以用作含有适于口服给药的活性成分的固体剂型。
液体剂型制剂包括溶液、悬浮液、保留灌肠剂和乳液,例如水或水-丙二醇溶液。对于肠胃外注射,液体制剂可以在水性聚乙二醇溶液中配制成溶液。
药物组合物可以是单位剂型。以此类剂型,将组合物再分成含有适量活性成分的单位剂量。单位剂型可以是经包装的制剂,该包装含有离散量的单位剂量。剂量可以根据患者的要求、治疗的病症的严重程度、化合物和使用的给药途径而变化。确定特定情况的合适剂量在本领域技术范围内。
而且,如果需要,药物组合物可以含有其它兼容性试剂,例如药物、治疗剂或预防剂。治疗剂或预防剂包括但不限于肽、多肽、蛋白质、融合蛋白、核酸分子、小分子、模拟剂、合成药物、无机分子和有机分子。此类试剂(例如,抗癌剂)的类型的实例包括但不限于细胞毒素、血管生成抑制剂、免疫调节剂、免疫肿瘤试剂和用于提供缓解疼痛或抵消一种或多种治疗剂有害作用的试剂(例如,用于减少糖皮质激素的高钙血症效应的二膦酸盐)。
适用于本文描述的组合物和方法中的血管生成抑制剂、试剂和疗法包括但不限于血管抑制素(血纤蛋白溶解酶原片段);抗血管生成抗凝血酶III;核酶。二膦酸盐包括但不限于阿仑膦酸盐、氯膦酸盐、依替膦酸盐、伊班膦酸盐、帕米膦酸盐、利塞膦酸盐、替鲁膦酸盐和唑来膦酸盐。
适用于本文描述的组合物和方法的免疫调节剂和疗法包括但不限于抗T细胞受体抗体,如抗CD3抗体(例如Nuvion(蛋白质设计实验室(Protein Design Labs))、OKT3(美国强生公司(Johnson&Johnson))、或抗CD20抗体Rituxan(IDEC))、抗CD52抗体(例如CAMPATH1H(Ilex))、抗CD11a抗体(例如Xanelim(Genentech));抗细胞因子或抗细胞因子受体抗体和拮抗剂,如抗IL-2受体抗体(赛尼哌(Zenapax)(蛋白质设计实验室(Protein DesignLabs))、抗IL-6受体抗体(例如MRA(中外制药(Chugai))、和抗IL-12抗体(CNTO1275(杨森公司(Janssen))、抗TNFα抗体(类克(Remicade)(杨森公司(Janssen))或TNF受体拮抗剂(依那西普(Enbrel)(英姆纳克斯公司(Immunex))、抗IL-6抗体(BE8(Diaclone)和siltuximab(CNTO32(山陶克公司(Centocor))、和免疫特异性结合肿瘤相关抗原的抗体(例如,曲妥单抗(基因泰克公司(Genentech))。
适用于本文描述的组合物和方法的免疫肿瘤剂包括但不限于伊匹木单抗(ipilimumab)(抗CTLA-4)、纳武单抗(nivolumab)(抗PD-1)、派姆单抗(pembrolizumab)(抗PD-1)、抗PD-L1抗体和抗LAG-3抗体。
该组合物优选制成含有治疗有效量的抗体或片段的剂量单位形式。剂量单位的实例是片剂和胶囊剂。为了治疗目的,除了活性成分之外,片剂和胶囊还可含有常规载体,如粘合剂(例如阿拉伯胶、明胶、聚乙烯吡咯烷酮、山梨糖醇或黄芪胶);填充剂(例如,磷酸钙、甘氨酸、乳糖、玉米淀粉、山梨糖醇或蔗糖);润滑剂(例如硬脂酸镁、聚乙二醇、二氧化硅或滑石);崩解剂(例如马铃薯淀粉)、调味剂或着色剂、或可接受的润湿剂。通常以水性或油性溶液、悬浮液、乳液、糖浆或酏剂形式的口服液体制剂可含有常规添加剂如悬浮剂、乳化剂、非水性剂、防腐剂、着色剂和调味剂。用于液体制剂的添加剂的实例包括阿拉伯胶、杏仁油、乙醇、分馏的椰子油、明胶、葡萄糖浆、甘油、氢化的食用脂肪、卵磷脂、甲基纤维素、对羟基苯甲酸甲酯或丙酯、丙二醇、山梨糖醇或山梨酸。
关于制备和使用本文描述的化合物和组合物的方法的其它一般细节在本领域中是熟知的。参见,例如美国专利号7,820,169,其内容通过引用以其整体结合在此。
治疗方法
考虑所选的试剂、药物制剂和给药途径、各种患者因素和其他考虑,本领域技术人员(例如临床医生)可以确定给予个体的特定抗体、片段或组合物的合适的剂量和给药途径。优选地,该剂量不会引起小的不良的副作用或或不产生任何不良的副作用。在标准的多剂量方案中,药理学试剂可以按照剂量方案施用,该剂量方案被设计为在经受治疗的受试者中维持已决定的或最佳的血浆浓度。这些抗体、片段和组合物能以适当的剂量范围或治疗有效量添加,例如0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.5mg/kg、2.0mg/kg、2.5mg/kg、3.0mg/kg、4.0mg/kg、5.0mg/kg、6.0mg/kg、7.0mg/kg、8.0mg/kg、9.0mg/kg、10.0mg/kg、11.0mg/kg、12.0mg/kg、13.0mg/kg、14.0mg/kg、15.0mg/kg、16.0mg/kg、17.0mg/kg、18.0mg/kg、19.0mg/kg、20.0mg/kg、30mg/kg、40mg/kg、50mg/kg 60mg/kg、70mg/kg、80mg/kg、90mg/kg和100mg/kg。在一个实施例中,给予的组合物、抗体或片段的剂量是每次给药0.1-15mg/kg。
该抗体或片段每天可以给药一次、至少一次、两次、至少两次、三次、至少三次。该抗体或片段可以每周给药一次、至少一次、两次、至少两次、三次、至少三次、四次、至少四次、五次、至少五次、每周六次或至少六次。该抗体或片段可以每月一次、每月至少一次、每月两次、每月至少两次、每月三次或每月至少三次给药。该抗体或抗体片段可以每年一次、每年至少一次、每年两次、每年至少两次、每年三次、每年至少三次、每年四次、每次至少四次、每年五次、每年至少五次、每年六次、或每年至少六次给药。
该抗VISTA抗体、片段和组合物可以例如通过肠胃外或非胃肠外方式给药,包括但不限于静脉内、皮下、口服、直肠、肌内、腹膜内、经粘膜、经皮、鞘内、鼻内或局部。本领域普通技术人员将认识到以下剂型可以包含作为活性成分的本发明化合物的化合物或相应的药学上可接受的盐。在一些实施例中,这些剂型可以包含作为活性成分的化合物或相应的化合物的药学上可接受的盐。
本发明的抗VISTA抗体可作为组合疗法的一部分(例如与彼此或与一种或多种其他治疗剂)给予。本发明的化合物可以在一种或多种其他治疗剂之前、之后或同时给予。在一些实施例中,本发明的化合物和其他治疗剂可以作为分开的制剂或作为联合制剂同时地(例如同时发生地)共同给予。可替代地,可以在熟练的临床医生确定的适当时间范围内(例如,足以允许疗法的药物作用重叠的时间),将该试剂作为单独的组合物顺序地给予。本发明的化合物和一种或多种其他治疗剂能以适合于实现所希望的治疗效果的顺序和时间表以单剂量或多剂量给予。
本发明还提供用于调节或治疗细胞、组织、器官、动物或患者中的至少一种恶性疾病的方法。在一些实施例中,将本发明的化合物和组合物用于治疗或预防癌症。癌症可以包括任何器官或身体系统的任何恶性或良性肿瘤。实例包括但不限于以下:乳腺、消化道癌/胃肠癌、内分泌癌、神经内分泌癌、眼睛癌、泌尿生殖癌、生殖细胞癌、妇科癌、头颈癌、血液学/血液癌、肌肉骨骼癌、神经癌、呼吸道癌/胸腔癌、膀胱癌、结肠癌、直肠癌、肺癌、子宫内膜癌、肾癌、胰腺癌、肝癌、胃癌、睾丸癌、食道癌、前列腺癌、脑癌、宫颈癌、卵巢癌和甲状腺癌。其他癌症可以包括白血病、黑色素瘤和淋巴瘤、以及本文描述的任何癌症。在一些实施例中,实体瘤被髓样和/或T细胞浸润。在一些实施例中,该癌症是白血病、淋巴瘤、骨髓增生异常综合征和/或骨髓瘤。在一些实施例中,该癌症可以是任何种类和类型的白血病,包括淋巴细胞白血病或髓细胞性白血病(如例如急性淋巴母细胞性白血病(ALL)、慢性淋巴细胞白血病(CLL)、急性骨髓(髓细胞性)白血病(AML)、慢性髓细胞性白血病(CML))、毛细胞白血病、T细胞幼淋巴细胞白血病、大颗粒淋巴细胞白血病或成人T细胞白血病。在一些实施例中,淋巴瘤是组织细胞性淋巴瘤、滤泡性淋巴瘤或霍奇金淋巴瘤,并且在一些实施例中,癌症是多发性骨髓瘤。在一些实施例中,该癌症是实体瘤,例如,黑色素瘤、或膀胱癌。在特定的实施例中,该癌症是肺癌,如非小细胞肺癌(NSCLC)。
本发明还提供用于在细胞、组织、器官、动物或患者中调节或治疗至少一种恶性疾病的方法,该恶性疾病包括但不限于以下中的至少一种:白血病,急性白血病,急性淋巴母细胞性白血病(ALL),B细胞、T细胞或FAB ALL,急性髓性白血病(AML),慢性粒细胞性白血病(CML),慢性淋巴细胞白血病(CLL),毛细胞白血病,骨髓增生异常综合征(MDS),淋巴瘤,霍奇金氏疾病,恶性淋巴瘤,非霍奇金氏淋巴瘤,伯基特淋巴瘤,多发性骨髓瘤,卡波西氏肉瘤,结肠直肠癌,胰腺癌,鼻咽癌,恶性组织细胞增生症,副肿瘤综合征/恶性高血钙症,实体瘤,腺癌,肉瘤,恶性黑色素瘤,血管瘤,转移性疾病,癌症相关的骨吸收,癌症相关的骨痛等。在一些实施例中,实体瘤被髓性和/或T细胞浸润。在特定的实施例中,实体瘤是肺癌,如非小细胞肺癌(NSCLC)。
在一些实施例中,本文描述的化合物和疗法与疫苗(例如病毒载体疫苗、细菌疫苗、基于细胞的疫苗、DNA疫苗、RNA疫苗、肽疫苗或蛋白质疫苗)共同给予。此类疫苗是本领域熟知的。参见,例如Jeffrey Schlom,“Therapeutic Cancer Vaccines:Current Statusand Moving Forward[治疗性癌症疫苗:现状和进展],”J Natl Cancer Inst[国际癌症研究所];104:599–613(2012),其内容通过引用以其整体结合在此。
在一些实施例中,本文描述的化合物和疗法与用于化学疗法、激素疗法和生物疗法的试剂和/或双膦酸盐共同给予。在一些实施例中,用于化学疗法的一种或多种试剂包括以下中的一种或多种:卡铂(carboplatin、Paraplatin))、顺铂(cisplatin、Platinol、Platinol-AQ)、环磷酰胺(cyclophosphamide、Cytoxan、Neosar)、多柔比星(阿霉素)、依托泊苷(etoposide、VePesid)、氟尿嘧啶(5-FU)、吉西他滨(健择(Gemzar))、伊立替康(irinotecan、Camptosar)、,紫杉醇(紫杉酚(Taxol))、拓扑替康(topotecan、Hycamtin)、长春新碱(vincristine、Oncovin、Vincasar PFS)、长春碱(vinblastine、Velban)。
在其他实施例中,本文描述的抗VISTA化合物和疗法与一种或多种免疫检查点抗体(如例如,纳武单抗、派姆单抗、替西木单抗(tremelimumab)、伊匹木单抗、抗PD-L1抗体、抗PD-L2抗体、抗TIM-3抗体、抗LAG-3v、抗OX40抗体和抗GITR抗体)共同给予。
在另一个实施例中,本文描述的抗VISTA化合物和疗法与吲哚胺2,3-加双氧酶(IDO)的小分子抑制剂共同给予。
可以将本发明的抗VISTA化合物和组合物给予对其有需要的受试者以预防(包括预防癌症的复发)或治疗(例如,管理或改善癌症或一种或多种其症状)癌症。用于预防、治疗、管理或改善癌症或其一种或多种症状的已知有用或已经使用的或正在使用的任何试剂或疗法(例如化学疗法、放射疗法、靶向疗法(例如伊马替尼、索拉非尼和威罗菲尼)、激素疗法和/或生物疗法或免疫疗法)可以与本文描述的本发明的化合物或组合物组合使用。抗癌剂包括但不限于:5-氟尿嘧啶;阿西维辛;阿地白介素;六甲蜜胺;氨鲁米特;安吖啶;阿那曲唑;安曲霉素;天冬酰胺酶;阿扎胞苷;阿扎替派;阿佐霉素;巴马司他;比卡鲁胺;硫酸博来霉素;布喹那钠;溴匹立明;白消安;卡铂;卡莫司汀;盐酸卡柔比星;卡折来新;西地芬戈;苯丁酸氮芥;西罗霉素;顺铂;克拉屈滨;甲横酸克立那托(crisnatol mesylate);环磷酰胺;阿糖胞苷;达卡巴嗪;更生霉素;盐酸柔红霉素;地西他滨;右奥马铂;地扎胍宁;甲磺酸地扎胍宁(dezaguanine mesylate);地吖醌;多西他赛;多柔比星;盐酸阿霉素;屈洛昔芬;柠檬酸屈洛昔芬;丙酸屈他雄酮;达佐霉素;依达曲沙;盐酸依氟鸟氨酸;恩洛铂;恩普氨酯;依匹哌啶;盐酸表柔比星;厄布洛唑;盐酸伊索比星;雌莫司汀;雌莫司汀磷酸钠;依他硝唑;依托泊苷;磷酸依托泊苷;法扎拉滨;芬维A胺;氟尿苷;磷酸氟达拉滨;氟尿嘧啶;氟西他滨;磷喹酮;福司曲星钠;吉西他滨;盐酸吉西他滨;羟基脲;盐酸伊达比星;异环磷酰胺;伊莫福新;白介素II(包括重组白介素II、或重组l2)、干扰素α-2a;干扰素α-2b;干扰素α-m;干扰素α-n3;干扰素β-I a;干扰素γ-I b;异丙铂;盐酸伊立替康;醋酸兰瑞肽;来曲唑;亮丙瑞林乙酸盐;盐酸利阿唑;洛美曲索钠;洛莫司汀;盐酸洛索蒽醌;马索罗酚;盐酸氮芥;醋酸甲地孕酮;乙酸甲烯雌醇;美法仑;美诺立尔;巯基嘌呤;甲氨蝶呤;甲氨蝶呤钠;氯苯氨啶;美妥替哌;丝裂霉素;米托司培;米托坦;盐酸米托蒽醌;麦考酚酸;诺考达唑;奥马铂;紫杉醇;培门冬酶;紫菜霉素(porfromycin);泼尼莫司汀;盐酸丙卡巴肼;嘌呤霉素;罗谷亚胺;盐酸沙芬戈;司莫司汀;辛曲秦;司泊索非钠;司帕霉素;螺莫司汀;螺铂;链黑霉素;链脲菌素;磺氯苯脲;太利苏霉素;替加氟;盐酸替洛蒽醌;替莫泊芬;替尼泊苷;替罗昔隆;睾内酯;硫咪嘌呤;硫鸟嘌呤;噻替派;噻唑呋林;替拉扎明;拓扑替康;三甲曲沙;葡萄糖醛酸三甲曲沙;曲普瑞林;乌拉莫司汀;乌瑞替派;伐普肽;维替泊芬(verteporfn);硫酸长春碱;硫酸长春新碱;长春地辛;硫酸长春地辛;硫酸长春匹定;硫酸长春甘酯;硫酸长春罗辛;酒石酸长春瑞滨;硫酸长春罗定;硫酸长春利定;伏氯唑;折尼铂;净司他丁;盐酸佐柔比星。靶向的治疗剂包括但不限于酪氨酸激酶抑制剂(例如,伊马替尼、索拉非尼、和威罗菲尼)。本发明还涵盖给予本发明的抗VISTA化合物与包含使用X射线、γ射线和其它辐射源以消灭癌细胞的放射疗法的组合。癌症治疗在本领域中是已知的,并已经在Physician's Desk Reference[医生案头参考](第57版,2003)等文献中描述。
本文描述的抗VISTA抗体也可用于治疗例如慢性感染性疾病,如HIV、HBV、HCV和HSV等。
VISTA蛋白质的检测
本文描述的本发明的抗体和抗原结合片段通常可用于例如检测样品(例如生物材料)中的VISTA蛋白质。本发明的抗体与本领域技术人员已知的许多蛋白质检测测定相容,例如包括但不限于以下的免疫学和免疫化学方法:流式细胞术(例如,FACS分析)、酶联免疫吸附测定(ELISA)(包括化学发光测定)、放射免疫测定、免疫印迹(例如蛋白质印迹)、免疫组织化学(IHC)、免疫沉淀反应和其他基于抗体的定量方法(例如,基于微珠的测定)。其他合适的方法包括例如质谱法。
本发明的VISTA检测方法通常包括使样品(例如细胞样品)与本文描述的本发明的抗VISTA抗体或抗原结合片段在抗体或抗原结合片段与样品中的VISTA蛋白质结合的条件下接触。用于将本发明的抗体或抗原结合片段与样品中的VISTA蛋白质结合的合适的条件可由本领域普通技术人员容易地确定,并包括并包括本领域已知的各种条件。此类条件包括例如,在本文实施例27中描述的那些。
例如,直接或间接使用例如免疫组织化学(IHC),VISTA抗体可用于来确定样品中VISTA的存在和/或表达水平。IHC特别地提供了原位检测样品或组织样本中的靶标的方法(参见Mokry 1996,ACTA MEDICA[药学学报]39:129)。样品的整体细胞完整性在IHC中保持,因此允许检测目的靶标的存在和位置。
IHC染色程序可以包含以下步骤:切割和修剪组织、固定、脱水、石蜡渗透、切割成薄片、放在载玻片上、烘烤、脱蜡、再水合、抗原修复、封闭步骤、应用第一抗体、洗涤、应用第二抗体-酶缀合物、洗涤、应用与聚合物缀合的并与酶连接的第三抗体、应用显色底物、洗涤、复染、应用盖玻片和显微镜检查。洗涤步骤可以用任何合适的缓冲液或溶剂(例如磷酸盐缓冲盐水、TRIS缓冲盐水、蒸馏水)进行。洗涤缓冲液可以任选地含有洗涤剂,例如-20或NP-40。
在一个实施例中,将IHC样品用福尔马林固定,包埋在石蜡中并切成节段用于染色,随后通过光学显微镜检查。IHC的现有方法使用直接标记或基于第二抗体或基于半抗原的标记。已知的IHC系统的实例包括例如,EnVisionTM(DakoCytomation)、(Immunovision,斯普林代尔(Springdale),亚利桑那州)、试剂盒(酶实验室公司(Zymed Laboratories Inc.),南旧金山,加利福尼亚)、(Nichirei Corp,东京、日本)。
可以在各种样品类型中检测VISTA蛋白质,这些样品类型包括但不限于组织样品、生物学流体样品(例如哺乳动物血浆、血清、淋巴、全血、脊髓、羊水或其他动物来源的流体)、一种或多种细胞(例如,肿瘤细胞、免疫细胞)样品等。样品可以包括,例如:(a)包含未固定的新鲜组织和/或细胞的制剂;(b)固定和包埋的组织样本,如存档的材料;以及(c)冷冻的组织或细胞。因此,样品可以是新鲜的或保存的,例如在液体溶液中,快速冷冻或冻干、涂抹或干燥的、包埋或固定在载玻片或其他支持物上。
