CN107184974A - 抗基质金属蛋白酶9的抗体 - Google Patents
抗基质金属蛋白酶9的抗体 Download PDFInfo
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Abstract
本发明提供涉及结合到基质金属蛋白酶‑9MMP9蛋白(MMP9又称为明胶酶‑B)的结合蛋白(例如抗体和其抗原结合片段)的组合物及使用方法,例如其中所述结合蛋白包含免疫球蛋白Ig重链(或其功能片段)和Ig轻链(或其功能片段)。
Description
本发明是基于申请日为2013年2月28日,申请号为“201380022489.6”(国际申请号为PCT/US2013/028456),发明名称为“抗基质金属蛋白酶9的抗体”的专利申请的分案申请。
相关申请案的交叉参考
本申请案主张2012年2月29日申请的美国临时申请案61/605,181、2013年1月22日申请的美国临时申请案61/755,444及2012年2月29日申请的PCT申请案第PCT/US2012/027160号的优先权。这些文献的内容以全文引用的方式并入本文中。
有关依据联邦政府资助的研究作出的发明的权利的声明
不适用。
技术领域
本发明属于细胞外酶、细胞外基质酶、蛋白酶及免疫学领域。
背景技术
基质金属蛋白酶(MMP)属于涉及到细胞外基质形成和重塑的细胞外酶家族。这些酶含有一个保守的催化结构域,其中锌原子经三个组氨酸残基配位。已知这一家族的超过20个成员,组织成包括胶原酶类、明胶酶类、基质溶解素类、基质溶素类、釉质溶解素类及膜MMP类在内的多个群组。
MMP2和MMP9属于基质金属蛋白酶的明胶酶群组。除含有大多数MMP共有的信号肽、前肽、催化结构域、锌结合结构域及血红素结合蛋白样结构域外,明胶酶还含有多个纤连蛋白样结构域和一个O-糖基化结构域。
MMP涉及到多种疾病。MMP抑制剂部分由于特异性和功效而并不完全令人满意。因此,需要具有特异性并且有效的MMP抑制剂。癌症以及炎症性疾病和自体免疫性疾病,例如结肠直肠癌、IBD(包括克罗恩氏病(Crohn's disease,CD)、溃疡性结肠炎(UC)及未定型结肠炎)、类风湿性关节炎(RA)等的治疗并不完全令人满意。因此,需要有效用于这些疾病,特别是用于可用治疗剂无效的个体的治疗。
发明内容
本发明提供涉及结合到基质金属蛋白酶-9(MMP9)蛋白(又称为明胶酶-B)的结合蛋白(例如抗体和其抗原结合片段)的组合物和使用方法。所述结合蛋白通常为抗体或其片段(例如,抗原结合片段)并且通常含有免疫球蛋白(Ig)重链(或其功能片段)和Ig轻链(或其功能片段)。重链通常为IgG,例如IgG1或IgG4,或其经修饰型式。轻链通常为κ链。
MMP9结合蛋白(例如抗体)为特异性结合到MMP9并且不结合其它相关基质金属蛋白酶的结合蛋白。这些MMP9结合蛋白可用于需要或希望获得对MMP9的特异性调节(例如,抑制),例如而不直接地影响其它基质金属蛋白酶的活性的应用中。因此,在本发明的某些实施例中,抗MMP9抗体或其片段是MMP9活性的特异性抑制剂。在一些方面中,本文所揭示的MMP9结合蛋白将可用于抑制MMP9,同时允许其它相关基质金属蛋白酶的正常功能。
所述抗体和片段可参照其氨基酸序列或其部分,和/或各种功能(例如与MMP9或其特定表位的结合特异性,或与特定抗体竞争结合的能力)和/或活性(例如抑制MMP9的能力,例如非竞争性抑制)进行描述。
所述抗体和片段可作为一种医药组合物的一部分,其中结合到基质金属蛋白酶9的抗体和其片段包含具有氨基酸序列为SEQ ID NO:15的重链互补决定区(CDR)的重链可变(VH)区,及医药学上可接受的赋形剂。所述VH区可另外包含氨基酸序列为SEQ ID NO:13和/或14的CDR。VH区也可包含如SEQ ID NO:3、5、6、7或8中所陈述的氨基酸序列。VH区也可包含与如SEQ ID NO:3、5、6、7或8中所陈述的氨基酸序列具有95%序列一致性的氨基酸序列。
在另一个实施例中,包含结合到基质金属蛋白酶9的抗体和其抗原结合片段的所揭示的医药组合物包含具有氨基酸序列为SEQ ID NO:18的轻链互补决定区(CDR)的轻链可变(VL)区,及医药学上可接受的赋形剂。所述VL区可另外包含氨基酸序列为SEQ ID NO:16和/或17的CDR。VL区也可包含如SEQ ID NO:4、9、10、11或12中所陈述的氨基酸序列。VL区也可包含与如SEQ ID NO:4、9、10、11或12中所陈述的氨基酸序列具有95%序列一致性的氨基酸序列。在一个实施例中,VH区具有SEQ ID NO:7中所陈述的氨基酸序列并且VL区具有SEQID NO:12中所陈述的氨基酸序列。
在另一个实施例中,MMP9结合蛋白包含VH区,其包含具有选自由SEQ ID NO:13、14、15、34、35、36及47组成的群组的氨基酸序列的CDR;及VL区,其具有含选自由SEQ ID NO:16、17、18、37、38、39、42、43、44及48组成的群组的氨基酸序列的CDR。另外,MMP9结合蛋白可包含VH区,其具有选自由SEQ ID NO:1、3、5、6、7、8、34、35、36及46组成的群组的氨基酸序列;及VL区,其具有选自由SEQ ID NO:2、4、9、10、11、12、37、38、39、42、43、44及45组成的群组的氨基酸序列。此外,MMP9结合蛋白可包含与选自由SEQ ID NO:30、32、46及47组成的群组的氨基酸序列具有95%序列一致性的VH区;及与选自由SEQ ID NO:31、33、41、45及48组成的群组的氨基酸序列具有95%序列一致性的VL区。此外,MMP9结合蛋白可包含具有选自由SEQ ID NO:30、32、46及47组成的群组的氨基酸序列的VH区;及具有选自由SEQ ID NO:31、33、41、45及48组成的群组的氨基酸序列的VL区。
本发明的另一实施例涉及一种医药组合物,其包含特异性结合到MMP9的表位的分离的抗体或其片段,其中所述表位包含在MMP9的区域内的氨基酸残基,所述区域由SEQ IDNO:27的残基104-119、残基159-166或残基191-202组成;及医药学上可接受的赋形剂。在一个方面中,所述表位包含SEQ ID NO:27的E111、D113、R162或I198。
在另一个实施例中,所揭示的医药组合物另外包含一或多种选自由以下组成的群组的治疗剂:消炎剂、免疫治疗剂、化学治疗剂、抗癌剂、抗纤维化药剂或其组合。治疗剂的实例包括(但不限于)白蛋白结合型紫杉醇(nab-paclitaxel)、mFOLFOX6、FOLFIRI、卡铂(carboplatin)、紫杉醇(paclitaxel)、培美曲塞(pemetrexed)、贝伐单抗(bevacizumab)、抗赖氨酰氧化酶样蛋白2(LOXL2)抗体、抗盘状结构域受体1(DDR1)抗体或其组合。
还提供了例如使用非竞争性抑制MMP9的药剂抑制个体中的MMP9活性和/或治疗个体的疾病或病况的方法,及用于这些方法中的药剂(例如上述抗MMP9抗体和其它MMP9结合蛋白中的任一种)。所述方法一般是通过向个体投予例如有效量的MMP9结合蛋白,例如,如本文所提供的MMP9结合抗体或其片段,例如上述结合蛋白或片段中的任一种来进行。所述抗体或片段一般特异性结合到并且非竞争性抑制MMP9,通常由此使个体中的MMP9活性得到抑制。在一些情形中,所述抗体或片段为结合在催化结构域外部的MMP9,例如结合于上述表位之一中的抗体或片段。在一些情形中,所述抗体或片段实质上不结合到除MMP9外的MMP蛋白和/或实质上不结合到MMP2。另外提供了检测或监测MMP9活性的方法,所述方法包含使样品与MMP9结合蛋白接触,及评估MMP9结合蛋白-MMP9复合物的存在或不存在;其中不存在所述MMP9结合蛋白-MMP9复合物指示所述样品不具有所述MMP9活性,并且存在所述MMP9结合蛋白-MMP9复合物指示所述样品具有所述MMP9活性。MMP9活性可通过使用本文所揭示的MMP9结合蛋白中的任一种来检测。
还提供了此处所揭示的医药组合物的方法和用途,其中向患有MMP-9相关性疾病或病况的有需要的个体投予有效抑制所述个体中的MMP9活性的有效量的所揭示的抗体或其片段,或包含所揭示的抗体或其片段的医药组合物。MMP9相关性疾病或病况的实例包括(但不限于)癌症、自体免疫性、炎症性或纤维化疾病或病况。MMP9相关性癌症的实例包括(但不限于)胰脏癌、食管胃腺癌、非小细胞肺癌、肺鳞状细胞癌、肺腺癌、胃腺癌、结肠直肠癌瘤、胰脏腺癌、头颈鳞状细胞癌、肝细胞癌瘤、结肠直肠癌、结肠直肠腺癌或肝细胞癌瘤。MMP9相关性自体免疫性或炎症性疾病或病况的实例为类风湿性关节炎、炎症性肠病(IBD)、败血病、多发性硬化、肌营养不良、狼疮、过敏症或哮喘。IBD的实例包括(但不限于)溃疡性结肠炎(UC)、克罗恩氏病(CD)或未定型结肠炎。
在一些实例中,所述抗体或其医药组合物是以约1mg/kg到约28mg/kg的剂量投予。在一些实例中,所述抗体或其医药组合物是以介于100mg/kg体重或约100mg/kg与1800mg/kg或约1800mg/kg之间的剂量投予。
在一些实例中,所述抗体或其医药组合物是以100、300、400、500、600、700、800、900、1000、1100、1200、1300、1400、1500、1600、1700或1800mg/kg体重或约100、300、400、500、600、700、800、900、1000、1100、1200、1300、1400、1500、1600、1700或1800mg/kg的剂量投予。在一些实例中,所述抗体是以一周、两周或三周的间隔,或每一周、两周或三周一次投予。在一些实例中,所述抗体或其片段是静脉内或皮下投予的。
在一些实施例中,所述抗体或其医药组合物是作为单药疗法单独投予。在其它实施例中,所述抗体或其医药组合物是作为与一或多种其它治疗剂的组合疗法的一部分投予的。所述治疗剂包括(但不限于)消炎剂、免疫治疗剂、化学治疗剂、抗癌剂、抗纤维化药剂或其组合。所述一或多种其它治疗剂可与所述抗体或其片段同时或依序投予。
附图说明
图1示出了小鼠单克隆抗MMP9抗体(AB0041)的重链可变区的氨基酸序列,以及重链的人类化变体(VH1-VH4)的氨基酸序列,其经比对以显示由人类化引起的构架氨基酸序列的差异。CDR是以斜体显示,并且人类化变体中与亲本小鼠单克隆抗体不同的氨基酸加下划线。
图2示出了小鼠单克隆抗MMP9抗体(AB0041)的轻链可变区的氨基酸序列,以及这一轻链的人类化变体(VH1-VH4)的氨基酸序列,其经比对以显示由人类化引起的构架氨基酸序列的差异。CDR是以斜体显示,并且人类化变体中与亲本小鼠单克隆抗体不同的氨基酸加下划线。
图3示出了MMP9蛋白的示意图。
图4示出了指定为AB0041、M4及M12的抗体的重链和轻链的氨基酸序列之间的比较。
图5示出了如实例4中所述,对来自媒剂治疗的小鼠(A)和AB0046治疗的小鼠(B)的结肠的冷冻连续切片进行的免疫组织化学(IHC)分析的结果,突出显示了在DSS诱发的结肠炎中所观察到的炎症和组织破坏。在浸润中性粒细胞(由MPO信号指示)和巨噬细胞中观察到MMP9的表达并且其与基底膜胶原蛋白IV(在图中标为“ColIV”)和MMP9底物共定位。患病的结肠(A)展现粘膜上皮细胞和粘膜下隐窝的破坏及稳固的炎性细胞浸润。在患病组织(A)中观察到极少MMP2表达的迹象。
图6示出了如实例4中所述,对福尔马林固定、石蜡包埋(FFPE)的从结肠取得的切片进行的MMP9免疫组织化学(IHC)分析的代表性图像。如所示,上皮细胞MMP9表达(箭头)在正常结肠(-DSS)中极少且在投予DSS之后得到高度诱导(+DSS)。
图7A-7B示出了在实例4中所述研究中,在研究第10天和第14天(终止日)对所有动物组进行的内窥镜检查评价的结果。图A示出了在第6-14天的平均内窥镜检查评分(+/-SEM),其中箭头指示投予AB0046(或其它治疗)的天数。图B示出了在第14天每个组的平均内窥镜检查评分(+/-SEM),其中星号指示疾病的显著减轻(这在第14天对于AB0046和治疗组观察到)。内窥镜检查评分反映了所观察到的每只动物的最严重病变。
图8示出了对于在实例4中所述的研究终止时所切除的结肠进行的组织病理学分析的结果。对炎症、浮肿及坏死的程度进行评估并且通过加上每只动物的每个所评估参数的平均结肠评分来计算总评分。抗MMP9(AB0046)治疗使组织病理学疾病显著减轻到与类似的程度。
图9示出了对来自实例4中所述研究的FFPE结肠切片进行的MMP9IHC的代表性图像。MMP9表达在正常结肠(无DSS)中极少并且在投予DSS之后得到高度诱导(媒剂)。AB0046和治疗组中MMP9的表达减少与总体疾病的减轻相关。
图10A-10B示出了实例4中所述研究的体重和腹泻结果。有关体重变化和腹泻发生率的曲线下面积(AUC)是通过梯形规则法计算。用抗MMP9抗体(AB0046)进行的治疗防止由DSS诱发的结肠炎引起的体重减轻并且与治疗的作用相当。腹泻发生率与AB0046和治疗类似地降低。
图11A1,11A2,11B1,11B2,11B3,11B4示出了如实例4中所述,在用抗MMP9抗体(AB0046)和其它治疗进行治疗之后,对DSS结肠炎模型中终末血清样品进行的多分析物ELISA分析的结果。这些结果披露,用AB0046治疗使疾病诱导的炎性细胞因子和生长因子广泛全身下调。图11B1-11B4示出了从同一研究获得的另外的血清标记物数据。
图12A示出了在实例4中所述的研究中,在DSS结肠炎模型中通过抗MMP9抗体(AB0047)治疗使内窥镜检查疾病减轻。图12B示出了在实例4中所述的研究中,在DSS结肠炎模型中通过抗MMP9抗体(AB0047)治疗使组织学疾病减轻。
图13A,13B示出了在实例5中所述的预防性治疗研究中,在指定日对所有动物组进行的内窥镜检查评价的结果。图A示出了在第6-14天的平均内窥镜检查评分(+/-SEM),其中箭头指示投予AB0046(或其它治疗)的天数。图B示出了在第10天每个组的平均内窥镜检查评分(+/-SEM),其中星号指示疾病的显著减轻(这在第14天对于AB0046和治疗组观察到)。内窥镜检查评分反映了所观察到的每只动物的最严重病变。
图14示出了对于在实例5中所述的研究终止时所切除的结肠进行的组织病理学分析的结果。对炎症、浮肿及坏死的程度进行评估并且通过加上每只动物的每个所评估参数的平均结肠评分来计算总评分。
图15示出了实例5中所述研究的体重和腹泻结果。有关体重变化和腹泻发生率的曲线下面积(AUC)是通过梯形规则法计算。用抗MMP9抗体(AB0046)进行的预防性治疗防止腹泻的发生。
图16示出了在实例6中所述的研究中,在确立的结肠直肠肿瘤发生模型(HCT116)中原发肿瘤生长的减少。左图示出了肿瘤体积的较小变化;右图示出了在起始治疗之后第32天时最终肿瘤重量减小(其中p值由曼-惠特尼测试(Mann-Whitney test)得出并且柱形表示组平均值±SEM)。
图17A1,17A2示出了由实例7中所述的研究得到的临床评分和腿评分结果,显示了在小鼠和大鼠CIA类风湿性关节炎模型中鼠类代用抗MMP9抗体(AB0046)和抗人类MMP9抗体(AB0041)的功效。图17B示出了由同一研究得到的抗MMP9抗体的滴度。MTX=甲氨蝶呤;NonDis.=无疾病。
图18A示出了在实例7中所述的大鼠CIA研究中炎性细胞因子的研究结束时血清水平;图18B示出了在实例7中所述的小鼠CIA研究中血清炎性细胞因子的研究结束时水平。MTX=甲氨蝶呤;Non Dis.=无疾病。
图19A1-19A7示出了在实例7中所述的大鼠CIA研究中的另外的血清标记物;图19B1-19B5示出了在实例7中所述的小鼠CIA研究中的另外的血清标记物。MTX=甲氨蝶呤;Non Dis.=无疾病。
图20示出了在如实例8中所述的LPS败血病大鼠模型中,在投予抗MMP9之后防止死亡和体温降低。每个图的下部线表示AC-1治疗组并且两条上部线表示未接受LPS的组(左图中的菱形;右图中的圆形)及抗MMP9治疗组(左图中的正方形及右图中的三角形)。
图21示出了AB0041治疗的大鼠、马立马司他(Marimastat)治疗的大鼠及对照物治疗的大鼠的平均日肌肉骨骼综合症(MSS)评分±标准偏差。
图22示出了在第1、7、10、14、17、21、24及28天时在AB0041治疗的大鼠中如通过ELISA测量的AB0041血清水平(血清滴度)。数据表示为平均值±标准偏差。
图23A-23F示出了在指定治疗之后小鼠结肠直肠癌异种移植模型中肿瘤体积(图23A、23C、23E)和体重(图23B、23D、23F)的变化。
图24A-24B示出了在指定治疗之后小鼠结肠直肠癌异种移植模型中肿瘤体积(图24A)和体重(图24B)的变化。
图25A-25D示出了在对照物和抗MMP9治疗之后小鼠结肠直肠癌异种移植模型中的血清蛋白质水平。
图26示出了在指定治疗之后,在大鼠CIA类风湿性关节炎模型中爪厚度、踝直径及体重的变化。
图27示出了在大鼠CIA类风湿性关节炎模型中进行指定治疗之后如通过免疫组织化学分析所测量的TNF-α和CD68评分。
图28-1至28-4示出了在大鼠CIA研究中炎性细胞因子的研究结束时血清水平。
图29示出了在指定治疗之后,在小鼠CIA类风湿性关节炎模型中爪厚度、踝直径及体重的变化。
图30示出了由肿瘤上皮细胞相关性MMP9蛋白的IHC分析得到的结果。
图31示出了由肿瘤上皮细胞相关性MMP9mRNA的CISH分析得到的结果。
具体实施方式
除非另作指示,否则本发明的实践采用了细胞生物学、毒理学、分子生物学、生物化学、细胞培养、免疫学、肿瘤学、重组DNA领域及相关领域中的标准方法和常规技术,其在所属领域的技术范围内。这些技术描述于文献中并由此是所属领域技术人员可用的。参见例如,艾伯特B.(Alberts,B.)等人,“细胞分子生物学(Molecular Biology of theCell),”第5版,加兰德科技出版社(Garland Science),纽约州纽约(New York,NY),2008;沃特D.(Voet,D.)等人,“基础生物化学:在分子水平上的生命(Fundamentals ofBiochemistry:Life at the Molecular Level),”第3版,约翰威立出版公司(John Wiley&Sons),新泽西州霍博肯(Hoboken,NJ),2008;萨姆布鲁克J.(Sambrook,J.)等人,“分子克隆实验指南(Molecular Cloning:A Laboratory Manual),”第3版,冷泉港实验室出版社(Cold Spring Harbor Laboratory Press),2001;奥苏贝尔F.(Ausubel,F.)等人,“现代分子生物学实验技术(Current Protocols in Molecular Biology),”约翰威立出版公司(John Wiley&Sons),纽约(New York),1987及定期更新;弗雷谢尼R.I.(Freshney,R.I.),“动物细胞培养:基本技术指南(Culture of Animal Cells:A Manual of BasicTechnique),”第4版,约翰威立出版公司,新泽西州桑莫塞县(Somerset,NJ),2000;及丛书“酶学方法(Methods in Enzymology),”学术出版社(Academic Press),加利福尼亚州圣地亚哥(San Diego,CA)。还参见例如,“现代免疫学实验技术(Current Protocols inImmunology),”(R.凯克(R.Coico),丛书编辑),威立公司(Wiley),2010年8月最新更新。
某些MMP的异常活性在肿瘤生长、转移、炎症、自体免疫性及血管疾病中起到作用。参见例如,胡(Hu)等人(2007)自然评述:药物发现(Nature Reviews:Drug Discovery)6:480-498。MMP9的一个值得注意的来源是肿瘤相关性巨噬细胞(TAM),其经由与原发肿瘤细胞的旁分泌相互作用来支持复杂共活化环中的转移和侵入。这种生理屏障蛋白水解分解导致细胞侵入加上使生长和血管生成活化的因子的释放的组合为肿瘤扩增开辟了道路,并且伴随着支持肿瘤长出的新血管形成的发生。
MMP9是例如RAS/RAF、PI3K/AKT/NFkB、及WNT/β-连锁蛋白等致癌信号传导路径的一个目标,并且经由调节整合素和受体酪氨酸激酶功能而起到这些路径的上游调控剂的作用。MMP9在多种肿瘤类型中增多,并且MMP9水平与包括胃癌、肺癌及结肠直肠癌在内的许多癌症的预后不良相关。MMP9还牵涉到化学抗性并且在若干肿瘤抑制蛋白缺失时上调。MMP9在许多不同肿瘤类型中上调并且可以促进癌细胞的原发生长和远端侵袭。
在某些治疗环境中可能需要抑制一或多种MMP的活性。然而,某些其它MMP(例如MMP2)的活性通常是正常功能所需的和/或防止疾病。由于大多数MMP抑制剂靶向保守性催化结构域,并因此抑制多种不同的MMP,故使用可用的MMP抑制剂因抑制必需的非致病相关性MMP而引起副作用。
与开发对一种特定MMP或多种所选MMP具特异性的抑制剂相关的挑战涉及以下事实:酶活性的抑制一般需要使所述抑制剂靶向催化结构域。MMP催化结构域的同源性可使抑制剂与超过一种MMP反应。所提供的实施例为特异性抑制单一MMP或多种所选MMP(例如MMP9)的催化活性并且不与某些其它MMP或任何其它MMP反应或者抑制某些其它MMP或任何其它MMP的药剂,包括治疗剂,例如抗体和其抗原结合片段。所提供的实施例还有其用于治疗包括癌症以及自体免疫性疾病和炎症性疾病在内的各种疾病的方法及用途。
MMP9结合蛋白
MMP9使基底膜胶原蛋白和其它细胞外基质(ECM)组分降解。凯森波克K(Kessenbrock K)等人,“基质金属蛋白酶:肿瘤微环境的调节剂(Matrixmetalloproteinases:regulators of the tumor microenvironment).”细胞(Cell)2010;141(1):52-67。基质降解有助于包括关节炎、癌症及溃疡性结肠炎在内的多种疾病的发病。罗伊R(Roy R)等人,“作为人类癌症中的新颖标记物和潜在治疗目标的基质金属蛋白酶(Matrix metalloproteinases as novel biomarkers and potential therapeutictargets in human cancer).”临床肿瘤学杂志(J Clin Oncol)2009;27(31):5287-97。广谱基质金属蛋白酶抑制剂(例如马立马司他)在动物炎症和癌症模型中有效(沃特森SA(Watson SA)等人,“在人类胃癌异种移植模型中通过马立马司他抑制肿瘤生长:与循环CEA水平的关系(Inhibition of tumour growth by marimastat in a human xenograftmodel of gastric cancer:relationship with levels of circulating CEA).”英国癌症杂志(Br J Cancer)1999;81(1):19-23;赛克AP(Sykes AP)等人,“基质金属蛋白酶抑制剂对三硝基苯磺酸大鼠炎症性肠病模型中结肠炎症的影响(The effect of an inhibitorof matrix metalloproteinases on colonic inflammation in atrinitrobenzenesulphonic acid rat model of inflammatory bowel disease).”营养药理学与治疗学(Aliment Pharmacol Ther)1999;13(11):1535-42)。然而,这些泛抑制剂在人类中通常可在马立马司他的有效剂量水平或接近其有效剂量水平下引起肌肉骨骼副作用,包括关节僵硬、炎症,及手、臂和肩疼痛,统称为肌肉骨骼综合症(MSS)。皮特森JT(Peterson JT.)“在基质金属蛋白酶抑制剂的开发中估计治疗指数的重要性(Theimportance of estimating the therapeutic index in the development of matrixmetalloproteinase inhibitors.)”心血管研究(Cardiovasc Res)2006;69(3):677-87;蒂尔尼GM(Tierney GM)等人,“有关基质金属蛋白酶抑制剂马立马司他在胃癌中的安全性和作用的初步研究(A pilot study of the safety and effects of the matrixmetalloproteinase inhibitor marimastat in gastric cancer).”欧洲癌症杂志(Eur JCancer)1999;35(4):563-8;沃托维兹-普拉嘉S(Wojtowicz-Praga S)等人,“经口投予晚期肺癌患者一种新颖基质金属蛋白酶抑制剂马立马司他的I期试验(Phase I trial ofMarimastat,a novel matrix metalloproteinase inhibitor,administered orally topatients with advanced lung cancer).”临床肿瘤学杂志(J Clin Oncol)1998;16(6):2150-6。这些症状是剂量和时间依赖性的,并且在停止用泛MMP抑制剂进行治疗之后不久即复发。沃托维兹-普拉嘉S,1998;尼姆提斯J(Nemunaitis J)等人,“有关基质金属蛋白酶抑制剂马立马司他对晚期癌症中血清肿瘤标记物的影响的研究的组合分析:用于长期研究的生物活性并且可耐受剂量的选择(Combined analysis of studies of the effects ofthe matrix metalloproteinase inhibitor marimastat on serum tumor markers inadvanced cancer:selection of a biologically active and tolerable dose forlonger-term studies).”临床癌症研究(Clin Cancer Res)1998;4(5):1101-9;哈钦森JW(Hutchinson JW)等人,“通过用基质金属蛋白酶抑制剂治疗诱发的迪皮特朗氏病和冻肩症(Dupuytren's disease and frozen shoulder induced by treatment with a matrixmetalloproteinase inhibitor).”骨与关节外科杂志(The Journal of bone and jointsurgery).英国卷(British volume)1998;80(5):907-8。马立马司他和相同类别的其它泛MMP抑制剂是锌螯合剂。皮特森JT,2006。纯合MMP9基因敲除小鼠未展示MSS样症状或MSS样组织改变。吴TH(Vu TH)等人,“MMP-9/明胶酶B为生长板血管生成和肥大软骨细胞凋亡的关键调控剂(MMP-9/gelatinase B is a key regulator of growth plate angiogenesisand apoptosis of hypertrophic chondrocytes).”细胞,1998;93(3):411-22。
本发明提供了结合到基质金属蛋白酶-9(MMP9)蛋白(MMP9又称为明胶酶-B),例如人类MMP9,例如具有SEQ ID NO:27或SEQ ID NO:28中所陈述的氨基酸序列的人类MMP9的结合蛋白,例如抗体和其片段(例如抗原结合片段)。本发明的结合蛋白一般包含免疫球蛋白(Ig)重链(或其功能片段)和Ig轻链(或其功能片段)。
