CN111542342A - 抗cd137抗体及其用途 - Google Patents
抗cd137抗体及其用途 Download PDFInfo
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- CN111542342A CN111542342A CN201880078625.6A CN201880078625A CN111542342A CN 111542342 A CN111542342 A CN 111542342A CN 201880078625 A CN201880078625 A CN 201880078625A CN 111542342 A CN111542342 A CN 111542342A
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Abstract
本文公开了激动性抗CD137抗体及其使用方法，用于引发CD137信号传导，从而增强免疫应答，例如T细胞功能。其中公开的抗体可用于治疗疾病，例如癌症和免疫病症。
Description
相关申请的交叉引用
本申请要求于2017年12月5日提交的标题为“抗CD137抗体及其用途”的国际申请PCT/CN2017/114569的申请日的权益，其内容通过引用全部合并于此。
背景技术
CD137，也称为4-1BB或肿瘤坏死因子受体亚家族9(TNFRSF9)，是肿瘤坏死因子(TNF)受体家族的成员。它由活化的T细胞(CD8+比CD4+更为普遍)以及树突状细胞、B细胞、滤泡性树突状细胞、天然杀伤细胞、粒细胞表达以及在炎症部位的血管壁细胞中表达。
CD137是活化T细胞的共刺激受体，CD137的交联可增强T细胞增殖、IL-2分泌、存活和细胞溶解活性。CD137还可以诱导外周单核细胞增殖，增强由TCR/CD3触发的激活和受调节的CD28共刺激诱导的T细胞凋亡，从而促进Th1细胞应答。它的表达是由淋巴细胞激活诱导的，并且除CD137配体(CD137L)外，还发现了TNF受体相关因子(TRAF)衔接子蛋白与受体结合，导致激活NF-κB的信号转导。
已经开发了对CD137特异的拮抗和激动抗体。US 6,569,997、US 8,137,667和Fisher等人,Cancer Immunol Immunother(2012)61:1721-1733。据报道，对CD137特异的激动剂抗体可增强T细胞功能并促进抗肿瘤活性。Fisher等人，Cancer Immunol Immunother(2012)61：1721-1733。另一方面，也已经报道了对CD137特异性的激动剂抗体在患者中诱导明显的肝毒性。Segal等人，Clin Can Res.，2017，23：1929-1936。
因此，感兴趣的是开发用于治疗应用的有效和安全的CD137激动剂。
发明内容
本发明至少部分地基于以高亲和力和强效地增强的免疫细胞的活性结合CD137的激动性抗CD137抗体的开发。此类抗体还显示出优异的抗肿瘤作用。因此，预期这些激动性抗CD137抗体及其功能变体可通过例如调节免疫应答例如CD4+细胞、CD8+细胞、树突状细胞和/或天然杀伤细胞的活性来有效治疗诸如癌症或自身免疫性疾病的疾病。
相应地，本公开的方面涉及与CD137结合并引发由CD137介导的细胞信号转导的分离的抗体。
在一些实施方案中，本文所述的抗CD137抗体结合与LYV370(20A12)、LYV371(11E10)、LYV372(23D2)、LYV375(22F2)、LYV390(30C11)和LYV402(26B3)的参考抗体相同的CD137的表位，或与所述参考抗体竞争与表位的结合。这样的抗体可以包含与参考抗体相同的重链互补决定区(CDR)和相同的轻链CDR。在一些实例中，分离的抗体包含与参考抗体相同的重链可变区(VH)和相同的轻链可变区(VL)。
在一些实施方案中，本文所述的抗CD137抗体结合人CD137。这样的抗体可以与来自另一物种(例如，小鼠、大鼠或非人灵长类)的CD137交叉反应。
本文中描述的任何抗CD137抗体可以是全长抗体(例如IgG分子)，其可以包含具有与FcγRIIB增强的结合亲和力的Fc变体或其抗原结合片段(例如Fab或单链抗体)。在一些实施方案中，本文所述的抗CD137抗体是人抗体或人源化抗体。可选地，抗体可以是嵌合抗体，其可以包含人重链恒定区或其片段和/或人轻链恒定区或其片段。在一些实例中，抗体是能够与CD137和FcγRIIB两者结合的双特异性抗体。
在另一方面，本公开包括分离的核酸或一组核酸，其编码(例如共同地)本文所述的任何抗CD137抗体。在一些实施方案中，核酸或核酸组位于一个或两个载体上，其可以是表达载体。
在另一方面，本公开提供了包含本文所述的分离的核酸或核酸组的宿主细胞。这样的宿主细胞可以用于产生抗CD137抗体。例如，可以在允许抗体表达的条件下培养宿主细胞，然后可以从细胞培养物中(例如从培养基中)收获宿主细胞。
本公开的另一方面包括药物组合物，其包含如本文所述的抗CD137抗体或编码该抗体的核酸/核酸组，以及药学上可接受的载体。
在另一方面，本公开还提供了一种调节受试者的免疫应答的方法，该方法包括向受试者施用有效量的本文所述的药物组合物，所述药物组合物包含抗CD137抗体或编码核酸。在一些实施方案中，有此需要的受试者是患有、怀疑患有本文所述的靶标疾病或处于诸如本文所述的靶标疾病例如癌症或免疫疾病如自身免疫疾病的人类患者。在一些实例中，将通过本文描述的任何方法治疗的对象(人类患者)已经或正在接受针对靶标疾病例如癌症或免疫疾病(例如自身免疫疾病)的治疗。
也在本公开的范围内的是用于治疗癌症或免疫疾病如自身免疫性疾病的药物组合物，其中所述药物组合物包含本文所述的任何抗CD137抗体或其编码核酸，以及抗体或编码核酸在制备用于治疗靶标疾病的药物中的用途。
下面的描述中阐述了本发明的一个或多个实施方案的细节。本发明的其它特征或优点将通过以下附图和对几个实施方案的详细描述并且还通过所附权利要求书变得显而易见。
附图说明
以下附图构成了本说明书的一部分并且被包含在内以进一步展示本公开的某些方面，结合对本文所呈现的具体实施方案的详细描述，通过参考附图，可以更好地理解所述方面。
图1是显示通过FACS分析的所示的抗CD137抗体在与CHO细胞上表达的人CD137结合中的剂量反应的图。
图2是一对柱状图，显示了所示的抗CD137抗体在与来自两个健康供体的人CD8+ T细胞的共同刺激试验中的活性。
图3是所示的抗CD137抗体的VH和VL序列的序列比对。互补决定区(通过Kabat CDR定义)被标示出(带框的)。从上到下的VH序列对应于SEQ ID NO：1、9、3、5、7和11。从上到下的VL序列对应于SEQ ID NO：2、6、8、10、4和12。
图4是显示通过ELISA确定的所示的重组嵌合抗体与人CD137蛋白的结合的图。
图5是显示通过FACS测定的所示嵌合抗体与细胞人CD137的结合的图。
图6是显示通过FACS测定的所示嵌合抗体与细胞食蟹猴CD137的结合的图。
图7包括两张图，显示了在体外在活化人CD8+ T细胞中所示嵌合抗体的活性。在证明了抗体的FcγRIIB依赖性活性的条件下测试了来自两个供体的T细胞。
图8是一组曲线图，显示了小鼠中所示的嵌合抗体的药代动力学。
图9是显示使用PC3癌细胞与人PBMC混合的肿瘤模型中所示的嵌合抗体的抗肿瘤活性的图。
具体实施方式
本文提供的是能够结合CD137和增强由CD137介导的信号传导的激动性抗体。发现此类抗CD137抗体以高亲和力结合CD137(例如人或猴)并促进T细胞活性。还发现本文所述的抗CD137抗体在动物模型中成功减少了肿瘤的生长。
CD137(也称为4-1BB或TNFRSF9)是肿瘤坏死因子(TNF)受体家族的成员。它由活化的T细胞(CD8+比CD4+更为普遍)(Gramaglia等人,Eur.J.Immunol.,30(2):392-402(2000))以及树突状细胞、B细胞、滤泡性树突状细胞、天然杀伤细胞、粒细胞表达以及在炎症部位的血管壁细胞中表达。已经证明树突状细胞上CD137表达导致IL-6和IL-12的分泌，以及DC刺激T细胞对同种抗原的反应以及浸润肿瘤的能力增强(Pan等，J.Immunol.,172(8):4779-89(2004))。活化的天然杀伤细胞在用细胞因子刺激后表达CD137，促进天然杀伤细胞的增殖和IFN-γ分泌，而不影响细胞溶解活性(Wilcox等人，J.Immunol.,169(8):4230-6(2002))。
激动性抗CD137抗体可以模拟CD137的天然配体的活性，并触发由CD137介导的细胞信号传导，从而诱导T细胞增殖，同时防止活化相关的细胞死亡。因此，激动性抗CD137抗体可用于调节免疫应答，例如，提高T细胞和其他免疫细胞的活性，从而有益于治疗疾病，例如癌症。还据报道，激动性抗CD137抗体可通过调节T细胞的活性，有效治疗免疫疾病，而T细胞的活性又调节其他类型的免疫细胞的活性，例如天然杀伤细胞、B细胞、巨噬细胞等。例如，激动性抗CD137抗体可以通过例如优先激活CD8+ T细胞同时降低CD4+ T细胞、天然杀伤细胞和/或B细胞的活性，有益于自身免疫疾病的治疗，从而导致并诱导高IFN-γ水平和调节Th17-Treg细胞平衡(Vinay等人，Expert Opin on Ther Targets,2016,20(3):361-373；Kim等人,J Immun.,2011,187:1120-1128)。因此，本文描述了抗CD137抗体(例如激动性抗CD137抗体)、编码此类抗体的核酸、包含该抗体或编码核酸的药物组合物以及此类抗体在治疗应用中的用途。
与CD137结合的抗体
本发明提供了抗体，其结合CD137，其可以是任何来源的，例如人和/或猴CD137。此类抗体可以是激动性抗体，其在与CD137结合后引发CD137介导的细胞信号传导。
CD137是本领域众所周知的蛋白质。例如，NCBI GenBank登录号NP_001552.2和NP_001253057.1分别提供了人和食蟹猴CD137的信息。下面提供的是示例性人和食蟹猴CD137多肽的氨基酸序列。
人CD137(SEQ ID NO：26)：
MGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQRTCDICRQCKG
VFRTRKECSSTSNAECDCTPGFHCLGAGCSMCEQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCS
LDGKSVLVNGTKERDVVCGPSPADLSPGASSVTPPAPAREPGHSPQIISFFLALTSTALLFLLFFLTLRF
SVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL食蟹猴(猕猴)CD137(SEQ IDNO：27)：
MGNSCYNIVATLLLVLNFERTRSLQDLCSNCPAGTFCDNNRSQICSPCPPNSFSSAGGQRTCDICRQCKG
VFKTRKECSSTSNAECDCISGYHCLGAECSMCEQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCS
LDGKSVLVNGTKERDVVCGPSPADLSPGASSATPPAPAREPGHSPQIIFFLALTSTVVLFLLFFLVLRFS
VVKRSRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
来自其他物种的CD137多肽在本领域是已知的并且可以使用人序列或食蟹猴序列作为查询从公众可得的基因数据库例如GenBank中获得。
抗体(可以以复数形式互换使用)是一种免疫球蛋白分子，其通过至少一个位于免疫球蛋白分子的可变区的抗原识别位点能够特异性结合靶标，例如碳水化合物、多核苷酸、脂质、多肽等。如本文所用，术语“抗体”不仅涵盖完整的(即全长)多克隆或单克隆抗体，而且涵盖其抗原结合片段(例如Fab、Fab'、F(ab')2、Fv)、单链(scFv)、其突变体、包含抗体部分的融合蛋白、人源化抗体、嵌合抗体、双抗体、纳米抗体、线性抗体、单链抗体、多特异性抗体(例如双特异性抗体)和免疫球蛋白分子的包含所需特异性的抗原识别位点的任何其他修饰构型，包括抗体的糖基化变体、抗体的氨基酸序列变体和共价修饰的抗体。抗体包括任何类别的抗体，例如IgD、IgE、IgG、IgA或IgM(或其亚类)，并且该抗体不必是任何特定类别。根据其重链恒定结构域的抗体氨基酸序列，免疫球蛋白可分为不同类别。免疫球蛋白有五种主要类别：IgA、IgD、IgE、IgG和IgM，其中这些中的几个可以进一步分为亚类(同种型)，例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。对应于不同类别的免疫球蛋白的重链恒定结构域分别称为α、δ、ε、γ和μ。不同类别的免疫球蛋白的亚基结构和三维构型是众所周知的。
典型的抗体分子包含重链可变区(VH)和轻链可变区(VL)，其通常涉及抗原结合。VH和VL区可以进一步细分为高可变性的区域，也称为“互补决定区”(“CDR”)，其散布有被称为“框架区”(“FR”)的更保守的区域。每个VH和VL通常由三个CDR和四个FR组成，从氨基末端到羧基末端按以下顺序排列：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。可以使用本领域已知的方法，例如通过Kabat定义、Chothia定义、AbM定义和/或接触定义，精确地识别框架区和CDR的范围，所有这些在本领域中是众所周知的。参见例如Kabat,E.A.等人(1991)Sequences ofProteins of Immunological Interest,第五版,U.S.Department of Health and HumanServices,NIH Publication No.91-3242；Chothia等人,(1989)Nature 342:877；Chothia,C.等人(1987)J.Mol.Biol.196:901-917；Al-lazikani等人(1997)J.Molec.Biol.273:927-948；和Almagro,J.Mol.Recognit.17:132-143(2004)。也参见hgmp.mrc.ac.uk andbioinf.org.uk/abs。
本文所述的抗CD137抗体可以是全长抗体，其包含两条重链和两条轻链，每条包含可变结构域和恒定结构域。或者，抗CD137抗体可以是全长抗体的抗原结合片段。全长抗体的术语“抗原结合片段”所涵盖的结合片段的实例包括：(i)Fab片段，由VL、VH、CL和CH1结构域组成的单价片段；(ii)F(ab')2片段，包括在铰链区通过二硫桥键连接的两个Fab片段的二价片段；(iii)由VH和CH1结构域组成的Fd片段；(iv)由抗体单臂的VL和VH结构域组成的Fv片段，(v)dAb片段(Ward等人，(1989)Nature 341：544-546)，其由VH结构域组成；和(vi)保留功能的分离的互补决定区(CDR)。此外，尽管Fv片段的两个结构域VL和VH由不同的基因编码，但是它们可以使用重组方法通过合成接头连接，合成接头使它们成为单条蛋白链，其中VL和VH区配对以形成称为单链Fv(scFv)的单价分子。参见例如Bird等人(1988)Science242:423-426；和Huston等人(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883。
在一些实施方案中，本文所述的抗CD137抗体可结合并引发由CD137介导的细胞信号转导。本文所述的抗CD137抗体的激动活性可以通过本领域已知的常规方法确定。
本文所述的抗体可以是鼠、大鼠、人或任何其他来源的(包括嵌合或人源化抗体)。这样的抗体是非天然存在的，即，如果没有人为行为，则不会在动物体内(例如用期望抗原或其片段免疫该动物或从抗体库中分离)。
本文所述的任何抗体可以是单克隆的或多克隆的。“单克隆抗体”是指同源抗体群，“多克隆抗体”是指异源抗体群。这两个术语不限制抗体的来源或制备方式。
