CN116406424A - 结合trop2的纳米抗体及其用途 - Google Patents
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Abstract
本申请提供一种与人TROP2特异性结合的重链抗体、或其抗原结合部分。还提供编码该抗体或其抗原结合部分的核酸分子,用于表达该抗体或其抗原结合部分的表达载体、宿主细胞和方法。本申请还提供包含该抗体或其抗原结合部分的免疫偶联物和药物组合物,以及使用该TROP2抗体或其抗原结合部分的治疗方法。
Description
相关申请和引用并入
本申请要求2020年11月3日提交的中国申请202011209105.X的优先权。
前述申请、在其中引用或在其审查过程中引用的所有文件(“申请引用文件”)、在本文中引用或提及的所有文件(包括但不限于本文引用的所有文献、专利、公开的专利申请)(“本文引用文件”)、以及在本文引用文件中引用或提及的所有文件,连同本文或任意本文引用并入文件中提及的任何制造商手册、说明书、产品规格和产品页,均通过引用的方式并入本文,且可能在实施本发明时采用。更具体而言,所有参考文件均通过引用的方式并入,如同各文件具体且个别地通过引用的方式并入。在本公开中提及的任何Genbank序列通过引用的方式并入,这些Genbank序列为本公开最早有效递交日的序列。
发明领域
本申请大体上涉及分离的单克隆重链抗体、或其抗原结合部分,其与人TROP2结合,具有高亲和力和功能性。还提供编码该抗体或其抗原结合部分的核酸分子,用于表达该抗体或其抗原结合部分的表达载体、宿主细胞和方法。本申请还提供可以包含该抗体或其抗原结合部分的双特异性分子、免疫偶联物、嵌合抗原受体、溶瘤病毒和药物组合物,以及使用本申请的TROP2抗体或其抗原结合部分的治疗方法。
背景技术
TROP2是一种跨膜糖蛋白,又称为表皮糖蛋白1(EGP-1)、膜成分表面标志物-1(M1S1)、肿瘤相关钙离子信号转导子2(TACSTD2)和胃肠肿瘤相关抗原733-1(GA733-1)。各TROP2分子由疏水性前导肽、胞外结构域、跨膜结构域和胞质尾部组成。其胞质尾部含有高度保守的磷脂酰肌醇4,5-二磷酸(PIP2)结合序列和位于303位的丝氨酸磷酸化位点(ZamanS et al.,(2019)Targeting Trop-2 in solid tumors:futureprospects.Onco TargetsTher.12:1781-1790)。TROP2的结合搭档包括IFG-1、Claudin-1、Claudin-7、cyclin D1和PKC(Shvartsur A et al.,(2015)Trop2 and its overexpression in cancers:regulation and clinical/therapeutic implications.Genes Cancer.6(3-4):84-105)。
TROP2在正常组织中低水平表达,在例如胚胎器官发育和胎儿生长中起作用,而在所有癌症类型中均发现TROP2表达上调,无论正常对应物的基线TROP2水平如何(MustataRC et al.,(2013)Identification of Lgr5-independent spheroid-generatingprogenitors of the mouse fetal intestinal epithelium.Cell Reports.5(2):421-432;Guerra E et al.,(2012)mTrop1/Epcam knockout mice develop congenitaltufting enteropathy through dysegulation of intestinal e-cadherin/β-catenin.PLoS ONE.7(11):e49302;Trerotola M et al.,(2013)Upregulation of Trop-2quantitatively stimulates human cancer growth.Oncogene.32(2):222-233)。研究显示,TROP2表达所依赖的一些转录因子与癌症发展相关,例如TP63/TP53L和Wilm肿瘤1(WT1),且已证实TROP2参与许多与肿瘤发生相关的细胞信号通路。例如,TROP2信号通路,通过β-连环蛋白信号通路来调节细胞的自我更新和增殖,从而促进肿瘤细胞的干细胞样特性(Stoyanova T et al.,(2012)Regulated proteolysis of Trop2 drives epithelialhyperplasia and stem cell self-renewal viaβ-catenin signaling.Genes Dev.26(20):2271-2285)。TROP2的过表达促进***、卵巢癌、结肠癌和甲状腺癌的肿瘤侵袭,敲降TROP2可降低癌细胞侵袭(Guan H et al.,(2017)Trop2 enhances invasion ofthyroid cancer by inducing MMP2 through ERK and JNK pathways.BMC Cancer.17(1):486;Liu T et al.,(2013)Overexpression of Trop2 predicts poor prognosis ofpatients with cervical cancer and promotes the proliferation and invasion ofcervical cancer cells by regulating ERK signaling pathway.PLoS One.8(9):e75864;Wu B et al.,(2017)Overexpression of Trop2 promotes proliferation andinvasion of ovarian cancer cells.Exp Ther Med.14(3):1947-1952;Zhao P et al.,(2018)TNF-αpromotes colon cancer cell migration and invasion by upregulatingTrop-2.Oncol Lett.15(3):3820-3827)。最近,进一步发现TROP2信号通路可调节细胞迁移的信号通路。例如,据报道,TROP2调节β1整合素的功能,从而促进***癌的转移(Trerotola M et al.,(2013)Trop-2 promotes prostate cancer metastasis bymodulatingβ(1)integrin functions.Cancer Res.73(10):3155-3167)。
临床上,TROP2高表达与例如肝门胆管癌、***、和胃癌的不良预后相关。在一项包括2,569例患者的元分析中,TROP2表达增加在统计学上与一些实体瘤的较差总生存期和无病生存期结果相关(Fong D et al.,(2008)High expression of Trop2 correlateswith poor prognosis in pancreatic cancer.Br J Cancer.99(8):1290-1295;Ning Set al.,(2013)Trop2 correlates with microvessel density and poor prognosis inhilar cholangiocarcinoma.J Gastrointest Surg.17(2):360-368;Liu T et al.,(2013)Overexpression of Trop2 predicts poor prognosis of patients withcervical cancer and promotes the proliferation and invasion of cervicalcancer cells by regulating ERK signaling pathway.PLoS One.8(9):e75864;Zhao Wet al.,(2016)Trop2 is overexpressed in gastric cancer and predicts poorprognosis.Oncotarget.7(5):6136-6145;Zeng P et al.,(2016)Impact of Trop2expression on prognosis in solid tumors:a systematic review and meta-analysis.Sci Rep.6:33658)。TROP2作为肿瘤标志物的作用也正在一些临床试验中测试。
由于其结构特点以及与癌症的相关性,TROP2是一个有吸引力的治疗靶点。已制备出一些TROP2抗体,且发现其中一些在异种移植小鼠模型中抑制乳腺癌进展和诱导细胞凋亡(Lin H et al.,(2014)A novel human Fab antibody for Trop2 inhibits breastcancer growth in vitro and in vivo.Int J Cancer.134(5):1239-1249)。然而,可能由于其高内化速率,没有抗体表现出作为裸抗体的治疗价值,直到2015年IKEDA等人发现了具有更高结合亲和力和更低内化活性的Pr1E11(Ikeda M et al.,(2015)Pr1E11,a novelanti-TROP-2 antibody isolated by adenovirus-based antibody screening,recognizes a unique epitope.Biochem Biophys Res Commun.458(4):877-82)。在后来的研究中,Pr1E11经确定在体内诱导有效的抗体依赖性细胞毒性,推测这与较高的细胞表面停留期相关(Ikeda M et al.,(2016)Cell Surface Antibody Retention InfluencesIn Vivo Antitumor Activity Mediated by Antibody-dependent CellularCytotoxicity.Anticancer Res.36(11):5937-5944)。当前,大多数处于临床前和临床试验中的TROP2靶向治疗剂是抗体-药物偶联物(ADC),包括DS-1062a、IMMU-1 32和PF-06664178,迄今为止在实体瘤治疗中取得了一些令人鼓舞的结果,且毒性较小(Zaman S etal.,(2019)同上)。
