CN102596245A - 无岩藻糖基化cd20抗体与苯达莫司汀的联合疗法 - Google Patents
无岩藻糖基化cd20抗体与苯达莫司汀的联合疗法 Download PDFInfo
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Abstract
本发明涉及无岩藻糖基化抗CD20抗体与苯达莫司汀用于治疗癌症的联合疗法,特别地涉及用无岩藻糖基化的人源化B-Ly1抗体和苯达莫司汀治疗表达CD20的癌症的联合疗法。
Description
本发明涉及无岩藻糖基化CD20抗体与苯达莫司汀用于治疗癌症的联合疗法。
发明背景
无岩藻糖基化的抗体
单克隆抗体的细胞介导的效应器功能可以通过工程化改造其寡糖组分来增强,如记载于P.等,Nature Biotechnol.17(1999)176-180及US6,602,684的。IgG1型抗体(即在癌症免疫疗法中最常使用的抗体)是在每个CH2域中的Asn297处具有保守的N连接的糖基化位点的糖蛋白。附着于Asn297的两个复合双触角寡糖掩埋于各CH2域间,与多肽主链形成广泛的接触,并且其存在对于抗体介导效应器功能诸如抗体依赖性细胞的细胞毒性(ADCC)是至关重要的(Lifely,M.R.等,Glycobiology 5(1995)813-822;Jefferis,R.等,Immunol.Rev.163(1998)59-76;Wright,A和Morrison,S.L.,TrendsBiotechnol.15(1997)26-32)。P.等.Nature Biotechnol.17(1999)176-180和WO99/154342显示了β(1,4)-N-乙酰葡糖胺转移酶III(“GnTIII”)(一种催化两分型寡糖形成的糖基转移酶)在中国仓鼠卵巢(CHO)细胞中的过表达显著提高抗体的体外ADCC活性。N297碳水化合物的组成变化或其消除也影响Fc结合FcγR和C1q(P.等,Nature Biotechnol.17(1999)176-180;Davies,J.等,Biotechnol.Bioeng.74(2001)288-294;Mimura,Y.等,J.Biol.Chem.276(2001)45539-45547;Radaev,S.等,J.Biol.Chem.276(2001)16478-16483;Shields,R.L.等,J.Biol.Chem.276(2001)6591-6604;Shields,R.L.等,J.Biol.Chem.277(2002)26733-26740;Simmons,L.C.等,J.Immunol.Methods 263(2002)133-147)。
已经报告了讨论无岩藻糖基化的和岩藻糖基化的抗体(包括抗CD20抗体)的活性的研究(例如Iida,S.等,Clin.Cancer Res.12(2006)2879-2887;Natsume,A.等,J.Immunol.Methods 306(2005)93-103;Satoh,M.等,ExpertOpin.Biol.Ther.6(2006)1161-1173;Kanda,Y.等,Biotechnol.Bioeng.94(2004)680-688;Davies,J.等,Biotechnol.Bioeng.74(2001)288-294。
CD20和抗CD20抗体
CD20分子(又称作人B淋巴细胞限制性分化抗原或Bp35)是一种已经广泛描述的位于前B和成熟B淋巴细胞上的疏水性跨膜蛋白(Valentine,M.A.等,J.Biol.Chem.264(1989)11282-11287;及Einfeld,D.A.等,EMBO J.7(1988)711-717;Tedder,T.F.等,Proc.Natl.Acad.Sci.U.S.A.85(1988)208-12;Stamenkovic,I.等,J.Exp.Med.167(1988)1975-80;Tedder,T.F.等,J.Immunol.142(1989)2560-8)。CD20在大于90%的B细胞非何杰金(Hodgkin)氏淋巴瘤(NHL)上表达(Anderson,K.C.等,Blood 63(1984)1424-1433)),但是在造血干细胞、原B细胞、正常的浆细胞、或其它正常的组织上没有找到(Tedder,T.F.等,J,Immunol.135(2)(1985)973-979)。
存在着在其CD20结合模式和生物学活性方面显著不同的两种不同类型的抗CD20抗体(Cragg,M.S.等,Blood 103(2004)2738-2743;及Cragg,M.S.等,Blood 101(2003)1045-1051)。I型抗体,如例如利妥昔单抗(rituximab)在补体介导的细胞毒性中是有力的,而II型抗体,如例如托西莫单抗(Tositumomab)(B1)、11B8、AT80或人源化B-Ly1抗体经由不依赖于胱天蛋白酶的凋亡及伴随的磷脂酰丝氨酸暴露而有效启动靶细胞死亡。
表1中汇总了I型和II型抗CD20抗体共享的共同特征。
表1:I型和II型抗CD20抗体的特性
苯达莫司汀(Bendamustine)
苯达莫司汀(商品名Ribomustin和Treanda;又称为SDX-105)是一种用于治疗慢性淋巴细胞性白血病(CLL)(Kath,R.等,J.Cancer Res.Clin.Oncol.127(2001)48-54)和非何杰金氏淋巴瘤(NHL)的氮芥。它属于称作烷化剂的药物的家族。还在对其研究用于治疗肉瘤(Bagchi,S.,Lancet Oncol.8(2007)674)。
已经与不同其它药剂,包括利妥昔单抗一起使用苯达莫司汀作为治疗剂(Cheson,B.D.等,J Clin Oncol.27(9)20091492-501;Knauf,W.,Expert RevAnticancer Ther.(2)9(2009)165-74;Plosker,G.L.等,Drugs.68(18)(2008)2645-60)。
发明概述
令人惊讶地,我们现在已经发现了同与非无岩藻糖基化CD20抗体利妥昔单抗的组合相比,苯达莫司汀与无岩藻糖基化抗CD20抗体的组合显示协同的(例如甚至大于叠加的)抗增殖效应。
本发明包括具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体用于制造与苯达莫司汀联合治疗癌症的药物的用途。
本发明的一方面是一种治疗患有癌症的患者的方法,其通过对需要此类治疗的患者与苯达莫司汀组合施用具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体来进行。
本发明的另一方面是具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体,其用于与苯达莫司汀联合治疗癌症。
在一个实施方案中,岩藻糖量占Asn297处的寡糖(糖)总量的40%至60%。
在另一个实施方案中,岩藻糖量占Asn297处的寡糖总量的0%。
在一个实施方案中,无岩藻糖基化抗CD20抗体是IgG1抗体。
在另一个实施方案中,所述无岩藻糖基化抗CD20抗体是人源化B-Ly1抗体,而所述癌症是表达CD20的癌症,其在一个实施方案中是B细胞非何杰金氏淋巴瘤(NHL)。
在一个实施方案中,在6周剂量周期的第1天、第8天、第15天以800至1200mg的剂量,然后在多至5个4周剂量周期的第1天以800至1200mg的剂量施用人源化B-Ly1抗体,并在多至6个4周剂量周期的第1天和第2天以80mg/m2至110mg/m2的剂量施用苯达莫司汀。
本发明的一个实施方案是一种用于治疗癌症的组合物,其包含具有60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体和苯达莫司汀。
