CN114702594A - 双重特异性抗体 - Google Patents
双重特异性抗体 Download PDFInfo
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- CN114702594A CN114702594A CN202210315371.3A CN202210315371A CN114702594A CN 114702594 A CN114702594 A CN 114702594A CN 202210315371 A CN202210315371 A CN 202210315371A CN 114702594 A CN114702594 A CN 114702594A
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Abstract
本发明提供双重特异性抗体和产生并使用这类抗体的方法。通常,通过以下方式产生双重特异性抗体:鉴定具有带静电或疏水的轻链可变区VL残基的单特异性抗体,单独地改变编码抗体VH中一个或多个溶剂可及性残基的核酸序列或与改变编码抗体VL的核酸序列组合。表达改变的VH和VL并且选择双重特异性抗体或其抗原结合片段。本发明还提供示例性双重特异性抗体以及使用所述抗体的方法。
Description
本申请是申请日为2014年12月18日的、发明名称为“双重特异性抗体”的中国专利申请201480067934.5(PCT/US2014/071193)的分案申请。
技术领域
本发明涉及双重特异性抗体和生产及使用这类抗体的方法。
发明背景
抗体是由脊椎动物免疫系统响应于外来蛋白、糖蛋白、细胞或其他抗原性外来物质攻击而产生的特异性免疫球蛋白多肽。这个过程的重要部分是产生与特定外来物质特异性结合的抗体。这类多肽对特定抗原的结合特异性高度精致,并且能够由各个脊椎动物生成的众多特异性在其复杂程度和变异程度方面令人瞩目。数千种抗原能够引发反应,每种反应几乎排他地指向激发它的特定抗原。
特异性抗原识别作用是抗体在适应性免疫反应中发挥作用必需的。在抗体库产生时,重链(HC)和轻链(LC)的组合性缔合在全部脊椎动物中均保守。然而,两条链中存在多样性的非对称性。HC可变结构域(VH)含有显著更高的序列多样性并且比LC可变结构域(VL)更经常地贡献抗原识别决定簇。然而,鉴于抗体识别及结合特定外来物质的变异性,一些抗体的抗原结合能十分依赖VL。
抗体和抗体片段对某种特定抗原或多种抗原的特异性使得抗体成为合乎需要的治疗药。抗体和抗体片段可以用来靶向具有多效生物学作用的特定抗原(例如,细胞因子)。因而,当前且持续需要鉴定和表征治疗性抗体、尤其是可用于治疗多种疾病和病症如过敏性疾病、炎性疾病、自身免疫疾病和增生性疾病的抗体、片段及其衍生物。
发明简述
本发明提供产生双重特异性抗体和抗体片段的方法。本发明也提供使用这些方法鉴定的特异性抗体以及它们的用途。
一般地,本发明的方法涉及,将抗体的VH多样化以产生可以在文库中稳定表达的双重特异性抗体变体。在一个实施方案中,抗体在多样化之前表征为:具有可以配对在一起以形成与第一表位特异性结合但不与第二表位特异性结合的抗原结合位点的VH和VL。抗体可以进一步表征为:在VL的位置32、50或91(Kabat编号体系)的任意一个、两个或三个氨基酸处具有带静电残基或疏水残基。随后在这些位置的一个或多个处具有疏水残基或带静电残基的这种抗体,在VH中一个或多个氨基酸残基(例如,溶剂暴露的氨基酸残基)处进行改变。随后可以将该VH和VL(例如,作为文库)表达,并且自表达的VH和VL选择能够特异性结合第一和第二表位的多样化双重特异性抗体或其抗原结合片段。
在一个方面,本发明涉及一种产生包含可变重链结构域(VH)和可变轻链结构域(VL)的双重特异性抗体或其抗原结合片段的方法,其中双重特异性抗体的VH和VL配对在一起以形成与第一表位和第二表位特异性结合的抗原结合位点,所述方法包括步骤:(a)提供包含VH和VL的抗体,其中VH和VL配对在一起以形成与第一表位结合但不与第二表位结合的抗原结合位点,并且其中所述抗体在VL的位置32、50或91处包含至少一个带静电或疏水的氨基酸;(b)改变编码步骤(a)的抗体的VH的核酸序列,其中改变一个或多个溶剂可及性氨基酸残基;(c)表达步骤(b)的VL和改变的VH;和(d)选择包含步骤(c)的VL和改变的VH的双重特异性抗体或其抗原结合片段,其中该VH和VL配对在一起以形成与第一表位和第二表位特异性结合的抗原结合位点。
在一些实施方案中,至少两个在位置32、50或91处的氨基酸是带静电或疏水的。在一些实施方案中,在位置32、50和91处的全部三个氨基酸是带静电或疏水的。在一些实施方案中,带静电残基是酪氨酸。在一些实施方案中,疏水性残基是色氨酸。在一些实施方案中,基于多个天然存在的重链氨基酸序列的多样性,改变编码VH的核酸序列。在一些实施方案中,溶剂暴露的残基位置是选自VH的位置33、34、50-58和95-97的氨基酸残基位置。在一些实施方案中,该方法还包括:改变编码步骤(a)的抗体的VL的核酸序列,其中改变一个或多个溶剂可及性氨基酸残基。在一些实施方案中,溶剂暴露的残基位置是选自VL的氨基酸93-96的氨基酸残基位置。在一些实施方案中,在步骤(d)的选择过程中,改变的VH与VL展示在噬菌体上。在一些实施方案中,步骤(a)的抗体包括包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的轻链可变区互补决定区CDRL1、包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2和包含氨基酸序列QQDYTSPWTF(SEQ ID NO:11)的CDRL3。在一些实施方案中,步骤(a)的抗体包括包含氨基酸序列DYSMH(SEQ ID NO:13)的重链可变区互补决定区CDR H1、包含氨基酸序列VWINTETGEPTYADDFK(SEQ ID NO:17)的CDR H2和包含氨基酸序列GGIFYGMDY(SEQ ID NO:20)的CDR H3。在一些实施方案中,步骤(d)的双重特异性抗体的抗原结合位点互斥地结合第一表位和第二表位。在其他实施方案中,步骤(d)的双重特异性抗体的抗原结合位点同时结合第一表位和第二表位。在一些实施方案中,第一表位来自一个生物分子并且第二表位来自相同的生物分子。在其他实施方案中,第一表位来自第一生物分子并且第二表位来自第二生物分子。在一些实施方案中,第一生物分子和第二生物分子选自IL4/IL5和IL4/IL13。在一些实施方案中,第一生物分子和第二生物分子是细胞因子。在一些实施方案中,第一或第二生物分子是在体内与抗体结合时可以增加双重特异性抗体半寿期的分子。在一些实施方案中,第一或第二生物分子是血清白蛋白或新生儿Fc受体(FcRn)。在一些实施方案中,第一或第二生物分子是在体内与抗体结合时可以增加双重特异性抗体的效应子功能的分子。在一些实施方案中,第一或第二生物分子与天然杀伤细胞或巨噬细胞上的细胞表面蛋白结合。在一些实施方案中,细胞表面蛋白是Fc受体或C1q。在一些实施方案中,双重特异性抗体的VH和VL配对在一起以形成以10-6或更低的KD与第一表位或第二表位特异性结合的抗原结合位点。在一些实施方案中,双重特异性抗体的VH和VL配对在一起以形成以10-9或更低的KD与第一表位或第二表位特异性结合的抗原结合位点。在一些实施方案中,双重特异性抗体的VH和VL配对在一起以形成以10-12或更低的KD与第一表位或第二表位特异性结合的抗原结合位点。在一些实施方案中,双重特异性抗体的VH和VL配对在一起以形成以10-6或更低的KD与第一表位和第二表位特异性结合的抗原结合位点。在一些实施方案中,双重特异性抗体的VH和VL配对在一起以形成以10-9或更低的KD与第一表位和第二表位特异性结合的抗原结合位点。在一些实施方案中,双重特异性抗体的VH和VL配对在一起以形成以10-12或更低的KD与第一表位和第二表位特异性结合的抗原结合位点。在一些实施方案中,第一生物分子和第二生物分子在结构上不是相似的。在一些实施方案中,步骤(d)的选择包括深度测序、超深度测序和/或下一代测序。
如下文描述,使用本发明方法产生的示例性抗体包括结合白介素4(IL4)和白介素5(IL5)二者的抗体,以及结合IL4和白介素13(IL13)二者的抗体。这些抗体的成功产生表明,改变抗体的重链可变结构域的序列可以充当产生具有双重特异性和功能的抗体的一般工程化路径。双重特异性抗体,包括但不限于本文所述的IL4/IL5抗体和IL4/IL13抗体,具有同时靶向两条途径(冗余或非冗余)的潜力并且可用于治疗多种疾病和病症,包括但不限于免疫疾病、炎性疾病和增生性疾病。
因此,在另一个方面,本发明涉及通过上文描述的本发明方法产生的分离的双重特异性抗体或其抗原结合片段。在一些实施方案中,双重特异性抗体是单克隆抗体。在一些实施方案中,片段是Fab或scFv。在一些实施方案中,双重特异性抗体是IgG。
在另一个方面,本发明涉及分离的双重特异性抗体或其抗原结合片段,其包含图4A、4B、4C、7A、7C或7D的任一种抗体的氨基酸序列。
在另一个方面,本发明涉及分离的双重特异性抗体或其抗原结合片段,其包含以下六个CDR:(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;(iii)包含氨基酸序列QQDYTSPWTF(SEQ ID NO:11)的CDRL3;(iv)包含氨基酸序列DYDIH(SEQ ID NO:14)的CDR H1;(v)包含氨基酸序列VWINTETGEPTYADDFK(SEQ ID NO:17)的CDR H2;和(vi)包含氨基酸序列EILFYGMDY(SEQ IDNO:21)的CDR H3。
在另一个方面,本发明涉及分离的双重特异性抗体或其抗原结合片段,其包含以下六个CDR:(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;(iii)包含氨基酸序列QQDYTSPWTF(SEQ ID NO:11)的CDRL3;(iv)包含氨基酸序列DYFIH(SEQ ID NO:15)的CDR H1;(v)包含氨基酸序列AGIVYDATGFTTYADDFK(SEQ ID NO:18)的CDR H2;和(vi)包含氨基酸序列GGIFYGMDY(SEQ IDNO:20)的CDR H3。
在另一个方面,本发明涉及分离的双重特异性抗体或其抗原结合片段,其包含以下六个CDR:(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;(iii)包含氨基酸序列QQDYTPFPLTF(SEQ ID NO:12)的CDRL3;(iv)包含氨基酸序列DYLMH(SEQ ID NO:16)的CDR H1;(v)包含氨基酸序列AVIVSITGRTYYADDFK(SEQ ID NO:19)的CDR H2;和(vi)包含氨基酸序列GGIFYGMDY(SEQ IDNO:20)的CDR H3。
在另一个方面,本发明涉及分离的双重特异性抗体或其抗原结合片段,其包含以下六个CDR:(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;(iii)包含氨基酸序列QQDYTSPWTF(SEQ ID NO:11)的CDRL3;(iv)包含氨基酸序列DYSMH(SEQ ID NO:13)的CDR H1;(v)包含氨基酸序列GVIFQSGATYYADDFK(SEQ ID NO:22)的CDR H2;和(vi)包含氨基酸序列GGIFYGMDY(SEQ IDNO:20)的CDR H3。
在另一个方面,本发明涉及分离的双重特异性抗体或其抗原结合片段,其包含以下六个CDR:(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;(iii)包含氨基酸序列QQDYTSPWTF(SEQ ID NO:11)的CDRL3;(iv)包含氨基酸序列DYSMH(SEQ ID NO:13)的CDR H1;(v)包含氨基酸序列GIIFYTGHTYYADDFK(SEQ ID NO:23)的CDR H2;和(vi)包含氨基酸序列GGIFYGMDY(SEQ IDNO:20)的CDR H3。
在另一个方面,本发明涉及分离的双重特异性抗体或其抗原结合片段,其包含以下六个CDR:(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;(iii)包含氨基酸序列QQDYX1X2PWTF(SEQ ID NO:24)的CDRL3,其中X1是Thr、Ile、Leu或Lys,并且X2是Ser或His;(iv)包含氨基酸序列DYFIH(SEQ IDNO:15)的CDR H1;(v)包含氨基酸序列X1GIVYDATGFTX2YA X3X4FK(SEQ ID NO:25)的CDR H2,其中X1是Ala或Gly,X2是Thr、Ile、Val或Ala,X3是Asp、Val或Glu,并且X4是Asp、Glu、Asn、Ser、Ile、Leu、Thr、Ala或Phe;和(vi)包含氨基酸序列GGIFYGMDY(SEQ ID NO:20)的CDR H3。在一些实施方案中,双重特异性抗体或其抗原结合片段包含以下六个CDR:(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;(iii)包含氨基酸序列QQDYTHPWTF(SEQ ID NO:27)的CDRL3;(iv)包含氨基酸序列DYFIH(SEQ ID NO:15)的CDR H1;(v)包含氨基酸序列GGIVYDATGFTTYAEEFK(SEQ ID NO:28)的CDR H2;和(vi)包含氨基酸序列GGIFYGMDY(SEQ ID NO:20)的CDR H3。在一些实施方案中,双重特异性抗体或其抗原结合片段包含以下六个CDR:(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;(iii)包含氨基酸序列QQDYKHPWTF(SEQ ID NO:31)的CDRL3;(iv)包含氨基酸序列DYFIH(SEQ ID NO:15)的CDR H1;(v)包含氨基酸序列AGIVYDATGFTVYADDFK(SEQ ID NO:32)的CDR H2;和(vi)包含氨基酸序列GGIFYGMDY(SEQ ID NO:20)的CDR H3。在一些实施方案中,双重特异性抗体或其抗原结合片段还包含构架区3(FR3),所述构架区3包含氨基酸序列GRX1TITX2DX3STSTX4(SEQ ID NO:26),其中X1是Val或Phe,X2是Arg或Ile,X3是Thr、Phe、Met或Pro,并且X4是Ala或Val。
在另一个方面,本发明涉及一种分离的双重特异性抗体或其抗原结合片段,其包含选自SEQ ID NO:1、5、29或33的氨基酸序列的轻链可变区和选自SEQ ID NO:2、3、4、6、7、8、30或34的重链可变区。在一些实施方案中,抗体或其抗原结合片段以500nM或更低的Kd结合IL4并且以约900nM或更低的Kd结合IL5。在一些实施方案中,抗体或其抗原结合片段以100nM或更低的Kd结合IL4并且以约100nM或更低的Kd结合IL5。在一些实施方案中,抗体或其抗原结合片段以10nM或更低的Kd结合IL4并且以约50nM或更低的Kd结合IL5。在其他实施方案中,分离的双重特异性抗体或其抗原结合片段以500nM或更低的Kd结合IL4并且以约900nM或更低的Kd结合IL13。在一些实施方案中,抗体或其抗原结合片段以100nM或更低的Kd结合IL4并且以约100nM或更低的Kd结合IL13。在一些实施方案中,抗体或其抗原结合片段抑制或阻断IL4、IL5或IL13与其受体的结合。在一些实施方案中,抗体是单克隆抗体。在一些实施方案中,抗体是IgG抗体。在一些实施方案中,抗原结合片段是Fab片段或单链可变片段(scFv)。在一些实施方案中,构架序列的至少一部分是人共有构架序列。在一些实施方案中,抗体是嵌合抗体、人源化抗体或全人抗体。
本发明还提供包含任一种前述双重特异性抗体或其抗原结合片段的药物组合物。在另一个方面,本发明涉及编码本文公开的任一种双重特异性抗体的分离的核酸,包括表达该抗体的载体(例如,表达载体)。
在另一个方面,本发明涉及包含前述核酸和/或载体的宿主细胞。在一些实施方案中,宿主细胞是哺乳动物细胞(例如,中国仓鼠卵巢(CHO)细胞)。在其他实施方案中,宿主细胞是原核细胞(例如,大肠杆菌(E.coli)细胞)。本发明还提供产生任一种前述双重特异性抗体的方法,所述方法包括培养产生双重特异性抗体的宿主细胞并且从宿主细胞或培养基回收双重特异性抗体。
在另一个方面,本发明涉及一种治疗受试者中哮喘的方法,所述方法包括向受试者施用本文公开的任一种双重特异性抗体,其中所述施用按足以治疗或预防受试者中哮喘的量和时间进行。在一些实施方案中,该方法还包括施用选自以下的至少一种额外的哮喘治疗药:IgE拮抗剂、抗组胺药、茶碱(theophylline)、沙丁胺醇(salbutamol)、丙酸倍氯米松(beclomethasone dipropionate)、色甘酸钠(sodium cromoglycate)、类固醇(steroid)和抗炎药。在一些实施方案中,哮喘是过敏性哮喘。
在又一个方面,本发明涉及一种治疗受试者中增生性疾病的方法,所述方法包括向受试者施用本文公开的任一种双重特异性抗体,其中所述施用按足以治疗受试者中增生性疾病的量和时间进行。在一些实施方案中,增生性疾病是癌症。在一些实施方案中,该方法还包括向受试者施用选自化疗药、细胞毒药物和抗血管生成药的额外抗增生药。
附图简述
图1A和图1B显示hu19C11抗体CDR的诱变作图。为了测量hu19C11 Fab变体的相对抗原结合亲和力,通过Fab表达和抗M13噬菌体辣根过氧化物酶(HRP)缀合物来定量抗原结合,检测了连续稀释的噬菌体展示的抗IL4 hu19C11野生型(wt)或LC CDR丙氨酸突变体与ELISA孔上包被的抗gD抗体(A)或IL4(B)的结合。gD是与轻链的C末端融合的表达肽标签。将抗gD抗体直接包被在ELISA孔上,而IL4用ELISA孔上包被的非阻断性抗IL4抗体捕获。
图1C显示,通过开展如图1A和图1B中的测定法比较噬菌体展示的Fab变体的相对IL4结合亲和力,检查了各CDR位点处丙氨酸突变的影响。使用氨基酸的单字母代码。通过以下方式确定相对IL4-结合强度:用线性回归模型拟合数据,随后以IL4结合作用的斜率(相对于噬菌体浓度)除以Fab表达的斜率。低值(点线下方)被认为相对hu1911 wt的低IL4结合亲和力,提示破坏性突变。
图2A是显示hu19C11的IL4结合作用的关键残基的结构示意图,作图在曲妥珠单抗Fab(PDB:1FDV)结构的俯视图上。分别使用POB条目3SQO和3BEI作为重链和轻链的模板,利用MOE生成hu19C11的结构模型。对IL4结合作用重要的残基是LC残基31、32、50、53、91、92和HC残基31、32、96、98及99(按Kabat编号)。在抗原结合位点的俯视图中这些残基在模型结构上以红色着色。通过位点定向突变生成在噬菌体上展示的hu19C11 Fab变体的文库。以粗体标记容许全部20种氨基酸(优选野生型残基)的HC残基,而标记的其他HC残基和LC残基被容许有限的突变以模拟天然多样性。
图2B的表格显示组合文库的设计,以募集第二抗原特异性至hu19C11。显示所选择克隆的CDR序列,所选择的克隆包括与亲本hu19C11野生型相比具有突变的抗IL5特异性(5A)、抗IL4/5特异性(E7、B1)和抗IL4/13特异性(F1、F2)抗体克隆。文库中随机化的残基和分离的克隆中的突变根据其特性而加阴影:具有芳族侧链的Y、W、F;疏水性L、I、V、A、M;碱性K、R、H;酸性D、E;极性S、T、N、Q;和P、G。显示了通过噬菌体竞争测定法的IC50所度量的相对抗原结合亲和力。将Fab展示噬菌体首先在溶液中与相应抗原的连续稀释物温育2小时,未结合的噬菌体随后被抗原包被的ELISA孔短暂捕获并且用抗M13 HRP缀合物检测。将抑制50%噬菌体与抗原包被孔结合的抗原浓度计算为IC50。NB指无可检测的、噬菌体克隆直接与抗原包被孔的结合。
图3显示10个生成的噬菌体展示文库(2144-1至2144-10)的IL4结合能力的滴定曲线。