需要另外的具有低内化活性的TROP2抗体用作裸抗体、或具有高内化活性用于制备ADC。
本申请中对于任何文件的引用或标识,并不是承认这些文件是本发明的现有技术。
发明内容
本申请提供一种分离的重链抗体、或其抗原结合部分,其结合TROP2(例如,人TROP2),且与现有技术TROP2抗体例如赛妥珠单抗(IMMU-132的抗体部分)相比,具有相当的(如果不是更高的话)与人和/或猴TROP2的结合亲和力/能力、以及相当的(如果不是更高的话)内化活性。
本申请的重链抗体或其抗原结合部分可以用于多种应用,包括体外和体内的TROP2蛋白检测(若放射性标记的话)、以及TROP2相关疾病(例如癌症)的治疗。
因此,在一个方面,本申请涉及结合TROP2的分离的单克隆重链抗体(例如,骆驼源、嵌合或人源化抗体)或其抗原结合部分,其具有可变区,该可变区可以包含VH CDR1区、VH CDR2区和VH CDR3区,其中该VH CDR1区、VH CDR2区和VH CDR3区可以分别包含与(1)SEQID NOs:1、2(X1=D、X2=G、X3=D、X4=S)和3(X1=D、X2=G);(2)SEQ ID NOs:1、2(X1=D、X2=G、X3=D、X4=S)和3(X1=E、X2=G);(3)SEQ ID NOs:1、2(X1=D、X2=G、X3=D、X4=S)和3(X1=D、X2=A);(4)SEQ ID NOs:1、2(X1=D、X2=G、X3=D、X4=S)和3(X1=I、X2=G);(5)SEQ ID NOs:1、2(X1=E、X2=G、X3=D、X4=S)和3(X1=E、X2=G);(6)SEQ ID NOs:1、2(X1=D、X2=A、X3=D、X4=S)和3(X1=E、X2=G);(7)SEQ ID NOs:1、2(X1=E、X2=G、X3=D、X4=S)和3(X1=D、X2=A);(8)SEQ ID NOs:1、2(X1=D、X2=A、X3=D、X4=S)和3(X1=D、X2=A);(9)SEQ ID NOs:1、2(X1=E、X2=G、X3=E、X4=S)和3(X1=E、X2=G);(10)SEQ IDNOs:1、2(X1=D、X2=A、X3=E、X4=S)和3(X1=E、X2=G);(11)SEQ ID NOs:1、2(X1=E、X2=G、X3=D、X4=T)和3(X1=D、X2=A);或(12)SEQ ID NOs:1、2(X1=D、X2=A、X3=D、X4=T)和3(X1=D、X2=A)具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。
本申请分离的单克隆重链抗体或其抗原结合部分可以包含可变区,其可以包含与SEQ ID NO:4(X1=S、X2=Q、X3=D、X4=G、X5=P;X1=S、X2=Q、X3=E、X4=G、X5=P;X1=S、X2=Q、X3=D、X4=A、X5=P;X1=S、X2=Q、X3=I、X4=G、X5=P;或X1=T、X2=G、X3=D、X4=G、X5=L)、5(X1=E、X2=G、X3=D;X1=D、X2=A、X3=D;X1=E、X2=G、X3=E;或X1=D、X2=A、X3=E)、6(X1=E、X2=G、X3=S;X1=D、X2=A、X3=S;X1=E、X2=G、X3=T;或X1=D、X2=A、X3=T)、7、8(X1=F、X2=Y、X3=K、X4=A;X1=L、X2=F、X3=K、X4=A;X1=L、X2=Y、X3=R、X4=A;X1=L、X2=Y、X3=K、X4=R;或X1=L、X2=Y、X3=K、X4=A)、9(X1=F、X2=Y、X3=K、X4=A;X1=L、X2=F、X3=K、X4=A;X1=L、X2=Y、X3=R、X4=A;X1=L、X2=Y、X3=K、X4=R;或X1=L、X2=Y、X3=K、X4=A)、10(X1=F、X2=Y、X3=K、X4=A;X1=L、X2=F、X3=K、X4=A;X1=L、X2=Y、X3=R、X4=A;X1=L、X2=Y、X3=K、X4=R;或X1=L、X2=Y、X3=K、X4=A)、11(X1=F、X2=Y、X3=K、X4=A;X1=L、X2=F、X3=K、X4=A;X1=L、X2=Y、X3=R、X4=A;X1=L、X2=Y、X3=K、X4=R;或X1=L、X2=Y、X3=K、X4=A)、12、或13(X1=V、X2=W;或X1=F、X2=G)具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。SEQ ID NOs:4(X1=S、X2=Q、x3=D、X4=G、X5=P)、6(X1=D、X2=A、X3=T)和9(X1=L、X2=Y、X3=K、X4=A)的氨基酸序列可分别由SEQ ID NOs:23、24和25的核苷酸序列编码。
本申请分离的单克隆重链抗体或其抗原结合部分可以包含恒定区或其功能片段,与可变区连接,其中可变区的C端与恒定区的N端相连。恒定区可以是具有增强的FcR结合力的重链恒定区,例如具有SEQ ID NO:14所示氨基酸序列的人IgG1重链恒定区或其功能片段。重链恒定区也可以是基因改造成具有增强的FcR结合力的人IgG2或IgG4恒定区或其功能片段。SEQ ID NO:14的氨基酸序列可由SEQ ID NO:26的核苷酸序列编码。
本申请还提供双特异性分子,其可以包含本申请的重链抗体或其抗原结合部分,与具有不同于本抗体或其抗原结合部分的结合特异性的第二功能基团(例如,第二抗体)连接。本申请还提供免疫偶联物,其可以包含本申请的重链抗体或其抗原结合部分,与治疗剂例如细胞毒性剂如SN-38、或放射性标记物连接。本申请的重链抗体或其抗原结合部分可以制备成嵌合抗原受体(CAR)的一部分。还提供包含该抗原嵌合受体的免疫细胞,例如T细胞和NK细胞。本申请的重链抗体或其抗原结合部分也可以由溶瘤病毒编码或与溶瘤病毒一起使用。
重链抗体或其抗原结合部分、免疫偶联物、或双特异性分子可以经放射性标记并应用于临床成像,以例如,示踪/检测肿瘤/癌症的分布,包括转移性肿瘤/癌症的分布。放射性标记物包括,但不限于,3H。
本申请还涉及编码本申请重链抗体或其抗原结合部分、双特异性分子、免疫偶联物、或CAR的核酸分子,以及可包含该核酸的表达载体、和可包含该表达载体的宿主细胞。还提供利用该宿主细胞制备本申请的TROP2重链抗体或其抗原结合部分的方法,其可以包括以下步骤:(i)在该宿主细胞中表达抗体或其抗原结合部分,以及(ii)从宿主细胞或其细胞培养物中分离抗体或其抗原结合部分。
还提供药物组合物,其可以包含本申请的重链抗体或其抗原结合部分、免疫偶联物、双特异性分子、溶瘤病毒、CAR或CAR-T细胞、核酸分子、表达载体或宿主细胞,以及药学上可接受的载体。在一些实施方式中,药物组合物还可以包含用于治疗特定疾病的治疗剂,例如抗癌剂。
在另一方面,本申请提供一种在有需求的受试者中治疗TROP2(例如TROP2过量表达)相关疾病的方法,其可以包括向受试者施用治疗有效量的本申请药物组合物。疾病可以是肿瘤或癌症。肿瘤可以是实体瘤或非实体瘤,包括,但不限于,乳癌、结直肠癌、胃腺癌、食管癌、肝细胞癌、非小细胞肺癌、小细胞肺癌、卵巢上皮癌、***癌、胰腺导管腺癌、头颈癌、鳞状细胞癌、肾细胞癌、***、***、子宫内膜癌、滤泡状甲状腺癌、和多形性胶质母细胞瘤。在实施方式中,可以进一步施用至少一种其他的抗癌抗体,例如VISTA抗体、PD-1抗体、PD-L1抗体、LAG-3抗体、CTLA-4抗体、TIM3抗体、STAT3抗体、和/或ROR1抗体。在某些实施方式中,受试者是人。
在另一方面,本申请提供一种在有需求受试者中进行癌症成像的方法,包括向受试者施用本申请的放射性标记的TROP2重链抗体或其抗原结合部位、免疫偶联物、或双特异性分子。该方法可以用于示踪/检测TROP2高表达的肿瘤或癌症的分布,包括,但不限于,食管鳞状细胞癌、结直肠癌、胰腺癌、结肠癌、甲状腺***状癌、乳癌、和膀胱癌。在某些实施方式中,受试者是人。
基于以下具体描述和实施例,当前公开内容的其他特征和优势之处将会是明晰的,具体描述和实施例不应解读为限制性的。在本申请中引用的所有文献、Genbank条目、专利和已公开专利申请的内容通过引用的方式明确地包含在本文中。
因而,本申请的目标是不在本申请中包含任何先前已知的产品、制造该产品的工艺或使用该产品的方法,从而申请人保留权利,并在此公开对任何先前已知的产品、过程或方法的弃权声明。需要进一步指出的是,本申请并不打算在本申请的范围内包含任何不符合USPTO(35U.S.C.§112,第一段)或EPO(EPC,第83条)书面描述要件和可实施性要求的产品、工艺、或产品制造方法或产品使用方法,从而申请人保留权利,并在此公开对任何先前描述的产品、产品制备工艺、或产品使用方法的弃权声明。在本发明的实施中,符合EPC第53条(c)和EPC细则第28条(b)和(c)是有利的。明确保留对本申请同族或任何其他同族或任何第三方在先申请中涉及本申请人任何已授权专利的主题的任何实施方式做出明确的弃权声明的所有权利。本文中的任何内容都不应被解释为承诺。
应当注意的是,在本申请中,特别是在权利要求和/或段落中,术语例如“包含”、“包括”等可以具有美国专利法所赋予的意义;例如它们可以表示“包含在内”等;且术语例如“基本由…组成”或“基本由…构成”具有美国专利法所赋予的意义,例如它们允许没有明确表述的元素的存在,但将现有技术中存在的元素、或影响本发明基本或新特性的元素排除在外。
