CN108348589B - 治疗性cd47抗体 - Google Patents
治疗性cd47抗体 Download PDFInfo
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- CN108348589B CN108348589B CN201680062144.7A CN201680062144A CN108348589B CN 108348589 B CN108348589 B CN 108348589B CN 201680062144 A CN201680062144 A CN 201680062144A CN 108348589 B CN108348589 B CN 108348589B
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Abstract
提供了具有如本文所述的不同功能分布的抗‑CD47单克隆抗体(抗‑CD47mAb)、产生抗‑CD47mAb的方法、以及使用这些抗‑CD47mAb作为治疗剂用于预防或治疗实体癌和血液癌、缺血再灌注损伤、心血管疾病、自身免疫性疾病、炎性疾病的治疗剂或作为诊断学用于确定组织样品中的CD47水平的方法。
Description
相关申请的交叉引用
本申请要求以下美国临时申请号的权益:2015年9月18日提交的62/220,691;2015年12月4日提交的62/263,544;2015年9月22日提交的62/221,852;2015年9月18日提交的62/220,725;2015年9月25日提交的62/232,681;2015年11月6日提交的62/252,171;以及2016年6月24日提交的62/354,592;这些申请的披露内容均通过引用结合在此,如同整体在此写出一般。
技术领域
本披露大体上涉及具有如本文所述的不同功能分布的抗-CD47单克隆抗体(抗-CD47 mAb)、产生抗-CD47 mAb的方法、以及使用这些抗-CD47mAb作为治疗剂用于预防或治疗实体癌和血液癌、缺血再灌注损伤、心血管疾病、自身免疫性疾病或炎性疾病或作为诊断学用于确定组织样品中的CD47水平的方法。
背景技术
CD47是一种细胞表面受体,其包括细胞外IgV组结构域、5跨膜结构域、以及替代性剪接的胞质尾区。两种配体结合CD47:信号抑制性受体蛋白α(SIRPα)和血小板应答蛋白-1(TSP1)。CD47表达和/或活性已牵涉到许多疾病和病症。因此,需要用于治疗人类和动物中与CD47相关的疾病和病状的治疗性组合物和方法,包括预防和治疗实体癌和血液癌、缺血再灌注损伤(IRI)、心血管疾病、或自身免疫性或炎性疾病。还需要用于确定肿瘤样品中的CD47表达水平的诊断组合物和方法。
发明内容
本披露描述了具有不同功能分布的抗-CD47 mAb。这些抗体具有选自以下各项的不同特性组合:1)表现出与CD47的一种或多种物种同系物的交叉反应性;2)阻断CD47与其配体SIRPα之间的相互作用;3)增加对人类肿瘤细胞的吞噬作用,4)诱导易感性人类肿瘤细胞的死亡;5)不诱导人类肿瘤细胞的细胞死亡;6)减少了与人类血红细胞(hRBC)的结合;
7)不具有可检测的与hRBC的结合;8)引起减少的hRBC凝集;9)不引起可检测的hRBC凝集;10)逆转一氧化氮(NO)的TSP1抑制,和/或11)不逆转NO途径的TSP1抑制。本披露的抗体适用于用以治疗人类和动物中与CD47相关的疾病和病状的不同治疗方法,包括预防和治疗实体癌和血液癌、自身免疫性疾病、炎性疾病、IRI、以及心血管疾病。本披露的抗体也适用作确定组织样品中的CD47表达水平的诊断学。本披露的实施例包括分离的抗体及其免疫活性结合片段;包含一种或多种抗-CD47单克隆抗体、优选嵌合或人源化形式的所述抗体的药物组合物;此类抗-CD47单克隆抗体的治疗性使用方法;以及产生这些抗-CD47单克隆抗体的细胞系。
本披露的实施例包括通过参考特异性结构特征(即CDR或整个重链可变结构域或轻链可变结构域的指定氨基酸序列)来定义的mAb或其抗原结合片段。所有这些抗体均结合CD47。
单克隆抗体或其抗原结合片段可包含至少一个、通常至少三个如本文所提供的CDR序列,这些序列通常与来自人类可变区的框架序列组合或呈分离的CDR肽的形式。在一些实施例中,抗体包含至少一条轻链和至少一条重链,该至少一条轻链包含本文提供的位于可变区框架中的三个轻链CDR序列,该可变区框架可以是但不限于鼠类或人类可变区框架,该至少一条重链包含本文提供的位于可变区框架中的三个重链CDR序列,该可变区框架可以是但不限于人类或鼠类可变区框架。
优选的实施例是包含重链可变结构域的抗-CD47 mAb或其抗原结合片段,该重链可变结构域包含可变重链CDR1、可变重链CDR2和可变重链CDR3,其中所述可变重链CDR1包含选自下组的氨基酸序列,该组由以下各项组成:
SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3;所述可变重链CDR2包含选自下组的氨基酸序列,该组由以下各项组成:SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6;并且所述可变重链CDR3包含选自下组的氨基酸序列,该组由以下各项组成:SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9以及SEQ ID NO:10。
重链可变结构域可包含所列出的可变重链CDR1序列(HCDR1)中的任一个与可变重链CDR2序列(HCDR2)中的任一个和可变重链CDR3序列(HCDR3)中的任一个的组合。然而,HCDR1和HCDR2以及HCDR3的某些实施例是特别优选的,这些实施例来源于单一常见VH结构域,该结构域的实例是本文所述的。
抗体或其抗原结合片段可另外包含轻链可变结构域(VL),该轻链可变结构域与VH结构域配对形成抗原结合结构域。优选的轻链可变结构域是包含可变轻链CDR1、可变轻链CDR2和可变轻链CDR3的那些轻链可变结构域,其中所述可变轻链CDR1包含选自下组的氨基酸序列,该组由以下各项组成:
SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14;所述可变轻链CDR2任选地包含选自下组的氨基酸序列,该组由以下各项组成:SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17;并且所述可变轻链CDR3任选地包含选自下组的氨基酸序列,该组由以下各项组成:SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20。
轻链可变结构域可包含所列出的可变轻链CDR1序列(LCDR1)中的任一个与可变轻链CDR2序列(LCDR2)中的任一个和可变轻链CDR3序列(LCDR3)中的任一个的组合。然而,LCDR1和LCDR2以及LCDR3的某些实施例是特别优选的,这些实施例来源于单一常见VL结构域,该结构域的实例是本文所述的。
包含于VL结构域配对的VH结构域的任何给定CD47抗体或其抗原结合片段将包含6个CDR的组合:可变重链CDR1(HCDR1)、可变重链CDR2(HCDR2)、可变重链CDR3(HCDR3)、可变轻链CDR1(LCDR1)、可变轻链CDR2(LCDR2)、以及可变轻链CDR1(LCDR1)。尽管选自以上所列出的CDR序列组的6个CDR的所有组合均是可允许的,并且在本披露的范围内,6个CDR的某些组合是特别优选的。
6个CDR的优选组合包括但不限于可变重链CDR1(HCDR1)、可变重链CDR2(HCDR2)、可变重链CDR3(HCDR3)、可变轻链CDR1(LCDR1)、可变轻链CDR2(LCDR2)、以及可变轻链CDR3(LCDR3)的组合,该组合选自由以下各项组成的组:
(i)包含SEQ ID NO:1的HCDR1、包含SEQ ID NO:4的HCDR2、包含SEQ ID NO:7的HCDR3、包含SEQ ID NO:11的LCDR1、包含SEQ ID NO:15的LCDR2、包含SEQ ID NO:18的LCDR3;
(ii)包含SEQ ID NO:1的HCDR1、包含SEQ ID NO:4的HCDR2、包含SEQ ID NO:8的HCDR3、包含SEQ ID NO:11的LCDR1、包含SEQ ID NO:15的LCDR2、包含SEQ ID NO:18的LCDR3;
(iii)包含SEQ ID NO:2的HCDR1、包含SEQ ID NO:5的HCDR2、包含SEQ ID NO:9的HCDR3、包含SEQ ID NO:12的LCDR1、包含SEQ ID NO:16的LCDR2、包含SEQ ID NO:19的LCDR3;
(iv)包含SEQ ID NO:2的HCDR1、包含SEQ ID NO:5的HCDR2、包含SEQ ID NO:9的HCDR3、包含SEQ ID NO:13的LCDR1、包含SEQ ID NO:16的LCDR2、包含SEQ ID NO:19的LCDR3;以及
(v)包含SEQ ID NO:3的HCDR1、包含SEQ ID NO:6的HCDR2、包含SEQ ID NO:10的HCDR3、包含SEQ ID NO:14的LCDR1、包含SEQ ID NO:17的LCDR2、包含SEQ ID NO:20的LCDR3。
进一步优选的抗-CD47抗体包括抗体或其抗原结合片段,其包含重链可变结构域,该重链可变结构域具有选自下组的氨基酸序列,该组由以下各项组成:氨基酸序列SEQ IDNO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:26、SEQ ID NO:27、SEQ IDNO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:31、SEQ ID NO:32、SEQ ID NO:33、SEQ IDNO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、以及SEQ ID NO:40、以及表现出与所述序列之一至少90%、95%、97%、98%或99%序列一致性的氨基酸序列。可替代地或另外地,优选的抗-CD47抗体(包括抗体或其抗原结合片段)可包含具有选自下组的氨基酸序列的轻链可变结构域,该组由以下各项组成:氨基酸序列SEQID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:46、SEQ ID NO:48、SEQID NO:49、SEQ ID NO:50、SEQ ID NO:51、以及SEQ ID NO:52、以及表现出与所述序列之一至少90%、95%、97%、98%或99%序列一致性的氨基酸序列。
尽管选自以上所列出的VH和VL结构域序列组的VH结构域和VL结构域的所有可能的配对均是可允许的,并且是处于本披露的范围内,但是VH和VL结构域的某些组合是特别优选的。因此,优选的CD47抗体或其抗原结合片段是包含重链可变结构域(VH)和轻链可变结构域(VL)的组合的那些,其中该组合选自下组,该组由以下各项组成:
(i)包含氨基酸序列SEQ ID NO:21的重链可变结构域和包含氨基酸序列SEQ IDNO:41的轻链可变结构域;
(ii)包含氨基酸序列SEQ ID NO:23的重链可变结构域和包含氨基酸序列SEQ IDNO:43的轻链可变结构域;
(iii)包含氨基酸序列SEQ ID NO:34的重链可变结构域和包含氨基酸序列SEQ IDNO:49的轻链可变结构域;
(iv)包含氨基酸序列SEQ ID NO:36的重链可变结构域和包含氨基酸序列SEQ IDNO:52的轻链可变结构域;
(v)包含氨基酸序列SEQ ID NO:38的重链可变结构域和包含氨基酸序列SEQ IDNO:52的轻链可变结构域;
(vi)包含氨基酸序列SEQ ID NO:39的重链可变结构域和包含氨基酸序列SEQ IDNO:52的轻链可变结构域;
(vii)包含氨基酸序列SEQ ID NO:24的重链可变结构域和包含氨基酸序列SEQ IDNO:43的轻链可变结构域;
(viii)包含氨基酸序列SEQ ID NO:37的重链可变结构域和包含氨基酸序列SEQID NO:52的轻链可变结构域;
(ix)包含氨基酸序列SEQ ID NO:33的重链可变结构域和包含氨基酸序列SEQ IDNO:48的轻链可变结构域;
(x)包含氨基酸序列SEQ ID NO:26的重链可变结构域和包含氨基酸序列SEQ IDNO:44的轻链可变结构域;
(xi)包含氨基酸序列SEQ ID NO:27的重链可变结构域和包含氨基酸序列SEQ IDNO:44的轻链可变结构域;以及
(xii)包含氨基酸序列SEQ ID NO:38的重链可变结构域和包含氨基酸序列SEQ IDNO:51的轻链可变结构域;
(xiii)包含氨基酸序列SEQ ID NO:39的重链可变结构域和包含氨基酸序列SEQID NO:51的轻链可变结构域;
(xiv)包含氨基酸序列SEQ ID NO:40的重链可变结构域和包含氨基酸序列SEQ IDNO:52的轻链可变结构域;
(xv)包含氨基酸序列SEQ ID NO:36的重链可变结构域和包含氨基酸序列SEQ IDNO:51的轻链可变结构域;
(xvi)包含氨基酸序列SEQ ID NO:29的重链可变结构域和包含氨基酸序列SEQ IDNO:47的轻链可变结构域;
(xvii)包含氨基酸序列SEQ ID NO:30的重链可变结构域和包含氨基酸序列SEQID NO:47的轻链可变结构域;
(xviii)包含氨基酸序列SEQ ID NO:31的重链可变结构域和包含氨基酸序列SEQID NO:47的轻链可变结构域;
(xix)包含氨基酸序列SEQ ID NO:32的重链可变结构域和包含氨基酸序列SEQ IDNO:47的轻链可变结构域;
(xx)包含氨基酸序列SEQ ID NO:33的重链可变结构域和包含氨基酸序列SEQ IDNO:47的轻链可变结构域;
(xxi)包含氨基酸序列SEQ ID NO:29的重链可变结构域和包含氨基酸序列SEQ IDNO:48的轻链可变结构域;
(xxii)包含氨基酸序列SEQ ID NO:30的重链可变结构域和包含氨基酸序列SEQID NO:48的轻链可变结构域;
(xxiii)包含氨基酸序列SEQ ID NO:31的重链可变结构域和包含氨基酸序列SEQID NO:48的轻链可变结构域;
(xxiv)包含氨基酸序列SEQ ID NO:32的重链可变结构域和包含氨基酸序列SEQID NO:48的轻链可变结构域;
(xxv)包含氨基酸序列SEQ ID NO:26的重链可变结构域和包含氨基酸序列SEQ IDNO:43的轻链可变结构域;
(xxvi)包含氨基酸序列SEQ ID NO:27的重链可变结构域和包含氨基酸序列SEQID NO:43的轻链可变结构域;
(xxvii)包含氨基酸序列SEQ ID NO:28的重链可变结构域和包含氨基酸序列SEQID NO:46的轻链可变结构域;
(xxviii)包含氨基酸序列SEQ ID NO:35的重链可变结构域和包含氨基酸序列SEQID NO:50的轻链可变结构域;
(xxix)包含氨基酸序列SEQ ID NO:29的重链可变结构域和包含氨基酸序列SEQID NO:48的轻链可变结构域;
(xxx)包含氨基酸序列SEQ ID NO:30的重链可变结构域和包含氨基酸序列SEQ IDNO:48的轻链可变结构域;
(xxxi)包含氨基酸序列SEQ ID NO:31的重链可变结构域和包含氨基酸序列SEQID NO:48的轻链可变结构域;
(xxxii)包含氨基酸序列SEQ ID NO:32的重链可变结构域和包含氨基酸序列SEQID NO:48的轻链可变结构域;
(xxxiii)包含氨基酸序列SEQ ID NO:37的重链可变结构域和包含氨基酸序列SEQID NO:51的轻链可变结构域;以及
(xxxiv)包含氨基酸序列SEQ ID NO:40的重链可变结构域和包含氨基酸序列SEQID NO:51的轻链可变结构域。
优选的抗-CD47抗体或其抗原结合片段也可包含重链可变结构域和轻链可变结构域的组合,其中该重链可变结构域包含与以上(i)至(xxxiv)所示出的重链氨基酸序列具有至少85%序列一致性、或至少90%序列一致性、或至少95%序列一致性、或至少97%、98%或99%序列一致性的VH序列,并且/或者该轻链可变结构域包含与以上(i)至(xxxiv)所示出的轻链氨基酸序列具有至少85%序列一致性、或至少90%序列一致性、或至少95%序列一致性、或至少97%、98%或99%序列一致性的VL序列。在(i)至(xxxiv)部分中的特定VH和VL配对或组合对于具有与这些参考序列有特定序列一致性百分比的VH和VL结构域序列的抗-CD47抗体而言可能是保守性的。
对于其中抗体或其抗原结合片段的重链可变结构域和/或轻链可变结构域通过与参考序列的特定序列一致性百分比来限定的所有实施例,VH和/或VL结构可保留与参考序列中存在的那些一致的CDR序列,以使得该变化仅存在于框架区域内。
在另一个实施例中,优选的CD47抗体或其抗原结合片段是包含重链(HC)和轻链(LC)的组合的那些,其中该组合选自下组,该组由以下各项组成:
(i)包含氨基酸序列SEQ ID NO:76的重链和包含氨基酸序列SEQ ID NO:66的轻链;
(ii)包含氨基酸序列SEQ ID NO:77的重链和包含氨基酸序列SEQ ID NO:68的轻链;
(iii)包含氨基酸序列SEQ ID NO:78的重链和包含氨基酸序列SEQ ID NO:69的轻链;
(iv)包含氨基酸序列SEQ ID NO:79的重链和包含氨基酸序列SEQ ID NO:70的轻链;
(v)包含氨基酸序列SEQ ID NO:80的重链和包含氨基酸序列SEQ ID NO:70的轻链;
(vi)包含氨基酸序列SEQ ID NO:81的重链和包含氨基酸序列SEQ ID NO:70的轻链;
(vii)包含氨基酸序列SEQ ID NO:82的重链和包含氨基酸序列SEQ ID NO:68的轻链;
(viii)包含氨基酸序列SEQ ID NO:83的重链和包含氨基酸序列SEQ ID NO:70的轻链;
(ix)包含氨基酸序列SEQ ID NO:84的重链和包含氨基酸序列SEQ ID NO:71的轻链;
(x)包含氨基酸序列SEQ ID NO:85的重链和包含氨基酸序列SEQ ID NO:72的轻链;
(xi)包含氨基酸序列SEQ ID NO:86的重链和包含氨基酸序列SEQ ID NO:72的轻链;
(xii)包含氨基酸序列SEQ ID NO:80的重链和包含氨基酸序列SEQ ID NO:73的轻链;
(xiii)包含氨基酸序列SEQ ID NO:81的重链和包含氨基酸序列SEQ ID NO:73的轻链;
(xiv)包含氨基酸序列SEQ ID NO:87的重链和包含氨基酸序列SEQ ID NO:70的轻链;
(xv)包含氨基酸序列SEQ ID NO:79的重链和包含氨基酸序列SEQ ID NO:73的轻链;
(xvi)包含氨基酸序列SEQ ID NO:88的重链和包含氨基酸序列SEQ ID NO:74的轻链;
(xvii)包含氨基酸序列SEQ ID NO:89的重链和包含氨基酸序列SEQ ID NO:74的轻链;
(xviii)包含氨基酸序列SEQ ID NO:90的重链和包含氨基酸序列SEQ ID NO:74的轻链;
(xix)包含氨基酸序列SEQ ID NO:91的重链和包含氨基酸序列SEQ ID NO:74的轻链;
(xx)包含氨基酸序列SEQ ID NO:84的重链和包含氨基酸序列SEQ ID NO:74的轻链;
(xxi)包含氨基酸序列SEQ ID NO:92的重链和包含氨基酸序列SEQ ID NO:71的轻链;
(xxii)包含氨基酸序列SEQ ID NO:89的重链和包含氨基酸序列SEQ ID NO:71的轻链;
(xxiii)包含氨基酸序列SEQ ID NO:90的重链和包含氨基酸序列SEQ ID NO:31的轻链;
(xxiv)包含氨基酸序列SEQ ID NO:91的重链和包含氨基酸序列SEQ ID NO:71的轻链;
(xxv)包含氨基酸序列SEQ ID NO:85的重链和包含氨基酸序列SEQ ID NO:68的轻链;
(xxvi)包含氨基酸序列SEQ ID NO:86的重链和包含氨基酸序列SEQ ID NO:68的轻链;
(xxvii)包含氨基酸序列SEQ ID NO:93的重链和包含氨基酸序列SEQ ID NO:100的轻链;
(xxviii)包含氨基酸序列SEQ ID NO:94的重链和包含氨基酸序列SEQ ID NO:75的轻链;
(xxix)包含氨基酸序列SEQ ID NO:95的重链和包含氨基酸序列SEQ ID NO:71的轻链;
(xxx)包含氨基酸序列SEQ ID NO:96的重链和包含氨基酸序列SEQ ID NO:71的轻链;
(xxxi)包含氨基酸序列SEQ ID NO:97的重链和包含氨基酸序列SEQ ID NO:71的轻链;
(xxxii)包含氨基酸序列SEQ ID NO:98的重链和包含氨基酸序列SEQ ID NO:71的轻链;
(xxxiii)包含氨基酸序列SEQ ID NO:83的重链和包含氨基酸序列SEQ ID NO:73的轻链;
(xxxiv)包含氨基酸序列SEQ ID NO:87的重链和包含氨基酸序列SEQ ID NO:73的轻链;
(xxxv)包含氨基酸序列SEQ ID NO:102的重链和包含氨基酸序列SEQ ID NO:101的轻链;
(xxxvi)包含氨基酸序列SEQ ID NO:104的重链和包含氨基酸序列SEQ ID NO:103的轻链;
其中该VH氨基酸序列与其具有至少90%、95%、97%、98%或99%一致性并且该VL氨基酸序列与其具有至少90%、95%、97%、98%或99%一致性。
本文所述的抗-CD47抗体的优选实施例的特征也在于建议用于人类治疗性用途的现有技术抗-CD47抗体未表现出的特性的组合。因此,本文所述的优选抗-CD47抗体的特征在于:
a.结合人类CD47,
b.阻断SIRPα与人类CD47的结合,
c.增加对人类肿瘤细胞的吞噬作用;并且
d.诱导易感性人类肿瘤细胞的死亡。
在本文所述的另一个优选实施例中,抗-CD47抗体的特征在于:
a.结合人类CD47,
b.阻断SIRPα与人类CD47的结合,
c.增加对人类肿瘤细胞的吞噬作用,
d.诱导易感性人类肿瘤细胞的死亡;并且
e.引起人类血红细胞(hRBC)不凝集。
在本文所述的另一个优选实施例中,抗-CD47抗体的特征在于:
a.结合人类CD47,
b.阻断SIRPα与人类CD47的结合,
c.增加对人类肿瘤细胞的吞噬作用,
d.诱导易感性人类肿瘤细胞的死亡;并且
e.引起人类血红细胞(hRBC)凝集减少。
在本文所述的另一个优选实施例中,抗-CD47抗体的特征在于:
a.特异性结合人类CD47,
b.阻断SIRPα与人类CD47的结合,
c.增加对人类肿瘤细胞的吞噬作用
d.诱导易感性人类肿瘤细胞的死亡;并且
e.减少了hRBC结合。
在本文所述的另一个优选实施例中,抗-CD47抗体的特征在于:
a.结合人类CD47,
b.阻断SIRPα与人类CD47的结合,
c.增加对人类肿瘤细胞的吞噬作用,
d.引起人类血红细胞(hRBC)不凝集;并且
e.不结合hRBC。
在本文所述的另一个优选实施例中,抗-CD47抗体的特征在于:
a.特异性结合人类CD47,
b.阻断SIRPα与人类CD47的结合,
c.增加对人类肿瘤细胞的吞噬作用,
d.引起人类血红细胞(hRBC)不凝集;并且
e.减少了hRBC结合。
在本文所述的另一个优选实施例中,单克隆抗体或其抗原结合片段也特异性结合非人灵长类CD47,其中非人灵长类可包括但不限于食蟹猴、绿猴、猕猴以及松鼠猴。
在本文所述的另一个实施例中,单克隆抗体或其抗原结合片段结合人类、非人灵长类、小鼠、兔、以及大鼠CD47。
本文考虑不同形式的所披露的抗-CD47 mAb。例如,抗-CD47 mAb可以是具有同种型IgA、IgD、IgE、IgG、以及IgM,更具体地是IgG1、IgG2、IgG3、IgG4的人类框架和恒定区并且在一些情况下具有改变Fc受体功能或防止Fab臂交换的不同突变的全长人源化抗体,或者如本文所披露的抗体片段,例如F(ab')2片段、F(ab)片段、单链Fv片段(scFv)等。
本披露的优选实施例提供药物组合物或兽医用组合物,这些组合物包含抗-CD47mAb或本文披露的片段(任选地是嵌合或人源化形式)中的一种或多种以及药学上可接受的载体、稀释剂、或赋形剂。
在本披露之前,需要鉴别具有如本文所述的功能分布的抗-CD47 mAb。本披露的抗-CD47 mAb表现出不同的特性组合,特别是使得mAb特别有利于或适用于在人类治疗中使用,特别是在预防和/或治疗实体癌和血液癌、缺血再灌注损伤、自身免疫和/或炎性疾病中使用的特性组合。
根据下文提供的详细说明,本披露可应用性的另外范围将变得明显。然而,应当理解,详细说明和具体实例,在指示本披露的优选实施例的同时,仅以说明的方式给出,因为根据本详细说明,在本披露的精神和范围内的各种变化和修改对于本领域技术人员而言将变得明显。
附图说明
根据以下结合附图的详细说明,将更好地理解本披露的以上和其他方面、特征、以及优点,所有这些附图都仅以说明的方式给出,而不限制本披露。
图1A.VLX4人源化mAb与表达人类CD47的人类OV10细胞的结合。使用表达人类CD47(OV10 hCD47)的OV10细胞系的基于细胞的ELISA测定VLX4人源化mAb(VLX4hum_01 IgG1、VLX4hum_02 IgG1、VLX4hum_01 IgG4 PE、以及VLX4hum_02 IgG4 PE)与人类CD47的结合。将OV10 hCD47细胞接种到96孔板中并且在测定时汇合。将不同浓度的mAb添加至细胞中,持续1小时。将细胞洗涤并且然后用HRP标记的第二抗体孵育1小时,随后添加过氧化物酶底物。
图1B.VLX4人源化mAb与表达人类CD47的人类OV10细胞的结合。使用基于OV10CD47细胞的ELISA测定VLX4人源化mAb(VLX4hum_06 IgG4 PE、VLX4hum_07 IgG4 PE、VLX4hum_12 IgG4 PE、以及VLX4hum_13 IgG4 PE)与人类CD47的结合。将OV10 hCD47细胞接种到96孔板中并且在测定时汇合。将不同浓度的VLX4代表性mAb添加至细胞中,持续1小时。将细胞洗涤并且然后用HRP标记的第二抗体孵育1小时,随后添加过氧化物酶底物。
图2A.VLX4人源化mAb与人类RBC(hRBC)的结合。使用新鲜分离的hRBC测定VLX4人源化mAb(VLX4hum_01 IgG1、VLX4hum_02 IgG1、VLX4hum_01 IgG4 PE、以及VLX4hum_02IgG4PE)与人类CD47的结合。将hRBC在37℃下使用不同浓度的VLX4 mAb孵育60分钟,将其洗涤并使用FITC标记的驴抗人类抗体孵育1小时。将细胞洗涤并使用流式细胞术测量抗体结合。
图2B.VLX4人源化mAb与人类RBC的结合。使用新鲜分离的hRBC测定VLX4人源化mAb(VLX4hum_07 IgG4 PE、VLX4hum_12 IgG4 PE、以及VLX4hum_13 IgG4 PE)与人类CD47的结合。将hRBC在37℃下使用不同浓度的VLX4 mAb孵育60分钟,将其洗涤并使用FITC标记的驴抗人类抗体孵育1小时。将细胞洗涤并使用流式细胞术测量抗体结合。
图3A.VLX8人源化mAb与人类OV10 hCD47细胞的结合。使用基于OV10 hCD47细胞的ELISA测定VLX8 IgG4PE嵌合(xi)或人源化mAb(VLX8hum_01 IgG4PE、VLX8hum_04 IgG4 PE、VLX8hum_07 IgG4 PE、以及VLX8hum_09 IgG4 PE)与人类CD47的结合。将OV10 hCD47细胞接种到96孔板中并且在测定时汇合。将不同浓度的VLX8代表性mAb添加至细胞中,持续1小时。将细胞洗涤并且然后用HRP标记的第二抗体孵育1小时,随后添加过氧化物酶底物。
图3B.VLX8人源化mAb与人类OV10 hCD47细胞的结合。使用基于OV10 hCD47细胞的ELISA测定VLX8嵌合或人源化mAb(VLX8hum_06 IgG2、VLX8hum_07 IgG2、VLX8hum_08 IgG2、以及VLX8hum_09 IgG2)与人类CD47的结合。将OV10 hCD47细胞接种到96孔板中并且在测定时汇合。将不同浓度的VLX8代表性mAb添加至细胞中,持续1小时。将细胞洗涤并且然后用HRP标记的第二抗体孵育1小时,随后添加过氧化物酶底物。
图4A.VLX8人源化mAb与人类RBC的结合。使用新鲜分离的人类RBC测定VLX8IgG4PE xi或人源化mAb(VLX8hum_01 IgG4PE、VLX8hum_03 IgG4PE、VLX8hum_07 IgG4PE、以及VLX8hum_10 IgG4PE)与人类CD47的结合。将RBC在37℃下使用不同浓度的VLX8 mAb孵育1小时,将其洗涤并使用FITC标记的驴抗人类抗体孵育1小时。将细胞洗涤并使用流式细胞术测量抗体结合。
图4B.VLX8人源化mAb与人类RBC的结合。使用新鲜分离的人类RBC测定VLX8IgG4PE xi或人源化mAb(VLX8hum_06 IgG2、VLX8hum_07 IgG2、VLX8hum_08 IgG2、以及VLX8hum_09 IgG2)与人类CD47的结合。将RBC在37℃下使用不同浓度的VLX8 mAb孵育1小时,将其洗涤并使用FITC标记的驴抗人类抗体孵育1小时。将细胞洗涤并使用流式细胞术测量抗体结合。
图5A.VLX9人源化mAb与人类OV10 hCD47细胞的结合。使用基于OV10人类CD47细胞的ELISA测定VLX9 IgG2 xi或人源化mAb(VLX9hum_01 IgG2、VLX9hum_02 IgG2、VLX9hum_03IgG2、VLX9hum_04 IgG2、以及VLX9hum_05 IgG2)与人类CD47的结合。将OV10 hCD47细胞接种到96孔板中并且在测定时汇合。将不同浓度的mAb添加至细胞中,持续1小时。将细胞洗涤并且然后用HRP标记的第二抗体孵育1小时,随后添加过氧化物酶底物。
图5B.VLX9人源化mAb与人类OV10 hCD47细胞的结合。使用基于OV10 hCD47细胞的ELISA测定VLX9 IgG2 xi或人源化mAb(VLX9hum_06 IgG2、VLX9hum_07 IgG2、VLX9hum_08IgG2、VLX9hum_09 IgG2、以及VLX9hum_10 IgG2)与人类CD47的结合。将OV10 hCD47细胞接种到96孔板中并且在测定时汇合。将不同浓度的mAb添加至细胞中,持续1小时。将细胞洗涤并且然后用HRP标记的第二抗体孵育1小时,随后添加过氧化物酶底物。
图6.VLX9人源化mAb与人类RBC的结合。使用新鲜分离的人类hRBC测定VLX9 IgG2xi或人源化mAb与人类CD47的结合。将RBC在37℃下使用不同浓度的VLX9 mAb孵育60分钟,将其洗涤并使用FITC标记的驴抗人类抗体孵育1小时。将细胞洗涤并使用流式细胞术测量抗体结合。
图7.VLX4、VLX8和VLX9人源化mAb阻断SIRPα与Jurkat细胞上的CD47的结合。将1.5×106个Jurkat细胞在37℃下使用含有10%培养基的RPMI中的5μg/ml VLX4、VLX8和VLX9CD47人源化mAb(VLX4hum_01 IgG4 PE、VLX4hum_07 IgG4 PE、VLX8hum_10 IgG4 PE、VLX4hum_11 IgG4 PE、VLX9hum_03 IgG2、VLX9hum_06 IgG2、以及VLX9hum_08 IgG2)或对照抗体孵育30分钟。添加等体积的荧光标记的SIRPα-Fc融合蛋白并且在37℃下将其再孵育30分钟。将细胞洗涤并使用流式细胞术评估结合。
图8.VLX4 CD47嵌合mAb增加人类巨噬细胞对Jurkat T细胞的吞噬作用。将人类巨噬细胞以1×104个细胞/孔的浓度接种在96孔板中并且使其附着24小时。将5×104个CFSE(1μM)标记的人类Jurkat T细胞和1μg/ml VLX4嵌合mAb添加到巨噬细胞培养物中并在37℃下孵育2小时。去除非吞噬性Jurkat细胞并且充分洗涤巨噬细胞培养物。将巨噬细胞胰酶消化并且针对CD14进行染色。使用流式细胞术测定总CD14+群体中的CD14+/CFSE+细胞的百分比。
图9A.VLX4人源化mAb增加人类巨噬细胞对Jurkat T细胞的吞噬作用。将人类巨噬细胞以1×104个细胞/孔的浓度接种在96孔板中并且使其附着24小时。将5×104个CFSE(1μM)标记的人类Jurkat T细胞和1μg/ml抗体添加到巨噬细胞培养物中并在37℃下孵育2小时。去除非吞噬性Jurkat T细胞并且充分洗涤巨噬细胞培养物。将巨噬细胞胰酶消化并且针对CD14进行染色。使用流式细胞术测定总CD14+群体中的CD14+/CFSE+细胞的百分比。
图9B.VLX4人源化mAb增加人类巨噬细胞对Jurkat T细胞的吞噬作用。将人类巨噬细胞以1×104个细胞/孔的浓度接种在96孔板中并且使其附着24小时。将5×104个CFSE(1μM)标记的人类Jurkat T细胞和1μg/ml抗体添加到巨噬细胞培养物中并在37℃下孵育2小时。去除非吞噬性Jurkat T细胞并且充分洗涤巨噬细胞培养物。将巨噬细胞胰酶消化并且针对CD14进行染色。使用流式细胞术测定总CD14+群体中的CD14+/CFSE+细胞的百分比。
图10A.VLX8 CD47嵌合mAb增加人类巨噬细胞对Jurkat T细胞的吞噬作用。将人类巨噬细胞以1×104个细胞/孔的浓度接种在96孔板中并且使其附着24小时。将5×104个CFSE(1μM)标记的人类Jurkat T细胞和1μg/ml VLX8嵌合mAb添加到巨噬细胞培养物中并在37℃下孵育2小时。去除非吞噬性Jurkat细胞并且充分洗涤巨噬细胞培养物。将巨噬细胞胰酶消化并且针对CD14进行染色。使用流式细胞术测定总CD14+群体中的CD14+/CFSE+细胞的百分比。
图10B.VLX8人源化mAb增加人类巨噬细胞对Jurkat细胞的吞噬作用。将人类巨噬细胞以1×104个细胞/孔的浓度接种在96孔板中并且使其附着24小时。将5×104个CFSE(1μM)标记的人类Jurkat T细胞和1μg/ml抗体添加到巨噬细胞培养物中并在37℃下孵育2小时。去除非吞噬性Jurkat T细胞并且充分洗涤巨噬细胞培养物。将巨噬细胞胰酶消化并且针对CD14进行染色。使用流式细胞术测定总CD14+群体中的CD14+/CFSE+细胞的百分比。
图11A VLX9 CD47嵌合mAb增加人类巨噬细胞对Jurkat T细胞的吞噬作用。将人类巨噬细胞以1×104个细胞/孔的浓度接种在96孔板中并且使其附着24小时。将5×104个CFSE(1μM)标记的人类Jurkat T细胞和1μg/ml VLX9嵌合mAb添加到巨噬细胞培养物中并在37℃下孵育两小时。去除非吞噬性Jurkat细胞并且充分洗涤巨噬细胞培养物。将巨噬细胞胰酶消化并且针对CD14进行染色。使用流式细胞术测定总CD14+群体中的CD14+/CFSE+细胞的百分比。
图11B.VLX9人源化mAb增加人类巨噬细胞对Jurkat T细胞的吞噬作用。将人类巨噬细胞以1×104个细胞/孔的浓度接种在96孔板中并且使其附着24小时。将5×104个CFSE(1μM)标记的人类Jurkat T细胞和1μg/ml抗体添加到巨噬细胞培养物中并在37℃下孵育两小时。去除非吞噬性Jurkat细胞并且充分洗涤巨噬细胞培养物。将巨噬细胞胰酶消化并且针对CD14进行染色。使用流式细胞术测定总CD14+群体中的CD14+/CFSE+细胞的百分比。
图12A.通过可溶性VLX4人源化mAb诱导人类Jurkat T细胞的细胞死亡。将JurkatT细胞(1×104)在37℃下使用1ml RPMI培养基中的1μg/ml VLX4人源化mAb孵育24小时。然后针对细胞的膜联蛋白V进行染色并通过流式细胞术检测信号。
图12B.通过可溶性VLX4人源化mAb诱导人类Jurkat T细胞的细胞死亡。将JurkatT细胞(1×104)在37℃下使用1ml RPMI培养基中的1μg/ml VLX4人源化mAb孵育24小时。然后针对细胞的膜联蛋白V进行染色并通过流式细胞术检测信号。
图13A.通过可溶性VLX8 CD47嵌合mAb诱导人类Jurkat细胞的细胞死亡。将JurkatT ALL细胞(1×104)在37℃下使用1ml RPMI培养基中的1μg/ml VLX8人源化mAb孵育24小时。然后针对细胞的膜联蛋白V进行染色并通过流式细胞术检测信号。
图13B.通过可溶性VLX8人源化mAb诱导人类Jurkat细胞的细胞死亡。将Jurkat TALL细胞(1×104)在37℃下使用1ml RPMI培养基中的1μg/ml VLX8人源化mAb孵育24小时。然后针对细胞的膜联蛋白V进行染色并通过流式细胞术检测信号。
图14A.通过可溶性VLX9鼠类/人类嵌合mAb诱导人类Jurkat细胞的细胞死亡。将1×104Jurkat细胞在37℃下使用0.1ml RPMI培养基中的1μg/ml VLX9 CD47嵌合mAb孵育24小时。然后使用膜联蛋白V对细胞进行染色并通过流式细胞术分析信号。
图14B.通过可溶性VLX9人源化mAb诱导人类Jurkat细胞的细胞死亡。将Jurkat TALL细胞(1×104)在37℃下使用1ml RPMI培养基中的1μg/ml VLX9人源化mAb孵育24小时。然后针对细胞的膜联蛋白V进行染色并通过流式细胞术检测信号。VLX9 IgG2(xi)是鼠类/人类嵌合体。
图15A.通过VLX4人源化mAb使hRBC凝集。在用不同浓度的人源化VLX4 mAb(25μg/mL-0.4ng/mL)孵育hRBC之后评估血凝集。将血液稀释(1:50)并使用PBS/EDTA/BSA洗涤3次。将hRBC添加到具有等体积抗体(75μl)的U形底部的96孔板中并且在37℃下孵育3小时并在4℃下孵育过夜。
图15B.通过VLX8嵌合和人源化mAb使hRBC凝集。在用不同浓度的人源化VLX4 mAb(25μg/mL-0.4ng/mL)孵育hRBC之后评估血凝集。将血液稀释(1:50)并使用PBS/EDTA/BSA洗涤3次。将hRBC添加到具有等体积抗体(75μl)的U形底部的96孔板中并且在37℃下孵育3小时并在4℃下孵育过夜。
图16.通过VLX9人源化mAb使人类RBC凝集。在用不同浓度的VLX9 IgG2嵌合(xi)和人源化VLX9 mAb孵育人类RBC之后评估血凝集。将血液稀释(1:50)并使用PBS/EDTA/BSA洗涤3次。将RBC添加到具有等体积抗体(75μl)的U形底部的96孔板中并且在37℃下孵育3小时并在4℃下孵育过夜。
图17.VLX4人源化mAb减少拉吉(Raji)异种移植模型中的肿瘤生长。使用含有5×106个拉吉肿瘤细胞悬浮液的0.1mL 30%RPMI/70%MatrigelTM(BD生物科学公司(BDBiosciences);马萨诸塞州贝德福德(Bedford,MA))皮下接种雌性NSG小鼠的侧翼。在接种之后五天,测量肿瘤体积并且将具有31-74mm3可触及肿瘤体积的小鼠随机分成8-10只/组。在此时开始VLX4hum_07或PBS(对照)给予。使用5mg/kg抗体5X/周通过腹膜内注射处理小鼠,持续4周。每周两次记录肿瘤体积和体重。
图18.VLX8人源化mAb减少拉吉异种移植模型中的肿瘤生长。使用含有5×106个拉吉肿瘤细胞悬浮液的0.1mL 30%RPMI/70%MatrigelTM(BD生物科学公司(BDBiosciences);马萨诸塞州贝德福德(Bedford,MA))皮下接种雌性NSG小鼠的侧翼。在接种之后五天,测量肿瘤体积并且将具有31-74mm3可触及肿瘤体积的小鼠随机分成8-10只/组。在此时开始VLX8hum_10或PBS(对照)给予。使用5mg/kg抗体5X/周通过腹膜内注射处理小鼠,持续4周。每周两次记录肿瘤体积和体重。
图19.VLX9人源化mAb减少拉吉异种移植模型中的肿瘤生长。使用含有5×106个拉吉肿瘤细胞悬浮液的0.1mL 30%RPMI/70%MatrigelTM(BD生物科学公司(BDBiosciences);马萨诸塞州贝德福德(Bedford,MA))皮下接种雌性NSG小鼠的侧翼。在接种之后五天,测量肿瘤体积并且将具有31-74mm3可触及肿瘤体积的小鼠随机分成8-10只/组。在此时开始VLX9hum_08 IgG2或PBS(对照)给予。使用5mg/kg抗体5X/周通过腹膜内注射处理小鼠,持续4周。每周两次记录肿瘤体积和体重。
