CN110536904A - Fgfr3结合分子 - Google Patents
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- CN110536904A CN110536904A CN201880022181.4A CN201880022181A CN110536904A CN 110536904 A CN110536904 A CN 110536904A CN 201880022181 A CN201880022181 A CN 201880022181A CN 110536904 A CN110536904 A CN 110536904A
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明涉及与成纤维细胞生长因子受体3同种型3b和3c(FGFR3b和FGFR3c)结合的多肽,其中该多肽包含选自下组的氨基酸序列,该组由以下组成:(a)GVTLFVALYDYEVYGPTPMLSFHKGEKFQIL(X1)(X2)(X3)(X4)GPYWEARSL(X5)TGETG(X6)IPSNYVAPVDSIQ(SEQ ID NO:1),其中氨基酸位置(X1)至(X6)可以是任何氨基酸序列;(b)与(a)的氨基酸序列具有至少95%同一性的氨基酸序列,其中同一性测定不包括氨基酸位置(X1)至(X6)并且条件是在SEQ ID NO:1的氨基酸位置12至19中的氨基酸序列EVYGPTPM(SEQ ID NO:2)是保守的,并且SEQ ID NO:1的氨基酸位置37和38中的氨基酸P和Y是保守的;(c)GVTLFVALYDYEVMSTTALSFHKGEKFQILSQSPHGQYWEARSLTTGETG(X6)IPSNYVAPVDSIQ(SEQ ID NO:19),其中氨基酸位置(X6)可以是任何氨基酸;以及(d)与(c)的氨基酸序列具有至少95%同一性的氨基酸序列,其中同一性测定不包括氨基酸位置(X6)并且条件是在SEQ ID NO:19的氨基酸位置12至18中的氨基酸序列EVMSTTA(SEQ ID NO:20)和SEQ ID NO:19的氨基酸位置31至35中的SQSPH(SEQ ID NO:21)是保守的,并且SEQ ID NO:19的氨基酸位置37和38中的氨基酸Q和Y是保守的。
Description
背景技术
FGFR3是参与细胞内信号传导途径的跨膜酪氨酸激酶受体FGFR家族的四个成员之一。已经显示,通过与成纤维细胞生长因子(FGF)的相互作用激活FGFR在胚胎发生和具有多效性后遗症(包括细胞增殖和存活、迁移、分化和生长停滞)的成人中具有关键作用[1]。
FGFR由细胞外配体结合区(具有两个或三个免疫球蛋白样结构域(IgD1-3))、单通道跨膜区和细胞质分裂酪氨酸激酶结构域组成。
在人中,信号传导由22种FGF配体中的1种介导,并且配体受体特异性由受体的差异细胞表达、调节相互作用的细胞表面蛋白的分泌和受体的选择性剪接控制[1]。FGFR1、2和3各自具有两个主要的可选择地剪接的同种型,命名为IIIb和IIIc。这些同种型在IgD3的后半部分中具有约50个氨基酸差异,并且具有不同的组织分布和配体特异性。FGF配体引起FGFR的二聚化,这导致细胞内酪氨酸激酶结构域的活化和磷酸化。这导致涉及致癌信号传导的若干个关键途径(包括促分裂原活化蛋白激酶(MAPK)和PI3K-AKT途径)的激活。
异常激活的FGFR与特定的人恶性肿瘤有关[2]。特别是,t(4;14)(p16.3;q32)染色体易位发生在约15%-20%的多发性骨髓瘤患者中,导致FGFR3的过表达,并与较短的总体存活相关[2]。FGFR3还涉及赋予培养中的骨髓瘤细胞系化学抗性[3],这与t(4;14)患者对常规化疗的不良临床应答一致[4]。突变激活的FGFR3的过表达足以在造血细胞和成纤维细胞[5-8]、转基因小鼠模型[9]和小鼠骨髓移植模型中诱导致癌转化[9,10]。
因此,已提出FGFR3作为多发性骨髓瘤的潜在治疗靶标。实际上,若干种靶向FGFR的小分子抑制剂尽管对FGFR3没有选择性并且对某些其他激酶具有交叉抑制活性,但已经证明在培养和小鼠模型中对FGFR3阳性骨髓瘤细胞具有细胞毒性[11-15]。
在高比例的膀胱癌中也记录到FGFR3过度表达[16,17]。此外,已经在60%-70%的乳头状癌和16%-20%的肌肉浸润性膀胱癌中鉴定出FGFR3中的体细胞激活突变[17,18]。在细胞培养实验中,RNA干扰[19]或FGFR3单链Fv抗体片段抑制膀胱癌细胞增殖[20]。最近的一项研究表明,FGFR3抗体-毒素缀合物通过FGFR3介导的毒素递送到肿瘤中减弱膀胱癌细胞系的异种移植物生长[21]。与FGFR3和抗FGFR3抗体有关的出版物包括US 2005/0147612;WO 2010/111367;Rauchenberger等人,J Biol Chem[生物化学杂志]278(40):38194-38205(2003)[22];WO 2006/048877;Martinez-Torrecuadrada等人,(2008)MolCancer Ther[分子癌症治疗]7(4):862-873;WO 2007/144893;Trudel等人.(2006)107(10):4039-4046;Martinez-Torrecuadrada等人(2005)Clin Cancer Res[临床癌症研究]11(17):6280-6290;Gomez-Roman等人(2005)Clin Cancer Res[临床癌症研究]11:459-465;和WO 2010/002862中。
这些抗体具有以下一个或多个缺点:它们仅具有识别一种同种型的能力,或者对不同同种型在亲和力方面显示显著差异。
因此,仍然需要能够以高亲和力和特异性结合剪接变体FGFR3b和FGFR3c并且同时能够很好地内化到细胞中的分子。
本发明解决了这种需要。
发明内容
从若干个不同的筛选,鉴定了一组Fynomer多肽,其具有多种不同的出人意料的特性,包括对FGFR3b和FGFR3c的高亲和力以及良好内化到细胞中的能力,该组多肽由于这些特性的组合而优于大量其他候选物质。本文公开了这些多肽的序列。除了多肽本身之外,本发明还提供了包含此类多肽的融合构建体,包括其与抗体的融合体。本发明还提供了编码本发明的多肽或融合构建体的核酸分子。此外,提供了包含本发明的多肽或融合构建体的药物或诊断组合物,以及用于治疗癌症或T细胞介导的疾病的此类药物组合物。
本发明的第一方面涉及与成纤维细胞生长因子受体3同种型3b和3c(FGFR3b和FGFR3c)结合的多肽,其中该多肽包含选自下组的氨基酸序列,该组由以下组成:(a)GVTLFVALYDYEVYGPTPMLSFHKGEKFQIL(X1)(X2)(X3)(X4)GPYWEARSL(X5)TGETG(X6)IPSNYVAPVDSIQ(SEQ ID NO:1),其中氨基酸位置(X1)至(X6)可以是任何氨基酸序列;(b)与(a)的氨基酸序列具有至少95%同一性的氨基酸序列,其中同一性测定不包括氨基酸位置(X1)至(X6)并且条件是在SEQ ID NO:1的氨基酸位置12至19中的氨基酸序列EVYGPTPM(SEQID NO:2)是保守的,并且SEQ ID NO:1的氨基酸位置37和38中的氨基酸P和Y是保守的;(c)
GVTLFVALYDYEVMSTTALSFHKGEKFQILSQSPHGQYWEARSLTTGETG(X6)IPSNYVAPVDSIQ
(SEQ ID NO:19),其中氨基酸位置(X6)可以是任何氨基酸;以及(d)与(c)的氨基酸序列具有至少95%同一性的氨基酸序列,其中同一性测定不包括氨基酸位置(X6)并且条件是在SEQ ID NO:19的氨基酸位置12至18中的氨基酸序列EVMSTTA(SEQ ID NO:20)和SEQID NO:19的氨基酸位置31至35中的SQSPH(SEQ ID NO:21)是保守的,并且SEQ ID NO:19的氨基酸位置37和38中的氨基酸Q和Y是保守的。
本文所用的术语“多肽”描述了氨基酸的线性分子链,包括含有多于约60个氨基酸的单链蛋白质或其片段。多肽可以进一步形成由至少两个相同或不同的分子组成的多聚体,例如低聚体。相应地,这种多聚体的相应的更高级结构被称为同二聚体或异二聚体,同三聚体或异三聚体等。此外,这些多肽的肽模拟物(其中一个或多个氨基酸和/或一个或多个肽键已被功能类似物取代)也被本发明也包括在内。这些功能类似物包括除20种基因编码的氨基酸之外的所有已知氨基酸,例如硒代半胱氨酸。术语“多肽”也指天然修饰的多肽,其中通过糖基化、乙酰化、磷酸化和本领域熟知的类似修饰实现修饰。
本发明的多肽是Fyn SH3衍生的多肽或Fynomer。Fyn SH3衍生的多肽或Fynomer是本领域熟知的,并且已经描述于例如Grabulovski等人.(2007)JBC,282,第3196-3204页;WO2008/022759;Bertschinger等人(2007)Protein Eng Des Sel[蛋白质工程化设计与选择]20(2):57-68;和Gebauer与Skerra(2009)Curr Opinion in Chemical Biology[化学与生物学当前观点]13:245-255。术语“Fyn SH3衍生的多肽”在本文中与术语“Fynomer”可互换使用,是指衍生自人Fyn SH3结构域的非免疫球蛋白衍生的结合多肽(例如Gebauer和Skerra(2009)Curr Opinion in Chemical Biology[化学与生物学当前观点]13:245-255中描述的所谓的支架)。Fynomer是约7-kDa的小球状多肽。人Fyn激酶的SH3结构域成功地用作支架对以高亲和力和特异性结合不同靶蛋白的蛋白(Fyn SH3衍生的结合蛋白,称为Fynomer)进行工程化(WO 2008/022759、WO 2011/023685、WO 2013/135588、WO 2014/170063、Grabulovski D.等人.,(2007)J Biol Chem[生物化学杂志]282,第3196-3204页,Bertschinger J.等人.(2007)Protein Eng Des Sel[蛋白质工程化设计与选择],20,第57-68页,和Schlatter等人.(2012)mAbs,4(4)第497-50页)。
如所使用的短语“与成纤维细胞生长因子受体3同种型3b和3c(FGFR3b和FGFR3c或FGFR3b和3c)结合”要求本发明的多肽与FGFR3b和FGFR3c形成结合相互作用(体内和/或体外)。同种型3b(FGFR3b)和3c(FGFR3c)通过选择性剪接形成。通过使用编码Ig结构域3的C-末端一半的两个选择性外显子3b和3c产生剪接变体。上皮细胞仅显示3b转录物,而成纤维细胞显示3b和3c转录物的混合物。人FGFR3b的氨基酸序列显示在SEQ ID NO:9中,并且人FGFR3c的氨基酸序列显示在SEQ ID NO:10中。本发明的多肽优选与人成纤维细胞生长因子受体3同种型3b和3c结合。优选地,本发明的多肽与两种同种型FGFR3b和FGFR3c结合,其KD为10-7至10-12M,更优选10-8至10-12M,最优选10-9至10-12M。在这方面,优选本发明的多肽特异性结合FGFR3,优选特异性结合FGFR3b和FGFR3c两种同种型,并且因此不与其他相关蛋白如FGFR1、FGFR2或FGFR4显著结合。在这方面,显著结合优选表示以>5x 10-6M的KD结合。
如上所示的SEQ ID NO:1和SEQ ID NO:19衍生自人Fyn激酶的SH3结构域的氨基酸序列(SEQ ID NO:11;由Kawakami等人和Semba等人在1986年报道的Fyn激酶的氨基酸83-145)。SEQ ID NO:11显示:GVTLFVALYDYEARTEDDLSFHKGEKFQILNSSEGDWWEARSLTTGETGYIPSNYVAPVDSIQ(SEQ ID NO:11)。在如上所示的SEQ ID NO:11中,RT和src环的序列分别用下划线和双下划线表示。Grabulovski等人.(2007)JBC,282,第3196-3204页研究了Fyn SH3结构域的RT和src环中突变的影响,并证明这些与疏水表面相邻的环中的突变可以决定该结构域参与分子间缔合的能力。此外,EP 2054432显示RT和/或src环中的和与其邻近的突变决定了SH3结构域的结合特异性。Fyn SH3结构域的氨基酸序列在人、小鼠、大鼠和猴(长臂猿)中是完全保守的。鸡Fyn SH3与相应的人结构域在一个氨基酸位置上不同,非洲爪蟾(Xenopus laevis)的Fyn SH3与相应的人结构域在两个氨基酸位置上不同。正如其他SH3结构域一样,Fyn SH3结构域由两个反平行β-折叠构成,并包含两个柔性环(称为RT和src环)以与其他蛋白质相互作用。
更详细地,SEQ ID NO:1是由SEQ ID NO 3至8的比对产生的序列(参见图1)。如从图1中显而易见的,SEQ ID NO:1的位置(X1)至(X4)对应于SEQ ID NO:11的Fyn激酶SH3结构域的src环。在SEQ ID NO 3至8中,src环内的氨基酸彼此不同。另一方面,src环的C-末端的第二和第三位置在野生型序列中是“DW”,而在所有SEQ ID NO 3到8中的相应氨基酸是“PY”。如从图1中进一步显而易见的,与野生型Fyn SH3序列相比,对应于SEQ ID NO:11的Fyn激酶SH3结构域的RT环的位置(即下划线序列和相邻的D)改变,但在SEQ ID NO:3至8中是保守的并且具有序列“EVYGPTPM”(SEQ ID NO:2)。RT和src环内的氨基酸位置(包括与这些环相邻的氨基酸)决定了对FGFR3b和3c的结合特异性。
根据SEQ ID NO:1,不仅氨基酸位置(X1)至(X4)可以是任何氨基酸,氨基酸位置(X5)和(X6)也可以是任何氨基酸。从图1可以看出,位置(X5)和(X6)中的氨基酸可以在SEQID NO 3至8之间不同或与SEQ ID NO:11的野生型Fyn SH3结构域不同。据信这些位置的氨基酸差异对于SEQ ID NO 3至8的结合特异性不是必需的。因此,在基本上不干扰对FGFR3b和3c的结合特异性情况下,可以交换或缺失氨基酸位置(X5)和(X6),或者可以添加其他氨基酸。如果与SEQ ID NO 1至8中发现的氨基酸相比在氨基酸位置(X5)至(X6)中的氨基酸被交换,则优选保守交换。
SEQ ID NO:19是由SEQ ID NO:22的抗FGFR3b和FGFR3c多肽产生的序列。SEQ IDNO:22(EVMSTTA(SEQ ID NO:20))的氨基酸位置12至18对应于SEQ ID NO:11的Fyn激酶SH3结构域的RT环,并且SEQ ID NO:22的氨基酸位置31至35(SQSPH(SEQ ID NO:21))对应于SEQID NO:11的Fyn激酶SH3结构域的src环。在src环的C-末端的第二和第三位置在野生型序列中是“DW”,而在SEQ ID NO:22中的相应氨基酸是“QY”。同样在SEQ ID NO:22中,RT和src环内的氨基酸位置(包括与这些环相邻的氨基酸)决定了对FGFR3b和3c的结合特异性。
根据SEQ ID NO:19,氨基酸位置(X6)可以是任何氨基酸。SEQ ID NO:19的氨基酸位置(X6)对应于SEQ ID NO:1的氨基酸位置(X6)。在SEQ ID NO 1和19中,氨基酸(X6)不同于SEQ ID NO:11的野生型Fyn SH3结构域。相应的氨基酸在SEQ ID NO:11中是Y,在SEQ IDNO:19中是W和在SEQ ID NO:3至8中是L。
根据本发明,术语“序列同一性百分比(%)”描述了与构成模板核酸或氨基酸序列的总长度的核苷酸或氨基酸残基的数量相比较,两个或更多个比对的核酸或氨基酸序列的相同核苷酸/氨基酸的匹配数(“命中数”)。换句话说,使用比对,对于两个或更多个序列或子序列,当(子)序列被比较并在比较窗口上或在指定区域上(如使用本领域已知的序列比较算法测量)以最大对应比对时,或当手动比对并目测检查时,可以确定相同的氨基酸残基或核苷酸的百分比(例如95%、97%或98%同一性)。因此,比较以确定序列同一性的序列可以由于核苷酸或氨基酸的一个或多个取代、一个或多个添加或一个或多个缺失而不同。该定义也适用于测试序列的互补序列。
技术人员还知道合适的程序以比对多肽序列。多肽序列的百分比序列同一性可以例如用程序确定,如上述程序CLUSTLAW、FASTA和BLAST。优选使用BLAST程序,即NCBI BLAST算法(Stephen F.Altschul,Thomas L.Madden,Alejandro A.Jinghui Zhang,Zheng Zhang,Webb Miller,和David J.Lipman(1997),“Gapped BLAST and PSI-BLAST:anew generation of protein database search programs[缺口型BLAST和PSI-BLAST:新一代蛋白质数据库搜索程序]”,Nucleic Acids Res[核酸研究].25:3389-3402)。
关于如上文项(b)中所述的序列同一性,优选序列同一性至少为至少98%。在这方面,还要注意的是,项(b)中所述的至少95%的序列同一性允许两个氨基酸改变,而至少98%的优选同一性允许仅一个氨基酸改变。因此,如上所述的项(b)还涉及氨基酸序列,该氨基酸序列与如上所述的项(a)的氨基酸序列的差异在于两个氨基酸改变,并且优选在于一个氨基酸改变,其中该一个或多个氨基酸改变可以在除以下各项之外的SEQ ID NO:1的氨基酸位置中发现:(X1)至(X6),SEQ ID NO:1的氨基酸位置12至19中的氨基酸序列EVYGPTPM(SEQ ID NO:2)和SEQ ID NO:1的氨基酸位置37和38中的氨基酸P和Y。认为除以下各项之外的SEQ ID NO:1的氨基酸对SEQ ID NO 3至8的结合特异性不是必需的:(X1)至(X6),SEQ ID NO:1的氨基酸位置12至19中的氨基酸序列EVYGPTPM(SEQ ID NO:2)和SEQ IDNO:1的氨基酸位置37和38中的氨基酸P和Y。因此,在基本上不干扰对FGFR3b和3c的结合特异性的情况下,可以交换或缺失这些氨基酸位置,或者可以添加氨基酸。优选交换这些氨基酸位置。如果交换氨基酸,则优选保守交换。
关于如上文项(d)中所述的序列同一性,优选序列同一性至少为至少97%。在这方面,还要注意的是,项(d)中所述的至少95%的序列同一性允许两个氨基酸改变,而至少97%的优选同一性允许仅一个氨基酸改变。因此,如上所述的项(d)还涉及氨基酸序列,该氨基酸序列与如上所述的项(c)的氨基酸序列的差异在于两个氨基酸改变,并且优选在于一个氨基酸改变,其中该一个或多个氨基酸改变可以在除以下各项之外的SEQ ID NO:19的其他氨基酸位置中发现:SEQ ID NO:19的氨基酸位置12至18中的氨基酸序列EVMSTTA(SEQID NO:20)和SEQ ID NO:19的氨基酸位置31至35中的SQSPH(SEQ ID NO:21)以及SEQ IDNO:19的氨基酸位置37和38中的氨基酸Q和Y。认为除以下各项之外的SEQ ID NO:19的其他氨基酸对SEQ ID NO:22的结合特异性不是必需的:SEQ ID NO:19的氨基酸位置12至18中的氨基酸序列EVMSTTA(SEQ ID NO:20)和SEQ ID NO:19的氨基酸位置31至35中的SQSPH(SEQID NO:21)以及SEQ ID NO:19的氨基酸位置37和38中的氨基酸Q和Y。因此,在基本上不干扰对FGFR3b和3c的结合特异性的情况下,可以交换或缺失这些氨基酸位置,或者可以添加氨基酸。优选交换这些氨基酸位置。如果交换氨基酸,则优选保守交换。