在一实例中，本文所述方法中使用的抗体是人源化抗体。人源化抗体是指非人(例如鼠)抗体的形式，其是特异性的嵌合免疫球蛋白、免疫球蛋白链或其抗原结合片段，其包含源自非人免疫球蛋白的最小序列。在大多数情况下，人源化抗体是人免疫球蛋白(受体抗体)，其中受体的CDR中的残基被具有期望特异性、亲和力和能力的非人物种(供体抗体)例如小鼠、大鼠或兔子的CDR残基取代。在一些情况下，人免疫球蛋白的Fv框架区(FR)残基被相应的非人残基取代。此外，人源化抗体可包含在受体抗体或导入的CDR或框架序列中均未发现的残基，但被包括在内以进一步完善和优化抗体性能。通常，人源化抗体将包含至少一个并且通常两个可变结构域的基本上全部，其中所有或基本上所有的CDR区域对应于非人免疫球蛋白的那些，以及所有或基本上所有的FR区域是人免疫球蛋白共有序列的那些。人源化抗体最佳地还将包含至少一部分免疫球蛋白恒定区或结构域(Fc)，通常包含至少一部分人免疫球蛋白恒定区或结构域。抗体可具有如WO 99/58572中所述修饰的Fc区。其他形式的人源化抗体具有相对于原始抗体有改变的一个或多个CDR(一个、两个、三个、四个、五个或六个)，也称为“源自”原始抗体的一个或多个CDR的一个或多个CDR。人源化抗体也可涉及亲和力成熟。
用于构建人源化抗体的方法也是本领域熟知的。参见例如Queen等人,《美国国家科学院院刊》,86:10029-10033(1989)。在一个实例中，按照本领域已知的方法对亲本非人抗体的VH和VL可变区进行三维分子建模分析。接下来，使用相同的分子建模分析来鉴别预测对于形成正确CDR结构具有重要性的框架氨基酸残基。平行地，使用亲本VH和VL序列作为搜索查询从任何抗体基因数据库中鉴别出具有与亲本非人抗体的氨基酸序列同源的氨基酸序列的人VH链和人VL链。然后选择人VH受体基因和人VL受体基因。
可以用来自亲本非人抗体或其功能变体的CDR区替换所选人受体基因内的CDR区。在必要时，可以使用母链的框架区内预测在与CDR区相互作用时具有重要性的残基来取代人受体基因中的对应残基。
在另一个实例中，本文描述的抗体是嵌合抗体，其可以包含来自人抗体的重恒定区或其一部分和/或轻恒定区或其一部分。嵌合抗体是指具有来自第一物种的可变区或可变区的一部分和来自第二物种的恒定区的抗体。通常，在这些嵌合抗体中，轻链和重链的可变区模仿衍生自一种哺乳动物(例如非人类哺乳动物，例如小鼠、兔和大鼠)的抗体的可变区，而恒定部分与来自另一种哺乳动物例如人的抗体中的序列同源。在一些实施方案中，可以在可变区和/或恒定区中进行氨基酸修饰。
在一些实施方案中，本文所述的抗CD137抗体特异性结合相应的靶抗原(例如CD137)或其表位。“特异性结合”抗原或表位的抗体是本领域众所周知的术语。如果分子相比于其与替代性靶标的反应更频繁地、更快速地、以更长的持续时间和/或以更大的亲和力与特定靶抗原反应，则称分子表现出“特异性结合”。如果抗体相比于其与其它物质的结合以更大的亲和力、亲合力、更容易地和/或以更长的持续时间结合，则该抗体与靶抗原或表位“特异性地结合”。例如，特异性地(或优先地)结合至抗原(CD137)或其中的抗原表位的抗体是与其结合其他抗原或同一抗原中的其他表位相比以更大的亲和力、亲合力、更容易地和/或以更长的持续时间结合该靶抗原的抗体。对于该定义还应理解，例如，与第一靶抗原特异性地结合的抗体可以与或可能不与第二靶抗原特异性地或优先地结合。如此，“特异性结合”或“优先结合”不一定需要(但是可以包含)排他性结合。在一些实例中，“特异性结合”靶抗原或其表位的抗体可能不与其他抗原或同一抗原中的其他表位结合(即，在常规方法中只能检测基线结合活性)。可选地或另外地，本文所述的抗CD137抗体可以相对于猴对应物特异性地结合人CD137或其片段，反之亦然(例如如在同一测定中在相同测定条件下测定的，一种抗原比另一种抗原，其具有高至少10倍的结合亲和力)。在其他情况下，本文所述的抗CD137抗体可与人和非人CD-137(例如猴)交叉反应，例如与人和非人CD137的结合亲和力的差异小于5倍，例如小于2倍，或基本相似。
在一些实施方案中，本文所述的抗CD137抗体对靶抗原(例如CD137)或其抗原表位具有合适的结合亲和力。如本文所使用的，“结合亲和力”是指表观缔合常数或KA。KA是解离常数(KD)的倒数。本文所描述的抗CD137抗体对于靶抗原或抗原表位的结合亲和力(KD)可以为至少10-5M、10-6M、10-7M、10-8M、10-9M、10-10M或更低。增大的结合亲和力对应于减小的KD。抗体相对于第二抗原对第一抗原的更高亲和力结合可以通过比用于结合第二抗原的KA(或数值KD)更高的用于结合第一抗原的KA(或更小的数值KD)来指示。在这种情况下，该抗体相对于第二抗原(例如第二构象的相同的第一蛋白质或其模拟物；或第二蛋白质)对第一抗原(例如第一构象的第一蛋白质或其模拟物)具有特异性。结合亲和力的差异(例如，对于特异性或其它比较)可以为至少1.5倍、2倍、3倍、4倍、5倍、10倍、15倍、20倍、37.5倍、50倍、70倍、80倍、91倍、100倍、500倍、1000倍、10,000倍或105倍。在一些实施方案中，可以将任何抗CD137抗体进一步亲和力成熟以增加抗体与靶抗原或其抗原表位的结合亲和力。
可以通过各种方法来确定结合亲和力(或结合特异性)，包含平衡透析、平衡结合、凝胶过滤、ELISA、表面等离子共振或光谱学(例如，使用荧光测定)。用于评估结合亲和力的示例性条件为处于HBS-P缓冲液(10mM HEPES pH 7.4，150mM NaCl，0.005％(v/v)表面活性剂P20)中。这些技术可以用于根据靶蛋白浓度测量结合的结合蛋白的浓度。结合的结合蛋白的浓度([结合(Bound)])通常通过以下方程与游离靶蛋白([游离(Free)])的浓度相关：
[结合]＝[游离]/(Kd+[游离])
然而，并不总是需要对KA进行精确测定，因为有时例如通过功能性测定例如体外或体内测定中的活性足以获得对亲和力的定量测量、获得对亲和力的定性测量或者获得对亲和力的推断，所述亲和力例如是使用如ELISA或FACS分析等方法确定的、与KA成正比并且因此可以用于比较，如确定更高的亲和力是否例如高2倍。
下面提供了许多示例性的抗CD137抗体(CDR以粗体显示)。
20A12D11
VH:
VL:
11E10D12
VH:
VL:
23D2D6
VH:
VL:
22F2C2
VH:
VL:
30C11B4
VH:
VL:
26B3D7
VH:
VL:
嵌合抗体：人IgG4SP中LYV370的HC＝20A12
QIQLVQSGPELKKPGETVKISCKASGYTFTTYGMSWVKQAPGKGLKWMGWINTYSGVPTYADDFKGRFAFSLETSASTAYLQINNLKNEDMAIYFCARGYGSPDYWGQGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:13)
嵌合抗体：人κ中LYV370的LC＝20A12
QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKRWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSGNPPISTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:14)
嵌合抗体：人IgG4SP中LYV371的HC＝11E10
QVQLQQSGAELVRPGASVTLSCKASGYTFAGFEMHWIKQTPVHGLGWIGAIDPKTGGTDYNQKFKDKALLTADKSSNTAYMELRSLTSEDSAVYYCTRDLGYFDVWGTGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:15)
嵌合抗体：人κ中LYV371的LC＝11E10
DIQMTQTTSSLSASLGDRVTISCRASQDIRSNLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQSEKLPRTFGGGTKLEIRRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:16)
嵌合抗体：人IgG4S中LYV372的HC＝23D2
QVQLQQSGAELVRPGSSVKISCKASGYAFSIYWMNWVKQRPGQGLEWIGQIYPGDGYTNYNGKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYFCARGQLGLDGYWGQGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:17)
嵌合抗体：人κ中LYV372的LC＝23D2b
QIVLTQSPTIMSASPGEKVTMTCSASSSVSYIYWYQQKPGSSPRLLIYDTSNLASGVPVRFSGSGSGTSYSLTISRMEAEDAATYYCQQWNIYPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:18)
嵌合抗体：人IgG4SP中LYV375的HC＝22F2
EVKLVESGAELVRPGSSVKISCKASGYAFSLYWMNWVKQRPGQGLEWIGQIYPGDGYTNYNGKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYFCARGQLGLDGYWGQGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(SEQ ID NO:19)
嵌合抗体：人κ中LYV375的LC＝22F2
QIVLTQSPAIMSASPGEKVTMTCSASSSVSYIYWYQQKPGSSPRLLIYDTSNLASGVPVRFSGSGSGTSYSLTISRMEAEDAATYYCQQWNIYPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:20)
嵌合抗体：hG4SP中LYV390的HC＝30C11
QIQLVQSGPELKKPGESVKISCKASGYTFTDYAMHWVKQAPGKALKWMGLINTYTGKPTYVDDLKGRFVFSLEASASTAKLQISNLKNEDTAIYFCARYYHDGTYYGWFANWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:21)
嵌合抗体：人κ中的LYV390的LC＝30C11
DTVLTQSPALAVSPGERVTVSCGATESVSTALNWYQQKPGQQPRLLIYGASNLESGVPARFSGSGSGTDFTLSIDPVEADDTATYFCQQTWNDPLTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:22)
嵌合抗体：hG4SP中LYV402的HC＝26B3b
EVKLLESGGGLVQPGGSLKLSCAASGFDFSRYWMSWVRQAPGKGLEWIGEINPDSNPINYTPSLKDKFIISRDNAKNTLYLQMSKVRSEDTALYYCARDGSSSRYFDVWGAGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:23)
嵌合抗体：人κ中LYV402的LC＝26B3b
DIVMTQSPATLSVTPGDRVSLSCRASQSISDYLHWYQQKSHESPRLLIKYVSQSISGIPSRFSGSGSGSDFTLSINSVEPEDVGVYYCQNGHSFPPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:24)
在一些实施方案中，本文所述的抗CD137抗体与本文所述的任何示例性抗体(例如，LYV370(20A12)、LYV371(11E10)、LYV372(23D2)、LYV375(22F2)、LYV390(30C11)和LYV402(26B3))结合至CD137多肽的相同表位或与所述示例性抗体竞争至CD137抗原。“表位”是指靶抗原上被抗体识别并结合的位点。该位点可以完全由氨基酸成分组成、完全由蛋白质的氨基酸的化学修饰(例如糖基部分)组成、或由其组合组成。重叠的表位包括至少一个常见的氨基酸残基。表位可以是线性的，其长度通常为6-15个氨基酸。或者，表位可以是构象的。抗体结合的表位可以通过常规技术确定，例如表位作图法(参见例如以下描述)。与本文所述的示例性抗体结合相同表位的抗体可以与示例性抗体结合完全相同的表位或基本上重叠的表位(例如包含少于3个非重叠氨基酸残基，少于2个非重叠氨基酸残基，或仅1个非重叠氨基酸残基)。两种抗体是否由于结合同源抗原而彼此竞争可以通过竞争测定法确定，这是本领域众所周知的。
在一些实例中，抗CD137抗体与本文所述的示例性抗体包含相同的VH和/或VL CDR。具有相同的VH和/或VL CDR的两种抗体意味着，当通过相同的方法(例如本领域已知的Kabat方法或Chothia方法)测定时，它们的CDR是相同的。与本文所述的示例性抗体相比，此类抗CD137抗体可具有相同的VH、相同的VL或两者。
同样在本公开内容的范围内的是本文公开的任何示例性抗CD137抗体的功能变体。这样的功能变体在结构和功能上与示例性抗体基本相似。功能变体与示例性抗体包含基本相同的VH和VL CDR。例如，它可以在抗体的总CDR区域中仅包含至多5个(例如4个、3个、2个或1个)氨基酸残基变异，并以基本相似的亲和力结合CD137的相同表位(例如具有相同量级的KD值)。替代地或另外地，氨基酸残基变异是保守的氨基酸残基取代。如本文所使用的，“保守氨基酸取代”是指不改变进行氨基酸取代的蛋白质的相对电荷或大小特性的氨基酸取代。可以根据用于改变本领域普通技术人员已知的多肽序列的方法来制备变体，所述方法如编制这种方法的参考文献中发现的，所述参考文献例如，《分子克隆：实验室手册(Molecular Cloning:A Laboratory Manual)》,J.Sambrook等人编,第二版,冷泉港实验室出版社(Cold Spring Harbor Laboratory Press),冷泉港,纽约,1989或《分子生物学实验室指南(Current Protocols in Molecular Biology)》,F.M.Ausubel等人编,约翰威利父子出版公司(John Wiley&Sons,Inc.),纽约。氨基酸的保守取代包含在以下组中的氨基酸之间进行的取代：(a)M、I、L、V；(b)F、Y、W；(c)K、R、H；(d)A、G；(e)S、T；(f)Q、N；以及(g)E、D。
在一些实施方案中，与本文所述的示例性抗体的VH CDR相比，抗CD137抗体可包含单独或共同具有至少80％(例如85％、90％、95％或98％)序列同一性的重链CDR。可选地或另外地，与如本文所述的示例性抗体的VL CDR相比，抗CD137抗体可包含单独或共同具有至少80％(例如85％、90％、95％或98％)序列同一性的轻链CDR。
使用Karlin和Altschul,《美国国家科学院院刊(Proc.Natl.Acad.Sci.USA)》,87:2264-68,1990的算法来确定两个氨基酸序列的“一致性百分比”，所述算法如Karlin和Altschul,《美国国家科学院院刊》,90:5873-77,1993中那样进行修改。将这种算法并入Altschul等人,《分子生物学杂志(J.Mol.Biol.)》,215:403-10,1990的NBLAST和XBLAST程序(2.0版)中。可以用XBLAST程序(分值＝50，字长＝3)来执行BLAST蛋白质检索，以获得与关注的蛋白质分子同源的氨基酸序列。当两个序列之间存在空位时，可以利用如Altschul等人,《核酸研究(Nucleic Acids Res)》,25(17):3389-3402,1997中描述的带空位BLAST(Gapped BLAST)。当利用BLAST程序和带空位BLAST程序时，可以使用对应程序(例如XBLAST和NBLAST)的默认参数。
在一些实施方案中，本文所述的任何抗CD137抗体的重链可进一步包含重链恒定区(CH)或其一部分(例如CH1、CH2、CH3或其组合)。重链恒定区可以具有任何合适的来源，例如人、小鼠、大鼠或兔子。在一个特定的实例中，重链恒定区来自如本文所述的任何IgG亚家族的人IgG(γ重链)。在一个实例中，恒定区来自人Ig分子，例如IgG4，其示例性氨基酸序列如下提供(SEQ ID NO：25)：
在一些实施方案中，抗CD137抗体包含SEQ ID NO：25的重链恒定区或其变体，其可在所示位置(粗体和下划线)包含S/P取代。可选地，本文描述的抗体的重链恒定区可以包含单个结构域(例如CH1、CH2或CH3)或任何单个结构域的组合。