图20A.在通过静脉输注向食蟹猴给予人源化VLX9 mAb之后血液中的血红蛋白水平。以一小时静脉输注形式以第1天5mg/kg的剂量和第18天15mg/kg的剂量给予VLX9hum_08IgG2或媒介物。在整个研究中监测血红蛋白水平并且将其归一化至对照值。
图20B.在通过静脉输注向食蟹猴给予人源化VLX9 mAb之后血液中的RBC水平。以一小时静脉输注形式以第1天5mg/kg的剂量和第18天15mg/kg的剂量给予VLX9hum_08 IgG2或媒介物。在整个研究中监测RBC水平并且将其归一化至对照值。
图21.使用抗鼠类/兔嵌合mAb对人类肿瘤组织中的CD47进行免疫组织化学染色。使用小鼠/兔嵌合mAb定位人类乳腺癌组织中的CD47。将石蜡包埋组织切片,使用4ug/ml纯化的抗体染色并且使用抗-兔HRP第二抗体定位。箭头指示CD47染色的阳性区域。
图22.抗-CD47抗体特性的汇总。
具体实施方式
定义
除非另外定义,否则结合本披露使用的科技术语应当具有本领域的普通技术人员通常所了解的意义。此外,除非上下文另外要求,单数术语应该包括复数含义并且复数术语应该包括单数含义。总体而言,与本文所述的细胞和组织培养、分子生物学、以及蛋白质和寡核苷酸和多核苷酸化学及杂交学结合使用的命名法是本领域中众所周知并且常用的那些。
如本文所用,术语“CD47”、“整合蛋白相关蛋白(IAP)”、“卵巢癌抗原OA3”、“Rh相关抗原”以及“MERG”是同义词并且可以互换使用。
术语“抗-CD47抗体”是指本披露的一种抗体,该抗体旨在用作治疗剂或诊断剂,并且因此典型地将具有适用作治疗剂和/或诊断剂所需要的结合亲和力。
如本文所用,术语“抗体”是指免疫球蛋白分子和免疫球蛋白(Ig)分子的免疫活性蛋白质,即含有特异性结合抗原(与抗原免疫反应)的抗原结合位点的分子。与...或针对...“特异性结合”或“免疫反应”意指抗体与所需抗原的一个或多个抗原决定簇反应并且不与其他多肽反应或以低得多的亲和力结合(Kd>10-6)。抗体包括但不限于多克隆抗体、单克隆抗体、嵌合抗体、Fab片段、Fab'片段、F(ab')2片段、单链Fv片段、以及单臂抗体。
如本文使用的,如应用于本发明抗体化合物的术语“单克隆抗体”是指抗体,该抗体来源于单个拷贝或克隆,包括例如任何真核、原核、或噬菌体克隆,而不是产生它的方法。本披露的mAb优选地以同质的或基本上同质的群体而存在。完全mAb含有2条重链和2条轻链。
“抗体片段”是指非完整抗体的分子,其包含完整抗体的一部分并结合完整抗体所结合的抗原。抗体片段的实例包括但不限于Fv、Fab、Fab'、Fab'-SH、F(ab')2;双抗体;线性抗体;单链抗体分子(例如scFv);以及由抗体片段形成的多特异性抗体。
如本文所披露,“抗体化合物”是指mAb及其抗原结合片段。根据本披露展现出类似功能特性的额外抗体化合物可通过常规方法生成。例如,可以用人类CD47或其片段免疫小鼠,可回收并纯化得到的抗体,并且可以通过在以下实例3-11中披露的方法评估确定它们是否具有与本文披露的这些抗体化合物相似或相同的结合与功能特性。也可以通过常规方法制备抗原结合片段。用于产生和纯化抗体和抗原结合片段的方法是本领域众所周知的并可以例如发现于Harlow和Lane(1988)Antibodies,A Laboratory Manual[抗体:实验室手册],Cold Spring Harbor Laboratory Press,Cold Spring Harbor,New York,chapters5-8and 15[冷泉港实验室出版社,冷泉港,纽约,第5-8章和第15章]。
单克隆抗体涵盖其中重链和/或轻链的一部分与鼠类抗体(具体地是鼠类CDR)中的相应序列相同或同源,同时该链或这些链的其余部分与人类抗体中的相应序列相同或同源的抗体。本披露的其他实施例包括这些单克隆抗体的表现出与单克隆抗体类似或相同的结合和生物特性的抗原结合片段。本披露的抗体可以包含κ或λ轻链恒定区和重链IgA、IgD、IgE、IgG、或IgM恒定区,包括IgG子类IgG1、IgG2、IgG3、以及IgG4和在一些情况下具有改变Fc受体功能的不同突变的那些。
含有目前披露的鼠类CDR的单克隆抗体可通过本领域技术人员已知的不同方法中的任一种来制备,这些方法包括重组DNA方法。
用于抗体工程化和改进的当前方法的综述可见于例如P.Chames编辑,(2012)Antibody Engineering:Methods and Protocols,Second Edition(Methods inMolecular Biology,Book 907),Humana Press[抗体工程化:方法和方案,第二版(分子生物学方法,第907册),胡马纳出版社],ISBN-10:1617799734;C.R.Wood编辑,(2011)Antibody Drug Discovery(Molecular Medicine and Medicinal Chemistry,Book 4),Imperial College Press[抗体药物发现(分子药物和药物化学,第4册),帝国学院出版社];R.Kontermann和S.Dubel编辑,(2010)Antibody Engineering Volumes 1and 2(Springer Protocols),Second Edition[抗体工程化第1卷和第2卷(施普林格协议),第二版];以及W.Strohl和L.Strohl(2012)Therapeutic antibody engineering:Current andfuture advances driving the strongest growth area in the pharmaceuticalindustry,Woodhead Publishing[治疗抗体工程化:驱动药物工业中的最强生长领域的当前和未来发展,伍德海德出版社]。
用于产生和纯化抗体和抗原结合片段的方法是本领域众所周知的并可以例如发现于Harlow和Lane(1988)Antibodies,A Laboratory Manual[抗体:实验室手册],ColdSpring Harbor Laboratory Press,Cold Spring Harbor,New York,chapters 5-8and 15[冷泉港实验室出版社,冷泉港,纽约,第5-8章和第15章]。
全长抗体当它以天然方式存在时是包含由二硫键互相连接的以下四条多肽链的“Y”形免疫球蛋白(Ig)分子:两条相同重(H)链和两条相同轻(L)链。每条链的氨基末端部分(称为片段抗原结合区(FAB))包括具有大约100-110个或更多个氨基酸的可变区,其经由包含在其中的互补决定区(CDR)主要负责抗原识别。每条链的羧基末端部分限定恒定区(“Fc”区),主要负责效应子功能。
这些CDR散布有更为保守的区域,称为框架(“FR”)。许多FR的氨基酸序列是本领域众所周知的。每个轻链可变区(LCVR)和重链可变区(HCVR)由3个CDR和4个FR构成,按以下顺序从氨基端到羧基端排列:FRl、CDRl、FR2、CDR2、FR3、CDR3、FR4。轻链的3个CDR被称为“LCDR1、LCDR2、和LCDR3”并且重链的3个CDR被称为“HCDR1、HCDR2、和HCDR3”。这些CDR含有形成与抗原的特异性相互作用的大多数残基。在LCVR和HCVR区域内的CDR氨基酸残基的编号和定位遵循众所周知的Kabat编号规则,Kabat等人,(1991)Sequences of Proteins ofImmunological Interest,Fifth Edition[具有免疫意义的蛋白质序列,第15版]。NIH公开号91-3242。
如本文所用,“抗原结合位点”也可以被定义为“高变区”、“HVR”或“HV”,并且是指抗体可变结构域的结构高变区,如Chothia和Lesk所定义的(Chothia和Lesk,Mol.Biol.[分子生物学]196:901-917,1987)。存在六个HVR,三个在VH中(H1、H2、H3)并且三个在VL中(L1、L2、L3)。本文使用除H-CDR1之外的CDR,如Kabat所定义的,其扩展到包括H1。
存在五种类型的哺乳动物免疫球蛋白(Ig)重链,其由希腊字母α(阿尔法)、δ(德尔塔)、ε(埃普西隆)、γ(伽马)、以及μ(谬)表示,这些重链将抗体的类别或同种型分别限定为IgA、IgD、IgE、IgG、或IgM。IgG抗体可进一步分为亚类,例如IgG1、IgG2、IgG3、以及IgG4。
每个重链类型由具有本领域熟知的序列的特定恒定区来表征。恒定区在相同同种型的所有抗体中均是相同的,但是在不同同种型的抗体中是不同的。重链γ、α和δ具有由三个串联免疫球蛋白(Ig)结构域组成的恒定区和用于增加柔性的铰链区。重链μ和ε具有由四个Ig结构域组成的恒定区。
铰链区是连接抗体的Fc部分和Fab部分的柔性氨基酸片段。此区域含有可形成二硫键从而将两条重链连接在一起的半胱氨酸残基。
重链的可变区在由不同B细胞产生的抗体中是不同的,但对于由单个B细胞或单独的B细胞产生的所有抗体而言是相同的。每条重链的可变区是大约110个氨基酸长度并且由单个Ig结构域组成。
在哺乳动物中,轻链分为卡帕(κ)或兰布达(λ),并且其由本领域已知的特定恒定区表征。轻链具有两个连续结构域:一个可变结构域在氨基末端处,并且一个结构域在羧基末端处。每种多肽含有一直相同的两条轻链;哺乳动物中的每种抗体仅存在一种类型的轻链κ或λ。
由根据抗体类别构成三个或四个恒定结构域的两条重链组成的Fc区在调节免疫细胞活性方面起作用。通过结合特异性蛋白,Fc区确保每种抗体都对给定抗原生成适当免疫应答。Fc区还结合不同细胞受体诸如Fc受体和其他免疫分子诸如补体蛋白。通过这样做,它介导了不同的生理效应,包括调理作用、细胞裂解、以及肥大细胞、嗜碱性粒细胞和嗜酸性粒细胞的去颗粒化作用。
如本文所用,术语“表位”是指抗体或抗体片段结合到其上的、位于肽或蛋白质上的氨基酸的特异性排列。表位通常由分子如氨基酸或糖侧链的化学活性表面基团组成,并且通常具有特异性三维结构特征,以及特异性电荷特性。表位可以是线性的,即涉及与氨基酸的单个序列结合,或者可以是构象性的,即涉及与抗原的不同区域中的在线性序列可能不一定相邻的氨基酸的两个或更多个序列结合。
如本文所用,如应用于本发明抗体化合物的术语“特异性地结合”、“特异地结合”、“特异结合”等,是指特异性结合剂(如抗体)相比于结合到其他分子种类上而优先结合到靶分子种类上的能力,藉此使该特异性结合剂与靶分子种类混合。当特异性结合剂能特异性结合到靶分子种类上时,它被看作特异性识别该靶标。
如本文所用,术语“结合亲和力“是指一个分子在该分子上的一个位点处结合到另一个分子上的强度。如果特定的分子将结合到另一个特定的分子上或者与之特异性地缔合,则这两个分子被看作展现出对于彼此而言的结合亲和力。结合亲和力与一对分子的缔合常数和离解常数有关,但这对于本文的这些方法不是关键的,因为这些常数可以测量或测定。相反,用来描述在这些所述方法的分子之间的相互作用的如本文使用的亲和力通常是在经验研究中观察到的表观亲和力(除非另有说明),其可以用来比较一个分子(例如,抗体或其他特异性结合配偶体)将藉此结合两个其他分子(例如,肽的两种形式或变体)的相对强度。结合亲和力、缔合常数、和离解常数的概念是众所周知的。
如本文所用,术语“序列一致性”表示当将序列进行比对使得序列匹配最大化时(即,考虑空位和插入),在两个或更多个序列中的相应位置处的相同核苷酸或氨基酸残基的百分比。一致性可容易通过已知方法来计算,这些方法包括但不限于在以下文献中描述的那些:Computational Molecular Biology,Lesk,A.M.,ed.,Oxford University Press,New York,1988[计算分子生物学,Lesk,A.M.编辑,牛津大学出版社,纽约,1988];Biocomputing:Informatics and Genome Projects,Smith,D.W.,ed.,Academic Press,New York,1993[生物计算:信息学和基因组项目,Smith,D.W.编辑,学术出版社,纽约,1993];Computer Analysis of Sequence Data,Part I,Griffin,A.M.,and Griffin,H.G.,eds.,Humana Press,New Jersey,1994[序列数据的计算机分析,第1部分,Griffin,A.M.和Griffin,H.G.编辑,胡玛纳出版社,新泽西州,1994];Sequence Analysis inMolecular Biology,von Heinje,G.,Academic Press,1987[分子生物学的序列分析,vonHeinje,G.,学术出版社,1987];以及Sequence Analysis Primer,Gribskov,M.andDevereux,J.,eds.,MStockton Press,New York,1991[序列分析引物,Gribskov,M.和Devereux,J.编辑,斯托克顿出版社,纽约,1991];以及Carillo,H.,and Lipman,D.,SIAMJ.Applied Math.,48:1073(1988)[Carillo,H.和Lipman,D.,工业和应用数学学会应用数学杂志,48:1073(1988)]。用于确定一致性的方法被设计为在测试的序列之间给出最大的匹配。而且,确定同一性的方法被编篡在可公开获得的计算机程序中。
例如,通过史密斯(Smith)和沃特曼(Waterman)的局部同源性算法,通过同源性比对算法,通过相似性捜索方法,或者通过这些算法的计算机化执行(在GCG威斯康星软件包(Wisconsin Package)中的GAP、BESTFIT、PASTA、和TFASTA,可获自阿森尼克斯公司(Accelrys,Inc.),圣地亚哥(San Diego),加利福尼亚州,美国),或者通过目测检查,可以进行用于比较的最佳序列比对。通常参见Altschul,S.F.et al.,J.Mol.Biol.215:403-410(1990)[Altschul,S.F.等人,分子生物学杂志215:403-410(1990)]和Altschul etal.Nucl.Acids Res.25:3389-3402(1997)[Altschul等人,核酸研究25:3389-3402(1997)]。
适合于确定序列一致性百分比和序列相似性的算法的一个实例是BLAST算法,其描述于(Altschul,S.,et al.,NCBI NLM NIH Bethesda,Md.20894[Altschul,S.等人,NCBINLM NIH,马里兰州贝塞斯达20894];以及Altschul,S.,et al.,J.Mol.Biol.215:403-410(1990)[Altschul,S.等人分子生物学杂志215:403-410(1990)]。用于执行BLAST分析的软件可通过美国国家生物技术信息中心(National Center for BiotechnologyInformation)公开地获得。这种算法涉及首先通过鉴定查询序列中具有长度W的短词而识别高得分序列对(HSP),这些短词当与数据库序列中具有相同长度的字比对时匹配或满足某个正值阈值得分T。T被称为相邻词得分阈。
这些初始相邻词命中用作开始检索以找到含有它们的更长HSP的种子。然后,沿着每个序列的两个方向对词命中进行延伸,直到累积比对得分可以增加。对于核苷酸序列,使用参数M(一对匹配残基的奖励分;总是;0)和N(错配残基的罚分;总是;0)计算累积评分。对于氨基酸序列,使用得分矩阵来计算累计得分。字命中在每个方向上的延伸在下列情况时停止:累积比对评分由其达到的最大值降低数量X、由于一个或者多个负评分残基比对的积累而使累积评分降至0或者以下、或者达到任一序列的末端。BLAST算法的参数W、T、以及X决定了该比对的灵敏度与速度。BLASTN程序(对核苷酸序列来说)使用字长(W)为11、期望值(E)为10、截止值(cutoff)为100、M=5、N=-4、以及两条链的比较作为默认值。对于氨基酸序列,BLASTP程序使用字长(W)为3、期望值(E)为10、以及BLOSUM62得分矩阵作为默认值。
除计算序列一致性百分比之外,BLAST算法还进行两个序列之间相似性的统计分析。由BLAST算法提供的相似性的一个量度是最小总和概率(P(N)),它提供了由此将偶然发生在两个核苷酸序列或氨基酸序列之间的匹配的概率的一个指示。例如,如果在测试核酸序列与参考核酸序列的比较中的最小总和概率在一个实施例中小于约0.1、在另一个实施例中小于约0.01、并且在又另一个实施例中小于约0.001,则认为测试核酸与参考序列相似。
如本文所用,术语“人源化的”、“人源化”等是指将本文所披露的鼠类单克隆抗体CDR移植到人类FR和恒定区。这些术语还涵盖通过例如以下分别披露的方法对鼠类CDR和人类FR进行的可能的进一步修饰:Kashmiri et al.(2005)Methods 36(1):25-34[Kashmiri等人,(2005)方法36(1):25-34]和Hou et al.(2008)J.Biochem.144(1):115-120[Hou等人,(2008)生物化学杂志144(1):115-120],以改进不同抗体特性,如下文所讨论的。
如本文所用,术语“人源化抗体”是指mAb及其抗原结合片段,包括本文披露的这些抗体化合物,它们具有根据本披露的类似于本文披露的那些的结合和功能特性,并且具有在来源于非人类抗体的CDR周围的基本上为人类或完全为人类的FR和恒定区。
如本文所用,术语“FR”或“框架序列”是指FR 1至4中的任一种。由本披露涵盖的人源化的抗体和抗原结合片段包括其中FR 1至4的任意一个或多个基本上或完全是人类的FR的分子,即,其中单独的基本上或完全为人类的FR 1至4的可能组合中的任一种是存在的。例如,这包括其中FR1和FR2;FR1和FR3;FR1、FR2和FR3;等基本上或完全为人类的分子。基本上为人类的框架区是与已知的人类种系框架序列具有至少80%序列一致性的那些。优选地,基本上为人类的框架区与本文披露的框架序列、或已知的人类种系框架序列具有至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、或至少99%的序列一致性。
完全为人类的框架区是与已知的人类种系框架序列完全相同的那些。人类FR种系序列可以从国际ImMunoGeneTics(IMGT)数据库以及Marie-Paule Lefranc和GerardLefranc的The Immunoglobulin FactsBook,Academic Press,2001[免疫球蛋白丛书,学术出版社,2001]获得,这些文献的内容通过引用整体结合在此。
免疫球蛋白丛书是用于创建人类抗体谱的人类种系免疫球蛋白基因的概略,并且包括203种基因和459种等位基因的条目,总计有837个展现的序列。个别条目包括所有人类免疫球蛋白恒定基因和具有至少一个功能性或开放阅读框等位基因并位于三个主要基因座中的种系可变基因、多样性基因和连接基因。例如,种系轻链FR可选自下组,该组由以下各项组成:IGKV3D-20、IGKV2-30、IGKV2-29、IGKV2-28、IGKV1-27、IGKV3-20、IGKV1-17、IGKV1-16、1-6、IGKV1-5、IGKV1-12、IGKV1D-16、IGKV2D-28、IGKV2D-29、IGKV3-11、IGKV1-9、IGKV1-39、IGKV1D-39以及IGKV1D-33和IGKJ1-5,并且种系重链FR可选自下组,该组由以下各项组成:IGHV1-2、IGHV1-18、IGHV1-46、IGHV1-69、IGHV2-5、IGHV2-26、IGHV2-70、IGHV1-3、IGHV1-8、IGHV3-9、IGHV3-11、IGHV3-15、IGHV3-20、IGHV3-66、IGHV3-72、IGHV3-74、IGHV4-31、IGHV3-21、IGHV3-23、IGHV3-30、IGHV3-48、IGHV4-39、IGHV4-59以及IGHV5-51和IGHJ1-6。
基本上为人类的FR是与已知的人类种系FR序列具有至少80%序列一致性的那些。优选地,基本上为人类的框架区与本文披露的框架序列、或已知的人类种系框架序列具有至少85%、至少90%、至少95%、至少96%、至少97%、至少98%、或至少99%的序列一致性。
由本披露涵盖的CDR不但包括本文具体披露的那些,而且包括与本文披露的CDR序列具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%、或至少99%的序列一致性的CDR序列。可替代地,由本披露涵盖的CDR不仅包括本文具体披露的那些,而且包括与本文披露的CDR序列相比在相应位置具有1、2、3、4、或5个氨基酸变化的CDR序列。这种序列一致的、或氨基酸修饰的CDR优选地结合到由完整抗体识别的抗原上。
可使用几种不同的方法来生成除了本文披露的那些之外的展现出根据本披露的类似功能特性的人源化抗体,Almagro et al.Frontiers in Biosciences.Humanizationof antibodies.(2008)Jan 1;13:1619-33[Almagro等人,生物科学前沿。抗体人源化。(2008)1月1日;13:1619-33]。
在一个方法中,将亲本抗体化合物CDR移植到与该亲本抗体化合物框架具有高度序列一致性的人框架上。该新框架的序列一致性大体上将是与亲本抗体化合物中的相应框架的序列至少80%、至少85%、至少86%、至少87%、至少88%、至少89%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、或至少99%一致。在具有少于100个氨基酸残基的框架的情况下,可以改变一个、二个、三个、四个、五个、六个、七个、八个、九个、或十个氨基酸残基。这种移植可导致与亲本抗体相比的结合亲和力的降低。如果情况如此,可以基于由Queen et al.(1991)Proc.Natl.Acad.Sci.USA88:2869[Queen等人,(1991)美国国家科学院院刊88:2869]披露的具体标准将该框架在某些位置处回复突变为亲本框架。描述适用于基于同源性和回复突变来生成人源化变体的方法的额外参考文献包括如以下所述的:Olimpieri et al.Bioinformatics.2015Feb 1;31(3):434-435[Olimpieri等人,生物信息学,2015年2月1日;31(3):434-435]和美国专利4,816,397、5,225,539、以及5,693,761;以及Winter及其同事的方法(Jones et al.(1986)Nature321:522-525[Jones等人,(1986)自然321:522-525];Riechmann et al.(1988)Nature 332:323-327[Riechmann等人,(1988)自然332:323-327];以及Verhoeyen et al.(1988)Science 239:1534-1536[Verhoeyen等人,(1988)科学239:1534-1536]。
在20世纪八十年代前中叶开发的一种方法是以嵌合开始人源化(Morrison,S.L.,M.J.Johnson,L.A.Herzenberg&V.T.Oi:Chimeric human antibody molecules:mouseantigen-binding domains with human constant regiondomains.Proc.Natl.Acad.Sci.USA.,81,6851-5(1984)[Morrison,S.L.、M.J.Johnson、L.A.Herzenberg以及V.T.Oi:嵌合人类抗体分子:具有人类恒定区结构域的小鼠抗原结合结构域,美国国家科学院院刊,81,6851-5(1984)]),该方法由以下组成:将鼠类抗体的可变(V)结构域与人类恒定(C)结构域组合以生成具有约70%人类内含物的分子。
使用若干种不同方法生成本文所述的人源化抗体。在一种方法中,将亲本抗体化合物CDR移植到与该亲本抗体化合物框架具有高度序列一致性的人类FR中。该新FR的序列一致性大体上将是与亲本抗体化合物中的相应FR的序列至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%、或至少99%一致。在具有少于100个氨基酸残基的FR的情况下,可以改变一个、二个、三个、四个、五个或更多个氨基酸残基。这种移植可导致与亲本抗体相比的结合亲和力的降低。如果情况如此,可以基于由Queen et al.(1991)Proc.Natl.Acad.Sci.USA 88:2869[Queen等人,(1991)美国国家科学院院刊88:2869]披露的具体标准将该FR在某些位置处回复突变为亲本框架。描述适用于基于同源性和回复突变来生成人源化变体的方法的额外参考文献包括如以下所述的:Olimpieri etal.Bioinformatics.2015Feb 1;31(3):434-435[Olimpieri等人,生物信息学,2015年2月1日;31(3):434-435]和美国专利4,816,397、5,225,539、以及5,693,761;以及Winter及其同事的方法(Jones et al.(1986)Nature321:522-525[Jones等人,(1986)自然321:522-525];Riechmann et al.(1988)Nature 332:323-327[Riechmann等人,(1988)自然332:323-327];以及Verhoeyen et al.(1988)Science 239:1534-1536[Verhoeyen等人,(1988)科学239:1534-1536]。
可以如下所述进行考虑回复突变的残基的鉴定。当氨基酸落入以下分类时,正在被使用的人类种系序列的框架氨基酸(“受体FR”)由来自该亲本抗体化合物的框架的框架氨基酸(“供体FR”)进行置换:
(a)受体框架的人类FR中的氨基酸在该位置处对于人类框架而言是不寻常的,而供体免疫球蛋白中的相应氨基酸在该位置处对于人类框架而言是典型的;
(b)氨基酸的位置紧邻着这些CDR之一;或者
(c)框架氨基酸的任何侧链原子处于三维免疫球蛋白模型的CDR氨基酸的任何原子的约5-6埃(中心距(center-to-center))内。
当在该受体框架的人类FR中的每个氨基酸也该供体框架中的相应氨基酸总体上对于在那个位置的人类框架而言为罕见的时候,这样的氨基可以由对于在那个位置的人类框架而言为典型的氨基酸进行置换。这种回复突变标准使人们能够恢复该亲本抗体化合物的活性。
生成展现出与本文披露的这些抗体化合物相似的功能特性的人源化抗体的另一种方法涉及使这些移植的CDR之内的氨基酸随机突变而不改变该框架,并且筛选得到的就结合亲和力和其他功能特性而言与这些亲本抗体化合物一样好或更好的分子。还可以在每个CDR内的每个氨基酸位置处引入单个突变,随后评估这样的突变对结合亲和力和其他功能特性的影响。可以将产生改进特性的单个突变进行组合,以便评估它们彼此组合的影响。
此外,两种前述方法的组合是可能的。在CDR移植之后,除了在这些CDR中引入氨基酸变化之外,可以使具体的FR回复突变。这种方法描述于Wu et al.(1999)J.Mol.Biol.294:151-162[Wu等人(1999)分子生物学杂志294:151-162]。
应用本披露的传授内容,本领域技术人员可以使用普通的技术,例如定向诱变,来取代在当前披露的CDR和FR序列之内的氨基酸,并且由此生成来源于当前序列的可变区氨基酸序列。多至所有天然存在的氨基酸可引入特定取代位置处。然后,可以使用本文披露的这些方法来筛选这些另外的可变区氨基酸序列,以便鉴定具有所指示的体内功能的序列。以这样的方式,可以鉴定出适合于制备根据本披露的人源化抗体及其抗原结合片段的其他序列。优选地,在框架之内的氨基酸取代局限于本文披露的四个轻链和/或重链FR的任何一个或多个之内的一个、二个、三个、四个、或五个位置。优选地,在CDR之内的氨基酸取代局限于三个轻链和/或重链CDR的任何一个或多个之内的一个、二个、三个、四个、或五个位置。在以上所述的这些FR和CDR之内的各种变化的组合也是可能的。
可以通过本文所披露的实例中的这些方法来证实通过引入以上讨论的氨基酸修饰而生成的、与本文所披露的具体分子所展现出的功能特性一致的这些抗体化合物的功能特性。
如以上所述,为了避免在患者引起人抗鼠抗体(HAMA)应答的问题,已遗传操纵鼠类抗体,以通过将其互补决定区(CDR)移植到人类可变轻(VL)链和可变重(VH)链框架上同时保留认为对于抗原结合位点的完整性所必需的那些鼠类框架残基来用存在于其人类对应物中的氨基酸残基逐渐置换其鼠类内容物。然而,人源化抗体的异种移植CDR可在患者中引起抗独特型(抗-Id)应答。
为了使抗-Id应答最小化,已开发通过仅将抗体-配体相互作用中最重要的CDR残基移植到人类框架上(称为“SDR移植”)来使异种移植抗体人源化的程序,其中仅CDRS的重要的特异性决定残基(SDR)移植到人类框架上。Kashmiri et al.(2005)Methods 36(1):25-34[Kashmiri等人,(2005)方法36(1):25-34]所述的此程序涉及藉由已知结构的抗原-抗体复合物的三维结构的数据库的帮助或者通过对抗体结合位点进行突变分析来鉴别SDR。涉及保留更多CDR残基的替代性人源化方法是基于包含所有SDR的CDR残基片段即‘缩短的’CDR的移植。Kashmiri等人还披露一种评估人源化抗体与来自已给予鼠类抗体的患者的血清的反应性的程序。
Hou et al.(2008)J.Biochem.144(1):115-120[Hou等人,(2008)生物化学杂志144(1):115-120]披露了用于构建具有改进的免疫原特性的人类抗体变体的另一种策略。这些作者通过使用藉由计算机辅助同源性建模建立的4C8分子模型进行CDR移植来由鼠抗人CD34单克隆抗体4C8开发一种人源化抗体。使用此分子模型,这些作者鉴定抗原结合中具有潜在重要性的FR残基。通过将这些关键性鼠类FR残基连同鼠类CDR残基转移到人类抗体框架上来生成人源化形式的4C8,该人类抗体框架基于与鼠类抗体FR的同源性来选择。所得人源化抗体已显示具有与初始鼠类抗体类似的抗原结合亲和力和特异性,这表明它可以是临床上常规使用的鼠类抗-CD34抗体的替代方案。
本披露的实施例涵盖创建为避免被人类免疫系统识别的抗体,该抗体含有本文所述的呈任何组合形式的CDR,使得所涵盖的mAb可以含有来自本文披露的单个鼠类mAb的CDR集合、或者含有包含来源于两种或三种所披露鼠类mAb的个别CDR的CDR集合的轻链和重链。此类mAb可以通过分子生物学的标准技术来创建并且使用本文所述的测定筛选其所需活性。以这种方式,本披露提供创建新型mAb的“混合配对”方法,该新型mAb包含来自所披露鼠类mAb的CDR混合物,以实现新的或改进的治疗活性。
由本披露所涵盖的、与本文披露的这些分子“竞争”的单克隆抗体或其抗原结合片段是在一个或多个部位结合人CD47的那些,该一个或多个部位与本发明分子结合的一个或多个部位相同或与之重叠。例如,可以通过抗体竞争测定来鉴定竞争性单克隆抗体或其抗原结合片段。例如,可以将纯化的或部分纯化的人CD47胞外结构域的样品结合到固体支持物上。然后,加入本披露的抗体化合物或其抗原结合片段、以及疑似能够与这种披露的抗体化合物竞争的单克隆抗体或其抗原结合片段。将这两种分子之一标记。如果该标记的化合物和该未标记的化合物结合到CD47上的分开且离散的部位,则该标记的化合物将结合相同的水平,而不论该疑似的竞争性化合物是否存在。然而,如果相互作用的这些部位是相同的或者重叠的,则该未标记的化合物将竞争,并且标记化合物结合到抗原上的量将被降低。如果该未标记的化合物以过量存在,则很少(如果有的话)的标记化合物将结合。出于本披露的目的,竞争性单克隆抗体或其抗原结合片段是使本发明抗体化合物与CD47的结合减少约50%、约60%、约70%、约80%、约85%、约86%、约87%、约88%、约89%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、或约99%的那些。用于进行此类竞争测定的程序的详情是本领域众所周知的并且可以例如发现于Harlow and Lane(1988)Antibodies,A Laboratory Manual,Cold Spring Harbor Laboratory Press,ColdSpring Harbor,N.Y.[Harlow和Lane(1988)抗体:实验室手册,冷泉港实验室出版社,冷泉港,纽约]。通过使用纯化抗体,这样的测定可以是定量的。通过针对自身滴定一种抗体来建立标准曲线,即,同一种抗体用于该标记物和该竞争物两者。滴定了未标记的竞争性单克隆抗体或其抗原结合片段抑制该标记分子结合到板上的能力。将这些结果绘图,并且比较了实现所希望的结合抑制程度所需要的浓度。
通过这些方法,结合在以下实例3-5中描述的这些方法,可以确定与在此类竞争测定中的本披露的抗体化合物竞争的mAb或其抗原结合片段是否具有与本发明的抗体化合物相同或相似的功能特性。在不同实施例中,用于在本文涵盖的治疗性方法中使用的竞争性抗体与本文所披露的抗体化合物相比具有约50%至约100%或约125%或更大范围内的如本文所述的生物活性。在一些实施例中,竞争性抗体与本文所披露的抗体化合物相比具有约50%、约60%、约70%、约80%、约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%、或相同的生物活性,如通过以下呈现的实例所披露的方法测定的。
mAb或其抗原结合片段、或适用于这些组合物和方法中的竞争性抗体可以是本文所述的任何同种型。此外,任何这些同种型可包含如下额外氨基酸修饰。
单克隆抗体或其抗原结合片段、或本文所述的竞争性抗体可以是人类IgG1同种型。
单克隆抗体、其抗原结合片段、或本文所述的竞争性抗体的人类IgG1恒定区可以被修饰以改变抗体半衰期。大部分通过与新生Fc受体的Fc依赖性相互作用来调节抗体半衰期(Roopenian和Alikesh,2007)。单克隆抗体、其抗原结合片段、或竞争性抗体的人类IgG1恒定区可以被修饰以增加半衰期,该修饰包括但不限于氨基酸序列N434A、T307A/E380A/N434A(Petkova等人,2006,Yeung等人,2009);M252Y/S254T/T256E(Dall’Acqua等人,2006);T250Q/M428L(Hinton等人,2006);以及M428L/N434S(Zalevsky等人,2010)。
与增加半衰期不同,存在需要减小半衰期的一些情况,诸如减少与高抗体依赖性细胞毒性(ADCC)和补体依赖性细胞毒性(CDC)抗体相关的不良事件的可能性(Presta2008)。单克隆抗体、其抗原结合片段、或本文所述的竞争性抗体的人类IgG1恒定区可以被修饰以减小半衰期和/或减小内源性IgG,该修饰包括但不限于氨基酸修饰I253A(Petkova等人,2006);P257I/N434H、D376V/N434H(Datta-Mannan等人,2007);以及M252Y/S254T/T256E/H433K/N434F(Vaccaro等人,2005)。
单克隆抗体、其抗原结合片段、或本文所述的竞争性抗体的人类IgG1恒定区可以被修饰以增加或减小抗体效应子功能。这些抗体效应子功能包括但不限于抗体依赖性细胞毒性(ADCC)、补体依赖性细胞毒性(CDC)、抗体依赖性细胞吞噬作用(ADCP)、C1q结合、以及改变的与Fc受体的结合。
单克隆抗体、其抗原结合片段、或本文所述的竞争性抗体的人类IgG1恒定区可以被修饰以增加抗体效应子功能,该修饰包括但不限于氨基酸修饰S298A/E333A/K334(Shields等人,2001);S239D/I332E和S239D/A330L/I332E(Lazar等人,2006);F234L/R292P/Y300L、F234L/R292P/Y300L/P393L、以及F243L/R292P/Y300L/V305I/P396L(Stevenhagen等人,2007);G236A、G236A/S239D/I332E、以及G236A/S239D/A330L/I332E(Richards等人,2008);K326A/E333A、K326A/E333S和K326W/E333S(Idusogie等人,2001);S267E和S267E/L328F(Smith等人,2012);H268F/S324T、S267E/H268F、S267E/S234T、以及S267E/H268F/S324T(Moore等人,2010);S298G/T299A(Sazinsky等人,2008);E382V/M428I(Jung等人,2010)。
单克隆抗体、其抗原结合片段、或本文所述的竞争性抗体的人类IgG1恒定区可以被修饰以减小抗体效应子功能,该修饰包括但不限于氨基酸修饰N297A和N297Q(Bolt等人,1993,Walker等人,1989);L234A/L235A(Xu等人,2000);K214T/E233P/L234V/L235A/G236-缺失/A327G/P331A/D356E/L358M(Ghevaert等人,2008);C226S/C229S/E233P/L234V/L235A(McEarchern等人,2007);S267E/L328F(Chu等人,2008)。
单克隆抗体、其抗原结合片段、或本文所述的竞争性抗体的人类IgG1恒定区可以被修饰以减小抗体效应子功能,该修饰包括但不限于氨基酸修饰V234A/G237A(Cole等人,1999);E233D、G237D、P238D、H268Q、H268D、P271G、V309L、A330S、A330R、P331S、H268Q/A330S/V309L/P331S、H268D/A330S/V309L/P331S、H268Q/A330R/V309L/P331S、H268D/A330R/V309L/P331S、E233D/A330R、E233D/A330S、E233D/P271G/A330R、E233D/P271G/A330S、G237D/H268D/P271G、G237D/H268Q/P271G、G237D/P271G/A330R、G237D/P271G/A330S、E233D/H268D/P271G/A330R、E233D/H268Q/P271G/A330R、E233D/H268D/P271G/A330S、E233D/H268Q/P271G/A330S、G237D/H268D/P271G/A330R、G237D/H268Q/P271G/A330R、G237D/H268D/P271G/A330S、G237D/H268Q/P271G/A330S、E233D/G237D/H268D/P271G/A330R,E233D/G237D/H268Q/P271G/A330R,E233D/G237D/H268D/P271G/A330S,E233D/G237D/H268Q/P271G/A330S,P238D/E233D/A330R,P238D/E233D/A330S,P238D/E233D/P271G/A330R,P238D/E233D/P271G/A330S,P238D/G237D/H268D/P271G,P238D/G237D/H268Q/P271G,P238D/G237D/P271G/A330R,P238D/G237D/P271G/A330S,P238D/E233D/H268D/P271G/A330R,P238D/E233D/H268Q/P271G/A330R,P238D/E233D/H268D/P271G/A330S,P238D/E233D/H268Q/P271G/A330S,P238D/G237D/H268D/P271G/A330R,P238D/G237D/H268Q/P271G/A330R,P238D/G237D/H268D/P271G/A330S,P238D/G237D/H268Q/P271G/A330S,P238D/E233D/G237D/H268D/P271G/A330R,P238D/E233D/G237D/H268Q/P271G/A330R,P238D/E233D/G237D/H268D/P271G/A330S,P238D/E233D/G237D/H268Q/P271G/A330S(An等人,2009,Mimoto,2013)。
单克隆抗体或其抗原结合片段、或本文所述的竞争性抗体可以是人类IgG2同种型。