图4A显示相对于抗IL4特异性hu19C11(SEQ ID NO:1)比对时,hu19C11的双重特异性抗IL4/IL5变体(E7(SEQ ID NO:1)和B1(SEQ ID NO:5))以及抗IL5特异性5A(SEQ ID NO:1)的轻链可变结构域氨基酸序列比对结果。
图4B显示相对于抗IL4特异性hu19C11(SEQ ID NO:2)比对时,hu19C11的双重特异性抗IL4/IL5变体(E7(SEQ ID NO:4)和B1(SEQ ID NO:6))以及抗IL5特异性5A(SEQ ID NO:3)的重链可变结构域氨基酸序列比对结果。
图4C显示相对于抗IL4特异性hu19C11(SEQ ID NO:2)比对时,hu19C11的双重特异性抗IL4/IL13变体(F1(SEQ ID NO:7)和F2(SEQ ID NO:8))的重链可变结构域氨基酸序列比对结果。
图5显示IgG形式的hu19C11的选定变体的双重特异性。将hu19C11的选定变体的抗原结合特异性评估为这些变体以人IgG1样式在250nM与包被在ELISA孔上的(一个或多个)靶抗原或几种无关蛋白质的结合,用抗Fc抗体HRP缀合物检测。
图6显示对hu19C11双重特异性变体(抗IL4特异性野生型:19C11;抗IL5特异性:5A;和抗IL4/5特异性:E7和B1)在所示抗体浓度在阻断IL5与其受体相互作用方面的结合特异性的表征。用链霉亲和素-HRP缀合物检测,在渐增加浓度的IgG形式的人源化19C11或变体存在下,与固定于ELISA孔上的IL5结合的生物素化IL5受体α的水平。
图7A的表格显示IL4/IL5特异性E7的亲和力成熟变体的氨基酸序列以及通过噬菌体竞争测定法所测量的其对靶抗原的相对亲和力。为了改善亲和力,构建展示E7变体的噬菌体文库,其中以“同源物”(粗体)、“有限”(斜体)和“柔性”(灰色)随机化策略突变选择的残基,所述策略分别容许野生型和同源氨基酸、基于天然抗体的有限多样性,或大约50%的野生型和50%的全部其他氨基酸。CDR H2主要经历同源突变以细致优化新募集的针对IL5的结合功能。对于其他CDR,则靶向对IL4结合作用并不关键的那些位点。将选定克隆的序列与E7比对并且显示突变。如上文,通过噬菌体IC50评定每个克隆的相对亲和力。
图7B的表格显示以Fab形式纯化的E7及其亲和力成熟变体1C36和1C60的亲和力,其中在25℃使用固定有人IL5(R&D Systems)或IL4的CM5传感芯片,通过BIAcore测量所述亲和力。
图7C显示相对于E7的轻链可变结构域氨基酸序列(SEQ ID NO:1)比对时,E7的亲和力改善的双重特异性抗IL4/IL5变体1C36(SEQ ID NO:29)和1C60(SEQ ID NO:33)的轻链可变结构域氨基酸序列比对结果。
图7D显示相对于E7的重链可变结构域氨基酸序列(SEQ ID NO:4)比对时,E7的亲和力改善的双重特异性抗IL4/IL5变体1C36(SEQ ID NO:30)和1C60(SEQ ID NO:34)的重链可变结构域氨基酸序列比对结果。
图8A和图8B显示对E7和E7的亲和力成熟变体(1C36和1C60)的结合特异性的表征。通过抗IgG-HRP检测E7和亲和力改善的E7变体(IgG形式)(100nM)与ELISA平板上的固定化抗原和无关蛋白质的直接结合(A)。通过链霉亲和素-HRP缀合物检测在缓冲液(PBS)或50nME7、1C36或1C60存在下生物素化的IL5与ELISA孔上包被的IL5受体的结合(B)。
发明详述
许多疾病途径通过不止一种蛋白质或一种具有不止一种功能的蛋白质的作用演进。例如,过敏性疾病、炎性疾病或自身免疫疾病(例如,哮喘)经常涉及多种细胞因子。双重特异性抗体可用于其中需要靶向多于一种抗原的治疗性和诊断性应用。我们已经发现一种用于产生双重特异性抗体的新方法。当抗体VL包含对抗体-抗原相互作用关键的残基时,则可以通过单独地或与额外的VL残基和构架残基组合地改变VH残基而多样化这类抗体。
一般地,本发明的方法涉及多样化抗体的VH以产生可以在文库中稳定表达的变体。一般地,与第一表位特异性结合、但不与第二表位特异性结合、并且特征为在VL的位置32、50或91(按Kabat编号)的任何一个、两个或三个氨基酸残基处具有带静电残基或疏水残基的抗体,在VH的一个、两个或三个氨基酸残基(例如,溶剂暴露的氨基酸残基)处被改变。随后表达该VH和VL,之后自表达的VH和VL选择能够与第一和第二表位特异性结合的多样化双重特异性抗体或其抗原结合片段。
如下文描述,使用本发明方法产生的示例性抗体包括结合白介素4(IL4)和白介素5(IL5)二者的抗体,以及结合IL4和白介素13(IL13)二者的抗体。这些抗体表明在IL4抗体的重链可变结构域(例如,CDR)中的突变可以赋予对额外的不相关蛋白质以及IL4的双重结合能力,并为改变VH中的残基以赋予双重特异性的一般策略提供了证据。本文所述的双重特异性抗体,包括但不限于IL4/IL5抗体和IL4/IL13抗体,具有同时靶向多种抗原(例如,冗余或非冗余细胞因子途径)的潜力,从而使得它们可用于治疗多种疾病和病症,包括细胞因子介导的疾病(例如,哮喘)。
I.定义
术语“多特异性抗体”以最广义使用,特别地覆盖包含重链可变结构域(VH)和轻链可变结构域(VL)的抗体,其中该VHVL单元具有多表位特异性(即,能够与一个生物分子上的两个不同表位或不同生物分子上的各一个表位结合)。这类多特异性抗体包括,但不限于,全长抗体、具有两个或更多个VL结构域和VH结构域的抗体、抗体片段如Fab、Fv、dsFv、scFv、双体抗体(diabody)、双特异性双体抗体和三体抗体(triabody)、已经共价或非共价连接的抗体片段。“多表位特异性”指与相同或不同靶上两个或两个以上不同表位特异性结合的能力。“双重特异性”或“双特异性”指与相同或不同靶上两个不同表位特异性结合的能力。但是,与双特异性抗体不同,双重特异性抗体是如下形式的天然IgG抗体,其中两个抗原结合臂具有相同的氨基酸序列并且每个Fab臂均能够识别两种抗原。双重特异性允许抗体以单个Fab或IgG分子形式以高亲和力与两种不同抗原相互作用。根据一个实施方案,IgG1形式的多特异性抗体以5μM至0.001pM、3μM至0.001pM、1μM至0.001pM、0.5μM至0.001pM、或者0.1μM至0.001pM的亲和力与每个表位结合。“单特异性”指仅结合一种表位的能力。
通常,抗体包括基本4链抗体单元,其是由两条相同轻链(L)和两条相同重链(H)组成的异源四聚体糖蛋白(IgM抗体由5个基本异源四聚体单元连同称作J链的额外多肽组成,并因此含有10个抗原结合位点,而分泌型IgA抗体可以聚合以形成包含2-5个基本4链单元连同J链的多价装配物)。在IgG的情况下,4链单元通常是约150,000道尔顿。每条L链通过一个共价二硫键连接至H链,而根据H链同种型,两条H链通过一个或多个二硫键彼此连接。每条H和L链还具有规则间隔的链内二硫键。每条H链在N端具有一个可变结构域(VH),后接3个恒定结构域(CH)(对于α链和γ链)或4个CH结构域(对于μ和ε同种型)。每条L链在N端具有一个可变结构域(VL),后接在其另一端的恒定结构域(CL)。VL与VH对齐,并且CL与重链的第一恒定结构域(CH1)对齐。据信,特定氨基酸残基形成轻链可变结构域和重链可变结构域之间的界面。VH和VL的配对共同形成抗原结合位点。关于不同类别抗体的结构和特性,参见,例如,Basic and Clinical Immunology,第8版,Daniel P.Stites,Abba I.Terr和TristramG.Parslow(编著),Appleton&Lange,Norwalk,CT,1994,第71页和第6章。任何脊椎动物物种的L链可以基于其恒定结构域的氨基酸序列而被划分至两个明显不同类型(称作κ和λ)之一。取决于抗体重链恒定结构域(CH)的氨基酸序列,免疫球蛋白可以被划分至不同的类别或同种型。存在五个主要类别的免疫球蛋白:IgA、IgD、IgE、IgG和IgM,具有分别命名为α、δ、γ、ε和μ的重链。基于CH序列和功能方面相对轻微的差异,γ和α类别进一步划分成亚类,例如,人类表达以下亚类:IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。
术语“可变”指抗体之间可变结构域的某些节段在序列方面极为不同的事实。可变或“V”结构域介导抗原结合并定义特定抗体对其特定抗原的特异性。然而,变异性在可变结构域的110个氨基酸跨度上并非均匀地分布。相反,V区由15-30个氨基酸的称作构架区(FR)的相对不变区段隔开称作“高变区”的各长9-12个氨基酸的极为可变的较短区域组成。天然重链和轻链的可变结构域各自包括由3个高变区连接的大体上采取β折叠构型的4个FR,其中高变区形成环,连接该β折叠结构并在一些情况下形成该β折叠结构的一部分。每条链中的高变区通过FR而紧靠在一起,并与来自其他链的高变区一起对抗体的抗原-结合部位的形成作出贡献(参见Kabat等人,Sequences of Proteins of Immunological Interest,第5版.Public Health Service,National Institutes of Health,Bethesda,MD.(1991))。恒定结构域不直接参与抗体与抗原结合,但是展示各种效应子功能,如使抗体参与依赖抗体的细胞毒性(ADCC)。
在本文中使用时,术语“高变区”指抗体中负责抗原结合的氨基酸残基。高变区通常包含来自“互补决定区”或“CDR”的氨基酸残基(例如,VL中约24-34位(L1)、50-56位(L2)和89-97位(L3)残基前后,和VH中约26-35位(H1)、49-65位(H2)和95-102位(H3)残基前后(在一个实施方案中,H1是在约31-35位残基前后);Kabat等人,Sequences of Proteins ofImmunological Interest,第5版.Public Health Service,National Institutes ofHealth,Bethesda,MD.(1991))和/或来自“高变环”的那些残基(例如VL中26-32位(L1)、50-52位(L2)和91-96位(L3)残基,和VH中26-32位(H1)、53-55位(H2)和96-101位(H3)残基;Chothia和Lesk,J.Mol.Biol.196:901-917(1987))。
如本文中所用的术语“单克隆抗体”指来自基本上均一的抗体群体中的抗体,即,除了在产生该单克隆抗体期间可能出现的可能变体(此类变体通常以微小量存在)之外,构成该群体的各个抗体是基本上相似并且结合相同的表位。单克隆抗体一般包括包含结合靶的可变区的抗体,其中所述抗体通过包括从多种抗体选出该抗体的方法获得。例如,该选择方法可以是从多个克隆(例如杂交瘤克隆、噬菌体克隆或重组DNA克隆的汇集物)选择单克隆。应当理解,可以进一步改变所选的抗体,例如以改善对该靶的亲和力、以使抗体人源化、以改善抗体在细胞培养物中的生产、以降低其体内免疫原性、以产生多特异性抗体等,并且应当理解,包含所述改变的可变区序列的抗体也是本发明的单克隆抗体。除了特异性外,单克隆抗体制备物还具有优点——它们一般不混杂其他免疫球蛋白。修饰语“单克隆”表明抗体从基本上同质的抗体群体获得的特征,而不应理解为要求通过任何特定方法产生该抗体。例如,根据本发明使用的单克隆抗体可以通过多种技术产生,包括杂交瘤方法(例如,Kohler等人,Nature,256:495(1975);Harlow等人,Antibodies:A Laboratory Manual,(Cold Spring Harbor Laboratory Press,第2版,1988);Hammerling等人,MonoclonalAntibodies and T-Cell Hybridomas 563-681(Elsevier,N.Y.,1981))、重组DNA方法(参见,例如,美国专利号4,816,567)、噬菌体展示技术(参见,例如,Clackson等人,Nature,352:624-628(1991);Marks等人,J.Mol.Biol.222:581-597(1991);Sidhu等人,J.Mol.Biol.338(2):299-310(2004);Lee等人,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004);和Lee等人,J.Immunol.Methods 284(1-2):119-132(2004))、以及从具有部分或全部人免疫球蛋白基因座或编码人免疫球蛋白序列的基因的动物中生产人抗体或人样抗体的技术(参见,例如,WO98/24893、WO/9634096、WO/9633735和WO91/10741;Jakobovits等人,Proc.Natl.Acad.Sci.USA 90:2551(1993);Jakobovits等人,Nature 362:255-258(1993);Bruggemann等人,Year in Immunol.7:33(1993);美国专利号5,545,806、5,569,825、5,591,669(均属于GenPharm);5,545,807;WO 97/17852、美国专利号5,545,807;5,545,806;5,569,825;5,625,126;5,633,425;和5,661,016;Marks等人,Bio/Technology,10:779-783(1992);Lonberg等人,Nature 368:856-859(1994);Morrison,Nature 368:812-813(1994);Fishwild等人,Nature Biotechnology,14:845-851(1996);Neuberger,NatureBiotechnology,14:826(1996);以及Lonberg和Huszar,Intern.Rev.Immunol.,13:65-93(1995))。
单克隆抗体在本文中特别地包括嵌合抗体、人源化抗体、全人抗体和亲和力成熟抗体。嵌合抗体是这样的抗体,在所述抗体中重链和/或轻链的一部分与源自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源,而所述链的其余部分与源自另一物种或属于另一抗体类别或亚类的抗体中的相应序列相同或同源;以及这种抗体的片段,只要它们展示想要的生物活性即可(美国专利号4,816,567;和Morrison等人,Proc.Natl.Acad.Sci.USA 81:6851-6855(1984))。目的嵌合抗体在本文中包括“灵长类化”抗体,所述灵长类化抗体包含源自非人灵长类(例如,旧世界猴、猿等)的可变结构域抗原结合序列和人恒定区序列。
非人(例如,啮齿类)抗体的“人源化”形式是含有源自非人抗体中最少序列的嵌合抗体。就大部分而言,人源化抗体是人免疫球蛋白(受体抗体),其中来自所述受体的高变区的残基由来自非人物种(供体抗体)(如小鼠、大鼠、兔或非人灵长类动物)的具有所需抗体特异性、亲和力和能力的高变区的残基替换。在一些情况下,该人免疫球蛋白的构架区(FR)残基由相应的非人残基替换。另外,人源化抗体可以包含在受体抗体中或在供体抗体中不存在的残基。作出这些修饰以进一步精化抗体性能。通常,人源化抗体将包含至少1个、并且一般2个,可变结构域的基本上全部,其中全部或基本上全部的高变环与非人免疫球蛋白的对应,而全部或基本上全部的FR区是人免疫球蛋白序列的。人源化抗体任选地也可以包含免疫球蛋白恒定区(Fc),一般是人免疫球蛋白恒定区,的至少一部分。对于进一步细节,参见Jones等人,Nature 321:522-525(1986);Reichmann等人,Nature 332:323-329(1988);和Presta,Curr.Op.Struct.Biol.2:593-596(1992)。
“人抗体”是这样的抗体,所述抗体具有与人产生的抗体的氨基酸序列相对应的氨基酸序列、和/或使用产生人抗体的任何技术产生。人抗体的该定义特别排除包含非人抗原结合残基的人源化抗体。
“亲和力成熟的”抗体是在一个或多个CDR中存在一个或多个改变的抗体,其中与没有这些改变的亲本抗体相比,所述改变导致抗体对抗原的亲和力改善。优选的亲和力成熟的抗体将对靶抗原具有纳摩尔或甚至皮摩尔亲和力。可以通过本领域已知的方法产生亲和力成熟的抗体。Marks等人,Bio/Technology 10:779-83(1992)描述了借助VH和VL结构域改组的亲和力成熟。CDR和/或构架残基的随机诱变由Barbas等人,Proc Nat.Acad.Sci.USA91:3809-13(1994);Schier等人,Gene 169:147-55(1995);Yelton等人,J.Immunol.155:1994-2004(1995);Jackson等人,J.Immunol.154(7):3310-19(1995);和Hawkins等人,J.Mol.Biol.226:889-96(1992)描述。
“完整抗体”是包含抗原结合位点以及CL和至少重链恒定结构域——CH1、CH2和CH3的抗体。恒定结构域可以是天然序列恒定结构域(例如,人天然序列恒定结构域)或其氨基酸序列变体。优选地,完整抗体具有一种或多种效应子功能。
“抗体片段”包含完整抗体的一部分,优选地完整抗体的抗原结合区或可变区。抗体片段的例子包括Fab、Fab'、F(ab')2和Fv片段;双体抗体;线性抗体(参见美国专利号5,641,870,实施例2;Zapata等人,Protein Eng.8(10):1057-1062(1995));单链抗体分子;和从抗体片段形成的多特异性抗体。
表述“线性抗体”通常指在Zapata等人,Protein Eng.8(10):1057-1062(1995)中描述的抗体。简而言之,这些抗体包含一对串联的Fd区段(VH-CH1-VH-CH1),它们与互补轻链多肽一起形成一对抗原结合区。线性抗体可以是双特异或单特异的。
木瓜蛋白酶消化抗体产生两个相同的抗原结合片段,称作“Fab”片段,和一个残余“Fc”片段——该命名反映易于结晶的能力。Fab片段由完整L链连同H链的可变区结构域(VH)和一条重链的第一恒定结构域(CH1)组成。胃蛋白酶处理抗体产生一个大的F(ab’)2片段,所述片段大致对应于二硫键连接的两个Fab片段,具有二价抗原结合活性并且仍然能够交联抗原。Fab'片段因在CH1结构域的羧基端处具有额外几个残基(包括来自抗体铰链区的一个或多个半胱氨酸)而与Fab片段不同。Fab'-SH在本文是Fab'的名称,其中恒定结构域的半胱氨酸残基携带游离巯基。F(ab')2抗体片段最初作为之间具有铰链半胱氨酸的成对Fab’片段产生。抗体片段的其他化学偶联也是已知的。
Fc片段包含通过二硫键结合在一起的两条H链的羧基端部分。抗体的效应子功能由Fc区中的序列决定;该区域也是某些类型细胞上存在的Fc受体(FcR)所识别的部分。
“Fv”由紧密、非共价缔合的一个重链可变区结构域和一个轻链可变区结构域的二聚体组成。自这两个结构域的折叠产生6个高变环(来自H和L链的各3个环),其贡献用于抗原结合的氨基酸残基并向该抗体赋予抗原结合特异性。然而,甚至单一可变结构域(或仅包含3个抗原特异性CDR的半个Fv)也可以具有识别并结合抗原的能力,虽然经常以小于完整结合部位的亲和力进行。
“单链Fv”也缩写为“sFv”或“scFv”,是包含连接成为单条多肽链的VH和VL抗体结构域的抗体片段。优选地,sFv多肽还包含在VH结构域和VL结构域之间的多肽接头,所述多肽接头能够使scFv形成抗原结合所需的结构。关于sFv的综述,参见Pluckthun,ThePharmacology of Monoclonal Antibodies,第113卷,Rosenburg和Moore编著,Springer-Verlag,New York,第269-315页(1994);Borrebaeck 1995。
术语“双体抗体”指通过以下方式制备的小抗体片段:构建在VH和VL结构域之间具有短接头(约5-10个残基)的sFv片段(参见前述段落),从而实现V结构域的链间而非链内配对,产生双价片段,即具有两个抗原结合位点的片段。双特异性双体抗体是两个“交叉”sFv片段的异源二聚体,其中这两个抗体的VH和VL结构域存在于不同的多肽链上。在例如EP404,097;WO 93/11161;和Hollinger等人,Proc.Natl.Acad.Sci.USA 90:6444-6448(1993)中更充分地描述了双体抗体。.
