CN106413752A - 结合cd147的抗体疗法 - Google Patents
结合cd147的抗体疗法 Download PDFInfo
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- CN106413752A CN106413752A CN201580030250.2A CN201580030250A CN106413752A CN 106413752 A CN106413752 A CN 106413752A CN 201580030250 A CN201580030250 A CN 201580030250A CN 106413752 A CN106413752 A CN 106413752A
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Abstract
本文公开了与抗‑CD147抗体相关或源自抗‑CD147抗体的组合物和方法。更具体地,本文公开了结合CD147的全人抗体、这类抗体的CD147‑结合片段和衍生物及包含这类片段的CD147‑结合多肽。再进一步地,本文公开了编码这类抗体、抗体片段和衍生物及多肽的核酸,包含这类多核苷酸的细胞,制备这类抗体、抗体片段和衍生物及多肽的方法,和使用这类抗体、抗体片段和衍生物及多肽的方法,包括治疗或诊断患有CD147相关障碍或病症的受试者的方法。本文还公开了用于治疗CD147‑表达肿瘤(包括肝细胞癌和和鳞状细胞癌)及选自类风湿性关节炎、实验性肺损伤、动脉粥样硬化、丙型肝炎病毒引起的慢性肝病、缺血性心肌损伤和心力衰竭的非肿瘤疾病的方法。
Description
技术领域
本公开提供了与抗-CD147抗体相关或源自抗-CD147抗体的组合物和方法。更具体地,本公开提供了结合CD147的全人抗体、这类抗体的CD147-结合片段和衍生物及包含这类片段的CD147-结合多肽。再进一步地,本公开提供了编码这类抗体、抗体片段和衍生物及多肽的核酸,包含这类多核苷酸的细胞,制备这类抗体、抗体片段和衍生物及多肽的方法,及使用这类抗体、抗体片段和衍生物及多肽的方法,包括治疗或诊断患有CD147相关障碍或病症的受试者的方法。本公开还提供了用于治疗CD147-表达肿瘤,(包括肝细胞癌和和鳞状细胞癌)及选自类风湿性关节炎、实验性肺损伤、动脉粥样硬化、丙型肝炎病毒引起的慢性肝病、缺血性心肌损伤和心力衰竭的非肿瘤疾病的方法。
背景技术
CD147涉及许多生理功能,如淋巴细胞反应性、精子发生、移植、受精和发育早期的神经功能。CD147是受体的免疫球蛋白家族的成员。这一家族的成员在涉及许多免疫相关功能、分化和发育的细胞间通讯中发挥作用。CD147在精子发生、淋巴细胞激活、单羧酸转运蛋白(MCT)的表达中发挥作用且已经鉴别为阿尔兹海默病淀粉样β-肽产生中的γ-分泌酶复合物的调控亚基(Gabison和Mourah Connect Tissue Res.49:175-179,2008;Inacono等,Exp.Mol.Pathol.83:283-295,2007;Nabeshima等,Pathol.Int.56:359-367,2006;Gabison等,Biochimie 87:361-368,2005和Muramatsu等,Histol.Histopathol.18:981-987,2003)。
这些见解中的一些从cd147-/-小鼠的研究获得。这些动物在基质金属蛋白酶(MMP)调节、精子发生、淋巴细胞反应性和发育早期的神经功能中是缺陷的。这样的雌性小鼠由于移植和受精的失败而是不育的(Muramatsu等,Histol.Histopathol.18:981-987,2003)。CD147参与MCT-1和MCT-3至质膜的转运,因为这些转运蛋白累积的降低已经在cd147敲除小鼠的视网膜中观察到。CD147在细胞粘附中的功能作用通过其参与血脑屏障及其与整合素的相互作用支持。
CD147牵涉到许多病理过程,如类风湿性关节炎、实验性肺损伤、动脉粥样硬化、丙型肝炎病毒诱导的慢性肝病、缺血性心肌损伤和心力衰竭(Gabison等Biochimie 87:361-368,2005)。移植患者用CD147抗体的治疗由于T-细胞活化的抑制而是有效的(Deeg等,Blood 98:2052-2058,2001)。
CD147,一种免疫球蛋白(Ig)超家族的跨膜蛋白在不同物种中独立地鉴别并在不同物种之间具有许多命名,如M6、Neurothelin、5A11、HT7、OX-47、CE9、EMMPRIN、Basigin和gp42(Kasinrerk等J.Immunol.149:847-854,1992;Altruda等Gene 85:445-451,1989;Miyauchi等,J.Biochem.107:316-323,1990;Seulberger等EMBO J.9:2151-2158,1990和Fossum等,Eur.J.Immunol.21:671-679,1991)。最常见的标准异形体是由21氨基酸的信号序列、186残基长的细胞外结构域(由两个Ig样结构域组成)、21氨基酸的跨膜结构域和41残基的胞质结构域构成的单链I型跨膜分子。
跨膜区带有亮氨酸拉链和带电残基(谷氨酸)。对应基因位于染色体19p13.3上并编码29kDa骨架蛋白。已经鉴别了三个N糖基化位点,且在十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)上的迁移根据糖基化程度在39和65kDa之间发生。
CD147在造血和非造血细胞如单核细胞、粒细胞、上皮细胞和内皮细胞上具有宽表达谱。弱表达在静息T淋巴细胞上注意到,而表达在激活的T淋巴细胞和单核细胞上增加(Kasinrerk等J.Immunol.149:847-854,1992;Altruda等Gene 85:445-451,1989;Miyauchi等J.Biochem.107:316-323,1990;Seulberger等EMBO J.9:2151-2158,1990;Fossum等,Eur.J.Immunol.21:671-679,1991和Ochrietor等Invest.Ophthalmol.Vis.Sci.44:4086-4096,2003)。跨膜序列的氨基酸序列如上所述在所有列出的物种之间的完美保守性(Iacono等Exp.Mol.Pathol.83:283-295,2007)是显著的特征,其包括保守的谷氨酸残基的存在。这一发现表明跨膜氨基酸参与质膜内的蛋白质-蛋白质相互作用。胞质结构域比细胞外结构域更保守,指出了关于与位于胞质中的蛋白质的保守蛋白质-蛋白质相互作用的类似考虑。CD147表达通过RNAi的抑制导致体外显著降低的血管生成。CD147可以通过几种机制(包括增殖、存活、MMP分泌和磷酸肌醇3激酶/蛋白激酶B(PBK/Akt)激活)调节血管生成。
在几种癌细胞系中,CD147鉴别为抗凋亡功能和化疗抗性的介质。在HO-8910卵巢癌细胞中,CD147RNAi减少肿瘤细胞侵入、致肿瘤性和对紫杉醇的化疗敏感性(Zou等CancerLett.248:211-218,2007)。CD147的上调在几种多药抗性癌细胞系中观察到(Toole等DrugResist.Update 11:110-121,2008)。
独立地,报告了CD147参与癌细胞对多种化疗剂的抗性(Li等Cell.Mol.LifeSci.66:504-515,2009)。另外,CD147鉴别为以透明质酸依赖性的方式促进肿瘤细胞的非雄激素依赖性生长的受体(Marieb等Cancer Res.64:1229-1232,2004)。在人口腔鳞状细胞癌细胞(SCC)中,CD147-指导的RNAi减少X-染色体连锁凋亡蛋白抑制剂(XIAP)表达和提高对5-氟尿嘧啶的化疗敏感性(Kuang等Cancer Lett.276:189-195,2009)。在乳腺癌细胞素中,其显示CD147赋予对失巢凋亡(anoikis)的抗性,如通过半胱天冬酶的激活证明的。
针对与不同表位的CD147相互作用的许多mAb已经建立(Koch等Int.Immunol.11:777-786,1999)。大多数抗体仅结合植物凝集素(PHA)刺激的T-细胞,不结合静息T-细胞。这一现象通过低亲和力抗体对激活的T-细胞上的簇集CD147分子的二价结合而不是通过在激活的T-细胞上特别展示的新表位(neoepitopes)来解释。高亲和力抗体能够在单价方式结合静息T-细胞,其是CD147的低表达者。
通过低亲和力抗体的二聚化诱导导致CD3-介导的T-细胞激活的抑制。高亲和力mAb MEM-M6/6(识别独特表位)抑制T细胞激活80%,且如前节中概述的,也抑制结肠癌和黑素瘤细胞而不是非转化的成纤维细胞的增殖(Baba等Biochem.Biophys.Res.Commun.374:111-116,2008)。CD147通过mAb的触发显示为引起来自人T-淋巴细胞中的微结构域的糖基磷脂酰肌醇(GPI)-锚定的共受体CD48和CD59的移位(Staffler等J.Immunol.171:1707-1714,2003)。微结构域的扰动造成T-细胞增殖的抑制。利用COS-7转染体和覆盖不同CD147表位的mAb,证明CD147包含参与细胞粘附(同型细胞聚集)和淋巴细胞激活的调节的不同表位(Chiampanichayakul等Immunobiology 211:167-78,2006)。
针对肝细胞癌(HCC)的治疗评估不同组的针对CD147的mAb(Xu等Mol.CancerRes.5:605-614,2007)。mAb Hb18G和Licartin(一种131I-标记的mAb Hb18G的F(ab')2片段)介导培养的成纤维细胞中MMP分泌的抑制并抑制侵入,且Licartin显著抑制HCC细胞的生长。mAb Hb18G和Licartin有效地降低生长和转移以及基质因子如MMP、VEGF和成纤维表面蛋白的表达(Xu等Mol.Cancer Res.5:605-614,2007)。临床研究报告了用Licartin对HCC患者的靶向放射免疫治疗(Xu等Hepatology 45:269-276,2007)。在II期临床试验中完成两个周期的73名患者中,6名(8%)注意到具有部分反应,14名(19%)具有轻微反应和43名(59%)具有稳定的疾病。患者无进展存活率显著高于具有进展疾病的患者。称为CNTO 3899的嵌合CD147抗体(IgG1)作为用于头颈鳞状细胞癌的潜在治疗的药剂进行评估(Dean等Clin.Cancer Res.15:4058-4065,2009)。该抗体抑制SSC-1和FaDu细胞的增殖高达57%。也注意到胶原蛋白降解的抑制。显著的肿瘤生长抑制在SSC-1异种移植物中注意到。CNTO3899在体外和在异种移植物中增强SSC-1和FaDu细胞的放射反应。此外,相同的研究证明CD147功能与促炎性和促血管生成因子如IL1β、IL6、IL8和VEGF的细胞因子产生相关。细胞因子,MMP和VEGF,的抑制看起来介导这一mAb的作用机制。所概述的研究表明,CD147mAb在不存在免疫效应细胞的情况下对肿瘤细胞增殖的抑制是细胞类型特异性的和/或可能依赖于mAb针对的不同表位。T-细胞激活和/或耗竭的抑制未用CNTO 3899、Hb18G或Licartin进行研究。
发明内容
本公开提供了以至少10-6M的结合亲和力结合CD147表位的IgG类的全人抗体,其具有与选自以下的氨基酸序列至少95%同一的重链可变域序列:SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ ID NO.11、SEQ ID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ ID NO.23、SEQ ID NO.26、SEQ IDNO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ ID NO.38、SEQ ID NO.41、SEQ IDNO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ ID NO.53、SEQ ID NO.56、SEQ IDNO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ ID NO.8、SEQ ID NO.10、SEQ IDNO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ ID NO.20、SEQ ID NO.22、SEQ IDNO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ ID NO.31、SEQ ID NO.32、SEQ IDNO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ ID NO.40、SEQ ID NO.42、SEQ IDNO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ ID NO.51、SEQ ID NO.52、SEQ IDNO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ ID NO.60、SEQ ID NO.61、SEQ IDNO.63及其组合。优选地,全人抗体具有重链和轻链两者,其中该抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2(本文中称为C4R1A2)、SEQ ID NO.3/SEQ IDNO.4(本文中称为C4R1A5)、SEQ ID NO.5/SEQ ID NO.6(本文中称为C4R1A6)、SEQ ID NO.7/SEQ ID NO.8(本文中称为C4R1A8)、SEQ ID NO.9/SEQ ID NO.10(本文中称为C4R1A9)、SEQID NO.11/SEQ ID NO.12(本文中称为C4R1B2)、SEQ ID NO.13/SEQ ID NO.14(本文中称为C4R1C10)、SEQ ID NO.15/SEQ ID NO.16(本文中称为C4R1C11)、SEQ ID NO.17/SEQ IDNO.18(本文中称为C4R1C3)、SEQ ID NO.19/SEQ ID NO.20(本文中称为C4R1D11)、SEQ IDNO.21/SEQ ID NO.22(本文中称为C4R1F12)、SEQ ID NO.13/SEQ ID NO.25(本文中称为C4R1G1)、SEQ ID NO.26/SEQ ID NO.27(本文中称为C4R1G4)、SEQ ID NO.28/SEQ ID NO.29(本文中称为C4R1G7)、SEQ ID NO.30/SEQ ID NO.31(本文中称为C4R1H10)、SEQ ID NO.13/SEQ ID NO.32(本文中称为C4R1H11)、SEQ ID NO.13/SEQ ID NO.33(本文中称为C4R1H4)、SEQ ID NO.34/SEQ ID NO.35(本文中称为C4sh1Al)、SEQ ID NO.36/SEQ ID NO.37(本文中称为C4sh1A2)、SEQ ID NO.38/SEQ ID NO.39(本文中称为C4sh1A3)、SEQ ID NO.38/SEQ IDNO.40(本文中称为C4sh1A4)、SEQ ID NO.41/SEQ ID NO.42(本文中称为C4sh1A5)、SEQ IDNO.43/SEQ ID NO.44(本文中称为C4sh1A6)、SEQ ID NO.38/SEQ ID NO.45(本文中称为C4sh1A9)、SEQ ID NO.46/SEQ ID NO.47(本文中称为C4sh1B10)、SEQ ID NO.48/SEQ IDNO.49(本文中称为C4sh1Bl1)、SEQ ID NO.50/SEQ ID NO.51(本文中称为C4sh1B2)、SEQ IDNO.38/SEQ ID NO.52(本文中称为C4sh1C10)、SEQ ID NO.53/SEQ ID NO.54(本文中称为C4sh1C5)、SEQ ID NO.41/SEQ ID NO.54(本文中称为C4sh1C6)、SEQ ID NO.56/SEQ IDNO.57(C4sh1E10)、SEQ ID NO.38/SEQ ID NO.58(本文中称为C4sh1E12)、SEQ ID NO.59/SEQ ID NO.60(本文中称为C4sh1Fl l)、SEQ ID NO.38/SEQ ID NO.61(本文中称为C4sh1G4)、SEQ ID NO.62/SEQ ID NO.63(本文中称为C4sh1H9)及其组合。
本公开提供了Fab全人抗体片段,其具有来自重链的可变域区域和来自轻链的可变域区域,其中重链可变域序列与选自以下的氨基酸序列至少95%同一:SEQ ID NO.1、SEQID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ ID NO.11、SEQ ID NO.13、SEQ IDNO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ ID NO.23、SEQ ID NO.26、SEQ IDNO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ ID NO.38、SEQ ID NO.41、SEQ IDNO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ ID NO.53、SEQ ID NO.56、SEQ IDNO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ ID NO.8、SEQ ID NO.10、SEQ IDNO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ ID NO.20、SEQ ID NO.22、SEQ IDNO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ ID NO.31、SEQ ID NO.32、SEQ IDNO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ ID NO.40、SEQ ID NO.42、SEQ IDNO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ ID NO.51、SEQ ID NO.52、SEQ IDNO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ ID NO.60、SEQ ID NO.61、SEQ IDNO.63及其组合。优选地,全人抗体Fab片段具有重链可变域区域和轻链可变域区域两者,其中该抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2、SEQ IDNO.3/SEQ ID NO.4、SEQ ID NO.5/SEQ ID NO.6、SEQ ID NO.7/SEQ ID NO.8、SEQ ID NO.9/SEQ ID NO.10、SEQ ID NO.11/SEQ ID NO.12、SEQ ID NO.13/SEQ ID NO.14、SEQ IDNO.15/SEQ ID NO.16、SEQ ID NO.17/SEQ ID NO.18、SEQ ID NO.19/SEQ ID NO.20、SEQ IDNO.21/SEQ ID NO.22、SEQ ID NO.13/SEQ ID NO.25、SEQ ID NO.26/SEQ ID NO.27、SEQ IDNO.28/SEQ ID NO.29、SEQ ID NO.30/SEQ ID NO.31、SEQ ID NO.13/SEQ ID NO.32、SEQ IDNO.13/SEQ ID NO.33、SEQ ID NO.34/SEQ ID NO.35、SEQ ID NO.36/SEQ ID NO.37、SEQ IDNO.38/SEQ ID NO.39、SEQ ID NO.38/SEQ ID NO.40、SEQ ID NO.41/SEQ ID NO.42、SEQ IDNO.43/SEQ ID NO.44、SEQ ID NO.38/SEQ ID NO.45、SEQ ID NO.46/SEQ ID NO.47、SEQ IDNO.48/SEQ ID NO.49、SEQ ID NO.50/SEQ ID NO.51、SEQ ID NO.38/SEQ ID NO.52、SEQ IDNO.53/SEQ ID NO.54、SEQ ID NO.41/SEQ ID NO.54、SEQ ID NO.56/SEQ ID NO.57、SEQ IDNO.38/SEQ ID NO.58、SEQ ID NO.59/SEQ ID NO.60、SEQ ID NO.38/SEQ ID NO.61、SEQ IDNO.62/SEQ ID NO.63及其组合。
