CN101835803A - 半胱氨酸改造的抗tenb2抗体和抗体药物偶联物 - Google Patents
半胱氨酸改造的抗tenb2抗体和抗体药物偶联物 Download PDFInfo
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- CN101835803A CN101835803A CN200880112091A CN200880112091A CN101835803A CN 101835803 A CN101835803 A CN 101835803A CN 200880112091 A CN200880112091 A CN 200880112091A CN 200880112091 A CN200880112091 A CN 200880112091A CN 101835803 A CN101835803 A CN 101835803A
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Abstract
半胱氨酸改造的抗TENB2抗体是通过用非交联的反应性半胱氨酸氨基酸替换亲本抗TENB2抗体的一个或多个氨基酸而改造的。提供了设计、制备、筛选、和选择半胱氨酸改造的抗TENB2抗体的方法。经由接头(L)给半胱氨酸改造的抗TENB2抗体(Ab)偶联一个或多个药物模块(D)以形成具有式I的半胱氨酸改造的抗TENB2抗体-药物偶联物:Ab-(L-D)p,其中p为1-4。公开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用途。
Description
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
已经为靶向治疗患有癌症、免疫学和血管生成性病症的患者建立了抗体疗法。已经将与正常的非癌性细胞相比在癌细胞的表面上特异性表达的跨膜的或别样的肿瘤相关多肽鉴定为癌症诊断和抗体疗法的细胞靶物。此类肿瘤相关细胞表面抗原多肽,即肿瘤相关抗原(TAA)的鉴定容许特异性靶向癌细胞以便通过基于抗体的疗法实现破坏作用。
抗体-药物偶联物(ADC)即免疫偶联物在局部递送细胞毒剂或细胞抑制剂即在癌症治疗中杀死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 et al(2005)NatureBiotechnology 23(9):1137-1146;Payne,G.(2003)Cancer Cell 3:207-212;Syrigos and Epenetos(1999)Anticancer Research 19:605-614;Niculescu-Duvazand Springer(1997)Adv.Drug Del.Rev.26:151-172;US 4975278)容许将药物模块靶向递送至肿瘤,并在其中发生胞内蓄积,其中系统施用这些未偶联的药剂在对试图消除的肿瘤细胞之外也对正常细胞产生了不可接受水平的毒性(Baldwin et al(1986)Lancet pp.(Mar.15,1986):603-05;Thorpe,(1985)″Antibody Carriers Of Cytotoxic Agents In Cancer Therapy:A Review″,于Monoclonal Antibodies′84:Biological And Clinical Applications,A.Pinchera etal(编),pp.475-506)。改进ADC的治疗指数(即最高的功效与最低的毒性)的努力已经聚焦于多克隆(Rowland et al(1986)Cancer Immunol.Immunother.,21:183-87)和单克隆抗体(mAb)的选择性以及药物连接和药物释放特性(Lambert,J.(2005)Curr.Opinion in Pharmacology 5:543-549)。抗体药物偶联物中所使用的药物模块包括细菌蛋白质毒素诸如白喉毒素,植物蛋白质毒素诸如蓖麻毒蛋白,小分子诸如auristatin、格尔德霉素(geldanamycin)(Mandler etal(2000)J.of the Nat.Cancer Inst.92(19):1573-1581;Mandler et al(2000)Bioorganic&Med.Chem.Letters 10:1025-1028;Mandler et al(2002)Bioconjugate Chem.13:786-791)、美登木素生物碱(EP 1391213;Liu et al(1996)Proc.Natl.Acad.Sci.USA 93:8618-8623)、加利车霉素(Lode et al(1998)Cancer Res.58:2928;Hinman et al(1993)Cancer Res.53:3336-3342)、柔红霉素、多柔比星、甲氨蝶呤、和长春地辛(Rowland et al(1986)supra)。药物模块可实行影响细胞毒性和细胞抑制性机制,包括微管蛋白结合、DNA结合、或拓扑异构酶抑制。有些细胞毒性药物在偶联至大的抗体或蛋白质受体配体时趋向于失活或活性降低。
已经将auristatin肽,auristatin E(AE)和单甲基auristatin(MMAE),多拉司他汀的合成类似物(WO 02/088172)作为药物模块偶联至:(i)嵌合单克隆抗体cBR96(对癌上的Lewis Y是特异性的);(ii)cAC10,其对血液学恶性肿瘤上的CD30是特异性的(Klussman,et al(2004),Bioconjugate Chemistry15(4):765-773;Doronina et al(2003)Nature Biotechnology 21(7):778-784;Francisco et al(2003)Blood 102(4):1458-1465;US 2004/0018194);(iii)抗CD20抗体,诸如用于治疗表达CD20的癌症和免疫病症的rituxan(WO04/032828);(iv)抗EphB2R抗体2H9,其用于治疗结肠直肠癌(Mao et al(2004)Cancer Research 64(3):781-788);(v)E选择蛋白抗体(Bhaskar et al(2003)Cancer Res.63:6387-6394);(vi)曲妥单抗(trastuzumab)(US2005/0238649);和(vi)抗CD30抗体(WO 03/043583)。auristatin E的变体披露于US 5767237和US 6124431。偶联至单克隆抗体的单甲基auristatin E披露于Senter et al,Proceedings of the American Association for Cancer Research,Volume 45,Abstract Number 623,presented March 28,2004。已经将auristatin类似物MMAE和MMAF偶联至多种抗体(US 2005/0238649)。
以常规手段(即经由共价键的连接)将药物模块附着至抗体一般产生不均一的分子混合物,其中药物模块附着于抗体上的许多位点。例如,通常经由抗体的通常大量的赖氨酸残基将细胞毒性药物偶联至抗体,产生不均一的抗体-药物偶联物混合物。取决于反应条件,所述不均一的混合物通常含有附着有0个到约8个或更多个药物模块的抗体的分布。此外,具有药物模块对抗体的特定整数比的偶联物各亚组是可能的不均一的混合物,其中药物模块附着于抗体上的各种位点。分析和制备方法可能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-药物偶联物种类分子。抗体是较大的、复杂的且结构多样的生物分子,常常带有许多反应性官能团。它们与接头试剂和药物-接头中间体的反应性取决于诸如pH、浓度、盐浓度、和共溶剂等因素。此外,多步骤偶联过程因控制反应条件和表征反应物和中间体方面的困难而可能不可再现。
半胱氨酸硫醇基在中性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多数胺不同。由于游离硫醇基(RSH,硫氢基)相对具有反应性,所以带有半胱氨酸残基的蛋白质常常以它们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接的二硫化物基团。胞外蛋白一般不具有游离硫醇基(Garman,1997,Non-Radioactive Labelling:A Practical Approach,Academic Press,London,p.55)。抗体半胱氨酸硫醇基一般对亲电子偶联试剂比对抗体胺或羟基更具反应性,即更具亲核性。已经通过遗传工程技术将半胱氨酸残基引入蛋白质以形成与配体的共价附着物或形成新的分子内二硫键(Better et al(1994)J.Biol.Chem.13:9644-9650;Bernhard et al(1994)Bioconjugate Chem.5:126-132;Greenwood et al(1994)TherapeuticImmunology 1:247-255;Tu et al(1999)Proc.Natl.Acad.Sci USA 96:4862-4867;Kanno et al(2000)J.of Biotechnology,76:207-214;Chmura et al(2001)Proc.Nat.Acad.Sci.USA 98(15):8480-8484;US 6248564)。然而,通过将蛋白质的各种氨基酸残基突变成半胱氨酸氨基酸进行的半胱氨酸硫醇基改造可能存在问题,特别是就未配对的(游离的Cys)残基或那些相对易于反应或氧化的残基而言。在蛋白质的浓缩溶液中,无论是在大肠杆菌的周质中,在培养物上清液中,或者是在部分或完全纯化的蛋白质中,蛋白质表面上的未配对的Cys残基能配对并氧化以形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没有与药物、配体、或其它标记物偶联的反应性。此外,如果蛋白质以氧化方式在新改造的Cys与已存在的Cys残基之间形成分子内二硫键,那么这两个Cys硫醇基对活性位点的参与和相互作用而言都是不可利用的。此外,可以通过错误折叠或丧失三级结构使蛋白质失去活性或特异性(Zhang et al(2002)Anal.Biochem.311:1-9)。
已经将半胱氨酸改造的抗体设计成Fab抗体片段(thioFab)并表达成全长IgG单克隆(thioMab)抗体(US 2007/0092940,通过述及收入其内容)。已经通过接头在新引入的半胱氨酸硫醇基处用硫醇反应性接头试剂或药物-接头试剂偶联ThioFab和ThioMab抗体以制备抗体药物偶联物(Thio ADC)。
TENB2是一种肿瘤相关抗原多肽(也称作PR1),而且TENB2蛋白质含有两个卵泡抑素样结构域和一个保守的EGF样结构域。编码该蛋白质的基因最初是自人脑cDNA文库表征的(参见Uchida,et al.(1999)Biochem.Biophys.Res.Commun.266:593-602),而且稍后自人胎脑cDNA文库分离(参见Horie,etal.(2000)Genomics 67:146-152)。还可参见例如Online Mendelian Inheritancein Man,No.605734;Unigene Cluster Hs.22791;LocusLink 23671;及其它链接站点。TENB2曾经称作PR1、肿瘤调素(tomoregulin)、TR、增生性息肉病基因1、HPP1、和TMEFF2。它的核酸序列可以由ATCC编号AF264150、AB004064、AB017269和AF179274来鉴定;而且它的氨基酸序列可以由ATCC编号AAF91397、BAA90820、BAA87897和AAD55776来鉴定。TENB2的UniGene Cluster识别号是hs.22791,Locuslink识别号是23671,而OMIM识别号是605734。
该基因还涉及某些癌性疾患。Young,et al.(2001)Proc.Nat′l Acad.Sci.USA 98:265-270报告了在结肠直肠息肉中的表达。Glynne-Jones,et al.(2001)Int.J.Cancer 94:178-184报告了它作为前列腺癌的标志物。
由于其在某些人肿瘤中的过表达,TENB2多肽和编码该多肽的核酸是各种哺乳动物组织样品间定量和定性比较的靶物。为了哺乳动物中某些类型的癌性肿瘤的诊断性和治疗性处理,可以利用TENB2多肽和编码该多肽的核酸的独特表达谱型。
最近,公开了某些抗TENB2抗体(包括抗TMEFF2抗体#19)并显示出被内在化且对于前列腺增殖性疾患的治疗是有用的,包括例如良性前列腺增生和前列腺癌(PCT/US03/07209;美国流水号10/383447,2003年3月7日提交;Vinay et al.,“Antibodies Against Cancer Antigen TMEFF2and Uses Thereof”,通过述及收录其内容)。
发明概述
在一个方面,本发明包括半胱氨酸改造的抗TENB2抗体,其包含一个或多个游离的半胱氨酸氨基酸和选自SEQ ID NO:8-23的序列。该半胱氨酸改造的抗TENB2抗体可结合TENB2多肽。可制备肿瘤相关抗原(TAA)诸如TENB2多肽,用于使用本领域公知的和例如PCT/US03/07209中的方法和信息来生成半胱氨酸改造的抗体。该半胱氨酸改造的抗TENB2抗体可通过如下方法来制备,包括用半胱氨酸替换亲本抗TENB2抗体的一个或多个氨基酸残基。
该半胱氨酸改造的抗TENB2抗体的一个或多个游离的半胱氨酸氨基酸残基位于轻链或重链中。
在一个方面,本发明包括测定怀疑含有TENB2蛋白的样品中测定所述蛋白质的存在的方法,所述方法包括以下步骤:将所述样品暴露于半胱氨酸改造的抗TENB2抗体;并测定所述抗体对所述样品中所述TENB2蛋白的结合,其中所述抗体对所述蛋白质的结合指示所述样品中存在所述蛋白质。
半胱氨酸改造的抗TENB2抗体可作为裸抗体(未偶联至药物或标记物模块)或作为抗体-药物偶联物(ADC)使用。可将该半胱氨酸改造的抗TENB2抗体共价附着至auristatin药物模块,由此抗体药物偶联物得以形成。该抗体-药物偶联物可包含半胱氨酸改造的抗TENB2抗体(Ab)和auristatin药物模块(D),其中所述半胱氨酸改造的抗TENB2抗体是经由一个或多个游离的半胱氨酸氨基酸通过接头模块(L)附着至D的;所述化合物具有式I:
Ab-(L-D)p I
其中p为1、2、3、或4。Auristatin药物模块包括MMAE和MMAF。
本发明的一个方面是用于检测癌细胞的测定法,包括:(a)将细胞暴露于抗体-药物偶联物化合物;并(b)测定所述抗体-药物偶联物化合物结合所述细胞的程度。
本发明的一个方面是药物配制剂,其包含抗体药物偶联物及药学可接受的稀释剂、载体或赋形剂。
本发明的一个方面是抑制细胞增殖的方法,包括用抗体-药物偶联物化合物处理细胞培养培养基中的哺乳动物肿瘤细胞,由此所述肿瘤细胞的增殖受到抑制。
本发明的一个方面是治疗癌症的方法,包括对患者施用药物配制剂。可以与抗体-药物偶联物化合物组合地给患者施用化疗剂。
本发明的一个方面是制品,其包括药物配制剂、容器、和包装插页或标签,该包装插页或标签指明所述化合物可用于治疗以TENB2多肽过表达为特征的癌症。
本发明的一个方面是用于制备式I抗体药物偶联物化合物的方法,包括以下步骤:(a)使半胱氨酸改造的抗体的改造的半胱氨酸基团与接头试剂反应以形成抗体-接头中间体Ab-L;并(b)使Ab-L与活化的药物模块D反应;由此抗体-药物偶联物化合物得以形成;或者包括以下步骤:(c)使药物模块的亲核基团与接头试剂反应以形成药物-接头中间体D-L;并(d)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;由此抗体-药物偶联物化合物得以形成。
附图简述
图1显示了人源化抗TENB2抗体hu TMEFF2#19的重链序列SEQ ID NO:1和轻链序列SEQ ID NO:2。
图2显示了人源化半胱氨酸改造的抗TENB2抗体A121C thio huTMEFF2#19的重链序列SEQ ID NO:3和轻链序列SEQ ID NO:2。抗TENB2抗体的连续编号中不包括信号序列。
图3显示了人源化曲妥单抗(trastuzumab)轻链(HuTMAb-LC,SEQ IDNO:4)和人hu TMEFF2#19轻链(SEQ ID NO:5)序列的比对。编号方式遵循连续编号规则。
图4显示了人源化曲妥单抗重链(HuTMAb-HC,SEQ ID NO:6)和huTMEFF2#19重链(Ch3A5-HC,SEQ ID NO:7)序列的比对。编号方式遵循连续编号规则。
图5显示了半胱氨酸改造的抗TENB2抗体药物偶联物(ADC)的绘图,其中药物模块附着至轻链(LC-ADC;重链(HC-ADC);和Fc区(Fc-ADC)中的改造的半胱氨酸基团。
图6显示了以下步骤:(i)还原半胱氨酸改造的抗TENB2抗体(ThioMab)中的半胱氨酸二硫化物加合物(adduct)及链间和链内二硫化物;(ii)部分氧化,即再氧化以重新形成链间和链内二硫化物;并(iii)偶联再氧化的抗体与药物-接头中间体以形成半胱氨酸改造的抗TENB2抗体药物偶联物(ADC)。
图7显示了癌症和正常人组织中的TENB2表达:对自4841份人组织样品提取的RNA实施了寡核苷酸微阵列分析。图中的每个框提供了所示组织的样品的TENB2信号强度(平均差异定标至100)。绿色框是正常组织,红色框是肿瘤,而蓝色框代表其它患病组织。
图8显示了人前列腺肿瘤中的TENB2表达:顶图和底图来自人前列腺外植体模型,分别为PC3TENB2Medium稳定细胞系(其具有载体对照)和前列腺肿瘤。
图9显示了PC3TENB2Medium细胞系和LuCaP 70肿瘤上TENB2单克隆抗体(Mab)的内在化。
图10显示了用thio或常规抗TENB2ADC处理的PC3TENB2Medium细胞的FACS数据。
图11显示了用常规抗TENB2和thio抗TENB2ADC(thio-anti-TENB2ADC)对PC3TENB2Medium细胞进行的细胞杀伤测定法。
图12显示了使用抗TENB2和thio抗TENB2ADC(偶联有vc-MMAE或MC-MMAF)对PC3TENB2Medium细胞进行的功效研究。
图13显示了使用人源化抗TENB2Ab(hu TMEFF2#19)对各种LuCaP外植体肿瘤组织进行的Western印迹。
图14显示了使用人前列腺癌LuCaP 70、77和96.1进行的异种移植物实验。
图15显示了使用thio抗TENB2和常规ADC对大鼠进行的药动学评估。
图16显示了用抗TENB2-vc-MMAE和MC-MMAF对大鼠进行的安全性评估。
图17显示了用抗TENB2-vc-MMAE和抗TENB2-MC-MMAF对猕猴进行的安全性评估。
图18显示了用thio-抗TENB2-vc-MMAE和抗TENB2-vc-MMAE对大鼠进行的安全性评估。
发明详述
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。
定义
除非另有定义,本文中所使用的技术和科学术语具有与本发明所属领域普通技术人员通常理解相同的含义,而且符合:Singleton et al(1994)Dictionary of Microbiology and Molecular Biology,第2版,J.Wiley&Sons,New York,NY;及Janeway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immunobiology,第5版,Garland Publishing,New York。
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的抗体。抗体为能够识别和结合特异性抗原的蛋白质(Janeway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immuno Biology,5th Ed.,Garland Publishing,New York).靶抗原一般具有由多种抗体的CDR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,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抗原结合位点的分子,所述抗原结合位点免疫特异性结合所关注靶标的抗原或其部分,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,诸如人、鼠或兔。关于不同类的抗体的结构和特性参见例如Basic and Clinical Immunology,第8版,Daniel P.Stites,Abba I.Terr and Tristram G.Parslow(编),Appleton&Lange,Norwalk,CT,1994,第71页和第6章。
“抗体片段“包含全长抗体的一部分,该部分通常指所述全长抗体的抗原结合区或可变区。抗体片段的例子包括:Fab、Fab′、F(ab′)2和Fv片段;双抗体;线性抗体;微抗体(minibody)(US 5641870,Example 2;Zapata et al(1995)Protein Eng.8(10):1057-1062);Olafsen et al(2004)Protein Eng.Design&Sel.17(4):315-323);由Fab表达文库生成的片段;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各项的表位结合片段;单链抗体分子;和由抗体片段形成的多特异性抗体。