附图说明
以下以示例方式给出但不意在将本发明限制于所述具体实施方式的具体描述,可以结合附图更好地进行理解。
图1示出在间接ELISA中单域抗体01-9F和01-5A与人TROP2的结合力。
图2示出在竞争ELISA检测中单域抗体01-9F和01-5A阻断对照基准物-人TROP2结合的能力。
图3示出单域抗体01-9F和01-5A的DT3C偶联物对293F-TROP2细胞的内化介导性细胞毒性。
图4示出重链抗体01-9F-CDR-V5-Fc、01-9F-CDR-V6-Fc、01-9F-CDR-V9-Fc和01-9F-CDR-V11-Fc的DT3C偶联物对293F-TROP2细胞的内化介导性细胞毒性。
图5示出人源化抗体01-9F-CDR-V11-V1-Fc、01-9F-CDR-V11-V9-Fc和01-9F-CDR-V11-V11-Fc的DT3C偶联物对293F-TROP2细胞的内化介导性细胞毒性。
图6示出在捕获ELISA中人源化抗体01-9F-CDR-V11-V11-Fc与人TROP2的结合力。
图7示出在间接ELISA中人源化抗体01-9F-CDR-V11-V11-Fc与人TROP2的结合力。
图8示出在间接ELISA中人源化抗体01-9F-CDR-V11-V11-Fc与猴TROP2的结合力。
图9示出在基于细胞的结合FACS检测中人源化抗体01-9F-CDR-V11-V11-Fc与表达人TROP2的293F-TROP2细胞的结合力。
图10示出在竞争ELISA检测中人源化抗体01-9F-CDR-V11-V11-Fc阻断对照基准物-人TROP2结合的能力。
图11A-11C示出抗体01-9F(A)、01-9F-CDR-V11-Fc(B)和01-9F-CDR-V11-V11-Fc(C)的蛋白热迁移试验的结果。
具体实施方式
为确保更容易地理解本申请,首先定义一些术语。其他的定义贯穿具体描述而给出。
术语“TROP2”是指肿瘤相关钙离子信号转导子2,又称为表皮糖蛋白1、胃肠肿瘤相关抗原733-1和膜成分表面标志物-1。术语“TROP2”包含变体、异构体、同源物、直系同源体和旁系同源体。例如,对人TROP2蛋白特异的抗体,在某些情况下,可以与除人以外物种例如猴的TROP2蛋白交叉反应。在其他实施方式中,对人TROP2蛋白特异的抗体可以完全地对人TROP2蛋白特异,并呈现为与其他物种或其他类型没有交叉反应性,或者可以对某些其他物种但非所有其他物种的TROP2发生交叉反应。
术语“人TROP2”是指具有来自人的氨基酸序列的TROP2蛋白,例如SEQ ID NO:20所示的人TROP2氨基酸序列。术语“猴TROP2”或“猕猴TROP2”是指具有来自豚尾猴或猕猴的氨基酸序列的TROP2蛋白,例如具有NCBI登录号为XP_001114599.1或XP_011762693.1的氨基酸序列。
在某些情况下,术语“抗体”具体指本申请的重链抗体或其抗原结合部位。术语“重链抗体”或“HCAb”是指一种功能性抗体,其仅包含重链,缺乏通常存在于4链免疫球蛋白的轻链。天然存在的重链抗体发现于例如骆驼科(例如骆驼、美洲驼或羊驼)。各骆驼重链抗体包含重链可变区/结构域,称为VHH结构域、VHH片段或单链抗体(sdAb),和重链恒定区。VHH的功能是与抗原相互作用。VHH包含三个互补决定区(CDR)和四个骨架区(FR),从氨基端到羧基端以FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4的顺序排布。重链恒定区包含铰链区、CH2结构域和CH3结构域。缺失的CH1结构域由延长的铰链区所替代。在嵌合或人源化重链抗体中,重链恒定区可以包含典型的IgG,例如IgG1、IgG2或IgG4,恒定区。恒定区可以介导重链抗体与宿主组织或因子,包括多种免疫***细胞(例如,效应细胞)和典型补体***的第一组分(C1q),的结合。
与重链抗体关联使用的“抗原结合部分”是指重链抗体中保留有特异性结合抗原(例如,TROP2)能力的一个或多个片段。已显示出,重链抗体的抗原结合功能可以通过全长重链抗体的片段来实施。重链抗体的“抗原结合部分”的实例包括,但不限于(i)分离的互补决定区(CDR);(ii)单价VHH片段;(iii)二价片段,其包含两个单价VHH片段;(iv)单价片段,其包含VHH片段与部分重链恒定区连接,例如VHH结构域与重链恒定区的CH2结构域、或CH2和CH3结构域区相连;(v)二价片段,其包含两个VHH片段,其各自与部分重链恒定区连接;(vi)经接头、或不经接头连接的多个单价VHH结构域。术语“单域抗体”、“sdAb”或“纳米抗体”是指单条抗原结合多肽,包含具有三个互补决定区(CDR)的单条单体可变抗体结构域,其能够与抗原结合而无需与相应的含CDR的多肽配对。在某些情况下,单域抗体由骆驼HCAb改造得到,也称为VHH结构域或HCAb片段。单域抗体是重链抗体的一种抗原结合部分。VHH也被称为纳米抗体。骆驼sdAb是已知最小的抗原结合抗体片段之一(参见例如,Hamers-Castermanet al.,Nature 363:446-8(1993);Greenberg et al.,Nature 374:168-73(1995);Hassanzadeh-Ghassabeh et al.,Nanomedicine(Lond),8:1013-26(2013))。
本文所用的“分离的抗体”是指基本不含具有不同抗原特异性的其他抗体的抗体(例如,分离出的与TROP2蛋白特异性结合的抗体,基本不含特异结合TROP2之外蛋白的抗体)。然而,分离出的与人TROP2蛋白特异性结合的抗体可能与其他抗原,例如其他物种的TROP2蛋白,有交叉反应性。此外,分离的抗体可以基本不含其他细胞材料和/或化学物质。
本文所用的术语“骆驼源抗体”意在包括骨架和CDR得自骆驼种系免疫球蛋白序列的可变区的抗体。此外,如果抗体包含恒定区,恒定区也得自骆驼种系免疫球蛋白序列。本申请的骆驼源抗体可以包含不由骆驼种系免疫球蛋白序列编码的氨基酸残基(例如,通过体外随机突变或点突变或通过体内体细胞突变而引入的突变)。然而,本文所用的术语“骆驼源抗体”不意在包括在骆驼骨架序列中植入得自另一哺乳动物物种种系的CDR序列的抗体。
术语“嵌合抗体”是指通过组合非人源遗传物质与人源遗传物质而制备的抗体。或者更笼统地说,嵌合抗体是含有某一物种的遗传物质以及另一物种遗传物质的抗体。
本文所用的术语“人源化抗体”是指来源于非人物种但其蛋白序列已经修改成以增加与人中天然生成的抗体变体的相似度的抗体。
本文所用的术语“单克隆抗体”是指从基本均质的抗体群中得到的抗体,即,除可能存在少量的可能自然发生的突变和/或翻译后修饰(例如异构化、酰胺化)外,含该群体的个体抗体是相同的。单克隆抗体为高度特异,针对单一抗原位点。与通常包含针对不同决定簇(表位)的不同抗体的多克隆抗体制剂不同,各单克隆抗体针对抗原上的单一决定簇。除其特异性外,单克隆抗体的优点是,它们通过杂交瘤培养而形成,不受其他免疫球蛋白的污染。修饰语“单克隆”是指该抗体从基本均质的抗体群中获得的的特性,不应解释为需要通过任何特定方法而生产该抗体。例如,根据本发明使用的单克隆抗体可以通过多种技术制备,包括例如,杂交瘤方法。
术语“同种型”是指由重链恒定区基因编码的抗体类别(如IgM或IgG1)。
词组“识别抗原的抗体”以及“对抗原特异的抗体”在本文中与术语“特异结合抗原的抗体”交替使用。
如本文所用的,“特异结合人TROP2”的抗体是指与人TROP2蛋白(以及可能的来自一种或多种非人物种的TROP2蛋白)结合但基本不与非TROP2蛋白结合的抗体。优选地,抗体以“高亲和力”,即以KD值为5.0×10-8M以下,更优选1.0×10-8M以下,更优选2.0×10-9M以下,结合人TROP2蛋白。
如本文所用的,术语“基本不结合”蛋白或细胞是指,不与蛋白或细胞结合,或者不以高亲和力与其结合,即以KD为1×10-6M以上,更优选1×10-5M以上,更优选1×10-4M以上,更优选1×10-3M以上,更优选1×10-2M以上,结合蛋白或细胞。
术语“高亲和性”对于IgG抗体而言,是指抗体对于靶抗原的KD为1.0×10-6M以下,更优选5.0×10-8M以下,更优选1.0×10-8M以下,更优选1.0×10-9M以下,更优选5.0×10-10M以下。然而,对于其他抗体同种型而言,“高亲和性”结合可能会变化。例如,IgM亚型的“高亲和性”结合是指抗体的KD为10-6M以下,优选10-7M以下,更优选10-8M以下。
本文所用术语“Kassoc”或“Ka”是指特定抗体-抗原相互作用的结合速率,而本文所用的术语“Kdis”或“Kd”是指特定抗体-抗原相互作用的解离速率。如本文所用,术语“KD”是指从Kd与Ka的比(即Kd/Ka)获得的解离常数,表达为摩尔浓度(M)。可以使用本领域公知的方法确定抗体的KD值。用于确定抗体KD的优选方法是使用表面等离子体共振,优选使用生物传感器***如BiacoreTM***。
术语“EC50”,也称为半最大效应浓度,是指在特定暴露时间后引起在基线和最高值之间的中间值反应的抗体浓度。
术语“IC50”,也称为半最大抑制浓度,是指相对于不存在抗体而言,抑制50%特定生物或生化功能的抗体浓度。
术语“受试者”包括任何人或非人动物。术语“非人动物”包括所有脊椎动物,例如哺乳类和非哺乳类,例如非人灵长类、羊、狗、猫、牛、马、鸡、两栖类、和爬行类,尽管优选哺乳动物,例如非人灵长类、羊、狗、猫、牛和马。
术语“治疗有效量”是指足以防止或减缓与疾病或病症(例如慢性炎症)相关的症状和/或减轻疾病或病症的严重程度的本申请抗体或抗原结合部分的量。治疗有效量在所治疗疾病的背景下进行理解,其中本领域技术人员可以方便地判别出实际有效量。
本申请的多个方面在以下小节中作进一步详细描述。
本申请的重链抗体或其抗原结合部分,特异性结合人TROP2,与现有技术TROP2抗体例如赛妥珠单抗(IMMU-132的抗体部分)相比,具有相当的(若不是更高的话)人和/或猴TROP2结合亲和力/能力,以及相当的(若不是更高的话)内化活性。