本公开提供了单链人抗体,其具有来自重链的可变域区域和来自轻链的可变域区域及连接该重链和轻链可变域区域的肽接头,其中重链可变域序列与选自以下的氨基酸序列至少95%同一:SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ ID NO.11、SEQ ID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ IDNO.21、SEQ ID NO.23、SEQ ID NO.26、SEQ ID NO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ IDNO.36、SEQ ID NO.38、SEQ ID NO.41、SEQ ID NO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ IDNO.50、SEQ ID NO.53、SEQ ID NO.56、SEQ ID NO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQID NO.6、SEQ ID NO.8、SEQ ID NO.10、SEQ ID NO.12、SEQ ID NO.14、SEQ ID NO.16、SEQID NO.18、SEQ ID NO.20、SEQ ID NO.22、SEQ ID NO.24、SEQ ID NO.25、SEQ ID NO.27、SEQID NO.29、SEQ ID NO.31、SEQ ID NO.32、SEQ ID NO.33、SEQ ID NO.35、SEQ ID NO.37、SEQID NO.39、SEQ ID NO.40、SEQ ID NO.42、SEQ ID NO.44、SEQ ID NO.45、SEQ ID NO.47、SEQID NO.49、SEQ ID NO.51、SEQ ID NO.52、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.57、SEQID NO.58、SEQ ID NO.60、SEQ ID NO.61、SEQ ID NO.63及其组合。优选地,全人单链抗体具有重链可变域区域和轻链可变域区域两者,其中单链全人抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2、SEQ ID NO.3/SEQ ID NO.4、SEQ ID NO.5/SEQ IDNO.6、SEQ ID NO.7/SEQ ID NO.8、SEQ ID NO.9/SEQ ID NO.10、SEQ ID NO.11/SEQ IDNO.12、SEQ ID NO.13/SEQ ID NO.14、SEQ ID NO.15/SEQ ID NO.16、SEQ ID NO.17/SEQ IDNO.18、SEQ ID NO.19/SEQ ID NO.20、SEQ ID NO.21/SEQ ID NO.22、SEQ ID NO.13/SEQ IDNO.25、SEQ ID NO.26/SEQ ID NO.27、SEQ ID NO.28/SEQ ID NO.29、SEQ ID NO.30/SEQ IDNO.31、SEQ ID NO.13/SEQ ID NO.32、SEQ ID NO.13/SEQ ID NO.33、SEQ ID NO.34/SEQ IDNO.35、SEQ ID NO.36/SEQ ID NO.37、SEQ ID NO.38/SEQ ID NO.39、SEQ ID NO.38/SEQ IDNO.40、SEQ ID NO.41/SEQ ID NO.42、SEQ ID NO.43/SEQ ID NO.44、SEQ ID NO.38/SEQ IDNO.45、SEQ ID NO.46/SEQ ID NO.47、SEQ ID NO.48/SEQ ID NO.49、SEQ ID NO.50/SEQ IDNO.51、SEQ ID NO.38/SEQ ID NO.52、SEQ ID NO.53/SEQ ID NO.54、SEQ ID NO.41/SEQ IDNO.54、SEQ ID NO.56/SEQ ID NO.57、SEQ ID NO.38/SEQ ID NO.58、SEQ ID NO.59/SEQ IDNO.60、SEQ ID NO.38/SEQ ID NO.61、SEQ ID NO.62/SEQ ID NO.63及其组合。
本公开进一步提供了用于治疗类风湿性关节炎、实验性肺损伤、动脉粥样硬化、由丙型肝炎病毒引起的慢性肝疾病、缺血性心肌损伤和心力衰竭的方法,该方法包括施用抗-CD147多肽,其中全人抗体具有与选自以下的氨基酸序列至少95%同一的重链可变域序列:SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ ID NO.11、SEQID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ ID NO.23、SEQID NO.26、SEQ ID NO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ ID NO.38、SEQID NO.41、SEQ ID NO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ ID NO.53、SEQID NO.56、SEQ ID NO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ ID NO.8、SEQID NO.10、SEQ ID NO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ ID NO.20、SEQID NO.22、SEQ ID NO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ ID NO.31、SEQID NO.32、SEQ ID NO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ ID NO.40、SEQID NO.42、SEQ ID NO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ ID NO.51、SEQID NO.52、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ ID NO.60、SEQID NO.61、SEQ ID NO.63及其组合;
其中Fab全人抗体片段具有与选自以下的氨基酸序列至少95%同一的重链可变域序列:SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ IDNO.11、SEQ ID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ IDNO.23、SEQ ID NO.26、SEQ ID NO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ IDNO.38、SEQ ID NO.41、SEQ ID NO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ IDNO.53、SEQ ID NO.56、SEQ ID NO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ IDNO.8、SEQ ID NO.10、SEQ ID NO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ IDNO.20、SEQ ID NO.22、SEQ ID NO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ IDNO.31、SEQ ID NO.32、SEQ ID NO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ IDNO.40、SEQ ID NO.42、SEQ ID NO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ IDNO.51、SEQ ID NO.52、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ IDNO.60、SEQ ID NO.61、SEQ ID NO.63及其组合;和
其中单链人抗体具有与选自以下的氨基酸序列至少95%同一的重链可变域序列:SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ ID NO.11、SEQID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ ID NO.23、SEQID NO.26、SEQ ID NO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ ID NO.38、SEQID NO.41、SEQ ID NO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ ID NO.53、SEQID NO.56、SEQ ID NO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ ID NO.8、SEQID NO.10、SEQ ID NO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ ID NO.20、SEQID NO.22、SEQ ID NO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ ID NO.31、SEQID NO.32、SEQ ID NO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ ID NO.40、SEQID NO.42、SEQ ID NO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ ID NO.51、SEQID NO.52、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ ID NO.60、SEQID NO.61、SEQ ID NO.63及其组合。
优选地,全人抗体具有重链和轻链两者,其中该抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2(本文中称为C4R1A2)、SEQ ID NO.3/SEQ ID NO.4(本文中称为C4R1A5)、SEQ ID NO.5/SEQ ID NO.6(本文中称为C4R1A6)、SEQ ID NO.7/SEQ IDNO.8(本文中称为C4R1A8)、SEQ ID NO.9/SEQ ID NO.10(本文中称为C4R1A9)、SEQ IDNO.11/SEQ ID NO.12(本文中称为C4R1B2)、SEQ ID NO.13/SEQ ID NO.14(本文中称为C4R1C10)、SEQ ID NO.15/SEQ ID NO.16(本文中称为C4R1C11)、SEQ ID NO.17/SEQ IDNO.18(本文中称为C4R1C3)、SEQ ID NO.19/SEQ ID NO.20(本文中称为C4R1D11)、SEQ IDNO.21/SEQ ID NO.22(本文中称为C4R1F12)、SEQ ID NO.13/SEQ ID NO.25(本文中称为C4R1G1)、SEQ ID NO.26/SEQ ID NO.27(本文中称为C4R1G4)、SEQ ID NO.28/SEQ ID NO.29(本文中称为C4R1G7)、SEQ ID NO.30/SEQ ID NO.31(本文中称为C4R1H10)、SEQ ID NO.13/SEQ ID NO.32(本文中称为C4R1H11)、SEQ ID NO.13/SEQ ID NO.33(本文中称为C4R1H4)、SEQ ID NO.34/SEQ ID NO.35(本文中称为C4sh1Al)、SEQ ID NO.36/SEQ ID NO.37(本文中称为C4sh1A2)、SEQ ID NO.38/SEQ ID NO.39(本文中称为C4sh1A3)、SEQ ID NO.38/SEQ IDNO.40(本文中称为C4sh1A4)、SEQ ID NO.41/SEQ ID NO.42(本文中称为C4sh1A5)、SEQ IDNO.43/SEQ ID NO.44(本文中称为C4sh1A6)、SEQ ID NO.38/SEQ ID NO.45(本文中称为C4sh1A9)、SEQ ID NO.46/SEQ ID NO.47(本文中称为C4sh1B10)、SEQ ID NO.48/SEQ IDNO.49(本文中称为C4sh1B11)、SEQ ID NO.50/SEQ ID NO.51(本文中称为C4sh1B2)、SEQ IDNO.38/SEQ ID NO.52(本文中称为C4sh1C10)、SEQ ID NO.53/SEQ ID NO.54(本文中称为C4sh1C5)、SEQ ID NO.41/SEQ ID NO.54(本文中称为C4sh1C6)、SEQ ID NO.56/SEQ IDNO.57(C4sh1E10)、SEQ ID NO.38/SEQ ID NO.58(本文中称为C4sh1E12)、SEQ ID NO.59/SEQ ID NO.60(本文中称为C4sh1F11)、SEQ ID NO.38/SEQ ID NO.61(本文中称为C4sh1G4)、SEQ ID NO.62/SEQ ID NO.63(本文中称为C4sh1H9)及其组合。优选地,全人抗体Fab片段具有重链可变域区域和轻链可变域区域两者,其中抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2(本文中称为C4R1A2)、SEQ ID NO.3/SEQ ID NO.4(本文中称为C4R1A5)、SEQ ID NO.5/SEQ ID NO.6(本文中称为C4R1A6)、SEQ ID NO.7/SEQID NO.8(本文中称为C4R1A8)、SEQ ID NO.9/SEQ ID NO.10(本文中称为C4R1A9)、SEQ IDNO.11/SEQ ID NO.12(本文中称为C4R1B2)、SEQ ID NO.13/SEQ ID NO.14(本文中称为C4R1C10)、SEQ ID NO.15/SEQ ID NO.16(本文中称为C4R1C11)、SEQ ID NO.17/SEQ IDNO.18(本文中称为C4R1C3)、SEQ ID NO.19/SEQ ID NO.20(本文中称为C4R1D11)、SEQ IDNO.21/SEQ ID NO.22(本文中称为C4R1F12)、SEQ ID NO.13/SEQ ID NO.25(本文中称为C4R1G1)、SEQ ID NO.26/SEQ ID NO.27(本文中称为C4R1G4)、SEQ ID NO.28/SEQ ID NO.29(本文中称为C4R1G7)、SEQ ID NO.30/SEQ ID NO.31(本文中称为C4R1H10)、SEQ ID NO.13/SEQ ID NO.32(本文中称为C4R1H11)、SEQ ID NO.13/SEQ ID NO.33(本文中称为C4R1H4)、SEQ ID NO.34/SEQ ID NO.35(本文中称为C4sh1Al)、SEQ ID NO.36/SEQ ID NO.37(本文中称为C4sh1A2)、SEQ ID NO.38/SEQ ID NO.39(本文中称为C4sh1A3)、SEQ ID NO.38/SEQ IDNO.40(本文中称为C4sh1A4)、SEQ ID NO.41/SEQ ID NO.42(本文中称为C4sh1A5)、SEQ IDNO.43/SEQ ID NO.44(本文中称为C4sh1A6)、SEQ ID NO.38/SEQ ID NO.45(本文中称为C4sh1A9)、SEQ ID NO.46/SEQ ID NO.47(本文中称为C4sh1B10)、SEQ ID NO.48/SEQ IDNO.49(本文中称为C4sh1B11)、SEQ ID NO.50/SEQ ID NO.51(本文中称为C4sh1B2)、SEQ IDNO.38/SEQ ID NO.52(本文中称为C4sh1C10)、SEQ ID NO.53/SEQ ID NO.54(本文中称为C4sh1C5)、SEQ ID NO.41/SEQ ID NO.54(本文中称为C4sh1C6)、SEQ ID NO.56/SEQ IDNO.57(C4sh1E10)、SEQ ID NO.38/SEQ ID NO.58(本文中称为C4sh1E12)、SEQ ID NO.59/SEQ ID NO.60(本文中称为C4sh1F11)、SEQ ID NO.38/SEQ ID NO.61(本文中称为C4sh1G4)、SEQ ID NO.62/SEQ ID NO.63(本文中称为C4sh1H9)及其组合。优选地,全人单链抗体具有重链可变域区域和轻链可变域区域两者,其中单链全人抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2、SEQ ID NO.3/SEQ ID NO.4、SEQ IDNO.5/SEQ ID NO.6、SEQ ID NO.7/SEQ ID NO.8、SEQ ID NO.9/SEQ ID NO.10、SEQ IDNO.11/SEQ ID NO.12、SEQ ID NO.13/SEQ ID NO.14、SEQ ID NO.15/SEQ ID NO.16、SEQ IDNO.17/SEQ ID NO.18、SEQ ID NO.19/SEQ ID NO.20、SEQ ID NO.21/SEQ ID NO.22、SEQ IDNO.13/SEQ ID NO.25、SEQ ID NO.26/SEQ ID NO.27、SEQ ID NO.28/SEQ ID NO.29、SEQ IDNO.30/SEQ ID NO.31、SEQ ID NO.13/SEQ ID NO.32、SEQ ID NO.13/SEQ ID NO.33、SEQ IDNO.34/SEQ ID NO.35、SEQ ID NO.36/SEQ ID NO.37、SEQ ID NO.38/SEQ ID NO.39、SEQ IDNO.38/SEQ ID NO.40、SEQ ID NO.41/SEQ ID NO.42、SEQ ID NO.43/SEQ ID NO.44、SEQ IDNO.38/SEQ ID NO.45、SEQ ID NO.46/SEQ ID NO.47、SEQ ID NO.48/SEQ ID NO.49、SEQ IDNO.50/SEQ ID NO.51、SEQ ID NO.38/SEQ ID NO.52、SEQ ID NO.53/SEQ ID NO.54、SEQ IDNO.41/SEQ ID NO.54、SEQ ID NO.56/SEQ ID NO.57、SEQ ID NO.38/SEQ ID NO.58、SEQ IDNO.59/SEQ ID NO.60、SEQ ID NO.38/SEQ ID NO.61、SEQ ID NO.62/SEQ ID NO.63及其组合。
优选地,该方法用于治疗各种癌症、类风湿性关节炎、实验性肺损伤、动脉粥样硬化、由丙型肝炎病毒引起的慢性肝病、缺血性心肌损伤和心力衰竭。
附图说明
图1和2显示七种抗-CD147抗体可以结合人或小鼠CD147两者。
图3-A显示示例性抗-CD147抗体与前列腺癌细胞(PC3)表面表达的人CD147的结合,如通过流式细胞术分析的。
图3-B显示示例性抗-CD147抗体与髓性白血病细胞(K562)表面表达的人CD147的结合,如通过流式细胞术分析的。
图3-C显示示例性抗-CD147抗体与非小细胞肺癌细胞(A549)表面表达的人CD147的结合,如通过流式细胞术分析的。
图4证明抗-CD147抗体在与蛋白G-DM1分子复合时的细胞毒性潜能。
具体实施方式
