CN111116745A - 抗CD79b抗体、其药物偶联物及其应用 - Google Patents
抗CD79b抗体、其药物偶联物及其应用 Download PDFInfo
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- CN111116745A CN111116745A CN201811296100.8A CN201811296100A CN111116745A CN 111116745 A CN111116745 A CN 111116745A CN 201811296100 A CN201811296100 A CN 201811296100A CN 111116745 A CN111116745 A CN 111116745A
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Abstract
本发明涉及抗CD79b抗体或其抗原结合片段、其药物偶联物及其应用。本发明的抗CD79b抗体或其抗原结合片段包含:HCDR1,其含有SEQ ID NO:1所示的氨基酸序列;HCDR2,其含有SEQ ID NO:2所示的氨基酸序列;HCDR3,其含有SEQ ID NO:3所示的氨基酸序列;LCDR1,其含有SEQ ID NO:4所示的氨基酸序列;LCDR2,其含有SEQ ID NO:5所示的氨基酸序列;和LCDR3,其含有SEQ ID NO:6所示的氨基酸序列。
Description
技术领域
本发明涉及抗CD79b抗体、其药物偶联物及其应用。
背景技术
CD79b(即Igβ或B29)是B细胞受体的信号成分,与CD79a(即Igα或mb-1)形成共价异二聚体起作用。CD79b含有一个胞外免疫球蛋白(Ig)域、一个跨膜域和一个胞内信号域。通过使用流式细胞术已在几乎所有非霍奇金淋巴瘤(NHL)和慢性淋巴细胞性白血病(CLL)患者中检测到CD79b的表面表达。除信号功能外,当B细胞受体交联时,它被靶向至II类主要组织相容性复合物隔室(一种溶酶体样隔室),作为B细胞进行的II类抗原呈递的一部分。
CD79b生物学的这种特征使得它成为抗体-药物偶联物(ADC)的靶点,因为针对CD79b的抗体被内在化并被递送至已知含有能释放细胞毒性药物的蛋白酶的溶酶体隔室。抗体-药物偶联物(ADC)能够将药物靶向递送至肿瘤并且在其中发生胞内蓄积。提高ADC的治疗指数(即最高的功效与最低的毒性)的努力已经集中到多克隆抗体和单克隆抗体的特异性以及药物连接和药物释放特性上。
已经制备了各种ADC,如人源化抗CD79b抗体(人源化SN8)通过蛋白酶可切割连接子偶联至单甲基奥瑞司他汀E(MMAE),该ADC临床上能有效治疗NHL。
发明内容
本文提供抗CD79b抗体或其功能性片段,其药物组合物或药物偶联物,及其在血液肿瘤治疗中的使用。
一方面,本文提供一种抗CD79b抗体或其抗原结合片段,其包含:
HCDR1,其含有SEQ ID NO:1所示的氨基酸序列;
HCDR2,其含有SEQ ID NO:2所示的氨基酸序列;
HCDR3,其含有SEQ ID NO:3所示的氨基酸序列;
LCDR1,其含有SEQ ID NO:4所示的氨基酸序列;
LCDR2,其含有SEQ ID NO:5所示的氨基酸序列;
LCDR3,其含有SEQ ID NO:6所示的氨基酸序列。
在一个或多个实施方案中,本文所述的抗CD79b抗体为单克隆抗体、人抗体、人源化抗体或嵌合抗体。
在一个或多个实施方案中,本文的抗CD79b抗体或其抗原结合片段的HCDR1的氨基酸序列如SEQ ID NO:1所示,HCDR2的氨基酸序列如SEQ ID NO:2所示,HCDR3的氨基酸序列如SEQ ID NO:3所示,LCDR1的氨基酸序列如SEQ ID NO:4所示;LCDR2的氨基酸序列如SEQID NO:5所示;LCDR3的氨基酸序列如SEQ ID NO:6所示。
在一个或多个实施方案中,本文的抗CD79b抗体的重链可变区的氨基酸序列如SEQID NO:7或11所示,和/或本文的抗CD79b抗体的轻链可变区的氨基酸序列如SEQ ID NO:8或12所示。
在一个或多个实施方案中,本文抗CD79b抗体的重链可变区的氨基酸序列选自SEQID NO:13-17中任一序列所示的氨基酸序列,和/或本文抗CD79b抗体的轻链可变区的氨基酸序列选自SEQ ID NO:18-22中任一序列所示的氨基酸序列。
在一个或多个实施方案中,本文抗CD78b抗体包含(a)与SEQ ID NO:25、27、29、31或33具有至少90%、优选至少95%、更优选至少98%的序列同源性的重链,(b)与SEQ IDNO:26、28、30、32或34具有至少90%、优选至少95%、更优选至少98%的序列同源性的轻链,或(c)(a)所述的重链和(b)所述的轻链。
在一个或多个实施方案中,本文的抗CD79b抗体的重链的氨基酸序列选自与SEQID NO:25、27、29、31和33中任一序列所示的氨基酸序列具有至少90%、优选至少95%的序列同一性的氨基酸序列,和/或本文的抗CD79b抗体的轻链的氨基酸序列选自与SEQ ID NO:26、28、30、32和34中任一序列所示的氨基酸序列具有至少90%、优选至少95%的序列同一性的氨基酸序列。
在一个或多个实施方案中,本文的抗CD79b抗体选自以下抗体:
(1)重链的氨基酸序列如SEQ ID NO:25所示、轻链的氨基酸序列如SEQ ID NO:26所示的抗体;
(2)重链的氨基酸序列如SEQ ID NO:27所示、轻链的氨基酸序列如SEQ ID NO:28所示的抗体;
(3)重链的氨基酸序列如SEQ ID NO:29所示、轻链的氨基酸序列如SEQ ID NO:30所示的抗体;
(4)重链的氨基酸序列如SEQ ID NO:31所示、轻链的氨基酸序列如SEQ ID NO:32所示的抗体;和
(5)重链的氨基酸序列如SEQ ID NO:33所示、轻链的氨基酸序列如SEQ ID NO:34所示的抗体。
另一方面,本文提供一种抗体-药物偶联物,其为本文所述抗体与细胞毒剂的偶联物。
在一个或多个实施方案中,所述细胞毒剂为化疗药物、生长抑制剂、毒素或放射性同位素。
另一方面,本文提供一种药物组合物,所述药物组合物包含本文所述的抗体或抗体-药物偶联物,及药学可接受的载体。
另一方面,本文提供一种制品,其包含容器和装在该容器内的组合物,其中所述组合物包含一种或多种本文所述的CD79b抗体。在某些实施方案中,所述制品是试剂盒,其包含第一容器,其中装有包含一种或多种本文所述CD79b抗体的组合物;及第二容器,其中装有缓冲液。
另一方面,本文提供本文所述的CD79b抗体或其抗原结合片段在制备用于治疗或预防CD79b介导的疾病的药物中的用途。在某些实施方案中,所述疾病血液肿瘤,尤其是B细胞增殖性病症。在某些实施方案中,所述疾病为淋巴瘤或白血病。在某些实施方案中,所述疾病为非霍奇金氏淋巴瘤(NHL)、攻击性NHL、复发性攻击性NHL、复发性无痛性NHL、顽固性NHL、顽固性无痛性NHL、小淋巴细胞性淋巴瘤、套细胞淋巴瘤、慢性淋巴细胞性白血病(CLL)、毛细胞白血病(HCL)或急性淋巴细胞性白血病(ALL)。
另一方面,本文还提供一种抑制表达CD79b的细胞生长的方法,所述方法包括使所述细胞接触本文所述的抗体或抗体-药物偶联物,由此引起对所述细胞生长的抑制。在某些实施方案中,所述细胞为B细胞。
另一方面,本文提供一种治疗CD79b介导的疾病的方法,所述方法包括给予有需要的哺乳动物治疗有效量的本文所述的抗体或抗体-药物偶联物。在某些实施方案中,所述CD79b介导的疾病为癌症。
再一方面,本文还提供一种测定怀疑含有CD79b的样品中CD79b的存在情况的方法,所述方法包括使所述样品暴露于本文所述的抗体,并测定所述抗体对所述样品中CD79b的结合,其中所述抗体结合所述样品中的CD79b指示所述样品中存在所述蛋白质。
再一方面,本文还提供一种诊断与表达CD79b的细胞(诸如B细胞)增多有关的细胞增殖性病症的方法,所述方法包括使生物学样品中的测试细胞接触本文所述抗体;通过检测所述抗体对CD79b的结合来测定结合至所述样品中测试细胞的抗体的水平;并比较结合至对照样品中细胞的抗体的水平,其中将所结合的抗体的水平相对于测试和对照样品中表达CD79b的细胞的数目标准化,且其中测试样品中所结合的抗体的水平高于对照样品指明存在与表达CD79b的细胞有关的细胞增殖性病症。在某些实施方案中,所述生物学样品为血液或血清。
附图说明
图1:人源化抗体的亲和力测试结果。
图2:AS11259-ADC-001、002、004对人B细胞淋巴瘤Ramos裸鼠皮下移植瘤的疗效。
图3:AS11259-ADC-010、0012、011、008对人B细胞淋巴瘤Ramos裸鼠皮下移植瘤的疗效。
图4:AS11259-ADC-001、002、004、对人淋巴瘤Granta-519裸鼠皮下移植瘤的疗效。
图5:AS11259-ADC-001、0012、011、010对人淋巴瘤Granta-519裸鼠皮下移植瘤的疗效。
图6:AS11259-ADC-001、004对人淋巴瘤WSU-DLCL2裸鼠皮下移植瘤的疗效。
图7:AS11259-ADC-001、0012、011、010对人淋巴瘤WSU-DLCL2裸鼠皮下移植瘤的疗效。
具体实施方式
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的技术方案。
除非另有定义,本发明的实施将采用分子生物学(包括重组技术)、微生物学、细胞生物学、生物化学和免疫学的常规技术,这些都在本领域的技术范围内。这些技术在文献中有充分解释,诸如Molecular Cloning:A Laboratory Manual(分子克隆:实验室手册),第二版(Sambrook等,1989);Oligonucleotide Synthesis(寡核苷酸合成)(M.J.Gait,编辑,1984);Animal Cell Culture(动物细胞培养)(R.I.Freshney,编辑,1987);Methods inEnzymology(酶学中的方法)(Academic Press,Inc.);Current Protocols in MolecularBiology(当代分子生物学方案)(F.M.Ausubel等,编辑1987,和定期更新);PCR:ThePolymerase Chain Reaction(PCR:聚合酶链反应),(Mullis等,编辑,1994);A PracticalGuide to Molecular Cloning(分子克隆实用指南)(Perbal Bernard V.,1988);PhageDisplay:A Laboratory Manual(噬菌体展示:实验室手册)(Barbas等,2001)。
本文中,“分离的”抗体指已经鉴定且与其天然环境的一种成分分开的抗体。在优选的实施方案中,将抗体纯化至(1)根据Lowry法的测定,抗体重量超过95%,最优选重量超过99%,(2)足以通过使用转杯式测序仪获得至少15个残基的N-末端或内部氨基酸序列的程度,或(3)根据还原性或非还原性条件下的SDS-PAGE及使用考马斯蓝或优选的银染色,达到同质。
术语“CD79b”指来自任何脊椎动物来源(包括哺乳动物,诸如灵长类(例如人、猕猴)和啮齿类(例如小鼠和大鼠)的任何天然CD79b,除非另有说明。术语“CD79b”涵盖“全长”、未加工的CD79b以及自细胞中加工得到的任何形式的CD79b。该术语还涵盖天然存在的CD79b变体,例如剪接变体、等位变体和同等型。本文所述CD79b多肽可以从多种来源分离,诸如人组织类型或其它来源,或者通过重组或合成方法制备。“天然序列CD79b多肽”包括与自然界衍生的相应CD79b多肽具有相同氨基酸序列的多肽。此类天然序列CD79b多肽可以从自然界分离,或者可以通过重组或合成方法制备。术语“天然序列CD79b多肽”明确涵盖天然存在的截短或分泌形式的特定CD79b多肽(例如胞外结构域序列)、该多肽的天然存在变异形式(例如可变剪接形式)和天然存在等位变体。
CD79b多肽“胞外结构域”或“ECD”指CD79b多肽基本上不含跨膜结构域和胞质结构域的形式。通常,CD79b多肽ECD具有少于1%的此类跨膜结构域和/或胞质结构域,优选具有少于0.5%的此类结构域。跨膜结构域的精确边界可以变化,优选的是,CD79b多肽的胞外结构域可包含实施例或说明书中所鉴定的跨膜结构域/胞外结构域边界任一侧的约5个或5个以下的氨基酸。在某些个实施方案中,本文所述的CD79b ECD的氨基酸序列如SEQ ID NO:35所示。
术语“抗体”包括单克隆抗体(包括具有免疫球蛋白Fc区的全长抗体),具有多表位特异性的抗体组合物,多特异性抗体(例如,双特异性抗体),双抗体和单链分子,以及抗体片段(例如,Fab,F(ab′)2,和Fv)。术语“免疫球蛋白”(Ig)和“抗体”可互换使用。
术语“CD79b抗体”或类似术语指能够以足够亲和力结合CD79b的抗体。优选的是,根据例如放射免疫测定法(RIA)的测量,CD79b抗体结合无关的非CD79b蛋白质的程度小于该抗体对CD79b的结合的约10%。在某些实施方案中,与CD79b结合的抗体具有≤10nM、≤1nM或≤0.1nM的解离常数(Kd)。在某些实施方案中,抗CD79b抗体结合在来自不同物种的CD79b间保守的CD79b表位。
抗体的“可变区”或“可变结构域”是指抗体的重链或轻链的氨基末端结构域。重链和轻链的可变结构域可分别称为“VH”和“VL”。这些结构域通常是抗体的最可变的部分(相对于相同类型的其它抗体)并含有抗原结合位点。
术语“可变的”指可变结构域中的某些区段在抗体序列中差异广泛的情况。可变结构域介导抗原结合并限定特定抗体对其特定抗原的特异性。然而,变异性并非均匀分布于可变域跨越的110个氨基酸。事实上,可变区由长15-30个氨基酸的称作框架区(FR)的相对不变异的区段和将框架区分开的每个长度为9-12个氨基酸的、称作“高变区”的极度变异的较短区域组成。天然重链和轻链的可变结构域各自包含四个FR区,它们大多采取β-折叠构象。每条链中的HVR通过FR区非常接近的保持在一起,并与另一条链的HVR一起促成抗体的抗原结合位点的形成。恒定结构域不直接参与抗体与抗原的结合,但展现出多种效应子功能。
术语“单克隆抗体”在本文指从一群基本上同质的抗体中获得的抗体,即除了可能以少量存在的可能的天然出现的突变和/或翻译后修饰(例如异构化、酰胺化)之外,构成群体的各个抗体是相同的。单克隆抗体是高度特异性的,针对单个抗原位点。与多克隆抗体制剂(其典型地包括针对不同表位的不同抗体)相比,每个单克隆抗体针对抗原上的单个决定簇。除它们的特异性外,单克隆抗体的优势在于它们通过杂交瘤培养合成,未受到其它免疫球蛋白的污染。“单克隆”表明抗体从基本上同质的抗体群获得,不应解释为要求通过任何特定方法来生产抗体。例如,将根据本发明使用的单克隆抗体可通过多种技术来生成,包括例如杂交瘤法(例如,Kohler和Milstein,Nature(自然),256:495-97(1975))中、重组DNA法(例如,美国专利No.4,816,567)、噬菌体展示技术(例如,Clackson等,Nature(自然),352:624-628(1991))、及用于从具有部分或整个人免疫球蛋白基因座或编码人免疫球蛋白序列的基因的动物生成人或人样抗体的技术(例如,WO1998/24893)。
术语“全长抗体”、“完整抗体”或“完全抗体”可互换地使用,指包含抗原结合位点以及CL和至少重链恒定域CH1、CH2和CH3的抗体。恒定结构域可以是天然序列恒定结构域(例如,人天然序列恒定结构域)或其氨基酸序列变体。在一些情况中,完整抗体可具有一种或多种效应子功能。
“抗体片段”包含完整抗体的一部分,优选包含完整抗体的抗原结合区和/或可变区。抗体片段的例子包括Fab、Fab’、F(ab’)2和Fv片段;双抗体;线性抗体(参见美国专利5,641,870);单链抗体(scFv)分子;及由抗体片段形成的多特异性抗体。用木瓜蛋白酶消化抗体产生称作“Fab”片段的两个相同的抗原结合片段,和一个残余“Fc”片段。Fab片段由完整轻链及重链可变结构域(VH)和一条重链第一恒定结构域(CH1)组成。每个Fab片段在抗原结合方面是单价的,即其具有单个抗原结合位点。胃蛋白酶处理抗体产生一个较大的F(ab’)2片段,它粗略相当于两个通过二硫键相连的Fab片段,具有不同的抗原结合活性且仍能够交联抗原。Fab’片段因在CH1结构域的羧基末端增加了一些另外的残基(包括来自抗体铰链区的一个或多个半胱氨酸)而与Fab片段有所不同。F(ab’)2抗体片段最初是作为成对Fab’片段生成的,在Fab’片段之间具有铰链半胱氨酸。抗体片段的其它化学偶联也是已知的。Fc片段包含通过二硫键保持在一起的两条重链的羧基末端部分。抗体的效应子功能是由Fc区中的序列决定的,该区还是由在某些类型细胞上发现的Fc受体(FcR)所识别的区。
“Fc区”或Fc片段在本文中用于定义免疫球蛋白重链的C-端区域,包括天然序列Fc区和变异Fc区。虽然免疫球蛋白重链Fc区的边界可以变化,但是人IgG重链Fc区通常定义为自其Cys226或Pro230位置的氨基酸残基至羧基末端的区段。Fc区的C-末端赖氨酸(残基447,依照EU编号系统)可以消除,例如在生产或纯化抗体的过程中,或者通过对编码抗体重链的核酸进行重组工程改造。因而,完整抗体的偶联物可以包括所有K447残基都被消除的抗体偶联物、无一K447残基被消除的抗体偶联物或者混合了有K447残基的抗体和没有K447残基的抗体的偶联物。“功能性Fc区”拥有天然序列Fc区的效应器功能。示例性的效应器功能包括C1q结合、CDC、Fc受体结合、ADCC、吞噬作用、细胞表面受体(例如B细胞受体)下调等。“天然序列Fc区”包含与在自然界中找到的Fc区的氨基酸序列相同的氨基酸序列。天然序列人Fc区包括天然序列人IgG1Fc区;天然序列人IgG2Fc区;天然序列人IgG3Fc区;和天然序列人IgG4Fc区;及其天然存在变体。“变异Fc区”包含由于至少一处氨基酸修饰(优选一处或多处氨基酸替代)而与天然序列Fc区有所不同的氨基酸序列。优选的是,变异Fc区与天然序列Fc区相比或与亲本多肽的Fc区相比具有至少一处氨基酸替代,例如在天然序列Fc区中或在亲本多肽的Fc区中具有约1处至约10处氨基酸替代,优选约1处至约5处氨基酸替代。变异Fc区在本文中优选与天然序列Fc区和/或亲本多肽的Fc区拥有至少约80%的同源性,最优选与它们具有至少约90%的同源性,更优选与它们具有至少约95%的同源性。
“Fv”是含有完整抗原识别和结合位点的最小抗体片段。该片段由紧密、非共价结合的一个重链可变结构域和一个轻链可变结构域的二聚体组成。从这两个结构域的折叠中突出了六个高变环(重链和轻链各3个环),贡献出抗原结合的氨基酸残基并赋予抗体以抗原结合特异性。然而,即使是单个可变结构域(或只包含对抗原特异的三个HVR的半个Fv)也具有识别和结合抗原的能力,尽管亲合力低于完整结合位点。
“单链Fv”也可缩写为“scFv”,是抗体VH和VL结构域连接成一条多肽链的抗体片段。优选的是,scFv多肽在VH和VL结构域之间还包含多肽连接子,使得sFv形成期望的抗原结合结构。
“双抗体”指具有两个抗原结合位点的抗体片段,该片段在同一条多肽链(VH-VL)中包含相连的重链可变域(VH)和轻链可变域(VL)。通过在VH和VL结构域之间使用短连接子(约5-10个残基)构建scFv片段来制备小型抗体片段,由于连接子短,使得可变结构域实行链间而非链内配对,导致二价片段,即具有两个抗原结合位点的片段。双抗体可以是二价的或双特异性的。双特异性双抗体是两个“交叉”scFv片段的异二聚体,其中两种抗体的VH和VL结构域存在于不同多肽链上。
本文所述抗体的“功能性片段”或“抗原结合片段”包括完整抗体的一部分,通常包括该完整抗体的抗原结合区或可变区,或抗体的保留或具有修饰的FcR结合能力的Fc区。抗体功能性片段的例子包括线性抗体、单链抗体(scFv)、和由抗体片段形成的多特异性抗体,尤其是指Fv、scFv、Fab、F(ab’)2、Fab’、scFv-Fc片段或者双抗体(diabody)、或者通过化学修饰或通过掺入脂质体中应能够增加半衰期的任何片段,所述化学修饰包括添加聚(亚烷基)二醇如聚乙二醇,即聚乙二醇(PEG)化修饰(被称为Fv-PEG、scFv-PEG、Fab-PEG、F(ab')2-PEG或Fab'-PEG的聚乙二醇化片段),所述片段具有CD79b结合活性。
优选地,本文所述抗体的功能性片段由其来源抗体的重链可变区或轻链可变区的部分序列构成或者包含它们,所述部分序列足以保留与其来源抗体相同的结合特异性和充分的亲和力。这种功能性片段将包含最少5个氨基酸,优选其来源的抗体序列的10、15、25、50和100个连续氨基酸。
单克隆抗体在本文中包括“嵌合”抗体(免疫球蛋白)。嵌合抗体中,重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源,而另一部分与衍生自另一物种或属于另一抗体类别或亚类的抗体中的相应序列相同或同源。
“人源化抗体”是“嵌合抗体”的一个具体种类。非人(例如啮齿类)抗体的“人源化”形式指最低限度包含衍生自非人抗体的序列的嵌合抗体。在极大程度上,人源化抗体指人免疫球蛋白(受体抗体)中的高变区残基用具有期望抗体特异性、亲和力和能力的非人物种(供体抗体)诸如小鼠、大鼠、兔或非人灵长类动物的高变区残基替换的免疫球蛋白。在有些情况中,将人免疫球蛋白的框架区(FR)残基用相应的非人残基替换。此外,人源化抗体可包含在受体抗体或供体抗体中没有找到的残基。进行这些修饰是为了进一步改进抗体的性能。一般而言,人源化抗体将包含至少一个、通常两个基本上整个如下可变域,其中所有或基本上所有高变环对应于非人免疫球蛋白的高变环,且所有或基本上所有FR是人免疫球蛋白序列的FR。人源化抗体任选还将包含至少部分免疫球蛋白恒定区(Fc),通常是人免疫球蛋白的恒定区。人源化抗体可由免疫小鼠产生的鼠源抗体经由计算机模拟设计并结合噬菌体展示技术而得到。
