CN102973947A - 抗体-药物偶联物和方法 - Google Patents
抗体-药物偶联物和方法 Download PDFInfo
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Abstract
本发明涉及抗体-药物偶联物和方法。本发明涉及式I的抗体-药物偶联化合物:Ab-(L-D)p I,其中一个或多个美登木素生物碱药物部分(D)通过L共价连接到抗体(Ab),所述抗体(Ab)结合ErbB受体,或者结合一种或多种肿瘤相关抗原或细胞表面受体。这些化合物可用于癌症、以及其它疾病和紊乱的诊断或治疗方法中。
Description
本申请是申请日为2005年5月31日、中国申请号为200580026066.7、发明名称为“抗体-药物偶联物和方法”的发明申请的分案申请。
此根据37CFR§1.53(b)提交的非临时申请,根据35USC§119(e),要求2004年6月1日提交的US临时申请60/576,517、2004年10月5日提交的US临时申请60/616,098的权益,这些均整体加入作为参考。
发明所属领域
本发明一般涉及具有抗癌活性的化合物,更特别地涉及与化疗美登木素生物碱药物或毒素偶联的抗体。本发明还涉及利用抗体-药物偶联化合物体外、原位、和体内诊断或治疗哺乳动物细胞、或相关病理学病症的方法。
发明背景
已经建立了用于癌症、免疫学和血管新生紊乱患者靶向治疗的单克隆抗体疗法。使用抗体-药物偶联物(ADC)即免疫偶联物局部递送细胞毒性或细胞抑制剂,即癌症治疗中杀伤或抑制肿瘤细胞的药物(Payne,G.(2003)CancerCell 3:207-212;Trail等(2003)Cancer Immunol.Immunother.52:328-337;Syrigos和Epenetos(1999)Anticancer Research 19:605-614;Niculescu-Duvaz和Springer(1997)Adv.Drug Del.Rev.26:151-172;US 4975278)理论上允许将药物部分靶向递送到肿瘤,并在肿瘤的细胞内累积,在此全身性施用这些非偶联药剂可能导致对正常细胞和所要去除的肿瘤细胞不可接受的毒性水平(Baldwin等,(1986)Lancet pp.(Mar.15,1986):603-05;Thorpe,(1985)"Antibody Carriers Of Cytotoxic Agents In Cancer Therapy:A Review,"inMonoclonal Antibodies'84:Biological And Clinical Applications,A.Pinchera等(编),pp.475-506)。因此所要寻求的是最大的功效同时毒性最小。设计和改进ADC的努力集中于单克隆抗体(mAbs)的选择性以及药物-连接和药物-释放特性。用于这些策略的多克隆抗体和单克隆抗体都已有报导(Rowland等,(1986)Cancer Immunol.Immunother.21:183-87)。用于这些方法的药物包括柔红霉素、阿霉素、氨甲蝶呤、丝裂霉素、新制癌菌素(Takahashi等(1988)Cancer 61:881-888)和长春地辛(Rowland等,(1986)同上)。用于抗体-毒素偶联物的毒素包括细菌毒素如白喉毒素、植物毒素如蓖麻毒素(US 4753894;US5629197;US 4958009;US 4956453)、小分子毒素如格尔德霉素(geldanamycin)(Mandler等(2000)J.of the Nat.Cancer Inst.92(19):1573-1581;Mandler等(2000)Bioorganic&Med.Chem.Letters 10:1025-1028;Mandler等(2002)Bioconjugate Chem.13:786-791)、美登木素生物碱(maytansinoids)(EP1391213;Liu等,(1996)Proc.Natl.Acad.Sci.USA 93:8618-8623)、以及加利车霉素(calicheamicin)(Lode等(1998)Cancer Res.58:2928;Hinman等(1993)Cancer Res.53:3336-3342)。所述毒素可能通过包括微管蛋白结合、DNA结合、或拓扑异构酶抑制机制影响其细胞毒性和细胞抑制效应。当偶联于大型抗体或蛋白质受体配体时,一些细胞毒性药物倾向于失活或活性减小。
已经批准了抗体-放射性同位素偶联物(ibritumomab tiuxetan,Biogen/Idec),其由抗CD20抗原的鼠IgG1kappa单克隆抗体和由硫脲接头(linker)-螯合剂结合的111In或90Y放射性同位素组成(Wiseman等(2000)Eur.J.Nucl.Med.27(7):766-77;Wiseman等(2002)Blood 99(12):4336-42;Witzig等(2002)J.Clin.Oncol.20(10):2453-63;Witzig等(2002)J.Clin.Oncol.20(15):3262-69)。2000年,批准了由连接到加利车霉素的hu CD33抗体组成的抗体-药物偶联物MYLOTARGTM(gemtuzumab ozogamicin,WyethPharmaceuticals),用于通过注射治疗急性髓细胞性白血病(Drugs of theFuture(2000)25(7):686;US 4970198;US 5079233;US 5585089;US 5606040;US 5693762;US 5739116;US 5767285;US 5773001)。由通过二硫化物接头SPP连接到美登木素生物碱药物部分DM1的huC242抗体组成的抗体-药物偶联物Cantuzumab mertansine(Immunogen,Inc.)(Xie等(2004)J.of Pharm.andExp.Ther.308(3):1073-1082;Tolcher等(2003)J.Clin.Oncology21(2):211-222;US 5208020)进行了治疗表达CanAg的癌症如结肠癌、胰腺癌、胃癌及其它癌症的I期试验。MLN-2704(Millennium Pharm.,BZLBiologics,Immunogen Inc.)是由连接到美登木素生物碱药物部分DM1的抗前列腺特异性膜抗原(PSMA)单克隆抗体组成的抗体-药物偶联物,正在开发以用于前列腺肿瘤的有效治疗。相同的美登木素生物碱药物部分DM1通过非二硫化物接头(non-disulfide linker)SMCC连接到小鼠的鼠单克隆抗体TA.1(Chari等(1992)Cancer Research 52:127-131)。据报导此偶联物比相应的二硫化物接头偶联物效力小200倍。认为在所述偶联物中SMCC接头是“不可裂解的”(也可参见:US 4981979)。已报导了通过SMCC连接到DM1的(曲妥单抗(trastuzumab)(WO 2005/037992)。
在寻找用于癌症诊断和治疗的有效细胞靶物的努力中,研究者已设法鉴定了跨膜或肿瘤相关多肽,与一种或多种正常非癌细胞相比,这些多肽特异地表达于一种或多种特定类型癌细胞的表面上。通常,与非癌细胞的表面上相比,这些肿瘤相关多肽更多地表达在癌细胞表面上。鉴定这些肿瘤相关细胞表面抗原多肽即肿瘤相关抗原(TAA)已产生了通过基于抗体治疗的特异地靶向癌细胞进行破坏的能力。
已经建立了用于癌症、免疫紊乱和血管新生紊乱患者的靶向治疗的单克隆抗体疗法。成功的抗体治疗的例子是重组DNA衍生的人源化单克隆抗体(曲妥单抗(trastuzumab)),在基于细胞的测试中,其选择性地以高亲合力(Kd=5nM)结合到人表皮生长因子受体2蛋白HER2的胞外区(ErbB2)(US 5821337;US 6054297;US 6407213;US 6639055;Coussens L等(1985)Science 230:1132-9;Slamon DJ等(1989)Science 244:707-12)。曲妥单抗为包含人框架区的IgG1kappa抗体,具有结合HER2的鼠抗体互补决定区(4D5)。曲妥单抗结合HER2抗原,因此抑制癌细胞的生长。因为曲妥单抗为人源化抗体,所以其最小化患者中的任何HAMA反应。该抗HER2人源化抗体由哺乳动物细胞(中华仓鼠卵巢(Chinese Hamster Ovary,CHO))悬浮培养物生产。HER2(或c-erbB2)原癌基因编码185kDa的跨膜受体蛋白,该跨膜受体蛋白在结构上与表皮生长因子受体有关。在25%–30%的原发性乳腺癌中观察到HER2蛋白过表达,可以利用基于免疫组化的固定肿瘤阻断评估测定HER2蛋白过表达(Press MF,等(1993)Cancer Res 53:4960-70)。已经显示,在体外测试和动物中,曲妥单抗抑制过表达HER2的人肿瘤细胞的增殖(Hudziak RM,等(1989)Mol Cell Biol 9:1165-72;Lewis GD,et al(1993)Cancer ImmunolImmunother;37:255-63;Baselga J,et al(1998)Cancer Res.58:2825-2831)。曲妥单抗是抗体依赖的细胞毒,ADCC,的介导物(Hotaling TE,等(1996)[摘要].Proc.Annual Meeting Am Assoc Cancer Res;37:471;Pegram MD,等(1997)[摘要].Proc Am Assoc Cancer Res;38:602;Sliwkowski等(1999)Seminars inOncology 26(4),Suppl 12:60-70;Yarden Y.和Sliwkowski,M.(2001)NatureReviews:Molecular Cell Biology,Macmillan Magazines,Ltd.,Vol.2:127-137)。临床上,在ErbB2-过表达转移性乳腺癌患者中是有活性的,所述患者先前已接受了大量的抗癌治疗(Baselga等,(1996)J.Clin.Oncol.14:737-744)。虽然HERCEPTIN是治疗ErbB2-过表达乳腺癌患者中的突破,所述患者先前已接受广泛的抗癌治疗,但此群体中大多数患者对HERCEPTIN治疗没有反应或者反应微弱。因此,临床上明显需要开发其它HER2引导的癌症疗法,用于患HER2-过表达肿瘤或与HER2表达相关的其它疾病,而对HERCEPTIN治疗没有反应或反应微弱的患者的治疗。除了HER2之外,靶向疗法也有可能利用其它肿瘤相关抗原。
概述
本发明提供具有抗癌细胞生物学活性的新的化合物。所述化合物可以抑制哺乳动物肿瘤生长,并且可用于治疗人类癌症患者。
本发明涉及将治疗性抗体-药物偶联物(ADC)化合物递送、运输、累积或保持在细胞内。本发明更具体地涉及在癌细胞中获得高浓度的活性代谢物分子。可以通过允许生物活性试剂在细胞内累积或保持的方法和化合物实现细胞内靶向。这种有效的靶向适用于多种治疗学制剂和方法。
已获得令人惊讶的发现,即抗体-药物偶联物导致增强的体外效价和体内功效,所述抗体-药物偶联物具有将美登木素生物碱药物部分连接于抗体的稳定的非二硫化物接头基团。此外,相对于某些二硫化物接头偶联物,所述抗体-药物偶联物在体内显示意料不到的更为安全的结果。
抗体-药物偶联物(ADC)化合物包含通过接头共价连接于一个或多个美登木素生物碱药物部分的抗体。ADC可以用式I表示∶
Ab-(L-D)p I
其中一个或多个美登木素生物碱药物部分(D)通过L共价连接到抗体(Ab)。Ab为结合ErbB受体,或者结合一种或多种肿瘤相关抗原或细胞表面受体的抗体。接头L在细胞外即胞外可以是稳定的。接头L、美登木素生物碱药物部分D、或者接头和美登木素生物碱药物部分一起(L-D)不包含二硫化物基团(disulfide group)。
在一个实施方案中,实质量(substantial amount)的药物部分直到抗体-药物偶联物进入具有细胞表面受体的细胞时才由所述抗体裂解,其中所述细胞表面受体特异于抗体-药物偶联物的抗体,并且所述药物部分在抗体-药物偶联物确实进入所述细胞时由所述抗体裂解。
在另一实施方案中,ADC特异地结合由ErbB基因编码的受体,如EGFR、HER2、HER3和HER4。ADC可以特异地结合HER2受体的胞外结构域。ADC可以抑制过表达HER2受体的肿瘤细胞的生长。
在另一实施方案中,式I的抗体(Ab)为人源化抗体如huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7或huMAb4D5-8(曲妥单抗)。
本发明的另一方面为药物组合物,其包括式I化合物或其药学上可接受的盐或溶剂化物,和药学上可接受的稀释剂、载体、或赋形剂。
另一方面提供药物组合(pharmaceutical combination),其包含式I化合物和具有抗癌特性或其它治疗学效果的第二种化合物。
另一方面包括此处公开的化合物和组合物的诊断和治疗学用途。
另一方面为杀伤或抑制肿瘤细胞或癌细胞增殖的方法,其包括用杀伤或抑制肿瘤细胞或癌细胞增殖有效的一定量的抗体-药物偶联物,或其药学上可接受的盐或溶剂化物处理所述细胞。
另一方面为治疗癌症的方法,其包括为患者施用式I化合物的制剂。一种方法用于治疗哺乳动物癌症,其中所述癌症以ErbB受体的过表达为特征。所述哺乳动物任选对非偶联抗ErbB抗体治疗不反应,或反应微弱。所述方法包括为所述哺乳动物施用治疗有效量的抗体-药物偶联化合物。
另一方面为抑制过表达生长因子受体的肿瘤细胞生长的方法,所述生长因子受体选自HER2受体和EGF受体,所述方法包括为患者施用特异地结合所述生长因子受体的抗体-药物偶联化合物和化疗剂,其中所述抗体-药物偶联物和所述化疗剂分别以有效抑制患者肿瘤细胞生长的量施用。
另一方面为治疗人类患者的方法,所述人类患者对以ErbB2受体过表达为特征的病症敏感或者被诊断为患有以ErbB2受体过表达为特征的病症,所述方法包括施用式I的抗体-药物偶联化合物和化疗剂的组合。
另一方面为检测癌细胞的测试方法,包括∶将细胞与抗体-药物偶联化合物接触,并测定抗体-药物偶联化合物与细胞的结合程度。
另一方面涉及筛选用于治疗疾病或紊乱的ADC候选药物的方法,其中疾病或紊乱以HER2的过表达为特征。
另一方面包括制品即试剂盒,包括抗体-药物偶联物、容器、和指导治疗的包装说明书或标签。
另一方面包括用抗体-药物偶联化合物治疗以患者中HER2过表达为特征的疾病或紊乱的方法。
另一方面包括抗体-药物偶联化合物的制造方法、制备方法、合成方法、偶联方法、和纯化方法和用于所述抗体-药物偶联化合物的制备、合成、和偶联的中间体。
本发明涉及下述各项。
1.抗体-药物偶联化合物,包括通过接头共价连接于一个或多个美登木素生物碱药物部分的抗体,所述化合物具有式I∶
Ab-(L-D)p I
或其药学上可接受的盐或溶剂化物,其中∶
Ab为结合ErbB受体,或者结合一种或多种肿瘤相关抗原或细胞表面受体的抗体,所述肿瘤相关抗原或细胞表面受体选自(1)-(36)∶
(1)BMPR1B(骨形态发生蛋白受体-IB型,Genbank登录号NM_001203);
(2)E16(LAT1、SLC7A5,Genbank登录号NM_003486);
(3)STEAP1(前列腺六次跨膜上皮抗原,Genbank登录号NM_012449);
(4)0772P(CA125、MUC16、Genbank登录号AF361486);
(5)MPF(MPF、MSLN、SMR、巨核细胞强化因子、mesothelin,Genbank登录号NM_005823);
(6)Napi3b(NAPI-3B、NPTIIb、SLC34A2、溶质载体家族34(磷酸钠),成员2,II型钠依赖的磷酸盐转运蛋白3b,Genbank登录号NM_006424);
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、脑信号蛋白5b Hlog,sema结构域,七个血小板反应蛋白重复(1型和类1型的),跨膜结构域(TM)和短的细胞质结构域,(脑信号蛋白)5B,Genbank登录号AB040878);
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA2700050C12、RIKEN cDNA 2700050C12基因,Genbank登录号AY358628);
(9)ETBR(内皮素B型受体,Genbank登录号AY275463);
(10)MSG783(RNF124,假想蛋白FLJ20315,Genbank登录号NM_017763);
(11)STEAP2(HGNC_8639、IPCA-1、PCANAP1、STAMP1、STEAP2、STMP、前列腺癌相关基因1、前列腺癌相关蛋白1、前列腺的六次跨膜上皮抗原2、六次跨膜前列腺蛋白,Genbank登录号AF455138);
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、瞬时受体潜在阳离子通道,亚家族M,成员4,Genbank登录号NM_017636);
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1,畸胎癌衍生生长因子,Genbank登录号NP_003203或NM_003212);
(14)CD21(CR2(补体受体2)或C3DR(C3d/埃巴病毒受体)或Hs.73792Genbank登录号M26004);
(15)CD79b(CD79B、CD79β、IGb(免疫球蛋白相关beta)、B29,Genbank登录号NM_000626);
(16)FcRH2(IFGP4、IRTA4、SPAP1A(含SH2结构域的磷酸酶锚定蛋白1a)、SPAP1B、SPAP1C,Genbank登录号NM_030764);
(17)HER2(Genbank登录号M11730);
(18)NCA(Genbank登录号M18728);
(19)MDP(Genbank登录号BC017023);
(20)IL20Rα(Genbank登录号AF184971);
(21)Brevican(Genbank登录号AF229053);
(22)EphB2R(Genbank登录号NM_004442);
(23)ASLG659(Genbank登录号AX092328);
(24)PSCA(Genbank登录号AJ297436);
(25)GEDA(Genbank登录号AY260763;
(26)BAFF-R(B细胞活化因子受体,BlyS受体3,BR3,NP_443177.1);
(27)CD22(B细胞受体CD22-B同种型,NP-001762.1);
(28)CD79a(CD79A,CD79α,免疫球蛋白相关alpha,与Ig beta(CD79B)共价相互作用并在表面上与Ig M分子形成复合体、转导涉及B细胞分化的信号的B细胞特异性蛋白,Genbank登录号NP_001774.1);
(29)CXCR5(伯基特淋巴瘤受体1,被CXCL13趋化因子活化的G蛋白偶联受体,在淋巴细胞迁移和体液防御中发挥作用,在HIV-2感染以及可能在AIDS、淋巴瘤、骨髓瘤、和白血病的发生中发挥作用,Genbank登录号NP_001707.1);
(30)HLA-DOB(MHC II类分子的Beta亚基(Ia抗原),其结合肽并将其呈递到CD4+T淋巴细胞,Genbank登录号NP_002111.1);
(31)P2X5(嘌呤受体P2X配体门控离子通道5,由胞外ATP门控的离子通道,可能涉及突触传递和神经发生,其缺陷可能导致特发性逼尿肌不稳定的病理生理状况,Genbank登录号NP_002552.2);
(32)CD72(B细胞分化抗原CD72,Lyb-2,Genbank登录号NP_001773.1);
(33)LY64(淋巴细胞抗原64(RP105),富含亮氨酸重复(LRR)的I型膜蛋白家族,调节B细胞活化和凋亡,功能的丧失与系统性红斑狼疮患者疾病活动增强有关,Genbank登录号NP_005573.1);
(34)FcRH1(Fc受体样蛋白1,免疫球蛋白Fc结构域的推定受体,包含C2型Ig样和ITAM结构域,可能在B淋巴细胞分化中起作用,Genbank登录号NP_443170.1);
(35)IRTA2(易位相关免疫球蛋白超家族受体2,推定的免疫受体,可能在B细胞发育和淋巴瘤发生中起作用;由易位导致的基因失调发生于一些B细胞恶性病中,Genbank登录号NP_112571.1);以及
(36)TENB2(推定的跨膜蛋白聚糖,与生长因子的EGF/生长因子的调蛋白家族和卵泡抑素相关,Genbank登录号AF179274;
条件是所述抗体不是TA.1;
L为非二硫化物接头;
D为美登木素生物碱药物部分;并且
p为1到8。
2.项1的抗体-药物偶联化合物,其中Ab为结合选自(1)-(16)和(18)-(36)的一种或多种肿瘤相关抗原或细胞表面受体的抗体。
3.项1或项2的抗体-药物偶联化合物,其中L为选自下述结构的接头∶
其中波浪线表示与Ab和D的共价连接;
X为:
Y是:
R独立地为H或C1-C6烷基;且n为1至12。
4.任一前述项的抗体-药物偶联化合物,其中D选自结构:
其中波浪线表示与L的共价连接,
R独立地为H或C1-C6烷基,并且
m为1、2、或3。
5.项4的抗体-药物偶联化合物,其中m为2,并且R为H。
6.任一前述项的抗体-药物偶联化合物,其中美登木素生物碱药物部分为DM1,具有结构:
7.项3的抗体-药物偶联化合物,其具有结构:
8.项7的抗体-药物偶联化合物,其具有结构:
9.项3的抗体-药物偶联化合物,其具有结构:
10.项1的抗体-药物偶联化合物,其具有结构:
11.项10的抗体-药物偶联物,其中Ab为曲妥单抗,并且p为1、2、3、或4。
12.项1的抗体-药物偶联化合物,其具有结构:
其中Tr为曲妥单抗,并且p为1、2、3、或4。
13.项1的抗体-药物偶联化合物,其具有结构:
其中n为0、1、或2;并且p为1、2、3、或4。
14.项13的抗体-药物偶联化合物,其中Ab为曲妥单抗。
15.项1的抗体-药物偶联化合物,其中p为1、2、3、或4。
16.项1的抗体-药物偶联化合物,其中所述抗体结合由ErbB基因编码的受体。
17.项16的抗体-药物偶联化合物,其中所述受体选自EGFR、HER2、HER3和HER4。
18.项17的抗体-药物偶联化合物,其中所述抗体特异地结合HER2受体。
19.项1的抗体-药物偶联化合物,其特异地结合HER2受体的胞外结构域并抑制过表达HER2受体的肿瘤细胞的生长。
20.任一前述项的抗体-药物偶联化合物,其中所述抗体选自单克隆抗体、抗体片段、嵌合抗体和人源化抗体。
21.项1的抗体-药物偶联化合物,其中所述抗体为选自huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7和huMAb4D5-8(曲妥单抗)的人源化抗体。
22.项21的抗体-药物偶联化合物,其中所述抗体为huMAb4D5-8(曲妥单抗)。
23.项20的抗体-药物偶联物,其中所述抗体为Fab片段。
24.项1的抗体-药物偶联化合物,其中所述抗体通过抗体的半胱氨酸硫醇连接于接头。
25.项24的抗体-药物偶联化合物,其中p为1、2、3、或4。
26.包含项1或项2的抗体-药物偶联化合物或其药学上可接受的盐、和药学上可接受的稀释剂、载体或赋形剂的药物组合物。
27.项26的药物组合物,其进一步包含治疗有效量的化疗剂,所述化疗剂选自:Erlotinib、Bortezomib、氟维司群、Sutent、来曲唑、甲磺酸伊马替尼、PTK787/ZK 222584、Oxaliplatin、5-FU、甲酰四氢叶酸、雷帕霉素、Lapatinib、Lonafarnib、Sorafenib和Gefitinib。
28.项26的药物组合物,其进一步包含治疗有效量的抗血管新生剂。
29.项26的药物组合物,其进一步包含治疗有效量的贝伐单抗。
30.抑制细胞增殖的方法,包括用项1或项2的抗体-药物偶联化合物处理细胞培养基中的哺乳动物细胞,由此抑制细胞的增殖。
31.项30的方法,其中所述哺乳动物细胞具有针对抗体-药物偶联化合物的HER2受体蛋白。
32.项31的方法,其中所述哺乳动物细胞是乳腺肿瘤细胞。
33.项30的方法,其中所述抗体-药物偶联化合物细胞毒性比包含抗体-药物偶联化合物的美登木素生物碱部分的美登木素生物碱化合物更强。
34.项30的方法,其中所述抗体-药物偶联物诱导凋亡。
35.治疗癌症的方法,包括为患者施用项1或项2的抗体-药物偶联化合物和药学上可接受的稀释剂、载体或赋形剂的制剂。
36.项35的方法,其中所述癌症选自乳腺、卵巢、胃部、子宫内膜、唾液腺、肺、肾脏、结肠、结肠直肠、甲状腺、胰腺、前列腺和膀胱癌。
37.项36的方法,其中所述癌症为以2+或更高水平过表达ErbB2的乳腺癌。
38.项35的方法,其中为患者施用的抗体-药物偶联化合物的量在每剂约0.1至约10mg/kg患者体重范围。
39.项35的方法,其中以约三周的间隔施用抗体-药物偶联物。
40.项35的方法,其中通过输注施用抗体-药物偶联物。
41.项35的方法,其中所述抗体-药物偶联物与药学上可接受的肠胃外载体一起配制。
42.项41的方法,其中所述抗体-药物偶联物配制为可注射的单位剂量形式。
43.项42的方法,其中静脉内施用抗体-药物偶联物。
44.项35的方法,其中与抗体-药物偶联化合物组合,为患者施用生长抑制性抗体。
45.项35的方法,其中与抗体-药物偶联化合物组合,为患者施用结合ErbB2并阻断ErbB受体的配体活化的第二种抗体。
46.项45的方法,其中第二种抗体包括单克隆抗体2C4或人源化2C4。
47.项46的方法,其中所述第二种抗体与细胞毒性试剂偶联。
48.项35的方法,其中与抗体-药物偶联化合物组合,为患者施用化疗剂,其中所述化疗剂选自:Erlotinib、Bortezomib、氟维司群、Sutent、来曲唑、甲磺酸伊马替尼、PTK787/ZK 222584、Oxaliplatin、5-FU、甲酰四氢叶酸、雷帕霉素、Lapatinib、Lonafarnib、Sorafenib、和Gefitinib。
49.项35的方法,其中与抗体-药物偶联化合物组合,为患者施用抗血管新生剂,其中所述抗血管新生剂选自贝伐单抗。
50.抑制过表达生长因子受体的肿瘤细胞生长的方法,包括为患者施用项1的抗体-药物偶联物和化疗剂,所述抗体-药物偶联物特异地结合选自HER2或EGF的生长因子受体,其中所述抗体-药物偶联物和所述化疗剂分别以有效抑制患者肿瘤细胞生长的量施用。
51.治疗人类患者的方法,所述人类患者对以ErbB2受体过表达为特征的疾病敏感或者经诊断患有所述疾病,所述方法包括联合施用项1的抗体-药物偶联物和化疗剂或生长抑制剂。
52.项51的方法,其中抗体-药物偶联物的抗体为抗ErbB2抗体。
53.项52的方法,其中所述抗ErbB2抗体具有4D5单克隆抗体的生物学特征。
54.项52的方法,其中所述抗ErbB2抗体结合与4D5单克隆抗体基本上相同的表位。
55.项52的方法,其中所述抗ErbB2抗体选自人源化抗体:huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7和huMAb4D5-8(曲妥单抗)。
56.用于检测癌细胞的测试方法,包括:
(a)将细胞与项1或项2的抗体-药物偶联化合物接触;和
(b)测定抗体-药物偶联化合物结合细胞的程度。
57.项56的测试方法,其中所述细胞是乳腺肿瘤细胞。
58.项56的测试方法,其中所述结合程度通过用荧光原位杂交(FISH)测定ErbB-编码核酸的水平来检测。
59.项56的测试方法,其中所述结合程度通过免疫组化(IHC)测定。
60.一种制品,包括:
项1或项2的抗体-药物偶联化合物;
容器;和
包装说明书或标签,其指明所述化合物可用于治疗以ErbB受体过表达为特征的癌症。
61.项60的制品,其中所述包装说明书或标签指明所述化合物可用于治疗以ErbB2受体过表达为特征的癌症。
62.项61的制品,其中所述癌症为乳腺癌。
63.项62的制品,其中所述癌症以ErbB2受体2+或以上水平的过表达为特征。
64.制备抗体-药物偶联化合物的方法,包括通过接头将抗体共价连接于一个或多个美登木素生物碱药物部分,所述化合物具有式I:
Ab-(L-D)p I
或其药学上可接受的盐或溶剂化物,其中:
Ab为结合ErbB受体,或者结合一种或多种肿瘤相关抗原或细胞表面受体的抗体,所述肿瘤相关抗原或细胞表面受体选自(1)-(36):
(1)BMPR1B(骨形态发生蛋白受体-IB型,Genbank登录号NM_001203);
(2)E16(LAT1、SLC7A5,Genbank登录号NM_003486);
(3)STEAP1(前列腺六次跨膜上皮抗原,Genbank登录号NM_012449);
(4)0772P(CA125、MUC16、Genbank登录号AF361486);
(5)MPF(MPF、MSLN、SMR、巨核细胞强化因子、mesothelin,Genbank登录号NM_005823);
(6)Napi3b(NAPI-3B、NPTIIb、SLC34A2、溶质载体家族34(磷酸钠),成员2,II型钠依赖的磷酸盐转运蛋白3b,Genbank登录号NM_006424);
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、脑信号蛋白5b Hlog,sema结构域,七个血小板反应蛋白重复(1型和类1型的),跨膜结构域(TM)和短的细胞质结构域,(脑信号蛋白)5B,Genbank登录号AB040878);
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA2700050C12、RIKEN cDNA 2700050C12基因,Genbank登录号AY358628);
(9)ETBR(内皮素B型受体,Genbank登录号AY275463);
(10)MSG783(RNF124,假想蛋白(hypothetical protein)FLJ20315,Genbank登录号NM_017763);
(11)STEAP2(HGNC_8639、IPCA-1、PCANAP1、STAMP1、STEAP2、STMP、前列腺癌相关基因1、前列腺癌相关蛋白1、前列腺的六次跨膜上皮抗原2、六次跨膜前列腺蛋白,Genbank登录号AF455138);
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、瞬时受体潜在阳离子通道,亚家族M,成员4,Genbank登录号NM_017636);
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1,畸胎癌衍生生长因子,Genbank登录号NP_003203或NM_003212);
(14)CD21(CR2(补体受体2)或C3DR(C3d/埃巴病毒受体)或Hs.73792Genbank登录号M26004);
(15)CD79b(CD79B、CD79β、IGb(免疫球蛋白相关beta)、B29,Genbank登录号NM_000626);
(16)FcRH2(IFGP4、IRTA4、SPAP1A(含SH2结构域的磷酸酶锚定蛋白1a)、SPAP1B、SPAP1C,Genbank登录号NM_030764);
(17)HER2(Genbank登录号M11730);
(18)NCA(Genbank登录号M18728);
(19)MDP(Genbank登录号BC017023);
(20)IL20Rα(Genbank登录号AF184971);
(21)Brevican(Genbank登录号AF229053);
(22)EphB2R(Genbank登录号NM_004442);
(23)ASLG659(Genbank登录号AX092328);
(24)PSCA(Genbank登录号AJ297436);
(25)GEDA(Genbank登录号AY260763;
(26)BAFF-R(B细胞活化因子受体,BlyS受体3,BR3,NP_443177.1);
(27)CD22(B细胞受体CD22-B同种型,NP-001762.1);
(28)CD79a(CD79A,CD79α,免疫球蛋白相关alpha,与Ig beta(CD79B)共价相互作用并在表面上与Ig M分子形成复合体,转导涉及B细胞分化的信号的B细胞特异性蛋白,Genbank登录号NP_001774.1);
(29)CXCR5(伯基特淋巴瘤受体1,被CXCL13趋化因子活化的G蛋白偶联受体,在淋巴细胞迁移和体液防御中发挥作用,在HIV-2感染以及可能在AIDS、淋巴瘤、骨髓瘤、和白血病中发挥作用,Genbank登录号NP_001707.1);
(30)HLA-DOB(MHC II类分子的Beta亚基(Ia抗原),其结合肽并将其呈递到CD4+T淋巴细胞,Genbank登录号NP_002111.1);
(31)P2X5(嘌呤受体P2X配体门控离子通道5,由胞外ATP门控的离子通道,可能涉及突触传递和神经再生,其缺陷可能导致特发性逼尿肌不稳定的病理生理状况,Genbank登录号NP_002552.2);
(32)CD72(B细胞分化抗原CD72,Lyb-2,Genbank登录号NP_001773.1);
(33)LY64(淋巴细胞抗原64(RP105),富含亮氨酸重复(LRR)的I型膜蛋白家族,调节B细胞活化和凋亡,功能的丧失与系统性红斑狼疮患者疾病活动增强有关,Genbank登录号NP_005573.1);
(34)FcRH1(Fc受体样蛋白1,推定的免疫球蛋白Fc结构域,包含C2型Ig样和ITAM结构域,可能在B淋巴细胞分化中起作用,Genbank登录号NP_443170.1);
(35)IRTA2(易位相关免疫球蛋白超家族受体2,推定的免疫受体,可能在B细胞发育和淋巴瘤发生中起作用;由易位导致的基因失调发生于一些B细胞恶性病中,Genbank登录号NP_112571.1);以及
(36)TENB2(推定的跨膜蛋白聚糖,与生长因子的EGF/调蛋白家族和卵泡抑素相关,Genbank登录号AF179274;
条件是所述抗体不是TA.1;
L为选自下述结构的接头:
其中波浪线表示与Ab和D的共价连接;
X为:
Y是:
其中R独立地为H或C1-C6烷基;且n为1至12;
D为选自下述结构的美登木素生物碱药物部分:
其中波浪线表示与L的共价连接;R独立地为H或C1-C6烷基;m为1、2、或3;并且p为1至8;
其中所述方法包括:
使Ab与接头试剂反应形成抗体-接头中间体Ab-L,然后使Ab-L与药物部分D反应形成抗体-药物偶联物;或者
使药物部分D与接头试剂反应形成药物-接头中间体D-L,然后使D-L与Ab反应形成抗体-药物偶联物。
65.项64的方法,其中Ab为结合选自(1)-(16)和(18)-(36)的一种或多种肿瘤相关抗原或细胞表面受体的抗体。
66.项64或项65的方法,其中所述接头试剂为SMCC。
67.项64或项65的方法,其中所述接头试剂为选自DTME、BMB、BMDB、BMH、BMOE、BM(PEO)3和BM(PEO)4的二-马来酰亚胺试剂。
附图简述
图1显示用抗体-药物偶联物处理的SK-BR-3细胞进行的体外细胞增殖测试∶-□-曲妥单抗-SPP-DM1,-Δ-曲妥单抗-SPDP-DM1,和-o-曲妥单抗-SMCC-DM1.