“带静电的”意指具有电荷。通常,带静电的氨基酸具有极性侧链或带电荷侧链。具有极性侧链的氨基酸的例子包括丝氨酸、苏氨酸、酪氨酸、半胱氨酸、天冬酰胺和谷氨酰胺。具有带负电荷侧链的氨基酸的例子包括天冬氨酸和谷氨酸。具有带正电荷侧链的氨基酸的例子包括赖氨酸、精氨酸和组氨酸。
“疏水性”意指与水不相容、或不易在水中溶解、不易吸收水或不易与水混合。通常,疏水性氨基酸具有非极性侧链并且示例包括丙氨酸、甘氨酸、异亮氨酸、亮氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、色氨酸和缬氨酸。
术语“细胞因子”是一个上位术语,用于指由一个细胞群体释放、作为细胞间介质而作用于另一细胞的蛋白质。细胞因子的例子包括淋巴因子、单核因子和传统的多肽激素。细胞因子包括生长激素如人生长激素、N-甲硫酰人生长激素和牛生长激素;甲状旁腺激素;甲状腺素;胰岛素和胰岛素原;松弛素和松弛素原;糖蛋白激素如促卵泡激素(FSH)、促甲状腺激素(TSH)和促黄体激素(LH);肝生长因子;成纤维细胞生长因子;催乳素;胎盘催乳激素;肿瘤坏死因子-α和-β;缪勒管抑制物质;小鼠促性腺激素相关肽;抑制素;活化素;血管内皮生长因子;整联蛋白;促血小板生成素(TPO);神经生长因子如NGF-β;血小板生长因子;转化生长因子(TGF)如TGF-α和TGF-β;胰岛素样生长因子-I和-II;促红细胞生成素(EPO);骨诱导因子;干扰素如干扰素-α、-β和-γ;集落刺激因子(CSF)如巨噬细胞-CSF(M-CSF);粒细胞-巨噬细胞-CSF(GM-CSF);和粒细胞-CSF(G-CSF);白介素(IL)如IL1、IL1α、IL2、IL3、IL4、IL5、IL6、IL7、IL8、IL11、IL12、IL13;肿瘤坏死因子如TNF-α或TNF-β;和其他多肽因子,包括LIF和kit配体(KL)。如本文所用,术语“细胞因子”包括来自天然来源或来自重组细胞培养物的蛋白质和天然序列细胞因子的生物活性等同物。
如本文所用,“密码子集合”指用来编码所需的变异氨基酸的一组不同的核苷酸三联体序列。可以合成,例如通过固相合成法合成,一组寡核苷酸,包括代表由密码子集合提供的核苷酸三联体的所有可能组合并编码所需氨基酸群组的序列。密码子命名的标准形式是本领域已知和本文所述的IUB代码形式。一个密码子集合一般由3个斜体大写字母表示,例如,NNK、NNS、XYZ、DVK等(例如,NNK密码子指密码子的位置1和2中N=A/T/G/C及位置3中K=G/T(按等摩尔比),以编码全部20种天然氨基酸)。如本文所用的“非随机密码子集合”因此指,密码子集合编码选定氨基酸,其中所述选定氨基酸部分满足、优选地完全满足本文中所述的氨基酸选择标准。合成在某些位置具有选定核苷酸“简并性”的寡核苷酸是本领域熟知的,例如TRIM法(Knappek等人,JJ.Mol.Biol.296:57-86,1999);Garrard和Henner,Gene128:103,1993)。具有某些密码子集合的寡核苷酸集合可以使用商业核酸合成仪(例如可从Applied Biosystems,Foster City,CA获得)合成,或可以商业地获得(例如,从LifeTechnologies,Rockville,MD)。因此,具有一定密码子集合的寡核苷酸集合一般将包括具有不同序列的多个寡核苷酸,差异由整个序列内部的密码子集合确定。如根据本发明使用的寡核苷酸具有允许与可变结构域核酸模板杂交的序列并且还可以,但不一定,包括限制性酶位点(例如,用于克隆目的)。
“结合”目的抗原的本发明抗体是这样的抗体,所述抗体以足够亲和力结合该抗原,从而所述抗体可以作为诊断剂和/或治疗剂用于靶向蛋白质或表达该抗原的细胞或组织,并且不明显与其他蛋白质交叉反应。在这类实施方案中,如荧光激活细胞分选(FACS)分析或放射免疫沉淀(RIA)或ELISA)所测定的,抗体与“非靶”蛋白结合的程度将小于该抗体与其特定靶蛋白的结合的约10%。就抗体与靶分子的结合而言,术语“特异性结合”或“特异结合于”或“特异于”特定多肽或特定多肽靶上的表位意指,该结合可测量地与非特异性相互作用不同。可以测量特异性结合,例如,通过与对照分子的结合相比来确定分子的结合。例如,可以通过与类似于靶的对照分子(例如过量的未标记靶)竞争来测定特异性结合。在这种情况下,如果标记的靶与探针的结合受过量未标记的靶竞争性抑制,则指示特异性结合。如本文所用的术语“特异性结合”或“特异结合于”或“特异于”特定多肽或特定多肽靶上的表位,可以,例如,通过分子对靶具有下述KD来显示:10-4M或更低、备选地10-5M或更低、备选地10-6M或更低、备选地10-7M或更低、备选地10-8M或更低、备选地10-9M或更低、备选地10- 10M或更低、备选地10-11M或更低、备选地10-12M或更低、或在10-4M至10-12M、或10-6M至10-10M、或10-7M至10-9M范围内。技术人员明了,亲和力和KD值反相关。对抗原的高亲和力由低KD值量度。在一个实施方案中,,术语“特异性结合”指这样的结合,其中分子与特定多肽或特定多肽上的表位结合而基本上不与任何其他多肽或多肽表位结合。
除非另外说明,否则就本发明的多肽而言“生物活性的”和“生物学活性”和“生物学特征”意指具有与生物分子结合的能力。
“生物分子”指核酸、蛋白质、糖、脂质及其组合。在一个实施方案中,生物分子存在于自然界中。
当用来描述本文中公开的各种抗体时,“分离的”意指抗体已经获得鉴定并从表达其的细胞或细胞培养物分离和/或回收。其自然环境的杂质组分是一般将会干扰该多肽的诊断性或治疗性用途的物质,并且可以包括酶、激素和其他蛋白质性或非蛋白质性溶质。在优选的实施方案中,将该抗体纯化至(1)足以通过转杯测序仪(spinning cup sequenator)获得至少15个残基的N端或内部氨基酸序列的程度;或(2)通过在非还原或还原条件下SDS-PAGE和使用考马斯蓝或优选地使用银染所确定的均一性。由于不存在多肽自然环境中的至少一种组分,在重组细胞内的原位抗体包括在分离的抗体中。然而,一般,分离的多肽通过至少一个纯化步骤制备。
术语“控制序列”指,在特定宿主生物中表达有效连接的编码序列所必需的DNA序列。适于原核生物的控制序列例如包括启动子、任选地操纵基因序列和核糖体结合位点。已知真核细胞利用启动子、多聚腺苷化信号和增强子。
当一个核酸与另一个核酸序列处于功能性关系中时,该核酸是“有效连接的”。例如,前序列或分泌性前导序列的DNA与编码多肽的DNA有效连接,则其可以表达为参与所述多肽分泌的前蛋白;启动子或增强子与编码序列有效连接,则其可以影响所述编码序列的转录;或者,核糖体结合位点与编码序列有效连接,则该核糖体结合位点被放置在利于翻译的位置。通常,“有效连接”意指连接的DNA序列是连续的,并且,在分泌性前导序列情况下,是连续的并在读框中。然而,增强子不必是连续的。连接通过在便利的限制性位点处连接而完成。如此类位点不存在,则可以根据常规实践使用合成性寡核苷酸衔接头或接头。
相对于本文中鉴定的多肽序列,“氨基酸序列同一性百分数(%)”定义为,比对序列并根据需要引入空位以实现最大序列同一性百分数并且不考虑任何保守性置换作为序列同一性的部分时,候选序列中与正在比较的多肽序列中的氨基酸残基相同的氨基酸残基的百分数。为了确定氨基酸序列同一性百分数的比对可以按本领域能力范围内的多种方式实现,例如,使用可公开获得的计算机软件如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员可以确定用于测量比对的适宜参数,包括为实现正在比较的序列全长范围内的最大比对所需要的任何算法。然而,出于本文目的,可以使用序列比较计算机程序ALIGN-2,产生氨基酸序列同一性%值。ALIGN-2序列比较计算机程序由Genentech,Inc.授权,并且源代码已经随用户文档提交至华盛顿特区20559的美国版权局,在那里它以美国版权登记号TXU510087登记。ALIGN-2程序可通过Genentech,Inc.,South San Francisco,加利福尼亚州公开获得。该ALIGN-2程序应当汇编用于UNIX操作系统、优选地数字式UNIXV4.0D上。全部序列比较参数由ALIGN-2程序设定,并且不变。
除非另外说明,否则本文所述的氨基酸序列是连续氨基酸序列。
本发明的“结构上不相似的”生物分子指,不属于相同类别(蛋白质、核酸、脂质、糖等)、或例如当指蛋白质时彼此具有小于60%氨基酸同一性、小于50%氨基酸同一性、小于40%氨基酸同一性、小于30%氨基酸同一性、小于20%氨基酸同一性或小于10%氨基酸同一性的生物分子。
杂交反应的“严格性”可由本领域普通技术人员容易地确定,并且通常是依赖于探针长度、洗涤温度和盐浓度的经验计算值。通常,较长的探针需要较高的温度以正确退火,而较短的探针需要较低的温度。当在低于其解链温度的环境中存在互补链时,杂交通常取决于变性的DNA再退火的能力。探针和可杂交序列之间的期望同源性程度越高,可以使用的相对温度越高。因此,随之而来,较高的相对温度将倾向于使反应条件更严格,而较低的温度将倾向于使反应条件的严格性较低。关于杂交反应严格性的其它细节和解释,参见Ausubel等人,Current Protocols in Molecular Biology,Wiley IntersciencePublishers,(1995)。
如本文定义,“严格条件”或“高严格条件”可以由以下确定:(1)使用低离子强度和高温进行洗涤,例如,0.015M氯化钠/0.0015M柠檬酸钠/0.1%十二烷基硫酸钠,在50℃;(2)在杂交期间使用变性剂,如甲酰胺,例如,50%(v/v)甲酰胺,以及0.1%牛血清白蛋白/0.1%Ficoll/0.1%聚乙烯吡咯烷酮/50mM磷酸钠缓冲液pH 6.5,和750mM氯化钠、75mM柠檬酸钠,在42℃;或(3)在使用50%甲酰胺、5x SSC(0.75M NaCl、0.075M柠檬酸钠)、50mM磷酸钠(pH 6.8)、0.1%焦磷酸钠、5x Denhardt溶液,超声的鲑精DNA(50μg/ml)、0.1%SDS和10%硫酸葡聚糖的溶液中在42℃过夜杂交,在42℃于0.2x SSC(氯化钠/柠檬酸钠)中洗涤10分钟,随后为由55℃含有EDTA的0.1x SSC组成的10分钟高严格洗涤。
“中等严格条件”可以如Sambrook等人,Molecular Cloning:A LaboratoryManual,New York:Cold Spring Harbor Press,1989所述确定,包括使用严格性比上文所述低的洗涤溶液和杂交条件(例如,温度、离子强度和%SDS)。中等严格条件的例子是在37℃于包含20%甲酰胺、5×SSC(150mM NaCl、15mM柠檬酸三钠)、50mM磷酸钠(pH 7.6)、5×Denhardt溶液、10%硫酸葡聚糖和20mg/ml变性剪切鲑精DNA的溶液中孵育过夜,随后在约37-50℃于1×SSC中洗涤滤膜。本领域技术人员明了如何按照需要调整温度、离子强度等以适应诸如探针长度等因素。
抗体“效应子功能”指,归因于抗体Fc区(天然序列Fc区或氨基酸序列变体Fc区)的那些生物活性,其随抗体同种型而变动。抗体效应子功能的例子包括:C1q结合和补体依赖的细胞毒性;Fc受体结合;抗体依赖的细胞介导的细胞毒性(ADCC);吞噬作用;细胞表面受体(例如,B细胞受体)的下调;和B细胞活化。
“抗体依赖的细胞介导的细胞毒性”或“ADCC”指一种形式的细胞毒性,其中结合到某些细胞毒性细胞(例如,天然杀伤(NK)细胞、嗜中性粒细胞和巨噬细胞)上存在的Fc受体(FcRs)上的分泌型Ig使得这些细胞毒效应细胞可以与携带抗原的靶细胞特异性结合并随后用细胞毒素杀伤靶细胞。抗体“武装”了细胞毒性细胞并且是这类杀伤作用绝对需要的。介导ADCC的主要细胞,即NK细胞,仅表达FcγRIII,而单核细胞表达FcγRI、FcγRII和FcγRIII。Ravetch和Kinet,Annu.Rev.Immunol.9:457-92(1991)的第464页表3中总结了造血细胞上的FcR表达。为了评估目的分子的ADCC活性,可以进行体外ADCC测定法,如美国专利号5,500,362或5,821,337中描述的测定法。可以用于此类测定法的效应细胞括外周血单个核细胞(PBMC)和天然杀伤(NK)细胞。备选或额外地,可以在体内,例如,在动物模型中,如在Clynes等人,(Proc.Natl.Acad.Sci.USA)95:652-656(1998)公开的动物模型中,评估目的分子的ADCC活性。
“Fc受体”或“FcR”描述与抗体的Fc区结合的受体。优选的FcR是天然序列人FcR。另外,优选的FcR是结合IgG抗体的受体(γ受体),并且包括FcγRI、FcγRII和FcγRIII亚类受体,包括这些受体的等位变体和可变剪接形式。FcγRII受体包括FcγRIIA(“激活性受体”)和FcγRIIB(“抑制性受体”),它们具有相似氨基酸序列,主要区别在于其胞质域。激活性受体FcγRIIA在其胞质域中含有免疫受体酪氨酸激活基序(ITAM)。抑制性受体FcγRIIB在其胞质域中含有免疫受体酪氨酸抑制基序(ITIM)(参见“Annu.Rev.Immunol.”15:203-234(1997)中的综述)。FcR在Ravetch和Kinet,(Annu.Rev.Immunol 9:457-492(1991));Capel等人,(Immunomethods 4:25-34(1994));和de Haas等人,(J.Lab.Clin.Med.126:330-41(1995))中综述。本文中的术语“FcR”涵盖其他FcR,包括将来鉴定的那些。该术语还包括负责转移母体IgG至胎儿的新生儿受体FcRn(Guyer等人,J.Immunol.117:587(1976)和Kim等人,J.Immunol.24:249(1994))。
“人效应细胞”是表达一种或多种FcR并执行效应子功能的白细胞。优选地,细胞至少表达FcγRIII并且执行ADCC效应子功能。介导ADCC的人白细胞的例子包括外周血单个核细胞(PBMC)、天然杀伤(NK)细胞、单核细胞、细胞毒T细胞和中性粒细胞,优选PBMC和NK细胞。效应细胞可以从天然来源(例如,从血液)分离。
“补体依赖的细胞毒性”或“CDC”指在补体存在下靶细胞的溶解。经典补体途径的活化由补体系统第一组分(C1q)与(适宜亚类)抗体的结合来启动,其中所述抗体结合至其关连抗原上。为评估补体激活,可以进行CDC测定法,例如,如Gazzano-Santoro等人,J.Immunol.Methods 202:163(1996)中所述。
“治疗有效量”指抗体或抗体片段在受试者中治疗疾病或病症的量。在变应性疾病、炎性疾病或自身免疫性疾病(例如,哮喘、关节炎等)情况下,治疗有效量的抗体或抗体片段(例如,针对IL4和IL5或IL4和IL13的双重特异性或多特异性抗体或抗体片段)可以改善或治疗疾病,或预防、减少、改善或治疗与疾病相关的症状。在增生性疾病(例如,癌性肿瘤)的情况下,治疗有效量的抗体或抗体片段可以减少癌细胞的数目;缩减原发肿瘤大小;抑制(即,某种程度减缓并且优选地终止)癌细胞浸润至外周器官中;抑制(即,某种程度减缓并且优选地终止)肿瘤转移;某种程度抑制肿瘤生长;和/或某种程度减轻一种或多种与该病症相关的症状。就抗体或抗体片段可以阻止生长和/或杀死现存癌细胞而言,它可以是抑制细胞的和/或细胞毒的。对于癌症疗法,可以例如通过评估存活持续时间、至病情进展时间(TTP)、无疾病存活持续时间(DFS)、无病情进展存活持续时间(PFS)、反应率(RR)、反应持续时间和/或生活质量,量度体内功效。
“减少或抑制”意指引起优选地20%或更多、更优选地50%或更多、并且最优选地75%、85%、90%、95%或更多的总体减少的能力。减少或抑制可以指正在治疗的病症的症状、转移的存在或大小、原发肿瘤的大小或血管发生性病症中血管的大小或数目。
如本文所用的“炎性疾病”指导致炎症的病理学状态,典型地由嗜中性粒细胞的趋化作用引起。
本文中所用的“自身免疫病”是起于并且针对个体的自身组织的疾病或病症,或者其共分离或表现,或从其导致的病状。
炎性、自身免疫性、或炎性自身免疫性疾病或病症的实例包括,但是不限于,哮喘(asthma)如支气管哮喘(asthma bronchiale)、支气管哮喘(bronchial asthma)和自身免疫性哮喘(auto-immune asthma)、关节炎(arthritis)(类风湿性关节炎(rheumatoidarthritis)如急性关节炎(acute arthritis)、慢性类风湿性关节炎(chronic rheumatoidarthritis)、痛风性关节炎(gouty arthritis)、急性痛风性关节炎(acute goutyarthritis)、慢性炎性关节炎(chronic inflammatory arthritis)、变性关节炎(degenerative arthritis)、感染性关节炎(infectious arthritis)、莱姆关节炎(Lymearthritis)、增生性关节炎(proliferative arthritis)、银屑病关节炎(psoriaticarthritis)、椎骨关节炎(vertebral arthritis),和幼年发作型类风湿性关节炎(juvenile-onset rheumatoid arthritis)、骨关节炎(osteoarthritis)、慢性进行性关节炎(arthritis chronica progrediente)、变形性关节炎(arthritis deformans)、慢性原发多发性关节炎(polyarthritis chronica primaria)、反应性关节炎(reactivearthritis)和强直性脊柱炎(ankylosing spondylitis))、炎性过度增生性皮肤病(inflammatory hyperproliferative skin diseases)、银屑病(psoriasis)如斑块状银屑病(plaque psoriasis)、滴状银屑病(gutatte psoriasis)、脓疱性银屑病(pustularpsoriasis)和趾甲银屑病(psoriasis of the nails)、皮炎(dermatitis),包括接触性皮炎(contact dermatitis)、慢性接触性皮炎(chronic contact dermatitis)、过敏性皮炎(allergic dermatitis)、过敏性接触性皮炎(allergic contact dermatitis)、疱疹样皮炎(dermatitis herpetiformis),和特异性皮炎(atopic dermatitis)、X连锁的IgM过多综合征(x-linked hyper IgM syndrome)、荨麻疹(urticaria)如慢性变应性荨麻疹(chronicallergic urticaria)和慢性特发性荨麻疹(chronic idiopathic urticaria),包括慢性自身免疫性荨麻疹(chronic autoimmune urticaria)、多发性肌炎/皮肌炎(polymyositis/dermatomyositis)、幼年型皮肌炎(juvenile dermatomyositis)、中毒性表皮坏死松解症(toxic epidermal necrolysis)、硬皮病(scleroderma)(包括全身性硬皮病(systemic scleroderma))、硬化(sclerosis)如系统性硬化病(systemic sclerosis)、多发性硬化(multiple sclerosis)(MS)如脊髓-视神经MS(spino-optical MS)、原发性进行性MS(primary progressive MS(PPMS))和复发缓解性MS(relapsing remitting MS(RRMS))、进行性系统性硬化病(progressive systemic sclerosis)、动脉粥样硬化(atherosclerosis)、动脉硬化(arteriosclerosis)、散播性硬化(sclerosisdisseminata)和共济失调性硬化(ataxic sclerosis)、炎性肠病(IBD)(例如,节段性回肠炎(Crohn's disease)、自身免疫介导的胃肠病、结肠炎如溃疡性结肠炎(ulcerativecolitis)、溃疡性结肠炎(colitis