CN109562172A - 抗HLA-DR抗体药物缀合物IMMU-140(hL243-CL2A-SN-38)在HLA-DR阳性癌症中的功效 - Google Patents
抗HLA-DR抗体药物缀合物IMMU-140(hL243-CL2A-SN-38)在HLA-DR阳性癌症中的功效 Download PDFInfo
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Abstract
本发明涉及包含与抗HLA‑DR抗体或抗原结合抗体片段连接的SN‑38的治疗性免疫缀合物。所述免疫缀合物可以以介于3mg/kg和18mg/kg之间,优选4、6、8、9、10、12、16或18mg/kg,更优选8、10或12mg/kg的剂量施用。当以指定的剂量和方案施用时,所述免疫缀合物可以减小实体瘤的大小,降低或消除转移,并且有效治疗对标准治疗如放射治疗、化学治疗或免疫治疗具有抗性的癌症。所述方法和组合物特别适用于治疗AML、ALL或多发性骨髓瘤。
Description
相关申请的交叉引用
本申请是2016年9月30日提交的美国专利申请序列号15/281,453的部分继续申请,美国专利申请序列号15/281,453是2015年3月25日提交的美国专利申请序列号14/667,982(现在为美国专利号9,493,573)的分案,美国专利申请序列号14/667,982是2013年7月23日提交的美国专利申请序列号13/948,732(现为美国专利号9,028,833)的分案,美国专利申请序列号13/948,732根据35U.S.C.119(e)要求2013年1月7日提交的临时美国专利申请序列号61/749,548和2012年12月13日提交的临时美国专利申请序列号序列号61/736,684的权益。本申请是2017年4月11日提交的美国专利申请序列号15/484,308的部分继续申请,美国专利申请序列号15/484,308根据35U.S.C.119(e)要求2016年8月11日提交的临时美国专利申请序列号62/373,591和2016年4月14日提交的临时美国专利申请序列号62/322,441的权益。本申请根据35U.S.C.119(e)要求2016年8月11日提交的临时美国专利申请序列号62/373,591和2016年11月30日提交的临时美国专利申请序列号62/428,231的权益。每个优先权申请的全文以引用的方式并入本文。
序列表
本申请包含序列表,其已经通过EFS-Web以ASCII格式提交,并且通过引用整体并入本文。2017年7月25日创建的所述ASCII拷贝命名为IMM369WO1_SL.txt,大小为9,661字节。
发明领域
本发明涉及抗体或抗原结合抗体片段和喜树碱(例如SN-38)的免疫缀合物的治疗用途,所述缀合物具有改善的靶向人受试者中多种癌细胞的能力。优选地,抗体或片段是抗HLA-DR抗体或片段,例如hL243。在另一些优选的实施方案中,抗体和治疗部分通过细胞内可切割键联而连接,这增加了治疗功效。在一些更优选的实施方案中,免疫缀合物以优化治疗效果的特定剂量和/或特定施用方案施用。本文公开的用于人治疗用途的SN-38缀合的抗HLA-DR抗体的优化剂量和施用方案显示出不能从动物模型研究预测的意想不到的优异功效,允许有效治疗对标准抗癌治疗(包括母体化合物伊立替康(CPT-11))具有抗性的癌症。免疫缀合物可以单独施用或与在免疫缀合物之前、同时或之后施用的一种或多种其它治疗剂组合施用。可以与抗HLA-DR组合使用的示例性治疗剂包括但不限于蛋白酶体抑制剂例如硼替佐米、布鲁顿激酶抑制剂(Bruton kinase inhibitor)例如依鲁替尼(ibrutinib)、或磷酸肌醇-3-激酶抑制剂例如艾代拉里斯(idelalisib)。在一些优选的实施方案中,待治疗的癌症是HLA-DR阳性癌症,例如B细胞淋巴瘤、B细胞白血病、皮肤癌、食道癌、胃癌、结肠癌、直肠癌、胰腺癌、肺癌、乳腺癌、卵巢癌、膀胱癌、子宫内膜癌、***、睾丸癌、黑素瘤、肾癌或肝癌。更优选地,癌症是AML(急性髓细胞白血病)、ALL(急性淋巴细胞白血病)或MM(多发性骨髓瘤)。最优选地,在用免疫缀合物治疗之前,待治疗的患者已经从至少一种标准抗癌治疗中复发或显示出对至少一种标准抗癌治疗的抗性。然而,普通技术人员将认识到,在一些实施方案中,免疫缀合物可用于一线治疗。
发明背景
多年来,特异性靶向药物治疗领域的科学家的目标是使用单克隆抗体(MAb)将毒性剂特异性递送至人癌症。已经开发了肿瘤相关MAb和合适毒性剂的缀合物,但在人类癌症治疗中成败参半,并且几乎没有应用于其它疾病,例如自身免疫疾病。毒性剂最常见的是化学治疗药物,尽管粒子发射放射性核素或者细菌或植物毒素也与MAb缀合,特别是用于治疗癌症(Sharkey和Goldenberg,CA Cancer J Clin.2006Jul-Aug;56(4):226-243)并且最近,利用放射性免疫缀合物用于某些传染病的临床前治疗(Dadachova和Casadevall,Q J NuclMed Mol Imaging2006,50(3):193-204)。
使用MAb-化学治疗药物缀合物的优点是(a)化学治疗药物本身在结构上明确确定;(b)通常在远离MAb的抗原结合区的特定位点,使用非常明确确定的缀合化学将化学治疗药物连接至MAb蛋白;(c)MAb-化学治疗药物缀合物可以更加可重复地制备,并且通常比涉及MAb和细菌或植物毒素的化学缀合物具有更低的免疫原性,并且因此更易于商业开发和监管批准;以及(d)MAb-化学治疗药物缀合物在***毒性方面比放射性核素MAb缀合物低几个数量级,特别是对辐射敏感的骨髓。
喜树碱(CPT)及其衍生物是一类有效的抗肿瘤剂。伊立替康(也称为CPT-11)和拓扑替康是CPT类似物,其是经批准的癌症治疗剂(Iyer和Ratain,CancerChemother.Phamacol.42:S31-S43(1998))。CPT通过使拓扑异构酶I-DNA复合物稳定以抑制拓扑异构酶I来作用(Liu等.The Camptothecins:Unfolding Their AnticancerPotential,Liehr J.G.,Giovanella,B.C.和Verschraegen(编),NY Acad Sci.,NY 922:1-10(2000))。CPT在缀合物的制备中存在特定问题。一个问题是大多数CPT衍生物在水性缓冲液中的不溶性。其次,CPT为针对缀合至大分子的结构修饰提供了特定的挑战。例如,CPT本身仅含有在环-E中的叔羟基。在CPT的情况下,羟基官能团必须与适于随后蛋白质缀合的接头偶联;并且在强效的CPT衍生物中,例如SN-38、化学治疗剂CPT-11的活性代谢产物以及其它含C-10-羟基的衍生物如拓扑替康和10-羟基-CPT中,C-10位置处酚羟基的存在使必要的C-20-羟基衍生化变得复杂。第三,在生理条件下,喜树碱的E-环的δ-内酯部分的不稳定性导致抗肿瘤功效大大降低。因此,进行缀合方案使得其在7或更低的pH下进行以避免内酯环开环。然而,具有胺反应性基团(例如活性酯)的双官能CPT的缀合通常需要8或更高的pH。第四,细胞内可切割的部分优选并入到连接CPT和抗体或其它结合部分的接头/间隔区中。
人白细胞抗原-DR(HLA-DR)是主要组织相容性复合物(MHC)II类抗原的三种同种型之一。HLA-DR在多种恶性血液病中高度表达,并且已经积极地用于基于抗体的淋巴瘤治疗(Brown等,2001,Clin Lymphoma 2:188-90;DeNardo等,2005,Clin Cancer Res 11:7075s-9s;Stein等,2006,Bloood 108:2736-44)。人HLA-DR抗原在非霍奇金氏淋巴瘤(NHL)、慢性淋巴细胞白血病(CLL)和其它B细胞恶性肿瘤中以显著高于典型B细胞标志物(包括CD20)的水平表达。初步研究表明,在淋巴瘤、白血病和多发性骨髓瘤的体外和体内实验中,抗HLA-DR mAb明显比目前临床感兴趣的其它裸mAb更有效(Stein等,未发表的结果)。
HLA-DR还在正常免疫细胞的亚组上表达,包括B细胞、单核细胞/巨噬细胞、朗格汉斯细胞、树突细胞和活化的T细胞(Dechant等,2003,Semin Oncol 30:465-75)。因此,开发抗HLA-DR抗体的先前尝试受到毒性,尤其是可能与补体激活有关的输注相关毒性的阻碍可能就不足为奇了(Lin等,2009,Leuk Lymphoma 50:1958-63;Shi等,2002,Leuk Lymphoma43:1303-12)。
L243抗体(以下称为mL243)是鼠IgG2a抗HLA-DR抗体。通过靶向HLA的D区,该抗体可潜在用于治疗诸如自身免疫疾病或癌症,特别是白血病或淋巴瘤的疾病。mL243显示出对体外免疫功能的有效抑制,并且对于所有HLA-DR蛋白是单形的。然而,对人患者施用小鼠抗体存在问题,例如诱导人抗小鼠抗体(HAMA)应答。需要具有改善的功效和降低的毒性的抗HLA-DR抗体的更有效的组合物和使用方法。还需要制备和施用抗体-CPT缀合物,例如抗HLA-DR-SN-38缀合物的更有效方法。优选地,所述方法包括优化的剂量和施用方案,其使用于人患者的治疗用途的抗体-CPT缀合物的功效最大化并使毒性最小化。
发明内容
如本文所用,缩写“CPT”可以指喜树碱或其任何衍生物,例如SN-38,除非另有明确说明。本发明通过提供用于制备和施用CPT-抗体免疫缀合物的改进方法和组合物解决了本领域未满足的需求。优选地,喜树碱是SN-38。所公开的方法和组合物可用于治疗用其它形式的治疗难以治疗或对其它形式的治疗响应较少的各种疾病和病症,并且可包括选择性靶向其的合适抗体或抗原结合抗体片段可以开发、是可获得的或已知的疾病,例如癌症。
优选地,靶向部分是抗体、抗体片段、双特异性抗体或其它多价抗体,或其它基于抗体的分子或化合物。更优选地,抗体或片段是抗HLA-DR抗体或片段。抗体可以是各种同种型,优选人IgG1、IgG2、IgG3或IgG4,更优选包含人IgG1铰链和恒定区序列。最优选地,抗体是人IgG4。抗体或其片段可以是嵌合的人-小鼠抗体、嵌合的人灵长类动物抗体、人源化的(人框架和鼠高变(CDR)区)抗体或完全人抗体,及其变体,例如半IgG4抗体(称为“单抗体(unibody)”),如van der Neut Kolfschoten等所述(Science 2007;317:1554-1557)。更优选地,可以设计或选择抗体或其片段以包含属于特定同种异型的人恒定区序列,当免疫缀合物施用于人受试者时,其可导致免疫原性降低。用于施用的优选同种异型包括非G1m1同种异型(nG1m1),例如G1m3、G1m3,1、G1m3,2或G1m3,1,2。更优选地,同种异型选自nG1m1、G1m3、nG1m1,2和Km3同种异型。
在疾病状态是癌症的情况下,许多由肿瘤细胞表达或以其它方式与肿瘤细胞相关的抗原是本领域已知的,包括但不限于碳酸酐酶IX、甲胎蛋白(AFP)、α-辅肌动蛋白-4、A3、对于A33抗体具有特异性抗原、ART-4、B7、Ba 733、BAGE、BrE3-抗原、CA125、CAMEL、CAP-1、CASP-8/m、CCL19、CCL21、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD66a-e、CD67、CD70、CD70L、CD74、CD79a、CD80、CD83、CD95、CD126、CD132、CD133、CD138、CD147、CD154、CDC27、CDK-4/m、CDKN2A、CTLA-4、CXCR4、CXCR7、CXCL12、HIF-1α、结肠特异性抗原-p(CSAp)、CEA(CEACAM5)、CEACAM6、c-Met、DAM、DLL3、DLL4、EGFR、EGFRvIII、EGP-1(TROP-2)、EGP-2、ELF2-M、Ep-CAM、成纤维细胞生长因子(FGF)、Flt-1、Flt-3、叶酸受体、G250抗原、GAGE、gp100、GRO-β、HLA-DR、HM1.24、人绒毛膜***(HCG)及其亚基、HER2/neu、HMGB-1、缺氧诱导因子(HIF-1)、HSP70-2M、HST-2、Ia、IGF-1R、IFN-γ、IFN-α、IFN-β、IFN-λ、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-2、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-23、IL-25、***-1(IGF-1)、KC4-抗原、KS-1-抗原、KS1-4、Le-Y、LDR/FUT、巨噬细胞移动抑制因子(MIF)、MAGE、MAGE-3、MART-1、MART-2、间皮素、NY-ESO-1、TRAG-3、mCRP、MCP-1、MIP-1A、MIP-1B、MIF、MUC1、MUC2、MUC3、MUC4、MUC5ac、MUC13、MUC16、MUM-1/2、MUM-3、NCA66、NCA95、NCA90、PAM4抗原、胰腺癌粘蛋白、PD-1受体、胎盘生长因子、p53、PLAGL2、***酸性磷酸酶、PSA、PRAME、PSMA、PlGF、ILGF、ILGF-1R、IL-6、IL-25、RS5、RANTES、T101、SAGE、S100、存活蛋白、存活蛋白-2B、TAC、TAG-72、腱生蛋白、TRAIL受体、TNF-α、Tn抗原、Thomson-Friedenreich抗原、肿瘤坏死抗原、VEGFR、ED-B纤连蛋白、WT-1、17-1A抗原、补体因子C3、C3a、C3b、C5a、C5、血管生成标志物、bcl-2、bcl-6、Kras、癌基因标志物和癌基因产物(参见例如,Sensi等,Clin Cancer Res2006,12:5023-32;Parmiani等,J Immunol 2007,178:1975-79;Novellino等.CancerImmunol Immunother2005,54:187-207)。优选地,抗体与CEACAM5、CEACAM6、EGP-1(TROP-2)、MUC-16、AFP、MUC5ac、CD74、CD19、CD20、CD22或HLA-DR结合。优选的抗HLA-DR抗体可以单独使用,或与另一种抗TAA(肿瘤相关抗原)抗体组合使用。
可以使用的示例性抗体包括但不限于hR1(抗IGF-1R,美国专利号9,441,043)、hPAM4(抗粘蛋白,美国专利号7,282,567)、hA20(抗CD20,美国专利号7,151,164)、hA19(抗CD19,美国专利号7,109,304)、hIMMU31(抗AFP,美国专利号7,300,655)、hLL1(抗CD74,美国专利号7,312,318)、hLL2(抗CD22,美国专利号5,789,554)、hMu-9(抗CSAp,美国专利号7,387,772)、hL243(抗HLA-DR,美国专利号7,612,180)、hMN-14(抗-CEACAM5,美国专利号6,676,924)、hMN-15(抗CEACAM6,美国专利号8,287,865)、hRS7(抗EGP-1,美国专利号7,238,785)、hMN-3(抗CEACAM6,美国专利号7,541,440)、Ab124和Ab125(抗CXCR4,美国专利号7,138,496),每个所引用专利或申请的实施例部分通过引用并入本文。更优选地,抗体是IMMU-31(抗AFP)、hRS7(抗TROP-2)、hMN-14(抗CEACAM5)、hMN-3(抗CEACAM6)、hMN-15(抗CEACAM6)、hLL1(抗CD74)、hLL2(抗CD22)、hL243或IMMU-114(抗HLA-DR)、hA19(抗CD19)或hA20(抗CD20)。最优选地,抗体是hL243。如本文所用,术语依帕珠单抗(epratuzumab)和hLL2是可互换的,同样情况还有术语维妥珠单抗(veltuzumab)和hA20以及术语hL243g4P、hL243γ4P和IMMU-114。
使用的替代抗体包括但不限于阿昔单抗(abciximab)(抗糖蛋白IIb/IIIa)、阿仑单抗(alemtuzumab)(抗CD52)、贝伐单抗(bevacizumab)(抗VEGF)、西妥昔单抗(cetuximab)(抗EGFR)、吉妥珠单抗(gemtuzumab)(抗CD33)、替伊莫单抗(ibritumomab)(抗CD20)、帕尼单抗(panitumumab)(抗EGFR)、利妥昔单抗(rituximab)(抗CD20),托西莫单抗(tositumomab)(抗CD20)、曲妥珠单抗(trastuzumab)(抗ErbB2)、派姆单抗(pembrolizumab)(抗PD-1受体)、纳武单抗(nivolumab)(抗PD-1受体)、伊匹单抗(ipilimumab)(抗CTLA-4)、阿巴伏单抗(abagovomab)(抗CA-125)、阿德木单抗(adecatumumab)(抗EpCAM)、阿特利珠单抗(atlizumab)(抗IL-6受体)、苯拉利珠单抗(benralizumab)(抗CD125)、奥比妥珠单抗(obinutuzumab)(GA101,抗CD20)、CC49(抗TAG-72)、AB-PG1-XG1-026(抗PSMA,美国专利申请11/983,372,保藏号ATCC PTA-4405和PTA-4406)、D2/B(抗PSMA,WO 2009/130575)、托珠单抗(tocilizumab)(抗IL-6受体)、巴利昔单抗(basiliximab)(抗CD25)、达利珠单抗(daclizumab)(抗CD25)、依法利珠单抗(efalizumab)(抗CD11a)、GA101(抗CD20;Glycart Roche)、莫罗单抗-CD3(muromonab-CD3)(抗CD3受体)、那他珠单抗(natalizumab)(抗α4整合素)、奥马珠单抗(omalizumab)(抗IgE);抗TNF-α抗体,如CDP571(Ofei等,2011,Diabetes 45:881-85)、MTNFAI、M2TNFAI、M3TNFAI、M3TNFABI、M302B、M303(Thermo Scientific,Rockford,IL)、英夫利昔单抗(infliximab)(Centocor,Malvern,PA)、赛妥珠单抗(certolizumab pegol)(UCB,Brussels,Belgium)、抗CD40L(UCB,Brussels,Belgium)、阿达木单抗(adalimumab)(Abbott,Abbott Park,IL)或贝利木单抗(Benlysta)(Human Genome Sciences)。
在一个优选的实施方案中,化学治疗部分选自喜树碱(CPT)及其类似物和衍生物,更优选SN-38。然而,可以使用的其它化学治疗部分包括紫杉烷类(例如,浆果赤霉素III(baccatin III)、紫杉醇)、埃博霉素(epothilone)、蒽环类(例如表柔比星(DOX)、表柔比星、吗啉代多柔比星(吗啉代-DOX)、氰基吗啉代-多柔比星(氰基吗啉代-DOX)、2-吡咯啉基多柔比星(2-PDOX)或2-PDOX的前药形式(pro-2-PDOX);参见,例如,Priebe W(编辑),ACSsymposium series 574,由American Chemical Society,Washington D.C.出版,1995(332pp)和Nagy等,Proc.Natl.Acad.Sci.USA 93:2464-2469,1996),苯醌安莎霉素(benzoquinoid ansamycin),例如格尔德霉素(geldanamycin)(DeBoer等,Journal ofAntibiotics 23:442-447,1970;Neckers等,Invest.NewDrugs 17:361-373,1999)等。优选地,抗体或其片段连接至至少一个化学治疗部分;优选1至约5个化学治疗部分;更优选6个或更多个化学治疗部分,更优选7至8个,最优选约6至约12个化学治疗部分。
水溶性CPT衍生物的实例是CPT-11。关于CPT-11的药理学及其在体内转化为活性SN-38可获得广泛临床数据(Iyer和Ratain,Cancer Chemother Pharmacol.42:S31-43(1998);Mathijssen等.,Clin Cancer Res.7:2182-2194(2002);Rivory,Ann NY AcadSci.922:205-215,2000))。活性形式SN-38比CPT-11强效约2至3个数量级。在特定的优选实施方案中,免疫缀合物可以是hMN-14-SN-38、hMN-3-SN-38、hMN-15-SN-38、IMMU-31-SN-38、hRS7-SN-38、hA20-SN-38、hL243-SN-38、hLLl-SN-38或hLL2-SN-38缀合物。
多个实施方案可涉及使用本发明的方法和组合物治疗癌症,包括但不限于非霍奇金氏淋巴瘤、B细胞急性和慢性淋巴性白血病、伯基特淋巴瘤(Burkitt lymphoma)、霍奇金氏淋巴瘤、急性大B细胞淋巴瘤、毛细胞白血病、急性髓性白血病、慢性髓性白血病、T细胞淋巴瘤和白血病、多发性骨髓瘤、瓦尔登斯特伦巨球蛋白血症(Waldenstrom'smacroglobulinemia)、癌、黑素瘤、肉瘤、神经胶质瘤、骨和皮肤癌。癌可包括口腔癌、食道癌、胃肠道癌、呼吸道癌、肺癌、胃癌、结肠癌、乳腺癌、卵巢癌、***癌、子宫癌、子宫内膜癌、子***、膀胱癌、胰腺癌、骨癌、脑癌、***癌、肝癌、胆囊癌、膀胱癌、肾癌、皮肤癌、中枢神经***癌和睾丸癌。
