CN104447992A - 半胱氨酸改造的抗体和偶联物 - Google Patents
半胱氨酸改造的抗体和偶联物 Download PDFInfo
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- CN104447992A CN104447992A CN201410584638.4A CN201410584638A CN104447992A CN 104447992 A CN104447992 A CN 104447992A CN 201410584638 A CN201410584638 A CN 201410584638A CN 104447992 A CN104447992 A CN 104447992A
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Abstract
本发明涉及半胱氨酸改造的抗体和偶联物。通过用具有非交联的高度反应性半胱氨酸氨基酸取代亲代抗体的一种或多种氨基酸改造抗体。还可以用一个或多个半胱氨酸氨基酸改造抗体片段而形成半胱氨酸改造的抗体片段(ThioFab)。提供了设计、制备、筛选和选择半胱氨酸改造的抗体的方法。使半胱氨酸改造的抗体(Ab),任选和具有清蛋白结合肽(ABP)序列,与一种或多种药物部分(D)通过连接基(L)偶联而形成半胱氨酸改造的抗体-药物偶联物,将具有式I:Ab-(L-D)p I其中p为1-4。披露了半胱氨酸改造的抗体药物化合物和组合物的诊断和治疗应用。
Description
本申请是申请日为2005年09月22日、中国申请号为200580040207.0、发明名称为“半胱氨酸改造的抗体和偶联物”的发明申请的分案申请。
该申请是在37CFR 1.53(b)(1)规定下提交的非临时申请,依照35USC119(e)的规定要求2004年9月23日提交的申请号为60/612,468的美国临时申请和2005年6月30日提交的申请号为60/696,353的美国临时申请的优先权,将这两篇文献各自的全部内容引入本文作为参考。
发明领域
本发明一般涉及用反应性半胱氨酸残基改造的抗体,且更具体地说,本发明涉及具有治疗或诊断应用的抗体。可以使半胱氨酸改造的抗体与化疗药;毒素;亲和配体,诸如生物素和检测标记,诸如荧光团偶联。本发明还涉及使用抗体和抗体-药物偶联物化合物在体外、原位和体内诊断或治疗哺乳动物细胞或相关病理性情况的方法。
发明背景
已经建立了靶向治疗患有癌症、免疫病症和血管生成病症的患者的抗体疗法。在发现用于使用抗体的癌症诊断和疗法有效细胞靶标的尝试中,研究人员寻求鉴定跨膜,或肿瘤相关多肽类,与正常非癌细胞相比,它们在癌细胞表面上得到特异性表达。鉴定这类肿瘤相关细胞表面抗原多肽类,即肿瘤相关抗原(TAA)已经带来了特异性靶向癌细胞的能力以便通过基于抗体的疗法产生破坏作用。
抗体-药物偶联物(ADC),即免疫偶联物在局部递送细胞毒性剂或细胞生长抑制剂,即在治疗癌症中杀伤或抑制肿瘤细胞的药物中的应用(Lambert,J.(2005)Curr.Opinion in Pharmacology 5:543-549;Wu等(2005)NatureBiotechnology 23(9):1137-1146;Payne,G.(2003)Cancer Cell 3:207-212;Syrigos和Epenetos(1999)Anticancer Research 19:605-614;Niculescu-Duvaz和Springer(1997)Adv.药物Del.Rev.26:151-172;US 4975278)在理论上能够将药物部分靶向递送至肿瘤并且在其中发生胞内蓄积,其中全身给予这些未偶联的药物活性剂在对肿瘤细胞消除的同时也对正常细胞产生了不可接受水平的毒性(Baldwin等(1986)Lancet pp.(Mar.15,1986):603-05;Thorpe,(1985)"Antibody Carriers Of Cytotoxic Agents In Cancer Therapy:AReview,"-Monoclonal Antibody′84:Biological and Clinical Applications,A.Pinchera等(ed.s),pp.475-506)。由此人们期望寻求到最高的功效与最低的毒性。设计和精制ADC的努力已经集中到单克隆抗体(mAbs)的特异性以及药物-连接和药物-释放特性上(Lambert,J.(2005)Curr.Opinion in Pharmacology5:543-549;已经报导了多克隆抗体和单克隆抗体可用于这些策略中(Rowland等(1986)Cancer Immunol.Immunother.,21:183-87)。用于这些方法的药物包括柔红霉素(daunomycin)、多柔比星(doxorubicin)、甲氨蝶呤(methotrexate)和长春地辛(vindesine)(Rowland等(1986),文献同上)。用于抗体-毒素偶联物的毒素包括:细菌毒素,诸如白喉毒素,植物毒素,诸如蓖麻毒素;小分子毒素,诸如格尔德霉素(geldanamycin)(Mandler等(2000)J.of the Nat.Cancer Inst.92(19):1573-1581;Mandler等(2000)Bioorganic&Med.Chem.Letters 10:1025-1028;Mandler等(2002)Bio偶联物Chem.13:786-791);美登木素生物碱(maytansinoids)(EP 1391213;Liu等(1996)Proc.Natl.Acad.Sci.USA 93:8618-8623);和加利车霉素(calicheamicin)(Lode等(1998)Cancer Res.58:2928;Hinman等(1993)Cancer Res.53:3336-3342)。毒素可以通过包括微管蛋白结合、DNA结合或拓扑异构酶抑制的机制完成其细胞毒性和细胞抑制作用。某些细胞毒性药物在与大的抗体或蛋白质受体配体偶联时趋向于失活或活性降低。
已经批准了抗体-放射性同位素偶联物。(替伊莫单抗(ibritumomab tiuxetan),Biogen/Idec)由定向于正常和恶性B淋巴细胞表面上的CD20抗原的鼠IgG1κ单克隆抗体和硫脲连接基-螯合剂结合的111In或90Y放射性同位素组成(Wiseman等(2000)Eur.J.Nucl.Med.27(7):766-77;Wiseman等(2002)Blood 99(12):4336-42;Witzig等(2002)J.Clin.Oncol.20(10):2453-63;Witzig等(2002)J.Clin.Oncol.20(15):3262-69)。尽管对B-细胞非何杰金(non-Hodgkin’s)淋巴瘤(NHL)具有活性,但是给药在大部分患者中产生严重和延长的细胞减少。MYLOTARGTM(吉姆单抗吉姆单抗(gemtuzumab ozogamicin),Wyeth Pharmaceuticals),即由与加利车霉素连接的hu CD33抗体组成的抗体-药物偶联物于2000年经批准用于通过注射治疗急性髓细胞样白血病(Drugs of the Future(2000)25(7):686;美国专利US4970198;5079233;5585089;5606040;5693762;5739116;5767285;5773001).Cantuzumab mertansine(Immunogen,Inc.);由通过二硫化物连接基SPP与美登木素生物碱药物部分DM1连接的huC242抗体组成的抗体-药物偶联物(Xie等(2004)J.of Pharm.And Exp.Ther.308(3):1073-1082)正在进入用于治疗表达CanAg的癌症,诸如结肠癌、胰腺癌、胃癌等的II期试验。MLN-2704(Millennium Pharm.,BZL Biologics,Immunogen Inc.),即与美登木素生物碱药物部分DM1连接的抗-前列腺特异性膜抗原(PSMA)单克隆抗体组成的抗体-药物偶联物正处于用于可能治疗前列腺肿瘤的研发中。
Auristatin肽类、auristatin E(AE)和monomethyl auristatin(MMAE)、多拉司他汀(dolastatin)的合成类似物(WO 02/088172)与下列偶联:(i)嵌合单克隆抗体cBR96(对癌上的Lewis Y具有特异性);(ii)对血液恶性肿瘤上的CD30具有特异性的cAC10(Klussman,等(2004),Bioconjugate Chemistry15(4):765-773;Doronina等(2003)Nature Biotechnology 21(7):778-784;Francisco等(2003)Blood 102(4):1458-1465;US 2004/0018194;(iii)用于治疗表达CD20的癌症和免疫病变的抗-CD20抗体,诸如B细胞单克隆抗体(rituxan)(WO 04/032828);(iv)用于治疗结肠直肠癌的抗-EphB2R抗体2H9和抗-IL-8(Mao等(2004)Cancer Research 64(3):781-788);(v)E-选择蛋白抗体(Bhaskar等(2003)Cancer Res.63:6387-6394);和(vi)其它抗-CD30抗体(WO 03/043583)。auristatin E的变体披露在US 5767237和US 6124431中。与单克隆抗体偶联的Monoemethyl auristatin E披露在Senter等的Proceedingsof the American Association for Cancer Research,Volume 45,Abstract Number623中,2004年3月28日提交。Auristatin类似物MMAE和MMAF与各种抗体偶联(WO 2005/081711)。
常规附着方式,即通过共价键连接,药物部分与抗体一般产生不均一的(heterogeneous)分子混合物,其中药物部分结合在抗体上的许多位点上。例如,细胞毒性药物一般与抗体通过抗体的通常大量的赖氨酸残基偶联,从而产生不均一的抗体-药物偶联物混合物。根据反应条件的不同,所述的不均一混合物一般含有抗体0-约8或8以上附着的药物部分的分布。此外,在具有特定整数比的药物部分与抗体的偶联物各亚组内可能是不均一的混合物,其中药物部分结合在抗体上的不同位点上。分析和制备方法不足以分离和表征由偶联反应产生的不均一混合物中的抗体-药物偶联物类分子。抗体为较大的复杂的并且结构多样的生物分子,通常带有许多反应性官能基。其与连接基试剂和药物-连接基中间体的反应性取决于如下因素:诸如pH、浓度、盐浓度和共溶剂。此外,多步骤偶联过程因控制反应条件和表征反应剂和中间体方面的困难而可能不可再现。
半胱氨酸巯基在中性pH具有反应性,这与在接近pH 7时质子化和亲核性降低的大部分胺类不同。由于游离巯基(RSH,硫氢基)具有相对的反应性,所以带有半胱氨酸残基的蛋白质通常以其作为二硫化物-连接的寡聚体的氧化形式存在或具有内部桥连的二硫化物基团。胞外蛋白一般不带有游离巯基(Garman,1997,Non-Radioactive Labelling:A Practical Approach,AcademicPress,London,55页上)。可以通过标准Ellman测定法估计蛋白质中游离巯基的量。免疫球蛋白M为二硫化物-连接的五聚体的实例,而免疫球蛋白G为带有彼此结合的亚单位的内部二硫键的蛋白质的实例。在诸如这种蛋白质中,用诸如二硫苏糖醇(DTT)或硒醇还原二硫键(Singh等(2002)Anal.Biochem.304:147-156)是产生反应性游离巯基所需的。这种手段可以导致抗体的三级结构和抗原结合特异性丧失。
抗体半胱氨酸巯基一般对亲电子偶联反应剂比对抗体胺或羟基更具反应性,即更具亲核性。已经通过遗传改造将半胱氨酸残基引入了蛋白质以便形成与配体的共价结合物或形成新的分子内二硫键(Better等(1994)J.Biol.Chem.13:9644-9650;Bernhard等(1994)Bioconjugate Chem.5:126-132;Greenwood等(1994)Therapeutic Immunology 1:247-255;Tu等(1999)Proc.Natl.Acad.Sci USA 96:4862-4867;Kanno等(2000)J.of Biotechnology,76:207-214;Chmura等(2001)Proc.Nat.Acad.Sci.USA 98(15):8480-8484;US 6248564)。然而,通过使蛋白质的不同氨基酸残基突变成半胱氨酸氨基酸的在半胱氨酸巯基上的设计可能存在问题,特别是就未配对的(游离Cys)残基或那些相对易于进行反应或氧化的残基而言。在蛋白质的浓溶液中,无论是在大肠杆菌(E.coli)的周质中,还是在培养物上清液或部分或完全纯化的蛋白质中,蛋白质表面上的未配对的Cys残基可以配对并且氧化成分子内二硫化物和由此的蛋白质二聚体或多聚体。二硫化物二聚体的形成使得新的Cys无法与药物、配体或其它标记发生偶联反应。此外,如果蛋白质以氧化方式在新改造的Cys和已存在的Cys残基之间形成分子内二硫键,那么两种Cys基团对活性位点的参与和相互作用而言均无法利用。此外,可以通过错误折叠或丧失三级结构使蛋白质失活或赋予其非特异性(Zhang等(2002)Anal.Biochem.311:1-9)。
概述
本发明的化合物包括半胱氨酸改造的抗体,其中亲代抗体的一种或多种氨基酸被游离半胱氨酸氨基酸替代。半胱氨酸改造的抗体包含一个或多个具有0.6-1.0范围的巯基反应值(thiol reactivity value)的游离半胱氨酸氨基酸。游离半胱氨酸氨基酸为已经被改造进入亲代抗体中并且不为二硫键的组成部分的半胱氨酸残基。
在一个方面中,通过包括下列步骤的方法制备半胱氨酸改造的抗体:
(a)用半胱氨酸替代亲代抗体的一种或多种氨基酸残基;和
(b)通过使半胱氨酸改造的抗体与巯基-反应试剂反应测定半胱氨酸改造的抗体的巯基反应性(thiol reactivity)。
半胱氨酸改造的抗体可以比亲代抗体更具与巯基-反应试剂的反应性。
游离半胱氨酸氨基酸残基可以位于重链或轻链中或恒定域或可变域中。还可以通过用一个或多个半胱氨酸氨基酸替代抗体片段的氨基酸来改造抗体片段,例如Fab,以便形成半胱氨酸改造的抗体片段。
本发明的另一个方面提供了制备半胱氨酸改造的抗体的方法,包括:
(a)将一个或多个半胱氨酸氨基酸引入亲代抗体以便生成半胱氨酸改造的抗体;和
(b)测定半胱氨酸改造的抗体与巯基-反应试剂的巯基反应性;
其中半胱氨酸改造的抗体比亲代抗体更具与巯基-反应试剂的反应性。
制备半胱氨酸改造的抗体的方法的步骤(a)可以包含:
(i)诱变编码半胱氨酸改造的抗体的核酸序列;
(ii)表达半胱氨酸改造的抗体;和
(iii)分离和纯化半胱氨酸改造的抗体。
制备半胱氨酸改造的抗体的方法的步骤(b)可以包含表达选自噬菌体或噬菌粒颗粒的病毒颗粒上的半胱氨酸改造的抗体。
制备半胱氨酸改造的抗体的方法的步骤(b)还可以包含:
(i)使半胱氨酸改造的抗体与巯基-反应性亲和试剂反应而生成亲和标记的半胱氨酸改造的抗体;和
(ii)测定亲和标记的半胱氨酸改造的抗体与俘获介质的结合。
本发明的另一个方面为筛选带有高反应性的未配对的半胱氨酸氨基酸的半胱氨酸改造的抗体的巯基反应性的方法,包含:
(a)将一个或多个半胱氨酸氨基酸导入亲代抗体以便产生半胱氨酸改造的抗体;
(b)使半胱氨酸改造的抗体与巯基-反应性亲和试剂反应而生成亲和标记的半胱氨酸改造的抗体;和
(c)测定亲和标记的半胱氨酸改造的抗体与俘获介质的结合;和
(d)测定半胱氨酸改造的抗体与巯基-反应试剂的巯基反应性。
筛选半胱氨酸改造的抗体的方法的步骤(a)可以包含:
(i)诱变编码半胱氨酸改造的抗体的核酸序列;
(ii)表达半胱氨酸改造的抗体;和
(iii)分离和纯化半胱氨酸改造的抗体。
筛选半胱氨酸改造的抗体的方法的步骤(b)可以包含表达选自噬菌体或噬菌粒颗粒的病毒颗粒上的半胱氨酸改造的抗体。
筛选半胱氨酸改造的抗体的方法的步骤(b)还可以包含:
(i)使半胱氨酸改造的抗体与巯基-反应性亲和试剂反应而生成亲和标记的半胱氨酸改造的抗体;和
(ii)测定亲和标记的半胱氨酸改造的抗体与俘获介质的结合。
半胱氨酸改造的抗体可以用于治疗癌症并且包括对细胞表面和跨膜受体和肿瘤相关抗原(TAA)具有特异性的各种抗体。这样的抗体可以用作裸抗体(未与药物或标记部分偶联)或用作式I抗体-药物偶联物(ADC)。
制备和筛选半胱氨酸改造的抗体的方法的实施方案包括:其中亲代抗体为抗体片段,诸如hu4D5Fabv8。亲代抗体还可以为包含清蛋白-结合肽序列(albumin-binding peptide)(ABP)的融合蛋白。亲代抗体还可以为选自huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7和huMAb4D5-8(曲妥单抗(trastuzumab))的人源化抗体。
本发明的半胱氨酸改造的抗体可以以位点特异性和有效的方式与巯基-反应试剂偶联。巯基-反应试剂可以为多官能连接基试剂(multifunctionallinker reagent)、俘获标记试剂(capture label reagent)、荧光团试剂(fluorophorereagent)或药物-连接基中间体(drug-linker intermediate)。
可以用可检测标记来标记半胱氨酸改造的抗体,使其固定在固相支持体上和/或与药物部分偶联。
本发明的另一个方面在于包含半胱氨酸改造的抗体(cysteine engineeredantibody)(Ab)和药物部分(drug moiety)(D)的抗体-药物偶联物化合物,其中半胱氨酸改造的抗体通过一个或多个游离半胱氨酸氨基酸经连接基部分(linker moiety)(L)与D结合;所述化合物即具有式I的化合物:
Ab-(L-D)p I
其中p为1、2、3或4;且其中所述的半胱氨酸改造的抗体是通过包含用一个或多个游离半胱氨酸氨基酸替代亲代抗体的一种或多种氨基酸残基的方法制备的。药物部分包括,但不限于美登木素生物碱、auristatin、多拉司他汀、单端孢霉烯(trichothecene)、CC1065、加利车霉素(calicheamicin)和其它烯二炔类抗生素、紫杉烷(taxane)、蒽环类抗生素(anthracycline)和它们的立体异构体、同电子排列体(isostere)、类似物或衍生物。典型的药物部分包括DM1、MMAE和MMAF。
式I的抗体-药物偶联物可以进一步包含清蛋白-结合肽(albumin-bindingpeptide)(ABP)序列;该组合物具有式Ia:
ABP-Ab-(L-D)p Ia
本发明的另一个方面在于包含半胱氨酸改造的抗体或半胱氨酸改造的抗体-药物偶联物和生理学或药学上可接受的载体或稀释剂的组合物。用于治疗应用的该组合物为无菌的并且可以是冻干的。
本发明的另一个方面包括本文披露的化合物和组合物的诊断和治疗应用。药物组合物包括式I化合物和一种或多种化疗剂的组合。
本发明的另一个方面为杀伤或抑制增殖的肿瘤细胞或癌细胞的方法,包含用有效杀伤或抑制增殖的肿瘤细胞或癌细胞用量的本发明的抗体-药物偶联物或其药学上可接受的盐或其溶剂合物治疗所述细胞。
本发明的其它方面包括治疗下列疾病的方法:癌症;自身免疫性疾病;或感染性疾病,包含对有此需要的患者给予有效量的本发明抗体-药物偶联物化合物或其药学上可接受的盐或溶剂合物。
本发明的另一个方面为治疗哺乳动物癌症的方法,其中所述的癌症的特征在于ErbB受体过表达。所述的哺乳动物任选对使用未偶联的抗-ErbB抗体治疗无应答或应答差。该方法包含对所述的哺乳动物给予治疗有效量的本发明抗体-药物偶联物化合物。
本发明的另一个方面为抑制过表达生长因子受体的肿瘤细胞生长的方法,所述的生长因子受体选自HER2受体和EGF受体组成的组,该方法包含对患者给予特异性结合所述生长因子受体的抗体-药物偶联物化合物和化疗剂,其中以有效抑制患者肿瘤细胞生长的用量给予所述的抗体-药物偶联物和所述的化疗剂。
本发明的另一个方面为治疗易患特征在于ErbB2受体过表达的病症或对已诊断患该病的人体患者的方法,包含给予有效量的抗体-药物偶联物化合物和化疗剂的联合用药。
本发明的另一个方面为用于检测癌细胞的测定方法,包含:将细胞暴露于抗体-药物偶联物化合物,并且测定抗体-药物偶联物化合物与细胞的结合程度。
本发明的另一个方面为一种制品,其包含:抗体-药物偶联物化合物;容器;和指示所述化合物可以用于治疗癌症的包装说明书或标签。
附图简述
附图1A表示通过X射线晶体坐标衍生的hu4D5Fabv7抗体片段的三维代表图。对重链和轻链的例示性改造的Cys残基的结构位置进行了编号(按照序列编号系统)。
附图1B表示4D5v7fabH的与Kabat编号方案(下排)对比在N-末端开始的序列编号方案(上排)。Kabat编号插入由a、b、c标注。
附图2A和2B表示通过与BSA(空心条柱)、HER2(具条纹的条柱)或链霉抗生物素(实心条柱)相互作用的PHESELECTOR测定法,使用在450nm处吸光度检测的hu4D5Fabv8和hu4D5Fabv8 Cys突变体(ThioFab)噬菌体变体的结合测定值:(A)未生物素化噬菌体-hu4D5Fabv8和(B)生物素化噬菌体-hu4D5Fabv8(B)。
附图3A和3B表示通过与BSA(空心条柱)、HER2(具条纹的条柱)和链霉抗生物素(实心条柱)相互作用的PHESELECTOR测定法,使用在450nm处吸光度检测的hu4D5Fabv8(左)和hu4D5Fabv8 Cys突变体(ThioFab)的结合测定值:(A)未生物素化噬菌体-hu4D5Fabv8和(B)生物素化噬菌体-hu4D5Fabv8。轻链变体位于左侧,而重链变体位于右侧。巯基反应性=链霉抗生物素结合的OD450nm÷HER2(抗体)结合的OD450nm。
附图4A表示野生型hu4D5Fabv8上残基的表面可接近分数值(FractionalSurface Accessibility Value)。轻链位点位于左侧,而重链位点位于右侧。
附图4B表示通过在450nm处检测吸光度测定的与HER2(第2天)、链霉抗生物素(SA)(第2天)、HER2(第4天)和SA(第4天)的相互作用的生物素化的hu4D5Fabv8和hu4D5Fabv8Cys变体(ThioFab)的结合测定值。分离噬菌体-hu4D5Fabv8 Cys变体并且储存在4℃下。在第2天或第4天时进行生物素偶联,随后进行PHESELECTOR分析以便如实施例2中所述监测其与Her2和链霉抗生物素的相互作用并且探测改造的ThioFab变体上反应性巯基的稳定性。
附图5表示通过在450nm处检测吸光度测定的生物素-马来酰亚胺偶联的-hu4D5Fabv8(A121C)和未生物素化的野生型hu4D5Fabv8在结合链霉抗生物素和HER2中的结合测定值。在2ng和20ng测试每种Fab。
附图6表示通过在450nm处检测生物素化的ABP-hu4D5Fabv8野生型(wt)和ABP-hu4D5Fabv8半胱氨酸突变体V110C和A121C在结合兔清蛋白、链霉抗生物素(SA)和HER2中的吸光度的ELISA分析。
附图7表示通过在450nm处检测吸光度对生物素化的ABP-hu4D5Fabv8半胱氨酸突变体(ThioFab变体):(左至右)单Cys变体ABP-V110C、ABP-A121C和双Cys变体ABP-V110C-A88C和ABP-V110C-A121C的在结合兔清蛋白、HER2和链霉抗生物素(SA)并且使用Fab-HRP或SA-HRP探测的ELISA分析。
附图8表示生物素化的ThioFab噬菌体和抗-噬菌体HRP抗体与HER2(上)和链霉抗生物素(下)的结合。
附图9表示ABP-ThioFab融合蛋白药物偶联物结合HER2受体抗原的例示图。ABP=清蛋白结合蛋白。
附图10表示用-●-曲妥单抗(trastuzumab);-▲-曲妥单抗-SMCC-DM1;和-◆-hu4D5Fabv8半胱氨酸突变体-(A121C)-BMPEO-DM1处理的SK-BR-3细胞的体外细胞增殖试验。
附图11表示用-○-曲妥单抗;-●-曲妥单抗-SMCC-DM1;和-□-hu4D5Fabv8半胱氨酸突变体(V110C)-BMPEO-DM1处理的SK-BR-3细胞的体外细胞增殖试验。
附图12表示在第0天给药的具有MMTV-HER2Fo5乳腺肿瘤同种异体移植物的无胸腺裸鼠随时间改变的肿瘤体积改变的平均值:媒介物(缓冲液);-■-ABP-hu4D5Fabv8半胱氨酸突变体(V110C轻链)-DM1;和-·-ABP-hu4D5Fabv8半胱氨酸突变体(A121C重链)-DM1。
附图13A表示结合固定的HER2的生物素化抗体在结合用于吸光度检测的HRP标记的二抗(second antibody)的卡通画描绘。
附图13B表示在450nm处检测吸光度测定的生物素-马来酰亚胺偶联的硫代-曲妥单抗变体(thio-trastuzumab variant)和未-生物素化的野生型曲妥单抗结合固定的HER2的结合测定。从左至右:V110C(单cys),A121C(单cys),V110C/A121C(双cys)和曲妥单抗。以1、10和100ng测试了各thio IgG变体和曲妥单抗。
附图14A表示结合固定的HER2的生物素化抗体和用于吸光度检测的生物素与抗-IgG-HRP结合的卡通图描绘。
附图14B表示在450nm下检测吸光度的生物素-马来酰亚胺偶联的-硫代曲妥单抗变体和未-生物素化的野生型曲妥单抗在结合固定的链霉抗生物素中的结合测定值。从左至右:V110C(单cys),A121C(单cys),V110C/A121C(双cys)和曲妥单抗。以1、10和100ng测试了各thio IgG变体和曲妥单抗。
附图15表示制备由细胞培养物表达的用于偶联的半胱氨酸改造的抗体(ThioMab)的一般方法。
附图16表示在固定的蛋白质A上纯化后2H9ThioMab Fc变体的非还原(上)和还原(下)变性聚丙烯酰胺凝胶电泳分析(左至右,泳道1-9):A339C;S337C;S324C;A287C;V284C;V282C;V279C;V273C;和2H9野生型。右侧的泳道为分子大小标记梯,表示完整蛋白质约为150kDa、重链片段约50kDa和轻链片段约25kDa。
附图17A表示在固定的蛋白质A上纯化后2H9ThioMab变体(左至右,泳道1-4):L-V15C;S179C;S375C;S400C的非还原(左)和还原(+DTT)(右)变性聚丙烯酰胺凝胶电泳分析。
附图17B表示在固定的蛋白质A上纯化后2H9和3A5ThioMab变体的非还原(左)和还原(+DTT)(右)变性聚丙烯酰胺凝胶电泳分析。
附图18表示生物素化thio-IgG变体的蛋白印迹分析。用还原的变性聚丙烯酰胺凝胶电泳分析2H9和3A5 ThioMab变体,将蛋白质转移到硝酸纤维素膜。分别用抗-IgG-HRP(上)和链霉抗生物素-HRP(下)探测抗体和偶联的生物素的存在。泳道1:3A5H-A121C。泳道2:3A5L-V110C。泳道3:2H9H-A121C。泳道4:2H9L-V110C。泳道5:2H9野生型。
附图19表示通过用抗-IgG-HRP探测和在450nm测定吸光度进行的生物素化的2H9变体与链霉抗生物素结合的ELISA分析(上部条柱形图)。下部示意图描绘了用于ELISA分析的实验设计。
附图20表示用下列处理的SK-BR-3细胞的体外细胞增殖试验:-●-曲妥单抗;-▲-具有3.4DM1/Ab药物负荷的曲妥单抗-SMCC-DM1;和-◆-具有1.6DM1/Ab药物负荷的硫代-曲妥单抗(A121C)-BMPEO-DM1。
附图21A表示用下列处理的HT 1080EphB2细胞的体外细胞增殖试验:亲代2H9抗-EphB2R;和thio2H9(A121C)BMPEO-DM1。
附图21B表示用下列处理的BT 474细胞的体外细胞增殖试验:亲代2H9抗-EphB2R;和thio2H9(A121C)BMPEO-DM1。
附图22表示用下列处理的PC3/neo细胞的体外细胞增殖试验:-◆-3A5抗MUC16-SMCC-DM1;和-■-thio3A5(A121C)BMPEO-DM1。
附图23表示用下列处理的PC3/MUC16细胞的体外细胞增殖试验:-◆-3A5抗MUC16-SMCC-DM1;和-■-thio3A5(A121C)BMPEO-DM1。
附图24表示用下列处理的OVCAR-3细胞的体外细胞增殖试验:-◆-3A5抗MUC16-SMCC-DM1;和-■-thio3A5(A121C)BMPEO-DM1。
附图25表示在第0天给予单剂量的下列物质给药后具有MMTV-HER2Fo5乳腺肿瘤同种异体移植物的无胸腺裸鼠21天内的肿瘤体积改变的平均值:媒介物(缓冲液);-●-曲妥单抗-SMCC-DM1 10mg/kg,具有3.4DM1/Ab的药物负荷(drug loading);-■-硫代曲妥单抗(A121C)-SMCC-DM121mg/kg,具有1.6DM1/Ab的药物负荷;和硫代曲妥单抗(A121C)-SMCC-DM1 10mg/kg,具有1.6DM1/Ab的药物负荷。
典型实施方案的详细描述
详细内容参照本发明的某些实施方案,其实施例在附带的结构和通式中例示。尽管结合列举的实施方案描述了本发明,但是应理解它们并非指定用于将本发明限定到那些实施方案。相反,本发明覆盖所有的备选、变型和等同技术方案,它们均包括在如权利要求定义的本发明范围内。
本领域技术人员知道可以用于实施本发明的与本文所述的那些相似或等同的许多方法和物质。本发明决不限于所述的方法和物质。
除非另做陈述,否则,本文所用的技术和科学术语具有本发明所属技术领域普通技术人员通常理解的相同的含义并且与如下文献中所述一致:Singleton等(1994)Dictionary of Microbiology and Molecular Biology,2nd Ed.,J.Wiley&Sons,New York,NY;和Janeway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immonobiology,5th Ed.,Garland Publishing,New York。
定义
除非另做陈述,否则,本文所用的下列术语和措词具有如下含义:
当本文中使用商品名时,申请人意欲独立地包括产品的商品名产品制剂、仿制药和商品名产品的活性药物组分。
本文的术语“抗体”以其最广泛的含义使用并且特别覆盖单克隆抗体、多克隆抗体、二聚体、多聚体、多特异性抗体(例如双特异性抗体)和抗体片段,只要它们表现出所需的生物活性(Miller等(2003)Jour.of Immunology170:4854-4861)。抗体可以为鼠、人、人源化、嵌合的抗体或来源于其它物种。抗体为由能够识别和结合特异性抗原的免疫系统产生的蛋白质(Janeway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immuno Biology,5th Ed.,GarlandPublishing,New York).靶抗原一般具有由多种抗体的CDRs识别的大量结合位点,也称作表位。特异性结合不同表位的各抗体具有不同的结构。因此,一种抗原可以具有一种以上相应的抗体。抗体包括全-长免疫球蛋白分子或全-长免疫球蛋白分子的免疫活性部分,即含有特异性结合所关注靶标的抗原或其部分的分子,这类靶标包括,但不限于癌细胞或产生与自身免疫性疾病相关的自身免疫抗体的细胞。本文披露的免疫球蛋白可以具有免疫球蛋白分子的任意类型(例如IgG、IgE、IgM、IgD和IgA)、类别(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类。免疫球蛋白可以来源于任意的物种。然而,在一个方面中,免疫球蛋白来源于人、鼠或兔。
"抗体片段"包含全长抗体的一部分,一般为其抗原结合区或可变区。抗体片段的实例包括:Fab、Fab′、F(ab′)2和Fv片段;双抗体;线性抗体;微抗体(minibody)(Olafsen等(2004)Protein Eng.Design&Sel.17(4):315-323);Fab表达文库制备的片段;抗-独特型(抗-Id)抗体;CDR(互补决定区);和以免疫特异性方式结合癌细胞抗原、病毒抗原或微生物抗原的上述任意的表位-结合片段;单-链抗体分子;和由抗体片段形成的多特异性抗体。
本文的术语“单克隆抗体”指从基本上同质的抗体群中获得的抗体,即除可能少量存在的天然发生的可能突变之外,包含在该群体中的各抗体是相同的。单克隆抗体是高度特异的靶向单个抗原位点的抗体。而且,与典型地包括靶向不同决定簇(表位)的不同抗体的多克隆抗体制品相反,每种单克隆抗体只靶向抗原上的单一决定簇。除其特异性外,单克隆抗体的优点还在于它们可以以不被其它抗体污染的方式合成。修饰语“单克隆”表示获自基本上同质的抗体群的抗体特性,并非解释为需要由任何特定方法生产抗体。例如,可以通过首先由Kohler等(1975)Nature 256:495描述的杂交瘤方法制备用于本发明的单克隆抗体或可以通过重组DNA方法制备(例如,参见:US4816567;US 5807715)。例如,还可以使用Clackson等(1991)Nature,352:624-628;Marks等(1991)J.Mol.Biol.,222:581-597所述的技术从噬菌体抗体文库分离单克隆抗体。
本文的单克隆抗体特别包括“嵌合”抗体,其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类型或亚型的抗体中的相应序列相同或同源,而所述链的剩余部分与来源于另一物种或属于另一抗体类型或亚型的抗体中的相应序列相同或同源,本文还包括嵌合抗体的片段,只要它们展示期望的生物学活性(US 4816567;和Morrison等(1984)Proc.Natl.Acad.Sci.USA,81:6851-6855)。本文关注的嵌合抗体包括“灵长化(primatized)”抗体,其包含来源于非人的灵长类(例如Old World Monkey、Ape等)的可变区抗原-结合序列和人恒定区序列。
本文的“完整抗体”为包含VL和VH结构域以及轻链恒定域(CL)和重链恒定域CH1、CH2和CH3的抗体。恒定域可以为天然序列恒定域(例如人天然序列恒定域)或其氨基酸序列变体。完整抗体可以具有一种或多种“效应子功能”,意旨归因于抗体的Fc恒定区(天然序列Fc区或氨基酸序列变体Fc区)的那些生物活性。抗体效应子功能的实例包括C1q结合;补体依赖的细胞毒性;Fc受体结合;抗体-依赖性细胞介导的细胞毒作用(ADCC);胞吞作用;和细胞表面受体,诸如B细胞受体和BCR的减量调节。
根据其重链恒定域的氨基酸序列的不同,可以将完整抗体指定为不同“类别”。存在5种主要类别的完整免疫球蛋白抗体:IgA、IgD、IgE、IgG和IgM,且可以将其中的几种进一步分成“亚类”(亚型),例如IgG1,IgG2,IgG3,IgG4,IgA1,和IgA2。对应于不同抗体类别的重链恒定域分别称作α、δ、ε、γ和μ。不同类别免疫球蛋白的亚单位结构和三维构型为众所周知的。Ig型包括铰链-修饰型或无铰链型(Roux等(1998)J.Immunol.161:4083-4090;Lund等(2000)Eur.J.Biochem.267:7246-7256;US 2005/0048572;US2004/0229310)。
“ErbB受体”为属于受体ErbB受体家族的蛋白酪氨酸激酶,其成员为细胞生长、分化和存活的重要介导物。ErbB受体家族包括4种不同的成员,包括表皮生长因子受体(EGFR、ErbB1、HER1)、HER2(ErbB2或p185neu)、HER3(ErbB3)和HER4(ErbB4或tyro2)。已经使用人乳腺肿瘤细胞系SKBR3表征了一组抗-ErbB2抗体(Hudziak等(1989)Mol.Cell.Biol.9(3):1165-1172。使用称作4D5的抑制细胞增殖达56%的抗体获得最大抑制作用。在本试验的一组抗体中的其它抗体降低细胞增殖的程度较弱。进一步发现抗体4D5可以使过表达ErbB2的乳腺肿瘤细胞系对TNF-α的细胞毒性效应敏感(US5677171)。Hudziak等讨论的抗-ErbB2抗体进一步在下列文献中得到表征:Fendly等(1990)Cancer Research 50:1550-1558;Kotts等(1990)In Vitro26(3):59A;Sarup等(1991)Growth Regulation 1:72-82;Shepard等J.(1991)Clin.Immunol.11(3):117-127;Kumar等(1991)Mol.Cell.Biol.11(2):979-986;Lewis等(1993)Cancer Immunol.免疫ther.37:255-263;Pietras等(1994)Oncogene 9:1829-1838;Vitetta等(1994)Cancer Research 54:5301-5309;Sliwkowski等(1994)J.Biol.Chem.269(20):14661-14665;Scott等(1991)J.Biol.Chem.266:14300-5;D′souza等Proc.Natl.Acad.Sci.(1994)91:7202-7206;Lewis等(1996)Cancer Research 56:1457-1465;和Schaefer等(1997)Oncogene15:1385-1394。
ErbB受体通常包含胞外结构域,其可以结合ErbB配体;亲脂性跨膜结构域;保守的胞内酪氨酸激酶结构域;和包含几个可以被磷酸化的酪氨酸残基的羧基-末端信号传导结构域。ErbB受体可以为“天然序列”ErbB受体或其“氨基酸序列变体”。优选ErbB受体为天然序列人ErbB受体。因此,“ErbB受体家族的成员”为EGFR(ErbB1)、ErbB2、ErbB3、ErbB4或其它任意目前已知或即将在未来鉴定的ErbB受体。
术语“ErbB1”、“表皮生长因子受体”、“EGFR”和“HER1”在本文中可以互换使用并且意旨例如在Carpenter等(1987)Ann.Rev.Biochem.,56:881-914中披露的EGFR,包括其天然存在的突变形式(例如作为在Humphrey等(1990)Proc.Nat.Acad.Sci.(USA)87:4207-4211中的缺失突变体EGFR)。本文的术语erbB1意旨编码EGFR蛋白质产物的基因。例如,Murthy等(1987)Arch.Biochem.Biophys.,252:549-560和WO 95/25167中描述了针对HER1的抗体。
术语"ERRP"、"EGF-受体相关蛋白""EGFR相关蛋白"和"表皮生长因子受体相关蛋白"在本文中可以互换使用并且意旨例如在US 6399743和US公开号2003/0096373中披露的ERRP。
表达方式“ErbB2”和“HER2”在本文中可以互换使用并且意旨例如Semba等(1985)Proc.Nat.Acad.Sci.(USA)82:6497-6501和Yamamoto等(1986)Nature,319:230-234(Genebank登记号X03363)中所述的人HER2蛋白。术语“erbB2”意旨编码人ErbB2的基因且“neu”意旨编码大鼠p185neu的基因。优选的ErbB2为天然序列人ErbB2。
“ErbB3”和“HER3”意旨例如在美国专利US5183884和US5480968以及Kraus等(1989)Proc.Nat.Acad.Sci.(USA)86:9193-9197中披露的受体多肽。本领域中已知针对ErbB3的抗体并且描述在例如美国专利US 5183884、US5480968和WO 97/35885中。
本文的术语“ErbB4”和“HER4”意旨例如EP专利申请599,274;Plowman等(1993)Proc.Natl.Acad.Sci.USA 90:1746-1750;和Plowman等(1993)Nature 366:473-475中披露的受体多肽,包括例如WO 99/19488中披露的其同种型。例如,WO 02/18444中描述了针对HER4的抗体。
对ErbB受体的抗体购自许多来源,包括,例如Santa Cruz Biotechnology,Inc.,California,USA。
术语“氨基酸序列变体”意旨在一定程度上具有不同于天然序列多肽的氨基酸序列的多肽。氨基酸序列变体一般与天然ErbB配体的至少一种受体结合结构域或与天然ErbB受体的至少一种配体结合结构域具有至少约70%的序列同一性,并且优选它们至少约80%,更优选至少约90%的序列与这类受体或配体结合结构域同源。氨基酸序列变体在天然氨基酸序列的氨基酸序列内的某些位置上具有替代、缺失和/或插入。按照常规的名称,即一字母密码和三字母密码命名氨基酸。
将“序列同一性”定义为对序列进行序列对比排列并在必要时引入缺口以获取最大百分比序列同一性后氨基酸序列变体中相同的残基的百分率。用于进行序列对比的方法和计算机程序为本领域众所周知的。一种这类计算机程序为Genentech,Inc.创建的“Align 2”,其中归档为1991年12月10日在United States Copyright Office,Washington,DC 20559的用户文件。