如本文结合SEQ ID NO:1所使用的短语“同一性测定不包括氨基酸位置(X1)至(X6)”指定关于SEQ ID NO:1的序列同一性的计算未考虑氨基酸位置(X1)至(X6)。同样地,如本文结合SEQ ID NO:19所使用的短语“同一性测定不包括氨基酸位置(X6)”指定关于SEQID NO:19的序列同一性的计算未考虑氨基酸位置(X6)。
如本文所用的条件“条件是SEQ ID NO:1的氨基酸位置12至19中的氨基酸序列EVYGPTPM(SEQ ID NO:2)是保守的”指定可以不将氨基酸改变引入SEQ ID NO:1的氨基酸位置12至19。同样地,如本文所用的条件“条件是SEQ ID NO:1的氨基酸位置37和38中的氨基酸P和Y是保守的”指定可以不将氨基酸改变引入SEQ ID NO:1的氨基酸位置37和38。换句话说,在属于本发明第一实施例的项(a)和(b)的范围内的所有多肽及其优选实例中,对应于SEQ ID NO:1的氨基酸位置12至19的氨基酸位置具有序列EVYGPTPM(SEQ ID NO:2),并且位置37和38中的氨基酸分别为P和Y。
如本文所用的条件“条件是SEQ ID NO:19的氨基酸位置12至18的氨基酸序列EVMSTTA(SEQ ID NO:20)和SEQ ID NO:19的氨基酸位置31至35的SQSPH(SEQ ID NO:21)是保守的”指定可以不将氨基酸改变引入SEQ ID NO:19的氨基酸位置12至18以及31至35。同样地,如本文所用的条件“条件是SEQ ID NO:19的氨基酸位置37和38中的氨基酸Q和Y是保守的”指定可以不将氨基酸改变引入SEQ ID NO:19的氨基酸位置37和38。换句话说,在属于本发明第一实施例的项(c)和(d)的范围内的所有多肽及其优选实例中,对应于SEQ ID NO:19的氨基酸位置12至18的氨基酸位置具有序列EVMSTTA(SEQ ID NO:20),对应于SEQ IDNO:19的氨基酸位置31至35的氨基酸位置具有序列SQSPH(SEQ ID NO:21),并且位置37和38的氨基酸分别为Q和Y。
如上所述,SEQ ID NO:1和SEQ ID NO:19中的任何氨基酸取代优选是保守氨基酸取代。保守取代指定将氨基酸用另一个氨基酸替代,所述另一个氨基酸具有与被替代的氨基酸相似的化学特性。优选地,本文提及的保守取代是选自下组的取代,该组由以下组成:(i)用不同的碱性氨基酸取代碱性氨基酸;(ii)用不同的酸性氨基酸取代酸性氨基酸;(iii)用不同的芳香族氨基酸取代芳香族氨基酸;(iv)用不同的非极性脂肪族氨基酸取代非极性脂肪族氨基酸;以及(v)用不同的极性不带电荷的氨基酸取代极性不带电荷的氨基酸。碱性氨基酸是精氨酸、组氨酸和赖氨酸。酸性氨基酸是天冬氨酸和谷氨酸。芳香族氨基酸是苯丙氨酸、酪氨酸和色氨酸。非极性脂肪族氨基酸是甘氨酸、丙氨酸、缬氨酸、亮氨酸、甲硫氨酸、异亮氨酸和脯氨酸。极性不带电荷的氨基酸是丝氨酸、苏氨酸、半胱氨酸、天冬酰胺和谷氨酰胺。与保守氨基酸取代相反,非保守氨基酸取代是一个氨基酸与不属于上述保守取代(i)至(v)的任何氨基酸的交换。
本文公开的抗FGFR3 Fynomer有利地对FGFR3c和3b具有优异的结合亲和力,并且还特别适合于内化到细胞中,其中它们可以发挥诊断作用或治疗作用。从下文的实例中可以看出,当筛选Fynomer的大文库时,发现了SEQ ID NO 3的抗FGFR3 Fynomer。已证明SEQID NO 3和19的抗FGFR3 Fynomer在其对FGFR3同种型3b和3c的结合亲和力以及它们的细胞内化特性方面具有突出的特性;参见实例1和7。因此,SEQ ID NO:19的Fynomer是SEQ IDNO:1的Fynomer的供替代的选择。出乎意料且有利地,两种Fynomer具有类似的有利特性组合。使用SEQ ID NO:3的抗FGFR3 Fynomer作为亲和力成熟的模板,并且甚至可能进一步改善对FGFR3b和3c的结合亲和力。更详细地,在由亲和力成熟过程产生的大量多肽中,发现SEQ ID NO:4至8的抗FGFR3 Fynomer与SEQ ID NO:3的抗FGFR3 Fynomer相比甚至更强地结合FGFR3b和3c。下文的实例还表明,SEQ ID NO 3至8和22的抗FGFR3 Fynomer可以重组产生并具有良好的可制造性,因此可以大规模生产,例如用于治疗应用和诊断应用。此外,SEQID NO:3至8和22的抗FGFR3 Fynomer不仅与人FGFR3c和3b结合,而且与小鼠和猴的FGFR3c(以及可能还有3b)结合。这种跨物种结合对于临床前测试是有利的。这些分子可用于诊断目的,并且还适合作为开发针对在其表面上表达FGFR3的肿瘤细胞的其他治疗剂的起点,例如如本文更详细描述的。通过初始筛选或随后的亲和力成熟过程鉴定的其他抗FGFR3Fynomer都不具有与SEQ ID NO 3至8和22的抗FGFR3 Fynomer相似的有利特性组合。由下文的实例将进一步显而易见,SEQ ID NO 3至8和22的抗FGFR3 Fynomer的特性的出人意料且不可预测的有利组合。
根据本发明第一方面的优选实施例,(X1)是N、R或K,并且优选是R或K;(X2)是S、G、K或R,并且优选是G、K或R;(X3)是S或G,并且优选是G;并且(X4)是E、Q、D、S或K,并且优选是Q、D、S或K。
根据本发明第一方面的另一个优选实施例,(X1)是N、R或K,并且优选是R或K;(X2)是S、G、K或R,并且优选是G、K或R;(X3)是S或G,并且优选是G;(X4)是E、Q、D、S或K,并且优选是Q、D、S或K;(X5)是T或A;并且(X6)是Y、W或L,并且优选是L或W。
SEQ ID NO:1中的氨基酸位置(X1)至(X4)是对应于形成人野生型Fyn SH3结构域的src环的氨基酸的氨基酸位置。下文的实例显示针对氨基酸位置(X1)至(X4)列出的氨基酸赋予对FGFR3b和FGFR3c的结合特异性,特别是具有SEQ ID NO:9的FGFR3b和具有SEQ ID NO:10的FGFR3c。更详细地,图1中本发明的SEQ ID NO 3至8的序列比对显示,在SEQ ID NO 3至8的抗FGFR3 Fynomer中,可以发现在上述优选实施例中列出的氨基酸位置(X1)至(X4)的氨基酸。在上述优选实施例中列出的氨基酸位置(X1)至(X4)的优选氨基酸可以在SEQ ID NO 4至8的相应氨基酸位置中找到,注意到通过亲和力成熟从SEQ ID NO:3获得了SEQ ID NO 4至8。可以预期,除了SEQ ID NO:3至8(优选地SEQ ID NO 4至8)中存在的(X1)至(X4)的特定氨基酸组合外,还有选自如上定义的(X1)至(X4)的其他氨基酸序列赋予对FGFR3b和3c结合特异性。
如上所述,SEQ ID NO:1中的氨基酸位置(X5)和SEQ ID NO 1和19中的氨基酸位置(X6)是不对应于人野生型Fyn SH3结构域的RT和src环的氨基酸也不对应于与这些环之一相邻的氨基酸的氨基酸位置。因此,据信可以在基本上不干扰对FGFR3b和3c的结合特异性情况下交换或缺失这些位置的氨基酸,或者可以添加另外的氨基酸。优选交换位置(X5)和(X6)中的氨基酸。更优选(X5)是T或A;(X6)是Y、W或L,并且最优选是L或W。从图1中可以看出,SEQ ID NO:1的(X5)和SEQ ID NO 1和19的(X6)的这些氨基酸可以在SEQ ID NO 3至8和22或人Fyn SH3野生型结构域(SEQ ID NO:11)或另一种结合FGFR3b和3c的Fynomer中找到。在位置(X6)的最优选氨基酸的情况下,该氨基酸可以在SEQ ID NO 3至8中找到。
根据本发明第一方面的更优选实施例,所述多肽包含选自下组的氨基酸序列,该组由以下组成:SEQ ID NO 3至8和22中任一个,优选选自SEQ ID NO 4至8或22。
从下文的实施例中可以看出,SEQ ID NO 3至8和22是产生和测试的具体抗FGFR3b和3c Fynomer的序列。
根据本发明第一方面的甚至更优选的实施例,所述多肽包含选自下组的氨基酸序列,该组由以下组成:SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、和SEQ ID NO:22。包含SEQ ID NO:6的氨基酸序列的多肽是特别优选的。另一个特别优选的实施例是包含SEQ ID NO:22的氨基酸序列的多肽。
在第一个筛选中已经获得具有低纳摩尔亲和力的Fynomer是非常出人意料的。从Fynomer文库中分离出具有SEQ ID NO 3的Fynomer,作为具有最突出的FGFR3b和3c结合亲和力和内化特性的Fynomer。具有SEQ ID NO 4至8的Fynomer衍生自SEQ ID NO:3,并且具有SEQ ID NO 4至8的Fynomer的FGFR3b和3c结合亲和力甚至进一步得到改善。
出人意料的是,具有SEQ ID NO:22的Fynomer也具有非常好的特性,与具有SEQ IDNO 4至8的那些相当,尽管它最初衍生自不同的Fynomer家族。
本发明在第二方面涉及融合构建体,其包含与另外化合物融合的本发明的多肽。
本文使用的“融合构建体”定义了本发明的多肽与另外化合物的融合体。该化合物可以是蛋白质化合物或非蛋白质化合物。在化合物是蛋白质化合物(例如细胞因子或趋化因子,或抗体或抗体片段,如下文所述)的情况下,融合构建体也可称为融合蛋白。如本文所用的术语“融合蛋白”一般性地涉及通过连接和表达编码分开的多肽或多肽和肽的两个或更多个基因而产生的多肽构建体。换句话说,融合基因的翻译产生具有来源于每种原始多肽的功能特性的单一多肽。多肽可以直接融合或通过接头(即短肽序列)融合。通常,融合蛋白是通过技术人员熟知的重组DNA技术(例如Alberts等人.,Molecular Biology of theCell[细胞分子生物学],第4版.加兰科学出版社(Garland Science),第518-519页)人工产生的。然而,本发明的多肽和融合蛋白可以通过许多常规和众所周知的技术(例如普通有机合成策略,固相辅助合成技术)中的任何一种或通过市售的自动合成仪制备。融合蛋白可用于生物研究,诊断或治疗。
作为另外化合物的非蛋白质化合物的实例是例如小有机分子,例如聚乙二醇(PEG)或Alexa Fluor,或放射性核素。以下讨论非蛋白质另外化合物的其他具体实例。
根据本发明第二方面的某些实施例,所述另外化合物是药学活性化合物、前药、药学上可接受的载体、诊断活性化合物、细胞穿透增强剂和/或调节血清半衰期的化合物。
药学活性化合物是在给予受试者后具有生物活性的化合物,其对受试者产生有益效果。前药是以下化合物,其以无活性(或低于完全活性)形式给予受试者,随后通过受试者的代谢过程转化为药学活性或药学上完全活性的化合物。药学上(完全)活性的化合物优选是适合于治疗或预防下文定义的任何特定疾病的化合物。
诊断活性化合物是在给予受试者时具有活性的化合物,其允许(辅助)确定或鉴定疾病或病症(如果个体受到折磨)。诊断活性化合物的实例包括可检测标志物,例如荧光染料、放射性核素或用于医学成像的造影剂。荧光染料、放射性核素和用于医学成像的造影剂的具体实例在下文中描述。与本发明的多肽融合的诊断活性化合物尤其可以用于辅助确定或鉴定,或确定或鉴定下文定义的特定疾病中的任何一种,所述特定疾病的共同点在于其起源和/或一个或多个症状与FGFR3有关,特别是FGFR3b和3c相关。可以通过与本发明的诊断活性化合物融合的本发明多肽检测或鉴定受试者体内这种疾病的部位。
细胞穿透增强剂是促进将本发明的多肽递送到(体外、离体或体内)细胞中的化合物。
调节血清半衰期的化合物是允许延长本发明多肽的体内半衰期(特别是在血液循环系统中的半衰期)的化合物。调节血清半衰期的组分优选是聚乙二醇(PEG)。
药学上可接受的载体是在给予受试者后促进或改善例如本发明多肽的递送和/或有效性的化合物。合适的药学上可接受的载体是本领域熟知的,并且包括例如稳定剂、抗氧化剂、pH调节物质等。
根据本发明第二方面的一个实施例,另外化合物是毒性化合物。
毒性化合物优选是小有机化合物或多肽,例如选自下组的毒性化合物,该组由以下组成:加利车霉素、美登木素生物碱、新抑癌蛋白、埃斯佩拉霉素(esperamicin)、内霉素(dynemicin)、可达菌素(kedarcidin)、maduropeptin、多柔比星、柔红霉素、瑞奥西汀(auristatin)、蓖麻毒素-A链、modeccin、截短的假单胞菌外毒素A、白喉毒素和重组白树毒素。
根据本发明第二方面的另一个实施例,本发明的其他化合物选自下组,该组由以下组成:(a)荧光染料,(b)光敏剂,(c)放射性核素,(d)用于医学成像的造影剂,(e)细胞因子,(f)趋化因子,(g)促凝血因子,(h)用于前药激活的酶,(i)白蛋白结合剂,(j)白蛋白,(k)IgG结合剂,或(l)聚乙二醇。
荧光染料的实例是Alexa Fluor和Cy染料。
光敏剂的实例是光毒性红色荧光蛋白KillerRed和血卟啉。
放射性核素的实例是γ-发射同位素,例如,99mTc,123I,111In,正电子发射体,例如18F、64Cu、68Ga、86Y、124I、β-发射体,例如131I、90Y、177Lu、67Cu,以及α-发射体,例如213Bi、211At。
如本文所用的造影剂是用于增强医学成像中体内结构或流体的对比度的物质。常见的造影剂基于X射线衰减和磁共振信号增强而工作。
细胞因子可以例如选自由以下组成的组:IL-2、IL-12、TNF-α、IFNα、IFNβ、IFNγ、IL-10、IL-15、IL-24、GM-CSF、IL-3、IL-4、IL-5、IL-6、IL-7、IL-9、IL-11、IL-13、LIF、CD80、B70、TNFβ、LT-β、CD-40配体、Fas-配体、TGF-β、IL-1α和IL-1β。如本领域众所周知的,细胞因子可能有利于免疫系统的促炎或抗炎应答。因此,取决于待治疗的疾病,可优选具有促炎或抗炎细胞因子的融合构建体。例如,对于炎性疾病的治疗,通常优选包含抗炎细胞因子的融合构建体,而对于癌症的治疗,通常优选包含促炎细胞因子的融合构建体。
趋化因子可以例如选自由以下组成的组:IL-8、GROα、GROβ、GROγ、ENA-78、LDGF-PBP、GCP-2、PF4、Mig、IP-10、SDF-1α/β、BUNZO/STRC33、I-TAC、BLC/BCA-1、MIP-1α、MIP-1β、MDC、TECK、TARC、RANTES、HCC-1、HCC-4、DC-CK1、MIP-3α、MIP-3β、MCP-1-5、嗜酸性粒细胞趋化因子、嗜酸性粒细胞趋化因子-2、I-309、MPIF-1、6Ckine、CTACK、MEC、淋巴细胞趋化因子和分形趋化因子(fractalkine)。
促凝血因子的实例是组织因子(TF)和癌促凝血剂(CP)。
用于前药激活的酶的实例是酶,例如羧肽酶、葡糖醛酸糖苷酶或葡糖苷酶。
白蛋白结合剂和IgG结合剂的实例描述于Gebauer和Skerra(2009),Curr OpinChem Biol[化学生物学当前观点].,13(3):245-255中。因此,白蛋白结合剂和IgG结合剂的实例是人单Ig结构域(双白蛋白Dab(dubbled Albumin Dab))、纳米抗体、衍生自链球菌蛋白G的天然存在的白蛋白结合结构域(ABD)和结合IgG的结构域。例如,这种融合构建体在给予患者后,特别是在血液循环系统中,增加了本发明多肽的半衰期。
根据本发明第二方面的其他实施例,本发明的另外化合物包含抗体轻链、抗体重链、抗体的Fc结构域、抗体或其组合。
术语“抗体”包括单克隆抗体、单链抗体或其片段,还包括双特异性抗体、合成抗体、除重链和轻链以外的保留结合能力的抗体片段,例如Fab、F(ab2)’、Fv或scFv片段等,或这些中的任何化学修饰的衍生物。抗体或其片段可以例如通过使用例如Harlow和Lane“Antibodies,A Laboratory Manual[抗体实验室手册]”,CSH出版社,冷泉港,1988中描述的方法获得。当通过噬菌体展示技术获得所述抗体的衍生物时,BIAcore系统中使用的表面等离子共振可用于提高结合本发明的肽或多肽的表位的噬菌体抗体的效率(Schier,HumanAntibodies Hybridomas 7[人抗体杂交瘤7](1996),97-105;Malmborg,J.Immunol.Methods[免疫方法杂志]183(1995),7-13)。嵌合抗体的产生描述于例如WO89/09622中。根据本发明使用的另外抗体来源是所谓的异种抗体。在例如WO 91/10741、WO 94/02602、WO 96/34096和WO 96/33735中描述了在小鼠中产生异种抗体如人抗体的一般原理。可以使用本领域已知的常规技术(例如,通过使用氨基酸的一个或多个缺失、一个或多个插入一个或多个取代、一个或多个添加和/或一个或多个重组合和/或本领域已知的一个或多个任何其他修饰(单独或组合))进一步修饰有待根据本发明使用的抗体或其相应的一个或多个免疫球蛋白链。在以免疫球蛋白链的氨基酸序列为基础的DNA序列中引入这些修饰的方法是本领域技术人员公知的;参见例如Sambrook,Molecular Cloning:A LaboratoryManual[分子克隆:实验室手册],冷泉港实验室,冷泉港,纽约,1989。
该术语抗体还涉及保留或基本保留其结合特异性的所述抗体的衍生物。尽管所述衍生物的特别优选的实施例在下文进一步说明,但此类抗体的其他优选衍生物是嵌合抗体,所述嵌合抗体包含例如小鼠或大鼠可变区和人恒定区。
抗体可以是人源化抗体。根据本发明,术语“人源化抗体”是指非人源抗体,其蛋白质序列已被修饰以增加其与人天然产生的抗体变体的相似性。人源化抗体的产生可以通过例如将适当的CDR编码区段(负责所需的结合特性)(例如CDR3,优选所有6个CDR)插入人抗体“支架”中来实现。用于产生人源化抗体的方法描述于例如EP-A1 0 239 400和WO 90/07861中。
术语“抗体轻链”表示抗体的小多肽亚基,而术语“抗体重链”表示抗体的大多肽亚基。典型的抗体由两条免疫球蛋白(Ig)重链和两条Ig轻链构成。每条轻链由两个串联免疫球蛋白结构域;一个恒定(CL)结构域和一个可变结构域(VL)(对结合抗原很重要)构成。重链决定抗体的类别或同种型。每条重链具有两个区域,即恒定区(其对于同一类别的所有免疫球蛋白相同但在类别之间不同)和可变区(其在不同B细胞之间不同的,但对于对于由相同B细胞或B细胞克隆产生的所有免疫球蛋白是相同的)。任何重链的可变结构域由单个免疫球蛋白结构域构成。
