CN113748130A - Tsg-6抗体和其用途 - Google Patents
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- CN113748130A CN113748130A CN202080028139.0A CN202080028139A CN113748130A CN 113748130 A CN113748130 A CN 113748130A CN 202080028139 A CN202080028139 A CN 202080028139A CN 113748130 A CN113748130 A CN 113748130A
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Abstract
本发明提供了新型抗TSG‑6抗体、包括此类抗体的药物组合物以及使用此类抗体和药物组合物治疗如癌症或自身免疫性疾病等疾病的治疗方法。
Description
相关申请的交叉引用
本申请要求于2019年3月12日提交的美国临时申请第62/817,152号的优先权权益，所述美国临时申请的内容出于所有目的整体清楚地并入本文。
序列表
本申请包含序列表，所述序列表已经以电子方式和ASCII格式提交，并且通过引用整体特此并入。创建于2020年3月6日的所述ASCII副本命名为011506-5023_ST25.txt，并且大小为71千字节。
技术领域
本公开涉及与TSG-6特异性结合的分子，例如，人TSG-6(hTSG-6)，以及包括此类其TSG-6结合抗体的药物组合物。本发明还涵盖了在治疗各种疾病，包含自身免疫性疾病、炎性疾病、纤维化疾病和癌症的过程中使用本发明的抗体来检测人TSG-6或调节人TSG-6活性的方法。
背景技术
由肿瘤坏死因子α诱导的蛋白6(TNFAIP6)基因在人体内编码的肿瘤坏死因子诱导基因6蛋白(TSG-6)是一种细胞外(分泌)蛋白，其属于一类被称为透明质酸黏附素的透明质酸结合蛋白。TSG-6包含结合透明质酸的N端链结构域和C端CUB结构域，后者是一种存在于许多参与蛋白质-蛋白质相互作用的蛋白质中的多功能结构域。TSG-6在调节免疫应答中发挥作用。通常，蛋白质被认为是一种抗炎介质，但是其作用可能因环境而异；对TSG-6进行编码的基因被破坏的小鼠在关节炎模型中显示出更快的进展和更糟糕的严重程度，但在过敏性哮喘模型中显示出减弱的炎症和减少的气道嗜酸性粒细胞增多症。TSG-6明显的主要功能是结合并共价修饰透明质酸，因此影响细胞外基质结构和功能；TSG-6还可以与各种趋化因子以及如硫酸软骨素、聚集蛋白聚糖(aggrecan)、多能蛋白聚糖(versican)、纤连蛋白和正五聚蛋白-3等其它细胞外基质相关分子结合并调节其活性。
透明质酸(玻尿酸或HA)是一种由重复的葡萄糖醛酸和N-乙酰氨基葡萄糖亚基构成的细胞外基质糖胺聚糖分子。透明质酸被认为在邻近组织层之间提供润滑和辅助运动，并且其还是高度水合的，因此有助于增加细胞外基质中的静水压力并提供抗压性。HA还是一种通过结合其细胞表面受体而影响细胞进程的信号传导分子，包含CD44、透明质酸相关运动受体(RHAMM，也被称为HMMR或CD168)和淋巴管内皮透明质酸受体1(LYVE1)。HA在提供了有利于肿瘤生长、血管生成和转移的微环境的许多肿瘤包含胰腺癌、一些乳腺癌和其它癌症的基质中以高丰度存在，并参与增加基质硬度和静水压力，从而形成免疫细胞和治疗药物进入的物理屏障。HA还大量存在于许多纤维化疾病中，在所述纤维化疾病中其发挥类似作用。
TSG-6主要由可能在炎症部位处外渗的具有强效的免疫抑制性性质的成纤维细胞、平滑肌细胞和间充质干细胞(MSC)、骨髓源性成纤维细胞样细胞分泌。TSG-6在酯交换反应中催化HC蛋白(也被称为血清透明质酸相关蛋白或SHAP)从IαI转移到HA。所得HC-HA复合物形成线缆状结构，而不是更分散的网络。这些线缆具有改变的性质，包含通过HA受体CD44粘附白细胞以及改变巨噬细胞对交替激活的“M2”表型的极化。HC-HA线缆被认为在癌症中起致病作用；在患有通常由潜在的肺纤维化引起的特发性肺动脉高压的患者的切除肺组织中也检测到了HC-HA。在不存在HC修饰的情况下，TSG-6还与HA结合并非共价交联；这种HA交联结合白细胞并使其保持在未激活的状态。
总的来说，这些发现表明，开发可用于抑制TSG-6的HC-HA转移活性的药物对于涉及较高的成纤维细胞活性和细胞外基质含量的疾病，包含慢性炎性疾病、纤维化疾病和癌症有很大的益处。
发明内容
一方面，本发明涉及新型抗TSG-6抗体。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:1的氨基酸序列的重链可变区和包括SEQ ID NO:2的氨基酸序列的轻链可变区。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:3的氨基酸序列的重链可变区和包括SEQ ID NO:4的氨基酸序列的轻链可变区。在一些实施例中，抗TSG-6抗体包含包括SEQ IDNO:5的氨基酸序列的重链可变区和包括SEQ ID NO:6的氨基酸序列的轻链可变区。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:7的氨基酸序列的重链可变区和包括SEQ IDNO:8的氨基酸序列的轻链可变区。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:9的氨基酸序列的重链可变区和包括SEQ ID NO:10的氨基酸序列的轻链可变区。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:11的氨基酸序列的重链可变区和包括SEQ ID NO:12的氨基酸序列的轻链可变区。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:13的氨基酸序列的重链可变区和包括SEQ ID NO:14的氨基酸序列的轻链可变区。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:15的氨基酸序列的重链可变区和包括SEQ ID NO:16的氨基酸序列的轻链可变区。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:17的氨基酸序列的重链可变区和包括SEQ ID NO:18的氨基酸序列的轻链可变区。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:19的氨基酸序列的重链可变区和包括SEQ ID NO:20的氨基酸序列的轻链可变区。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:21的氨基酸序列的重链可变区和包括SEQ ID NO:22的氨基酸序列的轻链可变区。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:23的氨基酸序列的重链可变区和包括SEQ ID NO:24的氨基酸序列的轻链可变区。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:25的氨基酸序列的重链可变区和包括SEQ ID NO:26的氨基酸序列的轻链可变区。
在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:27的vhCDR1、包括SEQ ID NO:28的vhCDR2、包括SEQ ID NO:29的vhCDR3、包括SEQ ID NO:30的vlCDR1、包括SEQ ID NO:31的vlCDR2和包括SEQ ID NO:32的vlCDR3。在一些实施例中，抗TSG-6抗体包含包括SEQ IDNO:33的vhCDR1、包括SEQ ID NO:34的vhCDR2、包括SEQ ID NO:35的vhCDR3、包括SEQ IDNO:36的vlCDR1、包括SEQ ID NO:37的vlCDR2和包括SEQ ID NO:38的vlCDR3。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:39的vhCDR1、包括SEQ ID NO:40的vhCDR2、包括SEQID NO:41的vhCDR3、包括SEQ ID NO:42的vlCDR1、包括SEQ ID NO:43的vlCDR2和包括SEQID NO:44的vlCDR3。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:45的vhCDR1、包括SEQ ID NO:46的vhCDR2、包括SEQ ID NO:47的vhCDR3、包括SEQ ID NO:48的vlCDR1、包括SEQ ID NO:49的vlCDR2和包括SEQ ID NO:50的vlCDR3。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:51的vhCDR1、包括SEQ ID NO:52的vhCDR2、包括SEQ ID NO:53的vhCDR3、包括SEQ ID NO:54的vlCDR1、包括SEQ ID NO:55的vlCDR2和包括SEQ ID NO:56的vlCDR3。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:57的vhCDR1、包括SEQ ID NO:58的vhCDR2、包括SEQ ID NO:59的vhCDR3、包括SEQ ID NO:60的vlCDR1、包括SEQ ID NO:61的vlCDR2和包括SEQ ID NO:62的vlCDR3。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:63的vhCDR1、包括SEQ ID NO:64的vhCDR2、包括SEQ ID NO:65的vhCDR3、包括SEQ ID NO:66的vlCDR1、包括SEQ ID NO:67的vlCDR2和包括SEQ ID NO:68的vlCDR3。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:69的vhCDR1、包括SEQ ID NO:70的vhCDR2、包括SEQ ID NO:71的vhCDR3、包括SEQ ID NO:72的vlCDR1、包括SEQ ID NO:73的vlCDR2和包括SEQ ID NO:74的vlCDR3。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:75的vhCDR1、包括SEQ IDNO:76的vhCDR2、包括SEQ ID NO:77的vhCDR3、包括SEQ ID NO:78的vlCDR1、包括SEQ IDNO:79的vlCDR2和包括SEQ ID NO:80的vlCDR3。在一些实施例中，抗TSG-6抗体包含包括SEQID NO:81的vhCDR1、包括SEQ ID NO:82的vhCDR2、包括SEQ ID NO:83的vhCDR3、包括SEQ IDNO:84的vlCDR1、包括SEQ ID NO:85的vlCDR2和包括SEQ ID NO:86的vlCDR3。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:87的vhCDR1、包括SEQ ID NO:88的vhCDR2、包括SEQID NO:89的vhCDR3、包括SEQ ID NO:90的vlCDR1、包括SEQ ID NO:91的vlCDR2和包括SEQID NO:92的vlCDR3。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:93的vhCDR1、包括SEQ ID NO:94的vhCDR2、包括SEQ ID NO:95的vhCDR3、包括SEQ ID NO:96的vlCDR1、包括SEQ ID NO:97的vlCDR2和包括SEQ ID NO:98的vlCDR3。在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:99的vhCDR1、包括SEQ ID NO:100的vhCDR2、包括SEQ ID NO:101的vhCDR3、包括SEQ ID NO:102的vlCDR1、包括SEQ ID NO:103的vlCDR2和包括SEQ ID NO:104的vlCDR3。
在一些实施例中，本文所述的抗TSG-6抗体结合人和/或小鼠TSG-6。
在一些实施例中，本文所述的抗TSG-6抗体包含具有与人IgG至少90％相同的氨基酸序列的恒定区。在一些实施例中，IgG选自IgG1、IgG2、IgG3或IgG4。在一些实施例中，IgG是IgG1。在一些实施例中，IgG是IgG2b。
另一方面，本发明涉及对本文所述的抗TSG-6抗体中的任一种进行编码的核酸组合物。在一些实施例中，核酸组合物包含包括重链的第一核酸和包括轻链的第二核酸。
本发明的另一方面涉及一种表达载体组合物，其包括对本文所述的抗TSG-6抗体中的任一种进行编码的核酸组合物中的任一种。在一些实施例中，第一核酸包含在第一表达载体中并且第二核酸包含在第二表达载体中。在一些其他实施例中，第一核酸和第二核酸包含在单个的表达载体中。
本发明的另一方面涉及一种宿主细胞，其包括本文所述的任何一种表达载体。还呈现了制备抗TSG-6抗体的方法，并且所述方法包含在抗体表达的条件下培养宿主细胞以及回收抗体。
另一方面，本发明涉及一种组合物，其包含本文所述的抗TSG-6抗体中的任一种以及药学上可接受的载体或稀释剂。
还描述了调节受试者的免疫应答的方法，并且所述方法包含向受试者施用有效量的本文所述的抗TSG-6抗体中的任一种或本文所述的组合物中的任一种。在一些实施例中，所述方法刺激受试者的免疫应答，并且所述方法包含向受试者施用有效量的充当TSG-6拮抗剂的抗TSG-6抗体或其组合物。在一些实施例中，所述方法抑制受试者的免疫应答，并且所述方法包含向受试者施用有效量的充当TSG-6激动剂的抗TSG-6抗体或其组合物。
在另外的实施例中并且根据上述中的任一项，本公开描述了治疗受试者的癌症的方法，所述方法包括向受试者施用有效量的抗体，其中所述抗体用作TSG-6拮抗剂。在一些实施例中，所治疗的癌症的TSG-6和/或HC-HA表达高。在另外的实施例中，待治疗受试者的TSG-6和/或HC-HA表达高。在一些实施例中，癌症是实体瘤。在另外的实施例中，癌症是黑色素瘤。在一些实施例中，抗体与一种或多种另外的治疗剂组合以治疗癌症。在另外的实施例中，另外的治疗剂是其它免疫检查点抑制剂。在一些实施例中，免疫检查点抑制剂选自由以下组成的组：PD-1抑制剂、PD-L1抑制剂、CTLA-4抑制剂、TIM-3抑制剂和LAG-3抑制剂。
另一方面，本发明涉及治疗受试者的纤维化的方法，所述方法包括向受试者施用有效量的抗体，其中所述抗体用作TSG-6拮抗剂。在一些实施例中，纤维化组织的TSG-6和/或HC-HA表达高。在一些实施例中，待治疗受试者的TSG-6和/或HC-HA表达高。在一些实施例中，抗体与一种或多种另外的治疗剂组合以治疗纤维化。
另一方面，本发明涉及治疗受试者的自身免疫性或炎性病症的方法，所述方法包括向受试者施用有效量的抗体，其中所述抗体用作TSG-6拮抗剂。在一些实施例中，自身免疫性或炎性病症是特发性肺动脉高压。在一些实施例中，受试者的TSG-6和/或HC-HA表达高。在一些实施例中，受试者还患有肺纤维化。在一些实施例中，抗体与一种或多种另外的治疗剂组合以治疗肺动脉高压和/或肺纤维化。在一些实施例中，自身免疫性或炎性病症是哮喘。在一些实施例中，待治疗受试者的TSG-6和/或HC-HA表达高。在一些实施例中，待治疗受试者的肺的TSG-6和/或HC-HA表达高。在一些实施例中，待治疗受试者患有增加的气道嗜酸性粒细胞增多症。
另一方面，本发明涉及治疗受试者的自身免疫性或炎性病症的方法，所述方法包括向受试者施用有效量的抗体，其中所述抗体用作TSG-6激动剂。在一些实施例中，自身免疫性或炎性病症是类风湿性关节炎。在一些实施例中，待治疗受试者的TSG-6和/或HC-HA表达低。在一些实施例中，抗体与一种或多种另外的治疗剂组合以治疗自身免疫性或炎性病症。
本发明涉及一种抗TSG-6抗体，其包括：包括SEQ ID NO:17的氨基酸序列的重链可变区和包括SEQ ID NO:18的氨基酸序列的轻链可变区。
在一些实施例中，抗TSG-6抗体包括：包括SEQ ID NO:75的vhCDR1、包括SEQ IDNO:76的vhCDR2、包括SEQ ID NO:77的vhCDR3、包括SEQ ID NO:78的vlCDR1、包括SEQ IDNO:79的vlCDR2和包括SEQ ID NO:80的vlCDR3。
在一些实施例中，抗体与人和/或小鼠TSG-6结合。
在一些实施例中，抗TSG-6抗体包括具有与人IgG至少90％相同的氨基酸序列的恒定区。在一些实施例中，人IgG选自由以下组成的组：IgG1、IgG2、IgG3和IgG4。在一些实施例中，IgG是IgG1。
另一方面，本发明涉及一种核酸组合物，其对本文所述的抗TSG-6抗体进行编码。
另一方面，本发明涉及一种核酸组合物，其对本文所述的抗TSG-6抗体进行编码。在一些实施例中，核酸组合物包含包括重链的第一核酸和包括轻链的第二核酸。
