CN101611059A - 针对胰岛素样生长因子i受体的抗体及其应用 - Google Patents
针对胰岛素样生长因子i受体的抗体及其应用 Download PDFInfo
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Abstract
一种结合IGF-IR并在Asn297上被糖链所糖基化的抗体在抗肿瘤治疗中具有提高的特性,所述抗体特征在于所述糖链内岩藻糖的量为20%-50%。
Description
本发明涉及针对人胰岛素样生长因子I受体(IGF-IR)的抗体,制备它们的方法,包含所述抗体的药物组合物及其应用。
胰岛素样生长因子I受体(IGF-IR,EC 2.7.112,CD 221抗原)属于跨膜蛋白酪氨酸激酶的家族(LeRoith,D.,等,内分泌综述(Endocrin.Rev.)16(1995)143-163;和Adams,T.E.,等,细胞分子生命科学(Cell.Mol.Life Sci.)57(2000)1050-1093)。IGF-IR高亲和力地结合IGF-I并且在体内激发对这种配体的生理响应。IGF-IR还结合IGF-II,但亲和性稍低。IGF-1系统,包括IGF-1R,在(正常和瘤)细胞增殖过程中起重要作用。IGF-1R存在例如来自胎盘、前列腺、膀胱、肾、十二指肠、小肠、胆囊、胆总管、肝内胆管、支气管、扁桃体、胸腺、乳房、皮脂腺、唾液腺、子宫颈、和输卵管的正常人组织上。IGF-IR的过量表达促进了细胞的致瘤性转化并且存在IGF-IR涉及细胞的恶性转化的证据,因此其是一个开发治疗癌症的治疗剂的有用靶标(Adams,T.E.,等,细胞分子生命科学(Cell.Mol.Life Sci.)57(2000)1050-1093)。
针对IGF-IR的抗体在现有技术中是众所周知的,并且在体外和体内对它们的抗肿瘤效果进行了研究(Benini,S.,等,临床癌症研究(Clin.CancerRes.)7(2001)1790-1797;Scotlandi,K.,等,癌症基因治疗(Cancer GeneTher.)9(2002)296-307;Scotlandi,K.,等,国际癌症杂志(Int.J.Cancer)101(2002)11-16;Brunetti,A.,等,生物化学生物物理研究通讯(Biochem.Biophys.Res.Commun.)165(1989)212-218;Prigent,S.A.,等,生物化学杂志(J.Biol.Chem.)265(1990)9970-9977;Li,S.L.,等,癌症免疫学和免疫疗法(Cancer Immunol.Immunother.)49(2000)243-252;Pessino,A.,等,生物化学生物物理研究通讯(Biochem.Biophys.Res.Commun.)162(1989)1236-1243;Surinya,K.H.,等,生物化学杂志(J.Biol.Chem.)277(2002)16718-16725;Soos,M.A.,等,生物化学杂志(J.Biol.Chem.),267(1992)12955-12963;Soos,M.A.,等,美国国家科学院院报(Proc.Natl.Acad.Sci.USA)86(1989)5217-5221;O′Brien,R.M.,等,EMBO J.6(1987)4003-4010;Taylor,R.,等,生物化学杂志(Biochem.J.)242(1987)123-129;Soos,M.A.,等,生物化学杂志(Biochem.J.)235(1986)199-208;Li,S.L.,等,生物化学生物物理研究通讯(Biochem.Biophys.Res.Commun.)196(1993)92-98;Delafontaine,P.,等,分子细胞学和心脏病学杂志(J.Mol.Cell.Cardiol.)26(1994)1659-1673;Kull,F.C.Jr.,等生物化学杂志(J.Biol.Chem.)258(1983)6561-6566;Morgan,D.O.,和Roth,R.A.,生物化学(Biochemistry)25(1986)1364-1371;Forsayeth,J.R.,等,美国国家科学院院报(Proc.Natl.Acad.Sci.USA)84(1987)3448-3451;Schaefer,E.M.,等,生物化学杂志(J.Biol.Chem.)265(1990)13248-13253;Gustafson,T.A.,和Rutter,W.J.,生物化学杂志(J.Biol.Chem.)265(1990)18663-18667;Hoyne,P.A.,等,FEBS Lett.469(2000)57-60;Tulloch,P.A.,等,结构生物学杂志(J.Struct.Biol.)125(1999)11-18;Rohlik,Q.T.,等,生物化学生物物理研究通讯(Biochem.Biophys.Res.Comm.)149(1987)276-281;和Kalebic,T.,等,癌症研究(Cancer Res.)54(1994)5531-5534;Adams,T.E.,等,细胞分子生命科学(Cell.Mol.Life Sci.)57(2000)1050-1093;Dricu,A.,等,糖生物学(Glycobiology)9(1999)571-579;Kanter-Lewensohn,L.,等,黑素瘤研究(Melanoma Res.)8(1998)389-397;Li,S.L.,等,癌症免疫学和免疫疗法(Cancer Immunol.Immunother.)49(2000)243-252)。针对IGF-IR的抗体还描述于许多其它出版物中,例如Arteaga,C.L.,等,乳腺癌研究和治疗(BreastCancer Res.Treatment)22(1992)101-106;和Hailey,J.,等,分子癌症治疗(Mol.Cancer Ther).1(2002)1349-1353。
具体地,将针对IGF-IR的称为αIR3的单克隆抗体广泛应用于研究IGF-IR介导的过程和IGF-I介导的疾病诸如癌症的研究中。α-IR-3在Kull,F.C.,生物化学杂志(J.Biol.Chem.)258(1983)6561-6566中有所描述。同时,已经公开了约百篇涉及αIR3的研究及其治疗应用的出版物,涉及αIR3单独和与细胞生长抑制剂诸如多柔比星和长春新碱一起的抗肿瘤效果。αIR3是一种鼠单克隆抗体,已知其抑制IGF-I与IGF受体的结合但是不抑制IGF-II与IGF-IR的结合。高浓度的αIR3刺激肿瘤细胞增殖和IGF-IR的磷酸化(Bergmann,U.,等,癌症研究(Cancer Res.)55(1995)2007-2011;Kato,H.,等,生物化学杂志(J.Biol.Chem.)268(1993)2655-2661)。存在其它抗体(例如,1H7,Li,S.L.,等,癌症免疫学和免疫疗法(Cancer Immunol.Immunother.)49(2000)243-252),与抑制IGF-I的结合比较,其更有效抑制IGF-II与IGF-IR的结合。抗体以及它们的特性和性状的现有技术的概要在Adams,T.E.,等.,细胞分子生命科学(Cell.Mol.Life Sci.)57(2000)1050-1093中有所描述。
描述在现有技术中的大多数抗体起源自小鼠。如在现有技术中众所周知的,在没有经过进一步的改变诸如嵌合化或人源化的情况下,这些抗体对于治疗人患者是没有作用的。基于这些缺陷,在治疗人患者中,明显优选将人抗体作为治疗剂。在现有技术中,人抗体是众所周知的(van Dijk,M.A.,和van de Winkel,J.G.,Curr.Opin.Chem.Biol.5(2001)368-374)。基于这项技术,可以制备针对许多种类靶目标的人抗体。针对IGF-IR的人抗体的实例在WO 2002/053596、WO 2004/071529、WO 2005/016967、WO 2006/008639、US 2005/0249730、US 2005/0084906、WO 2005/058967、WO 2006/013472、US 2003/0165502、WO 2005/082415、WO 2005/016970、WO 2003/106621、WO 2004/083248、WO 2003/100008、WO 2004/087756、WO 2005/005635和WO 2005/094376中有所描述。