“抗体依赖细胞介导的细胞毒作用”和“ADCC”意旨细胞介导的反应,其中非特异性细胞毒性细胞表达Fc受体(FcRs)(例如天然杀伤(NK)细胞、中性白细胞和巨噬细胞)识别靶细胞上结合的抗体并且随后导致靶细胞裂解。用于介导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。造血细胞上的FcR表达概括在Ravetch和Kinet,(1991)“Annu.Rev.Immunol.9:457-92”464页上的表3中。为了评价所关注的分子的ADCC活性,可以进行诸如描述在US 5500362和US 5821337中的体外ADCC试验。用于这类试验的有用的效应细胞包括外周血单个核细胞(PBMC)和天然杀伤(NK)细胞。或者或另外,可以在体内,例如在诸如Clynes等(1998)PROC.NAT.ACAD.SCI.(USA)(USA)95:652-656披露的动物模型中评价所关注的分子的ADCC活性。
“人效应细胞”为表达一种或多种恒定区受体(FcRs)和并且执行效应子功能的白细胞。优选该细胞至少表达FcγRIII并且执行ADCC效应子功能。介导ADCC的人白细胞的实例包括外周血单个核细胞(PBMC)、天然杀伤(NK)细胞、单核细胞、细胞毒性T细胞和中性白细胞;其中优选PBMC和NK细胞。可以如上所述将效应细胞从其天然来源,例如从血液或PBMC中分离。
术语“Fc受体”或“FcR”用于描述结合抗体Fc恒定区的受体。优选的FcR为天然序列人FcR。此外,优选的FcR为结合IgG抗体的FcR(γ受体)并且包括FcγRI、FcγRII和FcγRIII亚类的受体,包括等位基因变体和这些受体的不同剪接形式。FcγRII受体包括FcγRIIA(“活化受体”)和FcγRIIB(“抑制受体”),其具有相似的氨基酸序列,这些氨基酸序列主要在其胞质结构域方面不同。活化受体FcγRIIA在其胞质结构域中含有基于免疫受体酪氨酸的活化基序(ITAM)。抑制受体FcγRIIB在其胞质结构域中含有基于免疫受体酪氨酸的抑制基序(ITIM)(参见,综述在M.“Annu.Rev.Immunol.”15:203-234(1997)中)。FcRs综述在下列文献中:Ravetch和Kinet,“Annu.Rev.Immunol”.,9:457-92(1991);Capel等(1994)免疫methods 4:25-34;和de Haas等(1995)J.Lab.Clin.Med.126:330-41。本文的术语“FcR”中包括其它FcRs,包括那些在未来即将得到鉴定的FcRs。该术语还包括新生儿受体FcRn,其可导致母体IgGs转移至胎儿(Guyer等(1976)J.Immunol.,117:587和Kim等(1994)J.Immunol.24:249)。
“补体依赖性细胞毒性”或“CDC”意旨分子在补体存在下裂解靶标的能力。补体活化途径通过补体系统(C1q)的第一种成分与复合关连抗原的分子(例如抗体)结合而启动。为了评价补体活化,可以进行CDC试验,例如如Gazzano-Santoro等J.Immunol.Methods,202:163(1996)在所述。
“天然抗体”通常为由两种相同的轻(L)链和两种相同的重(H)链组成的约150,000道尔顿的异四聚化糖蛋白。每一轻链通过一个共价二硫键与重链连接,而二硫键的数量在不同免疫球蛋白同种型中可变。每一重链和轻链还具有有规则间隔的链间二硫键。每一重链在一端上带有可变域(VH),随后是大量恒定域。每一轻链在一端上带有可变(VL),而在另一端上带有恒定域。将轻链的恒定域与重链的第一恒定域进行序列对比并且将轻链的可变域与重链的可变域进行序列对比。认为特定的氨基酸残基在轻链域重链可变域之间形成界面。
术语“可变的”指可变区中的某些部分在抗体序列中差异广泛且用于每种特定抗体针对其特定抗原的结合和特异性的实情。然而,变异性并非均匀分布于抗体的整个可变区。它集中于轻链和重链可变区中称作高变区的三个区段。可变区中更加高度保守的部分称作框架区(FR)。天然重链和轻链的可变区各自包含四个FR,它们大多采取β-折叠构象,通过形成环状连接且在有些情况中形成β-折叠结构一部分的三个高变区连接。每条链中的高变区通过FR非常接近的保持在一起,并与另一条链的高变区一起促成抗体的抗原结合位点的形成(参见Kabat等人,1991,《Sequences of Proteins ofImmunological Interest》,第5版,Public Health Service,National Institutes ofHealth,Bethesda,MD)。恒定区不直接参与抗体与抗原的结合,但展现出多种效应物功能,诸如抗体依赖性细胞的细胞毒性(ADCC)中抗体的参与。
术语“高变区”在用于本文时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(例如轻链可变区中的残基24-34(L1)、50-56(L2)和89-97(L3)及重链可变区中的残基31-35(H1)、50-65(H2)和95-102(H3);Kabat等人,见上文)和/或那些来自“高变环”的残基(例如轻链可变区中的残基26-32(L1)、50-52(L2)和91-96(L3)及重链可变区中的残基26-32(H1)、53-55(H2)和96-101(H3);Chothia andLesk(1987)J.Mol.Biol.196:901-917)。“框架区”或“FR”残基指可变区中除了本文中所定义的高变区残基以外的那些残基。
用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,各自具有一个抗原结合位点,和一个残余“Fc”片段,其名称反映了它易于结晶的能力。胃蛋白酶处理产生一个F(ab′)2片段,它具有两个抗原结合位点且仍能够交联抗原。
“Fv”是包含完整抗原识别和抗原结合位点的最小抗体片段。此区由紧密、非共价结合的一个重链可变区和一个轻链可变区的二聚体组成。正是在这种构造中,各个可变区的三个高变区相互作用而在VH-VL二聚体表面确定了一个抗原结合位点。六个高变区共同赋予抗体以抗原结合特异性。然而,即使是单个可变区(或只包含对抗原特异的三个高变区的半个Fv)也具有识别和结合抗原的能力,尽管亲和力低于完整结合位点。
Fab片段还包含轻链的恒定区和重链的第一恒定区(CH1)。Fab’片段因在重链CH1结构域的羧基末端增加了少数残基而与Fab片段有所不同,包括来自抗体铰链区的一个或多个半胱氨酸。Fab’-SH是本文中对其中恒定区半胱氨酸残基携带至少一个游离硫醇基的Fab’的称谓。F(ab′)2抗体片段最初是作为成对Fab’片段生成的,在Fab’片段之间具有铰链半胱氨酸。还知道抗体片段的其它化学偶联。
根据其恒定区氨基酸序列,来自任何脊椎动物物种的抗体的“轻链”可归入两种截然不同类型中的一种,称作卡帕(κ)和拉姆达(λ)。
“单链Fv”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一条多肽链上。优选的是,该Fv多肽在VH和VL结构域之间还包含多肽接头,使得scFv能够形成抗原结合期望的结构。关于scFv的综述参见Plückthun,《The Pharmacology of Monoclonal Antibodies》,vol.113,Rosenburg和Moore编,Springer-Verlag,New York,pp.269-315,1994。抗ErbB2抗体scFv片段描述于WO 93/16185;美国专利5,571,894;和5,587,458。
术语“双抗体”指具有两个抗原结合位点的小型抗体片段,该片段在同一条多肽链(VH-VL)中包含相连的重链可变区(VH)和轻链可变区(VL)。通过使用过短的接头使得同一条链上的两个结构域之间不能配对,迫使结构域与另一条链的互补结构域配对,并产生两个抗原结合位点。双抗体更完整的描述于例如EP 404,097;WO 93/11161;Hollinger et al.(1993)Proc.Natl.Acad.Sci.USA,90:6444-6448。
非人(例如啮齿类)抗体的“人源化”形式指最低限度包含衍生自非人免疫球蛋白的序列的嵌合抗体。人源化是将鼠抗原结合信息转移至非免疫原性人抗体受体的方法,并且已经产生了许多治疗上有用的药物。人源化方法一般通过将所有6个鼠互补决定区(CDR)转移至人抗体框架开始(Jones等,(1986)Nature 321:522-525)。这些CDR移植的抗体一般不会保持其对抗原结合的最初亲和力,并且事实上,亲和力通常严重受损。除CDR外,还必须引入选定的非人抗体框架残基以便维持正确的CDR构象(Chothia等(1989)Nature 342:877)。已经证实,将关键的小鼠框架残基转移至人受体以便支持所移植CDR的结构构象恢复抗原结合和亲和力(Riechmann等(1992)J.Mol.Biol.224,487-499;Foote和Winter,(1992)J.Mol.Biol.224:487-499;Presta等(1993)J.Immunol.151,2623-2632;Werther等(1996)J.Immunol.Methods157:4986-4995;和Presta等(2001)Thromb.Haemost.85:379-389)。在极大程度上,人源化抗体指人免疫球蛋白(受体抗体)中的高变区残基用具有期望特异性、亲和力和能力的非人物种(供体抗体)诸如小鼠、大鼠、兔或非人灵长类的高变区残基替换的免疫球蛋白。在有些情况中,将人免疫球蛋白的框架区(FR)残基用相应的非人残基替换。此外,人源化抗体可包含在受体抗体或供体抗体中没有发现的残基。进行这些修饰是为了进一步改进抗体的性能。通常,人源化抗体包含至少一个、通常两个基本上整个如下可变区,其中整个或基本上整个高变环对应于非人免疫球蛋白的高变环,且整个或基本上整个FR是人免疫球蛋白序列的FR。人源化抗体任选还包含至少部分免疫球蛋白恒定区(Fc),通常是人免疫球蛋白的恒定区。更多细节参见US6,407,213;Jones et al.(1986)Nature 321:522-525;Riechmann et al.(1988)Nature 332:323-329;Presta(1992)Curr.Op.Struct.Biol.2:593-596。
“游离半胱氨酸氨基酸”指已经改造到亲本抗体中,带有巯基官能基(-SH),并且未作为分子内或分子间二硫键配对的半胱氨酸氨基酸残基。
术语“巯基反应性值”为游离半胱氨酸氨基酸的反应性的定量表征。巯基反应性值为半胱氨酸改造的抗体中与巯基反应性试剂起反应的游离半胱氨酸氨基酸的百分比,并且换算成最大值1。例如,半胱氨酸改造的抗体上以100%产率与巯基反应性试剂诸如生物素-马来酰亚胺试剂起反应而形成生物素标记的抗体的游离半胱氨酸氨基酸具有1.0的巯基反应性值。改造到相同或不同亲本抗体中的以80%产率与巯基反应性试剂起反应的另一个半胱氨酸氨基酸具有0.8的巯基反应性值。改造到相同或不同亲本抗体中的完全无法与巯基反应性试剂起反应的另一个半胱氨酸氨基酸具有0的巯基反应性值。可以通过ELISA测定法、质谱法、液相层析法、放射自显影法或其它定量分析试验测定特定半胱氨酸的巯基反应性值。
"亲本抗体"为所含氨基酸序列中的一个或多个氨基酸残基将用一个或多个半胱氨酸残基替代的抗体。亲本抗体可以包含天然或野生型序列。亲本抗体可以具有相对于其它天然、野生型或修饰形式的抗体而言预先存在的氨基酸序列修饰(诸如添加、缺失和/或替代)。亲本抗体可以针对所关注的靶抗原,例如生物学上重要的多肽。还关注针对非多肽抗原(诸如肿瘤相关糖脂抗原;参见US 5,091,178)的抗体。
例示性亲本抗体包括对细胞表面和跨膜受体和肿瘤相关抗原(TAA)具有亲和力和选择性的抗体。
其它例示性亲本抗体包括但不限于选自下组的抗体:抗雌激素受体抗体、抗孕酮受体抗体、抗p53抗体、抗HER-2/neu抗体、抗EGFR抗体、抗组织蛋白酶D抗体、抗Bcl-2抗体、抗E-钙粘着蛋白抗体、抗CA125抗体、抗CA15-3抗体、抗CA19-9抗体、抗c-erbB-2抗体、抗P-糖蛋白抗体、抗CEA抗体、抗视网膜母细胞瘤蛋白质抗体、抗ras癌蛋白抗体、抗Lewis X抗体、抗Ki-67抗体、抗PCNA抗体、抗CD3抗体、抗CD4抗体、抗CD5抗体、抗CD7抗体、抗CD8抗体、抗CD9/p24抗体、抗CD10抗体、抗CD11c抗体、抗CD13抗体、抗CD14抗体、抗CD15抗体、抗CD19抗体、抗CD20抗体、抗CD22抗体、抗CD23抗体、抗CD30抗体、抗CD31抗体、抗CD33抗体、抗CD34抗体、抗CD35抗体、抗CD38抗体、抗CD41抗体、抗LCA/CD45抗体、抗CD45RO抗体、抗CD45RA抗体、抗CD39抗体、抗CD100抗体、抗CD95/Fas抗体、抗CD99抗体、抗CD106抗体、抗遍在蛋白抗体、抗CD71抗体、抗c-myc抗体、抗细胞角蛋白抗体、抗波形蛋白抗体、抗HPV蛋白抗体、抗κ轻链抗体、抗λ轻链抗体、抗黑素体抗体、抗前列腺特异抗原抗体、抗S-100抗体、抗τ抗原抗体、抗纤维蛋白抗体、抗角蛋白抗体和抗Tn抗原抗体。
“分离的”抗体指已经鉴定且与/由其天然环境的一种成分分开和/或回收的抗体。其天然环境的污染性成分指会干扰该抗体的诊断或治疗用途的物质,可包括酶、激素、和其它蛋白质性质或非蛋白质性质的溶质。在优选的实施方案中,将抗体纯化至(1)根据Lowry方法的测定,抗体重量超过95%,最优选重量超过99%,(2)足以通过使用转杯式测序仪获得至少15个残基的N-末端或内部氨基酸序列的程度,或(3)根据使用考马斯蓝或优选银染色的还原性或非还原性条件下的SDS-PAGE,达到同质。既然抗体天然环境的至少一种成分不会存在,那么分离的抗体包括重组细胞内的原位抗体。然而,分离的抗体通常通过至少一个纯化步骤来制备。
“结合”分子靶标或所关注抗原例如ErbB2抗原的抗体为能够以足够亲和力结合抗原,使得该抗体可用于靶向表达该抗原的细胞的抗体。如果抗体为结合ErbB2的抗体,那么它通常优先结合ErbB2胜过其它ErbB受体,并且可以为不会与其它蛋白质,诸如EGFR、ErbB3或ErbB4发生显著交叉反应的抗体。在这类实施方案中,抗体与这些非ErbB2蛋白质结合(例如对内源受体的细胞表面结合)的程度将低于10%,正如通过荧光激活细胞分选术(FACS)分析或放射性免疫沉淀(RIA)测定的。有时,抗ErbB2抗体不会与大鼠neu蛋白发生显著的交叉反应,例如如Schecter等(1984)Nature 312:513和Drebin等(1984)Nature 312:545-548中所述。
本发明所涵盖的抗体的分子靶标包括CD蛋白及其配体,诸如,但不限于:(i)CD3、CD4、CD8、CD19、CD20、CD22、CD34、CD40、CD79α(CD79a)和CD79β(CD79b);(ii)ErbB受体家族的成员,诸如EGF受体、HER2、HER3或HER4受体;(iii)细胞粘附分子,诸如LFA-1、Mac1、p150,95、VLA-4、ICAM-1、VCAM和αv/β3整联蛋白,包括其α或β亚基(例如抗CD11a、抗CD18或抗CD11b抗体);(iv)生长因子,诸如VEGF;IgE;血型抗原;flk2/flt3受体;肥胖(OB)受体;mpl受体;CTLA-4;蛋白C、BR3、c-met、组织因子、β7等;和(v)细胞表面和跨膜肿瘤相关抗原(TAA)。
除非另做陈述,术语“单克隆抗体4D5”指具有或衍生自鼠4D5抗体(ATCC CRL 10463)的抗原结合残基的抗体。例如,单克隆抗体4D5可以为鼠单克隆抗体4D5或其变体,诸如人源化4D5。例示性人源化4D5抗体包括如US 5,821,337中所述的huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7和huMAb4D5-8(曲妥单抗(trastuzumab),)。
术语“治疗”或“处理”指治疗性处理及预防性或防范性措施二者,其中目标是预防或减缓(减轻)不想要的生理学变化或紊乱,诸如癌症的形成或传播。为了本发明,有利或期望的临床结果包括但不限于:缓解症状、削弱疾病的程度、疾病状态稳定(即不恶化)、延迟或减缓疾病进展、改善或减轻疾病状态、及康复(无论是部分的还是完全的),无论是可检测的还是不可检测的。“治疗”或“处理”还可以指与不接受治疗的预期存活相比延长存活。需要治疗的受试者包括早就患有状况或紊乱的受试者以及倾向于患上状况或紊乱的受试者或者要预防状况或紊乱的受试者。
术语“治疗有效量”指在哺乳动物中有效治疗疾病或紊乱的药物量。在癌症的情况中,药物的治疗有效量可减少癌细胞的数目;缩小肿瘤的尺寸;抑制(即在一定程度上减缓和优选阻止)癌细胞浸润到周围器官中;抑制(即在一定程度上减缓和优选阻止)肿瘤转移;在一定程度上抑制肿瘤生长;和/或在一定程度上减轻一种或多种与癌症有关的症状。在药物可阻止生长和/或杀死现有癌细胞的程度上,它可以是抑制细胞的和/或细胞毒性的。对于癌症疗法,可通过例如评估疾病进展时间(TTP)和/或测定响应速率(RR)来测量功效。
术语"生物利用度"指对患者施用的指定量药物的系统利用度(即血液/血浆水平)。生物利用度为表示药物从施用的剂量形式达到全身循环的时间(速率)和总量(程度)的测量的常数项(absolute term)。
术语“癌症”和“癌性”指或描述哺乳动物中特征通常为细胞生长不受调节的生理状况。“肿瘤”包含一个或多个癌性细胞。癌症的例子包括但不限于癌、淋巴瘤、母细胞瘤、肉瘤、及白血病或淋巴样恶性肿瘤。此类癌症的更具体例子包括鳞状细胞癌(例如上皮鳞状细胞癌)、肺癌包括小细胞肺癌、非小细胞肺癌(“NSCLC”)、肺的腺癌和肺的鳞状癌、腹膜癌、肝细胞癌、胃癌包括胃肠癌、胰腺癌、成胶质细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝瘤(hepatoma)、乳癌、结肠癌、直肠癌、结肠直肠癌、子宫内膜或子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、肝癌、肛门癌、阴茎癌、以及头和颈癌。
“表达ErbB的癌”指包含在其细胞表面上存在ErbB蛋白质的细胞的癌。“表达ErbB2的癌”指在其细胞表面上生成足够水平的ErbB2,使得抗ErbB2抗体可与其结合并对癌产生治疗效果的癌。
“过表达”抗原性受体的癌指与同一组织类型的非癌性细胞相比,在其细胞表面上具有显著更高水平的受体诸如ErbB2的癌。此类过表达可以是由基因扩增或者是由转录或翻译提高引起的。可在诊断或预后测定法中通过评估细胞表面上存在的受体蛋白质水平的升高(例如通过免疫组织化学测定法;IHC)来确定受体过表达。或者/另外,可测量细胞中受体编码核酸的水平,例如通过荧光原位杂交(FISH;参见WO 98/45479)、Southern印迹、或聚合酶链式反应(PCR)技术,诸如实时定量PCR(RT-PCR)。
过表达ErbB2(HER2)的肿瘤可根据对应于每个细胞表达的HER2分子拷贝数的免疫组化得分进行定级,并且可通过生化方法测定:0=0-10,000个拷贝/细胞,1+=至少约200,000个拷贝/细胞,2+=至少约500,000个拷贝/细胞,3+=约1-2x106个拷贝/细胞。导致酪氨酸激酶的配体依赖性活化的3+水平的HER2过表达(Hudziak et al.(1987)Proc.Natl.Acad.Sci.USA 84:7159-7163)发生于约30%的乳癌中,而且在这些患者中,无复发存活和总体存活减少(Slamon et al.(1989)Science 244:707-712;Slamon et al.(1987)Science 235:177-182)。
术语“细胞毒剂”在用于本文时指抑制或防止细胞的功能和/或引起细胞破坏的物质。该术语意图包括:放射性同位素,例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、C60和Lu的放射性同位素;化疗剂;和毒素,诸如小分子毒素或者细菌、真菌、植物或动物起源的酶活毒素,包括其合成类似物和衍生物。
“自身免疫病”在本文中指源于且针对个体自身组织或器官的疾病或紊乱或其共分离(co-segregate)或表现或由其导致的状况。在这些自身免疫病和炎症紊乱的许多中,可以存在许多临床和实验室标志,包括但不限于:高丙种球蛋白血症、高水平自身抗体、组织中抗原-抗体复合物沉积、得益于皮质类固醇或免疫抑制治疗、及受侵害组织中的淋巴样细胞集合体。不限于任意一种有关B细胞介导的自身免疫病的理论,认为B细胞通过众多机械途径在人自身免疫病中表现出致病作用,包括自身抗体产生、免疫复合物形成、树突细胞和T细胞活化、细胞因子合成、直接趋化因子释放和提供用于异位新淋巴生成的巢。这些途径中的每一种可以以不同程度参与自身免疫病的病理学。自身免疫病可以为器官特异性疾病(即免疫应答特异性针对一种器官系统,诸如内分泌系统、造血系统、皮肤、心肺系统、胃肠和肝系统、肾系统、甲状腺、耳、神经肌肉系统、中枢神经系统等)或可以影响多器官系统的系统性疾病(例如系统性红斑狼疮(SLE)、类风湿性关节炎、多肌炎等)。
术语“细胞抑制性”指限制细胞功能,诸如限制细胞生长或细胞增殖的效果。
"化疗剂"为可用于治疗癌症的化学化合物。化疗剂的实例包括:Erlotinib(Genentech/OSI Pharm.)、Bortezomib(MilleniumPharm.)、氟维司群(Fulvestrant)(Astrazeneca)、Sutent(SU11248,Pfizer)、来曲唑(Letrozole)(Novartis)、甲磺酸伊马替尼(Imatinibmesylate)(Novartis)、PTK787/ZK 222584(Novartis)、奥沙利铂(Oxaliplatin)(Sanofi)、5-FU(5-氟尿嘧啶(5-fluorouracil))、亚叶酸(Leucovorin)、雷帕霉素(Rapamycin)(Sirolimus,Wyeth)、Lapatinib(GSK572016,GlaxoSmithKline)、Lonafarnib(SCH 66336)、Sorafenib(BAY43-9006,Bayer Labs.)和Gefitinib(Astrazeneca)、AG1478、AG1571(SU 5271;Sugen);烷化剂类(alkylating agents),诸如塞替派(thiotepa)和环磷酰胺(cyclophosphamide);磺酸烷基酯类(alkylsulfonates),诸如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶类(aziridines),诸如苯佐替派(benzodepa)、卡波醌(carboquone)、美妥替派(meturedepa)和乌瑞替派(uredepa);乙撑亚胺类(ethylenimines)和甲基蜜胺类(methylamelamines),包括六甲蜜胺(altretamine)、三乙撑蜜胺(triethylenemelamine)、三乙撑磷酰胺(triethylenephosphoramide)、三乙撑硫代磷酰胺(triethylenethiophosphoramide)和三羟甲蜜胺(trimethylolomelamine);番荔枝内酯类(acetogenin)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱(camptothecin)(包括合成类似物托泊替康(topotecan));苔藓抑素(bryostatin);callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);隐藻素类(cryptophycins)(特别是隐藻素1和隐藻素8);多拉司他汀(dolastatin);duocarmycin(包括合成类似物,KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);pancratistatin;sarcodictyin;海绵抑素(spongistatin);氮芥类(nitrogen mustards),诸如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、胆磷酰胺(cholophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、双氯乙基甲胺(mechlorethamine)、盐酸氧氮芥(mechlorethamine oxide hydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亚硝脲类(nitrosoureas),诸如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimustine);抗生素类,诸如烯二炔类抗生素(enediyne)(如加利车霉素(calicheamicin),尤其是加利车霉素γ1I和加利车霉素ωI1(Angew(1994)Chem.Intl.Ed.Engl.33:183-186);蒽环类抗生素(dynemicin),包括dynemicin A;二膦酸盐类(bisphosphonates),诸如氯膦酸盐(clodronate);埃斯波霉素(esperamicin);以及新制癌素(neocarzinostatin)发色团和相关色蛋白烯二炔类抗生素发色团)、阿克拉霉素(aclacinomycin)、放线菌素(actinomycin)、氨茴霉素(anthramycin)、偶氮丝氨酸(azaserine)、博来霉素(bleomycin)、放线菌素C(cactinomycin)、carabicin、洋红霉素(carminomycin)、嗜癌霉素(carzinophilin)、色霉素(chromomycin)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-二氮-5-氧-L-正亮氨酸、多柔比星(doxorubicin)(包括吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯代多柔比星和脱氧多柔比星)、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素类(mitomycins)诸如丝裂霉素C、霉酚酸(mycophenolic acid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、potfiromycin、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物类,诸如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸(denopterin)、甲氨蝶呤、蝶酰三谷氨酸(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine)、6-巯基嘌呤(mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物,诸如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素类,诸如卡鲁睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、表硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺类,诸如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸(folinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);bestrabucil;比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defosfamide);地美可辛(demecolcine);地吖醌(diaziquone);elfornithine;依利醋铵(elliptinium acetate);epothilone;依托格鲁(etoglucid);硝酸镓;羟脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidamine);美登木素生物碱类(maytansinoids),诸如美登素(maytansine)和美登醇(maytansinol);安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidamol);二胺硝吖啶(nitracrine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基酰肼(ethylhydrazide);丙卡巴肼(procarbazine);多糖复合物(JHS Natural Products,Eugene,OR);雷佐生(razoxane);根霉素(rhizoxin);西索菲兰(sizofiran);螺旋锗(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2′,2″-三氯三乙胺;单端孢菌素类(trichothecenes)(尤其是T-2毒素、疣孢菌素(verrucarin)A、杆孢菌素(roridin)A和蛇行菌素(anguidin));乌拉坦(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside)(“Ara-C”);环磷酰胺(cyclophosphamide);塞替派(thiotepa);类紫杉醇(taxoids),例如紫杉醇(paclitaxel)(Bristol-Myers Squibb Oncology,Princeton,N.J.)、ABRAXANETM不含克列莫佛(Cremophor)、清蛋白改造的纳米颗粒剂型紫杉醇(American Pharmaceutical Partners,Schaumberg,Illinois)和多西他塞(doxetaxel)(Rorer,Antony,France);苯丁酸氮芥(chlorambucil);吉西他滨(gemcitabine);6-硫鸟嘌呤(thioguanine);巯基嘌呤(mercaptopurine);甲氨蝶呤(methotrexate);铂类似物,诸如顺铂(cisplatin)和卡铂(carboplatin);长春碱(vinblastine);铂;依托泊苷(etoposide)(VP-16);异环磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);长春新碱(vincristine);长春瑞滨(vinorelbine);能灭瘤(novantrone);替尼泊苷(teniposide);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基蝶呤(aminopterin);希罗达(xeloda);伊本膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(DMFO);类维A酸(retinoids),诸如维A酸(retinoicacid);卡培他滨(capecitabine);任何上述物质的药学可接受盐、酸或衍生物。
“化疗剂”的该定义还包括:(i)起调节或抑制激素对肿瘤的作用的抗激素药,诸如抗雌激素药和选择性雌激素受体调节剂(SERM),包括例如他莫昔芬(tamoxifen)(包括他莫昔芬)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、4-羟基他莫昔芬、曲沃昔芬(trioxifene)、那洛昔芬(keoxifene)、LY117018、奥那司酮(onapristone)和托瑞米芬(toremifene);(ii)抑制在肾上腺中调节雌激素生成的芳香酶的芳香酶抑制剂,诸如例如4(5)-咪唑、氨鲁米特(aminoglutethimide)、醋酸甲地孕酮(megestrol acetate)、依西美坦(exemestane)、福美坦(formestane)、法倔唑(fadrozole)、伏罗唑(vorozole)、来曲唑(letrozole)和阿那曲唑(anastrozole);(iii)抗雄激素类,诸如氟他米特(flutamide)、尼鲁米特(nilutamide)、比卡米特(bicalutamide)、亮丙瑞林(leuprolide)和戈舍瑞林(goserelin);以及曲沙他滨(troxacitabine)(1,3-二氧戊环核苷胞嘧啶类似物);(iv)芳香酶抑制剂;(v)蛋白激酶抑制剂;(vi)脂质激酶抑制剂;(vii)反义寡核苷酸,特别是抑制牵涉粘着细胞增殖的信号途经中的基因表达的反义寡核苷酸,诸如例如PKC-α、Raf和H-Ras;(viii)核酶,诸如VEGF表达抑制剂(例如核酶)和HER2表达抑制剂;(ix)疫苗,诸如基因疗法疫苗,例如疫苗、疫苗和疫苗;rIL-2;拓扑异构酶1抑制剂;rmRH;(x)抗血管发生剂,诸如贝伐单抗(bevacizumab)(Genentech);及(xi)任何上述物质的药学可接受盐、酸或衍生物。
在用于本文时,术语“EGFR靶向药物”指结合EGFR并任选抑制EGFR活化的治疗剂。此类药剂的例子包括结合EGFR的抗体和小分子。结合EGFR的抗体的例子包括MAb 579(ATCC CRL HB 8506)、MAb 455(ATCC CRLHB 8507)、MAb 225(ATCC CRL 8508)、MAb 528(ATCC CRL 8509)(参见Mendelsohn等人的US 4,943,533)及其变体,诸如嵌合化225(C225或Cetuximab;)和重构人225(H225)(参见Imclone SystemsInc.的WO 96/40210);结合II型突变体EGFR的抗体(美国专利5,212,290);结合EGFR的人源化和嵌合抗体,如US 5,891,996中所述;及结合EGFR的人抗体,诸如ABX-EGF(参见Abgenix的WO 98/50433)。抗EGFR抗体可与细胞毒剂偶联,由此产生免疫偶联物(参见例如EP 659,439A2,MerckPatent GmbH)。结合EGFR的小分子的实例包括ZD1839或Gefitinib(IRESSATM;Astra Zeneca)、Erlotinib HCl(CP-358774,TARCEVATM;Genentech/OSI)和AG1478、AG1571(SU 5271;Sugen)。
蛋白激酶抑制剂包括在一定程度上抑制酪氨酸激酶诸如ErbB受体的酪氨酸激酶活性的酪氨酸激酶抑制剂。此类抑制剂的例子包括上一段中提到的EGFR靶向药物以及喹唑啉类,诸如PD 153035,4-(3-氯苯胺基)喹唑啉;吡啶并嘧啶类;嘧啶并嘧啶类;吡咯并嘧啶类,诸如CGP 59326、CGP 60261和CGP 62706;吡唑并嘧啶类,4-(苯氨基)-7H-吡咯[2,3-d]嘧啶;姜黄素(二阿魏酰甲烷,4,5-双(4-氟苯胺基)-酞亚胺);含硝基噻吩模块的tyrphostines(酪氨酸磷酸化抑制剂);PD-0183805(Warner-Lambert);反义分子(例如那些结合ErbB编码核酸的反义分子);喹喔啉类(US 5,804,396);tryphostins(US 5,804,396);ZD6474(Astra Zeneca);PTK-787(Novartis/Schering AG);泛ErbB抑制剂,诸如CI-1033(Pfizer);Affinitac(ISIS 3521;Isis/Lilly);甲磺酸伊马替尼(Imatinib mesylate)(Gleevec;Novartis);PKI 166(Novartis);GW2016(Glaxo SmithKline);CI-1033(Pfizer);EKB-569(Wyeth);Semaxinib(Sugen);ZD6474(AstraZeneca);PTK-787(Novartis/Schering AG);INC-1C11(Imclone);或任何如下专利出版物中所记载的:WO 99/09016(American Cyanimid);WO 98/43960(American Cyanamid);WO 97/38983(Warner Lambert);WO 99/06378(Warner Lambert);WO 99/06396(WarnerLambert);WO 96/30347(Pfizer,Inc.);WO 96/33978(Zeneca);WO 96/33979(Zeneca);WO 96/33980(Zeneca)。
“抗血管发生剂”指阻断或在某种程度上干扰血管发育的化合物。抗血管发生因子可以是例如结合涉及促进血管发生的生长因子或生长因子受体的小分子或抗体。在本文中优选的抗血管发生因子是结合血管内皮生长因子(VEGF)的抗体。
术语“细胞因子”是由一种细胞群释放的、作为细胞间介质作用于另一细胞的蛋白质的通称。此类细胞因子的例子有淋巴因子、单核因子和传统的多肽激素。细胞因子中包括生长激素,诸如人生长激素、N-甲硫氨酰人生长激素和牛生长激素;甲状旁腺素;甲状腺素;胰岛素;胰岛素原;松驰素;松驰素原;糖蛋白激素类,诸如促卵泡激素(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;促乳素;胎盘催乳激素;肿瘤坏死因子-α和-β;穆勒氏(Mullerian)抑制性物质;小鼠促性腺激素相关肽;抑制素;激活素;血管内皮生长因子;整联蛋白;血小板生成素(TPO);神经生长因子,诸如NGF-β;血小板衍生生长因子;转化生长因子(TGF),诸如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,诸如干扰素-α、-β和-γ;集落刺激因子(CSF),诸如巨噬细胞CSF(M-CSF)、粒细胞-巨噬细胞CSF(GM-CSF)和粒细胞CSF(G-CSF);白介素(IL),诸如IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12;肿瘤坏死因子,诸如TNF-α或TNF-β;及其它多肽因子,包括LIF和kit配体(KL)。在用于本文时,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及天然序列细胞因子的生物学活性等效物。
术语“前体药物”在用于本申请时指与母药(parent drug)相比对肿瘤细胞的细胞毒性较小并能够酶促或水解活化或转变为更具活性母药形式的药用活性物质的前体和衍生物形式。参见例如Wilman,“Prodrugs in CancerChemotherapy”,Biochemical Society Transactions,14,pp.375-382,615thMeeting Belfast(1986)和Stella et al.,“Prodrugs:A Chemical Approach toTargeted Drug Delivery”,Directed Drug Delivery,Borchardt et al.,(ed.),pp.247-267,Humana Press(1985)。本发明的前体药物包括但不限于含磷酸盐/酯前体药物、含硫代磷酸盐/酯前体药物、含硫酸盐/酯前体药物、含肽前体药物、D-氨基酸修饰前体药物、糖基化前体药物、含β-内酰胺前体药物、含任选取代苯氧基乙酰胺的前体药物或含任选取代苯乙酰胺的前体药物、可转化为更具活性而无细胞毒性的药物的5-氟胞嘧啶和其它5-氟尿苷前体药物。可衍生为本发明使用的前体药物形式的细胞毒性药物的例子包括但不限于上文描述的那些化疗剂。
“脂质体”指由各种类型脂质、磷脂和/或表面活性剂构成的,可用于对哺乳动物投递药物(诸如本文中所披露的抗ErbB2抗体和任选的化疗剂)的小囊泡。与生物膜的脂质排列相似,脂质体的成分通常排列成双层形式。
术语“包装插页”用于指通常包括在治疗用产品的商品包装中的说明书,它们包含有关涉及此类治疗用产品应用的适应征、用法、剂量、施用、禁忌症和/或警告的信息。
“噬菌体展示”是将变异多肽作为与外壳蛋白的融合蛋白展示在噬菌体例如丝状噬菌体颗粒的表面上的技术。噬菌体展示的一种效用在于可对随机化蛋白质变体的大型文库快速且有效的分选那些以高亲和力结合靶分子的序列的事实。在噬菌体上展示肽和蛋白质文库已经用于对数以百万计的多肽筛选具有特定结合特性的多肽。多价噬菌体展示方法已经用于展示肽和小蛋白质的小型文库,通常通过与丝状噬菌体的pIII或pVIII融合(Wells andLowman,(1992)Curr.Opin.Struct.Biol.3:355-362及其引用的参考文献)。在单价噬菌体展示中,将蛋白质或肽文库与噬菌体外壳蛋白或其部分融合,且在存在野生型蛋白质时以低水平表达。亲合力效果与多价噬菌体相比降低,使得分选基于内在配体亲和力,并使用简化DNA操作的噬菌粒载体。Lowman and Wells,(1991)Methods:A companion to Methods in Enzymology 3:205-0216。噬菌体展示包括用于生成抗体样分子的技术(Janeway,C.,Travers,P.,Walport,M.,Shlomchik,(2001)Immunobiology,5th Ed.,Garland Publishing,New York,p627-628;Lee et al.)。