在涉及癌症治疗的某些实施方案中,药物缀合物可以与外科手术、放射治疗、化学治疗、用裸抗体的免疫治疗、放射免疫治疗、免疫调节剂、疫苗等组合使用。这样的组合治疗可以允许以这样的组合给予较低剂量的每种治疗剂,从而减少某些严重的副作用,并且可能减少所需的治疗过程。当重叠毒性没有或最小时,也可以给予每一种的全部剂量。
免疫缀合物的优选最佳剂量可包括介于3mg/kg和18mg/kg之间,更优选介于4和16mg/kg之间,更优选介于6和12mg/kg之间,最优选介于8和10mg/kg之间的剂量,优选每周、每周两次或每隔一周给予。最佳给药方案可包括以下的治疗循环:两个连续治疗周然后一个、两个、三个或四个休息周,或交替的治疗周和休息周,或一个治疗周然后两个、三个或四个休息周,或三个治疗周然后一个、两个、三个或四个休息周,或四个治疗周然后一个、两个、三个或四个休息周,或五个治疗周然后一个、两个、三个、四个或五个休息周,或每两周施用一次,每三周施用一次,或每月施用一次。治疗可延续任何数量的循环,优选至少2个、至少4个、至少6个、至少8个、至少10个、至少12个、至少14个、或至少16个循环。示例性使用剂量可包括1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg、11mg/kg、12mg/kg、13mg/kg、14mg/kg、15mg/kg、16mg/kg、17mg/kg和18mg/kg。普通技术人员将认识到,在选择免疫缀合物的最佳剂量时,可考虑多种因素,例如年龄、一般健康状况、特定器官功能或体重,以及先前治疗对特定器官***(例如,骨髓)的影响,并且在治疗过程中施用的剂量和/或频率可以增加或减少。在少至4至8剂量后观察到肿瘤收缩的迹象时,可根据需要重复剂量。本文公开的最佳剂量和施用方案在人受试者中显示出意想不到的优异功效和降低的毒性,这是动物模型研究中无法预测的。令人惊讶的是,优异的功效允许治疗先前发现对一种或多种标准抗癌治疗(包括母体化合物CPT-11,在体内由其衍生得到SN-38)具有抗性的肿瘤。
利用本发明要求保护的组合物和方法的令人惊讶的结果是高剂量抗体-药物缀合物的意料之外的耐受性,即使重复输注,仅观察到恶心和呕吐的相对低级毒性,或可控制的中性粒细胞减少。另一个令人惊讶的结果不存在抗体-药物缀合物的积累,不同于具有与白蛋白、PEG或其它载体缀合的SN-38的其它产物。即使在重复或增加给药后,不存在积累也与改善的耐受性和不存在严重毒性有关。这些令人惊讶的结果允许优化剂量和递送方案,具有出乎意料的高效率和低毒性。所要求保护的方法在具有先前抗性癌症的个体中提供15%或更多,优选20%或更多,优选30%或更多,更优选40%或更多的实体肿瘤的收缩(通过最长直径测量)。普通技术人员将认识到肿瘤尺寸可以通过各种不同的技术来测量,例如总肿瘤体积,任何维度的最大肿瘤尺寸或几个维度的尺寸测量的组合。这可以使用标准放射学程序,例如计算机断层扫描、超声波检查和/或正电子发射断层扫描。测量尺寸的方法不如通过免疫缀合物处理观察的肿瘤尺寸减小的趋势重要,优选导致肿瘤的消除。
虽然免疫缀合物可以作为定期推注施用,但在替代实施方案中,免疫缀合物可以通过连续输注抗体-药物缀合物来施用。为了增加血液中免疫缀合物的Cmax并延长PK,可以例如通过留置导管进行连续输注。这种装置在本领域中是已知的,例如 或PORT-A-导管(参见例如Skolnik等,Ther Drug Monit 32:741-48,2010),并且可以使用任何这样的已知留置导管。多种连续输注泵在本领域中也是已知的,并且可以使用任何这样的已知输注泵。更优选地,这些免疫缀合物可以在2至5小时,更优选2-3小时的相对短的时间内通过静脉内输注施用。
在特别优选的实施方案中,免疫缀合物和给药方案在对标准治疗有抗性的患者中可能是有效的。例如,可以将hL243-SN-38免疫缀合物施用于不响应于先前伊立替康(SN-38的母体试剂)治疗的患者。令人惊讶的是,伊立替康耐药患者可能对hL243-SN-38表现出部分或甚至完全的响应。免疫缀合物特异性靶向肿瘤组织的能力可以通过治疗剂的改善的靶向和增强的递送来克服肿瘤抗性。不同的SN-38免疫缀合物或与缀合至放射性核素、毒素或其它药物的抗体组合的SN-38-抗体缀合物的组合可提供甚至更高的功效和/或降低的毒性。
附图说明
以下附图构成本说明书的一部分,并且包括在内以进一步说明本发明的某些实施方案。通过参考这些附图中的一个或多个并结合本文给出的具体实施方案的详细描述,可以更好地理解实施方案。
图1.IMMU-140(hL243-CL2A-SN-38)的结构。
图2.IMMU-114和IMMU-140的可比较的结合。获得SN-38缀合的(IMMU-140)和裸露的(IMMU-1140形式的hL243)的结合曲线。对照非特异性抗体(h679)显示不与HLA-DR+细胞结合。
图3.MOLM-14 AML异种移植物中IMMU-140对比于IMMU-114的体内功效。
图4.MN-60 ALL异种移植物中IMMU-140对比于IMMU-114的体内功效。
图5.在CAG MM异种移植物中IMMU-140对比于IMMU-114的体内功效。
图6.JVM-3 CLL异种移植物中IMMU-140对比于IMMU-114的体内功效。
图7.hL243-γ4P与体外人黑素瘤细胞的结合。
图8.IMMU-140在体内人黑素瘤异种移植物中的功效。
具体实施方式
定义
在以下描述中,使用了许多术语,并且提供以下定义以便于理解所要求保护的主题。本文未明确定义的术语根据其普通和普通含义使用。
除非另有说明,否则一个(a)或一个(an)表示“一个或多个”。
术语“约”在本文中用于表示值的加或减百分之十(10%)。例如,“约100”指的是介于90和110之间的任何数字。
如本文所用,抗体是指全长(即,天然存在的或通过正常免疫球蛋白基因片段重组过程形成的)免疫球蛋白分子(例如,IgG抗体)或免疫球蛋白分子的抗原结合部分,例如抗体片段。抗体或抗体片段可以在要求保护的主题的范围内缀合或以其它方式衍生化。这样的抗体包括但不限于IgG1、IgG2、IgG3、IgG4(和IgG4亚型),以及IgA同种型。如下所用,缩写“MAb”可互换使用,指抗体、抗体片段、单克隆抗体或多特异性抗体。
抗体片段是抗体的一部分,例如F(ab')2、F(ab)2、Fab'、Fab、Fv、scFv(单链Fv)、单结构域抗体(DAB或VHH)和类似物,包括上面引用的IgG4的半分子(van der NeutKolfschoten等.(Science 2007;317(14 Sept):1554-1557)。无论结构如何,使用的抗体片段与完整抗体所识别的相同抗原结合。术语“抗体片段”还包括通过与特定抗原结合形成复合物而与抗体一样作用的合成或基因工程改造的蛋白质。例如,抗体片段包括由可变区组成的分离片段,例如由重链和轻链的可变区组成的“Fv”片段以及其中轻和重可变区通过肽接头连接的重组单链多肽分子(“scFv蛋白”)。片段可以以不同方式构建以产生多价和/或多特异性结合形式。
裸抗体通常是不与治疗剂缀合的完整抗体。裸抗体可以表现出治疗和/或细胞毒性作用,例如通过Fc依赖性功能,例如补体结合(CDC)和ADCC(抗体依赖性细胞细胞毒性)。然而,其它机制,例如细胞凋亡、抗血管生成、抗转移活性、抗粘附活性、抑制异型或同型粘附以及干扰信号传导途径也可提供治疗效果。裸抗体包括多克隆抗体和单克隆抗体,天然存在的抗体或重组的抗体,例如嵌合抗体、人源化抗体或人抗体及其片段。在一些情况下,“裸抗体”也可以指“裸”抗体片段。如本文所定义,“裸”与“未缀合”同义,并且意指不与治疗剂连接或缀合。
嵌合抗体是重组蛋白,其包含包括来自一个物种的抗体(优选啮齿类动物抗体,更优选鼠抗体)的互补决定区(CDR)的重链和轻链两者的可变结构域,而抗体分子的恒定结构域来自人抗体的恒定结构域。
人源化抗体是重组蛋白,其中来自一个物种的抗体(例如鼠抗体)的CDR从鼠抗体的重链和轻链可变链转移到人重和轻可变结构域(框架区)。抗体分子的恒定结构域来自人抗体的恒定结构域。在一些情况下,人源化抗体的框架区的特定残基,特别是与CDR序列接触或接近的那些残基可以被修饰,例如用来自来源鼠、啮齿类动物、近似人类的灵长类动物或其它抗体的相应残基替换。
人抗体是例如从转基因小鼠获得的抗体,所述转基因小鼠已经“工程改造”以响应于抗原攻击而产生人抗体。在该技术中,将人重链和轻链基因座的元件引入源自胚胎干细胞系的小鼠品系中,所述胚胎干细胞系含有内源性重链和轻链基因座的靶向破坏。转基因小鼠可以合成对各种抗原具有特异性的人抗体,并且小鼠可以用于产生分泌的人抗体杂交瘤。用于从转基因小鼠获得人抗体的方法由Green等,Nature Genet.7:13(1994),Lonberg等,Nature 368:856(1994),和Taylor等,Int.Immun.6:579(1994)描述。完全人抗体也可以通过遗传或染色体转染方法以及噬菌体展示技术构建,所有这些都是本领域已知的。参见例如McCafferty等,Nature 348:552-553(1990),用于从来自未免疫供体的免疫球蛋白可变结构域基因库中体外产生人抗体及其片段。在该技术中,将人抗体可变结构域基因框内克隆到丝状噬菌体的主要或次要外壳蛋白基因中,并在噬菌体颗粒的表面上展示为功能性抗体片段。因为丝状颗粒含有噬菌体基因组的单链DNA拷贝,所以基于抗体功能特性的选择也导致选择编码表现这些特性的抗体的基因。以这种方式,噬菌体模拟B细胞的一些特性。噬菌体展示可以以多种形式进行,对于这些的综述,参见例如Johnson和Chiswell,CurrentOpinion in Structural Biology 3:5564-571(1993)。人体抗体也可以通过体外活化的B细胞产生。参见美国专利号5,567,610和5,229,275,其各自的实施例部分通过引用并入本文。
治疗剂是可用于治疗疾病的原子、分子或化合物。治疗剂的实例包括但不限于抗体、抗体片段、免疫缀合物、药物、细胞毒性剂、促凋亡剂、毒素、核酸酶(包括DNA酶和RNA酶)、激素、免疫调节剂、螯合剂、硼化合物、光活性剂或染料、放射性核素、寡核苷酸、干扰RNA、siRNA、RNAi、抗血管生成剂、化学治疗剂、细胞因子、趋化因子、前药、酶、结合蛋白或肽或其组合。
免疫缀合物是与治疗剂缀合的抗体、抗原结合性抗体片段、抗体复合物或抗体融合蛋白。缀合可以是共价的或非共价的。优选地,缀合是共价的。
如本文所用,术语抗体融合蛋白是重组产生的抗原结合分子,其中一个或多个天然抗体、单链抗体或抗体片段与另一个部分例如蛋白质或肽、毒素、细胞因子、激素等连接。在某些优选的实施方案中,融合蛋白可以包含融合在一起的两个或更多个相同或不同的抗体、抗体片段或单链抗体,其可以结合至相同表位,相同抗原或不同抗原上的不同表位。
免疫调节剂是治疗剂,当其存在时,改变、抑制或刺激身体的免疫***。通常,使用的免疫调节剂刺激免疫细胞以在免疫应答级联中增殖或活化,例如巨噬细胞、树突细胞、B细胞和/或T细胞。然而,在一些情况下,免疫调节剂可以抑制免疫细胞的增殖或活化。如本文所述的免疫调节剂的实例是细胞因子,其是约5-20kDa的可溶性小蛋白,其一个细胞群(例如,引发的T-淋巴细胞)在与特定抗原接触时由释放,并且充当细胞间的细胞间介质。如技术人员将理解的,细胞因子的实例包括淋巴因子、单核因子、白细胞介素和多种相关的信号分子,例如肿瘤坏死因子(TNF)和干扰素。趋化因子是细胞因子的亚组。某些白细胞介素和干扰素是刺激T细胞或其它免疫细胞增殖的细胞因子的实例。示例性的干扰素包括干扰素-α、干扰素-β、干扰素-γ和干扰素-λ。
CPT是喜树碱的缩写,并且如本申请中所使用,CPT表示喜树碱本身或喜树碱的类似物或衍生物,例如SN-38。喜树碱及其一些类似物的结构(具有用字母A-E指示的编号和标记的环)在下式1和小图1中示出。
图1
喜树碱缀合物
以下描述了用于制备免疫缀合物的非限制性方法和组合物,所述免疫缀合物包含与抗体或抗原结合抗体片段连接的喜树碱治疗剂。在优选的实施方案中,通过在药物和抗体之间放置限定的聚乙二醇(PEG)部分(即,含有限定数量的单体单元的PEG)来增强药物的溶解度,其中限定的PEG是低分子量PEG,优选含有1-30个单体单元,更优选含有1-12个单体单元,最优选含有7-8个单体单元。
优选地,第一接头在一端连接药物,并且可以在另一端用乙炔或叠氮基团终止。该第一接头可包含限定的PEG部分,其在一端具有叠氮基或乙炔基,并且在另一端具有不同的反应性基团,例如羧酸或羟基。所述双官能的限定的PEG可以连接到氨基醇的胺基上,后者的羟基可以以碳酸酯的形式连接到药物上的羟基上。或者,所述限定的双官能PEG的非叠氮化物(或乙炔)部分任选连接于L-氨基酸或多肽的N-末端,其C-末端连接至氨基醇的氨基,并且后者的羟基分别以碳酸酯或氨基甲酸酯的形式连接至药物的羟基。
包含抗体偶联基团和与第一接头的叠氮化物(或乙炔)基团互补的反应性基团(即乙炔(或叠氮化物))的第二接头可以通过乙炔-叠氮化物环加成反应与药物-(第一接头)缀合物反应,以提供最终的双官能药物产品,其可用于与靶向疾病的抗体结合。抗体偶联基团优选为硫醇或硫醇反应性基团。
下面提供了在涉及CPT类似物如SN-38的药物-接头前体制剂中在C-20碳酸酯的存在下选择性再生10-羟基的方法。也可以使用药物中的反应性羟基(例如SN-38中的酚羟基)的其它保护基团,例如叔丁基二甲基甲硅烷基或叔丁基二苯基甲硅烷基,并且在将衍生化的药物与抗体偶联部分连接之前通过氟化四丁基铵对其脱保护。或者,除“BOC”之外,将CPT类似物的10-羟基替代地保护为酯或碳酸酯,使得双官能CPT与抗体缀合而无需事先将该保护基脱保护。在施用生物缀合物后,保护基易于在生理pH条件下脱保护。
在乙炔-叠氮化物偶联中(称为‘点击化学’),叠氮化物部分可以在L2上,乙炔部分在L3上。或者,L2可含有乙炔,L3含有叠氮化物。‘点击化学’是指乙炔部分和叠氮部分之间的铜(+1)-催化的环加成反应(Kolb HC和Sharpless KB,DrugDiscov Today 2003;8:1128-37),尽管替代形式的点击化学是已知的并且可以使用。点击化学在近中性pH条件下在水溶液中进行,因此适合于药物缀合。点击化学的优点在于它是化学选择性的,并且补充了其它众所周知的缀合化学,例如硫醇-马来酰亚胺反应。
虽然本申请集中于使用抗体或抗体片段作为靶向部分,但技术人员将认识到,当缀合物包含抗体或抗体片段时,另一种类型的靶向部分,例如适体、avimer、亲合体(affibody)或肽配体可以被取代。
示例性优选实施方案涉及通式2的药物衍生物和抗体的缀合物,
MAb-[L2]-[L1]-[AA]m-[A’]-药物 (2)
其中MAb是靶向疾病的抗体;L2是交联剂组分,其包含抗体偶联部分和一个或多个乙炔(或叠氮化物)基团;L1包含限定的PEG,其在一端具有与L2中的乙炔(或叠氮化物)部分互补的叠氮化物(或乙炔),并且在另一端具有反应性基团如羧酸或羟基;AA是L-氨基酸;m是整数,其值为0、1、2、3或4;A’是另外的间隔基,选自乙醇胺、4-羟基苄基醇、4-氨基苄基醇或者经取代的或未经取代的乙二胺。‘AA’的L氨基酸选自丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸。如果A’基团含有羟基,则其分别以碳酸酯或氨基甲酸酯的形式与药物的羟基或氨基连接。
在式2的一个优选实施方案中,A’是衍生自L-氨基酸的经取代的乙醇胺,其中氨基酸的羧酸基团被羟甲基部分取代。A’可以衍生自以下L-氨基酸中的任何一种:丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸。
称为MAb-CL2A-SN-38的优选实施方案如下所示。
在含有10-羟基的喜树碱(例如SN-38)的情况下,其它实施方案是可能的。在SN-38作为药物的实例中,药物的反应性更高的10-羟基被衍生化,而20-羟基不受影响。在通式2中,A’是经取代的乙二胺。
在另一个优选的实施方案中,缀合物的L1组分含有具有1-30个重复单体单元的限定的聚乙二醇(PEG)间隔基。在进一步优选的实施方案中,PEG是具有1-12个重复单体单元的限定的PEG。PEG的引入可涉及使用可商购获得的异双官能化PEG衍生物。异双官能PEG可含有叠氮化物或乙炔基团。含有8个重复单体单元,其中‘NHS’为琥珀酰亚胺基的异双官能的限定的PEG的实例在下面的式3中给出:
在一个优选的实施方案中,L2具有多个乙炔(或叠氮化物)基团,范围为2-40个,但优选2-20个,更优选2-5个,和单个抗体结合部分。
含有多个药物分子和单个抗体结合部分的抗体的代表性SN-38缀合物如下所示。该结构的‘L2’组分连接至2个炔基上,导致两个叠氮化物连接的SN-38分子的附接。与MAb的键合表示为琥珀酰亚胺。
其中R残基为:
在一些优选的实施方案中,当双官能药物含有硫醇反应性部分作为抗体结合基团时,使用硫醇化试剂在抗体的赖氨酸基团上产生抗体上的硫醇。通过修饰MAb的赖氨酸基团将硫醇基团引入抗体的方法是本领域熟知的(Wong,Chemistry of protein conjugationand cross-linking,CRC Press,Inc.,Boca Raton,FL(1991),第20-22页)。或者,使用还原剂如二硫苏糖醇(DTT)轻微还原抗体上的链间二硫键(Willner等,Bioconjugate Chem.4:521-527(1993))可以在抗体上产生7至10个硫醇;其优点是在MAb的远离抗原结合区的链间区域中引入多个药物部分。在更优选的实施方案中,SN-38与还原的二硫化物巯基的连接导致形成抗体-SN-38免疫缀合物,其中每个抗体分子共价连接有6至8个SN-38部分。提供用于连接药物或其它治疗剂的半胱氨酸残基的其它方法是已知的,例如使用半胱氨酸工程改造的抗体(参见美国专利号7,521,541,其实施例部分通过引用并入本文。)
在替代的优选实施方案中,化学治疗部分选自多柔比星(DOX)、表柔比星、吗啉代多柔比星(吗啉代-DOX)、氰基吗啉代-多柔比星(氰基吗啉代-DOX)、2-吡咯啉基-多柔比星(2-PDOX)、Pro-2PDOX、CPT、10-羟基喜树碱、SN-38、拓扑替康、勒托替康(lurtotecan)、9-氨基喜树碱、9-硝基喜树碱、紫杉烷、格尔德霉素(geldanamycin)、安沙霉素(ansamycins)和埃博霉素(epothilones)。在更优选的实施方案中,化学治疗部分是SN-38。优选地,在优选实施方案的缀合物中,抗体连接至至少一个化学治疗部分;优选1至约12个化学治疗部分;更优选约6至约12个化学治疗部分,最优选约6至8个化学治疗部分。
此外,在一些优选的实施方案中,接头组分‘L2’包含硫醇基团,其与在所述抗体的一个或多个赖氨酸侧链氨基处引入的硫醇反应性残基反应。在这种情况下,通过本领域充分描述的程序使抗体预衍生化有硫醇反应性基团,例如马来酰亚胺、乙烯基砜、溴乙酰胺或碘乙酰胺。
在该工作的背景下,令人惊讶地发现了一种方法,通过该方法可以制备CPT药物接头,其中CPT另外具有10-羟基。该方法包括但不限于将10-羟基保护为叔丁氧基羰基(BOC)衍生物,然后制备药物-接头缀合物的倒数第二个中间体。通常,去除BOC基团需要用强酸如三氟乙酸(TFA)处理。在这些条件下,含有待除去的保护基团的CPT20-O-接头碳酸酯也易于裂解,从而产生未经修饰的CPT。事实上,如本领域所阐述的,使用温和可去除的甲氧基三苯甲基(MMT)保护基团用于接头分子的赖氨酸侧链的基本原理正是为了避免这种可能性(Walker等,2002)。发现通过进行短时间的反应,最佳3至5分钟,可以选择性除去酚类BOC保护基团。在这些条件下,主要产物是去除了10-羟基位置的‘BOC’,而‘20’位置的碳酸酯是完整的。
另一种方法涉及用“BOC”以外的基团保护CPT类似物的10-羟基位置,使得最终产物准备与抗体偶联而不需要使10-OH保护基脱保护。将10-OH转化为酚碳酸酯或酚酯的10-羟基保护基易于在体内施用缀合物之后在生理pH条件下或通过酯酶脱保护。He等人已经描述了在生理条件下10-羟基喜树碱的10位置处的酚类碳酸酯相对于20位置的叔碳酸盐更快去除(He等,Bioorganic&Medicinal Chemistry 12:4003-4008(2004))。SN-38上的10-羟基保护基团可以是‘COR’,其中R可以是经取代的烷基,例如“N(CH3)2-(CH2)n-”,其中n是1-10并且其中末端氨基任选地为季盐的形式用于增强水溶性,或者简单的烷基残基,例如“CH3-(CH2)n-”,其中n是0-10,或者其可以是烷氧基部分,例如“CH3-(CH2)n-O-”其中n为0-10,或者“N(CH3)2-(CH2)n-O-”,其中n为2-10,或者“R1O-(CH2-CH2-O)n-CH2-CH2-O-”,其中R1是乙基或甲基,并且n是整数,其值为0-10。如果最终衍生物是碳酸酯,则通过用所选试剂的氯甲酸酯处理,可以容易地制备这些10-羟基衍生物。通常,使用三乙胺作为碱,用二甲基甲酰胺中的摩尔当量的氯甲酸酯处理含有10-羟基的喜树碱如SN-38。在这些条件下,20-OH位置不受影响。为了形成10-O-酯,使用所选试剂的酰氯。
在制备通式2的药物衍生物和抗体的缀合物的一个优选方法中,其中描述符L2、L1、AA和A-X如前面部分中所述,首先制备双官能药物部分[L2]-[L1]-[AA]m-[A-X]-药物,然后使双官能药物部分与抗体(在本文中表示为“MAb”)缀合。