当需要时，本文所述的抗CD137抗体可包含修饰的恒定区。例如，其可以包含免疫学上惰性的修饰恒定区，例如不触发补体介导的裂解，或不刺激抗体依赖性细胞介导的细胞毒性(ADCC)。ADCC活性可以使用美国专利5,500,362中公开的方法进行评估。在其他实施方案中，恒定区如在Eur.J.Immunol.(1999)29:2613-2624；PCT申请PCT/GB99/01441；和/或UK专利申请9809951.8中所述进行修饰。
本文所述的任何抗CD137抗体可包含进一步包含轻链恒定区的轻链，其可以是本领域已知的任何CL。在一些实例中，CL是κ轻链。在其他实例中，CL是λ轻链。
抗体重链和轻链恒定区是本领域众所周知的，例如在IMGT数据库(www.imgt.org)或在www.vbase2.org/vbstat.php中提供的那些，其均通过引用并入本文。
在一些实施方案中，与野生型对应物相比，在此描述的抗CD137抗体可含有突变的Fc区，使得该抗体具有与Fc受体例如FcγRIIB(CD32B)具有较高结合亲和力。这样的抗体可以有效地接合FcγRIIB表达细胞，从而增强治疗效果。
在一些实施方案中，抗CD137抗体是能够(不通过Fc-FcR相互作用)结合两个CD137和FcγRIIB的双特异性抗体。这样的双特异性抗体可以包含第一抗原结合区和第二抗原结合区，它们各自可以包含VH/VL对。第一抗原结合区结合CD137，而第二抗原结合区结合FcγRIIB。
抗CD137抗体的制备
如本文所述的能够结合CD137的抗体可以通过本领域已知的任何方法制备。参见例如Harlow和Lane,(1998),《抗体：实验室手册(Antibodies:A Laboratory Manual)》,冷泉港实验室,冷泉港,纽约。
在一些实施方案中，可以通过常规杂交瘤技术制备对靶抗原(例如CD137或其片段)具有特异性的抗体。可以使用任选地与如KLH等载体蛋白偶联的全长靶抗原或片段来使宿主动物免疫，以生成与所述抗原结合的抗体。如本文进一步描述的，宿主动物的免疫途径和方案通常与用于抗体刺激和产生的已建立的和常规的技术保持一致。用于产生小鼠抗体、人源化抗体和人类抗体的通用技术是本领域已知的并且在本文中进行描述。设想了，可以操纵包含人类在内的任何哺乳动物受试者或来自其的产生抗体的细胞，以用作产生哺乳动物(包含人)杂交瘤细胞系的基础。通常，对宿主动物腹膜内、肌肉内、口服、皮下、足底内和/或皮内接种一定量的免疫原，包含如本文所描述的免疫原。
可以使用Kohler,B.和Milstein,C.(1975)《自然(Nature)》256:495-497或如Buck,D.W.等人,《体外(In Vitro)》,18:377-381(1982)所修改的一般体细胞杂交技术由淋巴细胞和永生化骨髓瘤细胞来制备杂交瘤。可以在杂交中使用可用的骨髓瘤系，包含但不限于X63-Ag8.653和来自美国加利福尼亚州圣地亚哥索尔克研究所细胞分布中心(SalkInstitute,Cell Distribution Center,San Diego,Calif.,USA)的那些骨髓瘤系。所述技术通常涉及使用如聚乙二醇等融合剂或通过本领域技术人员熟知的电气装置融合骨髓瘤细胞和淋巴样细胞。融合之后，将细胞从融合培养基中分离并在如次黄嘌呤-氨基蝶呤-胸苷(HAT)培养基等选择性生长培养基中生长，以消除未杂交的亲本细胞。可以使用补充有或不含血清的本文所描述的任何培养基培养分泌单克隆抗体的杂交瘤。作为细胞融合技术的另一个替代性方案，可以使用EBV永生化B细胞来产生本文所描述的抗CD137单克隆抗体。使杂交瘤膨胀并在需要时进行亚克隆，并且通过常规免疫测定程序(例如放射免疫测定、酶免疫测定或荧光免疫测定)来测定上清液的抗免疫原活性。
可以用作抗体的来源的杂交瘤涵盖所有衍生物、产生能够增强CD137活性的单克隆抗体的亲本杂交瘤的子代细胞。可以使用已知程序在体外或体内生长产生这种抗体的杂交瘤。在需要时，可以通过如硫酸铵沉淀、凝胶电泳、透析、层析和超滤等常规免疫球蛋白纯化程序从培养基或体液中分离单克隆抗体。可以例如通过在由附着于固相的免疫原制成的吸附剂上运行制剂并从免疫原中洗脱或释放期望抗体来除去不期望的活性(如果存在的话)。用靶抗原或含有靶氨基酸序列的片段使宿主动物免疫可以产生抗体(例如单克隆抗体)群，所述靶氨基酸序列使用双功能制剂或衍生化制剂与在待免疫物种中具有免疫原性的蛋白质缀合，所述蛋白质例如钥孔虫戚血蓝蛋白、血清白蛋白、牛甲状腺球蛋白或大豆胰蛋白酶抑制剂，所述双功能制剂或衍生化制剂例如马来酰亚胺基苯甲酰基磺基琥珀酰亚胺酯(通过半胱氨酸残基缀合)、N-羟基琥珀酰亚胺(通过赖氨酸残基)、戊二醛、琥珀酸酐、SOCl或R1N＝C＝NR，其中R和R1是不同的烷基。
在需要时，可以对关注(例如，通过杂交瘤产生)的抗体(单克隆或多克隆抗体)进行测序，并且然后可以将多核苷酸序列克隆到载体中以供表达或传播。可以在载体中将对关注的抗体进行编码的序列维持在宿主细胞中，并且然后可以使宿主细胞膨胀并冷冻以供将来使用。在替代性方案中，多核苷酸序列可以用于遗传操纵，以使抗体“人源化”或改善亲和力(亲和力成熟)或抗体的其它特性。例如，如果将抗体用于人类的临床试验和治疗，则可以将恒定区工程化成更类似于人恒定区，以避免免疫应答。可以期望对抗体序列进行遗传操纵，以获得与靶抗原更大的亲和力和在增强CD137活性方面更大的功效。对本领域技术人员而言将显而易见的是，可以对抗体进行一种或多种多核苷酸改变，并且所述一种或多种多核苷酸改变仍维持其与靶抗原的结合特异性。
在其它实施方案中，可以通过使用已经被工程化以表达特异性人免疫球蛋白的可商购小鼠来获得完全人抗体。被设计成产生更期望的(例如完全人抗体)或更稳健的免疫应答的转基因动物也可以用于生成人源化抗体或人抗体。这种技术的实例为来自安进公司(Amgen,Inc.)(加利福尼亚州弗里蒙特)的XenomouseTM以及来自Medarex公司(新泽西州普林斯顿)的HuMAb-MouseTM和TC MouseTM。在另一个替代性方案中，可以通过噬菌体展示或酵母技术重组地制备抗体。参见例如美国专利第5,565,332号、第5,580,717号、第5,733,743号和第6,265,150号以及Winter等人,(1994),《免疫学年鉴(Annu.Rev.Immunol.》12:433-455。可选地，噬菌体展示技术(McCafferty等人，(1990)Nature 348：552-553)可用于在体外从未免疫供体的免疫球蛋白可变(V)结构域基因库产生人抗体和抗体片段。
或者，可以通过常规实践从合适的抗体文库中分离出能够结合本文所述的靶抗原的抗体。抗体文库可用于通过常规筛选过程鉴定与靶抗原(例如CD137)结合的蛋白质。在选择过程中，用靶抗原或其片段探测多肽组分，并且，如果多肽组分结合靶，则通常通过保留在支持物上来鉴定抗体文库成员。从支持物中回收保留的展示文库成员并进行分析。该分析可以包括在相似或不相似条件下的扩增和随后的选择。例如，可以选择正负选择。分析还可以包括确定多肽组分的氨基酸序列和纯化多肽组分以进行详细表征。
有许多本领域已知的常规方法可以鉴定和分离能够与本文所述的靶抗原结合的抗体，包括噬菌体展示、酵母展示、核糖体展示或哺乳动物展示技术。
可以经由常规方法制备完整抗体(全长抗体)的抗原结合片段。例如，可以通过胃蛋白酶消化抗体分子来产生F(ab')2片段，以及可以通过减少F(ab')2片段的二硫桥键生成Fab片段。
遗传工程抗体，例如人源化抗体、嵌合抗体、单链抗体和双特异性抗体，可以通过例如常规的重组技术产生。在一个实例中，可以容易地使用常规程序分离编码对靶抗原特异性的单克隆抗体的DNA并对其进行测序(例如通过使用能够特异性结合编码单克隆抗体的重链和轻链的基因的寡核苷酸探针)。杂交瘤细胞用作这种DNA的优选来源。分离后，可将DNA置于一种或多种表达载体中，然后将其转染入宿主细胞，例如大肠杆菌细胞、猿猴COS细胞、中国仓鼠卵巢(CHO)细胞或不会产生免疫球蛋白的骨髓瘤细胞，以获得重组宿主细胞中单克隆抗体的合成。参见例如，PCT公开号WO 87/04462。然后可以例如通过用人重链和轻链恒定结构域的编码序列代替同源鼠序列来修饰DNA，Morrison等人，(1984)Proc.Nat.Acad.Sci.81:6851，或通过共价结合非免疫球蛋白多肽的全部或部分编码序列到免疫球蛋白编码序列。以这种方式，可以制备具有靶抗原结合特异性的遗传工程抗体，例如“嵌合”或“杂交”抗体。
开发用于产生“嵌合抗体”的技术是本领域众所周知的。参加例如Morrison等人(1984)Proc.Natl.Acad.Sci.USA 81,6851；Neuberger等人(1984)Nature 312,604；和Takeda等人(1984)Nature 314:452。
用于构建人源化抗体的方法也是本领域熟知的。参见例如Queen等人,《美国国家科学院院刊》,86:10029-10033(1989)。在一个实例中，按照本领域已知的方法对亲本非人抗体的VH和VL可变区进行三维分子建模分析。接下来，使用相同的分子建模分析来鉴别预测对于形成正确CDR结构具有重要性的框架氨基酸残基。平行地，使用亲本VH和VL序列作为搜索查询从任何抗体基因数据库中鉴别出具有与亲本非人抗体的氨基酸序列同源的氨基酸序列的人VH链和人VL链。然后选择人VH受体基因和人VL受体基因。
可以用来自亲本非人抗体或其功能变体的CDR区替换所选人受体基因内的CDR区。在必要时，可以使用母链的框架区内预测在与CDR区相互作用时具有重要性的残基(参见以上描述)来取代人受体基因中的对应残基。
通过将编码重链可变区的核苷酸序列和编码轻链可变区的核苷酸序列连接，可以通过重组技术制备单链抗体。优选地，在两个可变区之间并入柔性接头。可选地，描述用于产生单链抗体的技术(美国专利号4,946,778和4,704,692)可以适于产生噬菌体或酵母scFv文库，并且可以按照常规程序从该文库中鉴定出对CD137特异的scFv克隆。可以对阳性克隆进行进一步筛选，以鉴定增强CD137活性的克隆。
按照本领域已知的和本文描述的方法获得的抗体可以使用本领域中熟知的方法表征。例如，一种方法是鉴定抗原结合的表位或“表位作图”。如上所述，本领域中有许多方法可用于作图和表征蛋白质上表位的位置，包括解决抗体-抗原复合物的晶体结构、竞争测定、基因片段表达测定和基于合成肽的测定，例如，在Harlow和Lane的Using Antibodies,aLaboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,1999中第11章所述的。在另一个实例中，表位作图可用于确定抗体结合的序列。表位可以是线性表位，即，包含在单个氨基酸片段中，或通过可能不一定在单个序列中包含的氨基酸的三维相互作用形成的构象性表位(一级结构线性序列)中。可以分离或合成(例如重组地)不同长度(例如至少4-6个氨基酸长)的肽，并将其用于与抗体的结合测定。在另一个实例中，可以通过使用来源于靶抗原序列的重叠肽并确定抗体的结合，在系统筛选中确定与抗体结合的表位。根据基因片段表达测定，编码靶抗原的开放阅读框被随机地或通过特定的遗传构建片段化，并且确定了抗原的表达片段与待测抗体的反应性。基因片段可以例如通过PCR产生，然后在放射性氨基酸存在下体外转录并翻译成蛋白质。然后通过免疫沉淀和凝胶电泳确定抗体与放射性标记的抗原片段的结合。某些表位也可以通过使用噬菌体颗粒表面显示的大型随机肽序列文库(噬菌体文库)鉴定。可选地，可以在简单的结合测定中测试定义的重叠肽片段文库与测试抗体的结合。在另一个实例中，可以进行抗原结合结构域的诱变、结构域交换实验和丙氨酸扫描诱变以鉴定表位结合所需、足够的和/或必需的残基。例如，可以使用靶抗原的突变体进行结构域交换实验，其中CD137的各个片段已被来自紧密相关但抗原性不同的蛋白质(例如肿瘤坏死因子受体家族的另一个成员)的序列替换(交换)。通过评估抗体与突变体CD137的结合，可以评估特定抗原片段对抗体结合的重要性。
或者，可以使用已知与相同抗原结合的其他抗体进行竞争测定，以确定抗体是否与其他抗体结合相同的表位。竞争测定法是本领域技术人员众所周知的。
在一些实例中，抗CD137抗体通过重组技术制备，如下文所例示。
可以将对如本文所描述的抗CD137抗体的重链和轻链进行编码的核酸克隆到一个表达载体中，每个核苷酸序列与适合的启动子可操作地连接。在一个实例中，对重链和轻链进行编码的核苷酸序列中的每个核苷酸序列与不同的启动子可操作地连接。可替代地，对重链和轻链进行编码的核苷酸序列可以与单个启动子可操作地连接，使得重链和轻链两者均从相同的启动子表达。在必要时，可以在对重链和轻链进行编码的序列之间插入内部核糖体进入位点(IRES)。
在一些实例中，将对抗体的两条链进行编码的核苷酸序列克隆到两个载体中，所述载体可以被引入到相同或不同的细胞中。当在不同的细胞中表达这两条链时，其中的每条链均可以从表达这种链的宿主细胞中分离，并且分离的重链和轻链可以混合并在允许形成抗体的适合的条件下培育。
通常，可以使用本领域已知的方法将对抗体的一条或所有链进行编码的核酸序列克隆到适合的表达载体中、与适合的启动子可操作地连接。例如，可以在适合的条件下使核苷酸序列和载体与限制酶相接触，以在每个分子上产生可以彼此配对并用连接酶连接在一起的互补端。可替代地，可以将合成核酸接头与基因的末端连接。这些合成接头含有对应于载体中的特定限制性位点的核酸序列。表达载体/启动子的选择将会取决于用于产生抗体的宿主细胞的类型。
可以使用各种启动子来表达本文所描述的抗体，所述启动子包含但不限于巨细胞病毒(CMV)中间早期启动子、如劳斯肉瘤(Rous sarcoma)病毒LTR、HIV-LTR、HTLV-1LTR等病毒LTR、猿猴病毒40(SV40)早期启动子、大肠杆菌(E.coli)lac UV5启动子和单纯性疱疹tk病毒启动子。
还可以使用可调节的启动子。这些可调节的启动子包含使用来自大肠杆菌的lac阻遏物作为转录调制剂对携带有lac操纵基因的哺乳动物细胞启动子的转录进行调节的那些启动子[Brown,M.等人,《细胞(Cell)》,49:603-612(1987)]、使用四环素阻遏物(tetR)的那些启动子[Gossen,M.和Bujard,H.,《美国国家科学院院刊》89:5547-5551(1992)；Yao,F等人,《人类基因疗法(Human Gene Therapy)》,9:1939-1950(1998)；Shockelt,P.等人,《美国国家科学院院刊》,92:6522-6526(1995)]。其它系统包含FK506二聚体、使用雄二醇(astradiol)的VP16或p65、RU486、二元酚米乐甾酮(diphenol murislerone)或雷帕霉素(rapamycin)。诱导型系统可从英杰公司(Invitrogen)、Clontech公司和阿瑞雅德公司(Ariad)获得。
可以使用包含具有操纵子的阻遏物的可调节启动子。在一个实施例中，来自大肠杆菌的lac阻遏物可以用作转录调制剂对携带有lac操纵基因的哺乳动物细胞启动子的转录进行调节[M.Brown等人,Cell,49:603-612(1987)；Gossen和Bujard(1992)；M.Gossen等人,《美国国家科学院院刊》,89:5547-5551(1992)]，所述携带有lac操纵基因的哺乳动物细胞启动子将四环素阻遏物(tetR)与转录激活子(VP 16)组合，以产生tetR-哺乳动物细胞转录激活子融合蛋白tTa(tetR-VP 16)，携带有tetO的哺乳动物启动子衍生自人巨细胞病毒(hCMV)主要立即早期启动子以用于产生tetR-tet操纵基因系统来控制哺乳动物细胞中的基因表达。在一个实施例中，使用四环素诱导型开关。当四环素操纵基因适当地定位在CMVIE启动子的TATA元件下游时，四环素阻遏物(tetR)而非tetR-哺乳动物细胞转录因子融合衍生物可以单独用作强效反式调制剂来调节哺乳动物细胞中的基因表达(Yao等人,Human Gene Therapy,10(16):1392-1399(2003))。这个四环素诱导型开关的一个特别的优点是其不需要使用四环素阻遏物-哺乳动物细胞反式激活子或阻遏物融合蛋白来实现其可调节作用，在一些情况下，所述四环素阻遏物-哺乳动物细胞反式激活子或阻遏物融合蛋白可能对细胞有毒(Gossen等人,《美国国家科学院院刊》,89:5547-5551(1992)；Shockett等人,《美国国家科学院院刊》,92:6522-6526(1995))。