本发明的另一方面涉及一种表达载体组合物，其包含对本文所述的抗TSG-6抗体进行编码的核酸组合物中的任一种。在一些实施例中，第一核酸包含在第一表达载体中并且第二核酸包含在第二表达载体中。在一些其他实施例中，第一核酸和第二核酸包含在单个的表达载体中。
本发明的另一方面涉及一种宿主细胞，其包括本文所述的任何一种表达载体。还呈现了制备抗TSG-6抗体的方法，并且所述方法包含在抗体表达的条件下培养宿主细胞以及回收抗体。
另一方面，本发明涉及一种组合物，其包含本文所述的抗TSG-6抗体以及药学上可接受的载体或稀释剂。
另一方面，本发明涉及调节受试者的免疫应答的方法，并且所述方法包含向受试者施用有效量的本文所述的抗TSG-6抗体或本文所述的组合物中的任一种。在一些实施例中，所述方法刺激受试者的免疫应答，并且所述方法包含向受试者施用有效量的充当TSG-6拮抗剂的抗TSG-6抗体或其组合物。
另一方面，本发明涉及治疗受试者的癌症的方法，所述方法包括向受试者施用有效量的抗TSG-6抗体，其中所述抗体用作TSG-6拮抗剂。在一些实施例中，癌症的TSG-6和/或HC-HA表达高。在一些实施例中，待治疗受试者的TSG-6和/或HC-HA表达高。在一些实施例中，癌症是实体瘤。在一些实施例中，癌症是黑色素瘤。在一些实施例中，抗体与一种或多种另外的治疗剂组合以治疗癌症。在一些实施例中，另外的治疗剂是其它免疫检查点抑制剂。在一些实施例中，其它免疫检查点抑制剂选自由以下组成的组：PD-1抑制剂、PD-L1抑制剂、CTLA-4抑制剂、TIM-3抑制剂和LAG-3抑制剂。
另一方面，本发明涉及治疗受试者的纤维化的方法，所述方法包括向受试者施用有效量的抗TSG-6抗体，其中所述抗体用作TSG-6拮抗剂。在一些实施例中，纤维化组织的TSG-6和/或HC-HA表达高。在一些实施例中，待治疗受试者的TSG-6和/或HC-HA表达高。在一些实施例中，抗体与一种或多种另外的治疗剂组合以治疗纤维化。
另一方面，本发明涉及治疗受试者的自身免疫性或炎性病症的方法，所述方法包括向受试者施用有效量的抗体，其中所述抗体用作TSG-6拮抗剂。在一些实施例中，自身免疫性或炎性病症是特发性肺动脉高压。在一些实施例中，待治疗受试者的TSG-6和/或HC-HA表达高。在一些实施例中，待治疗受试者还患有肺纤维化。在一些实施例中，抗体与一种或多种另外的治疗剂组合以治疗肺动脉高压和/或肺纤维化。在一些实施例中，自身免疫性或炎性病症是哮喘。在一些实施例中，待治疗受试者的TSG-6和/或HC-HA表达高。在一些实施例中，待治疗受试者的肺的TSG-6和/或HC-HA表达高。在一些实施例中，待治疗受试者患有增加的气道嗜酸性粒细胞增多症。在一些实施例中，抗体与一种或多种另外的治疗剂组合以治疗自身免疫性或炎性病症。
附图说明
当与附图一起阅读时，可以从以下详细描述中最好地理解本发明。附图中包含以下图：
图1示出了抗TSG-6抗体对与TSG-6结合的HA的抑制。
图2示出了抗TSG-6抗体对TSG-6HC-HA转酯酶活性的抑制。
图3示出了抗TSG-6抗体的药效动力学。
图4A到4C示出了抗TSG-6抗体在由与CAF共注射的B16F0黑色素瘤细胞产生的肿瘤中的抗肿瘤活性。
图5A到5E示出了抗TSG-6抗体的抗肿瘤活性和其与抗PD-1的组合活性。
具体实施方式
本公开提供了新型抗TSG-6抗体。本文所述的抗TSG-6抗体结合人和/或小鼠TSG-6。在一些实施例中，抗TSG-6抗体以高亲和力结合人和/或小鼠TSG-6。在一些实施例中，抗TSG-6抗体充当功能性TSG-6拮抗剂，并且在与TSG-6结合后阻断TSG-6与HA的相互作用，并阻断HC-HA转酯酶活性。在一些实施例中，抗TSG-6抗体充当功能性TSG-6激动剂，并且在与TSG-6结合后增加TSG-6与HA的相互作用，并促进HC-HA转酯酶活性。本公开还提供了使用此类抗体来调节受试者的免疫应答并且例如治疗癌症、纤维化或包含但不限于哮喘的自身免疫性或炎性病症的方法。
为了便于理解本发明，下面定义了许多术语和短语。
如本文所使用的，以下每个术语在本节中具有与其相关的含义。
冠词“一”和“一个”在本文中用于指代冠词的语法对象中的一个或多个(即，至少一个)。举例来说，“一个元件”是指一个元件或一个以上元件。
如本文所使用的，当提及诸如量、持续时间等可测量值时，“大约”意在涵盖指定值的±20％或±10％、更优选±5％、甚至更优选±1％，并且更优选地是±0.1％的变化，因为这样的变化适合于执行所公开的方法。
本文中通过“消融”意指活性的降低或消除。因此，例如，“消融FcγR结合”意指Fc区氨基酸变体与不含有特异性变体的Fc区相比具有少于50％的起始结合，优选少于70％-80％-90％-95％-98％的活性损失，并且通常所述活性低于Biacore测定中可检测结合的水平。
如本文所使用的，“ADCC”或“抗体依赖性细胞介导的细胞毒性”意指其中表达FcγR的非特异性细胞毒性细胞识别靶细胞上的结合抗体并且随后引起靶细胞溶解的细胞介导反应。ADCC与结合FcγRIIIa相关；与FcγRIIIa结合增加引起ADCC活性增加。如本文所讨论的，本发明的许多实施方式完全消融ADCC活性。
通过如本文所使用的“ADCP”或抗体依赖性细胞介导的吞噬作用意指细胞介导的反应，其中表达FcγR的非特异性细胞毒性细胞识别靶细胞上的结合抗体，并且随后引起靶细胞的吞噬作用。
本文中的“抗原结合结构域”或“ABD”意指一组六个互补决定区(CDR)在作为多肽序列的一部分存在时与如本文所讨论的靶抗原特异性地结合。因此，“抗原结合结构域”结合本文概述的靶抗原。如本领域中已知，这些CDR通常作为可变重CDR(vhCDR或VHCDR或CDR-HC)的第一组和可变轻CDR(vlCDR或VLCDR或CDR-LC)的第二组存在，其各自包括三个CDR：重链的vhCDR1、vhCDR2、vhCDR3和轻链的vlCDR1、vlCDR2和vlCDR3。CDR分别存在于可变重链结构域和可变轻链结构域中，并且一起形成Fv区。因此，在一些情况下，抗原结合结构域的六个CDR由可变重链和可变轻链提供。在“Fab”形式下，6个CDR的组由两条不同的多肽序列提供，可变重链结构域(vh或VH；包含vhCDR1、vhCDR2和vhCDR3)和可变轻链结构域(vl或VL；包含vlCDR1、vlCDR2和vlCDR3)，其中vh结构域的C-末端连接到重链CH1结构域的N-末端，vl结构域的C-末端连接到轻链恒定结构域的N-末端(且因此形成轻链)。在scFv形式中，VH和VL结构域通常通过使用如本文所述的接头共价连接成单个多肽序列，其可以是(从N-末端开始)vh-接头-vl或vl-接头-vh，前者通常是优选的(包括每侧的可选结构域接头，这取决于使用的形式)。如本领域所理解的，CDR在每个可变重结构域和可变轻结构域中被框架区隔开：对于轻可变区，这些是FR1-vlCDR1-FR2-vlCDR2-FR3-vlCDR3-FR4，对于重可变区，这些是FR1-vhCDR1-FR2-vhCDR2-FR3-vhCDR3-FR4，框架区显示出与人类种系序列的高度同一性。本发明的抗原结合结构域包括Fab、Fv和scFv。
本文中的“接头”意指在scFv和/或其它抗体结构中使用的接头。通常，有许多可以使用的合适的scFv接头，包含通过重组技术产生的传统肽键。连接子肽可以主要包括以下氨基酸残基：Gly、Ser、Ala或Thr。连接子肽应当具有足够以确保相对于彼此的正确构象以使得其保留所需活性的方式连接两个分子的长度。在一个实施方式中，接头具有约1-50个氨基酸的长度，优选约1-30个氨基酸的长度。在一个实施例中，可以使用长度为1个到20个氨基酸的连接子，在一些实施例中使用约5个到约10个氨基酸。有用的连接子包括甘氨酸-丝氨酸聚合物(包括例如(GS)n、(GSGGS)n、(GGGGS)n和(GGGS)n，其中n是至少为1(并且通常为3到4)的整数)、甘氨酸-丙氨酸聚合物、丙氨酸-丝氨酸聚合物和其它柔性连接子。可替代地，各种非蛋白质聚合物，包含但不限于聚乙二醇(PEG)、聚丙二醇、聚氧化烯或聚乙二醇和聚丙二醇的共聚物可以用作接头，即可以用作接头。其它连接子序列可以包括CL/CH1结构域的任何长度的任何序列，但不包括CL/CH1结构域的所有残基；例如CL/CH1结构域的前5-12个氨基酸残基。接头可以衍生自免疫球蛋白轻链，例如Cκ或Cλ。接头可以衍生自任何同种型的免疫球蛋白重链，包含例如Cγ1、Cγ2、Cγ3、Cγ4、Cα1、Cα2、Cδ、Cε和Cμ。接头序列还可以衍生自其它蛋白质，如Ig样蛋白(例如，TCR、FcR、KIR)、铰链区衍生序列以及来自其它蛋白质的其它天然序列。在一些实施方式中，接头是“结构域接头”，其用于将如本文所概述的任何两个结构域连接在一起。虽然可以使用任何适合的连接子，但是许多实施例利用甘氨酸-丝氨酸聚合物以及允许以足够允许每个结构域保持其生物学功能的长度和柔性来重组连接这两个结构域的任何肽序列，所述甘氨酸-丝氨酸聚合物包含例如(GS)n、(GSGGS)n、(GGGGS)n和(GGGS)n，其中n是至少为1(并且通常为3到4到5)的整数。
术语“抗体”以最广泛的含义使用，包括例如完整的免疫球蛋白或抗原结合部分。抗原结合部分可以通过重组DNA技术或通过完整抗体的酶促或化学切割产生。因此，术语抗体包括两条重链和两条轻链的传统四聚抗体，以及抗原结合片段，例如Fv、Fab和scFv。在一些情况下，本发明提供包含至少一个本文概述的抗原结合结构域的双特异性抗体。
本文中的“修饰”意指多肽序列中的氨基酸取代、插入和/或缺失或对与蛋白质化学连接的部分的更改。例如，修饰可以是附接于蛋白质的改变的碳水化合物或PEG结构。本文中通过“氨基酸修饰”意指多肽序列中的氨基酸取代、插入和/或缺失。为清楚起见，除非另外说明，否则氨基酸修饰总是针对由DNA编码的氨基酸，例如具有DNA和RNA中的密码子的20种氨基酸。
本文中通过“氨基酸取代”或“取代”意指用不同的氨基酸替换亲本多肽序列中特定位置的氨基酸。特别地，在一些实施例中，取代是针对并非天然存在于特定位置、并非天然存在于生物体内或任何生物体中的氨基酸。例如，取代M252Y是指变体多肽，在这一情况下是指Fc变体，其中位置252处的蛋氨酸用酪氨酸代替。为清楚起见，已经被工程改造以改变核酸编码序列但不改变起始氨基酸(例如，将CGG(编码精氨酸)换成CGA(仍然编码精氨酸)以增加宿主生物体表达水平)的蛋白质不是“氨基酸取代”；也就是说，尽管产生对相同蛋白质进行编码的新基因，但是如果蛋白质在其开始的特定位置处具有相同氨基酸，则所述蛋白质不是氨基酸取代。
如本文所使用的，“变体蛋白质”或“蛋白质变体”或“变体”意指凭借至少一个氨基酸修饰而不同于亲本蛋白质的蛋白质。蛋白质变体可以指蛋白质本身、包括蛋白质的组合物或编码其的氨基酸序列。优选地，蛋白变体与亲本蛋白相比具有至少一个氨基酸修饰，例如与亲本相比，具有约一个至约七十个氨基酸修饰，优选约一个至约五个氨基酸修饰。如下文所描述的，在一些实施例中，亲本多肽，例如，Fc亲本多肽，是人类野生型序列，如来自人IgG1、IgG2、IgG3或IgG4的Fc区。本文的蛋白变体序列将优选与亲本蛋白序列具有至少约80％的同一性，并且最优选至少约90％的同一性，更优选至少约95％-98％-99％的同一性。变体蛋白质可以指变体蛋白质本身、包括蛋白质变体的组合物或编码其的DNA序列。
因此，如本文所使用的“抗体变体”或“变体抗体”意指通过至少一个氨基酸修饰与亲本抗体不同的抗体，如本文所使用的“IgG变体”或“变体IgG”意指通过至少一个氨基酸修饰与亲本IgG(同样，在许多情况下，来自人类IgG序列)不同的抗体，并且如本文所使用的“免疫球蛋白变体”或“变体免疫球蛋白”意指通过至少一个氨基酸修饰与亲本免疫球蛋白序列不同的免疫球蛋白序列。如本文所使用的，“Fc变体”或“变体Fc”意指包括Fc结构域中的氨基酸修饰的蛋白质。本发明的Fc变体根据构成它们的氨基酸修饰来定义。因此，例如，M252Y或252Y是相对于亲本Fc多肽，在位置252处具有取代丝氨酸的Fc变体，其中编号是根据EU索引。同样，M252Y/S254T/T256E定义了相对于亲本Fc多肽，具有取代M252Y、S254T和T256E的Fc变体。野生型氨基酸的实体可以是非特异性的，在此情况下前述变体被称为252Y/254T/256E。应注意，提供取代的顺序是任意的，也就是说，例如，252Y/254T/256E是与254T/252Y/256E相同的Fc变体，诸如此类。关于本发明中所讨论的与抗体有关的所有位置，除非另外指出，否则氨基酸位置编号根据可变区编号的Kabat，以及包括Fc区在内的恒定区的EU索引。EU索引或如Kabat或EU编号方案中的EU索引是指EU抗体的编号(Edelman等人,1969,《美国国家科学院院刊(Proc Natl Acad Sci USA)》63:78-85，在此通过引用整体并入本文中)。修饰可以是添加、缺失或取代。取代可以包含天然存在的氨基酸，以及在一些情况下合成氨基酸。
如本文所使用的，本文的“蛋白”意指至少两个共价附接的氨基酸，包含蛋白、多肽、寡肽和肽。肽基可以包括天然存在的氨基酸和肽键。
如本文所使用的，“Fab”或“Fab区”意指包括VH、CH1、VL和CL免疫球蛋白结构域的多肽。Fab可以单独指代该区域，或者在全长抗体、抗体片段或Fab融合蛋白的背景下指代该区域。
本文所用的“Fv”或“Fv片段”或“Fv区”意指包括单一抗原结合域(ABD)的VL和VH结构域的多肽。如本领域技术人员所理解的，这些通常由两条链组成，或者可以组合(通常与本文所述的接头)以形成scFv。
如本文所使用的，“氨基酸”和“氨基酸实体”意指由DNA和RNA编码的20种天然存在的氨基酸之一。
如本文所使用的，“效应子功能”意指由抗体Fc区与Fc受体或配体相互作用产生的生物化学事件。效应子功能包括但不限于ADCC、ADCP和CDC。
如本文所使用的，“亲本多肽”意指随后经过修饰以产生变体的起始多肽。亲本多肽可以是天然存在的多肽或者天然存在的多肽的变体或改造形式。亲本多肽可以指多肽本身、包括亲本多肽的组合物或编码它的氨基酸序列。因此，如本文所使用的“亲本免疫球蛋白”意指未修饰的免疫球蛋白多肽，其被修饰以产生变体，并且如本文所使用的“亲本抗体”意指未修饰的抗体，其被修饰以产生变体抗体。应注意，“亲本抗体”包含如下文概述的已知的市售、以重组方式产生的抗体。
本文中的“重链恒定区”意指抗体的CH1-铰链-CH2-CH3部分，通常来自人IgG1、IgG2或IgG4。
如本文所使用的，“靶抗原”意指由给定抗体的可变区特异性结合的分子。在本案中，靶抗原是BTLA蛋白。
如本文所使用的，“靶细胞”意指表达靶抗原的细胞。
如本文所使用的，“可变区”意指免疫球蛋白的区域，其包括一个或多个基本上由分别构成κ、λ和重链免疫球蛋白基因座的V.κ、V.λ、和/或VH基因中的任一种编码的Ig结构域。
“野生型或WT”在本文中意指在自然界中发现的氨基酸序列或核苷酸序列，包括等位基因变体。WT蛋白质具有未经有意修饰的氨基酸序列或核苷酸序列。
如本文所使用的，“位置”意指蛋白序列中的位置。位置可以顺序地编号，或根据确定的形式，例如用于抗体编号的EU索引来编号。
如本文所使用的，“残基”意指蛋白质中的位置及其相关的氨基酸实体。例如，天冬酰胺297(也称为Asn297或N297)是人抗体IgG1中位置297处的残基。
本发明的抗体通常是重组的。“重组”意指使用重组核酸技术在外源宿主细胞中产生抗体。
相对于蛋白序列的“百分比(％)氨基酸序列同一性”定义为在对齐序列和在需要时引入缺口以实现最大序列同一性百分比之后，并且不考虑任何保守取代作为序列同一性的一部分，候选序列中与特定(亲本)序列中的氨基酸残基相同的氨基酸残基的百分比。出于确定氨基酸序列同一性百分比的目的的比对可以以本领域的能力范围内的各种方式实现，例如使用可共开获得的计算机软件，如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件实现。本领域的技术人员可以确定用于测量比对的适当参数，包括在进行比较的序列的全长内实现最大比对所需的任何算法。一种特定程序是美国公开号20160244525的[0279]到[0280]段落中所概述的ALIGN-2程序，所述公开特此以引用方式并入。核酸序列的另一种近似比对由Smith和Waterman《Advances in Applied Mathematics》,2:482-489(1981)的局部同源性算法提供。此算法可以通过使用由Dayhoff在《蛋白质序列和结构图集(Atlasof Protein Sequences and Structure)》,密苏里州Dayhoff编辑,增刊53:353-358,美国华盛顿国家生物医学研究基金会(National Biomedical Research Foundation)中开发的评分矩阵应用于氨基酸序列，并由Gribskov在《核酸研究(Nucl.Acids Res.)》14(6):6745-6763(1986)中进行标准化。