抗体的“功能性Fc结构域”是本领域技术人员公知的术语,并且基于抗体的木瓜蛋白酶切割来定义。根据其重链恒定区的氨基酸序列,免疫球蛋白分为以下类别:IgA、IgD、IgE、IgG和IgM并且其中的一些可以进一步分为亚类(同种型),例如,IgG1、IgG2、IgG3和IgG4、IgA1和IgA2。根据重链恒定区,不同类别的免疫球蛋白分别称为[α]、[δ]、[ε]、[γ]和[μ]。抗体的功能性Fc结构域直接参与ADCC(抗体依赖性细胞介导的细胞毒性)和基于补体激活、C1q结合和Fc受体结合的CDC(补体依赖性细胞毒性)。四种人IgG同种型结合不同的受体,例如新生儿Fc受体、激活性Fcγ受体、FcγRI、FcγRIIa和FcγRIIIa、抑制性受体FcγRIIb和具有不同亲和力的C1q,产生非常不同的活性。已知可以改造人抗体Fc结构域和激活性和抑制性受体的亲和力(参见Strohl W.(2009)Curr Opin Biotechnol[生物技术当前观点],20,第685-691页)。
优选地,Fc结构域是一个或多个人功能性Fc结构域,其允许延长本发明多肽的体内半衰期,并且其中一些例如在如下文所述的治疗、预防和/或诊断应用中指导哺乳动物对特异性靶向结合本发明的融合蛋白的多肽组分的位点的免疫应答。更优选地,这种人功能性Fc结构域是IgG1抗体。本发明的多肽可以与一个或多个功能性Fc结构域的N-或C-末端融合,或与一个或多个Fc结构域的N-和C-末端融合。在某些实施例中,本发明的融合蛋白还可包含多聚体,例如融合到Fc结构域的至少一侧,例如融合到Fc结构域N-末端的本发明多肽的四聚体、三聚体或二聚体。
Fc结构域可以是IgG1的一个或多个工程化的具有激活或沉默的效应子功能的人功能性Fc结构域,例如,IgG1的一个或多个工程化的具有沉默的效应子功能的人功能性Fc结构域,例如,IgG1的一个或多个工程化的具有L234和L235(编号是根据Kabat的EU索引(参见Johnson G.和Wu T.T.(2000)Nucleic Acids Res[核酸研究].28,第214-218页))中的突变(例如具有突变L234A和L235A)的具有沉默的效应子功能的人功能性Fc结构域。
本发明的多肽可位于所述另外化合物的C-末端的下游,所述另外化合物包含抗体轻链、抗体重链、抗体的Fc结构域、抗体或其组合。可选择地,本发明的多肽可位于所述另外化合物N-末端的下游,所述另外化合物包含抗体轻链、抗体重链、抗体的Fc结构域、抗体或其组合。
在本发明的融合构建体包含与抗体融合的本发明多肽的情况下,本发明的融合构建体优选包含本发明的多肽的两个拷贝。这两个拷贝可以是本发明的相同多肽的两个拷贝或本发明的不同多肽的两个拷贝,并且优选是本发明的相同多肽的两个拷贝。更优选地,本发明多肽的两个拷贝可以与抗体的两条轻链的N-末端、抗体的两条轻链的C-末端、抗体的两条重链的N-末端、或抗体的两条重链的C-末端融合。与单克隆抗体融合(产生具有双重特异性的所谓的Fynomabs)的Fynomer的实例及其制备,已例如在(例如Silacci等人,2016,mAbs 8:1,141-149;Brack等人,2014,Mol Cancer Ther[分子癌症治疗]13(8):第2030-9页;WO 2014/044758 A1;WO 2014/170063 A1;WO 2015/141862 A1)中充分描述。
包含与抗体融合的本发明多肽的根据本发明的融合构建体可以通过在合适的条件下将抗体的轻链和抗体重链集合在一起而离体或体外获得,注意本发明的多肽与这些链中的至少一个融合。技术人员知道合适的条件。这种在合适条件下集合在一起提供了由抗体轻链和抗体重链之间的相互作用触发的非共价组装。优选地,通常在抗体中发现的二硫键存在于本发明的这种构建体中。二硫键通常存在于铰链区附近并连接两条重链和/或轻链和重链。例如,这种构建体可以通过哺乳动物细胞中的标准重组表达来制备,并且然后通常从细胞中分泌包含完整的成对抗体的本发明的完整融合蛋白。
根据本发明第二方面的某些非限制性实施例,抗体针对选自下组的靶标,该组由以下组成:GM-2、CD38、ICAM-1、SLAMF7、CD45、CD40、CD74、IGFR-1、CD20、BAFF、BCMA、CD66、GRP78、CXCR4、EGFR、EPCAM、TROP-2、B7H3和CEACAM-1。
因此,本发明的另外化合物还可包含抗体轻链、抗体重链或抗体,该抗体针对选自下组的靶标,该组由以下组成:GM-2、CD38、ICAM-1、SLAMF7、CD45、CD40、CD74、IGFR-1、CD20、BAFF、BCMA、CD66、GRP78、CXCR4、EGFR、EPCAM、TROP-2、B7H3或CEACAM-1。
如上文所讨论的,已经在若干种癌症类型中记录了FGFR3过表达。也已经在若干种癌症类型中记录了GM-2、CD38、ICAM-1、SLAMF7、CD45、CD40、CD74、IGFR-1、CD20、BAFF、BCMA、CD66、GRP78、CXCR4、EGFR、EPCAM、TROP-2、B7H3和CEACAM-1过表达。因此,预期如下双特异性融合构建体特别适用于治疗癌症和相关疾病,所述双特异性融合构建体能够结合作为第一靶标的FGFR3b/3c以及作为第二靶标的以下化合物:GM-2、CD38、ICAM-1、SLAMF7、CD45、CD40、CD74、IGFR-1、CD20、BAFF、BCMA、CD66、GRP78、CXCR4、EGFR、EPCAM、TROP-2、B7H3以及CEACAM-1。
上文所述的另外化合物可以直接或通过接头与本发明的多肽融合。因此,多肽可以(直接)融合到例如另外化合物的C-末端(更具体地,通过在C-末端氨基酸的羧基与N-末端氨基酸的氨基之间形成肽键),或可以通过接头与另外化合物链的C-末端连接。
合适的接头是技术人员可以安排的。根据本发明的接头可以例如选自由以下组成的组:具有1至30个碳原子的烷基,具有1至20个乙烯部分的聚乙二醇,具有1至20个残基的聚丙氨酸,己酸,取代或未取代的聚对亚苯基和三唑。优选肽接头,更具体地,优选长度为1至30个氨基酸的寡肽。优选的长度范围是5至15个氨基酸。
特别优选的接头是肽,其由至少50%、至少60%、至少70%、至少80%、至少90%或100%的小氨基酸(例如甘氨酸、丝氨酸和丙氨酸)组成。特别优选的是仅由甘氨酸和丝氨酸组成的接头。合适的接头的非限制性实例是(G4S)3接头(Gly-Gly-Gly-Gly-Ser的3个重复)。
在第三方面,本发明涉及编码本发明多肽或本发明的融合构建体的核酸分子,或编码本发明的融合构建体的一种或多种核酸分子。
编码本发明的构建体的一个或多个核酸分子可以是,例如,两个核酸分子,其中一个核酸分子编码抗体的轻链,并且另一个核酸分子编码抗体的重链。如上所述,在这种情况下,本发明的多肽可以与轻链或重链C-末端地或N-末端地融合。
根据本发明,核酸分子包括DNA,例如cDNA和mRNA以及PNA。还包括本领域已知的核酸模拟分子,例如DNA或RNA的合成或半合成衍生物以及有义链和反义链的混合聚合物。它们可以含有另外的非天然或衍生的核苷酸碱基,这是本领域技术人员容易理解的。在优选的实施例中,多核苷酸或一个或多个核酸分子是DNA。根据本发明的这种核酸模拟分子或核酸衍生物包括硫代磷酸酯核酸,氨基磷酸酯核酸,2’-O-甲氧基乙基核糖核酸,吗啉代核酸,己糖醇核酸(HNA)和锁核酸(LNA)(参见例如,Braasch和Corey,Chemistry&Biology[化学和生物学]8,1-7(2001))。LNA是RNA衍生物,其中核糖环受2’-氧和4’-碳之间的亚甲基键的约束。
在核酸分子包含(而不是由其组成)所述序列的那些实施例中,额外的核苷酸在5’末端或3’末端或两者上延伸超过特定序列。
另外的异源序列可包括与上述分子的编码序列可操作地连接的异源启动子。因此,核酸分子可以与启动子可操作地连接。启动子是技术人员所熟知的并且在本领域中常规使用。非限制性实例是CMV立即早期启动子,其通常在哺乳动物细胞中驱动强表达。
本发明还涉及一种或多种载体(其包含一种或多种本发明的核酸分子)以及一种或多种宿主细胞(其包含一种或多种本发明的核酸分子或一种或多种本发明的载体)。
此外,本发明涉及细胞,优选分离的细胞,其包含本发明的核酸分子或载体。该细胞也称为宿主细胞。
载体和分离的细胞,特别是宿主细胞,可以是任何适合于以下目的的常规类型:例如,产生本发明的多肽和/或融合构建体,和/或治疗上有用的载体和宿主细胞。技术人员将能够从现有技术中选择那些载体和宿主细胞,并通过常规方法并且没有过度负担地确认它们对于所需目的的特定适合性。
本发明的一种或多种载体包含一种或多种本发明的核酸,并且优选能够产生本发明的多肽或融合蛋白。在某些实施例中,此类载体选自由以下组成的组:pQE载体,pET载体,pFUSE载体,pUC载体,YAC载体,噬菌粒载体,噬菌体载体,用于基因治疗的载体,例如逆转录病毒、腺病毒、腺相关病毒。对于载体修饰技术,参见Sambrook和Russel,MolecularCloning:A Laboratory Manual[分子克隆:实验室手册],第3版.,冷泉港实验室出版社,2001。通常,载体可含有一个或多个复制起点(ori)和用于克隆或表达的遗传系统,一个或多个用于在宿主中选择的标志物(例如抗生素抗性)和一个或多个表达盒。合适的复制起点(ori)包括,例如,Col E1、SV40病毒和M13的复制起点。
还可以将本发明的一种或多种核酸分子插入一种或多种载体中,从而产生与另一核酸分子的翻译融合体。其他核酸分子可以例如编码抗体的轻链和/或重链和/或接头,其优选实例如上所述。
一种或多种宿主细胞可以通过将本发明的一种或多种核酸分子或一种或多种载体引入一种或多种宿主细胞中来产生,所述宿主细胞在所述核酸分子或载体存在时介导由所述核酸分子或载体编码的多肽的表达。宿主细胞优选是分离的宿主细胞,这意味着细胞不在活生物体的背景下。宿主可以是任何原核或真核细胞。合适的真核宿主可以是哺乳动物细胞、两栖动物细胞、鱼细胞、昆虫细胞、真菌细胞或植物细胞。真核细胞可以是昆虫细胞(例如草地贪夜蛾细胞),酵母细胞(例如酿酒酵母或巴斯德毕赤酵母细胞),真菌细胞(例如曲霉细胞)或脊椎动物细胞。在后一方面,优选细胞是哺乳动物细胞,例如人细胞、仓鼠细胞或猴细胞。细胞可以是细胞系的一部分。
原核生物/细菌的合适实例是通常用于克隆的那些,例如大肠杆菌(例如,大肠杆菌菌株HB101、DH5a、XL1 Blue、Y1090和JM101)。
在第四方面,本发明涉及药物或诊断组合物,该药物或诊断组合物包含本发明的多肽、本发明的融合构建体、本发明的核酸分子、或其任何组合。
本发明的药物组合物优选包含药学上可接受的载体或赋形剂。“药学上可接受的载体或赋形剂”是指无毒固体、半固体或液体填充剂、稀释剂、包封材料或任何类型的配制品助剂。药学上可接受的载体或赋形剂的实例描述于例如Ansel等人.,“PharmaceuticalDosage Forms and Drug Delivery Systems[药物剂型和药物递送系统]”,第7版,利平科特威廉姆斯和威尔金斯出版社(Lippincott Williams&Wilkins Publishers),1999中。
如上文更详细讨论的,FGFR3涉及许多疾病,特别是癌症。因此,本发明的多肽、融合构建体、核酸分子、载体或其任何组合可用作药物。在所述药物组合物中,本发明的多肽、融合构建体、核酸分子、载体或其任何组合可以是唯一的活性剂,但是可选择地它们也可以与其他活性剂组合,例如以组合产品的形式。药物组合物可以例如施用于哺乳动物,例如家畜和宠物、小鼠、大鼠、兔、非人灵长类动物等。优选将其给予人。本文所述的药物组合物将以合适的剂量施用于受试者。
根据本发明使用的药物组合物可以根据本领域发现的方法使用一种或多种生理载体或赋形剂以常规方式配制,参见例如Ansel等人.,“Pharmaceutical Dosage Formsand Drug Delivery Systems[药物剂型和药物递送系统]”,第7版,利平科特威廉姆斯和威尔金斯出版社(Lippincott Williams&Wilkins Publishers),1999。因此,药物组合物可以通过包含常规的药学上可接受的赋形剂的剂量单位配制品口服、肠胃外、例如皮下、静脉内、肌肉内、腹膜内、鞘内、透皮、透粘膜、硬膜下、通过离子电渗疗法局部(locally或topically)、舌下、通过吸入喷雾、气溶胶或直肠等进行给予。而且,本发明的诊断组合物可以以任何常规方式制造。
本发明的药物组合物可以作为唯一的活性成分或与另一种活性成分(例如免疫抑制剂或免疫调节剂或其他抗炎剂)联合给予,例如用于治疗或预防上述疾病。例如,本发明的多肽、融合构建体和构建体可以与单克隆抗体组合使用,例如,对GM-2、CD38、ICAM-1、SLAMF7、CD45、CD40、CD74、IGFR-1、CD20、BAFF、BCMA、CD66、GRP78、CXCR4、EGFR、EPCAM、TROP-2、B7H3或CEACAM-1具有亲和力的单克隆抗体。
本发明的诊断组合物有用于检测不希望的生理FGFR3水平,特别是由于FGFR3的不希望的过表达。所述检测通常包括使样品与本发明的多肽、融合构建体、构建体、核酸分子、载体、宿主细胞或其任何组合接触,并检测FGFR3b和3c的存在,特别是样品中SEQ ID NO 9和10的FGFR3b和3c。因此,本发明的诊断组合物可用于评估发病或疾病状态,特别是与FGRF3过表达相关的癌症或相关疾病。
在上文所述的本发明的一个实施例中,本发明的多肽与荧光染料、光敏剂、放射性核素或用于医学成像的造影剂连接。这种融合构建体特别适用于诊断应用。这是因为FGFR3例如在癌症中过表达,因此本发明的可检测地标记的多肽可用于使患病的身体部位成像,从而诊断受试者患有癌症。
本发明的诊断组合物和药物组合物的剂量将根据以下而变化:特定多肽,融合构建体,构建体,本发明的一种或多种核酸分子、一种或多种载体或其任何组合,个体患者组或患者,任选存在的其他诊断或医学活性化合物以及待诊断或治疗的疾病的性质和严重程度。通常,诊断组合物或药物组合物的以约0.01mg至约20mg/千克体重,例如约0.1mg至约5mg/千克体重的剂量使用。诊断组合物或药物组合物可以多次给予,例如,在诊断组合物的情况下监测疾病的进程或在药物组合物的情况下延长治疗。例如,诊断组合物或药物组合物的给予频率可以是每日一次至约每3个月一次,例如约每2周一次至约每10周一次,例如每4至8周一次。在某些实施例中,给药方案包括每月一次给予本发明的诊断组合物或药物组合物至每2至3个月一次或更低频率。
根据某些实施例,本发明第四方面的药物组合物或诊断组合物用于治疗癌症或T细胞介导的疾病。
如上文所讨论的,已经报道了许多癌症类型中FGFR3的过表达,因此药物组合物或诊断组合物特别适合于治疗和诊断癌症。因此,癌症优选是癌细胞在其表面上表达FGFR3的癌症或与FGRF3过表达相关的癌症。
由于在癌症中的FGFR3表达的已知作用,本发明的药物组合物或诊断组合物通常也可用于治疗瘤形成,包括良性和恶性肿瘤。
在US 2008/044419中已经报道,抑制FGFR3活性是治疗T细胞介导的疾病,特别是T细胞介导的炎症和自身免疫疾病的手段。
根据本发明第四方面的某些实施例,癌症选自乳腺癌、宫颈癌、结肠直肠癌、子宫内膜癌、神经胶质瘤、头颈癌、肝癌、肺癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌和尿路上皮癌。
根据“人蛋白质图谱”(参见http://www.proteinatlas.org/ENSG00000068078- FGFR3/cancer),FGFR3的表达在以下癌症类型中被发现:乳腺癌、宫颈癌、结肠直肠癌、子宫内膜癌、神经胶质瘤、头颈癌、肝癌、肺癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌和尿路上皮癌。因此可以预期FGFR3的表达在这些癌症类型的发展中具有意义。
根据本发明第四方面的某些实施例,癌症选自多发性骨髓瘤、膀胱癌、宫颈癌、胰腺癌、鳞状细胞肺癌和结肠直肠癌。
上文已经讨论过在多发性骨髓瘤以及膀胱癌中已经报道了FGFR3的过表达。FGFR3的表达也与宫颈癌(Capellen等人.,Nat Genet[自然遗传].1999Sep;23(1):18-20.)、胰腺癌(Lafitte等人.,Mol Cancer[分子癌症学],2013,12:83)和结肠直肠癌(Sonvilla等人.,Br J Cancer[英国癌症杂志],2010;102(7):1145-1156)有关。此外,在鳞状细胞肺癌中观察到FGFR3的表达(Liao等人(2013),Cancer Research[癌症研究],73(16):5195-5205)。
根据本发明第四方面的某些实施例,T细胞介导的疾病选自类风湿性关节炎(RA)、胶原II型关节炎、多发性硬化症(MS)、系统性红斑狼疮(SLE)、银屑病、青少年发病型糖尿病、舍格伦综合征(Sjogren’s disease)、甲状腺疾病、结节病、自身免疫性葡萄膜炎、炎性肠病(克罗恩病和溃疡性结肠炎)、乳糜泻和重症肌无力。
上面列出的疾病是可以通过抑制FGFR3治疗的特定T细胞介导的疾病的非限制性实例。
在本说明书中,引用了许多文献,包括专利申请和制造商手册。这些文献的公开内容虽然不被认为与本发明的可专利性相关,但在此通过引用整体并入。更具体地,所有参考的文献通过引用结合在此,其程度如同将每个单独的文献具体并单独地指明通过引用结合在此。
在整个本发明中,术语“包含”是指包括所列出的所有要素。当使用该术语时,任选地还可以存在另外的未命名要素。因此,“包含”可以是指“由......组成”(即仅存在列出的要素)或者它可以是指“含有”(即除了列出的所有要素之外还存在其他要素)。因此,包含SEQ ID NO:x的多肽可以仅由SEQ ID NO:x组成,或者在其他实施例中可以包含另外的氨基酸,例如在融合蛋白中,例如在SEQ ID NO:x与抗体重链或轻链融合的实施例中。
除非另外定义,本文中使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常所理解的相同的含义。在有矛盾的情况下,将以专利说明书(包括定义)为准。
关于在本说明书中特别是在权利要求中表征的实施例,旨在将从属权利要求中提到的每个实施例与所述从属权利要求从属的每个权利要求(独立的或从属的)的每个实施例组合。例如,在独立权利要求1叙述3个供替代的选择A、B和C,从属权利要求2叙述3个供替代的选择D、E和F以及从属于权利要求1和2并且叙述3个供替代的选择G、H和I的权利要求3的情况下,应理解该说明书明确地披露了对应于以下组合的实施例:A、D、G;A、D、H;A、D、I;A、E、G;A、E、H;A、E、I;A、F、G;A、F、H;A、F、I;B、D、G;B、D、H;B、D、I;B、E、G;B、E、H;B、E、I;B、F、G;B、F、H;B、F、I;C、D、G;C、D、H;C、D、I;C、E、G;C、E、H;C、E、I;C、F、G;C、F、H;C、F、I,除非另有说明。
