CN109180815B - 抗ceacam5抗体及其用途 - Google Patents
抗ceacam5抗体及其用途 Download PDFInfo
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- CN109180815B CN109180815B CN201810935038.6A CN201810935038A CN109180815B CN 109180815 B CN109180815 B CN 109180815B CN 201810935038 A CN201810935038 A CN 201810935038A CN 109180815 B CN109180815 B CN 109180815B
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Abstract
本发明涉及抗CEACAM5抗体及其用途。本发明公开结合人和食蟹猴(Macaca fascicularis)CEACAM5蛋白的抗体,以及包含编码所述抗体的序列的分离的核酸、载体和宿主细胞。本发明还公开包含与生长抑制剂偶联或连接的所述抗体的免疫偶联物,和包含本发明抗体或免疫偶联物的药物组合物。本发明的抗体或免疫偶联物可用于治疗癌症或用于诊断目的。
Description
本申请是申请日为2013年11月20日、中国申请号为201380070899.8、发明名称为“抗CEACAM5抗体及其用途”的发明申请的分案申请。
技术领域
本发明公开特异性结合人和食蟹猴(Macaca fascicularis)CEACAM5蛋白的抗体和包含编码所述抗体的序列的分离的核酸、载体和宿主细胞。本发明还公开包含与生长抑制剂偶联或连接的所述抗体的免疫偶联物,和包含本发明抗体或免疫偶联物的药物组合物。本发明公开本发明的抗体或免疫偶联物用于癌症治疗或用于诊断目的的用途。
背景技术
癌胚抗原(CEA)是一种参与细胞粘附的糖蛋白。CEA于1965年(Gold和Freedman,JExp Med,121,439,1965)首次作为一种通常在妊娠的前六个月期间由胎肠表达的蛋白质得以鉴定,且发现于胰癌、肝癌和结肠癌中。CEA家族属于免疫球蛋白超家族。由18个基因组成的CEA家族细分为两个蛋白质亚群:癌胚抗原相关细胞粘附分子(CEACAM)亚群和妊娠特异性糖蛋白亚群(Kammerer和Zimmermann,BMC Biology 2010,8:12)。
在人中,CEACAM亚群由7个成员组成:CEACAM1、CEACAM3、CEACAM4、CEACAM5、CEACAM6、CEACAM7、CEACAM8。多项研究已表明,与最初鉴定的CEA相同的CEACAM5在结肠直肠、胃、肺、乳腺、前列腺、卵巢、子宫颈和膀胱肿瘤细胞的表面上具有高表达,并在少数正常上皮组织(例如结肠中的柱状上皮和杯状细胞、胃中的黏液颈细胞和食道和子宫颈中的鳞状上皮细胞)中具有弱表达(et al,2002,in"Tumor markers,Physiology,Pathobiology,Technology and Clinical Applications"Eds.Diamandis E.P.et al.,AACC Press,Washington pp 375)。因此,CEACAM5可构成适于肿瘤特异性靶向方法例如免疫偶联物的治疗靶。本发明提供针对CEACAM5的单克隆抗体,且表明其可与细胞毒性剂偶联以诱导能够在体外杀死肿瘤细胞的细胞毒性活性并在体内引起肿瘤消退。
CEACAM家族成员的胞外结构域由重复免疫球蛋白样(Ig样)结构域构成,根据序列同源性,所述重复免疫球蛋白样(Ig样)结构域已分为3种类型:A、B和N。CEACAM5包含7个这样的结构域,即N、A1、B1、A2、B2、A3和B3。
一方面CEACAM5 A1、A2和A3结构域与另一方面的B1、B2和B3结构域展示高序列同源性,人CEACAM5的A结构域呈现84%至87%成对序列相似性,且B结构域呈现69%至80%成对序列相似性。此外,其结构中呈现A和/或B结构域的其他人CEACAM成员(即CEACAM1、CEACAM6、CEACAM7和CEACAM8)展示与人CEACAM5的同源性。具体而言,人CEACAM6蛋白的A和B结构域分别展示与人CEACAM5的A1和A3结构域和B1至B3结构域中任一种的序列同源性,该序列同源性甚至高于在人CEACAM5的A结构域和B结构域中所观察到的序列同源性。
考虑到CEA靶向诊断或治疗目的生成了多种抗CEA抗体。关于相关抗原的特异性一直都作为本领域的担忧被提及,举例来说由Sharkey et al,(1990,Cancer Research 50,2823)提及。由于上文所述的同源性,一些之前描述的抗体可展示出与存在于不同免疫球蛋白结构域中的CEACAM5的重复表位的结合,表现出缺乏针对CEACAM5的特异性的与其他CEACAM成员(例如CEACAM1、CEACAM6、CEACAM7或CEACAM8)的交叉反应性。抗CEACAM5抗体的特异性对于靶向CEA的疗法而言是理想的,由此其与表达人CEACAM5的肿瘤细胞结合,而不与一些表达其他CEACAM成员的正常组织结合。值得注意的是,CEACAM1、CEACAM6和CEACAM8已描述可由人和非人灵长类动物的嗜中性粒细胞表达(Ebrahimmnejad et al,2000,ExpCell Res,260,365;Zhao et al,2004,J Immunol Methods 293,207;Strickland et al,2009 J Pathol,218,380),其中已显示其调控粒细胞生成且在免疫反应中起作用。
已对抗CEACAM6抗体药物偶联物进行了描述,例如由Genentech开发的类美登素(maytansinoid)抗CEACAM6抗体(Strickland et al,2009 J Pathol,218,380),已显示其诱导非人灵长类动物的CEACAM6依赖性造血毒性。作者认为因骨髓中抗体药物偶联物的累积和粒细胞和其细胞前体的消耗造成的该种毒性是主要安全问题。因此,更准确来说,出于治疗的目的,抗CEACAM5抗体与CEACAM1、CEACAM6、CEACAM7或CEACAM8的交叉反应性可能因为增加的对正常组织的毒性而降低了化合物的治疗指数。因此,非常有利的是获得不会与CEACAM家族的其他分子交叉反应的特异性针对CEACAM5的抗体,尤其对于用作抗体药物偶联物(ADC)的用途或利用任何其他导致靶细胞杀伤的作用模式。
此外,由于据记载CEACAM5在一些正常细胞组织中表达(尽管以低水平),建立能够与人CEACAM5结合以及与食蟹猴(Macaca fascicularis)CEACAM5结合的抗CEACAM5抗体至关重要,因为这样的抗体可以很容易地在食蟹猴的临床前毒理学研究中测试以评估其安全概貌。由于已表明在功能性抗体的情况(Doern et al,2009,J.Biol.Chem 284 10254)和涉及效应物功能的情况(Beers et al,Semin Hematol 47:107-114)二者中,治疗性抗体的效力可能依赖于表位在靶向物中的定位,因此必须表明人/猴交叉反应性抗体结合人和食蟹猴蛋白中相同的重复Ig样同源结构域中的表位。
鉴于人与食蟹猴CEACAM蛋白间整体序列的同源性,对这些抗体的物种交叉反应性的需求结合上对人和食蟹猴CEACAM5的特异性(即与其他食蟹猴和人CEACAM成员没有交叉反应性)进一步增加了复杂程度。
实际上,食蟹猴CEACAM5序列与人CEACAM5序列(AAA51967.1/GI:180223,702个氨基酸)的整体成对比对仅表明78.5%的同一性。克隆了食蟹猴CEACAM1、CEACAM5和CEACAM6基因并实施了人和食蟹猴A、B和N结构域的全局比对。该比对预测在极少数区域(如果存在)可定位将对人和猕猴CEACAM5通用且不与任何其他家族成员共享的理想表位。由于这些原因,开发与人和食蟹猴CEACAM5交叉反应而不与其他人和食蟹猴CEACAM成员交叉反应的抗体预期成功的可能性很低。值得注意的是,之前描述的抗CEACAM5抗体几乎从未有记录在案的食蟹猴交叉反应性,仅有极少数例外(MT111,参见下文)。
抗人CEACAM5抗体已用于临床试验,如Immunomedics拉贝珠单抗(labetuzumab)(还称为hMN14,Sharkey et al,1995,Cancer Research 55,5935)。该抗体已显示不与相关抗原结合,且其不与来自食蟹猴的CEACAM5交叉反应。值得注意的是,Micromet的MT111抗体(还称为MedImmune的MEDI-565抗体)是与人CEACAM5和人CD3结合的双特异性抗体(Peng etal,PLoS ONE 7(5):e3641;WO 2007/071426)。MT111据称已通过融合来自识别人和食蟹猴CEACAM5的抗体的单链可变片段(scFv)和来自识别人CD3的抗体的scFv而创建(Oberst etal.海报,AACR Annual Meeting April 2009 Denver,CO)。还已报导,MT111并不结合其他CEACAM家族成员(Peng et al,PLoS ONE 7(5):e3641)。MT111与人CEACAM5的A2结构域中的构象表位结合。该构象表位在人CEACAM5的剪接变体中丢失,该变体与全长CEACAM5同时在肿瘤上表达(Peng et al,PLoS ONE 7(5):e3641)。此外,并无证据表明MT111与食蟹猴CEACAM5中的相同表位结合。
在出于治疗的目的产生具有最佳特性的针对CEACAM5表面蛋白的新抗体的尝试中,发明人用重组蛋白和用肿瘤细胞免疫小鼠。其使用对CEACAM家族的数种重组蛋白进行的ELISA和使用相关细胞的流式细胞术对数百种杂交瘤进行了筛选,以仅选择具有有利特征(profile)的免疫球蛋白(IgG)。出乎意料的是,其能够选择杂交瘤克隆并产生包含所有预期特征的相应的成熟IgG。其以高亲和性与人CEACAM5的A3-B3结构域结合且并不识别人CEACAM1、CEACAM6、CEACAM7和CEACAM8蛋白。在细胞背景下,所述抗体展示针对肿瘤细胞的高亲和性(纳摩范围)。此外,这些抗体还与食蟹猴CEACAM5蛋白结合,伴随小于或等于10的猴/人亲和性比率。本发明抗体特异性与食蟹猴CEACAM5的A3-B3结构域结合且并不识别其他食蟹猴CEACAM成员。
通过靶向CEACAM5的A3-B3结构域,这些抗体具有增加的靶向肿瘤潜力,因此其同时具有与全长人CEACAM5结合和与由Peng et al,(PLoS ONE 7(5):e3641)鉴定的剪接变体结合的能力。
最后,CEACAM5在文献中被描述为内化较差的表面蛋白(综述于Schmidt等人,2008,Cancer Immunol.Immunother.57,1879中),且因此可能并非用于抗体药物偶联物的有利靶标。尽管存在本领域已报导的内容,但发明人展示了其产生的抗体能够在结合后使CEACAM5-抗体复合物内化,且当与细胞毒性剂组合时在体外能诱导对瘤细胞的细胞毒性活性。与细胞毒性剂组合的相同抗体也能够显著抑制带有人原发性结肠和胃肿瘤的小鼠中的肿瘤生长。
发明内容
定义
如本文所使用的“CEACAM5”指代“癌胚抗原相关细胞粘附分子5”,还称为“CD66e”(分化簇66e)或CEA。CEACAM5是一种参与细胞粘附的糖蛋白。CEACAM5尤其在结肠直肠、胃、肺和子宫肿瘤细胞的表面上高度表达。
全长人CEACAM5的参照序列可从GenBank数据库以登录号AAA51967.1(SEQ ID NO:52)获得,包含信号肽(位置1-34)和前肽(位置686-702)。已在白种人中鉴定了具有高于2%的频率的五个非同义SNP,其中的四个位于N结构域(在位置80、83、112、113)中,最后一个位于人CECAM5的A2结构域中(SEQ ID NO:58)(在位置398)。GenBank AAA51967.1包含主要单倍型(I80、V83、I112、I113和E398)。
由发明人克隆的食蟹猴CEACAM5的胞外结构域序列公开于SEQ ID NO:53中。
“结构域”可以是蛋白的任何区域,其通常基于序列同源性定义且通常与特定结构或功能性实体相关。已知CEACAM家族成员由Ig样结构域构成。在本文件中使用术语结构域来指代单独的Ig样结构域(例如“N-结构域”)或连续结构域的集合(例如“A3-B3结构域”)。
人CEACAM5的结构域组成如下(基于GenBank AAA51967.1序列;SEQ ID NO:52):
人CEACAM5结构域 | SEQ ID NO:52上的位置 |
结构域N | 35-142 |
结构域A1 | 143-237 |
结构域B1 | 238-320 |
结构域A2 | 321-415 |
结构域B2 | 416-498 |
结构域A3 | 499-593 |
结构域B3 | 594-685 |
相应地,人CEACAM5的A3-B3结构域由SEQ ID NO:52的位置499-685处的氨基酸组成:
食蟹猴CEACAM5的结构域组成如下(基于克隆的胞外结构域序列;SEQ ID NO:53):
食蟹猴CEACAM5的结构域 | SEQ ID NO:53上的位置 |
结构域N-A1-B1 | -1-286 |
结构域A2-B2 | -287-464 |
结构域A3-B3 | 465-654 |
相应地,食蟹猴CEACAM5的A3-B3结构域由SEQ ID NO:53的位置465-654处氨基酸组成。
“编码序列”或“编码”表达产物(如RNA、多肽、蛋白质或酶)的序列是表达时导致所述RNA、多肽、蛋白质或酶产生的核苷酸序列,即所述核苷酸序列编码用于该多肽、蛋白质或酶的氨基酸序列。蛋白质的编码序列可包含起始密码子(通常为ATG)和终止密码子。
如本文所使用,对特定蛋白质(例如抗体)的提及可包括具有天然氨基酸序列的多肽以及变体和修饰形式,而与其来源或制备模式无关。具有天然氨基酸序列的蛋白质是具有与从自然界获得的相同的氨基酸序列的蛋白质。这样的天然序列蛋白质可从自然界分离或可使用标准重组和/或合成方法制备。天然序列蛋白质特定涵盖天然存在的截短或可溶形式、天然存在的变体形式(例如,替代性剪接形式)、天然存在的等位基因变体和包含翻译后修饰的形式。天然序列蛋白质包括携载翻译后修饰的蛋白质,所述修饰如糖基化或磷酸化或一些氨基酸残基的其他修饰。
术语“基因”意为编码或对应于包含一种或多种蛋白质或酶的全部或部分的具体氨基酸序列的DNA序列,且可或可不包含如启动子序列等决定举例来说基因在何种条件表达的DNA调控序列。一些并非结构基因的基因可从DNA转录成RNA,但并不翻译成氨基酸序列。其他基因可作为结构基因的调节子或作为DNA转录的调节子发挥功能。具体而言,术语基因可意在针对编码蛋白质的基因组序列,即包含调节子、启动子、内含子和外显子序列的序列。
“与参照序列至少85%相同”的序列是基于其整个长度与参照序列的整个长度具有85%或更多、例如90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列同一性的序列。
“序列同一性”的百分比可通过比较在比较窗口中以最优方式对其的两个序列测定,其中与参照序列(其不包含添加或缺失)相比,比较窗口中多核苷酸或多肽序列的部分序列可包含添加或缺失(即,缺口),以供两序列的最优比对。该百分比通过以下方式来计算:测定两序列中相同核酸碱基或氨基酸残基出现的位置数以获得匹配位置数,用匹配位置数除以比较窗口中的位置总数,并用结果乘以100以获得序列同一性百分比。用于比较的序列的最佳比对通过全局成对比对使用例如Needleman算法和Wunsch J.Mol.Biol.48:443(1970)实施。序列同一性百分比可举例来说使用具有BLOSUM62矩阵的Needle程序和下列参数轻易测定:缺口开放=10、缺口延伸=0.5。
“保守氨基酸取代”是其中氨基酸残基由具有化学性质(例如电荷、大小或疏水性)相似的侧链R基团的另一氨基酸残基取代的一种取代。通常,保守氨基酸取代不会实质上改变蛋白质的功能性质。具有化学性质相似的侧链的氨基酸的组的实例包括1)脂肪族侧链:甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸;2)脂肪族-羟基侧链:丝氨酸和苏氨酸;3)含有酰胺的侧链:天冬酰胺和谷氨酰胺;4)芳香族侧链:苯丙氨酸、酪氨酸和色氨酸;5)碱性侧链:赖氨酸、精氨酸和组氨酸;6)酸性侧链:天冬氨酸和谷氨酸;和7)含硫侧链:半胱氨酸和甲硫氨酸。保守氨基酸取代基团还可基于氨基酸大小定义。
“抗体”可以是其中两条重链通过二硫键彼此连接且每一重链通过二硫键与轻链连接的天然或常规抗体。存在两种类型的轻链,λ(l)和κ(k)。存在五类(或同型)的决定抗体分子功能活性的主要重链:IgM、IgD、IgG、IgA和IgE。每种链含有不同序列结构域。轻链包含两个结构域或区:可变结构域(VL)和恒定结构域(CL)。重链包含四个结构域:一个可变结构域(VH)和三个恒定结构域(CH1、CH2和CH3,统称为CH)。轻链(VL)和重链(VH)二者的可变区决定对抗原的结合识别和特异性。轻链(CL)和重链(CH)的恒定区结构域赋予重要生物特性,如抗体链联合、分泌、经胎盘活动性、补体结合和与Fc受体(FcR)的结合。Fv片段是免疫球蛋白Fab片段的N端部分,且由一条轻链和一条重链的可变部分组成。抗体的特异性在于抗体结合位点与抗原决定区间的结构互补性。抗体结合位点是由主要来自超变或互补决定区(CDR)的残基构成。有时候,来自非超变或框架区(FR)的残基影响总体结构域结构,且因此影响结合位点。因此,互补决定区或CDR指共同定义天然免疫球蛋白结合位点的天然Fv区结合亲和性和特异性的氨基酸序列。免疫球蛋白的轻链和重链各具有三个CDR,分别称为CDR1-L、CDR2-L、CDR3-L和CDR1-H、CDR2-H、CDR3-H。因此,常规抗体抗原结合位点包含六个CDR,包括来自重链和轻链V区的各自CDR集合。
“框架区”(FR)指插入CDR间的氨基酸序列,即指单一物种的不同免疫球蛋白中相对保守的免疫球蛋白轻链和重链可变区中的那些部分。免疫球蛋白的轻链和重链各具有四个FR,分别称为FR1-L、FR2-L、FR3-L、FR4-L和FR1-H、FR2-H、FR3-H、FR4-H。
如本文所使用的“人框架区”是与天然存在的人抗体框架区实质上(约85%,或更多,例如90%、91%、92%、93%、94%、95%、96%、97%、98%或99%)相同的框架区。
在本发明背景下,免疫球蛋白轻链或重链中的CDR/FR定义基于IMGT的定义(Lefranc et al,Dev.Comp.Immunol.,2003,27(1):55-77;www.imgt.org)确定。
如本文所使用的术语“抗体”指代常规抗体及其片段,以及单一结构域抗体及其片段,特别是单一结构域抗体的可变重链,和嵌合、人源化、双特异性或多特异性抗体。
如本文所使用,抗体或免疫球蛋白还包括“单一结构域抗体”,最近已对其进行了描述且其为其互补决定区为单一结构域多肽的一部分的抗体。单一结构域抗体的实例包括重链抗体、天然不含轻链的抗体、源自常规四链抗体的单一结构域抗体、工程化的单一结构域抗体。单一结构域抗体可源自任何物种,包括但不限于小鼠、人、骆驼、美洲驼、山羊、兔、牛。单一结构域抗体可为天然存在的单一结构域抗体,其被认为是不含轻链的重链抗体。具体而言,骆驼科(Camelidae)物种举例来说骆驼、单峰骆驼、美洲驼、羊驼和原驼产生天然不含轻链的重链抗体。骆驼科重链抗体还缺少CH1结构域。
本领域已将这些不含轻链的单一结构域抗体的可变重链称为“VHH”或“纳米抗 体”。与常规VH结构域相似,VHH含有四个FR和三个CDR。纳米抗体具有优于常规抗体的优势:其比IgG分子小约10倍,且因此适当折叠的功能性纳米抗体可通过体外表达来产生,同时获得高产率。此外,纳米抗体非常稳定,且抗蛋白酶的作用。纳米抗体的性质和产生已由Harmsen和De Haard HJ(Appl.Microbiol.Biotechnol.2007年11月;77(1):13-22)加以综述。
如本文使用的术语“单克隆抗体”或“mAb”指单一氨基酸序列的抗体分子,其针对特定抗原且不应理解为该抗体需要通过任何具体方法产生。单克隆抗体可通过B细胞或杂交瘤的单克隆产生,但也可以是重组的,即通过蛋白工程化产生。
术语“嵌合抗体”一起最广的含义指包含来自一种抗体的一个或多个区和来自一个或多个其他抗体的一个或多个区的工程化抗体。在一实施方案中,嵌合抗体包含源自非人动物的抗体的VH结构域和VL结构域,其与另一抗体(在一实施方案中为人抗体)的CH结构域和CL结构域联合。作为非人动物,可使用任何动物如小鼠、大鼠、仓鼠、兔等等。嵌合抗体还可指代对至少两种不同抗原具有特异性的多特异性抗体。
术语“人源化抗体”指完全或部分为非人来源的抗体,且已对其修饰以替代某些氨基酸(举例来说,VH和VL结构域的框架区中的氨基酸)以避免或最小化人的免疫反应。人源化抗体的恒定结构域大多为人CH和CL结构域。
(常规)抗体的“片段”包含完整抗体的一部分,尤其完整抗体的抗原结合区或可变区。抗体片段的实例包括Fv、Fab、F(ab')2、Fab'、dsFv、(dsFv)2、scFv、sc(Fv)2、由抗体片段形成的双抗体、双特异性和多特异性抗体。常规抗体的片段还可以是单一结构域抗体,例如重链抗体或VHH。
术语“Fab”指代具有约50,000分子量和抗原结合活性的抗体片段,其中重链N末端约侧一半和整个轻链通过二硫键键结在一起。其通常从片段中通过蛋白酶木瓜蛋白酶处理IgG来获得。
术语“F(ab')2”指具有约100,000分子量和抗原结合活性的抗体片段,其经由铰链区的二硫键键结合稍大于2个相同Fab片段。其通常从片段中通过蛋白酶胃蛋白酶处理IgG来获得。
术语“Fab'”指具有约50,000分子量和抗原结合活性的抗体片段,其通过剪切F(ab')2铰链区的二硫键获得。
单链Fv(“scFv”)多肽是共价连接的VH::VL异源二聚体,其通常由包含通过肽编码接头连接的VH和VL编码基因的基因融合物表达。本发明的人scFv片段包含举例来说通过使用基因重组技术保持处于适当构象的CDR。二价和多价抗体片段可通过单价scFv的联合自发形成或可由肽接头通过偶联单价scFv生成,如二价sc(Fv)2。“dsFv”是通过二硫键稳定的VH::VL异源二聚体。“(dsFv)2”指代通过肽接头偶联的两个dsFv。
术语“双特异性抗体”或“BsAb”指代在单一分子内组合两种抗体的抗原结合位点的抗体。因此,BsAb能够同时结合两种不同抗原。如例如EP 2 050 764 A1中所述,基因工程已经越来越频繁地被用来设计、修饰和产生具有结合性质和效应物功能的理想组合的抗体或抗体衍生物。
术语“多特异性抗体”指代在单一分子内组合两种或更多种抗体的抗原结合位点的抗体。
术语“双抗体”指具有两个抗原结合位点的小抗体片段,所述片段在同一多肽链(VH-VL)中包含与轻链可变结构域(VL)连接的重链可变结构域(VH)。通过在相同链的两个结构域间使用短到不允许配对的接头迫使所述结构域与另一链的互补结构域配对并产生两个抗原结合位点。
术语“杂交瘤”指通过使B细胞与骨髓瘤细胞进行细胞融合获得的细胞,其中所述B细胞通过用抗原免疫非人哺乳动物制备,所述骨髓瘤细胞源自产生具有抗原特异性的单克隆抗体的小鼠等。
“纯化的”和“分离的”当指多肽(即本发明抗体)或核苷酸序列时意为所指分子以基本上缺乏相同类型的其他生物大分子的方式存在。如本文使用的术语“纯化的”意为存在至少75%、85%、95%、96%、97%或98%重量的相同类型的生物大分子。编码特定多肽的“分离的”核酸分子是指基本上不含不编码目标多肽的其他核酸分子的核酸分子;然而,该分子可包含一些对组合物的基本特征不造成有害影响的额外碱基或部分。
如本文所使用,术语“受试者”指哺乳动物,如啮齿类动物、猫、犬和灵长类动物。此外,根据本发明的受试者为人。
抗体
发明人已成功生成、筛选并选择对人和食蟹猴CEACAM5蛋白二者展现高亲和性的特异性小鼠抗CEACAM5抗体,且其并不与人CEACAM1、CEACAM6、CEACAM7和CEACAM8蛋白也不与食蟹猴CEACAM1、CEACAM6和CEACAM8蛋白显著交叉反应。
发明人已测定所述单克隆抗体(所谓的抗体MAb1、MAb2、MAb3、MAb4和MAb5)的可变重链和轻链的序列。
所谓的“抗体MAb1”包含:
-重链的可变结构域,其由下列序列组成:
EVMLVESGGGLVKPGGSLKLSCAASGFTFSSYAMSWVRQTPEKRLEWVATISSGGSYIYYLDSVKGRFTISRDNAKNTLYLQMSSLRSEDTAMYYCARPAYYGNPAMDYWGQGTSVTVSS(SEQ ID NO:31,CDR以粗体字母显示),其中FR1-H跨越氨基酸位置1至25,CDR1-H跨越氨基酸位置26至33(SEQ ID NO:1),FR2-H跨越氨基酸位置34至50,CDR2-H跨越氨基酸位置51至58(SEQ ID NO:2),FR3-H跨越氨基酸位置59至96,CDR3-H跨越氨基酸位置97至109(SEQ ID NO:3),且FR4-H跨越氨基酸位置110至120,和
-轻链的可变结构域,其由下列序列组成:
DILMTQSQKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKPLIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNSYPLYTFGGGTKLEIK(SEQ ID NO:32,CDR以粗体字母显示),其中FR1-L跨越氨基酸位置1至26,CDR1-L跨越氨基酸位置27至32(SEQ ID NO:4),FR2-L跨越氨基酸位置33至49,CDR2-L跨越氨基酸位置50至52,FR3-L跨越氨基酸位置53至88,CDR3-L跨越氨基酸位置89至98(SEQ ID NO:6),且FR4-L跨越氨基酸位置99至108。
所谓的“抗体MAb2”包含:
-重链的可变结构域,其由下列序列组成:EVQLQESGGVLVKPGGSLKLSCAASGFVFSSYDMSWVRQTPEKRLEWVAYISSGGGITYFPDTVQGRFTVSRDNAKNTLYLQMNSLKSEDTAIYYCAAHYFGSSGPFAYWGQGTLVTVSA(SEQ ID NO:33,CDR以粗体字母显示),其中FR1-H跨越氨基酸位置1至25,CDR1-H跨越氨基酸位置26至33(SEQ ID NO:7),FR2-H跨越氨基酸位置34至50,CDR2-H跨越氨基酸位置51至58(SEQ ID NO:8),FR3-H跨越氨基酸位置59至96,CDR3-H跨越氨基酸位置97至109(SEQ ID NO:9),且FR4-H跨越氨基酸位置110至120,和
-轻链的可变结构域,其由下列序列组成:DIQMTQSPASLSASVGETVTITCRASENIFSYLAWYQQKQGKSPQLLVYNTKTLAEGVPSRFSGSGSGTQFSLKINSLQPEDFGSYYCQHHYGTPFTFGSGTKLEIK(SEQ ID NO:34,CDR以粗体字母显示),其中FR1-L跨越氨基酸位置1至26,CDR1-L跨越氨基酸位置27至32(SEQ ID NO:10),FR2-L跨越氨基酸位置33至49,CDR2-L跨越氨基酸位置50至52,FR3-L跨越氨基酸位置53至88,CDR3-L跨越氨基酸位置89至97(SEQ ID NO:12),且FR4-L跨越氨基酸位置98至107。
抗体MAb2的变体还通过在CDR2-L中引进K52R取代生成。此变体(在本文中称为“Mab2K52R”)对人和食蟹猴CEACAM5具有与MAb2基本上相同的亲和性。
所谓的“抗体MAb3”包含:
-重链的可变结构域,其由下列序列组成:EVKLVESGGGLVKPGGSLTLPCAASGFTFSRYAMSWVRQTPEKRLEWVASISSGGDTYYPDSVKGRFTVSRDNARNILFLQMSSLRSEDTGMYYCARVNYYDSSFLDWWGQGTTLTVSS(SEQ ID NO:35,CDR以粗体字母显示),其中FR1-H跨越氨基酸位置1至25,CDR1-H跨越氨基酸位置26至33(SEQ ID NO:13),FR2-H跨越氨基酸位置34至50,CDR2-H跨越氨基酸位置51至57(SEQ ID NO:14),FR3-H跨越氨基酸位置58至95,CDR3-H跨越氨基酸位置96至108(SEQ ID NO:15),且FR4-H跨越氨基酸位置109至119,和
-轻链的可变结构域,其由下列序列组成:DIVMTQSQRFMSTLEGDRVSVTCKASQNVGTNVAWYQQKPGQSPKALIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNNYPLYTFGGGTKLEIK(SEQ ID NO:36,CDR以粗体字母显示),其中FR1-L跨越氨基酸位置1至26,CDR1-L跨越氨基酸位置27至32(SEQ ID NO:16),FR2-L跨越氨基酸位置33至49,CDR2-L跨越氨基酸位置50至52,FR3-L跨越氨基酸位置53至88,CDR3-L跨越氨基酸位置89至98(SEQ ID NO:18),且FR4-L跨越氨基酸位置99至108。
所谓的“抗体MAb4”包含:
-重链的可变结构域,其由下列序列组成:EVQLVESGGGLVKPGGSLKLSCAASGFTFSSYDMSWVRQTPEKRLEWVAFISSYGGRTYYADTVKGRFTISRDNAKNTLYLQMSSLKSEDTAMFYCAAHYFGTSGPFAYWGQGTLVTVSA(SEQ ID NO:37,CDR以粗体字母显示),其中FR1-H跨越氨基酸位置1至25,CDR1-H跨越氨基酸位置26至33(SEQ ID NO:19),FR2-H跨越氨基酸位置34至50,CDR2-H跨越氨基酸位置51至58(SEQ ID NO:20),FR3-H跨越氨基酸位置59至96,CDR3-H跨越氨基酸位置97至109(SEQ ID NO:21),且FR4-H跨越氨基酸位置110至120,和
-轻链的可变结构域,其由下列序列组成:DIQMTQSPASLSASVGETVTITCRASENIYSYFAWYQQKQGKSPQLLVYNAKILAEGVPSRFSGSGSGTQFSLKINSLQPEDFGTYYCQHHYGIPFTFGSGTKLELK(SEQ ID NO:38,CDR以粗体字母显示),其中FR1-L跨越氨基酸位置1至26,CDR1-L跨越氨基酸位置27至32(SEQ ID NO:22),FR2-L跨越氨基酸位置33至49,CDR2-L跨越氨基酸位置50至52,FR3-L跨越氨基酸位置53至88,CDR3-L跨越氨基酸位置89至97(SEQ ID NO:24),且FR4-L跨越氨基酸位置98至107。
所谓的“抗体MAb5”包含:
-重链的可变结构域,其由下列序列组成:ELQLVESGGVLVKPGGSLKLSCAASGFAFSSYDMSWVRQTPEKRLEWVTYINSGGGITYYPDTVKGRFTISRDNARNTLYLQMSSLKSEDTAIYYCTAHYFGSSGPFAYWGQGTLVTVSA(SEQ ID NO:39,CDR以粗体字母显示),其中FR1-H跨越氨基酸位置1至25,CDR1-H跨越氨基酸位置26至33(SEQ ID NO:25),FR2-H跨越氨基酸位置34至50,CDR2-H跨越氨基酸位置51至58(SEQ ID NO:26),FR3-H跨越氨基酸位置59至96,CDR3-H跨越氨基酸位置97至109(SEQ ID NO:27),且FR4-H跨越氨基酸位置110至120,和
-轻链的可变结构域,其由下列序列组成:DIQMTQSPASLSASVGETVTITCRASENIYSYLAWYQQKQGKSPQLLVYNAKTLTEGVPSRFSGSGSGTQFSLKINSLQPEDFGSYYCQHHYGTPFTFGSGTKLEIK(SEQ ID NO:40,CDR以粗体字母显示),其中FR1-L跨越氨基酸位置1至26,CDR1-L跨越氨基酸位置27至32(SEQ ID NO:28),FR2-L跨越氨基酸位置33至49,CDR2-L跨越氨基酸位置50至52,FR3-L跨越氨基酸位置53至88,CDR3-L跨越氨基酸位置89至97(SEQ ID NO:30),且FR4-L跨越氨基酸位置98至107。
因此,本发明是涉及与人和食蟹猴CEACAM5结合的抗体。
在实施方案中,本发明的抗体与人和食蟹猴CEACAM5的A3-B3结构域结合。更具体地,抗体可无差别地与人和食蟹猴A3-B3结构域结合,不论其以分离的形式表达还是存在于可溶胞外结构域或膜锚定全长CEACAM5蛋白中。
在人CEACAM5的A3-B3结构域中没有报道白种人群体中存在频率高于2%的SNP,因此针对该结构域的抗体的特异性具备优势,其使部分群体中CEACAM5上抗体表位有变化的风险最小化。
本发明还提供与包含选自称为抗体MAb1、MAb2、MAb2K52R、MAb3、MAb4和MAb5的抗体的可变重链和轻链的抗体竞争性结合人和食蟹猴CEACAM5蛋白的A3-B3结构域的抗体,所述称为抗体MAb1、MAb2、MAb2K52R、MAb3、MAb4和MAb5的抗体即选自下组的抗体:
a)包含序列SEQ ID NO:31的重链可变结构域和序列SEQ ID NO:32的轻链可变结构域的抗体;
b)包含序列SEQ ID NO:33的重链可变结构域和序列SEQ ID NO:34的轻链可变结构域的抗体;
c)包含序列SEQ ID NO:33的重链可变结构域和序列SEQ ID NO:34的轻链可变结构域的抗体,其中所述序列SEQ ID NO:34的轻链可变结构域中位点52的K已经由R替换;
d)包含序列SEQ ID NO:35的重链可变结构域和序列SEQ ID NO:36的轻链可变结构域的抗体;
e)包含序列SEQ ID NO:37的重链可变结构域和序列SEQ ID NO:38的轻链可变结构域的抗体;和
f)包含序列SEQ ID NO:39的重链可变结构域和序列SEQ ID NO:40的轻链可变结构域的抗体。
可通过例如竞争性ELISA很容易地分析候选抗体与包含选自MAb1、MAb2、MAb3、MAb4和MAb5的抗体的可变重链和轻链的抗体(下文称为“参照”抗体)竞争结合人和食蟹猴CEACAM5蛋白的A3-B3结构域的能力,其中抗原(即人或食蟹猴CEACAM5的A3-B3结构域,或包含或其组成为包含人或食蟹猴CEACAM5的A3-B3结构域、尤其胞外结构域的人或食蟹猴CEACAM5片段的多肽)结合至固体支持物,且添加分别含有候选抗体和参照抗体的两种溶液,并使抗体与抗原竞争性结合。随后可测量结合至抗原的参照抗体的量,且与针对阴性对照(例如不含抗体的溶液)测量时结合至抗原的参照抗体的量进行比较。与阴性对照存在下结合的参照抗体的量相比,候选抗体存在下结合的参照抗体的量减少,这表明候选抗体与参照抗体存在竞争。方便地,可标记参照抗体(例如,用荧光)以促进结合的参照抗体的检测。重复测量可使用候选和/或参照抗体的系列稀释物实施。
根据实施方案,这样的抗体和举例来说与如上文b)、c)、e)和f)中定义的竞争与人和食蟹猴CEACAM5蛋白的A3-B3结构域结合的抗体,与人CEACAM5蛋白的A3-B3结构域的两个区结合,该两个区分别由人CEACAM5蛋白的A3-B3结构域中位置109-115(SEQ ID NO:76)处的氨基酸和位置131-143(SEQ ID NO:77)处的氨基酸组成。事实上,已识别用于MAb2抗体的构象表位属于人CEACAM5蛋白的A3-B3结构域的区109-115和131-143,且MAb2、MAb4和MAb5在结构上密切相关,发明人假定所述抗体结合至相同表位。
根据实施方案,根据本发明的抗体特异性针对人和食蟹猴CEACAM5表面蛋白。在实施方案中,本发明抗体并不与下列蛋白质结合或并不与其显著交叉反应:人CEACAM1、人CEACAM6、人CEACAM7、人CEACAM8、食蟹猴CEACAM1、食蟹猴CEACAM6和食蟹猴CEACAM8蛋白。
具体而言,该抗体并不与前述人和食蟹猴CEACAM蛋白的胞外结构域结合或并不与其显著交叉反应。
人CEACAM1全长蛋白可在GenBank数据库中以登录号NP_001703.2(SEQ ID NO:11)获得。人CEACAM1的胞外结构域由SEQ ID NO:11的位置35-428处的氨基酸组成。人CEACAM6全长蛋白可在GenBank数据库中以登录号NP_002474.3(SEQ ID NO:71)获得。人CEACAM6的胞外结构域由SEQ ID NO:71的位置35-327处的氨基酸组成。
人CEACAM7全长蛋白可在GenBank数据库中以登录号NP_008821.1(SEQ ID NO:72)获得。人CEACAM7的胞外结构域由SEQ ID NO:72的位置36-248处的氨基酸组成。
