CN114478771B - Ox40抗体及其医药用途 - Google Patents
Ox40抗体及其医药用途 Download PDFInfo
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- CN114478771B CN114478771B CN202111525230.6A CN202111525230A CN114478771B CN 114478771 B CN114478771 B CN 114478771B CN 202111525230 A CN202111525230 A CN 202111525230A CN 114478771 B CN114478771 B CN 114478771B
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Abstract
本发明涉及免疫治疗和分子免疫学技术领域,具体而言,涉及一种OX40抗体及其医药用途。本发明提供了对OX40具有高亲和力、能阻断OX40/OX40L相互作用及其信号传导的特异性抗体或其抗原结合片段。
Description
技术领域
本发明涉及免疫治疗和分子免疫学技术领域,具体而言,涉及一种OX40抗体及其医药用途。
背景技术
OX40(也称为CD134、ACT35或TNFRSF4)属于TNFR超家族成员,是一个分子量为50kD的膜糖蛋白,由细胞质尾区、跨膜区和胞外区组成。OX40在非活化的初始T细胞中基本无表达,但在活化T细胞中高表达(Paterson,et al.,(1987),Mol.Immunol.24:1281–90;Mallett,et al.,(1990),EMBO J.9:1063–8;Calderhead,et al.,(1993),J.Immunol.151:5261–71)。OX40配体(OX40L)是一种34kD的II型膜蛋白,以三聚体的形式表达于抗原提呈细胞(Stuber,et al.,(1995),Immunity 2:507–21;Ohshima,et al.,(1997),J.Immunol.159:3838–48;Al-Shamkhani,et al.,(1997),J.Biol.Chem.272:5275-5282)。OX40基因敲除小鼠经抗原刺激后,其CD4和CD8 T细胞增殖减少,并产生缺陷型免疫记忆反应,表明内源性OX40在T细胞免疫调节中发挥重要作用(Kopf,et al.,(1999),Immunity11:699–708;Redmond,etal.,(2009),Crit.Rev.Immunol.29:187–201;Croft,et al.,(2010),Annu.Rev.Immunol.28:57–78)。
OX40是T细胞增殖和生存所必需的,缺失OX40的T细胞在***时和***后均不能有效存活,这与抗凋亡Bcl-2家族成员表达水平下降相关(Rogers,et al.,(2001),Immunity15:445-455;Gramaglia,et al.,(2000),J.Immunol.165:3043-3050)。利用天然配体(OX40L)或激活性抗体,结合T细胞表面的OX40受体,可以激活多个信号通路,包括转录因子Nuclear factor kappa-light-chain-enhancer of activated B(NF-kB)及活化T细胞转录因子(NFAT)通路,从而增强多个蛋白分子的表达,如存活蛋白、细胞周期蛋白A、周期蛋白依赖性激酶、Bcl-2抗凋亡分子等,并在抗原刺激后增加多种效应T细胞亚群的存活率和细胞增殖(Rogers,et al.,(2001),Immunity.15:445-455;Song,et al,(2005),Immunity.22:621-31;Sun,et al.,(2018),Cell Death&Disease 9:616-628;Croft,etal.,(2010),Annu.Rev.Immunol.28:57-78)。OX40L-OX40信号传递可以调节T细胞、抗原提呈细胞和NKT细胞的细胞因子分泌,并调节细胞因子受体传导通路的信号转导(Gramaglia,et al.,(1998),J.Immunol.161:6510–17;Diana,et al.,(2009),Immunity.30:289-99;Ohshima,et al.,(1997),J.Immunol.159:3838–48)。OX40主要在活化的CD4+T细胞及某些活化的CD8+T细胞中表达(Salek-Ardakani S etc.(2006)Curr.Immunol.Rev.2:37-53),并在一些慢性炎症及自体免疫疾病的记忆T细胞中有高水平表达,而它的配体(OX40L)也在提呈细胞中随着细胞的活化而表达。
近些年来,多种激活性OX40抗体已进入用于癌症免疫治疗的临床试验,而OX40的抑制性抗体也在多种自身免疫性疾病的动物模型中被证明具有保护作用,例如哮喘、肠易激性疾病、移植排斥、自身免疫性糖尿病、移植物抗宿主病(GvHD)、实验性自身免疫性脑脊髓炎以及特应性皮炎(AD)等。其中,特应性皮炎是一种慢性、复发性炎症性皮肤病,其特征是强烈的瘙痒(例如,瘙痒)和鳞状和干燥的湿疹病变,对患者的生活质量产生重大影响。目前,AD的治疗方法仍然有限,而阻断OX40/OX40L信号通路能够特异性地抑制诱发疾病的效应T细胞的功能,但不会引起广泛的免疫抑制。
发明内容
本发明的第一目的在于提供一种能够特异性识别OX40的抗体或其抗原结合片段,其包含重链互补决定区HCDR1、HCDR2和HCDR3,以及轻链互补决定区LCDR1、LCDR2和LCDR3,所述HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3的氨基酸序列选自a~f所示互补决定区组合中的一组:
组合名称 | HCDR1 | HCDR2 | HCDR3 | LCDR1 | LCDR2 | LCDR3 |
a | SEQ ID NO:13 | SEQ ID NO:14 | SEQ ID NO:15 | SEQ ID NO:16 | SEQ ID NO:17 | SEQ ID NO:18 |
b | SEQ ID NO:19 | SEQ ID NO:20 | SEQ ID NO:21 | SEQ ID NO:22 | SEQ ID NO:23 | SEQ ID NO:24 |
c | SEQ ID NO:25 | SEQ ID NO:26 | SEQ ID NO:27 | SEQ ID NO:28 | SEQ ID NO:29 | SEQ ID NO:30 |
d | SEQ ID NO:31 | SEQ ID NO:32 | SEQ ID NO:33 | SEQ ID NO:34 | SEQ ID NO:35 | SEQ ID NO:36 |
e | SEQ ID NO:37 | SEQ ID NO:38 | SEQ ID NO:39 | SEQ ID NO:40 | SEQ ID NO:41 | SEQ ID NO:42 |
f | SEQ ID NO:43 | SEQ ID NO:44 | SEQ ID NO:45 | SEQ ID NO:46 | SEQ ID NO:47 | SEQ ID NO:48 |
。
本发明的第二目的在于提供一种分离的核酸,其编码如上所述的抗体或其抗原结合片段。
本发明的第三目的在于提供一种载体,其包含如上所述的核酸。
本发明的第四目的在于提供一种宿主细胞,其如上所述的核酸或载体。
本发明的第五目的在于提供一种生产抗体或其抗原结合片段的方法,包括:
在合适的培养条件下培养如上所述的宿主细胞;以及
从培养基中或从所培养的细胞中回收如此产生的抗体或其抗原结合片段。
本发明的第六目的在于提供一种偶联物,包括如上所述的抗体或其抗原结合片段和偶联部分,所述偶联部分为选自放射性核素、药物、毒素、细胞因子、细胞因子受体片段、酶、荧光素和生物素中的一种或多种。
本发明的第七目的在于提供一种组合物或组合产品,其包含如上所述的抗体或其抗原结合片段中的一种或多种;和/或;如上所述的偶联物。
本发明的第八目的在于提供一种如上所述的抗体或其抗原结合片段和/或如上所述的偶联物在制备药物中的应用;所述药物用于***、哮喘、肠易激性疾病、移植排斥、自身免疫性糖尿病、移植物抗宿主病、实验性自身免疫性脑脊髓炎以及特应性皮炎中的一种或多种。
本发明提供了对OX40具有高亲和力、能阻断OX40/OX40L相互作用及其信号传导的特异性抗体或其抗原结合片段,其可应用于抑制和调节OX40的作用、水平以及显著抑制机体免疫炎性反应,并在开发用于治疗慢性炎症或自体免疫性疾病的相关药物方面具有广阔的应用前景。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施方式,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图,且下图中所给出的结论为本发明相应的特定实施例所提供方法的检测数据。
图1:用ELSIA测定OX40杂交瘤抗体与OX40-hFc蛋白结合的EC50;
图2:通过FACS测定OX40杂交瘤抗体与293T-OX40细胞结合的EC50;
图3:使用报告基因法测定OX40杂交瘤抗体阻断OX40L诱导信号激活的IC50;
图4:使用报告基因法测定OX40嵌合抗体阻断OX40L诱导的信号通路IC50;A:WT抗体;B:DE突变抗体;
图5:用FACS测定OX40嵌合抗体对MLR中CD4+T细胞增殖抑制作用;A:WT抗体;B:DE突变抗体;
图6:用FACS测定OX40嵌合抗体对CEF诱导的CD8+T细胞增殖抑制作用;A:WT抗体;B:DE突变抗体;
图7:用FACS测定OX40人源化抗体与293T-OX40细胞结合的EC50;
图8:用报告基因法测定OX40人源化抗体阻断OX40L诱导的信号通路IC50;