术语“单克隆抗体”在用于本文时指从一群基本上同质的抗体获得的抗体,即构成群体的各个抗体相同,除了可能以极小量存在的可能的天然存在突变形式。单克隆抗体是高度特异性的,针对单一抗原性位点。另外,与包含针对不同决定簇(表位)的不同抗体的多克隆抗体制备物不同,每种单克隆抗体针对抗原上的单一决定簇。在它们的特异性以外,单克隆抗体的优势在于它们可以在不受其它抗体污染的情况中合成。修饰语“单克隆”指示抗体从基本上同质的抗体群获得的特征,不应解释为要求通过任何特定方法来生成抗体。例如,有待依照本发明使用的单克隆抗体可以通过首次由Kohler et al.(1975)Nature 256:495记载的杂交瘤方法来制备,或者可以通过重组DNA方法来制备(参见例如US 4,816,567;US 5,807,715)。在杂交瘤方法中,如上所述免疫小鼠或其它适宜的宿主动物,诸如仓鼠或猕猴,以引发生成或能够生成如下抗体的淋巴细胞,所述抗体将特异性结合用于免疫的蛋白质。或者,可以在体外免疫淋巴细胞。免疫后,分离淋巴细胞,然后使用合适的融合剂诸如聚乙二醇与骨髓瘤细胞系融合,以形成杂交瘤细胞(Goding,(1986)Monoclonal Antibodies:Principles and Practice,pp.59-103Academic Press)。“单克隆抗体”也可以使用Clackson et al.(1991)Nature 352:624-628;Marks et al.(1991)J.Mol.Biol.222:581-597中记载的技术从噬菌体抗体库分离。
可以修饰编码抗体的DNA以生成嵌合抗体多肽或融合抗体多肽,例如通过用人重链和轻链恒定域(CH和CL)序列替代同源鼠序列(US 4816567;及Morrison,et al.,Proc.Natl Acad.Sci.USA,81:6851(1984)),或者通过融合免疫球蛋白编码序列与非免疫球蛋白多肽(异源多肽)的整个或部分编码序列。非免疫球蛋白多肽序列可替代抗体的恒定域,或者用它们替代抗体的一个抗原结合位点的可变域以创建嵌合二价抗体,其包含对一种抗原具有特异性的抗原结合位点和对不同抗原具有特异性的另一抗原结合位点。
“天然抗体”指通常由两条相同的轻(L)链和两条相同的重(H)链构成的约150,000道尔顿的异四聚体糖蛋白。每条轻链通过一个共价二硫键与重链连接,而二硫键的数目在不同免疫球蛋白同种型的重链间有变化。每条重链和轻链还具有间隔规律的链内二硫键。每条重链在一端具有可变域(VH),接着是多个恒定域。每条轻链在一端具有可变域(VL),而另一端是恒定域。轻链的恒定域与重链的第一恒定域排列在一起,而轻链的可变域与重链的可变域排列在一起。认为特定的氨基酸残基在轻链与重链可变域之间形成界面。
单克隆抗体在本文中明确包括“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别或亚类的抗体中的相应序列相同或同源,而链的剩余部分与衍生自另一物种或属于另一抗体类别或亚类的抗体中的相应序列相同或同源,以及此类抗体的片段,只要它们展现出期望的生物学活性(US 4,816,567;Morrison et al.(1984)Proc.Natl.Acad.Sci.USA81:6851-6855)。本文中感兴趣的嵌合抗体包括包含衍生自非人灵长类动物(例如旧大陆猴类(Old World Monkey)、猿等)的可变域抗原结合序列和人恒定区序列的“灵长类化”抗体。
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抗体的序列的嵌合抗体。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抗体特异性、亲和力和能力的非人物种(供体抗体)(诸如小鼠、大鼠、家兔或非人灵长类动物)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中或在供体抗体中没有找到的残基。进行这些修饰是为了进一步改进抗体的性能。一般而言,人源化抗体将包含至少一个、通常两个基本上整个如下的可变域,其中所有或基本上所有高变环对应于非人免疫球蛋白的高变环,且所有或基本上所有FR是人免疫球蛋白序列的FR。人源化抗体任选还将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。Fc片段包含通过二硫键保持在一起的所有两条重链的羧基末端部分。抗体的效应器功能是由Fc区中的序列决定的,该区还是受到在某些类型的细胞上找到的Fc受体(FcR)所识别的部分(Jones et al(1986)Nature 321:522-525;Riechmann et al(1988)Nature332:323-329;Presta,(1992)Curr.Op.Struct.Biol.2:593-596;Verhoeyen et al(1988)Science,239:1534-1536;Sims et al(1993)J.Immunol.151:2296;Chothia et al(1987)J.Mol.Biol.,196:901)。其它方法使用自特定轻链或重链亚组的所有人抗体的共有序列衍生的特定框架区(Carter et al(1992)Proc.Natl.Acad.Sci.USA,89:4285;Presta et al(1993)J.Immunol.151:2623)。
“人抗体”指拥有与由人生成的抗体的氨基酸序列对应的氨基酸序列和/或使用本文所公开的用于生成人抗体的任何技术生成的抗体。人抗体的这种定义明确排除包含非人抗原结合残基的人源化抗体。可得到能够在免疫后在没有内源免疫球蛋白生成的情况中生成人抗体完整全集的转基因动物(例如小鼠)。例如,已经描述了嵌合和种系突变小鼠中抗体重链连接区(JH)基因的纯合删除导致内源抗体生成的完全抑制。在此类种系突变小鼠中转移大量人种系免疫球蛋白基因将导致在抗原攻击时生成人抗体。(Jakobovits et al(1993)Proc.Natl.Acad.Sci.USA,90:2551;Jakobovits et al(1993)Nature,362:255-258;Bruggemann et al(1993)Year in Immuno.7:33;US 5545806;US5569825;US 5591669;US 5545807;及WO 97/17852)。
“亲和力成熟的”抗体指在抗体的一个或多个CDR中具有一处或多处改变、导致该抗体对抗原的亲和力与没有这些改变的抗体相比有所改进的抗体。优选的亲和力成熟的抗体具有纳摩尔或甚至皮摩尔量级的对靶抗原的亲和力。亲和力成熟的抗体可通过VH和VL域改组的亲和力成熟(Marks et al.,(1992)Bio/Technology 10:779-783)或CDR和/或框架残基的随机诱变(Barbas etal.,(1994)Proc.Nat.Acad.Sci.USA 91:3809-3813;Schier et al.,(1995)Gene169:147-155;Yelton et al.,(1995)J.Immunol.155:1994-2004;Jackson et al.,(1995)J.Immunol.154(7):3310-9;Hawkins et al.,(1992)J.Mol.Biol.226:889-896)来生成。
“完整抗体”在本文中指包含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。恒定域可以是天然序列恒定域(例如人天然序列恒定域)或其氨基酸序列变体。完整抗体可具有一项或多项“效应器功能”,指那些可归于抗体Fc区(天然序列Fc区或氨基酸序列变体Fc区)的生物学活性。抗体效应器功能的例子包括C1q结合;补体依赖性细胞毒性;Fc受体结合;抗体依赖性细胞介导的细胞毒性(ADCC);吞噬作用;和细胞表面受体(诸如B细胞受体和BCR)下调。
术语“氨基酸序列变体”指具有在一定程度上不同于天然序列多肽的氨基酸序列的多肽。通常,氨基酸序列变体会与至少一种天然序列多肽的受体结合域或与至少一种天然受体的配体结合域拥有至少约70%序列同一性,而且优选的是,它们会是在序列方面与此类受体或配体结合域至少约80%、更优选至少约90%同源的序列。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拥有替代、删除、和/或插入。氨基酸以惯用名、单字母和三字母代码来指代。
“序列同一性”定义为在比对序列并在必要时引入缺口以实现最大百分比序列同一性后,氨基酸序列变体中同样的残基的百分比。比对的方法和计算机程序是本领域公知的。一种这样的计算机程序是由Genentech公司编写的“Align 2”,其已经于1991年12月10日连同用户文档一起提交给美国版权局(United States Copyright Office,Washington,DC 20559),且其代码可见于PCT/US03/07209。
“抗体依赖性细胞介导的细胞毒性”和“ADCC”指由细胞介导的反应,其中表达Fc受体(FcR)的非特异性细胞毒性细胞(例如天然杀伤(NK)细胞、嗜中性粒细胞和巨噬细胞)识别靶细胞上结合的抗体,随后引起靶细胞溶解。介导ADCC的主要细胞,NK细胞,只表达FcγRIII,而单核细胞表达FcγRI、FcγRII和FcγRIII。Ravetch and Kinet,(1991)Annu.Rev.Immunol.9:457-92第464页表3总结了造血细胞上的FcR表达。为了评估目的分子的ADCC活性,可进行体外ADCC测定法,诸如US 5,500,362或US 5,821,337中所记载的。可用于此类测定法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/另外,可在体内评估目的分子的ADCC活性,例如在动物模型中,诸如Clynes et al.,(1998)Proc.Nat.Acad.Sci.(USA)95:652-656中所披露的。
“人效应细胞”指表达一种或多种恒定区受体(FcR)并行使效应器功能的白细胞。优选的是,该细胞至少表达FcγRIII并行使ADCC效应器功能。介导ADCC的人白细胞的例子包括外周血单个核细胞(PBMC)、天然杀伤(NK)细胞、单核细胞、细胞毒性T细胞和嗜中性粒细胞,优选PBMC和NK细胞。效应细胞可以从其天然来源分离,例如如本文所述从血液或PBMC分离。
术语“Fc受体”或“FcR”指结合抗体Fc恒定区的受体。优选的FcR是天然序列人FcR。此外,优选的FcR是能结合IgG抗体的FcR(γ受体),包括FcγRI、FcγRII和FcγRIII亚类的受体,包括这些受体的各等位变体和各可变剪接形式。FcγRII受体包括FcγRIIA(“活化受体”)和FcγRIIB(“抑制受体”),它们具有相似的氨基酸序列,区别主要在于其胞质结构域。活化受体FcγRIIA在其胞质结构域中包含免疫受体基于酪氨酸的活化基序(ITAM)。抑制受体FcγRIIB在其胞质结构域中包含免疫受体基于酪氨酸的抑制基序(ITIM)(综述参见(1997)Annu.Rev.Immunol.15:203-234)。FcR的综述参见Ravetchand Kinet,(1991)Annu.Rev.Immunol.9:457-492;Capel et al.,(1994)Immunomethods 4:25-34;及de Haas et al.,(1995)J.Lab.Clin.Med.126:330-341。术语“FcR”在本文中涵盖其它FcR,包括那些未来将会鉴定的。该术语还包括新生儿受体,FcRn,其负责将母体IgG转移给胎儿(Guyer et al.,(1976)J.Immunol.117:587及Kim et al.,(1994)J.Immunol.24:249)。
“补体依赖性细胞毒性”或“CDC”指存在补体时对靶细胞的溶解。经典补体途径的激活是由补体系统第一组分(C1q)结合其关联抗原所结合的抗体(适宜亚类的)起始的(Gazzano-Santoro et al.,(1996)J.Immunol.Methods202:163)。
术语“可变的”指可变域中的某些部分在抗体序列间差异广泛且用于每种特定抗体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域。它集中于轻链和重链可变域中称作高变区的三个区段。可变域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域各自包含四个FR,它们大多采取β-折叠片构象,通过形成环状连接且在有些情况中形成β-折叠片结构一部分的三个高变区连接。每条链中的高变区通过FR非常接近地保持在一起,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 et al.(1991)Sequences of Proteins of ImmunologicalInterest,第5版,Public Health Service,National Institutes of Health,Bethesda,MD.)。恒定域不直接参与抗体与抗原的结合,但展现出多种效应器功能,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”、“HVR”或“HV”在用于本文时指抗体可变域(区)中序列上高度可变和/或形成结构上定义的环的区域。通常,抗体包含六个高变区:三个在VH中(H1、H2、H3),三个在VL中(L1、L2、L3)。本文中使用且涵盖许多高变区的叙述。Kabat互补决定区(CDR)是以序列变异性为基础的且是最常用的(Kabat et al.,Sequences of Proteins of Immunological Interest,5thEd.Public Health Service,National Institutes of Health,Bethesda,MD.(1991))。Chothia改指结构环的位置(Chothia and Lesk(1987)J.Mol.Biol.196:901-917)。“接触”高变区是以对可获得的复合物晶体结构的分析为基础的。下文记录了这些高变区中每一个的残基。
除非另有说明,会采用依照Kabat蛋白质比对序列数据库的Kabat编号方式(Wu and Kabat(1970)J.Exp.Med.132:211-250;Johnson and Wu(2000)Nuc.Acids Res.28(1):214-218)。高变区位置通常如下:氨基酸24-34(HVR-L1),氨基酸49-56(HVR-L2),氨基酸89-97(HVR-L3),氨基酸26-35A(HVR-H1),氨基酸49-65(HVR-H2),和氨基酸93-102(HVR-H3)。高变区还可包括如下“延伸的高变区”:VL中的氨基酸24-36(L1)和氨基酸46-56(L2)。对于这些定义中的每一个,可变域残基是依照Kabat等,见上文编号的。“改变的高变区”就本文目的而言指其中包含一处或多处(例如1处至约16处)氨基酸替代的高变区。“未修饰的高变区”就本文目的而言指具有与衍生它的非人抗体相同的氨基酸序列的高变区,即其中缺少一处或多处氨基酸替代的高变区。
术语“如Kabat中的可变域残基编号方式”或“如Kabat中的氨基酸位置编号方式”及其变化形式指Kabat等,《Sequences of Proteins of ImmunologicalInterest》,第5版,Public Health Service,National Institutes of Health,Bethesda,MD(1991)中用于抗体重链可变域或轻链可变域编辑的编号系统。使用此编号系统,实际的线性氨基酸序列可以包含较少的或另外的氨基酸,对应于可变域FR或CDR的缩短或插入。例如,重链可变域可以包含H2残基52后的单一氨基酸插入(依照Kabat的残基52a)和重链FR残基82后的插入残基(例如依照Kabat的残基82a、82b和82c等)。给定抗体的Kabat残基编号可以通过将抗体序列与“标准”Kabat编号序列对比同源区来确定。
“结合亲和力”通常指分子(例如抗体)的单一结合位点与其结合配偶体(例如抗原)之间全部非共价相互作用总和的强度。除非另有说明,在用于本文时,“结合亲和力”指反映结合对的成员(例如抗体与抗原)之间1∶1相互作用的内在结合亲和力。分子X对其配偶体Y的亲和力通常可用解离常数(Kd)来表述。亲和力可通过本领域知道的常用方法来测量,包括本文中所描述的那些。低亲和力抗体通常缓慢地结合抗原且趋于容易解离,而高亲和力抗体通常更快速地结合抗原且趋于保持更长时间的结合。本领域知道测量结合亲和力的多种方法,其中任一种都可用于本发明的目的。下文描述了具体的示例性实施方案。
“抗原”指抗体能选择性结合的预定多肽、碳水化合物、核酸、脂质、半抗原或其它天然存在的或合成的化合物。
“框架区”或“FR”残基指可变域中那些除此处定义的高变区残基以外的残基。“人共有框架”指代表人免疫球蛋白VL或VH框架序列选集中最常见的氨基酸残基的框架。通常,人免疫球蛋白VL或VH序列选集来自可变区序列亚型。通常,序列亚型是如Kabat et al.,Sequences of Proteins of ImmunologicalInterest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,MD(1991)中的亚型。在一个实施方案中,对于VL,亚型是如Kabat等人中的亚型κI。在一个实施方案中,对于VH,亚型是如Kabat等人,见上文中的亚型III。“VH亚型III共有框架”包含从Kabat等人的可变重链亚型III中的氨基酸序列获得的共有序列。“VL亚型I共有框架”包含从Kabat等人的可变轻链κ亚型I中的氨基酸序列获得的共有序列。
“Fv”是包含完整抗原识别和抗原结合位点的最小抗体片段。该区域由紧密、非共价结合的一个重链可变域和一个轻链可变域的二聚体组成。正是在这种构造中,每个可变域的三个高变区相互作用而在VH-VL二聚体表面上限定了抗原结合位点。六个高变区一起赋予抗体以抗原结合特异性。然而,即使是单个可变域(或是只包含对抗原特异性的三个CDR的半个Fv)也具有识别和结合抗原的能力,只是亲和力低于完整结合位点。
Fab片段还包含轻链的恒定域和重链的第一恒定域(CH1)。Fab′片段与Fab片段的不同之处在于重链CH1结构域的羧基末端增加了少数残基,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域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在Fab′片段之间有铰链半胱氨酸的成对Fab′片段生成的。还知道抗体片段的其它化学偶联。
根据其恒定域的氨基酸序列,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的型中的一种,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,Fv多肽在VH与VL结构域之间进一步包含多肽接头,其使得scFv能够形成结合抗原的期望结构(Plückthun,于《ThePharmacology of Monoclonal Antibodies》,第113卷,Rosenburg和Moore编,Springer-Verlag,New York,第269-315页,1994)。
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域(VH)和轻链可变域(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,迫使这些结构域与另一条链的互补结构域配对,从而产生两个抗原结合位点(EP 404,097;WO93/11161;Hollinger et al.(1993)Proc.Natl.Acad.Sci.USA 90:6444-6448)。
“游离半胱氨酸”指已经工程改造入亲本抗体的、具有硫醇官能基(-SH)的、且没有配对或以其它方式成为分子内或分子间二硫桥一部分的半胱氨酸残基。
术语“硫醇反应性值(thiol reactivity value)”是游离半胱氨酸氨基酸的反应性的定量表征。硫醇反应性值指经过半胱氨酸工程改造的抗体中与硫醇反应性试剂反应的游离半胱氨酸氨基酸的百分比,且换算成最大值1。例如,经过半胱氨酸工程改造的抗体上与硫醇反应性试剂(诸如生物素-马来酰亚胺试剂)以100%产率反应(以形成生物素标记的抗体)的游离半胱氨酸氨基酸具有1.0的硫醇反应性值。已工程改造入相同或不同亲本抗体、与硫醇反应性试剂以80%产率反应的另一个半胱氨酸氨基酸具有0.8的硫醇反应性值。已工程改造入相同或不同亲本抗体、完全不能与硫醇反应性试剂反应的另一个半胱氨酸氨基酸具有0的硫醇反应性值。特定半胱氨酸的硫醇反应性值的测定可以通过ELISA测定法、质谱、液相层析、放射自显影、或其它定量分析测试来进行。容许捕捉经过半胱氨酸工程改造的抗体及比较和定量半胱氨酸反应性的硫醇反应性试剂包括生物素-PEO-马来酰亚胺((+)-生物素基-3-马来酰亚氨基丙酰氨基-3,6-二噁辛烷二胺((+)-biotinyl-3-maleimidopropionamidyl-3,6-dioxaoctainediamine),Oda等(2001)Nature Biotechnology 19:379-382,Pierce Biotechnology,Inc.)、生物素-BMCC、PEO-吲哚乙酰基生物素、吲哚乙酰基-LC-生物素、和生物素-HPDP(Pierce Biotechnology,Inc.)、及Nα-(3-马来酰亚氨基丙酰基)生物胞素(MPB,Molecular Probes,Eugene,OR)。生物素化、双功能和多功能接头试剂的其它商业来源包括Molecular Probes(Eugene,OR)和Sigma(St.Louis,MO)。