“噬菌粒”是具有细菌复制起点例如Co1E1和一个拷贝的噬菌体基因区间的噬菌体载体。噬菌粒可用于任何已知噬菌体,包括丝状噬菌体和λ形噬菌体。质粒通常还将包含抗生素抗性的选择标志。克隆到这些载体中的DNA区段可以像质粒一样增殖。当包含这些载体的细胞中配有生成噬菌体颗粒所必需的所有基因时,质粒的复制方式改变成滚环复制以生成质粒DNA的一条链的拷贝并包装噬菌体颗粒。噬菌粒可形成感染性或非感染性噬菌体颗粒。该术语包括包含噬菌体外壳蛋白基因或其片段且其与异源多肽基因连接成基因融合物,使得异源多肽展示在噬菌体颗粒表面上的噬菌粒。
“接头”、“接头单元”或“连接物”指包含使抗体与药物模块共价连接的共价键或原子链的化学模块。在各个实施方案中,将接头指定为L。接头包括:二价基,诸如亚烃基(alkyldiyl)、亚芳基、亚杂芳基,诸如-(CR2)nO(CR2)n-、烃氧基重复单元(例如聚亚乙基氧基(polyethylenoxy)、PEG、聚亚甲基氧基(polymethyleneoxy))和烃氨基(例如聚乙烯氨基,JeffamineTM)等模块;及二酸酯和酰胺类,包括琥珀酸酯、琥珀酰胺、二乙醇酸酯、丙二酸酯和己酰胺。
术语“标记物”指可以共价附着于抗体并发挥如下功能的任何模块:(i)提供可检测信号;(ii)与第二标记物相互作用以改变由第一或第二标记物提供的可检测信号,例如FRET(荧光共振能量转移);(iii)稳定与抗原或配体的相互作用或提供与之结合的亲和力;(iv)通过电荷、疏水性、形状或其它物理参数影响迁移率例如电泳迁移率或细胞通透性;或(v)提供俘获模块,以调节配体亲和力、抗体/抗原结合、或离子络合。
本文中使用的立体化学的定义和规则一般遵循S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill BookCompany,New York;Eliel,E.and Wilen,S.,Stereochemistry of OrganicCompunds(1994)John Wiley&Sons,Inc.,New York。许多有机化合物以旋光形式存在,即它们有能力旋转平面偏振光的平面。在描述旋光化合物时,前缀D和L或R和S用于表示分子关于其手性中心的绝对构型。前缀d和l或(+)和(-)用于表示化合物对平面偏振光的旋转的标记,其中(-)或1指化合物是左旋的。以(+)或d为前缀的化合物是右旋的。对于指定的化学结构,这些立体异构体是相同的,只是它们互为镜像。特定的立体异构体还可称作对映体,此类异构体的混合物通常称作对映混合物。对映体的50:50混合物称作外消旋混合物或外消旋物,它们可以在没有立体选择性或立体特异性的化学反应或方法中存在。术语“外消旋混合物”和“外消旋物”指两种对映体等摩尔混合从而丧失旋光性的混合物。
短语“药学可接受盐”在用于本文时指ADC的药学可接受的有机或无机盐。例示性的盐包括但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、丹宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和扑酸盐(即1,1’-亚甲基-双-(2-羟基-3-萘甲酸盐))。药学可接受盐可能牵涉包含另一种分子,诸如乙酸盐离子、琥珀酸盐离子或其它抗衡离子。抗衡离子可以是稳定母体化合物电荷的任何有机或无机模块。另外,药学可接受盐可以在其结构中具有超过一种带电荷原子。在多种带电荷原子作为药学可接受盐的组成部分的情况中可以具有多种抗衡离子。因此,药学可接受盐可具有一种或多种带电荷原子和/或一种或多种抗衡离子。
“药学可接受溶剂化物”指一个或多个溶剂分子和ADC的结合。形成药学可接受溶剂化物的溶剂的例子包括但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。
本文中使用了下列缩写,它们具有如下定义:BME为β-巯基乙醇,Boc为N-(叔丁氧羰基),cit为瓜氨酸(2-氨基-5-脲基戊酸),dap为dolaproine,DCC为1,3-二环己基碳二亚胺,DCM为二氯甲烷,DEA为二乙胺,DEAD为偶氮二羧酸二乙酯,DEPC为氰基膦酸二乙酯(diethylphosphorylcyanidate),DIAD为偶氮二羧酸二异丙酯,DIEA为N,N-二异丙基乙胺,dil为dolaisoleucine,DMA为二甲基乙酰胺,DMAP为4-二甲氨基吡啶,DME为乙二醇二甲醚(或1,2-二甲氧基乙烷),DMF为N,N-二甲基甲酰胺,DMSO为二甲亚砜,doe为dolaphenine,dov为N,N-二甲基缬氨酸,DTNB为5,5’-二硫代双(2-硝基苯甲酸),DTPA为二乙烯三胺五乙酸,DTT为二硫苏糖醇,EDCI为盐酸1-(3-二甲氨基丙基)-3-乙基碳二亚胺,EEDQ为2-乙氧基-1-乙氧羰基-1,2-二氢喹啉,ES-MS为电喷射质谱法,EtOAc为乙酸乙酯,Fmoc为N-(9-芴基甲氧羰基),gly为甘氨酸,HATU为O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate),HOBt为1-羟基苯并三唑,HPLC为高压液相层析法,ile为异亮氨酸,lys为赖氨酸,MeCN(CH3CN)为乙腈,MeOH为甲醇,Mtr为4-茴香基二苯甲基(或4-甲氧基三苯甲基),nor为(1S,2R)-(+)-去甲麻黄碱,PAB为对氨基苄基氨基甲酰基,PBS为磷酸盐缓冲盐水(pH 7),PEG为聚乙二醇,Ph为苯基,Pnp为对硝基苯基,MC为6-马来酰亚氨基己酰基,phe为L-苯丙氨酸,PyBrop为溴三吡咯烷膦六氟磷酸盐(bromo tris-pyrrolidino phosphonium hexafluorophosphate),SEC为大小排阻层析法,Su为琥珀酰亚胺,TFA为三氟乙酸,TLC为薄层层析法,UV为紫外线,而val为缬氨酸。
半胱氨酸改造的抗体
本发明的化合物包括半胱氨酸改造的抗体,其中野生型或亲代抗体中的一种或多种氨基酸被半胱氨酸氨基酸替代。由此可以改造任意形式的抗体,即使其突变。例如,可以将亲代Fab抗体片段改造成半胱氨酸改造的Fab,在本文中称作“ThioFab”。类似地,可以将亲代单克隆抗体改造成“ThioMab”。应注意单一位点突变在ThioFab中产生单一改造的半胱氨酸残基(singleengineered cysteine residue),而单一位点突变在ThioMab中产生两个改造的半胱氨酸残基,这是因IgG抗体的二聚化特性所致。评价被半胱氨酸(Cys)残基替代的(“改造的”)突变体的新引入的改造的半胱氨酸巯基反应性。巯基反应值为0-1.0范围内的相对数值范围并且可以测定任意半胱氨酸改造的抗体的该值。本发明半胱氨酸改造的抗体的巯基反应值在0.6-1.0;0.7-1.0;或0.8-1.0的范围。
本发明的设计、选择和制备方法能够使半胱氨酸改造的抗体能够与亲电子官能基(functionability)反应。这些方法进一步能够使抗体偶联物化合物,诸如抗体-药物偶联物(ADC)化合物与药物分子在指定、设计、选择的位点上反应。抗体表面上的反应性半胱氨酸残基能够通过巯基反应基,诸如马来酰亚胺或卤代乙酰基特异性地偶联药物部分。Cys残基的巯基官能基与马来酰亚胺基的亲核反应性约高于蛋白质中任意其它氨基酸官能基,诸如赖氨酸残基的氨基或N-末端氨基约1000倍。碘乙酰试剂和马来酰亚胺试剂中的巯基特异性官能基可以与胺基反应,但需要更高的pH(>9.0)和更长的反应时间(Garman,1997,Non-Radioactive Labelling:A Practical Approach,AcademicPress,London)。
本发明半胱氨酸改造的抗体优选保持其野生型亲代抗体对应物的抗原结合能力。因此,半胱氨酸改造的抗体能够结合,优选特异性结合抗原。这类抗原包括:例如肿瘤-相关抗原(TAA)、细胞表面受体蛋白和其它细胞表面分子、跨膜蛋白、信号传导蛋白、细胞存活调节因子、细胞增殖调节因子、与组织发育或分化相关(例如,已知或怀疑在功能上相关)的分子、淋巴因子、细胞因子、涉及细胞周期调节的分子、涉及血管发生的分子和与血管发生相关(例如,已知或怀疑在功能上相关)的分子。肿瘤-相关抗原可以为分化簇因子(即CD蛋白)。能够结合半胱氨酸改造的抗体的抗原可以为上述类型之一的亚组中的成员,其中所述类型中另一亚组包含具有不同特性的其它分子/抗原(就所关注的抗原而言)。
亲代抗体还可以为选自如上所述的US 5821337的表3中所述的huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7和huMAb4D5-8(曲妥单抗,)的人源化抗体,特别将该文献引入本文作为参考;人源化520C9(WO 93/21319)和如本文所述的人源化2C4抗体。
本发明的半胱氨酸改造的抗体可以位点-特异性和有效地与巯基-反应试剂偶联。巯基-反应试剂可以为多官能连接基试剂(multifunctional linkerreagent);俘获物,即亲和、标记试剂(例如生物素-连接基试剂);检测试剂(例如荧光团试剂);固相固定化试剂(例如SEPHAROSETM、聚苯乙烯或玻璃)或药物-连接基中间体(drug-linker intermediate)。巯基-反应试剂的一个实例为N-乙基马来酰亚胺(NEM)。在一个典型的实施方案中,ThioFab与生物素-连接基试剂反应得到生物素化的ThioFab,通过这种方式可以检测和测定改造的半胱氨酸残基的存在和反应性。ThioFab与多官能连接基试剂反应得到带有可以与药物部分试剂或其它标记进一步反应的官能化连接基的ThioFab。ThioFab与药物-连接基中间体反应得到ThioFab药物偶联物。
本文所述的典型方法一般可以应用于鉴定和生产抗体,并且更一般地通过使用本文所述的设计和筛选步骤用于其它蛋白质。
这类手段可以应用于偶联其它巯基反应试剂,其中反应基为例如马来酰亚胺、碘乙酰胺、吡啶基二硫化物或其它巯基反应偶联配偶体(Haugland,2003,Molecular Probes Handbook of Fluorescent Probes and Research Chemicals,Molecular Probes,Inc.;Brinkley,1992,Bioconjugate Chem.3:2;Garman,1997,Non-Radioactive Labelling:A Practical Approach,Academic Press,London;Means(1990)Bioconjugate Chem.1:2;Hermanson,G.inBioconjugate Techniques(1996)Academic Press,San Diego,pp.40-55,643-671)。所述的配偶体可以为细胞毒性剂(例如毒素,诸如多柔比星(doxorubicin)或百日咳毒素);荧光团,诸如荧光染料类荧光素或若丹明;用于成像的螯合剂或放射性治疗金属;肽基或非-肽基标记或检测标记;或清除-改进剂(clearance-modifying agent),诸如聚乙二醇的不同异构体;结合第三种成分的肽或另一种碳水化合物或亲脂性试剂。
在本文典型抗体片段hu4D5Fabv8上鉴定的位点主要位于抗体的恒定域中,其在所有抗体种类之间为充分保守的。这些位点可广泛适用于其它抗体,而无需进一步进行结构设计或有关特异性抗体结构的知识,并且不会干扰对抗体可变域而言固有的抗原结合特性。
可以用于治疗癌症的半胱氨酸改造的抗体包括,但不限于针对细胞表面受体和肿瘤-相关抗原(TAA)的抗体。这类抗体可以用作裸抗体(未与药物或标记部分偶联)或用作式I抗体-药物偶联物(ADC)。肿瘤-相关抗原为本领域中公知的并且可以制备它们以便用于使用本领域众所周知的方法和信息生产抗体。在发现用于癌症诊断和疗法的有效细胞靶标的尝试中,研究人员寻求鉴定与一种或多种正常非癌细胞相比在一种或多种特定类型的癌细胞表面上特异性表达的跨膜多肽,或肿瘤相关多肽。与非癌细胞相比,通常这类肿瘤-相关多肽更大量地在癌细胞表面上表达。对这类肿瘤-相关细胞表面抗原多肽的鉴定已经使人们能够特异性靶向癌细胞,通过基于抗体的疗法对其进行破坏。
TAA的实例包括,但不限于下述TAA(1)-(36)。为方便起见,均为本领域公知的有关这些抗原的信息如下所列,并且按照National Center forBiotechnology Information(NCBI)的核酸和蛋白质序列鉴定规定,包括名称,可选择的名称,Genbank登记号和主要参考文献。相当于TAA(1)-(36)的核酸和蛋白质序列可以在公共数据库,诸如GenBank中获得。由抗体靶向的肿瘤-相关抗原包括所有氨基酸序列变体和同种型,它们与引述的参考文献中鉴定的序列相比具有至少约70%,80%,85%,90%或95%序列同一性,或表现出基本上与具有引述参考文献中发现的序列的TAA相同的生物特性或特征。例如,具有变体序列的TAA一般能够特异性结合文献中所示相应序列TAA特异性结合的抗体。特别将本文特别引述的参考文献中的序列和披露内容引入作为参考。
肿瘤相关抗原S(1)-(36):
(1)BMPR1B(骨形态发生蛋白受体-IB型(bone morphogeneticreceptor-type IB),Genbank登记号NM_001203)
ten Dijke,P.,等Science 264(5155):101-104(1994),Oncogene14(11):1377-1382(1997));WO2004063362(权利要求2);WO2003042661(权利要求12);US2003134790-A1(38-39页);WO2002102235(权利要求13;页296);WO2003055443(91-92页);WO200299122(实施例2;528-530页);WO2003029421(权利要求6);WO2003024392(权利要求2;附图112);WO200298358(权利要求1;183页);WO200254940(100-101页);WO200259377(349-350页);WO200230268(权利要求27;376页);WO200148204(实施例;附图4)
NP_001194骨形态发生蛋白受体,IB型/pid=NP_001194.1-
交叉参考:MIM:603248;NP_001194.1;AY065994
(2)E16(LAT1,SLC7A5,Genbank登记号NM_003486)
Biochem.Biophys.Res.Commun.255(2),283-288(1999),Nature395(6699):288-291(1998),Gaugitsch,H.W.,等(1992)J.Biol.Chem.267(16):11267-11273);WO2004048938(实施例2);WO2004032842(实施例IV);WO2003042661(权利要求12);WO2003016475(权利要求1);WO200278524(实施例2);WO200299074(权利要求19;页127-129);WO200286443(权利要求27;222,393页);WO2003003906(权利要求10;293页);WO200264798(权利要求33;页93-95);WO200014228(权利要求5;133-136页);US2003224454(附图3);WO2003025138(权利要求12;150页);
NP_003477溶质载体家族7(solute carrier family 7)(阳离子氨基酸转运蛋白(cationic amino acid transporter),y+系统),成员5/pid=NP_003477.3–人类
交叉参考:MIM:600182;NP_003477.3;NM_015923;NM_003486_1
(3)STEAP1(前列腺的六跨膜上皮细胞抗原(six transmembrane epithelialantigen of prostate),Genbank登记号NM_012449)
Cancer Res.61(15),5857-5860(2001),Hubert,R.S.,等(1999)Proc.Natl.Acad.Sci.U.S.A.96(25):14523-14528);WO2004065577(权利要求6);WO2004027049(附图1L);EP1394274(实施例11);WO2004016225(权利要求2);WO2003042661(权利要求12);US2003157089(实施例5);US2003185830(实施例5);US2003064397(附图2);WO200289747(实施例5;页618-619);WO2003022995(实施例9;附图13A,实施例53;173页,实施例2;附图2A);
NP_036581前列腺的六跨膜上皮抗原
交叉参考:MIM:604415;NP_036581.1;NM_012449_1
(4)0772P(CA125,MUC16,Genbank登记号AF361486)
J.Biol.Chem.276(29):27371-27375(2001));WO2004045553(权利要求14);WO200292836(权利要求6;附图12);WO200283866(权利要求15;116-121页);US2003124140(实施例16);交叉参考P:GI:34501467;AAK74120.3;AF361486_1
(5)MPF(MPF,MSLN,SMR,巨核细胞强化因子(megakaryocytepotentiating factor),mesothelin,Genbank登记号NM_005823)Yamaguchi,N.,等Biol.Chem.269(2),805-808(1994),Proc.Natl.Acad.Sci.U.S.A.96(20):11531-11536(1999),Proc.Natl.Acad.Sci.U.S.A.93(1):136-140(1996),J.Biol.Chem.270(37):21984-21990(1995));WO2003101283(权利要求14);(WO2002102235(权利要求13;287-288页);WO2002101075(权利要求4;页308-309);WO200271928(320-321页);WO9410312(52-57页);交叉参考:MIM:601051;NP_005814.2;NM_005823_1
(6)Napi3b(NAPI-3B,NPTIIb,SLC34A2,溶质载体家族(solute carrierfamily)34(磷酸钠),成员2,II型钠依赖性磷酸转运蛋白3b,Genbank登记号NM_006424)J.Biol.Chem.277(22):19665-19672(2002),Genomics62(2):281-284(1999),Feild,J.A.,等(1999)Biochem.Biophys.Res.Commun.258(3):578-582);WO2004022778(权利要求2);EP1394274(实施例11);WO2002102235(权利要求13;326页);EP875569(权利要求1;17-19页);WO200157188(权利要求20;329页);WO2004032842(实施例IV);WO200175177(权利要求24;139-140页);
交叉参考:MIM:604217;NP_006415.1;NM_006424_1
(7)Sema 5b(FLJ10372,KIAA1445,Mm.42015,SEMA5B,SEMAG,脑信号蛋白(Semaphorin)5b Hlog,sema结构域,七血小板反应蛋白重复(seventhrombospondin repeats)(1型(type 1)和类1型(type 1-like)),跨膜结构域(TM)和短胞质域,(脑信号蛋白)5B,Genbank登记号AB040878)
Nagase T.,等(2000)DNA Res.7(2):143-150);WO2004000997(权利要求1);WO2003003984(权利要求1);WO200206339(权利要求1;50页);WO200188133(权利要求1;页41-43,48-58);WO2003054152(权利要求20);WO2003101400(权利要求11);
登记号:Q9P283;EMBL;AB040878;BAA95969.1.Genew;HGNC:10737;
(8)PSCA hlg(2700050C12Rik,C530008O16Rik,RIKEN cDNA2700050C12,RIKEN cDNA 2700050C12基因,Genbank登记号AY358628);Ross等(2002)Cancer Res.62:2546-2553;US2003129192(权利要求2);US2004044180(权利要求12);US2004044179(权利要求11);US2003096961(权利要求11);US2003232056(实施例5);WO2003105758(权利要求12);US2003206918(实施例5);EP1347046(权利要求1);WO2003025148(权利要求20);
交叉参考:GI:37182378;AAQ88991.1;AY358628_1
(9)ETBR(内皮缩血管肽B型受体(Endothelin type B receptor),Genbank登记号AY275463);
Nakamuta M.,等Biochem.Biophys.Res.Commun.177,34-39,1991;Ogawa Y.,等Biochem.Biophys.Res.Commun.178,248-255,1991;Arai H.,等Jpn.Circ.J.56,1303-1307,1992;Arai H.,等J.Biol.Chem.268,3463-3470,1993;Sakamoto A.,Yanagisawa M.,等Biochem.Biophys.Res.Commun.178,656-663,1991;Elshourbagy N.A.,等J.Biol.Chem.268,3873-3879,1993;Haendler B.,等J.Cardiovasc.Pharmacol.20,s1-S4,1992;Tsutsumi M.,等Gene228,43-49,1999;Strausberg R.L.,等Proc.Natl.Acad.Sci.U.S.A.99,16899-16903,2002;Bourgeois C.,等J.Clin.Endocrinol.Metab.82,3116-3123,1997;Okamoto Y.,等Biol.Chem.272,21589-21596,1997;Verheij J.B.,等Am.J.Med.基因t.108,223-225,2002;Hofstra R.M.W.,等Eur.J.Hum.Genet.5,180-185,1997;Puffenberger E.G.,等Cell 79,1257-1266,1994;Attie T.,et al,Hum.Mol.Genet.4,2407-2409,1995;Auricchio A.,等Hum.Mol.Genet.5:351-354,1996;Amiel J.,等Hum.Mol.Genet.5,355-357,1996;HofstraR.M.W.,等Nat.Genet.12,445-447,1996;Svensson P.J.,等Hum.Genet.103,145-148,1998;Fuchs S.,等Mol.Med.7,115-124,2001;Pingault V.,等(2002)Hum.Genet.111,198-206;WO2004045516(权利要求1);WO2004048938(实施例2);WO2004040000(权利要求151);WO2003087768(权利要求1);WO2003016475(权利要求1);WO2003016475(权利要求1);WO200261087(附图1);WO2003016494(附图6);WO2003025138(权利要求12;144页);WO200198351(权利要求1;页124-125);EP522868(权利要求8;附图2);WO200177172(权利要求1;页297-299);US2003109676;US6518404(附图3);US5773223(权利要求1a;Col 31-34);WO2004001004;
(10)MSG783(RNF124,推定蛋白(hypothetical protein)FLJ20315,Genbank登记号NM_017763);
WO2003104275(权利要求1);WO2004046342(实施例2);WO2003042661(权利要求12);WO2003083074(权利要求14;页61);WO2003018621(权利要求1);WO2003024392(权利要求2;附图93);WO200166689(实施例6);
交叉参考:LocusID:54894;NP_060233.2;NM_017763_1
(11)STEAP2(HGNC_8639,IPCA-1,PCANAP1,STAMP1,STEAP2,STMP,前列腺癌相关基因1,前列腺癌相关蛋白1,前列腺的六跨膜上皮细胞抗原2,六跨膜前列腺蛋白,Genbank登记号AF455138)
Lab.Invest.82(11):1573-1582(2002));WO2003087306;US2003064397(权利要求1;附图1);WO200272596(权利要求13;页54-55);WO200172962(权利要求1;附图4B);WO2003104270(权利要求11);WO2003104270(权利要求16);US2004005598(权利要求22);WO2003042661(权利要求12);US2003060612(权利要求12;附图10);WO200226822(权利要求23;附图2);WO200216429(权利要求12;附图10);
交叉参考:GI:22655488;AAN04080.1;AF455138_1
(12)TrpM4(BR22450,FLJ20041,TRPM4,TRPM4B,瞬时型受体电位阳离子通道(transient receptor potential cation channel),亚族M,成员4,Genbank登记号NM_017636)
Xu,X.Z.,等Proc.Natl.Acad.Sci.U.S.A.98(19):10692-10697(2001),Cell109(3):397-407(2002),J.Biol.Chem.278(33):30813-30820(2003));US2003143557(权利要求4);WO200040614(权利要求14;页100-103);WO200210382(权利要求1;附图9A);WO2003042661(权利要求12);WO200230268(权利要求27;391页);US2003219806(权利要求4);WO200162794(权利要求14;附图1A-D);
交叉参考:MIM:606936;NP_060106.2;NM_017636_1
(13)CRIPTO(CR,CR1,CRGF,CRIPTO,TDGF1,畸胎瘤-衍生的生长因子(teratocarcinoma-derived growth factor),Genbank登记号NP_003203或NM_003212)
Ciccodicola,A.,等EMBO J.8(7):1987-1991(1989),Am.J.Hum.Genet.49(3):555-565(1991));US2003224411(权利要求1);WO2003083041(实施例1);WO2003034984(权利要求12);WO200288170(权利要求2;页52-53);WO2003024392(权利要求2;附图58);WO200216413(权利要求1;页94-95,105);WO200222808(权利要求2;附图1);US5854399(实施例2;Col 17-18);US5792616(附图2);
交叉参考:MIM:187395;NP_003203.1;NM_003212_1
(14)CD21(CR2(补体受体2)或C3DR(C3d/EB病毒受体(Epstein Barrvirus receptor))或Hs.73792Genbank登记号M26004)
Fujisaku等(1989)J.Biol.Chem.264(4):2118-2125);Weis J.J.,等J.Exp.Med.167,1047-1066,1988;Moore M.,等Proc.Natl.Acad.Sci.U.S.A.84,9194-9198,1987;Barel M.,等Mol.Immunol.35,1025-1031,1998;Weis J.J.,等Proc.Natl.Acad.Sci.U.S.A.83,5639-5643,1986;Sinha S.K.,等(1993)J.Immunol.150,5311-5320;WO2004045520(实施例4);US2004005538(实施例1);WO2003062401(权利要求9);WO2004045520(实施例4);WO9102536(附图9.1-9.9);WO2004020595(权利要求1);
登记号:P20023;Q13866;Q14212;EMBL;M26004;AAA35786.1.
(15)CD79b(CD79B,CD79β,IGb(免疫球蛋白-相关β(immunoglobulin-associated beta),B29,Genbank登记号NM_000626或11038674)
Proc.Natl.Acad.Sci.U.S.A.(2003)100(7):4126-4131,Blood(2002)100(9):3068-3076,Muller等(1992)Eur.J.Immunol.22(6):1621-1625);WO2004016225(权利要求2,附图140);WO2003087768,US2004101874(权利要求1,页102);WO2003062401(权利要求9);WO200278524(实施例2);US2002150573(权利要求5,页15);US5644033;WO2003048202(权利要求1,306和309页);WO 99/558658,US6534482(权利要求13,附图17A/B);WO200055351(权利要求11,1145-1146页);
交叉参考:MIM:147245;NP_000617.1;NM_000626_1
(16)FcRH2(IFGP4,IRTA4,SPAP1A(含有SH2结构域的磷酸酶锚定蛋白1a(SH2domain containing phosphatase anchor protein 1a),SPAP1B,SPAP1C,Genbank登记号NM_030764,AY358130)
Genome Res.13(10):2265-2270(2003),Immunogenetics 54(2):87-95(2002),Blood 99(8):2662-2669(2002),Proc.Natl.Acad.Sci.U.S.A.98(17):9772-9777(2001),Xu,M.J.,等(2001)Biochem.Biophys.Res.Commun.280(3):768-775;WO2004016225(权利要求2);WO2003077836;WO200138490(权利要求5;附图18D-1-18D-2);WO2003097803(权利要求12);WO2003089624(权利要求25);
交叉参考:MIM:606509;NP_110391.2;NM_030764_1
(17)HER2(ErbB2,Genbank登记号M11730)
Coussens L.,等Science(1985)230(4730):1132-1139);Yamamoto T.,等Nature 319,230-234,1986;Semba K.,等Proc.Natl.Acad.Sci.U.S.A.82,6497-6501,1985;Swiercz J.M.,等J.Cell Biol.165,869-880,2004;Kuhns J.J.,等J.Biol.Chem.274,36422-36427,1999;Cho H.-S.,等Nature 421,756-760,2003;Ehsani A.,等(1993)Genomics 15,426-429;WO2004048938(实施例2);WO2004027049(附图1I);WO2004009622;WO2003081210;WO2003089904(权利要求9);WO2003016475(权利要求1);US2003118592;WO2003008537(权利要求1);WO2003055439(权利要求29;附图1A-B);WO2003025228(权利要求37;附图5C);WO200222636(实施例13;95-107页);WO200212341(权利要求68;附图7);WO200213847(71-74页);WO200214503(页114-117);WO200153463(权利要求2;41-46页);WO200141787(15页);WO200044899(权利要求52;附图7);WO200020579(权利要求3;附图2);US5869445(权利要求3;Col 31-38);WO9630514(权利要求2;页56-61);EP1439393(权利要求7);WO2004043361(权利要求7);WO2004022709;WO200100244(实施例3;附图4);
登记号:P04626;EMBL;M11767;AAA35808.1.EMBL;M11761;AAA35808.1.
(18)NCA(CEACAM6,Genbank登记号M18728);
Barnett T.,等Genomics 3,59-66,1988;Tawaragi Y.,等Biochem.Biophys.Res.Commun.150,89-96,1988;Strausberg R.L.,等Proc.Natl.Acad.Sci.U.S.A.99:16899-16903,2002;WO2004063709;EP1439393(权利要求7);WO2004044178(实施例4);WO2004031238;WO2003042661(权利要求12);WO200278524(实施例2);WO200286443(权利要求27;页427);WO200260317(权利要求2);
登记号:P40199;Q14920;EMBL;M29541;AAA59915.1.EMBL;M18728;
(19)MDP(DPEP1,Genbank登记号BC017023)
Proc.Natl.Acad.Sci.U.S.A.99(26):16899-16903(2002));WO2003016475(权利要求1);WO200264798(权利要求33;85-87页);JP05003790(附图6-8);WO9946284(附图9);
交叉参考:MIM:179780;AAH17023.1;BC017023_1
(20)IL20Rα(IL20Ra,ZCYTOR7,Genbank登记号AF184971);
Clark H.F.,等Genome Res.13,2265-2270,2003;Mungall A.J.,等Nature425,805-811,2003;Blumberg H.,等Cell 104,9-19,2001;Dumoutier L.,等J.Immunol.167,3545-3549,2001;Parrish-Novak J.,等J.Biol.Chem.277,47517-47523,2002;Pletnev S.,等(2003)Biochemistry 42:12617-12624;Sheikh F.,等(2004)J.Immunol.172,2006-2010;EP1394274(实施例11);US2004005320(实施例5);WO2003029262(74-75页);WO2003002717(权利要求2;63页);WO200222153(45-47页);US2002042366(20-21页);WO200146261(57-59页);WO200146232(63-65页);WO9837193(权利要求1;55-59页);
登记号:Q9UHF4;Q6UWA9;Q96SH8;EMBL;AF184971;AAF01320.1.
(21)Brevican(BCAN,BEHAB,Genbank登记号AF229053)
Gary S.C.,等Gene 256,139-147,2000;Clark H.F.,等Genome Res.13,2265-2270,2003;Strausberg R.L.,等Proc.Natl.Acad.Sci.U.S.A.99,16899-16903,2002;US2003186372(权利要求11);US2003186373(权利要求11);US2003119131(权利要求1;附图52);US2003119122(权利要求1;附图52);US2003119126(权利要求1);US2003119121(权利要求1;附图52);US2003119129(权利要求1);US2003119130(权利要求1);US2003119128(权利要求1;附图52);US2003119125(权利要求1);WO2003016475(权利要求1);WO200202634(权利要求1);
(22)EphB2R(DRT,ERK,Hek5,EPHT3,Tyro5,Genbank登记号NM_004442)
Chan,J.和Watt,V.M.,Oncogene 6(6),1057-1061(1991)Oncogene10(5):897-905(1995),Annu.Rev.Neurosci.21:309-345(1998),Int.Rev.Cytol.196:177-244(2000));WO2003042661(权利要求12);WO200053216(权利要求1;页41);WO2004065576(权利要求1);WO2004020583(权利要求9);WO2003004529(128-132页);WO200053216(权利要求1;42页);
交叉参考:MIM:600997;NP_004433.2;NM_004442_1
(23)ASLG659(B7h,Genbank登记号AX092328)
US20040101899(权利要求2);WO2003104399(权利要求11);WO2004000221(附图3);US2003165504(权利要求1);US2003124140(实施例2);US2003065143(附图60);WO2002102235(权利要求13;299页);US2003091580(实施例2);WO200210187(权利要求6;附图10);WO200194641(权利要求12;附图7b);WO200202624(权利要求13;附图1A-1B);US2002034749(权利要求54;45-46页);WO200206317(实施例2;320-321页,权利要求34;321-322页);WO200271928(468-469页);WO200202587(实施例1;附图1);WO200140269(实施例3;页190-192);WO200036107(实施例2;205-207页);WO2004053079(权利要求12);WO2003004989(权利要求1);WO200271928(233-234,452-453页);WO0116318;
(24)PSCA(前列腺干细胞抗原前体(prostate stem cell precursor),Genbank登记号AJ297436)
Reiter R.E.,等Proc.Natl.Acad.Sci.U.S.A.95,1735-1740,1998;Gu Z.,等Oncogene 19,1288-1296,2000;Biochem.Biophys.Res.Commun.(2000)275(3):783-788;WO2004022709;EP1394274(实施例11);US2004018553(权利要求17);WO2003008537(权利要求1);WO200281646(权利要求1;页164);WO2003003906(权利要求10;页288);WO200140309(实施例1;附图17);US2001055751(实施例1;附图1b);WO200032752(权利要求18;附图1);WO9851805(权利要求17;页97);WO9851824(权利要求10;94页);WO9840403(权利要求2;附图1B);
登记号:O43653;EMBL;AF043498;AAC39607.1.
