CN107198772A - Ii型抗cd20抗体与环磷酰胺、长春新碱和多柔比星联合治疗非霍奇金淋巴瘤的应用 - Google Patents
Ii型抗cd20抗体与环磷酰胺、长春新碱和多柔比星联合治疗非霍奇金淋巴瘤的应用 Download PDFInfo
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
Abstract
本发明涉及具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体在制备用于与一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂联合治疗癌症,尤其是表达CD20的癌症的药物中的应用。
Description
本申请是申请日为2009年3月23日、发明名称为“具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体与环磷酰胺、长春新碱和多柔比星联合治疗非霍奇金淋巴瘤的应用”的中国专利申请No.200980110181.0的分案申请。
本发明涉及具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体在制备用于与选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂联合治疗癌症,尤其是表达CD20的癌症的药物中的应用。
发明背景
CD20分子(也称为人B淋巴细胞限制性分化抗原或Bp35)是一种位于前B(pre-B)和成熟B淋巴细胞上的分子量约35kD的疏水跨膜蛋白(Valentine,M.A.,等人,J.Biol.Chem.(生物化学杂志)264(19)(1989)11282-11287;和Einfield,D,A,,等人,EMBO J.(EMBO杂志)7(3)(1988)711-717)。CD20见于90%以上的来自外周血或淋巴样器官的B细胞的表面上,其在早期前B细胞发育期间表达并且一直存在直至浆细胞分化。CD20存在于正常B细胞以及恶性B细胞上。具体地,CD20在90%以上的B细胞非霍奇金淋巴瘤(NHL)上表达(Anderson,K.C.等人,Blood(血液)63(6)(1984)1424-1433),但不存在于造血干细胞、原B细胞(pro-Bcells)、正常浆细胞或其他正常组织中(Tedder,T.F.等人,J,Immunol.(免疫学杂志)135(2)(1985)973-979)。
CD20蛋白的85个氨基酸羧基末端区位于胞质中。此区的长度与其他B细胞特异的表面结构相反,上述表面结构诸如IgM、IgD和IgG重链或组织相容性抗原I1类α或β链,它们具有相对短的胞质内区域,分别具有3、3、28、15和16个氨基酸(Komaromy,M.等人,NAR(核酸研究)11(1983)6775-6785)。在最后61个羧基末端氨基酸中,21个是酸性残基,而仅有2个是碱性残基,表明该区具有很强的净负电荷。GenBank登记号为NP-690605。CD20被认为可能参与调节B细胞活化和分化过程中的(多个)早期步骤(Tedder,T.F.等人,Eur.J.Immunol.(欧洲免疫学杂志)16(1986)881-887)并且可具有钙离子通道的功能(Tedder,T.F.等人,J.Cell.Biochem.(细胞生物化学杂志)14D(1990)195)。
存在有两种不同类型的抗CD20抗体,两者在其CD20结合模式和生物学活性方面明显不同(Cragg,M.S.等人,Blood(血液)103(2004)2738-2743;和Cragg,M.S.等人,Blood(血液)101(2003)1045-1052)。I型抗体,例如,利妥昔单抗(rituximab),在补体介导的细胞毒性中发挥作用,而II型抗体,例如,托西莫单抗(Tositumomab)(B1)、11B8、AT80或人源化B-Ly1抗体,能有效地经胱天蛋白酶(caspase)非依赖性凋亡启动靶细胞死亡并伴随着磷脂酰丝氨酸的暴露。
I型和II型抗CD20抗体共有的通用特性总结在表1中。
表1:
I型和II型抗CD20抗体的特性
发明概述
本发明包括具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体在制备用于与一种或多种选自由环磷酰胺(cyclophosphamide)、长春新碱(vincristine)和多柔比星(doxorubicine)组成的组的化疗剂联合治疗表达CD20的癌症的药物中的应用。
本发明进一步包括具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体在制备用于与一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂联合治疗患有表达CD20的癌症的患者的药物中的应用。
本发明进一步包括具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体与一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂联合用于治疗表达CD20的癌症。
本发明进一步包括具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体与一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂联合用于治疗患有表达CD20的癌症的患者。
优选地,所述使用具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体的治疗与环磷酰胺和长春新碱联合。
包括具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体和一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂的药物组合物用于表达CD20的癌症,特别是用于B细胞非霍奇金淋巴瘤(B-cell Non-Hodgkin’s lymphomas,NHL)。
优选地,所述II型抗CD20抗体是糖基化改造的、人源化B-Ly1抗体。发明详述
术语“抗体”包涵各种形式的抗体,其包括但不限于全抗体、人抗体、人源化抗体和基因工程抗体如单克隆抗体、嵌合抗体或重组抗体,以及这些抗体的片段,只要保留了根据本发明的特征性。如在此使用的术语“单克隆抗体”或“单克隆抗体组合物”指具有单一氨基酸组成的抗体分子的制剂。因此,术语“人单克隆抗体”指显示单一结合特异性的抗体,其具有来自人胚系免疫球蛋白序列的可变区和恒定区。在一个实施方案中,人单克隆抗体由杂交瘤产生,该杂交瘤包括与永生化细胞融合的从转基因非人动物,例如,转基因小鼠获得的B细胞,其具有包括人重链转基因和人轻链转基因的基因组。
优选地,所述II型抗CD20抗体是单克隆抗体。
术语“嵌合抗体”指通常通过重组DNA技术制备的包括来自一个来源或物种的可变区,即,结合区,和来自不同来源或物种的至少一部分恒定区的单克隆抗体。特别优选包括鼠可变区和人恒定区的嵌合抗体。这些鼠/人嵌合抗体是包括编码鼠免疫球蛋白可变区的DNA节段和编码人免疫球蛋白恒定区的DNA节段的免疫球蛋白基因表达的产物。本发明包涵的其他形式的“嵌合抗体”是其中原始抗体的类别或亚类已经被修饰或改变的那些抗体。此类“嵌合”抗体也称为“类别转换抗体(class-switched antibody)”。用于产生嵌合抗体的方法涉及现在本领域公知的常规重组DNA和基因转染技术。见,例如,Morrison,S.L.等人,Proc.Natl.Acad Sci.USA(美国科学院学报)81(1984)6851-6855;US 5,202,238和US 5,204,244。
术语“人源化抗体”指其中框架或“互补决定区”(CDR)已经被修饰从而包括特异性与亲代免疫球蛋白不同的免疫球蛋白的CDR的抗体。在优选的实施方案中,鼠CDR移植至人抗体的框架区以制备“人源化抗体”,见,例如,Riechmann,L.等人,Nature(自然)332(1988)323-327;和Neuberger,M.S.等人,Nature(自然)314(1985)268-270。对于嵌合和双功能抗体,特别优选CDR对应于那些识别上述抗原的代表序列。
在此使用的术语“人抗体”意在包括具有来源于人胚系免疫球蛋白序列的可变区和恒定区的抗体。人抗体在本领域中是公知的(van Dijk,M.A.和van de Winkel,J.G.,Curr.Opin.Chem Biol(化学与生物学新观点)5(2001)368-374)。基于此技术,可产生针对大量靶标的人抗体。人抗体的例子,例如,描述在Kellermann,S.A.等人,Curr OpinBiotechnol.(生物技术新观点)13(2002)593-597中。
在此使用的术语“重组人抗体”意在包括通过重组方式制备、表达、构建或分离的所有人抗体,诸如从诸如NS0或CHO细胞的宿主细胞分离的抗体或从人免疫球蛋白基因转基因的动物(例如,鼠)分离的抗体或使用转染进宿主细胞的重组表达载体表达的抗体。这些重组人抗体具有重排形式的来源于人胚系免疫球蛋白序列的可变区和恒定区。根据本发明的重组人抗体已经进行了体内体细胞高度突变。因此,重组抗体的VH和VL区的氨基酸序列是,尽管来源于人胚系VH和VL序列和并与两者相关,但可以不天然地存在于体内人抗体胚系所有成分之内的序列。
在此使用的“特异性结合”或“特异性地结合于”指抗体特异性地结合于CD20抗原。优选地,结合亲和力具有10-9mol/l或更低(例如,10-10mol/l)的KD值,优选地具有10-10mol/l或更低(例如,10-12mol/l)的KD值。结合亲和力采用标准的结合测定法诸如斯卡恰特作图分析(Scatchard plot analysis)在CD20表达细胞上测定。
在此使用的术语“核酸分子”意在包括DNA分子和RNA分子。核酸分子可以是单链或双链的,但优选是双链DNA。
“恒定区”不直接参与抗体与抗原的结合,但参与效应器功能(ADCC,补体结合以及CDC)。
