CN110167592A - 抗il-37抗体 - Google Patents
抗il-37抗体 Download PDFInfo
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- CN110167592A CN110167592A CN201780080084.6A CN201780080084A CN110167592A CN 110167592 A CN110167592 A CN 110167592A CN 201780080084 A CN201780080084 A CN 201780080084A CN 110167592 A CN110167592 A CN 110167592A
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Abstract
本发明涉及IL‑37,涉及与IL‑37结合的抗体及其相关片段,涉及所述抗体和片段的产生和所述抗体和片段检测和治疗各种病况的用途。例如,本发明涉及结合或特异性结合IL‑37并抑制IL‑37活性的抗原结合位点。
Description
技术领域
本发明涉及IL-37,涉及与IL-37结合的抗体及其相关片段,涉及所述抗体和片段的产生以及所述抗体和片段用于检测和治疗各种病况的用途。
相关申请
本申请要求澳大利亚临时申请AU 2016905344的优先权,其内容通过引用整体并入本文。
背景技术
白细胞介素(IL)-37(以前称为白细胞介素-1家族成员7,或IL-1F7)是IL-1家族的成员,IL-1家族由促炎配体IL-1α、IL-1β、IL-18、IL-33、IL-36α、IL-36β、IL-36γ和抗炎成员IL-1受体拮抗剂(IL-1Ra)、IL-36Ra、IL-37和IL-38组成。IL-37通过发挥抵抗广谱炎症攻击活性的功能而区别于大多数其他抗炎细胞因子,包括促炎细胞因子如IL-1β、肿瘤坏死因子(TNF)和干扰素(IFN)γ和Toll样受体(TLR)。因此,IL-37在人肺上皮细胞系A549中的表达抑制了诸如IL-1α和IL-6的促炎细胞因子的产生。由于尚未鉴定到IL-37的小鼠同源物,体内研究使用转人IL-37基因的小鼠。这些小鼠在许多动物疾病模型中受到保护,包括脂多糖(LPS)诱导的休克、实验性结肠炎、缺血性肝损伤和肥胖诱导的炎症。
IL-37通过各种促炎刺激物(例如IL-1β、IL-18、TNF、IFNγ或TLR激动剂)诱导。IL-37由IL1F7基因编码,以五种剪接变体表达,称为IL1F7a-e。IL-37b是最长的且唯一具有6个外显子中的5个的同种型,是目前研究最成熟的剪接变体。与其他IL-1家族配体如IL-1β和IL-18类似,IL-37作为前体分子表达并含有caspase-1切割位点。
IL-37通过两种不同的机制抑制炎症。一方面,IL-37通过转位进入细胞核并以依赖Smad3的方式抑制促炎细胞因子而在细胞内起作用。另一方面,IL-37从细胞中释放,然后通过与其细胞表面受体复合物结合来抑制炎症,所述细胞表面受体复合物包含IL-18受体α(IL-18Rα)和IL-1受体8(IL-1R8,之前称为单免疫球蛋白IL-1R-相关分子,SIGIRR)。
存在其中抑制抗炎反应是有益的情况,例如在治疗癌症中。
在说明书中对任何现有技术的提及并不是对该现有技术以任何权限形成一般常识一部分的承认或建议,或者可以合理地预期该现有技术被理解,被认为是相关的,和/或与本领域技术人员掌握的其他现有技术结合。
发明内容
本发明提供一种抗原结合位点,其结合或特异性结合IL-37并抑制IL-37活性。
优选地,抗原结合位点包含抗体的抗原结合结构域,抗原结合结构域结合或特异性结合IL-37并抑制IL-37活性。
由本发明的任何抗原结合位点抑制的IL-37活性包括:IL-37与IL-18受体α(IL-18Rα)、IL-1受体8或其包含IL-18受体α(IL-18Rα)和IL-1受体8的复合物的结合;IL-37与SMAD3结合或相互作用;IL-37与DNA结合或相互作用;IL-37介导的细胞信号传导;IL-37介导的体外或体内抗炎反应;IL-37介导的细胞因子产生或分泌的减少;和/或自分泌或旁分泌IL-37介导的细胞因子产生或分泌的减少。优选地,细胞因子是本文所述的任何一种或更多种,包括sICAM-1、IFN-γ、I-TAC、G-SCF、IL-16、IL-10、IL-13、TNF、I-309、IL-2、IL-7、M-CSF、TIMP-1、IL-1α、MIP-1α、RANTES、MIG、IL-1Ra、sTREM-1、MCP-5、IP-10、MCP-1、IL-23、KC、IL-1β、MIP-2、IL-17、IL-17F、IL-4、IL-5、IKL-33、IL-25、IL-21、IL-22、嗜酸性粒细胞趋化因子和IL-6。更优选地,细胞因子是M-CSF、TIMP-1、IL-1α、MIP-1α、RANTES、MIG、IL-1Ra、sTREM-1、MCP-5、IP-10、MCP-1、IL-23、KC、IL-1β、MIP-2、IL-17、嗜酸性粒细胞趋化因子和IL-6中的任何一种或更多种。最优选地,促炎细胞因子是IL-1β、IL-6和/或TNF。优选地,使用单核细胞、巨噬细胞、外周血单核细胞(PBMC)、癌细胞或自其衍生的细胞测定IL-37介导的活性。优选地,癌细胞是诸如A549的肺上皮细胞,或诸如THP-1的单核细胞白血病细胞。
在本发明的任何实施方案中,本发明的抗原结合位点结合或特异性结合人IL-37。应理解,由抗原结合位点结合的IL-37包括IL-37的任何同源物或序列变体。进一步,人IL-37可以是单体或二聚体形式。IL-37的单体形式可包括IL-37的变体,其具有降低的形成二聚体的倾向,包括具有D73K或Y85A突变的IL-37分子,或在PCT/AU2016/050495中描述的任何一种或更多种突变。更进一步,由本发明的抗原结合位点结合的人IL-37可以包含对应于IL-37前肽的氨基酸序列、基本上由其组成或由其组成。或者,IL-37可以是人IL-37肽的成熟形式,例如在除去(前肽序列的)N-末端氨基酸1至46或其相等序列后得到的人IL-37肽。IL-37可以是由PBMC产生的内源性IL-37。或者,IL-37可以来自外源性来源,并且作为治疗的一部分施用于个体。在这些情况下,本发明的抗原结合位点可用于抑制或阻断施用的外源性IL-37活性。优选地,抗原结合位点结合或特异性结合人IL-37分子,所述人IL-37分子包含SEQ ID NO:1中所示的氨基酸序列、基本上由其组成或由其组成。
优选地,抗原结合位点抑制或降低由促炎刺激诱导的IL-37活性。促炎刺激可以是任何促炎刺激,包括例如细菌感染(其中刺激可以是细菌内毒素脂多糖LPS)、病毒感染、由癌细胞产生的或任何其他生物、化学或物理因素的结果或已知的引发个体促炎反应的刺激。
本发明的IL-37结合抗原结合位点可以抑制单核细胞、巨噬细胞、PBMC、癌细胞、内皮细胞、上皮细胞、树突细胞或由其衍生的细胞中任何IL-37介导的细胞因子产生或分泌的减少。
例如,与不存在抗原结合位点时相比,抗原结合位点可以增加PBMC或由其衍生的细胞类型,或癌细胞中IL-1β的产生或分泌。可通过本文所述的任何方法测定IL-37活性的降低或抑制,包括通过实施例4、5或6中所述的任何方法。
本发明的抗原结合位点可结合IL-37,并且不可检测地结合或显著结合IL-18和/或IL-1β,和/或IL-1Ra,和/或IL-36和/或IL-36Ra和/或IL-38。抗原结合位点与IL-18和/或IL-1β的结合可以通过本文所述的任何方法测定,特别是如实施例3中所述的免疫印迹。
本发明提供与IL-37结合的抗原结合位点,该抗原结合位点包括:
FR1-CDR1–FR2–CDR2–FR3–CDR3–FR4–连接物-FR1a-CDR1a–FR2a–CDR2a–FR3a–CDR3a–FR4a
其中:
FR1、FR2、FR3和FR4每个均是框架区;
CDR1、CDR2和CDR3每个均是互补决定区;
FR1a、FR2a、FR3a和FR4a每个均是框架区;
CDR1a、CDR2a和CDR3a每个均是互补决定区;
其中任何一个框架区或互补决定区的序列均如本文所述。
本发明提供与IL-37结合的抗原结合位点,该抗原结合位点包括:
FR1-CDR1–FR2–CDR2–FR3–CDR3–FR4–连接物-FR1a-CDR1a–FR2a–CDR2a–FR3a–CDR3a–FR4a
其中:
FR1、FR2、FR3和FR4每个均是框架区;
CDR1、CDR2和CDR3每个均是互补决定区;
FR1a、FR2a、FR3a和FR4a每个均是框架区;
CDR1a、CDR2a和CDR3a每个均是互补决定区;
其中任何互补决定区的序列均具有如下表1所述的氨基酸序列。优选地,框架区具有如下表3所述的氨基酸序列。CDR1、CDR2和CDR3可以是来自可变重链(VH)的序列;CDR1a、CDR2a和CDR3a可以是来自可变轻链(VL)的序列。或者,CDR1、CDR2和CDR3是来自VL的序列,CDR1a、CDR2a和CDR3a是来自VH的序列。
本发明提供一种抗原结合位点,其包含如下氨基酸序列(按N至C末端或C至N末端的顺序)、基本上由其组成或由其组成:
-SEQ ID NO:8和9;
-SEQ ID NO:18和19;
-SEQ ID NO:44和45;
-SEQ ID NO:54和55;
-SEQ ID NO:64和65;
-SEQ ID NO:74和75;
-SEQ ID NO:84和85;
-SEQ ID NO:94和95;
-SEQ ID NO:104和105;
-SEQ ID NO:114和115;
-SEQ ID NO:124和125;
-SEQ ID NO:134和135;
-SEQ ID NO:144和145;
-SEQ ID NO:154和155;
-SEQ ID NO:164和165;
-SEQ ID NO:174和175;
-SEQ ID NO:184和185;
-SEQ ID NO:194和195;或
-SEQ ID NO:204和205。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:5所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:6所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:7所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:9所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:2所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:3所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:4所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:8所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:5所示序列,所述CDR2包含SEQ ID NO:6所示序列,所述CDR3包含SEQ ID NO:7所示序列;
(vi)VH,其包含SEQ ID NO:9所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:2所示序列,所述CDR2包含SEQ ID NO:3所示序列,所述CDR3包含SEQ ID NO:4所示序列;
(viii)VL,其包含SEQ ID NO:8所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:5所示序列,所述CDR2包含SEQ ID NO:6所示序列,所述CDR3包含SEQ ID NO:7所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:2所示序列,所述CDR2包含SEQ ID NO:3所示序列,所述CDR3包含SEQ ID NO:4所示序列;和
(x)VH,其包含SEQ ID NO:9所示序列,及VL,其包含SEQ ID NO:8所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:15所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:16所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:17所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:19所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:12所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:13所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:14所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:18所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:15所示序列,所述CDR2包含SEQ ID NO:16所示序列,所述CDR3包含SEQ ID NO:17所示序列;
(vi)VH,其包含SEQ ID NO:19所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:12所示序列,所述CDR2包含SEQ ID NO:13所示序列,所述CDR3包含SEQ ID NO:14所示序列;
(viii)VL,其包含SEQ ID NO:18所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:15所示序列,所述CDR2包含SEQ ID NO:16所示序列,所述CDR3包含SEQ ID NO:17所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:12所示序列,所述CDR2包含SEQ ID NO:13所示序列,所述CDR3包含SEQ ID NO:14所示序列;和
(x)VH,其包含SEQ ID NO:19所示序列,及VL,其包含SEQ ID NO:18所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:41所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:42所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:43所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:45所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:38所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:39所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:40所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:44所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:41所示序列,所述CDR2包含SEQ ID NO:42所示序列,所述CDR3包含SEQ ID NO:43所示序列;
(vi)VH,其包含SEQ ID NO:45所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:38所示序列,所述CDR2包含SEQ ID NO:39所示序列,所述CDR3包含SEQ ID NO:40所示序列;
(viii)VL,其包含SEQ ID NO:44所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:41所示序列,所述CDR2包含SEQ ID NO:42所示序列,所述CDR3包含SEQ ID NO:43所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:38所示序列,所述CDR2包含SEQ ID NO:39所示序列,所述CDR3包含SEQ ID NO:40所示序列;和
(x)VH,其包含SEQ ID NO:45所示序列,及VL,其包含SEQ ID NO:44所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:51所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:52所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:53所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:55所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:48所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:49所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:50所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:54所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:51所示序列,所述CDR2包含SEQ ID NO:52所示序列,所述CDR3包含SEQ ID NO:53所示序列;
(vi)VH,其包含SEQ ID NO:55所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:48所示序列,所述CDR2包含SEQ ID NO:49所示序列,所述CDR3包含SEQ ID NO:50所示序列;
(viii)VL,其包含SEQ ID NO:54所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:51所示序列,所述CDR2包含SEQ ID NO:52所示序列,所述CDR3包含SEQ ID NO:53所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:48所示序列,所述CDR2包含SEQ ID NO:49所示序列,所述CDR3包含SEQ ID NO:50所示序列;和
(x)VH,其包含SEQ ID NO:55所示序列,及VL,其包含SEQ ID NO:54所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:61所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:62所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:63所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:65所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:58所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:59所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:60所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:64所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:61所示序列,所述CDR2包含SEQ ID NO:62所示序列,所述CDR3包含SEQ ID NO:63所示序列;
(vi)VH,其包含SEQ ID NO:65所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:58所示序列,所述CDR2包含SEQ ID NO:59所示序列,所述CDR3包含SEQ ID NO:60所示序列;
(viii)VL,其包含SEQ ID NO:64所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:61所示序列,所述CDR2包含SEQ ID NO:62所示序列,所述CDR3包含SEQ ID NO:63所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:58所示序列,所述CDR2包含SEQ ID NO:59所示序列,所述CDR3包含SEQ ID NO:60所示序列;和
(x)VH,其包含SEQ ID NO:65所示序列,及VL,其包含SEQ ID NO:64所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:71所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:72所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:73所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:75所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:68所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:69所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:70所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:74所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:71所示序列,所述CDR2包含SEQ ID NO:72所示序列,所述CDR3包含SEQ ID NO:73所示序列;
(vi)VH,其包含SEQ ID NO:75所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:68所示序列,所述CDR2包含SEQ ID NO:69所示序列,所述CDR3包含SEQ ID NO:70所示序列;
(viii)VL,其包含SEQ ID NO:74所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:71所示序列,所述CDR2包含SEQ ID NO:72所示序列,所述CDR3包含SEQ ID NO:73所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:68所示序列,所述CDR2包含SEQ ID NO:69所示序列,所述CDR3包含SEQ ID NO:70所示序列;和
(x)VH,其包含SEQ ID NO:75所示序列,及VL,其包含SEQ ID NO:74所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:81所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:82所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:83所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:85所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:78所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:79所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:80所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:84所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:81所示序列,所述CDR2包含SEQ ID NO:82所示序列,所述CDR3包含SEQ ID NO:83所示序列;
(vi)VH,其包含SEQ ID NO:85所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:78所示序列,所述CDR2包含SEQ ID NO:79所示序列,所述CDR3包含SEQ ID NO:80所示序列;
(viii)VL,其包含SEQ ID NO:84所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:81所示序列,所述CDR2包含SEQ ID NO:82所示序列,所述CDR3包含SEQ ID NO:83所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:78所示序列,所述CDR2包含SEQ ID NO:79所示序列,所述CDR3包含SEQ ID NO:80所示序列;和
(x)VH,其包含SEQ ID NO:85所示序列,及VL,其包含SEQ ID NO:84所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:91所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:92所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:93所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:95所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:88所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:89所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:90所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:94所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:91所示序列,所述CDR2包含SEQ ID NO:92所示序列,所述CDR3包含SEQ ID NO:93所示序列;
(vi)VH,其包含SEQ ID NO:95所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:88所示序列,所述CDR2包含SEQ ID NO:89所示序列,所述CDR3包含SEQ ID NO:90所示序列;
(viii)VL,其包含SEQ ID NO:94所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:91所示序列,所述CDR2包含SEQ ID NO:92所示序列,所述CDR3包含SEQ ID NO:93所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:88所示序列,所述CDR2包含SEQ ID NO:89所示序列,所述CDR3包含SEQ ID NO:90所示序列;和
(x)VH,其包含SEQ ID NO:95所示序列,及VL,其包含SEQ ID NO:94所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:101所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:102所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:103所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:105所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:98所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:99所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:100所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:104所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:101所示序列,所述CDR2包含SEQ ID NO:102所示序列,所述CDR3包含SEQ ID NO:103所示序列;
(vi)VH,其包含SEQ ID NO:105所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:98所示序列,所述CDR2包含SEQ ID NO:99所示序列,所述CDR3包含SEQ ID NO:100所示序列;
(viii)VL,其包含SEQ ID NO:104所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:101所示序列,所述CDR2包含SEQ ID NO:102所示序列,所述CDR3包含SEQ ID NO:103所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:98所示序列,所述CDR2包含SEQ ID NO:99所示序列,所述CDR3包含SEQ ID NO:100所示序列;和
(x)VH,其包含SEQ ID NO:105所示序列,及VL,其包含SEQ ID NO:104所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:111所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:112所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:113所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:115所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:108所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:109所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:110所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:114所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:111所示序列,所述CDR2包含SEQ ID NO:112所示序列,所述CDR3包含SEQ ID NO:113所示序列;
(vi)VH,其包含SEQ ID NO:115所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:108所示序列,所述CDR2包含SEQ ID NO:109所示序列,所述CDR3包含SEQ ID NO:110所示序列;
(viii)VL,其包含SEQ ID NO:114所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:111所示序列,所述CDR2包含SEQ ID NO:112所示序列,所述CDR3包含SEQ ID NO:113所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:108所示序列,所述CDR2包含SEQ ID NO:109所示序列,所述CDR3包含SEQ ID NO:110所示序列;和
(x)VH,其包含SEQ ID NO:115所示序列,及VL,其包含SEQ ID NO:114所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:121所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:122所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:123所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:125所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:118所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:119所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:120所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:124所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:121所示序列,所述CDR2包含SEQ ID NO:122所示序列,所述CDR3包含SEQ ID NO:123所示序列;
(vi)VH,其包含SEQ ID NO:125所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:118所示序列,所述CDR2包含SEQ ID NO:119所示序列,所述CDR3包含SEQ ID NO:120所示序列;
(viii)VL,其包含SEQ ID NO:124所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:121所示序列,所述CDR2包含SEQ ID NO:122所示序列,所述CDR3包含SEQ ID NO:123所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:118所示序列,所述CDR2包含SEQ ID NO:119所示序列,所述CDR3包含SEQ ID NO:120所示序列;和
(x)VH,其包含SEQ ID NO:125所示序列,及VL,其包含SEQ ID NO:124所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:131所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:132所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:133所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:135所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:128所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:129所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:130所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:134所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:131所示序列,所述CDR2包含SEQ ID NO:132所示序列,所述CDR3包含SEQ ID NO:133所示序列;
(vi)VH,其包含SEQ ID NO:135所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:128所示序列,所述CDR2包含SEQ ID NO:129所示序列,所述CDR3包含SEQ ID NO:130所示序列;
(viii)VL,其包含SEQ ID NO:134所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:131所示序列,所述CDR2包含SEQ ID NO:132所示序列,所述CDR3包含SEQ ID NO:133所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:128所示序列,所述CDR2包含SEQ ID NO:129所示序列,所述CDR3包含SEQ ID NO:130所示序列;和
(x)VH,其包含SEQ ID NO:135所示序列,及VL,其包含SEQ ID NO:134所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:141所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:142所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:143所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:145所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:138所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:139所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:140所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:144所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:141所示序列,所述CDR2包含SEQ ID NO:142所示序列,所述CDR3包含SEQ ID NO:143所示序列;
(vi)VH,其包含SEQ ID NO:145所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:138所示序列,所述CDR2包含SEQ ID NO:139所示序列,所述CDR3包含SEQ ID NO:140所示序列;
(viii)VL,其包含SEQ ID NO:144所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:141所示序列,所述CDR2包含SEQ ID NO:142所示序列,所述CDR3包含SEQ ID NO:143所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:138所示序列,所述CDR2包含SEQ ID NO:139所示序列,所述CDR3包含SEQ ID NO:140所示序列;和