图9:用FACS测定OX40人源化抗体对MLR中CD4+T细胞增殖抑制作用;A:Donor1;B:Donor2;
图10:用FACS测定OX40人源化抗体对CEF诱导的CD8+T细胞增殖抑制作用;A:Donor1;B:Donor2;
图11:使用LDH法测定OX40人源化抗体引起的ADCC反应。
具体实施方式
现将详细地提供本发明实施方式的参考,其一个或多个实例描述于下文。提供每一实例作为解释而非限制本发明。实际上,对本领域技术人员而言,显而易见的是,可以对本发明进行多种修改和变化而不背离本发明的范围或精神。例如,作为一个实施方式的部分而说明或描述的特征可以用于另一实施方式中,来产生更进一步的实施方式。
除非另有说明,用于披露本发明的所有术语(包括技术和科学术语)的意义与本发明所属领域普通技术人员所通常理解的相同。通过进一步的指导,随后的定义用于更好地理解本发明的教导。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。
本文所使用的术语“和/或”、“或/和”、“及/或”的选择范围包括两个或两个以上相关所列项目中任一个项目,也包括相关所列项目的任意的和所有的组合,所述任意的和所有的组合包括任意的两个相关所列项目、任意的更多个相关所列项目、或者全部相关所列项目的组合。需要说明的是,当用至少两个选自“和/或”、“或/和”、“及/或”的连词组合连接至少三个项目时,应当理解,在本申请中,该技术方案毫无疑问地包括均用“逻辑与”连接的技术方案,还毫无疑问地包括均用“逻辑或”连接的技术方案。比如,“A及/或B”包括A、B和A+B三种并列方案。又比如,“A,及/或,B,及/或,C,及/或,D”的技术方案,包括A、B、C、D中任一项(也即均用“逻辑或”连接的技术方案),也包括A、B、C、D的任意的和所有的组合,也即包括A、B、C、D中任两项或任三项的组合,还包括A、B、C、D的四项组合(也即均用“逻辑与”连接的技术方案)。
本发明中所使用的术语“含有”、“包含”和“包括”是同义词,其是包容性或开放式的,不排除额外的、未被引述的成员、元素或方法步骤。
本发明中用端点表示的数值范围包括该范围内所包含的所有数值及分数,以及所引述的端点。
本发明中,涉及“多个”、“多种”等描述,如无特别限定,指在数量上指大于等于2。
本发明中,以开放式描述的技术特征中,包括所列举特征组成的封闭式技术方案,也包括包含所列举特征的开放式技术方案。
本发明中,“优选”、“更好”、“更佳”、“为宜”仅为描述效果更好的实施方式或实施例,应当理解,并不构成对本发明保护范围的限制。本发明中,“可选地”、“可选的”、“可选”,指可有可无,也即指选自“有”或“无”两种并列方案中的任一种。如果一个技术方案中出现多处“可选”,如无特别说明,且无矛盾之处或相互制约关系,则每项“可选”各自独立。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。除非和本申请的发明目的和/或技术方案相冲突,否则,本发明涉及的引用文献以全部内容、全部目的被引用。本发明中涉及引用文献时,相关技术特征、术语、名词、短语等在引用文献中的定义也一并被引用。本发明中涉及引用文献时,被引用的相关技术特征的举例、优选方式也可作为参考纳入本申请中,但以能够实施本发明为限。应当理解,当引用内容与本申请中的描述相冲突时,以本申请为准或者适应性地根据本申请的描述进行修正。
本发明涉及能够特异性识别OX40的抗体或其抗原结合片段,其包含重链互补决定区HCDR1、HCDR2和HCDR3,以及轻链互补决定区LCDR1、LCDR2和LCDR3,所述HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3的氨基酸序列选自a~f所示互补决定区组合中的一组:
组合名称 | HCDR1 | HCDR2 | HCDR3 | LCDR1 | LCDR2 | LCDR3 |
a | SEQ ID NO:13 | SEQ ID NO:14 | SEQ ID NO:15 | SEQ ID NO:16 | SEQ ID NO:17 | SEQ ID NO:18 |
b | SEQ ID NO:19 | SEQ ID NO:20 | SEQ ID NO:21 | SEQ ID NO:22 | SEQ ID NO:23 | SEQ ID NO:24 |
c | SEQ ID NO:25 | SEQ ID NO:26 | SEQ ID NO:27 | SEQ ID NO:28 | SEQ ID NO:29 | SEQ ID NO:30 |
d | SEQ ID NO:31 | SEQ ID NO:32 | SEQ ID NO:33 | SEQ ID NO:34 | SEQ ID NO:35 | SEQ ID NO:36 |
e | SEQ ID NO:37 | SEQ ID NO:38 | SEQ ID NO:39 | SEQ ID NO:40 | SEQ ID NO:41 | SEQ ID NO:42 |
f | SEQ ID NO:43 | SEQ ID NO:44 | SEQ ID NO:45 | SEQ ID NO:46 | SEQ ID NO:47 | SEQ ID NO:48 |
。
在一些实施方式中,所述的抗体或其抗原结合片段包含可变区,所述可变区的重链可变区(HCVR)和轻链可变区(LCVR)的序列具有选自A~F所示可变区序列组合中的一组:
在一些实施方式中,所述互补决定区组合选自b、c、d所示互补决定区组合中的一组,且所述的抗体或其抗原结合片段具有人源化可变区。
术语“人源化可变区”,也称为CDR移植抗体(CDR-grafted antibody)的可变区,是指将第一动物源性的CDR序列移植到人的抗体可变区框架,即不同类型的人种系抗体构架序列中产生的抗体。可以克服嵌合抗体由于携带大量鼠蛋白成分,从而诱导的异源性反应。此类构架序列可以从包括种系抗体基因序列的公共DNA数据库或公开的参考文献获得。如人重链和轻链可变区基因的种系DNA序列可以在“VBase”人种系序列数据库(www.mrccpe.com.ac.uk/vbase)获得,以及在Kabat,E.A.等人,1991,Sequences of Proteins of ImmunologicalInterest,第5版中找到。为避免免疫原性下降的同时,引起的活性下降,可对所述的人抗体可变区框架序列进行最少反向突变或回复突变,以保持活性。本发明的人源化抗体也包括进一步由噬菌体展示对CDR进行亲和力成熟后的人源化抗体。
在一些实施方式中,b、c、d所示互补决定区组合所对应的人源化的重链可变区(HCVR)和轻链可变区(LCVR)组合依次为B'、C'、D'所示:
组合名称 | HCVR | LCVR |
B' | SEQ ID NO:49 | SEQ ID NO:50 |
C' | SEQ ID NO:51 | SEQ ID NO:52 |
D' | SEQ ID NO:53 | SEQ ID NO:54 |
。
抗体或其抗原结合片段的变体也在本发明范围内,本发明的抗体或其抗原结合片段包含重链互补决定区HCDR1、HCDR2和HCDR3,以及轻链互补决定区LCDR1、LCDR2和LCDR3,其中所述HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3的序列与a~f所示互补决定区组合中的任一组相比,分别包含至多3个氨基酸的突变(例如1个、2个或3个氨基酸的置换、缺失或添加或其任意组合);优选地,所述突变为保守突变。在一些实施方式中,所述抗体或其抗原结合片段的HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3的序列与a~f所示互补决定区组合中的任一组相比,分别包含至多3个氨基酸的置换(例如1个、2个或3个氨基酸置换)。
在一些实施方式中,本发明的抗体或其抗原结合片段包含可变区,所述可变区的氨基酸序列包含与SEQ ID NO:1~12、49~54所示序列中任意一个或多个具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列。在一些实施方式中,所述抗体或其抗原结合片段包含HCVR和LCVR,所述HCVR的氨基酸序列包含与SEQID NO:1、3、5、7、9、11、49、51、53所示序列中任意一个具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列,和/或所述LCVR的氨基酸序列包含与SEQ ID NO:2、4、6、8、10、12、50、52、54所示序列中任意一个具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列。
在一些情况下,变体是在本发明所提供的抗体序列上发生保守突变(例如保守置换或修饰)所得到的。“保守突变”是指可正常维持蛋白质的功能的突变,优选为保守置换。“保守置换”是指具有类似特征(例如电荷、侧链大小、疏水性/亲水性、主链构象和刚性等)的其它氨基酸置换蛋白中的氨基酸,使得可频繁进行改变而不改变蛋白的生物学活性。
通常视为保守置换的置换是在脂肪族氨基酸Ala、Val、Leu和Ile中的彼此置换、羟基残基Ser和Thr的互换、酸性残基Asp和Glu的交换、酰胺残基Asn和Gln之间的置换、碱性残基Lys和Arg的交换以及芳香残基Phe、Tyr间的置换。本领域技术人员知晓,一般而言,多肽的非必需区域中的单个氨基酸置换基本上不改变生物学活性(参见例如Watson等(1987)Molecular Biology of the Gene,The Benjamin/Cummings Pub.Co.,第224页,(第4版))。另外,结构或功能类似的氨基酸的置换不大可能破环生物学活性。