WO 2004/087756描述与IGF-1R结合并抑制IGF-I和IGF-II与IGF-1R结合的抗体的特征在于,是人IgG1同种型,并显示出对IGF-I与IGF-IR结合的抑制和对IGFII与IGF-IR结合的抑制的比为1∶3-3∶1,且在100nM的所述抗体浓度下24小时后,由ADCC诱导表达IGF-IR细胞制剂的20%或更多细胞的细胞死亡。
单克隆抗体的细胞-介导效应子功能可以通过改造它们的寡糖成分得到增强,如P.,等,自然生物技术(Nature Biotechnol.)17(1999)176-180;和美国专利号6,602,684所述。IgG1型抗体,即癌症免疫疗法中最常用的抗体,是在每个CH2结构域中的Asn297处具有保守N-连接的糖基化位点的糖蛋白。附着于Asn297的两个复合二触角寡糖隐藏在CH2结构域之间,与多肽主链形成大范围的接触,且它们的存在对于抗体介导效应子功能,诸如抗体依赖性细胞毒性(ADCC)是必需的(Lifely,M.R.,等,糖生物学(Glycobiology)5(1995)813-822;Jefferis,R.,等,免疫学进展(Immunol.Rev.)163(1998)59-76;Wright,A.和Morrison,S.L.,生物技术趋势(TrendsBiotechnol.)15(1997)26-32)。P.,等.自然生物技术(NatureBiotechnol.)17(1999)176-180和WO 99/54342显示,在中国仓鼠卵巢(CHO)细胞中过表达β(1,4)-N-乙酰葡糖胺转移酶III(″GnTIII″),即催化二等分寡糖形成的糖基转移酶,显著增高抗体的体外ADCC活性。N297碳水化合物组成的变化或它的消除还影响对与FcγR和C1q结合的Fc的结合(P.,等,自然生物技术(Nature Biotechnol.)17(1999)176-180;Davies等,生物技术和生物工程(Biotechnol.Bioeng.)74(2001)288-294;Mimura,Y.,等,生物化学杂志(J.Biol.Chem.)276(2001)45539-45547;Radaev等,生物化学杂志(J.Biol.Chem.)276(2001)16478-16483;Shields,R.L.,等,生物化学杂志(J.Biol.Chem.)276(2001)6591-6604;Shields,R.L.,等,生物化学杂志(J.Biol.Chem.)277(2002)26733-26740;Simmons,L.C.,等,免疫学方法杂志(J.Immunol.Methods)263(2002)133-147)。
Iida,S.,等,临床癌症研究(Clin.Cancer Res.)12(2006)2879-2887显示非岩藻糖基化的抗-CD20抗体的功效受到添加岩藻糖基化的抗-CD20的抑制。非岩藻糖基化和岩藻糖基化的抗-CD20的1∶9混合物(10微克/mL)的功效不如单独的非岩藻糖基化抗-CD20的1000倍稀释物(0.01微克/mL)的功效。他们总结出,非岩藻糖基化的IgG1,不包括岩藻糖基化的对应物,能够通过它的高FcγRIIIa结合,而避免血浆IgG对ADCC的抑制作用。Natsume,A.,等,在免疫学方法杂志(J.Immunol.Methods)306(2005)93-103中显示,从人IgG1-型抗体的复合-型寡糖中去除岩藻糖导致抗体依赖性细胞毒性(ADCC)的巨大增强。Satoh,M.,等,生物学疗法的试验观点(Expert Opin.Biol.Ther.)6(2006)1161-1173讨论了作为下一代治疗抗体的非岩藻糖基化的治疗抗体。Satoh总结,认为仅由非-岩藻糖基化的人IgG1型组成的抗体是理想的。Kanda,Y.,等,生物技术和生物工程(Biotechnol.Bioeng.)94(2004)680-688比较了岩藻糖基化的CD20抗体(96%岩藻糖基化,CHO/DG441H5)和非-岩藻糖基化的CD20抗体。Davies,J.,等,生物技术和生物工程(Biotechnol.Bioeng.)74(2001)288-294报告对于CD20抗体,增高的ADCC与增高的与FcγRIII的结合相关。
增强单克隆抗体的细胞-介导的效应子功能的方法在WO 2005/018572、WO 2006/116260、WO 2006/114700、WO 2004/065540、WO 2005/011735、WO 2005/027966、WO 1997/028267、US 2006/0134709、US 2005/0054048、US 2005/0152894、WO 2003/035835、WO 2000/061739中有所描述。
对于需要抗肿瘤治疗的患者而言,仍然需要具有令人信服的益处的针对IGF-IR的抗体。简而言之,与患者有关的益处是通过用抗肿瘤发生的药剂治疗使肿瘤生长减少,并使其进展时间明显延长。
发明概述
本发明包括一种抗体,其结合IGF-IR,并且在Asn297上被糖链所糖基化,所述抗体特征在于所述糖链内岩藻糖的量为20%-50%,优选地,20%-40%。
按照本发明包括所述量的岩藻糖的抗体也称为部分岩藻糖基化的。
本发明包括一种抗体,其结合IGF-IR,并且在Asn297上被糖链所糖基化,所述抗体特征在于对FcγRIII显示出高结合亲和性。
优选地,所述抗体是人IgG1、IgG2、IgG3或IgG4型。特别优选地,所述抗体是人IgG1或IgG3型。
优选地,NGNA的量为1%或更少和/或N末端α-1,3-半乳糖的量为1%或更少。
优选地,NGNA的量为0.5%或更少,更优选地,0.1%或更少和甚至不能被检测(LCMS)。
优选地,N末端α-1,3-半乳糖的量为0.5%或更少更优选地,0.1%或更少和甚至不能被检测(LCMS)。
按照本发明,“岩藻糖的量”意指Asn297上糖链内所述糖的量,涉及通过MALDI-TOF质谱法测量和作为平均值计算的附着于Asn297的所有糖结构的总和(例如,复合、杂合和高甘露糖结构)(见实施例4)。
糖链优选地显示出如下特征:N-连接的聚糖附于抗体的Asn297上,所述抗体结合重组表达在CHO细胞中的IGF-IR。
优选地本发明包括部分岩藻糖基化抗体,其结合IGF-IR并抑制IGF-I和IGF-II与IGF-IR的结合,特征是所述抗体显示一种或多种选自由下列组成的组的特征:
a)显示其对IGF-I与IGF-IR结合的抑制的IC50值与其对IGF-II与IGF-IR结合的抑制的IC50值的比率为1∶3-3∶1,
b)当与没有所述抗体的这种测定比较时,其在5nM的浓度上,在使用HT 29细胞的细胞磷酸化测定中,抑制至少80%,优选地至少90%的IGF-IR磷酸化,所述HT 29细胞在包含0.5%的热灭活胎牛血清(FCS)和10nM人IGF-1的培养基中,
c)当与没有所述抗体的这种测定比较时,在使用3T3细胞的细胞磷酸化测定中,其在10μM的浓度上没有显示如PKB磷酸化所测量的IGF-IR的刺激活性(无信号传导,无IGF-1模拟活性),所述3T3细胞在包含0.5%的热灭活胎牛血清(FCS)的培养基中提供400,000-600,000分子IGF-IR/细胞。
按照本发明的抗体显示了对于需要抗肿瘤治疗的患者的益处并且使肿瘤生长减少以及明显延长进展时间。按照本发明的抗体具有新颖性和创造性的特性,其给患有与IGF失调有关的疾病,特别是肿瘤疾病的患者带来了益处。按照本发明的抗体,其特征在于上述特性。
