CN114057885A - 双特异性抗人cd20/人转铁蛋白受体抗体及使用方法 - Google Patents
双特异性抗人cd20/人转铁蛋白受体抗体及使用方法 Download PDFInfo
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Abstract
本文提供了双特异性抗人CD20/人转铁蛋白受体抗体及其使用方法。
Description
本申请是申请日为2016年9月30日的、发明名称为“双特异性抗人CD20/人转铁蛋白受体抗体及使用方法”的中国专利申请201680056969.8(PCT/EP2016/073413)的分案申请。
发明领域
本发明涉及抗人CD20和人转铁蛋白受体的双特异性抗体、其生产方法、含有这些抗体的药物组合物及其用途。
发明背景
淋巴细胞是几个白细胞群体中的一个。它们特异性地识别并应答外来抗原。三种主要类别的淋巴细胞是B淋巴细胞(B细胞)、T淋巴细胞(T细胞)和自然杀伤(NK)细胞。B淋巴细胞是负责抗体产生并提供体液免疫的细胞。B细胞在骨髓内成熟并使骨髓在其细胞表面上表达抗原结合抗体。幼稚B细胞第一次遇到对其膜结合抗体而言特异的抗原时,细胞开始快速分裂并且其后代分化成称为“浆细胞”的记忆B细胞和效应细胞。记忆B细胞具有更长的寿命并且持续表达与初始母细胞具有相同特异性的膜结合抗体。浆细胞不产生膜结合抗体,但替代地,产生分泌形式的抗体。分泌的抗体是体液免疫的主要效应分子。
CD20抗原(也称为人B淋巴细胞限制性分化抗原,Bp35)是位于前B淋巴细胞和成熟B淋巴细胞上的具有大约35kDa分子量的疏水性跨膜蛋白(Valentine等,J.Biol.Chem.264(1989)11282-11287;和Einfeld等,EMBO J.7(1988)711-717)。该抗原还在超过90%的B细胞非霍奇金淋巴瘤(NHL)上表达(Anderson等,Blood 63(1984)1424-1433),但在造血干细胞、祖B细胞(pro-B cell)、正常浆细胞或其他正常组织上没有发现(Tedder等,J.Immunol.135(1985)973-979)。认为CD20调节用于细胞周期启动和分化的激活过程的早期步骤(Tedder等,上文)并且可能起到钙离子通道的作用(Tedder等,J.Cell.Biochem.14D(1990)195)。
鉴于CD20在B细胞淋巴瘤中表达,该抗原已经是有用的治疗靶标来治疗这样的淋巴瘤。鉴于CD20在B细胞淋巴瘤中表达,该抗原可以作为用于“靶向”这样的淋巴瘤的候选物。实际上,这样的靶向可以概括如下:将特异于B细胞CD20表面抗原的抗体施用于患者。这些抗CD20抗体特异性地结合(表面上)正常的B细胞和恶性B细胞的CD20抗原;结合CD20表面抗原的抗体可以导致肿瘤B细胞的破坏和消耗。另外,具有破坏肿瘤潜能的化学剂或放射性标记可以与抗CD20抗体缀合,使得所述试剂特异性地被“递送”至肿瘤B细胞。无论什么方法,主要目标是破坏肿瘤;可以通过利用的特定抗CD20抗体来确定特定的方法,并且因此可用于靶向CD20抗原的方法可以有相当大程度的变化。例如,将利妥昔单抗抗体(其是遗传工程化的对抗人CD20抗原的嵌合小鼠/人单克隆抗体(商业上可从Genentech,Inc.,South San Francisco,California,USA获得))用于患有复发或难治性低级或滤泡性CD20阳性的B细胞非霍奇金淋巴瘤患者。利妥昔单抗是在US 5,736,137和US 5,776,456中称为“C2B8”的抗体。体外作用机理研究已经证明了结合人补体并通过补体依赖性细胞毒性(CDC)裂解淋巴B细胞系(Reff等,Blood 83(1994)435-445)。另外,该抗体在针对抗体依赖性细胞毒性(ADCC)的分析中具有显著活性。体内临床前研究已经表明消耗食蟹猴外周血、淋巴结和骨髓中的B细胞,推定是通过补体和细胞介导的过程实现(Reff等,Blood 83(1994)435-445)。表示用于NHL治疗的其他抗CD20抗体包括小鼠抗体ZevalinTM,其连接放射性同位素钇-90(IDECPharmaceuticals,San Diego,CA,USA),BexxarTM(其是另一种与I-131缀合的完全鼠抗体(Corixa,WA,USA))。
CD20还是用于治疗自身免疫疾病的有用靶抗原。已经在其中B细胞和自身抗体表现出在疾病病理生理学中起作用的各种非恶性自身免疫疾病中研究了利妥昔单抗(参见,例如Edwards等,Biochem.Soc.Trans.30(2002)824-828)。已经报道了利妥昔单抗可能缓解例如如下疾病的病征和症状:类风湿性关节炎(RA)(Leandro等,Ann.Rheum.Dis.61(2002)883-888;Edwards等,Arthritis Rheum.46(Suppl.9)(2002)S46;Stahl等,Ann.Rheum.Dis.62(Suppl.1)(2003)OP004;Emery等,Arthritis Rheum.48(2003)S439)、狼疮(Eisenberg,Arthritis.Res.Ther.5(2003)157-159;Leandro等,Arthritis Rheum.46(2002)2673-2677;Gorman等,Lupus,13(2004)312-316)、免疫性血小板减少性紫癜(D'Arena等,Leuk.Lymphoma 44(2003)561-562;Stasi等,Blood 98(2001)952-957;Saleh等,Semin.Oncol.27(Suppl.12)(2000)99-103;Zaia等,Haematologica 87(2002)189-195;Ratanatharathorn等,Ann.Int.Med.133(2000)275-279)、纯红细胞再生障碍(Auner等,Br.J.Hematol.116(2002)725-728)、自身免疫性贫血(Zaja等,Haematologica87(2002)189-195(勘误出现在Haematologica 87(2002)336)、冷凝集素病(Layios等,Leukemia 15(2001)187-188;Berentsen等,Blood 103(2004)2925-2928;Berentsen等,Br.J.Hematol.115(2001)79-83;Bauduer,Br.J.Hematol.112(2001)1083-1090;Damiani等,Br.J.Hematol.114(2001)229-234)、严重胰岛素抗性的B型综合征(Coll等,N.Engl.J.Med.350(2004)310-311)、混合型冷球蛋白血症(De Vita等,ArthritisRheum.46Suppl.9(2002)S206/S469)、重症肌无力(Zaja等,Neurology 55(2000)1062-1063;Wylam等,J.Pediatr.143(2003)674-677)、韦格纳肉芽肿(Specks等,Arthritis&Rheumatism 44(2001)2836-2840)、顽固性寻常型天疱疮(Dupuy等,Arch.Dermatol.140(2004)91-96)、皮肌炎(Levine,Arthritis Rheum.46(Suppl.9)(2002)S1299)、干燥综合征(Somer等,Arthritis&Rheumatism 49(2003)394-398)、主动型II型混合型冷球蛋白血症(Zaja等,Blood 101(2003)3827-3834)、寻常型天疱疮(Dupay等,Arch.Dermatol.140(2004)91-95)、自身免疫性神经病变(Pestronk等,J.Neurol.Neurosurg.Psychiatry 74(2003)485-489)、副肿瘤性眼阵挛-肌阵挛综合征(Pranzatelli等,Neurology 60(Suppl.1)(2003)PO5.128:A395)和复发缓解型多发性硬化(Cross等(摘要)"Preliminaryresults from a phase II trial of Rituximab in MS"Eighth Annual Meeting of theAmericas Committees for Research and Treatment in Multiple Sclerosis,(2003)20-21)。
涉及用利妥昔单抗治疗的出版物包括:Perotta和Abuel,Blood 10(l998)(部分1-2)88B;Perotta等,Blood 94(1999)49(摘要);Matthews,R.,Ann.Rheum.Di's,上文;Leandro等,Arthritis and Rheumatism 44(9):S370(2001);Leandro等,Arthritis andRheumatism 46(2002)2673-2677;Weide等,Lupus 12(2003)779-782;Edwards和Cambridge,Rheumatology 40(2001)205-211;Cambridge等,Arthritis Rheum.46(Suppl.9)(2002)S1350;Edwards等,Arthritis and Rheumatism 46(2002)S197;Levine和Pestronk,Neurology52(1999)1701-1704;De Vita等,Arthritis&Rheum.46(2002)2029-2033;Hidashida等,Annual Scientific Meeting of the American College ofRheumatology;Oct 24-29;New Orleans,LA 2002;Tuscano,J.,Annual ScientificMeeting of the American College of Rheumatology;Oct 24-29;New Orleans,LA2002;Martin和Chan,Immunity 20(2004)517-527;Silverman和Weisman,Arthritis andRheumatism 48(2003)1484-1492;Kazkaz和Isenberg,Current opinion in pharmacology4(2004)398-402;Virgolini和Vanda,Biomedicine&pharmacotherapy 58(2004)299-309;Klemmer等,Arthritis and Rheumatism 48(2003)9,S(SEP)S624-S624;Kneitz等,Immunobiology206(2002)519-527;Arzoo等,Annals of the Rheumatic Diseases 61(2002)p922-924;Comment in Ann.Rheum.Dis.61(2002)863-866;"Future Strategies inImmunotherapy",Lake和Dionne,见Burger's Medicinal Chemistry and Drug Discovery(2003by John Wiley&Sons,Inc.);Liang和Tedder,Wiley Encyclopedia of MolecularMedicine,Section:CD20 as an Immunotherapy Target,2002entitled"CD20";Appendix4A标题"Monoclonal Antibodies to Human Cell Surface Antigens",Stockinger等编辑:Coligan等,见Current Protocols in Immunology(2003John Wiley&Sons,Inc.);Penichet和Morrison,"CD Antibodies/molecules:Definition;Antibody Engineering",见Wiley Encyclopedia of Molecular Medicine Section:Chimeric,Humanized andHuman Antibodies;2001年1月15日在线发布,Specks等,Arthritis&Rheumatism 44(2001)2836-2840;Koegh等,"Rituximab for Remission Induction in Severe ANCA-Associated Vasculitis:Report of a Prospective Open-Label Pilot Trial in 10Patients",American College of Rheumatology,会议编号:28-100,会议标题:Vasculitis,Session Type:ACR Concurrent Session,Primary Category:28Vasculitis,Session 10/18/2004(http://www.abstractsonline.com/viewer/SearchResults.asp);Eriksson,Kidney and Blood Pressure Research 26(2003)294;Jayne等,Kidney and Blood Pressure Research,26(2003)294;Jayne,poster 88(第11届国际血管炎和ANCA专题研讨会),2003 American Society of Nephrology;Stone andSpecks in the Clinical Trial Research Summary of the 2002-2003 ImmuneTolerance Network,http://www.immunetolerance.org/reseaTclT/autoimmune/trials/stone.html;Leandro等,Arthritis Rheum.48(Suppl.9)(2003)Sl 160。
涉及CD20抗体的专利和专利文献包括US 5,776,456,US 5,736,137,US 5,843,439,US 6,399,061,US 6,682,734,US 2002/0197255 A1,US 2003/0021781A1,US 2003/0082172 Al,US 2003/0095963 Al,US 2003/0147885A1;US 6,455,043;WO 00/09160;WO00/27428;WO 00/27433;WO 00/44788;WO 01/10462;WO 01/10461;WO 01/10460;US 2001/0018041A1,US 2003/0180292 A1,WO 01/34194;US 2002/0006404;WO 02/04021;US 2002/0012665 Al;WO 01/74388;US 2002/0058029 Al;US 2003/0103971Al;US 2002/0009444A1;WO 01/80884;WO 01/97858;US 2002/0128488A1;WO 02/34790;WO 02/060955;WO 02/096948;WO 02/079255;US 6,171,586 B1;WO 98/56418;WO 98/58964;WO 99/22764;WO99/51642;US 6,194,551 B1;US 6,242,195 B1;US 6,528,624 B1;US 6,538,124;WO 00/42072;WO 00/67796;WO 01/03734;US 2002/0004587 Al;WO 01/77342;US 2002/0197256;US 2003/0157108 Al;US 6,565,827 B1;US 6,090,365B1;US 6,287,537B1;US 6,015,542;US 5,843,398;US 5,595,721;US 5,500,362;US 5,677,180;US 5,721,108;US 6,120,767;US 6,652,852B1;US 6,410,391 B1;US 6,224,866 B1;WO 00/20864;WO 01/13945;WO 00/67795;US 2003/0133930 Al;WO 00/74718;WO 00/76542;WO 01/72333;US6,368,596 B1;US 6,306,393;US 2002/0041847 Al;US 2003/0026801A1;WO 02/102312;US 2003/0068664;WO 03/002607;WO 03/049694;US 2002/0009427 A1;US 2003/0185796Al;WO 03/061694;US 2003/0219818Al;US 2003/0219433 Al;WO 03/068821;US 2002/0136719A1;WO 2004/032828;WO 2004/035607;US 2004/0093621;US 5,849,898;EP 0,330,191;US 4,861,579;EP 0,332,865;WO 95/03770;US 2001/0056066;WO 2004/035607;WO 2004/056312;US 2004/0093621;WO 2004/103404。涉及CD20抗体的出版物包括:Teeling,J.等,Blood 10(2004)1182。
WO 2014/033074涉及结合血脑屏障上的受体的血脑屏障穿梭体及其使用方法。WO2012/075037中报道了低亲合力血脑屏障受体抗体及其用途。WO 2014/189973涉及抗转铁蛋白受体抗体及其使用方法。WO 2015/101588中报道了包括脑效应实体、衔接物和一个结合血脑屏障受体的单价结合实体的血脑屏障穿梭模块。WO 2010/033587涉及用于治疗患者中渐进性多发性硬化的方法,以及用于这样的用途的制品和说明书。WO 2012/096924中报道了一种在患有应答抗-CD20抗体治疗的疾病的患者中治疗、阻止或防止该疾病的方法,包括将至少一个亚消耗剂量(sub-depleting dose)的抗CD20抗体施用于所述患者。Hawker,K等(Ann.Neurol.66(2009)460-471)报道了在患有原发性渐进性多发性硬化的患者中随机双盲安慰剂对照的利妥昔单抗多中心实验的结果。
发明概述
本文中所述的一个方面是双特异性抗体,包含
a)包含两个(全长)抗体轻链和(全长)抗体重链对的一个(全长)抗体,每对各一个(全长)抗体轻链和一个(全长)抗体重链,其中由每对(全长)重链和(全长)轻链形成的结合位点特异性地结合第一抗原,和
b)一个另外的Fab片段,其中另外的Fab片段与(全长)抗体的一条重链的C-末端融合,其中另外的Fab片段的结合位点特异性地结合第二抗原,
其中每条(全长)抗体轻链在恒定轻链结构域(CL)中在位置123包含氨基酸残基精氨酸(替代野生型谷氨酸残基;E123R突变),并且在位置124包含氨基酸残基赖氨酸(替代野生型谷氨酰胺残基;Q124K突变)(编号根据Kabat),
其中每条(全长)抗体重链在第一恒定重链结构域(CH1)中在位置147包含谷氨酸残基(替代野生型赖氨酸残基;K147E突变),并且在位置213包含谷氨酸残基(替代野生型赖氨酸氨基酸残基;K213E突变)(编号根据Kabat EU索引),
其中特异性地结合第二抗原的另外的Fab片段包含结构域交叉,使得恒定轻链结构域(CL)和恒定重链结构域1(CH1)彼此替换,和其中第一抗原是人CD20,而第二抗原是人转铁蛋白受体。
在一个实施方案中,另外的Fab片段通过肽衔接物与重链的C-末端融合。
在一个实施方案中,Fab片段的重链可变结构域的N-末端与(全长)重链的C-末端或肽衔接物的C-末端融合。
在一个实施方案中
a)与另外的Fab片段融合的(全长)重链具有三肽LSP作为C-末端(重链)氨基酸残基,其中其脯氨酸经由肽键与另外的Fab片段或肽衔接物的第一氨基酸残基直接融合,和
b)没有与另外的Fab片段融合的(全长)重链具有三肽LSP或SPG或PGK作为C-末端(重链)氨基酸残基。
在一个实施方案中,(全长)抗体是
a)人亚类IgG1的全长抗体,
b)人亚类IgG4的全长抗体,
c)具有突变L234A、L235A和P329G的人亚类IgG1的全长抗体,
d)具有突变S228P、L235E和P329G的人亚类IgG4的全长抗体,
e)在两条重链中都具有突变L234A、L235A和P329G、并且在一条重链中具有突变i)T366W和ii)S354C或Y349C以及在相应的另一条重链中具有突变i)T366S、L368A和Y407V和ii)Y349C或S354C的人亚类IgG1的全长抗体,
f)在两条重链中都具有突变S228P、L235E和P329G、并且在一条重链中具有突变i)T366W和ii)S354C或Y349C以及在相应的另一条重链中具有突变i)T366S、L368A和Y407V和ii)Y349C或S354C的人亚类IgG4的全长抗体,
g)在两条重链中都具有突变L234A、L235A、P329G、I253A、H310A和H435A、并且在一条重链中具有突变i)T366W和ii)S354C或Y349C以及在相应的另一条重链中具有突变i)T366S、L368A和Y407V和ii)Y349C或S354C的人亚类IgG1的全长抗体,或
h)在两条重链中都具有突变L234A、L235A、P329G、M252Y、S254T和T256E、并且在一条重链中具有突变i)T366W和ii)S354C或Y349C以及在相应的另一条重链中具有突变i)T366S、L368A和Y407V和ii)Y349C或S354C的人亚类IgG1的全长抗体,或
i)在两条重链中都具有突变L234A、L235A、P329G、H310A、H433A和Y436A、并且在一条重链中具有突变i)T366W和ii)S354C或Y349C、以及在相应的另一条重链中具有突变i)T366S、L368A和Y407V和ii)Y349C或S354C的人亚类IgG1的全长抗体。
在一个实施方案中,另外的Fab片段与包含突变T366W的重链的C-末端,或与包含突变T366S、L368A和Y407V的重链的C-末端融合。
在一个实施方案中
(全长)抗体是在两条重链中都具有突变L234A、L235A和P329G,并且在一条重链中具有突变T366W和S354C,以及在相应的另一条重链中具有突变T366S、L368A、Y407V和Y349C的人亚类IgG1,和
另外的Fab片段与包含突变T366W的重链的C-末端,或与包含突变T366S、L368A和Y407V的重链的C-末端融合。
在一个实施方案中,双特异性抗体包含
i)与SEQ ID NO:01具有70%或更高序列同一性的轻链,
ii)与SEQ ID NO:02具有70%或更高序列同一性的重链,
iii)与SEQ ID NO:03具有70%或更高序列同一性的轻链,和
iv)与SEQ ID NO:04具有70%或更高序列同一性的重链Fab片段,其中
SEQ ID NO:01具有氨基酸序列
SEQ ID NO:02具有氨基酸序列
SEQ ID NO:03具有氨基酸序列
SEQ ID NO:04具有氨基酸序列
本文公开的一个方面是包含具有SEQ ID NO:01的氨基酸序列的(全长)轻链、具有SEQ ID NO:02的氨基酸序列的(全长)重链、具有SEQ ID NO:03的氨基酸序列的(全长)轻链、和包含SEQ ID NO:04的氨基酸序列的抗体Fab片段的双特异性抗体。
在一个实施方案中,双特异性抗体是单克隆的。
本文中所述的一个方面是双特异性抗体,其包含
a)第一和第二Fab片段,其中第一和第二Fab片段的每个结合位点特异性地结合第一抗原,
b)第三Fab片段,其中第三Fab片段的结合位点特异性地结合第二抗原,并且其中第三Fab片段包含结构域交叉,使得可变轻链结构域(VL)和可变重链结构域(VH)彼此替换,和
c)包含第一Fc-区多肽和第二Fc-区多肽的Fc-区,
其中第一和第二Fab片段各自包含重链片段和全长轻链,
其中第一Fab片段的重链片段的C-末端与第一Fc-区多肽的N-末端融合,
其中第二Fab片段的重链片段的C-末端与第三Fab片段的可变轻链结构域的N-末端融合,并且第三Fab片段的重链恒定结构域1的C-末端与第二Fc-区多肽的N-末端融合,
其中第一和第二Fab片段的全长抗体轻链各自在恒定轻链结构域(CL)中位置123包含氨基酸残基精氨酸(替代野生型谷氨酸残基;E123R突变),并且在位置124包含氨基酸残基赖氨酸(替代野生型谷氨酰胺残基;Q124K突变)(编号根据Kabat),
其中第一和第二Fab片段的重链片段各自在第一恒定重链结构域(CH1)中位置147包含谷氨酸残基(替代野生型赖氨酸残基;K147E突变),并且在位置213包含谷氨酸残基(替代野生型赖氨酸氨基酸残基;K213E突变)(编号根据Kabat EU索引),
其中第一抗原是人CD20,而第二抗原是人转铁蛋白受体。