本申请的抗体或其抗原结合部分是骆驼源、嵌合和人源化的。本申请的抗体是重链抗体。
本申请的抗体或其抗原结合部分是在以下以及之后实施例中进行结构和化学表征的单克隆抗体。本申请的可变区和CDR的氨基酸序列ID编号总结于表1,一些抗体享有相同的VHH。抗体的恒定区可以是包含例如SEQ ID NO:14所示氨基酸序列的重链恒定区或其功能片段。本申请的抗体也可包含人IgG1、IgG2或IgG4重链恒定区。
表1中的可变区CDR已由Kabat编号体系确定。然而,如本领域所公知的,CDR区也可以基于可变区序列经其他体系例如Chothia、和IMGT、AbM或Contact编号体系/方法确定。
结合人TROP2的其他TROP2抗体的VHH序列(或CDR序列)可以与本申请的TROP2抗体的VHH序列(或CDR序列)“混合和匹配”。
因此,在一个实施方式中,本申请的抗体或其抗原结合部分可以包含可变区,其可以包含上述表1中所列的氨基酸序列,其中该抗体特异性结合人TROP2。
在另一实施方式中,本申请的抗体或其抗原结合部分可以包含列于上述表1中的重链可变区的CDR1、CDR2和CDR3,其中该抗体特异结合人TROP2。
在另一实施方式中,抗体或其抗原结合部分包括TROP2抗体的CDR2区,结合有其他结合人TROP2抗体的CDR区,例如不同TROP2抗体的可变区CDR1和/或CDR3。
另外,如本领域所公知的,CDR3结构域,独立于CDR1和/或CDR2结构域,可以单独决定抗体对同源抗原的结合特异性,且基于相同的CDR3序列,可预见能产生具有相同结合特异性的多个抗体。参见例如Klimka et al.,British J.of Cancer 83(2):252-260(2000);Beiboer et al.,J.Mol.Biol.296:833-849(2000);Rader et al.,Proc.Natl.Acad.Sci.U.S.A.95:8910-8915(1998);Barbas et al.,J.Am.Chem.Soc.116:2161-2162(1994);Barbas et al.,Proc.Natl.Acad.Sci.U.S.A.92:2529-2533(1995);Ditzel et al.,J.Immunol.157:739-749(1996);Berezov et al.,BIAjournal 8:Scientific Review 8(2001);Igarashi et al.,J.Biochem(Tokyo)117:452-7(1995);Bourgeois et al.,J.Virol 72:807-10(1998);Levi et al.,Proc.Natl.Acad.Sci.U.S.A.90:4374-8(1993);Polymenis and Stoller,J.Immunol.152:5218-5329(1994)以及Xu and Davis,Immunity 13:37-45(2000)。也可参见美国专利6,951,646;6,914,128;6,090,38;6,818,216;6,156,313;6,827,925;5,833,943;5,762,905和5,760,185。这些参考文献中的每一个都通过引用的方式整体并入本文。
本申请的抗体具有以下一个或多个上述的功能特点,例如与人TROP2的高结合亲和力。
在多个实施方式中,抗体可以是例如骆驼源、嵌合或人源化抗体。
本文所用的术语“保守的序列修饰”是指不会显著影响或改变含有这类氨基酸序列的抗体的结合特性的氨基酸修饰。这样的保守修饰包括氨基酸替换、添加和缺失。可以通过领域内已知的标准技术,例如点突变和PCR介导的突变,将修饰引入本申请抗体中。保守氨基酸替换是指将氨基酸残基用具有相似侧链的氨基酸残基替换。已定义出领域内具有相似侧链的氨基酸残基组。这些组包括具有碱性侧链(例如,赖氨酸、精氨酸、组氨酸)、酸性侧链(例如,天冬氨酸、谷氨酸)、不带电极性侧链(例如,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如,丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β-支链侧链(例如,苏氨酸、缬氨酸、异亮氨酸)和芳香族侧链(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。因此,本申请抗体的CDR区中的一个或多个氨基酸残基可以用同一侧链组的其他氨基酸残基替换,且改造后的抗体可以使用本文所述的功能检测测试其保留下来的功能(即上述的功能)。
本申请的抗体可以用具备本申请TROP2抗体的VHH序列的抗体为起始原料而进行制备,以基因改造修饰的抗体。抗体可以通过修饰可变区(即,VHH)内(例如,在一个或多个CDR区和/或一个或多个骨架区内)的一个或多个残基来进行基因修饰。此外以及可选地,抗体可以通过修饰恒定区的残基来进行工程改造,以例如改变抗体的效应功能。
在某些实施方式中,CDR植入可以用来工程改造抗体的可变区。抗体主要通过位于三个互补决定区(CDR)中的氨基酸残基与靶标抗原进行相互作用。出于这个原因,在个体抗体之间,CDR内的氨基酸序列比CDR外的序列更加多样。因为CDR序列负责大部分抗体-抗原相互作用,可以通过构建包含有将来自特定天然抗体的CDR序列植入到具有不同特性的不同抗体的骨架序列中的表达载体,来表达模拟特定天然抗体的特性的重组抗体(参见例如Riechmann et al.,(1998)Nature 332:323-327;Jones et al.,(1986)Nature 321:522-525;Queen et al.,(1989)Proc.Natl.Acad。又可参见U.S.A.86:10029-10033;U.S.Pat.Nos.5,225,539;5,530,101;5,585,089;5,693,762和6,180,370)。
因此,本申请的另一实施方式涉及分离的单克隆抗体或其抗原结合部分,其可以包含可变区,其可包含具有本申请上述序列的CDR1、CDR2和CDR3序列,如上所述。尽管这些抗体包含本申请单克隆抗体的VHH CDR序列,它们可以含有不同的骨架序列。
这些骨架序列可以从包括种系抗体基因序列的公开DNA数据库或公开参考文献中获得。例如,人重链和轻链可变区基因的种系DNA序列可以在“VBase”人种系序列数据库获得(可得自www.mrc-cpe.cam.ac.uk/vbase),也可以在Kabat et al.,(1991),同上;Tomlinson et al.,(1992)J.Mol.Biol.227:776-798;和Cox et al.,(1994)Eur.J.Immunol.24:827-836获得;上述文件各自的内容通过引用的方式明确并入本文。作为另一个例子,用于人重链和轻链可变区基因的种系DNA序列可以在Genbank数据库中得到。例如,下列HCo7 HuMAb小鼠中的重链种系序列可得自所附的Genbank登录号1-69(NG-0010109、NT--024637&BC070333)、3-33(NG--0010109&NT--024637)和3-7(NG--0010109&NT--024637)。作为另一例子,以下来自Hco12 HuMAb小鼠的重链种系序列可得自Genbank登录号1-69(NG-0010109、NT--024637&BC070333)、5-51(NG--0010109&NT--024637)、4-34(NG--0010109&NT--024637)、3-30.3(CAJ556644)&3-23(AJ406678)。
通过使用本领域公知的称为空格BLAST的序列相似性搜索方法(Altschul etal.,(1997),同上),将抗体蛋白序列与汇编蛋白序列数据库进行比较。
用于本申请抗体的优选骨架序列,是结构上与本申请抗体所用的骨架序列结构相似的那些。VHH CDR1、CDR2和CDR3序列可以植入到与得到该骨架序列的种系免疫球蛋白基因具有相同序列的骨架区中,或者CDR序列可以植入到与种系序列相比包含一个或多个突变的骨架区中。例如,已发现,在一些情况下,为保持或增强抗体的抗原结合能力,将骨架区中突变残基是有益的。(参见例如美国专利5,530,101;5,585,089;5,693,762和6,180,370)。
另一类的可变区修饰是将VHH CDR1、CDR2和/或CDR3区内的氨基酸残基进行突变,从而改进目标抗体的一种或多种结合特性(例如,亲和力)。可以进行点突变或PCR介导的突变来引入突变,且其对于抗体结合或其他目标功能特性的影响可以在本领域所知的体外或体内检测中进行评价。优选地,引入(本领域所知的)保守修饰。突变可以是氨基酸替换、添加或缺失,但优选为替换。此外,通常对CDR区的改变不多于一个、两个、三个、四个或五个残基。
因而,在另一实施方式中,本申请提供分离的TROP2单克隆抗体或其抗原结合部分,其包含可变区,其包含:(a)CDR1区,其可以包含本申请的序列,或含有一个、两个、三个、四个或五个氨基酸替换、缺失或添加的氨基酸序列;(b)CDR2区,其可以包含本申请的序列,或含有一个、两个、三个、四个或五个氨基酸替换、缺失或添加的氨基酸序列;(c)CDR3区,其包含本申请的序列,或含有一个、两个、三个、四个或五个氨基酸替换、缺失或添加的氨基酸序列。
本申请的基因改造抗体包括,例如为提高抗体特性,对VHH的骨架残基中做出基因修饰的抗体。通常而言,做出这些骨架修饰,以降低抗体的免疫原性。例如,一种方法是将一个或多个骨架残基“回复突变”成相应的种系序列。更加具体而言,经历体细胞突变的抗体可能包含不同于已得到抗体的种系序列的骨架残基。这些残基可以通过比较抗体骨架序列和得到抗体的种系序列而识别出来。
另一类的骨架修饰涉及对骨架区的、或者甚至一个或多个CDR区的一个或多个残基进行突变,以去除T细胞表位,从而减少抗体的潜在免疫原性。该方法也称为“去免疫化”,在美国专利公开20030153043中有更加详细的描述。