优选地所述抗体特异性结合IGF-IR,以上述比率抑制IGF-I和IGF-II与IGF-IR的结合,是IgG1同种型和部分岩藻糖基化的,以及甚至在其IC50值的200倍浓度或甚至20,000倍浓度的IGF-IR过量表达细胞中没有激活IGF-IR信号传导。
优选地,在5nM的浓度上,按照本发明的抗体完全抑制肿瘤细胞中由IGF-I介导的IGF-IR的信号转导。
优选地,所述抗体是单克隆抗体,并且除此之外,是嵌合抗体(人的恒定链),人源化的抗体并且特别优选地是人抗体。
优选地,所述抗体与抗体18竞争结合人IGF-IR (EC 2.7.1.112,SwissProt P08069)。
优选地,所述抗体的特征还在于亲和性是10-8M(KD)或更少,优选地是约10-9-10-13M。
优选地,所述抗体不显示可检测到的浓度依赖性的对胰岛素与胰岛素受体结合的抑制。
优选地,所述抗体是IgG1型。
和载体处理的动物比较,在相关异种移植肿瘤模型中,按照本发明的抗体相当长地延长了进展时间并且减少了肿瘤的生长。所述抗体优选地以对IGF-I和IGF-II大约等同的方式,在体外和体内抑制了IGF-I和IGF-II与IGF-IR的结合。
优选地,按照本发明的抗体包括重链互补决定区CDR3,即选自由SEQID NO:1或3组成的组的序列。
优选地,按照本发明的抗体包括下列序列作为互补决定区(CDRs):
a)包括作为CDRs的SEQ ID NO:1或3的CDR1(氨基酸31-35),
CDR2(氨基酸50-66)和CDR3(氨基酸99-107)的抗体重链;
b)包括作为CDRs的SEQ ID NO:2或4的CDR1(氨基酸24-34),
CDR2(氨基酸50-56)和CDR3(氨基酸89-98)的抗体轻链。
按照本发明的抗体的重链的优选可变区和CDRs,特别是CDR3由<IGF-1R>HUMAB克隆18(抗体18)和<IGF-1R>HUMAB克隆22(抗体22)提供,保藏在德意志微生物保藏中心(Deutsche Sammlung vonMikroorganismen und Zellkulturen GmbH(DSMZ)),德国。
细胞系 | 保藏号 | 保藏日期 |
<IGF-1R>HUMAB克隆18 | DSM ACC 2587 | 10.04.2003 |
<IGF-1R>HUMAB克隆22 | DSM ACC 2594 | 09.05.2003 |
优选地,按照本发明的抗体包括包含SEQ ID NO:1的抗体重链和包含SEQ ID NO:2的抗体轻链或包含SEQ ID NO:3的抗体重链和包含SEQ ID NO:4的抗体轻链。优选地,所述抗体是人IgG1型。
这些抗体在WO 2005/005635中详细描述。
本发明还提供重组生产这些抗体的方法。
下面定义多肽的优选核酸,所述多肽能够与各个其它的抗体链一起组配成按照本发明的抗体:
a)包括作为CDRs的SEQ ID NO:1或3的CDR1(氨基酸31-35),CDR2(氨基酸50-66)和CDR3(氨基酸99-107)的抗体重链;
b)包括作为CDRs的SEQ ID NO:2或4的CDR1(氨基酸24-34),CDR2(氨基酸50-56)和CDR3(氨基酸89-98)的抗体轻链。
优选地,所述核酸编码按照本发明的抗体,所述抗体包括包含SEQ ID NO:1的抗体重链和SEQ ID NO:2的抗体轻链或包含SEQ ID NO:3的抗体重链和SEQ ID NO:4的抗体轻链。
本发明还提供治疗癌症,优选地,乳腺癌、胰腺癌、前列腺癌、膀胱癌、恶性黑素瘤、尤因肉瘤(Ewing’s sarcoma)、成神经细胞瘤、骨肉瘤、横纹肌肉瘤、和/或NSCLC的方法,所述方法包括向被诊断患有癌症(因此需要抗肿瘤治疗)的患者施用按照本发明的针对IGF-IR的抗体。所述抗体可以以药物组合物的形式单独施用,或备选地与癌症相关信号传导通路的其他抑制剂,诸如EGFR、Her2/neu或雌激素受体结合,或与细胞毒性的治疗诸如放射疗法或细胞毒性试剂或其前药结合进行施用。以药物有效量施用所述抗体。
本发明还包括按照本发明的抗体用于癌症治疗,优选地乳腺癌、胰腺癌和/或NSCLC,以及制备按照本发明的药物组合物的用途。此外,本发明包括制备按照本发明的药物组合物的方法。
本发明还包括按照本发明的抗体,其用于癌症治疗,优选地乳腺癌、胰腺癌、前列腺癌、膀胱癌、恶性黑素瘤、尤因肉瘤、成神经细胞瘤、骨肉瘤、横纹肌肉瘤和/或NSCLC。
本发明还包括药物组合物,其包含按照本发明的抗体,以及任选地,对于药用的抗体的制剂是有用的缓冲剂和/或佐剂。
本发明还包括药物组合物,其包括按照本发明的抗体。
本发明还提供药物组合物,其在药用载体中包含这种抗体。在一个实施方案中,可以将药物组合物包含在制品中或试剂盒中。本发明还提供按照本发明的抗体用于制备治疗癌症的药物组合物的用途。以药物有效量使用所述抗体。
本发明还包括按照本发明的抗体用于制备治疗癌症,优选地乳腺癌、胰腺癌和/或NSCLC的药物组合物的用途。以药物有效量使用所述抗体。
本发明还包括制备按照本发明的重组人抗体的方法,其特征在于在CHO宿主细胞中表达编码结合IGF-1R的抗体的核酸,以及从所述细胞中回收所述抗体,所述宿主细胞将所述抗体部分岩藻糖基化。本发明还包括可通过这种重组方法获得的抗体
本发明还包括能够重组表达GnTIII和抗-IGF-1R抗体的CHO细胞。所述CHO细胞是用编码具有GnTIII活性的多肽的第一DNA序列、至少编码针对IGF-IR的抗体重链可变结构域的第二DNA序列、和至少编码针对IGF-IR的抗体轻链可变结构域的第三DNA序列转化的CHO细胞。优选地,所述第二和第三DNA序列编码针对人IgG1型IGF-IR的抗体的重链和轻链。
本发明还包括用于生产针对IGF-1R的抗体的方法,包括下列步骤:用编码具有GnTIII活性的多肽的第一DNA序列、至少编码针对IGF-IR的抗体重链可变结构域的第二DNA序列、和至少编码针对IGF-IR的抗体轻链可变结构域的第三DNA序列转化宿主细胞,优选地,CHO细胞,在发酵培养基中培养所述宿主细胞,所述宿主细胞在这样的条件下表达,优选地,独立地表达所述第一、第二和第三DNA序列,所述条件是所述宿主细胞分泌所述抗体到发酵培养基中,并分离所述抗体。
发明详述
术语“抗体”涵盖各种形式的抗体,其包括但不限于只要保留了按照本发明的性状特性的整个抗体、抗体片段、人抗体、人源化抗体以及遗传工程化的抗体。
“抗体片段”包括全长抗体的部分,通常至少是抗原结合部分或其可变区。抗体片段的实例包括双抗体、单链抗体分子、免疫毒素和由抗体片段形成的多特异性抗体。
用于本文时,术语“单克隆抗体”或“单克隆抗体组合物”指专一氨基酸组成(single amino acid composition)的抗体分子的制剂。因此,术语“人单克隆抗体”指显示单一结合特异性的抗体,其具有衍生自人胚系免疫球蛋白序列的可变区和恒定区。
术语“嵌合抗体”指一种单克隆抗体,其包括来自一种来源或物种的可变区域,即结合区域以及来源自不同来源或物种的恒定区域的至少一部分,通常通过重组DNA技术进行制备。特别优选包括鼠可变区和人恒定区的嵌合抗体。这种鼠/人嵌合抗体是表达免疫球蛋白基因的产物,所述免疫球蛋白基因包括编码鼠免疫球蛋白可变区的DNA区段和编码人免疫球蛋白恒定区的DNA区段。本发明涵盖的“嵌合抗体”的其它形式是其中类或亚类已经经过从初级抗体的修饰或改变的那些。也将这种“嵌合”抗体称作“类别转换抗体”。制备嵌合抗体的方法包括目前在本领域众所周知的常规重组DNA和基因转染技术。见,例如,Morrison,S.L.,等,美国国家科学院院报(Proc.Natl.Acad Sci.USA)81(1984)6851-6855;美国专利号5,202,238和5,204,244。
术语“人源化抗体”指其中的框架或“互补决定区”(CDR)已经被修饰从而包括与亲本免疫球蛋白的特异性不同的免疫球蛋白的CDR的抗体。在一个优选实施方案中,将鼠CDR移植到人抗体的框架区域以制备所述“人源化抗体”。见,例如,Riechmann,L.,等,自然(Nature)332(1988)323-327;和Neuberger,M.S.,等,自然(Nature)314(1985)268-270。特别优选的CDRs对应于识别上述特别指出的嵌合和双功能抗体的抗原的那些代表性序列。