另外，载体可以含有例如以下中的一些或全部：可选标志基因，如用于在哺乳动物细胞中选择稳定或瞬时转染子的新霉素基因；用于高水平转录的来自人CMV的立即早期基因的增强子/启动子序列；用于mRNA稳定的来自SV40的转录终止和RNA加工信号；用于适当的附加型复制的SV40多瘤复制起点和ColE1；内部核糖体结合位点(IRES)、通用多克隆位点；以及用于正义和反义RNA的体外转录的T7和SP6 RNA启动子。用于产生含有转基因的载体的适合的载体和方法是本领域熟知并且可获得的。
可用于实践本文所描述的方法的聚腺苷酸化信号的实例包含但不限于人胶原蛋白I聚腺苷酸化信号、人胶原蛋白II聚腺苷酸化信号和SV40聚腺苷酸化信号。
可以将包括对抗体中的任何抗体进行编码的核酸的一个或多个载体(例如表达载体)引入到适合的宿主细胞中以用于产生抗体。可以在适合的条件下培养宿主细胞以用于表达抗体或其任何多肽链。可以经由常规方法例如亲和力纯化通过培养的细胞(例如，来自细胞或培养上清液)来回收这种抗体或其多肽链。如果有必要，可以在适合的条件下在允许产生抗体的适合时间段内培育抗体的多肽链。
在一些实施例中，用于制备本文所描述的抗体的方法涉及对也如本文所描述的抗CD137抗体的重链和轻链进行编码的重组表达载体。可以通过常规方法例如磷酸钙介导的转染将重组表达载体引入到适合的宿主细胞(例如dhfr-
CHO细胞)中。可以选择并在允许表达形成抗体的这两条多肽链的适合条件下培养阳性转化体宿主细胞，这两条多肽链可以从细胞或从培养基中回收。在必要时，可以在允许形成抗体的适合条件下培育从宿主细胞中回收的这两条链。
在一个实例中，提供了两种重组表达载体，一种重组表达载体对抗CD137抗体的重链进行编码并且另一种重组表达载体对抗CD137抗体的轻链进行编码。可以通过常规方法例如磷酸钙介导的转染将这两种重组表达载体都引入到适合的宿主细胞(例如dhfr-CHO细胞)中。可替代地，可以将表达载体的每种表达载体引入到适合的宿主细胞中。可以选择并在允许表达抗体的多肽链的适合条件下培养阳性转化体。在将这两种表达载体引入到相同的宿主细胞中时，可以从宿主细胞或从培养基中回收其中产生的抗体。如果有必要，可以从宿主细胞或从培养基中回收多肽链，并且然后在允许形成抗体的适合条件下培育多肽链。当将这两种表达载体引入到不同的宿主细胞中时，可以从对应的宿主细胞或从对应的培养基中回收这两条多肽链中的每条多肽链。然后可以在适合的条件下培育这两条多肽链以用于形成抗体。
使用标准分子生物学技术来制备重组表达载体、转染宿主细胞、选择转化体、培养宿主细胞并从培养基中回收抗体。例如，可以用蛋白A或蛋白G偶联基质通过亲和层析来分离一些抗体。
编码如本文所述的抗CD137抗体的重链、轻链或两者的任何核酸，包含其的载体(例如表达载体)；和包含载体的宿主细胞都在本公开的范围内。
可以使用本领域已知的方法表征由此制备的抗CD137抗体，从而检测和/或测量CD137生物活性的增加。例如，ELISA型测定法可适合于定性或定量测量CD137促进T细胞增殖。
治疗方法
本公开提供了通过施用治疗有效量的抗CD137抗体治疗疾病例如癌症或免疫病症例如自身免疫性疾病的方法。
药物组合物
如本文所描述的抗体以及编码核酸和核酸组、包含其的载体、或包含载体的宿主细胞可以与药学上可接受的载剂(赋形剂)混合，以形成用于治疗靶标疾病的药物组合物。“可接受的”意味着载剂必须与组合物的活性成分相容(并且优选地，能够稳定活性成分)并且对待治疗受试者无害。药学上可接受的赋形剂(载剂)包含缓冲剂，所述缓冲剂是本领域熟知的。参见例如《雷明顿：药学科学与实践(Remington:The Science and Practice ofPharmacy)》第20版(2000),利平科特·威廉姆斯&威尔金斯公司(Lippincott Williams和Wilkins),K.E.Hoover编。
用于本发明方法的药物组合物可以包括冻干调配物或水溶液形式的药学上可接受的载剂、赋形剂或稳定剂。(《雷明顿：药学科学与实践》第20版(2000),利平科特·威廉姆斯&威尔金斯公司,K.E.Hoover编)。可接受的载剂、赋形剂或稳定剂在使用的剂量和浓度下对受者无毒，并且可以包括：缓冲剂，如磷酸盐、柠檬酸盐和其它有机酸；抗氧化剂，包含抗坏血酸和甲硫氨酸；防腐剂(如十八烷基二甲基苄基氯化铵；氯化六烃季铵；氯化苄烷铵、苄索氯铵；酚醇、丁醇或苯甲醇；烷基对羟苯甲酸酯，如甲基或丙基对羟苯甲酸酯；邻苯二酚；间苯二酚；环己醇；3-戊醇；以及间甲酚)；低分子量(少于约10个残基)多肽；蛋白质，如血清白蛋白、明胶或免疫球蛋白；亲水聚合物，如聚乙烯吡咯烷酮；氨基酸，如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸；单糖、双糖和其它碳水化合物，包含葡萄糖、甘露糖或葡聚糖；螯合剂，如EDTA；糖，如蔗糖、甘露醇、海藻糖或山梨糖醇；成盐反离子，如钠；金属络合物(例如Zn-蛋白络合物)；和/或非离子表面活性剂，如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。
在一些实例中，本文所描述的药物组合物包括含有抗体(或编码核酸)的脂质体，所述脂质体可以通过本领域已知的方法制备，如以下所描述的方法：Epstein等人,《美国国家科学院院刊》82:3688(1985)；Hwang等人,《美国国家科学院院刊》77:4030(1980)；以及美国专利第4,485,045号和第4,544,545号。美国专利第5,013,556号中公开了具有增强的循环时间的脂质体。可以利用包括磷脂酰胆碱、胆固醇和PEG衍生化磷脂酰乙醇胺(PEG-PE)的脂质组合物通过反相蒸发法来生成特别有用的脂质体。通过具有限定孔径的过滤器将脂质体挤出，以产生具有期望直径的脂质体。
还可以将抗体或一种或多种编码核酸包埋在例如通过凝聚法技术或通过界面聚合制备的微胶囊(例如分别是羟甲基纤维素或明胶微胶囊和聚(甲基丙烯酸甲酯)微胶囊)中、胶状药物递送系统(例如脂质体、白蛋白微球、微乳剂、纳米颗粒和纳米胶囊)中、或粗乳液中。这些技术是本领域已知的，参见例如《雷明顿：药学科学与实践》第20版马克出版公司(Mack Publishing)(2000)。
在其它实例中，可以以持续释放格式调配本文所描述的药物组合物。持续释放制剂的适合的实例包含含有抗体的固体疏水聚合物的半渗透基质，所述基质采用定型物品例如薄膜或微胶囊的形式。持续释放基质的实例包含聚酯、水凝胶(例如，聚(2-羟乙基-甲基丙烯酸酯)或聚(乙烯醇))、聚交酯(美国专利第3,773,919号)、L-谷氨酸和7-乙基-L-谷氨酸盐的共聚物、不可降解的乙烯-乙酸乙烯酯、如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林构成的可注射微球)等可降解的乳酸-乙醇酸共聚物、乙酸异丁酸蔗糖酯和聚-D-(-)-3-羟基丁酸。
用于体内施用的药物组合物必须是无菌的。这通过例如无菌过滤膜过滤容易地实现。通常将治疗性抗体组合物置于具有无菌进口端的容器中，例如具有可被皮下注射针刺穿的塞子的静脉内溶液袋或小瓶。
本文所描述的药物组合物可以采用单位剂型，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、溶液剂或混悬剂或栓剂，以用于口服、肠胃外或直肠施用或者通过吸入或吹入施用。
为了制备如片剂等固体组合物，可以将主要活性成分与药物载剂例如常规压片成分(如玉米淀粉、乳糖、蔗糖、山梨糖醇、滑石、硬脂酸、硬脂酸镁、磷酸二钙或树胶)和如水等其它药物稀释剂混合，以形成含有本发明的化合物的均相混合物固体预调配组合物或其药学上可接受的无毒盐。在称这些预调配组合物均相时，这意味着活性成分均匀地分散在整个组合物中，使得组合物可以容易地细分成等效单位剂型，如片剂、丸剂和胶囊剂。然后将这个固体预调配组合物细分成上述类型的单位剂型，所述单位剂型含有0.1至约500mg本发明的活性成分。可以包覆或以其它方式复合新组合物的片剂或丸剂，以提供给出延长作用的优点的剂型。例如，片剂或丸剂可以包括内剂量组分和外剂量组分，后者在前者之上采用被膜的形式。这两种组分可以通过肠溶层分开，所述肠溶层用于抵抗胃中的崩解并且允许内组分完整地传递进入十二指肠或被延迟释放。多种材料可以用于这种肠溶层或包衣，这种材料包含许多聚合酸以及聚合酸与如虫胶、十六醇和乙酸纤维素等这样的材料的混合物。
适合的表面活性剂尤其包含非离子剂，如聚氧乙烯山梨聚糖(例如TweenTM 20、40、60、80或85)和其它山梨聚糖(例如SpanTM 20、40、60、80或85)。具有表面活性剂的组合物将方便地包括介于0.05％与5％之间的表面活性剂，并且可以介于0.1％与2.5％之间。应当了解，如果必要的话，可以加入其它成分，例如甘露醇或其它药学上可接受的媒剂。
可以使用如IntralipidTM、LiposynTM、InfonutrolTM、LipofundinTM和LipiphysanTM等可商购脂肪乳剂来制备适合的乳剂。活性成分可以溶解在预混合的乳剂组合物中，或者可替代地，活性成分可以溶解在油(例如大豆油、红花油、棉籽油、芝麻油、玉米油或杏仁油)和在与磷脂(例如卵磷脂(egg phospholipid)、大豆磷脂或大豆卵磷脂(soybeanlecithin))和水混合形成的乳剂中。应当了解，可以加入其它成分，例如甘油或葡萄糖，以调整乳剂的张力。适合的乳剂通常将含有高达20％的油，例如介于5％与20％之间。脂肪乳剂可以包括介于0.1μm与1.0μm之间、尤其是0.1μm与0.5μm之间的脂肪滴，并且pH范围为5.5到8.0。
乳剂组合物可以是通过将抗体与IntralipidTM或其组分(大豆油、卵磷脂、甘油和水)混合而制备的那些乳剂组合物。
用于吸入或吹入的药物组合物包含药学上可接受的水性或有机溶剂或其混合物中的溶液和悬浮液以及粉末。液体或固体组合物可以含有如上文所列出的适合的药学上可接受的赋形剂。在一些实施例中，通过口服或鼻腔呼吸途径施用组合物，以产生局部或全身作用。
可以通过使用气体来雾化优选地无菌的药学上可接受的溶剂中的组合物。可以直接从雾化装置中呼吸雾化溶液，或者雾化装置可以附接到面罩、帐篷或间歇正压呼吸机。可以从以适当方式递送调配物的装置优选地通过口服或鼻腔施用溶液、悬浮液或粉末组合物。
治疗应用
为了实践本文所公开的方法，可以经由适合的途径向需要治疗的受试者(例如人)施用有效量的本文所描述的药物组合物，所述适合的途径如静脉内施用(例如如推注或通过一段时间内的连续输注)、通过肌肉内、腹膜内、脑脊髓内、皮下、关节内、滑膜内、鞘内、口服、吸入或局部途径。包含喷射雾化器和超声雾化器的用于液体调配物的可商购雾化器可用于施用。液体调配物可以直接雾化，并且冻干粉可以在重构之后雾化。可替代地，本文所描述的抗体可以使用碳氟化合物调配物和计量吸入器来雾化或者作为冻干粉和研磨粉吸入。
待通过本文所描述的方法治疗的受试者可以是哺乳动物、更优选地是人。哺乳动物包含但不限于家畜、运动动物(sport animal)、宠物、灵长类动物、马、狗、猫、小鼠和大鼠。需要治疗的人类受试者可以是患有、处于风险之中或被怀疑患有诸如癌症的目标疾病/病症或诸如自身免疫性疾病的免疫疾病的人类患者。
癌症的实例包括但不限于乳腺癌；胆道癌；膀胱癌；脑癌，包括胶质母细胞瘤和髓母细胞瘤；宫颈癌；绒毛膜癌；结肠癌；子宫内膜癌；食道癌；胃癌；血液肿瘤，包括急性淋巴细胞白血病和骨髓性白血病，例如B细胞CLL；T细胞急性淋巴细胞白血病/淋巴瘤；毛细胞白血病；慢性粒细胞性白血病，多发性骨髓瘤；艾滋病相关的白血病和成人T细胞白血病/淋巴瘤；上皮内肿瘤，包括鲍恩氏病和佩吉特氏病；肝癌；肺癌；淋巴瘤，包括霍奇金氏病和淋巴细胞性淋巴瘤；神经母细胞瘤；口腔癌，包括鳞状细胞癌；卵巢癌，包括源自上皮细胞、基质细胞、生殖细胞和间充质细胞的卵巢癌；胰腺癌；前列腺癌；直肠癌；肉瘤，包括平滑肌肉瘤、横纹肌肉瘤、脂肪肉瘤、纤维肉瘤和骨肉瘤；皮肤癌，包括黑色素瘤、默克尔细胞癌、卡波济肉瘤、基底细胞癌和鳞状细胞癌；睾丸癌，包括精原细胞瘤、非精原细胞瘤(畸胎瘤、绒毛膜癌)、生殖基质肿瘤和生殖细胞肿瘤等生发肿瘤；甲状腺癌，包括甲状腺腺癌和髓样癌；以及肾癌，包括腺癌和Wilms肿瘤。
可以通过常规医学检查(例如实验室检查、器官功能检查、CT扫描或超声检查)识别患有目标癌症的受试者。在一些实施方案中，通过本文描述的方法治疗的受试者可以是已经或正在接受抗癌疗法例如化学疗法、放射疗法、免疫疗法或手术的人类癌症患者。
免疫疾病是指免疫系统功能障碍。例子包括自身免疫性疾病、免疫缺陷或过敏。在一些实施方案中，治疗的目标疾病是自身免疫疾病。例子包括但不限于类风湿关节炎(RA)，系统性红斑狼疮(SLE)，重症肌无力(MG)，格雷夫斯病，特发性血小板减少性紫癜(ITP)，格林-巴利综合症，自身免疫性心肌炎，膜性肾小球肾炎，糖尿病，I型或II型糖尿病，多发性硬化症，雷诺氏综合征，自身免疫性甲状腺炎，胃炎，乳糜泻，白癜风，肝炎，原发性胆汁性肝硬化，炎性肠病，脊椎骨关节炎，实验性自身免疫性脑脊髓炎，免疫中性白细胞减少症，青少年发作性糖尿病，和由细胞因子(通常是在结核病、肉样瘤病和多发性肌炎中发现的T淋巴细胞)介导的超敏反应延迟相关的免疫反应，多动脉炎，皮肤血管炎，天疱疮，类天疱疮，Goodpasture综合征，川崎病，全身性硬化症，抗磷脂综合征，Sjogren综合征，移植物抗宿主(GVH)疾病和免疫性血小板减少症。
具有目标自身免疫性疾病的受试者可以通过常规医疗检查来鉴定，例如抗核抗体、抗线粒体抗体、抗中性粒细胞胞浆抗体、抗磷脂抗体、抗瓜氨酸肽(抗CCP)、抗类风湿因子、免疫球蛋白A的存在，C反应蛋白测试、补体测试、红细胞沉降率(ESR)测试、凝血特性以及蛋白质电泳/免疫固定电泳等。在一些实施方案中，通过本文描述的方法治疗的受试者可以是患有自身免疫疾病的人类受试者，其已经或正在经历自身免疫疾病的治疗，例如免疫抑制介导、激素替代疗法、输血、抗炎症药物和/或止痛药。
怀疑患有任何此类目标疾病/病症的受试者可能显示出该疾病/病症的一种或多种症状。具有疾病/病症风险的受试者可以是患有该疾病/病症的一种或多种风险因素的受试者。
如本文所使用的，“有效量”是指单独地或与一种或多种其它活性剂组合地赋予受试者治疗效果所需的每种活性剂的量。在一些实施方案中，治疗作用是增加的CD137活性，增加的T细胞增殖和存活和/或增加的抗肿瘤免疫应答。确定抗体的量是否达到治疗效果对于本领域技术人员而言将会是显而易见的。如本领域技术人员所认识到的，有效量有所不同，这取决于正在治疗的特定病状、病状的严重程度、包含年龄、身体状况、大小、性别和体重在内的个体患者参数、治疗持续时间、同时治疗的性质(如果有的话)、具体施用途径和在健康从业者的知识和专业技能内的相似因素。这些因素是本领域普通技术人员所熟知的并且可以仅通过常规实验来解决。通常优选使用个别组分或其组合的最大剂量，即根据合理的医学判断的最高安全剂量。
如半衰期等经验性考虑通常将有助于确定剂量。例如，可以使用如人源化抗体或完全人抗体等与人免疫系统相容的抗体来延长抗体的半衰期并防止抗体受到宿主的免疫系统的攻击。施用频率可以在治疗过程中确定并进行调整，并且通常但不一定是基于靶标疾病/病症的治疗和/或抑制和/或改善和/或延迟。可替代地，抗体的持续连续释放调配物可以是适当的。用于实现持续释放的各种调配物和装置是本领域已知的。
在一个实例中，可以在已经给予了抗体的一次或多次施用的个体中凭经验确定如本文所描述的抗体的剂量。给予个体增量剂量的激动剂。为了评估激动剂的功效，可以遵循疾病/病症的指标。
通常，对于本文所描述的任何抗体的施用，初始候选剂量可以为约2
mg/kg。出于本公开的目的，典型的日剂量的范围根据上述因素可以为约0.1
μg/kg到3μg/kg、到30μg/kg、到300μg/kg、到3mg/kg、到30mg/kg、到100mg/kg或更多中的任何剂量。对于在几天或更长时间内的重复施用，根据病状持续治疗，直至出现期望的症状抑制或直至达到足以减轻靶标疾病或病症或其症状的治疗水平。示例性给药方案包括施用约2mg/kg的初始剂量，之后施用约1mg/kg抗体的每周维持剂量或者之后每隔一周施用约1mg/kg的维持剂量。然而，根据从业者希望实现的药代动力学衰变模式，其它剂量方案可能是有用的。例如，设想每周给药一到四次。在一些实施例中，可以使用的剂量范围为约3μg/mg到约2mg/kg(如约3μg/mg、约10μg/mg、约30μg/mg、约100μg/mg、约300μg/mg、约1mg/kg和约2mg/kg)。在一些实施例中，给药频率为每周一次、每2周一次、每4周一次、每5周一次、每6周一次、每7周一次、每8周一次、每9周一次或每10周一次；或每月一次、每2个月一次或每3个月一次或更久一次。通过常规技术和测定，容易地监测这一疗法的进展。给药方案(包含使用的抗体)可以随时间推移而变化。