“亲本抗体”指包含其中一个或多个氨基酸残基有待用一个或多个半胱氨酸残基替换的氨基酸序列的抗体。亲本抗体可以包含天然的或野生型的序列。亲本抗体可具有相对于其它天然的、野生型的、或修饰形式的抗体而言的现有氨基酸序列修饰(诸如添加、删除和/或替代)。亲本抗体可以针对感兴趣的靶抗原,例如生物学重要的多肽。还涵盖针对非多肽抗原(诸如肿瘤相关糖脂抗原;参见US 5091178)的抗体。
“分离的”抗体指已经鉴定且自其天然环境的成分分开和/或回收的抗体。其天然环境的污染性成分指将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)根据还原性或非还原性条件下的SDS-PAGE及使用考马斯蓝或优选的银染色,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,分离的抗体通常将通过至少一个纯化步骤来制备。
“结合”靶分子或感兴趣抗原(例如TENB2或CA125抗原)的抗体指能够以足够亲和力结合该抗原,使得该抗体在靶向表达该抗原的细胞中是有用的的。若抗体是结合TENB2的抗体,则它通常会优先结合TENB2,而且可以是不显著与其它蛋白质发生交叉反应的抗体。在此类实施方案中,根据荧光激活细胞分选(FACS)分析或放射免疫沉淀(RIA)的测定,抗体结合这些非TENB2蛋白的程度(例如结合内源受体的细胞表面)会小于10%。
“处理”或“治疗”或“缓和”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)所针对的病理学状况或紊乱。需要治疗的受试者包括早就患有紊乱的受试者以及倾向于患上紊乱的受试者或要预防紊乱的受试者。如果在依照本发明的方法接受治疗量的抗CA125/O772P抗体诸如半胱氨酸改造的抗TENB2抗体或其抗体药物偶联物后,患者在如下一项或多项中显示出可观察和/或可测量的降低或消失,那么受试者或哺乳动物成功“治疗”了表达CA125/O772P多肽的癌症:癌细胞数减少或癌细胞消失;肿瘤体积缩小;癌细胞浸润到周围器官中,包括癌传播到软组织和骨中受到抑制(即一定程度的减缓,优选停止);肿瘤转移受到抑制(即一定程度的减缓,优选停止);肿瘤生长受到一定程度的抑制;和/或与特定癌症有关的一种或多种症状得到一定程度的减轻;发病率和死亡率降低;及生命质量提高。就半胱氨酸改造的抗TENB2抗体或其抗体药物偶联物可预防癌细胞生长和/或杀死现有癌细胞而言,它可能是抑制细胞的和/或毒害细胞的。这些体征或症状的减轻还可以由患者感受到。用于评估疾病的成功治疗和改善的上述参数可以容易地通过内科医师所熟悉的常规流程来测量。对于癌症治疗,可通过例如评估疾病进展时间(TTP,time to disease progression)和/或测定响应速率(RR,response rate)来测量功效。转移可通过分期测试(staging test)来测定,及通过骨扫描及钙水平和其它酶的测试以测定是否传播到骨。还可进行CT扫描以查明是否传播到骨盆及该区域中的淋巴结。分别使用胸腔X射线和通过已知方法进行的肝酶水平测量来查明是否转移到肺和肝。用于监测疾病的其它常规方法包括经直肠超声检查(TRUS)和经直肠针吸活组织检查(TRNB)。
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,而且指所有赘生性细胞生长和增殖,无论是恶性的或者是良性的,及所有癌前或癌性细胞和组织。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、肝肉瘤(hepatoma)、乳腺癌、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。
“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TENB2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)、Southem印迹、或聚合酶链式反应(PCR)技术,诸如实时定量逆转录酶PCR(qRT-PCR)。
“人效应细胞”指表达一种或多种FcR并行使效应器功能的白细胞。优选的是,该细胞至少表达FcγRIII并行使ADCC效应器功能。介导ADCC的人白细胞的例子包括外周血单个核细胞(PBMC)、天然杀伤(NK)细胞、单核细胞、细胞毒性T细胞和嗜中性粒细胞,优选PBMC和NK细胞。效应细胞可以从其天然来源(例如血液)分离。
术语“细胞增殖性病症”和“增殖性病症”指与一定程度的异常细胞增殖有关的病症。在一个实施方案中,细胞增殖性病症指癌症。
术语“治疗有效量”指在哺乳动物中有效治疗疾病或病症的药物(例如半胱氨酸改造的抗TENB2抗体药物偶联物或化疗剂)的量。在癌症的情况中,治疗有效量的药物可减少癌细胞的数目;缩小肿瘤的尺寸;抑制(即一定程度的减缓,优选阻止)癌细胞浸润入周围器官;抑制(即一定程度的减缓,优选阻止)肿瘤转移;一定程度地抑制肿瘤生长;和/或一定程度地减轻一种或多种与癌症有关的症状。根据药物可阻止现有癌细胞生长和/或杀死现有癌细胞的程度,它可以是细胞抑制性的和/或细胞毒性的。术语“细胞抑制性的”指限制细胞功能的效果,诸如限制细胞生长或细胞增殖。对于癌症疗法,功效可以通过例如评估距疾病进展的时间(TTP)和/或测定响应率(RR)来测量。
″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:ErlotinibGenentech/OSI Pharm.)、Bortezomib(MilleniumPharm.)、氟维司群(Fulvestrant)(Astrazeneca)、Sutent(SU 11248,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(SCH66336)、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(alkyl sulfonates),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(chlomaphazine)、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);elfomithine;依利醋铵(elliptiniumacetate);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 NaturalProducts,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),例如帕利他塞(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)(-Poulenc 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RFS 2000;二氟甲基鸟氨酸(DMFO);类维A酸(retinoids),诸如维A酸(retinoic acid);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。
术语“细胞因子”是由一种细胞群释放,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;红细胞生成素(EPO);骨诱导因子(osteoinductive factor);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“标记物”指可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高与之结合的亲和力;(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,以调控配体亲和力、抗体/抗原结合、或离子络合。
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。
“载体”在用于本文时包括药剂学可接受的载体、赋形剂或稳定剂,它们在所采用的剂量和浓度对暴露于其的细胞或哺乳动物是无毒的。通常,生理学可接受的载体是pH缓冲水溶液。生理学可接受载体的例子包括缓冲剂,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;低分子量(少于约10个残基)多肽;蛋白质,诸如血清清蛋白、明胶或免疫球蛋白;亲水性聚合物,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、精氨酸或赖氨酸;单糖、二糖和其它碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,诸如EDTA;糖醇,诸如甘露醇或山梨醇;成盐反荷离子,诸如钠;和/或非离子表面活性剂,诸如聚乙二醇(PEG)和
本文中使用的立体化学的定义和规则一般遵循S.P.Parker编,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill BookCompany,New York;及Eliel,E.和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l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没有旋光性的混合物。
下列缩写在本文中有使用,而且具有所规定的定义:BME指β-巯基乙醇;Boc指N-(叔丁氧羰基);cit指瓜氨酸(2-氨基-5-脲基戊酸);dap指dolaproine;DCC指1,3-二环己基碳二亚胺;DCM指二氯甲烷;DEA指二乙胺;DEAD指偶氮二羧酸二乙酯;DEPC指氰基磷酸二乙酯;DIAD指偶氮二羧酸二异丙酯;DIEA指N,N-二异丙基乙胺;dil指dolaisoleucine;DMA指二甲基乙酰胺;DMAP指4-二甲基氨基吡啶;DME指乙二醇二甲基醚(或1,2-二甲氧基乙烷);DMF指N,N-二甲基甲酰胺;DMSO指二甲基亚砜;doe指dolaphenine;dov指N,N-二甲基缬氨酸;DTNB指5,5’-二硫双(2-硝基苯甲酸);DTPA指二乙烯三胺五乙酸;DTT指二硫苏糖醇;EDCI指盐酸1-(3-二甲基氨基丙基)-3-乙基碳二亚胺;EEDQ指2-乙氧基-1-乙氧羰基-1,2-二氢喹啉;ES-MS指电喷雾质谱;EtOAc指乙酸乙酯;Fmoc指N-(9-芴基甲氧羰基);gly指甘氨酸;HATU指O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯;HOBt指1-羟基苯并三唑;HPLC指高压液相层析;ile指异亮氨酸;lys指赖氨酸;MeCN(CH3CN)指乙腈;MeOH指甲醇;Mtr指4-茴香基联苯基甲基(或4-甲氧基三苯甲基);nor指(1S,2R)-(+)-去甲麻黄碱;PAB指对氨基苯甲基氨基甲酰基;PBS指磷酸盐缓冲盐水(pH7);PEG指聚乙二醇;Ph指苯基;Pnp指对硝基苯基;MC指6-马来酰亚氨基己酰基;phe指L-苯丙氨酸;PyBrop指溴三吡咯烷膦六氟磷酸酯;SEC指大小排阻层析;Su指琥珀酰亚胺;TFA指三氟乙酸;TLC指薄层层析;UV指紫外线;而val指缬氨酸。
半胱氨酸改造的抗TENB2抗体
本发明的化合物包括半胱氨酸改造的抗TENB2抗体,其中任何形式的野生型或亲本抗TENB2抗体的一个或多个氨基酸被半胱氨酸氨基酸替换。改造的半胱氨酸氨基酸是游离的半胱氨酸,不是链内或链间二硫化物单元的一部分。可以对任何形式的抗TENB2抗体进行如此改造,即突变。例如,可以改造亲本Fab抗体片段以形成半胱氨酸改造的Fab,在本文中称为“ThioFab”。类似地,可以改造亲本单克隆抗体以形成“ThioMab”。应当注意,单位点突变在ThioFab中产生单个改造的半胱氨酸残基,而单位点突变在ThioMab中产生两个改造的半胱氨酸残基(由于IgG抗体的二聚体特性)。本发明的半胱氨酸改造抗TENB2抗体包括单克隆抗体,人源化的或嵌合的单克隆抗体,及抗体的抗原结合片段、融合多肽和类似物,其优先结合细胞结合TENB2多肽(cell-associated TENB2polypeptide)。
半胱氨酸改造的抗TENB2抗体保留它们野生型、亲本抗TENB2抗体对应物的抗原结合能力。如此,半胱氨酸改造的抗TENB2抗体能够结合TENB2抗原。
半胱氨酸改造的抗TENB2抗体包含一个或多个具有还原的硫氢(硫醇)基的游离的半胱氨酸氨基酸,其中所述半胱氨酸改造的抗TENB2抗体结合TENB2多肽。
在一个实施方案中,半胱氨酸改造的抗TENB2抗体是如下方法制备的,其包括用半胱氨酸替换亲本抗TENB2抗体的一个或多个氨基酸残基。
可以对具有替换的(“改造的”)半胱氨酸(Cys)残基的突变体评估新引入的、改造的半胱氨酸硫醇基团的反应性。硫醇反应性值是范围为0到1.0的相对数值术语,而且可以对任何半胱氨酸改造的抗体测量该值。本发明的半胱氨酸改造的抗体的硫醇反应性值可以在0.6到1.0;0.7到1.0;或0.8到1.0的范围内。
在一个方面中,本发明涉及一种分离的半胱氨酸改造抗TENB2抗体,其包含由如下核苷酸序列所编码的氨基酸序列,该核苷酸序列能与编码下列各项的DNA分子的互补链发生杂交:(a)半胱氨酸改造抗体,其具有如本文中所公开的全长氨基酸序列,(b)半胱氨酸改造抗体氨基酸序列,其缺乏如本文中所公开的信号肽,(c)跨膜的半胱氨酸改造抗体蛋白的胞外结构域,其带有或不带有如本文中所公开的信号肽,(d)由任何在本文中所公开的核酸序列所编码的氨基酸序列,或(e)如本文中所公开的全长的半胱氨酸改造抗体氨基酸序列的任何其它明确限定的片段。
在一个方面中,本发明提供了一种分离的半胱氨酸改造抗TENB2抗体,其不带有N末端信号序列和/或不带有起始甲硫氨酸,并且是由编码如本文中所描述的氨基酸序列的核苷酸序列所编码的。其产生方法在本文中也有描述,其中那些方法包括在适于表达半胱氨酸改造抗体的条件下培养包含含有合适的编码核酸分子的载体的宿主细胞和从该细胞培养物中回收所述半胱氨酸改造抗体。
本发明的另一个方面提供了一种分离的半胱氨酸改造抗TENB2抗体,其或是跨膜结构域删除的或是跨膜结构域失活的。其产生方法在本文中也有描述,其中那些方法包括在适于表达半胱氨酸改造抗体的条件下培养包含含有合适的编码核酸分子的载体的宿主细胞和从该细胞培养物中回收所述半胱氨酸改造抗体。
在其它实施方案中,本发明提供了分离的抗TENB2嵌合半胱氨酸改造抗体,其包含与异源(非TENB2)多肽融合的任何本文所述半胱氨酸改造抗体。此类嵌合分子的例子包括与异源多肽(诸如例如表位标签序列或免疫球蛋白Fc区)融合的任何本文所述半胱氨酸改造抗体。
半胱氨酸改造抗TENB2抗体可以是单克隆抗体、抗体片段、嵌合抗体、人源化抗体、单链抗体、或竞争性抑制抗TENB2多肽抗体与其相应抗原表位结合的抗体。本发明的抗体可以任选地偶联至生长抑制剂或细胞毒剂,诸如毒素,包括例如auristatin、抗生素、放射性同位素、核溶酶(nucleolytic enzyme)等。本发明的抗体可以任选地在CHO细胞或细菌细胞中产生,且优选地抑制它们所结合的细胞的生长或增殖或诱导与它们所结合的细胞的死亡。为了诊断目的,本发明的抗体可以带上可检测标记物、附着至固体支持物、等等。
在本发明的其它实施方案中,本发明提供了包含编码任何本文所述半胱氨酸改造抗TENB2抗体的DNA的载体。还提供了包含任何此类载体的宿主细胞。举例而言,所述宿主细胞可以是CHO细胞、大肠杆菌细胞或酵母细胞。用于产生任何本文所述多肽的方法有进一步的提供,且包括在适于表达期望多肽的条件下培养宿主细胞和从该细胞培养物中回收所述期望多肽。
亲本和半胱氨酸改造的抗TENB2抗体结合TENB2多肽或TENB2多肽变体,其记载于PCT/US03/07209。
TENB2多肽变体指与WO 2007/001851中披露的TENB2具有至少约80%氨基酸序列同一性的TENB2多肽,所述TENB2为:(i)全长天然序列;(ii)缺少信号肽的多肽序列;(iii)有或无信号肽的胞外结构域;或(iv)全长TENB2多肽序列的任何其它片段。此类TENB2多肽变体包括例如如下多肽,其中在全长天然氨基酸序列的N端或C端添加或删除了一个或多个氨基酸残基。通常,TENB2多肽变体会与全长天然序列TENB2多肽序列、缺少信号肽的TENB2多肽序列、有或无信号肽的TENB2多肽胞外结构域、或全长TENB2多肽序列的任何其它具体限定的片段具有至少约80%氨基酸序列同一性,或者至少约81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,或99%氨基酸序列同一性。通常,TENB2多肽变体的长度为至少约10个氨基酸,或者长度为至少约20,30,40,50,60,70,80,90,100,110,120,130,140,150,160,170,180,190,200,210,220,230,240,250,260,270,280,290,300,310,320,330,340,350,360,370,380,390,400,410,420,430,440,450,460,470,480,490,500,510,520,530,540,550,560,570,580,590,600个氨基酸,或更多。任选地,TENB2变体多肽会具有不超过一处与天然TENB2多肽序列相比的保守氨基酸替代,或者不超过2,3,4,5,6,7,8,9,或10处与天然TENB2多肽序列相比的保守氨基酸替代。
TENB2多肽可以通过在以下各项中重组表达来制备:(i)大肠杆菌,用pBR322载体;(ii)哺乳动物细胞,诸如人HEK293细胞(ATCC CCL 1573)、COS(猿成纤维细胞,SV-40)细胞、中国仓鼠卵巢(CHO)细胞,用pRK5载体;(iii)酵母,诸如酵母菌株AB110;或(iv)杆状病毒感染的昆虫细胞(PCT/US03/07209)。天然或重组TENB2多肽可通过蛋白质纯化领域中的多种标准技术来纯化。例如,使用对感兴趣TENB2多肽特异性的抗体通过亲和免疫层析来纯化pro-TENB2多肽、成熟TENB2多肽、或pre-TENB2多肽。一般而言,通过将抗TENB2多肽抗体共价偶联至活化后的层析树脂来构建免疫亲和柱。TENB2多肽可以作为与异源多肽的融合多肽而重组生产,所述异源多肽可以是在成熟蛋白质或多肽的N-末端具有特定切割位点的信号序列或其它多肽。或者,TENB2多肽可以作为与信号序列和容许纯化TENB2融合多肽的异源多肽序列的融合多肽来生产,此类异源多肽序列的例子有多组氨酸(His6(SEQ ID NO:24)或His8(SEQ ID NO:25))、人IgG Fc、FLAG表位(KDYKDDDDK(SEQ ID NO:26))、和gD表位(KYALADASLKMADPNRFRGKDLPVL(SEQ ID NO:27))。所述信号序列可以是载体的构件,或者它可以是插入载体的编码抗TENB2抗体或TENB2多肽的DNA的一部分。信号序列可以是原核信号序列,选自例如碱性磷酸酶、青霉素酶、lpp、或热稳定的肠毒素II前导序列。为了酵母分泌,信号序列可以是例如酵母转化酶前导序列、α因子前导序列(包括糖酵母和克鲁维酵母的α-因子前导序列(US 5,010,182)、或酸性磷酸酶前导序列、白色假丝酵母葡糖淀粉酶前导序列(EP 0362179)、或WO 90/13646中描述的信号。在哺乳动物细胞表达中,可以使用哺乳动物信号序列来指导蛋白质的分泌,诸如来自相同或相关物种的分泌型多肽的信号序列,以及病毒分泌前导序列。
“表达TENB2的细胞”或在细胞表面上或以分泌形式表达内源的或转染的TENB2多肽。“表达TENB2的癌”包含在细胞表面上存在TENB2多肽或生成和分泌TENB2抗原性多肽的细胞的癌。“表达TENB2的癌”任选在其细胞表面上生成足够水平的TENB2多肽,使得抗TENB2抗体或其抗体药物偶联物可与其结合并可对癌发挥治疗效果。过表达TENB2多肽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TENB2多肽或生成和分泌显著更高水平的TENB2多肽的癌。此类过表达可以是由基因扩增或者是由转录或翻译增强引起的。可在临床设置中通过评估细胞表面上存在的或细胞分泌的TENB2蛋白质水平的升高(例如通过免疫组织化学测定法(使用针对分离的TENB2多肽制备的抗TENB2抗体,所述多肽可使用重组DNA技术从编码TENB2多肽的分离的核酸制备);FACS分析;等)来确定TENB2多肽过表达。或者,或另外,可测量细胞中编码TENB2多肽的核酸或mRNA的水平,例如通过荧光原位杂交(FISH),使用对应于编码TENB2的核酸或其互补链的基于核酸的探针(WO 98/45479);Southern印迹;Northern印迹;或聚合酶链式反应(PCR)技术,诸如实时定量逆转录酶PCR(qRT-PCR)。还可使用基于抗体的测定法,通过测量生物学流体诸如血清中的脱落抗原来检测TENB2多肽过表达(US 4,933,294;WO 91/05264;US 5,401,638;Sias et al.,(1990)J.Immunol.Methods 132:73-80)。还可使用多种其它体内测定法。或者,可将患者身体内的细胞暴露于任选用可检测标记物例如放射性同位素标记的抗体,并且可评估抗体与患者体内细胞的结合,例如通过外部扫描放射性或通过分析取自事先已暴露于所述抗体的患者的活组织检查样品。