此外,或者作为对骨架或CDR区内修饰的另一种选择,本申请的抗体可以基因修饰成包含Fc区内的修饰,通常是为改变抗体的一个或多个功能特性,例如血清半衰期、补体结合、Fc受体结合、和/或抗体依赖的细胞毒性。此外,可以对本申请的抗体进行化学修饰(例如,可以向抗体附加一个或多个化学基团),或者修饰成改变其糖基化,同样是为改变抗体的一个或多个功能特性。
在一个实施方式中,CH1铰链区经修饰,改变,例如增加或减少,铰链区半胱氨酸残基的数量。该方法在美国专利5,677,425中作进一步描述。改变CH1铰链区的半胱氨酸残基的数量,以例如促进轻链和重链的组装或者增加或降低抗体的稳定性。
在另一个实施方式中,抗体的Fc铰链区经突变,以降低抗体的生物半衰期。更加具体地,将一个或多个氨基酸突变引入Fc铰链片段的CH2-CH3结构域连接区,从而相较于与天然Fc-铰链结构域的金黄色葡萄球菌蛋白A(SpA)的结合,该抗体具有削弱的SpA结合。该方法在美国专利6,165,745中有更详细的描述。
在另一实施方式中,对抗体的糖基化进行修饰。例如,可以制备去糖基化的抗体(即,抗体缺少糖基化)。可以改变糖基化,例如增加抗体对抗原的亲和性。这样的糖化修饰可以通过例如改变抗体序列中的一个或多个糖基化位点来达成。例如,可以进行一个或多个氨基酸替换,以消除一个或多个可变区骨架糖基化位点,从而消除该位置的糖基化。这样的去糖基化可以增加抗体对抗原的亲和性。参见,例如美国专利5,714,350和6,350,861。
另外地或者可选地,可以制备糖基化类型改变的抗体,例如岩藻糖残基量减少的低岩藻糖基抗体或者具有增加的平分型GlcNac结构的抗体。经证实,这些改变的糖基化形式增加或降低抗体的ADCC活性。这样的糖基化修饰可以通过例如在糖基化***改变的宿主细胞中表达抗体而完成。糖基化***改变的细胞在领域中已知,且可以用作表达本申请重组抗体的宿主细胞,以制备糖基化改变的抗体。例如,细胞系Ms704、Ms705和Ms709缺乏岩藻糖基转移酶基因FUT8(α(1,6)-岩藻糖基转移酶),从而在Ms704、Ms705和Ms709细胞系中表达的抗体在其糖中缺失岩藻糖。使用两种替换载体靶向破坏CHO/DG44细胞的FUT8基因,制备Ms704、Ms705和Ms709 FUT8-/-细胞系(参见美国专利20040110704和Yamane-Ohnuki etal.,(2004)Biotechnol Bioeng 87:614-22)。作为另一个例子,EP 1,176,195记载了具有功能破坏的FUT8基因(其编码岩藻糖基转移酶)的细胞系,从而通过降低或消除α-1,6键相关酶,在该细胞系中表达的抗体表现出低岩藻糖基化。EP 1,176,195也描述了一种细胞系,其具有较低的向结合抗体Fc区的N-乙酰氨基葡萄糖中添加岩藻糖的活性,或不具有酶活性,例如大鼠骨髓瘤细胞系YB2/0(ATCC CRL 1662)。PCT公开文本WO 03/035835描述了CHO变体细胞系,Lec13细胞,其向Asn(297)-连接糖添加岩藻糖的能力降低,从而使得宿主细胞中表达的抗体的低岩藻糖基化(参见Shields et al.,(2002)J.Biol.Chem.277:26733-26740)。具有改变的糖基化图谱的抗体也可以在鸡蛋中制备,如在PCT公开文本WO 06/089231中所述的。或者,具有改变的糖基化图谱的抗体可以在植物细胞如浮萍中制备。在植物体系中制备抗体的方法在对应Alston&Bird LLP律师记录号040989/314911的2006年8月11日提交的美国专利申请中有过记载。可以使用岩藻糖苷酶来切除抗体的岩藻糖残基,例如α-L-岩藻糖苷酶从抗体移除岩藻糖残基(Tarentino et al.,(1975)Biochem.14:5516-23)。
包含在本申请中的本文抗体的另一修饰是聚乙二醇化。抗体可以聚乙二醇化,例如增加抗体的生物(例如,血清)半衰期。为使抗体聚乙二醇化,抗体或其片段通常与聚乙二醇(PEG),例如PEG的活性酯或醛类衍生物,在使一个或多个PEG基团附于抗体或抗体片段的条件下反应。优选地,聚乙二醇化通过与活性PEG分子(或类似的有反应性的水溶性聚合物)的酰化反应或烷化反应进行。本文中所用的术语“聚乙二醇”意在包括任何形式的用于衍生其他蛋白的PEG,例如单(C1-C10)烷氧基-或芳氧基聚乙二醇或聚乙二醇马来酰亚胺。在某些实施方式中,需要聚乙二醇化的抗体是去糖基化的抗体。蛋白聚乙二醇化的方法在领域内已知,且可以应用于本申请的抗体。参见,例如EPO 154316和EP 0 401 384。
本申请的抗体可以用它们的多种物理特性进行表征,以检测和/或区别其不同分类。
例如,抗体可以在可变区包含一个或多个糖基化位点。这些糖基化位点可能引起抗体的免疫原性增高,或由于抗原结合的改变引起抗体pK的变化(Marshall et al(1972)Annu Rev Biochem 41:673-702;Gala and Morrison(2004)J Immunol 172:5489-94;Wallick et al(1988)J Exp Med 168:1099-109;Spiro(2002)Glycobiology 12:43R-56R;Parekh et al(1985)Nature 316:452-7;Mimura et al.,(2000)Mol Immunol 37:697-706)。已知糖基化发生在含有N-X-S/T序列的基序中。在一些情况下,优选不包含可变区糖基化的TROP2抗体。这可以通过选择在可变区不包含糖基化基序的抗体或者通过使糖基化区域内的残基发生突变来实现。
在优选实施方式中,抗体不包含天冬酰胺异构位点。天冬酰胺的脱酰胺可能发生在N-G或D-G序列处,引起异天冬氨酸残基的生成,其向多肽链引入链接并降低其稳定性(异天冬氨酸效果)。
各抗体将具有独特的等电点(pI),其基本落在6-9.5的pH范围内。IgG1抗体的pI通常落在7-9.5的pH范围内,而IgG4抗体的pI基本落在6-8的pH范围内。推测pI在正常范围外的抗体可能在体内条件下具有一些展开结构和不稳定性。因此,优选pI值落在正常范围内的TROP2抗体。这可以通过选择pI在正常范围内的抗体或通过突变带电表面残基来实现。
在另一方面,本申请提供编码本申请抗体可变区或CDR的核酸分子。核酸可以存在于完整细胞、细胞裂解液中或处于部分纯化或基本纯化的形式。当通过标准技术从其他细胞组分或者其他污染物例如其他细胞核酸或蛋白中纯化出来时,核酸是“分离的”或“处于基本纯化的状态”。本申请的核酸可以为例如DNA或RNA,且可能包含或可以不包含内含子序列。在优选实施方式中,核酸是cDNA分子。
本申请的核酸可使用标准分子生物学技术获得。对于杂交瘤(例如,从携带人免疫球蛋白基因的转基因小鼠制备的杂交瘤,下文将进一步说明)表达的抗体,编码由杂交瘤制备的抗体重链的cDNA可通过标准PCR扩增或cDNA克隆技术获得。对于(例如使用噬菌体展示技术)从免疫球蛋白基因库获得的抗体,可以从基因库中回收编码这类抗体的核苷酸。
优选的本申请核酸分子包括编码TROP2单克隆抗体VHH序列或CDR的那些。一旦获得编码VHH片段的DNA片段,这些DNA片段可以进一步通过标准的重组DNA技术进行操作,例如将可变区基因转变为全长抗体链基因,或转变为VHH片段基因。
编码VHH区的分离DNA可以通过可操作地连接编码VH的DNA与编码重链恒定区(CH1、CH2和CH3)的另一DNA分子而转变成全长重链基因。人重链恒定区基因的序列在领域内已知,且包括这些区域的DNA片段可以通过标准PCR扩增而获得。重链恒定区可以是IgG1、IgG2、IgG3、IgG4、IgA、IgE、IgM或IgD恒定区,但是最优选为IgG1或IgG4恒定区。
可以使用Kohler and Milstein(1975)Nature 256:495的本领域所公知的体细胞杂交(杂交瘤)技术制备本申请的单克隆抗体(mAb)。制备单克隆抗体的其他实施方式包括B淋巴细胞的病毒或致癌性转化以及噬菌体展示技术。嵌合的或人源化的抗体是本领域公知的。参见,例如美国专利4,816,567;5,225,539;5,530,101;5,585,089;5,693,762和6,180,370,上述文件的内容通过引用的方式整体并入本文。
本申请的抗体还可以使用例如本领域所公知的重组DNA技术和基因转染方法的组合在宿主细胞转染瘤中产生(e.g.,Morrison,S.(1985)Science 229:1202)。在一个实施方式中,将通过标准分子生物技术获得的编码部分或全长重链的DNA***到一个或多个表达载体中,从而使基因可操作地与转录和翻译调控序列相连接。在此背景下,术语“可操作地连接”是指将抗体基因连接到载体中,从而使载体内的转录和翻译调控序列发挥其调控抗体基因的转录和翻译的预期功能。
术语“调控序列”意在包括控制抗体基因转录或翻译的启动子、增强子和其他表达控制元件(例如,多腺苷酸化信号)。这样的调控序列在例如Goeddel(Gene ExpressionTechnology.Methods in Enzymology 185,Academic Press,San Diego,Calif.(1990))中有过描述。优选的用于哺乳动物宿主细胞表达的调控序列包括在哺乳动物细胞中引导高水平蛋白表达的病毒元件,例如得自巨细胞病毒(CMV)、猿猴病毒40(SV40)、腺病毒如腺病毒主要晚期启动子(AdMLP)和多瘤病毒的启动子和/或增强子。或者,可以使用非病毒调控序列,例如泛素启动子或β-珠蛋白启动子。另外,调控元件由不同来源的序列构成,例如SRα启动子***,其包含来自SV40早期启动子的序列和人T细胞白血病I型病毒的长末端重复(Takebe et al.,(1988)Mol.Cell.Biol.8:466-472)。选择与使用的表达宿主细胞兼容的表达载体和表达控制序列。
除抗体链基因和调控序列外,本申请的重组表达载体可以携带其他序列,例如,调控载体在宿主细胞中复制的序列(例如,复制起始点)和可选择标记基因。可选择标记基因有助于对导入载体的宿主细胞进行选择(参见例如,美国专利4,399,216;4,634,665和5,179,017)。例如,可选择标记基因通常会在导入载体的宿主细胞上赋予对药物如G418、潮霉素、或甲氨喋呤的抗性。优选的可选择标记基因包括二氢叶酸还原酶(DHFR)基因(用于具有甲氨喋呤选择/扩增的dhfr宿主细胞)和neo基因(用于G418选择)。