发明详述
本发明包括IgG1或IgG3同种型的(优选地IgG1同种型的)具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体用于制造与苯达莫司汀联合治疗癌症的药物的用途。在一个实施方案中,无岩藻糖基化抗CD20抗体以10-9M至10-13mol/l的KD结合CD20。
在一个实施方案中,岩藻糖量占Asn297处的寡糖(糖)总量的40%至60%。
术语“抗体”涵盖各种抗体形式,包括但不限于完整的抗体、人抗体、人源化抗体和遗传工程抗体,如单克隆抗体、嵌合抗体或重组抗体及此类抗体的片段,只要依照本发明的特征性特性得到保留。如本文中所使用的,术语“单克隆抗体”或“单克隆抗体组合物”指单一氨基酸组成的抗体分子的制备物。因而,术语“人单克隆抗体”指具有自人种系免疫球蛋白序列衍生的可变和恒定区的展现出单一结合特异性的抗体。在一个实施方案中,人单克隆抗体是由杂交瘤生成的,所述杂交瘤包含与永生化细胞融合的自具有包含人重链转基因和人轻链转基因的基因组的转基因非人动物,例如转基因小鼠获得的B细胞。
术语“嵌合抗体”指通常通过重组DNA技术制备的包含来自一种来源或物种的可变区,即结合区和自不同来源或物种衍生的恒定区的至少一部分的单克隆抗体。包含鼠可变区和人恒定区的嵌合抗体是特别优选的。此类鼠/人嵌合抗体是包含编码鼠免疫球蛋白可变区的DNA区段和编码人免疫球蛋白恒定区的DNA区段的所表达免疫球蛋白基因的产物。本发明所涵盖的“嵌合抗体”的其它形式是那些其中类别或亚类已经自初始抗体的类别或亚类修饰或改变的。此类“嵌合”抗体又称为“类别转换抗体”。用于生成嵌合抗体的方法牵涉本领域现在公知的常规重组DNA和基因转染技术。参见例如Morrison,S.L.等,Proc.Natl.Acad Sci.USA 81(1984)6851-6855;US 5,202,238和US 5,204,244。
术语“人源化抗体”指其中的框架或“互补决定区”(CDR)已经进行过修饰以包含与亲本免疫球蛋白的特异性相比不同特异性的免疫球蛋白的CDR的抗体。在一个优选的实施方案中,将鼠CDR嫁接入人抗体的框架区中以制备“人源化抗体”。参见例如Riechmann,L.等,Nature 332(1988)323-327;及Neuberger,M.S.等,Nature 314(1985)268-270。
如本文中所使用的,术语“人抗体”意图包括具有自人种系免疫球蛋白序列衍生的可变和恒定区的抗体。人抗体是现有技术中公知的(van Dijk,M.A.和van de Winkel,J.G.,Curr.Opin.Pharmacol.5(2001)368-374)。基于此类技术,可以生成针对极其多种靶物的人抗体。人抗体的例子记载于例如Kellermann,S.A.等,Curr.Opin.Biotechnol.13(2002)593-597。
如本文中所使用的,术语“重组人抗体”意图包括通过重组手段制备、表达、创建或分离的所有人抗体,诸如自宿主细胞诸如NS0或CHO细胞或者自对于使用转染入宿主细胞中的重组表达载体表达的人免疫球蛋白基因或抗体而言转基因的动物(例如小鼠)分离的抗体。此类重组人抗体具有重排形式的自人种系免疫球蛋白序列衍生的可变和恒定区。依照本发明的重组人抗体已经进行过体内体细胞超突变。如此,重组抗体的VH和VL区的氨基酸序列是虽然自人种系VH和VL序列衍生及与其相关,但可以不天然存在于体内的人抗体种系全集内的序列。
如本文中所使用的,术语“结合”或“特异性结合”指用纯化的野生型抗原在体外测定法中,优选地在等离振子共振测定法(BIAcore,GE-HealthcareUppsala,Sweden)中抗体对肿瘤抗原的表位的结合。结合亲和力通过术语ka(来自抗体/抗原复合物的抗体的结合速率常数)、kD(解离常数)、和KD(kD/ka)限定。结合或特异性结合意指10-8mol/l或更小,优选地10-9M至10-13mol/l的结合亲和力(KD)。如此,依照本发明的无岩藻糖基化抗体以10-8mol/l或更小,优选地10-9M至10-13mol/l的结合亲和力(KD)特异性结合肿瘤抗原。
如本文中所使用的,术语“核酸分子”意图包括DNA分子和RNA分子。核酸分子可以是单链或双链,但是优选的是双链DNA。
“恒定域”不直接牵涉抗体对抗原的结合,但是牵涉效应器功能(ADCC、补体结合、和CDC)。
如本文中所使用的,“可变区”(轻链可变区(VL)、重链可变区(VH))意为直接牵涉抗体结合抗原的轻链和重链域对之每种。人轻链和重链可变域具有相同的一般结构,并且每个域包含通过三个“高变区”(或互补决定区,CDR)连接的其序列广泛保守的四个框架(FR)区。框架区采用b-片层构象,而CDR可以形成连接b-片层结构的环。每条链中的CDR通过框架区保持其三维结构,并且与来自另一条链的CDR一起形成抗原结合位点。
术语“高变区”或“抗体的抗原结合部分”在本文中使用时指抗体中负责抗原结合的氨基酸残基。高变区包含来自“互补决定区”或“CDR”的氨基酸残基。“框架”或“FR”区是与如本文中所限定的高变区残基不同的那些可变域区。因此,抗体的轻链和重链包含自N至C端的域FR1、CDR1、FR2、CDR2、FR3、CDR3、和FR4。特别地,重链的CDR3是对抗原结合贡献最大的区。CDR和FR区依照Kabat等,Sequences of Proteins of ImmunologicalInterest,第5版,Public Health Service,National Institutes of Health,Bethesda,MD(1991)的标准定义和/或那些来自“高变环”的残基来确定。
苯达莫司汀是4-[5-[二(2-氯乙基)氨基]-1-甲基苯并咪唑-2-基]丁酸。商品名是Ribomustin和Treanda;苯达莫司汀又称为SDX-105)。苯达莫司汀是一种用于治疗慢性淋巴细胞性白血病(CLL)(Kath,R.等,J.Cancer Res.Clin.Oncol.127(2001)48-54)和非何杰金氏淋巴瘤(NHL)的氮芥。它属于称作烷化剂的药物的家族。还在对其研究用于治疗肉瘤(Bagchi,S.,Lancet Oncol.8(2007)674)。
术语“无岩藻糖基化抗体”指在Fc区中在Asn297处具有改变的糖基化样式且具有降低的岩藻糖残基水平的IgG1或IgG3同种型的(优选地IgG1同种型的)抗体。在Asn297处发生人IgG1或IgG3的糖基化,作为以多至两个Gal残基为末端的核心岩藻糖化双触角复合寡糖糖基化。根据末端Gal残基的量,这些结构称为G0、G1(α1,6或α1,3)或G2聚糖残基(Raju,T.S.,BioProcess Int.1(2003)44-53)。抗体Fc部分的CHO型糖基化例如由Routier,F.H.,Glycoconjugate J.14(1997)201-207描述。在非糖修饰的CHO宿主细胞中重组表达的抗体在Asn297处通常以至少85%的量进行岩藻糖基化。应当理解,如本文中所使用的,术语无岩藻糖基化抗体包括在其糖基化样式中没有岩藻糖的抗体。通常已知的是,抗体中典型的糖基化残基位置是依照EU编号系统的第297位的天冬酰胺(“Asn297”)。
“EU编号系统”或“EU索引”一般在提及免疫球蛋白重链恒定区中的残基时使用(例如Kabat等,Sequences of Proteins of Immunological Interest,第5版,Public Health Service,National Institutes of Health,Bethesda,MD(1991)中报告的EU索引,通过提及而将其明确收入本文)。