在一个实施方案中,第一和第二Fc-区多肽是
a)人亚类IgG1的,
b)人亚类IgG4的,
c)具有突变L234A、L235A和P329G的人亚类IgG1的,
d)具有突变S228P、L235E和P329G的人亚类IgG4的,
e)在两个F-区多肽中都具有突变L234A、L235A和P329G,并且在一个F-区多肽中具有突变T366W和S354C以及在相应的另一个F-区多肽中具有突变T366S、L368A、Y407V和Y349C的人亚类IgG1的,
f)在两个F-区多肽中都具有突变S228P、L235E和P329G,并且在一个F-区多肽中具有突变T366W和S354C以及在相应的另一个F-区多肽中具有突变T366S、L368A、Y407V和Y349C的人亚类IgG4的,
g)在两个F-区多肽中都具有突变L234A、L235A、P329G、I253A、H310A和H435A,并且在一个F-区多肽中具有突变T366W和S354C以及在相应的另一个F-区多肽中具有突变T366S、L368A、Y407V和Y349C的人亚类IgG1的,或
h)在两个F-区多肽中都具有突变L234A、L235A、P329G、M252Y、S254T和T256E,并且在一个F-区多肽中具有突变T366W和S354C以及在相应的另一个F-区多肽中具有突变T366S、L368A、Y407V和Y349C的人亚类IgG1的,或
i)在两个F-区多肽中都具有突变L234A、L235A、P329G、H310A、H433A和Y436A,并且在一个F-区多肽中具有突变T366W和S354C以及在相应的另一个F-区多肽中具有突变T366S、L368A、Y407V和Y349C的人亚类IgG1的。
在一个实施方案中,第三Fab片段的一条链与包含突变T366W的Fc-区多肽融合,或与包含突变T366S、L368A和Y407V的Fc-区多肽融合。
在一个实施方案中,双特异性抗体包含
i)与SEQ ID NO:14具有至少70%,或至少80%,或至少90%,或95%或更高序列同一性的轻链,
ii)与SEQ ID NO:15具有至少70%,或至少80%,或至少90%,或95%或更高序列同一性的重链,
iii)与SEQ ID NO:16具有至少70%,或至少80%,或至少90%,或95%或更高序列同一性的交叉抗体链,和
iv)与SEQ ID NO:17具有至少70%,或至少80%,或至少90%,或95%或更高序列同一性的修饰重链,
其中
SEQ ID NO:14具有氨基酸序列
SEQ ID NO:15具有氨基酸序列
SEQ ID NO:16具有氨基酸序列
SEQ ID NO:17具有氨基酸序列
本文中所述的一个方面是包含两条各自具有SEQ ID NO:14的氨基酸序列的全长轻链、具有SEQ ID NO:15的氨基酸序列的全长重链、具有SEQ ID NO:16的氨基酸序列的交叉抗体链、和具有SEQ ID NO:17的氨基酸序列的修饰重链的双特异性抗体。
在一个实施方案中,双特异性抗体是单克隆的。
本文中的一个方面是编码本文中所述的双特异性抗体的分离核酸。
本文中的一个方面是包含本文中所述的编码本文中所述的双特异性抗体的核酸的宿主细胞。
本文中的一个方面是一种生产本文中所述的双特异性抗体的方法,其包括以下步骤:
a)培养本文中所述的宿主细胞,使得产生所述双特异性抗体,和
b)从细胞或培养基回收所述双特异性抗体,并且由此产生本文中所述的双特异性抗体。
本文中的一个方面是包含本文中所述的双特异性抗体和细胞毒性剂的免疫缀合物。
本文中的一个方面是包含本文中所述的双特异性抗体和药物学上可接受载体的药物制剂。
本文中的一个方面是本文中所述的抗体用作药物。
本文中的一个方面是本文中所述的抗体用于治疗癌症。
本文中的一个方面是本文中所述的双特异性抗体用于治疗B细胞增殖性疾病。
本文中的一个方面是本文中所述的双特异性抗体用于抑制表达CD20的肿瘤细胞的生长。在一个实施方案中,所述抑制在脑中。
本文中的一个方面是本文中所述的双特异性抗体用于治疗癌(carcinoma)。在一个优选实施方案中,所述癌是脑的/在脑中的癌。
本文中的一个方面是本文中所述的双特异性抗体用于治疗淋巴瘤。在一个优选实施方案中,所述淋巴瘤是原发性中枢神经系统淋巴瘤(PCNSL)。
本文中的一个方面是本文中所述的双特异性抗体用于治疗自身免疫疾病。在一个实施方案中,所述自身免疫疾病是多发性硬化。在一个优选实施方案中,所述自身免疫疾病是继发性渐进性多发性硬化。
本文中的一个方面是本文中所述的双特异性抗体用于消耗表达CD20的肿瘤细胞。在一个实施方案中,所述消耗是在脑中。
本文中的一个方面是本文中所述的双特异性抗体用于消耗表达CD20的循环B细胞。在一个实施方案中,所述消耗是在脑中。
本文中的一个方面是本文中所述的双特异性抗体用于消耗脑隔离的表达CD20的B细胞。
本文中的一个方面是本文中所述的双特异性抗体在药物制造中的用途。
在一个实施方案中,所述药物用于治疗增殖型疾病。在一个实施方案中,所述增殖型疾病是B细胞增殖性疾病。在一个实施方案中,所述增殖型疾病是B细胞淋巴瘤。在一个优选实施方案中,所述增殖型疾病是原发性中枢神经系统淋巴瘤。
在一个实施方案中,所述药物用于肿瘤的治疗。
在一个实施方案中,所述药物用于人癌(carcinoma)的治疗。
在一个实施方案中,所述药物用于自身免疫疾病的治疗。在一个实施方案中,所述自身免疫疾病选自炎性反应,如炎性皮肤病,包括牛皮癣和皮炎(例如,特应性皮炎);全身性硬皮病与硬化;与炎性肠病相关的应答(如节段性回肠炎和溃疡性结肠炎);呼吸窘迫综合征(包括成人呼吸窘迫综合征;ARDS);皮炎;脑膜炎;脑炎;葡萄膜炎;结肠炎;肾小球性肾炎;过敏性病症,如湿疹和哮喘,以及涉及T细胞浸润和慢性炎性反应的其他病症;动脉粥样硬化;白细胞粘附缺陷;类风湿性关节炎;全身性红斑狼疮(SLE);糖尿病(例如,I型糖尿病或胰岛素依赖性糖尿病);多发性硬化;Reynaud’s综合征;自身免疫性甲状腺炎;过敏性脑脊髓炎;Sjogren’s综合征;青少年型糖尿病;以及通常在结核、结节病、多肌炎、肉芽肿病和脉管炎中发现的、与细胞因子和T淋巴细胞介导的急性和延迟型超敏反应相关的免疫应答;恶性贫血(Addison’s病);涉及白细胞渗出的疾病;中枢神经系统(CNS)炎性病症;多器官损伤综合征;溶血性贫血(包括但不限于冷球蛋白血症或Coombs阳性贫血);重症肌无力;抗原-抗体复合物介导的疾病;抗肾小球基底膜病;抗磷脂综合征;过敏性神经炎;Graves’病;Lambert-Eaton肌无力综合征;大疱性类天疱疮;天疱疮;自身免疫性多内分泌病;Reiter’s病;僵人综合征;Bechet病;巨细胞性动脉炎;免疫复合物性肾炎;IgA肾病;IgM多神经病;免疫性血小板减少性紫癜(ITP)或自身免疫性血小板减少症等。在一个实施方案中,所述药物是用于多发性硬化的治疗。在一个优选实施方案中,所述药物用于继发性渐进性多发性硬化的治疗。
在一个实施方案中,所述药物用于消耗表达CD20的肿瘤细胞。在一个实施方案中,所述消耗是在脑中。
在一个实施方案中,所述药物是用于消耗表达CD20的循环B细胞。在一个实施方案中,所述消耗是在脑中。
在一个实施方案中,所述药物是用于消耗脑隔离的表达CD20的B细胞。
本文的一个方面是治疗患有增殖型疾病的个体的方法,包括将有效量的本文中所述的双特异性抗体施用于个体。在一个实施方案中,所述增殖型疾病是B细胞增殖性疾病。
本文的一个方面是治疗患有癌(carcinoma)的个体的方法,包括将有效量的本文中所述的双特异性抗体施用于个体。在一个优选实施方案中,所述癌是脑的/在脑中的癌。
本文的一个方面是治疗患有淋巴瘤的个体的方法,包括将有效量的本文中所述的双特异性抗抗体施用于个体。在一个优选实施方案中,所述淋巴瘤是原发性中枢神经系统淋巴瘤(PCNSL)。
本文的一个方面是治疗患有自身免疫疾病的个体的方法,包括将有效量的本文中所述的双特异性抗体施用于个体。在一个实施方案中,所述自身免疫疾病是多发性硬化。在一个优选实施方案中,所述自身免疫疾病是继发性渐进性多发性硬化。
本文的一个方面是用于抑制个体中表达CD20的肿瘤细胞的生长的方法,包括将有效量的本文中所述的双特异性抗体施用于个体,以抑制表达CD20的肿瘤细胞的生长。在一个实施方案中,所述抑制是在脑中。
本文的一个方面是用于消耗个体中表达CD20的肿瘤细胞的生长的方法,包括将有效量的本文中所述的双特异性抗体施用于个体,以消耗表达CD20的肿瘤细胞。在一个实施方案中,所述抑制是在脑中。
本文的一个方面是用于消耗个体中表达CD20的循环B细胞的方法,包括将有效量的本文中所述的双特异性抗体施用于个体,以消耗表达CD20的循环B细胞。在一个实施方案中,所述抑制是在脑中。
本文的一个方面是用于个体中消耗脑隔离的表达CD20的B细胞的方法,包括将有效量的本文中所述的双特异性抗体施用于个体,以消耗脑隔离的表达CD20的B细胞。
本文的一个方面是治疗人多发性硬化的方法,包括将治疗有效量的本文中所述的结合人CD20并消耗B细胞的抗体施用于人,并且其中所述抗体没有与细胞毒性剂缀合。
发明实施方案详述
凸起进入孔洞(knobs into holes)二聚化模块及其在抗体工程化中的用途描述于Carter P.;Ridgway J.B.B.;Presta L.G.:Immunotechnology,第2卷,1996年2月1日,pp.73-73。CH3结构域中另外的二硫键报道于Merchant,A.M.等,Nat.Biotechnol.16(1998)677-681。
Kabat,E.A.等,Sequences of Proteins of Immunological Interest,第5版,Public Health Service,National Institutes of Health,Bethesda,MD(1991)中给出了关于人免疫球蛋白轻链和重链的核苷酸序列的一般信息。
如本文中使用的,重链和轻链的所有恒定区和结构域的氨基酸位置根据Kabat等,Sequences of Proteins of Immunological Interest,第5版,Public Health Service,National Institutes of Health,Bethesda,MD(1991)中所述的Kabat编号系统来编号,并且在本文中称为“根据Kabat编号”。具体地,将Kabat等,Sequences of Proteins ofImmunological Interest,第5版,Public Health Service,National Institutes ofHealth,Bethesda,MD(1991)的Kabat编号系统(参见第647-660页)用于κ和λ同种型的轻链恒定结构域CL,而将Kabat EU索引编号系统(参见第661-723页)用于恒定重链结构域(CH1、铰链、CH2和CH3,在此情况中其在本文中通过述及“根据Kabat EU索引编号”来进一步说明)。
1.定义
术语“血脑屏障”或“BBB”表示在外周循环与脑和脊髓之间的生理学屏障,其由脑毛细血管内皮细胞浆膜内的紧密连接形成,构成限制分子转运至脑中的紧密屏障,甚至是非常小的分子,如脲(60道尔顿)。脑内的BBB、脊髓内的血液-脊髓屏障和视网膜内的血液-视网膜屏障是CNS内的连续毛细管屏障,并且在本文中总称为血脑屏障或BBB。BBB还包括血液-CSF屏障(脉络丛),其中所述屏障由室管膜细胞而不是毛细管内皮细胞组成。
术语“抗人CD20抗体”和“特异性地结合人CD20的抗体”是指能够以足够的亲合力结合人CD20的抗体,使得所述抗体可以用作靶向CD20的诊断剂和/或治疗剂。
因此,所述术语还包括结合人CD20的截短片段的抗体。
结合CD20抗原的抗体的实例包括:“C2B8”,其现在称作“利妥昔单抗”(US 5,736,137);称为“Y2B8”的钇-[90]-标记的2B8鼠抗体(US5,736,137);鼠IgG2a“B1”,任选用131I标记以产生“131I-B1”抗体(BEXXARTM)(US 5,595,721);鼠单克隆抗体“1F5”(Press等,Blood 69(1987)584-591);“嵌合2H7”抗体(US 5,667,180);单克隆抗体L27、G28-2、93-1B3、B-C1或NU-B2,可从International Leukocyte TypingWorkshop(Valentine等,见:Leukocyte Typing III(McMichael编辑)p.440,OxfordUniversity Press(1987))获得;和US 8,883,980中描述的单克隆抗体。
“CD20”抗原是在超过90%的来自外周血或淋巴器官的B细胞表面上发现的大约35kDa、非糖基化的磷蛋白。CD20在早期前B细胞发育过程中表达并保持直至浆细胞分化。正常B细胞以及恶性B细胞上都存在CD20。文献中用于CD20的其他名称包括“B淋巴细胞限制性抗原”和“Bp35”。例如,CD20抗原描述于Clark等,Proc.Natl.Acad.Sci USA 82(1985)1766。还可以参见SEQ ID NO:05。
本文中的“自身免疫疾病”是由个体自身组织引起的并且对抗个体自身组织的非恶性疾病或病症。本文中使用的术语“自身免疫疾病”特意排除了恶性或癌性疾病或病症,尤其排除B细胞淋巴瘤、急性淋巴母细胞性白血病(ALL)、慢性淋巴细胞性白血病(CLL)、毛细胞白血病和慢性髓细胞性白血病。自身免疫疾病或病症的实例包括炎性反应,如炎性皮肤病,包括牛皮癣和皮炎(例如,特应性皮炎);全身性硬皮病与硬化;与炎性肠病相关的反应(如节段性回肠炎和溃疡性结肠炎);呼吸窘迫综合征(包括成人呼吸窘迫综合征;ARDS);皮炎;脑膜炎;脑炎;葡萄膜炎;结肠炎;肾小球性肾炎;过敏性病症,如湿疹和哮喘,以及涉及T细胞浸润和慢性炎性反应的其他病症;动脉粥样硬化;白细胞粘附缺陷;类风湿性关节炎;全身性红斑狼疮(SLE);糖尿病(例如,I型糖尿病或胰岛素依赖性糖尿病);多发性硬化;Reynaud’s综合征;自身免疫性甲状腺炎;过敏性脑脊髓炎;Sjogren’s综合征;青少年型糖尿病;以及通常在结核、结节病、多肌炎、肉芽肿病和脉管炎中发现的、与细胞因子和T淋巴细胞介导的急性和延迟型超敏反应相关的免疫应答;恶性贫血(Addison’s病);涉及白细胞渗出的疾病;中枢神经系统(CNS)炎性病症;多器官损伤综合征;溶血性贫血(包括但不限于冷球蛋白血症或Coombs阳性贫血);重症肌无力;抗原-抗体复合物介导的疾病;抗肾小球基底膜病;抗磷脂综合征;过敏性神经炎;Graves’病;Lambert-Eaton肌无力综合征;大疱性类天疱疮;天疱疮;自身免疫性多内分泌病;Reiter’s病;僵人综合征;Bechet病;巨细胞性动脉炎;免疫复合物性肾炎;IgA肾病;IgM多神经病;免疫性血小板减少性紫癜(ITP)或自身免疫性血小板减少症等。
“拮抗剂”是结合B细胞表面标志物时破坏、杀灭或消耗哺乳动物中的B细胞和/或干扰一种或多种B细胞功能的分子,例如,通过降低或阻止由B细胞引发的体液应答。拮抗剂能够消耗用其治疗的哺乳动物中的B细胞(即,降低循环B细胞水平)。这样的消耗可以经由各种机制来实现,如抗体依赖性细胞介导的细胞毒性(ADCC)和/或补体依赖性细胞毒性(CDC)、B细胞增殖的抑制和/或B细胞死亡的诱导(例如,经由凋亡)。拮抗剂包括结合B细胞标志物的抗体、合成或天然序列肽和小分子,任选与细胞毒性剂缀合或融合。
“生长抑制”拮抗剂是防止或降低表达与所述拮抗剂结合的抗原的细胞增殖的那些。例如,所述拮抗剂可以防止或降低体内和/或体外的B细胞增殖。
“诱导凋亡”的拮抗剂是诱导例如B细胞程序化死亡的那些,如通过标准凋亡试验测定的,所述试验如膜联蛋白V的结合、DNA的片段化、细胞收缩、内质网的扩张、细胞片段化和/或膜囊泡(称为凋亡体)的形成。
“结合”目标抗原(例如,B细胞表面标志物)的拮抗剂是能够以足够的亲合力和/或亲和性结合抗原的拮抗剂,使得所述拮抗剂可以用作治疗剂用于靶向表达所述抗原的细胞。
术语“中枢神经系统”或“CNS”是指控制身体功能的神经组织的复合物,并且包括脑和脊髓。
术语“血脑屏障受体”(在本文中缩写为“BBBR”)表示在脑内皮细胞上表达的胞外膜连接的受体蛋白,其能够穿过BBB运送分子,或可以用于运送外源性施用的分子。本文中BBBR的实例包括但不限于:转铁蛋白受体(TfR)、胰岛素受体、胰岛素-样生长因子受体(IGF-R)、低密度脂蛋白受体(包括但不限于低密度脂蛋白受体相关蛋白1(LRP1)和低密度脂蛋白受体相关蛋白8(LRP8)),以及肝素结合性表皮生长因子样生长因子(HB-EGF)。一种优选的BBBR是转铁蛋白受体(TfR)。
“转铁蛋白受体”(“TfR”)是跨膜糖蛋白(具有约180,000Da分子量),其由两个二硫键结合的亚基组成(每个亚基的表观分子量为约90,000Da)并且涉及脊椎动物中的铁吸收。在一个实施方案中,本文中提及的TrR是例如包括Schneider等(Nature 311(1984)675-678)中报道的氨基酸序列的人TfR。
“多特异性抗体”表示对同一抗原或两个不同抗原上的至少两个不同表位具有结合特异性的抗体。示例性多特异性抗体可以结合BBBR和脑抗原。多特异性抗体可以制成全长抗体或抗体片段(例如,F(ab’)2双特异性抗体)或其组合(例如,全长抗体加另外的scFv或Fab片段)。具有两个、三个或更多个(例如,四个)功能性抗原结合位点的工程化抗体也已经有报道(参见,例如,US 2002/0004587 A1)。
对于本文的目的,“受体人框架”是包括源自如下定义的人免疫球蛋白框架或人共有框架的轻链可变结构域(VL)框架或重链可变结构域(VH)框架的氨基酸序列的框架。“源自”人免疫球蛋白框架或人共有框架的受体人框架可以包括与其相同的氨基酸序列,或其可以含有氨基酸序列变化。在一些实施方案中,氨基酸变化的数量为10个或更少、9个或更少、8个或更少、7个或更少、6个或更少、5个或更少、4个或更少、3个或更少,或2个或更少。在一些实施方案中,VL受体人框架序列与VL人免疫球蛋白框架序列或人共有框架序列相同。
“亲合力”是指分子(例如,抗体)的单个结合位点与其结合配偶体(例如,抗原)之间的非共价相互作用的总和强度。除非另外指出,否则如本文中所使用的,“结合亲合力”是指反映结合对(例如,抗体和抗原)的成员之间1:1相互作用的内在结合亲合力。分子X对于其配偶体Y的亲合力通常可以通过解离常数(kd)来表示。亲合力可以通过本领域已知的常规方法来测量,例如等离子体共振,并包括本文中所述的那些方法。
“亲合力成熟的”抗体是指在一个或多个高变区(HVR)中具有一个或多个改变的抗体,与不具有这种改变的亲本抗体相比,这种改变导致抗体对其抗原的亲合力的提高。
本文中的术语“抗体”以最宽的含义来使用,并且包括各种抗体结构,包括但不限于单克隆抗体、多克隆抗体和多特异性抗体(例如双特异性抗体),只要它们呈现期望的抗原结合活性。
术语“抗体依赖性细胞毒性(ADCC”)是通过Fc受体介导的功能并且是指在效应细胞的存在下通过本文中所述抗体的靶细胞的裂解。在一个实施方案中,通过在效应细胞(如新鲜分离的PBMC(外周血单个核细胞)或从血沉棕黄层纯化的效应细胞(如单核细胞或NK(自然杀伤)细胞))的存在下,用本文中所述的抗体处理表达CD19的红细胞样细胞(例如,表达重组人CD19的K562细胞)制备物,来测量ADCC。用51Cr标记靶细胞,并随后用抗体孵育。用效应细胞孵育标记的细胞,并且针对释放的51Cr来分析上清液。对照包括用效应细胞孵育靶内皮细胞,但没有用抗体孵育。通过测量其与表达Fcγ受体的细胞(如重组表达FcγRI和/或FcγRIIA的细胞)或NK细胞(基本上地表达FcγRIIIA)的结合,来研究抗体诱导介导ADCC的初始步骤的能力。在一个优选实施方案中,测量与NK细胞上的FcγR的结合。
“抗体片段”是指非完整抗体的分子,其包含完整抗体的部分,该部分结合与该完整抗体结合的抗原。抗体片段的实例包括但不限于Fv、Fab、Fab'、Fab’-SH、F(ab')2;双链抗体(diabody);线性抗体;单链抗体分子(例如,scFv);以及从抗体片段形成的多特异性抗体。
术语“嵌合”抗体是指其中重链和/或轻链的一部分源自特定来源或物种,同时重链和/或轻链的剩余部分源自不同的来源或物种的抗体。
抗体的“类别”是指其重链具有的恒定结构域或恒定区的类别。存在五种主要的抗体类别:IgA、IgD、IgE、IgG和IgM,并且这些中的一些可以进一步分为亚类(同种型),例如,IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。对应于不同类别的免疫球蛋白的重链恒定结构域分别被称为α、δ、ε、γ和μ。
如本文中使用的术语“细胞毒性剂”是指抑制或阻止细胞功能和/或引起细胞死亡或破坏的物质。细胞毒性剂包括,但不限于,放射性同位素(例如,At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212和Lu的放射性同位素)、化疗剂或药物(例如,氨甲喋呤、阿霉素、长春花生物碱(长春新碱(vincristine)、长春碱(vinblastine)、依托泊苷(etoposide))、亚德里亚霉素(doxorubicin)、美法仑、丝裂霉素C、苯丁酸氮芥、道诺霉素或其他嵌入剂);生长抑制剂;酶及其片段,如溶核酶(nucleolytic enzyme);抗生素;毒素,如小分子毒素、或细菌、真菌、植物或动物来源的酶活性毒素,包括其片段和/或变体;和下文公开的各种抗肿瘤或抗癌剂。
术语“补体依赖性细胞毒性(CDC)”是指在补体的存在下通过本文中所述的抗体诱导的细胞裂解。在一个实施方案中,通过在补体的存在下,用本文中所述的抗体处理表达CD19的人内皮细胞来测量CDC。在一个实施方案中,用钙黄绿素标记细胞。如果在30μg/ml浓度下,抗体诱导20%或更多靶细胞裂解,则认为是CDC。可以在ELISA中测量与补体因子C1q的结合。在这样的测试中,原则上用一定浓度范围的抗体包被ELISA平板,向其添加纯化的人C1q或人血清。通过针对C1q的抗体,接着过氧化物酶标记的缀合物,来检测C1q结合。对于过氧化酶底物(2,2’-联氮-双-[3-乙基苯并噻唑啉-6-磺酸盐(6)]),以405nm(OD405)下光密度,测量结合(最大结合Bmax)。
“效应子功能”是指可归因于抗体的Fc-区的那些生物活性,其随抗体类型改变。抗体效应子功能的实例包括:C1q结合和补体依赖性的细胞毒性(CDC);Fc受体结合;抗体依赖性的细胞介导的细胞毒性(ADCC);吞噬作用;细胞表面受体(例如B细胞受体)的下调;和B-细胞激活。
Fc受体结合依赖性效应子功能可以通过抗体的Fc-区与Fc受体(FcR)的相互作用来介导,Fc受体是造血细胞上的特化细胞表面受体。Fc受体属于免疫球蛋白超家族,并且已经显示出介导:通过免疫复合物的吞噬作用除去抗体包被的病原体、以及经由抗体依赖性细胞介导的细胞毒性(ADCC)裂解被相应抗体包被的红细胞和各种其他细胞靶标(例如,肿瘤细胞)(参见,例如,Van de Winkel,J.G.和Anderson,C.L.,J.Leukoc.Biol.49(1991)511-524)。FcR通过其针对免疫球蛋白同种型的特异性来限定:将针对IgG抗体的Fc受体称为FcγR。Fc受体结合描述于例如Ravetch,J.V.和Kinet,J.P.,Annu.Rev.Immunol.9(1991)457-492;Capel,P.J.等,Immunomethods 4(1994)25-34;de Haas,M.等,J.Lab.Clin.Med.126(1995)330-341;和Gessner,J.E.等,Ann.Hematol.76(1998)231-248。
针对IgG抗体的Fc-区的受体(FcγR)的交联引发各种效应子功能,包括吞噬作用、抗体依赖性细胞毒性和炎性介质的释放,以及免疫复合物清除和抗体产生的调节。在人类中,已经表征了三种类型的FcγR,其为:
-FcγRI(CD64)以高亲合力结合单体IgG并且在巨噬细胞、单核细胞、嗜中性粒细胞和嗜酸粒细胞上表达。至少在氨基酸残基E233-G236、P238、D265、N297、A327和P329(编号根据Kabat的EU索引)中的一个上的Fc-区IgG修饰降低与FcγRI的结合。位置233-236的IgG2残基,替代入IgG1和IgG4中,使FcγRI结合降低了103-倍并且消除了对抗体敏化红细胞的人单核细胞应答(Armour,K.L.等,Eur.J.Immunol.29(1999)
2613-2624)。
-FcγRII(CD32)以中等至低的亲合力结合复合的IgG并且广泛表达。这种受体可以分成两个亚类,FcγRIIA和FcγRIIB。发现FcγRIIA在许多涉及杀灭的细胞(例如,巨噬细胞、单核细胞、嗜中性粒细胞)上存在,并且似乎能够激活杀灭过程。FcγRIIB似乎在抑制过程中起着作用并且发现在B-细胞、巨噬细胞以及肥大细胞和嗜酸性粒细胞上存在。在B-细胞上,FcγRIIB似乎具有抑制更多的免疫球蛋白产生和同种型转换成例如IgE类别的功能。在巨噬细胞上,FcγRIIB用来抑制通过FcγRIIA介导的吞噬作用。在嗜酸性粒细胞和肥大细胞上,B-形式可以帮助抑制这些细胞通过IgE结合其分开的受体而被激活。例如,对于包含至少在氨基酸残基E233-G236、P238、D265、N297、A327、P329、D270、Q295、A327、R292和K414(编号根据Kabat的EU索引)的一个上具有突变的IgG Fc-区的抗体,发现了降低的与FcγRIIA的结合。