类似地,并且在独立和/或从属权利要求没有叙述供替代的选择的那些情况下,应当理解,如果从属权利要求回引前述权利要求的大部分,则认为由此涵盖的主题的任何组合被明确披露。例如,在独立权利要求1的情况下,从属权利要求2回引权利要求1,并且从属权利要求3回引权利要求2和权利要求1,其结果是权利要求3和权利要求1的主题的组合与权利要求3、2和1的主题的组合一样清楚且明确地披露。在存在进一步的从属权利要求4,其引用权利要求1至3中的任一项的情况下,结果是权利要求4和1、权利要求4、2和1、权利要求4、3和1以及权利要求4、3、2和1的主题的组合被清楚且明确地披露。
上述考虑加以必要变更地适用于所有附加权利要求。
附图显示:
图1:SEQ ID NO 3至8的抗FGFR3 Fynomer的比对。
图2:抗FGFR3 Fynomer的内化特性。
图3:Fyn SH3衍生的FGFR3结合多肽的尺寸排阻特征:A)FF2L4C3-SEQ ID NO.3;B)FF44L65G12-SEQ ID NO.4;C)FF44L65G7-SEQ ID NO.5;D)FF48L66G7-SEQ ID NO.6;E)FF43L65D5-SEQ ID NO.7;F)FF44L65B7-SEQ ID NO.8。
图4:结合至FGFR3的Fyn-SH3衍生的多肽的与以下项的FACS结合:A)FGFR3-阳性KMS-11细胞和B)FGFR3-阴性N87细胞。
图5:Fyn SH3衍生的FGFR3结合多肽的特异性ELISA:A)FF2L4C3-SEQ ID NO.3;B)FF44L65G12-SEQ ID NO.4;C)FF44L65G7-SEQ ID NO.5;D)FF48L66G7-SEQ ID NO.6;E)FF43L65D5-SEQ ID NO.7;F)FF44L65B7-SEQ ID NO.8.测试的抗原:huFGFR3b=人FGFR3剪接变体b;huFGFR3c=人FGFR3剪接变体c;cyFGFR3c=食蟹猴FGFR3剪接变体c;muFGFR3c=鼠FGFR3剪接变体c;huFGFR3-D1=人FGFR3的结构域1;huFGFR3-D2=人FGFR3的结构域2;huFGFR3-D1D2=人FGFR3的结构域1和结构域2;IgG=多克隆人IgG混合物;PBS=磷酸盐缓冲盐水溶液。
图6:内化测定显示Fyn SH3衍生的FGFR3结合多肽的细胞毒性作用。
这些实例说明了本发明。
实例1:Fyn SH3衍生的多肽与FGFR3b和FGFR3c结合。
为了能够靶向FGFR3,我们开始从中获得特异性Fyn SH3衍生的结合分子。由于两种不同剪接变体(FGFR3b和FGFR3c)在不同肿瘤细胞上的分布和表达尚未完全了解,因此重要的是Fyn SH3衍生的多肽能够结合两者。
使用重组人FGFR3b-Fc(SEQ ID NO:12)和FGFR3c-Fc(SEQ ID NO:13)作为靶标,我们成功地选择并分离了能够结合人FGFR3的两种剪接变体(SEQ ID NO 9和10)的Fyn SH3衍生的结合蛋白的若干个家族。我们继续用最有希望的候选家族进行进一步研究。
有趣的是,携带RT环序列“EVYGPTP”(SEQ ID NO:2)的称为FF2L4C3(SEQ ID NO:3)的Fyn SH3衍生的多肽在选择过程中富集并在29种测试的抗FGFR3 Fynomer中显示出最有希望的内化特性(见图2)。更详细地,将5个其他序列家族排除在进一步分析之外。属于最有希望的序列家族的Fynomer显示出最佳的亲和力和内化特性。
为了获得具有更高亲和力和改善的内化特性的Fyn SH3衍生的FGFR3结合物,使用FF2L4C3(SEQ ID NO:3)作为亲和力成熟的模板。将RT环序列“EVYGPTP”(SEQ ID NO:2)保持恒定并与随机化的n-src环库组合(其中在SEQ ID NO:1中的位置(X1)至(X4)处引入一段4至6个随机化氨基酸残基)。亲和力成熟文库生成的过程基本上与克隆具有随机化的n-src环的原始文库(如[25]中所述的“文库0”)所描述的相同。
在原始和亲和力成熟选择后,通过裂解物ELISA针对与FGFR3的结合筛选富集的Fyn SH3衍生的多肽。将编码Fyn SH3衍生的结合蛋白的DNA克隆到细菌表达载体pQE12(凯杰公司(Qiagen))中,使得所得的构建体携带C末端myc-六组氨酸标签,如Grabulovski等人所述[26]。多肽在96孔形式中的大肠杆菌细菌的胞质溶胶中表达,并如Bertschinger等人所述制备200μl澄清的裂解物/孔[27]。简而言之,从琼脂平板上挑取转化的细菌菌落,并在含有100μg/ml氨苄青霉素和0.1%(w/v)葡萄糖的200μl 2xYT培养基中在圆底96孔板(Nunc,目录号163320)中生长。在37℃并在200r.p.m.旋转振荡生长3小时后通过添加1mMIPTG(应用化学公式(Applichem),德国)诱导蛋白质表达。蛋白质在旋转振荡器(200r.p.m.,30℃)中过夜表达。随后,将96孔板以1800g离心10分钟,并且弃去上清液。使用Bugplus(Millipore 70750-3)裂解细菌沉淀,并且随后通过以1800xg离心10分钟澄清裂解物。将60μl裂解物与170μl PBS混合,并通过0.45μm Multiscreen滤板(Millipore MSHVN4510)过滤,以消除任何残留的细菌碎片。
单克隆细菌裂解物用于ELISA。对于ELISA,将Maxisorp板用5μg/ml huFGFR3b-Fc(SEQ ID NO:12)、5μg/ml huFGFR3c-Fc(SEQ ID NO:13)或5μg/ml聚IgG包被过夜并用2%MPBS封闭至少1小时。将含有具有C末端myc标签和六组氨酸肽标签的可溶性Fynomer的澄清的裂解物在含有鼠单克隆抗myc标签抗体,克隆9E10(罗氏应用科学公司(Roche AppliedScience)11 667 203 001)的2%MPBS中添加至maxisorp板。通过抗小鼠IgG-辣根过氧化物酶缀合物(西格玛奥德里奇公司(Sigma-Aldrich)A2554)通过9E10检测结合的Fynomer。通过添加BM蓝色POD底物(罗氏公司(Roche))进行过氧化物酶活性的检测,并通过添加1MH2SO4来终止反应。
通过DNA测序验证特异性结合物的DNA序列。
结果
与FGFR3b和FGFR3c结合的ELISA阳性Fyn SH3衍生的优选多肽的氨基酸序列示于如序列表中所附的SEQ ID NO:3至8中。Fyn-SH3衍生的多肽SEQ ID NO:4至8是来自FF2L4C3(SEQ ID NO:3)亲和力成熟后获得的分子的大池中的结合物的选择,并且由于其改善的亲和力和内化特性而在此呈现(如实例2和5所示)。
更详细地,衍生自SEQ ID NO:3的超过80种Fynomer在其生物物理特性、亲和力和内化特性方面进行了表征。SEQ ID NO:4至8是在生物物理、亲和力和内化方面具有最佳特性组的结合物。
实例2:本发明的Fyn SH3衍生的FGFR3结合多肽的表达
该实施例显示了优选的Fyn SH3衍生的FGFR3结合多肽的表达产率和通过尺寸排阻色谱对这些多肽的表征。
方法
a)Fyn SH3衍生的FGFR3结合多肽的表达产率
Fyn SH3衍生的FGFR3结合多肽在TG1大肠杆菌细菌的胞质溶胶中表达,并如Grabulovski等人所述进行纯化[2]。
b)尺寸排阻色谱(SEC)
通过尺寸排阻色谱(TOSOH TSKgel PW G3000PWxL;安捷伦1260Infinity HPLC;PBS pH 7.4流动相)分析样品。将10μl未稀释的样品注射到柱上,并分析所得的谱。
结果
a)表达产率
本发明的单体Fyn SH3衍生的FGFR3结合多肽的表达产率在摇瓶中在非优化条件下为15至51mg/升细菌培养物(表1),并且在Fyn SH3衍生的多肽的典型范围内。
表1.在TG1大肠杆菌细菌中产生的Fyn SH3衍生的FGFR3结合多肽的表达产率
Fynomer | SEQ ID NO | 产率(mg/l) |
FF2L4C3 | 3 | 18 |
FF44L65G12 | 4 | 37 |
FF44L65G7 | 5 | 15 |
FF48L66G7 | 6 | 58 |
FF43L65D5 | 7 | 32 |
FF44L65B7 | 8 | 51 |
b)尺寸排阻色谱(SEC)
尺寸排阻色谱(SEC)图谱证明所有构建体主要作为单个单体峰洗脱(图3)。这通常表明良好的生物物理特性,这从Fynomer(Fyn SH3衍生的结合分子,包括Fynomab,其是与抗体的融合蛋白)的制造角度是有利的,并且与Fyn SH3衍生的分子的早期观察一致。
实例3:本发明的Fyn SH3衍生的多肽以高亲和力结合人FGFR3b和FGFR3c。
该实例显示了通过表面等离子共振和流式细胞术实验表征优选的Fyn SH3衍生的FGFR3结合多肽。
方法
a)BIAcore的亲和力测量
使用BIAcore T200仪器测量亲和力。使用胺偶联试剂盒(GE医疗集团BR100633),用抗myc抗体9E10(罗氏公司11 667 203 001;包被密度在6000RU和8000RU之间)包被CM5系列S芯片(GE医疗集团BR-1005-30)上的一个流动池。
将浓度为500nM的亲本Fynomer FF2L4C3(SEQ ID NO:3)和浓度为100nM的具有SEQID NO:4-8的Fynomer捕获在9E10表面上,然后注射不同浓度的huFGFR3b-Fc(SEQ ID NO:12)、huFGFR3c-Fc(SEQ ID NO:13)或cynoFGFR3c-Fc(SEQ ID NO:14)(对于测量亲本Fynomer FF2L4C3是0nM、3.9nM、7.8nM、15.6nM、31.25nM、62.5nM、125nM、250nM和500nM,对于具有SEQ ID NO:4-8的Fynomer是0nM、0.046nM、0.14nM、0.41nM、1.2nM、3.7nM、11.1nM、33.3nM和100nM)。记录传感图,并使用BIAevaluation 2.1软件中的1.1Langmuir相互作用模型通过曲线拟合确定表观动力学常数。
b)通过流式细胞术的亲和力测量
使用KMS-11细胞(JCRB1179)作为FGFR3阳性细胞和N87(ATCC,CRL-5822)作为FGFR3阴性对照细胞系,通过流式细胞术分析Fynomer与细胞上的huFGFR3的结合。将KMS-11和N87细胞维持在RPMI1640培养基(英杰公司(Invitrogen)52400-25)中。所有培养基补充有25U/ml青霉素,25μg/ml链霉素和10%FCS。为了从T150烧瓶中收获半粘附的KMS-11细胞,将上清液移入50ml falcon管中,并用也加入到falcon管中的10ml PBS洗涤细胞。向烧瓶中添加2ml Accutase(西格玛公司(Sigma)A6964),并在37℃下孵育10分钟。将Accutase通过添加10ml培养基进行失活并添加到falcon管中,然后将其离心(250x g,5分钟)以沉淀细胞。将细胞重悬浮于FACS缓冲液(PBS+1%FCS+0.2%叠氮化钠)至细胞浓度1x 106个细胞/ml,并且在96孔圆底板(Nunc 163320)中每孔使用100μl(1x 105个细胞/孔)进行流式细胞术染色。对于粘附的N87细胞,弃去上清液和洗涤液,仅收集和制备Accutase分离的细胞。
将Fynomer与小鼠抗myc抗体(克隆9E10;罗氏公司11667149001)共孵育,以允许在细胞结合之前交联myc标记的Fynomer。将Fynomer稀释至1μM并与FACS缓冲液中的667nM9E10抗myc抗体(3:2摩尔比)在冰上共孵育约10分钟。
将该混合物以1/4的比例连续稀释至Fynomer浓度为0.06nM(总共8个浓度)。对照仅包括二抗9E10(无Fynomer;667nM 9E10),仅细胞(仅FACS缓冲液)和浓度为10nM的抗FGFR3抗体(R&D系统公司;目录号MAB766)。将细胞在96孔板中离心(250x g,5分钟),并用上述样品重悬浮,然后在冰上孵育1小时。将板离心并洗涤(PBS+0.2%叠氮化钠),然后再次离心。然后将50μl二抗抗mIgG Alexa488(生命技术公司(Life Technologies)A21202)以4μg/ml的浓度添加至细胞,然后在黑暗中在冰上孵育45分钟。将板离心并用PBS+0.2%叠氮化钠洗涤两次,然后重悬于FACS缓冲液和FACS分析(Millipore Guava easyCyte 8HT)。
使用Prism 6进行FACS数据分析。将数据进行转化(X=logX),并使用非线性拟合,log(激动剂)相比于应答-可变斜率(4个参数)进行分析。
结果
a)BIAcore的亲和力测量
通过BIAcore芯片上的实时相互作用分析来分析结合特性,揭示所选FGFR3结合多肽的以下解离常数(KD):
表2.Fyn SH3衍生的FGFR3结合多肽与重组人FGFR3b、人FGFR3c和食蟹猴FGFR3c结合的表观动力学常数。
考虑到在仅经过一轮亲和力成熟后获得亚纳摩尔值的事实,测得的Fyn SH3衍生的多肽(SEQ ID NO:3至8)与FGFR3b和FGFR3c(SEQ ID NO 9和10)结合的表观亲和力(表2)出人意料地高。此外,这些测量证实了Fyn SH3衍生的多肽(SEQ ID NO:3至8)与FGFR3的两种人同种型(FGFR3b和FGFR3c;SEQ ID NOs 9和10)以及食蟹猴FGFR3c(未测试与食蟹猴FGFR3b的结合)的可比较的结合特性。
b)通过流式细胞术进行亲和力测量
使用FGFR3阳性KMS-11细胞和FGFR3阴性N87细胞作为阴性对照,通过流式细胞术分析结合特性。测量所选FGFR3结合多肽的以下EC50值,如表3和图4中所示。
表3.对于Fyn SH3衍生的FGFR3结合多肽,在FGFR3阳性KMS-11细胞上测定的EC50值。
Fynomer | SEQ ID NO | EC50(nM) |
FF2L4C3 | 3 | 5.9 |
FF44L65G12 | 4 | 2.2 |
FF44L65G7 | 5 | 4.2 |
FF48L66G7 | 6 | 2.3 |
FF43L65D5 | 7 | 1.2 |
FF44L65B7 | 8 | 0.6 |
在表达FGFR3的细胞系(图4A,KMS-11)上测量的低纳摩尔范围(表3)中的EC50值证实了通过表面等离子共振测量的高表观亲和力(表2),并证明了在细胞表面的自然环境中与FGFR3的结合。与FGFR3结合的所有Fyn SH3衍生的多肽(SEQ ID NO:3至8)未显示对不表达FGFR3的细胞系的非特异性结合(图4B)。
实例4:对FGFR3具有特异性的本发明的Fyn SH3衍生的多肽不干扰配体结合
优选的是,用于结合两种同种型FGFR3b和FGFR3c的Fyn SH3衍生的多肽不干扰配体(例如FGF1)结合,因为配体结合位点位于产生FGFR3b或FGFR3c的剪接位点附近。
为了验证Fyn SH3衍生多肽在其配体之一存在下与FGFR3结合的能力,建立了BIAcore实验以测量在FGF1(成纤维细胞生长因子1是FGFR3的主要配体之一)存在或不存在情况下Fynomer对FGFR3的亲和力。
类似于用于测量亲和力的方法(如实例3中所述),浓度为100nM的Fynomer(除了以浓度500nM使用的FF2L4C3-SEQ ID NO.3)被捕获在9E10表面上,然后在存在或不存在200nMFGF1(R&D系统公司232-FA-025/CF)的情况下注射不同浓度的huFGFR3c-Fc(SEQ ID NO:13)(0nM、11nM、33nM、100nM)。记录传感图并使用BIAevaluation 2.1软件计算表观动力学常数。
结果
独立于溶液中存在或不存在200nM FGF1的情况,Fyn SH3衍生的多肽与huFGFR3c的结合没有变化,表明Fynomer与FGFR3的结合不干扰配体结合。
表4:显示在存在或不存在200nM FGF1情况下获得的动力学常数。
即使这样,由于测定可变性,在不存在FGF1的情况下KD表观的值与在实例2中显示的实验中获得的值(表2)略有不同,该实验显示即使配体(在这种情况下为FGF1)与配体结合位点结合,Fyn SH3衍生的多肽也能够与FGFR3结合。
由此我们得出结论,由此处描述的Fyn SH3衍生的多肽结合的表位位于FGFR3的恒定区。
实例5:本发明的Fyn SH3衍生的多肽与FGFR3的结构域D1-D2结合。
通过ELISA测试Fyn-SH3衍生的多肽与FGFR3结合的特异性。
在板上包被不同的抗原(Maxisorp板;Nunc 439454):huFGFR3b-Fc(SEQ ID NO:12)、huFGFR3c-Fc(SEQ ID NO:13)、cyFGFR3c-Fc(SEQ ID NO:14)、muFGFR3c-His(SEQ IDNO:15)、huD1-Fc(SEQ ID NO:16)、huD2-Fc(SEQ ID NO:17)、huD1-D2-Fc(SEQ ID NO:18)。
将板用100μl的5μg/ml抗原(0.5μg/孔)包被,并在4℃孵育过夜。将孔用PBS洗涤3次,然后在室温下用200μl 4%MPBS封闭1小时。再次洗涤孔,并添加20μl含有15μg/ml 9E10的10%MPBS,然后添加80μl的250nM Fynomer(200nM最终Fynomer浓度)。将孔在室温下孵育45分钟,然后洗涤并添加在2%MPBS中1:1000稀释的100μl抗小鼠IgG-HRP(西格玛公司A2554)。将孔在室温下孵育30分钟,然后用PBS中的0.1%Tween-20洗涤3次,然后用PBS洗涤3次。向每个孔中添加100μl BM POD蓝色底物(罗氏公司11 484 281 001),然后添加50μl1M H2SO4以终止反应。使用Tecan M1000仪器记录450nm-650nm的吸光度。
结果
如图5A-F所示,Fyn SH3衍生的多肽均与食蟹猴和鼠FGFR3c交叉反应。有趣的是,所有结合物对只有当结构域D1和D2物理连接时才出现的表位具有特异性(参见图5A-F barhuFGFR3-D1D2),事实上如果单个结构域D1或D2(hFGFR3-D1或huFGFR3-D2)固定在ELISA板上,没有观察到结合。
实例6:本发明的Fyn SH3衍生的多肽引起FGFR3的有效内化
内化是本文所述的Fyn SH3衍生多肽的核心特征,并且提供了使用这些结合物在细胞内递送毒性负载和/或融合蛋白例如抗体的机会。
为了评估结合FGFR3的Fyn SH3衍生的多肽在与靶标结合后内化的能力,建立了基于细胞毒性剂的细胞内递送的内化测定。