在一些实施例中,将组织或细胞样品被固定或包埋。例如,使用固定剂以可重现和活生命样的方式保存细胞和组织。固定剂也稳定细胞和组织,从而保护它们免受严苛的加工和染色技术。例如,包含组织块、切片或涂片的样品可浸入固定液中,或在涂片的情况下,干燥。
许多固定和包埋组织标本的方法是已知的,例如,酒精固定和福尔马林固定以及随后的石蜡包埋(FFPE)。可以使用任何合适的固定剂。实例包括乙醇、乙酸、苦味酸、2-丙醇、3,3'-二氨基联苯胺二盐酸、乙偶姻(单体混合物)和二聚体、丙烯醛、巴豆醛(顺式+反式)、甲醛、戊二醛、乙二醛、重铬酸钾、高锰酸钾、四氧化锇、多聚甲醛、氯化汞、甲苯-2,4-二异氰酸酯、三氯乙酸、钨酸。其他实例包括福尔马林(水性甲醛)和中性缓冲福尔马林、戊二醛、碳化二亚胺、亚氨酸酯(imidates)、苯醌、锇酸和四氧化锇。用于IHC分析的新鲜活组织检查样本、细胞学制品(包括接触制品和血液涂片)、冷冻切片和组织可以固定在有机溶剂(包括乙醇、乙酸、甲醇和/或丙酮)上。
可以使用从受试者取样的任何手段(例如通过抽血、脊髓抽吸、组织涂片或刮取、或组织活组织检查)来获得样品。因此,样品可以是活组织检查样本(例如,肿瘤、息肉、肿块(固体、细胞))、抽吸物、涂片或血液样品。样品可以是具有肿瘤(例如,癌性生长)和/或肿瘤细胞的组织,或怀疑具有肿瘤和/或肿瘤细胞的组织。例如,可以在开放式活组织检查(其中从靶区域移除整个(切除活检)或部分(切除活组织检查)肿块的程序)中获得肿瘤活组织检查。可替代地,可以通过经皮活组织检查获得肿瘤样品,该检查是通过小切口或刺穿(借助或不借助成像装置)用针状仪器进行的程序以获得个体细胞或细胞群(例如,精细针抽吸(FNA))或组织的核心或片段(核心活组织检查)。
可以通过细胞学(例如,涂片)、组织学(例如,冷冻或石蜡切片)或使用任何其他合适的方法(例如分子诊断方法)来检查样品。也可以通过体外收获源自个体组织的培养的人类细胞来获得肿瘤样品。如果需要,肿瘤样品可以在分析之前通过合适的储存方式进行储存,该储存方式将样品的蛋白质和/或核酸保存在可分析的条件下,例如快速冷冻或受控冷冻方式。如果需要,可以在冷冻保护剂(例如二甲基亚砜(DMSO)、甘油或丙二醇-蔗糖)的存在下进行冷冻。为了分析的目的,可以在储存之前或之后合适地将肿瘤样品合并。
本发明的抗体可以包括标记(如例如,可检测标记),该标记允许在生物样品中检测抗体、和由抗体结合的蛋白质(例如,VISTA)。可检测标记特别适用于诊断应用。例如,VISTA抗体可以用放射性同位素(radioactive isotope、radioisotope)标记,其可以被本领域技术人员使用γ计数器、闪烁计数器或通过放射自显影或其他合适的手段来检测。对于本发明的目的有用的同位素包括但不限于:3H、125I、131I、32P、35S、14C、51Cr、36Cl、57Co、58Co、59Fe和75Se。
本发明的抗体也可以用荧光化合物(例如染料)标记。当荧光标记的抗体暴露于适当波长的光下时,由于该化合物的荧光,可以检测其存在。最常用的荧光标记包括异硫氰酸荧光素、若丹明、藻红蛋白、藻蓝蛋白、别藻蓝蛋白、邻苯二甲醛和荧光胺。本发明的抗体还可以使用荧光发射金属(如152Eu或其他镧系元素)来标记。可以使用金属螯合基团(如二亚乙基三胺五乙酸(DTPA)、四氮杂-环十二烷-四乙酸(DOTA)或乙二胺四乙酸(EDTA))将这些金属附接至抗体分子上。
本发明的抗体也可以偶联至化学发光化合物。有用的化学发光标记化合物的实例是鲁米诺、异鲁米诺、芳香(theromatic)吖啶酯、咪唑、吖啶盐和草酸酯。
同样地,可以使用生物发光化合物来标记本发明的抗体。生物发光是在生物系统中发现的一种化学发光,其中催化蛋白质增加了化学发光反应的效率。通过检测发光的存在来确定生物发光蛋白的存在。用于标记抗体目的的有用生物发光化合物是萤光素、萤光素酶和水母发光蛋白。
例如,如果可检测标记是放射性γ发射体,则可以通过闪烁计数器完成经标记的抗体的检测,或者如果例如可检测标记是荧光材料,则通过荧光计完成经标记的抗体的检测。在酶标记的情况下,检测可以通过采用酶底物的比色法完成。检测也可以通过目视比较底物与类似制备的标准品的酶促反应程度来完成。
在一些实施例中,样品中的VISTA蛋白质的近似量也被确定。例如,可以将来自样品的标记的强度与已知的标准或对照样品进行比较。估计样品中可检测靶标(例如,VISTA蛋白质)的量例如在各种诊断测试中是有用的,并且该估计可以用于计划疑似疾病或病症的治疗过程。一些商用光密度测量软件程序和相关仪器可用于定量样品中着色的靶标的强度,如从富士胶片公司(Fuji Film)、应用生物系统公司(Applied Biosystems)和分子动力学公司(Molecular Dynamics)中可获得的那些。
本文表1A、1B和2中提供了选择的本发明的抗VISTA抗体的各种性质和序列信息。
表1A:选择的全人类或人源化抗人类VISTA抗体的CDR序列
表1B:选择的全人类或人源化抗人类VISTA抗体的重链和轻链序列
*VSTB140、VSTB149和VSTB174中的恒定区序列加下划线。ΔVSTB149的重链中赋予蛋白酶抗性的氨基酸残基用粗体指示。
表2:选择的抗VISTA抗体的解离常数(KD)
实施例
实施例1:人造血细胞中的VISTA表达的分析
方法:
用于VISTA表达的新鲜人类PBMC的制备和染色
在来自若干个供体的新鲜分离的人类PBMC(外周血单核细胞)上测试了VISTA的表达。使用抗人类VISTA-生物素(GA-1)进行染色(5μg/ml)。将小鼠IgG1、K-生物素(克隆MOPC-21,在5μg/ml)用作同种型对照。
供体材料
血液样品从生物专业公司(Biological Specialty Corp.)(科尔马(Colmar),巴拿马)获得并收集并在同一天分析。将10ml含有硫酸肝素的全血用于分析。
样品制备
将血液在无菌的PBS中1:1稀释。将22ml稀释的脐带血铺在50ml锥形管中的20ml无菌Ficoll-Hypaque(GE保健公司(GE Healthcare)目录号17-144003)上。将试管在室温以1800rpm离心20分钟。使用1ml移液器收集离心后界面处的单核细胞,并合并至两个50ml锥形管中。将无菌的PBS添加至每个管中以使体积达到50ml,并且将细胞在4℃下以300g离心10分钟。丢弃上清液。将细胞重悬浮于50ml的无菌PBS中,并将试管在4℃下以300g旋转10分钟。丢弃上清液。计数前将细胞合并并重悬浮于50ml无菌PBS中。
染色方案:将含有5x107 PBMC的冷冻小瓶用于补偿控制并用作对照用于染色。
使用以下试剂和/或耗材:
来自BD生命科学公司(BD Biosciences)的FACS染色缓冲液(BSA)(目录号554657)补充有0.2%EDTA;磷酸盐缓冲盐水(PBS)(Gibco目录号14190);96-孔聚丙烯圆底平板(BD#3077);1.2ml聚丙烯簇状试管(康宁公司(Corning)#4451);来自ImmunoNext Lot#080612B的生物素酰化的抗VISTA克隆GA-1(以5μg/ml使用);生物素酰化的mIgG1、K同种型对照(克隆MOPC-21);博奇公司(Biolegend)目录号400104,Lot#B116649(以5μg/ml使用);抗人类抗体(参见以下染色表);近红外活/死染料(英杰公司(Invitrogen),目录号L10119);和链霉亲和素试剂,这些链霉亲和素试剂包括STP-APC(BD生命科学公司(BD Biosciences)目录号554067,Lot#04251)(在FACS缓冲液中1:200稀释使用)、STP-PE(博奇公司(Biolegend)目录号405203,Lot#B139688)(在FACS缓冲液1:200稀释使用)、STP-PE Cy7(在同种型对照样品中显示非特异性结合)、STP-Q605(英杰公司(Invitrogen)目录号Q10101MP,Lot#53449A)(在FACS缓冲液1:200稀释使用)。
细胞表面染色方案
在染色前,将1x106个细胞转移至96-孔圆底平板中并用150μl PBS洗涤。然后将这些板在1300rpm在4℃下离心3分钟。
随后,将细胞在PBS中再次洗涤并如上文所述离心。
然后在含有0.25μl的近红外活/死染料的50μl PBS中进行活/死染色。在10分钟之后,在室温下,将这些孔用150μl FACS染色缓冲液洗涤,并在1300rpm在4℃离心3分钟。丢弃上清液。
将细胞在50μl FACS染色缓冲液中以1:100用人类血清封闭。将这些板在4℃下孵育15分钟。然后将孔用150μl FACS染色缓冲液洗涤,并在1300rpm在4℃下离心3分钟。丢弃上清液。
然后将含有以下抗体的混合物添加至每个孔中用于表面染色:这些混合物描述在以下表3-6中。根据目的人群,每种混合物都将与其他混合物分开使用。
表3:谱系染色
表4:T细胞染色
表5:DC染色
表6:骨髓染色
在表面染色之后,如先前描述的用FACS染色缓冲液将细胞洗涤两次,并在1300rpm在4℃离心5分钟。将样品重悬浮于50μl的含有适当的荧光标记的链霉亲和素的FACS染色缓冲液中。将样品在4℃下孵育30分钟。将细胞用150μl FACS染色缓冲液洗涤,并在1300rpm在4℃离心5分钟。在将样品重悬浮于250μl的FACS染色缓冲液中之前,重复此洗涤步骤。在BDLSRFortessaTM细胞分析仪(BD生命科学公司(BD Biosciences))上在同一天分析样品。
数据分析
使用FlowJo版本9软件重新分析流式细胞术数据以门控特定的表型群体。使用几何平均值的计数来比较不同细胞子集中的VISTA表达。通过从抗VISTA处理的样品的平均值中减去同种型对照,将每个群体的背景归一化。在Prism中制作图表,并且如果仅比较两个样品,则使用学生T检验或者使用具有Bonferroni事后检验的单向ANOVA进行统计。
结果:
VISTA在人类骨髓和淋巴子集上的表达:
如在图2A-2E、3A-3G、4、5A-5B和6A-6C中显示,CD14+单核细胞上的VISTA表达与所有其他群体显著不同(p<0.001)。其他群体之间没有显著差异。单核细胞在外周血中表达最高水平的VISTA,CD14+CD16-亚群具有比CD14loCD16+细胞显著更高的表达。虽然APC显示VISTA的中等表达,但淋巴子集显示低表达水平。
人类T和NK子集上的VISTA表达:
如在图7A-7E、8A-8G和9中显示,对于NK子集,CD56lo细胞表现出比CD56Hi NK细胞显著更高的VISTA表达水平。在T细胞子集中,CD8+记忆细胞表达最高表达水平,尽管它们不显著高于CD8+原初或CD4+T细胞。
人类树突细胞子集上的VISTA表达:
如在图10A-10D、11A-11C和12中显示,没有看到VISTA表达的显著差异;DC和嗜碱粒细胞展现出VISTA的低表达,浆细胞样树突状细胞(pDC)通常更高但不显著。
结论:这些结果显示VISTA在各种免疫细胞子集上的表达,并且VISTA在单核细胞上表达最高,在不同的T细胞子集和NK细胞上有一些表达,在B细胞上很少至没有表达。
实施例2:外周血细胞上的VISTA表达
方法:
全血的染色:将新鲜分离的全血(100μl)用如下指示的抗体混合物通过在4℃孵育30分钟进行染色。将红血液细胞(RBC)用RBC裂解缓冲液裂解,并将剩余的细胞用染色缓冲液洗涤1x。将细胞重悬浮于200μl的染色缓冲液中。使用MACSQuant流式细胞仪收集数据并使用FlowJo分析软件进行分析。
外周血单核细胞(PBMC)的染色:使用菲柯尔(Ficoll)梯度将外周血单核细胞从全血分离。将新鲜分离的1x106 PBMC用抗体混合物在100μl的染色缓冲液中染色。将样品在4℃孵育30分钟,并然后用染色缓冲液洗涤一次。将细胞重悬浮于100μl的染色缓冲液中。使用流式细胞仪(美天旎生物技术公司(Miltenyi Biotec))收集数据,并使用FlowJo分析软件进行分析。
使用的抗体是CD11b、CD33、CD177、CD16、CD15、CD14、CD20、HLADR、CD3、CD4、CD8、CD127、CD69、和FOXP3抗体(博奇公司(Biolegend),圣地亚哥,加利福尼亚)。通过ImmuNext(Lebanon,NH)制得APC缀合的小鼠抗人类VISTA(克隆GG8)。
结论:
健康人类外周血细胞上的VISTA表达
使用多色流式细胞术,分析全血和外周血单核细胞VISTA表达。如在图15A和15B中显示,在单核细胞中检测到最高水平的VISTA表达,随后是中性粒细胞。如在图13C和13D中显示,CD4+和CD8+T细胞两者表达低水平的VISTA。
癌症患者外周血细胞上的VISTA表达
如在图14A-C中显示,分析来自肺癌患者的外周血单核细胞(PBMC)。图14A是显示对CD14+单核细胞和CD15+骨髓来源的抑制细胞(MDSC)分析的代表性流图。结果表明有表型的CD15+细胞是中性粒细胞来源的MDSC。另外,这些细胞在健康血液样品中不存在。图14B是健康和癌症患者来源的单核细胞上VISTA表达的代表性直方图,表明与健康对照相比,癌症患者细胞上更高水平的VISTA表达。如在图14C中显示,在癌症患者的MDSC上也发现了类似更高水平的VISTA。
图15A是显示结肠癌患者血液中的中性粒细胞衍生的MDSC的存在的代表性FACS图。图15B和15C是与健康供体血液样品相比在癌症患者单核细胞上显示更高水平的VISTA表达的代表性直方图。
猕猴外周血细胞上的VISTA表达
如在图16A和16B中显示,猴全血的流式细胞术分析显示与人类细胞相似的VISTA表达模式。与CD4+(图16C)和CD8+(图16D)T细胞相比,单核细胞和中性粒细胞均表达最高水平的VISTA。
实施例3:血红素恶性肿瘤细胞系中在RNA水平和蛋白质水平的VISTA表达
由于VISTA在血红素恶性肿瘤中表达,因此抗VISTA抗体可能潜在地靶向恶性肿瘤细胞以破坏,连同阻断VISTA并促进抗肿瘤免疫应答。
数据包括约140个血红素恶性肿瘤细胞系的RNAseq分析(一些细胞系在分析中重复)。数据显示在图17中。
将RNAseq值列为FPKM(片段/的千碱基外显子/每百万映射的片段)值。
实际上,这意味着所有落到基因外显子区域的读数都被计算并且通过基因长度和每个样本的总读数来归一化(以考虑样本间差异)。截断值是1;高于1对于VISTA表达(在RNA水平)是正的,低于1对于VISTA表达是负的。
结果表明许多细胞系在RNA水平是正的,主要是急性骨髓性白血病和慢性髓细胞性白血病。这可能是预期的,因为VISTA在正常的髓样细胞中高表达,并且因为其功能被认为是抑制免疫应答(包括抗肿瘤免疫应答)。
实施例4:产生针对VISTA的单克隆抗体
噬菌体淘选
进行24个噬菌体淘选实验以富集与猕猴VISTA-His反应的噬菌体。猕猴VISTA蛋白质用于这些实验,因为它比人类VISTA蛋白质显示更好的生物素缀合。为了确定噬菌体实验的成功,将来自单个淘选轮的噬菌体库添加至用生物素化的猕猴VISTA-His涂覆的中性抗生物素蛋白板,并用HRP缀合的抗M13抗体检测。从噬菌体选择轮中挑选单个菌落,并在96孔板中生产Fabs蛋白质。测定表达的Fab上清液与生物素酰化的猕猴VISTA-His的结合。这导致超过200个命中。
扩增来自Fab板的VH和VL区,提交用于DNA测序并作为FASTA文件输出。当挑选应该转化的克隆并作为MAB被测试时,基于序列多样性、以及具有有限的翻译后修饰风险和尽可能少的疏水性残基来选择克隆。
将来自噬菌体克隆的VH和VL亚克隆到哺乳动物IgG1/κ表达载体中并转染到HEK293细胞中。将抗体在蛋白A琼脂糖快速流动亲和树脂上纯化。通过定量ELISA使用Nanodrop测定确定噬菌体MAB的浓度。抗体组以高水平表达。SDS-PAGE分析展示了每个表达的抗体变体的完整性。
通过扩增来自最后一轮淘选的多克隆抗体混合物的VH结构域,用于克隆到在VL方面具有多样性的噬菌体载体中,进行噬菌体抗体的顺序成熟。这导致了一个丰富的VH池,对其取样,其中具有在VL方面具有另外的多样性。通过1-2轮严格的淘选获得噬菌体,期望鉴定对VISTA ECD His蛋白具有非常高亲和力的结合物。运行单克隆Fab ELISA以确定成熟的成功。将ELISA和表达数据归一化为从原始的初始淘选实验设定为100%的参考克隆,并且鉴定与猕猴VISTA抗原具有比参考克隆更高的结合信号的亲和力成熟克隆。此过程产生若干个克隆,当在低抗原浓度(1nM)下筛选时展示高达200%的结合,测序具有最高亲和力的克隆并产生为MAB。
杂交瘤产生
一组BALB/cAnNCrl小鼠接受一次腹膜内(IP)注射50μg Hu VISTA-Ig重组蛋白(Sino)(在完全弗氏佐剂中乳化),两周后进行一次IP注射50μg Hu VISTA-Ig重组蛋白(在不完全弗氏佐剂中乳化)。在两周之后,小鼠接受在不完全弗氏佐剂中乳化的50μg猕猴VISTA-Fc重组蛋白的一次IP注射。在脾脏收获前5天,所有小鼠接受在PBS中的25μg人类和25μg猕猴VISTA的尾静脉最终注射,用于融合。