在此使用的“可变区”(轻链的可变区(VL),重链的可变区(VH))是指直接参与抗体与抗原结合的一对轻链和重链中的每一个。可变的人轻链和重链的结构域具有相同的通用结构,并且各个结构域包括由三个“超变区”(或互补决定区,CDRs)连接的四个框架(FR)区,框架区的序列是广泛保守的。框架区采用b-折叠构象,并且CDRs可形成连接b-折叠结构的环。各个链内的CDRs通过框架区保持其三维结构,并且与来自其他链的CDRs一起形成抗原结合位点。抗体重链和轻链CDR3区在本发明所述的抗体的结合特异性/亲和力中具有特别重要的作用,并且因此提供了本发明的进一步的目的。
术语“超变区”或“抗体的抗原结合部分”当在此使用时指抗体负责抗原结合的氨基酸残基。超变区包括来自“互补决定区”或“CDRs”的氨基酸残基。“框架区”或“FR”区是如在此所定义的超变区残基之外的那些可变区结构域。因此,抗体的轻链和重链从N末端至C末端包括结构域FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。尤其是,重链的CDR3是对抗原结合贡献最多的区。根据Kabat,等人,Sequences of Proteins of Immunological Interest(具有免疫学重要性的蛋白序列),第五版,Public Health Service(公共医疗),NationalInstitutes of Health(国立卫生研究院),Bethesda,MD.(1991))的标准定义和/或来自“超变环”的那些残基来确定CDR和FR区。
术语“CD20”和“CD抗原”在此互换使用,并且包括由细胞天然表达的或用CD20基因转染的细胞上表达的人CD20的任何变异体、同种型和物种同源物。本发明的抗体与CD20抗原的结合通过使CD20失活来介导表达CD20的细胞(例如,肿瘤细胞)的杀伤。表达CD20的细胞的杀伤可通过下列机制的一种或多种来发生:细胞死亡/凋亡诱导、ADCC和CDC。
如本领域中公认的,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。
根据本发明术语“抗CD20抗体”是与CD20抗原特异性结合的抗体。取决于抗CD20抗体与CD20抗原的结合特性和生物活性,根据Cragg,M.S.等人,Blood(血液)103(2004)2738-2743;和Cragg,M.S.等人,Blood(血液)101(2003)1045-1052可区分为两种类型的抗CD20抗体(I型和II型抗CD20抗体),见表2。
表2:
I型和II型抗CD20抗体的特性
I型和II型抗CD20抗体的一个基本特性是其结合模式。因此,I型和II型抗CD20抗体可通过所述抗CD20抗体的与Raji细胞(ATCC编号:CCL-86)上CD20的结合力与利妥昔单抗相比较的比值来分类。
II型抗CD20抗体具有的所述抗CD20抗体的与Raji细胞(ATCC编号:CCL-86)上CD20的结合力与利妥昔单抗的比值为0.3~0.6,优选0.35~0.55,更优选0.4~0.5。此类II型抗CD20抗体的例子包括,例如,托西莫单抗(B1IgG2a),人源化B-Ly1抗体IgG1(如WO 2005/044859中所公开的嵌合人源化IgG1抗体)、11B8IgG1(如WO 2004/035607中所公开的)和AT80IgG1。优选地所述II型抗CD20抗体是与人源化B-Ly1抗体(如WO2005/044859中所公开的)结合相同的表位的单克隆抗体。
与II型抗体相反,I型抗CD20抗体具有的所述抗CD20抗体的与Raji细胞(ATCC编号:CCL-86)上CD20的结合力与利妥昔单抗的比值为0.8~1.2,优选0.9~1.1。此类I型抗CD20抗体的例子包括例如,利妥昔单抗、1F5IgG2a(ECACC,杂交瘤;Press,O.W.等人,Blood(血液)69/2(1987)584-591)、HI47IgG3(ECACC,杂交瘤)、2C6IgG1(如WO 2005/103081中所公开的)、2F2IgG1(如WO 2004/035607和WO 2005/103081中所公开的)以及2H7IgG1(如WO2004/056312中所公开的)。
“抗CD20抗体的与Raji细胞(ATCC编号:CCL-86)上CD20的结合力与利妥昔单抗的比值”通过直接免疫荧光测定法(测定平均荧光强度(MFI))使用与Cy5缀合的所述抗CD20抗体和与Cy5缀合的利妥昔单抗与Raji细胞(ATCC编号:CCL-86)在FACSArray(BectonDickinson)中测定,如实施例2中所述,并且如下进行计算:
与Raji细胞(ATCC编号:CCL-86)上CD20的结合力的比值=
MFI是平均荧光强度。在此使用的“Cy5-标记比例”指每分子抗体的Cy5-标记分子的数目。
典型地,所述II型抗CD20抗体具有的所述二级抗CD20抗体与Raji细胞(ATCC编号:CCL-86)上CD20的结合力与利妥昔单抗相比较的比值为0.3~0.6,优选为0.35~0.55,更优选为0.4~0.5。
按照本发明的所述II型抗CD20抗体具有增加的抗体依赖性细胞毒性(ADCC)。
“具有增加的抗体依赖性细胞毒性(ADCC)的抗体(antibody having increasedantibody dependent cellular cytotoxicity(ADCC))”或“具有增加的抗体依赖性细胞毒性(ADCC)的抗体(antibody with increased antibody dependent cellularcytotoxicity(ADCC))”是指如在此所定义的该术语一样,具有根据本领域普通技术人员已知的任何适当的方法测定的增加的ADCC的抗体。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)该测定法使用从随机选择的健康供体的血液分离的人外周血单核细胞(PBMCs)作为效应细胞;
3)该测定法根据下列的试验方案进行:
i)PBMC使用标准的密度离心步骤分离,并以5×106细胞/ml悬浮在RPMI细胞培养基中;
ii)靶细胞通过标准的组织培养方法生长,从指数生长期收获,活力大于90%,在RPMI细胞培养基中洗涤,用100微居里51Cr标记,用细胞培养基洗涤两次,并且以105细胞/ml的密度重新悬浮在细胞培养基中;
iii)将100微升的上述最终靶细胞悬液转移至96孔微量滴定板的各孔中;
iv)抗体在细胞培养基中从4000ng/ml连续稀释至0.04ng/ml,并将50微升所得抗体溶液加入至96孔微量滴定板中的靶细胞中,将上面全部浓度范围内的各个抗体浓度检测三次;
v)对于最大释放(MR)对照,含有标记靶细胞的板中的另外3个孔加入50微升2%(VN)非离子型去污剂(Nonidet,Sigma,St.Louis)的水溶液代替抗体溶液(上面的iv点);
vi)对于自发释放(SR)对照,含有标记靶细胞的板中的另外3个孔加入50微升RPMI细胞培养基代替抗体溶液(上面iv点);
vii)然后96孔微量滴定板以50×g离心1分钟,并在4℃下孵育1小时;
viii)将50微升PBMC悬液(上面i点)加入至各孔中以产生25:1的效应细胞:靶细胞比例,并且将平板置于培养箱中在5%CO2气氛中37℃下4小时;
ix)从各孔收获不含细胞的上清液,并且使用γ计数器定量实验释放的放射性(ER);
x)根据式(ER-MR)/(MR-SR)×100对各抗体浓度计算特异性溶解的百分数,其中ER是对该抗体浓度定量的平均放射性(见上面的ix点),MR为对MR对照(见上面的v点)定量的平均放射性(见上面的ix点),以及SR是对SR对照(见上面的vi点)定量的平均放射性(见上面的ix点);
4)“增加的ADCC”被规定为上面检测的抗体浓度范围内观察到的特异性溶解的最大百分数,和/或达到上面检测的抗体浓度范围内观察到的特异性溶解的最大百分数的一半所需的抗体浓度的减少。ADCC的增加是相对于采用上面测定法测定,使用本领域专业技术人员公知的相同的标准生产方法、纯化方法、配制和保存方法,由相同抗体介导的,由相同类型宿主细胞产生的,但不由被改造以过度表达GnTIII的宿主细胞产生的ADCC。
所述“增加的ADCC”可通过所述抗体的糖基化改造来获得,如Umana,P.等人,Nature Biotechnol.(自然生物技术)17(1999)176-180和US6,602,684中所述,意味着通过改造其寡糖成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。
术语“补体依赖性细胞毒性(CDC)”指由本发明所述的抗体在补体的存在下对人肿瘤靶细胞的溶解。CDC优选地通过用本发明所述的抗CD20抗体在补体的存在下处理表达CD20细胞的制剂来测定。如果4小时后抗体在100nM的浓度下诱发20%或更多的肿瘤细胞的溶解(细胞死亡),则存在CDC。该测定优选地用51Cr或Eu标记的肿瘤细胞并测定释放的51Cr或Eu来进行。对照包括肿瘤靶细胞与补体但不与抗体的孵育。
通常IgG1同种型的II型抗CD20抗体显示特征性的CDC特性。II型抗CD20抗体与IgG1同种型的I型抗体相比具有降低的CDC(如果为IgG1同种型)。优选地II型抗CD20抗体为IgG1同种型抗体。
“利妥昔单抗”抗体(参考抗体;I型抗CD20抗体的例子)是基因工程化的针对人CD20抗原的嵌合含人γ1鼠恒定区结构域的单克隆抗体。此嵌合抗体含有γ1人恒定区结构域,并且在于1998年4月17日授权并转让给IDEC制药公司(IDEC PharmaceuticalsCorporation)的US 5,736,137(Anderson,K.C.等人)中被鉴定为“C2B8”的名称。利妥昔单抗被批准用于治疗患有复发的或难治性低度或滤泡性CD20阳性的B细胞非霍奇金淋巴瘤的患者。体外作用机制研究已经显示利妥昔单抗显示人补体依赖性细胞毒性(CDC)(Reff,M.E.等人,Blood(血液)83(2)(1994)435-445)。另外,其在测定抗体依赖性细胞毒性(ADCC)的测定中显示明显的活性。
术语“人源化B-Ly1抗体”指如WO 2005/044859和WO 2007/031875中公开的人源化B-Ly1抗体,该抗体从鼠单克隆抗CD20抗体B-Ly1(鼠重链的可变区(VH):SEQ ID NO:1;鼠轻链的可变区(VL):SEQ ID NO:2-见Poppema,S.和Visser,L.,Biotest Bulletin(生物实验通报)3(1987)131-139;)通过与来自IgG1的人恒定区结构域的嵌合以及下述人源化作用(见WO2005/044859和WO 2007/031875)而获得。这些“人源化B-Ly1抗体”的详情公开在WO2005/044859和WO 2007/031875中。