如此,依照本发明的无岩藻糖基化抗体意指其中的岩藻糖量占Asn297处的寡糖(糖)总量的60%或更少(这意味着在Fc区中Asn297处的寡糖的至少40%或更多是无岩藻糖基化的)的IgG1或IgG3同种型的(优选地IgG1同种型的)抗体。在一个实施方案中,岩藻糖量占Fc区中Asn297处的寡糖的40%至60%。在另一个实施方案中,岩藻糖量是50%或更小,并且在又一个实施方案中,岩藻糖量占Fc区中Asn297处的寡糖的30%或更小。在一个备选的实施方案中,岩藻糖量占Fc区中Asn297处的寡糖的0%。依照本发明,“岩藻糖的量”意指通过MALDI-TOF质谱术测量的,并以平均值计算的,相对于附着于Asn297的所有寡糖(糖)(例如复合的、杂合的和高甘露糖结构)的总和,Asn297处寡糖(糖)链内所述寡糖(岩藻糖)的量(测定岩藻糖量的详细规程记载于例如WO 2008/077546)。此外,在一个实施方案中,Fc区的寡糖是两分的。可以在工程化改造成表达至少一种核酸的糖修饰的宿主细胞中表达依照本发明的无岩藻糖基化抗体,所述核酸编码具有GnTIII活性的多肽,其量足以部分岩藻糖基化Fc区中的寡糖。在一个实施方案中,具有GnTIII活性的多肽是融合多肽。或者,可以依照US 6,946,292降低或消除宿主细胞的α1,6-岩藻糖基转移酶活性以生成糖修饰的宿主细胞。可以例如通过发酵条件(例如发酵时间)或者通过组合至少两种具有不同岩藻糖基化量的抗体来预先确定抗体岩藻糖基化的量。此类无岩藻糖基化抗体及相应的糖工程方法记载于WO 2005/044859,WO 2004/065540,WO 2007/031875,Umana,P.等,Nature Biotechnol.17(1999)176-180,WO 99/154342,WO 2005/018572,WO2006/116260,WO 2006/114700,WO 2005/011735,WO 2005/027966,WO97/028267,US2006/0134709,US2005/0054048,US2005/0152894,WO2003/035835,WO 2000/061739。这些糖工程抗体具有升高的ADCC。依照本发明产生无岩藻糖基化抗体的其它糖工程方法记载于例如Niwa,R.等,J.Immunol.Methods 306(2005)151-160;Shinkawa,T.等,J.Biol.Chem.278(2003)3466-3473;WO 03/055993或US2005/0249722。
如此,本发明的一方面是IgG1或IgG3同种型的(优选地IgG1同种型的),特异性结合CD20的,具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体用于制造与苯达莫司汀联合治疗癌症的药物的用途。在一个实施方案中,岩藻糖量占Asn297处的寡糖(糖)总量的40%至60%。
CD20(又称为B淋巴细胞抗原CD20、B淋巴细胞表面抗原B1、Leu-16、Bp35、BM5、和LF5;序列以SwissProt数据库条目P11836为特征)是一种位于前B和成熟B淋巴细胞上的具有约35kD分子量的疏水性跨膜蛋白(Valentine,M.A.等,J.Biol.Chem.264(19)(1989)11282-11287;Tedder,T.F.等,Proc.Natl.Acad.Sci.U.S.A.85(1988)208-212;Stamenkovic,I.等,J.Exp.Med.167(1988)1975-80;Einfeld,D.A.等,EMBO J.7(1988)711-7;Tedder,T.F.等,J.Immunol.142(1989)2560-2568)。相应的人基因是4次跨膜域,A亚家族,成员1,又称为MS4A1。此基因编码跨膜4A基因家族的成员。此初生蛋白质家族的成员以共同的结构特征和相似的内含子/外显子剪接边界为特征,并且在造血细胞和非淋巴样组织中展现出独特的表达样式。此基因编码B淋巴细胞表面分子,其在B细胞发育及分化成浆细胞中发挥作用。在家族成员的簇中,此家族成员定位于11q12。此基因的可变剪接产生编码同一蛋白质的两种转录物变体。
术语“CD20”和“CD20抗原”在本文中可互换使用,包括由细胞天然表达的或者在用CD20基因转染的细胞上表达的人CD20的任何变体、同等型和物种同系物。本发明的抗体对CD20抗原的结合通过灭活CD20而介导对表达CD20的细胞(例如,肿瘤细胞)的杀伤。可以通过下列一项或多项机制而发生对表达CD20的细胞的杀死:细胞死亡/凋亡诱导、ADCC和CDC。
如本领域中认可的,CD20的同义词包括B淋巴细胞抗原CD20、B淋巴细胞表面抗原B1、Leu-16、Bp35、BM5、和LF5。
依照本发明的术语“抗CD20抗体”是特异性结合CD20抗原的抗体。根据针对CD20抗原的抗CD20抗体的结合特性和生物学活性,两种类型的抗CD20抗体(I型和II型抗CD20抗体)可以依照Cragg,M.S.等,Blood 103(2004)2738-2743;及Cragg,M.S.等,Blood 101(2003)1045-1051区别,参见表2。
表2:I型和II型抗CD20抗体的特性
II型抗CD20抗体的例子包括例如人源化B-Ly1抗体IgG1(一种嵌合的人源化IgG1抗体,如披露于WO 2005/044859中的)、11B8 IgG1(如披露于WO2004/035607中的)、和AT80 IgG1。通常,IgG1同种型的II型抗CD20抗体显示特征性的CDC特征。与IgG1同种型的I型抗体相比,II型抗CD20抗体具有降低的CDC(若为IgG1同种型的话)。
I型抗CD20抗体的例子包括例如利妥昔单抗、HI47 IgG3(ECACC,杂交瘤)、2C6 IgG1(如披露于WO 2005/103081中的)、2F2 IgG1(如披露于WO 2004/035607和WO 2005/103081的)和2H7 IgG1(如披露于WO2004/056312中的)。
依照本发明的无岩藻糖基化抗CD20抗体在一个实施方案中是II型抗CD20抗体,在一个更具体的实施方案中,II型抗CD20抗体是无岩藻糖基化的人源化B-Ly1抗体。
与没有降低岩藻糖的抗CD20抗体不一样,依照本发明的无岩藻糖基化抗CD20抗体具有升高的抗体依赖性细胞的细胞毒性(ADCC)。
“具有升高的抗体依赖性细胞的细胞毒性(ADCC)的无岩藻糖基化抗CD20抗体”意指具有如通过本领域普通技术人员已知的任何合适的方法测定的升高的ADCC的无岩藻糖基化抗CD20抗体,如该术语在本文中所定义的。一种公认的体外ADCC测定法如下:
1)该测定法使用已知表达被抗体的抗原结合区识别的靶抗原的靶细胞;
2)该测定法使用自随机选定的健康供体的血液分离的人外周血单个核细胞(PBMC)作为效应细胞;
3)依照下列方案来实施测定法:
i)使用标准的密度离心规程来分离PBMC,并将其以5x 106个细胞/ml在RPMI细胞培养基中悬浮;
ii)将靶细胞通过标准的组织培养方法来培养,自具有高于90%的存活力的指数生长期收获,在RPMI细胞培养基中清洗,用100微居里51Cr标记,用细胞培养基清洗两次,并以105个细胞/ml的密度在细胞培养基中重悬浮;
iii)将100微升上述最终靶细胞悬浮液转移至96孔微量滴定板的每孔;
iv)将抗体在细胞培养基中自4000ng/ml连续稀释至0.04ng/ml,并将50微升所得的抗体溶液添加至96孔微量滴定板中的靶细胞,一式三份测试覆盖上述整个浓度范围的多种抗体浓度;
v)对于最大释放(MR)对照,含有经标记的靶细胞的平板中的3个另外的孔接受50微升非离子型去污剂(Nonidet,Sigma,St.Louis)的2%(VN)水溶液,代替抗体溶液(上述第iv点);