另一组BALB/cAnNCrl小鼠接受在完全弗氏佐剂中乳化的50μg Hu VISTA-His重组蛋白的一次IP注射。在两周之后,小鼠接受在不完全弗氏佐剂中乳化的50μg Hu VISTA-His重组蛋白的一次IP注射。在两周之后,小鼠接受在不完全弗氏佐剂中乳化的50μg猕猴VISTA-His重组蛋白的一次IP注射。在两周之后,在脾脏收获前三天,所有小鼠接受在PBS中的25μg Hu VISTA-His和25μg猕猴VISTA-His的最终注射,用于融合。
在融合当天,通过CO2窒息使小鼠安乐死;取出脾脏并置于10mL冷的磷酸盐缓冲盐水中。脾细胞的单细胞悬浮液通过用小研磨杵通过精细筛网研磨脾并在室温下用PBS冲洗来制备。将细胞在PBS中洗涤一次并经受RBC裂解。简而言之,将细胞重悬浮于每个脾脏的3mL的RBC裂解缓冲液(西格玛公司(Sigma)#R7757)中,并置于冰上5分钟。将细胞在PBS中在室温再次洗涤,并标记用于磁性分选。按照制造商的说明,用抗鼠Thy1.2、抗鼠CD11b和抗鼠IgM磁性珠(分别为美天旎生物技术公司(Miltenyi Biotec)#130-049-101、130-049-601和130-047-301)标记,然后使用具有Midi MACS的MS柱进行分选。将阴性细胞级分(丢弃阳性细胞级分)与FO细胞融合。将鼠骨髓瘤细胞与活的脾脏细胞在1:1的比率进行融合。简而言之,将脾脏和骨髓瘤细胞混合在一起,沉淀并在50mL PBS中洗涤一次。用1mL的聚乙二醇(PEG)溶液(2g PEG分子量4000、2mL DMEM、0.4mL DMSO)/10e8脾细胞将沉淀物在37℃下重悬浮30秒。然后在温和搅拌下将细胞/融合混合物浸入37℃水浴中持续大约60秒。通过经1分钟缓慢地添加37℃DMEM终止融合反应。允许融合的细胞在室温下静置5分钟,然后在150xg离心5分钟。然后将细胞重悬浮于含有HAT(西格玛公司(Sigma)目录号H0262)的培养基E-HAT(培养基E(干细胞技术公司(StemCell Technologies)目录号03805)中,并接种在96-孔板底部聚苯乙烯组织培养板(康宁公司(Corning)#3997)上。
使用捕获EIA来筛选杂交瘤上清液中对抗体特异性的猕猴VISTA。简而言之,将板(Nunc-Maxisorp#446612)用涂覆缓冲液(Thermo 28382)中的山羊抗小鼠IgG(Fc)抗体(杰克逊公司(Jackson)#115-006-071)以4μg/ml涂覆至少60分钟。在室温下,将板用在PBS中的200μl/孔的0.4%(w/v)牛血清白蛋白(BSA)封闭30分钟。将板洗涤一次并添加50μl/孔的杂交瘤上清液,并在室温孵育至少30分钟。将板洗涤一次并添加50μl/孔的0.1μg/mL的猕猴VISTA-huIg,并在室温孵育30分钟。在室温下,将板洗涤一次,并将在0.4%BSA/PBS中的1:40,000链霉亲和素HRP(杰克逊公司(Jackson)016-030-084)添加至板中,并孵育30分钟。将板洗涤3x,随后使用100μl/孔的TMB Turbo底物(赛默飞世尔科技公司(ThermoScientific)34022)在室温孵育大约10分钟显色。使用25μl/孔4N硫酸将反应终止,并使用自动化平板分光光度计在450nm处测量吸光度。选择15个主要命中通过有限稀释进行亚克隆,并以相同的主要筛选格式进行筛选。
使用人类VISTA-Ig对有猕猴VISTA反应性杂交瘤细胞系进行交叉筛选所以评估交叉反应性。简而言之,将板(Nunc-Maxisorp#446612)以4μg/mL用0.1M碳酸钠-碳酸氢钠缓冲液(pH 9.4)(Pierce 28382BupHTM)O/N中的山羊抗ms Fc(杰克逊公司(Jackson)#115-006-071)在4℃涂覆。未经洗涤,将这些孔用200μl的在PBS(英杰公司(Invitrogen))中的封闭液(0.4%BSA(西格玛公司(Sigma)(w/v)在4℃封闭过夜。在去除封闭溶液之后,将未稀释的杂交瘤上清液在涂覆的板上在室温下孵育30分钟。将板用PBST(在PBS中的0.02%Tween 20(西格玛公司(Sigma)(w/v))洗涤,并然后与稀释至100ng/ml的Hu VISTA-Ig在封闭液中孵育30分钟。在室温下,将板用封闭液中1:10,000稀释的山羊抗人类-Fc-HRP(杰克逊公司(Jackson)#109-036-098)洗涤一次并探测持续30分钟。将板再次洗涤,随后使用100μl/孔的TMB Turbo底物(赛默飞世尔科技公司(Thermo Scientific)34022)在室温孵育大约10分钟显色。使用25μl/孔4N硫酸将反应终止,并使用自动化平板分光光度计在450nm处测量吸光度。
对人和猕猴VISTA均显示反应性的杂交瘤使其V区抗体序列被克隆。在用英杰公司(Invitrogen)的SuperScript III细胞直接cDNA系统(SuperScript III cells DirectcDNA System)进行逆转录酶(RT)反应之前制备杂交瘤细胞。简而言之,丢弃培养基,将板放置在冰上并重悬浮在200μl冷PBS中。将四十微升转移至MicroAmp fast 96孔反应PCR板,并将该板置于冷金属板基底上,用塑料膜密封并以700rpm旋转3分钟。丢弃PBS,并向每个孔中添加10μl重悬浮缓冲液和1μl裂解增强剂。将该板密封并在75℃孵育10min,并储存在-80℃。
对于RT反应,每个孔含有5μl水,1.6μl 10X DNA酶缓冲液、1.2μl 50mM EDTA、2μlOligo(dT)20(50mM)和1μl 10mM dNTP混合物。将该板在70℃孵育5min,随后在冰上孵育2min,然后将以下试剂添加至每个孔中;6μl 5X RT缓冲液、1μl RNaseOUTTM(40U/μl)、1μlSuperScriptTM III RT(200U/μl)和1μl of 0.1M DTT。将板密封并放置在预热至50℃的热循环仪上并在50℃孵育50分钟,随后失活(在85℃孵育5min)。将反应在冰上冷冻,并将单链cDNA储存在–80℃直至另外的使用。
对于V区扩增,建立20μl PCR反应。每个孔含有16.2μl水、2.0μl 10X PCR反应缓冲液、0.8μl MgSO4(50mM)、0.4μl 10mM dNTP、0.15μl 100uM正向引物混合0.05μl 100uM反向引物、0.2μl HiFi Tag酶。将如上文描述制备的cDNA(2μl/孔)转移至PCR组分混合物中,将该板密封并运行扩增反应;对于VH,程序是(i)94℃持续1min(ii)94℃持续15秒(iii)55℃持续30秒(iv)68℃持续1min。步骤(ii–iv)重复总共35个循环,随后在68℃最后延伸3min。对于VL,程序是(i)94℃持续1min(ii)94℃持续15秒(iii)55℃持续30sec(iv)65℃持续30sec,(v)68℃持续1min。步骤((ii–v)重复总共35个循环,随后在68℃最后延伸3min。
将正向引物预混合,并将该混合物与反向引物以3:1的比例使用。在琼脂糖凝胶上验证PCR产物。通过添加增强剂(In-Fusion HC克隆试剂盒,目录号639650,Clontech)制备反应用于融合克隆(infusion cloning)。将5微升PCR反应物转移至PCR板,然后转移2μl增强子/孔。将板密封,并在热循环仪中孵育(在37℃ 15min以及在80℃ 15min)。通过Esp3I消化制备目标载体(vDR243或vDR301);(将1.5μg载体在3μl Tango缓冲液、2l Esp3I和水在30μl反应中,在37℃消化2小时)。
为了融合克隆,将2μl增强剂处理的PCR产物与100ng Esp3I消化的载体和2μl of5X输注酶(Clontech)混合。融合反应在96-孔PCR板格式中进行。将板在50℃下在PCR仪上孵育15分钟,并且在42℃下将Stella感受态细胞热激转变40秒而不摇动,并将其涂布在具有选择的抗生素的LB琼脂平板上并在37℃孵育过夜。第二天,将菌落挑入含有LB/羧苄青霉素培养基的96孔深孔板中,在37℃生长过夜。从与等体积的30%w/v甘油混合的过夜培养物制备冷冻的原料。使用测序引物SPF0052对V区进行测序。分析序列,选择一个阳性孔/杂交瘤vH和vL,重新排列在新的平板上并在含有氨苄青霉素的富培养基中生长过夜。然后使用克隆制备小量DNA用于在96-孔板中小规模转染。
对于重链和轻链的四十八种选择的小鼠杂交瘤序列是使用内部软件程序改编的人类框架。为每个小鼠vH或vL选择一个人类框架。通过回译获得V区DNA序列。从集成DNA技术公司(Integrated DNA Technologies))(Coralville,IA)订购相应于HFA氨基酸序列的合成DNA区域。分别克隆进入预切割vDR149和vDR157,人类IgG1和人类κ。使用凯杰公司(Qiagen)Endo-free Maxi-prep试剂盒制备DNA。使用Expi293(100ml)培养物表达此抗体组。
实施例5:人类VISTA-Ig T细胞体外抑制测定方案
用GFP或人类VISTA稳定地转化小鼠A20细胞。将它们与ova肽并与DO11.10 T细胞一起孵育。在孵育开始之后24小时测量T细胞的CD25表达。A20-huVISTA细胞抑制T细胞的CD25表达,但是通过与VSTB95一起孵育,该读数显著恢复(图18)。
实施例6:抗VISTA抗体的人类框架区区域适应
用于重链和轻链的小鼠杂交瘤序列均是通过CDR-移植(Jones等,Nature[自然],321:522-525(1986))使用内部软件程序改适的人类框架区。该程序根据Kabat定义描绘V区序列的互补决定区(CDR)(Wu,T.T.&Kabat,E.A.(1970).J Exp Med[实验医学杂志],132,211-50),并使用Blast比较框架区与人类种系基因。选择与小鼠框架具有最高序列同一性的人类种系作为人框架适应(HFA)的受体基因。在一些情况下,基于以往使用具有良好表达的人类框架经验来选择密切相关的人类种系基因。通过回译获得针对小鼠vH或vL V区中的每一个选择的人类框架的DNA序列。从集成DNA技术公司(Integrated DNA Technologies))(Coralville,IA)订购相应于HFA氨基酸序列的合成DNA区域。分别克隆进入人类IgG1和人类κ中。
实施例7:抗VISTA抗体构建体
用于细胞系发育的分子的质粒和序列信息:产生质粒构建体用于具有VSTB112可变区和IgG1κ恒定区(VSTB174,由于恒定区的同种型变化产生的新编号)、IgG2σig恒定区(VSTB140)或IgG1蛋白酶耐性恒定区(VSTB149)的抗VISTA抗体。
龙沙(Lonza)载体
在生物制品研究(BR)和药物开发与制造科学(PDMS)中建立pEE6.4和pEE12.4中国仓鼠卵巢(CHO)表达载体系统(龙沙生物制品公司(Lonza Biologics),PLC),作为在哺乳动物表达细胞系中产生治疗性mAb的主要表达系统。每个载体含有驱动重链(HC)或轻链(LC)表达的人类巨细胞病毒(huCMV-MIE)启动子并含有氨苄青霉素抗性基因。pEE12.4载体还包括编码谷氨酰胺合成酶(GS)的基因。需要谷氨酰胺合成酶活性的生长条件对细胞施加选择性压力以保持表达载体(GS基因表达系统手册4.0版)。使用pEE6.4克隆HC基因并且使用pEE12.4克隆LC基因作为单基因载体。从这两个龙沙(Lonza)单基因载体产生龙沙(Lonza)双基因质粒。
选择的VISTA mAb的重链可变区的氨基酸序列
>VSTB112重链(SEQ ID NO:37)
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQ
GLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSSYGWSYEFDYWGQGTLVTVSS
>VSTB50重链(SEQ ID NO:38)
QVQLVQSGSELKKPGASVKVSCKASGYTFTNYGLNWVRQAPGG
LEWMGWINPYTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCAREGYGNYIFPYWGQGTLVTVSS
>VSTB53重链(SEQ ID NO:39)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTHYTIHWVRQAPG
QGLEWMGYIIPSSGYSEYNQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGAYDDYYDYYAMDYWGQGTLVTVSS
>VSTB95重链(SEQ ID NO:40)
EVQLVESGGGLVQPGGSLRLSCAASGFTFRNYGMSWVRQAPGK
GLEWVASIISGGSYTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARIYDHDGDYYAMDYWGQGTTVTVSS
>VSTB116重链(SEQ ID NO:64)
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQ
GLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSSYGWSYEFDYWGQGTLVTVSS
选择的VISTA mAb的轻链可变区的氨基酸序列
>VSTB50轻链(SEQ ID NO:41)
DIVMTQTPLSLSVTPGQPASISCRASESVDTYANSLMHWYLQKP
GQPPQLLIYRASNLESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQTNEDPRTFGQGTKLEIK
>VSTB53轻链(SEQ ID NO:42)
DIVMTQSPLSLPVTPGEPASISCRSSQTIVHSNGNTYLEWYLQKP
GQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQASHVPWTFGQGTKLEIK
>VSTB95轻链(SEQ ID NO:43)
DIVMTQSPLSLPVTPGEPASISCRSSQSIVHSNGNTYLEWYLQKP
GQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPWTFGQGTKLEIK
>VSTB112轻链(SEQ ID NO:44)
DIQMTQSPSSLSASVGDRVTITCRASQSIDTRLNWYQQKPGKAPK
LLIYSASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSAYNPITFGQGTKVEIK
>VSTB116轻链(SEQ ID NO:45)
DIQMTQSPSSLSASVGDRVTITCRASQSINTNLNWYQQKPGKA
PKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQARDTPITFGQGTKVEIK
实施例8:抗VISTA抗体的ELISA和FACS筛选
这些实验是为了确定产生的抗体在ELISA中结合人类或猕猴VISTA蛋白的能力,以及使用FACS筛选确定抗体结合K562细胞(这些细胞表达人或猕猴猴VISTA蛋白质)表面上的VISTA蛋白的能力(人类髓细胞性白血病细胞系)。
方法:
ELISA程序概要:将板在4℃用1μg/ml SB0361(人类)或SB0361(cyno(猕猴))蛋白质(其是来自各个物种的VISTA的细胞外结构域)涂覆过夜。以1:4逐步稀释将抗体稀释至1μg/ml作为起始浓度,总共4个浓度,并在室温(RT)孵育2小时。使用小鼠抗人类IgG1-HRP(辣根过氧化物酶)进行检测,并在室温孵育1小时。所有洗涤均使用PBS-Tween(0.05%)进行。
FACS程序概要:将2x105K562-G8(人类)或K562-C7cyno细胞用5μg/ml的每个测试抗体染色,并在4℃孵育30分钟。使用山羊抗人类IgG1-PE(藻红蛋白)抗体作为第二检测抗体(以5μg/ml)。将细胞在BD Fortessa上运行,并使用FlowJo软件(树星公司(Tree Star,Inc.),Ashlang,OR)对活的群体的MFI(平均荧光强度)进行分析。
数据分析/结果:对于每种抗体,给出主观评分(是/否),涉及针对4种测定中的每种的ELISA和FACS分析抗体是否强有力地结合。如果在任一测定中抗体给出“否”结合结果,则重复确认其为阴性。结果显示在以下表7以及图19A-19F和20A-20F中。
表7.