在制备药物衍生物和通式2的抗体的缀合物的一个优选方法中,其中描述符L2、L1、AA和A-OH如前面部分中所述,通过首先通过酰胺键将A-OH连接到AA的C-末端,然后将AA的胺末端偶联到L1的羧酸基团上来制备双官能药物部分。如果不存在AA(即m=0),则A-OH通过酰胺键直接连接到L1上。交联接头[L1]-[AA]m-[A-OH]与药物的羟基或氨基连接,然后通过点击化学在L1和L2中的叠氮化物(或乙炔)和乙炔(或叠氮化物)基团之间反应,使其连接到L1部分。
在一个实施方案中,抗体是单克隆抗体(MAb)。在另一些实施方案中,抗体可以是多价和/或多特异性MAb。抗体可以是鼠、嵌合、人源化或人单克隆抗体,并且所述抗体可以是完整的、片段(Fab、Fab’、F(ab)2、F(ab’)2)或亚片段(单链构建体)形式,或者为IgG1、IgG2a、IgG3、IgG4、IgA同种型或其亚分子。
在一个优选的实施方案中,抗体与癌症或恶性细胞上表达的抗原或抗原的表位结合。癌细胞优选是来自造血肿瘤、癌、肉瘤、黑素瘤或神经胶质瘤的细胞。根据本发明待治疗的优选恶性肿瘤是恶性实体瘤或造血肿瘤。
在一个优选的实施方案中,在通过MAb-药物缀合物与其受体结合内化到细胞中之后,细胞内可切割部分可以被切割,并且特别是被酯酶和肽酶切割。
抗HLA-DR抗体
在优选的实施方案中,免疫缀合物包含抗HLA-DR抗体,例如人源化L243抗体。人源化L243抗体与亲本鼠L243抗体结合HLA-DR上的相同表位,但具有降低的免疫原性。mL243是先前由Lampson和Levy(J Immunol,1980,125:293)描述的单克隆抗体,其已经以保藏号ATCC HB55保藏在American Type Culture Collection,Rockville,MD。
人源化L243抗体包含连接到人抗体FR和恒定区序列的L243重链CDR序列CDR1(NYGMN,SEQ ID NO:1)、CDR2(WINTYTREPTYADDFKG,SEQ ID NO:2)和CDR3(DITAVVPTGFDY,SEQ ID NO:3)以及轻链CDR序列CDR1(RASENIYSNLA,SEQ ID NO:4)、CDR2(AASNLAD,SEQ IDNO:5)和CDR3(QHFWTTPWA,SEQ ID NO:6)。在一个更优选的实施方案中,一个或多个鼠FR氨基酸残基被相应的人FR残基替换,特别是在CDR残基相邻或附近的位置。可在人源化设计中替换的示例性鼠VH残基在以下位置处:F27、K38、K46、A68和F91。可在人源化设计中替换的示例性鼠VL残基在以下位置处:R37、K39、V48、F49和G1。
在美国专利号7,612,180(其通过引用并入本文)中说明了特别优选的hL243抗体形式,其包含来自人RF-TS3、NEWM和REI抗体的FR序列。然而,在另一些实施方案中,FR残基可以来自任何合适的人免疫球蛋白,条件是人源化抗体可以折叠使得其保留与HLA-DR特异性结合的能力。优选地,使用的人框架(FR)的类型与供体抗体具有相同/相似的类别/类型。更优选地,选择人FR序列以与相应的鼠FR序列具有高度的序列同源性,特别是在空间上靠近或邻近CDR的位置。根据该实施方案,人源化L243VH或VL的框架(即FR1-4)可以来自人抗体的组合。可用于构建CDR-移植的人源化抗体的人框架的实例是LAY、POM、TUR、TEI、KOL、NEWM、REI、RF和EU。优选地,人RF-TS3FR1-3和NEWM FR4用于重链,并且REI FR1-4用于轻链。本文使用的可变结构域残基编号***描述于以下中:Kabat等,(1991),Sequences ofProteins of Immunological Interest,第5版,United States Department of Healthand Human Services
人源化抗体分子的轻链和重链可变结构域可以与人轻链或重链恒定结构域融合。可以针对所提出的抗体功能选择人恒定结构域。在一个实施方案中,可以基于效应功能的缺乏来选择人恒定结构域。与重链可变区融合的重链恒定结构域可以是人IgA(α1或α2链)、IgG(γ1、γ2、γ3或γ4链)或IgM(μ链)的那些。可以与轻链可变区融合的轻链恒定结构域包括人λ和κ链。
在本发明的一个具体实施方案中,使用γl链。在又一个特定实施方案中,使用γ4链。在某些情况下,使用γ4链可提高受试者中对hL243的耐受性(减少副作用和输注反应等)。
在一个实施方案中,可以使用人恒定结构域的类似物。这些包括但不限于与相应人结构域相比含有一个或多个额外氨基酸的那些恒定结构或者其中相应人结构域的一个或多个现有氨基酸已缺失或改变的那些恒定结构域。这些结构域可以通过例如寡核苷酸定向诱变获得。
在一个具体实施方案中,抗HLA-DR抗体或其片段可以是融合蛋白。融合蛋白可包含一种或多种抗HLA-DR抗体或其片段。在多个实施方案中,融合蛋白还可以包含一种或多种针对不同抗原的其它抗体,或者可以包含不同的效应蛋白或肽,例如细胞因子。例如,不同抗原可以是选自B细胞谱系抗原(例如,CD19、CD20或CD22)的肿瘤标志物,用于治疗B细胞恶性肿瘤。在另一个实例中,不同抗原可以在引起其它类型恶性肿瘤的其它细胞上表达。此外,细胞标志物可以是非B细胞谱系抗原,例如选自HLA-DR、CD3、CD33、CD52、CD66、MUC1和TAC。
在一个实施方案中,抗HLA-DR抗体可以与其它抗体组合并用于治疗患有或怀疑患有疾病的受试者。根据该实施方案,抗HLA-DR抗体或其片段可以与抗癌单克隆抗体例如人源化单克隆抗体(例如hA20,抗CD20Mab)组合并用于治疗癌症。本文预期抗HLA-DR抗体可以用作单独的抗体组合物与一种或多种其它单独的抗体组合物组合,或者用作含有例如一种抗HLA-DR和一种其它抗肿瘤抗体(例如hA20)的双功能抗体。在另一个具体实施方案中,抗体可以靶向B细胞恶性肿瘤。B细胞恶性肿瘤可由惰性形式的B细胞淋巴瘤、侵袭形式的B细胞淋巴瘤、慢性淋巴性白血病、急性淋巴性白血病、瓦尔登斯特伦巨球蛋白血症和多发性骨髓瘤组成。可以用本发明抗体治疗的其它非恶性B细胞病症和相关疾病包括许多自身免疫和免疫失调疾病,例如败血症和败血症性休克。
一般抗体技术
用于制备针对几乎任何靶抗原的单克隆抗体的技术是本领域熟知的。参见,例如,和Milstein,Nature 256:495(1975),和Coligan等.(编辑),CURRENT PROTOCOLSIN IMMUNOLOGY,第1卷,第2.5.1-2.6.7页(John Wiley&Sons 1991)。简单地说,可以通过以下方式获得单克隆抗体:向小鼠注射含有人抗原(如人HLA-DR)的组合物,去除脾脏以获得B淋巴细胞,将B淋巴细胞与骨髓瘤细胞融合以产生杂交瘤,克隆杂交瘤,选择产生针对人抗原的抗体的阳性克隆,培养产生针对抗原的抗体的克隆,并从杂交瘤培养物中分离抗体。
可以通过各种成熟的技术从杂交瘤培养物中分离和纯化MAb。这样的分离技术包括用蛋白-A或蛋白-G琼脂糖凝胶的亲和色谱、尺寸排阻色谱和离子交换色谱。例如,参见Coligan的第2.7.1-2.7.12页和第2.9.1-2.9.3页。还参见Baines等,“Purification ofImmunoglobulin G(IgG),”METHODS IN MOLECULAR BIOLOGY,第10卷,第79-104页(TheHumana Press,Inc.1992)。
在最初产生针对免疫原的抗体后,可以对抗体进行测序,并且随后通过重组技术制备。鼠抗体和抗体片段的人源化和嵌合化是本领域技术人员公知的,如下面讨论的。
本领域技术人员将认识到,要求保护的方法和组合物可以使用本领域已知的多种抗体中的任何一种。使用的抗体可以从多种已知来源商业获得。例如,多种分泌抗体的杂交瘤系可从美国典型培养物保藏中心(ATCC,Manassas,VA)获得。针对多种疾病靶标(包括但不限于肿瘤相关抗原)的大量抗体已经保藏在ATCC和/或具有已公开的可变区序列,并且可用于要求保护的方法和组合物。参见,例如,以下美国专利号:7,312,318;7,282,567;7,151,164;7,074,403;7,060,802;7,056,509;7,049,060;7,045,132;7,041,803;7,041,802;7,041,293;7,038,018;7,037,498;7,012,133;7,001,598;6,998,468;6,994,976;6,994,852;6,989,241;6,974,863;6,965,018;6,964,854;6,962,981;6,962,813;6,956,107;6,951,924;6,949,244;6,946,129;6,943,020;6,939,547;6,921,645;6,921,645;6,921,533;6,919,433;6,919,078;6,916,475;6,905,681;6,899,879;6,893,625;6,887,468;6,887,466;6,884,594;6,881,405;6,878,812;6,875,580;6,872,568;6,867,006;6,864,062;6,861,511;6,861,227;6,861,226;6,838,282;6,835,549;6,835,370;6,824,780;6,824,778;6,812,206;6,793,924;6,783,758;6,770,450;6,767,711;6,764,688;6,764,681;6,764,679;6,743,898;6,733,981;6,730,307;6,720,155;6,716,966;6,709,653;6,693,176;6,692,908;6,689,607;6,689,362;6,689,355;6,682,737;6,682,736;6,682,734;6,673,344;6,653,104;6,652,852;6,635,482;6,630,144;6,610,833;6,610,294;6,605,441;6,605,279;6,596,852;6,592,868;6,576,745;6,572,856;6,566,076;6,562,618;6,545,130;6,544,749;6,534,058;6,528,625;6,528,269;6,521,227;6,518,404;6,511,665;6,491,915;6,488,930;6,482,598;6,482,408;6,479,247;6,468,531;6,468,529;6,465,173;6,461,823;6,458,356;6,455,044;6,455,040,6,451,310;6,444,206’6,441,143;6,432,404;6,432,402;6,419,928;6,413,726;6,406,694;6,403,770;6,403,091;6,395,276;6,395,274;6,387,350;6,383,759;6,383,484;6,376,654;6,372,215;6,359,126;6,355,481;6,355,444;6,355,245;6,355,244;6,346,246;6,344,198;6,340,571;6,340,459;6,331,175;6,306,393;6,254,868;6,187,287;6,183,744;6,129,914;6,120,767;6,096,289;6,077,499;5,922,302;5,874,540;5,814,440;5,798,229;5,789,554;5,776,456;5,736,119;5,716,595;5,677,136;5,587,459;5,443,953,5,525,338,其每个的实施例部分通过引用并入本文。这些仅是示例性的,并且多种其它抗体及其杂交瘤在本领域中是已知的。技术人员将认识到,通过简单地搜索ATCC、NCBI和/或USPTO数据库以获得针对所选择的目的疾病相关靶标的抗体,可以获得针对几乎任何疾病相关抗原的抗体序列或分泌抗体的杂交瘤。可以使用本领域熟知的标准技术将克隆的抗体的抗原结合结构域扩增、切除、连接到表达载体中,转染到适应的宿主细胞中并用于蛋白质生产。可以使用本文公开的技术将分离的抗体缀合至治疗剂,例如喜树碱。
嵌合抗体和人源化抗体
嵌合抗体是重组蛋白,其中人抗体的可变区已经被例如包含小鼠抗体的互补决定区(CDR)的小鼠抗体的可变区替换。当施用于受试者时,嵌合抗体表现出降低的免疫原性和增加的稳定性。构建嵌合抗体的方法是本领域熟知的(例如,Leung等,1994,Hybridoma 13:469)。
嵌合单克隆抗体可以通过将小鼠CDR从小鼠免疫球蛋白的重链和轻链可变链转移到人抗体的相应可变结构域中而人源化。嵌合单克隆抗体中的小鼠框架区(FR)也被人FR序列替换。为了保持人源化单克隆的稳定性和抗原特异性,一个或多个人FR残基可以替换为小鼠对应残基。人源化单克隆抗体可用于受试者的治疗性治疗。用于产生人源化单克隆抗体的技术是本领域熟知的。(参见,例如,Jones等,1986,Nature,321:522;Riechmann等,Nature,1988,332:323;Verhoeyen等,1988,Science,239:1534;Carter等,1992,Proc.Nat'l Acad.Sci.USA,89:4285;Sandhu,Crit.Rev.Biotech.,1992,12:437;Tempest等,1991,Biotechnology 9:266;Singer等,J.Immun.,1993,150:2844.)
其它实施方案可涉及非人灵长类动物抗体。用于在狒狒中产生治疗上有用的抗体的一般技术可例如在Goldenberg等,WO 91/11465(1991),和Losman等,Int.J.Cancer46:310(1990)中找到。在另一个实施方案中,抗体可以是人单克隆抗体。这样的抗体可以从转基因小鼠获得,所述转基因小鼠已被工程改造以响应于抗原攻击产生特异性人抗体,如下所述。
人体抗体
使用组合方法或用人免疫球蛋白基因座转化的转基因动物产生完全人抗体的方法是本领域已知的(例如,Mancini等,2004,New Microbiol.27:315-28;Conrad和Scheller,2005,Comb.Chem.High Throughput Screen.8:117-26;Brekke和Loset,2003,Curr.Opin.Phamacol.3:544-50;各自通过引用并入本文)。预期这种完全人抗体比嵌合或人源化抗体表现出甚至更少的副作用,并且在体内起基本上内源人抗体的作用。在某些实施方案中,要求保护的方法和程序可以利用由这些技术产生的人抗体。
在一个替代方案中,噬菌体展示技术可用于产生人抗体(例如,Dantas-Barbosa等,2005,Genet.Mol.Res.4:126-40,通过引用并入本文)。人抗体可以由正常人或表现出特定疾病状态(例如癌症)的人产生(Dantas-Barbosa等,2005)。从患病个体构建人抗体的优点是循环抗体库可能偏向于针对疾病相关抗原的抗体。
在该方法的一个非限制性实例中,Dantas-Barbosa等(2005)构建了来自骨肉瘤患者的人Fab抗体片段的噬菌体展示文库。通常,从循环血液淋巴细胞获得总RNA(同上。)从μ、γ和κ链抗体库中克隆重组Fab并***噬菌体展示文库(同上。)使用针对重链和轻链免疫球蛋白序列的特异性引物将RNA转化为cDNA并用于制备Fab cDNA文库(Marks等,1991,J.Mol.Biol.222:581-97,通过引用并入本文)。根据Andris-Widhopf等(2000,PhageDisplay Laboratory Manual,Barbas等(编辑),第1版,Cold Spring Harbor LaboratoryPress,Cold Spring Harbor,NY第9.1至9.22页,通过引用并入本文)进行文库构建。用限制性内切核酸酶消化最终的Fab片段并***噬菌体基因组中以制备噬菌体展示文库。可以通过标准噬菌体展示方法筛选这些文库。技术人员将认识到该技术仅是示例性的,并且可以使用通过噬菌体展示制备和筛选人抗体或抗体片段的任何已知方法。
在另一个替代方案中,使用如上所述的标准免疫方案,已经遗传工程改造以产生人抗体的转基因动物可用于产生针对基本上任何免疫原性靶标的抗体。用于从转基因小鼠获得人抗体的方法由以下描述Green等,Nature Genet.7:13(1994),Lonberg等,Nature368:856(1994),和Taylor等,Int.Immun.6:579(1994)。这样的***的非限制性实例是来自Abgenix(Fremont,CA)的(例如,Green等,1999,J.Immunol.Methods231:11-23,通过引用并入本文)。在和类似动物中,小鼠抗体基因已被灭活并被功能性人抗体基因替换,而小鼠免疫***的其余部分保持完整。
用种系配置的YAC(酵母人工染色体)转化所述YAC沿着辅助基因和调节序列包含人IgH和Igκ基因座的一部分,包括大部分可变区序列。人可变区库可用于产生产生抗体的B细胞,所述B细胞可通过已知技术加工成杂交瘤。用靶抗原免疫的将通过正常免疫应答产生人抗体,其可以通过上述标准技术收获和/或产生。有多种品系可供选择,每种品系都能产生不同类别的抗体。已显示转基因产生的人抗体具有治疗潜力,同时保留正常人抗体的药代动力学特性(Green等,1999)。技术人员将认识到,要求保护的组合物和方法不限于使用***,而是可以利用经遗传工程改造以产生人抗体的任何转基因动物。
抗体片段的产生
所要求保护的方法和/或组合物的一些实施方案可涉及抗体片段。例如,可通过常规方法通过胃蛋白酶或木瓜蛋白酶消化完整抗体来获得这样的抗体片段。例如,可以通过用胃蛋白酶酶促切割抗体来产生抗体片段,以提供表示为F(ab')2的5S片段。可以使用硫醇还原剂和任选的由二硫键断裂产生的巯基的封闭基团进一步切割该片段,以产生3.5SFab'单价片段。或者,使用胃蛋白酶进行酶促切割产生两个单价Fab片段和Fc片段。用于产生抗体片段的示例性方法公开于以下:美国专利号4,036,945;美国专利号4,331,647;Nisonoff等,1960,Arch.Biochem.Biophys.,89:230;Porter,1959,Biochem.J.,73:119;Edelman等,1967,METHODS IN ENZYMOLOGY,第422页(Academic Press),以及Coligan等(编辑),1991,CURRENT PROTOCOLS IN IMMUNOLOGY,(John Wiley&Sons)。
可以使用切割抗体的其它方法,例如分离重链以形成单价轻-重链片段,进一步切割片段以及其它酶、化学或遗传技术,只要片段与被完整抗体识别的抗原结合即可。例如,Fv片段包含VH和VL链的缔合。这种缔合可以是非共价的,如Inbar等,1972,Proc.Nat'l.Acad.Sci.USA,69:2659中描述的。或者,可变链可以通过分子间二硫键连接或通过化学物质如戊二醛交联。参见Sandhu,1992,Crit.Rev.Biotech.,12:437。
优选地,Fv片段包含通过肽接头连接的VH和VL链。这些单链抗原结合蛋白(scFv)通过构建包含DNA序列的结构基因来制备,所述DNA序列编码通过寡核苷酸接头序列连接的VH和VL结构域。将结构基因***表达载体中,随后将表达载体引入宿主细胞,例如大肠杆菌。重组宿主细胞合成具有桥接两个V结构域的接头肽的单个多肽链。用于产生scFv的方法是本领域熟知的。参见Whitlow等,1991,Methods:A Companion to Methods in Enzymology2:97;Bird等,1988,Science,242:423;美国专利号4,946,778;Pack等,1993,Bio/Technology,11:1271,以及Sandhu,1992,Crit.Rev.Biotech.,12:437。
抗体片段的另一种形式是单结构域抗体(dAb),有时称为单链抗体。用于产生单结构域抗体的技术是本领域熟知的(参见,例如,Cossins等,Protein Expression andPurification,2007,51:253-59;Shuntao等,Molec Immunol 2006,43:1912-19;Tanha等,J.Biol.Chem.2001,276:24774-780)。其它类型的抗体片段可包含一个或多个互补决定区(CDR)。CDR肽(“最小识别单位”)可以通过构建编码目的抗体的CDR的基因来获得。例如,通过使用聚合酶链式反应合成来自抗体产生细胞的RNA的可变区来制备这样的基因。参见Larrick等,1991,Methods:A Companion to Methods in Enzymology 2:106;Ritter等.(编辑),1995,MONOCLONAL ANTIBODIES:PRODUCTION,ENGINEERING AND CLINICALAPPLICATION,第166-179页(Cambridge University Press);Birch等(编辑),1995,MONOCLONAL ANTIBODIES:PRINCIPLES AND APPLICATIONS,第137-185页(Wiley-Liss,Inc.)