单克隆抗体、其抗原结合片段、或本文所述的竞争性抗体的人类IgG2恒定区可以被修饰以增加或减小抗体效应子功能。这些抗体效应子功能包括但不限于抗体依赖性细胞毒性(ADCC)、补体依赖性细胞毒性(CDC)、抗体依赖性细胞吞噬作用(ADCP)、以及C1q结合、以及改变的与Fc受体的结合。
单克隆抗体、其抗原结合片段、或本文所述的竞争性抗体的人类IgG2恒定区可以被修饰以增加抗体效应子功能,该修饰包括但不限于氨基酸修饰K326A/E333S(Idusogie等人,2001)。
单克隆抗体、其抗原结合片段、或本文所述的竞争性抗体的人类IgG2恒定区可以被修饰以减小抗体效应子功能,该修饰包括但不限于氨基酸修饰V234A/G237A(Cole等人,1999);E233D、G237D、P238D、H268Q、H268D、P271G、V309L、A330S、A330R、P331S、H268Q/A330S/V309L/P331S、H268D/A330S/V309L/P331S、H268Q/A330R/V309L/P331S、H268D/A330R/V309L/P331S、E233D/A330R、E233D/A330S、E233D/P271G/A330R、E233D/P271G/A330S、G237D/H268D/P271G、G237D/H268Q/P271G、G237D/P271G/A330R、G237D/P271G/A330S、E233D/H268D/P271G/A330R、E233D/H268Q/P271G/A330R、E233D/H268D/P271G/A330S、E233D/H268Q/P271G/A330S、G237D/H268D/P271G/A330R、G237D/H268Q/P271G/A330R、G237D/H268D/P271G/A330S、G237D/H268Q/P271G/A330S、E233D/G237D/H268D/P271G/A330R、E233D/G237D/H268Q/P271G/A330R、E233D/G237D/H268D/P271G/A330S、E233D/G237D/H268Q/P271G/A330S、P238D/E233D/A330R、P238D/E233D/A330S、P238D/E233D/P271G/A330R、P238D/E233D/P271G/A330S、P238D/G237D/H268D/P271G、P238D/G237D/H268Q/P271G、P238D/G237D/P271G/A330R、P238D/G237D/P271G/A330S、P238D/E233D/H268D/P271G/A330R、P238D/E233D/H268Q/P271G/A330R、P238D/E233D/H268D/P271G/A330S、P238D/E233D/H268Q/P271G/A330S、P238D/G237D/H268D/P271G/A330R、P238D/G237D/H268Q/P271G/A330R、P238D/G237D/H268D/P271G/A330S、P238D/G237D/H268Q/P271G/A330S、P238D/E233D/G237D/H268D/P271G/A330R、P238D/E233D/G237D/H268Q/P271G/A330R、P238D/E233D/G237D/H268D/P271G/A330S、P238D/E233D/G237D/H268Q/P271G/A330S(An等人,2009,Mimoto,2013)。
单克隆抗体、其抗原结合片段、或本文所述的竞争性抗体的人类IgG2恒定区可以被修饰以改变同种型和/或激动活性,该修饰包括但不限于氨基酸修饰C127S(CH1结构域)、C232S、C233S、C232S/C233S、C236S、以及C239S(White等人,2015,Lightle等人,2010)。
单克隆抗体或其抗原结合片段、或本文所述的竞争性抗体可以是人类IgG3同种型。
单克隆抗体、或其抗原结合片段的人类IgG3恒定区,其中单克隆抗体、或其抗原结合片段的所述人类IgG3恒定区可以在一个或多个氨基酸处被修饰以增加抗体半衰期、抗体依赖性细胞毒性(ADCC)、补体依赖性细胞毒性(CDC)、或细胞凋亡活性。
单克隆抗体、或其抗原结合片段的人类IgG3恒定区,其中单克隆抗体、或其抗原结合片段的所述人类IgG3恒定区可以在氨基酸R435H处被修饰以增加抗体半衰期。
单克隆抗体或其抗原结合片段、或本文所述的竞争性抗体可以是人类IgG4同种型。
单克隆抗体、其抗原结合片段、或本文所述的竞争性抗体的人类IgG4恒定区可以被修饰以减小抗体效应子功能。这些抗体效应子功能包括但不限于抗体依赖性细胞毒性(ADCC)和抗体依赖性细胞吞噬作用(ADCP)。
单克隆抗体、其抗原结合片段、或本文所述的竞争性抗体的人类IgG4恒定区可以被修饰以防止Fab臂交换和/或减小抗体效应子功能,该修饰包括但不限于氨基酸修饰F234A/L235A(Alegre等人,1994);S228P、L235E和S228P/L235E(Reddy等人,2000)。
如本文所用,术语“肿瘤”是指无论恶性还是良性的所有赘生性细胞生长和增殖、以及所有癌前期与癌性细胞和组织。
术语“癌症”、“癌性的”以及“肿瘤”不相互排除地如本文使用。
术语“癌症”和“癌性的”是指或描述在哺乳动物中典型地以异常细胞生长/增殖为特征的生理状况。癌症的实例包括但不限于癌、淋巴瘤(即霍奇金淋巴瘤和非霍奇金淋巴瘤)、胚细胞瘤、肉瘤、以及白血病。此类癌症的更具体实例包括鳞状细胞癌、小细胞肺癌、非小细胞肺癌、肺腺癌、肺鳞状癌、腹膜癌、肝细胞癌、胃肠癌、胰腺癌、胶质瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝癌、乳腺癌、结肠癌、结肠直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、肝癌、前列腺癌、外阴癌、甲状腺癌、肝癌、白血病以及其他淋巴增生性病症、以及不同类型的头颈部癌。
如本文使用的术语“易感癌症(susceptible cancer)”是指其细胞表达CD47并且响应于用本披露的抗体或其抗原结合片段、或竞争性抗体或其抗原结合片段进行治疗的癌症。
如本文所用的术语“自身免疫性疾病”是指身体免疫系统针对自身并且错误地攻击健康细胞的情况。
如本文所用的术语“炎性疾病”是指特征为炎症的疾病,该炎症是由以下组成的基础病理学过程:响应于由物理、化学或生物试剂引起的损失或异常刺激而发生于受累血管和相邻组织中的组织学上清楚的细胞学变化、细胞浸润以及介质释放的动态复杂过程,包括局部反应和所得形态学变化;有害材料的破坏或移除;以及引起修复和愈合的应答。
如本文所用的术语“自身炎性疾病”是指当先天性免疫系统出于未知原因引起炎症时导致的疾病。
如本文所用,“缺血”是指其中例如通过一根或多根血管的收缩或闭塞引起到身体器官、组织、或部分的血液供应减少的血管现象。缺血有时是由血管收缩或血栓形成或栓塞导致的。缺血可导致直接缺血损伤、由于氧供应减少引起的细胞死亡所致的组织损害。缺血可急性发生,例如,在手术过程中,或者来自在事故、损伤和战争背景下遭受的对组织的创伤,或者在旨在用于后续移植的器官收获之后。它也可以亚急性地发生,如见于动脉硬化性外周血管疾病中,其中血管的进行性狭窄导致到组织和器官的血流不足。当组织经受缺血时,一些列的化学事件被起动,可最终导致细胞功能障碍和坏死。如果缺血以血流恢复结束,则第二系列的损伤性事件跟着发生,从而产生另外的损伤。因此,每当在受试者中存在短暂的血流减少或中断时,作为结果的损伤涉及两个组成部分-在缺血期间的直接损伤、以及在此之后的间接损伤或再灌注损伤。
“缺血性中风”可以由几种不同种类的疾病引起。最常见的问题是颈部或头部中的动脉的变窄。这常常是由动脉粥样硬化、或渐增的胆固醇沉积引起的。如果动脉变得太窄,则血细胞可聚集在其中并且形成血凝块(血栓)。这些血凝块可阻断在其中形成它们的动脉、或者可移动并被截留在更接近大脑的动脉中(栓塞)。当动脉粥样硬化斑块部分地从血管壁分离并且使通过该血管的血流闭塞时,可发生脑中风。
如本文所用,术语“再灌注”是指到由于血流减少导致的缺血组织的血流的恢复。再灌注是通过使能存活的缺血组织恢复从而控制进一步坏死的用于治疗梗死或其他缺血的程序。然而,再灌注自身可能进一步损害该缺血组织,从而引起再灌注损伤。除了在血流丧失期间发生的即时性损伤之外,“缺血/再灌注损伤”涉及在血流恢复之后发生的组织损伤。当前的了解在于,这种损伤大多是由化学产物、自由基、以及由缺血组织释放的活性生物物质引起的。
“一氧化氮(NO)供体、前体、或生成一氧化氮的局部药剂”是指递送NO、抑或可以通过酶促过程或非酶促过程转化成NO的化合物或药剂。实例包括但不限于,NO气体、二硝酸异山梨酯、亚硝酸盐、硝普钠、硝酸甘油、3-吗啉代斯德酮亚胺(SIN-1)、S-亚硝基-N-乙酰-青霉胺(SNAP)、二亚乙基三胺/NO(DETA/NO)、S-亚硝基硫醇、以及精氨酸。
“可溶性鸟苷酸环化酶(sGC)”是血管平滑肌中的一氧化氮受体。在心血管系统中,一氧化氮是以内源方式从L-精氨酸经由内皮一氧化氮合酶生成的,并激活在邻近血管平滑肌细胞中的可溶性鸟苷酸环化酶,以便增加cGMP水平,从而诱导血管舒张。一氧化氮结合到可溶性鸟苷酸环化酶的通常降低的血红素部分上,并且增加从GTP形成cGMP,导致细胞内钙的减少、血管舒张、以及抗炎作用。在sGC上的血红素铁的氧化降低了该酶对一氧化氮的反应性,并促进血管收缩。因此一氧化氮-sGC-cGMP途径在心血管疾病中起重要作用。已显示含氮化合物例如叠氮化钠、亚硝酸钠、羟胺、硝酸甘油、以及硝普钠刺激sGC,从而引起cGMP增加、以及血管舒张。相比于结合到降低的sGC上的sGC刺激剂,sGC激活剂激活对一氧化氮无反应的氧化的或血红素缺乏的sGC酶,即,它们刺激sGC而不依赖于氧化还原状态。虽然sGC刺激剂可增强降低的sGC对一氧化氮的敏感性,但是当sGC酶被氧化并因此对一氧化氮反应较低或无反应时,sGC激活剂可增加该sGC酶的活性。因此,sGC激活剂并非以一氧化氮为基础。请注意Nossaman et al.(2012)Critical Care Research and Practice,Volume2012,article 290805,and Derbyshire and Marletta(2012)Ann.Rev.Biochem.81:533-559[Nossaman等人(2012)重症护理研究与实践,第2012卷,文章编号290805,以及Derbyshire和Marletta(2012)生物化学年鉴81:533-559]的综述。
“激活可溶性鸟苷酸环化酶的试剂”例如是指有机硝酸盐(Artz et al.(2002)J.Biol.Chem.277:18253-18256[Artz等人(2002)生物化学杂志277:18253-18256]);原卟啉IX(Ignarro et al.(1982)Proc.Natl.Acad.Sci.USA 79:2870-2873[Ignarro等人(1982)美国国家科学院院刊79:2870-2873]);YC-1(Ko et al.(1994)Blood 84:4226-4233[Ko等人(1994)血液84:4226-4233]);BAY 41-2272和BAY 41-8543(Stasch et al.(2001Nature 410(6825):212-5[Stasch等人(2001自然410(6825):212-5])、CMF-1571以及A-350619(在Evgenov et al.(2006)Nat.Rev.Drug.Discov.5:755-768[Evgenov等人(2006)自然评论药物发现5:755-768]);BAY58-2667(Cinaciguat;Frey et al.(2008)Journal of Clinical Pharmacology 48(12):1400-10[Cinaciguat;Frey等人(2008)临床药理学杂志48(12):1400-10]);BAY 63-2521(Riociguat;Mittendorf et al.(2009)Chemmedchem4(5):853-65[Riociguat;Mittendorf等人(2009)药物化学4(5):853-65])。另外的可溶性鸟苷酸环化酶激活剂披露于Stasch et al.(2011)Circulation123:2263-2273[Stasch等人(2011)循环123:2263-2273];Derbyshire and Marletta(2012)Ann.Rev.Biochem.81:533-559[Derbyshire和Marletta(2012)生物化学年评81:533-559],以及Nossaman et al.(2012)Critical Care Research and Practice,Volume 2012,Article ID 290805,pages 1-12[Nossaman等人(2012)急救护理研究与实践,第2012卷,文章ID 290805,第1-12页]。
cGMP也可以通过使用磷酸二酯酶抑制剂抑制降解来增加。“抑制环核苷酸磷酸二酯酶的药剂”的实例包括他达拉非、伐地那非、乌地那非、以及西地那非、阿伐那非。
如本文所用,术语“治疗(treating)”或“治疗(treat)”或“治疗(treatment)”表示减缓、中断、阻止、控制、停止、减轻、或逆转一种体征、症状、失调、病症、或疾病的进展或严重性,但不一定涉及所有疾病相关体征、症状、病症、或失调的完全消除。术语“治疗(treating)”等是指在疾病已开始发展后改善疾病或病理状态的体征或症状的治疗干预。
如本文所用,术语“有效量”是指本披露的抗体化合物在以单个或多个剂量给予至患者或器官之后提供所希望的治疗或预防的量或剂量。
对于任何特定受试者精确的有效量将取决于其大小和健康状况、其病状的性质和程度、以及选择用于给药的治疗剂或治疗剂的组合。对于给定患者的有效量可通过常规实验来确定并且处于临床医师的判断范围内。本发明抗体化合物的治疗有效量还可以在给予至收获的器官或患者的每个单剂量中包括从约0.1mg/kg至约150mg/kg、从约0.1mg/kg至约100mg/kg、从约0.1mg/kg至约50mg/kg、或从约0.05mg/kg至约10mg/kg的范围的量。已知基于抗体的药物在此方面提供指导。例如,通过静脉内输注21mg/ml溶液来给予HerceptinTM,其中初始负荷剂量为每千克体重4mg并且每周维持剂量为每千克体重2mg;RituxanTM以375mg/m2每周给予一次;举例而言。
对于任何个别患者的治疗有效量可以由健康护理提供者通过监测抗体化合物对肿瘤消退、循环肿瘤细胞、肿瘤干细胞或抗肿瘤应答的作用来确定。通过这些方法获得的数据的分析允许在治疗期间修改治疗方案,使得最佳量的本披露的抗体化合物被给予(无论是单独地采用或者是彼此组合、或者与另一种治疗剂组合,或两者),并且使得还可以确定治疗持续时间。以这种方式,在疗程中可以修改给药/治疗方案,使得展现出满意的效果的最低量的抗体化合物(单独使用或组合使用)被给予,并且使得继续给予这样的化合物,时长只要是对于成功治疗患者必要的即可。已知基于抗体的药物提供与给药频率相关的指导,例如药物是否应每日、每周、每月等递送。频率和剂量也取决于症状的严重性。
在一些实施例中,本披露的抗体化合物可以用作人类医学和兽医学中的药物,该药物通过多种路径给药,包括但不限于口服、静脉内、肌肉内、动脉内、髓内、腹膜内、囊内、心室内、经皮、经皮肤、局部、皮下、肿瘤内、鼻内、肠内、舌下、阴道内、血管内或直肠路径。组合物还可以直接给予至病灶(诸如肿瘤)内。剂量治疗可以是单剂量方案或多剂量方案。皮下注射器也可以用于给予药物组合物。典型地,这些治疗组合物可以制备为可注射剂,即或者作为液体溶液或者悬浮液。也可以制备在注射前适于溶于或悬浮于液体媒剂中的固体形式。兽医应用包括治疗伴侣/宠物动物,诸如猫和狗;役用动物,诸如导盲犬或服务犬,以及马;运动动物,诸如马和狗;动物园动物,诸如灵长类动物、猫科动物(诸如狮子和老虎)、熊科动物等;以及其他圈养的珍稀动物。
可以通过本领域中熟知的方法制备这样的药物组合物。参见例如,Remington:TheScience and Practice of Pharmacy,21st Edition(2005),Lippincott Williams&Wilkins,Philadelphia,PA[雷明顿:药学科学与实践,第21版(2005),利平科特·威廉斯·威尔金斯出版公司,费城,宾夕法尼亚州],并且包括本文披露的一种或多种抗体化合物、以及药学上或兽医学上可接受的,例如生理学上可接受的载体、稀释剂、或赋形剂。
本披露描述了具有不同功能分布的抗-CD47 mAb。这些抗体具有选自以下各项的不同特性组合:1)表现出与CD47的一种或多种物种同系物的交叉反应性;2)阻断CD47与其配体SIRPα之间的相互作用;3)增加对人类肿瘤细胞的吞噬作用,4)诱导易感性人类肿瘤细胞的死亡;5)不诱导人类肿瘤细胞的细胞死亡;6)减少了与人类血红细胞(hRBC)的结合;
7)不具有可检测的与hRBC的结合;8)引起减少的hRBC凝集;9)不引起可检测的hRBC凝集;10)逆转一氧化氮(NO)的TSP1抑制,和/或11)不逆转NO途径的TSP1抑制。
本披露的抗-CD47抗体及其抗原结合片段具有不同于现有技术的抗-CD47抗体的特性的组合。这些特性和特征现在将进一步详细描述。
与不同物种的CD47的结合
本披露的抗-CD47抗体及其抗原结合片段结合人类CD47。在某些实施例中,抗-CD47抗体表现出与一种或多种CD47物种同系物(例如,非人灵长类起源的CD47同系物)的交叉反应性。在某些实施例中,本披露的抗-CD47抗体及其抗原结合片段结合人类CD47并且结合非人灵长类动物、小鼠、大鼠、和/或兔起源的CD47。与其他物种同系物的交叉反应物可以在治疗性抗体的开发和测试中是特别有利的。例如,治疗性抗体的临床前毒性测试频繁在非人灵长类物种中进行,这些物种包括但不限于食蟹猴、绿猴、猕猴以及松鼠猴。与这些物种同系物的交叉反应性可以因此对于开发抗体作为临床候选物是特别有利的。
阻断CD47与SIRPα之间的相互作用并促进吞噬作用
CD47也称为整合素相关蛋白(IAP),是包括以下各项的50kDa细胞表面受体:细胞外N-末端IgV结构域、五跨膜跨膜结构域、以及可替代地剪接的短C-末端细胞内尾。
两种配体结合CD47:信号调节性蛋白α(SIRP)和血小板应答蛋白-1(TSP1)。TSP1存在于血浆中并且被许多细胞(包括血小板)合成。SIRPα在包括巨噬细胞和树突细胞在内的造血细胞上表达。
当吞噬细胞上的SIRPα接合靶细胞上的CD47时,此相互作用防止对靶细胞的吞噬作用。CD47与SIRPα的相互作用有效地将“别吃我”信号发送至吞噬细胞(Oldenborg etal.Science 288:2051-2054,2000[Oldenborg等人,科学288:2051-2054,2000])。在治疗情况下,用抗-CD47 mAb阻断SIRPα与CD47的相互作用可以通过促进宿主免疫系统摄取并清除癌细胞来提供一种有效的抗癌治疗。因此,一些抗-CD47 mAb的重要功能特征是阻断CD47与SIRPα的相互作用从而使得巨噬细胞吞噬表达CD47的肿瘤细胞的能力。若干种抗-CD47 mAb已显示阻断CD47与SIRPα的相互作用,包括B6H12(Seiffert et al.Blood 94:3633-3643,1999[Seiffert等人,血液94:3633-3643,1999];Latour et al.J.Immunol.167:2547-2554,2001[Latour等人,免疫学杂志167:2547-2554,2001];Subramanian et al.Blood107:2548-2556,2006[Subramanian等人,血液107:2548-2556,2006];Liu et al.JBiol.Chem.277:10028-10036,2002[Liu等人,生物化学杂志277:10028-10036,2002];Rebres et al et al.J.Cellular Physiol.205:182-193,2005[Rebres等人,细胞生理学杂志205:182-193,2005])、BRIC126(Vernon-Wilson et al.Eur J Immunol.30:2130-2137,2000[Vernon-Wilson等人,欧洲免疫学杂志30:2130-2137,2000];Subramanian etal.Blood 107:2548-2556,2006[Subramanian等人,血液107:2548-2556,2006])、CC2C6(Seiffert et al.Blood 94:3633-3643,1999[Seiffert等人,血液94:3633-3643,1999])、以及1F7(Rebres et al.J.Cellular Physiol.205:182-193,2005[Rebres等人,细胞生理学杂志205:182-193,2005])。B6H12和BRIC126也已显示引起人类和小鼠巨噬细胞吞噬人类肿瘤细胞(Willingham et al.Proc Natl Acad Sci USA 109(17):6662-6667,2012[Willingham等人,美国国家科学院院刊109(17):6662-6667,2012];Chao et al.Cell142:699-713,2012[Chao等人,细胞142:699-713,2012];EP 2 242512B1)。其他存在的抗-CD47 mAb(诸如2D3)不阻断CD47与SIRPα的相互作用(Seiffert et al.Blood 94:3633-3643,1999[Seiffert等人,血液94:3633-3643,1999];Latour et al.J.Immunol.167:2547-2554,2001[Latour等人,免疫学杂志167:2547-2554,2001];Rebres etal.J.Cellular Physiol.205:182-193,2005[Rebres等人,细胞生理学杂志205:182-193,2005]),并且不引起对肿瘤细胞的吞噬作用(Willingham et al.Proc Natl Acad Sci USA109(17):6662-6667,2012[Willingham等人,美国国家科学院院刊109(17):6662-6667,2012];Chao et al.Cell 142:699-713,2012[Chao等人,细胞142:699-713,2012];EP 2242 512B1)。
如本文所用,术语“阻断SIRPα与人类CD47的结合”是指抗-CD47 mAb对SIRPα-Fc与Jurkat细胞上的CD47的结合减少大于50%。
本披露的本文所述的抗-CD47 mAb阻断CD47与SIRPα的相互作用并且增加对人类肿瘤细胞的吞噬作用。
对癌细胞的“吞噬作用”是指这样的细胞被巨噬细胞吞入和消化、以及这些癌细胞的最终消化或降解和所消化或降解的细胞组分以细胞外或细胞内的方式释放以便进一步加工。阻断SIRPα与CD47的结合的抗-CD47单克隆抗体增加巨噬细胞对癌细胞的吞噬作用。SIRPα与癌细胞上的CD47结合将使这些细胞逃脱巨噬细胞吞噬。癌细胞可以是能生存的或活的癌细胞。
诱导肿瘤细胞的死亡
一些可溶性抗-CD47 mAb在与肿瘤细胞上的CD47结合时启动细胞死亡程序,从而引起线粒体膜电势消失、ATP生成能力丧失、磷脂酰丝氨酸的细胞表面表达增加(通过增加的对膜联蛋白V的染色检测到)以及细胞死亡,而没有半胱天冬酶的参与或DNA的片段化。此类可溶性抗-CD47mAb具有治疗各种实体癌和血液癌的可能。若干种可溶性抗-CD47 mAb已显示诱导肿瘤细胞死亡,包括MABL-1、MABL-2及其片段(美国专利8,101,719;Uno etal.Oncol Rep.17:1189-94,2007[Uno等人,肿瘤学报告17:1189-94,2007];Kikuchi etal.Biochem Biophys Res.Commun.315:912-8,2004[Kikuchi等人,生物化学与生物物理学研究通讯315:912-8,2004])、Ad22(Pettersen et al.J.Immuno.166:4931-4942,2001[Pettersen等人,免疫学杂志166:4931-4942,2001];Lamy et al.J.Biol.Chem.278:23915-23921,2003[Lamy等人,生物化学杂志278:23915-23921,2003])、以及1F7(Manna etal.J.Immunol.170:3544-3553,2003[Manna等人,免疫学杂志170:3544-3553,2003];Mannaet al.Cancer Research,64:1026-1036,2004[Manna等人,癌症研究,64:1026-1036,2004])。本披露的本文所述的一些抗-CD47 mAb诱导人类肿瘤细胞的细胞死亡。
术语“诱导细胞死亡(inducing cell death)”、“杀灭(kills)”等,在本文中也可互换地使用,表示将本披露的抗体化合物添加到培养的癌细胞引起这些细胞展现出与细胞死亡相关的可量化的特征,这些特征包括以下各项中的一者或多者:
1.膜联蛋白V(在钙离子存在下)与这些肿瘤细胞的结合增加,如通过流式细胞术或共聚焦荧光显微技术检测的;
2.肿瘤细胞对荧光化合物碘化丙啶(如通过流式细胞术测定的)或7-氨基放线菌素D(7-AAD,如通过流式细胞术测定的)或台盼蓝(使用光学显微镜评分)的摄取增加
3.肿瘤细胞减少线粒体功能和膜电势,如通过若干种可用测量测定的(电势测定的荧光染料,诸如DiO-C6或JC1,或者基于甲臜的测定,诸如MTT或WST-1)。
诱导细胞死亡是指本文披露的某些可溶性抗-CD47抗体、鼠类抗体、嵌合抗体、人源化抗体、或其抗原结合片段(以及竞争性抗体及其抗原结合片段)在没有补体或其他细胞参与的情况下经由细胞自主机制而杀死癌细胞的能力,这些其他细胞包括但不限于T细胞、中性白细胞、自然杀伤细胞、巨噬细胞、或树突细胞。可定量地,诱导细胞死亡包括但不限于与使用阴性对照抗体(人源化同种型匹配抗体)获得的背景相比由可溶性抗-CD47 mAb引起的人类肿瘤细胞的膜联蛋白V染色的大于2倍增加。
在本发明人源化或嵌合mAb中,诱导人类肿瘤细胞的细胞死亡的那些引起与对于以下各项报道的发现类似的增加的膜联蛋白V结合:抗-CD47mAb Ad22(Pettersen etal.J.Immuno.166:4931-4942,2001[Pettersen等人,免疫学杂志166:4931-4942,2001];Lamy et al.J.Biol.Chem.278:23915-23921,2003[Lamy等人,生物化学杂志278:23915-23921,2003]);1F7(Manna and Frazier J.Immunol.170:3544-3553,2003[Manna和Frazier免疫学杂志170:3544-3553,2003];Manna and Frazier Cancer Res.64:1026-1036,2004[Manna和Frazier癌症研究64:1026-1036,2004]);以及MABL-1和2(美国专利7,531,643B2;美国专利7,696,325B2;美国专利8,101719B2)。
细胞活力测定描述于NCI/NIH指导手册中,该手册描述了可用于评估由CD47抗体对细胞死亡的诱导的许多类型的基于细胞的测定:“Cell Viability Assays[细胞活力测定]”,Terry L Riss,PhD,Richard A Moravec,BS,Andrew L Niles,MS,Helene A Benink,PhD,Tracy J Worzella,MS,and Lisa Minor,PhD.2013年5月1日出版的投稿人信息。
与hRBC的结合
CD47在人类红细胞(hRBC)上表达(Brown.J Cell Biol.111:2785-2794,1990[Brown.细胞生物学杂志111:2785-2794,1990];Avent.Biochem J.,(1988)251:499-505[Avent.生物化学杂志,(1988)251:499-505];Knapp.Blood,(1989)Vol.74,No.4,1448-1450[Knapp.血液,(1989)第74卷,第4期,1448-1450];Oliveira et al.Biochimica etBiophysica Acta 1818:481-490,2012[Oliveira等人,生物物理学报1818:481-490,2012];Petrova P.et al.Cancer Res 2015;75(15Suppl):Abstract nr 4271[Petrova P.等人,癌症研究2015;75(15增补版):摘要nr 4271])。已显示抗-CD47 mAb结合RBC,包括B6H12(Brown et al.J.Cell Biol.,1990[Brown等人,细胞生物学杂志,1990],Oliveiraet al.Biochimica et Biophysica Acta 1818:481-490,2012[Oliveira等人,生物物理学报1818:481-490,2012],Petrova P.et al.Cancer Res 2015;75(15Suppl):Abstract nr4271[Petrova P.等人,癌症研究2015;75(15增补版):摘要nr 4271])、BRIC125(Avent.Biochem J.,(1988)251:499-505[Avent.生物化学杂志,(1988)251:499-505])、BRIC126(Avent.Biochem J.,(1988)251:499-505[Avent.生物化学杂志,(1988)251:499-505];Petrova P.et al.Cancer Res 2015;75(15Suppl):Abstract nr 4271[Petrova P.等人,癌症研究2015;75(15增补版):摘要nr 4271])、5F9(Uger R.et al.Cancer Res2014;74(19Suppl):Abstract nr5011[Uger R.等人,癌症研究2014;74(19增补版):摘要nr5011],Liu et al.PLoS One.2015Sep 21;10(9):e0137345[Liu等人,公共科学图书馆期刊2015年9月21日;10(9):e0137345];Sikic B.et al.J Clin Oncol 2016;34(suppl;abstract 3019)[Sikic B.等人临床肿瘤学杂志2016;34(增补版;摘要3019)])、在专利公开2014/0161799、WO公开2014/093678、美国专利公开2014/0363442中披露的抗-CD47抗体、以及CC2C6(Petrova P.et al.Cancer Res 2015;75(15Suppl):Abstract nr 4271[Petrova P.等人,癌症研究2015;75(15增补版):摘要nr 4271],Uger R.et al.CancerRes 2014;74(19Suppl):Abstract nr 5011[Uger R.等人,癌症研究2014;74(19增补版):摘要nr 5011])。已显示结合人类CD47的SIRPα-Fc融合蛋白与其他人类细胞相比减少了与人类RBC的结合(Uger R.et al.Cancer Res 2014;74(19Suppl):Abstract nr 5011[UgerR.等人,癌症研究2014;74(19增补版):摘要nr 5011])。与RBC的结合可以通过使用仅一个CD47结合臂生成双特异性抗体来减少(Masternak et al.Cancer Res 2015;75(15Suppl):Abstract nr 2482[Masternak等人,癌症研究2015:75(15增补版):摘要nr 2482])。
因为一些抗-CD47 mAb已显示当给予至食蟹猴时导致RBC减少(Mounho-ZamoraB.et al.The Toxicologist,Supplement to Toxicological Sciences,2015;144(1):Abstract 596:127[Mounho-Zamora B.等人,毒理学家,毒理科学增补版,2015;144(1):摘要596:127],Liu et al.PLoS One.2015Sep 21;10(9):e0137345[Liu等人,公共科学图书馆期刊,2015年9月21日;10(9):e0137345];Pietsch et al.Cancer Res 2015;75(15Suppl):Abstract nr 2470[Pietsch等人,癌症研究2015;75(15增补版):摘要2470]),高度希望鉴别不结合表达CD47的RBC的抗-CD47 mAb。
如本文所用,术语“红血细胞(red blood cell(s))”和“红细胞(erythrocyte(s))”是同义词并且在本文中可互换使用。
如本文所用,术语“减少与hRBC的结合(reduced binding to hRBCs)”是指抗-CD47 mAb与hRBC结合的Kd比人类肿瘤细胞上的Kd大10倍或更大,其中该肿瘤细胞是OV10hCD47细胞。
如本文所用,术语“未结合(no binding)”或“NB”是指在高达并包括100μg/ml的抗-CD47 mAb浓度下不可测量的与hRBC的结合。
在本文所述的披露之前,未报道不结合表达CD47的人类RBC的抗-CD47 mAb。
本文所披露的一些抗-CD47 mAb减少了或不可检测的与人类RBC的结合。
RBC的凝集
红血细胞(RBC)凝集或血凝集是当与不同试剂(包括RBC抗原的抗体和细胞表面蛋白诸如CD47)一起孵育时RBC凝集或成块时发生的同型相互作用。据报道许多抗-CD47抗体在体外以浓度依赖性方式引起分离的人类RBC的血凝集,包括B6H12、BRIC126、MABL-1、MABL-2、CC2C6、以及5F9(Uger R.et al.Cancer Res 2014;74(19Suppl):Abstract nr5011[Uger R.等人,癌症研究2014;74(19增补版):摘要nr 5011],美国专利9,045,541,Unoet al.Oncol Rep.17:1189-94,2007[Uno等人,肿瘤学报告17:1189-94,2007];Kikuchi etal.Biochem Biophys Res.Commun.315:912-8,2004[Kikuchi等人,生物化学与生物物理学研究通讯315:912-8,2004];Sikic B.et al.J Clin Oncol 2016;34(suppl;abstract3019)[Sikic B.等人,临床肿瘤学杂志2016;34(增补版;摘要3019)])。此功能作用需要完整的二价抗体与RBC结合并且可以通过生成抗体片段即F(ab’)或svFv(Uno et al.OncolRep.17:1189-94,2007[Uno等人,肿瘤学报告17:1189-94,2007];Kikuchi et al.BiochemBiophys Res.Commun.315:912-8,2004[Kikuchi等人,生物化学与生物物理学研究通讯315:912-8,2004])或者仅具有一个CD47结合臂的双特异性抗体(Masternak et al.CancerRes 2015;75(15Suppl):Abstract nr 2482[Masternak等人,癌症研究2015;75(15增补版):摘要nr 2482])来减少或消除。这些片段的其他功能特性(包括细胞杀伤)已显示在这些片段中有所减少或保留(Uno et al.Oncol Rep.17:1189-94,2007[Uno等人,肿瘤学报告17:1189-94,2007];Kikuchi et al.Biochem Biophys Res.Commun.315:912-8,2004[Kikuchi等人,生物化学与生物物理学研究通讯315:912-8,2004])。小鼠抗体2D3是结合红血细胞上的CD47但不引起血凝集的抗-CD47抗体的实例(美国专利9,045,541,Petrova etal.Cancer Res 2015;75(15Suppl):Abstract nr 4271[Petrova等人,癌症研究2015;75(15增补版):摘要nr 4271])。
血凝集已显示通过使用SIRPα-Fc融合蛋白来减少与人类RBC而非其他细胞的选择性结合(Uger R.et al.Blood 2013;122(21):3935[Uger R.等人,血液2013;122(21):3935])。另外,据报道小鼠抗-CD47 mAb 2A1和人源化版本的2A1阻断CD47/SIRPα,但未表现出血凝集活性(美国专利9,045,541)。据报道少量一组小鼠抗人类CD47抗体(23中之3)不引起人类RBC的血凝集(Pietsch E et al.Cancer Res 2015;75(15Suppl):Abstract nr2470[Pietsch E等人,癌症研究2015;75(15增补版):摘要nr 2470])。因此,在本文所述的披露之前,需要鉴定阻断SIRPαCD47结合、不具有或减少了与RBC的结合和/或不引起血凝集的CD47 mAb。术语“凝集(agglutination)”是指细胞结块,而术语“血凝集(hemagglutination)”是指特定亚组的细胞即RBC结块。因此,血凝集是一种类型的凝集。
如本文所用,术语“减少的血凝集(reduced hemagglutination)”是指在大于1.85μg/ml的抗-CD47 mAb浓度下hRBC的可测量的凝集活性,以及在小于或等于1.85μg/ml的浓度下不可测量的凝集活性。
如本文所用,术语“不可检测的血凝集(no detectable hemagglutination)”是指在大于或等于0.3pg/mL的抗-CD47 mAb浓度至小于或等于50μg/mL的浓度下hRBC的不可测量的凝集活性。
本文所述的一些抗-CD47抗体引起减少的或不可检测的人类RBC的血凝集。
NO途径的调节
如以上所述,TSP1也是CD47的配体。TSP1/CD47途径在许多细胞类型中对抗NO途径的有利作用,这些细胞类型包括但不限于血管细胞。NO途径由利用精氨酸作为底物生成生物活性气体NO的三种酶(一氧化氮合酶、NOS I、NOS II和NOS III)的任一种组成。NO可在其中产生它的细胞内、或在相邻的细胞中起作用,从而激活产生信使分子环GMP(cGMP)的酶(可溶性鸟苷环化酶)。NO-cGMP途径的正确功能对于保护心血管系统对抗应激是重要的,这些应激包括但不限于由于创伤、炎症、高血压、代谢综合征、缺血、以及IRI所致的应激。在这些细胞应激的情况下,经由TSP1/CD47系统的NO/cGMP途径的抑制恶化了应激的效应。在cGMP和cAMP两者都起着重要保护作用的心血管系统中,这是一个特殊的问题。存在着许多其中缺血和再灌注损伤引起或造成疾病、外伤、以及外科手术的不良结局的情形。
如本文所披露的,一种或多种嵌合或人源化抗-CD47抗体将逆转cGMP产生的TSP1抑制。逆转将是完全的(>80%)或中级的(20%-80%)。cGMP产生的TSP1抑制的这种逆转将证明这些抗-CD47 mAb具有增加NO信号传导的能力,并且表明它们在保护心血管系统使其免于应激中的效用,这些应激包括但不限于由于创伤、炎症、高血压、代谢综合征、缺血、以及缺血再灌注损伤(IRI)所致的应激。也还预期另外的测定系统(例如平滑肌细胞收缩)显示一些嵌合或人源化抗体逆转TSP1对由NO信号传导的激活引起的下游效应的抑制性作用。
如本文所披露的,“完全逆转NO途径抑制(complete reversal of NO pathwayinhibition)”是指与阴性对照的人源化同种型匹配的抗体相比,抗-CD47 mAb逆转大于80%对NO信号传导的TSP1抑制。
如本文所披露的,“中级逆转NO途径抑制(intermediate reversal of NOpathway inhibition)”是指与阴性对照的人源化同种型匹配的抗体相比,抗-CD47 mAb逆转大于20%-80%的NO信号传导的TSP1抑制。