“人抗体”指这样的抗体,其具有与由人生成的抗体的氨基酸序列对应的氨基酸序列和/或使用本领域周知的用于生成人抗体的任何技术产生。人抗体明确排除包含非人抗原结合残基的人源化抗体。人抗体可使用本领域已知的多种技术来生成,包括噬菌体展示文库。
“结合亲和力”通常指分子(例如抗体)的单一结合位点与其结合配偶体(例如抗原)之间全部非共价相互作用总和的强度。除非另有说明,在用于本文时,“结合亲和力”指反映结合对的成员(例如抗体与抗原)之间1∶1相互作用的内在结合亲和力。分子X对其配偶体Y的亲和力通常可用解离常数(Kd)来表述。低亲和力抗体通常缓慢的结合抗原且趋于容易解离,而高亲和力抗体通常更快速的结合抗原且趋于保持更长时间的结合。亲和力可通过本领域知道的常用方法来测量,包括放射性标记抗原结合测定法(RIA)
“控制序列”指在特定宿主生物体中表达可操作连接的编码序列所必需的DNA序列。例如,适于原核生物的控制序列包括启动子、任选的操纵基因序列和核糖体结合位点。已知真核细胞利用启动子、多腺苷酸化信号和增强子。
若一段核酸与另一段核酸序列处于功能性相互关系中,则它是“可操作连接的”。例如,若前序列或分泌前导的DNA表达成参与多肽分泌的前蛋白质,则它与该多肽的DNA可操作连接;若启动子或增强子影响编码序列的转录,则它与该序列可操作连接;或者,若核糖体结合位点的位置促进翻译,则它与编码序列可操作连接。一般而言,“可操作连接的”意味着相连的DNA序列是相邻的,而且在分泌前导的情况中意味着相邻且处于阅读状态。然而,增强子不必相邻。连接可以通过在方便的限制性位点处的连接来实现。若没有此类位点,则依照常规实践使用合成的寡核苷酸衔接头或接头。
“载体”在本文中指能够运输与其连接的其它核酸的核酸分子。一类载体是“质粒”,指其中可连接另外的DNA区段的环状双链DNA环。另一类载体是噬菌体载体。另一类载体是病毒载体,其中可将另外的DNA区段连接到病毒基因组中。某些载体能够在其所导入的宿主细胞中自主复制(例如具有细菌复制起点的细菌载体和附加型哺乳动物载体)。其它载体(例如非附加型哺乳动物载体)可在导入宿主细胞后整合到宿主细胞的基因组中,由此随着宿主基因组一起复制。此外,某些载体能够指导与其可操作连接的基因表达。此类载体在本文中称为“重组表达载体”(或简称为“重组载体”)。通常,在重组DNA技术中有用的表达载体常常是质粒形式。在本说明书中,“质粒”和“载体”可互换使用,因为质粒是载体的最常用形式。
“多核苷酸”或“核酸”在本文中可互换使用,指任何长度的核苷酸聚合物,包括DNA和RNA。核苷酸可以是脱氧核糖核苷酸、核糖核苷酸、经过修饰的核苷酸或碱基和/或其类似物,或者是可通过DNA或RNA聚合酶或者通过合成反应掺入聚合物的任何底物。多核苷酸可包含经过修饰的核苷酸,诸如甲基化核苷酸及其类似物。如果有的话,对核苷酸结构的修饰可以在装配聚合物之前或之后进行。核苷酸序列可以由非核苷酸组分中断。多核苷酸可以在合成后进一步修饰,诸如通过与标记物偶联。
“寡核苷酸”一般指短的多核苷酸,一般是单链、合成的,长度一般但不是必需小于约200个核苷酸。
本文中,术语“肿瘤”指哺乳动物中特征通常为细胞生长不受调节的生理疾患。肿瘤可分为良性肿瘤和恶性肿瘤,恶性肿瘤又被称为癌症。肿瘤又可分为实体瘤或血液肿瘤。在某些实施方案中,本发明尤其涉及造血系统的癌症或血液相关的癌症的治疗。本文中,“造血系统”包括胸腺和骨髓及外周淋巴样组织,诸如脾、淋巴结、与粘膜有关的淋巴样组织,诸如肠相关淋巴样组织、扁桃体、派伊尔氏斑及与其它粘膜有关的附件和淋巴样组织,例如支气管内衬。因此,本文所述的造血系统的癌症或血液相关的癌症可包括淋巴瘤、白血病、骨髓瘤或淋巴样恶性肿瘤,也包括脾的癌症和淋巴结的癌症。造血系统的癌症或血液相关的癌症的更具体例子包括B细胞相关癌症,包括例如高级、中级和低级淋巴瘤,包括B细胞淋巴瘤,如粘膜相关淋巴样组织B细胞淋巴瘤和非何霍奇金淋巴瘤(NHL)、套细胞淋巴瘤、伯基特氏淋巴瘤、小淋巴细胞性淋巴瘤、边缘区淋巴瘤、弥漫性大细胞淋巴瘤、滤泡性淋巴瘤和霍奇金淋巴瘤及T细胞淋巴瘤);和白血病,包括继发性白血病、慢性淋巴细胞性白血病(CLL)如B细胞白血病(CD5+B淋巴细胞)、髓细胞性白血病诸如急性髓细胞样白血病、慢性髓细胞样白血病、淋巴样白血病诸如急性淋巴细胞白血病(ALL)和脊髓发育不良;和其它血液学和/或B细胞或T细胞相关癌症。造血系统的癌症或血液相关的癌症还包括其它造血细胞的癌症,所述造血细胞包括多形核白细胞,诸如嗜碱性粒细胞、嗜酸性粒细胞、嗜中性粒细胞和单核细胞、树突状细胞、血小板、红细胞和天然杀伤细胞。具体而言,可包括选自下组的癌性B细胞增殖性病症:非霍奇金淋巴瘤(NHL)、攻击性NHL、复发性攻击性NHL、复发性无痛性NHL、顽固性NHL、顽固性无痛性NHL、慢性淋巴细胞白血病(CLL)、小淋巴细胞淋巴瘤、毛细胞白血病(HCL)、急性淋巴细胞白血病(ALL)和套细胞淋巴瘤。
本文中,癌症也包括癌瘤、母细胞瘤和肉瘤。因此,癌症的其它例子包括鳞状细胞癌、小细胞肺癌、非小细胞肺癌、肺的腺癌、肺的鳞癌、腹膜癌、肝细胞癌、胃肠癌、胰腺癌、胶质瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝肉瘤、乳腺癌、结肠癌、结肠直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌及各种类型的头颈癌等。
“治疗”或“缓和”是指减缓(减轻)或治愈所针对的病理学状况或紊乱。如果在依照本文所述的方法接受治疗量的抗CD79b抗体后,患者在如下一项或多项中显示出可观察和/或可测量的降低或消失,那么受试者成功“治疗”了表达CD79b多肽的肿瘤(尤其是癌症):肿瘤细胞数减少或肿瘤细胞消失;肿瘤体积缩小;肿瘤细胞浸润受到抑制;肿瘤转移受到抑制;肿瘤生长受到一定程度的抑制;和/或与特定肿瘤有关的一种或多种症状得到一定程度的减轻;发病率和死亡率降低;及生命质量提高。就抗CD79b抗体可预防肿瘤细胞生长和/或杀死现有肿瘤细胞而言,它可能是抑制细胞和/或毒害细胞。这些征候或症状的减轻还可以由患者感受到。
“治疗有效量”是指足以显示其对于所施用对象益处的剂量。施用的实际量,以及施用的速率和时间过程会取决于所治疗者的自身情况和严重程度。治疗的处方(例如对剂量的决定等)最终是全科医生及其他医生的责任并依赖其做决定,通常考虑所治疗的疾病、患者个体的情况、递送部位、施用方法以及对于医生来说已知的其它因素。在肿瘤的情况中,药物的治疗有效量可减少肿瘤细胞数;缩小肿瘤体积;抑制癌细胞浸润到周围器官中;抑制肿瘤转移;一定程度的抑制肿瘤生长;和/或一定程度的减轻与肿瘤有关的一种或多种症状。“预防有效量”指在必需的剂量和时间上有效实现期望的预防效果的量。通常而非必然,由于预防剂量是在疾病发作之前或在疾病的早期用于受试者的,因此预防有效量将低于治疗有效量。
抗CD79b抗体的“生长抑制量”指能够在体外或在体内抑制细胞,尤其是肿瘤,例如癌细胞生长的数量。抗CD79b抗体为了抑制肿瘤性细胞生长的“生长抑制量”可凭经验且以常规方式来确定。
抗CD79b抗体的“细胞毒性量”指能够在体外或在体内引起细胞,尤其是肿瘤细胞,例如癌细胞破坏的量。抗CD79b抗体为了抑制肿瘤性细胞生长的“细胞毒性量”可凭经验且以常规方式来确定。
本文中,“个体”或“对象”指脊椎动物。在某些实施方案中,脊椎动物指哺乳动物。哺乳动物包括,但不限于,牲畜(诸如牛)、运动用动物、宠物(诸如猫、犬和马)、灵长类动物、小鼠和大鼠。优选的是,哺乳动物指人。
与一种或多种其它治疗剂“联合”施用包括同时(共同)施用和任何次序的序贯施用。
关于参照多肽序列的“序列同一性”定义为比对序列并在必要时引入缺口以获取最大百分比序列同一性后,且不将任何保守替代视为序列同一性的一部分时,候选序列中与参照多肽序列中的氨基酸残基相同的氨基酸残基的百分率。为测定百分比氨基酸序列同一性目的的对比可以以本领域技术范围内的多种方式进行,例如使用公众可得到的计算机软件,诸如BLAST,BLAST-2,ALIGN或Megalign(DNASTAR)软件。本文包括与本文所述的轻链可变区、重链可变区或抗体的重链和轻链(尤其是本文所述具体列出的各条序列)具有至少80%序列同一性,例如至少81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。优选的是,可在本文所述抗CD79b抗体中进行变异,例如使用例如美国专利5,364,934所述的保守和非保守突变的任何技术和指导方针。在某些实施方案中,变异不发生在本文SEQ ID NO:1-6所示的CDR内。变异可以是编码抗体或多肽的一个或多个密码子的替代、删除或插入,其导致氨基酸序列相对于天然序列抗体的改变。任选的是,变异是通过抗CD79b抗体的一个或多个结构域中至少一个氨基酸为任何其它氨基酸所替代。通过比较抗CD79b抗体的序列与同源已知蛋白质分子的序列,并将高同源区中进行的氨基酸序列改变的数目最少化,可发现确定哪些氨基酸残基可插入、替代或删除而不会对期望活性有不利影响的方针。氨基酸替代可以是将一种氨基酸用具有相似结构和/或化学特性的另一种氨基酸替代的结果,诸如用丝氨酸替代亮氨酸,即保守氨基酸替代。插入或删除可任选在约1个至5个氨基酸的范围内。可通过在序列中系统进行氨基酸插入、替代或删除,并对所得变体测试由全长或成熟天然序列展示的活性来确定可容许的变异。
变异可使用本领域知道的方法来进行,诸如寡核苷酸介导的(定点)诱变、丙氨酸扫描、及PCR诱变。可对克隆的DNA进行定点诱变、盒式诱变、限制性选择诱变或其它已知技术以产生抗CD79b抗体变体DNA。
任何不涉及保持抗CD79b抗体正确构象的半胱氨酸残基也可被替代,通常用丝氨酸,以改进分子的氧化稳定性和防止异常交联。相反,可向抗CD79b抗体中添加半胱氨酸键以改善其稳定性(特别是当抗体是抗体片段诸如Fv片段时)。
在某些实施方案中,替代变体涉及替代亲本抗体的一个或多个高变区残基(例如人源化或人抗体)。通常,选择用于进一步开发的所得变体相对于产生它们的亲本抗体将具有改进的生物学特性。产生此类替代变体的一种便利方法涉及使用噬菌体展示进行的亲和力成熟。简而言之,将数个高变区位点(例如6-7个位点)突变,在各个位点产生所有可能的氨基酸替代。如此产生的抗体变体以单价形式展示在丝状噬菌体颗粒上,作为与各个颗粒内包装的M13基因III产物的融合物。然后对噬菌体展示的变体进行筛选,获得生物学活性(例如结合亲和力)。为了鉴定用于修饰的候选高变区位点,可进行丙氨酸扫描诱变以鉴定对抗原结合有重要贡献的高变区残基。或者/另外,分析抗原-抗体复合物的晶体结构以鉴定抗体和CD79b多肽之间的接触点。此类接触残基及邻近残基是依照本文详述技术进行替代的候选位点。一旦产生此类变体,如本文所述对该组变体进行筛选,可选择在一种或多种相关测定法中有优良特性的抗体用于进一步的开发。“细胞毒剂”指抑制或防止细胞的功能和/或引起细胞破坏的物质。该术语包括:放射性同位素,例如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32和Lu的放射性同位素;化疗药物,例如甲氨蝶呤、阿霉素、长春花生物碱类(如长春新碱、长春碱、依托泊苷)、多柔比星、美法仑、丝裂霉素C、苯丁酸氮芥或柔红霉素;酶及其片段,诸如溶核酶;抗生素;和毒素,诸如小分子毒素或者细菌、真菌、植物或动物起源的酶活毒素,包括其片段和/或变体;及本领域周知的抗肿瘤药或抗癌药。
“药物组合物”表示组合在一起以实现某种特定目的的至少一种药物以及任选地可药用载体或辅料的组合。在某些实施方案中,所述药物组合物包括在时间和/或空间上分开的组合,只要其能够共同作用以实现本发明的目的。例如,所述药物组合物中所含的成分(例如本文所述的抗体、核酸分子、核酸分子组合和/或缀合物)可以以整体施用于对象,或者分开施用于对象。当所述药物组合物中所含的成分分开地施用于对象时,所述成分可以同时或依次施用于对象。优选地,所述可药用载体是水、缓冲水溶液、等渗盐溶液如PBS(磷酸盐缓冲液)、葡萄糖、甘露醇、右旋葡萄糖、乳糖、淀粉、硬脂酸镁、纤维素、碳酸镁、0.3%甘油、透明质酸、乙醇或聚亚烷基二醇如聚丙二醇、甘油三酯等。所用可药用载体的类型尤其依赖于根据本发明的组合物是否配制为用于口服、鼻、皮内、皮下、肌内或静脉施用。根据本发明的组合物可包含润湿剂、乳化剂或缓冲液物质作为添加剂。
根据本发明的药物组合物可通过任何适宜的途径施用,例如可口服、鼻、皮内、皮下、肌内或静脉内施用。
本发明提供了抗CD79b抗体或其功能性片段,其药物组合物或抗体-药物偶联物,及其在造血肿瘤治疗中的使用方法。
本文的抗体是与任何与CD79b是瘤治疗中的使用特异性结合的抗体,可以是单克隆抗体、抗体片段(包括Fab、Fab′、F(ab′)2和Fv片段)、双抗体、单域抗体、嵌合抗体、人源化抗体、单链抗体或竞争性抑制抗CD79b多肽抗体结合其相应抗原性表位的抗体。本发明的抗体可任选偶联至细胞毒剂,诸如毒素,包括例如auristatin、美登木素生物碱、多拉司他汀衍生物或加利车霉素、抗生素、放射性同位素和溶核酶等。本发明的抗体可任选在CHO细胞或细菌细胞中生成,且优选诱导它们所结合的细胞死亡。出于检测目的,本发明的抗体可以是可检测标记的,可附着至固体支持物。
本文的抗CD79b抗体包含SEQ ID NO:1-6所示的氨基酸序列中的至少一种、至少两种、至少三种、至少四种、至少五种或全部六种。在某些实施方案中,本文的抗CD79b抗体的重链可变区包含SEQ ID NO:1-3中任意一种、任意两种或全部三种,和/或其轻链可变区包含SEQ ID NO:4-6中任意一种、任意两种或全部三种。在某些实施方案中,本文的CD79b抗体的重链可变区含有SEQ ID NO:1-3所示的氨基酸序列,和/或其轻链可变区含有SEQ ID NO:4-6所示的氨基酸序列。在某些实施方案中,本文的抗CD79b抗体的重链可变区含有SEQ IDNO:1-3所示的氨基酸序列,轻链可变区含有SEQ ID NO:4-6所示的氨基酸序列。在某些实施方案中,本文的抗CD79b抗体包含:HCDR1,其含有SEQ ID NO:1所示的氨基酸序列;HCDR2,其含有SEQ ID NO:2所示的氨基酸序列;HCDR3,其含有SEQ ID NO:3所示的氨基酸序列;LCDR1,其含有SEQ ID NO:4所示的氨基酸序列;LCDR2,其含有SEQ ID NO:5所示的氨基酸序列;LCDR3,其含有SEQ ID NO:6所示的氨基酸序列。在某些实施方案中,本文的抗CD79b抗体包含SEQ ID NO:1-6所示的CDR序列。
在某些实施方案,本文的抗体是鼠源抗体104E1,其重链可变区的氨基酸序列可如SEQ ID NO:7所示,和/或其轻链可变区的氨基酸序列可如SEQ ID NO:8所示。
在某些实施方案中,本文的抗体是人源化抗体,该人源化抗体中,用SEQ ID NO:1-6中的至少一种、至少两种、至少三种、至少四种、至少五种或全部六种替换人抗体重链可变区和/或轻链可变区中对应的CDR区。在某些实施方案中,用来制备人源化抗体的重链可变区的氨基酸序列如SEQ ID NO:9所示,用来制备人源化抗体的轻链可变区的氨基酸序列如SEQ ID NO:10所示。在某些实施方案中,本文所述人源化抗体重链可变区的氨基酸序列如SEQ ID NO:11所示,和/或所述人源化抗体的轻链可变区的氨基酸序列如SEQ ID NO:12所示。
在某些实施方案中,为了找出鼠源FR区域中对抗体亲和力起重要作用的氨基酸位点,在PDB数据库中查找与本文所述鼠源抗体104E1同源性相似的晶体结构,结果找到抗多唾液酸抗体Ab735的scFv晶体结构,与104E1抗体序列的同源性为77%,且具有足够高的分辨率。本文以此晶体为结构模板,将两条序列对比,建立104E1抗体的3WBD scFvs的同源模型,根据这个同源模型找出104E1序列FR区内被CDR结构域包裹的,或距离CDR结构域在之内的氨基酸位点,然后将这些可能对抗体亲和力起重要作用的氨基酸位点在CDR-嫁接的序列(SEQ ID NO:11和SEQ ID NO:12)中做回复突变,同时避免糖基化、脱酰胺化、氧化位点等。在重链可变区内共找出15个可能需要做回复突变的位点,包括A24T、RV67KA、S84R、T98K、K12A、S16A、V20L、A24T、R38K、M48I、V68A、I70L、Y95F、T98K和V113L;在轻链可变区内共找出7个可能需要做回复突变的位点,包括V3L、F41Y、RR50KL、FQ41YL、R51L、V88L和V109L。然后根据金斯瑞的标准操作规程建立Fab文库,通过噬菌体展示平台进行筛选。筛选出亲和力不低于鼠源104E1抗体的人源化之后的序列,测序进行序列确认。因此,在某些实施方案中,本文所述抗CD79b抗体的重链可变区的氨基酸序列可选自SEQ ID NO:13-17中任一序列所示的氨基酸序列,和/或其轻链可变区的氨基酸序列选自SEQ ID NO:18-22中任一序列所示的氨基酸序列。本发明也包括与这些重链可变区具有至少90%、优选至少95%序列同一性的重链可变区序列,以及与这些轻链可变区具有至少90%、优选至少95%序列同一性的轻链可变区序列。在某些实施方案中,重链可变区和轻链可变区内的突变发生在FR内,而不发生在CDR中。
本发明的抗体还可含有恒定区。恒定区可为人IgM、IgD、IgG、IgA和IgE的恒定区。例如,恒定区可以是人IgGl、IgG2、IgG3、IgG4、IgAl或IgA2的恒定区。在某些实施方案中,本文所述的抗CD79b抗体的重链含有本文所述的重链可变区和重链Fc区,轻链含有本文所述的轻链可变区和轻链Fc区。示例性的重链Fc区的氨基酸序列可如SEQ ID NO:23所示,示例性的轻链Fc区的氨基酸序列可如SEQ ID NO:24所示。在某些实施方案中,适用于本发明的重链Fc区还包括与SEQ ID NO:23所示的氨基酸序列具有至少90%、优选至少95%序列同一性的重链Fc区,和/或适用于本发明的轻链Fc区还包括与SEQ ID NO:23所示的氨基酸序列具有至少90%、优选至少95%序列同一性的轻链Fc区。优选地,可在重链和/或轻链Fc区发生本领域周知的能改变Fc区的效应器功能的突变。例如,具有降低的效应器功能的Fc区,其残基238、265、269、270、297、327和329中的一个或多个发生了取代突变(见US 6,737,056)。具有改善的ADCC的一处或多处氨基酸取代可发生在Fc区的残基298、333和/或334(残基按EU编号方式编号)。
在某些实施方案中,本文所述抗CD79b抗体的重链的氨基酸序列可选自与SEQ IDNO:25、27、29、31和33中任一序列所示的氨基酸序列具有至少90%、优选至少95%序列同一性的氨基酸序列,和/或其轻链的氨基酸序列选自与SEQ ID NO:26、28、30、32和34中任一序列所示的氨基酸序列具有至少90%、优选至少95%序列同一性的氨基酸序列。
因此,在某些实施方案中,本文的抗CD79b抗体选自以下抗体:(1)重链的氨基酸序列如SEQ ID NO:25所示、轻链的氨基酸序列如SEQ ID NO:26所示的抗体;(2)重链的氨基酸序列如SEQ ID NO:27所示、轻链的氨基酸序列如SEQ ID NO:28所示的抗体;(3)重链的氨基酸序列如SEQ ID NO:29所示、轻链的氨基酸序列如SEQ ID NO:30所示的抗体;(4)重链的氨基酸序列如SEQ ID NO:31所示、轻链的氨基酸序列如SEQ ID NO:32所示的抗体;和(5)重链的氨基酸序列如SEQ ID NO:33所示、轻链的氨基酸序列如SEQ ID NO:34所示的抗体。
本文还提供本文所述CDR、轻链可变区、重链可变区、轻链以及重链的编码序列及其互补序列(核酸序列),含有所述编码序列或其互补序列的载体,以及含有所述核酸或载体的宿主细胞。示例性的编码序列如SEQ ID NO:36、37、38和39所示,其分别为SEQ ID NO:33、34、7和8的编码序列。
可使用标准重组技术来获得编码本文所述抗体或其功能性片段的多核苷酸序列。可以从抗体生成细胞诸如杂交瘤细胞分离期望的多核苷酸序列并测序。或者,可使用核苷酸合成仪或PCR技术合成多核苷酸。一旦得到,将编码多肽的序列插入能够在原核宿主中复制并表达异源多核苷酸的重组载体。为了本文目的,可使用本领域可获得的且知道的多种载体。适宜载体的选择主要取决于将要插入载体的核酸的大小和将要用载体转化的具体宿主细胞。根据其功能(扩增或表达异源多核苷酸,或二者兼之)及其与它在其中驻留的具体宿主细胞的相容性,每种载体含有多种构件。
载体可以是例如质粒、粘粒、病毒颗粒或噬菌体的形式。可以通过多种方法将适宜的核酸序列插入载体。通常,使用本领域已知的技术将感兴趣的DNA序列插入适宜的限制性内切酶位点。载体构件通常包括但不限于下列一种或多种:信号序列、复制起点、一种或多种标记基因、增强子元件、启动子和转录终止序列。可采用技术人员已知的标准连接技术构建包含一种或多种这些构件的合适载体。载体可以是克隆载体,也可以是表达载体。
CD79b不仅可以直接重组生产,而且可以作为与异源多肽的融合多肽,所述异源多肽可以是在成熟蛋白质或多肽的N-末端具有特定切割位点的信号序列或其它多肽。通常,信号序列可以是载体的构件,或者它可以是插入载体的编码抗CD79b抗体的DNA的一部分。信号序列可以是原核信号序列,选自例如碱性磷酸酶、青霉素酶、lpp或热稳定的肠毒素II前导序列。为了酵母分泌,信号序列可以是例如酵母转化酶前导序列、α因子前导序列(包括糖酵母和克鲁维酵母的α-因子前导序列)或酸性磷酸酶前导序列、白色假丝酵母葡糖淀粉酶前导序列等。在哺乳动物细胞表达中,可以使用哺乳动物信号序列来指导蛋白质的分泌,诸如来自相同或相关物种的分泌型多肽的信号序列,以及病毒分泌前导序列。
通常,哺乳动物表达载体不需要复制起点构件。例如,通常可使用SV40起点,只因其包含早期启动子。表达和克隆载体通常会包含选择基因,也称为选择标志。典型的选择基因编码如下蛋白质:(a)赋予对抗生素或其它毒素的抗性,例如氨苄青霉素、新霉素、甲氨蝶呤或四环素;(b)补足营养缺陷;或(c)提供不能从复合培养基获得的关键营养物,例如用于芽孢杆菌的编码D-丙氨酸消旋酶的基因。