抗体变型
在某些实施方案中,可以改变抗体序列(例如抗体的Fc部分)以优化缀合物的生理学特征,例如血清中的半衰期。替换蛋白质中氨基酸序列的方法在本领域中是众所周知的,例如通过定点诱变(例如Sambrook等,Molecular Cloning,A laboratory manual,第2版,1989)。在优选的实施方案中,变型可以包括在Fc序列中添加或去除一个或多个糖基化位点(例如,美国专利号6,254,868,其实施例部分通过引用并入本文)。在另一些优选的实施方案中,可以进行Fc序列中的特定氨基酸取代(例如,Hornick等,2000,J Nucl Med 41:355-62;Hinton等,2006,J Immunol 176:346-56;Petkova等.2006,Int Immunol 18:1759-69;美国专利号7,217,797;各自通过引用并入本文。
已知抗体
使用的抗体可以从多种已知来源商业获得。例如,多种分泌抗体的杂交瘤系可从美国典型培养物保藏中心(ATCC,Manassas,VA)获得。针对多种疾病靶标(包括但不限于肿瘤相关抗原)的大量抗体已经保藏在ATCC和/或具有已公开的可变区序列,并且可用于要求保护的方法和组合物。参见,例如,以下美国专利号:7,312,318;7,282,567;7,151,164;7,074,403;7,060,802;7,056,509;7,049,060;7,045,132;7,041,803;7,041,802;7,041,293;7,038,018;7,037,498;7,012,133;7,001,598;6,998,468;6,994,976;6,994,852;6,989,241;6,974,863;6,965,018;6,964,854;6,962,981;6,962,813;6,956,107;6,951,924;6,949,244;6,946,129;6,943,020;6,939,547;6,921,645;6,921,645;6,921,533;6,919,433;6,919,078;6,916,475;6,905,681;6,899,879;6,893,625;6,887,468;6,887,466;6,884,594;6,881,405;6,878,812;6,875,580;6,872,568;6,867,006;6,864,062;6,861,511;6,861,227;6,861,226;6,838,282;6,835,549;6,835,370;6,824,780;6,824,778;6,812,206;6,793,924;6,783,758;6,770,450;6,767,711;6,764,688;6,764,681;6,764,679;6,743,898;6,733,981;6,730,307;6,720,155;6,716,966;6,709,653;6,693,176;6,692,908;6,689,607;6,689,362;6,689,355;6,682,737;6,682,736;6,682,734;6,673,344;6,653,104;6,652,852;6,635,482;6,630,144;6,610,833;6,610,294;6,605,441;6,605,279;6,596,852;6,592,868;6,576,745;6,572;856;6,566,076;6,562,618;6,545,130;6,544,749;6,534,058;6,528,625;6,528,269;6,521,227;6,518,404;6,511,665;6,491,915;6,488,930;6,482,598;6,482,408;6,479,247;6,468,531;6,468,529;6,465,173;6,461,823;6,458,356;6,455,044;6,455,040;6,451,310;6,444,206;6,441,143;6,432,404;6,432,402;6,419,928;6,413,726;6,406,694;6,403,770;6,403,091;6,395,276;6,395,274;6,387,350;6,383,759;6,383,484;6,376,654;6,372,215;6,359,126;6,355,481;6,355,444;6,355,245;6,355,244;6,346,246;6,344,198;6,340,571;6,340,459;6,331,175;6,306,393;6,254,868;6,187,287;6,183,744;6,129,914;6,120,767;6,096,289;6,077,499;5,922,302;5,874,540;5,814,440;5,798,229;5,789,554;5,776,456;5,736,119;5,716,595;5,677,136;5,587,459;5,443,953,5,525,338。
这些仅是示例性的,并且多种其它抗体及其杂交瘤在本领域中是已知的。技术人员将认识到,通过简单地搜索ATCC、NCBI和/或USPTO数据库以获得针对所选择的目的疾病相关靶标的抗体,可以获得针对几乎任何疾病相关抗原的抗体序列或分泌抗体的杂交瘤。可以使用本领域熟知的标准技术将克隆的抗体的抗原结合结构域扩增、切除、连接到表达载体中,转染到适应的宿主细胞中并用于蛋白质生产。
可以使用的示例性抗体包括但不限于hR1(抗IGF-1R,美国专利号9,441,043)、hPAM4(抗粘蛋白,美国专利号7,282,567)、hA20(抗CD20,美国专利号7,151,164)、hA19(抗CD19,美国专利号7,109,304)、hIMMU31(抗AFP,美国专利号7,300,655)、hLL1(抗CD74,美国专利号7,312,318)、hLL2(抗CD22,美国专利号5,789,554)、hMu-9(抗CSAp,美国专利号7,387,772)、hL243(抗HLA-DR,美国专利号7,612,180)、hMN-14(抗CEACAM5,美国专利号6,676,924)、hMN-15(抗CEACAM6,美国专利号8,287,865)、hRS7(抗EGP-1,美国专利号7,238,785)、hMN-3(抗CEACAM6,美国专利号7,541,440)、Ab124和Ab125(抗CXCR4,美国专利号7,138,496),每个所引用专利或申请的实施例部分通过引用并入本文。更优选地,抗体是IMMU-31(抗AFP)、hRS7(抗TROP-2)、hMN-14(抗CEACAM5)、hMN-3(抗CEACAM6)、hMN-15(抗CEACAM6)、hLL1(抗CD74)、hLL2(抗CD22)、hL243或IMMU-114(抗HLA-DR)、hA19(抗CD19)或hA20(抗CD20)。如本文所用,术语依帕珠单抗和hLL2是可互换的,同样情况还有术语维妥珠单抗和hA20以及术语hL243g4P、hL243γ4P和IMMU-114。
使用的替代抗体包括但不限于阿昔单抗(抗糖蛋白IIb/IIIa)、阿仑单抗(抗CD52)、贝伐单抗(抗VEGF)、西妥昔单抗(抗EGFR)、吉妥珠单抗(抗CD33)、替伊莫单抗(抗CD20)、帕尼单抗(抗EGFR)、利妥昔单抗(抗CD20)、托西莫单抗(抗CD20)、曲妥珠单抗(抗ErbB2)、派姆单抗(抗PD-1受体)、纳武单抗(抗PD-1受体)、伊匹单抗(抗CTLA-4)、阿巴伏单抗(抗CA-125)、阿德木单抗(抗EpCAM)、阿特利珠单抗(抗IL-6受体)、benralizumab(抗CD125)、奥比妥珠单抗(GA101,抗CD20)、CC49(抗TAG-72)、AB-PG1-XG1-026(抗PSMA,美国专利申请11/983,372,保藏号ATCC PTA-4405和PTA-4406)、D2/B(抗PSMA,WO 2009/130575)、托珠单抗(抗IL-6受体)、巴利昔单抗(抗CD25)、达利珠单抗(抗CD25)、依法利珠单抗(抗CD11a)、GA101(抗CD20;Glycart Roche)、那他珠单抗(抗α4整合素)、奥马珠单抗(抗IgE);抗TNF-α抗体,如CDP571(Ofei等,2011,Diabetes 45:881-85)、MTNFAI、M2TNFAI、M3TNFAI、M3TNFABI、M302B、M303(Thermo Scientific,Rockford,Ill.)、英夫利昔单抗(Centocor,Malvern,Pa.)、赛妥珠单抗(certolizumab pegol)(UCB,Brussels,Belgium)、抗CD40L(UCB,Brussels,Belgium)、阿达木单抗(Abbott,Abbott Park,Ill)和贝利木单抗(HumanGenome Sciences)。
通过流式细胞术显示的造血恶性细胞上的合适抗原(Cluster Designation,或CD)靶标的综合分析,其可以作为选择用于药物缀合的免疫治疗的合适抗体的指导,是Craig和Foon,Blood prepublished online Jan.15,2008;DOL 10.1182/blood-2007-11-120535。
CD66抗原由具有相似结构的五个不同糖蛋白CD66a-e组成,其分别由癌胚抗原(CEA)基因家族成员BCG、CGM6、NCA、CGM1和CEA编码。这些CD66抗原(例如CEACAM6)主要在粒细胞、消化道的正常上皮细胞和各种组织的肿瘤细胞中表达。还包括作为癌症的合适靶标的是癌症睾丸抗原,例如NY-ESO-1(Theurillat等,Int.J.Cancer 2007;120(11):2411-7),以及骨髓性白血病中的CD79a(Kozlov等,Cancer Genet.Cytogenet.2005;163(l):62-7)以及B细胞疾病上的和非霍奇金氏淋巴瘤的CD79b(Poison等,Blood 110(2):616-623)。许多上述抗原公开于2002年11月15日提交的题为“Use of Multi-specific,Non-covalentComplexes for Targeted Delivery of Therapeutics”的美国临时申请序列号60/426,379中。癌症干细胞被描述为更具治疗抗性的前体恶性细胞群(Hill和Penis,J.Natl.Cancer Inst.2007;99:1435-40),其具有在某些癌症类型中可以靶向的抗原,例如***癌(Maitland等,Ernst Schering Found.Sympos.Proc.2006;5:155-79)、非小细胞肺癌(Donnenberg等,J.Control Release 2007;122(3):385-91)和成胶质细胞瘤(Beier等,Cancer Res.2007;67(9):4010-5)中的CD133,以及结肠直肠癌(Dalerba等,Proc.Natl.Acad.Sci.USA 2007;104(24)10158-63)、胰腺癌(Li等,Cancer Res.2007;67(3):1030-7)和头颈部鳞状细胞癌(Prince等,Proc.Natl.Acad.Sci.USA 2007;104(3)973-8)中的CD44。
对于多发性骨髓瘤治疗,已经描述了针对例如CD38和CD138(Stevenson,Mol Med2006;12(11-12):345-346;Tassone等,Blood 2004;104(12):3688-96)、CD74(Stein等,ibid.)、CS1(Tai等,Blood 2008;112(4):1329-37)和CD40(Tai等,2005;Cancer Res.65(13):5898-5906)的合适的靶向抗体。
巨噬细胞移动抑制因子(MIF)是先天性和适应性免疫和细胞凋亡的重要调节因子。据报道,CD74是MIF的内源受体(Leng等,2003,J Exp Med 197:1467-76)。拮抗性抗CD74抗体对MIF介导的细胞内途径的治疗作用可用于治疗广泛的疾病状态,例如膀胱癌、***癌、乳腺癌、肺癌、结肠癌和慢性淋巴细胞白血病(例如,Meyer-Siegler等,2004,BMCCancer 12:34;Shachar&Haran,2011,Leuk Lymphoma 52:1446-54);自身免疫疾病,例如类风湿性关节炎和***性红斑狼疮(Morand&Leech,2005,Front Biosci 10:12-22;Shachar&Haran,2011,Leuk Lymphoma 52:1446-54);肾脏疾病,例如肾同种异体移植物排斥(Lan,2008,Nephron Exp Nephrol.109:e79-83);和许多炎性疾病(Meyer-Siegler等,2009,Mediators Inflamm epub Mar.22,2009;Takahashi等,2009,RespirRes 10:33;米拉珠单抗(Milatuzumab)(hLLl)是用于治疗MIF介导的疾病的治疗用途的示例性抗CD74抗体。
抗TNF-α抗体是本领域已知的,并且可用于治疗免疫疾病,例如自身免疫疾病、免疫功能障碍(例如,移植物抗宿主病、器官移植排斥)或糖尿病。抗TNF-α的已知抗体包括人抗体CDP571(Ofei等,2011,Diabetes 45:881-85);鼠抗体MTNFAI、M2TNFAI、M3TNFAI、M3TNFABI、M302B和M303(Thermo Scientific,Rockford,Ill.);英夫利昔单抗(Centocor,Malvern,Pa.);赛妥珠单抗(UCB,Brussels,Belgium);和阿达木单抗(Abbott,AbbottPark,Ill.)。这些和许多其它已知的抗TNF-α抗体可用于要求保护的方法和组合物中。用于治疗免疫失调或自身免疫疾病的其它抗体包括但不限于抗B细胞抗体,例如维妥珠单抗、依帕珠单抗、米拉珠单抗或hL243;托珠单抗(抗IL-6受体);巴利昔单抗(抗CD25);达利珠单抗(抗CD25);依法利珠单抗(抗CD11a);莫罗单抗-CD3(抗CD3受体);抗CD40L(UCB,Brussels,Belgium);那他珠单抗(抗α4整联蛋白)和奥马珠单抗(抗IgE)。
用于癌症治疗的检查点抑制剂抗体的研究已经在先前被认为对癌症治疗具有抗性的癌症中产生前所未有的响应率(参见,例如,Ott&Bhardwaj,2013,Frontiers inImmunology4:346;Menzies&Long,2013,Ther Adv Med Oncol 5:278-85;Pardoll,2012,Nature Reviews 12:252-264;Mavilio&Lugli,)。使用针对CTLA-4、PD-1和PD-L1的拮抗性检查点阻断抗体的治疗是癌症和其它疾病的最有希望的免疫治疗的新途径之一。与大多数抗癌药物相反,检测点抑制剂不直接靶向肿瘤细胞,而是靶向淋巴细胞受体或其配体,以增强免疫***的内源抗肿瘤活性(Pardoll,2012,Nature Reviews 12:252-264)。因为这些抗体主要通过调节对疾病细胞的免疫应答而起作用,所以它们可以与其它治疗方式例如本发明的抗HLA-DR抗体组合使用,以增强它们的抗肿瘤作用。
程序性细胞死亡蛋白1(PD-1,也称为CD279)编码在B细胞和NK细胞中表达的免疫球蛋白超家族的细胞表面膜蛋白(Shinohara等,1995,Genomics 23:704-6;Blank等,2007,Cancer Immunol Immunother56:739-45;Finger等,1997,Gene 197:177-87;Pardoll,2012,Nature Reviews 12:252-264)。抗PD1抗体已被用于治疗黑素瘤、非小细胞肺癌、膀胱癌、***癌、结肠直肠癌、头颈癌、三阴性乳腺癌、白血病、淋巴瘤和肾细胞癌(Topalian等,2012,N Engl J Med 366:2443-54;Lipson等,2013,Clin Cancer Res 19:462-8;Berger等,2008,Clin Cancer Res 14:3044-51;Gildener-Leapman等,2013,Oral Oncol49:1089-96;Menzies&Long,2013,Ther Adv Med Oncol 5:278-85)。
示例性的抗PD1抗体包括派姆单抗(MK-3475,MERCK)、纳武单抗(BMS-936558,BRISTOL-MYERS SQUIBB)和伊匹单抗(CT-011,CURETECH LTD.)。抗PD1抗体可商购获得,例如来自(AB137132)、(EH12.2H7,RMP1-14)和AFFYMETRIXEBIOSCIENCE(J105,J116,MIH4)。
程序性细胞死亡1配体1(PD-L1,也称为CD274)是PD-1的配体,存在于活化的T细胞、B细胞、骨髓细胞和巨噬细胞上。PD-1和PD-L1的复合物抑制CD8+T细胞的增殖并降低免疫应答(Topalian等,2012,N Engl J Med 366:2443-54;Brahmer等,2012,N Eng J Med366:2455-65)。抗PDL1抗体已用于治疗非小细胞肺癌、黑素瘤、结肠直肠癌、肾细胞癌、胰腺癌、胃癌、卵巢癌、乳腺癌和恶性血液病(Brahmer等,N Eng J Med 366:2455-65;Ott等,2013,Clin Cancer Res19:5300-9;Radvanyi等,2013,Clin Cancer Res 19:5541;Menzies&Long,2013,Ther Adv Med Oncol 5:278-85;Berger等,2008,Clin CancerRes14:13044-51)。
示例性的抗PDL1抗体包括MDX-1105(MEDAREX)、MEDI4736(MEDIMMUNE)MPDL3280A(GENENTECH)和BMS-936559(BRISTOL-MYERS SQUIBB)。抗PDL1抗体也可商购获得,例如来自AFFYMETRIX EBIOSCIENCE(MIH1)。
细胞毒性T淋巴细胞抗原4(CTLA-4,也称为CD152)也是仅在T细胞上表达的免疫球蛋白超家族的成员。CTLA-4用于抑制T细胞活化,并且据报道抑制辅助性T细胞活性并增强调节性T细胞免疫抑制活性(Pardoll,2012,Nature Reviews 12:252-264)。抗CTL4A抗体已用于临床试验,用于治疗黑素瘤、***癌、小细胞肺癌、非小细胞肺癌(Robert&Ghiringhelli,2009,Oncologist 14:848-61;Ott等,2013,Clin Cancer Res 19:5300;Weber,2007,Oncologist 12:864-72;Wada等,2013,J Transl Med 11:89)。
示例性的抗CTLA-4抗体包括伊匹单抗(Bristol-Myers Squibb)和tremelimumab(PFIZER)。抗PD1抗体可商购获得,例如来自(AB134090)、SINO BIOLOGICALINC.(11159-H03H,11159-H08H)和THERMO SCIENTIFIC PIERCE(PA5-29572,PA5-23967,PA5-26465,MA1-12205,MA1-35914)。伊匹单抗最近获得FDA批准用于治疗转移性黑素瘤(Wada等,2013,J Transl Med 11:89)。
这些和其它已知的检查点抑制剂抗体可以单独与抗HLA-DR抗体组合使用,或者进一步与干扰素如干扰素-α组合使用,用于改善癌症治疗。
普通技术人员将意识到可以产生针对已知且充分表征的靶抗原(例如人HLA-DR)的任何数量的抗体。人HLA-DR抗原已在本领域中充分表征,例如通过其氨基酸序列(参见例如GenBank登录号ADM15723.1)。
双特异性和多特异性抗体
双特异性抗体可用于许多生物医学应用。例如,具有针对肿瘤细胞表面抗原和针对T细胞表面受体的结合位点的双特异性抗体可指导T细胞对特定肿瘤细胞的裂解。识别神经胶质瘤和T细胞上CD3表位的双特异性抗体已成功用于治疗人患者的脑肿瘤(Nitta等.Lancet.1990;355:368-371)。优选的双特异性抗体是抗CD3 X抗CD19抗体。在替代实施方案中,抗CD3抗体或其片段可以与抗另一种B细胞相关抗原的抗体或片段连接,例如抗CD3 X抗HLA-DR。在某些实施方案中,本文公开的用于治疗剂缀合的技术和组合物可以与双特异性或多特异性抗体一起用作靶向部分。
产生双特异性或多特异性抗体的许多方法是已知的,例如在美国专利号7,405,320中公开的,其实施例部分通过引用并入本文。双特异性抗体可以通过四价体瘤(quadroma)方法产生,所述方法涉及各自产生识别不同抗原位点的单克隆抗体的两种不同杂交瘤的融合(Milstein和Cuello,Nature,1983;305:537-540)。
用于产生双特异性抗体的另一种方法使用异双官能交联接头来化学地连接两种不同的单克隆抗体(Staerz等Nature,1985;314:628-631;Perez等Nature,1985;316:354-356)。双特异性抗体也可以通过以下方式产生:将两种亲本单克隆抗体中的每一种还原为相应的半分子,然后将其混合并使其再氧化以获得杂合结构(Staerz和Bevan.Proc NatlAcad Sci USA.1986;83:1453-1457)。另一种替代方案涉及使用合适的接头化学交联两个或三个单独纯化的Fab'片段。(参见例如欧洲专利申请0453082)。
其它方法包括通过以下方式来提高产生杂交杂交瘤的效率:通过逆转录病毒衍生的穿梭载体将不同的选择标记基因转移到各亲本杂交瘤中,所述杂交瘤随后融合(DeMonte等.Proc Natl Acad Sci USA.1990,87:2941-2945);或用含有不同抗体的重链和轻链基因的表达质粒转染杂交瘤细胞系。
可以用具有合适组成和长度的肽接头(通常由超过12个氨基酸残基组成)连接同源VH和VL结构域,以形成具有结合活性的单链Fv(scFv)。制备scFv的方法公开于美国专利号4,946,778和美国专利号5,132,405中,其每一个的实施例部分通过引用并入本文。将肽接头长度减少至少于12个氨基酸残基阻止了同一链上的VH和VL结构域的配对,并迫使VH和VL结构域与其它链上的互补结构域配对,导致形成功能性多聚体。用3至12个氨基酸残基的接头连接的VH和VL结构域的多肽链主要形成二聚体(称为二体(diabody))。利用0至2个氨基酸残基的接头,三聚体(称为三体(triabody))和四聚体(称为四体(tetrabody))是有利的,但是除了接头长度,寡聚化的确切模式似乎取决于V-结构域的组成和方向(VH-接头-VL或VL-接头-VH)。
用于产生多特异性或双特异性抗体的这些技术在低产率、需要纯化、低稳定性或劳动密集型技术方面表现出各种困难。最近,已经使用称为DOCK-AND-的技术来产生几乎任何所需抗体、抗体片段和其它效应分子的组合(参见,例如,美国专利号7,521,056;7,527,787;7,534,866;7,550,143;7,666,400;7,858,070;7,871,622;7,906,121;7,906,118;8,163,291;7,901,680;7,981,398;8,003,111和8,034,352,其各自的实施例部分通过引用并入本文)。该技术利用被称为锚定结构域(AD)以及二聚化和对接结构域(DDD)的互补蛋白结合结构域,它们彼此结合并允许组装复杂结构,包括二聚体、三聚体、四聚体、五聚体和六聚体。它们以高产率形成稳定的复合物,而无需大量纯化。DNL技术允许组装单特异性、双特异性或多特异性抗体。本领域已知的用于制备双特异性或多特异性抗体的任何技术均可用于本发明要求保护的方法的实践中。
在多个实施方案中,如本文中公开的缀合物可以是复合的多特异性抗体的一部分。此类抗体可含有两个或更多个不同的抗原结合位点,具有不同的特异性。多特异性复合物可以结合相同抗原的不同表位,或者可以结合两种不同的抗原。
这样的抗体不仅需要组合使用,而且可以组合成各种形式的融合蛋白,例如IgG、Fab、scFv等,如以下中所述:美国专利号6,083,477;6,183,744和6,962,702以及美国专利申请公开号