(x)VH,其包含SEQ ID NO:145所示序列,及VL,其包含SEQ ID NO:144所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:151所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:152所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:153所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:155所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:148所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:149所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:150所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:154所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:151所示序列,所述CDR2包含SEQ ID NO:152所示序列,所述CDR3包含SEQ ID NO:153所示序列;
(vi)VH,其包含SEQ ID NO:155所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:148所示序列,所述CDR2包含SEQ ID NO:149所示序列,所述CDR3包含SEQ ID NO:150所示序列;
(viii)VL,其包含SEQ ID NO:154所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:151所示序列,所述CDR2包含SEQ ID NO:152所示序列,所述CDR3包含SEQ ID NO:153所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:148所示序列,所述CDR2包含SEQ ID NO:149所示序列,所述CDR3包含SEQ ID NO:150所示序列;和
(x)VH,其包含SEQ ID NO:155所示序列,及VL,其包含SEQ ID NO:154所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:161所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:162所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:163所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:165所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:158所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:159所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:160所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:164所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:161所示序列,所述CDR2包含SEQ ID NO:162所示序列,所述CDR3包含SEQ ID NO:163所示序列;
(vi)VH,其包含SEQ ID NO:165所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:158所示序列,所述CDR2包含SEQ ID NO:159所示序列,所述CDR3包含SEQ ID NO:160所示序列;
(viii)VL,其包含SEQ ID NO:164所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:161所示序列,所述CDR2包含SEQ ID NO:162所示序列,所述CDR3包含SEQ ID NO:163所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:158所示序列,所述CDR2包含SEQ ID NO:159所示序列,所述CDR3包含SEQ ID NO:160所示序列;和
(x)VH,其包含SEQ ID NO:165所示序列,及VL,其包含SEQ ID NO:164所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:171所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:172所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:173所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:175所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:168所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:169所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:170所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:174所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:171所示序列,所述CDR2包含SEQ ID NO:172所示序列,所述CDR3包含SEQ ID NO:173所示序列;
(vi)VH,其包含SEQ ID NO:175所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:168所示序列,所述CDR2包含SEQ ID NO:169所示序列,所述CDR3包含SEQ ID NO:170所示序列;
(viii)VL,其包含SEQ ID NO:174所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:171所示序列,所述CDR2包含SEQ ID NO:172所示序列,所述CDR3包含SEQ ID NO:173所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:168所示序列,所述CDR2包含SEQ ID NO:169所示序列,所述CDR3包含SEQ ID NO:170所示序列;和
(x)VH,其包含SEQ ID NO:175所示序列,及VL,其包含SEQ ID NO:174所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:181所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:182所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:183所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:185所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:178所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:179所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:180所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:184所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:181所示序列,所述CDR2包含SEQ ID NO:182所示序列,所述CDR3包含SEQ ID NO:183所示序列;
(vi)VH,其包含SEQ ID NO:185所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:178所示序列,所述CDR2包含SEQ ID NO:179所示序列,所述CDR3包含SEQ ID NO:180所示序列;
(viii)VL,其包含SEQ ID NO:184所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:181所示序列,所述CDR2包含SEQ ID NO:182所示序列,所述CDR3包含SEQ ID NO:183所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:178所示序列,所述CDR2包含SEQ ID NO:179所示序列,所述CDR3包含SEQ ID NO:180所示序列;和
(x)VH,其包含SEQ ID NO:185所示序列,及VL,其包含SEQ ID NO:184所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:191所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:192所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:193所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:195所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:188所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:189所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:190所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:194所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:191所示序列,所述CDR2包含SEQ ID NO:192所示序列,所述CDR3包含SEQ ID NO:193所示序列;
(vi)VH,其包含SEQ ID NO:195所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:188所示序列,所述CDR2包含SEQ ID NO:189所示序列,所述CDR3包含SEQ ID NO:190所示序列;
(viii)VL,其包含SEQ ID NO:194所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:191所示序列,所述CDR2包含SEQ ID NO:192所示序列,所述CDR3包含SEQ ID NO:193所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:188所示序列,所述CDR2包含SEQ ID NO:189所示序列,所述CDR3包含SEQ ID NO:190所示序列;和
(x)VH,其包含SEQ ID NO:195所示序列,及VL,其包含SEQ ID NO:194所示序列。
本发明也提供包含抗体抗原结合结构域的抗原结合位点,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:201所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:202所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:203所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:205所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:198所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:199所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:200所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:204所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:201所示序列,所述CDR2包含SEQ ID NO:202所示序列,所述CDR3包含SEQ ID NO:203所示序列;
(vi)VH,其包含SEQ ID NO:205所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:198所示序列,所述CDR2包含SEQ ID NO:199所示序列,所述CDR3包含SEQ ID NO:200所示序列;
(viii)VL,其包含SEQ ID NO:204所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:201所示序列,所述CDR2包含SEQ ID NO:202所示序列,所述CDR3包含SEQ ID NO:203所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:198所示序列,所述CDR2包含SEQ ID NO:199所示序列,所述CDR3包含SEQ ID NO:200所示序列;和
(x)VH,其包含SEQ ID NO:205所示序列,及VL,其包含SEQ ID NO:204所示序列。
如本文所述,抗原结合位点可以以下形式存在:
(i)单链Fv片段(scFv);
(ii)scFv二聚体(di-scFv);
(iii)连接至抗体恒定区、Fc或重链恒定域(CH)2和/或CH3的(i)或(ii)的一种;或
(iv)连接至结合免疫效应细胞的蛋白的(i)或(ii)的一种。
进一步地,如本文所述,抗原结合位点以以下形式存在:
(i)二体;
(ii)三体;
(iii)四体;
(iv)Fab;
(v)F(ab’)2;
(vi)Fv;
(vii)连接至抗体恒定区、Fc或重链恒定域(CH)2和/或CH3的(i)至(vi)中的一种;
(viii)连接至结合免疫效应细胞的蛋白的(i)至(vi)的一种。
前述抗原结合位点也指抗体抗原结合结构域。
如本文所述的抗原结合位点可以是抗体或其抗原结合片段。通常,抗原结合位点是抗体,例如单克隆抗体。
如本文所用,抗原结合位点可以是可变结构域。
在任何方面或实施方案中,抗体是裸抗体。具体地,该抗体是非缀合形式存在,并且未被改造形成缀合物。
在一个实例中,根据Kabat编号系统来定义本发明的抗原结合位点的互补决定区序列(CDR)。
在另一个实例中,根据IMGT编号系统来定义CDR。
本文术语“结合”IL-37的蛋白或抗体为“特异性结合”IL-37的蛋白或抗体提供文字支持。
本发明还提供前述抗体的抗原结合结构域或抗原结合片段。
本发明还提供融合蛋白,其包含如本文所述的抗原结合位点、免疫球蛋白可变结构域、抗体、dab(单结构域抗体)、di-scFv、scFv、Fab、Fab'、F(ab')2、Fv片段、二体、三体、四体、线性抗体、单链抗体分子或多特异性抗体。
本发明还提供缀合至标记物或细胞毒性剂形式的如本文所述的抗原结合位点、免疫球蛋白可变结构域、抗体、dab、di-scFv、scFv、Fab、Fab'、F(ab')2、Fv片段、二体、三体、四体、线性抗体、单链抗体分子或多特异性抗体或融合蛋白的缀合物。
本发明还提供结合如本文所述的抗原结合位点、免疫球蛋白可变结构域、抗体、dab、di-scFv、scFv、Fab、Fab'、F(ab')2、Fv片段、二体、三体、四体、线性抗体、单链抗体分子或多特异性抗体、融合蛋白或缀合物的抗体。
本发明还提供了编码如本文所述的抗原结合位点、免疫球蛋白可变结构域、抗体、dab、di-scFv、scFv、Fab、Fab'、F(ab')2、Fv片段、二体、三体、四体、线性抗体、单链抗体分子或多特异性抗体、融合蛋白、或缀合物的核酸。因此,本发明还提供包含表2提供的核苷酸序列的任何一种的核酸,基本上由其组成的核酸,或由其组成的核酸。
在一个实例中,这种核酸包含在表达构建物中,其中核酸与启动子可操作地连接。这种表达构建物可以在载体中,例如质粒。
在针对单多肽链抗原结合位点的本发明实例中,表达构建物可包含与编码该多肽链的核酸连接的启动子。
在针对形成抗原结合位点的多条多肽链的实例中,表达构建物包含编码多肽的核酸,所述多肽包含例如与启动子可操作地连接的VH,和编码多肽的核酸,所述多肽包含例如与启动子可操作地连接的VL。
在另一个实例中,表达构建物是双顺反子表达构建物,例如,包含以下以5'至3'的顺序可操作地连接的成分:
(i)启动子;
(ii)编码第一多肽的核酸;
(iii)内部核糖体进入位点;和
(iv)编码第二多肽的核酸,
其中第一多肽包含VH,第二多肽包含VL,反之亦然。
本发明还涉及单独的表达构建物,其中一种编码包含VH的第一多肽,另一种编码包含VL的第二多肽。例如,本发明也提供组合物,包括:
(i)第一表达构建物,其包含编码多肽的核酸,所述多肽包含与启动子可操作地连接的VH;和
(ii)第二表达构建物,其包含编码多肽的核酸,所述多肽包含与启动子可操作地连接的VL。
本发明提供包含本文所述载体或核酸的细胞。优选地,细胞是分离的,基本上纯化的或重组的。在一个实例中,细胞包含本发明的表达构建物或:
(i)第一表达构建物,其包含编码多肽的核酸,所述多肽包含与启动子可操作地连接的VH;和
(ii)第二表达构建物,其包含编码多肽的核酸,所述多肽包含与启动子可操作地连接的VL,
其中所述第一和第二多肽缀合以形成本发明的抗原结合位点。
本发明的细胞的实例包括细菌细胞、酵母细胞、昆虫细胞或哺乳动物细胞。
本发明还提供药物组合物,其包含抗原结合位点,或包含如本文所述的CDR和/或FR序列,或如本文所述的免疫球蛋白可变结构域、抗体、dab、di-scFv、scFv、Fab、Fab'、F(ab')2、Fv片段、二体、三体、四体、线性抗体、单链抗体分子或多特异性抗体、融合蛋白或缀合物和药学上可接受的载体、稀释剂或赋形剂。
本发明还提供诊断组合物,其包含抗原结合位点,或包含如本文所述的CDR和/或FR序列,或如本文所述的抗原结合位点、免疫球蛋白可变结构域、抗体、dab、di-scFv、scFv、Fab、Fab'、F(ab')2、Fv片段、二体、三体、四体、线性抗体、单链抗体分子或多特异性抗体、融合蛋白或缀合物、稀释剂和任选的标记。
本发明还提供试剂盒或制品,其包含抗原结合位点,或包含如本文所述的CDR和/或FR序列,或如本文所述的免疫球蛋白可变结构域、抗体、dab、di-scFv、scFv、Fab、Fab'、F(ab')2、Fv片段、二体、三体、四体、线性抗体、单链抗体分子或多特异性抗体、融合蛋白或缀合物。
如本文所述的抗原结合位点、蛋白或抗体可包含人恒定区,例如IgG恒定区,如IgG1、IgG2、IgG3或IgG4恒定区或其混合物。在包含VH和VL的抗体或蛋白的情况下,VH可以与重链恒定区连接,并且VL可以与轻链恒定区连接。
在一个实例中,如本文所述的蛋白或抗体包含IgG4抗体的恒定区或IgG4抗体的稳定化的恒定区。在一个实例中,蛋白或抗体包含在241位具有脯氨酸的IgG4恒定区(根据Kabat的编号系统(Kabat等人,Sequences of Proteins of Immunological InterestWashington DC United States Department of Health and Human Services,1987和/或1991))。
在一个实例中,如本文所述的蛋白或抗体或如本文所述的蛋白或抗体的组合物包含重链恒定区,其包含稳定化的重链恒定区,其包含全部或部分具有或不具有C-末端赖氨酸残基的序列的混合物。
在一个实例中,本发明的抗体包含本文公开的与IgG4恒定区或稳定化的IgG4恒定区连接或融合的VH(例如,如上讨论),并且VL与κ轻链恒定区连接或融合。
本发明的抗原结合位点的功能性特征将作适当的修正后应用于本发明的抗体。
如本文所述的抗原结合位点可以是纯化的,基本上纯化的,分离的和/或重组的。
本发明的抗原结合位点可以是取自培养基的上清液的一部分,该培养基已经培养了表达本发明的抗原结合位点的杂交瘤。
本发明还提供治疗或预防与受试者中内源性IL-37的表达、产生、活化和/或分泌升高相关的病况的方法,该方法包括向受试者施用本发明的抗原结合位点,从而治疗或预防与内源性IL-37上升的表达、产生、活化和/或分泌相关的病况。
本发明还提供治疗或预防受试者中癌症的方法,该方法包括向受试者施用本发明的抗原结合位点,从而治疗或预防癌症。在这方面,抗原结合位点可用于预防病况的复发,并且这被认为是预防病况。
示例性癌症包括血液系统癌症、上皮来源的癌症、肝癌、胰腺癌、胃癌、骨肉瘤、子宫内膜癌和卵巢癌,或本文所述的任何其他癌症或肿瘤类型。
本发明还提供治疗或预防与受试者中免疫麻痹相关的病况的方法,该方法包括向受试者施用本发明的抗原结合位点,从而治疗或预防与免疫麻痹相关的病况。与免疫麻痹相关的示例性病况包括败血症,和急性和慢性肝衰竭。
本发明还提供包含本文所述的载体或核酸分子的细胞。
本发明还提供包含本文所述的细胞的动物或由其衍生的组织。
如本文所用,除非上下文另有要求,否则术语“包含”和该术语的变体,例如“含有”,并不意图排除其他添加剂、组分、整体或步骤。
从以下通过实施例并参考附图给出的描述中,本发明的进一步方面以及前述段落中所述的方面的进一步实施方案将变得明显。
附图简要说明
图1.融合后上清液人IL-37ELISA结果。通过微阵列评价抗体与靶抗原的结合后,通过ELISA进一步检测阳性克隆。显示的结果是通过ELISA测定的结合重组人IL-37的吸光度读数(原始吸光度读数),并以GST作为阴性对照。计算所述的阳性:阴性比率,并将阳性克隆鉴定为C3、D3和A3。
图2.用于检测特异性和交叉反应性的重组(rec)IL-18、rec IL-1β和rec IL-37的杂交瘤上清液的免疫印迹。用来自克隆D3的抗IL-37杂交瘤上清液探测印迹。未观察到与测试的蛋白的交叉反应性–泳道1:rec IL-18,泳道2:IL-1β,泳道3:标记物(突出显示25KDa标记物),和泳道4:rec人IL-37。
图3.用IL-1β阻断通过LPS诱导的内源性IL-37的ELISA读数。将从健康志愿者新鲜分离的PBMC与指定浓度的杂交瘤克隆D3上清液一起孵育。30分钟后,用LPS(500pg/ml)或载体刺激培养物。在加入LPS后0、1、3和6h收集上清液,并通过ELISA测定IL-1β。图表显示上清液IL-1β,为pg/ml±SEM(n=3个供体)。**,P<0.01;***,P<0.001,与单独的LPS相比。###,P<0.001,与t0后1小时的LPS+37bl1相比。
图4.IL-37阻断抗体的特征。首先用指定稀释度的IL-37阻断抗体(克隆D3)或对照处理新鲜分离的PBMC,然后在30分钟后加入指定浓度的D73K46-218或载体,并且再过30分钟后加入50pg/ml LPS。在加入LPS后20h,通过ELISA测定培养物上清液中IL-1β蛋白丰度,并计算在IL-37阻断抗体存在或不存在下用IL-37b变体处理所提供的百分比变化并作图±SEM;n=来自一个示例性供体的2个生物学重复。
图5.天然或单体IL-37的阻断。用表达天然1-218、D73K1-218或Y85A1-218的构建物转染THP-1细胞。用PMA(50ng/ml)分化24小时和培养基变化后,用IL-37阻断抗体(1:50稀释;克隆D3)或对照预处理培养物,然后用250ng/ml LPS或载体刺激培养物。对用IL-37阻断抗体和载体处理的培养物处理的培养物对(用相同的构建物转染的,即对照、天然、D73K或Y85A对,并用LPS刺激的)之间的IL-1β蛋白丰度的倍数变化进行计算并以平均值±SEM作图;n=每种LPS刺激条件的4个生物学重复;使用等级单因素方差分析(ANOVA on ranks)和Student-Newman-Keuls因果分析来评价统计学显著性;*,P<0.05对照vs IL-37b转染;#,P<0.05天然1-218vs D73K1-218或Y85A1-218。虚线表明在对照(即不是IL-37b)转染的培养物中IL-37阻断抗体诱导的IL-1β的背景。
图6.IL-37阻断抗体的特征。分离来自健康志愿者(n=2)的PBMC并用各种稀释度的杂交瘤上清液(克隆C3,1:5至1:500稀释度)预处理30分钟,然后在LPS刺激(500pg/mL)之前,用各种浓度(从1pg/mL至10ng/mL)天然重组IL-37(rIL-37)处理1小时。过夜孵育后,收集上清液,并通过ELISA测定IL-1β。
图7.用杂交瘤上清液阻断人外周血细胞中的重组IL-37的抗炎活性。分离来自两个供体的新鲜人PBMC,并以2.5×105个细胞/孔接种在96孔板中。将细胞搁置1小时,然后以指定的稀释度加入克隆RD1的杂交瘤上清液。孵育30min后,加入10pg/ml重组IL-37(Y85A变体)并孵育1h。然后用200pg/ml LPS过夜刺激细胞。通过ELISA测定上清液中的IL-1β,并通过与LPS+载体或LPS+RD1进行适当比较来计算IL-1β的变化。每个图显示来自一个供体的数据,其表示为百分比平均值±s.e.m。
图8.用杂交瘤上清液阻断小鼠脾细胞中的抗炎IL-37活性。从野生型(WT)和IL-37转基因(IL-37tg)小鼠中分离小鼠脾细胞(WT,n=2,IL-37tg,n=1),并以2.5x105个细胞/孔接种在96孔板中。将细胞搁置1h,然后在三个生物学重复中加入指定浓度的杂交瘤克隆RF1(左)和RF3(右)。孵育30min后,用LPS(250ng/mL)过夜刺激细胞。通过ELISA测定上清液中的IL-6,并通过比较LPS+杂交瘤上清液与LPS+载体来计算IL-6的变化。数据表示为百分比平均值±s.e.m。
具体实施方案
应理解,在本说明书中公开的和定义的发明扩展至提及的或从正文或附图明显可见的两个或更多个的单独特征的全部可替换组合。所有这些不同组合构成了本发明的各种可替换方面。
从下述实施例并参考附图给出的描述中,本发明进一步的方面以及前述段落中所述方面的进一步实施方案将变得明显。
现在将详细说明本发明的某些实施方案。虽然将结合实施方案描述本发明,但是应理解,本发明并不限于那些实施方案的发明。相反,本发明旨在覆盖所有替代、修饰和等价形式,其可以包括在由权利要求书所限定的本发明的范围内。
本发明人开发了结合并抑制或降低IL-37活性的抗原结合位点,例如抗体。IL-37通过抗炎信号传导抑制一系列细胞类型中的促炎细胞因子释放,包括人血细胞。如本文所述的抗原结合位点具有抑制或降低IL-37介导的抗炎活性的一个或多个方面的能力。
概述
贯穿本说明书,除非另外特别说明或上下文另有要求,否则术语单个步骤、物质组合物、步骤组或物质组合物组应包括一个和多个(即一个或更多个)那些步骤、物质组合物、步骤组或物质组合物组。因此,如本文所用,单数形式“一”、“一个”和“该”包括多个方面,反之亦然,除非上下文另有明确说明。例如,术语“一”包括单个以及两个或更多个;术语“一个”包括单个以及两个或更多个;术语“该”包括单个以及两个或更多个,等等。
本领域技术人员将理解,除了那些具体描述的之外,本发明易于进行变化和修改。应理解,本发明包括所有这些变化和修改。本发明还包括本说明书中单独或共同提及或指出的所有步骤、特征、组合物和化合物,以及所述步骤或特征的任意和所有组合或任何两个或更多个。
本领域技术人员将认识到许多类似于或等同于本文所述的方法和材料,这些方法和材料可用于本发明的实施中。本发明绝不限于所述的方法和材料。
本文提及的所有专利和出版物均通过引用整体并入。
本发明不限于本文所述的具体实例的范围,这些实例仅用于示例的目的。功能相等的产品、组分和方法显然在本发明的范围内。
除非另外特别说明,否则本文中本发明的任何实例或实施方案应经适当修改后适用于本发明的任何其它实例或实施方案。
除非另外特别定义,否则本文使用的所有技术和科学术语应被视为具有与本领域普通技术人员通常理解的含义相同的含义(例如,在细胞培养、分子遗传学、免疫学、免疫组织化学、蛋白质化学和生物化学中)。
除非另有说明,否则本公开中使用的重组蛋白、细胞培养和免疫学技术是本领域技术人员公知的标准程序。这些技术在整个源头文献中有描述和解释,例如J.Perbal,APractical Guide to Molecular Cloning,John Wiley and Sons(1984);J.Sambrook等人.Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory Press(1989);T.A.Brown(编辑),Essential Molecular Biology:A Practical Approach,第1卷和第2卷,IRL Press(1991);D.M.Glover和B.D.Hames(编辑),DNA Cloning:A PracticalApproach,第1-4卷,IRL Press(1995年和1996年);和F.M.Ausubel等人.(编辑),CurrentProtocols in Molecular Biology,Greene Pub.Associates和Wiley-Interscience(1988,包括直到现在的所有更新);Ed Harlow和David Lane(编辑)Antibodies:ALaboratory Manual,Cold Spring Harbor Laboratory,(1988);和J.E.Coligan等人.(编辑)Current Protocols in Immunology,John Wiley&Sons(包括直到现在的所有更新)。
本文中可变区及其部分、免疫球蛋白、抗体及其片段的描述和定义可通过KabatSequences of Proteins of Immunological Interest,National Institutes ofHealth,Bethesda,Md.,1987和1991;Bork等人.J Mol.Biol.242,309-320,1994;Chothia和Lesk J.Mol Biol.196:901-17,1987;Chothia等人.Nature 342,877-883,1989和/或或Al-Lazikani等人,J Mol Biol 273,927-948,1997中的讨论进一步阐明。
术语“和/或”,例如“X和/或Y”应理解为意指“X和Y”或“X或Y”,并应视为提供两者都的意思或二者任一的意思的明确支持。
如本文所用,术语“衍生自”应表示可以从特定来源获得指定的整体,但不一定必须直接来自该来源。
本文的术语例如残基的范围将被理解为包括在内。例如,将以包含在内的方式理解“包含氨基酸56至65的区域”,即该区域包含按指定的顺序排列的编号为56、57、58、59、60、61、62、63、64和65的氨基酸序列。
选择的定义
如本文所用,术语IL-37是指具有至少一种IL-37的生物化学或生物物理活性的分子,例如,它可以与白细胞介素18受体α(IL-18R1/IL-1Rrp)结合,并且可以是其配体。它还可以与白细胞介素18结合蛋白(IL-18BP)结合,白细胞介素18结合蛋白是白细胞介素18(IL-18)的抑制性结合蛋白,随后与IL-18受体β链形成复合物,并且通过它可以抑制IL-18活性。IL-37的其它生物化学或生物物理活性包括与IL-1R8(SIGIRR)结合,与SMAD3结合,与DNA结合,阻断由广谱炎症攻击引发的促炎细胞因子而非抗炎细胞因子(包括人或小鼠免疫细胞中的TLR配体、IFNγ、TNF和IL-1β)的产生、抑制树突状细胞的活化(降低CD86和MHC II的表面表达),引发细胞内激酶的特定调节模式(包括阻断mTOR、MAPK和NF-κB通路)以及抗炎激酶如Mer和PTEN的诱导。
IL-37也称为白细胞介素-37(FIL1ζ;IL-1ζ;IL-1F7b(IL-1H4、IL-1H、IL-1RP1);IL-1X蛋白;IL1F7(经典产物IL-1F7b);白细胞介素1家族成员7;白细胞介素1ζ;白细胞介素-1同系物4;白细胞介素-1超家族z;白细胞介素-1相关蛋白)。除非另有明确说明,当本文提及IL-37时,人IL-37具有5种同种型,a、b、c、d和e,其全都包括在内。人IL-37多肽的任何同种型或直系同源物也包括在本发明内。例如,本发明包括与任何人IL-37同种型a、b、c、d或e具有同一性的多肽。
仅出于命名目的而不对由本发明抗原结合位点结合的IL-37形式的范围进行任何限制,人IL-37分子的示例性序列示于SEQ ID NO:1。
短语“抑制IL-37活性”应理解为本发明的抗原结合位点抑制、拮抗、阻止或降低IL-37的任何一种或多种活性,包括但不限于,IL-37结合IL-18受体α(IL-18Rα)、IL-1受体8或其包含IL-18受体α(IL-18Rα)和IL-1受体8的复合物;IL-37与SMAD3结合或相互作用;IL-37与DNA结合或相互作用;IL-37介导的细胞信号传导;IL-37介导的体外或体内抗炎反应;IL-37介导细胞因子产生或分泌的减少;和/或自分泌或旁分泌IL-37介导的细胞因子产生或分泌的减少。
优选地,由IL-37降低其产生或分泌的细胞因子是促炎细胞因子。优选地,细胞因子是所述被IL-37调节的任何一种或多种,包括Nold等人.(2010)Nature Immunology 11(11):1014-22描述的那些,例如,sICAM-1、IFN-γ、I-TAC、G-SCF、IL-16、IL-10、IL-13、TNF、I-309、IL-2、IL-7、M-CSF、TIMP-1、IL-1α、MIP-1α、RANTES、MIG、IL-1Ra、sTREM-1、MCP-5、IP-10、MCP-1、IL-23、KC、IL-1β、MIP-2、IL-17、嗜酸细胞活化趋化因子和IL-6。更优选地,细胞因子是M-CSF、TIMP-1、IL-1α、MIP-1α、RANTES、MIG、IL-1Ra、sTREM-1、MCP-5、IP-10、MCP-1、IL-23、KC、IL-1β、MIP-2、IL-17、嗜酸细胞活化趋化因子和IL-6中的任何一种或更多种。最优选地,促炎细胞因子是IL-1β、IL-6和/或TNF。在Nold-Petry等.(2015)NatureImmunology 16,354–365中总结了由IL-37降低其产生或分泌的细胞因子和IL-37对细胞内通路的其它作用的实例。技术人员在其能力范围内能够确定哪个L-37介导的通路可以使用本发明的抗原结合位点来修饰。
优选地,使用单核细胞、巨噬细胞、外周血单核细胞(PBMC)、癌细胞或自其衍生的细胞测定IL-37介导的活性。优选地,癌细胞是诸如A549的肺上皮细胞,或诸如THP-1的单核细胞性白血病细胞。本文所述的抗原结合位点能够抑制IL-37对本文所述的任意细胞类型(包含单核细胞、巨噬细胞、外周血单核细胞(PBMC)、癌细胞或自其衍生的细胞)的作用。
术语“分离的蛋白”或“分离的多肽”是下述蛋白或多肽:由于其起源或衍生来源与其天然状态下伴随的天然相关组分无关;基本上不含来自相同来源的其他蛋白。使用本领域已知的蛋白纯化技术,可以使蛋白基本上不含天然相关组分或通过分离基本上纯化。“基本上纯化的”是指蛋白基本上不含污染剂,例如,至少约70%或75%或80%或85%或90%或95%或96%或97%或98%或99%不含污染剂。
术语“重组体”应理解为人工基因重组的产物。因此,在包含抗体抗原结合结构域的重组蛋白的背景下,该术语不包含在受试者体内天然存在的抗体,该抗体是在B细胞成熟期间产生的天然重组的产物。然而,如果分离该抗体,则认为其是包含抗体抗原结合结构域的分离蛋白。类似地,如果分离编码蛋白的核酸并使用重组方法表达,则所得蛋白是包含抗体抗原结合结构域的重组蛋白。重组蛋白还包括当它在细胞、组织或受试者体内时通过人工重组方法表达的蛋白质,例如其在其中表达的细胞、组织或受试者。
术语“蛋白”应理解为包括单条多肽链,即通过肽键连接的一系列连续氨基酸或彼此共价或非共价连接的一系列多肽链(即多肽复合物)。例如,使用合适的化学试剂或二硫键可以将该系列多肽链共价连接。非共价键的实例包括氢键、离子键、范德华力和疏水相互作用。
术语“多肽”或“多肽链”从前面的段落中理解为通过肽键连接的一系列连续氨基酸。
如本文所用,术语“抗原结合位点”可与“抗原结合结构域”互换使用,并且意指能够特异性结合抗原的抗体区域(即VH或VL或含有VH和VL两者的Fv)。抗原结合结构域在整个抗体的背景下是不必的,例如,其可以是分离的(例如结构域抗体)或其它形式,例如,如本文所述,如单链Fv片段(scFv)。
出于本公开的目的,术语“抗体”包括能够通过Fv中包含的抗原结合结构域特异性结合一种或几种密切相关的抗原(例如IL-37)的蛋白。该术语包括四链抗体(例如,两条轻链和两条重链)、重组或修饰的抗体(例如,嵌合抗体、人源化抗体、人抗体、CDR移植抗体、灵长类动物化(primatized)抗体、去免疫抗体、同人源(synhumanized)抗体、半抗体、双特异性抗体)。抗体通常包含恒定结构域,其可以排列成恒定区或恒定片段或可结晶片段(Fc)。抗体的示例性形式包括作为其基本单元的四链结构。全长抗体包含共价连接的两条重链(约50至70kD)和两条轻链(每条约23kDa)。轻链通常包含可变区(如果存在)和恒定结构域,并且在哺乳动物中是κ轻链或λ轻链。重链通常包含可变区和通过铰链区与另外的恒定结构域连接的一个或两个恒定结构域。哺乳动物的重链具有以下类型之一:α、δ、ε、γ或μ。每条轻链也与重链的一条共价连接。例如,两条重链以及重链和轻链通过链间二硫键和非共价相互作用连接在一起。链间二硫键的数量可以在不同类型的抗体之间变化。每条链具有N-末端可变区(VH或VL,其中每个长度约为110个氨基酸)和C-末端的一个或多个恒定结构域。轻链的恒定结构域(CL,长度约为110个氨基酸)与重链的第一个恒定结构域(CH1,长度为330至440个氨基酸)对齐并二硫键连接。轻链可变区与重链的可变区对齐。抗体重链可以包含2个或更多个额外的CH结构域(例如,CH2、CH3等),并且可以包含CH1和CH2恒定结构域之间的铰链区。抗体可以是任何类型(例如,IgG、IgE、IgM、IgD、IgA和IgY)、类别(例如,IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类。在一个实例中,抗体是鼠(小鼠或大鼠)抗体或灵长类动物(例如,人)抗体。在一个实例中,抗体重链缺少C端赖氨酸残基。在一个实例中,抗体是人源化的、同人源化的、嵌合的、CDR移植的或去免疫的。
术语“全长抗体”、“完整抗体”或“完全抗体”可互换使用,指基本上完整形式的抗体,与抗体的抗原结合片段相反。具体地,完全抗体包括具有包括Fc区的重链和轻链的抗体。恒定结构域可以是野生型序列恒定结构域(例如,人野生型序列恒定结构域)或其氨基酸序列变体。
如本文所用,“可变区”是指如本文所定义的抗体的轻链和/或重链的能够特异性结合抗原的部分,并且包括互补决定区(CDR),即CDR1,CDR2和CDR3,以及框架区(FR)的氨基酸序列。例如,可变区包含三个或四个FR(例如,FR1、FR2、FR3和任选的FR4)以及三个CDR。VH指重链的可变区。VL指轻链的可变区。