ulcerosa)、显微镜性结肠炎(microscopic colitis)、胶原性结肠炎(collagenous colitis)、息肉状结肠炎(colitis polyposa)、坏死性小肠结肠炎(necrotizing enterocolitis)和透壁性结肠炎(transmural colitis)、与自身免疫炎性肠病(autoimmune inflammatory bowel disease))、坏疽性脓皮病(pyodermagangrenosum)、结节性红斑(erythema nodosum)、原发性硬化胆管炎(primary sclerosingcholangitis)、表层巩膜炎(episcleritis))、呼吸窘迫综合症(respiratory distresssyndrome)、包括成人或急性呼吸窘迫综合症(adult or acute respiratory distresssyndrome(ARDS))、脑膜炎(meningitis)、全部或部分葡萄膜的炎症、虹膜炎(iritis)、脉络膜炎(choroiditis)、自身免疫血液病(autoimmune hematological disorder)、类风湿性脊椎炎(rheumatoid spondylitis)、突发性听力丧失(sudden hearing loss)、IgE-介导的疾病如过敏反应(anaphylaxis)和过敏性与特应性鼻炎(allergic and atopicrhinitis)、IgE过多综合征(hyper IgE syndrome)、脑炎(encephalitis)如Rasmussen脑炎(Rasmussen's encephalitis)和边缘性和/或脑干脑炎(limbic and/or brainstemencephalitis)、葡萄膜炎(uveitis)、如前葡萄膜炎(anterior uveitis)、急性前葡萄膜炎(acute anterior uveitis)、肉芽肿性葡萄膜炎(granulomatous uveitis)、非肉芽肿性葡萄膜炎(nongranulomatous uveitis)、晶状体抗原性葡萄膜炎(phacoantigenicuveitis)、后葡萄膜炎(posterior uveitis),或自身免疫性葡萄膜炎(autoimmuneuveitis)、伴有和不伴有肾病综合征的肾小球肾炎(GN)(glomerulonephritis(GN)withand without nephrotic syndrome),如慢性或急性肾小球肾炎(chronic or acuteglomerulonephritis)如原发性GN(primary GN)、免疫介导的GN(immune-mediated GN)、膜性GN(膜性肾病)(membranous GN(membranous nephropathy))、特发性膜性GN(idiopathicmembranous GN)或特发性膜性肾病(idiopathic membranous nephropathy)、膜(membrano-)或膜性(membranous)增生性GN(MPGN)(membrano-or membranousproliferative GN(MPGN)),包括I型和II型,和快速进行性GN(rapidly progressive GN)、过敏性体质(allergic conditions)、变态反应(allergic reaction)、湿疹(eczema),包括变应性或特发性湿疹(allergic or atopic eczema)、硬皮病(scleroderma)、惠普尔病(Whipple’s disease)、增生性瘢痕(hypertrophic scarring)、先兆子痫(preeclampsia)、腹腔粘连(abdominal adhesions)、涉及T细胞浸润和慢性炎症反应的病状、慢性肺部炎性疾病(chronic pulmonary inflammatory disease)、自身免疫性心肌炎(autoimmunemyocarditis)、白细胞黏附性缺陷(leukocyte adhesion deficiency)、系统性红斑狼疮(systemic lupus erythematosus(SLE))或系统性红斑狼疮(systemic lupuserythematodes)如皮肤SLE(cutaneous SLE)、亚急性皮肤型红斑狼疮(subacutecutaneous lupus erythematosus)、新生儿期狼疮综合征(NLE)(neonatal lupussyndrome(NLE))、播散性红斑狼疮(lupus erythematosus disseminatus)、狼疮(lupus)(包括肾炎(nephritis)、脑炎(cerebritis)、儿科(pediatric)、非肾(non-renal)、肾外(extra-renal)、盘状(discoid)、秃顶性狼疮(alopecia))、幼年发作型(I型)糖尿病(juvenile onset(Type I)diabetes mellitus),包括儿科胰岛素依赖性糖尿病(pediatric insulin-dependent diabetes mellitus(IDDM))、成人发作型糖尿病(II型糖尿病)(adult onset diabetes mellitus(Type II diabetes))、自身免疫性糖尿病(autoimmune diabetes)、特发性尿崩症(idiopathic diabetes insipidus)、与细胞因子及T淋巴细胞介导的急性和迟发型超敏反应相关的免疫反应、结核病(tuberculosis)、结节病(sarcoidosis)、肉芽肿(granulomatosis),包括淋巴瘤样肉芽肿(lymphomatoidgranulomatosis)、韦格纳肉芽肿病(Wegener’s granulomatosis)、粒细胞缺乏症(agranulocytosis)、血管炎类(vasculitides),包括血管炎(vasculitis)(包括大血管血管炎(large vessel vasculitis)(包括风湿性多肌痛(polymyalgia rheumatic)和巨细胞(Takayasu's)动脉炎(giant cell(Takayasu’s)arteritis))、中等血管血管炎(mediumvessel vasculitis)(包括Kawasaki病(Kawasaki’s disease)和结节性多动脉炎(polyarteritis nodosa))、显微镜下多动脉炎(microscopic polyarteritis)、CNS血管炎(CNS vasculitis)、坏死性、皮肤型或超敏性血管炎(necrotizing,cutaneous,orhypersensitivity vasculitis)、系统性坏死性血管炎(systemic necrotizingvasculitis),和ANCA相关的血管炎(ANCA-associated vasculitis),如Churg-Strauss血管炎或综合征(Churg-Strauss vasculitis or syndrome(CSS)))、颞动脉炎(temporalarteritis)、再生障碍性贫血(aplastic anemia)、自身免疫性再生障碍性贫血(autoimmune aplastic anemia)、Coombs阳性贫血(Coombs positive anemia)、先天性再生障碍性贫血(Diamond Blackfan anemia)、溶血性贫血(hemolytic anemia)或免疫性溶血性贫血(immune hemolytic anemia),包括自身免疫性溶血性贫血(autoimmunehemolytic anemia(AIHA))、恶性贫血(pernicious anemia(anemia perniciosa))、Addison病(Addison’s disease)、纯红细胞贫血或发育不良(pure red cell anemia oraplasia(PRCA))、因子VIII缺乏症(Factor VIII deficiency)、血友病A(hemophilia A)、自身免疫性嗜中性粒细胞减少症(autoimmune neutropenia)、泛白细胞减少症(pancytopenia)、白细胞减少症(leukopenia)、涉及白细胞渗出的疾病(diseasesinvolving leukocyte diapedesis)、CNS炎性疾病(CNS inflammatory disorders)、多器官损伤综合征(multiple organ injury syndrome),如继发于败血症、创伤或出血的那些多器官损伤综合征、抗原-抗体复合物介导的疾病(antigen-antibody complex-mediateddiseases)、抗肾小球基底膜病(anti-glomerular basement membrane disease)、抗磷脂抗体综合征(anti-phospholipid antibody syndrome)、变应性神经炎(allergicneuritis)、Bechet或Behcet病(Bechet’s or Behcet’s disease)、Castleman综合征(Castleman’s syndrome)、Goodpasture综合征(Goodpasture’s syndrome)、Reynaud综合征(Reynaud's syndrome)、Sjogren综合征(Sjogren’s syndrome)、Stevens-Johnson综合征(Stevens-Johnson syndrome)、类天疱疮(pemphigoid),如大疱性类天疱疮(pemphigoidbullous)和皮肤类天疱疮(skin pemphigoid)、天疱疮(pemphigus)(包括寻常性天疱疮(pemphigus vulgaris)、落叶状天疱疮(pemphigus foliaceus)、粘膜类天疱疮性天疱疮(pemphigus mucus-membrane pemphigoid)和红斑性天疱疮(pemphiguserythematosus))、自身免疫性多内分泌腺病(autoimmune polyendocrinopathies)、Reiter病或综合征(Reiter's disease or syndrome)、免疫复合物肾炎(immune complexnephritis)、抗体-介导的肾炎(antibody-mediated nephritis)、视神经脊髓炎(neuromyelitis optica)、多发性神经病(polyneuropathies)、慢性神经病(chronicneuropathy)如IgM多发性神经病(IgM polyneuropathies)或IgM-介导的神经病(IgM-mediated neuropathy)、血小板减少症(thrombocytopenia)(如由心肌梗死患者发展),包括血栓性血小板减少性紫癜(thrombotic thrombocytopenic purpura(TTP)),和自身免疫性或免疫介导的血小板减少症(autoimmune or immune-mediated thrombocytopenia),如特发性血小板减少性紫癜(idiopathic thrombocytopenic purpura(ITP))(包括慢性或急性ITP)、睾丸和卵巢的自身免疫病,包括自身免疫性睾丸炎(orchitis)和卵巢炎(oophoritis)、原发性甲状腺功能减退症(primary hypothyroidism)、甲状旁腺功能减退症(hypoparathyroidism)、自身免疫性内分泌疾病(autoimmune endocrine diseases)(包括甲状腺炎(thyroiditis)如自身免疫性甲状腺炎(autoimmune thyroiditis)、桥本病(Hashimoto's disease)、慢性甲状腺炎(chronic thyroiditis)(桥本甲状腺炎(Hashimoto’s thyroiditis))或亚急性甲状腺炎(subacute thyroiditis)、自身免疫性甲状腺疾病(autoimmune thyroid disease)、特发性甲状腺功能减退症(idiopathichypothyroidism)、Grave病(Grave's disease)、多内分泌腺综合征(polyglandularsyndromes),如自身免疫性多内分泌腺综合征(autoimmune polyglandular syndromes)(或多内分泌腺内分泌病综合征(polyglandular endocrinopathy syndromes))、副肿瘤性综合征(paraneoplastic syndromes),包括神经系统副肿瘤综合征(neurologicparaneoplastic syndromes)如Lambert-Eaton肌无力综合征(Lambert-Eaton myasthenicsyndrome)或Eaton-Lambert综合征(Eaton-Lambert syndrome)、僵人或僵者综合征(stiff-man or stiff-person syndrome)、脑脊髓炎(encephalomyelitis),如变应性脑脊髓炎(allergic encephalomyelitis)或过敏性脑脊髓炎(encephalomyelitis allergic)和实验性变应性脑脊髓炎(experimental allergic encephalomyelitis(EAE))、重症肌无力(myasthenia gravis)如胸腺肿瘤相关重症肌无力(thymoma-associated myastheniagravis)、小脑变性(cerebellar degeneration)、神经性肌强直(neuromyotonia)、视性眼阵挛或视性眼阵挛肌阵挛综合征(opsoclonus or opsoclonus myoclonus syndrome(OMS)),和感觉神经病(sensory neuropathy)、多灶性运动神经病(multifocal motorneuropathy)、Sheehan综合征(Sheehan’s syndrome)、自身免疫性肝炎(autoimmunehepatitis)、慢性肝炎(chronic hepatitis)、类狼疮肝炎(lupoid hepatitis)、巨细胞肝炎(giant cell hepatitis)、慢性活动性肝炎(chronic active hepatitis)或自身免疫性慢性活动性肝炎(autoimmune chronic active hepatitis)、淋巴细胞间质性肺炎(lymphoid interstitial pneumonitis)、闭塞性细支气管炎(非移植物)抗NSIP(bronchiolitis obliterans(non-transplant)vs NSIP)、Guillain-Barre综合征(Guillain-Barrésyndrome)、Berger病(Berger’s disease)(IgA神经病(IgAnephropathy))、特发性IgA神经病(idiopathic IgA nephropathy)、线状IgA皮肤病(linear IgA dermatosis)、原发性胆汁性肝硬化(primary biliary cirrhosis)、肺硬变(pneumonocirrhosis)、自身免疫性肠病综合征(autoimmune enteropathy syndrome)、腹腔疾病(Celiac disease)、乳糜泻(celiac sprue)(谷蛋白肠病(gluten enteropathy))、难治性口炎性腹泻(refractory sprue)、特发性口炎性腹泻(idiopathic sprue)、冷球蛋白血症(cryoglobulinemia)、肌萎缩侧索硬化(amylotrophic lateral sclerosis)(ALS;Lou Gehrig病)、冠状动脉病(coronary artery disease)、自身免疫性耳病(autoimmuneear disease)如自身免疫性内耳病(autoimmune inner ear disease(AIED))、自身免疫性听力丧失(autoimmune hearing loss)、视性眼阵挛肌阵挛综合征(opsoclonus myoclonussyndrome(OMS))、多软骨炎(polychondritis)如难治性或复发性多软骨炎(refractory orrelapsed polychondritis)、肺泡蛋白沉着症(pulmonary alveolar proteinosis)、淀粉样变性病(amyloidosis)、巩膜炎(scleritis)、非癌性淋巴细胞增多(non-cancerouslymphocytosis)、原发性淋巴细胞增多(primary lymphocytosis),其包括单克隆B细胞淋巴细胞增多(monoclonal B cell lymphocytosis)(例如,良性单克隆免疫球蛋白病(benign monoclonal gammopathy)和意义不确定性单克隆免疫球蛋白病(monoclonalgarnmopathy of undetermined significance(MGUS))、外周神经病(peripheralneuropathy)、副肿瘤性综合征(paraneoplastic syndrome)、离子通道病(channelopathies),如癫痫(epilepsy)、偏头痛(migraine)、心律失常(arrhythmia)、肌肉病(muscular disorders)、耳聋(deafness)、失明(blindness)、周期性麻痹(periodicparalysis),和CNS的离子通道病(channelopathies of the CNS)、自闭症(autism)、炎性肌病(inflammatory myopathy)、局灶节段性肾小球硬化(focal segmentalglomerulosclerosis(FSGS))、内分泌眼病(endocrine ophthalmopathy)、葡萄膜视网膜炎(uveoretinitis)、脉络膜视网膜炎(chorioretinitis)、自身免疫性肝病(autoimmunehepatological disorder)、纤维肌痛(fibromyalgia)、多发性内分泌衰竭(multipleendocrine failure)、Schmidt综合征(Schmidt’s syndrome)、肾上腺炎(adrenalitis)、胃萎缩(gastric atrophy)、早老性痴呆(presenile dementia)、脱髓鞘病(demyelinatingdiseases),如自身免疫性脱髓鞘病(autoimmune demyelinating diseases)、糖尿病性肾病(diabetic nephropathy)、Dressler综合征(Dressler's syndrome)、斑秃(alopeciaareata)、CREST综合征(CREST syndrome)(钙化(calcinosis)、雷诺现象(Raynaud’sphenomenon)、食管运动功能失常(esophageal dysmotility)、指端硬化(sclerodactyly)和毛细血管扩张症(telangiectasia))、男性和女性自身免疫性不育(male and femaleautoimmune infertility)、混合型结缔组织病(mixed connective tissue disease)、Chaga病(Chagas’disease)、风湿热(rheumatic fever)、反复流产(recurrent abortion)、霉尘肺(farmer's lung)、多形红斑(erythema multiforme)、心脏切开术后综合征(post-cardiotomy syndrome)、库欣综合征(Cushing’s syndrome)、养鸟人肺(bird-fancier'slung)、变应性肉芽肿性血管炎(allergic granulomatous