图2显示用抗体-药物偶联物处理的BT-474细胞进行的体外细胞增殖测试∶-□-曲妥单抗-SPP-DM1,-Δ-曲妥单抗-SPDP-DM1,和-o-曲妥单抗-SMCC-DM1.
图3显示用抗体-药物偶联物处理的MCF7细胞进行的体外细胞增殖测试∶-□-曲妥单抗-SPP-DM1,-Δ-曲妥单抗-SPDP-DM1,和-o-曲妥单抗-SMCC-DM1.
图4显示用抗体-药物偶联物处理的MDA-MB-468细胞进行的体外细胞增殖测试:-□-曲妥单抗-SPP-DM1,-Δ-曲妥单抗-SPDP-DM1,和-o-曲妥单抗-SMCC-DM1.
图5显示无肿瘤米色裸鼠中曲妥单抗-SMCC-DM1相对曲妥单抗-SPP-DM1的血清清除率,在7天中的六个时间点(服药后5分钟、1小时、6小时、24小时、72、168小时)测定偶联物和总抗体血清浓度。
图6显示无肿瘤裸鼠中下述偶联物随时间推移的稳定性∶曲妥单抗-SPDP-DM1、曲妥单抗-SPP-DM1、曲妥单抗-SPP-DM3、曲妥单抗-SPP-DM4、和曲妥单抗-SMCC-DM1,在7天中六个时间点(服药后5分钟、1小时、6小时、24小时、72、168小时)测定血清浓度。
图7显示处理7天后,有和没有肿瘤的小鼠中总曲妥单抗/曲妥单抗-SMCC-DM1和总曲妥单抗/曲妥单抗-SPP-DM1的血清浓度测量值。
图8显示为4只受试大鼠施用10mg/kg曲妥单抗-SPP-DM1后的血浆浓度清除率研究。测定了总的抗体和曲妥单抗-SPP-DM1浓度。(tr=曲妥单抗)
图9显示为4只受试大鼠施用10mg/kg曲妥单抗-SMCC-DM1后的血浆浓度清除率研究。测定了总的抗体和曲妥单抗-SMCC-DM1浓度。
图10显示随着时间推移,按剂量给予以下药物的小鼠平均肿瘤体积变化:载体(PBS pH 6.5)、曲妥单抗-SPP-DM1(370μgDM1/m2)、和曲妥单抗-SMCC-DM1(330μgDM1/m2),其中剂量指所施用的DM1的剂量。
图11显示随着时间推移,于第0天按剂量给予以下药物的Fo5肿瘤同种异体移植的无胸腺裸鼠平均肿瘤体积变化:载体(PBS pH 6.5)、10mg/g曲妥单抗-SIAB-DM1(3.4DM1/Ab;168μgDM1/kg)、和10mg/g曲妥单抗-SMCC-DM1(3.2DM1/Ab;158μgDM1/kg),其中剂量指所施用的抗体-药物偶联物的剂量。
图12显示随着时间推移,单次注射载体(PBS pH 6.5)、10mg/g曲妥单抗-SPP-DM1、10mg/kg曲妥单抗-SPP-DM4、10mg/g曲妥单抗-SPP-DM3、和10mg/kg曲妥单抗-SMCC-DM1的MMTV-Her2Fo5米色裸鼠(每组7只,都有肿瘤,Ti=7)的平均肿瘤体积变化。
图13显示在HER2-Fo5肿瘤中,载体(PBS pH 6.5)、曲妥单抗-SPP-DM1、曲妥单抗-SPP-DM4、曲妥单抗-SPP-DM3、和曲妥单抗-SMCC-DM1的肿瘤体积加倍的时间和对数细胞杀伤分析。
图14显示随着时间推移,按剂量给予以下药物的大鼠的体重变化:载体(10mM琥珀酸钠、100mg/mL蔗糖、0.1%Tween 20,pH 5.0)、曲妥单抗-SPP-DM1(1860μg DM1/m2)、曲妥单抗-SMCC-DM1(1860μg DM1/m2)、曲妥单抗-SMCC-DM1(3260μgDM 1/m2)、和无DM 1(650μg/m2)。
图15显示随着时间推移,按剂量给予以下药物的大鼠模型中测得的每升AST单位的肝功能测试值:载体(10mM琥珀酸钠、100mg/mL蔗糖、0.1%Tween 20,pH 5.0)、曲妥单抗-SPP-DM1(22.3mg/kg)、曲妥单抗-SMCC-DM1(10mg/kg)、曲妥单抗-SMCC-DM1(25mg/kg)、曲妥单抗-SMCC-DM1(50mg/kg)、和无DM1。
图16显示随着时间推移,按剂量给予以下药物的大鼠模型中测得的每升细胞中PLT单位的安全谱:载体(10mM琥珀酸钠、100mg/mL蔗糖、0.1%Tween 20,pH 5.0)、曲妥单抗-SPP-DM1(22.3mg/kg)、曲妥单抗-SMCC-DM1(10mg/kg)、曲妥单抗-SMCC-DM1(25mg/kg)、曲妥单抗-SMCC-DM1(50mg/kg)、和无DM1。
图17显示用抗体-药物偶联物处理的HT1080EphB2(C8)细胞进行的体外细胞增殖测试∶-▲-抗EphB2R 2H9-SPP-DM1,和抗EphB2R2H9-SMCC-DM1。
示例性实施方案的详细描述
现在将为本发明的特定实施方案详细地制订参考,以附随的结构和通式阐述其实施例。虽然将结合所列举的实施方案描述本发明,但会理解它们并不意味着将本发明限于那些实施方案。相反,本发明将涵盖所有的替代方案、改造方案、和等同方案,这些替代方案、改造方案、和等同方案包括在权利要求所定义的本发明的范围内。
本领域熟练技术人员会认识到与本文所述类似或等同的许多方法和材料能够用于实施本发明。本发明决不限于所述的方法和材料。
除非另有定义,本文所用技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的意义,且与Singleton等.,(1994)Dictionary ofMicrobiology and Molecular Biology,2nd Ed.,J.Wiley&Sons,New York,NY;和Janeway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immuno Biology,5thEd.,Garland Publishing,New York一致。
定义
除非另有说明,本文所用下述术语和短语将具有下述含义∶
本文使用商标名时,申请人意欲独立地包括所述商标名产品制剂、所述商标名产品的同类药物、和活性药物成分。
本文术语“抗体”以最广义使用,特别涵盖单克隆抗体、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,只要它们显示出所需的生物学活性(Miller等(2003)Jour.of Immunology170:4854-4861)。抗体可以为鼠的、人的、人源化的、嵌合的、或源于其它物种的抗体。抗体是由能够识别和结合特定抗原的免疫系统产生的蛋白。(Janeway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immuno Biology,5thEd.,Garland Publishing,New York).目标抗原一般具有由多种抗体的CDR识别的许多结合位点,也称为表位。每种特异地结合不同表位的抗体都具有不同的结构。因此,一种抗原可以具有一种以上的相应抗体。抗体包括全长免疫球蛋白分子或全长免疫球蛋白分子的免疫活性部分,即包含免疫特异地结合感兴趣目标的抗原的抗原结合位点或其一部分的分子,这种目标包括但不限于癌细胞或生产与自身免疫病相关的自身免疫抗体的细胞。本文公开的免疫球蛋白可以是任何类型(例如,IgG、IgE、IgM、IgD、和IgA)、类(例如,IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类的免疫球蛋白分子。所述免疫球蛋白可以源于任何物种。然而一个方面,所述免疫球蛋白是人、鼠、或兔源的。
"抗体片段"包含全长抗体的一部分,通常为其抗原结合或可变区。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;由Fab表达文库生产的片段、抗独特型(抗Id)抗体、CDR(互补决定区)、和上述任何免疫特异地结合癌细胞抗原、病毒抗原或微生物抗原的表位-结合片段、单链抗体分子;以及由抗体片段形成的多特异性抗体。
本文所用术语单克隆抗体指由基本上同质的抗体群体获得的抗体,即除了可能少量存在的天然发生的突变之外,组成所述群体的单个抗体是相同的。单克隆抗体是高度特异的,针对单个抗原位点。另外,与包括针对不同决定簇(表位)的不同抗体的多克隆抗体制品相反,每种单克隆抗体针对抗原上的单个决定簇。除了其特异性之外,单克隆抗体优势在于它们可以被合成但不被其它抗体所污染。所述修饰语“单克隆”指从基本上同质的抗体群体获得的抗体的特征,不能理解为需要以任何特定方法生产所述抗体。例如,根据本发明使用的单克隆抗体可以通过杂交瘤方法制备,所述杂交瘤方法由Kohler等(1975)Nature 256:495首次描述,或者可以通过重组DNA方法(参见,US 4816567)制备。例如,单克隆抗体也可以利用Clackson等(1991)Nature,352:624-628;Marks等(1991)J.Mol.Biol.,222:581-597描述的技术由噬菌体抗体文库分离。
此处单克隆抗体特别包括“嵌合”抗体,以及这些抗体的片段,其中重链和/或轻链的一部分与源于特定物种或属于特定抗体类或亚类的抗体中的相应序列等同或同源,而链的其余部分与源于其它物种或属于其它抗体类或亚类的抗体中的相应序列等同或同源,只要它们显示所需的生物学活性(US4816567;and Morrison et al(1984)Proc.Natl.Acad.Sci.USA,81:6851-6855)。此处感兴趣的嵌合抗体包括“灵长类化的”抗体,其包含源于非人灵长类(例如,旧世纪猴或猿(old world Monkey or Ape))的可变区抗原结合序列和人恒定区序列。
此处“完整抗体”为包含VL和VH结构域,以及轻链恒定区(CL)和重链恒定区CH1、CH2和CH3的抗体。恒定区可以是天然序列恒定区(例如,人天然序列恒定区)或其氨基酸序列变体。完整抗体可以具有一种或多种“效应器功能”,即可归因于抗体Fc区(天然序列Fc区或氨基酸序列变体Fc区)的那些生物学活性。抗体效应器功能的例子包括C1q结合;补体依赖的细胞毒;Fc受体结合;抗体依赖的细胞介导的细胞毒(ADCC);吞噬作用;和细胞表面受体如B细胞受体和BCR的负调节。
依据其重链恒定区的氨基酸序列,可以将完整抗体指定为不同的类别。有五种主要的完整抗体类别∶IgA、IgD、IgE、IgG、和IgM,其中几种可以进一步分为亚类(同种型),例如IgG1、IgG2、IgG3、IgG4、IgA、以及IgA2。相应于不同抗体类别的重链恒定区分别称为α、δ、ε、γ和μ。不同类别免疫球蛋白的亚单位结构和三维构象是熟知的。
“ErbB受体”是受体蛋白酪氨酸激酶,其属于ErbB受体家族,该家族是细胞生长、分化和存活的重要介导物。ErbB受体家族包括四种不同的成员,包括表皮生长因子受体(EGFR,ErbB1,HER1)、HER2(ErbB2或p185neu)、HER3(ErbB3)和HER4(ErbB4或tyro2)。用人乳腺肿瘤细胞系SKBR3已经鉴定了一组抗-ErbB2抗体(Hudziak et al (1989)Mol.Cell.Biol.9(3):1165-1172。用称为4D5的抗体获得了最大抑制,4D5抑制细胞增殖的百分比为56%。在该测试中,该组中的其它抗体将细胞增殖减小到更低程度。进一步发现抗体4D5使ErbB2过表达乳腺肿瘤细胞系对TNF-α的细胞毒性效应敏感(US5677171)。Fendly et al(1990)Cancer Research 50:1550-1558;Kotts et al.(1990)In Vitro 26(3):59A;Sarup et al.(1991)Growth Regulation 1:72-82;Shepard etal.J.(1991)Clin.Immunol.11(3):117-127;Kumar et al.(1991)Mol.Cell.Biol.11(2):979-986;Lewis et al.(1993)Cancer Immunol.Immunother.37:255-263;Pietras et al.(1994)Oncogene 9:1829-1838;Vitetta et al.(1994)Cancer Research54:5301-5309;Sliwkowski et al.(1994)J.Biol.Chem.269(20):14661-14665;Scott et al.(1991)J.Biol.Chem.266:14300-5;D'souza et al.Proc.Natl.Acad.Sci.(1994)91:7202-7206;Lewis et al.(1996)Cancer Research 56:1457-1465;andSchaefer et al.(1997)Oncogene 15:1385-1394中进一步鉴定了Hudziak等中讨论的抗ErbB2抗体。
Franklin et al(2004)Cancer Cell 5:317-328;Tagliabue et al(1991)Int.J.Cancer 47:933-937;McKenzie et al(1989)Oncogene 4:543-548;Maier etal(1991)Cancer Res.51:5361-5369;Bacus et al(1990)Molecular Carcinogenesis3:350-362;Stancovski et al(1991)PNAS(USA)88:8691-8695;Bacus et al(1992)Cancer Research 52:2580-2589;Xu et al(1993)Int.J.Cancer 53:401-408;WO94/00136;Kasprzyk et al(1992)Cancer Research 52:2771-2776;Hancock etal(1991)Cancer Res.51:4575-4580;Shawver et al(1994)Cancer Res.54:1367-1373;Arteaga et al(1994)Cancer Res.54:3758-3765;Harwerth etal(1992)J.Biol.Chem.267:15160-15167;US 5783186;and Klapper et al(1997)Oncogene 14:2099-2109中描述了具有不同特性的其它抗ErbB2抗体。
序列同一性筛选已鉴定了两种其它ErbB受体家族成员;ErbB3(US5,183,884;US 5,480,968;Kraus et al(1989)PNAS(USA)86:9193-9197)和ErbB4(EP 599274;Plowman et al(1993)Proc.Natl.Acad.Sci.USA,90:1746-1750;and Plowman et al(1993)Nature 366:473-475)。这两种受体在至少一些乳腺癌细胞系上都显示增强的表达。
ErbB受体通常会包括胞外结构域,其可以结合ErbB配体;亲脂性跨膜结构域;保守性胞内酪氨酸激酶结构域;和含有几个可以磷酸化的酪氨酸残基的羧基末端信号结构域。ErbB受体可以为“天然序列”ErbB受体或其“氨基酸序列变体”。ErbB受体可以为天然序列人ErbB受体。因此,“ErbB受体家族成员”为EGFR(ErbB1)、ErbB2、ErbB3、ErbB4或当前已知的或将来要鉴定的任何其它ErbB受体。
术语“ErbB1”、“表皮生长因子受体”、“EGFR”和“HER1”此处可互换使用,指例如Carpenter et al(1987)Ann.Rev.Biochem.56:881-914中公开的EGFR,包括其天然发生的突变形式(例如,Humphrey et al.,(1990)PNAS(USA),87:4207-4211中的缺失突变体EGFR)。术语erbB1指编码EGFR蛋白质产物的基因。例如,Murthy et al(1987)Arch.Biochem.Biophys.,252:549-560和WO 95/25167中描述了针对HER1的抗体。
术语"ERRP"、"EGF-受体相关蛋白"、"EGFR相关蛋白"和"表皮生长因子受体相关蛋白"此处可互换使用,指例如US 6399743和US 2003/0096373中公开的ERRP。
措辞“ErbB2”和“HER2”此处可互换使用,指例如Semba et al(1985)PNAS(USA),82:6497-6501和Yamamoto et al(1986)Nature,319:230-234(Genbank登录号X03363)中描述的人HER2蛋白。术语“erbB2”指编码人ErbB2的基因,“neu”指编码大鼠p185neu的基因。
“ErbB3”和“HER3”指例如US 5183884;US 5480968;Kraus et al(1989)PNAS(USA)86:9193-9197中公开的受体多肽。针对ErbB3的抗体是本领域已知的(US 5183884;US 5480968;WO 97/35885)。
此处术语“ErbB4”和“HER4”指例如EP专利申请599,274;Plowman et al.,Proc.Natl.Acad.Sci.USA,90:1746-1750(1993);和Plowman et al.,Nature,366:473-475(1993)中公开的受体多肽,包括其同种型,例如WO 99/19488中公开的。例如WO 02/18444中描述了针对HER4的抗体。
ErbB受体的抗体在商业上可从许多来源获得,包括例如Santa CruzBiotechnology,Inc.,California,USA。
“ErbB配体”意思是结合和/或活化ErbB受体的多肽。ErbB配体可以是天然序列人ErbB配体如表皮生长因子(EGF)(Savage et al(1972)J.Biol.Chem.,247:7612-7621);转化生长因子alpha(TGF-α)(Marquardt et al(1984)Science223:1079-1082);双调蛋白(amphiregulin),也称为神经鞘瘤(schwanoma)或角质细胞自分泌生长因子(keratinocyte autocrine growth factor)(Shoyab etal(1989)Science 243:1074-1076;Kimura et al(1990)Nature 348:257-260;Cooket al(1991)Mol.Cell.Biol.,11:2547-2557);β细胞素(betacellulin)(Shing etal(1993)Science 259:1604-1607;Sasada et al(1993)Biochem.Biophys.Res.Commun.190:1173);肝素结合表皮生长因子(HB-EGF)(Higashiyama etal(1991)Science 251:936-939);epiregulin(Toyoda et al(1995)J.Biol.Chem.270:7495-7500;Komurasaki et al(1997)Oncogene 15:2841-2848);调蛋白(heregulin)(参见下述);神经调节蛋白-2(NRG-2)(Carraway et al.,Nature,387:512-516(1997));神经调节蛋白-3(NRG-3)(Zhang et al(1997)Proc.Natl.Acad.Sci.,94:9562-9567);神经调节蛋白-4(NRG-4)(Harari et al(1999)Oncogene,18:2681-89)或cripto(CR-1)(Kannan et al(1997)J.Biol.Chem.,272(6):3330-3335)。结合EGFR的ErbB配体包括EGF、TGF-α、双调蛋白、β细胞素、HB-EGF和epiregulin。结合ErbB3的ErbB配体包括调蛋白。能够结合ErbB4的ErbB配体包括β细胞素、epiregulin、HB-EGF、NRG-2、NRG-3、NRG-4和调蛋白。ErbB配体也可以是合成的ErbB配体。合成的配体可以特异于特定ErbB受体,或者可以识别特定的ErbB受体复合物。合成配体的例子是合成的调蛋白/EGF嵌合体biregulin(参见,例如,Jones etal(1999)FEBS Letters,447:227-231,将其加入作为参考)。
“调蛋白(Heregulin)”(HRG)指由US 5641869或Marchionni et al(1993)Nature 362:312-318公开的调蛋白基因产物编码的多肽。调蛋白的例子包括调蛋白-α、调蛋白-β1、调蛋白-β2和调蛋白-β3(Holmes et al(1992)Science256:1205-1210;和US 5641869);neu分化因子(NDF)(Peles et al(1992)Cell 69:205-216);乙酰胆碱受体诱导活性(ARIA)(Falls et al(1993)Cell 72:801-815);神经胶质生长因子(GGFs)(Marchionni et al(1993)Nature,362:312-318);感觉和运动神经元衍生因子(SMDF)(Ho et al(1995)J.Biol.Chem.270:14523-14532);γ-调蛋白(Schaefer et al(1997)Oncogene,15:1385-1394)。该术语包括天然序列HRG多肽的生物学活性片段和/或氨基酸序列变体,如其EGF样结构域片段(例如,HRGβ1177-244)。
“ErbB异寡聚体”为包含至少两种不同ErbB受体的非共价结合的寡聚体。“ErbB二聚体”为包含两种不同ErbB受体的非共价结合寡聚体。表达两种或多种ErbB受体的细胞暴露于ErbB配体时可以形成这种复合体。例如ErbB寡聚体,如ErbB二聚体,可以如Sliwkowski et al(1994)J.Biol.Chem.,269(20):14661-14665中所述,通过免疫沉淀和SDS-PAGE分析而分离。这种ErbB异源寡聚体的例子包括EGFR-ErbB2(也称为HER1/HER2)、ErbB2-ErbB3(HER2/HER3)和ErbB3-ErbB4(HER3/HER4)复合体。另外,ErbB异源寡聚体可以包括与不同ErbB受体如ErbB3、ErbB4或EGFR(ErbB1)组合的两种或多种ErbB2受体。其它蛋白质如细胞因子受体亚单位(例如,gp130)可以包括于该异源寡聚体中。
“ErbB受体的配体活化”意指由ErbB配体与包含感兴趣的ErbB受体的ErbB异源寡聚体的结合所介导的信号转导(例如,由ErbB受体或底物多肽中ErbB受体磷酸化酪氨酸残基的胞内激酶结构域所引起的)。这通常会涉及ErbB配体与ErbB异源寡聚体的结合,该结合活化异源寡聚体中一个或多个ErbB受体的激酶结构域,并由此导致一个或多个ErbB受体中酪氨酸残基的磷酸化和/或其它底物多肽中酪氨酸残基的磷酸化。可以用多种酪氨酸磷酸化测试定量ErbB受体活化。
“天然序列”多肽为具有与源于自然界的多肽(例如,ErbB受体或ErbB配体)相同的氨基酸序列的多肽。这样的天然序列多肽可以从自然界分离,或者可以通过重组或合成手段生产。因此,天然序列多肽可以具有天然发生的人多肽、鼠多肽、或来自任何其它哺乳动物物种的多肽的氨基酸序列。
术语“氨基酸序列变体”指具有在某种程度上不同于天然序列多肽的氨基酸序列的多肽。通常,氨基酸序列变体与天然ErbB配体的至少一个受体结合结构域或者与天然ErbB受体的至少一个配体结合结构域将有至少约70%的序列同一性,或者与这样的受体或配体结合结构域至少约80%,或至少约90%同源。所述氨基酸序列变体在天然氨基酸序列的氨基酸序列内一些位置上具有取代、删除、和/或插入。
“序列同一性”定义为比对序列并且必要时引入空位以获得最大的序列同一性百分比后,氨基酸序列变体中相同残基的百分数。用于所述比对的方法和计算机程序是本领域熟知的。一种这样的计算机程序是Genentech,Inc.设计的“Align 2,”,其于1991年12月10日随同用户文档提交至美国版权局,华盛顿,DC 20559。
“抗体依赖的细胞介导的细胞毒”和“ADCC”指细胞介导的反应,其中表达Fc受体(FcRs)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,随后导致靶细胞裂解。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。造血细胞上FcR的表达概括于Ravetch和Kinet,Annu.Rev.Immunol,9:457-92(1991)第464页表3。为评估感兴趣分子的ADCC活性,可以进行体外ADCC测试(US 5500362l;US 5821337)。可用于此测试的效应细胞包括外周血单个核细胞(PBMC)和天然杀伤(NK)细胞。或者,或除此之外,可以体内评估感兴趣分子的ADCC活性,例如在如Clynes etal(1998)PNAS(USA),95:652-656中公开的动物模型中。
“美登木素生物碱药物部分”意思是具有美登素化合物结构的抗体-药物偶联物的亚结构。美登素最先从东非灌木齿叶美登木(Maytenus serrata)分离(US 3896111)。后来发现某些微生物也生产美登木素生物碱如美登醇(maytansinol)和C-3美登醇酯(US 4151042)。已报导了合成的美登醇和美登醇类似物。参见美国专利4137230;4248870;4256746;4260608;4265814;4294757;4307016;4308268;4308269;4309428;4313946;4315929;4317821;4322348;4331598;4361650;4364866;4424219;4450254;4362663;和4371533,以及Kawai et al(1984)Chem.Pharm.Bull.3441-3451),均特别加入作为参考。
术语“Fc受体”或“FcR”用于描述结合抗体Fc区的受体,如天然序列人FcR。FcR可以结合IgG抗体(gamma受体),包括受体FcγRI、FcγRII、和FcγRIII亚类,包括这些受体的等位变体和这些受体的不同剪接形式。FcγRII受体包括FcγRIIA(“活化受体”)和FcγRIIB(“抑制受体”),它们具有类似的氨基酸序列,主要在其细胞质结构域中有差异。活化受体FcγRIIA在其细胞质结构域中包含基于免疫受体酪氨酸的活化基序(ITAM)。抑制受体FcγRIIB在其细胞质结构域中包含基于免疫受体酪氨酸的抑制基序(ITIM)。(参见综述M.inAnnu.Rev.Immunol.,15:203-234(1997))。Ravetch and Kinet,Annu.Rev.Immunol.,9:457-92(1991);Capel et al(1994)Immunomethods,4:25-34;and de Haas et al(1995)J.Lab.Clin.Med.,126:330-41中综述了FcRs。此处术语"FcR"包括其它的FcR,还包括将来要鉴定的那些。所述术语还包括新生儿受体FcRn,其负责母体IgGs到胎儿的转移(Guyer et al(1976)J.Immunol.117:587,和Kim et al(1994)J.Immunol.24:249)。
"补体依赖的细胞毒"或"CDC"指分子在补体的存在下裂解靶物的能力。补体激活途径由补体系统的第一个组件(C1q)结合到与相关抗原复合的分子(例如抗体)所启动。为了评估补体激活,可以进行CDC测试,例如Gazzano-Santoro et al(1996)J.Immunol.Methods,202:163中所描述的。
"天然抗体"通常为约150,000道尔顿的异四聚体糖蛋白,由两条相同的轻(L)链和两条相同的重(H)链组成。每条轻链由一个共价二硫键连接于重链,然而二硫键的数目在不同免疫球蛋白同种型重链中有变化。每条重链和轻链还具有规则间隔的链内二硫键。每条重链一端具有可变区(VH),接下来是许多恒定区。每种轻链在一端具有可变区(VL),在其另一端具有恒定区。轻链的恒定区与重链的第一个恒定区并列,轻链可变区与重链的可变区并列。据信特定氨基酸残基形成轻链和重链可变区之间的接触面。
术语“可变的”指抗体中可变区的某些部分在序列中差异非常大,用于每种特定抗体对其特定抗原的结合和特异性。然而,可变性在所有抗体的可变区中不是均匀分布的。在轻链和重链可变区中,注意力都集中在三个称为高变区的片段。可变区更加保守的部分称为框架区(FRs)。天然重链和轻链的可变区各包含四个FRs,大量采用β-片层构象,通过三个高变区相连,其形成连接β-片层结构的环,有时构成β-片层结构的一部分。每条链中的高变区通过FRs非常紧密地结合在一起,并且与来自另一条链的高变区一起为抗体的抗原结合部位的形成作出贡献(参见Kabat et al(1991)Sequences of Proteinsof Immunological Interest,5th Ed.Public Health Service,National Institutes ofHealth,Bethesda,MD)。恒定区不直接涉及抗体与抗原的结合,但显示多种效应器功能,例如抗体依赖的细胞毒(ADCC)中抗体的参与。
此处使用术语“高变区”时指负责抗原结合的抗体的氨基酸残基。所述高变区通常包含来自“互补决定区”或“CDR”的氨基酸残基(例如,轻链可变区中的残基24-34(L1)、50-56(L2)和89-97(L3)以及重链可变区中的31-35(H1)、50-65(H2)和95-102(H3);Kabat et al同上)和/或来自“高变环”的那些残基(例如,轻链可变区中的残基26-32(L1)、50-52(L2)和91-96(L3)以及重链可变区中的26-32(H1)、53-55(H2)和96-101(H3);Chothia and Lesk(1987)J.Mol.Biol.,196:901-917)。“框架区”或“FR”残基为除了此处定义的高变区残基之外的那些可变区残基。
抗体的木瓜蛋白酶消化产生两条相同的抗原结合片段,称为“Fab”片段,每条都具有单一抗原结合部位,和残留的“Fc”片段,其名称反映了其易于结晶的能力。胃蛋白酶处理产生F(ab’)2片段,其具有两个抗原结合部位,仍然能够偶联抗原。
“Fv”是包含完全抗原识别和抗原结合部位的最小抗体片段。该区域由一条重链和一条轻链可变区紧密地、非共价结合的二聚体组成。正是以这种每个可变区的三个高变区相互作用的构象确定了VH-VL二聚体表面上的抗原结合部位。六个高变区共同赋予抗体抗原结合特异性。然而,即便是单一的可变区(或者是只包含抗原特异性的三个高变区的Fv的一半)也具有识别并结合抗原的能力,虽然其亲合力低于完整的结合部位。
Fab片段也包含轻链的恒定区和重链的第一个恒定区(CH1)。Fab'片段与Fab片段不同,其在重链CH1区的羧基末端添加了几个残基,包括一个或多个来自抗体绞链区的半胱氨酸。此处将恒定区的半胱氨酸残基具有至少一个自由硫醇基的Fab'称为Fab'-SH。F(ab')2抗体片段起初以Fab'片段对的形式产生,所述Fab'片段对在Fab'片段之间具有铰链半胱氨酸。抗体片段的其它化学偶联物也是已知的。
基于其恒定区的氨基酸序列,来自任何脊椎动物物种的抗体的“轻链”都可以指定为称为kappa(κ)和lambda(λ)的两种清楚确定的类型中的一种。
“单链Fv”或“scFv”意指单链可变区抗体片段,其包含抗体的VH和VL结构域,其中这些结构域存在于单一多肽链中。所述Fv多肽在VH和VL结构域之间可以进一步包含多肽接头,其能够使scFv形成抗原结合所需的结构(Plückthun in The Pharmacology of Monoclonal Antibodies,vol.113,Rosenburg and Moore eds.,Springer-Verlag,New York,pp.269-315(1994)。WO93/16185;US 5571894;US 5587458中描述了抗ErbB2抗体scFv片段。
术语“双抗体(diabodies)”指具有两个抗原结合部位的小抗体片段,所述片段包括同一多肽链(VH-VL)中连接到轻链可变区(VL)的重链可变区(VH)。通过使用太短而不允许同一条链上的两个结构域配对的连接序列,迫使所述结构域与另一条链的互补结构域配对,产生两个抗原结合部位。例如EP404,097;WO 93/11161;和Hollinger et al(1993)Proc.Natl.Acad.Sci.USA,90:6444-6448中更为详细地描述了双抗体。
“人源化”形式的非人(例如,啮齿类的)抗体为包含源于非人免疫球蛋白的最小序列的嵌合抗体。在很大程度上,人源化抗体为其中来自受体高变区的残基被来自非人物种(供体抗体)高变区的残基所置换的人免疫球蛋白(受体抗体),所述非人物种为例如具有所需特异性、亲合力、和能力的小鼠、大鼠、兔或非人灵长类。在一些情况下,人免疫球蛋白的框架区(FR)残基由相应的非人残基所置换。另外,人源化抗体可以包含受体抗体或供体抗体中未发现的残基。构建了这些修饰以进一步改善抗体性能。总的来说,人源化抗体基本上会包含所有的或至少一个、和典型地两个可变区,其中所有的或者基本上所有的高变环相应于非人免疫球蛋白的那些高变环,并且所有的或者基本上所有的FRs均为人免疫球蛋白序列的FRs。人源化抗体任选还将包含免疫球蛋白恒定区(Fc)(通常是人免疫球蛋白恒定区)的至少一部分。更多细节参见Jones et al(1986)Nature,321:522-525;Riechmann et al(1988)Nature 332:323-329;和Presta,(1992)Curr.Op.Struct.Biol.,2:593-596。
人源化抗ErbB2抗体包括US 5821337(此处特别加入作为参考)的表3中描述的huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7和huMAb4D5-8曲妥单抗);人源化520C9(WO 93/21319)和人源化2C4抗体。
“分离的”抗体指已经从其天然环境组分中鉴别和分离和/或回收的抗体。其天然环境的污染物组分指会干扰抗体的诊断或治疗用途的材料,可能包括酶、激素、和其它的蛋白质或非蛋白质溶解物。所述抗体可以纯化至(1)用Lowry法测定时以抗体的重量计大于95%,(2)使用转杯(spinning cup)蛋白质测序仪测定时达到足以获得N末端或内部氨基酸序列的至少15个残基的程度,或者(3)在还原性或非还原性条件下进行SDS-PAGE,用考马斯蓝或银染达到均质。由于抗体天然环境的至少一种组分将不存在,因而分离的抗体包括重组细胞内的原位抗体。然而,通常分离的抗体将通过至少一个纯化步骤制备。
“其结合”感兴趣的抗原,例如,ErbB2抗原的抗体指能够以足够的亲合力结合该抗原,以使所述抗体可用于靶向表达所述抗原的细胞的抗体。其中所述抗体指结合ErbB2的抗体,与其它ErbB受体相反,它通常将优先结合ErbB2,也指与其它蛋白质如EGFR、ErbB3或ErbB4不发生明显交叉反应的抗体。在这样的实施方案中,用荧光活化细胞分选(FACS)分析或放射免疫沉淀(RIA)测定时,所述抗体结合这些非ErbB2蛋白质(例如,结合内源性受体的细胞表面蛋白)的程度将小于10%。有时候,抗ErbB2抗体不会与大鼠neu蛋白发生显著的交叉反应,例如,Schecter et al(1984)Nature 312:513,和Drebin et al(1984)Nature,312:545-548中所述。
“阻断”ErbB受体的配体活化的抗体减少或阻止这种活化,其中与单克隆抗体4D5相比,所述抗体基本上能够更有效地阻断ErbB受体的配体活化,例如,大约与单克隆抗体7F3或2C4或其Fab片段一样有效。例如,阻断ErbB受体的配体活化的抗体可以是在阻断ErbB异源寡聚体形成方面比4D5的有效性高约50-100%的抗体。ErbB受体的配体活化的阻断可以以任何方式发生,例如,通过干扰∶配体结合ErbB受体、ErbB复合体形成、ErbB复合体中ErbB受体的酪氨酸激酶活性和/或ErbB受体中的或者由ErbB受体引起的酪氨酸激酶残基的磷酸化。
具有指定抗体,如单克隆抗体2C4(Omnitarg,Genentech,Inc.)的“生物学特征”的抗体指具有所述抗体的一种或多种生物学特性的抗体,所述生物学特性将其与结合相同抗原(例如,ErbB2)的其它抗体区别开。例如,具有2C4的生物学特征的抗体可以阻断包括ErbB2和ErbB3、ErbB1或ErbB4的ErbB异源寡聚体的HRG活化;阻断包括EGFR和ErbB2的ErbB受体的EGF、TGF-α、HB-EGF、epiregulin和/或双调蛋白活化;阻断MAPK的EGF、TGF-α和/或HRG介导的活化;和/或像2C4的结合那样,结合ErbB2胞外结构域中的相同表位(例如,阻断单克隆抗体2C4结合ErbB2的抗体)。
除非另有指明,措辞“单克隆抗体2C4”指具有下述例子的鼠2C4抗体的、或源于鼠2C4抗体的抗原结合残基的抗体。例如,单克隆抗体2C4可以为鼠单克隆抗体2C4或其变体,如人源化抗体2C4,其具有鼠单克隆抗体2C4的抗原结合氨基酸残基(WO 01/00245)。除非另有指明,此处使用措辞“rhuMAb 2C4”时,指包含分别为SEQ ID Nos.3和4的轻链可变区(VL)和重链可变区(VH)序列的抗体,所述轻链可变区(VL)和重链可变区(VH)序列融合到任选由中国仓鼠卵巢(CHO)细胞(WO 01/00245)表达的人轻链和重链IgG1(非A同种异型)恒定区序列。
除非另有指明,术语“单克隆抗体4D5”指具有鼠4D5抗体(ATCC CRL10463)的、或源于鼠4D5抗体的抗原结合残基的抗体。例如,单克隆抗体4D5可以为鼠单克隆抗体4D5或其变体,如人源化4D5,其具有鼠单克隆抗体4D5的抗原结合残基。示例性人源化4D5抗体包括US 5821337中的huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7和huMAb4D5-8