亲本和半胱氨酸改造的抗TENB2抗体能够结合、优选特异性结合TENB2多肽,如本文中所描述的。TENB2结合寡肽可使用众所周知的技术无需过多实验就得以鉴定。在这点上,注意到用于对寡肽文库筛选能够特异性结合多肽靶物的寡肽的技术是本领域众所周知的(US 5556762;US 5750373;US4708871;US 4833092;US 5223409;US 5403484;US 5571689;US 5663143;WO 84/03506;WO84/03564;Geysen et al(1984)Proc.Natl.Acad.Sci.USA,81:3998-4002;Geysen et al(1985)Proc.Natl.Acad.Sci.USA,82:178-182;Geysen et al.,于Synthetic Peptides as Antigens,130-149(1986);Geysen et al.,J.Immunol.Meth.,102:259-274(1987);Schoofs et al.,J.Immunol.,140:611-616(1988);Cwirla,S.E.et al.(1990)Proc.Natl.Acad.Sci.USA,87:6378;Lowman,H.B.et al.(1991)Biochemistry,30:10832;Clackson,T.et al.(1991)Nature,352:624;Marks,J.D.et al.(1991)J.Mol.Biol.,222:581;Kang,A.S.et al.(1991)Proc.Natl.Acad.Sci.USA,88:8363;及Smith,G.P.(1991)Current Opin.Biotechnol.,2:668)。
本发明的亲本和半胱氨酸改造的抗TENB2抗体包括多克隆的、单克隆的、人源化的、人的、双特异性的、或异源偶联的抗体。本发明涵盖各种形式的人源化抗TENB2抗体。例如,所述人源化抗体可以是抗体片段,诸如Fab。或者,所述人源化抗体可以是完整抗体,诸如完整IgG1抗体。
双特异性抗TENB2抗体指对至少两种不同表位具有结合特异性的抗体。例示性的双特异性抗TENB2抗体可结合本文所述TENB2多肽的两种不同表位。其它此类抗体可将TENB2结合位点与针对另一种蛋白质的结合位点组合。或者,可以将抗TENB2臂与结合白细胞上触发分子(诸如T细胞受体分子(例如CD3)或IgG的Fc受体(FcγR)诸如FcγRI(CD64)、FcγRII(CD32)和FcγRIII(CD16))的臂组合,从而将细胞防御机制聚焦和定位于表达TENB2的细胞。双特异性抗体还可用于将细胞毒剂定位于表达TENB2的细胞。这些抗体拥有TENB2结合臂及结合细胞毒剂(例如肥皂草毒蛋白(saporin)、抗干扰素-α、长春花生物碱(vinca alkaloid)、蓖麻毒蛋白A链、甲氨蝶呤或放射性同位素半抗原)的臂。可将双特异性抗体制备成全长抗体或抗体片段(例如F(ab′)2双特异性抗体)。全长双特异性抗体的传统生成基于两对免疫球蛋白重链-轻链的共表达,其中两种链具有不同的特异性(Millstein et al(1983)Nature305:537-539)。
异源偶联抗TENB2抗体也在本发明的范围内。异源偶联抗体由两种共价连接的抗体构成。此类抗体建议例如用于将免疫系统细胞靶向不想要的细胞(US 4,676,980)及用于治疗HIV感染(WO 91/00360;WO 92/200373;EP03089)。可以在体外使用合成蛋白质化学的已知方法来制备抗体,包括那些涉及交联剂的方法。
本发明的抗TENB2抗体可以是具有三个或更多抗原结合位点(例如四价抗体)的多价抗体,其可容易地通过编码抗体多肽链的核酸的重组表达来生成。多价抗体可包含二聚化结构域和三个或更多抗原结合位点。优选的二聚化结构域包含(或由其组成)Fc区或铰链区。在这种情况中,抗体可包含Fc区及Fc区氨基末端的三个或更多抗原结合位点。本文中优选的多价抗体包含(或由其组成)三个至约八个,但优选四个抗原结合位点。多价抗体包含至少一条多肽链(且优选两条多肽链),其中所述多肽链包含两个或多个可变域。例如,多肽链可包含VD1-(X1)n-VD2-(X2)n-Fc,其中VD1是第一可变域,VD2是第二可变域,Fc是Fc区的一条多肽链,X1和X2代表氨基酸或多肽,而n是0或1。例如,多肽链可包含:VH-CH1-柔性接头-VH-CH1-Fc区链;或VH-CH1-VH-CH1-Fc区链。本文中的多价抗体优选进一步包含至少两条(且优选四条)轻链可变域多肽。本文中的多价抗体可包含例如约两条至约八条轻链可变域多肽。本文涵盖的轻链可变域多肽包含轻链可变域,且任选进一步包含CL结构域。
可以通过在Fc区中引入一处或多处氨基酸替代来修饰抗TENB2抗体的效应器功能。此类修饰可增强抗TENB2抗体的抗体依赖性细胞介导的细胞毒性(ADCC)和/或补体依赖性细胞毒性(CDC)。如此生成的同二聚体抗体可具有改善的内在化能力和/或提高的补体介导的细胞杀伤和抗体依赖性细胞的细胞毒性(ADCC)。参阅Caron et al(1992)J.Exp Med.176:1191-1195及Shopes,B.J.(1992)Immunol.148:2918-2922。具有增强的抗肿瘤活性的同二聚体抗TENB2抗体还可使用异双功能交联剂来制备,如Wolff et al(1993)CancerResearch 53:2560-2565中所记载的。或者,可改造抗体,其具有双重Fc区,并可由此具有增强的补体溶解和ADCC能力(Stevenson et al(1989)Anti-Cancer Drug Design 3:219-230)。
可以通过掺入补救受体结合表位(例如抗体片段)来调控抗TENB2抗体的血清半衰期(US 5,739,277)。在用于本文时,术语“补救受体结合表位”指IgG分子(例如IgG1、IgG2、IgG3、或IgG4)Fc区中负责提高IgG分子体内血清半衰期的表位。
通过标准竞争结合分析和表位作图(PCT/US03/07209),确定了结合TENB2表位的单克隆抗体(包括TMEFF2#19)。
使用TMEFF2#19单克隆抗体(PCT/US03/07209;Sambrook et al MolecularCloning:A Laboratory Manual,New York:Cold Spring Harbor Press,1989;Ausubel et al.,Current Protocols of Molecular Biology,Unit 3.16,John Wileyand Sons,1997)实施了免疫组织化学分析。单克隆抗体TMEFF2#19展现出对241份人前列腺癌标本中176份的弱至强结合。
单克隆抗体TMEFF2#19以快速速率内在化进入细胞,TMEFF2#19就结合该细胞表面上的TENB2多肽。
对抗TENB2抗体的修饰
可在本文所述抗TENB2抗体中进行修饰和变异,例如使用例如US5,364,934所述的保守和非保守突变的任何技术和指导方针。变异可以是编码抗体或多肽的一个或多个密码子的替代、删除或插入,其导致氨基酸序列相对于天然序列抗TENB2抗体的改变。任选的是,变异是通过抗TENB2抗体的一个或多个结构域中至少一个氨基酸为任何其它氨基酸所替代。变异可使用本领域知道的方法来进行,诸如寡核苷酸介导的(定点)诱变、丙氨酸扫描、及PCR诱变。可对克隆的DNA进行定点诱变(Carter et al(1986)Nucl.AcidsRes.,13:4331;Zoller et al(1987)Nucl.Acids Res.,10:6487)、盒式诱变(Wells etal(1985)Gene,34:315)、限制性选择诱变(restriction selectionmutagenesis)(Wells et al(1986)Philos.Trans.R.Soc.London SerA,317:415)或其它已知技术以产生抗TENB2抗体变体DNA。氨基酸改变可改变抗TENB2抗体的翻译后加工,诸如改变糖基化位点的数目或位置或者改变膜锚定特征。其它修饰包括谷氨酰胺酰和天冬酰胺酰残基分别脱酰胺为谷氨酰和天冬氨酰残基,脯氨酸和赖氨酸的羟基化,丝氨酰或苏氨酰残基的羟基的磷酸化,赖氨酸、精氨酸和组氨酸侧链的α-氨基的甲基化(T.E.Creighton,Proteins:Structure and Molecular Properties,(1983)W.H.Freeman&Co.,San Francisco,pp.79-86),N-末端胺的乙酰化,及任何C-末端羧基的酰胺化。抗TENB2抗体可通过将适宜的核苷酸改变引入编码DNA和/或通过化学合成来制备。
例如,在与全长抗TENB2抗体比较时,抗TENB2抗体片段可在N-末端或C-末端截短,或者可缺少内部残基。某些片段缺少对于抗TENB2抗体的期望生物学活性不是至关重要的氨基酸残基。抗TENB2抗体片段可通过多种常规技术中的任一种来制备。期望的肽片段可化学合成。一种备选方法牵涉通过酶促消化产生抗体片段,例如通过用已知在由特定氨基酸残基限定的位点处切割蛋白质的酶处理蛋白质,或者通过用合适的限制酶消化DNA,并分离期望片段。还有一种合适的技术涉及分离并通过聚合酶链式反应(PCR)扩增编码期望抗体或其片段的DNA片段。限定DNA片段期望末端的寡核苷酸在PCR中用作5′和3′引物。优选的是,抗TENB2抗体片段与本文所公开的天然抗TENB2抗体共享至少一种生物学和/或免疫学活性。
特别优选的一类替代变体涉及替代人源化抗体或人抗体的一个或多个高变区残基。通常,选择用于进一步开发的所得变体相对于产生它们的抗体将具有改进的生物学特性。产生此类替代变体的一种便利方法涉及使用噬菌体展示进行的亲和力成熟。简而言之,将数个高变区位点(例如6-7个位点)突变,在各个位点产生所有可能的氨基酸替代。如此产生的抗体变体以单价形式展示在丝状噬菌体颗粒上,作为与各个颗粒内包装的M13基因III产物的融合物。然后如本文所公开的对噬菌体展示的变体筛选其生物学活性(例如结合亲和力)。为了鉴定用于修饰的候选高变区位点,可进行丙氨酸扫描诱变以鉴定对抗原结合有重要贡献的高变区残基。或者/另外,分析抗原-抗体复合物的晶体结构以鉴定抗体和人TENB2多肽之间的接触点可能是有益的。此类接触残基及邻近残基是依照本文详述技术进行替代的候选位点。一旦产生此类变体,如本文所述对该组变体进行筛选,可选择在一种或多种相关测定法中有优良特性的抗体用于进一步的开发。
本发明范围内所包括的对抗TENB2抗体的另一类共价修饰包括改变抗体或多肽的天然糖基化样式,即删除一个或多个在天然序列抗TENB2抗体中发现的碳水化合物模块(moiety)(或是通过消除潜在糖基化位点,或是通过以化学和/或酶促手段消除糖基化),和/或添加一个或多个在天然序列抗TENB2抗体中不存在的糖基化位点。另外,所述修饰包括天然蛋白质糖基化中的定性改变,牵涉所存在的多种碳水化合物模块的本质和比例的改变。抗体和其它多肽的糖基化通常或是N-连接的或是O-连接的。N-连接指碳水化合物模块附着于天冬酰胺残基的侧链。三肽序列天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸(其中X是除脯氨酸外的任何氨基酸)是将碳水化合物模块酶促附着于天冬酰胺侧链的识别序列。由此,多肽中这些三肽序列其中任一的存在产生潜在的糖基化位点。O-连接的糖基化指将糖类N-乙酰半乳糖胺、半乳糖或木糖之一附着于羟基氨基酸,最常见的是丝氨酸或苏氨酸,但也可使用5-羟脯氨酸或5-羟赖氨酸。向抗TENB2抗体中添加糖基化位点通过改变氨基酸序列使其包含一个或多个上述三肽序列(用于N-连接的糖基化位点)而便利地完成。这种改变还可通过向抗TENB2抗体的序列中添加或替代一个或多个丝氨酸或苏氨酸残基来进行(用于O-连接的糖基化位点)。可任选通过DNA水平的变化来改变抗TENB2抗体的氨基酸序列,特别是通过在预先选择的碱基处突变编码抗TENB2抗体的DNA,从而产生将翻译成期望氨基酸的密码子。
增加抗TENB2抗体上糖模块的数目的另一种方法是通过使糖苷与多肽化学或酶促偶联。本领域对此类方法有描述,例如1987年9月11日公开的WO87/05330,和Aplin and Wriston,CRC Crit.Rev.Biochem.,pp.259-306(1981)。
去除抗TENB2抗体上存在的糖模块可通过化学或酶促方法来实现,或者通过编码充当糖基化靶物的氨基酸残基的密码子的突变替代来实现。化学脱糖基化技术是本领域已知的,而且描述于例如Hakimuddin et al.,Arch.Biochem.Biophys.259:52(1987)和Edge et al.,Anal.Biochem.118:131(1981)。酶促切割糖模块可通过使用多种内切和外切糖苷酶来实现,如Thotakura et al.,(1987)Meth.Enzvmol.138:350所述。
对抗TENB2抗体的另一类共价修饰包括,以US 4,640,835;US 4,496,689;US 4,301,144;US 4,670,417;US 4,791,192或US 4,179,337所述方式,将抗体或多肽与多种非蛋白质性质的聚合物之一连接,例如聚乙二醇(PEG)、聚丙二醇或聚氧化亚烷基(polyoxyalkylene)。抗体或多肽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。此类技术公开于例如Remington′s Pharmaceutical Sciences,16th edition,Osol,A.Ed.,1980。
还可以形成嵌合分子的方式修饰本发明的抗TENB2抗体,所述嵌合分子包含与另一种异源多肽或氨基酸序列融合的抗TENB2抗体。在一个实施方案中,此类嵌合分子包括带有标签多肽的抗TENB2抗体的融合物,所述标签多肽提供了抗标签抗体可选择性结合的表位。表位标签通常位于抗TENB2抗体的氨基或羧基末端。此类表位标记形式的抗TENB2抗体的存在可使用针对所述标签多肽的抗体来检测。而且,表位标签的提供使抗TENB2抗体易于使用抗标签抗体或另一类结合所述表位标签的亲和基质通过亲和纯化来纯化。多种标签多肽及其各自抗体是本领域公知的。例子包括多组氨酸(poly-his)或多-组氨酸-甘氨酸(poly-his-gly)标签;流感HA标签多肽及其抗体12CA5(Field etal.,(1988)Mol.Cell.Biol.8:2159-2165);c-myc标签及其抗体8F9,3C7,6E10,G4,B7和9E10抗体(Evan et al.,(1985)Molecular and Cellular Biology 5:3610-3616);及单纯疱疹病毒糖蛋白D(gD)标签及其抗体(Paborsky et al.,(1990)Protein Engineering 3(6):547-553)。其它标签多肽包括Flag肽(Hopp etal.,(1988)BioTechnology 6:1204-1210);KT3表位肽(Martin et al.,(1992)Science 255:192-194);α-微管蛋白表位肽(Skinner et al.,(1991)J.Biol.Chem.266:15163-15166);及T7基因10蛋白肽标签(Lutz-Freyermuth et al.,(1990)Proc.Natl.Acad.Sci.USA 87:6393-6397)。
在一个备选实施方案中,嵌合分子可包括抗TENB2抗体与免疫球蛋白或免疫球蛋白特定区域的融合物。对于二价形式的嵌合分子(也称为“免疫粘附素”),此类融合物可以是与IgG分子Fc区的融合。Ig融合物优选包含用可溶形式(跨膜结构域删除或失活)的抗TENB2抗体置换Ig分子内至少一个可变区的替代。在一个特别优选的实施方案中,免疫球蛋白融合物包含IgG1分子的铰链区、CH2区和CH3区,或者铰链区、CH1区、CH2区和CH3区(US5,428,130)。
抗TENB2抗体的制备
可通过多种方法制备编码本发明的亲本抗TENB2抗体和半胱氨酸改造抗TENB2抗体的氨基酸序列变体的DNA,包括但不限于自天然来源分离(在天然存在的氨基酸序列变体的情况中)、通过定点诱变(或寡核苷酸介导的诱变)(Carter等(1985)Nucleic Acids Res.13:4431-4443;Ho等(1989)Gene(Amst.)77:51-59;Kunkel等(1987)Proc.Natl.Acad.Sci.USA 82:488;Liu等(1998)J.Biol.Chem.273:20252-20260)、PCR诱变(Higuchi,(1990)于PCRProtocols,pp.177-183,Academic Press;Ito等(1991)Gene 102:67-70;Bernhard等(1994)Bioconjugate Chem.5:126-132;及Vallette等(1989)Nuc.Acids Res.17:723-733)和对较早制备的编码所述多肽的DNA的盒式诱变(Wells等(1985)Gene 34:315-323)来制备。诱变方案、试剂盒和试剂可通过商业途径获得,例如多重定点诱变试剂盒(Stratagene,La Jolla,CA)。还可以使用双链质粒DNA作为模板通过基于PCR的诱变通过寡核苷酸介导的诱变来生成单一诱变(Sambrook和Russel,(2001)Molecular Cloning:A LaboratoryManual,第3版;Zoller等(1983)Methods Enzymol.100:468-500;Zoller,M.J.和Smith,M.(1982)Nucl.Acids Res.10:6487-6500)。还可以通过限制性片段操作或通过使用合成寡核苷酸的交叠延伸PCR构建重组抗体的变体。诱变引物编码半胱氨酸密码子替换物。标准诱变技术可以用于产生编码此类突变型半胱氨酸改造抗体的DNA(Sambrook等,Molecular Cloning,A LaboratoryManual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,1989;及Ausubel等,Current Protocols in Molecular Biology,Greene Publishing andWiley-Interscience,New York,N.Y.,1993)。
噬菌体展示技术(McCafferty等,(1990)Nature 348:552-553)可用于在体外从来自未免疫供体的免疫球蛋白可变域(V)基因全集生成抗TENB2人抗体和抗体片段。依照这种技术,将抗体可变域基因以符合读码框的方式克隆入丝状噬菌体诸如M13或fd的主要或次要外壳蛋白基因,并在噬菌体颗粒表面上展示为功能性抗体片段。因为丝状噬菌体颗粒包含噬菌体基因组的单链DNA拷贝,以抗体的功能特性为基础进行的选择也导致编码展示那些特性的抗体的基因得到选择。如此,噬菌体模拟B细胞的一些特性(Johnson等(1993)Current Opinion in Structural Biology 3:564-571;Clackson等(1991)Nature,352:624-628;Marks等(1991)J.Mol.Biol.222:581-597;Griffith等(1993)EMBO J.12:725-734;US 5565332;US 5573905;US 5567610;US 5229275)。
抗TENB2抗体可以使用已知的寡肽合成方法来化学合成,或者可以使用重组技术来制备和纯化。适宜的氨基酸序列或其部分可以使用固相技术通过直接肽合成来生成(Stewart等,Solid-Phase Peptide Svnthesis,(1969)W.H.Freeman Co.,San Francisco,CA;Merrifield,(1963)J.Am.Chem.Soc.,85:2149-2154)。体外蛋白质合成可以使用手动技术或通过自动化来进行。自动化固相合成可以例如采用受t-BOC或Fmoc保护的氨基酸并使用AppliedBiosystems肽合成仪(Foster City,CA)依照制造商的说明书来进行。抗TENB2抗体或TENB2多肽的各个部分可以分开地化学合成,并使用化学或酶促方法联合以生成期望的抗TENB2抗体或TENB2多肽。
已经开发了用于生成抗体片段的多种技术。传统上,通过蛋白水解消化完整抗体来衍生这些片段(Morimoto等(1992)Joumal of Biochemical andBiophysical Methods 24:107-117;及Brennan等(1985)Science,229:81),或者直接由重组宿主细胞生成这些片段。Fab、Fv和scFv抗TENB2抗体片段都可在大肠杆菌中表达及由大肠杆菌分泌,如此容许容易地生成大量的这些片段。可以从上文讨论的噬菌体抗体库中分离抗体片段。或者,可以直接从大肠杆菌回收Fab′-SH片段并化学偶联以形成F(ab′)2片段(Carter等(1992)Bio/Technology 10:163-167),或者,直接从重组宿主细胞培养物分离F(ab′)2片段。抗TENB2抗体可以是单链Fv片段(scFv)(WO 93/16185;US 5571894;US5587458)。抗TENB2抗体片段还可以是“线性抗体”(US 5,641,870)。此类线性抗体片段可以是单特异性的或双特异性的。
下文描述主要涉及通过培养经包含抗TENB2抗体编码核酸的载体转化或转染的细胞来生成抗TENB2抗体。编码抗TENB2抗体的DNA可以得自认为具有抗TENB2抗体mRNA且以可检测水平表达之的组织制备的cDNA文库。因而,人抗TENB2抗体或TENB2多肽DNA可以方便地得自自人组织制备的cDNA文库。抗TENB2抗体编码基因还可以得自基因组文库或已知的合成规程(例如自动化核酸合成)。