angiitis)、良性淋巴细胞血管炎(benign lymphocytic angiitis)、Alport综合征(Alport’s syndrome)、肺泡炎(alveolitis),如过敏性肺泡炎(allergic alveolitis)和纤维化肺泡炎(fibrosingalveolitis)、间质性肺病(interstitial lung disease)、输血反应(transfusionreaction)、麻风病(leprosy)、疟疾(malaria)、利什曼病(leishmaniasis)、kypanosomiasis、血吸虫病(schistosomiasis)、蛔虫病(ascariasis)、曲霉病(aspergillosis)、Sampter综合征(Sampter’s syndrome)、Caplan综合征(Caplan’ssyndrome)、登革热(dengue)、心内膜炎(endocarditis)、心肌内膜纤维化(endomyocardialfibrosis)、弥漫性间质性肺纤维化(diffuse interstitial pulmonary fibrosis)、间质性肺纤维化(interstitial lung fibrosis)、特发性肺纤维化(idiopathic pulmonaryfibrosis)、囊性纤维化(cystic fibrosis)、眼内炎(endophthalmitis)、持久性隆起性红斑(erythema elevatum et diutinum)、胎儿幼红细胞增多症(erythroblastosisfetalis)、嗜酸性细胞增多性肌膜炎(eosinophilic faciitis)、Shulman综合征(Shulman’s syndrome)、Felty综合征(Felty’s syndrome)、丝虫病(flariasis)、睫状体炎(cyclitis),如慢性睫状体炎(chronic cyclitis)、异色性睫状体炎(heterochroniccyclitis)、虹膜睫状体炎(iridocyclitis)或Fuch睫状体炎(Fuch’s cyclitis)、Henoch-Schonlein紫癜(Henoch-Schonlein purpura)、人免疫缺陷病毒(HIV)感染(humanimmunodeficiency virus(HIV)infection)、艾柯病毒感染(echovirus infection)、心肌病(cardiomyopathy)、阿尔茨海默病(Alzheimer’s disease)、细小病毒感染(parvovirusinfection)、风疹病毒感染(rubella virus infection)、接种后综合征(post-vaccination syndromes)、先天性风疹感染(congenital rubella infection)、Epstein-Barr病毒感染(Epstein-Barr virus infection)、腮腺炎(mumps)、Evan综合征(Evan’ssyndrome)、自身免疫性性腺衰竭(autoimmune gonadal failure)、Sydenham舞蹈病(Sydenham’s chorea)、链球菌感染后肾炎(post-streptococcal nephritis)、闭塞性血栓血管炎(thromboangitis ubiterans)、甲状腺毒症(thyrotoxicosis)、脊髓痨(tabesdorsalis)、脉络膜炎(chorioiditis)、巨细胞多肌痛(giant cell polymyalgia)、内分泌眼病(endocrine ophthamopathy)、慢性超敏性肺炎(chronic hypersensitivitypneumonitis)、干燥性角膜结膜炎(keratoconjunctivitis sicca)、流行性角膜结膜炎(epidemic keratoconjunctivitis)、特发性肾病综合征(idiopathic nephriticsyndrome)、微小病变性肾病(minimal change nephropathy)、良性家族性和缺血-再灌注损伤(benign familial and ischemia-reperfusion injury)、视网膜自体免疫(retinalautoimmunity)、关节炎症(joint inflammation)、支气管炎(bronchitis)、慢性阻塞性气道疾病(chronic obstructive airway disease)、矽肺病(silicosis)、口疮(aphthae)、口疮性口炎(aphthous stomatitis)、动脉硬化性疾病(arteriosclerotic disorders)、aspermiogenese、自身免疫性溶血(autoimmune hemolysis)、Boeck病(Boeck's disease)、冷球蛋白血症(cryoglobulinemia)、Dupuytren挛缩(Dupuytren’s contracture)、晶状体蛋白过敏性眼内炎(endophthalmia phacoanaphylactica)、过敏性肠炎(enteritisallergica)、麻风结节性红斑(erythema nodosum leprosum)、特发性面瘫(idiopathicfacial paralysis)、慢性疲劳综合征(chronic fatigue syndrome)、风湿热(febrisrheumatica)、Hamman-Rich病(Hamman-Rich's disease)、感觉神经性听力丧失(sensoneural hearing loss)、阵发性血红蛋白尿(haemoglobinuria paroxysmatica)、性腺功能减退症(hypogonadism)、局限性回肠炎(ileitis regionalis)、白细胞减少症(leucopenia)、传染性单核细胞增多症(mononucleosis infectiosa)、横贯性脊髓炎(traverse myelitis)、原发性特发性粘液性水肿(primary idiopathic myxedema)、肾变病(nephrosis)、交感性眼炎(ophthalmia symphatica)、肉芽肿性睾丸炎(orchitisgranulomatosa)、胰腺炎(pancreatitis)、急性多发性神经根炎(polyradiculitisacuta)、坏疽性脓皮病(pyoderma gangrenosum)、奎汶氏甲状腺炎(Quervain'sthyreoiditis)、获得性脾萎缩(acquired spenic atrophy)、因抗精子抗体所致的不育、非恶性胸腺肿瘤(non-malignant thymoma)、白癜风(vitiligo)、SCID和Epstein-Barr病毒相关性疾病、获得性免疫缺陷综合征(acquired immune deficiency syndrome(AIDS))、寄生虫病(parasitic diseases)如利什曼原虫(Lesihmania)、中毒性休克综合征(toxic-shocksyndrome)、食物中毒(food poisoning)、涉及T细胞浸润的病状(conditions involvinginfiltration of T cells)、白细胞黏附性缺陷(leukocyte-adhesion deficiency)、与细胞因子和T淋巴细胞介导的急性和迟发型超敏反应(acute and delayedhypersensitivity)相关的免疫应答、涉及白细胞渗出(leukocyte diapedesis)的疾病、多器官损伤综合征(multiple organ injury syndrome)、抗原-抗体复合物-介导的疾病(antigen-antibody complex-mediated diseases)、抗肾小球基底膜病(antiglomerularbasement membrane disease)、变应性神经炎(allergic neuritis)、自身免疫性多内分泌腺病(autoimmune polyendocrinopathies)、卵巢炎(oophoritis)、原发性粘液水肿(primary myxedema)、自身免疫性萎缩性胃炎(autoimmune atrophic gastritis)、交感性眼炎(sympathetic ophthalmia)、风湿性疾病(rheumatic diseases)、混合型结缔组织病(mixed connective tissue disease)、肾病综合征(nephrotic syndrome)、胰岛炎(insulitis)、多内分泌腺衰竭(polyendocrine failure)、外周神经病(peripheralneuropathy)、自身免疫性多内分泌腺综合征I型(autoimmune polyglandular syndrometype I)、成年发作型特发性甲状旁腺功能减退症(adult-onset idiopathichypoparathyroidism(AOIH))、全秃(alopecia totalis)、扩张型心肌病(dilatedcardiomyopathy)、获得性大疱性表皮松解症(epidermolisis bullosa acquisita(EBA))、血色素沉着症(hemochromatosis)、心肌炎(myocarditis)、肾病综合征(nephroticsyndrome)、原发性硬化胆管炎(primary sclerosing cholangitis)、化脓性或非化脓性鼻窦炎(purulent or nonpurulent sinusitis)、急性或慢性鼻窦炎(acute or chronicsinusitis)、筛窦炎(ethmoid sinusitis)、额窦炎(frontal sinusitis)、上颌窦炎(maxillary sinusitis)或蝶窦炎(sphenoid sinusitis)、自身免疫性起庖病(autoimmuneblistering disease)、嗜酸细胞相关病症(eosinophil-related disorder)如嗜酸粒细胞增多症(eosinophilia)、特发性嗜酸粒细胞增多症(idiopathic hypereosinophilsyndrome)、嗜酸细胞增多性肺浸润(pulmonary infiltration eosinophilia)、嗜酸粒细胞增多-肌痛综合征(eosinophilia-myalgia syndrome)、Loffler综合征(Loffler'ssyndrome)、慢性嗜酸细胞性肺炎(chronic eosinophilic pneumonia)、热带肺嗜酸粒细胞增多症(tropical pulmonary eosinophilia)、支气管肺曲霉病(bronchopneumonicaspergillosis)、曲霉肿(aspergilloma)、或含有嗜酸性细胞的肉芽肿(granulomascontaining eosinophils)、过敏反应(anaphylaxis)、血清阴性脊椎关节炎(seronegativespondyloarthritides)、多内分泌腺自身免疫病(polyendocrine autoimmune disease)、硬化胆管炎(sclerosing cholangitis)、巩膜(sclera)、巩膜外层(episclera)、慢性粘膜皮肤念珠菌病(chronic mucocutaneous candidiasis)、Bruton综合征(Bruton’ssyndrome)、婴儿期暂时性低γ球蛋白血症(transient hypogammaglobulinemia ofinfancy)、Wiskott-Aldrich综合征(Wiskott-Aldrich syndrome)、共济失调毛细血管扩张症(ataxia telangiectasia)、与胶原病相关的自身免疫功能紊乱(autoimmune disordersassociated with collagen disease)、风湿病(rheumatism)、神经学疾病(neurologicaldisease)、缺血性再灌注病(ischemic re-perfusion disorder)、血压下降反应(reduction in blood pressure response)、血管功能障碍(vascular dysfunction)、脉管扩张(antgiectasis)、组织损伤(tissue injury)、心血管缺血(cardiovascularischemia)、痛觉过敏(hyperalgesia)、脑缺血(cerebral ischemia),和伴血管化疾病(disease accompanying vascularization)、变应性超敏病(allergic hypersensitivitydisorders)、肾小球肾炎(glomerulonephritides)、再灌注损伤(reperfusion injury)、心肌或其他组织的再灌注损伤、具有急性炎症组分的皮肤病(dermatoses with acuteinflammatory components)、急性紫癜性脑膜炎(acute purulent meningitis)或其他中枢神经系统炎性疾病、眼和眼眶炎性疾病(ocular and orbital inflammatorydisorders)、粒细胞输血相关综合征(granulocyte transfusion-associatedsyndromes)、细胞因子诱导的中毒(cytokine-induced toxicity)、急性严重炎症(acuteserious inflammation)、慢性顽固性炎症(chronic intractable inflammation)、肾盂炎(pyelitis)、肺硬变(pneumonocirrhosis)、糖尿病性视网膜病变(diabeticretinopathy)、糖尿病性大动脉病(diabetic large-artery disorder)、动脉内增生(endarterial hyperplasia)、消化性溃疡(peptic ulcer)、心瓣炎(valvulitis)和子宫内膜异位(endometriosis)。
“变应性疾病”在本文中是其中个体对正常情况下无免疫原性的物质过度敏感并且发起针对这种物质的免疫反应的疾病或病症。变应性疾病总体上以肥大细胞被IgE活化为特征,导致炎症反应,所述炎症反应可能产生多种症状如良性症状如鼻漏直至危及生命的过敏性休克和死亡。变应性疾病的例子包括但不限于哮喘(例如,过敏性哮喘)、过敏性鼻炎(例如,干草热)、过敏性皮炎(例如,湿疹)、接触性皮炎、食物过敏和荨麻疹。
上文所列并非包括一切,并且技术人员将理解疾病或病症可以落于多种分类范围内。例如,哮喘既是变应性疾病,又是炎性疾病,并且被某些临床医生视为一种自身免疫疾病。
术语“癌症”和“癌性的”指或描述哺乳动物中一般以失调的细胞增殖为特征的生理状况。这个定义中包括良性癌和恶性癌。
术语“癌前期”指一般先于癌或形成癌的状况或生长。
如本文所用的术语“增生性疾病”是与某种程度的异常细胞增殖相关的病或病症。在一个实施方案中,细胞增生性疾病是癌症。在一些实施方案中,癌症选自乳腺癌、结直肠癌、非小细胞肺癌、非霍奇金淋巴瘤(NHL)、B细胞淋巴瘤、B细胞白血病、多发性骨髓瘤、肾癌、前列腺癌、肝癌、头颈癌、黑素瘤、卵巢癌、间皮瘤和成胶质细胞瘤。
如本文所用的术语“肿瘤”指全部赘生性细胞生长和增殖,无论为恶性或良性,以及全部癌前细胞和癌细胞及组织。
“非转移性”意指,癌为良性的或留在原发性部位、未穿透入淋巴系统或血管系统或穿透至原发性部位之外的组织。通常,非转移性癌是处于0期、I期或II期癌及偶尔地III期癌的任何癌症。
“受试者”是脊椎动物,优选地是哺乳动物,更优选地是人。哺乳动物包括,但不限于家畜(如牛)、竞赛动物、宠物(如猫、犬和马)、灵长类动物、小鼠和大鼠。
II.双重特异性抗体的产生
重链可变结构域(VH)含有显著更高的序列多样性并且比轻链可变结构域(VL)更经常地贡献抗原识别决定簇。我们的先前结果首次证实,可以改变轻链可变结构域以产生具有双重特异性的单一抗体(参见美国专利申请公布号20080069820和Bostrom等人,Science232:1610-1614(2009),所述文献通过引用方式完整并入本文)。我们已经发现,可以通过改变VH中的氨基酸残基(包括在缺少对VL的突变的情况下),从具有对抗原识别关键的VL残基的抗体,生成双重特异性抗体。下文详细描述这些新的和出乎意料的方法。
我们已经发现,可以在VL中鉴定特定残基,这些残基当带静电或疏水时表明该VL对抗原识别是关键的。在这种情况下,可以通过抗体VH的改变,产生与第一表位和第二表位结合的双重特异性抗体。特别地,如果抗体在位置32、50或91(按Kabat编号)处的任一个、两个或三个氨基酸残基带静电(例如,酪氨酸)或疏水(例如,色氨酸),则可以在VH的编码一个或多个溶剂可及性氨基酸残基的一个或多个密码子处,改变编码该抗体VH的核酸序列。
在多种实施方案中,可以改变的VH中残基包括氨基酸33、34、50-58或95-97中的任一者或多者。任选地,除这些重链残基之外,还可以改变轻链的氨基酸残基93-96。可以使用本领域已知的标准技术(包括但不限于结构作图法和丙氨酸扫描诱变法)确定重链的溶剂可及性或抗原识别重要性。
随后将VL和改变的VH表达(例如,作为文库)并且选择与第一表位和第二表位特异性结合的包含VL和改变的VH的双重特异性抗体或其抗原结合片段。除VH之外,还可以改变或可以不改变初始抗体的VL。除VH之外,还可以改变或可以不改变初始抗体的构架区中的氨基酸残基。
通过以上选择方法鉴定的双重特异性抗体或其抗原结合片段可以通过例如亲和力成熟法或本领域其他已知方法进一步修饰,以增加对一种或两种靶抗原的亲和力。亲和力成熟选择法可以包括应用大规模平行测序方案(例如,深度测序、超深度测序或下一代测序法)以鉴定有助于结合一种或两种靶抗原(例如,有助于靶抗原亲和力增加)的残基(例如,溶剂暴露的或非溶剂暴露的残基)。参见,例如,Fowler等人,Nat.Methods.7(9):741-746,2010。也可以修饰双重特异性抗体以增加稳定性或半寿期,或减少免疫原性。这类修饰是技术人员已知的。
III.治疗性用途
结合IL4和IL5(例如,B1、E7和E7亲和力成熟变体)或IL4和IL13(例如,F1和F2)的本文所述双重特异性抗体或其抗原结合片段可以用来治疗、抑制或预防疾病,如变应性、炎性和自身免疫疾病(例如,哮喘);IL4介导的疾病;IL5介导的疾病;IL13介导的疾病;IL4/IL5介导的疾病;IL4/IL13介导的疾病;和/或增生性疾病(例如,癌症)。
上文描述了可以用双重特异性抗体或其抗原结合片段治疗的炎性和自身免疫疾病或病症的例子。在一些实施方案中,疾病或病症包括,但不限于哮喘如支气管哮喘、支气管哮喘和自身免疫性哮喘。
哮喘被描述为涉及气道炎症、高反应性和阻塞的慢性肺病。在生理学上,将气道高反应性记录为用乙酰甲胆碱或组胺支气管激发后减少的支气管气流。激发气道阻塞的其他触发物包括冷空气、锻炼、病毒性上呼吸道感染、吸烟和呼吸道变应原。因变应原所致的支气管激发可以诱导免疫球蛋白E(IgE)介导的早期支气管气流迅速下降,在许多患者中接着是IgE介导的晚期反应,其中支气管气流下降持续4-8小时。早期反应由炎性物质(如组胺、PGD2、白三烯、类胰蛋白酶和血小板激活因子(PAF))的急性释放引起,而晚期反应由从头合成的促炎细胞因子(例如TNFα、IL4、IL13)和趋化因子(例如MCP-1和MIP-1α)引起(Busse等人,引自:Allergy:Principles and Practice,Middleston编著,1173(1998))。在慢性哮喘患者中,持续性肺症状由提高的Th2细胞反应介导。据信Th2细胞因子在疾病中发挥重要作用(Larche等人,J.Allergy Clin.Immunol.,111:450(2003)),特别是,如啮齿类动物哮喘模型所示,气道中由具有NK表型的Th2细胞(NKT)产生的IL13和IL4(Akbari等人,NatureMed.,9:582(2003))。哮喘性气道的大体病变显示肺过度充气、平滑肌肥大、网状基底层增厚、粘膜水肿、上皮细胞脱落、纤毛细胞破坏和粘液腺过度分泌。微观上,哮喘以支气管组织、支气管分泌物和粘液中存在增加数目的嗜酸性粒细胞、嗜中性粒细胞、淋巴细胞和浆细胞为特征。最初,活化的CD4+T-淋巴细胞将白细胞从血流召集至气道。该活化的T-淋巴细胞还指导炎性介质从嗜酸性粒细胞、肥大细胞和淋巴细胞释放。此外,Th2细胞产生IL4、IL5、IL9和IL13。IL4,连同IL13一起,发送从IgM抗体转换成IgE抗体的信号。