“生长抑制剂”指在体外或在体内抑制细胞,例如表达ErbB的癌细胞生长的化合物或组合物。因此,所述生长抑制剂可以为显著减少S期ErbB表达细胞的百分数的生长抑制剂。生长抑制剂的例子包括阻断细胞周期进行的试剂(使其在非S期位置),如诱导G1停滞和M-期停滞的试剂(The MolecularBasis of Cancer,Mendelsohn and Israel,eds.,Chapter 1,entitled“Cell cycleregulation,oncogenes,and antineoplastic drugs”by Murakami et al.(WBSaunders:Philadelphia,1995),especially p.13)。“生长抑制性”抗体的例子指结合ErbB2并抑制过表达ErbB2的癌细胞生长的那些抗体。在约0.5至30μg/ml的抗体浓度,生长抑制性抗ErbB2抗体可以抑制细胞培养物中Sk-Br-3乳腺肿瘤细胞生长的20%以上、或50%以上(例如,从大约50%至大约100%),其中在Sk-Br-3细胞接触所述抗体六天后测定生长抑制(US 5677171)。
“诱导细胞死亡”的抗体指导致活细胞成为非活细胞的抗体。所述细胞通常为表达ErbB2受体的细胞,尤其是过表达ErbB2受体的细胞。所述细胞可以是癌细胞,例如,乳腺、卵巢、胃、子宫内膜、唾液腺、肺、肾、结肠、甲状腺、胰腺或膀胱细胞。在体外,所述细胞可以是Sk-Br-3、BT474、Calu3、MDA-MB-453、MDA-MB-361或SKOV3细胞。可以在不存在补体和免疫效应细胞时体外测定细胞死亡,以区分由抗体依赖的细胞介导的细胞毒(ADCC)或补体依赖的细胞毒(CDC)诱导的细胞死亡。因此,可以用加热灭活的血清(即不存在补体)并在无免疫效应细胞的情况下进行细胞死亡测试。为测定所述抗体是否能够诱导细胞死亡,可以评估相对于未处理细胞的膜完整性的丧失,所述膜完整性的丧失通过碘化丙锭(PI)、台盼蓝(参见Moore etal(1995)Cytotechnology,17:1-11)或7AAD吸收评估。诱导细胞死亡的抗体指在BT474细胞的PI吸收测试中诱导PI吸收的那些抗体(参见下文)。
“诱导细胞凋亡”的抗体指诱导程序性细胞死亡的抗体,其通过膜联蛋白V结合、DNA片段化、细胞皱缩、内质网膨胀、细胞破碎、和/或膜囊形成(称为凋亡体)测定。所述细胞通常为过表达ErbB2受体的细胞,包括肿瘤细胞,例如,乳腺、卵巢、胃、子宫内膜、唾液腺、肺、肾、结肠、甲状腺、胰腺或膀胱细胞。在体外,所述细胞可以是Sk-Br-3、BT474、Calu 3细胞、MDA-MB-453、MDA-MB-361或SKOV3细胞。
术语“治疗(treat)”或“治疗(treatment)”均表示治疗学治疗和预防或阻止措施,其中目的是阻止或减慢(减轻)不希望的生理学改变或紊乱,如癌症的发展或蔓延。针对本发明的目的,有益的或所需的临床结果包括但不限于症状的减轻、疾病程度的减弱、疾病状况的稳定(即不恶化)、疾病进展的延迟或减缓、疾病状况的改善或缓和、以及症状缓解(无论是部分的还是全部的),无论是可检测的还是不可检测的。“治疗(Treatment)”还可以指与不接受治疗时所预期的存活相比较的延长的存活。需要治疗的患者包括那些已经患所述病症或紊乱的、以及容易患所述病症或紊乱的患者,或者要预防其病症或紊乱的那些患者。
“紊乱(disorder)”指将受益于本发明的治疗的任何病症。这包括慢性和急性紊乱或疾病,包括那些使哺乳动物易感染所述紊乱的病理学病症。此处所要治疗的紊乱的非限制性例子包括良性和恶性肿瘤;白血病和淋巴恶性疾病,特别是乳腺、卵巢、胃、子宫内膜、唾液腺、肺、肾、结肠、甲状腺、胰腺、前列腺或膀胱癌;神经元、神经胶质、星形细胞、下丘脑和其它腺体、巨噬细胞(macrophagal)、上皮、基质和囊胚(blastocoelic)紊乱;以及炎性、血管发生病症和免疫学病症。所要治疗的根据本发明的示例性紊乱为实体恶性肿瘤。
术语“治疗有效量”指有效治疗哺乳动物疾病或紊乱的药物的量。就癌症来说,药物的治疗有效量可以∶(i)减少癌细胞的数量;(ii)减小肿瘤大小;(iii)将癌细胞向外围器官中的浸润抑制、阻滞、减缓至一定程度并优选终止;(iv)抑制(即减缓至一定程度且优选停止)肿瘤转移;(v)抑制肿瘤生长;和/或(vi)将一种或多种与癌症有关的症状减轻至一定程度。达到药物能够阻止生长和/或杀死存在的癌细胞的程度时,其可能是细胞抑制和/或细胞毒性的。在动物模型中,可以通过施用ADC后的病程期间物理测量肿瘤,并通过测定肿瘤的部分和完全消退来评估功效。对于癌症治疗,例如可以通过评估疾病进展时间(time to disease progression)(TTP)和/或测定反应率(response rate)(RR)来测定功效。
术语"生物利用率"指施用到患者的给定量药物的系统可利用性(即,血液/血浆水平)。生物利用率为绝对性术语,指药物从施用的剂量型式到达体循环的时间(速率)和总量(程度)的测量值。
术语“癌症”和“癌症的”指或者描述典型地以无限制的细胞生长为特征的哺乳动物生理学病症。“肿瘤”包括一种或多种癌细胞。癌症的例子包括但不限于癌(carcinoma)、淋巴瘤、胚细胞瘤(blastoma)、肉瘤、和白血病或者淋巴恶性疾病。这种癌症的更具体的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”)、肺腺癌和肺鳞状细胞癌(squamous carcinoma)、腹膜癌、肝细胞癌、胃(gastric)或胃部(stomach)癌症,包括胃肠癌、胃肠基质肿瘤(gastrointestinal stromal tumor)(GIST)、胰腺癌、恶性胶质瘤(glioblastoma)、宫颈癌(cervical cancer)、卵巢癌、肝癌(livercancer)、膀胱癌、肝细胞瘤(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、肾脏或肾(kidney or renal)癌、前列腺癌、阴道癌、甲状腺癌、肝癌(hepatic carcinoma)、肛门癌、阴茎癌、以及头颈癌。
“表达ErbB的癌症”指包含在其细胞表面存在ErbB蛋白的细胞的癌症。“表达ErbB2的癌症”指在其细胞表面产生足够水平的ErbB2,因此抗ErbB2抗体能够与其结合并具有针对所述癌症的治疗学效果的癌症。
“过表达”受体例如ErbB受体的癌症指与相同组织类型的非癌细胞相比,在其细胞表面具有明显更高水平所述受体的癌症。这种过表达可以由基因增殖或增强的转录或翻译所致。ErbB受体过表达可以在诊断或预后测试中通过评估细胞表面上提高的ErbB蛋白水平来测定(例如,通过免疫组化测试;IHC)。或者,或除此之外,可以通过例如荧光原位杂交(FISH;参见WO 98/45479)、southern印迹、或聚合酶链式反应(PCR)技术如实时定量PCR(RT-PCR)测定细胞中编码ErbB的核酸的水平。ErbB配体的过表达可以在诊断学上通过评估患者中所述配体(或编码它的核酸)的水平来测定,例如,在肿瘤活组织检查中或者通过上述的多种诊断测试如IHC、FISH、southern印迹、PCR或体内测试。也可以通过测定生物流体如血清中的脱落抗原(例如,ErbB胞外结构域)来研究ErbB受体过表达(参见,例如,US 4933294;WO 91/05264;US 5401638;和Sias et al(1990)J.Immunol.Methods 132:73-80)。除了上述测试以外,熟练技术人员还可以采用多种其它体内测试。例如,可以将患者体内的细胞与抗体接触,所述抗体任选用可检测的标记,例如,放射性同位素标记过,可以评估抗体与患者细胞的结合,例如,通过放射性外部扫描,或者通过分析活组织切片,该活组织切片取自之前接触过所述抗体的患者。
通过对相应于每个细胞表达的HER2分子拷贝数进行免疫组化评分来为过表达HER2的肿瘤评定等级,并且可以进行生物化学测定∶0=0-10,000个拷贝/细胞,1+=至少约200,000拷贝/细胞,2+=至少约500,000拷贝/细胞,3+=约1-2x106拷贝/细胞。HER2以3+水平过表达导致酪氨酸激酶不依赖于配体的活化(Hudziak et al.,(1987)Proc.Natl.Acad.Sci.USA 84:7159-7163),发生在大约30%的乳腺癌中,并且在这些患者中,无复发存活期(relapse-free survival)和总体存活期(overal survival)减少(Slamon et al(1989)Science 244:707-712;Slamon et al(1987)Science,235:177-182)。相反,“不以ErbB2受体的过表达为特征的”癌症是在诊断测试中,与相同组织类型的非癌细胞相比,不表达高于正常水平的ErbB2受体的癌症。鼠单克隆抗HER2抗体抑制乳腺癌细胞系的生长,所述乳腺癌细胞系以2+和3+(每个细胞1-2x106HER2受体)水平过表达HER2,但对表达更低水平HER2的细胞没有活性(Lewis et al(1993)CancerImmunol.Immunother.37:255-263)。基于此观察结果,将抗体4D5人源化(huMAb4D5-8、rhuMAb HER2,US 5821337;Carter et al(1992)Proc.Natl.Acad.Sci.USA 89:4285-4289),并在乳腺癌患者体内测试,所述乳腺癌患者的肿瘤过表达HER2,但其在常规化疗后有进展(Cobleigh et al(1999)J.Clin.Oncol.17:2639-2648)。在此试验中,大多数患者肿瘤以3+水平表达HER2,而一部分为2+。
“不依赖于激素的”癌症为其增殖不取决于激素的存在的癌症,其中所述激素结合由癌细胞表达的受体。在实施减弱肿瘤内或肿瘤附近激素浓度的药理学或外科手术策略时,这样的癌症不经历临床退化作用(regression)。不依赖于激素的癌症的例子包括不依赖于雄激素的前列腺癌、不依赖于雌激素的乳腺癌、子宫内膜癌和卵巢癌。这样的癌症可以以激素依赖的肿瘤开始,并在抗激素治疗后从激素敏感性阶段发展到激素耐受性肿瘤。
此处所用术语“细胞毒性试剂”指抑制或者阻止细胞机能和/或导致细胞破坏的物质。所述术语将包括放射性同位素(例如211At、131I、125I、90Y、186Re、188Re、153Sm、212Bi、32P、60C、和Lu的放射性同位素)、化疗剂、以及毒素如小分子毒素或者细菌、真菌、植物或动物来源的酶学活性毒素,包括其合成类似物和衍生物。
"化疗剂"是用于癌症治疗的化合物。化疗剂的例子包括ErlotinibGenentech/OSI Pharm.)、BortezomibMillenium Pharm.)、氟维司群(Fulvestrant)Astrazeneca)、Sutent(SU11248,Pfizer)、来曲唑(letrozole)Novartis)、甲磺酸伊马替尼(Imatinib mesylate)Novartis)、PTK787/ZK222584(Novartis)、OxaliplatinSanofi)、5-FU(5-氟尿嘧啶)、甲酰四氢叶酸(leucovorin)、雷帕霉素(Rapamycin)(Sirolimus,Wyeth)、Lapatinib(GSK572016,GlaxoSmithKline)、Lonafarnib(SCH 66336)、Sorafenib(BAY43-9006,Bayer Labs.)、和GefitinibAstrazeneca)、AG1478、AG1571(SU 5271;Sugen),烷化剂,诸如噻替哌(thiotepa)和环磷酰胺(cyclophosphamide);磺酸烷基酯(alkyl sulfonate),诸如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶类,诸如苯佐替哌(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)、和乌瑞替哌(uredopa);乙撑亚胺类(ethylenimine)和甲基蜜胺类(methylamelamine),包括六甲蜜胺(altretamine)、三乙撑蜜胺(triethylenemelamine)、三乙撑磷酰胺(trietylenephosphoramide)、三乙撑硫化磷酰胺(triethiylenethiophosphoramide)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)(包括合成类似物拓扑替康(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(cryptophycin)(特别是隐藻素1和隐藻素8);多拉司他丁(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,诸如氯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、胆磷酰胺(cholophosphamide)、磷雌氮芥(estramustine)、异磷酰胺(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)、松龙苯芥(prednimustine)、三芥环磷酰胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);硝基脲类(nitrosurea),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(ranimnustine);抗生素类,诸如烯二炔类(enediyne)抗生素(如加利车霉素(calicheamicin),尤其是加利车霉素γ1I和加利车霉素ωI1(参阅如Agnew,Chem.Intl.Ed.Engl.33:183-186,1994));蒽环类抗生素(dynemicin),包括dynemicin A;二碳磷酸盐化合物(bisphosphonate),诸如氯膦酸盐(clodronate);埃斯波霉素(esperamicin);以及新抑癌菌素(neocarzinostatin)发色团和相关色蛋白烯二炔类抗生素发色团)、阿克拉霉素类(aclacinomysin)、放线菌素(actinomycin)、氨茴霉素(authramycin)、氮丝氨酸(azaserine)、博来霉素类(bleomycin)、放线菌素C(cactinomycin)、carabicin、洋红霉素(carminomycin)、嗜癌霉素(carzinophilin)、色霉素类(chromomycin)、更生霉素(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-氧-L-正亮氨酸、阿霉素(doxorubicin)(包括吗啉阿霉素、氰吗啉阿霉素、2-吡咯啉阿霉素和脱氧阿霉素)、表柔比星(epirubicin)、依索比星(esorubicin)、依达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素类(mitomycin)诸如丝裂霉素C、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素类(olivomycin)、培来霉素(peplomycin)、potfiromycin、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑霉素(streptonigrin)、链脲霉素(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,诸如甲氨蝶呤(methotrexate)和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸(denopterin)、甲氨蝶呤(methotrexate)、蝶酰三谷氨酸(pteropterin)、曲麦克特(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine)、6-巯基嘌呤、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物,诸如安西他滨(ancitabine)、氮杂胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷、脱氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素类,诸如卡鲁睾酮(calusterone)、羟甲雄酮丙酸酯(dromostanolonepropionate)、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)、曼托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸(frolinicacid);醋葡内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基酮戊酸;蒽尿嘧啶(eniluracil);氨苯吖啶(amsacrine);bestrabucil;比生群(bisantrene);依达曲沙(edatraxate);defofamine;秋水仙胺(demecolcine);地吖醌(diaziquone);elfornithine;醋酸羟哔咔唑(elliptiniumacetate);epothilone;环氧甘醚(etoglucid);硝酸镓;羟脲;蘑菇多糖(lentinan);氯尼达明(lonidainine);美登木素生物碱类(maytansinoid),诸如美登素(maytansine)和美坦西醇类(ansamitocin);丙米腙(mitoguazone);米托蒽醌(mitoxantrone);莫匹达谋(mopidanmol);nitraerine;喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);足叶草酸(podophyllinic acid);2-乙基酰肼;甲基苄肼(procarbazine);多糖复合物(JHS Natural Products,Eugene,OR);丙亚胺(razoxane);根霉素(rhizoxin);西作非兰(sizofiran);螺旋锗(spirogermanium);细格孢氮杂酸(tenuazonic acid);三亚胺醌(triaziquone);2,2',2"-三氯三乙胺;单端孢菌素类(trichothecene )(尤其是T-2毒素、verracurinA、杆孢菌素(roridin)A和蛇形菌素(anguidine));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(“Ara-C”);环磷酰胺;硫替哌;类紫杉醇类(taxoid),如紫杉醇(paclitaxel)(Bristol-Myers Squibb Oncology,Princeton,N.J.)、ABRAXANETM,紫杉醇不含克列莫佛(Cremophor)的清蛋白改造纳米颗粒剂型(American Pharmaceutical Partners,Schaumberg,Illinois)、和多西他塞(doxetaxel)Rorer,Antony,France);苯丁酸氮芥(chloranbucil);吉西他滨(gemcitabine);6-硫鸟嘌呤;巯基嘌呤;甲氨蝶呤;铂类似物,诸如顺铂和卡铂;长春碱(vinblastine);铂;依托泊苷(etoposide,VP-16);异磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);长春新碱(vincristine);长春瑞滨(vinorelbine);诺安托(novantrone);替尼泊苷(teniposide);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基蝶呤;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);类视黄醇(retinoids),诸如视黄酸;卡培他滨(capecitabine);及任何上述药剂的制药学可接受盐、酸或衍生物。
该定义“化疗剂”还包括(i)起调节或抑制激素对肿瘤作用的抗激素药,诸如抗雌激素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、曲奥昔芬(trioxifene)、那洛昔芬(keoxifene)、LY117018、奥那斯酮(onapristone)、和托瑞米芬(toremifene);(ii)抑制在肾上腺中调节雌激素生成的芳化酶的芳化酶(aromatase)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)、福美司坦(formestanie)、法倔唑(fadrozole)、伏罗唑(vorozole)、来曲唑(letrozole)、和阿纳托唑(anastrozole);(iii)抗雄激素,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)芳化酶抑制剂;(v)蛋白激酶抑制剂;(vi)脂质激酶抑制剂;(vii)反义寡核苷酸,特别是抑制涉及异常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(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)抗血管新生剂如贝伐单抗(bevacizumab)Genentech);以及(xi)上述任一种的药学上可接受的盐、酸或衍生物。
蛋白激酶抑制剂包括酪氨酸激酶抑制剂,其在某种程度上抑制酪氨酸激酶如ErbB受体的酪氨酸激酶活性。酪氨酸激酶抑制剂的例子包括EGFR-靶向药物如∶(i)结合EGFR的抗体,包括MAb 579(ATCC CRL HB 8506)、MAb455(ATCC CRL HB8507)、MAb 225(ATCC CRL 8508)、MAb 528(ATCC CRL8509)(参见,US 4943533、Mendelsohn et al.)及其变体,如嵌合化的225(C225或Cetuximab;Imclone)和重整型(reshaped)人225(H225)(WO96/40210,Imclone Systems Inc.);结合II型突变EGFR的抗体(US 5212290);结合EGFR的人源化和嵌合抗体(US 5891996);和结合EGFR的人抗体,如ABX-EGF(WO 98/50433);(ii)与细胞毒性试剂偶联的抗EGFR抗体(EP659439A2);和结合EGFR的小分子包括ZD1839或Gefitinib(IRESSATM;AstraZeneca)、Erlotinib HCl(CP-358774,TARCEVATM;Genentech/OSI)和AG1478,AG1571(SU 5271;Sugen),喹唑啉如PD 153035、4-(3-氯代苯胺)喹唑啉(4-(3-chloroanilino)quinazoline)、吡啶并嘧啶(pyridopyrimidines)、pyrimidopyrimidines、吡咯并嘧啶(pyrrolopyrimidines)、如CGP 59326、CGP60261和CGP 62706、以及吡唑基嘧啶(pyrazolopyrimidine)、4-(苯氨基)-7H-吡咯并[2,3-d]嘧啶(4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines)、姜黄素curcumin(二阿魏酰甲烷(diferuloyl methane)、4,5-二(4-氟代苯胺)酞酰亚胺)(4,5-bis(4-fluoroanilino)phthalimide)、含硝基噻吩(nitrothiophene)部分的tyrphostines;PD-0183805(Warner-Lambert);反义分子(例如,与ErbB-编码核酸结合的那些);喹噁啉(quinoxalines)(US 5804396);tryphostins(US5804396);ZD6474(Astra Zeneca);PTK-787(Novartis/Schering AG);pan-ErbB抑制剂如CI-1033(Pzer);Affinitac(ISIS 3521;Isis/Lilly);甲磺酸伊马替尼(Imatinib mesylate)(Gleevac;Novartis);PKI 166(Novartis);GW2016(GlaxoSmithKline);CI-1033(Pfizer);EKB-569(Wyeth);Semaxanib(Sugen);ZD6474(AstraZeneca);PTK-787(Novartis/Schering AG);INC-1C 11(Imclone);或者如US5804396;WO99/09016(American Cyanamid);WO98/43960(American Cyanamid);WO 97/38983(Warner Lambert);WO99/06378(Warner Lambert);WO 99/06396(Warner Lambert);WO96/30347(Pfizer,Inc);WO 96/33978(Zeneca);WO 96/3397(Zeneca);和WO96/33980(Zeneca)中所述的。
“抗血管新生剂”指在某种程度上阻断、或干扰血管发育的化合物。抗血管新生因子可以为例如结合生长因子或生长因子受体的小分子或抗体,所述生长因子或生长因子受体涉及促进血管新生。示例性抗血管新生剂为结合血管内皮生长因子(VEGF)的抗体如贝伐单抗(bevacizumab)Genentech)。
术语“细胞因子”是由一种细胞群体释放的蛋白质的通称,其作为细胞间介导物作用于另一种细胞。这种细胞因子的例子为淋巴因子、单核因子、和传统多肽激素。包括于所述细胞因子的是生长激素如人生长激素、N-蛋氨酰人生长激素(N-methionyl human growth hormone)、和牛生长激素;甲状旁腺激素;甲状腺素(thyroxine);胰岛素;胰岛素原;松弛素(relaxin);松弛素原(prorelaxin);糖蛋白激素如促卵泡素(follicle stimulating hormone)(FSH)、促甲状腺激素(thyroid stimulating hormone)(TSH)、和促黄体生成素(luteinizinghormone)(LH);肝生长因子;成纤维细胞生长因子;催乳素;胎盘催乳素;肿瘤坏死因子-α和-β;苗勒-抑制物质(mullerian-inhibiting substance);小鼠促性腺激素相关肽(mouse gonadotropin-associated peptide);抑制素(inhibin);活化素(activin);血管内皮生长因子;整联蛋白;促血小板生成素(thrombopoietin)(TPO);神经生长因子如NGF-β;血小板生长因子;转化生长因子(TGFs)如TGF-α和TGF-β;胰岛素样生长因子-I和-II;促红细胞生成素(EPO);成骨诱导因子(osteoinductive factors);干扰素如干扰素-α、-β、和-γ;集落刺激因子(CSFs)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(ILs)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;肿瘤坏死因子如TNF-α或TNF-β;以及其它多肽因子包括LIF和kit配体(kit ligand)(KL)。本文所用术语细胞因子包括天然来源的或来自重组细胞培养物的蛋白质和天然序列细胞因子的生物学活性等价物。
本申请所用术语“前药(prodrug)”指药学活性物质的前体或衍生形式,其与亲本药物相比对肿瘤细胞的细胞毒性较低,能够通过酶作用活化或者转变为更具活性的亲本形式。参见,例如,Wilman,“Prodrugs in CancerChemotherapy”Biochemical Society Transactions,14,pp.375-382,615thMeeting Belfast(1986)和Stella et al.,“Prodrugs:A Chemical Approach toTargeted Drug Delivery,”Directed Drug Delivery,Borchardt et al.,(ed.),pp.247-267,Humana Press(1985)。本发明的前药包括但不限于含磷酸盐(酯)前药、含硫代磷酸盐(酯)前药、含硫酸盐(酯)前药、含肽前药、D-氨基酸修饰的前药、糖基化前药、含β-内酰胺的前药、含任选取代的苯氧乙酰胺(phenoxyacetamide)的前药或含任选取代的苯乙酰胺(phenylacetamide)的前药、5-氟胞嘧啶和能够转化为更具活性的细胞毒性游离药物的其它5-氟尿苷前药。可以衍生为前药形式而用于本发明的细胞毒性药物的例子包括但不限于上述的那些化疗剂。
“脂质体”是由可用于将药物(如本文的公开的抗ErbB2抗体和任选化疗剂)递送至哺乳动物的多种类型的脂质、磷脂和/或表面活性剂组成的囊泡状物。脂质体的成分通常排列于双层结构中,类似于生物膜的脂质排列。
术语“包装说明书”用于指习惯上包括在治疗产品商业包装中的说明书,其包含有关适应症、用法、用量、服药方法、禁忌的信息和/或涉及此治疗产品使用的警告。
“心脏保护剂”指阻止或减弱心肌机能障碍(心肌病和/或充血性心力衰竭)的化合物或组合物,所述心肌机能障碍与为患者施用药物如蒽环类(anthracycline)抗生素和/或抗ErbB2抗体有关。所述心脏保护剂可以例如阻断或减弱自由基介导的心脏中毒效应和/或阻止或减弱氧化应激损伤。本定义所包含的心脏保护剂的例子包括铁螯合剂右雷佐生(dexrazoxane)(ICRF-187)(Seifert et al.,The Annals of Pharmacotherapy,28:1063-1072(1994));降脂质剂和/或抗氧化剂如普罗布考(probucol)(Singal etal.,J.Mol.Cell Cardiol.,27:1055-1063(1995));氨磷汀(氨基硫醇2-[(3-氨基丙基)氨基]乙硫醇-二氢磷酸酯(amifostine(aminothiol2-[(3-aminopropyl)amino]ethanethiol-dihydrogen phosphate ester),也称为WR-2721及其称为WR-1065的去磷酸细胞吸收形式)和S-3-(3-甲基氨丙基氨基)丙基硫代磷酸(S-3-(3-methylaminopropylamino)propylphosphorothioicacid),(WR-151327),参见Green et al.,(1994)Cancer Research,54:738-741;地高辛(digoxin)(Bristow,M.R.ed.(1980)Drug-Induced Heart Disease.NewYork:Elsevier 191-215);beta-阻断剂如美托洛尔(metoprolol)(Hjalmarsonet al(1994)Drugs 47:Suppl 4:31-9;和Shaddy et al(1995)Am.Heart J.,129:197-9);维生素E;抗坏血酸(维生素C);自由基清除剂如齐墩果酸(oleanolic acid)、熊果酸(ursolic acid)和N-乙酰半胱氨酸(NAC);旋转截留(spin trapping)化合物如α-苯基-叔丁基硝酮(alpha-phenyl-tert-butyl nitrone)(PBN)(Paracchini et al(1993)Anticancer Res.,13:1607-1612);硒化有机化合物(selenoorganic compounds)如P251(Elbesen);等等。
“分离的”核酸分子指由至少一种污染的核酸分子鉴定和分离的核酸分子,天然来源的抗体核酸中通常与其有关。分离的核酸分子指非自然界中发现的形式或组成的核酸分子。因此分离的核酸分子指不同于天然细胞中存在的核酸分子。然而,分离的核酸分子包括通常表达抗体的细胞中包含的核酸分子,例如,在所述细胞中,所述核酸分子处于与天然细胞不同的染色体位置。
"烷基"指C1-C18碳氢化合物,包含正、仲、叔或环碳原子。烷基的例子包括C1-C8碳氢化合物部分,例如但不限于∶甲基(Me,-CH3),乙基(Et,-CH2CH3),1-丙基(n-Pr,n-丙基,-CH2CH2CH3),2-丙基(i-Pr,i-丙基,-CH(CH3)2),1-丁基(n-Bu,n-丁基,-CH2CH2CH2CH3),2-甲基-1-丙基(i-Bu,i-丁基,-CH2CH(CH3)2),2-丁基(s-Bu,s-丁基,-CH(CH3)CH2CH3),2-甲基-2-丙基(t-Bu,t-丁基,-C(CH3)3),1-戊基(n-戊基,-CH2CH2CH2CH2CH3),2-戊基(-CH(CH3)CH2CH2CH3),3-戊基(-CH(CH2CH3)2),2-甲基-2-丁基(-C(CH3)2CH2CH3),3-甲基-2-丁基(-CH(CH3)CH(CH3)2),3-甲基-1-丁基(-CH2CH2CH(CH3)2),2-甲基-1-丁基(-CH2CH(CH3)CH2CH3),1-己基(-CH2CH2CH2CH2CH2CH3),2-己基(-CH(CH3)CH2CH2CH2CH3),3-己基(-CH(CH2CH3)(CH2CH2CH3)),2-甲基-2-戊基(-C(CH3)2CH2CH2CH3),3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3),4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2),3-甲基-3-戊基(-C(CH3)(CH2CH3)2),2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2),2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2),3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3。
“链烯基(alkenyl)”指C2-C18碳氢化合物,包含正、仲、叔或环碳原子,具有至少一个不饱和位点,即碳-碳sp2双键。链烯基的例子包括C2-C8碳氢化合物部分例如但不限于:乙烯或乙烯基(-CH=CH2)、烯丙基(-CH2CH=CH2)、环戊烯基(-C5H7)、和5-己烯基(-CH2CH2CH2CH2CH=CH2)。
“炔基(alkynyl)”指C2-C18碳氢化合物,包含正、仲、叔或环碳原子,具有至少一个不饱和位点,即碳-碳sp三键。炔基的例子包括C2-C8碳氢化合物部分例如但不限于:乙炔(-C≡CH)和炔丙基(-CH2C≡CH)。
“亚烷基(Alkylene)”指1-18个碳原子的饱和、支链或直链或环状碳氢化合物基团,并且具有两个单价基团中心,所述单价基团中心通过从亲本烷烃的同一个或两个不同碳原子去除两个氢原子而衍生得到。典型的亚烷基包括C1-C8碳氢化合物部分例如但不限于:亚甲基(-CH2-)1,2-乙基(-CH2CH2-)、1,3-丙基(-CH2CH2CH2-)、1,4-丁基(-CH2CH2CH2CH2-)等等。
“亚链烯基(alkenylene)”指2-18个碳原子的不饱和、支链或直链或环状碳氢化合物基团,并且具有两个单价基团中心,所述单价基团中心通过从亲本烯的同一个或两个不同碳原子去除两个氢原子而衍生得到。典型的亚链烯基包括C2-C8碳氢化合物部分例如但不限于∶1,2-乙烯(-CH(CH-)。
“亚炔基(Alkynylene)”指2-18个碳原子的不饱和、支链或直链或环状碳氢化合物基团,并且具有两个单价基团中心,所述单价基团中心通过从亲本炔的同一个或两个不同碳原子去除两个氢原子而衍生得到。典型的亚炔基包括C2-C8碳氢化合物部分例如但不限于:乙炔(-C≡C-)、炔丙基(-CH2C≡C-)、和4-戊炔基(-CH2CH2CH2C≡C-)。
单独或组合的"芳基"指6-20个碳原子的单价芳烃基团,其通过从亲本芳香环系统的单个碳原子去除一个氢原子而衍生得到。芳基可以包含一个、两个或三个环,其中这种环可以悬挂(pendent)方式附着在一起,例如联苯,或可以是稠合的,例如萘或蒽。一些芳烃基团以“Ar”的示例性结构表示。典型的芳烃基团包括C6-C12碳氢化合物部分例如但不限于源于苯、取代苯、萘、蒽、联苯等等的基团。
"芳烷基(arylalkyl)"指非环状烷基,其中与碳原子,典型地与末端或sp3碳原子键合的一个氢原子被芳基所置换。典型的芳烷基包括但不限于苄基、2-苯基乙烷-1-基、2-苯乙烯-1-基、萘甲基、2-萘乙烷-1-基、2-萘乙炔-1-基、萘苯基(naphthobenzyl)、2-萘苯乙烷-1-基(2-naphthophenylethan-1-yl)等等。芳烷基包含6至20个碳原子,例如芳烷基的烷基部分包括1至6个碳原子的烷酰基(alkanyl)、链烯基或炔基,芳基部分为5至14个碳原子。
"芳杂环烷基(heteroarylalkyl)"指非环状烷基,其中与碳原子,典型地与末端或sp3碳原子键合的一个氢原子被芳杂环所置换。典型的芳杂环烷基包括但不限于2-苯并咪唑亚甲基(2-benzimidazolylmethyl)、2-呋喃乙基等等。芳杂环烷基包含6至20个碳原子,例如芳杂环烷基的烷基部分包括1至6个碳原子的alkanyl、链烯基或炔基,芳杂环部分为5至14个碳原子,并且1至3个杂原子选自N、O、P、和S。芳杂环烷基的芳杂环部分可以是具有3至7个环成员的单环(2至6个碳原子)或者具有7至10个环成员的二环(4至9个碳原子,和选自N、O、P、和S的1至3个杂原子),例如∶二环[4,5]、[5,5]、[5,6]、或[6,6]系统。
烷基、烯烃基、芳基、芳烷基、和芳杂环烷基可以被取代,其中一个或多个氢原子分别独立地被取代基所置换。典型的取代基包括但不限于-X、-R、-O-、-OR、-SR、-S-、-NR2、-NR3、=NR、-CX3、-CN、-OCN、-SCN、-N=C=O、-NCS、-NO、-NO2、=N2、-N3、-NC(=O)R、-C(=O)R、-C(=O)NR2、-SO3 -、-SO3H、-S(=O)2R、-OS(=O)2OR、-S(=O)2NR、-S(=O)R、-OP(=O)(OR)2、-P(=O)(OR)2、-PO- 3、-PO3H2、-C(=O)R、-C(=O)X、-C(=S)R、-CO2R、-CO2 -、-C(=S)OR、-C(=O)SR、-C(=S)SR、-C(=O)NR2、-C(=S)NR2、-C(=NR)NR2,其中每个X独立地为卤素:F、Cl、Br、或I;每个R独立地为H、C1-C18烷基、C6-C20芳基、C3-C14杂环保护基或前药部分。上述烯烃基、亚烷基、和亚炔基也同样可以被取代。