如本文所披露的,“没有逆转NO途径抑制(no reversal of NO pathwayinhibition)”是指与阴性对照的人源化同种型匹配的抗体相比,抗-CD47mAb逆转小于20%的NO信号传导的TSP1抑制。
功能特性的优选组合
在现有技术中存在具有一些而非所有本文所述的功能特征的组合的抗-CD47mAb。先前,已显示人源化抗-CD47 mAb诸如AB6.12 IgG1、AB6.12-IgG4P和AB6.12-IgG4PE(美国专利9,045,541、美国专利公开2014/0161799、WO公开2014/093678、美国公开2014/0363442)以及5F9(Mounho-Zamora B.et al.The Toxicologist,Supplement toToxicological Sciences,2015;144(1):Abstract 596:127[Mounho-Zamora B.等人,毒理学家,毒理科学增补版,2015;144(1):摘要596:127],Liu et al.PLoS One.2015Sep 21;10(9):e0137345[Liu等人,公共科学图书馆期刊,2015年9月21日;10(9):e0137345])结合人类CD47,阻断CD47与SIRPα的相互作用并且引起对人类肿瘤细胞的吞噬。人源化CD47 mAbAB6.12IgG1、AB6.12-IgG4P和AB6.12-IgG4PE也不引起人类RBC的血凝集(美国专利9,045,541)。5F9人源化抗-CD47 mAb结合人类RBC并且引起这些人类RBC的血凝集(Uger R.etal.Cancer Res 2014;74(19Suppl):Abstractnr 5011[Uger R.等人,癌症研究2014;74(19增补版):摘要5011],Sikic B.等人,肿瘤学杂志2016;34(增补版;摘要3019)。鼠类抗-CD47mAb B6H12、BRIC126和CC2C6阻断CD47与SIRPα的相互作用,引起吞噬,并且结合人类RBC并引起这些RBC的血凝集(Petrova P.et al.Cancer Res2015;75(15Suppl):Abstract nr4271[Petrova P.等人,癌症研究2015;75(15增补版):摘要nr 4271],Seiffert etal.Blood 94:3633-3643,1999[Seiffert等人,血液94:3633-3643,1999];Vernon-Wilsonet al.Eur J Immunol.30:2130-2137,2000[Vernon-Wilson等人,欧洲免疫学杂志30:2130-2137,2000];Latour et al.J.Immunol.167:2547-2554,2001[Latour等人,免疫学杂志167:2547-2554,2001];Subramanian et al.Blood 107:2548-2556,2006[Subramanian等人,血液107:2548-2556,2006];Liu et al.J Biol.Chem.277:10028-10036,2002[Liu等人,生物化学杂志277:10028-10036,2002])。鼠类抗-CD47 mAb MABL-1和MABL-2结合人类CD47,诱导肿瘤细胞死亡并且引起RBC血凝集(美国专利8,101,719);鼠类mAb Ad22结合人类CD47并且诱导肿瘤细胞死亡(Pettersen et al.J.Immunol.166:4931-4942,2001[Pettersen等人,免疫学杂志166:4931-4942,2001];Lamy et al.J Biol Chem.278:23915-23921,2003[Lamy等人,生物化学杂志278:23915-23921,2003]);并且鼠类mAb 1F7结合人类CD47,阻断CD47与SIRPα的相互作用并且诱导肿瘤细胞死亡(Rebres etal.J.Cellular Physiol.205:182-193,2005[Rebres等人,细胞生理学杂志205:182-193,2005];Manna et al.J.Immunol.170:3544-3553,2003[Manna等人,免疫学杂志170:3544-3553,2003];Manna et al.Cancer Research,64:1026-1036,2004[Manna等人,癌症研究,64:1026-1036,2004])。
本文所述的抗-CD47抗体的优选实施例的特征也在于建议用于人类治疗性用途的现有技术抗-CD47抗体未表现出的特性的组合。因此,本文所述的优选抗-CD47抗体的特征在于:
a.结合人类CD47,
b.阻断SIRPα与人类CD47的结合,
c.增加对人类肿瘤细胞的吞噬作用;并且
d.诱导易感性人类肿瘤细胞的死亡。
在本文所述的另一个优选实施例中,抗-CD47抗体的特征在于:
a.结合人类CD47,
b.阻断SIRPα与人类CD47的结合,
c.增加对人类肿瘤细胞的吞噬作用,
d.诱导易感性人类肿瘤细胞的死亡;并且
e.引起人类血红细胞(hRBC)不凝集。
在本文所述的另一个优选实施例中,抗-CD47抗体的特征在于:
a.结合人类CD47,
b.阻断SIRPα与人类CD47的结合,
c.增加对人类肿瘤细胞的吞噬作用,
d.诱导易感性人类肿瘤细胞的死亡;并且
e.引起人类血红细胞(hRBC)凝集减少。
在本文所述的另一个优选实施例中,抗-CD47抗体的特征在于:
a.特异性结合人类CD47,
b.阻断SIRPα与人类CD47的结合,
c.增加对人类肿瘤细胞的吞噬作用
d.诱导易感性人类肿瘤细胞的死亡;并且
e.减少了hRBC结合。
在本文所述的另一个优选实施例中,抗-CD47抗体的特征在于:
a.结合人类CD47,
b.阻断SIRPα与人类CD47的结合,
c.增加对人类肿瘤细胞的吞噬作用,
d.引起人类血红细胞(hRBC)不凝集;并且
e.不结合hRBC。
在本文所述的另一个优选实施例中,抗-CD47抗体的特征在于:
a.特异性结合人类CD47,
b.阻断SIRPα与人类CD47的结合,
c.增加对人类肿瘤细胞的吞噬作用,
d.引起人类血红细胞(hRBC)不凝集;并且
e.减少了hRBC结合。
在本文所述的另一个优选实施例中,单克隆抗体或其抗原结合片段也特异性结合非人灵长类CD47,其中非人灵长类可包括但不限于食蟹猴、绿猴、猕猴以及松鼠猴。
在本文所述的另一个实施例中,单克隆抗体或其抗原结合片段结合人类、非人灵长类、小鼠、兔、以及大鼠CD47。
本文描述了具有不同功能分布的抗-CD47 mAb。这些抗体具有选自以下各项的不同特性组合:1)表现出与CD47的一种或多种物种同系物的交叉反应性;2)阻断CD47与其配体SIRPα之间的相互作用;3)增加对人类肿瘤细胞的吞噬作用,4)诱导易感性人类肿瘤细胞的死亡;5)不诱导人类肿瘤细胞的细胞死亡;6)减少了与人类血红细胞(hRBC)的结合;7)不具有可检测的与hRBC的结合;8)引起减少的hRBC凝集;9)不引起可检测的hRBC凝集;10)逆转一氧化氮(NO)的TSP1抑制,和/或11)不逆转NO途径的TSP1抑制。
CD47抗体
许多的人类癌症上调了CD47的细胞表面表达,并且那些表达最高水平的CD47的癌症似乎是最具侵袭性的并对患者是最致命的。CD47表达增加被认为通过经由SIRPα向巨噬细胞发送“不要吃掉我”信号而保护癌细胞使其免于被吞噬清除,该SIRPα是一种阻止带有CD47的细胞的吞噬作用的抑制性受体(Oldenborg et al.Science 288:2051-2054,2000[Oldenborg等人,科学288:2051-2054,2000];Jaiswal et al.(2009)Cell 138(2):271-85l[Jaiswal等人(2009)细胞(Cell)138(2):271-851];Chao et al.(2010)ScienceTranslational Medicine 2(63):63ra94[Chao等人(2010)科学转化医学2(63):63ra94])。因此,许多癌症的CD47表达增加为它们提供了“自我”掩护,减缓了它们被巨噬细胞和树突细胞的吞噬清除。
阻断CD47并且阻止它与SIRPα结合的抗体在鼠类(异种移植)肿瘤模型中的人肿瘤中显示出效力。表现出此特性的此类阻断性抗-CD47 mAb增加了巨噬细胞对癌细胞的吞噬作用,这可以减少肿瘤负荷(Majeti et al.(2009)Cell 138(2):286-99[Majeti等人(2009)细胞138(2):286-99];US 9,045,541;Willingham et al.(2012)Proc NatlAcad.Sci.USA 109(17):6662-6667[Willingham等人(2012)美国国家科学院院刊109(17):6662-6667];Xiao et al.(2015)Cancer Letters 360:302-309[Xiao等人(2015)癌症通讯360:302-309];Chao et al.(2012)Cell 142:699-713[Chao等人(2012)细胞142:699-713];Kim et al.(2012)Leukemia 26:2538-2545[Kim等人(2012)白血病26:2538-2545])并且最终可引起对肿瘤的适应性免疫应答生成(Tseng et al.(2013)PNAS 110(27):11103-11108[Tseng等人(2013)美国国家科学院院刊110(27):11103-11108];Soto-Pantoja et al.(2014)Cancer Res.74(23):6771-6783[Soto-Pantoja等人(2014)癌症研究74(23):6771-6783];Liu et al.(2015)Nat.Med.21(10):1209-1215[Liu等人(2015)自然医学21(10):1209-1215])。
然而,在癌症治疗中抗-CD47 mAb可攻击转化细胞的机制尚未探明。多个组已显示特定抗人类CD47 mAb诱导人类肿瘤细胞的细胞死亡。抗-CD47 mAb Ad22诱导多种人类肿瘤细胞系的细胞死亡(Pettersen et al.J.Immuno.166:4931-4942,2001[Pettersen等人,免疫学杂志166:4931-4942,2001];Lamy et al.J.Biol.Chem.278:23915-23921,2003[Lamy等人,生物化学杂志278:23915-23921,2003])。AD22已显示诱导快速线粒体功能障碍和具有早期磷脂酰丝氨酸暴露和线粒体膜电势降低的快速细胞死亡(Lamy etal.J.Biol.Chem.278:23915-23921,2003[Lamy等人,生物化学杂志278:23915-23921,2003])。抗-CD47 mAb MABL-2及其片段在体外诱导人类白血病细胞系而非正常细胞的细胞死亡并且在体内异种移植模型中具有抗肿瘤作用。(Uno et al.(2007)Oncol.Rep.17(5):1189-94[Uno等人(2007)肿瘤学报道17(5):1189-94])。抗人类CD47 mAb 1F7诱导人类T细胞白血病(Manna and Frazier(2003)J.Immunol.170:3544-53[Manna和Frazier(2003)免疫学杂志170:3544-53])和若干种乳腺癌(Manna和Frazier(2004)癌症研究64(3):1026-36)的细胞死亡。1F7杀死荷CD47肿瘤细胞,而没有补体的作用或NK细胞、T细胞或巨噬细胞的细胞介导的杀伤作用。相反,抗-CD47 mAb 1F7经由非凋亡机制起作用,该机制涉及对线粒体的直接的CD47依赖性攻击,从而使它们的膜电位放电并且破坏细胞的ATP生成能力,导致迅速的细胞死亡。值得注意的是,抗-CD47 mAb 1F7并不杀死同样表达CD47的静息白细胞,而是仅杀死那些经由转化而被“激活”的细胞。因此,正常的循环细胞(许多表达CD47)免于被杀死,而癌细胞经由肿瘤毒性CD47 mAb被选择性地杀死(Manna and Frazier(2003)J.Immunol.170:3544-53[Manna和Frazier(2003)免疫学杂志170:3544-53])。与借助于单纯阻断CD47/SIRPα结合而引起吞噬作用的被动机制相反,这种机制可以被认为是一种针对肿瘤细胞的主动的、选择性的直接攻击。重要的是,mAb 1F7还阻断SIRPα与CD47的结合(Rebres et al et al.J.Cellular Physiol.205:182-193,2005[Rebres等人,细胞生理学杂志205:182-193,2005])并且因此其可以经由以下两种机制起作用:(1)直接肿瘤毒性和(2)引起对癌细胞的吞噬作用。能够完成这两种功能的单种mAb可能优于仅阻断CD47/SIRPα结合的mAb。
在组织缺血期之后,血流的开始引起被称为“缺血再灌注损伤”或IRI的损害。在许多外科手术中IRI是不良结局的原因,其中IRI发生是由于在创伤的许多形式/原因中(其中血流被中断并且稍后通过治疗介入得以恢复)以及在需要器官移植的手术、心/肺旁路手术、断离身体部分的再附接、整形与美容手术以及涉及停止和重新开始血流的其他情形中必然停止血流一段时间。缺血本身引起许多生理改变,通过这些改变自身将最终导致细胞和组织坏死以及死亡。再灌注引起它自身一系列的损害事件,包括活性氧类的生成、血栓形成、炎症以及细胞因子介导的损害。由TSP1-CD47系统限制的这些途径精确而言是在对抗IRI损害中将最具有益处的那些途径,包括NO途径。因此,正如用本文披露的这些抗体阻断TSP1-CD47途径,将为这些内源保护途径提供更稳健的功能。抗-CD47 mAb已显示在以下各项的啮齿动物模型中减少器官损害:肾脏热缺血(Rogers et al.J Am Soc Nephrol.23:1538-1550,2012[Rogers等人,美国肾脏病学会23:1538-1550,2012])、肝脏缺血再灌注损伤(Isenberg et al.Surgery.144:752-761,2008[Isenberg等人,外科手术144:752-761,2008])、肾移植(Lin et al.Transplantation.98:394-401,2014[Lin等人,移植98:394-401,2014];Rogers et al.Kidney Interantional.90:334-347,2016)[Rogers等人,国际肾脏期刊90:334-347,2016])以及肝移植(包括脂肪变性肝)(Xiao et al.LiverTranspl.21:468-477,2015[Xiao等人,肝移植21:468-477,2015];Xiao etal.Transplantation.100:1480-1489,2016[Xiao等人,移植100:1480-1489,2016])。另外,抗-CD47 mAb种肺动脉高压的野百合碱模型中引起右心室收缩压和右心室肥大显著减少(Bauer et al.Cardiovasc Res.93:682-693,2012[Bauer等人,心血管研究93:682-693,2012])。皮瓣模型中的研究表明CD47的调节(包括使用抗-CD47 mAb)抑制了TSP1-介导的CD47信号传导。这导致NO途径的活性增加,从而使得IRI减小(Maxhimer et al.PlastReconstr Surg.124:1880-1889,2009[Maxhimer等人,整形修复手术124:1880-1889,2009];Isenberg et al.Arterioscler Throm Vasc Biol.27:2582-2588,2007[Isenberg等人,动脉粥样硬化、血栓形成和血管生物学27:2582-2588,2007];Isenberg et al.CurrDrug Targets.9:833-841,2008[Isenberg等人,当代药物靶标9:833-841,2008];Isenberget al.Ann Surg.247:180-190,2008[Isenberg等人,外科学年鉴247:180-190,2008])。
抗-CD47 mAb也已显示在其他心血管疾病模型中是有效的。在压力负荷左心室心力衰竭的小鼠主动脉缩窄模型中,抗-CD47 mAb减轻心肌细胞肥大,减少左室心纤维化,防止左心室重量增加,降低心室僵硬度,并且将压力容积闭合曲线的变化归一化(Sharifi-Sanjani et al.J Am Heart Assoc.,2014[Sharifi-Sanjani等人,美国心脏协会杂志,2014])。抗-CD47 mAb改善多种小鼠模型中的动脉粥样硬化(Kojima et al.Nature.,2016[Kojima等人,自然,2016])。
癌症适应症
目前披露了有效作为癌症治疗剂的抗-CD47 mAb及其抗原结合片段,这些治疗剂优选胃肠外给予至患有易感性血液癌和实体癌的患者,这些癌症包括但不限于白血病,包括全身性肥大细胞增多症、急性淋巴细胞(成淋巴细胞)白血病(ALL)、T细胞-ALL、急性髓性白血病(AML)、粒细胞性白血病、慢性淋巴细胞白血病(CLL)、慢性骨髓性白血病(CML)、骨髓增生障碍/赘生物、单核细胞白血病、以及浆细胞白血病;多发性骨髓瘤(MM);瓦尔登斯特伦巨球蛋白血症(Waldenstrom's Macroglobulinemia);淋巴瘤,包括组织细胞性淋巴瘤和T细胞淋巴瘤、B细胞淋巴瘤,包括霍奇金淋巴瘤和非霍奇金淋巴瘤,诸如低级别/滤泡性非霍奇金淋巴瘤(NHL)、细胞淋巴瘤(FCC)、套细胞淋巴瘤(MCL)、弥漫性大细胞淋巴瘤(DLCL)、小淋巴细胞性(SL)NHL、中等级别/滤泡性NHL、中等级别的弥漫性NHL、高级别成免疫细胞NHL、高级别成淋巴细胞NHL、高级别小非裂细胞NHL、巨大肿块(bulky disease)NHL;实体肿瘤,包括卵巢癌、乳腺癌、子宫内膜癌、结肠癌(结肠直肠癌)、直肠癌、膀胱癌、尿路上皮癌、肺癌(非小细胞肺癌、肺腺癌、肺鳞状细胞癌)、支气管癌、骨癌、前列腺癌、胰腺癌、胃癌、肝细胞癌(肝癌、肝细胞瘤)、胆囊癌、胆管癌、食道癌、肾细胞癌、甲状腺癌、头颈部鳞状细胞癌(头颈癌)、睾丸癌、内分泌腺癌、肾上腺癌、脑下垂体癌、皮肤癌、软组织癌、血管癌、脑癌、神经癌、眼癌、脑膜癌、口咽癌、下咽部癌、宫颈癌、以及子宫癌、成胶质细胞瘤、成神经管细胞瘤(meduloblastoma)、星形细胞瘤、胶质瘤、脑膜瘤、胃泌素瘤、成神经细胞瘤、骨髓增生异常综合征、以及肉瘤,该肉瘤包括但不限于骨肉瘤、尤因肉瘤、平滑肌肉瘤、滑膜肉瘤、腺泡状软组织肉瘤、血管肉瘤、脂肪肉瘤、纤维肉瘤、横纹肌肉瘤,以及软骨肉瘤(chrondrosarcoma);以及黑色素瘤。
癌症的治疗
正如本领域普通技术人员熟知的,当单药治疗或程序不能充分地治疗或治愈疾病或病症时,常常在癌症治疗中采用联合治疗。常规的癌症治疗常常涉及手术、放射治疗、联合给予细胞毒性药物以实现相加作用和协同作用、以及任何或所有这些方法的组合。特别有用的化学治疗与生物治疗组合采用通过不同的作用机制起作用的药物,从而增加癌细胞控制或杀死,增加免疫系统控制癌细胞生长的能力,降低在治疗期间的抗药性的可能,并且通过允许使用降低剂量的各种药物而将可能的重叠毒性降低到最低限度。
例如在Goodman&Gilman’s The Pharmacological Basis of Therapeutics,Twelfth Edition(2010)L.L.Brunton,B.A.Chabner,and B.C.Knollmann Eds.,SectionVIII,“Chemotherapy of Neoplastic Diseases”,Chapters 60-63,pp.1665-1770,McGraw-Hill,NY[古德曼和吉尔曼的治疗剂药理学基础,第十二版(2010),L.L.Brunton、B.A.Chabner和B.C.Knollmann编辑,第VIII部分,“肿瘤性疾病的化学疗法”,第60-63章,第1665-1770页,纽约麦格劳希尔集团]中披露了适用于在由本发明方法所涵盖的组合疗法中的常规抗肿瘤剂/抗赘生物剂类别,并且该类别包括例如烷化剂、抗代谢物、天然产品、多种杂类试剂、激素和拮抗剂、靶向药物、单克隆抗体以及其他蛋白质治疗剂。
除了前述内容之外,本披露的这些方法与癌症适应症的治疗相关,并且进一步包括经由手术、放射、和/或向有需要的患者给予有效量的化学小分子或生物药物来治疗患者,该化学小分子或生物药物包括但不限于,常规使用的或目前正在开发的用来治疗肿瘤病状的肽、多肽、蛋白质、核酸治疗剂。这包括除了本文披露的那些之外的抗体及其抗原结合片段、细胞因子、反义寡核苷酸、siRNA、以及miRNA。
本文披露和要求保护的治疗方法包括使用本文披露的单独抗体、和/或彼此的组合、和/或与本披露的结合CD47的其抗原结合片段的组合、和/或还与展现出适当的生物/治疗活性的竞争性抗体的组合,例如,这些抗体化合物实现最大治疗功效的所有可能组合。
另外,本发明治疗方法还涵盖使用这些抗体、其抗原结合片段、其竞争性抗体和组合、与以下各项的进一步组合:(1)选自手术、放射、抗肿瘤或抗赘生物药剂的任何一种或多种抗肿瘤治疗性治疗,以及任何这些的组合;或者(2)抗肿瘤生物剂中的任何一种或多种;或者(3)对于本领域普通技术人员显而易见的处于适当组合(一种或多种)中的(1)或(2)的任何前述内容的等效物,以便针对特定适应症实现所希望的治疗性治疗作用。
通过调节影响对肿瘤抗原的T细胞应答的共刺激性或抑制性相互作用增加对癌症的免疫应答的抗体和小分子药物(包括免疫检验点的抑制剂和共刺激分子的调节剂)在由本文所涵盖的组合治疗方法的背景下也具有特别的意义并且包括但不限于其他抗-CD47抗体。向患者给予结合CD47蛋白的治疗剂,例如结合CD47并防止CD47与SIRPα之间的相互作用的抗体或小分子的给药,从而使得癌细胞经由吞噬清除。结合CD47蛋白的治疗剂与针对以下一种或多种另外的细胞靶标的治疗剂诸如本文披露的抗体、化学小分子或生物药物组合:CD70(分化簇70)、CD200(OX-2膜糖蛋白,分化簇200)、CD154(分化簇154,CD40L,CD40配体,分化簇40配体)、CD223(淋巴细胞激活基因3,LAG3,分化簇223)、KIR(杀伤细胞免疫球蛋白样受体)、GITR(TNFRSF18,糖皮质激素诱导的TNFR相关蛋白,激活诱导的TNFR家族受体,AITR,肿瘤坏死因子受体超家族成员18)、CD28(分化簇28)、CD40(分化簇40,Bp50,CDW40,TNFRSF5,肿瘤坏死因子受体超家族成员5,p50)、CD86(B7-2,分化簇86)、CD160(分化簇160,BY55,NK1,NK28)、CD258(LIGHT,分化簇258,肿瘤坏死因子配体超家族成员14,TNFSF14,HVEML,HVEM配体,疱疹病毒进入调控因子配体,LTg)、CD270(HVEM,肿瘤坏死因子受体超家族成员14,疱疹病毒进入调控因子,分化簇270,LIGHTR,HVEA)、CD275(ICOSL,ICOS配体,诱导型T细胞共刺激物配体,分化簇275)、CD276(B7-H3,B7同系物3,分化簇276)、OX40L(OX40配体)、B7-H4(B7同系物4,VTCN1,含有V-set结构域的T-细胞激活抑制剂1)、GITRL(糖皮质激素诱导的肿瘤坏死因子受体-配体,糖皮质激素诱导的TNFR-配体)、4-1BBL(4-1BB配体)、CD3(分化簇3,T3D)、CD25(IL2Rα,分化簇25,白介素-2受体α链,IL-2受体α链)、CD48(分化簇48,B-淋巴细胞激活标记,BLAST-1,信号传导淋巴细胞激活分子2,SLAMF2)、CD66a(癌胚抗原细胞粘附分子-1,癌胚抗原相关细胞粘附分子1,胆汁糖蛋白,BGP,BGP1,BGPI,分化簇66a)、CD80(B7-1,分化簇80)、CD94(分化簇94)、NKG2A(自然杀伤组2A,杀伤细胞凝集素样受体亚家族D成员1,KLRD1)、CD96(分化簇96,TActILE,T细胞激活增加的晚期表达)、CD112(PVRL2,粘连蛋白,脊髓灰质炎病毒受体相关2,疱疹病毒进入调控因子B,HVEB,粘连蛋白-2,分化簇112)、CD115(CSF1R,集落刺激因子1受体,巨噬细胞集落刺激因子受体,M-CSFR,分化簇115)、CD205(DEC-205,LY75,淋巴细胞抗原75,分化簇205)、CD226(DNAM1,分化簇226,DNAX辅助分子-1,PTA1,血小板和T细胞激活抗原1)、CD244(分化簇244,自然杀伤细胞受体2B4)、CD262(DR5,TrailR2,TRAIL-R2,肿瘤坏死因子受体超家族成员10b,TNFRSF10B,分化簇262,KILLER,TRICK2,TRICKB,ZTNFR9,TRICK2A,TRICK2B)、CD284(Toll样受体-4,TLR4,分化簇284)、CD288(Toll样受体-8,TLR8,分化簇288)、TNFSF15(肿瘤坏死因子超家族成员15,血管内皮细胞生长抑制因子,VEGI,TL1A)、TDO2(色氨酸2,3-加双氧酶,TPH2,TRPO)、IGF-1R(1型胰岛素样生长因子)、GD2(双唾液酸神经节苷脂2)、TMIGD2(跨膜和含有免疫球蛋白结构域蛋白质2)、RGMB(RGM结构域家族,成员B)、VISTA(T细胞激活的含有V-结构域免疫球蛋白抑制因子,B7-H5,B7同系物5)、BTNL2(嗜乳脂蛋白样蛋白2)、Btn(嗜乳脂蛋白家族)、TIGIT(具有Ig和ITIM T结构域的细胞免疫受体,Vstm3,WUCAM)、Siglecs(唾液酸结合Ig样凝集素)、神经营养蛋白,VEGFR(血管内皮生长因子受体)、ILT家族(LIR,免疫球蛋白样转录家族,白细胞免疫球蛋白样受体)、NKG家族(自然杀伤组家族,C型凝集素跨膜受体)、MICA(MHC I类多肽相关序列A)、TGFβ(转化生长因子β)、STING途径(干扰素基因途径的刺激因子)、精氨酸酶(精氨酸脒基酶,刀豆氨酸酶,L-精氨酸酶,精氨酸转脒酶)、EGFRvIII(表皮生长因子受体变体III)、以及HHLA2(B7-H7,B7y,HERV-H LTR-相关蛋白2,B7同系物7)、PD-1的抑制剂(程序性细胞死亡蛋白1,PD-1,CD279,分化簇279)、PD-L1(B7-H1,B7同系物1,程序性死亡-配体1,CD274,分化簇274)、PD-L2(B7-DC,程序性细胞死亡1配体2,PDCD1LG2,CD273,分化簇273)、CTLA-4(细胞毒性T淋巴细胞相关蛋白4,CD152,分化簇152)、BTLA(B淋巴细胞和T淋巴细胞衰减子,CD272,分化簇272)、吲哚胺2,3-加双氧酶(IDO,IDO1)、TIM3(HAVCR2,甲型肝炎病毒细胞受体2,T细胞免疫球蛋白粘蛋白-3,KIM-3,肾损伤分子3,TIMD-3,T细胞免疫球蛋白粘蛋白-结构域3)、A2A腺苷受体(ADO受体)、CD39(外核苷三磷酸二磷酸水解酶-1,分化簇39,ENTPD1)、以及CD73(外-5'-核苷酸酶,5’-核苷酸酶,5’-NT,分化簇73)、CD27(分化簇27)、ICOS(CD278,分化簇278,诱导性T-细胞共刺激因子)、CD137(4-1BB,分化簇137,肿瘤坏死因子受体超家族成员9,TNFRSF9)、OX40(CD134,分化簇134)、以及TNFSF25(肿瘤坏死因子受体超家族成员25),包括本文还特别涵盖的抗体、小分子和激动剂。另外的药剂包括IL-10(白介素-10,人类细胞因子合成抑制因子,CSIF)和半乳凝素。
TECENTRIQTM(阿特珠单抗,罗氏)是批准的抗-PD-L1抗体的实例。缺血再灌注损伤(IRI)相关性、自身免疫性、自身炎性、炎性、心血管病状和疾病
本文披露的CD47 mAb或其抗原结合片段的给药可以用来治疗其中IRI是贡献特征的许多疾病和病症,并且用来治疗多种自身免疫性疾病、自身炎性疾病、炎性疾病和心血管疾病。这些包括:器官移植,其中本发明的mAb或其抗原结合片段在器官获得之前给予至供体、给予至器官保存溶液中获得的供体器官、给予至受体患者、或给予至其任何组合;皮肤移植;手术切除或组织重建,其中此mAb货片段通过注射局部给予至受累组织或胃肠外给予至患者;身体部分的再附接;创伤性损伤的治疗;肺高压;肺动脉高压;镰状细胞疾病(危象);心肌梗死;脑血管疾病;中风;手术诱导的缺血;急性肾疾病/肾衰竭;任何其他病状,其中IRI发生并且促成疾病的发病机理;自身免疫性疾病和炎性疾病,包括关节炎、类风湿性关节炎、多发性硬化、牛皮癣、牛皮癣关节炎、克罗恩病、炎性肠病、溃疡性结肠炎、狼疮、系统性红斑狼疮、幼年型类风湿性关节炎、幼年型特发性关节炎、格雷夫氏病、桥本氏甲状腺炎、艾迪生病、乳糜泻、皮肌炎、多发性硬化、重症肌无力、恶性贫血、舍格伦综合征、I型糖尿病、血管炎、葡萄膜炎以及强直性脊柱炎;自身炎性疾病,包括家族性地中海热、新生儿发病多系统炎性疾病、肿瘤坏死因子(TNF)受体相关周期性综合症、白介素1受体拮抗剂缺陷、白塞病;心血管疾病,包括冠心病、冠状动脉疾病、粥样硬化、心肌梗死、心力衰竭、以及左心室心力衰竭。
本发明的抗-CD47 mAb及其抗原结合片段也可以用于在对这样的治疗有需要的受试者中增加组织灌注。可以通过指示需要增加的组织灌注的诊断程序鉴定出这样的受试者。另外,由于该受试者已经、正在、或将经历选自以下各项的手术:外皮手术、软组织手术、复合组织手术、皮肤移植手术、实质器官的切除、器官移植手术、或附器或其他身体部分的再附接,因而可能出现对于增加组织灌注的需求。
缺血再灌注损伤(IRI)相关性适应症的治疗
本披露的方法(例如涉及IRI相关性适应症的治疗的那些方法)可以进一步包括向有需要的患者给予有效量的结合CD47蛋白和一氧化氮供体、前体或二者的治疗剂;一氧化氮局部生成剂;激活可溶性鸟苷酸环化酶的药剂;抑制环核苷酸磷酸二酯酶的药剂;或任一前述的任何组合。
在这些方法中,该一氧化氮供体或前体可以选自NO气体、二硝酸异山梨酯、亚硝酸盐、硝普钠、硝酸甘油、3-吗啉代斯德酮亚胺(SIN-1)、S-亚硝基-N-乙酰青霉胺(SNAP)、二亚乙基三胺/NO(DETA/NO)、S-亚硝基硫醇、以及精氨酸。
该激活可溶性鸟苷酸环化酶的药剂可以是增加血管细胞中cGMP水平的可溶性鸟苷酸环化酶的基于非NO(一氧化氮)的化学激活剂。这样的药剂在除了NO结合基序之外的区域中结合可溶性鸟苷酸环化酶,并且激活该酶,而不论是局部NO还是活性氧应激(ROS)。可溶性鸟苷酸环化酶的化学激活剂的非限制性实例包括有机硝酸盐(Artz et al.(2002)J.Biol.Chem.277:18253-18256[Artz等人(2002)生物化学杂志277:18253-18256]);原卟啉IX(Ignarro et al.(1982)Proc.Natl.Acad.Sci.USA 79:2870-2873[Ignarro等人(1982)美国国家科学院院刊79:2870-2873]);YC-1(Ko et al.(1994)Blood 84:4226-4233[Ko等人(1994)血液84:4226-4233]);BAY 41-2272和BAY 41-8543(Stasch et al.(2001Nature 410(6825):212-5[Stasch等人(2001自然410(6825):212-5])、CMF-1571以及A-350619(在Evgenov et al.(2006)Nat.Rev.Drug.Discov.5:755-768[Evgenov等人(2006)自然评论药物发现5:755-768]);BAY58-2667(Cinaciguat;Frey et al.(2008)Journal of Clinical Pharmacology 48(12):1400-10[Cinaciguat;Frey等人(2008)临床药理学杂志48(12):1400-10]);BAY 63-2521(Riociguat;Mittendorf et al.(2009)Chemmedchem4(5):853-65[Riociguat;Mittendorf等人(2009)药物化学4(5):853-65])。另外的可溶性鸟苷酸环化酶激活剂披露于Stasch et al.(2011)Circulation123:2263-2273[Stasch等人(2011)循环123:2263-2273];Derbyshire and Marletta(2012)Ann.Rev.Biochem.81:533-559[Derbyshire和Marletta(2012)生物化学年评81:533-559],以及Nossaman et al.(2012)Critical Care Research and Practice,Volume 2012,Article ID 290805,pages 1-12[Nossaman等人(2012)急救护理研究与实践,第2012卷,文章ID 290805,第1-12页]。
该抑制环核苷酸磷酸二酯酶的药剂可以选自他达拉非、伐地那非、乌地那非、西地那非、以及阿伐那非。
自身免疫性疾病、自身炎性疾病、炎性疾病和心血管疾病的治疗
结合CD47蛋白的用于治疗自身免疫性疾病、自身炎性疾病、炎性疾病和/或心血管疾病的治疗剂可以与一种或多种治疗剂诸如抗体、化学小分子、或生物剂、或医学或手术程序组合,该一种或多种治疗剂包括但不限于以下各项。对于自身免疫性疾病、自身炎性疾病和炎性疾病的治疗,组合的治疗剂是羟化氯喹、来氟米特、甲氨蝶呤、二甲胺四环素、柳氮磺胺吡啶、阿贝西普、利妥昔单抗、托珠单抗、抗-TNF抑制剂或阻断剂(阿达木单抗、依那西普、英夫利昔单抗、塞妥珠单抗、戈利木单抗)、非甾体抗炎药、糖皮质激素类、皮质类固醇、静脉内免疫球蛋白、阿那白滞素、康纳单抗、利纳西普、环磷酰胺、吗替麦考酚酯、咪唑硫嘌呤、6-巯嘌呤、贝利单抗、β干扰素、醋酸格拉替雷、富马酸二甲酯、芬戈莫德、特立氟胺、那他珠单抗、5-氨基水杨酸、氨水杨酸、环孢霉素、他克莫司、吡美莫司、维多珠单抗(vedolizumab)、优特克单抗、苏金单抗、ixekizumab、阿普斯特、布地缩松以及托法替尼。对于动脉粥样硬化的治疗,组合的治疗剂或程序是:医学程序和/或手术,包括经皮冠状动脉介入治疗(冠状动脉血管成形和支架放置)、冠状动脉旁路移植术、以及颈动脉内膜切除手术;治疗剂,包括血管紧张素转化酶(ACE)抑制剂(包括雷米普利、喹那普利、卡托普利、以及依那普利)、钙通道阻断剂(包括氨氯地平、硝苯地平、维拉帕米、非洛地平以及地尔硫卓)、血管紧张素受体阻断剂(包括依普沙坦(eposartan)、奥美沙坦(olmesarten)、阿齐沙坦、缬沙坦、替米沙坦、氯沙坦、坎地沙坦、以及厄贝沙坦)、依泽替米贝和辛伐他汀的组合、PCSK9抑制剂(包括阿立单抗和依伏库单抗)、安塞曲匹、以及HMG-CoA抑制剂(包括阿托伐他汀、普伐他汀、辛伐他汀、罗伐他汀、匹伐他汀、洛伐他丁以及氟伐他汀)。对于心力衰竭的治疗,组合的治疗剂是:ACE抑制剂、血管紧张素受体阻断剂、血管紧张素受体萘普生抑制剂(包括沙库比曲(sacubitril)和缬沙坦的组合)、利尿剂、地高辛、肌力剂(inotrope)、β阻断剂以及醛固酮拮抗剂。对于肺高压的治疗,组合物的治疗剂是:西地那非、他达拉非、安贝生坦、波生坦、马西替坦、利奥西呱、曲罗尼尔、依前列醇、伊洛前列素、以及赛乐西帕(selexipag)。
如本文所披露的,抗-CD47 mAb在组合的治疗剂或医学或手术程序之前、同时或之后给予。
用于本文所涵盖的组合疗法的另一类有用的化合物类别包括SIRPα/CD47结合的调节剂,诸如SIRPα的抗体,以及此配体或其CD47的可溶性蛋白质片段,其抑制SIRPα与CD47的结合或干扰该结合。应当指出的是,本文涵盖的治疗方法包括使用本文披露的单独抗体、彼此的组合、和/或还与其抗原结合片段的组合,例如这些抗体化合物的所有可能组合的用途。
这些实例展示了本披露的不同实施例,但是不应当被视为将本披露仅限制为这些具体披露的实施例。
用于CD47表达的诊断学
诊断(包括互补和陪伴)已为肿瘤学领域的关键性区域。已开发用于靶向治疗的许多诊断测定,诸如贺癌平(基因泰克公司(Genentech))、特罗凯(OSI医药公司(OSIPharmaceuticals)/基因泰克公司)、易瑞沙(阿斯利康公司(Astra Zeneca))、以及爱必妥(英克隆公司(Imclone)/百时美施贵宝(Bristol Myers Squibb))。本披露的抗-CD47 mAb抗体特别适合用于诊断应用中。因此,本披露提供一种使用本披露的抗-CD47 mAb测量肿瘤和/或免疫细胞中的CD47表达的方法。
本披露的抗-CD47 mAb可以用于诊断测定中和/或测量存在于患者肿瘤样品中的肿瘤和/或免疫细胞中的CD47的体外方法中。具体而言,与参考水平相比,本披露的抗-CD47mAb可以结合存在于患者样品中的大约1%或更多肿瘤和/或免疫细胞上的CD47。在另一个实施例中,与参考水平相比,抗-CD47 mAb可以例如结合存有患者样品中的大约5%或更多肿瘤和/或免疫系统,或者与参考水平相比结合至少10%、或至少20%、或至少30%、或至少约40%、或至少约50%、或至少约60%、或至少约70%、或至少约80%、或至少约90%、或10%-100%之间。在另一个实施例中,抗-CD47 mAb可以结合患者样品中的肿瘤和/或免疫细胞,与参考水平相比增加至少约2倍、或至少约3倍、或至少约4倍、或至少约5倍或增加至少约10倍、或2倍与10倍之间或更大。如本文所述,患者样品中CD47表达的测量提供能够决定潜在药物疗法的开发和使用的生物和/或临床信息,值得注意的是使用抗-CD47抗体用于治疗实体癌和血液癌、自身免疫性疾病、炎性疾病、动脉粥样硬化、心力衰竭,其中CD47受体起作用。
在一个实施例中,体外方法包括获得患者样品、使患者样品与特异性结合序列SEQID NO:65内的表位的单克隆抗体或其抗原结合片段接触、以及测定抗体与患者样品的结合,其中抗体与患者样品的结合用于诊断患者样品中的CD47表达。
在另一个实施例中,对于体外方法,优选的CD47抗体或其抗原结合片段是包含重链(HC)和轻链(LC)的组合的那些,该组合列出为以下组合:
(i)包含氨基酸序列SEQ ID NO:103的重链和包含氨基酸序列SEQ ID NO:102的轻链;
(ii)包含氨基酸序列SEQ ID NO:105的重链和包含氨基酸序列SEQ ID NO:104的轻链;
其中该VH氨基酸序列与其具有至少90%、95%、97%、98%或99%一致性并且该VL氨基酸序列与其具有至少90%、95%、97%、98%或99%一致性。
因此,根据本披露的诊断测定可包括使患者样品中的肿瘤和/或免疫细胞与抗-CD47 mAb或其抗原结合片段接触并测定抗-CD47 mAb与患者肿瘤样品的结合,其中抗-CD47mAb与患者样品的结合用于诊断CD47表达。优选地,患者样品是含有肿瘤细胞的样品。在此情况下,对于CD47表达,可以评估本披露的抗-CD47 mAb或其抗原结合片段与肿瘤细胞的结合。患者肿瘤样品的肿瘤细胞和/或免疫细胞的CD47表达水平可以预测患者中的临床结果。
抗-CD47 mAb与患者样品中的细胞的结合增加与CD47表达增加相关。在一个实施例中,本披露的抗-CD47 mAb可以结合患者样品中大约5%或更多的肿瘤细胞并且这可以指示患者将受益于对实体癌和血液癌的快速干预。此类型的诊断测定可以用于测定具有相对高的本披露的抗-CD47mAb的结合(即增加的CD47表达)的实体癌和血液癌的适合治疗方案。
将了解的是,本文披露的诊断测定具有许多优点。这些优点中最重要的是本披露的诊断测定可以允许使用者在肿瘤和/或免疫细胞中的CD47表达中具有更大量的置信度。本披露的诊断测定的增加的敏感性允许检测患者样品中比先前的情况更低的水平的CD47。
本披露的抗-CD47 mAb可以用作与许多形式的癌症相关的诊断测定。可以针对CD47表达有利地研究的具体癌症形式包括易感性血液癌和实体癌,包括但不限于白血病、淋巴瘤和实体肿瘤。
本披露的诊断测定可以利用用于检测抗-CD47 mAb的结合以测量CD47表达的任何适合的手段。适合的方法可以参考用于标记本披露的抗-CD47 mAb的任何报道部分的性质来选择。适合的技术包括但不以任何方式局限于流式细胞术和酶联免疫吸附测定(ELISA)以及利用纳米颗粒的测定。特别优选的是,本发明的诊断测定可以是涉及免疫组织化学的测定,其中肿瘤样品暴露于本披露的抗-CD47 mAb,并且通过免疫组织化学评估细胞标记水平。
实例
实例1
氨基酸序列
轻链CDR
重链CDR
鼠类轻链可变结构域