对于重链的表达,编码重链的表达载体通过标准技术转染到宿主细胞中。多种形式的术语“转染”意在包括多种将外源DNA导入原核或真核宿主细胞的常用技术,例如,电穿孔、磷酸钙沉淀、DEAE-葡聚糖转染等。尽管在原核或真核宿主细胞中表达本申请抗体在理论上是可行的,在真核细胞中表达抗体是最优选的,最优选在哺乳动物宿主细胞,因为这类真核细胞,特别是哺乳动物细胞,比原核细胞更可能组装并分泌出适当折叠且有免疫活性的抗体。
优选的用于表达本申请重组抗体的哺乳动物宿主细胞包括中国仓鼠卵巢(CHO细胞)(包括与DHFR可选择标记物一起使用的dhfr-CHO细胞,dhfr-CHO细胞在Urlaub andChasin,(1980)Proc.Natl.Acad.Sci.USA 77:4216-4220中有过描述,DHFR可选择标记物在例如R.J.Kaufman and P.A.Sharp(1982)J.Mol.Biol.159:601-621中有过描述)、NSO骨髓瘤细胞、COS细胞和SP2细胞。特别在使用NSO骨髓瘤细胞时,另一优选的表达***是GS基因表达***,记载于WO 87/04462、WO 89/01036和EP 338,841。当编码抗体基因的重组表达载体导入哺乳动物宿主细胞时,通过培养宿主细胞一段足以在宿主细胞种表达抗体的时间,或优选将抗体分泌在宿主细胞生长的培养基中,来制备抗体。使用标准的蛋白纯化方法从培养基中回收抗体。
另一方面,本申请提供双特异性分子,其可以包含本申请的一种或多种抗体,与至少一种其他功能分子例如另一种肽或蛋白(例如,用于受体的另一抗体或配体)连接,以产生与至少两个不同结合位点或靶分子结合的双特异性分子。因此,如本文所使用的,“双特异性分子”包括具有三种或更多种特异性的分子。
在实施方式中,除FcR结合特异性和TROP2结合特异性外,双特异性分子具有第三种特异性。
在另一方面,本发明提供诊断方法、组合物和试剂盒。在实施方式中,本发明的抗体或其抗原结合部分用于确定组织中TROP2的存在和表达。在实施方式中,诊断可提示预后和/或指导治疗和/或跟踪治疗。例如,TROP2信号通路已经被靶向用于肿瘤的治疗。在实施方式中,本发明的抗体或其抗原结合部分用于诊断试剂盒或方法,以确定TROP2相关肿瘤或癌症的预后和适当治疗与随访。
本申请的抗体可以与治疗剂、细胞毒素、或放射性标记物偶联,形成免疫偶联物。该细胞毒素可以是名为DT3C的重组蛋白,具有例如SEQ ID NO:22所示的氨基酸序列。
溶瘤病毒优先侵染并杀死癌细胞。本申请的抗体可以与溶瘤病毒联合使用。或者,可将编码本申请抗体的溶瘤病毒引入人体。
本文还提供包含TROP2 VHH片段的嵌合抗原受体(CAR),该TROP2 VHH可包含本文所述的CDR和重链可变区。
TROP2 CAR可以包含(a)可包含TROP2VHH的胞外抗原结合域;(b)跨膜结构域;和(c)胞内信号结构域。
CAR可以在胞外抗原结合域的N端含有指导新生受体进入内质网的信号肽,以及在胞外抗原结合域的N-端的使受体更容易结合的铰链肽。CAR优选地在胞内信号传导结构域包含主要的胞内信号传导域和一个或多个共刺激信号传导域。主要使用的和最有效的主要胞内信号传导域是包含ITAM的CD3-ζ胞质结构域,其磷酸化会引起T细胞活化。共刺激信号传导域可以衍生自共刺激蛋白,例如CD28、CD137和OX40。
CAR还可以添加增强T细胞扩增、持续性和抗肿瘤活性的因子,例如细胞因子和共刺激配体。
还提供基因修饰的免疫效应细胞,其可以包含本文提供的CAR。在一些实施方式中,免疫效应细胞是T细胞、NK细胞、外周血单核细胞(PBMC)、造血干细胞、多能干细胞、或胚胎干细胞。在一些实施方式中,免疫效应细胞是T细胞。
在另一方面,本申请提供一种药物组合物,其可以包含与药学上可接受的载体配制在一起的本申请的一种或多种抗体(或其抗原结合部分、双特异性分子、CAR-T细胞、溶瘤病毒、免疫偶联物、或能够表达上述分子的本申请核酸分子或表达载体)。当组合物中含有多于一种的抗体(或其抗原结合部分、双特异性分子、CAR-T细胞、溶瘤病毒、免疫偶联物、或能够表达这些分子的本申请核酸分子或表达载体)时,抗体(或其抗原结合部分、双特异性分子、CAR-T细胞、溶瘤病毒、免疫偶联物、或能够表达这些分子的本申请核酸分子或表达载体)可以分开给药。组合物可以任选地包含一种或多种其他药学上的活性成分,例如另一抗体或药物,例如抗肿瘤药物。
药物组合物可以包含任何数量的赋形剂。可以使用的赋形剂包括载体、表面活性剂、增稠或乳化剂、固体粘合剂、分散或混悬剂、增溶剂、染色剂、矫味剂、包衣、崩解剂、润滑剂、甜味剂、防腐剂、等渗剂及其组合。在Gennaro,ed.,Remington:The Science andPractice of Pharmacy,20th Ed.(Lippincott Williams&Wilkins 2003)中,对合适赋形剂的选择和使用有所讲解,其公开内容通过引用的方式并入本文。
优选地,该药物组合物适合于静脉内、肌内、皮下、肠道外、脊柱或表皮给药(例如通过注射或输注)。基于给药途径的不同,有效成分可以包在材料中,以保护其免受酸和其他可能使其失活的自然条件的影响。本文所用的术语“肠道外给药”是指非肠内和非局部外用的给药方式,通常通过注射进行,包括但不限于静脉内、肌内、动脉内、鞘内、囊内、眶内、心内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊膜下、蛛网膜下腔、椎管内、硬膜外和胸骨内注射和输注。或者,本申请的抗体可以通过非肠道外的途径给药,例如外用、表皮或粘膜给药,例如鼻内、经口、***、直肠、舌下、或局部外用。
药物组合物可呈无菌水溶液或分散液的形式。它们也可以配制成微乳液、脂质体或其他适合于高药物浓度的有序结构。
可与载体材料组合以产生单一剂型的活性成分的量将随治疗主体和特定给药方式而变,且通常是产生疗效的组合物的量。一般来说,以百分比计,这个量的范围是活性成分的约0.01%-约99%。
调整给药方案以提供最佳的所需的应答(例如,治疗应答)。例如,可以施用快速灌注剂,可以随时间推移施用多个分剂量,或者剂量可以随治疗情况的危急程度成比例降低或提高。特别有利的是,以方便施用和剂量均匀,配置剂量单位型的肠道外组合物。如本文所用的剂量单位形式是指适合作为单位剂量用于待治疗个体的物理离散单位;每一单位含有经计算以结合所需药物载体产生期望治疗效果的预定量的活性成分。另外,抗体也可以缓释剂型给药,这种情况下需要的给药频率较低。
对于组合物的给药,剂量范围可以为约0.0001-100mg/kg。示例性治疗方案是每月给药一次。
“治疗有效剂量”的本申请TROP2抗体或其抗原结合部分、或双特异性分子、CAR-T细胞、溶瘤病毒、免疫偶联物,优选地引起疾病症状严重程度的降低、疾病无症状期频率和持久度的增加,或预防疾病折磨造成的损伤或残疾。例如,对于荷瘤受试者的治疗,与未接受治疗的受试者相比,“治疗有效剂量”优选将炎症消除至少约20%、更优选为至少约40%,甚至更优选为至少约60%,更优选为至少约80%。
药物组合物可以是控释剂型,包括植入体、经皮贴剂和微胶囊递送***。可以使用生物可降解、生物相容的聚合物,例如乙烯-醋酸乙烯、聚酸酐、聚乙醇酸、胶原蛋白、聚原酸酯和聚乳酸。参见,例如,Sustained and Controlled Release Drug DeliverySystems.J.R.Robinson,ed.,Marcel Dekker,Inc.,New York,1978。
药学组合物可以经医学设备来给药,例如(1)无针皮下注射设备(例如,美国专利5,399,163;5,383,851;5,312,335;5,064,413;4,941,880;4,790,824和4,596,556);(2)微量输液泵(美国专利4,487,603);(3)经皮给药设备(美国专利4,486,194);(4)推注设备(美国专利4,447,233和4,447,224);和(5)渗透设备(美国专利4,439,196和4,475,196),上述文献的公开内容通过引用的方式并入本文。
在某些实施方式中,可以配制本申请的单克隆抗体,以确保在体内的合适分布。例如,为确保本申请的治疗抗体或其抗原结合部位可以穿越血脑屏障,它们可以配制在脂质体中,其还可以额外地包含靶向功能基团,以增强对特定细胞或器官的选择性输送。参见,例如美国专利4,522,811;5,374,548;5,416,016;和5,399,331;v.V.Ranade(1989)J.Clin.Pharmacol.29:685;Umezawa et al.,(1988)Biochem.Biophys.Res.Commun.153:1038;Bloeman et al.,(1995)FEBS Lett.357:140;M.Owais et al.,(1995)Antimicrob.Agents Chemother.39:180;Briscoe et al.,(1995)Am.J.Physiol.1233:134;Schreier et al.,(1994)J.Biol.Chem.269:9090;Keinanen and Laukkanen(1994)FEBS Lett.346:123;和Killion and Fidler(1994)Immunomethods 4:273。
可以包含本申请的抗体或其抗原结合部位、或双特异性分子、CAR-T细胞、溶瘤病毒、免疫偶联物、或可选地能够表达本申请上述分子的本申请的核酸分子或载体的药物组合物具有多种体外和体内用途,涉及例如对有过度TROP2信号通路的肿瘤的治疗。