膜结合型IgE分子通过变应原交联,造成肥大细胞脱粒,释放持久化气道炎症的组胺、白三烯和其他介质。IL5激活嗜酸性粒细胞的召集和活化。活化的肥大细胞和嗜酸性粒细胞也产生有助于持久化炎症的细胞因子。肺中这些重复的炎症循环,加上肺组织损伤和随后的修复,可以造成气道的长期结构变化(“重塑”)。
中度哮喘目前用每日吸入型抗炎皮质类固醇或肥大细胞抑制剂如色甘酸钠(Cromolyn sodium)或奈多罗米(nedocromil)治疗,根据需要外加吸入型β2-激动剂(每日3-4次)以减轻突现症状(breakthrough symptom)或变应原诱导或运动诱导的哮喘。色甘酸钠和奈多罗米阻断支气管痉挛和炎症,但是通常仅对与变应原或锻炼相关的哮喘有效并且一般仅对青少年哮喘有效。吸入型皮质类固醇改善炎症、气道高反应性和阻塞,并且减少急性恶化的次数。然而,需要至少一个月才会有明显效果,并需要多达一年才会出现明显改善。最频繁的副作用是嘶哑及口部真菌性感染,即,念珠菌病。已经报道了更严重的副作用,例如,局部肾上腺抑制、生长抑制和减少的骨形成,但是仅在使用更高剂量下如此。倍氯米松(beclomethasone),曲安西龙(triamcinolone)和氟尼缩松(flunisolide)可能具有相似的效力;而布地奈德(budesonide)和氟替卡松(fluticasone)更强力并且据报道称具有更少的全身性副作用。
甚至病情轻度的患者也显示气道炎症,包括活化的T细胞、肥大细胞和嗜酸性粒细胞浸润粘膜和上皮。T细胞和肥大细胞释放促进嗜酸性粒细胞生长和成熟和IgE抗体产生的细胞因子,并且这些细胞因子转而增加微血管通透性、破坏上皮并刺激神经反射和粘液分泌腺。结果是气道高反应性,支气管收缩和过度分泌,表现为哮鸣、咳嗽、和呼吸困难。
传统上,哮喘已经用口服和吸入型支气管扩张剂治疗。这些药剂帮助缓解哮喘症状,但是对作为基础的炎症无所作为。在过去10年期间认识到炎症在哮喘病因学中的重要性已经导致皮质类固醇的使用增加,但是许多患者继续患有无法控制的哮喘。
对IL4、IL5、和/或IL13具有特异性的双重特异性抗体或其抗原结合片段将靶向多个致病途径并且可以作为治疗药单独或与额外治疗药(例如,本领域已知的或上文描述的那些)组合用于治疗哮喘。
在额外的实施方案中,双重特异性抗体或其抗原结合片段可以用来治疗癌症。术语“癌症”包括一系列增生性病症,包括但不限于癌前生长、良性肿瘤和恶性肿瘤。良性肿瘤保持局限在发源部位并且不具有浸润、侵袭或转移至远处部位的能力。恶性肿瘤可以侵入并损伤它们周围的其他组织。它们还可以获得突破其起源部位并且扩散(转移)至身体其他部位的能力,这通常经血流或经其中存在淋巴结的淋巴系统进行。原发肿瘤根据原发肿瘤起源的组织类型分类;转移性肿瘤根据从中衍生该癌细胞的组织类型分类。随时间推移,恶性肿瘤细胞变得更为异常并且显得更不像正常细胞。癌细胞外观的这种变化被称作肿瘤分级,可以将癌细胞描述为充分分化的、中等分化的、不良分化的或未分化的。充分分化的细胞在外观上相当正常并且与它们所源自的正常细胞相似。未分化的细胞是已经变得十分异常以致于不再可能确定其起源的细胞。
IV.剂量和制剂
抗体或抗体片段组合物将以符合良好医学实践的方式配制、定剂量和施用。在这种情况下考虑的因素包括正在治疗的具体病症、正在治疗的具体哺乳动物、个体患者的临床状况、病症原因、送递药物的部位、施用方法、施用计划和医疗执业者已知的其他因素。“待施用的抗体或抗体片段的治疗有效量将由此类考虑事项决定,并且是为防止、改善或治疗变应性、炎性、自身免疫性或增生性疾病或病症或其症状必需的最小量。施用本发明抗体或抗体片段的剂量和时序将取决于多种临床因素,包括受试者的总体健康和(例如,变应性疾病的)症状的严重程度。本发明包括抗体或抗体片段用于治疗、预防或减少受试者中变应性疾病或其症状、或出现变应性疾病的风险的用途。抗体或抗体片段可以在任何时间(例如,在诊断或检测到变应性疾病或与变应性疾病相关的状况后)施用,或在确定变应性疾病发生风险后,在尚未诊断患有变应性疾病但面临发生这种病症的风险的受试者(例如,具有受损的免疫系统或正在因受损的免疫系统而治疗的受试者)中,用于预防变应性疾病。
可以将本发明的双重特异性抗体或其抗原结合片段以多种方式配制和施用,例如,已知用于特定适应症的那些途径,包括但不限于吸入、局部、经口、皮下、支气管注射、静脉内、脑内、鼻内、透皮、腹腔内、肌内、肺内、阴道、直肠、动脉内、脑室椎管内、关节内、滑膜内、病灶内、肠胃外地、脑室内或眼内途径。例如,抗体或抗体片段,可以采取下述形式:丸剂、片剂、胶囊剂、液体剂或口服施用缓释片剂;或静脉内、皮下施用液体剂;局部施用的聚合物或其他缓释溶媒;局部施用的油膏剂、乳膏剂、凝胶剂、液体剂或贴剂。
如果广泛副作用或毒性与IL4、IL5或IL13拮抗作用相关,则可能特别需要局部施用。离体策略也可以用于治疗性应用。离体策略包括用编码双重特异性抗体或其抗原结合片段的多核苷酸转染或转导从受试者获得的细胞。随后将转染或转导的细胞返回这位受试者。细胞可以是广泛类型细胞的任一种,包括而不限于造血细胞(例如,骨髓细胞、巨噬细胞、单核细胞、树突细胞、T细胞或B细胞)、成纤维细胞、上皮细胞、内皮细胞、角质形成细胞或肌肉细胞。
例如,双重特异性抗体或其抗原结合片段的连续全身性输注或定期注射可以用来治疗或预防病症。治疗可以继续从1天直至受试者终生的一段时间、更优选地1至100天,并且最优选地1至20天,以及最优选地,直至变应性、炎性、自身免疫性或增生性疾病或病症或其症状减少或移除。剂量根据化合物和病状严重程度变动。双重特异性抗体或其抗原结合片段可以通过使用恒定流量或可编程流量的植入式泵输注或通过定期注射,连续地施用。也可以使用缓释系统。在某些情况下,半透性、植入式膜装置也可用作递送双重特异性抗体或其抗原结合片段的手段。在另一个实施方案中,双重特异性抗体或其抗原结合片段局部施用,例如,通过吸入法,并且可以定期重复。也可以利用肺施用法,例如,通过使用吸入器或雾化器和含有雾化剂的制剂。抗体也可以按干粉组合物的形式施用至患者的肺中(参见例如,美国专利号6,514,496)。
双重特异性抗体或其抗原结合片段的剂量将取决于其他临床因素如受试者体重和状况及化合物的施用途径。为了治疗受试者,可以施用大约0.1mg/kg至500mg/kg体重之间的双重特异性抗体或其抗原结合片段。更优选的范围是1mg/kg至50mg/kg体重,最优选的范围是1mg/kg至25mg/kg体重。取决于抗体或抗体片段在具体受试者中的半寿期,抗体或抗体片段可以每天数次施用至每周一次施用。本发明的方法提供单一以及多次施用,同时或经延长的时间段给予。
优选地,将双重特异性抗体或其抗原结合片段肠胃外地施用或通过连续输注法静脉内施用或通过吸入器局部施用。剂量和剂量方案取决于疾病的严重程度和受试者的总体健康。为了肠胃外施用,可以将双重特异性抗体或其抗原结合片段与可药用肠胃外溶媒结合配制在单位剂量可注射形式(溶液剂、悬浮剂、乳剂)中。这类溶媒是固有无毒和无治疗性的。这类溶媒的例子是水、盐水、林格液、右旋糖溶液和5%人血清白蛋白。也可以使用非水性溶媒如非挥发性油和油酸乙酯。脂质体可以作为载体使用。该溶媒可以含有少量添加物,如增强等渗性和化学稳定性的物质,例如缓冲剂和防腐剂。双重特异性抗体或其抗原结合片段一般以约1mg/ml至10mg/ml的浓度配制在这类溶媒中。为了通过吸入施用,双重特异性抗体或其抗原结合片段可以按任何合适的方法配制以形成本发明的气溶胶形式。包含双重特异性抗体或其抗原结合片段的组合物在具有或没有可药用赋形剂的情况下挥发或雾化,以产生可以凝结并使用例如吸入器直接吸入肺中的蒸气。可药用赋形剂可以是挥发的,并且这类赋形剂的类别是本领域已知的并且包括,而不限于气态、超临界流体、液体和固态溶剂。这些类别内部的示例性载体包括而不限于水、无菌盐水、生理缓冲液溶液如磷酸盐缓冲盐水、萜类、醇类、丙二醇、甘油和其他相似醇、干冰、二甲基甲酰胺、二甲基乙酰胺、超临界二氧化碳及其混合物。
需要的剂量取决于施用途径的选择;制剂的性质;受试者疾病的性质;受试者的体格、体重、表面积、年龄和性别;正在施用的其他药物和主治医生的判断。鉴于可获得的多肽和片段的多样性和多种施用途径的不同效率,可以预期所需剂量的变化很大。例如,预计口服施用需要比通过静脉注射施用更高的剂量。如本领域中充分理解,可以使用标准的经验性优化途径,调整这些剂量水平的变动。施用可以是单次或多次(例如,2次、3次、6次、8次、10次、20次、50次、100次、150次或更多次)。将多肽包囊于合适的递送载具(例如,聚合性微粒或植入式装置)中可以增加递送效率,特别对于口服递送而言。
在治疗哮喘的一个实施方案中,双重特异性抗体或其抗原结合片段不必,但可选地,随目前用来预防或治疗哮喘或哮喘形成风险的一种或多种物质一起配制或与之组合(同时或依次)施用。抗体或其抗原结合片段可以与例如IgE拮抗剂、支气管扩张药物(例如,β2-肾上腺素激动剂、黄嘌呤、胆碱受体拮抗剂)、抗炎药(例如,色甘酸二钠(DSCG)、奈多罗米钠、抗组胺药如酮替芬(ketotifen)、皮质类固醇如泼尼松龙(prednisolone))、茶碱、沙丁胺醇、丙酸倍氯米松或本领域已知的其它治疗性哮喘药一起配制。这类其他药物的有效量取决于该制剂中存在的双重特异性抗体或其抗原结合片段的量、疾病类型或疗法和上文讨论的其他因素。
使用本领域已知的标准方法,通过将具有所需纯度的活性成分与任选的生理可接受载体、赋形剂或稳定剂混合,制备治疗性制剂(Remington’s Pharmaceutical Sciences(第20版).A.Gennaro,2000,Lippincott,Williams&Wilkins,Philadelphia,PA)。可接受的载体,包括盐水或缓冲剂如磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸;低分子量(小于约10个残基)多肽;蛋白质,如血清白蛋白、明胶或免疫球蛋白;亲水聚合物,如聚乙烯吡咯烷酮、氨基酸如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸;单糖、二糖和其他糖,包括葡萄糖、甘露糖、或糊精;螯合剂如EDTA;糖醇如甘露醇或山梨醇;成盐反离子如钠;和/或非离子表面活性剂如TWEENTM、PLURONICSTM或PEG。
任选的,但是优选地,制剂含有可药用盐、优选地氯化钠,并且优选地以约生理学浓度。任选地,本发明的制剂可以含有可药用的防腐剂。在一些实施方案中,防腐剂浓度是从0.1至2.0%,一般按v/v计。合适的防腐剂包括制药领域已知的那些。苄醇、苯酚、间甲酚、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯是示例性防腐剂。任选地,本发明的制剂可以按0.005%至0.02%的浓度包含可药用的表面活性剂。
本文中的制剂也可以根据正在治疗的特定适应症按需要而含有多于一种活性化合物,优选地是无不利相互影响并具有互补活性的那些活性化合物。这些分子适宜地以对预期目的有效的量组合地存在。
活性成分也可以截留在例如分别通过凝聚技术或界面聚合制备的微胶囊(例如,羟甲基纤维素微胶囊或明胶微胶囊和聚(甲基丙烯酸甲酯)微胶囊)、胶态药物递送系统(例如,脂质体、白蛋白微球体、微乳液、纳米粒子和纳米胶囊)或粗乳液中。这类技术在上文Remington's Pharmaceutical Sciences中公开。
可以制备持续释放制品。持续释放制品的合适例子包括含有抗体的固态疏水性聚合物半通透性基质,所述基质可以为成型制品(例如,薄膜或微胶囊)形式。持续释放基质的例子包括聚酯、水凝胶(例如,聚(甲基丙烯酸2-羟乙酯)或聚(乙烯醇)、聚乳酸(美国专利号3,773,919)、L-谷氨酸和γ-乙基-L-谷氨酸酯的共聚物、不可降解性乙烯-乙酸乙烯酯、可降解性乳酸-乙醇酸共聚物如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和亮丙瑞林乙酸酯组成的可注射微球体)和聚-D-(-)-3-羟基丁酸。尽管聚合物如乙烯-乙酸乙烯酯和乳酸-乙醇酸能够使分子的释放持续超过100日,但是某些水凝胶释放蛋白质的持续时间较短。当包囊化的抗体长时间留在体内时,它们可能因在37℃暴露于湿气而变性或聚集,导致生物活性丧失和可能的免疫原性改变。可以根据所涉及的机制,构思用于稳定的合理策略。例如,如果发现聚集机制是通过巯基-二硫键交换所致的分子间S-S键形成,则可以通过修饰硫氢基残基、从酸性溶液冻干、控制含湿量、使用适宜的添加物、和开发特定聚合物基质组合物来实现稳定作用。
在一个实例中,当病症允许时,局部施用双重特异性抗体或其抗原结合片段,例如,通过直接注射而局部施用,并且注射可以定期重复,或通过吸入局部施用。双重特异性抗体或其抗原结合片段也可以全身性递送至受试者或直接递送至患病区域。
本发明也提供一种包含双重特异性抗体或其抗原结合片段及可药用载体或稀释剂的组合物。用于治疗性用途的这种组合物是无菌的并且可以冻干。还构思本发明的双重特异性抗体或其抗原结合片段在制造治疗本文所述适应症的药物中的用途。组合物还可以包含第二治疗药,如抗哮喘药、抗炎药或抗增生药物(例如,化疗药、细胞毒性药或抗血管生成药)。
V.制造品和药盒
本发明的另一个实施方案是含有可用于治疗疾病或病症(例如,变应性疾病或病症或哮喘)的材料的制造品。本发明的又一个实施方案是含有可用于治疗炎性、自身免疫性和增生性疾病或病症的材料的制造品。制造品包括容器和在该容器上或与之结合的标签或包装插页。合适的容器例如包括瓶、小药瓶、注射器等。容器可以从多种材料如玻璃或塑料形成。容器容纳有效治疗所述病症的组合物并且可以具有无菌进口(例如容器可以是静脉内输液袋或是具有皮下注射针头可穿透的瓶塞的小药瓶)。组合物中的至少一种活性物质是本发明的双重特异性抗体或抗原结合片段。标签或包装插页说明该组合物用于治疗特定的病状。该标签或包装插页可以进一步包含用于施用该抗体组合物至患者的说明书。还考虑包含本文所述的组合性治疗药的制造品和药盒。
包装插页指治疗性产品的商业包装中习惯性包含的说明书,所述说明书含有关于适应症、用法、剂量、施用、禁忌症和/或涉及此类治疗产品应用之警告的信息。在一个实施方案中,包装插页说明该组合物用于治疗哮喘。
额外地,制造品还可以包含第二容器,所述容器包含可药用缓冲液,如抑菌性注射用水(BWFI)、磷酸盐缓冲盐水、Ringer溶液和葡萄糖溶液。它可以还包括从商业和用户观点看受欢迎的其他材料,包括其他缓冲液、稀释剂、滤器、针头和注射器。
还提供可用于多种目的(例如,从细胞纯化或免疫沉淀IL4、IL5或IL13)的药盒。为了分离和纯化IL4、IL5或IL13,药盒可以含有与珠(例如,琼脂糖珠)偶联的IL4/IL5或IL4/IL13抗体。可以提供含有抗体的药盒,用于在体外(例如在ELISA或蛋白质印迹法中)检测和定量IL4、IL5或IL13。与制造品一样,药盒包括容器和在该容器上或与之结合的标签或包装插页。容器容纳包含至少一种本发明双重特异性或多特异性抗体或抗体片段的组合物。可以包括含有例如稀释剂和缓冲液或对照抗体的额外容器。标签或包装插页可以提供有关组合物的描述以及对预期的体外或诊断用途的说明。
以下的实施例仅出于举例说明目的而提供,并不意在以任何方式限制本发明的范围。实际上,除了本文显示和描述的那些修改之外,本发明的各种修改将因前面的描述而对本领域技术人员是显而易见的并且落于所附权利要求书的范围内。
实施例
除非另外说明,否则下文实施例中提到的市售试剂根据制造商的说明书使用。以下实施例中和整个说明书中用ATCC保藏号所标识的那些细胞来源于美国典型培养物保藏中心,Manassas,VA。除非另外指出,否则本发明使用重组DNA技术的标准方法,如上文和以下教科书中所述的那些方法:Sambrook等人,上引文;Ausubel等人,Current Protocols inMolecular Biology(Green Publishing Associates and Wiley Interscience,N.Y.,1989);Innis等人,PCR Protocols:A Guide to Methods and Applications(AcademicPress,Inc.:N.Y.,1990);Harlow等人,Antibodies:A Laboratory Manual(Cold SpringHarbor Press:Cold Spring Harbor,1988);Gait,Oligonucleotide Synthesis(IRLPress:Oxford,1984);Freshney,Animal Cell Culture,1987;Coligan等人,CurrentProtocols in Immunology,1991。
实施例1.文库设计和构建
通过在轻链(LC)互补决定区(CDR)中突变,单特异性抗体可以募集到针对新抗原的第二结合特异性,同时维持其第一抗原特异性。另外,可以通过亲和力成熟,使该双重结合作用具有低纳摩尔KD。工程化双重特异性的该途径十分适用于主要利用重链(HC)CDR结合其第一抗原的抗体。在此描述:结合能量倚重于LC CDR的小鼠杂交瘤衍生的抗白介素4抗体,及该抗体通过仅在HC CDR中的突变或通过在LC CDR中的进一步突变而向双重特异性的演化。同时针对白介素4(IL4)和白介素5(IL5)的这样一种双重特异性变体经成熟而具有低纳摩尔KD的高双重亲和力。该结果进一步凸显了抗体演化双重特异性的能力并且证实了在任何抗体中演化双重特异性的一般适用性工程化途径,其中使用突变扫描策略鉴定抗原结合位点中可以忍受突变并允许演化第二结合特异性的区域。
我们着手向结合IL4并阻断它与IL4受体α结合的人源化抗体19C11(hu19C11,在种系VH1和κI的主链中人源化)引入第二抗原特异性。如所述(Lee等人,J.Mol.Biol.340:1073-93,2004),我们首先将其Fab克隆入“噬菌粒”构建体(pV0115),以共表达LC和(以双顺反子方式)C端与M13小外壳蛋白p3融合的HC的可变结构域和恒定结构域1(CH1)。具有氨基酸序列KTHTC的一部分IgG铰链区被包括在CH1和M13p3之间以允许双价Fab展示(Lee等人,J.Mol.Biol.340:1073-93,2004),从而增加与固定在固态表面支持物上的抗原的结合效率。我们首先验证了,展示Fab的噬菌体良好地结合针对表达标签(gD)(C端融合于LC)的抗体,并以高亲和力(噬菌体EC50=1nM)结合IL4,所述亲和力类似于该抗体作为IgG的实测亲和力。
为了确定将第二结合特异性募集至hu19C11的工程化策略,我们首先通过将每个LC CDR的两个或三个残基突变成丙氨酸,检验了抗体的三个LC CDR对于结合IL4的重要性。选择这些LC CDR位置,原因在于:先前已经鉴定到,在从第一抗原结合作用非常依赖于HCCDR的抗体选择双重特异性克隆的LC文库方案中,这些位置是组合诱变的关键位置(Bostrom等人,PLoS One.6:e17887,2011)。将展示hu19C11野生型、丙氨酸突变体L1(I30A/N31A/D32A)、L2(Y50A/H53A/R54A)或L3(D91A/Y92A)的噬菌体固定至抗gD抗体(图1A)或IL4(图1B),并且使用ELISA测定结合。我们发现LC CDR看起来在能量上是重要的。展示在三个LC CDR的任一个中具有丙氨酸突变的Fab的噬菌体未显示可检测的IL4结合,但与抗gD抗体结合,这表明这些突变体确实展示在噬菌体上(尽管水平低于野生型Fab),但是它们与IL4的结合严重受损(图1A和图1B)。因此,产生随机化LC CDR文库的方案将不可能产生双重特异性抗体,原因在于可用于演化第二抗原结合作用的氨基酸残基的数目相当有限。接下来,我们如先前所述突变了LC CDR的各个关键残基以及表面可及性HC CDR(Sidhu等人,J MolBiol.338:299-310,2004;Lee等人,J Mol Biol.340:1073-1093,2004),并且通过与野生型hu19C11相比确定这些丙氨酸突变体的相对结合亲和力,评价了它们在IL4结合中的作用。结果验证了这些关键LC CDR残基对IL4结合的重要性。然而,全部测试的CDR H2位置和半数CDR H1和H3位置看起来耐受突变(图1C)。