在一些实施例中，对于正常体重的成年患者，可以施用的剂量范围为约0.3mg/kg到5.00mg/kg。在一些实例中，本文所描述的抗CD137抗体的剂量可以是10mg/kg。特定的给药方案，即剂量、定时和重复，将取决于特定个体和所述个体的病史以及个别药剂的性质(如药剂的半衰期和本领域所熟知的其它考虑)。
出于本公开的目的，如本文所描述的抗体的适当剂量将取决于所采用的特异性抗体、抗体和/或非抗体肽(或其组合物)、疾病/病症的类型和严重程度、抗体是否出于预防或治疗目的而施用、既往疗法、患者的临床病史和对激动剂的应答、以及主治医生的判定。临床医生通常将施用抗体，直至达到实现期望结果的剂量。在一些实施方案中，期望的结果是在肿瘤微环境中抗肿瘤免疫应答的增加。确定剂量是否产生期望结果的方法对于本领域技术人员而言将会是显而易见的。一种或多种抗体的施用可以是连续的或间歇的，这取决于例如受者的生理状况、施用的目的是治疗性的还是预防性的以及熟练从业者已知的其它因素。抗体的施用可以在预选时间段内基本上是连续的，或者可以例如在发展靶标疾病或病症之前、期间或之后采用一系列间隔剂量。
如本文所使用的，术语“治疗”是指向受试者施加或施用包含一种或多种活性剂的组合物，所述受试者患有靶标疾病或病症、疾病/病症的症状或对疾病/症状有易感性，其目的是治疗、治愈、减轻、缓解、改变、补救、改善、改进或影响疾病、疾病的症状或对疾病或病症的易感性。
减轻靶标疾病/病症包含延迟疾病的发展或进展或者降低疾病严重程度或延长存活。减轻疾病或延长存活不一定需要治愈效果。如本文所使用的，“延迟”靶标疾病或病症的发展意指推迟、阻碍、减缓、放缓、稳定和/或延缓疾病的进展。这一延迟可以具有不同的时间长度，这取决于疾病的历史和/或正在治疗的个体。“延迟”或减轻疾病的发展或者延迟疾病的发作的方法是降低在给定时间帧内发展疾病的一种或多种症状的可能性和/或与不使用所述方法相比在给定时间帧内降低症状的程度的方法。这种比较通常是基于临床研究，使用了足以给出统计学上显著的结果的许多受试者。
疾病的“发展”或“进展”意指疾病的初始表现和/或后续进展。疾病的发展可以是可检测到的并且可以使用如本领域熟知的标准临床技术进行评估。然而，发展还指可能无法检测到的进展。出于本公开的目的，发展或进展是指症状的生物学过程。“发展”包含发生、复发和发作。如本文所使用的，靶标疾病或病症的“发作”或“发生”包含初始发作和/或复发。
在一些实施例中，在体内以足以将CD137的活性(和/或T细胞增殖)增加至少10％的量(例如20％、30％、40％、50％、60％、70％、80％、90％或更大)将本文所描述的抗体施用于需要治疗的受试者。
根据待治疗的疾病的类型或疾病的部位，可以使用医学领域普通技术人员已知的常规方法将药物组合物施用于受试者。这一组合物还可以经由其它常规途径施用，例如口服、肠胃外、通过吸入喷雾、局部、直肠、鼻腔、颊、阴道或经由植入式储药器施用。如本文所使用的术语“肠胃外”包含皮下、皮内、静脉内、肌肉内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内和颅内注射或输注技术。另外，可以经由可注射的贮库施用途径将组合物施用于受试者，如使用1个月、3个月或6个月贮库可注射或可生物降解材料和方法。在一些实例中，眼内或玻璃体内施用药物组合物。
可注射组合物可以含有各种载剂，如植物油、二甲基乙酰胺、二甲基甲酰胺、乳酸乙酯、碳酸乙酯、肉豆蔻酸异丙酯、乙醇和多元醇(甘油、丙二醇、液体聚乙二醇等)。对于静脉内注射，可以通过滴注方法施用水溶性抗体，由此输注含有抗体和生理学上可接受的赋形剂的药物调配物。生理学上可接受的赋形剂可以包含例如5％葡萄糖、0.9％盐水、林格氏溶液或其它适合的赋形剂。肌肉内制剂，例如抗体的适合的可溶性盐形式的无菌调配物，可以在如注射用水、0.9％盐水或5％葡萄糖溶液等药物赋形剂中溶解和施用。
在一个实施方案中，通过位点特异性或靶向的局部递送技术施用抗体。
位点特异性或靶向的局部递送技术的实例包括抗体或局部递送导管例如输液导管、留置导管或针导管的各种可植入储库来源，合成移植物，外膜包裹，分流器和支架或其他可植入装置，位点特异性的载体，直接注射或直接应用。参见例如PCT公开号WO 00/53211和美国专利5,981,568。
也可以使用含有反义多核苷酸、表达载体或亚基因组多核苷酸的治疗组合物的靶向递送。受体介导的DNA递送技术描述于例如Findeis等人,Trends Biotechnol.(1993)11:202；Chiou等人,Gene Therapeutics:Methods And Applications Of Direct GeneTransfer(J.A.Wolff,ed.)(1994)；Wu等人,J.Biol.Chem.(1988)263:621；Wu等人,J.Biol.Chem.(1994)269:542；Zenke等人,Proc.Natl.Acad.Sci.USA(1990)87:3655；Wu等人,J.Biol.Chem.(1991)266:338。
含有多核苷酸的治疗组合物(例如编码本文所述抗体的那些)在约100ng至约200mgDNA的范围内施用，用于基因治疗方案中的局部施用。在一些实施方案中，在基因治疗方案期间也可以使用约500ng至约50mg、约1μg至约2mg、约5μg至约500μg以及约20μg至约100μg的DNA或更高的浓度范围。
本文所述的治疗性多核苷酸和多肽可以使用基因递送载体来递送。基因递送载体可以是病毒或非病毒来源的(一般参见，Jolly,Cancer Gene Therapy(1994)1:51；Kimura,Human Gene Therapy(1994)5:845；Connelly,Human Gene Therapy(1995)1:185；和Kaplitt,Nature Genetics(1994)6:148)。可以使用内源性哺乳动物或异源启动子和/或增强子来诱导此类编码序列的表达。编码序列的表达可以是组成性的或调控的。
用于递送所需多核苷酸并在所需细胞中表达的基于病毒的载体是本领域众所周知的。基于病毒的示例性媒剂包括但不限于重组逆转录病毒(参见，例如PCT公开号WO 90/07936；WO 94/03622；WO 93/25698；WO 93/25234；WO 93/11230；WO 93/10218；WO 91/02805；美国专利号5,219,740和4,777,127；GB专利号2,200,651；和EP专利号0 345 242)，基于α病毒的载体(例如Sindbis病毒载体，Semliki森林病毒(ATCC)VR-67；ATCC VR-1247)，和罗斯河病毒(ATCC VR-373；ATCC VR-1246)和委内瑞拉马脑炎病毒(ATCC VR-923；ATCCVR-1250；ATCC VR 1249；ATCC VR-532)和腺相关病毒(AAV)载体(参见，例如PCT公开号WO94/12649，WO 93/03769；WO 93/19191；WO 94/28938；WO 95/11984和WO 95/00655)。也可以采用施用与杀死的腺病毒相关的DNA，如Curiel,Hum.Gene Ther.(1992)3:147中所述。
也可以使用非病毒递送媒剂和方法，包括但不限于单独与未杀灭的腺病毒连接或未连接的聚阳离子缩合DNA(参见，例如Curiel,Hum.Gene Ther.(1992)3:147)；配体连接的DNA(参见，例如Wu,J.Biol.Chem.(1989)264:16985)；真核细胞递送载体细胞(参见，例如美国专利号5,814,482；PCT公开号WO 95/07994；WO 96/17072；WO 95/30763；和WO 97/42338)以及核酸电荷中和或与细胞膜融合。也可以使用裸露的DNA。示例性裸露DNA引入方法在PCT公开号WO 90/11092和美国专利5,580,859中描述。可以用作基因递送载体的脂质体在美国专利5,422,120；PCT公开号WO 95/13796；WO 94/23697；WO 91/14445；和欧洲专利号0524968中描述。其他方法描述于Philip,Mol.Cell.Biol.(1994)14:2411和Woffendin,Proc.Natl.Acad.Sci.(1994)91:1581中。
本文所描述的方法中使用的特定给药方案，即剂量、定时和重复，将取决于特定受试者和所述受试者的病史。
在一些实施例中，可以向需要治疗的受试者施用多于一种抗体或抗体与另一种适合的治疗剂的组合。抗体还可以结合用于增强和/或补充药剂的有效性的其它药剂使用。
可以通过本领域熟知的方法对靶标疾病/病症的治疗功效进行评估。
联合疗法
本文所描述的抗CD137抗体可以结合用于如癌症或免疫病症等靶标疾病的其它类型的疗法使用。
当本文所述的抗CD137抗体用于治疗癌症时，它可以与抗癌疗法例如本领域已知的疗法组合。另外的抗癌疗法包含化学疗法、外科手术、放射、免疫疗法、基因疗法等。
可替代地，本公开的治疗可以与以下组合：化学治疗剂，例如嘧啶类似物(5-氟尿嘧啶、氟尿苷、卡培他滨(capecitabine)、吉西他滨(gemcitabine)和阿糖胞苷)、嘌呤类似物、叶酸拮抗剂和相关抑制剂(巯基嘌呤、硫鸟嘌呤、喷司他丁(pentostatin)和2-氯脱氧腺苷(克拉屈滨(cladribine)))；抗增殖/抗有丝分裂剂，包含如长春花生物碱(长春碱、长春新碱和长春瑞滨)等天然产物、如紫杉烷(紫杉醇、多西他赛(docetaxel))、长春新碱、长春碱、诺考达唑(nocodazole)、埃博霉素(epothilone)和诺维本(navelbine)等微管破坏剂、表鬼臼毒素(依托泊苷(etoposide)、替尼泊苷(teniposide))、DNA损伤剂(放线菌素、安吖啶(amsacrine)、蒽环霉素(anthracycline)、博莱霉素(bleomycin)、白消安(busulfan)、喜树碱(camptothecin)、卡铂、苯丁酸氮芥(chlorambucil)、顺铂、环磷酰胺(cyclophosphamide)、环磷酰胺(cytoxan)、更生霉素(dactinomycin)、柔红霉素(daunorubicin)、多柔比星(doxorubicin)、表柔比星(epirubicin)、六甲胺(hexamethylamine)、奥沙利铂(oxaliplatin)、异环磷酰胺、美法仑(melphalan)、二氯甲基二乙胺(mechlorethamine)、丝裂霉素(mitomycin)、米托蒽醌(mitoxantrone)、亚硝基脲、普卡霉素(plicamycin)、丙卡巴肼(procarbazine)、紫杉酚、泰索帝(taxotere)、替尼泊苷、三乙烯硫代磷酰胺和依托泊苷(VP16))；抗生素，如更生霉素(放线菌素D)、柔红霉素、多柔比星(阿霉素(adriamycin))、伊达比星(idarubicin)、蒽环霉素、米托蒽醌、博来霉素、普卡霉素(光辉霉素(mithramycin))和丝裂霉素；酶(系统地代谢L-天冬酰胺并且剥夺不具有合成其自己的天冬酰胺的能力的细胞的L-天冬酰胺酶)；抗血小板剂；抗增殖/抗有丝分裂烷化剂，如氮芥(二氯甲基二乙胺、环磷酰胺和类似物、美法仑、苯丁酸氮芥)、乙烯亚胺和甲基三聚氰胺(六甲基三聚氰胺和噻替派)、烷基磺酸盐-白消安、亚硝基脲(卡莫司汀(carmustine)(BCNU)和类似物、链脲霉素(streptozocin))、三氮缔-达卡巴嗪(trazenes-dacarbazine)(DTIC)；抗增殖/抗有丝分裂抗代谢物，如叶酸类似物(甲氨蝶呤)；铂配位络合物(顺铂、卡铂)、丙卡巴肼、羟基脲、米托坦(mitotane)、氨鲁米特(aminoglutethimide)；激素、激素类似物(雌激素、他莫昔芬(tamoxifen)、戈舍瑞林(goserelin)、比卡鲁胺(bicalutamide)、尼鲁米特(nilutamide))和芳香酶抑制剂(来曲唑(letrozole)、阿那曲唑(anastrozole))；抗凝血剂(肝素、合成肝素盐和其它凝血酶抑制剂)；纤维蛋白溶解剂(如组织纤溶酶原激活剂、链激酶和尿激酶)、阿司匹林(aspirin)、双嘧达莫(dipyridamole)、噻氯匹定(ticlopidine)、氯吡格雷(clopidogrel)、阿昔单抗(abciximab)；抗迁移剂；抗分泌剂(贝莱维定(breveldin))；免疫抑制剂(环孢菌素(cyclosporine)、他克莫司(tacrolimus)(FK-506)、西罗莫司(sirolimus)(雷帕霉素(rapamycin))、硫唑嘌呤、霉酚酸酯)；抗血管生成化合物(例如TNP-470、染料木黄酮、贝伐单抗(bevacizumab))和生长因子抑制剂(例如成纤维细胞生长因子(FGF)抑制剂)；血管紧张素受体阻断剂；一氧化氮供体；反义寡核苷酸；抗体(曲妥珠单抗(trastuzumab))；细胞周期抑制剂和分化诱导剂(维甲酸(tretinoin))；mTOR抑制剂、拓扑异构酶抑制剂(多柔比星(阿霉素)、安吖啶、喜树碱、柔红霉素、更生霉素、替尼泊苷、表柔比星、依托泊苷、伊达比星和米托蒽醌、托泊替康(topotecan)、伊立替康(irinotecan))、皮质类固醇(可的松(cortisone)、地塞米松(dexamethasone)、氢化可的松(hydrocortisone)、甲基强的松龙(methylprednisolone)、强的松(prednisone)和泼尼松龙(prednisolone))；生长因子信号转导激酶抑制剂；线粒体功能异常诱导剂和半胱天冬酶激活剂；以及染色质破坏剂。
当本文所述的抗CD137抗体用于治疗免疫病症时，它可以与其它免疫调节治疗一起使用，所述其它免疫调节治疗如例如治疗性疫苗(包含但不限于GVAX、基于DC的疫苗等)或检查点抑制剂(包含但不限于阻断CTLA4、PD1、LAG3、TIM3等的药剂)。在某些情况下，抗体可以与另一种针对自身免疫性疾病的疗法联合使用。实例包括但不限于静脉内Ig疗法；非甾体抗炎药(NSAID)；皮质类固醇；环孢菌素、雷帕霉素、ascomycins；环磷酰胺；硫唑嘌呤；甲氨蝶呤；brequinar；FTY 720；来氟米特(leflunomide)；咪唑立滨；麦考酚酸；吗替麦考酚酯；15-deoxyspergualine；免疫抑制剂或黏附分子抑制剂。
关于另外的有用药剂的实例，还参见：《内科医生案头参考(ThePhysician's DeskReference)》,补充第59版,(2005),Thomson P D R、Montvale N.J.；Gennaro等人编,《雷明顿药学科学与实践(Remington's The Science and Practice of Pharmacy)》,补充第20版,(2000),利平科特·威廉姆斯&威尔金斯公司,巴尔的摩,马里兰州；Braunwald等人编,《哈里森内科医学原理(Harrison's Principles of Internal Medicine)》,补充第15版,(2001),麦格劳·希尔公司(McGraw Hill),纽约州；Berkow等人编,《默克诊断与治疗手册(The Merck Manual of Diagnosis and Therapy)》,(1992),默克研究实验室(MerckResearch Laboratories),拉威(Rahway),纽约州。
当使用第二治疗剂时，这种药剂可以与本文所描述的治疗剂同时地或顺序地施用(按任何顺序)。当与另外的治疗剂共同施用时，可以根据相加作用或协同效应降低每种药剂的适合的治疗有效剂量。
用于治疗疾病的试剂盒
本公开还提供了用于治疗或减轻靶标疾病如本文所述的癌症和免疫疾病的试剂盒。这样的试剂盒可以包括一个或多个容器，所述容器包含抗CD137抗体，例如本文所述的那些的任一种，以及任选地与抗CD137抗体共同使用的第二治疗剂，其也在本文中描述。
在一些实施方案中，试剂盒可以包括根据本文所描述的任何方法使用的说明书。包含的说明书可以包括对施用用于治疗、延迟发作或减轻如本文所描述的那些的靶标疾病的抗CD137抗体和任选的第二治疗剂的描述。试剂盒进一步可以包括对基于鉴别所述个体是否患有靶标疾病来选择适于治疗的个体的描述，例如应用如本文所述的诊断方法。在仍其它实施方案中，说明书包括对向处于靶标疾病风险中的个体施用抗体的描述。