人CEACAM8全长蛋白可在GenBank数据库中以登录号NP_001807.2(SEQ ID NO:73)获得。人CEACAM8的胞外结构域由SEQ ID NO:73的位置35-332处的氨基酸组成。
食蟹猴CEACAM1胞外结构域由全长蛋白的位置35-428处的氨基酸(即SEQ ID NO:57的氨基酸1-394)组成。
食蟹猴CEACAM6胞外结构域由全长蛋白的位置35-327处的氨基酸(即SEQ ID NO:61的氨基酸1-293)组成。
食蟹猴CEACAM8胞外结构域由全长蛋白的位置35-332处的氨基酸(即SEQ ID NO:63的氨基酸1-298)组成。
理论上,“亲和性”通过整个抗体与抗原间的平衡缔合定义。其在实验上可通过多种已知方法来评估,如用表面等离子体共振测量缔合和解离速率或在免疫化学分析(ELISA、FACS)中测量EC50(或表观KD)。在这些试验中,EC50是在定义浓度的抗原(ELISA,酶联免疫吸附试验)或表达抗原的细胞(FACS,荧光激活细胞分选)下暴露某指定时间后,诱导介于基线与最大值间的一半应答的抗体浓度。
当对于两种抗原的EC50处于相似范围时,结合至抗原1(Ag1)的单克隆抗体对抗原2(Ag2)具有“交叉反应性”。在本申请中,当Ag2亲和性对Ag1亲和性的比率等于或小于10(例如5、2、1或0.5)时,结合至Ag1的单克隆抗体对Ag2具有交叉反应性,对于两种抗原的亲和性使用相同方法测量。
当对于两种抗原的亲和性非常不同时,与Ag1结合的单克隆抗体对Ag2“无显著交 叉反应性”。如果结合应答太低,则无法测量对于Ag2的亲和性。在本申请中,在相同实验设置和相同抗体浓度下,当单克隆抗体对Ag2的结合反应小于同一单克隆抗体对Ag1的结合反应的5%时,与Ag1结合的单克隆抗体对Ag2无显著交叉反应性。实践中,使用的抗体浓度可为EC50或达到用Ag1获得的饱和平台期所需浓度。
如果单克隆抗体对Ag2无显著交叉反应性,则其“特异性结合”至Ag1或“对Ag1具有特异性”。相应地,根据本发明的抗体对于人CEACAM5的亲和性与对食蟹猴CEACAM5的亲和性的比率≤10,例如≤5、≤2、≤1或≤0.5。由于在猴中观察到的毒性特征将与人中预期潜在不利影响相关,因此根据本发明的多肽可用于猴中实施的毒理学研究。
本发明的实施方案对人CEACAM5或食蟹猴CEACAM5或二者的亲和性≤10nM,例如≤5nM、≤3nM、≤1nM或≤0.1nM,举例来说亲和性为0.01nM至5nM,或和亲和性为0.1nM至5nM,或0.1nM至1nM。
使用可溶重组CEACAM5作为捕获抗原的ELISA中,可将对人CEACAM5或对食蟹猴CEACAM5的亲和性确定为EC50值。
本发明抗体还可具有表观解离常数(表观KD),如可通过对肿瘤细胞系MKN45(DSMZ,ACC 409)或对源自患者的异种移植肿瘤细胞(CR-IGR-034P,从OncodesignBiotechnology肿瘤集合CReMEC获得)进行FACS分析测定,该表观解离常数≤25nM,例如≤20nM、≤10nM、≤5nM、≤3nM或≤1nM。表观KD可在0.01-20nM范围或可在0.1-20nM、0.1-10nM或0.1-5nM范围。
此外,根据本发明的抗体以表明能够通过免疫组织化学检测冷冻并经福尔马林(formalin)固定和石蜡包埋(FFPE)的组织切片中的CEACAM5表达。
MAb1、MAb2、MAb3、MAb4和MAb5抗体的VH与VL区序列的比对示于图7。CRD-H与CDR-L序列的比较表明,一方面MAb2、MAb4和MAb5在结构上密切相关,而另一方面MAb1和MAb3在结构上密切相关,所述抗体可能与相同表位结合。CRD-H与CDR-L序列的比较进一步识别两组抗体间严格保守且因此认作对特异性至关重要的CDR位置,而其他位置可支持取代。
发明人已进一步识别MAb2VH的位置101-109处的残基(即CDR3-H的残基)和MAb2VL的位置47-54和88-104处的残基(即分别包含CDR2-L和CDR3-L的区)构成人CEACAM5-A3B3结构域抗体互补位的一部分或形成该抗体互补位。
此外,已通过单酸取代将MAb2VL的位置27、28、29、31、51、52、89、90、93、94、96和97处的残基(即CDR1-L、CDR2-L和CDR3-L内)和MAb2VH的位置26至31、51至58、97、103、104、107和109处的残基(即在CDR1-H内、所有CDR2-H和在CDR3-H内)识别为对于人和食蟹猴CEACAM5胞外结构域的结合呈中性。此外,MAb2VL的位置30和92处的残基(即在CDR1-L和CDR3-L内)和MAb2VH的位置98和100处的残基(即在CDR3-H内)已显示容许保守取代。由于MAb2、MAb4和MAb5携载相同的6个CDR集合或非常密切相关的那些,因此认为VH或VL或VH和CL序列二者中MAb4或MAb5相同位置处的变化还将导致保持对人和食蟹猴CEACAM5的结合特异性和/或亲和性的变体抗体。
值得注意的是,识别的CDR2-H的所有残基对于人和食蟹猴CEACAM5胞外结构域的结合呈中性,发明人假定CDR2-H可能不参与相互作用。相应地,在本发明的抗体中,CDR2-H可为6至10个氨基酸的任何序列,这是人抗体中CDR2-H序列的正常长度。
相应地,根据本发明的抗体包含:
CDR1-H,其由序列X1X2X3X4X5X6YD(SEQ ID NO:83)组成,其中X1、X2、X3、X4、X5和X6各为任何氨基酸;和
CDR2-H,其由6至10个氨基酸长的序列组成,优选为8个氨基酸长的序列,其中任何氨基酸可存在于任何位置;和
CDR3-H,其由序列X1X2HX3FGX4X5GPX6AX7(SEQ ID NO:84)组成,其中X1、X4、X5、X6和X7各为任何氨基酸,X2是A或S,且X3是Y、F或W;或
b)CDR1-L,其由序列X1X2X3X4X5Y(SEQ ID NO:85)组成,其中X1、X2、X3和X5各为任何氨基酸,且X4是Y、F或W;和
CDR2-L,其由序列NX1X2组成,其中X1和X2各为任何氨基酸;和
CDR3-L,其由序列X1X2HX3X4X5PX6X7(SEQ ID NO:86)组成,其中X1、X2、X4、X5、X6和X7各为任何氨基酸,X3是Y、F或W。
在实施方案中,由序列X1X2X3X4X5X6YD(SEQ ID NO:83)组成的CDR1-H中,X1是G,或X2是F,或X3是T、A或V,或X4是F,或X5是S,或X6是S或其任何组合。
在实施方案中,CDR2-H由序列IX1SX2GGX3T(SEQ ID NO:79)组成,其中X1是S或N(尤其S),X2是Y或G(尤其G),X3是R或I。在另一实施例中X3是I。
在实施方案中,在由序列X1X2HX3FGX4X5GPX6AX7(SEQ ID NO:84)组成的CDR3-H中,X1是A或T,或X4是T或S,或X5是S,或X6是F,或X7是Y或其任何组合。
在实施例中,在由序列X1X2X3X4X5Y(SEQ ID NO:85)组成的CDR1-L中,X1是E,或X2是N,或X3是I,或X5是S或其任何组合。
在实施例中,CDR2-L由序列NX1X2组成,其中X1是A或T,且X2是K或R。
在实施例中,在由序列X1X2HX3X4X5PX6X7(SEQ ID NO:86)组成的CDR3-L中,X1是Q,或X2是H,或X4是G,或X5是T,或X6是F,或X7是T或其任何组合。根据实施方案,根据本发明的抗体包含:
a)CDR1-H,其由序列GFX1FSSYD(SEQ ID NO:78)组成,其中X1是T、A或V;和
CDR2-H,其由序列IX1SX2GGX3T(SEQ ID NO:79)组成,其中X1是S或N,X2是Y或G,X3是R或I;和
CDR3-H,其是由序列X1AHYFGX2SGPFAY(SEQ ID NO:80)组成,其中X1是A或T,且X2是T或S;或
b)CDR1-L,其由序列ENIFSY(SEQ ID NO:10)或ENIYSY(SEQ ID NO:22)组成;和
CDR2-L,其由序列NX1X2组成,其中X1是A或T,且X2是K或R,特别是R;CDR2-L特别是由NAK、NTK和NTR组成;和
CDR3-L,其由序列QHHYGTPFT(SEQ ID NO:12)或QHHYGIPFT(SEQ ID NO:24)组成。
根据实施方案,在CDR2-H中,X1是S或N,X2是G且X3是I。
根据实施方案,CDR2-H由ISSGGGIT(SEQ ID NO:8)、ISSYGGRT(SEQ ID NO:20)或INSGGGIT(SEQ ID NO:26)组成。
根据实施方案,在CDR3-H中,X1是A或T,且X2是S。
根据实施方案,CDR3-H由AAHYFGSSGPFAY(SEQ ID NO:9)、AAHYFGTSGPFAY(SEQ IDNO:21)或TAHYFGSSGPFAY(SEQ ID NO:27)组成。
这些实施方案的任何组合构成本发明的一部分。
可替换地,根据本发明的抗体包含:
a)CDR1-H,其由序列GFTFSX1YX2(SEQ ID NO:81)组成,其中X1是R或S,特别是S,且X2是A或D;和
CDR2-H,其由序列ISSGGX1X2X3(SEQ ID NO:82)组成,其中X1不存在、或是S或G,特别是G,X2是D、Y或I,且X3是T或I;和
CDR3-H,其由序列ARPAYYGNPAMDY(SEQ ID NO:3)或ARVNYYDSSFLDW(SEQ ID NO:15)组成;和/或
b)CDR1-L,其由序列QNVGTN(SEQ ID NO:4)组成;和
CDR2-L,其由序列SAS组成;和
CDR3-L,其由序列QQYNSYPLYT(SEQ ID NO:6)或QQYNNYPLYT(SEQ ID NO:18)组成。
根据实施方案,CDR2-H由序列ISSGGSYI(SEQ ID NO:2)或ISSGGDT(SEQ ID NO:14)组成。
根据实施方案,CDR2-H由序列ISSGGSYI(SEQ ID NO:2)组成且CDR3-H是由序列ARPAYYGNPAMDY(SEQ ID NO:3)组成。
根据实施方案,CDR2-H由ISSGGDT(SEQ ID NO:14)组成且CDR3-H是由序列ARVNYYDSSFLDW(SEQ ID NO:15)组成。
根据实施方案,根据本发明的抗体包含称为抗CEACAM5抗体MAb1、MAb2、MAb2K52R、MAb3、MAb4和MAb5中之一的重链和/或轻链的CDR序列。
因此,本发明涉及抗体,其包含:
a)CDR1-H,其具有GFTFSSYA(SEQ ID NO:1)的序列或通过一个氨基酸取代与SEQID NO:1不同的序列;CDR2-H,其具有ISSGGSYI(SEQ ID NO:2)的序列或通过一个或多个氨基酸取代与SEQ ID NO:2不同的序列;CDR3-H,其具有ARPAYYGNPAMDY(SEQ ID NO:3)的序列或通过一个氨基酸取代与SEQ ID NO:3不同的序列;CDR1-L,其具有QNVGTN(SEQ ID NO:4)的序列或通过一个氨基酸取代与SEQ ID NO:4不同的序列;CDR2-L,其具有SAS的序列或通过一个氨基酸取代与SAS不同的序列;和CDR3-L,其具有QQYNSYPLYT(SEQ ID NO:6)的序列或通过一个氨基酸取代与SEQ ID NO:6不同的序列;或
b)CDR1-H,其具有GFVFSSYD(SEQ ID NO:7)的序列或通过一个氨基酸取代与SEQID NO:7不同的序列;CDR2-H,其具有ISSGGGIT(SEQ ID NO:8)的序列或通过一个或多个氨基酸取代与SEQ ID NO:8不同的序列;CDR3-H,其具有AAHYFGSSGPFAY(SEQ ID NO:9)的序列或通过一个或多个氨基酸取代与SEQ ID NO:9不同的序列;CDR1-L,其具有ENIFSY(SEQ IDNO:10)的序列或通过一个氨基酸取代与SEQ ID NO:10不同的序列;CDR2-L,其具有NTK或NTR的序列或通过一个氨基酸取代与NTK或NTR不同的序列;和CDR3-L,其具有QHHYGTPFT(SEQ ID NO:12)的序列或通过一个氨基酸取代与SEQ ID NO:12不同的序列;或
c)CDR1-H,其具有GFTFSRYA(SEQ ID NO:13)的序列或通过一个氨基酸取代与SEQID NO:13不同的序列;CDR2-H,其具有ISSGGDT(SEQ ID NO:14)的序列或通过一个或多个氨基酸取代与SEQ ID NO:14不同的序列;CDR3-H,其具有ARVNYYDSSFLDW(SEQ ID NO:15)的序列或通过一个氨基酸取代与SEQ ID NO:15不同的序列;CDR1-L,其具有QNVGTN(SEQ ID NO:16)的序列或通过一个氨基酸取代与SEQ ID NO:16不同的序列;CDR2-L,其具有SAS的序列或通过一个氨基酸取代与SAS不同的序列;和CDR3-L,其具有QQYNNYPLYT(SEQ ID NO:18)的序列或通过一个氨基酸取代与SEQ ID NO:18不同的序列;或
d)CDR1-H,其具有GFTFSSYD(SEQ ID NO:19)的序列或通过一个氨基酸取代与SEQID NO:19不同的序列;CDR2-H,其具有ISSYGGRT(SEQ ID NO:20)的序列或通过一个或多个氨基酸取代与SEQ ID NO:20不同的序列;CDR3-H,其具有AAHYFGTSGPFAY(SEQ ID NO:21)的序列或通过一个或多个氨基酸取代与SEQ ID NO:21不同的序列;CDR1-L,其具有ENIYSY(SEQ ID NO:22)的序列或通过一个氨基酸取代与SEQ ID NO:22不同的序列;CDR2-L,其具有NAK的序列或通过一个或多个氨基酸取代与NAK不同的序列;和CDR3-L,其具有QHHYGIPFT(SEQ ID NO:24)的序列或通过一个氨基酸取代与SEQ ID NO:24不同的序列;或
e)CDR1-H,其具有GFAFSSYD(SEQ ID NO:25)的序列或通过一个氨基酸取代与SEQID NO:25不同的序列;CDR2-H,其具有INSGGGIT(SEQ ID NO:26)的序列或通过一个或多个氨基酸取代与SEQ ID NO:26不同的序列;CDR3-H,其具有TAHYFGSSGPFAY(SEQ ID NO:27)的序列或通过一个或多个氨基酸取代与SEQ ID NO:27不同的序列;CDR1-L,其具有ENIYSY(SEQ ID NO:28)的序列或通过一个氨基酸取代与SEQ ID NO:28不同的序列;CDR2-L,其具有NAK的序列或通过一个或多个氨基酸取代与NAK不同的序列;和CDR3-L,其具有QHHYGTPFT(SEQ ID NO:30)的序列或通过一个氨基酸取代与SEQ ID NO:30不同的序列。
可通过取代、特别是通过保守取代在上述一个或多个CDR序列中改变一个或多个单独的氨基酸。该改变意在举例来说结合抗体的人源化去除糖基化位点或去酰胺化位点。
基于MAb1、MAb2、MAb3、MAb4和MAb5的VH与VL区序列的比对,并基于MAb2抗体变体中的单酸取代,可取代的氨基酸:
-在CDR1-H中:在CDR1-H序列GFVFSSYD(SEQ ID NO:7)、GFTFSSYD(SEQ ID NO:19)或GFAFSSYD(SEQ ID NO:25)的位置1至6的一处或多处,例如在位置3处;或在CDR1-H序列GFTFSSYA(SEQ ID NO:1)或GFTFSRYA(SEQ ID NO:13)的位置6处;和/或
-在CDR2-H中,在CDR2-H序列ISSGGGIT(SEQ ID NO:8)、ISSYGGRT(SEQ ID NO:20)或INSGGGIT(SEQ ID NO:26)的一个或多个任何位置处或在位置2、4和7中的一处、两处或三处;或在CDR2-H序列ISSGGSYI(SEQ ID NO:2)或ISSGGDT(SEQ ID NO:14)的位置6、7和8(其中该序列长度为8个氨基酸)中的一处、两处或三处;和/或参见上文
-在CDR3-H中,在CDR3-H序列AAHYFGSSGPFAY(SEQ ID NO:9)、AAHYFGTSGPFAY(SEQID NO:21)或TAHYFGSSGPFAY(SEQ ID NO:27)的位置1、7、8、11和13中的一处或多处,例如在位置1和7中的一处或两处;或在序列ARPAYYGNPAMDY(SEQ ID NO:3)或ARVNYYDSSFLDW(SEQID NO:15)的位置3、4、7、8、9、10或11处;和/或
-在CDR1-L中,在CDR1-L序列ENIFSY(SEQ ID NO:10)或ENIYSY(SEQ ID NO:28)的位置1至5中的一处或多处,尤其在位置1、2、3和5中的一处或多处或在位置4处;和/或
-在CDR2-L中,在序列NAK、NTK或NTR的位置2和/或位置3处,特别是如果K存在时至少在位置3处。在该情况中,R举例来说可取代CDR2-L的位置3处的K;和/或
-在CDR3-L中,在CDR3-L序列QHHYGIPFT(SEQ ID NO:24)或QHHYGTPFT(SEQ ID NO:30)的位置1、2、5、6、8和9中的一处或多处,例如在位置6处;或在CDR3-L序列QQYNSYPLYT(SEQ ID NO:6)或QQYNNYPLYT(SEQ ID NO:18)的位置5处。
根据实施方案,在本发明抗体中:
-CDR3-H序列AAHYFGSSGPFAY(SEQ ID NO:9)、AAHYFGTSGPFAY(SEQ ID NO:21)或TAHYFGSSGPFAY(SEQ ID NO:27)的位置5;和/或
-CDR1-L序列ENIFSY(SEQ ID NO:10)或ENIYSY(SEQ ID NO:28)的位置6;和/或
-CDR3-L序列QHHYGIPFT(SEQ ID NO:24)或QHHYGTPFT(SEQ ID NO:30)的位置3未经修饰。
根据实施方案,在CDR1-H序列GFVFSSYD(SEQ ID NO:7)、GFTFSSYD(SEQ ID NO:19)或GFAFSSYD(SEQ ID NO:25)中,用于CDR1-H位置3处氨基酸取代的氨基酸选自T、A或V。
根据实施方案,在CDR1-H序列GFTFSSYA(SEQ ID NO:1)或GFTFSRYA(SEQ ID NO:13)中,用于CDR1-H位置6处氨基酸取代的氨基酸是R或S。
根据实施方案,在CDR3-H序列AAHYFGSSGPFAY(SEQ ID NO:9)、AAHYFGTSGPFAY(SEQID NO:21)或TAHYFGSSGPFAY(SEQ ID NO:27)中,用于CDR3-H位置1处氨基酸取代的氨基酸是A或T,和/或用于CDR3-H位置7处氨基酸取代的氨基酸是T或S。
根据实施方案,在CDR3-H序列ARPAYYGNPAMDY(SEQ ID NO:3)或ARVNYYDSSFLDW(SEQ ID NO:15)中,用于CDR3-H位置3处氨基酸取代的氨基酸是V或P,位置4处是A或N,位置7处是D或G,位置8处是S或N,位置9处是S或P,位置10处是F或A,或位置11处是W或Y。
根据实施方案,用于CDR1-L位置4处氨基酸取代的氨基酸是Y或F。
根据实施方案,在CDR2-L序列NAK、NTK或NTR中,用于CDR2-L位置2处氨基酸取代的氨基酸是A或T。
根据实施方案,在CDR3-L序列QQYNSYPLYT(SEQ ID NO:6)或QQYNNYPLYT(SEQ IDNO:18)中,用于CDR3-L位置5处氨基酸取代的氨基酸是N或S。
根据实施方案,在CDR3-L序列QHHYGIPFT(SEQ ID NO:24)或QHHYGTPFT(SEQ IDNO:30)中,用于CDR3-L位置6处氨基酸取代的氨基酸是I或T。
上述实施方案的任何组合构成本发明的一部分。
在实施方案中,根据本发明的抗体是常规抗体,例如常规单克隆抗体或抗体片段、双特异性或多特异性抗体。
在实施方案中,根据本发明的抗体包含或由IgG或其片段组成。
本发明还提供如上文定义的抗体,其进一步包含至少五种称为抗CEACAM5抗体MAb1、MAb2、MAb3、MAb4和MAb5中的一种的重链可变结构域和/或轻链可变结构域。
因此,本发明的实施方案涉及抗体,其包含:
a)序列SEQ ID NO:31或与其至少85%相同的序列的重链可变结构域和/或序列SEQ ID NO:32或与其至少85%相同的序列的轻链可变结构域;或
b)序列SEQ ID NO:33或与其至少85%相同的序列的重链可变结构域和/或序列SEQ ID NO:34或与其至少85%相同的序列的轻链可变结构域;或
c)序列SEQ ID NO:35或与其至少85%相同的序列的重链可变结构域和/或序列SEQ ID NO:36或与其至少85%相同的序列的轻链可变结构域;或
d)序列SEQ ID NO:37或与其至少85%相同的序列的重链可变结构域和/或序列SEQ ID NO:38或与其至少85%相同的序列的轻链可变结构域;或
e)序列SEQ ID NO:39或与其至少85%相同的序列的重链可变结构域和/或序列SEQ ID NO:40或与其至少85%相同的序列的轻链可变结构域。举例来说,在适当时,重链或轻链可变结构域的序列可通过一个或多个氨基酸取代(特别是通过一个或多个保守氨基酸取代和/或用规范残基取代)与参照序列SEQ ID NO:31、32、33、34、35、36、37、38、39或40不同。在实施方案中,重链或轻链的可变结构域的序列可仅通过保守氨基酸取代与参照序列SEQ ID NO:31、32、33、34、35、36、37、38、39或40不同。
与序列SEQ ID NO:31、32、33、34、35、36、37、38、39或40相比序列的变化基本上将存在于框架区FR1-L、FR2-L、FR3-L、FR4-L和/或FR1-H、FR2-H、FR3-H、FR4-H的一个或多个中。
然而,在一个或多个CDR中的氨基酸取代存在可能。在实施方案中,轻链可变结构域的序列可至少通过SEQ ID NO:34位置52处的K至R取代(在CDR2-L中)与序列SEQ ID NO:34不同。
本发明的抗体及其片段可分别是鼠类抗体和鼠类抗体的片段。
抗体还可为嵌合抗体,且在实施方案中为鼠类/人抗体,例如包含鼠类重链和轻链可变结构域和人抗体的CH结构域和CL结构域的抗体。多肽可为该抗体的片段。
根据实施方案,本发明抗体是:
a)嵌合抗体,其包含或其组成为序列SEQ ID NO:41或与其至少85%相同的序列的重链或序列SEQ ID NO:42或与其至少85%相同的序列的轻链(即如实例5中所述的chMAb1的重链和/或轻链);或重链和轻链,或
b)嵌合抗体,其包含或其组成为序列SEQ ID NO:43或与其至少85%相同的序列的重链或序列SEQ ID NO:44或与其至少85%相同的序列的轻链;(即如实例5中所述的chMAb2的重链和/或轻链);或重链和轻链,或
c)嵌合抗体,其包含或其组成为序列SEQ ID NO:45或与其至少85%相同的序列的重链或序列SEQ ID NO:46或与其至少85%相同的序列的轻链(即如实例5中所述的chMAb3的重链和/或轻链);或重链和轻链,或
d)嵌合抗体,其包含或其组成为序列SEQ ID NO:47或与其至少85%相同的序列的重链或序列SEQ ID NO:48或与其至少85%相同的序列的轻链(即如实例5中所述的chMAb4的重链和/或轻链);或重链和轻链,或
e)嵌合抗体,其包含或其组成为序列SEQ ID NO:49或与其至少85%相同的序列的重链或序列SEQ ID NO:50或与其至少85%相同的序列的轻链(即如实例5中所述的chMAb5的重链和/或轻链);或重链和轻链,或
f)a)、b)、c)、d)或e)中所定义的嵌合抗体片段。
抗体还可是人源化抗体或人源化抗体片段。在实施方案中,本发明抗体可源自上文a)、b)、c)、d)、e)或f)中定义的任何嵌合抗体的人源化。
多种用于抗体序列人源化的方法为本领域已知;参见例如Almagro和Fransson(2008)Front Biosci.13:1619-1633。一种常用方法是CDR移植或抗体重塑,其牵涉将供体抗体、通常为小鼠抗体的CDR序列移植入具有不同特异性的人抗体的框架支架中。由于CDR移植可降低CDR移植的非人抗体的结合特异性和亲和性,且因此降低生物活性,所以可在CDR移植抗体的所选位置引入回复突变进而保留亲代抗体的结合特异性和亲和性。可使用可在文献和抗体数据库中获得的信息实施用于可能的恢复突变的位点识别。用于回复突变的候选者的氨基酸残基通常是位于抗体分子的表面的那些,而包埋或具有低表面暴露度的残基通常将不发生变化。CDR移植和回复突变的替换性人源化技术是表面重修,其中保留非人来源的非表面暴露残基,而将表面残基改变为人残基。另一可替换的技术称为“引导选择”(Jespers et al,(1994)Biotechnology 12,899)且可用于从鼠类抗体衍生保留亲代抗体表位和结合特征的全人抗体。
对于嵌合抗体,人源化通常牵涉可变区序列框架区的修饰。
作为CDR一部分的氨基酸残基通常并不随着人源化而发生改变,但在某些情况下比较理想的可能是改变个别CDR氨基酸残基,以举例来说去除糖基化位点、去酰胺化位点或不理想的半胱氨酸残基。N-连接的糖基化通过将寡糖链附着至三肽序列Asn-X-Ser或Asn-X-Thr中的天冬酰胺残基发生,其中X可是除Pro外的任何氨基酸。N-糖基化位点的去除可通过使Asn或Ser/Thr残基突变成不同残基获得,举例来说通过保守取代。天冬酰胺和谷氨酰胺残基的去酰胺化可依赖于如pH和表面暴露等因素发生。天冬酰胺残基主要在存在于序列Asn-Gly中时,和其次在其他二肽序列(例如Asn-Ala)中时,尤其易于去酰胺化。当CDR序列中存在该去酰胺化位点(举例来说Asn-Gly)时,可因此预期通常通过保守取代去除位点以去除一个密切相关的残基。为了移除密切相关残基之一而在CDR序列中进行的取代也意在涵盖于本发明中。
采用所谓的“抗体MAb2”作为实例,人源化抗体或其片段可在可变重链中包含下列突变:P替代位置9的G;和/或G替代位置10的V;和/或S替代位置19的K;和/或R替代位置43的K;和/或G替代位置44的R;和/或A替代位置60的F;和/或S替代位置62的D;和/或K替代位置65的Q;和/或T替代位置87的K;和/或V替代位置89的I;和/或S替代位置113的A;所述位置通过参照SEQ ID NO:33给出。
仍采用所谓的“抗体MAb2”作为实例,人源化抗体或其片段可在可变轻链中包含下列突变:D替代位置17的E;和/或R替代位置18的T;和/或P替代位置40的Q;和/或K替代位置45的Q;和/或R替代位置52的K;和/或D替代位置70的Q;和/或T替代位置74的K;和/或S替代位置76的N;和/或A替代位置84的G;和/或T替代位置85的S;所述位置通过参照SEQ ID NO:34给出。
在实施方案中,本发明抗体是包含或其组成为含有下列突变的重链的人源化抗体,所述位置通过参照SEQ ID NO:33给出:
a)P替代位置9的G;和G替代位置10的V;和S替代位置19的K;和R替代位置43的K;和S替代位置62的D;和K替代位置65的Q;和T替代位置87的K;或
b)P替代位置9的G;和G替代位置10的V;和S替代位置19的K;和R替代位置43的K;和G替代位置44的R;和A替代位置60的F;和S替代位置62的D;和K替代位置65的Q;和T替代位置87的K;和V替代位置89的I;和S替代位置113的A;和/或
包含含有下列突变的轻链的人源化抗体,所述位置通过参照SEQ ID NO:34给出:
c)D替代位置17的E;和P替代位置40的Q;和K替代位置45的Q;和T替代位置74的K;和S替代位置76的N;或
d)D替代位置17的E;和R替代位置18的T;和P替代位置40的Q;和K替代位置45的Q;和D替代位置70的Q;和T替代位置74的K;和S替代位置76的N;和A替代位置84的G;和T替代位置85的S;或
e)D替代位置17的E;和R替代位置18的T;和P替代位置40的Q;和K替代位置45的Q;和R替代位置52的K;和D替代位置70的Q;和T替代位置74的K;和S替代位置76的N;和A替代位置84的G;和T替代位置85的S。
在实施方案中,本发明的抗体是通过将本发明抗体的CDR移植入另外的抗体框架区(更具体而言移植至人框架区)获得的人源化抗体。采用MAb2作为实例,已将MAb2K52R的6个CDR移植入由IGHV3-23和IGKV1D-39基因组成的人框架,且对应VL(SEQ ID NO.34)中的位置34和位置53和VH(SEQ ID NO.33)中的位置50引进三个回复突变,从而导致包含重链可变结构域序列SEQ ID NO:74和轻链可变结构域序列SEQ ID NO:75的抗体。
在实施方案中,本发明的抗体是人源化抗体,其包含或其组成为序列SEQ ID NO:51、SEQ ID NO:5或SEQ ID NO:74或与其至少85%相同的序列的重链;和/或序列SEQ IDNO:17、SEQ ID NO:23、SEQ ID NO:29、SEQ ID NO:55或SEQ ID NO:75或与其至少85%相同的序列的轻链(MAb2的重链和轻链的人源化可变结构域)。
在实施方案中,本发明的抗体是人源化抗体,其包含序列SEQ ID NO:51或与其至少85%相同的序列的重链和序列SEQ ID NO:17或与其至少85%相同的序列的轻链,或序列SEQ ID NO:5或与其至少85%相同的序列的重链和序列SEQ ID NO:23或与其至少85%相同的序列的轻链,或序列SEQ ID NO:5或与其至少85%相同的序列的重链和序列SEQ ID NO:29或与其至少85%相同的序列的轻链,或序列SEQ ID NO:51或与其至少85%相同的序列的重链和序列SEQ ID NO:55或与其至少85%相同的序列的轻链,或序列SEQ ID NO:74或与其至少85%相同的序列的重链和序列SEQ ID NO:75或与其至少85%相同的序列的轻链。
在所述人源化抗体或其片段中,重链和轻链的可变结构域可包含人受体框架区。如果存在的话,人源化抗体进一步包含人重链和轻链恒定结构域。
在实施方案中,本发明的抗体是抗体huMAb2-3或其变体,即与人和食蟹猴CEACAM5蛋白的A3-B3结构域结合的分离的抗体,且其包含:
a)由序列SEQ ID NO:87或与其至少85%相同的序列组成的重链;或
b)由序列SEQ ID NO:88或与其至少85%相同的序列组成的轻链或重链和轻链。
在实施方案中,本发明的抗体是抗体huMAb2-4(MAb2_VL1d VH1-IgG1)或其变体,即与人和食蟹猴CEACAM5蛋白的A3-B3结构域结合的分离的抗体,且其包含:
c)由序列SEQ ID NO:89或与其至少85%相同的序列组成的重链;和/或
d)由序列SEQ ID NO:90或与其至少85%相同的序列组成的轻链。
根据本发明的抗体还可以是单一结构域抗体或其片段。在本发明的实施方案中,单一结构域抗体片段可由可变重链(VHH)组成,该可变重链包含如上文所述的抗体的CDR1-H、CDR2-H和CDR3-H。所述抗体还可以是重链抗体,即不含轻链的抗体,该抗体可包含或可不包含CH1结构域。
单一结构域抗体或其片段还可包含骆驼科单一结构域抗体的框架区,和任选的骆驼科单一结构域抗体的恒定结构域。
根据本发明的抗体还可以是选自下组的抗体片段(举例来说人源化抗体片段):Fv、Fab、F(ab')2、Fab'、dsFv、(dsFv)2、scFv、sc(Fv)2和双抗体。
抗体还可以是由抗体片段形成的双特异性或多特异性抗体(至少一个抗体片段是本发明的抗体片段)。多特异性抗体是如举例来说EP 2 050 764 A1或US 2005/0003403 A1所述的多价蛋白复合物。
根据本发明的双特异性或多特异性抗体可针对下列具有特异性:(a)由所谓的MAb1、MAb2、MAb3、MAb4和MAb5抗体之一靶向的人/食蟹猴CEACAM5上的A3-B3表位;和(b)至少一种其他抗原。根据实施方案,所述至少一种其他抗原并非为人或食蟹猴CEACAM家族成员,且在实施方案中并非为人和食蟹猴CEACAM1、人和猴CEACAM6、人和食蟹猴CEACAM7以及人和食蟹猴CEACAM8中至少之一或全部。根据另一实施方案,所述至少一种其他抗原可以是人食蟹猴CEACAM5上除了所谓的MAb1、MAb2、MAb3、MAb4和MAb5抗体之一靶向的所述A3-B3表位之外的表位。
所述抗体可通过本领域已知的任何技术来产生。在实施例中,所述抗体通过如下文所述的技术产生。
根据本发明的抗体及其片段可以分离的(例如纯化的)形式使用或含于载体(例如膜或脂质囊泡(例如脂质体))中。
核酸、载体和重组宿主细胞
本发明的另一目标涉及包含或由编码如上文定义的本发明的抗体序列组成的核酸序列。
通常,所述核酸为DNA或RNA分子,其可包含于任何合适的载体中,如质粒、黏粒、附加体、人工染色体、噬菌体或病毒载体。
术语“载体”、“克隆载体”和“表达载体”意为可通过其将DNA或RNA序列(例如,外源基因)引入宿主细胞以转化宿主并促进所引入序列的表达(例如,转录和翻译)的媒介。
因此,本发明的另一目标涉及包含本发明核酸的载体。
这种载体可包含调控元件,例如启动子、增强子、终止子等等,以在施用至受试者后引起或指导所述多肽的表达。用于动物细胞的表达载体中使用的启动子和增强子的实例包含早期SV40启动子和增强子(Mizukami T.et al,1987)、Moloney小鼠白血病病毒的LTR启动子和增强子(Kuwana Y et al,1987)、免疫球蛋白H链的启动子(Mason JO et al,1985)和增强子(Gillies SD et al,1983)等等。
只要可插入并表达编码人抗体C区的基因,可使用任何用于动物细胞的表达载体。合适的载体实例包括pAGE107(Miyaji H et al,1990)、pAGE103(Mizukami T et al,1987)、pHSG274(Brady G et al,1984)、pKCR(O'Hare K et al,1981)、pSG1 β d2-4-(Miyaji H et al,1990)等等。
质粒的其他实例包括含有复制起点的复制质粒或整合质粒,例如pUC、pcDNA、pBR等等。
病毒载体的其他实例包括腺病毒、逆转录病毒、疱疹病毒和AAV载体。这种重组病毒可通过本领域已知的技术产生,如通过转染包装细胞或通过用辅助质粒或病毒瞬时转染产生。病毒包装细胞的典型实例包括PA317细胞、PsiCRIP细胞、GPenv+细胞、293细胞等。用于产生这种复制缺陷重组病毒的详细方案可参见举例来说WO 95/14785、WO 96/22378、US5,882,877、US 6,013,516、US 4,861,719、US 5,278,056和WO 94/19478。
本发明的另一目标涉及已由本发明的核酸和/或载体转染、感染或转化的细胞。
术语“转化”意为“外源”(即外来)基因、DNA或RNA序列向宿主细胞的引进,进而宿主细胞将表达引进的基因或序列以产生预期的物质,通常为由引进的基因或序列编码的蛋白质或酶。接受并表达引进的DNA或RNA的宿主细胞已被“转化”。
可在合适的表达系统中使用本发明的核酸以产生本发明的重组抗体。术语“表达 系统”意为在合适的条件下的宿主细胞和兼容载体,用于举例来说表达由载体携载并引进宿主细胞的外源DNA所编码的蛋白质。
常用表达系统包括大肠杆菌(E.coli)宿主细胞和质粒载体、昆虫宿主细胞和杆状病毒载体以及哺乳动物宿主细胞和载体。宿主细胞的其他实例包括但不限于原核细胞(如细菌)和真核细胞(如酵母细胞、哺乳动物细胞、昆虫细胞、植物细胞等)。特定实例包括大肠杆菌、克鲁维酵母属(Kluyveromyce)或酿酒酵母属(Saccharomyce)酵母、哺乳动物细胞系(例如Vero细胞、CHO细胞、3T3细胞、COS细胞等)以及原代或已建立的哺乳动物细胞培养物(例如,由淋巴母细胞、成纤维细胞、胚胎细胞、上皮细胞、神经细胞、脂肪细胞等产生的)。实例还包括小鼠SP2/0-Ag14细胞(ATCC CRL1581)、小鼠P3X63-Ag8.653细胞(ATCC CRL1580)、CHO细胞(其中二氢叶酸还原酶基因(下文称为“DHFR基因”)是缺陷性的(Urlaub G et al,;1980))、大鼠YB2/3HL.P2.G11.16Ag.20细胞(ATCC CRL1662,下文称为“YB2/0细胞”)等等。当在YB2/0细胞细胞中表达时,由于嵌合或人源化抗体的ADCC活性增强,因此在实施方案中可使用该细胞。
为表达人源化抗体,表达载体可以是其中编码抗体重链的基因和编码抗体轻链的基因存在于不同载体上的载体类型或该两个基因存在于同一载体上的载体类型(串联型)。就构建人源化抗体表达载体的容易程度、引入动物细胞中的容易程度和动物细胞中抗体H链与L链表达水平之间的平衡,人源化抗体表达载体为串联型Shitara K et al,J ImmunolMethods.1994年1月3日;167(1-2):271-8)。串联型人源化抗体表达载体的实例包括pKANTEX93(WO 97/10354)、pEE18等等。