该测定测量了与MMAF(单甲基瑞奥西汀F)-缀合的9E10交联的抗FGFR3 Fynomer对KMS-11细胞的细胞毒性作用。MMAF是抗有丝分裂剂(阻断微管蛋白聚合)并且仅在内化到细胞中后才有活性。因此,该测定表明Fynomer促进MMAF内化的程度。将50μl的2x 105个细胞/ml的KMS-11细胞接种到96孔平底板(康宁公司(Corning Costar)3610)中,产生10,000个细胞/孔。将细胞孵育4小时以使细胞粘附(37℃,5%CO2)。将Fynomer和9E10-MMAF以3:1的比例混合。在RPMI培养基中制备4x Fynomer原液(4μM)和4x 9E10-MMAF原液(1.33μM)(参见5.4.1节)并以1:1(40μl+40μl)混合。然后将该混合物连续稀释1/3,得到浓度范围1000nM-50pM。将50μl样品加入50μl细胞中(如上所述),并孵育5天(37℃,5%CO2)。包括适当的对照,野生型Fynomer FynSH3,不含Fynomer的MMAF-9E10以及不添加任何试剂的细胞。一式两份地制备所有样品。5天后,向每个孔中添加100μl Cell titer glo(普洛麦格公司(Promega)G7573)并在黑暗中温和摇动孵育10分钟。作为细胞活力的读数,使用TecanM1000仪器测量发光。使用Prism 6进行分析。将数据进行转化(X=logX),并使用非线性拟合,log(抑制剂)相比于应答-可变斜率(4个参数)进行分析。
结果
与仅用MMAF标记的二抗(图6A中的9E10)或在所有3个实验中显示的野生型Fynomer FynSH3与MMAF标记的9E10组合(图6A-C,表示为FynSH3)处理的细胞(其仅在最高测试浓度下显示细胞毒性,可能是由于MMAF本身的毒性)相比,本文所述的所有Fyn SH3衍生的FGFR3结合多肽均显示出增加的细胞毒性(例如内化)。图6显示了在不同实验中获得的细胞毒性谱,表5显示了对于不同的Fyn SH3衍生的FGFR3结合多肽获得的EC50。
表5:在使用FGFR3+KMS-11细胞进行Fyn SH3衍生的FGFR3结合多肽的内化测定中测定的EC50值。
Fynomer | SEQ ID NO. | EC50(nM) |
FF2L4C3 | 3 | 28.5/21/26.4 |
FF44L65G12 | 4 | 2.5 |
FF44L65G7 | 5 | 2.6 |
FF48L66G7 | 6 | 2.4 |
FF43L65D5 | 7 | 0.8 |
FF44L65B7 | 8 | 1.8 |
注释:对于FF2L4C3,显示了在图6中所示的3个实验中获得的3个值。
图6和表5中所示的数据表明,增加的亲和力也导致更有效的内化。
实例7:选择性Fyn-SH3衍生的多肽,其显示出优异的结合和内化特性,并且衍生自不同的家族
除了优选的序列(SEQ ID NO:1)家族之外,我们鉴定了一种选择性Fynomer,FF40L54A5(SEQ ID NO:22),其出人意料地也显示出优异的结合和内化特性,并且与衍生自SEQ ID NO:1的Fynomer一样具有可制造性和交叉反应性(参见表6)。Fynomer FF40L54A5预计不具有优异的内化性能,因为其序列衍生自仅显示非常差的内化特性的Fynomer。
表6总结了Fynomer FF40L54A5的特性。
表6-第1部分
表6-第2部分
*:由于实验可变性而产生的差异
表6-第3部分
参考文献
1.Turner,N.and R.Grose,Fibroblast growth factor signalling:fromdevelopment to cancer.Nat Rev Cancer,2010.10(2):p.116-29.
2.Kalff,A.and A.Spencer,The t(4;14)translocation andFGFR3overexpression in multiple myeloma:prognostic implications and currentclinical strategies.Blood Cancer J,2012.2:p.e89.
3.Pollett,J.B.,et al.,Overexpression of the myeloma-associatedoncogene fibroblast growth factor receptor 3confers dexamethasoneresistance.Blood,2002.100(10):p.3819-21.
4.Fonseca,R.,et al.,Clinical and biologic implications of recurrentgenomic aberrations in myeloma.Blood,2003.101(11):p.4569-75.
5.Agazie,Y.M.,et al.,The phosphotyrosine phosphatase SHP2 is acritical mediator of transformation induced by the oncogenic fibroblastgrowth factor receptor 3.Oncogene,2003.22(44):p.6909-18.
6.Ronchetti,D.,et al.,Deregulated FGFR3 mutants in multiple myelomacell lines with t(4;14):comparative analysis of Y373C,K650E and the novelG384D mutations.Oncogene,2001.20(27):p.3553-62.
7.Chesi,M.,et al.,Activated fibroblast growth factor receptor 3 is anoncogene that contributes to tumor progression in multiple myeloma.Blood,2001.97(3):p.729-36.
8.Plowright,E.E.,et al.,Ectopic expression of fibroblast growthfactor receptor 3 promotes myeloma cell proliferation and preventsapoptosis.Blood,2000.95(3):p.992-8.
9.Chen,J.,et al.,Constitutively activated FGFR3 mutants signalthrough PLCgamma-dependent and-independent pathways for hematopoietictransformation.Blood,2005.106(1):p.328-37.
10.Li,Z.,et al.,The myeloma-associated oncogene fibroblast growthfactor receptor 3 is transforming in hematopoietic cells.Blood,2001.97(8):p.2413-9.
11.Trudel,S.,et al.,Inhibition of fibroblast growth factor receptor 3induces differentiation and apoptosis in t(4;14)myeloma.Blood,2004.103(9):p.3521-8.
12.Trudel,S.,et al.,CHIR-258,a novel,multitargeted tyrosine kinaseinhibitor for the potential treatment of t(4;14)multiple myeloma.Blood,2005.105(7):p.2941-8.
13.Chen,J.,et al.,FGFR3 as a therapeutic target of the small moleculeinhibitor PKC412 in hematopoietic malignancies.Oncogene,2005.24(56):p.8259-67.
14.Paterson,J.L.,et al.,Preclinical studies of fibroblast growthfactor receptor 3 as a therapeutic target in multiple myeloma.Br J Haematol,2004.124(5):p.595-603.
15.Grand,E.K.,et al.,Targeting FGFR3 in multiple myeloma:inhibitionof t(4;14)-positive cells by SU5402 and PD173074.Leukemia,2004.18(5):p.962-6.
16.Gomez-Roman,J.J.,et al.,Fibroblast growth factor receptor 3 isoverexpressed in urinary tract carcinomas and modulates the neoplastic cellgrowth.Clin Cancer Res,2005.11(2 Pt 1):p.459-65.
17.Tomlinson,D.C.,et al.,FGFR3 protein expression and itsrelationship to mutation status and prognostic variables in bladder cancer.JPathol,2007.213(1):p.91-8.
18.van Rhijn,B.W.,et al.,Frequent FGFR3 mutations in urothelialpapilloma.J Pathol,2002.198(2):p.245-51.
19.Tomlinson,D.C.,C.D.Hurst,and M.A.Knowles,Knockdown by shRNAidentifies S249C mutant FGFR3 as a potential therapeutic target in bladdercancer.Oncogene,2007.26(40):p.5889-99.
20.Martinez-Torrecuadrada,J.,et al.,Targeting the extracellulardomain of fibroblast growth factor receptor 3 with human single-chain Fvantibodies inhibits bladder carcinoma cell line proliferation.Clin CancerRes,2005.11(17):p.6280-90.
21.Martinez-Torrecuadrada,J.L.,et al.,Antitumor activity offibroblast growth factor receptor 3-specific immunotoxins in a xenograftmouse model of bladder carcinoma is mediated by apoptosis.Mol Cancer Ther,2008.7(4):p.862-73.
22.Rauchenberger,R.,et al.,Human combinatorial Fab library yieldingspecific and functional antibodies against the human fibroblast growth factorreceptor 3.J Biol Chem,2003.278(40):p.38194-205.
23.Brack,S.,et al.,A bispecific HER2-targeting FynomAb with superiorantitumor activity and novel mode of action.Mol Cancer Ther,2014.13(8):p.2030-9.
24.Silacci,M.,et al.,Discovery and characterization of COVA322,aclinical-stage bispecific TNF/IL-17A inhibitor for the treatment ofinflammatory diseases.MAbs,2016.8(1):p.141-9.
25.Schlatter,D.,et al.,Generation,characterization and structuraldata of chymase binding proteins based on the human Fyn kinase SH3domain.MAbs,2012.4(4):p.497-508.
26.Grabulovski,D.,M.Kaspar,and D.Neri,A novel,non-immunogenic FynSH3-derived binding protein with tumor vascular targeting properties.J BiolChem,2007.282(5):p.3196-204.
27.Bertschinger,J.,D.Grabulovski,and D.Neri,Selection of singledomain binding proteins by covalent DNA display.Protein Eng Des Sel,2007.20(2):p.57-68.
序列表
<110> 科瓦根股份公司
<120> FGFR3结合分子
<130> COV5008EP
<160> 22
<170> BiSSAP 1.3
<210> 1
<211> 64
<212> PRT
<213> 人工序列
<220>
<223> 共有序列抗FGFR3 Fynomer
<220>
<221> 变体
<222> 32
<223> 任何氨基酸
<220>
<221> 变体
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<223> 任何氨基酸
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<223> 任何氨基酸
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Gly Val Thr Leu Phe Val Ala Leu Tyr Asp Tyr Glu Val Tyr Gly Pro
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<212> PRT
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<223> RT环序列
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<223> FF2L4C3
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<211> 64
<212> PRT
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Gly Val Thr Leu Phe Val Ala Leu Tyr Asp Tyr Glu Val Tyr Gly Pro
1 5 10 15
Thr Pro Met Leu Ser Phe His Lys Gly Glu Lys Phe Gln Ile Leu Arg
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35 40 45
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<210> 6
<211> 64
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1 5 10 15
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<210> 7
<211> 64
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<400> 7
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Gly Val Thr Leu Phe Val Ala Leu Tyr Asp Tyr Glu Val Tyr Gly Pro
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Thr Pro Met Leu Ser Phe His Lys Gly Glu Lys Phe Gln Ile Leu Arg
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<210> 9
<211> 357
<212> PRT
<213> 智人
<220>
<223> FGFR3, 同种型b
<400> 9
Ile Ser Glu Ser Leu Gly Thr Glu Gln Arg Val Val Gly Arg Ala Ala
1 5 10 15
Glu Val Pro Gly Pro Glu Pro Gly Gln Gln Glu Gln Leu Val Phe Gly
20 25 30
Ser Gly Asp Ala Val Glu Leu Ser Cys Pro Pro Pro Gly Gly Gly Pro
35 40 45
Met Gly Pro Thr Val Trp Val Lys Asp Gly Thr Gly Leu Val Pro Ser
50 55 60
Glu Arg Val Leu Val Gly Pro Gln Arg Leu Gln Val Leu Asn Ala Ser
65 70 75 80
His Glu Asp Ser Gly Ala Tyr Ser Cys Arg Gln Arg Leu Thr Gln Arg
85 90 95
Val Leu Cys His Phe Ser Val Arg Val Thr Asp Ala Pro Ser Ser Gly
100 105 110
Asp Asp Glu Asp Gly Glu Asp Glu Ala Glu Asp Thr Gly Val Asp Thr
115 120 125
Gly Ala Pro Tyr Trp Thr Arg Pro Glu Arg Met Asp Lys Lys Leu Leu
130 135 140
Ala Val Pro Ala Ala Asn Thr Val Arg Phe Arg Cys Pro Ala Ala Gly
145 150 155 160
Asn Pro Thr Pro Ser Ile Ser Trp Leu Lys Asn Gly Arg Glu Phe Arg
165 170 175
Gly Glu His Arg Ile Gly Gly Ile Lys Leu Arg His Gln Gln Trp Ser