用于本文时,术语“人抗体”意欲包括具有来自人种系免疫球蛋白序列的可变区和恒定区的抗体。可变的重链优选地来自种系序列DP-50(GenBank LO6618)并且可变轻链优选地来自种系序列L6(GenBankX01688)或可变重链优选地衍生自DP61(GenBank M99682),并且可变轻链来自种系序列L15(GenBank K01323)。抗体的恒定区是人IgG1型的恒定区。这些区域可以是异型的并且在例如Johnson,G.,和Wu,T.T.,核酸研究(Nucleic Acids Res.)28(2000)214-218以及其参考的数据库中有所描述。
术语“重组人抗体”指以重排方式具有来自人种系免疫球蛋白序列的可变区和恒定区的抗体。按照本发明的重组人抗体已经经过体内体细胞高变。因此,重组抗体的VH和VL区域的氨基酸序列是尽管来自和涉及人种系VH和VL序列,但可能在体内非天然存在于人抗体种系所有组成成分中的序列。
用于本文时,“结合”指抗体以约10-13-10-8M(KD),优选地约10-13-10-9M的亲和性结合于IGF-IR。
用于本文时“核酸分子”意欲包括DNA分子和RNA分子。核酸分子可以是单链或双链的,但是优选地是双链DNA。
IgG1或IgG3型的人恒定结构域详细描述于Kabat E.A.等,免疫目的蛋白质序列(Sequences of Proteins of Immunological Interest),第5版.公众健康服务(Public Health Service),国立健康研究所(National Institutes ofHealth),Bethesda,MD.(1991)和Brüeggemann,M.,等,试验医学杂志(J.Exp.Med.)166(1987)1351-1361;Love,T.W.,等,酶学方法(MethodsEnzymol.)178(1989)515-527。实例显示于SEQ ID NOS:5-8。其它有用且优选的恒定结构域是可以从用于本发明以DSMZ保藏的杂交瘤细胞系中获得的抗体的恒定结构域。
人IgG1、IgG2或IgG3型的恒定结构域在Asn297上被糖基化。按照本发明的“Asn297”意指位于Fc区中大约位置297上的氨基酸天冬酰胺;基于抗体的较小序列变化,Asn297还可以位于上游或下游一些氨基酸上(通常不超过±3个氨基酸)。例如,在一种按照本发明的抗体(AK18)中,“Asn297”位于氨基酸位置298上。
用于本文时,“可变区”(轻链的可变区(VL),重链的可变区(VH))表示直接涉及抗体与抗原结合的每个轻链和重链对。可变人轻链和重链的结构域具有相同的一般结构并且每个结构域包括4个框架区域(FR),其序列是广泛保守的,并通过三个“高变区”(或互补决定区,CDRs)连接。所述框架区域采取β折叠构象并且所述CDRs可以形成连接β折叠结构的环。通过框架区域,每条链的CDRs保持在它们的三维结构中并且与来自其它链的CDRs一起形成抗原结合部位。抗体的重链和轻链CDR3区域在按照本发明的抗体的结合特异性/亲和性中具有特别重要的作用,并且因此提供本发明的另外的目的。
用于本文时,术语“高变区”或“抗体的抗原结合部分”指负责抗原结合的抗体的氨基酸残基。高变区包括来自“互补决定区”或“CDR”的氨基酸残基。“框架”或“FR”区域是除本文详细说明的高变区残基之外的那些可变结构域区域。因此,抗体的轻链和重链包括从N端到C端的结构域FR1,CDR1、FR2、CDR2、FR3、CDR3和FR4。特别地,重链的CDR3是最有助于抗原结合和表征抗体的区域。按照Kabat E.A.等的标准定义来确定CDR和FR区域,见上。
人IgG1或IgG3的糖基化作用发生在Asn297上,因为核心岩藻糖基化双触角复合物寡糖糖基化作用以多达2个Gal(半乳糖)残基终止。根据末端Gal残基的量,这些结构被命名为G0,G1(α1,6或α1,3)或G2聚糖残基(Raju,T.S.,BioProcess Int.1(2003)44-53)。抗体Fc部分的CHO型糖基化作用被例如Routier,F.H.,糖缀合物杂志(Glycoconjugate J.)14(1997)201-207所描述。在非糖修饰的CHO宿主细胞中重组表达的抗体至少85%通常在Asn297发生岩藻糖基化。
按照本发明部分岩藻糖基化的IGF-1R抗体可以在糖修饰的宿主细胞中表达,所述宿主细胞被改造为以足以部分岩藻糖基化Fc区域中寡糖的量,表达至少一种编码具有GnTIII活性的多肽的核酸。在一个实施方案中,具有GnTIII活性的多肽是融合多肽。备选地,按照US 6,946,292,可以降低或消除宿主细胞的α1,6-岩藻糖基转移酶活性,从而产生糖修饰的宿主细胞。可以例如通过发酵条件(例如发酵时间)或通过结合至少两种具有不同岩藻糖基化量的抗体预先确定抗体岩藻糖基化的量。
可以在宿主细胞中,通过包括下列步骤的方法生产按照本发明的IGF-1R抗体:(a)在这样的条件下培养被改造为表达至少一种编码具有GnTIII活性的融合多肽的多核苷酸的宿主细胞,所述条件容许生成具有在所述抗体的Fc区域上存在的寡糖的部分岩藻糖基化的抗体;和(b)分离所述抗体。在一个实施方案中,具有GnTIII活性的多肽是融合多肽,优选地,包括GnTIII的催化结构域和异源高尔基体残基多肽的高尔基体定位结构域,所述异源高尔基体残基多肽的高尔基体定位结构域选自由甘露糖苷酶II的定位结构域、β(1,2)-N-乙酰葡糖胺转移酶I(″GnTI″)的定位结构域、甘露糖苷酶I的定位结构域、β(1,2)-N-乙酰葡糖胺转移酶II(″GnTII″)的定位结构域、或α1-6核心岩藻糖基转移酶的定位结构域。优选地,高尔基体所定位结构域来自甘露糖苷酶II或GnTI。在另一方面,本发明涉及利用所述方法修饰抗-IGF-1R抗体的糖基化特征的方法。
另一方面,本发明涉及通过利用具有GnTIII活性并包括异源高尔基体残基多肽的高尔基体定位结构域的融合多肽修饰IGF-1R抗体的糖基化的方法。在一个实施方案中,本发明的融合多肽包括GnTIII的催化结构域。在另一个实施方案中,高尔基体定位结构域选自由下列各项组成的组:甘露糖苷酶II的定位结构域、GnTI的定位结构域、甘露糖苷酶I的定位结构域、GnTII的定位结构域和α1-6核心岩藻糖基转移酶的定位结构域。优选地,高尔基体定位结构域来自甘露糖苷酶II和GnTI。
按照本发明,IGF-1R抗体的这些修饰的寡糖是杂合的或复合的。优选地,所述二等分、非岩藻糖基化的寡糖是杂合的。在另一个实施方案中,所述二等分、非岩藻糖基化的寡糖是复合的。
用于本文中时,具有GnTIII活性的多肽指能够催化β-1-4键合中N-乙酰葡糖胺(G1cNAc)残基加入到N-连接的三甘露糖基核心的β-连接甘露糖苷中。如以具有或不具有剂量依赖性的具体生物学测定所测量地,这包括融合多肽,其表现出与按照国际生物化学和分子生物学协会命名委员会(Nomenclature Committee of the International Union of B iochemistry andMolecular Biology)(NC-IUBMB)也称为β-1,4-甘露糖基-糖蛋白4-β-N-乙酰葡糖胺转移酶(EC 2.4.1.144)的β(1,4)-N-乙酰葡糖胺转移酶III的活性类似,但不必须相同的酶活性。在剂量依赖性确实存在的情形中,其不需要与GnTIII相同,而只需在与GnTIII比较时,基本类似于给定活性中的剂量依赖性(即候选多肽应该表现出与GnTIII相比更高的活性或少于不超过约25倍和,优选地,少于不超过约10倍的活性,和最优选地,少于不超过约3倍的活性)。用于本文中时,术语高尔基体定位结构域指负责锚定位于高尔基体复合物中多肽的高尔基体残基多肽的氨基酸序列。通常,定位结构域包括酶的氨基末端“尾部”。