遗传学计算机组(麦迪逊，威斯康星州)在“BestFit”实用程序应用程序中提供了实施该算法以确定序列的百分比同一性的示例。该方法的默认参数在Wisconsin SequenceAnalysis Package Program Manual,Version 8(1995)(可从Genetics Computer Group,Madison,WI获得)中有所描述。在本发明的上下文中建立百分比同一性的另一种方法是使用由爱丁堡大学(University of Edinburgh)版权所有、由John F.Collins和ShaneS.Sturrok开发并由智生公司(IntelliGenetics,Inc.，加利福尼亚州山景城)分发的MPSRCH程序包。从这套程序包中，可以使用史密斯-沃特曼算法，其中默认参数用于评分表(例如，空位开放罚分为12、空位延伸罚分为1，并且空位为6)。从生成的数据中，“匹配”值反映了“序列同一性”。用于计算序列之间的百分比同一性或相似性的其他合适程序是本领域公知的，例如，另一种比对程序是BLAST，使用默认参数。例如，可以使用以下默认参数来使用BLASTN和BLASTP：遗传密码＝标准；过滤器＝无；链＝两者；截止＝60；期望＝10；矩阵＝BLOSUM62；描述＝50个序列；排序方式＝高分；数据库＝非冗余，GenBank+EMBL+DDBJ+PDB+GenBank CDS翻译+Swiss蛋白质+Spupdate+PIR。这些程序的详细信息可以通过将http://in front of blast.ncbi.nlm.nih.gov/Blast.cgi.的网址找到。
本发明的氨基酸序列(“发明序列”)与亲本氨基酸序列之间的同一性的程度被计算为在两个序列的比对中精确匹配的数除以“发明序列”的长度或亲本序列的长度，以最短者为准。结果以同一性百分比表示。
在一些实施例中，两个或更多个氨基酸序列具有至少50％、60％、70％、80％或90％同一性。在一些实施例中，两个或更多个氨基酸序列具有至少95％、97％、98％、99％或甚至100％同一性。
“特异性结合”或“特异性结合于”特定抗原或表位，或“对”特定抗原或表位“具有特异性”意指与非特异性相互作用可测量地不同的结合。特异性结合可以如下测量：例如相比于对照分子的结合来确定一种分子的结合，所述对照分子通常是不具有结合活性的类似结构分子。例如，可通过与类似于靶标的对照分子竞争来确定特异性结合。
如本文所使用的，术语“IC50”或“半数最大抑制浓度”旨在指响应(或结合)减半的抑制剂的浓度。抗体的IC50值可以使用本领域已建立的方法来确定。在一些实施例中，用于确定抗体的IC50的方法是通过使用4参数逻辑模型进行的。
“疾病”包括动物(包括人)的健康状态，其中动物不能维持体内稳态，并且其中如果疾病没有改善，则动物的健康继续恶化。
相比之下，动物(包括人类)的“疾患”包括动物能够维持体内稳态的健康状态，但动物的健康状态不如没有疾患时的健康状态。如果不加以治疗，疾患不一定会导致动物健康状况进一步下降。在一些情况下，“病症”可以与“疾病”互换使用。
术语“治疗(treatment/treating/treat)”和类似术语是指获得所需药理学和/或生理学效应。就完全或部分预防疾病或其症状或降低疾病或其症状的可能性而言，该效果可以是预防性的，和/或就部分或完全治愈疾病和/或可归因于该疾病的副作用而言，该效果可以是治疗性的。本文所使用的“治疗”涵盖对哺乳动物(特别是人)疾病的任何治疗，并且包括：(a)预防疾病在受试者发生，所述受试者可为易发生所述疾病但尚未被诊断为已患所述疾病者；(b)抑制疾病，即停止疾病的发展或进展；和(c)缓解疾病，即引起疾病消退和/或缓解一种或多种疾病症状。“治疗”也涵盖递送剂以提供药理学效应，甚至在疾病或病症不存在下。例如，“治疗”涵盖递送可在疾病病症不存在下(例如例如在疫苗的情况下)诱发免疫应答或赋予免疫力的组合物。
如本文所使用的，术语“哺乳动物”是指任何哺乳动物，包括但不限于啮齿目哺乳动物，例如小鼠和仓鼠，以及兔形目(Logomorpha)哺乳动物，例如兔。在一些实施例中，哺乳动物来自食肉目，包括猫科动物(猫)和犬科动物(狗)。在一些实施例中，哺乳动物来自偶蹄目，包括牛科(牛)和猪科(swines)(猪)或来自奇蹄目的，包括马科(马)。最优选哺乳动物属于灵长类、新大陆猴科(Ceboids)或Simoids(猴子)目或类人猿目(人和猿)。在一些实施例中，哺乳动物是人类。在一些实施例中，哺乳动物是食蟹猴。
如本文所使用的，术语“消退”以及源自其的词不一定意味着100％或完全回归。相反，存在不同程度的消退，本领域普通技术人员认识到其中具有潜在益处或治疗效果。在这方面，所公开的方法可以提供任何量的任何水平的哺乳动物癌症消退。此外，本发明方法提供的消退可以包括疾病(例如，癌症)的一种或多种病症或症状的消退。此外，出于本文的目的，“消退”可以包括延迟疾病的发作、延迟症状的发作和/或延迟其病症的发作。关于进行性疾病和病症，“消退”可以包括减缓疾病或疾患的进展、减缓疾病或疾患的症状的进展、和/或减缓其病症的进展。
组合物的“有效量”或“治疗有效量”包括足以为施用组合物的受试者提供有益效果的组合物的量。递送载体的“有效量”包括足以有效结合或递送组合物的量。
“个体”或“宿主”或“受试者”或“患者”是指需要诊断、治疗或治疗的任何哺乳动物受试者，特别是人类。其他受试者可包括食蟹猴、牛、狗、猫、豚鼠、兔、大鼠、小鼠、马等。
如本文所使用的，术语“与……组合”是指以下用途：其中例如在第二疗法的整个施用过程中施用第一疗法；其中第一种疗法的给药时间段与第二种疗法的给药重叠，例如，其中，第一疗法的施用在第二疗法的施用之前开始，并且第一疗法的施用在第二疗法的施用结束之前结束；其中，第二疗法的施用在第一疗法的施用之前开始，第二疗法的施用在第一疗法的施用结束之前结束；其中，第一治疗的施用在第二治疗的施用开始之前开始，并且第二治疗的施用在第一治疗的施用结束之前结束；其中，第二疗法的施用在第一疗法的施用开始之前开始，并且第一疗法的施用在第二疗法的施用结束之前结束。因此，“组合”也可以指涉及施用两种或更多种疗法的方案。如本文所使用的，“与……组合”还指两种或更多种疗法的施用，它们可以以相同或不同的调配物、通过相同或不同的途径以及以相同或不同的剂型类型施用。
“编码”包括多核苷酸如基因、cDNA或mRNA中核苷酸的特定序列的固有性质，以在生物过程中作为合成其它聚合物和大分子的模板，所述聚合物和大分子具有确定的核苷酸序列(即rRNA、tRNA和mRNA)或确定的氨基酸序列和由此产生的生物学性质。因此，如果，例如对应于该基因的mRNA的转录和翻译在细胞或其他生物系统中产生该蛋白，则该基因编码该蛋白。两条编码链，与mRNA序列相同且通常在序列表中提供的核苷酸序列，以及用作基因或cDNA的转录模板的非编码链都可以称为编码该基因或cDNA的蛋白或其他产物。
术语“核酸”包括具有多于一个核苷酸的任何形式的RNA或DNA分子，包括单链、双链、寡核苷酸或多核苷酸。术语“核苷酸序列”包括单链形式的核酸中寡核苷酸或多核苷酸中核苷酸的排序。
“核酸构建体”意指已被构建为包括一个或多个在自然界中未一起发现功能单元的核酸序列。实例包括环状、线性、双链、染色体外DNA分子(质粒)、粘粒(包含来自λ噬菌体的COS序列的质粒)、包括非天然核酸序列的病毒基因组等。
如本文所使用的，术语“可操作地连接”包括与第二个多核苷酸具有功能关系的多核苷酸，例如，包含以这样的方式排列在核酸部分内的两个多核苷酸的单链或双链核酸部分，其方式为两个多核苷酸中的至少一个能够对另一个多核苷酸施加生理学效应。例如来说，与基因编码区可操作地连接的启动子能够促进编码区的转录。指示可操作连接时指定的顺序并不重要。例如，短语：“启动子与核苷酸序列可操作地连接”和“核苷酸序列与启动子可操作地连接”在本文中可互换使用并且被认为是等效的。在一些情况下，当编码所需蛋白质的核酸进一步包括启动子/调节序列时，该启动子/调节序列位于所需蛋白质编码序列的5'端，从而驱动所需蛋白质在细胞中的表达。
术语“寡核苷酸”、“多核苷酸”和“核酸分子”在本文中可互换使用，是指任何长度的核苷酸的聚合形式，核糖核苷酸或脱氧核糖核苷酸。因此，该术语包含但不限于单链、双链或多链DNA或RNA、基因组DNA、cDNA、DNA-RNA杂交体，或包括嘌呤和嘧啶碱基或其他天然、化学或生化修饰的、非天然的或衍生的核苷酸碱基的聚合物。多核苷酸的主链可以包括糖和磷酸基团(如通常可在RNA或DNA中发现的)，或修饰或取代的糖或磷酸基团。
应用于多核苷酸的术语“重组”意指多核苷酸是克隆、限制或连接步骤以及导致构建体与自然界中发现的多核苷酸有区别和/或不同的其它程序的各种组合的产物。所述术语分别包含原始多核苷酸构建体的复制和原始病毒构建体的后代。
如本文所使用的，术语“启动子”包含可操作地连接到如对期望分子进行编码的核酸序列等待转录的核酸序列的DNA序列。启动子通常定位在待转录的核酸序列的上游，并为RNA聚合酶和其它转录因子的特异性结合提供位点。
“载体”能够将基因序列转移到靶细胞。典型地，“载体构建体”、“表达载体”和“基因转移载体”意指能够指导所关注基因的表达并且可以通过载体的全部或一部分的基因组整合或载体作为染色体外元件的短暂或可遗传维持将基因序列转移到靶细胞的任何核酸构建体。因此，所述术语包含克隆和表达媒剂以及整合载体。
如本文所使用的，术语“调控元件”包含控制核酸序列表达的某些方面的核苷酸序列。调控元件的实例示例性地包含有助于核酸序列的复制、转录和/或转录后加工的增强子、内部核糖体进入位点(IRES)、内含子、复制起点、聚腺苷酸化信号(pA)、启动子、增强子、转录终止序列和上游调节结构域。在某些情况下，调控元件还可以包含顺式调节DNA元件以及转座元件(TE)。本领域的普通技术人员能够在不超过常规实验的情况下选择和使用表达构建体中的这些和其它调控元件。表达构建体可以使用遗传重组途径或使用众所周知的方法以合成方式产生。
“控制元件”或“控制序列”是参与分子的相互作用的核苷酸序列，所述相互作用有助于对多核苷酸进行功能调节，包含多核苷酸的复制、重复、转录、剪接、翻译或降解。调节会影响过程的频率、速度或特异性并且在本质上会具有增强或抑制性。本领域已知的控制元件包含例如转录调节序列，如启动子和增强子。启动子是在某些条件下能够结合RNA聚合酶并且启动对通常位于启动子下游(沿3'方向)的编码区进行转录的DNA区域。
本文所使用的氨基酸残基被“磷酸化”的陈述意指磷酸基团与氨基酸残基的侧链酯连接。可以被磷酸化的典型氨基酸残基包含丝氨酸(Ser)、苏氨酸(Thr)和酪氨酸(Tyr)。
如本文所使用的，术语“药物组合物”是指活性剂与惰性或活性载体的组合，使得该组合物特别适用于体内或离体的诊断或治疗用途。
如本文所使用的，术语“药学上可接受的载体”是指任何标准药用载体，例如磷酸盐缓冲盐水溶液、水、乳剂(例如，例如油/水或水/油乳剂)和各种类型的润湿剂。组合物还可包括稳定剂和防腐剂。对于载体、稳定剂和佐剂的实例，参见例如，Martin,《雷明登氏药学全书(Remington's Pharmaceutical Sciences)》,第15th版,麦克出版公司(MackPubl.Co.),宾夕法尼亚州伊斯顿[1975]。
在整个说明书中，当组合物被描述为具有、包含或包括特定组分时，或当过程和方法被描述为具有、包含或包括特定步骤时，预期另外存在基本上由所述组分组成或由所述组分组成的本发明的组合物，并且存在基本上由所述加工步骤组成或由所述加工步骤组成的根据本发明的过程和方法。
一般而言，除非另外说明，否则规定百分比的组合物是按重量计的。进一步地，如果变量未附带定义，则对照该变量之前的定义。
本发明的各个方面在以下部分中阐述；然而，在一个特定部分中描述的本发明的方面不限于任何特定部分。
I.抗体
本公开提供了新型抗TSG-6抗体。此类抗体结合人和小鼠TSG-6。表1列出了重链可变区和轻链可变区的肽序列，所述肽序列以如表1所示组合，可以结合人和小鼠TSG-6。在一些实施例中，重链可变区和轻链可变区以Fab形式排列。在一些实施例中，重链可变区和轻链可变区融合在一起以形成scFv。
在一些实施例中，本公开中的抗TSG-6抗体包含具有与SEQ ID NO:1至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的重链可变区和具有与SEQID NO:2至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的轻链可变区。
在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:27的vhCDR1、包括SEQ ID NO:28的vhCDR2、包括SEQ ID NO:29的vhCDR3、包括SEQ ID NO:30的vlCDR1、包括SEQ ID NO:31的vlCDR2和包括SEQ ID NO:32的vlCDR3。在一些实施例中，这样的6个CDR中的一个或多个具有1、2、3、4或5个氨基酸修饰。在另外的实施例中，单个CDR包含1或2个氨基酸取代，并且经修饰的抗TSG-6抗体保持与人和/或小鼠TSG-6结合。
在一些实施例中，本公开中的抗TSG-6抗体包含具有与SEQ ID NO:3至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的重链可变区和具有与SEQID NO:4至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的轻链可变区。
在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:33的vhCDR1、包括SEQ ID NO:34的vhCDR2、包括SEQ ID NO:35的vhCDR3、包括SEQ ID NO:36的vlCDR1、包括SEQ ID NO:37的vlCDR2和包括SEQ ID NO:38的vlCDR3。在另外的实施例中，单个CDR包含1或2个氨基酸取代，并且经修饰的抗TSG-6抗体保持与人和/或小鼠TSG-6结合。
在一些实施例中，本公开中的抗TSG-6抗体包含具有与SEQ ID NO:5至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的重链可变区和具有与SEQID NO:6至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的轻链可变区。
在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:39的vhCDR1、包括SEQ ID NO:40的vhCDR2、包括SEQ ID NO:41的vhCDR3、包括SEQ ID NO:42的vlCDR1、包括SEQ ID NO:43的vlCDR2和包括SEQ ID NO:44的vlCDR3。在一些实施例中，这样的6个CDR中的一个或多个具有1、2、3、4或5个氨基酸修饰。在另外的实施例中，单个CDR包含1或2个氨基酸取代，并且经修饰的抗TSG-6抗体保持与人和/或小鼠TSG-6结合。
在一些实施例中，本公开中的抗TSG-6抗体包含具有与SEQ ID NO:7至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的重链可变区和具有与SEQID NO:8至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的轻链可变区。
在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:45的vhCDR1、包括SEQ ID NO:46的vhCDR2、包括SEQ ID NO:47的vhCDR3、包括SEQ ID NO:48的vlCDR1、包括SEQ ID NO:49的vlCDR2和包括SEQ ID NO:50的vlCDR3。在一些实施例中，这样的6个CDR中的一个或多个具有1、2、3、4或5个氨基酸修饰。在另外的实施例中，单个CDR包含1或2个氨基酸取代，并且经修饰的抗TSG-6抗体保持与人和/或小鼠TSG-6结合。
在一些实施例中，本公开中的抗TSG-6抗体包含具有与SEQ ID NO:9至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的重链可变区和具有与SEQID NO:10至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的轻链可变区。
在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:51的vhCDR1、包括SEQ ID NO:52的vhCDR2、包括SEQ ID NO:53的vhCDR3、包括SEQ ID NO:54的vlCDR1、包括SEQ ID NO:55的vlCDR2和包括SEQ ID NO:56的vlCDR3。在一些实施例中，这样的6个CDR中的一个或多个具有1、2、3、4或5个氨基酸修饰。在另外的实施例中，单个CDR包含1或2个氨基酸取代，并且经修饰的抗TSG-6抗体保持与人和/或小鼠TSG-6结合。
在一些实施例中，本公开中的抗TSG-6抗体包含具有与SEQ ID NO:11至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的重链可变区和具有与SEQID NO:12至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的轻链可变区。
在一些实施例中，包含包括SEQ ID NO:57的vhCDR1、包括SEQ ID NO:58的vhCDR2、包括SEQ ID NO:59的vhCDR3、包括SEQ ID NO:60的vlCDR1、包括SEQ ID NO:61的vlCDR2和包括SEQ ID NO:62的vlCDR3的抗TSG-6抗体。在一些实施例中，这样的6个CDR中的一个或多个具有1、2、3、4或5个氨基酸修饰。在另外的实施例中，单个CDR包含1或2个氨基酸取代，并且经修饰的抗TSG-6抗体保持与人和/或小鼠TSG-6结合。