如本文所用,术语“互补决定区”(即CDR;即CDR1、CDR2和CDR3)是指抗体可变区的氨基酸残基,其存在是特异性抗原结合的主要贡献者。每个可变区结构域(VH或VL)通常具有三个CDR,其被鉴定为CDR1、CDR2和CDR3。在一个实例中,根据Kabat Sequences ofProteins of Immunological Interest,National Institutes of Health,Bethesda,Md.,1987和1991(在本文中也称为“Kabat编号系统”)定义分配给CDR和FR的氨基酸位置。在另一个实例中,根据“Enhanced Chothia Numbering Scheme”(http://www.bioinfo.org.uk/mdex.html)定义分配给CDR和FR的氨基酸位置。本发明并不限于由Kabat编号系统所定义的FR和CDR,而是包括所有编号系统,包括规范编号系统或Chothia和Lesk J.Mol.Biol.196:901-917,1987;Chothia等人,Nature 342:877-883,1989;和/或Al-Lazikani等人,J.Mol.Biol.273:927-948,1997的编号系统;Honnegher和PlükthunJ.Mol.Biol.309:657-670,2001的编号系统;或者在Giudicelli等人,Nucleic AcidsRes.25:206-211 1997中讨论的IMGT系统。在一个实例中,CDR根据Kabat编号系统来定义。任选地,根据Kabat编号系统的重链CDR2不包含本文列出的五个C-末端氨基酸或者那些氨基酸中的任何一个或多个被另一个天然存在的氨基酸取代。在这方面,Padlan等人,FASEBJ.,9:133-139,1995确认了重链CDR2的五个C-末端氨基酸通常不参与抗原结合。
“框架区”(FR)是除CDR残基之外的那些可变区残基。
如本文所用,术语“Fv”意指任何蛋白质,无论是由多个多肽还是单个多肽组成,其中VL和VH结合并形成具有抗原结合结构域的复合物,即能够特异性地与抗原结合。形成抗原结合结构域的VH和VL可以在单个多肽链中或在不同的多肽链中。此外,本发明的Fv(以及本发明的任何蛋白质)可具有多个抗原结合结构域,其可以结合或不结合相同的抗原。该术语应理解为包括直接衍生自抗体的片段以及对应于使用重组方法产生的此类片段的蛋白质。在一些实例中,VH不与重链恒定结构域(CH)1连接和/或VL不与轻链恒定结构域(CL)连接。含有多肽或蛋白质的示例性Fv包括Fab片段、Fab'片段、F(ab')片段、scFv、二体、三体,四体或更高级复合物,或与恒定区或其结构域连接的任何前述物质,例如CH2或CH3结构域,例如微抗体。“Fab片段”由免疫球蛋白的单价抗原结合片段组成,并且可以通过用酶木瓜蛋白酶消化完整抗体来产生,以产生由完整轻链和一部分重链组成的片段或可以使用重组方法产生。通过用胃蛋白酶处理完整抗体,然后还原,可以获得抗体的“Fab'片段”,以产生由完整轻链和包含VH和单个恒定结构域的重链的一部分组成的分子。以这种方式处理每个抗体获得两个Fab'片段。Fab'片段也可以通过重组方法产生。抗体的“F(ab')2片段”由被两个二硫键连接在一起的两个Fab'片段的二聚体组成,并且通过用胃蛋白酶处理整个抗体分子而无随后的还原而获得。“Fab2”片段是包含使用例如亮氨酸拉链或CH3结构域连接的两个Fab片段的重组片段。“单链Fv”或“scFv”是含有抗体可变区片段(Fv)的重组分子,其中轻链的可变区和重链的可变区通过合适的、易弯曲的多肽连接物共价连接。
如本文所用,与抗原结合位点或其抗原结合结构域与抗原的相互作用相关的术语“结合”是指该相互作用取决于抗原上特定结构(例如,抗原决定簇或表位)的存在。例如,抗体通常识别并结合特定蛋白结构而不是多个蛋白。如果抗体与表位“A”结合,则含有表位“A”(或游离的,未标记的“A”)的分子在含有标记的“A”和蛋白的反应中的存在将减少与抗体结合的标记的“A”的量。
如本文所用,术语“特异性结合”意指本发明的抗原结合位点以与可替换的抗原或细胞相比更频繁地、更快速地、以更长的持续时间和/或以更大亲和力与特定抗原或表达该抗原的细胞反应或结合。例如,与其它白细胞介素或通常被多反应性天然抗体识别的抗原(即,已知结合天然存在于人类中的多种抗原的天然存在的抗体)相比,抗原结合位点与IL-37(例如,hIL-37)的结合具有实质上更大的亲和力(例如,1.5倍或2倍或5倍或10倍或20倍或40倍或60倍或80倍至100倍或150倍或200倍)。在本发明的一个实例中,与另一种白细胞介素(例如IL-18和/或11-1β相比,抗原结合位点“特异性结合”hIL-37的亲和力至少为1.5倍或2倍或更高(例如,5倍或10倍或20倍或50倍或100倍或200倍)。通常但不是必要的,术语结合指特异性结合,并且每个术语应被理解为提供对另一术语的明确支持。
如本文所用,术语“不可检测地结合”意指抗原结合位点(例如抗体)以少于10%或8%或6%或5%背景以上的水平与候选抗原结合。背景可以是在不存在蛋白和/或存在阴性对照蛋白质(例如,同种型对照抗体)的情况下检测的结合信号水平和/或在阴性对照抗原存在下检测的结合水平。可以使用生物传感器分析(例如,Biacore)检测结合水平,其中抗原结合位点被固定并与抗原接触。
如本文所用,术语“不显著结合”意指本发明的抗原结合位点与多肽的结合水平在统计学上不显著高于背景,例如,不存在抗原结合位点和/或存在阴性对照蛋白(例如,同种型对照抗体)的情况下检测的结合信号水平和/或在阴性对照多肽存在下检测的结合水平。可以使用生物传感器分析(例如,Biacore)检测结合水平,其中抗原结合位点被固定并与抗原接触。
出于澄清的目的并且基于本文示例性主题而对本领域技术人员明显的,本说明书中的术语“亲和力”是指蛋白或抗体的术语KD。
出于澄清的目的并且基于本文的描述而对本领域技术人员明显的,术语“至少约…的亲和力”意指亲和力(或KD)等于或大于所列举的值(即,当亲和力较低时所列举的值),即2nM的亲和力大于3nM的亲和力。换句话说,该术语可以是“X或更小的亲和力”,其中X是本文所列举的值。
如本文所用,术语“表位”(或“抗原决定簇”)意指IL-37的区域,包含抗体抗原结合结构域的抗原结合位点与其结合。该术语不必限于抗原结合位点与之接触的特定残基或结构。例如,该术语包括跨越被抗原结合位点接触的氨基酸的区域和该区域外5-10(或更多)或2-5或1-3个氨基酸。在一些实例中,表位包含一系列不连续的氨基酸,当抗原结合位点折叠时,它们位置彼此靠近,即“构象表位”。技术人员还将意识到术语“表位”不限于肽或多肽。例如,术语“表位”包括分子的化学活性表面基团,例如糖侧链、磷酰基侧链或磺酰基侧链,并且在某些实例中,可具有特定的三维结构特征,和/或特定的电荷特征。
如本文所用,术语“病况”是指正常功能的破坏或与其的干扰,并且不限于任何特定病况,并且将包括疾病或紊乱。
如本文所用,术语“预防”包括施用本发明的抗原结合位点,从而阻止或阻碍病况的至少一种症状的发展。该术语还包括治疗缓解中的受试者以预防或阻碍复发。
如本文所用,术语“治疗”包括施用本文所述的抗原结合位点,从而减少或消除特定疾病或病况的至少一种症状。
如本文所用,术语“受试者”意指包括人类在内的任何动物,例如哺乳动物。示例性受试者包括但不限于人和非人灵长类动物、伴侣动物如狗和猫,以及农场动物如马、绵羊和牛。优选地,受试者是人。
抗体
在一个实例中,根据任何实例的本文所述的抗原结合位点或IL-37结合蛋白是抗体。
产生抗体的方法是本领域已知的和/或描述于Harlow和Lane(编辑)Antibodies:ALaboratory Manual,Cold Spring Harbor Laboratory,(1988)。通常,在此类方法中,将IL-37(例如,hIL-37)或其区域(例如,细胞外区域)或免疫原性片段或其表位或表达和展示同样物质(即免疫原)的细胞,任选地与任何合适的或所需的载体、佐剂或药学上可接受的赋形剂配制,施用于非人动物,例如小鼠、禽、大鼠、兔、豚鼠、狗、马、牛、山羊或猪。免疫原可以鼻内、肌肉内、皮下、静脉内、皮内、腹膜内或通过其他已知途径施用。
可以通过在免疫后的不同时间点对免疫的动物的血液进行取样来检测多克隆抗体的产生。如果需要获得所需的抗体滴度,可以给予一次或多次进一步的免疫。重复加强免疫和滴度测定的过程,直到达到合适的滴度。当获得所需水平的免疫原性时,将免疫的动物放血并分离和储存血清,和/或使用动物产生单克隆抗体(mAb)。
单克隆抗体是本发明所考虑的一种示例性抗体形式。术语“单克隆抗体”或“imAb”是指能够与相同抗原结合的相同成分组成的抗体群,例如,与抗原内的相同表位结合。该术语不意图受限于抗体来源或其制备方式。
对于mAb的生产,可以使用许多已知技术中的任何一种,例如,如US4196265或上述Harlow和Lane(1988)中所例证的方法。
例如,在足以刺激产生抗体的细胞的条件下用免疫原免疫合适的动物。诸如兔、小鼠和大鼠的啮齿动物是示例性动物。经遗传工程化以表达人抗体的小鼠(例如,不表达鼠抗体的小鼠)也可用于产生本发明的抗体(例如,如WO2002/066630中所述)。
免疫接种后,选择具有产生抗体潜力的体细胞,特别是B淋巴细胞(B细胞),用于mAb产生方案。这些细胞可以从脾脏、扁桃体或淋巴结的活组织检查中获得,或从外周血样品中获得。然后将来自免疫的动物的B细胞与永生化骨髓瘤细胞的细胞融合,所述永生化骨髓瘤细胞通常衍生自与用免疫原免疫的动物相同的物种。
通过在选择性培养基中培养来扩增杂交体,所述培养基包含阻断组织培养基中核苷酸的从头合成的试剂。示例性药剂是氨基蝶呤、甲氨蝶呤和重氮丝氨酸。
对扩增的杂交瘤进行抗体特异性和/或滴度的功能性选择,例如通过流式细胞术和/或免疫组织化学和/或免疫测定(例如放射免疫测定、酶免疫测定、细胞毒性测定、噬斑测定、斑点免疫测定等)。
或者,使用ABL-MYC技术(NeoClone,Madison WI 53713,美国)产生分泌MAb的细胞系(例如,如Largaespada等,J.Immunol.Methods.197:85-95,1996所述)。
还可以通过筛选展示文库(例如噬菌体展示文库)来产生或分离抗体,例如,如US6300064和/或US5885793中所述。例如,本发明人从噬菌体展示文库中分离出完全人抗体。
本发明的抗体可以是合成抗体。例如,抗体是嵌合抗体、人源化抗体,人抗体、同人源化抗体、灵长类动物化抗体或去免疫抗体。
含有抗体结合结构域的蛋白
单结构域抗体
在一些实例中,本发明的蛋白是或包含单结构域抗体(其可与术语“结构域抗体”或“dAb”互换使用)。单结构域抗体是包含抗体的全部或部分重链可变区的单多肽链。在某些实例中,单结构域抗体是人单结构域抗体(Domantis,Inc.,Waltham,MA;参见例如US6248516)。
二体、三体、四体
在一些实例中,本发明的蛋白是或包含二体、三体、四体或更高级的蛋白复合物,例如在WO98/044001和/或WO94/007921中所述的那些。
例如,二体是包含两个缔合的多肽链的蛋白,每个多肽链包含结构VL-X-VH或VH-X-VL,其中VL是抗体轻链可变区,VH是抗体重链可变区,X是包含不足以允许单条多肽链中的VH和VL缔合(或形成Fv)或不存在的残基的连接物,并且其中一条多肽链的VH结合另一条多肽链的VL以形成抗原结合结构域,即形成能够特异性结合一种或更多种抗原的Fv分子。VL和VH在每条多肽链中可以是相同的,或者VL和VH在每条多肽链中可以是不同的,以便形成双特异性二体(即包含两种具有不同特异性的Fv)。
单链Fv(scFv)
技术人员将意识到scFv包含单条多肽链中的VH和VL区以及VH和VL之间的多肽连接物,其能够使scFv形成用于抗原结合的所需结构(即用于单条多肽链的VH和VL彼此缔合以形成Fv)。例如,连接物包含超过12个氨基酸残基,其中(Gly4Ser)3是scFv的更有利的连接物之一。
本发明还涉及二硫化物稳定的Fv(或diFv或dsFv),其中将单个半胱氨酸残基引入VH的FR和VL的FR以及通过二硫键连接半胱氨酸残基以产生稳定的Fv。
或者或另外,本发明包括二聚体scFv,即包含通过非共价或共价连接(例如,通过亮氨酸拉链结构域(例如衍生自Fos或Jun))的两个scFv分子的蛋白。或者,两个scFv通过足够长度的肽连接物连接以允许两个scFv形成并结合抗原,例如,如US20060263367中所述。
重链抗体
重链抗体在结构上与许多其它形式的抗体不同,因为到目前为止它们包含重链,但不包含轻链。因此,这些抗体也称为“仅重链抗体”。重链抗体发现于例如骆驼科动物和软骨鱼(也称为IgNAR)中。
天然存在的重链抗体中存在的可变区通常被称为骆驼抗体中的“VHH结构域”和IgNAR中的V-NAR,以便将它们与常规4-链抗体中存在的重链可变区(其被称为“VH结构域”)和来自常规4-链抗体中存在的轻链可变区(其被称为“VL结构域”)相区别。
来自骆驼科动物的重链抗体及其可变区的一般描述及其生产和/或分离和/或使用它们的方法尤其可在以下参考文献WO94/04678、WO97/49805和WO97/49805中找到。
来自软骨鱼的重链抗体及其可变区的一般描述及其生产和/或分离和/或使用它们的方法尤其在WO2005/118629中找到。
其他抗体和包含其抗原结合域的蛋白
本发明还涉及包含其他抗体和包含其抗原结合结构域的蛋白,例如:
(i)如US5731168中所述的“臼杵”(key and hole)双特异性蛋白;
(ii)异源偶联蛋白,例如,如US4676980中所述;
(iii)使用化学交联剂产生的异源偶联蛋白,例如,如US4676980中所述;和
(iv)Fab3(例如,如EP19930302894中所述)。
蛋白突变
本发明还提供抗原结合位点或编码其的核酸,其与本文公开的序列具有至少80%的同一性。在一个实例中,本发明的抗原结合位点或核酸包含与本文公开的序列至少约85%或90%或92%或95%或97%或98%或99%同一的序列。
或者或另外,抗原结合位点包含与根据任何实例如本文所述的VH或VL的CDR至少约80%或85%或90%或92%或95%或97%或98%或99%同一的CDR(例如,3个CDR)。
在另一个实例中,本发明的核酸包含与编码抗原结合位点的序列至少约80%或85%或90%或92%或95%或97%或98%或99%同一的序列,所述抗原结合位点具有根据任何实例如本文所述的功能。本发明还包括编码本发明的抗原结合位点的核酸,其作为遗传密码的简并性的结果而与本文示例的序列不同。
核酸或多肽的同一性百分比由具有空位产生罚分=5及空位延伸罚分=0.3的GAP(Needleman和Wunsch.Mol.Biol.48,443-453,1970)分析(GCG程序)测定。查询序列长度至少为50个残基,并且GAP分析在至少50个残基的区域上比对两个序列。例如,查询序列长度至少为100个残基,并且GAP分析在至少100个残基的区域上比对两个序列。例如,两个序列在其整个长度上比对。
本发明还涉及在严格杂交条件下与编码本文所述抗原结合位点的核酸杂交的核酸。“中等严格性”在本文中定义为在2x SSC缓冲液、0.1%(w/v)SDS中在45℃至65℃范围内的温度下或相等条件下进行的杂交和/或洗涤。“高严格性”在本文中定义为在0.1x SSC缓冲液、0.1%(w/v)SDS或更低的盐浓度中,并且在至少65℃的温度下,或相等条件下进行的杂交和/或洗涤。本文提及的特定严格性水平包括使用本领域技术人员已知的除SSC之外的洗涤/杂交溶液的相等条件。例如,用于计算双链核酸的链将分离的温度的方法(也称为解链温度,或Tm)是本领域已知的。与核酸的Tm相似(例如,在5℃或10℃内)或相等的温度被认为是高严格性。中等严格性被认为是在核酸的计算的Tm的10℃至20℃或10℃至15℃内。
本发明还涉及本发明的抗原结合位点的突变体形式,与本文所示序列相比,其包含一个或更多个保守氨基酸取代。在一些实例中,抗原结合位点包含10个或更少,例如9或8或7或6或5或4或3或2或1个保守氨基酸取代。“保守氨基酸取代”是其中氨基酸残基被具有相似侧链和/或亲水性(hydropathicity)和/或亲水性(hydrophilicity)的氨基酸残基所代替的一种。
本领域已经定义了具有相似侧链的氨基酸残基家族,包括碱性侧链(例如赖氨酸、精氨酸、组氨酸),酸性侧链(例如天冬氨酸、谷氨酸),不带电荷的极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸),非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸,脯氨酸、苯丙氨酸、蛋氨酸、色氨酸),β-支链侧链(例如苏氨酸、缬氨酸、异亮氨酸)和芳香族侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。例如在Kyte和Doolittle J.Mol.Biol.,157:105-132,1982中描述了亲水(hydropathic)指数并且在例如US4554101中描述了亲水(hydrophylic)指数。
本发明还涉及非保守氨基酸变化。例如,特别感兴趣的是带电荷的氨基酸被另一个带电荷的氨基酸和中性的或带正电荷的氨基酸所取代。在一些实例中,抗原结合位点包含10个或更少,例如9或8或7或6或5或4或3或2或1个非保守氨基酸取代。
在一个实例中,突变发生在本发明的抗原结合位点的抗原结合结构域的FR内。在另一个实例中,突变发生在本发明的抗原结合位点的CDR内。
产生抗原结合位点的突变体形式的示例性方法包括:
·DNA诱变(Thie等人,Methods Mol.Biol.525:309-322,2009)或RNA诱变(Kopsidas等人,Immunol.Lett.107:163-168,2006;Kopsidas等人,BMC Biotechnology,7:18,2007;和WO1999/058661);
·将编码多肽的核酸导入突变细胞,例如XL-1Red、XL-mutS和XL-mutS-Kanr细菌细胞(Stratagene);
·DNA改组,例如,如Stemmer,Nature 370:389-91,1994中所公开的;和
·定点突变,例如,如Dieffenbach(编辑)和Dveksler(编辑)(In:PCR Primer:ALaboratory Manual,Cold Spring Harbor Laboratories,NY,1995)中所述。
用于测定本发明的突变体抗原结合位点的生物活性的示例性方法对于技术人员是明显的和/或如本文描述,例如抗原结合。例如,本文描述了用于确定抗原结合、竞争性结合抑制、亲和力、缔合、分离和治疗功效的方法。
恒定区
本发明包括本文所述的抗原结合位点和/或抗体,其包含抗体的恒定区。这包括与Fc融合的抗体的抗原结合片段。
用于生产本发明蛋白的恒定区序列可从许多不同来源获得。在一些实例中,蛋白的恒定区或其部分衍生自人抗体。恒定区或其部分可以衍生自任何抗体类别,包括IgM、IgG、IgD、IgA和IgE,以及任何抗体同种型,包括IgG1、IgG2、IgG3和IgG4。在一个实例中,恒定区是人同种型IgG4或稳定化的IgG4恒定区。
在一个实例中,恒定区的Fc区具有降低的诱导效应物功能的能力,例如与天然的或野生型人IgG1或IgG3Fc区相比。在一个实例中,效应物功能是抗体依赖性细胞介导的细胞毒性(ADCC)和/或抗体依赖性细胞介导的吞噬作用(ADCP)和/或补体依赖性细胞毒性(CDC)。用于评价含有Fc区的蛋白的效应物功能的水平的方法是本领域已知的和/或如本文所述的。
在一个实例中,Fc区是IgG4Fc区(即来自IgG4恒定区),例如人IgG4Fc区。合适的IgG4Fc区的序列对于技术人员是明显的和/或可在公开可用的数据库中获得(例如,可从National Center for Biotechnology Information中获得)。
在一个实例中,恒定区是稳定化的IgG4恒定区。术语“稳定化的IgG4恒定区”意指已经被修饰以减少Fab臂交换或经历Fab臂交换的倾向或形成半抗体或形成半抗体的倾向的IgG4恒定区。“Fab臂交换”指人IgG4的蛋白修饰类型,其中IgG4重链和连接的轻链(半分子)被来自另一IgG4分子的重-轻链对所替换。因此,IgG4分子可以获得识别两种不同抗原的两个不同的Fab臂(产生双特异性分子)。Fab臂交换在体内天然发生,并且可以通过纯化的血细胞或诸如还原型谷胱甘肽的还原剂在体外诱导。当IgG4抗体解离形成两个分子时,形成“半抗体”,其中每个分子含有单条重链和单条轻链。
在一个实例中,稳定化的IgG4恒定区包含根据Kabat系统(Kabat等人,Sequencesof Proteins of Immunological Interest Washington DC United States Departmentof Health and Human Services,1987和/或1991)在铰链区的241位的脯氨酸。该位置对应于根据EU编号系统(Kabat等人,Sequences of Proteins of Immunological InterestWashington DC United States Department of Health and Human Services,2001和Edelman等人,Proc.Natl.Acad.USA,63,78-85,1969)的铰链区的228位。在人IgG4中,该残基通常是丝氨酸。在丝氨酸替代为脯氨酸后,IgG4铰链区包含序列CPPC。在这方面,技术人员将意识到“铰链区”是抗体重链恒定区的富含脯氨酸的部分,其连接Fc和Fab区,其赋予抗体的两个Fab臂移动性。铰链区包括参与重链间二硫键形成的半胱氨酸残基。通常根据Kabat编号系统定义为人IgG1的Glu226延伸至Pro243。通过将形成重链间二硫(S-S)键的第一个和最后一个半胱氨酸残基置于相同位置,可以使其它IgG同种型的铰链区与IgG1序列对齐(参见例如WO2010/080538)。
稳定化的IgG4抗体的其他实例是其中人IgG4的重链恒定区中在409位的精氨酸(根据EU编号系统)被赖氨酸、苏氨酸、蛋氨酸或亮氨酸替代的抗体(例如,如在WO2006/033386中所述)。恒定区的Fc区可以额外地或可选地包含选自由位置对应于405(根据EU编号系统)的丙氨酸、缬氨酸、甘氨酸、异亮氨酸和亮氨酸组成的组的残基。任选地,铰链区包含在241位的脯氨酸(即CPPC序列)(如上所述)。
在另一个实例中,Fc区是经修饰以具有降低的效应物功能的区域,即“非免疫刺激性Fc区”。例如,Fc区是IgG1Fc区,其包含选自由268、309、330和331组成的组一个或更多个位置的取代。在另一个实例中,Fc区是IgG1 Fc区,其包含以下一种或更多种变化:E233P、L234V、L235A和G236的缺失和/或以下一种或更多种变化:A327G、A330S和P331S(Armour等人,Eur J Immunol.29:2613-2624,1999;Shields等人,J Biol Chem.276(9):6591-604,2001)。非免疫刺激性Fc区的其他实例描述于例如Dall'Acqua等人,J Immunol.177:1129-1138 2006;和/或Hezareh J Virol;75:12161-12168,2001)中。
在另一个实例中,Fc区是嵌合Fc区,例如,包含来自IgG4抗体的至少一个CH2结构域和来自IgG1的至少一个CH3结构域,其中Fc区包含选自由240、262、264、266、297、299、307、309、323、399、409和427(EU编号)(例如,如WO2010/085682中所述)组成的组的一个或更多个氨基酸位置的取代。示例性取代包括240F、262L、264T、266F、297Q、299A、299K、307P、309K、309M、309P、323F、399S和427F。
其他修饰
本发明还涉及包含Fc区或恒定区的抗体或抗原结合位点的其他修饰。
例如,抗体包含一个或更多个氨基酸取代,其增加蛋白的半衰期。例如,抗体包含Fc区,其包含一个或更多个氨基酸取代,其增加Fc区对新产生的Fc区(FcRn)的亲和力。例如,Fc区在较低pH(例如,约pH 6.0)下对FcRn具有增加的亲和力,以促进内体中Fc/FcRn的结合。在一个实例中,与在约pH 7.4下的亲和力相比,Fc区在约pH 6下对FcRn具有增加的亲和力,这促进细胞再循环后Fc重新释放到血液中。这些氨基酸取代通过减少从血液的清除用于延长蛋白的半衰期。
根据EU编号系统,示例性氨基酸取代包括T250Q和/或M428L或T252A、T254S和T266F或M252Y、S254T和T256E或H433K和N434F。另外的或替代的氨基酸取代描述于,例如US20070135620或US7083784中。
蛋白生产
在一个实例中,根据任何实例的本文所述的抗原结合位点在足以产生蛋白的条件下通过培养杂交瘤来产生,例如,如本文所述和/或如本领域已知。
重组表达
在另一个实例中,根据任何实例的本文所述的抗原结合位点是重组的。
在重组蛋白的情况下,可以将编码其的核酸克隆到表达构建物或载体中,然后将其转染到宿主细胞中,例如大肠杆菌细胞、酵母细胞、昆虫细胞或哺乳动物细胞,例如猴COS细胞、中国仓鼠卵巢(CHO)细胞、人胚肾(HEK)细胞、或其它方面不产生所述蛋白的骨髓瘤细胞。用于表达蛋白的示例性细胞是CHO细胞、骨髓瘤细胞或HEK细胞。实现这些目的的分子克隆技术是本领域已知的,并描述于例如Ausubel等人,(编辑),Current Protocols inMolecular Biology,Greene Pub.Associates and Wiley-Interscience(1988,包括直到现在的所有更新)或Sambrook等人,Molecular Cloning:A Laboratory Manual,ColdSpring Harbor Laboratory Press(1989)中。多种克隆和体外扩增方法适用于构建重组核酸。产生重组抗体的方法也是本领域已知的,参见例如US4816567或US5530101。
分离后,将与启动子可操作连接的核酸插入到表达构建物或表达载体中,用于进一步克隆(DNA扩增)或用于在无细胞系统或细胞中表达。
如本文所用,术语“启动子”应在其最广泛的背景下应用,并且包括基因组基因的转录调控序列,包括TATA盒或起始因子,其在有或没有额外的调节元件(例如,上游激活序列、转录因子结合位点、增强子和沉默子)下是精确转录起始所必需的,其改变核酸的表达,例如,响应于发育和/或外部刺激,或以组织特异性方式。在本上下文中,术语“启动子”也用于描述重组、合成或融合核酸,或衍生物,其赋予、激活或增强与其可操作连接的核酸的表达。示例性启动子可含有一种或更多种特定调节元件的额外拷贝,以进一步增强所述核酸的表达和/或改变所述核酸的空间表达和/或时间表达。
如本文所用,术语“可操作地连接”意指相对于核酸放置启动子,使得该核酸的表达受启动子控制。
可获得许多用于在细胞中表达的载体。载体成分通常包括但不限于以下一种或更多种:信号序列、编码蛋白的序列(例如,衍生自本文提供的信息)、增强子元件、启动子和转录终止序列。技术人员知道用于表达蛋白的合适序列。示例性信号序列包括原核分泌信号(例如,pelB、碱性磷酸酶、青霉素酶、Ipp或热稳定肠毒素II)、酵母分泌信号(例如转化酶前导序列、α因子前导序列、或酸性磷酸酶前导序列)或哺乳动物分泌信号(例如,单纯疱疹gD信号)。
在哺乳动物细胞中有活性的示例性启动子包括巨细胞病毒即刻早期启动子(CMV-IE)、人延伸因子1-α启动子(EF1)、小核RNA启动子(U1a和U1b)、α-肌球蛋白重链启动子、猴病毒40启动子(SV40)、劳氏肉瘤病毒启动子(RSV)、腺病毒主要晚期启动子、β-肌动蛋白启动子;包含CMV增强子/β-肌动蛋白启动子或免疫球蛋白启动子或其活性片段的杂合调节元件。有用的哺乳动物宿主细胞系的实例是由SV40转化的猴肾CV1系(COS-7,ATCC CRL1651);人胚肾系(293或亚克隆用于在悬浮培养中培养的293细胞;幼仓鼠肾细胞(BHK,ATCCCCL 10);或中国仓鼠卵巢细胞(CHO)。
适于在酵母细胞(例如,如选自包含毕赤酵母、酿酒酵母和裂殖酵母的组的酵母细胞)中表达的典型启动子包括但不限于,ADH1启动子、GAL1启动子、GAL4启动子、CUP1启动子、PHO5启动子、nmt启动子、RPR1启动子或TEF1启动子。
用于将分离的核酸或包含其的表达构建物导入细胞用于表达的方法是本领域技术人员已知的。用于给定细胞的技术取决于已知的成功技术。用于将重组DNA导入细胞的方法包括显微注射、由DEAE-葡聚糖介导的转染、脂质体介导的转染(例如使用lipofectamine(Gibco,MD,美国)和/或cellfectin(Gibco,MD,美国))、PEG介导的DNA摄取、电穿孔和微粒轰击(例如通过使用DNA包裹的钨或金颗粒(Agracetus Inc.,WI,美国))等。
用于产生蛋白的宿主细胞可以在各种培养基中培养,这取决于所用的细胞类型。商业上可用的培养基例如Ham's Fl0(Sigma)、最小必须培养基((MEM)(Sigma)、RPMl-1640(Sigma)和Dulbecco改良Eagle培养基(DMEM)(Sigma)适合于培养哺乳动物细胞。本文讨论的用于培养其他细胞类型的培养基是本领域已知的。
蛋白分离
用于分离蛋白的方法是本领域已知的和/或本文所述。
当抗原结合位点分泌至培养基中时,可使用商业上可用的蛋白浓缩滤器,例如Amicon或Millipore Pellicon超滤单元首先浓缩来自此类表达系统的上清液。蛋白酶抑制剂如PMSF可以包括在任何前述步骤中以抑制蛋白水解,并且包括抗生素以防止外来污染物的生长。或者或另外,可以将上清液从表达蛋白的细胞中过滤和/或分离,例如使用连续离心。
可以使用例如离子交换、羟基磷灰石层析、疏水相互作用层析、凝胶电泳、透析、亲和层析(例如,蛋白A亲和层析或蛋白G层析)或以上任何组合来纯化从细胞制备的抗原结合位点。这些方法是本领域已知的,并描述于例如WO99/57134或Ed Harlow和David Lane(编辑)Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory,(1988)中。
本领域技术人员还将意识到可以修饰蛋白以包括易于纯化或检测的标签,例如,多组氨酸标签,例如六组氨酸标签,或流感病毒血凝素(HA)标签,或猴病毒5(V5)标签,或FLAG标签,或谷胱甘肽S-转移酶(GST)标签。然后使用本领域已知的方法,例如亲和纯化,来纯化所得蛋白。例如,通过使包含蛋白的样品与镍-次氮基三乙酸(Ni-NTA)接触来纯化包含六组氨酸标签的蛋白,所述镍-次氮基三乙酸特异性结合固定在固体或半固体支持物上的六组氨酸标签,洗涤样品以除去未结合的蛋白,然后洗脱结合的蛋白。或者,或另外,结合标签的配体或抗体用于亲和纯化方法中。
测定IL-37结合蛋白的活性
与IL-37及其突变体结合
从本文的公开内容本领域技术人员明显可知的,本发明的一些抗原结合位点与IL-37和IL-37的特定突变体形式结合。评价与蛋白结合的方法是本领域已知的,例如,如Scopes(In:Protein purification:principles and practice,第三版,SpringerVerlag,1994)中所述。这种方法通常涉及固定抗原结合位点并使其与标记的抗原接触。洗涤以除去非特异性结合蛋白后,检测标记物和作为结果的结合的抗原的量。当然,可以标记抗原结合位点并固定抗原。也可以使用淘选型测定。或者,或另外,可以使用表面等离子体共振测定。
任选地,测定IL-37或其表位的固定化抗原结合位点的解离常数(Kd)、缔合常数(Ka)和/或亲和常数(KD)。在一个实例中,通过放射性标记或荧光标记的IL-37结合测定来测量IL-37结合蛋白的“Kd”或“Ka”或“KD”。在“Kd”的情况下,该测定在未标记的IL-37滴定系列的存在下用最小浓度的标记的IL-37平衡抗原结合位点。洗涤已除去未结合的IL-37后,测定标记物的量,这指示蛋白的Kd。
根据另一个实例,通过使用表面等离子共振分析,例如使用BIAcore表面等离子共振(BIAcore,Inc.,Piscataway,NJ)测量固定的IL-37或其区域或固定的抗原结合位点的Kd、Ka或KD。
测定抑制活性
在本发明的一些实例中,抗原结合位点能够抑制IL-37活性。
本领域已知各种用于评价蛋白通过受体抑制或减少配体信号传导能力的测定。
在一个实例中,抗原结合位点促进表达IL-18受体α(IL-18Rα)和IL-1受体8的细胞(或者,修饰以表达这两种蛋白的细胞)(例如,PBMC)中诸如IL-1β的促炎细胞因子的产生或分泌,该细胞在recIL-37(重组IL-37)存在下培养。细胞(例如,约1x104个细胞)在存在reclL-37下(例如,在约1pg/mL至约10ng/mL(例如1pg/mL或10ng/mL)之间)及存在或不存在测试的抗原结合位点或促炎刺激和抗原结合位点下培养。用于评价促炎细胞因子的产生或分泌的方法是本领域已知的。与不存在抗原结合位点时观察到的水平相比,增强促炎细胞因子的产生或分泌水平的抗原结合位点被认为抑制或降低IL-37活性,特别是IL-37信号传导。
本公开内容涉及用于评价IL-37信号传导增强的其他方法,包括如实施例6中所述的THP-1细胞测定。
评价治疗功效
上文描述了用于评价与抗原结合位点的中和有关的治疗功效的测定。
在另一个实例中,使用体内测定评价蛋白治疗病况的效果。
例如,可以在癌症(例如胃癌)模型中测试抗原结合位点。例如,gp130的Y757F变体的小鼠同源物(gp130Y757F/Y757F)发展为胃肿瘤(Jenkins等人,Blood 109:2380-2388,2007)。用抗原结合位点处理小鼠(例如,8周龄小鼠)并评价胃息肉的数量和/或重量。减少息肉尺寸和/或重量的抗原结合位点被认为可用于治疗癌症。类似的测定可用于测试对结肠癌的作用,其中gp130Y757F/Y757F小鼠在用抗原结合位点处理前用氧化偶氮甲烷(AOM)处理,接着用葡聚糖硫酸钠(DSS)处理,基本上如Greten等人,Cell,118:285-296,2004所述,以诱导结肠癌。
另外或可替代地,可以在癌症转移或癌症相关骨病的模型中测试抗原结合位点,例如,如Li等人,Oncol.Lett.3:802-806,2012中所述。
待治疗或预防的病况
本发明的抗原结合位点可用于治疗或预防与内源性IL-37表达相关的病况,包括“正常”表达水平或升高的表达。内源性IL-37的升高表达可以通过测量受试者的循环或受试者特定位置(例如,在特定组织或器官中)的IL-37的量或浓度来测定。可以使用本领域技术人员已知的技术通过测量mRNA或蛋白水平来测定IL-37的表达。
进一步,本发明的抗原结合位点可用于治疗或预防癌症。广泛的实例包括乳腺肿瘤、结直肠肿瘤、腺癌、间皮瘤、膀胱肿瘤、前列腺肿瘤、生殖细胞肿瘤、肝癌/胆管癌、恶性上皮肿瘤(carcinoma)、神经内分泌肿瘤、垂体肿瘤、小圆细胞瘤、鳞状细胞癌、黑色素瘤、非典型纤维黄瘤、精原细胞瘤、非精原细胞瘤、基质睾丸间质细胞瘤、支持细胞瘤、皮肤肿瘤、肾肿瘤、睾丸肿瘤、脑肿瘤、卵巢肿瘤、胃肿瘤、口腔肿瘤、膀胱肿瘤、骨肿瘤、宫颈肿瘤、食管肿瘤、喉部肿瘤、肝肿瘤、肺肿瘤、阴道肿瘤和Wilm氏肿瘤。
特定癌症的实例包括但不限于腺癌、腺瘤、腺纤维瘤、腺淋巴瘤、牙瘤(adontoma)、AIDS相关癌症、听神经瘤、急性淋巴细胞白血病、急性髓性白血病、腺样囊性癌、肾上腺皮质癌、特发性骨髓外化生、秃头症、肺泡软部分肉瘤、成釉细胞瘤、血管角质瘤、血管淋巴样增生伴嗜酸粒细胞增多症、血管瘤硬化、血管瘤、胺前体摄取与脱羧细胞瘤、肛门癌、血管肉瘤、再生障碍性贫血、星形细胞瘤、共济失调性毛细血管扩张症、基底细胞癌(皮肤)、膀胱癌、骨癌、肠癌、脑干胶质瘤、脑和CNS肿瘤、乳腺癌、鳃原瘤、CNS肿瘤、类癌瘤、宫颈癌、儿童脑肿瘤、儿童癌症、儿童白血病、儿童软组织肉瘤、软骨肉瘤、绒毛膜癌、慢性淋巴细胞白血病、慢性粒细胞白血病、结直肠癌、皮肤T-细胞淋巴瘤、恶性上皮肿瘤(如Walker、基底细胞、基底鳞状细胞、Brown-Pearce、导管、Ehrlich肿瘤、Krebs 2、Merkel细胞、粘液性、非小细胞肺、燕麦细胞、乳头状、硬癌、细支气管、支气管、鳞状细胞和移行细胞)、癌肉瘤、宫颈发育不良、囊肿肉瘤、牙骨质瘤、脊索瘤、迷芽瘤、软骨肉瘤、软骨母细胞瘤、颅咽管瘤、胆管瘤、胆脂瘤、圆柱瘤、囊腺癌、囊腺瘤、皮肤纤维肉瘤-突起、促结缔组织增生性小圆形细胞肿瘤、导管癌、无性细胞瘤、内分泌癌、子宫内膜癌、室管膜瘤、食道癌、尤文氏肉瘤、肝外胆管癌、眼癌、眼:黑色素瘤、视网膜母细胞瘤、输卵管癌、范可尼贫血症、纤维瘤、纤维肉瘤、胆囊癌、胃癌、胃肠癌、胃肠类癌肿瘤、泌尿生殖系统癌、生殖细胞肿瘤、妊娠滋养细胞疾病、神经胶质瘤、妇科癌症、巨细胞瘤、神经节细胞瘤、胶质瘤、血管球瘤、颗粒细胞瘤、两性胚细胞瘤、血液系统恶性肿瘤、毛细胞白血病、头颈癌、肝细胞癌、遗传性乳腺癌、组织细胞增多症、霍奇金病、人乳头瘤病毒、葡萄胎、高钙血症、下咽癌、错构瘤、血管内皮瘤、血管瘤、血管外皮细胞瘤、血管肉瘤、血管肉瘤、组织细胞疾病、恶性组织细胞增多症、组织细胞瘤、肝癌、汗腺瘤、软骨肉瘤、小型免疫增殖、opoma、眼内黑色素瘤、胰岛细胞癌、卡波西氏肉瘤、肾癌、langerhan细胞组织细胞增生症、喉癌、平滑肌肉瘤、白血病、Ihfraumeni综合征、唇癌、脂肪肉瘤、肝癌、肺癌、淋巴水肿、淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、平滑肌肉瘤、白血病(例如b细胞、混合细胞、无效细胞、t细胞、慢性t细胞、htlv-ii相关、淋巴管肉瘤、淋巴细胞急性、淋巴细胞慢性、肥大细胞和髓样)、白细胞肉瘤、睾丸间质细胞瘤、脂肪肉瘤、平滑肌瘤、平滑肌肉瘤、淋巴管瘤、淋巴管细胞瘤、淋巴瘤、淋巴瘤、淋巴管肉瘤、男性乳腺癌、肾恶性横纹肌样肿瘤、髓母细胞瘤、黑色素瘤、Merkel细胞癌、间皮瘤、转移性癌、口腔癌、多发性内分泌肿瘤、蕈样真菌病、骨髓增生异常综合征、骨髓瘤、骨髓增生性疾病、恶性类癌综合征类癌性心脏病、髓母细胞瘤、脑膜瘤、黑色素瘤、间质瘤、中肾瘤、间皮瘤、成肌细胞瘤、肌瘤、肌肉瘤、粘液瘤、粘液肉瘤、鼻癌、鼻咽癌、肾母细胞瘤、神经母细胞瘤、神经纤维瘤病、奈梅亨断裂综合征、非黑色素瘤皮肤癌、非小细胞肺癌-(nsclc)、神经鞘瘤、神经母细胞瘤、神经上皮瘤、神经纤维瘤病、神经纤维瘤、神经瘤、肿瘤(neoplasma)(例如骨、乳腺、消化系统、结肠直肠、肝脏)、眼癌、食管癌、口腔癌、口咽癌、骨肉瘤、卵巢癌、胰腺癌、鼻窦癌、甲状旁腺癌、腮腺癌、阴茎癌、外周-神经外胚层肿瘤、垂体癌、真性红细胞增多症、前列腺癌、骨瘤、骨肉瘤、卵巢癌、乳头状瘤、副神经节瘤、副神经节瘤非嗜铬细胞瘤、松果体瘤、浆细胞瘤、原癌基因、罕见癌症和相关疾病、肾细胞癌、视网膜母细胞瘤、横纹肌肉瘤、Rothmund-Thomson综合征、网状内皮增生症、横纹肌瘤、唾液腺癌、肉瘤、神经鞘瘤、Sezary综合征、皮肤癌、小细胞肺癌(sclc)、小肠癌、软组织肉瘤、脊髓肿瘤、鳞状细胞癌-(皮肤)、胃癌、滑膜肉瘤、肉瘤(如尤因氏实验(Ewing's experimental),卡波西氏和肥大细胞肉瘤),支持细胞肿瘤、滑膜瘤、睾丸癌、胸腺癌、甲状腺癌、移行细胞癌-(膀胱)、移行细胞癌-(肾-骨盆-/-输尿管)、滋养细胞癌、畸胎瘤、卵泡膜细胞瘤、胸腺瘤、滋养细胞肿瘤、尿道癌、泌尿系统癌、尿空斑蛋白、子宫肉瘤、子宫癌、阴道癌、外阴癌、瓦尔登斯特伦氏巨球蛋白血症和Wilm氏肿瘤。
本发明还提供治疗或预防受试者中与免疫麻痹相关的病况的方法,该方法包括向受试者施用本发明的抗原结合位点,从而治疗或预防与免疫麻痹相关的病况。如本文所用,术语“免疫麻痹”是指以受试者的免疫系统的应答性降低或无应答性为特征的任何病况。免疫麻痹可能在响应于败血症或其他感染或疾病的过度免疫应答(包括细胞因子产生的强烈激增)期间之后。免疫麻痹可以免疫细胞的凋亡和/或高水平的抗炎细胞因子为特征,抗炎细胞因子抑制淋巴细胞和巨噬细胞并抑制促炎细胞因子的产生。与免疫麻痹相关的示例性病况包括败血症,和急性和慢性肝衰竭。
作为诊断/分析试剂的用途
应理解,本发明的抗原结合位点(包括包含抗原结合位点,或包含如本文所述的CDR或FR序列的抗体)也可用于测定生物样品中IL-37的水平。
例如,本发明的抗原结合位点(如上文进一步详述)与IL-37的结合可用作定量或评价从个体获得的生物样品中IL-37水平的方法。生物样品可以包括从那些要确定诊断的个体获得的任何样品,包括血液样品(其可以进一步处理成PBMC、血清或血浆)、唾液、汗液、组织活检等。
因此,在一个实施方案中,抗原结合位点可用作诊断试剂,以诊断与IL-37水平升高或降低相关的任何一种或更多种病况,视情况而定。抗原结合位点也可用于监测与IL-37改变的水平相关的病况的治疗进展(例如,抗原结合位点可用于确定个体中IL-37的水平是否改变以响应用于治疗或改善以异常IL-37水平为特征的病况的任何干预)。