实施例9:使用混合的淋巴细胞反应(MLR)和葡萄球菌肠毒素B(SEB)活化测定来筛选抗人类VISTA抗体的结果
此研究的目的是提供支持混合的淋巴细胞反应(MLR)测定以及葡萄球菌肠毒素B(SEB)活化测定中增强细胞免疫应答的多功能α-VISTA抗体的鉴定的数据。
混合的淋巴细胞反应(MLR)是依赖于MHC I类和II类错配以驱动同种异体T细胞应答的标准免疫学测定。从两个错配的个体中分离外周血单核细胞,一起孵育,并由于这些错配而发生增殖和细胞因子产生。
材料与方法:
通过将500ml的RPMI与50ml的人类AB血清、5ml的青霉素/链霉素(10,000U/ml)、5ml的L-谷氨酰胺(100x)和10ml的HEPES(1M)组合来制备10%AB培养基。培养基储存不超过14天。通过将0.2ml的胸苷储备液(1mCi/ml)在9.8ml的RPMI中稀释来制备1mCi氘化的胸苷。
在10%AB血清培养基中将可溶的VISTA抗体稀释至20μg/ml。将100μl的适当的抗体溶液添加至96孔U底部板(Falcon产品#353077或等价物)的适当的孔中。在添加各种细胞群后,最终浓度为10μg/ml。
白细胞的分离:供体是至少18岁,总体上健康,并从当地人口中随机选择的。将供体血液从分离试管转移至50ml锥形瓶。每25ml的血液铺设15ml的菲柯尔(Ficoll)1077,注意不要与血液混合。将细胞在1250g在室温离心25分钟没有中断。在菲柯尔(Ficoll)和血清的界面分离白细胞,并将细胞稀释到40ml汉克斯平衡盐溶液(Hanks Balances SaltSolution)(HBSS)中。将细胞在453g(1500rpm)在4℃离心10分钟。将细胞重悬浮于50ml的HBSS中,并通过将500μl转移到单独的试管中来计数。
混合的淋巴细胞反应(MLR)96孔板设置:基于待分析样品的数量确定测定所需的适当数量的“刺激细胞”和“应答细胞”。在96孔U底部板中,以0.5x105个细胞/孔接种刺激群体,并且以1.0x105个细胞/孔接种应答群体。所有条件必须一式三份进行。如先前描述将适当数量的“刺激细胞”吸取到新的锥形瓶中并离心。将细胞重悬浮于10ml中,并用4000rad辐射。如先前描述的离心细胞,并以1x106/ml的浓度重悬浮于10%AB血清培养基中,并将50μl添加至适当的孔中。分离所需数量的应答细胞并如先前描述的离心,并以2x106/ml的浓度重悬浮于10%AB血清培养基中,并将50μl添加至适当的孔中。将细胞在37℃和5%CO2孵育5天。在第五天,去除30μl的上清液用于分析干扰素γ(IFN-γ))生产。在第五天,将25μl的40μCi/ml氘化的胸苷溶液添加至每个孔中,并在37℃和5%CO2孵育8小时。按照制造商的说明,将细胞转移至96孔微量闪烁板(micro scintillation plate)中。按照制造商的说明,使用闪烁计数器计数。通过ELISA(eBioscience目录号88-7316-88),使用制造商的方案确定IFN-γ浓度。
数据分析:计算未处理孔的每分钟平均计数(CPM)或IFN-γ。计算每个测试组的平均CPM或IFN-γ。Log10转换数据集。使用每种化合物的12MLR倍得分,计算每种化合物的12个测试组的平均值。12次实验的平均得分=∑[(log10(测试化合物的一式三份的平均CPM))-(log10(无处理的一式三份的平均CPM))]/12
验收标准:所有测试试剂和适当的对照在运行测定前都进行了内毒素测试,并且具有<0.1Eu/mg的水平。仅应答细胞具有低于700CPM的平均CPM计数,表明单独孵育时这些细胞是休眠的。MLR组的CPM比单独孵育的应答细胞的CPM高至少2倍,表明反应已经发生并且供体不匹配。所有MLR测定包括人类IgG1阴性对照蛋白。基于使用学生t-检验,人类IgG1阴性对照的结果与未处理的样品没有统计学差异。
在MLR中筛选抗VISTA抗体:所有化合物的初始筛选。在用抗VISTA抗体运行MLR之前,经由FACS分析证实抗体与细胞结合的VISTA结合,并经由ELISA证实与VISTA蛋白质结合。抗体S26(VSTB77)、S30(VSTB86)、S31(VSTB88)、S32(VSTB90)和S39(VSTB74)未通过此初试筛选,但是在测定中仍然测试。出于初步筛选的目的,在MLR中以10μg/ml测试所有抗体,其中增殖和IFN-γ是测量的参数(图21A-21D和22A-22B)。
六种主要抗体的选择。从初始筛选中选择六种候选物进一步分析:VSTB112(S2)、VSTB116(S5)、VSTB95(S16)、VSTB50(S41)、VSTB53(S43)和VSTB60(S47)。
对MLR中的前六种候选物进行稀释研究:方案调整。该方案与先前描述的相同,伴随调整的是将抗体稀释至以下浓度:30μg/ml、10μg/ml、3μg/ml、1μg/ml、0.3μg/ml、0.1μg/ml、0.03μg/ml、0.01μg/ml和0μg/ml。
IC50值的确定:使用原始CPM计数和IFN-γ浓度来确定每种抗体的IC50。通过使用程序“EZ-R统计”确定IC50的计算。使用六名个体响应者来确定IC50值。MLR中伴随主要候选物的剂量滴定的个体CPM计数和IFN-γ浓度。
表8:MLR中的CPM和IFN-γ两者的IC50值
**值是以抗体浓度的log10。
结论:初步筛选指示多种VISTA特异性抗体能够增强MLR细胞免疫应答。然后基于功效和变化对抗体进行排名,并基于这些结果,选择VSTB112、VSTB116、VSTB95、VSTB50、VSTB53和VSTB60以在剂量滴定实验中进行评估。在剂量滴定实验中,VSTB60比其他五种抗体诱导更弱的反应。
葡萄球菌肠毒素B(SEB)活化测定:SEB是诱导特定Vβ+T细胞活化的细菌超级抗原。将外周血单核细胞分离并在培养中与SEB抗原孵育,其诱导强烈的细胞因子产生。此测定是对五种主要候选物进行的。
10%AB培养基的制备、1mCi氚化胸苷的制备、可溶的VISTA抗体的制备、白细胞的分离均如先前在MLR中描述的进行。
SEB96孔板设置:基于待分析样品的数量确定测定所需的适当数量的应答细胞。将应答群体以2.0x105个细胞/孔接种在96孔U底部板。所有条件必须一式三份进行。如先前描述的离心细胞,并以4x106/ml的浓度重悬浮于10%AB血清培养基中,并将50μl添加至适当的孔中。添加50μl的含有在40ng/ml浓度的SEB抗原的10%AB血清培养基。在描述的实验中,从西格玛奥德里奇公司(Sigma Aldrich)获得SEB(目录号S0812)。孔中的最终浓度是在10ng/ml。将细胞在37℃和5%CO2孵育3天。在第五天,去除30μl的上清液用于分析IFN-γ产生。将25μl的1mCi/ml氘化的胸苷溶液添加至每个孔,并在37℃和5%CO2孵育8小时。按照制造商的说明,将细胞转移至96孔微量闪烁板(micro scintillation plate)中。按照制造商的说明,使用闪烁计数器计数。通过ELISA(eBioscience目录号88-7316-88),使用制造商的方案确定IFN-γ浓度。
方案:数据分析。计算对于每种抗体所有浓度下的每分钟平均计数(CPM)或IFN-γ浓度。验收标准如先前描述进行。IC50值的确定如描述的进行。SEB测定中伴随主要候选物的剂量滴定的个体CPM计数和IFN-γ浓度。
表9:SEB中的CPM和IFN-γ两者的IC50值。
**值是以抗体浓度的log10
结论:在SEB测定中,VISTA特异性抗体以剂量依赖性方式增强细胞因子的产生和增殖。来自SEB研究的IC50值通常与来自MLR稀释研究的结果相似。
实施例10:表位分选测定
方法:使用ProteOn XPR36系统(伯乐公司(BioRad))进行表位分选(binning)。。使用针对胺偶联化学的制造商说明书(伯乐公司(BioRad),目录号176-2410),将ProteOn GLC芯片(伯乐公司(BioRad),目录号176-5011)用两组单克隆抗体(mAb)(每组6种)涂覆。
将竞争性mAb以过量与人类VISTA(25nM最终浓度)一起在室温下预孵育(250nM终浓度)4小时,每次6种在芯片上运行,该芯片用这些mAb组涂覆(4分钟的结合时间,然后解离5分钟)。每次运行之后,芯片用10 0mM磷酸再生。
数据分析涉及通过配体对所有传感图进行分组并应用对准向导,其自动执行X和Y轴对准以及去除假象。然后对这些数据进Interspot校正。
非竞争性mAb被定义为具有相同或>A1信号的结合信号(仅与人类VISTA结合)。
竞争性mAb被定义为具有<<A1信号的结合信号(即仅与人类VISTA结合)。
结果:在图23显示的实例传感图中,将VSTB85抗体包被在Proteon SPR芯片上,并将与所示竞争者预孵育的VISTA蛋白质在芯片上运行。VSTB50是非竞争性抗体的实例,因为当VISTA/VSTB50复合物运行时可见阳性反应。与VISTA复合的GG8、VSTB49和VSTB51不结合涂覆在芯片上的VSTB85,并因此被分类为与VSTB85竞争相同的VISTA结合位点。
表10:
mAb固定在传感器上
Y=是竞争(信号仅<<A1-人类VISTA)
N=没有竞争(信号仅>A1-人类VISTA)
I=不确定(仅与A1-人类VISTA相似的信号)
实施例11:确定ProteOn亲和力
使用抗IgG Fc涂覆的表面在ProteOn芯片上捕获抗体。测试在从0.39nM至100nM范围的VISTA蛋白质的浓度的抗体与人类和猕猴(cyno)VISTA细胞外结构域(ECD)的结合。允许抗原与抗体涂覆的芯片结合/缔合持续4分钟,在此时间之后,监测解离30分钟。将芯片用100mM磷酸的处理两次18秒使再生。所有的实验均在25℃下运行,数据拟合至1:1Langmuir结合模型。
实施例12:MB49小鼠膀胱肿瘤模型中抗VISTA治疗效果
方法:
将C57Bl/6小鼠用MB49肿瘤细胞注射。一旦肿瘤建立,开始抗VISTA治疗。然后监测肿瘤生长3次/周。一旦肿瘤在任意维度达到15mm,根据IACUC的规定将小鼠安乐死。
对于每个实验,将MB49细胞的冷冻的小瓶解冻,并在具有10%血清和青霉素/链霉素抗生素的RPMI 1640(+L-Glut)中生长。培养3天后,使用StemPro Accutase收获细胞,并以5x106细胞/ml的浓度重悬浮于RPMI中,每只小鼠注射50μl。
6-8周龄的雌性C57Bl/6小鼠购自国立癌症研究所(National CancerInstitute)。抵达后,在它们的右侧剃光以及它们尾巴刺图案前,允许它们适应一天。然后三-五天后对它们进行注射。
肿瘤注射(真皮内):在其剃毛侧向小鼠皮内(i.d.)注射50μl的MB49细胞悬浮液(约250,000个细胞)。
监测肿瘤生长:使用电子卡尺首先在最宽的尺寸(L)上测量肿瘤生长,其次以与第一测量(W)成90°的角度测量肿瘤生长。肿瘤体积推断为如下:
体积=(L2 *W2)/2
一旦其达到约5mm直径(约60mm3体积),就认为肿瘤已经建立。一旦建立,就开始治疗。在治疗过程中每周测量三次肿瘤生长,直到实验结束。
抗VISTA处理:将嵌合的13F3-mIgG2a单克隆抗体以10mg/kg腹腔内注射。注射时间表是每周三次,持续四周。
安乐死小鼠:根据IACUC的要求,一旦肿瘤的最长尺寸达到15mm,就将动物安乐死。
分析功效:分析小鼠肿瘤体积,使用Excel进行数据管理,并且使用GraphPadPrism用于作图。使用R统计计算软件的宏进行统计分析。
实验设计显示在图24中。
结果:
雌性小鼠中的Ch13F3-mIgG2a处理导致在70%的动物中的完全肿瘤排斥(CR),并且在30%中的部分缓解(PR)(n=7)(表13和图25B)。相反,所有对照mIgG2a-处理的小鼠显示肿瘤的渐进式生长(6/6)(图25A)。这些数据展示抗VISTA治疗可以对肿瘤生长产生深远的影响。
表11:完全缓解(CR)对比部分缓解(PR)
雌性13F3 IgG2a(n=7) | |
CR | 5 |
PR | 第2天直至第32天 |
人类VISTA序列显示在图26和27中,改变自Wang等人,2011,同上,其内容通过引用以其整体结合在此。
实施例13:使用氢/氘(H/D)交换研究的抗VISTA抗体表位作图
为了鉴定人类VISTA上的VSTB50、60、95和112的表位,使用相应的Fab进行溶液氢/氘交换质谱(HDX-MS)。对于H/D交换,用于分析Fab扰动的程序与先前描述的相似(Hamuro等人,J.Biomol.Techniques[生物分子技术杂志]14:171–182,2003;Horn等人,Biochemistry[生物化学]45:8488-8498,2006),具有一些修饰。使用Pierce Fab制备试剂盒(赛默科技公司(Thermo Scientific),目录号44985),用木瓜蛋白酶消化和蛋白A捕获从IgG制备Fab。人类VISTA蛋白质序列含有六个N-连接的糖基化位点。为了提高序列覆盖率,将蛋白质用PNG酶F去糖基化。将去糖基化的VISTA蛋白质在氘化的水溶液中孵育预定的时间,导致在可交换的氢原子处的氘掺入。将氘化的VISTA蛋白质与VSTB50、VSTB60、VSTB95或VSTB112的Fab在46μL氧化氘(D2O)中在4℃下复合30秒、2分钟、10分钟和60分钟。将该交换反应通过低pH淬灭,将蛋白质用胃蛋白酶消化。从LC-MS上的质量转移监测鉴定的肽处的氘水平。作为参考对照,将VISTA蛋白质类似地处理,除了它不与Fab分子复合。将与Fab结合的区域推测为是相对受到交换保护的位点,因此比参考VISTA蛋白质含有更高比例的氘。该蛋白质的约94%可以被映射到特定的肽。
VISTA与VSTB50/VSTB60、和VSTB95/VSTB112的溶液HDX-MS扰动图分别如图28上图和下图所示。鉴定了两个表位组。抗VISTA VSTB50识别与VSTB60相同的表位;VSTB95结合至另一个表位区域(如VSTB112结合至VISTA一样)。抗VISTA VSTB50和60共享相同的表位,其包含区段103NLTLLDSGL111(SEQ ID NO:62)、和136VQTGKDAPSNC146(SEQ ID NO:63)(图28,上)。抗VISTA VSTB95和112似乎靶向相同的表位,这些表位包含区段27PVDKGHDVTF36(SEQ IDNO:74)和54RRPIRNLTFQDL65(SEQ ID NO:65)(图28,下)。还有另外两个区段显示VSTB95和112造成的微弱扰动,包括残基39-52和118-134。但是,差异图中的减少水平并不像先前区域(27-36和54-65)那么强。尽管一个肽(100TMR102,显示出VSTB95和112造成的强烈扰动)位于VISTA表面的另一面,但其远离表位区域27-36和54-65。这种扰动可能是由于变构效应。这些HDX-MS结果提供了抗VISTA抗体的肽水平表位。这两个表位组没有重叠的表位区域。这些结果与先前的竞争分选数据是一致的,因为它们不会与彼此竞争。
实施例14:通过蛋白质结晶学确定人类VISTA ECD:VSTB112 Fab复合物的结构
为了确定VISTA结构并描绘表位和互补位(定义VISTA细胞外结构域(ECD)与前导抗体VSTB112的Fab片段之间相互作用),将该复合物结晶并且结构确定为分辨率。在确定VISTA ECD本身的结构并定义该相互作用的表位/互补位的工作中,确定与抗体VSTB112的Fab片段复合的人类VISTA的ECD结构。该结构揭示了VISTA采用具有与TCR Vα链相似的链拓扑结构的IgV折叠。除了在β-夹层的背面和正面桥接B和F链的典型二硫键之外,该结构还揭示了ECD具有两个另外的二硫键,一个将CC'环连接到前片上并且第二个在A'和G'链之间。尽管在VISTA分子之间存在晶体接触,但是它们是微小的,并且基于这种结构没有证据表明VISTA ECD的二聚体。显示VSTB112表位包含以下部分:VISTA BC、CC'和FG环以及与最接近那些环的前面β片层(C'CFG)的残基。互补位在很大程度上偏向与CDR L3相互作用的重链从而使接触最小。
定义VISTA:VSTB112的相互作用的表位/互补
VSTB112 Fab在结合VISTAECD时掩埋了2的表面积,埋入重链表面占此总数的2。在VISTA和VSTB112轻链之间形成7个氢键和4个盐桥相互作用,并且在VISTA和VSTB112重链之间形成10个氢键和2个盐桥相互作用。VSTB112识别最接近FG环的末端处的前片链C'、C、F、和G的残基以及BC、FG、和CC'环中的残基(图29和30)。与CC'环的相互作用说明大多数接触是与Fab轻链,其中只有FG环中的残基E125和R127产生另外的轻链相互作用。对应于VISTA FG环的残基119至127占结合VSTB112后埋藏的总表面积2的38%。值得注意的是,该环是高度极性的,由序列–IRHHHSEHR-(SEQ ID NO:75)组成。另外,VSTB112CDR H3中的W103与VISTA残基H122和H123的骨架很好地包装在一起,并且VISTAH121在CDRH2中与F55的芳香环相互作用方面具有优势。
结晶学和HDX鉴定的表位区域的比较显示在图31中。
实施例15:通过抗VISTA抗体激活T细胞和单核细胞
在两种体外测定(混合的白细胞反应(MLR)和SEB(葡萄球菌肠毒素B))中评估抗VISTA抗体的功能效果。两种测定均测量T细胞增殖和细胞因子诱导作为其主要读数,但是这些效果是由于不同的机制。在MLR中,将来自两个不同人类供体的外周血单核细胞(PBMC)一起孵育,一个供体的T细胞与另一个供体的树突状细胞之间的主要组织相容性复合体(MHC)错配导致T细胞增殖和干扰素(IFNγ)产生。在SEB测定中,将来自单个供体的PBMC与细菌超级抗原一起孵育,该超级抗原将在抗原呈递细胞(APC)表面上的MHC II类蛋白直接连接到T细胞上的T细胞受体(TCR),导致T细胞活化、增殖和细胞因子分泌。在两个测定中,作为VSTB174的母体分子的VSTB112展示了剂量依赖性的T细胞增殖和细胞因子产生的诱导,并且在候选物中是最有效的(图21A-21D,表12)。
表12.MLR测定读数的EC50值。VSTB112(VSTB174的母体)是最有效的分子。
候选物 | EC<sub>50</sub>增值(μg/ml) | EC<sub>50</sub> IFNγ产生(μg/ml) |
VSTB112 | 0.21 | 0.38 |
VSTB116 | 0.17 | 0.69 |
VSTB95 | 0.29 | 1.67 |
VSTB50 | 0.77 | 1.14 |
VSTB53 | 0.47 | 1.88 |
VSTB60 | 1.04 | 2.48 |
单核细胞激活测定
显示在表12中的测定数据是用VSTB112(VSTB174的母体分子)产生的。为了更好的理解VSTB174的活性,实施单核细胞激活测定。结果显示,VSTB174与全部PBMC的孵育诱导CD14+单核细胞上活化标志物(CD80和HLA-DR)的上调,表明抗体与已知表达高水平VISTA的免疫细胞亚类结合(图32)。另一个问题是,是否可以通过结合VISTA并具有IgG1Fc的任何抗体促进全部PBMC中单核细胞活化的作用。与VSTB112和VSTB111类似,抗体VSTB103和VSTB63以高亲和力与VISTA结合(分别为KD 6.36E-10和8.30E-10),并与表达VISTA蛋白质的细胞结合。VSTB103与VSTB112处于相同的表位库中,而VSTB63处于不同的表位库中;没有抗体促进单核细胞活化。总之,这些结果表明,VSTB174对T细胞活化/增殖起作用的一种机制是经由NK细胞促进的单核细胞活化。
制备培养基
将500ml的RPMI 1640(康宁公司(Corning),10-040-C)与50ml的人类AB血清(谷生物医学公司(Valley Biomedical,Inc),Lot#3C0405),5ml的青霉素/链霉素(龙沙公司(Lonza),17-602E),10,000U/ml、5ml的L-谷氨酰胺(100x)(Gibco,25030-081)和10ml的HEPES(1M)(Fisher BP299-100,Lot#-1)组合。培养基在4℃储存不超过14天。
制备可溶的VISTA和对照抗体
在10%AB血清培养基:VSTB174:lot VSTB174.003中将抗体稀释至2X所需浓度。
将100μl的适当的抗体溶液添加至96孔U底部板(Falcon,353077)的适当的孔中。在各种细胞群以100μl添加后,每种抗体的最终浓度为1g/ml、0.1g/ml或0.01g/ml。以1μg/ml的最终浓度添加IgG1对照抗体CNTO 3930(Lot 6405,ENDO<0.1EU/mg)。
分离PBMC
供体是至少18岁,总体上健康,并从当地人口中随机选择。
将供体血液从分离试管中转移至50ml锥形瓶中。
铺设15ml的菲柯尔(Ficoll)1077(SIGMA,10771)时小心地不要与血液混合。这是以每25ml的血液。
将细胞在室温在1250g离心25分钟没有中断。
在菲柯尔(Ficoll)和血清的界面分离白细胞,并将细胞稀释到40ml汉克斯平衡盐溶液(Hanks Balances Salt Solution)(HBSS)中。
将细胞在4C在453g(1500rpm)离心10分钟。
将细胞重悬浮于50ml的HBSS中,并通过将500μl转移到单独的eppendorf管中来计数。
另外,根据制造商的说明(目录号130-096-537),使用来自Miltenyi的泛单核细胞分离试剂盒,通过在若干个处理组中的阴性选择来分离CD14+细胞。
体外培养设置
根据待分析样品的数量确定测试所需的细胞的适当数量。将应答群体以2.0x105个细胞/孔在96孔U底部板接种。对于CD14阴性选择的群体,接种0.5x105个细胞。所有条件都是一式三份地进行。
如上文描述离心细胞,并以2x106/ml的浓度(对于全部PBMC群体而言)重悬浮并且以0.5x106/ml的浓度(对于CD14阴性选择群体而言)重悬浮于10%AB血清培养基中,并将100μl测试抗体添加至适当的孔中使每个孔的总体积达到200μl。
将细胞在37℃和5%CO2孵育1天、2天、或3天。
抗体染色和流式细胞术
将该96孔U底部板在453g离心5分钟并去除上清液。
将细胞用200μl PBS洗涤并如在步骤5.5.1中离心。
丢弃上清液并重悬浮于50μl的含有以下抗体的PBS中:
·CD14-APC(克隆HCD14)1:250(博奇公司(Biolegend),目录号325608)
·HLA-DR-PE Cy7(克隆L243)1:250(博奇公司(Biolegend),目录号307616)