20030124058;20030219433;20040001825;20040202666;20040219156;20040219203;
20040235065;20050002945;20050014207;20050025709;20050079184;20050169926;
20050175582;20050249738;20060014245和20060034759,
每个的实施例部分通过引用并入本文。
DOCK AND
在某些实施方案中,可以将抗HLA-DR抗体或片段并入多聚复合物中,例如使用称为DOCK-AND-的技术。该方法利用cAMP依赖性蛋白激酶(PKA)的调节(R)亚基与A激酶锚定蛋白(AKAP)的锚定结构域(AD)之间发生的特定蛋白质/蛋白质相互作用(Baillie等,FEBS Letters.2005;579:3264.Wong和Scott,Nat.Rev.Mol.Cell Biol.2004;5:959)。1968年首次从免骨骼肌(Walsh等.,J.Biol.Chem.1968;243:3763)中分离出PKA,其在由第二信使cAMP与R亚基结合引发的研究最充分的信号转导途径之一中发挥核心作用。全酶的结构由通过R亚基以无活性形式保持的两个催化亚基组成(Taylor,J.Biol.Chem.1989;264:8443)。发现PKA的同工酶具有两种类型的R亚基(RI和RII),并且每种类型具有α和β同种型(Scott,Pharmacol.Ther.1991;50:123)。R亚基仅作为稳定的二聚体被分离,并且已显示二聚化结构域由前44个氨基末端残基组成(Newlon等.,Nat.Struct.Biol.1999;6:222)。cAMP与R亚基的结合导致用于广谱的丝氨酸/苏氨酸激酶活性的活性催化亚基的释放,其通过与AKAP的对接通过PKA的区室化而被定向于选择的底物(Scott等,J.Biol.Chem.1990;265;21561)。
自从第一种AKAP微管相关蛋白-2在1984年被表征(Lohmann等,Proc.Natl.Acad.Sci USA.1984;81:6723)以来,已经在从酵母到哺乳动物的物种中鉴定了具有不同结构的超过50种AKAP,其定位于各种亚细胞位点,包括质膜、肌动蛋白细胞骨架、细胞核、线粒体和内质网(Wong和Scott,Nat.Rev.Mol.Cell Biol.2004;5:959)。用于PKA的AKAP的AD是14-18个残基的两亲性螺旋(Carr等,J.Biol.Chem.1991;266:14188),其被报道对RII二聚体的结合亲和力为2至90nM(Alto等,Proc.Natl.Acad.Sci.USA.2003;100:4445)。有趣的是,AKAP仅与二聚体R亚基结合。对于人RIIα,AD与由23个氨基末端残基形成的疏水表面结合(Colledge和Scott,Trends Cell Biol.1999;6:216)。因此,人RIIα的二聚化结构域和AKAP结合结构域两者都位于相同的N-末端44氨基酸序列内(Newlon等,Nat.Struct.Biol.1999;6:222;Newlon等,EMBO J.2001;20:1651),所述序列在本文称为DDD。
人RIIα的DDD和AKAP的AD作为接头模块
我们已经开发了平台技术以利用人RIIα的DDD和AKAP蛋白的AD作为一对优良的接头模块,用于将任何两个实体(下文称为A和B)对接成非共价复合物,其可以通过在策略性位置处在DDD和AD中引入半胱氨酸残基以促进二硫键的形成来进一步锁定在稳定的束缚结构。“对接和锁定(dock-and-lock)”方法的一般方法如下。通过将DDD序列连接至A的前体来构建实体A,得到第一组分,其在下文称为a。因为DDD序列会实现二聚体的自发形成,因此A将由a2组成。通过将AD序列连接至B的前体连接来构建实体B,从而产生第二组分,其在下文称为b。a2中包含的DDD的二聚体基序将产生用于与b中包含的AD序列结合的对接位点,从而促进a2和b的准备缔合以形成由a2b组成的二元三聚体复合物。利用随后通过二硫桥共价固定两个实体的反应使该结合事件不可逆,这基于有效局部浓度的原理非常有效地发生,因为初始结合相互作用应该将使DDD和AD上的反应性硫醇基团接近(Chimura等,Proc.Natl.Acad.Sci.USA.2001;98:8480)以位点特异性地连接。
在一些优选的实施方案中,抗HLA-DRMAb DNL构建体可以基于a2b结构的变异,其中IgG免疫球蛋白分子(例如,hL243)在其C-末端连接两个拷贝的AD部分。优选地,AD部分连接在每条轻链的C末端。每个AD部分能够与二聚体的形式的两个DDD部分结合。通过将细胞因子或其它治疗性蛋白质或肽附接到每个DDD部分,四个拷贝的细胞因子或其它治疗部分将与每个IgG分子缀合。
通过使DDD和AD远离两种前体的官能团附接,这种位点特异性连接也预期保留两种前体的原始活性。该方法本质上是模块化的,并且潜在地可应用于位点特异性和共价地连接广泛的物质。DNL方法公开在美国专利号7,550,143;7,521,056;76,534,866;7,527,787和7,666,400中,其各自的实施例部分通过引用并入本文。
在一些优选的实施方案中,效应部分是蛋白质或肽,更优选抗体、抗体片段或细胞因子,其可以与DDD或AD单元连接以形成融合蛋白或肽。已知多种制备融合蛋白的方法,包括核酸合成,杂交和/或扩增,以产生编码目的融合蛋白的合成双链核酸。可以通过标准分子生物学技术将这种双链核酸***表达载体中以产生融合蛋白(参见例如Sambrook等,Molecular Cloning,A laboratory manual,第2版,1989)。在这些优选的实施方案中,AD和/或DDD部分可以连接到效应蛋白或肽的N-末端或C-末端。然而,技术人员将认识到,AD或DDD部分在效应部分上的附接位点可以变化,这取决于效应部分的化学性质和效应部分参与其生理活性的部分。可以使用本领域已知的技术进行多种效应部分的位点特异性附接,例如使用二价交联接头和/或其它化学缀合技术。
DDD和AD序列变体
在某些实施方案中,并入到抗HLA-DR MAb DNL复合物中的AD和DDD序列包含下文DDD1(SEQ ID NO:7)和AD1(SEQ ID NO:9)的氨基酸序列。在更优选的实施方案中,AD和DDD序列包含DDD2(SEQ ID NO:8)和AD2(SEQ ID NO:10)的氨基酸序列,其被设计为促进DDD和AD部分之间的二硫键形成。
DDD1
DDD2
AD1
AD2
然而,在替代实施方案中,序列变体AD和/或DDD部分可用于构建抗HLA-DR MAbDNL复合物。AD和DDD结构域的结构-功能关系已成为研究的主题。(参见,例如,Burns-Hamuro等,2005,Protein Sci 14:2982-92;Carr等,2001,J Biol Chem 276:17332-38;Alto等,2003,Proc Natl Acad Sci USA 100:4445-50;Hundsrucker等,2006,BiochemJ396:297-306;Stokka等,2006,Biochem J 400:493-99;Gold等,2006,Mol Cell 24:383-95;Kinderman等,2006,Mol Cell 24:397-408,其各自的全部内容通过引用并入本文。)
例如,Kinderman等(2006)检查了AD-DDD结合相互作用的晶体结构,并得出结论,人DDD序列包含许多对二聚体形成或AKAP结合重要的保守氨基酸残基,下面在SEQ ID NO:7中加下划线(参见Kinderman等,2006的图1,通过引用并入本文)。技术人员将认识到,在设计DDD序列的序列变体时,期望避免任何加下划线的残基的变化,而保守氨基酸取代可以对对于二聚化和AKAP结合不太重要的残基进行。保守氨基酸取代在下面更详细地讨论,但可以涉及例如天冬氨酸残基取代谷氨酸残基,或者亮氨酸或缬氨酸残基取代异亮氨酸残基等。这样的保守氨基酸取代是本领域熟知的。
来自蛋白激酶A的人DDD序列
Alto等(2003)对多种AKAP蛋白的AD序列进行了生物信息学分析,设计了被称为AKAP-IS(SEQ ID NO:9)的RII选择性AD序列,其对于DDD的结合常数为0.4nM。将AKAP-IS序列设计为AKAP与PKA结合的肽拮抗剂。在SEQ ID NO:9中用下划线标出AKAP-IS序列中取代倾向于降低与DDD的结合的残基。
AKAP-IS序列
类似地,Gold(2006)利用结晶学和肽筛选来开发SuperAKAP-IS序列(SEQ ID NO:11),与RI同种型相比,其对于PKA的RII同种型表现出高5个数量级的选择性。加下划线的残基表示相对于AKAP-IS序列的氨基酸取代的位置,其提高与RIIα的DDD部分的结合。在该序列中,N末端Q残基编号为残基编号4,C末端A残基编号为残基编号20。可以进行取代以影响对RIIα的亲和力的残基是残基8、11、15、16、18、19和20(Gold等,2006)。预期在某些替代实施方案中,SuperAKAP-IS序列可以取代AKAP-IS AD部分序列以制备抗HLA-DRMAb DNL构建体。预期与SEQ ID NO:9中所示的AKAP-IS序列一样,AD部分还可包含额外的N-末端残基半胱氨酸和甘氨酸以及C-末端残基甘氨酸和半胱氨酸,如SEQ ID NO:10所示。
SuperAKAP-IS
Hundsrucker等(2006)也开发了AKAP与PKA结合的另一些肽竞争物,其与PKA的RII形式的DDD的结合常数低至0.4nM。Hundsrucker等的表1中提供了多种AKAP拮抗肽的序列(通过引用并入本文)。不同AKAP蛋白的AD结构域中高度保守的残基通过参考AKAP IS序列(SEQ ID NO:9)在下面用下划线指出。残基与Alto等(2003)观察到的相同,只是添加了C-末端丙氨酸残基。(参见Hundsrucker等(2006)的图4,其通过引用并入本文。)
AKAP-IS
Carr等(2001)检查来自人和非人蛋白质的不同AKAP结合DDD序列之间的序列同源性程度,并且鉴定了DDD序列中在不同DDD部分之间似乎最高度保守的残基。这些通过参考SEQ ID NO:7的人PKA RIIαDDD序列在下面用下划线指出。用斜体进一步指出了特别保守的残基。残基与由Kinderman等(2006)表明对于与AKAP蛋白的结合重要的那些重叠,但不相同。
本领域技术人员将认识到,一般来说,来自不同蛋白质的DDD和AD序列中高度保守的那些氨基酸残基是优选在进行氨基酸取代时保持恒定的那些,而较不非常保守的残基可以更容易地改变以产生本文所述的AD和/或DDD序列的序列变体。
抗体同种异型
治疗性抗体的免疫原性与输注反应的风险增加和治疗反应的持续时间减少相关(Baert等,2003,N Engl J Med 348:602-08)。治疗性抗体在宿主中诱导免疫应答的程度可部分地由抗体的同种异型决定(Stickler等,2011,Genes and Immunity 12:213-21)。抗体同种异型与抗体恒定区序列中特定位置的氨基酸序列变异有关。含有重链γ型恒定区的IgG抗体的同种异型被命名为Gm同种异型(1976,J Immunol 117:1056-59)。
对于常见的IgG1人抗体,最普遍的同种异型是G1m1(Stickler等,2011,Genes andImmunity 12:213-21)。然而,G1m3同种异型也经常在白种人中发生(同上)。据报道,G1m1抗体含有当向非G1m1(nG1ml)接受者(例如G1m3患者)施用时倾向于诱导免疫应答的同种异型序列(同上)。当向G1m1患者施用时,非G1m1同种异型抗体不具有免疫原性(同上)。
人G1m1同种异型包含重链IgG1的CH3序列中的氨基酸D12(Kabat位置356)和L14(Kabat位置358)。nG1m1同种异型在相同位置包含氨基酸E12和M14。G1m1和nG1m1同种异型两者在两个可变位点之间包含E13残基,并且该同种异型有时称为DEL和EEM同种异型。对于示例性抗体利妥昔单抗(SEQ ID NO:12)和维妥珠单抗(SEQ ID NO:13),示出了G1m1和nG1m1同种异型抗体的重链恒定区序列的非限制性实例。
利妥昔单抗重链可变区序列(SEQ ID NO:12)
维妥珠单抗重链可变区(SEQ ID NO:13)
关于治疗性抗体,维妥珠单抗和利妥昔单抗分别是抗CD20的人源化和嵌合IgG1抗体,用于治疗多种血液恶性肿瘤和/或自身免疫疾病。表1比较了利妥昔单抗与维妥珠单抗的同种异型序列。如表1中所示,利妥昔单抗(G1m17,1)是DEL同种异型IgG1,其在Kabat位置214(重链CH1)具有额外的序列变异,在利妥昔单抗为赖氨酸,对比于维妥珠单抗中的为精氨酸。据报道,维妥珠单抗在受试者中的免疫原性低于利妥昔单抗(参见,例如,Morchhauser等,2009,J Clin Oncol 27:3346-53;Goldenberg等,2009,Blood 113:1062-70;Robak&Robak,2011,BioDrugs 25:13-25),这种效应归因于人源化和嵌合抗体之间的差异。然而,EEM和DEL同种异型之间同种异型的差异可能也是维妥珠单抗免疫原性较低的原因。
表1.利妥昔单抗对比于维妥珠单抗的同种异型
为了降低nG1ml基因型的个体中治疗性抗体的免疫原性,期望选择抗体的同种异型以对应于EEM同种异型,其中Kabat位置356为谷氨酸残基,Kabat位置358为甲硫氨酸,并且Kabat位置214优选为精氨酸残基。令人惊讶地,发现长时间反复皮下施用G1m3抗体不会导致显著的免疫应答。
氨基酸取代
在替代实施方案中,所公开的方法和组合物可涉及产生和使用具有一个或多个经取代的氨基酸残基的蛋白质或肽。例如,用于制备构建体的DDD和/或AD序列可以如上所述修饰。
本领域技术人员将意识到,一般来说,氨基酸取代通常涉及将氨基酸替换为具有相对相似性质的另一种氨基酸(即保守氨基酸取代)。各种氨基酸的性质和氨基酸取代对蛋白质结构和功能的影响已成为本领域广泛研究的主题和知识。
例如,可以考虑氨基酸的亲水指数(Kyte和Doolittle,1982,J.Mol.Biol.,157:105-132)。氨基酸的相对亲水特性有助于所得蛋白质的二级结构,这又决定了蛋白质与其它分子的相互作用。根据其疏水性和电荷特征,每种氨基酸都被分配了亲水指数(Kyte和Doolittle,1982),它们是:异亮氨酸(+4.5);缬氨酸(+4.2);亮氨酸(+3.8);苯丙氨酸(+2.8);半胱氨酸/胱氨酸(+2.5);甲硫氨酸(+1.9);丙氨酸(+1.8);甘氨酸(-0.4);苏氨酸(-0.7);丝氨酸(-0.8);色氨酸(-0.9);酪氨酸(-1.3);脯氨酸(-1.6);组氨酸(-3.2);谷氨酸(-3.5);谷氨酰胺(-3.5);天冬氨酸(-3.5);天冬酰胺(-3.5);赖氨酸(-3.9);和精氨酸(-4.5)。在进行保守取代时,优选使用其亲水指数在±2以内,更优选±1以内,甚至更优选±0.5以内的氨基酸。
氨基酸取代也可以考虑氨基酸残基的亲水性(例如,美国专利号4,554,101)。已经为氨基酸残基分配了亲水性值:精氨酸(+3.0);赖氨酸(+3.0);天冬氨酸(+3.0);谷氨酸(+3.0);丝氨酸(+0.3);天冬酰胺(+0.2);谷氨酰胺(+0.2);甘氨酸(0);苏氨酸(-0.4);脯氨酸(-0.5.+-.1);丙氨酸(-0.5);组氨酸(-0.5);半胱氨酸(-1.0);甲硫氨酸(-1.3);缬氨酸(-1.5);亮氨酸(-1.8);异亮氨酸(-1.8);酪氨酸(-2.3);苯丙氨酸(-2.5);色氨酸(-3.4)。优选用具有相似亲水性的其它氨基酸替换氨基酸。
其它考虑因素包括氨基酸侧链的大小。例如,通常不优选将具有紧凑侧链的氨基酸(例如甘氨酸或丝氨酸)替换为具有庞大侧链的氨基酸(例如色氨酸或酪氨酸)。各种氨基酸残基对蛋白质二级结构的影响也是一个考虑因素。通过实证研究,已经确定了不同氨基酸残基对蛋白质结构域采用α-螺旋、β-折叠或反转二级结构的趋势的影响,并且是本领域已知的(参见,例如,Chou&Fasman,1974,Biochemistry,13:222-245;1978,Ann.Rev.Biochem.,47:251-276;1979,Biophys.J.,26:367-384)。
基于这些考虑和广泛的经验研究,已经构建了保守氨基酸取代表并且是本领域已知的。例如:精氨酸和赖氨酸;谷氨酸和天冬氨酸;丝氨酸和苏氨酸;谷氨酰胺和天冬酰胺;以及缬氨酸、亮氨酸和异亮氨酸。或者:Ala(A)leu,ile,val;Arg(R)gln,asn,lys;Asn(N)his,asp,lys,arg,gln;Asp(D)asn,glu;Cys(C)ala,ser;Gln(Q)glu,asn;Glu(E)gln,asp;Gly(G)ala;His(H)asn,gln,lys,arg;Ile(I)val,met,ala,phe,leu;Leu(L)val,met,ala,phe,ile;Lys(K)gln,asn,arg;Met(M)phe,ile,leu;Phe(F)leu,val,ile,ala,tyr;Pro(P)ala;Ser(S),thr;Thr(T)ser;Trp(W)phe,tyr;Tyr(Y)trp,phe,thr,ser;Val(V)ile,leu,met,phe,ala。
氨基酸取代的其它考虑因素包括残基是位于蛋白质内部还是暴露于溶剂。对于内部残基,保守取代包括:Asp和Asn;Ser和Thr;Ser和Ala;Thr和Ala;Ala和Gly;Ile和Val;Val和Leu;Leu和Ile;Leu和Met;Phe和Tyr;Tyr和Trp(参见,例如PROWL网站rockefeller.edu)。对于溶剂暴露的残基,保守取代包括:Asp和Asn;Asp和Glu;Glu和Gln;Glu和Ala;Gly和Asn;Ala和Pro;Ala和Gly;Ala和Ser;Ala和Lys;Ser和Thr;Lys和Arg;Val和Leu;Leu和Ile;Ile和Val;Phe和Tyr。(同上)已经构建了各种矩阵以帮助选择氨基酸取代,例如PAM250评分矩阵、Dayhoff矩阵、Grantham矩阵、McLachlan矩阵、Doolittle矩阵、Henikoff矩阵、Miyata矩阵、Fitch矩阵、Jones矩阵、Rao矩阵、Levin矩阵和Risler矩阵(同上)。
在确定氨基酸取代时,还可以考虑分子间或分子内键的存在,例如在带正电荷的残基(例如,His、Arg、Lys)和带负电荷的残基(例如,Asp、Glu)之间形成离子键(盐桥),或者在邻近的半胱氨酸残基之间形成二硫键。
在编码的蛋白质序列中将任何氨基酸取代为任何其它氨基酸的方法是公知的并且是本领域技术人员的常规实验的问题,例如通过定点诱变技术或通过合成和组装编码氨基酸取代的寡核苷酸并剪接到表达载体构建体中。
缀合方案
在某些实施方案中,抗HLA-DR抗体或片段可以与一种或多种治疗剂或诊断剂缀合。治疗剂不需要是相同的,但可以是不同的,例如,药物和放射性同位素。例如,131I可以并入抗体或融合蛋白的酪氨酸以及与赖氨酸残基的ε氨基连接的药物中。治疗和诊断剂也可以连接在例如还原的SH基团和/或碳水化合物侧链上。用于制备治疗剂或诊断剂与抗体或融合蛋白的共价或非共价缀合物的许多方法是本领域已知的,并且可以使用任何这样的已知方法。
治疗剂或诊断剂可以通过二硫键形成连接在还原的抗体组分的铰链区。或者,可以使用异双官能交联接头例如N-琥珀酰基3-(2-吡啶基二硫代)丙酸酯(SPDP)连接这些试剂。Yu等,Int.J.Cancer 56:244(1994)。用于这种缀合的一般技术在本领域中是众所周知的。参见,例如,Wong,CHEMISTRY OF PROTEIN CONJUGATION AND CROSS-LINKING(CRCPress 1991);Upeslacis等,“Modification of Antibodies by Chemical Methods,”MONOCLONAL ANTIBODIES:PRINCIPLES AND APPLICATIONS,Birch等(编辑),第187-230页(Wiley-Liss,Inc.1995);Price,“Production and Characterization of SyntheticPeptide-Derived Antibodies,”MONOCLONAL ANTIBODIES:PRODUCTION,ENGINEERING ANDCLINICAL APPLICATION,Ritter等(编辑),第60-84页(Cambridge University Press1995)。或者,治疗剂或诊断剂可以通过抗体Fc区中的碳水化合物部分缀合。碳水化合物基团可用于提高与硫醇键合的相同药剂的负载,或碳水化合物部分可用于键合不同的治疗剂或诊断剂。
用于通过抗体碳水化合物部分将肽与抗体组分缀合的方法是本领域技术人员熟知的。参见,例如,Shih等.,Int.J.Cancer 41:832(1988);Shih等,Int.J.Cancer 46:1101(1990);和Shih等,美国专利号5,057,313,其全部通过引用并入本文。一般方法包括使具有氧化碳水化合物部分的抗体组分与具有至少一个游离胺官能团的载体聚合物反应。该反应产生初始希夫碱(亚胺)键联,其可通过还原成仲胺来稳定以形成最终的缀合物。
如果用作免疫缀合物的抗体组分的抗体是抗体片段,则可以不存在Fc区。然而,可以向全长抗体或抗体片段的轻链可变区的中引入碳水化合物部分。参见,例如,Leung等,J.Immunol.154:5919(1995);Hansen等,美国专利号5,443,953(1995),Leung等,美国专利号6,254,868,其全部通过引用并入本文。工程改造的碳水化合物部分用于连接治疗剂或诊断剂。
在一些实施方案中,螯合剂可以与抗体、抗体片段或融合蛋白连接并用于螯合治疗剂或诊断剂,例如放射性核素。示例性的螯合剂包括但不限于DTPA(例如Mx-DTPA)、DOTA、TETA、NETA或NOTA。缀合和使用螯合剂将金属或其它配体连接到蛋白质上的方法是本领域熟知的(参见,例如,美国专利申请序列号12/112,289,其全部内容通过引用并入本文)。
在某些实施方案中,放射性金属或顺磁性离子可以通过与具有长尾部的试剂反应而连接到蛋白质或肽上,所述长尾部可以连接多个螯合基团用于结合离子。这种尾部可以是聚合物,例如聚赖氨酸、多糖、或具有侧基的衍生化或可衍生的链,其可以与螯合基团键合,例如乙二胺四乙酸(EDTA)、二亚乙基三胺五乙酸(DTPA)、卟啉、多胺、冠醚、双缩氨基硫脲、聚肟以及已知可用于此目的的类似基团。
螯合物可以直接与抗体或肽连接,例如美国专利4,824,659中所公开的,该专利通过引用整体并入本文。特别有用的金属-螯合物组合包括2-苄基-DTPA及其单甲基和环己基类似物,它们与60至4,000keV的一般能量范围的诊断同位素如125I、131I、123I、124I、62Cu、64Cu、18F、111In、67Ga、68Ga、99mTc、94mTc、11C、13N、15O、76Br一起使用,用于放射成像。当与非放射性金属(例如锰、铁和钆)络合时,相同的螯合物可用于MRI。大环螯合物如NOTA、DOTA和TETA可与各种金属和放射性金属,最特别是镓、钇和铜的放射性核素一起使用。通过将环尺寸调整至目标金属,可以使这种金属-螯合物复合物非常稳定。包括其它环型螯合物,例如大环聚醚,其对于稳定结合核素如用于RAIT的223Ra是有意义的。
最近,已经公开了在PET扫描技术中使用18F标记的方法,例如通过使F-18与金属或其它原子如铝反应。18F-Al缀合物可以与螯合基团例如DOTA、NOTA或NETA复合,其直接连接至抗体或用于在预靶向方法中用于标记可靶向构建体。这种F-18标记技术公开在2008年4月30日提交的美国专利申请序列号12/112,289中,其全部内容通过引用并入本文。
在一些优选的实施方案中,缀合方案基于在中性或酸性pH下易于进行硫醇-马来酰亚胺、硫醇-乙烯基砜、硫醇-溴乙酰胺、或硫醇-碘乙酰胺反应。这消除了缀合对更高pH条件的需要,例如,当使用活性酯时这是必需的。示例性缀合方案的进一步细节在以下实施例部分中描述。