需要诊断的个体可以是任何疑似患有或有风险患有以改变的IL-37产生或分泌水平为特征的病况的个体。与个体预期的相比,改变的水平可以是增加或减少的水平。根据具体情况,将IL-37的水平与参考数据集的已知水平进行比较。参考数据集可以对应于具备或不具备个体被诊断的病况的个体中IL-37的水平。或者,参考数据集可以是在较早时间点从个体获得的数据。
在替代实施方案中,抗原结合位点可用作分析试剂,以测定在体外或体内实验期间获得的样品中IL-37水平。例如,抗原结合位点可用于定量来自组织培养物的上清液中IL-37水平。
技术人员熟悉改造本文所述的抗原结合位点作为诊断或分析试剂的方法。例如,抗原结合位点可以改造用于酶联免疫吸附测定(ELISA),包括但不限于,间接ELISA、夹心ELISA、竞争性ELISA、多重和便携式ELISA;和放射免疫测定(RIA)等。
组合物
在一些实例中,如本文所述的抗原结合位点可以经口、胃肠外、经吸入喷雾、吸附、吸收、局部、直肠、鼻腔、颊、阴道、心室内、经含有常规无毒药学上可接受的载体的剂量制剂或任何其他方便的剂型中的植入储库来给药。本文所用的术语“肠胃外”包括皮下、静脉内、肌肉内、腹膜内、鞘内、心室内、胸骨内和颅内注射或输注技术。
将抗原结合位点制备成合适形式以施用于受试者(例如药物组合物)的方法是本领域已知的,并且包括例如,如Remington's Pharmaceutical Sciences(第18版,MackPublishing Co.,Easton,Pa.,1990)和U.S.Pharmacopeia:National Formulary(MackPublishing Company,Easton,Pa.,1984)中所述的方法。
本发明的药物组合物特别适用于肠胃外给药,例如静脉内给药或给药于器官或关节的体腔或内腔。用于给药的组合物通常包含溶解在药学上可接受的载体中的抗原结合位点的溶液,例如水性载体。可使用各种水性载体,例如缓冲盐水等。该组合物可含有接近生理条件所需的药学上可接受的辅助物质,例如pH调节剂和缓冲剂、毒性调节剂等,例如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。在这些制剂中,本发明的抗原结合位点的浓度可以广泛变化,并且将主要根据与所选择的特定给药方式和患者的需要对应的流体体积、粘度、体重等来选择。示例性载体包括水、盐水、林格氏溶液、右旋糖溶液和5%人血清白蛋白。也可以使用非水性载体如混合油和油酸乙酯。脂质体也可用作载体。载体可含有较少量增强等渗性和化学稳定性的添加剂,例如缓冲剂和防腐剂。
经配制,本发明的抗原结合位点将以与剂量制剂相容的方式并以治疗/预防有效的量给药。制剂易于以多种剂型给药,例如上述可注射溶液的类型,但也考虑其他药学上可接受的形式,例如片剂、丸剂、胶囊或其他口服给药固体、栓剂、阴道栓剂、鼻用溶液或喷雾剂、气溶胶、吸入剂、脂质体形式等。也可使用药物“缓释”胶囊或组分。通常设计缓释制剂以在延长的时间内提供恒定的药物水平,并且可以用于递送本发明的抗原结合位点。
给药的剂量和时间
本发明的抗原结合位点的合适剂量将根据特异性抗原结合位点、待治疗的病况和/或所治疗的受试者而变化。熟练医师能够确定合适的剂量,例如,通过以次优剂量开始并逐渐调整剂量以确定最佳或有用剂量。或者,为了确定用于治疗/预防的合适剂量,使用来自细胞培养测定或动物研究的数据,其中合适的剂量在包括具有很小毒性或无毒性的活性化合物的ED50的一系列循环浓度的范围内。剂量可在该范围内变化,这取决于所用的剂型和所用的给药途径。最初可以从细胞培养测定估计治疗/预防有效剂量。可以在动物模型中配制剂量以达到循环血浆浓度范围,其包括在细胞培养中所测定的IC50(即实现症状的半数最大抑制的化合物的浓度或量)。这些信息可用于更准确地确定人体中的有用剂量。例如,可以通过高效液相色谱法来测量血浆中的水平。
在一些实例中,本发明的方法包括施用预防或治疗的有效量的本文所述的蛋白。
当施用于需要治疗的受试者时,术语“治疗有效量”是改善受试者的预后和/或状态的量和/或是减少或抑制本文所述的临床病况的一种或更多种症状至低于作为该病况的临床诊断或临床特征所观察和接受的水平的量。施用于受试者的量将取决于待治疗病况的具体特征、所治疗病况的类型和阶段、给药方式和受试者的特征,例如一般健康、其他疾病、年龄、性别、基因型和体重。本领域技术人员能够根据这些和其他因素确定合适的剂量。因此,该术语不应解释为将本发明限制于特定的量,例如蛋白的重量或量,本发明应该包括足以在受试者中实现所述结果的任何量的抗原结合位点。
如本文所用,术语“预防有效量”意指预防或抑制或延迟临床病况的一种或更多种可检测症状发作的蛋白的足够量。技术人员将意识到,这样的量将根据例如施用的特定抗原结合位点和/或具体的受试者和/或病况的类型或严重性或水平和/或病况的倾向(遗传或以其他方式)而变化。因此,该术语不应解释为将本发明限制于特定的量,例如抗原结合位点的重量或量,本发明应该包括足以在受试者中实现所述结果的任何量的抗原结合位点。
试剂盒
本发明还包括试剂盒,其包含以下一种或更多种:
(i)本发明的抗原结合位点或编码其的表达构建物;
(ii)本发明的细胞;
(iii)本发明的复合物;或
(iii)本发明的药物组合物。
在用于检测IL-37的试剂盒的情况下,试剂盒可另外包含检测手段,例如与本发明的抗原结合位点连接。
在用于治疗/预防用途的试剂盒的情况下,试剂盒可另外包含药学上可接受的载体。
任选地,将本发明的试剂盒与说明书一起包装用于根据任何实例本文所述的方法中。
表1:轻链和重链CDR序列
表2:轻链和重链可变区序列
表3:框架区序列(轻链和重链)
本发明包括以下非限制性实施例。
实施例
实施例1
IL-37抑制抗体的生产
免疫和血清滴度:每隔两周用16μg IL-37抗原和与甲基化CpG组合的免疫佐剂(Sigma-Aldrich cat#S6322)的组合腹膜内免疫处理小鼠3次。从免疫的小鼠中收集血清样品,以1:250和1:1250的稀释度利用ELISA来测试针对抗原的反应性,并与免疫前的样品进行比较。选择具有最高滴度的小鼠用于融合。
所用的IL-37抗原是来自人的未标记的抗原,重组(rec)IL-37(46-218):
GSVHTSPKVKNLNPKKFSIHDQDHKVLVLDSGNLIAVPDKNYIRPEIFFALASSLSSASAEKGSPILLGVSKGEFCLYCDKDKGQSHPSLQLKKEKLMKLAAQKESARRPFIFYRAQVGSWNMLESAAHPGWFICTSCNCNEPVGVTDKFENRKHIEFSFQPVCKAEMSPSEVSD(SEQ ID NO:1)
杂交瘤融合:为了产生杂交瘤细胞,切除小鼠的脾脏,分离成单细胞悬浮液,并使用聚乙二醇将其融合至SP2/0-Ag14骨髓瘤细胞。使产成的杂交瘤细胞在20x 96孔组织培养板中在含有偶氮丝氨酸次黄嘌呤(Azaserine Hypoxanthine)的培养基中生长。
实施例2
筛选用于结合IL-37的抗体
使杂交瘤克隆生长10天,在这个点测定杂交瘤克隆的数目,并且进一步孵育3天后,取抗体上清液等份用于筛选。首先利用微阵列,然后利用任意IgG微阵列阳性克隆的ELISA来测定上清液针对抗原和任何筛选样品的反应性(图1)。阳性克隆包括C3、D3和A3(本文中也分别称为RC3、RD3和RA3)。
从免疫的小鼠收集血清样品,以1:250和1:1250的稀释度利用ELISA测试血清样品对抗原的反应性,并与免疫前的样品进行比较。选择具有最高滴度的小鼠用于融合。
图1所示的结果是吸光度读数(原始的吸光度读数)和阳性:阴性比率。
测序之前,筛选杂交瘤上清液的IL-37-阻断活性;基于这种功能测定的结果(克隆C3和D3显示好的阻断活性),选择克隆C3和D3用于测序。
然后对C3和D3进行测序,表1到3显示了该测序的结果,并使用IMGT分析测定CDR。
实施例3
抗体的结合特异性
进行rec IL-18、rec IL1β和rec IL-37的免疫印迹,以检测产生的抗体的特异性和交叉反应性。用抗IL-37杂交瘤上清液探测印迹。未观察到与IL-18或rec IL-1β的交叉反应性,这突出显示了产生的针对IL-37的抗体的特异性(图2)。尽管抗体(克隆D3)检测了IL-37,但IL-18(一种紧密相关的IL-1家族成员,IL-37与其共享关键的氨基酸和受体蛋白链)未被检测到。
实施例4
抗体对内源性IL-37的阻断活性
将新鲜分离的人PBMC以2.5x 105细胞/ml重悬于补充有1%人血清和1:500MycoZap Plus-PR的RPMI中,并在时间点t0用载体(Veh)或LPS(500pg/ml)进行处理。在t0或之后的1、3或6h,IL-37抗体(克隆D3)按照所示添加。t0后20h,利用ELISA针对IL-1β分析上清液。描述的是平均的IL-1β浓度±SEM;n=3个捐献者。**,P<0.01;***,P<0.001,与单独的LPS比较。###,P<0.001,与t0后1h的LPS+37bl1比较。
图3的结果显示,与只接受LPS的细胞相比,同时用LPS和IL-37抗体处理在20h导致了IL-1β的显著的、接近3倍的增加。这种IL-1β的增加是由于IL-37抗体在实验期间的任意时间阻断了细胞释放的内源性IL-37的作用。当在LPS刺激后1h加入抗体时,观察到相同的IL-1β增加,表明在用LPS刺激PBMC后的第1小时内细胞外IL-37功能没有增加。
然而,如果在LPS后3h加入抗体,则IL-1β浓度下降,这是由于在加入IL-37抗体之前,一些IL-37被释放,IL-37抗体然后可以发挥它的抗炎效果(图3)。如果在LPS刺激后6h后加入抗体,IL-1β的浓度等于只接受LPS的细胞中观察到的浓度。这个观察结果显示,本实验中在6h时间点后从细胞释放的IL-37生物活性不会对IL-37的抗炎效果作出重大的贡献。
实施例5
抗体对重组IL-37的阻断活性
如所述利用密度梯度离心(Nold等人,Biochemical Pharmacology 66,505–510(2003))从健康志愿者的外周静脉血分离PBMC。将PBMC铺板于补充有L-谷氨酰胺、25mMHEPES(Thermo Fisher Scientific)、1%v/v人血清(Sigma Aldrich)和1:500MycoZapPlus-PR(Lonza)的RPMI 1640培养基中,然后在用50pg/ml LPS(O55:B5,Sigma Aldrich)刺激20小时前,用载体或rec IL-37任何一种预处理30分钟。利用莫纳什抗体技术设施(Monash Antibody Technologies Facility)生产IL-37阻断抗体(克隆D3),并使用生物活性测定特征化杂交瘤上清液的IL-37阻断能力(图4)。新鲜分离的PBMC首先用指定稀释度的IL-37阻断抗体或对照处理,然后在30min后加入指定浓度的D73K46-218或载体,并再过30分钟后加入50pg/ml LPS。在加入LPS 20h后测定培养物上清液中的IL-1β蛋白丰度,计算在存在或缺乏IL-37阻断抗体时用IL-37b变体处理所提供的百分比变化并作图±SEM;n=来自一个示例性捐献者的2个生物学重复。
实施例6
抗体阻断转染的天然或单体IL-37
将表达天然1-218、D73K1-218或Y85A1-218的构建物转染THP-1细胞。在用PMA(50ng/ml)分化24h和改变培养基后,用IL-37阻断抗体克隆D3(1:50稀释)或对照的杂交瘤上清液预处理培养物,然后用250ng/ml LPS或载体刺激。对用IL-37阻断抗体处理的培养物和载体处理的培养物的对(用相同的载体转染的,即对照、天然、D73K或者Y85A的对(D73K:具有在位点73的从Asp到Lys的突变的IL-37;Y85A具有在位点85的从Tyr到Ala的突变)并用LPS刺激的)之间的IL-1β蛋白丰度的倍数变化进行计算并以平均值±SEM作图;n=每个LPS刺激条件下的4个生物学重复;使用等级单因素方差分析(ANOVA on ranks)和Student-Newman-Keuls因果分析来评价统计学显著性;*,P<0.05对于对照vs IL-37b转染;#,P<0.05对于天然1- 218vs D73K1-218或Y85A1-218。虚线表明在对照(即不是IL-37b)转染的培养物中由IL-37阻断抗体诱导的IL-1β的背景。
当用LPS刺激之前向转染的培养物加入IL-37阻断抗体(克隆D3)时,观察到每一个变体转染时IL-1β的增加(图5)。但是,与用二聚体天然1-218IL-37b相比,当用单体D73K1-218和Y85A1-218变体转染时,这种增加显著地更显著。
实施例7
抗体对重组L-37的阻断活性:IL-1β产生
从健康志愿者(n=2)分离PBMC,并用不同稀释度的杂交瘤上清液(克隆C3,1:5到1:500稀释度)预处理30分钟,然后在LPS刺激(500pg/mL)之前,用不同浓度(从1pg/mL至10ng/mL)的天然重组IL-37(rIL-37)处理1小时。过夜孵育后,收集上清液,并用ELISA测定IL-1β。
RecIL-37减少了从PBMC释放的IL-1β,然而当加入来自克隆C3的杂交瘤上清液时,该抗炎活性下降或丧失。
实施例8
抗体对重组IL-37的阻断活性:IL-1β产生
涉及人类血液的实验由莫纳什健康人类研究伦理委员会(Monash Health HumanResearch Ethics Committee)批准。按照制造商的说明,通过使用Leucosep Tubes(Greiner Bio-One,德国)的密度梯度离心从健康捐献者的新鲜外周静脉血分离PBMC。将分离的PBMC在补充有1%人血清(Sigma-Aldrich,USA)和1:500MycoZap Plus-PR(Lonza,瑞士)的RPMI1640(Thermo Fisher Scientific,USA)中重悬,并接种在96孔板中。然后,在加入杂交瘤克隆上清液(克隆RD1)之前,将细胞搁置1小时。孵育30分钟后,用200pg/ml LPS(Sigma-Aldrich)过夜刺激之前加入重组IL-37并进一步孵育1小时。依据制造商的说明,利用ELISA(BD Bioscience,USA)来检测上清液中的IL-1β。
通过LPS刺激诱导的IL-1β丰度的上升随着重组IL-37的加入降低多达40%。在加入IL-37之前用来自克隆RD1的上清液的预处理逆转了IL-37的抗炎活性,如通过IL-1β丰度所测定的(图7)。
实施例9
抗体对重组IL-37的阻断活性:IL-6产生
所有动物的工作由莫纳什大学动物伦理委员会批准,并依据赫尔辛基宣言(Declaration of Helsinki)的原则进行。57BL/6J野生型(WT)小鼠购买自JacksonLaboratories(USA),IL-37转基因(IL-37tg)小鼠是在Nold等人.(2010)NatureImmunology11(11):1014-22中公开的原始群体的纯合子后代。分离脾细胞并在补充有1%胎牛血清(Thermo Fisher Scientific)和1:500MycoZap Plus-PR(Lonza)的RPMI 1640(Thermo Fisher Scientific)中重悬,接种在96孔板中。在加入抗IL-37杂交瘤克隆上清液(RF1和RF3)之前搁置细胞1小时,并孵育30分钟。然后用250ng/mL LPS过夜刺激细胞。依据制造商的说明,利用ELISA(BD Bioscience)检测上清液中的IL-6。
与单独的LPS处理相比,在IL-37tg脾细胞中,在LPS刺激之前用抗IL-37杂交瘤上清液(克隆RF1和RF3)预处理小鼠脾细胞导致IL-6丰度增加多达40%,而在来自WT小鼠的细胞中,抗IL-37杂交瘤上清液作用很小或没有作用。因此,这些数据证明,杂交瘤上清液以特定的方式阻断IL-37的抗炎活性。
应理解,在本说明书中公开和定义的发明扩展至提及的或从正文或附图明显可见的两个或更多个单独特征的可替换结合。所有这些不同结合构成了本发明的各种可替换方面。
序列表
<110> 莫纳什大学(Monash University)
哈德森医学研究所(Hudson Institute of Medical Research)
<120> 抗IL-37抗体
<130> 50188504AZD
<150> AU2016905344
<151> 2016-12-23
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gaatctgggg tccctgatcg cttcacaggc agtggatctg ggacagattt cactctcacc 240
atcagcagtg tgaaggctga agacctggca gtttattact gtcagcaata ttatagctat 300
ccattcacgt tcggctcggg gacaaagttg gaaataaaa 339
<210> 21
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体C3 VH (DNA)
<400> 21
gaggttcagc tgcagcagtc tggggcagag cttgtgaagc caggggcctc agtcaagttg 60
tcctgcacag cttctggctt caacattaaa gacacctata tgcactgggt gaagcagagg 120
cctgaacagg gcctggagtg gattggaagg attgatcctg cgaatggtaa tactaaatat 180
gacccgaagt tccagggcaa ggccactata acagcagaca catcctccaa cacagcctac 240
ctgcagctca gcagcctgac atctgaggac actgccgtct attactgtgc taagagtagt 300
agccccacct ggtttgctta ctggggccaa gggactctgg tcactgtctc tgca 354
<210> 22
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体C3 LFR1
<400> 22
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys
20
<210> 23
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体C3 LFR2
<400> 23
Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
1 5 10 15
<210> 24
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体C3 LFR3
<400> 24
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
1 5 10 15
Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
20 25 30
<210> 25
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体C3 LFR4
<400> 25
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 26
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体C3 HFR1
<400> 26
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr
20 25 30
<210> 27
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体C3 HFR2
<400> 27
Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu Gly
1 5 10
<210> 28
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体C3 HFR3
<400> 28
Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Phe Lys
1 5 10 15
Met Asn Ser Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys
20 25 30
<210> 29
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体C3 HFR4
<400> 29
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
1 5 10
<210> 30
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体D3 LFR1
<400> 30
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys
20
<210> 31
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体D3 LFR2
<400> 31
Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 32
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体D3 LFR3
<400> 32
Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys
20 25 30
<210> 33
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体D3 LFR4
<400> 33
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 34
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体D3 HFR1
<400> 34
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys
20 25 30
<210> 35
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体D3 HFR2
<400> 35
Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 36
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体D3 HFR3
<400> 36
Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr Leu Gln
1 5 10 15
Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys
20 25 30
<210> 37
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体D3 HFR4
<400> 37
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
1 5 10
<210> 38
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) LCDR1
<400> 38
Arg Ala Ser Glu Ser Val Asp Ile Tyr Gly Asn Ser Phe Met His
1 5 10 15
<210> 39
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) LCDR2
<400> 39
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 40
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) LCDR3
<400> 40
Gln Gln Ser Tyr Glu Asp Pro Trp Thr
1 5
<210> 41
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) HCDR1
<400> 41
Asn Tyr Gly Met Asn
1 5
<210> 42
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) HCDR2
<400> 42
Trp Ile Asn Thr Tyr Ile Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys
1 5 10 15
Gly
<210> 43
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) HCDR3
<400> 43
Asn Tyr Gly Tyr Pro Trp Phe Ala Tyr
1 5
<210> 44
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 44
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Ile Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ile Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Cys Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Phe Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr
85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 45
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 45
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Lys Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Ile Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asp Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Asn Tyr Gly Tyr Pro Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 46
<211> 333
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) VL(DNA)
<400> 46
gacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gagggccatc 60
atatcctgca gagccagtga aagtgttgat atttatggca atagttttat gcactggtgc 120
cagcagaagc caggacagcc acccaaactc ctcatctttc gtgcatccaa cctagaatct 180
gggatccctg ccaggttcag tggcagtggg tctaggacag acttcaccct caccattaat 240
cctgtggagg ctgatgatgt tgcaacctat tactgtcaac aaagttatga ggatccgtgg 300
acgttcggtg gaggcaccaa gctggaaatc aaa 333
<210> 47
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) VH (DNA)
<400> 47
cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60
tcctgcaagg cttctgggta taccttcaaa aactatggaa tgaactgggt gaagcaggct 120
ccaggaaagg gtttaaagtg gatgggctgg ataaacacct atattggaga gccaacatat 180
gctgatgact tcaagggacg gtttgccttc tctttggaaa cctctgccag cactgcctat 240
ttgcagatca acaacctcaa agatgaggac acggctacat atttctgtgc aagaaactac 300
ggctacccct ggtttgctta ctggggccaa gggactctgg tcactgtctc tgca 354
<210> 48
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) LCDR1
<400> 48
Arg Ala Ser Glu Ser Val Asp Ile Tyr Gly Asn Ser Phe Met His
1 5 10 15
<210> 49
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) LCDR2
<400> 49
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 50
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) LCDR3
<400> 50
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 51
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) HCDR1
<400> 51
Asp Tyr Ser Met His
1 5
<210> 52
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) HCDR2
<400> 52
Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys
1 5 10 15
Gly
<210> 53
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) HCDR3
<400> 53
Ser Tyr Ala Tyr Ala Met Asp Tyr
1 5
<210> 54
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 54
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Ile Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ile Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Cys Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Phe Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr
85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 55
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 55
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ser Tyr Ala Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 56
<211> 333
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) VL (DNA)
<400> 56
gacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gagggccatc 60
atatcctgca gagccagtga aagtgttgat atttatggca atagttttat gcactggtgc 120
cagcagaagc caggacagcc acccaaactc ctcatctttc gtgcatccaa cctagaatct 180
gggatccctg ccaggttcag tggcagtggg tctaggacag acttcaccct caccattaat 240
cctgtggagg ctgatgatgt tgcaacctat tactgtcaac aaagttatga ggatccgtgg 300
acgttcggtg gaggcaccaa gctggaaatc aaa 333
<210> 57
<211> 351
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) VH (DNA)
<400> 57
cagatccagt tggtgcagtc tggacctgag ctggagaagc ctggagagac agtcaagatc 60
tcctgtaagg cttctggtta taccttcaca gactattcaa tgcactgggt gaagcaggct 120
ccaggaaagg gtttaaagtg gatgggctgg ataaacactg agactggtga gccaacatat 180
gcagatgact tcaagggacg gtttgccttc tcgttggaaa cctctgccag cactgcctat 240
ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc tagatcttac 300
gcctatgcta tggactactg gggtcaagga acctcagtca ccgtctcctc a 351
<210> 58
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (C) LCDR1
<400> 58
Lys Ala Ser Gln Asn Val Gly Thr Asn Val Ala
1 5 10
<210> 59
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (C) LCDR2
<400> 59
Ser Ala Ser Tyr Arg Tyr Ser
1 5
<210> 60
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (C) LCDR3
<400> 60
Gln Gln Tyr Asn Ser Tyr Pro Leu Thr
1 5
<210> 61
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (C) HCDR1
<400> 61
Asn Tyr Gly Met Asn
1 5
<210> 62
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (C) HCDR2
<400> 62
Trp Ile Asn Thr Tyr Ile Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys
1 5 10 15
Gly
<210> 63
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (C) HCDR3
<400> 63
Asn Tyr Gly Tyr Pro Trp Phe Ala Tyr
1 5
<210> 64
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (C) VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 64
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 65
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (C) VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 65
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Lys Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Ile Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asp Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Asn Tyr Gly Tyr Pro Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 66
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (C) VL (DNA)
<400> 66
gacattgtca tgacccagtc tcaaaaattc atgtccacat cagtaggaga cagggtcagc 60
gtcacctgca aggccagtca gaatgtgggt actaatgtag cctggtatca acagaaacca 120
gggcaatctc ctaaagcact gatttactcg gcatcctacc ggtacagtgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat ttcactctca ccatcagcaa tgtgcagtct 240
gaagacttgg cagagtattt ctgtcagcaa tataacagct atccgctcac gttcggtgct 300
gggaccaagc tggagctgaa a 321
<210> 67
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (C) VH (DNA)
<400> 67
cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60
tcctgcaagg cttctgggta taccttcaaa aactatggaa tgaactgggt gaagcaggct 120
ccaggaaagg gtttaaagtg gatgggctgg ataaacacct atattggaga gccaacatat 180
gctgatgact tcaagggacg gtttgccttc tctttggaaa cctctgccag cactgcctat 240
ttgcagatca acaacctcaa agatgaggac acggctacat atttctgtgc aagaaactac 300
ggctacccct ggtttgctta ctggggccaa gggactctgg tcactgtctc tgca 354
<210> 68
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) LCDR1