(25)GEDA(Genbank登记号AY260763);
AAP14954脂肪瘤HMGIC融合-配偶体-类蛋白(lipoma HMGICfusion-partner-like protein)/pid=AAP14954.1-人类
物种:人类(人)
WO2003054152(权利要求20);WO2003000842(权利要求1);
WO2003023013(实施例3,权利要求20);US2003194704(权利要求45);
交叉参考:GI:30102449;AAP14954.1;AY260763_1
(26)BAFF-R(B细胞-活化因子受体,BLyS受体3,BR3,Genbank登记号AF116456);BAFF受体/pid=NP_443177.1-人类
Thompson,J.S.,等Science 293(5537),2108-2111(2001);WO2004058309;WO2004011611;WO2003045422(实施例;32-33页);WO2003014294(权利要求35;附图6B);WO2003035846(权利要求70;615-616页);WO200294852(Col 136-137);WO200238766(权利要求3;133页);WO200224909(实施例3;附图3);
交叉参考:MIM:606269;NP_443177.1;NM_052945_1;AF132600
(27)CD22(B-细胞受体CD22-B同种型,BL-CAM,Lyb-8,Lyb8,SIGLEC-2,FLJ22814,Genbank登记号AK026467);
Wilson等(1991)J.Exp.Med.173:137-146;WO2003072036(权利要求1;附图1);
交叉参考:MIM:107266;NP_001762.1;NM_001771_1
(28)CD79a(CD79A,CD79α,免疫球蛋白-相关α,一种B细胞-特异性蛋白,其与Igβ(CD79B)共价相互作用并且在表面上与Ig M分子形成复合物,转导涉及B-细胞分化的信号),pI:4.84,MW:25028 TM:2[P]GeneChromosome:19q13.2,Genbank登记号NP_001774.10)
WO2003088808,US20030228319;WO2003062401(权利要求9);US2002150573(权利要求4,13-14页);WO9958658(权利要求13,附图16);WO9207574(附图1);US5644033;Ha等(1992)J.Immunol.148(5):1526-1531;Mueller等(1992)Eur.J.Biochem.22:1621-1625;Hashimoto等(1994)Immunogenetics 40(4):287-295;Preud’homme等(1992)Clin.Exp.Immunol.90(1):141-146;Yu等(1992)J.Immunol.148(2)633-637;Sakaguchi等(1988)EMBO J.7(11):3457-3464;
(29)CXCR5(伯基特淋巴瘤受体1(Burkitt’s lymphoma receptor 1),一种G蛋白偶联受体,由CXCL13趋化因子活化,在淋巴细胞迁移和体液防御中起作用,在HIV-2感染中起作用和可能在AIDS、淋巴瘤、黑素瘤和白血病发生中起作用);372aa,pI:8.54MW:41959 TM:7[P]Gene Chromosome:11q23.3,Genbank登记号NP_001707.1)
WO2004040000;WO2004015426;US2003105292(实施例2);US6555339(实施例2);WO200261087(附图1);WO200157188(权利要求20,页269);WO200172830(12-13页);WO200022129(实施例1,152-153页,实施例2,254-256页);WO9928468(权利要求1,页38);US5440021(实施例2,col 49-52);WO9428931(56-58页);WO9217497(权利要求7,附图5);Dobner等(1992)Eur.J.Immunol.22:2795-2799;Barella等(1995)Biochem.J.309:773-779;
(30)HLA-DOB(MHC II类分子的β亚单位(Ia抗原),其与肽结合并且将其呈递给CD4+T淋巴细胞);273aa,pI:6.56 MW:30820 TM:1[P]GeneChromosome:6p21.3,Genbank登记号NP_002111.1)
Tonnelle等(1985)EMBO J.4(11):2839-2847;Jonsson等(1989)Immunogenetics 29(6):411-413;Beck等(1992)J.Mol.Biol.228:433-441;Strausberg等(2002)Proc.Natl.Acad.Sci USA 99:16899-16903;Servenius等(1987)J.Biol.Chem.262:8759-8766;Beck等(1996)J.Mol.Biol.255:1-13;Naruse等(2002)Tissue Antigens 59:512-519;WO9958658(权利要求13,附图15);US6153408(Col 35-38);US5976551(col 168-170);US6011146(col145-146);Kasahara等(1989)Immunogenetics 30(1):66-68;Larhammar等(1985)J.Biol.Chem.260(26):14111-14119;
(31)P2X5(嘌呤能受体P2X配体门控离子通道5(purinergic receptor P2Xligand-gated ion channel 5),即由胞外ATP门控的离子通道,可能涉及突触传递和神经发生,其缺陷可以促使特发性逼尿肌不稳定病理生理学情况);422aa),pI:7.63,MW:47206 TM:1[P]Gene Chromosome:17p13.3,Genbank登记号NP_002552.2)
Le等(1997)FEBS Lett.418(1-2):195-199;WO2004047749;WO2003072035(权利要求10);Touchman等(2000)Genome Res.10:165-173;WO200222660(权利要求20);WO2003093444(权利要求1);WO2003087768(权利要求1);WO2003029277(82页);
(32)CD72(B-细胞分化抗原CD72,Lyb-2)PROTEIN SEQUENCE Fullmaeaity...tafrfpd(1..359;359aa),pI:8.66,MW:40225 TM:1[P]GeneChromosome:9p13.3,Genbank登记号NP_001773.1)
WO2004042346(权利要求65);WO2003026493(51-52,57-58页);WO200075655(105-106页);Von Hoegen等(1990)J.Immunol.144(12):4870-4877;Strausberg等(2002)Proc.Natl.Acad.Sci USA99:16899-16903;
(33)LY64(淋巴细胞抗原64(RP105),即富含亮氨酸重复(LRR)家族I型膜蛋白(type I memberane protein of the leucine rich repeat family),调节B-细胞细胞活化和程序性细胞死亡,其功能缺失与患有系统性红斑狼疮的患者的疾病活动增加有关);661aa,pI:6.20,MW:74147 TM:1[P]Gene Chromosome:5q12,Genbank登记号NP_005573.1)
US2002193567;WO9707198(权利要求11,39-42页);Miura等(1996)Genomics 38(3):299-304;Miura等(1998)Blood 92:2815-2822;WO2003083047;WO9744452(权利要求8,57-61页);WO200012130(24-26页);
(34)FcRH1(Fc受体-样蛋白1(Fc receptor-like protein 1),即含有C2型Ig-样结构域和ITAM结构域的免疫球蛋白Fc结构域的推定受体,可能在B-淋巴细胞分化中起作用);429aa,pI:5.28,MW:46925 TM:1[P]GeneChromosome:1q21-1q22,Genbank登记号NP_443170.1)
WO2003077836;WO200138490(权利要求6,附图18E-1-18-E-2);Davis等(2001)Proc.Natl.Acad.Sci USA 98(17):9772-9777;WO2003089624(权利要求8);EP1347046(权利要求1);WO2003089624(权利要求7);
(35)IRTA2(免疫球蛋白超家族受体易位相关2,即在B细胞发育和淋巴瘤的生成中具有可能的作用的推定的免疫受体;由于易位所导致的基因失调在某些B细胞恶性肿瘤中发生);977aa,pI:6.88 MW:106468 TM:1[P]Gene Chromosome:1q21,Genbank登记号人:AF343662,AF343663,AF343664,AF343665,AF369794,AF397453,AK090423,AK090475,AL834187,AY358085;小鼠:AK089756,AY158090,AY506558;NP_112571.1
WO2003024392(权利要求2,附图97);Nakayama等(2000)Biochem.Biophys.Res.Commun.277(1):124-127;WO2003077836;WO200138490(权利要求3,附图18B-1-18B-2);
(36)TENB2(TMEFF2,tomoregulin,TPEF,HPP1,TR,与EGF/调蛋白(heregulin)家族生长因子和卵泡抑素(follistatin)有关的推定的跨膜蛋白聚糖);374aa,NCBI登记号:AAD55776,AAF91397,AAG49451,NCBI RefSeq:NP_057276;NCBI基因:23671;OMIM:605734;SwissProt Q9UIK5;Genbank登记号AF179274;AY358907,CAF85723,CQ782436
WO2004074320(SEQ ID NO 810);JP2004113151(SEQ ID NOS 2,4,8);WO2003042661(SEQ ID NO 580);WO2003009814(SEQ ID NO 411);EP1295944(69-70页);WO200230268(329页);WO200190304(SEQ ID NO2706);US2004249130;US2004022727;WO2004063355;US2004197325;US2003232350;US2004005563;US2003124579;Horie等(2000)Genomics 67:146-152;Uchida等(1999)Biochem.Biophys.Res.Commun.266:593-602;Liang等(2000)Cancer Res.60:4907-12;Glynne-Jones等(2001)Int J Cancer.Oct 15;94(2):178-84.
亲代抗体还可以为包含清蛋白-结合肽(ABP)序列的融合蛋白(Dennis等(2002)“Albumin Binding As A General Strategy For Improving ThePharmacokinetics Of Proteins”J Biol Chem.277:35035-35043;WO 01/45746)。本发明的抗体包括具有下列文献中教导的ABP序列的融合蛋白:(i)Dennis等(2002)J Biol Chem.277:35035-35043,表III和IV,35038页;(ii)US20040001827,在[0076]SEQ ID NOS:9-22;和(iii)WO 01/45746,在12-13页,SEQ ID NOS:z1-z14,并且将所有这些文献引入本文作为参考。
诱变
可通过本领域中公知的多种方法制备编码起始多肽的氨基酸序列变体的DNA。这些方法包括,但不限于通过位点-定向(或寡核苷酸介导的)诱变、PCR诱变和对编码所述多肽的较早制备的DNA的盒式诱变制备。还可以通过限制片段操作或通过使用合成寡核苷酸的重叠延伸PCR构建重组抗体的变体。诱变引物编码半胱氨酸密码子替代物。标准诱变技术可以用于产生编码这类突变的半胱氨酸改造的抗体的DNA。一般指导原则可以在下列文献中找到:Sambrook等Molecular Cloning,A Laboratory Manual,Cold SpringHarbor Laboratory Press,Cold Spring Harbor,N.Y.,1989;和Ausubel等CurrentProtocols in Molecular Biology,Greene Publishing和Wiley-Interscience,NewYork,N.Y.,1993。
位点-定向诱变为一种制备替代变体,即突变蛋白的方法。这项技术为本领域众所周知(例如,参见,Carter(1985)等Nucleic Acids Res.13:4431-4443;Ho等(1989)基因(Amst.)77:51-59;和Kunkel等(1987)Proc.Natl.Acad.Sci.USA 82:488)。简言之,在进行DNA位点-定向诱变过程中,通过首先使编码所需突变的寡核苷酸与这类起始DNA的单链杂交来改变起始DNA。在杂交后,将DNA聚合酶用于使用杂交的寡核苷酸作为引物并且使用起始DNA单链作为模板合成完整的第二链。因此,将编码所需突变的寡核苷酸掺入所得双链DNA。位点-定向诱变可以在表达质粒中表达预进行诱变的蛋白质的基因中进行,并且可以对所得质粒测序以便证实引入了所需的半胱氨酸替代突变(Liu等(1998)J.Biol.Chem.273:20252-20260)。位点-定向方案和方式,包括那些商购的方案和方式,例如Multi Site-DirectedMutagenesis Kit(Stratagene,La Jolla,CA)。
PCR诱变还适合于制备起始多肽的氨基酸序列变体。参见Higuchi,(1990):PCR Protocols,pp.177-183,Academic Press;Ito等(1991)基因102:67-70;Bernhard等(1994)Bioconjugate Chem.5:126-132;和Vallette等(1989)Nuc.Acids Res.17:723-733。简言之,当将少量模板DNA用作PCR中的起始物时,在序列方面稍不同于模板DNA中相应区的引物可以用于产生相对大量的特异性DNA片段,这些片段仅在引物不同于模板的位置上不同于模板序列。
用于制备变体的另一种方法,即盒式诱变基于Wells等(1985)基因34:315-323所述的技术。起始物为包含预突变的起始多肽DNA的质粒(或其它载体)。鉴定预突变的起始DNA中的密码子。在鉴定的突变位点的每侧上必须存在独特的限制性内切核酸酶位点。如果不存在这类限制位点,那么可以使用上述寡核苷酸介导的诱变方法产生它们,以便将其引入起始多肽DNA的适当位置上。在这些位点上切割质粒DNA以使其线性化。使用标准操作步骤合成编码在限制位点之间但含有所需突变的DNA序列的双链寡核苷酸。其中分别合成寡核苷酸的两条链然后使用标准技术彼此杂交。这种双链寡核苷酸称作盒(cassette)。将这种盒设计成具有与线性化质粒末端相容的5′和3′末端,使得它可以直接连接质粒。这种质粒目前含有突变的DNA序列。可以通过DNA测序证实含有编码的半胱氨酸替代物的突变DNA。
还通过寡核苷酸定向诱变,使用经PCR的诱变的双链质粒DNA作为模板产生单突变(Sambrook和Russel,(2001)Molecular Cloning:A LaboratoryManual,3rd edition;Zoller等(1983)Methods Enzymol.100:468-500;Zoller,M.J.和Smith,M.(1982)Nucl.Acids Res.10:6487-6500)。
在本发明中,在M13噬菌体上展示的hu4D5Fabv8(Gerstner等(2002)“Sequence Plasticity In The Antigen-Binding Site Of A Therapeutic Anti-HER2Antibody”,J Mol Biol.321:851-62)作为模型系统用于实验。将半胱氨酸突变引入hu4D5Fabv8-噬菌体、hu4D5Fabv8和ABP-hu4D5Fabv8构建体。如上所述使用聚乙二醇(PEG)沉淀法进行hu4D5-ThioFab-噬菌体制备(Lowman,Henry B.(1998)Methods in Molecular Biology(Totowa,New Jersey)87(Combinatorial peptide Library Protocols)249-264)。
通过亚磷酰胺合成法(phosphoramidite synthesis method)制备寡核苷酸(US 4415732;US 4458066;Beaucage,S.和Iyer,R.(1992)"Advances in thesynthesis of oligonucleotides by the phosphoramidite approach",Tetrahedron48:2223-2311)。亚磷酰胺法要求核苷酸单体单元与反应性3’亚磷酰胺(phosphoramidite)部分环化加成而得到在由受控孔玻璃或高度交联的聚苯乙烯组成的固相支持体上生长的寡核苷酸链,并且通常以3′-5′方向,其中3′末端与合成开始时的固相支持物附着(US 5047524;US 5262530)。通常使用自动化商购合成仪(Applied Biosystems,Foster City,CA)实施该方法。可以使用非同位素部分化学标记的寡核苷酸以便检测、俘获、稳定或其它目的(Andrus,A."Chemical methods for 5′non-isotopic labelling of PCR probes andprimers"(1995):PCR 2:A Practical Approach,Oxford University Press,Oxford,pp.39-54;Hermanson,G.:Bioconjutate Techniques(1996)Academic Press,SanDiego,pp.40-55,643-671;Keller,G.和Manak,M.in DNA Probes SecondEdition(1993),Stockton Press,New York,pp.121-23)。
PHESELECTOR测定
PHESELECTOR(用于选择反应性巯基的噬菌体ELISA)测定法能够以ELISA噬菌体方式检测抗体中反应性半胱氨酸基团。实施例2中详细描述了在孔表面上包被所关注的蛋白质(例如抗体),随后与噬菌粒一起温育且然后使用吸光度检测HRP标记的二抗的过程。可以以快速、有力和高流通量方式筛选噬菌体上展示的突变蛋白。可以使用从抗体或其它蛋白的随机蛋白质-噬菌体文库鉴定游离Cys掺入的适当反应位点相同的手段生产半胱氨酸改造的抗体的文库并且进行结合筛选。这项技术包括使噬菌体上展示的半胱氨酸突变体与也为巯基反应性的亲和试剂或报告基团反应。附图8通过描绘Fab或ThioFab与HER2(上)和生物素化的ThioFab与链霉抗生物素(下)结合的示意图例示了PHESELECTOR测定。
蛋白质表达和纯化
易于使用常规操作步骤(例如通过使用能够特异性结合编码鼠抗体重链和轻链的基因的寡核苷酸探针)分离编码半胱氨酸改造的抗体的DNA并且对其进行测序。杂交瘤细胞用作这类DNA的来源。一旦分离,就可以将DNA放入表达载体,然后将其转染入宿主细胞,诸如大肠杆菌细胞、猿猴COS细胞、中国仓鼠卵巢(CHO)细胞或其它不额外产生抗体蛋白的哺乳动物宿主细胞,诸如骨髓瘤细胞(US 5807715;US 2005/0048572;US 2004/0229310),以便获得重组宿主中合成的单克隆抗体。hu4D5Fabv8半胱氨酸改造的抗体的产率与野生型hu4D5Fabv8相似。有关细菌中编码抗体的DNA的重组表达的综述文章包括Skerra等(1993)Curr.Opinion in Immunol.5:256-262和Plückthun(1992)Immumol.Revs.130:151-188。
在设计和选择后,可以通过下列方式生产具有高度反应性的未配对的Cys残基的半胱氨酸改造的抗体,例如ThioFabs:(i)在细菌,例如大肠杆菌系统或哺乳动物细胞培养系统中表达(WO 01/00245),例如中国仓鼠卵巢细胞(CHO);和(ii)使用常用的蛋白质纯化技术纯化(Lowman等(1991)J.Biol.Chem.266(17):10982-10988)。
在34B8,即非-阻抑性大肠杆菌菌株中诱导时表达ThioFabs(Baca等(1997)Journal Biological Chemistry 272(16):10678-84)。参见实施例3a。将收集的细胞沉淀重新悬浮于PBS(磷酸缓冲盐水)中,通过经过微流化仪(microfluidizer)进行总细胞裂解并且通过使用蛋白质GSEPHAROSETM(Amersham)的亲和层析法纯化ThioFabs。如上所述使ThioFabs与生物素-PEO-马来酰亚胺偶联并且通过Superdex-200TM(Amersham)凝胶过滤层析法进一步纯化生物素化-ThioFabs,从而消除了游离的生物素-PEO-马来酰亚胺和ThioFabs的寡聚化级分。
质谱分析
使用液相层析电喷射离子化质谱(LC-ESI-MS)分析对生物素偶联的Fab进行精确分子量测定(Cole,R.B.Electro Spray Ionization Mass Spectrometry:Fundamentals,Instrumentation and Applications.(1997)Wiley,New York)。通过胰蛋白酶消化,随后通过LC-ESI-串联MS分析测定生物素化的hu4D5Fabv8(A121C)的氨基酸序列(表4,实施例3b)。
抗体Fab片段hu4D5Fabv8含有约445个氨基酸残基,包括10个Cys残基(5个在轻链上,且5个在重链上)。已经确立了人源化4D5可变片段(Fv4D5)的高分辨结构,参见:Eigenbrot等“X-Ray Structures Of TheAntigen-Binding Domains From Three Variant Of Humanized Anti-P185her2Antibody 4D5和Comparison With Molecular Modeling”(1993)J Mol Biol.229:969-995)。所有的Cys残基均以二硫键形式存在,由此这些残基不具有任何与药物-马来酰亚胺偶联的反应性巯基(reactive-thiol group)(除非用还原剂处理)。因此,新改造的Cys残基可以保持不配对并且能够与亲电子连接基试剂或药物-连接基中间体(drug-linker intermediate),诸如药物-马来酰亚胺反应,即与之偶联。附图1A表示X-射线晶体坐标衍生的hu4D5Fabv8抗体片段的三维示意图。按照顺序标号系统给重链和轻链的改造的Cys残基的结构位置编号。这种顺序编号系统(sequential numbering system)与Kabat编号系统相关(Kabat等,(1991)Sequences of Proteins of Immunological Interest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD),而Kabat编号系统用于附图1B的曲妥单抗(trastuzumab)的4d5v7fabH变体,该附图表示从N-末端开始的顺序编号方案(上行),它不同于Kabat编号方案(下行)的方面在于a、b、c标注的插入。使用Kabat编号系统,实际的线性氨基酸序列可以含有相当于可变域的FR或CDR的缩短或插入的较少或额外的氨基酸。通过下表中的顺序编号和Kabat编号方案鉴定半胱氨酸改造的重链变体位点:
4D5Fab重链变体 | 顺序编号 | Kabat编号 |
A40C | Ala-40 | Ala-40 |
A88C | Ala-88 | Ala-84 |
S119C | Ser-119 | Ser-112 |
S120C | Ser-120 | Ser-113 |
A121C | Ala-121 | Ala-114 |
S122C | Ser-122 | Ser-115 |
A175C | Ala-175 | Ala-168 |
与Fab蛋白比较可以快速筛选M13噬菌粒-Cys突变体Fabs(附图3A和3B)。可以通过在ELISA平板上分别包被HER2和链霉抗生物素,随后如实施例2中所述和附图8中描绘的用抗-Fab-HRP(辣根过氧化物酶)探测测试结合抗原和链霉抗生物素的噬菌粒-ThioFab。该方法能够用改造的Cys残基/偶联的生物素分子同时监测对抗原结合和巯基反应性的作用。此外,该方法可以应用于筛选在M13噬菌体上展示的任意蛋白质的反应性巯基。通过单纯PEG沉淀纯化偶联或未偶联的噬菌粒-ThioFabs。
人源化4D5的抗原-结合片段(hu4D5Fab)在大肠杆菌中充分表达并且已经在噬菌体上得到展示(Garrard等(1993)基因128:103-109)。在基于ELISA的测定法中在作为模型系统的M13噬菌体上展示抗体Fab片段hu4D5Fabv8以便探测巯基反应性。附图8为PHESELECTOR测定法的示意图,其描绘了生物素化的ThioFab噬菌体和抗-噬菌体HRP抗体与HER2(上)和链霉抗生物素(下)的结合。最初从作为距抗原结合表面较远的晶体结构信息中选择5个氨基酸残基(L-Ala43、H-Ala40、H-Ser119、H-Ala121和H-Ser122)(Eigenbrot等(1993)J Mol Biol.229:969-995)。将蛋白质数据库X-射线晶体结构命名为1FVC。通过位点定向诱变在这些位置上改造Cys残基。分离ThioFab-噬菌体制品并且使其与生物素化试剂反应。
使用基于ELISA的PHESELECTOR测定法(附图8,实施例2)与HRP(辣根过氧化物酶)-偶联的抗-噬菌体抗体测试生物素偶联和未偶联物的变体的HER2和链霉抗生物素结合。通过显色标准HRP反应并且在450nm处测定吸光度用抗-M13-辣根过氧化物酶(HRP)抗体监测未-生物素化的噬菌体-hu4D5Fabv8(附图2A)和生物素化的噬菌体-hu4D5Fabv8(附图2B)与BSA(空心条)、HER2(灰色条)或链霉抗生物素(实心条)的相互作用。在450nm处测定因显色底物的更新(turnover)产生的吸光度。ThioFab与HER2的反应性确定抗原结合。ThioFab与链霉抗生物素的反应性确定生物素化程度。ThioFab与BSA的反应性为非特异性相互作用的阴性对照。正如在附图2A中观察到的,所有ThioFab-噬菌体变体均具有与野生型hu4D5Fabv8-噬菌体相似的与HER2的结合。此外,与生物素偶联不会干扰ThioFab与HER2结合(附图2B)。
令人惊奇和出人意料的是,ThioFabs-噬菌体样品表现出可变水平的链霉抗生物素结合活性。在来自所有测试的噬菌体-ThioFabs中,A121C半胱氨酸改造的抗体表现出最大的巯基反应性。尽管将野生型hu4D5Fabv8-噬菌体与相同量的生物素-马来酰亚胺一起孵育,但是这些噬菌体几乎没有链霉抗生物素结合,表明预先存在来自hu4D5Fabv8和M13噬菌体包膜蛋白的半胱氨酸残基(涉及二硫键形成)不会干扰生物素-马来酰亚胺的位点-特异性偶联。这些结果表明可以将噬菌体ELISA测定法成功地用于筛选Fab表面上的反应性巯基。
PHESELECTOR测定法能够筛选抗体中的反应性巯基。通过该方法鉴定A121C变体是典型的。可以有效地研究完整的Fab分子以便鉴定更多的带有反应性巯基的ThioFab变体。参数,表面可接近分数(fractional surfaceaccessibility),用于鉴定和定量溶剂与多肽中的氨基酸残基的可接近性。将表面可接近性表示为可以由溶剂分子,例如水接触的表面积水占据的空间近似为半径球体。软件为自由可获得的或经许可的(Secretary toCCP4,Daresbury Laboratory,Warrington,WA44AD,United Kingdom,Fax:(+44)1925603825,或通过因特网:www.ccp4.ac.uk/dist/html/INDEX.html),如使用计算具有已知X射线衍射晶体分析法衍生的坐标的每种蛋白质的氨基酸的表面可接近性的算法的晶体学程序CCP4Suite(“The CCP4Suite:Programs for ProteinCrystallography”(1994)Acta.Cryst.D50:760-763)。执行表面可接近性计算的两种典型的软件模块为“AREAIMOL”和“SURFACE”,其基于B.Lee和F.M.Richards的算法(1971)J.Mol.Biol.55:379-400。AREAIMOL将蛋白质的溶剂可接近表面定义为探针球(probe sphere)(代表溶剂分子)中心的位置,此时它在蛋白质的Van der Waals表面上翻转。AREAIMOL计算溶剂可接近的表面积,通过在有关每一原子的扩充的球体上产生表面点(在距等于原子和探针半径总和的原子中心的距离处),并且消除属于与相邻原子结合的等同球体内的那些点来进行。AREAIMOL测定了PDB坐标文件中原子的溶剂可接近面积并且概括了残基、链和完整分子的可接近面积。可以将各原子的可接近面积(或面积差)存储成假拟-PDB输出文件。AREAIMOL推定了每一成分的单一半径并且仅识别有限数量的不同成分。将未知原子类型(即那些在AREAIMOL内部数据库中没有的原子类型)指定为的缺省半径。识别的原子的列表为:
AREAIMOL和SURFACE报导了绝对可接近性,即平方埃数。通过参比多肽内的相关氨基酸的标准状态计算表面可接近分数。参比状态为三肽Gly-X-Gly,其中X为所关注的氨基酸,且参比状态应为′扩展的′构象,即如那些在β-链中的构象。扩展的构象使可接近性X达到最大值。用计算的可接近面积除以Gly-X-Gly三肽参比状态中可接近的面积并且报导商数,其为可接近分数。可接近性百分比为可接近分数乘以100。
计算表面可接近性的另一种典型算法基于程序xsae的SOLV模块(Broger,C.,F.Hoffman-LaRoche,Basel),它基于多肽的X-射线坐标计算氨基酸残基与水球体的可接近分数。
使用晶体结构信息计算hu4D5Fabv7中的每个氨基酸的表面可接近分数(Eigenbrot等(1993)J Mol Biol.229:969-995)。hu4D5Fabv7的轻链和重链氨基酸的表面可接近分数值如下表1中的下行顺序所示。
表1.
hu4D5Fabv7-轻链
hu4D5Fabv7-重链
将下列两个标准应用于鉴定可以改造以便用Cys残基替代的hu4D5Fabv8的残基:
1.消除完全掩蔽的氨基酸残基,即小于10%的表面可接近分数。表1表示存在于hu4D5Fabv8中的大于10%可接近性(表面可接近分数)的134(轻链)和151(重链)个残基。选择上部的10个最可接近的Ser、Ala和Val残基是因其它氨基酸与Cys的结构更相似,从而由新改造的Cys向抗体中引入了仅为最小的结构约束。还可以筛选其它半胱氨酸替代位点并且可以用于偶联。
2.基于其在Fab的功能和结构相互作用中的作用分选残基。进一步选择抗原相互作用中未涉及并且远离存在的二硫键的残基。新改造的Cys残基应不参与(distinct from)并且不干扰抗原结合,也不会与二硫键形成中涉及的半胱氨酸错配。
下列hu4D5Fabv8的残基具有上述标准并且可被选择用于Cys替代:L-V15、L-A43、L-V110、L-A144、L-S168、H-A88、H-A121、H-S122、H-A175和H-S179(如附图1中所示)。
巯基反应性可以广泛化至任意的抗体,其中氨基酸被反应性半胱氨酸氨基酸替代在选自下列的轻链范围内进行:L-10-L-20;L-38-L-48;L-105-L-115;L-139-L-149;L-163-L-173;和选自下列的重链范围内进行:H-35-H-45;H-83-H-93;H-114-H-127;和H-170-H-184;和选自下列范围的Fc区中进行:H-268-H-291;H-319-H-344;H-370-H-380;和H-395-H-405。
巯基反应性可以广泛化至抗体的某些结构域,诸如轻链恒定域(CL)和重链恒定域CH1、CH2和CH3。产生0.6和0.6以上巯基反应值的半胱氨酸替代可以在如下完整抗体的重链恒定域α、δ、ε、γ和μ中进行:分别为IgA、IgD、IgE、IgG和IgM,包括IgG亚类:IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。
从晶体结构数据中显然可以看出选择的10种Cys突变体远离抗原-结合部位,诸如在这种情况下的与HER2的界面。可以通过实验测试这些突变体对功能相互作用的间接影响。测定所有Cys Fab变体的巯基反应性并且如实施例1和2中所述计算且列在表2中。残基L-V15C、L-V110C、H-A88C和H-A121C具有反应性且稳定的巯基(附图3A和3B)。突变体V15C、V110C、A144C、S168C为轻链Cys变体。突变体A88C、A121C、A175C、S179C为重链Cys变体。令人惊奇和出人意料的是具有高表面可接近分数的位点不具有通过PHESELECTOR测定法计算的最高巯基反应性(表2)。换句话说,表面可接近分数(表1、2)与巯基反应性不相关(表2)。实际上,在具有20%-80%的中度表面可接近性的位点上改造的Cys残基(附图4A,表1)或部分暴露的位点,如Ala或Val残基表现出优于在Ser残基上引入的Cys的巯基反应性,即>0.6(附图3B,表2),由此必须在巯基反应位点筛选中使用PHESELECTOR测定,因为仅晶体结构信息不足以选择这些位点(附图3B和4A)。
巯基反应性数据如附图3A和3B中对4D5ThioFab Cys突变体:(3A)未-生物素化(对照组)和(3B)生物素化的噬菌体-ThioFabs的氨基酸残基所示。通过对未-生物素化的噬菌体-hu4D5Fabv8(3A)和生物素化的噬菌体-hu4D5Fabv8(3B)与BSA(空心条)、HER2(灰色条)或链霉抗生物素(实心条)相互作用的PHESELECTOR测定分析鉴定抗体/Fab上的反应性巯基。如实施例2中所述进行测定。轻链变体位于左侧,而重链变体位于右侧。未-生物素化的4D5ThioFab Cys突变体的结合如所预计的低,但与HER2的强力结合得到保持。与链霉抗生物素和与生物素化的4D5ThioFab Cys突变体的HER2结合比得到表2中的巯基反应值。在450nm处的背景吸光度或生物素化的4D5ThioFab Cys突变体与BSA的少量非特异性蛋白结合也在附图3B中显而易见。被Cys残基替代的选择的氨基酸残基的表面可接近分数值如附图4A中所示。根据可得到的hu4D5Fabv7结构计算表面可接近分数并且显示在表1上(Eigenbrot等(1993)J Mol Biol.229:969-995)。hu4D5Fabv7和hu4D5Fabv8结构的构象参数高度一致并且能够测定hu4D5Fabv7的表面可接近分数计算与hu4D5Fabv8半胱氨酸突变体的巯基反应性之间的任何相关性。在部分暴露的残基(Ala或Val)上引入的噬菌体ThioFab Cys残基的经测定的巯基反应性具有优于在Ser残基上引入的Cys残基巯基反应性(表2)。从来自表2的ThioFab Cys突变体中可以观察到在巯基反应性值与表面可接近分数之间几乎没有或无相关性。
抗体的L-15、L-43、L-110、L-144、L-168、H-40、H-88、H-119、H-121、H-122、H-175和H-179位置上的氨基酸一般可以被游离半胱氨酸氨基酸突变(替代)。在这些位置的每侧上约5个氨基酸残基内的范围也可以被游离半胱氨酸替代,即L-10-L-20;L-38-L-48;L-105-L-115;L-139-L-149;L-163-L-173;H-35-H-45;H-83-H-93;H-114-H-127;和H-170-H-184,以及选自下列的Fc区的范围内:H-268-H-291;H-319-H-344;H-370-H-380;和H-395-H-405,从而得到本发明的半胱氨酸改造的抗体。
表2.噬菌体-ThioFabs的巯基反应性
L=轻链,H=重链,A=丙氨酸,S=丝氨酸,V=缬氨酸,C=半胱氨酸
*将巯基反应性测定为链霉抗生物素结合的OD450nm与HER2(抗体)结合的OD450nm之比(实施例2)。巯基反应性值为1表示半胱氨酸巯基的完全生物素化。
选择两种来自轻链的Cys变体(L-V15C和L-V110C)和两种来自重链的Cys变体(H-A88C和H-A121C)用于进一步分析,因为这些变体表现出最高的巯基反应性(表2)。
不同于噬菌体纯化,Fab制备可能需要2-3天,这取决于生产规模。在此期间,因氧化而导致巯基反应性丧失。为了探测hu4D5Fabv8-噬菌体上巯基的稳定性,测定了噬菌体-thioFabs的巯基反应性的稳定性(附图4B)。在第1天、第2天和第4天进行ThioFab-噬菌体纯化后,使所有样品与生物素-PEO-马来酰亚胺偶联并且用噬菌体ELISA测定法(PHESELECTOR)探测以测试HER2和链霉抗生物素结合。L-V15C、L-V110C、H-A88C和H-A121C与其它ThioFab变体相比保持了显著的巯基反应性(附图4B)。
标记的半胱氨酸改造的抗体
本发明的半胱氨酸改造的抗体可以与任意标记部分(label moiety)偶联,所述的标记部分可以通过反应性半胱氨酸巯基与该抗体共价结合(Singh等(2002)Anal.Biochem.304:147-15;Harlow E.和Lane,D.(1999)UsingAntibody:A Laboratory Manual,Cold Springs Harbor Laboratory Press,ColdSpring Harbor,NY;Lundblad R.L.(1991)Chemical试剂for ProteinModification,2nd ed.CRC Press,Boca Raton,FL)。结合的标记可以起如下作用:(i)提供可检测标记信号;(ii)与第二种标记发生相互作用以改变由第一种或第二种标记提供的可检测信号,例如得到FRET(荧光共振能量转移);(iii)使相互作用稳定或增加与抗原或配体的结合亲和力;(iv)通过电荷、亲水性、形状或其它物理参数影响运动性,例如电泳迁移率或细胞渗透性;或(v)提供俘获部分(capture moiety),以调节配体亲和力、抗体/抗原结合或离子络合。
标记的半胱氨酸改造的抗体可以用于诊断试验,例如用于检测所关注抗原在特异性细胞、组织或血清中的表达。就诊断应用而言,一般用可检测部分标记该抗体。可利用大量标记,一般可以将它们分成如下类:
(a)放射性同位素(放射性核素),诸如3H、11C、14C、18F、32P、35S、64Cu、68Ga、86Y、99Tc、111In、123I、124I、125I、131I、133Xe、177Lu、211At、或213Bi。放射性同位素标记的抗体用于受体靶向的成像实验。可以使用CurrentProtocols in Immunology,Volumes 1和2,Coligen等,Ed.Wiley-Interscience,New York,NY,Pubs.(1991)中所述的技术用配体试剂标记抗体,所述配体试剂结合、螯合乃至复合放射性同位素金属,其中所述试剂与改造的抗体的半胱氨酸巯基反应。可以复合金属离子的螯合配体包括DOTA、DOTP、DOTMA、DTPA和TETA(Macrocyclics,Dallas,TX)。可以通过与本发明的抗体-药物偶联物复合靶向放射性核素(Wu等(2005)Nature Biotechnology23(9):1137-1146)。
如下文献披露了用于成像实验的适合于作为抗体标记的金属-螯合物复合物:US 5342606;US 5428155;US 5316757;US 5480990;US 5462725;US 5428139;US 5385893;US 5739294;US 5750660;US 5834456;Hnatowich等(1983)J.Immunol.Methods 65:147-157;Meares等(1984)Anal.Biochem.142:68-78;Mirzadeh等(1990)Bioconjugate Chem.1:59-65;Meares等(1990)J.Cancer1990,Suppl.10:21-26;Izard等(1992)Bioconjugate Chem.3:346-350;Nikula等(1995)Nucl.Med.Biol.22:387-90;Camera等(1993)Nucl.Med.Biol.20:955-62;Kukis等(1998)J.Nucl.Med.39:2105-2110;Verel等(2003)J.Nucl.Med.44:1663-1670;Camera等(1994)J.Nucl.Med.21:640-646;Ruegg等(1990)Cancer Res.50:4221-4226;Verel等(2003)J.Nucl.Med.44:1663-1670;Lee等(2001)Cancer Res.61:4474-4482;Mitchell,等(2003)J.Nucl.Med.44:1105-1112;Kobayashi等(1999)Bioconjugate Chem.10:103-111;Miederer等(2004)J.Nucl.Med.45:129-137;DeNardo等(1998)Clinical Cancer Research4:2483-90;Blend等(2003)Cancer Biotherapy&Radiopharmaceuticals18:355-363;Nikula等(1999)J.Nucl.Med.40:166-76;Kobayashi等(1998)J.Nucl.Med.39:829-36;Mardirossian等(1993)Nucl.Med.Biol.20:65-74;Roselli等(1999)Cancer Biotherapy&Radiopharmaceuticals,14:209-20。
(b)荧光标记,诸如稀土元素螯合物(铕螯合物);荧光素类,包括FITC、5-羧基荧光素、6-羧基荧光素;若丹明类,包括TAMRA;丹酰;丽丝胺(Lissamine);花青(cyanines);藻红蛋白;德克萨斯红;及其类似物。例如,可以使用同上文的Current Protocols in Immunology中披露的技术使荧光标记与抗体偶联。荧光染料和荧光标记试剂包括商购自Invitrogen/MolecularProbes(Eugene,OR)和Pierce Biotechnology,Inc.(Rockford,IL)的那些荧光染料和荧光标记试剂。
(c)各种酶-底物标记为可得到的或披露的(US 4275149)。酶一般催化可以使用各种技术测定的显色底物的化学改变。例如,酶可催化底物中的颜色改变,而这种改变可以通过分光光度法测定。或者,酶可以改变底物的荧光或化学发光。用于定量荧光改变的技术如上所述。化学发光底物通过化学反应变成电激发的且然后可以发射可测定的光(例如使用化学发光计)或给荧光接受器提供能量。酶促标记的实例包括:荧光素酶(例如荧火虫荧光素酶和细菌荧光素酶;US 4737456);萤光素;2,3-二酞嗪二酮类;苹果酸脱氢酶;尿素酶;过氧化物酶,诸如辣根过氧化物酶(HRP);碱性磷酸酶(AP);β-半乳糖苷酶;葡萄糖淀粉酶;溶菌酶;糖氧化酶(例如葡萄糖氧化酶、半乳糖氧化酶和葡萄糖-6-磷酸脱氢酶);杂环氧化酶(诸如尿酸酶和黄嘌呤氧化酶);乳过氧化物酶;微过氧化物酶等。用于使酶与抗体偶联的技术描述在O′Sullivan等(1981)“Methods for the Preparation of Enzyme-Antibody Cojugatefor use in Enzyme Immunoassay”:Methods in Enzym.(ed J.Langone & H.VanVunakis),Academic Press,New York,73:147-166中。
酶-底物组合的实例包括,例如:
(i)辣根过氧化物酶(HRP)与作为底物的过氧化氢酶,其中过氧化氢酶氧化染料前体(例如邻苯二胺(OPD)或3,3′,5,5′-四甲基联苯胺盐酸盐(TMB));
(ii)碱性磷酸酶(AP)与作为显色底物的磷酸对-硝基苯基酯;和
(iii)β-D-半乳糖苷酶(β-D-Gal)与显色底物(例如对-硝基苯基-β-D-半乳糖苷酶)或荧光底物4-甲基伞形基(umbelliferyl)-β-D-半乳糖苷酶。
大量的其它酶-底物组合为本领域技术人员可得到的。就一般性综述而言,参见US 4275149和US 4318980。
标记可以与半胱氨酸改造的抗体间接偶联。例如,抗体可以与生物素偶联,并且上述三大类标记中的任意类可以与抗生物素蛋白或链霉抗生物素偶联,或反之亦然。生物素选择性地结合链霉抗生物素,且由此标记可以按照这种间接方式与抗体偶联。或者,为了实现标记与多肽变体的间接偶联,使多肽变体与小的半抗原(例如地高辛)偶联并且上述不同类型标记之一与抗-半抗原多肽变体偶联(例如抗-地高辛抗体)。因此,可以实现标记与多肽变体的间接偶联(Hermanson,G.(1996)in Biocojugate Techniques Academic Press,San Diego)。
本发明的多肽变体可以用于任意已知的测定方法中,诸如ELISA、竞争性结合测定法、直接和间接夹心式测定法和免疫沉淀测定法(Zola,(1987)Monoclonal Antibodies:A Manual of Techniques,pp.147-158,CRC Press,Inc.).