修饰可以为通过天然过程(诸如加工和其他翻译后修饰),或通过化学修饰技术所得到衍生物,例如通过添加一个或多个聚乙二醇分子、糖、磷酸酯和/或其他这样的分子来进行化学修饰,其中一个或多个分子不是天然地附着到蛋白质。衍生物包括盐。这样的化学修饰在基础教科书和更详细的专论中以及在大量研究文献中有详细描述,并且它们是本领域技术人员熟知的。应当理解,相同类型的修饰可以以相同或不同程度存在于给定抗体或其抗原结合片段中的几个位点。此外,给定的抗体或其抗原结合片段可以含有许多类型的修饰。修饰可发生在抗体或其抗原结合片段中的任何位置,包括肽骨架,氨基酸侧链以及氨基或羧基末端。修饰包括例如乙酰化、酰化、ADP-核糖基化、酰胺化、共价连接黄素、共价连接血红素部分、共价连接核苷酸或核苷酸衍生物、共价连接脂质或脂质衍生物、共价连接磷脂酰肌醇、交联、环化、形成二硫键、脱甲基化、形成共价交联、形成半胱氨酸、形成焦谷氨酸、甲基化、γ-羧化、糖基化、形成GPI锚接、羟基化、碘化、甲基化、肉豆蔻酰化、氧化、蛋白质酶解加工、磷酸化、异戊二烯化、外消旋化、糖基化、脂质连接、硫酸化、谷氨酸残基的γ-羧化、烃基化和ADP-核糖基化、硒化、硫酸化、蛋白质的氨基酸的传递RNA介导加成(诸如精氨酰化)以及泛素化。它们还可以结合至维生素,例如生物素、叶酸或维生素B12。参见例如Proteins--Structure And Molecular Properties,2nd Ed.,T.E.Creighton,W.H.Freeman and Company,New York(1993)和Wold,F.,“Posttranslational ProteinModifications:Perspectives and Prospects,”pgs.1-12in PosttranslationalCovalent Modification Of Proteins,B.C.Johnson,Ed.,Academic Press,New York(1983);Seifter等人.,MetH.Enzymol.182:626-646(1990)和Rattan等人,“ProteinSynthesis:Posttranslational Modifications and Aging,”Ann.N.Y.Acad.Sci.663:48-621992)。
变体保留特异性结合OX40的能力。所属领域技术人员将能够使用熟知的技术确定如本文所阐明的抗原结合分子的合适变体。在某些实施方案中,所属领域技术人员可鉴别抗体或其抗原结合片段中对于特异性结合OX40的活性而言不重要的区来改变而不破坏活性的合适区域。
在本发明中,“抗体”此技术术语是结合特定抗原的蛋白,其泛指包含CDR区的一切蛋白及蛋白片段,特别是全长抗体。“全长抗体”此用语包括多克隆抗体及单克隆抗体,术语“抗原结合片段”是包含抗体CDR的一部分或全部的物质,其缺乏至少一些存在于全长链中的氨基酸但仍能够特异性结合至抗原。此类片段具生物活性,因为其结合至靶抗原,且可与其他抗原结合分子(包括完整抗体)竞争结合至给定表位。在一些实施方式中,能够特异性识别OX40的抗体或其抗原结合片段,或其变体,具有阻断OX40与其受体OX40L结合功能。在一个方面中,此类片段将包含单个重链和单个轻链,或其部分。所述片段可通过重组核酸技术产生,或可通过抗原结合分子(包括完整抗体)的酶裂解或化学裂解产生。
术语“互补性决定区”或“CDR”是指免疫球蛋白的重链和轻链的高度可变区,在本发明中采用Kabat等人所定义(Kabat等人,Sequences of proteins of immunologicalinterest,5th Ed"USDepartment of Health and Human Services,NIH,1991,和后来的版本)。有三个重链CDR(HCDR)和三个轻链CDR(LCDR)。此处,取决于情况,术语“CDR”和“CDRs”用于指包含一种或多种或者甚至全部的对抗体与其识别的抗原或表位的结合亲和力起作用的主要氨基酸残基的区域。
“抗原结合片段”此用语包括这些抗体的抗原化合物结合片段,包括Fab、F(ab')2、Fd、Fv、scFv、抗体最小识别单位,以及这些抗体和片段的单链衍生物,例如scFv-Fc等,优选地为F(ab')2、Fab、scFv。
术语“特异性结合”和“特异性地结合”是指抗体对预先确定的抗原上的表位的结合。通常,抗体以大约小于10-7M,例如大约小于10-8M、10-9M、10-10M、10-11M、10-12M或更强的亲和力(KD)结合。
在一些实施方式中,所述抗体或其抗原结合片段还包含抗体恒定区序列。
在一些实施方式中,所述抗体具有恒定区,重链恒定区序列选自IgG、IgA、IgM、IgE、IgD任意一种的恒定区序列。
在一些实施方式中,轻链恒定区为κ或λ链。
在一些实施方式中,所述重链恒定区和/或所述轻链恒定区的种属来源选自大鼠、小鼠、兔、牛、马、猪、羊、狗、猫、骆驼、驴、鹿、貂、鸡、鸭、鹅或人。
在一些实施方式中,所述重链恒定区为人的IgG,进一步分成亚类,如IgG1、IgG2、IgG3或IgG4中任意一种。在一些实施方式中,IgG1的Ser239、Ala330和Ile332分别突变为Asp、Leu和Glu。
本发明还涉及核酸,其编码如上所述的抗体或其抗原结合片段。
在本文中,核酸包含其保守置换的变体(例如简并密码子的置换)和互补序列,亦包括通过密码子优化以在期望的宿主细胞中更高效表达的变体。核酸通常是RNA或DNA,包含基因、cDNA分子、mRNA分子以及它们的片段例如寡核苷酸。核酸分子可以是单链或双链的,但优选是双链DNA。当将核酸与另一个核酸序列置于功能关系中时,核酸是“有效连接的”。例如,如果启动子或增强子影响编码序列的转录,那么启动子或增强子有效地连接至所述编码序列。当其连入载体时优选采用DNA核酸。
此外,鉴于抗体为膜蛋白,所以核酸通常带有信号肽序列。
本发明还涉及载体,其包含如上所述的核酸。
术语“载体(vector)”是指,可将多聚核苷酸***其中的一种核酸运载工具。当载体能使***的多核苷酸编码的蛋白获得表达时,载体称为表达载体。载体可以通过转化,转导或者转染导入宿主细胞,使其携带的遗传物质元件在宿主细胞中获得表达。载体是本领域技术人员公知的,包括但不限于:质粒;噬菌粒;柯斯质粒;人工染色体,例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。可用作载体的动物病毒包括但不限于,逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、***瘤病毒、***多瘤空泡病毒(如SV40)。在一些实施方式中,本发明所述载体中包含基因工程中常用的调控元件,例如增强子、启动子、内部核糖体进入位点(IRES)和其他表达控制元件(例如转录终止信号,或者多腺苷酸化信号和多聚U序列等)。
在本发明中,载体可以为组合物,例如为多种质粒的混合物,不同质粒负载抗体或其抗原结合片段的一部分。
本发明还提供宿主细胞,其包含如上所述的核酸或如上所述的载体。
适用于表达本发明的抗原结合蛋白的宿主细胞或细胞系包括:哺乳动物细胞诸如NS0、Sp2/0、CHO、COS、HEK、成纤维细胞和骨髓瘤细胞。可以使用人细胞,因而允许分子用人糖基化模式来修饰。或者,可以采用其他真核细胞系。合适的哺乳动物宿主细胞的选择,以及用于转化、培养、扩增、筛选和产物产生和纯化的方法,是本领域已知的。
可以证明,细菌细胞可用作宿主细胞,其适合表达本发明的重组Fab或其他实施方案。但是,由于在细菌细胞中表达的蛋白倾向于未折叠的形式或不正确地折叠的形式或非糖基化形式,必须筛选在细菌细胞中产生的任何重组Fab,以保留抗原结合能力。如果细菌细胞表达的分子以适当地折叠的形式产生,该细菌细胞将是期望的宿主,或者,在可替代的实施方案中,可以在细菌宿主中表达分子,随后进行重新折叠。例如,用于表达的各种大肠杆菌菌株,是生物技术领域中众所周知的宿主细胞。枯草芽孢杆菌、链霉菌属、其他芽孢杆菌属等的各种菌株,也可以用于该方法中。
如果需要,本领域技术人员已知的酵母细胞菌株以及昆虫细胞,例如果蝇和鳞翅目昆虫和病毒表达***,也可用作宿主细胞。
在一些实施方式中,所述细胞基因组中***有所述核酸,并且能稳定表达。
***的方式可选用如上所述的载体,或者核酸不连入载体直接转入细胞内(例如脂质体介导的转染技术)。
本发明还涉及一种生产抗体或其抗原结合片段的方法,包括:
在合适的培养条件下培养如上所述的宿主细胞;以及
从培养基中或从所培养的细胞中回收如此产生的抗体或其抗原结合片段。
本发明培养方法通常是无血清培养方法,通常通过无血清悬浮培养细胞。同样地,一旦产生本发明抗体,可将其根据本领域标准程序从细胞培养内容物纯化出,所述标准程序包括硫酸铵沉淀、亲和柱、柱层析、凝胶电泳等。这类技术在本领域技术范围内,不限定本发明。表达抗体的另一种方法可以利用在动物(特别是转基因动物或者裸鼠)中的表达。这涉及利用动物酪蛋白启动子的表达***,当其被转基因地并入哺乳动物中时,允许雌性动物在其奶中产生希望的重组蛋白。分泌了抗体的培养液可以用常规技术纯化。比如,用含调整过的缓冲液的A或G Sepharose FF柱进行纯化。洗去非特异性结合的组分。再用pH梯度法洗脱结合的抗体,用SDS-PAGE检测抗体片段,收集。抗体可用常规方法进行过滤浓缩。可溶的混合物和多聚体,也可以用常规方法去除,比如分子筛、离子交换。得到的产物需立即冷冻,如-70℃,或者冻干。
本发明还提供偶联物,其包括如上所述的抗体或其抗原结合片段和偶联部分,所述偶联部分为选自放射性核素、药物、毒素、细胞因子、细胞因子受体片段、酶、荧光素和生物素中的一种或多种。
本发明还提供组合物或组合产品,其包含如上所述的抗体或其抗原结合片段中的一种或多种(特别地,a~f中的一种或多种,或A~F中的一种或多种,或B'、C'、D'中的一种或多种);和/或;如上所述的偶联物。
在一些实施方式中,所述的组合物还包含药学上可接受的赋形剂、稀释剂或载体中的一种或多种。