在一些实施例中，本公开中的抗TSG-6抗体包含具有与SEQ ID NO:13至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的重链可变区和具有与SEQID NO:14至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的轻链可变区。
在一些实施例中，包含包括SEQ ID NO:63的vhCDR1、包括SEQ ID NO:64的vhCDR2、包括SEQ ID NO:65的vhCDR3、包括SEQ ID NO:66的vlCDR1、包括SEQ ID NO:67的vlCDR2和包含括SEQ ID NO:68的vlCDR3的抗TSG-6抗体。在一些实施例中，这样的6个CDR中的一个或多个具有1、2、3、4或5个氨基酸修饰。在另外的实施例中，单个CDR包含1或2个氨基酸取代，并且经修饰的抗TSG-6抗体保持与人和/或小鼠TSG-6结合。
在一些实施例中，本公开中的抗TSG-6抗体包含具有与SEQ ID NO:15至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的重链可变区和具有与SEQID NO:16至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的轻链可变区。
在一些实施例中，包含包括SEQ ID NO:69的vhCDR1、包括SEQ ID NO:70的vhCDR2、包括SEQ ID NO:71的vhCDR3、包括SEQ ID NO:72的vlCDR1、包括SEQ ID NO:73的vlCDR2和包含括SEQ ID NO:74的vlCDR3的抗TSG-6抗体。在一些实施例中，这样的6个CDR中的一个或多个具有1、2、3、4或5个氨基酸修饰。在另外的实施例中，单个CDR包含1或2个氨基酸取代，并且经修饰的抗TSG-6抗体保持与人和/或小鼠TSG-6结合。
在一些实施例中，本公开中的抗TSG-6抗体包含具有与SEQ ID NO:17至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的重链可变区和具有与SEQID NO:18至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的轻链可变区。
在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:75的vhCDR1、包括SEQ ID NO:76的vhCDR2、包括SEQ ID NO:77的vhCDR3、包括SEQ ID NO:78的vlCDR1、包括SEQ ID NO:79的vlCDR2和包括SEQ ID NO:80的vlCDR3。在一些实施例中，这样的6个CDR中的一个或多个具有1、2、3、4或5个氨基酸修饰。在另外的实施例中，单个CDR包含1或2个氨基酸取代，并且经修饰的抗TSG-6抗体保持与人和/或小鼠TSG-6结合。
在一些实施例中，本公开中的抗TSG-6抗体包含具有与SEQ ID NO:19至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的重链可变区和具有与SEQID NO:20至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的轻链可变区。
在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:81的vhCDR1、包括SEQ ID NO:82的vhCDR2、包括SEQ ID NO:83的vhCDR3、包括SEQ ID NO:84的vlCDR1、包括SEQ ID NO:85的vlCDR2和包括SEQ ID NO:86的vlCDR3。在一些实施例中，这样的6个CDR中的一个或多个具有1、2、3、4或5个氨基酸修饰。在另外的实施例中，单个CDR包含1或2个氨基酸取代，并且经修饰的抗TSG-6抗体保持与人和/或小鼠TSG-6结合。
在一些实施例中，本公开中的抗TSG-6抗体包含具有与SEQ ID NO:21至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的重链可变区和具有与SEQID NO:22至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的轻链可变区。
在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:87的vhCDR1、包括SEQ ID NO:88的vhCDR2、包括SEQ ID NO:89的vhCDR3、包括SEQ ID NO:90的vlCDR1、包括SEQ ID NO:91的vlCDR2和包括SEQ ID NO:92的vlCDR3。在一些实施例中，这样的6个CDR中的一个或多个具有1、2、3、4或5个氨基酸修饰。在另外的实施例中，单个CDR包含1或2个氨基酸取代，并且经修饰的抗TSG-6抗体保持与人和/或小鼠TSG-6结合。
在一些实施例中，本公开中的抗TSG-6抗体包含具有与SEQ ID NO:23至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的重链可变区和具有与SEQID NO:24至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的轻链可变区。
在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:93的vhCDR1、包括SEQ ID NO:94的vhCDR2、包括SEQ ID NO:95的vhCDR3、包括SEQ ID NO:96的vlCDR1、包括SEQ ID NO:97的vlCDR2和包括SEQ ID NO:98的vlCDR3。在一些实施例中，这样的6个CDR中的一个或多个具有1、2、3、4或5个氨基酸修饰。在另外的实施例中，单个CDR包含1或2个氨基酸取代，并且经修饰的抗TSG-6抗体保持与人和/或小鼠TSG-6结合。
在一些实施例中，本公开中的抗TSG-6抗体包含具有与SEQ ID NO:25至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的重链可变区和具有与SEQID NO:26至少80％(例如，80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)相同的氨基酸序列的轻链可变区。
在一些实施例中，抗TSG-6抗体包含包括SEQ ID NO:99的vhCDR1、包括SEQ ID NO:100的vhCDR2、包括SEQ ID NO:101的vhCDR3、包括SEQ ID NO:102的vlCDR1、包括SEQ IDNO:103的vlCDR2和包括SEQ ID NO:104的vlCDR3。在一些实施例中，这样的6个CDR中的一个或多个具有1、2、3、4或5个氨基酸修饰。在另外的实施例中，单个CDR包含1或2个氨基酸取代，并且经修饰的抗TSG-6抗体保持与人和/或小鼠TSG-6结合。
在一些实施例中，本公开包含对本文所述的氨基酸序列变体中的任一种进行编码的核酸。在一些实施例中，本公开包含包括本文所述的核酸中的任何核酸的表达载体。在一些实施例中，本公开包含包括本文所述的表达载体中的任一种的宿主细胞。
除了本文所述的重链和轻链可变区和/或CDR中的序列变体之外，还可以对重链和/或轻链可变区的框架区进行改变。在一些实施例中，框架区中的变体(例如，不包括CDR)与种系序列保持至少约80、85、90或95％的同一性。可以制备变体以与轻链V-GENE、轻链J-GENE、重链V-GENE、重链J-GENE和重链D-GENE等位基因中的任一项保持至少约80％、85％、90％或95％的同一性。
在一些实施例中，在保持与种系基因序列至少80％、85％、90％或95％同一性的框架区中进行变异，同时保持6个CDR不变。
在一些实施例中，在与种系基因序列保持至少80％、85％、90％或95％同一性的框架区和6CDR两者中都进行了变异。或者，CDR可具有氨基酸修饰(例如来自所述组的CDR中的1、2、3、4或5个氨基酸修饰(即，CDR可为经修饰的，只要所述组6个CDR中的改变的总数小于6个氨基酸修饰，其中改变CDR的任何组合；例如，vlCDR1中可存在一个变化，vhCDR2中可存在两个变化，vhCDR3中可不存在变化等)。
通过从本文所述的那些中选择CDR和/或重链和轻链的可变区的氨基酸序列并适当地将其与框架区和/或抗体的重链和轻链的恒定区的氨基酸序列组合，本领域技术人员将能够根据本发明设计抗TSG-6抗体。本发明中描述的抗体框架区和/或恒定区(Fc结构域)可以来源于任何物种的抗体，例如来源于人、兔、狗、猫、小鼠、马或猴。
在一些实施例中，恒定区源自人，并且包括源自IgG、IgA、IgM、IgE和IgD亚型或其变体的重链恒定区，以及源自κ或λ亚型或其变体的轻链恒定区。在一些实施例中，重链恒定区源自人IgG，包括IgG1、IgG2、IgG3和IgG4。在一些实施例中，重链恒定区的氨基酸序列与人IgG1、IgG2、IgG3或IgG4恒定区至少80％、85％、90％或95％相同。在一些其他实施例中，恒定区的氨基酸序列与另一种哺乳动物(如兔子、狗、猫、小鼠、马或猴)的抗体恒定区至少80％、85％、90％或95％相同。在一些实施例中，抗体恒定区包括铰链、CH2结构域、CH3结构域和任选的CH1结构域。
在一些实施例中，本文的抗体可源自来自不同物种的混合物，例如嵌合抗体和/或人源化抗体。通常，“嵌合抗体”和“人源化抗体”都是指组合来自超过一种物种的区域的抗体。例如，“嵌合抗体”传统上包括来自小鼠(或在一些情况下为大鼠)的可变区和来自人类的恒定区。“人源化抗体”通常是指非人类抗体，其具有与人类抗体中发现的序列交换的可变结构域框架区。通常，在人源化抗体中，除CDR之外的整个抗体由人类来源的多核苷酸编码或除了在其CDR内之外，与这种抗体相同。CDR(部分或全部由源自非人类生物体的核酸编码)被移植到人类抗体可变区的β-折叠框架中以形成抗体，其特异性由移植的CDR决定。这类抗体的形成描述于例如WO 92/11018,Jones,1986,Nature 321:522-525,Verhoeyen etal.,1988,Science239:1534-1536中，其以引用的方式整体并入本文中。所选择的受体框架残基“回复突变”到相应的供体残基通常需要重新获得在初始移植构筑体中丧失的亲和力(US 5530101；US5585089；US 5693761；US 5693762；US 6180370；US 5859205；US 5821337；US 6054297；US 6407213，其以引用的方式整体并入本文中)。人类化抗体最佳还包括免疫球蛋白恒定区的至少一部分，通常是人类免疫球蛋白的至少一部分，并且因此通常将包括人类Fc区。使用具有基因工程化免疫系统的小鼠也可以产生人源化抗体，例如Roque等人,2004,《生物技术进展(Biotechnol.Prog.)》20:639-654，其以引用的方式整体并入本文中。用于人源化和重塑非人类抗体的多种技术和方法是本领域熟知的(参见Tsurushita和Vasquez,2004,《单克隆抗体的人源化(Humanization of Monoclonal Antibodies)》,《B细胞分子生物学(Molecular Biology of B Cells)》,533-545,爱思唯尔科学公司(ElsevierScience)(美国)和其中引用的参考文献，其以引用的方式整体并入本文中)。人源化方法包括但不限于以下文献中所述的方法：Jones等人,1986,《自然》321:522-525；Riechmann等人,1988,《自然》332:323-329；Verhoeyen等人,1988,《科学》239:1534-1536；Queen等人,1989,《美国国家科学院院刊》86:10029-33；He等人,1998,《免疫学杂志(J.Immunol.)》160:1029-1035；Carter等人,1992,《美国国家科学院院刊》89:4285-9；Presta等人,1997,《癌症研究(Cancer Res.)》57(20):4593-9；Gorman等人,1991,《美国国家科学院院刊》88:4181-4185；O'Connor等人,1998,《蛋白质工程(Protein Eng)》11:321-8，所有所述文献通过引用整体并入。降低非人类抗体可变区免疫原性的人源化或其它方法可以包括表面再塑方法，如例如Roguska等人,1994,《美国国家科学院院刊》91:969-973中所述，其以引用的方式整体并入本文中。其它人源化方法可涉及仅移植部分CDR，包括但不限于以下文献中所述的方法：Tan等人,2002,《免疫学杂志》169:1119-1125；De Pascalis等人,2002,《免疫学杂志》169:3076-3084，所有所述文献都以引用的方式整体并入本文中。
在一些实施例中，本发明的抗体包括源自特定种系重链免疫球蛋白基因的重链可变区和/或源自特定种系轻链免疫球蛋白基因的轻链可变区。例如，由于自然发生的体细胞的突变或定点突变的有意引入，与人类种系序列相比，此类抗体可能包含氨基酸差异。然而，人源化抗体通常与由人类种系免疫球蛋白基因编码的氨基酸序列在氨基酸序列上具有至少80％相同，并且在与其它物种的种系免疫球蛋白氨基酸序列(例如，鼠种系序列)进行比较时，包含将抗体鉴定为源自人类序列的氨基酸残基。在某些情况下，人源化抗体可以与由种系免疫球蛋白基因编码的氨基酸序列在氨基酸序列上至少95％、96％、97％、98％或99％，或甚至至少96％、97％、98％或99％相同。通常，衍生自特定人类种系序列的人源化抗体将显示与人类种系免疫球蛋白基因编码的氨基酸序列不超过10-20个氨基酸差异。在某些情况下，人源化抗体可显示与种系免疫球蛋白基因编码的氨基酸序列不超过5个，或甚至不超过4个、3个、2个或1个氨基酸差异。
在一些实施例中，如本领域已知的，本公开的抗体是人源化的并且是亲和力成熟的。基于结构的方法可用于人源化和亲和力成熟，例如美国专利第7,657,380号中所述。基于选择的方法可以用于人源化和/或亲和成熟抗体可变区，包括但不限于以下文献中所述的方法：Wu等人,1999,《分子生物学杂志》294:151-162；Baca等人,1997,《生物化学杂志(J.Biol.Chem.)》272(16):10678-10684；Rosok等人,1996,《生物化学杂志》271(37):22611-22618；Rader等人,1998，《美国国家科学院院刊》95:8910-8915；Krauss等人,2003,《蛋白质工程化(Protein Engineering)》16(10):753-759，所有所述文献都以引用的方式整体并入本文中。
II.抗体的特性
在一些实施例中，本文所述的抗TSG-6抗体与人和/或小鼠TSG-6结合。在一些实施例中，通过使用ELISA研究与HA的结合来测量抗TSG-6抗体与人和/或小鼠TSG-6的结合，如实例2中描述的示例性测定。在此类实施例中，本文所述的抗体显示出IC50的范围可以为10-2000nM，如通过此类测定测量的。在一些实施例中，通过使用ELISA研究TSG-6HC-HA转酯酶活性来测量抗TSG-6抗体与人和/或小鼠TSG-6的结合，如实例2中描述的示例性测定。在此类实施例中，本文所述的抗体显示出IC50的范围可以为4-3000nM，如通过ELISA测量的。在另外的实施例中，本文所述的抗体的IC50的范围为约0.1-4000、0.1-3000、1-2800、2-2600、3-2400、4-2200、5-2000、6-1800、7-1600、8-1400或9-1200nM，如通过ELISA测量的。在一些实施例中，本文所述的抗体的IC50的范围为50-3500、100-3000、150-2500、200-2000、250-1500和300-1000nM，如通过ELISA测量的。
在一些实施例中，抗TSG-6抗体充当TSG-6拮抗剂，并阻断TSG-6与HA的相互作用以及HC-HA的产生。因此，此类抗TSG-6抗体刺激免疫应答。
在一些实施例中，本文所述的抗TSG-6抗体降低HC-HA的水平。在一些实施例中，HC-HA的减少使用ELISA测量，如在实例3中描述的示例性测定中。
在一些实施例中，本文所述的抗TSG-6抗体减少肿瘤体积，如在实例4中描述的示例性测定中。
在一些其它实施例中，本文所述的抗TSG-6抗体充当TSG-6激动剂，并抑制免疫细胞功能，包含促炎性T细胞功能。因此，此类抗TSG-6抗体抑制免疫应答。
在其它实施例中，本文所述的抗TSG-6抗体增加HC-HA的水平。在一些实施例中，HC-HA的增加使用ELISA测量，如在实例3中描述的示例性测定中。
III.本发明的核酸
对抗TSG-6抗体进行编码的核酸以及含有此类核酸的表达载体和用此类核酸和/或表达载体转化的宿主细胞也落入本发明的范围内。如本领域技术人员所理解的，由于遗传密码的简并性，蛋白质序列可以由任何数量的可能的核酸序列进行编码。