检测标记可以用于定位、显影和定量结合或识别结果。本发明标记的抗体可以检测细胞-表面受体。另一种用于检测标记的抗体的应用在于基于珠的免疫俘获,包含使珠与荧光标记的抗体偶联并且检测配体结合时的荧光信号。类似的结合检测方法使用表面等离子共振(SPR)效应以测定和检测抗体-抗原相互作用。
检测标记,诸如荧光染料和化学发光染料(Briggs等(1997)"Synthesis ofFunctionalised Fluorescent Dyes和Their Coupling to Amines and Amino acids,"J.Chem.Soc.,Perkin-Trans.1:1051-1058)提供了可检测信号并且一般应用于标记抗体,这些抗体优选具有如下特性:(i)标记的抗体应产生极高的信号与低背景,使得可以在无细胞和基于细胞的试验中灵敏地检测少量抗体;和(ii)标记的抗体应是光稳定的,以便可以观察、监测和记录荧光信号,而无显著的光漂白。就涉及标记抗体与膜或细胞表面,尤其是活细胞的细胞表面结合的应用而言,标记优选(iii)具有良好的水溶性以便获得有效偶联物浓度和检测灵敏度和(iv)对活细胞无毒性,以便不会破坏细胞的正常代谢过程或导致过早细胞死亡。
可以使用一种系统(8100HTS System,Applied Biosystems,Foster City,Calif.)对荧光标记的事件,例如肽-染料偶联物的细胞表面结合的细胞荧光强度和计数进行直接定量,该系统可使应用活细胞或珠的混合-和-读取非放射性试验自动化(Miraglia,"Homogeneous cell-and bead-based assaysfor high throughput screening using fluorometric microvolume assaytechnology",(1999)J.of Biomolecular Screening 4:193-204)。标记抗体的应用还包括细胞表面受体结合测定、免疫俘获测定、荧光连接的免疫吸附测定(FLISA)、胱天蛋白酶-裂解(Zheng,"Caspase-3controls both cytoplasmic andnuclear events associated with Fas-mediated apoptosis in vivo",(1998)Proc.Natl.Acad.Sci.USA 95:618-23;US 6372907)、程序性细胞死亡(Vermes,"A novelassay for apoptosis.Flow cytometric detection of phosphatidylserine expressionon early apoptotic cell using fluorescein labelled Annexin V"(1995)J.Immunol.Methods 184:39-51)和细胞毒性测定。荧光微容量测定技术可以用于鉴定靶向至细胞表面的分子的增量调节或减量调节(Swartzman,"A homogeneous andmultiplexed immunoassay for high-throughput screening using fluorometricmicrovolume assay technology",(1999)Anal.Biochem.271:143-51)。
本发明标记的半胱氨酸改造的抗体用作生物医学和分子成像的各种方法和技术的成像生物标记物和探针,所述的方法和技术诸如:(i)MRI(磁共振成像);(ii)MicroCT(电子计算机化断层x线摄影法);(iii)SPECT(单光子发射计算机断层术);(iv)PET(正电子发射断层照相术)Chen等(2004)Bioconjugate Chem.15:41-49;(v)生物发光;(vi)荧光;和(vii)超声。免疫闪烁成像为一种成像方法,其中将放射性物质标记的抗体给予动物或人体患者并且取抗体定位的部位的图像(US 6528624)。可以客观测定成像生物标记物并且作为正常生理过程、病理过程或对治疗干预的药理反应的指示评价。生物标记物可以具有几种类型:0型为疾病的天然历史标记物并且与已知的临床指标纵向相关,例如类风湿性关节炎中滑液炎症的MRI评价;I型标记俘获按照作用机制干预的作用,即使该机制与临床结果无关;II型标记作为替代终点(surrogate endpoint)起作用,其中生物标记的改变或信号预测临床有益性以便“验证”靶向的反应,诸如通过CT在类风湿性关节炎中测定的骨质侵蚀。成像生物标记物由此可以提供有关下列的药效(PD)治疗信息:(i)靶蛋白的表达;(ii)治疗剂与靶蛋白的结合,即选择性;和(iii)清除和半衰期药代动力学数据。与基于实验室的生物标记物有关的体内成像生物标记物的优点包括:非-侵害性治疗;可定量;整体评价;重复给药和评价,即多时间点;和从前期临床(小动物)到临床(人)结果的潜在可转移的作用。就某些应用而言,生物成像替代了前期临床研究中的动物实验或将其次数减少到了最低限度。
放射性核素成像标记包括放射性核素,诸如3H、11C、14C、18F、32P、35S、64Cu、68Ga、86Y、99Tc、111In、123I、124I、125I、131I、133Xe、177Lu、211At或213Bi。放射性核素的金属离子可以与螯合连接剂,诸如DOTA复合。可以按照Axworthy等(2000)Proc.Natl.Acad.Sci.USA 97(4):1802-1807)的操作步骤,通过使氨基苄基-DOTA与用异丙基氯甲酸酯(Aldrich)活化的4-马来酰亚氨基丁酸(Fluka)反应制备连接基试剂,诸如DOTA-马来酰亚胺(4-马来酰亚氨基丁酰氨基苄基-DOTA)。DOTA-马来酰亚胺试剂与半胱氨酸改造的抗体的游离半胱氨酸氨基酸反应并且得到抗体上的金属复合配体(Lewis等(1998)Bioconj.Chem.9:72-86)。螯合连接基标记试剂,诸如DOTA-NHS(1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸一(N-羟基琥珀酰亚胺酯)为商购的(Macrocyclics,Dallas,TX)。使用放射性核素标记的抗体成像的受体靶标可以通过检测和定量肿瘤组织中抗体的进行性蓄积提供活化途径标记(Albert等(1998)Bioorg.Med.Chem.Lett.8:1207-1210)。偶联的放射性-金属可以在溶酶体降解后保留在胞内。
肽标记方法为众所周知的。参见Haugland,2003,Molecular ProbesHandbook of Fluorescent Probes and Research Chemicals,Molecular Probes,Inc.;Brinkley,1992,Bioconjugate Chem.3:2;Garman,(1997)Non-RadioactiveLabelling:A Practical Approach,Academic Press,London;Means(1990)Biogconjugate Chem.1:2;Glazer等(1975)Chemical Modification of Proteins.Laboratory Techniques in Biochemistry和Molecular Biology(T.S.Work和E.Work,Eds.)American Elsevier Publishing Co.,New York;Lundblad,R.L.和Noyes,C.M.(1984)Chemical Reagents for Protein Modification,Vols.I和II,CRC Press,New York;Pfleiderer,G.(1985)“Chemical Modification ofProteins”,Modern Methods in Protein Chemistry,H.Tschesche,Ed.,WalterDeGryter,Berlin和New York;和Wong(1991)Chemistry of ProteinConjugation and Cross-linking,CRC Press,Boca Raton,Fla.);DeLeon-Rodriguez等(2004)Chem.Eur.J.10:1149-1155;Lewis等(2001)Bioconjugate Chem.12:320-324;Li等(2002)Bioconjugate Chem.13:110-115;Mier等(2005)Bioconjugate Chem.16:240-237。
使用两部分,即荧光报道基团和猝灭物标记的肽类和蛋白质能够充分近似地进行荧光共振能量转移(FRET)。报道基团一般为由一定波长的光激发的荧光染料并且可以将能量转移至接受或猝灭基团,其中对于在最大亮度时发射而言存在适当的Stokes偏移。荧光染料包括具有延长的芳香性的分子,诸如荧光素和若丹明及其衍生物。可以通过完整肽的猝灭物部分部分或明显地使荧光报道分子猝灭。在通过肽酶或蛋白酶裂解肽时,可以测定荧光中的可检测到的增加(Knight,C.(1995)“Fluorimetric Assays of Proteolytic Enzymes”,Methods in Enzymology,Academic Press,248:18-34)。
还可以将本发明标记的抗体用作亲和纯化试剂。在该方法中,使用本领域众所周知的方法将标记的抗体固定在固相上,诸如Sephadex树脂或滤纸上。使固定化抗体与含有预纯化的抗原的样品接触,且此后用可基本上除去样品中除预纯化的抗原外的所有物质的适当溶剂洗涤支持物,所述抗原与固定的多肽变体结合。最终用另一种合适的溶剂,诸如pH 5.0的甘氨酸缓冲液洗涤支持物,该溶剂能够使所述抗原从所述多肽变体中释放。
标记试剂一般具有反应性官能基,它可以与:(i)半胱氨酸改造的抗体的半胱氨酸巯基直接反应而形成标记的抗体;(ii)与连接基试剂反应而形成连接基-标记中间体;或(iii)与连接基抗体反应而形成标记的抗体。标记试剂的反应性官能基包括:马来酰亚胺、卤代乙酰基、碘乙酰胺琥珀酰亚胺基酯(例如NHS,N-羟基琥珀酰亚胺)、异硫氰酸酯、磺酰氯、2,6-二氯三嗪基、五氟苯基酯和亚磷酰胺,不过,也可以使用其它的官能基。
典型的反应性官能基为可检测标记,例如生物素或荧光染料的羧基取代基的N-羟基琥珀酰亚胺基酯(NHS)。可以形成、分离、纯化和/或表征标记的NHS酯,或它可以在原位形成并且与抗体的亲核基团反应。一般而言,通过与某些碳二亚胺试剂的组合反应活化标记的羧基形式,所述的碳二亚胺试剂例如:二环己基碳二亚胺、二异丙基碳二亚胺或脲鎓试剂,例如TSTU(O-(N-琥珀酰亚胺基)-N,N,N’,N’-四甲基脲鎓四氟硼酸盐(酯)、HBTU(O-苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(酯))或HATU(O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(酯));活化剂,诸如1-羟基苯并三唑(HOBt)和N-羟基琥珀酰亚胺,从而得到标记的NHS酯。在某些情况中,标记和抗体可以通过标记的原位活化和与抗体反应而偶联以在一步中形成标记-抗体偶联物。其它活化和偶联试剂包括TBTU(2-(1H-苯并三唑-1-基)-1-1,3,3-四甲基脲鎓六氟磷酸盐(酯))、TFFH(N,N’,N”,N’”-四甲基脲鎓2-氟-六氟磷酸盐(酯))、PyBOP(苯并三唑-1-基-氧基-三-吡咯烷-磷鎓六氟磷酸盐(酯)、EEDQ(2-乙氧基-1-乙氧羰基-1,2-二氢-喹啉)、DCC(二环己基碳二亚胺);DIPCDI(二异丙基碳二亚胺)、MSNT(1-(-2-磺酰基)-3-硝基-1H-1,2,4-三唑和芳基磺酰基卤化物,例如三异丙基苯磺酰氯。
生物素-马来酰亚胺与THIOFABS的偶联
在有噬菌体存在下建立上述ThioFab特性,因为Fab与噬菌体包膜蛋白的融合体能够改变Cys巯基可接近性或反应性。因此,将ThioFab构建体在碱性磷酸酶启动子控制下克隆入表达载体(Chang等(1987)Gene 55:189-196)并且通过使大肠杆菌细胞在不含磷酸盐的培养基中生长诱导ThioFab表达。使用蛋白质G SEPHAROSETM柱纯化ThioFabs并且使用还原和非-还原SDS-PAGE凝胶分析。这些分析能够评价ThioFabs是否可以保持其反应性巯基或因形成分子内或分子间二硫键而被失活。通过蛋白质-GSEPHAROSETM柱层析法表达和纯化ThioFabs L-V15C、L-V110C、H-A88C和H-A121C(参见方法的详细描述部分)。使用SDS-PAGE凝胶在还原(使用DTT)和非-还原(不用DTT)条件下分析纯化的蛋白质。其它还原剂,诸如BME(β-巯基乙醇)可以用于凝胶以便裂解链间二硫键。从SDS-PAGE凝胶分析中显而易见ThioFab的主要(~90%)级分为单体形式,而野生型hu4D5Fabv8基本上为单体形式(47kDa)。
将ThioFab(A121C)和野生型hu4D5Fabv8与100倍过量的生物素-马来酰亚胺一起在室温温育3小时并且使生物素化的Fabs上样至Superdex-200TM凝胶过滤柱。该纯化步骤用于从寡聚化Fab并且还从过量的游离生物素-马来酰亚胺(或游离细胞毒性药物)中分离单体Fab。
附图5表示在没有噬菌体背景存在下ThioFab变体特性的验证。表达不含噬菌体融合体、hu4D5Fabv8和hu4D5Fabv8-A121C(ThioFab-A121C)的蛋白质并且使用蛋白质-G琼脂糖柱纯化,随后与100倍摩尔过量的生物素-马来酰亚胺一起温育。比较生物素化的cys改造的ThioFab和未-生物素化的野生型Fab的链霉抗生物素和HER2结合。通过ELISA分析监测生物素偶联程度(与链霉抗生物素相互作用)及其与HER2的结合能力。以2ng和20ng测试每种Fab。
生物素化的A121C ThioFab保持与野生型hu4D5Fabv8相差无几的HER2结合性(附图5)。通过凝胶过滤柱层析法纯化野生型Fab和A121C-ThioFab。通过ELISA,使用山羊抗-Fab-HRP作为二抗测试两种样品的HER2和链霉抗生物素结合性。野生型(空心条)和ThioFab(带虚线的条)均具有与HER2的类似结合性,但仅ThioFab保持链霉抗生物素结合性。使用未-生物素化的野生型hu4D5Fabv8仅观察到与链霉抗生物素背景水平的相互作用(附图5)。对生物素化-ThioFab(A121C)的质谱(LC-ESI-MS)分析产生了与野生型hu4D5Fabv8(47737道尔顿)相比具有48294.5道尔顿的主峰。在两种分子之间存在537.5道尔顿差正相当于与ThioFab偶联的单一生物素-马来酰亚胺。质谱蛋白质测序(LC-ESI-串联质谱分析(LC-ESI-Tandem massspec analysis))结果进一步证实了偶联的生物素分子是在新改造的Cys残基上(表4,实施例3)。
生物素-马来酰亚胺与清蛋白结合肽(ABP)-THIOFABS的位点特异性偶
联
血浆蛋白结合可以为改善短寿命分子的药代动力学特性的有效方式。清蛋白为血浆中最丰富的蛋白质。血清清蛋白结合肽类(ABP)可以改变融合的活性结构域蛋白的药效学特性,包括组织摄取、渗透和扩散的改变。可以通过特异性选择合适的血清清蛋白结合肽序列调节这些药效学参数(US20040001827)。通过噬菌体展示筛选鉴定一系列清蛋白结合肽(Dennis等(2002)“Albumin Binding As A General Strategy For Improving ThePharmacokinetics Of Proteins”J Biol Chem.277:35035-35043;WO 01/45746)。本发明的化合物包括由下列文献中教导的ABP序列:(i)Dennis等(2002)JBiol Chem.277:35035-35043,表III和IV,35038页;(ii)US 20040001827,[0076]SEQ ID NOS:9-22;和(iii)WO 01/45746,12-13页,SEQ ID NOS:z1-z14,并且将所有这些文献引入本文作为参考。
通过按照1:1(1ABP/1Fab)化学计算比融合清蛋白结合肽与Fab重链的C-末端改造清蛋白结合(ABP)-Fabs。经证实这些ABP-Fabs与清蛋白结合将其在兔和小鼠中的半衰期增加了25倍以上。由此可以将上述反应性Cys残基引入这些ABP-Fabs并且用于与细胞毒性药物的位点-特异性偶联,随后进行体内动物研究。附图9表示图解的清蛋白结合肽-Fab融合体(ABP-Fab)连接基药物偶联物。
典型的清蛋白结合肽序列包括,但不限于SEQ ID NOS:1-5中所列的氨基酸序列:
清蛋白结合肽(ABP)序列结合来自多物种(小鼠、大鼠、兔、牛、猕猴、狒狒和人)的清蛋白,具有的Kd(兔)=0.3μM。清蛋白结合肽不与已知配体竞争性结合清蛋白并且在兔中具有的半衰期(T1/2)为2.3小时。如上述部分中所述使用BSA-SEPHAROSETM纯化ABP-ThioFab蛋白,随后进行生物素-马来酰亚胺偶联并且使用Superdex-S200柱层析法纯化。纯化的生物素化的蛋白质为均一性的(homogeneous)并且无任何寡聚化形式(实施例4)。
附图6表示清蛋白结合肽(ABP)-ThioFab变体的特性。进行ELISA分析以测试ABP-hu4D5Fabv8-wt、ABP-hu4D5Fabv8-V110C和ABP-hu4D5Fabv8-A121C与兔清蛋白、链霉抗生物素和HER2的结合能力。生物素化的ABP-ThioFabs能够以与野生型ABP-hu4D5Fabv8相似的亲和力结合清蛋白和HER2,正如通过ELISA(附图6)和BIAcore结合动力学分析(表3)所证实的。如所述的给ELISA平板包被清蛋白、HER2和SA。用抗-Fab HRP探测生物素化的ABP-ThioFabs与清蛋白、HER2和SA的结合。与非生物素化的对照ABP-hu4D5Fabv8-wt相比,生物素化的ABP-ThioFabs能够结合链霉抗生物素,这表明ABP-ThioFabs与生物素马来酰亚胺类ThioFabs以位点特异性方式偶联,因为相同的Cys突变体用于两种变体(附图6)。
表3.生物素化的ABP-hu4D5Fabv8野生型和ThioFabs结合HER2和兔清蛋白的BIAcore动力学分析
抗体 | kon(M-1s-1) | koff(s-1) | Kd(nM) |
HER2结合 | |||
野生型 | 4.57x105 | 4.19x10-5 | 0.0917 |
V110C | 4.18x105 | 4.05x10-5 | 0.097 |
A121C | 3.91x105 | 4.15x10-5 | 0.106 |
兔清蛋白结合 | |||
野生型 | 1.66x105 | 0.0206 | 124 |
V110C | 2.43x105 | 0.0331 | 136 |
A121C | 1.70x105 | 0.0238 | 140 |
ABP=清蛋白结合肽
或者,可以通过经连接基部分的共价结合使清蛋白-结合肽与抗体连接。
每个FAB使用两个游离巯基对ABP-THIOFABS改造
上述结果表明所有四种(L-V15C、L-V110C、H-A88C和H-A121C)thioFab(半胱氨酸改造的Fab抗体)变体具有可以用于与标记试剂、连接基试剂或药物-连接基中间体的位点特异性偶联的反应性巯基。可以表达和纯化L-V15C,但产率相对低。然而,L-V110C、H-A88C和H-A121C变体的表达和纯化产率与hu4D5Fabv8的类似。因此,这些突变体可以用于进一步分析并且重组成每个Fab中有一个以上巯基。为了这一目的,构建轻链上的一个巯基和重链上的一个巯基以获得每个Fab分子中有两个巯基(L-V110C/H-A88C和L-V110C/H-A121C)。在大肠杆菌表达系统中表达这两种双Cys变体并且纯化。发现纯化的生物素化的ABP-ThioFabs的均一性(homogeneity)与单Cys变体的均一性类似。
研究每个Fab中改造两个反应性Cys残基的作用(附图7)。通过使用链霉抗生物素-HRP探测生物素化的ABP-ThioFab与SA的结合测试第二生物素的存在(附图7)。为了进行HER2/Fab分析,用HER2包被ELISA平板并且使用抗-Fab HRP探测。为了进行SA/Fab分析,用SA包被ELISA平板并且用抗-Fab HRP探测,为了进行SA/SA分析,用SA包被ELISA平板并且用SA-HRP探测。附图7。ELISA分析了生物素化的ABP-hu4D5Fabv8cys变体与HER2、链霉抗生物素(SA)的相互作用。HER2/Fab、SA/Fab和SA/SA分别表示通过抗-Fab-HRP、SA-HRP监测其相互作用。SA/Fab监测每个Fab中存在的单一生物素并且通过SA/SA分析监测每个Fab的一个以上生物素。HER2与双cys突变体结合与单Cys变体类似(附图7)。然而,双Cys突变体上生物素化程度高于单Cys变体,这是因每个Fab分子中有一个以上游离巯基所致(附图7)。
曲妥单抗的thioIgG变体的改造
将半胱氨酸引入全长单克隆抗体曲妥单抗(GenentechInc.)的某些残基上。通过在含有1mM半胱氨酸的培养基中瞬时发酵在CHO(中国仓鼠卵巢)细胞中表达曲妥单抗的单cys突变体H-A88C、H-A121C和L-V110C和曲妥单抗的双cys突变体V110C-A121C和V110C-A121C。A88C突变体重链序列(450aa)为SEQ ID NO:6。A121C突变体重链序列(450aa)为SEQ ID NO:7。V110C突变体轻链序列(214aa)为SEQ ID NO:8。
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRCEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:6
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSCSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:7
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTCAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:8
按照一个实施方案,半胱氨酸改造的thio-曲妥单抗抗体包含下列具有游离半胱氨酸氨基酸的可变区重链序列(SEQ ID NOS:9-1 6)中的一种或多种。
突变体 | 序列 | SEQ ID NO: |
A40C | WVRQCPGKGL | SEQ ID NO:9 |
A88C | NSLRCEDTAV | SEQ ID NO:10 |
S119C | LVTVCSASTKGPS | SEQ ID NO:11 |
S120C | LVTVSCASTKGPS | SEQ ID NO:12 |
A121C | LVTVSSCSTKGPS | SEQ ID NO:13 |
S122C | LVTVSSACTKGPS | SEQ ID NO:14 |
A175C | HTFPCVLQSSGLYS | SEQ ID NO:15 |
S179C | HTFPAVLQCSGLYS | SEQ ID NO:16 |
按照另一个实施方案,半胱氨酸改造的硫代-曲妥单抗抗体包含下列具有游离半胱氨酸氨基酸的可变区轻链序列(SEQ ID NOS:17-27)中的一种或多种。
突变体 | 序列 | SEQ ID NO: |
V15C | SLSASCGDRVT | SEQ ID NO:17 |
A43C | QKPGKCPKLLI | SEQ ID NO:18 |
V110C | EIKRTCAAPSV | SEQ ID NO:19 |
S114C | TCAAPCVFIFPP | SEQ ID NO:20 |
S121C | FIFPPCDEQLK | SEQ ID NO:21 |
S127C | DEQLKCGTASV | SEQ ID NO:22 |
A144C | FYPRECKVQWK | SEQ ID NO:23 |
A153C | WKVDNCLQSGN | SEQ ID NO:24 |
N158C | ALQSGCSQESV | SEQ ID NO:25 |
S168C | VTEQDCKDSTY | SEQ ID NO:26 |
V205C | GLSSPCTKSFN | SEQ ID NO:27 |
检测所得全长硫代-曲妥单抗IgG变体的巯基反应性和HER2结合活性。附图13A表示生物素化抗体结合固定化HER2和HRP标记的用于吸光度检测的二抗的卡通画描绘。附图13B表示在450nm处对下列(左至右)物质进行吸光度检测的与固定化HER2的结合测定值:非-生物素化的野生型曲妥单抗(Wt)、生物素-马来酰亚胺偶联的硫代-曲妥单抗变体V110C(单cys)、A121C(单cys)和V110C-A121C(双cys)。在1、10和100ng测试每种thioIgG变体和曲妥单抗。测定值表示生物素化的抗-HER2ThioMabs保持HER2结合活性。
附图14A表示结合固定化HER2的生物素化抗体在用于吸光度检测的生物素与抗-IgG-HRP结合方面的卡通图描绘。附图14B表示在450nm检测吸光度的生物素-马来酰亚胺偶联的-硫代曲妥单抗变体和未-生物素化的野生型曲妥单抗在结合链霉抗生物素中的结合测定值。从左至右:V110C(单cys)、A121C(单cys)、V110C/A121C(双cys)和曲妥单抗。在1、10和100ng测试每种thioIgG曲妥单抗变体和亲代曲妥单抗。测定值表示HER2ThioMabs具有高巯基反应性。
将半胱氨酸引入全长2H9抗-EphB2R抗体的某些残基上。通过在含有1mM半胱氨酸的培养基中瞬时发酵在CHO(中国仓鼠卵巢)细胞中表达2H9的单cys突变体H-A121C。A121C 2H9突变体重链序列(450aa)为SEQ IDNO:28。
EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYWMHWVRQAPGKGLEWVGFINPSTGYTDYNQKFKDRFTISADTSKNTAYLQMNSLRAEDTAVYYCTRRPKIPRHANVFWGQGTLVTVSSCSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:28
半胱氨酸改造的thio-2H9抗体包含下列具有游离半胱氨酸氨基酸的Fc恒定区重链序列(SEQ ID NOS:29-38)。
突变体 | 序列 | SEQ ID NO: |
V273C | HEDPECKFNWYVDGVEVHNAKTKPR | SEQ ID NO:29 |
V279C | HEDPEVKFNWYCDGVEVHNAKTKPR | SEQ ID NO:30 |
V282C | HEDPEVKFNWYVDGCEVHNAKTKPR | SEQ ID NO:31 |
V284C | HEDPEVKFNWYVDGVECHNAKTKPR | SEQ ID NO:32 |
A287C | HEDPEVKFNWYVDGVEVHNCKTKPR | SEQ ID NO:33 |
S324C | YKCKVCNKALP | SEQ ID NO:34 |
S337C | IEKTICKAKGQPR | SEQ ID NO:35 |
A339C | IEKTISKCKGQPR | SEQ ID NO:36 |
S375C | KGFYPCDIAVE | SEQ ID NO:37 |
S400C | PPVLDCDGSFF | SEQ ID NO:38 |
附图16表示在固定化蛋白质A上纯化后对2H9ThioMab Fc变体(左至右,泳道1-9)的未-还原(上)和还原(下)变性SDS-PAGE(聚丙烯酰胺凝胶电泳)分析:A339C;S337C;S324C;A287C;V284C;V282C;V279C;和V273C;与2H9野生型。右侧的泳道为大小标志物梯,表明完整蛋白质约为150kDa,重链片段约为50kDa,且轻链片段约为25kDa。附图17A表示在固定化蛋白质A上纯化后对2H9ThioMab Fc变体的未-还原(左)和还原(右)变性聚丙烯酰胺凝胶电泳分析(左至右,泳道1-4):L-V15C;S179C;S375C;S400C。附图17B表示在固定化蛋白质A上纯化后对额外的2H9和3A5ThioMab变体的未-还原(左)和还原(+DTT)(右)变性聚丙烯酰胺凝胶电泳分析。如所述的表达和纯化2H9ThioMab变体(在Fab以及Fc区中)。正如附图16、17A和17B中观察到的,所有蛋白质在SDS-PAGE上均为同质的(homogenous),随后进行实施例11的还原和氧化操作步骤,以制备用于偶联的反应性ThioMabs(实施例12)。
将半胱氨酸引入全长3A5抗-MUC16抗体的某些残基上。通过在含有1mM半胱氨酸的培养基中瞬时发酵在CHO(中国仓鼠卵巢)细胞中表达3A5的单cys突变体H-A121C。A121C 3A5突变体重链序列(446aa)包含SEQ IDNO:39。
DVQLQESGPGLVNPSQSLSLTCTVTGYSITNDYAWNWIRQFPGNKLEWMGYINYSGYTTYNPSLKSRISITRDTSKNQFFLHLNSVTTEDTATYYCARWDGGLTYWGQGTLVTVSACSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ IDNO:39
半胱氨酸改造的thio-3A5抗-MUC16抗体包含下列具有游离半胱氨酸氨基酸(SEQ ID NOS:40-44)的可变区重链序列。
突变体 | 序列 | SEQ ID NO: |
F45C | NWIRQCPGNK | SEQ ID NO:40 |
A90C | LNSCTTEDTAT | SEQ ID NO:41 |
A121C | GQGTLVTVSACSTKGPSVFPL | SEQ ID NO:42 |
A175C | HTFPCVLQSSGLYS | SEQ ID NO:43 |
V176C | HTFPACLQSSGLYS | SEQ ID NO:44 |
半胱氨酸改造的thio-3A5抗-MUC16抗体包含下列具有游离半胱氨酸氨基酸的可变区轻链序列(SEQ ID NOS:45-49)。
突变体 | 序列 | SEQ ID NO: |
L15C | FLSVSCGGRVT | SEQ ID NO:45 |
A43C | QKPGNCPRLLI | SEQ ID NO:46 |
V110C | EIKRTCAAPSV | SEQ ID NO:47 |
A144C | FYPRECKVQWK | SEQ ID NO:48 |
S168C | VTEQDCKDSTY | SEQ ID NO:49 |
THIOMABS的巯基反应性
通过生物素化和链霉抗生物素结合测定全长IgG半胱氨酸改造的抗体(ThioMabs)的巯基反应性。设定蛋白质印迹试验以筛选与生物素-马来酰亚胺特异性偶联的ThioMab。在本试验中,在还原SDS-PAGE上分析抗体并且通过与链霉抗生物素-HRP一起温育特异性探测生物素的存在。正如从附图18中看出的,根据使用哪种改造的cys变体和使用野生型未观察到相互作用的不同,在重链或轻链中观察到了链霉抗生物素-HRP相互作用,表明ThioMab变体特异性偶联改造的Cys残基上的生物素。附图18表示在固定化抗-IgG-HRP(上部凝胶)和链霉抗生物素-HRP(下部凝胶)上俘获后还原的生物素化的Thio-IgG变体的变性凝胶分析。泳道1:3A5H-A121C。泳道2:3A5L-V110C。泳道3:2H9H-A121C。泳道4:2H9L-V110C。泳道5:抗-EphB2R 2H9亲代野生型。通过使用HRP检测(上部),使用抗-IgG俘获每种突变体(泳道1-4),表明保持了选择性和亲和力。通过使用HRP检测(下部)固定化链霉抗生物素的俘获证实了生物素在重链和轻链上的位置。在泳道1和3中半胱氨酸改造的抗体上的半胱氨酸突变位置为重链。在泳道2和4中半胱氨酸改造的抗体上的半胱氨酸突变位置为轻链。半胱氨酸突变位点经历与生物素-马来酰亚胺试剂的偶联。
LC/MS对附图18的ThioMab半胱氨酸改造的抗体和2H9V15C变体的分析给出了对巯基反应性的定量表示(表5).