优选地,“人源化B-Ly1抗体”具有选自SEQ ID No.3~SEQ ID No.20(WO 2005/044859和WO 2007/031875的B-HH2至B-HH9和B-HL8至B-HL17)的重链可变区(VH)。特别优选Seq.ID No.3、4、7、9、11、13和15(WO 2005/044859和WO 2007/031875的B-HH2、BHH-3、B-HH6、B-HH8、B-HL8、B-HL11和B-HL13)。优选地,“人源化B-Ly1抗体”具有SEQ ID No.20(WO2005/044859和WO 2007/031875的B-KV1)的轻链可变区(VL)。此外,人源化B-Ly1抗体优选是IgG1抗体。根据本发明所述人源化B-Ly1抗体根据WO 2005/044859、WO 2004/065540、WO2007/031875,Umana,P.等人,Nature Biotechnol.(自然生物技术)17(1999)176-180和WO 99/154342中所述的方法在Fc区被糖基化改造(GE)。该“糖基化改造的人源化B-Ly1抗体”在Fc区具有改变的糖基化模式,优选具有降低水平的岩藻糖残基。优选地Fc区的寡糖的至少40%或更多(在一个实施方案中为40%~60%,在另一个实施方案中为至少50%,并且还在另一个实施方案中为至少70%或更多)为非岩藻糖化的。此外,Fc区的寡糖优选地是对切的(bisected)。
寡糖成分可显著地影响与治疗性糖蛋白的功效相关的特性,包括物理稳定性,对蛋白酶攻击的抗性,与免疫***的相互作用,药物代谢动力学,和特异的生物活性。这些特性可不仅取决于寡糖的存在与否,还取决于寡糖的特定结构。可对寡糖结构和糖蛋白功能之间做一些概括。例如,某些寡糖结构通过与特定的糖结合蛋白的相互作用而介导糖蛋白从血流中的快速清除,而其他一些寡糖则可被抗体结合并触发不需要的免疫反应。(Jenkins,N.等人,Nature Biotechnol.(自然生物技术)14(1996)975-81)。
哺乳动物细胞是生产治疗性糖蛋白的优选宿主,因为其具有以对人类应用最相容形式的糖基化蛋白的能力。(Cumming,D.A.等人,Glycobiology(糖生物学)1(1991)115-30;Jenkins,N.等人,Nature Biotechnol.(自然生物技术)14(1996)975-81)。细菌对蛋白的糖基化很罕见,并且类似于其他类型的常用宿主,诸如酵母、丝状真菌、昆虫和植物细胞,其产生与从血流中快速清除、不需要的免疫相互作用相关的糖基化模式,并且在一些特定情况下,降低生物活性。在哺乳动物细胞中,在近二十年中最常使用中国仓鼠卵巢(CHO)细胞。除了产生适当的糖基化模式以外,这些细胞能够不断地产生遗传稳定的、高产的克隆细胞系。它们可在简单的生物反应器中使用无血清培养基培养至高密度,并且允许安全可靠的发育和可重现的生物过程。其他常用的动物细胞包括幼仓鼠肾(BHK)细胞、NSO-和SP2/0-小鼠骨髓瘤细胞。近年来,还试验了由转基因动物的生产。(Jenkins,N.等人,Nature Biotechnol.(自然生物技术)14(1996)975-981)。
所有抗体在重链恒定区中的保守部位处都含有糖结构,各个同种型拥有不同的N-连接糖结构阵列,其可变地影响蛋白组装、分泌或功能性活动。(Wright,A.,和Monison,S.L.,Trends Biotech.(生物技术趋势)15(1997)26-32)。附着的N-连接糖的结构变化相当大,取决于加工程度,并且可包括高甘露糖、多分支以及双分支的复合寡糖。(Wright,A.,和Morrison,S.L.,Trends Biotech.(生物技术趋势)15(1997)26-32)。通常,存在附着在特定糖基化位点处的核心寡糖结构的不均一加工,使得单克隆抗体甚至以多种糖型存在。同样,已经显示细胞系之间存在抗体糖基化主要差别,并且甚至在不同培养条件下生长的指定细胞系也能见到较小的差异。(Lifely,M.R.等人,Glycobiology(糖生物学)5(8)(1995)813-22)。
获得大幅度增加的效力,同时保持简单的生产工艺并潜在地避免明显的不良副作用的一种方式是如Umana,P.等人,Nature Biotechnol.(自然生物技术)17(1999)176-180和US 6,602,684中所述,通过改造其寡糖成分来增强单克隆抗体的天然、细胞介导的效应器功能。IgG1型抗体,是在癌症免疫治疗中最常使用的抗体,其是在各个CH2结构域中Asn297处具有保守N-连接糖基化位点的糖蛋白。附着在Asn297的两个复合双分支寡糖埋藏在CH2结构域之间,形成与多肽主链的广泛接触,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毒性(ADCC)是很重要的(Lifely,M.R.等人,Glycobiology(糖生物学)5(1995)813-822;Jefferis,R.等人,Immunol.Rev.(免疫学综述)163(1998)59-76;Wright,A.和Morrison,S.L.,Trends Biotechnol.(生物技术趋势)15(1997)26-32)。
以前显示β(1,4)-N-乙酰葡糖胺转移酶I11(“GnTII17y”)(其是一种催化对切(bisected)寡糖形成的糖基转移酶)在中国仓鼠卵巢(CHO)细胞中的过度表达显著地增加了由工程化CHO细胞产生的抗成神经细胞瘤嵌合单克隆抗体(chCE7)的体外ADCC活性。(见Umana,P.等人,Nature Biotechnol.(自然生物技术)17(1999)176-180;和WO 99/154342,其全部内容以引用方式合并于此)。抗体chCE7属于一大类未缀合的单克隆抗体,该类抗体具有很高的肿瘤亲和力和特异性,但当在缺少GnTIII酶的标准工业化细胞系中生产时效力太低而不能用于临床(Umana,P.等人,Nature Biotechnol.(自然生物技术)17(1999)176-180)。该研究首次显示通过改造抗体生产细胞以表达GnTIII将获得ADCC活性的大幅增加,还导致恒定区(Fc)相关的对切寡糖,包括对切的非岩藻糖化寡糖的比例高于天然抗体中存在的水平的增加。
术语“CD20抗原的表达”意指CD20抗原在分别来自肿瘤或癌症,优选地非实体肿瘤的细胞,优选地T细胞或B细胞、更优选地B细胞的细胞表面上的显著表达水平。患有“表达CD20的癌症”的患者可通过本领域中已知的标准测定法来确定。例如,使用免疫组织化学(IHC)检测、FACS或经相应mRNA的基于PCR的检测来测定CD20抗原表达。
在此使用的术语“表达CD20的癌症”指其中癌细胞显示表达CD20抗原的所有癌症。这些表达CD20的癌症可以是,例如,淋巴瘤(lymphomas)、淋巴细胞性白血病(lymphocyticleukemias)、肺癌(lung cancer)、非小细胞肺(NSCL)癌(non small cell lung(NSCL)cancer)、支气管肺泡细胞肺癌(bronchioloalviolar cell lung cancer)、骨癌(bonecancer)、胰腺癌(pancreatic cancer)、皮肤癌(skin cancer)、头或颈癌(cancer of thehead or neck)、皮肤或眼内黑色素瘤(cutaneous or intraocular melanoma)、子宫癌(uterine cancer)、卵巢癌(ovarian cancer)、直肠癌(rectal cancer)、肛区癌症(cancerof the anal region)、胃癌(stomach cancer)、胃癌(gastric cancer)、结肠癌(coloncancer)、乳腺癌(breast cancer)、子宫癌(uterine cancer)、输卵管癌(carcinoma ofthe fallopian tubes)、子宫内膜癌(carcinoma of the endometrium)、***(carcinoma of the cervix)、***癌(carcinoma of the vagina)、外阴癌(carcinoma ofthe vulva)、霍奇金病(Hodgkin's Disease)、食管癌(cancer of the esophagus)、小肠癌(cancer of the small intestine)、内分泌***癌症(cancer of the endocrinesystem)、甲状腺癌(cancer of the thyroid gland)、甲状旁腺癌(cancer of theparathyroid gland)、肾上腺癌(cancer of the adrenal gland)、软组织肉瘤(sarcomaof soft tissue)、尿道癌(cancer of the urethra)、***癌(cancer of the penis)、***癌(prostate cancer)、膀胱癌(cancer of the bladder)、肾癌或输尿管癌(cancerof the kidney or ureter)、肾细胞癌(renal cell carcinoma)、肾盂癌(carcinoma ofthe renal pelvis)、间皮瘤(mesothelioma)、肝细胞癌(hepatocellular cancer)、胆囊癌(biliary cancer)、中枢神经***肿瘤(neoplasms of the central nervous system(CNS))、脊轴肿瘤(spinal axis tumors)、脑干神经胶质瘤(brain stem glioma)、多形性成胶质细胞瘤(glioblastoma multiforme)、星形细胞瘤(astrocytomas)、神经鞘瘤(schwanomas)、室管膜瘤(ependymonas)、髓母细胞瘤(medulloblastomas)、脑膜瘤(meningiomas)、鳞状细胞癌(squamous cell carcinomas)、垂体腺瘤(pituitaryadenoma),包括上述癌症的任意一种的难治性类型,和上述癌症的一种或多种的组合。