180 185 190
Leu Val Met Glu Ser Val Val Pro Ser Asp Arg Gly Asn Tyr Thr Cys
195 200 205
Val Val Glu Asn Lys Phe Gly Ser Ile Arg Gln Thr Tyr Thr Leu Asp
210 215 220
Val Leu Glu Arg Ser Pro His Arg Pro Ile Leu Gln Ala Gly Leu Pro
225 230 235 240
Ala Asn Gln Thr Ala Val Leu Gly Ser Asp Val Glu Phe His Cys Lys
245 250 255
Val Tyr Ser Asp Ala Gln Pro His Ile Gln Trp Leu Lys His Val Glu
260 265 270
Val Asn Gly Ser Lys Val Gly Pro Asp Gly Thr Pro Tyr Val Thr Val
275 280 285
Leu Lys Ser Trp Ile Ser Glu Ser Val Glu Ala Asp Val Arg Leu Arg
290 295 300
Leu Ala Asn Val Ser Glu Arg Asp Gly Gly Glu Tyr Leu Cys Arg Ala
305 310 315 320
Thr Asn Phe Ile Gly Val Ala Glu Lys Ala Phe Trp Leu Ser Val His
325 330 335
Gly Pro Arg Ala Ala Glu Glu Glu Leu Val Glu Ala Asp Glu Ala Gly
340 345 350
Ser Val Tyr Ala Gly
355
<210> 10
<211> 355
<212> PRT
<213> 智人
<220>
<223> FGFR3, 同种型c
<400> 10
Ile Ser Glu Ser Leu Gly Thr Glu Gln Arg Val Val Gly Arg Ala Ala
1 5 10 15
Glu Val Pro Gly Pro Glu Pro Gly Gln Gln Glu Gln Leu Val Phe Gly
20 25 30
Ser Gly Asp Ala Val Glu Leu Ser Cys Pro Pro Pro Gly Gly Gly Pro
35 40 45
Met Gly Pro Thr Val Trp Val Lys Asp Gly Thr Gly Leu Val Pro Ser
50 55 60
Glu Arg Val Leu Val Gly Pro Gln Arg Leu Gln Val Leu Asn Ala Ser
65 70 75 80
His Glu Asp Ser Gly Ala Tyr Ser Cys Arg Gln Arg Leu Thr Gln Arg
85 90 95
Val Leu Cys His Phe Ser Val Arg Val Thr Asp Ala Pro Ser Ser Gly
100 105 110
Asp Asp Glu Asp Gly Glu Asp Glu Ala Glu Asp Thr Gly Val Asp Thr
115 120 125
Gly Ala Pro Tyr Trp Thr Arg Pro Glu Arg Met Asp Lys Lys Leu Leu
130 135 140
Ala Val Pro Ala Ala Asn Thr Val Arg Phe Arg Cys Pro Ala Ala Gly
145 150 155 160
Asn Pro Thr Pro Ser Ile Ser Trp Leu Lys Asn Gly Arg Glu Phe Arg
165 170 175
Gly Glu His Arg Ile Gly Gly Ile Lys Leu Arg His Gln Gln Trp Ser
180 185 190
Leu Val Met Glu Ser Val Val Pro Ser Asp Arg Gly Asn Tyr Thr Cys
195 200 205
Val Val Glu Asn Lys Phe Gly Ser Ile Arg Gln Thr Tyr Thr Leu Asp
210 215 220
Val Leu Glu Arg Ser Pro His Arg Pro Ile Leu Gln Ala Gly Leu Pro
225 230 235 240
Ala Asn Gln Thr Ala Val Leu Gly Ser Asp Val Glu Phe His Cys Lys
245 250 255
Val Tyr Ser Asp Ala Gln Pro His Ile Gln Trp Leu Lys His Val Glu
260 265 270
Val Asn Gly Ser Lys Val Gly Pro Asp Gly Thr Pro Tyr Val Thr Val
275 280 285
Leu Lys Thr Ala Gly Ala Asn Thr Thr Asp Lys Glu Leu Glu Val Leu
290 295 300
Ser Leu His Asn Val Thr Phe Glu Asp Ala Gly Glu Tyr Thr Cys Leu
305 310 315 320
Ala Gly Asn Ser Ile Gly Phe Ser His His Ser Ala Trp Leu Val Val
325 330 335
Leu Pro Ala Glu Glu Glu Leu Val Glu Ala Asp Glu Ala Gly Ser Val
340 345 350
Tyr Ala Gly
355
<210> 11
<211> 63
<212> PRT
<213> 智人
<220>
<223> Fyn 激酶SH3 结构域
<400> 11
Gly Val Thr Leu Phe Val Ala Leu Tyr Asp Tyr Glu Ala Arg Thr Glu
1 5 10 15
Asp Asp Leu Ser Phe His Lys Gly Glu Lys Phe Gln Ile Leu Asn Ser
20 25 30
Ser Glu Gly Asp Trp Trp Glu Ala Arg Ser Leu Thr Thr Gly Glu Thr
35 40 45
Gly Tyr Ile Pro Ser Asn Tyr Val Ala Pro Val Asp Ser Ile Gln
50 55 60
<210> 12
<211> 586
<212> PRT
<213> 人工序列
<220>
<223> huFGFR3b-Fc
<400> 12
Ile Ser Glu Ser Leu Gly Thr Glu Gln Arg Val Val Gly Arg Ala Ala
1 5 10 15
Glu Val Pro Gly Pro Glu Pro Gly Gln Gln Glu Gln Leu Val Phe Gly
20 25 30
Ser Gly Asp Ala Val Glu Leu Ser Cys Pro Pro Pro Gly Gly Gly Pro
35 40 45
Met Gly Pro Thr Val Trp Val Lys Asp Gly Thr Gly Leu Val Pro Ser
50 55 60
Glu Arg Val Leu Val Gly Pro Gln Arg Leu Gln Val Leu Asn Ala Ser
65 70 75 80
His Glu Asp Ser Gly Ala Tyr Ser Cys Arg Gln Arg Leu Thr Gln Arg
85 90 95
Val Leu Cys His Phe Ser Val Arg Val Thr Asp Ala Pro Ser Ser Gly
100 105 110
Asp Asp Glu Asp Gly Glu Asp Glu Ala Glu Asp Thr Gly Val Asp Thr
115 120 125
Gly Ala Pro Tyr Trp Thr Arg Pro Glu Arg Met Asp Lys Lys Leu Leu
130 135 140
Ala Val Pro Ala Ala Asn Thr Val Arg Phe Arg Cys Pro Ala Ala Gly
145 150 155 160
Asn Pro Thr Pro Ser Ile Ser Trp Leu Lys Asn Gly Arg Glu Phe Arg
165 170 175
Gly Glu His Arg Ile Gly Gly Ile Lys Leu Arg His Gln Gln Trp Ser
180 185 190
Leu Val Met Glu Ser Val Val Pro Ser Asp Arg Gly Asn Tyr Thr Cys
195 200 205
Val Val Glu Asn Lys Phe Gly Ser Ile Arg Gln Thr Tyr Thr Leu Asp
210 215 220
Val Leu Glu Arg Ser Pro His Arg Pro Ile Leu Gln Ala Gly Leu Pro
225 230 235 240
Ala Asn Gln Thr Ala Val Leu Gly Ser Asp Val Glu Phe His Cys Lys
245 250 255
Val Tyr Ser Asp Ala Gln Pro His Ile Gln Trp Leu Lys His Val Glu
260 265 270
Val Asn Gly Ser Lys Val Gly Pro Asp Gly Thr Pro Tyr Val Thr Val
275 280 285
Leu Lys Ser Trp Ile Ser Glu Ser Val Glu Ala Asp Val Arg Leu Arg
290 295 300
Leu Ala Asn Val Ser Glu Arg Asp Gly Gly Glu Tyr Leu Cys Arg Ala
305 310 315 320
Thr Asn Phe Ile Gly Val Ala Glu Lys Ala Phe Trp Leu Ser Val His
325 330 335
Gly Pro Arg Ala Ala Glu Glu Glu Leu Val Glu Ala Asp Glu Ala Gly
340 345 350
Ser Val Tyr Ala Gly Arg Ser Asp Lys Thr His Thr Cys Pro Pro Cys
355 360 365
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
370 375 380
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
385 390 395 400
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
405 410 415
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
420 425 430
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
435 440 445
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
450 455 460
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
465 470 475 480
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
485 490 495
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
500 505 510
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
515 520 525
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
530 535 540
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
545 550 555 560
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
565 570 575
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
580 585
<210> 13
<211> 584
<212> PRT
<213> 人工序列
<220>
<223> huFGFR3c-Fc
<400> 13
Ile Ser Glu Ser Leu Gly Thr Glu Gln Arg Val Val Gly Arg Ala Ala
1 5 10 15
Glu Val Pro Gly Pro Glu Pro Gly Gln Gln Glu Gln Leu Val Phe Gly
20 25 30
Ser Gly Asp Ala Val Glu Leu Ser Cys Pro Pro Pro Gly Gly Gly Pro
35 40 45
Met Gly Pro Thr Val Trp Val Lys Asp Gly Thr Gly Leu Val Pro Ser
50 55 60
Glu Arg Val Leu Val Gly Pro Gln Arg Leu Gln Val Leu Asn Ala Ser
65 70 75 80
His Glu Asp Ser Gly Ala Tyr Ser Cys Arg Gln Arg Leu Thr Gln Arg
85 90 95
Val Leu Cys His Phe Ser Val Arg Val Thr Asp Ala Pro Ser Ser Gly
100 105 110
Asp Asp Glu Asp Gly Glu Asp Glu Ala Glu Asp Thr Gly Val Asp Thr
115 120 125
Gly Ala Pro Tyr Trp Thr Arg Pro Glu Arg Met Asp Lys Lys Leu Leu
130 135 140
Ala Val Pro Ala Ala Asn Thr Val Arg Phe Arg Cys Pro Ala Ala Gly
145 150 155 160
Asn Pro Thr Pro Ser Ile Ser Trp Leu Lys Asn Gly Arg Glu Phe Arg
165 170 175
Gly Glu His Arg Ile Gly Gly Ile Lys Leu Arg His Gln Gln Trp Ser
180 185 190
Leu Val Met Glu Ser Val Val Pro Ser Asp Arg Gly Asn Tyr Thr Cys
195 200 205
Val Val Glu Asn Lys Phe Gly Ser Ile Arg Gln Thr Tyr Thr Leu Asp
210 215 220
Val Leu Glu Arg Ser Pro His Arg Pro Ile Leu Gln Ala Gly Leu Pro
225 230 235 240
Ala Asn Gln Thr Ala Val Leu Gly Ser Asp Val Glu Phe His Cys Lys
245 250 255
Val Tyr Ser Asp Ala Gln Pro His Ile Gln Trp Leu Lys His Val Glu
260 265 270
Val Asn Gly Ser Lys Val Gly Pro Asp Gly Thr Pro Tyr Val Thr Val
275 280 285
Leu Lys Thr Ala Gly Ala Asn Thr Thr Asp Lys Glu Leu Glu Val Leu
290 295 300
Ser Leu His Asn Val Thr Phe Glu Asp Ala Gly Glu Tyr Thr Cys Leu
305 310 315 320
Ala Gly Asn Ser Ile Gly Phe Ser His His Ser Ala Trp Leu Val Val
325 330 335
Leu Pro Ala Glu Glu Glu Leu Val Glu Ala Asp Glu Ala Gly Ser Val
340 345 350
Tyr Ala Gly Arg Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
355 360 365
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
370 375 380
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
385 390 395 400
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
405 410 415
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
420 425 430
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
435 440 445
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
450 455 460
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
465 470 475 480
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
485 490 495
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
500 505 510
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
515 520 525
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