本公开提供了以10-6M或更小的结合亲和力结合CD147表位的IgG类的全人抗体,其具有与选自以下的氨基酸序列至少95%同一的重链可变域序列:SEQ ID NO.1、SEQ IDNO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ ID NO.11、SEQ ID NO.13、SEQ IDNO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ ID NO.23、SEQ ID NO.26、SEQ IDNO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ ID NO.38、SEQ ID NO.41、SEQ IDNO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ ID NO.53、SEQ ID NO.56、SEQ IDNO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ ID NO.8、SEQ ID NO.10、SEQ IDNO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ ID NO.20、SEQ ID NO.22、SEQ IDNO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ ID NO.31、SEQ ID NO.32、SEQ IDNO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ ID NO.40、SEQ ID NO.42、SEQ IDNO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ ID NO.51、SEQ ID NO.52、SEQ IDNO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ ID NO.60、SEQ ID NO.61、SEQ IDNO.63及其组合。优选地,全人抗体具有重链和轻链两者,其中该抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2(本文中称为C4R1A2)、SEQ ID NO.3/SEQ IDNO.4(本文中称为C4R1A5)、SEQ ID NO.5/SEQ ID NO.6(本文中称为C4R1A6)、SEQ ID NO.7/SEQ ID NO.8(本文中称为C4R1A8)、SEQ ID NO.9/SEQ ID NO.10(本文中称为C4R1A9)、SEQID NO.11/SEQ ID NO.12(本文中称为C4R1B2)、SEQ ID NO.13/SEQ ID NO.14(本文中称为C4R1C10)、SEQ ID NO.15/SEQ ID NO.16(本文中称为C4R1C11)、SEQ ID NO.17/SEQ IDNO.18(本文中称为C4R1C3)、SEQ ID NO.19/SEQ ID NO.20(本文中称为C4R1D11)、SEQ IDNO.21/SEQ ID NO.22(本文中称为C4R1F12)、SEQ ID NO.13/SEQ ID NO.25(本文中称为C4R1G1)、SEQ ID NO.26/SEQ ID NO.27(本文中称为C4R1G4)、SEQ ID NO.28/SEQ ID NO.29(本文中称为C4R1G7)、SEQ ID NO.30/SEQ ID NO.31(本文中称为C4R1H10)、SEQ ID NO.13/SEQ ID NO.32(本文中称为C4R1H11)、SEQ ID NO.13/SEQ ID NO.33(本文中称为C4R1H4)、SEQ ID NO.34/SEQ ID NO.35(本文中称为C4sh1Al)、SEQ ID NO.36/SEQ ID NO.37(本文中称为C4sh1A2)、SEQ ID NO.38/SEQ ID NO.39(本文中称为C4sh1A3)、SEQ ID NO.38/SEQ IDNO.40(本文中称为C4sh1A4)、SEQ ID NO.41/SEQ ID NO.42(本文中称为C4sh1A5)、SEQ IDNO.43/SEQ ID NO.44(本文中称为C4sh1A6)、SEQ ID NO.38/SEQ ID NO.45(本文中称为C4sh1A9)、SEQ ID NO.46/SEQ ID NO.47(本文中称为C4sh1B10)、SEQ ID NO.48/SEQ IDNO.49(本文中称为C4sh1B11)、SEQ ID NO.50/SEQ ID NO.51(本文中称为C4sh1B2)、SEQ IDNO.38/SEQ ID NO.52(本文中称为C4sh1C10)、SEQ ID NO.53/SEQ ID NO.54(本文中称为C4sh1C5)、SEQ ID NO.41/SEQ ID NO.54(本文中称为C4sh1C6)、SEQ ID NO.56/SEQ IDNO.57(C4sh1E10)、SEQ ID NO.38/SEQ ID NO.58(本文中称为C4sh1E12)、SEQ ID NO.59/SEQ ID NO.60(本文中称为C4sh1F11)、SEQ ID NO.38/SEQ ID NO.61(本文中称为C4sh1G4)、SEQ ID NO.62/SEQ ID NO.63(本文中称为C4sh1H9)及其组合。优选地,全人抗体Fab片段具有重链可变域区域和轻链可变域区域两者,其中抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2(本文中称为C4R1A2)、SEQ ID NO.3/SEQ ID NO.4(本文中称为C4R1A5)、SEQ ID NO.5/SEQ ID NO.6(本文中称为C4R1A6)、SEQ ID NO.7/SEQID NO.8(本文中称为C4R1A8)、SEQ ID NO.9/SEQ ID NO.10(本文中称为C4R1A9)、SEQ IDNO.11/SEQ ID NO.12(本文中称为C4R1B2)、SEQ ID NO.13/SEQ ID NO.14(本文中称为C4R1C10)、SEQ ID NO.15/SEQ ID NO.16(本文中称为C4R1C11)、SEQ ID NO.17/SEQ IDNO.18(本文中称为C4R1C3)、SEQ ID NO.19/SEQ ID NO.20(本文中称为C4R1D11)、SEQ IDNO.21/SEQ ID NO.22(本文中称为C4R1F12)、SEQ ID NO.13/SEQ ID NO.25(本文中称为C4R1G1)、SEQ ID NO.26/SEQ ID NO.27(本文中称为C4R1G4)、SEQ ID NO.28/SEQ ID NO.29(本文中称为C4R1G7)、SEQ ID NO.30/SEQ ID NO.31(本文中称为C4R1H10)、SEQ ID NO.13/SEQ ID NO.32(本文中称为C4R1H11)、SEQ ID NO.13/SEQ ID NO.33(本文中称为C4R1H4)、SEQ ID NO.34/SEQ ID NO.35(本文中称为C4sh1Al)、SEQ ID NO.36/SEQ ID NO.37(本文中称为C4sh1A2)、SEQ ID NO.38/SEQ ID NO.39(本文中称为C4sh1A3)、SEQ ID NO.38/SEQ IDNO.40(本文中称为C4sh1A4)、SEQ ID NO.41/SEQ ID NO.42(本文中称为C4sh1A5)、SEQ IDNO.43/SEQ ID NO.44(本文中称为C4sh1A6)、SEQ ID NO.38/SEQ ID NO.45(本文中称为C4sh1A9)、SEQ ID NO.46/SEQ ID NO.47(本文中称为C4sh1B10)、SEQ ID NO.48/SEQ IDNO.49(本文中称为C4sh1B11)、SEQ ID NO.50/SEQ ID NO.51(本文中称为C4sh1B2)、SEQ IDNO.38/SEQ ID NO.52(本文中称为C4sh1C10)、SEQ ID NO.53/SEQ ID NO.54(本文中称为C4sh1C5)、SEQ ID NO.41/SEQ ID NO.54(本文中称为C4sh1C6)、SEQ ID NO.56/SEQ IDNO.57(C4sh1E10)、SEQ ID NO.38/SEQ ID NO.58(本文中称为C4sh1E12)、SEQ ID NO.59/SEQ ID NO.60(本文中称为C4sh1F11)、SEQ ID NO.38/SEQ ID NO.61(本文中称为C4sh1G4)、SEQ ID NO.62/SEQ ID NO.63(本文中称为C4sh1H9)及其组合。
本公开提供了Fab全人抗体片段,其具有来自重链的可变域区域和来自轻链的可变域区域,其中重链可变域序列与选自以下的氨基酸序列至少95%同一:SEQ ID NO.1、SEQID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ ID NO.11、SEQ ID NO.13、SEQ IDNO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ ID NO.23、SEQ ID NO.26、SEQ IDNO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ ID NO.38、SEQ ID NO.41、SEQ IDNO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ ID NO.53、SEQ ID NO.56、SEQ IDNO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ ID NO.8、SEQ ID NO.10、SEQ IDNO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ ID NO.20、SEQ ID NO.22、SEQ IDNO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ ID NO.31、SEQ ID NO.32、SEQ IDNO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ ID NO.40、SEQ ID NO.42、SEQ IDNO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ ID NO.51、SEQ ID NO.52、SEQ IDNO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ ID NO.60、SEQ ID NO.61、SEQ IDNO.63及其组合。优选地,全人抗体Fab片段具有重链可变域区域和轻链可变域区域两者,其中该抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2、SEQ IDNO.3/SEQ ID NO.4、SEQ ID NO.5/SEQ ID NO.6、SEQ ID NO.7/SEQ ID NO.8、SEQ ID NO.9/SEQ ID NO.10、SEQ ID NO.11/SEQ ID NO.12、SEQ ID NO.13/SEQ ID NO.14、SEQ IDNO.15/SEQ ID NO.16、SEQ ID NO.17/SEQ ID NO.18、SEQ ID NO.19/SEQ ID NO.20、SEQ IDNO.21/SEQ ID NO.22、SEQ ID NO.13/SEQ ID NO.25、SEQ ID NO.26/SEQ ID NO.27、SEQ IDNO.28/SEQ ID NO.29、SEQ ID NO.30/SEQ ID NO.31、SEQ ID NO.13/SEQ ID NO.32、SEQ IDNO.13/SEQ ID NO.33、SEQ ID NO.34/SEQ ID NO.35、SEQ ID NO.36/SEQ ID NO.37、SEQ IDNO.38/SEQ ID NO.39、SEQ ID NO.38/SEQ ID NO.40、SEQ ID NO.41/SEQ ID NO.42、SEQ IDNO.43/SEQ ID NO.44、SEQ ID NO.38/SEQ ID NO.45、SEQ ID NO.46/SEQ ID NO.47、SEQ IDNO.48/SEQ ID NO.49、SEQ ID NO.50/SEQ ID NO.51、SEQ ID NO.38/SEQ ID NO.52、SEQ IDNO.53/SEQ ID NO.54、SEQ ID NO.41/SEQ ID NO.54、SEQ ID NO.56/SEQ ID NO.57、SEQ IDNO.38/SEQ ID NO.58、SEQ ID NO.59/SEQ ID NO.60、SEQ ID NO.38/SEQ ID NO.61、SEQ IDNO.62/SEQ ID NO.63及其组合。
本公开提供了单链人抗体,其具有来自重链的可变域区域和来自轻链的可变域区域及连接该重链和轻链可变域区域的肽接头,其中重链可变域序列与选自以下的氨基酸序列至少95%同一:SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ ID NO.11、SEQ ID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ IDNO.21、SEQ ID NO.23、SEQ ID NO.26、SEQ ID NO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ IDNO.36、SEQ ID NO.38、SEQ ID NO.41、SEQ ID NO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ IDNO.50、SEQ ID NO.53、SEQ ID NO.56、SEQ ID NO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQID NO.6、SEQ ID NO.8、SEQ ID NO.10、SEQ ID NO.12、SEQ ID NO.14、SEQ ID NO.16、SEQID NO.18、SEQ ID NO.20、SEQ ID NO.22、SEQ ID NO.24、SEQ ID NO.25、SEQ ID NO.27、SEQID NO.29、SEQ ID NO.31、SEQ ID NO.32、SEQ ID NO.33、SEQ ID NO.35、SEQ ID NO.37、SEQID NO.39、SEQ ID NO.40、SEQ ID NO.42、SEQ ID NO.44、SEQ ID NO.45、SEQ ID NO.47、SEQID NO.49、SEQ ID NO.51、SEQ ID NO.52、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.57、SEQID NO.58、SEQ ID NO.60、SEQ ID NO.61、SEQ ID NO.63及其组合。优选地,全人单链抗体具有重链可变域区域和轻链可变域区域两者,其中单链全人抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2、SEQ ID NO.3/SEQ ID NO.4、SEQ ID NO.5/SEQ IDNO.6、SEQ ID NO.7/SEQ ID NO.8、SEQ ID NO.9/SEQ ID NO.10、SEQ ID NO.11/SEQ IDNO.12、SEQ ID NO.13/SEQ ID NO.14、SEQ ID NO.15/SEQ ID NO.16、SEQ ID NO.17/SEQ IDNO.18、SEQ ID NO.19/SEQ ID NO.20、SEQ ID NO.21/SEQ ID NO.22、SEQ ID NO.13/SEQ IDNO.25、SEQ ID NO.26/SEQ ID NO.27、SEQ ID NO.28/SEQ ID NO.29、SEQ ID NO.30/SEQ IDNO.31、SEQ ID NO.13/SEQ ID NO.32、SEQ ID NO.13/SEQ ID NO.33、SEQ ID NO.34/SEQ IDNO.35、SEQ ID NO.36/SEQ ID NO.37、SEQ ID NO.38/SEQ ID NO.39、SEQ ID NO.38/SEQ IDNO.40、SEQ ID NO.41/SEQ ID NO.42、SEQ ID NO.43/SEQ ID NO.44、SEQ ID NO.38/SEQ IDNO.45、SEQ ID NO.46/SEQ ID NO.47、SEQ ID NO.48/SEQ ID NO.49、SEQ ID NO.50/SEQ IDNO.51、SEQ ID NO.38/SEQ ID NO.52、SEQ ID NO.53/SEQ ID NO.54、SEQ ID NO.41/SEQ IDNO.54、SEQ ID NO.56/SEQ ID NO.57、SEQ ID NO.38/SEQ ID NO.58、SEQ ID NO.59/SEQ IDNO.60、SEQ ID NO.38/SEQ ID NO.61、SEQ ID NO.62/SEQ ID NO.63及其组合。
本公开进一步提供了用于治疗类风湿性关节炎、实验性肺损伤、动脉粥样硬化、由丙型肝炎病毒引起的慢性肝疾病、缺血性心肌损伤和心力衰竭的方法,该方法包括施用抗-CD147多肽,其中所述抗-CD147多肽选自以至少10-6M的结合亲和力结合CD147表位的IgG类的全人抗体、具有来自重链的可变域区域和来自轻链的可变域区域的Fab全人抗体片段、具有来自重链的可变域区域和来自轻链的可变域区域及连接所述重链和轻链可变域区域的肽接头的单链人抗体,及其组合;
其中全人抗体具有与选自以下的氨基酸序列至少95%同一的重链可变域序列:SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ ID NO.11、SEQID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ ID NO.23、SEQID NO.26、SEQ ID NO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ ID NO.38、SEQID NO.41、SEQ ID NO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ ID NO.53、SEQID NO.56、SEQ ID NO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ ID NO.8、SEQID NO.10、SEQ ID NO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ ID NO.20、SEQID NO.22、SEQ ID NO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ ID NO.31、SEQID NO.32、SEQ ID NO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ ID NO.40、SEQID NO.42、SEQ ID NO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ ID NO.51、SEQID NO.52、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ ID NO.60、SEQID NO.61、SEQ ID NO.63及其组合;