按照本发明的抗体对FcyRIII(CD16a)显示出高结合亲和性。对FcγRIII的高结合亲和性表示与CHO DG44宿主细胞中表达的wt抗体(95%岩藻糖基化)作为标准相比较(见实施例5),CD16a/F158的结合增强至少10倍,且与通过利用处于100nM抗体浓度的固定的CD16a进行表面等离子共振(SPR)测量的wt抗体相比较(见实施例5),CD16a/V158的结合增强至少20倍。可以通过按照现有技术的方法,通过修饰抗体Fc部分的氨基酸序列或Fc部分的糖基化,增强FcγRIII结合。以上描述了优选的方法。
用于本文时,术语“与IGF-IR结合”意味着在体外试验中,优选地在结合试验中进行抗体与IGF-IR的结合,在所述试验中,所述抗体与表面结合并且通过表面等离子共振(Surface Plasmon Resonance)(SPR)来测量与IGF-IR的结合。结合意味着10-8M或更少,优选地10-13-10-9M的结合亲和性(KD)。
通过BIAcore分析(Pharmacia Biosensor AB,Uppsala,Sweden)可以研究抗体与IGF-IR或FcγRIII的结合。通过术语ka(靶抗体的关联的速率常数)、kd(解离常数)以及KD(kd/ka)来定义结合的亲和性。按照本发明的抗体对结合IGF-1R显示出10-9M或更少的KD,优选地10-10M或更少的KD。
IGF-I和IGF-II与IGF-IR的结合还受到按照本发明的抗体的抑制。在进行肿瘤细胞上IGF-I/IGF-II与IGF-IR的结合的试验中,测量抑制,表示为IC50。在这种试验中,在不增加和增加抗体的浓度情况下,测量与所述肿瘤细胞(例如HT29)表面提供的IGF-IR结合的放射性标记的IGF-I或IGF-II或IGF-IR结合片段的量。对于IGF-I和IGF-II与IGF-IR的结合而言,按照本发明的抗体的IC50值不超过2nM,并且IGF-I/IGF-II与IGF-IR的结合的IC50值的比率是约1∶3-3∶1。测量的IC50值是至少三次独立测量的平均值或中位值。单个IC50可不在这个范围内。
用于本文时,术语“抑制IGF-I和IGF-II与IGF-IR的结合”指在体外试验中,抑制I125标记的IGF-I或IGF-II与存在于HT29(ATCC HTB-38)肿瘤细胞表面的IGF-IR的结合。抑制意味着IC50值为2nM或更低。
术语“IGF-IR表达细胞”指过量表达IGF-I受体到约至少20,000受体/细胞的这种细胞。这些细胞是,例如,肿瘤细胞系诸如NCI H322M或HT29,或在用IGF-IR的表达载体转染后,过量表达IGF-IR的细胞系(例如3T3ATCC CRL1658)。按照Lammers,R.,等EMBO J.8(1989)1369-1375来测量每个细胞的受体的量。
术语“抑制IGF-IR磷酸化”指一种细胞磷酸化测定,其在包含0.5%热灭活胎牛血清(FCS)和10nM人IGF-1的培养基中使用提供400,000-600,000分子IGF-IR/细胞,优选地1.0-1.5Mio分子IGF-IR/细胞的3T3细胞,届时与没有所述抗体的这种测定比较。使用特异于酪氨酸磷酸化的蛋白质的抗体通过蛋白质印迹法来检测磷酸化。通过短期加热到56℃进行FCS的热灭活从而钝化补体系统。
术语“抑制PKB磷酸化”指一种细胞磷酸化测定,其在包含0.5%热灭活胎牛血清(FCS)和10nM人IGF-1的培养基中使用提供400,000-600,000分子IGF-IR/细胞,优选地1.0-1.5Mio分子IGF-IR/细胞的3T3细胞,届时与没有所述抗体的这种测定比较。使用特异于在PKB的丝氨酸473被磷酸化的PKB的抗体(Akt 1,Swiss Prot Acc.No.P31749)通过蛋白质印迹法来检测磷酸化。
术语“抗体-依赖型细胞的细胞毒性(ADCC)”指在存在效应细胞的情况下,通过按照本发明的抗体裂解人肿瘤靶细胞。在存在效应细胞诸如新鲜分离的PBMC或来自暗黄覆盖层(buffy coats)的纯化效应细胞,象单核细胞或NK细胞的情况下,优选地通过用按照本发明的抗体处理表达IGF-IR的细胞制剂进行ADCC的测量。
术语“IGF-I介导的信号转导的完全抑制”指IGF-I介导的对IGF-IR的磷酸化的抑制。对于这种分析,用IGF-I对IGF-IR表达细胞,优选地H322M细胞进行刺激,并用按照本发明的抗体进行处理(5nM的抗体浓度或更高是有效的)。随后,进行SDS PAGE,并且通过以特异于磷酸化的酪氨酸的抗体进行的蛋白质印迹法分析来测量IGF-IR磷酸化。如果在蛋白质印迹中,明显不能观察到指示磷酸化的IGF-IR的条带,则发现信号转导的完全抑制。
优选地按照本发明的抗体显示结合于与抗体18相同的IGF-IR的表位,或者由于抗体18的结合的空间位阻,在与IGF-IR结合中被抑制。使用20-50nM浓度的固定化的抗体18和IGF-IR以及在100nM浓度上待检测的抗体通过SPR分析可以检测结合抑制。50%或更多的信号减少显示所述抗体与抗体18竞争。通过将抗体22用作固定化抗体,以相同的方式可以进行这种分析。
术语“表位”表示能够特异性地与抗体结合的蛋白质决定簇。表位通常由分子的化学活性表面基团诸如氨基酸或糖侧链组成,并且通常具有特异性三维结构特性,以及特异性电荷特性。构象和非构象表位的区别在于在变性溶剂存在下,对前者的结合而不是后者的结合丢失。
按照本发明的抗体抑制IGF-IR酪氨酸磷酸化并优选地也抑制PKB丝氨酸磷酸化到相似的程度。
按照本发明的抗体优选地在肿瘤细胞,和肿瘤例如异种移植的肿瘤中下调IGF-IR蛋白质水平。
按照本发明的抗体优选地在集落形成试验中抑制肿瘤细胞的三维生长以及抑制IGF-IR表达细胞(例如NIH 3T3细胞)的增殖。
使用200nmol/l浓度的所述抗体,在胰岛素受体过量表达的3T3细胞的结合竞争分析中,优选地按照本发明的抗体不抑制胰岛素与胰岛素受体的结合。
用于本文中时,术语宿主细胞包括能够被改造生成本发明的多肽和抗原-结合分子的任何类型的细胞系统。在一个实施方案中,宿主细胞能够且被改造为容许生成具有修饰的糖形的抗原结合分子。进一步处理宿主细胞,使其表达增高水平的一种或多种具有GnTIII活性的多肽。CHO细胞作为宿主细胞是优选的。
为了宿主细胞中的蛋白质表达,通过标准方法将编码轻链和重链或其片段的核酸插入表达载体。表达在所述宿主细胞中进行,并从细胞(细胞溶解后的上清液或细胞)中回收抗体。
重组制备抗体的一般方法在现有技术中众所周知,并且,描述于例如,Makrides,S.C.,蛋白质实验纯化(Protein Expr.Purif.)17(1999)183-202;Geisse,S.,等,蛋白质实验纯化(Protein Expr.Purif.)8(1996)271-282;Kaufman,R.J.,分子生物技术(Mol.Biotechnol.)16(2000)151-161;Werner,R.G.,Arzneimittelforschung药物研究(Drug Res.)48(1998)870-880的综述文献中。
所述抗体可以存在于整个细胞中,在细胞溶解产物中,或以部分纯化或基本纯化形式存在。通过标准技术,包括碱/SDS处理、CsCl显带法、柱层析、琼脂糖凝胶电泳,以及其它本领域众所周知的技术来进行纯化以去除其它细胞成分或其它污染物,例如其它细胞的核酸或蛋白质。见,Ausubel,F.,等,(编辑)现代分子生物学操作方法(Current Protocols inMolecular Biology),Greene Publishing and Wiley Interscience,纽约(1987)。
例如,适合于原核生物的调控序列,包括启动子、任选地操纵序列,和核糖体结合位点。已知真核细胞利用启动子、增强子和多腺苷酸化信号。
当核酸被置于与另外的核酸序列的功能性关联中时,核酸被“可操作地连接”。例如,如果前序列或分泌前导区的DNA被表达为参与多肽分泌的前蛋白,所述DNA可操作地与多肽的DNA连接;如果启动子或增强子影响序列的转录,其可操作地与编码序列连接;或如果将核糖体结合部位定位以促进翻译,其可操作地与编码序列连接。通常,“可操作地连接”意味着被连接的DNA序列是连续的,并且在分泌前导区的情况中,是连续的,并且在阅读框中。但是,增强子不一定是连续的。通过在适宜限制性位点的连接反应来完成连接。如果这些位点不存在,依照常规惯例,使用合成的寡核苷酸连接物或接头。