·CD80-PE(克隆2D10)1:250(博奇公司(Biolegend),目录号305208)
·Hu FcR结合抑制剂(eBioscience目录号14-9161-73)
在黑暗的湿冰上孵育20分钟。
添加150μl的PBS并如在步骤5.5.1中离心。
添加150μl的PBS缓冲液并经由FACS进行分析。
将样品在Miltenyi MACSQuant 10参数流式细胞术上运行,并使用FlowJo 9.7.5分析CD14+群体上HLA-DR和CD80的表达。几何平均荧光强度(MFI)是定义一组数字的中心趋势的统计量,被用作定义统计量来比较治疗。
统计分析
所有统计均在Prism GraphPad第6版中进行。在这些组之间的成对比较在每个时间点进行,使用具有针对多重性的Tukey校正的单程ANOVA。对于所有测试P值小于0.05,并且比较认为是显著的。对于所有图和表,*p<0.05、**p<0.01、***p<0.001、****p<0.0001。
实施例16:抗VISTA抗体的ADCC和ADCP活性
VSTB174具有IgG1 Fc,其可以赋予抗体依赖的细胞介导的细胞毒作用(ADCC)和抗体-依赖的细胞介导的吞噬作用(ADCP)活性。分析两种类型的测定并显示VSTB174可以裂解或吞噬K562-VISTA细胞(图33-34),但不是K562骨髓瘤细胞系亲本细胞(数据没有显示)。激活VSTB174以调整VISTA的抑制作用的另外的作用机制可以是细胞的裂解作用或吞噬作用,这些细胞表达高水平的VISTA,因此从局部微环境中去除它们。
实施例17:另外的抗VISTA抗体的ADCP活性
使用体外吞噬测定来研究细胞的巨噬细胞介导的吞噬作用的增强,这些细胞通过抗人类VISTAmAb(VSTB173和VSTB174)异位表达VISTA。这些mAb被克隆到不同的Fc骨架(IgG1 WT(野生型)、IgG1 PR(蛋白酶抗性)和IgG2σ)中,并假定可能在增强吞噬作用方面具有不同的活性。IgG1和IgG1 PR骨架能够与Fc受体结合并可能引起ADCP,而IgG2σ不与Fc受体结合并且不应该介导ADCP。
用K562亲本和K562-VISTA靶细胞在ADCP测定中测试抗VISTA抗体。如在图35-36中显示,VSTB174、VSTB149、VSTB173和VSTB145增强了K562-VISTA细胞的hMac吞噬作用。具有不结合Fc受体的IgG2σFc的VISTA抗体VSTB140或VSTB132不如预期的那样增强吞噬作用。具有IgG1 Fc的VISTAmAb VSTB174和VSTB173显示出比具有IgG1PR Fc的VSTB149和VSTB145更强的吞噬作用(EC50值参见表13和14)。
表13.抗人类VISTA mAb EC50值。
处理 | VSTB174 | VSTB149 | VSTB140 |
EC<sub>50</sub> | 0.0782 | 0.1142 | NA |
表14.抗人类VISTA mAb EC50值。
处理 | VSTB173 | VSTB145 | VSTB132 |
EC<sub>50</sub> | 0.0146 | 0.1075 | NA |
VSTB174和VSTB173在最高浓度时表现出对K562亲本细胞的吞噬作用弱的增强(图35-36),这可能是由于K562细胞的VISTA低表达。其他抗VISTA抗体不增强K562细胞的吞噬作用。
阴性对照抗体在K562-VISTA吞噬作用测定中各自以两种不同浓度进行测试,但不诱导任何吞噬作用。此结果指示由抗VISTA抗体介导的吞噬作用是特异性的,并且是归因于K562-VISTA细胞的VISTA抗原表达。
实施例18:另外的抗VISTA抗体的ADCC活性
为了测试它们诱导ADCC的能力,测试了以下三种人类抗VISTA抗体:
VSTB174(IgG1)
VSTB149(IgG1 PR)
VSTB174.LF(IgG1 LF(低海藻糖))
在相同板内以六个不同浓度测试每种抗体,一式三份共两个独立试验,总共六个数据点。
在10μg/mL、1μg/mL、0.1μg/mL和0.01μg/mL,VSTB174、VSTB149、和VSTB174.LF每个展示可测量的ADCC活性,而只有LF抗体在0.001μg/mL展示出可测量的ADCC活性;在0.0001μg/mL没有抗体展示ADCC。由于这些抗体中的每一个都具有IgG1或IgG1变体Fc,所以该结果是预料之中。如与常规IgG1抗体曲线(0.02381μg/mL)相比LF抗体曲线的较小EC50值(0.002293μg/mL)所证实的,LF抗体展示增加的ADCC效价。IgG1 PR抗体曲线具有与常规IgG1曲线相似的EC50值(0.01846μg/mL)。
表15.通过ADCC分析确定的三种经测试的抗VISTA抗体的EC50值(μg/mL)。
抗VISTA抗体 | EC<sub>50</sub>(μg/mL) |
VSTB174(IgG1) | 0.02381 |
VSTB149(IgG1 PR) | 0.01846 |
VSTB174.LF(IgG1 LF) | 0.002293 |
人类IgG1、人类IgG1 PR和人类IgG1 LF抗体均在10μg/mL、1μg/mL、0.1μg/mL和0.01μg/mL抗体浓度下显示可测量的ADCC介导的杀伤,而只有LF抗体显示在0.001μg/mL抗体浓度下的杀伤。没有抗VISTA抗体显示在0.0001μg/mL抗体浓度下的杀伤。
LF抗体显示出比常规IgG1抗体或IgG1 PR抗体大约10倍更有效的ADCC杀伤,如在EC50值中所见。
实施例19:VSTB174对人类和猕猴VISTA的亲和力
通过在ProteOn仪器上的表面等离子体共振(SPR)方法确定VSTB174对人类和猕猴VISTA细胞外结构域(ECD)的亲和力。对于每种蛋白质,VSTB174展示非常相似的KD值,对于人VISTA ECD为1.56E-10M,对猕猴VISTA为8.66E-11M。
实施例20:VISTA抗体在在鼠肿瘤模型中展现功效
小鼠品系、试剂和肿瘤模型
对于体内研究,使用回交到C57Bl/6背景上的人类VISTA敲入(VISTA-KI)小鼠。
产生抗人类VISTA抗体以使得能够使用嫁接到小鼠Fc IgG2a(VSTB123)上的VSTB174可变区在VISTA-KI小鼠中进行测试。
在VISTAKI小鼠中评估MB49膀胱癌。
除了公开的研究证明抗VISTA抗体治疗抑制野生型小鼠中的肿瘤生长(LeMercier等人,2014)之外,在wt小鼠中使用不同剂量方案以及在使用VSTB123处理的VISTA-KI小鼠中),利用替代性仓鼠抗体已经证实了抗肿瘤功效。
VISTA-KI小鼠中MB49肿瘤模型的体内功效研究
MB49功效研究在雌性VISTA-KI小鼠中进行,测试从1-10mg/kg范围的若干剂量的VSTB123。在第0天,向小鼠皮内注射250,000个MB49肿瘤细胞。在第6天,如图37中指示开始给药(10mg/kg同种型对照mIgG2a或指定剂量的VSTB123;10只小鼠/组)。
如在图37中显示,VSTB123在较高剂量比在较低剂量更有效。10mg/kg和7.5mg/kg的剂量是等价的,而在5mg/kg或1mg/kg给药的小鼠中肿瘤生长得更快。
实施例21:用抗VISTA抗体检测人肿瘤中的VISTA表达
图1显示了AML肿瘤细胞系的VISTA表达-这和图17中的RNA序列表达数据支持以下想法:VISTA通过AML细胞表达,并且抗VISTA药物通过直接靶向这些细胞进行免疫调节或抗体介导的杀伤起效。
评估VISTA在肺癌中的表达的数据从外科手术切除的肺肿瘤样品中获得。将细胞解离并表征VISTA和许多其他标记的表达。结果显示13/13肺肿瘤(鳞状细胞癌或腺癌)含有CD14+VISTA+髓样细胞(图38)。
实施例22:使用抗VISTA抗体检测肺肿瘤中的VISTA表达
使用克隆GG8(抗人类VISTA小鼠IgG1)对免疫组织化学测定进行优化。该mAb用于研究非小细胞肺癌(NSCLC)FFPE肿瘤切片中的VISTA染色。
在染色之前,将FFPE肿瘤切片用标准抗原修复方法处理。以1:500稀释度使用GG8小鼠抗人类VISTA抗体。使用兔抗小鼠多克隆抗体,随后使用抗兔聚合物HRP检测GG8结合。随后用苏木精复染色,然后对肿瘤切片进行评分。
VISTA在肺癌中的表达大多局限于免疫浸润(实例显示在图39中),并且高水平的VISTA阳性细胞存在于许多肺癌样品中。
实施例23:与Vstb174的Fab片段复合的人类VISTA的细胞外结构域(ECD)的结构
产生VISTA抗原变体并纯化用于结晶学。重组体his标记的VSTB174 Fab在内部表达并纯化。生成晶体并用于使用同步辐射收集VISTA ECD:VSTB174 Fab复合物的更高分辨率数据,并且使用同源性模型和电子密度分析的组合来解决结构确定(图29(上))。
VISTA ECD:VSTB174 Fab复合物的结构通过X射线晶体学确定至的分辨率,提供了VISTA ECD的第一结构并描绘了VSTB174表位和互补位。VISTA ECD采用具有类似于CTLA-4ECD的拓扑结构的IgV折叠,但是具有延伸β-夹层前片的独特的G'链。A'和G'通过在A'链中的残基C12和G'链中的C146之间形成的二硫键而进一步化学连接。发现六个半胱氨酸参与三个分子内二硫键,并且基于晶体接触,没有二聚体VISTA的证据。
VSTB174识别最接近FG环的末端处的前片链C’、C、F、和G的残基以及BC、FG、和CC’环中的残基。
实施例24:将VSTB116 VH和VL区域克隆到小鼠IgG1骨架中
将VSTB116重链(SEQ ID NO:57)和轻链(SEQ ID NO:58)可变区亚克隆到小鼠IgG1骨架中以产生VSTB175。使用载体vDR000367(编码小鼠IgG1 Balb C恒定区的pUnder载体)和来自pDR17582的VSTB116可变区产生VSTB175重链表达质粒pDR23170。在Genewiz进行具有HindIII_BamH1位点的pDR23170的标准合成,并在HindIII_BamH1位点将其定制克隆到载体vDR000367(pUnder_mG1 Balb C)中,从而制备pDR23170的最终产物。通过在GeneArt标准合成可变区,并添加接头,产生VSTB175轻链表达质粒pDR21003。使用Esp3I位点线性化vDR000371(编码小鼠κ恒定区的pUnder载体)。然后将VSTB175轻链可变区序列的合成的片段融合克隆到vDR000371中,生成pDR21003。将所得到的初级转录物进行测序证实,并且大规模的DNA制备物被制备用于转染。
表16:用于VSTB175的完整轻链和重链序列
*恒定区序列是下划线的;推定的CDR序列是斜体化的。
实施例25:VSTB175的表达、纯化和分析
Expi293F细胞(生命技术公司(Life Technologies Corporation)目录号A14527)在37℃;7%CO2;130RPM下,在Expi293表达培养基(生命技术公司(Life TechnologiesCorporation)目录号A14351-01)中生长。在转染前两天,细胞以7e5细胞/ml分裂。在转染时,对细胞进行计数并证实其浓度为至少30e5细胞/ml,并且高于95%存活。对于每个转染30-mL;30ug的质粒DNA与Opti-MEM I血清减少培养基(生命技术公司(Life TechnologiesCorporation)目录号31985-070)混合至1.5mL的总体积(15ug的pAdvantage DNA和15ug的表达载体DNA(对于抗体而言,HC:LC表达构建体的比例为1:3))。将81uL的ExpiFectamine293试剂(生命技术公司(Life Technologies Corporation)目录号A14525)然后稀释进Opti-MEM I培养基中至1.5mL的总体积。然后将稀释的DNA和ExpiFectamine溶液温和地混合并在室温孵育5分钟。将稀释的DNA添加至稀释的ExpiFectamine 293试剂中,温和地混合,并在室温孵育20分钟。在孵育之后,然后将混合物添加至在125ml摇瓶中的25.5ml的细胞中。转染后立即将150uL的ExpiFectamine293转染增强子1和1.5mL的ExpiFectamine293转染增强子2添加至每个烧瓶(生命技术公司(Life Technologies Corporation)目录号A14525)中。转染后5天,通过离心收获细胞上清液并通过0.2微米过滤器澄清。
将两个VSTB175瞬时293Expi转染收获物汇集并将1xDPBS+0.5M NaCl作为缓冲液。使用AKTA纯化器在2℃-10℃将样品纯化。将样品捕获到MabSelect SuRe树脂(20mL,1.6cmID x 10cm H)上。用1xDPBS+0.5M NaCl将未结合的样品从树脂上洗掉。将mAb用0.1M Na+醋酸盐(pH3.5)洗脱。收集洗脱级分(8-mL),然后OD280是>25mAU/2mm。将洗脱级分用每个级分2-mL 2.5M Tris HCl pH 7.2中和,并且储存在2℃-10℃,待进一步处理。通过OD280和SE-HPLC分析洗脱峰级分以确定蛋白质浓度和%聚集体。由于在此分析中观察到大量聚集体,样品需要SEC精制。将样品浓缩并使用Superdex 200柱(26/60柱,2.5mL/min 1xDPBS,4-mL级分)进行SEC分级分离。通过OD280(蛋白质浓度)、LAL(内毒素含量)、SE-HPLC(%单体mAb)、和SDS-PAGE分析样品。通过SE-HPLC分析,该样品是98.22%单体mAb。
1)在运行测定前,将抗人类Fc生物传感器浸泡在转染培养基(例如Freestyle 293表达培养基(生命技术公司(Life Technologies Corporation))或CHO)中10min。将120μl培养基添加至FIA 96孔板中。将96孔板置于生物传感器托盘中,并将电极头放入托盘中的培养基中。2)在转染培养基中以1:10稀释样品(或者以1:25浓缩样品)。3)将120μl的每个纯的和1:10稀释的样品转移到第二个96孔黑色FIA板中。4)标准曲线已经加载到Octet机器上。5)在已经添加所有未知样品后,添加三个标准样品(40μg/ml、20μg/ml和10μg/ml标准对照抗体)。用转染培养基填充该柱的其余孔作为参考。6)根据制造商的说明在ForteBioOctet中运行样品。
实施例26:VSTB175分子病理学免疫组织化学测定开发
建议浓度:10μg/ml;稀释剂:Dako普通抗体
使用的修复方法:将新鲜制备的Dako低pH修复溶液在加压容器(修复器)中在121℃持续20分钟,然后在修复器中冷却40分钟。去除并在室温冷却15min。
检测系统:抗小鼠聚合物Envision+系统DAB(Dako)。
仪器:Biogenex i6000
方案步骤:1)将4μm石蜡切片脱蜡至去离子水。2)抗原修复。3)在去离子水中漂洗。4)过氧化酶封闭(3%H2O2)15min。5)用洗涤缓冲液漂洗至少15min。6)在室温,将蛋白质封闭(达科公司(Dako),Carpinteria,加利福尼亚)持续60min。7)第一抗体在室温60min。8)在洗涤缓冲液中漂洗五次。8)过氧化物酶标记聚合物抗小鼠30min。9)在洗涤缓冲液中漂洗五次。10)工作DAB持续5min。11)在去离子水中漂洗三次。12)在洗涤缓冲液中漂洗五次。13)Mayers苏木精复染5分钟。14)在使用盖玻片之前,用自来水漂洗并耗尽溶剂。
结果示于图41和表17-18中。
表17:肿瘤微环境隔区
表18:肿瘤隔区
实施例27:肺癌组织中的vstb175抗体克隆
材料与方法:
VISTA VSTB175抗体和NSCLC样品:提供VISTA VSTB175抗体的冷冻等分试样用于人类NSCLC组织样品中的优化。选择9个福尔马林固定的石蜡包埋(FFPE)的样品进行评估,一旦鉴定了优化的VISTA(VSTB175)IHC测定,将载玻片上的未染色切片用于免疫组织化学(IHC)染色。
IHC测定优化:在扁桃体和脾脏组织中进行VISTA(VSTB175)IHC测定。在一定范围的抗体稀释度(1:500、1:1000、和1:2000)下,评估在pH 6的柠檬酸钠下两种抗原修复时间(20min和40min)。扁桃体和脾脏组织中的染色呈现通过职业认证的兽医病理学家评估,并确定了最佳的测定条件。最佳IHC测定使用柠檬酸钠(在pH 6)在90℃(选择此温度是因为实验室高海拔位置)持续40min进行抗原修复,VISTA(VSTB175)抗体稀释度为1:500(6.36mg/ml起始浓度)持续60min,并用DAB显影10min。根据以下方案,使用Leica Bond RXAutostainer进行IHC测定:
详细的方案(使用Leica Bond RX或Max Autostainer):
1.按照通常的载玻片方案将载玻片切成4微米。允许载玻片风干,并然后在60℃烘烤60分钟。一般在切割2周内使用载玻片进行染色。
2.将烘烤的载玻片放在Leica载玻片架上,将盖玻片放在载玻片上,然后将支架插入Autostainer中。
3.用Leica抗体稀释剂(#AR9352)将第一抗体稀释至1:500。
在Leica Bond RX/Max Autostainer上进行以下步骤:
1.在72°℃,施用结合的脱蜡溶液(Bond Dewax Solution)(#AR9222)三次。
2.施用100%乙醇三次
3.施用Leica结合洗涤1X溶液(#AR9590)三次。
4.Leica ER 1表位修复溶液(#AR9961)在90℃孵育40分钟。
5.施用Leica结合洗涤1X溶液五次。
6.Thermo Pierce无蛋白封闭缓冲液(#37584)孵育5分钟。
7.在施用抗体前没有冲洗。
8.抗体稀释孵育60分钟。
9.施用Leica结合洗涤1X溶液三次。
10.在主要连接(Leica结合聚合物Refine试剂盒#DS9800)之后,孵育8分钟。
11.施用Leica结合洗涤1X溶液持续2分钟三次。
12.聚合物(Leica结合聚合物Refine试剂盒#DS9800)孵育8分钟。
13.施用Leica结合洗涤1X溶液持续2分钟两次。
14.DI水漂洗。
15.过氧化物封闭(Leica BPR试剂盒)孵育10分钟。
16.施用Leica结合洗涤1X溶液两次。
17.DI水漂洗。
18.DAB发色团/底物(Leica BPR试剂盒)孵育10分钟。
19.施用Leica结合洗涤1X溶液三次。
20.苏木精复染(Leica BPR试剂盒)孵育2分钟。
21.DI水漂洗。
22.施用Leica结合洗涤1X溶液一次。
23.DI水漂洗。
24.从Leica Bond RX/Max去除载玻片。
如以下手动进行脱水和盖玻片:
23. 95%乙醇的两次更换(每次1分钟)
24. 100%乙醇的两次更换(每次1分钟)
25.二甲苯的两次更换(每次2分钟)
26.具有Cytoseal封片剂的盖玻片。
载玻片扫描和注释:IHC染色完成后,使用Aperio型号CS和XT扫描仪将载玻片数字化。一旦将每个载玻片数字化,利用注释来识别分析区域(ROA)。ROA捕获每个样品和周围的基质组织隔区内的可分析的肿瘤组织。通过注释从分析中去除不希望的组织特征,例如坏死、大面积的煤肺病(碳色素)和淋巴滤泡(如非肿瘤相关的预先存在的淋巴群体)。在进行图像分析之前,通过注释识别的每个ROA由病理学家评估和核准。
图像分析:项目启动前,VISTA阳性细胞数/mm2被确定为本次研究的主要终点。肿瘤细胞巢和相关的浸润性炎症细胞被作为肿瘤组织隔区进行分析。基质细胞区和相关的浸润性炎症细胞被作为肿瘤微环境(TME)组织隔区进行分析。结果:
结果显示在以上表17和表18中。
用于VISTA(VSTB175)的IHC测定开发:对IHC测定条件的基质进行测试以鉴定VISTA VSTB175抗体试剂的最佳IHC测定。表19概述了优化过程中评估的条件。图42展示了对于两个独立的染色日,人类扁桃体切片(阳性对照组织)的染色。通过评估扁桃体(阳性对照)和脾脏(阴性对照)组织切片来鉴定最佳测定条件。通常,在扁桃体卵泡中鉴定到少量阳性细胞。另外,在卵泡外的上皮细胞下区域观察到VISTA染色,难以解释。
表19:评估的用于优化的测定条件
一旦鉴定了最佳测定条件,用VISTA(VSTB175)IHC测定法对九个人类肺癌样品进行染色。图43显示在研究样品中观察到的VISTA+(VSTB175)染色的三个实例。每个研究样品的初始主观评估显示极少(如果有的话)VISTA+细胞。在每个研究样品的许多细胞中观察到染色。
VISTA分析溶液开发:评估一系列敏感的DAB(即VISTA)阳性门控,以确定用于鉴定在细胞中观察到的低水平VISTA染色同时最小化假阳性细胞的最佳门控。在两个抗体克隆之间样品的排名顺序保留得很差,并且表明每个抗体在肿瘤组织隔区中捕获不同的现象。这些发现与以下观点一致:VISTA VSTB175克隆的提高的特异性导致肿瘤组织隔区中较少假阳性细胞检测。最后,基于VSTB175克隆的样品的排名顺序不依赖于VISTA阳性门控,并进一步指示两个门控以不同的灵敏度测量样品生物信息。
表20:VISTA VSTB175的排名顺序比较;在TME组织隔区中基于VISTA+细胞密度的研究样品排名顺序。
表21:VISTA VSTB175的排名顺序比较;在肿瘤组织隔区中针对VISTA+细胞密度的排名顺序。
实施例28:免疫组织化学
方法:
用由杨森公司(Janssen)提供的抗体进行抗体滴定实验。用VSTB175(嵌合抗体)和一种即用型小鼠IgG1同种型对照抗体(BioGenex目录号HK119-7M,称为BGX-Ms-IgG1)进行免疫组织化学染色以建立将导致检测的最小背景和最大信号的浓度。用由LifeSpan提供的福尔马林固定的石蜡包埋的组织上的两种实验抗体,以及由Janssen提供的阳性(VistaK562)和阴性(Raji)对照细胞系,在20μg/ml、10μg/ml、5μg/ml、和2.5μg/ml进行连续稀释。同型对照抗体仅在一种即用型浓度下使用。将抗体VSTB175和BGX-Ms-IgG1用作第一抗体,并且主要检测系统由载体抗小鼠第二(BA-2000)和载体ABC-AP试剂盒(AK-5000)、以及载体红底物试剂盒(SK-5100)组成,将其用于生产紫红色沉积物。
还用阳性对照抗体(CD31和波形蛋白)对组织进行染色以确保组织抗原被保存并可用于免疫组织化学分析。对于本研究的剩余部分仅选择CD31阳性和波形蛋白染色的组织。
阴性对照由在没有第一抗体的情况下对相邻切片进行完整的免疫组织化学程序组成,并且这些载玻片适当地为阴性。
在所报道的浓度下染色的载玻片用与尼康(Nikon)显微镜偶联的DVC1310C数码相机成像。将图像用Adobe Photoshop一起存储为TIFF文件。结果显示在图44-53中。