>Vx4murL01
DVLMTQTPLSLPVNLGDQASISCRSRQSIVHTNGNTYLGWFLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISRVEAEDLGVYYCFQGSHVPYTFGGGTKLEIK(SEQ ID NO:41)。
>Vx4murL02
DVLMTQTPLSLPVNLGDQASISCRSRQSIVHTNGNTYLGWFLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISRVEAEDLGVYYCFQGSHVPYTFGQGTKVEIK(SEQ ID NO:42)。
>Vx8murL03
DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSRLYSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFGGGTKLEIK(SEQ ID NO:46)。
>Vx9murL04
DVFMTQTPLSLPVSLGDQASISCRSSQNIVQSNGNTYLEWYLQKPGQSPKLLIYKVFHRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPWTFGGGTKVEIK(SEQ ID NO:50)
鼠类重链可变结构域
>Vx4murH01
EVQLQQSGPELVKPGASVKMSCKASGYTFTNYVIHWVKRRPGQGLEWIGYIYPYNDGILYNEKFKGKATVTSDKSSSTAYMDLSSLTSEDSAVYYCTRGGYYVPDYWGQGTTLTVSS(SEQ ID NO:21)。
>Vx4mur-H02
EVQLQQSGPELVKPGASVKMSCKASGYTFTNYVIHWVKRRPGQGLEWIGYIYPYNDGILYNEKFKGKATVTSDKSSSTAYMDLSSLTSEDSAVYYCTRGGYYVPDYWGQGTLVTVSS(SEQ ID NO:22)。
>Vx8murH03
EVQLQQSGPELMKPGASVKISCKASGYSFTNYYIHWVNQSHGKSLEWIGYIDPLNGDTTYNQKFKGKATLTVDKSSSTAYMRLSSLTSADSAVYYCARGGKRAMDYWGQGTSVTVSS(SEQ ID NO:28)。
>Vx9murH04
QVQLQQFGAELAKPGASVQMSCKASGYTFTNYWIHWVKQRPGQGLEWIGYTDPRTDYTEYNQKFKDKATLAADRSSSTAYMRLSSLTSEDSAVYYCAGGGRVGLGYWGHGSSVTVSS(SEQ ID NO:35)
人类轻链可变结构域
>Vx4humL01
DIVMTQSPLSLPVTPGEPASISCRSRQSIVHTNGNTYLGWYLQKPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEADDVGIYYCFQGSHVPYTFGQGTKLEIK(SEQ ID NO:43)
>Vx4humL02
DVVMTQSPLSLPVTLGQPASISCRSRQSIVHTNGNTYLGWFQQRPGQSPRRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGTKLEIK(SEQ ID NO:44)
>Vx4humL03
DIVMTQSPDSLAVSLGERATINCRSRQSIVHTNGNTYLGWYQQKPGQPPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCFQGSHVPYTFGQGTKLEIK(SEQ ID NO:45)
>Vx8humL04
DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLYSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPWTFGQGTKVEIK(SEQ ID NO:47)。
>Vx8humL05
DIQMTQSPSSLSASVGDRVTITCRASQSISNYLNWYQQKPGKAPKLLIYYTSRLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK(SEQ ID NO:48)。
>Vx8humL06
DIVMTQSPLSLPVTPGEPASISCRASQDISNYLNWYLQKPGQSPRLLIYYTSRLYSGVPDRFSGSGSGTDFTLKISRVEADDVGIYYCQQGNTLPWTFGQGTKLEIK(SEQ ID NO:49)
>Vx9humL07
DVVMTQSPLSLPVTLGQPASISCRSSQNIVQSNGNTYLEWFQQRPGQSPRRLIYKVFHRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGTKLEIK(SEQ ID NO:51)。
>Vx9humL08
DIVMTQSPDSLAVSLGERATINCRSSQNIVQSNGNTYLEWYQQKPGQPPKLLIYKVFHRFSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCFQGSHVPYTFGQGTKLEIK(SEQ ID NO:52)。
人类重链可变结构域
>Vx4humH01
QVQLVQSGAEVKKPGASVQVSCKASGYTFTNYVIHWLRQAPGQGLEWMGYIYPYNDGILYNEKFKGRVTMTSDTSISTAYMELSSLRSDDTAVYYCARGGYYVPDYWGQATLVTVSS(SEQ ID NO:23)。
>Vx4humH02
QVQLVQSGAEVKKPGASVQVSCKASGYTFTNYVIHWLRQAPGQGLEWMGYIYPYNDGILYNEKFKGRVTMTSDTSISTAYMELSSLRSDDTAVYYCARGGYYVYDYWGQATLVTVSS(SEQ ID NO:24)。
>Vx4humH03
EVQLVQSGAEVKKPGATVKISCKVSGYTFTNYVIHWVQQAPGKGLEWMGYIYPYNDGILYNEKFKGRVTITADTSTDTAYMELSSLRSEDTAVYYCATGGYYVPDYWGQGTTVTVSS(SEQ ID NO:25)
>Vx4humH04
EVQLVQSGAEVKKPGESLKISCKGSGYTFTNYVIHWVRQMPGKGLEWMGYIYPYNDGILYNEKFKGQVTISADKSISTAYLQWSSLKASDTAMYYCARGGYYVPDYWGQGTTVTVSS(SEQ ID NO:26)
>Vx4humH05
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYVIHWVRQAPGQGLEWMGYIYPYNDGILYNEKFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARGGYYVPDYWGQGTTVTVSS(SEQ ID NO:27)
>Vx8humH06
QVQLVQSGAEVKKPGASVKVSCKASGYSFTNYYIHWVRQAPGQGLEWMGYIDPLNGDTTYNQKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGKRAMDYWGQGTLVTVSS(SEQ ID NO:29)。
>Vx8humH07
QVQLVQSGAEVKKPGSSVKVSCKASGYSFTNYYIHWVRQAPGQGLEWMGYIDPLNGDTTYNQKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGKRAMDYWGQGTLVTVSS(SEQ ID NO:30)。
>Vx8humH08
EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYYIHWVRQMPGKGLEWMGYIDPLNGDTTYNQKFKGQVTISADKSISTAYLQWSSLKASDTAMYYCARGGKRAMDYWGQGTLVTVSS(SEQ ID NO:31)。
>Vx8humH09
QVQLVQSGAEVKKPGSSVKVSCKASGYSFTNYYIHWVRQAPGQGLEWMGYIDPLNGDTTYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGKRAMDYWGQGTLVTVSS(SEQ ID NO:32)。
>Vx8humH10
EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYYIHWVRQMPGKGLEWMGYIDPLNGDTTYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGGKRAMDYWGRGTLVTVSS(SEQ ID NO:33)。
>Vx8humH11
QVQLVQSGAEVKKPGASVQVSCKASGYSFTNYYIHWLRQAPGQGLEWMGYIDPLNGDTTYNQKFKGRVTMTSDTSISTAYMELSSLRSDDTAVYYCARGGKRAMDYWGQATLVTVSS(SEQ ID NO:34)
>Vx9humH12
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIHWVRQAPGQGLEWMGYTDPRTDYTEYNQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGRVGLGYWGQGTLVTVSS(SEQ ID NO:36)。
>Vx9humH13
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYWIHWVRQAPGQGLEWMGYTDPRTDYTEYNQKFKDRVTITADESTSTAYMELSSLRSEDTAVYYCARGGRVGLGYWGQGTLVTVSS(SEQ ID NO:37)。
>Vx9humH14
EVQLVQSGAEVKKPGESLKISCKGSGYTFTNYWIHWVRQMPGKGLEWMGYTDPRTDYTEYNQKFKDQVTISADKSISTAYLQWSSLKASDTAMYYCARGGRVGLGYWGQGTLVTVSS(SEQ ID NO:38)。
>Vx9humH15
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYWIHWVRQAPGQGLEWMGYTDPRTDYTEYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGRVGLGYWGQGTLVTVSS(SEQ ID NO:39)。
>Vx9humH16
EVQLVQSGAEVKKPGESLKISCKGSGYTFTNYWIHWVRQMPGKGLEWMGYTDPRTDYTEYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGGRVGLGYWGQGTLVTVSS(SEQ ID NO:40)。
人类IgG-Fc
>人类Fc IgG1
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:53)。
>人类Fc IgG1-N297Q
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:54)。
>人类Fc-IgG2
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:55)。
>人类Fc-IgG3
ASTKGPSVFPLAPCSRSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYTCNVNHKPSNTKVDKRVELKTPLGDTTHTCPRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGK(SEQ ID NO:56)
>人类Fc-IgG4
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG(SEQ ID NO:57)。
>人类Fc-IgG4 S228P
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG(SEQ ID NO:58)。
>人类Fc-IgG4 PE
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:59)
>人类Fc-IgG4 PE’
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG(SEQ ID NO:99)
>人类κLC
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:60)。
>大鼠Fc-IgG2c
ARTTAPSVYPLVPGCSGTSGSLVTLGCLVKGYFPEPVTVKWNSGALSSGVHTFPAVLQSGLYTLSSSVTVPSSTWSSQTVTCSVAHPATKSNLIKRIEPRRPKPRPPTDICSCDDNLGRPSVFIFPPKPKDILMITLTPKVTCVVVDVSEEEPDVQFSWFVDNVRVFTAQTQPHEEQLNGTFRVVSTLHIQHQDWMSGKEFKCKVNNKDLPSPIEKTISKPRGKARTPQVYTIPPPREQMSKNKVSLTCMVTSFYPASISVEWERNGELEQDYKNTLPVLDSDESYFLYSKLSVDTDSWMRGDIYTCSVVHEALHNHHTQKNLSRSPGK(SEQ ID NO:61)。
>大鼠κLC
RADAAPTVSIFPPSMEQLTSGGATVVCFVNNFYPRDISVKWKIDGSEQRDGVLDSVTDQDSKDSTYSMSSTLSLTKVEYERHNLYTCEVVHKTSSSPVVKSFNRNEC(SEQ ID NO:62)。
兔IgG-Fc
>图IgG
GQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK(SEQ ID NO:63)。
>兔κLC
RDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC(SEQ ID NO:64)。
>CD47
MWPLVAALLLGSACCGSAQLLFNKTKSVEFTFCNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFDGALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELTREGETIIELKYRVVSWFSPNENILIVIFPIFAILLFWGQFGIKTLKYRSGGMDEKTIALLVAGLVITVIVIVGAILFVPGEYSLKNATGLGLIVTSTGILILLHYYVFSTAIGLTSFVIAILVIQVIAYILAVVGLSLCIAACIPMHGPLLISGLSILALAQLLGLVYMKFVE(SEQID NO:65)。
嵌合和人类轻链
>Vx4murL01全长
DVLMTQTPLSLPVNLGDQASISCRSRQSIVHTNGNTYLGWFLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISRVEAEDLGVYYCFQGSHVPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:66)。
>Vx4murL01全长
DVLMTQTPLSLPVNLGDQASISCRSRQSIVHTNGNTYLGWFLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISRVEAEDLGVYYCFQGSHVPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:67)。
>Vx4humL01全长LC
DIVMTQSPLSLPVTPGEPASISCRSRQSIVHTNGNTYLGWYLQKPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEADDVGIYYCFQGSHVPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:68)。
>Vx8humL03全长LC
DIVMTQSPLSLPVTPGEPASISCRASQDISNYLNWYLQKPGQSPRLLIYYTSRLYSGVPDRFSGSGSGTDFTLKISRVEADDVGIYYCQQGNTLPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:69)。
>Vx9humL02全长LC
DIVMTQSPDSLAVSLGERATINCRSSQNIVQSNGNTYLEWYQQKPGQPPKLLIYKVFHRFSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCFQGSHVPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:70)。
>Vx8humL02全长LC
DIQMTQSPSSLSASVGDRVTITCRASQSISNYLNWYQQKPGKAPKLLIYYTSRLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:71)。
>Vx4humL02全长LC
DVVMTQSPLSLPVTLGQPASISCRSRQSIVHTNGNTYLGWFQQRPGQSPRRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:72)。
>Vx9humL07全长LC
DVVMTQSPLSLPVTLGQPASISCRSSQNIVQSNGNTYLEWFQQRPGQSPRRLIYKVFHRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:73)。
>Vx8humL01全长LC
DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKLLIYYTSRLYSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:74)。
>Vx8murL03全长LC
DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSRLYSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:100)。
>Vx9mur_L04全长LC
DVFMTQTPLSLPVSLGDQASISCRSSQNIVQSNGNTYLEWYLQKPGQSPKLLIYKVFHRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:75)。
嵌合和人类重链
>Vx4murH01全长HC
EVQLQQSGPELVKPGASVKMSCKASGYTFTNYVIHWVKRRPGQGLEWIGYIYPYNDGILYNEKFKGKATVTSDKSSSTAYMDLSSLTSEDSAVYYCTRGGYYVPDYWGQGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:76)。
>Vx4humH01全长HC
QVQLVQSGAEVKKPGASVQVSCKASGYTFTNYVIHWLRQAPGQGLEWMGYIYPYNDGILYNEKFKGRVTMTSDTSISTAYMELSSLRSDDTAVYYCARGGYYVPDYWGQATLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:77)。
>Vx8humH11全长HC
QVQLVQSGAEVKKPGASVQVSCKASGYSFTNYYIHWLRQAPGQGLEWMGYIDPLNGDTTYNQKFKGRVTMTSDTSISTAYMELSSLRSDDTAVYYCARGGKRAMDYWGQATLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:78)。
>Vx9humH12全长HC
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYWIHWVRQAPGQGLEWMGYTDPRTDYTEYNQKFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGRVGLGYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQID NO:79)。
>Vx9humH14全长HC
EVQLVQSGAEVKKPGESLKISCKGSGYTFTNYWIHWVRQMPGKGLEWMGYTDPRTDYTEYNQKFKDQVTISADKSISTAYLQWSSLKASDTAMYYCARGGRVGLGYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQID NO:80)。
>Vx9humH15全长HC
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYWIHWVRQAPGQGLEWMGYTDPRTDYTEYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGRVGLGYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQID NO:81)。
>Vx4humH02全长HC
QVQLVQSGAEVKKPGASVQVSCKASGYTFTNYVIHWLRQAPGQGLEWMGYIYPYNDGILYNEKFKGRVTMTSDTSISTAYMELSSLRSDDTAVYYCARGGYYVYDYWGQATLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:82)。
>Vx9humH13全长HC
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYWIHWVRQAPGQGLEWMGYTDPRTDYTEYNQKFKDRVTITADESTSTAYMELSSLRSEDTAVYYCARGGRVGLGYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQID NO:83)。
>Vx8humH10全长HC
EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYYIHWVRQMPGKGLEWMGYIDPLNGDTTYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGGKRAMDYWGRGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:84)。
>Vx4humH04全长HC
EVQLVQSGAEVKKPGESLKISCKGSGYTFTNYVIHWVRQMPGKGLEWMGYIYPYNDGILYNEKFKGQVTISADKSISTAYLQWSSLKASDTAMYYCARGGYYVPDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:85)。
>Vx4humH05全长HC
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYVIHWVRQAPGQGLEWMGYIYPYNDGILYNEKFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARGGYYVPDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:86)。
>Vx9humH16全长HC
EVQLVQSGAEVKKPGESLKISCKGSGYTFTNYWIHWVRQMPGKGLEWMGYTDPRTDYTEYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGGRVGLGYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQID NO:87)。
>Vx8humH06全长HC
QVQLVQSGAEVKKPGASVKVSCKASGYSFTNYYIHWVRQAPGQGLEWMGYIDPLNGDTTYNQKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGKRAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:88)。
>Vx8humH07全长HC
QVQLVQSGAEVKKPGSSVKVSCKASGYSFTNYYIHWVRQAPGQGLEWMGYIDPLNGDTTYNQKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGKRAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:89)。
>Vx8humH08全长HC
EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYYIHWVRQMPGKGLEWMGYIDPLNGDTTYNQKFKGQVTISADKSISTAYLQWSSLKASDTAMYYCARGGKRAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:90)。
>Vx8humH09全长HC
QVQLVQSGAEVKKPGSSVKVSCKASGYSFTNYYIHWVRQAPGQGLEWMGYIDPLNGDTTYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGKRAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:91)。
>Vx8humH06全长HC
QVQLVQSGAEVKKPGASVKVSCKASGYSFTNYYIHWVRQAPGQGLEWMGYIDPLNGDTTYNQKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGKRAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:92)。
>Vx8mur-H03全长HC
EVQLQQSGPELMKPGASVKISCKASGYSFTNYYIHWVNQSHGKSLEWIGYIDPLNGDTTYNQKFKGKATLTVDKSSSTAYMRLSSLTSADSAVYYCARGGKRAMDYWGQGTSVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:93)。
>Vx9mur-H04全长HC
QVQLQQFGAELAKPGASVQMSCKASGYTFTNYWIHWVKQRPGQGLEWIGYTDPRTDYTEYNQKFKDKATLAADRSSSTAYMRLSSLTSEDSAVYYCAGGGRVGLGYWGHGSSVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQID NO:94)。
>Vx8humH06全长HC
QVQLVQSGAEVKKPGASVKVSCKASGYSFTNYYIHWVRQAPGQGLEWMGYIDPLNGDTTYNQKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGKRAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQID NO:95)。
>Vx8humH07全长HC
QVQLVQSGAEVKKPGSSVKVSCKASGYSFTNYYIHWVRQAPGQGLEWMGYIDPLNGDTTYNQKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGKRAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQID NO:96)。
>Vx8humH08全长HC
EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYYIHWVRQMPGKGLEWMGYIDPLNGDTTYNQKFKGQVTISADKSISTAYLQWSSLKASDTAMYYCARGGKRAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQID NO:97)。
>Vx8humH09全长HC
QVQLVQSGAEVKKPGSSVKVSCKASGYSFTNYYIHWVRQAPGQGLEWMGYIDPLNGDTTYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGKRAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQID NO:98)。
>Vx4mur-ratL01全长LC
DVLMTQTPLSLPVNLGDQASISCRSRQSIVHTNGNTYLGWFLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISRVEAEDLGVYYCFQGSHVPYTFGGGTKLEIKRADAAPTVSIFPPSMEQLTSGGATVVCFVNNFYPRDISVKWKIDGSEQRDGVLDSVTDQDSKDSTYSMSSTLSLTKVEYERHNLYTCEVVHKTSSSPVVKSFNRNEC(SEQ ID NO:101)。
>Vx4mur-ratH01全长HC
EVQLQQSGPELVKPGASVKMSCKASGYTFTNYVIHWVKRRPGQGLEWIGYIYPYNDGILYNEKFKGKATVTSDKSSSTAYMDLSSLTSEDSAVYYCTRGGYYVPDYWGQGTTLTVSSARTTAPSVYPLVPGCSGTSGSLVTLGCLVKGYFPEPVTVKWNSGALSSGVHTFPAVLQSGLYTLSSSVTVPSSTWSSQTVTCSVAHPATKSNLIKRIEPRRPKPRPPTDICSCDDNLGRPSVFIFPPKPKDILMITLTPKVTCVVVDVSEEEPDVQFSWFVDNVRVFTAQTQPHEEQLNGTFRVVSTLHIQHQDWMSGKEFKCKVNNKDLPSPIEKTISKPRGKARTPQVYTIPPPREQMSKNKVSLTCMVTSFYPASISVEWERNGELEQDYKNTLPVLDSDESYFLYSKLSVDTDSWMRGDIYTCSVVHEALHNHHTQKNLSRSPGK(SEQ ID NO:102)。
>Vx4mur-rabL01全长LC
DVLMTQTPLSLPVNLGDQASISCRSRQSIVHTNGNTYLGWFLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISRVEAEDLGVYYCFQGSHVPYTFGGGTKLEIKRDPVAPTVLIFPPAADQVATGTVTIVCVANKYFPDVTVTWEVDGTTQTTGIENSKTPQNSADCTYNLSSTLTLTSTQYNSHKEYTCKVTQGTTSVVQSFNRGDC(SEQID NO:103)。
>Vx4mur-rabH01全长HC
EVQLQQSGPELVKPGASVKMSCKASGYTFTNYVIHWVKRRPGQGLEWIGYIYPYNDGILYNEKFKGKATVTSDKSSSTAYMDLSSLTSEDSAVYYCTRGGYYVPDYWGQGTTLTVSSGQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSQDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHQDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK(SEQ IDNO:104)。
实例2
CD47抗体的生产
本文披露的嵌合抗体包含分别与人类κ或人类Fc IgG1、IgG1-N297Q、IgG2、IgG4、IgG4 S228P、以及IgG4 PE恒定结构域组合的小鼠重链可变结构域和轻链可变结构域。这些被设计来结合分泌信号并将其克隆到哺乳动物表达系统中,并转移到CHO细胞中以生成嵌合(鼠类-人类)抗体。将嵌合变体表达为全长IgG分子、分泌到培养基中并使用蛋白质A纯化。
这样,本文披露的这些人源化抗体包含来源于人类基因组的框架。该系列涵盖发现于人类种系序列中的多样性,从而在体内产生功能性表达的抗体。本文描述了鼠类和嵌合(鼠类-人类)的轻链和重链可变区的互补决定区(CDR)并且通过遵循以下披露的普遍接受的规则来确定:“Protein Sequence and Structure Analysis of Antibody VariableDomains[抗体可变结构域的蛋白质序列和结构分析]”,于以下中:Antibody EngineeringLab Manual,eds.S.Duebel and R.Kontermann,Springer-Verlag,Heidelberg(2001)[抗体工程化实验室手册,S.Duebel和R.Kontermann编辑,施普林格公司,海德尔堡(2001)])。然后设计人类轻链可变结构域。然后将人源化可变结构域与分泌信号和人类κ以及人类FcIgG1、IgG1-N297Q、IgG2、IgG3、IgG4 S228P以及IgG4 PE恒定结构域组合,将其克隆到哺乳动物表达系统中,并且转移到CHO细胞中以生成人源化mAb。将人源化变体表达为全长IgG分子、分泌到培养基中并使用蛋白质A纯化。
通过对重链位置297进行定点诱变以将天冬酰胺改变成谷氨酰胺(人类Fc IgG1-N297Q,SEQ ID NO:54)来创建非糖基化形式(IgG1-N297Q)。通过在位置228处进行定点诱变以将丝氨酸改变成脯氨酸从而防止体外Fab臂交换来创建IgG4变体。通过在位置228(丝氨酸至脯氨酸)和235(亮氨酸至谷氨酸)处进行定点诱变以防止Fab臂交换并进一步减小Fc效应子功能来创建IgG4双突变体。通过将重链可变结构域克隆在具有人类IgG2、IgG3、IgG4S228P和IgG4PE恒定结构域的框架(人类Fc-IgG2,SEQ ID NO:55;人类Fc-IgG3,SEQ ID NO:56;人类Fc-IgG4 S228P,SEQ ID NO:58;以及人类Fc-IgG4 PE,SEQ ID NO:59)内来构建恒定结构域IgG2、IgG3、IgG4 S228P以及IgG4 PE。
实例3
CD47单克隆抗体(mAb)的结合
本披露的嵌合(鼠类-人类)和人源化抗体的结合通过使用用人类CD47(OV10hCD47)转染的OV10细胞或者使用新鲜分离的人类红血细胞(hRBC)进行ELISA来测定,这些细胞在其表面上展示CD47(Kamel et al.(2010)Blood.Transfus.8(4):260-266[Kamel等人(2010)输血8(4):260-266])。
使用利用表达细胞表面人类CD47的人类OV10 hCD47细胞的基于细胞的ELISA测定来确定VLX4、VLX8和VLX9嵌合(鼠类-人类)和人源化mAb的结合活性。使OV10 hCD47细胞在含有10%热灭活胎牛血清(BioWest;S01520)的IMDM培养基中生长。在测定前一天,将3×104个细胞接种在96孔细胞结合板(科宁公司(Corning)#3300,VWR#66025-626)中并且在测定时是95%-100%汇合的。将细胞洗涤并将不同浓度的纯化的抗体添加到IMDM中,在37℃下在95%O2/5%CO2中持续1小时。然后用培养基洗涤细胞并且在37℃下用以培养基稀释1/2500的HRP标记的第二抗人类抗体(普洛麦格公司(Promega))孵育另外一小时。将细胞用PBS洗涤三次,并且添加过氧化物酶底物3,3',5,5'-四甲基联苯胺(西格玛公司目录号T4444)。通过添加HCl至0.7N终止反应,使用帝肯(Tecan)型Infinite M200酶标仪在450nM测定吸光度。通过非线性拟合(Prism GraphPad软件)测定这些克隆与人类OV10 hCD47细胞的表观结合亲和力。
还使用流式细胞术测定嵌合(鼠类-人类)和人源化VLX4、VLX8和VLX9 mAb与hRBC上的人类CD47的结合亲和力。将hRBC在37℃下使用磷酸盐缓冲盐水pH 7.2、2.5mM EDTA(PBS+E)溶液中不同浓度的嵌合或人源化抗体孵育60分钟。然后用冷PBS+E洗涤细胞,并且与在PBS+E中的FITC标记的驴抗人抗体(杰克逊免疫研究实验室(Jackson ImmunoResearch Labs),西格罗夫(West Grove),宾夕法尼亚州;目录号709-096-149)一起在冰上再孵育一个小时。用PBS+E洗涤细胞,使用C6Accuri流式细胞仪(碧迪公司(BectonDickinson))分析抗体结合并且通过在不同抗体浓度下对中等荧光强度的非线性拟合(Prism GraphPad软件)来测定表观结合亲和力。
所有VLX4嵌合(鼠类-人类)mAb以皮摩尔(pM)范围内的表观亲和力结合至人类OV10 hCD47肿瘤细胞(表1)。
类似地,人源化VLX4 mAb以浓度依赖性方式(图1A和1B)以皮摩尔至低纳摩尔范围内的表观亲和力结合人类OV10 hCD47肿瘤细胞(表2)。
所有嵌合VLX4 mAb以皮摩尔范围的表观Kd值结合人类RBC并且这些值类似于通过ELISA对于OV10 hCD47肿瘤细胞获得的Kd值(表1)。
人源化VLX4 mAb VLX4hum_01 IgG1 N297Q、VLX4hum_02 IgG1N297Q、VLX4hum_01IgG4 PE、VLX4hum_02 IgG4 PE、VLX4hum_12 IgG4PE、以及VLX4hum_13 IgG4以类似于对于OV10 hCD47肿瘤细胞所获得的值的Kd值结合人类RBC,而VLX4hum_06 IgG4 PE和VLX4hum_07 IgG4 PE表现出减少的与hRBC的结合(图2A、图2B和表2)。当VLX4IgG4PE嵌合mAb以类似表观Kd值结合肿瘤和RBC CD47时,人源化mAb与肿瘤细胞和RBC的差别结合是出乎意料的(表1)。
如表1所示,所有VLX8嵌合(鼠类-人类)mAb以浓度依赖性方式以皮摩尔(pM)范围内的表观亲和力结合至人类OV10 hCD47肿瘤细胞。
类似地,人源化VLX8 mAb以浓度依赖性方式(图3A和3B)以皮摩尔范围内的表观亲和力结合人类OV10 hCD47肿瘤细胞(表2)。
所有VLX8嵌合mAb以皮摩尔范围的表观Kd值结合人类hRBC并且这些值类似于通过ELISA对于OV10 hCD47肿瘤细胞获得的Kd值(表1)。