治疗性治疗
在另一个方面,本发明涉及治疗受试者的方法,包括向受试者施用治疗有效量的如本文所述的治疗性缀合物。可用本文所述的治疗性缀合物治疗的疾病包括但不限于使用抗HLA-DR免疫缀合物的B细胞恶性肿瘤(例如,非霍奇金氏淋巴瘤、套细胞淋巴瘤、多发性骨髓瘤、霍奇金氏淋巴瘤、弥漫性大B细胞淋巴瘤、伯基特淋巴瘤、滤泡性淋巴瘤、急性淋巴性白血病、慢性淋巴性白血病、毛细胞白血病)。更优选地,癌症是AML(急性髓细胞白血病)、ALL(急性淋巴细胞白血病)或MM(多发性骨髓瘤)。然而,任何HLA-DR阳性肿瘤都可以用本发明免疫缀合物治疗,例如皮肤癌、食道癌、胃癌、结肠癌、直肠癌、胰腺癌、肺癌、乳腺癌、卵巢癌、膀胱癌、子宫内膜癌、***、睾丸癌、黑素瘤、肾癌或肝癌。这些治疗剂可以一次或重复给予,这取决于疾病状态和缀合物的耐受性,并且还可以任选地与其它治疗方式组合使用,例如手术、外部放射、放射免疫治疗、免疫治疗、化学治疗、反义治疗、干扰RNA治疗、基因治疗等。每种组合将适应肿瘤类型、阶段、患者状况和先前治疗,以及管理医师考虑的其它因素。
如本文所用,术语“受试者”是指任何动物(即脊椎动物和无脊椎动物),包括但不限于哺乳动物,包括人。该术语旨在不限于特定年龄或性别。因此,该术语包括成年受试者和新生受试者以及胎儿,无论是雄性还是雌性。本文给出的剂量用于人的,但可根据体重或平方米大小调整至其它哺乳动物以及儿童的大小。
在一个示例性实施方案中,hL243抗体是人源化抗体,其包含重链CDR序列CDR1(NYGMN,SEQ ID NO:1)、CDR2(WINTYTREPTYADDFKG,SEQ ID NO:2)和CDR3(DITAVVPTGFDY,SEQ ID NO:3)以及轻链CDR序列CDR1(RASENIYSNLA,SEQ ID NO:4)、CDR2(AASNLAD,SEQ IDNO:5)和CDR3(QHFWTTPWA,SEQ ID NO:6)。
在一个优选的实施方案中,用于治疗人疾病的抗体是人或人源化(CDR-移植)形式的抗体;虽然可以使用鼠和嵌合形式的抗体。相同物种IgG分子作为递送剂是最优选的,以使免疫应答最小化。在考虑重复治疗时,这一点尤为重要。对于人、人或人源化IgG抗体不太可能在患者中产生抗IgG免疫应答。诸如hLL1和hLL2的抗体在与靶细胞上的内化抗原结合后快速内化,这意味着携带的化学治疗药物也快速内化到细胞中。然而,具有较慢内化速率的抗体也可用于实现选择性治疗。
在另一个优选的实施方案中,治疗性缀合物可用于治疗自身免疫疾病或免疫***功能障碍(例如,移植物抗宿主病、器官移植排斥)。用于治疗自身免疫疾病/免疫功能障碍疾病的抗体可以与示例性抗原结合,包括但不限于BCL-1、BCL-2、BCL-6、CD1a、CD2、CD3、CD4、CD5、CD7、CD8、CD10、CD11b、CD11c、CD13、CD14、CD15、CD16、CD19、CD20、CD21、CD22、CD23、CD25、CD33、CD34、CD38、CD40、CD40L、CD41a、CD43、CD45、CD55、CD56、CCD57、CD59、CD64、CD71、CD74、CD79a、CD79b、CD117、CD138、FMC-7和HLA-DR。如上所述,与这些和其它靶抗原结合的抗体可用于治疗自身免疫疾病或免疫功能障碍疾病。可用免疫缀合物治疗的自身免疫疾病可包括急性特发性血小板减少性紫癜、慢性特发性血小板减少性紫癜、皮肌炎、Sydenham舞蹈病、重症肌无力、***性红斑狼疮、狼疮性肾炎、风湿热、多腺体综合征、大疱性类天疱疮、糖尿病、Henoch-Schonlein紫癜、链球菌感染后肾炎、结节性红斑、大动脉炎、ANCA相关血管炎、阿狄森氏病、类风湿性关节炎、多发性硬化症、结节病、溃疡性结肠炎、多形性红斑、IgA肾病、结节性多动脉炎、强直性脊柱炎、Goodpasture综合征、闭塞性血栓性脉管炎、干燥综合征、原发性胆汁性肝硬化、桥本氏甲状腺炎、甲状腺毒症、硬皮病、慢性活动性肝炎、多发性肌炎/皮肌炎、多软骨炎、大疱性类天疱疮、寻常型天疱疮、韦格纳肉芽肿病、膜性肾病、肌萎缩侧索硬化症、脊髓痨(tabes dorsalis)、巨细胞动脉炎/多肌痛、恶性贫血、快速进展性肾小球肾炎、银屑病或纤维化肺泡炎。
在另一个优选的实施方案中,与本发明的喜树碱缀合物组合使用的治疗剂可包含一种或多种同位素。可用于治疗疾病组织的放射性同位素包括但不限于111In,177Lu,212Bi,213Bi,211At,62Cu,67Cu,90Y,125I,131I,32P,33P,47Sc,111Ag,67Ga,142Pr,153Sm,161Tb,166Dy,166Ho,186Re,188Re,189Re,212Pb,223Ra,225Ac,59Fe,75Se,77As,89Sr,99Mo,105Rh,109Pd,143Pr,149Pm,169Er,194Ir,198Au,199Au,227Th和211Pb。
治疗性放射性核素的衰变能量优选为20至6,000keV,优选地对于Auger发射体为60至200keV,对于β发射体为100-2,500keV,并且对于α发射体优选为4,000至6,000keV。有用的β粒子发射核素的最大衰变能量优选为20-5,000keV,更优选为100-4,000keV,最优选为500-2,500keV。还优选的是基本上以Auger发射粒子衰变的放射性核素。例如,Co-58、Ga-67、Br-80m、Tc-99m、Rh-103m、Pt-109、In-111、Sb-119、I-125、Ho-161、Os-189m和Ir-192。有用的β粒子发射核素的衰变能量优选<1,000keV,更优选<100keV,最优选<70keV。还优选的是放射性核素基本上以产生α-粒子衰变。这样的放射性核素包括但不限于:Dy-152、At-211、Bi-212、Ra-223、Rn-219、Po-215、Bi-211、Ac-225、Fr-221、At-217、Bi-213、Th-227和Fm-255。有用的α粒子发射放射性核素的衰变能量优选为2,000-10,000keV,更优选为3,000-8,000keV,最优选为4,000-7,000keV。使用的其它潜在的放射性同位素包括11C,13N,15O,75Br,198Au,224Ac,126I,133I,77Br,113mIn,95Ru,97Ru,103Ru,105Ru,107Hg,203Hg,121mTe,122mTe,125mTe,165Tm,167Tm,168Tm,197Pt,109Pd,105Rh,142Pr,143Pr,161Tb,166Ho,199Au,57Co,58Co,51Cr,59Fe,75Se,201Tl,225Ac,76Bt,169Yb等。
可以例如使用与抗体或缀合物连接的螯合基团递送放射性核素和其它金属。大环螯合物如NOTA、DOTA和TETA可用于多种金属和放射性金属,最特别是镓、钇和铜的放射性核素。通过将环尺寸调整到目标金属,可以使这种金属-螯合物复合物非常稳定。可以使用其它环型螯合物,例如用于络合223Ra的大环聚醚。
与本文所述的喜树碱缀合物组合使用的治疗剂还包括,例如,化学治疗药物,例如长春花生物碱、蒽环类、表鬼臼毒素、紫杉烷、抗代谢物、酪氨酸激酶抑制剂、烷化剂、抗生素、Cox-2抑制剂、抗有丝***剂、抗血管生成和促凋亡剂、特别是多柔比星、甲氨蝶呤、紫杉醇、其它喜树碱,以及来自这些和其它种类的抗癌剂的其它类似物。其它癌症化学治疗药物包括氮芥、烷基磺酸盐、亚硝基脲、三氮烯、叶酸类似物、嘧啶类似物、嘌呤类似物、铂配位络合物、激素等。合适的化学治疗剂描述于REMINGTON′S PHARMACEUTICAL SCIENCES,第19版.(Mack Publishing Co.1995),和GOODMAN AND GILMAN′S THE PHARMACOLOGICAL BASIS OFTHERAPEUTICS,第7版.(MacMillan Publishing Co.1985),以及这些出版物的修订版中。其它合适的化学治疗剂例如实验药物是本领域技术人员已知的。
使用的示例性药物包括但不限于5-氟尿嘧啶、阿法替尼(afatinib)、阿普立定(aplidin)、阿扎立平(azaribine)、阿那曲唑(anastrozole)、蒽环类、阿西替尼(axitinib)、AVL-101、AVL-291、苯达莫司汀(bendamustine)、博来霉素(bleomycin)、硼替佐米(bortezomib)、博舒替尼(bosutinib)、苔藓抑素-1(bryostatin-1)、白消安、卡利奇霉素(calicheamycin)、喜树碱(camptothecin)、卡铂、10-羟基喜树碱、卡莫司汀(carmustine)、塞来昔布(celecoxib)、苯丁酸氮芥(chlorambucil)、顺铂(CDDP)、Cox-2抑制剂、伊立替康(CPT-11)、SN-38、卡铂、克拉屈滨(cladribine)、camptothecan、克唑替尼(crizotinib)、环磷酰胺、阿糖胞苷、达卡巴嗪、达沙替尼、dinaciclib、多西他赛(docetaxel)、放线菌素D、柔红霉素、多柔比星、2-吡咯啉多柔比星(2-pyrrolinodoxorubicine)(2P-DOX)、氰基吗啉代多柔比星、多柔比星葡糖苷酸、表柔比星葡糖苷酸、厄洛替尼(erlotinib)、雌莫司汀、表鬼臼毒素、厄洛替尼、恩替诺特(entinostat)、***受体结合剂、依托泊苷(VP16)、依托泊苷葡糖苷酸、磷酸依托泊苷、依西美坦、芬戈莫德(fingolimod)、氟尿苷(FUdR)、3',5'-O-二油酰基-FudR(FUdR-dO)、氟达拉滨(fludarabine)、氟他胺、法呢基蛋白转移酶抑制剂、夫拉平度(flavopiridol)、fostamatinib、ganetespib、GDC-0834、GS-1101、吉非替尼、吉西他滨、羟基脲、依鲁替尼、伊达比星、艾代拉里斯、异环磷酰胺、伊马替尼、L-天冬酰胺酶、拉帕替尼、来那度胺(lenolidamide)、甲酰四氢叶酸、LFM-A13、洛莫司汀、氮芥(mechlorethamine)、美法仑、巯基嘌呤、6-巯基嘌呤、甲氨蝶呤、米托蒽醌、光辉霉素、丝裂霉素、米托坦、诺维本(navelbine)、来那替尼(neratinib)、尼罗替尼、亚硝基脲(nitrosurea)、奥拉帕尼、林可霉素(plicomycin)、丙卡巴肼、紫杉醇、PCI-32765、喷司他丁(pentostatin)、PSI-341、雷洛昔芬、司莫司汀、索拉非尼、链脲佐菌素、SU11248、舒尼替尼、他莫昔芬(tamoxifen)、替莫唑胺(temazolomide)、反铂(transplatinum)、沙利度胺、硫鸟嘌呤、塞替派(thiotepa)、替尼泊苷、拓扑替康、尿嘧啶氮芥(uracil mustard)、瓦他拉尼(vatalanib)、长春瑞滨、长春碱、长春新碱、长春花生物碱和ZD1839。这些药剂可以是本文所述缀合物的一部分,或者可以在缀合物之前、同时或之后与所述缀合物组合施用。或者,可以将本领域已知的一种或多种治疗性裸抗体与所述缀合物组合使用。示例性治疗性裸抗体如上文所述。
在优选的实施方案中,与DNA-阻断抗体缀合物(例如,SN-38-ADC)组合使用的治疗剂是微管抑制剂,例如长春花生物碱、紫杉烷、美登木素生物碱(maytansinoid)或奥瑞斯他汀(auristatin)。示例性已知的微管抑制剂包括紫杉醇、长春新碱、长春碱、mertansine、埃博霉素(epothilone)、多西他赛、圆皮海绵内酯(discodermolide)、考布他汀(combrestatin)、鬼臼毒素、CI-980、phenylahistins、五加前胡素(steganacins)、curacins、2-甲氧基***、E7010、甲氧基苯磺酰胺、长春瑞滨、长春氟宁、长春地辛、多拉司他汀(dolastatins)、spongistatin、根霉素(rhizoxin)、tasidotin、软海绵素(halichondrins)、哈米特林(hemiasterlins)、念珠藻素(cryptophycin)52、MMAE和甲磺酸艾瑞布林(eribulin mesylate)。
在另一个优选的实施方案中,与DNA-阻断ADC(例如SN-38-抗体缀合物)组合使用的治疗剂是PARP抑制剂,例如奥拉帕尼(olaparib)、他拉唑巴(talazoparib)(BMN-673)、芦卡帕利(rucaparib)、维利帕尼(veliparib)、CEP 9722、MK 4827、BGB-290、ABT-888、AG014699、BSI-201、CEP-8983或3-氨基苯甲酰胺。
在另一个替代方案中,与抗体或免疫缀合物组合使用的治疗剂是布鲁顿激酶抑制剂,例如依鲁替尼(PCI-32765)、PCI-45292、CC-292(AVL-292)、ONO-4059、GDC-0834、LFM-A13或RN486。
在另一个替代方案中,与抗体或免疫缀合物组合使用的治疗剂是PI3K抑制剂,例如艾代拉里斯、渥曼青霉素(Wortmannin)、脱甲绿胶酶素(demethoxyviridin)、哌立福辛(perifosine)、PX-866、IPI-145(duvelisib)、BAY 80-6946、BEZ235、RP6530、TGR1202、SF1126、INK1117、GDC-0941、BKM120、XL147、XL765、Palomid 529、GSK1059615、ZSTK474、PWT33597、IC87114、TG100-115、CAL263、PI-103、GNE477、CUDC-907、AEZS-136或LY294002。
可与喜树碱缀合物一起使用的治疗剂还可包含与靶向部分缀合的毒素。可用于此方面的毒素包括蓖麻毒蛋白(ricin)、相思豆毒素(abrin)、核糖核酸酶(RNA酶)、豹蛙酶(ranpirnase)、DNA酶I、葡萄球菌肠毒素-A、商陆抗病毒蛋白(pokeweed antiviralprotein)、白树毒素(gelonin)、白喉毒素、假单胞菌外毒素和假单胞菌内毒素。(参见,例如,Pastan.等,Cell(1986),47:641,以及Sharkey和Goldenberg,CACancerJClin.2006Jul-Aug;56(4):226-43。)其它适合本文使用的毒素是本领域技术人员已知的并且在US 6,077,499中公开。
另一类治疗剂可包括一种或多种免疫调节剂。使用的免疫调节剂可选自细胞因子、干细胞生长因子、淋巴毒素、造血因子、集落刺激因子(CSF)、干扰素(IFN)、***、促血小板生成素及其组合。特别有用的是淋巴毒素,如肿瘤坏死因子(TNF);造血因子,如白细胞介素(IL);集落刺激因子,如粒细胞集落刺激因子(G-CSF)或粒细胞巨噬细胞集落刺激因子(GM-CSF);干扰素,如干扰素-α,-β,-γ或-λ;以及干细胞生长因子,如称为“SI因子”的那些。细胞因子包括生长激素,如人生长激素,N-甲硫氨酰人生长激素和牛生长激素;甲状旁腺激素;甲状腺素;胰岛素;胰岛素原;松弛素;松弛素原;糖蛋白激素,如促卵泡激素(FSH),促甲状腺激素(TSH)和***(LH);肝生长因子;***素,成纤维细胞生长因子;催乳素;胎盘催乳素,OB蛋白;肿瘤坏死因子-α和-β;苗勒抑制物质(mullerian-inhibiting substance);小鼠***相关肽;抑制素;激活素;血管内皮生长因子;整合素;血小板生成素(TPO);神经生长因子,如NGF-β;血小板生长因子;转化生长因子(TGF)如TGF-α和TGF-β;***-I和-II;***(EPO);骨诱导因子;干扰素,如干扰素-α、-β和-γ;集落刺激因子(CSF),如巨噬细胞-CSF(M-CSF);白细胞介素(IL),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;IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、IL-21、IL-25、LIF、kit配体或FLT-3,血管抑制素,血小板反应蛋白,内皮抑素,肿瘤坏死因子和淋巴毒素(LT)。如本文所用,术语细胞因子包括来自天然来源或来自重组细胞培养物的蛋白质和天然序列细胞因子的生物活性等同物。
使用的趋化因子包括RANTES、MCAF、MIP1-α,MIP1-β和IP-10。
本领域普通技术人员将认识到,包含与抗体或抗体片段缀合的喜树碱的本发明免疫缀合物可单独使用或与一种或多种其它治疗剂组合使用。所述其它治疗剂例如第二抗体、第二抗体片段、第二免疫缀合物、放射性核素、毒素、药物、化学治疗剂、放射治疗、趋化因子、细胞因子、免疫调节剂、酶、激素、寡核苷酸、RNAi或siRNA。这些其它治疗剂可以与本发明抗体-药物免疫缀合物分开施用、组合施用或附接于本发明抗体-药物免疫缀合物施用。
制剂和施用
缀合物的合适的施用途径包括但不限于口服、肠胃外、皮下、直肠、经粘膜、肠内施用、肌肉内、髓内、鞘内、直接心室内、静脉内、玻璃体内、腹膜内、鼻内或眼内注射。优选的施用途径是肠胃外施用。或者,可以以局部而非全身方式施用化合物,例如,通过将化合物直接注射到实体瘤中。
可以根据已知方法配制免疫缀合物以制备药学上有用的组合物,其中免疫缀合物与药学上合适的赋形剂组合成混合物。无菌磷酸盐缓冲盐水是药学上合适的赋形剂的一个实例。其它合适的赋形剂是本领域技术人员所熟知的。参见,例如,Ansel等,PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS,第5版(Lea&Febiger1990),以及Gennaro(编辑),REMINGTON’S PHARMACEUTICAL SCIENCES,第18版(MackPublishing Company1990)及其修订版本。
在一个优选的实施方案中,使用选自以下的缓冲剂将免疫缀合物配制在Good生物缓冲液(pH 6-7)中:N-(2-乙酰胺基)-2-氨基乙磺酸(ACES);N-(2-乙酰胺基)亚氨基二乙酸(ADA);N,N-双(2-羟乙基)-2-氨基乙磺酸(BES);4-(2-羟乙基)哌嗪-1-乙磺酸(HEPES);2-(N-吗啉代)乙磺酸(MES);3-(N-吗啉代)丙磺酸(MOPS);3-(N-吗啉基)-2-羟基丙磺酸(MOPSO);和哌嗪-N,N’-双(2-乙磺酸)[Pipes]。更优选的缓冲剂是MES或MOPS,优选浓度为20至100mM,更优选约25mM。最优选的是25mM MES,pH 6.5。制剂可以进一步包含25mM海藻糖和0.01%v/v聚山梨醇酯80作为赋形剂,由于添加赋形剂,最终缓冲剂浓度改变为为22.25mM。优选的储存方法是作为缀合物的冻干制剂,储存在-20℃至2℃的温度范围内,最优选的储存在2℃至8℃。
可以配制免疫缀合物用于静脉内施用,例如通过推注、缓慢输注或连续输注。优选地,本发明的抗体经过少于约4小时的时间,更优选地,经过少于约3小时的时间输注。例如,前25-50mg可以在30分钟内输注,优选甚至15分钟,其余的在接下来的2-3小时内输注。用于注射的制剂可以以单位剂型存在,例如在安瓿或多剂量容器中,其具有添加的防腐剂。组合物可以采取例如油性或水性媒介物中的悬浮液、溶液或乳液的形式,并且可以含有配制剂,例如助悬剂、稳定剂和/或分散剂。或者,活性成分可以是粉末形式,用于在使用前用合适的媒介物(例如无菌无热原水)构建。
可以采用另外的药学方法来控制治疗性缀合物的作用持续时间。可以通过使用聚合物来复合或吸附免疫缀合物来制备控释制剂。例如,生物相容性聚合物包括聚(乙烯-共-乙酸乙烯酯)基质以及硬脂酸二聚体和癸二酸的聚酐共聚物的基质。Sherwood等,Bio/Technology 10:1446(1992)。免疫缀合物从这种基质中的释放速率取决于免疫缀合物的分子量、基质内免疫缀合物的量和分散颗粒的大小。Saltzman等,Biophys.J.55:163(1989);Sherwood等,同上。其它固体剂型描述于以下中:Ansel等,PHARMACEUTICAL DOSAGE FORMSAND DRUG DELIVERY SYSTEMS,第5版(Lea&Febiger 1990),和Gennaro(编辑),REMINGTON’SPHARMACEUTICAL SCIENCES,第18版(MackPublishing Company 1990),及其修订版本。
通常,向人施用的免疫缀合物的剂量将根据诸如患者的年龄、体重、身高、性别、一般身体状态和既往病史等因素而变化。例如,对于70kg的患者,1-20mg/kg的剂量为70-1,400mg,或对于1.7m患者为41-824mg/m2。剂量可以根据需要重复,例如,每周一次持续4-10周,每周一次持续8周,或者每周一次持续4周。根据维持治疗的需要,其也可以较不频繁地给予,例如每隔一周持续数月,或每月或每季度持续数月。优选的剂量可包括但不限于1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg、11mg/kg、12mg/kg、13mg/kg、14mg/kg、15mg/kg、16mg/kg、17mg/kg和18mg/kg。剂量优选多次施用,每周一次或两次。可以使用持续4周,更优选8周,更优选16周或更久的最小剂量方案。施用方案可包括以选自以下的循环每周施用一次或两次:(i)每周;(ii)每隔一周;(iii)治疗一周,然后停用两周、三周或四周;(iv)治疗两周,然后停用一周、两周、三周或四周;(v)治疗三周,然后停用一周、两周、三周、四周或五周;(vi)治疗四周,然后停用一周、两周、三周、四周或五周;(vii)治疗五周,然后停用一周、两周、三周、四周或五周;(viii)每月。该循环可以重复4次、6次、8次、10次、12次、16次或20次或更多次。
或者,免疫缀合物可以每2或3周作为一个剂量施用,重复总共至少3个剂量。或者,每周两次,持续4-6周。如果剂量降低至约200-300mg/m2(对于1.7m患者为每剂量340mg),可以每周施用一次或甚至两次,持续4至10周。或者,剂量方案可以降低,即每2或3周持续2-3个月。然而,已经确定甚至更高的剂量,例如每周一次或每2-3周一次12mg/kg可以通过缓慢静脉内输注施用,用于重复给药周期。给药方案可任选地以其它间隔重复,并且剂量可通过各种肠胃外途径给予,并适当调整剂量和方案。
在某些优选的实施方案中,SN-38缀合的抗HLA-DR可以皮下施用。对于皮下施用,ADC(例如IMMU-140(hL243-CL2A-SN-38))的剂量可能受限于能够在没有沉淀或聚集的情况下浓缩ADC的能力,以及可以皮下施用的施用体积(优选,1、2或3ml或更少)。因此,对于皮下施用,ADC可以2至4mg/kg给予,每天给予持续1周,或每周3次持续2周,或每周两次持续2周,然后休息。可以在诱导后每二至三周或每月静脉内或皮下施用维持剂量的ADC。或者,可以如下进行诱导:以8-10mg/kg静脉内施用的2至4个周期(在两个21天周期中,每个周期在第1天和第8天施用ADC,其间具有一周的休息期),然后皮下施用作为每周一次或多次的活性剂量,或者作为维持治疗。可以基于临时肿瘤扫描和/或通过分析Trop-2阳性循环肿瘤细胞来调整剂量。
在一些优选的实施方案中,免疫缀合物用于治疗癌症。癌症的实例包括但不限于癌、淋巴瘤、成胶质细胞瘤、黑素瘤、肉瘤和白血病、骨髓瘤或淋巴恶性肿瘤。这些癌症的更具体的实例如下所述,包括:鳞状细胞癌(例如,上皮鳞状细胞癌)、尤文肉瘤、肾母细胞瘤、星形细胞瘤、肺癌(包括小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞癌)、腹膜癌、胃部或胃癌(包括胃肠癌)、胰腺癌、多形性胶质母细胞瘤、***、卵巢癌、肝癌症、膀胱癌、肝癌、肝细胞癌、神经内分泌肿瘤、甲状腺髓样癌症、分化型甲状腺癌、乳腺癌、卵巢癌、结肠癌、直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌症或肾癌、***癌、外阴癌、***癌、***癌,以及头颈部癌症。术语“癌症”包括原发性恶性细胞或肿瘤(例如,其细胞未迁移到受试者身体中除原始恶性肿瘤或肿瘤部位以外的部位的那些)和继发性恶性细胞或肿瘤(例如,由转移引起的那些,恶性细胞或肿瘤细胞迁移到与原始肿瘤部位不同的第二部位)。