本发明还涉及产生表达根据本发明抗体的重组宿主细胞的方法,所述方法包括下列步骤:(i)将如上文所述的重组核酸或载体以体外或离体方式引入感受态宿主细胞中,(ii)以体外或离体方式培养获得的重组宿主细胞,和(iii)任选地,选择表达和/或分泌所述抗体的细胞。
可使用这样的重组宿主细胞用于产生本发明的抗体。
产生本发明抗体的方法
本发明的抗体可通过本领域已知的任何技术产生,如但不限于单独或组合的任何化学、生物、遗传或酶技术。
知晓预期序列的氨基酸序列,本领域的技术人员可通过用于产生多肽的标准技术轻易产生所述抗体或免疫球蛋白链。举例来说,其可使用熟知的固相方法使用市场有售的肽合成装置(如由Applied Biosystems,Foster City,California制造者)并遵循制造商的说明书来合成。可替换地,本发明的抗体和免疫球蛋白链可通过本领域熟知的重组DNA技术合成。举例来说,这些片段可作为DNA表达产物在将编码预期(多)肽的DNA序列并入表达载体并将所述载体引入将表达预期多肽的合适的真核或原核宿主中后获得,随后可使用熟知技术将其从所述宿主分离。
本发明进一步涉及产生本发明抗体的方法,该方法包含以下步骤:(i)培养根据本发明的转化宿主细胞;(ii)表达所述抗体或多肽;和(iii)回收所表达的抗体或多肽。
本发明抗体可通过常规免疫球蛋白纯化步骤从培养基合适地分离,所述纯化步骤为举例来说蛋白质A-琼脂糖、羟基磷灰石层析、凝胶电泳、透析或亲和层析。
在实施方案中,本发明的人源化嵌合抗体可通过以下方式来产生:获得编码如前文所述的人源化VL和VH结构域的核酸序列,通过将所述序列插入具有编码人抗体CH和人抗体CL基因的用于动物细胞的表达载体来构建人嵌合抗体表达载体,并通过将表达载体引入动物细胞中来表达编码序列。
作为人嵌合抗体的CH结构域,其可以是属于人免疫球蛋白重链的任何区域,但那些IgG类型是合适的且还可使用属于IgG类的任一子类,如IgG1、IgG2、IgG3和IgG4。而且,作为人嵌合抗体的CL,其可以是属于人免疫球蛋白轻链的任一区域,且可使用那些κ类或λ类。
涉及常规重组DNA和基因转染技术用于产生人源化或嵌合抗体的方法为本领域熟知(参见Morrison SL.et al,(1984)和专利文件US5,202,238;和US5,204,244)。
基于常规重组DNA和基因转染技术用于产生人源化抗体的方法为本领域熟知(例如,参见Riechmann L.et al,1988;Neuberger MS.et al,1985)。抗体可使用多种本领域已知的技术来人源化,其包括举例来说申请WO2009/032661中公开的技术、CDR移植(EP 239,400;PCT公开案WO91/09967;美国专利第5,225,539号;第5,530,101号和第5,585,089号)、镶饰(veneering)或表面重修(EP 592,106;EP 519,596;Padlan EA(1991);Studnicka GMet al,(1994);Roguska MA.et al,(1994))和链改组(美国专利第5,565,332号)。还已知用于制备所述抗体的一般重组DNA技术(参见欧洲专利申请EP 125023和国际专利公开案WO96/02576)。
本发明的Fab可通过用蛋白酶(例如木蛋白瓜酶)处理与CEACAM5特异性反应的抗体获得。而且,该Fab可通过将编码抗体的两条Fab链的DNA序列插入用于原核表达或用于真核表达的载体中并将载体引入原核或真核细胞(如果合适)中以表达Fab来产生。
本发明的F(ab')2可用蛋白酶胃蛋白酶处理与CEACAM5特异性反应的抗体获得。而且,该F(ab')2可通过经由硫醚键或二硫键结合下文所述的Fab'来产生。
本发明的Fab'可通过用还原剂如二硫苏糖醇处理与CEACAM5特异性反应的F(ab')2来获得。而且,该Fab'可通过将编码抗体Fab'链的DNA序列插入用于原核表达的载体或用于真核表达的载体中并将载体引入原核或真核细胞(如果合适的话)中以实施其表达来产生。
本发明的scFv可通过采取如前文所述的CDR或VH和VL结构域的序列,构建编码scFv片段的DNA,将DNA插入原核或真核表达载体中,且随后将表达载体引入原核或真核细胞(如果合适的话)中以表达scFv来产生。为生成人源化scFv片段,可使用称为CDR移植的熟知技术,该技术涉及选择根据本发明的互补决定区(CDR),并将其移植至已知三维结构的人scFv片段框架上(例如,参见W098/45322;WO 87/02671;US5,859,205;US5,585,089;US4,816,567;EP0173494)。
本发明抗体的修饰
本文所述抗体的氨基酸序列修饰也在考虑之内。举例来说,可预期改善抗体的结合亲和性和/或其他生物学性质。已知当人源化抗体是通过仅简单移植源自非人动物的抗体VH和VL中的CDR至人抗体VH和VL的FR中产生时,抗原结合活性与源自非人动物的初始抗体的抗原结合活性相比可能有所降低。认为非人抗体VH和VL的不仅CDR还有FR中的数个氨基酸残基可能与抗原结合活性直接或间接相关。因此,源自人抗体VH和VL的FR的不同氨基酸残基对所述这些氨基酸残基的取代将降低结合活性。为解决该问题,在用非人CDR移植的人抗体中,必须进行尝试以识别人抗体VH和VL的FR的氨基酸序列中与抗体的结合直接相关,或与CDR的氨基酸残基相互作用,或维持抗体的三维结构并与抗原的结合直接相关的氨基酸残基。降低的抗原结合活性可通过用源自非人动物的初始抗体的氨基酸残基替换识别出的氨基酸来提高。
在本发明的一个实施方案中,将本发明的鼠类抗体的六个CDR和来自其框架的三个氨基酸移植至人框架中,产生具有重链序列SEQ ID NO:74和轻链序列SEQ ID NO:75的人源化抗体(MAb2_VLg5VHg2),该人源化抗体维持与人和食蟹猴CEACAM5的结合特征。
可对本发明的抗体结构和编码本发明抗体的DNA序列作出修饰和改变,并仍产生具有预期特性的功能抗体或多肽。
在对多肽的氨基酸序列作出改变中,可考虑氨基酸的亲疏水指数。氨基酸亲疏水指数在赋予蛋白质相互作用的生物功能中的重要性通常为本领域所理解。已被接受的是氨基酸的相对亲疏水特征促成所得蛋白质的二级结构,进而限定该蛋白与其他分子举例来说酶、底物、受体、DNA、抗体、抗原等等的相互作用。已基于氨基酸的疏水和电荷特征对每一氨基酸指派亲疏水指数,它们是:异亮氨酸(+4.5);缬氨酸(+4.2);亮氨酸(+3.8);苯丙氨酸(+2.8);半胱氨酸/胱氨酸(+2.5);甲硫氨酸(+1.9);丙氨酸(+1.8);甘氨酸(-0.4);苏氨酸(-0.7);丝氨酸(-0.8);色氨酸(-0.9);酪氨酸(-1.3);脯氨酸(-1.6);组氨酸(-3.2);谷氨酸(-3.5);谷氨酰胺(-3.5);天冬氨酸(-3.5);天冬酰胺(-3.5);赖氨酸(-3.9);和精氨酸(-4.5)。
本发明的另一目标还涵盖本发明多肽的功能保守变体。
举例来说,在蛋白质结构中在不显著损失活性的情况下,某些氨基酸可由其他氨基酸取代。由于蛋白质的相互作用能力和性质定义其生物功能活性,因此可在蛋白质序列中(且当然在其DNA编码序列中)作出某些氨基酸取代,而同时仍获得具有类似性质的蛋白质。因此,预期可对本发明的抗体序列或编码所述多肽的相应DNA序列作出各种改变,而不会对其生物活性造成明显损失。
本领域已知,某些氨基酸可由具有相似亲疏水指数或评分的其他氨基酸取代并仍产生具有相似生物活性的蛋白质,即仍获得在生物功能上等价的蛋白质。还可使用已完善的技术如丙氨酸扫描的方式来识别本发明抗体或多肽中所有可被取代而不会对抗原结合造成显著损失的氨基酸。由于并不参与抗原结合或维持抗体的结构,可将这些残基定性为中性。这些中性位置中的一个或多个可由丙氨酸或由另一氨基酸取代而不改变本发明抗体或多肽的主要特征。
这在本发明中通过对MAb2K52R的CDR实施丙氨酸扫描方法来阐述,由于丙氨酸确实可被取代而不对与人和食蟹猴CEACAM5的结合造成显著影响,表明这些CDR的数个位置呈现为中性。因此,源自所述中性取代的抗体变体预期与亲代抗体保持功能相同。在所提供的实例6.4中,对MAb2的人源化变体进行取代,由于这些相关抗体都携载同组6个CDR或非常密切相关的CDR,但可预测的是在MAb2、Mab4或Mab5的任一变体中引入相同变化时还将维持生物功能。中性位置可定义为该抗体家族VL序列(SEQ ID NO:34或SEQ ID NO:38或SEQ ID NO:40或SEQ ID NO:17或SEQ ID NO:23或SEQ ID NO:29或SEQ ID NO:55或SEQ ID NO:75)的残基27、28、29、31、51、52、89、90、93、94、96、97和该抗体家族VH序列(SEQ ID NO:33或SEQ IDNO:37或SEQ ID NO:39或SEQ ID NO:5或SEQ ID NO:51或SEQ ID NO:74)的残基26至31、51至58、97、103、104、107、109。
中性位置可视为Mab2、Mab4或Mab5CDR中可并入任一氨基酸取代的位置。实际上,在丙氨酸扫描的原理中,选择丙氨酸是由于该残基不携带特异性结构或化学特征。通常认为,如果丙氨酸可取代特定氨基酸而不改变蛋白质的性质,许多其他(如果不是所有的)氨基酸取代也可能呈中性。在丙氨酸为野生型氨基酸的相反情况中,如果表明特异性取代为中性,其他取代也可能为中性。
在提供的实例6.4中,在丙氨酸扫描背景下,还识别出Mab2、Mab4或Mab5的CDR中的四个位置并非中性,但其中保守类型的氨基酸取代具有中性效果(此抗体家族VL序列的残基30和92以及VH序列的残基98和100)。
还可预期两条抗体链序列的任一条或两条中不同位置的两个或更多个中性突变组合时通常产生基本上保持亲代抗体的功能活性的抗体。这已由举例来说MAb2_VLg5VHg2中的组合取代LC_T51A与LC_T94A、VL_S31A和VH_G54Y、或VL_T53I和VH_S53A阐述。
如上文概述,因此氨基酸取代通常基于氨基酸侧链取代基的相对相似性,举例来说,其疏水性、亲水性、电荷、大小等等。考虑任一前述特性的示例性取代为本领域的技术人员所熟知且包括:精氨酸与赖氨酸;谷氨酸与天冬氨酸;丝氨酸与苏氨酸;谷氨酰胺与天冬酰氨酸;以及缬氨酸、亮氨酸与异亮氨酸。
改变本发明抗体的效应物功能也可能是理想的,例如用于增强抗体的抗原依赖性细胞介导的细胞毒性(ADCC)和/或补体依赖性细胞毒性(CDC)。这可以通过在抗体的Fc区引入一个或多个氨基酸取代实现。可替换地或此外,可在Fc区中引入半胱氨酸残基,由此允许在此区域中形成链间二硫键。因此产生的同二聚抗体可具有改良的内化能力和/或增强的补体介导的杀细胞和/或抗体依赖性细胞毒性(ADCC)(Caron PC.et al,1992;和ShopesB.1992)。
本发明抗体的另一氨基酸修饰类型可用于改变抗体的初始糖基化模式,即通过缺失一个或多个在抗体中发现的碳水化合物部分和/或添加一个或多个抗体中不存在的糖基化位点来实施。三肽序列天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸中任一种的存在产生潜在糖基化位点,其中X是除脯氨酸外的任一氨基酸。可通过改变氨基酸序列以使抗体中含有一个或多个上文所述的三肽序列(对于N-连接的糖基化位点)来向抗体中方便地完成糖基化位点的添加或缺失。
另一修饰类型涉及以计算机模拟或实验性移除经识别为可能导致抗体制剂的降解产物或异质性的序列。作为实例,天冬酰胺和谷氨酰胺残基的去酰胺化可取决于诸如pH和表面暴露等因素而发生。天冬酰胺残基主要在存在于序列Asn-Gly中时,且其次在其他二肽序列(例如Asn-Ala)中时,尤其易于去酰胺化。因此,当本发明抗体或多肽中存在该去酰胺化位点(尤其Asn-Gly)时,移除该位点可能是理想的,这通常通过保守取代移除一个相关残基来进行。为了移除一个或多个相关残基而在序列中进行的所述取代来也意图涵盖于本发明中。
另一共价修饰类型涉及使糖苷与抗体化学或酶偶联。这些步骤的优点在于其无需在宿主细胞中产生对N-或O-连接的糖基化具有糖基化能力的抗体。取决于所使用偶联模式,可使糖附着至以下各项:(a)精氨酸和组氨酸;(b)游离羧基;(c)游离巯基,例如半胱氨酸的游离巯基;(d)游离羟基,例如丝氨酸、苏氨酸或羟基脯氨酸的游离羟基;(e)芳香族残基,例如苯丙氨酸、酪氨酸或色氨酸的芳香族残基;或(f)谷氨酰胺的酰胺基团。举例来说,所述方法描述于WO87/05330中。
抗体上存在的任何碳水化合物部分的移除可以化学或酶方式来完成。化学去糖基化需要将抗体暴露于化合物三氟甲磺酸或等效化合物。此处理使得除连接糖(N-乙酰基葡糖胺或N-乙酰基半乳糖胺)外的大部分或所有糖裂解,同而保留抗体完整。化学去糖基化描述于Sojahr H.et al,(1987)和Edge,AS.et al,(1981)中。抗体上碳水化合物部分的酶裂解可通过使用多种内切和外切糖苷酶来实现,如Thotakura,NR.et al,(1987)中所述。
抗体的另一共价修饰类型包括抗体与多种非蛋白质性聚合物之一例如聚乙二醇、聚丙二醇或聚氧乙烯以美国专利号4,640,835、4,496,689、4,301,144、4,670,417、4,791,192或4,179,337中所描述的方式连接。
免疫偶联物
本发明还包括细胞毒性偶联物、或免疫偶联物、或抗体-药物偶联物、或偶联物。如本文所使用,所有这些术语具有相同含义且可互换。
已通过SPDB接头(吡啶基二硫丁酸N-琥珀酰亚胺基酯)将鼠类抗体MAb1、MAb2、MAb3、MAb4和MAb5偶联至类美登素(DM4)。发现所得抗体-药物偶联物(ADC)对MKN45人胃癌细胞具有细胞毒性活性,且IC50值≤1nM。
相似地,抗体-SPDB-DM4偶联物基于MAb1、MAb2、MAb4和MAb5中每一种的嵌合形式制备。针对皮下植入雌性SCID小鼠中的可测量原发性结肠CR-IGR-034P肿瘤来评估两种剂量的所得chMAb1-SPDB-DM4、chMAb2-SPDB-DM4、chMAb3-SPDB-DM4和chMAb4-SPDB-DM4。对每一治疗组和对照组的肿瘤体积变化和肿瘤消退%的分析表明,chMAb2-SPDB-DM4、chMAb4-SPDB-DM4和chMAb5-SPDB-DM4至少在所分析的最高剂量下具有高活性,且chMAb2-SPDB-DM4在两种分析剂量下都有活性。值得注意的是获得直至82%的肿瘤消退百分比。
抗体-SPDB-DM4偶联物还使用MAb2的人源化变体(huMAb2-1-SPDB-DM4、huMAb2-2-SPDB-DM4和huMAb2-3-SPDB-DM4)来制备。比较包含MAb2的嵌合(chMAb2-SPDB-DM4)或人源化变体的ADC与不相关抗体-SPDB-DM4对MKN45细胞的细胞毒性活性。MAb2ADC的所有嵌合和人源化变体都展现≤1nM的IC50值,即IC50值比所测量不相关DM4偶联物细胞毒性活性低35至53倍,由此表明抗CEACAM5偶联物的CEACAM5介导的细胞毒性活性。
评估huMAb2-3-SPDB-DM4和huMAb2-4-SPDB-DM4对皮下植入雌性CD-1裸小鼠中的可测量原发性结肠CR-IGR-034P肿瘤的抗肿瘤活性且与chMAb2-SPDB-DM4进行比较。所有偶联物在所分析的最高剂量(10mg/kg)下都具有高活性。
进一步评估huMAb2-3-SPDB-DM4和huMAb2-3-磺基-SPDB-DM4对皮下植入雌性SCID小鼠中的可测量原发性结肠CR-IGR-034P肿瘤的抗肿瘤活性。huMAb2-3-SPDB-DM4在5mg/kg和2.5mg/kg下具有活性,huMAb2-3-磺基-SPDB-DM4在5mg/kg下具有高活性且在2.5mg/kg下具有活性。
进一步评估huMAb2-3-SPDB-DM4对皮下植入雌性SCID小鼠中的可测量原发性肺LUN-NIC-0014肿瘤的抗肿瘤活性且发现其在10mg/kg和5mg/kg下具有高活性。
每一DM4偶联物包含2至5平均数目的DM4分子(或“药物对抗体比率”或“DAR”)。
相应地,本发明涉及包含连接或偶联至至少一种生长抑制剂如细胞毒性剂或放射性同位素的本发明抗体的“免疫偶联物”。
“生长抑制剂”或“抗增殖剂”可无差别地使用,指在体外或体内抑制细胞、尤其肿瘤细胞生长的化合物或组合物。
如本文所使用的术语“细胞毒性剂”指抑制或阻止细胞功能和/或引起细胞破坏的物质。术语“细胞毒性剂”意在包含化学治疗剂、酶、抗生素和毒素例如细菌、真菌、植物或动物来源的小分子毒素或酶活性毒素,包含其片段和/或变体,和下文所揭示的各种抗肿瘤或抗癌药。在一些实施方案中,细胞毒性剂是类紫杉醇、长春碱类、类美登素或类美登素类似物如DM1或DM4、小药物、茅屋霉素(tomaymycin)或吡咯并苯并二氮衍生物、念珠藻素(cryptophycin)衍生物、来普霉素(leptomycin)衍生物、奥里斯他汀(auristatin)或多拉司他汀(dolastatin)类似物、前药、拓扑异构酶II抑制剂、DNA烷基化剂、抗微管蛋白剂、CC-1065或CC-1065类似物。
如本文所使用,“类美登素”指示类美登素和类美登素类似物。类美登素是抑制微管形成且对哺乳动物细胞具有高毒性的药物。
合适的类美登素的实例包含美登木醇(maytansinol)和美登木醇类似物。
合适的美登木醇类似物的实例包含那些具有经修饰芳香环和那些具有其他位置修饰的那些。所述合适的类美登素公开于美国专利号4,424,219;4,256,746;4,294,757;4,307,016;4,313,946;4,315,929;4,331,598;4,361,650;4,362,663;4,364,866;4,450,254;4,322,348;4,371,533;6,333,410;5,475,092;5,585,499;和5,846,545中。
具有修饰的芳香环的合适美登木醇类似物的特定实例包括:
(1)C-19-去氯(美国专利号4,256,746)(通过安丝菌素(ansamytocin)P2的LAH还原来制备);
(2)C-20-羟基(或C-20-去甲基)+/-C-19-去氯(美国专利第4,361,650号和第4,307,016号)(通过使用链霉菌属(Streptomyces)或放线菌属(Actinomyces)去甲基化或使用LAH去氯来制备);和
(3)C-20-去甲氧基、C-20-酰基氧基(-OCOR)、+/-去氯(美国专利号4,294,757)(通过使用酰氯酰化来制备)。
具有其他位置修饰的合适的美登木醇类似物的特定实施例包含:
(1)C-9-SH(美国专利号4,424,219)(通过使美登木醇与H2S或P2S5反应来制备);
(2)C-14-烷氧基甲基(去甲氧基/CH2OR)(美国专利号4,331,598);
(3)C-14-羟基甲基或酰氧基甲基(CH2OH或CH2OAc)(美国专利号4,450,254)(从诺卡氏菌属(Nocardia)制备);
(4)C-15-羟基/酰氧基(美国专利第4,364,866号)(通过链霉菌属转化美登木醇来制备);
(5)C-15-甲氧基(美国专利号4,313,946和4,315,929)(从滑桃树(Trewianudiflora)分离);
(6)C-18-N-去甲基(美国专利第4,362,663号和第4,322,348号)(通过链霉菌属对美登木醇去甲基化来制备);和
(7)4,5-脱氧基(美国专利号4,371,533)(通过美登木醇的三氯化钛/LAH还原制备)。
在本发明的实施方案中,本发明的细胞毒性偶联物利用含有硫醇的类美登素(DM1)(在形式上称为N2’-去乙酰基-N2’-(3-巯基-1-氧代丙基)-美登素(maytansine))作为细胞毒性剂。DM1由以下结构式(I)表示:
在另一实施方案中,本发明的细胞毒性偶联物利用含有硫醇的类美登素DM4(在形式上称为N2’-去乙酰基-N2’-(4-甲基-4-巯基-1-氧代戊基)-美登素)作为细胞毒性剂。DM4由以下结构式(II)表示:
在本发明的另一实施方案中,可使用其他美登素,包含在带有硫原子的碳原子上带有单或二烷基取代的含有硫醇和二硫化物的类美登素。这些类美登素包括在C-3、C-14羟基甲基、C-15羟基或C-20去甲基处具有经带有阻断巯基的酰基酰化的氨基酸侧链的类美登素,其中带有硫醇功能基的酰基的碳原子具有一个或两个取代基,所述取代基为CH3、C2H5、线性或支链烷基或烯基,具有可存在于溶液中的1至10种试剂和任何聚集物。
这些细胞毒性剂和偶联方法的实例进一步在申请WO2008/010101中给出,该申请以引用方式并入本文中。
术语“放射性同位素”意在包含适用于治疗癌症的放射性同位素,例如At211、Bi212、Er169、I131、I125、Y90、In111、P32、Re186、Re188、Sm153、Sr89和Lu的放射性同位素。所述放射性同位素通常主要发射β-辐射。在实施方案中,放射性同位素为α-发射体同位素,更精确而言为发射α辐射的钍227。根据本发明的免疫偶联物可如申请WO2004/091668中所述制备。
在一些实施方案中,本发明抗体直接或经由可裂解或不可裂解接头共价附着至至少一种生长抑制剂。
如本文所使用,“接头”意为包含将多肽共价连接至药物部分的共价键或原子链的化学部分。
偶联物可通过体外方法来制备。为将药物或前药与抗体连接,使用连接基团。合适的连接基团为本领域所熟知且包含二硫化物基团、硫醚基团、酸不稳定性基团、光不稳定性基团、肽酶不稳定性基团和酯酶不稳定性基团。本发明抗体与细胞毒性剂或生长抑制剂的偶联可使用多种双功能蛋白偶联剂来制造,所述双功能蛋白偶联剂包括但不限于吡啶基二硫丁酸N-琥珀酰亚胺基酯(SPDB)、丁酸4-[(5-硝基-2-吡啶基)二硫]-2,5-二氧代-1-吡咯烷基酯(硝基-SPDB)、4-(吡啶-2-基二硫基)-2-磺基-丁酸(磺基-SPDB)、(2-吡啶基二硫基)丙酸N-琥珀酰亚胺基酯(SPDP)、(N-马来酰亚胺基甲基)环己烷-1-甲酸琥珀酰亚胺基酯(SMCC)、亚胺基硫烷(IT)、亚胺基酯的双功能衍生物(例如二亚胺代己二酸二甲酯(dimethyl adipimidate)HCL)、活性酯(例如辛二酸二琥珀酰亚胺酯(disuccinimidylsuberate))、醛(例如戊二醛)、双-叠氮基化合物(例如双(对-叠氮基苯甲酰基)己二胺)、双-重氮衍生物例如双-(对-重氮苯甲酰基)-乙二胺、二异氰酸酯(例如甲苯2,6-二异氰酸酯)和双-活性氟化合物(例如1,5-二氟-2,4-二硝基苯)。举例来说,蓖麻毒素免疫毒素可如Vitetta et al,(1987)中所述来制备。经碳标记的1-异硫氰酸苄基甲基二乙烯基三胺五乙酸(MX-DTPA)是用于偶联放射性核苷酸与抗体的示例性螯合剂(WO 94/11026)。
接头可为促进细胞毒性剂或生长抑制剂在细胞中释放的“可裂解接头”。举例来说,可使用酸不稳定性接头、肽酶敏感性接头、酯酶不稳定性接头、光不稳定性接头或含有二硫化物的接头(例如,参见美国专利号5,208,020)。接头还可为在一些情况中可能引起更佳耐受的“不可裂解接头”(举例来说SMCC接头)。
可替换地,包含本发明抗体和细胞毒性或生长抑制性多肽的融合蛋白可通过重组技术或肽合成来制造。DNA的长度可包含编码偶联物的两个部分的各别区域,其彼此相邻或通过编码接头肽的区域隔开,该编码接头肽的区域不会破坏偶联物的预期性质。
本发明抗体还可通过使多肽与激活前药的酶偶联来用于酶介导的依赖性前药疗法中,所述酶将前药(例如,肽基化学治疗剂,参见WO81/01145)转换为活性抗癌药物(例如,参见WO 88/07378和美国专利第4,975,278号)。可用于ADEPT的免疫偶联物的酶组份包含任何能够以将前药转化为其活性、细胞毒性更强的形式的方式作用于前药的酶。可用于本发明方法中的酶包含但不限于碱性磷酸酶,其可用于将含磷酸酯的前药转化为游离药物;芳基硫酸酯酶,其可用于将含硫酸酯的前药转化为游离药物;胞嘧啶去胺酶,其可用于将非毒性氟胞嘧啶转化为抗癌药物5-氟尿嘧啶;蛋白酶,例如沙雷氏菌(serratia)蛋白酶、嗜热菌蛋白酶、枯草杆菌蛋白酶、羧肽酶和组织蛋白酶(例如组织蛋白酶B和L),其可用于将含肽前药转化为游离药物;D-丙胺酰羧肽酶,其可用于转换含有D-氨基酸取代基的前药;碳水化合物裂解酶,例如O-半乳糖苷酶和神经胺糖酸苷酶,其可用于将糖基化前药转化为游离药物;P-内酰胺酶,其可用于将经P-内酰胺衍生的药物转化为游离药物;和青霉素(penicillin)酰胺酶,例如青霉素V酰胺酶或青霉素G酰胺酶,其可用于将胺氮处分别经苯氧基乙酰基或苯基乙酰基衍生的药物转化为游离药物。所述酶可通过本领域熟知的技术(例如使用上文所论述的异双功能性交联试剂)共价结合至本发明多肽。
根据实施方案,在本发明偶联物中,生长抑制剂为类美登素,在实施方案中为DM1或DM4。
在所述偶联物中,抗体通过连接基团偶联至所述至少一种生长抑制剂。在实施方案中,所述连接基团为可裂解或不可裂解接头,例如SPDB、磺基-SPDB或SMCC。
偶联物可选自下组:
i)式(III)的抗体-SPDB-DM4偶联物
ii)式(IV)的抗体-磺基-SPDB-DM4偶联物,和
iii)式(V)的抗体-SMCC-DM1偶联物
在所述实施方案中,偶联物中所包含的抗体选自下组:
i)包含重链序列SEQ ID NO:51和轻链序列SEQ ID NO:17的人源化抗体,
ii)包含重链序列SEQ ID NO:5和轻链序列SEQ ID NO:23的人源化抗体,
iii)包含重链序列SEQ ID NO:5和轻链序列SEQ ID NO:29的人源化抗体,和
iv)包含重链序列SEQ ID NO:51和轻链序列SEQ ID NO:55的人源化抗体。
在实施方案中,偶联物是如上文所定义的式(III)、(IV)或(V)偶联物,其中抗体是包含重链序列SEQ ID NO:5和轻链序列SEQ ID NO:29的人源化抗体。
通常,所述偶联物可通过包含以下步骤的方法获得:
(i)使任选地缓冲的细胞结合剂(例如根据本发明的抗体)水溶液与接头和细胞毒性化合物的溶液接触;
(ii)随后任选地从未反应的细胞结合剂分离(i)中所形成的偶联物。
细胞结合剂水溶液可使用如磷酸钾、乙酸盐、柠檬酸盐或N-2-羟乙基哌嗪-N’-2-乙磺酸(Hepes缓冲液)等缓冲液缓冲。缓冲液取决于细胞结合剂的性质。细胞毒性化合物在极性有机溶剂中(例如二甲基亚砜(DMSO)或二甲基乙酰胺(DMA))溶液中。
反应温度通常为20℃与40℃。反应时间可为1小时至24小时。细胞结合剂与细胞毒性剂间的反应可通过尺寸排阻层析(SEC)使用折射和/或UV检测器来监测。如果偶联物产率过低,可延长反应时间。
本领域的技术人员可使用多种不同层析方法实施步骤(ii)的分离:可通过例如SEC、吸附层析(例如离子交换层析、IEC)、疏水相互作用层析(HIC)、亲和层析、混合支持层析(例如羟基磷灰石层析)或高效液相层析(HPLC)来纯化偶联物。还可使用透析或渗滤纯化。
如本文所使用,术语“聚集物”意为可在两个或多个细胞结合剂间形成的缔合,所述试剂可通过偶联修饰或不经修饰。聚集物可在多个参数的影响下形成,所述参数是如溶液中细胞结合剂的高浓度、溶液pH、高剪切力、所键结二聚体的数目和其疏水特征、温度(参见Wang和Gosh,2008,J.Membrane Sci.,318:311-316和其中所引用的参照文献);应该注意的是,并未明确建立这些参数中一些的相对影响。在蛋白质和抗体的情况中,本领域的技术人员可参照Cromwell et al,(2006,AAPS Jounal,8(3):E572-E579)。可使用诸如SEC等本领域的技术人员熟知的技术来测定聚集物中的含量(content)(参见Walter et al,1993,Anal.Biochem.,212(2):469-480)。
在步骤(i)或(ii)后,可将含有偶联物的溶液提交至层析、超滤和/或渗滤的额外步骤(iii)。
在这些步骤结束时在水溶液中回收偶联物。
根据实施方案,根据本发明偶联物的特征在1至10、举例来说2至5、尤其3至4的“药物对抗体比率”(或“DAR”)。包含类美登素分子的偶联物通常如此。
此DAR值可随所使用抗体和药物(即生长抑制剂)的性质以及用于偶联的实验条件(如生长抑制剂/抗体比率、反应时间、溶剂和共溶剂(如果存在)的性质)而变化。因此,抗体与生长抑制剂间的接触导致包含数种药物对抗体比率彼此不同的偶联物、任选地裸抗体、任选地聚集物的混合物。因此,所测定的DAR为平均值。
可用于测定DAR的方法包括以分光光度计方式测量基本上上纯化的偶联物溶液在λD与280nm下的吸收的比率。280nm是通常用于测量蛋白质浓度例如抗体浓度的波长。选择波长λD以便辨别药物与抗体,即如本领域的技术人员所易知,λD是药物具有高吸收的波长且λD与280nm距离足够远以避免药物与抗体吸收峰的大量重叠。在类美登素分子的情况中λD可选择为252nm。DAR计算的方法可源自Antony S.Dimitrov(编辑),LLC,2009,TherapeuticAntibodies and Protocols,第525,445卷,Springer Science:
偶联物在λD(AλD)和280nm(A 280)下的吸收在尺寸排阻层析(SEC)分析的单体峰(允许计算“DAR(SEC)”参数)上或使用典型分光光度计装置(以允许计算“DAR(UV)”参数)测量。吸收可如下表示:
AλD=(cD x εDλD)+(cA x εAλD)
A280=(cD x εD280)+(cA x εA280)
其中:
·cD和cA分别为溶液中药物和抗体的浓度
·εDλD和εD280分别为药物在λD和280nm下的摩尔消光系数
·εAλD和εA280分别为抗体在λD和280nm下的摩尔消光系数。
对所述两个具有未知数的等式进行解析产生以下等式:
cD=[(εA280 x AλD)-(εAλD x A280)]/[(εDλD x εA280)-(εAλD x εD280)]
cA=[A280–(cD x εD280)]/εA280
随后自药物浓度对抗体浓度的比率计算平均DAR:DAR=cD/cA。
药物组合物
本发明抗体或免疫偶联物可与药学上可接受的赋形剂和任选地持续释放基质(例如生物可降解聚合物)组合,以形成治疗性组合物。
因此,本发明的另一目标涉及包含本发明的抗体或免疫偶联物和药学上可接受的载剂或赋形剂的药物组合物。
本发明还涉及根据本发明的多肽或免疫偶联物,用于作为药物的使用。
“药学上”或“药学上可接受”指当施用至哺乳动物、尤其人(如果合适)时并不产生不利、过敏或其他不良反应的分子实体和组合物。药学上可接受的载剂或赋形剂是指无毒性固体、半固体或液体填充剂、稀释剂、封装材料或任何类型的配制辅助剂。
如本文所使用,“药学上可接受的载剂”包含任何和所有溶剂、分散介质、涂层、抗细菌和抗真菌剂和生理上相容的类似试剂。合适的载剂、稀释剂和/或赋形剂的实例包括一种或多种水、氨基酸、盐水、磷酸盐缓冲盐水、磷酸盐缓冲液、乙酸盐缓冲液、柠檬酸盐缓冲液、琥珀酸盐缓冲液;氨基酸和衍生物,例如组氨酸、精氨酸、甘氨酸、脯氨酸、甘胺酰甘氨酸;无机盐NaCl、氯化钙;糖或多元醇,例如右旋糖、甘油、乙醇、蔗糖、海藻糖、甘露醇;表面活性剂,例如聚山梨醇酯80、聚山梨醇酯20、泊洛沙姆(poloxamer)188;等等,及其组合。在许多情况中,在组合物中优选包括等渗剂,例如糖、多元醇或氯化钠,且配制物还可含有抗氧化剂如色胺和稳定剂如Tween 20。
药物组合物的形式、施用途径、剂量和方案通常取决于欲治疗的病况、疾病的严重程度、患者的年龄、体重和性别等而定。
本发明的药物组合物可经配制以供局部、口服、非胃肠、鼻内、静脉内、肌内、皮下或眼内施用等等。
在实施方案中,药物组合物含有对于能够注射的配制剂为药学上可接受的媒介。所述媒介可为等渗、无菌、盐水溶液(磷酸一钠或磷酸二钠、氯化钠、氯化钾、氯化钙或氯化镁等等或所述盐的混合物)或在视情况添加无菌水或生理盐水后允许构成可注射溶液的干燥、尤其是冻干的组合物。
药物组合物可经通过药物组合装置来施用。
用于施用的剂量可作为各种参数的函数,和例如作为相关病理的所使用施用模式的函数或可替换地治疗预期持续时间的函数来调整。
为制备药物组合物,可将有效量的本发明抗体或免疫偶联物溶解或分散于药学上可接受的载剂或水介质中。
适于可注射使用的药物形式包括无菌水溶液或分散液;配制物,其包含芝麻油、花生油或丙二醇水溶液;和无菌粉末,其用于临场制备无菌可注射溶液或分散液。在所有情况中,所述形式必须无菌且可使用合适装置或系统注射用于递送而不降解。其必须在制造和储存条件下稳定且必须针对如细菌和真菌等微生物的污染作用进行防腐。
呈游离碱或药理上可接受的盐形式的活性化合物的溶液可在与表面活性剂适当混合的水中制备。分散液还可在甘油、液体聚乙二醇和其混合物中和在油中制备。在普通储存和使用条件下,这些配制物包括防腐剂以防止微生物生长。
可将本发明的多肽、抗体或免疫偶联物配制成呈中性或盐形式的组合物。药学上可接受的盐包含酸加成盐(使用蛋白质的游离胺基形成),并且其使用无机酸如盐酸或磷酸或有机酸如乙酸、草酸、酒石酸、苦杏仁酸等等形成。使用游离羧基形成的盐还可源自举例来说氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁等无机碱和如异丙胺、三甲胺、甘氨酸、组氨酸或普鲁卡因(procaine)等等有机碱。
载剂还可为溶剂或分散介质,其包括例如水、乙醇、多元醇(如甘油、丙二醇和液体聚乙二醇等等)、其合适的混合物和植物油。例如,可通过使用包衣如卵磷脂、在分散液情况中通过维持所需粒径和通过使用表面活性剂来维持适当流动性。可通过各种抗细菌剂或抗真菌剂如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等等来防止微生物作用。在许多情况中,优选应包括等渗剂,例如糖或氯化钠。可注射组合物的延长吸收可通过在组合物中使用延迟吸收试剂举例来说单硬脂酸铝和明胶带来。
无菌可注射溶液可通过将所需量的活性化合物并入视需要具有上文所列举的任一其他成份的适当溶剂中,随后进行过滤灭菌进行制备。通常,分散液通过将各种无菌活性成份并入含有基本分散介质和来自那些上文所列举成份的所需其他成份的无菌媒介中进行制备。在使用无菌粉末制备无菌可注射溶液的情况中,优选制备方法是真空干燥和冷冻干燥技术,其可从预先经无菌过滤的溶液产生由活性成份加上任一期望的额外成份构成的粉末。
本文还涵盖用于直接注射的更浓或高度浓缩溶液的制备,其中预期使用DMSO作为溶剂以导致极快速渗透,从而将高浓度的活性剂递送至小肿瘤区域。
配制后,溶液将以与剂量配制物兼容的方式并以治疗有效量来施用。配制物可容易地以诸如上文所述的可注射溶液类型等多种剂型施用,但还可采用药物释放胶囊等等。
举例来说,对于水溶液的非胃肠施用,溶液(如果需要)应经适当缓冲且借助足量盐水或葡萄糖首先使液体稀释剂等渗。所述水溶液尤其适于静脉内、肌内、皮下和腹膜内施用。就此而言,本发明采用的无菌水介质将为本领域的技术人员所知。举例来说,可将某一剂量溶解于1ml NaCl等渗溶液中并添加至1000ml皮下灌注液中或在所提出的输注位点处注射(例如,参见“Remington's Pharmaceutical Sciences”第15版,第1035-1038页和第1570-1580页)。取决于所治疗受试者的病况,剂量必然将发生一些变化。负责施用的人在任何情况中将决定个体受试者的合适剂量。
本发明抗体或免疫偶联物可在治疗混合物内经配制以使每剂量包含约0.01毫克至100毫克左右。
除经配制用于非胃肠施用(例如静脉内或肌内注射)的抗体或免疫偶联物外,其他药学上可接受的形式包含例如片剂或用于口服施用的其他固体、时间释放胶囊和当前所使用的任何其他形式。
在某些实施方案中,涵盖使用脂质体和/或纳米微粒将多肽引入宿主细胞中。脂质体和/或纳米微粒的形成和使用为本领域的技术人员所知。
纳米胶囊通常可以稳定且再现的方式捕获化合物。为避免因细胞内聚合物过载而产生的副作用,通常使用能够在体内降解的聚合物来设计这类超细微粒(大小约为0.1μm)。预期在本发明中使用满足这些要求的生物可降解的聚氰基丙烯酸烷基酯纳米微粒或生物可降解的聚乳酸或聚乳酸羟基乙酸共聚物纳米微粒,且可容易地制造这样的微粒。
脂质体是自分散于水介质中且自发形成多层同心双层囊泡(还称为多层囊泡(MLV))的磷脂形成。MLV通常具有25nm至4μm的直径。对MLV进行超声处理可导致单层小囊泡(SUV)的形成,其直径为至核心中包含水溶液。脂质体的物理特征取决于pH、离子强度和二价阳离子的存在。
治疗方法和用途
发明人已展示,五种已由他们产生的抗体在结合后能够内化CEACAM5-抗体复合物。此外其已展示,这些抗体与细胞毒性类美登素(DM4)的组合体外诱导针对人MKN45肿瘤细胞的细胞毒性活性。其还已展示,在源自患者的人原发性结肠肿瘤异种移植物的鼠类模型中,这些免疫偶联物在以5mg/kg和2.5mg/kg的剂量使用且以在植入肿瘤后第14天单次注射时在体内诱导了显著的抗肿瘤活性。
因此,本发明的多肽、抗体、免疫偶联物或药物组合物可用于治疗癌症。