所有专利、公开的申请以及在此引用的参考文献的传授内容都通过引用将其全文进行结合。
虽然本发明参考其示例性的实施例已经进行了具体显示和描述,本领域的技术人员应当理解的是,在不偏离由所附权利要求书所涵盖的本发明的范围的情况下,可以在其中做出在形式和细节方面的多种改变。
序列表
<110> 詹森药业有限公司(JANSSEN PHARMACEUTICA NV)
<120> 抗VISTA抗体和片段
<130> 0148.1142-017
<150> US 62/184,108
<151> 2015-06-24
<150> US 62/187,659
<151> 2015-07-01
<160> 77
<170> FastSEQ,用于Windows版本4.0
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Gly Tyr Thr Phe Thr Asn Tyr Gly
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Ile Asn Pro Tyr Thr Gly Glu Pro
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Ala Arg Glu Gly Tyr Gly Asn Tyr Ile Phe Pro Tyr
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Glu Ser Val Asp Thr Tyr Ala Asn Ser Leu
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Arg Ala Ser
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Gln Gln Thr Asn Glu Asp Pro Arg Thr
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Gly Tyr Thr Phe Thr His Tyr Thr
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<212> PRT
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Ile Ile Pro Ser Ser Gly Tyr Ser
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<212> PRT
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Ala Arg Gly Ala Tyr Asp Asp Tyr Tyr Asp Tyr Tyr Ala Met Asp Tyr
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Gln Thr Ile Val His Ser Asn Gly Asn Thr Tyr
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Lys Val Ser
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<212> PRT
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Phe Gln Ala Ser His Val Pro Trp Thr
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Gly Tyr Thr Phe Thr Asn Tyr Gly
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Ile Asn Thr Tyr Thr Gly Glu Ser
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Ala Arg Asp Tyr Tyr Gly Ile Tyr Val Ser Ala Tyr
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Glu Ser Val Asp Asn Tyr Ala Asn Ser Phe
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Arg Ala Ser
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<212> PRT
<213> 智人(Homo sapiens)
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Gln Gln Ser His Glu Asp Pro Tyr Thr
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<212> PRT
<213> 智人(Homo sapiens)
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Gly Phe Thr Phe Arg Asn Tyr Gly
1 5
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<212> PRT
<213> 智人(Homo sapiens)
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Ile Ile Ser Gly Gly Ser Tyr Thr
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<211> 15
<212> PRT
<213> 智人(Homo sapiens)
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Ala Arg Ile Tyr Asp His Asp Gly Asp Tyr Tyr Ala Met Asp Tyr
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<212> PRT
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Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr
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Lys Val Ser
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<212> PRT
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Phe Gln Gly Ser His Val Pro Trp Thr
1 5
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<212> PRT
<213> 智人(Homo sapiens)
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Gly Gly Thr Phe Ser Ser Tyr Ala
1 5
<210> 26
<211> 8
<212> PRT
<213> 智人(Homo sapiens)
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Ile Ile Pro Ile Phe Gly Thr Ala
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<212> PRT
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Ala Arg Ser Ser Tyr Gly Trp Ser Tyr Glu Phe Asp Tyr
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<211> 6
<212> PRT
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Gln Ser Ile Asp Thr Arg
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<211> 3
<212> PRT
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Ser Ala Ser
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<212> PRT
<213> 智人(Homo sapiens)
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Gln Gln Ser Ala Tyr Asn Pro Ile Thr
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<211> 8
<212> PRT
<213> 智人(Homo sapiens)
<400> 31
Gly Gly Thr Phe Ser Ser Tyr Ala
1 5
<210> 32
<211> 8
<212> PRT
<213> 智人(Homo sapiens)
<400> 32
Ile Ile Pro Ile Phe Gly Thr Ala
1 5
<210> 33
<211> 13
<212> PRT
<213> 智人(Homo sapiens)
<400> 33
Ala Arg Ser Ser Tyr Gly Trp Ser Tyr Glu Phe Asp Tyr
1 5 10
<210> 34
<211> 6
<212> PRT
<213> 智人(Homo sapiens)
<400> 34
Gln Ser Ile Asn Thr Asn
1 5
<210> 35
<211> 3
<212> PRT
<213> 智人(Homo sapiens)
<400> 35
Ala Ala Ser
1
<210> 36
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
<400> 36
Gln Gln Ala Arg Asp Thr Pro Ile Thr
1 5
<210> 37
<211> 120
<212> PRT
<213> 智人(Homo sapiens)
<400> 37
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Gly Trp Ser Tyr Glu Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 38
<211> 119
<212> PRT
<213> 智人(Homo sapiens)
<400> 38
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Leu Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Cys Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Tyr Gly Asn Tyr Ile Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 39
<211> 123
<212> PRT
<213> 智人(Homo sapiens)
<400> 39
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr His Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Ile Pro Ser Ser Gly Tyr Ser Glu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Tyr Asp Asp Tyr Tyr Asp Tyr Tyr Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 40
<211> 122
<212> PRT
<213> 智人(Homo sapiens)
<400> 40
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ile Ser Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Tyr Asp His Asp Gly Asp Tyr Tyr Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 41
<211> 111
<212> PRT
<213> 智人(Homo sapiens)
<400> 41
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Ala Asn Ser Leu Met His Trp Tyr Leu Gln Lys Pro Gly Gln Pro Pro
35 40 45
Gln Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser
65 70 75 80
Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Thr Asn
85 90 95
Glu Asp Pro Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 42
<211> 112
<212> PRT
<213> 智人(Homo sapiens)
<400> 42
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Ala
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 43
<211> 112
<212> PRT
<213> 智人(Homo sapiens)
<400> 43
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 44
<211> 107
<212> PRT
<213> 智人(Homo sapiens)
<400> 44
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asp Thr Arg
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ala Tyr Asn Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 45
<211> 107
<212> PRT
<213> 智人(Homo sapiens)
<400> 45
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Thr Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Arg Asp Thr Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 46
<211> 295
<212> PRT
<213> 智人(Homo sapiens)
<400> 46
Met Gly Val Pro Thr Ala Leu Glu Ala Gly Ser Trp Arg Trp Gly Ser
1 5 10 15
Leu Leu Phe Ala Leu Phe Leu Ala Ala Ser Leu Gly Pro Val Ala Ala
20 25 30
Phe Lys Val Ala Thr Pro Tyr Ser Leu Tyr Val Cys Pro Glu Gly Gln
35 40 45
Asn Val Thr Leu Thr Cys Arg Leu Leu Gly Pro Val Asp Lys Gly His
50 55 60
Asp Val Thr Phe Tyr Lys Thr Trp Tyr Arg Ser Ser Arg Gly Glu Val
65 70 75 80
Gln Thr Cys Ser Glu Arg Arg Pro Ile Arg Asn Leu Thr Phe Gln Asp
85 90 95
Leu His Leu His His Gly Gly His Gln Ala Ala Asn Thr Ser His Asp
100 105 110
Leu Ala Gln Arg His Gly Leu Glu Ser Ala Ser Asp His His Gly Asn
115 120 125
Phe Ser Ile Thr Met Arg Asn Leu Thr Leu Leu Asp Ser Gly Leu Tyr
130 135 140
Cys Cys Leu Val Val Glu Ile Arg His His His Ser Glu His Arg Val
145 150 155 160
His Gly Ala Met Glu Leu Gln Val Gln Thr Gly Lys Asp Ala Pro Ser
165 170 175
Asn Cys Val Val Tyr Pro Ser Ser Ser Gln Glu Ser Glu Asn Ile Thr
180 185 190
Ala Ala Ala Leu Ala Thr Gly Ala Cys Ile Val Gly Ile Leu Cys Leu
195 200 205
Pro Leu Ile Leu Leu Leu Val Tyr Lys Gln Arg Gln Ala Ala Ser Asn
210 215 220
Arg Arg Ala Gln Glu Leu Val Arg Met Asp Ser Asn Ile Gln Gly Ile
225 230 235 240
Glu Asn Pro Gly Phe Glu Ala Ser Pro Pro Ala Gln Gly Ile Pro Glu
245 250 255
Ala Lys Val Arg His Pro Leu Ser Tyr Val Ala Gln Arg Gln Pro Ser
260 265 270
Glu Ser Gly Arg His Leu Leu Ser Glu Pro Ser Thr Pro Leu Ser Pro
275 280 285
Pro Gly Pro Gly Asp Val Phe
290 295
<210> 47
<211> 449
<212> PRT
<213> 智人(Homo sapiens)
<400> 47
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Leu Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Cys Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Tyr Gly Asn Tyr Ile Phe Pro Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 48
<211> 218
<212> PRT
<213> 智人(Homo sapiens)
<400> 48
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Thr Tyr
20 25 30
Ala Asn Ser Leu Met His Trp Tyr Leu Gln Lys Pro Gly Gln Pro Pro
35 40 45
Gln Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser
65 70 75 80
Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Thr Asn
85 90 95
Glu Asp Pro Arg Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 49
<211> 453
<212> PRT
<213> 智人(Homo sapiens)
<400> 49
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr His Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Ile Pro Ser Ser Gly Tyr Ser Glu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Tyr Asp Asp Tyr Tyr Asp Tyr Tyr Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Lys
450
<210> 50
<211> 219
<212> PRT
<213> 智人(Homo sapiens)
<400> 50
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Ala
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 51
<211> 449
<212> PRT
<213> 智人(Homo sapiens)
<400> 51