优选地,在此使用的表达CD20的癌症指淋巴瘤(优选B细胞非霍奇金淋巴瘤(B-Cell Non-Hodgkin’s lymphomas)(NHL))和淋巴细胞性白血病。这些淋巴瘤和淋巴细胞性白血病包括,例如,a)滤泡性淋巴瘤(follicular lymphomas)、b)小而未裂细胞的淋巴瘤(Small Non-Cleaved Cell Lymphomas)/伯基特淋巴瘤(Burkitt's lymphoma)(包括地方性伯基特淋巴瘤(endemic Burkitt's lymphoma))、散发性伯基特淋巴瘤(sporadicBurkitt's lymphoma)和非伯基特淋巴瘤(Non-Burkitt's lymphoma),c)边缘区淋巴瘤(marginal zone lymphomas)(包括结外边缘区B细胞淋巴瘤(extranodal marginal zoneB cell lymphoma)(粘膜相关淋巴组织淋巴瘤(Mucosa-associated lymphatic tissuelymphomas),MALT)、结性边缘区B细胞淋巴瘤(nodal marginal zone B cell lymphoma)和脾边缘区淋巴瘤(splenic marginal zone lymphoma),d)外套膜细胞淋巴瘤(Mantle celllymphoma)(MCL),e)大细胞淋巴瘤(Large Cell Lymphoma)(包括B细胞弥散性大细胞淋巴瘤(B-cell diffuse large cell lymphoma)(DLCL)、弥散性混合细胞淋巴瘤(DiffuseMixed Cell Lymphoma)、免疫母细胞性淋巴瘤(Immunoblastic Lymphoma)、原发性纵隔B细胞淋巴瘤(Primary Mediastinal B-Cell Lymphoma)、血管中心性淋巴瘤-肺B细胞淋巴瘤(Angiocentric Lymphoma-Pulmonary B-Cell Lymphoma),f)毛细胞性白血病(hairy cellleukemia),g)淋巴细胞性白血病(lymphocytic lymphoma)、瓦尔登斯特伦巨球蛋白血症(waldenstrom’s macroglobulinemia)、h)急性淋巴细胞性白血病(acute lymphocyticleukemia)(ALL)、慢性淋巴细胞性白血病(chronic lymphocytic leukemia)(CLL)/小淋巴细胞性淋巴瘤(small lymphocytic lymphoma)(SLL)、B细胞型幼淋巴细胞性白血病(B-cell prolymphocytic leukemia),i)浆细胞赘生物(plasma cell neoplasms)、浆细胞骨髓瘤(plasma cell myeloma)、多发性骨髓瘤(multiple myeloma)、浆细胞瘤(plasmacytoma),j)霍奇金病(Hodgkin’s disease)。
更优选地,表达CD20的癌症是B细胞非霍奇金淋巴瘤(NHL)。特别地,表达CD20的癌症是外套膜细胞淋巴瘤(MCL)、急性淋巴细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、B细胞弥散性大细胞淋巴瘤(DLCL)、伯基特淋巴瘤、毛细胞性白血病、滤泡性淋巴瘤、多发性骨髓瘤、边缘区淋巴瘤、移植后淋巴增生性疾病(post transplantlymphoproliferative disorder)(PTLD)、HIV相关淋巴瘤(HIV associated lymphoma)、瓦尔登斯特伦巨球蛋白血症、或原发性中枢神经***淋巴瘤(primary CNS lymphoma)。
术语“治疗的方法”或其等效形式,当应用于,例如,癌症时,指被设计成减少或消除患者的癌细胞的数目,或减轻癌症的症状的操作步骤或过程。癌症或另一种增生性疾病的“治疗方法”不一定是指癌细胞或其他病症实际上被消除,细胞的数目或病症实际上被减少,或癌症或其他病症的症状实际上被减轻。经常进行治疗癌症的方法,即使成功的可能性很低,但考虑到患者的医学史和估计的预期生存期,该治疗方法仍然被认为引起了总体有益的行为过程。
在一个实施方案中,使用具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体的治疗与环磷酰胺和长春新碱联合。
在另一个实施方案中,使用具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体的治疗与多柔比星联合。
在另一个实施方案中,使用具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体的治疗与环磷酰胺联合。
在另一个实施方案中,使用具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体的治疗与环磷酰胺、长春新碱和多柔比星联合。
术语“共同施用”、“共施用”或“联合”用在本文中具有相同的意思,指所述II型抗CD20抗体和所述化疗剂作为一个单一制剂或作为两个独立制剂的施用。共同施用可以是同时的或以任何顺序相继的,其中优选在两种(或所有)活性剂同时发挥其生物活性时持续一定的时间段。所述II型抗CD20抗体和所述化疗剂同时或相继地共施用(例如,通过连续输注经静脉内(i.v.)(对于抗体输注一次,最后对化疗剂输注一次;或化疗剂口服给药))。当两种治疗剂相继地共施用时,用药量在同一天以两次独立的给药来施用,或一种药剂在第1天施用,第二种在第2~第7天,优选在第2~第4天共施用。因此,术语“相继地”是指在第一抗体的用药后7天内,优选在第一抗体的用药后4天内;并且术语“同时地”是指在同一时刻。就II型CD20抗体和化疗剂的维持剂量而言,术语“共同施用”是指如果治疗周期对两种药物都适合,维持剂量可例如,每周同时地共施用。或例如化疗剂,例如,每第1~第3天施用,II型抗CD20抗体每周施用一次。或者维持剂量是在1天内或在几天内相继共施用。
不言而喻,抗体以“治疗有效量”(或简单地说“有效量”)施用于患者,该治疗有效量是将引起被研究者、兽医、内科医生(medical doctor)或其它临床医生所探寻的组织、***、动物或人的生物或医学反应的各化合物或组合的量。
所述II型抗CD20抗体和所述化疗剂共同施用的量和共同施用的时间将取决于被治疗的患者的类型(人种、性别、年龄、体重等)和状况以及被治疗的疾病或病症的严重性。所述II型抗CD20抗体和所述化疗剂被适当地一次或经一系列治疗共施用于患者。根据疾病的类型和严重性,约1μg/kg~50mg/kg(例如,0.1-20mg/kg)的所述II型抗CD20抗体和1μg/kg~50mg/kg(例如,0.1-20mg/kg)的所述化疗剂是用于将两种药物共同施用给患者的初次候选用药量。如果施用为静脉内给药,对于所述II型抗CD20抗体或所述化疗剂的初次输注时间可以比随后的输注时间长,例如,对于初次输注约90分钟,对于随后的输注约30分钟(如果良好地耐受初次输注)。
所述II型抗CD20抗体的优选用药量在约0.05mg/kg~约30mg/kg的范围内。因此,约0.5mg/kg、2.0mg/kg、4.0mg/kg、10mg/kg或30mg/kg(或其任意组合)的一次或多次剂量可共施用于患者。所述化疗剂的优选用药量在0.01mg/kg~约30mg/kg,例如对于硼替佐米(bortezomib)为0.1mg/kg~10.0mg/kg范围之内。根据患者的类型(人种、性别、年龄、体重等)和状况以及抗CD20抗体和化疗剂的类型,所述抗CD20抗体的用药量和施用日程可不同于化疗剂的用药量。例如,所述抗CD20抗体可例如,每1-3周施用,并且所述化疗剂可每天或每2-10天施用。也可施用较高的初次负荷剂量,紧接着一次或多次较低剂量。
在一个优选的实施方案中,药物用于预防或减少患有表达CD20的癌症的患者的转移或进一步播散。通过测定生存期、无进展生存期、反应率或反应持续时间,该药物有效用于增加该患者的生存期,增加该患者无进展生存期,增加反应持续时间,引起被治疗患者统计学显著的和临床意义的改善。在优选的实施方案中,药物用于增加患者组中的反应率。
可以使用II型抗CD20抗体和化疗剂联合治疗表达CD20的癌症。这些分子适当地以有效地用于预期目的的量联合存在。因此,在一个实施方案中,在使用具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体联合一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂的治疗中,施用一种另外的皮质类固醇(corticosteroid),优选***(prednisone)。
在一个实施方案中,在不使用另外的皮质类固醇的条件下,使用所述II型抗CD20抗体和化疗剂的联合治疗。
在化疗方案中上述的皮质类固醇的应用在癌症治疗领域中通常是被充分表征的,并且在此其应用同样要基于监测耐受性和疗效、并且控制给药途径和用药量的考虑,做一些调整。例如,化疗剂和皮质类固醇的实际用药量可根据通过组织培养方法测定的患者的培养细胞反应而发生变化。一般来说,与缺少附加的其他药剂时的用量相比,用药量会减少。
有效的化疗剂和/或皮质类固醇的典型用药量可以为供应商所推荐的范围,并且在由体外反应或动物模型中的反应来表示时,可以减少至多约一个数量级的浓度或用量。因此,实际用药量将取决于医生的判断、患者的情况、以及基于原代培养的恶性细胞或组织培养的组织样品的体外反应性、或在适当的动物模型中观察到的反应而判断的治疗方法的有效性。