选择方案的一个例子利用药物来阻滞宿主细胞的生长。经异源基因成功转化的那些细胞生成赋予药物抗性的蛋白质,因而幸免于选择方案。此类显性选择的例子使用药物新霉素、霉酚酸和潮霉素。
表达和克隆载体通常包含与编码抗CD79b抗体的核酸序列可操作连接的启动子以指导mRNA合成。受到多种潜在宿主细胞识别的启动子是众所周知的。适用于酵母宿主的启动子序列的例子包括3-磷酸甘油酸激酶或其它糖酵解酶的启动子,诸如烯醇酶、甘油醛-3-磷酸脱氢酶、己糖激酶、丙酮酸脱羧酶、磷酸果糖激酶、葡萄糖-6-磷酸异构酶、3-磷酸甘油酸变位酶、丙酮酸激酶、磷酸丙糖异构酶、磷酸葡萄糖异构酶和葡糖激酶。
在哺乳动物宿主细胞中由载体转录抗CD79b抗体受到例如从病毒(如多瘤病毒、禽痘病毒、腺病毒(如2型腺病毒)、牛乳头瘤病毒、禽类肉瘤病毒、巨细胞病毒、逆转录病毒、乙肝病毒和猿病毒40(SV40))基因组获得的、来自异源哺乳动物启动子(例如肌动蛋白启动子或免疫球蛋白启动子)的和来自热休克启动子的启动子的控制。在某些实施方案中,使用SV40病毒的早期和晚期启动子,该片段还包含SV40病毒复制起点。
可通过在载体中插入增强子序列来提高高等真核细胞对编码抗CD79b抗体的DNA的转录。增强子是DNA的顺式作用元件,通常大约10至300bp,作用于启动子以增加转录。已知来自哺乳动物基因(球蛋白、弹性蛋白酶、清蛋白、α-胎蛋白和胰岛素)的许多增强子序列。然而,通常使用来自真核细胞病毒的增强子。例子包括SV40复制起点晚期一侧的增强子(bp100-270)、巨细胞病毒早期启动子增强子、多瘤病毒复制起点晚期一侧的增强子和腺病毒增强子。增强子可以剪接到载体中,位于抗CD79b抗体编码序列的5′或3′位置,但是优选位于启动子的5′位点。
用于真核宿主细胞(酵母、真菌、昆虫、植物、动物、人或来自其它多细胞生物体的有核细胞)的表达载体还将包含终止转录和稳定mRNA所必需的序列。此类序列通常可以由真核或病毒DNA或cDNA非翻译区的5′端和偶尔的3′端获得。这些区域包含在编码抗CD79b抗体的mRNA的非翻译部分中转录成聚腺苷酸化片段的核苷酸区段。一种有用的转录终止构件是牛生长激素聚腺苷酸化区。
可采用本领域周知的方法将含有本文所述核酸序列的载体转入宿主细胞中。适于在体外将核酸转移到宿主细胞中的技术包括使用脂质体、电穿孔、显微注射、细胞融合、DEAE-右旋糖苷、磷酸钙沉淀法等。
宿主细胞可以是原核生物细胞和真核生物细胞。合适的原核生物包括但不限于古细菌和真细菌,诸如革兰氏阴性或革兰氏阳性生物体,例如肠杆菌科,诸如大肠杆菌。其它合适的原核生物宿主细胞包括肠杆菌属(Enterobacter)、欧文氏菌属(Erwinia)、克雷伯氏菌属(Klebsiella)、变形菌属(Proteus)、沙门氏菌属(Salmonella)例如鼠伤寒沙门氏菌(Salmonellatyphimurium)、沙雷氏菌属(Serratia)例如粘质沙雷氏菌(Serratiamarcescans)和志贺氏菌属(Shigella),以及芽孢杆菌属(Bacilli)诸如枯草芽孢杆菌(B.subtilis)和地衣芽孢杆菌(B.licheniformis)、假单胞菌属(Pseudomonas)诸如铜绿假单胞菌(P.aeruginosa)、根瘤菌属(Rhizobia)、透明颤菌属(Vitreoscilla)副球菌属(Paracoccus)和链霉菌属(Streptomyces)。
全长抗体、抗体片段及抗体融合物蛋白质可在细菌中制备,特别是在不需要糖基化和Fc效应器功能时,如当治疗用抗体与细胞毒剂(例如毒素)偶联且免疫偶联物自身显示出肿瘤细胞破坏的效力时。全长抗体在循环中具有较长半衰期。大肠杆菌中的制备更快且更加省钱。对于抗体片段和多肽在细菌中的表达,可参见例如US5,648,237、US5,789,199和US5,840,523,它们描述了用于优化表达和分泌的翻译起始区(TIR)和信号序列。表达后,从大肠杆菌细胞糊在可溶性级分中分离抗体,并且可例如根据同种型通过蛋白A或G柱来纯化。最终的纯化可以与用于纯化例如在CHO细胞中表达的抗体的方法类似的进行。
真核微生物,如丝状真菌或酵母也是编码抗CD79b抗体的载体的合适克隆或表达宿主。酿酒糖酵母是常用的低等真核宿主微生物。其它的包括粟酒裂殖糖酵母、克鲁维酵母属等。
适用于表达糖基化抗CD79b抗体的宿主细胞衍生自多细胞生物体。无脊椎动物细胞的例子包括昆虫细胞诸如果蝇S2和夜蛾Sf9,以及植物细胞诸如棉、玉米、马铃薯、大豆、矮牵牛、番茄、烟草的细胞培养物。已经鉴定了许多杆状病毒株和变体及相应的允许的昆虫宿主细胞,它们来自诸如草地夜蛾、埃及伊蚊、白纹伊蚊、黑腹果蝇和家蚕等宿主。
有用的哺乳动物宿主细胞系的例子是用SV40转化的猴肾CV1系(COS-7,ATCCCRL1651)、人胚肾系(293或为了在悬浮培养中生长而亚克隆的293细胞)、幼仓鼠肾细胞(BHK,ATCCCCL10)、中国仓鼠卵巢细胞/-DHFR(CHO)、小鼠塞托利(sertoli)细胞(TM4)、猴肾细胞(CV1,ATCCCCL70)、非洲绿猴肾细胞(VERO-76,ATCCCRL-1587)、人宫颈癌细胞(HELA,ATCCCCL2)、犬肾细胞(MDCK,ATCCCCL34)、牛鼠(buffalorat)肝细胞(BRL3A,ATCCCRL1442)、人肺细胞(W138,ATCCCCL75)、人肝细胞(HepG2,HB8065)、小鼠乳腺肿瘤(MMT060562,ATCCCCL51)、TRI细胞、MRC5细胞、FS4细胞和人肝肉瘤系(HepG2)等。
可以在多种培养基中在本领域周知的培养条件下培养用于生产本发明抗CD79b抗体的宿主细胞。
可以从培养液或从宿主细胞裂解物中回收各种形式的抗CD79b抗体。如果是膜结合的,可使用合适的去污剂溶液(例如Triton-X100)或通过酶促裂解使其从膜释放。抗CD79b抗体表达中所采用的细胞可通过多种物理或化学手段破裂,诸如冻融循环、超声处理、机械破裂或细胞溶解剂。
可以使用例如羟磷灰石层析、凝胶电泳、透析和亲和层析来纯化由细胞制备的抗体组合物,优选的纯化技术是亲和层析。根据待回收的抗体,也可使用其它蛋白质纯化技术,诸如离子交换柱上的分级分离、乙醇沉淀、反相HPLC、硅土上的层析、肝素SEPHAROSETM上的层析、阴离子或阳离子交换树脂(诸如聚天冬氨酸柱)上的层析、层析聚焦、SDS-PAGE和硫酸铵沉淀。
另一个方面,本文提供包含偶联有细胞毒剂的抗体的免疫偶联物或抗体-药物偶联物(ADC)及其使用和制备方法。适用于本发明的细胞毒剂可以是药物(如化疗药物)、生长抑制剂、毒素(例如细菌、真菌、植物或动物起源的酶活性毒素或其片段)或放射性同位素(即放射偶联物)。通常,免疫偶联物包含共价连接于细胞毒剂或可检测试剂的任何上述抗CD79b抗体。
本文中,“药物”指任何具有期望的生物活性的化合物。期望的生物活性包括诊断、治愈、缓解、治疗、预防人或其它动物的疾病。因此,术语“药物”涉及的化合物包括正式国家药典,以及例如美国正式同种疗法药典,正式全国处方集,或者其任何增补本等确认的药物。典型的药物列于医师案头用药参考(PDR)和美国食品药品监督管理局(FDA)的橙皮书。随着新型药物不断被发现和发展,这些药物也应纳入本文所述偶联药物的前药。优选地,所述药物具有反应性官能团以便可用于制备本文所述的偶联物。
示例性的适用于本文的药物包括但不限于:用于癌症治疗的细胞毒性药物;具有期望生物活性的蛋白或多肽,如毒素,如相思子毒素、蓖麻毒素A、假单胞菌外毒素和白喉毒素,其他合适的蛋白包括肿瘤坏死因子、α-干扰素、β-干扰素、神经原生长因子、血小板衍生生长因子、组织型纤酶溶原生长因子以及生物反应调节制剂,例如淋巴因子、白细胞介素-1(IL-1)、白细胞介素-2(IL-2)、白细胞介素-6(IL-6)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、粒细胞集落刺激因子或其它生长因子。
示例性的药物包括:美登素;类美登素;耳抑素肽类药物(如单甲基耳抑素肽E(MMAE)和单甲基耳抑素肽F(MMAF));卡奇霉素类(如卡奇霉素);阿霉素类(如阿霉素);苯并二吡咯类抗生素(如duocarmycins、CC-1065等)和其它的环丙基吡咯吲哚-4-酮(cyclopropapyrroloind-4-one,CPI)衍生物,如环丙苯并吲哚-4-酮类似物,如:
以及吡咯并苯二氮卓类(PBD)或者PBD二聚体类,如:
抗体可直接地或经连接子偶联至药物。连接子可分为两类:不可断裂连接子和可断裂连接子。对于含有不可断裂连接子的抗体药物偶联物,其药物释放机制为:偶联物与抗原结合并被细胞内吞后,抗体在溶酶体中被酶解,释放出由小分子药物,连接子,和抗体氨基酸残基共同组成的活性分子。由此带来的药物分子结构改变并不减弱其细胞毒性,但由于活性分子是带电荷的(氨基酸残基),从而导致其不能渗入邻近细胞。因此,此类活性药物不能杀死邻近不表达靶向抗原(抗原阴性细胞)的肿瘤细胞(旁观者效应,bystandereffect)(Ducry等,2010,Bioconjugate Chem.21:5-13)。可断裂连接子可以在目标细胞内断裂并释放出活性药物。可断裂连接子可分为两个主要的类别:化学不稳定连接子和酶不稳定连接子。化学不稳定连接子可以由于血浆和细胞质性质的不同而选择性的断裂。这样的性质包括pH值、谷胱甘肽浓度等。对pH值敏感的连接子,通常又称为酸断裂连接子,这样的连接子在血液的中性环境下相对稳定(pH7.3-7.5),但是在弱酸性的内涵体(pH5.0-6.5)和溶酶体(pH 4.5-5.0)内将会被水解。对于谷胱甘肽敏感的连接子,又称二硫键连接子。药物释放是基于细胞内谷胱甘肽的高浓度(毫摩尔范围)与血液中相对较低的谷胱甘肽浓度(微摩尔范围)差异引起的。对于肿瘤细胞而言尤其如此,其低含氧量导致还原酶的活性增强,因而导致更高的谷胱甘肽浓度。二硫键具有热力学稳定性,因此在血浆中具有较好的稳定性。酶不稳定连接子,如肽连接子,能够更好地控制药物释放。肽连接子能够被溶酶体内蛋白酶,如组织蛋白酶(Cathepsin B)或纤溶酶(在一些肿瘤组织中此类酶含量增加)有效地切断。这种肽连接被认为在血浆循环中非常稳定,这是因为细胞外不合宜的pH值及血清蛋白酶抑制剂导致蛋白酶通常在不具备活性。鉴于较高的血浆稳定性和良好的细胞内断裂选择性和有效性,酶不稳定连接子被广泛用做抗体药物偶联物的可断裂连接子。典型的酶不稳定连接子包括Val-Cit(vc)、Phe-Lys等。自杀式连接子一般嵌合在可断裂连接子与活性药物之间,或者本身就是可断裂连接子的一部分。自杀式连接子的作用机制是:当可断裂连接子在合宜的条件下断裂后,自杀式连接子能够自发地进行结构重排,进而释放与之连接的活性药物。常见的自杀式连接子包括对氨基苄醇类(PAB)和β-葡萄糖醛酸苷类(β-Glucuronide)等。
连接子可以包含一种或多种连接子构件。例如,在某些实施方案中,连接子的结构可以为V-L,其中V构件可存在或不存在,为下文所述的三齿型连接子构件或四马来酰亚胺型连接子构件,L构件可以是前文所述的不可断裂连接子和可断裂连接子,如酸不稳定连接子(例如腙)、蛋白酶敏感(例如肽酶敏感)连接子、光不稳定连接子、二甲基连接子或含二硫化物连接子等。例示性的连接子构件包括6-马来酰亚氨基己酰基、马来酰亚氨基丙酰基缬氨酸-瓜氨酸、丙氨酸-苯丙氨酸、对氨基苄氧羰基、N-琥珀酰亚氨基4-(2-吡啶基硫代)戊酸酯、N-琥珀酰亚氨基4-(N-马来酰亚氨基甲基)环己烷-1羧酸酯和N-琥珀酰亚氨基(4-碘-乙酰基)氨基苯甲酸酯。其它示例性的连接子构件还可以是包含氨基酸单元以容许蛋白酶切割的连接子,由此便于在暴露于胞内蛋白酶(诸如溶酶体酶)后从免疫偶联物释放药物。例示性的氨基酸单元包括但不限于二肽、三肽、四肽和五肽。例示性的二肽包括:缬氨酸-瓜氨酸;丙氨酸-苯丙氨酸;苯丙氨酸-赖氨酸;或N-甲基-缬氨酸-瓜氨酸。例示性的三肽包括:甘氨酸-缬氨酸-瓜氨酸和甘氨酸-甘氨酸-甘氨酸。
示例性的三齿型(或双马来酰亚胺型)连接子构件可具有以下结构:
示例性的四马来酰亚胺型连接子构件可具有以下结构:
其它合适的连接子、药物或连接子-药物的例子可参见CN 103933575A和CN107652219A,包括但不限于CN 103933575A所披露的抗体药物偶联物H-1-vcMMAE、H-1-MMAF、H-3-vcMMAE、H-3-MMAF、H-4-vcMMAE、H-4-MMAF中所示的连接子-药物,以及CN107652219A所披露的编号为1-vcMMAE到12-vcMMAE。本文将这两篇申请的全部内容以引用的方式纳入本文。因此,在某些实施方案中,本发明的抗体-药物偶联物可具有以下结构:
A-(V-L-D)n
其中,A为本文的抗体;V-L为连接子,V可存在或不存在,可以是如前文所述的任一三齿型连接子构件或四马来酰亚胺型连接子构件,L为可断裂连接子或不可断裂连接子,V和L中至少存在一个;D为感兴趣的细胞毒剂;n为1-4的整数。
在某些实施方案中,L是前文所述的包含氨基酸单元以容许蛋白酶切割的连接子。
本文示例性的抗体-药物偶联物的例子可参见本申请的实施例,包括但不限于AS11259-ADC-001、AS11259-ADC-002、AS11259-ADC-003、AS11259-ADC-004、AS11259-ADC-005、AS11259-ADC-006、AS11259-ADC-007、AS11259-ADC-008、AS11259-ADC-010、AS11259-ADC-011和AS11250-ADC-0012。
在某些实施方案中,免疫偶联物可包含高度放射性原子。多种放射性同位素可用于生成放射偶联抗体。实例包括At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212和Lu的放射性同位素。在将免疫偶联物用于检测时,可包含放射性原子用于闪烁照相研究,例如Tc99m或I123,或是包含自旋标记物用于核磁共振(NMR)成像(也称为磁共振成像,MRI),诸如碘-123、碘-131、铟-111、氟-19、碳-13、氮-15、氧-17、钆、锰或铁。
可以已知方式将放射性或其它标记物掺入免疫偶联物。例如,可生物合成肽,或是通过化学氨基酸合成法合成肽,其中使用涉及例如氟-19代替氢的合适氨基酸前体。可经肽中的半胱氨酸残基来附着标记物,诸如Tc99m或I123、Re186、Re188和In111。可以经赖氨酸残基来附着钇-90。
可以采用本领域技术人员知道的有机化学反应、条件和试剂通过数种路径来制备本文的ADC,包括:(1)抗体的亲核基团经共价键与二价连接子试剂反应,经共价键形成抗体-连接子,接着与药物反应;和(2)药物模块的亲核基团与二价连接子试剂反应,经共价键形成药物-连接子,接着与抗体的亲核基团反应。
可以通过适合于待治疗疾患的任何路径来施用本文的抗体、其功能性片段或抗体-药物偶联物,这些给药方式包括口服、胃肠外、皮下、肌肉内、静脉内、真皮内、鞘内和硬膜外等。
对于疾病的预防或治疗,本文所述抗体、其功能性片段或抗体-药物偶联物的适宜剂量(在单独使用或联合一种或多种其它别的药剂诸如化疗药物时)将取决于待治疗疾病的类型,抗体、其功能性片段或抗体-药物偶联物的类型,疾病的严重程度和进程、施用抗体、其功能性片段或抗体-药物偶联物出于预防还是治疗目的,先前的疗法,患者的临床病史和对抗体、其功能性片段或抗体-药物偶联物的响应,及主治医师的判断。合适的是,一次性或通过一系列治疗将抗体、其功能性片段或抗体-药物偶联物施用于患者。根据疾病的类型和严重程度,施用于患者的初始候选剂量可以是约1μg/kg至100mg/kg(例如0.1mg/kg-20mg/kg)抗体、其功能性片段或抗体-药物偶联物,例如或是通过一次或多次分开施药或是通过连续输注。根据上文所述因素,典型日剂量的范围可以是约1μg/kg至100mg/kg或更多。对于持续数天或更长的重复施药,根据状况,通常持续治疗直至疾病症状发生期望的抑制。抗体、其功能性片段或抗体-药物偶联物的例示剂量的范围可以是约0.05mg/kg至约10mg/kg。如此,可对患者施用约0.5mg/kg、2.0mg/kg、4.0mg/kg或10mg/kg(或其任意组合)的一剂或多剂抗体、其功能性片段或抗体-药物偶联物。这些剂量可间歇施用,例如每周或每三周(例如使得患者接受约2剂至约20剂,例如约6剂抗体或免疫偶联物)。可施用一剂较高的初始加载剂量,后续一剂或多剂较低剂量。例示性剂量给药方案包括施用一剂约4mg/kg抗体的初始加载剂量,后续每周一剂约2mg/kg的维持剂量。然而,其它剂量方案也可能是有用的。这种疗法的进程易于通过常规技术和测定法来监测。
除了将抗体蛋白质施用给患者,本申请设想通过基因疗法来施用抗体。关于使用基因疗法来产生胞内抗体的用途参见例如WO96/07321。有两种主要方法使核酸(任选包含在载体中)进入患者的细胞,即体内和回体。对于体内投递,通常在需要抗体的部位将核酸直接注射到患者体内。对于回体治疗,采集患者的细胞,将核酸导入这些分离的细胞,并将经过修饰的细胞或是直接施用于患者,或是例如装入多孔膜内并植入患者体内(参见例如美国专利4,892,538和5,283,187)。有多种技术可用于将核酸导入活细胞。这些技术根据是将核酸转移至预期宿主的体外培养细胞还是体内细胞而有所变化。适于在体外将核酸转移到哺乳动物细胞中的技术包括使用脂质体、电穿孔、显微注射、细胞融合、DEAE-右旋糖苷、磷酸钙沉淀法等。常用于回体投递基因的载体是逆转录病毒。
目前优选的体内核酸转移技术包括用病毒载体(诸如腺病毒、I型单纯疱疹病毒或腺伴随病毒)和基于脂质的系统(可用于脂质介导的基因转移的脂质有例如DOTMA、DOPE和DC-Chol)进行的转染。
本文还提供包含至少一种本文所述抗CD79b抗体和/或至少一种其免疫偶联物和/或至少一种本文所述抗CD79b抗体-药物偶联物的药物组合物。在某些实施方案中,药物组合物包含:(1)本文的抗CD79b抗体和/或其免疫偶联物,和(2)药学可接受载体。在某些实施方案中,药物组合物包含:(1)本文的抗CD79b抗体和/或其免疫偶联物,和任选的(2)至少一种已知的治疗制剂,例如已知的可用于治疗CD79b介导的疾病的治疗制剂。
依照本文使用的、包含抗CD79b抗体或抗CD79b抗体-药物偶联物的药物组合物通过将具有期望纯度的抗体或抗体-药物偶联物与任选的药学可接受载体、赋形剂或稳定剂混合来制备成冻干剂型或水溶液的形式供贮存。可接受的载体、赋形剂或稳定剂在所采用的剂量和浓度对接受者是无毒的,并且包括:缓冲剂,诸如乙酸盐、Tris、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;氯己双铵;苯扎氯铵、苄索氯铵;酚、丁醇或苄醇;对羟基苯甲酸烃基酯,诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;邻苯二酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(少于约10个残基)多肽;蛋白质,诸如血清蛋白、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;张力调节剂,诸如海藻糖和氯化钠;糖类,诸如蔗糖、甘露醇、海藻糖或山梨醇;表面活性剂,诸如聚山梨醇酯;成盐抗衡离子,诸如钠;金属复合物(例如Zn-蛋白质复合物);和/或非离子表面活性剂,诸如或聚乙二醇(PEG)。用于体内施用的药物配制剂一般是无菌的。这易于通过无菌滤膜过滤来实现。
本文抗CD79b抗体可用于治疗哺乳动物中表达CD79b的肿瘤或减轻所述肿瘤的一种或多种症状。此类肿瘤包括但不限于造血系统的癌症或血液相关的癌症,诸如淋巴瘤、白血病、骨髓瘤或淋巴样恶性肿瘤,以及脾的癌症和淋巴结的癌症。表达CD79b的肿瘤尤其包括B细胞相关癌症,其具体例子包括例如高级、中级和低级淋巴瘤(包括B细胞淋巴瘤,诸如例如粘膜相关淋巴样组织B细胞淋巴瘤和非霍奇金淋巴瘤、套细胞淋巴瘤、伯基特氏淋巴瘤、小淋巴细胞性淋巴瘤、边缘区淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤和霍奇金淋巴瘤及T细胞淋巴瘤)和白血病(包括继发性白血病、慢性淋巴细胞白血病诸如B细胞白血病(CD5+B淋巴细胞)、髓细胞白血病诸如急性髓细胞样白血病、慢性髓细胞样白血病、淋巴样白血病诸如急性淋巴细胞白血病和脊髓发育不良)。癌症涵盖任何前述的转移癌。抗体能够结合哺乳动物中表达CD79b多肽的肿瘤细胞的至少一部分。在一个优选的实施方案中,抗体在体外或在体内在结合细胞上的CD79b多肽时有效破坏或杀死表达CD79b的肿瘤细胞或抑制此类肿瘤细胞的生长。此类抗体包括裸露的抗CD79b抗体(未与任何药剂偶联)。具有细胞毒性或细胞生长抑制特性的裸抗体可以进一步与细胞毒剂合作,使得它们在破坏肿瘤细胞上更有效。可以通过例如将抗体与细胞毒剂偶联形成本文所述免疫偶联物,而赋予抗CD79b抗体以细胞毒性特性。
本文还提供包含可用于治疗、预防和/或诊断表达CD79b的肿瘤的物质的制品。制品包括容器和所述容器上或与其相关的标签或包装插页。合适的容器包括例如瓶子、小管、注射器等。容器可用各种材料制成,诸如玻璃或塑料。容器中装有有效治疗、预防和/或诊断肿瘤状况的组合物,而且可具有无菌存取口(例如容器可以是具有皮下注射针头可刺穿的塞子的静脉内溶液袋或小管)。组合物中的至少一种活性剂是本文的抗CD79b抗体。标签或包装插页指示该组合物用于治疗、预防和/或诊断肿瘤。标签或包装插页进一步包含给肿瘤(尤其是癌症)患者施用抗体组合物的说明书。另外,制品还可包括第二容器,其中装有药学可接受的缓冲剂,诸如注射用抑菌水(BWFI)、磷酸盐缓冲盐水、林格氏(Ringer)溶液和右旋糖溶液。它还可包括商业和用户立场上所需的其它物质,包括其它缓冲剂、稀释剂、滤器、针头和注射器。