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Cys Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Tyr Tyr Gly Ile Tyr Val Ser Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 52
<211> 218
<212> PRT
<213> 智人(Homo sapiens)
<400> 52
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Ala Asn Ser Phe Met His Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro
35 40 45
Gln Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser
65 70 75 80
Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Ser His
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 53
<211> 452
<212> PRT
<213> 智人(Homo sapiens)
<400> 53
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ile Ser Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Tyr Asp His Asp Gly Asp Tyr Tyr Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 54
<211> 219
<212> PRT
<213> 智人(Homo sapiens)
<400> 54
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 55
<211> 450
<212> PRT
<213> 智人(Homo sapiens)
<400> 55
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Gly Trp Ser Tyr Glu Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 56
<211> 214
<212> PRT
<213> 智人(Homo sapiens)
<400> 56
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asp Thr Arg
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ala Tyr Asn Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 57
<211> 450
<212> PRT
<213> 智人(Homo sapiens)
<400> 57
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Gly Trp Ser Tyr Glu Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 58
<211> 214
<212> PRT
<213> 智人(Homo sapiens)
<400> 58
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Thr Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Arg Asp Thr Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 59
<211> 446
<212> PRT
<213> 智人(Homo sapiens)
<400> 59
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Gly Trp Ser Tyr Glu Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val
210 215 220
Glu Cys Pro Pro Cys Pro Ala Pro Pro Ala Ala Ala Ser Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Ala Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 60
<211> 449
<212> PRT
<213> 智人(Homo sapiens)
<400> 60
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Gly Trp Ser Tyr Glu Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
225 230 235 240
Asp Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Ala Ala Leu Pro Ala Pro Ile Ala Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 61
<211> 450
<212> PRT
<213> 智人(Homo sapiens)
<400> 61
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Gly Trp Ser Tyr Glu Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 62
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
<400> 62
Asn Leu Thr Leu Leu Asp Ser Gly Leu
1 5
<210> 63
<211> 11
<212> PRT
<213> 智人(Homo sapiens)
<400> 63
Val Gln Thr Gly Lys Asp Ala Pro Ser Asn Cys
1 5 10
<210> 64
<211> 120
<212> PRT
<213> 智人(Homo sapiens)
<400> 64
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Gly Trp Ser Tyr Glu Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 65
<211> 12
<212> PRT
<213> 智人(Homo sapiens)
<400> 65
Arg Arg Pro Ile Arg Asn Leu Thr Phe Gln Asp Leu
1 5 10
<210> 66
<211> 309
<212> PRT
<213> 小家鼠(Mus musculus)
<400> 66
Met Gly Val Pro Ala Val Pro Glu Ala Ser Ser Pro Arg Trp Gly Thr
1 5 10 15
Leu Leu Leu Ala Ile Phe Leu Ala Ala Ser Arg Gly Leu Val Ala Ala
20 25 30
Phe Lys Val Thr Thr Pro Tyr Ser Leu Tyr Val Cys Pro Glu Gly Gln
35 40 45
Asn Ala Thr Leu Thr Cys Arg Ile Leu Gly Pro Val Ser Lys Gly His
50 55 60
Asp Val Thr Ile Tyr Lys Thr Trp Tyr Leu Ser Ser Arg Gly Glu Val
65 70 75 80
Gln Met Cys Lys Glu His Arg Pro Ile Arg Asn Phe Thr Leu Gln His
85 90 95
Leu Gln His His Gly Ser His Leu Lys Ala Asn Ala Ser His Asp Gln
100 105 110
Pro Gln Lys His Gly Leu Glu Leu Ala Ser Asp His His Gly Asn Phe
115 120 125
Ser Ile Thr Leu Arg Asn Val Thr Pro Arg Asp Ser Gly Leu Tyr Cys
130 135 140
Cys Leu Val Ile Glu Leu Lys Asn His His Pro Glu Gln Arg Phe Tyr
145 150 155 160
Gly Ser Met Glu Leu Gln Val Gln Ala Gly Lys Gly Ser Gly Ser Thr
165 170 175
Cys Met Ala Ser Asn Glu Gln Asp Ser Asp Ser Ile Thr Ala Ala Ala
180 185 190
Leu Ala Thr Gly Ala Cys Ile Val Gly Ile Leu Cys Leu Pro Leu Ile
195 200 205
Leu Leu Leu Val Tyr Lys Gln Arg Gln Val Ala Ser His Arg Arg Ala
210 215 220
Gln Glu Leu Val Arg Met Asp Ser Ser Asn Thr Gln Gly Ile Glu Asn
225 230 235 240
Pro Gly Phe Glu Thr Thr Pro Pro Phe Gln Gly Met Pro Glu Ala Lys
245 250 255
Thr Arg Pro Pro Leu Ser Tyr Val Ala Gln Arg Gln Pro Ser Glu Ser
260 265 270
Gly Arg Tyr Leu Leu Ser Asp Pro Ser Thr Pro Leu Ser Pro Pro Gly
275 280 285
Pro Gly Asp Val Phe Phe Pro Ser Leu Asp Pro Val Pro Asp Ser Pro
290 295 300
Asn Ser Glu Ala Ile
305
<210> 67
<211> 312
<212> PRT
<213> 红大袋鼠(Macropus rufus)
<400> 67
Met Asn Val Pro Thr Ser Val Leu Glu Ser Gly Gly Arg Arg Trp Gly
1 5 10 15
Pro Leu Leu Leu Ala Phe Phe Leu Ala Ala Ser Arg Gly Leu Val Ala
20 25 30
Ala Phe Lys Val Ala Thr Pro Tyr Ser Leu Tyr Val Cys Pro Glu Gly
35 40 45
Glu Asn Ile Thr Leu Ala Cys Gln Leu Leu Gly Pro Val Pro Lys Gly
50 55 60
His Asp Val Ser Phe Tyr Lys Thr Trp Phe Arg Ser Ser Arg Gly Glu
65 70 75 80
Val Gln Val Cys Ser Glu His Arg Pro Ile Arg Asn Val Thr Leu Gln
85 90 95
Asn Leu His Pro Tyr His Gly Gly His Gln Ala Ser Asn Thr Ser His
100 105 110
Asn Leu Leu Gln Ser His Gly Leu Glu Thr Ala Ser Asp His His Gly
115 120 125
Asn Phe Ser Ile Thr Met Arg Asn Leu Thr Val Gln Asp Gly Gly Leu
130 135 140
Tyr Cys Cys Leu Val Val Glu Met Arg His Arg His Ser Glu His Arg
145 150 155 160
Val His Ala Ala Met Glu Leu Gln Val Gln Lys Gly Lys Asp Ala Pro
165 170 175
Ser Lys Cys Ile Thr Tyr Pro Ser Ser Pro Glu Glu Ser Asp Asn Ile
180 185 190
Thr Ala Ala Ala Leu Ala Thr Gly Ala Cys Ile Val Gly Ile Leu Cys
195 200 205
Leu Pro Leu Ile Leu Leu Leu Val Tyr Lys Gln Arg Gln Val Ala Ser
210 215 220
His Arg Arg Ala Gln Glu Leu Val Arg Met Asp Ser Ser Pro Gln Gly
225 230 235 240
Ile Glu Asn Pro Gly Phe Glu Ala Pro Pro Ser Ser Gln Gly Leu Pro
245 250 255
Glu Ala Lys Val Arg Pro Pro Leu Ser Tyr Met Ala Gln Arg Gln Pro
260 265 270
Ser Glu Ser Gly Arg His Leu Leu Ser Glu Pro Asn Thr Pro Leu Ser
275 280 285
Pro Pro Gly Pro Gly Asp Val Phe Phe Pro Ser Leu Asp Pro Val Pro
290 295 300
Asp Ser Pro Asn Ser Glu Phe Asn
305 310
<210> 68
<211> 310
<212> PRT
<213> 短吻真海豚(Delphinus delphis)
<400> 68
Met Gly Val Pro Pro Val Pro Glu Ala Gly Ser Trp Arg Arg Gly Pro
1 5 10 15
Val Leu Leu Ala Phe Phe Leu Ala Ala Ser Arg Gly Leu Val Ala Ala
20 25 30
Phe Lys Val Ala Thr Pro Tyr Ser Leu Tyr Val Cys Pro Glu Gly Gln
35 40 45
Asn Val Thr Leu Thr Cys Arg Leu Leu Gly Pro Leu Ala Lys Gly His
50 55 60
Asp Val Thr Phe Tyr Lys Thr Trp Tyr Arg Ser Ser Arg Gly Glu Val
65 70 75 80
Gln Ala Cys Ser Glu Arg Arg Pro Ile Arg Asn Leu Thr Phe Gln Asp
85 90 95
Leu His Leu His His Gly Gly His Gln Ala Asn Ser Ser Gln Asp Leu
100 105 110
Ala Gln Arg His Gly Leu Glu Ser Ala Ser Asp His His Gly Asn Phe
115 120 125
Thr Ile Thr Met Arg Asn Leu Thr Leu Leu Asp Gly Gly Leu Tyr Cys
130 135 140
Cys Leu Val Val Glu Ile Arg His Arg His Ser Glu Gln Arg Leu Tyr
145 150 155 160
Gly Ala Met Glu Leu Gln Val Gln Arg Gly Glu Glu Ala Pro Ser Lys
165 170 175
Cys Thr Val Tyr Pro Pro Ser Ser Lys Glu Ser Glu Ser Ile Thr Ala
180 185 190
Ala Ala Leu Ala Thr Ser Ala Cys Ile Val Gly Ile Leu Cys Leu Pro
195 200 205
Leu Ile Leu Leu Leu Val Tyr Lys Gln Arg Gln Val Ala Ser Asn Arg
210 215 220
Arg Ala Gln Glu Leu Val Arg Met Asp Ser Asn Thr Gln Gly Ile Glu
225 230 235 240
Asn Pro Gly Phe Glu Thr Ser Pro Pro Ser His Gly Met Pro Glu Thr
245 250 255
Lys Pro Arg Gln Pro Leu Thr Tyr Met Ala Arg Arg Gln Pro Ser Glu
260 265 270
Ser Gly Arg His Leu Leu Ser Glu Pro Asn Thr Pro Leu Ser Pro Pro
275 280 285
Gly Pro Gly Asp Val Phe Phe Pro Ser Leu Asp Pro Val Pro Asp Ser
290 295 300
Pro Asn Ser Glu Ala Ile
305 310
<210> 69
<211> 288
<212> PRT
<213> 原鸡(Gallus gallus)
<400> 69
Gly Gly Thr Ala Ala Phe Leu Val Thr Val Pro Tyr Thr Leu Cys Ile
1 5 10 15
Cys Pro Glu Gly Gln Asn Val Thr Leu Ser Cys Arg Val Ser Gly Pro
20 25 30
Pro Ala Asp His His Asp Leu Ile Phe Lys Thr Trp Tyr Phe Ser Asn
35 40 45
Asn Gly Asp Gln Ser Cys Ser Glu Lys Arg His Val Arg Asn Leu Thr
50 55 60
Glu Lys Glu Leu Arg His Asp Pro Gly Arg His His Ser Thr Ala Ala
65 70 75 80
Asn Ser Thr Ala Arg Ser Pro His Gly Ser Leu Ala Ser His His Gly
85 90 95
Val Glu Phe Val Pro Asp His His Gly Ala Phe His Ile Val Val Met
100 105 110
Asn Leu Thr Leu Gln Asp Ser Gly Asn Tyr Cys Cys Tyr Ala Met Glu
115 120 125
Thr Arg Arg Asp His Gly Lys Ala His Thr Leu His Ile Ala His Gly
130 135 140
Phe Val Glu Leu Gln Ile Gln Arg Gly Arg Gly Ser Leu Gln Asn Cys
145 150 155 160
Thr Phe His Thr Ala Thr Ser Lys Asp Ile Thr Ala Ala Ala Leu Ala
165 170 175
Thr Gly Ala Cys Ile Val Gly Ile Leu Cys Leu Pro Leu Ile Leu Leu
180 185 190
Leu Ile Tyr Lys Gln Arg Gln Ala Val Ser His Arg Arg Ala His Glu
195 200 205
Leu Val Arg Met Glu Ser Ser Ala Gln Gly Ile Glu Asn Pro Val Phe
210 215 220
Glu Ala Leu Pro Ala Gly Ser Thr Glu Gln Arg Pro Arg Pro Gln Leu
225 230 235 240
Ser Tyr Leu Gly Gly Arg Gln Leu Ser Glu Ser Gly Arg His Leu Leu
245 250 255
Ser Glu Pro Asn Thr Pro Leu Ser Pro Pro Ala Pro Gly Glu Cys Phe
260 265 270
Phe Pro Thr Leu Asp Pro Val Pro Asp Ser Pro Asn Ser Leu Lys Ala
275 280 285
<210> 70
<211> 260
<212> PRT
<213>非洲爪蟾(Xenopus laevis)
<400> 70
Asp Ala Ile Thr Ala Phe Ser Val Ser Ala Leu Tyr Ser His Ile Thr
1 5 10 15
Cys Pro Glu Gly Gln Asn Val Asn Leu Thr Cys Thr Val Ser Gly His
20 25 30
Val Ala Asp Lys His Asp Val Leu Phe Ser Leu Trp His Phe Ser Lys
35 40 45
Asp Lys Asn Ser Asn Cys Leu Glu Arg Arg His Ile Gln Asn Thr Thr
50 55 60
Glu Arg Asp His Leu His Lys Glu His Leu Ser His Ser Met His Asn
65 70 75 80
Gly Ala Phe Gln Ile Thr Leu Thr Asn Val Ser Gln Gln Asp Ser Gly
85 90 95
Gly Tyr Cys Cys Tyr Val Ile Glu Ala Ser Lys Lys His His Thr Arg
100 105 110
His Tyr Ser Tyr Ile Glu Phe Gln Val Lys Thr Asp Asp Leu Asn Leu