可以用设计用于鉴定目的基因或由其编码的蛋白质的探针(诸如至少约20-80个碱基的寡核苷酸)筛选文库。用选定探针筛选cDNA或基因组文库可使用标准流程进行,诸如Sambrook等,Molecular Cloning:A LaboratoryManual,New York,Cold Spring Harbor Laboratory Press,1989所述。分离编码抗TENB2抗体或TENB2多肽的基因的一种备选方法是PCR方法学(Sambrook等,见上文;Dieffenbach等,PCR Primer:A Laboratory Manual,Cold SpringHarbor Laboratory Press,1995)。
将宿主细胞用本文所述用于抗TENB2抗体或TENB2多肽生成的表达或克隆载体转染或转化,并在为了诱导启动子、选择转化子、或扩增编码期望序列的基因而恰当调整的常规营养培养基中培养。培养条件,诸如培养基、温度、pH等等,可以由本领域技术人员无需过多实验进行选择。通常,用于使细胞培养物产量最大化的原理、方案和实用技术可参见Mammalian CellBiotechnology:a Practical Approach,M.Butler,ed.,IRL Press,1991和Sambrook等,见上文。
适于克隆或表达本文载体中的DNA的宿主细胞包括原核生物、酵母、或高等真核细胞。合适的原核生物包括但不限于真细菌,诸如革兰氏阴性或革兰氏阳性生物体,例如肠杆菌科,诸如大肠杆菌。多种大肠杆菌菌株是公众可获得的,诸如大肠杆菌K12菌株MM294(ATCC 31,446);大肠杆菌X1776(ATCC 31,537);大肠杆菌菌株W3110(ATCC 27,325)和K5 772(ATCC53,635)。其它合适的原核生物宿主细胞包括肠杆菌科,诸如埃希氏菌属(Escherichia)例如大肠埃希氏菌(大肠杆菌)(E.coli)、肠杆菌属(Enterobacter)、欧文氏菌属(Erwinia)、克雷伯氏菌属(Klebsiella)、变形菌属(Proteus)、沙门氏菌属(Salmonella)例如鼠伤寒沙门氏菌(Salmonellatyphimurium)、沙雷氏菌属(Serratia)例如粘质沙雷氏菌(Serratiamarcescans)、和志贺氏菌属(Shigella),以及芽孢杆菌属(Bacilli)诸如枯草芽孢杆菌(B.subtilis)和地衣芽孢杆菌(B.licheniformis)(例如1989年4月12日出版的DD 266,710中公开的地衣芽孢杆菌41P)、假单胞菌属(Pseudomonas)诸如铜绿假单胞菌(P.aeruginosa)、和链霉菌属(Streptomyces)。这些例子是例示性的而非限制性的。菌株W3110是用于重组DNA产物发酵的例示性宿主菌株。优选的是,宿主细胞分泌最小量的蛋白水解酶。例如,菌株W3110可以修饰,在编码对宿主而言内源的蛋白质的基因中产生遗传突变,此类宿主的例子包括大肠杆菌W3110菌株1A2,其具有完整基因型tonA;大肠杆菌W3110菌株9E4,其具有完整基因型tonA ptr3;大肠杆菌W3110菌株27C7(ATCC 55,244),其具有完整基因型tonA ptr3 phoAE15(argF-lac)169 degP ompT kanr;大肠杆菌W3110菌株37D6,其具有完整基因型tonA ptr3 phoA E15(argF-lac)169 degP ompT rbs7 ilvG kanr;大肠杆菌W3110菌株40B4,它是具有非卡那霉素抗性degP删除突变的菌株37D6;及具有突变型周质蛋白酶(US 4,946,783)的大肠杆菌菌株。或者,体外克隆方法,例如PCR或其它核酸聚合酶反应也是合适的。
全长抗体、抗体片段及抗体融合物蛋白质可在细菌中制备,特别是在不需要糖基化和Fc效应器功能时,诸如当治疗用抗体与细胞毒剂(例如毒素)偶联且免疫偶联物自身显示出肿瘤细胞破坏的效力时。全长抗体在循环中具有较长半衰期。使用例如抗体片段和多肽在细菌中的表达及用于优化表达和分泌的翻译起始区(TIR)和信号序列(US 5,648,237;US 5,789,199;和US5,840,523),大肠杆菌中的制备可以更快且更加省钱。表达后,从大肠杆菌细胞糊在可溶性级分中分离抗体,并且可例如根据同种型通过蛋白A或G柱来纯化。最终的纯化可以与用于纯化例如在CHO细胞中表达的抗体的方法类似地进行。
除了原核生物以外,真核微生物,诸如丝状真菌或酵母也是编码抗TENB2抗体或TENB2多肽的载体的合适克隆或表达宿主。酿酒糖酵母(Saccharomyces cerevisiae)是常用的低等真核宿主微生物。其它的包括粟酒裂殖糖酵母(Schizosaccharomyces pombe)(Beach和Nurse,(1981)Nature290:140;EP 139,383);克鲁维酵母属(Kluyveromyces)宿主(US 4,943,529;Fleer等,(1991)Bio/Technology 9:968-975)诸如例如乳酸克鲁维酵母(K.lactis)(MW98-8C,CBS683,CBS4574;Louvencourt等,(1983)J.Bacteriol.154(2):737-742)、脆壁克鲁维酵母(K.fragilis)(ATCC 12,424)、保加利亚克鲁维酵母(K.bulgaricus)(ATCC 16,045)、威克克鲁维酵母(K.wickeramii)(ATCC24,178)、K.waltii(ATCC 56,500)、果蝇克鲁维酵母(K.drosophilarum)(ATCC36,906;Van den Berg等,(1990)Bio/Technology 8:135)、耐热克鲁维酵母(K.thermotolerans)、和马克思克鲁维酵母(K.marxianus);亚罗酵母属(Yarrowia)(EP 402,226);巴斯德毕赤酵母(Pichia pastoris)(EP 183,070;Sreekrishna等,(1988)J.Basic Microbiol.28:265-278);假丝酵母属(Candida);瑞氏木霉(Trichoderma reesia)(EP 244,234);粗糙脉孢菌(Neurospora crassa)(Case等,(1979)Proc.Natl.Acad.Sci.USA 76:5259-5263);许旺酵母属(Schwanniomyces)诸如许旺酵母(Schwanniomyces occidentalis)(EP394,538);和丝状真菌诸如例如脉孢菌属(Neurospora)、青霉属(Penicillium)、弯颈霉属(Tolypocladium)(WO 91/00357)、和曲霉属(Aspergillus)宿主诸如构巢曲霉(A.nidulans)(Balance等,(1983)Biochem.Biophys.Res.Commun.112:284-289;Tilbum等,(1983)Gene26:205-221;Yelton等,(1984)Proc.Natl. Acad.Sci.USA81:1470-1474)和黑曲霉(A.niger)(Kelly和Hynes,(1985)EMBO J.4:475-479)。甲基营养型酵母(Methylotropic yeast)适于本发明,包括但不限于能够在甲醇上生长的、选自以下属的酵母:汉逊氏酵母属(Hansenula)、假丝酵母属(Candida)、克勒克氏酵母属Kloeckera)、毕赤氏酵母属(Pichia)、糖酵母属(Saccharomyces)、球拟酵母属(Torulopsis)、和红酵母属(Rhodotorula)。
适用于表达糖基化抗TENB2抗体或TENB2多肽的宿主细胞还可衍生自多细胞生物体。无脊椎动物细胞的例子包括昆虫细胞诸如果蝇S2和夜蛾Sf9,以及植物细胞诸如棉、玉米、马铃薯、大豆、矮牵牛、番茄、烟草的细胞培养物。。已经鉴定了许多杆状病毒株和变体及相应的允许的昆虫宿主细胞,它们来自诸如草地夜蛾Spodoptera frugiperda(毛虫)、埃及伊蚊Aedes aegypti(蚊子)、白纹伊蚊Aedes albopictus(蚊子)、黑腹果蝇Drosophila melanogaster(果蝇)、和家蚕Bombyx mori等宿主。公众可获得多种病毒株用于转染,例如苜蓿尺蠖(Autographa californica)NPV的L-1变体和家蚕(Bombyx mori)NPV的Bm-5株,而且此类病毒可依照本发明用作本文的病毒,特别是用于转染草地夜蛾细胞。
有用的哺乳动物宿主细胞系的例子是用SV40转化的猴肾CV1系(COS-7,ATCC CRL 1651);人胚肾系(293或为了在悬浮培养中生长而亚克隆的293细胞,Graham等,(1977)J.Gen Virol.36:59);幼仓鼠肾细胞(BHK,ATCC CCL 10);中国仓鼠卵巢细胞/-DHFR(CHO,Urlaub等,(1980)Proc.Natl.Acad.Sci.USA 77:4216);小鼠塞托利(sertoli)细胞(TM4,Mather,(1980)Biol.Reprod.23:243-251);猴肾细胞(CV1,ATCC CCL 70);非洲绿猴肾细胞(VERO-76,ATCC CRL-1587);人宫颈癌细胞(HELA,ATCC CCL 2);犬肾细胞(MDCK,ATCC CCL 34);牛鼠(buffalo rat)肝细胞(BRL 3A,ATCCCRL 1442);人肺细胞(W138,ATCC CCL 75);人肝细胞(Hep G2,HB 8065);小鼠乳腺肿瘤(MMT 060562,ATCC CCL 51);TRI细胞(Mather等,(1982)Annals N.Y.Acad.Sci.383:44-68);MRC5细胞;FS4细胞;和人肝瘤系(HepG2)。
用上述用于抗TENB2抗体生成的表达或克隆载体转化宿主细胞,并在为了诱导启动子、选择转化子、或扩增编码期望序列的基因而恰当调整的常规营养培养基中培养。可以将编码抗TENB2抗体或TENB2多肽的核酸(例如cDNA或基因组DNA)插入复制型载体用于克隆(DNA扩增)或表达。载体可以是例如质粒、粘粒、病毒颗粒、或噬菌体的形式。可以通过多种规程将适宜的核酸序列插入载体中。
在体外或在体内对肿瘤细胞的生长抑制可以以本领域已知的多种方式来测定,诸如与未处理的肿瘤细胞相比,在体外或在体内将表达TENB2的肿瘤细胞的细胞增殖抑制约25-100%,或约30-100%,或约50-100%或70-100%,在一个实施方案中,处于约0.5-30μg/ml的抗体浓度。可通过本领域已知的方法例如使用内源性或在用TENB2基因转染后表达TENB2多肽的细胞,来评估抗TENB2抗体的体外生长抑制效果。例如,可将适宜的肿瘤细胞系和TENB2转染细胞用不同浓度的抗TENB2单克隆抗体处理几天(例如2-7天),并用结晶紫或MTT染色,或者通过一些其它比色测定法来分析。降低的信号指示生长抑制。测量增殖的另一种方法是通过比较在存在或缺乏抗TENB2抗体时所处理细胞的3H-胸苷摄取。处理后,收获细胞并在闪烁计数器中对掺入DNA的放射性的量定量。对增殖的抑制会通过放射性的降低来证明。为了选择诱导细胞死亡的抗TENB2抗体,可以相对于对照评估膜完整性的丧失,例如通过碘化丙啶(PI)、台盼蓝或7AAD摄取所指示的。适宜的阳性对照包括用已知抑制所选细胞系生长的生长抑制性抗体处理该细胞系。可在细胞培养物中在抗体浓度为约0.5-30μg/ml或约0.5nM至200nM时测量生长抑制,其中在使肿瘤细胞暴露于抗体后1-10天测量生长抑制。如果以约1μg/kg至约100mg/kg体重施用抗TENB2抗体导致在自首次施用抗体起约5天至3个月内、优选约5天至30天内肿瘤体积缩小或肿瘤细胞增殖降低,那么该抗体是体内生长抑制性的。
半胱氨酸改造抗TENB2抗体的制备
本发明的设计、选择和制备方法能够得到具有亲电子官能度(functionality)反应性的半胱氨酸改造抗TENB2抗体。这些方法进一步能够获得抗体偶联物化合物,诸如在指定的、设计的、选择性的位点上具有药物分子的抗体-药物偶联物(ADC)化合物。抗体表面上的反应性半胱氨酸残基容许通过硫醇反应性基团,诸如马来酰亚胺或卤代乙酰基特异性地偶联药物模块。Cys残基的硫醇官能度与马来酰亚胺基团的亲核反应性高于蛋白质中任何其它氨基酸官能度,诸如赖氨酸残基的氨基或N-末端氨基约1000倍。碘乙酰基和马来酰亚胺试剂中的硫醇特异性官能度可以与胺基团反应,但需要更高的pH(>9.0)和更长的反应时间(Garman,1997,Non-Radioactive Labelling:APractical Approach,Academic Press,London)。可以通过标准Ellman测定法来估计蛋白质中游离硫醇的量。免疫球蛋白M为二硫化物连接的五聚体的例子,而免疫球蛋白G为内部二硫桥将各亚基键合在一起的蛋白质的例子。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)是产生反应性游离硫醇所需的。这种方法可以导致抗体的三级结构和抗原结合特异性丧失。
PHESELECTOR(用于选择反应性硫醇的噬菌体ELISA)测定法容许以ELISA噬菌体形式检测抗体-Fab中反应性半胱氨酸基团,由此辅助半胱氨酸改造抗体的设计(US 2007/0092940)。在孔表面上包被半胱氨酸改造抗体与之结合的抗原,随后与展示半胱氨酸改造的Fab的噬菌体颗粒一起温育,添加HRP标记的二抗,并检测吸光度。可以以快速、强有力和高流通量方式筛选噬菌体上展示的突变蛋白。可以使用与从抗体或其它蛋白质的随机蛋白质-噬菌体文库鉴定游离Cys掺入的适当反应性位点相同的方法生成半胱氨酸改造抗体的文库并且进行结合选择。这项技术包括使噬菌体上展示的半胱氨酸突变蛋白与也为硫醇反应性的亲和试剂或报告基团反应。
PHESELECTOR测定法容许筛选抗体中的反应性硫醇基团。通过该方法鉴定A121C变体是例示性的。可以高效地搜索整个Fab分子以鉴定更多的带有反应性硫醇基团的ThioFab变体。采用参数,表面可及分数(fractional surfaceaccessibility)来鉴定和量化溶剂对多肽中氨基酸残基的可及性。将表面可及性表述为可以由溶剂分子,例如水接触的表面和水占据的空间近似为半径球体。软件为自由可获得的或可许可的(Secretary to CCP4,DaresburyLaboratory,Warrington,WA4 4AD,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射线晶体学衍生坐标的蛋白质的每个氨基酸的表面可及性的算法的晶体学程序CCP4Suite(“The CCP4 Suite:Programs for Protein Crystallography”(1994)Acta.Cryst.D50:760-763)。执行表面可及性计算的两种例示性软件模块为“AREAIMOL”和“SURFACE”,其基于B.Lee和F.M.Richards(1971)J.Mol.Biol.55:379-400的算法。AREAIMOL将蛋白质的溶剂可及表面定义为探针球(probe sphere)(代表溶剂分子)在蛋白质的Van der Waals表面上翻转时其中心的位置。AREAIMOL如下计算溶剂可及表面积,即在约每个原子的扩充球体上产生表面点(距原子中心的距离等于原子和探针半径的总和),并且消除那些位于与相邻原子相关的等同球体内的点。AREAIMOL找到了PDB坐标文件中原子的溶剂可及面积并概括了残基、链和整个分子的可及面积。可以将各原子的可及面积(或面积差)存储成假拟-PDB输出文件。AREAIMOL假设了每个成分的单一半径并仅识别有限数量的不同成分。
AREAIMOL和SURFACE报导了绝对可及性,即平方埃数。通过参比多肽内氨基酸相关标准状态来计算表面可及分数。参比状态为三肽Gly-X-Gly,其中X为感兴趣的氨基酸,且参比状态应为“扩展的”构象,即像那些在β链中的构象。扩展的构象使X的可及性达到最大值。用计算的可及面积除以Gly-X-Gly三肽参比状态中的可及面积并报告商数,其为可及性分数。可及性百分比为可及性分数乘以100。计算表面可及性的另一种例示性算法基于程序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对水球体的可及性分数。可以使用可得到的晶体结构信息来计算抗体中每个氨基酸的表面可及性分数(Eigenbrot等(1993)J Mol Biol.229:969-995)。
编码半胱氨酸改造抗体的DNA易于使用常规规程来分离和测序(例如通过使用能够与编码鼠抗体重链和轻链的基因特异性结合的寡核苷酸探针)。杂交瘤细胞充当此类DNA的来源。一旦分离,可以将DNA置入表达载体,然后转染入原本不生成抗体蛋白质的宿主细胞,诸如大肠杆菌细胞、猿COS细胞、中国仓鼠卵巢(CHO)细胞、或其它哺乳动物宿主细胞,诸如骨髓瘤细胞(US 5807715;US 2005/0048572;US 2004/0229310),以获得单克隆抗体在重组宿主细胞中的合成。
在设计和选择后,可如下生成具有改造的、高度反应性的未配对的Cys残基的半胱氨酸改造抗体,例如ThioFab:(i)在细菌例如大肠杆菌系统(Skerra等(1993)Curr.Opinion in Immunol.5:256-262;Plückthun(1992)Immunol.Revs.130:151-188)或哺乳动物细胞培养物系统(WO 01/00245)例如中国仓鼠卵巢细胞(CHO)中表达;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)。
改造的Cys硫醇基团与亲电子的接头试剂和药物-接头中间体起反应而形成半胱氨酸改造抗体-药物偶联物和其它经标记的半胱氨酸改造抗体。半胱氨酸改造抗体的和存在于亲本抗体中的、配对并形成链间和链内二硫键的Cys残基不具有任何反应性硫醇基团(除非用还原剂处理)且不与亲电子的接头试剂或药物-接头中间体起反应。新近改造的Cys残基可以保持不配对,而且能够与亲电子的接头试剂或药物-接头中间体(诸如药物-马来酰亚胺)起反应(即偶联)。例示性的药物-接头中间体包括:MC-MMAE、MC-MMAF、MC-vc-PAB-MMAE、和MC-vc-PAB-MMAF。重链和轻链中经改造的Cys残基的结构位置依照连续编号系统来编号。此连续编号系统与自N末端起始的Kabat编号系统(Kaba等(1991)Sequences of Proteins of ImmunologicalInterest,第5版,Public Health Service,National Institutes of Health,Bethesda,MD)有关,与Kabat编号方案(底行)的区别在于以a、b、c来标示插入。使用Kabat编号系统,实际的线性氨基酸序列可包含减少的或添加的氨基酸,对应于可变域FR或CDR中的缩短或插入。经半胱氨酸改造的重链变体位点通过连续编号方式和Kabat编号方案来标示。
在一个实施方案中,通过包括下列步骤的方法制备半胱氨酸改造的抗TENB2抗体:
(a)用半胱氨酸替代亲代抗TENB2抗体的一个或多个氨基酸残基;和
(b)通过使半胱氨酸改造的抗TENB2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(区)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。
本发明的另一个实施方案提供了制备半胱氨酸改造的抗TENB2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TENB2抗体以便生成半胱氨酸改造的抗TENB2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。
本发明的另一个实施方案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。
TMEFF2#19IgG变体的半胱氨酸改造
通过本文所述半胱氨酸工程改造方法,在重链121(连续编号方式,排除信号序列)位点处将半胱氨酸导入全长、人源化亲本单克隆抗TENB2TMEFF2#19抗体,以给出A121C thio hu抗TENB2TMEFF2#19人源化变体(其具有重链序列SEQ ID NO:1和轻链序列SEQ ID NO:2,图1)。通过含1mM半胱氨酸的培养基中的瞬时发酵,在CHO(中国仓鼠卵巢)细胞中表达这些半胱氨酸改造的单克隆抗体。
依照一个实施方案,人源化TMEFF2#19半胱氨酸改造的抗TENB2抗体包含一个或多个具有游离半胱氨酸氨基酸的如下可变区重链序列(表1)。
表1:hu TMEFF2#19半胱氨酸改造的抗TENB2抗体变体的连续、Kabat和Eu编号方式的重链比较
Cys突变附近的序列 连续编号 Kabat编号 Eu编号 SEQ I.D.
DVQLCESGPG Q5C Q5C 8
LSLTCCVSGYS A23C A23C 9
LSSVTCADTAV A88C A84C 10
TLVTVCSASTK S119C S112C 11
VTVSSCSTKGP A121C A114C A118C 12
VSSASCKGPSV T123C T116C T120C 13
WYVDGCEVHNA V285C V278C V282C 14
KGFYPCDIAVE S378C S371C S375C 15
PPVLDCDGSFF S403C S396C S400C 16
依照一个实施方案,人源化TMEFF2#19半胱氨酸改造的抗TENB2抗体包含一个或多个具有游离半胱氨酸氨基酸的如下轻链可变区序列(表2)。
表2:hu TMEFF2#19半胱氨酸改造的抗TENB2抗体变体的连续和Kabat编号方式的轻链比较
Cys突变附近的序列 连续编号 Kabat编号 SEQ I.D.