通过在作为模型的曲妥珠单抗Fab(PDB:1FDV)结构上作图定位对IL4结合作用非常重要的残基(LC残基30、31、32、50、53、54、91,92;HC残基31、32、98、99(按Kabat编号)),我们鉴定了以CDR H2为中心的耐受突变并且可能适合演化第二特异性的区域(图2A)。我们随后在CDR H1(33,34)、H2(50-58)、H3(95-97)和L3(93-96)中选择了耐受丙氨酸突变的一组残基用于该突变方案中进行以CDR H2为中心的随机化;并且使用一组合成寡核苷酸根据Kunkel等人(Kunkel等人,Methods Enzymol.154:367-82,1987)的诱变方法在这四个CDR之每一个处定向地随机化这些选定的残基。在CDR H2和CDR L3的氨基酸组成和长度变异性方面,该随机化方案受天然抗体中多样性的引导(图2B)。诱变用模板仅在CDR H2中含有终止密码子,这确保了Fab展示文库中该CDR的突变。我们生成了10个噬菌体展示文库,每个具有108-109的大小。通过10个HC文库(2144-1至2144-10)与非阻断性抗IL4抗体捕获的固定化IL4(PeproTech)的结合和hu19C11的噬菌体滴定进行评估,每个文库作为汇集物显示了某种低水平的IL4结合作用,所述结合作用与模板抗体hu19C11相比通常低得多,指示平均地不同水平的IL4结合破坏(图3)。
我们选择IL5和IL13作为第二抗原。尽管这两种白介素如IL4一样属于4-螺旋束细胞因子家族,但是它们在氨基酸序列和结构组织层面相当趋异(LaPorte等人,Cell.132:259-272,2008;Patino等人,Structure.19:1864-1875,2011;Finkelman等人,JImmunol.184:1663-1674,2010)。IL4和IL13之间的序列同一性是12%,而IL4和IL5之间的序列同一性是11%。在结构上,IL5形成独特的绞缠的同二聚体,其中来自一条链的一个α-螺旋与来自另一条链的三个α-螺旋形成4-螺旋束(Milburn等人,Nature.363:172-176,1993;Patino等人,Structure.19:1864-1875,2011);IL4和IL13均是单体。然而,这三个细胞因子在它们的生物学功能上相关并且结合并阻断这些细胞因子中两种的双重特异性抗体可以具有作为变应性疾病如哮喘治疗药的潜力实用性9(Finkelman等人,JImmunol.184:1663-1674,2010;Haldar等人,N Engl J Med.360:973-984,2009)。
如先所述(Bostrom等人,Science.323:1610-1614,2009),我们自构建的噬菌体展示文库进行了保留IL4结合作用的IL5或IL13结合性克隆的几轮淘洗和富集。通过各筛选大约100个克隆,我们找到分别显示出与IL5/IL4或IL13/IL4双重结合的3至8个克隆。并且从测序中,鉴定了两个结合IL4/IL5的独特克隆(B1、E7)和两个结合IL4/IL13的独特克隆(FI、F2)(图2B)。我们还分离到与IL5唯一结合的克隆(例如,克隆5A)。除克隆B1之外,与它们的单特异性亲本模板相比,其余全部克隆均仅在HC CDR中含有突变(图4A-4C)。这显示,突变单特异性抗体的HC CDR可以赋予双重特异性。我们使用噬菌体结合竞争测定法,将克隆亲和力评估为抑制50%Fab展示噬菌体与固定化白介素结合所需的白介素浓度(IC50)。我们发现,与第二抗原的结合作用弱,IC50在微摩尔范围中,而IL4结合作用维持在低纳摩尔范围。
实施例2.文库性能的评价
为了验证双重结合特异性,将克隆B1、E7、F2和5A表达为IgG形式,验证了所得到的IgG与预期抗原结合,但不与几种其他蛋白质结合(图5)。通过用流式细胞术显示IgG与不表达IL4、IL5和IL13的人上皮肾细胞系293细胞极少结合,以及用ELISA(Hotzel等人,MAbs.4:753-760,2012)显示IgG与从昆虫细胞系生成的杆状病毒(BV)颗粒极少结合,我们进一步检验了结合特异性。另外,证实IL4/IL5双重特异性抗体B1和E7和单特异性IL5结合抗体可以阻断IL5结合IL5受体α,提示IL5上的结合表位与IL5受体的结合位点重叠(图6)。通过表面等离子体共振(SPR)测量,IL4/IL5双重特异性克隆E7对IL5具有低亲和力(KD=905nM),但是维持其亲本抗体hu19C11的高亲和力IL4结合作用(KD=3.4nM),如通过所表面等离子体共振法(SPR)测量的(图7A和图7B)。
实施例3.双重特异性抗原结合片段的亲和力成熟
为了改善E7的双重亲和力,我们通过位点定向诱变法随机化E7 CDR,并且将变体展示在噬菌体上以便选择结合作用。生成了靶向CDR H2和CDR L3残基(H2/L3文库)、CDRH1、H2和H3残基(H1/H2/H3文库)、或CDR H2残基和HC构架区3(FR3)中的选定位点(H2/FR3文库)的三个文库,以如所述随机化(Lee等人,J Mol Biol.340:1073-1093,2004;Bostrom等人,Methods Mol Biol.525:1-24,2009;Lee等人,Blood.108:3103-3111,2006)(图7A)。由于克隆E7维持高的IL4结合亲和力,所以我们将文库的选择聚焦于IL5结合作用的改善上。从H1/H2/H3文库中,我们找到对IL5的亲和力改善、但对IL4的亲和力大幅度减低的多个克隆,而来自H2/L3文库和H2/FR3文库的克隆显示出改善的IL5结合作用而不丧失IL4-结合亲和力(图4A)。选择的克隆纯化为IgG并且与E7比较。来自H2/L3文库的许多变体以IgG形式显示出更高的双重结合作用,且与一组非靶蛋白质的结合作用不增长(图8A)。如上使用BV结合和293细胞FACS,我们还证实了低的脱靶结合作用,并且证实了这些改善型克隆仍然阻断IL5与其受体结合(图8B)。通过SPR测量Fab与固定化IL4或IL5的结合作用,确定了两种改善型变体1C36和1C60的单价结合亲和力(图7C和7D)。两种变体均维持高的IL4亲和力(KD=3-4nM)和改善的IL5亲和力,分别达37倍和20倍(1C36的KD=24.1nM,1C60的KD=44.4nM)(图7B)。
总之,我们证实,在单特异性抗体的HC CDR中的突变可以募集第二结合特异性,并且我们将分离的双重特异性抗体之一改善成了针对两种抗原的低nM亲和力。先前,我们证实,曲妥珠单抗Fab通过LC CDR中的突变可以演化出双重特异性;此后,使用相同的LC方案,已经生成了其他双重特异性抗体。连同本研究的结果,我们指明了抗体结合特异性的可演化性。我们发现,通过在不只是轻链侧还有重链侧的CDR中的有限突变,抗体可以增加另一种结合特异性。在自然界中,抗体总是通过基因改组和体细胞突变在进行重塑。已经显示,抗体可以被“重利用”,通过体细胞突变而变成具有不同结合特性、因此具有不同功能的抗体。抗体可能具有一种对于通过有限突变而进化出结合特异性而言理想的折叠和结构,这应在天然免疫反应识别基本上无限变化的外来抗原的庞大能力中发挥作用。另外,本工作首次给出了一种可以从任何单特异性抗体演化双重特异性抗体的通用工程化途径,总结如下。通过诱变分析(例如,丙氨酸扫描法),可以首先鉴定出能够忍受突变而不严重破坏第一抗原结合的抗原结合位点区域。
其他实施例
本说明书中援引或参考的全部专利、专利申请、专利申请公布和其他出版物通过引用方式并入此,其并入程度就如同专门且逐个地指出通过引用的方式并入了每份单独的专利、专利申请、专利申请公布和出版物。
序列表
<110> 豪夫迈·罗氏有限公司(F. Hoffmann-La Roche AG)
<120> 双重特异性抗体
<130> 50474-029WO3
<150> US 61/946,547
<151> 2014-02-28
<150> US 61/919,552
<151> 2013-12-20
<160> 34
<170> PatentIn version 3.5
<210> 1
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
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Ala Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser His Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Thr Ser Pro Trp Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 2
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 2
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Val Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ile Phe Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 3
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 3
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Val Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Ile Leu Phe Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 4
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 4
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Ala Gly Ile Val Tyr Asp Ala Thr Gly Phe Thr Thr Tyr Ala Asp Asp
50 55 60
Phe Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala
65 70 75 80
Tyr Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Gly Ile Phe Tyr Gly Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 5
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 5
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 Ser Val Ile Asn Asp
20 25 30
Ala Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser His Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Thr Pro Phe Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 6
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 6
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Leu Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Ala Val Ile Val Ser Ile Thr Gly Arg Thr Tyr Tyr Ala Asp Asp Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ile Phe Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 7
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 7
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Phe Gln Ser Gly Ala Thr Tyr Tyr Ala Asp Asp Phe Lys
50 55 60
Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr Leu
65 70 75 80
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Ile Phe Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 8
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 8
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Ser Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Ile Ile Phe Tyr Thr Gly His Thr Tyr Tyr Ala Asp Asp Phe Lys
50 55 60
Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala Tyr Leu
65 70 75 80
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Ile Phe Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 9
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 9
Lys Ala Ser Gln Ser Val Ile Asn Asp Ala Ala
1 5 10
<210> 10
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 10
Tyr Thr Ser His Arg Tyr Thr
1 5
<210> 11
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 11
Gln Gln Asp Tyr Thr Ser Pro Trp Thr Phe
1 5 10
<210> 12
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 12
Gln Gln Asp Tyr Thr Pro Phe Pro Leu Thr Phe
1 5 10
<210> 13
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 13
Asp Tyr Ser Met His
1 5
<210> 14
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 14
Asp Tyr Asp Ile His
1 5
<210> 15
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 15
Asp Tyr Phe Ile His
1 5
<210> 16
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 16
Asp Tyr Leu Met His
1 5
<210> 17
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 17
Val Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe
1 5 10 15
Lys
<210> 18
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 18
Ala Gly Ile Val Tyr Asp Ala Thr Gly Phe Thr Thr Tyr Ala Asp Asp
1 5 10 15
Phe Lys
<210> 19
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 19
Ala Val Ile Val Ser Ile Thr Gly Arg Thr Tyr Tyr Ala Asp Asp Phe
1 5 10 15
Lys
<210> 20
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 20
Gly Gly Ile Phe Tyr Gly Met Asp Tyr
1 5
<210> 21
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 21
Glu Ile Leu Phe Tyr Gly Met Asp Tyr
1 5
<210> 22
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 22
Gly Val Ile Phe Gln Ser Gly Ala Thr Tyr Tyr Ala Asp Asp Phe Lys
1 5 10 15
<210> 23
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 23
Gly Ile Ile Phe Tyr Thr Gly His Thr Tyr Tyr Ala Asp Asp Phe Lys
1 5 10 15
<210> 24
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa是Thr, Ile, Lys,或Leu
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa是Ser或His
<400> 24
Gln Gln Asp Tyr Xaa Xaa Pro Trp Thr Phe
1 5 10
<210> 25
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa是Ala或Gly
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa是Thr, Ile, Val,或Ala
<220>
<221> MISC_FEATURE
<222> (15)..(15)
<223> Xaa是Asp, Val,或Glu
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa是Asp, Glu, Asn, Ser, Ile, Leu, Thr, Ala,或Phe
<400> 25
Xaa Gly Ile Val Tyr Asp Ala Thr Gly Phe Thr Xaa Tyr Ala Xaa Xaa
1 5 10 15
Phe Lys
<210> 26
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa是Val或Phe
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa是Arg或Ile
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa是Thr, Phe, Met,或Pro
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa是Ala或Val.