表5 ThioMabs的生物素化的LC/MS定量-巯基反应性
ThioMab变体 | 每个ThioMab中生物素的数量 |
2H9wt | 0.0 |
2H9L-V15C | 0.6 |
2H9L-V110C | 0.5 |
2H9H-A121C | 2.0 |
3A5L-V110C | 1.0 |
3A5H-A121C | 2.0 |
半胱氨酸改造在IgG抗体的恒定域,即Fc区中进行。将多种氨基酸位点转化成半胱氨酸位点并且评价表达的突变体,即半胱氨酸改造的抗体的巯基反应性。在ELISA测定法中通过HRP定量,经在固定化链霉抗生物素俘获评价生物素化的2H9ThioMab Fc变体的巯基反应性(附图19)。建立快速筛选具有反应性巯基的Cys残基的ELISA测定法。正如附图19的示意图中所示,通过用抗-IgG-HRP探测,随后在450nm处测定吸光度监测链霉抗生物素-生物素相互作用。这些结果证实2H9-ThioFc变体V282C、A287C、A339C、S375C和S400C具有中度到最高的巯基反应性。通过如表6中报导的LS/MS分析对2H9ThioMab Fc变体的生物素偶联程度定量。LS/MS分析证实A282C、S375C和S400C变体具有100%生物素偶联且V284C和A339C具有50%的偶联,表明存在反应性半胱氨酸巯基。其它ThioFc变体和亲代野生型2H9有极弱的生物素化或没有生物素化。
表6 2H9Fc ThioMabs的生物所化的LC/MS定量
2H9ThioMab Fc变体 | 生物素化% |
V273C | 0 |
V279C | 31 |
V282C | 100 |
V284C | 50 |
A287C | 0 |
S324C | 71 |
S337C | 0 |
A339C | 54 |
S375C | 100 |
S400C | 100 |
(野生型2H9) | 0 |
THIO-4D5FAB轻链变体的巯基反应性
正如通过附图8的PHESELECTOR测定法测定的,筛选抗ErbB2抗体4D5的多种半胱氨酸改造的轻链变体Fabs得到了大量具有0.6和0.6以上巯基反应值的变体(表7)。将表7的巯基反应值对设定为100%的重链4D5ThioFab变体(HC-A121C)校准,推定HC-A121C变体完全生物素化并且表示为百分比值。
表7 4D5ThioFab轻链变体的巯基反应性百分比值
4D5ThioFab变体 | 巯基反应值(%) |
V15C | 100 |
V110C | 95 |
S114C | 78 |
S121C | 75 |
S127C | 75 |
A153C | 82 |
N158C | 77 |
V205C | 78 |
(HC-A121C) | 100 |
(4D5野生型) | 25 |
抗体-药物偶联物
本发明的半胱氨酸改造的抗体可以与任意的治疗剂,即药物部分偶联,所述的治疗剂可以通过反应性半胱氨酸巯基与抗体共价结合。
抗体-药物偶联物(ADC)化合物的典型实施方案包含半胱氨酸改造的抗体(Ab)和药物部分(D),其中抗体具有一个或多个具有0.6-1.0的巯基反应值的游离半胱氨酸氨基酸,并且抗体通过连接D的连接基部分(L)与一个或多个游离半胱氨酸氨基酸附着(结合);该组成具有式I:
Ab-(L-D)p I
其中p为1、2、3或4。可以通过巯基反应连接基部分与抗体分子偶联的药物部分的数量受到通过本文所述方法引入的半胱氨酸残基数量的限制。式I的典型ADC由此包含具有1、2、3或4个改造的半胱氨酸氨基酸的抗体。
抗体-药物偶联物化合物(ADC)的另一个典型实施方案包含半胱氨酸改造的抗体(Ab)、清蛋白-结合肽(ABP)和药物部分(D),其中抗体通过连接基部分(L)与药物部分结合并且抗体通过酰胺键或第二种连接基部分与清蛋白-结合肽结合;该组成具有式Ia:
ABP-Ab-(L-D)p Ia
其中p为1、2、3或4。
本发明的ADC化合物包括那些用于抗癌活性的化合物。特别地,化合物包括与药物部分,即毒素,通过连接基与之偶联,即与之共价结合的半胱氨酸-改造的抗体。当所述药物不与抗体偶联时,药物具有细胞毒性或抑制细胞效应。由此通过与抗体偶联调节药物部分的生物活性。本发明的抗体-药物偶联物(ADC)将有效剂量的细胞毒性剂选择性地递送至肿瘤组织,由此可以获得更大的选择性,即较低的效应剂量(efficacious dose)。
在一个实施方案中,当与包含ADC的药物部分的药物化合物比较时,本发明ADC的生物利用度或ADC的胞内代谢在哺乳动物中得到改善。此外,当与不含药物部分的ADC类似物比较时,ADC的生物利用度或ADC的胞内代谢在哺乳动物中得到改善。
药物部分
抗体-药物偶联物(ADC)的药物部分(D)包括具有细胞毒性或抑制细胞效应的任意化合物、部分(moiety)或基团。药物部分包括:(i)可以起微管蛋白抑制剂、有丝分裂抑制剂、拓扑异构酶抑制剂或DNA嵌入剂作用的化疗剂;(ii)可以通过酶促方式起作用的蛋白毒素;和(iii)放射性同位素。
典型的药物部分包括,但不限于美登木素生物碱、auristatin、多拉司他汀(dolastatin)、单端孢霉烯(trichothecene)、CC1065、加利车霉素(Calicheamicin)和其它烯二炔类(enediyne)抗生素、紫杉烷(taxane)、蒽环类抗生素(anthracycline)及其立体异构体、同电子排列体(isostere)、类似物或衍生物。
适合于用作美登木素生物碱药物部分的美登素化合物为本领域众所周知并且可以按照公知方法分离自天然来源,使用遗传工程技术生产(参见Yu等(2002)PROC.NAT.ACAD.SCI.(USA)99:7968-7973)或按照已知方法通过合成制备的美登醇和美登醇类似物。
典型的美登木素生物碱药物部分包括那些具有修饰的芳族环的化合物,诸如:C-19-去氯(US 4256746)(通过ansamytocin P2的氢化铝锂还原制备);C-20-羟基(或C-20-去甲基)+/-C-19-去氯(US 4361650和4307016)(通过使用链霉菌属(Streptomyces)或放线菌属(Actinomyces)脱甲基化或使用LAH脱氯制备);和C-20-去甲氧基、C-20-酰氧基(-OCOR)、+/-去氯(US4,294,757)(通过使用酰基氯酰化制备)和那些在其它位置上具有修饰的化合物。
典型的美登木素生物碱药物部分还包括那些具有诸如如下修饰的化合物:C-9-SH(US 4424219)(通过使美登醇与H2S或P2S5反应制备);C-14-烷氧基甲基(去甲氧基/CH2OR)(US 4331598);C-14-羟甲基或酰氧基甲基(CH2OH或CH2OAc)(US 4450254)(由Nocardia制备);C-15-羟基/酰氧基(US4364866)(通过由链霉菌属转化美登醇制备);C-15-甲氧基(US 4313946和4315929)(分离自Trewia nudlflora);C-18-N-去甲基(US 4362663和4322348)(通过用链霉菌属使美登醇脱甲基化制备);和4,5-脱氧(US4371533)(通过美登醇的三氯化酞/LAH还原制备)。已知美登素化合物上的许多位置用作连接位置,这取决于连接的类型。例如,为了形成酯键,具有羟基的C-3位、用羟甲基修饰的C-14位、用羟基修饰的C-15位和具有羟基的C-20位均是合适的。
式I的抗体-药物偶联物(ADC)的药物部分(D)包括具有如下结构的美登木素生物碱:
其中波状线表示D的硫原子与抗体-药物偶联物(ADC)的连接基(L)共价结合。R可以独立为H或C1-C6烷基,所述的C1-C6烷基选自甲基、乙基、1-丙基、2-丙基、1-丁基、2-甲基-1-丙基、2-丁基、2-甲基-2-丙基、1-戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基和3,3-二甲基-2-丁基。使酰胺基与硫原子结合的亚烷基链可以为methanyl、乙基(ethanyl)或丙基,即m为1、2或3。
美登素化合物通过抑制有丝分裂过程中的微管蛋白形成抑制细胞增殖,所述的抑制有丝分裂过程中的微管蛋白形成通过抑制微管蛋白,即微管素的聚合来进行(Remillard等(1975)Science 189:1002-1005)。美登素和美登木素生物碱具有高度毒性,但其在癌症疗法中的临床应用因其主要由于对肿瘤的选择性差导致的严重的全身副作用而非常有限。因对中枢神经系统和胃肠系统的严重不良作用而已中断了使用美登素的临床试验(Issel等(1978)Can.Treatment.Rev.5:199-207)。
美登木素生物碱药物部分为抗体-药物偶联物中有吸引力的药物部分,因为它们:(i)相对易于接近以便通过发酵或化学修饰、衍生发酵产物来制备;(ii)易于使用适合于通过非二硫化物连接基与抗体偶联的官能基衍生;(iii)在血浆中稳定;和(iv)对多种肿瘤细胞系有效(US 2005/0169933;WO2005/037992;US 5208020)。
作为其它药物部分,对本发明的化合物而言,关注美登木素生物碱药物部分的所有立体异构体,即在D的手性碳上的R和S构型的任意组合。在一个实施方案中,美登木素生物碱药物部分(D)具有下列立体化学:
美登木素生物碱药物部分的典型实施方案包括:DM1,(CR2)m=CH2CH2;DM3,(CR2)m=CH2CH2CH(CH3);和DM4,(CR2)m=CH2CH2C(CH3)2,它们具有如下结构:
根据连接类型的不同,连接基可以在不同位置上与美登木素生物碱分子结合。例如,可以通过使用常规偶联技术与羟基反应形成酯键。该反应可以在具有羟基的C-3位置上进行。该反应可以在具有羟基的C-3位置,使用羟甲基修饰的C-14位置,使用羟基修饰的C-15位置和具有羟基的C-20上进行。在一个优选的实施方案中,键在美登醇或美登醇类似物的C-3位置上形成。
式I的抗体-药物偶联物(ADC)的药物部分(D)还包括多拉司他汀及其肽类似物和衍生物auristatins(美国专利US5635483;5780588)。已经证实多拉司他汀和auristatins可干扰微管动力学、GTP水解以及核和细胞分裂(Woyke等(2001)Antimicrob.Agents and Chemother.45(12):3580-3584)并且具有抗癌(US 5663149)和抗真菌活性(Pettit等(1998)Antimicrob.Agents Chemother.42:2961-2965)。多拉司他汀或auristatin药物部分的不同形式可以通过肽药物部分的N(氨基)末端或C(羧基)末端与抗体共价结合(WO 02/088172;Doronina等(2003)Nature Biotechnology 21(7):778-784;Francisco等(2003)Blood 102(4):1458-1465)。
药物部分包括多拉司他汀、auristatins(US 5635483;US 5780588;US5767237;US 6124431)及其类似物和衍生物。已经证实多拉司他汀和auristatins可干扰微管动力学、GTP水解以及核和细胞分裂(Woyke等(2001)Antimicrob.Agents and Chemother.45(12):3580-3584)并且具有抗癌(US5663149)和抗真菌活性(Pettit等(1998)Antimicrob.Agents Chemother.42:2961-2965)。多拉司他汀或auristatin药物部分的不同形式可以通过肽药物部分的N(氨基)末端或C(羧基)末端与抗体结合(WO 02/088172)。
典型auristatin实施方案包括N-末端连接的monomethylauristatin药物部分DE和DF,其披露在下列文献中:WO 2005/081711;Senter等Proceedingsof the American Association for Cancer Research,Volume 45,Abstract Number623,2004年3月28日提交,特别将这些文献各自全部披露的内容引入本文作为参考。
式I的抗体-药物偶联物(ADC)的药物部分(D)包括通过N-末端与抗体连接的monomethylauristatin药物部分MMAE和MMAF,并且具有如下结构:
一般而言,可以通过在两种或多种氨基酸和/或肽片段之间形成肽键制备基于肽的药物部分。例如,可以按照肽化学领域众所周知的液相合成法制备这类肽键(参见E.和K.Lübke,“The Peptides”,volume 1,pp 76-136,1965,Academic Press)。
药物部分包括加利车霉素及其类似物和衍生物。加利车霉素族抗生素能够产生亚-皮摩尔浓度的双链DNA断裂。为了制备加利车霉素族抗生素的偶联物,参见US 5712374;US 5714586;US 5739116;US 5767285;US 5770701,US 5770710;US 5773001;US 5877296。可以使用的加利车霉素的结构类似物包括,但不限于γ1 I、α2 I、α3 I、N-乙酰基-γ1 I、PSAG和θI 1(Hinman等CancerResearch 53:3336-3342(1993),Lode等Cancer Research 58:2925-2928(1998)。
蛋白毒素包括:白喉毒素A链、白喉毒素的非结合活性片段、外毒素A链(来自铜绿假单胞菌(Pseudomonas aeruginosa))、蓖麻毒素A链(ricin Achain)(Vitetta等(1987)Science,238:1098)、相思豆毒蛋白A链(abrin Achain)、蒴莲根毒素A链(modeccin A chain)、α-八叠球菌(alpha-sarcin)、油桐(Aleurites fordii)蛋白、石竹素蛋白(dianthin proteins)、美洲商陆(Phytolaca americana)蛋白(PAPI、PAPII和PAP-S)、苦瓜(momordicacharantia)抑制剂、泻果素(curcin)、巴豆毒蛋白(crotin)、sapaonaria officinalis抑制剂、白树毒素(gelonin)、米托洁林(mitogellin)、局限曲菌素(restrictocin)、酚霉素(phenomycin)、依诺霉素(enomycin)和tricothecenes(WO 93/21232)。
治疗放射性同位素包括:32P、33P、90Y、125I、131I、131In、153Sm、186Re、188Re、211At、212Bi、212Pb和Lu的放射性同位素。
可以按照公知方式将放射性同位素或其它标记掺入偶联物(Fraker等(1978)Biochem.Biophys.Res.Commun.80:49-57;"Monoclonal Antibody inImmunoscintigraphy"Chatal,CRC Press 1989)。碳-14-标记的1-异硫氰酸根合苄基-3-甲二乙烯三胺五乙酸(MX-DTPA)为用于放射性核素与抗体偶联的典型螯合剂(WO 94/11026)。
连接基
“连接基”(L)为具有用于连接一种或多种药物部分(D)和抗体单元(Ab)而形成式I的抗体-药物偶联物(ADC)的双官能或多官能部分。可以使用具有结合药物和抗体的反应性官能基的连接基便利地制备抗体-药物偶联物(ADC)。半胱氨酸改造的抗体(Ab)的半胱氨酸巯基可以与连接基试剂、药物部分或药物-连接基中间体的官能基形成键。
一个方面,连接基具有反应位置,该位置上带有与存在于抗体上的亲核半胱氨酸反应的亲电子基团。抗体的半胱氨酸巯基与连接基上的亲电子基团反应并且与连接基形成共价键。有用的亲电子基团包括,但不限于马来酰亚胺和卤代乙酰胺基团。
半胱氨酸改造的抗体与连接基试剂或药物-连接基中间体,与亲电子官能基,诸如马来酰亚胺或α-卤代羰基按照Klussman等(2004)在BioconjugateChemistry 15(4):765-773,766页上的方法和实施例4的方案反应。
在一个实施方案中,ADC的连接基L具有下式:
-Aa-Ww-Yy-
其中:
-A-为与抗体(Ab)的半胱氨酸巯基共价结合的Stretcher单元;
a为0或1;
每个-W-各自独立为氨基酸单元;
w独立为0-12的整数;
-Y-为与药物部分共价结合的间隔基单元;且
y为0、1或2。
STRETCHER单元
当存在时,那么Stretcher单元(-A-)能够连接抗体单元与氨基酸单元(-W-)。在这方面,抗体(Ab)具有可以与Stretcher单元的亲电子官能基形成键的游离半胱氨酸巯基。式IIIa和IIIb的方括号内描绘了该实施方案的有代表性的Stretcher单元,其中Ab-、-W-、-Y-、-D、w和y如上述所定义并且R17为选自下列的二价基团:(CH2)r、C3-C8碳环基、O-(CH2)r、亚芳基、(CH2)r-亚芳基、-亚芳基-(CH2)r-、(CH2)r-(C3-C8碳环基)、(C3-C8碳环基)-(CH2)r、C3-C8杂环基、(CH2)r-(C3-C8杂环基)、-(C3-C8杂环基)-(CH2)r-、-(CH2)rC(O)NRb(CH2)r-、-(CH2CH2O)r-、-(CH2CH2O)r-CH2-、-(CH2)rC(O)NRb(CH2CH2O)r-、-(CH2)rC(O)NRb(CH2CH2O)r-CH2-、-(CH2CH2O)rC(O)NRb(CH2CH2O)r-、-(CH2CH2O)rC(O)NRb(CH2CH2O)r-CH2-和-(CH2CH2O)rC(O)NRb(CH2)r-;其中Rb为H、C1-C6烷基、苯基或苄基;且r独立为1-10的整数。
亚芳基包括通过从母体芳族环系中除去两个氢原子衍生的6-20s个碳原子的二价芳族烃基。典型的亚芳基包括,但不限于来源于苯、取代的苯、萘、蒽、联苯等的基团。
杂环基包括一个或多个环原子为杂原子,例如氮、氧和硫的环系。杂环基包含1-20个碳原子和1-3个选自N、O、P和S的杂原子。杂环可以为带有3-7个环的成员的单环(2-6个碳原子和1-3个选自N、O、P和S的杂原子)或带有7-10个环的成员的双环(4-9个碳原子和1-3个选自N、O、P和S的杂原子),例如:双环[4,5],[5,5],[5,6]或[6,6]系统。杂环描述在下列文献中:Paquette,Leo A.;“Principles of Modern HeterocyclicChemistry”(W.A.Benjamin,New York,1968),特别是1,3,4,6,7,和9章;“TheChemistry of Heterocyclic Compound,A series of Monographs”(John Wiley &Sons,New York,1950to present),特别是Volumes 13,14,16,19,和28;和J.Am.Chem.Soc.(1960)82:5566。
杂环的实例包括:作为实例,但不限于:吡啶基、二氢吡啶基、四氢吡啶基(哌啶基)、噻唑基、四氢噻吩基(tetrahydrothiophenyl)、硫氧化的四氢噻吩基、嘧啶基、呋喃基、噻吩基(thienyl)、吡咯基、吡唑基、咪唑基、四唑基、苯并呋喃基、硫杂萘基(thianaphthalenyl)、吲哚基、indolenyl、喹啉基、异喹啉基、苯并咪唑基、哌啶基、4-哌啶酮基、吡咯烷基、2-吡咯烷酮基、吡咯啉基、四氢呋喃基、双-四氢呋喃基(bis-tetrahydrofuranyl)、四氢吡喃基、双-四氢吡喃基(bis-tetrahydropyranyl)、四氢喹啉基、四氢异喹啉基、十氢喹啉基、八氢喹啉基、吖辛因基(azocinyl)、三嗪基、6H-1,2,5-噻二嗪基、2H,6H-1,5,2-二噻嗪基、噻吩基、噻蒽基、吡喃基、异苯并呋喃基、色烯基、呫吨基、吩噁嗪基、2H-吡咯基、异噻唑基、异噁唑基、吡嗪基、哒嗪基、吲嗪基、异吲哚基、3H-吲哚基、1H-吲唑基、嘌呤基、4H-喹嗪基、酞嗪基、萘啶基、喹喔啉基、喹唑啉基、噌啉基、蝶啶基、4Ah-咔唑基、咔唑基、β-咔啉基、菲啶基、吖啶基、嘧啶基、菲咯啉基、吩嗪基、吩噻嗪基、呋咱基、吩噁嗪基、异苯并二氢吡喃基、苯并二氢吡喃基、咪唑烷基、咪唑啉基、吡唑烷基、吡唑啉基、哌嗪基、二氢吲哚基、异二氢吲哚基、奎宁环基、吗啉基、噁唑烷基、苯并三唑基、苯并异噁唑基、羟吲哚基、苯并噁唑啉基和靛红酰基。
碳环基包括带有3-7个碳原子的作为单环或7-12个碳原子的作为双环的饱和或不饱和环。单环碳环带有3-6个环原子,更通常地为5或6个环原子。双环碳环带有7-12个环原子,例如作为双环[4,5],[5,5],[5,6]或[6,6]系统排列的7-12个环原子或作为双环[5,6]或[6,6]系统排列的9或10个环原子。单环碳环的实例包括环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基、环庚基和环辛基。
应理解式I ADC的所有典型实施方案,诸如III-VI,即使未特别表示,但1-4药物部分仍然与抗体连接(p=1-4),这取决于改造的半胱氨酸残基数量。
例示性Stretcher单元为式IIIa并且来源于马来酰亚氨基-己酰基(MC),其中R17为-(CH2)5-:
例示性Stretcher单元为式IIIa并且来源于马来酰亚氨基-丙酰基(MP),其中R17为-(CH2)2-:
另一个例示性Stretcher单元为式IIIa,其中R17为-(CH2CH2O)r-CH2–且r为2:
另一个例示性Stretcher单元为式IIIa,其中R17为-(CH2)rC(O)NRb(CH2CH2O)r-CH2-,其中Rb为H和r各自为2:
另一个例示性Stretcher单元为式IIIb,其中R17为-(CH2)5-:
在另一个实施方案中,Stretcher单元通过抗体单元的硫原子与Stretcher单元的硫原子之间的二硫键与抗体连接。该实施方案的有代表性的Stretcher单元在式IV的方括号内描绘,其中R17、Ab-、-W-、-Y-、-D、w和y如上述所定义。
在另一个实施方案中,Stretcher的反应基含有可以与抗体的游离半胱氨酸巯基形成键的巯基-反应性官能基。巯基-反应官能基的实例包括,但不限于:马来酰亚胺;α-卤代乙酰基;活化的酯类,诸如琥珀酰亚胺酯类、4-硝基苯基酯类、五氟苯基酯类、四氟苯基酯类;酸酐类;酰基氯类;磺酰氯类;异氰酸酯类和异硫氰酸酯类。该实施方案的有代表性的Stretcher单元在式Va和Vb的方括号内描绘,其中R17、Ab-、-W-、-Y-、-D、w和y如上述所定义。
在另一个实施方案中,连接基可以为树枝状类型连接基(dendritic typelinker),其用于通过支化多官能连接基部分与抗体共价结合一个以上药物部分(Sun等(2002)Bioorganic&Medicinal Chemistry Letters 12:2213-2215;Sun等(2003)Bioorganic&Medicinal Chemistry 11:1761-1768;King(2002)Tetrahedron Letters 43:1987-1990)。树枝状连接基可以增加药物与抗体的摩尔比,即负荷,它与ADC的效能相关。因此,如果半胱氨酸改造的抗体仅带有一个反应性半胱氨酸巯基,那么可以通过树枝状连接基结合众多药物部分。
氨基酸单元
连接基可以包含氨基酸残基。如果存在,那么氨基酸单元(-Ww-)使抗体(Ab)与本发明的半胱氨酸改造的抗体-药物偶联物(ADC)的药物部分(D)连接。
-Ww-为二肽、三肽、四肽、五肽、六肽、七肽、八肽、九肽、十肽、十一肽或十二肽单元。包含氨基酸单元的氨基酸残基包括那些天然存在的以及最小的氨基酸和非-天然存在的氨基酸类似物,诸如瓜氨酸。各-W-单元各自独立地具有如下所示的方括号内的式子,并且w为0-12的整数:
其中R19为氢、甲基、异丙基、异丁基、仲-丁基、苄基、对-羟基苄基、-CH2OH、-CH(OH)CH3、-CH2CH2SCH3、-CH2CONH2、-CH2COOH、-CH2CH2CONH2、-CH2CH2COOH、-(CH2)3NHC(=NH)NH2、-(CH2)3NH2、-(CH2)3NHCOCH3、-(CH2)3NHCHO、-(CH2)4NHC(=NH)NH2、-(CH2)4NH2、-(CH2)4NHCOCH3、-(CH2)4NHCHO、-(CH2)3NHCONH2、-(CH2)4NHCONH2、-CH2CH2CH(OH)CH2NH2、2-吡啶基甲基-、3-吡啶基甲基-、4-吡啶基甲基-、苯基、环己基、
可以用一种或多种酶,包括肿瘤相关蛋白酶以酶促方式裂解氨基酸单元,以便释放药物部分(-D),该药物部分在一个实施方案中在体内释放时被质子化以提供药物(D)。
可以设计和优化有用的-Ww-单元在通过特定的酶,例如肿瘤相关蛋白酶进行酶促裂解中的选择性。在一个实施方案中,-Ww-单元是其裂解由组织蛋白酶B、C和D或纤维蛋白溶酶蛋白酶催化的单元。
典型的-Ww-氨基酸单元包括二肽、三肽、四肽或五肽。典型的二肽包括:缬氨酸-瓜氨酸(vc或val-cit)、丙氨酸-苯丙氨酸(af或ala-phe)。典型的三肽包括:甘氨酸-缬氨酸-瓜氨酸(gly-val-cit)和甘氨酸-甘氨酸-甘氨酸(gly-gly-gly)。
当R19不为氢时,R19所连接的碳原子为手性的。R19所连接的碳原子各自独立地在(S)或(R)构型或外消旋混合物中。氨基酸单元由此可以为对映体纯的、外消旋或非对映异构体。
间隔基单元
间隔基单元(-Yy-)存在(y=1或2)时使氨基酸单元(-Ww-)与氨基酸单元存在时(w=1-12)的药物部分(D)连接。或者,在氨基酸单元不存在时,间隔基单元使Stretcher单元与药物部分连接。在氨基酸单元和Stretcher单元都不存在(w,y=0)时,间隔基单元还使药物部分与抗体单元连接。间隔基单元具有两种一般类型:自我提供(self-immolative)和非自我提供的。非自我提供的间隔基单元为部分或所有间隔基单元在从抗体-药物偶联物或药物部分-连接物裂解,特别是酶促裂解氨基酸单元后保持与药物部分结合的间隔单元。当含有甘氨酸-甘氨酸间隔基单元或甘氨酸间隔基单元的ADC通过肿瘤-细胞相关蛋白酶、癌-细胞-相关蛋白酶或淋巴细胞-相关蛋白酶进行酶促裂解时,甘氨酸-甘氨酸-药物部分或甘氨酸-药物部分从Ab-Aa-Ww-上裂解。在一个实施方案中,在靶细胞中发生独立的水解反应,从而裂解甘氨酸-药物部分的键并且释放药物。
在另一个实施方案中,-Yy-为对-氨基苄基氨基甲酰基(PAB)单元(参见方案2和3),其亚苯基部分被Qm取代,其中Q为-C1-C8烷基、-O-(C1-C8烷基)、-卤素、-硝基或-氰基;并且m为0-4的整数。
非自我提供的间隔基单元(-Y-)的典型实施方案为:-Gly-Gly-;-Gly-;-Ala-Phe-;-Val-Cit-。
在一个实施方案中,提供了药物部分-连接物(drug moiety-linker)或ADC或其药学上可接受的盐或溶剂合物,其中间隔基单元不存在(y=0)。
或者,含有自我提供的间隔基单元的ADC可以释放-D。在一个实施方案中,-Y-为通过PAB基团的氨基氮原子连接到-Ww-的PAB基团和通过碳酸酯(carbonate)、氨基甲酸酯或醚基团直接连接到-D的PAB基团,其中ADC具有如下典型结构:
其中Q为-C1-C8烷基、-O-(C1-C8烷基)、-卤素、-硝基或-氰基;m为0-4的整数;并且p为1-4。
自我提供的间隔基的其它实例包括,但不限于在带电方式上与PAB基团类似的芳族化合物,诸如2-氨基咪唑-5-甲醇衍生物(Hay等(1999)Bioorg.Med.Chem.Lett.9:2237)和邻位或对位-氨基苄基乙缩醛类。可以使用在酰胺键水解时进行环化的间隔基,诸如取代和未被取代的4-氨基丁酸酰胺类(Rodrigues等(1995)Chemistry Biology 2:223)、适当取代的双环[2.2.1]和双环[2.2.2]环系(Storm等(1972)J.Amer.Chem.Soc.94:5815)和2-氨基苯基丙酸酰胺类(Amsberry,等(1990)J.Org.Chem.55:5867)。消去在甘氨酸上被取代的含胺的药物(Kingsbury等(1984)J.Med.Chem.27:1447)也是用于ADCs的自我提供的(self-immolative)间隔基的实例。
在一个实施方案中,间隔基单元为支链双(羟甲基)苯乙烯(BHMS),它可以用于掺入和释放众多药物(multiple drugs),其具有如下结构:
该结构中包含2-(4-氨基亚苄基)丙烷-1,3-二醇树枝状大分子单元(WO2004/043493;de Groot等(2003)Angew.Chem.Int.Ed.42:4490-4494),其中Q为-C1-C8烷基,-O-(C1-C8烷基)、-卤素、-硝基或-氰基;m为0-4的整数;n为0或1;并且p为1-4。
树枝状连接基
在另一个实施方案中,连接基L可以为用于通过支化多官能连接基部分使一种以上药物部分共价结合抗体的树枝状类型的连接基(dendritic typelinker)(Sun等(2002)Bioorganic&Medicinal Chemistry Letters12:2213-2215;Sun等(2003)Bioorganic&Medicinal Chemistry11:1761-1768)。树枝状连接基可以增加药物与抗体的摩尔比,即负荷,它与ADC的效能相关。因此,如果半胱氨酸改造的抗体仅带有一个反应性半胱氨酸巯基,那么可以通过树枝状连接基结合众多药物部分。
下列树枝状连接基试剂的典型实施方案允许通过与氯乙基氮芥官能基反应偶联多至9种亲核药物部分试剂:
在间隔基单元的另一个实施方案中,带有自我提供的2,6-双(羟甲基)-对-甲酚和2,4,6-三(羟甲基)-苯酚树枝状分子单元的支化树枝状连接基(WO2004/01993;Szalai等(2003)J.Amer.Chem.Soc.125:15688-15689;Shamis等(2004)J.Amer.Chem.Soc.126:1726-1731;Amir等(2003)Angew.Chem.Int.Ed.42:4494-4499)可以用作本发明化合物中的连接基。
在另一个实施方案中,D部分相同。
在另一个实施方案中,D部分不同。
在一个方面中,间隔基单元(-Yy-)由式(X)-(XII)表示:
其中Q为-C1-C8烷基,-O-(C1-C8烷基)、-卤素、-硝基或-氰基;并且m为0-4的整数;
式I抗体-药物偶联物化合物的实施方案包括XIIIa(val-cit)、XIIIb(MC-val-cit)、XIIIc(MC-val-cit-PAB):
式Ia抗体-药物偶联物化合物的其它典型实施方案包括XIVa-e:
其中X为:
Y为:
且R独立为H或C1-C6烷基;并且n为1-12。
在另一个实施方案中,连接基带有反应性官能基,该反应性官能基具有与存在于抗体上的亲电子基团反应的亲核基团。抗体上有用的亲电子基团包括,但不限于醛和酮羰基。连接基的亲核基团的杂原子可以与抗体上的亲电子基团反应并且与抗体单元形成共价键。连接基上有用的亲核基团包括,但不限于酰肼、肟、氨基、肼、缩氨基硫脲(thiosemicarbazone)、肼羧酸酯和芳基酰肼。抗体上的亲电子基团提供了用于结合(附着)连接基的便利位置。
一般而言,可以通过在两种或多种氨基酸和/或肽片段之间形成肽键制备肽-类连接基。例如,可以按照肽化学领域众所周知的液相合成法(E.和K.Lübke(1965)“The Peptides”,volume 1,pp 76-136,AcademicPress)制备这类肽键。
可以给连接基中间体(linker intermediate)装配反应的任意组合或顺序,包括间隔基(spacer)、Stretcher和氨基酸单元。间隔基、Stretcher和氨基酸单元可以使用本质上为亲电子、亲核或游离基团的反应性官能基。反应性官能基包括,但不限于:
其中X为离去基(leaving group),例如O-甲磺酰基、O-甲苯基磺酰基、-Cl、-Br、-I;或马来酰亚胺。
在另一个实施方案中,连接基可以被调节溶解性或反应性的基团取代。例如,带电荷的取代基,诸如磺酸基(-SO3 -)或铵可以增加试剂的水溶性并且有利于连接基试剂与抗体或药物部分的偶联反应,或有利于Ab-L(抗体-连接基中间体)与D或D-L(药物-连接基中间体)与Ab的偶联反应,这取决于用于制备ADC的合成途径。
特别关注本发明的化合物,但不限于:用如下连接基试剂制备的ADC:BMPEO、BMPS、EMCS、GMBS、HBVS、LC-SMCC、MBS、MPBH、SBAP、SIA、SIAB、SMCC、SMPB、SMPH、磺基-EMCS、磺基-GMBS、磺基-KMUS、磺基-MBS、磺基-SIAB、磺基-SMCC和磺基-SMPB以及SVSB(琥珀酰亚胺基-(4-乙烯基砜)苯甲酸酯);并且包括双-马来酰亚胺试剂:DTME、BMB、BMDB、BMH、BMOE、BM(PEO)3和BM(PEO)4,它们商购自PierceBiotechnology,Inc.,Customer Service Department,P.O.Box 117,Rockford,IL.61105 U.S.A,U.S.A 1-800-874-3723,International+815-968-0747。参见467-498页,2003-2004Applications Handbook and Catalog、双-马来酰亚胺试剂能够使半胱氨酸改造的抗体的巯基与含巯基的药物部分、标记或连接基中间体按照依次或同时的方式结合。除马来酰亚胺外的其它与半胱氨酸改造的抗体、药物部分、标记或连接基中间体的巯基反应的官能基包括碘乙酰胺、溴乙酰胺、乙烯基吡啶、二硫化物、吡啶基二硫化物、异氰酸酯(盐)和异硫氰酸酯(盐)。
还可以通过其它商业渠道,诸如Molecular Biosciences Inc.(Boulder,CO)获得或按照下列文献中所述的操作步骤合成有用的连接基试剂:Toki等(2002)J.Org.Chem.67:1866-1872;Walker,M.A.(1995)J.Org.Chem.60:5352-5355;Frisch等(1996)Bioconjugate Chem.7:180-186;US 6214345;WO 02/088172;US 2003130189;US2003096743;WO 03/026577;WO03/043583;和WO 04/032828。
可以通过使下列连接基试剂与氨基酸单元的N-末端反应将式(IIIa)的Stretchers引入连接基:
其中n为1-10的整数且T为-H或-SO3Na;
其中n为0-3的整数;
可以通过使下列双官能试剂与氨基酸单元的N-末端反应将Stretchers单元引入连接基:
其中X为Br或I。还可以通过使下列双官能试剂与氨基酸单元的N-末端反应将式的Stretcher单元引入连接基:
可以通过使下列中间体与氨基酸单元的N-末端反应将式(Va)的Stretcher单元引入连接基:
可以如Angew.Chem.,(1975)87(14),517中所述由异硫氰酸根合羧酰氯化物制备如下所示的式的Stretchers。
其中-R17-如本文所述。
具有马来酰亚胺Stretcher和对-氨基苄基氨基甲酰基(PAB)自我提供的间隔基的典型缬氨酸-瓜氨酸(val-cit或vc)二肽连接基试剂具有如下结构:
其中Q为-C1-C8烷基、-O-(C1-C8烷基)、-卤素、-硝基或-氰基;且m为0-4的整数。
可以按照Dubowchik等(1997)Tetrahedron Letters,38:5257-60所述制备具有马来酰亚胺Stretcher单元和对-氨基苄基自我提供的间隔基的典型phe-lys(Mtr)二肽连接基试剂并且其具有如下结构:
其中Mtr为一-4-甲氧基三苯甲基,Q为-C1-C8烷基、-O-(C1-C8烷基)、-卤素、-硝基或-氰基;且m为0-4的整数。
本发明典型的抗体-药物偶联物化合物包括:
Ab-MC-vc-PAB-MMAF
Ab-MC-vc-PAB-MMAE
Ab-MC-MMAE
Ab-MC-MMAF
其中Val为缬氨酸;Cit为瓜氨酸;p为1、2、3或4;且Ab为半胱氨酸改造的抗体。其它典型的抗体药物偶联物具有如下结构,其中美登木素生物碱药物部分DM1通过BMPEO连接基与曲妥单抗的巯基连接:
其中Ab为半胱氨酸改造的抗体;n为0、1或2;和p为1、2、3或4。
抗体-药物偶联物的制备
可以通过几种途径,使用本领域技术人员公知的有机化学反应、条件和试剂制备式I的ADC,包括:(1)半胱氨酸改造的抗体的半胱氨酸基团与连接基试剂反应,从而通过共价键形成抗体-连接基中间体Ab-L,随后与活化的药物部分D反应;和(2)使药物部分的亲核基团与连接基试剂反应,从而通过共价键形成药物-连接基中间体D-L,随后与半胱氨酸改造的抗体的半胱氨酸基团反应。偶联方法(1)和(2)可以用于各种半胱氨酸改造的抗体、药物部分和连接基以便制备式I的抗体-药物偶联物。
抗体半胱氨酸巯基为亲核性的并且能够与连接基试剂和药物-连接基中间体上的亲电子基团反应而形成共价键,所述的药物-连接基中间体包括:(i)活性酯类,诸如NHS酯类、HOBt酯类、卤代甲酸酯类和酰基卤类;(ii)烷基和苄基卤化物,诸如卤代乙酰胺类;(iii)醛类、酮类、羧基和马来酰亚胺基;和(iv)通过硫化物交换的二硫化物,包括吡啶基二硫化物。药物部分上的亲核基团包括,但不限于:胺、巯基、羟基、酰肼、肟、肼、缩氨基硫脲、肼羧酸酯和芳基酰肼基团,它们能够与连接基部分和连接基试剂上的亲电子基团反应而形成共价键。
例如,可以将美登素转化成May-SSCH3,可以将其还原成游离巯基May-SH并且使之与修饰的抗体反应(Chari等(1992)Cancer Research52:127-131)而生成带有二硫化物连接基的美登木素生物碱-抗体免疫偶联物。已经报导了带有二硫化物连接基的抗体-美登木素生物碱偶联物(WO04/016801;US 6884874;US 2004/039176A1;WO 03/068144;US 2004/001838A1;美国专利US6441163,5208020,5416064;WO 01/024763)。使用连接基试剂N-琥珀酰亚胺基4-(2-吡啶硫基)戊酸酯构建二硫化物连接基SPP。