-FcγRIII(CD16)以中等至低的亲合力结合IgG并且作为两种类型存在。在NK细胞、巨噬细胞、嗜酸性粒细胞以及一些单核细胞和T细胞上发现了FcγRIIIA,其介导ADCC。FcγRIIIB在嗜中性粒细胞上高度表达。例如,对于包含至少在氨基酸残基E233-G236、P238、D265、N297、A327、P329、D270、Q295、A327、S239、E269、E293、Y296、V303、A327、K338和D376(编号根据Kabat的EU索引)的一个上具有突变的IgG Fc-区的抗体,发现了降低的与FcγRIIA的结合。
针对人IgG1上的Fc受体结合位点、上述突变位点的作图、以及用于测量与FcγRI和FcγRIIA的结合的方法,描述于Shields,R.L.等,J.Biol.Chem.276(2001)6591-6604。
药剂(例如,药物制剂)的“有效量”是指在所需的剂量和持续时间段下,能有效获得所需治疗或预防结果的量。
如本文中使用的术语“Fc受体”是指,特征在于与受体相关的胞质ITAM序列的存在的激活受体(参见,例如,Ravetch,J.V.和Bolland,S.,Annu.Rev.Immunol.19(2001)275-290)。这样的受体是FcγRI、FcγRIIA和FcγRIIIA。术语“无FcγR的结合”表示在10μg/ml的抗体浓度下,本文中所述的抗体与NK细胞的结合是针对如WO 2006/029879中所述的抗-OX40L抗体LC.001发现的结合的10%或更低。
尽管IgG4显示出了降低的FcR结合,而其他IgG亚类的抗体显示出强烈的结合。然而,Pro238、Asp265、Asp270、Asn297(失去Fc碳水化合物)、Pro329和234、235、236和237、Ile253、Ser254、Lys288、Thr307、Gln311、Asn434和His435是提供,如果改变的话,也是降低的FcR结合的残基(Shields,R.L.等,J.Biol.Chem.276(2001)6591-6604;Lund,J.等,FASEBJ.9(1995)115-119;Morgan,A.等,Immunology 86(1995)319-324;和EP 0 307 434)。在一个实施方案中,本文中所述的抗体是IgG1或IgG2亚类的,并且包含突变PVA236、GLPSS331和/或L234A/L235A。在一个实施方案中,本文中所述的抗体是IgG4亚类的,并且包含突变L253E。在一个实施方案中,所述抗体进一步包含突变S228P。
本文中的术语“Fc区”用于限定含有至少一部分的恒定区的免疫球蛋白重链的C-末端区域。该术语包括天然序列Fc-区和变体Fc-区。在一个实施方案中,人IgG重链Fc-区从Cys226或从Pro230延伸至重链的羧基端。然而,Fc-区的C-端赖氨酸(Lys447)可以存在或可以不存在。
在一个实施方案中,本文中所述的抗体包含源自人来源的Fc-区作为Fc-区。在一个实施方案中,所述Fc-区包含人恒定区的所有部分。抗体的Fc区直接参与补体激活、C1q结合、C3激活和Fc受体结合。尽管抗体对补体系统的影响取决于特定条件,但结合C1q是由Fc-区中限定的结合位点引起的。这样的结合位点是现有技术中已知的并且描述于例如Lukas,T.J.等,J.Immunol.127(1981)2555-2560;Brunhouse,R.和Cebra,J.J.,Mol.Immunol.16(1979)907-917;Burton,D.R.等,Nature 288(1980)338-344;Thommesen,J.E.等,Mol.Immunol.37(2000)995-1004;Idusogie,E.E.等,J.Immunol.164(2000)4178-4184;Hezareh,M.等,J.Virol.75(2001)12161-12168;Morgan,A.等,Immunology 86(1995)319-324;和EP 0 307434。这样的结合位点是例如L234、L235、D270、N297、E318、K320、K322、P331和P329(编号根据Kabat的EU索引)。亚类IgG1、IgG2和IgG3的抗体通常显示出补体激活、C1q结合和C3激活,而IgG4不激活补体系统,不结合C1q和不激活C3。
“抗体的Fc-区”是本领域技术人员公知的术语,并且是基于抗体的木瓜蛋白酶断裂来限定的。在一个实施方案中,所述Fc-区是人Fc-区。在一个实施方案中,所述Fc区是包含突变S228P和/或L253E(编号根据Kabat的EU索引)的人IgG4亚类的。在一个实施方案中,所述Fc-区是包含突变L234A和L235A(编号根据Kabat的EU索引)的人IgG1亚类的。
“框架”或“FR”是指除了高变区(HVR)残基之外的可变结构域残基。可变结构域的FR通常由四个FR结构域组成:FR1、FR2、FR3和FR4。因此,HVR和FR序列通常以以下顺序出现在VH(或VL)中:FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4。
术语“全长抗体”、“完整抗体”和“全抗体”在本文中可互换使用,是指具有与天然抗体结构基本上类似的结构或具有包含本文中定义的Fc-区的重链的抗体。“全长抗体”是包含抗原结合可变区以及轻链恒定结构域(CL)和重链恒定结构域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。更详细地,全长抗体包含两条抗体轻链(各自包含轻链可变结构域和轻链恒定结构域)和两条抗体重链(各自包含重链可变结构域、铰链区和重链恒定结构域CH1、CH2和CH3)。C-末端氨基酸残基K或GK可以彼此独立地存在或不存在于全长抗体的两条抗体重链中。
术语“宿主细胞”、“宿主细胞系”和“宿主细胞培养物”可互换使用,并且是指其中已经引入外源核酸的细胞,包括这种细胞的后代。宿主细胞包括“转化体”和“转化的细胞”,其包括原代转化的细胞和由其衍生的后代,不考虑传代数。后代在核酸内容物方面可以与亲本细胞不完全相同,而是可以含有突变。就针对最初转化的细胞筛选或选择的功能或生物活性而言,具有相同功能或生物活性的突变体后代被包括在本文中。
“人共有框架”是代表在选择的人免疫球蛋白VL或VH框架序列中最常出现的氨基酸残基的框架。通常,从可变结构域序列的亚组选择人免疫球蛋白VL或VH序列。通常,序列的亚组是如Kabat,E.A.等,Sequences of Proteins of Immunological Interest,第5版,Bethesda MD(1991),NIH Publication 91-3242,第1-3卷中的亚组。在一个实施方案中,对于VL,所述亚组是如在Kabat等(出处同上)中的亚组κI。在一个实施方案中,对于VH,所述亚组是如在Kabat等(出处同上)中的亚组III。
“人源化”抗体是指包含来自非人HVR的氨基酸残基和来自人FR的氨基酸残基的嵌合抗体。在某些实施方案中,人源化抗体将包含至少一个和通常两个可变结构域的基本上全部,其中所有或基本上所有的HVR(例如,CDR)对应于非人抗体的HVR,并且所有或基本上所有FR对应于人抗体的FR。人源化抗体任选地可以包含源自人抗体的抗体恒定区的至少一部分。抗体(例如,非人抗体)的“人源化形式”表示已经经历人源化的抗体。
本文中使用的术语“高变区”或“HVR”表示抗体可变结构域的每个区域,所述区域包含在序列上高变(“互补性决定区”或“CDR”)和/或形成在结构上确定的环(“超变环”)和/或含有抗原接触残基(“抗原接触点”)的氨基酸残基链。通常,抗体包含六个HVR;三个在VH中(H1、H2、H3),以及三个在VL(L1、L2、L3)中。
HVR包括
(a)在氨基酸残基26-32(L1)、50-52(L2)、91-96(L3)、26-32(H1)、53-55(H2)和96-101(H3)处存在的超变环(Chothia,C.和Lesk,A.M.,J.Mol.Biol.196(1987)901-917);
(b)在氨基酸残基24-34(L1)、50-56(L2)、89-97(L3)、31-35b(H1)、50-65(H2)和95-102(H3)处存在的CDR(Kabat,E.A.等,Sequences of Proteins of ImmunologicalInterest,第5版Public Health Service,National Institutes of Health,Bethesda,MD(1991),NIH Publication 91-3242);
(c)在氨基酸残基27c-36(L1)、46-55(L2)、89-96(L3)、30-35b(H1)、47-58(H2)和93-101(H3)处存在的抗原接触点(MacCallum等,J.Mol.Biol.262:732-745(1996));和
(d)(a)、(b)和/或(c)的组合,包括氨基酸残基46-56(L2)、47-56(L2)、48-56(L2)、49-56(L2)、26-35(H1)、26-35b(H1)、49-65(H2)、93-102(H3)和94-102(H3)。
除非另有说明,可变结构域中的HVR残基和其它残基(例如,FR残基)在本文中根据Kabat等(出处同上)编号。
“免疫缀合物”是与一个或多个异源分子(包括但不限于细胞毒性剂)缀合的抗体。
“个体”或“受试者”是哺乳动物。哺乳动物包括,但不限于,驯养动物(例如,牛、绵羊、猫、狗和马),灵长类动物(例如,人和非人灵长类动物,如猴),兔和啮齿类动物(例如,小鼠和大鼠)。在某些实施方案中,所述个体或受试者是人。
“分离的”抗体是已经与其天然环境的组分分离的抗体。在一些实施方案中,将抗体纯化至大于95%或99%纯度,所述纯度通过例如电泳(例如,SDS-PAGE、等电聚焦(IEF)、毛细管电泳)或色谱(例如,离子交换或反相HPLC)来测定。关于评价抗体纯度的方法的综述,参见,例如,Flatman,S.等,J.Chrom.B 848(2007)79-87。
“分离的”核酸表示已经与其天然环境的组分分离的核酸分子。分离的核酸包括在通常含有该核酸分子的细胞中包含的该核酸分子,但是所述核酸分子存在于染色体外或在不同于其天然染色体位置的染色体位置。
“分离的编码抗人CD20/人转铁蛋白受体抗体的核酸”是指一个或多个编码抗体重链和轻链(或其片段)的核酸分子,包括在单个载体或分开的载体中的这样核酸分子,以及在宿主细胞中的一个或多个位置存在的这样的核酸分子。
本文中使用的术语“单克隆抗体”表示得自基本上同质的抗体群体的抗体,即,构成所述群体的各个抗体是相同的和/或结合相同表位,除了可能的变体抗体(例如,含有天然存在的突变或在单克隆抗体制品的生产过程中产生)以外,这样的变体通常以微量存在。与通常包括针对不同决定簇(表位)的不同抗体的多克隆抗体制品不同,单克隆抗体制品中的每个单克隆抗体针对抗原上的单个决定簇。因而,修饰语“单克隆”表示所述抗体得自基本上同质抗体群体的特征,并且不应解释为需要通过任何特定方法生产所述抗体。例如,要根据本发明使用的单克隆抗体可以通过多种技术来制备,所述技术包括但不限于杂交瘤方法、重组DNA方法、噬菌体展示方法、以及利用包含人免疫球蛋白基因座的全部或部分的转基因动物的方法,本文描述了这样的方法和其它示例性的制备单克隆抗体的方法。
“裸抗体”是指没有与异源部分(例如,细胞毒性部分)或放射性标记缀合的抗体。裸抗体可以存在于药物制剂中。
“天然抗体”是指具有不同结构的天然存在的免疫球蛋白分子。例如,天然IgG抗体是约150,000道尔顿的异源四聚体糖蛋白,由二硫键合的两条相同的轻链和两条相同的重链组成。从N-端至C-端,每条重链具有可变区(VH),也称为可变重链结构域或重链可变结构域,接着是三个恒定结构域(CH1、CH2和CH3),由此铰链区位于所述第一和第二个恒定结构域之间。类似地,从N-端至C-端,每条轻链具有可变区(VL),也称为可变轻链结构域或轻链可变结构域,接着是轻链恒定(CL)结构域。抗体的轻链可以基于其恒定结构域的氨基酸序列归入两种类型(称为kappa(κ)和lambda(λ))中的一种。
术语“包装说明书”用于表示治疗性产品的商业包装中通常包括的指令,其含有关于这样的治疗性产品的使用的适应症、用法、剂量、施用、联合治疗、禁忌和/或告诫的信息。
相对于参考多肽序列的“氨基酸序列同一性百分比(%)”被定义为,比对所述序列并且如果必要的话引入空位以实现最大序列同一性百分比后,且不考虑任何保守置换作为序列同一性的一部分,候选序列中与参考多肽序列中的氨基酸残基相同的氨基酸残基的百分比。用于确定氨基酸序列同一性百分比目的的比对可以以本领域技术中的多种方式实现,例如,使用公众可得到的计算机软件,如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员可以确定用于比对序列的适当参数,包括实现在要比较的序列的全长上的最大对齐所需的任何算法。但是,为了本文的目的,使用序列比较计算机程序ALIGN-2,产生%氨基酸序列同一性值。ALIGN-2序列比较计算机程序由Genentech,Inc.创造,并且源代码已经在美国版权局,Washington D.C.,20559与用户文档一起提交,其在美国版权登记号TXU510087下登记。ALIGN-2程序可以从Genentech,Inc.,South San Francisco,California公开获得,或可以从源代码编译。应该编译ALIGN-2程序以在UNIX操作系统(包括数字UNIX V4.0D)上使用。所有序列比较参数由ALIGN-2程序设定并且不改变。
在采用ALIGN-2进行氨基酸序列比较的情况下,如下计算给定氨基酸序列A相对、与,或针对给定氨基酸序列B的%氨基酸序列同一性(其可以可替换地叙述为相对、与,或针对给定氨基酸序列B具有或包含特定%氨基酸序列同一性的给定氨基酸序列A):
100×分数X/Y
其中X是通过序列比对程序ALIGN-2在该程序的A和B的比对中评分为相同匹配的氨基酸残基的数目,并且其中Y是B中的氨基酸残基的总数。应当理解,在氨基酸序列A的长度不等于氨基酸序列B的长度的情况下,A相对B的%氨基酸序列同一性将不等于B相对A的%氨基酸序列同一性。除非另外特别说明,本文使用的所有%氨基酸序列同一性值如在紧邻的上一段中所述使用ALIGN-2计算机程序获得。
术语“药物制剂”是指这样的制品:其呈现为使得包含在其中的活性成分的生物活性有效的形式,并且所述制剂不含有对所述制剂要施用的受试者有不可接受的毒性的额外组分。
“药物学上可接受的载体”表示药物制剂中除了活性成分之外的成分,其对受试者无毒。药物学上可接受的载体包括、但不限于缓冲剂、赋形剂、稳定剂或防腐剂。
本文中使用的“治疗(treatment)”(及其语法变体,如“治疗(treat)”或“治疗(treating)”)表示试图改变治疗的个体的天然进程的临床干预,并且可以为了预防或在临床病理学进程中执行。期望的治疗效果包括但不限于,防止疾病的发生或复发,缓解征状,减少疾病的任何直接或间接病理学后果,防止转移,降低疾病进展的速度,提高或减轻疾病状态,以及缓解或提高的预后。在一些实施方案中,本文中所述的抗体用于延迟疾病的发展或减缓疾病的进展。
术语“可变区”或“可变结构域”表示抗体重链或轻链中参与所述抗体与其抗原的结合的结构域。天然抗体的重链和轻链的可变结构域(分别是VH和VL)通常具有类似的结构,每个结构域包含四个保守框架区(FR)和三个高变区(HVR)(参见,例如,Kindt,T.J.等,Kuby Immunology,第6版,W.H.Freeman and Co.,N.Y.(2007),第91页)。单个VH或VL结构域可能足以赋予抗原-结合特异性。此外,结合特定抗原的抗体可以使用来自结合所述抗原的抗体的VH或VL结构域分别筛选互补VL或VH结构域文库来分离(参见,例如,Portolano,S.等,J.Immunol.150(1993)880-887;Clackson,T.等,Nature 352(1991)624-628)。
本文中使用的术语“载体”表示能够扩增与其连接的另一核酸的核酸分子。该术语包括作为自我复制的核酸结构的载体以及整合进它已经引入其中的宿主细胞的基因组中的载体。某些载体能够指导与其可操作地连接的核酸的表达。这样的载体在本文被称为“表达载体”。
如本文中针对辅助治疗使用的术语“免疫抑制剂”是指,用于抑制或遮掩本文中待治疗哺乳动物的免疫系统的物质。这将包括抑制细胞因子产生、下调或抑制自身抗原表达或遮掩MHC抗原的物质。这样的试剂的实例包括2-氨基-6-芳基-5-取代的嘧啶(参见US 4,665,077);硫唑嘌呤;环磷酰胺;溴麦角隐亭;达那唑;氨苯砜;戊二醛(其遮掩MHC抗原,如US4,120,649中所述的);针对MHC抗原和MHC片段的抗独特型抗体;环孢菌素A;类固醇,如糖皮质激素,例如,泼尼松、甲基强的松龙和地塞米松;细胞因子或细胞因子受体拮抗剂,包括抗干扰素-γ、-β或-α抗体,抗肿瘤坏死因子-α抗体,抗肿瘤坏死因子-β抗体,抗白细胞间介素-2抗体和抗IL-2受体抗体;抗LFA-1抗体,包括抗CD11a和抗CD18抗体;抗L3T4抗体;异源抗淋巴细胞球蛋白;pan-T抗体,优选抗CD3或抗CD4/CD4a抗体;含有LFA-3结合结构域的可溶性肽(WO 90/08187);链激酶;TGF-β;链道酶(streptodornase);来自宿主的RNA或DNA;FK506;RS-61443;脱氧精胍菌素(deoxyspergualin);雷帕霉素;T-细胞受体(US 5,114,721);T-细胞受体片段(Offner等,Science 251(1991)430-432;WO 90/11294;Ianeway,Nature 341(1989)482;和WO 91/01133);以及T细胞受体抗体(EP0,340,109),如T10B9。
“化疗剂”是癌症治疗中有用的化合物。化疗剂的实例包括烷化剂,如噻替哌和环磷酰胺(CYTOXANTM);烷基磺酸酯,如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);吖丙啶类(aziridines),如苯佐替派(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙撑亚胺类(ethylenimines)和甲基蜜胺类(methylamelamines),包括六甲蜜胺(altretamine)、三乙蜜胺(triethylenemelamine)、三亚乙基磷酰胺(trietylenephosphoramide)、三乙烯硫代磷酸胺(triethylenethiophosphoramide)和三羟甲蜜胺(trimethylolomelamine);氮芥类(nitrogen mustards),如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、胆磷酰胺(cholophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、氮芥(mechlorethamine)、盐酸氧氮芥(mechlorethamine oxide hydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亚硝基脲类(nitrosureas),如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimustine);抗生素,如阿克拉霉素(aclacinomysins)、放线菌素(actinomycin)、蒽霉素(authramycin)、偶氮丝氨酸(azaserine)、博来霉素(bleomycins)、放线菌素C(cactinomycin)、卡奇霉素(calicheamicin)、carabicin、洋红霉素(carminomycin)、嗜癌霉素(carzinophilin)、色霉素(chromomycins)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-氧代-L-正亮氨酸(6-diazo-5-oxo-L-norleucine)、多柔比星(doxorubicin)、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、马塞罗霉素(marcellomycin)、丝裂霉素类(mitomycins)、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、紫菜霉素(potfiromycin)、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑霉素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物,如甲氨喋呤(methotrexate)和5-氟尿嘧啶(5-fluorouracil,5-FU);叶酸类似物,如二甲叶酸(denopterin)、甲氨喋呤(methotrexate)、喋罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,如氟达拉滨(fludarabine)、6-巯嘌呤(6-mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物,如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine)、5-FU;雄激素类(androgens),如卡鲁睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺药(anti-adrenals),如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补偿剂(folicacid replenisher),如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);羟醛磷酰胺配糖(aldophosphamide glycoside);5-氨基酮戊酸(aminolevulinic acid);安吖啶(amsacrine);bestrabucil;比生群(bisantrene);依达曲沙(edatraxate);defofamine;秋水仙胺(demecolcine);地吖醌(diaziquone);elfornithine;依利醋铵(elliptiniumacetate);依托格鲁(etoglucid);硝酸镓(gallium nitrate);羟基脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidamine);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidamol);尼曲吖啶(nitracrine);喷司他丁(pentostatin);异丙嗪(phenamet);吡柔比星(pirarubicin);podophyllinic acid;2-乙基酰肼(2-ethylhydrazide);丙卡巴肼(procarbazine);雷佐生(razoxane);西佐喃(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2’,2”-三氯三乙胺(2,2′,2″-trichloro triethylamine);乌拉坦(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside,“Ara-C”);环磷酰胺(cyclophosphamide);噻替哌(thiotepa);紫杉烷类化合物(taxoids),例如紫杉醇(paclitaxel,Bristol-Myers Squibb Oncology,Princeton,N.J.)和多西他赛(doxetaxel,Rorer,Antony,法国);苯丁酸氮芥(chlorambucil);吉西他滨(gemcitabine);6-硫鸟嘌呤(6-thioguanine);巯嘌呤(mercaptopurine);甲氨喋呤(methotrexate);铂类似物(platinum analogs),如顺铂(cisplatin)和卡铂(carboplatin);长春碱(vinblastine);铂(platinum);依托泊苷(etoposide,VP-16);异环磷酰胺(ifosfamide);丝裂霉素C(mitomycin C);米托蒽醌(mitoxantrone);长春新碱(vincristine);长春瑞滨(vinorelbine);去甲长春碱(navelbine);诺安托(novantrone);替尼泊苷(teniposide);道诺霉素(daunomycin);氨基喋呤(aminopterin);希罗达(xeloda);伊班膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂(topoisomeraseinhibitor)RFS 2000;二氟甲基鸟氨酸(difluoromethylornithine(DMFO));视黄酸(retinoic acid);埃斯培拉霉素(esperamicins);卡培他滨(capecitabine);以及以上任一种的药物学上可接受的盐、酸或衍生物。这个定义中还包括用于调节或抑制对肿瘤的激素作用的抗激素剂,如抗雌激素剂,例如他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)、抑制芳香酶的4(5)-咪唑、4-羟基他莫西芬(4-hydroxytamoxifen)、曲沃昔芬(trioxifene)、keoxifene、LY117018、奥那司酮(onapristone)和托瑞米芬(toremifene,Fareston);和抗雄激素剂,如氟他胺(flutamide)、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、亮脯利特(leuprolide)和戈舍瑞林(goserelin);以及以上任一种的药物学上可接受的盐、酸或衍生物。