本发明还提供了特异性结合到MMP9并且不结合例如MMP1、MMP2、MMP3、MMP7、MMP9、MMP10、MMP12及MMP13等其它基质金属蛋白酶的MMP9结合蛋白。因此,此类特异性MMP9结合蛋白一般不与非MMP9基质金属蛋白酶显著地或可检测地交叉反应。特异性结合MMP9的MMP9结合蛋白可用于需要或希望获得对MMP9的特异性调节(例如,抑制),例如而不直接地影响其它基质金属蛋白酶的活性的应用中。
在本发明的某些实施例中,抗MMP9抗体为MMP9活性的一种抑制剂并且可为特异性MMP9抑制剂。确切地说,本文所揭示的MMP9结合蛋白将可用于抑制MMP9,同时允许其它相关基质金属蛋白酶的正常功能。“MMP抑制剂”或“MMP9活性的抑制剂”可为直接或间接抑制MMP9活性,包括(但不限于)酶加工、抑制MMP9对其底物的作用(例如,通过抑制底物结合、底物裂解等)等的抗体或其抗原结合片段。
在一些实施例中,如本文的实例中所证实的,用泛MMP抑制剂(例如小分子泛抑制剂,例如马立马司他)进行治疗引起肌肉骨骼疾病的症状,例如肌肉骨骼综合症(MSS),包括对步态、姿势及移动意愿的显著影响,而特异性抑制MMP9,例如本申请案中的抗体或其抗原结合片段,不会引起这些症状并且不会诱发MSS。
本发明还提供了特异性结合到非小鼠MMP9(例如人类MMP9、食蟹猴MMP9及大鼠MMP9)的MMP9结合蛋白。
本发明还提供了充当非竞争性抑制剂的MMP9结合蛋白(例如抗MMP9抗体和其功能片段)。“非竞争性抑制剂”是指结合于远离酶的底物结合位点的位点,并因此可结合所述酶并且影响抑制活性,而不管所述酶是否结合到其底物的一种抑制剂。此类非竞争性抑制剂可例如提供一定水平的抑制作用,所述抑制作用可与底物浓度实质上无关。
本发明的MMP9结合蛋白(例如抗体和其功能片段)包括结合MMP9,特别是人类MMP9,并且具有与本文所揭示的重链多肽具有至少约80%、85%、90%、95%或更高氨基酸序列一致性的重链多肽(或其功能片段)的结合蛋白。在一些实例中,本发明的MMP9结合蛋白(例如抗体和其功能片段)包括结合MMP9,特别是人类MMP9,并且具有与本文所揭示的重链多肽具有至少约90%、95%、97%、98%、99%或更高氨基酸序列一致性的重链多肽(或其功能片段)的结合蛋白。
本发明的MMP9结合蛋白(例如抗体和其功能片段)包括结合MMP9,特别是人类MMP9,并且具有与本文所揭示的重链多肽具有至少约80%、85%、90%、95%或更高氨基酸序列一致性的轻链多肽(或其功能片段)的结合蛋白。
本发明的MMP9结合蛋白(例如抗体和其功能片段)包括结合MMP9,特别是人类MMP9,并且具有如本文所揭示的重链多肽的互补决定区(“CDR”)的重链多肽(或其功能片段)以及轻链多肽(或其功能片段)的CDR的结合蛋白。
如本文所使用,“同源性”或“一致性”或“相似性”在核酸和多肽的情形中是指分别基于氨基酸序列或核酸序列比对,两个多肽或两个核酸分子之间的关系。同源性和一致性可各自通过比较出于比较的目的对准的每个序列的位置来测定。当所比较的序列中的相同位置被相同碱基或氨基酸占据时,则这些分子在所述位置相同;当相同位点被相同或相似的氨基酸残基(例如空间性和/或电子性质类似)占据时,则这些分子可称为在所述位置同源(相似)。以同源性/相似性或一致性百分比表示是指在多个位置处所比较的序列共有的一致或相似氨基酸的数量的函数。在比较两个序列时,残基(氨基酸或核酸)的不存在或额外残基的存在也会降低一致性和同源性/相似性。
如本文所使用,“一致性”意谓当将两个或两个以上序列对准以使序列匹配达到最大(即,考虑空位和插入)时,在这些序列中相应位置处一致核苷酸或氨基酸残基的百分比。序列一般在指定区域内,例如至少约20、25、30、35、40、45、50、55、60、65或更多个氨基酸或核苷酸长的区域内对准以达到最大对应,并且可长达参考氨基酸或核苷酸的全长。为进行序列比较,通常一个序列充当参考序列,以与测试序列相比较。当使用序列比较算法时,将测试序列和参考序列输入计算机程序中,必要时,指定子序列座标,并且指定序列算法的程序参数。随后序列比较算法基于指定的程序参数计算测试序列相对于参考序列的序列一致性百分比。
适用于测定序列一致性百分比的算法的实例为BLAST和BLAST 2.0算法,其分别描述于奥兹楚尔(Altschul)等人(1990)分子生物学杂志(J.Mol.Biol.)215:403-410及奥兹楚尔等人(1977)核酸研究(Nucleic Acids Res.)25:3389-3402中。执行BLAST分析的软件可经由国家生物技术资讯中心(National Center for Biotechnology Information;www.ncbi.nlm.nih.gov)公开获得。其它示例性算法包括ClustalW(海金思D.(Higgins D.)等人(1994)核酸研究(Nucleic Acids Res)22:4673-4680),在www.ebi.ac.uk/Tools/clustalw/index.html上可得。
不一致的残基位置可因保守氨基酸取代而不同。保守氨基酸取代是指具有类似侧链的残基的可互换性。举例来说,一组具有脂肪族侧链的氨基酸为甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸;一组具有脂肪族羟基侧链的氨基酸为丝氨酸和苏氨酸;一组具有含酰胺的侧链的氨基酸为天冬酰胺和谷氨酰胺;一组具有芳香族侧链的氨基酸为苯丙氨酸、酪氨酸及色氨酸;一组具有碱性侧链的氨基酸为赖氨酸、精氨酸和组氨酸;并且一组具有含硫侧链的氨基酸为半胱氨酸和甲硫氨酸。
两个核酸之间的序列一致性也可以关于两个分子彼此在严格条件下的杂交来描述。杂交条件是遵循所属领域中的标准方法选择(参见例如,萨姆布鲁克(Sambrook)等人,分子克隆实验指南,第二版,(1989)纽约冷泉港(Cold Spring Harbor,N.Y.))。严格杂交条件的一个实例是在50℃或更高温度及0.1×SSC(15mM氯化钠/1.5mM柠檬酸钠)下杂交。严格杂交条件的另一个实例为在42℃下于以下溶液中过夜培育:50%甲酰胺、5×SSC(150mMNaCl、15mM柠檬酸三钠)、50mM磷酸钠(pH7.6)、5×丹哈特氏溶液(Denhardt's solution)、10%硫酸葡聚糖及20mg/ml变性剪切的鲑鱼精DNA;随后在约65℃下于0.1×SSC中洗涤过滤器。严格杂交条件是至少与上述代表性条件同样严格的杂交条件,其中如果这些条件与上述特定严格条件至少约80%同样严格,通常至少90%同样严格,就认为其为至少同样严格的。
因此,本发明提供了例如这样一些抗体或其抗原结合片段,其包含与本文所述的重链可变区的氨基酸序列(例如SEQ ID NO:1或5-8)具有至少80%、85%、90%、95%、96%、97%、98%、99%或更高氨基酸序列一致性的重链可变区多肽,及与如本文所陈述的轻链多肽的氨基酸序列(例如SEQ ID NO:2或9-12)具有至少80%、85%、90%、95%、96%、97%、98%、99%或更高氨基酸序列一致性的可变轻链多肽。
本发明的抗MMP9抗体的实例将于以下更详细地描述。
抗体
MMP9结合蛋白包括抗体和其功能片段,例如特异性结合到MMP9的那些。如本文所使用,术语“抗体”意谓包含特异性结合抗原表位的肽序列(例如可变区序列)的分离的或重组多肽结合剂。所述术语是以其最广泛意义使用并且特别涵盖单克隆抗体(包括全长单克隆抗体)、多克隆抗体、人类抗体、人类化抗体、嵌合抗体、纳米抗体、双功能抗体、多特异性抗体(例如双特异性抗体),及抗体片段,包括(但不限于)Fv、scFv、Fab、Fab'、F(ab')2及Fab2,只要其展现所需的生物活性即可。术语“人类抗体”是指除可能的非人类CDR区外,含有人类来源的序列的抗体,并且并非暗指存在免疫球蛋白分子的完整结构,只是指所述抗体在人体中具有极少免疫原性作用(即,不会诱导产生针对其自身的抗体)。
“抗体片段”包含全长抗体的一部分,例如全长抗体的抗原结合区或可变区。此类抗体片段也可以在本文中称为“功能片段”或“抗原结合片段”。抗体片段的实例包括Fab、Fab'、F(ab')2及Fv片段;双功能抗体;线性抗体(扎帕塔(Zapata)等人(1995)蛋白质工程(Protein Eng.)8(10):1057-1062);单链抗体分子;及由抗体片段形成的多特异性抗体。木瓜蛋白酶消化抗体产生两个相同的抗原结合片段,称为“Fab”片段,其各自具有单个抗原结合位点;及一个残留的“Fc”片段,其名称反映了易于结晶的能力。胃蛋白酶处理得到F(ab')2片段,其具有两个抗原组合位点并且仍能够交联抗原。
“Fv”是含有完整抗原识别和结合位点的最小抗体片段。这一区域是由紧密非共价缔合的一个重链可变结构域和一个轻链可变结构域构成的二聚物组成。在这种构型中,每个可变结构域的三个互补决定区(CDR)相互作用以在VH-VL二聚物的表面上界定抗原结合位点。六个CDR共同地赋予抗体抗原结合特异性。然而,每个单一可变结构域(或仅包含对于抗原具特异性的六个CDR中的三个的分离的VH或VL区)能够识别并结合抗原,不过亲和力一般低于完整Fv片段。
“Fab”片段除重链和轻链可变区外,还含有轻链恒定结构域和重链的第一恒定结构域(CH1)。Fab片段最初是在木瓜蛋白酶消化抗体之后观察到。Fab'片段与Fab片段的不同之处在于,F(ab')片段在重链CH1结构域的羧基末端处含有若干其它残基,包括抗体铰链区中的一或多个半胱氨酸。F(ab')2片段含有在铰链区附近通过二硫键接合的两个Fab片段,并且最初是在胃蛋白酶消化抗体之后观察到。Fab'-SH在本文中指定为Fab'片段,其中恒定结构域的半胱氨酸残基带有游离硫醇基。抗体片段的其它化学偶合也是已知的。
来自任何脊椎动物物种的抗体(免疫球蛋白)的“轻链”基于其恒定结构域的氨基酸序列可以被分配到两种明显相异的类型之一中,称为κ和λ。取决于重链恒定结构域的氨基酸序列,可将免疫球蛋白分为五个主要类别:IgA、IgD、IgE、IgG及IgM,并且这些类别中的若干类别可进一步细分成子类(同型),例如IgG1、IgG2、IgG3、IgG4、IgA1及IgA2。
“单链Fv”或“sFv”或“scFv”抗体片段包含抗体的VH和VL结构域,其中这些结构域存在于单一多肽链中。在一些实施例中,Fv多肽进一步包含在VH与VL结构域之间的多肽连接子,所述连接子使sFv能够形成抗原结合所需的结构。关于sFv的评述,参见普鲁可敦(Pluckthun),单克隆抗体药理学(The Pharmacology of Monoclonal Antibodies),第113卷(罗森博格(Rosenburg)和摩尔(Moore)编)斯普林格-维拉格出版社(Springer-Verlag),纽约(New York),第269-315页(1994)。
术语“双功能抗体”是指具有两个抗原结合位点的小抗体片段,这些片段包含连接到同一多肽链(VH-VL)中的轻链可变结构域(VL)的重链可变结构域(VH)。通过使用太短而无法使同一链中的两个结构域之间配对的连接子,迫使这些结构域与另一条链的互补结构域配对,由此产生两个抗原结合位点。双功能抗体另外描述于例如EP 404,097;WO93/11161;及霍林格(Hollinger)等人(1993)美国国家科学院院刊(Proc.Natl.Acad.Sci.USA)90:6444-6448中。
“分离的”抗体为从自然环境的组分鉴别并且分离和/或回收的抗体。其自然环境的组分可包括酶、激素及其它蛋白质或非蛋白质溶质。在一些实施例中,分离的抗体被纯化(1)达到如通过劳里法(Lowry method)所测定的超过95重量%,例如超过99重量%的抗体;(2)达到例如通过使用旋杯式顺序分析仪足以获得N末端或内部氨基酸序列的至少15个残基的程度;或(3)达到通过在还原或非还原条件下进行凝胶电泳(例如SDS-PAGE)并且通过考马斯蓝(Coomassie blue)或银染色检测的均质性。术语“分离的抗体”包括一种在重组细胞内原位的抗体,因为所述抗体的自然环境的至少一种组分将不存在。在某些实施例中,分离的抗体是通过至少一个纯化步骤制备。
如本文所使用,“免疫反应性”是指对氨基酸残基的序列(“结合位点”或“表位”)具有特异性,但又与其它肽/蛋白质交叉反应,在将其调配用于投予人类使用的水平下无毒的抗体或其片段。“表位”是指抗原中能够与抗体或其抗原结合片段形成结合相互作用的部分。表位可为线性肽序列(即,“连续的”)或可由非邻接的氨基酸序列(即,“构象”或“不连续”)构成。术语“优先结合”意谓结合剂结合到结合位点的亲和力高于其结合不相关氨基酸序列的亲和力。
抗MMP9抗体可关于重链和轻链的CDR进行描述。如本文所使用,术语“CDR”或“互补决定区”打算意谓在重链多肽与轻链多肽的可变区内发现的非邻接抗原组合位点。这些特定区域已描述于卡贝特(Kabat)等人,生物化学杂志(J.Biol.Chem.)252:6609-6616(1977);卡贝特等人,美国卫生和公众服务部(U.S.Dept.of Health and HumanServices),“免疫相关蛋白质的序列(Sequences of proteins of immunologicalinterest)”(1991);查赛(Chothia)等人,分子生物学杂志(J.Mol.Biol.)196:901-917(1987);及麦克卡伦(MacCallum)等人,分子生物学杂志,262:732-745(1996)中,其中当彼此相比较时,这些定义包括氨基酸残基的重叠或亚组。尽管如此,用以指抗体或移植抗体或其变体的CDR的任一定义的应用打算在如本文所定义和使用的术语的范围内。涵盖如以上引用的每一参考文献所定义的CDR的氨基酸残基陈述于下表1A中供比较。
表1A:CDR定义
1残基编号遵循卡贝特等人(同上文)的命名法
2残基编号遵循查赛等人(同上文)的命名法
3残基编号遵循麦克卡伦等人(同上文)的命名法
如本文所使用,当提及抗体可变区时使用的术语“构架”打算意谓在抗体可变区内的除CDR区外的所有氨基酸残基。可变区构架一般是长度在约100-120个氨基酸之间的不连续氨基酸序列,但打算仅提到除CDR外的氨基酸。如本文所使用,术语“构架区”打算意谓所述构架被CDR分开的每个结构域。
在一些实施例中,抗体是人类化抗体或人类抗体。人类化抗体包括来自受体互补决定区(CDR)的残基被来自具有所需特异性、亲和力和容量的非人类物种(供体抗体;例如小鼠、大鼠或兔)的CDR的残基置换的人类免疫球蛋白(受体抗体)。因此,非人类(例如,鼠类)抗体的人类化形式为含有源自于非人类免疫球蛋白的最小序列的嵌合免疫球蛋白。非人类序列主要位于可变区中,特别是互补决定区(CDR)中。在一些实施例中,人类免疫球蛋白的Fv构架残基被相应非人类残基置换。人类化抗体也可包含在受体抗体和引入的CDR或构架序列中都未发现的残基。在某些实施例中,人类化抗体包含实质上所有的至少一个并且通常两个可变结构域,其中所有或实质上所有的CDR都与非人类免疫球蛋白的CDR对应并且所有或实质上所有的构架区都为人类免疫球蛋白共同序列的构架区。出于本发明的目的,人类化抗体也可包括免疫球蛋白片段,例如Fv、Fab、Fab'、F(ab')2或抗体的其它抗原结合子序列。
人类化抗体还可包含免疫球蛋白恒定区(Fc)的至少一部分,通常为人类免疫球蛋白恒定区的至少一部分。参见例如,琼斯(Jones)等人(1986)自然(Nature)321:522-525;瑞奇曼(Riechmann)等人(1988)自然332:323-329;及普雷斯塔(Presta)(1992)结构生物学新观点(Curr.Op.Struct.Biol.)2:593-596。
用于使非人类抗体人类化的方法是所属领域中已知的。一般来说,人类化抗体在其中引入了一或多个来自非人类来源的氨基酸残基。这些非人类氨基酸残基通常称为“输入”或“供体”残基,这些残基通常是从“输入”或“供体”可变结构域获得。举例来说,人类化可基本上根据维特(Winter)和其同事的方法,通过用啮齿动物CDR或CDR序列取代人类抗体的相应序列来进行。参见例如,琼斯等人,同上文;瑞奇曼等人,同上文;维霍恩(Verhoeyen)等人(1988)科学(Science)239:1534-1536。因此,此类“人类化”抗体包括嵌合抗体(美国专利第4,816,567号),其中实质上少于完整人类可变结构域被来自非人类物种的相应序列取代。在某些实施例中,人类化抗体是一些CDR残基和任选地一些构架区残基被来自啮齿动物抗体(例如鼠类单克隆抗体)中类似位点的残基取代的人类抗体。
人类抗体也可例如通过使用噬菌体展示文库来产生。霍格波姆(Hoogenboom)等人(1991)分子生物学杂志(J.Mol.Biol),227:381;马克斯(Marks)等人(1991)分子生物学杂志,222:581。用于制备人类单克隆抗体的其它方法描述于科勒(Cole)等人(1985)“单克隆抗体和癌症疗法(Monoclonal Antibodies and Cancer Therapy),”艾伦R.利斯(AlanR.Liss),第77页;及博纳(Boerner)等人(1991)免疫学杂志(J.Immunol.)147:86-95中。
还可以通过将人类免疫球蛋白基因座引入转基因动物(例如小鼠)中来制备人类抗体,在这些转基因动物中,已经使内源免疫球蛋白基因部分地或完全地失活。在免疫激发之后,观察到人类抗体的产生,其在所有方面都紧密地类似于在人类所见,包括基因重排、组装及抗体谱系。这一方法描述于例如美国专利第5,545,807号、第5,545,806号、第5,569,825号、第5,625,126号、第5,633,425号、第5,661,016号,以及以下科技出版物中:马克斯(Marks)等人(1992)生物技术(Bio/Technology)10:779-783(1992);朗伯格(Lonberg)等人(1994)自然,368:856-859;莫里森(Morrison)(1994)自然,368:812-813;费西沃德(Fishwald)等人(1996)自然-生物技术(Nature Biotechnology)14:845-851;纽伯格(Neuberger)(1996)自然-生物技术,14:826;及朗伯格等人(1995)国际免疫学评论(Intern.Rev.Immunol.)13:65-93。
抗体可使用如以上所描述的已知的选择和/或诱变方法进行亲和力成熟。在一些实施例中,亲和力成熟的抗体的亲和力是用于制备所述成熟抗体的起始抗体(一般为鼠类、兔、鸡、人类化或人类抗体)的亲和力的五倍或更高、十倍或更高、二十倍或更高,或三十倍或更高。
抗体还可以为双特异性抗体。双特异性抗体是单克隆的,并且可为对至少两种不同抗原具有结合特异性的人类或人类化抗体。在本情形中,所述两种不同结合特异性可针对两种不同的MMP,或针对单一MMP(例如MMP9)上的两个不同表位。
如本文所揭示的抗体还可以是免疫偶联物。所述免疫偶联物包含与第二分子(例如报导子)偶联的抗体(例如针对MMP9的抗体)。免疫偶联物还可包含与细胞毒性剂(例如化学治疗剂)、毒素(例如,细菌、真菌、植物或动物起源的酶活性毒素,或其片段)或放射性同位素(即,放射性偶联物)偶联的抗体。
“特异性结合到”特定多肽或表位,或对特定多肽或表位“具特异性”的抗体是指所述抗体选择性结合到目标抗原或表位;这些术语及用于确定特异性结合的方法是所属领域中众所周知的。如果抗体结合特定目标抗原或表位的亲和力、亲合力、容易性和/或持续时间高于其与其它物质的结合,那么其展现对所述目标抗原或表位的“特异性结合”。在一些实施例中,特异性结合到多肽或表位的抗体是结合到所述特定多肽或表位,而不实质上结合到任何其它多肽或多肽表位的抗体。在一些实施例中,如在约4℃、25℃、37℃或42℃温度下所测量,所提供的抗体以单克隆抗体、scFv、Fab形式或其它抗体形式以等于或小于100nM,任选地小于10nM,任选地小于1nM,任选地小于0.5nM,任选地小于0.1nM,任选地小于0.01nM或任选地小于0.005nM,在某些实例中介于0.1与0.2nM之间,或介于0.1与10pM之间,例如介于0.4与9pm之间,例如介于0.4与8.8pm之间的解离常数(Kd)特异性结合到人类MMP9。
在某些实施例中,本发明的抗体结合到MMP9中的一或多个加工位点(例如,蛋白水解裂解位点),由此有效地阻断酶原或前酶原加工成催化活性酶,并且因此降低MMP9的蛋白水解活性。
在某些实施例中,根据本发明的抗体结合到MMP9的亲和力是其对另一MMP的结合亲和力的至少2倍、至少5倍、至少10倍、至少25倍、至少50倍、至少100倍、至少500倍或至少1000倍。结合亲和力可通过所属领域中已知的任何方法测量并且可以例如缔合速率、解离速率、解离常数(Kd)、平衡常数(Keq)或所属领域中的任何术语表示。
在某些实施例中,根据本发明的抗体是抑制MMP9的酶活性(即,催化活性)的抗体,例如MMP9催化活性的非竞争性抑制剂。在某些实施例中,根据本发明的抗体在MMP9的催化结构域内结合。在其它实施例中,根据本发明的抗体在MMP9的催化结构域外部结合。
还提供了与本文描述的一或多种抗MMP9抗体或其抗原结合片段竞争结合到MMP9的抗体或其抗原结合片段。因此,本发明涵盖与例如具有SEQ ID NO:1或5-8中任一种的重链多肽、SEQ ID NO:2或9-12的轻链多肽或其组合的抗体竞争结合的抗MMP9抗体及其功能片段。在一个实施例中,抗MMP9抗体或其功能片段与本文描述为AB0041的抗体竞争结合到人类MMP9。
还提供了结合到与任一种或多种本文所述的抗体相同的表位(例如MMP9表位)的抗体和其片段。还提供了特异性结合到MMP9表位的抗体和片段,其中所述表位包括在MMP9的一个特定区域或MMP9的多个区域内的氨基酸残基。这些区域可包括例如MMP9的结构环和/或其它结构性结构域,例如经显示对结合到本文所述的示例性抗体很重要的那些结构域。通常,这些区域是根据氨基酸残基在全长MMP9序列(例如SEQ ID NO:27)上的位置界定。在一些实例中,所述表位含有SEQ ID NO:27的氨基酸残基104-202。在一个实例中,所述表位含有在SEQ ID NO:27的残基104-119、残基159-166或残基191-202的区域内的氨基酸残基(即,一或多个氨基酸残基)。在一些方面中,所述表位包括在作为SEQ ID NO:27的残基104-119的MMP9区域内的氨基酸残基(即,一或多个氨基酸残基)、在作为SEQ ID NO:27的残基159-166的MMP9区域内的氨基酸残基,及在作为SEQ ID NO:27的残基191-202的MMP9区域内的氨基酸残基。在一些情形中,所述表位包括SEQ ID NO:27的E111、D113、R162或I198。在一些情形中,其包括SEQ ID NO:27的R162。在一些情形中,其包括SEQ ID NO:27的E111、D113、R162及I198。
MMP9序列
人类MMP9蛋白的氨基酸序列如下:
蛋白质结构域示意性显示于图3中并且指示于下:
成熟全长人类MMP9的氨基酸序列(其为不含信号肽的具有SEQ ID NO:27的前肽的氨基酸序列)为:
APRQRQSTLVL FPGDLRTNLT DRQLAEEYLY RYGYTRVAEM RGESKSLGPA
LLLLQKQLSL PETGELDSAT LKAMRTPRCG VPDLGRFQTF EGDLKWHHHN
ITYWIQNYSE DLPRAVIDDA FARAFALWSA VTPLTFTRVY SRDADIVIQF
GVAEHGDGYP FDGKDGLLAH AFPPGPGIQG DAHFDDDELW SLGKGVVVPT
RFGNADGAAC HFPFIFEGRS YSACTTDGRS DGLPWCSTTA NYDTDDRFGF
CPSERLYTRD GNADGKPCQF PFIFQGQSYS ACTTDGRSDG YRWCATTANY
DRDKLFGFCP TRADSTVMGG NSAGELCVFP FTFLGKEYST CTSEGRGDGR
LWCATTSNFD SDKKWGFCPD QGYSLFLVAA HEFGHALGLD HSSVPEALMY
PMYRFTEGPP LHKDDVNGIR HLYGPRPEPE PRPPTTTTPQ PTAPPTVCPT
GPPTVHPSER PTAGPTGPPS AGPTGPPTAG PSTATTVPLS PVDDACNVNI
FDAIAEIGNQ LYLFKDGKYW RFSEGRGSRP QGPFLIADKW PALPRKLDSV
FEEPLSKKLF FFSGRQVWVY TGASVLGPRR LDKLGLGADV AQVTGALRSG
RGKMLLFSGR RLWRFDVKAQ MVDPRSASEV DRMFPGVPLD THDVFQYREK
AYFCQDRFYW RVSSRSELNQ VDQVGYVTYD ILQCPED(SEQ ID NO:28)。
信号肽的氨基酸序列为MSLWQPLVLVLLVLGCCFA(SEQ ID NO:29)。
还提供了MMP9多肽,包括突变体MMP9多肽。这些肽可用于例如产生并选择如本文所提供的抗体和片段。示例性多肽包括具有含SEQ ID NO:27的残基111-198的氨基酸序列的多肽,及具有含SEQ ID NO:27的残基111-198的氨基酸序列并且在SEQ ID NO:27的残基111、113、162或198处具有氨基酸取代或在所有这些残基处具有氨基酸取代的多肽。这些多肽可用于例如选择结合到含这些残基的表位和/或MMP9的这些残基对于结合很重要的抗体,例如本文所述的抗体。
本发明涵盖结合MMP9(例如人类MMP9)的任何部分的MMP9结合蛋白,其中相对于其它MMP,优先结合MMP9的MMP9结合蛋白是特别值得关注的。
抗MMP9抗体和其功能片段可根据所属领域中众所周知的方法产生。示例性抗MMP9抗体提供于下。
小鼠单克隆抗MMP9抗体
针对人类MMP9的小鼠单克隆抗体如下获得。这一抗体含有小鼠IgG2b重链和小鼠κ轻链,并且称为AB0041。
AB0041重链的氨基酸序列如下:
信号序列加下划线,并且IgG2b恒定区的序列以斜体表示。
AB0041轻链的氨基酸序列如下:
信号序列加下划线,并且κ恒定区的序列以斜体表示。
以下氨基酸序列包含AB0041的IgG2b重链可变区的构架区和互补决定区(CDR)(其中CDR加下划线):
QVQLKESGPGLVAPSQSLSITCTVSGFSLLSYGVHWVRQPPGKGLEWLGVIWTGGTTNYNSALMSRLSISKDDSKSQVFLKMNSLQTDDTAIYYCARYYYGMDYWGQGTSVTVSS(SEQ ID NO:3)。
以下氨基酸序列包含AB0041的κ轻链可变区的构架区和互补决定区(CDR)(其中CDR加下划线):
DIVMTQSHKFMSTSVGDRVSITCKASQDVRNTVAWYQQKTGQSPKLLIYSSSYRNTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYFCQQHYITPYTFGGGTKLEIK(SEQ ID NO:4)。
其它示例性小鼠抗人类MMP9抗体(例如M4和M12)描述于本文中。示例性抗小鼠MMP9抗体(AB0046)描述于本文中。在一些实施例中,提供了这些抗小鼠抗体作为代用抗体用于测试并评估如本文所提供的MMP9抑制方法(例如治疗方法)的用途。
重链变体
通过改变AB0041重链和轻链可变区中的构架区序列来单独地修饰所述重链和轻链可变区的氨基酸序列。这些序列改变的影响是使人类T细胞表位的抗体耗尽,从而减少或消除其在人体中的免疫原性(安提托普公司(Antitope),英国巴布拉汉(Babraham,UK)。
在含有使铰链结构域稳定的S241P氨基酸改变的人类IgG4重链背景下构建四个重链变体(安格(Angal)等人(1993)分子免疫学(Molec.Immunol.)30:105-108),并且称为VH1、VH2、VH3及VH4。其构架区和CDR的氨基酸序列如下:
VH1