通过常规免疫球蛋白纯化方法诸如,例如蛋白质A-Sepharose、羟基磷灰石层析、凝胶电泳、透析,或亲和层析来适当地从培养基中分离单克隆抗体。使用常规方法,容易分离并测序编码所述单克隆抗体的DNA和RNA。杂交瘤细胞可以作为这种DNA和RNA的来源。
本发明还涉及免疫缀合物,其包括与细胞毒性试剂诸如化疗剂、毒素(例如,细菌、真菌、植物或动物来源的酶促活性毒素,或其片段)、放射性活性同位素(即放射性缀合物)或细胞毒性试剂的前体药物缀合的按照本发明的抗体。上面已描述了有效用在产生这些免疫缀合物中的试剂。可以使用的酶促活性毒素及其片段包括白喉A链、白喉毒素的非结合活性片段、外毒素A链(来自Pseudomonas aeruginosa)、蓖麻毒蛋白A链、相思豆毒蛋白A链、塑莲根毒蛋白II A链、α-帚曲霉素、Aleuritesfordii蛋白质、香石竹毒蛋白质、Phytolaca americana蛋白质(PAPI,PAPII,和PAP-S)、momordica charantia抑制剂、麻风树毒蛋白、巴豆毒蛋白、sapaonariaofficinalis抑制剂、多花白树毒蛋白、mitogellin、局限曲菌素、酚霉素、伊诺霉素和tricothecenes。
使用许多双官能的蛋白质偶联剂诸如N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丙酸酯(SPDP)、iminothiolane(IT)、亚氨酸酯的双官能衍生物;(诸如二甲基adipimidate HCL)、活性酯(诸如二琥珀酰亚胺基辛二酸酯)、醛(诸如戊二醛)、双-叠氮基化合物(诸如双(对-叠氮基苯甲酰基)己二胺)、双-重氮化衍生物(诸如双-(对-二重氮化苯甲酰基)-ethylenediatnine)、二异氰酸酯(诸如tolyene 2,6-二异氰酸酯)和双活性的氟化合物(诸如1,5-二氟-2,4-二硝基苯)制备抗体和细胞毒性试剂的缀合物。例如,可以如在Vitetta,E.S.,等,Science(科学)238(1987)1098-1104)中所描述的制备蓖麻毒蛋白免疫毒素。碳14标记的1-异硫氰酸苄基-3-甲基二亚乙基三胺五乙酸(MX-DTPA)是放射性核苷酸与抗体结合的示范性螯合剂。见WO 94/11026。
在另一个方面,本发明提供一种组合物,例如,药物组合物,其包含与药用载体一起配制的本发明的抗体。
还可以在组合疗法中,即与其它试剂,像化疗剂,细胞毒性剂或前体药物组合来施用本发明药物组合物。例如,组合疗法可以包括本发明的组合物与至少一种抗肿瘤试剂或其它常规疗法。
“化疗剂”是在癌症治疗中有用的化合物。化疗剂的实例包括阿霉素、多柔比星、5-氟尿嘧啶、阿糖胞苷(″Ara-C″)、环磷酰胺、塞替派、泰索帝(多西他赛)、白消胺、吉西他滨、Cytoxin、泰素、甲氨蝶呤,顺铂、美法仑、长春碱,博来霉素、依托泊苷、异环磷酰胺、丝裂霉素C、米托蒽醌、Vincreistine、长春瑞滨、卡铂、替尼泊苷、道诺红霉素、洋红霉素、氨蝶呤、放线菌素D、丝裂霉素(Mitomycins)、Esperamicins(见美国专利号4,675,187)、美法仑和其它相关的氮芥。
用于本文时,术语“细胞毒性试剂”指抑制或阻止细胞功能和/或导致细胞损伤的物质。该术语意欲包括放射性同位素、化疗剂和毒素诸如细菌、真菌、植物或动物起源的酶促活性毒素或其片段。
用于本申请时,术语“前体药物”指与亲本药物相比对肿瘤细胞具有较少细胞毒性的药用活性物质的前体或衍生物形式,并且其能够被酶促地活化或转化为更有活性的亲本形式。见,例如,Wilman,DE,生物化学社会学报(Biochem.Soc.Trans.)14(1986),375-382,和Stella V.J.和Himmelstein,K.J.,前药:靶向药物递送的化学方法(Prodrugs:A ChemicalApproach to Targeted Drug Delivery),在定向药物递送(Directed DrugDelivery),Borchardt R.T.等,(编辑),Humana Press,Clifton,NJ(1985),247-267页中。本发明的前体药物包括,但不限于:含磷酸盐(酯)的前体药物、含硫代磷酸盐(酯)的前体药物、含硫酸盐(酯)的前体药物、含肽的前体药物、D-氨基酸修饰的前体药物、糖基化的前体药物、β-内酰胺环前体药物,包含任何取代的苯氧基乙酰胺的前体药物或含任选取代的苯乙酰胺的前体药物,可以被转化为更具活性的无细胞毒性的药物的5-氟胞嘧啶和其它5-氟尿嘧啶前体药物。可以被衍生为用在本发明中的前体药物形式的细胞毒性药物的实例包括但不限于上述的那些化疗剂。
用于本文时,“药用载体”包括生理相容的任何和所有的溶剂、分散介质、包衣剂、抗细菌剂和抗真菌剂、等渗和吸收延缓试剂等。优选地,所述载体适合于静脉内的、肌内的、皮下的、肠胃外的或脊柱的施用(例如,通过注射或灌输)。
“药用盐”指保留抗体的所需的生物学活性并不带来任何不需要的毒理作用的盐(见例如,Berge,S.M.,等,药物科学杂志(J.Pharm.Sci.)66(1977)1-19)。将这些盐包括在本发明中。这些盐的实例包括酸式加成盐和碱式加成盐。酸式加成盐包括从非毒性无机酸衍生的那些,诸如盐酸盐。
通过许多本领域已知的各种方法可以施用本发明的组合物。如本领域技术人员将理解,施用路径和/或模式将取决于所需结果而变化。
为了通过某些施用路径来施用本发明化合物,用一种材料来包被化合物,或与一种材料共同施用化合物以预防其失活可能是必需的。例如,可以以适当载体,例如脂质体或稀释剂来给受试者施用所述化合物。药用稀释剂包括盐水和水性缓冲溶液。
药用载体包括用于即时制备灭菌的可注射溶液或分散体的灭菌水溶液或分散体和灭菌粉末。将这些介质和试剂用于药用活性物质的应用为本领域所知。
在用于本文时,短语“肠胃外的施用”和“经肠胃外施用”表示除肠内的和局部施用以外的通常通过注射的施用模式,包括但不局限于,静脉内的、肌内的、动脉内的、鞘内的、囊内的、眶内的、心内的、皮内的、腹膜内的、经气管的、皮下的、表皮下的、关节内的、囊下的、蛛网膜下的、脊柱内的、硬膜外的、胸骨内的注射和灌输。
这些组合物还可以包含佐剂诸如防腐剂、湿润剂、乳化剂和分散剂。可以通过上述的灭菌方法以及加入各种抗细菌和抗真菌试剂,例如,对羟基苯甲酸酯、氯代丁醇、苯酚、山梨酸等都可以确保预防微生物的存在。将等渗试剂,诸如糖、氯化钠等包括在组合物中也可能是理想的。此外,通过将延缓吸收的试剂诸如单硬脂酸铝和明胶加入可导致可注射的药用形式的延长吸收。
无论选择何种施用路径,通过用本领域技术人员已知的常规方法,将可以以适合的水合形式和/或本发明的药物组合物形式使用的本发明的化合物配制成可药用剂型。
对于特定患者、组合物和施用方式,本发明药物组合物的活性成分的实际剂量水平可以变化以获得有效实现理想的治疗反应而不会对患者具有毒性的活性成分的量。选定的剂量水平将取决于许多药物动力学因素,其包括所用的本发明特定组合物的活性,施用的路径,施用的时间,所用的特定化合物的排泄率,治疗的持续时间,与所用的特定化合物组合使用的其它药物、化合物和/或物质,待治疗的患者的年龄、性别、体重、疾病状况、一般健康和以前的疾病史等医学领域众所周知的类似因素。优选的剂量显著低于非糖修饰的CHO宿主细胞如CHO DG44中生成的抗体的剂量。
所述组合物必须灭菌并且形成流体到组合物可以通过注射器进行传递的程度。除了水之外,载体优选是等渗缓冲盐水溶液。
例如,通过应用包衣诸如磷脂酰胆碱,通过在分散状况下维持所需的颗粒大小,以及通过表面活性剂的使用可以保持适当的流动性。在许多情况中,将等渗试剂,例如,糖,多元醇诸如甘露糖醇或山梨糖醇和氯化钠包括在组合物中是优选的。
提供下列实施例、附图和序列表以协助理解本发明,在后附的权利要求中要求其实际范围。要理解的是可以在不背离本发明精神的情况下在提出的方法中进行修改。