对抗TSG-6抗体和/或TSG-6结合结构域进行编码的核酸组合物也落入本发明的范围内。本领域技术人员将理解，在抗原结合结构域的情况下，核酸组合物通常包括编码重链可变区的第一核酸和编码轻链可变区的第二核酸。在scFv的情况下，可以制备编码重链可变区和轻链可变区的单个核酸，由本文所述的接头分开。在传统抗体的情况下，核酸组合物通常包括编码重链的第一核酸和编码轻链的第二核酸，它们将在细胞中表达时自发组装成“传统”四聚体形式的两条重链和两条轻链。
如本领域所知，编码本发明组分的核酸可并入表达载体中，并取决于宿主细胞，用于产生本发明抗体。这两种核酸可以并入单个表达载体或两个不同的表达载体中。通常，核酸可操作地连接到任何数量的位于表达载体上的调控元件(启动子、复制起点、可选择标记、核糖体结合位点、诱导剂等)。表达载体可以是染色体外的或整合的载体。
本发明的核酸和/或表达载体可以引入本领域公知的任何类型的宿主细胞，包括哺乳动物、细菌、酵母、昆虫和真菌细胞。转染后，可以使用本领域已知的方法，例如有限稀释、ELISA、FACS、显微镜检查或Clonepix，分离单细胞克隆用于细胞库生成。克隆可以在适合生物反应器放大和保持抗体表达的条件下培养。可以使用本领域已知的方法分离和纯化抗体，包括离心、深度过滤、细胞裂解、匀浆、冻融、亲和纯化、凝胶过滤、离子交换色谱法、疏水相互作用交换色谱法和混合模式色谱法。
IV.治疗应用
本公开提供了一种调节受试者的免疫应答的方法，并且所述方法包含向受试者施用有效量的本文所述的抗TSG-6抗体或含有抗TSG-6抗体的药物组合物。
在一些实施例中，本公开所涵盖的调节免疫应答的方法包括刺激受试者的免疫应答，并且在另外的实施例中，此类方法包括向受试者施用有效量的充当TSG-6拮抗剂的抗TSG-6抗体，或通过施用含有拮抗性抗TSG-6抗体的药物组合物。
在一些实施例中，本公开提供了用于例如通过向受试者施用有效量的充当TSG-6激动剂的抗TSG-6抗体或通过向受试者施用含有此类激动性抗TSG-6抗体的药物组合物来抑制受试者的免疫应答的方法。
本公开还提供了治疗受试者的癌症的方法，并且此类方法包含向受试者施用有效量的充当TSG-6拮抗剂的抗TSG-6抗体或含有此类抗TSG-6抗体的药物组合物。在一些实施例中，与对应的非癌组织相比，待治疗癌症的HC-HA和/或TSG-6表达高。在一些实施例中，待治疗的癌症使用TSG-6/HA途径来促进癌症进展。在一些实施例中，待治疗的癌症使用TSG-6在酯交换反应中催化HC蛋白从α间抑制剂(IaI)转移到HA，从而形成HC-HA复合物。在一些实施例中，HC-HA复合物形成已经改变了结合性质、改变巨噬细胞向“M2”表型的极化并增加癌症的发病机制的线缆状结构。在一些实施例中，待治疗的癌症对靶向如CTLA-4、PD-1或PD-L1等其它免疫检查点的现有免疫调节抗体无反应。
在一些实施例中，癌症是实体瘤，如胃癌、结肠直肠癌、肝细胞癌、黑色素瘤或食管鳞状细胞癌。在一些实施例中，癌症是B细胞慢性淋巴细胞白血病、霍奇金氏(Hodgkin's)淋巴瘤、B细胞非霍奇金氏淋巴瘤或T细胞非霍奇金氏淋巴瘤。
在一些其他实施例中，癌症是脑癌、膀胱癌、乳腺癌、宫颈癌、子宫内膜癌、食道癌、白血病、肺癌、肝癌、黑色素瘤、卵巢癌、胰腺癌、前列腺癌、直肠癌、肾癌、睾丸癌或子宫癌。在其他实施例中，癌症是血管化肿瘤、鳞状细胞癌、腺癌、小细胞癌、神经母细胞瘤、肉瘤(例如血管肉瘤或软骨肉瘤)、喉癌、腮腺癌、胆道癌、甲状腺癌、肢端黑色素瘤、光化性角化病、急性淋巴细胞白血病、急性髓性白血病、腺样囊性癌、腺瘤、腺肉瘤、腺鳞癌、肛管癌、肛门癌、肛门直肠癌、星形细胞瘤、前庭大腺癌、基底细胞癌、胆道癌、骨癌、骨髓癌、支气管癌、支气管腺癌、类癌、胆管癌、软骨肉瘤、脉络丛乳头状瘤/癌、慢性淋巴细胞白血病、慢性粒细胞白血病、透明细胞癌、结缔组织癌、囊腺瘤、消化系统癌症、十二指肠癌、内分泌系统癌症、内胚窦瘤、子宫内膜增生、子宫内膜间质肉瘤、子宫内膜样瘤腺癌、内皮细胞癌、室管膜癌、上皮细胞癌、尤文氏肉瘤、眼眶癌、女性生殖器癌、局灶性结节性增生、胆囊癌、胃窦癌、胃底癌、胃泌素瘤、胶质母细胞瘤、胰高血糖素瘤、心脏病、血管母细胞瘤、血管内皮瘤、血管瘤、肝腺瘤、肝腺瘤病、肝胆癌、肝细胞癌、霍奇金病、回肠癌、胰岛素瘤、上皮内瘤变、上皮间鳞状细胞瘤、肝内胆管癌、浸润性鳞状细胞癌、空肠癌、关节癌卡波西肉瘤、盆腔癌、大细胞癌、大肠癌、平滑肌肉瘤、恶性痣黑色素瘤、淋巴瘤、男性生殖器癌、恶性黑色素瘤、恶性间皮肿瘤、髓母细胞瘤、髓上皮瘤、脑膜癌、间皮癌、转移性癌、口腔癌、粘膜表皮癌、多发性骨髓瘤、肌肉癌、鼻道癌、神经系统癌、神经上皮腺癌结节性黑色素瘤、非上皮性皮肤癌、燕麦细胞癌、少突胶质细胞癌、口腔癌、骨肉瘤、乳头状浆液性腺癌、阴茎癌、咽癌、垂体瘤、浆细胞瘤、假肉瘤、肺母细胞瘤、直肠癌、肾细胞癌、呼吸系统癌、视网膜母细胞瘤、横纹肌肉瘤、肉瘤、浆液性癌、鼻窦癌、皮肤癌、小细胞癌、小肠癌、平滑肌癌、软组织癌、生长抑素分泌肿瘤、脊柱癌、鳞状细胞癌、横纹肌癌、间皮下癌、浅表扩散性黑色素瘤、T细胞白血病、舌癌、未分化癌、输尿管癌、尿道癌、膀胱癌、泌尿系统癌、子宫颈癌、子宫体癌症、葡萄膜黑色素瘤、阴道癌、疣状癌、血管活性肠肽瘤、外阴癌、高分化癌(well-differentiated carcinoma)或肾母细胞瘤。
在一些其他实施例中，待治疗的癌症是非霍奇金淋巴瘤，例如B细胞淋巴瘤或T细胞淋巴瘤。在某些实施例中，非霍奇金淋巴瘤是B细胞淋巴瘤，例如弥漫性大B细胞淋巴瘤、原发性纵隔B细胞淋巴瘤、滤泡性淋巴瘤、小淋巴细胞淋巴瘤、套细胞淋巴瘤、边缘区B细胞淋巴瘤、结外边缘区B细胞淋巴瘤、淋巴结边缘区B细胞淋巴瘤、脾边缘区B细胞淋巴瘤、伯基特淋巴瘤、淋巴浆细胞淋巴瘤、毛细胞白血病或原发性中枢神经系统(CNS)淋巴瘤。在某些其他实施例中，非霍奇金淋巴瘤是T细胞淋巴瘤，例如前体T淋巴细胞淋巴瘤、外周T细胞淋巴瘤、皮肤T细胞淋巴瘤、血管免疫母细胞T细胞淋巴瘤、结外自然杀伤细胞/T-细胞淋巴瘤、肠病型T细胞淋巴瘤、皮下脂膜炎样T细胞淋巴瘤、间变性大细胞淋巴瘤或外周T细胞淋巴瘤。
本公开还提供了治疗受试者的纤维化的方法，并且所述方法包含向受试者施用有效量的充当TSG-6拮抗剂的抗TSG-6抗体或含有此类抗TSG-6抗体的药物组合物。在一些实施例中，纤维化组织的TSG-6和/或HC-HA表达高。在一些实施例中，受试者的TSG-6和/或HC-HA表达高。在一些实施例中，HC-HA复合物形成已经改变了结合性质、改变巨噬细胞向“M2”表型的极化并增加纤维化的发病机制的线缆状结构。在一些实施例中，抗体与一种或多种另外的治疗剂组合以治疗纤维化。
在一些实施例中，纤维化包含但不限于胶原病、间质性肺病、人纤维化肺病(例如，闭塞性细支气管炎、特发性肺纤维化、已知病因引起的肺纤维化、肺病中的肿瘤基质、影响肺的系统性硬化症、赫曼斯基-普德拉克综合征(Hermansky-Pudlak syndrome)、煤工尘肺、石棉肺、矽肺、慢性肺动脉高压、AIDS相关肺动脉高压、结节病等)、纤维化血管疾病、动脉硬化、动脉粥样硬化、静脉曲张、冠状动脉梗塞、脑梗塞、心肌纤维化、肌肉骨骼纤维化、术后粘连、人类肾脏疾病(例如，肾炎综合征、阿尔波特氏综合征(Alport's syndrome)、HIV相关肾病、多囊肾病、法布里氏病(Fabry's disease)、糖尿病肾病、慢性肾小球肾炎、系统性红斑狼疮相关肾炎等)、皮肤瘢痕疙瘩形成、进行性系统性硬化症(PSS)、原发性硬化性胆管炎(PSC)、肝纤维化、肝硬化、肾纤维化、肺纤维化、囊性纤维化、慢性移植物抗宿主病、硬皮病(局部和全身)、格雷夫氏眼病(Grave's opthalmopathy)、糖尿病视网膜病变、青光眼、佩罗尼氏病(Peyronie's disease)、阴茎纤维化、使用膀胱镜检查后的尿道狭窄、手术后内部增生、疤痕、骨髓纤维化、特发性腹膜后纤维化、已知病因引起的腹膜纤维化、药物诱导的麦角中毒、良性或恶性癌症引起的纤维化、微生物感染(例如，病毒、细菌、寄生虫、真菌等)引起的纤维化、阿尔茨海默氏病(Alzheimer's disease)、炎性肠病引起的纤维化(包含克罗恩氏病(Crohn's disease)和显微镜下结肠炎中的狭窄形成)、化学或环境损伤(例如，癌症化疗、杀虫剂、辐射(例如，癌症放疗)等)诱发的纤维化等。在一些实施例中，“纤维化组织”是受包括这些实例之一的纤维化影响但不限于纤维化的任何组织。
本公开还提供了治疗受试者的自身免疫性或炎性病症的方法，并且所述方法包含向受试者施用有效量的抗TSG-6抗体或含有此类抗TSG-6抗体的药物组合物。在一些实施例中，TSG-6抗体是拮抗剂。在其它实施例中，TSG-6抗体是激动剂。
一方面，治疗受试者的自身免疫性或炎性病症的方法包含向受试者施用有效量的充当TSG-6拮抗剂的抗TSG-6抗体或含有此类抗TSG-6抗体的药物组合物。在一些实施例中，待治疗受试者的TSG-6和/或HC-HA表达高。在一些实施例中，待治疗受试者的发炎组织中的TSG-6和/或HC-HA表达高。施用充当TSG-6拮抗剂的抗TSG-6抗体可以刺激免疫应答以解决由自身免疫性或炎性病症引起的炎症。
在一些实施例中，待用拮抗性抗TSG-6抗体治疗的自身免疫性或炎性病症是哮喘。在一些实施例中，待治疗受试者的肺的TSG-6和/或HC-HA表达高。在一些实施例中，待治疗受试者患有增加的气道嗜酸性粒细胞增多症。在一些实施例中，抗体与一种或多种另外的治疗剂组合以治疗哮喘。
在一些实施例中，待用拮抗性抗TSG-6抗体治疗的自身免疫性或炎性病症是特发性肺动脉高压。在一些实施例中，受试者的TSG-6和/或HC-HA表达高。在一些实施例中，待治疗受试者还患有肺纤维化。在一些实施例中，抗体与另外的治疗剂组合以治疗特发性肺动脉高压和/或肺纤维化。
另一方面，治疗受试者的自身免疫性或炎性病症的方法包含向受试者施用有效量的充当TSG-6激动剂的抗TSG-6抗体或含有此类抗TSG-6抗体的药物组合物。在一些实施例中，待治疗受试者的TSG-6和/或HC-HA表达低。在一些实施例中，待治疗受试者的发炎组织中的TSG-6和/或HC-HA表达低。施用充当TSG-6激动剂的抗TSG-6抗体可以抑制促炎性免疫应答，包含促炎性T细胞应答，并调节患有自身免疫性或炎性病症的受试者的免疫应答。
在一些实施例中，要用激动性抗TSG-6抗体治疗的自身免疫性或炎性病症是类风湿性关节炎。施用充当TSG-6激动剂的抗TSG-6抗体可以通过抑制病原细胞的迁移来抑制促炎免疫应答。
在一些实施例中，待用拮抗性或激动性抗TSG-6抗体治疗的自身免疫性或炎性病症是动脉粥样硬化、多发性硬化、爱迪生氏病(Addison's disease)、肌萎缩性侧索硬化、克罗恩氏病、库欣氏综合征(Cushing's Syndrome)、1型糖尿病、移植物抗宿主病、格雷夫氏病、格林-巴利综合征(Guillain-Barrésyndrome)、炎性肠病、红斑狼疮、银屑病、银屑病性关节炎、类风湿性关节炎、结节病、硬皮病、系统性红斑狼疮、移植排斥或血管炎。
在一些实施例中，待用拮抗性或激动性抗-TSG-6抗体治疗的自身免疫性或炎性病症是肾上腺、膀胱、骨、骨髓、脑、乳腺、子宫颈、胆囊、神经节、胃肠道、心脏、肾、肝、肺、肌肉、卵巢、胰腺、甲状旁腺、阴茎、前列腺、唾液腺、皮肤、脾、脊髓、睾丸、胸腺、甲状腺或子宫炎性病症。
在一些其它实施例中，待用拮抗性或激动性抗TSG-6抗体治疗的自身免疫性或炎性病症包含但不限于急性播散性脑脊髓炎(ADEM)、无丙种球蛋白血症、斑秃、强直性脊柱炎、抗磷脂综合征、抗合成酶综合征、特应性过敏、特应性皮炎、自身免疫性再生障碍性贫血、自身免疫性心肌病、自身免疫性肠病、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性内耳病、自身免疫性淋巴增生综合征、自身免疫性胰腺炎、自身免疫性周围神经病变、自身免疫性多内分泌综合征、自身免疫性孕酮皮炎、自身免疫性血小板减少性紫癜、自身免疫性荨麻疹、自身免疫性葡萄膜炎、巴娄病(Balo disease)/巴娄同心硬化、白塞氏病(Behcet's disease)、伯格氏病(Berger's disease)、比克斯塔夫氏脑炎(Bickerstaffsencephalitis)、布劳综合征(Blau syndrome)、大疱性类天疱疮、支气管肺发育不良、癌症、卡斯特莱曼氏病(Castleman's disease)、脂泻病、恰加斯病(Chagas disease)、慢性炎性脱髓鞘性多发性神经病、慢性炎性脱髓鞘性多发性神经病、慢性阻塞性肺病、慢性复发性多灶性骨髓炎、丘-施综合征(Churg-Strauss syndrome)、瘢痕性类天疱疮、柯根综合症(Cogan syndrome)、冷凝集素病、补体成分2缺乏、接触性皮炎、颅动脉炎、CREST综合征、皮肤白细胞增生性血管炎、德戈氏病(Dego's disease)、德尔肯氏病(Dercum's disease)、疱疹样皮炎、皮肌炎、弥漫性皮肤系统性硬化、盘状红斑狼疮、德雷勒斯综合征(Dressler'ssyndrome)、药物性狼疮、湿疹、子宫内膜异位症、嗜酸性筋膜炎、嗜酸性胃肠炎、嗜酸性肺炎、获得性大疱性表皮松解症、结节性红斑、胎儿红细胞增多症、原发性混合冷球蛋白血症、埃文氏综合征(Evan's syndrome)、进行性骨化性纤维发育不良、纤维性肺泡炎(或特发性肺纤维化)、胃炎、胃肠道类天疱疮、肾小球肾炎、古德帕斯彻氏综合征(Goodpasture'ssyndrome)、桥本脑病(Hashimoto's encephalopathy)、桥本甲状腺炎(Hashimoto'sthyroiditis)、过敏性紫癜(Henoch-Schonlein purpura)、妊娠疱疹又称妊娠类天疱疮、化脓性汗腺炎、休-斯二氏综合征(Hughes-Stovin syndrome)、低丙种球蛋白血症、特发性炎性脱髓鞘疾病、特发性肺纤维化、特发性血小板减少性紫癜、IgA肾病、包涵体肌炎、间质性膀胱炎、幼年特发性关节炎又称幼年类风湿性关节炎、川崎病(Kawasaki's disease)、莱伯特-伊顿肌无力综合征(Lambert-Eaton myasthenic syndrome)、白细胞增生性血管炎、扁平苔藓、硬化性苔藓、线性IgA病、狼疮性肝炎又称自身免疫性肝炎、马吉德综合征(Majeedsyndrome)、显微镜下结肠炎、显微镜下多血管炎、米勒-费舍尔综合征(Miller-Fishersyndrome)、混合结缔组织病、硬斑病、穆哈-赫伯曼病(Mucha-Habermann disease)又称苔藓样糠疹和尖锐湿疹、多发性硬化、重症肌无力、肌炎、美尼尔氏病(Ménière's disease)、发作性睡病、视神经脊髓炎、神经肌强直、隐匿性瘢痕性类天疱疮、眼阵挛肌阵挛综合征、奥德氏甲状腺炎(Ord's thyroiditis)、复发性风湿病、PANDAS(与链球菌相关的儿童自身免疫性神经精神病)、副肿瘤性小脑变性、阵发性夜间血红蛋白尿(PNH)、帕罗二氏综合征(Parry Romberg syndrome)、扁平部炎、帕森那-特纳综合征(Parsonage-Turnersyndrome)、寻常型天疱疮、静脉周围脑脊髓炎、恶性贫血、POEMS综合征、结节性多动脉炎、风湿性多肌痛、多发性肌炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、进行性炎性神经病、纯红细胞再生障碍、坏疽性脓皮病、拉斯穆森氏脑炎(Rasmussen's encephalitis)、雷诺现象(Raynaud phenomenon)、莱特尔氏综合征(莱特尔氏综合征)、复发性多软骨炎、不宁腿综合征、腹膜后纤维化、风湿热、精神分裂症、施密特综合征(Schmidt syndrome)、施尼茨勒综合征(Schnitzler syndrome)、巩膜炎、血清病、舍格伦综合征(
syndrome)、脊椎关节病、僵硬人综合征、斯蒂尔氏病(Still's disease)、亚急性细菌性心内膜炎(SBE)、苏萨克氏综合征(Susac's syndrome)、斯威特氏综合征(Sweet's syndrome)、西登哈姆舞蹈病(Sydenham chorea)、交感性眼炎、高安氏动脉炎(Takayasu's arteritis)、颞动脉炎、血小板减少症、托洛萨-亨特综合征(Tolosa-Hunt syndrome)、横纹肌炎、溃疡性结肠炎、未分化脊柱关节病、荨麻疹性血管炎、白癜风、韦格纳氏肉芽肿病(Wegener'sgranulomatosis)。
V.组合疗法
本文所述的抗TSG-6抗体可以与另外的治疗剂组合使用，以治疗癌症、纤维化或自身免疫性或炎性病症。
可用作治疗癌症的组合疗法的一部分的示例性治疗剂包括，例如，辐射、丝裂霉素、维甲酸、核莫司汀(ribomustin)、吉西他滨、长春新碱、依托泊苷、克拉屈滨、米溴醇、甲氨蝶呤、多柔比星、碳醌、喷司他丁、硝基苯、齐诺他汀、西曲瑞克、来曲唑、雷替曲塞、柔红霉素、法卓唑、福替莫司汀、胸腺法新、索布唑烷、奈达铂、阿糖胞苷、比卡鲁胺、长春瑞滨、维纳里酮、氨基鲁米特、氨嘧啶、醋酸丁内酯、氟哌啶醇酯、氟他胺、屈罗尼、布托辛、卡莫夫、雷佐生(razoxane)、sizofilan、卡铂、米托内酯、替加氟、异环磷酰胺、泼尼莫司汀、哌替巴尼、左旋咪唑、替尼泊苷、丙磺胺、依西他滨、麦角乙脲、羟甲烯龙、甲氧咪唑、甲氧吡酮、干扰素-2α、干扰素-β、干扰素-γ、集落刺激因子-1、集落刺激因子-2、地尼白介素(denileukindiftitox)、白细胞介素-2、促黄体激素释放因子和上述药剂的变体，可能表现出与其同源受体的不同结合，并增加或减少血清半衰期。