QVQLQESGPGLVKPSETLSLTCTVSGFSLLSYGVHWVRQPPGKGLEWLGVIWTGGTTNYNSALMSRLTISKDDSKSTVYLKMNSLKTEDTAIYYCARYYYGMDYWGQGTSVTVSS(SEQ ID NO:5)
VH2
QVQLQESGPGLVKPSETLSLTCTVSGFSLLSYGVHWVRQPPGKGLEWLGVIWTGGTTNYNSALMSRLTISKDDSKNTVYLKMNSLKTEDTAIYYCARYYYGMDYWGQGTLVTVSS(SEQ ID NO:6)
VH3
QVQLQESGPGLVKPSETLSLTCTVSGFSLLSYGVHWVRQPPGKGLEWLGVIWTGGTTNYNSALMSRFTISKDDSKNTVYLKMNSLKTEDTAIYYCARYYYGMDYWGQGTLVTVSS(SEQ ID NO:7)
VH4
QVQLQESGPGLVKPSETLSLTCTVSGFSLLSYGVHWVRQPPGKGLEWLGVIWTGGTTNYNSALMSRFTISKDDSKNTLYLKMNSLKTEDTAIYYCARYYYGMDYWGQGTLVTVSS(SEQ ID NO:8)
图1示出了人类化重链可变区的氨基酸序列的比对并且指示这四个变体的构架区中的氨基酸序列存在差异。
轻链变体
在人类κ链背景下构建四个轻链变体,并且称为Vk1、Vk2、Vk3及Vk4。其构架区和CDR的氨基酸序列如下:
Vk1
DIVMTQSPSFLSASVGDRVTITCKASQDVRNTVAWYQQKTGKAPKLLIYSSSYRNTGVPDRFTGSGSGTDFTLTISSLQAEDVAVYFCQQHYITPYTFGGGTKVEIK(SEQ ID NO:9)
Vk2
DIVMTQSPSSLSASVGDRVTITCKASQDVRNTVAWYQQKPGKAPKLLIYSSSYRNTGVPDRFTGSGSGTDFTLTISSLQAEDVAVYFCQQHYITPYTFGGGTKVEIK(SEQ ID NO:10)
Vk3
DIQMTQSPSSLSASVGDRVTITCKASQDVRNTVAWYQQKPGKAPKLLIYSSSYRNTGVPDRFSGSGSGTDFTLTISSLQAEDVAVYFCQQHYITPYTFGGGTKVEIK(SEQ ID NO:11)
Vk4
DIQMTQSPSSLSASVGDRVTITCKASQDVRNTVAWYQQKPGKAPKLLIYSSSYRNTGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYITPYTFGGGTKVEIK(SEQ ID NO:12)
图2示出了人类化轻链可变区的氨基酸序列的比对并且指示这四个变体的构架区中的氨基酸序列存在差异。
人类化重链和轻链以所有可能的逐对组合方式组合以产生多种功能性人类化抗MMP9抗体。举例来说,提供了含具有SEQ ID NO:3、5、6、7及8中的任一个中所陈述的氨基酸序列的重链可变(VH)区的抗体;含具有SEQ ID NO:4、9、10、11及12中的任一个中所陈述的氨基酸序列的轻链可变(VL)区的抗体;及含具有SEQ ID NO:3、5、6、7及8中的任一个中所陈述的氨基酸序列的重链可变(VH)区及具有SEQ ID NO:4、9、10、11及12中的任一个中所陈述的氨基酸序列的轻链可变(VL)区的抗体,以及与这些抗体竞争结合到MMP9的抗体和与这些抗体具有至少或约75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高序列一致性的抗体。在一个实例中,所述抗体具有VH区,所述VH区的氨基酸序列与SEQ ID NO:7具有至少或约75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高的序列一致性;及VL区,所述VL区的氨基酸序列与SEQ ID NO:12具有至少或约75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高序列一致性;或具有SEQ ID NO:7的VH区和SEQ ID NO:12的VL区。
还提供了与本文所揭示的重链可变区序列具有75%或更高,80%或更高,90%或更高,95%或更高,或99%或更高同源性的其它重链可变区氨基酸序列。此外,还提供了与本文所揭示的轻链可变区序列具有75%或更高,80%或更高,90%或更高,95%或更高,或99%或更高同源性的其它轻链可变区氨基酸序列。
还提供了与本文所揭示的重链可变区序列具有75%或更高,80%或更高,90%或更高,95%或更高,或99%或更高序列一致性的其它重链可变区氨基酸序列。此外,还提供了与本文所揭示的轻链可变区序列具有75%或更高,80%或更高,90%或更高,95%或更高,或99%或更高序列一致性的其它轻链可变区氨基酸序列。
互补决定区(CDR)
在一些实施例中,如本文所揭示的示例性提供的抗MMP9抗体的重链CDR具有以下氨基酸序列:
CDR1:GFSLLSYGVH(SEQ ID NO:13)
CDR2:VIWTGGTTNYNSALMS(SEQ ID NO:14)
CDR3:YYYGMDY(SEQ ID NO:15)。
因此,所提供的抗MMP9抗体为具有含如SEQ ID NO:13中所陈述的氨基酸序列的重链CDR1区的抗体、具有含如SEQ ID NO:14中所陈述的氨基酸序列的重链CDR2区的抗体,及具有含如SEQ ID NO:15中所陈述的氨基酸序列的重链CDR3区的抗体,以及与这些抗体竞争结合或结合到MMP9上与这些抗体相同的表位的抗体。在一些情形中,所述抗体含有具SEQID NO:15中所陈述的序列的VH CDR。在一些情形中,所述抗体含有具SEQ ID NO:13和14中所陈述的序列的VH CDR。在一些情形中,所述抗体含有具SEQ ID NO:13和15中所陈述的序列的VH CDR。在一些情形中,所述抗体含有具SEQ ID NO:14和15中所陈述的序列的VH CDR。在一些情形中,所述抗体含有具SEQ ID NO:13、14及15中所陈述的序列的VH CDR。
在一些实施例中,如本文所揭示的示例性抗MMP9抗体的轻链CDR具有以下氨基酸序列:
CDR1:KASQDVRNTVA(SEQ ID NO:16)
CDR2:SSSYRNT(SEQ ID NO:17)
CDR3:QQHYITPYT(SEQ ID NO:18)。
因此,所提供的抗MMP9抗体为具有含如SEQ ID NO:16中所陈述的氨基酸序列的轻链CDR1区的抗体、具有含如SEQ ID NO:17中所陈述的氨基酸序列的轻链CDR2区的抗体,及具有含如SEQ ID NO:18中所陈述的氨基酸序列的轻链CDR3区的抗体,以及与这些抗体竞争结合或结合到MMP9上与这些抗体相同的表位的抗体。在一些情形中,所述抗体含有具SEQID NO:18中所陈述的序列的VL CDR。在一些情形中,所述抗体含有具SEQ ID NO:16和17中所陈述的序列的VL CDR。在一些情形中,所述抗体含有具SEQ ID NO:16和18中所陈述的序列的VL CDR。在一些情形中,所述抗体含有具SEQ ID NO:17和18中所陈述的序列的VL CDR。在一些情形中,所述抗体含有具SEQ ID NO:16、17及18中所陈述的序列的VL CDR。
示例性人类化变体抗MMP9抗体AB0045(人类化的经修饰IgG4(S241P))含有人类化AB0041重链变体VH3(具有SEQ ID NO:7(QVQLQESGPGLVKPSETLSLTCTVSGFSLLSYGVHWVRQPPGKGLEWLGVIWTGGTTNYNSALMSRFTISKDDSKNTVYLKMNSLKTEDTAIYYCARYYYGMDYWGQGTLVTVSS)中所陈述的序列)和人类化AB0041轻链变体VH4(具有Vk4(具有SEQ ID NO:12(DIQMTQSPSSLSASVGDRVTITCKASQDVRNTVAWYQQKPGKAPKLLIYSSSYRNTGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYITPYTFGGGTKVEIK)中所陈述的序列)中所陈述的轻链序列)。
AB0045抗体含有1312个氨基酸的长度,由两个重链和两个轻链构成并且具有约7.90的理论pI值、对于1g/L在280nm下约1.50AU/cm的消光系数、约144kDa的分子量及在调配缓冲液中约1g/mL的密度(50-100mg/mL产物浓度)。
AB0045抗体的重链具有SEQ ID NO:49 (信号序列加下划线;恒定区序列以斜体呈现))中所陈述的序列;AB0045抗体的轻链具有SEQ ID NO:50 (信号序列加下划线;恒定区序列以斜体呈现)中所陈述的序列。
所述抗体另外包括通过称为M4的杂交瘤所产生的抗体,即,含有以下重链(IgG2b)序列: (信号肽以加下划线文字陈述,可变区以无格式文字陈述,并且恒定区以斜体陈述),及以下轻链(κ)序列: (信号肽以加下划线文字陈述,可变区以无格式文字陈述,并且恒定区以斜体陈述)(SEQ ID NO:31)的抗体。M4抗体具有含以下氨基酸序列的可变重链:QVQLKESGPGLVAPSQSLSITCTVSGFSLLSYGVHWVRQPPGKGLEWLGVIWTGGSTNYNSALMSRLSISKDDSKSQVFLKMNSLQTDDTAMYYCARYYYAMDYWGQGTSVTVSS(CDR 1、2及3(分别为SEQ ID NO:34、35及36)加下划线)(SEQ ID NO:32);及含以下氨基酸序列的可变轻链:DIVMTQSHKFMFTSVGDRVSITCKASQDVRNTVAWYQQKTGQSPKLLIYSASYRNTGVPDRFTGSISGTDFTFTISSVQAEDLALYYCQQHYSTPYTFGGGTKLEVK(CDR 1、2及3(分别为SEQ ID NO:37、38及39)加下划线)(SEQ ID NO:33)。
这些抗体另外包括通过称为M12的杂交瘤产生的抗体,即,仅具有κ链的抗体,其具有以下序列: (信号肽以加下划线文字陈述,可变区以无格式文字陈述,并且恒定区以斜体陈述)(SEQ IDNO:40)。M12抗体具有含以下氨基酸序列的可变轻链:DIVMTQSQKFMSTSVGDRVSVTCKASQNVGTN VAWYQQKPGQSPKALIYSASYRFSGVPDRFTGSGSGTDFTLTISNVQSEDLAEYFCQQYNSYPYTFGGGTKLEIK(CDR 1、2及3(分别为SEQ ID NO:42、43及44)加下划线)(SEQ ID NO:41)。
这些抗体另外包括称为AB0046的小鼠抗体,其具有含以下氨基酸序列的κ轻链: (信号肽以加下划线文字陈述,可变区以无格式文字陈述,并且恒定区以斜体陈述);及含以下氨基酸序列的IgG1重链: (信号肽以加下划线文字陈述,可变区以无格式文字陈述,并且恒定区以斜体陈述)。
以下氨基酸序列包含AB0046的IgG1重链可变区的构架区和互补决定区(CDR)(其中CDR加下划线):
QVQLQQPGSVLVRPGASVKLSCTASGYTFTSYWMNWVKQRPGQGLEWIGEIYPISGRTNYNEKFKVKATLTVDTSSSTAYMDLNSLTSEDSAVYYCARSRANWDDYWGQGTTLTVSS(SEQ ID No:47)。
以下氨基酸序列包含AB0046的κ轻链可变区的构架区和互补决定区(CDR)(其中CDR加下划线):
DIQMTQTTSSLSASLGDRVTISCSASQGISNYLNWYQQKPDGTFKLLIYYTSILHSGVPSRFSGSGSGTDYSLTISNLEPEDIATYYCQQYGWLPRTFGGGTKLEIK(SEQ ID No:48)。
用于目前所提供的方法、组合物及组合中的抗体可包括本文所述抗体中的任一种,包括抗体和抗体片段,包括含有各种示例性重链和轻链、重链和轻链可变区及CDR的任何组合的那些。
编码抗MMP9抗体的核酸
本发明提供了编码抗MMP9抗体和其功能片段的核酸。因此,本发明提供了一种编码如本文所述的抗体或抗原结合片段的分离的多核苷酸(核酸)、含有这些多核苷酸的载体及用于将这些多核苷酸转录并翻译成多肽的宿主细胞和表达系统。
本发明还涵盖呈质粒、载体、转录或表达盒形式的构建体,其包含至少一种如上述的多核苷酸。
本发明还提供一种包含一或多种如上述的构建体的重组宿主细胞,以及制造本文所述的抗体或其抗原结合片段的方法,所述方法包含在重组宿主细胞中表达编码重链多肽和轻链多肽的核酸(在相同或不同宿主细胞中并且来自相同或不同构建体)。表达可以通过在适当条件下培养含有所述核酸的重组宿主细胞来实现。在通过表达进行制造之后,可使用任何适合的技术分离和/或纯化抗体或抗原结合片段,随后在适当时使用。
用于在多种不同宿主细胞中克隆并表达多肽的系统是众所周知的。适合宿主细胞包括细菌、哺乳动物细胞、酵母及杆状病毒系统。所属领域中可用于表达异源多肽的哺乳动物细胞系包括中国仓鼠卵巢细胞、海拉细胞(HeLa cell)、幼仓鼠肾细胞、NSO小鼠黑素瘤细胞及许多其它细胞。常用的细菌宿主是大肠杆菌。
所选择或构建的适合载体可含有适当调控序列,包括可操作地连接的启动子序列、终止子序列、聚腺苷酸化序列、增强子序列、标记物基因和/或(适当时)其它序列。适当时,载体可为质粒、病毒,例如噬菌体或噬菌粒。有关进一步详情,参见例如,分子克隆实验指南:第2版,萨姆布鲁克等人,1989,冷泉港实验室出版社(Cold Spring HarborLaboratory Press)。许多已知的用于操作核酸,例如制备核酸构建体、诱变、测序、将DNA引入细胞中和基因表达,以及蛋白质分析的技术和方案详细描述于精编分子生物学实验指南(Short Protocols in Molecular Biology),第二版,奥苏贝尔等人编,约翰威立出版公司(John Wiley&Sons),1992中。萨姆布鲁克等人和奥苏贝尔等人的揭示内容以全文引用的方式并入本文中。
编码所关注多肽的核酸被整合到宿主细胞基因组中或可维持稳定或短暂游离体元件形式。
多种表达控制序列(即,控制可操作地连接到的DNA序列的表达的序列)中的任一种都可用于这些载体中以表达DNA序列。举例来说,编码所关注多肽的核酸可以可操作地连接到启动子,并且提供于表达构建体中以用于制造重组MMP9蛋白或其部分的方法中。
所属领域技术人员应了解,编码本文所揭示的抗体链的核酸可使用分子生物学中的标准知识和程序合成。
编码本文所揭示的重链和轻链氨基酸序列的核苷酸序列的实例如下:
由于抗体结构,包括可变区中的CDR和构架区的并置、构架区的结构以及重链和轻链恒定区的结构是所属领域中众所周知的;故获得编码抗MMP-9抗体的相关核酸正在所属领域的技能范围内。因此,还提供了包含与本文所揭示的核苷酸序列中的任一种具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%及至少99%同源性的核酸序列的多核苷酸。因此,还提供了包含与本文所揭示的核苷酸序列中的任一种具有至少75%、至少80%、至少85%、至少90%、至少95%、至少98%及至少99%一致性的核酸序列的多核苷酸。在一个实例中,所述多核苷酸与SEQ ID NO:21含有至少或约75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高序列一致性,或包括或为SEQ ID NO:21,和/或与SEQ ID NO:26含有至少或约75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或更高序列一致性,或包括或为SEQ ID NO:26。
医药组合物
提供的MMP9结合蛋白,以及编码MMP9结合蛋白的核酸(例如DNA或RNA)可为例如与医药学上可接受的载剂或赋形剂组合的医药组合物形式。所述医药组合物可用于例如在体内或离体投予个体,并且用于用MMP9结合蛋白诊断和/或治疗个体,例如用于本文所提供的治疗或诊断方法中的任一种中。
医药学上可接受的载剂或赋形剂为经投药的患者生理学上可接受的并且保持与其一起投予的抗体或肽的治疗特性。医药学上可接受的载剂或赋形剂及其调配物大体上描述于例如雷氏药学大全(Remington'pharmaceutical Sciences)(第18版,A.杰纳罗(A.Gennaro)编,默克出版公司(Mack Publishing Co.),宾夕法尼亚州伊斯顿(Easton,PA)1990)中。一种示例性医药载剂是生理盐水。在与所述调配物的其它成分可相容并且对患者实质上无害的意义上看,每种载剂或赋形剂为“医药学上可接受的”。
医药组合物可经调配以与特定投药途径(全身或局部)相容。因此,医药组合物包括适于通过各种途径投药的载剂、稀释剂或赋形剂。
医药组合物可包括医药学上可接受的添加剂。添加剂的实例包括(但不限于)糖,例如甘露糖醇、山梨糖醇、葡萄糖、木糖醇、海藻糖、山梨糖、蔗糖、半乳糖、葡聚糖、右旋糖、果糖、乳糖及其混合物。医药学上可接受的添加剂可与医药学上可接受的载剂和/或赋形剂(例如右旋糖)组合。添加剂还包括表面活性剂,例如聚山梨醇酯20或聚山梨醇酯80。
所述调配物和递送方法一般将根据有待治疗的部位和疾病来调整。示例性调配物包括(但不限于)适于肠胃外投药(例如静脉内、动脉内、肌肉内或皮下投药)或经口投药的调配物。
供肠胃外递送的医药组合物包括例如水、生理盐水、磷酸盐缓冲的生理盐水、汉克氏溶液(Hank's solution)、林格氏溶液(Ringer's solution)、右旋糖/生理盐水、及葡萄糖溶液。所述调配物可含有用于模拟生理条件的辅助物质,例如缓冲剂、张力调节剂、润湿剂、清洁剂等。添加剂还可包括其它活性成分,例如杀菌剂或稳定剂。举例来说,所述溶液可含有乙酸钠、乳酸钠、氯化钠、氯化钾、氯化钙、脱水山梨糖醇单月桂酸酯或三乙醇胺油酸酯。其它肠胃外调配物和方法描述于白(Bai)(1997)神经免疫学杂志(J.Neuroimmunol.)80:65 75;瓦伦(Warren)(1997)神经科学杂志(J.Neurol.Sci.)152:31 38;及托尼盖瓦(Tonegawa)(1997)实验医学杂志(J.Exp.Med.)186:507 515中。肠胃外制剂可封装于由玻璃或塑料制成的安瓿、一次性注射器或多剂量小瓶中。
供静脉内、真皮内或皮下投药的医药组合物可包括无菌稀释剂,例如水、生理盐水溶液、非挥发性油、聚乙二醇、甘油、丙二醇或其它合成溶剂;抗细菌剂,例如苯甲醇或对羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸、谷胱甘肽或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸;缓冲剂,例如乙酸盐、柠檬酸盐或磷酸盐;及用于调整张力的试剂,例如氯化钠或右旋糖。
供注射的医药组合物包括水溶液(在水溶性情况下)或分散液及在临用前制备无菌可注射溶液或分散液的无菌粉末。对于静脉内投药,适合载剂包括生理盐水、抑菌性水、Cremophor ELTM(巴斯夫公司(BASF),新泽西州帕西帕尼(Parsippany,N.J.))或磷酸盐缓冲的生理盐水(PBS)。载剂可为含有例如水、乙醇、多元醇(例如,甘油、丙二醇及液体聚乙二醇等)及其适合混合物的溶剂或分散介质。可例如利用包衣(例如卵磷脂),在分散液的情况通过保持所需粒度及利用表面活性剂来维持流动性。抗细菌剂和抗真菌剂包括例如对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸及硫柳汞。在所述组合物中可包括等渗剂,例如糖、多元醇(例如甘露糖醇、山梨糖醇)及氯化钠。所得溶液可经包装以按原样使用,或经冻干;冻干的制剂可以后在投药之前与无菌溶液组合。
医药学上可接受的载剂可含有使吸收或清除稳定、增加或延迟的化合物。所述化合物包括例如碳水化合物,例如葡萄糖、蔗糖或葡聚糖;低分子量蛋白质;降低肽清除率或水解的组合物;或赋形剂或其它稳定剂和/或缓冲剂。延迟吸收的试剂包括例如单硬脂酸铝和明胶。也可以使用清洁剂来使医药组合物的吸收稳定或者增加或减少,包括脂质体载剂。为了防止消化,可使所述化合物与组合物形成复合物,以使其对酸性和酶促水解具有抗性,或可使所述化合物与具有适当抗性的载剂(例如脂质体)形成复合物。保护化合物免于消化的手段是所属领域中已知的(参见例如,费克斯(Fix)(1996)药学研究(Pharm Res.)13:1760 1764;萨曼伦(Samanen)(1996)药学与药理学杂志(J.Pharm.Pharmacol.)48:119135;及美国专利第5,391,377号,其描述了供经口递送治疗剂的脂质组合物)。
本发明的组合物可与如本文所提供的其它治疗部分或成像/诊断部分组合。治疗部分和/或成像部分可作为单独组合物,或作为MMP9结合蛋白上存在的偶联的部分提供。
供体内投药的调配物一般为无菌的。在一个实施例中,所述医药组合物被调配成不含热原质,由此使其可接受用于投予人类患者。
依据本发明,各种其它医药组合物及其制备和使用技术将为所属领域技术人员所知。有关适合药理学组合物和相关投药技术的详细清单,可参考本文的详细教示,其可通过例如雷氏药物学与实践(Remington:The Science and Practice of Pharmacy)第20版(利平科特威廉姆斯威尔金斯出版公司(Lippincott,Williams&Wilkins)2003)等课本进一步补充。
医药组合物可基于需要治疗的患者/个体的身体特征、投药途径等进行调配。这些可包装于适合医药包装中,并附上适当标记供分配到医院和诊所,其中所述标记是用于指示治疗个体的如本文所述的病症。药物可按单一或多个单位形式包装。有关本发明的医药组合物的剂量和投药的说明书可包括在以下所述的医药包装和试剂盒中。
使用方法
本发明的MMP9结合蛋白,包括抗MMP9抗体及其片段可用于例如治疗和诊断方法中,例如检测样品中的MMP9的方法、治疗方法(例如,如在抑制血管生成的方法中)及诊断和预后方法。因此,提供了抗MMP9抗体的诊断和治疗方法及用途。使用方法的实例描述于下。
治疗方法
本文提供了治疗方法,包括治疗与MMP9表达和/或活性有关的疾病和病症(包括癌症以及炎症性疾病和自体免疫性疾病和相关病况)的方法,以及所提供的抗体和组合物在这些方法中的用途。所述疾病和病症包括(但不限于)癌症,例如肿瘤(例如原发性或转移性肿瘤),例如表达MMP9或安置于表达MMP9的组织中的那些,例如结肠直肠癌和其它癌症,例如胃腺癌、结肠直肠腺癌、肝细胞癌瘤,和其它肿瘤类型,以及炎症性和自体免疫性疾病和病况,例如IBD(包括UC、克罗恩氏病)、胶原性结肠炎、类风湿性关节炎,及与炎症和MMP9介导的组织破坏相关的其它病症。
在一些情形中,所述疾病或病况是晚期胰腺或食管胃腺癌、非小细胞肺癌、肺鳞状细胞癌瘤、肺腺癌、胃腺癌、结肠直肠癌瘤、胰脏腺癌、头颈鳞状细胞癌瘤或肝细胞癌瘤。
如实例中所证实,基质金属蛋白酶(MMP)并且特别是MMP9的表达与多种疾病的病理学(包括炎症性疾病和肿瘤学)相关。MMP9可通过其对基底膜和其它结构蛋白的破坏性重塑和/或通过增加例如TGFβ、VEGF、TNFα、IL-6及IL-1β等生长因子和细胞因子的血管渗透性和生物利用率来促进疾病。MMP9调控ECM隔离的VEGF和FGF-2,以及膜拴系的EGF的生物利用率。如实例中所述,使用如本文所述的抗体特异性抑制MMP9在公认的小鼠癌症和炎症性疾病模型(例如类风湿性关节炎、原发性和转移性结肠直肠癌,及溃疡性结肠炎(UC)模型)中有效。
如本文所使用,“治疗(treat/treatment)”意谓与本文所述疾病或病症有关的一或多种症状的停滞或发生延缓,或改善现有的不受控制或不想要的症状、预防其它症状,或改善或预防症状的潜在代谢原因。因此,所述术语表示已赋予患有疾病或症状,或有可能发生所述疾病或症状的哺乳动物个体有益结果。当患者经历疾病的病征或症状的部分或完全减轻,或减少时,实现反应,并且具体地包括(不限于)存活期延长。取决于预后因子,包括复发次数、疾病的阶段及其它因素,所测量的预期无进展存活时间可为数月到数年。
还提供了结合这些方法使用的医药组合物,例如含有本文所述抗体或其片段中的任一种的医药组合物。组合物可适于通过任何适合途径局部或全身投予。
一般来说,MMP9结合蛋白是以治疗有效量投予,例如以实现个体中肿瘤生长的抑制、抑制转移、抑制MMP9活性或治疗特定疾病或病况(例如癌症、炎症性疾病或病况,或自体免疫性疾病或病况)的量投予。
如本文所使用,除非另作具体说明,否则术语“治疗有效量”或“有效量”是指当投予(单独或与另一治疗剂组合,如可能具体说明的)个体时有效预防或改善疾病病况或疾病的进展,或使症状改善,例如使相关医学病况得到治疗、治愈、预防或改善,或使这些病况的治疗、治愈、预防或改善的几率增加的药剂或化合物或组合物的量。当应用于单独投予的个别活性成分时,治疗有效剂量仅指所述成分。当应用于组合时,治疗有效剂量是指引起治疗作用的多种活性成分的组合量,无论是依序还是同时组合投予。在一个实例中,当采用抗MMP9抗体的体内投予时,取决于投药途径,标准剂量可在每天每公斤哺乳动物体重约10ng到100mg或更高,优选地每天约1μg/kg到50mg/kg,任选地每天约100μg/kg到20mg/kg、每天500μg/kg到10mg/kg,或每天1mg/kg到10mg/kg间变化。
在一些实例中,所述抗体或其片段是例如以约1mg/kg到30mg/kg或约30mg/kg剂量静脉内投予。在一些实例中,所述抗体或片段是例如以约2mg/kg到约28mg/kg剂量静脉内投予。在一些实例中,所述抗体或片段是例如以约4mg/kg到约28mg/kg剂量静脉内投予。在其它实例中,所述抗体或片段是以约1mg/kg到14mg/kg或约14mg/kg,例如2mg/kg或约2mg/kg到14mg/kg或约14mg/kg剂量,每14天一次(q14d)静脉内投予。在一些实施例中,有效剂量是每7到28天一次投予。在一个实施例中,有效剂量是每7天一次投予。在另一个实施例中,有效剂量是每28天一次投予。
在一个实施例中,所述抗体或其片段是例如以约1mg/kg到30mg/kg或约30mg/kg剂量皮下投予。在其它实施例中,皮下剂量在1mg/kg或约1mg/kg到28mg/kg或约28mg/kg范围内,例如在2mg/kg或约2mg/kg到28mg/kg或约28mg/kg范围内,每14天一次。在其它实例中,所述抗体或片段是以约1mg/kg到14mg/kg或约14mg/kg,例如2mg/kg或约2mg/kg到14mg/kg或约14mg/kg剂量,每14天一次皮下投予。在一些实施例中,有效剂量是每7到28天一次投予。在一个实施例中,有效剂量是每7天一次投予。在另一个实施例中,有效剂量是每28天一次投予。
在一些实例中,抗体是例如以每公斤体重50、75、100、125、150、175、200、225、250、275、300、325、350、375、400、425、450、475、500、525、550、570、600、625、650、675、700、725、750、775、800、825、850、875、900、925、950、975或1000mg剂量静脉内投予。在其它实例中,抗体是例如以1100、1200、1300、1400、1500、1600、1700或1800mg/Kg剂量静脉内投予。在一些实例中,抗体是例如以每公斤体重100、200、400、600、1200或1800mg剂量,并且在一些实例中以133、267、400、600或1200mg/Kg剂量静脉内投予。在一些事例中,所述抗体是以一周、两周或三周的间隔,或每一周、两周或三周一次投予。在一些实例中,适当剂量是用0.9%氯化钠制备。
所选剂量方案将取决于多种因素,包括MMP9结合蛋白的活性、投药途径、投药时间、所用特定化合物的排泄速率、治疗持续时间、与所用特定组合物组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、病况、一般健康状况和前病史,及医疗技术中众所周知的类似因素。