图1显示样品1和2的释放的寡糖的MALDI-MS-分析。
图2显示按照实施例3测量的肿瘤体积(曲线1:对照)。
实施例
质粒
表达系统包含CMV启动子系统(EP 0323997)并且描述于表1和2中。作为抗体使用针对IGF-1R的IgG1抗体(WO2005005635;AK18或AK22)。
表1:pETR 2880(抗体表达载体)
元件 | 长度 | 描述 |
IR18HC | 1404 | 编码AK18或AK22的重链 |
IR18LC | 714 | 编码AK18或AK22的轻链 |
GS | 1122 | 编码谷氨酰胺-合成酶 |
SV40E | 343 | 启动子 |
hCMV启动子 | 1142 | 启动子 |
内含子 | 947 | 内含子 |
表2:pETR 2273(糖基化载体)
元件 | 长度 | 描述 |
嵌合MPSV启动子(含有hCMV启动子的增强子) | 875 | 启动子 |
合成的内含子 | 1324 | 内含子 |
GnTIII | 1644 | 编码N-乙酰葡糖胺-转移酶III |
ManII | 3435 | 编码甘露糖苷酶II |
pac | 600 | 编码来自白黑链霉菌(Streptomyces alboniger)的嘌呤霉素乙酰基转移酶 |
polyA | 49 | 多腺苷酸化信号 |
将这两种质粒共转染到谷氨酰胺原养型CHO或HEK293宿主细胞(EP 0256055)中。在无血清培养基中培养作为补料分批培养物细胞系至多14天,从而生成具有不同量岩藻糖基化的抗体批次(样品1-2,CHO)。从上清液中分离抗体,并通过层析法纯化。
在中国仓鼠卵巢(CHO)细胞系,即CHO-DG44中重组产生WT抗体(AK18表现出95%岩藻糖基化)(Flintoff,W.F.,等,体细胞遗传学(Somat.Cell Genet.)2(1976)245-261;Flintoff,W.F.,等,分子细胞生物学(Mol.Cell.Biol.)2(1982)275-285;Urlaub,G.,等,细胞(Cell)33(1983)405-412;Urlaub,G.,等,体细胞分子遗传学(Somat.Cell Mol.Genet.)12(1986)555-566)。CHO-DG44细胞在MEMα负型培养基(Gibco No.22561),10%渗析的FCS(Gibco No.26400-044)和2mmol/L L-谷氨酰胺,100μMHypoxanthin,16μM Thymidin(HT增补物)中生长。
实施例1
测定抗-IGF-IR抗体与IGF-IR的亲和性
芯片:CM5
偶联:胺偶联
缓冲液:HBS(HEPES,NaCl),pH 7.4,25℃
对于亲和性测试,已经将抗人Fcγ抗体(来自山羊)与芯片表面偶联,从而显现针对IGF-IR的糖基改造抗体。以各种浓度将IGF-IR胞外结构域添加到溶液中。通过IGF-IR注射2分钟来测量关联性;通过用缓冲液洗涤芯片表面3分钟来测量解离。将抗体18和22的亲和性数据显示于表3中。
表3:
抗体 | ka(1/Ms) | kd(1/s) | KD(M) |
No.1 | 1.98x105 | 2.02x10-4 | 1.02x10-9 |
No.2 | 1.86x105 | 2.68x10-4 | 1.44x10-9 |
实施例2
通过抗-IGF-IR HuMAb确定抗体介导的效应子功能
为了确定生成的HuMAb抗体引发免疫效应子机制抗体-依赖性细胞毒性(ADCC)的能力,进行了研究。
为了研究抗体在ADCC中的作用,在细胞培养器中,用1μl/mlBATDA溶液(Perkin Elmer),在37℃下,标记H322M、DU145或其他表达IGF-IR的合适细胞(1x106个细胞/ml)25分钟。然而,用10mlRPMI-FM/PenStrep清洗细胞4次,并在200xg离心沉淀10分钟。在最后的离心步骤前,确定细胞数量,并然后将细胞沉淀在RPMI-FM/PenStrep培养基中稀释为1x105个细胞/ml。将细胞以5,000/孔涂布到圆底板中,体积为50μl。将HuMAb抗体,以在体积为50μl的细胞培养基中25-0.1μg/ml的最终浓度范围,加入到50μl细胞混悬液中。随后,以25∶1的E∶T比加入50μl效应子细胞,即新鲜分离的PBMC。在200xg离心该板1分钟,随后进行在37℃下2小时的培养步骤。培养后,在200xg离心沉淀细胞10分钟,并收获20μl上清液并转移到Optiplate 96-F板中。加入200μl铕溶液(Perkin Elmer,室温下),并在摇动台上培养该板15分钟。利用来自Perkin Elmer的Eu-TDA方案,在时间-分辨的荧光计(Victor 3,Perkin Elmer)上量化荧光。
将由ADCC引起的细胞溶解物的数量级表示为由洗涤剂溶解的靶细胞最大释放TDA荧光增强剂的%,该%是针对由相应靶细胞自发释放的TDA校正的。结果显示在表4中:
表4:
样品 | 特异性肿瘤细胞溶解 |
No.1 | 66% |
No.2 | 84% |
实施例3
分析抗体糖结构
为了确定包含岩藻糖-和非-岩藻糖(a-岩藻糖)的寡糖结构的相对比例,通过MALDI-Tof-质谱法分析纯化的抗体物质的释放聚糖。为此,用处于0.1M磷酸钠缓冲液,pH6.0中的5mU N-糖苷酶F(Prozyme#GKE-5010B),在37℃温育抗体样品(约50μg)过夜,从而从蛋白质主链中释放寡糖。随后,利用NuTip-碳吸移头(获自Glygen:NuTip1-10μl,Cat.Nr#NT1CAR)对释放的聚糖结构进行分离和脱盐。作为第一步,通过用3μl 1M NaOH以及随后用20μl纯水(例如,来自Baker的HPLC-梯度级,#4218),3μL 30%v/v乙酸和再一次20μl纯水清洗,准备NuTip-碳吸移头,以用于结合寡糖。为此,将各自的溶液加载到NuTip-碳吸移头中层析材料上,并挤压从其中通过。然后,通过将上述N-糖苷酶F消化物上下吸拉4-5次,使相当于10μg抗体的聚糖结构与NuTip-碳吸移头中材料结合。以上述方式,用20μL纯水清洗与NuTip-碳吸移头中材料结合的聚糖,并分别用0.5μL 10%和2.0μL 20%乙腈对其进行逐步洗脱。为了该步骤,将洗脱溶液装入0.5mL反应器中,并各上下吸拉4-5次。为了通过MALDI-Tof质谱法分析,组合这两份洗出液。为了该测量,将0.4μL组合的洗出液在MALDI靶标上与1.6μL SDHB基质溶液(以5mg/ml溶解在20%乙醇/5mM NaCl中的2.5-二羟基苯甲酸/2-羟基-5-甲氧基苯甲酸[Bruker Daltonics#209813])混合,用合适调谐的Bruker Ultraflex TOF/TOF仪对其进行分析。常规地,记录50-300个点,并总结为单次试验。通过拐点分析软件(flex analysis software)(Bruker Daltonics)评估获得的波谱,并确定每个检测到的峰的质量。随后,通过比较关于各个结构的计算的质量和理论预期的质量,将峰确定为包含岩藻糖或a-岩藻糖(无-岩藻糖)的糖结构(例如,分别地,具有和不具有岩藻糖的复合的、杂合的和寡-或高-甘露糖)。
为了确定杂合的结构的比例,用N-糖苷酶F和内切糖苷酶H共同(concomitantly)消化抗体样品。N-糖苷酶F使所有N-键合的聚糖结构(复合的、杂合的和寡-和高甘露糖结构)从蛋白质主链中释放出来,且内切糖苷酶H又在聚糖还原末端上的两个GlcNAc-残基之间分裂所有杂合类型的聚糖。随后,以与上述N-糖苷酶F消化的样品相同的方式,通过MALDI-Tof质谱法处理和分析该消化物。通过比较来自N-糖苷酶F消化物和组合N-糖苷酶F/内切H消化物的模式,使用特定糖结构信号的还原程度来估计杂合的结构的相对含量。
由各个糖结构的峰高和所有检测到的糖结构峰高合的比,计算每种糖结构的相对量。a岩藻糖的相对量是缺乏岩藻糖的结构相对于N-糖苷酶F处理的样品中识别的所有糖结构(例如,分别地,复合的、杂合的和寡-和高-甘露糖结构)的百分数。见表5.