在某些条件下,可以通过用还原剂,诸如DTT(Cleland试剂,二硫苏糖醇)或TCEP(三(2-羧乙基)膦盐酸盐处理使半胱氨酸改造的抗体反应以便偶联连接基试剂;Getz等(1999)Anal.Biochem.Vol 273:73-80;Soltec Ventures,Beverly,MA)。在37℃用约50倍过量的TCEP将在CHO细胞中表达的全长半胱氨酸改造的单克隆抗体(ThioMabs)还原3小时以便还原可以在新引入的半胱氨酸残基与存在于培养基中的半胱氨酸之间形成的二硫键。用10mM乙酸钠,pH 5稀释还原的ThioMab并且上样至10mM乙酸钠,pH 5中的HiTrap S柱上并且用含有0.3M氯化钠的PBS洗脱。在室温在存在稀(200nM)硫酸铜水溶液(CuSO4)的条件下过夜,使亲代Mab中的半胱氨酸残基之间重新建二硫键。可以使用本领域公知的其它氧化剂,即氧化剂和氧化条件。环境空气氧化也是有效的。这种适度的部分再氧化步骤有效地形成具有高保真度的链间二硫键。加入约10倍过量的药物-连接基中间体,例如BM(PEO)4-DM1,混合并且在室温下保持约1小时,以便进行偶联并且形成ThioMab抗体-药物偶联物。将偶联混合物进行凝胶过滤并且上HiTrap S柱且洗脱该柱以便除去过量的药物-连接基中间体和其它杂质。
附图15表示制备由细胞培养物表达的用于偶联的半胱氨酸改造的抗体的一般方法。推定带有各种链间二硫键的半胱氨酸加合物被还原裂解成抗体的还原形式。在部分氧化条件下,诸如接触环境氧重新形成配对半胱氨酸残基之间的链间二硫键。新引入的,改造的和未配对的半胱氨酸残基仍然可以用于与连接基试剂或药物-连接基中间体反应而形成本发明的抗体偶联物。哺乳动物细胞系中表达的ThioMabs通过–S-S-键形成产生与改造的Cys产生外部偶联的Cys加合物,因此,纯化的ThioMabs必须如实施例11中所述通过还原和氧化操作步骤处理以便产生反应性ThioMabs。这些ThioMabs用于偶联含有马来酰亚胺的细胞毒性药物、荧光团和其它标记。
制备各种ThioFab和ThioMab抗体-药物偶联物(实施例4-8)。使半胱氨酸突变体hu4D5Fabv8(V110C)通过双-马来酰亚氨基连接基试剂BMPEO与美登木素生物碱药物部分DM1偶联而形成hu4D5Fabv8(V110C)-BMPEO-DM1(实施例8)。
体外细胞增殖试验
一般而言,通过下列步骤测定抗体-药物偶联物(ADC)的细胞毒性或细胞生长抑制活性:使具有受体蛋白,例如HER2的哺乳动物细胞在细胞培养基中接触ADC的抗体;将细胞培养约6小时-约5天的时间;和测定细胞存活率。基于细胞的体外试验用于测定存活率(增殖)、细胞毒性和本发明ADC的程序性细胞死亡诱导(胱天蛋白酶活化)。
通过细胞增殖试验测定抗体-药物偶联物的体外功效(附图10和11,实施例9)。Luminescent Cell Viability Assay为商购的(PromegaCorp.,Madison,WI)基于鞘翅目(Coleoptera)荧光素酶的重组表达的同质性试验方法(homogeneous assay method)(美国专利US5583024;5674713和5700670)。该细胞增殖试验基于对存在的ATP进行定量测定了培养物中存活细胞的数量,其中存在的ATP为代谢活性细胞的指示剂(Crouch等(1993)J.Immunol.Meth.160:81-88;US 6602677)。在96孔板中进行Assay,使得它易于进行自动化高流通量筛选(HTS)(Cree等(1995)AntiCancerDrugs 6:398-404)。同质性试验操作步骤包括将单一试剂(Reagent)直接加入到在血清补充的培养基中培养的细胞中。无需进行细胞洗涤、除去培养基和多次吸移的步骤。该系统可以在添加试剂并且混合后10分钟内检测384-孔格中低至15个细胞/孔。可以用ADC连续处理细胞,或可以处理它们并且从ADC中分离、一般而言,暂短,即3小时处理的细胞表现出与连续处理的细胞相同的功效作用。
同质性“添加-混合-测定”方式导致细胞裂解并且产生与存在的ATP量成比例的发光信号。ATP的量与培养物中存在的细胞数量成正比。Assay产生由荧光素酶反应产生的“辉光-型”发光信号,它具有一般大于5小时的半衰期,这取决于所用的细胞类型和培养基。以相对发光单位(RLU)反映出存活细胞。底物甲虫荧光素被重组荧火虫荧光素酶氧化脱羧化,而同时ATP转化成AMP并且产生光子。延长的半衰期消除了使用试剂注射器的需求并且为连续或分批方式的多平板加工提供了灵活性。这种细胞增殖试验可以与各种多孔板联用,例如96或384孔板。通过发光计或CCD照相机成像装置记录数据。将发光输出表示为在一段时间内测定的相对光单位(RLU)。或者,可以在有闪烁剂存在下在闪烁计数器中对来自发光的光子进行计数。然后可以将光单位表示为CPS–每秒计数。
通过上述针对SK-BR-3乳腺肿瘤细胞系的细胞增殖体外细胞杀伤试验测定抗体-药物偶联物的抗-增殖作用(附图10和11)。对已知过表达HER2受体蛋白的SK-BR-3细胞建立ADC的IC50值。
附图10表示曲妥单抗-SMCC-DM1(IC50=0.008-0.015μg/ml)比重链半胱氨酸突变体偶联物hu4D5Fabv8-(A121C)-BMPEO-DM1(IC50=0.04μg/ml)更为有效。两种偶联物在杀伤细胞方面均明显比裸曲妥单抗(IC50=0.1μg/ml)更为有效。药物负荷(drug loading)对曲妥单抗-SMCC-DM1而言为2.8DM1/Ab并且对hu4D5Fabv8(A121C)-BMPEO-DM1而言为0.6DM1/Ab。
附图11表示曲妥单抗-SMCC-DM1(IC50=0.008-0.015μg/ml)比轻链半胱氨酸突变体hu4D5Fabv8(V110C)-BMPEO-DM1(IC50=0.07μg/ml)更为有效。两种偶联物在杀伤细胞方面均明显比裸曲妥单抗(IC50=0.1μg/ml)更为有效。药物负荷对曲妥单抗-SMCC-DM1而言为2.8DM1/Ab并且对hu4D5Fabv8(V110C)-BMPEO-DM1而言为0.9DM1/Ab。
测试全长IgG ThioMab偶联物的体外细胞增殖功效并且与亲代抗体比较。附图20表示用下列物质处理的SK-BR-3细胞的试验结果:亲代抗体曲妥单抗(Genentech,Inc.);具有约3.4DM1/Ab药物负荷的曲妥单抗-SMCC-DM1;和具有约1.6DM1/Ab药物负荷的硫代-曲妥单抗(thio-trastuzumab)(A121C)-BMPEO-DM1。曲妥单抗-SMCC-DM1偶联物通过氨基反应性NHS酯SMCC连接基试剂与抗体连接,而硫代-曲妥单抗(A121C)-BMPEO-DM1偶联物通过巯基反应性马来酰亚胺BMPEO连接基试剂连接。两种偶联物对SK-BR-3细胞均有效并且表现出相差无几的活性,而曲妥单抗不会发挥细胞毒性作用。附图21A表示用下列物质处理的HT1080EphB2细胞的试验结果:亲代2H9抗-EphB2R;和thio2H9(A121C)BMPEO-DM1偶联物。附图21B表示用下列物质处理的BT 474细胞的试验结果:亲代2H9抗-EphB2R;和thio2H9(A121C)BMPEO-DM1偶联物。针对HT 1080EphB2和BT 474细胞,2H9ThioMab偶联物均比亲代2H9抗体偶联物更为有效。与仅观察到微弱活性的非EphB2细胞系BT474相比,偶联物Thio-2H9-BMPEO-DM1在EphB2特异性细胞系(HT1080EphB2)中表现出功能性细胞杀伤活性。
比较抗体药物偶联物,其中抗体为亲代抗体和其中抗体为半胱氨酸改造的抗体。附图22表示用下列物质处理的PC3/neo细胞的试验结果:3A5抗MUC16-SMCC-DM1;和thio3A5(A121C)BMPEO-DM1。附图23表示用下列物质处理的PC3/MUC16细胞的试验结果:3A5抗MUC16-SMCC-DM1;和thio3A5(A121C)BMPEO-DM1.附图24表示用下列物质处理的OVCAR-3细胞的试验结果:3A5抗MUC16-SMCC-DM1;和thio3A5(A121C)BMPEO-DM1。Thio-3A5-BMPEO-DM1在对照PC3/neo细胞系中没有表现出任何明显的细胞杀伤活性,而在PC3/MUC16细胞系中表现出与3A5-SMCC-DM1相当的活性。Thio-3A5-DM1偶联物在表达内源性MUC16抗原的OVCAR-3中也表现出活性。
体内功效
通过高度表达HER2的转基因外植体小鼠模型测定本发明两种清蛋白结合肽-DM1(美登木素生物碱)-抗体-药物偶联物(ADC)的体内功效(附图12,实施例10)。使同种异体移植物从不对疗法起反应或对它的反应差的Fo5mmtv转基因小鼠增殖。用ABP-rhuFab4D5-cys(轻链)-DM1;ABP-rhuFab4D5-cys(重链)-DM1;和安慰剂PBS缓冲液对照品(媒介物)治疗受试者并且在3周内检测以便测定肿瘤体积倍增的时间、log细胞杀伤和肿瘤缩小。
术语Ti为研究组中T=0时有肿瘤的动物数量÷组中动物总数。术语PR为取得肿瘤部分消退的动物数量÷组中T=0时有肿瘤的动物数量。术语CR为取得肿瘤完全消退的动物数量v组中T=0时有肿瘤的动物数量。术语TDV为肿瘤体积倍增时间,即对照组肿瘤体积加倍的天数。
用25mg/kg(1012ug/m2的DM1)的ABP-rhuFab4D5-cys(轻链)-DM1治疗的7只小鼠均为肿瘤阳性的并且在20天后1只动物肿瘤部分消退。用37.5mg/kg(1012ug/m2的DM1)的ABP-rhuFab4D5-cys(重链)-DM1治疗的7只小鼠均为肿瘤阳性的并且在20天后有4只动物肿瘤部分消退。
在携带MMTV-HER2 Fo5肿瘤的小鼠中对亲代曲妥单抗-SMCC-DM1偶联物和具有A121C半胱氨酸突变并且与BMPEO连接基和DM1药物部分偶联的全长IgG ThioMab抗体变体进行测试。在第0天注射时的肿瘤大小约为100-200mm。附图25表示在第0天时使用单剂(a single dose)的如下物质后具有MMTV-HER2 Fo5乳腺肿瘤同种异体移植物的无胸腺裸小鼠中21天内平均肿瘤体积改变:媒介物(缓冲液);曲妥单抗-SMCC-DM1 10mg/kg;硫代曲妥单抗(A121C)-SMCC-DM1 21mg/kg和硫代曲妥单抗(thio trastuzumab)(A121C)-SMCC-DM1 10mg/kg。
从附图25中可以观察到每种偶联物均发挥出比安慰剂(媒介物)显著的延缓肿瘤生长的作用。在上述4组中的10只小鼠中的每一只在第1天时均接受单次注射。与半胱氨酸改造的硫代-曲妥单抗(A121C)-BMPEO-DM1偶联物(1.6DM1/Ab)相比,亲代曲妥单抗-SMCC-DM1偶联物加载了2倍以上(3.4DM1/Ab)数量的药物部分。。DM1的有效量由此在亲代曲妥单抗-SMCC-DM1与较高剂量的(21mg Ab)硫代-曲妥单抗(A121C)-BMPEO-DM1之间近似相等。这两种样品均表现出最大功效。在注射后的14天后,接受这些偶联物的大部分动物肿瘤部分或完全消退。较低剂量的硫代-曲妥单抗(A121C)-BMPEO-DM1样品的功效较低证实了DM1的剂量与反应相关。以与对照组曲妥单抗-SMCC-DM1偶联物等同的抗体(10mg/kg)或DM1药物(21mg/kg)用量给予的Thio-曲妥单抗-DM1。正如可以从附图25中观察到的,Thio-BMPEO-DM1(21mg/kg)表现出稍优于曲妥单抗-SMCC-DM1组的反应,因为某些动物在使用Thiomab-DM1后完全应答(complete response),而使用曲妥单抗-SMCC-DM1仅产生部分应答(partical response)。
抗体-药物偶联物的给药
可以通过适合于所治疗疾病的任意途径给予本发明的抗体-药物偶联物(ADC)。一般通过肠胃外途径给予ADC,即输注、皮下、肌肉内、静脉内、真皮内、鞘内和硬膜外。
药用配制剂
本发明的治疗性抗体-药物偶联物(ADC)通常与药学上可接受的肠胃外媒介物一起配制成单位剂量可注射形式的药用配制剂供肠胃外施用,即快速灌注(bolus)、静脉内注射、肿瘤内注射。任选将具有所需纯度的抗体-药物偶联物(ADC)与药学上可接受的稀释剂、载体、赋形剂或稳定剂混合(Remington′s Pharmaceutical Sciences(1980)16th edition,Osol,A.Ed.)成冻干剂型或水溶液形式。
可接受的稀释剂、载体、赋形剂和稳定剂在所采用的剂量和浓度对接受者是无毒的,并且包括:缓冲剂,诸如磷酸盐、柠檬酸盐和其它有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(诸如氯化十八烷基二甲基苄基铵;氯己双铵;苯扎氯铵、苄索氯铵;苯、丁醇或苄醇;对羟基苯甲酸烷基酯,诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(低于约10个残基)多肽;蛋白质,诸如血清清蛋白、明胶或免疫球蛋白;亲水聚合物,诸如聚乙烯吡咯烷酮;氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖类、二糖类和其它碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,诸如EDTA;糖类,诸如蔗糖、甘露醇、海藻糖或山梨醇;成盐抗衡离子,诸如钠;金属复合物(例如Zn-蛋白质复合物);和/或非离子表面活性剂,诸如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。例如,冻干的抗ErbB2抗体配制剂如WO 97/04801中所述,明确将其引入本文作为参考。
活性药物成分还可包载于例如通过凝聚技术或通过界面聚合制备的微胶囊中(例如分别是羟甲基纤维素或明胶微胶囊和聚(甲基丙烯酸甲酯)微胶囊)、在胶状药物投递系统中(例如脂质体、清蛋白微球体、微乳剂、纳米颗粒和纳米胶囊)、或在粗滴乳状液中。此类技术公开于Remington′sPharmaceutical Sciences,16th edition,Osol,A.Ed.(1980)。
可以制备持续释放制剂。持续释放制剂的合适例子包括含有ADC的固体疏水聚合物的半透性基质,该基质是定型产品的形式,例如薄膜或微胶囊。持续释放基质的例子包括聚酯、水凝胶(例如聚(2-羟乙基-甲基丙烯酸酯)或聚(乙烯醇))、聚交酯(US 3,773,919)、L-谷氨酸和L-谷氨酸γ-乙酯的共聚物、不可降解的乙烯-乙酸乙烯、可降解的乳酸-乙醇酸共聚物诸如LUPRONDEPOTTM(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林构成的可注射微球体)及聚-D-(-)-3-羟基丁酸。
用于体内施用的配制剂必须是无菌的,这易于通过无菌滤膜过滤来实现。
制剂包括某些适合于上述给药途径的制剂。可以便利地将制剂制成单位剂型(unit dosage form)并且可以通过制药领域众所周知的任意方法制备。药物制备的各种技术和配制一般在Remington′s Pharmaceutical Sciences(MackPublishing Co.,Easton,PA)中找到。这类方法包括使活性组分与构成一种或多种辅助组分的载体混合的步骤。一般而言,通过均匀和紧密混合活性组分与液体载体或细粉固体载体或它们两者,且然后,如果必要,使产物成形来制备产品。
本发明的含水混悬液含有活性物质与适合于制备含水混悬液的赋形剂的混合。这类赋形剂包括:悬浮剂,诸如羧甲基纤维素钠、交联羧甲纤维素、聚维酮、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、西黄蓍胶和阿拉伯胶;和分散剂或湿润剂,诸如天然存在的磷脂(例如卵磷脂)、烯化氧与脂肪酸(例如聚氧乙烯硬脂酸酯)的缩合产物、环氧乙烷与长链脂族醇(例如十七碳乙烯氧基鲸蜡醇)的缩合产物、环氧乙烷与来源于脂肪酸和己糖醇酐的偏酯的缩合产物(例如聚氧乙烯山梨糖醇酐单油酸酯)。含水混悬液还可以含有一种或多种防腐剂,诸如对羟基苯甲酸乙酯或对羟基苯甲酸丙酯;一种或多种着色剂;一种或多种矫味剂;和一种或多种增甜剂,诸如蔗糖或糖精。
ADC的药物组合物可以为无菌可注射制剂形式,诸如无菌可注射含水或油混悬液。可以按照本领域公知的方法,使用上述那些合适的分散剂或湿润剂和悬浮剂配制混悬液。无菌可注射制剂还可以为在无毒性非肠道可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液,诸如在1,3-丁-二醇中的溶液或制备成冻干纷。在可以使用的可接受的媒介物和溶剂中有水、林格液和等渗氯化钠溶液。此外,可以便利地将无菌非挥发油(fixed oil)用作溶剂或悬浮介质。为了这一目的,可以使用任意温和的固定油(bland fixed oil),包括合成的单酸甘油酯或二脂酰甘油酯类。此外,诸如油酸这类脂肪酸同样可以用于制备可注射制剂。
可以与载体物质合并而产生单剂型(single dosage form)的活性组分的量将根据所治疗宿主和特定给药方式的不同而改变。例如,指定用于静脉内输注的水溶液可以含有约3-500μg的活性组分/毫升溶液,以便可以以约30mL/小时的速率输注适当的体积。
适合于非肠道给药的制剂包括:含水和非水无菌注射溶液,其可以含有抗氧化剂、缓冲剂、抑菌剂和赋予制剂与接受者的血液等渗的溶质;和含水和非水无菌混悬液,其可以包括悬浮剂和增稠剂。
尽管因在肠中水解或变性而不赞成使用蛋白质治疗剂的口服给药,但是可以将适合于口服给药的ADC制剂制备成分散单位,诸如含有预定量ADC的胶囊、扁囊剂或片剂。
可以将制剂包装在单剂或多剂容器内,例如密封的安瓿和小瓶内,并且可以将其在冷冻干燥(冻干)条件下贮存,在使用前仅需要即刻添加无菌液体载体,例如水以便注射。由上述类型的无菌粉末、颗粒和片剂制备临时注射的溶液和混悬液。优选的单位剂型为那些含有如上所述每日剂量或单位每日亚剂量或其合适的部分的活性组分的剂型。
本发明进一步提供了兽用组合物,其包含至少一种上述定义的活性组分及其兽用载体。兽用载体为用于给予所述组合物目的的物质,并且可以为固体、液体或气态物质,或为惰性物质或在兽药领域中可接受的,并且与活性组分相容的物质。可以通过非肠道、口服或通过任意其它所需的途径给予这些兽用组合物。
抗体-药物偶联物治疗
关注本发明的抗体-药物偶联物(ADC)可以用于治疗各种疾病或病症,例如其特征在于肿瘤抗原的过表达的疾病或病症。典型的疾病或过度增殖性病症包括良性或恶性肿瘤;白血病和淋巴样恶性肿瘤。其它疾病包括神经元、神经胶质、星形胶质细胞、下丘脑、腺体、巨噬细胞、上皮细胞、间质、囊胚腔、炎性、血管发生和免疫性疾病,包括自身免疫性疾病。
可以在具有肿瘤的高级灵长类和人体临床试验中进一步测试在动物模型和基于细胞的试验中鉴定的ADC化合物。可以设计与测试抗-HER2单克隆抗体在具有过表达HER2的转移乳腺癌的患者中的功效的临床试验类似的人体临床试验,所述的具有过表达HER2的转移乳腺癌的患者已经预先如Baselga等(1996)J.Clin.Oncol.14:737-744报导的接受了广泛的抗癌疗法。可以设计临床试验以便评价ADC与已知治疗方案的组合的功效,所述的已知治疗方案诸如包括已知化疗剂和/或细胞毒性剂的放疗和/或化疗。
一般而言,所治疗的疾病或病症为过度增殖性疾病,诸如癌症。癌症的实例包括,但不局限于癌、淋巴瘤、母细胞瘤、肉瘤和白血病或淋巴样恶性肿瘤。更具体地说,这类癌症包括:鳞状细胞癌(例如上皮鳞状细胞癌);肺癌,包括小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞癌;腹膜癌;肝细胞癌;胃癌,包括胃肠癌;胰腺癌、成胶质细胞瘤;宫颈癌;卵巢癌;肝癌(livercancer);膀胱癌;肝细胞癌(hepatoma);乳腺癌;结肠癌;直肠癌;结直肠癌;子宫内膜癌或子宫癌;唾液腺癌;肾癌;前列腺癌、外阴癌;甲状腺癌;肝癌(hepatic carcinoma);肛门癌;阴茎癌和头颈部癌。
癌症可以包含过表达HER2的细胞,使得本发明的ADC能够结合癌细胞。为了测定癌症中ErbB2的表达,可以利用各种诊断/预后试验。在一个实施方案中,可以通过IHC,例如使用HERCEPTEST(Dako)分析ErbB2过表达。可以对来自肿瘤活组织检查的石蜡包埋的组织切片进行IHC试验并且给予如下的ErbB2蛋白质染色强度标准:得分0,未观察到染色或在低于10%的肿瘤细胞中观察到的膜染色;得分1+,在大于10%的肿瘤细胞中检测到微弱/勉强能觉察到的膜染色,细胞仅在其部分膜上染色;得分2+,在大于10%的肿瘤细胞中观察到微弱到中度的完全膜染色;得分3+,在大于10%的肿瘤细胞中观察到中度到强的完全膜染色。ErbB2过表达评价得分0或1+的肿瘤定义为非过表达ErbB2的肿瘤,得分2+或3+的肿瘤定义为过表达ErbB2的肿瘤。
或者或另外,可以对福尔马林固定的石蜡包埋的肿瘤组织进行FISH试验,诸如INFORMTM(Ventana Co.,Ariz.)或PATHVISIONTM(Vysis,Ill.),以便测定肿瘤中ErbB2过表达的程度(如果有的话)。
ADC化合物可以用于治疗的自身免疫性疾病包括风湿病(诸如,例如类风湿性关节炎;斯耶格仑氏综合征;硬皮病;狼疮,诸如SLE和狼疮性肾炎;多肌炎/皮肌炎;冷球蛋白血症;抗-磷脂抗体综合征;和牛皮癣性关节炎)、骨关节炎、自身免疫性胃肠和肝病(诸如,例如炎症性肠病(例如溃疡性结肠炎和克罗恩(Crohn′s)病)、自身免疫性胃炎和恶性贫血、自身免疫性肝炎、原发性胆汁性肝硬变、原发性硬化性胆管炎和乳糜泻(celiacdisease))、血管炎(诸如,例如ANCA-相关血管炎,包括丘-施(Churg-Strauss)血管炎、韦格纳(Wegener′s)肉芽肿和多动脉炎)、自身免疫性神经疾病(诸如,例如多发性硬化、斜视眼肌阵挛综合征(opsoclonus myoclonus syndrome)、重症肌无力、眼脑脊髓病、帕金森(Parkinson’s)病、阿尔茨海默(Alzheimer’s)病和自身免疫性多神经病)、肾脏疾病(诸如,例如肾小球肾炎、古德帕斯彻(Goodpasture’s)综合征和贝格尔(Berger’s)病)、自身免疫性皮肤病(诸如,例如银屑病、荨麻疹(urticaria)、荨麻疹(hives)、寻常天疱疮、大疱性类天疱疮和皮肤红斑狼疮)、血液病(诸如,例如血小板减少性紫癜、血栓性血小板减少性紫癜、输血后紫癜和自身免疫性溶血性贫血)、动脉粥样硬化、眼色素层炎、自身免疫性听觉疾病(诸如,例如内耳疾病和,听力丧失)、贝切特(Behcet′s)病、雷诺(Raynaud′s)综合征、器官移植和自身免疫性内分泌病症(诸如,例如糖尿病相关性自身免疫性疾病,诸如胰岛素依赖性糖尿病(IDDM),阿狄森(Addison’s)病和自身免疫性甲状腺病(例如格雷夫斯(Graves’)病和甲状腺炎))。更优选的这类疾病包括:例如类风湿性关节炎、溃疡性结肠炎、ANCA-相关血管炎、狼疮、多发性硬化、斯耶格仑综合征、格雷夫斯病、IDDM、恶性贫血、甲状腺炎和肾小球肾炎。
为了预防或治疗疾病,ADC的适当剂量取决于如上述定义的所治疗的疾病类型、疾病的严重程度和时程、给予所述分子是为了预防还是为了治疗目的、先前的治疗、患者的临床病史和对抗体的反应以及主治医师的判定。将所述的分子适当对患者给予一次或在一系列治疗过程中给予。根据疾病类型和严重程度的不同,对患者给药的分子的初始候选剂量约为1μg/kg-15mg/kg(例如0.1-20mg/kg),例如,无论是通过一次或多次分开的给药,还是通过连续输注。典型的每日剂量可以在约1μg/kg-100mg/kg或更大的范围,这取决于上述因素。对患者给予的典型的ADC的剂量在约0.1-约10mg/kg患者体重的范围。
为了在几天或几天以上时程中反复给药,根据病情的不同,将治疗持续至对所需疾病症状的抑制发生为止。典型的给药方案包含给予约4mg/kg的起始负荷剂量,随后给予约2mg/kg抗-ErbB2抗体的每周维持剂量。其它剂量方案也是有用的。该疗法的进展易于通过常规技术和试验监测。
联合疗法
可以将本发明的抗体-药物偶联物(ADC)与具有抗癌特性的第二种化合物合并在联用药物制剂(pharmaceutical combination formulation)中或作为联合疗法的给药方案。联用药物制剂或给药方案中的第二种化合物优选具有对联合用药中的ADC的补充活性,使得它们彼此不会产生不良影响。
第二种化合物可以为化疗剂、细胞毒性剂、细胞因子、生长抑制剂、抗激素药和/或心脏保护剂。这类分子以有效用于指定目的的用量适当存在于联合用药中。含有本发明ADC的药物组合物还可以具有治疗有效量的化疗剂,诸如微管蛋白形成抑制剂、拓扑异构酶抑制剂或DNA结合剂。
可以将其它治疗方案与给予本发明鉴定的抗癌药联用。可以将这种联合疗法作为同时或依次方案给予。当依次给药时,可以将所述的组合分两次或多次给药进行给予。联合给药包括使用分开的制剂或单一药物制剂共同给药和按顺序依次给药,其中优选存在两种(或所有的)活性剂同时发挥其生物活性的时间段。
在一个实施方案中,使用ADC治疗包括联合给予本文确定的抗癌药和一种或多种化疗剂或生长抑制剂,包括共同给予不同化疗剂的混合物。化疗剂包括紫杉烷类(诸如紫杉醇和多西他赛(docetaxel))和/或蒽环类抗生素。可以按照制造商的说明或如本领域技术人员根据经验确定的使用所述化疗剂的制剂和给药方案。这类化疗剂的制剂和给药方案还描述在“ChemotherapyService”,(1992)Ed.,M.C.Perry,Williams & Wilkins,Baltimore,Md中。
可以将ADC与如下抗激素化合物联用;例如抗-雌激素化合物,诸如他莫昔芬(tamoxifen);抗-孕酮药,诸如奥那司酮(onapristone)(EP 616812);或抗-雄激素药,诸如氟他胺(flutamide),使用的剂量为这类分子的已知剂量。如果所治疗的癌症为激素非依赖性的癌症时,患者可能预先进行过抗激素疗法,并且在癌症变成激素非依赖性后,可以对患者给予ADC(和任选本文所述的其它活性剂)。有益的是还对患者共同给予心脏保护剂(以便预防或减轻与疗法相关的心肌机能障碍)或一种或多种细胞因子。除上述治疗方案外,还可以对患者进行癌细胞的手术除去细胞和/或放疗。
任意上述共同给予的活性剂的合适的剂量为那些目前使用的剂量并且可以因新确定的活性剂和其它化疗剂或治疗的联合作用(协同作用)而降低。
联合疗法可以提供“协同作用(synergy)”并且证实有“协同作用(synergistic)”,即当共同使用活性组分时,其作用大于因单独使用所述化合物产生的作用之和。当活性组分为如下情况时可以获得协同作用:(1)共同配制和给药或在合并的单位剂型中同时递送;(2)作为单独的制剂交替或平行递送;或(3)通过某些其它方案。当在交替疗法中递送时,可以获得例如通过在不同注射器中的不同注射依次给予或递送所述化合物时获得的协同作用。一般而言,在交替疗法过程中,依次,即顺序给予每种活性组分的有效剂量,而在联合疗法中,共同给予两种或多种活性组分的有效剂量。
抗体-药物偶联物的代谢物
另外属于本发明范围的的是本文所述的ADC化合物的体内代谢产物,这类产物为新的并且在现有技术中是非显而易见的。这类产物可能因例如所给予的化合物的氧化、还原、水解、酰胺化、酯化、酶促裂解等而产生。因此,本发明包括通过这样的方法产生的新的和非显而易见的化合物,所述方法包含使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间段。
一般通过下列步骤鉴定代谢产物:制备放射性标记的(例如14C或3H)ADC;通过非肠道方式对动物,诸如大鼠、小鼠、豚鼠、猪、猴或人给予其可检测的剂量(例如大于约0.5mg/kg);允许代谢发生足够的时间(一般约30秒-30小时);和从尿、血液或其它生物样品中分离其转化产物。这些产物易于分离,因为它们是标记的(通过使用能够结合在代谢物中存在的结合表位的抗体分离其它产物)。按照常规方式,例如通过MS、LC/MS或NMR分析测定代谢物的结构。一般而言,按照与本领域技术人员众所周知的常规药物代谢研究相同的方式对代谢物进行分析。转化产物,只要没在体内发现它们,即可用于诊断试验以用于监测本发明ADC化合物的治疗给药。
标记的抗体成像方法
在本发明的另一个实施方案中,可以用放射性核素、荧光染料、激发生物发光的底物部分、激发化学发光的部分、酶和其它检测标记通过半胱氨酸巯基来标记半胱氨酸改造的抗体以便用于具有诊断、药效学和治疗应用的成像实验。一般而言,通过注射、灌注或口服摄入对活生物体,例如人、啮齿动物或其它小动物、灌注器官或组织样品给予标记的半胱氨酸改造的抗体,即“生物标记物”或“探针”。在一定时间过程中检测探针的分布并且由影像显示。
制品
在本发明的另一个实施方案中,提供了含有用于治疗上述病症的物质的制品或“试剂盒”。所述的制品包含容器和在容器上或与其相连的标签或包装说明书。合适的容器包括:例如瓶、小瓶、注射器、泡罩包等,容器可以由各种材料,诸如玻璃或塑料形成。容器可以容纳有效治疗疾病的抗体-药物偶联物(ADC)组合物并且可以具有无菌存取口(例如容器可以为静脉用溶液袋或具有可刺入皮下注射针头的塞的小瓶)。组合物中至少一种活性剂为ADC。标签或包装说明书表示组合物用于治疗选择的疾病,诸如癌症。或者或另外,所述制品可以进一步含有第二种(或第三种)容器,该容器包含药学上可接受的缓冲剂,诸如抑菌性注射用水(BWFI)、磷酸缓冲盐水、林格液和葡萄糖溶液。它可以进一步包括从商业和使用者角度而言需要的其它物质,包括其它缓冲液、稀释剂、过滤器、针头和注射器。
实施例
实施例1-生物素化的ThioFab噬菌体的制备
使ThioFab-噬菌体(5x 1012噬菌体颗粒)与150倍过量的生物素-PEO-马来酰亚胺((+)-生物素基-3-马来酰亚氨基丙酰胺基-3,6-二氧杂辛二胺(biotin-PEO-maleimide((+)-biotinyl-3-maleimidopropionamidyl-3,6-dioxaoctainediamine),Oda等(2001)Nature Biotechnology 19:379-382,PierceBiotechnology,Inc.)在室温反应3小时。通过重复PEG沉淀(3-4次)从生物素-偶联的噬菌体中除去过量的生物素-PEO-马来酰亚胺。可以使用其它商购的带有亲电子基团的与半胱氨酸巯基反应的生物素化试剂,包括生物素-BMCC、PEO-碘乙酰基生物素、碘乙酰基-LC-生物素和生物素-HPDP(PierceBiotechnology,Inc.)和Nα-(3-马来酰亚胺基丙酰基)生物胞素(Nα-(3-maleimidylpropionyl)biocytin)(MPB,Molecular Probes,Eugene,OR)。其它生物素化的双官能和多官能连接基试剂的商品来源包括Molecular Probes,Eugene,OR和Sigma,St.Louis,MO。
生物素-PEO-马来酰亚胺
实施例2–PHESELECTOR测定法
将牛血清清蛋白(BSA)、erbB2胞外结构域(HER2)和链霉抗生物素(100μl的2μg/ml)分别包被在Maxisorp 96孔平板上。在用0.5%Tween-20(在PBS中)封闭后,在室温孵育生物素化和未-生物素化的hu4D5Fabv8-ThioFab-噬菌体(2x1010个噬菌体颗粒)1小时,随后与辣根过氧化物酶(HRP)标记的二抗(抗-M13噬菌体包膜蛋白,pVIII蛋白抗体)一起孵育。附图8通过描绘Fab或ThioFab与HER2(上)和生物素化的ThioFab与链霉抗生物素(下)结合的图示例示了PHESELECTOR测定法。
进行标准HRP反应并且在450nm处测定吸光度。通过计算链霉抗生物素的OD450/HER2的OD450之比测定巯基反应性。巯基反应值为1表示半胱氨酸巯基完全生物素化。就Fab蛋白结合测定而言,使用hu4D5Fabv8(2-20ng),随后与HRP标记的山羊多克隆抗-Fab抗体一起温育。
实施例3a–ThioFabs的表达和纯化
在非阻抑性大肠杆菌菌株34B8中诱导时表达ThioFabs(Baca等(1997)Journal Biological Chemistry 272(16):10678-84)。将收集的细胞沉淀重新悬浮于PBS(磷酸缓冲盐水)中,使所述细胞沉淀经过微流化仪(microfluidier)进行完全细胞裂解并且通过使用蛋白质G SEPHAROSETM(Amersham)的亲和层析法纯化ThioFabs。
表达ThioFabs L-V15C、L-V110C、H-A88C和H-A121C并且通过蛋白质-G SEPHAROSETM柱层析法纯化。寡聚-Fab存在于级分26-30中,并且大部分单体形式存在于级分31-34中。收集由单体形式组成的级分并且通过SDS-PAGE分析它们以及野生型hu4D5Fabv8,并且用SDS-PAGE凝胶在还原(使用DTT或BME)和非-还原(不使用DTT或BME)条件下分析。使用非-还原SDS-PAGE分析A121C-ThioFab的凝胶过滤级分。
如上所述使ThioFabs与生物素-PEO-马来酰亚胺偶联并且通过Superdex-200TM(Amersham)凝胶过滤层析法进一步纯化生物素化-ThioFabs,该过程消除了游离的生物素-PEO-马来酰亚胺和ThioFabs的寡聚级分。将野生型hu4D5Fabv8和hu4D5Fabv8A121C-ThioFab(用量0.5mg)各自和单独与100倍摩尔过量的生物素-PEO-马来酰亚胺在室温温育3小时并且上样至Superdex-200凝胶过滤柱,以便从单体形式中分离游离的生物素和寡聚Fabs。
实施例3b–ThioFabs的分析
通过液相层析电喷射离子化质谱(LS-ESI-MS)分析生物素化的hu4D5Fabv8(A121C)ThioFab和野生型hu4D5Fabv8的酶促消化片段。生物素化的hu4D5Fabv8(A121C)的原始质量48294.5与野生型hu4D5Fabv8的原始质量47737.0之差为557.5质量单位。该片段表明存在单一生物素-PEO-马来酰亚胺部分(C23H36N5O7S2)。表4显示了片段化值,其证实了该序列。
表4.胰蛋白酶消化后生物素化的hu4D5Fabv8 ThioFab A121C的LC-ESI-质谱分析
氨基酸 | b片段 | y片段 |
A(丙氨酸) | 72 | |
M(甲硫氨酸) | 203 | 2505 |
D(天冬氨酸) | 318 | 2374 |
Y(酪氨酸) | 481 | 2259 |
W(色氨酸) | 667 | 2096 |
G(甘氨酸) | 724 | 1910 |
Q(谷氨酰胺) | 852 | 1853 |
G(甘氨酸) | 909 | 1725 |
T(苏氨酸) | 1010 | 1668 |
L(亮氨酸) | 1123 | 1567 |
V(缬氨酸) | 1222 | 1454 |
T(苏氨酸) | 1323 | 1355 |
V(缬氨酸) | 1422 | 1254 |
S(丝氨酸) | 1509 | 1155 |
S(丝氨酸) | 1596 | 1068 |
C(半胱氨酸)+生物素 | 2242 | 981 |
S(丝氨酸) | 2329 | 335 |
T(苏氨酸) | 2430 | 248 |
K(赖氨酸) | 175 |
在Superdex-200凝胶过滤前后,对生物素化的ABP-hu4D5Fabv8-A121C、生物素化的ABP-hu4D5Fabv8-V110C、生物素化的双Cys ABP-hu4D5Fabv8-(V110C-A88C)和生物素化的双CysABP-hu4D5Fabv8-(V110C-A121C)进行使用和不使用DTT或BME还原的SDS-PAGE凝胶分析。
hu4D5Fabv8-(V110C)-BMPEO-DM1的质谱分析(MS/MS)(Superdex-200凝胶过滤纯化后):Fab+1 51607.5;Fab 50515.5。该数据表示91.2%偶联。hu4D5Fabv8-(V110C)-BMPEO-DM1(还原的)的MS/MS分析:LC 23447.2;LC+1 24537.3;HC(Fab)27072.5。该数据表示所有DM1偶联均在Fab的轻链上。
实施例4-通过偶联ABP-hu4D5Fabv8-(V110C)和MC-MMAE制备
ABP-hu4D5Fabv8-(V110C)-MC-MMAE
用已知浓度的乙腈和水稀释溶于DMSO的药物连接基试剂马来酰亚氨基辛酰基-一甲基auristatin E(maleimidocaproyl-monomethyl auristatin E)(MMAE),即MC-MMAE并且加入到冷却的在磷酸缓冲盐水(PBS)中的ABP-hu4D5Fabv8-(V110C)ThioFab中。在约1小时后,加入过量的马来酰亚胺以使反应猝灭并且将任何未反应的抗体巯基封端。通过离心超滤浓缩该反应混合物并且纯化ABP-hu4D5Fabv8-(V110C)-MC-MMAE且通过经在PBS中的G25树脂洗脱而脱盐,通过0.2μm滤膜在无菌条件下过滤并且冷冻以便贮存。
实施例5–通过偶联ABP-hu4D5Fabv8-(V110C)和MC-MMAF制备
ABP-hu4D5Fabv8-(V110C)-MC-MMAF
按照实施例4的操作步骤,通过偶联ABP-hu4D5Fabv8-(V110C)ThioFab和MC-MMAF制备ABP-hu4D5Fabv8-(V110C)-MC-MMAF。
实施例6–通过偶联ABP-A121C-ThioFab和MC-val-cit-PAB-MMAE制
备ABP-A121C-ThioFab-MC-val-cit-PAB-MMAE
按照实施例4的操作步骤,通过偶联ABP-hu4D5Fabv8-(A121C)和MC-val-cit-PAB-MMAE制备ABP-hu4D5Fabv8-(A121C)-MC-val-cit-PAB-MMAE。
实施例7–通过偶联ABP-A121C-ThioFab和MC-val-cit-PAB-MMAF制
备ABP-A121C-ThioFab-MC-val-cit-PAB-MMAF
按照实施例4的操作步骤,通过偶联ABP-hu4D5Fabv8-(A121C)和MC-val-cit-PAB-MMAF制备ABP-hu4D5Fabv8-(A121C)-MC-val-cit-PAB-MMAF。
MC-val-cit-PAB-MMAF
实施例8-hu4D5Fabv8-(V110C)ThioFab-BMPEO-DM1的制备