癌症或恶性肿瘤的其它实例包括但不限于:急性儿童成淋巴细胞白血病、急性成淋巴细胞白血病、急性淋巴细胞白血病、急性髓性白血病、肾上腺皮质癌、成人(原发性)肝细胞癌、成人(原发性)肝癌、成人急性淋巴细胞白血病、成人急性髓性白血病、成人霍奇金氏淋巴瘤、成人淋巴细胞白血病、成人非霍奇金氏淋巴瘤、成人原发性肝癌、成人软组织肉瘤、AIDS相关淋巴瘤、AIDS相关恶性肿瘤、***癌、星形细胞瘤、胆管癌、膀胱癌、骨癌、脑干胶质瘤、脑肿瘤、乳腺癌、肾盂和输尿管癌、中枢神经***(原发性)淋巴瘤、中枢神经***淋巴瘤、小脑星形细胞瘤、大脑星形细胞瘤、***、儿童(原发性)肝细胞癌、儿童(原发性)肝癌、儿童急性成淋巴细胞白血病、儿童急性髓性白血病、儿童脑干胶质瘤、儿童小脑星形细胞瘤、儿童大脑星形细胞瘤、儿童颅外生殖细胞肿瘤、儿童霍奇金病、儿童霍奇金氏淋巴瘤、儿童下丘脑和视觉通路胶质瘤、儿童成淋巴细胞白血病、儿童成神经管细胞瘤、儿童期非霍奇金氏淋巴瘤、儿童松果体和幕上原始神经外胚层肿瘤、儿童原发性肝癌、儿童横纹肌肉瘤、儿童软组织肉瘤、儿童视觉通路和下丘脑神经胶质瘤、慢性淋巴细胞白血病、慢性髓性白血病、结肠癌、皮肤T细胞淋巴瘤、内分泌胰腺胰岛细胞癌、子宫内膜癌症、室管膜瘤、上皮癌、食道癌、尤因氏肉瘤和相关肿瘤、外分泌胰腺癌、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、肝外胆管癌、眼癌、女性乳腺癌、戈谢病(Gaucher's Disease)、胆囊癌、胃癌癌症、胃肠道类癌肿瘤、胃肠道肿瘤、生殖细胞肿瘤、妊娠滋养细胞肿瘤、毛细胞白血病、头颈癌、肝细胞癌、霍奇金氏淋巴瘤、高丙球蛋白血症、下咽癌、肠癌、眼内黑素瘤、胰岛细胞癌、胰岛细胞胰腺癌症、卡波西氏肉瘤、肾癌、喉癌、唇和口腔癌、肝癌、肺癌、淋巴组织增生性疾病、巨球蛋白血症、男性乳腺癌、恶性间皮瘤、恶性胸腺瘤、成神经管细胞瘤、黑素瘤、间皮瘤、转移性隐匿性原发性鳞状颈癌、转移性原发性鳞状颈癌、转移性鳞状颈癌、多发性骨髓瘤、多发性骨髓瘤/浆细胞肿瘤、骨髓增生异常综合征、骨髓性白血病、髓性白血病、骨髓增生性疾病、鼻腔和鼻窦癌、鼻咽癌、神经母细胞瘤、非霍奇金氏淋巴瘤、非黑素瘤皮肤癌症、非小细胞肺癌、隐匿性原发性转移性鳞状颈癌、口咽癌、骨质/恶性纤维肉瘤、骨/恶性纤维组织细胞瘤、骨肉瘤/骨恶性纤维组织细胞瘤、卵巢上皮癌、卵巢生殖细胞肿瘤、卵巢低恶性潜在肿瘤、胰腺癌、副蛋白血症(Paraproteinemias)、真性红细胞增多症、甲状旁腺癌、***癌、嗜铬细胞瘤、垂体瘤、原发性中枢神经***淋巴瘤、原发性肝癌、***癌、直肠癌、肾细胞癌、肾盂和输尿管癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、肉芽肿肉瘤、Sezary综合征、皮肤癌、小细胞肺癌、小肠癌、软组织肉瘤、鳞状颈癌、胃癌、幕上原始神经外胚层和松果体肿瘤、T细胞淋巴瘤、睾丸癌、胸腺瘤、甲状腺癌、肾盂和输尿管移行细胞癌、移行肾盂和输尿管癌、滋养细胞肿瘤、输尿管和肾盂细胞癌、尿道癌、子宫癌、子宫肉瘤、***癌、视觉通路和下丘脑胶质瘤、外阴癌、瓦尔登斯特伦巨球蛋白血症、维尔姆斯瘤以及位于上面列出的器官***中的除了赘生物以外的任何其它过度增生性疾病。
本文描述和要求保护的方法和组合物可用于治疗恶性或恶化前病症并预防进展至肿瘤或恶性状态,包括但不限于上述那些病症。这样的用途表示已知或怀疑先前发展为瘤赘生物或癌症的病症,特别是在发生由增生、化生或最特别是发育异常引起的非肿瘤细胞生长的情况下(对于这种异常生长情况的综述,参见Robbins和Angell,BasicPathology,第2版,W.B.Saunders Co.,Philadelphia,第68-79页(1976))。
发育异常通常是癌症的先兆,并且主要在上皮细胞中发现。它是非肿瘤细胞生长中最无序的形式,涉及个体细胞均匀性和细胞结构方向的丧失。发育异常特征性地发生在存在慢性刺激或炎症的地方。可以治疗的发育异常疾病包括但不限于无汗性外胚层发育异常(anhidrotic ectodermal dysplasia)、异侧发育异常(anterofacial dysplasia)、窒息性胸廓发育异常(asphyxiating thoracic dysplasia)、心房-手指发育异常(atriodigital dysplasia)、支气管肺发育异常(bronchopulmonary dysplasia)、大脑发育异常(cerebral dysplasia)、宫颈发育异常(cervical dysplasia)、软骨外胚层发育异常(chondroectodermal dysplasia)、锁骨头颅发育异常(cleidocranial dysplasia)、先天性外胚层发育异常、颅骨骨干发育异常(craniodiaphysial dysplasia)、颅腕跖骨发育异常(craniocarpotarsal dysplasia)、颅骨干骺端发育异常(craniometaphysialdysplasia)、牙质发育异常、骨干发育异常(diaphysial dysplasia)、外胚层发育异常、釉质发育异常(enamel dysplasia)、脑-眼发育异常(encephalo-ophthalmic dysplasia)、偏侧骨骺发育异常(dysplasia epiphysialis hemimelia)、多发性骨骺发育异常(dysplasiaepiphysialis multiplex)、点状骨骺发育异常(dysplasia epiphysialis punctata)、上皮发育异常、脸指生殖器发育异不良(faciodigitogenital dysplasia)、家族性颌骨纤维异常增生(familial fibrous dysplasia of jaws)、家族性白色皱襞性发育异常(familial white folded dysplasia)、纤维肌性发育异常、骨纤维发育异常(fibrousdysplasia of bone)、旺盛骨性发育异常(florid osseous dysplasia)、遗传性肾-视网膜发育异常、有汗性外胚层发育异常(hidrotic ectodermal dysplasia)、少汗性外胚层发育异常(hypohidrotic ectodermal dysplasia)、淋巴减少性胸腺发育异常(lymphopenicthymic dysplasia)、乳腺发育异常、下颌面骨发育异常(mandibulofacial dysplasia)、干骺端发育异常(metaphysial dysplasia)、蒙迪尼发育异常(Mondini dysplasia)、单骨纤维性骨发育异常(monostotic fibrous dysplasia)、粘膜上皮发育异常(mucoepithelialdysplasia)、多发性骺发育异常(multiple epiphysial dysplasia)、眼耳脊椎发育异常(oculoauriculovertebral dysplasia)、眼齿指发育异常(oculodentodigitaldysplasia)、眼椎骨发育异常(oculovertebral dysplasia)、牙源性发育异常(odontogenic dysplasia)、眼下颌支发育异常(opthalmomandibulomelic dysplasia)、根尖周牙骨质发育异常(periapical cemental dysplasia)、多骨纤维发育异常(polyostotic fibrous dysplasia)、假性软骨发育不全性脊椎骨骺发育异常(pseudoachondroplastic spondyloepiphysial dysplasia)、视网膜发育异常(retinaldysplasia)、中隔-眼发育异常(septo-optic dysplasia)、脊柱骨骺发育异常(spondyloepiphysial dysplasia)和室径向发育异常(ventriculoradial dysplasia)。
可以治疗的其它肿瘤前疾病包括但不限于良性增生性疾病(例如,良性肿瘤、纤维囊性病症、组织肥大、肠息肉或腺瘤和食道发育异常)、白斑、角化病(keratoses)、Bowen病、Farmer皮肤、日光性唇炎和日光性角化病。
在一些优选的实施方案中,本发明的方法用于抑制癌症的生长、发展和/或转移,特别是上面列出的那些。
另外的过度增殖性疾病、病症和/或病症包括但不限于恶性肿瘤和相关病症的进展和/或转移,例如白血病(包括急性白血病;例如,急性淋巴细胞性白血病、急性髓细胞性白血病[包括成髓细胞、早幼粒细胞、髓单核细胞、单核细胞和红白血病])和慢性白血病(例如,慢性髓细胞性[粒细胞性]白血病和慢性淋巴细胞性白血病);真性红细胞增多症(polycythemia vera)、淋巴瘤(例如,霍奇金氏病和非霍奇金氏病)、多发性骨髓瘤、瓦尔丹斯特伦氏巨球蛋白血症、重链病,以及实体瘤,包括但不限于肉瘤和癌,例如纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、***肉瘤、***内皮肉瘤(lymphangioendotheliosarcoma)、滑膜瘤、间皮瘤、尤因氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳癌、卵巢癌、***癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、***状癌、***状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝细胞瘤、胆管癌、绒毛膜癌、***瘤、胚胎性癌、威尔姆斯氏瘤(Wilm's tumor)、***、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤(emangioblastoma)、听神经瘤、少突神经胶质瘤、脑膜瘤、黑素瘤、成神经细胞瘤和成视网膜细胞瘤。
可用免疫缀合物治疗的自身免疫疾病可包括急性和慢性免疫性血小板减少症、皮肌炎、Sydenham舞蹈病、重症肌无力、***性红斑狼疮、狼疮性肾炎、风湿热、多腺体综合征、大疱性类天疱疮、糖尿病、Henoch-Schonlein紫癜、链球菌感染后肾炎、结节性红斑、大动脉炎、ANCA相关血管炎、阿狄森氏病、类风湿性关节炎、多发性硬化症、结节病、溃疡性结肠炎、多形性红斑、IgA肾病、结节性多动脉炎、强直性脊柱炎、Goodpasture综合征、闭塞性血栓性脉管炎、干燥综合征、原发性胆汁性肝硬化、桥本氏甲状腺炎、甲状腺毒症、硬皮病、慢性活动性肝炎、多发性肌炎/皮肌炎、多软骨炎、大疱性类天疱疮、寻常型天疱疮、韦格纳肉芽肿病、膜性肾病、肌萎缩侧索硬化症、脊髓痨、巨细胞动脉炎/多肌痛、恶性贫血、快速进展性肾小球肾炎、银屑病或纤维化肺泡炎。
试剂盒
多个实施方案可涉及包含适合于治疗患者的疾病组织的组分的试剂盒。示例性试剂盒可含有至少一种如本文所述的缀合抗体或其它靶向部分。如果含有用于施用的组分的组合物不配制用于通过消化道递送,例如通过口服递送,则可以包括能够通过一些其它途径递送试剂盒组分的装置。用于诸如肠胃外递送应用的一种类型的装置是用于将组合物注射到受试者体内的注射器。也可以使用吸入装置。
试剂盒组分可以包装在一起或分成两个或更多个容器。在一些实施方案中,容器可以是小瓶,其含有适于复原的组合物的无菌冻干制剂。试剂盒还可含有一种或多种适于复原和/或稀释其它试剂的缓冲液。可以使用的其它容器,包括但不限于小袋、托盘、盒子、管等。试剂盒组分可以在容器内无菌包装和维持。可以包括的另一个组件是对于使用试剂盒的人员的使用说明书。
实施例
通过以下实施例说明本发明的多个实施方案,但不限制其范围。
概述
以下使用的缩写是:DCC,二环己基碳二亚胺;NHS,N-羟基琥珀酰亚胺,DMAP,4-二甲基氨基吡啶;EEDQ,2-乙氧基-1-乙氧基羰基-1,2-二氢喹啉;MMT,单甲氧基三苯甲基;PABOH,对氨基苄醇;PEG,聚乙二醇;SMCC,4-(N-马来酰亚胺甲基)环己烷-1-羧酸琥珀酰亚胺酯;TBAF,四丁基氟化铵;TBDMS,叔丁基二甲基甲硅烷基氯。
以下实施例中的羟基化合物的氯甲酸酯根据Moon等(J.Medicinal Chem.51:6916-6926,2008)描述的方法,使用三光气和DMAP制备。萃取后处理是指用氯仿、二氯甲烷或乙酸乙酯萃取,并任选用饱和碳酸氢盐、水和饱和氯化钠洗涤。除非另有说明,否则快速色谱使用230-400目硅胶和甲醇-二氯甲烷梯度进行,使用至多15%v/v甲醇-二氯甲烷。反相HPLC通过方法A进行,其使用7.8×300mm C18HPLC柱,配备有柱前过滤器,并使用100%溶剂A至100%溶剂B的溶剂梯度以3mL/分钟的流速进行10分钟,并以4.5mL/分钟的流速保持在100%溶剂B,持续5或10分钟;或通过方法B,其使用4.6×30mmXbridge C18,2.5μm柱,配备有柱前过滤器,并使用100%溶剂A至100%溶剂B的溶剂梯度,流速为1.5mL/分钟,持续4分钟,和100%的溶剂B,流速为2mL/分钟,持续1分钟。溶剂A为0.3%乙酸铵水溶液,pH4.46,而溶剂B为9:1乙腈-乙酸铵水溶液(0.3%),pH 4.46。通过设定在360nm和254nm的双在线吸光度检测器监测HPLC。
实施例1.抗HLA-DR抗体药物缀合物IMMU-140(hL243-CL2A-SN-38)在HLA-DR+癌症中的体外和体内功效
复发的AML(急性髓细胞白血病)、ALL(急性淋巴细胞白血病)和MM(多发性骨髓瘤)继续是治疗挑战。IMMU-114(hL243)是一种人源化抗HLA-DR IgG4单克隆抗体,其被工程改造以缺少效应细胞功能,但保留了HLA-DR结合以及在多种血液肿瘤中的广泛抗肿瘤作用(SteinR等,Blood.2010;115:5180-90)。当皮下给予时,其在复发或难治性NHL和CLL的初始I期临床试验中证明有效,具有良好的安全性(ClinicalTrials.gov,NCT01728207)。
在体外,尽管HLA-DR的表达水平高,但已证明AML对IMMU-114的抗肿瘤作用具有抗性。同样,在多种不同的人ALL、CLL和MM细胞系中,IMMU-114表现出从低至9%至高达69%的一系列抗肿瘤作用。
为了改善IMMU-114的抗肿瘤活性,制备称为IMMU-140的抗体-药物缀合物(ADC),其中IMMU-114与伊立替康的活性代谢物SN-38缀合。在实体肿瘤中研究的另一种利用SN-38的ADC(sacituzumab govitecan)具有良好的耐受性,在超过6个月的多个周期中给予的患者中具有临床显著的客观响应,其中可控的中性粒细胞减少症是主要毒性。因此,我们的目标是确定SN-38(一种不常用于造血***癌症的药物)在用IMMU-114抗体靶向时是否会被证明是一种有效且安全的治疗药物。
在本研究中,在人AML、ALL、MM和CLL异种移植物中检查了hL243-SN-38(IMMU-140)对比于亲本IMMU-114的体外和体内活性。
方法
先前已经描述了用于SN-38与hL243 IgG4缀合的方法,并且导致药物与抗体的比率为6.1至6.6(Moon SJ等.J.Med.Chem.2008;51:6916-26)。SN-38接头(下面,左侧)含有短的聚乙二醇(PEG)部分以赋予水溶性。引入了马来酰亚胺基团以快速硫醇-马来酰亚胺缀合至轻度还原的抗体。苄基碳酸酯位点提供pH介导的切割位点以从接头释放药物。将交联接头连接到SN-38的20-羟基位置,以保持药物的内酯环在生理条件下不打开成活性较低的羧酸形式。ADC的结构如图1所示。
通过尺寸排阻HPLC(未显示)表征缀合物。比较了未经修饰的IMMU-114和具有6.1的药物/抗体摩尔取代的IMMU-140缀合物。未经修饰的IMMU-114在280nm处检测到,而缀合物在SN-38的吸收波长处即360nm处检测到。缀合物>98%单体(未显示)。
没有ADC的结合特异性的任何损失的证据,如通过基于细胞的ELISA,如由IMMU-140和IMMU-114与HLA-DR阳性人黑素瘤细胞系(A-374)的可比较的结合证明(图2)。当与b链缔合时,两者都识别a链。KD值显示在下表2中。抗体对照(h679)是人源化抗组胺-琥珀酰-甘氨酸(HSG)IgG。
表2.IMMU-140对比于IMMU-114的结合亲和力
K<sub>D</sub>(nM) | 95%C.I. | R<sup>2</sup> | |
IMMU-140 | 0.77 | 0.62至0.91 | 0.97 |
IMMU-114 | 0.65 | 0.53至0.77 | 0.97 |
对于体外细胞毒性测定,将细胞接种在96孔板(1×104细胞/孔)中,然后加入每种测试剂:游离SN-38(2.5×10-7至3.8×10-12M)、IMMU-140(2.5×10-7至3.8×10-12M,SN-38当量)和IMMU-114(4×10-8至6.2×10-13M)。将板孵育96小时,然后通过MTS测定细胞活力。抑制被确定为与未处理的对照相比,处理孔中的活细胞百分比。
在用10nM蛋白质浓度的IMMU-114或IMMU-140处理的细胞(2×106)中测定细胞凋亡信号传到,然后裂解并通过SDS-PAGE解析蛋白质(25mg)。将蛋白质转移到PVD膜上进行Western印迹。
对于AML和MM疾病模型,NSG/SCID和C.B.-17SCID小鼠分别在静脉内注射MOLM-14(2×106)或CAG细胞(1×107)前24小时接受2Gy照射。
在静脉内注射1×107细胞的C.B-17SCID小鼠中建立ALL(MN-60)和CLL(JVM-3)。
所有治疗在肿瘤细胞注射后5天开始。包括非靶向对照SN-38-ADC在内的测试剂以图中所示的剂量(100至500mg)施用,每周两次,持续4周。动物在疾病进展时处死,所述疾病进展通过后肢***发作或超过15%体重的损失表征。
结果
在多种人癌细胞系中检查HLA-DR表达。从组织培养物中收获人ALL、MM、CLL和AML细胞系,并使用AlexaFluor-647标记的IMMU-114通过FACS分析HLA-DR(α链)表达。IMMU-114和非靶向对照h679抗体的平均荧光强度(MFI)证明在所有四种细胞系中HLA-DR的高表达,其中IMMU-114的MFI值分别为6.58×104(MN-60 ALL细胞系)、8.07×104(CAG MM细胞系)、7.87×104(JVM-3CLL细胞系)和5.75×103(MOLM-14AML细胞系)。相比之下,与AML细胞系MOLM-14相比,CAG、MN-60和JVM-3表现出>10倍高的表达。
在体外,IMMU-140在所有四种造血肿瘤类型(ALL、MM、CLL和AML)中在低nM浓度(0.8至7.1nM)下达到IC50值,如下表3中所示。在体外,JVM-3对IMMU-140和IMMU-114两者表现出最高的敏感性。其余三种细胞系在SN-38和IMMU-140存在下仅表现出50%或更高的生长抑制。虽然利用IMMU-114在那些细胞系中未实现50%抑制,但与非靶向对照抗体相比,未缀合的抗体在40nM下在CAG(MM)和MN-60(ALL)中介导显著的生长抑制。如先前报道的,利用另外两种AML细胞系(Stein R等,Blood.2010;115:5180-90),MOLM-14也对IMMU-114具有抗性,但对IMMU-140敏感。
表3.在AML、ALL、CLL和MM细胞中IMMU-140对比于IMMU-114的体外细胞毒性。
显示为SN-38当量的IMMU-140浓度
*与MOLM-14中的IMMU-140相比,游离SN-38的IC50显著不同(P=0.0266)
与对照抗体相比显著抑制(P<0.0061)
IMMU-140证明了通过其靶细胞的抗HLA-DR结合和SN-38的递送介导的双凋亡信号传导途径。在NHL、ALL、MM和CLL中,IMMU-114通过p-ERK-1/2和凋亡诱导因子(AIF)发出细胞凋亡信号,但是在AML中没有(SteinR等.Blood.2010;115(25):5180-5190)。在这里,我们证明了IMMU-114和IMMU-140两者在三种不同造血细胞系中均能够介导ERK1/2的磷酸化和上调AIF(未显示),包括AML细胞系MOLM-14(未显示),提示在AML中该途径的其它信号传导组分的缺陷,因为其在体外和体内对IMMU-114都不敏感。
重要的是,IMMU-140通过其SN-38有效负载也在包括包括MOLM-14在内的所有三种细胞系中介导PARP裂解(未显示)。如通过增加的p-H2A.X水平所证明的,所得的双链DNA(dsDNA)断裂在用IMMU-140处理的细胞中最明显(未显示)。
在实验性MOLM-14 AML中,盐水对照和IMMU-114处理的小鼠死于快速的疾病进展,中值存活时间(MST)分别仅为14天和15天(图3)。相比之下,用IMMU-140处理的小鼠的存活率增加超过1.5倍(MST=37天,P=0.0031)(图3)。此外,与以相同剂量的施用的盐水和对照ADC(抗CEA-SN-38IMMU-130)相比,剂量减少至250mg IMMU-140仍然提供了统计学上显著的大于80%的存活率改善(MST=21天,P=0.0031)(图3)。
在具有MN-60ALL异种移植物的小鼠中(图4),IMMU-114与盐水对照相比提供了>60%的存活率改善(MST分别=37天对比于22.5天;P<0.0001),而IMMU-140使这再增加80%(MST=66.5天),这显著优于包括IMMU-114在内的所有其它治疗(P<0.0001)(图4)。用IMMU-140的治疗被小鼠很好地耐受,体重没有明显的损失。
当用IMMU-140治疗时,具有CAG MM异种移植物的小鼠(图5)具有更高的151天的MST,相比之下盐水对照为32天(P<0.0001)。该存活益处也显著高于用硼替佐米(0.89mg/kg)或对照ADC+硼替佐米治疗的小鼠(两者的MST=32.5天;P<0.0001)(图5)。虽然不显著,但IMMU-140确实提供了与IMMU-114治疗(MST=94.5天,P=0.0612)相比>60%的存活率改善(图5)。硼替佐米治疗与IMMU-114或IMMU-140组合并未将存活率提高到高于单一治疗(图5)。
具有JVM-3 CLL异种移植物的小鼠(图6)显示出对IMMU-140和IMMU-114两者的相似敏感性。与盐水或对照ADC处理的小鼠相比,在用高剂量(500mg)或低剂量(100mg)剂量的IMMU-140处理的小鼠中存在显著的存活(P<0.0002)(图6)。同样,用任一剂量的IMMU-114治疗的小鼠具有>96天的MST(对比于盐水P<0.0001,并且对比于对照ADC,P<0.0003)(图6)。在向小鼠施用的剂量下用IMMU-140和IMMU-114处理的小鼠之间没有显著差异(图6)。这些结果表明,在小于100mg的剂量下可以实现功效,这表明IMMU-140在该疾病中临床上具有广泛的治疗窗口。
在所有实验中,使用IMMU-140的治疗耐受性良好,如由体重没有明显损失所证明。
结论
IMMU-114是缺乏免疫功能的IgG4Mab,消除了先前HLA-DR Mab的已知不良事件。被IMMU-114识别的HLA-DR在广泛的人类造血和实体癌症类型中表达。通过可切割的接头将6-8个SN-38分子与IMMU-114缀合(hL243-SN-38)不改变其与HLA-DR阳性细胞的结合。
hL243-SN-38(IMMU-140)通过由IMMU-114HLA-DR结合部分(p-ERK1/2和AIF信号传导)介导的直接抗肿瘤活性和递送至细胞的SN-38的额外细胞毒性作用(半胱天冬酶级联和PARP切割)提供双重治疗剂的额外益处。IMMU-140抗体-药物缀合物在ALL和AML中在临床前显示出比裸IMMU-114更高的功效,并且在实验MM和CLL中增加的(如果不是显著的)存活益处。总体而言,SN-38-缀合的IMMU-114(IMMU-140)的双重治疗潜力允许治疗多种HLA-DR阳性造血和实体癌症的能力。
在AML和ALL两种异种移植物中,使用IMMU-140ADC的治疗证明优于IMMU-114(其在NHL和CLL中是临床上活性的),并且在MM和CLL中是有益的。最重要的是,在IMMU-114难治性AML中,IMMU-140显示出显著的抗肿瘤作用,而没有任何不适当的毒性。数据显示这种新型ADC可用于这些难治性恶性肿瘤。