SLSASCGDRVT V15C V15C 17
EIKRTCAAPSV V110C V110C 18
TVAAPCVFIFP S114C S114C 19
FIFPPCDEQLK S121C S121C 20
DEQLKCGTASV S127C S127C 21
VTEQDCKDSTY S168C S168C 22
GLSSPCTKSFN V205C V205C 23
经过标记的半胱氨酸改造的抗TENB2抗体
半胱氨酸改造的抗TENB2抗体可以位点特异性地和有效地与硫醇反应性试剂偶联。硫醇反应性试剂可以是多官能接头试剂(multifunctional linkerreagent);捕捉(即亲和、标记)试剂(例如生物素-接头试剂);检测标记物(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-接头中间体。硫醇反应性试剂的一个例子是N-乙基马来酰亚胺(NEM)。在一个例示性的实施方案中,ThioFab与生物素-接头试剂反应得到生物素化的ThioFab,通过这种方式可以检测和测量改造的半胱氨酸残基的存在和反应性。ThioFab与多官能接头试剂反应得到带有可以与药物模块试剂或其它标记物进一步反应的官能化接头的ThioFab。ThioFab与药物-接头中间体反应得到ThioFab药物偶联物。
本文所述例示性方法一般可应用于鉴定和生产抗体,并且更一般地通过应用本文所述的设计和筛选步骤用于其它蛋白质。
此类办法可应用于偶联其它硫醇反应性试剂,其中反应性基团是例如马来酰亚胺、碘乙酰胺、吡啶基二硫化物、或其它硫醇反应性偶联配偶体(Haugland,2003,Molecular Probes Handbook of Fluorescent Probes andResearch Chemicals,Molecular Probes,Inc.;Brinkley,1992,Bioconjugate Chem.3:2;Garman,1997,Non-Radioactive Labelling:A Practical Approach,AcademicPress,London;Means(1990)Bioconjugate Chem.1:2;Hermanson,G.inBioconjugate Techniques(1996)Academic Press,San Diego,pp.40-55,643-671)。硫醇反应性试剂可以是药物模块;荧光团,诸如荧光染料,像荧光素或若丹明;用于成像的螯合剂或放射性治疗金属;肽基或非肽基标记物或检测标记;或清除改性剂(clearance-modifying agent),诸如聚乙二醇的各种异构体;结合第三种成分的肽或另一种碳水化合物或亲脂性试剂。
半胱氨酸改造的抗TENB2抗体的用途
半胱氨酸改造的抗TENB2抗体及其偶联物可用作治疗和/或诊断试剂。本发明进一步提供了预防、管理(manage)、治疗或改善与TENB2相关病症有关的一种或多种症状的方法。具体而言,本发明提供了预防、管理、治疗、或改善与细胞增殖性病症诸如癌症有关的一种或多种症状的方法,所述癌症例如卵巢癌、宫颈癌、子宫癌、胰腺癌、肺癌和乳腺癌。本发明还进一步提供了诊断TENB2相关病症或发生此类病症的素因的方法,以及鉴定优先结合细胞结合(cell-associated)TENB2多肽的抗体和抗体的抗原结合片段的方法。
本发明的另一个实施方案致力于半胱氨酸改造的抗TENB2抗体用于制备药物的用途,所述药物在对抗TENB2抗体有响应的TENB2相关病症的治疗中是有用的。
半胱氨酸改造的抗TENB2抗体-药物偶联物
本发明的另一个方面是抗体-药物偶联物化合物,其包含半胱氨酸改造的抗TENB2抗体(Ab)和auristatin药物模块(D),其中半胱氨酸改造的抗体经由一个或多个游离的半胱氨酸氨基酸通过接头模块(L)附着至D;该化合物具有式I:
Ab-(L-D)p I
其中p为1,2,3,或4;且其中所述半胱氨酸改造的抗体是通过如下方法制备的,即包括用一个或多个游离的半胱氨酸氨基酸替换亲本抗TENB2抗体的一个或多个氨基酸残基。
图5显示了半胱氨酸改造的抗TENB2抗体药物偶联物(ADC)的实施方案,其中auristatin药物模块附着至轻链(LC-ADC)、重链(HC-ADC)、和Fc区(Fc-ADC)中的改造的半胱氨酸基团。
半胱氨酸改造的抗TENB2抗体药物偶联物的潜在优点包括安全性改善(治疗指数更大)、PK参数改进、抗体的链间二硫键保留(其可稳定偶联物并保持其活性结合构象)、药物偶联位点确定、和自半胱氨酸改造抗体与药物-接头试剂的偶联而制备半胱氨酸改造抗体-药物偶联物导致更均一的产物。
药物模块
式I的抗体-药物偶联物(ADC)的Auristatin药物模块包括多拉司他汀、auristatins(US 5635483;US 5780588;US 5767237;US 6124431)、及其类似物和衍生物。已经证实多拉司他汀和auristatins干扰微管动力学、GTP水解、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药物模块的不同形式可以通过肽药物模块的N(氨基)末端或C(羧基)末端共价附着至抗体(WO 02/088172;Doronina等(2003)Nature Biotechnology 21(7):778-784;Francisco等(2003)Blood 102(4):1458-1465)。
例示性的auristatin实施方案包括N-末端连接的monomethylauristatin药物模块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,明确将这些文献各自全部披露的内容引入本文作为参考。例示性的auristatin药物模块包括MMAE和MMAF。
式I的抗体-药物偶联物(ADC)的auristatin药物模块(D)包括monomethylauristatin药物模块MMAE和MMAF。MMAE或MMAF药物模块的N-末端经接头共价附着至抗体的改造的半胱氨酸。
其它例示性的auristatin药物模块包括在五肽auristatin药物模块的C末端具有苯丙氨酸羧基修饰的单甲基缬氨酸化合物(WO 2007/008848)和在五肽auristatin药物模块的C末端具有苯丙氨酸侧链修饰的单甲基缬氨酸化合物(WO 2007/008603)。
典型地,可以通过在两个或多个氨基酸和/或肽片段之间形成肽键制备基于肽的药物模块。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)。
接头
“接头”、“接头单元”、或“连接”指包含使抗体共价附着于药物模块的共价键或原子链的化学模块。在各个实施方案中,接头以L表示。“接头”(L)为可用于连接一个或多个药物模块(D)和抗体单元(Ab)而形成通式I的抗体-药物偶联物(ADC)的双功能或多功能模块。可以使用具有供结合药物和抗体用的反应性官能度的接头而便利地制备抗体-药物偶联物(ADC)。半胱氨酸改造抗体(Ab)的半胱氨酸硫醇可以与接头试剂、药物模块或药物-接头中间体的亲电子官能团形成键。
一方面,接头具有反应性位点,该位点具有与存在于抗体上的亲核半胱氨酸具有反应性的亲电子基团。抗体的半胱氨酸硫醇与接头上的亲电子基团具有反应性并且与接头形成共价键。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。
接头包括:二价基,诸如亚烃基(alkyldiyl)、亚芳基、亚杂芳基;模块,诸如-(CR2)nO(CR2)n-、烷氧基重复单元(例如聚亚乙基氧基(polyethylenoxy)、PEG、聚亚甲基氧基(polymethyleneoxy))和烷氨基(例如聚乙烯氨基,JeffamineTM);及二酸酯和酰胺,包括琥珀酸酯、琥珀酰胺、二乙醇酸酯、丙二酸酯和己酰胺。
半胱氨酸改造抗体与接头试剂或药物-接头中间体,与亲电子官能团诸如马来酰亚胺或α-卤代羰基依照Klussman等(2004)Bioconjugate Chemistry15(4):765-773,766页上的偶联方法和依照实施例3的方案起反应。
接头可以由一种或多种接头构件构成。例示性的接头构件包括6-马来酰亚氨基己酰基(“MC”)、马来酰亚氨基丙酰基(“MP”)、缬氨酸-瓜氨酸(“val-cit”或“vc”)、丙氨酸-苯丙氨酸(“ala-phe”或“af”)、对氨基苄氧羰基(“PAB”)、N-琥珀酰亚氨基4-(2-吡啶基硫代)戊酸酯(“SPP”)、N-琥珀酰亚氨基4-(N-马来酰亚氨基甲基)环己烷-1羧酸酯(“SMCC”)、和N-琥珀酰亚氨基(4-碘-乙酰基)氨基苯甲酸酯(“SIAB”)、亚乙基氧基-CH2CH2O-作为一个或多个重复单元(“EO”或“PEO”)。本领域知道别的接头构件,本文中也描述了一些。
在一个实施方案中,ADC的接头L具有通式:
-Aa-Ww-Yy-
其中:
-A-为共价附着于抗体(Ab)半胱氨酸硫醇的延伸物(stretcher)单元;
a为0或1;
每个-W-独立为氨基酸单元;
w独立为0-12的整数;
-Y-为共价附着于药物模块的间隔物(spacer)单元;且
y为0、1或2。
延伸物单元
当存在时,延伸物单元(-A-)能够连接抗体单元与氨基酸单元(-W-)。在这方面,抗体(Ab)具有能与延伸物单元的亲电子官能团形成键的游离半胱氨酸硫醇基团。式II和III描绘了式I中的例示性延伸物单元,其中Ab-、-W-、-Y-、-D、w和y如上文所定义且R17为选自下列的二价基:(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烃基(烷基)、苯基或苄基;且r独立地为范围1-10的整数。
亚芳基包括通过从芳族环体系中除去两个氢原子而衍生的6-20个碳原子的二价芳族烃基。典型的亚芳基包括但不限于衍生自苯、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)的环体系。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。杂环可以为具有3-7个环成员的单环(2-6个碳原子和1-3个选自N、O、P和S的杂原子)或具有7-10个环成员的双环(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]体系。杂环记载于Paquette,Leo A.;“Principles of Modern Heterocyclic Chemistry”,W.A.Benjamin,New York,1968,特别是1,3,4,6,7,和9章;“The Chemistry ofHeterocyclic Compound,Aseries of Monographs”,John Wiley&Sons,New York,1950至今,特别是卷13,14,16,19,和28;及J.Am.Chem.Soc.(1960)82:5566。
举例而言而非限制,杂环的例子包括: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、酚噁噻基(phenoxathinyl)、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、异色满基、色满基、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(isatinoyl)。
碳环基包括具有3-7个碳原子(作为单环)或7-12个碳原子(作为双环)的饱和或不饱和环。单环碳环具有3-6个环原子,更通常地为5或6个环原子。双环碳环具有7-12个环原子,例如排列成双环[4,5],[5,5],[5,6]或[6,6]体系,或者9或10个环原子,排列成双环[5,6]或[6,6]体系。单环碳环的例子包括环丙基、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。
根据式I ADC的所有例示性实施方案诸如II-V应当理解,即使在未明确表述的情况中,有1-4个药物模块与抗体连接(p=1-4),这取决于改造的半胱氨酸残基的数目。
一种例示性式II延伸物单元衍生自马来酰亚氨基-己酰基(MC),其中R17为-(CH2)5-:
一种例示性式II延伸物单元衍生自马来酰亚氨基-丙酰基(MP),其中R17为-(CH2)2-:
另一种例示性式II延伸物单元,其中R17为-(CH2CH2O)r-CH2-且r为2:
另一种例示性式II延伸物单元,其中R17为-(CH2)rC(O)NRb(CH2CH2O)r-CH2-,其中Rb为H且每个r为2:
另一种例示性式III延伸物单元,其中R17为-(CH2)5-:
在另一个实施方案中,延伸物单元通过抗体的改造半胱氨酸的硫原子与延伸物单元的硫原子之间的二硫键与半胱氨酸改造抗TENB2抗体连接。该实施方案的代表性延伸物单元以式IV描绘,其中R17、Ab-、-W-、-Y-、-D、w和y如上文所定义。
在又一个实施方案中,延伸物的反应性基团含有能与抗体的游离半胱氨酸硫醇形成键的硫醇反应性官能团。硫醇反应性官能团的例子包括但不限于:马来酰亚胺;α-卤代乙酰基;活化的酯类,诸如琥珀酰亚胺酯、4-硝基苯基酯、五氟苯基酯、四氟苯基酯;酸酐类;酸性氯化物或酰基氯类(acidchloride);磺酰氯类;异氰酸酯类和异硫氰酸酯类。该实施方案的代表性延伸物单元以式Va和Vb描绘,其中-R17-、Ab-、-W-、-Y-、-D、w和y如上文所定义。
在另一个实施方案中,接头可以为树状类型接头(dendritic type linker),其用于通过分支的多功能接头模块将超过一个药物模块共价附着于抗体(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)。树状接头能增加药物与抗体的摩尔比,即载荷,它与ADC的效能相关。如此,如果半胱氨酸改造抗体仅携带一个反应性半胱氨酸硫醇基团,那么可以通过树状接头附着众多药物模块。
氨基酸单元
接头可以包含氨基酸残基。如果存在,那么氨基酸单元(-Ww-)使本发明的半胱氨酸改造抗体-药物偶联物(ADC)的抗体(Ab)与药物模块(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次要的氨基酸(minor amino acid)和非天然存在的氨基酸类似物,诸如瓜氨酸。各个-W-单元独立地具有如下所示的方括号内的通式,且w为范围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、
当R19不为氢时,R19所附着的碳原子为手性的。R19所附着的各个碳原子独立地以(S)或(R)构型或外消旋混合物附着。氨基酸单元如此可以为对映体方面纯的、外消旋的或非对映异构体的。
例示性的-Ww-氨基酸单元包括二肽、三肽、四肽或五肽。例示性的二肽包括:缬氨酸-瓜氨酸(vc或val-cit)、丙氨酸-苯丙氨酸(af或ala-phe)。例示性的三肽包括: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)。构成氨基酸接头构件的氨基酸残基包括天然存在的氨基酸,以及次要氨基酸和非天然存在的氨基酸类似物,诸如瓜氨酸。
可以用一种或多种酶(包括肿瘤相关蛋白酶)酶促切割氨基酸单元,以释放药物模块(-D),其在一个实施方案中在体内释放时被质子化以提供药物(D)。可以在特定酶(例如肿瘤相关蛋白酶,组织蛋白酶B、C和D,或纤溶酶蛋白酶)的酶促切割的选择性方面设计和优化氨基酸接头构件。
间隔物单元
在氨基酸单元存在时(w=1-12),间隔物单元(-Yy-)(在存在时,y=1或2)使氨基酸单元-(Ww-)与药物模块(D)连接。或者,在氨基酸单元不存在时,间隔物单元使延伸物单元与药物模块连接。在氨基酸单元和延伸物单元都不存在时(w,y=0),间隔物单元还使药物模块与抗体单元连接。间隔物单元有两大类:自我牺牲的(self-immolative)和非自我牺牲的。非自我牺牲的间隔物单元为部分或所有间隔物单元在从抗体-药物偶联物或药物模块-接头切割(特别是酶促切割)氨基酸单元后保持与药物模块结合的间隔物单元。当含有甘氨酸-甘氨酸间隔物单元或甘氨酸间隔物单元的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切割时,甘氨酸-甘氨酸-药物模块或甘氨酸-药物模块从Ab-Aa-Ww-上切割下来。在一个实施方案中,在靶细胞内发生独立的水解反应,其切割甘氨酸-药物模块的键并释放药物。
在另一个实施方案中,-Yy-为对氨基苄基氨基甲酰基(PAB)单元,其亚苯基部分被Qm取代,其中Q为-C1-C8烃基(烷基,alkyl)、-O-(C1-C8烃基(烷基,alkyl))、-卤素、-硝基或-氰基;且m为范围0-4的整数。
非自我牺牲的间隔物单元(-Y-)的例示性实施方案为:-Gly-Gly-;-Gly-;-Ala-Phe-;-Val-Cit-。
在一个实施方案中,提供了药物模块-接头或ADC或其药学可接受的盐或溶剂化物,其中间隔物单元不存在(y=0)。
或者,含有自我牺牲的间隔物单元的ADC能释放-D。在一个实施方案中,-Y-为通过PAB基团的氨基氮原子连接至-Ww-,且通过碳酸酯、氨基甲酸酯或醚基团直接连接至-D的PAB基团,其中ADC具有如下例示性结构:
其中Q为-C1-C8烃基(烷基,alkyl)、-O-(C1-C8烃基(烷基,alkyl))、-卤素、-硝基或-氰基;m为范围0-4的整数;且p范围为1-4。
自我牺牲的间隔物的其它例子包括但不限于在电子方面与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)、杂环PAB类似物(US 2005/0256030)、β-葡糖苷酸(WO2007/011968)、和邻位或对位氨基苄基乙缩醛。可以使用在酰胺键水解时进行环化的间隔物,诸如取代和未取代的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]环体系(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)。消去在甘氨酸上取代的含胺药物(Kingsbury等(1984)J.Med.Chem.27:1447)也是可用于ADC的自我牺牲的间隔物的例子。
例示性的间隔物单元(-Yy-)以式X-XII表示:
树状接头
在另一个实施方案中,接头L可以为树状类型接头(dendritic type linker),其用于通过分支的多功能接头模块将超过一个药物模块共价附着于抗体(Sun等(2002)Bioorganic&Medicinal Chemistry Letters 12:2213-2215;Sun等(2003)Bioorganic&Medicinal Chemistry 11:1761-1768)。树状接头能增加药物与抗体的摩尔比,即载荷,它与ADC的效能相关。如此,如果半胱氨酸改造抗体仅携带一个反应性半胱氨酸硫醇基团,那么可以通过树状接头附着众多药物模块。分支的树状接头的例示性实施方案包括2,6-双(羟甲基)-对-甲酚和2,4,6-三(羟甲基)-酚树状聚物(dendrimer)单元(dendrimer unit)(WO 2004/01993;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)。
在一个实施方案中,间隔物单元为分支的双(羟甲基)苯乙烯(BHMS),它可以用于掺入和释放众多药物,其具有如下结构:
其包含2-(4-氨基亚苄基)丙烷-1,3-二醇树状聚物单元(WO 2004/043493;deGroot等(2003)Angew.Chem.Int.Ed.42:4490-4494),其中Q为-C1-C8烃基(烷基,alkyl),-O-(C1-C8烃基(烷基,alkyl))、-卤素、-硝基或-氰基;m为范围0-4的整数;n为0或1;且p范围为1-4。
式I抗体-药物偶联物化合物的例示性实施方案包括XIIIa(MC)、XIIIb(val-cit)、XIIIc(MC-val-cit)、和XIIId(MC-val-cit-PAB):
式Ia抗体-药物偶联物化合物的其它例示性实施方案包括XIVa-e:
其中X为:
Y为:
其中R独立为H或C1-C6烃基(烷基,alkyl);且n为1-12。
在另一个实施方案中,接头具有反应性官能团,该反应性官能团具有与存在于抗体上的亲电子基团具有反应性的亲核基团。抗体上有用的亲电子基团包括但不限于醛和酮羰基。接头的亲核基团的杂原子能与抗体上的亲电子基团反应并且与抗体单元形成共价键。接头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附着接头的便利位点。
典型地,可以通过在两个或更多氨基酸和/或肽片段之间形成肽键来制备肽类型的接头。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”,卷1,pp 76-136,Academic Press)来制备此类肽键。可以通过包括间隔物、延伸物和氨基酸单元的反应的任意组合或顺序来装配接头中间体。间隔物、延伸物和氨基酸单元可以采用本质上为亲电子、亲核或游离基的反应性官能团。反应性官能团包括但不限于羧基、羟基、对硝基苯基碳酸根、异硫氰酸根和离去基团,诸如O-甲磺酰基、O-甲苯磺酰基、-Cl、-Br、-I;或马来酰亚胺。
在另一个实施方案中,接头可以用调节溶解性或反应性的基团取代。例如,带电荷的取代基,诸如磺酸根(-SO3 -)或铵可以增加试剂的水溶性并且有利于接头试剂与抗体或药物模块的偶联反应,或有利于Ab-L(抗体-接头中间体)与D的偶联反应或D-L(药物-接头中间体)与Ab的偶联反应,这取决于用于制备ADC的合成途径。
接头试剂
可以使用多种双功能接头试剂来制备包含抗体和auristatin的偶联物,诸如N-琥珀酰亚氨基3-(2-吡啶基二硫代)丙酸酯(SPDP),琥珀酰亚氨基-4-(N-马来酰亚氨基甲基)环己烷-1-羧酸酯(SMCC),亚氨基硫烷(IT),亚氨酸酯(诸如盐酸己二酰亚氨酸二甲酯)、活性酯类(诸如辛二酸二琥珀酰亚氨基酯)、醛类(诸如戊二醛)、双叠氮化合物(诸如双(对-叠氮苯甲酰基)己二胺)、双重氮衍生物(诸如双(对-重氮苯甲酰基)-乙二胺)、二异硫氰酸酯(诸如甲苯2,6-二异氰酸酯)、和双活性氟化合物(诸如1,5-二氟-2,4-二硝基苯)的双功能衍生物。
也可以用如下接头试剂来制备抗体-药物偶联物:BMPEO、BMPS、EMCS、GMBS、HBVS、LC-SMCC、MBS、MPBH、SBAP、SIA、SIAB、SMPB、SMPH、sulfo-EMCS、sulfo-GMBS、sulfo-KMUS、sulfo-MBS、sulfo-SIAB、sulfo-SMCC和sulfo-SMPB、及SVSB(琥珀酰亚氨基-(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,它们可购自Pierce Biotechnology,Inc.,Customer Service Department,P.O.Box 117,Rockford,IL.61105 U.S.A,U.S.A1-800-874-3723,International+815-968-0747。双马来酰亚胺试剂任选将半胱氨酸改造抗体的硫醇基团按照依次或同时的方式附着至含硫醇药物模块、标记物或接头中间体。除马来酰亚胺外的其它与半胱氨酸改造抗体、药物模块、标记物或接头中间体的硫醇基团具有反应性的官能团包括碘乙酰胺、溴乙酰胺、乙烯基吡啶、二硫化物、吡啶基二硫化物、异氰酸根和异硫氰酸根。