用双-马来酰亚胺试剂BM(PEO)4(Pierce Chemical)修饰hu4D5Fabv8-(V110C)ThioFab上的游离半胱氨酸,在抗体的表面上留下未反应的马来酰亚胺基。该过程通过下列步骤完成:将BM(PEO)4溶于50%乙醇/水混合物至10mM浓度并且向在磷酸缓冲盐水中含有hu4D5Fabv8-(V110C)ThioFab的溶液中加入10倍摩尔过量的约1.6mg/ml(10微摩尔)的BM(PEO)4,且使其反应1小时。通过在含有150mM NaCl缓冲液的30mM柠檬酸盐,pH 6中的凝胶过滤除去过量的BM(PEO)4(HiTrap column,Pharmacia)。向hu4D5Fabv8-(V110C)ThioFab-BMPEO中间体中加入约10倍摩尔过量的溶于二甲基乙酰胺(DMA)的DM1。还可以将二甲基甲酰胺(DMF)用于溶解药物部分试剂。使该反应混合物反应过夜,此后进行凝胶过滤或透析入PBS以便除去未反应的药物。将在PBS中的S200柱上的凝胶过滤用于除去高分子量聚集物并且得到纯化的hu4D5Fabv8-(V110C)ThioFab-BMPEO-DM1。
通过相同的方案制备hu4D5Fabv8(A121C)ThioFab-BMPEO-DM1。
实施例9–体外细胞增殖试验
通过使用下列方案的细胞增殖试验测定ADC功效(CellTiter GloLuminiscent Cell Viability Assay,Promega Corp.Technical Bulletin TB288;Mendoza等(2002)Cancer Res.62:5485-5488):
1.使在培养基中含有约104个细胞(SKBR-3、BT474、MCF7或MDA-MB-468)的100μl细胞培养物等份沉积在96-孔不透明壁的平板的各孔中。
2.制备含有培养基,但不含细胞的对照孔。
3.将ADC加入到实验孔中并且温育3-5天。
4.使平板平衡至室温约30分钟。
5.加入等于存在于各孔中的细胞培养基的体积的CellTiter-Glo Reagent。
6.将内含物在定轨振荡器上混合2分钟以便诱导细胞裂解。
7.将平板在室温温育10分钟以便稳定发光信号。
8.记录发光并且作为RLU=相对发光单位在图中报导。
将某些细胞以1000-2000/孔(PC3系)或2000-3000/孔(OVCAR-3)接种在96-孔平板上,50uL/孔。在1(PC3)或2(OVCAR-3)天后,加入在50μL体积中的ADC至终浓度为9000,3000,1000,333,111,37,12.4,4.1或1.4ng/mL,其中"无ADC"对照孔仅接受培养基。条件为一式两份或一式三份。3(PC3)或4-5(OVCAR-3)天后,加入100μL/孔Cell TiterGlo II(基于荧光素酶的试验;根据ATP水平测定的增殖)并且使用发光计测定细胞计数。将数据绘制成各组重复测定的发光平均值,其中使用标准偏差条柱形图。该方案为CellTiterGlo Luminiscent Cell Viability Assay(Promega)的修改方案:
1.用1000细胞/孔的PC3/Muc16,PC3/neo(在50μL/孔中)的培养基铺板。应将Ovcar3细胞以2000细胞/孔(在50μL中)的其培养基铺板(培养基的配方如下)。允许细胞附着过夜。
2.以18μg/ml的工作浓度开始按照顺序在培养基中以1:3连续稀释ADC(这导致终浓度为9μg/ml)。将50μL稀释的ADC加入到已经在孔中的50μL细胞和培养基中。
3.孵育72-96小时(标准品为72小时,但在细胞达到85-95%融合率时,观察到0ug/mL浓度,终止试验)。
4.加入100μL/孔的Promega Cell Titer Glo试剂,振摇3分钟并且在发光计上读数。
培养基:PC3/neo和PC3/MUC16生长在50/50/10%FBS/谷氨酰胺/250μg/mL G-418OVCAR-3生长在RPMI/20%FBS/谷氨酰胺中。
实施例10–高度表达HER2的转基因外植体小鼠的肿瘤生长抑制体内功
效
适合于转基因实验的动物可以获自标准商业来源,诸如Taconic(Germantown,N.Y.)。许多品系都是合适的,但优选FVB雌性小鼠,因为它们对肿瘤形成高度易感。将FVB雄小鼠用于交配并且将切除输精管的CD.1种畜用于刺激假性妊娠。切除输精管的小鼠可以获自任何商品供应商。使用FVB小鼠或129/BL6 x FVB p53杂合型小鼠繁殖建立者(Founder)。将在p53等位基因上具有杂合性的小鼠用于潜在地增加肿瘤形成。然而,已经证实这是不必要的。因此,某些F1肿瘤具有混合的品系。建立者的肿瘤仅为FVB。获得了有某种程度的肿瘤发生但未产仔的6个建立者。
通过IV注射ADC用单剂量或多剂治疗具有肿瘤(由Fo5mmtv转基因小鼠繁殖的同种异体移植物)的动物。在注射后的不同时间点评价肿瘤体积。
肿瘤易于在转基因小鼠中产生,这些小鼠表达neu的突变活化形式,即大鼠HER2的同源物,而在人乳腺癌中过表达的HER2未突变并且肿瘤形成远低于过表达未突变HER2的转基因小鼠(Webster等(1994)Semin.Cancer Biol.5:69-76)。
为了改善具有未突变的HER2的肿瘤形成,使用HER2cDNA质粒生成转基因小鼠,其中ATG的上游缺失,以便防止在这类上游ATG密码子上起始翻译,否则就可能减少从HER2的下游真正起始密码子起始翻译的频率(例如,参见Child等(1999)J.Biol.Chem.274:24335-24341)。另外,将嵌合内含子添加到5’末端上,这也应如以前报导的提高表达水平(Neuberger和Williams(1988)Nucleic Acids Res.16:6713;Buchman和Berg(1988)Mol.Cell.Biol.8:4395;Brinster等(1988)Proc.Natl.Acad.Sci.USA 85:836)。嵌合内含子来源于Promega载体,即Pci-neo哺乳动物表达载体(bp 890-1022)。cDNA 3’-末端位于人生长激素外显子4和5和聚腺苷酸化序列的侧翼。此外,使用FVB小鼠,因为该品系更易感肿瘤发生。来自MMTV-LTR的启动子用于确保在乳腺中的组织特异性HER2表达。给动物饲喂AIN 76A膳食以便增加对肿瘤形成的易感性(Rao等(1997)Breast Cancer Res.and Treatment 45:149-158)。
实施例11–用于偶联的ThioMabs的还原/氧化
用约50倍过量的TCEP(三(2-羧乙基)膦盐酸盐(tris(2-carboxyethyl)phosphine hydrochloride);Getz等(1999)Anal.Biochem.Vol 273:73-80;Soltec Ventures,Beverly,MA)在37℃将在CHO细胞中表达的全长半胱氨酸改造的单克隆抗体(ThioMabs)还原3小时。稀释还原的ThioMab(附图15)并且上样到10mM乙酸钠,pH 5中的HiTrap S柱上并且用含有0.3M氯化钠的PBS洗脱。在室温用200nM硫酸铜水溶液(CuSO4)将洗脱的还原的ThioMab处理过夜。环境空气氧化也是有效的。
实施例12–ThioMabs的偶联
将来自实施例11的再氧化的ThioMabs,包括硫代-曲妥单抗(A121C)、thio-2H9(A121C)和thio-3A5(A121C)与10倍过量的药物-连接基中间体BM(PEO)4-DM1合并,混合并且在室温保持约1小时,以便进行偶联并且形成ThioMab抗体-药物偶联物,包括硫代-曲妥单抗(A121C)-BMPEO-DM1、thio-2H9(A121C)-BMPEO-DM1和thio-3A5(A121C)-BMPEO-DM1。将该偶联混合物进行凝胶过滤或上柱并且通过HiTrap S柱洗脱以便除去过量的药物-连接基中间体和其它杂质。
本发明并不限于由实施例中披露的具体实施方案的范围,这些实施例用来例示本发明的几个方面并且在功能上等效的任意实施方案均属于本发明的范围。实际上,除本文所示和所述的外,本发明的各种变型也对本领域技术人员而言也是显而易见的并且属于本文所附权利要求的范围。
本发明涉及下述各项。
1.半胱氨酸改造的抗体,包含具有0.6-1.0的巯基反应值的一个或多个游离半胱氨酸氨基酸;
其中通过包含用半胱氨酸取代亲代抗体的一种或多种氨基酸残基的方法制备半胱氨酸改造的抗体。
2.项1所述的半胱氨酸改造的抗体,其中半胱氨酸改造的抗体比亲代抗体更易于与巯基-反应试剂反应。
3.项1所述的半胱氨酸改造的抗体,其中所述的方法进一步包含通过使半胱氨酸改造的抗体与巯基-反应试剂反应测定半胱氨酸改造的抗体的巯基反应性;
其中半胱氨酸改造的抗体比亲代抗体更易于与巯基-反应试剂反应。
4.项1所述的半胱氨酸改造的抗体,其中一个或多个游离半胱氨酸氨基酸残基位于轻链上。
5.项4所述的半胱氨酸改造的抗体,其中一个或多个游离半胱氨酸氨基酸残基位于轻链,选自如下范围:L-10-L-20;L-38-L-48;L-105-L-115;L-139-L-149;和L-163-L-173。
6.项1所述的半胱氨酸改造的抗体,包含选自下列的一种或多种序列:
7.项1所述的半胱氨酸改造的抗体,包含选自下列的一种或多种序列:
8.项1所述的半胱氨酸改造的抗体,包含选自下列的一种或多种序列:
9.项1所述的半胱氨酸改造的抗体,其中一个或多个游离半胱氨酸氨基酸残基位于重链上。
10.项9所述的半胱氨酸改造的抗体,其中一个或多个游离半胱氨酸氨基酸残基位于重链,选自如下范围:H-35-H-45;H-83-H-93;H-114-H-127;和H-170-H-184。
11.项1所述的半胱氨酸改造的抗体,包含选自下列的一种或多种序列:
12.项9所述的半胱氨酸改造的抗体,其中一个或多个游离半胱氨酸氨基酸残基位于重链的Fc区中,选自:H-268-H-291、H-319-H-344、H-370-H-380和H-395-H-405范围。
13.项1所述的半胱氨酸改造的抗体,包含选自下列的一种或多种序列:
14.项1所述的半胱氨酸改造的抗体,其中一个或多个游离半胱氨酸氨基酸残基选自重链或轻链可变区中的位置。
15.项1所述的半胱氨酸改造的抗体,其中一个或多个游离半胱氨酸氨基酸残基选自恒定区中的位置。
16.项1所述的抗体,其中巯基反应值在0.7-1.0的范围。
17.项1所述的半胱氨酸改造的抗体,其中巯基反应值在0.8-1.0的范围。
18.通过一种方法制备的项1的半胱氨酸改造的抗体,所述的方法包含:
(i)诱变编码半胱氨酸改造的抗体的核酸序列;
(ii)表达半胱氨酸改造的抗体;和
(iii)分离和纯化半胱氨酸改造的抗体。
19.项18所述的半胱氨酸改造的抗体,其中诱变包含位点定向诱变。
20.项18所述的半胱氨酸改造的抗体,其中在选自噬菌体或噬菌粒颗粒的病毒颗粒上表达半胱氨酸改造的抗体。
21.项18所述的半胱氨酸改造的抗体,进一步包含:
(i)使半胱氨酸改造的抗体与巯基-反应性亲和试剂反应而生成亲和标记的半胱氨酸改造的抗体;和
(ii)测定亲和标记的半胱氨酸改造的抗体与俘获培养基的结合。
22.项21所述的半胱氨酸改造的抗体,其中巯基-反应性亲和试剂包含生物素部分。
23.项22所述的半胱氨酸改造的抗体,其中巯基-反应试剂包含马来酰亚胺部分。
24.项21所述的半胱氨酸改造的抗体,其中俘获培养基包含链霉抗生物素。
25.项1所述的半胱氨酸改造的抗体,其中亲代抗体为包含清蛋白结合肽(ABP)的融合蛋白。
26.项21所述的半胱氨酸改造的抗体,其中ABP包含选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4和SEQ ID NO:5的序列。
27.项1所述的半胱氨酸改造的抗体,其中亲代抗体选自单克隆抗体、双特异性抗体、嵌合抗体、人抗体和人源化抗体。
28.项27所述的半胱氨酸改造的抗体,其中亲代抗体为huMAb4D5-8(曲妥单抗)。
29.项27所述的半胱氨酸改造的抗体,其中亲代抗体为抗-EphB2R抗体。
30.项27所述的半胱氨酸改造的抗体,其中亲代抗体为抗-MUC16抗体。
31.项2所述的半胱氨酸改造的抗体,包含选自SEQ ID NO:6、SEQ IDNO:7、SEQ ID NO:8、SEQ ID NO:28和SEQ ID NO:39的氨基酸序列。
32.项1所述的半胱氨酸改造的抗体,其中亲代抗体为选自IgA、IgD、IgE、IgG和IgM的完整抗体。
33.项32所述的半胱氨酸改造的抗体,其中IgG选自IgG1、IgG2、IgG3、IgG4、IgA和IgA2亚类。
34.项1所述的半胱氨酸改造的抗体,其中亲代抗体为抗体片段。
35.项34所述的半胱氨酸改造的抗体,其中抗体片段为Fab片段。
36.项35所述的半胱氨酸改造的抗体,其中Fab片段为hu4D5Fabv8。
37.项36所述的半胱氨酸改造的抗体,其中被半胱氨酸取代的hu4D5Fabv8的氨基酸残基中的一种或多种选自L-V15、L-A43、L-V110、L-A144、L-S168、H-A40、H-A88、H-S119、H-S120、H-A121、H-S122、H-A175和H-S179。
38.项1所述的半胱氨酸改造的抗体,其中半胱氨酸改造的抗体或亲代抗体结合受体(1)-(36)中的一种或多种:
(1)BMPR1B(骨形态发生蛋白受体-IB型,Genbank登记号NM_001203);
(2)E16(LAT1,SLC7A5,Genbank登记号NM_003486);
(3)STEAP1(前列腺的六跨膜上皮细胞抗原,Genbank登记号NM_012449);
(4)0772P(CA125,MUC16,Genbank登记号AF361486);
(5)MPF(MPF,MSLN,SMR,巨核细胞强化因子,mesothelin,Genbank登记号NM_005823);
(6)Napi3b(NAPI-3B,NPTIIb,SLC34A2,溶质载体家族34(磷酸钠),成员2,II型钠依赖性磷酸转运蛋白3b,Genbank登记号NM_006424);
(7)Sema 5b(FLJ10372,KIAA1445,Mm.42015,SEMA5B,SEMAG,脑信号蛋白5b Hlog,sema结构域,七血小板反应蛋白重复(1型和类1型),跨膜结构域(TM)和短胞质域,(脑信号蛋白)5B,Genbank登记号AB040878);
(8)PSCA hlg(2700050C12Rik,C530008O16Rik,RIKEN cDNA2700050C12,RIKEN cDNA 2700050C12基因,Genbank登记号AY358628);
(9)ETBR(内皮缩血管肽B型受体,Genbank登记号AY275463);
(10)MSG783(RNF124,推定蛋白FLJ20315,Genbank登记号NM_017763);
(11)STEAP2(HGNC_8639,IPCA-1,PCANAP1,STAMP1,STEAP2,STMP,前列腺癌相关基因1,前列腺癌相关蛋白1,前列腺的六跨膜上皮细胞抗原2,六跨膜前列腺蛋白,Genbank登记号AF455138);
(12)TrpM4(BR22450,FLJ20041,TRPM4,TRPM4B,瞬时型受体电位阳离子通道,亚家族M,成员4,Genbank登记号NM_017636);
(13)CRIPTO(CR,CR1,CRGF,CRIPTO,TDGF1,畸胎瘤-衍生的生长因子,Genbank登记号NP_003203或NM_003212);
(14)CD21(CR2(补体受体2)或C3DR(C3d/EB病毒受体)或Hs.73792Genbank登记号M26004);
(15)CD79b(CD79B,CD79β,IGb(免疫球蛋白-相关β),B29,Genbank登记号NM_000626);
(16)FcRH2(IFGP4,IRTA4,SPAP1A(含有磷酸酶锚定蛋白1a的SH2结构域),SPAP1B,SPAP1C,Genbank登记号NM_030764);
(17)HER2(Genbank登记号M11730);
(18)NCA(Genbank登记号M18728);
(19)MDP(Genbank登记号BC017023);
(20)IL20Rα(Genbank登记号AF184971);
(21)Brevican(Genbank登记号AF229053);
(22)EphB2R(Genbank登记号NM_004442);
(23)ASLG659(Genbank登记号AX092328);
(24)PSCA(Genbank登记号AJ297436);
(25)GEDA(Genbank登记号AY260763;
(26)BAFF-R(B细胞-活化因子受体,BLyS受体3,BR3,NP_443177.1);
(27)CD22(B-细胞受体CD22-B同种型,NP-001762.1);
(28)CD79a(CD79A,CD79α,免疫球蛋白-相关α,即与Igβ(CD79B)发生共价相互作用并且在表面上与IgM分子形成复合物,转导B-细胞分化中涉及的信号的B细胞-特异性蛋白,Genbank登记号NP_001774.1);
(29)CXCR5(伯基特淋巴瘤受体1,即被CXCL13趋化因子活化,在淋巴细胞迁移和体液防御中起作用,在HIV-2感染并且可能是AIDS、淋巴瘤、骨髓瘤和白血病发生中起作用的G蛋白-偶联受体,Genbank登记号NP_001707.1);
(30)HLA-DOB(结合肽类并且将它们呈递给CD4+T淋巴细胞的MHC II类分子β亚单位(Ia抗原),Genbank登记号NP_002111.1);
(31)P2X5(嘌呤能受体P2X配体门控性离子通道5,即胞外ATP门控的离子通道可能涉及突触传递和神经发生,缺乏可能促使特发性逼尿肌不稳定病理生理学情况,Genbank登记号NP_002552.2);
(32)CD72(B-细胞分化抗原CD72,Lyb-2,Genbank登记号NP_001773.1);
(33)LY64(淋巴细胞抗原64(RP105),即富亮氨酸重复(LRR)家族的I型膜蛋白,调节B-细胞活化和程序性细胞死亡,功能缺失与患有系统性红斑狼疮的患者中疾病活动增加有关,Genbank登记号NP_005573.1);
(34)FcRH1(Fc受体-样蛋白1,即含有C2型Ig-样和ITAM结构域的免疫球蛋白Fc结构域的推定受体,可能在B-淋巴细胞分化中有作用,Genbank登记号NP_443170.1);
(35)IRTA2(免疫球蛋白超家族受体易位相关蛋白2,即在B细胞发育和淋巴瘤的生成中具有可能的作用的推定免疫受体;基因因易位而失调在某些B细胞恶性肿瘤中发生,Genbank登记号NP_112571.1);和
(36)TENB2(推定的跨膜蛋白聚糖,涉及生长因子的EGF/调蛋白家族和卵泡素抑制素,Genbank登记号AF179274。
39.项1所述的半胱氨酸改造的抗体,其中该抗体与药物部分共价结合。
40.项1所述的半胱氨酸改造的抗体,其中该抗体与俘获标记、检测标记或固相支持物共价结合。
41.项40所述的半胱氨酸改造的抗体,其中该抗体与生物素俘获标记共价结合。
42.项40所述的半胱氨酸改造的抗体,其中该抗体与荧光染料检测标记共价结合。
43.项42所述的半胱氨酸改造的抗体,其中荧光染料选自荧光素类染料、若丹明类染料、丹酰、丽丝胺、花菁、藻红蛋白、德克萨斯红及其类似物。
44.项40所述的半胱氨酸改造的抗体,其中该抗体与放射性核素检测标记共价结合,所述的放射性核素检测标记选自3H、11C、14C、18F、32P、35S、64Cu、68Ga、86Y、99Tc、111In、123I、124I、125I、131I、133Xe、177Lu、211At和213Bi。
45.项40所述的半胱氨酸改造的抗体,其中该抗体通过螯合配体与检测标记共价结合。
46.项45所述的半胱氨酸改造的抗体,其中螯合配体选自DOTA、DOTP、DOTMA、DTPA和TETA。
47.筛选半胱氨酸改造的抗体的巯基反应性的方法,包含:
(a)将一个或多个半胱氨酸氨基酸导入亲代抗体以便产生半胱氨酸改造的抗体;
(b)使半胱氨酸改造的抗体与巯基-反应性亲和试剂反应而产生亲和标记的半胱氨酸改造的抗体;和
(c)测定亲和标记的半胱氨酸改造的抗体与俘获培养基的结合。
48.项47所述的筛选方法,进一步包含测定半胱氨酸改造的抗体与巯基-反应试剂的巯基反应性。
49.项47所述的筛选方法,其中该方法的步骤(a)包含:
(i)双链质粒中编码半胱氨酸改造的抗体的基因的位点定向诱变;和
(ii)表达半胱氨酸改造的抗体。
50.项49所述的筛选方法,进一步包含分离和纯化表达的半胱氨酸改造的抗体。
51.项47所述的筛选方法,其中巯基反应性亲和试剂包含生物素部分。
52.项47所述的筛选方法,其中巯基-反应试剂包含马来酰亚胺部分。
53.项47所述的筛选方法,其中俘获培养基包含链霉抗生物素。
54.项47所述的筛选方法,其中亲代抗体为包含清蛋白结合肽(ABP)的融合蛋白。
55.项54所述的筛选方法,其中ABP包含选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4和SEQ ID NO:5的序列。
56.项47所述的筛选方法,其中亲代抗体为抗体片段Fab。
57.抗体-药物偶联物化合物,包含半胱氨酸改造的抗体(Ab)和药物部分(D),其中半胱氨酸改造的抗体通过经连接基部分(L)的一个或多个游离半胱氨酸氨基酸与D结合;该化合物具有式I:
Ab-(L-D)p I
其中p为1、2、3或4;并且其中通过这样的方法制备半胱氨酸改造的抗体,该方法包含用一个或多个游离半胱氨酸氨基酸取代亲代抗体的一种或多种氨基酸残基。
58.项57所述的抗体-药物偶联物化合物,其中半胱氨酸改造的抗体比亲代抗体更易于与巯基-反应试剂反应。
59.项57所述的抗体-药物偶联物化合物,其中通过如下方法制备半胱氨酸改造的抗体,该方法包含:
(a)用半胱氨酸取代亲代抗体的一种或多种氨基酸残基;和
(b)通过使半胱氨酸改造的抗体与巯基-反应试剂反应测定半胱氨酸改造的抗体的巯基反应性;
其中半胱氨酸改造的抗体比亲代抗体更易于与巯基-反应试剂反应。
60.项57所述的抗体-药物偶联物化合物,进一步包含清蛋白-结合肽(ABP)序列。
61.项60所述的抗体-药物偶联物化合物,其中ABP包含选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4和SEQ ID NO:5的序列。
62.项57所述的抗体-药物偶联物化合物,其中半胱氨酸改造的抗体结合选自EGFR、HER2、HER3和HER4的ErbB受体。
63.项57所述的抗体-药物偶联物化合物,其中半胱氨酸改造的抗体或亲代抗体结合受体(1)-(36)中的一种或多种:
(1)BMPR1B(骨形态发生蛋白受体-IB型,Genbank登记号NM_001203);
(2)E16(LAT1,SLC7A5,Genbank登记号NM_003486);
(3)STEAP1(前列腺的六跨膜上皮细胞抗原,Genbank登记号NM_012449);
(4)0772P(CA125,MUC16,Genbank登记号AF361486);
(5)MPF(MPF,MSLN,SMR,巨核细胞强化因子,mesothelin,Genbank登记号NM_005823);
(6)Napi3b(NAPI-3B,NPTIIb,SLC34A2,溶质载体家族34(磷酸钠),成员2,II型钠依赖性磷酸转运蛋白3b,Genbank登记号NM_006424);
(7)Sema 5b(FLJ10372,KIAA1445,Mm.42015,SEMA5B,SEMAG,脑信号蛋白5b Hlog,sema结构域,七血小板反应蛋白重复(1型和类1型),跨膜结构域(TM)和短胞质域,(脑信号蛋白)5B,Genbank登记号AB040878);
(8)PSCA hlg(2700050C12Rik,C530008O16Rik,RIKEN cDNA2700050C12,RIKEN cDNA 2700050C12基因,Genbank登记号AY358628);
(9)ETBR(内皮缩血管肽B型受体,Genbank登记号AY275463);
(10)MSG783(RNF124,推定蛋白FLJ20315,Genbank登记号NM_017763);
(11)STEAP2(HGNC_8639,IPCA-1,PCANAP1,STAMP1,STEAP2,STMP,前列腺癌相关基因1,前列腺癌相关蛋白1,前列腺的六跨膜上皮细胞抗原2,六跨膜前列腺蛋白,Genbank登记号AF455138);
(12)TrpM4(BR22450,FLJ20041,TRPM4,TRPM4B,瞬时型受体电位阳离子通道,亚族M,成员4,Genbank登记号NM_017636);
(13)CRIPTO(CR,CR1,CRGF,CRIPTO,TDGF1,畸胎瘤-衍生的生长因子,Genbank登记号NP_003203或NM_003212);
(14)CD21(CR2(补体受体2)或C3DR(C3d/EB病毒受体)或Hs.73792Genbank登记号M26004);
(15)CD79b(CD79B,CD79β,IGb(免疫球蛋白-相关β),B29,Genbank登记号NM_000626);
(16)FcRH2(IFGP4,IRTA4,SPAP1A(含有磷酸酶锚定蛋白1a的SH2结构域),SPAP1B,SPAP1C,Genbank登记号NM_030764);
(17)HER2(Genbank登记号M11730);
(18)NCA(Genbank登记号M18728);
(19)MDP(Genbank登记号BC017023);
(20)IL20Rα(Genbank登记号AF184971);
(21)Brevican(Genbank登记号AF229053);
(22)EphB2R(Genbank登记号NM_004442);
(23)ASLG659(Genbank登记号AX092328);
(24)PSCA(Genbank登记号AJ297436);
(25)GEDA(Genbank登记号AY260763;
(26)BAFF-R(B细胞-活化因子受体,BLyS受体3,BR3,NP_443177.1);
(27)CD22(B-细胞受体CD22-B同种型,NP-001762.1);
(28)CD79a(CD79A,CD79α,免疫球蛋白-相关α,即与Igβ(CD79B)发生共价相互作用并且在表面上与Ig M分子形成复合物,转导B-细胞分化中涉及的信号的B细胞-特异性蛋白,Genbank登记号NP_001774.1);
(29)CXCR5(伯基特淋巴瘤受体1,即被CXCL13趋化因子活化,在淋巴细胞迁移和体液防御中起作用,在HIV-2感染并且可能是AIDS、淋巴瘤、骨髓瘤和白血病发生中起作用的G蛋白-偶联受体,Genbank登记号NP_001707.1);
(30)HLA-DOB(结合肽类并且将它们呈递给CD4+T淋巴细胞的MHC II类分子β亚单位(Ia抗原),Genbank登记号NP_002111.1);
(31)P2X5(嘌呤能受体P2X配体门控性离子通道5,即胞外ATP门控的离子通道可以涉及突触传递和神经发生,缺乏可能促使特发性逼尿肌不稳定病理生理学情况,Genbank登记号NP_002552.2);
(32)CD72(B-细胞分化抗原CD72,Lyb-2,Genbank登记号NP_001773.1);
(33)LY64(淋巴细胞抗原64(RP105),即富亮氨酸重复(LRR)家族的I型膜蛋白调节B-细胞活化和程序性细胞死亡,功能缺失与患有系统性红斑狼疮的患者中疾病活动增加有关,Genbank登记号NP_005573.1);
(34)FcRH1(Fc受体-样蛋白1,即含有C2型Ig-样结构域和ITAM结构域的免疫球蛋白Fc结构域的推定受体,可能在B-淋巴细胞分化中有作用,Genbank登记号NP_443170.1);
(35)IRTA2(免疫球蛋白超家族受体易位相关蛋白2,即在B细胞发育和淋巴瘤的生成中具有可能的作用的推定免疫受体;基因因易位而失调在某些B细胞恶性肿瘤中发生,Genbank登记号NP_112571.1);和
(36)TENB2(推定的跨膜蛋白聚糖,与生长因子的EGF/调蛋白家族和卵泡素抑制素有关,Genbank登记号AF179274。
64.项57所述的抗体-药物偶联物化合物,其中p为1。
65.项57所述的抗体-药物偶联物化合物,其中p为2。
66.项57所述的抗体-药物偶联物化合物,其中L具有下式:
-Aa-Ww-Yy-
其中:
A为与半胱氨酸改造的抗体(Ab)的半胱氨酸巯基共价结合的Stretcher单元;
a为0或1;
W各自独立为氨基酸单元;
w为0-12的整数;
Y为与药物部分共价结合的间隔基;且
y为0、1或2。
67.项66所述的抗体-药物偶联物化合物,具有下式:
其中PAB为对-氨基苄基氨基甲酰基,且R17为二价基团,该二价基团选自(CH2)r、C3-C8碳环基、O-(CH2)r、亚芳基、(CH2)r-亚芳基、-亚芳基-(CH2)r-、(CH2)r-(C3-C8碳环基)、(C3-C8碳环基)-(CH2)r、C3-C8杂环基、(CH2)r-(C3-C8杂环基)、-(C3-C8杂环基)-(CH2)r-、-(CH2)rC(O)NRb(CH2)r-、-(CH2CH2O)r-、-(CH2CH2O)r-CH2-、-(CH2)rC(O)NRb(CH2CH2O)r-、-(CH2)rC(O)NRb(CH2CH2O)r-CH2-、-(CH2CH2O)rC(O)NRb(CH2CH2O)r-、-(CH2CH2O)rC(O)NRb(CH2CH2O)r-CH2-和-(CH2CH2O)rC(O)NRb(CH2)r-;其中Rb为H、C1-C6烷基、苯基或苄基;并且r独立为1-10的整数。
68.项67所述的抗体-药物偶联物化合物,其中Ww为缬氨酸-瓜氨酸。
69.项67所述的抗体-药物偶联物化合物,其中R17为(CH2)5或(CH2)2。
70.项66所述的抗体-药物偶联物化合物,具有下式:
71.项70所述的抗体-药物偶联物化合物,其中R17为(CH2)5或(CH2)2。
72.项66所述的抗体-药物偶联物化合物,具有下式:
73.项57所述的抗体-药物偶联物化合物,其中L为SMCC。
74.项57所述的抗体-药物偶联物化合物,其中L为BMPEO。
75.项57所述的抗体-药物偶联物化合物,其中药物部分D选自微管蛋白抑制剂、有丝分裂抑制剂、拓扑异构酶抑制剂和DNA嵌入剂。
76.项57所述的抗体-药物偶联物化合物,其中药物部分D选自美登木素生物碱、auristatin、多拉司他汀和加利车霉素。
77.项57所述的抗体-药物偶联物化合物,其中D为具有如下结构的MMAE:
其中波状线表示与连接基L的附着点。
78.项57所述的抗体-药物偶联物化合物,其中D为具有如下结构的MMAF:
其中波状线表示与连接基L的附着点。
79.项57所述的抗体-药物偶联物化合物,其中D为具有如下结构的DM1:
其中波状线表示与连接基L的附着点。
80.项57所述的抗体-药物偶联物化合物,其中亲代抗体为包含清蛋白-结合肽(ABP)的融合蛋白。
81.项57所述的抗体-药物偶联物化合物,其中亲代抗体选自单克隆抗体、双特异性抗体、嵌合抗体、人抗体和人源化抗体。
82.项57所述的抗体-药物偶联物化合物,其中亲代抗体为huMAb4D5-8(曲妥单抗)。
83.项57所述的抗体-药物偶联物化合物,其中亲代抗体为抗-ErbB2抗体。
84.项57所述的抗体-药物偶联物化合物,其中亲代抗体为抗-EphB2R抗体。
85.项57所述的抗体-药物偶联物化合物,其中亲代抗体为抗-CD22抗体.
86.项57所述的抗体-药物偶联物化合物,其中亲代抗体为抗-MUC16抗体.
87.项57所述的抗体-药物偶联物化合物,其中亲代抗体为选自IgA、IgD、IgE、IgG和IgM的完整抗体。
88.项87所述的抗体-药物偶联物化合物,其中IgG选自如下亚类:IgG1、IgG2、IgG3、IgG4、IgA和IgA2。
89.项57所述的抗体-药物偶联物化合物,其中亲代抗体为抗体片段。
90.项89所述的抗体-药物偶联物化合物,其中抗体片段为Fab片段。
91.项90所述的抗体-药物偶联物化合物,其中Fab片段为hu4D5Fabv8。
92.项91所述的抗体-药物偶联物化合物,其中被半胱氨酸取代的hu4D5Fabv8的氨基酸残基中的一种或多种选自L-V15、L-A43、L-V110、L-A144、L-S168、H-A40、H-A88、H-S119、H-A121、H-S122、H-A175和H-S179。
93.选自如下结构的抗体-药物偶联物化合物:
Ab-MC-vc-PAB-MMAF
Ab-MC-vc-PAB-MMAE
Ab-MC-MMAE
和
Ab-MC-MMAF
其中Val为缬氨酸;Cit为瓜氨酸;p为1、2、3或4;且Ab为通过如下方法制备的半胱氨酸改造的抗体,该方法包含用一个或多个游离半胱氨酸氨基酸取代亲代抗体的氨基酸残基中的一种或多种。
94.选自具有如下结构的抗体-药物偶联物化合物:
其中p为1、2、3或4;n为0、1或2;且Ab为通过如下方法制备的半胱氨酸改造的抗体,该方法包含用一个或多个游离半胱氨酸取代亲代抗体的氨基酸残基中的一种或多种。
95.药物组合物,包含项57所述的抗体-药物偶联物化合物或其药学上可接受的盐和药学上可接受的稀释剂、载体或赋形剂。
96.项95所述的药物组合物,进一步包含治疗有效量的额外的化疗剂。
97.杀伤或抑制肿瘤细胞或癌细胞增殖的方法,包含用有效杀伤或抑制肿瘤细胞或癌细胞增殖量的项57所述的抗体-药物偶联物化合物或其药学上可接受的盐或其溶剂合物处理肿瘤细胞或癌细胞。
98.抑制细胞增殖的方法,包含:
(a)使细胞培养基中的哺乳动物细胞暴露于项57所述的抗体-药物偶联物化合物;和
(b)测定所述的抗体-药物偶联物化合物的细胞毒性或抑制细胞活性,
由此使细胞增殖得到抑制。
99.抑制过表达选自HER2受体和EGF受体的生长因子受体的肿瘤细胞生长的方法,包含对患者给予特异性结合所述生长因子受体的项57所述的抗体-药物偶联物化合物和化疗剂,其中所述的抗体-药物偶联物和所述的化疗剂各自以有效抑制患者肿瘤细胞生长的量给予。
100.项99所述的方法,其中所述的抗体-药物偶联物化合物使肿瘤细胞对所述的化疗剂敏感。
101.制品,包含:
项57的抗体-药物偶联物化合物;
容器;和
表示所述化合物可以用于治疗癌症的包装说明书或标签。
102.制备包含半胱氨酸改造的抗体(Ab)和药物部分(D)的抗体药物偶联物化合物的方法,其中使半胱氨酸改造的抗体通过经连接基部分(L)的一个或多个改造的半胱氨酸氨基酸与D结合;所述的化合物具有式I:
Ab-(L-D)p I
其中p为1、2、3或4;该方法包含用一个或多个游离半胱氨酸氨基酸取代亲代抗体的氨基酸残基中的一种或多种,以制备半胱氨酸改造的抗体。
103.项102所述的方法,进一步包含下列步骤:
(a)使半胱氨酸改造的抗体的改造的半胱氨酸基团与连接基试剂反应而形成抗体-连接基中间体Ab-L;和
(b)使Ab-L与活化的药物部分D反应;由此形成抗体-药物偶联物。
104.项102所述的方法,进一步包含下列步骤:
(a)使药物部分的亲核基团与连接基试剂反应而形成药物-连接基中间体D-L;和
(b)使D-L与半胱氨酸改造的抗体的改造的半胱氨酸基团反应;
由此形成抗体-药物偶联物。
105.项102所述的方法,进一步包含表达中国仓鼠卵巢(CHO)细胞中半胱氨酸改造的抗体的步骤。
106.项102所述的方法,其中表达的半胱氨酸改造的抗体为IgG抗体。
107.项102所述的方法,进一步包含用还原剂处理表达的半胱氨酸改造的抗体的步骤。
108.项107所述的方法,其中还原剂选自TCEP和DTT。
109.项107所述的方法,进一步包含在用还原剂处理后,用氧化剂处理表达的半胱氨酸改造的抗体的步骤。
110.项109所述的方法,其中氧化剂为硫酸铜。
Claims (9)
1.半胱氨酸改造的抗体,包含具有0.6-1.0的巯基反应值的一个或多个游离半胱氨酸氨基酸;
其中通过包含用半胱氨酸取代亲代抗体的一种或多种氨基酸残基的方法制备半胱氨酸改造的抗体。
2.筛选半胱氨酸改造的抗体的巯基反应性的方法,包含:
(a)将一个或多个半胱氨酸氨基酸导入亲代抗体以便产生半胱氨酸改造的抗体;
(b)使半胱氨酸改造的抗体与巯基-反应性亲和试剂反应而产生亲和标记的半胱氨酸改造的抗体;和
(c)测定亲和标记的半胱氨酸改造的抗体与俘获培养基的结合。
3.抗体-药物偶联物化合物,包含半胱氨酸改造的抗体(Ab)和药物部分(D),其中半胱氨酸改造的抗体通过经连接基部分(L)的一个或多个游离半胱氨酸氨基酸与D结合;该化合物具有式I:
Ab-(L-D)p I
其中p为1、2、3或4;并且其中通过这样的方法制备半胱氨酸改造的抗体,该方法包含用一个或多个游离半胱氨酸氨基酸取代亲代抗体的一种或多种氨基酸残基。
4.药物组合物,包含权利要求3所述的抗体-药物偶联物化合物或其药学上可接受的盐和药学上可接受的稀释剂、载体或赋形剂。
5.杀伤或抑制肿瘤细胞或癌细胞增殖的方法,包含用有效杀伤或抑制肿瘤细胞或癌细胞增殖量的权利要求3所述的抗体-药物偶联物化合物或其药学上可接受的盐或其溶剂合物处理肿瘤细胞或癌细胞。
6.抑制细胞增殖的方法,包含:
(a)使细胞培养基中的哺乳动物细胞暴露于权利要求3所述的抗体-药物偶联物化合物;和
(b)测定所述的抗体-药物偶联物化合物的细胞毒性或抑制细胞活性,
由此使细胞增殖得到抑制。
7.抑制过表达选自HER2受体和EGF受体的生长因子受体的肿瘤细胞生长的方法,包含对患者给予特异性结合所述生长因子受体的权利要求3所述的抗体-药物偶联物化合物和化疗剂,其中所述的抗体-药物偶联物和所述的化疗剂各自以有效抑制患者肿瘤细胞生长的量给予。
8.制品,包含:
权利要求3的抗体-药物偶联物化合物;
容器;和
表示所述化合物可以用于治疗癌症的包装说明书或标签。
9.制备包含半胱氨酸改造的抗体(Ab)和药物部分(D)的抗体药物偶联物化合物的方法,其中使半胱氨酸改造的抗体通过经连接基部分(L)的一个或多个改造的半胱氨酸氨基酸与D结合;所述的化合物具有式I:
Ab-(L-D)p I
其中p为1、2、3或4;该方法包含用一个或多个游离半胱氨酸氨基酸取代亲代抗体的氨基酸残基中的一种或多种,以制备半胱氨酸改造的抗体。
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