vi)对于自发释放(SR)对照,含有经标记的靶细胞的平板中的3个另外的孔接受50微升RPMI细胞培养基,代替抗体溶液(上述第iv点);
vii)然后,将96孔微量滴定板以50x g离心1分钟,并于4℃温育1小时;
viii)将50微升PBMC悬浮液(上述第i点)添加至每孔以产生效应:靶细胞比率25∶1,并将平板在培养箱中在5%CO2气氛下于37℃放置4小时;
ix)收获来自每孔的无细胞上清液,并使用γ计数器来量化实验释放的放射性(ER);
x)依照公式(ER-MR)/(MR-SR)x 100对每个抗体浓度计算特异性溶解的百分比,其中ER是对所述抗体浓度量化(参见上述第ix点)的平均放射性,MR是对MR对照(参见上述第v点)量化(参见上述第ix点)的平均放射性,而SR是对SR对照(参见上述第vi点)量化(参见上述第ix点)的平均放射性;
4)“升高的ADCC”定义为上文测试的抗体浓度范围内观察到的特异性溶解的最大百分比的增加和/或达到上文测试的抗体浓度范围内观察到的特异性溶解的最大百分比的一半所需要的抗体浓度降低。ADCC的升高相对于用上述测定法测量的,使用本领域技术人员已知的相同的标准生成、纯化、配制和贮存方法,由相同类型的宿主细胞产生的,但是并非由工程化改造成过表达GnTIII的宿主细胞产生的相同抗体介导的ADCC。
可以通过所述抗体的糖工程来获得所述“升高的ADCC”,其意味着通过工程化改造其寡糖组分来增强单克隆抗体的所述天然的、细胞介导的效应器功能,如记载于Umana,P.等,Nature Biotechnol.17(1999)176-180及US6,602,684的。
术语“补体依赖性细胞毒性(CDC)”指在存在补体的情况中依照本发明的抗体对人肿瘤靶细胞的溶解。优选地,通过在存在补体的情况中用依照本发明的抗CD20抗体处理表达CD20的细胞的制备物来测量CDC。若抗体在浓度100nM时在4小时后诱导20%或更多的肿瘤细胞溶解(细胞死亡),则发现CDC。优选地,用经51Cr或Eu标记的肿瘤细胞及释放的51Cr或Eu测量来实施测定法。对照包括将肿瘤靶细胞与补体但不与抗体一起温育。
“利妥昔单抗”抗体(参照抗体;I型抗CD20抗体的例子)是一种针对人CD20抗原的含有遗传工程嵌合人γ1鼠恒定域的单克隆抗体。此嵌合抗体含有人γ1恒定域,并且以1998年4月17日公告的归于IDEC PharmaceuticalsCorporation的US 5,736,137(Andersen等)中的名称“C2B8”鉴定。利妥昔单抗批准用于治疗复发性或顽固性低度或滤泡性、CD20阳性、B细胞非何杰金氏淋巴瘤患者。体外作用机制研究已经显示了利妥昔单抗展现出人补体依赖性细胞毒性(CDC)(Reff,M.E等,Blood 83(2)(1994)435-445)。另外,它在测量抗体依赖性细胞的细胞毒性(ADCC)的测定法中展现出显著的活性。利妥昔单抗不是无岩藻糖基化的。
术语“人源化B-Ly1抗体”指如WO 2005/044859和WO 2007/031875中所披露的人源化B-Ly1抗体,其通过用来自IgG1的人恒定域嵌合化及接着的人源化自鼠单克隆抗CD20抗体B-Ly1(鼠重链可变区(VH):SEQ ID NO:1;鼠轻链可变区(VL):SEQ ID NO:2,参见Poppema,S.和Visser,L.,Biotest Bulletin3(1987)131-139)获得(参见WO 2005/044859和WO2007/031875)。这些“人源化B-Ly1抗体”详细披露于WO 2005/044859和WO 2007/031875中。
在一个实施方案中,“人源化B-Ly1抗体”具有选自下组的重链可变区(VH):SEQ ID NO:3至SEQ ID NO:20(WO 2005/044859和WO 2007/031875的B-HH2至B-HH9和B-HL8至B-HL17)。特别优选的是Seq.ID No.3、4、7、9、11、13和15(WO 2005/044859和WO 2007/031875的B-HH2、B-HH3、B-HH6、B-HH8、B-HL8、B-HL11和B-HL13)。在一个具体的实施方案中,“人源化B-Ly1抗体”具有轻链可变区(VL)SEQ ID No:20(WO 2005/044859和WO2007/031875的B-KV1)。在另一个具体的实施方案中,“人源化B-Ly1抗体”具有重链可变区(VH)SEQ ID NO:7(WO 2005/044859和WO 2007/031875的B-HH6)和轻链可变区(VL)SEQ ID No:20(WO 2005/044859和WO2007/031875的B-KV1)。此外,在一个实施方案中,人源化B-Ly1抗体是IgG1抗体。依照本发明,依照记载于WO 2005/044859、WO 2004/065540、WO2007/031875、Umana,P.等,Nature Biotechnol.17(1999)176-180及WO99/154342中的规程在Fc区中糖工程化改造(GE)此类无岩藻糖基化的人源化B-Ly1抗体。在本发明的一个实施方案中,所使用的抗CD20抗体是无岩藻糖基化的糖工程人源化B-Ly1,称为B-HH6-B-KV1 GE。此类糖工程人源化B-Ly1抗体在Fc区中具有改变的糖基化样式,优选地具有降低的岩藻糖残基水平。在一个实施方案中,岩藻糖量占Asn297处的寡糖总量的60%或更少(在一个实施方案中,岩藻糖的量是40%至60%,在另一个实施方案中,岩藻糖的量是50%或更少,且在又一个实施方案中,岩藻糖的量是30%或更少,且在又一个实施方案中,岩藻糖的量是0%。此外,在一个具体的实施方案中,Fc区的寡糖是两分的。这些糖工程人源化B-Ly1抗体具有升高的ADCC。
寡糖组分可以显著影响与治疗性糖蛋白的功效有关的特性,包括物理稳定性、对蛋白酶攻击的抗性、与免疫系统的相互作用、药动学、和特定(specific)生物学活性。此类特性可能不仅取决于寡糖的存在或缺乏,而且还取决于寡糖的特定结构。可以做出寡糖结构与糖蛋白功能间的一些概括。例如,某些寡糖结构经由与特定碳水化合物结合蛋白的相互作用而介导糖蛋白自血流的快速清除,而其它寡糖结构可以被抗体结合,并触发不想要的免疫反应(Jenkins,N.等,Nature Biotechnol.14(1996)975-981)。
由于哺乳动物细胞以对于人应用最相容的形式糖基化蛋白质的性能,它是用于生成治疗性糖蛋白的卓越的宿主(Cumming,D.A.等,Glycobiology 1(1991)115-30;Jenkins,N.等,Nature Biotechnol.14(1996)975-981)。细菌糖基化蛋白质非常罕见,并且与其它类型的常见宿主,诸如酵母、丝状真菌、昆虫和植物细胞一样,其产生与自血流快速清除、不想要的免疫相互作用、和(在一些特定的情况中)降低的生物学活性有关的糖基化样式。在哺乳动物细胞中,在过去二十年期间最常使用中国仓鼠卵巢(CHO)细胞。在给予合适的糖基化样式外,这些细胞容许遗传稳定的、高生产性克隆细胞系的一致生成。它们可以使用无血清培养基在简单的生物反应器中培养至高密度,并容许开发安全且可再现的生物工艺。其它通常使用的动物细胞包括幼仑鼠肾(BHK)细胞、NSO和SP2/0小鼠骨髓瘤细胞。新近,还已经测试了自转基因动物的生成(Jenkins,N.等,Nature Biotechnol.14(1996)975-981)。