在某些方面，作为治疗癌症的组合疗法的一部分，参与免疫应答的一种或多种蛋白质的表达被抑制。充当“抑制剂”的药剂可以直接与蛋白质，例如抗体、抗体-药物缀合物、可溶性蛋白质和融合蛋白结合。在一些实施例中，在组合疗法中使用的抑制剂是例如寡核苷酸、siRNA、miRNA、piRNA和shRNA。在一些实施例中，在组合疗法中使用的抑制剂阻断蛋白酶体功能。在一些实施例中，在组合疗法中使用的抑制剂阻断DNA甲基化。
在本发明中使用的抑制剂是免疫检查点抑制剂。示例性免疫检查点抑制剂包括抑制一种或多种(i)细胞毒性T-淋巴细胞相关抗原4(CTLA4)、(ii)程序性细胞死亡蛋白1(PD1)、(iii)PDL1、(iv)LAG3、(v)B7-H3、(vi)B7-H4和(vii)TIM3，例如伊普利单抗、纳武单抗OPDIVO(Nivolumab)、帕博利珠单抗(Pembrolizumab)、阿维鲁单抗、杜瓦鲁单抗和阿替利珠单抗。另外的示例性免疫检查点抑制剂包含西米普利单抗(cemiplimab)、曲美木单抗(tremelimumab)、德瓦鲁单抗(durvalumab)、斯巴达珠单抗(spartalizumab)、瑞拉利单抗(relatlimab)、IMP321、LAG525、MBG453、MEDI9447和依诺利珠单抗(enoblitzumab)。
可以用作治疗癌症的组合疗法的一部分的又其它药剂是靶向癌症相关成纤维细胞或癌症相关细胞外基质的药剂。这些药剂包含例如：如西罗珠单抗(sibrotuzumab)或FAP疫苗等成纤维细胞活化蛋白α(FAP)阻断抗体、聚乙二醇透明质酸酶α(PEGPH20)、如RG7356/RO5429083等CD44靶向抗体、二甲双胍、如辛妥珠单抗(simtuzumab)等赖氨酰氧化酶抑制剂或阻断抗体、如非苏木单抗(fresolimumab)等TGF-β阻断抗体以及如galunisertib等TGF-β受体抑制剂。
可用作治疗癌症的组合疗法的一部分的其他药剂是靶向非检查点靶标(例如赫赛汀)和非细胞毒性药剂(例如酪氨酸激酶抑制剂)的单克隆抗体药剂。
其他类别的抗癌剂包括，例如：(i)选自ALK抑制剂、ATR抑制剂、A2A拮抗剂、碱基切除修复抑制剂、Bcr Abl酪氨酸激酶抑制剂、布鲁顿酪氨酸激酶抑制剂、CDC7抑制剂、CHK1抑制剂、细胞周期蛋白依赖性激酶抑制剂、DNA-PK抑制剂、DNA-PK和mTOR抑制剂、DNMT1抑制剂、DNMT1抑制剂加2-氯脱氧腺苷、HDAC抑制剂、刺猬信号通路抑制剂、IDO抑制剂，JAK抑制剂、mTOR抑制剂、MEK抑制剂、MELK抑制剂、MTH1抑制剂、PARP抑制剂、磷酸肌醇3-激酶抑制剂、PARP1和DHODH抑制剂、蛋白酶体抑制剂、拓扑异构酶II抑制剂、酪氨酸激酶抑制剂、VEGFR抑制剂和WEE1抑制剂；(ii)OX40、CD137、CD40、GITR、CD27、HVEM、TNFRSF25或ICOS的激动剂；(iii)选自IL-12、IL-15、GM-CSF和G-CSF的细胞因子。
本发明的抗体还可用作从原发病变手术切除癌症的辅助手段。
可以用作用于治疗纤维化的与抗TSG-6抗体的组合疗法的一部分的示例性治疗剂包含例如尼达尼布(nintedanib)、吡非尼酮(pirfenidone)、皮质类固醇、质子泵抑制剂、二甲双胍、如辛妥珠单抗等赖氨酰氧化酶抑制剂或阻断抗体、如非苏木单抗等TGF-β阻断抗体以及如galunisertib等TGF-β受体抑制剂。
可以用作用于治疗自身免疫性或炎性病症、延迟其进展、预防其复发或减轻其症状的与抗TSG-6抗体的组合疗法的一部分的示例性治疗剂包含例如多种已知的抗炎疗法和/或免疫抑制疗法中的任一种。在一些实施例中，抗炎和/或免疫抑制疗法包括但不限于甲氨蝶呤、环孢菌素A(包括例如环孢菌素微乳)、他克莫司、皮质类固醇、他汀类药物、干扰素β、非甾体抗炎药和6-MP(巯基嘌呤，也称为6-巯基嘌呤或嘌呤醇)。
在一些实施例中，用于与抗TSG-6抗体组合的抗炎和/或免疫抑制疗法包含但不限于TOPK抑制剂(例如，OTS964((R)-9-(4-(1-(二甲氨基)丙烷-2-基)苯基)-8-羟基-6-甲基噻吩[2,3-c]喹啉-4(5H)-酮)(肿瘤治疗科学))、酪氨酸激酶抑制剂(例如，阿西替尼(axitinib)、达沙替尼(dasatinib)、伊可替尼(icotinib))、拓扑异构酶抑制剂(例如，拓扑替康(topotecan))、鞘氨醇-1-磷酸受体激动剂(例如，芬戈利莫(fingolimod)、KRP-203)、抗T细胞免疫球蛋白(例如AtGam)、抗IL-2受体抗体(例如达利珠单抗(daclizumab))、酰胺类(CTX)、异环磷酰胺(IFO)、阿霉素(ADM)、柔红霉素(DNR)、长春新碱(VCR)、长春花碱(VBL)、依托泊苷(VP16)、维米尔(Vumon)、卡铂(CBP)、他克莫司(tacrolimus)、西罗莫司(sirolimus)、依维莫司(everolimus)、硫唑嘌呤、布喹那(brequinar)、来氟米特(leflunomide)、LEA-29Y、抗CD3抗体(例如OKT3)、阿司匹林(aspirin)、B7-CD28阻断分子(例如贝拉西普(belatacept)、阿巴西普(abatacept))、CD40-CD154阻断分子(抗CD40抗体)、醋氨酚、布洛芬(ibuprofen)、萘普生(naproxen)、吡罗昔康(piroxicam)和抗炎类固醇(例如泼尼松龙(prednisolone)或地塞米松(dexamethasone))。
在一些实施例中，用于与抗TSG-6抗体组合的抗炎和/或免疫抑制疗法包含例如通过施用TNF-α、CFA、白介素-1(IL-1)、蛋白酶体抑制剂、NFκB抑制剂、抗炎药、组织纤溶酶原激活剂(TPA)、脂多糖、UV光和TNF-α信号传导途径的细胞内介质来消融自身免疫细胞。此类药剂通过阻断TNF-α受体信号传导下游的途径或在TNF-α受体结合的下游起作用，从而诱导自身反应性淋巴细胞的凋亡。(Baldwin等人,《免疫学年鉴(Ann.Rev.Immunol.)》(1996)12:141；Baltimore,《细胞(Cell)》(1996)87:13)。
可以用作用于治疗特发性肺动脉高压的与抗TSG-6抗体的组合疗法的一部分的示例性治疗剂包含例如钙通道阻断剂、血管扩张剂、前列环素途径激动剂、内皮素受体拮抗剂、一氧化氮(NO)-cGMP增强剂、血液稀释剂、利尿剂、地高辛、抗凝疗法和手术。
可以用作用于治疗特发性肺动脉高压的与抗TSG-6抗体的组合疗法的一部分的示例性治疗剂还可以包含用以下治疗潜在的纤维化：例如，尼达尼布、吡非尼酮、皮质类固醇、质子泵抑制剂、二甲双胍、如辛妥珠单抗等赖氨酰氧化酶抑制剂或阻断抗体、如非苏木单抗等TGF-β阻断抗体以及如galunisertib等TGF-β受体抑制剂。
在一些实施例中，与抗TSG-6抗体组合的抗炎和/或免疫抑制疗法包含但不限于短效β2-激动剂、长效β2-激动剂、抗胆碱能药、皮质类固醇、全身性皮质类固醇、肥大细胞稳定剂、白三烯调节剂、甲基黄嘌呤、β2激动剂、沙丁胺醇、左旋沙丁胺醇、吡布特罗(pirbuterol)、阿特福莫特罗(artformoterol)、福莫特罗(formoterol)、沙美特罗(salmeterol)、包含异丙托溴铵和噻托溴铵的抗胆碱能药；皮质类固醇，包含倍氯米松(beclomethasone)、布地奈德(budesonide)、氟尼缩松(flunisolide)、氟替卡松(fluticasone)、莫米松(mometasone)、曲安西龙(triamcinolone)、甲泼尼龙(methyprednisolone)、泼尼松龙(methyprednisolone)、泼尼松(prednisone)；白三烯调节剂，包含孟鲁司特(montelukast)、扎鲁司特(zafirlukast)和齐留通(zileuton)；肥大细胞稳定剂，包含色甘酸和奈多罗米(nedocromil)；甲基黄嘌呤，包含茶碱；组合药物，包含异丙托溴铵和沙丁胺醇、氟替卡松和沙美特罗、布地奈德和福莫特罗；抗组胺药，包含羟嗪、苯海拉明、氯雷他定、西替利嗪和氢化可的松；免疫系统调节药物，包含他克莫司和吡美莫司；环孢菌素；硫唑嘌呤；吗替麦考酚酯；及其组合。
可以选择抗体和另外的治疗剂的量以及相对的给药时间，以获得期望的联合治疗效果。例如，当对需要这种施用的患者施用组合疗法时，组合中的治疗剂或包括治疗剂的药物组合物或组合物可以以任何顺序施用，例如顺序、同时施用，一起，同时等等。此外，例如，多特异性结合蛋白可以在另外的治疗剂发挥其预防或治疗作用的时间期间给药，反之亦然。
VI.药物组合物和给药
本公开的特征还在于包含治疗有效量的本文所述的抗TSG-6抗体的药物组合物/调配物。该组合物可以配制用于多种药物递送系统。一种或多种生理学上可接受的赋形剂或载体也可以包含在组合物中以用于适当的调配物。在《雷明登氏药学全书》,麦克出版公司,宾夕法尼亚州费城,第17版,1985中可以找到用于本公开的合适的调配物。此外，药物递送的方法的简要评述参见Langer，《科学(Science)》249:1527-1533(1990)，其以引入的方式并入本文中。
本公开的抗体可以存在于冻干调配物或液体水性药物调配物中。本文有关的水性载体是一种药学上可接受的(对人体给药安全且无毒)并且可用于制备液体调配物。示例性载体包括无菌注射用水(SWFI)、抑菌注射用水(BWFI)、pH缓冲溶液(例如磷酸盐缓冲盐水)、无菌盐水溶液、林格氏溶液或葡萄糖溶液。
本公开的抗体可以存在于包含蛋白质和冻干保护剂的冻干调配物中。冻干保护剂可以是糖，例如二糖。在某些实施例中，冻干保护剂是蔗糖或麦芽糖。冻干调配物还可以包含缓冲剂、表面活性剂、填充剂和/或防腐剂中的一种或多种。
本发明的药物组合物中活性成分的实际剂量水平可以变化，以获得有效实现特定患者、组合物和给药方式的所需治疗反应的活性成分的量，而不对患者有毒。对于成人，其可以以0.1mg至1g的范围并且优选地在0.5mg至500mg的活性抗体的范围内每次施用来施用。或者，可以根据患者的大致体重或表面积调整患者的剂量。确定合适剂量的其他因素可包括待治疗或预防的疾病或病症、疾病的严重程度、给药途径以及患者的年龄、性别和医学病症。本领域技术人员通常根据本文公开的剂量信息和测定对确定适当治疗剂量所需的计算进行进一步细化。剂量也可以通过使用已知的测定结合适当的剂量反应数据来确定剂量来确定。当监测疾病的进展时，可以调整个体患者的剂量。可以测量患者体内可靶向构建体或复合物的血液水平，以确定是否需要调整剂量以达到或维持有效浓度。药物基因组学可用于确定哪些可靶向构建体和/或复合物及其剂量最有可能对特定个体有效(Schmitz等人,Clinica Chimica Acta308：43-53，2001；Steimer等人,《临床化学学报》308:33-41,2001)。
剂量可以每天、每周、每月或每年给药一次或多次，甚至每2至20年给药一次。本领域普通技术人员可以基于测量的停留时间和可靶向构建体或复合物在体液或组织中的浓度容易地估计给药的重复率。本发明的给药可以是静脉内、动脉内、腹膜内、肌肉内、皮下、胸膜内、鞘内、腔内、通过导管灌注或通过直接病灶内注射。这可以每天给药一次或多次、每周一次或多次、每月一次或多次、以及每年一次或多次。
实例
现在对本发明进行一般性描述，通过参考以下实施例将更容易理解，包括这些实施例仅用于说明本发明的某些方面和实施例，并不旨在限制本发明。
实例1——TSG-6抗体的产生
使用常规小鼠单克隆抗体技术产生针对小鼠TSG-6蛋白(mTSG-6)的小鼠抗体。简言之，用KLH偶联的重组小鼠TSG-6(R&D生物系统公司(R&D Biosystems)，目录#2326-TS)接种小鼠(SJL/J品系)。增强后，通过ELISA确定抗体滴度，使用非相关His6标记的蛋白作为对照。处死选择用于融合的小鼠，并使用P3X63Ag8.653鼠骨髓瘤细胞系作为融合伴侣执行杂交瘤融合。通过有限稀释分离克隆，并通过杂交瘤上清液的ELISA进行选择。使用重组人TSG-6(R&D生物系统公司，目录#2104-TS)作为ELISA测定的底物，因此促进人和小鼠交叉反应性克隆的选择(两种蛋白质在氨基酸水平上92％相同)。杂交瘤mRNA被转录成cDNA，并通过cDNA末端的5'快速扩增(RACE)进行扩增。PCR产物被克隆到适当的测序载体中，并通过双脱氧桑格方法进行测序。对多个拷贝进行测序以验证每个克隆的克隆性。将经翻译的蛋白质序列输入到NCBI IgBLAST搜索工具(Ye,J.等人,2013,《核酸研究》41,W34-40)中以鉴定CDR。
实例2——抗TSG-6抗体对与TSG-6结合的HA的抑制
重组人TSG-6以100ng/孔固定在96孔聚苯乙烯微量滴定板(MaxiSorp，Nunc)上。将孔用1％BSA的PBS溶液封闭。在存在各种浓度的抗TSG-6抗体的情况下，将孔用1μg/mL的透明质酸-生物素(西格玛公司(Sigma)，B1557)温育。用TBST洗涤板后，用亲和素-HRP(e-Biosciences公司，18-4100-51)检测与TSG-6结合的生物素，并用TMB ELISA底物溶液(e-Biosciences公司，00-4201-56)显色。用1M H3PO4停止显色，并在SpectraMax M5板读取器(分子装置公司(Molecular Devices))上读取板。(图1)使用4参数逻辑模型(XLfit，IDBS)确定IC50值。
实例3——抗TSG-6抗体对TSG-6HC-HA转酯酶活性的抑制
将重组人TSG-6(1nM/PBS)在存在1％人血浆(作为IαI的来源)、5mM MgCl2、1μg/mLHA和各种浓度的抗TSG-6抗体的情况下在37℃下温育1-2小时。使用EDTA(10mM)作为对照，以100％抑制金属离子依赖性转酯酶活性。然后将这些培养物以100ng/孔加载到预先涂有牛软骨透明质酸结合蛋白(密理博公司(Millipore)，385910)的96孔聚苯乙烯微量滴定板(MaxiSorp公司，Nunc)上，并用1％BSA的PBS溶液封闭。在室温下温育1小时后，用PBST冲洗板，然后用抗HC(ITIH1)抗体(亚诺法公司(Abnova)，H00003697)和随后的HRP连接的抗兔抗体(GE生命科学公司(GE Life Sciences)，NA934)检测HC-HA。用TMB ELISA底物溶液(e-Biosciences公司，00-4201-56)显色，并用1M H3PO4停止显色。在SpectraMax M5板读取器(分子装置)上读取板，并使用4参数逻辑模型(XLfit，IDBS)确定IC50值。(图2)
实例4——抗TSG-6抗体药效动力学测定的演示
C57Bl/6小鼠(每组n＝3)在治疗前1天不接种或接种B16F0黑色素瘤细胞(1×106)。以1mg固定剂量腹腔内注射PBS(媒剂)或抗TSG-6抗体3C6进行治疗。给药十天后，收集血清样品并用PBS以1:10稀释。然后将这些样品以100ng/孔加载到预先涂有牛软骨透明质酸结合蛋白(密理博公司(Millipore)，385910)的96孔聚苯乙烯微量滴定板(MaxiSorp公司，Nunc)上，并用1％BSA的PBS溶液封闭。在室温下温育1小时后，用PBST冲洗板，然后用抗HC(ITIH1)抗体(亚诺法公司(Abnova)，H00003697)和随后的HRP连接的抗兔抗体(GE生命科学公司(GE Life Sciences)，NA934)检测HC-HA。用TMB ELISA底物溶液(e-Biosciences公司，00-4201-56)显色，并用1M H3PO4停止显色。(图3)(由于技术错误，从未接种的未处理组和未接种的处理组中的每一个中去除一个重复；这些异常值来自板布局上的邻近孔)。
实例5——抗TSG-6抗体3C6在由与CAF共注射的B16F0黑色素瘤细胞产生的肿瘤中的抗肿瘤活性
通过分解肿瘤，随后用磁性分选法(Miltenyi Biotec)分选对上皮标志物、内皮标志物和白细胞标志物呈阴性的细胞和对PDGFRα呈阳性的细胞，从常规生长的B16F0肿瘤(接种106个细胞，在约1500mm3下切除)中分离CAF。然后将这些CAF与B16F0黑色素瘤细胞(1000B16F0：1000CAF细胞)共注射到初始雌性C57Bl/6小鼠中。在细胞接种时(第0天)开始治疗。每7天(每组n＝8)使用PBS(媒剂对照)或抗TSG-6抗体3C6(1mg固定剂量)进行治疗(图4A-4C)。个体肿瘤生长曲线在右侧示出。
实例6——抗TSG-6抗体3C6的抗肿瘤活性和其与抗PD-1的组合活性
小鼠(C57Bl/6，雌性，每组n＝8)在治疗前六天接种B16F0黑色素瘤细胞。将小鼠用作为阴性对照的大鼠IgG2a(与抗PD-1抗体同种型相同)、抗小鼠PD-1(CD279)RMP1-14(BioXcell)(150μg第0天、第3天、第6天、第10天)、抗TSG-6抗体3C6(1mg第0天、第7天)或其组合进行治疗。个体肿瘤生长曲线在右侧示出。使用抗IL2捕获抗体(R&D系统MAB602)通过ELISA测量上清液中的IL-2(图5A-5E)。
通过引用结合
在此提及的每篇专利文件和科学文章的全部公开内容均以引用方式并入用于所有目的。
等同物
在不脱离本发明的精神或基本特征的情况下，本公开可以以其它特定形式来体现。因此，前述实施例在所有方面都应被认为是说明性的，而不是对本文所述的发明的限制。因此，本发明的范围由所附权利要求而不是前述描述来指示，并且在权利要求的含义和等效范围内的所有变化都旨在包含在其中。
序列表
<110> 多伦多综合医院（University Health Network）
Brokx, Richard
Mason, Jacqueline M.
Bray, Mark R.