还提供了可用于多种目的的试剂盒,例如用于表达CD79b的细胞的杀伤测定法,用于从细胞中纯化或免疫沉淀CD79b多肽。为了分离和纯化CD79b,试剂盒可包含与珠子(例如sepharose珠子)偶联的抗CD79b抗体。可以提供包含抗体的试剂盒,用于CD79b多肽的体外检测和定量,例如在ELISA或Western印迹中。与制品相同,试剂盒包括容器和所述容器上或与其相关的标签或包装插页。容器中装有包含至少一种本文抗CD79b抗体的组合物。可包括另外的容器,其中装有例如稀释剂和缓冲剂、对照抗体。标签或包装插页可提供对组合物的描述以及用于预期体外或检测用途的说明书。
实施例
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。所有反应都是在氮气保护下进行的(氢化反应除外)。
除非另行定义,文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的实施方法与材料仅作示范用。
缩略语
Ab 抗体
ACN 乙腈
ADC 抗体药物偶联物
BOC(Boc) 叔丁氧羰基
DCM 二氯甲烷
DIPEA 二异丙基乙基胺
DMF N,N-二甲基甲酰胺
ELISA 酶联免疫吸附测定
EtOAc 乙酸乙酯
Eq(eq) 当量
g 克
HATU O-(7-氮杂苯并三唑-1-基)-N,N,N,N-四甲基脲六氟磷酸酯
HOSu N-羟基琥珀酰亚胺
HIC 疏水作用色谱
HPLC 高效液相色谱
LC-MS 液相色谱-质谱联用
mAb 单克隆抗体
min 分钟
mL 毫升
MS 质谱
nm 纳米
μL 微升
PE 石油醚
rt 室温
Rt 保留时间
SDS-PAGE 聚丙烯酰胺凝胶电泳
SEC 尺寸排阻色谱
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
除非另外说明,所有的无水试剂都是直接从供应商购买的,并保存在氮气下。购买的所有其它试剂和溶剂都是高纯度的,并且使用前不经过进一步纯化。
核磁共振波谱是在Bruker Avance III 500兆核磁共振波谱仪上采集的。化学位移(δ)单位是ppm,以四甲基硅烷为参照系(化学位移为0)。
液相色谱-质谱联用分析方法中,低分辨质谱数据是在一台与惠普Agilent 1200高效液相色谱仪接口的Agilent 6110(酸法)或6120B(碱法)质谱仪上采集的。
方法1:酸法高效液相色谱方法采用沃特世Sunfire C18反相色谱柱(4.60×50mm,3.5μm)进行分离,洗脱液梯度为1.4分钟内5%-95%B相(乙腈,含0.01%TFA)在A相(水相,含0.01%TFA)中,流速为2.0mL/min,柱温为50℃;
方法2:酸法高效液相色谱方法采用Poroshell 120EC-C18反相色谱柱(4.6×30mm,2.7μm)进行分离,洗脱液梯度为2分钟内5%-95%B相(乙腈,含0.01%TFA)在A相(水相,含0.01%TFA)中,流速为1.5mL/min,柱温为50℃;
方法3:碱法高效液相色谱方法采用沃特世Xbridge C18反相色谱柱(4.60×50mm,3.5μm)进行分离,洗脱液梯度为1.5分钟内5%-95%B相(乙腈)在A相(水相,含10mM碳酸氢铵)中,流速为2.0mL/min,柱温为40℃。
制备用反相-高效液相色谱纯化(prep-RP-HPLC)在吉尔森(Gilson)仪器上完成,使用的分离柱为沃特世Sunfire C18反相色谱柱(250×19mm,10μm)。
方法4:酸法制备。流动相:A:含0.1%TFA的水相;B:ACN。流速:20mL/min。
方法5:碱法制备。流动相:A:含10mM碳酸氢铵的水相;B:ACN。流速:20mL/min。
除非另有说明,实施例中提及的商品化试剂依照制造商的说明书使用。
1、抗原抗体结合实验(ELISA)
实施例中利用酶联免疫吸附检验抗CD79b抗体(包括小鼠血清、杂交瘤上清或重组表达的单克隆抗体等)在体外对CD79b抗原的亲和力。
实验步骤为:用包被液(PBS)(10mM磷酸盐,138mM NaCl,pH7.2)稀释抗原(人CD79b-ECD,novoprotein,CA29)至1ug/ml,加入100ul/孔于96孔酶标板(Corning,CAT#9018),在4℃孵育过夜。次日将包被有抗原的96孔酶标板恢复至室温,用洗涤液(PBS+0.05%Tween-20(Sangon,CAT#TB0560)洗涤三次。随后加入250ul/孔封闭液(PBS+1%BSA(Sangon,CAT#A0332),在25℃孵育1到3小时。用洗涤液洗涤三次。加入待测抗CD79b抗体于96孔酶标板,在25℃孵育2小时。用洗涤液洗涤三次。加入封闭液10000倍稀释二抗(抗小鼠IgG(Fc)-HRP,Sigma,CAT#A00168或抗人IgG F(ab')2-HRP,Sigma,CAT#A0293)100ul/孔至96孔酶标板,在25℃孵育1小时,用洗涤液洗涤三次。加入100ul/孔显色液TMB(Sangon,CAT#TB0954,现用现配)至96孔酶标板,在25℃静置15分钟。加入100ul/孔终止液(1N H2SO4)至96孔酶标板。酶标仪10分钟内读取OD450/630nm。
2、FACS检测抗体与细胞表面CD79b的结合
实施例中利用流式细胞术(FACS)检测抗CD79b抗体(包括小鼠血清、杂交瘤抗体等)在体外对癌细胞表面的天然CD79b胞外区的结合能力。
从DSMZ或ATCC处购买CD79b阳性表达或阴性表达的癌细胞珠,用细胞膜表面受体定量试剂盒QIFIKIT(DAKO,K0078)对细胞表面的CD79b进行定量。结果见下表:
利用SU-DHL-4细胞株进行免疫小鼠及杂交瘤上清的检测与筛选。具体做法为,收集处于对数生长期的SU-DHL-4细胞,用PBS洗涤后,分装于1.5ml EP管,约10万个细胞每管,加入稀释后的小鼠血清或杂交瘤上清100ul/管,于4℃孵育1小时。用PBS-2%BSA洗涤两次,再加入PBS-2%BSA 1:400配置的Alexa Fluor 488山羊抗小鼠IgG(H+L)(Molecularprobes,Cat#A11001),100ul/管,于4℃避光放置45分钟。用PBS-2%BSA洗涤两次,再用500ul PBS-2%BSA重悬细胞,使用流式细胞仪Guava(Millipore,8HT)读取细胞,通过分析细胞表面的荧光强度(MFI值)来判定抗体与细胞表面CD79b受体的结合强弱。
3、药物偶联物的制备
为了验证抗CD79b抗体的功效,将抗体利用不同的连结子偶联上不同的小分子药物,制备成药物偶联物,具体偶联方式如下。
向抗体溶液(20mM磷酸二氢钠-磷酸氢二钠缓冲液,150mM氯化钠,pH值7.2)中加入三(2-羧乙基)膦盐酸盐(TCEP,10eq,储备液浓度10mM)。反应液于37℃恒温水浴锅内孵育2小时。将反应液冷却至约室温,经超滤(Millipore Ultra,50000MWCO)或凝胶过滤置换到缓冲液(100mM磷酸二氢钾-磷酸氢二钾,100mM氯化钠,1mM二乙烯三胺五乙酸,pH7.0-8.0)或缓冲液(20mM柠檬酸-柠檬酸三钠,50mM氯化钠,1mM二乙烯三胺五乙酸,pH 6.0)中,加入二甲亚砜和相应的连接子-药物化合物(二甲亚砜储备液,相对抗体3-10当量),并保证反应液中二甲亚砜体积占比达10-15%左右。偶联反应在10℃进行0.5小时。
向反应液加入过量的半胱氨酸溶液,以淬灭未反应的连接子-药物化合物,淬灭反应在10℃进行30分钟。将反应液先经超滤(Millipore Ultra,50000MWCO)或凝胶过滤除去连接子-药物-半胱氨酸加合物以及过量的半胱氨酸并将样品置换到保存缓冲液(20mM磷酸二氢钠-磷酸氢二钠缓冲液,150mM氯化钠,pH值7.2)中,然后经由0.22μm孔径的过滤装置(Millex-GV Filter)除菌,得到抗体药物偶联物anti-CD79b-ADC,并在4℃条件下保存。
4、二度ADC实验检测杂交瘤上清对淋巴瘤细胞BJAB增殖的抑制作用
对于量较少或比较难纯化的抗体,没有足够的量去完成与连接子及小分子毒素的偶联实验,这时通过让其先与一个已经偶联了连接子及毒素小分子的抗体相结合,然后再与癌细胞共孵育,通过目标抗体的内吞作用,将与之结合的抗体药物偶联物带进细胞内部,杀死癌细胞。把这种间接反应抗体的内吞性质及对癌细胞的增殖抑制作用,称为二度ADC实验。
为了实施二度ADC实验,从ATCC购买HB58细胞株(HB-58TM),该细胞株为大鼠B细胞与P3X63Ag8.653骨髓瘤细胞融合后得到的杂交瘤细胞,分泌的抗体能特异性结合鼠源抗体。纯化获得足够的HB58抗体,并制备抗体药物偶联物HB58-ADC。
人淋巴瘤细胞BJAB按1×105个细胞/100ul/孔接种至96孔细胞培养板(BDfalcon,Cat#353072),培养基为ATCC改良的RPMI1640培养基(Gibco,Cat#A10491)+10%胎牛血清(FBS)(Gibco,Cat#10099141)。37℃培养箱(SANYO,MC0018AIC)中培养一天,第二天加入已经与HB58-ADC按1:1浓度比预混好的含抗CD79b抗体的杂交瘤上清及相关对照,100ul/孔,三倍梯度稀释,共九个浓度孔加一个对照孔。在37℃培养箱中培养三天。第五天,使用细胞增殖检测试剂盒(Cell Counting Kit-8)(DOJINDO,CK04)显色。按试剂盒说明书方法检测细胞增殖情况。用酶标仪(BioTek Synergy MX)读取450/630nm的吸光度值,计算IC50及抑制率。
5、表面等离子共振法测定抗体亲和力
实施例中利用表面等离子共振法(SPR)检测抗CD79b抗体(包括人鼠嵌合抗体及人源化抗体等)在体外对重组CD79b胞外区蛋白的结合能力。
该实验在Biacore T200(GE)机器上进行检测,将待测抗体用HBS-EP(GE,BR100826)缓冲液稀释至10ug/ml,按照Amine-Coupling Kit(GE,BR-1000-50)的说明,将待测抗体固定到CM5芯片(GE,BR-1006-68)上,固定时间是300秒,流速为10ul/min,采用Kinetics程序将HBS缓冲液梯度稀释的不同浓度(0.25nm,0.5nm,1nm,2nm,4nm,8(×2)nm,16nm)的重组CD79b胞外区蛋白进行捕获反应,设置抗原抗体的结合时间为300秒,解离时间为900秒,抗原蛋白的流速为30ul/min。拟合解离曲线计算不同单抗的KD值。以上实验均在25℃的条件下进行。
实施例1:抗人CD79b的小鼠单克隆抗体细胞株的产生及筛选
通过免疫小鼠,脾细胞融合,杂交瘤筛选方法得到小鼠来源的抗人CD79b单克隆细胞株,委托南京金斯瑞生物科技有限公司完成。免疫所用的抗原为重组表达的人CD79b胞外区蛋白(上海近岸科技有限公司,品名为重组人CD79B,货号为CA29,氨基酸序列如SEQIDNO:35所示),免疫共选用四个种属的小鼠,分别为Balb/C、C3H、SJL、C57BL/6,每个种属六只。免疫佐剂为常规福氏佐剂,初次免疫的剂量为每只小鼠接种50ug抗原。间隔两周加强免疫,剂量降为25ug,从第一次加强免疫开始,每次加强免疫7天后采集小鼠血清用ELISA测定效价(方法见“材料与方法”部分的第1点)。用第二次加强免疫7天后采集的小鼠血清做FACS检测(方法见“材料与方法”部分的第2点),看其能不能与CD79b阳性表达的细胞株SU-DHL4表面上的CD79b相结合,同时测定每只小鼠的结合效价。
两次加强免疫后,根据ELISA及FACS的检测结果,选取效价最高的小鼠进行细胞融合(采用电融合的方式),融合效率约为每3000个脾内B细胞可融合成一个杂交瘤细胞,所有融合后的细胞铺到96孔板中,每个融合铺40块板。一周之后进行ELISA检测(方法见“材料与方法”部分的第1点)。收集ELISA检测中呈阳性的克隆的上清做FACS检测(方法见“材料与方法”部分的第2点)。将FACS检测阳性的克隆全部进行亚克隆。收集一次亚克隆后出现单克隆的孔中的上清做二度ADC的检测(见“材料与方法”部分的第3点)。对在二度ADC检测中能抑制CD79b阳性表达的癌细胞BJAB增殖的克隆继续亚克隆,直至形成稳定的单克隆细胞株。
本实施例共做了三个有效融合,筛选后得到FACS阳性克隆共31株,最后选取增殖抑制效果最好的18株(见下表1)进行了完全亚克隆。
表1
克隆号 | 对BJAB的IC<sub>50</sub>(ng/ml) | 采用ELISA获得的EC<sub>50</sub>(ng/ml) |
35B5 | 7.89 | 11.1 |
38E4 | 62.1 | 50.8 |
33H10 | 3.25 | 3.86 |
50B10 | 3.52 | 6.75 |
34B4 | 3.36 | 1.99 |
82F12 | 2.23 | 3.07 |
75G3 | 12.4 | 8.82 |
81C3 | 16.0 | 11.0 |
85B3 | 7.9 | 12.1 |
85B5 | 6.25 | 11.9 |
83A10 | 8.87 | 11.8 |
85G11 | 7.64 | 10.3 |
78B6 | 10.7 | 13.4 |
88B12 | 14.0 | 11.8 |
104E1 | 9.3 | 14.9 |
104A2 | 8.64 | 12.1 |
110A4 | 13.4 | 13.7 |
110D5 | 11.1 | 12.9 |
实施例2:抗CD79b抗体序列克隆及重组嵌合抗体的表达
将实施例1表1所列的18株单克隆细胞株进行cDNA序列克隆,然后重组表达出恒定区为人IgG1的嵌合单克隆抗体,并进行活性检测。本实施例用逆转录PCR扩增抗体基因的重链和轻链可变区,连接到载体,测序得到单克隆抗体轻重链序列。具体而言,首先采用RNA纯化试剂盒(Qiagen,Cat#74104)提取各单克隆细胞株的细胞总RNA。然后使用cDNA合成试剂盒(Invitrogen公司的货号为18080-051)制备cDNA单链,即Oligo-dTprimers cDNA反转录。以此为模板,采用PCR方法合成抗体轻重链可变区序列,PCR产物克隆到TA载体pMD-18T,然后测序。
通过分析重链及轻链的CDR区的序列,找出潜在的可能会发生翻译后修饰的位点,最后选定六株单克隆(35B5、78B6、85G11、88B12、104A2及104E1)进行抗体的重组表达。首先将抗体的轻重链序列经密码子优化后进行全基因合成,并在重链的两端带上HindIII/NheI酶切位点,在轻链的两端带上HindIII/BsiWI酶切位点,采用这两对酶切位点将重轻链可变区基因连到含有人IgG1恒定区X序列及K链恒定区序列的表达载体PTT5上,构建嵌合抗体的表达载体。在293F细胞中瞬转表达得到重组抗体。
实施例3、抗CD79b抗体的药物偶联物对淋巴癌细胞增殖的抑制作用
分别将六株单克隆(35B5、78B6、85G11、88B12、104A2及104E1)产生的重组嵌合抗体偶联上BMP-vcMMAE(连接子-药物1),做成抗体药物偶联物(ADC),在七种CD79b阳性表达的淋巴癌细胞株BJAB、Ramos、DoHH2、SU-DHL-4、U-698-M、Granta-519、WSU-DLCL2及两种CD79b阴性表达的淋巴癌细胞株Raji与Jurkat验证重组抗体药物偶联物对细胞增殖的抑制作用,培养条件均相同(见“材料与方法”部分第3点)铺板密度及ADC用药起始浓度见下表2,第二天加药时只需加入抗CD79b的抗体药物偶联物,不需要加入HB58-ADC。
表2
淋巴瘤细胞株 | 铺板数细胞/孔 | ADC用药起始浓度(ng/ml) |
BJAB | 10000 | 400 |
Ramos | 40000 | 400 |
DoHH2 | 40000 | 400 |
SU-DHL-4 | 30000 | 400 |
U-698-M | 20000 | 1000 |
Granta-519 | 50000 | 2000 |
WSU-DLCL2 | 20000 | 2000 |
Raji | 40000 | 2000 |
Jurkat | 20000 | 2000 |
抗体药物偶联物对淋巴癌细胞增殖的抑制结果如表3所示。
表3
实施例4:抗CD79b抗体人源化
因104E1株表达的重组嵌合抗体的药物偶联物对Granta-519及WSU-DLCL2这两个CD79b表达量相对较低的淋巴瘤细胞的增殖的抑制作用明显好于其他五株抗体,因此,选择104E1进行人源化工作。
104E1表达的单抗的序列信息(基于Kabat系统划分)如下:
HCDR1:GNTFTSYGIN(SEQ ID NO:1)
HCDR2:GEIFPRSGNIYYNEKFKG(SEQ ID NO:2)
HCDR3:AKGGTGDFDY(SEQ ID NO:3)
LCDR1:RSSQNIVHSDGNTYLE(SEQ ID NO:4)
LCDR2:KVSFRLS(SEQ ID NO:5)
LCDR3:FQGSHVPWT(SEQ ID NO:6)
mVH:
QVQLQQSGSELARPGASVKLSCKTSGNTFTSYGINWVKQRTGQGLEWIGEIFPRSGNIYYNEKFKGKATLTADKSSSTAYMELRSLTSEDSAVYFCAKGGTGDFDYWGQGTTLTVSS(SEQ ID NO:7,核苷酸序列如SEQID NO:38所示)
mVL:
DVLMTQTPLSLPVSLGDQASISCRSSQNIVHSDGNTYLEWYLQKPGQSPKLLIYKVSFRLSGVPDRFSGSGSGTDFTLKIRRVEAEDLGTYYCFQGSHVPWTFGGGTKLEIK(SEQID NO:8,核苷酸序列如SEQ IDNO:39所示)
委托南京金斯瑞对104E1株表达的单抗序列进行人源化改造。具体流程如下:将鼠源抗CD79b的单克隆抗体104E1的重轻链可变区序列在人类种系序列数据库里进行同源性比较,找到与104E1重链可变区同源性最高的人种系序列IGHV1-69*02,同源度为64.3%,与104E1轻链可变区同源性最高的人种系序列IGKV2-30*02,同源度为79.0%。接下来在人的抗体库里找到由这两条种系序列生成的抗体AGC78785.1(重链可变区,SEQ ID NO:9)与BAC01734.1(轻链可变区,SEQ ID NO:10)的序列,序列信息如下,
AGC78785.1immunoglobulin heavy chain variable region[Homo sapiens]
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYTISWVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCATSGVGLHFGYFDYWGQGTLVTVSS(SEQ ID NO:9)
BAC01734.1immunoglobulin kappa light chain Variable region[Homosapiens]
MKYLLPTAAAGLLLLAAQPAMADVVMTQSPLSLPVTLGQPASISCRSSQSLVHSDGNTYLNWFQQRPGQSPRRLIYKVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGTHWPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSARQSTPFVCEYQGQSSDLPQPPVNAGGGSGGGSGG(SEQ ID NO:10)
用这两个人源抗体的FR区为框架,将其CDR区序列替换为相应的鼠源104E1的CDR区序列,生成CDR-嫁接式人源化抗体,序列如下:
嫁接HCDR的VH:
QVQLVQSGAEVKKPGSSVKVSCKASGNTFTSYGINWVRQAPGQGLEWMGEIFPRSGNIYYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCATGGTGDFDYWGQGTLVTVSS(SEQ ID NO:11);
嫁接LCDR的VL:
DVVMTQSPLSLPVTLGQPASISCRSSQNIVHSDGNTYLEWFQQRPGQSPRRLIYKVSFRLSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPWTFGGGTKVEIK(SEQ ID NO:12)。
为了找出鼠源FR区域中对抗体亲和力起重要作用的氨基酸位点,在PDB数据库中查找与鼠源104E1抗体同源性相似的晶体结构。结果找到抗多唾液酸抗体Ab735的scFV晶体结构,与104E1抗体序列的同源性为77%,且具有足够高的分辨率。以此晶体为结构模板,将两条序列对比,建立104E1抗体的3WBD scFvs的同源模型,根据这个同源模型找出104E1序列FR区内被CDR结构域包裹的,或距离CDR结构域在之内的氨基酸位点,然后将这些可能对抗体亲和力起重要作用的位点在CDR嫁接的序列(SEQ ID NO:11和SEQ ID NO:12)中做回复突变,同时避免糖基化、脱酰胺化、氧化位点等。在重链可变区内共找出15个可能需要做回复突变的位点,包括A24T,RV67KA,S84R,T98K,K12A,S16A,V20L,A24T,R38K,M48I,V68A,I70L,Y95F,T98K和V113L,在轻链可变区内共找出7个可能需要做回复突变的位点,包括V3L,F41Y,RR50KL、FQ41YL,R51L,V88L和V109L。然后根据金斯瑞的标准操作规程建立Fab文库,通过噬菌体展示平台进行筛选。筛选出亲和力不低于鼠源104E1抗体的人源化之后的序列,测序进行序列确认。
人源化以后的轻重链可变区如下:
1、重链可变区
AS11161:
QVQLVQSGAEVKKPGSSVKVSCKTSGNTFTSYGINWVRQAPGQGLEWMGEIFPRSGNIYYNEKFKGKVTITADKSTSTAYMELSSLRSEDTAVYYCAKGGTGDFDYWGQGTLVTVSS(SEQ ID NO:13);
AS11164:
QVQLVQSGAEVKKPGSSVKVSCKTSGNTFTSYGINWVRQAPGQGLEWMGEIFPRSGNIYYNEKFKGKVTITADKSTSTAYMELSSLRSEDTAVYYCAKGGTGDFDYWGQGTLVTVSS(SEQ ID NO:14);
AS11252:
QVQLVQSGAEVKKPGSSVKLSCKTSGNTFTSYGINWVKQAPGQGLEWIGEIFPRSGNIYYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKGGTGDFDYWGQGTLVTVSS(SEQ ID NO:15);
AS11254:
QVQLVQSGAEVKKPGASVKVSCKTSGNTFTSYGINWVKQAPGQGLEWMGEIFPRSGNIYYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKGGTGDFDYWGQGTLVTVSS(SEQ ID NO:16);
AS11259:
QVQLVQSGAEVKKPGSSVKVSCKTSGNTFTSYGINWVKQAPGQGLEWIGEIFPRSGNIYYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKGGTGDFDYWGQGTLVTVSS(SEQ ID NO:17);
2、轻链可变区
AS11161:
DVVMTQSPLSLPVTLGQPASISCRSSQNIVHSDGNTYLEWYQQRPGQSPRLLIYKVSFRLSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPWTFGGGTKVEIK(SEQ ID NO:18);
AS11164:
DVLMTQSPLSLPVTLGQPASISCRSSQNIVHSDGNTYLEWYQQRPGQSPKLLIYKVSFRLSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPWTFGGGTKVEIK(SEQ ID NO:19);
AS11252:
DVVMTQSPLSLPVTLGQPASISCRSSQNIVHSDGNTYLEWYQQRPGQSPRLLIYKVSFRLSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPWTFGGGTKVEIK(SEQ ID NO:20);
AS11254:
DVVMTQSPLSLPVTLGQPASISCRSSQNIVHSDGNTYLEWYQQRPGQSPRLLIYKVSFRLSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPWTFGGGTKVEIK(SEQ ID NO:21);
AS11259:
DVVMTQSPLSLPVTLGQPASISCRSSQNIVHSDGNTYLEWYQQRPGQSPRLLIYKVSFRLSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPWTFGGGTKVEIK(SEQ ID NO:22)。
人源化以后的轻重链和IgG1Fc区段重组,得到本发明人源化抗CD79b单克隆抗体。所用的Fc序列如下:
重链恒定区:
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:23);
轻链恒定区:
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:24)。
用基因克隆、重组表达的方法分别克隆、表达、纯化上述抗体,经Biacore测定抗体亲和力(由金斯瑞完成),最终选出活性保持最好的人源化抗体AS11161,AS11164、AS11252、AS11254、AS11259,序列如下:
人源化抗体AS11161
重链
QVQLVQSGAEVKKPGSSVKVSCKTSGNTFTSYGINWVRQAPGQGLEWMGEIFPRSGNIYYNEKFKGKVTITADKSTSTAYMELSSLRSEDTAVYYCAKGGTGDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:25)
轻链
DVVMTQSPLSLPVTLGQPASISCRSSQNIVHSDGNTYLEWYQQRPGQSPRLLIYKVSFRLSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:26)
人源化抗体AS11164
重链
QVQLVQSGAEVKKPGSSVKVSCKTSGNTFTSYGINWVRQAPGQGLEWMGEIFPRSGNIYYNEKFKGKVTITADKSTSTAYMELSSLRSEDTAVYYCAKGGTGDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:27)
轻链
DVLMTQSPLSLPVTLGQPASISCRSSQNIVHSDGNTYLEWYQQRPGQSPKLLIYKVSFRLSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:28)
人源化抗体AS11252
重链
QVQLVQSGAEVKKPGSSVKLSCKTSGNTFTSYGINWVKQAPGQGLEWIGEIFPRSGNIYYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKGGTGDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:29)
轻链
DVVMTQSPLSLPVTLGQPASISCRSSQNIVHSDGNTYLEWYQQRPGQSPRLLIYKVSFRLSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:30)
人源化抗体AS11254
重链
QVQLVQSGAEVKKPGASVKVSCKTSGNTFTSYGINWVKQAPGQGLEWMGEIFPRSGNIYYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKGGTGDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:31)
轻链
DVVMTQSPLSLPVTLGQPASISCRSSQNIVHSDGNTYLEWYQQRPGQSPRLLIYKVSFRLSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:32)
人源化抗体AS11259
重链
QVQLVQSGAEVKKPGSSVKVSCKTSGNTFTSYGINWVKQAPGQGLEWIGEIFPRSGNIYYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCAKGGTGDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:33,核苷酸序列如SEQ ID NO:36所示)
轻链
DVVMTQSPLSLPVTLGQPASISCRSSQNIVHSDGNTYLEWYQQRPGQSPRLLIYKVSFRLSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:34,核苷酸序列如SEQ ID NO:37所示)。
采用“材料与方法”部分第4点所述方法测试人源化之后的抗体的亲和力,结果如下表4及图1所示。
表4
结果显示,本发明人源化抗体体外与CD79b抗原的结合力KD值约为0.02nM(由金斯瑞进行Biacore测定),与人鼠嵌合抗体相比较,人源化改造并没有使抗体的亲和力有大的改变。
实施例5:抗CD79b人源化抗体对人CD79b胞外区体外的结合活性及其药物偶联物对淋巴癌细胞的增殖抑制作用的测定
采用“材料与方法”部分第1点所述的ELISA检测了CD79b人源化抗体对人CD79b胞外区体外的结合活性,结果见表5。
表5
人源化抗体 | ELISA检测EC50(ng/ml) |
AS11161 | 43.1 |
AS11164 | 64 |
AS11252 | 49.9 |
AS11254 | 50.1 |
AS11259 | 58.3 |
制备人源化抗体的抗体药物偶联物,并检测其对淋巴癌细胞体外增殖的抑制作用(方法参见实施例3),结果见表6。
表6
实施例6:抗CD79b人源化抗体生物物理稳定性特性分析
为了评估本发明抗体的稳定性,分别将五种人源化抗体置换到pH不同的缓冲溶液(pH4.5、6.0、7.4)中,然后放置在40℃的环境下,分别于第1、6、12、26天取样,用“材料与方法”部分第1点所述的ELISA分析抗体的活性,SEC(TOSOH,TSKgel,G3000SWXL)检测抗体的纯度,4℃放置样品为对照。
结果显示,五种人源化抗体在三种不同pH条件下,40℃放置26天,不同时间段取样的样品经ELISA检测的活性并没有明显区别,在SEC检测中,纯度也都在98%以上,未见明显多聚体的产生。
实施例7:抗CD79b人源化抗体的药物偶联物对淋巴癌细胞荷瘤鼠的体内药效评价
为了验证抗CD79b人源化抗体的功效,选择人源化后的一个变体AS11259,依据材料与方法3中描述的方法,制备药物偶联物AS11259-ADCs,然后在Ramos、DoHH2、Granta519和WSU-DLCL2荷瘤鼠模型中观察药物偶联物AS11259-ADCs的体内肿瘤抑制效果。
连接子-药物的合成
连接子-药物1的合成
连接子-药物1的合成参考WO 2014114207。
连接子-药物2的合成
连接子-药物2的合成参考WO 2014114207。
连接子-药物3的合成
合成步骤:
将N-叔丁氧羰基乙二胺(710mg,4.43mmol)和二异丙基乙基胺(1.55mL,8.86mmol)溶解于二氯甲烷(10mL)中,然后向其中滴加氯乙酰氯(500mg,4.43mmol)。反应液在室温下搅拌16小时,然后加入二氯甲烷稀释,依次用饱和氯化铵溶液,饱和碳酸氢铵溶液,水和饱和食盐水洗涤。有机相用无水硫酸钠干燥,过滤和减压浓缩得到白色固体11。
将所得粗品11溶于丙酮(10mL),然后加入碘化钠(3.32g,22.2mmol)。反应液在50℃搅拌16小时,然后加入二氯甲烷稀释,依次用水和饱和食盐水洗涤。有机相用无水硫酸钠干燥,过滤和减压浓缩。所得粗品用硅胶柱色谱纯化(石油醚/乙酸乙酯1:1)得到白色固体12(400mg)。LC-MS(方法1):保留时间1.61分钟;[M+Na]+351.0。
将化合物DM1(40mg,0.054mmol)和化合物12(35.4mg,0.108mmol)溶解于N,N-二甲基甲酰胺(2mL),然后向其中加入二异丙基乙基胺(29μL,0.163mmol)。反应液在室温下搅拌2小时,然后用制备高效液相色谱仪纯化(方法4:8分钟内50%-80%B→4分钟内95%B)得到白色固体13(40mg)。
将化合物13(40mg,0.043mmol)溶于二氯甲烷(3mL),然后向其中加入三氟乙酸(97mg,0.852mmol)。反应液在室温下搅拌3小时,然后减压浓缩得到粗品。将粗品和化合物14(18.7mg,0.0639mmol)溶于N,N-二甲基甲酰胺(2mL),然后向其中依次加入HATU(32.4mg,0.0852mmol)和二异丙基乙基胺(74μL,0.426mmol)。反应液在室温下搅拌2小时,然后用制备高效液相色谱仪(方法4:8分钟内50%-80%B→4分钟内95%B)纯化得到白色固体连接子-药物3(8.3mg)。LCMS(A018):保留时间1.92分钟,[M+Na]+1134.3。
连接子-药物4的合成
合成步骤:
将化合物15(0.25g,0.305mmol,合成参考WO 2014114207),化合物16(0.20g,0.208mmol,合成参考WO2016192527)和HOBt(28.1mg,0.208mmol)溶于N,N-二甲基甲酰胺(4mL),然后向其中加入吡啶(1mL)。反应液在室温下搅拌16小时,然后用制备高效液相色谱仪(方法5:8分钟内50%-80%B→4分钟内95%B)纯化得到淡粉色固体连接子-药物4(45mg)。LCMS(方法3):保留时间2.127分钟,1/2[M+2H]2+822.0。
连接子-药物5的合成
合成步骤:
将化合物15(14mg,0.017mmol),化合物17(14mg,0.014mmol,合成参考WO2016192527)和HOBt(3mg,0.017mmol)溶于N,N-二甲基甲酰胺(2mL),然后向其中加入吡啶(0.5mL)。反应液在室温下搅拌16小时,然后用制备高效液相色谱仪(方法5:8分钟内45%-75%B→4分钟内95%B)纯化得到红色固体连接子-药物5(1.8mg)。LCMS(方法2):保留时间1.40分钟,1/2[M+2H]2+843.9。
连接子-药物6的合成
合成步骤:
将化合物15(14mg,0.017mmol),化合物18(14m g,0.013mmol,合成参考WO2016192527)和HOBt(3mg,0.017mmol)溶于N,N-二甲基甲酰胺(2mL),然后向其中加入吡啶(0.5mL)。反应液在室温下搅拌16小时,然后用制备高效液相色谱仪(方法5:8分钟内45%-75%B→4分钟内95%B)纯化得到红色固体连接子-药物6(2.0mg)。LCMS(方法2):保留时间1.40分钟,1/2[M+2H]2+865.3。
连接子-药物7的合成
合成步骤:
将化合物15(10mg,0.012mmol),化合物19(8mg,0.024mmol,合成参考WO2013/149948A1)溶解于N,N-二甲基甲酰胺(1mL)和吡啶(0.2mL)的混合溶液,然后向其中加入HOBt(3.2mg,0.024mmol)。反应液在室温下搅拌2小时,然后用制备高效液相色谱仪(方法4:8分钟内60%-90%B→4分钟内95%B)纯化得到白色固体20(6.0mg)。LC-MS(方法3):保留时间2.24分钟,[M+Na]+1028.3。
将化合物20(6.0mg,0.006mmol)溶解于二氯甲烷(1mL),然后向其中加入二氯乙酸(15mg,0.12mmol)。反应液在室温下搅拌2小时,然后浓缩除去溶剂。残余物用正己烷/乙醚(1mL/1mL)洗涤,过滤,干燥得到白色固体21(4.5mg)。LC-MS(方法3):保留时间1.57分钟,[M+H]+768.3。
将化合物21(4.5mg,0.005mmol)和化合物22(5mg,0.008mmol,合成参考US8389697B2)溶解于N,N-二甲基甲酰胺(1mL),然后向其中加入二异丙基乙基胺(2.6mL,0.02mmol)和HATU(3.8mg,0.01mmol)。反应液在室温下搅拌1小时,然后用制备高效色谱仪(方法5:8分钟内50%-80%B→4分钟内95%B)纯化得到红色固体连接子-药物7(0.9mg)。LCMS(方法3):保留时间2.05分钟,[M+H]+1378.3。
连接子-药物8的合成
合成步骤:
将化合物15(100mg,0.122mmol),化合物23(60mg,0.071mmol,合成参考WO2016192527)和HOBt(10mg,0.071mmol)溶解于干燥的DMF(2mL),然后向其中加入吡啶(0.5mL)。反应液在室温下搅拌16小时,然后用制备高效液相色谱仪(方法5:8分钟内50%-80%B→4分钟内95%B)纯化得到白色固体化合物24(30mg)。LCMS(方法3):保留时间2.41分钟,1/2[M+2H]2+762.0。
将化合物24(30mg,0.0197mmol)溶解于二氯甲烷(1.5mL),然后向其中加入三氟乙酸(0.5mL)。反应液在室温下搅拌3小时,然后浓缩除去溶剂,残余物用制备高效液相色谱仪(方法X)纯化得到白色粉末状固体化合物25(15mg)。
将化合物25(15mg,0.0197mmol),化合物26(7mg,0.0189mmol,合成参考Journalof Organic Chemistry,2001,66,4494-4503)溶解于干燥DMF(0.4mL),然后向其中加入HATU(7.2mg,0.0189mmol)和DIPEA(3.7mg,0.0286mmol)。反应液在室温下搅拌2小时,然后用制备高效液相色谱仪(方法5:8分钟内50%-80%B→4分钟内95%B)纯化得到白色粉末状固体连接子-药物8(4.8mg)。LCMS(方法2):保留时间1.37分钟,1/2[M+2H]2+909.5。
连接子-药物9的合成
合成步骤:
将化合物27(165mg,0.132mmol,合成参考WO2007011968)和化合物28(90mg,0.231mmol,合成参考WO 2014114207)溶解于DMF(2mL),然后向其中加入DIPEA(51mg,0.395mmol)。反应液在室温下搅拌0.5小时,然后加入冰醋酸(50μL)淬灭反应,溶液用制备高效液相色谱仪(方法4:8分钟内50%-80%B→4分钟内95%B)纯化得到白色粉末状固体连接子-药物9(128mg)。LCMS(方法2):保留时间1.51分钟,1/2[M+2H]2+702.8。
连接子-药物10的合成
连接子-药物10的合成参考CN 201710691056.X。
抗体药物偶联物的制备
向抗体AS11259(IgG1)溶液(20mM磷酸二氢钠-磷酸氢二钠缓冲液,150mM氯化钠,pH值7.2)中加入三(2-羧乙基)膦盐酸盐(TCEP,10eq,储备液浓度10mM)。反应液于37℃恒温水浴锅内孵育2小时。将反应液冷却至约室温,经超滤(Merck MilliporeUltra,50000MWCO)或凝胶过滤置换到缓冲液(100mM磷酸二氢钾-磷酸氢二钾,100mM氯化钠,1mM二乙烯三胺五乙酸,pH 7.0-8.0)或缓冲液(20mM柠檬酸-柠檬酸三钠,50mM氯化钠,1mM二乙烯三胺五乙酸,pH 6.0),加入二甲亚砜和实施例1制得的连接子-药物1(二甲亚砜储备液,相对抗体3-10当量),并保证反应液中二甲亚砜体积占比达10-15%左右。偶联反应在10℃进行0.5小时。
向反应液加入过量的半胱氨酸溶液,以淬灭未反应的连接子-药物1,淬灭反应在10℃进行30分钟。将反应液先经超滤(Merck MilliporeUltra,50000MWCO)或凝胶过滤除去连接子-药物1-半胱氨酸的加合物以及过量的半胱氨酸并将样品置换到保存缓冲液(20mM磷酸二氢钠-磷酸氢二钠缓冲液,150mM氯化钠,pH值7.2)中,然后经由0.22μm孔径的过滤装置(Merck Millex-GV Filter)除菌,得到抗体药物偶联物AS11259-ADC-001,并在4℃条件下保存。
利用上述制备方法,以AS11259为抗体,以连接子-药物2-10分别代替连接子-药物1,制得本发明其它抗体药物偶联物AS11259-002至AS11259-011。抗体偶联药物AS11259-ADC-0012是由抗体AS11259与连接子-药物1偶联得到的,其中抗体还原部分选择部分还原方式,平均打开两对二硫键。
表6显示本实施例制备得到的抗体药物偶联物的总结。
表6
*:TCEP相对抗体当量数为3。
抗体药物偶联物的表征
1)平均DAR值测定
平均DAR值计算方法采用疏水色谱HIC色谱法(参考Anal.Chem.2013,85,1699-1704)。疏水作用色谱是在安捷伦1100(Agilent 1100)色谱仪上测定的。固定相采用TSKgel丁基-NPR柱(4.6×35mm,2.5μm,东曹(上海)生物科技有限公司)。洗脱梯度为线性梯度,25分钟内从100%缓冲液A[50mM磷酸钾(pH 7.0)+1.5M硫酸铵]置换到100%缓冲液B[80%v/v50mM磷酸钾(pH 7.0)+20%v/v异丙醇]。流速为0.8mL/min,柱温设在30℃,检测波长设在230nm和280nm。
本发明抗体药物偶联物的平均DAR值测定结果如下面表7所示。
表7:抗体药物偶联物的平均DAR值结果
抗体药物偶联物 | 平均DAR值 | 抗体药物偶联物 | 平均DAR值 |
AS11259-ADC-001 | 4.0 | AS11259-ADC-007 | NA |
AS11259-ADC-002 | NA | AS11259-ADC-008 | 4.1 |
AS11259-ADC-003 | NA | AS11259-ADC-010 | 4.0 |
AS11259-ADC-004 | 4.0 | AS11259-ADC-011 | 2.1 |
AS11259-ADC-005 | 4.2 | AS11259-ADC-0012 | 1.7 |
AS11259-ADC-006 | 4.1 |
NA:未检测,但基于连接子共性,其平均DAR值亦应接近4左右。
抗体药物偶联物对抗原的亲和力测定
采用间接ELISA方法考察待测抗体或抗体药物偶联物与对应抗原的结合能力:将CD79b抗原与固相载体(96孔酶标板)连接,形成固相抗原,洗涤除去未结合的抗原;加梯度稀释的本发明制得的抗体药物偶联物或其对应的抗体,其中的特异抗体与抗原结合,形成固相抗原-抗体复合物,未结合固相抗原的抗体或抗体药物偶联物经洗涤除去;加酶标抗抗体,使其与结合在固相抗原上的抗体或ADC抗体结合,未结合的抗抗体经洗涤除去;加入底物溶液,用酶标仪读取450nm/630nm处的光密度值,绘制曲线,计算EC50。
本发明的抗体药物偶联物对CD79b抗原的亲和力测定结果如表8所示。
表8:抗体药物偶联物对CD79b抗原的亲和力测定结果
抗体药物偶联物 | EC<sub>50</sub>(ng/mL) | 抗体药物偶联物 | EC<sub>50</sub>(ng/mL) |
AS11259 | 17.8 | AS11259-ADC-006 | 50.2 |
AS11259-ADC-001 | 31.7 | AS11259-ADC-007 | 62.9 |
AS11259-ADC-002 | 24.1 | AS11259-ADC-008 | 29.0 |