VLX8人源化mAb VLX8hum_01 IgG4 PE、VLX8hum_02 IgG4 PE、VLX8hum_03 IgG4PE、VLX8hum_04 IgG4 PE、VLX8hum_05 IgG4 PE、and VLX8hum_06 IgG4 PE、VLX8hum_07IgG4 PE、VLX8hum_08 IgG4 PE、VLX8hum_09 IgG4 PE、VLX8hum_11 IgG4 PE、VLX8hum_06IgG2、VLX8hum_07 IgG2、VLX8hum_08以及VLX8hum_09 IgG2 IgG2以类似于对于OV10 hCD47肿瘤细胞获得的值的Kd值结合人类RBC,而VLX8hum_10 IgG4 PE表现出减小的但可测量的与hRBC的结合(图4A、图4B和表2)。出乎意料的是人源化mAb与肿瘤细胞和RBC的差别结合为VLX8 IgG4PE嵌合mAb以类似表观Kd值结合肿瘤和RBC CD47(表1)。
表1示出VLX9鼠类-人类嵌合mAb与人类OV10 hCD47细胞和与人类RBC的表观结合亲和力。所有嵌合mAb均以皮摩尔范围内的表观Kd值结合OV10 hCD47肿瘤细胞。类似地,人源化VLX9 mAb以浓度依赖性方式(图5A和5B)以皮摩尔至纳摩尔范围内的表观亲和力结合人类OV10hCD47肿瘤细胞(表2)。
所有VLX9嵌合mAb以皮摩尔范围的表观Kd值结合人类hRBC并且这些值类似于通过ELISA对于OV10 hCD47肿瘤细胞获得的Kd值(表1)。与嵌合mAb相比,VLX9人源化mAbVLX9hum_01 IgG2、VLX9hum_02 IgG2和VLX9hum_07 IgG2表现出减小的但可测量的与人类RBC的结合(图6,表2)。人源化mAb VLX9hum_03、04、05、06、08、09以及10 IgG2表现出不可测量的与RBC的结合(表2)。当VLX9 IgG2嵌合mAb以类似表观Kd值结合肿瘤和RBC CD47时,人源化mAb与肿瘤细胞和RBC的此差别结合是出乎意料的(表1)。
表1:VLX4、VLX8和VLX9嵌合(xi)mAb与OV10 hCD47细胞和人类血红细胞(hRBC)的 结合。
表2.VLX4、VLX8和VLX9人源化mAb与人类OV10 hCD47和人类血红细胞(hRBC)的结 合。
*NB-在高达100μg/mL的mAb浓度下未检测到结合。
**-减少的RBC结合。
***R-减少的血凝集。
使用流式细胞术测定人源化VLX4、VLX8和VLX9 mAb的交叉物种结合。将小鼠、大鼠、兔或食蟹猴RBC在37℃下使用磷酸盐缓冲盐水pH7.2、2.5mM EDTA(PBS+E)溶液中不同浓度的人源化抗体孵育60分钟。然后用冷PBS+E洗涤细胞,并且与在PBS+E中的FITC标记的驴抗人抗体(杰克逊免疫研究实验室(Jackson Immuno Research Labs),西格罗夫(WestGrove),宾夕法尼亚州;目录号709-096-149)一起在冰上再孵育一个小时。用PBS+E洗涤细胞,并且使用C6 Accuri流式细胞仪(碧迪公司)分析抗体结合。
表3示出人源化VLX4和VLX8 mAb与来自小鼠、大鼠和食蟹猴的RBC的表观结合亲和力,这通过在不同抗体浓度下对中等荧光强度进行非线性拟合(Prism GraphPad软件)来测定。此数据表明人源化VLX4和VLX8mAb以皮摩尔至纳摩尔范围的表观Kd值结合小鼠、大鼠、兔(数据未示出)和食蟹猴RBC(表3)。
表3.VLX4和VLX8人源化mAb与小鼠和大鼠RBC的结合。
实例4
CD47抗体阻断CD47/SIRPα结合
为了在体外评估人源化CD47 mAb对于CD47与SIRPα的结合的作用,采用以下方法,该方法使用荧光标记的SIRPα-Fc融合蛋白与表达CD47的Jurkat T细胞的结合。
使用Alexa抗体标记试剂盒(英杰公司(Invitrogen)目录号A20186)标记SIRPα-Fc融合蛋白(安迪生物公司(R&D Systems),目录号4546-SA)。在37℃下使用含有10%培养基的RPMI或者单独的培养基中的人类对照抗体人源化mAb(5μg/ml)孵育1.5×106个Jurkat T细胞,持续30min。添加等体积的荧光标记的SIRPα-Fc融合蛋白并且在37℃下将其再孵育30分钟。将细胞用PBS洗涤一次并且通过流式细胞仪分析标记的SIRPα-Fc结合Jurkat T细胞的量。
如图7所示,人源化VLX4、VLX8和VLX9 mAb阻断Jurkat T细胞上表达的CD47与SIPRα的相互作用,而人类对照抗体(不结合CD47)或单独的培养基不阻断CD47/SIRPα相互作用。
实例5
CD47抗体增加吞噬作用
为了在体外评估嵌合(鼠类-人类)和人源化VLX4、VLX8和VLX9CD47 mAb对于巨噬细胞吞噬肿瘤细胞的作用,采用使用流式细胞术的以下方法(Willingham et al.(2012)Proc Natl Acad Sci USA 109(17):6662-7[Willingham等人(2012)美国国家科学院院刊109(17):6662-7]和Tseng et al.(2013)Proc Natl Acad Sci U S A110(27):11103-8[Tseng等人(2013)美国国家科学院院刊110(27):11103-8])。
人类来源的巨噬细胞来源于健康人类周围血液的白细胞除去法并且在AIM-V培养基(生命技术公司(Life Technologies)中孵育7-10天。对于体外吞噬测定,将巨噬细胞以1×104个细胞/孔的浓度再接种在100ul AIM-V培养基的96孔板中并且使其附着24小时。一旦效应子巨噬细胞附着至培养皿,使用1μM 5(6)-羧基荧光素二乙酸N-琥珀酰亚胺酯(CFSE;西格玛奥德里奇公司(Sigma Aldrich))标记靶人类癌细胞(Jurkat)并且将其以1mlAIM-V培养基5×104个细胞的浓度(5:1靶标比效应子比率)添加到巨噬细胞培养物中。在靶细胞和效应子细胞混合时添加VLX4、VLX8和VLX9 CD47 mAb(1μg/ml)并且使其在37℃下孵育2-3小时。在2-3小时之后,去除所有未吞噬细胞并且将其余细胞用磷酸盐缓冲盐水(PBS;西格玛奥德里奇公司)洗涤三次。然后将细胞冻干,收集到微量离心管中,并且在100ng别藻蓝蛋白(APC)标记的CD14抗体(BD生物科学公司)中孵育30分钟,洗涤一次,并且通过流式细胞术(Accuri C6;BD生物科学公司)分析CD14+细胞的百分比,这些细胞也是指示完全吞噬的CFSE+。
如图8所示,VLX4嵌合(鼠类-人类)mAb VLX4 IgG1、VLX4 IgG1N297Q、VLX4 IgG4PE、以及VLX4 IgG4 S228P通过阻断CD47/SIRPα相互作用来增加人类巨噬细胞对Jurkat细胞的吞噬作用并且此增强的吞噬作用独立于Fc功能。
类似地,如图9A和图9B,VLX4hum_01 IgG1、VLX4hum_01 IgG4 PE、VLX4hum_06IgG4 PE、VLX4hum_07 IgG4 PE、VLX4hum_12 IgG4 PE、以及VLX4hum_13 IgG4 PE通过阻断CD47/SIRPα相互作用来增加人类巨噬细胞对Jurkat细胞的吞噬作用。
如图10A所示,VLX8嵌合(鼠类-人类)VLX8 IgG1 N297Q和VLX8 IgG4 PE经由阻断CD47/SIRPα相互作用来增加人类巨噬细胞对Jurkat T细胞的吞噬作用并且此增强的吞噬作用独立于Fc功能。
类似地,如图10B所示,VLX8hum_01 IgG4 PE、VLX8hum_03 IgG4PE、VLX8hum_07IgG4 PE、VLX8hum_08 IgG4 PE、以及VLX8hum_09 IgG4 PE通过阻断CD47/SIRPα相互作用来增加人类巨噬细胞对Jurkat细胞的吞噬作用并且此增强的吞噬作用独立于Fc功能。
如图11A所示,VLX9 IgG1N297Q、VLX9 IgG2和VLX9 IgG4 PE嵌合mAb全部通过阻断CD47/SIRPα相互作用来增加人类巨噬细胞对Jurkat T细胞的吞噬作用并且此增强的吞噬作用独立于Fc效应子功能。类似地,如图11B所示,全部人源化VLX9 IgG2 mAb都增加对Jurkat T细胞的吞噬作用。
实例6
通过可溶性CD47抗体诱导细胞死亡
以下可溶性CD47抗体已显示诱导肿瘤细胞的选择性细胞死亡。与仅阻断SIRPα与CD47的结合的mAb相比,预期这种针对癌细胞的选择性毒性的附加特性具有优势。
在体外测量可溶性抗-CD47 mAb对细胞死亡的诱导(Manna et al.(2003)J.Immunol.107(7):3544-53[Manna等人(2003)免疫学杂志107(7):3544-53])。对于体外细胞死亡测定,在37℃下将1×105个转化的人类T细胞(Jurkat T细胞)用可溶性人源化VLX4、VLX8和VLX9 CD47mAb(1μg/ml)孵育24小时。随着细胞死亡的发生,线粒体膜电势降低,细胞膜的内叶颠倒,从而暴露磷脂酰丝氨酸(PS),并且碘化丙啶(PI)能够结合到核DNA中。为了检测这些细胞变化,然后用荧光标记的膜联蛋白V和PI或7-氨基放线菌素D(7-AAD)(BD生物技术公司)染色细胞并且使用Accuri C6流式细胞仪(BD生物技术公司)检测信号。PS暴露的增加通过测量膜联蛋白V信号增加百分比来确定并且死亡细胞百分比通过测量PI或7-AAD信号的增加百分比来确定。对于治疗目的重要的是,这些mAb直接诱导肿瘤细胞的细胞死亡并且不需要补充或干预其他细胞(例如,NK细胞、T细胞或巨噬细胞)以杀灭。因此,该机制独立于其他细胞和Fc效应子功能。因此,由这些mAb开发的治疗性抗体可以被工程化以减少Fc效应子功能诸如ADCC和CDC并且因此限制对于具有完整Fc效应子功能的人源化mAb常见的副作用的可能性。
如图12A和图12B所示,可溶性VLX4人源化mAb诱导Jurkat T ALL细胞的细胞死亡,如通过增加的膜联蛋白V染色和7-AAD染色(未示出)测量的。人源化mAb VLX4hum_01 IgG1、VLX4hum_01 IgG4 PE、VLX4hum_02 IgG1、VLX4hum_02 IgG4 PE、VLX4hum_06 IgG4 PE、VLX4hum_07 IgG4 PE、VLX4hum_12 IgG4 PE、以及VLX4hum_13 IgG4 PE引起细胞死亡。相反,人源化mAb VLX4hum_08 IgG4 PE和VLX4hum_11 IgG4 PE不引起Jurkat T细胞的细胞死亡。诱导细胞死亡和促进易感癌症细胞的吞噬作用赋予癌症治疗中额外希望的抗体特性和治疗益处。
如图13A和图13B所示,可溶性VLX8嵌合和人源化mAb诱导Jurkat T ALL细胞的细胞死亡,如通过增加的膜联蛋白V染色和7-AAD染色(未示出)测量的。嵌合mAb VLX8 IgG1N297Q(xi)和VLX8 IgG4 PE以及人源化mAb VLX8hum_07 IgG4 PE和VLX8hum_08 IgG4 PE诱导Jurkat TALL细胞的细胞死亡。相反,人源化mAb VLX8hum_02 IgG4 PE和VLX8hum_04IgG4 PE不引起Jurkat T细胞的细胞死亡。诱导细胞死亡和促进易感癌症细胞的吞噬作用赋予癌症治疗中额外希望的抗体特性和治疗益处。
如图14A所示,可溶性VLX9嵌合抗体诱导Jurkat细胞的细胞死亡,如通过增加的膜联蛋白V染色和7-AAD染色(未示出)测量的。另外,如图14B所示,嵌合VLX9 IgG2xi mAb和人源化mAb VLX9hum_06 IgG2、VLX9hum_07 IgG2、VLX9hum_08 IgG2、以及VLX9hum_09 IgG2诱导Jurkat细胞的细胞死亡(在膜联蛋白V染色中大于2倍的增加)。相反,人源化mAbVLX9hum_01 IgG2、VLX9hum_02 IgG2、VLX9hum_03 IgG2、VLX9hum_04 IgG2、VLX9hum_05IgG2以及VLX9hum_010 IgG2不引起Jurkat细胞的细胞死亡。。诱导细胞死亡和促进易感癌症细胞的吞噬作用赋予癌症治疗中额外希望的抗体特性和治疗益处。
实例7
人类血红细胞(hRBC)的血凝集
许多CD47抗体(包括B6H12、BRIC126、MABL1、MABL2、CC2C6、5F9)已显示在体内或体外引起洗涤的RBC的血凝集(HA)(Petrova P.et al.Cancer Res 2015;75(15Suppl):Abstract nr 4271[Petrova P.等人,癌症研究2015;75(15增补版):摘要nr 4271];美国专利9,045,541;Uno et al.Oncol Rep.17:1189-94,2007[Uno等人,肿瘤学报道17:1189-94,2007];Kikuchi et al.Biochem Biophys Res.Commun.315:912-8,2004[Kikuchi等人,生物化学与生物物理学研究通讯315:912-8,2004];Sikic B.et al.J Clin Oncol 2016;34(suppl;abstract 3019)[Sikic B.等人,临床肿瘤学杂志2016;34(增补版;摘要3019)])。在体外用不同浓度的嵌合和人源化VLX4、VLX8和VLX9 mAb孵育hRBC之后评估hRBC的血凝集,大致上如Kikuchi et al.Biochem Biophys Res.Commun(2004)315:912-918[Kikuchi等人,生物化学与生物物理学研究通讯(2004)315:912-918]所述的。从健康供体获得血液,以PBS/1mM EDTA/BSA稀释(1:50)并且用PBS/EDTA/BSA洗涤3次。将hRBC添加到具有等体积抗体(各自75μl)的U形底部的96孔板中并且在37℃下孵育3小时并在4℃下孵育过夜。
如图15A和表1和2所示,VLX4hum_01 IgG1 N297Q引起hRBC的血凝集,而人源化VLX4hum_01 IgG4 PE mAb不引起该血凝集(mAb浓度50μg/ml至0.3ng/ml)。VLX4hum_01IgG4 PE使血凝集缺乏赋予癌症治疗中额外希望的抗体特性和治疗益处。
如图15B和表1和2所示,嵌合抗体VLX8 IgG4 PE(xi)和人源化抗体VLX8hum_08IgG4 PE、VLX8hum_09 IgG4 PE以及VLX8hum_010 IgG4 PE引起hRBC的血凝集,而VLX8人源化Ab VLX8hum_01 IgG4 PE、VLX8hum_02 IgG4 PE、VLX8hum_03 IgG4 PE以及VLX8hum_11IgG4 PE不引起该血凝集(mAb浓度50μg/ml至0.3ng/ml)。
人源化抗体VLX4hum_01 IgG4 PE、VLX8hum_01 IgG4 PE、VLX8hum_02 IgG4 PE、VLX8hum_03 IgG4 PE以及VLX8hum_11 IgG4 PE使血凝集缺乏赋予癌症治疗中额外希望的抗体特性和治疗益处。
如图16A和图16B所示,嵌合抗体VLX9 IgG2引起hRBC的血凝集,而所有人源化VLX9mAb除了VLX9hum_07 IgG2之外全部不引起该血凝集(浓度为从50ug/ml至0.3pg/ml)。然而,由VLX9hum_07引起的血凝集的量与VLX9 IgG2嵌合mAb相比有所减少。而且,VLX9人源化mAb使血凝集缺乏赋予癌症治疗中额外希望的抗体特性和治疗益处。
实例8
体内抗肿瘤活性
此实验的目的在于证实VLX4、VLX8和VLX9人源化抗体(例如VLX4_07 IgG4PE、VLX8_10 IgG4PE和VLX9hum_08 IgG2)减少淋巴瘤小鼠异种移植模型中的体内肿瘤负荷。
将拉吉人类伯基特氏淋巴瘤细胞(ATCC#CCL-86,维吉尼亚州马纳萨斯(Manassas,VA))维持在5%CO2气氛内补充有10%牛胎儿血清(FBS;欧美加科技公司(OmegaScientific);加利福尼亚州圣弗南度谷(Tarzana,CA))的RPMI-1640(龙沙公司(Lonza);马里兰州沃克斯维尔(Walkersville,MD))。在组织培养烧瓶中扩增培养物。
从杰克逊实验室(Jackson Laboratory)(缅因州巴尔港(Bar Harbor,ME))获得5-6周大的雌性NSG(NOD-Cg-PrkdcscidI12rgtm1Wjl/SzJ)。在处理之前使小鼠适应环境并且在特定无热源条件下在微型隔离笼(实验室产品公司(Lab Products),特拉华州锡福德(Seaford,DE))中圈养。向小鼠给料Teklad Global2920x照射的实验室动物膳食(Envigo,Formerly Harlan;印第安纳州印第安纳波利斯(Indianapolis,IN))并且随意提供高压灭菌水。在研究所动物照管与使用指南(Institutional Animal Care and Useguidelines)下进行所有程序。
使用含有5×106个拉吉肿瘤细胞悬浮液的0.1mL 30%RPMI/70%MatrigelTM(BD生物科学公司(BD Biosciences);马萨诸塞州贝德福德(Bedford,MA))皮下接种雌性NSG小鼠的侧翼。在接种之后五天,使用数显卡尺测量肿瘤的宽度和长度直径。利用以下等式计算肿瘤体积:肿瘤体积(mm3)=(a×b2/2),其中‘b’是最小的直径并且‘a’是最大的直径。将具有31-74mm3可触及肿瘤体积的小鼠随机分成8-10/组并且在此时开始VLX9hum_08或PBS(对照)给予。使用5mg/kg抗体5X/周通过腹膜内注射处理小鼠,持续4周。每周两次记录肿瘤体积和体重。
如图17所示,使用人源化VLX4hum_07 IgG4 PE进行处理显著减少了拉吉肿瘤的肿瘤生长(p<0.05,双侧ANOVA),这证实了体内抗肿瘤功效。
如图18所示,使用人源化抗-CD47 mAb VLX8hum_10 IgG4 PE进行处理显著减少了(p<0.0001,双侧ANOVA)拉吉肿瘤的肿瘤生长,这证实了体内抗肿瘤功效。
如图19所示,使用人源化抗-CD47 mAb VLX9hum_08 IgG2进行处理显著减少了(p<0.05,ANOVA)拉吉肿瘤的肿瘤生长,这证实了体内抗肿瘤功效。
实例9
对循环红血细胞参数的作用
此实验的目的在于证实在体外不结合人类RBC的VLX9人源化抗体(表2)(例如hum1017_08 IgG2)在给予至食蟹猴之后不引起血红蛋白(Hg)或循环RBC的减少。
根据研究所动物照管与使用指南使用雌性中国食蟹猴(查尔斯河实验室(CharlesRiver Laboratories),德克萨斯州休斯顿(Houston,TX))2.5-3kg。以1小时静脉输注形式在第1天以5mg/kg的剂量并且在第18天以15mg/kg的剂量给予VLX9hum_08 IgG2或媒介物(PBS)(3只动物/组)。在整个研究中在第-7天、第-3天、第3天、第8天、第12天、第18天(给药前)、第20天、第25天、第29天、第35天以及第41天测量血液学参数并且将其与对照动物的平均值相比较/将其归一化至这些平均值。在VLX9hum_08 IgG2组中在第0天处理前的RBC和Hg值低于对照组。在用任一剂量的VLX9hum_08 IgG2处理之后,与对照相比Hg(图20A)或RBC计数(图20B)存在微小变化(<10%),这证实在体外不结合人类RBC的抗体当给予至食蟹猴时不引起RBC血液学参数的减小。
实例10
CD47的免疫组织化学染色
在来自患有多种类型的癌症的患者的福尔马林固定的、石蜡包埋的(FFPE)块(从商业来源获得)中使用小鼠/兔嵌合抗-CD47 mAb确定CD47表达的定位。从FFPE块切下3-4微米切片,将其脱蜡并且用抗原修复液处理。然后用4μg/ml第一抗-CD47小鼠/兔嵌合mAb孵育切片1小时并且用抗兔HRP标记的第二抗体孵育20分钟。使用过氧化物底物3,3',5,5'-四甲基联苯胺可视化结合至人类CD47的抗-CD47抗体。使用苏木精复染切片并且使用标准光学显微镜评价。如图21所示,在人类乳腺癌组织中使用CD47小鼠/兔嵌合mAb(例如VLX4小鼠/兔嵌合mAb)检测到高CD47表达,该区域如箭头所指示的黑色区域所示出。这证实这些mAb可以用于在诊断测定中在从FFPE块获得的肿瘤组织切片中对人类CD47进行免疫组织化学定位。
实例11
CD47的抗体调节一氧化氮信号传导
结合CD47的TSP1激活异源三聚体G蛋白Gi,导致细胞内的环AMP(cAMP)水平的抑制。另外,TSP1-CD47途径对抗所有血管细胞中的一氧化氮(NO)途径的有益作用。NO途径由利用精氨酸作为底物生成生物活性气体NO的三种酶(NOS I、NOS II和NOS III)的任一种组成。NO可在其中产生它的细胞内、或在相邻的细胞中起作用,从而激活产生信使分子环GMP(cGMP)的酶(可溶性鸟苷环化酶)。NO-cGMP途径的正确功能对于保护心血管系统对抗应激是重要的,这些应激包括但不限于由于创伤、炎症、高血压、代谢综合征、缺血、以及缺血再灌注损伤(IRI)所致的应激。在这些细胞应激的情况下,TSP1/CD47系统对NO/cGMP途径的抑制恶化了应激的效应。在cGMP和cAMP两者都起着重要保护作用的心血管系统中,这是一个特殊的问题。存在着许多其中缺血和再灌注损伤引起或造成疾病、外伤、以及外科手术的不良结局的情形。
这些实验的目的在于证实本披露的人源化抗-CD47 mAb展现出逆转NO刺激性cGMP合成的TSP1介导抑制的能力,例如,正如先前使用针对CD47的小鼠单克隆抗体描述的,如Isenberg et al.(2006)J.Biol.Chem.281:26069-80[Isenberg等人(2006)生物化学杂志281:26069-80]所披露,或者可替代地NO信号传导的其他下游标记或由该信号传导引起的作用,例如平滑肌细胞松弛或血小板聚集,如先前Miller et al.(2010)BrJ.Pharmacol.159:1542-1547[Miller等人(2010)英国药理学杂志159:1542-1547]所述的。
将用来测量cGMP的方法正如制造商的说明(CatchPoint Cyclic-GMP荧光分析试剂盒,分子仪器公司(Molecular Devices),加利福尼亚州森尼维耳市(Sunnyvale,CA))。将使用Jurkat JE6.1细胞(ATCC,维吉尼亚州马纳萨斯(Manassas,VA);目录号TIB-152)或其他细胞类型,这些细胞当在培养基中生长时保留了NO-cGMP信号传导途径,并且对CD47的TSP1连接展现出稳健的且可再现的抑制反应。细胞将以小于1×106个细胞/mL的密度在伊斯科夫氏改性杜氏培养基(Iscove’s modified Dulbeccco’s medium)中生长,该培养基含有5%(v/v)热灭活牛胎儿血清(BioWest;目录号S01520)、100个单位/mL青霉素、100μg mL链霉素(西格玛公司;目录号P4222)。对于cGMP测定,细胞将以1×105个细胞/ml的密度接种在96孔组织培养板中的伊斯科夫改性杜氏培养基中持续24小时,该培养基含有5%(v/v)热灭活牛胎儿血清(BioWest;目录号S01520)、100个单位/mL青霉素、100μg/mL链霉素(西格玛公司;#P4222),并且然后将其转移至无血清培养基中过夜。
然后,将添加20ng/ml最终浓度的从如以上实例3中瞬时转染的CHO细胞中纯化的如本文披露的人源化抗体、以及对照嵌合抗体,在15分钟之后,添加0或1μg/ml人类TSP1(雅典研究与技术公司(Athens Research and Technology),乔治亚州阿森斯(Athens,GA),目录号16-20-201319)。在另外的15分钟之后,将以1μM的最终浓度向半数孔中加入NO供体二乙胺(DEA)一氧化氮(沙依曼化学公司(Cayman Chemical),密歇根州安娜堡(Ann Arbor,MI),目录号82100)。五分钟后,将用提供在cGMP试剂盒中的缓冲液裂解细胞,并且测定每个孔的等分试样的cGMP含量。
预期一些嵌合或人源化抗体将逆转cGMP的TSP1抑制。逆转将是完全的(>80%)或中级的(20%-80%)。cGMP的TSP1抑制的这种逆转将证明它们具有增加NO信号传导的能力,并且表明它们在保护心血管系统使其免于应激中的效用,这些应激包括但不限于由于创伤、炎症、高血压、代谢综合征、缺血、以及缺血再灌注损伤(IRI)所致的应激。也还预期另外的测定系统(例如平滑肌细胞收缩)显示一些嵌合或人源化抗体克隆逆转TSP对由NO信号传导的激活引起的下游效应的抑制性作用。
序列表
<110> 蒂奥玛医疗公司
罗宾·普罗
P·T·曼宁
胡安·C·阿尔马格罗
罗伯特·W·卡尔
<120> 治疗性CD47抗体
<130> VLX0005-401-PC
<150> 62/220,691
<151> 2015-09-18
<150> 62/221,852
<151> 2015-09-22
<150> 62/220,725
<151> 2015-09-18
<150> 62/232,681
<151> 2015-09-25
<150> 62/252,171
<151> 2015-11-06
<150> 62/354,592
<151> 2016-06-24
<150> 62/263,544
<151> 2015-12-04
<160> 104
<170> PatentIn 3.5版
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<400> 12
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 13
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> Vx8-LCDR1
<400> 13
Arg Ala Ser Gln Ser Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 14
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> Vx9-LCDR1
<400> 14
Arg Ser Ser Gln Asn Ile Val Gln Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 15
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> KVSNRFS
<400> 15
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 16
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Vx8-LCDR2
<400> 16
Tyr Thr Ser Arg Leu Tyr Ser
1 5
<210> 17
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> Vx9-LCDR2
<400> 17
Lys Val Phe His Arg Phe Ser
1 5
<210> 18
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Vx4-LCDR3
<400> 18
Phe Gln Gly Ser His Val Pro Tyr Thr
1 5
<210> 19
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Vx8-LCDR3
<400> 19
Gln Gln Gly Asn Thr Leu Pro Trp Thr
1 5
<210> 20
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> Vx9-LCDR3
<400> 20
Phe Gln Gly Ser His Val Pro Trp Thr
1 5
<210> 21
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx4murH01
<400> 21
Glu Val Gln Leu Gln Gln Ser Gly Pro 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
Val Ile His Trp Val Lys Arg Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Asp Gly Ile Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Val Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Gly Gly Tyr Tyr Val Pro Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 22
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx4mur-H02
<400> 22
Glu Val Gln Leu Gln Gln Ser Gly Pro 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
Val Ile His Trp Val Lys Arg Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Asp Gly Ile Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Val Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Gly Gly Tyr Tyr Val Pro Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 23
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx4humH01
<400> 23
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Gln Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Val Ile His Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Asp Gly Ile Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Ser Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Val Pro Asp Tyr Trp Gly Gln Ala Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 24
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx4humH02
<400> 24
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Gln Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Val Ile His Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Asp Gly Ile Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Ser Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Val Tyr Asp Tyr Trp Gly Gln Ala Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 25
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx4humH03
<400> 25
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Val Ile His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Asp Gly Ile Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Gly Gly Tyr Tyr Val Pro Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 26
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx4humH04
<400> 26
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Val Ile His Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Asp Gly Ile Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Val Pro Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 27
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx4humH05
<400> 27
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Asp Gly Ile Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Val Pro Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 28
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx8murH03
<400> 28
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Asn Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr 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 Arg Leu Ser Ser Leu Thr Ser Ala Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 29
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH06
<400> 29
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 30
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH07
<400> 30
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 31
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH08
<400> 31
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 32
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> >Vx8humH09
<400> 32
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 33
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH10
<400> 33
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Arg Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 34
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH11
<400> 34
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Gln Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Ser Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Ala Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 35
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx9murH04
<400> 35
Gln Val Gln Leu Gln Gln Phe Gly Ala Glu Leu Ala Lys Pro Gly Ala
1 5 10 15
Ser Val Gln Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Thr Asp Pro Arg Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Ala Ala Asp Arg Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Arg Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Gly Gly Gly Arg Val Gly Leu Gly Tyr Trp Gly His Gly Ser Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 36
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx9humH12
<400> 36
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Thr Asp Pro Arg Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Arg Val Gly Leu Gly Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 37
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx9humH13
<400> 37
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Thr Asp Pro Arg Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Arg Val Gly Leu Gly Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 38
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx9humH14
<400> 38
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Thr Asp Pro Arg Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Arg Val Gly Leu Gly Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 39
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx9humH15
<400> 39
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Thr Asp Pro Arg Thr Asp Tyr Thr Glu Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Arg Val Gly Leu Gly Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 40