“芳杂环”也称为杂环或杂环基(heterocyclyl)指环状系统基团,其中一个或多个环原子是杂原子,例如氮、氧、和硫。芳杂环基团包含5至14个碳原子和1至3个选自N、O、P、和S的杂原子。芳杂环烷基的芳杂环部分可以是具有3至7个环成员的单环(2至6个碳原子和选自N、O、P和S的1至3个杂原子)或者具有7至10个环成员的二环(4至9个碳原子,和选自N、O、P、和S的1至3个杂原子),例如∶二环[4,5]、[5,5]、[5,6]、或[6,6]系统。芳杂环化合物描述于Paquette,Leo A.;"Principles of Modern HeterocyclicChemistry"(W.A.Benjamin,NewYork,1968),特别是第1、3、4、6、7、和9章;"The Chemistry of Heterocyclic Compounds,A series of Monographs"(JohnWiley&Sons,New York,1950至今),特别是第13、14、16、19、和28卷;以及J.Am.Chem.Soc.(1960)82:5566。
“接头”或“连接”指包含将抗体共价连接于药物部分的共价键或原子链的化学部分。在许多实施方案中,接头以L表示。接头包括二价基团如烯烃基、亚芳基、杂环亚芳基(heteroarylene),诸如∶-(CR2)nO(CR2)n-、烷氧基(例如聚乙烯氧、PEG、聚亚甲基氧)和烷氨基(例如聚乙烯氨、JeffamineTM)的重复单元;以及二酸酯和酰胺,包括琥珀酸酯、琥珀酰胺、二乙醇酸酯、丙二酸酯、和己酰胺。
术语"手性"分子指具有镜像伴侣不能重叠(superimposability)特性的分子,而术语"非手性的"分子指镜像伴侣可重叠(superimposable)的分子。
术语"立体异构体"指具有相同化学组成,但在原子或基团空间排列上有所不同的化合物。
"非对应异构体"指具有两个或多个手性中心,并且其分子彼此不为镜像的立体异构体。非对应异构体具有不同的物理特性,例如熔点、沸点、光谱特性、和反应性。非对应异构体的混合物可以在高分辨率分析方法如电泳和层析下分离。
"对映异构体"指彼此为不重叠镜像的化合物的两个立体异构体。
本文所用立体化学定义和惯例一般按照S.P.Parker,Ed.,McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company,N ew York;and Eliel,E.and Wilen,S.,Stereochemistry of Organic Compounds(1994)JohnWiley&Sons,Inc.,New York。许多有机化合物以旋光活性形式存在,即它们具有旋转平面偏振光平面的能力。在描述旋光活性化合物中,前缀D和L、或R和S用于表示有关其手性中心的分子的绝对构型。前缀d和l或(+)和(-)用于指明由所述化合物引起的平面偏振光的旋转方向,(-)或l指化合物是左旋的。加前缀(+)或d的化合物是右旋的。对于给定化学结构,除了他们彼此为镜像之外,这些立体异构体是相同的。特定立体异构体也可称为对映体,这种异构体的混合物通常称为对映体混合物。50:50的对映体混合物称为外消旋混合物或外消旋物,其可以在一直没有立体选择性或立体特异性的化学反应或进程中发生。术语"外消旋混合物"和"外消旋物"指两类对映体的等摩尔混合物,其缺少旋光活性。
本文所用短语“药学上可接受的盐,”指ADC的药学上可接受的有机或无机盐。示例性盐包括但不限于硫酸、柠檬酸、醋酸、草酸、氯化物、溴化物、碘化物、硝酸、酸式硫酸盐、磷酸、酸式磷酸、异烟酸、乳酸、水杨酸、酸性柠檬酸、酒石酸、油酸、鞣酸、泛酸、洒石酸氢盐、抗坏血酸、琥珀酸、马来酸、gentisinate、延胡索酸、葡糖酸、葡糖醛酸、糖酸、甲酸、苯甲酸、谷氨酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、和双羟萘酸(即1,1’-亚甲基-双-(2-羟-3-萘甲酸))盐。药学上可接受的盐可以涉及包含另一种分子如醋酸离子、琥珀酸离子或其它反荷离子。所述反荷离子可以为稳定母体化合物上的电荷的任何有机或无机部分。另外,药学上可接受的盐在其结构中可以具有超过一个带电原子。其中多电荷原子为药学上可接受盐的一部分的例子可能具有多个反荷离子。因此,药学上可接受的盐可能具有一个或多个带电原子和/或一个或多个反荷离子。
“药学上可接受的溶剂化物”指一个或多个溶剂分子与ADC的结合。形成药学上可接受的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、醋酸、和乙醇胺。
抗体-药物偶联物
本发明的化合物包括具有抗癌活性效用的那些化合物。特别是,所述化合物包括偶联的即通过接头共价连接于药物部分的抗体,其中所述药物不偶联于抗体时具有细胞毒性或细胞抑制效应。这样,通过偶联于抗体所述药物部分的生物学活性得到调节。本发明的抗体-药物偶联物(ADC)可以选择性地将有效量的细胞毒性试剂递送到肿瘤组织,由此可以获得更强的选择性,即以较低剂量即可达到期望的功效。
在一个实施方案中,与仅有相应的美登木素生物碱化合物相比,哺乳动物中ADC或者ADC的胞内代谢物的生物利用率提高。同时,与仅有相应的抗体(ADC的抗体,无药物部分或接头)相比,哺乳动物中ADC或者ADC的胞内代谢物的生物利用率提高。
在一个实施方案中,ADC的美登木素生物碱药物部分直到抗体-药物偶联物结合到细胞表面受体或进入细胞时才从抗体裂解,其中所述细胞具有抗体-药物偶联物的抗体特异的细胞表面受体。在抗体-药物偶联物进入所述细胞后,药物部分可以从所述抗体裂解。在哺乳动物体内,美登木素生物碱药物部分可以通过酶学作用、水解、氧化、或其它机制,在细胞内从所述化合物或所述化合物的胞内代谢物的抗体裂解。例如,同时决不意味着将本发明限制于特定的作用机理,ADC的美登木素生物碱药物部分的硫原子可以氧化为砜或亚砜基团。在细胞内,结合到砜和亚砜的碳上的质子可以在一般催化作用或酶学催化作用下去除,并引起beta-消除碎裂作用,该碎裂作用从ADC的抗体裂解并分离药物部分。或者,接头中的其它吸电子基团如酰胺、抗体或药物部分能够在细胞内引起类似的碎裂/裂解机制。
抗体-药物偶联物(ADC)可以用式I表示∶
Ab-(L-D)p I
或其药学上可接受的盐或溶剂化物,其中∶
Ab为结合ErbB受体,或者结合一种或多种肿瘤相关抗原或细胞表面受体的抗体,所述细胞表面受体选自(1)-(36)∶
(1)BMPR1B(骨形态发生蛋白受体(bone morphogenetic proteinreceptor)-IB型,Genbank登录号NM_001203);
(2)E16(LAT1,SLC7A5,Genbank登录号NM_003486);
(3)STEAP1(前列腺六次跨膜上皮抗原(six transmembrane epithelialantigen),Genbank登录号NM_012449);
(4)0772P(CA125、MUC16、Genbank登录号AF361486);
(5)MPF(MPF、MSLN、SMR、巨核细胞强化因子(megakaryocytepotentiating factor)、mesothelin,Genbank登录号NM_005823);
(6)Napi3b(NAPI-3B、NPTIIb、SLC34A2,溶解物载体家族(solute carrierfamily)34(磷酸钠),成员2,II型钠依赖的磷酸盐转运蛋白(sodium-dependentphosphate transporter)3b,Genbank登录号NM_006424);
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、脑信号蛋白(Semaphorin)5b Hlog,sema结构域,七个血小板反应蛋白重复(seven thrombospondin repeats)(1型和类1型的),跨膜结构域(TM)和短的细胞质结构域,(脑信号蛋白)5B,Genbank登录号AB040878);
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA2700050C12、RIKEN cDNA 2700050C12基因,Genbank登录号AY358628);
(9)ETBR(内皮素(Endothelin)B型受体,Genbank登录号AY275463);
(10)MSG783(RNF124、假想蛋白(hypothetical protein)FLJ20315,Genbank登录号NM_017763);
(11)STEAP2(HGNC_8639、IPCA-1、PCANAP1、STAMP1、STEAP2、STMP、前列腺癌相关基因1、前列腺癌相关蛋白1、前列腺的六次跨膜上皮抗原2、六次跨膜前列腺蛋白(six transmembrane prostate protein),Genbank登录号AF455138);
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、瞬时受体潜在阳离子通道(transient receptor potential cation channel)、亚家族M(subfamily M),成员4(member 4),Genbank登录号NM_017636);
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1,畸胎癌衍生生长因子(teratocarcinoma-derived growth factor),Genbank登录号NP_003203或NM_003212);
(14)CD21(CR2(补体受体2)或C3DR(C3d/埃巴病毒(Epstein Barr virus)受体)或Hs.73792Genbank登录号M26004);
(15)CD79b(CD79B、CD79β、IGb(免疫球蛋白相关beta(immuneoglobulin-associated beta)、B29,Genbank登录号NM_000626);
(16)FcRH2(IFGP4、IRTA4、SPAP1A(含SH2结构域的磷酸酶锚定蛋白(phosphatase anchor protein)1a)、SPAP 1B、SPAP 1C,Genbank登录号NM_030764);
(17)HER2(Genbank登录号M11730);
(18)NCA(Genbank登录号M18728);
(19)MDP(Genbank登录号BC017023);
(20)IL20Rα(Genbank登录号AF184971);
(21)Brevican(Genbank登录号AF229053);
(22)EphB2R(Genbank登录号NM_004442);
(23)ASLG659(Genbank登录号AX092328);
(24)PSCA(Genbank登录号AJ297436);
(25)GEDA(Genbank登录号AY260763;
(26)BAFF-R(B细胞活化因子受体、BlyS受体3、BR3,NP_443177.1);
(27)CD22(B细胞受体CD22-B同种型(isoform),NP-001762.1);
(28)CD79a(CD79A、CD79α、免疫球蛋白相关alpha(immuneoglobulin-associated alpha),与Ig beta(CD79B)共价相互作用并在表面上与Ig M分子形成复合体,转导涉及B细胞分化的信号的B细胞特异性蛋白,Genbank登录号NP_001774.1);
(29)CXCR5(伯基特氏(Burkitt's)淋巴瘤受体1,被CXCL13趋化因子活化的G蛋白偶联受体,在淋巴细胞迁移和体液防御中发挥作用,在HIV-2感染以及可能在AIDS、淋巴瘤、骨髓瘤、和白血病中发挥作用,Genbank登录号NP_001707.1);
(30)HLA-DOB(MHC II类分子的Beta亚基(Ia抗原),其结合肽并将其呈递到CD4+T淋巴细胞,Genbank登录号NP_002111.1);
(31)P2X5(嘌呤受体(purinergic receptor)P2X配体门控离子通道(ligand-gated ion channel)5,由胞外ATP门控的离子通道,可能涉及突触传递和神经新生,其缺陷可能导致特发性逼尿肌不稳定的病理生理状况(pathophysilolgy of idiopathic detrusor instability),Genbank登录号NP_002552.2);
(32)CD72(B细胞分化抗原CD72、Lyb-2,Genbank登录号NP_001773.1);
(33)LY64(淋巴细胞抗原64(RP105),富含亮氨酸重复的I型膜蛋白(LRR)家族,调节B细胞活化和凋亡,功能的丧失与系统性红斑狼疮患者疾病活动增强有关,Genbank登录号NP_005573.1);
(34)FcRH1(Fc受体样蛋白1,推定的免疫球蛋白Fc结构域受体,包含C2型Ig样和ITAM结构域,可能在B淋巴细胞分化中起作用,Genbank登录号NP_443170.1);
(35)IRTA2(易位(translocation)相关免疫球蛋白超家族受体2,推定的免疫受体,可能在B细胞发育和淋巴瘤产生中起作用;由易位导致的基因失调发生于一些B细胞恶性病中,Genbank登录号NP_112571.1);以及
(36)TENB2(推定的跨膜蛋白聚糖,与生长因子的EGF/调蛋白(heregulin)家族和卵泡抑素(follistatin)相关,Genbank登录号AF179274;
条件是所述抗体不是TA.1。
L为非二硫化物接头。L包括但不限于结构∶
其中波浪线表示与Ab和D的共价连接;
X为:
Y为:
R独立地为H或C1-C6烷基;且n为1至12;
D为美登木素生物碱药物部分。美登木素生物碱包括但不限于结构∶
其中波浪线表示与L的共价连接;
R独立地为H或C1-C6烷基;并且
M为1、2、或3。
药物与抗体的比例或药物负载以式I化合物的p表示。药物负载值p为1至8。式I化合物包括不同负载并连接的抗体-药物偶联物的所有混合物,其中1、2、3、4、5、6、7、和8个药物部分共价连接于所述抗体。
在另一实施方案中,Ab为结合一种或多种肿瘤相关抗原或细胞表面受体的抗体,所述肿瘤相关抗原或细胞表面受体选自(1)-(16)和(18)-(36),即不结合ErbB受体,包括HER2。
抗体
在其范围内,式I的抗体单位(Ab-)包括与受体、抗原或其它接受性部分结合或反应性相关或复合的任何抗体单位,所述受体、抗原或其它接受性部分与给定目标细胞群相关。抗体可以是任何的蛋白或蛋白样分子,其与所要治疗学或生物学修饰的细胞群体部分结合、复合、或反应。一个方面,抗体单位发挥作用将美登木素生物碱药物部分递送到抗体单位与其反应的特定目标细胞群。这样的抗体包括但不限于大分子量蛋白如全长抗体和抗体片段。
包含本发明的抗体-药物偶联物的抗体优选保留其天然、野生型相应物的抗原结合能力。如此,本发明的抗体能够结合抗原,优选特异性地结合。这样的抗原包括例如肿瘤相关抗原(TAA)、细胞表面受体蛋白和其它细胞表面分子、细胞存活调节因子、细胞增殖调节因子、与组织发育或分化相关(例如,已知或怀疑在功能上有助于组织发育或分化)的分子、淋巴因子、细胞因子、涉及细胞周期调节的分子、涉及血管发生的分子和与血管新生相关的(例如,已知或怀疑在功能上有助于血管发生的)分子。肿瘤相关抗原可以是分化簇因子(即,CD蛋白)。本发明的抗体能够与其结合的抗原可以是上述类别之一的亚组的成员,其中所述类别的其它亚组包含具有区别特征(相对于感兴趣的抗原而言)的其它分子/抗原。
在一个实施方案中,抗体-药物偶联物(ADC)的抗体特异地结合由ErbB基因编码的受体。所述抗体可以特异地结合选自EGFR、HER2、HER3和HER4的ErbB受体。ADC可以特异地结合HER2的胞外结构域(ECD)并抑制过表达HER2受体的肿瘤细胞的生长。ADC的抗体可以为单克隆抗体,例如鼠单克隆抗体、嵌合抗体、或人源化抗体。人源化抗体可以是huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7或huMAb4D5-8(曲妥单抗)。所述抗体可以是抗体片段,例如Fab片段。
式I的抗体-药物偶联物(ADC)中的并且能够用于癌症治疗的抗体包括但不限于抗细胞表面受体和肿瘤相关抗原(TAA)的抗体。这样的肿瘤相关抗原是本领域已知的,可以用本领域熟知的方法和信息制备以用于生产抗体。在寻找用于癌症诊断和治疗的有效细胞靶物的努力中,研究者已设法鉴定了跨膜或肿瘤相关多肽,与一种或多种正常非癌细胞相比,这些多肽特异地表达于一种或多种特定类型癌细胞的表面上。通常,与非癌细胞的表面上相比,这些肿瘤相关多肽更多地表达在癌细胞表面上。鉴定这些肿瘤相关细胞表面抗原多肽已产生了通过基于抗体治疗的特异地靶向癌细胞进行破坏的能力。
TAA的例子包括但不限于以下所列肿瘤相关抗原(1)-(36)。为方便起见,以下列出有关这些抗原的所有本领域已知的信息,包括名称、替代名称、Genbank登录号和原始参考,遵循国家生物技术信息中心(NCBI)的核酸和蛋白质序列鉴别惯例。对应于TAA(1)-(36)的核酸和蛋白质序列可以在公共数据库如GenBank中获得。抗体靶向的肿瘤相关抗原包括相对于引证参考文献中鉴定的序列,拥有至少约70%、80%、85%、90%、或95%序列同一性的所有氨基酸序列变体和同种型,或者基本上显示与TAA相同的生物学特性或特征的所有氨基酸序列变体和同种型,其中所述TAA具有引证参考文献中发现的序列。例如,具有通常能够特异地结合抗体的变体序列的TAA,所述抗体特异地结合具有所列相应序列的TAA。本文特别引用的参考文献中的序列和内容特别加入作为参考。
肿瘤相关抗原(1)-(36)∶
(1)BMPR1B(骨形态发生蛋白受体-IB型,Genbank登录号NM_001203)
ten Dijke,P.,et al Science 264(5155):101-104(1994),Oncogene14(11):1377-1382(1997));WO2004063362(权利要求2);WO2003042661(权利要求12);US2003134790-A1(第38-39页);WO2002102235(权利要求13;第296页);WO2003055443(第91-92页);WO200299122(实施例2;第528-530页);WO2003029421(权利要求6);WO2003024392(权利要求2;图112);WO200298358(权利要求1;第183页);WO200254940(第100-101页);WO200259377(第349-350页);WO200230268(权利要求27;第376页);WO200148204(实施例;图4)
NP 001194骨形态发生蛋白受体,IB/pid型=NP_001194.1-
交叉参考:MIM:603248;NP_001194.1;AY065994
(2)E16(LAT1、SLC7A5,Genbank登录号NM_003486)
Biochem.Biophys.Res.Commun.255(2),283-288(1999),Nature395(6699):288-291(1998),Gaugitsch,H.W.,et al(1992)J.Biol.Chem.267(16):11267-11273);WO2004048938(实施例2);WO2004032842(实施例IV);WO2003042661(权利要求12);WO2003016475(权利要求1);WO200278524(实施例2);WO200299074(权利要求19;第127-129页);WO200286443(权利要求27;第222、393页);WO2003003906(权利要求10;第293页);WO200264798(权利要求33;第93-95页);WO200014228(权利要求5;第133-136页);US2003224454(图3);WO2003025138(权利要求12;第150页);US20050107595;US20050106644;
NP_003477溶解物载体家族7(阳离子氨基酸转运蛋白,y+系统),成员5/pid=NP_003477.3-人(Homo Sapiens)
交叉参考:MIM:600182;NP_003477.3;NM_015923;NM_003486_1
(3)STEAP1(前列腺的六次跨膜上皮抗原,Genbank登录号NM_012449)
Cancer Res.61(15),5857-5860(2001),Hubert,R.S.,et al(1999)Proc.Natl.Acad.Sci.U.S.A.96(25):14523-14528);WO2004065577(权利要求6);WO2004027049(图1L);EP1394274(实施例11);WO2004016225(权利要求2);WO2003042661(权利要求12);US2003157089(实施例5);US2003185830(实施例5);US2003064397(图2);WO200289747(实施例5;第618-619页);WO2003022995(实施例9;图13A,实施例53;第173页,实施例2;图2A);
NP_036581前列腺的六次跨膜上皮抗原
交叉参考:MIM:604415;NP_036581.1;NM_012449_1
(4)0772P(CA125、MUC16,Genbank登录号AF361486)
J.Biol.Chem.276(29):27371-27375(2001));WO2004045553(权利要求14);WO200292836(权利要求6;图12);WO200283866(权利要求15;第页116-121);US2003124140(实施例16);US2003091580(权利要求6);WO200206317(权利要求6;第400-408页);
交叉参考:GI:34501467;AAK74120.3;AF361486_1
(5)MPF(MPF、MSLN、SMR,巨核细胞强化因子,mesothelin,Genbank登录号NM_005823)
Yamaguchi,N.,et al Biol.Chem.269(2),805-808(1994),Proc.Natl.Acad.Sci.U.S.A.96(20):11531-11536(1999),Proc.Natl.Acad.Sci.U.S.A.93(1):136-140(1996),J.Biol.Chem.270(37):21984-21990(1995));WO2003101283(权利要求14);(WO2002102235(权利要求13;第287-288页);WO2002101075(权利要求4;第308-309页);WO200271928(第320-321页);WO9410312(第52-57页);
交叉参考:MIM:601051;NP_005814.2;NM_005823_1
(6)Napi3b(NAPI-3B、NPTIIb、SLC34A2,溶解物载体家族34(磷酸钠),成员2,II型钠依赖的磷酸转运蛋白3b,genbank登录号NM_006424)
J.Biol.Chem.277(22):19665-19672(2002),Genomics 62(2):281-284(1999),Feild,J.A.,et al(1999)Biochem.Biophys.Res.Commun.258(3):578-582);WO2004022778(权利要求2);EP1394274(实施例11);WO2002102235(权利要求13;第326页);EP875569(权利要求1;第17-19页);WO200157188(权利要求20;第329页);WO2004032842(实施例IV);WO200175177(权利要求24;第139-140页);
交叉参考:MIM:604217;NP_006415.1;NM_006424_1
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、脑信号蛋白(semaphorin)5b Hlog,sema结构域,七个血小板反应蛋白重复(1型和类1型的),跨膜结构域(TM)和短的细胞质结构域,(脑信号蛋白)5B,Genbank登录号AB040878)
Nagase T.,et al(2000)DNA Res.7(2):143-150);WO2004000997(权利要求1);WO2003003984(权利要求1);WO200206339(权利要求1;第50页);WO200188133(权利要求1;第41-43,48-58页);WO2003054152(权利要求20);WO2003101400(权利要求11);
登录号:Q9P283;EMBL;AB040878;BAA95969.1.Genew;HGNC:10737;
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA2700050C12、RIKEN cDNA 2700050C12基因,Genbank登录号AY358628);Ross et al(2002)Cancer Res.62:2546-2553;US2003129192(权利要求2);US2004044180(权利要求12);US2004044179(权利要求11);US2003096961(权利要求11);US2003232056(实施例5);WO2003105758(权利要求12);US2003206918(实施例5);EP1347046(权利要求1);WO2003025148(权利要求20);
交叉参考:GI:37182378;AAQ88991.1;AY358628_1
(9)ETBR(内皮素B型受体,Genbank登录号AY275463);
Nakamuta M.,et al Biochem.Biophys.Res.Commun.177,34-39,1991;Ogawa Y.,et al Biochem.Biophys.Res.Commun.178,248-255,1991;Arai H.,et al Jpn.Circ.J.56,1303-1307,1992;Arai H.,et al J.Biol.Chem.268,3463-3470,1993;Sakamoto A.,Yanagisawa M.,et al Biochem.Biophys.Res.Commun.178,656-663,1991;Elshourbagy N.A.,et al J.Biol.Chem.268,3873-3879,1993;Haendler B.,et al J.Cardiovasc.Pharmacol.20,s1-S4,1992;Tsutsumi M.,et al Gene 228,43-49,1999;Strausberg R.L.,et al Proc.Natl.Acad.Sci.U.S.A.99,16899-16903,2002;Bourgeois C.,et al J.Clin.Endocrinol.Metab.82,3116-3123,1997;Okamoto Y.,et al Biol.Chem.272,21589-21596,1997;Verheij J.B.,et al Am.J.Med.Genet.108,223-225,2002;Hofstra R.M.W.,et al Eur.J.Hum.Genet.5,180-185,1997;Puffenberger E.G.,et al Cell 79,1257-1266,1994;Attie T.,et al,Hum.Mol.Genet.4,2407-2409,1995;Auricchio A.,et al Hum.Mol.Genet.5:351-354,1996;Amiel J.,et al Hum.Mol.Genet.5,355-357,1996;Hofstra R.M.W.,et al Nat.Genet.12,445-447,1996;Svensson P.J.,et al Hum.Genet.103,145-148,1998;Fuchs S.,et al Mol.Med.7,115-124,2001;Pingault V.,et al(2002)Hum.Genet.111,198-206;WO2004045516(权利要求1);WO2004048938(实施例2);WO2004040000(权利要求151);WO2003087768(权利要求1);WO2003016475(权利要求1);WO2003016475(权利要求1);WO200261087(图1);WO2003016494(图6);WO2003025138(权利要求12;第144页);WO200198351(权利要求1;第124-125页);EP522868(权利要求8;图2);WO200177172(权利要求1;第297-299页);US2003109676;US6518404(图3);US5773223(权利要求1a;第31-34栏);WO2004001004;
(10)MSG783(RNF124,假想蛋白(hypothetical protein)FLJ20315,Genbank登录号NM_017763);
WO2003104275(权利要求1);WO2004046342(实施例2);WO2003042661(权利要求12);WO2003083074(权利要求14;第页61);WO2003018621(权利要求1);WO2003024392(权利要求2;图93);WO200166689(实施例6);
交叉参考:LocusID:54894;NP_060233.2;NM_017763_1
(11)STEAP2(HGNC_8639、IPCA-1、PCANAP1、STAMP1、STEAP2、STMP,前列腺癌相关基因1,前列腺癌相关蛋白1,前列腺的六次跨膜上皮抗原2,六次跨膜前列腺蛋白,Genbank登录号AF455138)
Lab.Invest.82(11):1573-1582(2002));WO2003087306;US2003064397(权利要求1;图1);WO200272596(权利要求13;第54-55页);WO200172962(权利要求1;图4B);WO2003104270(权利要求11);WO2003104270(权利要求16);US2004005598(权利要求22);WO2003042661(权利要求12);US2003060612(权利要求12;图10);WO200226822(权利要求23;图2);WO200216429(权利要求12;图10);
交叉参考:GI:22655488;AAN04080.1;AF455138_1
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B,瞬时受体潜在阳离子通道,亚家族M,成员4,Genbank登录号NM_017636)
Xu,X.Z.,et al Proc.Natl.Acad.Sci.U.S.A.98(19):10692-10697(2001),Cell 109(3):397-407(2002),J.Biol.Chem.278(33):30813-30820(2003));US2003143557(权利要求4);WO200040614(权利要求14;第100-103页);WO200210382(权利要求1;图9A);WO2003042661(权利要求12);WO200230268(权利要求27;第391页);US2003219806(权利要求4);WO200162794(权利要求14;图1A-D);
交叉参考:MIM:606936;NP_060106.2;NM_017636_1
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1,畸胎癌衍生生长因子,Genbank登录号NP_003203或NM_003212)
Ciccodicola,A.,et al EMBO J.8(7):1987-1991(1989),Am.J.Hum.Genet.49(3):555-565(1991));US2003224411(权利要求1);WO2003083041(实施例1);WO2003034984(权利要求12);WO200288170(权利要求2;第52-53页);WO2003024392(权利要求2;图58);WO200216413(权利要求1;第94-95,105页);WO200222808(权利要求2;图1);US5854399(实施例2;第17-18栏);US5792616(图2);
交叉参考:MIM:187395;NP_003203.1;NM_003212_1。
(14)CD21(CR2(补体受体2)或C3DR(C3d/埃巴病毒受体)或Hs.73792Genbank登录号M26004)
Fujisaku et al(1989)J.Biol.Chem.264(4):2118-2125);Weis J.J.,et al J.Exp.Med.167,1047-1066,1988;Moore M.,et al Proc.Natl.Acad.Sci.U.S.A.84,9194-9198,1987;Barel M.,et al Mol.Immunol.35,1025-1031,1998;Weis J.J.,et al Proc.Natl.Acad.Sci.U.S.A.83,5639-5643,1986;Sinha S.K.,etal(1993)J.Immunol.150,5311-5320;WO2004045520(实施例4);US2004005538(实施例1);WO2003062401(权利要求9);WO2004045520(实施例4);WO9102536(图9.1-9.9);WO2004020595(权利要求1);
登录号:P20023;Q13866;Q14212;EMBL;M26004;AAA35786.1。
(15)CD79b(CD79B、CD79β、IGb(免疫球蛋白相关beta)、B29,Genbank登录号NM_000626或11038674)
Proc.Natl.Acad.Sci.U.S.A.(2003)100(7):4126-4131,Blood(2002)100(9):3068-3076,Muller et al(1992)Eur.J.Immunol.22(6):1621-1625);WO2004016225(权利要求2,图140);WO2003087768,US2004101874(权利要求1,第102页);WO2003062401(权利要求9);WO200278524(实施例2);US2002150573(权利要求5,第15页);US5644033;WO2003048202(权利要求1,第306和309页);WO 99/558658,US6534482(权利要求13,图17A/B);WO200055351(权利要求11,第1145-1146页);
交叉参考:MIM:147245;NP_000617.1;NM_000626_1
(16)FcRH2(IFGP4、IRTA4、SPAP1A(含SH2结构域的磷酸酶锚定蛋白1a)、SPAP1B、SPAP1C,Genbank登录号NM_030764、AY358130)
Genome Res.13(10):2265-2270(2003),Immunogenetics 54(2):87-95(2002),Blood 99(8):2662-2669(2002),Proc.Natl.Acad.Sci.U.S.A.98(17):9772-9777(2001),Xu,M.J.,et al(2001)Biochem.Biophys.Res.Commun.280(3):768-775;WO2004016225(权利要求2);WO2003077836;WO200138490(权利要求5;图18D-1-18D-2);WO2003097803(权利要求12);WO2003089624(权利要求25);
交叉参考:MIM:606509;NP_110391.2;NM_030764_1
(17)HER2(ErbB2,Genbank登录号M11730)
Coussens L.,et al Science(1985)230(4730):1132-1139);Yamamoto T.,etal Nature 319,230-234,1986;Semba K.,et al Proc.Natl.Acad.Sci.U.S.A.82,6497-6501,1985;Swiercz J.M.,et al J.Cell Biol.165,869-880,2004;KuhnsJ.J.,et al J.Biol.Chem.274,36422-36427,1999;Cho H.-S.,et al Nature 421,756-760,2003;Ehsani A.,et al(1993)Genomics 15,426-429;WO2004048938(实施例2);WO2004027049(图1I);WO2004009622;WO2003081210;WO2003089904(权利要求9);WO2003016475(权利要求1);US2003118592;WO2003008537(权利要求1);WO2003055439(权利要求29;图1A-B);WO2003025228(权利要求37;图5C);WO200222636(实施例13;第95-107页);WO200212341(权利要求68;图7);WO200213847(第页71-74);WO200214503(第114-117页);WO200153463(权利要求2;第41-46页);WO200141787(第15页);WO200044899(权利要求52;图7);WO200020579(权利要求3;图2);US5869445(权利要求3;第1-38栏);WO9630514(权利要求2;第56-61页);EP1439393(权利要求7);WO2004043361(权利要求7);WO2004022709;WO200100244(实施例3;图4);
登录号:P04626;EMBL;M11767;AAA35808.1.EMBL;M11761;AAA35808.1.