所有抗体在重链恒定区中的保守位置处都含有碳水化合物结构,其中每种同种型拥有独特的一批N连接的碳水化合物结构,其易变地影响蛋白质装配、分泌或功能性活性(Wright,A.和Monison,S.L.,Trends Biotech.15(1997)26-32)。根据加工程度,附着的N连接的碳水化合物结构变化得相当大,并且可以包括高甘露糖的、多分支的及双触角的复合寡糖(Wright,A.和Morrison,S.L.,Trends Biotech.15(1997)26-32)。通常,存在着特定糖基化位点处附着的核心寡糖结构的异质加工,使得甚至单克隆抗体以多种糖形存在。同样地,已经显示了细胞系间存在抗体糖基化的主要差异,而且甚至对不同培养条件下培养的给定细胞系看到次要差异(Lifely,M.R.等,Glycobiology 5(8)(1995)813-22。
一种在维持简单的生成过程并潜在地避免显著的、不想要的副作用的情况中获得效力大幅升高的方式是通过工程化改造单克隆抗体的寡糖组分来增强其天然的、细胞介导的效应器功能,如记载于Umana,P.等,NatureBiotechnol.17(1999)176-180及US 6,602,684的。IgG1型抗体(即在癌症免疫疗法中最常使用的抗体)是在每个CH2域中的Asn297处具有保守的N连接的糖基化位点的糖蛋白。附着于Asn297的两个复合双触角寡糖掩埋于各CH2域间,与多肽主链形成广泛的接触,并且其存在对于抗体介导效应器功能诸如抗体依赖性细胞的细胞毒性(ADCC)是至关重要的(Lifely,M.R.等,Glycobiology 5(1995)813-822;Jefferis,R.等,Immunol.Rev.163(1998)59-76;Wright,A和Morrison,S.L.,Trends Biotechnol.15(1997)26-32)。
先前显示了β(1,4)-N-乙酰葡糖胺转移酶I11(“GnTII17y”)(一种催化两分型寡糖形成的糖基转移酶)在中国仓鼠卵巢(CHO)细胞中的过表达显著提高由工程化改造的CHO细胞生成的抗成神经细胞瘤嵌合单克隆抗体(chCE7)的体外ADCC活性。(参见Umana,P.等,Nature Biotechnol.17(1999)176-180;及WO 99/154342,在此通过提及而收录其全部内容)。抗体chCE7属于具有高肿瘤亲和力和特异性,但是在缺乏GnTIII酶的标准工业细胞系中生产时具有太少的效力以致在临床上无用的一大类未缀合的单克隆抗体(Umana,P.等,Nature Biotechnol.17(1999)176-180)。所述研究第一次显示了可以通过工程化改造抗体生成细胞以表达GnTIII来获得ADCC活性的大幅升高,其还导致恒定区(Fc)结合的两分型寡糖(包括两分型非岩藻糖基化寡糖)比例的增加,高于天然存在的抗体中找到的水平。
如本文中所使用的,术语“癌症”包括淋巴瘤、淋巴细胞性白血病、肺癌、非小细胞肺(NSCL)癌、细支气管肺泡细胞肺癌、骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃癌(stomachcancer)、胃癌(gastric cancer)、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、何杰金(Hodgkin)氏病、食管癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、膀胱癌、肾或输尿管癌、肾细胞癌、肾盂癌、间皮瘤、肝细胞癌、胆癌(biliary cancer)、中枢神经系统(CNS)新生物、脊柱轴肿瘤、脑干胶质瘤、多形性成胶质细胞瘤(glioblastoma multiforme)、星形细胞瘤、神经鞘瘤(schwanoma)、室鼓膜瘤(ependymona)、髓母细胞瘤、脑脊膜瘤、鳞状细胞癌、垂体腺瘤,包括任何上述癌症的顽固性型式、或一种或多种上述癌症的组合。在一个实施方案中,术语癌症指表达CD20的癌症。
术语“表达CD20”抗原意图指示分别来自肿瘤或癌症,优选地非实体瘤的细胞中,优选地在T或B细胞,更优选地B细胞的细胞表面上的CD20抗原的显著水平的表达。可以通过本领域已知的标准测定法来确定患有“表达CD20的癌症”的患者。例如,可以使用免疫组织化学(IHC)检测、FACS或者经由相应mRNA的基于PCR的检测来测量CD20抗原表达。
如本文中所使用的,术语“表达CD20的癌症”指癌细胞显示CD20抗原表达的所有癌症。优选地,如本文中所使用的表达CD20的癌症指淋巴瘤(优选地B细胞非何杰金氏淋巴瘤(NHL))和淋巴细胞性白血病。此类淋巴瘤和淋巴细胞性白血病包括例如a)滤泡性淋巴瘤、b)小无核裂细胞淋巴瘤(SmallNon-Cleaved Cell Lymphoma)/伯基特(Burkitt)氏淋巴瘤(包括地方性伯基特氏淋巴瘤、散发性伯基特氏淋巴瘤和非伯基特氏淋巴瘤)、c)边缘区淋巴瘤(包括结外边缘区B细胞淋巴瘤(粘膜相关淋巴组织淋巴瘤,MALT)、结边缘区B细胞淋巴瘤和脾边缘区淋巴瘤)、d)套细胞淋巴瘤(MCL)、e)大细胞淋巴瘤(包括B细胞弥漫性大细胞淋巴瘤(DLCL)、弥漫性混合细胞淋巴瘤、免疫母细胞性淋巴瘤、原发性纵隔B细胞淋巴瘤、血管中心性淋巴瘤-肺B细胞淋巴瘤)、f)毛细胞白血病、g)淋巴细胞性淋巴瘤、瓦尔登斯特伦(waldenstrom)氏巨球蛋白血症、h)急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)/小淋巴细胞性淋巴瘤(SLL)、B细胞幼淋巴细胞白血病、i)浆细胞新生物、浆细胞骨髓瘤、多发性骨髓瘤、浆细胞瘤、j)何杰金氏病。
在一个别的实施方案中,表达CD20的癌症是B细胞非何杰金氏淋巴瘤(NHL)。在另一个实施方案中,表达CD20的癌症是套细胞淋巴瘤(MCL)、急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、B细胞弥漫性大细胞淋巴瘤(DLCL)、伯基特氏淋巴瘤、毛细胞白血病、滤泡性淋巴瘤、多发性骨髓瘤、边缘区淋巴瘤、移植后淋巴增殖性病症(PTLD)、HIV有关的淋巴瘤、瓦尔登斯特伦氏巨球蛋白血症、或原发性CNS淋巴瘤。
术语“治疗方法”或其等同用语在应用于例如癌症时指设计为降低或消除患者中的癌细胞数目,或者减轻癌症症状的规程或作用过程。癌症或另一种增殖性病症的“治疗方法”不必意味着实际上会消除癌细胞或其它病症,实际上会降低细胞数目或病症,或实际上会减轻癌症或其它病症的症状。经常,甚至会实施具有较低的成功概率,但是然而鉴于医学史和估计的患者存活预期认为诱导总体有益的作用过程的治疗癌症的方法。
术语“共施用”指施用所述无岩藻糖基化抗CD20和苯达莫司汀作为一种单一配制剂或者作为两种不同配制剂。共施用可以是同时的或者以任意次序序贯的,其中优选地,存在着所有活性剂同时施加其生物学活性的时段。同时或序贯(例如经由静脉内(i.v)经由连续输注(对于抗CD20抗体一次,及最终对于苯达莫司汀一次))共施用所述无岩藻糖基化抗CD20抗体和苯达莫司汀。在序贯共施用这两种治疗剂时,在同一天在两次分开的施用中施用剂量,或者在第1天施用药剂之一,而在第2天至第7天,优选地在第2天至第4天共施用第二种。如此,术语“序贯地”意指在第一组分(苯达莫司汀或抗体)的剂量后7天内,优选地在第一组分的剂量后4天内;而术语“同时地”意指同时。术语“共施用”就所述无岩藻糖基化抗CD20抗体和苯达莫司汀的维持剂量而言意指若治疗周期对于这两种药物都是合适的,例如每周,则可以或是同时共施用维持剂量。或者,例如,例如每第一至第三天施用苯达莫司汀,而每周施用所述无岩藻糖基化抗体。或者,在一天内或在几天内序贯共施用维持剂量。
不证自明的是,以“治疗有效量”(或仅为“有效量”)对患者施用抗体,所述治疗有效量是各种化合物或组合会引发研究人员、兽医、医学医生或其它临床医生寻找的组织、系统、动物或人的生物学或医学应答的量。