其中所述Fab全人抗体片段具有与选自以下的氨基酸序列至少95%同一的重链可变域序列:SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ IDNO.11、SEQ ID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ IDNO.23、SEQ ID NO.26、SEQ ID NO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ IDNO.38、SEQ ID NO.41、SEQ ID NO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ IDNO.53、SEQ ID NO.56、SEQ ID NO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ IDNO.8、SEQ ID NO.10、SEQ ID NO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ IDNO.20、SEQ ID NO.22、SEQ ID NO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ IDNO.31、SEQ ID NO.32、SEQ ID NO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ IDNO.40、SEQ ID NO.42、SEQ ID NO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ IDNO.51、SEQ ID NO.52、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ IDNO.60、SEQ ID NO.61、SEQ ID NO.63及其组合;和
其中所述单链人抗体具有与选自以下的氨基酸序列至少95%同一的重链可变域序列:SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ IDNO.11、SEQ ID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ IDNO.23、SEQ ID NO.26、SEQ ID NO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ IDNO.38、SEQ ID NO.41、SEQ ID NO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ IDNO.53、SEQ ID NO.56、SEQ ID NO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ IDNO.8、SEQ ID NO.10、SEQ ID NO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ IDNO.20、SEQ ID NO.22、SEQ ID NO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ IDNO.31、SEQ ID NO.32、SEQ ID NO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ IDNO.40、SEQ ID NO.42、SEQ ID NO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ IDNO.51、SEQ ID NO.52、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ IDNO.60、SEQ ID NO.61、SEQ ID NO.63及其组合。
优选地,全人抗体具有重链和轻链两者,其中该抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2、SEQ ID NO.3/SEQ ID NO.4、SEQ ID NO.5/SEQ IDNO.6、SEQ ID NO.7/SEQ ID NO.8、SEQ ID NO.9/SEQ ID NO.10、SEQ ID NO.11/SEQ IDNO.12、SEQ ID NO.13/SEQ ID NO.14、SEQ ID NO.15/SEQ ID NO.16、SEQ ID NO.17/SEQ IDNO.18、SEQ ID NO.19/SEQ ID NO.20、SEQ ID NO.21/SEQ ID NO.22、SEQ ID NO.13/SEQ IDNO.25、SEQ ID NO.26/SEQ ID NO.27、SEQ ID NO.28/SEQ ID NO.29、SEQ ID NO.30/SEQ IDNO.31、SEQ ID NO.13/SEQ ID NO.32、SEQ ID NO.13/SEQ ID NO.33、SEQ ID NO.34/SEQ IDNO.35、SEQ ID NO.36/SEQ ID NO.37、SEQ ID NO.38/SEQ ID NO.39、SEQ ID NO.38/SEQ IDNO.40、SEQ ID NO.41/SEQ ID NO.42、SEQ ID NO.43/SEQ ID NO.44、SEQ ID NO.38/SEQ IDNO.45、SEQ ID NO.46/SEQ ID NO.47、SEQ ID NO.48/SEQ ID NO.49、SEQ ID NO.50/SEQ IDNO.51、SEQ ID NO.38/SEQ ID NO.52、SEQ ID NO.53/SEQ ID NO.54、SEQ ID NO.41/SEQ IDNO.54、SEQ ID NO.56/SEQ ID NO.57、SEQ ID NO.38/SEQ ID NO.58、SEQ ID NO.59/SEQ IDNO.60、SEQ ID NO.38/SEQ ID NO.61、SEQ ID NO.62/SEQ ID NO.63及其组合。优选地,全人抗体Fab片段具有重链可变域区域和轻链可变域区域两者,其中该抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2、SEQ ID NO.3/SEQ ID NO.4、SEQ IDNO.5/SEQ ID NO.6、SEQ ID NO.7/SEQ ID NO.8、SEQ ID NO.9/SEQ ID NO.10、SEQ IDNO.11/SEQ ID NO.12、SEQ ID NO.13/SEQ ID NO.14、SEQ ID NO.15/SEQ ID NO.16、SEQ IDNO.17/SEQ ID NO.18、SEQ ID NO.19/SEQ ID NO.20、SEQ ID NO.21/SEQ ID NO.22、SEQ IDNO.13/SEQ ID NO.25、SEQ ID NO.26/SEQ ID NO.27、SEQ ID NO.28/SEQ ID NO.29、SEQ IDNO.30/SEQ ID NO.31、SEQ ID NO.13/SEQ ID NO.32、SEQ ID NO.13/SEQ ID NO.33、SEQ IDNO.34/SEQ ID NO.35、SEQ ID NO.36/SEQ ID NO.37、SEQ ID NO.38/SEQ ID NO.39、SEQ IDNO.38/SEQ ID NO.40、SEQ ID NO.41/SEQ ID NO.42、SEQ ID NO.43/SEQ ID NO.44、SEQ IDNO.38/SEQ ID NO.45、SEQ ID NO.46/SEQ ID NO.47、SEQ ID NO.48/SEQ ID NO.49、SEQ IDNO.50/SEQ ID NO.51、SEQ ID NO.38/SEQ ID NO.52、SEQ ID NO.53/SEQ ID NO.54、SEQ IDNO.41/SEQ ID NO.54、SEQ ID NO.56/SEQ ID NO.57、SEQ ID NO.38/SEQ ID NO.58、SEQ IDNO.59/SEQ ID NO.60、SEQ ID NO.38/SEQ ID NO.61、SEQ ID NO.62/SEQ ID NO.63及其组合。优选地,全人单链抗体具有重链可变域区域和轻链可变域区域两者,其中单链全人抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2、SEQ ID NO.3/SEQ IDNO.4、SEQ ID NO.5/SEQ ID NO.6、SEQ ID NO.7/SEQ ID NO.8、SEQ ID NO.9/SEQ IDNO.10、SEQ ID NO.11/SEQ ID NO.12、SEQ ID NO.13/SEQ ID NO.14、SEQ ID NO.15/SEQ IDNO.16、SEQ ID NO.17/SEQ ID NO.18、SEQ ID NO.19/SEQ ID NO.20、SEQ ID NO.21/SEQ IDNO.22、SEQ ID NO.13/SEQ ID NO.25、SEQ ID NO.26/SEQ ID NO.27、SEQ ID NO.28/SEQ IDNO.29、SEQ ID NO.30/SEQ ID NO.31、SEQ ID NO.13/SEQ ID NO.32、SEQ ID NO.13/SEQ IDNO.33、SEQ ID NO.34/SEQ ID NO.35、SEQ ID NO.36/SEQ ID NO.37、SEQ ID NO.38/SEQ IDNO.39、SEQ ID NO.38/SEQ ID NO.40、SEQ ID NO.41/SEQ ID NO.42、SEQ ID NO.43/SEQ IDNO.44、SEQ ID NO.38/SEQ ID NO.45、SEQ ID NO.46/SEQ ID NO.47、SEQ ID NO.48/SEQ IDNO.49、SEQ ID NO.50/SEQ ID NO.51、SEQ ID NO.38/SEQ ID NO.52、SEQ ID NO.53/SEQ IDNO.54、SEQ ID NO.41/SEQ ID NO.54、SEQ ID NO.56/SEQ ID NO.57、SEQ ID NO.38/SEQ IDNO.58、SEQ ID NO.59/SEQ ID NO.60、SEQ ID NO.38/SEQ ID NO.61、SEQ ID NO.62/SEQ IDNO.63及其组合。
优选地,该方法用于治疗类风湿性关节炎、实验性肺损伤、动脉粥样硬化、由丙型肝炎病毒引起的慢性肝病、缺血性心肌损伤和心力衰竭。
“抗原结合蛋白”是包含结合至抗原的部分和,任选地,允许抗原结合部分采取促进抗原结合蛋白与抗原结合的构象的骨架或框架部分的蛋白质。抗原结合蛋白的例子包括抗体、抗体片段(例如,抗体的抗原结合部分)、抗体衍生物和抗体类似物。抗原结合蛋白可以包含,例如,具有移植的CDR或CDR衍生物的可选的蛋白质骨架或人工骨架。这些骨架包括,但不限于抗体衍生的骨架(包含引入以例如使抗原结合蛋白的三维结构稳定的突变)以及完全合成的骨架(包含,例如,生物相容性聚合物)。参见,例如,Korndorfer等人,2003,Proteins:Structure,Function,and Bioinformatics,Volume 53,Issue 1:121-129;Roque等人,2004,Biotechnol.Prog.20:639-654。此外,可以使用肽抗体模拟物(“PAM”)以及基于抗体模拟物的骨架(利用纤维连接蛋白组分作为骨架)。
抗原结合蛋白可以具有,例如,天然存在的免疫球蛋白的结构。“免疫球蛋白”是四聚体分子。在天然存在的免疫球蛋白中,每个四聚体由两个相同的多肽链对组成,每对具有一条“轻”链(约25kDa)和一条“重”链(约50-70kDa)。每条链的氨基端部分包括主要负责抗原识别的约100至110或更多个氨基酸的可变区。每条链的羧基端部分限定主要负责效应子功能的恒定区。人轻链分类为κ或λ轻链。重链分类为μ、δ、γ、α或ε,并分别定义抗体同种型为IgM、IgD、IgG、IgA和IgE。在轻链和重链内,可变区和恒定区通过约12或更多个氨基酸的“J”区连接,并且重链还包括约10个或更多个氨基酸的“D”区。通常参见,FundamentalImmunology第7章(Paul,W.编辑,第二版,Raven出版社,N.Y.(1989))(通过引用结合其全部内容用于所有目的)。每个轻/重链对的可变区形成抗体结合位点,使得完整的免疫球蛋白具有两个结合位点。
天然存在的免疫球蛋白链的可变区表现出相同的总体结构:由通过三个高变区(也称为互补决定区或CDR)连接的相对保守的框架区(FR)。从N端至C端,轻链和重链都包含结构域FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。每个结构域的氨基酸的指定按照Kabat等人在Sequences of Proteins of Immunological Interest,第5版,US Dept.of Health andHuman Services,PHS,NIH,NIH出版号91-3242,1991中的定义命名。免疫球蛋白链中氨基酸的其它编号系统包括IMGT.RTM(国际ImMunoGeneTics信息系统;Lefranc等人,Dev.Comp.Immunol.29:185-203;2005)和AHo(Honegger和Pluckthun,J.Mol.Biol.309(3):657-670;2001)。
可以从含有具有变化的抗原特异性的免疫球蛋白的来源比如血清或血浆获得抗体。如果将这样的抗体进行亲和纯化,它们可以针对特定的抗原特异性富集。通常由少于约10%的对特定抗原具有特异性结合活性的抗体制备这类富集的抗体制剂。使这些制剂进行若干轮亲和纯化可以提高对抗原具有特异性结合活性的抗体的比例。以这种方式制备的抗体通常称为“单特异性的”。单特异性抗体制剂可以由约10%、20%、30%、40%、50%、60%、70%、75%、80%、85%、90%、95%、97%、99%或99.9%的对特定抗原具有特异性结合活性的抗体构成。
除非另有说明,“抗体”是指完整的免疫球蛋白或与完整抗体为特异性结合而竞争的其抗原结合部分。可以通过重组DNA技术或通过完整抗体的酶促或化学切割产生抗原结合部分。抗原结合部分包括,特别是,Fab、Fab'、F(ab')2、Fv、域抗体(dAb)和互补决定区(CDR)片段、单链抗体(scFv)、嵌合抗体、双抗体(diabodies)、三抗体(triabodies)、四抗体(tetrabodies)和含有至少足以赋予多肽对抗原的特异性结合的免疫球蛋白的部分的多肽。
Fab片段为具有VL、VH、CL和CH1结构域的单价片段;F(ab')2片段为具有通过在铰链区的二硫键连接的2个Fab片段的双价片段;Fd片段具有VH和CH1结构域;Fv片段具有抗体单臂的VL和VH结构域;并且dAb片段具有VH结构域、VL结构域或者VH或VL结构域的抗原结合片段(美国专利号6,846,634、6,696,245,美国申请公开号20/0202512、2004/0202995、2004/0038291、2004/0009507、2003/0039958和Ward等人,Nature 341:544-546,1989)。
单链抗体(scFv)为其中VL和VH区通过接头(例如,合成的氨基酸残基的序列)连接以形成连续的蛋白链(其中该接头足够长以允许蛋白链自身回折并形成单价抗原结合位点)的抗体(参见,例如Bird等人,1988,Science 242:423-26和Huston等人,1988,Proc.Natl.Acad.Sci.USA 85:5879-83)。双抗体为包含2条多肽链的二价抗体,其中每条多肽链包含由接头连接的VH和VL结构域,该接头太短而不允许相同链上的2个结构域之间配对,因此使得每个结构域与在另一多肽链上的互补结构域配对(参见,例如Holliger等人,1993,Proc.Natl.Acad.Sci.USA 90:6444-48和Poljak等人,1994,Structure 2:1121-23)。如果双抗体的两条多肽链是相同的,那么由其配对产生的双抗体将具有2个相同的抗原结合位点。具有不同序列的多肽链可以用于形成具有2个不同抗原结合位点的双抗体。类似地,三抗体和四抗体分别为包含3条和4条多肽链并分别形成3个和4个抗原结合位点(其可以是相同的或不同的)的抗体。
可以利用Kabat等人(同上)、Lefranc等人(同上)和/或Honegger和Pluckthun(同上)描述的系统确定给定抗体的互补决定区(CDR)和框架区(FR)。可以将一个或多个CDR共价或非共价地整合到分子中以使其成为抗原结合蛋白。抗原结合蛋白可以使CDR作为较大多肽链的部分并入,可以共价地将CDR连接至另一多肽链,或可以非共价地并入CDR。CDR允许抗原结合蛋白特异性地结合特定的目标抗原。
抗原结合蛋白可以具有一个或多个结合位点。如果存在多于一个结合位点,那么结合位点可以彼此相同或可以不同。例如,天然存在的人免疫球蛋白通常具有两个相同的结合位点,而“双特异性”或“双功能”抗体具有两个不同的结合位点。
术语“人抗体”包括具有源自人免疫球蛋白序列的一个或多个可变区和恒定区的所有抗体。在一个实施方式中,所有的可变域和恒定域源自人免疫球蛋白序列(全人抗体)。这些抗体可以以多种方式制备,其实例如下文所述,包括通过用目标抗原对小鼠(其经遗传修饰以表达来源于人重链和/或轻链编码基因的抗体)进行免疫。
人源化抗体的序列与来源于非人物种的抗体的序列不同在于一个或多个氨基酸置换、删除和/或添加,以使得在施用于人类受试者时,人源化抗体与非人物种的抗体相比较少可能诱导免疫应答和/或诱导较不严重的免疫应答。在一个实施方式中,非人物种抗体的重链和/或轻链的框架和恒定域中的某些氨基酸突变以产生人源化抗体。在另一实施方式中,来自人抗体的恒定域与非人物种的可变域融合。在另一实施方式中,改变非人抗体的一个或多个CDR序列中的一个或多个氨基酸残基以降低非人抗体在施用于人类受试者时可能的免疫原性,其中改变的氨基酸残基对于抗体与其抗原的免疫特异性结合不是关键的,或对氨基酸序列进行的改变是保守性改变,使得人源化抗体与抗原的结合不会比非人抗体与抗原的结合明显更差。如何制备人源化抗体的例子可以在美国专利号6,054,297、5,886,152和5,877,293中找到。
术语“嵌合抗体”指的是含有来自一个抗体的一个或多个区域和来自一个或多个其它抗体的一个或多个区域的抗体。在一个实施方式中,一个或多个CDR来源于人抗-CD147抗体。在另一实施方式中,所有的CDR来源于人抗-CD147抗体。在另一实施方式中,来自多于一个人抗-CD147抗体的CDR混合并在嵌合抗体中匹配。例如,嵌合抗体可以包含来自第一人抗体的轻链的CDR1,来自第二人抗-CD147抗体的轻链的CDR2和CDR3,以及来自第三抗-CD147抗体的重链的CDR。其它组合是可能的。
此外,框架区可以来源于相同抗-CD147抗体中的一个、来自一个或多个不同抗体(比如人抗体)或来自人源化抗体。在嵌合抗体的一个例子中,重链和/或轻链的一部分与来自特定物种或者属于特定抗体类别或子类的抗体相同、同源或来源于该抗体,而链的其余部分与来自另一物种或者属于另一抗体类别或子类的抗体相同、同源或来源于该抗体。也包括这些抗体的表现出所需生物活性(即,特异性结合CD147的能力)的片段。
本领域技术人员可以根据本说明书的教导并使用本领域已知技术容易地制备抗体片段或类似物。片段或类似物的优选氨基端和羧基端存在于功能域的边界附近。可以通过将核苷酸和/或氨基酸序列数据与公共或专有序列数据库比较识别结构域和功能域。计算机化的比较方法可用于识别在已知结构和/或功能的其它蛋白质中存在的序列基序或预测的蛋白质构象结构域。识别折叠成已知三维结构的蛋白质序列的方法是已知的。参见,Bowie等人,1991,Science 253:164。
“CDR移植抗体”是包含来源于特定物种或同种型的抗体的一个或多个CDR和相同或不同物种或同种型的另一抗体的框架的抗体。
“多特异性抗体”是识别在一个或多个抗原上的超过一个表位的抗体。这种类型的抗体的子类为“双特异性抗体”,其识别在相同或不同抗原上的2个不同的表位。
如果抗原结合蛋白以1纳摩尔或更小的解离常数结合抗原(例如,人CD147),那么该抗原结合蛋白“特异性地结合”该抗原。
“抗原结合结构域”、“抗原结合区”或“抗原结合位点”为含有与抗原相互作用并造成抗原结合蛋白对抗原的特异性和亲和力的氨基酸残基(或其它部分)的抗原结合蛋白的部分。对于特异性地结合其抗原的抗体,这包括其CDR域中至少一个的至少一部分。
“表位”为分子的被抗原结合蛋白(例如,抗体)结合的部分。表位可以包括分子的非邻近部分(例如在多肽中,在多肽的一级序列中非连续的但在多肽的三级和四级结构的情况下彼此足够接近以被抗原结合蛋白结合的氨基酸残基)。
两个多核苷酸或两个多肽序列的“百分同一性”通过利用GAP计算机程序(GCGWisconsin Package的部分,版本10.3(Accelrys,圣地亚哥,加利福尼亚州)使用其默认参数比较该序列来确定。
术语“多核苷酸”、“寡核苷酸”和“核酸”在全文中可互换地使用并包括DNA分子(例如,cDNA或基因组DNA)、RNA分子(例如,mRNA)、用核苷酸类似物(例如,肽核酸和非天然存在的核苷酸类似物)产生的DNA或RNA的类似物及其杂合体。核酸分子可以为单链或双链的。在一个实施方式中,本发明的核酸分子包含编码抗体或其片段、衍生物、突变蛋白或变体的连续开放阅读框。