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> Vx9humH16
<400> 40
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Thr Asp Pro Arg Thr Asp Tyr Thr Glu Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Arg Val Gly Leu Gly Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 41
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> Vx4murL01
<400> 41
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Asn Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser Ile Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Phe 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 Thr 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 Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 42
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> Vx4murL02
<400> 42
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Asn Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser Ile Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Phe 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 Thr 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 Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 43
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> Vx4humL01
<400> 43
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser Ile Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Arg 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 Asp Asp Val Gly Ile Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 44
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> Vx4humL02
<400> 44
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser Ile Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 45
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> Vx4humL03
<400> 45
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ser Arg Gln Ser Ile Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Tyr Gln Gln Lys Pro Gly Gln Pro
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 Thr Ile
65 70 75 80
Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 46
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> Vx8murL03
<400> 46
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 47
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> Vx8humL04
<400> 47
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 48
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> Vx8humL05
<400> 48
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 49
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> Vx8humL06
<400> 49
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Arg Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Tyr Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala
65 70 75 80
Asp Asp Val Gly Ile Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 50
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> Vx9murL04
<400> 50
Asp Val Phe 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 Asn Ile Val Gln 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 Phe His 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 Val Glu Ile Lys
100 105 110
<210> 51
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> Vx9humL07
<400> 51
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val Gln Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Phe His Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 52
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> Vx9humL08
<400> 52
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Asn Ile Val Gln Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Lys Pro Gly Gln Pro
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Phe His Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 53
<211> 330
<212> PRT
<213> 智人(Homo sapiens)
<400> 53
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 54
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 人类Fc IgG1-N297Q
<400> 54
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Gln Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 55
<211> 326
<212> PRT
<213> 智人
<400> 55
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165 170 175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195 200 205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly Lys
325
<210> 56
<211> 377
<212> PRT
<213> 智人
<400> 56
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro
100 105 110
Arg Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg
115 120 125
Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys
130 135 140
Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro
145 150 155 160
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
165 170 175
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
180 185 190
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr
195 200 205
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
210 215 220
Gln Tyr Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His
225 230 235 240
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
245 250 255
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
260 265 270
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
275 280 285
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
290 295 300
Ser Asp Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn Asn
305 310 315 320
Tyr Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
325 330 335
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile
340 345 350
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln
355 360 365
Lys Ser Leu Ser Leu Ser Pro Gly Lys
370 375
<210> 57
<211> 326
<212> PRT
<213> 智人
<400> 57
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly
325
<210> 58
<211> 326
<212> PRT
<213> 人工序列
<220>
<223> 人类Fc-IgG4 S228P
<400> 58
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly
325
<210> 59
<211> 326
<212> PRT
<213> 人工序列
<220>
<223> 人类Fc-IgG4 PE
<400> 59
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly
325
<210> 60
<211> 107
<212> PRT
<213> 智人
<400> 60
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 61
<211> 329
<212> PRT
<213> 黑家鼠(Rattus rattus)
<400> 61
Ala Arg Thr Thr Ala Pro Ser Val Tyr Pro Leu Val Pro Gly Cys Ser
1 5 10 15
Gly Thr Ser Gly Ser Leu Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Lys Trp Asn Ser Gly Ala Leu Ser Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Gly Leu Tyr Thr Leu
50 55 60
Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Ser Ser Gln Thr Val
65 70 75 80
Thr Cys Ser Val Ala His Pro Ala Thr Lys Ser Asn Leu Ile Lys Arg
85 90 95
Ile Glu Pro Arg Arg Pro Lys Pro Arg Pro Pro Thr Asp Ile Cys Ser
100 105 110
Cys Asp Asp Asn Leu Gly Arg Pro Ser Val Phe Ile Phe Pro Pro Lys
115 120 125
Pro Lys Asp Ile Leu Met Ile Thr Leu Thr Pro Lys Val Thr Cys Val
130 135 140
Val Val Asp Val Ser Glu Glu Glu Pro Asp Val Gln Phe Ser Trp Phe
145 150 155 160
Val Asp Asn Val Arg Val Phe Thr Ala Gln Thr Gln Pro His Glu Glu
165 170 175
Gln Leu Asn Gly Thr Phe Arg Val Val Ser Thr Leu His Ile Gln His
180 185 190
Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys
195 200 205
Asp Leu Pro Ser Pro Ile Glu Lys Thr Ile Ser Lys Pro Arg Gly Lys
210 215 220
Ala Arg Thr Pro Gln Val Tyr Thr Ile Pro Pro Pro Arg Glu Gln Met
225 230 235 240
Ser Lys Asn Lys Val Ser Leu Thr Cys Met Val Thr Ser Phe Tyr Pro
245 250 255
Ala Ser Ile Ser Val Glu Trp Glu Arg Asn Gly Glu Leu Glu Gln Asp
260 265 270
Tyr Lys Asn Thr Leu Pro Val Leu Asp Ser Asp Glu Ser Tyr Phe Leu
275 280 285
Tyr Ser Lys Leu Ser Val Asp Thr Asp Ser Trp Met Arg Gly Asp Ile
290 295 300
Tyr Thr Cys Ser Val Val His Glu Ala Leu His Asn His His Thr Gln
305 310 315 320
Lys Asn Leu Ser Arg Ser Pro Gly Lys
325
<210> 62
<211> 107
<212> PRT
<213> 黑家鼠
<400> 62
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Met Glu
1 5 10 15
Gln Leu Thr Ser Gly Gly Ala Thr Val Val Cys Phe Val Asn Asn Phe
20 25 30
Tyr Pro Arg Asp Ile Ser Val Lys Trp Lys Ile Asp Gly Ser Glu Gln
35 40 45
Arg Asp Gly Val Leu Asp Ser Val Thr Asp Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Met Ser Ser Thr Leu Ser Leu Thr Lys Val Glu Tyr Glu
65 70 75 80
Arg His Asn Leu Tyr Thr Cys Glu Val Val His Lys Thr Ser Ser Ser
85 90 95
Pro Val Val Lys Ser Phe Asn Arg Asn Glu Cys
100 105
<210> 63
<211> 323
<212> PRT
<213> 穴兔(Oryctolagus cuniculus)
<400> 63
Gly Gln Pro Lys Ala Pro Ser Val Phe Pro Leu Ala Pro Cys Cys Gly
1 5 10 15
Asp Thr Pro Ser Ser Thr Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Leu Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Thr Leu Thr Asn
35 40 45
Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser Gln Pro Val Thr Cys
65 70 75 80
Asn Val Ala His Pro Ala Thr Asn Thr Lys Val Asp Lys Thr Val Ala
85 90 95
Pro Ser Thr Cys Ser Lys Pro Thr Cys Pro Pro Pro Glu Leu Leu Gly
100 105 110
Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
115 120 125
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
130 135 140
Asp Asp Pro Glu Val Gln Phe Thr Trp Tyr Ile Asn Asn Glu Gln Val
145 150 155 160
Arg Thr Ala Arg Pro Pro Leu Arg Glu Gln Gln Phe Asn Ser Thr Ile
165 170 175
Arg Val Val Ser Thr Leu Pro Ile Ala His Gln Asp Trp Leu Arg Gly
180 185 190
Lys Glu Phe Lys Cys Lys Val His Asn Lys Ala Leu Pro Ala Pro Ile
195 200 205
Glu Lys Thr Ile Ser Lys Ala Arg Gly Gln Pro Leu Glu Pro Lys Val
210 215 220
Tyr Thr Met Gly Pro Pro Arg Glu Glu Leu Ser Ser Arg Ser Val Ser
225 230 235 240
Leu Thr Cys Met Ile Asn Gly Phe Tyr Pro Ser Asp Ile Ser Val Glu
245 250 255
Trp Glu Lys Asn Gly Lys Ala Glu Asp Asn Tyr Lys Thr Thr Pro Ala
260 265 270
Val Leu Asp Ser Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val
275 280 285
Pro Thr Ser Glu Trp Gln Arg Gly Asp Val Phe Thr Cys Ser Val Met
290 295 300
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Ile Ser Arg Ser
305 310 315 320
Pro Gly Lys
<210> 64
<211> 104
<212> PRT
<213> 穴兔
<400> 64
Arg Asp Pro Val Ala Pro Thr Val Leu Ile Phe Pro Pro Ala Ala Asp
1 5 10 15
Gln Val Ala Thr Gly Thr Val Thr Ile Val Cys Val Ala Asn Lys Tyr
20 25 30
Phe Pro Asp Val Thr Val Thr Trp Glu Val Asp Gly Thr Thr Gln Thr
35 40 45
Thr Gly Ile Glu Asn Ser Lys Thr Pro Gln Asn Ser Ala Asp Cys Thr
50 55 60
Tyr Asn Leu Ser Ser Thr Leu Thr Leu Thr Ser Thr Gln Tyr Asn Ser
65 70 75 80
His Lys Glu Tyr Thr Cys Lys Val Thr Gln Gly Thr Thr Ser Val Val
85 90 95
Gln Ser Phe Asn Arg Gly Asp Cys
100
<210> 65
<211> 293
<212> PRT
<213> 智人
<400> 65
Met Trp Pro Leu Val Ala Ala Leu Leu Leu Gly Ser Ala Cys Cys Gly
1 5 10 15
Ser Ala Gln Leu Leu Phe Asn Lys Thr Lys Ser Val Glu Phe Thr Phe
20 25 30
Cys Asn Asp Thr Val Val Ile Pro Cys Phe Val Thr Asn Met Glu Ala
35 40 45
Gln Asn Thr Thr Glu Val Tyr Val Lys Trp Lys Phe Lys Gly Arg Asp
50 55 60
Ile Tyr Thr Phe Asp Gly Ala Leu Asn Lys Ser Thr Val Pro Thr Asp
65 70 75 80
Phe Ser Ser Ala Lys Ile Glu Val Ser Gln Leu Leu Lys Gly Asp Ala
85 90 95
Ser Leu Lys Met Asp Lys Ser Asp Ala Val Ser His Thr Gly Asn Tyr
100 105 110
Thr Cys Glu Val Thr Glu Leu Thr Arg Glu Gly Glu Thr Ile Ile Glu
115 120 125
Leu Lys Tyr Arg Val Val Ser Trp Phe Ser Pro Asn Glu Asn Ile Leu
130 135 140
Ile Val Ile Phe Pro Ile Phe Ala Ile Leu Leu Phe Trp Gly Gln Phe
145 150 155 160
Gly Ile Lys Thr Leu Lys Tyr Arg Ser Gly Gly Met Asp Glu Lys Thr
165 170 175
Ile Ala Leu Leu Val Ala Gly Leu Val Ile Thr Val Ile Val Ile Val
180 185 190
Gly Ala Ile Leu Phe Val Pro Gly Glu Tyr Ser Leu Lys Asn Ala Thr
195 200 205
Gly Leu Gly Leu Ile Val Thr Ser Thr Gly Ile Leu Ile Leu Leu His
210 215 220
Tyr Tyr Val Phe Ser Thr Ala Ile Gly Leu Thr Ser Phe Val Ile Ala
225 230 235 240
Ile Leu Val Ile Gln Val Ile Ala Tyr Ile Leu Ala Val Val Gly Leu
245 250 255
Ser Leu Cys Ile Ala Ala Cys Ile Pro Met His Gly Pro Leu Leu Ile
260 265 270
Ser Gly Leu Ser Ile Leu Ala Leu Ala Gln Leu Leu Gly Leu Val Tyr
275 280 285
Met Lys Phe Val Glu
290
<210> 66
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> Vx4murL01全长
<400> 66
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Asn Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser Ile Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Phe 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 Thr 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 Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 67
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> Vx4murL01全长
<400> 67
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Asn Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser Ile Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Phe 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 Thr 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 Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 68
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> Vx4humL01全长LC
<400> 68
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser Ile Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Arg 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 Asp Asp Val Gly Ile Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 69
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> Vx8humL03全长LC
<400> 69
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Arg Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Tyr Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala
65 70 75 80
Asp Asp Val Gly Ile Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 70
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> Vx9humL02全长LC
<400> 70
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Asn Ile Val Gln Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Lys Pro Gly Gln Pro
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Phe His Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 71
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> Vx8humL02全长LC
<400> 71
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 72
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> Vx4humL02全长LC
<400> 72
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser Ile Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 73
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> Vx9humL07全长LC
<400> 73
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val Gln Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Phe His Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 74
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> Vx8humL01全长LC
<400> 74
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 75
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> Vx9mur_L04全长LC
<400> 75
Asp Val Phe 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 Asn Ile Val Gln 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 Phe His 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 Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 76
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> Vx4murH01全长HC
<400> 76
Glu Val Gln Leu Gln Gln Ser Gly Pro 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
Val Ile His Trp Val Lys Arg Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Asp Gly Ile Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Val Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Gly Gly Tyr Tyr Val Pro Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 77
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> Vx4humH01全长HC
<400> 77
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Gln Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Val Ile His Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Asp Gly Ile Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Ser Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Val Pro Asp Tyr Trp Gly Gln Ala Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 78
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH11全长HC
<400> 78
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Gln Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Ser Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Ala Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 79
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> Vx9humH12全长HC
<400> 79
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Thr Asp Pro Arg Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Arg Val Gly Leu Gly Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
180 185 190
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
210 215 220
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
290 295 300
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 80
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> Vx9humH14全长HC
<400> 80
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Thr Asp Pro Arg Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Arg Val Gly Leu Gly Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
180 185 190
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
210 215 220
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
290 295 300
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 81
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> Vx9humH15全长HC
<400> 81
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Thr Asp Pro Arg Thr Asp Tyr Thr Glu Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Arg Val Gly Leu Gly Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
180 185 190
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
210 215 220
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
290 295 300
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 82
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> Vx4humH02全长HC
<400> 82
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Gln Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Val Ile His Trp Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Asp Gly Ile Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Ser Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Val Tyr Asp Tyr Trp Gly Gln Ala Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 83