将使用本发明的抗体、免疫偶联物或药物组合物治疗的癌症是表达CEACAM5、尤其与相同组织来源的正常(即非肿瘤)细胞相比过表达CEACAM5的癌症。癌细胞表达CEACAM5可容易地通过例如使用本发明抗体如以下“诊断用途”部分所述且尤其通过如实施例8中所述的免疫组织化学方法来分析。
在实施方案中,癌症可为结肠直肠癌、胃癌、肺癌、子宫颈癌、胰癌、食道癌、卵巢癌、甲状腺癌、膀胱癌、子宫内膜癌、乳腺癌、肝癌如胆管癌、前列腺癌或皮肤癌。通过免疫组织化学使用本发明的小鼠抗人CEACAM5抗体对一组人肿瘤的筛选确实显示在这些类型的癌症中的抗体染色,如实施例8中进一步详细描述。
本发明的抗体或免疫偶联物可单独使用或与任何合适的生长抑制剂组合使用。
本发明抗体可偶联或连接至如前文所述的生长抑制剂、细胞毒性剂或激活前药的酶。本发明抗体确实可用于使所述生长抑制剂、细胞毒性剂或前药靶向在其表面上表达或过表达CEACAM5的癌细胞。
本领域还熟知治疗性单克隆抗体可导致带有抗体所特异性识别的抗原的细胞的消耗。此消耗可通过至少三种机制介导:抗体介导的细胞毒性(ADCC)、补体依赖性溶解和经由抗体所靶向的抗原给出的信号对肿瘤生长的直接抗肿瘤抑制。
“补体依赖性细胞毒性”或“CDC”指补体存在下靶细胞的溶解。典型补体通路的激活是通过结合补体系统的第一组份与结合至其同源抗原的抗体来起始。为评价补体激活,可实施如Gazzano-Santoro et al,(1997)中所述的CDC试验。
“抗体依赖性细胞介导的细胞毒性”或“ADCC”是指结合至存在于某些细胞毒性细胞(例如自然杀伤(NK)细胞、中性粒细胞和巨噬细胞)上的Fc受体(FcR)上的分泌抗体使这些细胞毒性效应细胞能够特异性结合至带有抗原的靶细胞且随后杀死该靶细胞的细胞毒性形式。为评价所关注分子的ADCC活性,可实施方案如美国专利号5,500,362或5,821,337所述的体外ADCC分析。
因此,本发明的目标涉及用于治疗癌症的方法,该方法包括向有需要的受试者施用治疗有效量的本发明多肽、抗体、免疫偶联物或其药物组合物。
在本发明背景下,如本文所使用的术语“治疗”或“处理”意为逆转、减轻、抑制该术语所应用的病症或病况或该病症或病况的一种或多种症状的进展、或预防该术语所应用的病症或病况,或该病症或病况的一种或多种症状。如本文所使用的术语“治疗癌症”意为抑制恶性肿瘤细胞的生长和/或来自所述肿瘤的转移的进展。该治疗还可导致肿瘤生长消退,即减小可测量肿瘤的大小。具体而言,该治疗导致肿瘤或转移完全消退。
根据本发明,术语“患者”或“有需要的患者”意为受恶性肿瘤影响或可能受其影响的人或非人哺乳动物。具体而言,该患者可以是举例来说根据如下文所述的方法已确定对靶向CEACAM5的治疗剂、尤其本发明的抗体或免疫偶联物影响易感的患者。
本发明多肽的“治疗有效量”意为足以以合理益处/风险比可应用于任一医学治疗来治疗所述癌症疾病的多肽的量。然而,应理解的是本发明多肽和组合物的总日用量将由主治医生在合理的医学判断范畴内决定。任一具体患者的特定治疗有效剂量水平将取决于多种因素,包含所治疗的病症和该病症的严重程度;所采用特定多肽的活性;所采用的特定组合物;患者的年龄、体重、总体健康状况、性别和饮食;所采用特定多肽的施用时间、施用途径和排泄速率;治疗持续时间;与所采用的特定多肽组合或同时使用的药物;和医学领域中所熟知的类似因素。例如,本领域的技术人员熟知以低于那些达成预期治疗效果所需的量来起始化合物的剂量,并逐步增加剂量直至达成预期效果。
本发明的另一目标涉及本发明的多肽、抗体、免疫偶联物或药物组合物用于治疗恶性肿瘤。
多肽、抗体、免疫偶联物或药物组合物可用于抑制恶性肿瘤转移的进展。
本发明多肽可与任何其他治疗策略(例如辅助疗法)组合使用用于治疗恶性肿瘤和/或减缓转移性肿瘤的生长。
使用根据本发明的抗体或免疫偶联物治疗的效力可容易地在体内进行分析,例如在小鼠癌症模型上且通过测量例如如实施例5.3中所定义的治疗组与对照组间的肿瘤体积变化、肿瘤消退%、部分消退和/或完全消退来分析。
诊断用途
已报导,CEACAM5在结肠直肠、胃、肺、子宫肿瘤细胞的表面上具有高表达且在少数正常上皮细胞(例如结肠和食道上皮细胞)中具有弱表达。此外,通过免疫组织化学使用根据本发明的小鼠抗人CEACAM5抗体对一组人肿瘤的筛选展示结肠直肠癌、胃癌、肺癌、子宫颈癌、胰癌、食道癌、卵巢癌、甲状腺癌、膀胱癌、子宫内膜癌、乳腺癌、肝癌(尤其胆管癌)、前列腺癌和皮肤癌中的抗体染色。
因此,CEACAM5构成癌症标记,且因此具有用于指示抗癌疗法的有效性或检测疾病复发的潜力。
在实施方案中,本发明抗体是用作靶向表达CEACAM5的肿瘤的疗法背景下的试验的组份,以测定患者对治疗剂的易感性,监测抗癌疗法的有效性或检测治疗后疾病的复发。具体而言,本发明的相同抗体可用作治疗剂组份和诊断试验的组份二者。
因此,本发明的又一目标涉及根据本发明的抗体用于体内检测受试者中的CEACAM5表达或用于离体检测受试者的生物样品中的CEACAM5表达的用途。所述检测可尤其意在用于通过检测肿瘤细胞上表面蛋白CEACAM5的表达,由此来
a)诊断受试者中癌症的存在,或
b)测定患有癌症的患者对靶向CEACAM5的治疗剂、尤其本发明的免疫偶联物的易感性,或
c)监测抗CEACAM5癌症疗法的有效性或检测抗CEACAM5癌症疗法、尤其使用根据本发明免疫偶联物的疗法后的癌症复发。
在实施方案中,抗体意在用于体外或离体用途。举例来说,可使用本发明抗体以体外或离体方式检测从受试者获得的生物样品中的CEACAM5。本发明的用途还可为体内用途。例如,向受试者施用根据本发明的抗体并检测和/或量化抗体-细胞复合物,由此所述复合物的检测可指示癌症。
本发明进一步涉及检测受试者中癌症存在的体外或离体方法,该方法包括步骤:
(a)使个体的生物样品与本发明抗体接触,尤其是在抗体与该生物样品足以形成复合物的条件下;
(b)测量结合至该生物样品的抗体的水平,
(c)通过比较结合抗体与对照的测量水平来检测癌症的存在,结合抗体比对照增加的水平可指示癌症。
本发明还涉及测定患有癌症的患者对靶向CEACAM5的治疗剂、尤其本发明免疫偶联物的易感性的体外或离体方法,该方法包括步骤:
(a)使患有癌症的患者的生物样品与本发明抗体接触,尤其是在抗体与该生物样品足以形成复合物的条件下;
(b)测量结合至该生物样品的抗体的水平,
(c)比较结合至该生物样品的抗体的测量水平与结合至对照的抗体的水平;
其中结合至该生物样品的抗体比结合至对照的抗体增加的水平可指示患者易受靶向CEACAM5的治疗剂影响。
在上述方法中,所述对照可为相同类型的正常非癌性生物样品,或将参照值确定为相同类型的正常生物样品中抗体结合水平的代表。
在实施方案中,本发明抗体可用于诊断表达CEACAM5的癌症,例如结肠直肠癌、胃癌、肺癌、子宫颈癌、胰癌、食道癌、卵巢癌、甲状腺癌、膀胱癌、子宫内膜癌、乳腺癌、肝癌(尤其胆管癌)、前列腺癌或皮肤癌。
本发明进一步涉及监测抗CEACAM5癌症疗法的有效性的体外或离体方法,该方法包括步骤:
(a)使经受抗CEACAM5癌症疗法的受试者的生物样品与本发明抗体接触,尤其是在抗体与该生物样品足以形成复合物的条件下;
(b)测量结合至该生物样品的抗体的水平,
(c)比较结合抗体的测量水平与结合至对照的抗体的水平;
其中结合至该生物样品的抗体比结合至对照的抗体减少的水平可指示该抗CEACAM5癌症疗法的有效性。
在该方法中,结合至该生物样品的抗体比结合至对照的抗体增加的水平可指示该抗CEACAM5癌症疗法的无效性。
在实施方案中,所述对照是与提交至分析的生物样品类型相同的生物样品,但该对照在抗CEACAM5癌症疗法之前、在疗程期间从受试者获得。
本发明进一步涉及检测抗CEACAM5癌症疗法后癌症复发的体外或离体方法,该方法包括步骤:
(a)使完成了抗CEACAM5癌症疗法的受试者的生物样品与本发明抗体接触,尤其在抗体与该生物样品足以形成复合物的条件下;
(b)测量结合至该生物样品的抗体的水平,
(c)比较结合抗体的测量水平与结合至对照的抗体的水平;
其中结合至该生物样品的抗体比结合至对照的抗体增加的水平可指示抗CEACAM5癌症疗法后的癌症复发。
所述对照尤其是与提交至分析的生物样品类型相同的生物样品,但该对照在完成抗CEACAM5癌症疗法之前、之中或之后获得。
所述抗CEACAM5癌症疗法尤其是使用根据本发明的抗体或免疫偶联物的疗法。所述抗CEACAM5癌症疗法靶向表达CEACAM5的癌症,尤其结肠直肠癌、胃癌、肺癌、子宫颈癌、胰癌、食道癌、卵巢癌、甲状腺癌、膀胱癌、子宫内膜癌、乳腺癌、肝癌(尤其胆管癌)、前列腺癌或皮肤癌。
在实施方案中,本发明抗体可以用可检测分子或物质(例如荧光分子、放射性分子或本领域已知提供(直接或间接)信号的任何其他标记)标记。
如本文所使用,关于本发明抗体的术语“标记”意在涵盖通过将可检测物质如放射性药剂或荧光团(如荧光异硫氰酸盐(FITC)或藻红素(PE)或绿靛花青(Indocyanine)(Cy5))偶联(即物理连接)至多肽的抗体直接标记以及通过与可检测物质的反应性的多肽间接标记。
本发明抗体可通过本领域已知的任何方法使用放射性分子来标记。例如,放射性分子包括但不限于用于闪烁扫描法研究的放射性原子,例如I123、I124、In111、Re186、Re188、Tc99。本发明多肽还可用用于核磁共振(NMR)成像(还称为磁共振成像,MRI)的自旋标记来标记,例如碘-123、铟-111、氟-19、碳-13、氮-15、氧-17、钆、锰或铁。
“生物样品”涵盖自受试者获得的多种样品类型且可用于诊断或监测试验中。生物样品包括但不限于生物来源的血液和其他液体样品、固体组织样品如源自其的活检样本或组织培养物或细胞和其子代。因此,生物样品涵盖临床样品、培养的细胞、细胞上清液、细胞裂解物、血清、血浆、生物流体和组织样品,尤其肿瘤样品。
在实施方案中,生物样品可是经福尔马林固定且经石蜡包埋(FFPE)的组织样品。实际上,本发明抗体可有利地用于由大多数医院所使用来收集并归档组织样品的格式的FFPE组织上。
本发明还涉及检测受试者中癌症存在的体内方法,该方法包括步骤:
a)向患者施用以可检测方式标记的根据本发明抗体;
b)通过成像检测患者中所述以可检测方式标记的抗体的定位。
本发明抗体可用于癌症分期(例如在放射性成像中)。其可单独使用或与其他癌症标记组合使用。
如本文所使用的术语“检测”或“检测的”包含在参照或不参照对照下的定性和/或定量检测(测量水平)。
在本发明内容中,如本文所使用,术语“诊断”意为从大量收集的数据识别影响受试者的病理的医学病况性质的确定过程。
在所述方法中,癌症是表达CEACAM5的癌症,尤其结肠直肠癌、胃癌、肺癌、子宫颈癌、胰癌、食道癌、卵巢癌、甲状腺癌、膀胱癌、子宫内膜癌、乳腺癌、肝癌(尤其胆管癌)、前列腺癌或皮肤癌。
试剂盒
最后,本发明还提供包含至少一种本发明抗体或免疫偶联物的试剂盒。含有本发明抗体的试剂盒可用于检测表面蛋白CEACAM5或治疗或诊断分析。本发明的试剂盒可含有偶联至如组织培养平板或微珠(例如琼脂糖珠)等固体支持物的多肽或抗体。可提供含有用于在体外例如在ELISA或免疫印迹分析中检测并量化表面蛋白CEACAM5的抗体的试剂盒。可用于检测的这种抗体可与如荧光或放射性标记等标记一起提供。
序列简述
SEQ ID NO:1-4和6展示称为“MAb1”的抗体的CDR1-H、CDR2-H、CDR3-H、CDR1-L和CDR3-L序列。
SEQ ID NO:5展示人源化MAb2抗体的VH变体序列VH1a。
SEQ ID NO:7-10和12展示称为“MAb2”的抗体的CDR1-H、CDR2-H、CDR3-H、CDR1-L和CDR3-L序列。
SEQ ID NO:11展示如可自GenBank NP_001703.2获得的人CEACAM1的序列。
SEQ ID NO:13-16和18展示称为“MAb3”的抗体的CDR1-H、CDR2-H、CDR3-H、CDR1-L和CDR3-L序列。
SEQ ID NO:17展示人源化MAb2抗体的VL变体序列VL1。
SEQ ID NO:19-22和24展示称为“MAb4”的抗体的CDR1-H、CDR2-H、CDR3-H、CDR1-L和CDR3-L序列。
SEQ ID NO:23展示人源化MAb2抗体的VL变体序列VL1a。
SEQ ID NO:25-28和30展示称为“Mab5”的抗体的CDR1-H、CDR2-H、CDR3-H、CDR1-L和CDR3-L序列。
SEQ ID NO:29展示人源化MAb2抗体的VL变体序列VL1c。
SEQ ID NO:31展示“MAb1”抗体的VH序列。
SEQ ID NO:32展示“MAb1”抗体的VL序列。
SEQ ID NO:33展示“MAb2”抗体的VH序列。
SEQ ID NO:34展示“MAb2”抗体的VL序列。
SEQ ID NO:35展示“MAb3”抗体的VH序列。
SEQ ID NO:36展示“MAb3”抗体的VL序列。
SEQ ID NO:37展示“MAb4”抗体的VH序列。
SEQ ID NO:38展示“MAb4”抗体的VL序列。
SEQ ID NO:39展示“MAb5”抗体的VH序列。
SEQ ID NO:40展示“MAb5”抗体的VL序列。
SEQ ID NO:41展示chMAb1抗体的重链序列。
SEQ ID NO:42展示chMAb1抗体的轻链序列。
SEQ ID NO:43展示chMAb2抗体的重链序列。
SEQ ID NO:44展示chMAb2抗体的轻链序列。
SEQ ID NO:45展示chMAb3抗体的重链序列。
SEQ ID NO:46展示chMAb3抗体的轻链序列。
SEQ ID NO:47展示chMAb4抗体的重链序列。
SEQ ID NO:48展示chMAb4抗体的轻链序列。
SEQ ID NO:49展示chMAb5抗体的重链序列。
SEQ ID NO:50展示chMAb5抗体的轻链序列。
SEQ ID NO:51展示人源化MAb2抗体的VH变体序列VH1。
SEQ ID NO:52展示如可以登录号AAA51967.1从GenBank数据库获得的全长人CEACAM5的序列。
SEQ ID NO:53展示食蟹猴CEACAM5的胞外结构域的序列。
SEQ ID NO:54展示包含K52至R52突变的嵌合抗体(源自“MAb2”抗体)轻链的序列。
SEQ ID NO:55展示人源化MAb2抗体的VL变体序列VL1d。
SEQ ID NO:56展示hCEACAM1胞外结构域的序列(全长hCEACAM1(NP_001703.2)的位置35-428,其后为含有His标签的24个氨基酸延伸)。
SEQ ID NO:57展示cCEACAM1胞外结构域的序列,随后为含有His标签的24个氨基酸延伸。
SEQ ID NO:58展示hCEACAM5胞外结构域的序列(全长hCEACAM5(AAA51967.1)的位置35-685,其后为含有His标签的24个氨基酸延伸)。
SEQ ID NO:59展示cCEACAM5胞外结构域的序列,其后为含有His标签的24个氨基酸延伸。
SEQ ID NO:60展示hCEACAM6胞外结构域的序列(全长hCEACAM6(NP_002474.3)的位置35-327,其后为含有His标签的24个氨基酸延伸)。
SEQ ID NO:61展示cCEACAM6胞外结构域的序列,其后为含有His标签的24个氨基酸延伸。
SEQ ID NO:62展示hCEACAM8胞外结构域的序列(全长hCEACAM8(NP_001807.2)的位置35-332,其后为含有His标签的24个氨基酸延伸。
SEQ ID NO:63展示cCEACAM8胞外结构域的序列,其后为含有His标签的24个氨基酸延伸。
SEQ ID NO:64展示hCEACAM7胞外结构域的序列(全长hCEACAM7(NP_008821.1)的位置36-248,其后为含有His标签的24个氨基酸延伸)。
SEQ ID NO:65展示hCEACAM5N-A1-B1的序列(全长hCEACAM5(AAA51967.1.)的位置35-320),其后为6氨基酸His标签。
SEQ ID NO:66展示hCEACAM5-A2-B2的序列(全长hCEACAM5(AAA51967.1.)的位置321-498),其后为6氨基酸His标签。
SEQ ID NO:67展示hCEACAM5 A3-B3的序列(全长hCEACAM5(AAA51967.1.)的位置499-685),其后为6氨基酸His标签。
SEQ ID NO:68展示cCEACAM5N-A1-B1的序列,其后为含有His标签的24个氨基酸延伸。
SEQ ID NO:69展示cCEACAM5 A2-B2的序列,其后为含有His标签的24个氨基酸延伸。
SEQ ID NO:70展示cCEACAM5 A3-B3的序列,其后为含有His标签的24个氨基酸延伸。
SEQ ID NO:71展示如可从GenBank NP_002474.3获得的人CEACAM6全长蛋白的序列。
SEQ ID NO:72展示如可从GenBank NP_008821.1获得的人CEACAM7全长蛋白的序列。
SEQ ID NO:73展示如可从GenBank NP_001807.2获得的人CEACAM8全长蛋白的序列。
SEQ ID NO:74展示人源化变体MAb2_VLg5VHg2的VH序列。
SEQ ID NO:75展示人源化变体MAb2_VLg5VHg2的VL序列。
SEQ ID NO:76展示人CEACAM5 A3-B3的位置109-115处的氨基酸序列。
SEQ ID NO:77展示人CEACAM5 A3-B3的位置131-143处的氨基酸序列。
SEQ ID NO:78展示基于序列比较的MAb2/MAb4/MAb5抗体家族CDR1-H的共有序列。
SEQ ID NO:79展示基于序列比较的MAb2/MAb4/MAb5抗体家族CDR2-H的共有序列。
SEQ ID NO:80展示基于序列比较的MAb2/MAb4/MAb5抗体家族CDR3-H的共有序列。
SEQ ID NO:81展示MAb1/MAb3抗体家族CDR1-H的共有序列。
SEQ ID NO:82展示MAb1/MAb3抗体家族CDR2-H的共有序列。
SEQ ID NO:83展示基于在人和食蟹猴CEACAM5胞外结构域的结合中识别为中性的残基的MAb2/MAb4/MAb5抗体家族CDR1-H的共有序列。
SEQ ID NO:84展示基于在人和食蟹猴CEACAM5胞外结构域的结合中鉴别为中性的残基的MAb2/MAb4/MAb5抗体家族CDR3-H的共有序列。
SEQ ID NO:85展示基于在人和食蟹猴CEACAM5胞外结构域的结合中鉴别为中性的残基的MAb2/MAb4/MAb5抗体家族CDR1-L的共有序列。
SEQ ID NO:86展示基于在人和食蟹猴CEACAM5胞外结构域的结合中鉴别为中性的残基的MAb2/MAb4/MAb5抗体家族CDR3-L的共有序列。
SEQ ID NO:87展示huMAb2-3(MAb2_VL1cVH1a-IgG1)的重链序列。
SEQ ID NO:88展示huMAb2-3(MAb2_VL1cVH1a-IgG1)的轻链序列。
SEQ ID NO:89展示huMAb2-4(MAb2_VL1dVH1-IgG1)的重链序列。
SEQ ID NO:90展示huMAb2-4(MAb2_VL1d VH1-IgG1)的轻链序列。
附图简述
图1:抗CEACAM5抗体选择性的评估。
图2:人CEACAM5上抗CEACAM5抗体的结构域定位。
图3:食蟹猴CEACAM5上抗CEACAM5抗体的结构域定位。
图4:在SCID雌性小鼠中chMAb4-SPDB-DM4、chMAb1-SPDB-DM4、chMAb5-SPDB-DM4和chMAb2-SPDB-DM4偶联物对原发性人结肠腺癌CR-IGR-034P的抗肿瘤活性的评估。
图5:在SCID雌性小鼠中huMAb2-3-SPDB-DM4、huMAb2-4-SPDB-DM4和chMAb2-SPDB-DM4偶联物对原发性人结肠腺癌CR-IGR-034P的抗肿瘤活性的评估。
图6:在SCID雌性小鼠中huMAb2-3-SPDB-DM4偶联物对原发性人胃腺癌STO-IND-006的抗肿瘤活性的评估。
图7:MAb1、MAb2、MAb3、MAb4和MAb5抗体的VH与VL区的序列比对。
图8:chMAb1-SPDB-DM4偶联物的HRMS分析。
图9:chMAb2-SPDB-DM4偶联物的HRMS分析。
图10:chMAb4-SPDB-DM4偶联物的HRMS分析。
图11:chMAb5-SPDB-DM4偶联物的HRMS分析。
图12:huMAb2-2-SPDB-DM4偶联物的HRMS分析。
图13:huMAb2-1-SPDB-DM4偶联物的HRMS分析。
图14:huMAb2-3-SPDB-DM4偶联物的HRMS分析。
图15:huMAb2-4-SPDB-DM4偶联物的HRMS分析。
图16:MAb2的人源化变体至人与猴CEACAM5胞外结构域的结合活性。
图17:MAb2的人源化变体至人与猴CEACAM5胞外结构域的结合的稳定性。
图18:在SCID雌性小鼠中huMAb2-3-SPDB-DM4偶联物对原发性人肺腺癌LUN-NIC-0014的抗肿瘤活性的评估。
图19:在CD1雌性裸小鼠中huMAb2-3-SPDB-DM4和huMAb2-3-磺基-SPDB-DM4偶联物对原发性人结肠腺癌CR-IGR-034P的抗肿瘤活性的评估。
图20:huMAb2-3-磺基SPDB-DM4的HRMS分析。
图21:huMAb2-3-SMCC-DM1的HRMS分析。
图22:MAb2、MAb4、MAb5、人源化VH1a、人源化VH1和人源化VHg2的重链可变结构域比对。
图23:MAb2、MAb4、MAb5、人源化VL1、人源化VL1a、人源化VL1c、人源化VL1d和人源化VLg5的轻链可变结构域比对。
实施例
本发明通过以下实施例进行进一步描述,其不应视为是对本发明的进一步限制。
序列表、图和贯穿本申请所引用的所有参照文献、专利和公开专利申请的全部内容都以其全文通过提述并入本文。
实施例1:CEACAM蛋白的重组胞外结构域的制备
在本实施例中,已通过在人胚胎肾HEK293细胞中使用可表达如表1中所概述的各cDNA的质粒瞬时表达制备了人(h)或食蟹猴(c)来源的CEACAM的细胞外蛋白结构域(ECD)。
每一表达质粒都与293fectin TM(Life Technologies)复合且添加至悬浮培养的293-F细胞(源自HEK293细胞)中。转染后第8天,收集培养物上清液且通过IMAC(GEHealthcare)纯化相应的可溶蛋白以产生蛋白批次(参见表1)。
表1:CEACAM蛋白的重组胞外结构域的描述
实施例2:小鼠抗CEACAM5单克隆抗体的产生
在本实施例中,单克隆抗体根据可产生抗CEACAM5 mAb的方案在小鼠免疫后产生。
实施例2.1:免疫和杂交瘤生成
免疫、融合和筛选使用具有人CEACAM5的胞外结构域、食蟹猴CEACAM5的胞外结构域的P3X63-Ag8.653骨髓瘤细胞或使用如Wennerberg A.E et al,1993.Am.J.Pathol.,143(4),1050-1054和Kilpatrick et al,1997.Hybridoma 16:381389中所述的人UMC11肿瘤细胞来实施。
使用如Kilpatrick et al(1997.Hybridoma 16:381389)所述的RIMMS方法,使6-8周大的雌性BALB/c小鼠(S082342;Charles River Labs,Bar Harbor,ME)以3-4天间隔在14天过程中各自接受四轮免疫。向沿小鼠背部与引流淋巴结相邻的六个位点和沿腹部的六个并排位点皮下施用在Titermax佐剂(TierMax Gold佐剂;Sigma编号T2684)中乳化的抗原。在最后一次注射后第4天时处死小鼠。无菌分离双边腘窝、腹股沟浅、腋窝及鳃淋巴结并用新鲜RPMI培养基洗涤。
使用如Wennerberg A.E et al,(1993.Am.J.Pathol.,143(4),1050-1054)所述的典型方法,使6-8周大的雌性BALB/c小鼠(S082342;Charles River Labs,Bar Harbor,ME)在41天过程中各自接受三轮免疫。向小鼠的腹面位点腹膜内施用抗原。最后一次注射后第3天处死小鼠,且无菌分离脾并用新鲜RPMI培养基洗涤。
从淋巴结或脾释放淋巴细胞且用RPMI培养基将单细胞悬浮液洗涤两次,随后使用聚乙二醇与P3X63-AG8.653骨髓瘤细胞融合。融合后,在37℃下在温育箱中将细胞混合物温育16-24小时。将所得细胞制剂转移至选择性半固体培养基中且无菌平铺于100mm Petri平板上并在37℃下温育。在选择起始10天后,检查用于杂交瘤生长的板,且挑取活菌落并置于含有200μL生长培养基的96孔板中。将96孔板于温育箱中于37℃保持2天至4天。
实施例2.2:鼠类抗CEACAM5抗体的筛选和体外表征
用于抗CEACAM5 IgG产生的初步筛选通过使用人CEACAM5蛋白(如实施例1中所述制备)作为捕获抗原的酶联免疫吸附分析(ELISA)和通过使用数种人肿瘤细胞(H460、MKN45、SW1463、SKMEL28和UMC11)的FACS来实施。对于ELISA分析,使用在PBS中的0.25μg/孔的人CEACAM5蛋白包被板并将100μL/孔的抗CEACAM5抗体添加至板中。将板在37℃温育1h并用含有0.05%Tween-20的PBS(PBS-T)洗涤5次。随后,将100μL偶联有辣根过氧化物酶的兔抗小鼠IgG(Sigma;编号A9044)的1:50,000稀释物添加至每一孔中。在37℃下在黑暗中温育1h后,用PBS-T将板洗涤5次。抗体结合通过添加TMB-H2O2缓冲液可视化并在450nm波长读取。对于FACS分析,以40,000个细胞/孔在96孔高结合板(MSD L15XB-3)上包被人肿瘤细胞,且在4℃添加100μL/孔的抗CEACAM5抗体持续45min,并用PBS 1%BSA洗涤3次。在4℃下添加100μL/孔的与Alexa647偶联的山羊抗小鼠IgG(Invitrogen;编号A2135)持续45min,且用PBS 1%BSA洗涤3次。通过离心并添加200μl/孔PBS 1%BSA重悬细胞后评估抗体结合并使用easyCyte TM 8HT流式细胞术系统读取。
为评估抗CEACAM5抗体对CEACAM5的特异性,使用与之前所述相同的包被条件用重组人CEACAM1、CEACAM6、CEACAM7和CEACAM8蛋白(如实施例1中所述来制备)包被96孔板。将抗CEACAM5抗体添加至板中并通过使用与辣根过氧化物酶偶联的兔抗小鼠IgG(Sigma;编号A9044)来检测。抗体结合通过添加TMB-H2O2缓冲液可视化且在450nm波长读取。图1中所呈现的结果表明,抗CEACAM5抗体对人CEACAM5的选择性优于对人CEACAM1、CEACAM6、CEACAM7和CEACAM8的选择性。
实施例2.3:mAb结合表征
抗CEACAM5抗体对在人MKN45(DSMZ,ACC 409)肿瘤细胞表面上表达的hCEACAM5的表观亲和性通过easyCyte TM 8HT流式细胞术系统测定。以40,000个细胞/孔在96孔高结合板(MSD L15XB-3)上包被MKN45肿瘤细胞,并在4℃下添加100μL/孔的抗CEACAM5抗体于分析稀释剂中的2倍系列稀释(自20μg/ml开始,直至12次稀释)持续45min,并用PBS1%BSA洗涤3次。在4℃下添加100μL/孔的与Alexa647偶联的山羊抗小鼠IgG(Invitrogen;编号A2135)持续45min,且用PBS 1%BSA洗涤3次。抗体结合通过离心并添加200μl/孔PBS1%BSA重悬细胞后评估并使用easyCyte TM 8HT流式细胞术系统读取。分别使用BIOST@T-BINDING和BIOST@T-SPEED软件来估计表观KD和EC50值。
表2:在MKN45细胞上获得的EC50
抗体 | MAb1 | MAb2 | MAb3 | MAb4 | MAb5 |
EC50值 | 16nM | 3.4nM | 6.2nM | 4.9nM | 0.73nM |
抗CEACAM5抗体对人CEACAM5和食蟹猴CEACAM5蛋白的结构域定位通过ELISA测定。使用与之前所述相同的包被条件用CEACAM5蛋白的重组人A1(143-237)、A1-B1(143-320)、A2-B2(321-498)和A3-B3(499-685)结构域(如实施例1中所述制备)和CEACAM5蛋白的重组食蟹猴N-A1-B1(1-320)、A1-B1(143-320)、A2-B2(321-498)和A3-B3(499-688)结构域(如实施例1中所述来制备)来包被96孔板。将经纯化抗体添加至板中且通过使用与辣根过氧化物酶偶联的兔抗小鼠IgG(Sigma;编号A9044)来检测。抗体结合通过添加TMB-H2O2缓冲液可视化并在450nm波长下读取。结果呈现于图2和图3中且表明,抗CEACAM5抗体结合至人和食蟹猴CEACAM5蛋白的A3-B3结构域。
个别mAb的同型根据制造商的说明书使用小鼠IgG同型分型试剂盒(SEROTEC参照MMT1)测定。五种CEACAM5特异性mAb为k同型IgG1。
实施例3:鼠类抗CEACAM5抗体的表征
实施例3.1:鼠类抗CEACAM5抗体的体外表征
在T500烧瓶中产生表达CEACAM5特异性Ab的小鼠杂交瘤并在生长7天后收集条件培养基。通过使条件化培养基通过蛋白质-G柱纯化了CEACAM5特异性Ab,洗涤并用甘氨酸/HCl 100mM pH 2.7缓冲液洗脱。针对PBS透析洗脱物,随后无菌过滤且储存在4℃。
通过ELISA评估所有CEACAM5特异性mAb结合人和灵长类动物CEACAM5蛋白的能力。用人或灵长类动物CEACAM5蛋白包被板,将抗hCEACAM5mAb添加至板中并用与辣根过氧化物酶偶联的兔抗小鼠IgG(Sigma;编号A9044)检测。抗体结合通过添加TMB-H2O2缓冲液可视化并在450nm波长读取。
表3:对应CEACAM5特异性mAb对灵长类动物CEACAM5蛋白的结合能力的EC50值
实施例3.2:通过流式细胞术检测的抗CEACAM5抗体与晚期人原发性结肠肿瘤细胞CR-IGR-034P的表观亲和性和抗体结合能力
小鼠中的晚期人原发性结肠肿瘤CR-IGR-034P(Julien et al,Clin Cancer Res2012年10月1日,18:5314-5328)从源自患者的异种移植物获得。在4℃下使用IV型胶原酶(Invitrogen;编号17104-019)和脱氧核糖核酸酶I(Invitrogen;编号18047-019)将肿瘤CR-IGR-034P酶解离1h。使用easyCyte TM 8HT流式细胞术系统通过应用Viacount来估计细胞活力。为估计表观亲和性,以40,000个细胞/孔在96孔高结合板(MSD L15XB-3)上包被CR-IGR-034P肿瘤细胞,并在4℃添加100μL/孔的抗CEACAM5抗体于分析稀释剂中的2倍系列稀释(自20μg/ml开始,直至12次稀释)持续45min,并用PBS 1%BSA洗涤3次。在4℃添加100μL/孔的与Alexa647偶联的山羊抗小鼠IgG(Invitrogen;编号A2135)或与Alexa488偶联的山羊抗人IgG(Invitrogen;编号A11013)持续45min,并用PBS 1%BSA洗涤3次。通过离心并添加200μl/孔PBS 1%BSA重悬细胞后评估抗体结合且使用easyCyte TM 8HT流式细胞术系统读取。分别使用BIOST@T-BINDING和BIOST@T-SPEED软件来估计表观KD和EC50值。
根据制造商的说明书使用小鼠IgG校准物试剂盒(Biocytex编号7208)或人IgG校准物试剂盒(Biocytex编号CP010)来测定抗CEACAM5抗体的抗体结合能力。
表4:在晚期人原发性结肠肿瘤细胞CR-IGR-034P上获得的KD和EC50值
抗体 | MAb1 | MAb2 | MAb3 | MAb4 | MAb5 |
KD值 | 1.92nM | 0.38nM | 1.01nM | 0.16nM | 0.5nM |
EC50值 | 1nM | 0.53nM | 2.8nM | 0.2nM | 1.4nM |
实施例3.3:鼠类CEACAM5特异性抗体的内化活性
为评估抗CEACAM5抗体MAb1、MAb2、MAb3、MAb4和MAb5的内化,将MKN45活细胞与10μg/ml经AlexaFluor488预先标记的抗CEACAM5抗体于37℃/5%CO2(或4℃冰上,用于阴性对照)下温育24h。随后,用培养基冲洗一部分孔并通过将细胞与抗AlexaFluor 488抗体(50μg/mL)在冰上一起温育30min来淬灭结合至细胞的细胞外经AF标记的抗体(细胞内荧光水平)。将另一部分孔在相同时间条件下仅与培养基一起温育(总荧光水平)。
随后脱附细胞并洗涤,并在培养基中收集,随后使用MACSQUANT Vyb分析仪进行流式细胞术分析。测量1×104个细胞的细胞相关荧光,并量化门控活细胞的平均荧光强度。通过用淬灭的细胞相关荧光除以总细胞相关荧光乘以100来确定内化比率(%)。数据表示为平均值±标准偏差(SD)。
表5:MKN45细胞系中24小时抗CEACAM5鼠类抗体的内化
五种CEACAM5特异性抗体在结合于细胞表面膜上表达的CEACAM5后经受内化,支持其在抗体免疫偶联物领域中特异性地向癌细胞呈送细胞毒性的用途。抗CEACAM5抗体MAb1、MAb2、MAb3、MAb4和MAb5在温育24小时后分别显示在MKN45人癌细胞系中49.9%、45%、51.1%、42.5%、51.7%的内化。
实施例3.4:相应鼠类ADC对MKN45细胞系的细胞毒性活性
偶联鼠类抗体以定义其体外细胞毒性活性。在15ml管中,在室温(23℃),在磁力搅拌下相继引入mAb、缓冲液A/HEPES(4%)、DMA(二甲基乙酰胺,20%v/v),随后引入6当量SPDB接头。在室温保持一夜后,添加在15mM DMA溶液中的DM4(类美登素,9.6当量),并反应5小时。在Superdex 200pg 16/60或G25 26/10柱(PBS-Na pH7.4/5%NMP)上纯化粗偶联混合物,以5000g在Amicon 15上浓缩,并在0.22μm Millex上过滤。
随后使用Cell Titer-Glo试剂盒(Promega)测试抗CEACAM5类美登素偶联物对肿瘤细胞活力的效果。为此,将MKN45人胃癌细胞平铺于96孔板中且使其在37℃/5%CO2气氛中在4小时期间附着。将不同浓度的抗CEACAM5偶联物添加至接种细胞中。随后将细胞于相同气氛中温育96小时。随后在室温将Cell Titer-Glo试剂添加至孔中持续10min,并使用EnVision板计数器(Perkin-Elmer)测量发光信号。
表6:CEACAM5特异性鼠类ADC对CEACAM5+MKN45细胞系的细胞毒性活性
偶联至类美登素(DM4)的抗CEACAM5抗体MAb1-SPDB-DM4、MAb2-SPDB-DM4、MAb3-SPDB-DM4、MAb4-SPDB-DM4和MAb5-SPDB-DM4表明了体外细胞毒性活性,且IC50分别为0.89nM、0.14nM、0.53nM、0.96nM和0.24nM。
实施例4:抗CEACAM5mAb的重链和轻链的序列测定
从杂交瘤检索(retrieve)mAb的可变结构域序列并克隆入表达载体中以确保克隆的mAb具有与初始鼠类mAb相同的特征。
衍生的氨基酸序列提供与通过重链和轻链(LC、HC)的N端测序和质谱(LC/MS)基于源自杂交瘤的经纯化mAb获得的数据一致的信息(参见表7)。
表7:来自杂交瘤的抗CEACAM5 mAb的质谱分析
*:MAb2i是由一种克隆的杂交瘤产生的抗体且由其引进规范残基至VL和VH的框架区衍生出所谓的“MAb2”的抗体,如实施例5中所解释。
实施例5:抗体药物偶联物(ADC)(嵌合体)
实施例5.1:裸嵌合体mAb
将可变结构域VH、VL的核酸序列分别与人IgG1或人Cκ恒定结构域编码序列融合克隆至表达载体中以随后以如实施例1所述通过在HEK293中瞬时表达来产生嵌合体mAb批次。人和食蟹猴CEACAM5对鼠类和嵌合体mAb的亲和性保持相似。在表8中,亲和性由使用人或食蟹猴CEACAM5的ELISA获得的EC50来阐述。
表8:对于鼠类杂交瘤和相应的嵌合体mAb的由CEACAM5获得的EC50
用IMGT命名法从蛋白质序列推导CDR区的序列。其与SEQ ID NO:1-4、6、7-10、12、13-16、18、19-22、24、25-28、30对应。
应该注意的是,与所克隆杂交瘤产生的抗体(MAb2i)相比,已将规范残基引入克隆MAb2 VL上的位置41G、42K和45Q处和VH上的位置5Q和7S处。
此外,克隆MAb2 CEA-4的VL上位置52处的赖氨酸位于CDR2中,其在克隆Mab2K52R中已由精氨酸替换。在与对应于克隆MAb2的条件相同的条件下产生一批次,且其产生与表7中所显示相似的对人和食蟹猴CEACAM5胞外结构域的亲和性。应强调的是可在CDR中生成此点突变而不对结合造成任何影响。