与抗CD137抗体的使用有关的说明书通常包含关于用于预期治疗的剂量、给药方案和施用途径的信息。容器可以是单位剂量、散装包装(例如多剂量包装)或亚单位剂量。本发明的试剂盒中提供的说明书通常是在标签或包装插页(例如包含在试剂盒中的纸张)上的书面说明，但机器可读说明书(例如磁性或光学存储盘上携带的说明书)也是可接受的。
标签或包装插页表明组合物用于治疗、延缓疾病发作和/或缓解疾病，例如癌症或免疫病症(例如自身免疫疾病)。可以提供说明书以用于实践本文所描述的任何方法。
本发明的试剂盒采用适合的包装。适合的包装包含但不限于小瓶、瓶、广口瓶、软包装(例如密封的密拉(Mylar)或塑料袋)等。还设想了与特定装置组合地使用的包装，所述特定装置如吸入器、鼻腔施用装置(例如雾化器)或如微型泵等输注装置。试剂盒可以具有无菌进口端(例如，容器可以是具有可被皮下注射针刺穿的塞子的静脉内溶液袋或小瓶)。容器也可以具有无菌进口端(例如，容器可以是具有可被皮下注射针刺穿的塞子的静脉内溶液袋或小瓶)。组合物中的至少一种活性剂是如本文所描述的那些的抗CD137抗体。
试剂盒可以任选地提供如缓冲剂等另外的组分以及解释性信息。试剂盒通常包括容器和在容器上或与容器相关联的标签或包装插页。在一些实施方案中，本发明提供了包括上文所描述的试剂盒的内容物的制品。
通用技术
除非另有指示，否则本发明的实践将采用在本领域的技术内的分子生物学(包含重组技术)、微生物学、细胞生物学、生物化学和免疫学的常规技术。这种技术在如以下等文献中进行了充分解释：《分子克隆：实验室手册(Molecular Cloning:A LaboratoryManual)》,第二版(Sambrook等人,1989)冷泉港出版社；《寡核苷酸合成(OligonucleotideSynthesis)》(M.J.Gait编,1984)；《分子生物学方法(Methods in Molecular Biology)》,胡玛纳出版社(Humana Press)；
《细胞生物学：实验室手册(Cell Biology:A Laboratory Notebook)》(J.E.Cellis编,1998)学术出版社(Academic Press)；《动物细胞培养(Animal CellCulture)》
(R.I.Freshney编,1987)；《细胞和组织培养简介(Introduction to Cell andTissue Culture)》(J.P.Mather和P.E.Roberts,1998),普莱纽姆出版社(Plenum Press)；
《细胞和组织培养：实验室程序(Cell and Tissue Culture:LaboratoryProcedures》(A.Doyle，J.B.Griffiths和D.G.Newell编,1993-8)约翰威利父子出版公司(J.Wiley and Sons)；《酶学方法(Methods in Enzymology)》(学术出版社有限公司)；《实验免疫学手册(Handbook of Experimental Immunology)》(D.M.Weir和C.C.Blackwell编)；《哺乳动物细胞基因转移载体(Gene Transfer Vectors for Mammalian Cells)》(J.M.Miller和M.P.Calos编,1987)；《分子生物学实验指南(Current Protocols inMolecular Biology)》(F.M.Ausubel等人编,1987)；《PCR：聚合酶链反应(PCR:ThePolymerase Chain Reaction)》(Mullis等人编,1994)；
《免疫学实验指南(Current Protocols in Molecular Biology)》(J.E.Coligan等人编,1991)；《精编分子生物学实验指南(Short Protocols in Molecular Biology)》(约翰威利父子出版公司(Wiley and Sons),1999)；《免疫生物学(Immunobiology)》
(C.A.Janeway和P.Travers,1997)；《抗体(Antibodies)》(P.Finch,1997)；《抗体：实用方法(Antibodies:a practical approach)》(D.Catty.编,IRL出版社,1988-1989)；《单克隆抗体实用方法(Monoclonal antibodies:a practical approach)》(P.Shepherd和C.Dean编,牛津大学出版社(Oxford University Press),2000)；《使用抗体：实验室手册(Using antibodies:a laboratory manual)》(E.Harlow和D.Lane,冷泉港实验室出版社,1999)；《抗体(The Antibodies)》(M.Zanetti和J.D.Capra编,哈伍德学术出版社(HarwoodAcademic Publishers),1995)。
无需进一步详细阐述，相信本领域技术人员可以基于以上描述在最大程度上利用本发明。因此，以下具体实施例应被解释为仅是说明性的并且不以任何方式限制本公开的其余部分。出于本文中提及的目的或主题，本文所引用的所有出版物均通过引用的方式并入。
实施例
实施例1：抗CD137抗体的产生
试剂和通用方法
人CD137/4-1BB/TNFRSF9蛋白(目录号838-4B，Fc嵌合体)和人4-1BB/TNFRSF9 MAb(克隆145501，小鼠IgG2B，目录号MAB838)购自R&D Systems(美国)。通过用全长人CD137cDNA(基因ID：3604)或食蟹猴CD137cDNA(基因ID：102127961)转染，开发了表达人或食蟹猴CD137的稳定的CHO细胞系。
使用标准ELISA检测抗CD137抗体。用CD137蛋白包被平板，并与抗CD137抗体一起孵育。使用与过氧化物酶缀合的二抗(山羊抗小鼠或大鼠IgG)检测与CD137结合的抗体分子。
使用CHO-CD137细胞系进行FACS以检测抗CD137抗体。与抗体样品孵育一段时间后，使用FACS通过市售的PE或FITC标记的二抗分析CHO-CD137细胞。
杂交瘤的发育和先导抗体鉴定
Balb/c和SJLmice和Wistar大鼠用重组人CD137/4-1BB/TNFRSF9蛋白(目录号838-4B，Fc嵌合体)和pCDNA3.1-人CD137质粒进行免疫接种。使用人CD137和人IgG作为对照，使用ELISA监测免疫动物的抗CD137血清滴度。使用FACS筛选CHO-人CD137细胞来进一步确认阳性滴度。处死具有最高滴度的三只小鼠和一只大鼠；分离收获的脾细胞，并使用标准杂交瘤方案将其与SP2/0骨髓瘤细胞融合。
使用ELISA筛选了小鼠或大鼠杂交瘤的八十个96孔板，该ELISA测量与人CD137蛋白的结合。然后通过人Fc计数器筛选，测试阳性样品。接下来，通过FACS测试这些阳性CD137特异性克隆与CHO-人CD137的结合，并通过有限的稀释进行两轮单细胞克隆。获得了十四个稳定的杂交瘤克隆(2只大鼠和12只鼠)。
培育杂交瘤细胞克隆以生产抗体。通过FACS评估这些纯化的抗体与人细胞CD137的结合。图1显示了已证实的杂交瘤抗体的结合结果。这六种抗体也在人CD8阳性T细胞的共刺激测定中进行了测试(Fisher等人,Cancer Immunol Immunother,(2012),61:1721-1733)，结果如图2所示，确认了这些抗体的潜在激动剂活性。
嵌合抗体的制备
六个已确认杂交瘤的抗体可变结构域的测序如下。简言之，使用NucleoZOL(MACHEREY-NAGEL，目录号740404.2)，从杂交瘤细胞中提取总RNA，然后通过5'-RACE，用
RACE 5’/3’Kit(Clontech,目录#634858)逆转录成cDNA。通过使用特异性引物(Novagen，目录#69831-3)进行PCR，扩增重链和轻链可变区，并使用
Gel和PCR Clean-up Kit(MACHEREY-NAGEL，目录#740609.25)纯化扩增子。然后使用TA克隆，将扩增子克隆到pMD18-T载体(Takara，目录号D101A)中。在将克隆转化到DH5α细胞中之后，分析了15个带有VH和VL片段的单个克隆，以获得抗体可变区的序列。使用以下规则确定VH/VL序列：来自几个菌落的插入片段的氨基酸序列是相同的，并且在每个序列中都发现了FR和CDR(Kabat定义)。认为所得的共有序列是杂交瘤产生的抗体的序列，其显示在图3和SEQ IDNO：1-12中。
将编码抗CD137抗体可变结构域序列的cDNA序列作为嵌合体合成为人IgG4重链恒定区，其包含铰链S228P(EU编号；Kabat编号241)，其稳定突变(Angal等，Mol.Immunol 30:105,1993)，或人类κ轻链恒定区。用含有相应重链和轻链序列的质粒进行HEK293和/或CHO瞬时表达。这些嵌合抗体通过蛋白质亲和色谱法纯化。检查纯化的抗体的内毒素(<5EU/mg)和单体化(>95％)。
实施例2：抗CD137嵌合抗体的评估
CD137抗原结合的KD测量
在Octet Red 96上的抗原结合测定中测试了嵌合抗体，以估计结合动力学。将抗体加载到抗人Fc(AHC)生物传感器上。将加载的传感器浸入在测定缓冲液(含0.1％BSA、0.02％Tween-20的PBS(pH 7.2))中的每种抗体的系列稀释液(300nM，1：3下降，7个点)。使用单价(1：1)模型计算的动力学常数示于下表1中。
表1.嵌合抗体的动力学常数
| 抗体 | K<sub>D</sub>(M) | k<sub>on</sub>(1/Ms) | k<sub>dis</sub>(1/s) |
| LYV370(20A12-IgG4) | 5.70E-09 | 1.80E+05 | 1.00E-03 |
| LYV371(11E10-IgG4) | 3.80E-09 | 2.80E+05 | 1.10E-03 |
| LYV372(23D2-IgG4) | 5.80E-09 | 2.80E+05 | 1.60E-03 |
| LYV375(22F2-IgG4) | 8.20E-09 | 2.80E+05 | 2.30E-03 |
| LYV390(30C11-IgG4) | 5.30E-09 | 2.60E+05 | 1.40E-03 |
| LYV402(26B3-IgG4) | 2.10E-09 | 1.60E+05 | 3.40E-04 |
CD137结合ELISA
将CD137蛋白(人CD137-His标签蛋白(新诺生物技术有限公司(Sino BiologicalInc.)，目录号#10377-H08H-100)或恒河猴CD137-His(新诺生物技术有限公司，目录号#90305-K08H-100))在PBS中稀释至1μg/ml并且用于以50μl/孔的浓度涂覆ELISA板(康宁公司(Corning)，目录号#9018，高结合)。将板在4℃下培育过夜。然后将板倾析并用PBS-T洗涤，并且加入200μl/孔的测定稀释剂(1x PBS/1％BSA/0.05％Tween-20/0.05％proclin300)。在室温下培育3小时之后，用PBS-T将板洗涤三次。将测试抗体在测定稀释剂中稀释至0μg/ml、0.000003μg/ml、0.00003μg/ml、0.0003μg/ml、0.003μg/ml、0.03μg/ml和0.3μg/ml或大约0nM、0.00002nM、0.0002nM、0.002nM、0.02nM、0.2nM和2nM，然后加入到平板(50μl/孔)。将板在37℃下培育一小时，并且然后用PBS-T洗涤三次。向板中加入以1:10,000稀释的抗人IgG-HRP缀合物(Bethyl公司，目录号#A80-319P)(100μl/孔)。将板在37℃下培育0.5小时，之后用PBS-T洗涤三次。加入TMB底物溶液(100μl/孔)。允许颜色显影8分钟，之后用100μl/孔的2N H2SO4使其停止。用ELISA读数器测定450nm处的吸光度。嵌合抗体的剂量反应曲线如图4所示。
CD137结合FACS
使用胰蛋白酶-EDTA部分消化，然后以1000rpm离心5分钟，收集过表达人CD137或食蟹猴CD137的CHO细胞。将细胞以5x106/ml重悬于冷的PBS-BSA(2％)中，并分装至100ul/管。将嵌合抗CD137抗体在PBS-BSA中稀释三倍(最终浓度为0.01、0.1、1和10ug/ml)，并将每种浓度的50ul加入CHO-CD137细胞中。将细胞溶液混合，并在4℃在黑暗中孵育2小时。然后将细胞用PBS-BSA洗涤两次。将浓度为100ul/小瓶的二抗缀合物(山羊F(ab')2抗人IgG-Fc(PE)，预吸附(ab98596))加入，并且将细胞混合，并在4℃黑暗中温育1小时。然后将细胞用PBS-BSA洗涤两次，然后固定在2％PFA中，然后用FACScaliber进行FACS分析。如图5所示，这些抗体表现出与过量表达人CD137的CHO细胞的饱和结合。然而，这些抗体与细胞食蟹猴CD137的结合不同，如图6所示，因为仅三种抗体(LYV371、LYV390和LYV402)表现出与食蟹猴CD137的高亲和力结合。
T细胞功能测定
从两名健康志愿者中分离出新鲜的PBMC，并将其以1x106/ml的浓度悬浮在含有10％FBS的PRMI-1640中。使用EasySepTM人CD8+ T细胞分离试剂盒(Stemcell，17953)从样品中分离出CD8 T细胞。将所得的T细胞在RPMI 1640(10％FBS)中稀释至5x105/ml的浓度。
在三种条件下进行人CD8阳性T细胞的共刺激测定：无共培养，与亲本CHO细胞共培养以及与表达人FcγRIIB的CHO细胞共培养。为了进行共培养测定，将亲本CHO细胞或经工程改造FcγRIIB的CHO细胞以2.5x104个细胞/孔的浓度铺板在96孔培养板中。使细胞在37℃和5％CO2的细胞培养培养箱中过夜培养期间附着。以1x105个细胞/孔添加人CD8 T细胞，以0.1ug/mL添加OKT3，和以0、0.03、0.1、0.3、1和3ug/mL终浓度添加CD137抗体。将培养板在37℃和5％CO2的细胞培养培养箱中培养3天。在培养物上清液中的IFNγ含量通过ELISA(eBioscience公司，88-7316-88)测定。如图7所示，嵌合抗体显示出在FcγRIIB表达CHO细胞的存在下共刺激人CD8阳性T淋巴细胞的能力。
实施例3：嵌合抗体的药代动力学研究
研究中使用C57BL/6小鼠(6-7周大，19-20g，雄性，购自SLAC Laboratory AnimalCo.LTD)。在PBS中配制抗体，并在4只小鼠的一组中通过尾静脉注射以3mg/kg施用。
通过连续放血，在给药前、1h、2h、4h、8h、1d、2d、3d、5d、8d、11d、15d和21d进行血液取样。将每个时间点的10uL血液加入到40uL PBS-BSA溶液中。然后将样本充分混合并在4℃下以2000g离心5分钟。收集后立即将上清液放置于干冰上并且在分析之前储存在大约-70℃下。如上文所述，通过ELISA确定血液抗体浓度。图8显示了单次静脉内注射3mg/kg后嵌合抗体的血液抗体浓度。
实施例4：PC-3人前列腺癌的抗体治疗功效的体内评价(MiXeno模型)
将PC-3肿瘤细胞在体外以单层培养物在37℃、在空气中5％CO2的环境中保持在补充了10％FBS的Ham's F12K培养基中。每周将肿瘤细胞传代培养两次。收获在指数生长期生长的细胞，并计数肿瘤接种量。
从两个健康供体(供体A和供体B)的血液中分离出人PBMC。离心后，将细胞用PBS溶液洗涤并重悬于PBS中。将细胞数调整到1.5×107个细胞
/ml(1.5×106/100ul)以接种。
使用8-10周龄，体重为18.5-21.5g的SCID/米色小鼠进行研究。在肿瘤接种前一天，对所有小鼠进行亚致命性的60Co(150rad)照射。首先，将104只小鼠按体重分为两队。在每队中的小鼠的右胁区域皮下接种3×106个PC-3肿瘤细胞/小鼠，其与0.2ml PBS中的1.5×106个来自供体A或B的PBMC预混合。肿瘤细胞接种的日期表示为第0天。在第1天，根据体重将小鼠分为组(n＝5)，然后开始给药。在分组和治疗之前，将所有动物称重并使用卡尺测量肿瘤体积。由于肿瘤体积会影响任何给定治疗的有效性，因此将肿瘤体积用作数值参数，以将选定的动物随机分为指定的组。因此，系统误差被最小化。通过使用StudyDirectorTM软件(美国加利福尼亚州Studylog Systems，Inc.)进行分组。一种最佳的随机设计(由匹配分布生成)显示基于组分配的最小组间肿瘤体积变化。