530 535 540
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
545 550 555 560
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
565 570 575
Ser Leu Ser Leu Ser Pro Gly Lys
580
<210> 14
<211> 583
<212> PRT
<213> 人工序列
<220>
<223> cyFGFR3c-Fc
<400> 14
Ser Glu Ser Leu Gly Thr Glu Gln Arg Val Val Gly Arg Val Ala Glu
1 5 10 15
Val Ser Gly Pro Glu Pro Ser Gln Gln Glu Gln Leu Val Phe Gly Ser
20 25 30
Gly Asp Ala Val Glu Leu Ser Cys Pro Pro Pro Gly Gly Gly Pro Met
35 40 45
Gly Pro Thr Val Trp Val Lys Asp Gly Ala Gly Leu Val Pro Ser Glu
50 55 60
Arg Val Leu Val Gly Pro Gln Arg Leu Gln Val Leu Asn Ala Ser His
65 70 75 80
Glu Asp Ser Gly Ala Tyr Ser Cys Arg Gln Arg Leu Thr Gln Leu Val
85 90 95
Leu Cys His Phe Ser Val Arg Val Thr Asp Ala Pro Ser Ser Gly Asp
100 105 110
Asp Glu Asp Gly Glu Asp Glu Ala Glu Asp Thr Gly Val Asp Thr Gly
115 120 125
Ala Pro Tyr Trp Thr Arg Pro Glu Arg Met Asp Lys Lys Leu Leu Ala
130 135 140
Val Pro Ala Ala Asn Thr Val Arg Phe Arg Cys Pro Ala Ala Gly Asn
145 150 155 160
Pro Thr Pro Ser Ile Ser Trp Leu Lys Asn Gly Lys Glu Phe Arg Gly
165 170 175
Glu His Arg Ile Gly Gly Ile Lys Leu Arg His Gln Gln Trp Ser Leu
180 185 190
Val Met Glu Ser Val Val Pro Ser Asp Arg Gly Asn Tyr Thr Cys Val
195 200 205
Val Glu Asn Lys Phe Gly Ser Ile Arg Gln Thr Tyr Thr Leu Asp Val
210 215 220
Leu Glu Arg Ser Pro His Arg Pro Ile Leu Gln Ala Gly Leu Pro Ala
225 230 235 240
Asn Gln Thr Ala Val Leu Gly Ser Asp Val Glu Phe His Cys Lys Val
245 250 255
Tyr Ser Asp Ala Gln Pro His Ile Gln Trp Leu Lys His Val Glu Val
260 265 270
Asn Gly Ser Lys Val Gly Pro Asp Gly Thr Pro Tyr Val Thr Val Leu
275 280 285
Lys Thr Ala Gly Ala Asn Thr Thr Asp Lys Glu Leu Glu Val Leu Ser
290 295 300
Leu His Asn Val Thr Phe Glu Asp Ala Gly Glu Tyr Thr Cys Leu Ala
305 310 315 320
Gly Asn Ser Ile Gly Phe Ser His His Ser Ala Trp Leu Val Val Leu
325 330 335
Pro Ala Glu Glu Glu Leu Val Glu Ala Asp Glu Ala Gly Ser Val Tyr
340 345 350
Ala Gly Arg Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
355 360 365
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
370 375 380
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
385 390 395 400
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
405 410 415
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
420 425 430
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
435 440 445
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
450 455 460
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
465 470 475 480
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
485 490 495
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
500 505 510
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
515 520 525
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
530 535 540
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
545 550 555 560
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
565 570 575
Leu Ser Leu Ser Pro Gly Lys
580
<210> 15
<211> 347
<212> PRT
<213> 人工序列
<220>
<223> muFGFR3c-His
<400> 15
Ala Ala Glu Val Pro Gly Pro Glu Pro Ser Gln Gln Glu Gln Val Ala
1 5 10 15
Phe Gly Ser Gly Asp Thr Val Glu Leu Ser Cys His Pro Pro Gly Gly
20 25 30
Ala Pro Thr Gly Pro Thr Val Trp Ala Lys Asp Gly Thr Gly Leu Val
35 40 45
Ala Ser His Arg Ile Leu Val Gly Pro Gln Arg Leu Gln Val Leu Asn
50 55 60
Ala Ser His Glu Asp Ala Gly Val Tyr Ser Cys Gln His Arg Leu Thr
65 70 75 80
Arg Arg Val Leu Cys His Phe Ser Val Arg Val Thr Asp Ala Pro Ser
85 90 95
Ser Gly Asp Asp Glu Asp Gly Glu Asp Val Ala Glu Asp Thr Gly Ala
100 105 110
Pro Tyr Trp Thr Arg Pro Glu Arg Met Asp Lys Lys Leu Leu Ala Val
115 120 125
Pro Ala Ala Asn Thr Val Arg Phe Arg Cys Pro Ala Ala Gly Asn Pro
130 135 140
Thr Pro Ser Ile Ser Trp Leu Lys Asn Gly Lys Glu Phe Arg Gly Glu
145 150 155 160
His Arg Ile Gly Gly Ile Lys Leu Arg His Gln Gln Trp Ser Leu Val
165 170 175
Met Glu Ser Val Val Pro Ser Asp Arg Gly Asn Tyr Thr Cys Val Val
180 185 190
Glu Asn Lys Phe Gly Ser Ile Arg Gln Thr Tyr Thr Leu Asp Val Leu
195 200 205
Glu Arg Ser Pro His Arg Pro Ile Leu Gln Ala Gly Leu Pro Ala Asn
210 215 220
Gln Thr Ala Ile Leu Gly Ser Asp Val Glu Phe His Cys Lys Val Tyr
225 230 235 240
Ser Asp Ala Gln Pro His Ile Gln Trp Leu Lys His Val Glu Val Asn
245 250 255
Gly Ser Lys Val Gly Pro Asp Gly Thr Pro Tyr Val Thr Val Leu Lys
260 265 270
Thr Ala Gly Ala Asn Thr Thr Asp Lys Glu Leu Glu Val Leu Ser Leu
275 280 285
His Asn Val Thr Phe Glu Asp Ala Gly Glu Tyr Thr Cys Leu Ala Gly
290 295 300
Asn Ser Ile Gly Phe Ser His His Ser Ala Trp Leu Val Val Leu Pro
305 310 315 320
Ala Glu Glu Glu Leu Met Glu Thr Asp Glu Ala Gly Ser Val Tyr Ala
325 330 335
Gly His His His His His His His His His His
340 345
<210> 16
<211> 361
<212> PRT
<213> 人工序列
<220>
<223> huD1-Fc
<400> 16
Ser Glu Ser Leu Gly Thr Glu Gln Arg Val Val Gly Arg Ala Ala Glu
1 5 10 15
Val Pro Gly Pro Glu Pro Gly Gln Gln Glu Gln Leu Val Phe Gly Ser
20 25 30
Gly Asp Ala Val Glu Leu Ser Cys Pro Pro Pro Gly Gly Gly Pro Met
35 40 45
Gly Pro Thr Val Trp Val Lys Asp Gly Thr Gly Leu Val Pro Ser Glu
50 55 60
Arg Val Leu Val Gly Pro Gln Arg Leu Gln Val Leu Asn Ala Ser His
65 70 75 80
Glu Asp Ser Gly Ala Tyr Ser Cys Arg Gln Arg Leu Thr Gln Arg Val
85 90 95
Leu Cys His Phe Ser Val Arg Val Thr Asp Ala Pro Ser Ser Gly Asp
100 105 110
Asp Glu Asp Gly Glu Asp Glu Ala Glu Asp Thr Gly Val Asp Thr Gly
115 120 125
Ala Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
130 135 140
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
145 150 155 160
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
165 170 175
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
180 185 190
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
195 200 205
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
210 215 220
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
225 230 235 240
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
245 250 255
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
260 265 270
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
275 280 285
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
290 295 300
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
305 310 315 320
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
325 330 335
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
340 345 350
Lys Ser Leu Ser Leu Ser Pro Gly Lys
355 360
<210> 17
<211> 340
<212> PRT
<213> 人工序列
<220>
<223> huD2-Fc
<400> 17
Ala Pro Tyr Trp Thr Arg Pro Glu Arg Met Asp Lys Lys Leu Leu Ala
1 5 10 15
Val Pro Ala Ala Asn Thr Val Arg Phe Arg Cys Pro Ala Ala Gly Asn
20 25 30
Pro Thr Pro Ser Ile Ser Trp Leu Lys Asn Gly Arg Glu Phe Arg Gly
35 40 45
Glu His Arg Ile Gly Gly Ile Lys Leu Arg His Gln Gln Trp Ser Leu
50 55 60
Val Met Glu Ser Val Val Pro Ser Asp Arg Gly Asn Tyr Thr Cys Val
65 70 75 80
Val Glu Asn Lys Phe Gly Ser Ile Arg Gln Thr Tyr Thr Leu Asp Val
85 90 95
Leu Glu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
100 105 110
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
115 120 125
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
130 135 140
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
145 150 155 160
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
165 170 175
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
180 185 190
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
195 200 205
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
210 215 220
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
225 230 235 240
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
245 250 255
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
260 265 270
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
275 280 285
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
290 295 300
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
305 310 315 320
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
325 330 335
Ser Pro Gly Lys
340
<210> 18
<211> 468
<212> PRT
<213> 人工序列
<220>
<223> huD1-D2-Fc
<400> 18
Ser Glu Ser Leu Gly Thr Glu Gln Arg Val Val Gly Arg Ala Ala Glu
1 5 10 15
Val Pro Gly Pro Glu Pro Gly Gln Gln Glu Gln Leu Val Phe Gly Ser
20 25 30
Gly Asp Ala Val Glu Leu Ser Cys Pro Pro Pro Gly Gly Gly Pro Met
35 40 45
Gly Pro Thr Val Trp Val Lys Asp Gly Thr Gly Leu Val Pro Ser Glu
50 55 60