<400> 68
Lys Ala Ser Gln Asn Val Gly Thr Asn Val Ala
1 5 10
<210> 69
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) LCDR2
<400> 69
Ser Ala Ser Tyr Arg Tyr Ser
1 5
<210> 70
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) LCDR3
<400> 70
Gln Gln Tyr Asn Ser Tyr Pro Leu Thr
1 5
<210> 71
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) HCDR1
<400> 71
Asp Tyr Ser Met His
1 5
<210> 72
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) HCDR2
<400> 72
Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys
1 5 10 15
Gly
<210> 73
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) HCDR3
<400> 73
Ser Tyr Ala Tyr Ala Met Asp Tyr
1 5
<210> 74
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 74
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 75
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 75
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ser Tyr Ala Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 76
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) VL (DNA)
<400> 76
gacattgtca tgacccagtc tcaaaaattc atgtccacat cagtaggaga cagggtcagc 60
gtcacctgca aggccagtca gaatgtgggt actaatgtag cctggtatca acagaaacca 120
gggcaatctc ctaaagcact gatttactcg gcatcctacc ggtacagtgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat ttcactctca ccatcagcaa tgtgcagtct 240
gaagacttgg cagagtattt ctgtcagcaa tataacagct atccgctcac gttcggtgct 300
gggaccaagc tggagctgaa a 321
<210> 77
<211> 351
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) VH (DNA)
<400> 77
cagatccagt tggtgcagtc tggacctgag ctggagaagc ctggagagac agtcaagatc 60
tcctgtaagg cttctggtta taccttcaca gactattcaa tgcactgggt gaagcaggct 120
ccaggaaagg gtttaaagtg gatgggctgg ataaacactg agactggtga gccaacatat 180
gcagatgact tcaagggacg gtttgccttc tcgttggaaa cctctgccag cactgcctat 240
ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc tagatcttac 300
gcctatgcta tggactactg gggtcaagga acctcagtca ccgtctcctc a 351
<210> 78
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 LCDR1
<400> 78
Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 79
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 LCDR2
<400> 79
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 80
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 LCDR3
<400> 80
Ser Gln Cys Arg His Val Pro Phe Thr
1 5
<210> 81
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 HCDR1
<400> 81
Asp Thr Tyr Met His
1 5
<210> 82
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 HCDR2
<400> 82
Arg Ile Asp Pro Ala Asn Gly Asn Ser Ile Tyr Asp Pro Thr Phe Gln
1 5 10 15
Gly
<210> 83
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 HCDR3
<400> 83
Gly Asn Trp Asp Trp Phe Val Phe
1 5
<210> 84
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 84
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Cys
85 90 95
Arg His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 85
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 85
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Thr Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asn Gly Asn Ser Ile Tyr Asp Pro Thr Phe
50 55 60
Gln Gly Lys Ala Thr Val Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ser Asn Gly Asn Trp Asp Trp Phe Val Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 86
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 VL (DNA)
<400> 86
gatgttgtga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagccttgta cacagtaatg gaaacaccta tttacattgg 120
tacctgcaga agccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tatttctgct ctcaatgtag acatgttcca 300
ttcacgttcg gctcggggac aaagttggaa ataaaa 336
<210> 87
<211> 351
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 VH (DNA)
<400> 87
gaggttcagc tgcagcagtc tggggcagaa cttgtgaagc caggggcctc agtcacgttg 60
tcctgcacag cttctggctt caacattaaa gacacctata tgcactgggt gaagcagagg 120
cctgaacagg gcctggagtg gattggaagg attgatcctg cgaatggtaa ttctatatat 180
gacccgacgt tccagggcaa ggccactgta acagctgaca catcctccaa cacagcctac 240
ctgcagctca gcagcctgac atctgaggac actgccgtct atttctgttc taatgggaac 300
tgggactggt ttgttttctg gggccaaggg actctggtca ctgtctctgc a 351
<210> 88
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 LCDR1
<400> 88
Lys Ala Ser Gln Asn Val Asp Thr His Val Ala
1 5 10
<210> 89
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 LCDR2
<400> 89
Ser Ala Ser Tyr Arg Tyr Ser
1 5
<210> 90
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 LCDR3
<400> 90
Gln Gln Tyr His Ser Tyr Pro Leu Thr
1 5
<210> 91
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 HCDR1
<400> 91
Lys Lys Gly Val Thr
1 5
<210> 92
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 HCDR2
<400> 92
Ile Ile Trp Asp Asp Gly Ser Ile Asn Tyr His Ser Ala Leu Ile Ser
1 5 10 15
<210> 93
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 HCDR3
<400> 93
Arg Gly Asp Val Ser Arg Gly Ala Trp Phe Val Tyr
1 5 10
<210> 94
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 94
Asp Ile Val Met Thr Gln Ser Gln Glu Phe Leu Ser Thr Leu Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Asp Thr His
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Thr Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Lys Tyr Phe Cys Gln Gln Tyr His Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 95
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 95
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Thr Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Lys Lys
20 25 30
Gly Val Thr Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Ile Ile Trp Asp Asp Gly Ser Ile Asn Tyr His Ser Ala Leu Ile
50 55 60
Ser Arg Leu Arg Ile Thr Lys Asp Asn Phe Lys Ser Gln Val Phe Leu
65 70 75 80
His Leu Asn Ser Leu Gln Thr Asp Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Arg Arg Gly Asp Val Ser Arg Gly Ala Trp Phe Val Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 96
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 VL (DNA)
<400> 96
gacattgtga tgacccagtc tcaagaattc ttgtccacat tagtaggaga cagggtcagc 60
gtcacctgca aggccagtca gaatgtggat actcatgtag cctggtatca acagaaacca 120
gggcagtctc ctaaaacact gatttactcg gcatcttacc ggtacagtgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat ttcactctca ccatcagcag tgtgcagtct 240
gaagacttgg caaagtattt ctgtcaacaa tatcacagct atcctctcac gttcggaggg 300
gggaccaagc tggaactgaa a 321
<210> 97
<211> 360
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 VH (DNA)
<400> 97
caggtgcagt tgaaggagtc aggacctggc ctggtggcgc cctcacagag cctgaccatc 60
acatgcactg tctcagggtt ctccttaacc aaaaaaggtg taacgtgggt tcgccagcct 120
ccaggaaagg gtctggagtg gctgggaata atatgggatg acgggagcat taattatcac 180
tcagctctca tatccagatt gcgcatcact aaggataatt tcaagagcca agttttcctg 240
cacctgaaca gtctgcaaac tgatgataca gccacgtatt actgtgccag aagaggggac 300
gttagtaggg gggcctggtt tgtctattgg ggccaaggga ctctggtcac tgtctctgca 360
<210> 98
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) LCDR1
<400> 98
Arg Ala Ser Glu Ser Val Asp Ile Tyr Gly Asn Ser Phe Met His
1 5 10 15
<210> 99
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) LCDR2
<400> 99
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 100
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) LCDR3
<400> 100
Gln Gln Ser Tyr Glu Asp Pro Trp Thr
1 5
<210> 101
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) HCDR1
<400> 101
Asp Tyr Ser Met His
1 5
<210> 102
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) HCDR2
<400> 102
Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys
1 5 10 15
Gly
<210> 103
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) HCDR3
<400> 103
Ser Tyr Ala Tyr Ala Met Asp Tyr
1 5
<210> 104
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 104
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Ile Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ile Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Cys Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Phe Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr
85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 105
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 105
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ser Tyr Ala Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 106
<211> 333
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) VL (DNA)
<400> 106
gacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gagggccatc 60
atatcctgca gagccagtga aagtgttgat atttatggca atagttttat gcactggtgc 120
cagcagaagc caggacagcc acccaaactc ctcatctttc gtgcatccaa cctagaatct 180
gggatccctg ccaggttcag tggcagtggg tctaggacag acttcaccct caccattaat 240
cctgtggagg ctgatgatgt tgcaacctat tactgtcaac aaagttatga ggatccgtgg 300
acgttcggtg gaggcaccaa gctggaaatc aaa 333
<210> 107
<211> 351
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) VH (DNA)
<400> 107
cagatccagt tggtgcagtc tggacctgag ctggagaagc ctggagagac agtcaagatc 60
tcctgtaagg cttctggtta taccttcaca gactattcaa tgcactgggt gaagcaggct 120
ccaggaaagg gtttaaagtg gatgggctgg ataaacactg agactggtga gccaacatat 180
gcagatgact tcaagggacg gtttgccttc tcgttggaaa cctctgccag cactgcctat 240
ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc tagatcttac 300
gcctatgcta tggactactg gggtcaagga acctcagtca ccgtctcctc a 351
<210> 108
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) LCDR1
<400> 108
Arg Ala Ser Glu Ser Val Asp Ile Tyr Gly Asn Ser Phe Met His
1 5 10 15
<210> 109
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) LCDR2
<400> 109
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 110
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) LCDR3
<400> 110
Gln Gln Ser Tyr Glu Asp Pro Trp Thr
1 5
<210> 111
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) HCDR1
<400> 111
Asn Tyr Gly Met Asn
1 5
<210> 112
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) HCDR2
<400> 112
Trp Ile Asn Thr Phe Thr Gly Glu Pro Ser Tyr Ala Asp Asp Phe Lys
1 5 10 15
Gly
<210> 113
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) HCDR3
<400> 113
Asn Tyr Gly Tyr Pro Trp Phe Ala Tyr
1 5
<210> 114
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 114
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Ile Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Ile Tyr
20 25 30
Gly Asn Ser Phe Met His Trp Cys Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Phe Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr
85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 115
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 115
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Phe Thr Gly Glu Pro Ser Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Asn Tyr Gly Tyr Pro Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 116
<211> 333
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) VL (DNA)
<400> 116
gacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gagggccatc 60
atatcctgca gagccagtga aagtgttgat atttatggca atagttttat gcactggtgc 120
cagcagaagc caggacagcc acccaaactc ctcatctttc gtgcatccaa cctagaatct 180
gggatccctg ccaggttcag tggcagtggg tctaggacag acttcaccct caccattaat 240
cctgtggagg ctgatgatgt tgcaacctat tactgtcaac aaagttatga ggatccgtgg 300
acgttcggtg gaggcaccaa gctggaaatc aaa 333
<210> 117
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) VH (DNA)
<400> 117
cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60
tcctgcaagg cttctgggta taccttcaca aactatggaa tgaactgggt gaagcaggct 120
ccaggaaagg gtttaaagtg gatgggctgg ataaacacct tcactggaga gccatcatat 180
gctgatgact tcaagggacg gtttgccttc tctttggaaa cctctgccag cactgcctat 240
ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc aagaaactac 300
ggctacccct ggtttgctta ctggggccaa gggactctgg tcactgtctc tgca 354
<210> 118
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) LCDR1
<400> 118
Arg Ala Ser Lys Ser Val Ser Thr Ser Gly Tyr Ser Tyr Met His
1 5 10 15
<210> 119
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) LCDR2
<400> 119
Leu Val Ser Asn Leu Glu Ser
1 5
<210> 120
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) LCDR3
<400> 120
Gln Gln Ser Tyr Glu Asp Pro Trp Thr
1 5
<210> 121
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) HCDR1
<400> 121
Asp Tyr Ser Met His
1 5
<210> 122
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) HCDR2
<400> 122
Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys
1 5 10 15
Gly
<210> 123
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) HCDR3
<400> 123
Ser Tyr Ala Tyr Ala Met Asp Tyr
1 5
<210> 124
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 124
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Tyr Arg Ala Ser Lys Ser Val Ser Thr Ser
20 25 30
Gly Tyr Ser Tyr Met His Trp Asn Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Arg Leu Leu Ile Tyr Leu Val Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr
85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 125
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 125
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Ser Tyr Ala Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 126
<211> 333
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) VL (DNA)
<400> 126
gacattgtgc tgacacagtc tcctgcttcc ttagctgtat ctctggggca gagggccacc 60
atctcataca gggccagcaa aagtgtcagt acatctggct atagttatat gcactggaac 120
caacagaaac caggacagcc acccagactc ctcatctatc ttgtatccaa cctagaatct 180
gggatccctg ccaggttcag tggcagtggg tctaggacag acttcaccct caccattaat 240
cctgtggagg ctgatgatgt tgcaacctat tactgtcaac aaagttatga ggatccgtgg 300
acgttcggtg gaggcaccaa gctggaaatc aaa 333
<210> 127
<211> 351
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) VH (DNA)
<400> 127
cagatccagt tggtgcagtc tggacctgag ctggagaagc ctggagagac agtcaagatc 60
tcctgtaagg cttctggtta taccttcaca gactattcaa tgcactgggt gaagcaggct 120
ccaggaaagg gtttaaagtg gatgggctgg ataaacactg agactggtga gccaacatat 180
gcagatgact tcaagggacg gtttgccttc tcgttggaaa cctctgccag cactgcctat 240
ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc tagatcttac 300
gcctatgcta tggactactg gggtcaagga acctcagtca ccgtctcctc a 351
<210> 128
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) LCDR1
<400> 128
Arg Ala Ser Lys Ser Val Ser Thr Ser Gly Tyr Ser Tyr Met His
1 5 10 15
<210> 129
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) LCDR 2
<400> 129
Leu Val Ser Asn Leu Glu Ser
1 5
<210> 130
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) LCDR3
<400> 130
Gln Gln Ser Tyr Glu Asp Pro Trp Thr
1 5
<210> 131
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D HCDR1
<400> 131
Asn Tyr Gly Met Asn
1 5
<210> 132
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) HCDR2
<400> 132
Trp Ile Asn Thr Phe Thr Gly Glu Pro Ser Tyr Ala Asp Asp Phe Lys
1 5 10 15
Gly
<210> 133
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) HCDR3
<400> 133
Asn Tyr Gly Tyr Pro Trp Phe Ala Tyr
1 5
<210> 134
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1(D) VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 134
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Tyr Arg Ala Ser Lys Ser Val Ser Thr Ser
20 25 30
Gly Tyr Ser Tyr Met His Trp Asn Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Arg Leu Leu Ile Tyr Leu Val Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr
85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 135
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 135
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Phe Thr Gly Glu Pro Ser Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Asn Tyr Gly Tyr Pro Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 136
<211> 333
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) VL (DNA)
<400> 136
gacattgtgc tgacacagtc tcctgcttcc ttagctgtat ctctggggca gagggccacc 60
atctcataca gggccagcaa aagtgtcagt acatctggct atagttatat gcactggaac 120
caacagaaac caggacagcc acccagactc ctcatctatc ttgtatccaa cctagaatct 180
gggatccctg ccaggttcag tggcagtggg tctaggacag acttcaccct caccattaat 240
cctgtggagg ctgatgatgt tgcaacctat tactgtcaac aaagttatga ggatccgtgg 300
acgttcggtg gaggcaccaa gctggaaatc aaa 333
<210> 137
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) VH (DNA)
<400> 137
cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60
tcctgcaagg cttctgggta taccttcaca aactatggaa tgaactgggt gaagcaggct 120
ccaggaaagg gtttaaagtg gatgggctgg ataaacacct tcactggaga gccatcatat 180
gctgatgact tcaagggacg gtttgccttc tctttggaaa cctctgccag cactgcctat 240
ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc aagaaactac 300
ggctacccct ggtttgctta ctggggccaa gggactctgg tcactgtctc tgca 354
<210> 138
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 LCDR1
<400> 138
Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asp Ser Tyr Leu His
1 5 10 15
<210> 139
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 LCDR2
<400> 139
Lys Val Ser Asn Arg Leu Ser
1 5
<210> 140
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 LCDR3
<400> 140
Ser Gln Ser Thr His Val Pro Tyr Thr
1 5
<210> 141
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 HCDR1
<400> 141
Asn Tyr Trp Leu His
1 5
<210> 142
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 HCDR2
<400> 142
Met Ile Asp Pro Ser Asp Ser Phe Thr Thr Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 143
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 HCDR3
<400> 143
Val Asp His
1
<210> 144
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 144
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Met Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asp Ser Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Leu Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 145
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 145