II.组合物和方法
在一个方面中,本发明部分基于发现——本文中所述的双特异性抗人CD20/人转铁蛋白受体抗体具有改善的特性。在某些实施方案中,提供了双特异性抗人CD20/人转铁蛋白受体抗体。本文中所述的抗体例如对于帕金森病或多发性硬化的诊断或治疗是有用的。
A.示例性双特异性抗人CD20/人转铁蛋白受体抗体
在一个方面中,本发明提供了分离的结合人CD20和人转铁蛋白受体的双特异性抗体。所述抗体是由(全长)核心抗体和融合的Fab片段(其中某些结构域是交叉交换的)组成的双特异性抗体。因此,所得到的双特异性抗体是不对称的。因此,可以使用具有称为凸起突变的第一重链(HCknob)和具有称为孔洞突变(HChole)的第二重链,使用称为凸起进入孔洞的异源二聚化技术,来产生所述双特异性抗体。
抗体0039,其也是本发明的一个方面,由四个具有SEQ ID NO:06至09的氨基酸序列的多肽组成。
抗体0039是双特异性抗体,其包含
a)包含两个全长抗体轻链和全长抗体重链对的一个全长抗体,每对各具有一个全长抗体轻链和一个全长抗体重链,其中由每对全长重链和全长轻链形成的结合位点特异性地结合第一抗原,和
b)一个另外的Fab片段,其中所述另外的Fab片段与全长抗体的一条重链的C-末端融合,其中所述另外的Fab片段的结合位点特异性地结合第二抗原,
其中每条全长抗体轻链在恒定轻链结构域(CL)中位置123包含氨基酸残基精氨酸(替代野生型谷氨酸残基;E123R突变),并且在位置124包含氨基酸残基赖氨酸(替代野生型谷氨酰胺残基;Q124K突变)(编号根据Kabat),
其中每条全长抗体重链在第一恒定重链结构域(CH1)中位置147包含谷氨酸残基(替代野生型赖氨酸残基;K147E突变),并且在位置213包含谷氨酸残基(替代野生型赖氨酸氨基酸残基;K213E突变)(编号根据Kabat EU索引),
其中所述特异性地结合第二抗原的另外的Fab片段包含结构域交叉,使得轻链可变结构域(VL)和重链可变结构域(VH)彼此替换,和
其中所述第一抗原是人CD20,而所述第二抗原是人转铁蛋白受体。
抗体0041,其也是本发明的一个方面,由四个具有SEQ ID NO:01至03和SEQ IDNO:10的氨基酸序列的多肽组成。
抗体0041是双特异性抗体,其包含
a)包含两个全长抗体轻链和全长抗体重链对的一个全长抗体,每对各包含一个全长抗体轻链和一个全长抗体重链,其中由每对全长重链和全长轻链形成的结合位点特异性地结合第一抗原,和
b)一个另外的Fab片段,其中所述另外的Fab片段与全长抗体的一条重链的C-末端融合,其中所述另外的Fab片段的结合位点特异性地结合第二抗原,
其中每条全长抗体轻链在恒定轻链结构域(CL)中位置123包含氨基酸残基精氨酸(替代野生型谷氨酸残基;E123R突变),并且在位置124包含氨基酸残基赖氨酸(替代野生型谷氨酰胺残基;Q124K突变)(编号根据Kabat),
其中每条全长抗体重链在第一恒定重链结构域(CH1)中位置147包含谷氨酸残基(替代野生型赖氨酸残基;K147E突变),并且在位置213包含谷氨酸残基(替代野生型赖氨酸氨基酸残基;K213E突变)(编号根据Kabat EU索引),
其中所述特异性地结合第二抗原的另外的Fab片段包含结构域交叉,使得恒定轻链结构域(CL)和恒定重链结构域1(CH1)彼此替换,和其中所述第一抗原是人CD20,而所述第二抗原是人转铁蛋白受体。
抗体0040,其也是本发明的一个方面,由三个具有SEQ ID NO:11至13和SEQ IDNO:22的氨基酸序列的多肽组成。
抗体0040是双特异性抗体,其包含
a)包含两个全长抗体轻链和全长抗体重链对的一个全长抗体,每对各包含一个全长抗体轻链和一个全长抗体重链,其中由每对全长重链和全长轻链形成的结合位点特异性地结合第一抗原,和
b)一个另外的Fab片段,其中所述另外的Fab片段与全长抗体的一条重链的C-末端融合,其中所述另外的Fab片段的结合位点特异性地结合第二抗原,
其中所述特异性地结合第二抗原的另外的Fab片段包含结构域交叉,使得恒定轻链结构域(CL)和恒定重链结构域1(CH1)彼此替换,和其中所述第一抗原是人CD20,而所述第二抗原是人转铁蛋白受体。
抗体0042,其也是本发明的一个方面,由四个具有SEQ ID NO:14至17的氨基酸序列的多肽组成。
抗体0042是双特异性抗体,其包含
a)源自特异性地结合第一抗原的第一抗体的第一轻链和第一重链;和
b)源自特异性地结合第二抗原的第二抗体的第二轻链和第二重链,其中
在第二轻链中,恒定结构域CL由第二重链的恒定结构域CH1替代;和
在第二重链中,恒定结构CH1由第二轻链的恒定结构域CL替代;且
i)其中在第一轻链的恒定结构域CL中,位置124和123(编号根据Kabat)的氨基酸彼此独立地被选自K、R和H的氨基酸置换;并且其中在第一重链的恒定结构域CH1中,位置147和213(编号根据Kabat的EU索引)的氨基酸彼此独立地被选自E或D的氨基酸置换;或
ii)其中在第二重链的恒定结构域CL中,位置124和123(编号根据Kabat)的氨基酸彼此独立地被选自K、R和H的氨基酸置换;并且其中在第二轻链的恒定结构域CH1中,位置147和213(编号根据Kabat的EU索引)的氨基酸彼此独立地被选自E或D的氨基酸置换。
通过CHO细胞中的瞬时表达获得了本文中所述的双特异性抗体。产量如下表中所示。
抗体 | 0039 | 0040 | 0041 | 0042 |
c[μg/ml] | 8.4 | 25.3 | 32 | 22.5 |
量[mg] | 29.4 | 88.6 | 112.0 | 78.8 |
各多肽在不同表达质粒上的不同配置/组合和所得质粒的不同比例已经用于所述双特异性抗体的重组生产。在HEK293细胞中获得的结果呈现于下表中。
所述双特异性抗体已经在CHO细胞中小规模生产,并且在使用蛋白A亲合色谱的第一个纯化步骤后以及在使用制备性大小排阻色谱的第二纯化步骤后,分析了副产物分布。结果呈现于下表中。
在不同细胞系中生产了所述双特异性抗体。结果显示于下表中。
测定了抗体0039、0040、0041和0042的聚集温度分别为大约54-56℃、大约50-53℃、大约51-53℃和大约55-57℃。
总的说来,抗体0041显示出改善的性质,并且因此是本发明的优选方面。这种改善的特性特别是改善的副产物谱。
本文的一个方面是一种双特异性抗体,其包含
a)包含两对全长抗体轻链和全长抗体重链的一个全长抗体,每对为一个全长抗体轻链和一个全长抗体重链,其中由每对全长重链和全长轻链形成的结合位点特异性地结合第一抗原,和
b)一个另外的Fab片段,其中所述另外的Fab片段与全长抗体的一条重链的C-末端融合,其中所述另外的Fab片段的结合位点特异性地结合第二抗原,
其中每条全长抗体轻链在恒定轻链结构域(CL)中位置123包含氨基酸残基精氨酸(替代野生型谷氨酸残基;E123R突变),并且在位置124包含氨基酸残基赖氨酸(替代野生型谷氨酰胺残基;Q124K突变)(编号根据Kabat),
其中每条全长抗体重链在第一恒定重链结构域(CH1)中位置147包含谷氨酸残基(替代野生型赖氨酸残基;K147E突变),并且在位置213包含谷氨酸残基(替代野生型赖氨酸氨基酸残基;K213E突变)(编号根据Kabat EU索引),
其中所述特异性地结合第二抗原的另外的Fab片段包含结构域交叉,使得恒定轻链结构域(CL)和恒定重链结构域1(CH1)彼此替换,和其中所述第一抗原是人CD20,而所述第二抗原是人转铁蛋白受体。
本文的一个方面是双特异性抗体,其包含
a)包含两对全长抗体轻链和全长抗体重链的一个全长抗体,每对为一个全长抗体轻链和一个全长抗体重链,其中由每对全长重链和全长轻链形成的结合位点特异性地结合第一抗原,和
b)一个另外的Fab片段,其中所述另外的Fab片段与全长抗体的一条重链的C-末端融合,其中所述另外的Fab片段的结合位点特异性地结合第二抗原,
其中每条全长抗体轻链在恒定轻链结构域(CL)中位置123包含氨基酸残基精氨酸(替代野生型谷氨酸残基;E123R突变),并且在位置124包含氨基酸残基赖氨酸(替代野生型谷氨酰胺残基;Q124K突变)(编号根据Kabat),
其中每条全长抗体重链在第一恒定重链结构域(CH1)中位置147包含谷氨酸残基(替代野生型赖氨酸残基;K147E突变),并且在位置213包含谷氨酸残基(替代野生型赖氨酸氨基酸残基;K213E突变)(编号根据Kabat EU索引),
其中所述特异性地结合第二抗原的另外的Fab片段包含结构域交叉,使得恒定轻链结构域(CL)和恒定重链结构域1(CH1)彼此替换,
其中所述第一抗原是人CD20,而所述第二抗原是人转铁蛋白受体,
其中所述人CD20结合位点包含与SEQ ID NO:18的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的重链可变结构域(VH)序列以及与SEQ ID NO:19的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的轻链可变结构域(VL)序列,和
其中所述人转铁蛋白受体结合位点包含与SEQ ID NO:20的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的重链可变结构域(VH)序列以及与SEQ ID NO:21的氨基酸序列具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的轻链可变结构域(VL)序列。
在某些实施方案中,具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的VH序列相对于参照序列含有置换(例如,保守性置换)、插入或删除,但包含该序列的结合位点保留结合其抗原的能力。在某些实施方案中,在SEQ IDNO:18或20中总共1至10个氨基酸被置换、插入和/或删除。在某些实施方案中,置换、插入或删除出现在HVR外的区域中(即,在FR中)。
在某些实施方案中,具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的VL序列相对于参照序列含有置换(例如,保守性置换)、插入或删除,但包含该序列的结合位点保留结合其抗原的能力。在某些实施方案中,在SEQ IDNO:19或21中总共1至10个氨基酸被置换、插入和/或删除。在某些实施方案中,置换、插入或删除出现在HVR外的区域中(即,在FR中)。
在一个实施方案中,所述人CD20结合位点包含SEQ ID NO:18的VH序列,包括该序列的翻译后修饰,以及SEQ ID NO:19的VL序列,包括该序列的翻译后修饰。
在一个实施方案中,所述人转铁蛋白结合位点包含SEQ ID NO:20的VH序列,包括该序列的翻译后修饰,以及SEQ ID NO:21的VL序列,包括该序列的翻译后修饰。
在一个实施方案中,所述双特异性抗体包含
i)与SEQ ID NO:01具有至少70%,至少80%,至少90%,或95%或更高的序列同一性的轻链,
ii)与SEQ ID NO:02具有至少70%,至少80%,至少90%,或95%或更高的序列同一性的重链,
iii)与SEQ ID NO:03具有至少70%,至少80%,至少90%,或95%或更高的序列同一性的轻链,和
iv)与SEQ ID NO:04具有至少70%,至少80%,至少90%,或95%或更高的序列同一性的重链Fab片段,
其中
SEQ ID NO:1具有氨基酸序列
SEQ ID NO:2具有氨基酸序列
SEQ ID NO:03具有氨基酸序列
SEQ ID NO:04具有氨基酸序列
本文的一个方面是一种双特异性抗体,其包含
a)包含两对全长抗体轻链和全长抗体重链的一个全长抗体,每对为一个全长抗体轻链和一个全长抗体重链,其中由每对全长重链和全长轻链形成的结合位点特异性地结合第一抗原,和
b)一个另外的Fab片段,其中所述另外的Fab片段与全长抗体的一条重链的C-末端融合,其中所述另外的Fab片段的结合位点特异性地结合第二抗原,
其中每条全长抗体轻链在恒定轻链结构域(CL)中位置123包含氨基酸残基精氨酸(替代野生型谷氨酸残基;E123R突变),并且在位置124包含氨基酸残基赖氨酸(替代野生型谷氨酰胺残基;Q124K突变)(编号根据Kabat),
其中每条全长抗体重链在第一恒定重链结构域(CH1)中位置147包含谷氨酸残基(替代野生型赖氨酸残基;K147E突变),并且在位置213包含谷氨酸残基(替代野生型赖氨酸氨基酸残基;K213E突变)(编号根据Kabat EU索引),
其中所述特异性地结合第二抗原的另外的Fab片段包含结构域交叉,使得恒定轻链结构域(CL)和恒定重链结构域1(CH1)彼此替换,
其中所述第一抗原是人CD20,而所述第二抗原是人转铁蛋白受体,
其中所述人CD20结合位点包含具有SEQ ID NO:18的氨基酸序列的重链可变区(VH)和具有SEQ ID NO:19的氨基酸序列的轻链可变区,和
其中所述人转铁蛋白受体结合位点包含具有SEQ ID NO:20的氨基酸序列的重链可变区(VH)和具有SEQ ID NO:21的氨基酸序列的轻链可变区。
本文的一个方面是一种双特异性抗体,其包含
a)包含两对全长抗体轻链和全长抗体重链的一个全长抗体,每对为一个全长抗体轻链和一个全长抗体重链,其中由每对全长重链和全长轻链形成的结合位点特异性地结合第一抗原,其中所述全长抗体包含由两条全长重链的Fc-区多肽形成的Fc-区,所述Fc区各自包含CH1、CH2和CH3结构域,和
b)一个另外的Fab片段,其中所述另外的Fab片段与全长抗体的一条重链的C-末端融合,其中所述另外的Fab片段的结合位点特异性地结合第二抗原,
其中每条全长抗体轻链在恒定轻链结构域(CL)中位置123包含氨基酸残基精氨酸(替代野生型谷氨酸残基;E123R突变),并且在位置124包含氨基酸残基赖氨酸(替代野生型谷氨酰胺残基;Q124K突变)(编号根据Kabat),
其中每条全长抗体重链在第一恒定重链结构域(CH1)中位置147包含谷氨酸残基(替代野生型赖氨酸残基;K147E突变),并且在位置213包含谷氨酸残基(替代野生型赖氨酸氨基酸残基;K213E突变)(编号根据Kabat EU索引),
其中所述特异性地结合第二抗原的另外的Fab片段包含结构域交叉,使得恒定轻链结构域(CL)和恒定重链结构域1(CH1)彼此替换,
其中所述第一抗原是人CD20,而所述第二抗原是人转铁蛋白受体,
其中所述人CD20结合位点包含具有SEQ ID NO:18的氨基酸序列的重链可变区(VH)和具有SEQ ID NO:19的氨基酸序列的轻链可变区,
其中所述人转铁蛋白受体结合位点包含具有SEQ ID NO:20的氨基酸序列的重链可变区(VH)和具有SEQ ID NO:21的氨基酸序列的轻链可变区(VL),
其中所述Fc-区多肽是
a)人亚类IgG1的,
b)人亚类IgG4的,
c)具有突变L234A、L235A和P329G的人亚类IgG1的,
d)具有突变S228P、L235E和P329G的人亚类IgG4的,
e)在两个Fc-区多肽中都具有突变L234A、L235A和P329G,并且在一个Fc-区多肽中具有突变T366W和S354C以及在相应的另一个Fc-区多肽中具有突变T366S、L368A、Y407V和Y349C的人亚类IgG1的,
f)在两个Fc-区多肽中都具有突变S228P和P329G,并且在一个Fc-区多肽中具有突变T366W和S354C以及在相应的另一个Fc-区多肽中具有突变T366S、L368A、Y407V和Y349C的人亚类IgG4的,
g)在两个Fc-区多肽中都具有突变L234A、L235A、P329G、I253A、H310A和H435A,并且在一个Fc-区多肽中具有突变T366W和S354C以及在相应的另一个Fc-区多肽中具有突变T366S、L368A、Y407V和Y349C的人亚类IgG1的,
h)在两个Fc-区多肽中都具有突变L234A、L235A、P329G、M252Y、S254T和T256E,并且在一个Fc-区多肽中具有突变T366W和S354C以及在相应的另一个Fc-区多肽中具有突变T366S、L368A、Y407V和Y349C的人亚类IgG1的,或
i)在两条重链中都具有突变L234A、L235A、P329G、H310A、H433A和Y436A,并且在一条重链中具有突变i)T366W和ii)S354C或Y349C以及在相应的另一条重链中具有突变i)T366S、L368A和Y407V和ii)Y349C或S354C的人亚类IgG1的全长抗体。
在进一步的方面中,根据以上任一个实施方案的双特异性抗人CD20/人转铁蛋白受体抗体可以结合以下部分1-3中所述的单个或组合的任意特征。
1.嵌合和人源化抗体
在某些实施方案中,本文提供的抗体是嵌合抗体。一些嵌合抗体例如在US4,816,567;和Morrison,S.L.等,Proc.Natl.Acad.Sci.USA 81(1984)6851-6855中描述。在一个实例中,嵌合抗体包含非人可变区(例如衍生自小鼠、大鼠、仓鼠、兔或非人灵长类动物,如猴的可变区)和人恒定区。在进一步的实例中,嵌合抗体是“类别转换的”抗体,其中所述类别或亚类已相对于亲本抗体发生改变。嵌合抗体包括其抗原结合片段。
在某些实施方案中,嵌合抗体是人源化抗体。通常,将非人抗体人源化,以减少对人的免疫原性,同时保留亲本非人抗体的特异性和亲和力。通常,人源化抗体包含一个或多个可变结构域,其中HVR,例如CDR(或其部分)源自非人抗体,并且FR(或其部分)源自人抗体序列。人源化抗体任选地还可以包含人恒定区的至少部分。在一些实施方案中,在人源化抗体中的一些FR残基被置换为来自非人抗体(例如从其产生HVR残基的抗体)的相应残基,例如以恢复或改善抗体特异性或亲和力。
人源化抗体及其制备方法例如在Almagro,J.C.和Fransson,J.,Front.Biosci.13(2008)1619-1633中综述,并且例如在下述文献中进一步描述:Riechmann,I.等,Nature332(1988)323-329;Queen,C.等,Proc.Natl Acad.Sci.USA 86(1989)10029-10033;US5,821,337,US7,527,791,US6,982,321和US7,087,409;Kashmiri,S.V.等,Methods 36(2005)25-34(描述特异性决定区(SDR)嫁接);Padlan,E.A.,Mol.Immunol.28(1991)489-498(描述“表面重建”(resurfacing));Dall’Acqua,W.F.等,Methods 36(2005)43-60(描述“FR改组”);和Osbourn,J.等,Methods 36(2005)61-68和Klimka,A.等,Br.J.Ccancer,83(2000)252-260(描述“引导选择”方法到FR改组)。
可以用于人源化的人构架区包括但不限于:使用“最佳配合”法选择的构架区(参见,例如,Sims,M.J.等J.Immumol.151:2296(1993));源自特定亚组的轻或重链可变区的人抗体共有序列的构架区(参见,例如,Carter,P.等,Proc.Natl.Acad.Sci.USA 89(1992)4285;和Presta,L.G.等,J.Immumol.,151(1993)2623;人成熟(体细胞成熟的)构架区或人种系构架区(参见,例如,Almagro,J.C.和Fransson,J.,Front.Biosci.13(2008)1619-1633;和源自筛选FR文库得到的构架区(参见,例如,Baca,M.等,J.Biol.Chem.272(1997)10678-10684和Rosok,M.J.等,J.Biol.Chem.271(1996)22611-22618)。
2.人抗体
在某些实施方案中,本文中所述的抗体是人抗体。可以使用本领域已知的各种技术来产生人抗体。人抗体概括地描述于van Dijk,M.A.和van de Winkel,J.G.,Curr.Opin.Pharmacol.5(2001)368-374和Lonberg,N.,Curr.Opin.Immunol.20(2008)450-459。
可以通过将免疫原给予转基因动物来制备人抗体,所述转基因动物已经改进成应答抗原挑战而产生完整的人抗体或具有人可变区的完整抗体。这样的动物通常含有全部或部分人免疫球蛋白基因座,其替代了内源性免疫球蛋白基因座,或其存在于染色体外或随机整合至动物的染色体中。在这样的转基因小鼠中,内源性免疫球蛋白基因座通常已经被灭活。对于从转基因动物获得人抗体的方法的综述,参见,Lonberg,N.,Nat.Biotech.23(2005)1117-1125。还可以参见,例如,描述XENOMOUSETM技术的US 6,075,181和US6,150,584;描述技术的US5,770,429;描述K-M技术的US7,041,870;和描述技术的US2007/0061900。例如,通过结合不同的人恒定区,可以进一步修饰来自通过这样的动物产生的完整抗体的人可变区。
还可以通过基于杂交瘤的方法来制得人抗体。已经描述了用于人单克隆抗体生产的人骨髓瘤和小鼠-人杂交骨髓瘤细胞系(参见,例如,Kozbor,D.,J.Immunol.133(1984)3001-3005;Brodeur,B.R.等,Monoclonal Antibody Production Techniques andApplications,Marcel Dekker,Inc.,New York(1987),pp.51-63;和Boerner,P.等,J.Immunol.147(1991)86-95)。通过人B-细胞杂交瘤技术产生的人抗体还描述于Li,J.等,Proc.Natl.Acad.Sci.USA 103(2006)3557-3562。其他方法包括例如US7,159,826(描述从杂交瘤细胞系生产单克隆人IgM抗体)和Ni,J.,Xiandai Mianyixue 26(2006)265-268(描述人-人杂交瘤)中描述的那些。人杂交瘤技术(Trioma技术)还描述于Vollmers,H.P.和Brandlein,S.,Histology and Histopathology 20(2005)927-937以及Vollmers,H.P.和Brandlein,S.,Methods and Findings in Experimental and Clinical Pharmacology27(2005)185-191中。
还可以通过从人衍生的噬菌体展示文库分离选定的Fv克隆可变结构域序列来产生人抗体。随后将这样的可变结构域序列与所需的人恒定结构域结合。
3.抗体变体
在某些实施方案中,考虑本文提供的双特异性抗体的氨基酸序列变体。例如,可能期望提高抗体的结合亲和力和/或其他生物性质。抗体的氨基酸序列变体可以通过将合适修饰引入编码抗体的核苷酸序列内,或通过肽合成,进行制备。此类修饰包括例如在抗体的氨基酸序列内的残基的删除,和/或插入和/或置换。可以制备删除、插入和置换的任何组合,以获得最终构建体,只要最终构建体具有所需特征,例如抗原结合。
a)置换、插入和删除变体
在某些实施方案中,提供了具有一个或多个氨基酸置换的抗体变体。用于置换诱变的目的位点包括HVR和FR。保守置换显示于下表中标题“保守性置换”下。更实质性的变化在表1中标题“示例性置换”下提供,并且在下文参考氨基酸侧链种类进一步描述。可以将氨基酸置换引入目的抗体内且就所需活性筛选产物,例如保留/提高的抗原结合、降低的免疫原性或提高的ADCC或CDC。
表
原始残基 | 示例性置换 | 保守性置换 |
Ala(A) | Val;Leu;Ile | Val |
Arg(R) | Lys;Gln;Asn | Lys |
Asn(N) | Gln;His;Asp,Lys;Arg | Gln |
Asp(D) | Glu;Asn | Glu |
Cys(C) | Ser;Ala | Ser |
Gln(Q) | Asn;Glu | Asn |
Glu(E) | Asp;Gln | Asp |