在一些实施例中,剂量是基于展示目标介导的处置的抗体的药物动力学模型确定。相较于所观察的针对可溶性受体目标的抗体的相对呈线性的药物动力学,针对基于组织的目标受体的抗体常常展现非线性药物动力学。马格D.E.(Mager,D.E.)(2006),先进药物递送评述(Adv Drug Deliv Rev)58(12-13):1326-1356。非线性处置的基础涉及抗体与目标的高亲和力结合以及结合程度(相对于剂量),由此使相互作用以抗体的药物动力学特征反映。马格D.E.和W.J.乔斯科(W.J.Jusko)(2001),药物动力学与药效学杂志(JPharmacokinet Pharmacodyn)28(6):507-532。目标介导的药物处置内包括受体介导的抗体-受体复合物的内吞作用(内化作用)。王W.(Wang,W.),E.Q.王(E.Q.Wang)等人(2008),临床药理学与治疗学(Clin Pharmacol Ther)84(5):548-558。
在有关具有目标介导的处置作用的抗体的药物动力学模型中,在不存在药物(抗体)的情况下,目标受体是以恒定速率合成并且通过一级过程消除。因此,目标受体在不存在药物(抗体)的情况下是以稳态浓度存在。当将药物添加到体内时,其可与目标受体通过双分子反应相互作用,分配到灌注不太好的组织中,或经由一级过程消除。在较低药物浓度下,药物因高亲和力结合而主要移动到受体上。由于进入体内的药物量变得足以结合可用质量的受体,故药物分配到组织中和组织外并且被消除。当药物浓度降低并且组织中的药物达到平衡时,此提供另外的储集器以结合新合成的受体。
具有所属领域普通技术的临床医生能容易地确定所需医药组合物的有效量(ED50)并开具处方。举例来说,医师或兽医可以比获得所需治疗作用所需水平低的水平的以医药组合物形式使用的本发明化合物的剂量开始并逐步增加剂量直到达成所需作用。
在一些情形中,治疗方法包括肠胃外投药,例如静脉内、动脉内、真皮内、肌肉内或皮下投药;或经口投予药物,例如抗MMP9抗体或含有其的组合物。
如本文所使用,术语“个体”意谓哺乳动物个体。示例性个体包括(但不限于)人类、猴、狗、猫、小鼠、大鼠、母牛、马、山羊及绵羊。在一些实施例中,所述个体患有癌症、炎症性疾病或病况,或自体免疫性疾病或病况,并且可用如以下所述的本发明的药剂治疗。在某些实施例中,所述个体是患有癌症、炎症性疾病或病况,或自体免疫性疾病或病况的人类,并且可用如以下所述的本发明的药剂治疗。
必要时,为进行治疗,方法可进一步包括其它疗法,例如在癌症的情况下,除MMP9结合蛋白外,手术去除癌症和/或投予抗癌剂或治疗。此类抗癌剂或治疗的投予可与本文所揭示的组合物的投予同时或依序进行。
在一些实施例中,抗体是作为单药疗法单独投予的。在其它实施例中,所述抗体是作为与一或多种其它治疗剂的组合疗法的一部分投予的。所述治疗剂包括(但不限于)适于治疗炎症、自体免疫性疾病、纤维化疾病或癌症的药剂。治疗剂可为化学治疗剂、免疫治疗剂、抗癌剂、消炎剂或抗纤维化药剂。在组合疗法中,本申请案的抗体可作为一次或前线(front-line)药剂或者二次或另外的药剂用于治疗有需要的患者。在一些方面中,对于治疗炎症性疾病、纤维化疾病或自体免疫疾病,例如IBD、UC、克罗恩氏病、癌症或类风湿性关节炎,抗体是单独或与抑制或调节激酶(例如细胞凋亡信号调控激酶、脾酪氨酸激酶、磷脂酰肌醇3-激酶,或贾纳斯激酶(Janus kinase)或赖氨酰氧化酶、赖氨酰氧化酶样(LOXL)蛋白(例如LOXL2)和/或盘状结构域受体(DDR)(例如DDR1))活性的其它治疗剂一起投予。举例来说,抑制或调节LOXL2和DDR1活性的治疗剂是特异性结合到LOXL2和/或DDR1的抗体。在一个方面中,描述于US2009/0104201、US2009/0053224及US 2011-0200606中的抗LOXL2抗体及描述于美国临时申请案第61/705,044号中的抗DDR1抗体被用于组合疗法中;这些文献全部以引用的方式并入本文中。在其它方面中,对于治疗患有癌症的患者,抗体是单独或与一或多种化学治疗剂或抗赘瘤剂组合投予,所述化学治疗剂或抗赘瘤剂例如为吉西他滨(gemcitabine)、白蛋白结合型紫杉醇、mFOLFOX6(mFOLFOX6由亚叶酸、氟尿嘧啶(5-FU)及奥沙利铂(oxaliplatin)组成)、FOLFIRI(由亚叶酸、氟尿嘧啶(5-FU)及伊立替康(irinotecan)组成)、卡铂、紫杉醇、培美曲塞和/或贝伐单抗。在一个实例中,对于胰脏腺癌,抗体是以两周的时间间隔单独投予或与周期为28天的吉西他滨和/或白蛋白结合型紫杉醇化学疗法一起投予。在一个实例中,对于食管胃腺癌,抗体是以两周的时间间隔单独投予或与周期为28天的mFOLFOX6化学疗法(其以28天周期投予)一起投予。在一个实例中,对于非小细胞肺癌,抗体是以三周的时间间隔单独投予,或与周期为21天的卡铂和紫杉醇化学疗法,或与培美曲塞和/或贝伐单抗一起投予。在一个实例中,对于结肠直肠癌,抗体是以两周的时间间隔单独投予,或与周期为14天的FOLFIRI化学疗法一起投予。在所述组合治疗中,化学疗法可以已知剂量和程序投予。
在一些实施例中,抗体(例如AB0045)被用于治疗患有晚期胰脏腺癌或食管胃腺癌、非小细胞肺癌、溃疡性结肠炎、结肠直肠癌、克罗恩氏病或类风湿性关节炎的患者。在这些实施例的一些方面中,向患者以一周、两周或三周的时间间隔静脉内投予每公斤体重100、200、300、400、500、600、700、800、900、1000、1100、1200、1300、1400、1500、1600、1700或1800mg剂量的所述抗体。在一些方面中,适当剂量是用0.9%氯化钠制备。在一些方面中,患者接受作为单药疗法或作为与其它治疗剂的组合疗法的一部分的抗体(例如AB0045)。
在一些实施例中,对于治疗UC、癌症(例如结肠直肠癌、胰脏癌、胃癌)、克罗恩氏病、炎症性或纤维化疾病或病症,或类风湿性关节炎,抗体(例如AB0045)是单独或与其它免疫治疗剂,包括针对LOXL2(赖氨酰氧化酶样2)和/或DDR1(盘状结构域受体1)的抗体一起投予。
在一些实施例中,对于胰脏腺癌,抗体是以两周的时间间隔单独投予或与周期为28天的吉西他滨和/或白蛋白结合型紫杉醇化学疗法一起投予。
在一些实例中,对于食管胃腺癌,抗体是以两周的时间间隔单独投予或与周期为28天的mFOLFOX6化学疗法(其以28天周期投予)一起投予。
在一些实例中,对于非小细胞肺癌,抗体是以三周的时间间隔单独投予,或与周期为21天的卡铂和紫杉醇化学疗法,或与培美曲塞和/或贝伐单抗一起投予。
在一个实例中,对于结肠直肠癌,抗体是以两周的时间间隔单独投予,或与周期为14天的FOLFIRI化学疗法一起投予。在组合治疗的一些方面中,化学疗法或免疫疗法药剂是以已知剂量和程序投予。
在一些方面中,MMP9抗体的剂量可经调整并以每公斤体重133、267、400、600或1200mg投予。在每个治疗周期之后,监测患者的MMP9抗体、MMP9或其它适合生物标记物的水平。
组合疗法中的药剂可经由上述适合途径同时(在同一组合物中或分开地)或以任何次序依序投予。
在一些实施例中,治疗方法包括用于监测治疗,包括监测功效或活性(例如药效学活性)的步骤。在一些实例中,这些方法包括使用所述方法和组合物检测或测量从所治疗的个体获得的生物测试样品中标记物(例如细胞因子和指示治疗功效的其它炎性标记物)的存在、不存在、水平和/或表达。所述样品通常为血液样品或血清样品,还可包括如本文所述的其它生物样品。用于这些方法中的标记物有组织金属蛋白酶抑制剂1(TIMP-1)、肿瘤坏死因子α(TNF-α)、巨噬细胞炎性蛋白-2(MIP-2)、白细胞介素-17A(IL-17A)、CXCL10、淋巴细胞趋化蛋白、巨噬细胞炎性蛋白-1β(MIP-1β)、抑瘤素-M(OSM)、白细胞介素-6(IL-6)、单核细胞趋化蛋白3(MCP-3)、血管内皮生长因子A(VEGF-A)、单核细胞趋化蛋白-5(MCP-5)、白细胞介素-1α(IL-1α)、巨噬细胞集落刺激因子-1(M-CSF-1)、髓过氧化物酶(MPO)、生长调控α蛋白(KC/GRO)、白细胞介素-7(IL-7)、白血病抑制因子(LIF)、载脂蛋白A-I(Apo A-I)、C反应蛋白(CRP)、粒细胞趋化蛋白-2(GCP-2)、白细胞介素-11(IL-11)、单核细胞趋化蛋白1(MCP-1)、温韦伯氏因子(von Willebrand factor,vWF)及干细胞因子(SCF)基因产物。在一些实施例中,例如,当疾病为IBD(例如UC)时,标记物选自KC/GRO、LIF、CXCL10、MPO、MIP-2及MCP-5基因产物。
在一些实施例中,在每个治疗周期之后,监测患者的MMP9抗体、MMP9或其它适合生物标记物的水平。
所提供的方法是使安全性型态相较于可用治疗和治疗方案有所改善和/或在治疗所述疾病和病况时持续长期功效的方法。
炎症性和自体免疫性疾病和病况
在一些实施例中,所述方法和组合物(例如抗体和其片段)例如通过抑制患有炎症性疾病或自体免疫性疾病的个体中的MMP9而用于治疗所述疾病和病况。炎症性疾病和自体免疫性疾病为炎症性肠病(IBD)(包括克罗恩氏病、溃疡性结肠炎(UC)及未定型结肠炎)、胶原性结肠炎、类风湿性关节炎、败血病、多发性硬化、肌营养不良、狼疮、过敏症及哮喘。
如实例中所述,MMP9和其它MMP涉及于炎症性疾病和自体免疫性疾病中。
在RA患者的血清、滑液及滑膜中诱导基质金属蛋白酶-9(MMP9),并且MMP9/TIMP-1比率发生有利于蛋白水解活性增加的改变。MMP9是由疾病介导的破骨细胞以及单核细胞/巨噬细胞谱系的活化细胞分泌。在MMP9基因敲除小鼠品系中观察到对于抗体诱发的关节炎疾病表型的抗性。MMP9使由胶原酶(例如MMP8)的裂解活性所产生的松散的胶原蛋白II降解,并且由此引起关节软骨的破坏。
然而,鉴于其它MMP的重要作用,需要特异性MMP9抑制剂来治疗这些疾病。如本文的实例中所示,使用公认的动物模型证实,本发明的抗体在包括IBD、类风湿性关节炎(RA)及败血病在内的各种炎症性疾病和自体免疫性疾病中有效。因此,在一些实施例中,所述方法、组合物及用途治疗患有炎症性疾病和自体免疫性疾病的个体。在一些实施例中,所述抑制剂、方法和用途抑制MMP9,而不抑制其它MMP,例如不抑制MMP2,或不抑制此类其它MMP达到显著程度。在一个实施例中,所述方法防止或减少患有此类疾病或病况的个体的组织损伤、全身炎症和/或局部炎症;在一些实例中,组织损伤和炎症两者是通过所述方法治疗的。在另一实施例中,与用泛MMP抑制剂(例如马立马司他)所观察到的相比较,所述方法与毒性降低和/或肌肉骨骼综合症(MSS)或类似症状的诱发减少相关。在一些实例中,个体对针对炎症性疾病的另一种疗法(例如TNF拮抗剂,例如抗TNF抗体,例如英利昔单抗(infliximab))具有不当反应,即,患有TNF拮抗剂难治性疾病。因此,所提供的方法为有效治疗这些个体的炎症的方法。
炎症性肠病
炎症性肠病(IBD)包括克罗恩氏病、溃疡性结肠炎(UC)及未定型结肠炎。溃疡性结肠炎(UC)是两种主要IBD之一,以结肠的弥漫性粘膜炎症及相关溃疡为特征。UC的慢性过程包括间歇性疾病恶化继之以缓解期。许多患者经历对例如抗TNFα靶向性治疗剂等药剂的不足反应并且持续受到疾病相关性症状的影响。UC患者在疾病活动8-10年之后患结肠癌的风险显著升高。
炎症性肠病(IBD)治疗剂可通过防止炎性细胞募集及接近疾病部位,防止疾病部位处细胞的活化和/或抑制细胞活化的下游效应来调节疾病。
UC的药理治疗一般是基于疾病的严重程度和疾病的位置或范围‘分期(by line)’进行。基于患者的症状、内窥镜检查发现及实验室结果,疾病的严重程度是以轻度、中度或重度表征并且在临床试验环境中通常以梅奥评分(Mayo Score)定义,如表1B中所示。
表1B:UC梅奥评分
如实例中所述,有证据支持MMP9在溃疡性结肠炎(UC)及其它炎症性肠病(IBD)的病理学中的作用。广谱MMP抑制剂在TNBS和DSS结肠炎模型中有效(内藤(Naito)和吉川(Yoshikawa)2005;梅迪纳(Medina)和拉多米斯基(Radomski)2006)。尽管MMP9和MMP2是两种最密切相关的MMP,具有类似的底物特异性,但MMP9蛋白和活性在IBD和临床前结肠炎动物模型中被诱导达到较高程度,并且在人类UC中被较强地诱导并且与进行性疾病相关;MMP2较普遍地表达并且对于未患病组织的动态平衡很重要。MMP9的缺乏在小鼠硫酸葡聚糖钠(DSS)诱导的模型中防止结肠炎,而MMP2对于结肠具有保护作用。在DSS模型中,中性粒细胞和淋巴细胞积累是MMP9依赖性的;存在上皮细胞来源的MMP9引起组织损害的证据。
MMP9在人类UC组织而非健康结肠隐窝中检测到(其中胶原蛋白IV染色的不同环标记出完整基底膜),而且在具有混乱的胶原蛋白IV的区域中检测到,此指示基底膜完整性的丧失。MMP9降解胶原蛋白IV和其它ECM组分,从而允许炎性细胞浸润。在结肠炎中,粘膜中的MMP9活性可导致隐窝下伏的基底膜降解和粘膜损害,并使粘膜下层暴露于内腔细菌。MMP9使血管周围的基底膜降解可促进白细胞外渗至疾病部位。细胞外基质中MMP9的活性可活化并释放炎性细胞因子,例如TNFα、IL-6及IL1-B,从而引起疾病进展。
可用的UC疗法并不完全令人满意。举例来说,不同的治疗一般是基于疾病的严重程度、位置和/或范围给出。对于不太严重的疾病,治疗包括5'-氨基水杨酸(5'-ASA)灌肠剂、皮质类固醇灌肠剂及口服5'-ASA制剂。患有较严重疾病的患者,和/或无法对一线疗法起反应的患者一般是用一段时间的口服皮质类固醇治疗。免疫调节剂,例如硫唑嘌呤(azathioprine)和6-巯基嘌呤(6-MP),被用于帮助个体戒掉类固醇并且维持缓解。抗TNFα疗法,例如嵌合抗体(英利昔单抗)一般被用于患有较严重疾病的患者及皮质类固醇难治或有依赖性的患者。英利昔单抗治疗一般无法长期诱导并维持无类固醇缓解。仅20%的患者到第8周时实现缓解并且保持缓解直到54周,其中大多数患者在第30周时复发。仅26%的患者能够实现完全无皮质类固醇的长期缓解。当评价不太严格的反应终点来代替缓解(指示症状的不完全减少)时,约60%的患者无法维持这种程度的减轻达30或54周。
环孢霉素(Cyclosporine)已帮助住院治疗爆发性UC的患者延迟对手术的需要,但其作为维持疗法的功效尚未确定。手术是有疗效的,其由全结肠切除术与回肠贮袋肛管吻合术(IPAA)两个步骤组成。然而,全结肠切除术对于许多患者来说是不合需要的结果,使其终生经历频繁的肠移动,具有较高的性功能障碍的风险,并且有50%的发生结肠袋炎的风险,结肠袋炎是J袋炎症,其引起腹泻,伴随或不伴随直肠出血、下坠、急迫、疼痛、失禁及发烧。此外,在IPAA手术后,雌性不孕的风险明显增加。
如本文实例中所证实,本发明的特异性抗MMP9抗体被证实在公认的UC动物模型中有效,有效防止组织破坏和异常组织重塑,以及促炎性因子的局部和全身下调。这些抗体对于治疗小鼠中DSS诱发的结肠炎(一种充分确立的用于评价考虑用于治疗UC的药剂的临床前模型)的多个终点具有稳固功效。因此,在一些实施例中,使用了所述方法和组合物来治疗患有炎症性肠病,例如溃疡性结肠炎(UC)、克罗恩氏病或未定型结肠炎的个体。在一些实施例中,所述方法和抗体抑制MMP9,而不抑制其它MMP,例如MMP2。
在一些实例中,所述方法和组合物防止基底膜破坏、粘膜损害、粘膜下层暴露于内腔细菌、炎症、细胞因子活化及白细胞外渗。在一些实施例中,个体患有中度到重度UC,例如患有重度UC。在一些实施例中,个体患有类固醇依赖性UC。在一些方面中,治疗方法代替皮质类固醇治疗或作为皮质类固醇治疗的替代方案投予。
在一些实施例中,个体对例如TNF(例如TNF-α)拮抗剂,例如抗TNF抗体(例如英利昔单抗和/或阿达木单抗(adalimumab))等其它UC疗法无反应,即,TNF拮抗剂难治性患者。举例来说,在一些实施例中,个体是用英利昔单抗疗法或其它TNF-α靶向性治疗无法实现长期缓解的患者。在其它情形中,个体对另一UC疗法无反应,所述UC疗法例如为口服或直肠施用例如灌肠剂、栓剂及泡沫剂等治疗、5-氨基水杨酸(5-ASA)、口服和直肠施用皮质类固醇、免疫抑制剂(例如6-巯基嘌呤、硫唑嘌呤、甲氨蝶呤和/或环孢霉素)。在一些方面中,所述方法提供了使用相较于这些治疗安全性有所改善的方案的治疗,或提供了具有更持久、长期功效的治疗。
在一些情形中,所述方法抑制MMP9,而不影响其它MMP或特定的其它MMP,例如MMP2。
在一些实施例中,在UC的情形中,如果在梅奥评分降低至少3分和30%,其中直肠出血分项评分降低至少1分或绝对直肠出血分项评分为0-1分,那么实现了对治疗“反应”。在一些实施例中,“缓解”定义为梅奥评分≤2,其中无个别分项评分>1。在一些实施例中,“粘膜愈合”定义为内窥镜检查分项评分≤1。在一些实施例中,“类固醇节制”定义为在开始类固醇治疗的患者不继续使用类固醇的情况下的缓解。在一些实施例中,生活质量是一个终点并且是使用已知方法(例如,经过验证的生活质量测量法,例如IBD-QoL或SF-36)评估的。
克罗恩氏病(CD)是一种由复发和缓解阶段定义的胃肠道慢性炎症性病症,并伴随并发症的进展,例如瘘形成、脓肿或狭窄。在超过40%的患者中发生肠外表现,例如葡萄膜炎、关节炎、皮肤病变及肾结石。轻度到中度克罗恩氏病的治疗范例是抗生素(例如环丙沙星(ciprofloxacin)和灭滴灵(flagyl))、5-ASA、布地奈德(budesonide)或全身性皮质类固醇,不过,全身性类固醇的长期副作用极大地阻碍了其效用。用这些一线疗法失败的患有轻度到中度疾病的患者在一年时通常用硫唑嘌呤来保持改善。对于硫唑嘌呤失败的患者或患有较严重疾病的患者,用例如英利昔单抗等药剂阻断TNF-α成了最终的选择。与手术切除有疗效的UC相反,此种疗法由于两个原因而更难用于克罗恩氏病患者:1)疾病弥漫到整个GI道并且在孤立性疾病(例如回肠末端)的情况下,切除常常伴随切除部位处的疾病复发;2)由于所述疾病是透壁的,故手术切除为患者带来了将来发生狭窄和/或瘘的风险。
尽管使用硫唑嘌呤和英利昔单抗的组合疗法对于在第26周时诱导缓解和粘膜愈合方面可能优于任一单独疗法,但同时使用这些药剂增加了感染和恶性疾病(肝脾T细胞淋巴瘤)的风险,从而限制了其效用。与UC相同,反应、缓解、粘膜愈合、类固醇节制及生活质量都将是重要的终点,但在CD中,克罗恩氏病活动性指数(CDAI)一般是经过验证的结果选择手段,并且描述于表1C中:
表1C:克罗恩氏病活动性指数:
评分<150=缓解
中度疾病≥220
重度疾病≥450
对疗法有反应=可使用超过70分降低或者100分降低来确定反应。
在一些实施例中,个体患有中度到重度CD,例如患有重度CD。在一些实施例中,个体患有类固醇依赖性CD。在一些方面中,治疗方法代替皮质类固醇治疗或作为皮质类固醇治疗的替代方案投予。
在一些实施例中,个体对例如TNF拮抗剂,例如抗TNF抗体(例如英利昔单抗和/或阿达木单抗)等其它CD疗法无反应,即,TNF拮抗剂难治性患者。举例来说,在一些实施例中,个体是用英利昔单抗疗法或其它TNF-α靶向性治疗无法实现长期缓解的患者。在其它情形中,个体对另一CD疗法无反应。在一些方面中,所述方法提供了安全性方案相较于这些治疗有所改善的治疗,或提供了具有更持久、长期功效的治疗。
癌症
在一些实施例中,所述方法和组合物(例如抗体和其片段)被用于治疗癌症和肿瘤以及相关疾病和病况。示例性癌症包括结肠直肠癌、胃腺癌、结肠直肠腺癌及肝细胞癌瘤。TNF-α在恶性疾病的监视中起到重要作用,并因此用抗TNF-α药剂使肿瘤形成的风险增加。如本文在本申请案的实例中所证实,防止结肠直肠肿瘤发生进一步使抗MMP9单克隆抗体疗法与抗TNF-α疗法相区分。MMP9在细胞侵入、转移、血管生成及血管发生中起到作用。与在炎症性疾病中的观察结果类似,IHC分析显示,MMP9和MMP2在人类肿瘤组织(包括结肠直肠癌)中具有截然不同的染色模式,其中对于MMP-9观察到更一致的肿瘤相关性阳性。
MMP9的检测方法
本发明还涵盖检测个体中的MMP9,例如检测表达MMP9的肿瘤或肿瘤相关性组织,或者与如本文所述的疾病(例如自体免疫性疾病或炎症性疾病)相关的组织或流体或其它生物样品的方法。因此,提供了诊断、监测、分期或检测具有MMP9活性的肿瘤的方法。
可分析来自个体(例如,怀疑患有或已知患有与MMP9表达相关的肿瘤,或怀疑患有或已知患有另一疾病或病况,例如本文所述的炎症性疾病或自体免疫性疾病的个体)的样品(例如,测试生物样品)中MMP9的存在、不存在、表达和/或水平。举例来说,可收集这些样品,并通过检测MMP9结合蛋白(例如,如本文所述的抗体或片段)与样品中的物质(例如蛋白质)的结合的存在或不存在来进行分析。在一些实例中,所述方法另外包括将检测到的结合的量与结合到对照样品的量相比较,或将所检测的MMP9水平与对照MMP9水平相比较。在一些情形中,所述方法指示如本文所述的疾病或病况的存在、不存在或严重程度。
这一分析可在使用如本文所述的MMP9结合蛋白的治疗起始之前进行,或可作为监测癌症治疗的进展的一部分进行。在一些实施例中,提供了治疗方法,其是通过进行检测分析,并例如基于诊断分析的结果起始、改变或中断个体的治疗来进行。所述诊断分析可使用任何样品进行,包括(但不限于)组织、从所述组织分离的细胞等。在一些情形中,所述方法是对例如血液、血浆、血清、全血、唾液、尿液或精液等液体样品进行的。组织样品包括例如福尔马林固定或冷冻的组织切片。
用于检测和分析MMP9的任何适合方法均可使用。所属领域中已知的各种诊断分析技术可用于所述目的,例如竞争性结合分析、直接或间接夹心分析和在非均质或均质相中进行的免疫沉淀分析。
用于检测方法中的MMP9结合蛋白可用可检测部分标记。可检测部分直接或间接地产生可检测信号。举例来说,可检测部分可为本文所述部分中的任一种,例如放射性同位素,例如3H、14C、32P、35S或125I;荧光或化学发光化合物,例如荧光素异硫氰酸酯(FITC)、德克萨斯红(Texas red)、花青苷、光青素(photocyan)、罗丹明(rhodamine)或虫荧光素;或酶,例如碱性磷酸酶、β-半乳糖苷酶或辣根过氧化物酶。
检测可通过使样品在适于MMP9结合蛋白结合到MMP9的条件下接触,并评估MMP9结合蛋白-MMP9复合物的存在(例如水平)或不存在来实现。将样品中MMP9的水平与参考样品中的水平相比较可指示具有MMP9活性的肿瘤或肿瘤相关性组织的存在。参考样品可为在较早时间点从个体取得的样品或来自另一个体的样品。
在一些方面中,例如通过杂交,例如通过显色原位杂交(CISH)来检测MMP9mRNA。在一些方面中,当通过其它检测方法,例如通过IHC不能确定所需细胞类型(例如肿瘤上皮细胞)中高水平炎性细胞源性MMP9的信号时,使用这些检测方法。
本发明的各种方面将借助于以下若干实例进一步描述并说明,这些实例不打算限制本发明的范围。
实例
实例1.免疫原性
结果证实,AB0045和AB0041具有相当的结合和抑制特性,并且AB0046可例如在小鼠人类疾病模型中用作相关小鼠代用抗体。
对嵌合MMP9抗体AB0041和人类化MMP9抗体AB0045的潜在临床免疫原性进行评估。使用了离体人类T细胞活化分析EpiScreen(安提托普公司,英国剑桥(Cambridge,UK))。在EpiScreen分析中,T细胞活化已与患者体内的抗体/蛋白质治疗性反应相关。对代表多种HLA单体型的20位健康供体中的CD4+T细胞的反应进行检查。结果显示,AB0045抗体在任何供体中都不诱导反应并且AB0041在20%的供体中诱导反应,并且量值为2.29+/-0.36(平均值+/-标准偏差)。KLH的阳性对照在95%的供体中诱导反应,并且量值为6.34+/-2.77(平均值+/-标准偏差)。这些结果显示,AB0045抗体不可能具有免疫原性。
实例2:在患病和健康结肠样品中MMP9的表达
通过免疫组织化学(IHC)分析,使用MMP9特异性抗体检查来自溃疡性结肠炎(UC)人类患者和健康个体的活检样品。使用了针对髓过氧化物酶(MPO,一种中性粒细胞标记物;维兹(Wirtz)2007)、胶原蛋白IV(COLIV,基底膜)及CD31(内皮细胞)的抗体来评估疾病严重程度和组织基础结构。还对TIMP1和MMP2的染色模式进行检查。还评估了PMK2(一种巨噬细胞标记物)。
在健康样品中,仅在固有层和粘膜下区域内的一小组移行组织细胞、中性粒细胞及淋巴细胞中检测到MMP9免疫反应性。相比之下,在全部七份UC样品中,检测到更强烈的疾病相关性信号。在这些样品中,5份是由速冻方法制备并且2份是福尔马林固定并且石蜡包埋的。
在急性疾病区(包括脓肿和坏死的隐窝以及含有中性粒细胞浸润的隐窝炎区域)中检测到增加的MMP9信号。更分散的MMP9信号在固有层内的广泛炎症性浸润(大型组织细胞)中显而易见。MMP9蛋白位于组织细胞、中性粒细胞及粒细胞中,并且还在与患病隐窝和血管结构的基底膜相关的细胞外基质(ECM)中检测到。此外,在隐窝脓肿、溃疡区及内腔和隐窝上皮细胞中观察到MMP9免疫反应性。通常与MMP9共表达的TIMP1蛋白也与患病隐窝和炎性浸润相关,但程度低于MMP9。除少数淋巴细胞外,在UC样品中未检测到MMP2蛋白。
在急性疾病区域(包括脓肿和坏死的隐窝以及含有中性粒细胞浸润的隐窝炎区域)和疾病区域的上皮细胞中观察到强烈的MMP9表达。MMP9表达在固有层内的广泛炎性浸润中也显而易见并且主要位于组织细胞和中性粒细胞中。胶原蛋白IV染色的截然不同的环标出了健康隐窝的完整基底膜,而混乱的胶原蛋白IV指示患病隐窝中基底膜完整性的丧失;MMP9染色与基底膜破坏的区域共定位。TIMP1蛋白也与患病隐窝和炎性浸润相关,但程度比MMP9低。在克罗恩氏病样品中,MMP9信号也与患病区域相关。在肉芽瘤、间质组织细胞中检测到MMP9并且其与血管基底膜和ECM胶原蛋白IV共定位。此外,在淋巴细胞和内腔上皮细胞中检测到MMP。观察到某种MMP2反应性但不太显著。
在健康结肠隐窝中未检测到MMP9信号,但其在具有混乱的胶原蛋白IV的区域中较强,这指示了基底膜完整性的丧失。这指示了MMP9在溃疡性结肠炎的病理学中的作用。
在来自用(英利昔单抗,一种治疗性抗TNFα抗体)积极治疗的UC患者的结肠组织中评价MMP9的表达,证实了与所评估的其它UC患者结肠组织类似的染色模式。这一观察结果与本研究中抗TNF-α疗法无法防止UC中MMP9的诱导作用的结论一致。
IHC分析证实,人类化变体抗MMP9抗体AB0045结合到UC患者结肠组织中的MMP9,并且染色模式类似于用经过验证的IHC抗MMP9抗体观察到的染色模式。
实例3:正常组织中MMP9的表达
通过IHC分析人类、大鼠及食蟹猴的正常健康组织中MMP9蛋白的水平。从3位个体获得来自淋巴结、骨骼肌、前列腺、肾、肝、肺、胃、食道、心脏、结肠、小肠、脑、卵巢、胰腺、胎盘、皮肤、脊髓、脾、骨骼肌、睾丸、甲状腺及子宫细胞类型的二十二种人类速冻组织。用在IHC中表现良好的两种不同抗MMP9抗体进行IHC:兔单克隆抗体(艾比康公司(Abcam),目录号ab76003)和兔多克隆抗体(西格玛公司(Sigma),目录号HPA001238)。使用两种抗体检测到类似的染色模式。在人类胸腺、扁桃腺及骨髓中也检测到MMP9。对来自健康食蟹猴(cynomolgus monkey/Macaca fascicularis,1只个体动物)和大鼠(斯普拉-道来品系(Sprague-Dawley strain),2只个体动物)的一些速冻组织进行其它表征。
在心脏、骨骼肌、前列腺、肾、外周神经、小脑、大脑、唾液腺、输尿管及子宫颈中未检测到MMP9。在其余测试器官中,在例如巨噬细胞、组织细胞、淋巴细胞、肥大细胞及中性粒细胞等免疫细胞的细胞质染色中检测到MMP9。在所检查的所有人类、食蟹猴及大鼠组织中检测到类似的MMP9蛋白表达模式。在所分析的组织中,在食蟹猴淋巴结、胸腺及扁桃腺中检测到少量MMP9阳性炎性细胞。在所有物种中,MMP9染色都在细胞内而非分泌或位于细胞外基质中。