AS11259-ADC-003 | 16.2 | AS11259-ADC-010 | 23.2 |
AS11259-ADC-004 | 32.2 | AS11259-ADC-011 | 23.6 |
AS11259-ADC-005 | 46.9 | AS11259-ADC-0012 | 31.4 |
由上表8可知,本发明制得的抗体药物偶联物,其对抗原的亲和力与裸抗AS11259相比,均无显著性差异。
抗体药物偶联物抑制细胞增殖抑制的作用
抗体或抗体药物偶联物的细胞抑制活性是通过以下方法测定的:将表达肿瘤相关抗原或受体蛋白的哺乳动物细胞(本试验采用表达CD79b抗原的Ramos细胞)接种在96孔板上,每孔接种40000个细胞,悬浮于含10%FBS的RPMI 1640培养基(GIBCO)100μL;ADC样品初始浓度2μg/mL,用含2%FBS(GIBCO)的RPMI 1640培养基进行3倍梯度稀释;在原培养基中,每孔加入100μL梯度稀释的ADC样品,药物的起始终浓度为1ug/ml。在37℃和5%CO2条件下继续孵育72小时;移除原培养基50μL,每孔加入CCK-8显色液70μL(CCK-8:RPMI 1640=2:5),继续培养60-75分钟;用酶标仪读取450nm/630nm的吸光度值,绘制曲线,计算IC50。
本发明的抗体药物偶联物抑制细胞增殖作用的结果如表9所示。
表9:抗体药物偶联物抑制细胞增殖作用的结果
结果显示,本实施例制得的抗体药物偶联物均具有良好的细胞增殖抑制作用。
Ramos模型
Ramos细胞用含10%胎牛血清的RPMI1640培养液培养,培养条件为37℃,5%CO2。在对数生长期计数并且收集细胞,将细胞重悬在1:1的PBS与基质胶中,在小鼠(CB17/SCID小鼠,雌性,8-9周,平均体重18.4g,购自上海灵畅生物科技有限公司,动物合格证编号:2013001832088。饲养环境:SPF级)右侧皮下接种,每只小鼠接种的细胞体积是0.1ml,接种的细胞量为1×107个,待肿瘤平均体积197mm3时,称量体重,随机分组,开始给药,给药方式为尾静脉给药,给药频率为一次。
结果判断标准
相对肿瘤抑制率TGI(%):TGI=1-T/C(%)。T/C%为相对肿瘤增值率,即在某一时间点,治疗组和对照组相对肿瘤体积或瘤重的百分比值。T和C分别为治疗组和对照组在某一特定时间点的相对肿瘤体积(RTV)。
计算公式如下:T/C%=TRTV/CRTV*100%(TRTV:治疗组平均RTV;CRTV:溶媒对照组平均RTV;RTV=Vt/V0,V0为分组时该动物的瘤体积,Vt为治疗后该动物的瘤体积)。
肿瘤体积计算公式为:长径×短径2/2。肿瘤细胞接种当天定义为第0天。给药后每周两次测量肿瘤。
溶媒对照组在给药后第14天(PG-D14)平均肿瘤体积达到3003mm3。进行安乐死,同时计算其他用药组在给药后第14天的相对肿瘤抑制率。在给药后第45天,结束实验,持续观察的小鼠进行安乐死,同时记录每组中肿瘤完全消退的小鼠的数量。
实验结果
实验结果如表10和图2、图3所示。
表10:AS11259-ADC-001、002、004、008、010、011对人B细胞淋巴瘤Ramos裸鼠皮下移植瘤的疗效
溶媒对照组在给药后第14天(PG-D14)平均肿瘤体积达到3003mm3。
测试药AS11259-ADC-001治疗组在三个给药计量下(1mg/kg、2.5mg/kg、5mg/kg)与溶媒对照组相比均产生了显著的抗肿瘤效果,且呈现出明显的剂量-效应关系。三个给药计量的给药组,在给药后第14天(PG-D14)平均肿瘤体积分别为1558mm3、337mm3和14mm3,相对肿瘤抑制率TGI分别为48.7%、90.1%和99.6%,统计学上与对照组相比均具有显著性差异(p值分别为0.023、0.001、0.001)。高剂量(5mg/kg)组小鼠在给药后,其肿瘤生长明显受到抑制,在给药后第10天(PG-D10)6只小鼠有3只小鼠肿瘤开始消失,在给药后第24天(PG-D24)6只小鼠肿瘤已全部消失,在实验结束时(PG-D45),小鼠肿瘤未见恢复生长。
测试药AS11259-ADC-002治疗组在1mg/kg和2.5mg/kg的给药计量下,与溶媒对照组相比均产生了一定的抗肿瘤效果,在给药后第14天(PG-D14)平均肿瘤体积分别为2171mm3和1986mm3,相对肿瘤抑制率TGI分别为28.4%和33.2%,但相对溶媒对照组统计学上没有显著性差异(p值分别为0.195和0.126);测试药AS11259-ADC-002治疗组在5mg/kg的给药计量下,与溶媒对照组相比产生了显著的抗肿瘤效果,在给药后第14天(PG-D14)平均肿瘤体积为1294mm3,相对肿瘤抑制率TGI为60.1%,统计学上与对照组相比具有显著性差异(p=0.014)。测试药AS11259-ADC-002的抗肿瘤效果呈现出明显的剂量-效应关系。
测试药AS11259-ADC-004治疗组在1mg/kg给药计量下,与溶媒对照组相比产生了一定的抗肿瘤效果,在给药后第14天(PG-D14)平均肿瘤体积为1762mm3,相对肿瘤抑制率TGI为42.6%,但相对溶媒对照组统计学上没有显著性差异(p=0.075);测试药AS11259-ADC-004治疗组在2.5mg/kg和5mg/kg的给药计量下,与溶媒对照组相比均产生了显著的抗肿瘤效果,在给药后第14天(PG-D14)平均肿瘤体积分别为1835mm3和1030mm3,相对肿瘤抑制率TGI分别为41.2%和66.0%,相对溶媒对照组统计学上均具有显著性差异(p值分别为0.027和0.003)。测试药AS11259-ADC-004的抗肿瘤效果呈现出明显的剂量-效应关系。
测试药AS11259-ADC-010治疗组在三个给药浓度下(1mg/kg、2.5mg/kg、5mg/kg)与溶媒对照组相比均产生了显著的抗肿瘤效果,且呈现出明显的剂量-效应关系。三个给药计量的给药组,在给药后第14天(PG-D14)平均肿瘤体积分别为1241mm3、15mm3和12mm3,相对肿瘤抑制率TGI分别为57.8%、99.5%和99.6%,统计学上与对照组相比均具有显著性差异(p值分别为0.014、0.001、0.001)。中剂量(2.5mg/kg)组小鼠在给药后,其肿瘤生长明显受到抑制,在给药后第10天(PG-D10)6只小鼠有2只小鼠肿瘤开始消失,在给药后第28天(PG-D28)6只小鼠肿瘤已全部消失,之后有一只小鼠肿瘤恢复生长,其余5只小鼠,在实验结束时(PG-D45),小鼠肿瘤未见恢复生长;高剂量(5mg/kg)组小鼠在给药后,其肿瘤生长明显受到抑制,在给药后第10天(PG-D10)6只小鼠有1只小鼠肿瘤开始消失,在给药后第24天(PG-D24)6只小鼠肿瘤已全部消失,在实验结束时(PG-D45),小鼠肿瘤未见恢复生长。
测试药AS11259-ADC-0012治疗组在5mg/kg给药计量下与溶媒对照组相比产生了显著的抗肿瘤效果,在给药后第14天(PG-D14)平均肿瘤体积为13mm3,相对肿瘤抑制率TGI为99.6%,统计学上与对照组相比具有显著性差异(p=0.001)。此治疗组组小鼠在给药后,其肿瘤生长明显受到抑制,在给药后第10天(PG-D10)6只小鼠有2只小鼠肿瘤开始消失,在给药后第31天(PG-D31)6只小鼠中5只小鼠肿瘤已全部消失,在实验结束时(PG-D45),此5只小鼠肿瘤未见恢复生长。
测试药AS11259-ADC-011治疗组在2mg/kg和5mg/kg的给药计量下,与溶媒对照组相比均产生了显著的抗肿瘤效果,抗肿瘤效果呈现出明显的剂量-效应关系。在给药后第14天(PG-D14)平均肿瘤体积分别为818mm3和17mm3,相对肿瘤抑制率TGI分别为73.8%和99.4%,相对溶媒对照组统计学上均具有显著性差异(p值均为0.001)。高剂量(5mg/kg)组小鼠在给药后,其肿瘤生长明显受到抑制,在给药后第10天(PG-D10)6只小鼠有1只小鼠肿瘤开始消失,在给药后第28天(PG-D28)6只小鼠肿瘤已全部消失,在实验结束时(PG-D45),小鼠肿瘤未见恢复生长。
测试药AS11259-ADC-008治疗组在2.5mg/kg给药计量下与溶媒对照组相比产生了显著的抗肿瘤效果,在给药后第14天(PG-D14)平均肿瘤体积为1390mm3,相对肿瘤抑制率TGI为54.8%,统计学上与对照组相比具有显著性差异(p=0.009)。
Granta-519模型
Granta-519细胞用含10%胎牛血清的RPMI1640培养液培养,培养条件为37℃,5%CO2。在对数生长期计数并且收集细胞,将细胞重悬在1:1的PBS与基质胶中,在小鼠(NOD/SCID小鼠,雌性,8-9周,平均体重20.5g,购自北京安凯毅博生物技术有限公司,动物合格证编号:11402400012442。饲养环境:SPF级。)右侧皮下接种,每只小鼠接种的细胞体积是0.1ml,接种的细胞量为1×107个,待肿瘤平均体积约200mm3时,称量体重,随机分组,开始给药,给药方式为尾静脉给药,给药频率为一次。
结果判断标准
第一批实验的溶媒对照组在给药后第17天(PG-D17)平均肿瘤体积达到2744mm3进行安乐死,同时计算其他用药组在给药后第17天的相对肿瘤抑制率。在给药后第46天,结束实验,持续观察的小鼠进行安乐死,同时记录每组中肿瘤完全消退的小鼠的数量。第二批实验的溶媒对照组在给药后第17天(PG-D17)平均肿瘤体积达到2535mm3进行安乐死,同时计算其他用药组在给药后第17天的相对肿瘤抑制率。在给药后第45天,结束实验,持续观察的小鼠进行安乐死,同时记录每组中肿瘤完全消退的小鼠的数量。
实验结果
结果如下表11和12以及图4和5所示。
表11:AS11259-ADC-001、002和004对人淋巴瘤Granta-519裸鼠皮下移植瘤的疗效
表12:AS11259-ADC-001、0012、011和010对人淋巴瘤Granta-519裸鼠皮下移植瘤的疗效
第一批实验的溶媒对照组在给药后第17天(PG-D17)平均肿瘤体积达到2744mm3。
测试药AS11259-ADC-001治疗组在三个给药浓度下(3.5mg/kg、7mg/kg、14mg/kg)与溶媒对照组相比均产生了显著的抗肿瘤效果。三个给药浓度的给药组,在给药后第17天(PG-D17)平均肿瘤体积分别为68mm3、68mm3和49mm3,相对肿瘤抑制率TGI分别为97.5%、97.6%和98.2%,统计学上与对照组相比均具有极显著性差异(p值均小于0.001)。在给药后第45天(PG-D45),三个给药浓度的给药组,平均肿瘤体积分别达到1268mm3、536mm3和184mm3,表明此测试物在抗肿瘤效果上,呈现出明显的剂量-效应关系。
测试药AS11259-ADC-002治疗组在三个给药浓度下(3.5mg/kg、7mg/kg、14mg/kg)与溶媒对照组相比均产生了显著的抗肿瘤效果,且呈现出明显的剂量-效应关系。低浓度(3.5mg/kg)给药组,在给药后第17天(PG-D17)平均肿瘤体积为871mm3,相对肿瘤抑制率TGI为68.5%,相对溶媒对照组统计学上具有极显著性差异(p<0.001)。中浓度(7mg/kg)给药组,在给药后第17天(PG-D17)平均肿瘤体积为246mm3,相对肿瘤抑制率TGI为90.8%,相对溶媒对照组统计学上具有极显著性差异(p<0.001)。高浓度(14mg/kg)给药组,在给药后第17天(PG-D17)平均肿瘤体积为101mm3,相对肿瘤抑制率TGI为96.3%,相对溶媒对照组统计学上具有极显著性差异(p<0.001)。
测试药AS11259-ADC-004治疗组在三个给药浓度下(3.5mg/kg、7mg/kg、14mg/kg)与溶媒对照组相比均产生了显著的抗肿瘤效果,且呈现出明显的剂量-效应关系。低浓度3.5mg/kg)给药组,在给药后第17天(PG-D17)平均肿瘤体积为703mm3,相对肿瘤抑制率TGI为74.3%,相对溶媒对照组统计学上具有极显著性差异(p<0.001)。中浓度(7mg/kg)给药组,在给药后第17天(PG-D17)平均肿瘤体积为222mm3,相对肿瘤抑制率TGI为92.1%,相对溶媒对照组统计学上具有极显著性差异(p<0.001)。高浓度(14mg/kg)给药组,在给药后第17天(PG-D17)平均肿瘤体积为117mm3,相对肿瘤抑制率TGI为95.7%,相对溶媒对照组统计学上具有极显著性差异(p<0.001)。
第二批实验的溶媒对照组在给药后第17天(PG-D17)平均肿瘤体积分别达到2535mm3。
测试药AS11259-ADC-001(2.5mg/kg)、AS11259-ADC-0012(6mg/kg)、AS11259-ADC-011(5mg/kg)和AS11259-ADC-010(2.5mg/kg)治疗组在给药后都显著抑制了肿瘤的生长,在给药后第17天(PG-D17)其平均肿瘤体积分别为17mm3、6mm3、11mm3和9mm3,相对肿瘤抑制率TGI分别为99.3%、99.8%、99.6%和99.6%,相对溶媒对照组统计学上均具有极显著性差异(p值均为0.001)。
WSU-DLCL2模型
WSU-DLCL2细胞用含10%胎牛血清的RPMI1640培养液培养,培养条件为37℃,5%CO2。在对数生长期计数并且收集细胞,将细胞重悬在1:1的PBS与基质胶中,在小鼠(NOD/SCID小鼠,雌性,8-9周,平均体重19.6g,购自北京安凯毅博生物技术有限公司,动物合格证编号:11402400012441。饲养环境:SPF级)右侧皮下接种,每只小鼠接种的细胞体积是0.1ml,接种的细胞量为1×107个,待肿瘤平均体积约200mm3时,称量体重,随机分组,开始给药,给药方式为尾静脉给药,给药频率为一次。
结果判断标准
第一批实验的溶媒对照组在给药后第32天(PG-D32)平均肿瘤体积达到2146mm3,
进行安乐死,同时计算其他用药组在给药后第32天的相对肿瘤抑制率。在给药后第43天,结束实验,持续观察的小鼠进行安乐死,同时记录每组中肿瘤完全消退的小鼠的数量。
第二批实验的溶媒对照组在给药后第35天(PG-D17)平均肿瘤体积达到2360mm3进行安乐死,同时计算其他用药组在给药后第35天的相对肿瘤抑制率。在给药后第42天,结束实验,持续观察的小鼠进行安乐死,同时记录每组中肿瘤完全消退的小鼠的数量。
实验结果
实验结果如下表13、14以及图6和7所示。
表13:AS11259-ADC-001、004对人淋巴瘤WSU-DLCl2裸鼠皮下移植瘤的疗效
表14:AS11259-ADC-001、0012、011、010对人淋巴瘤WSU-DLCL2裸鼠皮下移植瘤的疗效
第一批实验的溶媒对照组在给药后第32天(PG-D32)平均肿瘤体积达到2146mm3。
测试药AS11259-ADC-001治疗组在三个给药浓度下(3.5mg/kg、7mg/kg、14mg/kg)与溶媒对照组相比均产生了显著的抗肿瘤效果,且呈现出明显的剂量-效应关系。低浓度(3.5mg/kg)给药组,在给药后第32天(PG-D32)平均肿瘤体积为845mm3,相对肿瘤抑制率TGI为60.4%,相对溶媒对照组统计学上具有极显著性差异(p=0.004)。中浓度(7mg/kg)给药组,在给药后第32天(PG-D32)平均肿瘤体积为273mm3,相对肿瘤抑制率TGI为87.6%,相对溶媒对照组统计学上具有极显著性差异(p=0.001)。高浓度(14mg/kg)给药组,在给药后第32天(PG-D32)平均肿瘤体积为132mm3,相对肿瘤抑制率TGI为93.7%,相对溶媒对照组统计学上具有极显著性差异(p=0.001)。
测试药AS11259-ADC-004治疗组在三个给药浓度下(3.5mg/kg、7mg/kg、14mg/kg)与溶媒对照组相比产生了轻微的抗肿瘤效果,但统计学上没有显著性差异。三个给药浓度的给药组,在给药后第32天(PG-D32)平均肿瘤体积分别为1526mm3、1632mm3和1521mm3,相对肿瘤抑制率TGI分别为28.3%、24.0%和28.6%,p值分别为0.080、0.123和0.080。
第二批实验的溶媒对照组在给药后第35天(PG-D35)平均肿瘤体积达到2360mm3。
测试药AS11259-ADC-001(3.5mg/kg)、AS11259-ADC-0012(8.4mg/kg)、AS11259-ADC-011(7mg/kg)和AS11259-ADC-010(3.5mg/kg)治疗组在给药后都显著抑制了肿瘤的生长,在给药后第35天(PG-D35)其平均肿瘤体积分别为912mm3、840mm3、700mm3和913mm3,相对肿瘤抑制率TGI分别为61.0%、64.4%、71.4%和62.0%,p值分别为<0.001、<0.001、<0.001和0.001。各组小鼠对受试药物耐受良好。
在本发明提及的所有文献在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 上海新理念生物医药科技有限公司
<120> 抗CD79b抗体、其药物偶联物及其应用
<130> 17A472
<160> 39
<170> SIPOSequenceListing 1.0
<210> 1
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Gly Asn Thr Phe Thr Ser Tyr Gly Ile Asn
1 5 10
<210> 2
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Gly Glu Ile Phe Pro Arg Ser Gly Asn Ile Tyr Tyr Asn Glu Lys Phe
1 5 10 15
Lys Gly
<210> 3
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Ala Lys Gly Gly Thr Gly Asp Phe Asp Tyr
1 5 10
<210> 4
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Arg Ser Ser Gln Asn Ile Val His Ser Asp Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 5
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Lys Val Ser Phe Arg Leu Ser
1 5
<210> 6
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Phe Gln Gly Ser His Val Pro Trp Thr
1 5
<210> 7
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Gln Val Gln Leu Gln Gln Ser Gly Ser Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Asn Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Asn Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Phe Pro Arg Ser Gly Asn Ile Tyr Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Lys Gly Gly Thr Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 8
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Phe Arg Leu 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
Arg Arg Val Glu Ala Glu Asp Leu Gly Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 9
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
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 Gly Thr Phe Ser Ser Tyr
20 25 30
Thr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln 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 Thr Ser Gly Val Gly Leu His Phe Gly Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 10
<211> 277
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Met Lys Tyr Leu Leu Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu Ala
1 5 10 15
Ala Gln Pro Ala Met Ala Asp Val Val Met Thr Gln Ser Pro Leu Ser
20 25 30
Leu Pro Val Thr Leu Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln
50 55 60
Gln Arg Pro Gly Gln Ser Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn
65 70 75 80
Arg Asp Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