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Leu His Trp Val Met Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile Asp Pro Ser Asp Ser Phe Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Phe
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Val Asp His Trp Gly Arg Gly Thr Thr Leu Thr Val Ser Ser
100 105 110
<210> 146
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 VL (DNA)
<400> 146
gatgttgtga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atgtcttgca gatctagtca gagccttgta cacagtaatg gagactccta tttacattgg 120
tacctgcaga agccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattg 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240
agcagagtgg aggctgagga tctgggaatt tatttctgct ctcaaagtac acatgttccg 300
tacacgttcg gaggggggac caagctggaa ataaaa 336
<210> 147
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 VH (DNA)
<400> 147
caggtccaac tgcagcagcc tggggctgag ctggtgaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggcta caccttcacc aactactggt tgcactgggt gatgcagagg 120
cctggacaag gccttgagtg gatcggaatg attgatcctt ctgatagttt tactacctac 180
aatcaaaagt tcaagggcaa ggccacattg actgtagaca catcctccag cacagccttc 240
atgcagctca gcagcctgac atctgaagac tctgcggtct attattgtac tacggtggac 300
cactggggcc gaggcaccac tctcacagtc tcctca 336
<210> 148
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 LCDR1
<400> 148
Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 149
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 LCDR2
<400> 149
Ile Val Ser Asn Arg Phe Ser
1 5
<210> 150
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 LCDR3
<400> 150
Ser Gln Ser Thr His Ile Pro Tyr Thr
1 5
<210> 151
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 HCDR1
<400> 151
Asn Tyr Trp Met Asn
1 5
<210> 152
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 HCDR2
<400> 152
Met Ile Asp Pro Ser Asp Ser Glu Thr His Tyr Asn Gln Val Phe Lys
1 5 10 15
Asp
<210> 153
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 HCDR3
<400> 153
Asp Phe Gly
1
<210> 154
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 154
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Ile Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Met Lys
100 105 110
<210> 155
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 155
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Met Asn Trp Trp Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile Asp Pro Ser Asp Ser Glu Thr His Tyr Asn Gln Val Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Ile Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Phe Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
100 105 110
<210> 156
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 VL (DNA)
<400> 156
gatgttgtga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagccttgta cacagtaatg gaaacaccta tttacactgg 120
tacctgcaga agccaggcca gtctccaaag ctcctgatct acatagtttc caaccgattt 180
tctggggtcc cagacaggtt cggtggcagt ggatcaggga cagatttcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tatttctgct ctcaaagtac acatattccg 300
tacacgttcg gaggggggac caagctggaa atgaaa 336
<210> 157
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 VH (DNA)
<400> 157
caggtccaac tgcagcagcc tggggctgag ctggtgaggc ctggggcttc agtgaagctg 60
tcttgcaagg cttctggcta caccttcacc aattactgga tgaactggtg gaaacagagg 120
cctggacaag gccttgaatg gattggtatg attgatcctt cagacagtga aactcactac 180
aatcaagtgt tcaaggacaa ggccacattg actgtagaca tatcctccac cacagcctac 240
atgcacctca gcagcctgac atctgaggac tctgcggtct attactgtgc aagagacttc 300
ggctggggcc aagggactct ggtcactgtc tctgca 336
<210> 158
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) LCDR1
<400> 158
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 159
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) LCDR2
<400> 159
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 160
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) LCDR3
<400> 160
Phe Gln Gly Ser His Val Pro Trp Thr
1 5
<210> 161
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) HCDR1
<400> 161
Asn Tyr Leu Ile Glu
1 5
<210> 162
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) HCDR2
<400> 162
Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 163
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) HCDR3
<400> 163
Asp Asp Ser Ala Tyr
1 5
<210> 164
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 164
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 165
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 165
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Asp Asp Ser Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ala
<210> 166
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) VL (DNA)
<400> 166
gatgttttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagtattgta catagtaatg gaaacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tattactgtt ttcaaggttc acatgttccg 300
tggacgttcg gtggaggcac caagctggaa atcaaa 336
<210> 167
<211> 342
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) VH (DNA)
<400> 167
caggtccagc tgcagcagtc tggagctgag ctggtaaggc ctgggacttc agtgaaggtg 60
tcctgcaagg cttctggata cgccttcact aattacttga tagagtgggt aaagcagagg 120
cctggacagg gccttgagtg gattggagtg attaatcctg gaagtggtgg tactaactac 180
aatgagaagt tcaagggcaa ggcaacactg actgcagaca aatcctccag cactgcctac 240
atgcagctca gcagcctgac atctgatgac tctgcggtct atttctgtgc aagagacgac 300
agtgcttact ggggccaagg gactctggtc actgtctctg ca 342
<210> 168
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) LCDR1
<400> 168
Arg Ala Ser Gln Ser Ile Ser Asn Asn Leu His
1 5 10
<210> 169
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) LCDR2
<400> 169
Tyr Ala Ser Gln Ser Ile Ser
1 5
<210> 170
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) LCDR3
<400> 170
Gln Gln Ser Asn Ser Trp Pro Leu Thr
1 5
<210> 171
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) HCDR1
<400> 171
Asn Tyr Leu Ile Glu
1 5
<210> 172
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) HCDR2
<400> 172
Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 173
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) HCDR3
<400> 173
Asp Asp Ser Ala Tyr
1 5
<210> 174
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 174
Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Ser Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Asn
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Thr
65 70 75 80
Glu Asp Phe Gly Met Tyr Phe Cys Gln Gln Ser Asn Ser Trp Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 175
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 175
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr
20 25 30
Leu Ile Glu Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Asp Asp Ser Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ala
<210> 176
<211> 321
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) VL (DNA)
<400> 176
gatattgtgc taactcagtc tccagccacc ctgtctgtga ctccaggaga tagcgtcagt 60
ctttcctgca gggccagcca aagtattagc aacaacctac actggtatca acaaaaatca 120
catgagtctc caaggcttct catcaagtat gcttcccagt ccatctctgg gatcccctcc 180
aggttcagtg gcagtggatc agggacagat ttcactctca gtatcaacag tgtggagact 240
gaagattttg gaatgtattt ctgtcaacag agtaacagct ggcctctcac gttcggtgct 300
gggaccaagc tggagctgaa a 321
<210> 177
<211> 342
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) VH (DNA)
<400> 177
caggtccagc tgcagcagtc tggagctgag ctggtaaggc ctgggacttc agtgaaggtg 60
tcctgcaagg cttctggata cgccttcact aattacttga tagagtgggt aaagcagagg 120
cctggacagg gccttgagtg gattggagtg attaatcctg gaagtggtgg tactaactac 180
aatgagaagt tcaagggcaa ggcaacactg actgcagaca aatcctccag cactgcctac 240
atgcagctca gcagcctgac atctgatgac tctgcggtct atttctgtgc aagagacgac 300
agtgcttact ggggccaagg gactctggtc actgtctctg ca 342
<210> 178
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 LCDR1
<400> 178
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 179
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 LCDR2
<400> 179
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 180
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 LCDR3
<400> 180
Phe Gln Gly Ser His Val Pro Trp Thr
1 5
<210> 181
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 HCDR1
<400> 181
Ser Tyr Trp Met His
1 5
<210> 182
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 HCDR2
<400> 182
Glu Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 183
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 HCDR3
<400> 183
Met Ile Thr Thr Gln Gly Tyr Phe Asp Tyr
1 5 10
<210> 184
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 184
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 185
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 185
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Asn Met Ile Thr Thr Gln Gly Tyr Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 186
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 VL (DNA)
<400> 186
gatgttttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttccg 300
tggacgttcg gtggaggcac caagctggaa atcaaa 336
<210> 187
<211> 357
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 VH (DNA)
<400> 187
caggtccaac tgcagcagcc tggggctgag cttgtgaagc ctggggcttc agtgaagctg 60
tcctgcaagg cttctggcta caccttcacc agctactgga tgcactgggt gaagcagagg 120
cctggacaag gccttgagtg gatcggagag attgatcctt ctgatagtta tactaactac 180
aatcaaaagt tcaagggcaa ggccacattg actgtagaca aatcctccag cacagcctac 240
atgcagctca gcagcctgac atctgaggac tctgcggtct attactgtgc aaatatgatt 300
acgacgcagg gctactttga ctactggggc caaggcacca ctctcacagt ctcctca 357
<210> 188
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 LCDR1
<400> 188
Arg Ser Ser Leu Ser Leu Val Tyr Ser Asn Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 189
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 LCDR2
<400> 189
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 190
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 LCDR3
<400> 190
Ser Gln Asn Thr His Val Pro Phe Thr
1 5
<210> 191
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 HCDR1
<400> 191
Asp Thr Tyr Ile His
1 5
<210> 192
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 HCDR2
<400> 192
Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Pro Lys Phe Gln
1 5 10 15
Asp
<210> 193
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 HCDR3
<400> 193
Gly Asn Trp Asp Trp Phe Ala Tyr
1 5
<210> 194
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 194
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Leu Ser Leu Val Tyr Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Phe Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Asn
85 90 95
Thr His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 195
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 195
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Leu Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Asp Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu His Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Asn Gly Asn Trp Asp Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 196
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 VL (DNA)
<400> 196
gatgttgtga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgta gatctagtct gagccttgta tacagtaatg gaaacaccta tttacattgg 120
taccagcaga agccaggcca gtctccaaag ctcctgatct tcaaagtttc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tatttctgct ctcaaaatac acatgttcca 300
ttcacgttcg gctcggggac aaagttggaa ataaaa 336
<210> 197
<211> 351
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 VH (DNA)
<400> 197
gaggttcagc tgcagcagtc tggggcagag cttgtgaagc caggggcctc agtcaagttg 60
tcctgcacag cttctggcct caacattaaa gacacctata tacactgggt gaagcagagg 120
cctgaacagg gcctggagtg gattggaagg attgatcctg cgaatggaaa tactaaatat 180
gacccgaagt tccaggacaa ggccactata acagcagaca catcctccaa cacagcctac 240
ctgcacctca gcagcctgac atctgaggac actgccgtct attactgtac taatgggaac 300
tgggactggt ttgcttactg gggccaaggg actctggtca ctgtctctgc a 351
<210> 198
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 LCDR1
<400> 198
Lys Ser Gly Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu Arg
1 5 10 15
<210> 199
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 LCDR2
<400> 199
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 200
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 LCDR3
<400> 200
Ser Gln Ser Thr His Val Pro Leu Thr
1 5
<210> 201
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 HCDR1
<400> 201
Asp Tyr Tyr Met His
1 5
<210> 202
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 HCDR2
<400> 202
Trp Ile Asp Pro Glu Asn Gly Asn Thr Ile Tyr Asp Pro Lys Phe Gln
1 5 10 15
Gly
<210> 203
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 HCDR3
<400> 203
Glu Asp Tyr
1
<210> 204
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 VL (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 204
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Lys Ser Gly Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Arg Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 205
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 VH (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4)
<400> 205
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Leu Val Lys Leu Ser Ser Lys Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly Asn Thr Ile Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Thr Tyr
65 70 75 80
Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Glu Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
100 105 110
<210> 206
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 VL (DNA)
<400> 206
gatattgtga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca aatctggtca gagccttgta cacagtaatg gaaacaccta tttacgttgg 120
tacctgcaga agccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tatttctgct ctcaaagtac acatgttccg 300
ctcacgttcg gtgctgggac caagctggag ctgaaa 336
<210> 207
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 VH (DNA)
<400> 207
gaggttcagc tgcagcagtc tggggctgag cttgtgaggc caggggcctt agtcaagttg 60
tcctccaaag cttctggctt caacattaaa gactactata tgcactgggt gaagcagagg 120
cctgaacagg gcctggagtg gattggatgg attgatcctg agaatggtaa tactatatat 180
gacccgaagt tccagggcaa ggccactata acagcagaca catcctccaa cacaacctac 240
ctccagctca gcagcctgac atctgaggac actgccgtct attactgtac tcgagaggac 300
tactggggtc aaggaacctc agtcaccgtc tcctca 336
<210> 208
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) LFR1
<400> 208
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Ile Ile Ser Cys
20
<210> 209
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) LFR2
<400> 209
Trp Cys Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Phe
1 5 10 15
<210> 210
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) LFR3
<400> 210
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys
20 25 30
<210> 211
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) LFR4
<400> 211
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 212
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) HFR1
<400> 212
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Lys
20 25 30
<210> 213
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) HFR2
<400> 213
Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met Gly
1 5 10
<210> 214
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) HFR3
<400> 214
Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu Gln
1 5 10 15
Ile Asn Asn Leu Lys Asp Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg
20 25 30
<210> 215
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (A) HFR4
<400> 215
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
1 5 10
<210> 216
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) LFR1
<400> 216
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Ile Ile Ser Cys
20
<210> 217
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) LFR2
<400> 217
Trp Cys Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Phe
1 5 10 15
<210> 218
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) LFR3
<400> 218
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys
20 25 30
<210> 219
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) LFR4
<400> 219
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 220
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) HFR1
<400> 220
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 221
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) HFR2
<400> 221
Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met Gly
1 5 10
<210> 222
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) HFR3
<400> 222
Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu Gln
1 5 10 15
Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg
20 25 30
<210> 223
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (B) HFR4
<400> 223
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
1 5 10
<210> 224
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体 RD1 (C) LFR1
<400> 224
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys
20
<210> 225
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体 RD1 (C) LFR2
<400> 225
Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile Tyr
1 5 10 15
<210> 226
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体 RD1 (C) LFR3
<400> 226
Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Asn Val Gln Ser Glu Asp Leu Ala Glu Tyr Phe Cys
20 25 30
<210> 227
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体 RD1 (C) LFR4
<400> 227
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
1 5 10
<210> 228
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体 RD1 (C) HFR1
<400> 228
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Lys