克隆MAb2和克隆Mab2K52R的嵌合体mAb的LC和HC序列对应于SEQ ID NO:43、44、54。
如实施例4所述构建chMAb2。其是源自具有人Ck同型IgG1的克隆MAb2的嵌合体mAb。所述序列对应于SEQ ID NO:43和44。通过在HEK293中瞬时表达随后进行蛋白质A亲和层析纯化来制备300mg规模的批次,结合数据参见表7。使用裸mAb来产生ADC。
实施例5.2:ADC的产生和表征
在此实施例中,从裸嵌合体mAb制备免疫偶联物。随后评价体内效力。
DAR计算:
偶联物通常包含1分子至10分子共价连接至抗体的类美登素(称为“药物对抗体比率”或“DAR”)。此数值可随所使用抗体和类美登素的性质和用于偶联的实验条件(如类美登素/抗体比率、反应时间、溶剂和共溶剂(如果存在)的性质)而变化。因此,抗体与类美登素间的接触形成包含数种药物对抗体比率彼此不同的偶联物、任选的裸抗体、任选的聚集物的混合物。因此,所测定的DAR为平均值。
本文用于测定DAR的方法在于以分光光度计测量基本上纯化的偶联物溶液在252nm和280nm的吸收比率。特别地,该DAR可以分光光度计使用抗体和类美登素分别在280nm和252nm测量的消光系数(εD280=5,180M-1cm-1andεD252=26,159M-1cm-1)测定。计算方法源自Antony S.Dimitrov(编辑),LLC,2009,Therapeutic Antibodies and Protocols,第525,445卷,Springer Science,且更详细描述于下文中:
偶联物在252nm的吸收(A252)和在280nm的吸收(A280)是在尺寸排阻层析(SEC)分析的单体峰(允许计算“DAR(SEC)”参数)上或使用典型分光光度计装置(允许计算“DAR(UV)”参数)测量。吸收可如下表示:
A252=(cD x εD252)+(cA x εA252)
A280=(cD x εD280)+(cA x εA280)
其中:
·cD和cA分别为溶液中类美登素和抗体的浓度
·εD252和εD280分别为类美登素在252nm和280nm的摩尔消光系数
·εA252和εA280分别为抗体在252nm和280nm的摩尔消光系数。
对这两个具有两个未知数的方程式的解析产生以下等式:
cD=[(εA280 x A252)-(εA252 x A280)]/[(εD252 x εA280)-(εA252 x εD280)]
cA=[A280–(cD x εD280)]/εA280
随后自药物浓度对抗体浓度的比率计算平均DAR:DAR=cD/cA。
偶联物的去糖基化和高分辨率质谱(HRMS)
去糖基化是一种通过糖苷酶进行的酶消化技术。去糖基化是从500μl偶联物+100μl 50mM Tris HCl缓冲液+10μl聚糖酶-F酶(100单位冻干酶/100μl水)制造。涡旋振荡培养基并在37℃下维持一夜。随后准备在HRMS中分析去糖基化样品。基于Waters Q-Tof-2系统以电喷射阳模式(ES+)获得质谱。层析条件如下:柱:4μm BioSuite 250 URH SEC 4.6×300mm(Waters);溶剂:A:25mM甲酸铵+1%甲酸;B:CH3CN;柱温度:30℃;流速0.4ml/min;等梯度洗脱70%A+30%B(15min)。
分析型尺寸排阻层析(SEC)
-柱:TSKgel G3000 SWXL 5μm柱,7.8mm×30cm,TOSOH BIOSCIENCE,LLC Part#08541+保护柱TSK-GEL SWXL 7μM,40mm×6mm,TOSOH BIOSCIENCE,LLC Part#08543
-流动相:KCl(0.2M)、KH2PO4(0.052M)、K2HPO4(0.107M)、iPrOH(20体积%)
-分析条件:等梯度洗脱,0.5ml/min,30min
-在Lachrom Elite HPLC系统(Merck)使用L2455 DAD分光光度计检测器实施分析。
缓冲液内容物
-缓冲液A(pH 6.5):NaCl(50mM)、磷酸钾缓冲液(50mM)、EDTA(2mM)
-缓冲液HGS(pH 5.5):组氨酸(10mM)、甘氨酸(130mM)、5%蔗糖(w/v)、HCl(8mM)
使用的缩写
CV:柱体积;DAR:药物抗体比率;DMA:二甲基乙酰胺;HEPES:4-(2-羟基乙基)-1-哌嗪-乙磺酸;HRMS:高分辨率质谱;NHS:N-羟基琥珀酰亚胺;硝基-SPDB:丁酸4-[(5-硝基-2-吡啶基)二硫基]-,2,5-二氧代-1-吡咯烷基酯(可如WO2004016801专利中所述制备);NMP:N-甲基吡咯烷酮;RT:室温;SEC:尺寸排阻层析
ADC(嵌合体):
chMAb1-SPDB-DM4
分析数据:
MW(Ab)=148438g/mol;MW(DM4)=780.38g/mol
ε280nm(Ab)=213320;ε252nm(Ab)=73473
ε280nm(DM4)=5180etε252nm(DM4)=26159
在搅拌下于室温,在容器中引进3.59ml chMAb1(C=5.72mg/ml,在PBS缓冲液(pH=7.4)中),随后引进0.312ml DMA和0.046ml硝基-SPDB接头溶液(5.0当量-在DMA中的15mM溶液)。将溶液涡旋振荡30sec且随后在室温缓慢搅拌3小时。在磁力搅拌下,相继添加3.8mlPBS缓冲液(pH7.5)、0.389ml DMA和0.074ml DM4溶液(在DMA中的15mM溶液)。在室温保持2.5小时后,在经1CV 1M NaOH、2CV水和含有5体积%NMP的2CV PBS缓冲液(pH7.4)预处理的HiLoad 26/60脱盐柱(Superdex 200pg;GE Healthcare)上纯化粗反应混合物。用含有5%NMP的PBS缓冲液(pH7.4)洗脱偶联物,且汇集单体偶联物组分,在Amicon Ultra-15(Ultracel 10k,Millipore)上浓缩,并在0.22μm过滤器上过滤。
由此获得了7.6ml呈无色透明溶液形式的chMAb1-SPDB-DM4偶联物(c=2.19mg/ml)。随后分析偶联物的最终药物载量和单体纯度:DAR(UV)=3.38;DAR(SEC)=3.34;RT=17.54min;单体纯度=99.8%。
HRMS分析的结果显示于图8中。
chMAb2-SPDB-DM4
分析数据:
MW(Ab)=147900g/mol;MW(DM4)=780.38g/mol
ε280nm(Ab)=201400;ε252nm(Ab)=70889
ε280nm(DM4)=5180etε252nm(DM4)=26159
在搅拌下于室温,在容器中引进3.8ml chMAb2(C=5.08mg/ml,在PBS缓冲液(pH=7.4)中),随后引进0.337ml DMA和0.0433ml硝基-SPDB接头溶液(5.0等价-在DMA中的15mM溶液)。将溶液涡旋振荡30sec且随后在室温缓慢搅拌3小时。在磁力搅拌下,相继添加3.12ml PBS缓冲液(pH7.5)、0.319ml DMA和0.069ml DM4溶液(在DMA中的15mM溶液)。在室温保持2小时后,在0.45μm过滤器上过滤粗反应混合物,并在经1CV 1M NaOH、2CV水和含有5体积%NMP的2CV PBS缓冲液(pH7.4)预处理的HiLoad 26/60脱盐柱(Superdex 200pg;GEHealthcare)上纯化。用含有5%NMP的PBS缓冲液(pH7.4)洗脱偶联物,且汇集单体偶联物组分,在Amicon Ultra-15(Ultracel 10k,Millipore)上浓缩,并在0.22μm过滤器上过滤。
由此获得了7.5ml呈无色透明溶液的chMAb2-SPDB-DM4偶联物(c=1.8mg/ml)。随后分析偶联物的最终药物载量和单体纯度:DAR(UV)=4.10;DAR(SEC)=4.05;RT=17.52min;单体纯度=99.9%。
HRMS分析的结果显示于图9中。
chMAb4-SPDB-DM4
分析数据:
MW(Ab)=148124g/mol;MW(DM4)=780.38g/mol
ε280nm 280nm(Ab)=204380;ε280nm 252nm(Ab)=73142
ε280nm 280nm(DM4)=5180etε280nm 252nm(DM4)=26159
在搅拌下于室温,在容器中引进3.63ml chMAb4(C=5.69mg/ml,在PBS缓冲液(pH=7.4)中),随后引进0.316ml DMA和0.0465ml硝基-SPDB接头溶液(5.0当量-在DMA中的15mM溶液)。将溶液涡旋振荡30sec且随后在室温缓慢搅拌3小时。在磁力搅拌下,相继添加3.8ml PBS缓冲液(pH7.5)、0.389ml DMA和0.074ml DM4溶液(在DMA中的15mM溶液)。在室温保持2小时后,在经1CV 1M NaOH、2CV水和含有5体积%NMP的2CV PBS缓冲液(pH7.4)预处理的HiLoad 26/60脱盐柱(Superdex 200pg;GE Healthcare)上纯化粗反应混合物。用含有5%NMP的PBS缓冲液(pH7.4)洗脱偶联物,并汇集单体偶联物组分,在Amicon Ultra-15(Ultracel 10k,Millipore)上浓缩,并在0.22μm过滤器上过滤。
由此获得了6.5ml呈无色透明溶液的chMAb4-SPDB-DM4偶联物(c=2.20mg/ml)。随后分析偶联物的最终药物载量和单体纯度:DAR(UV)=3.87;DAR(SEC)=3.85;RT=17.52min;单体纯度=99.8%。
HRMS分析的结果显示于图10中。
chMAb5-SPDB-DM4
分析数据:
MW(Ab)=148040g/mol;MW(DM4)=780.38g/mol
ε280nm 280nm(Ab)=207360;ε280nm 252nm(Ab)=72288
ε280nm 280nm(DM4)=5180etε280nm 252nm(DM4)=26159
在搅拌下于室温,在容器中引进3.15ml chMAb5(C=6.38mg/ml,在PBS缓冲液(pH=7.4)中),随后引进0.269ml DMA和0.0453ml硝基-SPDB接头溶液(5.0当量-在DMA中的15mM溶液)。将溶液涡旋振荡30sec且随后在室温缓慢搅拌3小时。在磁力搅拌下,相继添加4.1ml PBS缓冲液(pH7.5)、0.317ml DMA和0.072ml DM4溶液(在DMA中的15mM溶液)。在室温保持2小时后,在0.45μm过滤器上过滤粗反应混合物,且在经1CV 1M NaOH、2CV水和含有5体积%NMP的2CV PBS缓冲液(pH7.4)预处理的HiLoad 26/60脱盐柱(Superdex 200pg;GEHealthcare)上纯化。用含有5%NMP的PBS缓冲液(pH7.4)洗脱偶联物,且汇集单体偶联物组分,在Amicon Ultra-15(Ultracel 10k,Millipore)上浓缩,并在0.22μm过滤器上过滤。
由此获得了7.5ml呈无色透明溶液的抗CEACAM5_hyb_1917CEA4_VH5Q7S_VL41G42K45Q_IgG1-SPDB-DM4偶联物(c=3.4mg/ml)。随后分析偶联物的最终药物载量和单体纯度:DAR(UV)=3.4;DAR(SEC)=3.4;RT=17.49min;单体纯度=99.8%。
HRMS分析的结果显示于图11中。
实施例5.3:体内效力
针对皮下植入雌性SCID小鼠的可测量原发性结肠CR-IGR-034P肿瘤评估2种剂量的四种嵌合偶联物(chMAb4-SPDB-DM4、chMAb1-SPDB-DM4、chMAb5-SPDB-DM4和chMAb2-SPDB-DM4)。对照组未经处理。偶联物的剂量是以mg/kg给出。其在肿瘤植入后第14天时通过静脉内(IV)团注以5mg/kg和2.5mg/kg施用。
为评估偶联物的抗肿瘤活性,每天对动物称重且每周藉助卡尺对肿瘤测量2次。将在最低点产生20%重量损失(组的平均值)或10%或更大药物死亡的剂量视为毒性过高剂量。动物体重包含肿瘤重量。肿瘤体积使用下式计算:质量(mm3)=[长度(mm)×宽度(mm)2]/2。初始效力终点为ΔT/ΔC、中值消退百分数、部分和完全消退(PR和CR)。
通过自指定观察日的肿瘤体积减去第一治疗日(分期日)的肿瘤体积来计算每一治疗组(T)和对照组(C)中每一肿瘤的肿瘤体积变化。计算治疗组的中值ΔT并计算对照组的中值ΔC。随后计算ΔT/ΔC比率且表示为百分比:ΔT/ΔC=(ΔT/ΔC)×100。
当ΔT/ΔC低于40%时,将剂量视为具有治疗活性,且当ΔT/ΔC低于10%时,将剂量视为非常有活性。如果ΔT/ΔC低于0,则将剂量视为具有高活性且记录消退百分比(Plowman J、Dykes DJ、Hollingshead M、Simpson-Herren L和Alley MC.Human tumorxenograft models in NCI drug development.In:Feibig HH BA编辑Basel:Karger.;1999第101-125页):
肿瘤消退%定义为治疗组在指定观察日的肿瘤体积与其在第一治疗的第一日的体积相比减小的%。
在特定时间点计算每一动物的消退%。随后计算该组的中值消退%:
部分消退(PR):如果肿瘤体积减小至开始治疗时肿瘤体积的50%,则消退定义为部分消退。
完全消退(CR):当肿瘤体积=0mm3时达成完全消退(当无法记录肿瘤体积时视为CR)。
结果:
结果呈现于图4和表9(下文)中。使用2.5mg/kg和5mg/kg的单次施用方案,此研究中所测试的所有偶联物都未引起毒性。
chMAb1-SPDB-DM4在5mg/kg和2.5mg/kg非常具有活性且ΔT/ΔC分别为0%和7%(相对于对照p<0.0001且p=0.0170)。chMAb4-SPDB-DM4和chMAb5-SPDB-DM4在5mg/kg下具有高活性且ΔT/ΔC分别为-5%和-7%(相对于对照p<0.0001),且肿瘤消退分别为25%和65%。其在2.5mg/kg非常具有活性且ΔT/ΔC分别为7%和2%(相对于对照p=0.0152和p=0.0020)。chMAb2-SPDB-DM4在5mg/kg和2.5mg/kg下具有高活性且ΔT/ΔC分别为-10%和-8%(相对于对照p<0.0001),肿瘤消退分别为82%和39%,且CR/6分别为3和1。
从这些结果可看出,所有嵌合偶联物chMAb4-SPDB-DM4、chMAb1-SPDB-DM4、chMAb5-SPDB-DM4和chMAb2-SPDB-DM4都可用于研发治疗性ADC。
序列表
<110> 赛诺菲
<120> 抗CEACAM5抗体及其用途
<130> FR2012/065
<150> EP12306444
<151> 2012-11-20
<160> 90
<170> PatentIn版本3.5
<210> 1
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 1
Gly Phe Thr Phe Ser Ser Tyr Ala
1 5
<210> 2
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 2
Ile Ser Ser Gly Gly Ser Tyr Ile
1 5
<210> 3
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 3
Ala Arg Pro Ala Tyr Tyr Gly Asn Pro Ala Met Asp Tyr
1 5 10
<210> 4
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 4
Gln Asn Val Gly Thr Asn
1 5
<210> 5
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人源化 MAb2抗体的VH1a
<400> 5
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Thr Pro Glu Arg Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Gly Gly Ile Thr Tyr Ala Pro Ser Thr Val
50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 6
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 6
Gln Gln Tyr Asn Ser Tyr Pro Leu Tyr Thr
1 5 10
<210> 7
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 7
Gly Phe Val Phe Ser Ser Tyr Asp
1 5
<210> 8
<211> 8
<212> PRT
<213> 人工
<220>
<223> CDR
<400> 8
Ile Ser Ser Gly Gly Gly Ile Thr
1 5
<210> 9
<211> 13
<212> PRT
<213> 人工
<220>
<223> CDR
<400> 9
Ala Ala His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr
1 5 10
<210> 10
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 10
Glu Asn Ile Phe Ser Tyr
1 5
<210> 11
<211> 526
<212> PRT
<213> Homo sapiens
<400> 11
Met Gly His Leu Ser Ala Pro Leu His Arg Val Arg Val Pro Trp Gln
1 5 10 15
Gly Leu Leu Leu Thr Ala Ser Leu Leu Thr Phe Trp Asn Pro Pro Thr
20 25 30
Thr Ala Gln Leu Thr Thr Glu Ser Met Pro Phe Asn Val Ala Glu Gly
35 40 45
Lys Glu Val Leu Leu Leu Val His Asn Leu Pro Gln Gln Leu Phe Gly
50 55 60
Tyr Ser Trp Tyr Lys Gly Glu Arg Val Asp Gly Asn Arg Gln Ile Val
65 70 75 80
Gly Tyr Ala Ile Gly Thr Gln Gln Ala Thr Pro Gly Pro Ala Asn Ser
85 90 95
Gly Arg Glu Thr Ile Tyr Pro Asn Ala Ser Leu Leu Ile Gln Asn Val
100 105 110
Thr Gln Asn Asp Thr Gly Phe Tyr Thr Leu Gln Val Ile Lys Ser Asp
115 120 125
Leu Val Asn Glu Glu Ala Thr Gly Gln Phe His Val Tyr Pro Glu Leu
130 135 140
Pro Lys Pro Ser Ile Ser Ser Asn Asn Ser Asn Pro Val Glu Asp Lys
145 150 155 160
Asp Ala Val Ala Phe Thr Cys Glu Pro Glu Thr Gln Asp Thr Thr Tyr
165 170 175
Leu Trp Trp Ile Asn Asn Gln Ser Leu Pro Val Ser Pro Arg Leu Gln
180 185 190
Leu Ser Asn Gly Asn Arg Thr Leu Thr Leu Leu Ser Val Thr Arg Asn
195 200 205
Asp Thr Gly Pro Tyr Glu Cys Glu Ile Gln Asn Pro Val Ser Ala Asn
210 215 220
Arg Ser Asp Pro Val Thr Leu Asn Val Thr Tyr Gly Pro Asp Thr Pro
225 230 235 240
Thr Ile Ser Pro Ser Asp Thr Tyr Tyr Arg Pro Gly Ala Asn Leu Ser
245 250 255
Leu Ser Cys Tyr Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser Trp Leu
260 265 270
Ile Asn Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn
275 280 285
Ile Thr Val Asn Asn Ser Gly Ser Tyr Thr Cys His Ala Asn Asn Ser
290 295 300
Val Thr Gly Cys Asn Arg Thr Thr Val Lys Thr Ile Ile Val Thr Glu
305 310 315 320
Leu Ser Pro Val Val Ala Lys Pro Gln Ile Lys Ala Ser Lys Thr Thr
325 330 335
Val Thr Gly Asp Lys Asp Ser Val Asn Leu Thr Cys Ser Thr Asn Asp
340 345 350
Thr Gly Ile Ser Ile Arg Trp Phe Phe Lys Asn Gln Ser Leu Pro Ser
355 360 365
Ser Glu Arg Met Lys Leu Ser Gln Gly Asn Thr Thr Leu Ser Ile Asn
370 375 380
Pro Val Lys Arg Glu Asp Ala Gly Thr Tyr Trp Cys Glu Val Phe Asn
385 390 395 400
Pro Ile Ser Lys Asn Gln Ser Asp Pro Ile Met Leu Asn Val Asn Tyr
405 410 415
Asn Ala Leu Pro Gln Glu Asn Gly Leu Ser Pro Gly Ala Ile Ala Gly
420 425 430
Ile Val Ile Gly Val Val Ala Leu Val Ala Leu Ile Ala Val Ala Leu
435 440 445
Ala Cys Phe Leu His Phe Gly Lys Thr Gly Arg Ala Ser Asp Gln Arg
450 455 460
Asp Leu Thr Glu His Lys Pro Ser Val Ser Asn His Thr Gln Asp His
465 470 475 480
Ser Asn Asp Pro Pro Asn Lys Met Asn Glu Val Thr Tyr Ser Thr Leu
485 490 495
Asn Phe Glu Ala Gln Gln Pro Thr Gln Pro Thr Ser Ala Ser Pro Ser
500 505 510
Leu Thr Ala Thr Glu Ile Ile Tyr Ser Glu Val Lys Lys Gln
515 520 525
<210> 12
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 12
Gln His His Tyr Gly Thr Pro Phe Thr
1 5
<210> 13
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 13
Gly Phe Thr Phe Ser Arg Tyr Ala
1 5
<210> 14
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 14
Ile Ser Ser Gly Gly Asp Thr
1 5
<210> 15
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 15
Ala Arg Val Asn Tyr Tyr Asp Ser Ser Phe Leu Asp Trp
1 5 10
<210> 16
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 16
Gln Asn Val Gly Thr Asn
1 5
<210> 17
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人源化MAb2抗体的VL1
<400> 17
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Phe Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Val
35 40 45
Tyr Asn Thr Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 18
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 18
Gln Gln Tyr Asn Asn Tyr Pro Leu Tyr Thr
1 5 10
<210> 19
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 19
Gly Phe Thr Phe Ser Ser Tyr Asp
1 5
<210> 20
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段
<400> 20
Ile Ser Ser Tyr Gly Gly Arg Thr
1 5
<210> 21
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 21
Ala Ala His Tyr Phe Gly Thr Ser Gly Pro Phe Ala Tyr
1 5 10
<210> 22
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 22
Glu Asn Ile Tyr Ser Tyr
1 5
<210> 23
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人源化MAb2抗体的VL1a
<400> 23
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Phe Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Val
35 40 45
Tyr Asn Thr Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 24
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 24
Gln His His Tyr Gly Ile Pro Phe Thr
1 5
<210> 25
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 25
Gly Phe Ala Phe Ser Ser Tyr Asp
1 5
<210> 26
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 26
Ile Asn Ser Gly Gly Gly Ile Thr
1 5
<210> 27
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 27
Thr Ala His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr
1 5 10
<210> 28
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CDR
<400> 28
Glu Asn Ile Tyr Ser Tyr
1 5
<210> 29
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人源化MAb2抗体的VL1c
<400> 29
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Phe Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Val
35 40 45
Tyr Asn Thr Arg Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 30
<211> 9
<212> PRT
<213> 人工
<220>
<223> CDR
<400> 30
Gln His His Tyr Gly Thr Pro Phe Thr
1 5
<210> 31
<211> 120
<212> PRT
<213> 人工
<220>
<223> 抗体片段
<400> 31
Glu Val Met Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Gly Ser Tyr Ile Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Pro Ala Tyr Tyr Gly Asn Pro Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 32
<211> 108
<212> PRT
<213> 人工
<220>
<223> 抗体片段
<400> 32
Asp Ile Leu Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Pro Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 33
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段
<400> 33
Glu Val Gln Leu Gln Glu Ser Gly Gly Val Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Gly Gly Ile Thr Tyr Phe Pro Asp Thr Val
50 55 60
Gln Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 34
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段
<400> 34
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Phe Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
35 40 45
Tyr Asn Thr Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 35
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段
<400> 35
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Pro Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Asp Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Arg Asn Ile Leu Phe Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Gly Met Tyr Tyr Cys Ala
85 90 95
Arg Val Asn Tyr Tyr Asp Ser Ser Phe Leu Asp Trp Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 36
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段
<400> 36
Asp Ile Val Met Thr Gln Ser Gln Arg Phe Met Ser Thr Leu Glu Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Asn Tyr Pro Leu
85 90 95
Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 37
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段
<400> 37
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Phe Ile Ser Ser Tyr Gly Gly Arg Thr Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Phe Tyr Cys
85 90 95
Ala Ala His Tyr Phe Gly Thr Ser Gly Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 38
<211> 107
<212> PRT
<213> 人工
<220>
<223> 抗体片段
<400> 38
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr
20 25 30
Phe Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
35 40 45
Tyr Asn Ala Lys Ile Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Gly Thr Tyr Tyr Cys Gln His His Tyr Gly Ile Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 39
<211> 120
<212> PRT
<213> 人工
<220>
<223> 抗体片段
<400> 39
Glu Leu Gln Leu Val Glu Ser Gly Gly Val Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Thr Tyr Ile Asn Ser Gly Gly Gly Ile Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Thr Ala His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 40
<211> 107
<212> PRT
<213> 人工
<220>
<223> 抗体片段
<400> 40
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
35 40 45
Tyr Asn Ala Lys Thr Leu Thr Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 41
<211> 449
<212> PRT
<213> 人工
<220>
<223> 抗体片段
<400> 41
Glu Val Met Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Ser Gly Gly Ser Tyr Ile Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Pro Ala Tyr Tyr Gly Asn Pro Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 42
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段