Tyr Tyr Cys Met Gln Gly Thr His Trp Pro Leu Thr Phe Gly Gly Gly
115 120 125
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
130 135 140
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
165 170 175
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
180 185 190
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
210 215 220
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
225 230 235 240
Cys Ser Ala Arg Gln Ser Thr Pro Phe Val Cys Glu Tyr Gln Gly Gln
245 250 255
Ser Ser Asp Leu Pro Gln Pro Pro Val Asn Ala Gly Gly Gly Ser Gly
260 265 270
Gly Gly Ser Gly Gly
275
<210> 11
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
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 Asn Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Arg Ser Gly Asn Ile Tyr Tyr Asn Glu 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 Thr Gly Gly Thr Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 12
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Phe Arg Leu 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 Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 13
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
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 Thr Ser Gly Asn Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Arg Ser Gly Asn Ile Tyr Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys 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 Lys Gly Gly Thr Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 14
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
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 Thr Ser Gly Asn Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Arg Ser Gly Asn Ile Tyr Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys 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 Lys Gly Gly Thr Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 15
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Asn Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Phe Pro Arg Ser Gly Asn Ile Tyr Tyr Asn Glu 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 Lys Gly Gly Thr Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 16
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
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 Thr Ser Gly Asn Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Arg Ser Gly Asn Ile Tyr Tyr Asn Glu 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 Lys Gly Gly Thr Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 17
<211> 117
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
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 Thr Ser Gly Asn Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Phe Pro Arg Ser Gly Asn Ile Tyr Tyr Asn Glu 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 Lys Gly Gly Thr Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 18
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Phe Arg Leu 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 Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 19
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Asp Val Leu Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Phe Arg Leu 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 Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 20
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Phe Arg Leu 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 Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 21
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Phe Arg Leu 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 Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 22
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Phe Arg Leu 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 Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 23
<211> 330
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 24
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 25
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
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 Thr Ser Gly Asn Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Arg Ser Gly Asn Ile Tyr Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys 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 Lys Gly Gly Thr Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 26
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Phe Arg Leu 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 Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 27
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
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 Thr Ser Gly Asn Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Arg Ser Gly Asn Ile Tyr Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys 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 Lys Gly Gly Thr Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 28
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Asp Val Leu Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Phe Arg Leu 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 Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 29
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Asn Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Phe Pro Arg Ser Gly Asn Ile Tyr Tyr Asn Glu 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 Lys Gly Gly Thr Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 30
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Phe Arg Leu 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 Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 31
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
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 Thr Ser Gly Asn Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Arg Ser Gly Asn Ile Tyr Tyr Asn Glu 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 Lys Gly Gly Thr Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 32
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Phe Arg Leu 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 Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 33
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
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 Thr Ser Gly Asn Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Phe Pro Arg Ser Gly Asn Ile Tyr Tyr Asn Glu 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 Lys Gly Gly Thr Gly Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 34
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Phe Arg Leu 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 Phe Gln Gly
85 90 95
Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 35
<211> 139
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Ala Arg Ser Glu Asp Arg Tyr Arg Asn Pro Lys Gly Ser Ala Cys Ser
1 5 10 15
Arg Ile Trp Gln Ser Pro Arg Phe Ile Ala Arg Lys Arg Gly Phe Thr
20 25 30
Val Lys Met His Cys Tyr Met Asn Ser Ala Ser Gly Asn Val Ser Trp
35 40 45
Leu Trp Lys Gln Glu Met Asp Glu Asn Pro Gln Gln Leu Lys Leu Glu
50 55 60
Lys Gly Arg Met Glu Glu Ser Gln Asn Glu Ser Leu Ala Thr Leu Thr
65 70 75 80
Ile Gln Gly Ile Arg Phe Glu Asp Asn Gly Ile Tyr Phe Cys Gln Gln
85 90 95
Lys Cys Asn Asn Thr Ser Glu Val Tyr Gln Gly Cys Gly Thr Glu Leu
100 105 110
Arg Val Met Gly Phe Ser Thr Leu Ala Gln Leu Lys Gln Arg Asn Thr
115 120 125
Leu Lys Asp Val Asp His His His His His His
130 135
<210> 36
<211> 1344
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 36
caagttcagc tggttcagtc tggcgccgaa gtgaagaaac ctggcagcag cgtgaaggtg 60
tcctgcaaga ccagcggcaa cacctttacc agctacggca tcaactgggt caagcaggcc 120
cctggacaag gcttggagtg gatcggcgag atcttcccca ggagcggcaa catctactac 180
aacgagaaat tcaagggccg cgtgaccatc accgccgaca agagcacaag caccgcctac 240
atggaactga gcagcctgag aagcgaggac accgccgtgt actattgtgc caagggcggc 300
acaggcgact tcgactactg gggacagggc acactggtca cagtgtctag cgcaagcact 360
aaaggacctt ccgtgttccc actggcacca tcctctaaga gcacttccgg aggaaccgcc 420
gctctgggat gtctggtgaa ggactacttc ccagagcccg tcacagtgtc atggaacagc 480
ggggccctga ccagcggagt ccatacattt cctgctgtgc tgcagagttc aggcctgtat 540
agcctgagct ccgtggtcac tgtcccatct agttcactgg ggactcagac ctacatctgc 600
aacgtgaatc acaaaccatc taataccaag gtcgacaaga aagtggaacc caaaagttgt 660
gataagacac atacttgccc accttgtcct gcaccagagc tgctgggagg accaagcgtg 720
ttcctgtttc cacccaaacc taaggacacc ctgatgatta gccgcacacc agaagtcact 780
tgcgtggtcg tggacgtgag ccacgaggat cccgaagtca agtttaactg gtacgtggat 840
ggcgtcgagg tgcataatgc caaaacaaag cccagggagg aacagtataa ctctacatac 900
cgcgtcgtga gtgtcctgac tgtgctgcac caggactggc tgaacggcaa ggaatacaaa 960
tgcaaggtgt ccaacaaggc cctgcccgcc cctatcgaga agaccatttc taaagccaag 1020
gggcagcctc gagaaccaca ggtgtataca ctgcctccaa gccgggacga gctgactaaa 1080
aaccaggtgt ccctgacctg tctggtgaag gggttctacc cctccgatat tgctgtggag 1140
tgggaatcta atggacagcc tgagaacaat tataagacca caccccctgt gctggactcc 1200
gatggatctt tctttctgta ctcaaaactg accgtggata agagccgatg gcagcagggc 1260
aatgtctttt cttgtagtgt gatgcacgag gcactgcaca accactacac ccagaagtca 1320
ctgtcactgt caccaggcaa gtga 1344
<210> 37
<211> 660
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 37
gacgtggtca tgacccagtc tccactgagc ctgccagtga cactgggaca gccagccagc 60
atctcctgtc ggagctccca gaacatcgtg cacagcgacg gcaataccta cctggagtgg 120
tatcagcagc ggcctggcca gtccccaaga ctgctgatct acaaggtgtc cttcaggctg 180
tctggagtgc cagaccgctt ttctggcagc ggctccggca ccgatttcac actgaagatc 240
tctcgggtgg aggccgagga tgtgggcgtg tactattgct tccagggcag ccatgtgccc 300
tggacctttg gcggcggcac aaaggtggag atcaagagaa ccgtggccgc ccctagcgtg 360