实施例2.IMMU-140在HLA-DR+人黑素瘤中的功效
HLA-DR抗原的表达不限于造血***癌,而是还存在于皮肤癌、食道癌、胃癌、结肠癌、直肠癌、胰腺癌、肺癌、乳腺癌、卵巢癌、膀胱癌、子宫内膜癌、***、睾丸癌、黑素瘤、肾癌和肝癌中。本研究旨在检查IMMU-140在非造血HLA-DR+肿瘤中的功效。
细胞结合研究
化学发光底物***用于检测与细胞结合的抗体。简单地说,将A-375人黑素瘤细胞接种到96黑孔平透明底板(black-well,flat-clear-bottom plate)中过夜。将hL243-γ4P抗体加入一式三份孔中(孔中最终浓度为2μg/mL)。作为非特异性结合的对照,将人源化抗CD22抗体同样地加入另一组一式三份孔中。设置两个板,其中一个在室温(RT)孵育,一个在4℃孵育。孵育1小时后,除去培养基,用新鲜的冷培养基洗涤细胞,然后加入1:20,000稀释的山羊抗人辣根过氧化物酶缀合的第二抗体,在4℃下保持1小时。再次洗涤板,然后加入试剂。
使用ENVISIONTM酶标仪读取板的发光。确定平均发光值并如图7所示绘图。在4℃和室温下,hL243γ4在A-375细胞上的平均发光为背景48倍,为非特异性对照的25倍,这与这种人黑素瘤细胞系上HLA-DR的高表达一致。总之,测试的4种人黑素瘤细胞系(A-375、SK-MEL-28、SK-MEL-5和SK-MEL-2)中的4种对hL243-γ4P结合呈阳性(分别为背景的48倍、25倍、12倍和2倍)。
在A-375肿瘤异种移植物中的体内功效
对无胸腺NCr nu/nu裸鼠皮下注射5×106个A-375细胞/小鼠。一旦肿瘤大小达到约0.3cm3,将动物分成6个不同的处理组,每组10只小鼠。小鼠每周两次接受250μg皮内注射的IMMU-140(hL243-SN-38)(DAR=5.05),持续四周。ADC对照组由以相同方案接受相同剂量的非肿瘤靶向抗CD20ADC(hA20-CL2A-SN-38;DAR=6.08)的小鼠组成。另外,一组小鼠接受单独的裸hL243-γ4P(250μg),并且一组以等于ADC剂量的剂量接受hL243-γ4P加伊立替康(250μg MAb+7.5μg伊立替康)。最后一组仅接受伊立替康,其剂量为hL243-SN-38携带的SN-38的量的10倍(即75μg)。所有伊立替康注射均以静脉注射施用。最后一组小鼠仅接受盐水(100μL腹膜内注射)。处理组总结于下表4中。
表4.具有黑素瘤的裸鼠的处理组
测量肿瘤并每周对小鼠称重。如果肿瘤体积大小超过2.0cm3,则将动物因疾病进展处死。部分响应定义为肿瘤从初始大小缩小>30%。当肿瘤体积保持在初始大小的70%至120%时,疾病稳定。肿瘤进展时间(TTP)确定为肿瘤从其最低点增长超过20%的时间。
肿瘤生长数据的统计分析基于曲线下面积(AUC)和TTP。通过线性曲线建模获得个体肿瘤生长的概况。在对生长曲线进行的统计分析之前,采用F检验来确定组间方差的相等性。双尾t检验用于评估所有各个处理组和对照之间的统计学显著性,除了盐水对照组,在盐水对照组中分析中使用单尾t检验。由于一些生长曲线的不完整性(由于死亡),AUC的统计学比较仅进行到组中第一只动物被处死的时间。使用双尾t检验比较组之间的TTP值。
治疗开始时所有组的平均肿瘤体积为0.314±0.078cm3。平均肿瘤生长曲线显示在图8中。该疾病模型被证明是非常具有侵袭性的,其中盐水对照肿瘤进展迅速(TTP=7天;表5)。虽然在对照组中肿瘤同样进展,但所有治疗都能够相对于盐水对照减缓肿瘤生长(P<0.0142,AUC)(图8和表5)。然而,与所有其它组相比,仅用hL243-SN-38处理的小鼠显示出显著的抗肿瘤效果(P<0.0244;AUC)(图8和表5)。该组中的所有小鼠都是部分响应者,其中两只小鼠在治疗第70天实验结束时没有肿瘤。与所有其它非ADC对照组相比,这导致肿瘤进展延迟超过3倍(P<0.0005)(图8和表5)。虽然这种肿瘤对非特异性ADC敏感,但是用hL243-SN-38的处理与用对照ADC处理的小鼠相比使TTP延迟大于80%(分别为28±9.9天对比于15.6±7.7天;P=0.012)(图8和表5)。这些数据表明即使在侵袭性人黑素瘤肿瘤的小鼠疾病模型中,用hL243-SN-38治疗也导致显著的肿瘤消退和疾病进展的延迟(图8和表5)。
实施例3.CL2A-SN-38的制备
在室温下向市售的Fmoc-Lys(MMT)-OH(0.943g)、对氨基苯甲醇(0.190g)在二氯甲烷(10mL)中的混合物中加入EEDQ(0.382g)并搅拌4小时。萃取后处理,然后进行快速色谱,得到1.051g白色泡沫状物质。所有HPLC分析通过0148部分的‘概述’中所述的方法B进行。HPLC保留时间:3.53分钟,电喷雾质谱显示在m/e 745.8(M+H)和m/e 780.3(M+Cl-)处的峰,与结构一致。将该中间体(0.93g)溶解在二乙胺(10mL)中并搅拌2小时。除去溶剂后,将残余物在己烷中洗涤,得到0.6g作为无色沉淀的中间体(方案3中的(2))(HPLC纯度为91.6%)。HPLC保留时间:2.06分钟。电喷雾质谱显示在m/e 523.8(M+H)、m/e 546.2(M+Na)和m/e522.5(M-H)处的峰。
将该粗制中间体(0.565g)在二氯甲烷(10mL)中使用EEDQ与市售的O-(2-叠氮基乙基)-O’-(N-二乙醇酰基-2-氨基乙基)七甘醇(‘PEG-N3’,0.627g)偶联。溶剂去除和快速色谱法得到0.99g产物(方案3中的(3);浅黄色油状物;87%产率)。HPLC保留时间:2.45分钟。电喷雾质谱显示在m/e 1061.3(M+H)、m/e 1082.7(M+Na)和m/e 1058.8(M-H)处的峰,与结构一致。在氩气下,将该中间体(0.92g)与10-O-TBDMS-SN-38-20-O-氯甲酸酯在二氯甲烷(10mL)中反应10分钟。将混合物通过快速色谱法纯化,得到0.944g浅黄色油状物(方案3中的(6);产率=68%)。HPLC保留时间:4.18分钟。向该中间体(0.94g)的二氯甲烷(10mL)溶液中加入TBAF(THF中1M,0.885mL)和乙酸(0.085mL)在二氯甲烷(3mL)中的混合物,然后搅拌10分钟。将混合物用二氯甲烷(100mL)稀释,用0.25M柠檬酸钠和盐水洗涤。除去溶剂,得到0.835g黄色油状产物。HPLC保留时间:2.80分钟,(99%纯度)。电喷雾质谱显示在m/e 1478(M+H)、m/e 1500.6(M+Na)、m/e 1476.5(M-H)、m/e 1590.5(M+TFA)处的峰,与结构一致。
方案3:CL2A-SN-38的制备
在CuBr(0.0083g)、DIEA(0.01mL)和三苯基膦(0.015g)的存在下,使该叠氮基衍生的SN-38中间体(0.803g)在二氯甲烷(10mL)中与4-(N-马来酰亚胺基甲基)-N-(2-丙炔基)环己烷-1-甲酰胺(0.233g)反应18小时。萃取后处理,包括用0.1M EDTA(10mL)洗涤,快速色谱法得到0.891g黄色泡沫(产率=93%),HPLC保留时间:2.60分钟。电喷雾质谱显示在m/e1753.3(M+H)、m/e 1751.6(M-H)、1864.5(M+TFA)处的峰,与结构一致。最后,用二氯乙酸(0.3mL)和苯甲醚(0.03mL)在二氯甲烷(3mL)中的混合物对该倒数第二个中间体(0.22g)进行脱保护,然后用醚沉淀,得到0.18g(97%产率)的CL2A-SN-38;方案3中的(7),为浅黄色粉末。HPLC保留时间:1.88分钟。电喷雾质谱显示在m/e 1480.7(M+H)、1478.5(M-H)处的峰,与结构一致。
实施例4.双官能SN-38产物与轻度还原的抗体缀合
在含有5.4mM EDTA的40mM PBS(pH 7.4)中,在37℃(浴)下用二硫苏糖醇(DTT)以50-70倍摩尔过量还原各抗体45分钟。通过尺寸排阻色谱法和/或渗滤法纯化还原产物,并缓冲液交换为pH 6.5的合适缓冲液。通过Ellman测定法测定硫醇含量,并且为6.5至8.5SH/IgG。或者,将抗体用pH 5-7的磷酸盐缓冲液中的三(2-羧乙基)膦(TCEP)还原,然后原位缀合。使用7-15%v/v的DMSO作为共溶剂,使还原的MAb与CL2A-SN-38反应,并在环境温度下孵育20分钟。通过离心SEC,通过疏水柱,最后通过超滤-渗滤纯化缀合物。通过366nm处的吸光度测定产物的SN-38并与标准值相关联,而蛋白质浓度由280nm处的吸光度推断,在该波长下校正SN-38吸光度的溢出。这样,确定了SN-38/MAb取代比。将纯化的缀合物作为冻干制剂储存在玻璃小瓶中,在真空下封盖并储存在-20℃冰箱中。对于这些缀合物中的一些获得了SN-38摩尔取代比(MSR),其通常为5-7,显示在表6中。
表6.一些缀合物中的SN-38/MAb摩尔取代比(MSR)
MAb | 缀合物 | MSR |
hMN-14 | hMN-14-[CL2A-SN-38] | 6.1 |
hRS7 | hRS7-CL2A-SN-38,使用实施例10的药物接头 | 5.8 |
hA20 | hA20-CL2A-SN-38,使用实施例10的药物接头 | 5.8 |
hLL2 | hLL2-CL2A-SN-38,使用实施例10的药物接头 | 5.7 |
hPAM4 | hPAM4-CL2A-SN-38,使用实施例10的药物接头 | 5.9 |
实施例5.使用hL243-SN-38治疗难治性转移性结肠癌(mCRC)
患者为患有转移性结肠癌的67岁的男性。在诊断后不久进行横向结肠切除术之后,患者然后在新辅助疗法环境中接受了4个周期的FOLFOX化学治疗,然后进行部分肝切除术以去除肝左叶中的转移性病变。接下来是辅助FOLFOX方案,总共10个FOLFOX周期。
CT显示向肝脏的转移。他的靶病变是肝左叶的3.0cm肿瘤。非靶病变包括肝脏中的几种低衰减肿块。基线CEA为685ng/mL。
在患者签署知情同意书后,每隔一周给予hL243-SN-38(10mg/kg),持续4个月。患者在第一次治疗后出现恶心(2级)和疲劳(2级)并继续治疗而没有重大不良事件。完成的第一次响应评估(8次剂量后)通过计算机断层扫描(CT)显示靶病变收缩26%,并且他的CEA水平降低至245ng/mL。在第二次响应评估中(12次剂量后),靶病变缩小了35%。他的整体健康和临床症状得到了显著改善。
实施例6.用IMMU-140(抗HLA-DR-SN-38)治疗复发的滤泡性淋巴瘤
在接受对于表现为多个区域***(宫颈、腋窝、纵隔、腹股沟、腹部)中的广泛疾病和骨髓受累的滤泡性淋巴瘤的R-CHOP化学治疗之后,给予这名68岁的男性实验药物IMMU-114-SN-38(抗HLA-DR-SN-38),每周10mg/kg的剂量,持续3周,休息3周,然后是另外3周的第二疗程。然后通过CT评估他的指数肿瘤病变的变化,并根据CHESON标准显示减少23%。该治疗重复另外2个疗程,然后通过CT显示肿瘤减少55%,这是部分响应。
实施例7.用IMMU-140治疗复发的慢性淋巴性白血病
根据国际慢性淋巴细胞白血病研讨会和世界卫生组织分类所定义的,具有CLL病史的67岁男性在先前用氟达拉滨、***和利妥昔单抗以及CVP方案治疗之后表现出疾病复发。他现在具有与全身***肿大、血红蛋白和血小板产生减少以及白细胞计数迅速上升有关的发烧和盗汗。他的LDH升高,并且β-2-微球蛋白几乎是正常的两倍。给予患者使用IMMU-114-SN-38缀合物的治疗,给药方案为每周8mg/kg,持续4周,休息2周,然后再次重复该循环。评估显示患者的血液学参数改善,并且他的循环CLL细胞数量似乎减少。然后恢复治疗另外3个循环,之后他的血液学和实验室值表明他具有部分响应。
实施例8.免疫缀合物储存
将上述缀合物纯化并将用2-(N-吗啉代)乙烷磺酸(MES)(pH 6.5)进行缓冲液交换,并进一步用海藻糖(25mM终浓度)和聚山梨醇酯80(0.01%v/v终浓度)配制,加入赋形剂后,最终缓冲液浓度变为22.25mM。将配制的缀合物冻干并储存在密封的小瓶中,在2℃-8℃下储存。冻干的免疫缀合物在储存条件下是稳定的。保持其生理活性。
***
从前面的描述中,本领域技术人员可以容易地确定本发明的基本特征,并且在不脱离其精神和范围的情况下,可以对本发明进行各种改变和修改以使其适应各种用途和条件而不需要过多的实验。本文引用的所有专利、专利申请和出版物均通过引用并入本文。
Claims (40)
1.一种治疗HLA-DR+癌症的方法,其包括向患有HLA-DR+癌症的人患者施用免疫缀合物,所述免疫缀合物包含与抗HLA-DR抗体或其抗原结合片段缀合的SN-38。
2.如权利要求1所述的方法,其中所述抗HLA-DR抗体是hL243抗体,其包含重链CDR序列CDR1 (NYGMN,SEQ ID NO: 1)、CDR2 (WINTYTREPTYADDFKG,SEQ ID NO: 2)和CDR3(DITAVVPTGFDY,SEQ ID NO: 3)以及轻链CDR序列CDR1 (RASENIYSNLA,SEQ ID NO: 4)、CDR2 (AASNLAD,SEQ ID NO: 5)和CDR3 (QHFWTTPWA,SEQ ID NO: 6)。
3.如权利要求1所述的方法,其中所述癌症是造血***癌症或实体瘤。
4.如权利要求3所述的方法,其中所述造血***癌症选自淋巴瘤、白血病、多发性骨髓瘤、急性髓性白血病、急性淋巴性白血病、非霍奇金氏淋巴瘤、慢性淋巴性白血病、慢性髓性白血病、DLBCL (弥漫性大B细胞淋巴瘤)、滤泡性淋巴瘤、SLL (小淋巴细胞淋巴瘤)、套细胞淋巴瘤、霍奇金氏淋巴瘤、伯基特淋巴瘤、毛细胞白血病和边缘区淋巴瘤。
5.如权利要求3所述的方法,其中所述实体瘤选自皮肤癌、食道癌、胃癌、结肠癌、直肠癌、胰腺癌、肺癌、乳腺癌、卵巢癌、膀胱癌、子宫内膜癌、***、睾丸癌、恶性黑素瘤、肾癌和肝癌。
6.如权利要求1所述的方法,其中所述HLA-DR+癌症选自AML (急性髓细胞白血病)、ALL(急性淋巴细胞白血病)和MM (多发性骨髓瘤)。
7.如权利要求1所述的方法,其中所述HLA-DR+癌症不响应于用未缀合的抗HLA-DR抗体的治疗。
8.如权利要求1所述的方法,其中将所述免疫缀合物作为一线治疗施用于先前未接受过针对所述癌症的治疗的患者。
9.如权利要求1所述的方法,其中将所述免疫缀合物施用于先前已经从至少一种抗癌治疗中复发或者已经对至少一种抗癌治疗具有抗性的患者。
10.如权利要求1所述的方法,其中将所述免疫缀合物施用于不适合干细胞或骨髓移植的患者。
11.如权利要求1所述的方法,其中所述免疫缀合物以介于3 mg/kg和18 mg/kg之间的剂量施用。
12.如权利要求11所述的方法,其中所述剂量选自4 mg/kg、6 mg/kg、8 mg/kg、9 mg/kg、10 mg/kg、12 mg/kg、16 mg/kg和18 mg/kg。
13.如权利要求1所述的方法,其中所述免疫缀合物以介于6 mg/kg和12 mg/kg之间的剂量施用。
14.如权利要求1所述的方法,其中所述免疫缀合物以介于8 mg/kg和10 mg/kg之间的剂量施用。
15.如权利要求3所述的方法,其中所述癌症是实体瘤,并且所述治疗导致肿瘤尺寸减小至少15%、至少20%、至少30%或至少40%。
16.如权利要求1所述的方法,其中所述癌症是转移性的。
17.如权利要求16所述的方法,其还包括减小所述转移瘤的尺寸或消除所述转移瘤。
18.如权利要求9所述的方法,其中在用所述免疫缀合物治疗之前,所述患者不响应于用伊立替康的治疗。
19.如权利要求1所述的方法,其中在所述SN-38和所述抗体之间存在接头。
20.如权利要求19所述的方法,其中所述接头是CL2A,并且所述免疫缀合物的结构为MAb-CL2A-SN-38
。
21.如权利要求20所述的方法,其中MAb-CL2A-SN-38中SN-38的10-羟基位置是10-O-酯或使用‘COR’部分的10-O-碳酸酯衍生物,其中“CO”是羰基,并且“R”基团选自(i) N,N-二取代氨基烷基“N(CH3)2-(CH2)n-”,其中n为1-10,并且其中末端氨基任选地为季盐的形式;(ii)烷基残基“CH3-(CH2)n-,其中n为0-10;(iii)烷氧基部分“CH3-(CH2)n-O-”,其中n为0-10;(iv) “N(CH3)2-(CH2)n-O-”,其中n为2-10;或(v) “R1O-(CH2-CH2-O)n-CH2-CH2-O-”,其中R1是乙基或甲基,n是值为0-10的整数。
22.如权利要求1所述的方法,其中每个抗体分子连接有6个或更多个SN-38分子。
23.如权利要求1所述的方法,其中所述免疫缀合物包含7至8个与所述抗体或其抗原结合片段缀合的SN-38分子。
24.如权利要求1所述的方法,其中所述抗体是IgG1或IgG4抗体。
25.如权利要求1所述的方法,其中所述抗体是IgG4抗体。
26.如权利要求1所述的方法,其中所述抗体具有选自以下的同种异型:G1m3、G1m3,1、G1m3,2、G1m3,1,2、nG1m1、nG1m1,2和Km3同种异型。
27.如权利要求1所述的方法,其中将所述免疫缀合物剂量以具有选自以下的循环的方案每周向人患者施用一次或两次:(i)每周;(ii)每隔一周;(iii)治疗一周,然后停用两周、三周或四周;(iv)治疗两周,然后停用一周、两周、三周或四周;(v)治疗三周,然后停用一周、两周、三周、四周或五周;(vi)治疗四周,然后停用一周、两周、三周、四周或五周;(vii)治疗五周,然后停用一周、两周、三周、四周或五周;以及(viii)每月。
28.如权利要求27所述的方法,其中所述循环重复4次、6次、8次、10次、12次、16次或20次。
29.如权利要求1所述的方法,其中所述免疫缀合物与一种或多种治疗方式组合施用,所述治疗方式选自未缀合的抗体、放射性标记的抗体、药物缀合的抗体、毒素缀合的抗体、基因治疗、化学治疗、治疗性肽、细胞因子治疗、寡核苷酸、局部放射治疗、手术和干扰RNA治疗。
30.如权利要求29所述的方法,其中所述治疗方式包括利用选自以下的治疗剂的治疗:5-氟尿嘧啶、阿法替尼、阿普立定、阿扎立平、阿那曲唑、蒽环类、阿西替尼、AVL-101、AVL-291、苯达莫司汀、博来霉素、硼替佐米、博舒替尼、苔藓抑素-1、白消安、卡利奇霉素、喜树碱、卡铂、10-羟基喜树碱、卡莫司汀、塞来昔布、苯丁酸氮芥、顺铂、Cox-2抑制剂、伊立替康(CPT-11)、SN-38、卡铂、克拉屈滨、camptothecan、环磷酰胺、克唑替尼、阿糖胞苷、达卡巴嗪、达沙替尼、dinaciclib、多西他赛、放线菌素D、柔红霉素、多柔比星、2-吡咯啉多柔比星(2P-DOX)、氰基吗啉代多柔比星、多柔比星葡糖苷酸、表柔比星葡糖苷酸、厄洛替尼、雌莫司汀、表鬼臼毒素、恩替诺特、***受体结合剂、依托泊苷(VP16)、依托泊苷葡糖苷酸、磷酸依托泊苷、依西美坦、芬戈莫德、夫拉平度、氟尿苷(FUdR)、3',5'-O-二油酰基-FudR (FUdR-dO)、氟达拉滨、氟他胺、法呢基蛋白转移酶抑制剂、fostamatinib、ganetespib、GDC-0834、GS-1101、吉非替尼、吉西他滨、羟基脲、依鲁替尼、伊达比星、艾代拉里斯、异环磷酰胺、伊马替尼、L-天冬酰胺酶、拉帕替尼、来那度胺、甲酰四氢叶酸、LFM-A13、洛莫司汀、氮芥、美法仑、巯基嘌呤、6-巯基嘌呤、甲氨蝶呤、米托蒽醌、光辉霉素、丝裂霉素、米托坦、诺维本、来那替尼、尼罗替尼、亚硝基脲、奥拉帕尼、林可霉素、丙卡巴肼、紫杉醇、PCI-32765、喷司他丁、PSI-341、雷洛昔芬、司莫司汀、索拉非尼、链脲佐菌素、SU11248、舒尼替尼、他莫昔芬、替莫唑胺(DTIC的含水形式)、反铂、沙利度胺、硫鸟嘌呤、塞替派、替尼泊苷、拓扑替康、尿嘧啶氮芥、瓦他拉尼、长春瑞滨、长春碱、长春新碱、长春花生物碱和ZD1839。
31.如权利要求29所述的方法,其中所述免疫缀合物与第二抗体或其抗原结合片段组合施用,所述第二抗体或其抗原结合片段与选自以下的肿瘤相关抗原(TAA)结合:碳酸酐酶IX、甲胎蛋白(AFP)、α-辅肌动蛋白-4、ART-4、Ba 733、BAGE、BrE3-抗原、CA125、CAMEL、CAP-1、CASP-8/m、CCL19、CCL21、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD66a-e、CD67、CD70、CD70L、CD74、CD79a、CD80、CD83、CD95、CD126、CD132、CD133、CD138、CD147、CD154、CDC27、CDK-4/m、CDKN2A、CTLA-4、CXCR4、CXCR7、CXCL12、HIF-1α、结肠特异性抗原-p(CSAp)、CEA (CEACAM5)、CEACAM6、c-Met、DAM、EGFR、EGFRvIII、EGP-1 (TROP-2)、EGP-2、ELF2-M、Ep-CAM、成纤维细胞生长因子(FGF)、Flt-1、Flt-3、叶酸受体、G250抗原、GAGE、gp100、GRO-β、HLA-DR、HM1.24、人绒毛膜***(HCG)、HER2/neu、HMGB-1、缺氧诱导因子(HIF-1)、HSP70-2M、HST-2、Ia、IGF-1R、IFN-γ、IFN-α、IFN-β、IFN-λ、IL-4R、IL-6R、IL-13R、IL-15R、IL-17R、IL-18R、IL-2、IL-6、IL-8、IL-12、IL-15、IL-17、IL-18、IL-23、IL-25、***-1 (IGF-1)、KS1-4、Le-Y、LDR/FUT、巨噬细胞移动抑制因子(MIF)、MAGE、MAGE-3、MART-1、MART-2、NY-ESO-1、TRAG-3、CRP、MCP-1、MIP-1A、MIP-1B、MUC1、MUC2、MUC3、MUC4、MUC5ac、MUC13、MUC16、MUM-1/2、MUM-3、NCA66、NCA95、NCA90、胰腺癌粘蛋白、PD-1受体、胎盘生长因子、p53、PLAGL2、***酸性磷酸酶、PSA、PRAME、PSMA、PlGF、ILGF、ILGF-1R、IL-6、IL-25、RS5、RANTES、T101、SAGE、S100、存活蛋白、存活蛋白-2B、TAC、TAG-72、腱生蛋白、TRAIL受体、TNF-α、Tn抗原、Thomson-Friedenreich抗原、肿瘤坏死抗原、VEGFR、ED-B纤连蛋白、WT-1、17-1A抗原、补体因子C3、C3a、C3b、C5a、C5、血管生成标志物、bcl-2、bcl-6、Kras和癌基因产物。
32.如权利要求31所述的方法,其中所述TAA选自CD19、CD20、CD22和CD74。
33.如权利要求31所述的方法,其中所述第二抗体选自hA19、hA20、hLL1和hLL2。
34.如权利要求1所述的方法,其中所述抗HLA-DR抗体包含具有Ser241Pro取代的人重链γ4恒定区序列。
35.如权利要求1所述的方法,其中所述抗HLA-DR抗体是嵌合抗体、人源化抗体或人抗体。
36.如权利要求35所述的方法,其中所述抗HLA-DR抗体是人源化抗体,其包含轻链鼠L243 FR残基R37、K39、V48、F49和G100以及重链鼠L243 FR残基F27、K38、K46、A68和F91。
37.如权利要求1所述的方法,其中皮下施用所述抗HLA-DR-SN-38免疫缀合物。
38.如权利要求37所述的方法,其中以2至4 mg/kg的剂量施用所述免疫缀合物。
39.如权利要求37所述的方法,其中以1、2或3 ml或更少的体积施用所述免疫缀合物。
40.如权利要求37所述的方法,其中在将免疫缀合物静脉内施用于同一受试者之后,皮下施用维持剂量的所述免疫缀合物。
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PCT/US2017/045516 WO2018031408A1 (en) | 2016-08-11 | 2017-08-04 | EFFICACY OF ANTI-HLA-DR ANTIBODY DRUG CONJUGATE IMMU-140 (hL243-CL2A-SN-38) IN HLA-DR POSITIVE CANCERS |
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