如果两个单链多核苷酸的序列可以按反平行定向对齐以使得一个多核苷酸中的每个核苷酸与另一多核苷酸中的其互补核苷酸相对的而没有引入空位和在任一序列的5'或3'端没有未配对的核苷酸,那么这两个单链多核苷酸是彼此的“互补序列”。如果两个多核苷酸可以在中等严格条件下彼此杂交,那么一个多核苷酸与另一多核苷酸互补。因此,多核苷酸可以与另一多核苷酸互补而不是其互补序列。
“载体”为可以用于将与其连接的另一核酸引入细胞中的核酸。一种类型的载体为“质粒”,其指的是线性或环状双链DNA分子,可以将另外的核酸片段连接至该双链DNA分子中。另一类型的载体为病毒载体(例如,复制缺陷型逆转录病毒、腺病毒和腺相关病毒),其中可将另外的DNA片段引入到病毒基因组中。某些载体能够在其所引入的宿主细胞中自主复制(例如,包含细菌复制起点的细菌载体和附加型哺乳动物载体)。其它载体(例如,非附加型哺乳动物载体)在引入宿主细胞中后被整合到宿主细胞的基因组中,且由此与宿主基因组一起复制。“表达载体”为可以直接指导选定多核苷酸的表达的载体类型。
如果调控序列影响核苷酸序列的表达(例如,表达的水平、时机或位置),那么该核苷酸序列“可操作地连接”于调控序列。“调控序列”为影响其可操作地连接的核酸的表达(例如,表达的水平、时机或位置)的核酸。调控序列可以,例如,直接在所调节的核酸上,或通过一个或多个其它分子(例如,结合于该调控序列和/或该核酸的多肽)的作用施加其影响。调控序列的例子包括启动子、增强子和其它表达控制元件(例如,聚腺苷酸化信号)。调控序列的另外的例子在,例如,Goeddel,1990,Gene Expression Technology:Methods inEnzymology 185,Academic Press,San Diego,Calif.和Baron等人,1995,Nucleic AcidsRes.23:3605-06中描述。
“宿主细胞”为可以用于表达核酸(例如,本发明的核酸)的细胞。宿主细胞可以是原核细胞,例如,大肠杆菌,或其可以是真核细胞,例如,单细胞真核生物(例如,酵母或其它真菌)、植物细胞(例如,烟草或番茄植物细胞)、动物细胞(例如,人细胞、猴细胞、仓鼠细胞、大鼠细胞、小鼠细胞或昆虫细胞)或杂交瘤。宿主细胞的例子包括COS-7系猴肾细胞(ATCCCRL 1651)(参见Gluzman等人,1981,Cell 23:175)、L细胞、C127细胞、3T3细胞(ATCC CCL163)、中国仓鼠卵巢(CHO)细胞或其衍生物如Veggie CHO和相关细胞系(其在无血清培养基中生长)(参见Rasmussen等人,1998,Cytotechnology 28:31)或CHO株DX-B11(其为DHFR缺陷的)(参见Urlaub等人,1980,Proc.Natl.Acad.Sci.USA 77:4216-20)、HeLa细胞、BHK(ATCC CRL 10)细胞系、来源于非洲绿猴肾细胞系CV1的CV1/EBNA细胞系(ATCC CCL 70)(参见McMahan等人,1991,EMBO J.10:2821)、人胚肾细胞(比如293、293EBNA或MSR293)、人表皮A431细胞,人Colo205细胞、其它转化的灵长类细胞系、正常二倍体细胞、来源于原代组织、原代外植体的体外培养物的细胞株、HL-60、U937、HaK或Jurkat细胞。通常,宿主细胞是可用多肽编码核酸(其随后可以在宿主细胞中表达)转化或转染的培养细胞。短语“重组宿主细胞”可以用于表示已经用待表达的核酸转化或转染的宿主细胞。宿主细胞也可以为包含核酸,但除非将调控序列引入到该宿主细胞中以使该调控序列可操作地与该核酸连接,该核酸不以所需的水平表达的细胞。应该理解,术语宿主细胞不仅仅指特定的受试细胞,还指这种细胞的后代或潜在的后代。因为在后续的世代中可能由于例如突变或环境影响而出现一些变化,因此实际上这类后代可能与亲代细胞不相同,但仍然包含在本文使用的术语的范围内。
可以利用本领域已知的任何标准方法产生本公开的多肽。在一个实例中,通过重组DNA方法将编码多肽的核酸序列(例如,cDNA)插入到重组表达载体中并且在促进表达的条件下表达DNA序列来产生该多肽。
可以化学合成编码本文公开的各种多肽中任何一种的核酸。可以选择密码子使用以改善在细胞中的表达。这类密码子选择取决于选择的细胞类型。已经开发了用于大肠杆菌和其它细菌以及哺乳动物细胞、植物细胞、酵母细胞和昆虫细胞的专用的密码子使用模式。参见,例如:Mayfield等人,Proc.Natl.Acad.Sci.USA.2003,100(2):438-42、Sinclair等人,Protein Expr.Purif.2002(1):96-105、Connell N D.Curr.Opin.Biotechnol.2001,12(5):446-9、Makrides等人,Microbiol.Rev.1996,60(3):512-38和Sharp等人,Yeast.1991,7(7):657-78。
用于核酸操作的一般技术在,例如,Sambrook等人,Molecular Cloning:ALaboratory Manual,Vols.1-3,Cold Spring Harbor Laboratory Press,2ed.,1989或F.Ausubel等人,Current Protocols in Molecular Biology(Green Publishing andWiley-Interscience:NewYork,1987)及其定期更新中描述,其内容通过引用结合于本文中。编码多肽的DNA可操作地连接至源自哺乳动物、病毒或昆虫基因的合适的转录或翻译调控元件。这些调控元件包括转录启动子、任选的控制转录的操纵子序列、编码合适的mRNA核糖体结合位点的序列及控制转录和翻译的终止的序列。在宿主中复制的能力(通常由复制起点赋予)和帮助识别转化体的选择基因另外地并入。
重组DNA也可以包括可以用于纯化蛋白质的任何类型的蛋白质标签序列。蛋白质标签的例子包括,但不限于组氨酸标签、FLAG标签、myc标签、HA标签或GST标签。用于细菌、真菌、酵母和哺乳动物细胞宿主的合适的克隆和表达载体可以在Cloning Vectors:ALaboratory Manual,(Elsevier,N.Y.,1985)中找到。
利用适合于宿主细胞的方法将表达构建体引入宿主细胞中。本领域已知将核酸引入宿主细胞中的多种方法,包括但不限于:电穿孔,采用氯化钙、氯化铷、磷酸钙、DEAE-葡聚糖或其它物质的转染,基因枪法,脂质转染和感染(其中载体是传染剂)。合适的宿主细胞包括原核细胞、酵母、哺乳动物细胞或细菌细胞。合适的细菌包括革兰氏阴性或革兰氏阳性有机体,例如,大肠杆菌或芽孢杆菌属。酵母,优选来自酵母属物种,比如酿酒酵母,也可用于产生多肽。各种哺乳动物或昆虫细胞培养系统也可以用于表达重组蛋白。Luckow和Summers综述了在昆虫细胞中用于产生异源蛋白质的杆状病毒系统(Bio/Technology,6:47,1988)。合适的哺乳动物宿主细胞系的例子包括内皮细胞、COS-7猴肾细胞、CV-1、L细胞、C127、3T3、中国仓鼠卵巢(CHO)、人胚肾细胞、HeLa、293、293T和BHK细胞系。纯化的多肽通过培养合适的宿主/载体系统以表达重组蛋白来制备。对于许多应用,本文公开的许多多肽的小尺寸使得在大肠杆菌中表达成为优选的表达方法。然后从培养基或细胞提取物纯化蛋白质。
本文公开的蛋白质也可以使用细胞翻译系统产生。为了此类目的,必须修饰编码多肽的核酸以允许进行体外转录而产生mRNA并且允许利用在特定的无细胞系统(真核的,比如哺乳动物或酵母无细胞翻译系统,或原核的,比如,细菌无细胞翻译系统)中的mRNA无细胞翻译。CD147-结合多肽也可以通过化学合成产生(例如,通过在Solid Phase PeptideSynthesis,2nd ed.,1984,The Pierce Chemical Co.,Rockford,111中描述的方法)。也可以通过化学合成产生对蛋白质的修饰。本公开的多肽可以通过蛋白质化学领域公知的蛋白质分离/纯化方法进行纯化。非限制性例子包括萃取、重结晶、盐析(例如,用硫酸铵或硫酸钠)、离心、透析、超滤、吸附色谱、离子交换色谱、疏水性色谱、正相色谱、反相色谱、凝胶过滤、凝胶渗透色谱,亲和色谱、电泳、逆流分布或这些的任意组合。纯化后,可以通过本领域已知的多种方法中的任何一种,包括但不限于,过滤和透析,使多肽交换到不同的缓冲液中和/或浓缩。
纯化的多肽优选至少85%纯,更优选至少95%纯,并且最优选至少98%纯。无论纯度的确切数值如何,多肽都足够纯以用作药物产品。
多肽的翻译后修饰
在某些实施方式中,本发明的结合多肽可以进一步包括翻译后修饰。示例性的蛋白质翻译后修饰包括磷酸化、乙酰化、甲基化、ADP-核糖基化、泛素化、糖基化、羰基化、SUMO化、生物素化或者多肽侧链或疏水性基团的添加。结果,修饰的可溶性多肽可含有非氨基酸成分,例如脂质、多糖或单糖和磷酸类。糖基化的优选形式是唾液酸化,其将一个或多个唾液酸部分与多肽结合。唾液酸部分改善溶解性和血清半衰期,同时还降低该蛋白质的可能的免疫原性。参见Raju等人,Biochemistry.2001,31;40(30):8868-76。
在一个实施方式中,所述可溶性多肽的修饰形式包括将所述可溶性多肽连接至非蛋白质性的聚合物。在一个实施方式中,该聚合物为聚乙二醇("PEG")、聚丙二醇或聚氧化烯类,如美国专利号4,640,835、4,496,689、4,301,144、4,670,417、4,791,192或4,179,337中所述的方式。
PEG是可在市场上买到或可以根据本领域公知的方法通过乙二醇的开环聚合制备(Sandler和Karo,Polymer Synthesis,Academic Press,New York,Vol.3,138-161页)的水溶性聚合物。术语“PEG”广泛地用于涵盖任何聚乙二醇分子而不考虑大小或在PEG末端的修饰,并且可以由下式表示:X-O(CH2CH2O)n-CH2CH2OH(1),其中n为20至2300,并且X为H或末端修饰,例如:C1-4烷基。在一个实施方式中,本发明的PEG在一端以羟基或甲氧基封端,即,X为H或CH3("甲氧基PEG")。PEG可以包含结合反应所需的进一步的化学基团,其由分子的化学合成产生,或者是使分子的部分具有最佳距离的间隔物。另外,这种PEG可以由一条或多条连接在一起的PEG侧链组成。具有多于一条PEG侧链的PEG被称为多臂或枝化PEG。枝化PEG可以通过,例如,将聚环氧乙烷添加到各种多元醇(包括甘油、季戊四醇和山梨糖醇)而制备。例如,四臂的枝化PEG可以由季戊四醇和环氧乙烷制备。例如,EP-A0473084和美国专利号5,932,462描述了枝化PEG。PEG的一种形式包括由赖氨酸的伯氨基基团连接的两个PEG侧链(PEG2)(Monfardini等人,Bioconjugate Chem.6(1995)62-69)。
相对于未修饰的结合多肽的清除率,PEG修饰的多肽的血清清除速率可以降低约10%、20%、30%、40%、50%、60%、70%、80%或甚至90%。PEG修饰的多肽的半衰期(t 1/2)相对于未修饰蛋白质的半衰期增加。相对于未修饰的结合多肽的半衰期,PEG结合多肽的半衰期可以增加至少10%、20%、30%、40%、50%、60%、70%、80%、90%、100%、125%、150%、175%、200%、250%、300%、400%或500%,或者甚至1000%。在一些实施方式中,在体外测定蛋白质半衰期,比如,在缓冲盐水溶液中或在血清中。在其它实施方式中,蛋白质半衰期是体内半衰期,比如在动物的血清或其它体液中的蛋白质半衰期。
治疗性制剂和施用方式
本公开特征用于治疗或预防金黄色葡萄球菌的方法,包括施用抗-CD147抗体。施用的技术和剂量根据特定多肽的类型和待治疗的特定病症而不同,但可以由技术人员容易地确定。通常,管理机构要求用作治疗剂的蛋白质试剂进行配制以具有可接受的低水平热原。因此,治疗性制剂与其它制剂的区别通常在于:其基本上是无热原的,或者至少含有的热原不超过由适当的管理机构(例如,FDA)确定的可接受水平。
本公开的治疗性组合物可以以单位剂量形式与药学上可接受的稀释剂、载体或赋形剂一起施用。作为非限制性的例子,可以肠胃外(例如,静脉内、皮下)、口服或局部施用。此外,可以采用任何基因治疗技术(使用编码本发明多肽的核酸),例如裸DNA递送、重组基因和载体、基于细胞的递送,包括患者细胞的离体操作,等。
该组合物可以是用于口服施用的丸剂、片剂、胶囊、液体或持续释放片剂,或者用于静脉内、皮下或肠胃外施用的液体,或者用于局部施用的凝胶、洗剂、软膏、霜剂或者聚合物或其它持续释放媒介的形式。
在例如"Remington:The Science and Practice of Pharmacy"(20th ed.,ed.A.R.Gennaro A R.,2000,Lippincott Williams&Wilkins,Philadelphia,Pa.)中可以找到本领域公知的用于制备制剂的方法。用于肠胃外施用的制剂可以,例如,含有赋形剂、无菌水、盐水、聚烷撑二醇比如聚乙二醇、植物来源的油或氢化萘类。生物相容性的、可生物降解的交酯聚合物、丙交酯/乙交酯共聚物或聚氧乙烯-聚氧丙烯共聚物可以用于控制化合物的释放。纳米颗粒制剂(例如,可生物降解的纳米颗粒、固体脂质纳米颗粒、脂质体)可用于控制化合物的生物分布。其它潜在有用的肠胃外递送体系包括乙烯-乙酸乙烯酯共聚物颗粒、渗透泵、可植入式输注系统和脂质体。制剂中化合物的浓度根据许多因素变化,包括待施用药物的剂量和施用途径。
多肽可任选地作为药学上可接受的盐施用,比如在制药工业中常用的无毒的酸加成盐或金属复合物。酸加成盐的例子包括有机酸,比如乙酸、乳酸、扑酸、马来酸、柠檬酸、苹果酸、抗坏血酸、琥珀酸、苯甲酸、棕榈酸、辛二酸、水杨酸、酒石酸、甲磺酸、甲苯磺酸,或三氟乙酸等;聚合酸,比如单宁酸、羧甲基纤维素等;和无机酸,如盐酸、氢溴酸、硫酸、磷酸等。金属复合物包括锌、铁等等。在一个实例中,多肽在乙酸钠存在的情况下配制以提高热稳定性。
用于口服用途的制剂包括含有与非毒性的药物学可接受的赋形剂混合的活性成分的片剂。这些赋形剂可以是例如惰性稀释剂或填充剂(例如,蔗糖和山梨醇)、润滑剂、助流剂和抗粘剂(例如,硬脂酸镁、硬脂酸锌、硬脂酸、硅石、氢化植物油或滑石)。
用于口服用途的制剂也可以作为可咀嚼片剂,或作为硬明胶胶囊(其中活性成分与惰性固体稀释剂混合)或作为软明胶胶囊剂(其中活性成分与水或油介质混合)提供。
治疗有效剂量是指产生用于施用目的的治疗效果的剂量。确切的剂量取决于待治疗的病症,并且本领域技术人员可以利用已知技术确定。通常,多肽以每天约0.01μg/kg至约50mg/kg,优选每天0.01mg/kg至约30mg/kg,最优选每天0.1mg/kg至约20mg/kg施用。多肽可以每天(例如,每天一次、二次、三次或四次)或优选以较低频率(例如、每周、每两周、每三周、每月或每季度)给予。此外,如本领域已知的,根据年龄以及体重、一般健康状况、性别、饮食、给药时间、药物相互作用和疾病的严重程度做出调整可能是必要的,并且将由本领域技术人员通过常规实验确定。
示例性用途
CD147结合多肽可单独或与一种或多种另外的治疗如化疗、放疗、免疫疗法、外科手术介入或这些方法的任何组合联合施用。如上所述的,长期治疗在其它治疗策略的情况下作为辅助疗法同样是可能的。
在这些方法的某些实施方式中,可以一起(同时地)或在不同时间(依次地)施用一种或多种多肽治疗剂。此外,多肽治疗剂可以与用于治疗癌症或用于治疗CD147-表达肿瘤(包括肝细胞癌和鳞状细胞癌)和非肿瘤疾病(选自类风湿性关节炎、实验性肺损伤、动脉粥样硬化、由丙型肝炎病毒引起的慢性肝病、缺血性心肌损伤和心力衰竭)的另一类型的化合物一起施用。
在某些实施方式中,可以单独使用本发明的所述抗-CD147抗体。
在某些实施方式中,为了诊断的目的,可以标记或不标记结合多肽或其片段。通常诊断分析需要检测由结合多肽与CD147的结合产生的复合物的形成。与抗体类似,可以直接标记结合多肽或片段。可以采用多种标记,包括,但不限于:放射性核素、荧光剂、酶、酶底物、酶辅因子、酶抑制剂和配体(如,生物素、半抗原)。本领域技术人员已知许多合适的免疫分析法(参见,例如,美国专利号3,817,827、3,850,752、3,901,654和4,098,876)。在未标记时,结合多肽可以用于分析中,比如凝集分析。未标记的结合多肽也可以与另外(一种或多种)合适的试剂结合使用,该试剂可以用于检测结合多肽,比如,与结合多肽反应的标记抗体或其它合适的试剂(例如,标记的蛋白A)。
在一个实施方式中,本发明的结合多肽可以用于酶免疫分析法中,其中所述多肽与酶偶联。当包含CD147蛋白的生物样品与所述结合多肽组合时,在结合多肽和CD147蛋白之间发生结合。在一个实施方式中,含有表达CD147蛋白的细胞(例如,内皮细胞)的样品与所述抗体组合,并且在结合多肽和携带被该结合多肽识别的CD147蛋白的细胞之间发生结合。这些结合的细胞可以与未结合的试剂分离并且可以测定特异地结合细胞的结合多肽-酶偶联物的存在,例如,通过将样品与酶的底物(其在受到酶的作用时产生颜色变化或其它可检测的变化)接触。在另一实施方式中,所述结合多肽可以是未标记的,并且可以加入识别所述结合多肽的第二标记多肽(例如,抗体)。
在某些方面,还可以制备用于检测生物样品中CD147蛋白的存在的试剂盒。这些试剂盒将包括与CD147蛋白或所述受体的部分结合的CD147结合多肽,以及一种或多种适于检测结合多肽和受体蛋白或其部分之间的复合物的存在的辅助试剂。本发明的多肽组合物可以单独地或与对于其它表位特异性的另外的抗体组合以冻干形式提供。结合多肽和/或抗体(其可以是标记或未标记的)可以与辅助成分(例如,缓冲剂如Tris、磷酸盐和碳酸盐,稳定剂,赋形剂,杀生物剂和/或惰性蛋白质,例如,牛血清白蛋白)一起包括在试剂盒中。例如,结合多肽和/或抗体可以作为与辅助成分的冻干混合物提供,或辅助成分可以单独地提供用于由使用者组合。一般地,这些辅助材料重量基于活性结合多肽或抗体的量以小于约5%重量存在,且通常基于多肽或抗体浓度以至少约0.001%重量的总量存在。当采用能够与结合多肽结合的第二抗体时,这种抗体可以在试剂盒中提供,例如在单独的小瓶或容器中。第二抗体(如果存在)通常是标记的,并且可以以与上文描述的抗体制剂相似的方式配制。
使用标准的一字母或三字母的缩写表示多肽序列。除非另有说明,每条多肽序列具有左侧的氨基端和右侧的羧基端;各单链核酸序列和各双链核酸序列的顶部链具有左铡的5'端和右铡的3'端。还可以通过解释特定多肽序列与参考序列如何不同来描述该特定多肽序列。
除非另有说明,以下术语应该理解为具有下面的意思:
术语“肽”、“多肽”和“蛋白质”各自指包含通过肽键彼此接合的两个或更多个氨基酸残基的分子。这些术语包含,例如,天然和人工蛋白质、蛋白质片段和蛋白质序列的多肽类似物(比如突变蛋白、变体和融合蛋白)以及翻译后或者以其它方式共价或非共价地修饰的蛋白质。肽、多肽或蛋白质可以为单体的或多聚的。
多肽(例如,抗体)的“变体”包括其中相对于另一多肽序列,一个或多个氨基酸残基插入氨基酸序列中、从氨基酸序列删除和/或被置换的氨基酸序列。公开的变体包括,例如,融合蛋白。
多肽的“衍生物”为已经进行化学修饰的多肽(例如,抗体),例如,通过与另一化学部分(比如,聚乙二醇或白蛋白,例如,人血清白蛋白)偶联、磷酸化和糖基化。除非另有说明,除了包括2条全长重链和两条全长轻链的抗体之外,术语“抗体”包括其衍生物、变体、片段或突变蛋白,其例子在下文有描述。
“抗原结合蛋白”是包含与抗原结合的部分和,任选地,允许抗原结合部分采取利于抗原结合蛋白与抗原结合的构象的骨架或框架部分的蛋白质。抗原结合蛋白的例子包括抗体、抗体片段(例如,抗体的抗原结合部分)、抗体衍生物和抗体类似物。抗原结合蛋白可以包括,例如,具有移植的CDR或CDR衍生物的可替代的蛋白质骨架或人工骨架。这些骨架包括,但不限于,抗体来源的骨架(包含引入以例如使抗原结合蛋白的三维结构稳定的突变)以及完全合成的骨架(包含,例如,生物相容性聚合物)。参见,例如,Korndorfer等人,2003,Proteins:Structure,Function,and Bioinformatics,Volume 53,Issue 1:121-129;Roque等人,2004,Biotechnol.Prog.20:639-654。此外,可以使用肽抗体模拟物(“PAM”)以及基于抗体模拟物的骨架(利用纤维连接蛋白组分作为骨架)。