在本发明的上下文中,除了具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体和化疗剂联合治疗表达CD20的癌症以外可进行有效量的电离辐射和/或可使用放射性药物。辐射源可以在被治疗的患者的外部或内部。当辐射源在患者的外部时,治疗被称为外光束放射疗法(external beam radiation therapy)(EBRT)。当辐射源在患者的内部时,则治疗被称为近程放射治疗(brachytherapy)(BT)。用于本发明的情形中的放射性原子可选自包括但不限于镭、铯-137、铱-192、镅-241、金-198、钴-57、铜-67、锝-99、碘-123、碘-131和铟-111的组。有可能使用这些放射性同位素来标记抗体。优选地,具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体和化疗剂的联合治疗不使用这些电离辐射。
放射治疗是用于控制不能切除或不能手术的肿瘤和/或肿瘤转移的一种标准治疗方法。当放射治疗与化疗组合时已经看到有改善的结果。放射治疗基于下面的原理,即,递送至靶区域的高剂量辐射将导致肿瘤和正常组织两者中的繁殖细胞的死亡。放射给药方案通常规定辐射吸收剂量(Gy)、时间和分级,并且必须由肿瘤学专家来小心地确定。患者接受的辐射量将取决于多种考虑事项,但两个最重要的事项是肿瘤的位置与机体的其他重要结构或器官的关系,以及肿瘤已经扩散的程度。经受放射治疗的患者的典型疗程为在1~6周的治疗日程中,施用于患者的总剂量为10~80Gy,每天约1.8~2.0Gy级分,每周5天。在本发明的优选实施方案中,当人类患者中的肿瘤采用本发明的联合治疗和放射来治疗时有协同作用。换句话说,当与放射、任选地与附加的化疗剂或抗癌剂联合使用时,通过包括本发明的组合的药剂对肿瘤生长的抑制作用得以增强。辅助放射治疗的参数,例如,见WO 99/60023。
II型抗CD20抗体根据已知方法,通过静脉推注给药或在一段时间内连续输注,通过肌内、腹膜内、脑脊液内、皮下、关节内、滑膜内或鞘内途径而施用于患者。优选抗体的静脉内或皮下给药。
化疗剂根据已知方法,例如,通过静脉推注给药或在一段时间内连续输注,通过肌内、腹膜内、脑脊液内、皮下、关节内、滑膜内、鞘内或经口途径而施用于患者。优选化疗剂的静脉内、皮下或口服给药。
本发明进一步包括一种试剂盒,其包括用于联合治疗患有表达CD20的癌症的患者的具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体和一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂。在一个优选的实施方案中,该试剂盒容器可进一步包括药用载体。该试剂盒可进一步包括无菌稀释剂,其优选地保存在独立的附加容器中。该试剂盒可进一步包括包装插页,该插页包括指导使用该联合治疗作为表达CD20的癌症疾病、优选B细胞非霍奇金淋巴瘤(NHL)的治疗方法的印刷说明书。
术语“包装插页”指习惯上包括在治疗产品的市售包装中的说明书,其可包括与关于这些治疗产品的应用的适应证、用法、用药量、给药、禁忌症和/或警告有关的信息。
在优选的实施方案中,产品容器的物品可进一步包括药用载体。产品的物品可进一步包括无菌稀释剂,其优选地保存在单独的附加容器中。
在此所使用的“药用载体”意在包括与药物施用相容的任何和所有物质,包括溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂,以及与药物施用相容的其他物质和化合物。除非任何常规的介质或药剂与活性化合物不相容,则其被考虑用于本发明的组合物中。补充的活性化合物也可以合并入该组合物中。
药物组合物:
可通过将本发明所述的具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体和/或选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂与药用无机或有机载体加工而获得药物组合物。可使用,例如,乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐类等作为用于片剂、包衣片剂、糖衣丸(dragées)和硬明胶胶囊的此类载体。用于软明胶胶囊的适当载体为,例如,植物油、蜡、脂肪、半固体和液体多元醇类等。然而,根据活性物质的特性,在软明胶胶囊中通常不需要载体。用于生产溶液和糖浆剂的适当载体为,例如,水、多元醇类、甘油、植物油等。用于栓剂的适当载体为,例如,天然或硬化油、蜡、脂肪、半固体或液体多元醇类等。
而且,药物组合物可含有防腐剂、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类、缓冲剂、掩蔽剂或抗氧化剂。它们也可含有其他的治疗上有价值的物质。
本发明的一个实施方案是一种特别用于表达CD20的癌症的的药物组合物,其包括所述具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体和一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂两者。
所述药物组合物可进一步包括一种或多种药用载体。
本发明进一步提供一种特别用于癌症的药物组合物,其包括:(i)第一有效量的具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体,和(ii)第二有效量的一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂。该组合物任选地包括药用载体和/或赋形剂。
通过将具有所需纯度的抗体与任选的药用载体、赋形剂或稳定剂(Remington'sPharmaceutical Sciences(雷明顿制药学),第16版,Osol,A.主编(1980))混合,以冻干制剂或水溶液的形式制备根据本发明单独使用的具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体的药物组合物用于储存。可接受的载体、赋形剂或稳定剂在采用的用药量和浓度下对接受者无毒性,并且包括下列各项:缓冲剂诸如磷酸盐、柠檬酸和其他有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(诸如十八烷基二甲基苄基氯化铵(octadecyldimethylbenzyl ammonium chloride);氯化六甲双胺(hexamethoniumchloride);苯扎氯铵(benzalkonium chloride)、苄索氯铵(benzethonium chloride);苯酚、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;儿茶酚(catechol);间苯二酚(resorcinol);环己醇;3-戊醇;以及间甲酚;低分子量(小于约10个残基)多肽;蛋白质,诸如血清白蛋白、明胶或免疫球蛋白;亲水聚合物诸如聚乙烯吡咯烷酮;氨基酸诸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖类、二糖类和其他糖类包括葡萄糖、甘露糖或糊精;螯合剂诸如EDTA;糖类诸如蔗糖、甘露醇、海藻糖或山梨醇;形成盐的平衡离子诸如钠;金属络合物(例如,Zn-蛋白复合物);和/或非离子型表面活性剂诸如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。
选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂的药学组合物,取决于其药学特性;例如,对于小的化学化合物诸如,例如,硼替佐米,例如,一种制剂可以如下:
a)片剂制剂(湿法制粒):
制备步骤:
1.将第1、2、3和4项混合并用纯水制粒。
2.将颗粒在50℃下干燥。
3.使颗粒通过适当的研磨装置。
4.加入第5项并混合3分钟;在适当的压片机上挤压。
b)胶囊制剂:
制备步骤:
1.将第1、2和3项在适当的混合机中混合30分钟。
2.加入第4和5项并混合3分钟。
3.填充至适当的胶囊中。
在本发明的一个进一步的实施方案中,根据本发明的药物组合物优选为关于所述具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体和关于选自由环磷酰胺、长春新碱和多柔比星组成的组的所述化疗剂的两个单独的制剂。活性成分也可包埋在例如通过凝聚技术或通过界面聚合(interracial polymerization)制备的微胶囊中,所述微胶囊例如,分别用于胶体药物递送***(例如,脂质体、白蛋白微球、微乳液、纳米颗粒和纳米胶囊)或在大乳液(macroemulsion)中的羟甲基纤维素或明胶-微胶囊和聚(甲基丙烯酸甲酯)微胶囊。这些技术公开在Remington's Pharmaceutical Sciences(雷明顿制药学),第16版,Osol,A.主编(1980)中。
可制备缓释制剂。缓释制剂的适当例子包括含有抗体的固体疏水聚合物的半透性基质,该基质采用成形制品的形式,例如,膜,或微胶囊。缓释基质的例子包括聚酯、水凝胶(例如,聚(甲基丙烯酸2-羟基乙酯)或聚(乙烯醇))、聚丙交酯(US 3,773,919)、L-谷氨酸和L-谷氨酸γ-乙酯的共聚物、非可降解乙烯-乙酸乙酯、可降解的乳酸-乙醇酸共聚物诸如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和乙酸亮丙立德(leuprolide acetate)组成的可注射微球)、和聚-D-(-)-3-羟丁酸。
要用于体内施用的制剂必需是无菌的。这很容易地通过无菌过滤膜经过滤来完成。
本发明进一步提供了一种治疗癌症的方法,其包括对需要此治疗的患者施用(i)第一有效量的具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体;以及(ii)第二有效量的一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂。
本发明进一步提供了一种治疗癌症的方法,其包括对需要此治疗的患者施用(i)第一有效量的具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体;以及(ii)第二有效量的一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂。