术语“药学上可接受的赋形剂、稀释剂或载体”是指在药理学和/或生理学上与受试者和活性成分相容的赋形剂、稀释剂或载体,其是本领域公知的,包括但不限于:pH调节剂,表面活性剂,佐剂,离子强度增强剂。例如,pH调节剂包括但不限于磷酸盐缓冲液;表面活性剂包括但不限于阳离子,阴离子或者非离子型表面活性剂,例如Tween-80;离子强度增强剂包括但不限于氯化钠。
根据本发明的再一方面,还涉及如上所述的抗体或其抗原结合片段;和/或;如上所述的偶联物在制备药物中的应用;所述药物用于***、哮喘、肠易激性疾病、移植排斥、自身免疫性糖尿病、移植物抗宿主病、实验性自身免疫性脑脊髓炎以及特应性皮炎中的一种或多种。
在一些实施方式中,所述肿瘤选自血液肿瘤、胰腺癌、膀胱癌、结肠直肠癌、乳腺癌、***癌、肾癌、肝细胞癌、肺癌、卵巢癌、***、胃癌、食管癌、头颈部癌、黑素瘤、神经内分泌癌、CNS癌、脑肿瘤、骨癌和软组织肉瘤。
下面将结合实施例对本发明的实施方案进行详细描述。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,优先参考本发明中给出的指引,还可以按照本领域的实验手册或常规条件,还可以参考本领域已知的其它实验方法,或者按照制造厂商所建议的条件。
下述的具体实施例中,涉及原料组分的量度参数,如无特别说明,可能存在称量精度范围内的细微偏差。涉及温度和时间参数,允许仪器测试精度或操作精度导致的可接受的偏差。
实施例1鼠源杂交瘤抗体的制备、筛选与亚克隆
(1)小鼠免疫和杂交瘤细胞融合。用人的OX40-ECD-mFc融合蛋白作为抗原,与等体积完全弗氏佐剂(Sigma,Cat No:F5581)充分乳化后,经皮下免疫6-8周龄Balb/c小鼠(购自昭衍(苏州)新药研究中心有限公司),抗原免疫量为20μg/只。随后每隔2周,用相同剂量的抗原与不完全弗氏佐剂(Sigma,Cat No:F5506)充分乳化后,经皮下免疫小鼠三次。免疫三次后测定小鼠血清效价,融合前3天经腹腔进行加强免疫。以PEG Hybri-Max(Sigma,CatNo:7181)作为融合剂,将小鼠脾脏细胞与SP2/0细胞按照4:1的比例混合。将融合后的细胞加入到96孔板中(1×105细胞/孔),每孔含有0.1mL 1×HAT培养基(Invitrogen,Cat No:21060-017)。在第3天加入0.1mL HT(Invitrogen,Cat No:11067-030)培养基,在第7天吸掉96孔板中的培养基,补加0.2mL新鲜的HT培养基。在第9天,收取上清液进行ELISA和FACS检测。
(2)与OX40-ECD结合抗体的ELISA筛选。用OX40-ECD-hFc包被96孔ELISA板(Corning,Cat No:9018),置4度过夜,用洗涤缓冲液(PBS+0.05%Tween20)洗涤3次后,加入封闭缓冲液(PBS+1%BSA(Sigma,Cat No:V90093))孵育1小时;洗涤96孔板3次;加入杂交瘤上清孵育1小时,洗涤3次;每孔加入100μL 1:10000倍稀释的羊抗鼠IgG二抗(Thermo,CatNo:31432),室温孵育1小时后洗涤3次;每孔加入100μL TMB(北京百奥赛博,Cat No:ES-002)显色3分钟,再加入100μL/孔的终止液(2N H2SO4)终止反应,用Tecan Spark酶标仪测定各样品的OD450信号。
(3)与OX40-ECD结合抗体的FACS筛选。取50μL在上述ELISA检测中呈阳性的杂交瘤上清与50μL 293T-OX40细胞混合(1×105细胞/孔)加入到U形底96孔板中孵育1小时,用FACS缓冲液(PBS+3%FCS)离心洗涤2次后加入1:400倍稀释的PE标记羊抗鼠二抗(Biolegend,CatNo:405307),孵育30分钟,经FACS缓冲液洗涤后,用BD C6流式细胞仪检测293T-OX40细胞的PE信号。
(4)采用报告基因(Gene Reporter)法检测杂交瘤抗体对OX40L激活OX40信号通路的抑制作用。取50μL在上述ELISA检测中呈阳性的杂交瘤上清或纯化的杂交瘤抗体与25μL的Jurkat-OX40细胞(4×104个/孔)混合,加至96孔半区平底板,再加入25μL浓度为1μg/ml的OX40L,混匀后置于37℃培养箱中孵育4小时。每孔加入25μL预热的Bright-Glo溶液(Promega,Cat.No.:E2620),室温避光静置3分钟,用酶标仪(Tecan Spark)测定各样品孔冷光(Luminescence)信号值。该实验中使用的Jurkat-OX40细胞整合了NF-κB-luciferase基因。
(5)杂交瘤的亚克隆。用有限稀释法,对有较强结合活性、能阻断OX40与OX40L结合的杂交瘤进行亚克隆,随后再采用ELISA和FACS分析杂交瘤抗体与OX40的结合力以及采用报告基因法检测筛选阻断OX40L/OX40信号通路的杂交瘤单克隆抗体。
实施例2拮抗性OX40单克隆杂交瘤抗体的测试
将阳性的单克隆杂交瘤细胞置于50mL无血清培养基中(Invitrogen,CatNo:12045-076)培养9天,离心收取上清液。用Protein A亲和层析纯化单克隆抗体。纯化后的抗体样品经超滤离心管(Millipore,Cat No:ACS500024)换液浓缩后,用BCA方法测定蛋白浓度,用鳌试剂(厦门鲎试剂生物科技股份有限公司)检测抗体样品的内毒素含量。
用ELISA和FACS检测纯化的抗体样品与OX40的结合及其阻断OX40与OX40L结合的活性,具体方法如实施例1中步骤(2)、(3)和(4)所述。对6个单克隆OX40杂交瘤抗体1G2、3G4、9G7、177G5、118A10、119H2进行了测试,实验结果见表1~表3和图1~图3。
表1.用ELSIA方法检测OX40杂交瘤抗体与OX40结合的EC50
1G2 | 3G4 | 9G7 | 177G5 | 118A10 | 119H2 | |
EC50(ng/mL) | 15.68 | 16.28 | 19.78 | 21.49 | 24.89 | 23.02 |
表2.用FACS方法检测OX40杂交瘤抗体结合293T-OX40细胞的EC50
1G2 | 3G4 | 9G7 | 177G5 | 118A10 | 119H2 | |
EC50(ng/mL) | 80.53 | 53.71 | 36.90 | 49.90 | 73.52 | 41.26 |
表3.报告基因测定OX40杂交瘤抗体阻断OX40L诱导信号激活的IC50
1G2 | 3G4 | 9G7 | 177G5 | 118A10 | 119H2 | |
IC50(ng/mL) | 117.3 | 36.06 | ~36.14 | 253.0 | 198.0 | 178.6 |
结果显表明,鼠源OX40杂交瘤抗体1G3、3G4、9G7、117G5、118A10、119H2对人OX40具有较强的结合活性,并能阻断人OX40与其配体的相互结合。
实施例3拮抗性OX40抗体可变区的基因克隆
本发明对6个单克隆杂交瘤抗体1G2、3G4、9G7、177G5、118A10、119H2进行了可变区的基因克隆和序列分析;具体的方法如下:用TRIzon(Cwbiotech,Cat No:CW0580)裂解OX40单克隆杂交瘤细胞株,提取杂交瘤细胞的总RNA。用HiFi Script cDNA合成试剂盒(Cwbiotech,Cat No:CW2569)将杂交瘤细胞的RNA反转录为cDNA。以cDNA为模板,用简并引物通过PCR方法(Kettleborough et al.(1993)Eur J Immunology 23:206-211;Strebe etal.(2010)Antibody Engineering 1:3-14)扩增抗体的重链和轻链的可变区基因。将PCR扩增产物连接到T/A载体后,转化DH5a感受态细胞,涂板并置37℃过夜培养。从培养板上挑取单克隆,扩大培养后抽提质粒,测定抗体的基因序列。根据抗体的基因序列,分析其CDR和骨架区。一些抗体的重链和轻链的可变区基因序列和氨基酸序列编号见下表4。
表4.抗体的重链和轻链的可变区氨基酸序列编号
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实施例4拮抗性OX40嵌合抗体ch1G2、ch3G4、ch9G7、ch177G5、ch118A10、ch119H2的制备及测试
将1G2、3G4、9G7、177G5、118A10、119H2杂交瘤抗体的鼠源Fc替换为人源Fc,构建以人源IgG1为基础的嵌合抗体,并将抗体恒定区Ser239,Ala330,Ile332分别突变为Asp,Leu和Glu(即DLE突变)。对这些抗体进行了各项测试,包括用报告基因测试OX40嵌合抗体对OX40L功能的阻断作用、用MLR反应测试OX40嵌合抗体对CD4+T细胞增殖的抑制作用及其对CEF诱导的CD8+记忆T细胞增殖的抑制作用。结果如图4、图5和图6所示(其中,GBR830为Glenmark的阳性对照抗体)。测试的方法如下:
(1)在报告基因中测试OX40嵌合抗体对OX40L功能的阻断作用:具体方法如实施例1中的步骤(4);结果如图4所示。
(2)在MLR反应中测试OX40嵌合抗体对CD4+T细胞增殖的抑制作用:复苏冻存的PBMC(购自上海澳能生物技术有限公司,妙顺(上海)生物科技有限公司),加至预热的RPMI1640完全培养基中,混匀,置离心机中1500rpm离心5分钟,加入含有丝裂霉素C(终浓度:50μg/mL)的完全培养基重悬细胞,置37℃,5% CO2培养箱中孵育2小时,用10倍体积的完全培养基清洗细胞3次,离心后用完全培养基重悬细胞后计数,备用。复苏另一个供体冻存的PBMC,加至预热的完全培养基中,混匀,置离心机中1500rpm离心5分钟,用CFSE细胞增殖染料标记后,加入预冷的完全培养基猝灭游离染料并清洗细胞3次,用完全培养基重悬PBMC并计数。在96孔板中加入100μL经CFSE标记的PBMC细胞(2×105/孔);在对应细胞孔中加入50μL经稀释的不同浓度的OX40抗体(终浓度:2μg/mL,4倍梯度稀释);同时在对应孔中加入50μL经丝裂霉素C处理过的PBMC细胞(6.5×104/孔),混匀细胞后,将96孔细胞培养板置于37℃,5%CO2培养箱中孵育7天,离心后收集细胞。用流式缓冲液(PBS+3%FCS)重悬细胞,加入荧光标记的抗人CD4抗体和细胞活性染料,4℃孵育1小时,用流式缓冲液清洗细胞两次,用流式细胞仪检测并分析***的CD4+T细胞(CD4+CFSElow/dim)占总效应CD4+T细胞(CD4+CFSE+)的比例,本发明中列举的OX40抗体在MLR实验中均能显著抑制效应CD4+T细胞的增殖,实验结果如图5所示。