20 25 30
<210> 229
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体 RD1 (C) HFR2
<400> 229
Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met Gly
1 5 10
<210> 230
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体 RD1 (C) HFR3
<400> 230
Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu Gln
1 5 10 15
Ile Asn Asn Leu Lys Asp Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg
20 25 30
<210> 231
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体 RD1 (C) HFR4
<400> 231
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
1 5 10
<210> 232
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) LFR1
<400> 232
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys
20
<210> 233
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) LFR2
<400> 233
Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile Tyr
1 5 10 15
<210> 234
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) LFR3
<400> 234
Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Asn Val Gln Ser Glu Asp Leu Ala Glu Tyr Phe Cys
20 25 30
<210> 235
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) LFR4
<400> 235
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
1 5 10
<210> 236
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) HFR1
<400> 236
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 237
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) HFR2
<400> 237
Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met Gly
1 5 10
<210> 238
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) HFR3
<400> 238
Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu Gln
1 5 10 15
Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg
20 25 30
<210> 239
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD1 (D) HFR4
<400> 239
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
1 5 10
<210> 240
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 LFR1
<400> 240
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys
20
<210> 241
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 LFR2
<400> 241
Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 242
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 LFR3
<400> 242
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys
20 25 30
<210> 243
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 LFR4
<400> 243
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 244
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 HFR1
<400> 244
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Thr Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys
20 25 30
<210> 245
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 HFR2
<400> 245
Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 246
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 HFR3
<400> 246
Lys Ala Thr Val Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr Leu Gln
1 5 10 15
Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys Ser Asn
20 25 30
<210> 247
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RE1 HFR4
<400> 247
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
1 5 10
<210> 248
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 LFR1
<400> 248
Asp Ile Val Met Thr Gln Ser Gln Glu Phe Leu Ser Thr Leu Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys
20
<210> 249
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 LFR2
<400> 249
Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Thr Leu Ile Tyr
1 5 10 15
<210> 250
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 LFR3
<400> 250
Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Leu Ala Lys Tyr Phe Cys
20 25 30
<210> 251
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 LFR4
<400> 251
Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys
1 5 10
<210> 252
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 HFR1
<400> 252
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Thr Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr
20 25 30
<210> 253
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 HFR2
<400> 253
Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu Gly
1 5 10
<210> 254
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 HFR3
<400> 254
Arg Leu Arg Ile Thr Lys Asp Asn Phe Lys Ser Gln Val Phe Leu His
1 5 10 15
Leu Asn Ser Leu Gln Thr Asp Asp Thr Ala Thr Tyr Tyr Cys Ala Arg
20 25 30
<210> 255
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RB6 HFR4
<400> 255
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
1 5 10
<210> 256
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) LFR1
<400> 256
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Ile Ile Ser Cys
20
<210> 257
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) LFR2
<400> 257
Trp Cys Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Phe
1 5 10 15
<210> 258
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) LFR3
<400> 258
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys
20 25 30
<210> 259
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) LFR4
<400> 259
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 260
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) HFR1
<400> 260
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 261
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) HFR2
<400> 261
Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met Gly
1 5 10
<210> 262
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) HFR3
<400> 262
Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu Gln
1 5 10 15
Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg
20 25 30
<210> 263
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (A) HFR4
<400> 263
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
1 5 10
<210> 264
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) LFR1
<400> 264
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Ile Ile Ser Cys
20
<210> 265
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) LFR2
<400> 265
Trp Cys Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Phe
1 5 10 15
<210> 266
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) LFR3
<400> 266
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys
20 25 30
<210> 267
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) LFR4
<400> 267
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 268
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) HFR1
<400> 268
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 269
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) HFR2
<400> 269
Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met Gly
1 5 10
<210> 270
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) HFR3
<400> 270
Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu Gln
1 5 10 15
Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg
20 25 30
<210> 271
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (B) HFR4
<400> 271
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
1 5 10
<210> 272
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) LFR1
<400> 272
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Tyr
20
<210> 273
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) LFR2
<400> 273
Trp Asn Gln Gln Lys Pro Gly Gln Pro Pro Arg Leu Leu Ile Tyr
1 5 10 15
<210> 274
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) LFR3
<400> 274
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys
20 25 30
<210> 275
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) LFR4
<400> 275
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 276
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) HFR1
<400> 276
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 277
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) HFR2
<400> 277
Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met Gly
1 5 10
<210> 278
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) HFR3
<400> 278
Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu Gln
1 5 10 15
Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg
20 25 30
<210> 279
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (C) HFR4
<400> 279
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
1 5 10
<210> 280
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) LFR1
<400> 280
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Tyr
20
<210> 281
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) LFR2
<400> 281
Trp Asn Gln Gln Lys Pro Gly Gln Pro Pro Arg Leu Leu Ile Tyr
1 5 10 15
<210> 282
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) LFR3
<400> 282
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys
20 25 30
<210> 283
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) LFR4
<400> 283
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 284
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) HFR1
<400> 284
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 285
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) HFR2
<400> 285
Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met Gly
1 5 10
<210> 286
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) HFR3
<400> 286
Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu Gln
1 5 10 15
Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg
20 25 30
<210> 287
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RH1 (D) HFR4
<400> 287
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
1 5 10
<210> 288
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 LFR1
<400> 288
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Met Ser Cys
20
<210> 289
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 LFR2
<400> 289
Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 290
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 LFR3
<400> 290
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Phe Cys
20 25 30
<210> 291
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 LFR4
<400> 291
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 292
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 HFR1
<400> 292
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 293
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 HFR2
<400> 293
Trp Val Met Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 294
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 HFR3
<400> 294
Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Phe Met Gln
1 5 10 15
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Thr Thr
20 25 30
<210> 295
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF1 HFR4
<400> 295
Trp Gly Arg Gly Thr Thr Leu Thr Val Ser Ser
1 5 10
<210> 296
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 LFR1
<400> 296
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys
20
<210> 297
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 LFR2
<400> 297
Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 298
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 LFR3
<400> 298
Gly Val Pro Asp Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys
20 25 30
<210> 299
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 LFR4
<400> 299
Phe Gly Gly Gly Thr Lys Leu Glu Met Lys
1 5 10
<210> 300
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 HFR1
<400> 300
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 301
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 HFR2
<400> 301
Trp Trp Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 302
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 HFR3
<400> 302
Lys Ala Thr Leu Thr Val Asp Ile Ser Ser Thr Thr Ala Tyr Met His
1 5 10 15
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 303
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF3 HFR4
<400> 303
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
1 5 10
<210> 304
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) LFR1
<400> 304
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys
20
<210> 305
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) LFR2
<400> 305
Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 306
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) LFR3
<400> 306
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys
20 25 30
<210> 307
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) LFR4
<400> 307
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 308
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) HFR1
<400> 308
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr
20 25 30
<210> 309
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) HFR2
<400> 309
Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 310
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) HFR3
<400> 310
Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln
1 5 10 15
Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys Ala Arg
20 25 30
<210> 311
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (A) HFR4
<400> 311
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
1 5 10
<210> 312
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) LFR1
<400> 312
Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Ser Val Ser Leu Ser Cys
20
<210> 313
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) LFR2
<400> 313
Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile Lys
1 5 10 15
<210> 314
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) LFR3
<400> 314
Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Ser Ile Asn Ser Val Glu Thr Glu Asp Phe Gly Met Tyr Phe Cys
20 25 30
<210> 315
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) LFR4
<400> 315
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
1 5 10
<210> 316
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) HFR1
<400> 316
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr
20 25 30
<210> 317
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) HFR2
<400> 317
Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 318
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) HFR3
<400> 318
Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln
1 5 10 15
Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys Ala Arg
20 25 30
<210> 319
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RA5 (B) HFR4
<400> 319
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
1 5 10
<210> 320
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 LFR1
<400> 320
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys
20
<210> 321
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 LFR2
<400> 321
Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 322
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 LFR3
<400> 322
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys
20 25 30
<210> 323
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 LFR4
<400> 323
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 324
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 HFR1
<400> 324
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 325
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 HFR2
<400> 325
Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 326
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 HFR3
<400> 326
Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln
1 5 10 15
Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Asn
20 25 30
<210> 327
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RD3 HFR4
<400> 327
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
1 5 10
<210> 328
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 LFR1
<400> 328
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys
20
<210> 329
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 LFR2
<400> 329
Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Phe
1 5 10 15
<210> 330
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 LFR3
<400> 330
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys
20 25 30
<210> 331
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 LFR4
<400> 331
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 332
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 HFR1
<400> 332
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Leu Asn Ile Lys
20 25 30
<210> 333
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 HFR2
<400> 333
Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 334
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 HFR3
<400> 334
Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr Leu His
1 5 10 15
Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys Thr Asn
20 25 30
<210> 335
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RC1 HFR4
<400> 335
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
1 5 10
<210> 336
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 LFR1
<400> 336
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys
20
<210> 337
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 LFR2
<400> 337
Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 338
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 LFR3
<400> 338
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys
20 25 30
<210> 339
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 LFR4
<400> 339
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
1 5 10
<210> 340
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 HFR1
<400> 340
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Leu Val Lys Leu Ser Ser Lys Ala Ser Gly Phe Asn Ile Lys
20 25 30
<210> 341
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 HFR2
<400> 341
Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 342
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 HFR3
<400> 342
Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Thr Tyr Leu Gln