<400> 42
Asp Ile Leu Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Pro Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 43
<211> 449
<212> PRT
<213> 人工
<220>
<223> 抗体片段
<400> 43
Glu Val Gln Leu Gln Glu Ser Gly Gly Val Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Gly Gly Ile Thr Tyr Phe Pro Asp Thr Val
50 55 60
Gln Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 44
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段
<400> 44
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Phe Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
35 40 45
Tyr Asn Thr Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe
85 90 95
Thr Phe Gly Ser 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> 45
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段
<400> 45
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Thr Leu Pro Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Asp Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Arg Asn Ile Leu Phe Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Gly Met Tyr Tyr Cys Ala
85 90 95
Arg Val Asn Tyr Tyr Asp Ser Ser Phe Leu Asp Trp Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 46
<211> 215
<212> PRT
<213> 人工
<220>
<223> 抗体片段
<400> 46
Asp Ile Val Met Thr Gln Ser Gln Arg Phe Met Ser Thr Leu Glu Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Asn Tyr Pro Leu
85 90 95
Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 47
<211> 449
<212> PRT
<213> 人工
<220>
<223> 抗体片段
<400> 47
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Phe Ile Ser Ser Tyr Gly Gly Arg Thr Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Phe Tyr Cys
85 90 95
Ala Ala His Tyr Phe Gly Thr Ser Gly Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 48
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段
<400> 48
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr
20 25 30
Phe Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
35 40 45
Tyr Asn Ala Lys Ile Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Gly Thr Tyr Tyr Cys Gln His His Tyr Gly Ile Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Leu 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> 49
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段
<400> 49
Glu Leu Gln Leu Val Glu Ser Gly Gly Val Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Thr Tyr Ile Asn Ser Gly Gly Gly Ile Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Thr Ala His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 50
<211> 214
<212> PRT
<213> 人工
<220>
<223> 抗体片段
<400> 50
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
35 40 45
Tyr Asn Ala Lys Thr Leu Thr Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe
85 90 95
Thr Phe Gly Ser 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> 51
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 抗体片段
<400> 51
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Thr Pro Glu Arg Arg Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Gly Gly Ile Thr Tyr Phe Pro Ser Thr Val
50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Thr Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 52
<211> 702
<212> PRT
<213> Homo sapiens
<400> 52
Met Glu Ser Pro Ser Ala Pro Pro His Arg Trp Cys Ile Pro Trp Gln
1 5 10 15
Arg Leu Leu Leu Thr Ala Ser Leu Leu Thr Phe Trp Asn Pro Pro Thr
20 25 30
Thr Ala Lys Leu Thr Ile Glu Ser Thr Pro Phe Asn Val Ala Glu Gly
35 40 45
Lys Glu Val Leu Leu Leu Val His Asn Leu Pro Gln His Leu Phe Gly
50 55 60
Tyr Ser Trp Tyr Lys Gly Glu Arg Val Asp Gly Asn Arg Gln Ile Ile
65 70 75 80
Gly Tyr Val Ile Gly Thr Gln Gln Ala Thr Pro Gly Pro Ala Tyr Ser
85 90 95
Gly Arg Glu Ile Ile Tyr Pro Asn Ala Ser Leu Leu Ile Gln Asn Ile
100 105 110
Ile Gln Asn Asp Thr Gly Phe Tyr Thr Leu His Val Ile Lys Ser Asp
115 120 125
Leu Val Asn Glu Glu Ala Thr Gly Gln Phe Arg Val Tyr Pro Glu Leu
130 135 140
Pro Lys Pro Ser Ile Ser Ser Asn Asn Ser Lys Pro Val Glu Asp Lys
145 150 155 160
Asp Ala Val Ala Phe Thr Cys Glu Pro Glu Thr Gln Asp Ala Thr Tyr
165 170 175
Leu Trp Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg Leu Gln
180 185 190
Leu Ser Asn Gly Asn Arg Thr Leu Thr Leu Phe Asn Val Thr Arg Asn
195 200 205
Asp Thr Ala Ser Tyr Lys Cys Glu Thr Gln Asn Pro Val Ser Ala Arg
210 215 220
Arg Ser Asp Ser Val Ile Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro
225 230 235 240
Thr Ile Ser Pro Leu Asn Thr Ser Tyr Arg Ser Gly Glu Asn Leu Asn
245 250 255
Leu Ser Cys His Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser Trp Phe
260 265 270
Val Asn Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn
275 280 285
Ile Thr Val Asn Asn Ser Gly Ser Tyr Thr Cys Gln Ala His Asn Ser
290 295 300
Asp Thr Gly Leu Asn Arg Thr Thr Val Thr Thr Ile Thr Val Tyr Ala
305 310 315 320
Glu Pro Pro Lys Pro Phe Ile Thr Ser Asn Asn Ser Asn Pro Val Glu
325 330 335
Asp Glu Asp Ala Val Ala Leu Thr Cys Glu Pro Glu Ile Gln Asn Thr
340 345 350
Thr Tyr Leu Trp Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg
355 360 365
Leu Gln Leu Ser Asn Asp Asn Arg Thr Leu Thr Leu Leu Ser Val Thr
370 375 380
Arg Asn Asp Val Gly Pro Tyr Glu Cys Gly Ile Gln Asn Glu Leu Ser
385 390 395 400
Val Asp His Ser Asp Pro Val Ile Leu Asn Val Leu Tyr Gly Pro Asp
405 410 415
Asp Pro Thr Ile Ser Pro Ser Tyr Thr Tyr Tyr Arg Pro Gly Val Asn
420 425 430
Leu Ser Leu Ser Cys His Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser
435 440 445
Trp Leu Ile Asp Gly Asn Ile Gln Gln His Thr Gln Glu Leu Phe Ile
450 455 460
Ser Asn Ile Thr Glu Lys Asn Ser Gly Leu Tyr Thr Cys Gln Ala Asn
465 470 475 480
Asn Ser Ala Ser Gly His Ser Arg Thr Thr Val Lys Thr Ile Thr Val
485 490 495
Ser Ala Glu Leu Pro Lys Pro Ser Ile Ser Ser Asn Asn Ser Lys Pro
500 505 510
Val Glu Asp Lys Asp Ala Val Ala Phe Thr Cys Glu Pro Glu Ala Gln
515 520 525
Asn Thr Thr Tyr Leu Trp Trp Val Asn Gly Gln Ser Leu Pro Val Ser
530 535 540
Pro Arg Leu Gln Leu Ser Asn Gly Asn Arg Thr Leu Thr Leu Phe Asn
545 550 555 560
Val Thr Arg Asn Asp Ala Arg Ala Tyr Val Cys Gly Ile Gln Asn Ser
565 570 575
Val Ser Ala Asn Arg Ser Asp Pro Val Thr Leu Asp Val Leu Tyr Gly
580 585 590
Pro Asp Thr Pro Ile Ile Ser Pro Pro Asp Ser Ser Tyr Leu Ser Gly
595 600 605
Ala Asn Leu Asn Leu Ser Cys His Ser Ala Ser Asn Pro Ser Pro Gln
610 615 620
Tyr Ser Trp Arg Ile Asn Gly Ile Pro Gln Gln His Thr Gln Val Leu
625 630 635 640
Phe Ile Ala Lys Ile Thr Pro Asn Asn Asn Gly Thr Tyr Ala Cys Phe
645 650 655
Val Ser Asn Leu Ala Thr Gly Arg Asn Asn Ser Ile Val Lys Ser Ile
660 665 670
Thr Val Ser Ala Ser Gly Thr Ser Pro Gly Leu Ser Ala Gly Ala Thr
675 680 685
Val Gly Ile Met Ile Gly Val Leu Val Gly Val Ala Leu Ile
690 695 700
<210> 53
<211> 654
<212> PRT
<213> Macaca fascicularis
<400> 53
Gln Leu Thr Ile Glu Ser Arg Pro Phe Asn Val Ala Glu Gly Lys Glu
1 5 10 15
Val Leu Leu Leu Ala His Asn Val Ser Gln Asn Leu Phe Gly Tyr Ile
20 25 30
Trp Tyr Lys Gly Glu Arg Val Asp Ala Ser Arg Arg Ile Gly Ser Cys
35 40 45
Val Ile Arg Thr Gln Gln Ile Thr Pro Gly Pro Ala His Ser Gly Arg
50 55 60
Glu Thr Ile Asp Phe Asn Ala Ser Leu Leu Ile Gln Asn Val Thr Gln
65 70 75 80
Ser Asp Thr Gly Ser Tyr Thr Ile Gln Val Ile Lys Glu Asp Leu Val
85 90 95
Asn Glu Glu Ala Thr Gly Gln Phe Arg Val Tyr Pro Glu Leu Pro Lys
100 105 110
Pro Tyr Ile Thr Ser Asn Asn Ser Asn Pro Ile Glu Asp Lys Asp Ala
115 120 125
Val Ala Leu Thr Cys Glu Pro Glu Thr Gln Asp Thr Thr Tyr Leu Trp
130 135 140
Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg Leu Glu Leu Ser
145 150 155 160
Ser Asp Asn Arg Thr Leu Thr Val Phe Asn Ile Pro Arg Asn Asp Thr
165 170 175
Thr Ser Tyr Lys Cys Glu Thr Gln Asn Pro Val Ser Val Arg Arg Ser
180 185 190
Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro Thr Ile
195 200 205
Ser Pro Leu Asn Thr Pro Tyr Arg Ala Gly Glu Tyr Leu Asn Leu Thr
210 215 220
Cys His Ala Ala Ser Asn Pro Thr Ala Gln Tyr Phe Trp Phe Val Asn
225 230 235 240
Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn Ile Thr
245 250 255
Val Asn Asn Ser Gly Ser Tyr Met Cys Gln Ala His Asn Ser Ala Thr
260 265 270
Gly Leu Asn Arg Thr Thr Val Thr Ala Ile Thr Val Tyr Ala Glu Leu
275 280 285
Pro Lys Pro Tyr Ile Thr Ser Asn Asn Ser Asn Pro Ile Glu Asp Lys
290 295 300
Asp Ala Val Thr Leu Thr Cys Glu Pro Glu Thr Gln Asp Thr Thr Tyr
305 310 315 320
Leu Trp Trp Val Asn Asn Gln Arg Leu Ser Val Ser Ser Arg Leu Glu
325 330 335
Leu Ser Asn Asp Asn Arg Thr Leu Thr Val Phe Asn Ile Pro Arg Asn
340 345 350
Asp Thr Thr Phe Tyr Glu Cys Glu Thr Gln Asn Pro Val Ser Val Arg
355 360 365
Arg Ser Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro
370 375 380
Thr Ile Ser Pro Leu Asn Thr Pro Tyr Arg Ala Gly Glu Asn Leu Asn
385 390 395 400
Leu Ser Cys His Ala Ala Ser Asn Pro Ala Ala Gln Tyr Phe Trp Phe
405 410 415
Val Asn Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn
420 425 430
Ile Thr Val Asn Asn Ser Gly Ser Tyr Met Cys Gln Ala His Asn Ser
435 440 445
Ala Thr Gly Leu Asn Arg Thr Thr Val Thr Ala Ile Thr Val Tyr Val
450 455 460
Glu Leu Pro Lys Pro Tyr Ile Ser Ser Asn Asn Ser Asn Pro Ile Glu
465 470 475 480
Asp Lys Asp Ala Val Thr Leu Thr Cys Glu Pro Val Ala Glu Asn Thr
485 490 495
Thr Tyr Leu Trp Trp Val Asn Asn Gln Ser Leu Ser Val Ser Pro Arg
500 505 510
Leu Gln Leu Ser Asn Gly Asn Arg Ile Leu Thr Leu Leu Ser Val Thr
515 520 525
Arg Asn Asp Thr Gly Pro Tyr Glu Cys Gly Ile Gln Asn Ser Glu Ser
530 535 540
Ala Lys Arg Ser Asp Pro Val Thr Leu Asn Val Thr Tyr Gly Pro Asp
545 550 555 560
Thr Pro Ile Ile Ser Pro Pro Asp Leu Ser Tyr Arg Ser Gly Ala Asn
565 570 575
Leu Asn Leu Ser Cys His Ser Asp Ser Asn Pro Ser Pro Gln Tyr Ser
580 585 590
Trp Leu Ile Asn Gly Thr Leu Arg Gln His Thr Gln Val Leu Phe Ile
595 600 605
Ser Lys Ile Thr Ser Asn Asn Asn Gly Ala Tyr Ala Cys Phe Val Ser
610 615 620
Asn Leu Ala Thr Gly Arg Asn Asn Ser Ile Val Lys Asn Ile Ser Val
625 630 635 640
Ser Ser Gly Asp Ser Ala Pro Gly Ser Ser Gly Leu Ser Ala
645 650
<210> 54
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗体
<400> 54
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Phe Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
35 40 45
Tyr Asn Thr Arg Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe
85 90 95
Thr Phe Gly Ser 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> 55
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 抗体
<400> 55
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Phe Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Val
35 40 45
Tyr Asn Thr Arg Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 56
<211> 418
<212> PRT
<213> Homo sapiens
<220>
<221> 结构域
<222> (1)..(394)
<223> 人CEACAM1的胞外结构域
<220>
<221> MISC_FEATURE
<222> (395)..(418)
<223> 用 His-tag延伸
<400> 56
Gln Leu Thr Thr Glu Ser Met Pro Phe Asn Val Ala Glu Gly Lys Glu
1 5 10 15
Val Leu Leu Leu Val His Asn Leu Pro Gln Gln Leu Phe Gly Tyr Ser
20 25 30
Trp Tyr Lys Gly Glu Arg Val Asp Gly Asn Arg Gln Ile Val Gly Tyr
35 40 45
Ala Ile Gly Thr Gln Gln Ala Thr Pro Gly Pro Ala Asn Ser Gly Arg
50 55 60
Glu Thr Ile Tyr Pro Asn Ala Ser Leu Leu Ile Gln Asn Val Thr Gln
65 70 75 80
Asn Asp Thr Gly Phe Tyr Thr Leu Gln Val Ile Lys Ser Asp Leu Val
85 90 95
Asn Glu Glu Ala Thr Gly Gln Phe His Val Tyr Pro Glu Leu Pro Lys
100 105 110
Pro Ser Ile Ser Ser Asn Asn Ser Asn Pro Val Glu Asp Lys Asp Ala
115 120 125
Val Ala Phe Thr Cys Glu Pro Glu Thr Gln Asp Thr Thr Tyr Leu Trp
130 135 140
Trp Ile Asn Asn Gln Ser Leu Pro Val Ser Pro Arg Leu Gln Leu Ser
145 150 155 160
Asn Gly Asn Arg Thr Leu Thr Leu Leu Ser Val Thr Arg Asn Asp Thr
165 170 175
Gly Pro Tyr Glu Cys Glu Ile Gln Asn Pro Val Ser Ala Asn Arg Ser
180 185 190
Asp Pro Val Thr Leu Asn Val Thr Tyr Gly Pro Asp Thr Pro Thr Ile
195 200 205
Ser Pro Ser Asp Thr Tyr Tyr Arg Pro Gly Ala Asn Leu Ser Leu Ser
210 215 220
Cys Tyr Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser Trp Leu Ile Asn
225 230 235 240
Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn Ile Thr
245 250 255
Val Asn Asn Ser Gly Ser Tyr Thr Cys His Ala Asn Asn Ser Val Thr
260 265 270
Gly Cys Asn Arg Thr Thr Val Lys Thr Ile Ile Val Thr Glu Leu Ser
275 280 285
Pro Val Val Ala Lys Pro Gln Ile Lys Ala Ser Lys Thr Thr Val Thr
290 295 300
Gly Asp Lys Asp Ser Val Asn Leu Thr Cys Ser Thr Asn Asp Thr Gly
305 310 315 320
Ile Ser Ile Arg Trp Phe Phe Lys Asn Gln Ser Leu Pro Ser Ser Glu
325 330 335
Arg Met Lys Leu Ser Gln Gly Asn Thr Thr Leu Ser Ile Asn Pro Val
340 345 350
Lys Arg Glu Asp Ala Gly Thr Tyr Trp Cys Glu Val Phe Asn Pro Ile
355 360 365
Ser Lys Asn Gln Ser Asp Pro Ile Met Leu Asn Val Asn Tyr Asn Ala
370 375 380
Leu Pro Gln Glu Asn Gly Leu Ser Pro Gly Ser Gly Ser Gly Ser Gly
385 390 395 400
Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His His His His
405 410 415
His His
<210> 57
<211> 418
<212> PRT
<213> Macaca fascicularis
<220>
<221> 结构域
<222> (1)..(394)
<223> 食蟹猴CEACAM1的胞外结构域
<220>
<221> MISC_FEATURE
<222> (395)..(418)
<223> 用 His-tag延伸
<400> 57
Gln Leu Thr Ile Glu Ser Arg Pro Phe Asn Val Ala Glu Gly Lys Glu
1 5 10 15
Val Leu Leu Leu Ala His Asn Leu Ser Gln Asn Leu Ile Gly Tyr Asn
20 25 30
Trp His Lys Gly Glu Arg Val Asp Ala Lys Arg Leu Ile Val Ala Tyr
35 40 45
Val Ile Glu Thr Lys Gln Thr Thr Pro Gly Pro Ala His Ser Gly Arg
50 55 60
Glu Met Ile Tyr Ser Asn Ala Ser Leu Leu Ile Gln Asn Val Thr Gln
65 70 75 80
Asn Asp Thr Gly Ser Tyr Thr Leu Gln Val Ile Lys Gly Asp Leu Val
85 90 95
Asn Glu Glu Ala Thr Gly Gln Phe Arg Val Tyr Pro Glu Leu Pro Lys
100 105 110
Pro Asn Ile Thr Ile Asn Asn Ser Asn Pro Val Glu Asp Lys Asp Val
115 120 125
Val Thr Phe Thr Cys Glu Ser Glu Ala Gln Asp Thr Thr Tyr Leu Trp
130 135 140
Trp Val Asn Asn Gln Ser Leu Pro Val Ser Ser Arg Leu Gln Leu Ser
145 150 155 160
Asn Gly Asn Lys Thr Leu Thr Leu Leu Ser Val Leu Arg Asn Asp Thr
165 170 175
Gly Pro Tyr Glu Cys Glu Ile Gln Asn Pro Val Ser Ala Asn Arg Ser
180 185 190
Asp Pro Val Thr Leu Asn Val Thr Tyr Gly Pro Asp Thr Pro Thr Ile
195 200 205
Ser Pro Ser Asp Thr Tyr Tyr Arg Pro Gly Ala Asn Leu Ser Leu Ser
210 215 220
Cys Ser Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser Trp Leu Ile Asn
225 230 235 240
Glu Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn Ile Thr
245 250 255
Val Asn Asn Ser Gly Ser Tyr Thr Cys His Ala Asn Asn Ser Val Thr
260 265 270
Gly Arg Asn Arg Thr Thr Val Lys Met Ile Ile Val Ser Glu Gln Ser
275 280 285
Leu Val Val Ala Gln Pro Gln Ile Lys Ala Ser Lys Thr Thr Val Thr
290 295 300
Glu Asp Lys Asp Tyr Val Asn Leu Thr Cys Ser Thr Asn Asp Thr Gly
305 310 315 320
Ile Ser Ile Ser Trp Phe Phe Lys Asp Gln Ser Leu Pro Ser Ser Glu
325 330 335
Arg Met Lys Leu Ser Gln Asp Asn Ala Thr Leu Ser Ile Asn Pro Val
340 345 350
Lys Arg Glu Asp Ala Gly Asn Tyr Ser Cys Glu Val Phe Asn Leu Ile
355 360 365
Ser Lys Asn Arg Ser Asp Pro Ile Val Leu Ile Val Asn Tyr Asn Asn
370 375 380
Arg Ala Gln Glu Asn Ile Leu Pro Ala Gly Ser Gly Ser Gly Ser Gly
385 390 395 400
Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His His His His
405 410 415
His His
<210> 58
<211> 675
<212> PRT
<213> Homo sapiens
<220>
<221> 结构域
<222> (1)..(651)
<223> 人CEACAM5的胞外结构域
<220>
<221> MISC_FEATURE
<222> (652)..(675)
<223> 用 His-tag延伸
<400> 58
Lys Leu Thr Ile Glu Ser Thr Pro Phe Asn Val Ala Glu Gly Lys Glu
1 5 10 15
Val Leu Leu Leu Val His Asn Leu Pro Gln His Leu Phe Gly Tyr Ser
20 25 30
Trp Tyr Lys Gly Glu Arg Val Asp Gly Asn Arg Gln Ile Ile Gly Tyr
35 40 45
Val Ile Gly Thr Gln Gln Ala Thr Pro Gly Pro Ala Tyr Ser Gly Arg
50 55 60
Glu Ile Ile Tyr Pro Asn Ala Ser Leu Leu Ile Gln Asn Ile Ile Gln
65 70 75 80
Asn Asp Thr Gly Phe Tyr Thr Leu His Val Ile Lys Ser Asp Leu Val
85 90 95
Asn Glu Glu Ala Thr Gly Gln Phe Arg Val Tyr Pro Glu Leu Pro Lys
100 105 110
Pro Ser Ile Ser Ser Asn Asn Ser Lys Pro Val Glu Asp Lys Asp Ala
115 120 125
Val Ala Phe Thr Cys Glu Pro Glu Thr Gln Asp Ala Thr Tyr Leu Trp
130 135 140
Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg Leu Gln Leu Ser
145 150 155 160
Asn Gly Asn Arg Thr Leu Thr Leu Phe Asn Val Thr Arg Asn Asp Thr
165 170 175
Ala Ser Tyr Lys Cys Glu Thr Gln Asn Pro Val Ser Ala Arg Arg Ser
180 185 190
Asp Ser Val Ile Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro Thr Ile