所述抗CD20无岩藻糖基化的抗体和苯达莫司汀的共施用量和共施用时机会取决于所治疗患者的类型(物种、性别、年龄、重量、等)和状况和所治疗疾病或状况的严重性。可以一次或在一系列治疗里对患者适当地共施用所述无岩藻糖基化抗CD20抗体和苯达莫司汀。
若施用是静脉内的,则所述无岩藻糖基化抗CD20抗体或苯达莫司汀的初始输注时间可以比随后的输注时间长,例如初始输注为约90分钟,而随后的输注为约30分钟(若初始输注耐受良好的话)。
根据疾病的类型和严重性,约1μg/kg至50mg/kg(例如0.1-20mg/kg)所述无岩藻糖基化抗CD20抗体和1μg/kg至50mg/kg(例如0.1-20mg/kg)苯达莫司汀是对患者共施用这两种药物的初始候选剂量。在一个实施方案中,所述无岩藻糖基化抗CD20抗体(优选地无岩藻糖基化的人源化B-Ly1抗体)的优选剂量会在约0.05mg/kg至约30mg/kg的范围中。如此,可以对患者共施用约0.5mg/kg、2.0mg/kg、4.0mg/kg、10mg/kg或30mg/kg(或其任何组合)的一剂或多剂。在一个实施方案中,苯达莫司汀的剂量会在0.01mg/kg至约30mg/kg,例如0.1mg/kg至10.0mg/kg的范围中。根据患者的类型(物种、性别、年龄、重量、等)和状况及无岩藻糖基化抗CD20抗体的类型,所述无岩藻糖基化抗体和苯达莫司汀的剂量和施用日程表可以有所不同,例如,可以例如每1至3周施用所述无岩藻糖基化抗CD20抗体,并且可以每天或每2至10天施用苯达莫司汀。也可以施用较高的初始加载剂量,接着是较低的一剂或多剂。
在一个优选的实施方案中,所述无岩藻糖基化抗CD20抗体(优选地,无岩藻糖基化的人源化B-Ly1抗体)的优选剂量会是在6周剂量周期的第1天、第8天、第15天的800至1200mg,然后是多至5个4周剂量周期的第1天的800至1200mg的剂量,而苯达莫司汀的优选剂量会是例如在多至6个4周剂量周期的第1天和第2天(在第1天和第2天在30分钟里静脉内输注)的80mg/m2至110mg/m2(在一个实施方案中为110mg/m2,在另一个实施方案中为90mg/m2)。或者,所述无岩藻糖基化抗CD20抗体的剂量可以是在多至8个3周剂量周期的第1天的800至1200mg(例如1000mg)。
在一个实施方案中,药物可用于预防或降低患有癌症,优选地表达CD20的癌症的此类患者中的转移或进一步散布。药物可用于延长此类患者的存活持续时间,延长此类患者的无进展存活,延长响应的持续时间,导致经治疗的患者的统计学显著的且临床上有意义的改善,如通过存活的持续时间、无进展存活、响应率或响应的持续时间所测量的。在一个具体的实施方案中,药物可用于提高患者组中的响应率。
在本发明的上下文中,可以在无岩藻糖基化抗CD20抗体和苯达莫司汀的癌症联合治疗中使用额外的其它细胞毒剂、化疗剂或抗癌剂、或增强此类药剂的效果的化合物(例如细胞因子)。合适地,此类分子以对于意图的目的有效的量组合存在。在一个实施方案中,所述无岩藻糖基化抗CD20抗体和苯达莫司汀联合治疗不与所述额外的细胞毒剂、化疗剂或抗癌剂、或增强此类药剂的效果的化合物一起使用。
此类药剂包括例如:烷化剂或具有烷基化作用的药剂,诸如环磷酰胺(cyclophosphamide)(CTX;例如cytoxan)、苯丁酸氮芥(chlorambucil)(CHL;例如瘤可宁(leukeran))、顺铂(cisplatin)(CisP;例如platinol)、白消安(busulfan)(例如,马利兰(myleran))、美法仑(melphalan)、卡莫司汀(carmustine)(BCNU)、链脲菌素(streptozotocin)、三乙烯三聚氰胺(triethylenemelamine)(TEM)、丝裂霉素C(mitomycin C),等等;抗代谢物,诸如甲氨蝶呤(methotrexate)(MTX)、依托泊苷(etoposide)(VP16;例如凡毕士(vepesid))、6-巯嘌呤(6-mercaptopurine)(6MP)、6-硫鸟嘌呤(6-thiocguanine)(6TG)、阿糖胞苷(cytarabine)(Ara-C)、5-氟尿嘧啶(5-fluorouracil)(5-FU)、卡培他滨(capecitabine)(例如,希罗达(Xeloda))、达卡巴嗪(dacarbazine)(DTIC),等等;抗生素,诸如放线菌素D(actinomycin D)、多柔比星(doxorubicin)(DXR;例如阿霉素(adriamycin))、柔红霉素(daunorubicin)(道诺霉素(daunomycin))、博来霉素(bleomycin)、光神霉素(mithramycin),等等;生物碱,诸如长春花生物碱诸如长春新碱(vincristine)(VCR)、长春碱(vinblastine),等等;及其它抗肿瘤剂,诸如帕西他赛(paclitaxel)(例如泰素(taxol))和帕西他赛衍生物、细胞抑制剂、糖皮质激素诸如地塞米松(dexamethasone)(DEX;例如地卡特隆(decadron))和皮质类固醇诸如泼尼松(prednisone)、核苷酶抑制剂诸如羟基脲、氨基酸消减酶(amino acid depleting enzyme)诸如天冬酰胺酶、甲酰四氢叶酸(leucovorin)和其它叶酸衍生物、和相似的多种多样的抗肿瘤剂。也可以使用下列药剂作为额外的药剂:氨磷汀(arnifostine)(例如ethyol)、更生霉素(dactinomycin)、双氯乙基甲胺(mechlorethamine)(氮芥)、链佐星(streptozocin)、环磷酰胺(cyclophosphamide)、洛莫司汀(lomustine)(CCNU)、多柔比星脂质体(doxorubicin lipo)(例如,doxil)、吉西他滨(gemcitabine)(例如健择(gemzar))、柔红霉素脂质体(daunorubicin lipo)(例如daunoxome)、丙卡巴肼(procarbazine)、丝裂霉素(mitomycin)、多西他赛(docetaxel)(例如泰索帝(taxotere))、阿地白介素(aldesleukin)、卡铂(carboplatin)、奥沙利铂(oxaliplatin)、克拉屈滨(cladribine)、喜树碱(camptothecin)、CPT 11(伊立替康(irinotecan))、10-羟基7-乙基-喜树碱(SN38)、氟尿苷(floxuridine)、氟达拉滨(fludarabine)、异环磷酰胺(ifosfamide)、伊达比星(idarubicin)、美司钠(mesna)、干扰素β、干扰素α、米托蒽醌(mitoxantrone)、托泊替康(topotecan)、亮丙瑞林(leuprolide)、甲地孕酮(megestrol)、美法仑(melphalan)、巯嘌呤、普卡霉素(plicamycin)、米托坦(mitotane)、培门冬酶(pegaspargase)、喷司他丁(pentostatin)、哌泊溴烷(pipobroman)、普卡霉素(plicamycin)、他莫昔芬(tamoxifen)、替尼泊苷(teniposide)、睾内酪(testolactone)、硫鸟嘌呤(thioguanine)、塞替派(thiotepa)、尿嘧啶芥(uracilmustard)、长春瑞滨(vinorelbine)、苯丁酸氮芥(chlorambucil)。优选地,无岩藻糖基化抗CD20抗体和苯达莫司汀联合治疗不与此类额外的药剂一起使用。