(18)NCA(CEACAM6,Genbank登录号M18728);
Barnett T.,et al Genomics 3,59-66,1988;Tawaragi Y.,et al Biochem.Biophys.Res.Commun.150,89-96,1988;Strausberg R.L.,et al Proc.Natl.Acad.Sci.U.S.A.99:16899-16903,2002;WO2004063709;EP1439393(权利要求7);WO2004044178(实施例4);WO2004031238;WO2003042661(权利要求12);WO200278524(实施例2);WO200286443(权利要求27;第427页);WO200260317(权利要求2);
登录号:P40199;Q14920;EMBL;M29541;AAA59915.1.EMBL;M18728;
(19)MDP(DPEP1,Genbank登录号BC017023)
Proc.Natl.Acad.Sci.U.S.A.99(26):16899-16903(2002));WO2003016475(权利要求1);WO200264798(权利要求33;第页85-87);JP05003790(图6-8);WO9946284(图9);
交叉参考:MIM:179780;AAH17023.1;BC017023_1
(20)IL20Rα(IL20Ra、ZCYTOR7,Genbank登录号AF184971);
Clark H.F.,et al Genome Res.13,2265-2270,2003;Mungall A.J.,et alNature 425,805-811,2003;Blumberg H.,et al Cell 104,9-19,2001;Dumoutier L.,et al J.Immunol.167,3545-3549,2001;Parrish-Novak J.,et al J.Biol.Che m.277,47517-47523,2002;Pletnev S.,et al(2003)Biochemistry42:12617-12624;Sheikh F.,et al(2004)J.Immunol.172,2006-2010;EP1394274(实施例11);US2004005320(实施例5);WO2003029262(第74-75页);WO2003002717(权利要求2;第63页);WO200222153(第45-47页);US2002042366(第20-21页);WO200146261(第57-59页);WO200146232(第63-65页);WO9837193(权利要求1;第55-59页);
登录号:Q9UHF4;Q6UWA9;Q96SH8;EMBL;AF184971;AAF01320.1.
(21)Brevican(BCAN、BEHAB,Genbank登录号AF229053)
Gary S.C.,et al Gene 256,139-147,2000;Clark H.F.,et al Genome Res.13,2265-2270,2003;Strausberg R.L.,et al Proc.Natl.Acad.Sci.U.S.A.99,16899-16903,2002;US2003186372(权利要求11);US2003186373(权利要求11);US2003119131(权利要求1;图52);US2003119122(权利要求1;图52);US2003119126(权利要求1);US2003119121(权利要求1;图52);US2003119129(权利要求1);US2003119130(权利要求1);US2003119128(权利要求1;图52);US2003119125(权利要求1);WO2003016475(权利要求1);WO200202634(权利要求1);
(22)EphB2R(DRT、ERK、Hek5、EPHT3、Tyro5,Genbank登录号NM_004442)
Chan,J.and Watt,V.M.,Oncogene 6(6),1057-1061(1991)Oncogene10(5):897-905(1995),Annu.Rev.Neurosci.21:309-345(1998),Int.Rev.Cytol.196:177-244(2000));WO2003042661(权利要求12);WO200053216(权利要求1;第41页);WO2004065576(权利要求1);WO2004020583(权利要求9);WO2003004529(第128-132页);WO200053216(权利要求1;第42页);
交叉参考:MIM:600997;NP_004433.2;NM_004442_1
(23)ASLG659(B7h,Genbank登录号AX092328)
US20040101899(权利要求2);WO2003104399(权利要求11);WO2004000221(图3);US2003165504(权利要求1);US2003124140(实施例2);US2003065143(图60);WO2002102235(权利要求13;第299页);US2003091580(实施例2);WO200210187(权利要求6;图10);WO200194641(权利要求12;图7b);WO200202624(权利要求13;图1A-1B);US2002034749(权利要求54;第45-46页);WO200206317(实施例2;第320-321页,权利要求34;第321-322页);WO200271928(第468-469页);WO200202587(实施例1;图1);WO200140269(实施例3;Pages 190-192);WO200036107(实施例2;第页205-207);WO2004053079(权利要求12);WO2003004989(权利要求1);WO200271928(第233-234,452-453页);WO0116318;
(24)PSCA(前列腺干细胞抗原前体,Genbank登录号AJ297436)
Reiter R.E.,et al Proc.Natl.Acad.Sci.U.S.A.95,1735-1740,1998;Gu Z.,et al Oncogene 19,1288-1296,2000;Biochem.Biophys.Res.Commun.(2000)275(3):783-788;WO2004022709;EP1394274(实施例11);US2004018553(权利要求17);WO2003008537(权利要求1);WO200281646(权利要求1;第164页);WO2003003906(权利要求10;第288页);WO200140309(实施例1;图17);US2001055751(实施例1;图1b);WO200032752(权利要求18;图1);WO9851805(权利要求17;第97页);WO9851824(权利要求10;第94页);WO9840403(权利要求2;图1B);
登录号:O43653;EMBL;AF043498;AAC39607.1.
(25)GEDA(Genbank登录号AY260763);
AAP14954脂肪瘤(lipoma)HMGIC融合伴侣样蛋白/pid=AAP14954.1–人
物种:智人(人)
WO2003054152(权利要求20);WO2003000842(权利要求1);WO2003023013(实施例3,权利要求20);US2003194704(权利要求45);
交叉参考:GI:30102449;AAP14954.1;AY260763_1
(26)BAFF-R(B细胞活化因子受体、BlyS受体3、BR3,Genbank登录号:AF116456);BAFF受体/pid=NP_443177.1-智人
Thompson,J.S.,et al Science 293(5537),2108-2111(2001);WO2004058309;WO2004011611;WO2003045422(实施例;第32-33页);WO2003014294(权利要求35;图6B);WO2003035846(权利要求70;第615-616页);WO200294852(第136-137栏);WO200238766(权利要求3;第133页);WO200224909(实施例3;图3);
交叉参考:MIM:606269;NP_443177.1;NM_052945_1;AF132600
(27)CD22(B细胞受体CD22-B同种型、BL-CAM、Lyb-8、Lyb8、SIGLEC-2、FLJ22814,Genbank登录号:AK026467);
Wilson et al(1991)J.Exp.Med.173:137-146;WO2003072036(权利要求1;图1);
交叉参考:MIM:107266;NP_001762.1;NM_001771_1
(28)CD79a(CD79A、CD79α,免疫球蛋白相关的alpha,与Ig beta(CD79B)共价相互作用,与Ig M分子在表面上形成复合体,转导涉及B细胞分化的信号的B细胞特异性蛋白)PROTEIN SEQUENCE Fullmpggpgv...dvqlekp(1..226;226aa),pI:4.84,MW:25028TM:2[P]GeneChromosome:19q13.2,Genbank登录号:NP_001774.10)
WO2003088808,US20030228319;WO2003062401(权利要求9);US2002150573(权利要求4,第13-14页);WO9958658(权利要求13,图16);WO9207574(图1);US5644033;Ha et al(1992)J.Immunol.148(5):1526-1531;Mueller et al(1992)Eur.J.Biochem.22:1621-1625;Hashimoto et al(1994)Immunogenetics 40(4):287-295;Preud’homme etal(1992)Clin.Exp.Immunol.90(1):141-146;Yu et al(1992)J.Immunol.148(2)633-637;Sakaguchi et al(1988)EMBO J.7(11):3457-3464;
(29)CXCR5(伯基特淋巴瘤受体1、由CXCL13趋化因子活化的G蛋白偶联受体,在淋巴细胞迁移和体液防御中发挥作用,在HIV-2感染以及或许在AIDS、淋巴瘤、骨髓瘤、和白血病发生中起作用)PROTEINSEQUENCE Full mnypltl...atslttf(1..372;372aa),pI:8.54MW:41959TM:7[P]Gene Chromosome:11q23.3,Genbank登录号:NP_001707.1)
WO2004040000;WO2004015426;US2003105292(实施例2);US6555339(实施例2);WO200261087(图1);WO200157188(权利要求20,第269页);WO200172830(第12-13页);WO200022129(实施例1,第152-153页,实施例2,第254-256页);WO9928468(权利要求1,第38页);US5440021(实施例2,第49-52栏);WO9428931(第56-58页);WO9217497(权利要求7,图5);Dobner et al(1992)Eur.J.Immunol.22:2795-2799;Barella et al(1995)Biochem.J.309:773-779;
(30)HLA-DOB(MHC II类分子的Beta亚基(Ia抗原),其结合肽并将其呈递到CD4+T淋巴细胞)PROTEIN SEQUENCE Full mgsgwvp...vllpqsc(1..273;273aa,pI:6.56MW:30820TM:1[P]Gene Chromosome:6p21.3,Genbank登录号:NP_002111.1)
Tonnelle et al(1985)EMBO J.4(11):2839-2847;Jonsson et al(1989)Immunogenetics 29(6):411-413;Beck et al(1992)J.Mol.Biol.228:433-441;Strausberg et al(2002)Proc.Natl.Acad.Sci USA 99:16899-16903;Servenius etal(1987)J.Biol.Chem.262:8759-8766;Beck et al(1996)J.Mol.Biol.255:1-13;Naruse et al(2002)Tissue Antigens 59:512-519;WO9958658(权利要求13,图15);US6153408(第35-38栏);US5976551(第168-170栏);US6011146(第145-146栏);Kasahara et al(1989)Immunogenetics 30(1):66-68;Larhammar etal(1985)J.Biol.Chem.260(26):14111-14119;
(31)P2X5(嘌呤受体P2X配体门控离子通道5,由胞外ATP门控的离子通道,可能涉及突触传递和神经发生,其缺陷可能导致特发性逼尿肌不稳定病理生理状况)PROTEIN SEQUENCE Full mgqagc k...lephrst(1..422;422aa),pI:7.63,MW:47206TM:1[P]Gene Chromosome:17p13.3,Genbank登录号:NP_002552.2)
Le et al(1997)FEBS Lett.418(1-2):195-199;WO2004047749;WO2003072035(权利要求10);Touchman et al(2000)Genome Res.10:165-173;WO200222660(权利要求20);WO2003093444(权利要求1);WO2003087768(权利要求1);WO2003029277(第82页);
(32)CD72(B细胞分化抗原CD72、Lyb-2)PROTEIN SEQUENCE Fullmaeaity...tafrfpd(1..359;359aa),pI:8.66,MW:40225TM:1[P]GeneChromosome:9p13.3,Genbank登录号:NP_001773.1)
WO2004042346(权利要求65);WO2003026493(第51-52,57-58页);WO200075655(第105-106页);Von Hoegen et al(1990)J.Immunol.144(12):4870-4877;Strausberg et al(2002)Proc.Natl.Acad.Sci USA99:16899-16903;
(33)LY64(淋巴细胞抗原64(RP105),富含亮氨酸重复(LRR)的I型膜蛋白家族,调节B细胞活化和凋亡,功能的丧失与系统性红斑狼疮患者疾病活动增强有关)PROTEIN SEQUENCE Full mafdvsc...rwkyqhi(1..661;661aa),pI:6.20,MW:74147TM:1[P]Gene Chromosome:5q12,Genbank登录号:NP_005573.1)
US2002193567;WO9707198(权利要求11,第页39-42);Miura et al(1996)Genomics 38(3):299-304;Miura et al(1998)Blood 92:2815-2822;WO2003083047;WO9744452(权利要求8,第57-61页);WO200012130(第24-26页);
(34)FcRH1(Fc受体样蛋白1,Fc结构域推定的免疫球蛋白受体,其包含C2型Ig样和ITAM结构域,可能在B淋巴细胞分化中有作用)PROTEINSEQUENCE Full mlprlll...vdyedam(1..429;429aa),pI:5.28,MW:46925 TM:1[P]Gene Chromosome:1q21-1q22,Genbank登录号:NP_443170.1)
WO2003077836;WO200138490(权利要求6,图18E-1-18-E-2);Davis etal(2001)Proc.Natl.Acad.Sci USA 98(17):9772-9777;WO2003089624(权利要求8);EP1347046(权利要求1);WO2003089624(权利要求7);
(35)IRTA2(易位相关的免疫球蛋白超家族受体2,在B细胞发育和淋巴瘤发生中可能有作用的推定的免疫受体;与发生在一些B细胞恶性疾病中的由易位引起的基因失调有关)PROTEIN SEQUENCE Fullmllwvil...assaphr(1..977;977aa),pI:6.88MW:106468TM:1[P]GeneChromosome:1q21,Genbank登录号:Human:AF343662、AF343663、AF343664、AF343665、AF369794、AF397453、AK090423、AK090475、AL834187、AY358085;Mouse:AK089756、AY158090、AY506558;NP_112571.1
WO2003024392(权利要求2,图97);Nakayama et al(2000)Biochem.Biophys.Res.Commun.277(1):124-127;WO2003077836;WO200138490(权利要求3,图18B-1-18B-2);
(36)TENB2(TMEFF2、tomoregulin、TPEF、HPP 1、TR、推定的跨膜蛋白聚糖,涉及生长因子和卵泡抑素(follistatin)的EGF/调蛋白家族)PROTEINSEQUENCE Full mvlwesp...rastrli(1..374;374aa,NCBI登录号:AAD55776、AAF91397、AAG49451、NCBI RefSeq:NP_057276;NCBI Gene:23671;OMIM:605734;SwissProt Q9UIK5;Genbank登录号:AF179274、AY358907、CAF85723、CQ782436
WO2004074320(SEQ ID NO 810);JP2004113151(SEQ ID NOS 2,4,8);WO2003042661(SEQ ID NO 580);WO2003009814(SEQ ID NO 411);EP1295944(第69-70页);WO200230268(第329页);WO200190304(SEQ IDNO 2706);US2004249130;US2004022727;WO2004063355;US2004197325;US2003232350;US2004005563;US2003124579;US 6410506;US 6642006l;Horie et al(2000)Genomics 67:146-152;Uchida et al(1999)Biochem.Biophys.Res.Commun.266:593-602;Liang et al(2000)Cancer Res.60:4907-12;Glynne-Jones et al(2001)Int J Cancer.Oct 15;94(2):178-84。
抗体的生产
许多方法已用于生产单克隆抗体(MAbs)。杂交瘤技术,指生产单一抗体类型的克隆细胞系,使用许多物种包括小鼠(鼠)、仓鼠、大鼠、和人的细胞。制备MAbs包括嵌合和人源化抗体的其它方法使用遗传工程即重组DNA技术。
可以通过多次皮下(sc)或腹膜内(ip)注射相关抗原和佐剂在动物体内制备多克隆抗体。单克隆抗体由实质上同质的抗体群体获得,即除了可能少量存在的天然发生的突变之外,组成所述群体的单个抗体是相同的。
也已描述了人骨髓瘤和小鼠-人杂交瘤细胞系用于人单克隆抗体的生产(Kozbor,J.Immunol.,133:3001(1984);和Brodeur et al.Monoclonal AntibodyProduction Techniques and Applications,pp.51-63(Marcel Dekker,Inc.,NewYork,1987))。测试了其中培养有杂交瘤细胞的培养基,用于针对所述抗原的单克隆抗体的生产。可以通过免疫沉淀法或者通过体外结合测试如放射免疫测定(RIA)或酶联免疫吸附测试(ELISA)测定由杂交瘤细胞生产的单克隆抗体的结合特异性。例如可以通过Munson et al(1980)Anal.Biochem.,107:220的Scatchard分析测定单克隆抗体的结合亲合力。
利用常规程序(例如,通过使用能够特异地结合编码鼠抗体重链和轻链的寡核苷酸探针)可以很容易地分离编码单克隆抗体的DNA并测序。所述杂交瘤细胞作为这种DNA的来源。一旦分离了DNA,可以将其置于表达载体中,然后将其转染到原本不生产抗体蛋白的宿主细胞如大肠杆菌细胞、猿COS细胞、中华仓鼠卵巢(CHO)细胞、或骨髓瘤细胞中,以获得单克隆抗体在重组宿主细胞中的合成(US 2005/0048572;US 2004/0229310)。有关编码抗体的DNA在细菌中重组表达的综述包括Skerra et al(1993)Curr.Opinion inImmunol.,5:256-262和Plückthun(1992)Immunol.Revs.,130:151-188。
在另一实施方案中,可以从抗体噬菌体文库分离单克隆抗体或抗体片段,所述抗体噬菌体文库用McCafferty et al(1990)Nature 348:552-554;Clackson et al(1991)Nature 352:624-628;and Marks et al(1991)J.Mol.Biol.,222:581-597描述的技术获得,这些文献描述了用噬菌体文库分别分离鼠和人抗体。后来的出版物描述了高亲合力(nM范围)人抗体的生产,其通过链替换(Marks et al(1992)Bio/Technology,10:779-783)、以及作为构建极大噬菌体文库策略的组合感染和体内重组(Waterhouse et al(1993)Nuc.Acids.Res.,21:2265-2266)进行。因此,这些技术是分离单克隆抗体的传统单克隆抗体杂交瘤技术的可行性替代技术。
也可以修饰DNA,例如通过用人重链和轻链恒定区取代同源鼠序列(US4816567;和Morrison et al(1984)Proc.Natl Acad.Sci.USA,81:6851),或者通过将非免疫球蛋白多肽的编码序列全部或部分共价连接到免疫球蛋白编码序列来修饰。
典型地,用这样的非免疫球蛋白多肽取代抗体的恒定区,或者取代抗体的一个抗原结合部位的可变区,形成嵌合二价抗体,其包括具有抗原特异性的一个抗原结合部位和具有不同抗原特异性的另一个抗原结合部位。
说明书按照本发明抗体-药物偶联物(ADC)中使用的抗体(Ab)的示例性生产技术。将参考抗ErbB2抗体阐述抗体的生产,但对于本领域技术人员来说,很明显可以按类似方式生产并修饰ErbB受体家族的其它成员以及任何其它受体或肿瘤相关抗原或靶物的抗体。
用于生产抗体的ErbB2抗原可以是例如可溶形式的ErbB2胞外结构域或其包含所需表位的部分。或者,在其细胞表面表达ErbB2的细胞,例如经转化过表达ErbB2的NIH-3T3细胞;或癌细胞系如Sk-Br-3细胞(Stancovski etal(1991)PNAS(USA)88:8691-8695)可用于生产抗体。用于生产抗体的其它形式的ErbB2对本领域技术人员来说是显而易见的。
实施例1描述示例性人源化抗ErbB2抗体的生产。人源化抗体可以例如包含掺入到人可变区重链结构域的非人高变区残基,并且可以进一步包含在选自下组位点的框架区(FR)取代:运用Kabat et al.,Sequences of Proteins ofImmunological Interest,5th Ed.Public Health Service,National Institutes ofHealth,Bethesda,MD(1991)中提供的可变区编号系统的69H、71H和73H。在一个实施方案中,人源化抗体在位点69H、71H和73H的两个或所有位点包含FR取代。
作为人源化的替代方案,可以生产人抗体。例如,现在生产转基因动物(例如,小鼠)是可能的,在没有内源免疫球蛋白产生的情况下,所述转基因动物在免疫时能够生产全套(full repertoire)人抗体。(Jakobovits et al(1993)Proc.Natl.Acad.Sci.USA,90:2551;Jakobovits et al(1993)Nature 362:255-258;Bruggermann et al(1993)Year in Immuno.7:33;and US 5591669;US 5589369;US 5545807)。
或者,噬菌体展示技术(McCafferty et al(1990)Nature 348:552-553)可用于从来自非免疫供体的免疫球蛋白可变(V)区全套基因体外生产人抗体和抗体片段。(Johnson,Kevin S.and Chiswell,David J.(1993)Current Opinion inStructural Biology 3:564-571)。可以构建来自非免疫人供体的全套V基因,并且基本上可以分离各种抗原(包括自身抗原)的抗体(Marks et al(1991)J.Mol.Biol.222:581-597;Griffith et al(1993)EMBO J.12:725-734;US 5565332;US 5573905)。也可以通过体外活化的B细胞生产人抗体(US 5567610;US5229275)。描述了人抗ErbB2抗体(US 5772997和WO 97/00271)。
已经开发了多种生产抗体片段的技术。传统上,这些片段通过完整抗体的蛋白水解消化而衍生(参见,例如,Morimoto et al(1992)Journal ofBiochemical and Biophysical Methods 24:107-117;和Brennan et al(1985)Science,229:81)。也可以由重组宿主细胞和以上讨论的抗体噬菌体文库直接生产抗体片段。或者,可以直接从大肠杆菌回收Fab'-SH片段并进行化学偶联以形成F(ab')2片段(Carter et al(1992)Bio/Technology 10:163-167)。根据另一种方法,可以直接从重组宿主细胞培养物中分离F(ab')2片段。其它生产抗体片段的技术对于熟练技术人员来说将是显而易见的。在其它实施方案中,所选择的抗体是单链Fv片段(scFv)。参见WO 93/16185;US 5571894;以及US 5587458。例如,抗体片段也可以是“线性抗体”,例如US 5641870中所述。这种线性抗体片段可以是单特异性的或双特异性的。
具有针对至少两个不同表位的结合特异性的双特异性抗体(Millstein etal(1983),Nature 305:537-539)可以结合ErbB2蛋白的两个不同表位。其它的这种抗体可以将ErbB2结合部位与EGFR、ErbB3和/或ErbB4的结合部位组合。或者,抗ErbB2的臂可以与结合白细胞上的激发分子如T细胞受体分子(例如CD2或CD3)、或IgG的Fc受体(FcγR),如FcγRI(CD64)、FcγRII(CD32)和FcγRIII(CD16)的臂组合,以将细胞的防御机制集中于表达ErbB2的细胞。双特异性抗体也可用于将细胞毒性试剂定位于表达ErbB2的细胞(WO96/16673;US 5837234;WO98/02463;US 5821337)。已经披露了双特异性抗体的纯化方法(WO 93/08829;Traunecker et al(1991)EMBO J.10:3655-3659;WO 94/04690;Suresh et al(1986)Methods in Enzymology121:210;US 5731168)。可以利用亮氨酸拉链(Kostelny et al(1992)J.Immunol.148(5):1547-1553),和单链Fv(sFv)二聚体(Gruber et al(1994)J.Immunol.152:5368)生产双特异性抗体。
也已描述了从抗体片段生产双特异性抗体的技术,例如利用完整抗体在其位置经蛋白水解裂解产生F(ab')2片段的化学键(Brennan et al(1985)Science229:81)。可以从大肠杆菌回收Fab'-SH片段并化学偶联以形成双特异性抗体(Shalaby et al(1992)J.Exp.Med.175:217-225。"双抗体"技术提供了制备双特异性抗体片段的替代方法(Hollinger et al(1993)Proc.Natl.Acad.Sci.USA90:6444-6448)。
可以制备超过二价的抗体。可以通过编码抗体多肽链的核酸的重组表达很容易地生产具有三个或更多个抗原结合部位和两个或多个可变区的多价“章鱼”样的抗体(US 2002/0004586;WO 01/77342)。例如,可以制备三特异性抗体(Tutt et al(1991)J.Immunol.147:60)。
可以预期抗体的氨基酸序列修饰。例如,预期结合肿瘤相关抗原的抗体突变体和许多同种型提高抗体的结合亲合力和/或其它生物学特性。通过向编码抗体的核酸引入合适的核苷酸改变或通过肽合成制备抗体的氨基酸序列变体。这种修饰包括,例如,从抗体的氨基酸序列内删除残基、和/或往抗体的氨基酸序列内插入残基和/或取代抗体氨基酸序列内的残基。实施删除、插入、和取代的任意组合以得到最终的构建体,以使所述最终构建体拥有所需的特征。氨基酸变化也可能改变抗体的翻译后加工,例如改变糖基化位点的数目或位置。
用于鉴定抗体的特定残基或区域的有用方法称为"丙氨酸扫描诱变",其中所述的特定残基或区域为优选的诱变部位(Cunningham和Wells(1989)Science,244:1081-1085,其中鉴定了氨基酸残基或一组目标残基(例如,带电残基如arg、asp、his、lys、和glu),并用中性或带负电氨基酸,例如丙氨酸或聚丙氨酸取代,以优化氨基酸与抗原的相互作用。氨基酸序列插入包括从一个残基到包含一百个或更多残基的多肽的氨基和/或羧基末端的融合,以及单个或多个氨基酸残基的序列内插入。末端插入的例子包括具有N端蛋氨酰残基的抗ErbB2抗体或融合于细胞毒性多肽的抗体。抗ErbB2抗体分子的其它插入变体包括酶(例如对于ADEPT∶Tietze et al(2003)Current Pharm.Design 9:2155-2175)或多肽与抗ErbB2抗体N-或C-末端的融合物,所述多肽增加抗体的血清半衰期,例如白蛋白-结合肽。
血浆-蛋白结合可能是提高短命分子的药代动力学特性的有效手段。白蛋白是血浆中最丰富的蛋白质。血清白蛋白结合肽(ABP)能够改变融合的活性结构域蛋白的药效学,包括组织吸收、穿透、和扩散的改变。可以通过特异性选择合适的血清白蛋白结合肽序列调节这些药效参数(US20040001827)。通过噬菌体展示筛选鉴定了一系列白蛋白结合肽(Dennis etal(2002)“Albumin Binding As A General Strategy For Improving ThePharmacokinetics Of Proteins”J Biol Chem.277:35035-35043;WO 01/45746)。本发明的化合物包括∶(i)Dennis et al(2002)J Biol Chem.277:35035-35043中表III和IV、第35038页;(ii)US 20040001827中[0076]SEQ ID NOS:9-22;和(iii)WO 01/45746中第12-13页、SEQ ID NOS:z1-z14教导的ABP序列,本文中这些均加入作为参考。