<120> TSG-6抗体和其用途
<130> 011506-5023
<150> US 62/817,152
<151> 2019-03-12
<160> 104
<170> PatentIn版本3.5
<210> 1
<211> 262
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 1
Met Glu Arg His Trp Ile Phe Leu Ser Leu Leu Ser Val Ile Ala Gly
1 5 10 15
Val His Ser Gln Val Arg Leu Gln Gln Ser Gly Ala Glu Leu Ala Lys
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Ile Ile Pro Ser Ser Gly Tyr Thr Lys Asn Lys
65 70 75 80
Gln Asn Phe Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Ser Asn Leu Thr Tyr Glu Asp Ser Ala Val
100 105 110
Tyr Ser Cys Ala Arg Ser Asp Gly Ser Tyr Pro Tyr Tyr Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro
130 135 140
Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser
145 150 155 160
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
195 200 205
Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala
210 215 220
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp
225 230 235 240
Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
245 250 255
Phe Ile Phe Pro Pro Lys
260
<210> 2
<211> 225
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 2
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Glu Asn Val Leu Thr Gln Ser Pro Ala Ile
20 25 30
Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys Ser Ser Thr Ser
50 55 60
Pro Lys Leu Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro
65 70 75 80
Gly Arg Phe Ser Gly Ser Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile
85 90 95
Ser Ser Met Glu Ala Glu Asp Val Ala Thr Tyr Tyr Cys Phe Gln Gly
100 105 110
Ser Gly Tyr Pro Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
130 135 140
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
165 170 175
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
195 200 205
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
210 215 220
Pro
225
<210> 3
<211> 287
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 3
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Asp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Trp Ile Tyr Pro Arg Asp Gly Ser Thr Lys Tyr Asn
65 70 75 80
Glu Lys Phe Lys Asp Lys Ala Thr Trp Thr Ile Asp Thr Ser Ser Asn
85 90 95
Arg Ala Tyr Met Glu Ile His Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Phe Cys Ala Arg Gly Leu Trp Tyr Tyr Val Ser Gly Met Asp Tyr
115 120 125
Trp Gly Pro Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro
130 135 140
Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser
145 150 155 160
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
195 200 205
Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala
210 215 220
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp
225 230 235 240
Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
245 250 255
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
260 265 270
Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Gln
275 280 285
<210> 4
<211> 228
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 4
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala
1 5 10 15
Ser Ser Ser Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val
20 25 30
Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu
35 40 45
Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro
50 55 60
Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Arg Gly Ser Gly Ile Asp Phe Thr
85 90 95
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys
100 105 110
Ser Gln Ser Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro
130 135 140
Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly
165 170 175
Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp
195 200 205
Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr
210 215 220
Ser Thr Ser Pro
225
<210> 5
<211> 287
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 5
Met Glu Arg His Trp Ile Phe Leu Ser Leu Leu Ser Val Ile Ala Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Lys
20 25 30
Pro Gly Ala Ser Val Arg Leu Ser Cys Gln Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Trp Met His Trp Val Lys Gln Arg Pro Arg Gln Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Ile Ile Pro Ser Ser Gly Tyr Thr Lys Cys His
65 70 75 80
Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Tyr Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Thr Ser Gly Tyr Pro Tyr Tyr Phe Asp Ser
115 120 125
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro
130 135 140
Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser
145 150 155 160
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
195 200 205
Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala
210 215 220
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp
225 230 235 240
Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
245 250 255
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
260 265 270
Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Gln
275 280 285
<210> 6
<211> 225
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 6
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Glu Asn Val Leu Thr Gln Ser Pro Ala Ile
20 25 30
Met Ser Ala Ser Pro Gly Glu Arg Val Thr Met Thr Cys Ser Ala Thr
35 40 45
Ser Ser Val Ser Phe Met His Trp Tyr Gln Gln Lys Ser Ser Thr Ser
50 55 60
Pro Lys Leu Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro
65 70 75 80
Gly Arg Phe Ser Gly Ser Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile
85 90 95
Ser Ser Met Glu Ala Glu Asp Val Ala Thr Tyr Tyr Cys Phe Gln Gly
100 105 110
Ser Trp Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
115 120 125
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
130 135 140
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
165 170 175
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
195 200 205
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
210 215 220
Pro
225
<210> 7
<211> 287
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 7
Met Glu Arg His Trp Ile Phe Leu Ser Leu Leu Ser Val Ile Ala Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Lys
20 25 30
Pro Gly Ala Ser Val Arg Leu Ser Cys Gln Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Thr Tyr Trp Met His Trp Val Lys Gln Arg Pro Arg Gln Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Ile Ile Pro Ser Ser Gly Tyr Ser Lys Cys His
65 70 75 80
Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn
85 90 95
Thr Ala Ser Met Gln Leu Ser Ser Leu Thr Tyr Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Thr Ser Gly Tyr Pro Tyr Tyr Phe Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro
130 135 140
Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser
145 150 155 160
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
195 200 205
Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala
210 215 220
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp
225 230 235 240
Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
245 250 255
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
260 265 270
Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Gln
275 280 285
<210> 8
<211> 225
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 8
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Glu Asn Val Leu Thr Gln Ser Pro Ala Ile
20 25 30
Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Thr
35 40 45
Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys Ser Ser Thr Ser
50 55 60
Pro Lys Leu Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro
65 70 75 80
Gly Arg Phe Ser Gly Ser Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile
85 90 95
Ser Ser Met Glu Ala Glu Asp Val Ala Thr Tyr Tyr Cys Phe Gln Gly
100 105 110
Ser Trp Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
115 120 125
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
130 135 140
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
165 170 175
Gln Asp Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
195 200 205
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
210 215 220
Pro
225
<210> 9
<211> 285
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 9
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Tyr Asn
65 70 75 80
Glu Lys Phe Lys Asn Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Pro Arg Met Phe Asp Asp Tyr Asp Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser
130 135 140
Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val
145 150 155 160
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro
195 200 205
Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro
210 215 220
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly
225 230 235 240
Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile
245 250 255
Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys
260 265 270
Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Gln
275 280 285
<210> 10
<211> 226
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 10
Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser Val
1 5 10 15
Ile Met Ser Arg Gly Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met
20 25 30
Ser Ala Ser Leu Gly Glu Arg Val Thr Met Thr Cys Thr Ala Ser Ser
35 40 45
Ser Val Ser Ser Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Ser
50 55 60
Ser Pro Lys Leu Trp Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val
65 70 75 80
Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr
85 90 95
Ile Ser Arg Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His His
100 105 110
Tyr His Arg Ser Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
115 120 125
Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser
130 135 140
Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu
165 170 175
Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr
195 200 205
Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr
210 215 220
Ser Pro
225
<210> 11
<211> 286
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 11
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Tyr Met Asn Trp Val Lys Gln Ser His Glu Lys Ser Leu
50 55 60
Glu Trp Ile Gly Asp Ile Asn Pro Asn Asn Gly Gly Thr Ser Tyr Asn
65 70 75 80
Gln Lys Phe Met Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Arg
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Thr Val
100 105 110
Tyr Tyr Cys Ala Arg Trp Gly Ile Tyr Asp Arg Phe Thr Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Ser Val Ser Ala Ala Lys Thr Thr Pro Pro Ser
130 135 140
Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val
145 150 155 160
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro
195 200 205
Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro
210 215 220
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly
225 230 235 240
Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile
245 250 255
Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys
260 265 270
Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Gln Gly
275 280 285
<210> 12
<211> 226
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 12
Met Asp Met Arg Thr Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ile Lys Cys Asp Ile Lys Met Thr Gln Ser Pro Ser Ser
20 25 30
Met Tyr Ala Ser Leu Gly Glu Arg Val Thr Ile Ala Cys Lys Ala Ser
35 40 45
Gln Asp Ile Asn Ser Phe Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys
50 55 60
Ser Pro Lys Thr Leu Ile Tyr Arg Ala Asn Arg Leu Val Asp Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr
85 90 95
Ile Ser Ser Leu Glu Tyr Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln
100 105 110
Tyr Asp Glu Phe Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
115 120 125
Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser
130 135 140
Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu
165 170 175
Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr
195 200 205
Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr
210 215 220
Ser Pro
225
<210> 13
<211> 287
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 13
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Asp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Trp Ile Tyr Pro Ser Asp Gly Ser Thr Lys Phe Asn
65 70 75 80
Glu Lys Phe Lys Gly Met Ala Thr Leu Thr Val Asp Thr Ser Ser Ser
85 90 95
Thr Ala Tyr Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Thr Val
100 105 110
Tyr Phe Cys Ala Arg Gly Leu Trp Tyr Tyr Gly Gly Gly Val Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro
130 135 140
Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser
145 150 155 160
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
195 200 205
Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala
210 215 220
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp
225 230 235 240
Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
245 250 255
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
260 265 270
Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Gln
275 280 285
<210> 14
<211> 228
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 14
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala
1 5 10 15
Ser Ser Ser Asp Ala Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val
20 25 30
Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Thr Gln Ser Leu
35 40 45
Glu Asp Ser Asn Gly Asn Thr Tyr Leu Asn Trp Tyr Leu Gln Lys Pro
50 55 60
Gly Gln Ser Pro Gln Leu Leu Ile Tyr Arg Val Ser Asn Arg Phe Ser
65 70 75 80
Gly Val Leu Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys
100 105 110
Leu Gln Val Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro
130 135 140
Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly
165 170 175
Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp
195 200 205
Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr
210 215 220
Ser Thr Ser Pro
225
<210> 15
<211> 285
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 15
Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu
50 55 60
Glu Trp Ile Gly Asp Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Trp Gly Ile Phe Asp Arg Phe Thr Tyr Trp Gly
115 120 125
Gln Gly Thr Val Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro Ser
130 135 140
Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val
145 150 155 160
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro
195 200 205
Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro
210 215 220
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly
225 230 235 240
Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile
245 250 255
Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys
260 265 270
Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Gln
275 280 285
<210> 16
<211> 225
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 16
Met Asp Met Arg Thr Pro Ala Gln Phe Leu Gly Ile Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ile Lys Cys Asp Ile Lys Met Thr Gln Ser Pro Ser Ser
20 25 30
Met Tyr Ala Ser Arg Gly Glu Arg Val Thr Ile Thr Cys Lys Ala Ser
35 40 45
Gln Asp Ile Asn Ser Phe Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys
50 55 60
Ser Pro Lys Thr Leu Ile Tyr Arg Ala Asn Arg Leu Val Asp Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr
85 90 95
Ile Ser Ser Leu Glu Tyr Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln
100 105 110
Tyr Asp Glu Phe Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
115 120 125
Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser
130 135 140
Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu
165 170 175
Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr
195 200 205
Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr
210 215 220
Lys
225
<210> 17
<211> 259
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 17
Met Gly Trp Ser Trp Ile Phe Leu Leu Ser Leu Pro Gly Thr Ala Gly
1 5 10 15
Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Ile Pro Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Asn Met Asp Trp Val Lys Gln Ser His Gly Glu Ser Leu
50 55 60
Glu Trp Ile Gly Asp Ile Tyr Pro Asn Asn Gly Gly Thr Ile Tyr Asn
65 70 75 80
Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Asn Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Lys Thr Gly Thr Gly Phe Asp Tyr Trp Gly Gln
115 120 125
Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val
130 135 140
Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr
145 150 155 160
Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr
165 170 175
Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val
180 185 190
Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser
195 200 205
Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala
210 215 220
Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys
225 230 235 240
Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe
245 250 255
Pro Pro Lys
<210> 18
<211> 225
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 18
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Arg
35 40 45
Ser Ser Val Ile Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Phe Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
115 120 125
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
130 135 140
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
165 170 175
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
195 200 205
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
210 215 220
Pro
225
<210> 19
<211> 256
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 19
Met Gly Trp Ser Tyr Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Gln Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Met Ile His Pro Asn Ser Gly Ser Thr Asn Asn Asn
65 70 75 80
Glu Lys Phe Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Thr Arg Trp Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
115 120 125
Val Thr Ala Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu
130 135 140
Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys
145 150 155 160
Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser
165 170 175
Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
180 185 190
Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp
195 200 205
Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr
210 215 220
Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys
225 230 235 240
Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys
245 250 255
<210> 20
<211> 228
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 20
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala
1 5 10 15
Ser Ser Thr Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val
20 25 30
Ser Leu Gly Asp Leu Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu
35 40 45
Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro
50 55 60
Gly Gln Ser Pro Lys Leu Leu Ile Phe Lys Val Ser Asn Arg Phe Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys
100 105 110
Ser Gln Ser Thr His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro
130 135 140
Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly
165 170 175
Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp
195 200 205
Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr
210 215 220
Ser Thr Ser Pro
225
<210> 21
<211> 291
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 21
Met Lys Leu Trp Leu Asn Trp Ile Phe Leu Val Thr Leu Leu Asn Gly
1 5 10 15
Ile Gln Cys Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Thr Asp Tyr Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Ala Leu
50 55 60
Glu Trp Leu Gly Phe Ile Arg His Lys Ala Lys Gly Tyr Thr Ala Glu
65 70 75 80
Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
85 90 95
Gln Ser Ile Leu Tyr Leu Gln Met Asn Ala Leu Arg Ala Glu Asp Ser
100 105 110
Ala Thr Tyr Tyr Cys Ala Arg Leu Tyr Tyr Tyr Gly Ser Pro His Trp
115 120 125
Tyr Phe Asp Val Trp Gly Thr Gly Thr Thr Val Thr Val Ser Ser Ala
130 135 140
Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala
145 150 155 160
Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe
165 170 175
Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly
180 185 190
Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser
195 200 205
Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr
210 215 220
Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile
225 230 235 240
Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu
245 250 255
Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr
260 265 270
Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys
275 280 285
Asp Asp Gln
290
<210> 22
<211> 225
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 22
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Ile Ser Arg Gly Gln Ile Val Leu Thr Gln Ser Pro Ala Ile
20 25 30
Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser
35 40 45
Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys Ser Gly Thr Ser
50 55 60
Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