抗原结合蛋白可以具有,例如,天然存在的免疫球蛋白的结构。“免疫球蛋白”是四聚体分子。在天然存在的免疫球蛋白中,每个四聚体由两个相同的多肽链对组成,每对具有一条“轻”链(约25kDa)和一条“重”链(约50-70kDa)。每条链的氨基端部分包括主要负责抗原识别的约100至110或更多个氨基酸的可变区。每条链的羧基端部分限定主要负责效应子功能的恒定区。人轻链分类为κ或λ轻链。重链分类为μ、δ、γ、α或ε,并分别定义抗体同种型为IgM、IgD、IgG、IgA和IgE。优选地,本文公开的抗EGFR抗体的特征在于在重链VH和轻链VL氨基酸序列中的其可变域区域序列。优选的抗体为A6,其为κIgG抗体。在轻链和重链内,可变区和恒定区通过约12或更多个氨基酸的“J”区连接,其中重链还包括约10个或更多个氨基酸的“D”区。通常参见,Fundamental Immunology,第7章(Paul,W.编辑,第二版.Raven出版,N.Y.(1989))。每个轻/重链对的可变区形成抗体结合位点,使得完整的免疫球蛋白具有两个结合位点。
“多特异性抗体”是识别在一个或多个抗原上的超过一个表位的抗体。该类型抗体的子类为“双特异性抗体”,其识别在相同或不同抗原上的2个不同的表位。
如果抗原结合蛋白以100纳摩尔或更小的解离常数结合抗原(例如,人CD147),那么其“特异性地结合”该抗原。
“抗原结合结构域”、“抗原结合区”或“抗原结合位点”为含有与抗原相互作用并造成抗原结合蛋白对抗原的特异性和亲和力的氨基酸残基(或其它部分)的抗原结合蛋白的部分。对于特异性地结合其抗原的抗体,这包括其CDR结构域中至少一个的至少一部分。
“表位”为分子的被抗原结合蛋白(例如,被抗体)结合的部分。表位可以包括分子的非邻近部分(例如在多肽中,在多肽的一级序列中不邻近但在多肽的三级和四级结构的情况下彼此足够接近从而能够被抗原结合蛋白结合的氨基酸残基)。
两条多核苷酸或两条多肽序列的“百分同一性”通过利用GAP计算机程序(GCGWisconsin Package的部分,版本10.3(Accelrys,圣地亚哥,加利福尼亚州))使用其默认参数比较序列来确定。
“宿主细胞”为可以用于表达核酸的细胞。宿主细胞可以是原核细胞,例如,大肠杆菌,或其可以是真核细胞,例如,单细胞真核生物(例如,酵母或其它真菌)、植物细胞(例如,烟草或番茄植物细胞)、动物细胞(例如,人细胞、猴细胞、仓鼠细胞、大鼠细胞、小鼠细胞或昆虫细胞)或杂交瘤。宿主细胞的例子包括COS-7系猴肾细胞(ATCC CRL 1651)(参见Gluzman等人,1981,Cell 23:175)、L细胞、C127细胞、3T3细胞(ATCC CCL 163)、中国仓鼠卵巢(CHO)细胞或其衍生物如Veggie CHO和相关细胞系(其在无血清培养基中生长)(Rasmussen等人,1998,Cytotechnology 28:31)或CHO菌株DX-B11(其是DHFR缺陷的)(参见Urlaub等人,1980,Proc.Natl.Acad.Sci.USA 77:4216-20)、HeLa细胞、BHK(ATCC CRL 10)细胞系、源于非洲绿猴肾细胞系CV1的CV1/EBNA细胞系(ATCC CCL 70)(McMahan等人,1991,EMBO J.10:2821)、人胚肾细胞(如293、293EBNA或MSR 293)、人表皮A431细胞、人Colo205细胞、其它转化的灵长类细胞系、正常二倍体细胞、来源于原代组织、原代外植体的体外培养物的细胞株、HL-60、U937、HaK或Jurkat细胞。通常,宿主细胞是可以用多肽编码核酸(其随后可以在宿主细胞中表达)转化或转染的培养细胞。短语“重组宿主细胞”可以用于表示已经用待表达的核酸转化或转染的宿主细胞。宿主细胞也可以为包含核酸但除非将调控序列引入到该宿主细胞中以使得该调控序列可操作地与该核酸连接,否则该核酸不以所需的水平表达的细胞。应该理解,术语宿主细胞不仅仅指特定的受试细胞,还指这种细胞的后代或潜在的后代。因为某些改变可能由于例如突变或环境影响而在后续的世代中出现,因此实际上,这些后代可能与亲代细胞不相同,但仍然包括在本文使用的术语的范围内。
抗原结合蛋白
抗原结合蛋白(例如,抗体、抗体片段、抗体衍生物、抗体突变蛋白和抗体变体)为结合CD147的多肽。
包含一个或多个抗原结合蛋白的寡聚体可以用作CD147拮抗剂。寡聚体可以为共价连接或非共价连接的二聚体、三聚体或更高级的寡聚体的形式。考虑使用包含两个或更多个抗原结合蛋白的寡聚体,一个例子是同源二聚体。其它寡聚体包括异源二聚体、同源三聚体、异源三聚体、同源四聚体、异源四聚体等。
一个实施方式涉及包含通过在与抗原结合蛋白融合的肽部分之间的共价或非共价相互作用连接的多个抗原结合蛋白的寡聚体。这类肽可以是肽接头(间隔物),或具有促进低聚化的性质的肽。亮氨酸拉链和来源于抗体的某些多肽属于能够促进与其连接的抗原结合蛋白的低聚化的肽,如下文更详细描述的。
在特定实施方式中,寡聚体包含两个至四个抗原结合蛋白。寡聚体的抗原结合蛋白可以是任何形式的,如上述形式的任何一种,例如,变体或片段。优选地,寡聚体包含具有CD147结合活性的抗原结合蛋白。
在一个实施方式中,寡聚体使用源自免疫球蛋白的多肽制备。例如,Ashkenazi等人,1991,Proc.Natl.Acad.Sci.USA 88:10535、Byrn等人,1990,Nature 344:677和Hollenbaugh等人,1992"Construction of Immunoglobulin Fusion Proteins",CurrentProtocols in Immunology,Suppl.4,第10.19.1-10.19.11页已经描述了包含与抗体来源的多肽的各个部分(包括Fc结构域)融合的某些异源多肽的融合蛋白的制备。
一个实施方式涉及通过将抗-CD147抗体的CD147结合片段与抗体的Fc区融合产生的包含两个融合蛋白的二聚体。可以通过例如,将编码融合蛋白的基因融合体插入合适的表达载体中,在用重组表达载体转化的宿主细胞中表达该基因融合体和使表达的融合蛋白非常像抗体分子一样地组装,由此在Fc部分之间形成链间二硫键以产生二聚体来制备该二聚体。
术语“Fc多肽”包括源自抗体Fc区的多肽的天然和突变蛋白形式。也包括含有促进二聚化的铰链区的这种多肽的截短形式。包含Fc部分的融合蛋白(以及由其形成的寡聚体)具有如下优势:易于通过在蛋白A或蛋白G柱上的亲和色谱纯化。
制备低聚抗原结合蛋白的另一方法包括使用亮氨酸拉链。亮氨酸拉链结构域为促进亮氨酸拉链结构域存在于其中的蛋白质的低聚化的肽。亮氨酸拉链最初在几种DNA结合蛋白中识别(Landschulz等人,1988,Science 240:1759),并且此后在多种不同的蛋白质中发现。已知的亮氨酸拉链中有二聚化或三聚化的天然存在的肽及其衍生物。WO94/10308中描述了适于产生可溶性低聚蛋白的亮氨酸拉链结构域的例子,并且Hoppe等人,1994,FEBSLetters 344:191中描述了来源于肺表面活性蛋白D(SPD)的亮氨酸拉链。Fanslow等人,1994,Semin.Immunol.6:267-78中描述了修饰的亮氨酸拉链的使用,该修饰的亮氨酸拉链允许与其融合的异源蛋白质稳定地三聚化。在一种方法中,在合适的宿主细胞中表达包含与亮氨酸拉链肽融合的抗CD147抗体片段或衍生物的重组融合蛋白,并从培养物上清液回收形成的可溶性低聚抗-CD147抗体片段或衍生物。
可以通过常规技术产生本发明的抗原结合蛋白的抗原结合片段。这些片段的例子包括,但不限于Fab和F(ab')2片段。
本公开提供了结合CD147的单克隆抗体。单克隆抗体可以利用本领域已知的任何技术产生,例如,通过使在完成免疫方案后从转基因动物中收集的脾细胞永生化。可以使用本领域已知的任何技术使脾细胞永生化,例如,通过使脾细胞与骨髓瘤细胞融合以产生杂交瘤。在产生杂交瘤的融合过程中使用的骨髓瘤细胞优选为不产生抗体的,具有高融合效率和酶缺陷的(这使得该骨髓瘤细胞不能在仅支持期望的融合细胞(杂交瘤)生长的某些选择培养基中生长)。在小鼠融合中使用的合适的细胞系的例子包括Sp-20、P3-X63/Ag8、P3-X63-Ag8.653、NS1/1.Ag 41、Sp210-Ag14、FO、NSO/U、MPC-11、MPC11-X45-GTG1.7和S194/5XX0Bul;在大鼠融合中使用的细胞系的例子包括R210.RCY3、Y3-Ag1.2.3、IR983F和48210。可用于细胞融合的其它细胞系为U-266、GM1500-GRG2、LICR-LON-HMy2和UC729-6。
针对CD147的抗原结合蛋白可以在体外或体内用于,例如,检测CD147多肽的存在的分析中。也可以采用该抗原结合蛋白通过免疫亲和色谱纯化CD147蛋白。阻断性抗原结合蛋白可以用于本文公开的方法中。可以使用作为CD147拮抗剂发挥作用的抗原结合蛋白治疗任何CD147诱导的病症,包括但不限于各种癌症。
抗原结合蛋白可以在体外过程中使用,或体内施用以抑制CD147诱导的生物活性。因此,可以治疗由CD147的蛋白水解活化(直接或间接地)引起或恶化的病症,本文提供了其实例。在一个实施方式中,本发明提供治疗方法,包括对需要的哺乳动物体内施用有效降低CD147诱导的生物活性的量的CD147阻断抗原结合蛋白。
抗原结合蛋白包括抑制CD147的生物活性的全人单克隆抗体。
可以通过许多常规技术的任何一种制备抗原结合蛋白。例如,它们可以从天然表达该抗原结合蛋白的细胞纯化(例如,抗体可以从产生该抗体的杂交瘤纯化),或利用本领域已知的任何技术在重组表达体系中产生。参见,例如,Monoclonal Antibodies,Hybridomas:A New Dimension in Biological Analyses,Kennet等人.(编辑),Plenum出版社,纽约(1980)和Antibodies:A Laboratory Manual,Harlow and Land(编辑),ColdSpring Harbor Laboratory出版社,冷泉港实验室,纽约(1988)。
可以使用本领域已知的任何表达系统制备本发明的重组多肽。通常,用包含编码所需多肽的DNA的重组表达载体转化宿主细胞。可以采用的宿主细胞包括原核细胞、酵母或高等真核细胞。原核细胞包括革兰氏阴性或革兰氏阳性生物体,例如,大肠杆菌或芽孢杆菌。高等真核细胞包括昆虫细胞和哺乳动物来源的已建立细胞系。合适的哺乳动物宿主细胞系的例子包括COS-7系猴肾细胞(ATCC CRL 1651)(Gluzman等人,1981,Cell 23:175)、L细胞、293细胞、C127细胞、3T3细胞(ATCC CCL 163)、中国仓鼠卵巢(CHO)细胞、HeLa细胞、BHK(ATCC CRL 10)细胞系和如McMahan等人,1991,EMBO J.10:2821所述的源自非洲绿猴肾细胞系CV1的CV1/EBNA细胞系(ATCC CCL 70)。Pouwels等人,(Cloning Vectors:ALaboratory Manual,Elsevier,N.Y.,1985)描述了用于细菌、真菌、酵母和哺乳动物细胞宿主的合适的克隆和表达载体。
转化的细胞可以在促进多肽表达的条件下培养,并且多肽通过常规蛋白质纯化过程回收。一种这样的纯化过程包括使用亲和色谱,例如在CD147的全部或部分(例如,细胞外结构域)与其结合的基质上。本文考虑使用的多肽包括基本上没有污染的内源物质的基本上同源的重组哺乳动物抗-CD147抗体多肽。
可以通过许多已知技术中的任何一种制备抗原结合蛋白并针对所需的性质进行筛选。某些技术包括分离编码目标抗原结合蛋白(例如,抗-CD147抗体)的多肽链(或其部分)的核酸,和通过重组DNA技术操作该核酸。例如,核酸可以与另一目标核酸融合,或被改变(例如,通过诱突或其它常规技术)以添加、删除或置换一个或多个氨基酸残基。
单链抗体可以通过经由氨基酸桥(短肽接头)连接重链和轻链可变域(Fv区)片段而得到单一多肽链来形成。这样的单链Fv(scFv)通过将编码肽接头的DNA在编码两个可变域多肽(VL和VH)的DNA之间融合来制备。取决于在两个可变域之间的柔性接头的长度,得到的多肽可以本身回折以形成抗原结合单体,或其可以形成多聚体(例如,二聚体、三聚体或四聚体)(Kortt等人,1997,Prot.Eng.10:423;Kortt等人,2001,Biomol.Eng.18:95-108)。通过将不同的包含VL和VH的多肽组合可以形成结合不同表位的多聚scFv(Kriangkum等人,2001,Biomol.Eng.18:31-40)。为产生单链抗体而开发的技术包括在美国专利4,946,778;Bird,1988,Science 242:423;Huston等人,1988,Proc.Natl.Acad.Sci.USA 85:5879;Ward等人,1989,Nature 334:544和de Graaf等人,2002,Methods Mol.Biol.178:379-87中描述的那些技术。
已知用于从目标抗体衍生不同亚类或同种型的抗体(即,亚类转换)的技术。因此,例如,可以从IgM抗体衍生IgG抗体,反之亦然。这些技术允许制备具有给定抗体(亲本抗体)的抗原结合性质,但也展示与不同于亲本抗体的抗体同种型或亚类相关的生物学性质的新抗体。可以采用重组DNA技术。在这些过程中可以采用编码特定抗体多肽的克隆的DNA,例如,编码所需同种型的抗体的恒定域的DNA(Lantto等人,2002,Methods Mol.Biol.178:303-16)。此外,如果IgG4是需要的,那么在铰链区中引入点突变(CPSCP->CPPCP)(Bloom等人,1997,Protein Science 6:407)以减轻形成H链内二硫键(其可以导致IgG4抗体的异质性)的趋势也可能是理想的。
在特定实施方式中,本发明的抗原结合蛋白对CD147的结合亲和力(Ka)为至少106。在其它实施方式中,抗原结合蛋白表现的Ka为至少107、至少108、至少109或至少1010。在另一实施方式中,该抗原结合蛋白表现的Ka与本文实施例中描述的抗体的Ka基本上相同。
在另一实施方式中,本公开提供了对CD147具有低解离速率的抗原结合蛋白。在一个实施方式中,该抗原结合蛋白的Koff为1×10-4至10-1或更低。在另一实施方式中,该Koff为5×10-5至10-1或更低。在另一实施方式中,该Koff与本文描述的抗体的Koff基本上相同。在另一实施方式中,该抗原结合蛋白以与本文描述的抗体基本上相同的Koff结合CD147。
在另一方面,本公开提供抑制CD147的活性的抗原结合蛋白。在一个实施方式中,该抗原结合蛋白的IC50为1000nM或更低。在另一实施方式中,该IC50为100nM或更低;在另一实施方式中,该IC50为10nM或更低。在另一实施方式中,该IC50与在本文实施例中描述的抗体的IC50基本上相同。在另一实施方式中,该抗原结合蛋白以与本文描述的抗体基本上相同的IC50抑制CD147的活性。
在另一方面,本公开提供了结合在细胞表面上表达的人CD147的抗原结合蛋白,且在如此结合时,其抑制细胞中的CD147信号传导活性而不导致细胞表面上CD147量的显著下降。可以使用任何测定或估算细胞表面上和/或内部的CD147量的方法。在其它实施方式中,抗原结合蛋白与CD147表达细胞的结合导致少于约75%、50%、40%、30%、20%、15%、10%、5%、1%或0.1%的细胞表面CD147内化。
在另一方面,本公开提供了在体外或体内(例如,当施用于人类受试者时)具有至少一天的半衰期的抗原结合蛋白。在一个实施方式中,抗原结合蛋白的半衰期为至少三天。在另一实施方式中,抗原结合蛋白的半衰期为四天或更长。在另一实施方式中,该抗原结合蛋白的半衰期为八天或更长。在另一实施方式中,抗原结合蛋白被衍生化或修饰以使得其相比于未衍生化或未修饰的抗原结合蛋白具有更长的半衰期。在另一实施方式中,抗原结合蛋白含有一个或多个点突变以增加血清半衰期,比如在WO00/09560中所述,该文献通过引入并入本文。
本公开进一步提供了多特异性抗原结合蛋白,例如,双特异性抗原结合蛋白,比如,通过两个不同的抗原结合位点或区域结合CD147的两个不同表位,或结合CD147的表位和另一分子的表位的抗原结合蛋白。此外,本文公开的双特异性抗原结合蛋白可以包含来自本文描述的抗体之一的CD147结合位点和来自本文描述抗体中另一种(包括通过引用其它公开文献在本文中描述的那些)的第二CD147结合区域。可选地,双特异性抗原结合蛋白可以包含来自本文描述的抗体之一的抗原结合位点和来自本领域已知的另一CD147抗体或来自通过已知的方法或本文描述的方法制备的抗体的第二抗原结合位点。
本领域已知许多用于制备双特异性抗体的方法。这些方法包括如Milstein等人,1983,Nature 305:537描述的杂种-杂交瘤的使用和抗体片段的化学偶联(Brennan等人,1985,Science 229:81;Glennie等人,1987,J.Immunol.139:2367;美国专利号6,010,902)。此外。可以通过重组手段产生双特性抗体,例如,通过利用亮氨酸拉链部分(即,来自Fos和Jun蛋白,其优先形成异源二聚体;Kostelny等人,1992,J.Immunol.148:1547)或如美国专利号5,582,996中描述的其它“锁-钥”相互作用的结构域结构。另外的有用技术包括美国专利号5,959,083和5,807,706中描述的那些技术。
在另一方面,该抗原结合蛋白包括抗体的衍生物。衍生化的抗体可以包含赋予该抗体所需的性质(比如,在特定用途中增加的半衰期)的任何分子或物质。衍生化的抗体可以包含,例如,可检测(或标记)的部分(例如,放射性的、比色的、抗原性的或酶性的分子),可检测的珠(例如,磁珠或电子致密(例如,金)珠)或者结合另一分子(例如,生物素或链霉亲和素)的分子,治疗或诊断部分(例如,放射性的、细胞毒性的或在药学活性的部分),或者增加抗体对特定用途(例如,施用于受试者如人类受试者,或其它体内或体外用途)的适用性的分子。可以用于抗体衍生化的分子的例子包括白蛋白(例如,人血清白蛋白)和聚乙二醇(PEG)。可以利用本领域公知的技术制备白蛋白连接的和聚乙二醇化的抗体衍生物。在一个实施方式中,抗体与转甲状腺素蛋白(TTR)或TTR变体缀合或以其他方式连接。TTR或TTR变体可以用例如选自以下的化学物质进行化学修饰:葡聚糖、聚(n-乙烯基吡咯烷酮)、聚乙二醇、丙二醇均聚物、聚环氧丙烷/环氧乙烷共聚物、聚氧乙烯化多元醇和聚乙烯醇。
所有鉴别的mAb使用ELISA筛选与重组人和鼠CD147蛋白(可从R&D Systems或SinoBiologies商购)交叉反应。使用OctetRed仪,公开的mAb评估针对重组人CD147蛋白的亲和力并基于亲和力数据分级。所公开的克隆显示出针对人CD147的至少单位数纳摩尔的亲和力。
优选地,所公开的抗体通过吸入施用,但完全IgG抗体的雾化可能证明由于其分子大小(~150kDa)导致的限制。为使可商购的雾化装置最大化,较小的Fab片段可能是需要的。在这种情况下,我们也可能需要从亲本IgG分子生成Fab片段。因此,我们使用标准酶基消化方法进行初步研究以生成Fab片段,其然后与全IgG分子平行地表征。
实施例1
本实施例提供CD147结合剂对重组小鼠CD147的交叉反应性的分析。简言之,NI-NTA ELISA板捕获有重组人或小鼠CD147,且然后用抗-CD147抗体孵育。测量抗体的结合。图1和2显示七种抗-CD147抗体可以结合人或小鼠CD147两者。
实施例2
本实施例显示抗-CD147抗体与人癌细胞上表达的内源人CD147的结合,如通过流式细胞术测定的。抗体的EC50值如下测定。
CD147表达细胞(PC-3、A549或K562)用无酶细胞解离缓冲剂(GIBCO)收获并转移到V-形底96孔板(50,000细胞/孔)。细胞用FACS缓冲液(PBS+2%FBS)中的系列稀释的抗-CD147抗体在冰上孵育45min。在FACS缓冲液中2次洗涤后,添加1:1000稀释的藻红蛋白偶联抗-人IgG(γ-链特异性的)并孵育20min。在最终洗涤后,荧光强度在Intellicyt HighThroughput Flow Cytometer(HTFC)上测量。数据使用Graphpad Prism软件和非线性回归拟合进行分析。数据点显示为阳性标记的细胞的中位荧光强度(MFI)+/-标准误。EC50值报告为获得50%的最大CD147抗体与CD147表达细胞的结合的抗体浓度。
如图3A-C和表1中所示,所选择的抗体以可变的亲和力与表达的细胞CD147结合,并显示0.6-168nM范围的EC50值。表1:表1总结抗-CD147抗体与任一表达CD147的细胞的结合特征(EC50,以NanoMol.L-1计)。
表1
实施例2
本实施例阐明了显示抗-CD147抗体在使用第二抗体-药物偶联物技术(*)的细胞毒性分析中的评估的体外数据。本实施例证明抗-CD147用作抗体药物偶联物的潜能。
*"Secondary Antibody-Drug Conjugates As Tools for ADC Discovery".Helen Mao,Poster(IBC 24*Annual,2013).