通常通过改变基本的核酸序列来改变氨基酸序列。编码抗体氨基酸序列变体的核酸分子通过本领域已知的多种方法制备。这些方法包括但不限于从天然来源分离(在天然发生的氨基酸序列变体的情况下)或者通过寡核苷酸介导的(或定点)诱变、PCR诱变、以及对抗体的早先制备的变体或非变异型式所进行的盒式诱变。最感兴趣的取代诱变部位包括高变区,但也可预期FR改变。
抗体生物学特性的实质性修饰通过选择取代完成,所述选择取代对维持(a)取代区域中多肽骨架的结构,例如片层或螺旋构象,(b)分子目标部位的电荷或疏水性,或(c)侧链的大小的影响方面差异显著。基于常见侧链特性将天然发生的残基分为以下的组∶
(1)疏水性的:正亮氨酸、met、ala、val、leu、ile;
(2)中性亲水性的:cys、ser、thr;
(3)酸性的:asp、glu;
(4)碱性的:asn、gln、his、lys、arg;
(5)影响链方向的残基:gly、pro;和
(6)芳香族的:trp、tyr、phe。
非保守性取代必然会伴随用这些类别中其中一类的成员交换另一类。
通常也可以用丝氨酸取代不涉及维持抗体的正确构象的任何半胱氨酸残基,以改善分子的氧化稳定性并阻止异常偶联。反之,可以将半胱氨酸键加至抗体以改善其稳定性(特别是抗体为抗体片段如Fv片段时)。
为了增加抗体的血清半衰期,例如可以如US 5739277所述将补救受体结合表位掺入到抗体(尤其是抗体片段)中。本文所用术语"补救受体结合表位"指IgG分子(例如,IgG1、IgG2、IgG3、或IgG4)Fc区的表位,其负责增强IgG分子的体内血清半衰期(US 2003/0190311、US6821505;US 6165745;US 5624821;US 5648260;US 6165745;US 5834597)。
抗体的糖基化变体指其中抗体的糖基化型式被改变的变体。改变指删除一个或多个抗体中发现的碳水化合物部分、向抗体添加一个或多个碳水化合物部分、改变糖基化的组成(糖基化型式)、或糖基化的程度。
抗体可以是在其恒定区中的保守性位点糖基化的(N-连接或O-连接的)(Hse et al(1997)J.Biol.Chem.272:9062-9070;Jefferis and Lund,(1997)Chem.Immunol.65:111-128;Wright and Morrison,(1997)TibTECH 15:26-32)。免疫球蛋白的寡糖侧链影响蛋白质的功能(Boyd et al(1996)Mol.Immunol.32:1311-1318;Wittwe and Howard,(1990)Biochem.29:4175-4180),和糖蛋白部分之间的分子内相互作用,这种分子内相互作用能够影响所述构象并提供糖蛋白的三维表面(Hefferis and Lund,supra;Wyss and Wagner(1996)CurrentOpin.Biotech.7:409-416)。基于特异性识别结构,寡糖也可用于将给定糖蛋白引导至特定分子(Malhotra et al(1995)Nature Med.1:237-243;Umana etal(1999)Nature Biotech.17:176-180)。去除寡糖可以优化抗体的抗原结合和其它特性(Boyd et al(1996)Mol.Immunol.32:1311-1318)。
抗体重组生产期间影响糖基化的因素包括生长模式、培养基配方、培养物密度、氧化、pH、纯化方案等等(US 5047335;US 5510261;US 5278299)。可以从糖蛋白通过酶学方法去除糖基化或特定类型的糖基化,例如使用内切糖苷酶H(Endo H)。此外,可以遗传工程化重组宿主细胞,例如使之在加工特定类型多糖中是缺陷型的。这些技术以及类似的技术是本领域熟知的。
可以很容易地通过碳水化合物分析的传统技术分析抗体的糖基化结构,所述技术包括凝集素层析、NMR、质谱分析、HPLC、GPC、单糖组成分析、连续酶学消化、以及HPAEC-PAD,其中HPAEC-PAD以电荷为基础,使用高pH阴离子交换层析分离寡糖。为了分析的目的而释放寡糖的方法也是已知的,包括但不限于酶学处理(一般使用肽-N-糖苷酶F/内切-β-半乳糖苷酶进行)、利用苛性碱环境消除以主要释放O-连接结构、以及利用无水肼化学方法释放N-和O-连接寡糖。
美登木素生物碱药物部分
美登素化合物通过抑制有丝分裂期间微管蛋白的聚合微管的形成而抑制细胞增殖(Remillard et al(1975)Science 189:1002-1005;US 5208020)。美登素和美登木素生物碱是高度细胞毒性的,但其严重全身性副作用已大大限制了其在癌症治疗中的临床应用,所述严重全身性副作用主要归因于其弱的肿瘤选择性。由于对中枢神经系统和胃肠系统的严重副作用,美登素的临床试验已经中断(Issel et al(1978)Can.Treatment.Rev.5:199-207)。
美登木素生物碱药物部分在抗体-药物偶联物中是有吸引力的药物部分,因为它们∶(i)通过发酵或化学修饰、由发酵产品衍生而制备相对容易,(ii)易于用官能团衍生化,所述官能团适合于通过非二硫化物接头偶联于抗体,(iii)在血浆中稳定,和(iv)对多种肿瘤细胞系有效。
适合于用作美登木素生物碱药物部分的美登素化合物是本领域熟知的,其可以依照已知的方法从天然来源分离,用遗传工程技术生产(参见Yu etal(2002)PNAS 99:7968-7973),或者依照已知的方法合成制备美登醇和美登醇类似物。
示例性美登木素生物碱药物部分包括那些具有修饰的芳香环的,如∶C-19-脱氯(dechloro)(US 4256746)(通过ansamitocin P2的锂铝氢化物还原制备);C-20-羟基(或C-20-去甲基)+/-C-19-脱氯(美国专利4361650和4307016)(通过用链霉菌(Streptomyces)或放线菌(Actinomyces)脱甲基或者用LAH脱氯制备);和C-20-去甲氧基、C-20-酰氧基(-OCOR)、+/-脱氯(US4294757)(通过用酰氯酰化制备),以及在其它位点有修饰的那些。
示例性美登木素生物碱药物部分还包括具有如下修饰的那些∶C-9-SH,通过美登醇与H2S或P2S5(US 4424219)反应制备;C-14-烷氧甲基(去甲氧基/CH2OR)(US 4331598);C-14-羟甲基或酰氧基甲基(CH2OH或CH2OAc),自诺卡氏菌(Nocardia)(US 4450254)制备;C-15-羟基/酰氧基,通过用链霉菌转化美登醇制备(US 4364866);C-15-甲氧基,从滑桃树(Trewia nudiflora)分离(US 4313946和US 4315929);C-18-N-脱甲基,通过用链霉菌对美登醇脱甲基制备(US 4362663和US 4322348);以及4,5-脱氧的,通过美登醇的三氯化钛/LAH还原制备(US 4371533)。
已知根据连接的类型,美登素化合物上的许多位点可用作连接位点。例如,对于形成酯键,具有羟基的C-3位点、由羟甲基修饰的C-14位点、由羟基修饰的C-15位点和具有羟基的C-20位点都是适合的。
美登木素生物碱药物部分(D)包括具有如下结构的那些∶
其中波浪线表示D的硫原子与抗体-药物偶联物(ADC)接头(L)的共价连接。R独立地可以是H或C1-C6烷基。将酰胺基连接于硫原子的亚烷基(alkylene)链可以是甲烷基(methanyl)、乙烷基(ethanyl)、或丙基,即m是1、2、或3(US633410,5208020,Chari et al(1992)Cancer Res.52:127-131;Liu et al(1996)Proc.Natl.Acad.Sci 93:8618-8623)。
美登木素生物碱药物部分的所有立体异构体都是预期的本发明的化合物,即D的手性碳位置R和S构象的任何组合。在一个实施方案中,美登木素生物碱药物部分(D)将具有以下立体化学结构∶
D的具体方案包括∶
DM1(N2’-脱乙酰-N2’-(3-巯基-1-氧代丙基)-美登素)其中(CR2)m=CH2CH2;
DM3(N2’-脱乙酰基-N-2’(4-巯基-1-氧代戊基)-美登素)其中(CR2)m=CH2CH2CH(CH3);
DM4(N2’-脱乙酰基-N2’-(4-甲基-4-巯基-1-氧代戊基)-美登素)其中(CR2)m=CH2CH2C(CH3)2:
烷基如甲基对DM3和DM4的硫原子附近的碳提供的空间位阻可能影响ADC的胞内裂解速率(US 2004/0235840A1)。因此可变烷基单元(CR2)m可能影响体外和体内效力(petency)、功效(efficacy)、和安全性/毒性。
接头
接头L通过共价键,不包括二硫基(disulfide group),将抗体连接到药物部分。接头为双功能或多功能的部分,其可用于连接一个或多个药物部分(D)和抗体单元(Ab),以形成式I的抗体-药物偶联物(ADC)。可以用具有结合药物和结合抗体的反应功能性的接头方便地制备抗体-药物偶联物(ADC)。抗体(Ab)的半胱氨酸硫醇、或胺,例如N-末端或氨基酸侧链如赖氨酸能够与接头试剂、药物部分或药物-接头试剂的官能团形成键。
接头优选在细胞外是稳定的。在转运或递送到细胞中前,抗体-药物偶联物(ADC)优选是稳定且完整的,即抗体仍然连接到药物部分。接头在靶细胞外是稳定的,并且在细胞内可以以一定的功效速率(efficacious rate)裂解。有效的接头将∶(i)保持抗体的特异性结合特性;(ii)允许偶联物或药物部分的细胞内递送;(iii)保持稳定和完整,即直到偶联物已被递送或转运到其目标位置才裂解;和(iv)保持美登木素生物碱药物部分的细胞毒性、细胞杀伤效应或细胞抑制效应。ADC的稳定性可以通过标准分析技术如质谱学、HPLC、和分离/分析技术LC/MS测定。
抗体与药物部分的共价连接要求接头具有两个反应官能团,即在反应性意义上是二价的。可用于连接两个或多个功能或生物学活性部分的二价接头试剂如肽、核酸、药物、毒素、抗体、半抗原、以及报道分子基团是已知的,已经描述了所述方法以及由其获得的偶联物(Hermanson,G.T.(1996)Bioconjugate Techniques;Academic Press:New York,p234-242)。
接头可以具有选自下述的结构∶
其中波浪线表示以任何方向的与Ab和D的共价连接;X可以具有任何方向的下述结构∶
其中R独立地为H或C1-C6烷基;且n为1至12;Y可以具有任何方向的下述结构∶
其中R独立地为H或C1-C6烷基;且n为1至12。
例如,接头可以具有下述称为SMCC的结构∶
在另一实施方案中,接头(L)具有下述结构∶
其中波浪线表示以任何方向的与Ab和D的共价连接。
例如,接头可以具有下述称为SIAB的结构∶
在另一实施方案中,接头(L)具有下述结构∶
在另一实施方案中,接头可以被调节溶解性或反应性的基团所取代。例如,磺酸酯(sulfonate)取代基可以增强试剂的水溶性并促进接头试剂与抗体或药物部分的偶联反应,或者促进Ab-L与D、或D-L与Ab的偶联反应,这取决于制备ADC所使用的合成路线。
在另一实施方案中,接头具有含亲核基团的反应性官能团,即对抗体上存在的亲电子基团是反应性的。抗体上有用的亲电子基团包括但不限于醛和酮的羰基。接头亲核基团的杂原子能够与抗体上的亲电子基团反应,与抗体单元形成共价键。接头上可用的亲核基团包括但不限于酰肼、肟、氨基、肼、缩氨基硫脲、肼羧酸酯、和芳基酰肼(arylhydrazide)。抗体上的亲电子基团提供与接头连接的便利的位点。
接头可以是包含一个或多个氨基酸单位的肽的接头。肽接头试剂可以通过固相或液相合成法在自动合成仪如Rainin Symphony PeptideSynthesizer(Protein Technologies,Inc.,Tucson,AZ)、或Model 433(AppliedBiosystems,Foster City,CA)上制备(E.and K.Lübke,The Peptides,volume 1,pp 76-136(1965)Academic Press),这是肽化学包括t-BOC化学(Geiser et al"Automation of solid-phase peptide synthesis"in MacromolecularSequencing and Synthesis,Alan R.Liss,Inc.,1988,pp.199-218)和Fmoc/HBTU化学(Fields,G.and Noble,R.(1990)"Solid phase peptide synthesis utilizing9-fluoroenylmethoxycarbonyl amino acids",Int.J.Peptide Protein Res.35:161-214)领域熟知的。
所述化合物在措辞上指但不限于用如下交联剂制备的ADC:BMPEO、BMPS、EMCS、GMBS、HBVS、LC-SMCC、MBS、MPBH、SBAP、SIA、SIAB、SMCC、SMPB、SMPH、磺基(sulfo)-EMCS、磺基(sulfo)-GMBS、磺基-KMUS、磺基-MBS、磺基-SIAB、磺基-SMCC、和磺基-SMPB、以及SVSB(琥珀酰亚胺基-(4-乙烯砜)苯甲酸酯),并且包括二-马来酰亚胺试剂:DTME、BMB、BMDB、BMH、BMOE、BM(PEO)3、和BM(PEO)4,其在商业上可从Pierce Biotechnology,Inc.,Customer ServiceDepartment,P.O.Box 117,Rockford,I L.61105U.S.A,U.S.A 1-800-874-3723,International+815-968-0747获得。参见第467-498页,2003-2004ApplicationsHandbook and Catalog。二-马来酰亚胺试剂允许抗体半胱氨酸残基的游离硫醇基以序贯或同时的形式连接于含硫醇的药物部分、标记、或接头中间体。除马来酰亚胺之外,与抗体、美登木素生物碱药物部分、或接头中间体的硫醇基反应的其它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、异氰酸酯、和异硫氰酸酯。
其中DM1通过BMPEO接头连接至曲妥单抗的硫醇基的示例性抗体-药物偶联物具有下述结构∶
其中Tr是曲妥单抗;n为0、1、或2;并且p为1、2、3、或4。
可用的接头试剂也可经由其它商业来源获得,如Molecular BiosciencesInc.(Boulder,CO),或者按照Toki et al(2002)J.Org.Chem.67:1866-1872;US6214345to Firestone et al;WO 02/088172;US 2003130189;US2003096743;WO 03/026577;WO 03/043583;and WO 04/032828中描述的方法合成。
接头可以为超过一个药物部分通过分支、多功能接头部分共价连接于抗体的树枝状类型接头(Sun et al(2002)Bioorganic&Medicinal ChemistryLetters 12:2213-2215;Sun et al(2003)Bioorganic&Medicinal Chemistry11:1761-1768;King et al(2002)Tetrahedron Letters 43:1987-1990)。树枝状接头能够提高药物与抗体的摩尔比,即负载的比例,其与ADC的效力有关。这样,在只拥有一个反应性半胱氨酸硫醇基的抗体上,可以通过树枝状接头连接许多药物部分。
树枝状接头试剂的下述示例性具体形式允许高达九个亲核药物部分试剂通过与氯乙烷氮芥官能团反应而被偶联∶
药物负载
在式I的分子中,以p表示药物负载,代表每个抗体负载的美登木素生物碱药物的平均数目。药物负载可以为每个抗体(Ab)1至8个药物(D),即其中1、2、3、4、5、6、7、和8个药物部分共价连接于抗体。式I的ADC的组成包括与1至8个药物偶联的抗体的集合。来自偶联反应的ADC制品中,每个抗体的药物平均数目可以通过传统方法如质谱学方法、ELISA测试、电泳、和HPLC鉴定。也可以测定ADC依据p的定量分布。通过ELISA可以测定特定ADC制品中的p平均值(Hamblett et al(2004)Clinical Cancer Res.10:7063-7070;Sanderson et al(2005)Clinical Cancer Res.11:843-852)。然而,p(药物)值分布不能通过抗体-抗原结合和ELISA的检测限制来辨别。同时,检测抗体-药物偶联物的ELISA测试不测定药物部分于何处连接于抗体,如重链或轻链片段、或特定氨基酸残基。在一些情况下,可以通过如反相HPLC或电泳等手段实现同质ADC的分离、纯化、和鉴定,其中p为来自ADC与其它药物负载的特定值。
对于一些抗体-药物偶联物,p可能受限于抗体上的连接位点数目。例如,连接的位点是半胱氨酸硫醇,如上述示例性实施方案中,抗体可能仅有一个或几个半胱氨酸硫醇基,或者可能仅有一个或几个充分反应性的硫醇基,接头可以通过此硫醇基连接。更高的药物负载,例如p>5,可能导致某些抗体-药物偶联物的聚集、不可溶性、毒性、或细胞通透性的丧失。
典型地,偶联反应期间,偶联于抗体的药物部分小于理论最大值。抗体可以包含例如许多不与药物-接头中间体(D-L)或接头试剂反应的赖氨酸残基。只有反应性最强的赖氨酸基团能够与胺反应性接头试剂反应。同样,只有反应性最强的半胱氨酸硫醇基能够与硫醇反应性接头试剂反应。通常,即便有,抗体也不会包含许多能够连接到药物部分的游离的反应性半胱氨酸硫醇基。抗体化合物中的大多数半胱氨酸硫醇残基都以二硫键形式存在,必须用还原剂如二硫苏糖醇(DTT)或TCEP在不完全或完全还原条件下还原。此外,抗体必须置于变性条件下以暴露反应性亲核基团如赖氨酸或半胱氨酸。ADC的负载(药物/抗体比)可以以几种不同的方式得到控制,包括∶(i)限制相对于抗体的药物-接头中间体(D-L)或接头试剂的过量摩尔数,(ii)限制偶联反应时间或温度,和(iii)针对半胱氨酸硫醇修饰的不完全的或者限制的还原条件。
抗体中超过一个亲核或亲电子基团与药物-接头中间体或接头试剂反应,之后与药物部分试剂反应,然后所得产物为ADC化合物的混合物,其具有例如1、2、3等连接于抗体的药物部分的分布。液相色谱方法如聚合物反相(PLRP)和疏水性相互作用(HIC)能够通过药物负载值分离混合物中的化合物。可以分离具有单一药物负载值(p)的ADC制品(“Effect of drug loadingon the pharmacology,pharmacokinetics,and toxicity of an anti-CD30antibody-drug conjugate”,Hamblett,K.J.,et al,Abstract No.624,AmericanAssociation for Cancer Research;2004Annual Meeting,March 27-31,2004,Proceedings of the AACR,Volume 45,March 2004;“Controlling the Locationof Drug Attachment in Antibody-Drug Conjugates”,Alley,S.C.,et al,AbstractNo.627,American Association for Cancer Research;2004Annual Meeting,March 27-31,2004,Proceedings of the AACR,Volume 45,March 2004)。然而,这些单一负载值ADCs可能仍然是异源混合物,因为药物部分可以经由接头连接于抗体上的不同位点。
抗体-药物偶联物的制备
式I的ADC可以通过几个路线,使用本领域技术人员已知的有机化学反应、条件、和试剂制备,包括∶(1)抗体亲核基团或亲电子基团与二价接头试剂反应,形成由共价键连接的抗体-接头中间体Ab-L,之后与活化的药物部分D反应;和(2)药物部分的亲核基团或亲电子基团与接头试剂反应,形成由共价键连接的药物-接头中间体D-L,之后与抗体的亲核基团或亲电子基团反应。可以利用多种抗体、药物部分、和接头来应用偶联方法(1)和(2),以制备式I的抗体-药物偶联物。
抗体上的亲核基团包括但不限于∶(i)N端氨基,(ii)侧链氨基,例如赖氨酸,(iii)侧链硫醇基,例如半胱氨酸,和(iv)糖羟基或氨基,其中抗体是糖基化的。氨、硫醇、和羟基是亲核的,能够与接头部分(linker moieties)和接头试剂上的亲电子基团反应形成共价键,所述亲电子基团包括∶(i)活性酯如NHS酯、HOBt酯、卤代甲酸酯(haloformates)、和酸性卤化物;(ii)烷基和苄基卤化物如卤代乙酰胺;(iii)醛、酮、羧基、和马来酰亚胺基团。某些抗体具有可还原的链间二硫键,即半胱氨酸桥。抗体可以通过用还原剂如DTT(Cleland's reagent,二硫苏糖醇)或TCEP(三(2-羧乙基)膦盐酸盐(tris(2-carboxyethyl)phosphine hydrochloride);Getz et al(1999)Anal.Biochem.Vol 273:73-80;Soltec Ventures,Beverly,MA)处理而使之对于与接头试剂的偶联为反应性的。这样,每个半胱氨酸二硫桥理论上将形成两个反应性硫醇亲核物。可以通过赖氨酸与2-亚氨基噻吩(Traut's试剂)反应将其它的亲核基团引入抗体中,所述反应将胺转化为硫醇。
也可以通过修饰抗体以引入亲电子部分来生产抗体-药物偶联物,亲电子部分能够与接头试剂或药物上的亲核取代基反应。例如可以用高碘酸氧化剂氧化糖基化抗体的糖,形成醛或酮基,醛或酮基可以与接头试剂或药物部分(drug moieties)的胺基反应。所得亚胺席夫碱基团可以形成稳定的键,或可以例如通过氢硼化物试剂还原形成稳定的胺键。在一个实施方案中,糖基化抗体的碳水化合物部分与半乳糖氧化酶或高碘酸钠(sodium meta-periodate)反应可以在蛋白质中产生羰基(醛和酮),羰基能够与药物上的适当基团反应(Hermanson,G.T.(1996)Bioconjugate Techniques;Academic Press:New York,p234-242)。在另一实施方案中,包含N端丝氨酸或苏氨酸残基的蛋白质能够与高碘酸钠反应,导致醛取代第一个氨基酸(Geoghegan&Stroh,(1992)Bioconjugate Chem.3:138-146;US 5362852)。这样的醛能够与药物部分或接头亲核试剂反应。
同样,药物部分上的亲核基团包括但不限于∶氨、硫醇、羟基、酰肼、肟、肼、缩氨基硫脲、肼羧酸酯、和芳基酰肼(arylhydrazide)基团,这些基团能够与接头部分和接头试剂上的亲电子基团反应形成共价键,所述亲电子基团包括∶(i)活性酯如NHS酯、HOBt酯、卤代甲酸酯、和酸性卤化物;(ii)烷基和苄基卤化物如卤代乙酰胺;(iii)醛、酮、羧基、和马来酰亚胺基团。
美登素可以例如转变为May-SSCH3,其可以还原为游离硫醇May-SH,并与修饰的抗体反应(Chari et al(1992)Cancer Research 52:127-131),和二硫化物接头一起形成美登木素生物碱-抗体免疫偶联物。已经报导了与二硫化物接头一起形成的抗体-美登木素生物碱偶联物(WO 04/016801;US6884874;US 2004/039176A1;WO 03/068144;US 2004/001838A1;US6441163;US 5208020;US 5416064;WO 01/024763)。二硫化物接头SPP用接头试剂N-琥珀酰亚胺4-(2-吡啶硫代)戊酸构建。抗体-SPP-DM1偶联物用下述结构表示∶
为了与本发明的非二硫化物接头ADC对比,测试了二硫化物(S-S)接头抗体-药物偶联物。按实施例3制备曲妥单抗-SPP-DM1(Ranson,M.andSliwkowski M.(2002)Oncology 63(suppl 1):17-24)。还测试了二硫化物抗体-药物偶联物∶曲妥单抗(trastuzumab)-SPDP-DM1、曲妥单抗(trastuzumab)-SPP-DM3、和曲妥单抗-SPP-DM4,其具有以下结构∶
本发明的ADC包括SMCC接头和DM1美登木素生物碱药物部分,以Ab-SMCC-DM1表示∶
Ab-SMCC-DM1的一个具体形式是曲妥单抗-SMCC-DM1,其中p为1、2、3、或4(Ab=曲妥单抗,Tr,WO 2005/037992)。ADC的另一种具体形式为曲妥单抗-SIAB-DM1(曲妥单抗=Tr),其具有下述结构∶
针对肿瘤相关抗原和细胞表面受体的抗体-药物偶联物(ADC)的筛选
转基因动物和细胞系尤其可用于筛选具有预防性或治疗性治疗疾病或紊乱潜力的抗体-药物偶联物(ADC),所述疾病或紊乱涉及肿瘤相关抗原和细胞表面受体例如HER2的过表达(US 6632979)。筛选可用的ADC可能涉及为转基因动物施用一定剂量范围的候选ADC,并在不同时间点测试ADC对所评估的疾病或紊乱的影响。或者,或除此之外,可以在暴露于疾病诱导因素之前或与之同时施用所述药物,如果适用的话。候选ADC可以在培养基或高通量筛选阵列下连续并分别地,或者同时筛选。筛选ADC的速率仅受合成速率或包括检测/测定/数据分析的筛选方法学速率的限制,ADC的筛选用于疾病或紊乱的预防性或治疗性治疗的应用。
筛选方法的具体方案包括(a)将细胞从稳定的乳腺癌细胞系移植到非人动物中,(b)为所述非人动物施用ADC候选药物以及(c)测定候选药物抑制肿瘤自移植细胞系形成的能力。本发明还涉及筛选用于治疗疾病或紊乱的候选ADC的方法,所述疾病或紊乱以受体蛋白的过表达为特征,所述方法包括(a)将来自稳定的乳腺癌细胞系的细胞与候选药物接触,和(b)评估候选ADC抑制稳定细胞系生长的能力。
筛选方法的一个具体方案包括(a)将来自稳定的乳腺癌细胞系的细胞与ADC候选药物接触,和(b)评估候选ADC阻断HER2的配体活化的能力。另一实施方案评估了候选ADC阻断调蛋白(heregulin)结合的能力。在另一实施方案中,评估了候选ADC阻断配体刺激的酪氨酸磷酸化的能力。
筛选方法的另一具体方案包括(a)将来自稳定的乳腺癌细胞系的细胞与ADC候选药物接触,和(b)评估候选ADC诱导细胞死亡的能力。在一个实施方案中,评估了候选ADC诱导凋亡的能力。
筛选方法的另一实施方案包括(a)为例如在其乳腺细胞中过表达天然人蛋白质,例如HER2或其片段的转基因非人哺乳动物施用ADC候选药物,其中这种转基因哺乳动物已将编码天然人蛋白质或其具有天然人蛋白质的生物学活性的片段的核酸序列稳定地整合到其基因组中,所述核酸序列可操作地连接到引导其表达的转录调控序列,并且发育出对抗体治疗例如抗HER2抗体无反应或反应很弱的肿瘤,例如乳房肿瘤,或者施用于拥有从所述转基因非人哺乳动物移植的肿瘤的非人哺乳动物;和(b)评估候选ADC对目标疾病或紊乱的影响。非限制性地,所述疾病或紊乱可以是HER2-过表达的癌症,如乳腺、卵巢、胃、子宫内膜、唾液腺、肺、肾脏、结肠、甲状腺、胰腺和膀胱癌。所述癌症可以是以每个细胞至少约500,000个拷贝,或者每个细胞至少约2,000,000个拷贝表达HER2的乳腺癌。例如可以用本领域熟知的和以下描述的测试方法评估ADC候选药物诱导细胞死亡和/或凋亡的能力。
在一个实施方案中,通过为转基因动物施用一定剂量范围的候选ADC,并随着时间推移评估所述动物对所述化合物的生理反应来筛选候选ADC。施用可以是口服,或者通过合适的注射,这取决于要评估的化合物的化学性质。有时,与会增强化合物功效的辅助因子(co-factor)一起施用所述化合物可能是合适的。如果源于受试转基因动物的细胞系用于筛选可用于治疗不同病症的化合物,其中所述病症与某些肿瘤相关抗原蛋白或细胞表面受体的过表达,例如HER2-过表达相关,则于合适的时间将受试化合物添加到细胞培养基,并随着时间推移用适当的生物化学和/或组织学测试评估对所述化合物的细胞反应。有时,与会增强化合物功效的辅助因子一起将感兴趣的化合物应用到所述培养基可能是合适的。
因此,本发明提供用于鉴定ADC的测试方法,所述ADC特异地靶向并结合过表达的HER2蛋白,HER2蛋白的存在与异常的细胞功能相关连,并与乳腺肿瘤发生病因有关的乳腺细胞增生和/或分化的发病机理有关。
为了鉴定阻断ErbB(例如ErbB2)受体的配体活化的ADC,可以测定化合物阻断ErbB配体与表达ErbB(ErbB2)受体(例如处在与另一种ErbB受体偶联中,其中感兴趣的所述ErbB受体与所述另一种ErbB受体形成ErbB异源寡聚体)的细胞结合的能力。例如,从过表达HER2的转基因动物分离并转染以表达另一种ErbB受体(HER2与其一起形成异源寡聚体)的细胞可以与ADC一起保温即培养,然后与标记的ErbB配体接触。然后可以评估化合物阻断配体与ErbB异源寡聚体中的ErbB受体结合的能力。
例如,可以用24孔平板在冰上进行单层培养,来评价候选ADC抑制调蛋白(HRG)与乳腺肿瘤细胞系的结合,所述细胞系过表达HER2,并由本文的转基因非人哺乳动物(例如小鼠)建立。抗ErbB2单克隆抗体可以添加到每个小孔并保温30分钟。然后可以添加125I-标记的rHRGβ1177-224(25,000cpm),可以继续保温4至16个小时。可以制定剂量反应曲线,并且可以计算感兴趣化合物的IC50值。
或者,或除此之外,可以评估ADC阻断ErbB受体的ErbB配体刺激的酪氨酸磷酸化,所述ErbB受体存在于ErbB异源寡聚体中。例如,此处从转基因动物建立的细胞系可以与受试ADC一起保温,然后用抗磷酸化酪氨酸单克隆抗体(其任选与可检测标记偶联)测试ErbB配体依赖的酪氨酸磷酸化活性。US5766863中描述的激酶受体活化测试也可用于测定ErbB受体活化和化合物对活性的阻断。
在一个实施方案中,基本上可以如下所述在MCF7细胞中筛选ADC,所述ADC抑制pl80酪氨酸磷酸化的HRG刺激。例如,从HER2转基因动物建立的细胞系可以加入到24孔平板中,可以将化合物添加到每个小孔并在室温保温30分钟;可以将rHRGβ1177-244添加到每个小孔至0.2nM终浓度,可以继续保温约8分钟。培养基可以从每个小孔吸出,可以通过添加100μl SDS样品缓冲液(5%SDS、25mM DTT、和25mM Tris-HCl,pH6.8)来终止反应。每个样品(25μl)可以在4-12%梯度凝胶(Novex)上电泳,然后电泳转移到聚偏氟乙烯膜。可以使抗磷酸化酪氨酸(以1μg/ml)免疫印迹显影,可以通过反射密度测定法定量Mr-180,000的主要反应条带的强度。评估对受体磷酸化的抑制的替代方法是KIRA(激酶受体活化)测试(Sadick et al(1998)Jour.of Pharm.andBiomed.Anal.1-9)。在该测试中,一些公认的抗HER2单克隆抗体可以用作阳性对照,已知所述单克隆抗体抑制HRG刺激的p180酪氨酸磷酸化。可以制定对HRG刺激的p180酪氨酸磷酸化的抑制的剂量反应曲线,所述抑制通过反射密度测定法测得,还可以计算感兴趣化合物的IC50。
也可以评估受试ADC对源于HER2转基因动物的细胞系的生长抑制效应(Schaefer et al(1997)Oncogene 15:1385-1394)。根据该测试,可以用不同浓度的受试化合物处理细胞4天,并用龙胆紫或氧化还原染料Alamar Blue染色。与所述化合物一起保温可以显示对该细胞系的生长抑制效应,其类似于单克隆抗体2C4对MDA-MB-175细胞所显示的效应(Schaefer et al.,同上)。在另一实施方案中,外源HRG不会明显逆转此抑制。
为鉴定特异地靶向HER2的生长抑制性ADC化合物,可以筛选抑制源于转基因动物的HER2-过表达癌细胞生长的ADC(US 5677171)。根据该测试,HER2过表达细胞培养于F12和DMEM培养基的1:1混合物中,其中添加有10%胎牛血清、谷氨酰胺和青霉素链霉素。细胞以35mm细胞培养皿中20,000个细胞(2mls/35mm皿)铺板,以不同浓度添加受试化合物。六天后,用电子COULTERTM细胞计数器统计与未处理细胞相比的细胞数目。抑制细胞生长约20-100%或约50-100%的那些ADC可以选择为生长抑制性化合物。