鉴于TROP2与肿瘤细胞增殖相关,本申请提供用于治疗TROP2相关肿瘤或癌症的方法,其可以包括向受试者施用本申请的药物组合物。肿瘤可以是实体瘤或血液肿瘤,包括,但不限于,乳癌、结直肠癌、胃腺癌、食管癌、肝细胞癌、非小细胞肺癌、小细胞肺癌、卵巢上皮癌、***癌、胰腺导管腺癌、头颈癌、鳞状细胞癌、肾细胞癌、***、***、子宫内膜癌、滤泡性甲状腺癌、和胶质母细胞瘤。在一些实施方式中,还可以施用至少一种其他的抗癌抗体,例如VISTA抗体、PD-1抗体、PD-L1抗体、LAG-3抗体、CTLA-4抗体、TIM 3抗体、STAT3抗体、和/或ROR1抗体。在某些实施方式中,受试者是人。
在另一个方面,本申请提供联合治疗方法,其中本申请的药物组合物与一个或多个对抑制受试者中肿瘤生长有效的其他抗体共同施用。在一个实施方式中,本申请提供一种用于抑制受试者中肿瘤生长的方法,其可以包括向受试者施用本申请的药物组合物和一种或多种其他抗体,例如OX40抗体、TIM-3抗体、CD137抗体、GITR抗体、LAG-3抗体、PD-L1抗体和PD-1抗体。在某些实施方式中,受试者是人。TROP2信号通路阻断还可以与标准肿瘤治疗相结合。例如,TROP2信号通路阻断可以与LAG-3和/或PD-1阻断以及化疗方案相结合。例如,化疗试剂可以与TROP2抗体一起施用,其可以为细胞毒试剂。例如,将表阿霉素、奥沙利ROP2疗法的患者。可选地,TROP2抗体与一种或多种其他抗体(例如,LAG-3抗体和/或PD-1抗体)的联合还可以与免疫原剂例如癌细胞、纯化的肿瘤抗原(包括重组蛋白、肽和碳水化合物分子)和转染有编码免疫刺激细胞因子的基因的细胞相结合(He et al.,(2004)J.Immunol.173:4919-28)。可以使用的肿瘤疫苗的非限制性实例包括黑色素瘤抗原肽,例如gp100肽,MAGE抗原,Trp-2,MART1和/或酪氨酸酶,或转染表达细胞因子GM-CSF的肿瘤细胞。其他可以与TROP2抗体相结合的疗法包括,但不仅限于,施用白介素-2(IL-2)、放疗、手术或激素抑制。
本文讨论的治疗剂的联合可以作为在药学上可接受载体中的单一组合物同步给药,或者作为各药物处于药学上可接受载体中的分开的组合物同步给药。在另一个实施方式中,治疗剂的联用可以是按序施用。
此外,如果多于一剂的联合疗法需按序施用,按序给药的顺序可以在每个给药时间点颠倒或者保持相同的顺序,按序给药可以与同步给药相结合,或者任意组合。
本申请还提供对有需求受试者中的TROP2阳性组织,例如癌症组织,进行成像的方法,包括向受试者施用本申请的经放射性标记的TROP2抗体或其抗原结合部分、免疫偶联物、或双特异性分子。该方法可用于追踪/检测TROP2高表达的肿瘤或癌症的分布,包括,但不限于,食管鳞状细胞癌、结直肠癌、胰腺癌、结肠癌、***状甲状腺癌、乳癌和膀胱癌。在某些实施方式中,受试者是人。
尽管已经对本申请及其优势进行了详细的阐述,应当理解的是,可以在不脱离在所附权利要求中限定的本发明宗旨和范围的情况下,在本文中做出多种改变、替换和变动。
本申请在以下实施例中进一步阐明,实施例不应当解读为进一步的限制。所有图片和本申请中引用的参考文献、Genbank序列、专利和公开的专利申请的内容通过引用的方式明确地全部并入本文。
实施例
实施例1.制备TROP2单域抗体
文库构建及筛选
根据E Harlow,D.Lane,Antibody:A Laboratory Manual,Cold Spring HarborLaboratoryPress,Cold SpringHarbor,N.Y.,1998中所述的方法免疫健康的成年骆驼。将内部制备的C端带人IgG1 Fc的重组人TROP2蛋白(氨基酸序列为SEQ ID NO:15)作为免疫原。对于初次免疫,免疫剂量包含1.0mg人TROP2-Fc/骆驼/注射,对于增强免疫,包含0.5mg人TROP2-Fc/骆驼/注射。为增加免疫应答,在初次免疫和增强免疫中分别使用弗氏完全佐剂和弗氏不完全佐剂(Sigma,St.Louis,Mo.,USA)。5次免疫后,从100ml骆驼外周血中分离出淋巴细胞,并用FastPure细胞/组织总RNA提取试剂盒(Vazyme,Cat#RC101)提取总RNA。根据操作手册,使用Hiscript III第一链cDNA合成试剂盒(+gDNA清除剂)(Vazyme,Cat#R312-01)将提取的RNA逆转录成cDNA。通过巢式PCR扩增编码VHH的核酸片段。
使用核酸内切酶Pst和NotI(购自NEB),将目标VHH核酸片段克隆至噬菌体展示载体pMECS中。然后将产物电转化至大肠杆菌(E.coli)感受态细胞TG1(购自LucigenCorporation),构建TROP2单域抗体的噬菌体展示文库,并进行验证。通过平板梯度稀释,确定库容量为约2.0×108。为确定文库***率,随机筛选95个克隆用于菌落PCR。结果显示,***率高于89.5%。
TROP2单域抗体的淘选
使用人TROP2-his蛋白(内部制备,SEQ ID NO:16),在噬菌体ELISA中检测TROP2抗体与人TROP2蛋白的交叉反应。将特异性结合TROP2的噬菌体用甘氨酸(pH=2.2,100mM)解离,用于感染对数增长期的大肠杆菌TG1,产生噬菌体,该噬菌体经纯化用于下一轮的筛选。相同的筛选重复进行2轮。
噬菌体酶联免疫检测(ELISA)筛选个体阳性克隆
用经2轮淘选得到的结合TROP2的阳性噬菌体感染空白大肠杆菌,然后用其铺板。总共选出940个单克隆,并接种于补充有100μg/mL氨苄西林的2YT培养基。当菌液的光密度(OD)达到0.6-0.8时,以1000∶1的比例添加1M IPTG(QIAGEN,Cat#RT108-01),然后30℃过夜诱导抗体表达。
用100μl 1μg/ml人TROP2-his蛋白(内部制备,SEQ ID NO:16)或1μg/ml猴TROP2-his蛋白(内部制备,SEQ ID NO:19)的碳酸盐/碳酸氢盐缓冲液(pH9.6)包被ELISA板,4℃过夜,用洗涤缓冲液(PBS+0.05%v/v吐温-20,PBST)冲洗一次,再于37℃用200μl/孔封闭缓冲液(含5%w/v脱脂牛奶的PBST)封闭2小时。板冲洗4次,分别与100μl细菌培养上清液、以及200ng/ml于含5%w/v脱脂牛奶的PBST中的赛妥珠单抗(作为对照基准物,在下文中又称为BM或BM1,内部制备,重链和轻链氨基酸序列为SEQ ID NOs:17和18),于37℃孵育40分钟。板冲洗4次,与THETM HA标签抗体[HRP],mAb,小鼠抗体(1∶5000稀释于PBST,GenScript,Cat#A01296,100μl/孔,用于含本公开细菌培养上清液的板)或过氧化物酶亲和纯化F(ab′)2片段山羊抗人IgG,Fcγ片段特异(Jackson Immunoresearch,Cat#109-036-098,用于含对照基准物的板),37℃孵育40分钟。在终洗后,板与100μl/孔ELISA底物TMB(Innoreagents,Cat#TMB-S-002)室温孵育。3-10分钟后用50μl/孔1MH2SO4中止反应,在酶标仪中对各孔的吸光度进行读数,使用双波长模式,450nm用于TMB,630nm作为参照波长。当样品孔的OD高于空白孔OD的2倍时,可确定样品为阳性。示例性上清液的结果如表2所示。
表2.克隆对TROP2的结合活性
将阳性孔中的细菌转移至补充有100μg/ml氨苄西林的LB液体培养基中进行培养,以用于质粒提取和之后的测序。
根据序列比对软件Vector NTI,分析每个克隆产生的抗体的氨基酸序列,最终获得两个单域抗体,其CDR和VHH序列列于表1。
实施例2.TROP2单域抗体的初步评价
将各个包含编码VHH的核苷酸的载体瞬时转染到100ml含有3μg/ml PEI的293F悬浮细胞培养物中。在摇瓶中培养6天,收获含有单域抗体的细胞上清液,旋转使细胞成团,然后用蛋白A琼脂糖柱(bestchrom(Shanghai)Biosciences,Cat#AA0273)从细胞上清液中纯化出单域抗体。简单地说,使用5-10倍柱体积的PBS缓冲液冲洗柱子。使细胞上清液流经柱子,然后用PBS缓冲液冲洗柱子,直至蛋白吸光度达到基线。用洗脱缓冲液(0.1M甘氨酸-HCl,pH2.7)洗脱柱子,并立即收集到含有中性缓冲液(1M Tris-HCl,pH 9.0)的1.5ml管中。将含有单域抗体的部分集中,并于4℃在PBS中透析过夜。
按照下述的实验操作规程,对纯化的单域抗体进行间接ELISA、表位聚类、BIAcore亲和力测试和基于细胞的内化实验。
在间接ELISA中检测本公开单域抗体与猴TROP2蛋白的交叉反应。简单来说,用100μl 2μg/ml人TROP2-his蛋白(内部制备,SEQ ID NO:16)的碳酸盐/碳酸氢盐缓冲液(pH9.6)包被96孔微孔板,4℃过夜。ELISA板用洗涤缓冲液(PBS+0.05%v/v吐温-20,PBST)冲洗一次,再于37℃用200μl/孔封闭缓冲液(含5%w/v脱脂牛奶的PBST)封闭2小时。板冲洗4次,与100μl/孔梯度稀释的本申请TROP2抗体或对照(起始于66.7nM,用含2.5%w/v脱脂牛奶的PBST 5倍梯度稀释)于37℃孵育40分钟。ELISA板再冲洗4次,与过氧化物酶亲和纯化F(ab′)2片段山羊抗人IgG,Fcγ片段特异(Jackson Immuno Research,Cat#109-036-098,1∶5000稀释于PBST缓冲液,100μl/孔)于37℃孵育40分钟。在终洗后,板与100μl/孔TMB(InnoReagents)室温孵育。室温3-10分钟后用50μl/孔1M H25O4中止反应,在酶标仪中对各孔的吸光度进行读数,使用双波长模式,450nm用于TMB,630nm作为参照波长。用OD(450-630)值和抗体浓度做图。使用Graphpad Prism软件对数据进行分析,得出EC50值。结果如图1所示。