(3)测试OX40嵌合抗体对CEF诱导的CD8+T细胞增殖的抑制作用:复苏冻存的PBMC(购自上海澳能生物技术有限公司,妙顺(上海)生物科技有限公司),加至预热的RPMI1640完全培养基中,混匀,置离心机中1500rpm离心5分钟,用CFSE细胞增殖染料标记后,加入预冷的完全培养基猝灭游离染料并清洗细胞3次,用完全培养基重悬PBMC并计数。在96孔板中加入100μL经CFSE标记的PBMC细胞(2×105/孔);在对应细胞孔中加入50μL经稀释的不同浓度的OX40抗体(终浓度:4μg/mL,4倍梯度稀释);同时在对应孔中加入50μL CEF peptide(终浓度:200ng/mL),混匀,将96孔细胞培养板置于37℃,5% CO2培养箱中孵育7天,离心后收集细胞。用流式缓冲液(PBS+3%FCS)重悬细胞,加入荧光标记的抗人CD8抗体和细胞活性染料,4℃孵育1小时,用流式缓冲液清洗细胞两次,用流式细胞仪检测并分析***的CD8+T细胞(CD8+CFSElow/dim)占总效应CD8+T细胞(CD8+CFSE+)的比例,本发明中列举的OX40抗体均可显著抑制CEF诱导的记忆性CD8+T细胞的增殖,实验结果如图6所示。
结果显示,OX40嵌合抗体能够阻断OX40/OX40信号通路,抑制CD4+T细胞增殖以及CEF诱导的CD8+记忆T细胞增殖。
实施例5拮抗性鼠源OX40抗体3G4、9G7和177G5的人源化
根据各嵌合抗体的活性,选择对3G4、9G7和177G5杂交瘤抗体进行人源化改造。
采用互补决定区嫁接法进行OX40抗体的人源化。首先,在IMGT数据库中分别搜寻与鼠源抗体的轻、重链可变区同源性最高的人胚系抗体(germline antibody)序列。3G4抗体轻链可变区人源化选取的胚系为IGKV1-33*01,重链可变区人源化选取IGHV1-3*01。9G7抗体轻链可变区人源化选取的胚系为IGKV4-1*01,重链可变区人源化选取IGHV3-48*01。177G5抗体轻链人源化选取IGKV1-39*01,重链人源化选取IGHV3-11*01。保留鼠源抗体的CDR区,将鼠源抗体的框架区(framework)序列用人胚系抗体的框架区序列置换。其次,建立鼠源抗体的结构模型,逐个对比人源抗体与相应鼠源抗体结构模型中的每个不同氨基酸位点,如果在框架区的某个位点采用人的氨基酸序列没有导致CDR区域空间结构的破坏或改变,则该位点使用人的氨基酸序列,否则在该位点使用对应的鼠源序列(即回复突变为鼠源序列)。根据结构模拟,将人源化抗体框架区的部分氨基酸回复突变为鼠源序列。
3G4抗体人源化重链的第28位Thr回复突变为Arg,第48位Met回复突变为Ile,第67位Val回复突变为Ala,第69位Ile回复突变为Leu,第71位Arg回复突变为Ser,第73位Thr回复突变为Lys,第93位Ala回复突变为Ser。9G7抗体人源化重链的第49位Ser回复突变为Ala。9G7抗体人源化轻链的第48位Ile回复突变为Val。177G5抗体人源化重链的第49位Ser回复突变为Ala,第79位Tyr回复突变为Asn。177G5抗体人源化轻链的第48位Ile回复突变为Val,第71位Phe回复突变为Tyr。
如表5所列,hu3G4人源化抗体重链和轻链的可变区氨基酸序列号分别为SEQ IDNO:49和SEQ ID NO:50。hu9G7人源化抗体重链和轻链的可变区氨基酸序列号分别为SEQ IDNO:51和SEQ ID NO:52。hu177G5人源化抗体重链和轻链的可变区氨基酸序列号分别为SEQID NO:53和SEQ ID NO:54。将3G4、9G7、177G5人源化抗体构建为IgG1亚型,并将恒定区Ser239,Ala330,Ile332分别突变为Asp,Leu和Glu。
表5.人源化OX40抗体的氨基酸序列编号
合成编码3G4、9G7、177G5人源化抗体轻链和重链的核酸序列,并***到表达载体pcDNA3.1。用抗体轻链和重链表达质粒各0.1mg共转染200毫升293细胞(细胞密度为1×106),在37℃振摇培养6天,离心收集上清液,用Protein A纯化人源化抗体,纯化后的人源化抗体用于活性检测。
实施例6-拮抗性人源化OX40抗体的活性检测
用FACS检测纯化的人源化抗体样品与OX40的结合,用报告基因法检测人源化抗体阻断OX40L/OX40信号通路的活性,具体方法参考实施例1;结果见表6、表7和图7、图8。检测了人源化抗体对原代T细胞的功能影响,包括用MLR反应测试OX40人源化抗体对CD4+T细胞增殖的抑制作用、测试OX40人源化抗体对CEF诱导的CD8+T细胞增殖的抑制作用。具体方法见实施例4;结果如图9、图10所示。
表6.用FACS方法检测人源化OX40抗体与293T-OX40细胞结合的EC50
hu3G4-DE | hu9G7-DE | hu177G5-DE | |
EC50(ng/mL) | 71,32 | 62.29 | 95.96 |
表7.用报告基因测定OX40人源化抗体阻断OX40L诱导OX40信号通路的IC50
hu3G4-DE | hu9G7-DE | hu177G5-DE | GBR830-DE | |
IC50(ng/mL) | 18.12 | 57.55 | 309.0 | 117.8 |
另外,本发明还对拮抗性人源化OX40抗体,检测了抗体依赖的细胞毒杀活性(ADCC,Antibody-Dependent Cellular Cytotoxicity)。拮抗性OX40抗体有可能通过ADCC活性杀伤炎症反应中OX40表达水平较高的T细胞,从而起到进一步抑制炎反应的作用。测试中,使用复苏冻存的PBMC(购自上海澳能生物技术有限公司,妙顺(上海)生物科技有限公司),加至预热的RPMI1640完全培养基中,混匀,置离心机中1500rpm离心5分钟,用完全培养基重悬细胞后,将细胞加入培养瓶并置37℃,5% CO2培养箱中孵育18小时,离心收集PBMC,重悬并计数。在96孔板中加入25μL靶细胞Jurkat-OX40(2×104/孔),在对应细胞孔中加入25μL经稀释的不同浓度的OX40抗体(终浓度:20μg/mL,5倍梯度稀释),混匀后,将96孔细胞培养板置37℃,5% CO2培养箱中孵育30分钟;在对应孔中加入50μL PBMC细胞(5×105/孔),同时设定好各细胞单独对照孔,混匀细胞后,将96孔细胞培养板置于培养箱中孵育4-6小时。离心并收集上清液,转移50μL上清液至新的96孔板,同时在每孔中加入50μL的LDH底物显色液,室温孵育20~30分钟,加入50μL终止显色液,用酶标仪检测OD490的读值。结果表明,本发明中列举的OX40抗体均具有显著的ADCC活性,能够诱导靶细胞死亡。表8和图11显示了拮抗性OX40人源化抗体对OX40阳性细胞具较强的ADCC活性。
表8.OX40人源化抗体的ADCC活性
hu3G4-DE | hu9G7-DE | hu177G5-DE | GBR830-DE | |
EC50(ng/mL) | 1.522 | 1.426 | 2.364 | 3.054 |
结果表明,人源化抗体hu3G4、hu9G7、hu177G5与OX40具有较高的结合活性,并能阻断OX40/OX40信号通路,特别是在原代T细胞功能测试中,具有比阳性对照抗体GBR830更显著的抑制CD4+T细胞增殖和CEF诱导的CD8+T细胞增值的作用,并对OX40阳性细胞具较强的ADCC活性。
上述实施例采用哺乳动物细胞表达***制备重组OX40作为抗原免疫小鼠,将小鼠脾脏细胞与骨髓瘤细胞融合获得杂交瘤细胞。通过对大量杂交瘤细胞的多次克隆及筛选后,得到一些单克隆杂交瘤细胞株。这些杂交瘤细胞能产生与OX40有特异性高亲和力的单克隆抗体,并且这些单克隆抗体能有效阻断OX40与OX40L的结合、抑制混合淋巴细胞包括记忆T细胞反应中IL-2和INF-γ等细胞因子的分泌、以及T细胞的增殖作用。通过RT-PCR克隆编码抗体轻链和重链可变区的基因,采用互补决定簇嫁接法构建人源化抗体。体外功能试验表明,这些人源化的OX40抗体能特异性高亲和力结合OX40蛋白、高效阻断OX40L与OX40结合、并能抑制T细胞分泌细胞因子如IL-2和INF-γ以及T细胞的增殖。以上实验结果表明,本发明所述的单克隆抗体或其抗原结合片段,或者包含本发明所述单克隆抗体或其抗原结合片段的偶联物在制备阻断OX40L与OX40结合的药物、解除OX40对机体免疫激活的药物、抑制炎性疾病中T淋巴细胞的药物、减少T淋巴细胞表达IL-2和INF-γ的药物、以及在预防和治疗或者辅助治疗慢性炎症或自体免疫疾病的药物方面具有良好的应用前景。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准,说明书及附图可以用于解释权利要求的内容。
SEQUENCE LISTING
<110> 英诺湖医药(杭州)有限公司
<120> OX40抗体及其医药用途
<160> 54
<170> PatentIn version 3.5
<210> 1
<211> 119
<212> PRT
<213> artificial sequence
<220>
<223> 1G2 重链可变区
<400> 1