实例4:鼠类UC模型中的抗MMP9抗体
硫酸葡聚糖钠(DSS)诱发结肠炎模型是一种公认的用于评价炎症性肠病治疗的模型。在这一模型中,向小鼠或大鼠经口投予DSS引起结肠粘膜的损害。接受DSS的动物发生带血腹泻和体重减轻。在这一模型中观察到的炎症和组织降解局限于粘膜并且大体上影响整个结肠。DSS诱发的结肠炎以与在人类UC中所见到相同的炎症-发育不良-腺癌疾病进程为特征。在这一模型中所观察到的疾病定位和病理学被认为提示人类溃疡性结肠炎(UC),包括类似的炎性细胞浸润、溃疡和隐窝脓肿。在DSS模型中,被批准用于治疗UC的药物,例如类固醇、甲硝唑(metronidazole)、5-氨基水杨酸、环孢霉素及抗TNFα免疫疗法,已在降低疾病严重程度方面展现功效。
AB0046被用于DSS结肠炎模型(一种14天治疗的模型)中。根据以下实验设计,治疗在经口暴露于含3%DSS的饮用水5天之后开始:从第0天开始到第5天,用3%DSS诱发疾病,并且治疗在第6天开始(有关第1-5组中动物的治疗详情提供于下表2中);在第14天处死动物。在这一模型中,使用依他普特(Etanercept;以商品名销售)作为抗TNFα疗法的治疗作用的参考化合物。使用AC-1(一种同型相配(IgG1)的不相关抗体)作为对照物。
表2:第1-5组中动物的治疗详情
N=动物数量;ROA=投药途径;IP=腹膜内注射
通过视频内窥镜检查(第6、10及14天)、动物体重测量、粪便稠度观察及后续研究结肠组织病理学分析来评价疾病过程。
在来自DSS处理的结肠的速冻组织切片中进行免疫组织化学分析以评价在研究起始之后14天(DSS停止之后9天)的疾病程度并确定这一模型中MMP9的表达。结果显示于图5中。如所示,患病区域显示组织、结肠上皮边界和隐窝结构破坏,及炎性细胞浸润。在患病结肠的固有层中观察到针对MMP9的强染色,并且此与浸润性中性粒细胞(MPO IHC)和巨噬细胞相关。MMP9免疫反应性也与在隐窝和血管结构周围基底膜胶原蛋白IV染色的区域共定位,表明这种已知的ECM蛋白质底物的活性降解有助于疾病进展。MMP2的表达未受到强烈诱导。如图6中所示,还观察到DSS暴露动物的结肠上皮细胞中MMP9的表达。
使用小动物内窥镜以不知情方式进行下部结肠的视频内窥镜检查;基于组织中存在的溃疡程度、易脆性及血管分布,在1-4分量表上进行结肠炎目测评分。对每只小鼠赋予一个单一评分,其对应于在所检查的整个结肠长度内所观察到的最严重损害。结果显示于图7中。如所示,在研究终止(第14天)时,相较于媒剂和AC-1同型对照组,AB0046治疗的动物显示平均内窥镜检查评分的显著改善。治疗也引起内窥镜检查评分的显著改善,在第10天较明显并且在第14天时量值降低。
在研究终止时,从每只动物切除大部分远端结肠,用福尔马林固定,接着包埋于石蜡中,并切片用于组织学分析。用苏木精和伊红对载片染色并由对治疗组不知情的经过认证的兽医病理学家进行检查。根据有关每一参数的1-4分的评分量表,针对炎症、浮肿及粘膜坏死对组织进行评分。通过将三种个别参数评分的平均值(炎症、浮肿及坏死)相加来计算总病理学评分。结果显示于图8中。
如图8中所示,组织学评估确定,当与未治疗的对照动物相比较时,投予DSS诱导显著的炎性细胞浸润(主要由中性粒细胞构成,含有较低数量的巨噬细胞)、浮肿及粘膜组织坏死。粘膜坏死是有变化地存在并且以通常影响约25%的周围粘膜表面的部分或完全的表面上皮和隐窝损失为特征。相较于媒剂治疗,用AB0046或进行治疗性治疗使疾病病理学的全部三个方面都显著减少。抗MMP9抗体(AB0046)的功效当与媒剂相比较时是显著的并且类似于通过所实现的功效。
对来自经选择以反映平均组织病理学和内窥镜检查评分的每个研究组的三个结肠进行的免疫组织学分析披露,在抗MMP9抗体(AB0046)治疗之后,MMP9表达减少,此与在这些组织中疾病迹象减少相关(参见图9),指示了抑制MMP9不会引起补偿性诱导作用。一般来说,MMP9蛋白的存在与患病区域充分相关。MMP9减少也与治疗相关,不过仍检测到大量的MMP9蛋白。结果证实,MMP9减少与总体疾病减轻相关。
在研究过程中,每天记录下体重和腹泻发生率。体重变化的评价是通过用梯形规则法计算曲线下面积(AUC)来进行;类似的有关粪便稠度的AUC计算是通过赋予腹泻发生率100分和没有腹泻0分来进行。结果显示于图10中。如所示,当与AC-1同型对照或媒剂相比较时,抗MMP9抗体(AB0046)治疗引起对于体重减轻的显著保护作用。AB0046治疗也使腹泻发生率降低约30%,这类似于治疗的作用,不过任一疗法的所述作用都未达到统计学显著性。
在DSS模型中,投予参考化合物很少使内窥镜检查和组织学疾病减少超过50%,并且典型的反应在25-30%范围内。在这一情形中,考虑了利用AB0046的功效程度。在这一研究中,AB0046在减少组织学疾病达到统计学显著程度方面的功效,以及所评价的所有参数之间的相关性都是特别值得关注的。尽管(鉴于在起始给药之后有限的给药和组织储存作用的迹象)抗体给药方案可能未达到最佳治疗水平,但仍观察到功效。
与用内窥镜检查、组织病理学分析及体重终点所观察到的功效一致,对来自确定疾病的治疗模型的终末血清样品的多分析物酶连免疫吸附剂分析(ELISA)披露,抗MMP9(AB0046)治疗引起UC炎症性过程中许多已知介体和标记物的全身减少,这在DSS模型中上调。如图11A中所示,这些介体包括中性粒细胞趋化因子KC/GRO、单核细胞和活性T细胞趋化分子CXCL10(UC中的治疗目标)、中性粒细胞标记物MPO、IL-6类炎性细胞因子LIF、中性粒细胞趋化因子MIP-2及单核细胞趋化分子MCP-5(与人类MCP-1共有同源性的小鼠因子)。观察到AB0046使全身疾病相关性细胞因子减少的倾向。如图11B中所示,一些细胞因子接近或为定量或检测的下限水平,包括IL-17A(观察到AB0046治疗组平均减少的倾向)和TNF-α(信号太低而无法评估各组之间的差异)。用AB0046治疗还观察到IL-6的减少,但与AC-1同型对照(一种展现非特异性活性的抗体)无法区别。血清MMP-9水平未受到诱导(即,无DSS组与媒剂组之间无差异;对于MMP9血清水平测量,药物抗体的干扰无法排除)。除在抗MMP9抗体(AB0046)治疗的动物中观察到MCP-5水平降低外,用这一治疗也使疾病相关性MCP-1和MCP-3增加减少,与嗜酸性粒细胞亲合素(eotaxin)相同。
使用AB0047(由不相关的杂交瘤产生的抗MMP9抗体)进行了另一项小鼠DSS结肠炎治疗研究。如图12A中所示,结果证实,抗MMP9AB0047与具有类似的减少内窥镜检查疾病的倾向。另外,如图12B中所示,AB0047治疗引起与用AB0046研究类似的组织病理学发现的倾向。
实例5:鼠类DSS结肠炎模型中的抗MMP9抗体
对AB0046在预防环境中的功效进行评估并与参考药剂泼尼松龙(Prednisolone)相比较。治疗组显示于表3中。在第-1天以指定给药时程给与指定治疗。在第0天起始用3%DSS诱发疾病并如以上所述。在第14天处死动物。
表3:在预防性研究中第1-5组中动物的治疗详情
N=动物数量;ROA=投药途径;IP=腹膜内注射
如图13中所示,在第10天内窥镜检查评价时观察到AB0046预防性治疗功效。
如图14中所示,在研究终止时,预防性抗MMP9(AB0046)治疗使炎症、浮肿及坏死减少,并由此使病理学总分降低。如图15中所示,预防性投予AB0046减少腹泻的发生率。
实例6:原位直肠结肠癌模型中的抗MMP9抗体
在异种移植小鼠结肠直肠癌模型中,使用AB0046和AB0041的混合液进一步显示特异性MMP9抑制的有效性。将来源于人类结肠直肠癌细胞系(HCT-116;KRAS G13D突变体)的皮下肿瘤的片段手术植入裸小鼠的结肠中,并使其生长到100mm3,之后起始治疗。如图16中所示,在起始治疗之后第32天,所述抗体混合液使肿瘤体积变化减小并且使最终肿瘤重量减小(图16)。抗体混合液还使转移频率降低(数据未示出)。结果显示,使用抗体混合液抑制MMP9使原发肿瘤生长显著减少。
实例7:类风湿性关节炎模型中的抗MMP9抗体
抗MMP9抗体AB0041在佐剂和胶原蛋白诱发的关节炎(AIA、CIA)大鼠确定性疾病类风湿性关节炎模型中有效治疗炎症和关节损伤。结果示于图17A中。使用抗MMP9单克隆抗体AB0041治疗使关节炎临床评分降低到与在治疗模型(确定疾病的治疗)中用确定的疗法和甲氨蝶呤(MTX)所观察到的程度类似的程度。对于疾病的客观关节测量和组织病理学评估观察到类似的发现(炎症和关节破坏的多个参数的总评分,50mg/kg组)。如图17A中所示,每周两次(共计4剂)用50mg/kg、10mg/kg及2mg/kg剂量AB0041观察到关节炎临床评分降低。
如图17B中所示,在大鼠CIA中,在研究结束(EOS)时取得抗体滴度以确定暴露,并且还在治疗第10天时取得抗体滴度。在2mg/kg剂量水平下,在血清中不可检测到AB0046。
AB0041治疗也有效降低例如TNFα、IL-6及IL-17A等关键炎性细胞因子的血清水平,这些细胞因子在人类炎症性肠病中也为特征性疾病驱动剂。结果显示于图18A中。图19A示出了在这一研究中观察到的其它血清标记物。
在CIA小鼠类风湿性关节炎模型中,使用鼠类代用抗体AB0046观察到临床和组织病理学疾病的减少以及抗MMP9治疗的全身性消炎作用的类似结果。细胞因子结果显示于图18B中;图19B示出了在这一研究中所观察的其它血清标记物。
实例8:LPS诱发的败血病模型中的抗MMP9抗体
在另一全身性炎症性疾病模型中,抗MMP9抗体AB0041治疗在大鼠败血病模型(阿戈恩生物科技公司(Aragen Biosciences),加利福尼亚州吉尔罗伊(Gilroy,CA))中防止脂多糖(LPS)诱发的动物死亡,其中AB0041治疗的动物中有70%在四天之后存活,与在同型对照治疗组中20%存活形成对比。结果显示于图20中。
实例9:肌肉骨骼综合症(MSS)研究
在28天的研究中,相较于泛MMP抑制剂马立马司他,评价AB0041与在路易斯大鼠(Lewis rat)中的安全性。
经显示,临床上投予小分子泛MMP抑制剂(例如马立马司他)可引起肌肉骨骼综合症(MSS),这是一种以肩关节疼痛和僵硬、关节痛、手挛缩及患者生活质量下降为特征的病症。用泛MMP抑制剂治疗的大鼠也展现MSS(具有的症状包括在后足上休息的能力减弱、无法移动及高跨阈步态)并且被用作这一病症的模型系统。这些动物的关节展示与在人类疾病中所观察的组织病理学类似的滑膜增生和细胞结构增加。使用这一大鼠肌肉骨骼综合症(MSS)模型(描述于雷凯维兹R(Renkiewicz R)等人,“大鼠中广谱基质金属蛋白酶抑制剂马立马司他诱发的肌肉骨骼副作用(Broad spectrum matrix metalloproteinaseinhibitor marimastat-induced musculoskeletal side effects in rats.)”关节炎和风湿病(Arthritis Rheum)2003;48(6):1742-9),马立马司他治疗被用作MSS诱发的阳性对照。
每周两次,向每组六只大鼠静脉内投予50mg/kg的AB0041或媒剂-A(10mM磷酸钠(pH 6.5)、140mM氯化钠、0.01%吐温20(Tween20))。此外,通过手术植入皮下奥泽特泵(Alzet pump)(奥泽特公司(Alzet),加利福尼亚州库比蒂诺(Cupertino,CA),用马立马司他或媒剂-M(50%DMSO/50%水)治疗每组六只大鼠,所述奥泽特泵以每小时2.5μl的速率递送,持续28天时间。马立马司他的释放速率介于每天6.8到5.7mg/kg之间。
每天观察动物并针对MSS病征(例如不愿移动和避免使用后足)进行评分。使用以下系统来对休息姿势、步态及移动意愿评分:休息姿势评分为0分(正常)、1分(在一只足上休息)或2分(既不在一只足上也不在两只足上休息)。步态评为0分(正常)、1分(避免使用一只后足)或2分(避免使用两只后足)。在刺激后的移动意愿评为0分(正常移动)、1分(略有些不愿的移动)、2分(中等地不愿移动)或3分(非常不愿移动)。此外,每周两次记录下体重。
总评分是以每只动物的步态评分、休息姿势评分及移动意愿评分的总和计算。每组的平均总评分是以每天每组所有个别动物的总评分的平均值计算。
在投药前一天及投药后第1、7、10、14、17、21、24、28天,从所有大鼠收集血清。将血清以10,000x g离心10分钟并收集起来以在-20℃下储存。对血清进行多分析物血清蛋白分析(RodentMAPv2.0,IDEXX实验室(IDEXX Laboratories))。
采集大鼠的组织和肢体,并固定于10%中性缓冲福尔马林中以使用苏木精和伊红(H&E)进行组织病理学分析。
使用标准分级系统,相对于媒剂组比较微观变化:0分(无变化)、1分(极少变化)、2分(轻微变化)、3分(中等变化)及4分(重度变化)。
通过间接结合ELISA来测量大鼠血清中的AB0041水平。在4℃下用含2μg/mlAB0041的50mM硼酸钠涂覆ELISA板过夜。用含5%牛血清白蛋白(BSA)的磷酸盐缓冲生理盐水pH 7.4(PBS)阻断这些板并用含0.05%吐温20的PBS(PBST)洗涤。通过在PBST中连续稀释AB0041以产生在3,000ng/ml到1.5ng/ml范围内的连续稀释液来制备标准曲线。血清样品在PBST中以至少1:100进行稀释,接着添加到预先涂覆的ELISA板中。一小时培育之后,洗涤这些板并将多克隆山羊抗小鼠IgG-HRP检测抗体(赛默科技公司(Thermo Scientific),新泽西州法尔劳恩(Fair Lawn,NJ))以于0.5%BSA/PBS中的1:10,000稀释液添加到板中。洗涤这些板并通过添加3,3′,5,5′-四甲基联苯胺(TMB)(西格玛阿尔德里奇公司(SigmaAldrich),密苏里州圣路易斯(St.Louis,MO))保持2分钟来检测信号。通过添加1M盐酸(HCl)来停止反应并测量在450nm下的吸光度。在SoftMax软件包(分子装置公司(MolecularDevices))中使用四参数曲线拟合来反演计算血清中的AB0041水平。
结果
在任一治疗组中都未观察到体重减轻的迹象;所有动物在整个研究中持续体重增加。
每个组的平均每日MSS评分±标准偏差概述于图21中。在整个研究中,在AB0041治疗的大鼠中无MSS评分的迹象。在研究第12天,五只马立马司他治疗的大鼠显示略有跛行并且避免使用一只后足(步态评分=1)。在用AB0041、媒剂A或媒剂M治疗的任何动物中未检测到症状。在第13天,媒剂M组中的四只动物显示略有跛行(步态评分=1),这可能是由包埋的泵的重量引起。在第18天,马立马司他治疗的大鼠展现高于4.0的平均每日总评分,而媒剂M治疗的大鼠具有低评分。到第25天,马立马司他组的平均评分为5.8分,并且AB0041组的平均评分仍为零。从植入奥泽特泵后第14天起,马立马司他组与媒剂-M组之间的每天平均总评分存在统计学上显著差异(p<0.05),其中从第20天到第28天研究终止时,p值<0.0001。用AB0041治疗的大鼠和用媒剂-A治疗的大鼠在研究过程期间都未显示肌肉骨骼疾病的任何症状。
图22示出了如在第1、7、10、14、17、21、24及28天时在AB0041治疗的大鼠中通过ELISA测量的AB0041血清水平(血清滴度)。从第0天到第28天,平均稳态水平在2-4mg/ml范围内,指示在研究过程期间,大鼠暴露于抗体。
通过血清生化检查和组织病理学分析来评估AB0041治疗作用与媒剂-A治疗作用的比较。血清生化检查含有碱性磷酸酶、血清谷氨酸丙酮酸和草酰乙酸转胺酶、肌酸磷酸激酶、白蛋白、总蛋白质、球蛋白、总胆红素、血脲氮、肌酸酐、胆固醇、葡萄糖、钙、磷、碳酸氢盐、氯化物、钾及钠。在两个组中,血清生化检查的水平类似并且都在正常范围内并类似(数据未示出)。这指示AB0041治疗不会对正常动态平衡引起任何显著混乱。
此外,对来自AB0041和媒剂-A组的初级器官进行组织病理学分析。收集来自心脏、肺、肝、脾、肾、淋巴结、胃、肠、皮肤、肌肉及胸骨的组织并用H&E染色,并且用显微镜检查。在AB0041组或媒剂-A组中都未观察到治疗相关性异常(数据未示出)。
另外,评价来自AB0041治疗的大鼠和马立马司他治疗的大鼠的肢体的软组织变化以及骨骼和关节变化。在马立马司他组中观察到纤维化和滑膜炎,但在AB0041组中未观察到。在马立马司他治疗的大鼠中,纤维化在轻度到重度范围内并且常在踝和腕仲观察到。在马立马司他治疗的大鼠的大多数关节中还发现滑膜炎并且为轻度的,并以滑膜细胞增殖、滑液增加及炎性细胞浸润为特征。
对来自两组大鼠的后膝关节的H&E染色观察到类似结果。在AB0041治疗的大鼠中未观察到滑膜炎或纤维化,而在马立马司他治疗的大鼠中见到纤维组织形成的组织病理学证据。这一发现与AB0041治疗组大鼠的MSS临床症状缺乏一致。
因此,从起始治疗之后第12天开始,路易斯大鼠的治疗引起所有动物的肌肉骨骼疾病的多种症状,包括MSS的特征性病征,包括对步态、姿势及移动意愿的显著影响。相比之下,仅用AB0041或媒剂治疗路易斯大鼠不诱导MSS的任何临床、身体或组织学症状。在AB0041组或媒剂组中,以血清化学或组织学参数未检测到明显差异或异常。AB0041治疗组中MSS症状的缺乏不是由药物生物利用率不良引起,因为血清滴度分析显示,在整个研究持续期间保持较高的AB0041暴露量。与由马立马司他引起的泛MMP抑制作用相比,AB0041对MMP9的特异性抑制不诱发MSS。
实例10:原位异种移植模型中的抗MMP9抗体
如实例6中所述,在原位异种移植小鼠CRC模型中检查AB0041和AB0046的活性。异种移植模型的免疫组织化学分析显示,MMP9存在于基质炎性细胞和肿瘤上皮细胞中。
在研究I(植入后17天)、II(植入后14天)及III(植入后14天)中,在治疗之前,使肿瘤生长到约70mm3。在研究I中,用媒剂、对照IgG AC-1(AC-1)、AB0041(h)、或AB0041与AB0046的1:1混合物(m+h)治疗每组十五只小鼠。在AC-1、h及m+h组中,一周两次对小鼠腹膜内投予15mg/kg的每种抗体。在m+h组中,在治疗第一天,对小鼠预投予50mg/kg的AB0046。在媒剂组中,一周两次对小鼠腹膜内投予媒剂。
在研究II中,用媒剂、AC-1、AB0041(h)、AB0041与AB0046的1:1混合物(m+h)、5-氟尿嘧啶(5-FU)、或5-FU及AB0041与AB0046的1:1混合物的组合(5-FU+m+h)治疗每组十五只小鼠。在AC-1、h、m+h及5-FU+m+h组中,一周两次对小鼠腹膜内投予15mg/kg的每种抗体。在m+h和5-FU+m+h组中,在治疗第一天,对小鼠预投予50mg/kg的AB0046。在5-FU和5-FU+m+h组中,一周两次对小鼠腹膜内投予20mg/kg的5-FU。在媒剂组中,一周两次对小鼠腹膜内投予媒剂。
在研究III中,用媒剂或AB0041与AB0046的1:1混合物(m+h)治疗每组五只小鼠,其中体重比研究II中平均重20%。如研究II中所述,对小鼠投药。
在研究期间,测量AB0041和AB0046的滴度。一周一次,分别使用测径器和电子秤测量原发肿瘤大小和体重。通过测量触及的肿瘤的垂直次要尺寸(W)和主要尺寸(L)来获得基于测径器的大小估计值。通过公式(W2x L)/2来计算近似肿瘤体积(mm3)。使用非参数曼-惠特尼秩和测试来测定p值(*=0.05到0.01,**=0.01到0.001,***=<0.001)。对于RodentMAP分析,还使用了错误发现率(FDR)分析来测定q值;最大可接受的错误发现率设定为0.05。正规化肿瘤体积计算如下:将在每个测量时间点时个别小鼠的肿瘤体积针对其“第0天”肿瘤体积(在治疗起始时的肿瘤体积)正规化,并且接着对所述组中每只小鼠的这些正规化值求平均值以得到每个时间点的组平均正规化体积。
当观察到最大肿瘤负荷时结束研究,收集并检查原发结肠肿瘤和具有转移的任何器官。
用靶向人类MMP9与小鼠MMP9的抗体的1:1混合物治疗引起与实例6中类似的功效(图16和23)。在研究II中,m+h组的治疗功效与5-FU组中的功效相当(图23C、23D)。5-FU是一种起到抗代谢物作用并具有抗赘生活性的嘧啶类似物。
在研究I中,仅抑制hMMP9在限制肿瘤生长方面的作用类似于抑制MMP9的抑制作用(m+h)(图24)。表4和5概述了如研究I和II所测量的肿瘤体积和体重的曼-惠特尼p值。
表4:研究II数据的曼-惠特尼p值
*=0.05到0.01,**=0.01到0.001,***=<0.001
表5:研究I数据的曼-惠特尼p值
*=0.05到0.01,**=0.01到0.001,***=<0.001,-=>0.05
与对照组相比较,hMMP9和mMMP9的关节抑制使研究I中的转移发生率降低。仅抑制肿瘤来源的MMP9也不太有效。这一结果与基质MMP9在导致远端转移的侵袭过程中的较强作用(相对于肿瘤来源的MMP9)一致。
在研究III中,两个组的正规化肿瘤体积之间的差异是显著的(图23E和23F)。在植入后36天或在治疗后21天,媒剂组相对于m+h组的p值为0.0362。
在研究I中,来自媒剂治疗的小鼠的肿瘤的免疫组织化学(IHC)分析证实肿瘤细胞产生的MMP9水平低于基质来源(例如定居巨噬细胞、成纤维细胞及内皮细胞)的MMP9。异种移植模型肿瘤中MMP9的表达模式类似于人类CRC中的表达模式;MMP9的肿瘤细胞表达是不均匀的,并且表达水平在给定的肿块区域内可变化极大。
在研究I中,肿瘤切片的H&E染色和坏死组织百分比的目测评估未披露对照动物相对于抗MMP9治疗的动物中坏死程度的任何显著差异。如果通过最终重量将肿瘤划分成单独组并且接着进行分析,那么对于最终重量小于或等于0.4g的肿瘤,在抗MMP9治疗组中存在坏死增加的微小倾向(相对于对照组)(所有对照肿瘤为约11%并且所有MMP9抗体治疗的肿瘤为约7%),但所述差异不具有统计学显著性(p=0.146;曼-惠特尼分析)。
如实例6中所述,对研究再进行血清分析。通过RodentMAP评估一组58种分析物中的血清蛋白质。通过曼-惠特尼测试评估显著性,随后通过错误发现率分析提供q值。如图25中所示,当与媒剂组相比较时,C反应蛋白(一种炎症标记物)、CXCL2/MIP-2(一种中性粒细胞吸引剂和活化剂)、VEGF-A及CCL7/MCP-3(一种使大多数白细胞类型活化并且刺激单核细胞释放MMP9的趋化因子)、T淋巴细胞及NK细胞在抗MMP9(m+h)组中显著减少。
在研究I和II结束时收集的血清中测量AB0041(抗hMMP9抗体)和AB0046(抗mMMP9抗体)滴度。平均起来,AB0041和AB0046的终末血清浓度在100到300μg/mL范围内(数据未示出)。
这些研究的结果证实,在小鼠异种移植模型中用人类特异性和小鼠特异性单克隆抗体的混合液靶向MMP9使四个独立研究中的原发肿瘤的生长减少,并且也使转移的发生率降低。
仅用抗人类MMP9抗体治疗得到与用抗人类MMP9抗体和抗小鼠MMP9抗体治疗类似的肿瘤生长减少。这表明,在这一异种移植模型中,肿瘤来源的人类MMP9(而非基质来源的小鼠MMP9)是肿瘤细胞增殖的比较占优势的驱动剂。用抗人类MMP9和抗小鼠MMP9的混合液治疗的小鼠中小鼠血清蛋白水平的变化(如与媒剂处理的小鼠相比较)证实,如与媒剂治疗的小鼠相比较,血管生成因子VEGF以及炎性因子C反应蛋白CXCL2和CCL7在抗MMP9治疗的小鼠中显著减少,与MMP9在炎症和血管生成中的作用一致。又,肿瘤上皮来源的MMP9涉及到原发肿瘤的长出并且靶向基质MMP9增加针对转移发生率的功效。
实例11:使用抗MMP9抗体的治疗性治疗
AB0045被用于治疗患有晚期胰脏腺癌或食管胃腺癌、非小细胞肺癌、溃疡性结肠炎、克罗恩氏病或类风湿性关节炎的患者。以一周、两周或三周的时间间隔,对这些患者静脉内投予每公斤体重100、200、400、600、1200或1800mg剂量的抗体。适当剂量是用0.9%氯化钠制备。患者接受作为单药疗法或作为与其它治疗剂的组合疗法的一部分的AB0045。
对于治疗UC、克罗恩氏病或类风湿性关节炎,将AB0045单独或与包括针对LOXL2(赖氨酰基氧化酶样2)和/或DDR1(盘状结构域受体1)的抗体在内其它免疫治疗剂一起投予。
对于胰脏腺癌,抗体是以两周的时间间隔单独投予或与周期为28天的吉西他滨和/或白蛋白结合型紫杉醇化学疗法一起投予。
对于食管胃腺癌,抗体是以两周的时间间隔单独投予或与周期为28天的mFOLFOX6化学疗法(其以28天周期投予)一起投予。
对于非小细胞肺癌,抗体是以三周的时间间隔单独投予,或与周期为21天的卡铂和紫杉醇化学疗法,或与培美曲塞和/或贝伐单抗一起投予。
在这些组合治疗中,化学疗法是以已知剂量和程序投予。
MMP9抗体的剂量可经调整并以每公斤体重133、267、400、600或1200mg投予。在每个治疗周期之后,监测患者的MMP9抗体、MMP9或其它适合生物标记物的水平。
实例12:类风湿性关节炎模型中的抗MMP9抗体
实例7显示了AB0041在治疗大鼠和小鼠类风湿性关节炎方面的功效。本实例提供了对实例7中动物的另外表征,所述动物是用媒剂;2、10或50mg/Kg的AB0041(在大鼠模型中)或AB0046(在小鼠模型中);10mg/Kg的Enbrel;或0.5mg/Kg的甲氨蝶呤(MTX)治疗。
除表6中所示的在实例7中进行的临床评分外,还测量所治疗动物的爪肿胀、踝直径及体重。这些测量在随机分组之前一周一次进行并且在随机分组之后一周三次进行。如图26(大鼠)和29(小鼠)中所示,在大鼠中投予AB0041和在小鼠中投予AB0046在所有剂量下引起临床疾病的定性和定量测量值的显著逆转/缓和。结果还显示,用AB0041或AB0046治疗在50mg/kg下使软组织疾病、关节损害及破坏的所有测量值减小。抗MMP9抗体的功效与用Enbrel和甲氨蝶呤(MTX)所观察到的功效相当。
表6:有关爪临床评分的量表和标准
量表a | 临床病征 |
0.0 | 无红斑或肿胀的迹象 |
0.5 | 局限于一小块区域的少量红斑或肿胀 |
1.0 | 踝或腕的少量红斑或肿胀 |
1.5 | 局限于踝或腕的中度红斑和轻度肿胀 |
2.0 | 局限于一半爪的中度红斑和轻度肿胀 |
2.5 | 扩展到超过一半爪的中度红斑和轻度肿胀 |
3.0 | 扩展到超过一半爪的中度红斑和中度肿胀 |
3.5 | 扩展到超过3/4的爪的重度红斑和肿胀 |
4.0 | 发生于整个爪的重度红斑和肿胀 |
a每个爪接受其自身的评分并且对于理论最大值16,合计每只动物的这些值
此外,用显微镜检查后肢的软组织变化(浮肿、组织/血管坏死、炎性细胞浸润及纤维组织形成)以及软骨和骨骼变化(软骨侵蚀、骨骼侵蚀、骨膜骨骼形成、滑膜炎、关节翳形成及关节破坏)。使用以下标准严重程度评分:0=无显著变化;1=极少;2=轻度;3=中度;以及4=重度。严重程度评分是基于每个肢体的总体变化。
进行免疫组织化学(IHC)分析以评估MMP9、TNF-α、CD68及组织蛋白酶K的水平。在范围为0-4分的定性量表上进行抗TNF-α染色和抗CD68的评分,其中0分是未患病关节的水平,并且4分是在媒剂治疗的肢体中观察到的最高表达。对于抗TNF-α评分,对肢体在跖跗关节前面的整个区域进行评分。使用每个肢体3-4张由距骨形成的关节中的滑膜的图像来评价抗CD68染色,其中每个膜的评分求平均值并且将所述值指定为总体炎症评分。从IHC得到的结果显示了在包括软骨损害和骨骼侵蚀前面的活动性患病区的区域中以及在关节翳组织中MMP9的表达。另外,表达MMP9的细胞被鉴别为破骨细胞和单核细胞/巨噬细胞谱系的细胞。
在用50mg/kg AB0041治疗的大鼠中,对CD68和TNF-α进行定量。由IHC得到的结果披露,与媒剂治疗组相比较,在这一组中CD68和TNF-α显著减少(图27)。这些结果指示了骨骼和软骨降解细胞类型(破骨细胞和单核细胞/巨噬细胞谱系细胞)以及炎症和关节炎的全身介体(TNF-α)的减少。