肿瘤细胞接种后，每天检查动物的发病率和死亡率。在常规监测时，检查动物是否有肿瘤生长和治疗对正常行为的任何影响，例如活动性，肉眼估计的食物和水消耗，体重增/减(分组后每周两次测量体重)，眼睛/毛发消光以及任何其他异常影响。根据每个子集中的动物数量记录死亡和观察到的临床体征。在第1天和第5天，通过腹膜内注射施用3mg/kg的抗体或对照载体。分组后，使用卡尺每周两次在二维上测量肿瘤体积，并使用以下公式以mm3表示体积：0.5a×b2，其中a和b分别是肿瘤的长径和短径。整个给药过程以及肿瘤和体重的测量均在层流柜中进行。肿瘤生长曲线示于图9，其表明两种抗体LYV371m和LYV372m显示出抗肿瘤活性。
其它实施方案
本说明书中公开的所有特征可以以任何组合来组合。本说明书中公开的每个特征可以由用于相同、等同或类似目的的替代性特征替换掉。因此，除非另外明确说明，否则所公开的每个特征仅仅是通用系列的同等或类似特征的实例。
通过以上描述，本领域技术人员可以很容易地确定本发明的实质特性，并且在不偏离本发明的精神和范围的情况下，可以对本发明进行各种改变和修改，以使其适于各种用途和条件。因此，其它实施方案也在权利要求书范围内。
等同物
尽管本文已经描述和展示了若干个发明实施方案，但本领域普通技术人员将容易想到用于执行功能和/或获得结果和/或本文所描述的优点中的一个或多个优点的各种其它装置和/或结构，并且此类变型和/或修改中的每一个均被视为在本文所描述的发明实施方案的范围内。更一般来讲，本领域的技术人员将容易认识到，本文中描述的所有参数、尺寸、材料和配置意味着是示例性的，并且实际参数、尺寸、材料和/或配置将取决于本发明教导所用于的一种或多种具体应用。本领域技术人员仅使用常规实验就将认识到或能够确认本文所描述的具体发明实施方案的许多等同物。因此，应理解，前述实施方案是仅通过举例的方式来呈现的，并且在所附权利要求书和其等同物的范围内，发明实施方案可以按与具体地描述和要求保护的方式不同的方式来实践。本公开的发明实施方案涉及本文中描述的每个单独的特征、系统、物品、材料、试剂盒和/或方法。另外，如果此类特征、系统、物品、材料、试剂盒和/或方法并不相互矛盾，则两个或更多个此类特征、系统、物品、材料、试剂盒和/或方法的任何组合包含在本公开的发明范围内。
如本文所定义和使用的，所有定义应被理解为控制字典定义、通过引用的方式并入的文档中的定义和/或所定义术语的普通含义。
本文所公开的所有参考文献、专利和专利申请都相对于每个参考文献、专利和专利申请被引用的主题通过引用的方式并入，这在一些情况下可以涵盖文档的全部内容。
除非清楚地作出相反指示，否则如本文在说明书和权利要求书中使用的，不定冠词“一个/种(a/an)”应被理解为是指“至少一个”。
如本文在说明书和权利要求书中使用的，短语“和/或”应被理解为是指这样结合的要素中的“任一个或两个”要素，即，要素在一些情况下联合地存在而在其它情况下分离地存在。用“和/或”列出的多个元素应当以相同的方式解释，即这样结合的要素中的“一个或多个”要素。除了用“和/或”从句具体标识的要素，其它要素可以任选地存在，无论是与具体标识的那些要素相关还是不相关。因此，作为非限制性实例，当结合如“包括”等开放式语言使用时，对“A和/或B”的引用可以：在一个实施例中，仅指A(任选地包含除了B之外的要素)；在另一个实施例中，仅指B(任选地包含除了A之外的要素)；在又另一个实施例中，指A和B两者(任选地包含其它要素)；等。
如本文在说明书和权利要求中使用的，“或”应被理解为具有与如上所定义的“和/或”相同的含义。例如，当分隔列表中的项时，“或”或“和/或”应被解释为包容性的，即包含多个要素或要素列表中的至少一个要素、而且还包含其中的多于一个要素、以及任选地其它未列出的项。仅相反地清楚指示的术语，如“……中的仅一个”或“……中的恰好一个”或者当在权利要求中使用时“由……组成”将指包含多个要素或要素列表中的恰好一个要素。一般而言，当之前有排他性术语如“任一个”、“……之一”、“……中的仅一个”、或“……中的恰好一个”时，如本文所使用的术语“或”应当仅被解释为指示排他性替代形式(即，“一个或另一个，但非两者”)。当在权利要求书中使用时，“主要由……组成”应当具有如在专利法领域中使用的普通含义。
如本文在说明书和权利要求书中使用的，关于具有一个或多个要素的列表的短语“至少一个”应被理解为意指选自要素列表中的任一个或多个要素中的至少一个要素、但不一定包含要素列表内具体列出的每一个要素中的至少一个，并且不排除要素列表中的要素的任何组合。这个定义还允许可以任选地存在除了短语“至少一个”所指的要素清单内具体标识的要素之外的要素，无论与具体标识的那些要素相关还是不相关。因此，作为非限制性实例，“A和B中的至少一个”(或等同地，“A或B中的至少一个”，或等同地“A和/或B中的至少一个”)可以：在一个实施例中指至少一个，任选地包含多于一个A，而不存在B(并且任选地包含除B之外的要素)；在另一个实施例中指至少一个B，任选地包含多于一个B，而不存在A(并且任选地包含除A之外的要素)；在又一个实施例中指至少一个A，任选地包含多于一个A，以及至少一个B，任选地包含多于一个B(并且任选地包括其它要素)；等。
还应当理解，除非明确相反地指出，否则在本文所要求保护的包含多于一个步骤或动作的任何方法中，所述方法的步骤或动作的顺序不一定限于叙述了所述方法的步骤或动作的顺序。
序列表
<110> 礼进生物医药科技（上海）有限公司
<120> 抗CD137抗体及其用途
<130> L0839.70006WO00
<140> 未指定
<141> 同时
<150> PCT/CN2017/114569
<151> 2017-12-05
<160> 27
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<220>
<223> 合成多肽
<400> 11
Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Asp Ser Asn Pro Ile Asn Tyr Thr Pro Ser Leu
50 55 60
Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Lys Val Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Ser Ser Ser Arg Tyr Phe Asp Val Trp Gly Ala Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 12
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 12
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Val Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Pro
65 70 75 80
Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 13
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 13
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Gly Met Ser Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Met Ala Ile Tyr Phe Cys
85 90 95
Ala Arg Gly Tyr Gly Ser Pro Asp Tyr Trp Gly Gln Gly Thr Thr Leu
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 14
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 14
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Gly Asn Pro Pro Ile
85 90 95
Ser Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 15
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 15
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ala Gly Phe
20 25 30
Glu Met His Trp Ile Lys Gln Thr Pro Val His Gly Leu Gly Trp Ile
35 40 45
Gly Ala Ile Asp Pro Lys Thr Gly Gly Thr Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Leu Leu Thr Ala Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Asp Leu Gly Tyr Phe Asp Val Trp Gly Thr Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 16
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 16
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Arg Ser Asn
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Ser Glu Lys Leu Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg 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> 17
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 17
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ile Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Tyr Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gly Gln Leu Gly Leu Asp Gly Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 18
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 18
Gln Ile Val Leu Thr Gln Ser Pro Thr Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Asn Ile Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 19
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 19
Glu Val Lys Leu Val Glu Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Leu Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Tyr Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gly Gln Leu Gly Leu Asp Gly Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 20
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 20
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Arg Leu Leu Ile Tyr
35 40 45
Asp Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Asn Ile Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 21
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 21
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ala Met His Trp Val Lys Gln Ala Pro Gly Lys Ala Leu Lys Trp Met
35 40 45
Gly Leu Ile Asn Thr Tyr Thr Gly Lys Pro Thr Tyr Val Asp Asp Leu
50 55 60
Lys Gly Arg Phe Val Phe Ser Leu Glu Ala Ser Ala Ser Thr Ala Lys
65 70 75 80
Leu Gln Ile Ser Asn Leu Lys Asn Glu Asp Thr Ala Ile Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr His Asp Gly Thr Tyr Tyr Gly Trp Phe Ala Asn Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
210 215 220
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe 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 Gln Glu Asp
260 265 270
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 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 Gly Leu Pro Ser Ser 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 Gln 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 Arg Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Glu 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 Leu Gly
435 440 445
Lys
<210> 22
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 22
Asp Thr Val Leu Thr Gln Ser Pro Ala Leu Ala Val Ser Pro Gly Glu
1 5 10 15
Arg Val Thr Val Ser Cys Gly Ala Thr Glu Ser Val Ser Thr Ala Leu
20 25 30
Asn Trp Tyr Gln Gln Lys Pro Gly Gln Gln Pro Arg Leu Leu Ile Tyr
35 40 45
Gly Ala Ser Asn Leu Glu Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asp Pro Val Glu Ala Asp
65 70 75 80
Asp Thr Ala Thr Tyr Phe Cys Gln Gln Thr Trp Asn Asp Pro Leu Thr
85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 23
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 23