在此使用的术语“患者”优选地指需要出于任何目的用II型抗CD20抗体治疗的人(例如,患有表达CD20的癌症的患者),并更优选地指需要该治疗来治疗癌症、或癌前病症或病变的人。然而,术语“患者”还可指非人动物,其中优选地是诸如犬、猫、马、牛、猪、羊和非人灵长类的哺乳动物。
本发明进一步包括用于与一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂联合治疗表达CD20的癌症的具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体。
本发明进一步包括用于与一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂联合治疗患有表达CD20的癌症的患者的具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体。
本发明进一步包括用于治疗表达CD20的癌症的具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体和一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂。
本发明进一步包括用于治疗患有表达CD20的癌症的患者的具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体和一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂。
优选地,所述具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体是糖基化改造的、人源化B-Ly1抗体。
优选地,所述表达CD20的癌症是B细胞非霍奇金淋巴瘤(NHL)。
下列的实施例、序列表和附图提供用于辅助理解本发明,本发明的真正范围在附加的权利要求中给出。要理解的是在不背离本发明的精神的前提下可对给出的程序进行修改。
序列表描述:
SEQ ID NO:1 鼠单克隆抗CD20抗体B-Ly1的重链可变区(VH)的氨基酸序列
SEQ ID NO:2 鼠单克隆抗CD20抗体B-Ly1的轻链可变区(VL)的氨基酸序列
SEQ ID NO:3-19 人源化B-Ly1抗体(B-HH2至B-HH9、B-HL8以及B-HL10至B-HL17)的重链可变区(VH)的氨基酸序列
SEQ ID NO:20 人源化B-Ly1抗体B-KV1的轻链可变区(VL)的氨基酸序列
附图说明
图1a)具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体(B-HH6-B-KV1GE)与环磷酰胺和长春新碱的联合治疗的协同抗肿瘤活性,和
b)与I型抗CD20抗体(利妥昔单抗)与环磷酰胺和长春新碱对WSU-DLCL2人B细胞非霍奇金淋巴瘤(NHL)的联合治疗的比较。
肿瘤体积的平均值[mm3]+/-IQR在y-轴上作图;注射肿瘤细胞后的天数在x-轴上作图。图例:A)赋形剂(圆圈),B)环磷酰胺(25mg/kg)和长春新碱(0.25mg/kg)每周一次(十字交叉形),C)利妥昔单抗(30mg/kg)每周一次(三角形),D)糖基化改造的、人源化B-ly1(B-HH6-B-KV1GE)(30mg/kg)每周一次(正方形),E)利妥昔单抗(30mg/kg)与环磷酰胺(25mg/kg)和长春新碱(0.25mg/kg)每周一次(菱形),和F)糖基化改造的、人源化B-ly1(B-HH6-B-KV1GE)(30mg/kg)与环磷酰胺(25mg/kg)和长春新碱(0.25mg/kg)每周一次(加号)。
图2I型抗CD20抗体(Cy5-利妥昔单抗=白色条形)和II型抗CD20抗体(Cy5-糖基化改造的、人源化B-Ly1B-HH6-B-KV1GE=黑色条形)在Raji细胞(ATCC编号:CCL-86)上的平均荧光强度(MFI,左侧y-轴);I型抗CD20抗体(利妥昔单抗)和II型抗CD20抗体(B-HH6-B-KV1GE)与CD20的结合力与利妥昔单抗比较的比值(按比例绘制在右侧y-轴上)。
图3a)具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体(B-HH6-B-KV1GE)与多柔比星的联合治疗的协同抗肿瘤活性,和
b)与I型抗CD20抗体(利妥昔单抗)与多柔比星对RL人滤泡非霍奇金淋巴瘤(NHL)的联合治疗的比较。
肿瘤体积的平均值[mm3]+/-IQR在y-轴上作图;注射肿瘤细胞后的天数在x-轴上作图。图例:A)赋形剂(加号),B)多柔比星(3mg/kg)每周一次(十字交叉形),C)利妥昔单抗(30mg/kg)每周一次(三角形),D)糖基化改造的、人源化B-ly1(B-HH6-B-KV1GE)(30mg/kg)每周一次(正方形),E)利妥昔单抗(30mg/kg)与多柔比星(3mg/kg)每周一次(菱形),和F)糖基化改造的、人源化B-ly1(B-HH6-B-KV1GE)(30mg/kg)与多柔比星(3mg/kg)每周一次(圆圈)。
图4a)具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体(B-HH6-B-KV1GE)与环磷酰胺的联合治疗的协同抗肿瘤活性,和
b)与I型抗CD20抗体(利妥昔单抗)与环磷酰胺对RL人滤泡非霍奇金淋巴瘤(NHL)的联合治疗的比较。
肿瘤体积的平均值[mm3]+/-IQR在y-轴上作图;注射肿瘤细胞后的天数在x-轴上作图。图例:A)赋形剂(圆圈),B)环磷酰胺(50mg/kg)每周一次(十字交叉形),C)利妥昔单抗(30mg/kg)每周一次(三角形),D)糖基化改造的、人源化B-ly1(B-HH6-B-KV1GE)(30mg/kg)每周一次(正方形),E)利妥昔单抗(30mg/kg)与环磷酰胺(50mg/kg)每周一次(菱形),和F)糖基化改造的、人源化B-ly1(B-HH6-B-KV1GE)(30mg/kg)与环磷酰胺(50mg/kg)每周一次(加号)。
试验程序
实施例1
具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体(B-HH6-B-KV1GE)与环磷酰胺和长春新碱的联合治疗的抗肿瘤活性
测试药剂:
II型抗CD20抗体B-HH6-B-KV1GE(=人源化B-Ly1,糖基化改造的B-HH6-B-KV1,见WO 2005/044859和WO 2007/031875)由瑞士施利伦格黎卡特(GlycArt,Schlieren,Switzerland)作为储液(c=9.4mg/ml)提供。抗体缓冲液包括组氨酸、海藻糖和聚山梨酸酯20。注射前,将抗体溶液由储液在PBS中适当地稀释。
利妥昔单抗由巴塞尔霍夫曼拉罗奇公司(Hoffmann La Roche,Basel)提供。
环磷酰胺和长春新碱作为临床制剂分别购自德国Baxter Oncology GmbH,Halle或德国汉堡medac,Gesellschaft für klinischembH(。从重构的储液调整稀释。
细胞系和培养条件:
WSU-DLCL2人非霍奇金淋巴瘤(NHL)细胞由美国新泽西Nutley霍夫曼拉罗奇有限公司(Hoffmann-La Roche,Inc.,Nutley,NJ,USA)友好提供。肿瘤细胞系常规地在添加了10%胎牛血清(PAA Laboratories,奥地利)和2mM L-谷氨酰胺的RPMI培养基(PAA,Laboratories,奥地利)中在37℃下在水饱和气氛中在5%CO2中培养。第4代用于移植。细胞与基质胶(matrigel)共同注射。
动物:
雌性SCID拜格小鼠(beige mice);到达时7–8周龄(购自Charles River,Sulzfeld,德国)根据被批准的指导方针(GV-Solas;Felasa;TierschG)在无特异病原菌条件下饲养,每天12小时昼/12小时夜循环。试验研究方案由当地政府评审并批准。到达后,动物在动物设施的检疫区饲养一周以使其适应新环境并用于观察。定期进行连续的健康监测。随意提供进食食物(Provimi Kliba 3337)和饮水(酸化至pH 2.5-3)。
监测:
每天监控动物的临床症状并检测不良反应。为了在整个试验中进行监测,动物的体重每周记录两次,并在分级后用测径器测量肿瘤体积。
动物的治疗:
在细胞植入后9天随机的一天开始动物治疗。糖基化改造的、人源化II型抗CD20抗体B-HH6-B-KV1GE或利妥昔单抗作为单一药剂在第9、15、23、30、37、44、51和58研究日时以30mg/kg的指定用药量经静脉内给药每7天1次(q7d)。在同一天给予相应的赋形剂。环磷酰胺和长春新碱在第9、15、23、30、37、44、51和58天分别以25mg/kg或0.25mg/kg每周一次经静脉内给药。在联合治疗组中,在施用化疗剂后24小时在第10,16,24,31,38,45,52和59天施用两种抗体。
体内肿瘤生长抑制研究:
在细胞植入后第35天,与对照组相比,在给予利妥昔单抗、抗CD20抗体B-HH6-B-KV1GE,化疗,化疗和抗CD20抗体联合或化疗和利妥昔单抗联合的动物中分别有73%,85%,66%,94%或90%的显著的肿瘤生长抑制。在实验结束时,与化疗/利妥昔单抗联合组相比较,在化疗/抗-CD20抗体B-HH6-B-KV1GE联合组中观察到显著更好的肿瘤生长抑制。
直到细胞植入后第64天研究结束时不同治疗的作用由肿瘤生长延迟值(T-C,其中T是治疗组肿瘤达到1500mm3的预定尺寸所需要的平均时间,以天为单位,C是对照组肿瘤达到相同尺寸的平均时间,以天为单位)表示。结果显示在下表中:
表3:
与对照组相比较治疗组的肿瘤生长延迟(以天为单位)
实施例2
II型抗CD20抗体的与Raji细胞(ATCC编号:CCL-86)上CD20的结合力与利妥昔单抗相比较的比值的测定