为选择诱导细胞死亡的ADC,由例如PI、台盼蓝或7AAD吸收指示的膜完整性丧失,可以相对于对照评估。PI吸收测试使用从转基因动物乳腺肿瘤组织分离的细胞。根据该测试,细胞培养于Dulbecco's Modified EagleMedium(-MEM):Ham's F-12(50:50)中,所述培养基添加有10%热灭活FBS(Hyclone)和2mM L-谷氨酰胺。这样,所述测试在不存在补体和免疫效应细胞的情况下实施。细胞以3x106每培养皿的密度接种在100x20mm培养皿中,使之过夜附着。然后去除培养基并仅用新鲜培养基或用含不同浓度化合物的培养基更换。所述细胞保温3天时间。每次处理之后,用PBS冲洗细胞单层,并通过胰酶消化去附着。然后细胞在4°C 1200rpm离心5分钟,沉淀重悬于3ml冰冷Ca2+结合缓冲液(10mM Hepes、pH 7.4、140mM NaCl、2.5mMCaCl2)中,等分到35mm带帽粗滤器12x75mm试管(每管1ml,每个处理组3管)中,以去除细胞凝块。然后往试管加入PI(10μg/ml)。样品可以用FACSCANTM流式细胞仪和FACSCONVERTTM CellQuest软件(BectonDickinson)分析。通过PI吸收测得的诱导统计学显著细胞死亡水平的那些化合物可以选择为细胞死亡诱导化合物。
为了选择诱导凋亡的化合物,用从转基因动物乳腺肿瘤组织建立的细胞实施膜联蛋白结合测试。如前面段落讨论的那样,将细胞培养并接种在培养皿中。然后除去培养基并仅用新鲜培养基或者用含10μg/ml抗体-药物偶联物(ADC)的培养基更换。三天的保温期之后,用PBS冲洗细胞单层,并通过胰酶消化解附着。然后离心细胞,重悬于Ca2+结合缓冲液中,并等分到上述试管中用于细胞死亡测试。然后试管中加入标记的膜联蛋白(例如膜联蛋白V-FITC)(1μg/ml)。样品可以用FACSCANTM流式细胞仪和FACSCONVERTTMCellQuest软件(Becton Dickinson)分析。相对于对照而言,诱导统计学上显著膜联蛋白结合水平的那些化合物选择为凋亡诱导化合物。
体外细胞增殖测试
通常,通过如下所述测定抗体-药物偶联物(ADC)的细胞毒性或细胞抑制活性∶在细胞培养基中,将具有肿瘤相关抗原或受体蛋白的哺乳动物细胞与ADC的抗体接触;培养细胞约6小时至约5天的时间;测定细胞存活力(viability)。基于细胞的体外测试用于测定存活力,即ADC的增殖(IC50)、细胞毒性(EC50)、和凋亡诱导(胱天蛋白酶活化)。
抗体-药物偶联物的体外效力通过细胞增殖测试测定(图1-4)。Luminescent Cell Viability Assay是可在商业上利用的(PromegaCorp.,Madison,WI)均相测试(homogeneous assay)方法,其以鞘翅目(Coleoptera)荧光素酶的重组表达为基础(US 5583024;US 5674713;US5700670)。该细胞增殖测试以所存在的ATP的定量为基础测定培养物中的活细胞数目,ATP为代谢活性细胞的指示剂(Crouch et al(1993)J.Immunol.Meth.160:81-88;US 6602677)。测试在96孔板中实施,使之易于进行自动化高通量筛选(HTS)(Cree(1995)AntiCancer Drugs 6:398-404)。同相测试方法涉及直接将单一试剂Reagent)添加到培养在补充有血清的培养基中的细胞。不需要细胞冲洗、去除培养基和多个移液步骤。在添加试剂并混合后10分钟,所述系统在384-孔阵列中探测15个细胞/孔。
均相"添加-混合-测定"的形式导致细胞裂解,并产生与所存在的ATP的量成正比的发光信号。ATP的量直接与培养物中存在的细胞数目成正比。测试产生"辉光型(glow-type)"发光信号,其由荧光素酶反应产生,通常具有大于五小时的半衰期,这取决于所使用的细胞类型和培养基。活细胞以相对光单位(RLU)反映。底物Beetle荧光素由重组萤火虫荧光素酶氧化脱羧,同时伴随ATP转化为AMP并产生光子。延长的半衰期消除了使用试剂注射器(reagent injector)的需要,并提供多平板连续或分批方式处理的灵活性。可以以多种多孔阵列例如96或384孔阵列使用该细胞增殖测试。可以用光度计或CCD照相机成像装置记录数据。以相对光单位(RLU)提供荧光输出,其随着时间的推移而测定。
针对四种不同乳腺肿瘤细胞系,通过上述细胞增殖、体外细胞杀伤测试测定了三种抗体-药物偶联物的抗增殖效应(图1-4)。图1显示,处理SK-BR-3(HER23+)乳腺肿瘤细胞3天后,逐渐提高曲妥单抗-SPP-DM1、曲妥单抗-SPDP-DM1和曲妥单抗-SMCC-DM1浓度时的效力测量值。图2显示,处理BT-474(HER23+)乳腺肿瘤细胞3天后,逐渐提高曲妥单抗-SPP-DM1、曲妥单抗-SPDP-DM1和曲妥单抗-SMCC-DM1浓度时的效力测量值。图3显示,处理MCF7(HER2低)乳腺肿瘤细胞3天后,逐渐提高曲妥单抗-SPP-DM1、曲妥单抗-SPDP-DM和曲妥单抗-SMCC-DM1浓度时的效力测量值。图4显示,处理MDA-MB-468(HER2阴性)乳腺肿瘤细胞3天后,逐渐提高曲妥单抗-SPP-DM1、曲妥单抗-SPDP-DM1和曲妥单抗-SMCC-DM1浓度时的效力测量值。
确定了已知过表达HER2受体蛋白的SK-BR-3和BT-474的IC50值。对于针对SK-BR-3细胞的6个试验,许多偶联物,曲妥单抗-SPP-DM1(每个曲妥单抗2.8个DM1(药物/Ab))得到14.4μg/ml的平均IC50,其范围为9.1至22.3μg/ml,针对BT-474细胞的4个试验,得到51.7μg/ml的平均IC50,其范围为28.7至63.1μg/ml。针对SK-BR-3细胞的4个试验,许多偶联物曲妥单抗-SMCC-DM1(每个曲妥单抗2.7个DM1(药物/Ab))得到15.2μg/ml的平均IC50,其范围为12.6至18.8μg/ml,针对BT-474细胞的2个试验,得到94.9μg/ml的平均IC50,其范围为75.2至114.6μg/ml。所述偶联物对不过表达HER2的细胞MCF7和MDA-MB-468无活性。
用Raji细胞显示了抗CD19-SMCC-DM1强烈的体外细胞杀伤(IC50=<0.25μg/ml),其中在Raji细胞中裸抗体和对照ADC、曲妥单抗-SMCC-DM1未显示影响。用Ramos细胞显示了抗CD79a-SMCC-DM1和抗CD79b-SMCC-DM1强烈的体外细胞杀伤(IC50=<0.25μg/ml),其中在Raji细胞中裸抗体和对照ADC、曲妥单抗-SMCC-DM1未显示影响。
图17显示利用HT1080EphB2(C8)细胞实施的体外细胞增殖测试(实施例5),所述HT1080EphB2(C8)细胞用抗EphB2R 2H9抗体-药物偶联物∶2H9-SPP-DM 1(IC5080ng/ml)、和2H9-SMCC-DM 1(IC5050ng/ml)处理过。
小鼠体内血清清除率和稳定性
在裸的首次用于实验的(nude,naive)(没有通过外源移植接受肿瘤)小鼠中研究了ADC的血清清除率和稳定性。图5显示无曲妥单抗-SMCC-DM1肿瘤相对无曲妥单抗-SPP-DM1肿瘤的米色裸鼠中的血清清除率,在7天时间于六个时间点测定偶联物和总抗体血清浓度。总抗体和ADC在量上的差异显示接头的裂解和抗体从其DM1部分的分离。如更高偶联抗体血清浓度于第七天时所显示的,SMCC-连接的ADC在体内保持完整的时间要长于SPP-连接的偶联物。
图6显示无肿瘤裸鼠中下述偶联物随时间推移的稳定性∶曲妥单抗-SPDP-DM1、曲妥单抗-SPP-DM1、曲妥单抗-SPP-DM3、曲妥单抗-SPP-DM4、和曲妥单抗-SMCC-DM1,在7天中六个时间点测定血清浓度。在体内具有SMCC接头的ADC比由SPP或SPDP连接的偶联物更稳定,尽管曲妥单抗-SMCC-DM1具有大约与最阻碍的二硫化物偶联物(most hindered sulfideconjugate)曲妥单抗-SPP-DM4相同的稳定性。
图5和6中所示试验在无肿瘤裸鼠中进行。然而,在具有肿瘤的裸鼠中,与SPP连接的偶联物相比,SMCC连接的偶联物显示相同的增强的稳定性。如图7所示,处理7天后,大约72%的初始曲妥单抗-SMCC-DM1仍然为偶联物,而在处理7天后,只有大约10%的初始曲妥单抗-SPP-DM1仍然为偶联物,显示了非酶学可裂解的曲妥单抗-SMCC-DM1偶联物在具有肿瘤的裸鼠中增强的稳定性。
大鼠体内血清清除率和稳定性
图8和9显示二硫化物接头ADC(曲妥单抗-SPP-DM1)和非二硫化物接头ADC(曲妥单抗-SMCC-DM1)在大鼠中的相对稳定性和清除率图谱。研究的参数包括∶
参数 | 曲妥单抗-SPP-DM 1 | 曲妥单抗-SMCC-DM 1 |
Vd(ml/kg | 41 | 41 |
清除率(ml/天/kg) | 52 | 15 |
T1/2alpha | 0.09 | 0.15 |
T1/2beta | 0.7 | 0.85 |
T1/2gamma(天) | 2.6 | 5.5 |
与二硫化物接头(disulfide linker)ADC曲妥单抗-SPP-DM1(图8)相比,非二硫化物接头ADC曲妥单抗-SMCC-DM1(图9)在大鼠血清中显示更好的稳定性。
体内功效
可以通过在啮齿类动物中植入癌细胞的同种异体移植物或异种移植物并用ADC处理肿瘤而测定本发明的抗体-药物偶联物的功效。取决于细胞系、ADC与癌细胞上存在的受体的抗体结合特异性、剂量给药方案、和其它因素,预期结果是不同的。抗HER2ADC的体内功效用高表达HER2转基因外植体(explant)小鼠模型测定。从Fo5mmtv转基因小鼠繁殖同种异体移植物,所述Fo5mmtv转基因小鼠对HERCEPTIN治疗无反应或反应很弱。受试者用ADC处理一次,并监测3-6周,以测定肿瘤加倍时间、细胞杀伤对数、和肿瘤缩小的时间。跟踪剂量-反应并进行多个剂量试验。
肿瘤很容易在表达突变活化型neu的转基因小鼠中发生,突变活化型neu是HER2的大鼠同系物,但在乳腺癌中过表达的HER2未突变,并且在过表达非突变HER2的转基因小鼠中,肿瘤形成的强度小得多(Webster et al(1994)Semin.Cancer Biol.5:69-76)。
为了用非突变HER2增强肿瘤形成,用HER2cDNA质粒生产转基因小鼠,其中在HER2cDNA质粒中删除了上游ATG,以阻止翻译在此上游ATG密码子处起始,否则其将减少自下游真正的HER2起始密码子启动翻译的频率(例如,参见Child et al(1999)J.Biol.Chem.274:24335-24341)。除此之外,将嵌合内含子添加到5’端,也将如早先报导的,增强表达水平(Neuberger andWilliams(1988)Nucleic Acids Res.16:6713;Buchman and Berg(1988)Mol.Cell.Biol.8:4395;Brinster et al(1988)Proc.Natl.Acad.Sci.USA 85:836)。所述嵌合内含子源于Promega载体,pCI-neo哺乳动物表达载体(bp 890-1022)。cDNA 3’端一侧是人生长激素外显子4和5、和多聚腺苷序列。另外,使用了FVB小鼠,因为此株系对肿瘤产生更敏感。来自MMTV-LTR的启动子用于确保组织特异性HER2在乳腺中表达。为动物饲喂AIN 76A饲料以增强对肿瘤形成的敏感性(Rao et al(1997)Breast Cancer Res.and Treatment45:149-158)。
图10-13显示ADC在HER2阳性肿瘤(Fo5)的同种异体移植物中具有强烈的抗肿瘤活性,所述HER2阳性肿瘤(Fo5)起初发生在MMTV-HER2转基因小鼠中。在此模型中,仅仅抗体(例如曲妥单抗)不具有显著的抗肿瘤活性(Erickson et al US 6632979)。如图10和11所示,与对照(载体(vehicle))生长水平相比,用ADC处理阻滞了肿瘤的生长。用曲妥单抗-SMCC-DM1和曲妥单抗-SIAB-DM1偶联物处理,肿瘤生长减缓得最多。如图10、12和13所示,曲妥单抗-SMCC-DM1偶联物对肿瘤生长的减缓大于具有SPP接头的偶联物,即更有效,无论是测定肿瘤在裸鼠中加倍的时间还是测定对应于所示加倍时间测量值的对数细胞杀伤(Log Cell Kill)(图13)。
用小鼠肿瘤异种移植物模型测定了抗CD22ADC的体内功效。在第1天(有指明的除外),定量给予试验组小鼠抗CD22抗体-药物偶联物或裸(naked)抗体一次,每个试验组八只SCID小鼠,每只小鼠有2千万个Bjab-luc(表达荧光素酶的Bjab细胞)异种移植物肿瘤细胞(实施例8)。
测定了肿瘤大小加倍的时间(MTD,平均肿瘤加倍时间)。相对于非特异性结合的ADC(曲妥单抗-SMCC-DM1),三种裸抗CD22抗体基本上不显示功效。相应偶联物都显示明显的阻滞肿瘤生长的效果。用RFB4-SMCC-DM1确立了多次给药的效果,其中对于单次给药的小鼠MTD为18天,而对于第1、7、和14天给药三次的小鼠MTD为55天。肿瘤完全消退发生在三次给药组的所有8只小鼠中。在每只小鼠具有2千万个Bjab-luc异种移植物肿瘤细胞的SCID小鼠中,施用单一剂量(400μgDM1/m2)7天后,其中抗体为12F7、9A8、8C9、8G10、3F11、10D2、6C9、14D1、和11H10的其它抗CD22-SMCC-DM1偶联物相对于对照(曲妥单抗-SMCC-DM1)显示初始肿瘤体积的缩小或肿瘤生长的延迟。在每只小鼠具有5百万个Ramos RA1异种移植物肿瘤细胞的SCID小鼠中,施用单一剂量(200μgDM1/m2)11天后,抗CD22偶联物RFB4-SMCC-DM1、5E8-SMCC-DM1、和7A2-SMCC-DM1相对于对照(曲妥单抗-SMCC-DM1)在阻滞肿瘤生长方面也是有效的。
在每组十只具有Bjab-luc异种移植物的SCID小鼠的试验组上,以三种不同的药物负载研究了偶联物RFB4-SMCC-DM1(实施例8)。低(1.95)和中等(3.7)药物负载偶联物分别显示明显的阻滞肿瘤生长的效果,MTD为约15天。高负载(6.75)偶联物没有显示出明显不同于对照偶联物GP120-SMCC-DM1、或裸抗体RFB4的效果。
抗CD19-SMCC-DM1和抗CD22-SMCC-DM1偶联物在Raji细胞小鼠肿瘤异种移植物模型中没有显示体内活性。其它抗CD19和抗CD22偶联物针对其它癌细胞肿瘤模型可具有体内活性。
用小鼠肿瘤异种移植物模型测定了抗CD79a(alpha)和抗CD79b(beta)ADC的体内功效。用下表和之后的实施例8中的样品于第1天为每组8只SCID小鼠、每只小鼠具有2千万个Bjab-luc异种移植物肿瘤细胞的小鼠试验组给药。
7天后,偶联物SN8抗CD79b-SMCC-DM 1、17A7抗CD79b-SMCC-DM1、和8H9抗CD79a-SMCC-DM1均显示出初始肿瘤体积的缩小(平均160mm3)。在8只小鼠的试验组中,偶联物SN8抗CD79b-SMCC-DM1在4只动物中获得部分消退(PR),在2只动物中获得完全消退(CR)。偶联物17A7抗CD79b-SMCC-DM 1在1只动物中获得CR。偶联物8H9抗CD79a-SMCC-DM1在2只动物中获得PR,在1只动物中获得CR。在每只小鼠具有2千万个Bjab-luc异种移植物肿瘤细胞的CB17ICR SCID小鼠中,施用单一剂量(192μgDM1/m2)8天后,其中抗体为2F2、5C3、7H7、8D11、15E4、和16C11的其它抗CD79b-SMCC-DM1偶联物相对于对照(曲妥单抗-SMCC-DM1)显示初始肿瘤体积的缩小或肿瘤生长的阻滞。
测定了施用抗CD79b-SMCC-DM1的小鼠的剂量反应效果。用下表(实施例8)中的样品于第1天为每组8只SCID小鼠、每只小鼠具有2千万个Bjab-luc异种移植物肿瘤细胞的小鼠试验组给药。抗CD79b-SMCC-DM1以0.5、2.0、和3.64mg Ab/kg小鼠的水平给药。
用小鼠肿瘤异种移植物模型测定了抗TENB2ADC的体内功效。TENB2为肿瘤抗原,已显示TENB2几乎只在人前列腺中表达并在人前列腺肿瘤中过表达(Glynne-Jones et al(2001)Int J Cancer.Oct 15;94(2):178-84)。PC3-TVA-919cv1:5为表达高水平TENB2的人前列腺癌细胞系。
以每只小鼠0.2ml的体积为无胸腺裸鼠皮下注射5百万PC3-TVA-919高表达或中等表达细胞。将细胞悬浮于HBSS中。当平均肿瘤大小达到100-200mm3时,将小鼠随机分为8组,每组分别有8-10只小鼠,给予下述样品的单次IV处理(实施例8)。
相对于阴性对照和载体对照,鼠抗TENB2-DM1偶联物显示针对PC3-TENB2肿瘤的抗肿瘤功效。相对于阴性对照和载体对照,鼠10H1抗NaPi3b-SMCC-DM1偶联物未显示针对PC3-NaPi3b肿瘤的抗肿瘤功效。抗NaPi3b偶联物的其它抗体变体可具有针对PC3-NaPi3b肿瘤或其它癌细胞系的体内活性。
啮齿类动物毒性
在急性毒性大鼠模型中评估了抗体-药物偶联物和无ADC的对照“载体(vehicle)”。通过用ADC处理雌性Sprague-Dawley大鼠,随后观察和分析对多种器官的影响,如此研究了ADC的毒性。以总的观察结果(体重)、临床病理学参数(血清化学和血液学)和组织病理学为基础,可以观察、鉴定、和测定ADC的毒性。发现在等同剂量水平,与曲妥单抗-SPP-DM1相比,曲妥单抗-SMCC-DM1与更小的急性毒性相关。
通过曲妥单抗-SMCC-DM1的单次注射(两个剂量∶1860和3260μgDM1/m2),与二硫化物ADC、曲妥单抗-SPP-DM1(两个剂量∶1860和3260μgDM1/m2)、游离DM1美登素(硫醇)和对照载体的单次注射(第0天)相对比,对青春期雌性大鼠(100-125gms)实施了5-天急性毒性研究。每天测定体重。于第3天和第5天进行临床化学、血清酶和血液学分析;由组织病理学评估的完全尸体解剖一起作结论。毒性信号包括体重损失的临床观察。
定量给予ADC后,相对于仅给予载体的动物而言,动物体重损失、或体重改变是全身或局部毒性的总的和一般性指示。图14显示5天时间体重(克)的变化。接受二硫化物ADC、曲妥单抗-SPP-DM1的大鼠显示明显的、剂量依赖的毒性,这通过较高剂量时的致死现象和较低剂量时的体重减少显现出来。相反,接受曲妥单抗-SMCC-DM1的大鼠增加了体重,相对于给予安慰剂载体的大鼠,给予较低剂量的大鼠未显示增重速率的降低。给予较高水平曲妥单抗-SMCC-DM1的大鼠,与游离DM1细胞毒素相比也增加了体重。
通过肝酶的增高、有丝分裂和凋亡征象数目的增加以及肝细胞坏死测定了肝脏毒性。通过白细胞、主要粒细胞(嗜中性粒细胞)、和/或血小板损耗、以及淋巴器官介入,即萎缩或凋亡活性观测对血液淋巴(Hematolymphoid)系统的毒性。毒性也表现为胃肠道病变如有丝分裂和凋亡征象数的增加以及退化性肠炎(degenerative entercolitis)。
所研究的肝损伤的酶指标包括∶
AST(天冬氨酸转氨酶)
–定位∶细胞质;肝、心脏、骨骼肌、肾脏
-肝∶7000:1的血浆比率
–T1/2∶17小时
ALT(丙氨酸转氨酶)
–定位∶细胞质;肝、肾脏、心脏、骨骼肌
-肝:3000:1的血浆比率(plasma ratio)
-T1/2∶42小时;昼夜变化
GGT(g-谷氨酰转移酶)
-定位∶具有高分泌或吸收能力的细胞的质膜;肝、肾脏、肠
-肝损伤的弱预测物;通常在胆管疾病中升高
上述测定的三种酶都不是肝特异性的。发现本发明的ADC导致肝酶ALT和AST的瞬时、轻微上升,和瞬时的网状细胞减少(图15)。没有观察到对外周血粒细胞或血小板的影响(图16)。
图15和16显示,在此五天急性毒性研究中,暴露于22.3mg/kg曲妥单抗-SPP-DM1(第2组)的大鼠显示出最严重的临床毒性。这些动物显示出最严重的体重减轻、肝功能测试值升高、白细胞和血小板减少以及针对造血淋巴组织的形态学毒性迹象。与先前使用25mg/kg剂量的研究所得到的结果相比,毒性程度是类似的。相反,分别以10和25mg/kg的剂量给予曲妥单抗-SMCC-DM1的第3组和第4组动物不能与载体处理的动物以临床病理学和体重数据为基础区别开。在形态学上,这些动物肝中显示有丝分裂像数轻微增加,然而,外围淋巴和造血组织在正常范围内。
第5组50mg/kg曲妥单抗-SMCC-DM1的动物显示出毒性迹象。然而,除一种肝功能测试(ALT)之外,毒性严重程度小于接受50%的与曲妥单抗-SPP-DM1相同药物剂量的动物(第2组)。在大约相同的剂量,曲妥单抗-SMCC-DM1(第4组,22.3mg/kg)显示大约25%的曲妥单抗-SPP-DM1(第2组,25mg/kg)的AST水平。到该研究的第5天,第5组动物显示体重增加(继第3天和第4天短暂的体重损耗之后),血清胆红素降低且血小板数升高(图15)。
暴露于游离美登木素生物碱DM1的动物(第6组)显示出与用曲妥单抗偶联物处理的动物相同的毒性模式。此游离DM1的剂量相当于先前研究中给予的10mg/kg曲妥单抗-SPP-DM1剂量的药物量。第6组动物中的毒性严重程度小于第2组动物所看到的,但大于之前在用10mg/kg曲妥单抗-SPP-DM1处理的动物中所看到的。看起来康复相当快∶在用游离美登素处理的动物中,脾脏切片显示不成熟造血成分数量增加;同时,到第5天时,在第6组动物中,显示LFTs和临床血液学参数明显趋于正常化的趋势。
猕猴毒性/安全性
可以评估施用于猕猴(Cynomolgus monkey)的ADC的毒性和安全性。用猕猴进行了抗体-药物偶联物曲妥单抗-SMCC-DM1的毒性/安全性研究。研究了三组猴子以评估静脉注射施用的曲妥单抗-SMCC-DM1相对于对照(载体)的毒性,所注射的曲妥单抗-SMCC-DM1的剂量逐步升高。第1组(4个受试者)在第1天和第22天只接受载体(PBS,pH 6.5,即去除ADC的制剂),此后于第36天进行尸体解剖。第2组(4个受试者)于第1天和第22天接受曲妥单抗-SMCC-DM1 4900μg/m2。第3组(4个受试者)于第22天接受曲妥单抗-SMCC-DM1 7200μg/m2。
由啮齿类动物毒性研究中升高的肝酶测量值来推断肝脏毒性。定量给予猕猴载体(第1组)和曲妥单抗-SMCC-DM1(第2组∶4900μg/m2;第3组∶7200μg/m2)。在猕猴中测定了针对曲妥单抗-SMCC-DM1的肝酶AST、血小板数、白细胞、绝对嗜中性粒细胞、红细胞和网织红细胞,和2次IV给药方案作对比(实施例10)。
抗体-药物偶联物药物制剂的施用
治疗性抗体-药物偶联物(ADC)可以通过任何适合于所要治疗的病症的途径施用。典型地,肠胃外即输注、皮下、肌肉内、静脉内、皮内、鞘内、快速推注(bolus)、肿瘤内注射或硬膜外施用ADC(Shire et al(2004)J.Pharm.Sciences 93(6):1390-1402)。治疗性抗体-药物偶联物(ADC)的药物制剂典型地随同药学上可接受的肠胃外载体制备用于肠胃外施药,并且为可注射的单位剂量形式。具有所需纯度的抗体-药物偶联物(ADC)任选与药学上可接受的稀释剂、载体、赋形剂或稳定剂混合,可为冻干制剂或水溶液形式(Remington's Pharmaceutical Sciences(1980)16th edition,Osol,A.Ed.)。
可接受的肠胃外媒介物、稀释剂、载体、赋形剂、和稳定剂在所用剂量和浓度对受试者来说是无毒的,其包括缓冲液如磷酸盐、柠檬酸盐、和其它有机酸;抗氧化剂,包括抗坏血酸和蛋氨酸;防腐剂(如八癸二甲基苄基氯化铵;氯化六烃季铵;苯扎氯铵、氯化苄甲乙氧铵;苯酚、丁基或苯甲醇;烷基对羟基苯甲酸酯类如甲基或丙基对羟苯甲酸酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(小于约10个残基)多肽;蛋白质,如血清白蛋白、明胶、或免疫球蛋白;亲水性聚合物如聚乙烯吡咯烷酮;氨基酸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、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;螯合剂如EDTA;糖如蔗糖、甘露醇、海藻糖或山梨醇;形成盐的反离子如钠;金属复合物(例如锌-蛋白质复合物);和/或非离子表面活性剂如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。例如,WO 97/04801中描述了冻干的抗ErbB2抗体制剂,此处特别加入作为参考。ADC的示例性制剂如曲妥单抗-SMCC-DM1包含约100mg/ml的海藻糖(2-(羟甲基)-6-[3,4,5-三羟基-6-(羟甲基)四氢吡喃-2-基]氧-四氢吡喃-3,4,5-三醇;C12H22O11;CAS第99-20-7号)和约0.1%TWEENTM20(多山梨醇酯20;月桂酸2-[2-[3,4-二(2-羟乙氧基)四氢呋喃-2-基]-2-(2-羟乙氧基)乙氧基]乙酯;C26H50O10;CAS第9005-64-5号),pH约为6。
治疗性抗体-药物偶联物(ADC)的药物制剂可以包含一定量的不反应药物部分(D)、抗体-接头中间体(Ab-L)、和/或药物-接头中间体(D-L),其为ADC制备过程中过量试剂、杂质、和副产品不完全纯化和分离;或者为批量ADC存储过程中或制剂化ADC组合物存储过程中受时间/温度影响水解或降解的结果。例如,ADC制剂曲妥单抗-SMCC-DM1可以包含可检测量的游离药物DM1。或者,或除此之外,其可以包含可检测量的药物-接头中间体DM1-SMCC。或者,或除此之外,其可以包含可检测量的抗体曲妥单抗。曲妥单抗-SMCC-DM1的示例性制剂可以包含直至10%摩尔当量的DM1-SMCC。出乎意料地,经体外细胞增殖测试测定(实施例5),对于SK-BR-3和BT-474乳腺癌细胞,与游离药物DM1(IC500.0045μM)相比,DM1-SMCC(IC500.05μM)在细胞杀伤方面效力大约小20倍。
例如,也可以通过凝聚技术或界面聚合将活性药物成分包装于所制备的微胶囊中,例如分别包装于羟甲基纤维素或明胶-微胶囊和聚(甲基丙烯酸甲酯)微胶囊中,包装于胶状药物递送系统(例如,脂质体、白蛋白微球、微乳剂、纳米颗粒和纳米胶囊)或者包装于大颗粒乳液(macroemulsion)中。这些技术公开于Remington's Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980)。
可以制备缓释制品。适当的缓释制品的例子包括包含ADC的固态疏水性聚合物半透性基质,其中基质为成形颗粒产品形式的,例如薄膜、或微胶囊。缓释基质的例子包括聚酯、水凝胶(例如,聚(2-羟乙基-丙烯酸甲酯)、或聚乙烯醇、聚交酯(US 3773919)、L-谷氨酸和gamma-乙基-L-谷氨酸的共聚物、不可降解的乙烯-醋酸乙烯酯、可降解的乳酸-羟基乙酸共聚物如LUPRON DEPOTTM(由乳酸-羟基乙酸共聚物和醋酸亮丙瑞林组成的可注射微球)、以及聚-D-(-)-3-羟丁酸。
用于体内施用的制剂必须是无菌的,这很容易通过无菌滤过膜过滤实现。
所述制剂包括那些适合于前述施药途径的制剂。所述制剂可以方便地以单位剂量形式提供,可以通过任何制药领域熟知的方法制备。技术和制剂通常可见于Remington的Pharmaceutical Sciences(Mack Publishing Co.,Easton,PA)。这样的方法包括将活性成分与组成一种或多种辅助组分的载体结合的步骤。大体上,将活性成分与液态载体或细碎的固态载体或两者均一紧密地结合,然后,如有必要,将产品成形,由此制得所述制剂。
水悬浮液包含与赋形剂混合的活性材料(ADC),所述赋形剂适合于生产水悬浮液。这样的赋形剂包括悬浮剂,如羧甲基纤维素钠、croscarmellose、聚维酮、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄芪胶和阿拉伯树胶、和分散或润湿剂如天然产生的磷脂(例如,卵磷脂)、环氧烷烃(ethylene oxide)与脂肪酸的缩合产物(例如,聚氧乙烯硬脂酸酯)、环氧乙烷与长链脂肪醇的缩合产物(例如,heptadecaethyleneoxycetanol)、环氧乙烷与源于脂肪酸和己糖醇酐的偏酯的缩合产物(例如,聚氧化乙烯山梨醇单油酸酯)。水悬浮液还可以包含一种或多种防腐剂如乙基或正丙基p-羟基-苯甲酸酯、一种或多种着色剂、一种或多种调味剂和一种或多种甜味剂,如蔗糖或糖精。
ADC的药物组合物可以为无菌可注射制品形式的,如无菌可注射的水或油质悬浮液。该悬浮液可以按照已知技术,利用上面已经提到的那些合适的分散剂或润湿剂和悬浮剂配制。所述无菌可注射制品也可以为溶于无毒的肠胃外可接受的稀释剂或溶剂的无菌可注射溶液或悬浮液,如溶于1,3-丁烷-二醇的溶液或者制成冻干粉末。可用的可接受载体和溶剂为水、Ringer氏溶液和等渗氯化钠溶液。此外,无菌非挥发油传统上可以用作溶剂或悬浮介质。对于该目的,可以使用任何温和的非挥发油,包括合成的单或二脂酰甘油脂。此外,脂肪酸如油酸同样可用于可注射产品的制备。
可与载体材料组合以生产单一剂量形式的活性成分的量将根据所治疗的主体和特定施用方式而改变。例如,用于静脉内输注的水溶液可以包含每毫升溶液约3至500μg的活性成分,以便能够产生合适体积的约30mL/hr速率的输注。可以用约1.5ml或更小的总体积和约100mg ADC每ml的浓度完成皮下(快注(bolus))施用。对于需要频繁并长期施用的ADC,可以使用皮下途径,如通过预填充的注射器或自动注射装置技术。
作为一般性建议,所施用的ADC每个剂量的药学上初始有效量将在约0.01-100mg/kg范围,即约0.1至20mg/kg患者体重每天,其中所用化合物的典型初始范围为约0.3至15mg/kg/天。例如,起初可以以约1.5mg ADC每kg患者体重为人类患者定量给药。所述剂量可以逐步升高到最大耐受剂量(MTD)。剂量给药方案可以为约每3周,但根据所诊断的病症或反应,所述方案可以更加频繁或更不频繁。在治疗过程中,所述剂量可以进一步调整到等于或低于MTD,其可以安全地多次循环施用,如约4次或更多次。
适合于肠胃外施药的制剂包括水和非水无菌注射液,其可以包含抗氧化剂、缓冲液、抑菌剂和使所述制剂与欲受试者的血液等渗的溶质;和水和非水无菌悬浮液,其可以包括悬浮剂和增稠剂。
尽管通常不赞成口服蛋白质治疗剂,因为有限的肠(gut)吸收、水解或变性导致低的生物利用率,但适合于口服的ADC制剂可以制备为分散的单位如均包含预先确定量的ADC的胶囊、扁囊剂或片剂。
所述制剂可以包装在单位剂量或多剂量容器中,例如密封的安瓿瓶和管形瓶中,可以保存在冷冻干燥的(冻干的)条件下,此条件只需要在马上要使用前添加无菌液态载体,例如水用于注射。即时注射液和悬浮液从之前所述类型的无菌粉末、颗粒和药片制备。示例性单位剂量制剂包含活性成分的每日剂量或单位每日亚剂量(unit daily sub-dose)、或其适当部分。
本发明进一步提供兽医组合物,其包含至少一种如上定义的活性成分连同兽医学载体。兽医学载体是用于施用所述组合物目的的材料,其可以为固态的、液态的或气体材料,另外其在兽医学领域还应该是惰性的或可接受的,并可与所述活性成分相容的。这些兽医学组合物可以肠胃外、口服或通过任何其它所需途径施用。
抗体-药物偶联物治疗
本发明的抗体-药物偶联物将可用于治疗多种疾病或紊乱,如癌症和自身免疫病症。示例性病症或紊乱包括良性或恶性肿瘤;白血病和淋巴恶性疾病;其它疾病如神经元、神经胶质、星形细胞、下丘脑、腺体、巨噬细胞(macrophagal)、上皮、基质、囊胚(blastocoelic)、炎性、血管新生和免疫学疾病。对ADC治疗敏感的癌症包括以特定肿瘤相关抗原或细胞表面受体例如HER2过表达为特征的那些癌症。
在动物模型和基于细胞的测试中鉴定的ADC化合物可以进一步在拥有肿瘤的高等灵长类和人类临床试验中测试。人类临床试验可以设计为类似于测试HER2过表达的转移性乳腺癌患者中,抗HER2单克隆抗体HERCEPTIN的功效的临床试验,其中所述患者先前已接受了大量抗癌治疗,如Baselga etal.(1996)J.Clin.Oncol.14:737-744所报导的。可以设计临床试验以评估ADC与已知治疗方案,如辐射和/或涉及已知化疗剂和/或细胞毒性试剂的化疗相组合的功效(Pegram et al(1999)Oncogene 18:2241-2251)。