上文所描述的细胞毒剂和抗癌剂及抗增殖性靶物特异性抗癌药物,如蛋白质激酶抑制剂在化学疗法方案中的使用一般在癌症疗法领域中得到充分表征,并且其在本文中的使用归入关于监测耐受性和效力及关于控制施用路径和剂量的相同考虑,伴有一些调整。例如,细胞毒剂的实际剂量可以随通过使用组织培养方法测定的患者的培养细胞应答而变化。一般地,与在没有额外的其它药剂的情况中使用的量相比,剂量会是降低的。
有效细胞毒剂的典型剂量可以在制造商推荐的范围中,并且在通过体外应答或动物模型中的应答指示的情况中,可以降低多至约一个数量级的浓度或量。如此,实际剂量会取决于内科医生的判断、患者的状况、和治疗方法的效力,其基于原代培养的恶性细胞或组织培养组织样品的体外响应性,或合适的动物模型中观察到的响应。
在本发明的上下文中,在表达CD20的癌症的无岩藻糖基化抗CD20抗体和苯达莫司汀联合治疗外,可以实施有效量的电离辐射和/或可以使用放射性药物。放射源可以是在所治疗的患者外部或内部。在来源在患者外部时,已知疗法为外部束放射疗法(EBRT)。在放射源在患者内部时,治疗称作近程治疗(BT)。本发明的上下文中使用的放射性原子可以选自下组,包括但不限于镭、铯-137、铱-192、镅-241、金-198、钴-57、铜-67、锝-99、碘-123、碘-131、和碘-111。也有可能用此类放射性同位素标记抗体。优选地,无岩藻糖基化抗CD20抗体和苯达莫司汀联合治疗不与此类电离辐射一起使用。
放射疗法是一种用于控制不可切除的或不能手术的肿瘤和/或肿瘤转移的标准治疗。已经在组合放射疗法与化学疗法时看到改善的结果。放射疗法基于如下的原则,即对靶区域投递的高剂量放射会导致肿瘤和正常组织两者中的生殖细胞(reproductive cell)死亡。放射剂量方案一般在放射吸收剂量(Gy)、时间和分级方面限定,并且必须由肿瘤学家仔细限定。患者接受的放射量会取决于各种考虑因素,但是两项最重要的是肿瘤相对于身体的其它重要结构或器官的位置和肿瘤已经扩散的程度。经历放射疗法的患者的典型治疗过程会是在1至6周时段里的治疗日程表,以单一每日分数约1.8至2.0Gy一周5天对患者施用10-80Gy的总剂量。在本发明的一个优选的实施方案中,在用本发明的联合治疗和放射治疗人患者中的肿瘤时存在着协同。换言之,在与放射,任选地有额外的化学治疗剂或抗癌剂组合时,依靠构成本发明的组合的药剂对肿瘤生长的抑制得到增强。例如,辅助放射疗法的参数包含在WO99/60023中。
可以依照已知的方法,诸如通过静脉内施用(以推注或者通过在一段时间里连续输注),通过肌肉内、腹膜内、脑脊髓内、皮下、关节内、滑膜内、或鞘内路径对患者施用无岩藻糖基化抗CD20抗体。在一个实施方案中,此类抗体通过静脉内或皮下施用来施用。
依照已知的方法,例如通过静脉内施用(以推注或者通过在一段时间里连续输注),通过肌肉内、腹膜内、脑脊髓内、皮下、关节内、滑膜内、鞘内、或经口路径对患者施用苯达莫司汀。依照一个实施方案,通过静脉内或腹膜内施用来施用此类抗体。
如本文中所使用的,“药学可接受载体”意图包括与药学施用相容的任何和所有材料,包括溶剂、分散介质、涂层材料、抗细菌和抗真菌剂、等张和吸收延迟剂、和与药学施用相容的其它材料和化合物。除非任何常规的介质或药剂与活性化合物不相容,涵盖其在本发明的组合物中的用途。也可以将补充的活性化合物掺入组合物中。
药物组合物:
可以通过用药学可接受的无机或有机载体加工依照本发明的抗CD20抗体和/或苯达莫司汀来获得药物组合物。可以使用乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等,例如诸如片剂、包衣片剂、锭剂和硬明胶胶囊的载体。适合于软明胶胶囊的载体是例如植物油、蜡、脂肪、半固体和液体多元醇等。然而,根据活性物质的性质,通常在软明胶胶囊的情况中不需要载体。适合于生成溶液和糖浆剂的载体是例如水、多元醇、甘油、植物油等。适合于栓剂的载体是例如天然的或硬化的油、蜡、脂肪、半液体或液体多元醇等。
此外,药物组合物可以含有防腐剂、增溶剂、稳定剂、湿润剂、乳化剂、增甜剂、着色剂、香料、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们也可以含有其它治疗上有价值的物质。
本发明的一个实施方案,组合物包含具有60%或更小的岩藻糖量的所述无岩藻糖基化抗CD20抗体(在一个实施方案中,所述抗体是无岩藻糖基化的人源化B-Ly1抗体)和苯达莫司汀两者,其在治疗癌症,特别是表达CD20的癌症中使用。
所述药物组合物可以进一步包含一种或多种药学可接受载体。
本发明进一步提供了特别在癌症中使用的药物组合物,其包含(i)第一有效量的具有60%或更小的岩藻糖量的无岩藻糖基化抗CD20抗体(在一个实施方案中为无岩藻糖基化的人源化B-Ly1抗体),和(ii)第二有效量的苯达莫司汀。任选地,此类组合物包含药学可接受载体和/或赋形剂。
通过将具有期望纯度的抗体与任选的药学可接受载体、赋形剂或稳定剂(Remington’s Pharmaceutical Sciences第16版,Osol,A.编(1980))混合以冻干配制剂或水溶液形式为贮存制备依照本发明使用的仅无岩藻糖基化抗CD20抗体的药物组合物。可接受的载体、赋形剂、或稳定剂在所采用的剂量和浓度对于接收者无毒,并且包括缓冲剂诸如磷酸盐、柠檬酸盐、和其它有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(诸如氯化十八烷基二甲基苄基铵;氯化己烷双胺;苯扎氯铵、苄索氯铵;酚、丁醇或苯甲醇;对羟基苯甲酸烷基酯,诸如对羟基苯甲酸甲酯或丙酯;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,诸如血清清蛋白、明胶、或免疫球蛋白;亲水性聚合物诸如聚乙烯吡咯烷酮;氨基酸诸如甘氨酸、谷氨酰胺、天冬酰胺、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;螯合剂诸如EDTA;糖诸如蔗糖、甘露醇、海藻糖或山梨糖醇;成盐反荷离子诸如钠;金属复合物(例如,Zn-蛋白质复合物);和/或非离子型表面活性剂诸如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。
苯达莫司汀的药物组合物可以与上文对无岩藻糖基化抗CD20抗体描述的药物组合物类似。
在本发明的又一个实施方案中,将无岩藻糖基化抗CD20抗体和苯达莫司汀以两种不同配制剂配制。
活性成分还可以包载于例如通过凝聚技术或通过界面聚合制备的微胶囊中(例如分别是羟甲基纤维素或明胶微胶囊和聚(甲基丙烯酸甲酯)微胶囊),在胶状药物投递系统中(例如脂质体、清蛋白微球体、微乳剂、纳米颗粒和纳米胶囊),或在粗滴乳状液中。此类技术披露于例如Remington’sPharmaceutical Sciences,第16版,Osol,A.编(1980)。
可以制备持续释放制剂。持续释放制剂的合适例子包括含有抗体的固体疏水性聚合物半透性基质,该基质是定型产品的形式,例如薄膜或微胶囊。持续释放基质的例子包括聚酯、水凝胶(例如聚(2-羟乙基-甲基丙烯酸酯)或聚(乙烯醇))、聚交酯(US 3,773,919)、L-谷氨酸和L-谷氨酸γ-乙酯的共聚物、不可降解的乙烯-乙酸乙烯、可降解的乳酸-乙醇酸共聚物诸如LUPRONDEPOTTM(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林构成的可注射微球体)、及聚-D-(-)-3-羟基丁酸。
要用于体内施用的配制剂必须是无菌的。这容易通过过滤流过无菌滤膜来实现。
本发明进一步提供了一种用于治疗癌症的方法,包括对需要此类治疗的患者施用(i)第一有效量的具有60%或更小的岩藻糖量的无岩藻糖基化抗CD20抗体(在一个实施方案中为无岩藻糖基化的人源化B-Ly1抗体),和(ii)第二有效量的苯达莫司汀。