此外,使用ELISA对终末血清样品的血清盘分析进行表征。概述于图18A和28(大鼠)以及18B和19B(小鼠)中的结果显示了炎症介体和疾病进展的一致减少。如图28中所示,在大鼠中AB0041治疗引起内源MMP9抑制剂组织金属蛋白酶抑制剂(TIMP)-1、白细胞有丝分裂因子粒细胞-巨噬细胞集落刺激因子(GM-CSF)、中性粒细胞吸引剂和活化剂巨噬细胞炎性蛋白(MIP)-2、自然杀手细胞和单核细胞趋化因子MIP-1β、造血干细胞分化剂巨噬细胞集落刺激因子(M-CSF)-1、IL-6家族细胞因子抑瘤素M(OSM)、趋化剂C-X-C基元趋化因子(CXCL)10和单核细胞趋化蛋白(MCP)-5、自然杀手细胞和T细胞活化蛋白IL-12p70,及免疫系统调节剂干扰素(INF)-γ、IL-12和IL-7的统计学显著减少。在Enbrel治疗的大鼠中未观察到血清标记物的减少,而甲氨蝶呤治疗引起这些标记物的一致性增加。如图19B中所示,在小鼠中AB0046治疗引起中性粒细胞吸引剂和/或活化剂KC/GRO、MIP-2及GCP-2;NK和T细胞吸引剂淋巴细胞趋化蛋白;单核细胞趋化剂MCP-1和MCP-3;淋巴细胞和树突状细胞趋化剂CXCL-10;IL-6样细胞因子OSM;粒细胞活化剂MIP-1β和MIP-1γ;及载脂蛋白(Apo)A-1的统计学显著减少。在终末血清样品中测量AB0046滴度。此外,10mg/kg和50mg/kg的给药方案引起可测量的药物水平。
这些数据显示,在大鼠CIA治疗模型中用抑制性抗MMP9单克隆抗体治疗引起临床观察结果和关节炎症客观测量值的缓和及逆转、关节炎症和破坏的组织病理学表现的减少,及疾病介导的细胞类型和因子的减少。治疗作用与参考化合物Enbrel和甲氨蝶呤相当。用抗MMP9治疗观察到广泛的全身消炎作用,但投予Enbrel或甲氨蝶呤则未观察到。
实例13:人类肿瘤中MMP9的表达
通过免疫组织化学(IHC)并通过显色原位杂交来检查MMP9和MMP2的蛋白质和mRNA水平。对来自人类肺鳞状细胞癌瘤、肺腺癌、胃腺癌、结肠直肠腺癌、胰脏腺癌、肝细胞癌瘤及头颈鳞状细胞癌瘤的组织进行表征。
在IHC分析中,使用以下两种截然不同的MMP9特异性抗体对样品进行染色:多克隆抗体西格玛HPA001238和单克隆抗体艾比康(ab76003)。通过目测评估对给定肿瘤样品的MMP9阳性肿瘤上皮细胞百分比进行评分。通过在免疫印迹中针对一组MMP进行测试来评价用于IHC分析的抗MMP9抗体的特异性。抗体未针对除MMP9外的任何所测试的MMP展示任何值得关注的交叉反应性。
在所调查的所有肿瘤中,在数小组组织细胞(组织定居巨噬细胞)、中性粒细胞、内皮细胞及成纤维细胞中,以及在非赘生性上皮细胞和肿瘤上皮细胞中见到MMP9的免疫反应性。还在细胞外基质中发现分泌的MMP9蛋白,并且其一般与肿瘤内的炎性浸润相关。在所有癌症样品中,MMP9表达的检测通常与坏死区域相关。
在分散在整个肿瘤中的数小组组织细胞中检测到MMP2信号,并且其存在于肿瘤微环境的反应性平滑肌、内皮细胞、小动脉的平滑肌及非赘生性上皮细胞中。大多数肿瘤上皮细胞对MMP2呈阳性,但弥漫性染色模式多于关于MMP9所观察的。与MMP9更不均匀的表达相比较,MMP2表达在整个组织(赘生性和非赘生性)中更广泛分布。
图30概述了在本研究中所观察到的MMP9阳性肿瘤上皮细胞的百分比。基质MMP9阳性也存在于所有样品中,但并未评分。图30的x轴上显示了归于“阳性”类别的指定肿瘤类型的样品的百分比。分析显示在所有肿瘤类型中表达以及关于MMP9阳性的程度和来源的每种癌症类型的图案特征。
CISH分析通过数小组免疫细胞(特别是巨噬细胞和中性粒细胞)以及例如内皮细胞等其它基质成分检测到肿瘤上皮细胞中的MMP9mRNA。CISH分析的结果显示,MMP9mRNA存在于巨噬细胞/组织细胞、中性粒细胞及肿瘤上皮细胞中。另外,MMP9mRNA表达在肿瘤类型内和肿瘤类型间不同。在所分析的所有肿瘤中,表达MMP9mRNA的细胞类型包括数小组的组织细胞、中性粒细胞及肿瘤细胞。类似于在IHC分析中的不均匀性,MMP9mRNA表达水平不同。
图31概述了肿瘤上皮细胞相关性MMP9mRNA的CISH分析。x轴上显示了归于每个“阳性”类别的指定肿瘤类型的组织样品的百分比。分析披露在所有肿瘤类型中表达以及关于MMP9阳性的程度和来源的每种癌症类型的图案特征。
由CISH和IHC分析得到的结果显示在肿瘤上皮细胞中MMP9的表达。在一些样品中,CISH检测到MMP9mRNA,其中未检测到蛋白质信号。由于肿瘤来源的MMP9的丰度常常不如炎性细胞来源的MMP9,故CISH分析适于检测具有高水平炎性细胞来源的MMP9的样品中MMP9的表达,其使肿瘤上皮细胞来源的MMP9的IHC信号不明显。
序列表修正本
<110> 吉联亚生物科技有限公司
乔安妮•亚当肯维克兹
维多莉亚•史密斯
宗•蔡
迈克尔•J•霍金斯
<120> 抗基质金属蛋白酶9抗体
<130> 246102008440
<140> Not Yet Assigned
<141> Concurrently Herewith
<150> US 61/755,444
<151> 2013-01-22
<150> US 61/605,181
<151> 2012-02-29
<150> PCT/US2012/027160
<151> 2012-02-29
<160> 50
<170> FastSEQ for Windows Version 4.0
<210> 1
<211> 470
<212> PRT
<213> 小家鼠
<220>
<221> CHAIN
<222> (1)...(470)
<223> AB0041重链
<220>
<221> PEPTIDE
<222> (1)...(19)
<223> 信号肽
<220>
<221> misc_feature
<222> (135)...(470)
<223> IgG2b恒定区
<400> 1
Met Ala Val Leu Val Leu Phe Leu Cys Leu Val Ala Phe Pro Ser Cys
1 5 10 15
Val Leu Ser Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala
20 25 30
Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu
35 40 45
Leu Ser Tyr Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu
50 55 60
Glu Trp Leu Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser
65 70 75 80
Ala Leu Met Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gln
85 90 95
Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr
100 105 110
Tyr Cys Ala Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr
115 120 125
Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro
130 135 140
Leu Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly
145 150 155 160
Cys Leu Val Lys Gly Tyr Phe Pro Glu Ser Val Thr Val Thr Trp Asn
165 170 175
Ser Gly Ser Leu Ser Ser Ser Val His Thr Phe Pro Ala Leu Leu Gln
180 185 190
Ser Gly Leu Tyr Thr Met Ser Ser Ser Val Thr Val Pro Ser Ser Thr
195 200 205
Trp Pro Ser Gln Thr Val Thr Cys Ser Val Ala His Pro Ala Ser Ser
210 215 220
Thr Thr Val Asp Lys Lys Leu Glu Pro Ser Gly Pro Ile Ser Thr Ile
225 230 235 240
Asn Pro Cys Pro Pro Cys Lys Glu Cys His Lys Cys Pro Ala Pro Asn
245 250 255
Leu Glu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Ile Lys Asp
260 265 270
Val Leu Met Ile Ser Leu Thr Pro Lys Val Thr Cys Val Val Val Asp
275 280 285
Val Ser Glu Asp Asp Pro Asp Val Arg Ile Ser Trp Phe Val Asn Asn
290 295 300
Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn
305 310 315 320
Ser Thr Ile Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp
325 330 335
Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro
340 345 350
Ser Pro Ile Glu Arg Thr Ile Ser Lys Ile Lys Gly Leu Val Arg Ala
355 360 365
Pro Gln Val Tyr Ile Leu Pro Pro Pro Ala Glu Gln Leu Ser Arg Lys
370 375 380
Asp Val Ser Leu Thr Cys Leu Val Val Gly Phe Asn Pro Gly Asp Ile
385 390 395 400
Ser Val Glu Trp Thr Ser Asn Gly His Thr Glu Glu Asn Tyr Lys Asp
405 410 415
Thr Ala Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Ile Tyr Ser Lys
420 425 430
Leu Asp Ile Lys Thr Ser Lys Trp Glu Lys Thr Asp Ser Phe Ser Cys
435 440 445
Asn Val Arg His Glu Gly Leu Lys Asn Tyr Tyr Leu Lys Lys Thr Ile
450 455 460
Ser Arg Ser Pro Gly Lys
465 470
<210> 2
<211> 234
<212> PRT
<213> 小家鼠
<220>
<221> CHAIN
<222> (1)...(234)
<223> AB0041轻链
<220>
<221> PEPTIDE
<222> (1)...(20)
<223> 信号肽
<220>
<221> misc_feature
<222> (128)...(234)
<223> κ恒定区
<400> 2
Met Glu Ser Gln Ile Gln Val Phe Val Phe Val Phe Leu Trp Leu Ser
1 5 10 15
Gly Val Asp Gly Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser
20 25 30
Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp
35 40 45
Val Arg Asn Thr Val Ala Trp Tyr Gln Gln Lys Thr Gly Gln Ser Pro
50 55 60
Lys Leu Leu Ile Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val Pro Asp
65 70 75 80
Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser
85 90 95
Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln His Tyr
100 105 110
Ile Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
130 135 140
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
145 150 155 160
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
165 170 175
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
195 200 205
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
210 215 220
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 3
<211> 115
<212> PRT
<213> 小家鼠
<220>
<221> CHAIN
<222> (1)...(115)
<223> AB0041的IgG2b重链的可变区
<220>
<221> misc_feature
<222> (26)...(35)
<223> 互补决定区(CDR)
<220>
<221> misc_feature
<222> (50)...(65)
<223> 互补决定区(CDR)
<220>
<221> misc_feature
<222> (98)...(104)
<223> 互补决定区(CDR)
<400> 3
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Leu Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser
115
<210> 4
<211> 107
<212> PRT
<213> 小家鼠
<220>
<221> CHAIN
<222> (1)...(107)
<223> AB0041的κ轻链的可变区
<220>
<221> misc_feature
<222> (24)...(34)
<223> 互补决定区(CDR)
<220>
<221> misc_feature
<222> (50)...(56)
<223> 互补决定区(CDR)
<220>
<221> misc_feature
<222> (89)...(97)
<223> 互补决定区(CDR)
<400> 4
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Asn Thr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Thr Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln His Tyr Ile Thr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 5
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> VARIANT
<222> (1)...(115)
<223> VH1重链变体
<400> 5
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Leu Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Asp Ser Lys Ser Thr Val Tyr Leu
65 70 75 80
Lys Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser
115
<210> 6
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> VARIANT
<222> (1)...(115)
<223> VH2重链变体
<400> 6
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Leu Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Asp Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Lys Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 7
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> VARIANT
<222> (1)...(115)
<223> VH3重链变体
<400> 7
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Leu Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Phe Thr Ile Ser Lys Asp Asp Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Lys Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 8
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> VARIANT
<222> (1)...(115)
<223> VH4重链变体
<400> 8
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Leu Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Phe Thr Ile Ser Lys Asp Asp Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Lys Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 9
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> VARIANT
<222> (1)...(107)
<223> Vk1轻链变体
<400> 9
Asp Ile Val Met Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Asn Thr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Thr Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Phe Cys Gln Gln His Tyr Ile Thr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 10
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> VARIANT
<222> (1)...(107)
<223> Vk2轻链变体
<400> 10
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 Lys Ala Ser Gln Asp Val Arg Asn Thr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Phe Cys Gln Gln His Tyr Ile Thr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 11
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> VARIANT
<222> (1)...(107)
<223> Vk3轻链变体
<400> 11
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Asn Thr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Phe Cys Gln Gln His Tyr Ile Thr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 12
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> VARIANT
<222> (1)...(107)
<223> Vk4轻链变体
<400> 12
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Asn Thr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ser Ser Tyr Arg Asn Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln His Tyr Ile Thr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 13
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (1)...(10)
<223> 抗MMP9抗体重链的互补决定区(CDR1)
<400> 13
Gly Phe Ser Leu Leu Ser Tyr Gly Val His
1 5 10
<210> 14
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (1)...(16)
<223> 抗MMP9抗体重链的互补决定区(CDR2)
<400> 14
Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser Ala Leu Met Ser
1 5 10 15
<210> 15
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (1)...(7)
<223> 抗MMP9抗体重链的互补决定区(CDR3)
<400> 15
Tyr Tyr Tyr Gly Met Asp Tyr
1 5
<210> 16
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (1)...(11)
<223> 抗MMP9抗体轻链的互补决定区(CDR1)
<400> 16
Lys Ala Ser Gln Asp Val Arg Asn Thr Val Ala
1 5 10
<210> 17
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (1)...(7)
<223> 抗MMP9抗体轻链的互补决定区(CDR2)
<400> 17
Ser Ser Ser Tyr Arg Asn Thr
1 5
<210> 18
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (1)...(9)
<223> 抗MMP9抗体轻链的互补决定区(CDR3)
<400> 18
Gln Gln His Tyr Ile Thr Pro Tyr Thr
1 5
<210> 19
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (1)...(345)
<223> 编码VH1重链氨基酸序列的核苷酸序列
<400> 19
caggtgcagc tgcaggaatc cggccctggc ctggtcaagc cctccgagac actgtccctg 60
acctgcaccg tgtccggctt ctccctgctg tcctacggcg tgcactgggt ccgacagcct 120
ccagggaagg gcctggaatg gctgggcgtg atctggaccg gcggcaccac caactacaac 180
tccgccctga tgtcccggct gaccatctcc aaggacgact ccaagtccac cgtgtacctg 240
aagatgaact ccctgaaaac cgaggacacc gccatctact actgcgcccg gtactactac 300
ggcatggact actggggcca gggcacctcc gtgaccgtgt cctca 345
<210> 20
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (1)...(345)
<223> 编码VH2重链氨基酸序列的核苷酸序列
<400> 20
caggtgcagc tgcaggaatc cggccctggc ctggtcaagc cctccgagac actgtccctg 60
acctgcaccg tgtccggctt ctccctgctg tcctacggcg tgcactgggt ccgacagcct 120
ccaggcaaag gcctggaatg gctgggcgtg atctggaccg gcggcaccac caactacaac 180
tccgccctga tgtcccggct gaccatctcc aaggacgact ccaagaacac cgtgtacctg 240
aagatgaact ccctgaaaac cgaggacacc gccatctact actgcgcccg gtactactac 300
ggcatggact actggggcca gggcaccctg gtcaccgtgt cctca 345
<210> 21
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (1)...(345)
<223> 编码VH3重链氨基酸序列的核苷酸序列
<400> 21
caggtgcagc tgcaggaatc cggccctggc ctggtcaagc cctccgagac actgtccctg 60
acctgcaccg tgtccggctt ctccctgctg tcctacggcg tgcactgggt ccgacagcct 120
ccaggcaaag gcctggaatg gctgggcgtg atctggaccg gcggcaccac caactacaac 180
tccgccctga tgtcccggtt caccatctcc aaggacgact ccaagaacac cgtgtacctg 240
aagatgaact ccctgaaaac cgaggacacc gccatctact actgcgcccg gtactactac 300
ggcatggact actggggcca gggcaccctg gtcaccgtgt cctca 345