1 5 10 15
Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys Thr Arg
20 25 30
<210> 343
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221>
<222>
<223> 抗体RF2 HFR4
<400> 343
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
1 5 10
Claims (42)
1.一种抗原结合位点,其结合或特异性结合IL-37并且抑制IL-37活性。
2.根据权利要求1所述的抗原结合位点,其中抗原结合位点包含抗体的抗原结合结构域,抗原结合结构域结合或特异性结合IL-37并且抑制IL-37活性。
3.根据权利要求1或2所述的抗原结合位点,其中被抑制的IL-37活性是IL-37结合IL-18受体α(IL-18Rα)、IL-1受体8或包含IL-18受体α(IL-18Rα)和IL-1受体8的复合物。
4.根据权利要求1至3任一项所述的抗原结合位点,其中被抑制的IL-37活性是IL-37介导的细胞信号传导。
5.根据权利要求1至4任一项所述的抗原结合位点,其中被抑制的IL-37活性是IL-37介导的体外或体内抗炎应答。
6.根据权利要求1至4任一项所述的抗原结合位点,其中被抑制的IL-37活性是IL-37介导的体外或体内先天性免疫应答。
7.根据权利要求1至4任一项所述的抗原结合位点,其中被抑制的IL-37活性是IL-37介导的体外或体内适应性免疫应答。
8.根据权利要求1至7任一项所述的抗原结合位点,其中被抑制的IL-37活性是IL-37介导的细胞因子产生或分泌的减少。
9.根据权利要求8所述的抗原结合位点,其中细胞因子是选自由sICAM-1、IFN-γ、I-TAC、G-SCF、IL-16、IL-10、IL-13、TNF、I-309、IL-2、IL-7、M-CSF、TIMP-1、IL-1α,MIP-1α、RANTES、MIG、IL-1Ra、sTREM-1、MCP-5、IP-10、MCP-1、IL-23、KC、IL-1β、MIP-2、IL-17、IL-17F、IL-4、IL-5、IL-33、IL-25、IL-21、IL-22、嗜酸性粒细胞趋化因子和IL-6组成的组的任意一种或多种。
10.根据权利要求9所述的抗原结合位点,其中细胞因子是选自IL-1β、IL-6和TNF的促炎细胞因子。
11.根据权利要求8至10任一项所述的抗原结合位点,其中IL-37介导的细胞因子产生或分泌的减少来自单核细胞、巨噬细胞、外周血单核细胞(PBMC)、癌症细胞、内皮细胞、上皮细胞或树突细胞或自其衍生的细胞。
12.根据权利要求1至11任一项所述的抗原结合位点,其中抗原结合位点结合或特异性结合人IL-37。
13.根据权利要求12所述的抗原结合位点,其中人IL-37是二聚体形式。
14.根据权利要求12所述的抗原结合位点,其中人IL-37是单体形式。
15.根据权利要求1至14任一项所述的抗原结合位点,其中抗原结合位点结合或特异性结合人IL-37分子,该分子包含如SEQ ID NO:1所示的氨基酸序列、基本由或由如SEQ IDNO:1所示的氨基酸序列组成。
16.根据权利要求1至15任一项所述的抗原结合位点,其中抗原结合位点不可检测地结合或显著结合IL-18和/或IL-1β。
17.根据权利要求1到16任一项所述的抗原结合位点,其中抗原结合位点包含:
FR1-CDR1–FR2–CDR2–FR3–CDR3–FR4–连接物-FR1a-CDR1a–FR2a–CDR2a–FR3a–CDR3a–FR4a
其中:
FR1、FR2、FR3和FR4每个均是框架区;
CDR1、CDR2和CDR3每个均是互补决定区;
FR1a、FR2a、FR3a和FR4a每个均是框架区;
CDR1a、CDR2a和CDR3a每个均是互补决定区;
其中任何一个框架区或互补决定区的序列均如本文所述。
18.根据权利要求17所述的抗原结合位点,其中任何一个互补决定区的序列均包含本文表1所述的氨基酸序列。
19.根据权利要求17或18所述的抗原结合位点,其中任何一个框架区的序列均包含本文表3所述的氨基酸序列。
20.一种抗原结合位点,其包含抗体的抗原结合结构域,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:5所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:6所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:7所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:9所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:2所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2与SEQ ID NO:3所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3与SEQ ID NO:4列出的序列至少大约80%,至少85%,至少90%,至少92%,至少95%,至少97%,至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:8所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:5所示序列,所述CDR2包含SEQ ID NO:6所示序列,所述CDR3包含SEQ ID NO:7所示序列;
(vi)VH,其包含SEQ ID NO:9所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:2所示序列,所述CDR2包含SEQ ID NO:3所示序列,所示CDR3包含SEQ ID NO:4所示序列;
(viii)VL,其包含SEQ ID NO:8所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:5所示序列,所述CDR2包含SEQ ID NO:6所示序列,所述CDR3包含SEQ ID NO:7所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:2所示序列,所述CDR2包含SEQ ID NO:3所示序列,所述CDR3包含SEQ ID NO:4所示序列;和
(x)VH,其包含SEQ ID NO:9所示序列,及VL,其包含SEQ ID NO:8所示序列。
21.一种抗原结合位点,其包含抗体的抗原结合结构域,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:15所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:16所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:17所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:19所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:12所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:13所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一序列,所述CDR3包含与SEQ ID NO:14所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:18所示序列至少95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:15所示序列,所述CDR2包含SEQ ID NO:16所示序列,所述CDR3包含SEQ ID NO:17所示序列;
(vi)VH,其包含SEQ ID NO:19所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:12所示序列,所述CDR2包含SEQ ID NO:13所示序列,所述CDR3包含SEQ ID NO:14所示序列;
(viii)VL,其包含SEQ ID NO:18所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:15所示序列,所述CDR2包含SEQ ID NO:16所示序列,所述CDR3包含SEQ ID NO:17所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:12所示序列,所述CDR2包含SEQ ID NO:13所示序列,所述CDR3包含SEQ ID NO:14所示序列;和
(x)VH,其包含SEQ ID NO:19所示序列,及VL,其包含SEQ ID NO:18所示序列。
22.一种抗原结合位点,其包含抗体的抗原结合结构域,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:41所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:42所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:43所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:51所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:52所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:53所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iii)VH,其包含与SEQ ID NO:44或55所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iv)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:38所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:39所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:40所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(v)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:58所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:59所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:60所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(vi)VL,其包含与SEQ ID NO:44或64所示序列至少大约95%同一的序列;
(vii)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:41所示序列,所述CDR2包含SEQ ID NO:42所示序列,所述CDR3包含SEQ ID NO:43所示序列;
(viii)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:51所示序列,所述CDR2包含SEQ ID NO:52所示序列,所述CDR3包含SEQ ID NO:53所示序列;
(ix)VH,其包含SEQ ID NO:45或55所示序列;
(x)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:38所示序列,所述CDR2包含SEQ ID NO:39所示序列,所述CDR3包含SEQ ID NO:40所示序列;
(xi)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:58所示序列,所述CDR2包含SEQ ID NO:59所示序列,所述CDR3包含SEQ ID NO:60所示序列;
(xii)VL,其包含SEQ ID NO:44或64所示序列;
(xiii)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:41所示序列,所述CDR2包含SEQ ID NO:42所示序列,所述CDR3包含SEQ ID NO:43所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:38所示序列,所述CDR2包含SEQ ID NO:39所示序列,所述CDR3包含SEQ ID NO:40所示序列;和
(xiv)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:51所示序列,所述CDR2包含SEQ ID NO:52所示序列,所述CDR3包含SEQ ID NO:53所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:48所示序列,所述CDR2包含SEQ ID NO:49所示序列,所述CDR3包含SEQ ID NO:50所示序列;和
(xv)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:61所示序列,所述CDR2包含SEQ ID NO:62所示序列,所述CDR3包含SEQ ID NO:63所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:58所示序列,所述CDR2包含SEQ ID NO:59所示序列,所述CDR3包含SEQ ID NO:60所示序列;和
(xvi)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:71所示序列,所述CDR2包含SEQ ID NO:72所示序列,所述CDR3包含SEQ ID NO:73所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:68所示序列,所述CDR2包含SEQ ID NO:69所示序列,所述CDR3包含SEQ ID NO:70所示序列;和
(xvii)VH,其包含SEQ ID NO:44所示序列,及VL,其包含SEQ ID NO:45所示序列;
(xviii)VH,其包含SEQ ID NO:54所示序列,及VL,其包含SEQ ID NO:55所示序列;
(xix)VH,其包含SEQ ID NO:64所示序列,及VL,其包含SEQ ID NO:65所示序列;
(xx)VH,其包含SEQ ID NO:74所示序列,及VL,其包含SEQ ID NO:75所示序列。
23.一种抗原结合位点,其包含抗体的抗原结合结构域,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:141所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:142所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:143所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:145所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:138所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:139所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:140所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:144所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:141所示序列,所述CDR2包含SEQ ID NO:142所示序列,所述CDR3包含SEQ ID NO:143所示序列;
(vi)VH,其包含SEQ ID NO:145所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:138所示序列,所述CDR2包含SEQ ID NO:139所示序列,所述CDR3包含SEQ ID NO:140所示序列;
(viii)VL,其包含SEQ ID NO:144所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:141所示序列,所述CDR2包含SEQ ID NO:142所示序列,所述CDR3包含SEQ ID NO:143所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:138所示序列,所述CDR2包含SEQ ID NO:139所示序列,所述CDR3包含SEQ ID NO:140所示序列;和
(x)VH,其包含SEQ ID NO:145所示序列,及VL,其包含SEQ ID NO:144所示序列。
24.一种抗原结合位点,其包含抗体的抗原结合结构域,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区(CDR)1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:151所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:152所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:153所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(ii)VH,其包含与SEQ ID NO:155所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含与SEQ ID NO:148所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR2包含与SEQ ID NO:149所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列,所述CDR3包含与SEQ ID NO:150所示序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列;
(iv)VL,其包含与SEQ ID NO:154所示序列至少大约95%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:151所示序列,所述CDR2包含SEQ ID NO:152所示序列,所述CDR3包含SEQ ID NO:153所示序列;
(vi)VH,其包含SEQ ID NO:155所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:148所示序列,所述CDR2包含SEQ ID NO:149所示序列,所述CDR3包含SEQ ID NO:150所示序列;
(viii)VL,其包含SEQ ID NO:154所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:151所示序列,所述CDR2包含SEQ ID NO:152所示序列,所述CDR3包含SEQ ID NO:153所示序列;以及VL,其包含CDR1、CDR2和CDR3,所述CDR1包含SEQ ID NO:148所示序列,所述CDR2包含SEQ ID NO:149所示序列,所述CDR3包含SEQ ID NO:150所示序列;和
(x)VH,其包含SEQ ID NO:155所示序列,及VL,其包含SEQ ID NO:154所示序列。
25.一种抗原结合位点,其包含抗体的抗原结合结构域,其中抗原结合结构域结合或特异性结合IL-37,其中抗原结合结构域包含以下至少一种:
(i)VH,其包含互补决定区域(CDR)1、CDR2和CDR3,所述CDR1、CDR2和CDR3分别包含与下述序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列:
-SEQ ID NO:5、6和7;
-SEQ ID NO:15、16和17;
-SEQ ID NO:41、42和43;
-SEQ ID NO:51、52和53;
-SEQ ID NO:61、62和63;
-SEQ ID NO:71、72和73;
-SEQ ID NO:81、82和83;
-SEQ ID NO:91、92和93;
-SEQ ID NO:101、102和103;
-SEQ ID NO:111、112和113;
-SEQ ID NO:121、122和123;
-SEQ ID NO:131、132和133;
-SEQ ID NO:141、142和143;
-SEQ ID NO:151、152和153;
-SEQ ID NO:161、162和163;
-SEQ ID NO:171、172和173;
-SEQ ID NO:181、182和183;
-SEQ ID NO:191、192和193;或
-SEQ ID NO:201、202和203;
(ii)VH,其包含与SEQ ID NO:9、SEQ ID NO:19、SEQ ID NO:45、SEQ ID NO:55、SEQ IDNO:65、SEQ ID NO:75、SEQ ID NO:85、SEQ ID NO:95、SEQ ID NO:105、SEQ ID NO:115、SEQID NO:125、SEQ ID NO:135、SEQ ID NO:145、SEQ ID NO:155、SEQ ID NO:165、SEQ ID NO:175、SEQ ID NO:185、SEQ ID NO:195或SEQ ID NO:205所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(iii)VL,其包含CDR1、CDR2和CDR3,所述CDR1、CDR2和CDR3分别包含与下述序列至少大约80%、至少85%、至少90%、至少92%、至少95%、至少97%、至少99%同一的序列:
-SEQ ID NO:2、3和4;
-SEQ ID NO:12、13和14;
-SEQ ID NO:38、39和40;
-SEQ ID NO:48、49和50;
-SEQ ID NO:58、59和60;
-SEQ ID NO:68、69和70;
-SEQ ID NO:78、79和80;
-SEQ ID NO:88,89和90;
-SEQ ID NO:98、99和100;
-SEQ ID NO:108、109和110;
-SEQ ID NO:118、119和120;
-SEQ ID NO:128、129和130;
-SEQ ID NO:138、139和140;
-SEQ ID NO:148、149和150;
-SEQ ID NO:158、159和160;
-SEQ ID NO:168、169和170;
-SEQ ID NO:178、179和180;
-SEQ ID NO:188、189和190;或
-SEQ ID NO:198、199和200;
(iv)VL,其包含与SEQ ID NO:8、SEQ ID NO:18、SEQ ID NO:44、SEQ ID NO:54、SEQ IDNO:64、SEQ ID NO:74、SEQ ID NO:84、SEQ ID NO:94、SEQ ID NO:104、SEQ ID NO:114、SEQID NO:124、SEQ ID NO:134、SEQ ID NO:144、SEQ ID NO:154、SEQ ID NO:164、SEQ ID NO:174、SEQ ID NO:184、SEQ ID NO:194或SEQ ID NO:204所示序列至少大约95%或96%或97%或98%或99%同一的序列;
(v)VH,其包含CDR1、CDR2和CDR3,所述CDR1、CDR2和CDR3分别包含以下所示的任意一种序列:
-SEQ ID NO:5、6和7;
-SEQ ID NO:15、16和17;
-SEQ ID NO:41、42和43;
-SEQ ID NO:51、52和53;
-SEQ ID NO:61、62和63;
-SEQ ID NO:71、72和73;
-SEQ ID NO:81、82和83;
-SEQ ID NO:91、92和93;
-SEQ ID NO:101、102和103;
-SEQ ID NO:111、112和113;
-SEQ ID NO:121、122和123;
-SEQ ID NO:131、132和133;
-SEQ ID NO:141、142和143;
-SEQ ID NO:151、152和153;
-SEQ ID NO:161、162和163;
-SEQ ID NO:171、172和173;
-SEQ ID NO:181、182和183;
-SEQ ID NO:191、192和193;或
-SEQ ID NO:201、202和203;
(vi)VH,其包含SEQ ID NO:9、SEQ ID NO:19、SEQ ID NO:45、SEQ ID NO:55、SEQ ID NO:65、SEQ ID NO:75、SEQ ID NO:85、SEQ ID NO:95、SEQ ID NO:105、SEQ ID NO:115、SEQ IDNO:125、SEQ ID NO:135、SEQ ID NO:145、SEQ ID NO:155、SEQ ID NO:165、SEQ ID NO:175、SEQ ID NO:185、SEQ ID NO:195或SEQ ID NO:205所示序列;
(vii)VL,其包含CDR1、CDR2和CDR3,所述CDR1、CDR2和CDR3分别包含以下所示的任意一种序列:
-SEQ ID NO:2、3和4;
-SEQ ID NO:12、13和14;
-SEQ ID NO:38、39和40;
-SEQ ID NO:48、49和50;
-SEQ ID NO:58、59和60;
-SEQ ID NO:68、69和70;
-SEQ ID NO:78、79和80;
-SEQ ID NO:88、89和90;
-SEQ ID NO:98、99和100;
-SEQ ID NO:108、109和110;
-SEQ ID NO:118、119和120;
-SEQ ID NO:128、129和130;
-SEQ ID NO:138、139和140;
-SEQ ID NO:148、149和150;
-SEQ ID NO:158、159和160;
-SEQ ID NO:168、169和170;
-SEQ ID NO:178、179和180;
-SEQ ID NO:188、189和190;或
-SEQ ID NO:198、199和200;
(viii)VL,其包含SEQ ID NO:8、SEQ ID NO:18、SEQ ID NO:44、SEQ ID NO:54、SEQ IDNO:64、SEQ ID NO:74、SEQ ID NO:84、SEQ ID NO:94、SEQ ID NO:104、SEQ ID NO:114、SEQID NO:124、SEQ ID NO:134、SEQ ID NO:144、SEQ ID NO:154、SEQ ID NO:164、SEQ ID NO:174、SEQ ID NO:184、SEQ ID NO:194或SEQ ID NO:204所示序列;
(ix)VH,其包含CDR1、CDR2和CDR3,以及VL,其包含CDR1、CDR2和CDR3,所述CDR1、CDR2和CDR3分别包含以下所示的任意一种序列:
-SEQ ID NO:5、6、7和2、3和4;
-SEQ ID NO:15、16、17和12、13和14;
-SEQ ID NO:41、42、43和38、39和40;
-SEQ ID NO:51、52、53和48、49和50;
-SEQ ID NO:61、62、63和58、59和60;
-SEQ ID NO:71、72、73和68、69和70;
-SEQ ID NO:81、82、83和78、79和80;
-SEQ ID NO:91、92、93和88、89和90;
-SEQ ID NO:101、102、103和98、99和100;
-SEQ ID NO:111、112、113和108、109和110;
-SEQ ID NO:121、122、123和118、119和120;
-SEQ ID NO:131、132、133和128、129和130;
-SEQ ID NO:141、142、143和138、139和140;
-SEQ ID NO:151、152、153和148、149和150;
-SEQ ID NO:161、162、163和158、159和160;
-SEQ ID NO:171、172、173和168、169和170;
-SEQ ID NO:181、182,183、178、179和180;
-SEQ ID NO:191、192、193和188、189和190;或
-SEQ ID NO:201、202、203和198、199和200;
(x)VH和VL,VH和VL分别包含以下所示的任意一种序列:
-SEQ ID NO:9和8;
-SEQ ID NO:19和18;
-SEQ ID NO:45和44;
-SEQ ID NO:55和54;
-SEQ ID NO:65和64;
-SEQ ID NO:75和74;
-SEQ ID NO:85和84;
-SEQ ID NO:95和94;
-SEQ ID NO:105和104;
-SEQ ID NO:115和114;
-SEQ ID NO:125和124;
-SEQ ID NO:135和134;
-SEQ ID NO:145和144;
-SEQ ID NO:155和154;
-SEQ ID NO:165和164;
-SEQ ID NO:175和174;
-SEQ ID NO:185和184;
-SEQ ID NO:195和194;或
-SEQ ID NO:205和204。
26.根据权利要求1至25任一项所述的抗原结合位点,其中抗原结合位点以以下形式存在:
(i)单链Fv片段(scFv);
(ii)scFv二聚体(di-scFv);
(iii)连接至抗体恒定区、Fc或重链恒定域(CH)2和/或CH3的(i)或(ii)的一种;或
(iv)连接至结合免疫效应细胞的蛋白的(i)或(ii)的一种。
27.根据权利要求1至25任一项所述的抗原结合位点,其中抗原结合位点以以下形式存在:
(i)二体;
(ii)三体;
(iii)四体;
(iv)Fab;
(v)F(ab’)2;
(vi)Fv;
(vii)连接至抗体恒定区、Fc或重链恒定域(CH)2和/或CH3的(i)至(vi)中的一种;
(viii)连接至结合免疫效应细胞的蛋白的(i)至(vi)的一种。
28.根据权利要求1至27任一项所述的抗原结合位点,其中抗原结合位点是抗体或其抗原结合片段。
29.一种编码根据权利要求1至28任一项所述的抗原结合位点的核酸。
30.一种载体,其包含根据权利要求29所述的核酸。
31.根据权利要求30所述的载体,其中核酸与启动子有效连接。
32.根据权利要求31所述的载体,其中,以5’到3’的顺序,载体包含下列有效连接的组分:
(i)启动子;
(ii)编码第一多肽的核酸;
(iii)内部核糖体进入位点;和
(iv)编码第二多肽的核酸,
其中第一多肽包含VH,且第二多肽包含VL,反之亦然。
33.一种细胞,其包含根据权利要求29至32任一项所述的载体或核酸。
34.根据权利要求33所述的细胞,其中细胞是细菌细胞、酵母细胞、昆虫细胞或哺乳动物细胞。
35.一种药物组合物,其包含根据权利要求1至28任一项所述的抗原结合位点,和药学上可接受的载体、稀释剂或赋形剂。
36.一种试剂盒或制品,其包含根据权利要求1至28任一项所述的抗原结合位点。
37.一种治疗或预防受试者中与上升的内源性IL-37表达相关的病况的方法,所述方法包括将根据权利要求1至28任一项所述的抗原结合位点施用于受试者,从而治疗或预防与上升的内源性IL-37表达相关的病况。
38.一种治疗或预防受试者癌症的方法,所述方法包括将根据权利要求1至28任一项所述的抗原结合位点施用于受试者,从而治疗或预防癌症。
39.一种治疗或预防与受试者的免疫麻痹相关的病况的方法,所述方法包括将根据权利要求1至28任一项所述的抗原结合位点施用于受试者,从而治疗或预防与免疫麻痹相关的病况。
40.根据权利要求39所述的方法,其中与免疫麻痹相关的病况是败血症、急性肝衰竭或慢性肝衰竭。
41.根据权利要求1至28任一项所述的抗原结合位点用于测定获自个体的生物样品中IL-37水平的用途。
42.根据权利要求41所述的用途,其中检测生物样品中IL-37水平能够诊断个体的疾病或以改变的IL-37水平为表征的病况。
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AU2016905344 | 2016-12-23 | ||
AU2016905344A AU2016905344A0 (en) | 2016-12-23 | Antibodies to IL-37 | |
PCT/AU2017/051443 WO2018112549A1 (en) | 2016-12-23 | 2017-12-22 | Antibodies to il-37 |
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EP (1) | EP3558367A1 (zh) |
JP (1) | JP2020511118A (zh) |
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Cited By (6)
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CN111848786A (zh) * | 2020-07-29 | 2020-10-30 | 中牧实业股份有限公司 | 一种单克隆抗体、其制备方法及用途 |
CN114057871A (zh) * | 2020-08-07 | 2022-02-18 | 沈阳何氏眼产业集团有限公司 | 抗人periostin单克隆嵌合抗体及应用 |
CN114246937A (zh) * | 2020-09-21 | 2022-03-29 | 上海市公共卫生临床中心 | 白细胞介素37与干扰素联用在治疗病毒感染中的应用 |
WO2023155132A1 (zh) * | 2022-02-18 | 2023-08-24 | 绍兴守仁医疗健康科技有限公司 | Rac1蛋白单克隆抗体及其制备方法与应用 |
WO2023246570A1 (zh) * | 2022-06-20 | 2023-12-28 | 广东克冠达医药科技有限公司 | 白介素-9的抗体及其用途 |
CN114246937B (zh) * | 2020-09-21 | 2024-05-31 | 上海市公共卫生临床中心 | 白细胞介素37与干扰素联用在治疗病毒感染中的应用 |
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WO2021142269A1 (en) * | 2020-01-10 | 2021-07-15 | Dyne Therapeutics, Inc. | Muscle targeting complexes and uses thereof for modulation of genes associated with muscle atrophy |
WO2021142331A1 (en) * | 2020-01-10 | 2021-07-15 | Dyne Therapeutics, Inc. | Muscle targeting complexes and uses thereof for modulation of genes associated with cardiac muscle disease |
CN114516915B (zh) * | 2020-11-19 | 2023-03-28 | 东莞市朋志生物科技有限公司 | 抗n末端脑钠肽前体的抗体以及制备抗体的方法 |
WO2023137291A1 (en) * | 2022-01-11 | 2023-07-20 | Board Of Regents, The University Of Texas System | Anti-cd94 antibody and chimeric antigen receptor and methods of use thereof |
WO2023250381A2 (en) * | 2022-06-22 | 2023-12-28 | The Regents Of The University Of California | Antibodies to botulinum neurotoxins |
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- 2017-12-22 WO PCT/AU2017/051443 patent/WO2018112549A1/en unknown
Non-Patent Citations (1)
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LI,S: "Extracellular form of IL-37 inhibit innate inflammation in vitro but require the IL-1family decoy receptor IL-1R8", 《PNAS》 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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CN111848786A (zh) * | 2020-07-29 | 2020-10-30 | 中牧实业股份有限公司 | 一种单克隆抗体、其制备方法及用途 |
CN114057871A (zh) * | 2020-08-07 | 2022-02-18 | 沈阳何氏眼产业集团有限公司 | 抗人periostin单克隆嵌合抗体及应用 |
CN114057871B (zh) * | 2020-08-07 | 2023-08-01 | 沈阳何氏眼产业集团有限公司 | 抗人periostin单克隆嵌合抗体及应用 |
CN114246937A (zh) * | 2020-09-21 | 2022-03-29 | 上海市公共卫生临床中心 | 白细胞介素37与干扰素联用在治疗病毒感染中的应用 |
CN114246937B (zh) * | 2020-09-21 | 2024-05-31 | 上海市公共卫生临床中心 | 白细胞介素37与干扰素联用在治疗病毒感染中的应用 |
WO2023155132A1 (zh) * | 2022-02-18 | 2023-08-24 | 绍兴守仁医疗健康科技有限公司 | Rac1蛋白单克隆抗体及其制备方法与应用 |
WO2023246570A1 (zh) * | 2022-06-20 | 2023-12-28 | 广东克冠达医药科技有限公司 | 白介素-9的抗体及其用途 |
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JP2020511118A (ja) | 2020-04-16 |
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