85 90 95
Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asn Pro Pro Thr Phe Gly Ser Gly Thr Glu Leu Glu Ile Lys
115 120 125
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
130 135 140
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
165 170 175
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
195 200 205
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
210 215 220
Pro
225
<210> 23
<211> 299
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 23
Met Gly Trp Ser Cys Ile Met Leu Phe Leu Ala Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Ala Ser Asp Tyr Thr Phe
35 40 45
Thr Asn Tyr Trp Met His Trp Val Lys Gln Arg Pro Gly Arg Gly Leu
50 55 60
Glu Trp Ile Gly Arg Ile Asp Pro Ser Ser Gly Gly Ala Lys Tyr Asn
65 70 75 80
Glu Lys Phe Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Pro Ser Ser
85 90 95
Thr Ala Tyr Met Glu Phe Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Val Arg Ser Arg Tyr Asp Tyr Asp Gly Trp Phe Ala Tyr
115 120 125
Trp Gly Leu Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro
130 135 140
Pro Ser Val Tyr Pro Leu Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser
145 150 155 160
Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Ser Val
165 170 175
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Ser Val His Thr Phe
180 185 190
Pro Ala Leu Leu Gln Ser Gly Leu Tyr Thr Met Ser Ser Ser Val Thr
195 200 205
Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Ser Val Ala
210 215 220
His Pro Ala Ser Ser Thr Thr Val Asp Lys Lys Leu Glu Pro Ser Gly
225 230 235 240
Pro Ile Ser Thr Ile Asn Pro Cys Pro Pro Cys Lys Glu Cys His Lys
245 250 255
Cys Pro Ala Pro Asn Leu Glu Gly Gly Pro Ser Val Phe Ile Phe Pro
260 265 270
Pro Asn Ile Lys Asp Val Leu Met Ile Ser Leu Thr Pro Lys Val Thr
275 280 285
Cys Val Val Val Asp Val Ser Glu Asp Asp Gln
290 295
<210> 24
<211> 229
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 24
Met Arg Cys Leu Ala Glu Phe Leu Gly Leu Leu Val Leu Trp Ile Pro
1 5 10 15
Gly Ala Ile Gly Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro
20 25 30
Val Thr Pro Gly Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser
35 40 45
Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg
50 55 60
Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala
65 70 75 80
Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe
85 90 95
Thr Leu Arg Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr
100 105 110
Cys Met Gln His Leu Glu Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys
115 120 125
Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro
130 135 140
Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe
145 150 155 160
Leu Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp
165 170 175
Gly Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp
180 185 190
Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys
195 200 205
Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys
210 215 220
Thr Ser Thr Ser Pro
225
<210> 25
<211> 285
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 25
Met Glu Trp Ile Trp Ile Phe Leu Phe Ile Leu Ser Gly Thr Ala Gly
1 5 10 15
Val Gln Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Lys Ala Ser Asp Asp Thr Phe
35 40 45
Ile Asn Tyr Gly Ile Asn Trp Val Lys Gln Arg Thr Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Glu Thr Phe Pro Ser Asn Gly Asn Thr Phe Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Ser
85 90 95
Thr Thr Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ala Ala Val
100 105 110
Tyr Phe Cys Ala Arg His Ser Asn Leu Pro Tyr Phe Asp His Trp Gly
115 120 125
Gln Gly Ser Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser
130 135 140
Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val
145 150 155 160
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro
195 200 205
Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro
210 215 220
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly
225 230 235 240
Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile
245 250 255
Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys
260 265 270
Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Gln
275 280 285
<210> 26
<211> 230
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 26
Met Glu Ser Gln Thr Gln Val Leu Ile Ser Leu Leu Phe Trp Val Ser
1 5 10 15
Gly Thr Cys Gly Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Val Ser Ala Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser
35 40 45
Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln
50 55 60
Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg
65 70 75 80
Glu Ser Gly Val Pro Glu Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr
100 105 110
Tyr Cys Gln Asn Asp His Ser Tyr Pro Phe Thr Phe Gly Gly Gly Thr
115 120 125
Asn Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe
130 135 140
Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys
145 150 155 160
Phe Leu Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile
165 170 175
Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln
180 185 190
Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr
195 200 205
Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His
210 215 220
Lys Thr Ser Thr Ser Pro
225 230
<210> 27
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 27
Gly Tyr Thr Phe Thr Ser Tyr Trp
1 5
<210> 28
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 28
Ile Ile Pro Ser Ser Gly Tyr Thr
1 5
<210> 29
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 29
Ala Arg Ser Asp Gly Ser Tyr Pro Tyr Tyr Phe Asp Tyr
1 5 10
<210> 30
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 30
Ser Ser Val Ser Tyr
1 5
<210> 31
<400> 31
000
<210> 32
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 32
Phe Gln Gly Ser Gly Tyr Pro Leu Thr
1 5
<210> 33
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 33
Gly Tyr Thr Phe Thr Ser Tyr Asp
1 5
<210> 34
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 34
Ile Tyr Pro Arg Asp Gly Ser Thr
1 5
<210> 35
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 35
Ala Arg Gly Leu Trp Tyr Tyr Val Ser Gly Met Asp Tyr
1 5 10
<210> 36
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 36
Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr
1 5 10
<210> 37
<400> 37
000
<210> 38
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 38
Gln Ser Thr His Val Pro Pro Thr
1 5
<210> 39
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 39
Gly Tyr Thr Phe Thr Ser Tyr Trp
1 5
<210> 40
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 40
Ile Ile Pro Ser Ser Gly Tyr Thr
1 5
<210> 41
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 41
Ala Arg Ser Thr Ser Gly Tyr Pro Tyr Tyr Phe Asp Ser
1 5 10
<210> 42
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 42
Ser Ser Val Ser Phe
1 5
<210> 43
<400> 43
000
<210> 44
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 44
Phe Gln Gly Ser Trp Tyr Pro Leu Thr
1 5
<210> 45
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 45
Gly Tyr Thr Phe Thr Thr Tyr Trp
1 5
<210> 46
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 46
Ile Ile Pro Ser Ser Gly Tyr Ser
1 5
<210> 47
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 47
Ala Arg Ser Thr Ser Gly Tyr Pro Tyr Tyr Phe Asp
1 5 10
<210> 48
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 48
Ser Ser Val Ser Tyr
1 5
<210> 49
<400> 49
000
<210> 50
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 50
Phe Gln Gly Ser Trp Tyr Pro Leu Thr
1 5
<210> 51
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 51
Gly Tyr Thr Phe Thr Ser Tyr Trp
1 5
<210> 52
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 52
Ile His Pro Asn Ser Gly Ser Thr
1 5
<210> 53
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 53
Ala Pro Arg Met Phe Asp Asp Tyr Asp Asp Tyr
1 5 10
<210> 54
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 54
Ser Ser Val Ser Ser Ser Tyr
1 5
<210> 55
<400> 55
000
<210> 56
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 56
His His Tyr His Arg Ser Pro Tyr Thr
1 5
<210> 57
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 57
Gly Tyr Thr Phe Thr Asp Tyr Tyr
1 5
<210> 58
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 58
Ile Asn Pro Asn Asn Gly Gly Thr
1 5
<210> 59
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 59
Ala Arg Trp Gly Ile Tyr Asp Arg Phe Thr Tyr
1 5 10
<210> 60
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 60
Gln Asp Ile Asn Ser Phe
1 5
<210> 61
<400> 61
000
<210> 62
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 62
Leu Gln Tyr Asp Glu Phe Pro Leu Thr
1 5
<210> 63
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 63
Gly Tyr Thr Phe Thr Ser Tyr Asp
1 5
<210> 64
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 64
Ile Tyr Pro Ser Asp Gly Ser Thr
1 5
<210> 65
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 65
Ala Arg Gly Leu Trp Tyr Tyr Gly Gly Gly Val Asp Tyr
1 5 10
<210> 66
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 66
Gln Ser Leu Glu Asp Ser Asn Gly Asn Thr Tyr
1 5 10
<210> 67
<400> 67
000
<210> 68
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 68
Leu Gln Val Thr His Val Pro Tyr Thr
1 5
<210> 69
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 69
Gly Tyr Thr Phe Thr Asp Tyr Tyr
1 5
<210> 70
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 70
Ile Asn Pro Asn Asn Gly Gly Thr
1 5
<210> 71
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 71
Ala Arg Trp Gly Ile Phe Asp Arg Phe Thr Tyr
1 5 10
<210> 72
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 72
Gln Asp Ile Asn Ser Phe
1 5
<210> 73
<400> 73
000
<210> 74
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 74
Leu Gln Tyr Asp Glu Phe Pro Leu Thr
1 5
<210> 75
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 75
Gly Tyr Thr Phe Thr Asp Tyr Asn
1 5
<210> 76
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 76
Ile Tyr Pro Asn Asn Gly Gly Thr
1 5
<210> 77
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 77
Ala Arg Lys Thr Gly Thr Gly Phe Asp Tyr
1 5 10
<210> 78
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 78
Ser Val Ile Tyr
1
<210> 79
<400> 79
000
<210> 80
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 80
Gln Gln Trp Ser Ser Asn Pro Pro Thr
1 5
<210> 81
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 81
Gly Tyr Thr Phe Thr Ser Gln Trp
1 5
<210> 82
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 82
Ile His Pro Asn Ser Gly Ser Thr
1 5
<210> 83
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 83
Thr Arg Trp Ala Met Asp Tyr
1 5
<210> 84
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 84
Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr
1 5 10
<210> 85
<400> 85
000
<210> 86
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 86
Ser Gln Ser Thr His Val Pro Trp Thr
1 5
<210> 87
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 87
Gly Phe Thr Phe Thr Asp Tyr Tyr
1 5
<210> 88
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 88
Ile Arg His Lys Ala Lys Gly Tyr Thr Ala
1 5 10
<210> 89
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 89
Ala Arg Leu Tyr Tyr Tyr Gly Ser Pro His Trp Tyr Phe Asp Val
1 5 10 15
<210> 90
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 90
Ser Ser Val Ser Tyr
1 5
<210> 91
<400> 91
000
<210> 92
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 92
Gln Gln Trp Ser Ser Asn Pro Pro Thr
1 5
<210> 93
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 93
Asp Tyr Thr Phe Thr Asn Tyr Trp
1 5
<210> 94
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 94
Ile Asp Pro Ser Ser Gly Gly Ala
1 5
<210> 95
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 95
Val Arg Ser Arg Tyr Asp Tyr Asp Gly Trp Phe Ala Tyr
1 5 10
<210> 96
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 96
Lys Ser Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Tyr
1 5 10
<210> 97
<400> 97
000
<210> 98
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 98
Met Gln His Leu Glu Tyr Pro Phe Thr
1 5
<210> 99
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 99
Asp Asp Thr Phe Ile Asn Tyr Gly
1 5
<210> 100
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 100
Thr Phe Pro Ser Asn Gly Asn Thr
1 5
<210> 101
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 101
Ala Arg His Ser Asn Leu Pro Tyr Phe Asp His
1 5 10
<210> 102
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 102
Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr
1 5 10
<210> 103
<400> 103
000
<210> 104
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 104
Gln Asn Asp His Ser Tyr Pro Phe Thr
1 5
Claims (77)
1.一种抗体，其包括：
a)包括SEQ ID NO:1的氨基酸序列的重链可变区和包括SEQ ID NO:2的氨基酸序列的轻链可变区；
b)包括SEQ ID NO:3的氨基酸序列的重链可变区和包括SEQ ID NO:4的氨基酸序列的轻链可变区；
c)包括SEQ ID NO:5的氨基酸序列的重链可变区和包括SEQ ID NO:6的氨基酸序列的轻链可变区；
d)包括SEQ ID NO:7的氨基酸序列的重链可变区和包括SEQ ID NO:8的氨基酸序列的轻链可变区；
e)包括SEQ ID NO:9的氨基酸序列的重链可变区和包括SEQ ID NO:10的氨基酸序列的轻链可变区；
f)包括SEQ ID NO:11的氨基酸序列的重链可变区和包括SEQ ID NO:12的氨基酸序列的轻链可变区；
g)包括SEQ ID NO:13的氨基酸序列的重链可变区和包括SEQ ID NO:14的氨基酸序列的轻链可变区；
8)包括SEQ ID NO:15的氨基酸序列的重链可变区和包括SEQ ID NO:16的氨基酸序列的轻链可变区；
h)包括SEQ ID NO:17的氨基酸序列的重链可变区和包括SEQ ID NO:18的氨基酸序列的轻链可变区；
i)包括SEQ ID NO:19的氨基酸序列的重链可变区和包括SEQ ID NO:20的氨基酸序列的轻链可变区；
j)包括SEQ ID NO:21的氨基酸序列的重链可变区和包括SEQ ID NO:22的氨基酸序列的轻链可变区；
k)包括SEQ ID NO:23的氨基酸序列的重链可变区和包括SEQ ID NO:24的氨基酸序列的轻链可变区；
l)包括SEQ ID NO:25的氨基酸序列的重链可变区和包括SEQ ID NO:26的氨基酸序列的轻链可变区。
2.一种抗体，其包括：
a)包括SEQ ID NO:27的vhCDR1、包括SEQ ID NO:28的vhCDR2、包括SEQ ID NO:29的vhCDR3、包括SEQ ID NO:30的vlCDR1、包括SEQ ID NO:31的vlCDR2和包括SEQ ID NO:32的vlCDR3；
b)包括SEQ ID NO:33的vhCDR1、包括SEQ ID NO:34的vhCDR2、包括SEQ ID NO:35的vhCDR3、包括SEQ ID NO:36的vlCDR1、包括SEQ ID NO:37的vlCDR2和包括SEQ ID NO:38的vlCDR3；
c)包括SEQ ID NO:39的vhCDR1、包括SEQ ID NO:40的vhCDR2、包括SEQ ID NO:41的vhCDR3、包括SEQ ID NO:42的vlCDR1、包括SEQ ID NO:43的vlCDR2和包括SEQ ID NO:44的vlCDR3；
d)包括SEQ ID NO:45的vhCDR1、包括SEQ ID NO:46的vhCDR2、包括SEQ ID NO:47的vhCDR3、包括SEQ ID NO:48的vlCDR1、包括SEQ ID NO:49的vlCDR2和包括SEQ ID NO:50的vlCDR3；
e)包括SEQ ID NO:51的vhCDR1、包括SEQ ID NO:52的vhCDR2、包括SEQ ID NO:53的vhCDR3、包括SEQ ID NO:54的vlCDR1、包括SEQ ID NO:55的vlCDR2和包括SEQ ID NO:56的vlCDR3；
f)包括SEQ ID NO:57的vhCDR1、包括SEQ ID NO:58的vhCDR2、包括SEQ ID NO:59的vhCDR3、包括SEQ ID NO:60的vlCDR1、包括SEQ ID NO:61的vlCDR2和包括SEQ ID NO:62的vlCDR3；
g)包括SEQ ID NO:63的vhCDR1、包括SEQ ID NO:64的vhCDR2、包括SEQ ID NO:65的vhCDR3、包括SEQ ID NO:66的vlCDR1、包括SEQ ID NO:67的vlCDR2和包括SEQ ID NO:68的vlCDR3；
h)包括SEQ ID NO:69的vhCDR1、包括SEQ ID NO:70的vhCDR2、包括SEQ ID NO:71的vhCDR3、包括SEQ ID NO:72的vlCDR1、包括SEQ ID NO:73的vlCDR2和包括SEQ ID NO:74的vlCDR3；
i)包括SEQ ID NO:75的vhCDR1、包括SEQ ID NO:76的vhCDR2、包括SEQ ID NO:77的vhCDR3、包括SEQ ID NO:78的vlCDR1、包括SEQ ID NO:79的vlCDR2和包括SEQ ID NO:80的vlCDR3；
j)包括SEQ ID NO:81的vhCDR1、包括SEQ ID NO:82的vhCDR2、包括SEQ ID NO:83的vhCDR3、包括SEQ ID NO:84的vlCDR1、包括SEQ ID NO:85的vlCDR2和包括SEQ ID NO:86的vlCDR3；
k)包括SEQ ID NO:87的vhCDR1、包括SEQ ID NO:88的vhCDR2、包括SEQ ID NO:89的vhCDR3、包括SEQ ID NO:90的vlCDR1、包括SEQ ID NO:91的vlCDR2和包括SEQ ID NO:92的vlCDR3；
l)包括SEQ ID NO:93的vhCDR1、包括SEQ ID NO:94的vhCDR2、包括SEQ ID NO:95的vhCDR3、包括SEQ ID NO:96的vlCDR1、包括SEQ ID NO:97的vlCDR2和包括SEQ ID NO:98的vlCDR3；
m)包括SEQ ID NO:99的vhCDR1、包括SEQ ID NO:100的vhCDR2、包括SEQ ID NO:101的vhCDR3、包括SEQ ID NO:102的vlCDR1、包括SEQ ID NO:103的vlCDR2和包括SEQ ID NO:104的vlCDR3。
3.根据前述权利要求中任一项所述的抗体，其中所述抗体与人和/或小鼠TSG-6结合。
4.根据前述权利要求中任一项所述的抗体，其中所述抗体包括具有与人IgG至少90％相同的氨基酸序列的恒定区。
5.根据权利要求4所述的抗体，其中所述人IgG选自由IgG1、IgG2、IgG3和IgG4组成的组。
6.根据权利要求5所述的抗体，其中所述IgG是IgG1。
7.根据权利要求5所述的抗体，其中所述IgG是IgG2b。
8.一种核酸组合物，其对根据前述权利要求中任一项所述的抗体进行编码。
9.一种表达载体组合物，其包括根据权利要求8所述的核酸组合物，其中第一核酸包含在第一表达载体中并且第二核酸包含在第二表达载体中。
10.一种表达载体组合物，其包括根据权利要求8所述的核酸组合物，其中第一核酸和第二核酸包含在单个表达载体中。
11.一种宿主细胞，其包括根据权利要求9或10所述的表达载体组合物。
12.一种制备抗体的方法，所述方法包括：在抗体表达的条件下培养根据权利要求11所述的宿主细胞；以及回收所述抗体。
13.一种组合物，其包括根据权利要求1到8中任一项所述的抗体以及药学上可接受的载体或稀释剂。
14.一种调节受试者的免疫应答的方法，所述方法包括向所述受试者施用有效量的根据权利要求1到8中任一项所述的抗体或根据权利要求13所述的组合物。
15.根据权利要求14所述的方法，其中所述方法刺激受试者的免疫应答，所述方法包括向所述受试者施用有效量的根据权利要求1到8中任一项所述的抗体或根据权利要求13所述的组合物，其中所述抗体用作TSG-6拮抗剂。
16.根据权利要求14所述的方法，其中所述方法抑制受试者的免疫应答，所述方法包括向所述受试者施用有效量的根据权利要求1到8中任一项所述的抗体或根据权利要求13所述的组合物，其中所述抗体用作TSG-6激动剂。
17.一种治疗受试者的癌症的方法，所述方法包括向所述受试者施用有效量的根据权利要求1到8中任一项所述的抗体或根据权利要求13所述的组合物，其中所述抗体用作TSG-6拮抗剂。
18.根据权利要求17所述的方法，其中所述癌症的TSG-6和/或HC-HA表达高。
19.根据权利要求15、17或18所述的方法，其中所述待治疗受试者的TSG-6和/或HC-HA表达高。
20.根据权利要求17到19中任一项所述的方法，其中所述癌症是实体瘤。
21.根据权利要求17到20中任一项所述的方法，其中所述癌症是黑色素瘤。
22.根据权利要求17到21中任一项所述的方法，其中所述抗体与一种或多种另外的治疗剂组合以治疗癌症。
23.根据权利要求22所述的方法，其中所述另外的治疗剂是其它免疫检查点抑制剂。
24.根据权利要求23所述的方法，其中所述其它免疫检查点抑制剂选自由以下组成的组：PD-1抑制剂、PD-L1抑制剂、CTLA-4抑制剂、TIM-3抑制剂和LAG-3抑制剂。
25.一种治疗受试者的纤维化的方法，所述方法包括向所述受试者施用有效量的根据权利要求1到8中任一项所述的抗体或根据权利要求13所述的组合物，其中所述抗体用作TSG-6拮抗剂。
26.根据权利要求25所述的方法，其中纤维化组织的TSG-6和/或HC-HA表达高。
27.根据权利要求25或26所述的方法，其中所述待治疗受试者的TSG-6和/或HC-HA表达高。
28.根据权利要求25到27中任一项所述的方法，其中所述抗体与一种或多种另外的治疗剂组合以治疗纤维化。
29.一种治疗受试者的自身免疫性或炎性病症的方法，所述方法包括向所述受试者施用有效量的根据权利要求1到8中任一项所述的抗体或根据权利要求13所述的组合物，其中所述抗体用作TSG-6拮抗剂。
30.根据权利要求29所述的方法，其中所述自身免疫性或炎性病症是特发性肺动脉高压。
31.根据权利要求29或30所述的方法，其中所述待治疗受试者的TSG-6和/或HC-HA表达高。
32.根据权利要求30或31所述的方法，其中所述待治疗受试者还患有肺纤维化。
33.根据权利要求29到32中任一项所述的方法，其中所述抗体与一种或多种另外的治疗剂组合以治疗肺动脉高压和/或肺纤维化。
34.根据权利要求29所述的方法，其中所述自身免疫性或炎性病症是哮喘。
35.根据权利要求34所述的方法，其中所述待治疗受试者的TSG-6和/或HC-HA表达高。
36.根据权利要求34或35所述的方法，其中所述待治疗受试者的肺的TSG-6和/或HC-HA表达高。
37.根据权利要求34到36中任一项所述的方法，其中所述待治疗受试者患有增加的气道嗜酸性粒细胞增多症。
38.一种治疗受试者的自身免疫性或炎性病症的方法，所述方法包括向所述受试者施用有效量的根据权利要求1到8中任一项所述的抗体或根据权利要求13所述的组合物，其中所述抗体用作TSG-6激动剂。
39.根据权利要求38所述的方法，其中所述自身免疫性或炎性病症是类风湿性关节炎。
40.根据权利要求16、38或39中任一项所述的方法，其中所述待治疗受试者的TSG-6和/或HC-HA表达低。
41.根据权利要求29到40中任一项所述的方法，其中所述抗体与一种或多种另外的治疗剂组合以治疗自身免疫性或炎性病症。
42.一种抗体，其包括：
a)包括SEQ ID NO:17的氨基酸序列的重链可变区和包括SEQ ID NO:18的氨基酸序列的轻链可变区。
43.一种抗体，其包括：
a)包括SEQ ID NO:75的vhCDR1、包括SEQ ID NO:76的vhCDR2、包括SEQ ID NO:
77的vhCDR3、包括SEQ ID NO:78的vlCDR1、包括SEQ ID NO:79的vlCDR2和包括SEQ IDNO:80的vlCDR3。
44.根据权利要求42或43所述的抗体，其中所述抗体与人和/或小鼠TSG-6结合。
45.根据权利要求42到44中任一项所述的抗体，其中所述抗体包括具有与人IgG至少90％相同的氨基酸序列的恒定区。
46.根据权利要求45所述的抗体，其中所述人IgG选自由IgG1、IgG2、IgG3和IgG4组成的组。
47.根据权利要求46所述的抗体，其中所述IgG是IgG1。
48.一种核酸组合物，其对根据权利要求42到47中任一项所述的抗体进行编码。
49.一种表达载体组合物，其包括根据权利要求48所述的核酸组合物，其中第一核酸包含在第一表达载体中并且第二核酸包含在第二表达载体中。
50.一种表达载体组合物，其包括根据权利要求48所述的核酸组合物，其中第一核酸和第二核酸包含在单个表达载体中。
51.一种宿主细胞，其包括根据权利要求49或50所述的表达载体组合物。
52.一种制备抗体的方法，所述方法包括：在抗体表达的条件下培养根据权利要求51所述的宿主细胞；以及回收所述抗体。
53.一种组合物，其包括根据权利要求42到48中任一项所述的抗体以及药学上可接受的载体或稀释剂。
54.一种调节受试者的免疫应答的方法，所述方法包括向所述受试者施用有效量的根据权利要求42到48中任一项所述的抗体或根据权利要求53所述的组合物。
55.根据权利要求54所述的方法，其中所述方法刺激受试者的免疫应答，所述方法包括向所述受试者施用有效量的根据权利要求42到48中任一项所述的抗体或根据权利要求53所述的组合物，其中所述抗体用作TSG-6拮抗剂。
56.一种治疗受试者的癌症的方法，所述方法包括向所述受试者施用有效量的根据权利要求42到48中任一项所述的抗体或根据权利要求53所述的组合物，其中所述抗体用作TSG-6拮抗剂。
57.根据权利要求56所述的方法，其中所述癌症的TSG-6和/或HC-HA表达高。
58.根据权利要求55到57中任一项所述的方法，其中所述待治疗受试者的TSG-6和/或HC-HA表达高。
59.根据权利要求56到58中任一项所述的方法，其中所述癌症是实体瘤。
60.根据权利要求56到59中任一项所述的方法，其中所述癌症是黑色素瘤。
61.根据权利要求56到60中任一项所述的方法，其中所述抗体与一种或多种另外的治疗剂组合以治疗癌症。
62.根据权利要求61所述的方法，其中所述另外的治疗剂是其它免疫检查点抑制剂。
63.根据权利要求62所述的方法，其中所述其它免疫检查点抑制剂选自由以下组成的组：PD-1抑制剂、PD-L1抑制剂、CTLA-4抑制剂、TIM-3抑制剂和LAG-3抑制剂。
64.一种治疗受试者的纤维化的方法，所述方法包括向所述受试者施用有效量的根据权利要求42到48中任一项所述的抗体或根据权利要求53所述的组合物，其中所述抗体用作TSG-6拮抗剂。
65.根据权利要求64所述的方法，其中纤维化组织的TSG-6和/或HC-HA表达高。
66.根据权利要求64或65所述的方法，其中所述待治疗受试者的TSG-6和/或HC-HA表达高。
67.根据权利要求64到66中任一项所述的方法，其中所述抗体与一种或多种另外的治疗剂组合以治疗纤维化。
68.一种治疗受试者的自身免疫性或炎性病症的方法，所述方法包括向所述受试者施用有效量的根据权利要求42到48中任一项所述的抗体或根据权利要求53所述的组合物，其中所述抗体用作TSG-6拮抗剂。
69.根据权利要求68所述的方法，其中所述自身免疫性或炎性病症是特发性肺动脉高压。
70.根据权利要求68或69所述的方法，其中所述待治疗受试者的TSG-6和/或HC-HA表达高。
71.根据权利要求69或70所述的方法，其中所述待治疗受试者还患有肺纤维化。
72.根据权利要求69到71中任一项所述的方法，其中所述抗体与一种或多种另外的治疗剂组合以治疗肺动脉高压和/或肺纤维化。
73.根据权利要求68所述的方法，其中所述自身免疫性或炎性病症是哮喘。
74.根据权利要求73所述的方法，其中所述待治疗受试者的TSG-6和/或HC-HA表达高。
75.根据权利要求73或74所述的方法，其中所述待治疗受试者的肺的TSG-6和/或HC-HA表达高。
76.根据权利要求73到75中任一项所述的方法，其中所述待治疗受试者患有增加的气道嗜酸性粒细胞增多症。
77.根据权利要求68到76中任一项所述的方法，其中所述抗体与一种或多种另外的治疗剂组合以治疗自身免疫性或炎性病症。
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| WO2023192829A2 (en) * | 2022-03-28 | 2023-10-05 | University Of Florida Research Foundation, Incorporated | Alpha-1 antitrypsin z- and m-specific binding proteins |
| KR102582500B1 (ko) | 2022-10-27 | 2023-09-26 | 서울대학교산학협력단 | Tnfaip6 -조작된 종양 세포 및 이의 이용 |
| WO2024102759A1 (en) * | 2022-11-07 | 2024-05-16 | Board Of Regents, The University Of Texas System | Methods involving detecting tnf stimulated gene 6 (tsg-6) for improving anti-tumor responses to immune therapy in cancer patients |
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| SG11202109708TA (en) | 2021-10-28 |
| IL286216A (en) | 2021-10-31 |
| AU2020234533A1 (en) | 2021-09-16 |
| US20220153834A1 (en) | 2022-05-19 |
| MX2021010766A (es) | 2021-12-10 |
| EP3938389A1 (en) | 2022-01-19 |
| CA3129302A1 (en) | 2020-09-17 |
| WO2020181376A1 (en) | 2020-09-17 |
| JP2022522815A (ja) | 2022-04-20 |
| BR112021017810A2 (pt) | 2021-11-23 |
| EA202192488A1 (ru) | 2022-02-08 |
| KR20210138674A (ko) | 2021-11-19 |
| EP3938389A4 (en) | 2022-11-09 |
| TW202100551A (zh) | 2021-01-01 |
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