表5:
平 | A-岩藻糖基化(%) |
No.1 | 64% |
No.2 | 61% |
No.3(HEK293) | 79% |
实施例4
确定抗-IGF-IR抗体对FcgR III(CD16a)的亲和性
His-CD 16a与CM5-芯片表面胺-偶联(~660RU)。
仪器:Biacore 3000
运行和稀释缓冲液:HBS-P
测量:25℃下1个数据点/秒;注射100nM抗体5分钟;以50μl/分钟的流速解离5分钟;在12℃预冷却样品;用7.5mM NaOH/1M NaCl再生(regeneration)表面。结果:wt的RU:11;45%岩藻糖基化的RU:65;60%岩藻糖基化的RU:72。
实施例5
毒性研究
在猕猴中进行了2周毒性研究。以10mg/kg/日的剂量,在第1、4、7、11天,施用部分岩藻糖基化的抗体。与wt抗体相比,在一般身体状态和行为、体重、食物消耗量、血液学、ECG、临床化学(除去ALAT)、肉眼检查或器官重量中没有观察到与药物相关的变化。
序列表
<110>霍夫曼-拉罗奇有限公司
<120>针对胰岛素样生长因子I受体的抗体及其应用
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<150>EP 06026651
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PCT/RO/134表
PCT/RO/134表的中文译文(共2页)
PCT/EP2004/010047
申请人或代理机构文件参考24061WO-SR | 国际申请号PCT/EP2007/011159 |
涉及保藏的微生物或其它生物材料的指示
(PCT细则13bis)
C.附加指示(附页)
申请人:霍夫曼-拉罗奇有限公司,等
申请人文件参考号:24061WO-SR
国际申请号:PCT/EP2007/011159
关于说明书引用的保藏生物材料的专家解决方案相关的指示
涉及保藏的生物材料的指示全部包含在说明书中。下列另外的指示不要求是说明书的一部分,并且应当作为“分开的指示”对待。它们仅涉及专家解决方案。以下作出的另外的指示涉及在说明书第7页(注:中文第7页)中称为:
<IGF-IR>HUMAB-克隆18DSM ACC 2587
<IGF-IR>HUMAB-克隆22DSM ACC 2594
的保藏的生物材料。
另外的指示是:
对于CA(加拿大)指定:
对于加拿大的指定,按照加拿大专利法案专利细则第107和108条规定,只有通过将样品签发给局长提名的独立专家(细则10(4)),直到授予加拿大专利,或直到申请被驳回或被放弃且不再要求恢复、或被撤回的日期,才可以提供保藏的生物材料的样品。
对于EP(欧专局)指定:
关于EPO的指定,按照EPC实施细则的细则28(3)的规定,只有通过将样品签发给请求人提名的专家(细则28(4)EPC),直到欧洲专利授权通知公开,或者如果申请被驳回或撤回或视撤,直至从申请日起20年,才可以提供保藏的生物材料的样品。
对于SG(新加坡)指定:
申请人由此提请注意,我们意欲根据1995年专利法则目录四的第3段,上述培养物仅可提供给专家。
Claims (19)
1.结合IGF-IR并在Asn297上被糖链所糖基化的抗体,所述抗体特征在于所述糖链内岩藻糖的量为20%-50%。
2.按照权利要求1的抗体,其特征在于所述糖链内岩藻糖的量为20%-40%。
3.按照权利要求1或2的抗体,其特征在于NGNA的量为1%或更少和/或N末端α-1,3-半乳糖的量为1%或更少。
4.按照权利要求1-3的抗体,其特征在于NGNA的量为0.5%或更少。
5.按照权利要求1-4的抗体,其特征在于N末端α-1,3-半乳糖的量为0.5%或更少。
6.按照权利要求1-5的抗体,其特征在于所述抗体是嵌合的、人源化的或人抗体。
7.按照权利要求1-6的抗体,其特征在于所述抗体显示一种或多种选自由下列组成的组的特性:
a)显示其对IGF-I与IGF-IR结合的抑制的IC50值与其对IGF-II与IGF-IR结合的抑制的IC50值的比率为1∶3-3∶1;
b)当与没有所述抗体的这种测定比较时,其在5nM的浓度上,在使用HT29细胞的细胞磷酸化测定中,抑制至少80%,优选地至少90%的IGF-IR磷酸化,所述HT29细胞在包含0.5%的热灭活胎牛血清(FCS)和10nM人IGF-1的培养基中;
c)当与没有所述抗体的这种测定比较时,在使用3T3细胞的细胞磷酸化测定中,其在10μM的浓度上没有显示如PKB磷酸化所测量的IGF-IR的刺激活性(无信号传导,无IGF-1模拟活性),所述3T3细胞在包含0.5%的热灭活胎牛血清(FCS)的培养基中提供400,000-600,000分子IGF-IR/细胞。
8.按照权利要求1-7的抗体,其特征在于亲和性为约10-13到10-9M(KD)。
9.按照权利要求1-8的抗体,其特征在于包含作为互补决定区(CDRs),具有下列序列:
a)包括作为CDRs的SEQ ID NO:1或3的CDR1(氨基酸31-35),CDR2(氨基酸50-66)和CDR3(氨基酸99-107)的抗体重链;
b)包括作为CDRs的SEQ ID NO:2或4的CDR1(氨基酸24-34),CDR2(氨基酸50-56)和CDR3(氨基酸89-98)的抗体轻链。
10.按照权利要求1-9的抗体用于制备药物组合物的应用。
11.药物组合物,其包含按照权利要求1-9的抗体。
12.按照权利要求1-9的抗体用于制备治疗癌症的药物组合物的应用。
13.按照权利要求12的应用,其特征在于组合细胞毒性剂、其前体药物或细胞毒性放疗施用所述抗体。
14.治疗需要抗肿瘤治疗的患者的方法,其特征是向该患者施用按照权利要求1-9的抗体。
15.按照权利要求14的方法,其特征在于组合细胞毒性剂、其前体药物或细胞毒性放疗施用所述抗体。
16.能够重组表达GnTIII和抗-IGF-1R的抗体的CHO细胞。
17.结合IGF-IR并在Asn297上被糖链所糖基化的抗体,所述抗体特征在于对FcγRIII表现出高结合亲和性。
18.按照权利要求1-9的抗体,其用于治疗癌症,优选地,乳腺癌、胰腺癌和/或NSCLC。
19.按照权利要求1-9的抗体,其用于治疗乳腺癌、胰腺癌和/或NSCLC。
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US6946292B2 (en) * | 2000-10-06 | 2005-09-20 | Kyowa Hakko Kogyo Co., Ltd. | Cells producing antibody compositions with increased antibody dependent cytotoxic activity |
CN100422316C (zh) * | 2002-05-24 | 2008-10-01 | 先灵公司 | 抗胰岛素样生长因子受体(igfr)的人源中和抗体 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105164158A (zh) * | 2013-04-29 | 2015-12-16 | 豪夫迈·罗氏有限公司 | 消除对FcRn-结合的抗-IGF-1R抗体及其在血管性眼病治疗中的用途 |
WO2022217923A1 (zh) * | 2021-04-14 | 2022-10-20 | 苏州普乐康医药科技有限公司 | 一种抗igf-1r抗体及其应用 |
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CL2007003726A1 (es) | 2008-05-16 |
KR20120080663A (ko) | 2012-07-17 |
CR10810A (es) | 2009-08-12 |
MX2009006333A (es) | 2009-06-23 |
TW200833712A (en) | 2008-08-16 |
NZ576956A (en) | 2011-07-29 |
KR20090088911A (ko) | 2009-08-20 |
AR064620A1 (es) | 2009-04-15 |
MA31066B1 (fr) | 2010-01-04 |
BRPI0722062A2 (pt) | 2014-04-01 |
PE20081832A1 (es) | 2008-12-27 |
ECSP099440A (es) | 2009-07-31 |
WO2008077546A1 (en) | 2008-07-03 |
ZA200904324B (en) | 2010-04-28 |
EP2102242A1 (en) | 2009-09-23 |
AU2007338402A1 (en) | 2008-07-03 |
IL198778A0 (en) | 2011-08-01 |
CA2672715A1 (en) | 2008-07-03 |
JP2010513352A (ja) | 2010-04-30 |
US20080226635A1 (en) | 2008-09-18 |
RU2009127846A (ru) | 2011-01-27 |
US20120076778A1 (en) | 2012-03-29 |
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