Glu Val Lys Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Ser Arg Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Asp Ser Asn Pro Ile Asn Tyr Thr Pro Ser Leu
50 55 60
Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Lys Val Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Ser Ser Ser Arg Tyr Phe Asp Val Trp Gly Ala Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 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 Gln 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 Tyr 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 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln 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 Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu 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 Leu Gly Lys
435 440 445
<210> 24
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 24
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Val Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Pro
65 70 75 80
Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu 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> 25
<211> 327
<212> PRT
<213> 智人
<400> 25
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
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<211> 255
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<213> 智人
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Met Gly Asn Ser Cys Tyr Asn Ile Val Ala Thr Leu Leu Leu Val Leu
1 5 10 15
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20 25 30
Ala Gly Thr Phe Cys Asp Asn Asn Arg Asn Gln Ile Cys Ser Pro Cys
35 40 45
Pro Pro Asn Ser Phe Ser Ser Ala Gly Gly Gln Arg Thr Cys Asp Ile
50 55 60
Cys Arg Gln Cys Lys Gly Val Phe Arg Thr Arg Lys Glu Cys Ser Ser
65 70 75 80
Thr Ser Asn Ala Glu Cys Asp Cys Thr Pro Gly Phe His Cys Leu Gly
85 90 95
Ala Gly Cys Ser Met Cys Glu Gln Asp Cys Lys Gln Gly Gln Glu Leu
100 105 110
Thr Lys Lys Gly Cys Lys Asp Cys Cys Phe Gly Thr Phe Asn Asp Gln
115 120 125
Lys Arg Gly Ile Cys Arg Pro Trp Thr Asn Cys Ser Leu Asp Gly Lys
130 135 140
Ser Val Leu Val Asn Gly Thr Lys Glu Arg Asp Val Val Cys Gly Pro
145 150 155 160
Ser Pro Ala Asp Leu Ser Pro Gly Ala Ser Ser Val Thr Pro Pro Ala
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Pro Ala Arg Glu Pro Gly His Ser Pro Gln Ile Ile Ser Phe Phe Leu
180 185 190
Ala Leu Thr Ser Thr Ala Leu Leu Phe Leu Leu Phe Phe Leu Thr Leu
195 200 205
Arg Phe Ser Val Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
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Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
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Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
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<211> 254
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Met Gly Asn Ser Cys Tyr Asn Ile Val Ala Thr Leu Leu Leu Val Leu
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Asn Phe Glu Arg Thr Arg Ser Leu Gln Asp Leu Cys Ser Asn Cys Pro
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Ala Gly Thr Phe Cys Asp Asn Asn Arg Ser Gln Ile Cys Ser Pro Cys
35 40 45
Pro Pro Asn Ser Phe Ser Ser Ala Gly Gly Gln Arg Thr Cys Asp Ile
50 55 60
Cys Arg Gln Cys Lys Gly Val Phe Lys Thr Arg Lys Glu Cys Ser Ser
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Thr Ser Asn Ala Glu Cys Asp Cys Ile Ser Gly Tyr His Cys Leu Gly
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Ala Glu Cys Ser Met Cys Glu Gln Asp Cys Lys Gln Gly Gln Glu Leu
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Thr Lys Lys Gly Cys Lys Asp Cys Cys Phe Gly Thr Phe Asn Asp Gln
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Ser Pro Ala Asp Leu Ser Pro Gly Ala Ser Ser Ala Thr Pro Pro Ala
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180 185 190
Leu Thr Ser Thr Val Val Leu Phe Leu Leu Phe Phe Leu Val Leu Arg
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Phe Ser Val Val Lys Arg Ser Arg Lys Lys Leu Leu Tyr Ile Phe Lys
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Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys
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Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
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Claims (23)
1.一种分离的和非天然存在的抗CD137抗体，其与参考抗体结合相同的CD137表位，所述参考抗体选自20A12D11、30C11B4、11E10D12、23D2D6、22F2C2和26B3D7。
2.根据权利要求1所述的分离的和非天然存在的抗体，其中所述抗CD137抗体结合人CD137。
3.根据权利要求1所述的分离的和非天然存在的抗体，其中所述抗CD137抗体结合人CD137和非人CD137两者。
4.根据权利要求3所述的分离的和非天然存在的抗体，其中所述非人CD137是食蟹猴CD137。
5.根据权利要求1所述的分离的和非天然存在的抗体，其中所述抗体与所述参考抗体包含相同的重链互补决定区(CDR)和相同的轻链CDR。
6.根据权利要求5所述的分离的和非天然存在的抗体，其中所述抗体与所述参考抗体包含相同的重链可变区(VH)和相同的轻链可变区(VL)。
7.根据权利要求1-6中任一项所述的分离的和非天然存在的抗体，其中所述抗体是全长抗体或其抗原结合片段。
8.根据权利要求7所述的分离的和非天然存在的抗体，其中所述抗体是全长抗体，其是IgG分子。
9.根据权利要求7所述的分离的和非天然存在的抗体，其中所述抗体是Fab或单链抗体。
10.根据权利要求1-9中任一项所述的抗体，其中所述抗体是人抗体、人源化抗体或嵌合抗体。
11.根据权利要求1-9中任一项所述的抗体，其中所述抗体是双特异性抗体，其结合CD137和FcγRIIB两者。
12.根据权利要求11所述的抗体，其中所述嵌合抗体包含人重链恒定区或其片段、人轻链恒定区或其片段、或两者。
13.一种分离的核酸或核酸组，其共同编码权利要求1-12中任一项所述的抗CD137抗体。
14.根据权利要求13所述的分离的核酸或核酸组，其中所述核酸或核酸组位于一个载体或两个载体上。
15.根据权利要求14所述的分离的核酸或核酸组，其中所述一个或两个载体是一个或两个表达载体。
16.一种宿主细胞，其包含权利要求14或权利要求15所述的分离的核酸或核酸组。
17.一种药物组合物，其包含权利要求1-12中任一项所述的抗CD137抗体或权利要求13所述的核酸/核酸组，以及药学上可接受的载体。
18.一种调节受试者中的免疫应答的方法，所述方法包括向有需要的受试者施用有效量的根据权利要求17所述的药物组合物。
19.根据权利要求18所述的方法，其中所述有需要的受试者是患有、疑似患有、或处于癌症或免疫病症的风险中的人患者。
20.根据权利要求19所述的方法，其中所述癌症选自前列腺癌、结肠癌和黑素瘤。
21.根据权利要求29所述的方法，其中所述有需要的受试者是患有、疑似患有、或处于自身免疫性疾病的风险中的人患者，所述自身免疫性疾病选自类风湿性关节炎(RA)、系统性红斑狼疮(SLE)、I型糖尿病、多发性硬化症、乳糜泻和移植物抗宿主(GVH)病。
22.根据权利要求18-21中任一项所述的方法，其中所述受试者已经经历或者正在经历用于所述癌症或所述免疫病症的治疗。
23.一种制备抗CD137抗体的方法，包括：
(i)在允许表达所述抗CD137抗体的条件下培养权利要求16所述的宿主细胞；和
(ii)收获由此从细胞培养物中产生的所述抗CD137抗体。
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|---|---|---|---|
| CNPCT/CN2017/114569 | 2017-12-05 | ||
| PCT/CN2017/114569 WO2019109238A1 (en) | 2017-12-05 | 2017-12-05 | Anti-cd137 antibodies and uses thereof |
| PCT/US2018/063809 WO2019113039A1 (en) | 2017-12-05 | 2018-12-04 | Anti-cd137 antibodies and uses thereof |
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| EP (1) | EP3720491A4 (zh) |
| JP (1) | JP2021505206A (zh) |
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| CN (1) | CN111542342B (zh) |
| AU (1) | AU2018381290A1 (zh) |
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| WO2019109238A1 (en) | 2017-12-05 | 2019-06-13 | Lyvgen Biopharma Co., Ltd. | Anti-cd137 antibodies and uses thereof |
| AU2020276500A1 (en) | 2019-05-10 | 2021-12-16 | Lyvgen Biopharma Holdings Limited | Humanized anti-CD137 antibodies and uses thereof |
| TW202144395A (zh) * | 2020-02-12 | 2021-12-01 | 日商中外製藥股份有限公司 | 用於癌症之治療的抗cd137抗原結合分子 |
| WO2021167908A1 (en) | 2020-02-17 | 2021-08-26 | Board Of Regents, The University Of Texas System | Methods for expansion of tumor infiltrating lymphocytes and use thereof |
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| AU2018381290A1 (en) | 2020-08-06 |
| EP3720491A4 (en) | 2022-01-12 |
| WO2019113039A1 (en) | 2019-06-13 |
| US20200385479A1 (en) | 2020-12-10 |
| CA3101590A1 (en) | 2019-06-13 |
| KR20200092976A (ko) | 2020-08-04 |
| CN111542342B (zh) | 2024-01-02 |
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| US11505615B2 (en) | 2022-11-22 |
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