在一个实施方案中,岩藻糖量是40%至60%。
优选地,所述癌症是表达CD20的癌症。
优选地,所述表达CD20的癌症是B细胞非何杰金氏淋巴瘤(NHL)。
优选地,所述无岩藻糖基化抗CD20抗体是II型抗CD20抗体。
优选地,所述抗体是人源化B-Ly1抗体。
优选地,在6周剂量周期的第1天、第8天、第15天以800至1200mg的剂量,然后在多至5个4周剂量周期的第1天以800至1200mg的剂量施用所述人源化B-Ly1抗体,并在多至6个4周剂量周期的第1天和第2天以80mg/m2至110mg/m2的剂量施用苯达莫司汀。
如本文中所使用的,术语“患者”优选地指出于任何目的需要用无岩藻糖基化抗CD20抗体治疗的人(例如,患有表达CD20的癌症的患者),且更优选地需要此类治疗以治疗癌症、或癌前状况或损伤的人。然而,术语“患者”也可以指非人动物,优选地哺乳动物诸如犬、猫、马、牛、猪、绵羊和非人灵长类,等等。
本发明进一步包括与苯达莫司汀联合治疗癌症的无岩藻糖基化抗CD20抗体。
本发明进一步包括在治疗癌症中使用的具有60%或更小的岩藻糖量的无岩藻糖基化抗CD20抗体和苯达莫司汀。
优选地,所述无岩藻糖基化抗CD20抗体是人源化B-Ly1抗体。
优选地,癌症是表达CD20的癌症,更优选地B细胞非何杰金氏淋巴瘤(NHL)。
优选地,在6周剂量周期的第1天、第8天、第15天以800至1200mg的剂量,然后在多至5个4周剂量周期的第1天以800至1200mg的剂量施用所述人源化B-Ly1抗体,并在多至6个4周剂量周期的第1天和第2天以80mg/m2至110mg/m2的剂量施用苯达莫司汀。
提供以下实施例和图以帮助理解本发明,其真正的范围在所附权利要求书中列出。应当理解,可以在不背离本发明精神的前提下对列出的规程做出修饰。
序列表
附图描述
图1无岩藻糖基化II型抗CD20抗体(B-HH6-B-KV1GE)与苯达莫司汀的联合治疗的体内抗肿瘤活性(与利妥昔单抗(岩藻糖基化I型抗CD20抗体)与苯达莫司汀的组合相比及与各种单一疗法相比)。
实施例
实验规程
II型抗CD20抗体(B-HH6-B-KV1GE)与苯达莫司汀的联合治疗的抗肿瘤活性
测试剂
无岩藻糖基化抗CD20抗体B-HH6-B-KV1 GE(无岩藻糖基化的人源化B-Ly1,糖工程化改造的B-HH6-B-KV1,参见WO 2005/044859和WO2007/031875)以来自GlycArt,Schlieren,Switzerland的储备溶液(9.4mg/ml)提供。抗体缓冲液包含组氨酸、海藻糖和聚山梨酯20。自储液将抗体溶液在PBS中适当稀释,用于在先注射。
临床级利妥昔单抗(Mabthera)获自Hoffmann La Roche,Basel。
细胞系和培养条件
将人Z138套细胞淋巴瘤细胞系在补充有10%胎牛血清(PAA Laboratories,Austria)和2mM L-谷氨酰胺的DMEM中于37℃在水饱和气氛中于8%CO2常规培养。使用传代4来移植。将细胞与Matrigel共注射。
动物
将雌性SCID米色小鼠;到达时年龄为3-4周(购自Charles River,Sulzfeld,Germany)在无特定病原体的条件下以12小时光照/12小时黑暗的日周期依照约定的准则(GV-Solas;Felasa;TierschG)维持。实验研究方案得到地方政府审阅并批准。到达后,将动物在动物房的检疫部分维持1周以习惯于新的环境及观察。定期实施连续健康监测。饮食食物(Provimi Kliba 3337)和水(酸化的pH 2.5-3)任意提供。
监测
每天对动物控制临床症状和不利作用的检测。对于贯穿整个实验的监测,每周两次记录动物的体重,并在分期后通过测径器测量肿瘤体积。
动物的处理
动物处理在肿瘤细胞接种后19天的随机化当天开始。在研究第19天和第26天以指定剂量1mg/kg i.p.q7d以单一药剂施用人源化的无岩藻糖基化抗CD20抗体B-HH6-B-KV1GE或利妥昔单抗。在同一天施用相应的媒介物。在第19天、第20天、第21天和第22天以3mg/kg i.p.给予苯达莫司汀。在联合疗法组中,在第19天在这两种抗体后8小时施用化疗剂。
体内肿瘤生长抑制研究
在肿瘤细胞接种后第33天在实验结束时,与对照组相比,给予利妥昔单抗、抗CD20抗体B-HH6-B-KV1 GE、利妥昔单抗和苯达莫司汀组合、或抗CD20抗体和苯达莫司汀组合的动物中分别有如表1中给出的肿瘤生长抑制(TGI)。仅用苯达莫司汀的处理在本实验中没有显示任何抗肿瘤活性。
通过比较抗CD20抗体B-HH6-B-KV1 GE/苯达莫司汀组合组与仅抗CD20抗体B-HH6-B-KV1 GE的处理,存在着大于叠加的效应。
统计学评估
在第33天终止研究。统计学评估基于sAUC。与媒介物组(组1)相比,肿瘤生长在组2(B-HH6-B-KV1 GE,1mg/kg,一周一次,i.p.)中(以TCR为0.72(CI 0.59-0.86)指示)、在组3(利妥昔单抗,1mg/kg,一周一次,i.p.)中(以TCR为0.78(CI 0.65-0.93)指示)、在组5(B-HH6-B-KV1 GE,1mg/kg,一周一次,i.p.,与苯达莫司汀组合,3mg/kg,研究日19-22,i.p.)中(以TCR为0.46(CI 0.34-0.59)指示)及在组6(利妥昔单抗,1mg/kg,一周一次,i.p.,与苯达莫司汀组合,3mg/kg,研究日19-22,i.p.)中(以TCR为0.67(CI 0.54-0.81)指示)受到统计学显著抑制。在研究结束时,组4(苯达莫司汀,3mg/kg,研究日19-22,i.p.)显示与对照组相当的肿瘤生长。
通过Tukey-Kramer检验(p<0.001)分析,与单一处理相比,B-HH6-B-KV1GE与苯达莫司汀的组合对肿瘤生长抑制显示大于叠加的(协同的)且统计学显著的影响(参见表1和图1)。
表1:基于sAUC和TGI(%)的参数TCR及低的和高的置信区间(CI)
Claims (11)
1.具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体用于制造与苯达莫司汀联合治疗癌症的药物的用途。
2.依照权利要求1的用途,其特征在于岩藻糖量在40%和60%之间。
3.依照权利要求1的用途,其特征在于岩藻糖量是50%或更小。
4.依照权利要求1至3中任一项的用途,其特征在于所述癌症是表达CD20的癌症。
5.依照权利要求4的用途,其特征在于所述表达CD20的癌症是B细胞非何杰金氏淋巴瘤(NHL)。
6.依照权利要求1至5中任一项的用途,其特征在于所述无岩藻糖基化抗CD20抗体是II型抗CD20抗体。
7.依照权利要求6的用途,其特征在于所述抗体是人源化B-Ly1抗体。
8.依照权利要求1至7中任一项的用途,其特征在于施用一种或多种额外的其它细胞毒剂、化疗剂或抗癌剂、或增强此类药剂的效果的化合物或电离辐射。
9.依照权利要求1至8中任一项的用途,其特征在于在6周剂量周期的第1天、第8天、第15天以800至1200mg的剂量,然后在多至5个4周剂量周期的第1天以800至1200mg的剂量施用所述人源化B-Ly1抗体,并在多至6个4周剂量周期的第1天和第2天以80mg/m2至110mg/m2的剂量施用苯达莫司汀。
10.一种用于治疗癌症的组合物,其包含具有占Asn297处的寡糖(糖)总量的60%或更少的岩藻糖量的无岩藻糖基化抗CD20抗体和苯达莫司汀。
11.依照权利要求10的组合物,其特征在于所述无岩藻糖基化抗CD20抗体是人源化B-Ly1抗体。
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