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> Vx9humH13全长HC
<400> 83
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Thr Asp Pro Arg Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Arg Val Gly Leu Gly Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
180 185 190
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
210 215 220
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
290 295 300
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 84
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH10全长HC
<400> 84
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Arg Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 85
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> Vx4humH04全长HC
<400> 85
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Val Ile His Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Asp Gly Ile Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Val Pro Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 86
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> Vx4humH05全长HC
<400> 86
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Asp Gly Ile Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Tyr Val Pro Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 87
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> Vx9humH16全长HC
<400> 87
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Thr Asp Pro Arg Thr Asp Tyr Thr Glu Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Arg Val Gly Leu Gly Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
180 185 190
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
210 215 220
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
290 295 300
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 88
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH06全长HC
<400> 88
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 89
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH07全长HC
<400> 89
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 90
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH08全长HC
<400> 90
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 91
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH09全长HC
<400> 91
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 92
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH06全长HC
<400> 92
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 93
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> Vx8mur-H03全长HC
<400> 93
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Asn Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr 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 Arg Leu Ser Ser Leu Thr Ser Ala Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 94
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> Vx9mur-H04全长HC
<400> 94
Gln Val Gln Leu Gln Gln Phe Gly Ala Glu Leu Ala Lys Pro Gly Ala
1 5 10 15
Ser Val Gln Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Trp Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Thr Asp Pro Arg Thr Asp Tyr Thr Glu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Ala Ala Asp Arg Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Arg Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Gly Gly Gly Arg Val Gly Leu Gly Tyr Trp Gly His Gly Ser Ser
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
180 185 190
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
210 215 220
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
290 295 300
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 95
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH06全长HC
<400> 95
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
180 185 190
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
210 215 220
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
290 295 300
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 96
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH07全长HC
<400> 96
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
180 185 190
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
210 215 220
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
290 295 300
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 97
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH08全长HC
<400> 97
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
180 185 190
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
210 215 220
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
290 295 300
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 98
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> Vx8humH09全长HC
<400> 98
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asn Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asp Pro Leu Asn Gly Asp Thr Thr Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Lys Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
180 185 190
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro
210 215 220
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val
290 295 300
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 99
<211> 326
<212> PRT
<213> 人工序列
<220>
<223> 人类Fc-IgG4 PE'
<400> 99
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly
325
<210> 100
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> Vx8murL03全长LC
<400> 100
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 101
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> Vx4mur-ratL01全长
<400> 101
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Asn Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser Ile Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Phe 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 Thr 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 Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Met Glu
115 120 125
Gln Leu Thr Ser Gly Gly Ala Thr Val Val Cys Phe Val Asn Asn Phe
130 135 140
Tyr Pro Arg Asp Ile Ser Val Lys Trp Lys Ile Asp Gly Ser Glu Gln
145 150 155 160
Arg Asp Gly Val Leu Asp Ser Val Thr Asp Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Met Ser Ser Thr Leu Ser Leu Thr Lys Val Glu Tyr Glu
180 185 190
Arg His Asn Leu Tyr Thr Cys Glu Val Val His Lys Thr Ser Ser Ser
195 200 205
Pro Val Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 102
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> Vx4mur-ratH01全长
<400> 102
Glu Val Gln Leu Gln Gln Ser Gly Pro 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
Val Ile His Trp Val Lys Arg Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Asp Gly Ile Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Val Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Gly Gly Tyr Tyr Val Pro Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser Ala Arg Thr Thr Ala Pro Ser Val Tyr Pro Leu
115 120 125
Val Pro Gly Cys Ser Gly Thr Ser Gly Ser Leu Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Lys Trp Asn Ser
145 150 155 160
Gly Ala Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Gly Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp
180 185 190
Ser Ser Gln Thr Val Thr Cys Ser Val Ala His Pro Ala Thr Lys Ser
195 200 205
Asn Leu Ile Lys Arg Ile Glu Pro Arg Arg Pro Lys Pro Arg Pro Pro
210 215 220
Thr Asp Ile Cys Ser Cys Asp Asp Asn Leu Gly Arg Pro Ser Val Phe
225 230 235 240
Ile Phe Pro Pro Lys Pro Lys Asp Ile Leu Met Ile Thr Leu Thr Pro
245 250 255
Lys Val Thr Cys Val Val Val Asp Val Ser Glu Glu Glu Pro Asp Val
260 265 270
Gln Phe Ser Trp Phe Val Asp Asn Val Arg Val Phe Thr Ala Gln Thr
275 280 285
Gln Pro His Glu Glu Gln Leu Asn Gly Thr Phe Arg Val Val Ser Thr
290 295 300
Leu His Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys
305 310 315 320
Lys Val Asn Asn Lys Asp Leu Pro Ser Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Pro Arg Gly Lys Ala Arg Thr Pro Gln Val Tyr Thr Ile Pro Pro
340 345 350
Pro Arg Glu Gln Met Ser Lys Asn Lys Val Ser Leu Thr Cys Met Val
355 360 365
Thr Ser Phe Tyr Pro Ala Ser Ile Ser Val Glu Trp Glu Arg Asn Gly
370 375 380
Glu Leu Glu Gln Asp Tyr Lys Asn Thr Leu Pro Val Leu Asp Ser Asp
385 390 395 400
Glu Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Thr Asp Ser Trp
405 410 415
Met Arg Gly Asp Ile Tyr Thr Cys Ser Val Val His Glu Ala Leu His
420 425 430
Asn His His Thr Gln Lys Asn Leu Ser Arg Ser Pro Gly Lys
435 440 445
<210> 103
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> Vx4mur-rabL01全长
<400> 103
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Asn Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Arg Gln Ser Ile Val His Thr
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Phe 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 Thr 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 Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Asp Pro Val Ala Pro Thr Val Leu Ile Phe Pro Pro Ala Ala Asp
115 120 125
Gln Val Ala Thr Gly Thr Val Thr Ile Val Cys Val Ala Asn Lys Tyr
130 135 140
Phe Pro Asp Val Thr Val Thr Trp Glu Val Asp Gly Thr Thr Gln Thr
145 150 155 160
Thr Gly Ile Glu Asn Ser Lys Thr Pro Gln Asn Ser Ala Asp Cys Thr
165 170 175
Tyr Asn Leu Ser Ser Thr Leu Thr Leu Thr Ser Thr Gln Tyr Asn Ser
180 185 190
His Lys Glu Tyr Thr Cys Lys Val Thr Gln Gly Thr Thr Ser Val Val
195 200 205
Gln Ser Phe Asn Arg Gly Asp Cys
210 215
<210> 104
<211> 440
<212> PRT
<213> 人工序列
<220>
<223> Vx4mur-rabH01全长
<400> 104
Glu Val Gln Leu Gln Gln Ser Gly Pro 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
Val Ile His Trp Val Lys Arg Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Asp Gly Ile Leu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Val Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Gly Gly Tyr Tyr Val Pro Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser Gly Gln Pro Lys Ala Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Cys Gly Asp Thr Pro Ser Ser Thr Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Leu Pro Glu Pro Val Thr Val Thr Trp Asn Ser
145 150 155 160
Gly Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser Ser
180 185 190
Gln Pro Val Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys Val
195 200 205
Asp Lys Thr Val Ala Pro Ser Thr Cys Ser Lys Pro Thr Cys Pro Pro
210 215 220
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Asp Asp Pro Glu Val Gln Phe Thr Trp Tyr Ile
260 265 270
Asn Asn Glu Gln Val Arg Thr Ala Arg Pro Pro Leu Arg Glu Gln Gln
275 280 285
Phe Asn Ser Thr Ile Arg Val Val Ser Thr Leu Pro Ile Ala His Gln
290 295 300
Asp Trp Leu Arg Gly Lys Glu Phe Lys Cys Lys Val His Asn Lys Ala
305 310 315 320
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Arg Gly Gln Pro
325 330 335
Leu Glu Pro Lys Val Tyr Thr Met Gly Pro Pro Arg Glu Glu Leu Ser
340 345 350
Ser Arg Ser Val Ser Leu Thr Cys Met Ile Asn Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ser Val Glu Trp Glu Lys Asn Gly Lys Ala Glu Asp Asn Tyr
370 375 380
Lys Thr Thr Pro Ala Val Leu Asp Ser Asp Gly Ser Tyr Phe Leu Tyr
385 390 395 400
Ser Lys Leu Ser Val Pro Thr Ser Glu Trp Gln Arg Gly Asp Val Phe
405 410 415
Thr Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Ile Ser Arg Ser Pro Gly Lys
435 440
Claims (13)
1.一种结合人类CD47的单克隆抗体或其抗原结合片段,该单克隆抗体或其抗原结合片段包含可变重链CDR1(HCDR1)、可变重链CDR2(HCDR2)、以及可变重链CDR3(HCDR3)、可变轻链CDR1(LCDR1)、可变轻链CDR2(LCDR2)、以及可变轻链CDR3(LCDR3)的组合,其中该组合选自下组,该组由以下各项组成:
(i)SEQ ID NO:1的HCDR1、SEQ ID NO:4的HCDR2、SEQ ID NO:7的HCDR3、SEQ ID NO:11的LCDR1、SEQ ID NO:15的LCDR2、SEQ ID NO:18的LCDR3;
(ii)SEQ ID NO:1的HCDR1、SEQ ID NO:4的HCDR2、SEQ ID NO:8的HCDR3、SEQ ID NO:11的LCDR1、SEQ ID NO:15的LCDR2、SEQ ID NO:18的LCDR3;
(iii)SEQ ID NO:2的HCDR1、SEQ ID NO:5的HCDR2、SEQ ID NO:9的HCDR3、SEQ ID NO:12的LCDR1、SEQ ID NO:16的LCDR2、SEQ ID NO:19的LCDR3;
(iv)SEQ ID NO:3的HCDR1、SEQ ID NO:6的HCDR2、SEQ ID NO:10的HCDR3、SEQ ID NO:14的LCDR1、SEQ ID NO:17的LCDR2、SEQ ID NO:19的LCDR3;以及
(v)SEQ ID NO:3的HCDR1、SEQ ID NO:6的HCDR2、SEQ ID NO:10的HCDR3、SEQ ID NO:14的LCDR1、SEQ ID NO:17的LCDR2、SEQ ID NO:18的LCDR3。
2.如权利要求1所述的单克隆抗体或抗原结合片段,其中该抗体或其抗原结合片段包含重链可变结构域(VH)和轻链可变结构域(VL)的组合,该组合选自由以下各项组成的组:
(i)氨基酸序列SEQ ID NO:21的重链可变结构域和氨基酸序列SEQ ID NO:41的轻链可变结构域;
(ii)氨基酸序列SEQ ID NO:23的重链可变结构域和氨基酸序列SEQ ID NO:43的轻链可变结构域;
(iii)氨基酸序列SEQ ID NO:34的重链可变结构域和氨基酸序列SEQ ID NO:49的轻链可变结构域;
(iv)氨基酸序列SEQ ID NO:36的重链可变结构域和氨基酸序列SEQ ID NO:52的轻链可变结构域;
(v)氨基酸序列SEQ ID NO:38的重链可变结构域和氨基酸序列SEQ ID NO:52的轻链可变结构域;
(vi)氨基酸序列SEQ ID NO:39的重链可变结构域和氨基酸序列SEQ ID NO:52的轻链可变结构域;
(vii)氨基酸序列SEQ ID NO:24的重链可变结构域和氨基酸序列SEQ ID NO:43的轻链可变结构域;
(viii)氨基酸序列SEQ ID NO:37的重链可变结构域和氨基酸序列SEQ ID NO:52的轻链可变结构域;
(ix)氨基酸序列SEQ ID NO:33的重链可变结构域和氨基酸序列SEQ ID NO:48的轻链可变结构域;
(x)氨基酸序列SEQ ID NO:26的重链可变结构域和氨基酸序列SEQ ID NO:44的轻链可变结构域;
(xi)氨基酸序列SEQ ID NO:27的重链可变结构域和氨基酸序列SEQ ID NO:44的轻链可变结构域;
(xii)氨基酸序列SEQ ID NO:38的重链可变结构域和氨基酸序列SEQ ID NO:51的轻链可变结构域;
(xiii)氨基酸序列SEQ ID NO:39的重链可变结构域和氨基酸序列SEQ ID NO:51的轻链可变结构域;
(xiv)氨基酸序列SEQ ID NO:40的重链可变结构域和氨基酸序列SEQ ID NO:52的轻链可变结构域;
(xv)氨基酸序列SEQ ID NO:36的重链可变结构域和氨基酸序列SEQ ID NO:51的轻链可变结构域;
(xvi)氨基酸序列SEQ ID NO:29的重链可变结构域和氨基酸序列SEQ ID NO:47的轻链可变结构域;
(xvii)氨基酸序列SEQ ID NO:30的重链可变结构域和氨基酸序列SEQ ID NO:47的轻链可变结构域;
(xviii)氨基酸序列SEQ ID NO:31的重链可变结构域和氨基酸序列SEQ ID NO:47的轻链可变结构域;
(xix)氨基酸序列SEQ ID NO:32的重链可变结构域和氨基酸序列SEQ ID NO:47的轻链可变结构域;
(xx)氨基酸序列SEQ ID NO:33的重链可变结构域和氨基酸序列SEQ ID NO:47的轻链可变结构域;
(xxi)氨基酸序列SEQ ID NO:29的重链可变结构域和氨基酸序列SEQ ID NO:48的轻链可变结构域;
(xxii)氨基酸序列SEQ ID NO:30的重链可变结构域和氨基酸序列SEQ ID NO:48的轻链可变结构域;
(xxiii)氨基酸序列SEQ ID NO:31的重链可变结构域和氨基酸序列SEQ ID NO:48的轻链可变结构域;
(xxiv)氨基酸序列SEQ ID NO:32的重链可变结构域和氨基酸序列SEQ ID NO:48的轻链可变结构域;
(xxv)氨基酸序列SEQ ID NO:26的重链可变结构域和氨基酸序列SEQ ID NO:43的轻链可变结构域;
(xxvi)氨基酸序列SEQ ID NO:27的重链可变结构域和氨基酸序列SEQ ID NO:43的轻链可变结构域;
(xxvii)氨基酸序列SEQ ID NO:28的重链可变结构域和氨基酸序列SEQ ID NO:46的轻链可变结构域;
(xxviii)氨基酸序列SEQ ID NO:35的重链可变结构域和氨基酸序列SEQ ID NO:50的轻链可变结构域;
(xxix)氨基酸序列SEQ ID NO:29的重链可变结构域和氨基酸序列SEQ ID NO:48的轻链可变结构域;
(xxx)氨基酸序列SEQ ID NO:30的重链可变结构域和氨基酸序列SEQ ID NO:48的轻链可变结构域;
(xxxi)氨基酸序列SEQ ID NO:31的重链可变结构域和氨基酸序列SEQ ID NO:48的轻链可变结构域;
(xxxii)氨基酸序列SEQ ID NO:32的重链可变结构域和氨基酸序列SEQ ID NO:48的轻链可变结构域;
(xxxiii)氨基酸序列SEQ ID NO:37的重链可变结构域和氨基酸序列SEQ ID NO:51的轻链可变结构域;
(xxxiv)氨基酸序列SEQ ID NO:40的重链可变结构域和氨基酸序列SEQ ID NO:51的轻链可变结构域;或者
该VH氨基酸序列与以上(i)至(xxxiv)所示出的重链氨基酸序列具有至少90%、95%、97%、98%或99%一致性并且该VL氨基酸序列与以上(i)至(xxxiv)所示出的轻链氨基酸序列具有至少90%、95%、97%、98%或99%一致性。
3.根据权利要求1或2所述的单克隆抗体,该单克隆抗体包含选自下组的至少一条重链和至少一条轻链,该组由以下各项组成:
(i)氨基酸序列SEQ ID NO:76的重链和氨基酸序列SEQ ID NO:66的轻链;
(ii)氨基酸序列SEQ ID NO:77的重链和氨基酸序列SEQ ID NO:68的轻链;
(iii)氨基酸序列SEQ ID NO:78的重链和氨基酸序列SEQ ID NO:69的轻链;
(iv)氨基酸序列SEQ ID NO:79的重链和氨基酸序列SEQ ID NO:70的轻链;
(v)氨基酸序列SEQ ID NO:80的重链和氨基酸序列SEQ ID NO:70的轻链;
(vi)氨基酸序列SEQ ID NO:81的重链和氨基酸序列SEQ ID NO:70的轻链;
(vii)氨基酸序列SEQ ID NO:82的重链和氨基酸序列SEQ ID NO:68的轻链;
(viii)氨基酸序列SEQ ID NO:83的重链和氨基酸序列SEQ ID NO:70的轻链;
(ix)氨基酸序列SEQ ID NO:84的重链和氨基酸序列SEQ ID NO:71的轻链;
(x)氨基酸序列SEQ ID NO:85的重链和氨基酸序列SEQ ID NO:72的轻链;
(xi)氨基酸序列SEQ ID NO:86的重链和氨基酸序列SEQ ID NO:72的轻链;
(xii)氨基酸序列SEQ ID NO:80的重链和氨基酸序列SEQ ID NO:73的轻链;
(xiii)氨基酸序列SEQ ID NO:81的重链和氨基酸序列SEQ ID NO:73的轻链;
(xiv)氨基酸序列SEQ ID NO:87的重链和氨基酸序列SEQ ID NO:70的轻链;
(xv)氨基酸序列SEQ ID NO:79的重链和氨基酸序列SEQ ID NO:73的轻链;
(xvi)氨基酸序列SEQ ID NO:88的重链和氨基酸序列SEQ ID NO:74的轻链;
(xvii)氨基酸序列SEQ ID NO:89的重链和氨基酸序列SEQ ID NO:74的轻链;
(xviii)氨基酸序列SEQ ID NO:90的重链和氨基酸序列SEQ ID NO:74的轻链;
(xix)氨基酸序列SEQ ID NO:91的重链和氨基酸序列SEQ ID NO:74的轻链;
(xx)氨基酸序列SEQ ID NO:84的重链和氨基酸序列SEQ ID NO:74的轻链;
(xxi)氨基酸序列SEQ ID NO:92的重链和氨基酸序列SEQ ID NO:71的轻链;
(xxii)氨基酸序列SEQ ID NO:89的重链和氨基酸序列SEQ ID NO:71的轻链;
(xxiii)氨基酸序列SEQ ID NO:90的重链和氨基酸序列SEQ ID NO:31的轻链;
(xxiv)氨基酸序列SEQ ID NO:91的重链和氨基酸序列SEQ ID NO:71的轻链;
(xxv)氨基酸序列SEQ ID NO:85的重链和氨基酸序列SEQ ID NO:68的轻链;
(xxvi)氨基酸序列SEQ ID NO:86的重链和氨基酸序列SEQ ID NO:68的轻链;
(xxvii)氨基酸序列SEQ ID NO:93的重链和氨基酸序列SEQ ID NO:100的轻链;
(xxviii)氨基酸序列SEQ ID NO:94的重链和氨基酸序列SEQ ID NO:75的轻链;
(xxix)氨基酸序列SEQ ID NO:95的重链和氨基酸序列SEQ ID NO:71的轻链;
(xxx)氨基酸序列SEQ ID NO:96的重链和氨基酸序列SEQ ID NO:71的轻链;
(xxxi)氨基酸序列SEQ ID NO:97的重链和氨基酸序列SEQ ID NO:71的轻链;
(xxxii)氨基酸序列SEQ ID NO:98的重链和氨基酸序列SEQ ID NO:71的轻链;
(xxxiii)氨基酸序列SEQ ID NO:83的重链和氨基酸序列SEQ ID NO:73的轻链;
(xxxiv)氨基酸序列SEQ ID NO:87的重链和氨基酸序列SEQ ID NO:73的轻链;
(xxxv)氨基酸序列SEQ ID NO:102的重链和氨基酸序列SEQ ID NO:101的轻链;
(xxxvi)氨基酸序列SEQ ID NO:104的重链和氨基酸序列SEQ ID NO:103的轻链;或者
该VH氨基酸序列与以上(i)至(xxxiv)所示出的重链氨基酸序列具有至少90%、95%、97%、98%或99%一致性并且该VL氨基酸序列与以上(i)至(xxxiv)所示出的轻链氨基酸序列具有至少90%、95%、97%、98%或99%一致性。
4.一种药物组合物,该药物组合物包含如权利要求1-3中任一项所述的单克隆抗体或其抗原结合片段、以及药学上或生理学上可接受的载体、稀释剂、或赋形剂。
5.权利要求1-3中任一项所述的单克隆抗体或其抗原结合片段或者权利要求4所述的药物组合物在制备用于在i)减少、预防和/或治疗缺血再灌注损伤、或自身免疫性疾病、炎性疾病或心血管疾病,或ii)减少、预防和/或治疗心力衰竭,或iii)预防或治疗人类患者中的癌症的药物中的用途。
6.权利要求1-3中任一项所述的单克隆抗体或其抗原结合片段或者权利要求4所述的药物组合物在制备用于在减少、预防和/或治疗自身炎性疾病的药物中的用途。
7.如权利要求5所述的用途,其中所述癌症选自下组,该组由以下各项组成:白血病、淋巴瘤、卵巢癌、乳腺癌、结肠癌、直肠癌、膀胱癌、尿路上皮癌、肺癌、支气管癌、骨癌、前列腺癌、胰腺癌、胃癌、肝细胞癌、胆囊癌、胆管癌、食道癌、肾细胞癌、甲状腺癌、头颈部鳞状细胞癌、睾丸癌、内分泌腺癌、肾上腺癌、皮肤癌、血管癌、脑癌、神经癌、眼癌、口咽癌、宫颈癌、子宫癌、黑色素瘤、以及肉瘤。
8.如权利要求7所述的用途,其中所述白血病选自下组,该组由以下各项组成:全身性肥大细胞增多症、急性淋巴细胞(成淋巴细胞)白血病(ALL)、T细胞-ALL、急性髓性白血病(AML)、粒细胞性白血病、慢性淋巴细胞白血病(CLL)、慢性骨髓性白血病(CML)、骨髓增生障碍/赘生物、单核细胞白血病、以及浆细胞白血病;
其中所述淋巴瘤选自下组,该组由以下各项组成:组织细胞性淋巴瘤和T细胞淋巴瘤、B细胞淋巴瘤,霍奇金淋巴瘤、低级别/滤泡性非霍奇金淋巴瘤(NHL)、细胞淋巴瘤(FCC)、套细胞淋巴瘤(MCL)、弥漫性大细胞淋巴瘤(DLCL)、小淋巴细胞性(SL)NHL、中等级别/滤泡性NHL、中等级别的弥漫性NHL、高级别成免疫细胞NHL、高级别成淋巴细胞NHL、高级别小非裂细胞NHL、巨大肿块NHL、以及瓦尔登斯特伦巨球蛋白血症;
其中所述肺癌选自下组,该组由以下各项组成:非小细胞肺癌、肺腺癌和肺鳞状细胞癌;并且
其中所述肉瘤选自下组,该组由以下各项组成:骨肉瘤、尤文肉瘤、平滑肌肉瘤、滑膜肉瘤、腺泡状软组织肉瘤、血管肉瘤、脂肪肉瘤、纤维肉瘤、横纹肌肉瘤、以及软骨肉瘤。
9.如权利要求5所述的用途,其中所述癌症选自下组,该组由以下各项组成:子宫内膜癌、结肠直肠癌、骨髓增生异常综合征、头颈癌、软组织癌、脑下垂体癌、脑膜癌、胃泌素瘤、下咽部癌、成胶质细胞瘤、成神经管细胞瘤和星形细胞瘤。
10.如权利要求5所述的用途,其中所述癌症选自下组,该组由以下各项组成:非霍奇金淋巴瘤、脑膜瘤、胶质瘤和成神经细胞瘤。
11.如权利要求5所述的用途,其中所述癌症是多发性骨髓瘤(MM)。
12.如权利要求5-11中任一项所述的用途,其中静脉内或皮下给药所述单克隆抗体或其抗原结合片段。
13.权利要求1-3中任一项所述的单克隆抗体或其抗原结合片段在制备测定肿瘤和/或免疫细胞中的CD47表达的药物中的用途,该单克隆抗体或其抗原结合片段特异性结合序列SEQ ID NO:65中的表位。
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NZ740686A (en) | 2021-12-24 |
WO2017049251A3 (en) | 2017-04-20 |
US10239945B2 (en) | 2019-03-26 |
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