Gly(G) | Ala | Ala |
His(H) | Asn;Gln;Lys;Arg | Arg |
Ile(I) | Leu;Val;Met;Ala;Phe;正亮氨酸 | Leu |
Leu(L) | 正亮氨酸;Ile;Val;Met;Ala;Phe | Ile |
Lys(K) | Arg;Gln;Asn | Arg |
Met(M) | Leu;Phe;Ile | Leu |
Phe(F) | Trp;Leu;Val;Ile;Ala;Tyr | Tyr |
Pro(P) | Ala | Ala |
Ser(S) | Thr | Thr |
Thr(T) | Val;Ser | Ser |
Trp(W) | Tyr;Phe | Tyr |
Tyr(Y) | Trp;Phe;Thr;Ser | Phe |
Val(V) | Ile;Leu;Met;Phe;Ala;正亮氨酸 | Leu |
氨基酸可以根据共同侧链性质进行分组:
(1)疏水性:正亮氨酸、Met、Ala、Val、Leu、Ile;
(2)中性亲水性:Cys、Ser、Thr、Asn、Gln;
(3)酸性:Asp、Glu;
(4)碱性:His、Lys、Arg;
(5)影响链方向的残基:Gly、Pro;
(6)芳香族:Trp、Tyr、Phe。
非保守性置换造成这些类型之一的成员交换为另一类型的成员。
一类置换变体涉及置换亲本抗体(例如人源化或人抗体)的一个或多个超变区残基。通常,选择用于进一步研究的所得变体将相对于亲本抗体在特定生物性质(例如增加的亲和力、减少的免疫原性)上具有修饰(例如改善),和/或基本上了保留亲本抗体的特定生物性质。示例性置换变体是亲和力成熟抗体,其可以例如使用基于噬菌体展示的亲和力成熟技术,例如本文描述的,方便地生成。简而言之,使一个或多个HVR残基突变,并且将变体抗体展示在噬菌体上且筛选特定生物活性(例如结合亲和力)。
可以在HVR中作出改变(例如置换),例如以改善抗体亲和力。此类改变可以在HVR“热点”(即,由在体细胞成熟过程中高频率经历突变的密码子编码的残基)(参见,例如Chowdhury,P.S.,Methods Mol.Biol.207(2008)179-196)、和/或接触抗原的残基中作出,测试所得到的变体VH或VL的结合亲和力。通过构建二级文库且从中再选择而进行的亲和力成熟,例如描述于Hoogenboom,H.R.等,Methods in Molecular Biology 178(2002)1-37中。在亲和力成熟的一些实施方案中,可以通过多种方法中的任一种(例如易错PCR、链改组、或寡核苷酸定向诱变),将多样性引入选择用于成熟的可变基因内。随后制备二级文库。随后筛选文库以鉴定具有所需亲和力的任何抗体变体。引入多样性的另一种方法涉及HVR定向的方法,其中几个HVR残基(例如一次4-6个残基)被随机化。可以特意鉴定参与抗原结合的HVR残基,例如使用丙氨酸扫描诱变或建模。特别地,常常靶向CDR-H3和CDR-L3。
在某些实施方案中,置换、插入或删除可以在一个或多个HVR内发生,只要此类改变基本上不降低抗体结合抗原的能力即可。例如,可以在HVR中进行基本上不降低结合亲和力的保守性改变(例如如本文提供的保守性置换)。此类改变可以例如在HVR中的抗原接触残基外。在上文提供的变体VH和VL序列的某些实施方案中,每个HVR或者是未改变的,或者含有不超过一个、两个或三个氨基酸置换。
用于鉴定可以作为靶标进行诱变的抗体残基或区域的一个有用方法称为“丙氨酸扫描诱变”,如通过Cunningham,B.C.和Wells,J.A.,Science 244(1989)1081-1085描述的。在此方法中,鉴定残基或靶标残基组(例如荷电残基例如Arg、Asp、His、Lys和Glu),并且替换为中性或带负电荷的氨基酸(例如丙氨酸或聚丙氨酸),以确定抗体与抗原的相互作用是否受影响。可以在对该最初置换显示出功能性敏感的氨基酸位置上引入进一步的置换。可替代地或另外地,可以利用抗原-抗体复合物的晶体结构,鉴定在抗体和抗原之间的接触点。此类接触残基和邻近残基可以作为用于置换的候选物被靶向或消除。可以筛选变体,以确定它们是否含有所需性质。
氨基酸序列插入包括氨基和/或羧基末端融合(长度范围从一个残基到含有一百个或更多个残基的多肽),以及单个或多个氨基酸残基的序列内插入。末端插入的实例包括具有N末端甲硫氨酰残基的抗体。抗体分子的其他插入变体包括抗体的N或C末端与酶(例如对于ADEPT)或增加抗体血清半衰期的多肽的融合。
b)糖基化变体
在某些实施方案中,改变本文提供的抗体,以提高或降低抗体糖基化的程度。对抗体添加或删除糖基化位点,可以通过改变氨基酸序列从而形成或去除一个或多个糖基化位点而方便地完成。
当抗体包含Fc区时,可以改变与之连接的碳水化合物。通过哺乳动物细胞产生的天然抗体一般包含分支的、双叉型寡糖,其一般通过N键连接Fc区的CH2结构域的Asn297(参见,例如,Wright,A和Morrison,S.L.,TIBTECH 15(1997)26-32。寡糖可以包括各种碳水化合物,例如甘露糖、N-乙酰葡糖胺(GlcNAc)、半乳糖和唾液酸,以及连接双叉型寡糖结构的“茎”中的GlcNAc上的岩藻糖。在一些实施方案中,可以在本文提供的抗体中进行寡糖的修饰,以便产生具有特定提高性质的抗体变体。
在一个实施方案中,提供了具有缺乏(直接或间接)连接Fc区上的岩藻糖的碳水化合物结构的抗体变体。例如,此类抗体中的岩藻糖量可以是1%至80%、1%至65%、5%至65%或20%至40%。如例如WO 2008/077546中所述的,通过MALDI-TOF质谱法测量,相对于连接Asn 297的所有糖结构(例如复合的、杂合的和高甘露糖的结构)的总和,通过计算在Asn297的糖链内岩藻糖的平均量,确定岩藻糖的量。Asn297指位于Fc区的大约位置297上的天冬酰胺残基(Fc区残基的EU编号);然而,由于抗体中的微小序列变异,Asn297也可以位于位置297的上游或下游的约±3个氨基酸处,即位置294和300之间。此类岩藻糖基化变体可以具有改善的ADCC功能。参见,例如,US 2003/0157108;US 2004/0093621。与“去岩藻糖化的”或“岩藻糖缺陷的”抗体变体有关的出版物实例包括:US 2003/0157108;WO 2000/61739;WO 2001/29246;US 2003/0115614;US 2002/0164328;US 2004/0093621;US 2004/0132140;US 2004/0110704;US 2004/0110282;US 2004/0109865;WO 2003/085119;WO2003/084570;WO 2005/035586;WO 2005/035778;WO2005/053742;WO2002/031140;Okazaki,A。等,J.Mol.Biol.336(2004)1239-1249;Yamane-Ohnuki,N.等Biotech.Bioeng.87(2004)614。能够产生去岩藻糖基化的抗体的细胞系实例包括具有蛋白质岩藻糖基化缺陷的Lec13 CHO细胞(Ripka,J.等,Arch.Biochem.Biophys.249(1986)533-545;US 2003/0157108;和WO 2004/056312 A1,尤其是实施例11),和敲除细胞系,例如α-1,6-岩藻糖基转移酶基因,FUT8,敲除CHO细胞(参见,例如,Yamane-Ohunki,N.等,Biotech.Bioeng.87(2004)614-612;Kanda,Y.等,Biotechnol.Bioeng.,94(2006)680-688和WO2003/085107)。
进一步提供了具有平分型寡糖(bisected oligosaccharide)的抗体变体,例如其中与抗体的Fc区附着的二天线寡糖通过GlcNAc平分。此类抗体变体可以具有减少的岩藻糖化和/或提高的ADCC功能。此类抗体变体的实例描述于例如WO 2003/011878;US 6,602,684;和US 2005/0123546中。还提供了在与Fc区附着的寡糖中具有至少一个半乳糖残基的抗体变体。此类抗体变体可以具有提高的CDC功能。此类抗体变体描述于例如WO 1997/30087;WO 1998/58964;和WO 1999/22764。
c)Fc区变体
在某些实施方案中,可以将一个或多个氨基酸修饰引入本文提供的双特异性抗体的Fc区内,从而生成Fc区变体。Fc区变体可以包括包含在一个或多个氨基酸位置的氨基酸修饰(例如置换)的人Fc区序列(例如人IgG1、IgG2、IgG3或IgG4 Fc区)。
在某些实施方案中,本发明提供具有一些但并非所有效应物功能的抗体变体,这使得其成为用于如下应用的期望候选物,在所述应用中抗体在体内的半衰期是重要的,而一些效应物功能(例如补体和ADCC)是不需要的或有害的。可以进行体外和/或体内细胞毒性测定,以证实CDC和/或ADCC活性的降低/耗竭。例如,可以进行Fc受体(FcR)结合测定试验,以确保抗体缺乏FcγR结合(从而可能缺乏ADCC活性),但保留FcRn结合能力。用于介导ADCC的主要细胞即NK细胞仅表达FcγRIII,而单核细胞表达FcγRI、FcγRII和FcγRIII。在造血细胞上的FcR表达概括在Ravetch,J.V.和Kinet,J.P.,Annu.Rev.Immunol.9(1991)457-492的第464页表3中。评估目的分子的ADCC活性的体外测定试验的非限制性实例描述于US5,500,362中(参见,例如Hellstrom,I.等,Proc.Nat’l Acad.Sci.USA 83(1986)7059-7063;和Hellstrom,I等,Proc.Nat’l Acad.Sci.USA 82(1985)1499-1502;US 5,821,337(参见Bruggemann,M.等,J.Exp.Med.166(1987)1351-1361)。可替代地,可以采用非放射性测定试验方法(参见例如,用于流式细胞术的ACTITM非放射性细胞毒性测定试验(CellTechnology,Inc.Mountain View,CA);和CytoTox非放射性细胞毒性测定试验(Promega,Madison,WI)。可以用于此类测定试验的效应细胞包括外周血单个核细胞(PBMC)和自然杀伤(NK)细胞。可替代地或另外地,目的分子的ADCC活性可以在体内评估,例如在动物模型中,例如公开于Clynes,R.等,Proc.Nat’l Acad.Sci.USA 95(1988)652-656中的。还可以进行C1q结合测定试验,以证实抗体不能结合C1q并因此缺乏CDC活性。参见,例如,WO2006/029879和WO 2005/100402中C1q和C3c结合ELISA。为了评估补体激活,可以进行CDC测定试验(参见,例如,Gazzano-Santoro,H.等,J.Immunol.Methods 202(1996)163;Cragg,M.S.等,Blood 101(2003)1045-1052;以及Cragg,M.S.和M.J.Glennie,Blood 103(2004)2738-2743。FcRn结合和体内清除率/半衰期确定还可以使用本领域已知的方法进行(参见,例如,Petkova,S.B.等,Int’l.Immunol.18(2006)1759-1769)。
具有降低的效应物功能的抗体包括具有Fc区残基238、265、269、270、297、327和329中的一个或多个的置换的那些(US 6,737,056)。此类Fc突变体包括在氨基酸位置265、269、270、297和327的两个或更多个上具有置换的Fc突变体,包括具有残基265和297置换成丙氨酸的所谓“DANA”Fc突变体(US 7,332,581)。
描述了具有提高或降低的FcRs结合的特定抗体变体。(参见,例如,US 6,737,056;WO 2004/056312和Shields,R.L.等,J.Biol.Chem.276(2011)6591-6604)。
在某些实施方案中,抗体变体包含具有提高ADCC的一个或多个氨基酸置换的Fc区,例如在Fc区的位置298、333和/或334上的置换(残基的EU编号)。
在一些实施方案中,在Fc区中作出改变,以导致改变的(例如提高或降低的)C1q结合和/或补体依赖性细胞毒性(CDC),例如US 6,194,551,WO 99/51642,和Idusogie,E.E.等,J.Immunol.164(2000)4178-4184中所述的。
在US2005/0014934A1中描述了具有增加的半衰期和提高的新生儿Fc受体(FcRn)结合的抗体,所述新生儿Fc受体负责母源IgGs至胎儿的转移(Guyer,R.L.等,J.Immunol.117(1976)587和Kim,J.K.等,J.Immunol.24(1994)249)。这些抗体包含其中具有一个或多个置换的Fc区,所述一个或多个置换改善Fc区与FcRn的结合。此类Fc变体包括在如下Fc区残基的一个或多个上具有置换的那些:238、256、265、272、286、303、305、307、311、312、317、340、356、360、362、376、378、380、382、413、424或434,例如Fc区残基434的置换(US 7,371,826)。
关于Fc区变体的其他实例,还参见Duncan,A.R.&Winter,G.,Nature 322(1988)738-40;US 5,648,260;US 5,624,821;和WO 94/29351。
d)半胱氨酸工程化抗体变体
在特定实施方案中,可能期望制备半胱氨酸工程化抗体,例如“硫代MAbs”,其中抗体的一个或多个残基由半胱氨酸残基置换。在特定实施方案中,被置换的残基位于抗体的可接近位点上。通过用半胱氨酸置换这些残基,从而将反应性巯基基团置于抗体的可接近位点上,这些巯基基团可以用于使抗体缀合至其他部分例如药物部分或衔接物-药物部分,以产生免疫缀合物,如本文进一步描述的。在特定实施方案中,下述残基中的任何一个或多个可以由半胱氨酸残基置换:轻链的V205(Kabat编号);重链的A118(EU编号);和重链Fc区的S400(EU编号)。可以如例如US7,521,541中所述的,产生半胱氨酸工程化抗体。
e)抗体衍生物
在特定实施方案中,本文提供的双特异性抗体可以进一步被修饰,以含有本领域已知的且可容易获得的另外非蛋白质性部分。适于衍生抗体的部分包括但不限于水溶性聚合物。水溶性聚合物的非限制性实例包括但不限于聚乙二醇(PEG)、乙二醇/丙二醇的共聚物、羧甲基纤维素、葡聚糖、聚乙烯醇、聚乙烯吡咯烷酮、聚-1,3-二噁烷、聚-1,3,6-三噁烷、乙烯/马来酸酐共聚物、聚氨基酸(同聚物或无规共聚物)和葡聚糖或聚(n-乙烯吡咯烷酮)聚乙二醇、propropylene glycol同聚物、环氧丙烷/环氧乙烷共聚物、聚氧乙基化多元醇(例如甘油)、聚乙烯醇,及其混合物。聚乙二醇丙醛,由于其在水中的稳定性,可以在制造中具有优点。聚合物可以具有任何分子量,并且可以是分支或未分支的。连接抗体的聚合物数目可以改变,并且如果连接超过一个聚合物,那么它们可以是相同或不同分子。通常,用衍生的聚合物的数目和/或类型可以基于如下考虑进行确定,所述考虑包括但不限于待提高的抗体的特定性质或功能,抗体衍生物是否用于在限定条件下的治疗中等。
在另一个实施方案中,提供了抗体和可以通过暴露于辐射线而被选择性加热的非蛋白质性部分的缀合物。在一个实施方案中,非蛋白质性部分是碳纳米管(Kam,N.W.等,Proc.Natl.Acad.Sci.USA 102(2005)11600-11605)。辐射可以是任何波长,并且包括但不限于,不伤害普通细胞,但使非蛋白质性部分加热至可杀死抗体-非蛋白质性部分附近的细胞的温度的波长。
B.重组方法和组合物
抗体可以使用重组方法和组合物进行生产,例如如US 4,816,567中所述的。在一个实施方案中,提供了编码本文中所述的双特异性抗人CD20/人转铁蛋白受体抗体的分离核酸。在进一步的实施方案中,提供包含此核酸的一个或多个载体(例如表达载体)。在进一步的实施方案中,提供了包含此核酸的宿主细胞。在一个这样的实施方案中,宿主细胞是真核的,例如中国仓鼠卵巢(CHO)细胞或淋巴样细胞(例如Y0、NS0、Sp20细胞)。在一个实施方案中,提供了制备双特异性抗人CD20/人转铁蛋白受体抗体的方法,其中所述方法包括在适于抗体表达的条件下培养如上文提供的包含编码抗体的核酸的宿主细胞,且任选从宿主细胞(或宿主细胞培养基)中回收抗体。
对于双特异性抗人CD20/人转铁蛋白受体抗体的重组生产,分离编码抗体的核酸,例如如上所述的核酸,并且插入一个或多个用于进一步克隆和/或在宿主细胞中表达的载体内。此核酸可以使用常规程序(例如通过使用能够与编码抗体重和轻链的基因特异性结合的寡核苷酸探针)容易地分离且测序。
用于抗体编码载体的克隆或表达的合适宿主细胞包括本文描述的原核或真核细胞。例如,特别是当不需要糖基化和Fc效应物功能时,抗体可以在细菌中生产。对于抗体片段和多肽在细菌中的表达,参见例如US 5,648,237,US 5,789,199,和US 5,840,523(还参见Charlton,K.A.,Methods in Molecular Biology,第248卷,Lo,B.K.C.(编辑),HumanaPress,Totowa,NJ(2003),pp.245-254,描述抗体片段在大肠杆菌中的表达)。在表达后,抗体可以在可溶级分中从细菌细胞糊分离且可以进一步纯化。
除了原核生物外,真核微生物例如丝状真菌或酵母是用于抗体编码载体的合适克隆或表达宿主,包括其糖基化途径已被“人源化”的真菌和酵母菌株,这导致具有部分或全人糖基化模式的抗体生产。参见Gerngross,Nat.Biotech.22(2004)1409-1414;和Li,H.等,Nat.Biotech(2006)24:210-215。
用于糖基化抗体表达的合适宿主细胞也可以源自多细胞生物(无脊椎动物和脊椎动物)。无脊椎动物细胞的实例包括植物和昆虫细胞。已经鉴定了众多杆状病毒株,其可以与昆虫细胞结合使用,特别用于草地贪夜蛾(Spodoptera frugiperda)细胞的转染。
植物细胞培养物也可以用作宿主。参见,例如,US 5,959,177,US 6,040,498,US6,420,548,US 7,125,978和US 6,417,429(描述用于在转基因植物中生产抗体的PLANTIBODIESTM技术)。
脊椎动物细胞也可以用作宿主。例如,悬浮生长适应化的哺乳动物细胞系可以是有用的。有用的哺乳动物宿主细胞系的其他例子是SV40转化的猴肾CV1系(COS-7);人胚肾系(293或如例如Graham,F.L.等,J.Gen Virol.36(1997)59中所述的293细胞);幼仓鼠肾细胞(BHK);小鼠塞尔托利细胞(如例如Mather,J.P.,Biol.Reprod.23(1980)243-251中所述的TM4细胞);猴肾细胞(CV1);非洲绿猴肾细胞(VERO-76);人宫颈癌细胞(HELA);犬肾细胞(MDCK;Buffalo大鼠肝细胞(BRL 3A);人肺细胞(W138);人肝细胞(Hep G2);小鼠乳房肿瘤(MMT 060562);TRI细胞,如例如Mather,J.P.等,Annals N.Y.Acad.Sci.383(1982)44-68中所述的;MRC 5细胞;和FS4细胞。其他有用的哺乳动物宿主细胞系包括中国仓鼠卵巢(CHO)细胞,包括DHFR-CHO细胞(Urlaub,G.等,Proc.Natl.Acad.Sci.USA 77(1980)4216-4220);和骨髓瘤细胞系,如Y0、NS0和Sp2/0。对于适合于抗体生产的一些哺乳动物宿主细胞系的综述,参见,例如,Yazaki,P.和Wu,A.M.,Methods in Molecular Biology,Vol.248,Lo.B.K.C.(编辑),Humana Press,Totowa,NJ(2004)pp.255-268。
C.用于诊断和检测的方法和组合物
在某些实施方案中,将本文中提供的任一种双特异性抗人CD20/人转铁蛋白受体抗体用于检测生物样品中CD20的存在。本文中使用的术语“检测”包括定量或定性检测。在特定实施方案中,生物样品包括细胞或组织。
在一个实施方案中,提供了用于诊断或检测方法中的双特异性抗人CD20/人转铁蛋白受体抗体。在进一步的方面中,提供了检测生物样品中CD20存在的方法。在某些实施方案中,所述方法包括在允许双特异性抗人CD20/人转铁蛋白受体抗体结合CD20的条件下,将生物样品接触本文中所述的双特异性抗人CD20/人转铁蛋白受体抗体,并检测双特异性抗人CD20/人转铁蛋白受体抗体和CD20之间是否形成了复合物。这样的方法可以是体外或体内方法。
在某些实施方案中,提供了标记的双特异性抗人CD20/人转铁蛋白受体抗体。标记包括,但不限于,可以直接检测的标记或部分(如荧光、生色、电子致密、化学发光和放射性标记),以及可以间接(例如通过酶促反应或分子相互作用)检测的部分,如酶或配体。示例性标记包括但不限于,放射性同位素32P、14C、125I、3H和131I,荧光团,如稀土螯合物或荧光素及其衍生物,罗丹明及其衍生物,丹磺酰,伞形酮,萤光素酶,如萤火虫萤光素酶和细菌萤光素酶(US 4,737,456),萤光素,2,3-二氢酞嗪二酮,辣根过氧化物酶(HRP),碱性磷酸酶,β-半乳糖苷酶,葡糖淀粉酶,溶菌酶,糖氧化酶,例如葡萄糖氧化酶、半乳糖氧化酶和6-磷酸葡萄糖脱氢酶,杂环氧化酶,如尿酸酶和黄嘌呤氧化酶,与采用过氧化氢以氧化染料前体的酶如HRP、乳过氧化物酶或微过氧化物酶偶联,生物素/抗生物素蛋白,自旋标记,噬菌体标记,稳定自由基等。
D.免疫缀合物
本发明还提供了包含与一种或多种细胞毒性剂缀合的本文中所述的抗人CD20/人转铁蛋白受体抗体的免疫缀合物,所述细胞毒性剂如化疗剂或药物、生长抑制剂、毒素(例如,蛋白毒素,细菌、真菌、植物或动物来源的酶活性毒素,或其片段),或放射性同位素。
在一个实施方案中,免疫缀合物是抗体-药物缀合物(ADC),其中双特异性抗体与一种或多种药物缀合,所述药物包括但不限于美登素(参见US 5,208,020、US 5,416,064和EP 0 425 235 B1);auristatin,如单甲基auristatin药物部分DE和DF(MMAE和MMAF)(参见,US 5,635,483、US 5,780,588和US 7,498,298);多拉司他汀;卡奇霉素或其衍生物(参见US 5,712,374、US 5,714,586、US 5,739,116、US 5,767,285、US 5,770,701、US 5,770,710、US 5,773,001和US 5,877,296;Hinman,L.M.等,Cancer Res.53(1993)3336-3342和Lode,H.N.等,Cancer Res.58(1998)2925-2928);蒽环类,如道诺霉素或阿霉素(参见Kratz,F.等,Curr.Med.Chem.13(2006)477-523;Jeffrey,S.C.等,Bioorg.Med.Chem.Lett.16(2006)358-362;Torgov,M.Y.等,Bioconjug.Chem.16(2005)717-721;Nagy,A.等,Proc.Natl.Acad.Sci.USA 97(2000)829-834;Dubowchik,G.M.等,Bioorg.&Med.Chem.Letters 12(2002)1529-1532;King,H.D.等,J.Med.Chem.45(200294336-4343;和US 6,630,579);氨甲喋呤;长春地辛;紫杉烷,如多西紫杉醇、紫杉醇、larotaxel、tesetaxel和ortataxel;单端孢霉烯;和CC1065。
在另一个实施方案中,免疫缀合物包括与酶活性毒素或其片段缀合的本文中所述的双特异性抗体,所述毒素或其片段包括但不限于白喉毒素A链、白喉毒素的非结合活性片段、外毒素A链(来自铜绿假单胞菌)、蓖麻毒素A链、相思豆毒素A链、蒴莲根毒素A链、α-sarcin、油桐蛋白、香石竹蛋白、美洲商陆蛋白(PAPI、PAPII和PAP-S)、苦瓜抑制剂、泻果素、巴豆毒素、肥皂草抑制剂、白树毒素、mitogellin、局限曲菌素、酚霉素、依诺霉素和tricothecene。例如,参见1993年10月28日公开的WO 93/21232。
在另一个实施方案中,免疫缀合物包括与放射性原子缀合的本文中所述的双特异性抗体,形成放射性缀合物。各种放射性同位素可用于生产放射性缀合物。实例包括At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212和Lu的放射性同位素。将放射性缀合物用于检测时,可以包括放射性原子用于闪烁法研究,例如,TC99m或I123,或包括自旋标记物用于核磁共振(NMR)成像(也称为磁共振成像,MRI),如碘-123、碘-131、铟-111、氟-19、碳-13、氮-15、氧-17、钆、锰或铁。