195 200 205
Ser Pro Leu Asn Thr Ser Tyr Arg Ser Gly Glu Asn Leu Asn Leu Ser
210 215 220
Cys His Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser Trp Phe Val Asn
225 230 235 240
Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn Ile Thr
245 250 255
Val Asn Asn Ser Gly Ser Tyr Thr Cys Gln Ala His Asn Ser Asp Thr
260 265 270
Gly Leu Asn Arg Thr Thr Val Thr Thr Ile Thr Val Tyr Ala Glu Pro
275 280 285
Pro Lys Pro Phe Ile Thr Ser Asn Asn Ser Asn Pro Val Glu Asp Glu
290 295 300
Asp Ala Val Ala Leu Thr Cys Glu Pro Glu Ile Gln Asn Thr Thr Tyr
305 310 315 320
Leu Trp Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg Leu Gln
325 330 335
Leu Ser Asn Asp Asn Arg Thr Leu Thr Leu Leu Ser Val Thr Arg Asn
340 345 350
Asp Val Gly Pro Tyr Glu Cys Gly Ile Gln Asn Glu Leu Ser Val Asp
355 360 365
His Ser Asp Pro Val Ile Leu Asn Val Leu Tyr Gly Pro Asp Asp Pro
370 375 380
Thr Ile Ser Pro Ser Tyr Thr Tyr Tyr Arg Pro Gly Val Asn Leu Ser
385 390 395 400
Leu Ser Cys His Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser Trp Leu
405 410 415
Ile Asp Gly Asn Ile Gln Gln His Thr Gln Glu Leu Phe Ile Ser Asn
420 425 430
Ile Thr Glu Lys Asn Ser Gly Leu Tyr Thr Cys Gln Ala Asn Asn Ser
435 440 445
Ala Ser Gly His Ser Arg Thr Thr Val Lys Thr Ile Thr Val Ser Ala
450 455 460
Glu Leu Pro Lys Pro Ser Ile Ser Ser Asn Asn Ser Lys Pro Val Glu
465 470 475 480
Asp Lys Asp Ala Val Ala Phe Thr Cys Glu Pro Glu Ala Gln Asn Thr
485 490 495
Thr Tyr Leu Trp Trp Val Asn Gly Gln Ser Leu Pro Val Ser Pro Arg
500 505 510
Leu Gln Leu Ser Asn Gly Asn Arg Thr Leu Thr Leu Phe Asn Val Thr
515 520 525
Arg Asn Asp Ala Arg Ala Tyr Val Cys Gly Ile Gln Asn Ser Val Ser
530 535 540
Ala Asn Arg Ser Asp Pro Val Thr Leu Asp Val Leu Tyr Gly Pro Asp
545 550 555 560
Thr Pro Ile Ile Ser Pro Pro Asp Ser Ser Tyr Leu Ser Gly Ala Asn
565 570 575
Leu Asn Leu Ser Cys His Ser Ala Ser Asn Pro Ser Pro Gln Tyr Ser
580 585 590
Trp Arg Ile Asn Gly Ile Pro Gln Gln His Thr Gln Val Leu Phe Ile
595 600 605
Ala Lys Ile Thr Pro Asn Asn Asn Gly Thr Tyr Ala Cys Phe Val Ser
610 615 620
Asn Leu Ala Thr Gly Arg Asn Asn Ser Ile Val Lys Ser Ile Thr Val
625 630 635 640
Ser Ala Ser Gly Thr Ser Pro Gly Leu Ser Ala Ser Gly Ser Gly Ser
645 650 655
Gly Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His His His
660 665 670
His His His
675
<210> 59
<211> 678
<212> PRT
<213> Macaca fascicularis
<220>
<221> 结构域
<222> (1)..(654)
<223> 食蟹猴CEACAM5的胞外结构域
<220>
<221> MISC_FEATURE
<222> (655)..(678)
<223> 用 His-tag延伸
<400> 59
Gln Leu Thr Ile Glu Ser Arg Pro Phe Asn Val Ala Glu Gly Lys Glu
1 5 10 15
Val Leu Leu Leu Ala His Asn Val Ser Gln Asn Leu Phe Gly Tyr Ile
20 25 30
Trp Tyr Lys Gly Glu Arg Val Asp Ala Ser Arg Arg Ile Gly Ser Cys
35 40 45
Val Ile Arg Thr Gln Gln Ile Thr Pro Gly Pro Ala His Ser Gly Arg
50 55 60
Glu Thr Ile Asp Phe Asn Ala Ser Leu Leu Ile Gln Asn Val Thr Gln
65 70 75 80
Ser Asp Thr Gly Ser Tyr Thr Ile Gln Val Ile Lys Glu Asp Leu Val
85 90 95
Asn Glu Glu Ala Thr Gly Gln Phe Arg Val Tyr Pro Glu Leu Pro Lys
100 105 110
Pro Tyr Ile Thr Ser Asn Asn Ser Asn Pro Ile Glu Asp Lys Asp Ala
115 120 125
Val Ala Leu Thr Cys Glu Pro Glu Thr Gln Asp Thr Thr Tyr Leu Trp
130 135 140
Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg Leu Glu Leu Ser
145 150 155 160
Ser Asp Asn Arg Thr Leu Thr Val Phe Asn Ile Pro Arg Asn Asp Thr
165 170 175
Thr Ser Tyr Lys Cys Glu Thr Gln Asn Pro Val Ser Val Arg Arg Ser
180 185 190
Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro Thr Ile
195 200 205
Ser Pro Leu Asn Thr Pro Tyr Arg Ala Gly Glu Tyr Leu Asn Leu Thr
210 215 220
Cys His Ala Ala Ser Asn Pro Thr Ala Gln Tyr Phe Trp Phe Val Asn
225 230 235 240
Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn Ile Thr
245 250 255
Val Asn Asn Ser Gly Ser Tyr Met Cys Gln Ala His Asn Ser Ala Thr
260 265 270
Gly Leu Asn Arg Thr Thr Val Thr Ala Ile Thr Val Tyr Ala Glu Leu
275 280 285
Pro Lys Pro Tyr Ile Thr Ser Asn Asn Ser Asn Pro Ile Glu Asp Lys
290 295 300
Asp Ala Val Thr Leu Thr Cys Glu Pro Glu Thr Gln Asp Thr Thr Tyr
305 310 315 320
Leu Trp Trp Val Asn Asn Gln Arg Leu Ser Val Ser Ser Arg Leu Glu
325 330 335
Leu Ser Asn Asp Asn Arg Thr Leu Thr Val Phe Asn Ile Pro Arg Asn
340 345 350
Asp Thr Thr Phe Tyr Glu Cys Glu Thr Gln Asn Pro Val Ser Val Arg
355 360 365
Arg Ser Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro
370 375 380
Thr Ile Ser Pro Leu Asn Thr Pro Tyr Arg Ala Gly Glu Asn Leu Asn
385 390 395 400
Leu Ser Cys His Ala Ala Ser Asn Pro Ala Ala Gln Tyr Phe Trp Phe
405 410 415
Val Asn Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn
420 425 430
Ile Thr Val Asn Asn Ser Gly Ser Tyr Met Cys Gln Ala His Asn Ser
435 440 445
Ala Thr Gly Leu Asn Arg Thr Thr Val Thr Ala Ile Thr Val Tyr Val
450 455 460
Glu Leu Pro Lys Pro Tyr Ile Ser Ser Asn Asn Ser Asn Pro Ile Glu
465 470 475 480
Asp Lys Asp Ala Val Thr Leu Thr Cys Glu Pro Val Ala Glu Asn Thr
485 490 495
Thr Tyr Leu Trp Trp Val Asn Asn Gln Ser Leu Ser Val Ser Pro Arg
500 505 510
Leu Gln Leu Ser Asn Gly Asn Arg Ile Leu Thr Leu Leu Ser Val Thr
515 520 525
Arg Asn Asp Thr Gly Pro Tyr Glu Cys Gly Ile Gln Asn Ser Glu Ser
530 535 540
Ala Lys Arg Ser Asp Pro Val Thr Leu Asn Val Thr Tyr Gly Pro Asp
545 550 555 560
Thr Pro Ile Ile Ser Pro Pro Asp Leu Ser Tyr Arg Ser Gly Ala Asn
565 570 575
Leu Asn Leu Ser Cys His Ser Asp Ser Asn Pro Ser Pro Gln Tyr Ser
580 585 590
Trp Leu Ile Asn Gly Thr Leu Arg Gln His Thr Gln Val Leu Phe Ile
595 600 605
Ser Lys Ile Thr Ser Asn Asn Asn Gly Ala Tyr Ala Cys Phe Val Ser
610 615 620
Asn Leu Ala Thr Gly Arg Asn Asn Ser Ile Val Lys Asn Ile Ser Val
625 630 635 640
Ser Ser Gly Asp Ser Ala Pro Gly Ser Ser Gly Leu Ser Ala Ser Gly
645 650 655
Ser Gly Ser Gly Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp
660 665 670
His His His His His His
675
<210> 60
<211> 317
<212> PRT
<213> Homo sapiens
<220>
<221> 结构域
<222> (1)..(293)
<223> 人CEACAM6的胞外结构域
<220>
<221> MISC_FEATURE
<222> (294)..(317)
<223> 用 His-tag延伸
<400> 60
Lys Leu Thr Ile Glu Ser Thr Pro Phe Asn Val Ala Glu Gly Lys Glu
1 5 10 15
Val Leu Leu Leu Ala His Asn Leu Pro Gln Asn Arg Ile Gly Tyr Ser
20 25 30
Trp Tyr Lys Gly Glu Arg Val Asp Gly Asn Ser Leu Ile Val Gly Tyr
35 40 45
Val Ile Gly Thr Gln Gln Ala Thr Pro Gly Pro Ala Tyr Ser Gly Arg
50 55 60
Glu Thr Ile Tyr Pro Asn Ala Ser Leu Leu Ile Gln Asn Val Thr Gln
65 70 75 80
Asn Asp Thr Gly Phe Tyr Thr Leu Gln Val Ile Lys Ser Asp Leu Val
85 90 95
Asn Glu Glu Ala Thr Gly Gln Phe His Val Tyr Pro Glu Leu Pro Lys
100 105 110
Pro Ser Ile Ser Ser Asn Asn Ser Asn Pro Val Glu Asp Lys Asp Ala
115 120 125
Val Ala Phe Thr Cys Glu Pro Glu Val Gln Asn Thr Thr Tyr Leu Trp
130 135 140
Trp Val Asn Gly Gln Ser Leu Pro Val Ser Pro Arg Leu Gln Leu Ser
145 150 155 160
Asn Gly Asn Met Thr Leu Thr Leu Leu Ser Val Lys Arg Asn Asp Ala
165 170 175
Gly Ser Tyr Glu Cys Glu Ile Gln Asn Pro Ala Ser Ala Asn Arg Ser
180 185 190
Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp Gly Pro Thr Ile
195 200 205
Ser Pro Ser Lys Ala Asn Tyr Arg Pro Gly Glu Asn Leu Asn Leu Ser
210 215 220
Cys His Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser Trp Phe Ile Asn
225 230 235 240
Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn Ile Thr
245 250 255
Val Asn Asn Ser Gly Ser Tyr Met Cys Gln Ala His Asn Ser Ala Thr
260 265 270
Gly Leu Asn Arg Thr Thr Val Thr Met Ile Thr Val Ser Gly Ser Ala
275 280 285
Pro Val Leu Ser Ala Ser Gly Ser Gly Ser Gly Leu Asn Asp Ile Phe
290 295 300
Glu Ala Gln Lys Ile Glu Trp His His His His His His
305 310 315
<210> 61
<211> 317
<212> PRT
<213> Macaca fascicularis
<220>
<221> 结构域
<222> (1)..(293)
<223> 食蟹猴CEACAM6的胞外结构域
<220>
<221> MISC_FEATURE
<222> (294)..(317)
<223> 用 His-tag延伸
<400> 61
Gln Leu Thr Ile Glu Ser Arg Pro Phe Asn Val Ala Glu Gly Lys Glu
1 5 10 15
Val Leu Leu Leu Ala His Asn Leu Pro Gln Asn Thr Leu Gly Phe Asn
20 25 30
Trp Tyr Lys Gly Glu Arg Val Asp Ala Lys Arg Leu Ile Val Ala Tyr
35 40 45
Val Ile Gly Thr Gln Gln Thr Thr Pro Gly Pro Ala His Ser Gly Arg
50 55 60
Glu Met Ile Tyr Ser Asn Ala Ser Leu Leu Ile Gln Asn Val Thr Gln
65 70 75 80
Asn Asp Thr Gly Ser Tyr Thr Leu Gln Val Ile Lys Gly Asp Leu Val
85 90 95
Thr Glu Glu Ala Thr Gly Arg Phe Trp Val Tyr Pro Glu Leu Pro Lys
100 105 110
Pro Tyr Ile Thr Ser Asn Asn Ser Asn Pro Val Glu Asp Lys Asp Ala
115 120 125
Val Asp Phe Thr Cys Glu Pro Asp Ile His Ser Thr Thr Tyr Leu Trp
130 135 140
Trp Val Asn Asp Gln Ser Leu Pro Val Ser Pro Arg Leu Gln Leu Ser
145 150 155 160
Asn Gly Asn Arg Thr Leu Thr Leu Leu Ser Val Lys Arg Asn Asp Ala
165 170 175
Gly Ala Tyr Glu Cys Glu Ile Gln Asn Pro Val Ser Ala Asn Leu Ser
180 185 190
Asp Pro Val Ile Leu Asn Val Leu Tyr Gly Pro Asp Val Pro Thr Ile
195 200 205
Ser Pro Ser Asn Ser Asn Tyr Arg Pro Gly Glu Asn Leu Asn Leu Ser
210 215 220
Cys His Ala Ala Ser Asn Pro Thr Ala Gln Tyr Ser Trp Phe Val Asn
225 230 235 240
Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn Ile Thr
245 250 255
Val Asn Asn Ser Gly Ser Tyr Met Cys Gln Ala Tyr Asn Ser Ala Thr
260 265 270
Gly Leu Asn Arg Thr Thr Val Met Met Ile Thr Val Ser Gly Ser Ala
275 280 285
Pro Gly Leu Ser Ala Ser Gly Ser Gly Ser Gly Leu Asn Asp Ile Phe
290 295 300
Glu Ala Gln Lys Ile Glu Trp His His His His His His
305 310 315
<210> 62
<211> 322
<212> PRT
<213> Homo sapiens
<220>
<221> 结构域
<222> (1)..(298)
<223> 人CEACAM8的胞外结构域
<220>
<221> MISC_FEATURE
<222> (299)..(322)
<223> 用 His-tag延伸
<400> 62
Gln Leu Thr Ile Glu Ala Val Pro Ser Asn Ala Ala Glu Gly Lys Glu
1 5 10 15
Val Leu Leu Leu Val His Asn Leu Pro Gln Asp Pro Arg Gly Tyr Asn
20 25 30
Trp Tyr Lys Gly Glu Thr Val Asp Ala Asn Arg Arg Ile Ile Gly Tyr
35 40 45
Val Ile Ser Asn Gln Gln Ile Thr Pro Gly Pro Ala Tyr Ser Asn Arg
50 55 60
Glu Thr Ile Tyr Pro Asn Ala Ser Leu Leu Met Arg Asn Val Thr Arg
65 70 75 80
Asn Asp Thr Gly Ser Tyr Thr Leu Gln Val Ile Lys Leu Asn Leu Met
85 90 95
Ser Glu Glu Val Thr Gly Gln Phe Ser Val His Pro Glu Thr Pro Lys
100 105 110
Pro Ser Ile Ser Ser Asn Asn Ser Asn Pro Val Glu Asp Lys Asp Ala
115 120 125
Val Ala Phe Thr Cys Glu Pro Glu Thr Gln Asn Thr Thr Tyr Leu Trp
130 135 140
Trp Val Asn Gly Gln Ser Leu Pro Val Ser Pro Arg Leu Gln Leu Ser
145 150 155 160
Asn Gly Asn Arg Thr Leu Thr Leu Leu Ser Val Thr Arg Asn Asp Val
165 170 175
Gly Pro Tyr Glu Cys Glu Ile Gln Asn Pro Ala Ser Ala Asn Phe Ser
180 185 190
Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro Thr Ile
195 200 205
Ser Pro Ser Asp Thr Tyr Tyr His Ala Gly Val Asn Leu Asn Leu Ser
210 215 220
Cys His Ala Ala Ser Asn Pro Pro Ser Gln Tyr Ser Trp Ser Val Asn
225 230 235 240
Gly Thr Phe Gln Gln Tyr Thr Gln Lys Leu Phe Ile Pro Asn Ile Thr
245 250 255
Thr Lys Asn Ser Gly Ser Tyr Ala Cys His Thr Thr Asn Ser Ala Thr
260 265 270
Gly Arg Asn Arg Thr Thr Val Arg Met Ile Thr Val Ser Asp Ala Leu
275 280 285
Val Gln Gly Ser Ser Pro Gly Leu Ser Ala Ser Gly Ser Gly Ser Gly
290 295 300
Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His His His His
305 310 315 320
His His
<210> 63
<211> 322
<212> PRT
<213> Macaca fascicularis
<220>
<221> 结构域
<222> (1)..(298)
<223> 食蟹猴CEACAM8的胞外结构域
<220>
<221> MISC_FEATURE
<222> (299)..(322)
<223> 用 His-tag延伸
<400> 63
Gln Leu Thr Ile Glu Ala Val Pro Ser Asn Ala Ala Glu Gly Lys Glu
1 5 10 15
Val Leu Leu Leu Ala His Asn Leu Pro Gln Asp Pro Leu Gly Tyr Asn
20 25 30
Trp Tyr Lys Gly Glu Thr Val Asp Ala Asn Arg Arg Ile Ile Gly Tyr
35 40 45
Val Ile Ala Thr Gln Val Asn Ile Ser Gly Pro Ala Asp Ser Gly Arg
50 55 60
Glu Thr Ile Tyr Pro Asn Ala Thr Leu Leu Met Gln Asn Val Thr Arg
65 70 75 80
Asn Asp Thr Gly Ser Tyr Thr Leu Gln Val Ile Thr Leu Asn Leu Val
85 90 95
Asn Glu Glu Val Thr Gly Gln Phe Ser Val His Pro Glu Thr Pro Lys
100 105 110
Pro Ser Ile Ser Ser Asn Asn Ser Asn Pro Val Glu Asp Arg Asp Ala
115 120 125
Val Ala Leu Thr Cys Glu Pro Glu Thr Gln Asn Thr Thr Tyr Leu Trp
130 135 140
Trp Val Asn Gly Gln Ser Leu Pro Val Ser Pro Arg Leu Gln Leu Ser
145 150 155 160
Asp Gly Asn Arg Thr Leu Thr Leu Leu Asn Val Thr Arg Asn Asp Thr
165 170 175
Gly Pro Tyr Glu Cys Glu Ile Gln Asn Pro Val Ser Val Asn Phe Ser
180 185 190
Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro Asn Ile
195 200 205
Ser Pro Ser Asp Thr Tyr Tyr Leu Pro Gly Val Asn Leu Asn Leu Ser
210 215 220
Cys His Ala Ala Ser Asn Pro Leu Ala Gln Tyr Ser Trp Ser Val Asn
225 230 235 240
Gly Thr Phe Gln Gln His Thr Gln Asn Leu Phe Ile Pro Asn Ile Thr
245 250 255
Ala Lys Asn Ser Gly Ser Tyr Ala Cys His Ala Thr Asn Ser Ala Thr
260 265 270
Gly His Asn Gly Thr Thr Val Arg Met Ile Thr Val Ser Asp Ala Ser
275 280 285
Val Gln Gly Ser Ser Pro Gly Leu Ser Ala Ser Gly Ser Gly Ser Gly
290 295 300
Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp His His His His
305 310 315 320
His His
<210> 64
<211> 237
<212> PRT
<213> Homo sapiens
<220>
<221> 结构域
<222> (1)..(213)
<223> 人CEACAM7的胞外结构域
<220>
<221> 结构域
<222> (214)..(237)
<223> 用 His-tag延伸
<400> 64
Thr Asn Ile Asp Val Val Pro Phe Asn Val Ala Glu Gly Lys Glu Val
1 5 10 15
Leu Leu Val Val His Asn Glu Ser Gln Asn Leu Tyr Gly Tyr Asn Trp
20 25 30
Tyr Lys Gly Glu Arg Val His Ala Asn Tyr Arg Ile Ile Gly Tyr Val
35 40 45
Lys Asn Ile Ser Gln Glu Asn Ala Pro Gly Pro Ala His Asn Gly Arg
50 55 60
Glu Thr Ile Tyr Pro Asn Gly Thr Leu Leu Ile Gln Asn Val Thr His
65 70 75 80
Asn Asp Ala Gly Ile Tyr Thr Leu His Val Ile Lys Glu Asn Leu Val
85 90 95
Asn Glu Glu Val Thr Arg Gln Phe Tyr Val Phe Ser Glu Pro Pro Lys
100 105 110
Pro Ser Ile Thr Ser Asn Asn Phe Asn Pro Val Glu Asn Lys Asp Ile
115 120 125
Val Val Leu Thr Cys Gln Pro Glu Thr Gln Asn Thr Thr Tyr Leu Trp
130 135 140
Trp Val Asn Asn Gln Ser Leu Leu Val Ser Pro Arg Leu Leu Leu Ser
145 150 155 160
Thr Asp Asn Arg Thr Leu Val Leu Leu Ser Ala Thr Lys Asn Asp Ile
165 170 175
Gly Pro Tyr Glu Cys Glu Ile Gln Asn Pro Val Gly Ala Ser Arg Ser
180 185 190
Asp Pro Val Thr Leu Asn Val Arg Tyr Glu Ser Val Gln Ala Ser Ser
195 200 205
Pro Asp Leu Ser Ala Ser Gly Ser Gly Ser Gly Leu Asn Asp Ile Phe
210 215 220
Glu Ala Gln Lys Ile Glu Trp His His His His His His
225 230 235
<210> 65
<211> 292
<212> PRT
<213> Homo sapiens
<220>
<221> 结构域
<222> (1)..(286)
<223> hCEACAM5 N-A1-B1
<220>
<221> MISC_FEATURE
<222> (287)..(292)
<223> His-tag
<400> 65
Lys Leu Thr Ile Glu Ser Thr Pro Phe Asn Val Ala Glu Gly Lys Glu
1 5 10 15
Val Leu Leu Leu Val His Asn Leu Pro Gln His Leu Phe Gly Tyr Ser
20 25 30
Trp Tyr Lys Gly Glu Arg Val Asp Gly Asn Arg Gln Ile Ile Gly Tyr
35 40 45
Val Ile Gly Thr Gln Gln Ala Thr Pro Gly Pro Ala Tyr Ser Gly Arg
50 55 60
Glu Ile Ile Tyr Pro Asn Ala Ser Leu Leu Ile Gln Asn Ile Ile Gln
65 70 75 80
Asn Asp Thr Gly Phe Tyr Thr Leu His Val Ile Lys Ser Asp Leu Val
85 90 95
Asn Glu Glu Ala Thr Gly Gln Phe Arg Val Tyr Pro Glu Leu Pro Lys
100 105 110
Pro Ser Ile Ser Ser Asn Asn Ser Lys Pro Val Glu Asp Lys Asp Ala
115 120 125
Val Ala Phe Thr Cys Glu Pro Glu Thr Gln Asp Ala Thr Tyr Leu Trp
130 135 140
Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg Leu Gln Leu Ser
145 150 155 160
Asn Gly Asn Arg Thr Leu Thr Leu Phe Asn Val Thr Arg Asn Asp Thr
165 170 175
Ala Ser Tyr Lys Cys Glu Thr Gln Asn Pro Val Ser Ala Arg Arg Ser
180 185 190
Asp Ser Val Ile Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro Thr Ile
195 200 205
Ser Pro Leu Asn Thr Ser Tyr Arg Ser Gly Glu Asn Leu Asn Leu Ser
210 215 220
Cys His Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser Trp Phe Val Asn
225 230 235 240
Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn Ile Thr
245 250 255
Val Asn Asn Ser Gly Ser Tyr Thr Cys Gln Ala His Asn Ser Asp Thr
260 265 270
Gly Leu Asn Arg Thr Thr Val Thr Thr Ile Thr Val Tyr Ala His His
275 280 285
His His His His
290
<210> 66
<211> 184
<212> PRT
<213> Homo sapiens
<220>
<221> 结构域
<222> (1)..(178)
<223> hCEACAM5 A2-B2
<220>
<221> MISC_FEATURE
<222> (179)..(184)
<223> His-tag
<400> 66
Glu Pro Pro Lys Pro Phe Ile Thr Ser Asn Asn Ser Asn Pro Val Glu
1 5 10 15
Asp Glu Asp Ala Val Ala Leu Thr Cys Glu Pro Glu Ile Gln Asn Thr
20 25 30
Thr Tyr Leu Trp Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg
35 40 45
Leu Gln Leu Ser Asn Asp Asn Arg Thr Leu Thr Leu Leu Ser Val Thr
50 55 60