<210> 22
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (1)...(345)
<223> 编码VH4重链氨基酸序列的核苷酸序列
<400> 22
caggtgcagc tgcaggaatc cggccctggc ctggtcaagc cctccgagac actgtccctg 60
acctgcaccg tgtccggctt ctccctgctg tcctacggcg tgcactgggt ccgacagcct 120
ccaggcaaag gcctggaatg gctgggcgtg atctggaccg gcggcaccac caactacaac 180
tccgccctga tgtcccggtt caccatctcc aaggacgact ccaagaacac cctgtacctg 240
aagatgaact ccctgaaaac cgaggacacc gccatctact actgcgcccg gtactactac 300
ggcatggact actggggcca gggcaccctg gtcaccgtgt cctca 345
<210> 23
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (1)...(321)
<223> 编码Vk1轻链氨基酸序列的核苷酸序列
<400> 23
gacatcgtga tgacccagtc ccccagcttc ctgtccgcct ccgtgggcga cagagtgacc 60
atcacatgca aggcctctca ggacgtgcgg aacaccgtgg cctggtatca gcagaaaacc 120
ggcaaggccc ccaagctgct gatctactcc tcctcctacc ggaacaccgg cgtgcccgac 180
cggtttaccg gctctggctc cggcaccgac tttaccctga ccatcagctc cctgcaggcc 240
gaggacgtgg ccgtgtactt ctgccagcag cactacatca ccccctacac cttcggcgga 300
ggcaccaagg tggaaataaa a 321
<210> 24
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (1)...(321)
<223> 编码Vk2轻链氨基酸序列的核苷酸序列
<400> 24
gacatcgtga tgacccagtc cccctccagc ctgtccgcct ctgtgggcga cagagtgacc 60
atcacatgca aggcctctca ggacgtgcgg aacaccgtgg cctggtatca gcagaagccc 120
ggcaaggccc ccaagctgct gatctactcc tcctcctacc ggaacaccgg cgtgcccgac 180
cggtttaccg gctctggctc cggcaccgac tttaccctga ccatcagctc cctgcaggcc 240
gaggacgtgg ccgtgtactt ctgccagcag cactacatca ccccctacac cttcggcgga 300
ggcaccaagg tggaaataaa a 321
<210> 25
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (1)...(321)
<223> 编码Vk3轻链氨基酸序列的核苷酸序列
<400> 25
gacatccaga tgacccagtc cccctccagc ctgtccgcct ctgtgggcga cagagtgacc 60
atcacatgca aggcctccca ggacgtgcgg aacaccgtgg cctggtatca gcagaagccc 120
ggcaaggccc ccaagctgct gatctactcc tcctcctacc ggaacaccgg cgtgcccgac 180
cggttctctg gctctggaag cggcaccgac tttaccctga ccatcagctc cctgcaggcc 240
gaggacgtgg ccgtgtactt ctgccagcag cactacatca ccccctacac cttcggcgga 300
ggcaccaagg tggaaataaa a 321
<210> 26
<211> 321
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> misc_feature
<222> (1)...(321)
<223> 编码Vk4轻链氨基酸序列的核苷酸序列
<400> 26
gacatccaga tgacccagtc cccctccagc ctgtccgcct ctgtgggcga cagagtgacc 60
atcacatgca aggcctctca ggacgtgcgg aacaccgtgg cctggtatca gcagaagccc 120
ggcaaggccc ccaagctgct gatctactcc tcctcctacc ggaacaccgg cgtgcccgac 180
cggttctctg gctctggaag cggcaccgac tttaccctga ccatcagctc cctgcaggcc 240
gaggacgtgg ccgtgtacta ctgccagcag cactacatca ccccctacac cttcggcgga 300
ggcaccaagg tggaaataaa a 321
<210> 27
<211> 707
<212> PRT
<213> 智人
<220>
<221> misc_feature
<222> (1)...(707)
<223> 基质金属蛋白酶9 (MMP9)
<220>
<221> PEPTIDE
<222> (1)...(19)
<223> 信号肽
<220>
<221> DOMAIN
<222> (38)...(98)
<223> 肽聚糖结合结构域
<220>
<221> SITE
<222> (98)...(99)
<223> 前肽裂解位点
<220>
<221> DOMAIN
<222> (112)...(445)
<223> Zn依赖性金属蛋白酶结构域
<220>
<221> DOMAIN
<222> (223)...(271)
<223> 纤连蛋白II型结构域(明胶结合结构域)
<220>
<221> DOMAIN
<222> (281)...(329)
<223> 纤连蛋白II型结构域(明胶结合结构域)
<220>
<221> DOMAIN
<222> (340)...(388)
<223> 纤连蛋白II型结构域(明胶结合结构域)
<220>
<221> misc_feature
<222> (400)...(411)
<223> Zn结合区
<220>
<221> DOMAIN
<222> (521)...(565)
<223> 血红素结合蛋白样结构域
<220>
<221> DOMAIN
<222> (567)...(608)
<223> 血红素结合蛋白样结构域
<220>
<221> DOMAIN
<222> (613)...(659)
<223> 血红素结合蛋白样结构域
<220>
<221> DOMAIN
<222> (661)...(704)
<223> 血红素结合蛋白样结构域
<400> 27
Met Ser Leu Trp Gln Pro Leu Val Leu Val Leu Leu Val Leu Gly Cys
1 5 10 15
Cys Phe Ala Ala Pro Arg Gln Arg Gln Ser Thr Leu Val Leu Phe Pro
20 25 30
Gly Asp Leu Arg Thr Asn Leu Thr Asp Arg Gln Leu Ala Glu Glu Tyr
35 40 45
Leu Tyr Arg Tyr Gly Tyr Thr Arg Val Ala Glu Met Arg Gly Glu Ser
50 55 60
Lys Ser Leu Gly Pro Ala Leu Leu Leu Leu Gln Lys Gln Leu Ser Leu
65 70 75 80
Pro Glu Thr Gly Glu Leu Asp Ser Ala Thr Leu Lys Ala Met Arg Thr
85 90 95
Pro Arg Cys Gly Val Pro Asp Leu Gly Arg Phe Gln Thr Phe Glu Gly
100 105 110
Asp Leu Lys Trp His His His Asn Ile Thr Tyr Trp Ile Gln Asn Tyr
115 120 125
Ser Glu Asp Leu Pro Arg Ala Val Ile Asp Asp Ala Phe Ala Arg Ala
130 135 140
Phe Ala Leu Trp Ser Ala Val Thr Pro Leu Thr Phe Thr Arg Val Tyr
145 150 155 160
Ser Arg Asp Ala Asp Ile Val Ile Gln Phe Gly Val Ala Glu His Gly
165 170 175
Asp Gly Tyr Pro Phe Asp Gly Lys Asp Gly Leu Leu Ala His Ala Phe
180 185 190
Pro Pro Gly Pro Gly Ile Gln Gly Asp Ala His Phe Asp Asp Asp Glu
195 200 205
Leu Trp Ser Leu Gly Lys Gly Val Val Val Pro Thr Arg Phe Gly Asn
210 215 220
Ala Asp Gly Ala Ala Cys His Phe Pro Phe Ile Phe Glu Gly Arg Ser
225 230 235 240
Tyr Ser Ala Cys Thr Thr Asp Gly Arg Ser Asp Gly Leu Pro Trp Cys
245 250 255
Ser Thr Thr Ala Asn Tyr Asp Thr Asp Asp Arg Phe Gly Phe Cys Pro
260 265 270
Ser Glu Arg Leu Tyr Thr Arg Asp Gly Asn Ala Asp Gly Lys Pro Cys
275 280 285
Gln Phe Pro Phe Ile Phe Gln Gly Gln Ser Tyr Ser Ala Cys Thr Thr
290 295 300
Asp Gly Arg Ser Asp Gly Tyr Arg Trp Cys Ala Thr Thr Ala Asn Tyr
305 310 315 320
Asp Arg Asp Lys Leu Phe Gly Phe Cys Pro Thr Arg Ala Asp Ser Thr
325 330 335
Val Met Gly Gly Asn Ser Ala Gly Glu Leu Cys Val Phe Pro Phe Thr
340 345 350
Phe Leu Gly Lys Glu Tyr Ser Thr Cys Thr Ser Glu Gly Arg Gly Asp
355 360 365
Gly Arg Leu Trp Cys Ala Thr Thr Ser Asn Phe Asp Ser Asp Lys Lys
370 375 380
Trp Gly Phe Cys Pro Asp Gln Gly Tyr Ser Leu Phe Leu Val Ala Ala
385 390 395 400
His Glu Phe Gly His Ala Leu Gly Leu Asp His Ser Ser Val Pro Glu
405 410 415
Ala Leu Met Tyr Pro Met Tyr Arg Phe Thr Glu Gly Pro Pro Leu His
420 425 430
Lys Asp Asp Val Asn Gly Ile Arg His Leu Tyr Gly Pro Arg Pro Glu
435 440 445
Pro Glu Pro Arg Pro Pro Thr Thr Thr Thr Pro Gln Pro Thr Ala Pro
450 455 460
Pro Thr Val Cys Pro Thr Gly Pro Pro Thr Val His Pro Ser Glu Arg
465 470 475 480
Pro Thr Ala Gly Pro Thr Gly Pro Pro Ser Ala Gly Pro Thr Gly Pro
485 490 495
Pro Thr Ala Gly Pro Ser Thr Ala Thr Thr Val Pro Leu Ser Pro Val
500 505 510
Asp Asp Ala Cys Asn Val Asn Ile Phe Asp Ala Ile Ala Glu Ile Gly
515 520 525
Asn Gln Leu Tyr Leu Phe Lys Asp Gly Lys Tyr Trp Arg Phe Ser Glu
530 535 540
Gly Arg Gly Ser Arg Pro Gln Gly Pro Phe Leu Ile Ala Asp Lys Trp
545 550 555 560
Pro Ala Leu Pro Arg Lys Leu Asp Ser Val Phe Glu Glu Pro Leu Ser
565 570 575
Lys Lys Leu Phe Phe Phe Ser Gly Arg Gln Val Trp Val Tyr Thr Gly
580 585 590
Ala Ser Val Leu Gly Pro Arg Arg Leu Asp Lys Leu Gly Leu Gly Ala
595 600 605
Asp Val Ala Gln Val Thr Gly Ala Leu Arg Ser Gly Arg Gly Lys Met
610 615 620
Leu Leu Phe Ser Gly Arg Arg Leu Trp Arg Phe Asp Val Lys Ala Gln
625 630 635 640
Met Val Asp Pro Arg Ser Ala Ser Glu Val Asp Arg Met Phe Pro Gly
645 650 655
Val Pro Leu Asp Thr His Asp Val Phe Gln Tyr Arg Glu Lys Ala Tyr
660 665 670
Phe Cys Gln Asp Arg Phe Tyr Trp Arg Val Ser Ser Arg Ser Glu Leu
675 680 685
Asn Gln Val Asp Gln Val Gly Tyr Val Thr Tyr Asp Ile Leu Gln Cys
690 695 700
Pro Glu Asp
705
<210> 28
<211> 688
<212> PRT
<213> 智人
<220>
<221> misc_feature
<222> (1)...(688)
<223> 成熟全长基质金属蛋白酶9 (MMP9)
<400> 28
Ala Pro Arg Gln Arg Gln Ser Thr Leu Val Leu Phe Pro Gly Asp Leu
1 5 10 15
Arg Thr Asn Leu Thr Asp Arg Gln Leu Ala Glu Glu Tyr Leu Tyr Arg
20 25 30
Tyr Gly Tyr Thr Arg Val Ala Glu Met Arg Gly Glu Ser Lys Ser Leu
35 40 45
Gly Pro Ala Leu Leu Leu Leu Gln Lys Gln Leu Ser Leu Pro Glu Thr
50 55 60
Gly Glu Leu Asp Ser Ala Thr Leu Lys Ala Met Arg Thr Pro Arg Cys
65 70 75 80
Gly Val Pro Asp Leu Gly Arg Phe Gln Thr Phe Glu Gly Asp Leu Lys
85 90 95
Trp His His His Asn Ile Thr Tyr Trp Ile Gln Asn Tyr Ser Glu Asp
100 105 110
Leu Pro Arg Ala Val Ile Asp Asp Ala Phe Ala Arg Ala Phe Ala Leu
115 120 125
Trp Ser Ala Val Thr Pro Leu Thr Phe Thr Arg Val Tyr Ser Arg Asp
130 135 140
Ala Asp Ile Val Ile Gln Phe Gly Val Ala Glu His Gly Asp Gly Tyr
145 150 155 160
Pro Phe Asp Gly Lys Asp Gly Leu Leu Ala His Ala Phe Pro Pro Gly
165 170 175
Pro Gly Ile Gln Gly Asp Ala His Phe Asp Asp Asp Glu Leu Trp Ser
180 185 190
Leu Gly Lys Gly Val Val Val Pro Thr Arg Phe Gly Asn Ala Asp Gly
195 200 205
Ala Ala Cys His Phe Pro Phe Ile Phe Glu Gly Arg Ser Tyr Ser Ala
210 215 220
Cys Thr Thr Asp Gly Arg Ser Asp Gly Leu Pro Trp Cys Ser Thr Thr
225 230 235 240
Ala Asn Tyr Asp Thr Asp Asp Arg Phe Gly Phe Cys Pro Ser Glu Arg
245 250 255
Leu Tyr Thr Arg Asp Gly Asn Ala Asp Gly Lys Pro Cys Gln Phe Pro
260 265 270
Phe Ile Phe Gln Gly Gln Ser Tyr Ser Ala Cys Thr Thr Asp Gly Arg
275 280 285
Ser Asp Gly Tyr Arg Trp Cys Ala Thr Thr Ala Asn Tyr Asp Arg Asp
290 295 300
Lys Leu Phe Gly Phe Cys Pro Thr Arg Ala Asp Ser Thr Val Met Gly
305 310 315 320
Gly Asn Ser Ala Gly Glu Leu Cys Val Phe Pro Phe Thr Phe Leu Gly
325 330 335
Lys Glu Tyr Ser Thr Cys Thr Ser Glu Gly Arg Gly Asp Gly Arg Leu
340 345 350
Trp Cys Ala Thr Thr Ser Asn Phe Asp Ser Asp Lys Lys Trp Gly Phe
355 360 365
Cys Pro Asp Gln Gly Tyr Ser Leu Phe Leu Val Ala Ala His Glu Phe
370 375 380
Gly His Ala Leu Gly Leu Asp His Ser Ser Val Pro Glu Ala Leu Met
385 390 395 400
Tyr Pro Met Tyr Arg Phe Thr Glu Gly Pro Pro Leu His Lys Asp Asp
405 410 415
Val Asn Gly Ile Arg His Leu Tyr Gly Pro Arg Pro Glu Pro Glu Pro
420 425 430
Arg Pro Pro Thr Thr Thr Thr Pro Gln Pro Thr Ala Pro Pro Thr Val
435 440 445
Cys Pro Thr Gly Pro Pro Thr Val His Pro Ser Glu Arg Pro Thr Ala
450 455 460
Gly Pro Thr Gly Pro Pro Ser Ala Gly Pro Thr Gly Pro Pro Thr Ala
465 470 475 480
Gly Pro Ser Thr Ala Thr Thr Val Pro Leu Ser Pro Val Asp Asp Ala
485 490 495
Cys Asn Val Asn Ile Phe Asp Ala Ile Ala Glu Ile Gly Asn Gln Leu
500 505 510
Tyr Leu Phe Lys Asp Gly Lys Tyr Trp Arg Phe Ser Glu Gly Arg Gly
515 520 525
Ser Arg Pro Gln Gly Pro Phe Leu Ile Ala Asp Lys Trp Pro Ala Leu
530 535 540
Pro Arg Lys Leu Asp Ser Val Phe Glu Glu Pro Leu Ser Lys Lys Leu
545 550 555 560
Phe Phe Phe Ser Gly Arg Gln Val Trp Val Tyr Thr Gly Ala Ser Val
565 570 575
Leu Gly Pro Arg Arg Leu Asp Lys Leu Gly Leu Gly Ala Asp Val Ala
580 585 590
Gln Val Thr Gly Ala Leu Arg Ser Gly Arg Gly Lys Met Leu Leu Phe
595 600 605
Ser Gly Arg Arg Leu Trp Arg Phe Asp Val Lys Ala Gln Met Val Asp
610 615 620
Pro Arg Ser Ala Ser Glu Val Asp Arg Met Phe Pro Gly Val Pro Leu
625 630 635 640
Asp Thr His Asp Val Phe Gln Tyr Arg Glu Lys Ala Tyr Phe Cys Gln
645 650 655
Asp Arg Phe Tyr Trp Arg Val Ser Ser Arg Ser Glu Leu Asn Gln Val
660 665 670
Asp Gln Val Gly Tyr Val Thr Tyr Asp Ile Leu Gln Cys Pro Glu Asp
675 680 685
<210> 29
<211> 19
<212> PRT
<213> 智人
<400> 29
Met Ser Leu Trp Gln Pro Leu Val Leu Val Leu Leu Val Leu Gly Cys
1 5 10 15
Cys Phe Ala
<210> 30
<211> 470
<212> PRT
<213> 小家鼠
<220>
<221> CHAIN
<222> (1)...(470)
<223> M4重链(IgG2b)
<400> 30
Met Ala Val Leu Val Leu Phe Leu Cys Leu Val Ala Phe Pro Ser Cys
1 5 10 15
Val Leu Ser Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala
20 25 30
Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu
35 40 45
Leu Ser Tyr Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu
50 55 60
Glu Trp Leu Gly Val Ile Trp Thr Gly Gly Ser Thr Asn Tyr Asn Ser
65 70 75 80
Ala Leu Met Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gln
85 90 95
Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr
100 105 110
Tyr Cys Ala Arg Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr
115 120 125
Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro
130 135 140
Leu Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly
145 150 155 160
Cys Leu Val Lys Gly Tyr Phe Pro Glu Ser Val Thr Val Thr Trp Asn
165 170 175
Ser Gly Ser Leu Ser Ser Ser Val His Thr Phe Pro Ala Leu Leu Gln
180 185 190
Ser Gly Leu Tyr Thr Met Ser Ser Ser Val Thr Val Pro Ser Ser Thr
195 200 205
Trp Pro Ser Gln Thr Val Thr Cys Ser Val Ala His Pro Ala Ser Ser
210 215 220
Thr Thr Val Asp Lys Lys Leu Glu Pro Ser Gly Pro Ile Ser Thr Ile
225 230 235 240
Asn Pro Cys Pro Pro Cys Lys Glu Cys His Lys Cys Pro Ala Pro Asn
245 250 255
Leu Glu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Ile Lys Asp
260 265 270
Val Leu Met Ile Ser Leu Thr Pro Lys Val Thr Cys Val Val Val Asp
275 280 285
Val Ser Glu Asp Asp Pro Asp Val Arg Ile Ser Trp Phe Val Asn Asn
290 295 300
Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn
305 310 315 320
Ser Thr Ile Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp
325 330 335
Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro
340 345 350