通常,所要治疗的疾病或紊乱是癌症。此处所要治疗的癌症的例子包括但不限于癌(carcinoma)、淋巴瘤、胚细胞瘤(blastoma)、肉瘤(sarcoma)、和白血病或者淋巴恶性疾病。这种癌症更具体的例子包括鳞状细胞癌(例如,鳞状上皮细胞癌)、肺癌,包括小细胞肺癌、非小细胞肺癌(“NSCLC”)、肺腺癌和肺鳞状细胞癌、腹膜癌、肝细胞癌、胃或胃部癌症,包括胃肠癌、胃肠基质肿瘤(GIST)、胰腺癌、恶性胶质瘤、宫颈癌、卵巢癌、肝脏癌症、膀胱癌、肝细胞瘤(hepatoma)、乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫内膜或子宫癌、唾腺癌、肾脏或肾癌、前列腺癌、阴道癌、甲状腺癌、肝癌(hepaticcarcinoma)、肛门癌、阴茎癌、以及头颈癌。
此处所要治疗癌症可以是通过ErbB受体例如HER2的过度活化而鉴定的一种癌症。此过度活化可能归因于ErbB受体或ErbB配体的过表达或生成增加。在一个实施方案中,将进行诊断或预后测试以测定患者的癌症是否以ErbB受体的过度活化为特征。例如,在癌症中可以测定ErbB受体的ErbB基因扩增和/或过表达。本领域有多种用于测定这种扩增/过表达的测试方法,包括上述的IHC、FISH和脱落抗原测试。或者,或除此之外,可以依照已知的方法测定肿瘤中或与肿瘤相关的ErbB配体,如TGF-alpha的水平。这样的测试可以探测所要测试的样品中的蛋白质和/或编码它的核酸。在一个实施方案中,肿瘤中的ErbB配体水平可以利用免疫组化(IHC)测定;参见,例如,Scher et al.(1995)Clin.Cancer Research 1:545-550。或者,或除此之外,可以评估所要测试的样品中ErbB配体编码核酸的水平;例如通过FISH、southern印迹、或PCR技术。在一个实施方案中,可以用IHC分析ErbB2过表达,例如使用HERCEPTEST(Dako)。可以对来自肿瘤活组织切片的石蜡包埋组织切片进行IHC测试,所依据的ErbB2蛋白质染色强度标准如下∶分数0,没有观察到染色或者在小于10%的肿瘤细胞中观察到膜染色;分数1+,在超过10%的肿瘤细胞中检测到模糊的/依稀可辨的膜染色,所述细胞只有一部分膜染色;分数2+,在超过10%的肿瘤细胞中观察到弱的至中度的完全膜染色;分数3+,在超过10%的肿瘤细胞中观察到中度至强烈的完全膜染色。ErbB2过表达评估分数为0或1+的那些肿瘤可以鉴定为未过表达ErbB2,而分数为2+或3+的那些肿瘤可以鉴定为过表达ErbB2。
或者,或除此之外,可以对福尔马林固定的、石蜡包埋的肿瘤组织进行FISH测试如INFORMTM (Ventana Co.,Ariz.)或PATHVISIONTM(Vysis,Ill.),以测定肿瘤中ErbB2过表达的程度(如果有的话)。
另外,ErbB受体或ErbB配体过表达或扩增可以利用体内诊断测试评估,例如通过施用结合要检测的分子并带有可探测标记(例如放射性同位素)的分子(如抗体),并从外部扫描患者以定位所述标记。
为预防或治疗疾病,ADC的合适剂量将取决于如上定义的要治疗的疾病的类型、疾病的严重程度和病程、施用所述分子是否用于预防或治疗目的、以前的治疗、患者的病史和对所述抗体的反应、以及主治医师的判断。所述分子适于一次或者在一系列治疗中施用于患者。根据疾病的类型和严重程度,无论是例如一次或多次单独施用、还是连续输注,施用于患者的初始候选剂量都是约1μg/kg至15mg/kg(例如0.1-20mg/kg)的分子。根据上述因素,典型的每日剂量可为约1μg/kg至100mg/kg或更多。所要施用于患者的ADC的示例性剂量在约0.1至约10mg/kg患者体重范围内。
对于几天或更长时间的重复施用,根据所述病症,所述治疗将一直持续到所需疾病症状得到所期望的抑制。示例性剂量给药方案包含施用约4mg/kg的初始加载剂量,之后每周约2mg/kg抗ErbB2抗体的维持剂量。也可以使用其它的给药方案。此治疗的进展可以轻易地通过传统技术和测试方法监测。
联合治疗
抗体-药物偶联物(ADC)可以与第二种具有抗癌特性的化合物组合成药物组合制剂、或组合为联合疗法的剂量给药方案。所述药物组合制剂或剂量给药方案的第二种化合物优选具有与组合中的ADC互补的活性,以免它们相互产生不利影响。
第二种化合物可以是化疗剂、细胞毒性试剂、细胞因子、生长抑制剂、抗激素剂、芳化酶抑制剂、蛋白激酶抑制剂、脂质激酶抑制剂、抗雄激素、反义寡核苷酸、核酶、基因治疗疫苗、抗血管新生剂和/或心脏保护剂。这样的分子在组合药物中适合以对预定目标有效的量提供。包含ADC的药物组合物也可以具有治疗有效量的化疗剂如微管蛋白形成抑制剂、拓扑异构酶抑制剂、或DNA结合物。
或者,或除此之外,第二种化合物可以为结合ErbB2和阻断ErbB受体的配体活化的抗体。第二抗体可以为单克隆抗体2C4或人源化2C4“Omnitarg”(WO 01/00245)。第二抗体可以与细胞毒性剂或化疗剂,例如美登木素生物碱、auristatin、加利车霉素、或1,8二-萘酰亚胺部分偶联。例如,可能期望在一种制剂或剂量给药方案中进一步提供结合EGFR、ErbB2、ErbB3、ErbB4、或血管内皮因子(VEGF)的抗体。
其它的治疗方案可以与施用按照本发明鉴定的抗癌剂组合。组合治疗可以作为同时的或顺序的方案施用。当顺序施用时,所述组合可以在两次或多次施用中施用。联合施用包括同时施用,其利用分开的制剂或单个药物制剂,也包括以任何顺序连续施用,其中优选有两种(或所有)活性试剂同时发挥其生物学活性的时期。
在一个实施方案中,用本发明的ADC治疗涉及组合施用此处鉴定的抗癌剂、和一种或多种化疗剂或生长抑制剂,包括共同施用不同化疗剂的鸡尾酒样混合物,任选与抗ErbB2抗体如曲妥单抗一起治疗。化疗剂包括盐酸Erlotinib(CP-358774,TARCEVATM;Genentech/OSI)、紫杉烷(如紫杉醇和多西紫杉醇)和/或蒽环类抗生素。这种化疗剂的制备和剂量给药方案可以依照厂商的说明使用,或者依照熟练技术人员根据经验所确定的使用。Chemotherapy Service Ed.,M.C.Perry,Williams&Wilkins,Baltimore,Md.(1992)中也描述了这种化疗剂的制备和剂量给药方案。
抗癌剂可以与抗激素化合物组合;例如抗雌激素化合物如他莫昔芬;抗黄体酮如奥那司酮(EP 616812);或者抗雄激素如氟他胺(flutamide),其中以这些分子已知的剂量使用。在所要治疗的癌症为与激素无关的癌症中,所述患者可以事先已经接受抗激素治疗,并且,在癌症变得与激素无关之后,可以为患者施用抗ErbB2抗体(以及任选此处描述的其它试剂)。为患者共同施用心脏保护剂(以预防或减少与治疗相关的心肌机能障碍)或一种或多种细胞因子可能是有益的。除了上述治疗方法,可以对患者实施外科手术去除癌细胞,和/或实施放射疗法。
任何上述共同施用的试剂的合适剂量均为目前使用的那些剂量,并且,由于新鉴定的试剂和其它化疗剂或治疗的联合作用(协同作用),所述剂量可以有所降低。
所述组合治疗可以提供“协同作用”并证实有“协同作用的”,即当一同使用所述活性成分时所获得的效果大于分别用所述化合物获得的效果的总和。当所述活性成分∶(1)共同配制并以组合的单位剂量制剂形式同时施用或递送;(2)作为不同的制剂交替或并行递送;或(3)通过其它一些方案施用时,可以获得协同效应。以交替疗法递送时,顺序施用或递送化合物,例如通过在不同的注射器中分开注射时,可以获得协同效应。大体上,在交替治疗期间,顺序即连续施用有效剂量的各种活性成分,而在组合治疗中,有效剂量的两种或多种活性成分一起施用。
抗体-药物偶联物的代谢物
此处描述的ADC化合物的体内代谢产物也落入本发明的范围内,所述范围包括直至这样的产物是新的并且相对于现有技术是非显而易见的程度。这样的产物可以例如源于所施用化合物的氧化、还原、水解、酰胺化、酯化、酶学裂解等等。相应地,本发明包括通过所述方法生产的新的和非显而易见的化合物,该方法包括将本发明的化合物与哺乳动物接触,所接触的时间足以产生其代谢产物。
可以通过制备放射性同位素标记的(例如14C或3H)ADC,以可检测剂量(例如大于约0.5mg/kg)将其肠胃外施用于动物如大鼠、小鼠、豚鼠、猴子或施用于人,提供代谢足以发生的时间(典型地约30秒至30小时)并从尿、血液或其它生物样品分离其转化产物来鉴定代谢产物。这些产物很容易分离,因为它们是经标记的(其它的通过利用能够结合代谢物中存留的表位的抗体来分离)。以常规方式测定代谢物结构例如通过MS、LC/MS或NMR分析。大体上,代谢物的分析以与本领域技术人员熟知的传统药物代谢研究相同的方式完成。所述转化产物,只要它们未在体内发现,就可用于ADC化合物治疗给药的诊断测试中。
代谢物包括ADC体内裂解的产物,其中裂解发生在将药物部分连接到抗体的任何键。因此代谢性裂解能够产生裸抗体(naked antibody)、或抗体片段。抗体代谢物可以连接到接头的一部分、或整个接头。代谢性裂解也可能导致产生药物部分(drug moiety)或该药物部分的一部分。药物部分的代谢物可以连接到接头的一部分、或整个接头。
制品
在另一实施方案中,提供了包含ADC和用于治疗上述紊乱的材料的制品、或“试剂盒”。所述制品包含容器和容器上的或与容器相连的标签或包装说明书。合适的容器包括例如瓶子、管形瓶、注射器、或薄膜包装。所述容器可以由多种材料如玻璃或塑料构成。所述容器装有治疗所选病症有效的抗体-药物偶联物(ADC)组合物,可以具有无菌存取口(例如,所述容器可以为静脉内溶液袋或管形瓶,所述管形瓶具有可用皮下注射针穿透的塞子)。组合物中至少一种活性试剂是ADC。标签或包装说明书指明所述组合物用于治疗所选病症如癌症。在一个实施方案中,标签或包装说明书指明包含结合ErbB2的抗体的组合物可用于治疗癌症,所述癌症表达选自表皮生长因子受体(EGFR)、ErbB2、ErbB3和ErbB4的ErbB受体。此外,标签或包装说明书可以指明所要治疗的患者患有癌症,所述癌症以选自EGFR、ErbB2、ErbB3或ErbB4的ErbB受体过度活化为特征。例如,所述癌症可以为过表达这些受体和/或过表达ErbB配体(如TGF-α)之一的一种癌症。标签或包装说明书也可以指明所述组合物可用于治疗癌症,其中所述癌症不以ErbB2受体的过表达为特征。在其它实施方案中,包装说明书可以指明ADC组合物也可以用于治疗与激素无关的癌症、前列腺癌、结肠癌或结肠直肠癌。
所述制品可以包含(a)其中含有化合物的第一容器,其中所述化合物包含本发明的ADC,其中ADC的抗体为结合ErbB2并抑制过表达ErbB2的癌细胞生长的第一抗体;和(b)其中含有化合物的第二容器,其中所述化合物包含结合ErbB2和阻断ErbB受体的配体活化的第二抗体,或该第二抗体与美登木素生物碱的偶联物。该实施方案中的制品可以进一步包含包装说明书,所述包装说明书指明第一种和第二种化合物可用于治疗癌症。或者,或除此之外,所述制品可以进一步包含第二(或第三)容器,该容器包含药学上可接受的缓冲液,如注射用抑菌水(BWFI)、磷酸盐缓冲盐水、Ringer氏溶液和右旋糖溶液。其可以进一步包括从商业和用户的观点来看所需的其它材料,包括其它缓冲液、稀释剂、滤器、针头、和注射器。
实施例
实施例1-抗ErbB2单克隆抗体4D5的生产、鉴定和人源化
特异性结合ErbB2胞外结构域的鼠单克隆抗体4D5如Fendly et al(1990)Cancer Research 50:1550-1558所述生产。简单地说,用含25mM EDTA的磷酸盐缓冲盐水(PBS)收获如Hudziak et al(1987)Proc.Natl.Acad.Sci.(USA)84:7158-7163所述生产的NIH 3T3/HER2-3400细胞(表达大约1x 105个ErbB2分子/细胞),并用于免疫BALB/c小鼠。于第0、2、5和7周为小鼠i.p.注射0.5ml PBS中的107个细胞。于第9和13周为小鼠i.p.注射麦胚凝集素-琼脂糖凝胶(wheat germ agglutinin-sepharose)(WGA)纯化的ErbB2膜提取物,所述小鼠具有免疫沉淀32P标记的ErbB2的抗血清。此后i.v.注射0.1ml的ErbB2制品,将脾细胞与小鼠骨髓瘤系X63-Ag8.653融合。根据ErbB2-结合用ELISA和放射免疫沉淀筛选杂交瘤上清。
鼠单克隆抗体4D5采用"基因转换诱变(gene conversion mutagenesis)"策略人源化,如US 5821337所述,此处将其全部内容特别加入作为参考。以下试验中使用的人源化单克隆抗体4D5称为huMAb4D5-8。该抗体为IgG1同种型。
实施例2-曲妥单抗的纯化
实施例3-抗体-药物偶联物∶曲妥单抗-SPP-DM1的制备∶
用N-琥珀酰亚胺-4-(2-吡啶硫代)戊酸酯衍生纯化的曲妥单抗,以引入二硫代吡啶(dithiopyridyl)基。用SPP(2.3mL乙醇中5.3摩尔当量)处理曲妥单抗,曲妥单抗(376.0mg,8mg/ml)溶于含NaCl(50mM)和EDTA(1mM)的44.7mL 50mM的磷酸钾缓冲液(pH6.5)中。在氩气中周围温度保温90分钟后,反应混合物通过用35mM柠檬酸钠、154mM NaCl、2mM EDTA平衡过的Sephadex G25柱子凝胶过滤。收集并测试含抗体的级分。如上所述测定抗体的修饰程度。修饰抗体(曲妥单抗-SPP-Py)的回收率为337mg(89.7%),其中每个抗体(P’)连接4.5个可释放的2-硫代吡啶基。
用上述35mM柠檬酸钠缓冲液、pH6.5将曲妥单抗-SPP-Py(337.0mg,9.5μmols的可释放的2-硫代吡啶(thiopyridine)基)稀释至终浓度2.5mg/mL。然后向抗体溶液添加溶于3.0mM二甲基乙酰胺(DMA,最终反应混合物中3%v/v)中的DM1(N2’-脱乙酰基-N2’-(3-巯基-1-氧代丙酰)-美登素)(1.7当量,16.1μmols),其结构如图1所示。反应在周围温度于氩气中进行20个小时。
将反应液上样在用35mM柠檬酸钠、154mM NaCl、pH 6.5平衡过的Sephacryl S300凝胶过滤柱(5.0cmx90.0cm,1.77L)上。流速为5.0mL/min,收集了65个级分(每个20.0mL)。主峰以47号级分为中心(图3)。主峰包括单体曲妥单抗-SPP-DM1。收集并测试级分44-51。通过测量252nm和280nm处的吸光值来测定每个抗体分子连接的DM1药物分子的数目(p’),发现为每个抗体分子3.7个药物分子。
实施例4-抗体-药物偶联物∶曲妥单抗-SMCC-DM1的制备∶
用(琥珀酰亚胺4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯,SMCC,PierceBiotechnology,Inc)衍生纯化的曲妥单抗,以引入SMCC接头。如实施例2所述从纯化曲妥单抗,并用7.5至10摩尔当量的SMCC(DMSO或DMA(二甲基乙酰胺)中20mM,6.7mg/mL)在50mM磷酸钾/50mM氯化钠/2mM EDTA、pH 6.5中以20mg/mL缓冲交换处理。在氩气中周围温度下搅动2至4小时后,反应混合物通过用50mM磷酸钾/50mM氯化钠/2mM EDTA、pH 6.5平衡过的Sephadex G25柱子过滤。或者,用30mM柠檬酸盐和150mM氯化钠于pH 6凝胶过滤反应混合物。收集并测试含抗体的级分。曲妥单抗-SMCC的回收率为88%。
以上获得的药物-接头中间体曲妥单抗-SMCC用50mM磷酸钾/50mM氯化钠/2mM EDTA、pH 6.5稀释至终浓度10mg/mL,在二甲基乙酰胺中与10mM DM1的溶液(1.7当量拥有5个SMCC/曲妥单抗,7.37mg/ml)反应。周围温度下在氩气中搅拌反应液4至约16小时。偶联反应混合物用1x PBS于pH 6.5通过Sephadex G25凝胶过滤柱(1.5x 4.9cm)过滤。或者,用10mM琥珀酸盐和150mM氯化钠于pH 5凝胶过滤反应混合物。DM1/曲妥单抗比(p)为3.1,其通过252nm和280nm处的吸光值测得。药物与抗体比(p)也可以通过质谱分析测定。也可以通过SDS聚丙烯酰胺凝胶电泳监测偶联。可以通过激光散射分析评估聚集。
抗体-SMCC-DM 1偶联物∶
遵循该方案,用SMCC接头和DM1药物部分制备了其它的抗体-药物偶联物,包括∶
抗体-BMPEO-DM 1偶联物∶
为进行半胱氨酸偶联,可以用还原剂如二硫苏糖醇(DTT)或TCEP在EDTA存在下还原抗体。37°C下保温约1小时后,用100mM磷酸钾将pH调到约为7。用二-马来酰亚胺试剂BM(PEO)4(Pierce Chemical)修饰还原的抗体,在抗体表面上留下未反应的马来酰亚胺基。这可以通过将BM(PEO)4溶解在50%乙醇/水混合物中至浓度为10mM,并以十倍过量的摩尔数添加到浓度大约为1.6mg/ml(10μM)的磷酸盐缓冲盐水中的含抗体溶液,使之反应1小时形成Ab-BMPEO而实现。在30mM柠檬酸盐、pH 6,还有150mMNaCl的缓冲液中凝胶过滤(HiTrap柱,Pharmacia)去除过量的BM(PEO)4。将大约10倍摩尔过量的DM1溶解在二甲基乙酰胺(DMA)中,并添加到Ab-BMPEO中间体。二甲基甲酰胺(DMF)也可以用于溶解药物部分试剂。在凝胶过滤或透析到PBS中去除不反应的DM1前,使反应混合物反应过夜。在PBS中于S200柱上凝胶过滤以去除高分子量聚集体并提供纯化的Ab-BMPEO-DM1。
遵循该方案,用BMPEO接头和DM1药物部分制备了其它的抗体-药物偶联物,包括∶
实施例5-体外细胞增殖测试
使用以下方案通过细胞增殖测试测定ADC的功效(Promega Corp.Technical Bulletin TB288;Mendoza et al(2002)Cancer Res.62:5485-5488)∶
1.将培养基中的100μl含约104个细胞(SKBR-3、BT474、MCF7或MDA-MB-468)的细胞培养物等份试样放置在96-孔不透明带壁板的每个孔中。
2.制备了含培养基而无细胞的对照孔。
3.ADC添加到试验孔并保温3-5天。
4.将平板平衡至室温大约30分钟。
5.添加与每个孔中存在的细胞培养基体积相同的CellTiter-Glo试剂。
6.内容物在轨道振荡器上混合2分钟以诱导细胞裂解。
7.平板在室温下保温10分钟以稳定荧光信号。
8.记录发光并按照RLU=相对发光单位反映在图表中。
实施例6-小鼠血清清除率和稳定性
研究了六组米色突变、裸鼠(无肿瘤),每组四只动物。第0天,除了只接受载体的载体组之外,每只小鼠均接受溶于200μl水性载体中的2mg/kg单一剂量ADC。于给药后的每个时间点(5分钟、1小时、6小时、24小时、72小时、和168小时)在麻醉状态下通过心脏穿刺收集血液。分离血清,测定抗体和ADC。
第1组∶载体(PBS,pH 6.5,无ADC)
第2组∶曲妥单抗-SMCC-DM1
第3组∶曲妥单抗-SPP-DM1
第4组∶曲妥单抗-SPDP-DM1
第5组∶曲妥单抗-SPP-DM3
第5组∶曲妥单抗-SPP-DM4
实施例7-大鼠中血清稳定性
研究了每个剂量组6只Sprague-Dawley大鼠(每只100-125gms)的六个剂量组。于第0天,以10ml/kg的体积剂量通过一侧尾静脉为动物施用单次IV剂量的载体、10mg/kg曲妥单抗-SPP-DM1、或10mg/kg曲妥单抗-SMCC-DM1。在给药后0(给药前)、10、和30分钟;1、2、4、8、24和36小时;和2、3、4、7、14、21、28天的每个时间点收集大约300μl全血。
实施例8-肿瘤体积体内功效
高表达HER2转基因外植体小鼠∶
适合于转基因试验的动物可以从标准商业来源如Taconic(Germantown,N.Y.)获得。许多株系都是合适的,但由于对肿瘤形成的更高敏感性,FVB雌性小鼠是优选的。FVB雄性用于交配,切除输精管的CD.1种鼠用于刺激假妊娠。切除输精管的小鼠可以从任何商业供应商获得。创建小鼠(Founders)用FVB小鼠或者用129/BL6x FVB p53杂合型小鼠培育。p53等位基因杂合性小鼠用于潜在地增加肿瘤形成。然而,这已被证实是不必要的。因此,一些F1代肿瘤是混合株系。创建小鼠肿瘤只有FVB。获得了六只创建小鼠,其具有一些生长的肿瘤,没有幼仔。
通过单次曲妥单抗-DM1美登木素生物碱偶联物(10mg/kg剂量)注射治疗有肿瘤(从Fo5mmtv转基因小鼠扩增的同种异体移植物)的动物,注射后的20天中评估肿瘤体积。
Bjab-luc异种移植物SCID小鼠∶
每组八至十只SCID小鼠、每只小鼠具有2千万个Bjab-luc异种移植物肿瘤细胞的试验组于第1天给予抗体-药物偶联物、或裸抗体。八只小鼠的组每组均用抗CD22ADC、裸抗CD22抗体、和对照测试。对照ADC(曲妥单抗-SMCC-DM1;负载∶DM1/曲妥单抗=3.2)不是特异性结合物,以200μgDM1/m2、4.2曲妥单抗/kg小鼠施用,结果是肿瘤加倍平均时间为约3天。抗CD22偶联物7A2-SMCC-DM1(负载∶DM1/Ab=3.6)、5E8-SMCC-DM1(负载∶DM1/Ab=3.6)、和RFB4-SMCC-DM1(负载∶DM1/Ab=4.3)。裸抗体7A2、5E8、和RFB4以4mg/kg小鼠给予。
实施例9-对大鼠的毒性
评估了与游离DM1和曲妥单抗-SMCC-DM1(非二硫化物接头)相比较的曲妥单抗-SPP-DM1(二硫化物接头)的急性毒性谱。在第1天注射动物,于第3天和第5天获得基线位置的完全化学和血液学图谱,并于第5天进行完全尸体解剖。对于每个组,随机用三只动物对以下组织∶胸骨、肝脏、肾脏、胸腺、脾脏、大小肠进行常规组织学分析。试验组如下∶
第1组∶载体(10mM琥珀酸钠、100mg/mL蔗糖、0.1%Tween 20,pH5.0)
第2组∶曲妥单抗-SPP-DM1,22.3mg/kg
第3组∶曲妥单抗-SMCC-DM1,10mg/kg
第4组∶曲妥单抗-SMCC-DM1,25mg/kg
第5组∶曲妥单抗-SMCC-DM1,50mg/kg
第6组∶游离DM1,160μg/kg
实施例10-对猕猴的毒性/安全性
研究了每个组四只(2只雄性,2只雌性)幼食蟹猴(Macaca fascicularis)(猕猴(Cynomolgus monkey))的三个组。
第1组∶(4只动物)在第1天和第22天只接受载体(PBS,pH 6.5,即去除ADC的制剂),此后于第36天进行尸体解剖。
第2组∶(4只动物)于第1天和第22天接受曲妥单抗-SMCC-DM14900μg/m2。
第3组∶(4只动物)于第22天接受曲妥单抗-SMCC-DM17200μg/m2。
剂量给药以动物的表面积表示,以使与其它物种相应,即不管何物种,以剂量μg/m2表示,并且因此可以在物种之间比较。用于第2组和第3组研究的曲妥单抗-SMCC-DM1制剂包含PBS、5.4mM磷酸钠、4.2mM磷酸钾、140mM氯化钠,pH 6.5。
在第一次剂量给药前(驯化期)和第一次给药后第3、7、11、和14天(第1和2组)以及第二次给药后第3、7、11、14、和21天(第1、2和3组)收集血液用于血液学分析。红血球(RBC)和血小板(PLT)计数通过光散射法测定。白细胞(WBC)计数通过过氧化物酶/嗜碱细胞法测定。网织红细胞计数通过利用阳离子染料的光散射法测定。细胞计数在Advia 120仪器上测定。ALT(丙氨酸转氨酶)和AST(天冬氨酸转氨酶)以U/L,通过UV/NADH;IFCC方法学,在Olympus AU400仪器上采用Total Ab ELISA-ECD/GxhuFc-HRP.Conj.Ab ELISA-xDM 1/ECD-Bio/SA-HRP测试测定。
整个说明书中引证的所有专利、专利申请、和参考文献都清楚加入作为参考。
Claims (16)
2.包含权利要求1的抗体-药物偶联化合物或其药学上可接受的盐、和药学上可接受的稀释剂、载体或赋形剂的药物组合物,其用于治疗乳腺癌。
3.权利要求2的药物组合物,其进一步包含治疗有效量的化疗剂,所述化疗剂选自:Erlotinib、Bortezomib、氟维司群、Sutent、来曲唑、甲磺酸伊马替尼、PTK787/ZK 222584、Oxaliplatin、5-FU、甲酰四氢叶酸、雷帕霉素、Lapatinib、Lonafarnib、Sorafenib和Gefitinib
4.权利要求2的药物组合物,其进一步包含治疗有效量的抗血管新生剂。
5.权利要求4的药物组合物,其进一步包含治疗有效量的贝伐单抗。
6.权利要求2的药物组合物,其中所述乳腺癌以2+或更高水平过表达ErbB2。
7.权利要求2的药物组合物,其中为患者施用的抗体-药物偶联化合物的量在每剂0.1至10mg/kg患者体重范围中。
8.权利要求2的药物组合物,其中以三周的间隔施用抗体-药物偶联化合物。
9.权利要求2的药物组合物,其中通过输注施用抗体-药物偶联化合物。
10.权利要求2的药物组合物,其中所述抗体-药物偶联化合物与药学上可接受的肠胃外载体一起配制。
11.权利要求10的药物组合物,其中所述抗体-药物偶联化合物配制为可注射的单位剂量形式。
12.权利要求11的药物组合物,其中静脉内施用抗体-药物偶联化合物。
13.权利要求2的药物组合物,其中所述组合物进一步包含生长抑制性抗体,与抗体-药物偶联化合物组合。
14.一种制品,包括:
权利要求1的抗体-药物偶联化合物;
容器;和
包装说明书或标签,其指明所述化合物可用于治疗以ErbB受体过表达为特征的乳腺癌。
15.制备权利要求1的抗体-药物偶联化合物的方法,其中所述方法包括:使Ab与接头试剂琥珀酰亚胺4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯(SMCC)反应形成抗体-接头中间体Ab-L,然后使Ab-L与药物部分N2’-脱乙酰-N2’-(3-巯基-1-氧代丙基)-美登素(DM1)反应形成抗体-药物偶联物。
16.抗体-药物偶联化合物,包括通过接头共价连接于一个或多个美登木素生物碱药物部分的抗体,所述化合物具有式I∶
Ab-(L-D)p I
或其药学上可接受的盐或溶剂化物,其中∶
Ab为结合ErbB受体,或者结合一种或多种肿瘤相关抗原或细胞表面受体的抗体,所述肿瘤相关抗原或细胞表面受体选自(1)-(36):
(1)BMPR1B(骨形态发生蛋白受体-IB型,Genbank登录号NM_001203);
(2)E16(LAT1、SLC7A5,Genbank登录号NM_003486);
(3)STEAP1(前列腺六次跨膜上皮抗原,Genbank登录号NM_012449);
(4)0772P(CA125、MUC16、Genbank登录号AF361486);
(5)MPF(MPF、MSLN、SMR、巨核细胞强化因子、mesothelin,Genbank登录号NM_005823);
(6)Napi3b(NAPI-3B、NPTIIb、SLC34A2、溶质载体家族34(磷酸钠),成员2,II型钠依赖的磷酸盐转运蛋白3b,Genbank登录号NM_006424);
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、脑信号蛋白5b Hlog,sema结构域,七个血小板反应蛋白重复(1型和类1型的),跨膜结构域(TM)和短的细胞质结构域,(脑信号蛋白)5B,Genbank登录号AB040878);
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA2700050C12、RIKEN cDNA 2700050C12基因,Genbank登录号AY358628);
(9)ETBR(内皮素B型受体,Genbank登录号AY275463);
(10)MSG783(RNF124,假想蛋白FLJ20315,Genbank登录号NM_017763);
(11)STEAP2(HGNC_8639、IPCA-1、PCANAP1、STAMP1、STEAP2、STMP、前列腺癌相关基因1、前列腺癌相关蛋白1、前列腺的六次跨膜上皮抗原2、六次跨膜前列腺蛋白,Genbank登录号AF455138);
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、瞬时受体潜在阳离子通道,亚家族M,成员4,Genbank登录号NM_017636);
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1,畸胎癌衍生生长因子,Genbank登录号NP_003203或NM_003212);
(14)CD21(CR2(补体受体2)或C3DR(C3d/埃巴病毒受体)或Hs.73792Genbank登录号M26004);
(15)CD79b(CD79B、CD79β、IGb(免疫球蛋白相关beta)、B29,Genbank登录号NM_000626);
(16)FcRH2(IFGP4、IRTA4、SPAP1A(含SH2结构域的磷酸酶锚定蛋白1a)、SPAP1B、SPAP1C,Genbank登录号NM_030764);
(17)HER2(Genbank登录号M11730);
(18)NCA(Genbank登录号M18728);
(19)MDP(Genbank登录号BC017023);
(20)IL20Rα(Genbank登录号AF184971);
(21)Brevican(Genbank登录号AF229053);
(22)EphB2R(Genbank登录号NM_004442);
(23)ASLG659(Genbank登录号AX092328);
(24)PSCA(Genbank登录号AJ297436);
(25)GEDA(Genbank登录号AY260763;
(26)BAFF-R(B细胞活化因子受体,BlyS受体3,BR3,NP_443177.1);
(27)CD22(B细胞受体CD22-B同种型,NP-001762.1);
(28)CD79a(CD79A,CD79α,免疫球蛋白相关alpha,与Ig beta(CD79B)共价相互作用并在表面上与Ig M分子形成复合体、转导涉及B细胞分化的信号的B细胞特异性蛋白,Genbank登录号NP_001774.1);
(29)CXCR5(伯基特淋巴瘤受体1,被CXCL13趋化因子活化的G蛋白偶联受体,在淋巴细胞迁移和体液防御中发挥作用,在HIV-2感染以及可能在AIDS、淋巴瘤、骨髓瘤、和白血病的发生中发挥作用,Genbank登录号NP_001707.1);
(30)HLA-DOB(MHC II类分子的Beta亚基(Ia抗原),其结合肽并将其呈递到CD4+T淋巴细胞,Genbank登录号NP_002111.1);
(31)P2X5(嘌呤受体P2X配体门控离子通道5,由胞外ATP门控的离子通道,可能涉及突触传递和神经发生,其缺陷可能导致特发性逼尿肌不稳定的病理生理状况,Genbank登录号NP_002552.2);
(32)CD72(B细胞分化抗原CD72,Lyb-2,Genbank登录号NP_001773.1);
(33)LY64(淋巴细胞抗原64(RP105),富含亮氨酸重复(LRR)的I型膜蛋白家族,调节B细胞活化和凋亡,功能的丧失与系统性红斑狼疮患者疾病活动增强有关,Genbank登录号NP_005573.1);
(34)FcRH1(Fc受体样蛋白1,免疫球蛋白Fc结构域的推定受体,包含C2型Ig样和ITAM结构域,可能在B淋巴细胞分化中起作用,Genbank登录号NP_443170.1);
(35)IRTA2(易位相关免疫球蛋白超家族受体2,推定的免疫受体,可能在B细胞发育和淋巴瘤发生中起作用;由易位导致的基因失调发生于一些B细胞恶性病中,Genbank登录号NP_112571.1);以及
(36)TENB2(推定的跨膜蛋白聚糖,与生长因子的EGF/生长因子的调蛋白家族和卵泡抑素相关,Genbank登录号AF179274;
条件是所述抗体不是TA.1;
L为非二硫化物接头,选自下述结构:
其中波浪线表示与Ab和D的共价连接;
X为:
Y是:
R独立地为H或C1-C6烷基;且n为1至12;
D为美登木素生物碱药物部分;并且
p为1到8。
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