Raji细胞(ATCC-编号:CCL-86)在含有 10%FCS(Gibco,Cat.-No.10500-064)的RPMI-1640培养基(PanBiotech GmbH,Cat.-No.PO4-18500)中维持培养。II型抗CD20抗体B-HH6-B-KV1GE(糖基化改造的、人源化B-Ly1抗体)和利妥昔单抗使用Cy5单NHS酯(AmershamGE Healthcare(安玛西亚GE卫生保健),目录号PA15101)根据供应商的说明书进行标记。Cy5-缀合的利妥昔单抗的标记比为2.0分子Cy5/抗体。Cy5-缀合的B-HH6-B-KV1的标记比为2.2分子Cy5/抗体。为了测定和比较两个抗体的结合力和模式,使用伯基特淋巴瘤细胞系Raji(ATCC-编号:CCL-86)通过直接免疫荧光生成结合曲线(通过滴定Cy5-缀合的利妥昔单抗和Cy5-缀合的B-HH6-B-KV1GE)。分别将Cy5-缀合的利妥昔单抗和Cy5-缀合的B-HH6-B-KVGE的平均荧光强度(MFI)作为EC50(最大强度的50%)来分析。5*105细胞/样品在4℃下染色30分钟。然后,细胞在培养基中洗涤。使用碘化丙啶(PI)染色来排除死细胞。使用FACSArray(Becton Dickinson)进行测量。在远红外A(Far Red A)处测量碘化丙啶(PI),并且在红外-A(Red-A)处测量Cy5。图2显示在Cy5-标记的B-HH6-B-KV1GE(黑色条形)和Cy5-标记的利妥昔单抗(白色条形)的EC50(最大强度的50%)处结合的平均荧光强度(MFI)。
然后根据下式计算与Raji细胞(ATCC-编号:CCL-86)上CD20的结合力的比值:
与Raji细胞(ATCC-编号:CCL-86)上CD20的结合力的比值=
因此,作为典型的II型抗CD20抗体的B-HH6-B-KV1GE显示结合力与利妥昔单抗相比较是减小的。
实施例3
具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体(B-HH6-B-KV1GE)与多柔比星的联合治疗的抗肿瘤活性
测试药剂:
II型抗CD20抗体B-HH6-B-KV1GE(=人源化B-Ly1,糖基化改造的B-HH6-B-KV1,见WO 2005/044859和WO 2007/031875)由瑞士施利伦格黎卡特(GlycArt,Schlieren,Switzerland)作为储液(c=9.4mg/ml)提供。抗体缓冲液包括组氨酸、海藻糖和聚山梨酸酯20。注射前,将抗体溶液由储液在PBS中适当地稀释。
利妥昔单抗由巴塞尔霍夫曼拉罗奇(Hoffmann La Roche,Basel)提供。
多柔比星作为临床制剂购自Hexal,Holzkirchen,德国。从重构的储液调整稀释。
细胞系和培养条件:
人RL滤泡非霍奇金淋巴瘤细胞由法国里昂INSERM 590的Charles Dumontet博士友好提供。肿瘤细胞系常规地在添加了10%胎牛血清(PAA Laboratories,奥地利)和2mML-谷氨酰胺的RPMI培养基(PAA,Laboratories,奥地利)中,在37℃下在水饱和气氛中在5%CO2中培养。第2代用于移植。
动物:
雌性SCID拜格小鼠;到达时7–8周龄(购自Charles River,Sulzfeld,德国)根据被批准的指导方针(GV-Solas;Felasa;TierschG)在无特异病原菌条件下饲养,每天12小时昼/12小时夜循环。试验研究方案由当地政府评审并批准。到达后,动物在动物设施的检疫区饲养一周以使其适应新环境并用于观察。定期进行连续的健康监测。随意提供进食食物(Provimi Kliba3337)和饮水(酸化至pH 2.5-3)。
监测:
每天监控动物的临床症状并检测不良反应。为了在整个试验中进行监测,动物的体重每周记录两次,并在分级后用测径器测量肿瘤体积。
动物的治疗:
在细胞植入后14天随机的一天时开始动物治疗。糖基化改造的、人源化II型抗CD20抗体(B-HH6-B-KV1GE)或利妥昔单抗作为单一药剂在第14、21、28、36和42研究日时以30mg/kg或60mg/kg的指定用药量经静脉内给药每7天1次(q7d)。在相同的日子施用相对应的赋形剂以及多柔比星,其以3mg/kg每周一次静脉内给药。在联合治疗组中,多柔比星在第15、22、29、37和43天以3mg/kg每周一次静脉内给药,并且在联合治疗组中,利妥昔单抗在相同的日子以30mg/kg每周一次静脉内给药。
实施例4
II型抗CD20抗体(B-HH6-B-KV1GE)和环磷酰胺在RL细胞系中的联合治疗的抗肿瘤活性
测试药剂:
II型抗CD20抗体B-HH6-B-KV1GE(=人源化B-Ly1,糖基化改造的B-HH6-B-KV1,见WO 2005/044859和WO 2007/031875)由瑞士施利伦格黎卡特(GlycArt,Schlieren,Switzerland)作为储液(c=9.4mg/ml)提供。抗体缓冲液包括组氨酸、海藻糖和聚山梨酸酯20。注射前,将抗体溶液由储液在PBS中适当地稀释。
I型抗CD20抗体利妥昔单抗由瑞士巴塞尔霍夫曼拉罗奇(Hoffmann La Roche,Basel,Switzerland)作为储液(c=10mg/ml)提供。缓冲液包含聚山梨酸酯80,氯化钠和柠檬酸钠。
环磷酰胺作为临床制剂购自德国Baxter Oncology GmbH,Halle(BaxterOncology GmbH,Halle,Germany)或德国汉堡medac,Gesellschaft für klinischembH(medac,Gesellschaft für klinischembH,Hamburg,Germany)。从重构的储液调整稀释。
细胞系和培养条件:
人RL滤泡非霍奇金淋巴瘤细胞系常规地在添加了10%胎牛血清和抗生素的RPMI1640培养基中培养。RL细胞以悬浮式生长并且形成簇。将指数生长的细胞皮下注射到SCID小鼠中。
动物:
所用的动物是6周龄的雌性SCID小鼠,由具有IPSOS地位(status)的CharlesRiver(L’Arbresle,France)提供。动物在注射RL细胞前笼养至少一周。各笼容纳5只动物。
监测:
每天监控动物的临床症状并检测不良反应。为了在整个试验中进行监测,动物的体重每周记录两次,并在分级后用测径器测量肿瘤体积。动物的研究排除标准由当地实验动物委员会记述并核准。
动物的治疗:
治疗随机地在细胞植入后31天开始。将人源化的II型抗CD20抗体B-HH6-B-KV1GE、赋形剂或利妥昔单抗以30mg/kg的剂量每周一次(在第31、38、45和52天)静脉内给予动物。环磷酰胺在相同的日子以50mg/kg的剂量注射。使用之前,由储液新鲜制备抗体稀释液。
体内肿瘤生长抑制研究:
在细胞植入后第66天,在给予利妥昔单抗和环磷酰胺、抗CD20抗体B-HH6-B-KV1GE和利妥昔单抗或抗CD20抗体B-HH6-B-KV1GE和环磷酰胺的组合的动物中,存在54%,85%或91%的显著的肿瘤生长抑制。因此,与仅使用环磷酰胺治疗相比,抗CD20抗体B-HH6-B-KV1GE和环磷酰胺的联合治疗产生最佳抗肿瘤活性。
序列表
<110> 霍夫曼-拉罗奇有限公司
<120> 具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体的组合疗法
<130> 24858
<150> 08005554.4
<151> 2008-03-25
<150> 08007172.3
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<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HH4)的重链可变区(VH)的氨基酸序列
<400> 5
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 6
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HH5)的重链可变区(VH)的氨基酸序列
<400> 6
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 7
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HH6)的重链可变区(VH)的氨基酸序列
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 8
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HH7)的重链可变区(VH)的氨基酸序列
<400> 8
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 9
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HH8)的重链可变区(VH)的氨基酸序列
<400> 9
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 10
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HH9)的重链可变区(VH)的氨基酸序列
<400> 10
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 11
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL8)的重链可变区(VH)的氨基酸序列
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 12
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL10)的重链可变区(VH)的氨基酸序列
<400> 12
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 13
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL11)的重链可变区(VH)的氨基酸序列
<400> 13
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 14
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL12)的重链可变区(VH)的氨基酸序列
<400> 14
Glu Val Gln Leu Val Glu Ser Gly Ala Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 15