还可以通过其它商业来源,诸如Molecular Biosciences Inc.(Boulder,CO)获得或按照下列文献中所述的规程合成有用的接头试剂: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;WO 03/043583;和WO04/032828。
可以通过使下列接头试剂与氨基酸单元的N-末端反应将式(IIIa)的延伸物引入接头:
其中n为1-10的整数且T为-H或-SO3Na;
其中n为0-3的整数;
可以通过使下列双功能试剂与氨基酸单元的N-末端反应将延伸物单元引入接头:
其中X为Br或I。
还可以通过使下列双功能试剂与氨基酸单元的N-末端反应将式中的延伸物单元引入接头:
具有马来酰亚胺延伸物和对氨基苄基氨基甲酰基(PAB)自我牺牲间隔物的例示性缬氨酸-瓜氨酸(val-cit或vc)二肽接头试剂具有如下结构:
具有马来酰亚胺延伸物单元和PAB自我牺牲间隔物单元的例示性phe-lys(Mtr,单-4-甲氧基三苯甲基)二肽接头试剂可以按照Dubowchik等(1997)Tetrahedron Letters,38:5257-60所述制备且具有如下结构:
例示性的药物-接头中间体包括:
本发明的例示性抗体-药物偶联物化合物包括:
其中Val为缬氨酸;Cit为瓜氨酸;p为1、2、3或4;且Ab为半胱氨酸改造抗TENB2抗体。
半胱氨酸改造抗TENB2抗体-药物偶联物的制备
可以通过数种途径,采用本领域技术人员公知的有机化学反应、条件和试剂来制备式I的ADC,包括:(1)使半胱氨酸改造抗体的半胱氨酸基团与接头试剂反应,从而通过共价键形成抗体-接头中间体Ab-L,随后与活化的药物模块D反应;和(2)使药物模块的亲核基团与接头试剂反应,从而通过共价键形成药物-接头中间体D-L,随后与半胱氨酸改造抗体的半胱氨酸基团反应。偶联方法(1)和(2)可以与各种半胱氨酸改造抗体、药物模块和接头一起使用以制备式I的抗体-药物偶联物。
抗体半胱氨酸硫醇基团为亲核性的并且能够与接头试剂和药物-接头中间体上的亲电子基团反应而形成共价键,所述亲电子基团包括:(i)活性酯类,诸如NHS酯类、HOBt酯类、卤代甲酸酯类和酸性氯化物类;(ii)烃基和苄基卤化物,诸如卤代乙酰胺类;(iii)醛类、酮类、羧基和马来酰亚胺基团;和(iv)通过硫化物交换的二硫化物,包括吡啶基二硫化物。药物模块上的亲核基团包括但不限于:胺、硫醇、羟基、酰肼、肟、肼、缩氨基硫脲、肼羧酸酯和芳基酰肼基团,它们能够与接头模块和接头试剂上的亲电子基团反应而形成共价键。
可以如下使半胱氨酸改造抗体变成反应性的以便偶联接头试剂,即用还原剂,诸如DTT(Cleland氏试剂,二硫苏糖醇)或TCEP(三(2-羧乙基)膦盐酸盐)处理(Getz等(1999)Anal.Biochem.273:73-80;Soltec Ventures,Beverly,MA),接着再氧化以再形成链间和链内二硫键(实施例2)。例如,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(ThioMab)还原3小时以还原半胱氨酸加合物中的二硫键,其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。用10mM乙酸钠,pH5稀释还原后的ThioMab并且加载至10mM乙酸钠,pH5中的HiTrap S柱上并且用含有0.3M氯化钠的PBS洗脱。在室温用稀(200nM)硫酸铜(CuSO4)水溶液重新建立亲本Mab中存在的半胱氨酸残基之间的二硫键过夜。或者,脱氢抗坏血酸(DHAA)是有效的氧化剂,用于在半胱氨酸加合物的还原性切割之后重新建立半胱氨酸改造抗体的链内二硫化物基团。可以使用本领域公知的其它氧化剂,即氧化性试剂和氧化性条件。环境空气氧化也是有效的。这种温和的部分再氧化步骤有效地高保真度地形成链内二硫键并保护新引入的半胱氨酸残基的硫醇基团。加入相对于抗体约3倍过量的(相对于新引入的半胱氨酸残基约1.5倍过量的)药物-接头中间体,例如MC-vc-PAB-MMAE,混合并且在室温放置约1小时,以进行偶联并形成TMEFF2#19抗TENB2抗体-药物偶联物。将偶联混合物进行凝胶过滤、加载和通过HiTrap S柱洗脱以除去过量的药物-接头中间体和其它杂质。
附图6显示了制备由细胞培养物表达的用于偶联的半胱氨酸改造抗体的一般方法。当细胞培养基含有半胱氨酸时,可以在新引入的半胱氨酸氨基酸和培养基中的半胱氨酸之间形成二硫化物加合物。必须将这些半胱氨酸加合物(描绘为图6中的例示性ThioMab(左)中的环)还原以生成具有偶联反应性的半胱氨酸改造抗体。将半胱氨酸加合物,可能还有多个链间二硫键用还原剂诸如TCEP还原性切割以产生还原形式的抗体。在部分氧化条件下,用硫酸铜、DHAA、或暴露于环境氧而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用于与接头试剂或药物-接头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通过形成-S-S-键产生偶联至改造的Cys的外部偶联Cys加合物。因此,纯化的ThioMabs如实施例2所述通过还原和再氧化规程处理以产生反应性ThioMabs。这些ThioMabs用于偶联含有马来酰亚胺的细胞毒性药物、荧光团和其它标记物。
对半胱氨酸改造的抗体药物偶联物反应的分析显示了相对于通过还原链间或链内二硫键,接着(标准ADC)与硫醇反应性药物接头中间体偶联而制备的抗体药物偶联物降低的异质性。
筛选方法
本发明的又一个实施方案致力于测定怀疑含有TENB2多肽的样品中TENB2多肽的存在的方法,其中该方法包括使所述样品暴露于结合TENB2多肽的半胱氨酸改造抗TENB2抗体或其抗体-药物偶联物,并测定半胱氨酸改造抗TENB2抗体或其抗体-药物偶联物与样品中TENB2多肽的结合,其中存在有所述结合表明样品中存在TENB2多肽。任选地,所述样品可包含怀疑表达TENB2多肽的细胞(其可以是癌细胞)。所述方法中所采用的半胱氨酸改造抗TENB2抗体或其抗体-药物偶联物可任选地可检测地标记、附着至固体支持物、等等。
本发明的另一个实施方案致力于诊断哺乳动物中肿瘤的存在的方法,其中该方法包括:(a)使包含得自哺乳动物的组织细胞的测试样品接触结合TENB2多肽的半胱氨酸改造抗TENB2抗体或其抗体-药物偶联物,并(b)检测半胱氨酸改造抗TENB2抗体或其抗体-药物偶联物与测试样品中的TENB2多肽之间复合物的形成,其中形成了复合物表明哺乳动物中存在肿瘤。任选地,半胱氨酸改造抗TENB2抗体或其抗体-药物偶联物是可检测地标记的、附着至固体支持物的、等等,和/或组织细胞的测试样品得自怀疑具有癌性肿瘤的个体。
体外细胞增殖测定法
本发明的一个实施方案致力于抑制表达TENB2多肽的细胞生长的方法,其中该方法包括使细胞接触针对TENB2多肽的半胱氨酸改造的抗TENB2抗体或其抗体药物偶联物,引起对表达TENB2的细胞生长的抑制。所述细胞可以是癌细胞,而且半胱氨酸改造的抗体或其抗体药物偶联物对TENB2多肽的结合引起表达TENB2多肽的细胞死亡。
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:使表达TENB2多肽的哺乳动物细胞在细胞培养基中暴露于ADC;将细胞培养约6小时-约5天的时间;和测定细胞存活率。对于细胞增殖测定法有用的哺乳动物细胞包括:(1)表达TENB2多肽的LuCaP77肿瘤异种移植物;(2)改造成在其细胞表面上稳定表达TENB2多肽一部分的PC3衍生的细胞系(PC3/TENB2);和(3)不表达TENB2多肽的PC3细胞系(PC3/neo)。基于细胞的体外试验用于测定存活力(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)。
药动学-血清清除和稳定性
通过单个静脉内推注剂量注射入Sprague-Dawley大鼠后测量抗体和药物偶联物的血清浓度,分析了抗TENB2抗体-药物偶联物的体内部署。携带至少一个细胞毒性药物的抗体-药物偶联物的浓度以ELISA测量,其使用抗MMAE进行捕捉及使用生物素化TENB2胞外结构域(ECD)和链霉亲合素-辣根过氧化物酶(HRP)进行检测。血清中的总TMEFF2#19和ThioTMEFF2#19浓度以ELISA测量,其使用TENB2ECD进行捕捉及使用抗人Fc HRP作为二抗。此测定法测量任何抗TENB2抗体,有和无偶联的MMAE均可。这些测定法具有定量下限16.4ng/mL,最低稀释度1∶100。使用具有IV推注输入、一阶消除(first order elimination)、和宏观速率常数(macro-rate constant)的两隔室模型(Model 8,WinNonlin Pro v.5.0.1,Pharsight Corporation,Mountain View,CA)分析了来自每只动物的血清浓度时间数据。拟合的整体优度基于预测估值、预测的标准误差、和主要和次要参数的变异系数的百分比,以及对观察的和预测的浓度-时间数据之间的参差图(residual plot)的审查。个别主要PK参数包含分别与α和β阶段有关的零-时间截距(A和B),及微-速率常数(micro-rateconstants)(α和β)。使用了以下建模选项:使用WinNonlin来确定初始估值;通过预测浓度平方的倒数来对浓度加权;使用Nelder-Mead最小化算法。报告了以下PK参数:CL、Cmax、MRT、t1/2,a、t1/2,b、V1和Vss
在大鼠中进行的28天药动学分析的结果显示于图15。给大鼠服用5mg/kg体重的thio TMEFF2#19-VC-MMAE或5mg/kg TMEFF2#19-VC-MMAE。在服药后5分钟、1小时、6小时、24小时、及2,3,4,8,11,15,21,和28天自大鼠收集血清。对ch TMEFF2#19-VC-MMAE在0.5和5mg/kg剂量之间观察到动力学的剂量线性,所以算术转换5mg/kg剂量数据以反映5mg/kg时的预测数据,用于与TMEFF2#19-VC-MMAE进行比较。
啮齿类毒性
在急性毒性大鼠和猕猴模型中评估半胱氨酸改造的抗TENB2抗体-药物偶联物的毒性。通过用ADC处理雌性Sprague-Dawley大鼠和猕猴并随后检查和分析对各种器官的影响来调查ADC的毒性。基于总体观察(体重)、临床病理学参数(血清化学和血液学)和组织病理学,可观察、表征、和测量ADC的毒性。发现在等同的剂量水平,没有出现靶物依赖性效应。在动物肿瘤模型中在超出有效剂量的剂量观察到靶物非依赖性毒性。
治疗方法
本发明的另一个实施方案致力于治疗性处理具有癌性肿瘤(其包含表达TENB2多肽的细胞)的哺乳动物的方法,其中该方法包括对哺乳动物施用治疗有效量的结合TENB2多肽的半胱氨酸改造的抗体或其抗体药物偶联物,由此导致对肿瘤的有效治疗性处理。
本发明的另一个实施方案致力于治疗或预防与改变的、优选升高的TENB2多肽表达或活性有关的细胞增殖性病症的方法,该方法包括对需要此类治疗的受试者施用有效量的半胱氨酸改造的抗TENB2抗体或其抗体药物偶联物。一种例示性的细胞增殖性病症是癌症。对细胞增殖性病症的优选治疗或预防可以是用半胱氨酸改造的抗TENB2抗体或其抗体药物偶联物直接杀死表达TENB2多肽的细胞或抑制表达TENB2多肽的细胞生长或拮抗TENB2多肽的细胞生长增强活性的结果。
本发明的又一个实施方案致力于使半胱氨酸改造的抗TENB2抗体或其抗体药物偶联物结合表达TENB2多肽的细胞的方法,其中该方法包括在适合半胱氨酸改造的抗TENB2抗体或其抗体药物偶联物结合所述TENB2多肽的条件下使表达TENB2多肽的细胞与所述半胱氨酸改造的抗TENB2抗体或其抗体药物偶联物接触并容许它们之间的结合。在优选的实施方案中,半胱氨酸改造的抗TENB2抗体或其抗体药物偶联物是用对于定性和/或定量测定半胱氨酸改造的抗TENB2抗体或其抗体药物偶联物结合所述细胞的位置和/或量而言有用的分子或化合物标记的。
本发明的其它实施方案致力于半胱氨酸改造的抗TENB2抗体或其抗体药物偶联物在制备药物中的用途,所述药物可用于(i)癌症或肿瘤的治疗性处理或诊断性检测,或(ii)细胞增殖性病症的治疗性处理或预防。
本发明的另一个实施方案致力于抑制癌细胞生长的方法,其中所述癌细胞的生长至少部分依赖于TENB2多肽的生长增强效应,其中该方法包括使TENB2多肽与半胱氨酸改造的抗TENB2抗体或其抗体药物偶联物接触,由此拮抗TENB2多肽的生长增强效应,并继而抑制癌细胞的生长,由此癌细胞的生长得到抑制。
本发明的另一个实施方案致力于治疗性处理哺乳动物中的肿瘤的方法,其中所述肿瘤的生长至少部分依赖于TENB2多肽的生长增强效应,其中该方法包括对哺乳动物施用治疗有效量的结合TENB2多肽的抗TENB2半胱氨酸改造的抗体或其抗体药物偶联物,由此拮抗所述TENB2多肽的生长增强效应并导致对肿瘤的有效治疗性处理。
抗体、抗体片段、和其偶联物识别释放入胞外流体中的质膜TENB2蛋白的胞外表位。本发明进一步提供了使用抗体、抗体片段和其偶联物检测、监测和治疗恶性肿瘤(诸如乳腺癌或卵巢癌)的方法。
本发明的抗体-药物偶联物(ADC)可用于治疗各种疾病或病症,例如特征为TENB2肿瘤抗原过表达的。例示性的疾患或过度增殖性病症包括良性或恶性肿瘤,包括前列腺癌。
可以在具有肿瘤的较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。
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,将治疗持续至对疾病症状的所需抑制发生为止。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TENB2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测定法(包括超声成像)监测。
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、腹膜内、肌肉内、静脉内、真皮内、鞘内和硬膜外。
药物配制剂
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无菌可注射形式的药物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)。
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。
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(association)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粉。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、抑菌剂和赋予所述制剂与预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位制剂(unit dose)或多剂(multi-dose)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(unit daily sub-dose)或其合适量一部分的活性组分的剂型。
本发明的组合物还可配制成免疫脂质体。脂质体是由各种类型脂质、磷脂和/或表面活性剂构成的,可用于对哺乳动物递送药物的小囊泡。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。含有抗体的脂质体可通过本领域已知方法来制备,诸如Epstein等(1985)Proc.Natl.Acad.Sci.USA82:3688;Hwang等(1980)Proc.Natl.Acad.Sci.USA 77:4030;美国专利No.4,485,045;4,544,545;5,013,556;WO 97/38731中所述。可用包含磷脂酰胆碱、胆固醇和PEG衍生化磷脂酰乙醇胺(PEG-PE)的脂类组合物通过反相蒸发法生成脂质体。可以将脂质体挤过具有设定孔径的滤器,以产生具有期望直径的脂质体。可以将本发明组合物的Fab’片段经二硫化物交换反应与脂质体偶联(Martin等(1982)J.Biol.Chem.257:286-288)。任选在脂质体中包含化疗剂(Gabizon等(1989)J.National Cancer Inst.81(19):1484)。
联合疗法
可以将本发明的抗体-药物偶联物(ADC)与第二种具有抗癌特性的化合物以药物组合配制剂的形式联合应用或作为联合疗法的给药方案联合应用。所述药物组合配制剂或给药方案中的第二种化合物优选具有对组合中的ADC的补充活性,使得它们彼此不会产生不利影响。
所述第二种化合物可以为化疗剂、细胞毒剂、细胞因子、生长抑制剂、抗激素剂和/或心脏保护剂。此类分子以对指定目的有效的量适当地联合存在。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、DNA插入剂、或DNA结合剂。
可以将其它治疗方案与依照本发明所鉴定的抗癌药联合施用。联合疗法可以作为同时或序贯方案施用。当序贯施用时,可以以两次或更多次施用来施用所述组合。联合施用包括使用分开的配制剂或单一药物配制剂的共施用,和任意次序的序贯施用,其中优选有一段时间所有活性剂同时发挥其生物学活性。
在一个实施方案中,使用ADC的治疗牵涉联合施用半胱氨酸改造的抗TENB2抗体或其抗体-药物偶联物和一种或多种化疗剂、治疗性生物制品、或生长抑制剂,包括共施用不同化疗剂鸡尾酒样混合物。化疗剂包括但不限于紫杉烷类(诸如帕利他塞(paclitaxel)和多西他塞(docetaxel))、含铂化合物(诸如卡铂)、EGFR抑制剂(诸如erlotinib和gefitinib)、酪氨酸激酶抑制剂(诸如imatinib)、和蒽环类抗生素(诸如多柔比星或doxil)。要与半胱氨酸改造的抗TENB2抗体或其抗体-药物偶联物组合使用的治疗性生物制品药剂包括bevacizumab()或pertuzumab(OmnitargTM,Genentech Inc)。熟练从业人员可以按照制造商的说明书或凭经验确定地使用此类化疗剂的制备和剂量给药方案。此类化疗剂的制备和剂量给药方案还记载于“Chemotherapy Service”,(1992)M.C.Perry编,Williams&Wilkins,Baltimore,Md。
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(以便预防或减轻与所述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去除和/或放疗的治疗。
任何上述共施用的药剂的合适剂量就是那些当前使用的剂量,而且可以由于新鉴定的药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”并且证实是“协同性”的,即当一起使用活性组分时所实现的效果大于分开使用所述化合物时所产生的效果之和。当活性组分为如下情况时可以获得协同效应:(1)共同配制和施用或以组合的单位剂量配制剂(unit dosage formulation)形式同时投递;(2)作为分开的配制剂交替或平行投递;或(3)通过一些其它方案。当在交替疗法中投递时,在序贯施用或投递所述化合物时,例如通过不同注射器中的不同注射,可以获得协同效应。一般而言,在交替疗法中,序贯地,即依序地施用每种活性组分的有效剂量,而在联合疗法中,一起施用两种或更多活性组分的有效剂量。
抗体-药物偶联物的代谢物
本文中所描述的ADC化合物的体内代谢产物也落在本发明的范围内,就此类产物相对于现有技术是新颖的且非显而易见的而言。此类产物可源自例如所施用化合物的氧化、还原、水解、酰胺化、酯化、酶促切割、诸如此类。因而,本发明包括由如下方法生成的新颖的且非显而易见的化合物,所述方法包括使本发明的化合物接触哺乳动物一段时间,该时间足以产生本发明化合物的代谢产物。
代谢产物典型地是如下制备的,即制备放射性标记的(例如14C或3H)ADC,以可检测剂量(例如大于大约0.5mg/kg)将其胃肠外施用于哺乳动物,诸如大鼠、小鼠、豚鼠、猴或人,容许足够时间让代谢发生(典型的是大约30秒至30小时),并自尿液、血液或其它生物学样品分离它的转化产物。这些产物是易于分离的,因为它们是带标记物的(其它的通过使用能够结合代谢物中幸存的结合表位的抗体来分离)。代谢物结构以常规方式来测定,例如通过MS、LC/MS或NMR分析。一般而言,代谢物的分析是以与本领域技术人员公知的常规药物代谢研究相同的方式进行的。转化产物在用于本发明ADC化合物的治疗性剂量给药的诊断测定法中是有用的,只要没有在体内在其它情况中找到它们。
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。包装插页可以指通常包括在治疗用产品商品化包装中的说明书,它包含有关此类治疗用产品使用的适应症、用法、剂量、施用、禁忌和/或警告信息。合适的容器包括:例如瓶、小瓶、注射器、泡罩包等,所述容器可以由各种材料,诸如玻璃或塑料形成。
在一个实施方案中,所述制品包括容器和装在该容器内的半胱氨酸改造的抗TENB2抗体或其抗体-药物偶联物的配制剂。所述制品可进一步任选地包含贴在容器上的标签或包括在容器内的包装插页,其指出所述组合物用于肿瘤的治疗性处理或诊断性检测的用途。装有所述配制剂的容器有效存储和投递治疗剂,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)。标签或包装插页表示所述配制剂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(或第三)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。
提供以下实施例仅用于例示目的,而非意图以任何方式限制本发明的范围。
通过述及将本说明书中引用的所有专利和参考文献完整收入本文。
实施例
除非另有说明,实施例中提及的商品化试剂依照制造商的说明书使用。下文实施例和整篇说明书中以ATCC编号所鉴别的那些细胞的来源是美国典型培养物保藏中心(American Type Culture Collection,Manassas,VA)。
实施例1:抗TMEFF2#19抗体的制备
人源化TMEFF2#19抗体是依照PCT/US03/07209制备的。图1显示了重链氨基酸序列(SEQ ID NO:1)和轻链氨基酸序列(SEQ ID NO:2)。
实施例2:半胱氨酸改造的抗TENB2抗体的制备,供通过还原和再氧化进行的偶联用