Ser Pro Ile Glu Arg Thr Ile Ser Lys Ile Lys Gly Leu Val Arg Ala
355 360 365
Pro Gln Val Tyr Ile Leu Pro Pro Pro Ala Glu Gln Leu Ser Arg Lys
370 375 380
Asp Val Ser Leu Thr Cys Leu Val Val Gly Phe Asn Pro Gly Asp Ile
385 390 395 400
Ser Val Glu Trp Thr Ser Asn Gly His Thr Glu Glu Asn Tyr Lys Asp
405 410 415
Thr Ala Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Ile Tyr Ser Lys
420 425 430
Leu Asp Ile Lys Thr Ser Lys Trp Glu Lys Thr Asp Ser Phe Ser Cys
435 440 445
Asn Val Arg His Glu Gly Leu Lys Asn Tyr Tyr Leu Lys Lys Thr Ile
450 455 460
Ser Arg Ser Pro Gly Lys
465 470
<210> 31
<211> 234
<212> PRT
<213> 小家鼠
<220>
<221> CHAIN
<222> (1)...(234)
<223> M4轻链(κ)
<400> 31
Met Glu Ser Gln Ile Gln Val Phe Val Phe Val Phe Leu Trp Leu Ser
1 5 10 15
Gly Val Asp Gly Asp Ile Val Met Thr Gln Ser His Lys Phe Met Phe
20 25 30
Thr Ser Val Gly Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp
35 40 45
Val Arg Asn Thr Val Ala Trp Tyr Gln Gln Lys Thr Gly Gln Ser Pro
50 55 60
Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Asn Thr Gly Val Pro Asp
65 70 75 80
Arg Phe Thr Gly Ser Ile Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser
85 90 95
Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr
100 105 110
Ser Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
130 135 140
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
145 150 155 160
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
165 170 175
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
195 200 205
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
210 215 220
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 32
<211> 115
<212> PRT
<213> 小家鼠
<400> 32
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Leu Ser Tyr
20 25 30
Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Thr Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asp Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr
100 105 110
Val Ser Ser
115
<210> 33
<211> 107
<212> PRT
<213> 小家鼠
<400> 33
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Phe Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Arg Asn Thr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Thr Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Asn Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Ile Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Lys
100 105
<210> 34
<211> 10
<212> PRT
<213> 小家鼠
<400> 34
Gly Phe Ser Leu Leu Ser Tyr Gly Val His
1 5 10
<210> 35
<211> 10
<212> PRT
<213> 小家鼠
<400> 35
Val Ile Trp Thr Gly Gly Ser Thr Asn Tyr
1 5 10
<210> 36
<211> 7
<212> PRT
<213> 小家鼠
<400> 36
Tyr Tyr Tyr Ala Met Asp Tyr
1 5
<210> 37
<211> 11
<212> PRT
<213> 小家鼠
<400> 37
Lys Ala Ser Gln Asp Val Arg Asn Thr Val Ala
1 5 10
<210> 38
<211> 7
<212> PRT
<213> 小家鼠
<400> 38
Ser Ala Ser Tyr Arg Asn Thr
1 5
<210> 39
<211> 9
<212> PRT
<213> 小家鼠
<400> 39
Gln Gln His Tyr Ser Thr Pro Tyr Thr
1 5
<210> 40
<211> 229
<212> PRT
<213> 小家鼠
<220>
<221> CHAIN
<222> (1)...(229)
<223> M12 κ链
<400> 40
Gln Val Phe Val Tyr Met Leu Leu Trp Leu Ser Gly Val Asp Gly Asp
1 5 10 15
Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly Asp
20 25 30
Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val
35 40 45
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile Tyr
50 55 60
Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Asp Arg Phe Thr Gly Ser
65 70 75 80
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser Glu
85 90 95
Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr Thr
100 105 110
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro
115 120 125
Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly
130 135 140
Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn
145 150 155 160
Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn
165 170 175
Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser
180 185 190
Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr
195 200 205
Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe
210 215 220
Asn Arg Asn Glu Cys
225
<210> 41
<211> 107
<212> PRT
<213> 小家鼠
<400> 41
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Phe Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 42
<211> 11
<212> PRT
<213> 小家鼠
<400> 42
Lys Ala Ser Gln Asn Val Gly Thr Asn Val Ala
1 5 10
<210> 43
<211> 7
<212> PRT
<213> 小家鼠
<400> 43
Ser Ala Ser Tyr Arg Phe Ser
1 5
<210> 44
<211> 9
<212> PRT
<213> 小家鼠
<400> 44
Gln Gln Tyr Asn Ser Tyr Pro Tyr Thr
1 5
<210> 45
<211> 233
<212> PRT
<213> 小家鼠
<220>
<221> CHAIN
<222> (1)...(233)
<223> AB0046 κ轻链
<400> 45
Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln Gly
1 5 10 15
Thr Arg Cys Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala
20 25 30
Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Gly Ile
35 40 45
Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe Lys
50 55 60
Leu Leu Ile Tyr Tyr Thr Ser Ile Leu His Ser Gly Val Pro Ser Arg
65 70 75 80
Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn
85 90 95
Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Gly Trp
100 105 110
Leu Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala
115 120 125
Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu
130 135 140
Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro
145 150 155 160
Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn
165 170 175
Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr
180 185 190
Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His
195 200 205
Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile
210 215 220
Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 46
<211> 460
<212> PRT
<213> 小家鼠
<220>
<221> CHAIN
<222> (1)...(460)
<223> AB0046 IgG1重链
<400> 46
Met Gly Trp Ser Ser Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ser Val Leu Val Arg
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Ser Tyr Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Glu Ile Tyr Pro Ile Ser Gly Arg Thr Asn Tyr Asn
65 70 75 80
Glu Lys Phe Lys Val Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser
85 90 95
Thr Ala Tyr Met Asp Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Arg Ala Asn Trp Asp Asp Tyr Trp Gly Gln
115 120 125
Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val
130 135 140
Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr
145 150 155 160
Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr
165 170 175
Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val
180 185 190
Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser
195 200 205
Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala
210 215 220
Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys
225 230 235 240
Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe
245 250 255
Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val
260 265 270
Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe
275 280 285
Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro
290 295 300
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro
305 310 315 320
Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val
325 330 335
Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
340 345 350
Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys
355 360 365
Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp
370 375 380
Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro
385 390 395 400
Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser
405 410 415
Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala
420 425 430
Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His
435 440 445
His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455 460
<210> 47
<211> 117
<212> PRT
<213> 小家鼠
<400> 47
Gln Val Gln Leu Gln Gln Pro Gly Ser Val Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Ile Ser Gly Arg Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Val Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Arg Ala Asn Trp Asp Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 48
<211> 107
<212> PRT
<213> 小家鼠
<400> 48
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Gly Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Ile Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Gly Trp Leu Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 49
<211> 461
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<220>
<221> CHAIN
<222> (1)...(461)
<223> AB0045重链
<400> 49
Met Gly Trp Ser Leu Ile Leu Leu Phe Leu Val Ala Val Ala Thr Arg
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys
20 25 30
Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu
35 40 45
Leu Ser Tyr Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu
50 55 60
Glu Trp Leu Gly Val Ile Trp Thr Gly Gly Thr Thr Asn Tyr Asn Ser
65 70 75 80
Ala Leu Met Ser Arg Phe Thr Ile Ser Lys Asp Asp Ser Lys Asn Thr
85 90 95
Val Tyr Leu Lys Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr
100 105 110
Tyr Cys Ala Arg Tyr Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr
115 120 125
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
130 135 140
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly
145 150 155 160
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
165 170 175
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Claims (30)
1.一种医药组合物,其包含:
结合到基质金属蛋白酶9MMP9的分离的抗体或其片段,其包含:具有氨基酸序列为SEQID NO:15的互补决定区CDR的重链可变VH区;和
医药学上可接受的赋形剂。
2.根据权利要求1所述的医药组合物,其中所述VH区另外包含氨基酸序列为SEQ IDNO:13和/或14的CDR。
3.一种医药组合物,其包含:
结合到基质金属蛋白酶9的分离的抗体或其片段,其包含:具有氨基酸序列为SEQ IDNO:18的互补决定区CDR的轻链可变VL区;和
医药学上可接受的赋形剂。
4.根据权利要求1到3中任一权利要求所述的医药组合物,其中所述VL区另外包含氨基酸序列为SEQ ID NO:16和/或17的CDR。
5.根据权利要求1、2及4中任一权利要求所述的医药组合物,其中所述VH区具有SEQ IDNO:3、5、6、7或8中所陈述的氨基酸序列。
6.根据权利要求1到5中任一权利要求所述的医药组合物,其中所述VL区具有SEQ IDNO:4、9、10、11或12中所陈述的氨基酸序列。
7.根据权利要求6所述的医药组合物,其中所述VH区具有SEQ ID NO:7中所陈述的氨基酸序列并且所述VL区具有SEQ ID NO:12中所陈述的氨基酸序列。
8.一种医药组合物,其包含:
特异性结合到MMP9的表位的分离的抗体或其片段,其中所述表位包含在MMP9的区域内的氨基酸残基,所述区域由SEQ ID NO:27的残基104-119、残基159-166或残基191-202组成;及医药学上可接受的赋形剂。
9.根据权利要求8所述的医药组合物,其中所述表位包含SEQ ID NO:27的E111、D113、R162或I198。
10.根据权利要求1到9中任一权利要求所述的医药组合物,其中所述抗体或片段抑制MMP9的酶活性。
11.根据权利要求10所述的医药组合物,其中所述酶活性的所述抑制是非竞争性的。
12.根据权利要求1到11中任一权利要求所述的医药组合物,其另外包含一或多种选自由以下组成的群组的治疗剂:消炎剂、免疫治疗剂、化学治疗剂、抗癌剂、抗纤维化药剂或其组合。
13.根据权利要求12所述的医药组合物,其中所述一或多种治疗剂选自由以下组成的群组:白蛋白结合型紫杉醇、mFOLFOX6、FOLFIRI、卡铂、紫杉醇、培美曲塞、贝伐单抗、抗赖氨酰氧化酶样蛋白2LOXL2抗体、抗盘状结构域受体1DDR1抗体或其组合。
14.一种抑制个体中的MMP9活性的方法,其包含以有效抑制罹患MMP9相关性疾病或病况的所述个体中的MMP9活性的量向所述个体投予根据权利要求1到13中任一权利要求所述的医药组合物。
15.根据权利要求14所述的方法,其中所述MMP9相关性疾病或病况是癌症、自体免疫性、炎症性或纤维化疾病或病况。
16.根据权利要求15所述的方法,其中所述MMP9相关性癌症为胰脏癌、食管胃腺癌、非小细胞肺癌、肺鳞状细胞癌瘤、肺腺癌、胃腺癌、结肠直肠癌瘤、胰脏腺癌、头颈鳞状细胞癌瘤、肝细胞癌瘤、结肠直肠癌、结肠直肠腺癌或肝细胞癌瘤。
17.根据权利要求16所述的方法,其中所述MMP9相关性自体免疫性或炎症性疾病或病况为类风湿性关节炎、炎症性肠病IBD、败血病、多发性硬化、肌营养不良、狼疮、过敏症或哮喘。
18.根据权利要求17所述的方法,其中所述IBD为溃疡性结肠炎UC、克罗恩氏病CD或未定型结肠炎。
19.根据权利要求15到18中任一权利要求所述的方法,其中所述抗体或片段是以约1mg/kg到约28mg/kg的剂量投予。
20.根据权利要求15到18中任一权利要求所述的方法,其中所述抗体或片段是以介于100mg/kg体重或约100mg/kg与1800mg/kg或约1800mg/kg之间的剂量投予。
21.根据权利要求20所述的方法,其中所述剂量为100、200、300、400、500、600、700、800、900、1000、1100、1200、1300、1400、1500、1600、1700或1800mg/kg体重或约100、200、300、400、500、600、700、800、900、1000、1100、1200、1300、1400、1500、1600、1700或1800mg/kg。
22.根据权利要求15到21中任一权利要求所述的方法,其中所述抗体或片段是每周一次、每两周一次或每三周一次投予。
23.根据权利要求15到22中任一权利要求所述的方法,其中所述抗体或片段是静脉内、真皮内或皮下投予。
24.根据权利要求12到23中任一权利要求所述的方法,其中所述抗体或片段是与所述一或多种治疗剂同时或依序投予。
25.一种检测或监测MMP9活性的方法,其包含:
使样品与MMP9结合蛋白接触,
评估MMP9结合蛋白-MMP9复合物的存在或不存在;
其中所述MMP9结合蛋白包含VH区,所述VH区包含具有选自由SEQ ID NO:13、14、15、34、35、36及47组成的群组的氨基酸序列的CDR;及VL区,所述VL区具有含选自由SEQ ID NO:16、17、18、37、38、39、42、43、44及48组成的群组的氨基酸序列的CDR;
由此不存在所述MMP9结合蛋白-MMP9复合物指示所述样品不具有所述MMP9活性,由此存在所述MMP9结合蛋白-MMP9复合物指示所述样品具有所述MMP9活性。
26.根据权利要求25所述的方法,其中所述MMP9结合蛋白包含VH区,所述VH区具有选自由SEQ ID NO:1、3、5、6、7、8、34、35、36及46组成的群组的氨基酸序列;及VL区,所述VL区具有选自由SEQ ID NO:2、4、9、10、11、12、37、38、39、42、43、44及45组成的群组的氨基酸序列。
27.一种MMP9结合蛋白,其包含VH区,所述VH区包含具有SEQ ID NO:34、35、36及47的氨基酸序列的CDR;及VL区,所述VL区具有含选自由SEQ ID NO:37、38、39、42、43、44及48组成的群组的氨基酸序列的CDR。
28.根据权利要求27所述的MMP9结合蛋白,其中所述VH区与所述选自由SEQ ID NO:30、32、46及47组成的群组的氨基酸序列具有95%序列一致性;并且所述VL区与所述选自由SEQID NO:31、33、41、45及48组成的群组的氨基酸序列具有95%序列一致性。
29.根据权利要求27到28中任一权利要求所述的MMP9结合蛋白,其中所述VH区具有选自由SEQ ID NO:30、32、46及47组成的群组的氨基酸序列;并且所述VL区具有选自由SEQ IDNO:31、33、41、45及48组成的群组的氨基酸序列。
30.一种抑制MMP9活性的方法,其包含:使样品与根据权利要求27到29中任一权利要求所述的MMP9结合蛋白接触。
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