<400> 26
Gly Arg Xaa Thr Ile Thr Xaa Asp Xaa Ser Thr Ser Thr Xaa
1 5 10
<210> 27
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 27
Gln Gln Asp Tyr Thr His Pro Trp Thr Phe
1 5 10
<210> 28
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 28
Gly Gly Ile Val Tyr Asp Ala Thr Gly Phe Thr Thr Tyr Ala Glu Glu
1 5 10 15
Phe Lys
<210> 29
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 29
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 Ser Val Ile Asn Asp
20 25 30
Ala Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser His Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Thr His Pro Trp Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 30
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 30
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gly Ile Val Tyr Asp Ala Thr Gly Phe Thr Thr Tyr Ala Glu Glu
50 55 60
Phe Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala
65 70 75 80
Tyr Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Gly Ile Phe Tyr Gly Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 31
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 31
Gln Gln Asp Tyr Lys His Pro Trp Thr Phe
1 5 10
<210> 32
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 32
Ala Gly Ile Val Tyr Asp Ala Thr Gly Phe Thr Val Tyr Ala Asp Asp
1 5 10 15
Phe Lys
<210> 33
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 33
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 Ser Val Ile Asn Asp
20 25 30
Ala Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser His Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Tyr Lys His Pro Trp Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 34
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成性构建体
<400> 34
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Phe Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Ala Gly Ile Val Tyr Asp Ala Thr Gly Phe Thr Val Tyr Ala Asp Asp
50 55 60
Phe Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Thr Ser Thr Ala
65 70 75 80
Tyr Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Gly Ile Phe Tyr Gly Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
Claims (68)
1.制备包含可变重链结构域(VH)和可变轻链结构域(VL)的双重特异性抗体或其抗原结合片段的方法,其中双重特异性抗体的VH和VL配对在一起形成与第一表位和第二表位特异性结合的抗原结合位点,所述方法包括步骤:
(a)提供包含VH和VL的抗体,其中VH和VL配对在一起形成与第一表位结合但不与第二表位结合的抗原结合位点,并且其中所述抗体在VL的位置32、50或91包含至少一个带静电或疏水的氨基酸;
(b)改变编码步骤(a)的抗体的VH的核酸序列,其中改变一个或多个溶剂可及性氨基酸残基;
(c)表达VL和步骤(b)的改变的VH;和
(d)选择包含步骤(c)的该VL和改变的VH的双重特异性抗体或其抗原结合片段,其中该VH和VL配对在一起形成与第一表位和第二表位特异性结合的抗原结合位点。
2.根据权利要求1所述的方法,其中在位置32、50或91处的至少两个氨基酸是带静电或疏水的。
3.根据权利要求1所述的方法,其中在位置32、50和91处的全部三个氨基酸是带静电或疏水的。
4.根据权利要求1-3中任一项所述的方法,其中带静电残基是酪氨酸。
5.根据权利要求1-3中任一项所述的方法,其中疏水性残基是色氨酸。
6.根据权利要求1-5中任一项所述的方法,其中基于多个天然存在的重链氨基酸序列的多样性,改变编码VH的核酸序列。
7.根据权利要求1-6中任一项所述的方法,其中溶剂暴露残基的位置是选自VH的位置33、34、50-58和95-97的氨基酸残基位置。
8.根据权利要求1-7中任一项所述的方法,还包括改变编码步骤(a)的抗体的VL的核酸序列,其中改变一个或多个溶剂可及性氨基酸残基。
9.根据权利要求8所述的方法,其中溶剂暴露残基的位置是选自VH的氨基酸93-96的氨基酸残基位置。
10.根据权利要求1-9中任一项所述的方法,其中在步骤(d)的选择过程中,改变的VH与VL展示在噬菌体上。
11.根据权利要求1-10中任一项所述的方法,其中步骤(a)的抗体包含:包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的轻链可变区互补决定区CDRL1、包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2和包含氨基酸序列QQDYTSPWTF(SEQ ID NO:11)的CDRL3。
12.根据权利要求1-11中任一项所述的方法,其中步骤(a)的抗体包含:包含氨基酸序列DYSMH(SEQ ID NO:13)的重链可变区互补决定区CDR H1、包含氨基酸序列VWINTETGEPTYADDFK(SEQ ID NO:17)的CDR H2、和包含氨基酸序列GGIFYGMDY(SEQ ID NO:20)的CDR H3。
13.根据权利要求1-12中任一项所述的方法,其中步骤(d)的双重特异性抗体的抗原结合位点互斥地结合第一表位和第二表位。
14.根据权利要求1-12中任一项所述的方法,其中步骤(d)的双重特异性抗体的抗原结合位点同时结合第一表位和第二表位。
15.根据权利要求1-14中任一项所述的方法,其中第一表位来自一种生物分子并且第二表位来自相同的生物分子。
16.根据权利要求1-14中任一项所述的方法,其中第一表位来自第一生物分子并且第二表位来自第二生物分子。
17.根据权利要求16所述的方法,其中第一生物分子和第二生物分子选自IL4/IL5、IL4/IL13。
18.根据权利要求16所述的方法,其中第一生物分子和第二生物分子是细胞因子。
19.根据权利要求16所述的方法,其中第一或第二生物分子是在体内与抗体结合时可以增加双重特异性抗体半寿期的分子。
20.根据权利要求16所述的方法,其中第一或第二生物分子是血清白蛋白或新生儿Fc受体(FcRn)。
21.根据权利要求16所述的方法,其中第一或第二生物分子是在体内与抗体结合时可以增加双重特异性抗体的效应子功能的分子。
22.根据权利要求16所述的方法,其中第一或第二生物分子与天然杀伤细胞或巨噬细胞上的细胞表面蛋白结合。
23.根据权利要求22所述的方法,其中所述细胞表面蛋白是Fc受体或C1q。
24.根据权利要求1-23中任一项所述的方法,其中双重特异性抗体的VH和VL配对在一起,形成以10-6或更低的KD与第一表位或第二表位特异性结合的抗原结合位点。
25.根据权利要求24所述的方法,其中双重特异性抗体的VH和VL配对在一起,形成以10-9或更低的KD与第一表位或第二表位特异性结合的抗原结合位点。
26.根据权利要求25所述的方法,其中双重特异性抗体的VH和VL配对在一起,形成以10-12或更低的KD与第一表位或第二表位特异性结合的抗原结合位点。
27.根据权利要求1-23中任一项所述的方法,其中双重特异性抗体的VH和VL配对在一起,形成以10-6或更低的KD与第一表位和第二表位特异性结合的抗原结合位点。
28.根据权利要求27所述的方法,其中双重特异性抗体的VH和VL配对在一起,形成以10-9或更低的KD与第一表位和第二表位特异性结合的抗原结合位点。
29.根据权利要求28所述的方法,其中双重特异性抗体的VH和VL配对在一起,形成以10-12或更低的KD与第一表位和第二表位特异性结合的抗原结合位点。
30.根据权利要求1-29中任一项所述的方法,其中第一生物分子和第二生物分子在结构上不相似。
31.根据权利要求1-30中任一项所述的方法,其中步骤(d)的选择包括深度测序。
32.通过权利要求1的方法产生的分离的双重特异性抗体或其抗原结合片段。
33.根据权利要求32所述的分离的双重特异性抗体,其中双重特异性抗体是单克隆抗体。
34.根据权利要求32所述的分离的双重特异性抗体,其中片段是Fab或scFv。
35.根据权利要求32所述的分离的双重特异性抗体,其中双重特异性抗体是IgG。
36.分离的双重特异性抗体或其抗原结合片段,其包含图4A、4B、4C、7A、7C或7D的任一种抗体的氨基酸序列。
37.分离的双重特异性抗体或其抗原结合片段,包含以下六个CDR:
(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;
(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;
(iii)包含氨基酸序列QQDYTSPWTF(SEQ ID NO:11)的CDRL3;
(iv)包含氨基酸序列DYDIH(SEQ ID NO:14)的CDR H1;
(v)包含氨基酸序列VWINTETGEPTYADDFK(SEQ ID NO:17)的CDR H2;和
(vi)包含氨基酸序列EILFYGMDY(SEQ ID NO:21)的CDR H3。
38.分离的双重特异性抗体或其抗原结合片段,包含以下六个CDR:
(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;
(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;
(iii)包含氨基酸序列QQDYTSPWTF(SEQ ID NO:11)的CDRL3;
(iv)包含氨基酸序列DYFIH(SEQ ID NO:15)的CDR H1;
(v)包含氨基酸序列AGIVYDATGFTTYADDFK(SEQ ID NO:18)的CDR H2;和
(vi)包含氨基酸序列GGIFYGMDY(SEQ ID NO:20)的CDR H3。
39.分离的双重特异性抗体或其抗原结合片段,包含以下六个CDR:
(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;
(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;
(iii)包含氨基酸序列QQDYTPFPLTF(SEQ ID NO:12)的CDRL3;
(iv)包含氨基酸序列DYLMH(SEQ ID NO:16)的CDR H1;
(v)包含氨基酸序列AVIVSITGRTYYADDFK(SEQ ID NO:19)的CDR H2;和
(vi)包含氨基酸序列GGIFYGMDY(SEQ ID NO:20)的CDR H3。
40.分离的双重特异性抗体或其抗原结合片段,包含以下六个CDR:
(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;
(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;
(iii)包含氨基酸序列QQDYTSPWTF(SEQ ID NO:11)的CDRL3;
(iv)包含氨基酸序列DYSMH(SEQ ID NO:13)的CDR H1;
(v)包含氨基酸序列GVIFQSGATYYADDFK(SEQ ID NO:22)的CDR H2;和
(vi)包含氨基酸序列GGIFYGMDY(SEQ ID NO:20)的CDR H3。
41.分离的双重特异性抗体或其抗原结合片段,包含以下六个CDR:
(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;
(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;
(iii)包含氨基酸序列QQDYTSPWTF(SEQ ID NO:11)的CDRL3;
(iv)包含氨基酸序列DYSMH(SEQ ID NO:13)的CDR H1;
(v)包含氨基酸序列GIIFYTGHTYYADDFK(SEQ ID NO:23)的CDR H2;和
(vi)包含氨基酸序列GGIFYGMDY(SEQ ID NO:20)的CDR H3。
42.分离的双重特异性抗体或其抗原结合片段,包含以下六个CDR:
(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;
(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;
(iii)包含氨基酸序列QQDYX1X2PWTF(SEQ ID NO:24)的CDRL3,其中X1是Thr、Ile、Leu或Lys,并且X2是Ser或His;
(iv)包含氨基酸序列DYFIH(SEQ ID NO:15)的CDR H1;
(v)包含氨基酸序列X1GIVYDATGFTX2YA X3X4FK(SEQ ID NO:25)的CDR H2,其中其中X1是Ala或Gly,X2是Thr、Ile、Val或Ala,X3是Asp、Val或Glu,并且X4是Asp、Glu、Asn、Ser、Ile、Leu、Thr、Ala或Phe;和
(vi)包含氨基酸序列GGIFYGMDY(SEQ ID NO:20)的CDR H3。
43.根据权利要求41所述的分离的双重特异性抗体或其抗原结合片段,包含以下六个CDR:
(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;
(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;
(iii)包含氨基酸序列QQDYTHPWTF(SEQ ID NO:27)的CDRL3;
(iv)包含氨基酸序列DYFIH(SEQ ID NO:15)的CDR H1;
(v)包含氨基酸序列GGIVYDATGFTTYAEEFK(SEQ ID NO:28)的CDR H2;和
(vi)包含氨基酸序列GGIFYGMDY(SEQ ID NO:20)的CDR H3。
44.根据权利要求41所述的分离的双重特异性抗体或其抗原结合片段,包含以下六个CDR:
(i)包含氨基酸序列KASQSVINDAA(SEQ ID NO:9)的CDRL1;
(ii)包含氨基酸序列YTSHRYT(SEQ ID NO:10)的CDRL2;
(iii)包含氨基酸序列QQDYKHPWTF(SEQ ID NO:31)的CDRL3;
(iv)包含氨基酸序列DYFIH(SEQ ID NO:15)的CDR H1;
(v)包含氨基酸序列AGIVYDATGFTVYADDFK(SEQ ID NO:32)的CDR H2;和
(vi)包含氨基酸序列GGIFYGMDY(SEQ ID NO:20)的CDR H3。
45.根据权利要求42-44中任一项所述的分离的双重特异性抗体或其抗原结合片段,还包含构架区3(FR3),所述构架区3包含氨基酸序列GRX1TITX2DX3STSTX4(SEQ ID NO:26),其中X1是Val或Phe,X2是Arg或Ile,X3是Thr、Phe、Met或Pro,并且X4是Ala或Val。
46.分离的双重特异性抗体或其抗原结合片段,包含选自SEQ ID NO:1、5、29或33的氨基酸序列的轻链可变区和选自SEQ ID NO:2、3、4、6、7、8、30或34的重链可变区。
47.根据权利要求38、39和42-46中任一项所述的分离的双重特异性抗体或其抗原结合片段,其中所述抗体或其抗原结合片段以500nM或更低的Kd结合IL4并且以约900nM或更低的Kd结合IL5。
48.根据权利要求38、39和42-46中任一项所述的分离的双重特异性抗体或其抗原结合片段,其中所述抗体以100nM或更低的Kd结合IL4并且以约100nM或更低的Kd结合IL5。
49.根据权利要求38、39和42-46中任一项所述的分离的双重特异性抗体或其抗原结合片段,其中所述抗体以10nM或更低的Kd结合IL4并且以约50nM或更低的Kd结合IL5。
50.根据权利要求40、41和46中任一项所述的分离的双重特异性抗体或其抗原结合片段,其中所述抗体以500nM或更低的Kd结合IL4并且以约900nM或更低的Kd结合IL13。
51.根据权利要求40、41和46中任一项所述的分离的双重特异性抗体,其中所述抗体以100nM或更低的Kd结合IL4并且以约100nM或更低的Kd结合IL13。
52.根据权利要求36-51中任一项所述的分离的双重特异性抗体或其抗原结合片段,其中所述抗体抑制或阻断IL4、IL5或IL13与其受体的结合。
53.根据权利要求36-51中任一项所述的分离的双重特异性抗体或其抗原结合片段,其中所述抗体是单克隆抗体。
54.根据权利要求36-51中任一项所述的分离的双重特异性抗体或其抗原结合片段,其中所述抗体是IgG抗体。
55.根据权利要求36-51中任一项所述的分离的双重特异性抗体或其抗原结合片段,其中所述片段是Fab片段或单链可变片段(scFv)。
56.根据权利要求36-51中任一项所述的分离的双重特异性抗体或其抗原结合片段,其中构架序列的至少一部分是人共有构架序列。
57.根据权利要求32-51中任一项所述的分离的双重特异性抗体或其抗原结合片段,其中抗体是嵌合抗体、人源化抗体或全人抗体。
58.药物组合物,包含根据权利要求32-57任一项所述的抗体。
59.多核苷酸,编码根据权利要求32-57中任一项所述的分离的双重特异性抗体或其抗原结合片段。
60.载体,包含根据权利要求59所述的多核苷酸。
61.宿主细胞,包含根据权利要求60所述的载体。
62.产生根据权利要求32-57中任一项所述的抗体或其抗原结合片段方法,所述方法包括培养包含根据权利要求60所述的载体的宿主细胞以及回收所述抗体。
63.治疗受试者中哮喘的方法,所述方法包括向所述受试者施用根据权利要求32-57中任一项所述的抗体或其抗体片段,其中所述施用按足以治疗或预防所述受试者中所述哮喘的量和持续时间进行。
64.根据权利要求61所述的方法,其中所述方法还包括施用选自以下的至少一种额外的哮喘治疗药:IgE拮抗剂、抗组胺药、茶碱、沙丁胺醇、丙酸倍氯米松、色甘酸钠、类固醇和抗炎药。
65.根据权利要求63或64所述的方法,其中哮喘是过敏性哮喘。
66.治疗受试者中增生性疾病的方法,所述方法包括向所述受试者施用根据权利要求32-57中任一项所述的抗体或其抗体片段,其中所述施用按足以治疗所述受试者中所述增生性疾病的量和持续时间进行。
67.根据权利要求66所述的方法,其中所述增生性疾病是癌症。
68.根据权利要求67所述的方法,还包括向所述受试者施用选自化疗药、细胞毒药物和抗血管生成药的额外抗增生药。
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Also Published As
Publication number | Publication date |
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CN105849124A (zh) | 2016-08-10 |
CA3204788A1 (en) | 2015-06-25 |
RU2016129247A (ru) | 2018-01-25 |
MX2016006529A (es) | 2016-08-03 |
KR102597804B1 (ko) | 2023-11-07 |
JP2020162609A (ja) | 2020-10-08 |
JP2023179409A (ja) | 2023-12-19 |
JP2017501711A (ja) | 2017-01-19 |
US10683348B2 (en) | 2020-06-16 |
WO2015095539A1 (en) | 2015-06-25 |
BR112016011027A2 (pt) | 2017-12-05 |
KR20230155605A (ko) | 2023-11-10 |
CA2931113A1 (en) | 2015-06-25 |
RU2020129339A (ru) | 2020-10-02 |
EP3083682A1 (en) | 2016-10-26 |
CN105849124B (zh) | 2022-04-12 |
JP7325166B2 (ja) | 2023-08-14 |
US20160257744A1 (en) | 2016-09-08 |
US20200255512A1 (en) | 2020-08-13 |
EP3083682B1 (en) | 2024-04-17 |
MX2021003549A (es) | 2021-05-27 |
CA2931113C (en) | 2023-07-11 |
RU2732032C2 (ru) | 2020-09-10 |
KR20160099086A (ko) | 2016-08-19 |
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