Arg Val Leu Val Gly Pro Gln Arg Leu Gln Val Leu Asn Ala Ser His
65 70 75 80
Glu Asp Ser Gly Ala Tyr Ser Cys Arg Gln Arg Leu Thr Gln Arg Val
85 90 95
Leu Cys His Phe Ser Val Arg Val Thr Asp Ala Pro Ser Ser Gly Asp
100 105 110
Asp Glu Asp Gly Glu Asp Glu Ala Glu Asp Thr Gly Val Asp Thr Gly
115 120 125
Ala Pro Tyr Trp Thr Arg Pro Glu Arg Met Asp Lys Lys Leu Leu Ala
130 135 140
Val Pro Ala Ala Asn Thr Val Arg Phe Arg Cys Pro Ala Ala Gly Asn
145 150 155 160
Pro Thr Pro Ser Ile Ser Trp Leu Lys Asn Gly Arg Glu Phe Arg Gly
165 170 175
Glu His Arg Ile Gly Gly Ile Lys Leu Arg His Gln Gln Trp Ser Leu
180 185 190
Val Met Glu Ser Val Val Pro Ser Asp Arg Gly Asn Tyr Thr Cys Val
195 200 205
Val Glu Asn Lys Phe Gly Ser Ile Arg Gln Thr Tyr Thr Leu Asp Val
210 215 220
Leu Glu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
225 230 235 240
Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
245 250 255
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
260 265 270
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
275 280 285
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
290 295 300
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
305 310 315 320
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
325 330 335
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
340 345 350
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
355 360 365
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
370 375 380
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
385 390 395 400
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
405 410 415
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
420 425 430
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
435 440 445
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
450 455 460
Ser Pro Gly Lys
465
<210> 19
<211> 64
<212> PRT
<213> 人工序列
<220>
<223> 共有序列抗FGFR3 Fynomer
<220>
<221> 变体
<222> 51
<223> 任何氨基酸
<400> 19
Gly Val Thr Leu Phe Val Ala Leu Tyr Asp Tyr Glu Val Met Ser Thr
1 5 10 15
Thr Ala Leu Ser Phe His Lys Gly Glu Lys Phe Gln Ile Leu Ser Gln
20 25 30
Ser Pro His Gly Gln Tyr Trp Glu Ala Arg Ser Leu Thr Thr Gly Glu
35 40 45
Thr Gly Xaa Ile Pro Ser Asn Tyr Val Ala Pro Val Asp Ser Ile Gln
50 55 60
<210> 20
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> RT环序列
<400> 20
Glu Val Met Ser Thr Thr Ala
1 5
<210> 21
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> src环序列
<400> 21
Ser Gln Ser Pro His
1 5
<210> 22
<211> 64
<212> PRT
<213> 人工序列
<220>
<223> FF40L54A5
<400> 22
Gly Val Thr Leu Phe Val Ala Leu Tyr Asp Tyr Glu Val Met Ser Thr
1 5 10 15
Thr Ala Leu Ser Phe His Lys Gly Glu Lys Phe Gln Ile Leu Ser Gln
20 25 30
Ser Pro His Gly Gln Tyr Trp Glu Ala Arg Ser Leu Thr Thr Gly Glu
35 40 45
Thr Gly Trp Ile Pro Ser Asn Tyr Val Ala Pro Val Asp Ser Ile Gln
50 55 60
Claims (14)
1.一种与成纤维细胞生长因子受体3同种型3b和3c(FGFR3b和FGFR3c)结合的多肽,其中该多肽包含选自下组的氨基酸序列,该组由以下组成:
(a)GVTLFVALYDYEVYGPTPMLSFHKGEKFQIL(X1)(X2)(X3)(X4)GPYWEARSL(X5)TGETG(X6)IPSNYVAPVDSIQ(SEQ ID NO:1);
其中氨基酸位置(X1)至(X6)可以是任何氨基酸序列;和
(b)与(a)的氨基酸序列具有至少95%同一性的氨基酸序列,其中同一性测定不包括氨基酸位置(X1)至(X6)并且条件是在SEQ ID NO:1的氨基酸位置12至19中的氨基酸序列EVYGPTPM(SEQ ID NO:2)是保守的,并且SEQ ID NO:1的氨基酸位置37和38中的氨基酸P和Y是保守的;
(c)GVTLFVALYDYEVMSTTALSFHKGEKFQILSQSPHGQYWEARSLTTGETG(X6)IPSNY
VAPVDSIQ(SEQ ID NO:19),
其中氨基酸位置(X6)可以是任何氨基酸;以及
(d)与(c)的氨基酸序列具有至少95%同一性的氨基酸序列,其中同一性测定不包括氨基酸位置(X6)并且条件是在SEQ ID NO:19的氨基酸位置12至18中的氨基酸序列EVMSTTA(SEQ ID NO:20)和SEQ ID NO:19的氨基酸位置31至35中的SQSPH(SEQ ID NO:21)是保守的,并且SEQ ID NO:19的氨基酸位置37和38中的氨基酸Q和Y是保守的。
2.根据权利要求1所述的多肽,其中
(X1)是N、R或K,并且优选是R或K;
(X2)是S、G、K或R,并且优选是G、K或R;
(X3)是S或G,并且优选是G;
(X4)是E、Q、D、S或K,并且优选是Q、D、S或K;
(X5)是T或A;以及
(X6)是Y、W或L,并且优选是L或W。
3.根据权利要求1或2所述的多肽,其中该多肽包含选自由以下组成的组的氨基酸序列:SEQ ID NO 3至8和22中任一个。
4.根据权利要求3所述的多肽,其中该多肽包含选自由以下组成的组的氨基酸序列:
SEQ ID NO:4、
SEQ ID NO:5、
SEQ ID NO:6、
SEQ ID NO:7、
SEQ ID NO:8、和
SEQ ID NO:22。
5.一种融合构建体,其包含与另外化合物融合的根据权利要求1至4中任一项所述的多肽。
6.根据权利要求5所述的融合构建体,其中该另外化合物是毒性化合物。
7.根据权利要求5所述的融合构建体,其中该另外化合物包括抗体轻链、抗体重链、抗体的Fc结构域、抗体或其组合。
8.根据权利要求7所述的融合构建体,其中该抗体针对选自下组的靶标,该组由以下组成:GM-2、CD38、ICAM-1、SLAMF7、CD45、CD40、CD74、IGFR-1、CD20、BAFF、BCMA、CD66、GRP78、CXCR4、EGFR、EPCAM、TROP-2、B7H3和CEACAM-1。
9.一种编码根据权利要求1至4中任一项所述的多肽或根据权利要求5或7所述的融合构建体的核酸分子,或者一种或多种编码根据权利要求7或8所述的融合构建体的核酸分子。
10.一种药物组合物或诊断组合物,该药物组合物或诊断组合物包含根据权利要求1至4中任一项所述的多肽、根据权利要求5至8中任一项所述的融合构建体、根据权利要求9所述的核酸分子、或其任何组合。
11.根据权利要求10所述的药物组合物,其用于治疗癌症或T细胞介导的疾病。
12.根据权利要求11所述使用的药物组合物,其中该癌症选自乳腺癌、宫颈癌、结肠直肠癌、子宫内膜癌、神经胶质瘤、头颈癌、肝癌、肺癌、多发性骨髓瘤、膀胱癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌和尿路上皮癌。
13.根据权利要求11所述使用的药物组合物,其中该癌症选自多发性骨髓瘤、膀胱癌、宫颈癌、胰腺癌、鳞状细胞肺癌和结肠直肠癌。
14.根据权利要求11所述使用的药物组合物,其中该T细胞介导的疾病选自类风湿性关节炎(RA)、胶原II型关节炎、多发性硬化症(MS)、系统性红斑狼疮(SLE)、银屑病、青少年发病型糖尿病、舍格伦综合征、甲状腺疾病、结节病、自身免疫性葡萄膜炎、炎性肠病(克罗恩病和溃疡性结肠炎)、乳糜泻和重症肌无力。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101506230A (zh) * | 2006-08-21 | 2009-08-12 | 瑞士联邦苏黎世技术大学 | 包含fyn激酶的修饰的sh3结构域的特异性的且高亲和力的结合蛋白 |
CN105189544A (zh) * | 2013-04-19 | 2015-12-23 | 科瓦根股份公司 | 具有抗肿瘤活性的新颖的双特异性结合分子 |
CN106211782A (zh) * | 2014-03-17 | 2016-12-07 | 田边三菱制药株式会社 | 抗体‑fynomer缀合物 |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
EP0362371A4 (en) | 1988-04-15 | 1990-10-24 | Protein Design Labs, Inc. | Il-2 receptor-specific chimeric antibodies |
IL162181A (en) | 1988-12-28 | 2006-04-10 | Pdl Biopharma Inc | A method of producing humanized immunoglubulin, and polynucleotides encoding the same |
AU633698B2 (en) | 1990-01-12 | 1993-02-04 | Amgen Fremont Inc. | Generation of xenogeneic antibodies |
NZ255101A (en) | 1992-07-24 | 1997-08-22 | Cell Genesys Inc | A yeast artificial chromosome (yac) vector containing an hprt minigene expressible in murine stem cells and genetically modified rodent therefor |
EP1978033A3 (en) | 1995-04-27 | 2008-12-24 | Amgen Fremont Inc. | Human antibodies derived from immunized xenomice |
CA2219486A1 (en) | 1995-04-28 | 1996-10-31 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
JP2005500034A (ja) | 2001-06-20 | 2005-01-06 | プロション バイオテク リミテッド | 受容体型タンパク質チロシンキナーゼ活性化を遮断する抗体、そのスクリーニング方法、及びその使用 |
IL156495A0 (en) | 2003-06-17 | 2004-01-04 | Prochon Biotech Ltd | Use of fgfr3 antagonists for treating t cell mediated diseases |
EP1824513A4 (en) | 2004-11-04 | 2010-06-09 | Fibron Ltd | TREATMENT OF B-CELL TUMORS |
EP2046384A4 (en) | 2006-06-15 | 2009-12-02 | Fibron Ltd | ANTIBODIES BLOCKING FIBROBLAST GROWTH FACTOR RECEPTOR ACTIVATION AND METHODS OF USING THE SAME |
WO2010002862A2 (en) | 2008-07-01 | 2010-01-07 | Aveo Pharmaceuticals, Inc. | Fibroblast growth factor receptor 3 (fgfr3) binding proteins |
HUE061117T2 (hu) | 2009-03-25 | 2023-05-28 | Genentech Inc | Anti-FGFR3 antitestek és eljárások alkalmazásukra |
BR112012004314A2 (pt) | 2009-08-27 | 2016-11-29 | Covagen Ag | compostos de ligação a il-17 e usos medicinais desses compostos |
BR112014022932A2 (pt) * | 2012-03-16 | 2017-07-18 | Covagen Ag | molécula de ligação, seu uso e seu método de produção, molécula de ácido nucleico, vetor, célula hospedeira, e composição |
EP2711016A1 (en) | 2012-09-21 | 2014-03-26 | Covagen AG | Novel IL-17A binding molecules and medical uses thereof |
-
2018
- 2018-04-02 US US15/943,137 patent/US10722589B2/en active Active
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-
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-
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- 2020-06-15 US US16/901,160 patent/US11351267B2/en active Active
-
2021
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101506230A (zh) * | 2006-08-21 | 2009-08-12 | 瑞士联邦苏黎世技术大学 | 包含fyn激酶的修饰的sh3结构域的特异性的且高亲和力的结合蛋白 |
CN105189544A (zh) * | 2013-04-19 | 2015-12-23 | 科瓦根股份公司 | 具有抗肿瘤活性的新颖的双特异性结合分子 |
CN106211782A (zh) * | 2014-03-17 | 2016-12-07 | 田边三菱制药株式会社 | 抗体‑fynomer缀合物 |
Non-Patent Citations (5)
Title |
---|
DRAGAN GRABULOVSKI等: "A Novel, Non-immunogenic Fyn SH3-derived Binding Protein with Tumor Vascular Targeting Properties", 《THE JOURNAL OF BIOLOGICAL CHEMISTRY》 * |
JORGE L. MARTI´NEZ-TORRECUADRADA等: "Antitumor activity of fibroblast growth factor receptor 3–specific immunotoxins in a xenograft mouse model of bladder carcinoma is mediated by apoptosis", 《MOLECULAR CANCER THERAPEUTICS》 * |
JULIAN BERTSCHINGER等: "Selection of single domain binding proteins by covalent DNA display", 《PROTEIN ENGINEERING》 * |
刘文艳等: "Src基因研究进展¹", 《家畜生态学报》 * |
杜培娟: "成纤维细胞生长因子及其受体抑制剂的研究进展", 《化学与生物工程》 * |
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