115 120 125
Tyr Thr Cys Met Phe His Ser Pro Thr Glu Gly Asp Asn Ser Ser Thr
130 135 140
Ala Ala Ala Leu Ala Ile Val Ser Cys Val Ile Gly Ile Leu Cys Met
145 150 155 160
Pro Leu Ile Leu Phe Leu Val Tyr Lys Gln Arg Arg Ala Ile Ser His
165 170 175
Arg Arg Ser Tyr His Phe Val Phe Ile Asp Phe Ser Glu Ala Gln Gly
180 185 190
Ile Glu Asn Pro Val Phe Asp Asp Pro Pro Pro Ala Asn Val Val Glu
195 200 205
Gln Arg Pro Arg Leu Ala Phe Met Ala Ser Arg Gln Gln Ser Glu Ser
210 215 220
Asp Arg His Leu Leu Ser Glu Pro Asn Thr Pro Leu Ser Pro Ser Cys
225 230 235 240
Pro Asn Glu Cys Phe Phe Pro Ser Leu Pro Val Pro Asp Ser Pro Asp
245 250 255
Pro Gly Asn Val
260
<210> 71
<211> 315
<212> PRT
<213> 斑胸草雀(Taeniopygia guttata)
<400> 71
Gly His Pro Ala Thr Met Gly Thr Ala Ser Pro Arg Pro Gly Leu Leu
1 5 10 15
Leu Ala Ala Leu Cys Leu Leu Ala Ser His Gly Gly Ala Asp Ala Phe
20 25 30
Leu Ile Ser Thr Pro Tyr Ser Leu Cys Val Cys Pro Glu Gly Gln Asn
35 40 45
Val Thr Leu Ser Cys Arg Ile Ser Gly Ala Leu Ala Glu Arg His Asp
50 55 60
Leu Leu Tyr Lys Thr Trp Tyr Phe Ser Ser Thr Gly Asp Gln Ser Cys
65 70 75 80
Ser Asp Lys Arg His Ile Arg Asn Val Thr Asp Lys Glu Leu Arg His
85 90 95
Asp Leu Gly Arg His His Glu Leu Pro Gly Asn Ala Ser Gln Lys Pro
100 105 110
Pro Phe Gly Trp Gln Ser Gly His His Gly Val Glu Leu Val Leu Asp
115 120 125
His His Gly Ala Phe His Leu Val Val Met Asn Leu Thr Leu Gln Asp
130 135 140
Ser Gly Asn Tyr Cys Cys Tyr Ala Val Glu Val Arg Arg Glu Gly His
145 150 155 160
Ser Lys Pro His Thr Val Gln Ala Ala His Gly Phe Val Glu Leu Gln
165 170 175
Ile Gln Arg Gly Glu Pro Cys Ser His Ala Arg Ala Gln Ser Gln Arg
180 185 190
Ala Ala Asp Asp Ile Thr Ala Ala Val Leu Ala Thr Gly Ala Cys Ile
195 200 205
Val Gly Ile Leu Cys Leu Pro Leu Ile Leu Leu Leu Ile Tyr Lys Gln
210 215 220
Arg Gln Ala Ala Ser Ser Arg Arg Ala His Glu Leu Val Arg Met Asp
225 230 235 240
Ser Gly Ala Gln Gly Ile Glu Asn Pro Val Phe Glu Ala Val Pro Ser
245 250 255
Ala Gly Ala Glu Pro Arg Pro Arg Ala Gln Leu Ser Tyr Val Ala Ser
260 265 270
Arg Leu Pro Ser Glu Ser Gly Arg His Leu Leu Ser Glu Pro Ser Thr
275 280 285
Pro Leu Ser Pro Pro Gly Pro Gly Asp Cys Phe Phe Pro Thr Leu Asp
290 295 300
Pro Val Pro Asp Ser Pro Asn Ser Leu Lys Ala
305 310 315
<210> 72
<211> 275
<212> PRT
<213> 斑马鱼(Danio rerio)
<400> 72
Met Asp Val Phe Arg Ala Val Leu Leu Cys Phe His Val Phe Thr Ala
1 5 10 15
Ile Gln Ala Ser Gly Asp His His Ser Leu Arg Val Ser Val Pro His
20 25 30
Arg Thr Tyr Glu Cys Pro Glu Gly Ala Asp Val Ile Leu Lys Cys Val
35 40 45
Pro Ser Gly Thr Lys Ala Tyr Pro Gln Asp Thr Phe Trp Thr Thr Trp
50 55 60
Leu Tyr Thr Pro Arg Ser Gln Asp His Cys Gln Lys Gly Ala His Pro
65 70 75 80
Arg Lys Ala Asn His Thr Asn Arg Ser Leu Gly Val Val Tyr Ser Ser
85 90 95
Gly Asp Lys Val Phe Ser Val Ser Leu Lys Asn Val Lys His Thr Asp
100 105 110
Gln Gly Lys Tyr Cys Cys Trp Leu Leu Asp Leu His Gly Arg His Lys
115 120 125
Glu Gln Glu Ala His Asp Phe Met Tyr Leu Ser Val Met Pro Thr Pro
130 135 140
Lys Asp Ala His Asn Gly Ser Leu Lys Cys Leu Glu Tyr Ser His Thr
145 150 155 160
Ala Ser Asp Asp Ser Val Ala Glu Gly Leu Ala Ile Ala Ala Cys Val
165 170 175
Ala Phe Val Leu Cys Leu Pro Leu Ile Leu Met Leu Val Tyr Arg Gln
180 185 190
Arg Gln Thr Val Glu Arg His Arg Arg Ala His Glu Leu Val Arg Met
195 200 205
Asp Ser Glu Ala Gln Gly His Glu Asn Pro Val Phe Leu Gly Asp Ser
210 215 220
Pro Glu Pro Lys Met Arg Thr Val Ser Gln Ile Met Met Arg Gln Pro
225 230 235 240
Ser Glu Thr Gly His His Leu Leu Ser Glu Pro Gly Thr Pro Phe Ser
245 250 255
Pro Asn Ile Gln Gly Glu Leu Phe Phe Ser Ala Gln Gly Leu Pro Glu
260 265 270
Ser Asn Ile
275
<210> 73
<211> 293
<212> PRT
<213> 红鳍东方鲀(Fugu rubripes)
<400> 73
Leu Glu Lys Phe Thr Ser Ala His His Thr Lys Gln Thr Leu Glu Lys
1 5 10 15
Gly Leu Asn Leu Leu Cys Leu Thr Lys Ser Asn Ala His His Gly His
20 25 30
Pro Ala Met Ser Val Ser Ala Ser His Leu Tyr Tyr Thr Cys Pro Glu
35 40 45
Gly Ala Asn Ala Thr Leu Val Cys Asn Gln Arg Gly Gly Ala Leu His
50 55 60
Pro Asn Asp Ser Leu Trp Arg Leu Trp Phe Phe Thr Pro His Lys Asp
65 70 75 80
Gln His Cys Thr Lys His Gly Pro Arg Asn Val Thr Phe Lys His Ser
85 90 95
Lys Leu Ser Ser Gly Leu His Phe Gly Ala Thr Gln Glu Asn Phe Trp
100 105 110
Val Gln Leu Gln Asn Val Thr His Ala Asp Gln Gly Arg Tyr Cys Cys
115 120 125
Ala Ala Leu Glu Ile Glu Ser Ile His His Glu Ala Val Gln Arg Thr
130 135 140
His Ser His Met Phe Leu Asn Ile Ile Pro Arg Gly Thr Gly Ser Pro
145 150 155 160
Asn Cys Thr Val Ser Ala Pro Ser Ala Pro Glu Gly Asn Ala Thr Leu
165 170 175
Cys Thr Val Pro Val Ala Leu Ala Met Gly Ala Cys Ile Leu Ala Leu
180 185 190
Leu Ser Leu Pro Leu Ile Leu Leu Leu Val Tyr Arg Gln Arg Gln Ser
195 200 205
Ala Gln Ser Arg Arg Arg Ala Gln Glu Leu Val Arg Met Asp Ser Glu
210 215 220
Ala His Gly His Glu Asn Pro Val Phe Leu Gly Gly Ser Pro Gln Ile
225 230 235 240
Lys Asn Arg Thr Val Ser Gln Ile Met Ala Arg Gln Ser Ser Glu Thr
245 250 255
Gly Arg His Leu Leu Ser Glu Pro Gly Thr Pro Leu Ser Pro Pro Ala
260 265 270
His Gly Asp Val Phe Phe Pro Ala Glu Asp Thr Ile Phe Glu Thr Pro
275 280 285
Glu Leu Arg Gln Val
290
<210> 74
<211> 10
<212> PRT
<213> 智人(Homo sapiens)
<400> 74
Pro Val Asp Lys Gly His Asp Val Thr Phe
1 5 10
<210> 75
<211> 9
<212> PRT
<213> 智人(Homo sapiens)
<400> 75
Ile Arg His His His Ser Glu His Arg
1 5
<210> 76
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 嵌合抗体重链
<400> 76
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ser Tyr Gly Trp Ser Tyr Glu Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val
115 120 125
Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr
130 135 140
Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr
145 150 155 160
Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Glu Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser
180 185 190
Ser Pro Arg Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala
195 200 205
Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys
210 215 220
Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val
245 250 255
Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe
260 265 270
Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro
290 295 300
Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val
305 310 315 320
Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
325 330 335
Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys
340 345 350
Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp
355 360 365
Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro
370 375 380
Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asn Thr Asn Gly Ser
385 390 395 400
Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala
405 410 415
Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His
420 425 430
His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440
<210> 77
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 嵌合抗体轻链
<400> 77
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Thr Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Arg Asp Thr Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys Val
210 215
Claims (8)
1.一种组合物,该组合物包含(i)至少一种源自患有或疑似患有癌症的人受试者的生物样品和(ii)分离的抗体或其抗原结合片段,该分离的抗体或抗原结合片段包含抗原结合区域,该抗原结合区域与人T细胞活化的V结构域Ig抑制剂(VISTA)蛋白质结合,其中所述抗体包含:
a)抗体VH结构域,该抗体VH结构域包含具有SEQ ID NO:31的氨基酸序列的VH CDR1、具有SEQ ID NO:32的氨基酸序列的VH CDR2和具有SEQ IDNO:33的氨基酸序列的VH CDR3;
b)抗体VL结构域,该抗体VL结构域包含具有SEQ ID NO:34的氨基酸序列的VL CDR1、具有SEQ ID NO:35的氨基酸序列的VL CDR2和具有SEQ IDNO:36的氨基酸序列的VL CDR3;
c)非人抗体重链恒定区;和
d)非人抗体轻链恒定区。
2.如权利要求1所述的组合物,其中,所述抗体或抗原结合片段包含以下中的至少一种:
(i)包含SEQ ID NO:64的抗体VH结构域;
(ii)包含SEQ ID NO:45的抗体VL结构域;
(iii)包含鼠抗体重链恒定区的非人抗体重链恒定区;
(iv)包含鼠IgG1重链恒定区的非人抗体重链恒定区;
(v)包含SEQ ID NO:76中的鼠IgG1重链恒定区的非人抗体重链恒定区;
(vi)包含鼠IgG2a重链恒定区的非人抗体重链恒定区;
(vii)非人抗体轻链恒定区,该非人抗体轻链恒定区是鼠抗体轻链恒定区;
(viii)非人抗体轻链恒定区,该非人抗体轻链恒定区是鼠IgG1轻链恒定区;
(ix)包含SEQ ID NO:77中的鼠IgG1轻链恒定区的非人抗体轻链恒定区;或
(x)包含鼠IgG2a轻链恒定区的非人抗体轻链恒定区。
3.如权利要求1或2所述的组合物,其中,所述抗体或抗原结合片段与SEQ ID NO:46中的表位结合,并且所述抗体包括完整抗体或抗体片段。
4.如权利要求1或2所述的组合物,其中,所述抗体或抗原结合片段包含抗原结合区域,该抗原结合区域与人T细胞活化的V结构域Ig抑制剂(VISTA)蛋白质结合,其中所述抗体包含:包含SEQ ID NO:76的抗体重链和包含SEQ ID NO:77的抗体轻链。
5.如权利要求1至4中任一项所述的组合物,其中,所述抗体或其抗原结合片段与所述样品中包含的人VISTA蛋白质结合。
6.如权利要求1至5中任一项所述的组合物,其中,所述样品包含以下中的任一种:
(i)人细胞;
(ii)人组织;
(iii)人免疫细胞;
(iv)人基质细胞;
(v)人髓样细胞、单核细胞或T细胞;
(vi)人癌细胞;
(vii)人癌细胞或组织,该人癌细胞或组织包括以下的人癌细胞或组织的任一种:人肺癌细胞、前列腺癌细胞、急性髓性白血病(AML)细胞、黑色素瘤细胞、卵巢癌细胞和结肠癌细胞;
(viii)人癌细胞或组织,该人癌细胞或组织包括以下人癌细胞或组织的任一种:人乳腺的、胃肠的、内分泌的、神经内分泌的、眼的、泌尿生殖的、生殖细胞的、妇科的、头颈的、血液的、肌肉骨骼的、神经的、呼吸道的、膀胱的、结肠的、直肠的、肺的、子宫内膜的、肾的、胰腺的、肝的、胃的、睾丸的、食道的、前列腺的、脑的、宫颈的、卵巢的、甲状腺的、白血病、淋巴瘤、和骨髓增生异常综合征,其中所述人癌细胞或组织可以被髓样细胞和/或T细胞浸润;
(ix)人癌细胞或组织,该人癌细胞或组织包括以下人癌细胞或组织的任一种:人淋巴细胞白血病、髓细胞性白血病、急性淋巴母细胞性白血病(ALL)、慢性淋巴细胞白血病(CLL)、急性髓性(髓细胞性)白血病(AML)、慢性髓细胞性白血病(CML)、毛细胞白血病、T细胞幼淋巴细胞白血病、大颗粒淋巴细胞白血病、成人T细胞白血病、组织细胞性淋巴瘤、滤泡性淋巴瘤、霍奇金淋巴瘤、多发性骨髓瘤、黑色素瘤、膀胱癌和非小细胞肺癌(NSCLC);或
(x)任何上述的组合。
7.如权利要求1至6中任一项所述的组合物,其中,所述抗体或抗原结合片段包含可检测标记。
8.如权利要求7所述的组合物,其中,所述可检测标记包括放射性核体、荧光团、酶、生色原或免疫组织化学染色剂。
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PCT/IB2016/000886 WO2016207717A1 (en) | 2015-06-24 | 2016-06-23 | Anti-vista antibodies and fragments |
CN201680048121.0A CN107922497B (zh) | 2015-06-24 | 2016-06-23 | 抗vista抗体和片段 |
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EP3313882A1 (en) | 2018-05-02 |
DK3313882T3 (da) | 2020-05-11 |
CN107922497A (zh) | 2018-04-17 |
BR112017027870A2 (pt) | 2018-08-28 |
US20210318322A1 (en) | 2021-10-14 |
CA2990360C (en) | 2024-02-13 |
MX2017016647A (es) | 2019-04-25 |
WO2016207717A8 (en) | 2017-04-13 |
JP2024028906A (ja) | 2024-03-05 |
JP2022065094A (ja) | 2022-04-26 |
CA2990360A1 (en) | 2016-12-29 |
HK1254953A1 (zh) | 2019-08-02 |
WO2016207717A1 (en) | 2016-12-29 |
US20180306799A1 (en) | 2018-10-25 |
EP3722314A1 (en) | 2020-10-14 |
CN107922497B (zh) | 2022-04-12 |
JP2018530514A (ja) | 2018-10-18 |
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JP7026509B2 (ja) | 2022-02-28 |
US11009509B2 (en) | 2021-05-18 |
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