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL13)的重链可变区(VH)的氨基酸序列
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 16
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL14)的重链可变区(VH)的氨基酸序列
<400> 16
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Lys Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 17
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL15)的重链可变区(VH)的氨基酸序列
<400> 17
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ser
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 18
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL16)的重链可变区(VH)的氨基酸序列
<400> 18
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Val Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 19
<211> 119
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体(B-HL17)的重链可变区(VH)的氨基酸序列
<400> 19
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 20
<211> 115
<212> PRT
<213> 人工的
<220>
<223> 人源化B-Ly1抗体B-KV1的轻链可变区(VL)的氨基酸序列
<400> 20
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn
85 90 95
Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val
115
Claims (13)
1.具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体用于制备用于与一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂联合治疗表达CD20的癌症的药物的应用。
2.具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体用于制备用于与一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂联合治疗患有表达CD20的癌症的患者的药物的应用。
3.根据权利要求1或2任意一项所述的应用,其特征在于所述使用II型抗CD20抗体的治疗与环磷酰胺和长春新碱联合。
4.根据权利要求1或2任意一项所述的应用,其特征在于所述使用II型抗CD20抗体的治疗与多柔比星联合。
5.根据权利要求1或2任意一项所述的应用,其特征在于所述使用II型抗CD20抗体的治疗与环磷酰胺联合。
6.根据权利要求1或2任意一项所述的应用,其特征在于所述使用II型抗CD20抗体的治疗与环磷酰胺、长春新碱和多柔比星联合。
7.根据权利要求1-5中任意一项所述的应用,其特征在于所述II型抗CD20抗体是糖基化改造的、人源化B-Ly1抗体。
8.根据权利要求1-6中任意一项所述的应用,其特征在于所述表达CD20的癌症是B细胞非霍奇金淋巴瘤(NHL)。
9.根据权利要求1-7中任意一项所述的应用,其特征在于施用一种另外的皮质类固醇,优选***。
10.药物组合物,其用于表达CD20的癌症特别是B细胞非霍奇金淋巴瘤(NHL),所述药物组合物包括具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体和一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂。
11.具有增加的抗体依赖性细胞毒性(ADCC)的II型抗CD20抗体,其与一种或多种选自由环磷酰胺、长春新碱和多柔比星组成的组的化疗剂联合用于治疗患有表达CD20的癌症的患者。
12.根据权利要求11所述的II型抗CD20抗体,其特征在于所述II型抗CD20抗体是糖基化改造的、人源化B-Ly1抗体。
13.根据权利要求12所述的II型抗CD20抗体,其特征在于所述表达CD20的癌症是B细胞非霍奇金淋巴瘤(NHL)。
Applications Claiming Priority (5)
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EP08005554 | 2008-03-25 | ||
EP08005554.4 | 2008-03-25 | ||
EP08007172 | 2008-04-11 | ||
EP08007172.3 | 2008-04-11 | ||
CN2009801101810A CN101983071A (zh) | 2008-03-25 | 2009-03-23 | 具有增加的抗体依赖性细胞毒性(adcc)的ⅱ型抗cd20抗体与环磷酰胺、长春新碱和多柔比星联合治疗非霍奇金淋巴瘤的应用 |
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CN2009801101810A Division CN101983071A (zh) | 2008-03-25 | 2009-03-23 | 具有增加的抗体依赖性细胞毒性(adcc)的ⅱ型抗cd20抗体与环磷酰胺、长春新碱和多柔比星联合治疗非霍奇金淋巴瘤的应用 |
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CN201611215290.7A Pending CN107198772A (zh) | 2008-03-25 | 2009-03-23 | Ii型抗cd20抗体与环磷酰胺、长春新碱和多柔比星联合治疗非霍奇金淋巴瘤的应用 |
CN2009801101810A Pending CN101983071A (zh) | 2008-03-25 | 2009-03-23 | 具有增加的抗体依赖性细胞毒性(adcc)的ⅱ型抗cd20抗体与环磷酰胺、长春新碱和多柔比星联合治疗非霍奇金淋巴瘤的应用 |
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CN2009801101810A Pending CN101983071A (zh) | 2008-03-25 | 2009-03-23 | 具有增加的抗体依赖性细胞毒性(adcc)的ⅱ型抗cd20抗体与环磷酰胺、长春新碱和多柔比星联合治疗非霍奇金淋巴瘤的应用 |
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EP (1) | EP2268310B1 (zh) |
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CN (2) | CN107198772A (zh) |
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BR (1) | BRPI0909227B8 (zh) |
CA (1) | CA2716884C (zh) |
CL (1) | CL2009000713A1 (zh) |
CR (1) | CR11687A (zh) |
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MA (1) | MA32140B1 (zh) |
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PE (1) | PE20091821A1 (zh) |
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PT (1) | PT2268310T (zh) |
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TW201438738A (zh) | 2008-09-16 | 2014-10-16 | Genentech Inc | 治療進展型多發性硬化症之方法 |
AR078161A1 (es) | 2009-09-11 | 2011-10-19 | Hoffmann La Roche | Formulaciones farmaceuticas muy concentradas de un anticuerpo anti cd20. uso de la formulacion. metodo de tratamiento. |
MX342405B (es) | 2010-06-03 | 2016-09-28 | Pharmacyclics Inc | El uso de inhibidores de la tirosina quinasa de bruton (btk). |
KR20130088170A (ko) * | 2010-12-16 | 2013-08-07 | 로슈 글리카트 아게 | 비푸코실화 cd20 항체와 mdm2 저해제와의 조합 치료 |
US20130302274A1 (en) * | 2011-11-25 | 2013-11-14 | Roche Glycart Ag | Combination therapy |
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