CD147表达细胞(A549或PC-3)用无酶细胞解离缓冲剂(GIBCO)收获,接种到白色96-孔透明底平板(1,000细胞/孔,90ul)中并允许在37℃下粘附过夜。抗体在细胞培养基中以1:4的摩尔比与ProteinG-DM1(Concortis Biosystems)预复合。在室温下10min后,系列稀释的抗体-ProteinG-DM1复合物在细胞培养基中制备,在室温下再孵育10min,并一式三份添加到细胞(10μl/孔)。在37℃下96H孵育后,细胞增殖如下分析:100μl的Cell TiterGlo缓冲液(Promega)添加到各孔。平板在室温下伴随振摇孵育20min。发光信号然后在Flexstation 3读板仪(Molecular Device)上测量。数据报告为相对发光单位。剂量-反应曲线在GraphPad prism中生成,且IC50值使用非线性回归拟合计算(log(抑制剂)vs.反应-变量斜率方程(variable slope equation))。
图2中显示的结果表明抗-CD147抗体,特别是C4sh1A6和C4sh1B2,可以在与细胞毒素如DM-1复合时诱导细胞杀伤。这阐明了CD147抗体作为抗体-药物偶联物的潜能。
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<213> 智人
<400> 12
Gln Ser Val Val Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr
20 25 30
Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Thr Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Arg Ser
85 90 95
Ser Thr Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105 110
<210> 13
<211> 119
<212> PRT
<213> 智人
<400> 13
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
Gly Leu Ile Lys Pro Ser Ser Gly Ser Thr Thr Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Glu Gly Ile Gly Ala Ala Ser Asn Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 14
<211> 109
<212> PRT
<213> 智人
<400> 14
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
20 25 30
His Tyr Pro Tyr Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Thr
35 40 45
Leu Ile Tyr Asp Thr Ser Asn Lys His Ser Trp Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Leu Leu Ser Tyr Ser Gly
85 90 95
Ala Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105
<210> 15
<211> 119
<212> PRT
<213> 智人
<400> 15
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
Gly Leu Ile Lys Pro Ser Ser Gly Ser Thr Thr Tyr Pro Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Glu Gly Ile Gly Ala Ala Ser Asn Asp Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 16
<211> 109
<212> PRT
<213> 智人
<400> 16
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Asp Val Thr Ser Gly
20 25 30
His Tyr Pro Tyr Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Thr
35 40 45
Leu Ile Tyr Asp Thr Ser Asn Lys His Ser Trp Thr Pro Ala Arg Phe
50 55 60
Ser Ala Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Leu Leu Ala Tyr Ser Glu
85 90 95
Val Arg Val Phe Gly Gly Gly Thr Gln Leu Thr Val Leu
100 105
<210> 17
<211> 124
<212> PRT
<213> 智人
<400> 17
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Arg Ser Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Phe Leu Asn Pro Ser Asp Gly Gly Thr Thr Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Val Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asn Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Gly Ile Thr Ser Thr Glu Thr Arg Ala Glu Tyr Phe Gln
100 105 110
His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 18
<211> 110
<212> PRT
<213> 智人
<400> 18
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Val Thr Ile Ser Cys Thr Gly Ser Ala Ser Asp Ile Gly His Ser
20 25 30
Phe Tyr Val Ser Trp Tyr Arg Gln Tyr Pro Gly Lys Ala Pro Asp Leu
35 40 45
Leu Ile Phe Gln Val Asn Gln Arg Pro Ser Gly Val Pro Asn Arg Phe
50 55 60
Ser Ala Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu
65 70 75 80
Gln Ile Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Ala Gly Gly
85 90 95
Thr Ser Ile Val Phe Gly Ser Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 19
<211> 118
<212> PRT
<213> 智人
<400> 19
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Trp Val His Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45
Gly Leu Ile Lys Pro Arg Asp Gly Ala Thr Thr Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Leu Thr Arg Asp Thr Ser Thr Thr Thr Val Tyr
65 70 75 80
Met Glu Leu Thr Ser Leu Arg Ser Glu Asp Thr Gly Ile Tyr Tyr Cys
85 90 95
Gly Leu Leu Glu Gly Asp Asp Ala Phe Asp Val Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser
115
<210> 20
<211> 109
<212> PRT
<213> 智人
<400> 20
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
20 25 30
His Tyr Pro Tyr Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Arg Thr
35 40 45
Leu Ile Tyr Asp Thr Ser Asn Lys His Ser Trp Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Leu Leu Ser Tyr Ser Gly
85 90 95
Ala Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 21
<211> 119
<212> PRT
<213> 智人
<400> 21
Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Ser Tyr Gly Ser Gly Ser Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 22
<211> 108
<212> PRT
<213> 智人
<400> 22
Glu Thr Thr Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Gln
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 23
<211> 125
<212> PRT
<213> 智人
<400> 23
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Gly Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val
35 40 45
Ala Gly Ile Ile Trp Asn Gly Gly Thr Thr Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Asp Leu Asn Tyr Tyr Ile Ser Gly Asp Tyr Tyr Asp Ala Phe
100 105 110
Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120 125
<210> 24
<211> 108
<212> PRT
<213> 智人
<400> 24
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala
20 25 30
Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45
Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 25
<211> 109
<212> PRT
<213> 智人
<400> 25
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Asp Thr Gly Ala Val Asn Ser Gly
20 25 30
His Tyr Pro Tyr Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Ala
35 40 45
Leu Ile Tyr Asp Thr Gly Asn Lys His Ser Trp Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Leu Leu Ser Tyr Ser Gly
85 90 95
Thr Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 26
<211> 122
<212> PRT
<213> 智人
<400> 26
Glu Val Gln Leu Leu Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Pro Lys Gly His Ser Gly Gly Trp Tyr Ala Phe Asp Ile Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 27
<211> 110
<212> PRT
<213> 智人
<400> 27
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Arg Arg
20 25 30
Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Asn Asp Arg Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Glu Leu Gln
65 70 75 80
Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Thr Asn Leu
85 90 95
Ser Ala Gly Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 28
<211> 119
<212> PRT
<213> 智人
<400> 28
Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ala Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Ser
20 25 30
Arg Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu
35 40 45
Trp Leu Gly Arg Thr Phe Tyr Arg Ser Arg Trp Asn Asn Glu Tyr Ala
50 55 60
Glu Thr Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Thr Asn
65 70 75 80
His Phe Ser Leu Gln Leu Thr Ser Val Ser Pro Glu Asp Thr Ala Ile
85 90 95
Tyr Tyr Cys Ala Arg Gly Gly Gly Asn Phe Asp Ser Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 29
<211> 90
<212> PRT
<213> 智人
<400> 29
Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Tyr Val Ser Trp Tyr Gln
1 5 10 15
Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Asp Asn Asn Lys
20 25 30
Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr
35 40 45
Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln Thr Gly Asp Glu Ala Asp
50 55 60
Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu Ser Ala Gly Asp Val Val
65 70 75 80
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
85 90
<210> 30
<211> 119
<212> PRT
<213> 智人
<400> 30
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Ser Glu Asp Ser Ile Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 31
<211> 109
<212> PRT
<213> 智人
<400> 31
Ala Ile Gln Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ala Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Ile Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Asn Arg Ala Thr Asp Ile Pro Ala Arg Phe Ile
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro
85 90 95
Arg Asn Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 32
<211> 109
<212> PRT
<213> 智人
<400> 32
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Asn Thr Gly Ala Val Thr Ser Gly
20 25 30
His Tyr Pro Tyr Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Thr
35 40 45
Leu Ile Tyr Asp Ala Thr Asn Lys Gln Ser Trp Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Asp Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Leu Leu Ser Tyr Ser Gly
85 90 95
Val Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 33
<211> 109
<212> PRT
<213> 智人
<400> 33
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
20 25 30
His Tyr Pro Tyr Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Thr
35 40 45
Leu Ile Tyr Asp Thr Ser Asn Lys His Ser Trp Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Asp Tyr Phe Cys Leu Leu Ser Ser Ser Gly
85 90 95
Ala Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 34
<211> 117
<212> PRT
<213> 智人
<400> 34
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Arg Lys Pro Gly Ala
1 5 10 15
Ser Val Met Val Ser Cys Lys Ala Ser Gly Tyr Pro Phe Thr Ser Tyr
20 25 30
Ala Ile His Trp Leu Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met
35 40 45
Gly Trp Ile Lys Pro Ala Asn Gly Asp Ile Thr Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Gly Asp Ile Ser Ala Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Thr Lys Gly Gly Gly Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 35
<211> 110
<212> PRT
<213> 智人
<400> 35
Gln Ser Val Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val His Lys Arg Pro Ser Gly Thr Ser Thr Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Arg Ser Gly
85 90 95
Ser Thr Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105 110
<210> 36
<211> 118
<212> PRT
<213> 智人
<400> 36
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Arg Ile Ser Cys Gln Gly Ser Gly Tyr Ser Phe Ile Asn His
20 25 30
Trp Ile Ser Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Arg Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Ser Pro Ser Val
50 55 60
Gln Gly His Val Thr Ile Ser Val Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg His Asp Arg Asn Val Tyr Phe Asp Pro Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 37
<211> 110
<212> PRT
<213> 智人
<400> 37
Ser Tyr Glu Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Lys Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105 110
<210> 38
<211> 117
<212> PRT
<213> 智人
<400> 38
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Arg Lys Pro Gly Ala
1 5 10 15
Ser Val Met Val Ser Cys Lys Ala Ser Gly Tyr Pro Phe Thr Ser Tyr
20 25 30
Ala Ile His Trp Leu Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met
35 40 45
Gly Trp Ile Lys Pro Ala Asn Gly Asp Ile Thr Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Gly Asp Ile Ser Ala Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Lys Gly Gly Gly Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 39
<211> 110
<212> PRT
<213> 智人
<400> 39
Ser Tyr Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asn Tyr
20 25 30
Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Leu Val Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Thr Ser
85 90 95
Ser Thr Tyr Val Phe Gly Ile Gly Thr Lys Val Thr Val Leu
100 105 110
<210> 40
<211> 117
<212> PRT
<213> 智人
<400> 40
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Arg Lys Pro Gly Ala
1 5 10 15
Ser Val Met Val Ser Cys Lys Ala Ser Gly Tyr Pro Phe Thr Ser Tyr
20 25 30
Ala Ile His Trp Leu Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met
35 40 45
Gly Trp Ile Lys Pro Ala Asn Gly Asp Ile Thr Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Gly Asp Ile Ser Ala Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Lys Gly Gly Gly Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 41
<211> 110
<212> PRT
<213> 智人
<400> 41
Gln Ser Val Leu Thr Gln Pro Ala Ser Met Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr
20 25 30
Asp Leu Val Ser Trp Tyr Gln Gln Tyr Pro Gly Lys Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Asp Val Ala Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Ala Gly Thr
85 90 95
Lys Val Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105 110
<210> 42
<211> 115
<212> PRT
<213> 智人
<400> 42
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Trp Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 43
<211> 107
<212> PRT
<213> 智人
<400> 43
Asp Val Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ala Thr Asn
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Ala Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Phe Gly Thr Tyr Tyr Cys Gln Gln Tyr Asn Asn Tyr Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 44
<211> 117
<212> PRT
<213> 智人
<400> 44
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val
35 40 45
Ala Gly Ile Ser Tyr Asp Gly Ser Asn Lys Tyr His Ala Asp Pro 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 Asn Leu Arg Val Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Gly Asp Arg Ser Gly Gly Leu Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 45
<211> 107
<212> PRT
<213> 智人
<400> 45
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Ser Gly Lys Ala Pro Lys Leu Leu Leu
35 40 45
Tyr Ala Ala Ser Gly Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Met Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 46
<211> 112
<212> PRT
<213> 智人
<400> 46
Gln Pro Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Leu Val Ala Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Ser His Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105 110
<210> 47
<211> 116
<212> PRT
<213> 智人
<400> 47
Glu Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val
100 105 110
Thr Val Ser Ser
115
<210> 48
<211> 110
<212> PRT
<213> 智人
<400> 48
Gln Ala Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr
20 25 30
Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Glu Val Arg Lys Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Ala Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Thr Ser Ser
85 90 95
Ser Thr Phe Val Phe Gly Ala Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 49
<211> 115
<212> PRT
<213> 智人
<400> 49
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Trp Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 50
<211> 110
<212> PRT
<213> 智人
<400> 50
Ser Tyr Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Thr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Phe Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Met
85 90 95
Arg Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 51
<211> 116
<212> PRT
<213> 智人
<400> 51
Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Ile Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ser Thr Asn Phe Asp Ser Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 52
<211> 110
<212> PRT
<213> 智人
<400> 52
Gln Ala Gly Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Ser Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Ile Asn Ser
85 90 95
Gly Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 53
<211> 110
<212> PRT
<213> 智人
<400> 53
Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ala Asp Val Gly His Tyr
20 25 30
Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Ser Thr Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ser Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Tyr Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 54
<211> 120
<212> PRT
<213> 智人
<400> 54
Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Asp Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Ser Glu Ala Tyr Tyr His Gly Met Asp Val Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 55
<211> 110
<212> PRT
<213> 智人
<400> 55
Asn Phe Met Leu Thr Gln Pro Pro Ser Ala Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Thr Ser Asn Ile Gly Ser Asn
20 25 30
Tyr Val Phe Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu
85 90 95
Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 56
<211> 107
<212> PRT
<213> 智人
<400> 56
Glu Ile Val 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 Arg Asn Ile Lys Thr Ala
20 25 30
Leu Ala Trp Phe Gln Gln Arg Pro Gly Gln Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu His Ser Gly Val Thr Ser Arg Phe Ser Gly
50 55 60
Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ser Tyr Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 57
<211> 117
<212> PRT
<213> 智人
<400> 57
Glu Val Gln Leu Leu Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Pro Phe Thr Ser Tyr
20 25 30
Ala Ile His Trp Leu Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Met
35 40 45