可以使用各种双官能偶联剂来制得双特异性抗体和细胞毒性剂的缀合物,所述偶联剂如N-琥珀酰亚胺-3-(2-吡啶基二硫)丙酸酯(SPDP)、琥珀酰亚胺4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯(SMCC)、亚氨基硫烷(IT)、亚氨酸酯的双官能衍生物(如,己二亚氨二盐酸二甲酯)、活性酯(如,辛二酸二琥珀酰亚胺酯)、醛(如,戊二醛)、双-叠氮化合物(如,双(p-叠氮苯甲酰)己二胺)、双-重氮衍生物(如,双-(p-重氮苯甲酰)-乙二胺)、二异氰酸酯(如甲苯2,6-二异氰酸酯)和双活性氟化合物(如,1,5-二氟-2,4-二硝基苯)。例如,可以按照Vitetta,E.S.等,Science 238(1987)1098-1104中所述的制备蓖麻毒素免疫毒素。碳-14标记的1-异硫氰苄基-3-甲基二乙烯三胺五乙酸(MX-DTPA)是用于缀合放射性核苷酸与抗体的示例性螯合剂。参见WO 94/11026。衔接物可以是“可断裂衔接物”,有助于细胞毒性药物在细胞中的释放。例如,可以使用酸不稳定性衔接物、肽酶敏感性衔接物、光不稳定性衔接物、二甲基衔接物或含二硫化物衔接物(Chari,R.V.等,Cancer Res.52(1992)127-131;US 5,208,020)。
本文中的免疫缀合物或ADC明确考虑但不限于用交联剂制备的缀合物,所述交联剂包括但不限于BMPS、EMCS、GMBS、HBVS、LC-SMCC、MBS、MPBH、SBAP、SIA、SIAB、SMCC、SMPB、SMPH、磺基-EMCS、磺基-GMBS、磺基-KMUS、磺基-MBS、磺基-SIAB、磺基-SMCC和磺基-SMPB,以及SVSB(琥珀酰亚胺-(4-乙烯砜)苯甲酸酯),其是可商业购得的(例如,购自PierceBiotechnology,Inc.,Rockford,IL.,U.S.A)。
本文中还考虑了本文中所述的双特异性抗体和一种或多种小分子毒素的缀合物,所述毒素如卡奇霉素、美登素(US 5,208,020)、trichothene和CC1065。在本发明的一个实施方案中,所述双特异性分子与一个或多个美登素分子缀合(例如,每个拮抗剂分子约1至约10个美登素分子)。例如,美登素可以转化成May-SS-Me,其可以还原成May-SH3并且与修饰的拮抗剂反应(Chari等,Cancer Research 52:127-131(1992)),以产生美登素类化合物-抗体缀合物。
或者,本文中所述的双特异性抗体可以与一个或多个卡奇霉素分子缀合。抗生素的卡奇霉素家族能够在亚皮摩尔浓度下产生双链DNA断裂。可以使用的卡奇霉素的结构类似物包括,但不限于,γ1I、α2I、α3I、N-乙酰基-γ1I、PSAG和θI 1(Hinman等,CancerResearch 53:3336-3342(1993)和Lode等,Cancer Research 58:2925-2928(1998))。
本发明进一步考虑了与具有溶核酸活性的化合物(例如,核酸核糖酶或DNA内切酶,如脱氧核糖核酸酶;DNase)缀合的本文中所述的双特异性抗体。
或者,例如,通过重组技术或肽合成,制得包括本文中所述的双特异性抗体和细胞毒性剂的融合蛋白。
E.药物制剂
通过使具有所需纯度的抗体与一种或多种任选的药学可接受的载体(Remington’s Pharmaceutical Science,第16版,Osol,A.(编辑)(1980))混合,以冻干制剂或水溶液的形式来制备如本文所述的双特异性抗人CD20/人转铁蛋白受体抗体的药物制剂。药物学上可接受的载体在采用的剂量和浓度下对接受者一般是无毒的,并且包括但不限于:缓冲剂,如磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(如十八基二甲基苄基氯化铵;氯己双铵;苯扎氯铵;苄索氯铵;苯酚、丁醇或苯甲醇;对羟基苯甲酸烷基酯例如对羟基苯甲酸甲或丙酯;儿茶酚;间苯二酚;环己醇;3-戊醇;和间甲酚);低分子量(小于约10个残基)多肽;蛋白质,如血清白蛋白、明胶或免疫球蛋白;亲水聚合物,如聚(乙烯吡咯烷酮);氨基酸,如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖及其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,如EDTA;糖,如蔗糖、甘露醇、海藻糖或山梨糖醇;成盐抗衡离子,如钠;金属络合物(例如Zn-蛋白质络合物);和/或非离子型表面活性剂,如聚乙二醇(PEG)。示例性药物学上可接受的载体在本文中进一步包括间质(insterstitial)药物分散剂,如可溶性中性-活性透明质酸酶糖蛋白(sHASEGP),例如人可溶性PH-20透明质酸酶糖蛋白,例如rhuPH20(Baxter International,Inc.)。US 2005/0260186和US 2006/0104968中描述了某些示例性sHASEGP及其使用方法,包括rhuPH20。在一个方面中,将sHASEGP与一种或多种另外的葡糖胺聚糖酶(如软骨素酶)组合。
示例性冻干抗体制剂描述于US 6,267,958。水性抗体制剂包括US 6,171,586和WO2006/044908中所述的那些,后面的制剂包括组氨酸-乙酸盐缓冲液。示例性抗CD20抗体制剂描述于WO98/56418中,明确按引用并入本文中。
适用于皮下施用的冻干制剂描述于WO 97/04801中。这样的冻干制剂可以用合适的稀释剂重建成高蛋白浓度并且重建的制剂可以皮下施用于本文中待治疗的哺乳动物。
本文中的制剂还可以针对所治疗的特定适应症按照需要含有一种以上的活性成分,优选具有互补活性且不会不利地彼此影响的那些。此类活性成分适于以对于预期目的有效的量组合存在。
活性成分可以截留在例如通过凝聚技术(coacervation)或通过界面聚合制备的微囊中(例如分别地羟甲基纤维素或明胶-微囊和聚-(甲基丙烯酸甲酯)微囊)、在胶体药物递送系统(例如脂质体、白蛋白微球体、微乳液、纳米颗粒和纳米囊)中,或在粗乳液中。此类技术公开于Remington’s Pharmaceutical Sciences,第16版,Osol,A(编辑)(1980)。
可以制备持续释放的制剂。持续释放的制剂的合适实例包括含有抗体的固体疏水聚合物的半透性基质,所述基质可以为成形物品的形式,例如薄膜或微胶囊。持续释放基质的实例包括聚酯、水凝胶(例如,聚(2-羟乙基-丙烯酸甲酯)或聚(乙烯醇)、聚交酯(US 3,773,919)、L-谷氨酸和γ乙基-L-谷氨酸酯的共聚物、不可降解的乙烯-醋酸乙烯酯、可降解的乳酸-乙醇酸共聚物,如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林组成的可注射微球体),以及聚-D-(-)-3-羟丁酸。
待用于体内施用的制剂一般是无菌的。无菌性可以通过例如经由无菌过滤膜过滤而容易地达到。在一个实施方案中,制剂是等渗的。
F.治疗方法和组合物
本文中提供的任一种双特异性抗人CD20/人转铁蛋白受体抗体可以用于治疗方法中。
在一个方面中,提供了双特异性抗人CD20/人转铁蛋白受体抗体用作药物。在进一步的方面中,提供了双特异性抗人CD20/人转铁蛋白受体抗体用于预防和/或治疗B细胞增殖性疾病。在某些实施方案中,提供了双特异性抗人CD20/人转铁蛋白受体抗体用于治疗方法中。在某些实施方案中,本文中提供了双特异性抗人CD20/人转铁蛋白受体抗体用于治疗患有B细胞增殖性疾病的个体的方法中,所述方法包括将有效量的双特异性抗人CD20/人转铁蛋白受体抗体施用于个体。在一个这样的实施方案中,所述方法进一步包括将有效量的至少一种其他治疗剂施用于所述个体,所述其他治疗剂如以下所列。在进一步的实施方案中,本文提供了双特异性抗人CD20/人转铁蛋白受体抗体用于消耗脑隔离的表达CD20的B细胞。在某些实施方案中,本文提供了双特异性抗人CD20/人转铁蛋白受体抗体用于消耗个体中的脑隔离的表达CD20的B细胞的方法,所述方法包括将有效量的双特异性抗人CD20/人转铁蛋白受体抗体施用于个体,以消耗脑隔离的表达CD20的B细胞。根据以上任一个实施方案的“个体”优选是人。
在进一步的方面中,本文提供了双特异性抗人CD20/人转铁蛋白受体抗体在制造或制备药物中的用途。在一个实施方案中,所述药物是用于治疗B细胞增殖性疾病。在进一步的实施方案中,所述药物是用于治疗B细胞增殖性疾病的方法,所述方法包括将有效量的药物施用于患有B细胞增殖性疾病的个体。在一个这样的实施方案中,所述方法进一步包括将有效量的至少一种其他治疗剂施用于个体,所述治疗剂如以下所列。在进一步的实施方案中,所述药物是用于消耗脑隔离的表达CD20的B细胞。在进一步的实施方案中,所述药物是用于消耗个体中脑隔离的表达CD20的B细胞的方法中,所述方法包括将有效量的药物施用于个体,以消耗脑隔离的表达CD20的B细胞。根据以上任一个实施方案的“个体”优选是人。
在进一步的方面中,本文提供了用于治疗B细胞增殖性疾病的方法。在一个实施方案中,所述方法包括将有效量的双特异性抗人CD20/人转铁蛋白受体抗体施用于患有B细胞增殖性疾病的个体。在一个这样的实施方案中,所述方法进一步包括将有效量的至少一种其他治疗剂施用于个体,所述治疗剂如以下所列。根据以上任一个实施方案的“个体”优选是人。
在进一步的方面中,本文中提供了一种用于消耗个体中的表达CD20的循环B细胞的方法。在一个实施方案中,所述方法包括将有效量的双特异性抗人CD20/人转铁蛋白受体抗体施用于个体,以消耗表达CD20的循环B细胞。在一个实施方案中,“个体”是人。
在进一步的方面中,本文中提供了包含本文中提供的任一种双特异性抗人CD20/人转铁蛋白受体抗体的药物制剂,例如,用于以上任一种治疗方法中。在一个实施方案中,药物制剂包括本文中提供的任一种双特异性抗人CD20/人转铁蛋白受体抗体和药物学上可接受的载体。在另一个实施方案中,药物组合物包括本文提供的任一种双特异性抗人CD20/人转铁蛋白受体抗体和至少一种其他的治疗剂,所述治疗剂例如如以下所列。
本文中所述的抗体在治疗中可以单独使用或结合其他药剂。例如,本文中所述的抗体可以与至少一种其他治疗剂共同施用。在某些实施方案中,其他治疗剂是有效治疗与本文中所述的双特异性抗体待用于治疗的相同或不同B细胞增殖性疾病的治疗剂。
上述的联合治疗包括组合施用(其中在同一或分开制剂中包括两种或更多种治疗剂)和分开施用,在这种情况中,本文中所述抗体的施用可以在其他一种或多种治疗剂的施用之前、同时和/或之后进行。在一个实施方案中,双特异性抗人CD20/人转铁蛋白受体抗体的施用和其他治疗剂的施用彼此可以在约一个月内,或在约一周、两周或三周内,或在约一天、两天、三天、四天、五天或六天内进行。本文中所述的抗体还可以结合其他干预疗法组合使用,所述干预疗法如,但不限于,放疗、行为疗法或本领域已知并且适用于待治疗或预防的神经学病症的其他疗法。
本文中所述的抗体(和任何其他治疗剂)可以通过任何合适的方式来施用,包括非肠道、肺内和鼻内,并且如果需要局部治疗时,损伤内施用。非肠道输注包括肌内、静脉内、动脉内、腹膜内或皮下施用。定量施用可以通过任何合适的途径,例如,通过注射,如静脉内或皮下注射,这部分取决于施用是短期的还是长期的。本文中考虑了各种定量施用时间表,包括但不限于不同时间点的单次或多次施用、快速浓注施用和脉冲式输注。
此外,所述双特异性抗体可以合适地通过脉冲式输注来施用,例如,使用递减剂量的双特异性抗体。可以通过注射(静脉内或皮下注射)来给予定量施用,这部分取决于施用是短期的或是长期的。
本文中所述的抗体将以与良好医学实践一致的方式来配制、定量和施用。在这个内容中考虑的因素包括待治疗的特定病症、待治疗的特定哺乳动物、个体患者的临床状况、病症起因、药剂传送部位、施用方法、施用时间表和医学从业者已知的其他因素。抗体并不是必需,而是任选地可以与目前用于预防或治疗所讨论病症的一种或多种药剂一起配制。这样的其他药剂的有效量取决于制剂中存在的抗体含量、病症或治疗的类型和以上讨论的其他因素。这些通常以本文中所述的相同剂量和施用途径来使用,或本文中所述剂量的约1至99%来使用,或以凭经验/临床上确定为合适的任何剂量和任何途径来使用。
将融合构建体或化合物穿过BBB转运的基于脂质的方法包括,但不限于,将融合构建体或化合物包裹在偶联单价结合实体的脂质体中,所述单价结合实体结合BBB血管内皮上的受体(参见,例如,US 2002/0025313)以及将单价结合实体包被在低密度脂蛋白颗粒中(参见,例如,US2004/0204354)或载脂蛋白E中(参见,例如,US 2004/0131692)。
对于疾病的预防或治疗,本文中所述抗体的合适剂量(单独使用或结合一种或多种其他另外的治疗剂使用时)将取决于待治疗疾病的类型、抗体类型、疾病的严重程度和过程、抗体是用于预防目的或是治疗目的、之前的治疗、患者的临床史和对抗体的应答,以及主治医生的判断。在一个时间点或在一系列治疗中,将抗体合适地施用于患者。根据疾病的类型和严重程度,约1μg/kg至15mg/kg(例如,0.5mg/kg-10mg/kg)的抗体可以是用于施用于患者的初始候选剂量,不管是例如通过一次或多次分开施用,或通过连续输注。一个典型的日剂量范围可以为约1μg/kg至100mg/kg或更高,这取决于上述因素。对于在几天或更长时间内的重复施用,根据病况,治疗通常将持续直至出现所需的疾病症状的抑制。一个示例性抗体剂量将在约0.05mg/kg至约10mg/kg范围中。因此,可以将约0.5mg/kg、2.0mg/kg、4.0mg/kg或10mg/kg的一个或多个剂量(或其任意组合)施用于患者。这样的剂量可以间歇地施用,例如,每周或每三周(例如,使得患者接受约二至约二十剂,或,例如,约六剂抗体)。可以施用初始较高载荷剂量,接着一个或多个较低剂量。然而,其他剂量方案可以是有用的。这种疗法的进程容易通过常规技术和测试来监控。
将理解,可以替代或附加双特异性抗人CD20/人转铁蛋白受体抗体,使用本文中所述的免疫缀合物,来实施以上任何制剂或治疗方法。
包含本文中所述的结合B细胞表面抗原的双特异性抗体的组合物将以与良好医学实践一致的方式来配制、定量和施用。在这个内容中考虑的因素包括待治疗的特定疾病或病症、待治疗的特定哺乳动物、个体患者的临床状况、疾病或病症的起因、药剂传送部位、施用方法、施用时间表和医学从业者已知的其他因素。待施用的拮抗剂的治疗有效量将通过这些考虑因素来控制。
除了B细胞增殖性疾病的治疗,本文中所述的双特异性抗体可以用于自身免疫疾病的治疗中。自身免疫疾病或病症的实例包括,但不限于,免疫介导的血小板减少症,如急性特发性血小板减少性紫癜和慢性特发性血小板减少性紫癜、皮肌炎、Sydenham's舞蹈症、狼疮性肾炎、风湿热、多腺性综合征、Henoch-Schonlein紫癜、链球菌感染后肾炎、结节性红斑、Takayasu's动脉炎、Addison's病、多形性红斑、结节性多动脉炎、强直性脊柱炎、Goodpasture's综合征、血栓闭塞性脉管炎(thromboangitis ubiterans)、原发性胆汁性肝硬化、Hashimoto's甲状腺炎、甲状腺毒症、慢性活动性肝炎、多发性肌炎/皮肌炎、多软骨炎、寻常性天疱疮、韦格纳氏肉芽肿病、膜性肾病、肌萎缩性侧索硬化、脊髓痨(tabesdorsalis)、多肌痛、恶性贫血、急进性肾小球性肾炎和纤维化肺泡炎,炎性应答,如炎性皮肤病,包括牛皮癣和皮炎(例如,特应性皮炎);全身性硬皮病与硬化;与炎性肠病相关的反应(如节段性回肠炎和溃疡性结肠炎);呼吸窘迫综合征(包括成人呼吸窘迫综合征;ARDS);皮炎;脑膜炎;脑炎;葡萄膜炎;结肠炎;肾小球性肾炎;过敏性病症,如湿疹和哮喘,以及涉及T细胞浸润和慢性炎性应答的其他病症;动脉粥样硬化;白细胞粘附缺陷;类风湿性关节炎;全身性红斑狼疮(SLE);糖尿病(例如,I型糖尿病或胰岛素依赖性糖尿病);多发性硬化;Reynaud’s综合征;自身免疫性甲状腺炎;过敏性脑脊髓炎;Sjogren’s综合征;青少年型糖尿病;以及通常在结核、结节病、多肌炎、肉芽肿病和脉管炎中发现的、与细胞因子和T淋巴细胞介导的急性和延迟型超敏反应相关的免疫应答;恶性贫血(Addison’s病);涉及白细胞渗出的疾病;中枢神经系统(CNS)炎性病症;多器官损伤综合征;溶血性贫血(包括但不限于冷球蛋白血症或Coombs阳性贫血);重症肌无力;抗原-抗体复合物介导的疾病;抗肾小球基底膜病;抗磷脂综合征;过敏性神经炎;Graves’病;Lambert-Eaton肌无力综合征;大疱性类天疱疮;天疱疮;自身免疫性多内分泌病;Reiter’s病;僵人综合征;Bechet病;巨细胞性动脉炎;免疫复合物性肾炎;IgA肾病;IgM多神经病;免疫性血小板减少性紫癜(ITP)或自身免疫性血小板减少症等。在本发明的这个方面中,将本发明的ABM用于延长时间段地消耗正常B细胞的血液。
然而,如上所述,对这些建议的双特异性抗体的量,可以有很大的治疗自由裁量权。在合适剂量和时间表的选择中,关键因素是所获得的结果,如上所述。例如,相对较高的剂量可能是正在进行的和急性疾病治疗最初所需的。为了获得最有效的结果,根据疾病或病症,可以在尽可能地接近疾病或病症的第一征状、诊断、出现或发生时或在疾病或病症缓和过程中施用所述拮抗剂。
除了将本文中所述的分离双特异性抗体施用于患者以外,本申请考虑了通过基因治疗来施用双特异性抗体。这样的编码双特异性抗体的核酸的施用包括在表述“施用治疗有效量的双特异性抗体”中。参见,例如,关于使用基因治疗来产生胞内抗体的WO96/07321。
存在两种主要的方法使核酸(任选包含在载体中)进入患者细胞中:体内和离体(ex vivo)。对于体内递送,将核酸直接注入患者中,通常在需要双特异性抗体的部位。对于离体治疗,取出患者的细胞,将核酸引入这些分离的细胞中并将修饰的细胞直接施用于患者,或例如,包裹在多孔膜内,将其植入患者中(参见,例如,US 4,892,538和US 5,283,187)。存在各种可用于将核酸引入活细胞的技术。所述技术可以根据是否将核酸转移至体外培养的细胞中或体内的预期宿主细胞中而改变。适用于在体外将核酸转移至哺乳动物细胞中的技术包括使用脂质体、电穿孔、微注射、细胞融合、DEAE-葡聚糖、磷酸钙沉淀方法等。常用的用于基因离体递送的载体是逆转录病毒。
目前优选的体内核酸转移技术包括使用病毒载体(如腺病毒、单纯疱疹I病毒或腺相关病毒)和基于脂质的系统(对于基因的脂质介导的转移有用的脂质是例如DOTMA、DOPE和DC-Chol)的转染。在一些情况中,期望提供具有靶向靶细胞物质的核酸源,所述物质如细胞表面膜蛋白或靶细胞特异性的抗体、针对靶细胞上的受体的配体等。在使用脂质体的情况中,可以使用结合与内吞作用相关的细胞表面膜蛋白的蛋白,用于靶向和/或促进吸收,例如对于特定细胞类型具有向性的衣壳蛋白或其片段、针对在循环中经历内在化的蛋白的抗体、以及靶向胞内定位和增强胞内半衰期的蛋白。受体介导的内吞作用的技术描述于例如Wu等,J.Biol.Chem.262:4429-4432(1987);和Wagner等,Proc.Natl.Acad.Sci.USA 87:3410-3414(1990)。对于目前已知的基因标记和基因疗法方案的综述,参见Anderson等,Science 256:808-813(1992)。还可以参见WO 93/25673和其中引用的参考文献。
用于将另外的治疗剂与抗体缀合的一般技术是公知的(参见,例如,Arnon等,"Monoclonal Antibodies for Immunotargeting of Drugs in Cancer Therapy",inMonoclonal Antibodies and Cancer Therapy,Reisfeld等(编辑),pp.243-56(AlanR.Liss,Inc.1985);Hellstrom等,"Antibodies For Drug Delivery",见Controlled DrugDelivery(第2版),Robinson等(编辑),pp.623-53(Marcel Dekker,Inc.1987);Thorpe,"Antibody Carriers Of Cytotoxic Agents In Cancer Therapy:A Review",见Monoclonal Antibodies'84:Biological And Clinical Applications,Pinchera等(编辑),pp.475-506(1985);和Thorpe等,"The Preparation And Cytotoxic Properties OfAntibody-Toxin Conjugates",Immunol.Rev.,62(1982)119-58)。
III.制成品
在一些实施方案中,提供含有可以用于治疗、预防和/或诊断上述病症的材料的制成品。制成品可以包含容器和在容器上或与容器结合的标签或包装说明书。合适的容器包括例如瓶、小瓶、注射器、IV溶液袋等。容器可以由多种材料例如玻璃或塑料形成。容器容纳单独的或与对于治疗、预防和/或诊断所述状况有效的另外组合物组合的组合物,且可以具有无菌进入口(例如容器可以是具有可被皮下注射针穿透的塞子的静脉溶液袋或小瓶)。组合物中至少一种活性剂是本文中所述的抗体。标签或包装说明书指示组合物用于治疗所选择的状况。此外,制成品可以包含(a)其中含有组合物的第一容器,其中所述组合物包含本文中所述的抗体;和(b)其中含有组合物的第二容器,其中所述组合物包含其它的细胞毒性剂或另外的治疗剂。在本发明的这个实施方案中,制成品可以进一步包含指示组合物可以用于治疗特定状况的包装说明书。可替代地或另外地,制成品可以进一步包括包含药学可接受的缓冲液的第二(或第三)容器,所述药学可接受的缓冲液例如抑菌注射用水(BWFI)、磷酸盐缓冲盐水、林格氏溶液和葡萄糖溶液。它可以进一步包括从商业和用户观点来看希望的其他材料,包括其他缓冲液、稀释剂、滤器、针头和注射器。
将理解,本文中所述的免疫缀合物可以替代或附加本文中所述的双特异性抗体,包括在任何上述制成品中。
VI.实施例
以下是本发明方法和组合物的实例。应当理解,鉴于上文提供的一般描述,可以实施多种其他实施方案。
材料&方法
在Kabat,E.A.等,Sequences of Proteins of Immunological Interest,第5版,Public Health Service,National Institutes of Health,Bethesda,MD(1991)中给出了关于人免疫球蛋白轻链和重链的核苷酸序列的一般信息。根据Kabat(Kabat,E.A.等,Sequences of Proteins of Immunological Interest,第5版,Public Health Service,National Institutes of Health,Bethesda,MD(1991))的编号,编号并提及抗体链的氨基酸。
重组DNA技术
按照Sambrook,J.等,Molecular cloning:A laboratory manual(分子克隆:实验室手册);Cold Spring Harbor Laboratory Press,Cold Spring Harbor,New York,1989中所述的,使用标准方法来操纵DNA。分子生物试剂根据制造商的说明使用。
基因合成
从通过化学合成制备的寡核苷酸,产生所需的基因片段。通过退火和连接寡核苷酸(包括PCR扩增)来装配两侧为单限制性核酸内切酶位点的长基因区段,并且随后经由所示的限制位点克隆。通过DNA测序来证实亚克隆的基因片段的DNA序列。根据在Geneart(Regensburg,德国)给出的规格来订购基因合成片段。
DNA序列测定
通过在MediGenomix GmbH(Martinsried,德国)或SequiServe GmbH(Vaterstetten,德国)进行的双链测序来测定DNA序列。
DNA和蛋白序列分析和序列数据管理
将GCG’s(Genetics Computer Group,Madison,Wisconsin)软件包版本10.2和Infomax’s Vector NT1 Advance suite版本8.0用于序列形成、作图、分析、注释和说明。
表达载体
为了所述双特异性抗体的表达,可以使用用于瞬时表达(例如,在HEK293细胞)的表达质粒,所述质粒基于使用或未用CMV-内含子A启动子的cDNA组织或基于基因组组织。
除了抗体表达盒,所述载体含有:
-复制起点,其允许这种质粒在大肠杆菌中复制,和
-β-内酰胺酶基因,其给予大肠杆菌中的氨苄青霉素抗性。
抗体基因的转录单位由以下元件组成:
-5’端的独特限制位点
-来自人巨细胞病毒的立即早期增强子和启动子,
-cDNA组织情况中,内含子A序列,
-源自人抗体基因的5’-非翻译区,
-免疫球蛋白重链信号序列,
-作为cDNA或具有基因组外显子-内含子组织的相应抗体链编码核酸,
-具有聚腺苷酸化信号序列的3’非翻译区,
-终止子序列,和
-3’端的独特限制位点。
通过PCR和/或基因合成来产生编码抗体链的融合基因,并例如使用各自载体中的独特限制位点,通过相应核酸区段的连接,通过已知重组方法和技术来装配。通过DNA测序来验证亚克隆的核酸序列。对于瞬时转染,通过来自转化的大肠杆菌培养物的质粒制备(Nucleobond AX,Macherey-Nagel),来制备较大量的质粒。
对于所有构建体,凸起-进入-孔洞杂二聚化技术与第一CH3结构域中的典型凸起(T366W)置换和第二CH3结构域中的相应孔洞置换(T366S、L368A和Y407V)(以及两个另外引入的半胱氨酸残基S354C/Y349C)(包含在上述相应的重链(HC)序列中)一起使用。