Glu Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Arg Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Asn Thr Arg Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Tyr Tyr Gly Asp Tyr Val Tyr Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 2
<211> 109
<212> PRT
<213> artificial sequence
<220>
<223> 1G2 轻链可变区
<400> 2
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Asn Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ile Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala
100 105
<210> 3
<211> 120
<212> PRT
<213> artificial sequence
<220>
<223> 3G4 重链可变区
<400> 3
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Thr
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Arg Phe Thr Ser Tyr
20 25 30
Val Leu His Trp Val Arg Arg Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Val Asn Pro Phe Asn Asp Asn Thr Arg Tyr Asn Glu Lys Phe
50 55 60
Lys Ala Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Val Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Gly Leu Tyr Asp Tyr Ser Tyr Val Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 4
<211> 109
<212> PRT
<213> artificial sequence
<220>
<223> 3G4 轻链可变区
<400> 4
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Gly Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Arg Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Ile Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Lys Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Gly Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Asn Leu Asp Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Ser Gln Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala
100 105
<210> 5
<211> 119
<212> PRT
<213> artificial sequence
<220>
<223> 9G7 重链可变区
<400> 5
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Asn Gly Asp Ile Ser Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Arg Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Asp Asp Gly Tyr Ser Ala Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 6
<211> 115
<212> PRT
<213> artificial sequence
<220>
<223> 9G7 轻链可变区
<400> 6
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Met Ser Val Gly
1 5 10 15
Gln Lys Val Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln
85 90 95
His Tyr Tyr Thr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Ala
115
<210> 7
<211> 119
<212> PRT
<213> artificial sequence
<220>
<223> 177G5 重链可变区
<400> 7
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Phe
20 25 30
Tyr Met Tyr Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asp Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Ile Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Asn Leu Asn
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Asp Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Thr Thr Lys Asn Gly Asn His Ile Gly Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 8
<211> 109
<212> PRT
<213> artificial sequence
<220>
<223> 177G5 轻链可变区
<400> 8
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Val Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val
35 40 45
Tyr Ala Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His Phe Trp Gly Ile Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala
100 105
<210> 9
<211> 115
<212> PRT
<213> artificial sequence
<220>
<223> 118A10 重链可变区
<400> 9
Glu Val Lys Leu Asp Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Pro Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Trp Leu Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Asn Lys Pro Tyr His Tyr Glu Thr Phe Tyr Ser Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser
65 70 75 80
Val Tyr Leu Gln Met Asn Asp Leu Arg Gly Glu Asp Thr Gly Ile Tyr
85 90 95
Tyr Cys Thr Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser
115
<210> 10
<211> 113
<212> PRT
<213> artificial sequence
<220>
<223> 118A10 轻链可变区
<400> 10
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Thr Ile Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Thr Tyr Ser Tyr Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Arg Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Gly Ile Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Ala
<210> 11
<211> 115
<212> PRT
<213> artificial sequence
<220>
<223> 119H2 重链可变区
<400> 11
Glu Val Lys Leu Asp Ala Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Pro Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Gln Ile Arg Asn Lys Pro Tyr Asn Tyr Glu Thr Phe Tyr Ser Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser
65 70 75 80
Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Met Gly Ile Tyr
85 90 95
Tyr Cys Thr Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser
115
<210> 12
<211> 113
<212> PRT
<213> artificial sequence
<220>
<223> 119H2 轻链可变区
<400> 12
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser
20 25 30
Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp
85 90 95
Gly Ile Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Ala
<210> 13
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> 1G2 重链CDR1
<400> 13
Ser Tyr Val Met His
1 5
<210> 14
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 1G2 重链CDR2
<400> 14
Tyr Ile Asn Pro Tyr Asn Asp Asn Thr Arg Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 15
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 1G2 重链CDR3
<400> 15
Tyr Tyr Gly Asp Tyr Val Tyr Leu Asp Tyr
1 5 10
<210> 16
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 1G2 轻链CDR1
<400> 16
Arg Ala Ser Gln Asp Ile Asn Asn Tyr Leu Asn
1 5 10
<210> 17
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 1G2 轻链CDR2
<400> 17
Tyr Thr Ser Arg Leu His Ser
1 5
<210> 18
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 1G2 轻链CDR3
<400> 18
Gln Gln Gly Asn Thr Leu Pro Trp Thr
1 5
<210> 19
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> 3G4 重链CDR1
<400> 19
Ser Tyr Val Leu His
1 5
<210> 20
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 3G4 重链CDR2
<400> 20
Tyr Val Asn Pro Phe Asn Asp Asn Thr Arg Tyr Asn Glu Lys Phe Lys
1 5 10 15
Ala
<210> 21
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 3G4 重链CDR3
<400> 21
Gly Leu Tyr Asp Tyr Ser Tyr Val Met Asp Tyr
1 5 10
<210> 22
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 3G4 轻链CDR1
<400> 22
Gln Ala Ser Gln Asp Ile Arg Asn Tyr Leu Asn
1 5 10
<210> 23
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 3G4 轻链CDR2
<400> 23
His Thr Ser Lys Leu His Ser
1 5
<210> 24
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 3G4 轻链CDR3
<400> 24
Gln Gln Ser Gln Thr Leu Pro Tyr Thr
1 5
<210> 25
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> 9G7 重链CDR1
<400> 25
Asp Tyr Tyr Met Tyr
1 5
<210> 26
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 9G7 重链CDR2
<400> 26
Tyr Ile Ser Asn Gly Asp Ile Ser Thr Tyr Tyr Pro Asp Thr Val Lys
1 5 10 15
Gly
<210> 27
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 9G7 重链CDR3
<400> 27
Asp Asp Gly Tyr Ser Ala Trp Phe Ala Tyr
1 5 10
<210> 28
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 9G7 轻链CDR1
<400> 28
Lys Ser Ser Gln Ser Leu Leu Asn Ser Ser Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 29
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 9G7 轻链CDR2
<400> 29
Phe Ala Ser Thr Arg Glu Ser
1 5
<210> 30
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 9G7 轻链CDR3
<400> 30
Gln Gln His Tyr Tyr Thr Pro Phe Thr
1 5
<210> 31
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> 177G5 重链CDR1
<400> 31
Asp Phe Tyr Met Tyr
1 5
<210> 32
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> 177G5 重链CDR2
<400> 32
Thr Ile Ser Asp Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Ile Val Lys
1 5 10 15
Gly
<210> 33
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> 177G5 重链CDR3
<400> 33
Lys Asn Gly Asn His Ile Gly Phe Ala Tyr
1 5 10
<210> 34
<211> 11
<212> PRT
<213> artificial sequence
<220>
<223> 177G5 轻链CDR1
<400> 34
Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala
1 5 10
<210> 35
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 177G5 轻链CDR2
<400> 35
Ala Ala Thr Asn Leu Ala Asp
1 5
<210> 36
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 177G5 轻链CDR3
<400> 36
Gln His Phe Trp Gly Ile Pro Trp Thr
1 5
<210> 37
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> 118A10 重链CDR1
<400> 37
Asp Tyr Trp Leu Asn
1 5
<210> 38
<211> 19
<212> PRT
<213> artificial sequence
<220>
<223> 118A10 重链CDR2
<400> 38
Gln Ile Arg Asn Lys Pro Tyr His Tyr Glu Thr Phe Tyr Ser Glu Ser
1 5 10 15
Val Lys Gly
<210> 39
<211> 4
<212> PRT
<213> artificial sequence
<220>
<223> 118A10 重链CDR3
<400> 39
Tyr Phe Asp Tyr
1
<210> 40
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> 118A10 轻链CDR1
<400> 40
Arg Ala Ser Gln Ser Val Ser Thr Ser Thr Tyr Ser Tyr Ile His
1 5 10 15
<210> 41
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 118A10 轻链CDR2
<400> 41