Arg Asn Asp Val Gly Pro Tyr Glu Cys Gly Ile Gln Asn Glu Leu Ser
65 70 75 80
Val Asp His Ser Asp Pro Val Ile Leu Asn Val Leu Tyr Gly Pro Asp
85 90 95
Asp Pro Thr Ile Ser Pro Ser Tyr Thr Tyr Tyr Arg Pro Gly Val Asn
100 105 110
Leu Ser Leu Ser Cys His Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser
115 120 125
Trp Leu Ile Asp Gly Asn Ile Gln Gln His Thr Gln Glu Leu Phe Ile
130 135 140
Ser Asn Ile Thr Glu Lys Asn Ser Gly Leu Tyr Thr Cys Gln Ala Asn
145 150 155 160
Asn Ser Ala Ser Gly His Ser Arg Thr Thr Val Lys Thr Ile Thr Val
165 170 175
Ser Ala His His His His His His
180
<210> 67
<211> 193
<212> PRT
<213> Homo sapiens
<220>
<221> 结构域
<222> (1)..(187)
<223> hCEACAM5 A3-B3
<220>
<221> MISC_FEATURE
<222> (188)..(193)
<223> His-tag
<400> 67
Glu Leu Pro Lys Pro Ser Ile Ser Ser Asn Asn Ser Lys Pro Val Glu
1 5 10 15
Asp Lys Asp Ala Val Ala Phe Thr Cys Glu Pro Glu Ala Gln Asn Thr
20 25 30
Thr Tyr Leu Trp Trp Val Asn Gly Gln Ser Leu Pro Val Ser Pro Arg
35 40 45
Leu Gln Leu Ser Asn Gly Asn Arg Thr Leu Thr Leu Phe Asn Val Thr
50 55 60
Arg Asn Asp Ala Arg Ala Tyr Val Cys Gly Ile Gln Asn Ser Val Ser
65 70 75 80
Ala Asn Arg Ser Asp Pro Val Thr Leu Asp Val Leu Tyr Gly Pro Asp
85 90 95
Thr Pro Ile Ile Ser Pro Pro Asp Ser Ser Tyr Leu Ser Gly Ala Asn
100 105 110
Leu Asn Leu Ser Cys His Ser Ala Ser Asn Pro Ser Pro Gln Tyr Ser
115 120 125
Trp Arg Ile Asn Gly Ile Pro Gln Gln His Thr Gln Val Leu Phe Ile
130 135 140
Ala Lys Ile Thr Pro Asn Asn Asn Gly Thr Tyr Ala Cys Phe Val Ser
145 150 155 160
Asn Leu Ala Thr Gly Arg Asn Asn Ser Ile Val Lys Ser Ile Thr Val
165 170 175
Ser Ala Ser Gly Thr Ser Pro Gly Leu Ser Ala His His His His His
180 185 190
His
<210> 68
<211> 310
<212> PRT
<213> Macaca fascicularis
<220>
<221> 结构域
<222> (1)..(286)
<223> 食蟹猴CEACAM5的结构域N-A1-B1
<220>
<221> MISC_FEATURE
<222> (287)..(310)
<223> 用 His-tag延伸
<400> 68
Gln Leu Thr Ile Glu Ser Arg Pro Phe Asn Val Ala Glu Gly Lys Glu
1 5 10 15
Val Leu Leu Leu Ala His Asn Val Ser Gln Asn Leu Phe Gly Tyr Ile
20 25 30
Trp Tyr Lys Gly Glu Arg Val Asp Ala Ser Arg Arg Ile Gly Ser Cys
35 40 45
Val Ile Arg Thr Gln Gln Ile Thr Pro Gly Pro Ala His Ser Gly Arg
50 55 60
Glu Thr Ile Asp Phe Asn Ala Ser Leu Leu Ile Gln Asn Val Thr Gln
65 70 75 80
Ser Asp Thr Gly Ser Tyr Thr Ile Gln Val Ile Lys Glu Asp Leu Val
85 90 95
Asn Glu Glu Ala Thr Gly Gln Phe Arg Val Tyr Pro Glu Leu Pro Lys
100 105 110
Pro Tyr Ile Thr Ser Asn Asn Ser Asn Pro Ile Glu Asp Lys Asp Ala
115 120 125
Val Ala Leu Thr Cys Glu Pro Glu Thr Gln Asp Thr Thr Tyr Leu Trp
130 135 140
Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg Leu Glu Leu Ser
145 150 155 160
Ser Asp Asn Arg Thr Leu Thr Val Phe Asn Ile Pro Arg Asn Asp Thr
165 170 175
Thr Ser Tyr Lys Cys Glu Thr Gln Asn Pro Val Ser Val Arg Arg Ser
180 185 190
Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro Thr Ile
195 200 205
Ser Pro Leu Asn Thr Pro Tyr Arg Ala Gly Glu Tyr Leu Asn Leu Thr
210 215 220
Cys His Ala Ala Ser Asn Pro Thr Ala Gln Tyr Phe Trp Phe Val Asn
225 230 235 240
Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn Ile Thr
245 250 255
Val Asn Asn Ser Gly Ser Tyr Met Cys Gln Ala His Asn Ser Ala Thr
260 265 270
Gly Leu Asn Arg Thr Thr Val Thr Ala Ile Thr Val Tyr Ala Ser Gly
275 280 285
Ser Gly Ser Gly Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp
290 295 300
His His His His His His
305 310
<210> 69
<211> 202
<212> PRT
<213> Macaca fascicularis
<220>
<221> 结构域
<222> (1)..(178)
<223> 食蟹猴CEACAM5的结构域 A2-B2
<220>
<221> MISC_FEATURE
<222> (179)..(202)
<223> 用 His-tag延伸
<400> 69
Glu Leu Pro Lys Pro Tyr Ile Thr Ser Asn Asn Ser Asn Pro Ile Glu
1 5 10 15
Asp Lys Asp Ala Val Thr Leu Thr Cys Glu Pro Glu Thr Gln Asp Thr
20 25 30
Thr Tyr Leu Trp Trp Val Asn Asn Gln Arg Leu Ser Val Ser Ser Arg
35 40 45
Leu Glu Leu Ser Asn Asp Asn Arg Thr Leu Thr Val Phe Asn Ile Pro
50 55 60
Arg Asn Asp Thr Thr Phe Tyr Glu Cys Glu Thr Gln Asn Pro Val Ser
65 70 75 80
Val Arg Arg Ser Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp
85 90 95
Ala Pro Thr Ile Ser Pro Leu Asn Thr Pro Tyr Arg Ala Gly Glu Asn
100 105 110
Leu Asn Leu Ser Cys His Ala Ala Ser Asn Pro Ala Ala Gln Tyr Phe
115 120 125
Trp Phe Val Asn Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile
130 135 140
Pro Asn Ile Thr Val Asn Asn Ser Gly Ser Tyr Met Cys Gln Ala His
145 150 155 160
Asn Ser Ala Thr Gly Leu Asn Arg Thr Thr Val Thr Ala Ile Thr Val
165 170 175
Tyr Val Ser Gly Ser Gly Ser Gly Leu Asn Asp Ile Phe Glu Ala Gln
180 185 190
Lys Ile Glu Trp His His His His His His
195 200
<210> 70
<211> 214
<212> PRT
<213> Macaca fascicularis
<220>
<221> 结构域
<222> (1)..(190)
<223> 食蟹猴CEACAM5的结构域 A3-B3
<220>
<221> MISC_FEATURE
<222> (191)..(214)
<223> 用 His-tag延伸
<400> 70
Glu Leu Pro Lys Pro Tyr Ile Ser Ser Asn Asn Ser Asn Pro Ile Glu
1 5 10 15
Asp Lys Asp Ala Val Thr Leu Thr Cys Glu Pro Val Ala Glu Asn Thr
20 25 30
Thr Tyr Leu Trp Trp Val Asn Asn Gln Ser Leu Ser Val Ser Pro Arg
35 40 45
Leu Gln Leu Ser Asn Gly Asn Arg Ile Leu Thr Leu Leu Ser Val Thr
50 55 60
Arg Asn Asp Thr Gly Pro Tyr Glu Cys Gly Ile Gln Asn Ser Glu Ser
65 70 75 80
Ala Lys Arg Ser Asp Pro Val Thr Leu Asn Val Thr Tyr Gly Pro Asp
85 90 95
Thr Pro Ile Ile Ser Pro Pro Asp Leu Ser Tyr Arg Ser Gly Ala Asn
100 105 110
Leu Asn Leu Ser Cys His Ser Asp Ser Asn Pro Ser Pro Gln Tyr Ser
115 120 125
Trp Leu Ile Asn Gly Thr Leu Arg Gln His Thr Gln Val Leu Phe Ile
130 135 140
Ser Lys Ile Thr Ser Asn Asn Asn Gly Ala Tyr Ala Cys Phe Val Ser
145 150 155 160
Asn Leu Ala Thr Gly Arg Asn Asn Ser Ile Val Lys Asn Ile Ser Val
165 170 175
Ser Ser Gly Asp Ser Ala Pro Gly Ser Ser Gly Leu Ser Ala Ser Gly
180 185 190
Ser Gly Ser Gly Leu Asn Asp Ile Phe Glu Ala Gln Lys Ile Glu Trp
195 200 205
His His His His His His
210
<210> 71
<211> 344
<212> PRT
<213> Homo sapiens
<400> 71
Met Gly Pro Pro Ser Ala Pro Pro Cys Arg Leu His Val Pro Trp Lys
1 5 10 15
Glu Val Leu Leu Thr Ala Ser Leu Leu Thr Phe Trp Asn Pro Pro Thr
20 25 30
Thr Ala Lys Leu Thr Ile Glu Ser Thr Pro Phe Asn Val Ala Glu Gly
35 40 45
Lys Glu Val Leu Leu Leu Ala His Asn Leu Pro Gln Asn Arg Ile Gly
50 55 60
Tyr Ser Trp Tyr Lys Gly Glu Arg Val Asp Gly Asn Ser Leu Ile Val
65 70 75 80
Gly Tyr Val Ile Gly Thr Gln Gln Ala Thr Pro Gly Pro Ala Tyr Ser
85 90 95
Gly Arg Glu Thr Ile Tyr Pro Asn Ala Ser Leu Leu Ile Gln Asn Val
100 105 110
Thr Gln Asn Asp Thr Gly Phe Tyr Thr Leu Gln Val Ile Lys Ser Asp
115 120 125
Leu Val Asn Glu Glu Ala Thr Gly Gln Phe His Val Tyr Pro Glu Leu
130 135 140
Pro Lys Pro Ser Ile Ser Ser Asn Asn Ser Asn Pro Val Glu Asp Lys
145 150 155 160
Asp Ala Val Ala Phe Thr Cys Glu Pro Glu Val Gln Asn Thr Thr Tyr
165 170 175
Leu Trp Trp Val Asn Gly Gln Ser Leu Pro Val Ser Pro Arg Leu Gln
180 185 190
Leu Ser Asn Gly Asn Met Thr Leu Thr Leu Leu Ser Val Lys Arg Asn
195 200 205
Asp Ala Gly Ser Tyr Glu Cys Glu Ile Gln Asn Pro Ala Ser Ala Asn
210 215 220
Arg Ser Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp Gly Pro
225 230 235 240
Thr Ile Ser Pro Ser Lys Ala Asn Tyr Arg Pro Gly Glu Asn Leu Asn
245 250 255
Leu Ser Cys His Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser Trp Phe
260 265 270
Ile Asn Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn
275 280 285
Ile Thr Val Asn Asn Ser Gly Ser Tyr Met Cys Gln Ala His Asn Ser
290 295 300
Ala Thr Gly Leu Asn Arg Thr Thr Val Thr Met Ile Thr Val Ser Gly
305 310 315 320
Ser Ala Pro Val Leu Ser Ala Val Ala Thr Val Gly Ile Thr Ile Gly
325 330 335
Val Leu Ala Arg Val Ala Leu Ile
340
<210> 72
<211> 265
<212> PRT
<213> Homo sapiens
<400> 72
Met Gly Ser Pro Ser Ala Cys Pro Tyr Arg Val Cys Ile Pro Trp Gln
1 5 10 15
Gly Leu Leu Leu Thr Ala Ser Leu Leu Thr Phe Trp Asn Leu Pro Asn
20 25 30
Ser Ala Gln Thr Asn Ile Asp Val Val Pro Phe Asn Val Ala Glu Gly
35 40 45
Lys Glu Val Leu Leu Val Val His Asn Glu Ser Gln Asn Leu Tyr Gly
50 55 60
Tyr Asn Trp Tyr Lys Gly Glu Arg Val His Ala Asn Tyr Arg Ile Ile
65 70 75 80
Gly Tyr Val Lys Asn Ile Ser Gln Glu Asn Ala Pro Gly Pro Ala His
85 90 95
Asn Gly Arg Glu Thr Ile Tyr Pro Asn Gly Thr Leu Leu Ile Gln Asn
100 105 110
Val Thr His Asn Asp Ala Gly Phe Tyr Thr Leu His Val Ile Lys Glu
115 120 125
Asn Leu Val Asn Glu Glu Val Thr Arg Gln Phe Tyr Val Phe Ser Glu
130 135 140
Pro Pro Lys Pro Ser Ile Thr Ser Asn Asn Phe Asn Pro Val Glu Asn
145 150 155 160
Lys Asp Ile Val Val Leu Thr Cys Gln Pro Glu Thr Gln Asn Thr Thr
165 170 175
Tyr Leu Trp Trp Val Asn Asn Gln Ser Leu Leu Val Ser Pro Arg Leu
180 185 190
Leu Leu Ser Thr Asp Asn Arg Thr Leu Val Leu Leu Ser Ala Thr Lys
195 200 205
Asn Asp Ile Gly Pro Tyr Glu Cys Glu Ile Gln Asn Pro Val Gly Ala
210 215 220
Ser Arg Ser Asp Pro Val Thr Leu Asn Val Arg Tyr Glu Ser Val Gln
225 230 235 240
Ala Ser Ser Pro Asp Leu Ser Ala Gly Thr Ala Val Ser Ile Met Ile
245 250 255
Gly Val Leu Ala Gly Met Ala Leu Ile
260 265
<210> 73
<211> 349
<212> PRT
<213> Homo sapiens
<400> 73
Met Gly Pro Ile Ser Ala Pro Ser Cys Arg Trp Arg Ile Pro Trp Gln
1 5 10 15
Gly Leu Leu Leu Thr Ala Ser Leu Phe Thr Phe Trp Asn Pro Pro Thr
20 25 30
Thr Ala Gln Leu Thr Ile Glu Ala Val Pro Ser Asn Ala Ala Glu Gly
35 40 45
Lys Glu Val Leu Leu Leu Val His Asn Leu Pro Gln Asp Pro Arg Gly
50 55 60
Tyr Asn Trp Tyr Lys Gly Glu Thr Val Asp Ala Asn Arg Arg Ile Ile
65 70 75 80
Gly Tyr Val Ile Ser Asn Gln Gln Ile Thr Pro Gly Pro Ala Tyr Ser
85 90 95
Asn Arg Glu Thr Ile Tyr Pro Asn Ala Ser Leu Leu Met Arg Asn Val
100 105 110
Thr Arg Asn Asp Thr Gly Ser Tyr Thr Leu Gln Val Ile Lys Leu Asn
115 120 125
Leu Met Ser Glu Glu Val Thr Gly Gln Phe Ser Val His Pro Glu Thr
130 135 140
Pro Lys Pro Ser Ile Ser Ser Asn Asn Ser Asn Pro Val Glu Asp Lys
145 150 155 160
Asp Ala Val Ala Phe Thr Cys Glu Pro Glu Thr Gln Asn Thr Thr Tyr
165 170 175
Leu Trp Trp Val Asn Gly Gln Ser Leu Pro Val Ser Pro Arg Leu Gln
180 185 190
Leu Ser Asn Gly Asn Arg Thr Leu Thr Leu Leu Ser Val Thr Arg Asn
195 200 205
Asp Val Gly Pro Tyr Glu Cys Glu Ile Gln Asn Pro Ala Ser Ala Asn
210 215 220
Phe Ser Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro
225 230 235 240
Thr Ile Ser Pro Ser Asp Thr Tyr Tyr His Ala Gly Val Asn Leu Asn
245 250 255
Leu Ser Cys His Ala Ala Ser Asn Pro Pro Ser Gln Tyr Ser Trp Ser
260 265 270
Val Asn Gly Thr Phe Gln Gln Tyr Thr Gln Lys Leu Phe Ile Pro Asn
275 280 285
Ile Thr Thr Lys Asn Ser Gly Ser Tyr Ala Cys His Thr Thr Asn Ser
290 295 300
Ala Thr Gly Arg Asn Arg Thr Thr Val Arg Met Ile Thr Val Ser Asp
305 310 315 320
Ala Leu Val Gln Gly Ser Ser Pro Gly Leu Ser Ala Arg Ala Thr Val
325 330 335
Ser Ile Met Ile Gly Val Leu Ala Arg Val Ala Leu Ile
340 345
<210> 74
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> MAb2_VHg2
<400> 74
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Gly Gly Gly Ile Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 75
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> MAb2_VLg5
<400> 75
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 Glu Asn Ile Phe Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asn Thr Arg Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 76
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人CEACAM5-A3B3位置109-115的残基
<400> 76
Ser Gly Ala Asn Leu Asn Leu
1 5
<210> 77
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人 CEACAM5-A3B3位置131-143的残基
<400> 77
Ile Asn Gly Ile Pro Gln Gln His Thr Gln Val Leu Phe
1 5 10
<210> 78
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDR
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa 是 T、A或V
<400> 78
Gly Phe Xaa Phe Ser Ser Tyr Asp
1 5
<210> 79
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDR
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa是S或N (尤其是S)
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa是Y或G (尤其是 G)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa是R或I(尤其是I)
<400> 79
Ile Xaa Ser Xaa Gly Gly Xaa Thr
1 5
<210> 80
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CDR
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa是A或T (尤其是 A)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa是T或S(尤其是S)
<400> 80
Xaa Ala His Tyr Phe Gly Xaa Ser Gly Pro Phe Ala Tyr
1 5 10
<210> 81
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDR
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa是R或S, 尤其是S
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa是A或D
<400> 81
Gly Phe Thr Phe Ser Xaa Tyr Xaa
1 5
<210> 82
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDR
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa是不存在、S或G (尤其是G)
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa是D、Y或I
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa是T或I (尤其是T)
<400> 82
Ile Ser Ser Gly Gly Xaa Xaa Xaa
1 5
<210> 83
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> CDR
<220>
<221> MISC_FEATURE
<222> (1)..(6)
<223> Xaa 是任何氨基酸
<400> 83
Xaa Xaa Xaa Xaa Xaa Xaa Tyr Asp
1 5
<210> 84
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> CDR
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa是任何氨基酸
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa 是A或S
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa是Y、F或W
<220>
<221> MISC_FEATURE
<222> (7)..(8)
<223> Xaa是任何氨基酸
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa是任何氨基酸
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa是任何氨基酸
<400> 84
Xaa Xaa His Xaa Phe Gly Xaa Xaa Gly Pro Xaa Ala Xaa
1 5 10
<210> 85
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> CDR
<220>
<221> MISC_FEATURE
<222> (1)..(3)
<223> Xaa是任何氨基酸
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa是Y、F或W
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa is any amino acid
<400> 85
Xaa Xaa Xaa Xaa Xaa Tyr
1 5
<210> 86
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDR
<220>
<221> MISC_FEATURE
<222> (1)..(2)
<223> Xaa是任何氨基酸
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa是Y、F或W
<220>
<221> MISC_FEATURE
<222> (5)..(6)
<223> Xaa是任何氨基酸
<220>
<221> MISC_FEATURE
<222> (8)..(9)
<223> Xaa是任何氨基酸
<400> 86
Xaa Xaa His Xaa Xaa Xaa Pro Xaa Xaa
1 5
<210> 87
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> huMAb2-3的重链序列
<400> 87
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Thr Pro Glu Arg Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Gly Gly Ile Thr Tyr Ala Pro Ser Thr Val
50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 88
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> huMAb2-3的轻链序列
<400> 88
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Phe Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Val
35 40 45
Tyr Asn Thr Arg Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe
85 90 95
Thr Phe Gly Ser 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> 89
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> MAb2重链VH1-IgG1
<400> 89
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Thr Pro Glu Arg Arg Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Gly Gly Ile Thr Tyr Phe Pro Ser Thr Val
50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Thr Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 90
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> MAb2轻链VL1d
<400> 90
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Phe Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Val
35 40 45
Tyr Asn Thr Arg Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe
85 90 95
Thr Phe Gly Ser 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
Claims (8)
1.一种包含抗体或其片段的免疫偶联物,其中所述抗体或其片段包含:
序列SEQ ID NO:5的重链,其中CDR1-H为序列SEQ ID NO:7,CDR2-H为序列SEQ ID NO:8,且CDR3-H为序列SEQ ID NO:9;和
序列SEQ ID NO:29的轻链,其中CDR1-L为序列SEQ ID NO:10,CDR2-L为序列NTK或NTR,且CDR3-L为SEQ ID NO:12的序列,
其中所述抗体通过N-琥珀酰亚胺吡啶基二硫代丁酸酯(SPDB)共价连接到N2’-脱乙酰基-N2’-(4-甲基-4-巯基-1-氧代戊基)-美登素(DM4)。
2.根据权利要求1所述的免疫偶联物,其中所述抗体或其片段包含
a)由序列SEQ ID NO:87组成的重链;和
b)由序列SEQ ID NO:88组成的轻链。
3.根据权利要求1或2所述的免疫偶联物,其中所述抗体为双特异性或多特异性抗体。
4.根据权利要求1-3中任一项所述的免疫偶联物,其中所述抗体片段为选自下组的片段:Fv、Fab、F(ab')2、Fab'、dsFv、(dsFv)2、scFv、sc(Fv)2和双抗体(diabodies)。
5.一种药物组合物,其包含根据权利要求1-4中任一项所述的免疫偶联物,和药学上可接受的载剂。
6.根据权利要求1-4中任一项所述的免疫偶联物在制备用于治疗癌症的药物组合物中的用途。
7.根据权利要求6所述的用途,其中所述癌症为结肠直肠癌、胃癌、肺癌、子宫颈癌、胰癌、食道癌、卵巢癌、甲状腺癌、膀胱癌、子宫内膜癌、乳腺癌、肝癌、前列腺癌或皮肤癌。
8.根据权利要求7所述的用途,其中所述癌症为胰腺癌、乳腺癌、肺癌或胃癌。
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