细胞培养技术
使用标准细胞培养技术,如Current Protocols in Cell Biology(2000),Bonifacino,J.S.,Dasso,M.,Harford,J.B.,Lippincott-Schwartz,J.和Yamada,K.M.(编辑),John Wiley&Sons,Inc.中所述的。
HEK293系统中的瞬时转染
通过瞬时表达来产生所述双特异性抗体。因此,根据制造商的说明书,使用HEK293系统(Invetrogen),使用相应的质粒,进行转染。简而言之,在摇瓶或搅拌发酵器中,在无血清FreeStyleTM 293表达培养基(Invitrogen)中,用相应表达质粒和293fectinTM或fectin(Invitrogen)的混合物,转染悬浮生长中的HEK293细胞(Invitrogen)。对于2L摇瓶(Corning),以1.0*106细胞/mL的密度将HEK293细胞接种于600mL中,并在120rpm,8%CO2下孵育。第二天,在大约1.5*106细胞/mL的细胞密度下,用大约42mL的A)20mL包含600μg总质粒DNA(1μg/mL)的Opti-MEM培养基(Invitrogen)和B)补充了1.2mL 293fectin或fectin(2μl/mL)的20ml Opti-MEME培养基的混合物转染细胞。根据葡萄糖消耗,在发酵过程中,加入葡萄糖溶液。在5-10天后,收集含有分泌的抗体的上清液,并且直接从上清液纯化抗体或将上清液冷冻并储存。
蛋白质测定
根据Pace等,Protein Science 4(1995)2411-1423,使用基于氨基酸序列计算的摩尔消光系数,通过测定280nm的光密度(OD),来测定纯化抗体和衍生物的蛋白质浓度。
上清液中的抗体浓度测定
通过用蛋白A琼脂糖-珠子(Roche Diagnostics GmbH,Mannheim,德国)免疫沉淀,估算了细胞培养物上清液中的抗体和衍生物的浓度。因此,将60μL蛋白A琼脂糖珠子在TBS-NP40(50mM Tris缓冲液,pH7.5,补充了150mM NaCl和1%Nonidet-P40)中洗涤三次。随后,将1-15mL细胞培养物上清液应用于TBS-NP40中预平衡的蛋白A琼脂糖珠子。在室温下孵育1小时后,在Ultrafree-MC-过滤器柱子(Amicon)上用0.5mL TBS-NP40洗涤珠子一次,用0.5mL 2×磷酸盐缓冲盐水(2×PBS,Roche Diagnostics GmbH,Mannheim,德国)洗涤两次,并用0.5mL 100mM柠檬酸钠缓冲液(pH5.0)简短洗涤四次。通过添加35μlLDS样品缓冲液(Invitrogen)洗脱结合的抗体。分别将一半的样品与LDS样品还原剂混合或保留未还原的,并且在70℃下加热10min。因此,将5-30μl应用于4-12%Bis-Tris SDS-PAGE凝胶(Invitrogen)上(使用MOPS缓冲液用于非还原SDS-PAGE,和含有抗氧化剂运行缓冲液添加剂的MES缓冲液(Invitrogen)用于还原SDS-PAGE),并用考马斯蓝染色。
通过亲合力HPLC色谱定量测量了细胞培养物上清液中的抗体的浓度。简而言之,在Agilent HPLC 1100系统上将含有结合蛋白A的抗体的细胞培养物上清液施加于200mMKH2PO4,100mM柠檬酸钠,pH7.4中的Applied Biosystems Poros A/20柱子,用200mM NaCl、100mM柠檬酸,pH2.5洗脱。通过UV吸光度和峰面积的积分来定量洗脱的抗体。将纯化的标准IgG1抗体用作为标准。
或者,通过夹层-IgG-ELISA来测量细胞培养物上清液中的抗体和衍生物的浓度。简而言之,用0.1μL/mL的100μL/孔生物素化的抗人IgG捕获分子F(ab’)2<h-Fcγ>BI(Dianova)包被StreptaWell高结合链霉亲和素A-96孔微滴定平板(Roche DiagnosticsGmbH,Mannheim,德国),在室温下1小时,或替换地,在4℃下过夜,并且随后用200μL/孔PBS,0.05%Tween(PBST,Sigma)洗涤三次。此后,将各自含抗体的细胞培养物上清液在PBS(Sigma)中连续稀释液以100μL/孔加入孔中,并在室温下在摇床上孵育1-2小时。用200μL/孔PBST将孔洗涤三次,并通过在室温下在摇床上孵育1-2小时,用100μl 0.1μg/mL的F(ab’)2<hFcγ>POD(Dianova)作为检测抗体检测结合的抗体。通过用200μL/孔PBST洗涤三次来除去未结合的检测抗体。通过添加100μL ABST/孔,接着孵育来检测结合的检测抗体。在405nm的测量波长下(参照波长492nm),在Tecan Fluor分光光度计上进行吸光度的测定。
制备性抗体纯化
参照标准实验方案从过滤的细胞培养物上清液纯化抗体。简而言之,将抗体施加于蛋白A Sepharose柱子(GE healthcare),并用PBS洗涤。在pH2.8下进行抗体的洗脱,接着立即中和。通过PBS中或包含150mM NaCl的20mM组氨酸缓冲液(pH6.0)中的大小排阻色谱(Superdex 200,GE Healthcare),从单体抗体分离聚集的蛋白。将单体抗体级分合并,(如果需要)使用例如MILLIPORE Amicon Ultra(30MWCO)离心浓缩机浓缩,冷冻并储存在-20℃或-80℃。将部分样品提供用于随后的蛋白质分析和分析性表征,例如,通过SDS-PAGE、大小排阻色谱(SEC)或质谱。
SDS-PAGE
根据制造商的说明,使用了Pre-Cast凝胶系统(Invitrogen)。特别地,使用了10%或4-12%Bis-Tris Pre-Cast凝胶(pH6.4)和MES(还原凝胶,使用抗氧化剂运行缓冲液添加剂)或MOPS(非还原凝胶)运行缓冲液。
CE-SDS
使用微流体Labchip技术(PerkinElmer,USA),通过CE-SDS分析了纯度和抗体完整性。因此,根据制造商的说明,使用HT蛋白表达试剂盒,制备5μl抗体溶液,用于CE-SDS分析,并使用HT蛋白表达芯片,在LabChip GXII系统上分析。使用LabChip GX软件来分析数据。
分析性大小排阻色谱
通过HPLC色谱来进行用于抗体的聚集和寡聚状态的测定的大小排阻色谱(SEC)。简而言之,将蛋白A纯化的抗体施加于Dionex系统(Thermo FischerScientific)上300mM NaCl,50mM KH2PO4/K2HPO4缓冲液(pH7.5)中的Tosoh TSKgelG3000SW柱,或施加于Dionex HPLC-系统上2×PBS中的Superdex200柱(GE Heathcare)。通过UV吸光度和峰面积的积分,来定量洗脱的抗体。将BioRad凝胶过滤标准151-1901用作标准。
质谱
这个部分描述了双特异性抗体的特征,重点在于其正确装配。通过去糖基化完整抗体并且在特定情况中去糖基化/限制性LysC消化抗体的电喷雾电离质谱(ESI-MS)来分析预期的主要结构。
在1mg/ml蛋白浓度下,在磷酸盐或Tris缓冲液中,在37℃下,用N-糖苷酶F,将抗体去糖基化长达17h。在Tris缓冲液(pH8)中,用100μg去糖基化抗体,实施限制性LysC(RocheDiagnostics GmbH,Mannheim,德国)消化,分别在室温下进行120小时,或在37℃下进行40分钟。在质谱分析之前,将样品在Sephadex G25柱(GE Healthcare)上通过HPLC脱盐。在配备了TriVersa NanoMate源(Advion)的maXis 4G UHR-QTOF MS系统上,通过ESI-MS,测定了总质量。
化学降解测试
将样品分成三等份,并且分别再次缓冲至20Mm His/His*HCl、140mM NaCl,pH6.0或PBS中,并且储存在40℃(His/NaCl)或37℃(PBS)。对照样品储存在-80℃。
孵育结束后,分析样品的相对活性浓度(BIAcore)、聚集(SEC)和片段化(毛细管电泳或SDS-PAGE),并与未处理的对照进行比较。
热稳定性
在20mM组氨酸/组氨酸盐酸盐、140mM NaCl,pH6.0中制备1mg/mL浓度的样品,并通过0.4μm过滤平板离心转移至光学384-孔平板中,并用石蜡油覆盖。通过DynoPro平板阅读器(Wyatt)上的动态光散射重复测量流体动力学半径,同时以0.05℃/min的速率,将样品从25℃加热至80℃。
或者,将样品转移至10μL微槽阵列中,并用Opim1000仪器(Avacta Inc.)记录静态光散射数据以及用266nm激光激发时的荧光数据,同时以0.1℃/min的速率将样品从25℃加热至90℃。
将聚集开始温度定义为流体动力学半径(DLS)或散射光强度(Optim1000)开始提高时的温度。
或者,将样品转移至9μL多槽阵列中。将所述多槽阵列在Optim1000仪器(AvactaAnalytical Inc.)中以0.1℃/min的恒定速率,从35℃加热至90℃。所述仪器连续记录266nm激光的散射光强度,大约每0.5℃一个数据点。将光散射强度相对温度进行作图。将聚集开始温度(T_agg)定义为散射光强度开始提高时的温度。
将熔化温度定义为荧光强度的拐点vs.波长。
实施例1
表达和纯化
如以上一般材料和方法部分中所述的,产生了双特异性抗体。
通过蛋白A亲合色谱和大小排阻色谱的组合,从上清液纯化双特异性抗体。通过质谱表征所获产物的身份,并通过CS-SDS、单体含量和稳定性表征分析性特性,如纯度。
如一般方法部分中所述的,通过去糖基化的完整抗体和去糖基化的/纤维蛋白溶酶消化的或替换地去糖基化的/限制性LysC消化的抗体的电喷雾电离质谱(ESI-MS),来分析预期的主要结构。
蛋白A和SEC纯化后,只应用其他分析方法(例如,热稳定性、质谱和功能性评估)。
实施例2
测定体外转铁蛋白受体结合
通过小鼠X63.AG8-563骨髓瘤细胞上的FACS分析,测试双特异性抗体与小鼠转铁蛋白受体的结合。如果Aβ抗体显示出非特异性地结合Ag8细胞的某些倾向,则可以通过与20倍过量的抗小鼠TfR抗体的共同孵育来定量特异性结合。通过离心收集细胞,用PBS洗涤一次,并在100μLRPMI/10%FCS中在冰上用1.5pM至10nM稀释系列的多肽融合物孵育5×104个细胞1.5h,其中添加或不添加200nM抗小鼠TfR抗体。用RPMI/10%FCS洗涤2次后,用RPMI/19%FCS中1:600稀释度的偶联藻红蛋白(Jackson Immuoresearch)的山羊抗人IgG,在冰上孵育细胞1.5h。将细胞再次洗涤,重悬浮于RPMI/10%FCS中,并且在FACS-阵列仪器(Becton-Dicknson)上测量了藻红蛋白荧光。
实施例3
针对人TfR抗体相互作用的基于表面等离子体共振的结合试验
根据供应商的手册,使用标准胺偶联化学程序,在配备有预先用抗人Fab抗体(GEHealthcare,目录号28-9583-25)处理的C1传感器芯片(GE Healthcare,目录号BR1005-35)的BIAcore B400(GE Healthcare)上,进行了结合实验。
对于动力学测量,在25℃下,在磷酸盐缓冲盐水pH7.4,0.05%Tween20中,使用60秒的接触时间和10μL/min的流速,将样品抗体固定化。以递增浓度添加重组的His6-标记的人转铁蛋白受体(R&D systems,目录号2474-TR-050),并且随着时间监控信号。记录到30μL/min流速下150秒结合时间和600秒解离时间的平均时间跨度。使用1:1结合模型(Langmuir isotherm)来拟合数据。
本发明的一些实施方案:
1.一种双特异性抗体,其包含
a)包含两个抗体轻链和抗体重链对的一个抗体,其中每对为一个抗体轻链和一个抗体重链,其中由每对重链和轻链形成的结合位点特异性地结合第一抗原,和
b)一个另外的Fab片段,其中另外的Fab片段与抗体的一条重链的C-末端融合,其中另外的Fab片段的结合位点特异性地结合第二抗原,
其中每条抗体轻链在恒定轻链结构域(CL)中位置123包含氨基酸残基精氨酸(替代野生型谷氨酸残基;E123R突变),并且在位置124包含氨基酸残基赖氨酸(替代野生型谷氨酰胺残基;Q124K突变)(编号根据Kabat),
其中每条抗体重链在第一恒定重链结构域(CH1)中位置147包含谷氨酸残基(替代野生型赖氨酸残基;K147E突变),并且在位置213包含谷氨酸残基(替代野生型赖氨酸氨基酸残基;K213E突变)(编号根据Kabat EU索引),
其中特异性地结合第二抗原的另外的Fab片段包含结构域交叉,使得恒定轻链结构域(CL)和恒定重链结构域1(CH1)彼此替换,和
其中第一抗原是人CD20,而第二抗原是人转铁蛋白受体。
2.根据权利要求1的抗体,其中所述另外的Fab片段通过肽衔接物与重链的C-末端融合。
3.根据权利要求1和2任一项的抗体,其中
a)与另外的Fab片段融合的重链具有三肽LSP作为C-末端重链氨基酸残基,其中其脯氨酸经由肽键与另外的Fab片段或肽衔接物的第一氨基酸残基直接融合,和
b)没有与另外的Fab片段融合的重链具有三肽LSP或SPG或PGK作为C-末端重链氨基酸残基。
4.根据权利要求1至3任一项的抗体,其中所述抗体是
a)人亚类IgG1的全长抗体,或
b)人亚类IgG4的全长抗体,或
c)具有突变L234A、L235A和P329G的人亚类IgG1的全长抗体,
d)具有突变S228P、L235E和P329G的人亚类IgG4的全长抗体,
e)在两条重链中都具有突变L234A、L235A和P329G、并且在一条重链中具有突变T366W和S354C以及在相应的另一条重链中具有突变T366S、L368A、Y407V和Y349C的人亚类IgG1的全长抗体,
f)在两条重链中都具有突变S228P和P329G、并且在一条重链中具有突变T366W和S354C以及在相应的另一条重链中具有突变T366S、L368A、Y407V和Y349C的人亚类IgG4的全长抗体,
g)在两条重链中都具有突变L234A、L235A、P329G、I253A、H310A和H435A、并且在一条重链中具有突变T366W和S354C以及在相应的另一条重链中具有突变T366S、L368A、Y407V和Y349C的人亚类IgG1的全长抗体,或
h)在两条重链中都具有突变L234A、L235A、P329G、M252Y、S254T和T256E、并且在一条重链中具有突变T366W和S354C以及在相应的另一条重链中具有突变T366S、L368A、Y407V和Y349C的人亚类IgG1的全长抗体,或
i)在两条重链中都具有突变L234A、L235A、P329G、H310A、H433A和Y436A、并且在一条重链中具有突变i)T366W和ii)S354C或Y349C、以及在相应的另一条重链中具有突变i)T366S、L368A和Y407V和ii)Y349C或S354C的人亚类IgG1的全长抗体。
5.根据权利要求1至4任一项的抗体,其中所述双特异性抗体包括
i)与SEQ ID NO:01具有70%或更高序列同一性的轻链,
ii)与SEQ ID NO:02具有70%或更高序列同一性的重链,
iii)与SEQ ID NO:03具有70%或更高序列同一性的轻链,和
iv)与SEQ ID NO:04具有70%或更高序列同一性的重链Fab片段。
6.根据权利要求1至4任一项的抗体,其中所述双特异性抗体包括具有SEQ ID NO:01的氨基酸序列的轻链,具有SEQ ID NO:02的氨基酸序列的重链,具有SEQ ID NO:03的氨基酸序列的轻链、和包含SEQ ID NO:04的氨基酸序列的抗体Fab片段。
7.根据权利要求1至6任一项的抗体,其中所述抗体是单克隆抗体。
8.一种药物组合物,其包括根据权利要求1至7任一项的抗体和药物学上可接受的载体。
9.根据权利要求1至7任一项的抗体用作药物。
10.根据权利要求1至7任一项的抗体用于多发性硬化的治疗。
11.根据权利要求1至7任一项的抗体在药物制造中的用途。
12.权利要求11的用途,其中所述药物用于多发性硬化的治疗。
13.权利要求11的用途,其中所述药物用于消耗脑隔离的表达CD20的B细胞。
14.一种治疗患有多发性硬化的个体的方法,包括将有效量的根据权利要求1至7任一项的抗体施用于个体。
15.一种消耗个体中脑隔离的表达CD20的B细胞的方法,包括将有效量的根据权利要求1至7任一项的抗体施用于个体,以消耗脑隔离的表达CD20的B细胞。
序列表
<110> 豪夫迈·罗氏有限公司(F. Hoffmann-La Roche AG)
<120> 双特异性抗人CD20/人转铁蛋白受体抗体及使用方法
<130> P33110
<150> EP15188067.1
<151> 2015-10-02
<160> 22
<170> PatentIn版本3.5
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Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Tyr Ala Ser Ser Asn
85 90 95
Val Asp Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Ser
100 105 110
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
115 120 125
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
130 135 140
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
145 150 155 160
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
165 170 175
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
180 185 190
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
195 200 205
Lys Val Glu Pro Lys Ser Cys
210 215
<210> 4
<211> 229
<212> PRT
<213> 人工序列
<220>
<223> 0041-Fab
<400> 4
Gln Ser Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Thr
1 5 10 15
Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Ala
20 25 30
Met Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Tyr Ile Trp Ser Gly Gly Ser Thr Asp Tyr Ala Ser Trp Ala Lys Ser
50 55 60
Arg Val Thr Ile Ser Lys Thr Ser Thr Thr Val Ser Leu Lys Leu Ser
65 70 75 80
Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Tyr
85 90 95
Gly Thr Ser Tyr Pro Asp Tyr Gly Asp Ala Ser Gly Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Val Ala Ala Pro
115 120 125
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
130 135 140
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
145 150 155 160
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
165 170 175
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
180 185 190
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
195 200 205
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
210 215 220
Asn Arg Gly Glu Cys
225
<210> 5
<211> 297
<212> PRT
<213> 智人(Homo sapiens)
<400> 5
Met Thr Thr Pro Arg Asn Ser Val Asn Gly Thr Phe Pro Ala Glu Pro
1 5 10 15
Met Lys Gly Pro Ile Ala Met Gln Ser Gly Pro Lys Pro Leu Phe Arg
20 25 30
Arg Met Ser Ser Leu Val Gly Pro Thr Gln Ser Phe Phe Met Arg Glu
35 40 45
Ser Lys Thr Leu Gly Ala Val Gln Ile Met Asn Gly Leu Phe His Ile
50 55 60
Ala Leu Gly Gly Leu Leu Met Ile Pro Ala Gly Ile Tyr Ala Pro Ile
65 70 75 80
Cys Val Thr Val Trp Tyr Pro Leu Trp Gly Gly Ile Met Tyr Ile Ile
85 90 95
Ser Gly Ser Leu Leu Ala Ala Thr Glu Lys Asn Ser Arg Lys Cys Leu
100 105 110
Val Lys Gly Lys Met Ile Met Asn Ser Leu Ser Leu Phe Ala Ala Ile
115 120 125
Ser Gly Met Ile Leu Ser Ile Met Asp Ile Leu Asn Ile Lys Ile Ser
130 135 140
His Phe Leu Lys Met Glu Ser Leu Asn Phe Ile Arg Ala His Thr Pro
145 150 155 160
Tyr Ile Asn Ile Tyr Asn Cys Glu Pro Ala Asn Pro Ser Glu Lys Asn
165 170 175
Ser Pro Ser Thr Gln Tyr Cys Tyr Ser Ile Gln Ser Leu Phe Leu Gly
180 185 190
Ile Leu Ser Val Met Leu Ile Phe Ala Phe Phe Gln Glu Leu Val Ile
195 200 205
Ala Gly Ile Val Glu Asn Glu Trp Lys Arg Thr Cys Ser Arg Pro Lys
210 215 220
Ser Asn Ile Val Leu Leu Ser Ala Glu Glu Lys Lys Glu Gln Thr Ile
225 230 235 240
Glu Ile Lys Glu Glu Val Val Gly Leu Thr Glu Thr Ser Ser Gln Pro
245 250 255
Lys Asn Glu Glu Asp Ile Glu Ile Ile Pro Ile Gln Glu Glu Glu Glu
260 265 270
Glu Glu Thr Glu Thr Asn Phe Pro Glu Pro Pro Gln Asp Gln Glu Ser
275 280 285
Ser Pro Ile Glu Asn Asp Ser Ser Pro
290 295
<210> 6
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 0039-LC1
<400> 6
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn
85 90 95
Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Arg
115 120 125
Lys 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> 7
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 0039-HC1
<400> 7
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 8
<211> 229