Tyr Ala Ser Asn Leu Glu Ser
1 5
<210> 42
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 118A10 轻链CDR3
<400> 42
Gln His Ser Trp Gly Ile Pro Pro Thr
1 5
<210> 43
<211> 5
<212> PRT
<213> artificial sequence
<220>
<223> 119H2 重链CDR1
<400> 43
Asp Tyr Trp Met Asn
1 5
<210> 44
<211> 19
<212> PRT
<213> artificial sequence
<220>
<223> 119H2 重链CDR2
<400> 44
Gln Ile Arg Asn Lys Pro Tyr Asn Tyr Glu Thr Phe Tyr Ser Asp Ser
1 5 10 15
Val Lys Gly
<210> 45
<211> 4
<212> PRT
<213> artificial sequence
<220>
<223> 119H2 重链CDR3
<400> 45
Tyr Phe Asp Tyr
1
<210> 46
<211> 15
<212> PRT
<213> artificial sequence
<220>
<223> 119H2 轻链CDR1
<400> 46
Arg Ala Ser Gln Ser Val Ser Thr Ser Ser Tyr Ser Tyr Met His
1 5 10 15
<210> 47
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> 119H2 轻链CDR2
<400> 47
Tyr Ala Ser Asn Leu Glu Ser
1 5
<210> 48
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> 119H2 轻链CDR3
<400> 48
Gln His Ser Trp Gly Ile Pro Pro Thr
1 5
<210> 49
<211> 120
<212> PRT
<213> artificial sequence
<220>
<223> hu3G4 人源化重链
<400> 49
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Arg Phe Thr Ser Tyr
20 25 30
Val Leu His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Tyr Val Asn Pro Phe Asn Asp Asn Thr Arg Tyr Asn Glu Lys Phe
50 55 60
Lys Ala Arg Ala Thr Leu Thr Ser Asp Lys Ser Ala 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
Ser Arg Gly Leu Tyr Asp Tyr Ser Tyr Val Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 50
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> hu3G4 人源化轻链
<400> 50
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Arg Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Lys Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 51
<211> 119
<212> PRT
<213> artificial sequence
<220>
<223> hu9G7 人源化重链
<400> 51
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Asn Gly Asp Ile Ser Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Asp Gly Tyr Ser Ala Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 52
<211> 113
<212> PRT
<213> artificial sequence
<220>
<223> hu9G7 人源化轻链
<400> 52
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
His Tyr Tyr Thr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 53
<211> 119
<212> PRT
<213> artificial sequence
<220>
<223> hu177G5 人源化重链
<400> 53
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Phe
20 25 30
Tyr Met Tyr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Asp Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Ile Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Asn
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Lys Asn Gly Asn His Ile Gly Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 54
<211> 107
<212> PRT
<213> artificial sequence
<220>
<223> hu177G5 人源化轻链
<400> 54
Asp Ile Gln Met 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 Glu Asn Ile Tyr Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Val
35 40 45
Tyr Ala Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe Trp Gly Ile Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
Claims (15)
1.能够特异性识别OX40的抗体或其抗原结合片段,其包含重链互补决定区HCDR1、HCDR2和HCDR3,以及轻链互补决定区LCDR1、LCDR2和LCDR3,所述HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3的氨基酸序列选自a~b、d~f所示互补决定区组合中的一组:
。
2.根据权利要求1所述的抗体或其抗原结合片段,其包含可变区,所述可变区的重链可变区HCVR和轻链可变区LCVR的序列具有选自A~B、D~F所示可变区序列组合中的一组:
。
3.根据权利要求1所述的抗体或其抗原结合片段,所述互补决定区组合选自b、d所示互补决定区组合中的一组,且所述的抗体或其抗原结合片段具有人源化可变区,b、d所示互补决定区组合所对应的人源化的重链可变区HCVR和轻链可变区LCVR组合优选依次为B'、D'所示:
。
4.根据权利要求1~3任一项所述的抗体或其抗原结合片段,所述抗体具有恒定区,重链恒定区序列选自IgG、IgA、IgM、IgE、IgD任意一种的恒定区序列;轻链恒定区为κ或λ链。
5.根据权利要求4所述的抗体或其抗原结合片段,所述重链恒定区和/或所述轻链恒定区的种属来源选自大鼠、小鼠、兔、牛、马、猪、羊、狗、猫、骆驼、驴、鹿、貂、鸡、鸭、鹅或人。
6.根据权利要求5所述的抗体或其抗原结合片段,所述重链恒定区为人的IgG1,且Ser239、Ala330和Ile332分别突变为Asp、Leu和Glu。
7.根据权利要求1~3任一项所述的抗体或其抗原结合片段,所述抗原结合片段为F(ab')2、Fab、scFv以及双特异抗体中的一种。
8.分离的核酸,其编码权利要求1~7任一项所述的抗体或其抗原结合片段。
9.载体,其包含权利要求8所述的核酸。
10.宿主细胞,其包含权利要求8所述的核酸或权利要求9所述的载体。
11.生产抗体或其抗原结合片段的方法,包括:
在合适的培养条件下培养权利要求10所述的宿主细胞;以及
从培养基中或从所培养的细胞中回收如此产生的抗体或其抗原结合片段。
12.偶联物,包括权利要求1~7任一项所述的抗体或其抗原结合片段和偶联部分,所述偶联部分为选自放射性核素、药物、毒素、细胞因子、细胞因子受体片段、酶、荧光素和生物素中的一种或多种。
13.组合物或组合产品,其包含权利要求1~7任一项所述的抗体或其抗原结合片段中的一种或多种;和/或;权利要求12所述的偶联物。
14.根据权利要求13所述的组合物或组合产品,其还包含药学上可接受的赋形剂、稀释剂或载体中的一种或多种。
15.权利要求1~7任一项所述的抗体或其抗原结合片段和/或权利要求12所述的偶联物在制备药物中的应用;所述药物用于治疗哮喘、肠易激性疾病、移植排斥、自身免疫性糖尿病、移植物抗宿主病、实验性自身免疫性脑脊髓炎以及特应性皮炎中的一种或多种。
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