Gly Trp Ile Lys Pro Ala Asn Gly Asp Ile Thr Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Gly Asp Ile Ser Ala Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Lys Gly Gly Gly Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 58
<211> 110
<212> PRT
<213> 智人
<400> 58
Gln Ala Gly Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Trp Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ala Tyr
20 25 30
Asn Leu Val Ser Trp Tyr Gln Gln Tyr Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Thr Thr Tyr Val Phe Gly Thr Gly Thr Gln Leu Thr Val Leu
100 105 110
<210> 59
<211> 112
<212> PRT
<213> 智人
<400> 59
Gln Pro Val Leu Thr Gln Pro Arg Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Arg Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asp Arg Pro Ser Gly Val Ser Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Phe Thr Ser Arg
85 90 95
Thr Thr Pro Ala Tyr Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 60
<211> 120
<212> PRT
<213> 智人
<400> 60
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Thr Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ser Lys Asn Ala Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Gly Trp Val Val His Ala Met Asp Val Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 61
<211> 109
<212> PRT
<213> 智人
<400> 61
Gln Ser Val Val Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln
65 70 75 80
Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser Asn
85 90 95
Thr Leu Ile Phe Gly Gly Gly Thr Lys Val Thr Val Leu
100 105
<210> 62
<211> 111
<212> PRT
<213> 智人
<400> 62
Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr
20 25 30
Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Glu Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Leu Tyr Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 63
<211> 115
<212> PRT
<213> 智人
<400> 63
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Trp Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 64
<211> 110
<212> PRT
<213> 智人
<400> 64
Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln His His Pro Asp Arg Ala Pro Lys Leu
35 40 45
Met Leu Tyr His Val Thr Gln Arg Pro Ser Gly Ile Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Thr
85 90 95
Ser Thr Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
100 105 110
Claims (12)
1.一种以至少10-6M的结合亲和力结合CD147表位的IgG类的全人抗体,其具有与选自以下的氨基酸序列至少95%相同的重链可变域:SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ ID NO.11、SEQ ID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ ID NO.23、SEQ ID NO.26、SEQ ID NO.28、SEQ IDNO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ ID NO.38、SEQ ID NO.41、SEQ ID NO.43、SEQ IDNO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ ID NO.53、SEQ ID NO.56、SEQ ID NO.59、SEQ IDNO.62及其组合,且具有与以下的氨基酸序列至少95%相同的轻链可变域:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ ID NO.8、SEQ ID NO.10、SEQ ID NO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ ID NO.20、SEQ ID NO.22、SEQ ID NO.24、SEQ IDNO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ ID NO.31、SEQ ID NO.32、SEQ ID NO.33、SEQ IDNO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ ID NO.40、SEQ ID NO.42、SEQ ID NO.44、SEQ IDNO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ ID NO.51、SEQ ID NO.52、SEQ ID NO.54、SEQ IDNO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ ID NO.60、SEQ ID NO.61、SEQ ID NO.63及其组合。
2.如权利要求1所述的全人抗体,其中所述抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2(本文中称为C4R1A2)、SEQ ID NO.3/SEQ ID NO.4(本文中称为C4R1A5)、SEQ ID NO.5/SEQ ID NO.6(本文中称为C4R1A6)、SEQ ID NO.7/SEQ ID NO.8(本文中称为C4R1A8)、SEQ ID NO.9/SEQ ID NO.10(本文中称为C4R1A9)、SEQ ID NO.11/SEQ ID NO.12(本文中称为C4R1B2)、SEQ ID NO.13/SEQ ID NO.14(本文中称为C4R1C10)、SEQ ID NO.15/SEQ ID NO.16(本文中称为C4R1C11)、SEQ ID NO.17/SEQ ID NO.18(本文中称为C4R1C3)、SEQ ID NO.19/SEQ ID NO.20(本文中称为C4R1D11)、SEQ ID NO.21/SEQ IDNO.22(本文中称为C4R1F12)、SEQ ID NO.13/SEQ ID NO.25(本文中称为C4R1G1)、SEQ IDNO.26/SEQ ID NO.27(本文中称为C4R1G4)、SEQ ID NO.28/SEQ ID NO.29(本文中称为C4R1G7)、SEQ ID NO.30/SEQ ID NO.31(本文中称为C4R1H10)、SEQ ID NO.13/SEQ IDNO.32(本文中称为C4R1H11)、SEQ ID NO.13/SEQ ID NO.33(本文中称为C4R1H4)、SEQ IDNO.34/SEQ ID NO.35(本文中称为C4sh1Al)、SEQ ID NO.36/SEQ ID NO.37(本文中称为C4sh1A2)、SEQ ID NO.38/SEQ ID NO.39(本文中称为C4sh1A3)、SEQ ID NO.38/SEQ IDNO.40(本文中称为C4sh1A4)、SEQ ID NO.41/SEQ ID NO.42(本文中称为C4sh1A5)、SEQ IDNO.43/SEQ ID NO.44(本文中称为C4sh1A6)、SEQ ID NO.38/SEQ ID NO.45(本文中称为C4sh1A9)、SEQ ID NO.46/SEQ ID NO.47(本文中称为C4sh1B10)、SEQ ID NO.48/SEQ IDNO.49(本文中称为C4sh1B11)、SEQ ID NO.50/SEQ ID NO.51(本文中称为C4sh1B2)、SEQ IDNO.38/SEQ ID NO.52(本文中称为C4sh1C10)、SEQ ID NO.53/SEQ ID NO.54(本文中称为C4sh1C5)、SEQ ID NO.41/SEQ ID NO.54(本文中称为C4sh1C6)、SEQ ID NO.56/SEQ IDNO.57(C4sh1E10)、SEQ ID NO.38/SEQ ID NO.58(本文中称为C4sh1E12)、SEQ ID NO.59/SEQ ID NO.60(本文中称为C4sh1F11)、SEQ ID NO.38/SEQ ID NO.61(本文中称为C4sh1G4)、SEQ ID NO.62/SEQ ID NO.63(本文中称为C4sh1H9)及其组合。
3.一种Fab全人抗体片段,具有来自重链的可变域区域和来自轻链的可变域区域,其中所述重链可变域序列与选自以下的氨基酸序列至少95%同一:SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ ID NO.11、SEQ ID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ ID NO.23、SEQ ID NO.26、SEQ IDNO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ ID NO.38、SEQ ID NO.41、SEQ IDNO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ ID NO.53、SEQ ID NO.56、SEQ IDNO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ ID NO.8、SEQ ID NO.10、SEQ IDNO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ ID NO.20、SEQ ID NO.22、SEQ IDNO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ ID NO.31、SEQ ID NO.32、SEQ IDNO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ ID NO.40、SEQ ID NO.42、SEQ IDNO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ ID NO.51、SEQ ID NO.52、SEQ IDNO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ ID NO.60、SEQ ID NO.61、SEQ IDNO.63及其组合。
4.权利要求3所述的全人抗体Fab片段,其中所述抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2、SEQ ID NO.3/SEQ ID NO.4、SEQ ID NO.5/SEQ IDNO.6、SEQ ID NO.7/SEQ ID NO.8、SEQ ID NO.9/SEQ ID NO.10、SEQ ID NO.11/SEQ IDNO.12、SEQ ID NO.13/SEQ ID NO.14、SEQ ID NO.15/SEQ ID NO.16、SEQ ID NO.17/SEQ IDNO.18、SEQ ID NO.19/SEQ ID NO.20、SEQ ID NO.21/SEQ ID NO.22、SEQ ID NO.13/SEQ IDNO.25、SEQ ID NO.26/SEQ ID NO.27、SEQ ID NO.28/SEQ ID NO.29、SEQ ID NO.30/SEQ IDNO.31、SEQ ID NO.13/SEQ ID NO.32、SEQ ID NO.13/SEQ ID NO.33、SEQ ID NO.34/SEQ IDNO.35、SEQ ID NO.36/SEQ ID NO.37、SEQ ID NO.38/SEQ ID NO.39、SEQ ID NO.38/SEQ IDNO.40、SEQ ID NO.41/SEQ ID NO.42、SEQ ID NO.43/SEQ ID NO.44、SEQ ID NO.38/SEQ IDNO.45、SEQ ID NO.46/SEQ ID NO.47、SEQ ID NO.48/SEQ ID NO.49、SEQ ID NO.50/SEQ IDNO.51、SEQ ID NO.38/SEQ ID NO.52、SEQ ID NO.53/SEQ ID NO.54、SEQ ID NO.41/SEQ IDNO.54、SEQ ID NO.56/SEQ ID NO.57、SEQ ID NO.38/SEQ ID NO.58、SEQ ID NO.59/SEQ IDNO.60、SEQ ID NO.38/SEQ ID NO.61、SEQ ID NO.62/SEQ ID NO.63及其组合。
5.一种单链人抗体,其具有来自重链的可变域区域和来自轻链的可变域区域及连接所述重链和轻链可变域区域的肽接头,其中所述重链可变域序列与选自以下的氨基酸序列至少95%同一:SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ IDNO.11、SEQ ID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ IDNO.23、SEQ ID NO.26、SEQ ID NO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ IDNO.38、SEQ ID NO.41、SEQ ID NO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ IDNO.53、SEQ ID NO.56、SEQ ID NO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ IDNO.8、SEQ ID NO.10、SEQ ID NO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ IDNO.20、SEQ ID NO.22、SEQ ID NO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ IDNO.31、SEQ ID NO.32、SEQ ID NO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ IDNO.40、SEQ ID NO.42、SEQ ID NO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ IDNO.51、SEQ ID NO.52、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ IDNO.60、SEQ ID NO.61、SEQ ID NO.63及其组合。
6.权利要求5所述的全人单链抗体,其中所述单链全人抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2、SEQ ID NO.3/SEQ ID NO.4、SEQ ID NO.5/SEQ IDNO.6、SEQ ID NO.7/SEQ ID NO.8、SEQ ID NO.9/SEQ ID NO.10、SEQ ID NO.11/SEQ IDNO.12、SEQ ID NO.13/SEQ ID NO.14、SEQ ID NO.15/SEQ ID NO.16、SEQ ID NO.17/SEQ IDNO.18、SEQ ID NO.19/SEQ ID NO.20、SEQ ID NO.21/SEQ ID NO.22、SEQ ID NO.13/SEQ IDNO.25、SEQ ID NO.26/SEQ ID NO.27、SEQ ID NO.28/SEQ ID NO.29、SEQ ID NO.30/SEQ IDNO.31、SEQ ID NO.13/SEQ ID NO.32、SEQ ID NO.13/SEQ ID NO.33、SEQ ID NO.34/SEQ IDNO.35、SEQ ID NO.36/SEQ ID NO.37、SEQ ID NO.38/SEQ ID NO.39、SEQ ID NO.38/SEQ IDNO.40、SEQ ID NO.41/SEQ ID NO.42、SEQ ID NO.43/SEQ ID NO.44、SEQ ID NO.38/SEQ IDNO.45、SEQ ID NO.46/SEQ ID NO.47、SEQ ID NO.48/SEQ ID NO.49、SEQ ID NO.50/SEQ IDNO.51、SEQ ID NO.38/SEQ ID NO.52、SEQ ID NO.53/SEQ ID NO.54、SEQ ID NO.41/SEQ IDNO.54、SEQ ID NO.56/SEQ ID NO.57、SEQ ID NO.38/SEQ ID NO.58、SEQ ID NO.59/SEQ IDNO.60、SEQ ID NO.38/SEQ ID NO.61、SEQ ID NO.62/SEQ ID NO.63及其组合。
7.权利要求5所述的全人单链抗体,其中所述全人单链抗体具有重链可变域区域和轻链可变域区域两者,其中所述单链全人抗体具有选自以下的重链/轻链可变域序列:SEQ IDNO.1/SEQ ID NO.2、SEQ ID NO.3/SEQ ID NO.4、SEQ ID NO.5/SEQ ID NO.6、SEQ ID NO.7/SEQ ID NO.8、SEQ ID NO.9/SEQ ID NO.10、SEQ ID NO.11/SEQ ID NO.12、SEQ ID NO.13/SEQ ID NO.14、SEQ ID NO.15/SEQ ID NO.16、SEQ ID NO.17/SEQ ID NO.18、SEQ IDNO.19/SEQ ID NO.20、SEQ ID NO.21/SEQ ID NO.22、SEQ ID NO.13/SEQ ID NO.25、SEQ IDNO.26/SEQ ID NO.27、SEQ ID NO.28/SEQ ID NO.29、SEQ ID NO.30/SEQ ID NO.31、SEQ IDNO.13/SEQ ID NO.32、SEQ ID NO.13/SEQ ID NO.33、SEQ ID NO.34/SEQ ID NO.35、SEQ IDNO.36/SEQ ID NO.37、SEQ ID NO.38/SEQ ID NO.39、SEQ ID NO.38/SEQ ID NO.40、SEQ IDNO.41/SEQ ID NO.42、SEQ ID NO.43/SEQ ID NO.44、SEQ ID NO.38/SEQ ID NO.45、SEQ IDNO.46/SEQ ID NO.47、SEQ ID NO.48/SEQ ID NO.49、SEQ ID NO.50/SEQ ID NO.51、SEQ IDNO.38/SEQ ID NO.52、SEQ ID NO.53/SEQ ID NO.54、SEQ ID NO.41/SEQ ID NO.54、SEQ IDNO.56/SEQ ID NO.57、SEQ ID NO.38/SEQ ID NO.58、SEQ ID NO.59/SEQ ID NO.60、SEQ IDNO.38/SEQ ID NO.61、SEQ ID NO.62/SEQ ID NO.63及其组合。
8.一种用于治疗包括肝细胞癌和鳞状细胞癌的CD147-表达肿瘤和选自类风湿性关节炎、实验性肺损伤、动脉粥样硬化、由丙型肝炎病毒引起的慢性肝疾病、缺血性心肌损伤和心力衰竭的非癌症疾病的方法,该方法包括施用有效量的抗-CD147多肽,其中所述抗-CD147多肽选自以至少10-6M的结合亲和力结合CD147表位的IgG类的全人抗体、具有来自重链的可变域区域和来自轻链的可变域区域的Fab全人抗体片段、具有来自重链的可变域区域和来自轻链的可变域区域及连接所述重链和轻链可变域区域的肽接头的单链人抗体,及其组合;
其中所述全人抗体具有与选自以下的氨基酸序列至少95%同一的重链可变域序列:SEQ ID SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ IDNO.11、SEQ ID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ IDNO.23、SEQ ID NO.26、SEQ ID NO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ IDNO.38、SEQ ID NO.41、SEQ ID NO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ IDNO.53、SEQ ID NO.56、SEQ ID NO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ IDNO.8、SEQ ID NO.10、SEQ ID NO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ IDNO.20、SEQ ID NO.22、SEQ ID NO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ IDNO.31、SEQ ID NO.32、SEQ ID NO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ IDNO.40、SEQ ID NO.42、SEQ ID NO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ IDNO.51、SEQ ID NO.52、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ IDNO.60、SEQ ID NO.61、SEQ ID NO.63及其组合;
其中所述Fab全人抗体片段具有与选自以下的氨基酸序列至少95%同一的重链可变域序列:SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ IDNO.11、SEQ ID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ IDNO.23、SEQ ID NO.26、SEQ ID NO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ IDNO.38、SEQ ID NO.41、SEQ ID NO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ IDNO.53、SEQ ID NO.56、SEQ ID NO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ IDNO.8、SEQ ID NO.10、SEQ ID NO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ IDNO.20、SEQ ID NO.22、SEQ ID NO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ IDNO.31、SEQ ID NO.32、SEQ ID NO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ IDNO.40、SEQ ID NO.42、SEQ ID NO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ IDNO.51、SEQ ID NO.52、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ IDNO.60、SEQ ID NO.61、SEQ ID NO.63及其组合;和
其中所述单链人抗体具有与选自以下的氨基酸序列至少95%同一的重链可变域序列:SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5、SEQ ID NO.7、SEQ ID NO.9、SEQ ID NO.11、SEQID NO.13、SEQ ID NO.15、SEQ ID NO.17、SEQ ID NO.19、SEQ ID NO.21、SEQ ID NO.23、SEQID NO.26、SEQ ID NO.28、SEQ ID NO.30、SEQ ID NO.34、SEQ ID NO.36、SEQ ID NO.38、SEQID NO.41、SEQ ID NO.43、SEQ ID NO.46、SEQ ID NO.48、SEQ ID NO.50、SEQ ID NO.53、SEQID NO.56、SEQ ID NO.59、SEQ ID NO.62及其组合,且具有与由以下组成的氨基酸序列至少95%同一的轻链可变域序列:SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6、SEQ ID NO.8、SEQID NO.10、SEQ ID NO.12、SEQ ID NO.14、SEQ ID NO.16、SEQ ID NO.18、SEQ ID NO.20、SEQID NO.22、SEQ ID NO.24、SEQ ID NO.25、SEQ ID NO.27、SEQ ID NO.29、SEQ ID NO.31、SEQID NO.32、SEQ ID NO.33、SEQ ID NO.35、SEQ ID NO.37、SEQ ID NO.39、SEQ ID NO.40、SEQID NO.42、SEQ ID NO.44、SEQ ID NO.45、SEQ ID NO.47、SEQ ID NO.49、SEQ ID NO.51、SEQID NO.52、SEQ ID NO.54、SEQ ID NO.55、SEQ ID NO.57、SEQ ID NO.58、SEQ ID NO.60、SEQID NO.61、SEQ ID NO.63及其组合。
9.权利要求8所述的用于治疗包括肝细胞癌和鳞状细胞癌的CD147-表达肿瘤和选自类风湿性关节炎、实验性肺损伤、动脉粥样硬化、由丙型肝炎病毒引起的慢性肝疾病、缺血性心肌损伤和心力衰竭的非癌症疾病的方法,其中所述全人抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2、SEQ ID NO.3/SEQ ID NO.4、SEQ ID NO.5/SEQ IDNO.6、SEQ ID NO.7/SEQ ID NO.8、SEQ ID NO.9/SEQ ID NO.10、SEQ ID NO.11/SEQ IDNO.12、SEQ ID NO.13/SEQ ID NO.14、SEQ ID NO.15/SEQ ID NO.16、SEQ ID NO.17/SEQ IDNO.18、SEQ ID NO.19/SEQ ID NO.20、SEQ ID NO.21/SEQ ID NO.22、SEQ ID NO.13/SEQ IDNO.25、SEQ ID NO.26/SEQ ID NO.27、SEQ ID NO.28/SEQ ID NO.29、SEQ ID NO.30/SEQ IDNO.31、SEQ ID NO.13/SEQ ID NO.32、SEQ ID NO.13/SEQ ID NO.33、SEQ ID NO.34/SEQ IDNO.35、SEQ ID NO.36/SEQ ID NO.37、SEQ ID NO.38/SEQ ID NO.39、SEQ ID NO.38/SEQ IDNO.40、SEQ ID NO.41/SEQ ID NO.42、SEQ ID NO.43/SEQ ID NO.44、SEQ ID NO.38/SEQ IDNO.45、SEQ ID NO.46/SEQ ID NO.47、SEQ ID NO.48/SEQ ID NO.49、SEQ ID NO.50/SEQ IDNO.51、SEQ ID NO.38/SEQ ID NO.52、SEQ ID NO.53/SEQ ID NO.54、SEQ ID NO.41/SEQ IDNO.54、SEQ ID NO.56/SEQ ID NO.57、SEQ ID NO.38/SEQ ID NO.58、SEQ ID NO.59/SEQ IDNO.60、SEQ ID NO.38/SEQ ID NO.61、SEQ ID NO.62/SEQ ID NO.63及其组合。
10.权利要求8所述的用于治疗包括肝细胞癌和鳞状细胞癌的CD147-表达肿瘤和选自类风湿性关节炎、实验性肺损伤、动脉粥样硬化、由丙型肝炎病毒引起的慢性肝疾病、缺血性心肌损伤和心力衰竭的非癌症疾病的方法,其中所述全人抗体Fab片段具有重链可变域区域和轻链可变域区域两者,其中所述抗体具有选自以下的重链/轻链可变域序列:SEQ IDNO.1/SEQ ID NO.2,SEQ ID NO.3/SEQ ID NO.4、SEQ ID NO.5/SEQ ID NO.6、SEQ ID NO.7/SEQ ID NO.8、SEQ ID NO.9/SEQ ID NO.10、SEQ ID NO.11/SEQ ID NO.12、SEQ ID NO.13/SEQ ID NO.14、SEQ ID NO.15/SEQ ID NO.16、SEQ ID NO.17/SEQ ID NO.18、SEQ IDNO.19/SEQ ID NO.20、SEQ ID NO.21/SEQ ID NO.22、SEQ ID NO.13/SEQ ID NO.25、SEQ IDNO.26/SEQ ID NO.27、SEQ ID NO.28/SEQ ID NO.29、SEQ ID NO.30/SEQ ID NO.31、SEQ IDNO.13/SEQ ID NO.32、SEQ ID NO.13/SEQ ID NO.33、SEQ ID NO.34/SEQ ID NO.35、SEQ IDNO.36/SEQ ID NO.37、SEQ ID NO.38/SEQ ID NO.39、SEQ ID NO.38/SEQ ID NO.40、SEQ IDNO.41/SEQ ID NO.42、SEQ ID NO.43/SEQ ID NO.44、SEQ ID NO.38/SEQ ID NO.45、SEQ IDNO.46/SEQ ID NO.47、SEQ ID NO.48/SEQ ID NO.49、SEQ ID NO.50/SEQ ID NO.51、SEQ IDNO.38/SEQ ID NO.52、SEQ ID NO.53/SEQ ID NO.54、SEQ ID NO.41/SEQ ID NO.54、SEQ IDNO.56/SEQ ID NO.57、SEQ ID NO.38/SEQ ID NO.58、SEQ ID NO.59/SEQ ID NO.60、SEQ IDNO.38/SEQ ID NO.61、SEQ ID NO.62/SEQ ID NO.63及其组合。
11.权利要求8所述的用于治疗包括肝细胞癌和鳞状细胞癌的CD147-表达肿瘤和选自类风湿性关节炎、实验性肺损伤、动脉粥样硬化、由丙型肝炎病毒引起的慢性肝疾病、缺血性心肌损伤和心力衰竭的非癌症疾病的方法,其中所述全人单链抗体具有重链可变域区域和轻链可变域区域两者,其中所述单链全人抗体具有选自以下的重链/轻链可变域序列:SEQ ID NO.1/SEQ ID NO.2、SEQ ID NO.3/SEQ ID NO.4、SEQ ID NO.5/SEQ ID NO.6、SEQID NO.7/SEQ ID NO.8、SEQ ID NO.9/SEQ ID NO.10、SEQ ID NO.11/SEQ ID NO.12、SEQ IDNO.13/SEQ ID NO.14、SEQ ID NO.15/SEQ ID NO.16、SEQ ID NO.17/SEQ ID NO.18、SEQ IDNO.19/SEQ ID NO.20、SEQ ID NO.21/SEQ ID NO.22、SEQ ID NO.13/SEQ ID NO.25、SEQ IDNO.26/SEQ ID NO.27、SEQ ID NO.28/SEQ ID NO.29、SEQ ID NO.30/SEQ ID NO.31、SEQ IDNO.13/SEQ ID NO.32、SEQ ID NO.13/SEQ ID NO.33、SEQ ID NO.34/SEQ ID NO.35、SEQ IDNO.36/SEQ ID NO.37、SEQ ID NO.38/SEQ ID NO.39、SEQ ID NO.38/SEQ ID NO.40、SEQ IDNO.41/SEQ ID NO.42、SEQ ID NO.43/SEQ ID NO.44、SEQ ID NO.38/SEQ ID NO.45、SEQ IDNO.46/SEQ ID NO.47、SEQ ID NO.48/SEQ ID NO.49、SEQ ID NO.50/SEQ ID NO.51、SEQ IDNO.38/SEQ ID NO.52、SEQ ID NO.53/SEQ ID NO.54、SEQ ID NO.41/SEQ ID NO.54、SEQ IDNO.56/SEQ ID NO.57、SEQ ID NO.38/SEQ ID NO.58、SEQ ID NO.59/SEQ ID NO.60、SEQ IDNO.38/SEQ ID NO.61、SEQ ID NO.62/SEQ ID NO.63及其组合。
12.权利要求8所述的用于治疗包括肝细胞癌和鳞状细胞癌的CD147-表达肿瘤和选自类风湿性关节炎、实验性肺损伤、动脉粥样硬化、由丙型肝炎病毒引起的慢性肝疾病、缺血性心肌损伤和心力衰竭的非癌症疾病的方法,其中所述疾病选自肝细胞癌、结肠腺癌、肺癌、乳腺癌、类风湿性关节炎、实验性肺损伤、动脉粥样硬化、由丙型肝炎病毒引起的慢性肝疾病、缺血性心肌损伤和心力衰竭。
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CN108261544B (zh) * | 2016-12-30 | 2023-05-05 | 江苏太平洋美诺克生物药业股份有限公司 | 稳定的包含cd147单克隆抗体的药物制剂 |
EP3762420A1 (en) * | 2018-03-09 | 2021-01-13 | CytomX Therapeutics, Inc. | Activatable cd147 antibodies and methods of making and use thereof |
EP4087657A1 (en) | 2020-01-08 | 2022-11-16 | Synthis Therapeutics, Inc. | Alk5 inhibitor conjugates and uses thereof |
WO2023174147A1 (en) * | 2022-03-18 | 2023-09-21 | Alphelix Biotech Co., Ltd. | Antibodies specifically binding to cd147 and uses thereof |
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