<212> PRT
<213> 人工序列
<220>
<223> 0039-LC2
<400> 8
Gln Ser Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Thr
1 5 10 15
Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Ala
20 25 30
Met Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Tyr Ile Trp Ser Gly Gly Ser Thr Asp Tyr Ala Ser Trp Ala Lys Ser
50 55 60
Arg Val Thr Ile Ser Lys Thr Ser Thr Thr Val Ser Leu Lys Leu Ser
65 70 75 80
Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Tyr
85 90 95
Gly Thr Ser Tyr Pro Asp Tyr Gly Asp Ala Ser Gly Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Val Ala Ala Pro
115 120 125
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
130 135 140
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
145 150 155 160
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
165 170 175
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
180 185 190
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
195 200 205
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
210 215 220
Asn Arg Gly Glu Cys
225
<210> 9
<211> 681
<212> PRT
<213> 人工序列
<220>
<223> 0039-HC2
<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 Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
465 470 475 480
Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser
485 490 495
Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
500 505 510
Leu Ile Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe
515 520 525
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
530 535 540
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Tyr Ala Ser
545 550 555 560
Ser Asn Val Asp Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
565 570 575
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
580 585 590
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
595 600 605
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
610 615 620
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
625 630 635 640
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
645 650 655
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
660 665 670
Asp Lys Lys Val Glu Pro Lys Ser Cys
675 680
<210> 10
<211> 695
<212> PRT
<213> 人工序列
<220>
<223> 0041-HC2
<400> 10
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Gln Ser Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser
465 470 475 480
Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser
485 490 495
Tyr Ala Met Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
500 505 510
Ile Gly Tyr Ile Trp Ser Gly Gly Ser Thr Asp Tyr Ala Ser Trp Ala
515 520 525
Lys Ser Arg Val Thr Ile Ser Lys Thr Ser Thr Thr Val Ser Leu Lys
530 535 540
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
545 550 555 560
Arg Tyr Gly Thr Ser Tyr Pro Asp Tyr Gly Asp Ala Ser Gly Phe Asp
565 570 575
Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Val Ala
580 585 590
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
595 600 605
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
610 615 620
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
625 630 635 640
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
645 650 655
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
660 665 670
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
675 680 685
Ser Phe Asn Arg Gly Glu Cys
690 695
<210> 11
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 0040-LC1
<400> 11
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn
85 90 95
Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val 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> 12
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 0040-HC1
<400> 12
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 13
<211> 695
<212> PRT
<213> 人工序列
<220>
<223> 0040-HC2
<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 Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Gln Ser Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser
465 470 475 480
Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser
485 490 495
Tyr Ala Met Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp
500 505 510
Ile Gly Tyr Ile Trp Ser Gly Gly Ser Thr Asp Tyr Ala Ser Trp Ala
515 520 525
Lys Ser Arg Val Thr Ile Ser Lys Thr Ser Thr Thr Val Ser Leu Lys
530 535 540
Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
545 550 555 560
Arg Tyr Gly Thr Ser Tyr Pro Asp Tyr Gly Asp Ala Ser Gly Phe Asp
565 570 575
Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Val Ala
580 585 590
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
595 600 605
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
610 615 620
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
625 630 635 640
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
645 650 655
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
660 665 670
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
675 680 685
Ser Phe Asn Arg Gly Glu Cys
690 695
<210> 14
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 0042-LC1
<400> 14
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn
85 90 95
Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Arg
115 120 125
Lys 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> 15
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 0042-HC1
<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 Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser
355 360 365
Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 16
<211> 229
<212> PRT
<213> 人工序列
<220>
<223> 0042-LC2
<400> 16
Gln Ser Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Thr
1 5 10 15
Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Ala
20 25 30
Met Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Tyr Ile Trp Ser Gly Gly Ser Thr Asp Tyr Ala Ser Trp Ala Lys Ser
50 55 60
Arg Val Thr Ile Ser Lys Thr Ser Thr Thr Val Ser Leu Lys Leu Ser
65 70 75 80
Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Tyr
85 90 95
Gly Thr Ser Tyr Pro Asp Tyr Gly Asp Ala Ser Gly Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Val Ala Ala Pro
115 120 125
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
130 135 140
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
145 150 155 160
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
165 170 175
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
180 185 190
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
195 200 205
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
210 215 220
Asn Arg Gly Glu Cys
225
<210> 17
<211> 674
<212> PRT
<213> 人工序列
<220>
<223> 0042-HC2
<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 Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Gly
210 215 220
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ile Gln Leu Thr Gln Ser
225 230 235 240
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
245 250 255
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys
260 265 270
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Arg Ala Ser Thr Leu Ala
275 280 285
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
290 295 300
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
305 310 315 320
Cys Gln Gln Asn Tyr Ala Ser Ser Asn Val Asp Asn Thr Phe Gly Gly
325 330 335
Gly Thr Lys Val Glu Ile Lys Ser Ser Ala Ser Thr Lys Gly Pro Ser
340 345 350
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
355 360 365
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
370 375 380
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
385 390 395 400
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
405 410 415
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
420 425 430
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
435 440 445
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
450 455 460
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
465 470 475 480
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
485 490 495
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
500 505 510
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
515 520 525
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
530 535 540
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile
545 550 555 560
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
565 570 575
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
580 585 590
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
595 600 605
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
610 615 620
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
625 630 635 640
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
645 650 655
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
660 665 670
Pro Gly
<210> 18
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 抗CD20抗体VH
<400> 18
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 19
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 抗CD20抗体VL
<400> 19
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn
85 90 95
Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 20
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 299-023 VH人源化变体_DASG
<400> 20
Gln Ser Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Thr
1 5 10 15
Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Ala
20 25 30
Met Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly
35 40 45
Tyr Ile Trp Ser Gly Gly Ser Thr Asp Tyr Ala Ser Trp Ala Lys Ser
50 55 60
Arg Val Thr Ile Ser Lys Thr Ser Thr Thr Val Ser Leu Lys Leu Ser
65 70 75 80
Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Tyr
85 90 95
Gly Thr Ser Tyr Pro Asp Tyr Gly Asp Ala Ser Gly Phe Asp Pro Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 21
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 299-009 VL人源化变体_NYA
<400> 21
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Tyr Ala Ser Ser Asn
85 90 95
Val Asp Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 22
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 0040-LC2
<400> 22
Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asn Tyr Ala Ser Ser Asn
85 90 95
Val Asp Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Ser
100 105 110
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
115 120 125
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
130 135 140
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
145 150 155 160
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
165 170 175
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
180 185 190
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
195 200 205
Lys Val Glu Pro Lys Ser Cys
210 215
Claims (2)
1.一种生产双特异性抗体的方法,包括以下步骤:
a)培养包含编码该双特异性抗体的一个或多个核酸的细胞,使得双特异性抗体产生,和
b)从细胞或培养基回收该双特异性抗体,由此产生该双特异性抗体,
其中所述双特异性抗体特异性结合人CD20和人转铁蛋白受体,并包含:
-包含两个抗体轻链和抗体重链对的一个全长抗体,其中每对为一个抗体轻链和一个抗体重链,其中由每对重链和轻链形成的结合位点特异性地结合人CD20,和
-一个另外的Fab片段,其中另外的Fab片段的结合位点特异性地结合人转铁蛋白受体,
所述双特异性抗体包含
-SEQ ID NO:06至09,或
-SEQ ID NO:01至04,或
-SEQ ID NO:01至03和SEQ ID NO:10,或
-SEQ ID NO:11至13和SEQ ID NO:22,或
-SEQ ID NO:14至17。
2.根据权利要求1的方法,其中所述双特异性抗体是单克隆抗体。
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