由于细胞培养条件,在CHO细胞中表达的全长半胱氨酸改造的抗TENB2单克隆抗体(ThioMab)在改造的半胱氨酸上携带半胱氨酸加合物(胱氨酸)。为了解放改造的半胱氨酸的反应性硫醇基团,将ThioMab溶解在约pH8.0的500mM硼酸钠和500mM氯化钠中并用约50-100倍过量的1mM TCEP(盐酸三(2-羧乙基)膦;Getz et al(1999)Anal.Biochem.Vol 273:73-80;Soltec Ventures,Beverly,MA)于37℃还原约1-2小时。将还原的ThioMab(图6)稀释并加载到10mM乙酸钠pH5中的HiTrap S柱上,并用含0.3M氯化钠的PBS洗脱。将洗脱的还原的ThioMab用pH7的2mM脱氢抗坏血酸(dhAA)处理3小时,或用2mM硫酸铜(CuSO4)水溶液于室温处理过夜。环境空气氧化也可以是有效的。通过Sephadex G25树脂上的洗脱来更换缓冲液,并用含1mM DTPA的PBS洗脱。根据溶液在280nm的吸光度来测定还原的抗体浓度,通过与DTNB(Aldrich,Milwaukee,WI)反应并测定412nm的吸光度来测定硫醇浓度,由此检查硫醇/抗体值(thio/Ab value)。
实施例3:半胱氨酸改造的抗TENB2抗体与药物-接头中间体的偶联
在实施例2的还原和再氧化规程后,将半胱氨酸改造的抗TENB2抗体溶解在PBS(磷酸盐缓冲盐水)缓冲液中,并在冰上冷却。将相对于每个抗体的改造的半胱氨酸约1.5个摩尔当量的带有硫醇反应性官能团(诸如马来酰亚胺基)的auristatin药物接头中间体(诸如MC-MMAE(马来酰亚胺己酰基-单甲基auristatin E)、MC-MMAF、MC-val-cit-PAB-MMAE、或MC-val-cit-PAB-MMAF)溶解在DMSO中,在乙腈和水中稀释,并添加至冷却的PBS中的还原的、再氧化的抗体。约一小时后,添加过量的马来酰亚胺以淬灭反应并给任何未反应的抗体硫醇基团加帽。通过离心超滤浓缩反应混合物,并将半胱氨酸改造的抗TENB2抗体药物偶联物通过穿过PBS中G25树脂的洗脱来纯化和脱盐,在无菌条件下用0.2μm滤器过滤,并冷冻储存。
通过上述规程,制备了以下半胱氨酸改造的抗TENB2抗体药物偶联物:thio hu TMEFF2#19-MC-MMAF,通过偶联A114C(Kabat)thio hu TMEFF2#19与MC-MMAF;和
thio hu TMEFF2#19-MC-val-cit-PAB-MMAE,通过偶联A 114C(Kabat)thio huTMEFF2#19与MC-val-cit-PAB-MMAE。
实施例4:用于IHC、内在化研究、FACS、细胞杀伤测定法、Western印迹、异种移植物研究、药动学研究和安全性评估的材料和方法
抗体和重组蛋白:人源化抗tenb2 Mab PR1得自PDL。ThioMab抗tenB2PR1(HC-A121C;连续编号方式)和tenB2ECD Flag蛋白是如上所述生成的。
细胞系和人肿瘤异种移植物:PC3是人前列腺癌细胞系(ATCC)。PC3TenB2 Medium稳定细胞系是由Genentech制备的。人前列腺外植体模型LuCap70、77和96.1得自华盛顿大学。
RNA和蛋白质表达:RNA表达分析、免疫学规程(IHC、Western)、抗体结合(FACS)和内在化遵循先前发表的方法(Cancer research 64,781-788(2004))。
常规或ThioMab抗TenB2-缬氨酸-瓜氨酸(vc)-单甲基auristatine E(MMAE)和MC-MMAF武装的药物偶联物(ADC)的制备:常规、thio-mab和对照mab与vc-MMAE、MC-MMAF ADC的偶联是如上所述实施的。
体外细胞杀伤和体内研究:与Cancer research 64,781-788(2004)所述类似地进行细胞杀伤测定法。通过在来自Charles River实验室的经阉割的(不依赖雄激素的模型,LuCap70)或未阉割的(依赖雄激素的模型,LuCAP77和LuCAP96.1)雄性SCID-米色小鼠中连续移植来维持每种前列腺外植体模型肿瘤细胞系。在研究期间每周一次至两次测量肿瘤。
用于安全性评估的大鼠和猕猴模型:抗tenb2 Mab特异性识别人、猴和大鼠tenb2靶物(FSI域)。
药动学研究:使用标准方案和测定方法。
数据证明了人TenB2(TMEFF2)一般局限于在前列腺和CNS中表达,在癌性前列腺中有显著升高的水平。抗TenB2抗体还展现出快速内在化。这些抗体在偶联至MMAE和MMAF时显示出在各种细胞杀伤测定法中在体外和在体内杀死前列腺肿瘤细胞。而且,TENB2-ADC的有效剂量显著低于在啮齿类和灵长类中引发毒性效应所需要的剂量。
认为前述书面说明足以使本领域技术人员能够实践本发明。本发明并不限于所保藏构建物的范围,因为所保藏实施方案意图作为本发明某些方面的单一例示,而且功能上相当的任何构建物都在本发明的范围内。本文中的材料保藏并非承认本文中所包含的书面说明不足以能够实践本发明的任何方面,包括其最佳模式,也不能解释为将权利要求的范围限制于它所描述的具体例示。实际上,除了本文所显示和描述的以外,根据上面的描述,对本发明的多种变化对于本领域技术人员而言也是显而易见的,而且在所附权利要求的范围内。
序列表
<110>健泰科生物技术公司(GENENTECH,INC.)
MAO,WEIGUANG
JUNUTULA,JAGATH REDDY
POLAKIS,PAUL
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<130>GNE-0311PCT
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Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210>7
<211>450
<212>PRT
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<220>
<223>人工序列的描述:合成的多肽
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Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
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Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Thr Ser Gly
20 25 30
Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Met Gly Phe Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Asn Pro Ser Leu
50 55 60
Lys Asn Arg Ile Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Arg Arg Gly Asp Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210>8
<211>10
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>8
Asp Val Gln Leu Cys Glu Ser Gly Pro Gly
1 5 10
<210>9
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>9
Leu Ser Leu Thr Cys Cys Val Ser Gly Tyr Ser
1 5 10
<210>10
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>10
Leu Ser Ser Val Thr Cys Ala Asp Thr Ala Val
1 5 10
<210>11
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>11
Thr Leu Val Thr Val Cys Ser Ala Ser Thr Lys
1 5 10
<210>12
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>12
Val Thr Val Ser Ser Cys Ser Thr Lys Gly Pro
1 5 10
<210>13
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>13
Val Ser Ser Ala Ser Cys Lys Gly Pro Ser Val
1 5 10
<210>14
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>14
Trp Tyr Val Asp Gly Cys Glu Val His Asn Ala
1 5 10
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<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>15
Lys Gly Phe Tyr Pro Cys Asp Ile Ala Val Glu
1 5 10
<210>16
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>16
Pro Pro Val Leu Asp Cys Asp Gly Ser Phe Phe
1 5 10
<210>17
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>17
Ser Leu Ser Ala Ser Cys Gly Asp Arg Val Thr
1 5 10
<210>18
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>18
Glu Ile Lys Arg Thr Cys Ala Ala Pro Ser Val
1 5 10
<210>19
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>19
Thr Val Ala Ala Pro Cys Val Phe Ile Phe Pro
1 5 10
<210>20
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>20
Phe Ile Phe Pro Pro Cys Asp Glu Gln Leu Lys
1 5 10
<210>21
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>21
Asp Glu Gln Leu Lys Cys Gly Thr Ala Ser Val
1 5 10
<210>22
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>22
Val Thr Glu Gln Asp Cys Lys Asp Ser Thr Tyr
1 5 10
<210>23
<211>11
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>23
Gly Leu Ser Ser Pro Cys Thr Lys Ser Phe Asn
1 5 10
<210>24
<211>6
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的6x His标签
<400>24
His His His His His His
1 5
<210>25
<211>8
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的8x His标签
<400>25
His His His His His His His His
1 5
<210>26
<211>9
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>26
Lys Asp Tyr Lys Asp Asp Asp Asp Lys
1 5
<210>27
<211>25
<212>PRT
<213>人工序列
<220>
<223>人工序列的描述:合成的肽
<400>27
Lys Tyr Ala Leu Ala Asp Ala Ser Leu Lys Met Ala Asp Pro Asn Arg
1 5 10 15
Phe Arg Gly Lys Asp Leu Pro Val Leu
20 25
Claims (60)
1.一种半胱氨酸改造的抗TENB2抗体,其包含一个或多个游离的半胱氨酸氨基酸和选自SEQ ID NO:8-23的序列。
2.权利要求1的半胱氨酸改造的抗TENB2抗体,其中所述半胱氨酸改造的抗TENB2抗体结合TENB2多肽。
3.权利要求1的半胱氨酸改造的抗TENB2抗体,其是通过包括用半胱氨酸替换亲本抗TENB2抗体的一个或多个氨基酸残基的过程制备的。
4.权利要求1的半胱氨酸改造的抗TENB2抗体,其中所述一个或多个游离的半胱氨酸氨基酸残基位于轻链中。
5.权利要求4的半胱氨酸改造的抗TENB2抗体,其包含选自下组的一种或多种序列:
6.权利要求1的半胱氨酸改造的抗TENB2抗体,其中所述一个或多个游离的半胱氨酸氨基酸残基位于重链中。
7.权利要求6的半胱氨酸改造的抗TENB2抗体,其包含选自下组的一种或多种序列:
8.权利要求1的半胱氨酸改造的抗TENB2抗体,其包含重链序列,该重链序列包含:
MAVLGLLLCLVTFPSCVLSDVQLQESGPGLVKPSETLSLTCAVSGYSI
TSGYYWSWIRQPPGKGLEWMGFISYDGSNKYNPSLKNRITISRDTSK
NQFSLKLSSVTAADTAVYYCARGLRRGDYSMDYWGQGTLVTVSSCS
TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK
VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT
VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS
RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD
GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:3。
9.权利要求1的半胱氨酸改造的抗TENB2抗体,其包含轻链序列,该轻链序列包含:
MDFQVQIFSFLLISASVIMSRGDIQMTQSPSSLSASVGDRVTITCKASQ
NVVTAVAWYQQKPGKAPKLLIYSASNRHTGVPSRFSGSGSGTDFTLTI
SSLQPEDFATYYCQQYSSYPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQ
LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK
DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:2。
10.权利要求1的半胱氨酸改造的抗TENB2抗体,其中亲本抗TENB2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。
11.权利要求1的半胱氨酸改造的抗TENB2抗体,其是抗体片段。
12.权利要求11的半胱氨酸改造的抗TENB2抗体,其中所述抗体片段是Fab片段。
13.权利要求1的半胱氨酸改造的抗TENB2抗体,其选自嵌合抗体、人抗体、或人源化抗体。
14.权利要求1的半胱氨酸改造的抗TENB2抗体,其是在细菌中生成的。
15.权利要求1的半胱氨酸改造的抗TENB2抗体,其是在CHO细胞中生成的。
16.一种测定怀疑含有TENB2蛋白的样品中测定所述蛋白质的存在的方法,所述方法包括:
将所述样品暴露于权利要求1的半胱氨酸改造的抗TENB2抗体;并测定所述抗体对所述样品中所述TENB2蛋白的结合,其中所述抗体对所述蛋白质的结合指示所述样品中存在所述蛋白质。
17.权利要求16的方法,其中所述样品包含怀疑表达所述TENB2蛋白质的细胞。
18.权利要求16的方法,其中所述细胞是前列腺癌细胞、卵巢癌细胞、乳腺癌细胞、肺癌细胞、或胰腺癌细胞。
19.权利要求16的方法,其中所述抗体是共价附着至选自下组的标记物的:荧光染料、放射性同位素、生物素、或金属络合配体。
20.一种药物配制剂,其包含结合权利要求1的半胱氨酸改造的抗TENB2抗体及药学可接受的稀释剂、载体或赋形剂。
21.权利要求1的半胱氨酸改造的抗TENB2抗体,其中所述抗体是共价附着至auristatin药物模块的,由此抗体-药物偶联物得以形成。
22.权利要求21的抗体-药物偶联物,其包含半胱氨酸改造的抗TENB2抗体(Ab)和auristatin药物模块(D),其中所述半胱氨酸改造的抗TENB2抗体是经由一个或多个游离的半胱氨酸氨基酸通过接头模块(L)附着至D的;所述化合物具有式I:
Ab-(L-D)p I
其中p为1、2、3、或4。
23.权利要求22的抗体-药物偶联物化合物,其中p为2。
24.权利要求22的抗体-药物偶联物化合物,其中L具有式:
-Aa-Ww-Yy-
其中:
A为延伸物单元,其共价附着至所述半胱氨酸改造的抗体(Ab)的半胱氨酸硫醇;
a为0或1;
每个W独立地为氨基酸单元;
w为范围为0-12的整数;
Y为间隔物单元,其共价附着至所述药物模块;且
y为0、1或2。
25.权利要求24的抗体-药物偶联物化合物,其具有式:
其中PAB为对-氨基苄基氨甲酰基,且R17为选自下组的二价基:(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烃基,苯基,或苄基;
且r独立地为范围为1-10的整数。
26.权利要求24的抗体-药物偶联物化合物,其中Ww为缬氨酸-瓜氨酸。
27.权利要求24的抗体-药物偶联物化合物,其中R17为(CH2)5或(CH2)2。
28.权利要求24的抗体-药物偶联物化合物,其具有式:
29.权利要求28的抗体-药物偶联物化合物,其中R17为(CH2)5或(CH2)2。
30.权利要求24的抗体-药物偶联物化合物,其具有式:
31.权利要求22的抗体药物偶联物化合物,其中L为SMCC或BMPEO。
34.权利要求21的抗体-药物偶联物化合物,其中亲本抗TENB2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。
35.权利要求21的抗体-药物偶联物化合物,其中亲本抗TENB2抗体是抗体片段。
36.权利要求35的抗体-药物偶联物化合物,其中所述抗体片段是Fab片段。
37.权利要求21的抗体-药物偶联物化合物,其中auristatin为MMAE或MMAF。
38.权利要求21的抗体-药物偶联物化合物,其中L为MC-val-cit-PAB或MC。
39.权利要求21的抗体-药物偶联物化合物,其中L为SMCC、SPP、或BMPEO。
41.权利要求40的抗体药物偶联物,其中Ab包含SEQ ID NO:1。
42.权利要求40的抗体药物偶联物,其中Ab包含SEQ ID NO:2。
43.权利要求40的抗体药物偶联物,其中Ab包含SEQ ID NO:1和SEQ IDNO:2。
44.一种用于检测癌细胞的方法,包括:
(a)将细胞暴露于权利要求21的抗体-药物偶联物化合物;并
(b)测定所述抗体-药物偶联物化合物结合所述细胞的程度。
45.权利要求44的测定法,其中所述细胞是前列腺肿瘤细胞、胰腺肿瘤细胞、肺肿瘤细胞、乳腺肿瘤细胞、结肠肿瘤细胞或卵巢肿瘤细胞。
46.一种抑制细胞增殖的方法,包括用权利要求21的抗体-药物偶联物化合物处理细胞培养基中的哺乳动物肿瘤细胞,由此肿瘤细胞的增殖得到抑制。
47.权利要求46的方法,其中所述哺乳动物肿瘤细胞是卵巢肿瘤细胞。
48.一种药物配制剂,其包含权利要求21的抗体-药物偶联物及药学可接受的稀释剂、载体或赋形剂。
49.权利要求48的药物配制剂,其进一步包含治疗有效量的选自下组的化疗剂:来曲唑、奥沙利铂、多西他塞、5-FU、lapatinib、卡培他滨、亚叶酸、erlotinib、pertuzumab、贝伐单抗和吉西他滨。
50.一种治疗癌症的方法,包括给患者施用权利要求48的药物配制剂。
51.权利要求50的方法,其中所述癌症选自下组:前列腺癌、尿道癌、胰腺癌、肺癌、乳腺癌、结肠癌和卵巢癌。
52.权利要求50的方法,其中给所述患者施用与所述抗体-药物偶联物化合物组合的化疗剂,其中所述化疗剂选自下组:来曲唑、顺铂、卡铂、紫杉醇、帕利他塞、奥沙利铂、多西他塞、5-FU、亚叶酸、erlotinib、pertuzumab、贝伐单抗、lapatinib和吉西他滨。
53.一种制品,其包括
权利要求48的药物配制剂;
容器;和
包装插页或标签,其指明所述化合物可用于治疗以TENB2多肽过表达为特征的癌症。
54.权利要求53的制品,其中所述癌症是卵巢癌、前列腺癌、尿道癌、胰腺癌、肺癌、乳腺癌或结肠癌。
55.一种制备抗体药物偶联物化合物的方法,所述抗体药物偶联物化合物包含权利要求1的半胱氨酸改造的抗TENB2抗体(Ab)和auristatin药物模块(D),其中所述半胱氨酸改造的抗体是经由一个或多个改造的半胱氨酸氨基酸通过接头模块(L)附着至D的;所述化合物具有式I:
Ab-(L-D)p I
其中p为1、2、3、或4;所述方法包括以下步骤:
(a)使所述半胱氨酸改造的抗体的改造的半胱氨酸基团与接头试剂反应以形成抗体-接头中间体Ab-L;并
(b)使Ab-L与活化的药物模块D反应;由此所述抗体-药物偶联物得以形成;
或者包括以下步骤:
(c)使药物模块的亲核基团与接头试剂反应以形成药物-接头中间体D-L;并
(d)使D-L与所述半胱氨酸改造的抗体的改造的半胱氨酸基团反应;由此所述抗体-药物偶联物得以形成。
56.权利要求55的方法,其进一步包括在中国仓鼠卵巢(CHO)细胞中表达所述半胱氨酸改造的抗体的步骤。
57.权利要求56的方法,其进一步包括用还原剂处理所表达的半胱氨酸改造的抗体的步骤。
58.权利要求57的方法,其中所述还原剂选自TCEP和DTT。
59.权利要求57的方法,其进一步包括在用所述还原剂处理后用氧化剂处理所表达的半胱氨酸改造的抗体的步骤。
60.权利要求59的方法,其中所述氧化剂选自硫酸铜、脱氢抗坏血酸和空气。
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US11827703B2 (en) | 2018-05-09 | 2023-11-28 | Legochem Biosciences, Inc. | Compositions and methods related to anti-CD19 antibody drug conjugates |
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WO2023207710A1 (zh) * | 2022-04-29 | 2023-11-02 | 四川科伦博泰生物医药股份有限公司 | 一类抗体药物偶联物、其药物组合物及应用 |
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