ttcatctttc cccctagcga cgagcagctg aagagcggca cagcctccgt ggtgtgcctg 420
ctgaacaact tctaccctag ggaggccaag gtgcagtgga aggtggataa cgccctgcag 480
tccggcaatt ctcaggagag cgtgaccgag caggactcca aggattctac atatagcctg 540
tctagcaccc tgacactgtc caaggccgac tacgagaagc acaaggtgta tgcatgcgag 600
gtgacccacc agggcctgtc ctctcccgtg acaaagagct ttaaccgcgg cgagtgttag 660
<210> 38
<211> 351
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 38
caggttcagc tgcagcagtc tggatctgag ctggcgaggc ctggggcttc agtgaagctg 60
tcctgcaaga cttctggcaa caccttcaca agttatggta taaactgggt gaagcagaga 120
actggacagg gccttgagtg gattggagag atttttccta gaagtggtaa tatttactac 180
aatgagaagt tcaagggcaa ggccacactg actgcagaca aatcctccag cacagcgtac 240
atggagctcc gcagcctgac atctgaggac tctgcggtct atttctgtgc aaaaggggga 300
actggggact ttgactactg gggccaaggc accactctca cagtctcctc a 351
<210> 39
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 39
gatgttttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gaacattgta catagtgatg gaaacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaaa ctcctgattt acaaagtttc cttccgactt 180
tctggggtcc cagacaggtt cagtggcagt ggatccggga cagatttcac actcaagatc 240
agaagagtgg aggctgagga tctgggaact tattattgtt ttcaaggttc acatgttccg 300
tggacgttcg gtggaggcac caagctggaa atcaaa 336
Claims (19)
1.一种抗CD79b抗体或其抗原结合片段,其特征在于,所述抗CD79b抗体或其抗原结合片段包含:
HCDR1,其含有SEQ ID NO:1所示的氨基酸序列;
HCDR2,其含有SEQ ID NO:2所示的氨基酸序列;
HCDR3,其含有SEQ ID NO:3所示的氨基酸序列;
LCDR1,其含有SEQ ID NO:4所示的氨基酸序列;
LCDR2,其含有SEQ ID NO:5所示的氨基酸序列;和
LCDR3,其含有SEQ ID NO:6所示的氨基酸序列。
2.如权利要求1所述的抗CD79b抗体或其抗原结合片段,其特征在于,所述抗CD79b抗体或其抗原结合片段的HCDR1的氨基酸序列如SEQ ID NO:1所示,HCDR2的氨基酸序列如SEQID NO:2所示,HCDR3的氨基酸序列如SEQ ID NO:3所示,LCDR1的氨基酸序列如SEQ ID NO:4所示,LCDR2的氨基酸序列如SEQ ID NO:5所示,LCDR3的氨基酸序列如SEQ ID NO:6所示。
3.如权利要求1或2所述的抗CD79b抗体或其抗原结合片段,其特征在于,
所述抗CD79b抗体为单克隆抗体,和/或
所述抗CD79b抗体为人抗体、人源化抗体或嵌合抗体。
4.如权利要求1所述的抗CD79b抗体或其抗原结合片段,其特征在于,
所述抗CD79b抗体的重链可变区的氨基酸序列如SEQ ID NO:7或11所示,和/或所述抗CD79b抗体的轻链可变区的氨基酸序列如SEQ ID NO:8或12所示;或
所述抗CD79b抗体的重链可变区的氨基酸序列选自SEQ ID NO:13-17中任一序列所示的氨基酸序列,和/或所述抗CD79b抗体的轻链可变区的氨基酸序列选自SEQ ID NO:18-22中任一序列所示的氨基酸序列。
5.如权利要求1所述的抗CD79b抗体或其抗原结合片段,其特征在于,所述抗CD79b抗体的重链的氨基酸序列选自与SEQ ID NO:25、27、29、31和33中任一所示的氨基酸序列具有至少90%序列同一性的氨基酸序列,和/或所述抗CD79b抗体的轻链的氨基酸序列选自与SEQID NO:26、28、30、32和34中任一所示的氨基酸序列具有至少90%序列同一性的氨基酸序列。
6.如权利要求1所述的抗CD79b抗体或其抗原结合片段,其特征在于,所述抗CD79b抗体选自以下抗体:
(1)重链的氨基酸序列如SEQ ID NO:25所示、轻链的氨基酸序列如SEQ ID NO:26所示的抗体;
(2)重链的氨基酸序列如SEQ ID NO:27所示、轻链的氨基酸序列如SEQ ID NO:28所示的抗体;
(3)重链的氨基酸序列如SEQ ID NO:29所示、轻链的氨基酸序列如SEQ ID NO:30所示的抗体;
(4)重链的氨基酸序列如SEQ ID NO:31所示、轻链的氨基酸序列如SEQ ID NO:32所示的抗体;和
(5)重链的氨基酸序列如SEQ ID NO:33所示、轻链的氨基酸序列如SEQ ID NO:34所示的抗体。
7.一种抗体-药物偶联物,其特征在于,所述偶联物为权利要求1-6中任一项所述的抗体或其抗原结合片段与细胞毒剂的偶联物。
8.如权利要求7所述的抗体-药物偶联物,其特征在于,所述偶联物的结构如下所示:
A-(V-L-D)n
其中,
A为抗体;
V-L为连接子,V可存在或不存在,为双马来酰亚胺型或四马来酰亚胺型连接子构件,L可存在或不存在,为可断裂连接子或不可断裂连接子;V和L中至少存在一个;
D为感兴趣的细胞毒剂;和
n为1-4的整数。
9.如权利要求7或8所述的抗体-药物偶联物,其特征在于,所述细胞毒剂为化疗药物、生长抑制剂、毒素或放射性同位素。
10.一种药物组合物,其特征在于,所述药物组合物包含权利要求1-6中任一项所述的抗体或其与药物的偶联物,及药学可接受的载体。
11.如权利要求10所述的药物组合物,其特征在于,所述药物组合物含有权利要求7-9中任一项所述的抗体-药物偶联物。
12.一种多核苷酸序列,选自:
(1)编码SEQ ID NO:1-8、11-22和25-34中任一所示的氨基酸序列的多核苷酸序列;
(2)编码权利要求1-6中任一项所述抗体或其抗原结合片段的多核苷酸序列;和
(3)(1)和(2)所述多核苷酸序列的互补序列。
13.如权利要求12所述的多核苷酸序列,其特征在于,所述多核苷酸序列选自:
(a)SEQ ID NO:36-39中任一所示的多核苷酸序列;和
(b)(a)所述多核苷酸序列的互补序列。
14.一种载体,其含有编码权利要求1-6中任一项所述抗体或其抗原结合片段的多核苷酸序列或其互补序列;其中,所述载体为克隆载体或表达载体。
15.权利要求1-6中任一项所述的抗CD79b抗体或其抗原结合片段、或所述抗体或其抗结合片段与药物的偶联物在制备用于治疗或预防CD79b介导的疾病的药物中的用途;优选地,所述偶联物如权利要求7-9中任一项所述。
16.如权利要求15所述的用途,其特征在于,所述疾病是造血系统的癌症,优选为B细胞增殖性病症;优选地,所述疾病为淋巴瘤或白血病;更优选地,所述疾病为非霍奇金氏淋巴瘤(NHL)、攻击性NHL、复发性攻击性NHL、复发性无痛性NHL、顽固性NHL、顽固性无痛性NHL、小淋巴细胞性淋巴瘤、套细胞淋巴瘤、慢性淋巴细胞性白血病(CLL)、毛细胞白血病(HCL)或急性淋巴细胞性白血病(ALL)。
17.权利要求1-6中任一项所述的抗CD79b抗体或其抗原结合片段在制备与表达CD79b的细胞增多有关的细胞增殖性病症的诊断试剂中的用途。
18.一种制品,包括第一容器,所述第一容器含有一组合物,该组合物含有权利要求1-6中任一项所述的抗CD79b抗体或其抗原结合片段,或该抗CD79b抗体或其抗原结合片段与药物的偶联物,或所述抗CD79b抗体或其抗原结合片段或所述偶联物的药物组合物。
19.如权利要求18所述的制品,其特征在于,
所述制品还包括第二容器,所述第二容器含有药学可接受的缓冲剂;或
所述组合物含有权利要求1-6中任一项所述的抗CD79b抗体或其抗原结合片段,所述制品还包括装有检测用的稀释剂、缓冲剂或对照抗体的容器。
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CN201811296100.8A CN111116745B (zh) | 2018-11-01 | 2018-11-01 | 抗CD79b抗体、其药物偶联物及其应用 |
JP2021523617A JP2022506310A (ja) | 2018-11-01 | 2019-10-31 | 抗CD79b抗体、その薬物複合体及びその応用 |
EP19878515.6A EP3873931A4 (en) | 2018-11-01 | 2019-10-31 | Anti-cd79b antibodies, drug conjugates, and applications thereof |
US17/286,759 US20210388082A1 (en) | 2018-11-01 | 2019-10-31 | Anti-CD79b Antibodies, Drug Conjugates, and Applications Thereof |
BR112021006919-4A BR112021006919A2 (pt) | 2018-11-01 | 2019-10-31 | anticorpos anti-cd79b, conjugados de fármacos e suas aplicações |
CA3113864A CA3113864A1 (en) | 2018-11-01 | 2019-10-31 | Anti-cd79b antibodies, drug conjugates, and applications thereof |
AU2019370755A AU2019370755A1 (en) | 2018-11-01 | 2019-10-31 | Anti-CD79b Antibodies, Drug Conjugates, and Applications thereof |
KR1020217015203A KR20210087044A (ko) | 2018-11-01 | 2019-10-31 | 항-CD79b 항체, 약물 컨쥬게이트 및 그의 응용 |
PCT/CN2019/114676 WO2020088587A1 (en) | 2018-11-01 | 2019-10-31 | Anti-CD79b Antibodies, Drug Conjugates, and Applications thereof |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111592598A (zh) * | 2020-07-16 | 2020-08-28 | 西安迪赛生物药业有限责任公司 | 高三尖杉酯碱靶向治疗剂及其应用 |
CN111840571A (zh) * | 2020-08-03 | 2020-10-30 | 杭州皓阳生物技术有限公司 | 一种抗体药物偶联物及其用途 |
WO2022022508A1 (zh) * | 2020-07-27 | 2022-02-03 | 上海拓界生物医药科技有限公司 | 抗cd79b抗体药物偶联物、其制备方法及其医药用途 |
WO2023041007A1 (zh) * | 2021-09-16 | 2023-03-23 | 正大天晴药业集团股份有限公司 | 抗her2抗体药物偶联物及其组合物和用途 |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP4225792A1 (en) | 2020-10-08 | 2023-08-16 | Affimed GmbH | Trispecific binders |
AU2022320948A1 (en) | 2021-07-30 | 2024-01-18 | Affimed Gmbh | Duplexbodies |
AR127568A1 (es) | 2021-11-03 | 2024-02-07 | Affimed Gmbh | Ligandos biespecíficos de cd16a |
WO2023239803A1 (en) * | 2022-06-08 | 2023-12-14 | Angiex, Inc. | Anti-tm4sf1 antibody-drug conjugates comprising cleavable linkers and methods of using same |
WO2024033362A1 (en) * | 2022-08-08 | 2024-02-15 | Atb Therapeutics | Humanized antibodies against cd79b |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009012268A1 (en) * | 2007-07-16 | 2009-01-22 | Genentech, Inc. | Anti-cd79b antibodies and immunoconjugates and methods of use |
WO2009012256A1 (en) * | 2007-07-16 | 2009-01-22 | Genentech, Inc. | Humanized anti-cd79b antibodies and immunoconjugates and methods of use |
AU2013267010A1 (en) * | 2007-07-16 | 2014-01-09 | Genentech, Inc. | Anti-CD79b antibodies and immunoconjugates and methods of use |
WO2014011519A1 (en) * | 2012-07-09 | 2014-01-16 | Genentech, Inc. | Immunoconjugates comprising anti-cd79b antibodies |
WO2016090210A1 (en) * | 2014-12-05 | 2016-06-09 | Genentech, Inc. | ANTI-CD79b ANTIBODIES AND METHODS OF USE |
CN107108740A (zh) * | 2014-11-05 | 2017-08-29 | 豪夫迈·罗氏有限公司 | 抗fgfr2/3抗体及其使用方法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2016273960B2 (en) * | 2007-07-16 | 2019-01-24 | Genentech, Inc. | Anti-CD79b antibodies and immunoconjugates and methods of use |
-
2018
- 2018-11-01 CN CN201811296100.8A patent/CN111116745B/zh active Active
-
2019
- 2019-10-31 EP EP19878515.6A patent/EP3873931A4/en active Pending
- 2019-10-31 WO PCT/CN2019/114676 patent/WO2020088587A1/en unknown
- 2019-10-31 KR KR1020217015203A patent/KR20210087044A/ko active Search and Examination
- 2019-10-31 BR BR112021006919-4A patent/BR112021006919A2/pt unknown
- 2019-10-31 CA CA3113864A patent/CA3113864A1/en active Pending
- 2019-10-31 JP JP2021523617A patent/JP2022506310A/ja active Pending
- 2019-10-31 US US17/286,759 patent/US20210388082A1/en active Pending
- 2019-10-31 AU AU2019370755A patent/AU2019370755A1/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009012268A1 (en) * | 2007-07-16 | 2009-01-22 | Genentech, Inc. | Anti-cd79b antibodies and immunoconjugates and methods of use |
WO2009012256A1 (en) * | 2007-07-16 | 2009-01-22 | Genentech, Inc. | Humanized anti-cd79b antibodies and immunoconjugates and methods of use |
AU2013267010A1 (en) * | 2007-07-16 | 2014-01-09 | Genentech, Inc. | Anti-CD79b antibodies and immunoconjugates and methods of use |
WO2014011519A1 (en) * | 2012-07-09 | 2014-01-16 | Genentech, Inc. | Immunoconjugates comprising anti-cd79b antibodies |
CN107108740A (zh) * | 2014-11-05 | 2017-08-29 | 豪夫迈·罗氏有限公司 | 抗fgfr2/3抗体及其使用方法 |
WO2016090210A1 (en) * | 2014-12-05 | 2016-06-09 | Genentech, Inc. | ANTI-CD79b ANTIBODIES AND METHODS OF USE |
Non-Patent Citations (2)
Title |
---|
DAVID DORNAN等: ""Therapeutic potential of an anti-CD79b antibody–drug conjugate, anti–CD79b-vc-MMAE, for the treatment of non-Hodgkin lymphoma"", 《BLOOD》 * |
刘思初等: ""2017 年淋巴瘤研究新进展"", 《循证医学》 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111592598A (zh) * | 2020-07-16 | 2020-08-28 | 西安迪赛生物药业有限责任公司 | 高三尖杉酯碱靶向治疗剂及其应用 |
WO2022022508A1 (zh) * | 2020-07-27 | 2022-02-03 | 上海拓界生物医药科技有限公司 | 抗cd79b抗体药物偶联物、其制备方法及其医药用途 |
CN111840571A (zh) * | 2020-08-03 | 2020-10-30 | 杭州皓阳生物技术有限公司 | 一种抗体药物偶联物及其用途 |
CN111840571B (zh) * | 2020-08-03 | 2022-09-20 | 杭州皓阳生物技术有限公司 | 一种抗体药物偶联物及其用途 |
WO2023041007A1 (zh) * | 2021-09-16 | 2023-03-23 | 正大天晴药业集团股份有限公司 | 抗her2抗体药物偶联物及其组合物和用途 |
WO2023041006A1 (zh) * | 2021-09-16 | 2023-03-23 | 正大天晴药业集团股份有限公司 | 抗her3抗体药物偶联物及其组合物和用途 |
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BR112021006919A2 (pt) | 2021-07-20 |
CA3113864A1 (en) | 2020-05-07 |
US20210388082A1 (en) | 2021-12-16 |
JP2022506310A (ja) | 2022-01-17 |
CN111116745B (zh) | 2022-10-14 |
WO2020088587A1 (en) | 2020-05-07 |
KR20210087044A (ko) | 2021-07-09 |
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