用BiacoreT200***(GEhealthcare,Pittsburgh,PA,USA)对纯化TROP2小鼠源单克隆抗体(mAb)进行结合亲和力和结合动力学的表征。简单来说,使用Biacore提供的标准胺偶联试剂盒(GE healthcare,Pittsburgh,PA,USA),将山羊抗人IgG(GE healthcare,Cat#BR100839,人抗体捕获试剂盒)经伯胺共价连接到CM5芯片(羧甲基右旋糖包被芯片,GEhealthcare,#BR100530)。芯片(生物传感器)表面未反应的基团用乙醇胺封闭。使本申请TROP2抗体和对照基准物以2μg/ml的浓度分别流至芯片,流速为10μL/min。然后,将梯度稀释的人TROP2-his蛋白(内部制备,SEQ ID NO:16)或猴TROP2-his蛋白(内部制备,SEQ IDNO:19),2倍稀释于HBS-EP+缓冲液(Biacore提供),起始浓度160nM,,以30μL/min的流速流到芯片上。抗原-抗体结合动力学检测2分钟,解离动力学检测10分钟。用BIAcore评估软件将结合与解离曲线拟合到1∶1 Langmuir结合模型中。结果如表3所示。
在竞争ELISA检测中,测定TROP2抗体的表位结合。简单地说,用100μl 1μg/mL于PBS中的对照基准物包被96孔微孔板,37℃2小时。ELISA板用冲洗缓冲液(PBS+0.05%v/v吐温-20,PBST)冲洗一次,再用200μl封闭缓冲液(含5%w/v脱脂牛奶的PBST)于37℃封闭2小时。封闭时,用生物素标记的人TROP2-his蛋白(SEQ ID NO:16,34ng/mL于含2.5%w/v脱脂牛奶的PBST中)稀释本申请TROP2抗体或对照,起始浓度80nM,5倍梯度稀释,并于室温孵育40分钟。板冲洗4次后,将抗体/TROP2-his蛋白混合物加至对照基准物包被的板中,100μl/孔。37℃孵育40分钟后,用洗涤缓冲液再次冲洗板4次。之后加入100μl链霉亲和素-过氧化物酶(1∶10000稀释于PBST缓冲液,Jackson Immunoresearch,Cat#016-030-084),板于37℃孵育40分钟。用洗涤缓冲液终洗板。最后,加入TMB,用1M H25O4终止反应。在酶标仪中对各孔吸光度进行读数,使用双波长模式,450nm用于TMB,630nm作为参照波长。用OD(450-630)值和抗体浓度做图。使用Graphpad Prism软件对数据进行分析,得出IC50值。结果如图2所示。
对于基于细胞的内化实验,使用Biosion内部制备的在细胞膜上稳定表达全长人TROP2(uniprot#P09758,SEQ ID NO:20)的293F-TROP2细胞(克隆ID#3A8)精准评估TROP2抗体的内化效率。293F-TROP2细胞的制备根据lipofectamine 3000转染试剂(ThermoFisher)的说明书,用在EcoRI和XbaI位点之间***有TROP2编码序列的pCMV-T-P质粒转染293F细胞(ThermofisherInc.,Cat#11625019)。首先,将于100μL补充有10%v/vFBS(Gibco,Cat#10099-141)的FreeStyle293培养液(Gibco,Cat#12338-018)中的5×103个293F-TROP2细胞在96孔平底板(Thermo Fisher Scientific Inc.,Cat#167008)中铺板。在细胞接种的次日,将本申请TROP2抗体或对照(1.6μg/mL于含10%v/v FBS的FreeStyle293培养液中)与DTTP 1170(使用SEQ ID NO:22所示氨基酸序列合成的重组蛋白,1.6μg/mL于含10%v/vFBS的FreeStyle293培养液中)以1∶1体积比混合,室温孵育30分钟,之后梯度稀释于细胞培养液,3倍梯度稀释,起始浓度0.8μg/mL。然后,将100μl梯度稀释的抗体/DTTP1170混合物加至细胞板中,在CO2孵育器中,37℃孵育72小时。向板中加入细胞滴度Glo试剂(VazymeBiotech Co.,Ltd,Cat#DD1101-02),室温孵育3-5分钟。然后,使用Tecan infinite 200Pro酶标仪分析细胞培养板。使用Graphpad prism软件分析数据,以达到细胞活力50%最大抑制的抗体浓度为IC50值。结果如图3所示。当mAb-DTTP偶联物由靶细胞内化时,靶细胞活力明显下降。如果偶联物没有被内化,则培养基中游离的DTTP1170没有或几乎没有的细胞杀伤活性。
从表3可以看出,本申请的单域抗体与人TROP2特异性结合,结合亲和力高于对照基准物,并且与猴TROP2特异性结合,亲和力与对照基准物相当。
图1示出,本申请的单域抗体与人TROP2蛋白特异性结合,与对照基准物相比,具有相似的Bmax,但EC50略低。
表3.单域抗体的结合亲和力
如图2所示,本申请的单域抗体能够阻断人TROP2-对照基准物结合,表明它们结合在与对照基准物相同或相似的表位。
此外,如图3所示,本申请单域抗体的DT3C偶联物比对照基准物-DT3C偶联物更高效地造成靶细胞死亡。
实施例3.单域抗体01-9F的基因改造
将01-9F单域抗体(VHH)在可读框内克隆至人IgG1 Fc区(内部制备,SEQ ID NO:14),其中VHH的C端与Fc区的N端相连。
将各个包含编码与人IgG1-Fc区相连的VHH的核苷酸的载体,瞬时转染到100ml含有3μg/ml PEI的293F悬浮细胞培养物中。在摇瓶中6天后,收集含有重链抗体(VHH-Fc)的细胞上清液,旋转使细胞成团,然后从上述细胞上清液中纯化出所得的重链抗体(在本文中又称为01-9F-Fc)。
为避免或降低例如CDR区中某些氨基酸残基的可能不利地影响抗体的生产、稳定性、安全性和/或效力的翻译后修饰例如异构化,对单域抗体01-9F进一步在CDR2或CDR3区进行修饰,得到共11个修饰变体,即01-9F-CDR-V1至01-9F-CDR-V1 1,其CDR和VHH序列ID号列于表1。
将各个包含编码与人IgG1重链恒定区(SEQ ID NO:14)相连的01-9F-CDR-V1至01-9F-CDR-V1 1之一的VHH的核苷酸的载体,瞬时转染到100ml含有3μg/ml PEI的293F悬浮细胞培养物中。
实施例4.01-9F-Fc变体的表征
在摇瓶中6天后,收集含有重链抗体(01-9F-Fc变体),即01-9F-CDR-V1-Fc至01-9F-CDR-V11-Fc,的细胞上清液,旋转使细胞成团,然后根据加以后述修改的前述实施例中的操作规程,在BIAcore亲和测试和基于细胞的内化实验中进行测定。
对于BIAcore测试,使含有01-9F-Fc变体的细胞上清液,而非纯化的TROP2抗体,以10μL/min的流速分别流至芯片,并使40nM在HBS-EP+缓冲液(Biacore提供)中的人TROP2-his蛋白(内部制备,SEQ ID NO:16),而非梯度稀释的人TROP2-his蛋白,流至芯片,流速为30μL/min。确定KD、Ka和Kd值,并总结在以下表4中。
表4. 01-9F-Fc变体的结合亲和力
在基于细胞的内化实验中,将DT3C用于偶联重链抗体,内部制备的CD22抗体作为阴性对照。简单地说,将于100μL补充有10%v/vFBS(Gibco,Cat#10099-141)的FreeStyle293培养液(Gibco,Cat#12338-018)中的1.5×103个293F-TROP2细胞在96孔平底板(Thermo Fisher Scientific Inc.,Cat#167008)中铺板。将01-9F-Fc变体或对照(40nM于含10%v/v FBS的FreeStyle293培养液中)与DT3C蛋白(40nM于含10%v/vFBS的FreeStyle293培养液中)以1∶1体积比混合,室温孵育30分钟,之后梯度稀释于细胞培养液,3倍梯度稀释,起始浓度20nM。结果如图4所示。
从表4可以看出,本申请的01-9F-CDR-Fc变体与人TROP2特异性结合,其与01-9F和01-9F-Fc相比,结合亲和力相当。
根据图4,01-9F-Fc变体的DT3C偶联物,包括01-9F-CDR-V5-Fc、01-9F-CDR-V9-Fc和01-9F-CDR-V11-Fc,与对照基准物-DT3C偶联物相比,更高效地造成靶细胞死亡。
实施例5.01-9F-CDR-V11的人源化
将变体01-9F-CDR-V11-Fc进行纯化和人源化,得到共24个示例性人源化抗体,即01-9F-CDR-V11-V1-Fc至01-9F-CDR-V11-V24-Fc,其VHH序列ID号列于表1。
将各自包含编码与人IgG1重链恒定区(SEQ ID NO:14)相连的01-9F-CDR-V11-V1至01-9F-CDR-V11-V24之一的VHH的核苷酸的载体,瞬时转染到100ml含有3μg/ml PEI的293F悬浮细胞培养物中。
实施例6.示例性人源化01-9F-CDR-V11抗体的表征
在摇瓶中6天后,收获含有人源化01-9F-CDR-V11抗体的细胞上清液,旋转使细胞成团,根据加以后述修改的上述实施例中的操作规程,经BiAcore T200***(GEhealthcare,Pittsburgh,PA,USA)测试其与人TROP2的结合亲和力。
表5.人源化01-9F-CDR-V11抗体的结合亲和力
对于BIAcore测试,使含有人源化01-9F-CDR-V1 1抗体的细胞上清液以10μL/min的流速分别流至芯片,且使40nM在HBS-EP+缓冲液(Biacore提供)中的人TROP2-his蛋白(内部制备,SEQ ID NO:16)以30μL/min的流速流至芯片。确定KD、Ka和Kd值,并总结在以上表5中。
从表5可以看出,人源化01-9F-CDR-V11抗体具有较高的人TROP2结合亲和力,01-9F-CDR-V11-V1、01-9F-CDR-V11-V9和01-9F-CDR-V11-V11显示出最高的结合亲和力。
实施例7.示例性人源化01-9F-CDR-V11抗体的进一步表征
如上所述,纯化人源化抗体01-9F-CDR-V11-V1-Fc、01-9F-CDR-V11-V9-Fc和01-9F-CDR-V11-V11-Fc,并在基于细胞的内化实验中,按照上述实施例的操作规程(做后述修改)进行测试。
在基于细胞的内化实验中,使用DT3C偶联这些抗体,内部制备的CD22抗体作为阴性对照。简单地说,将于100μL补充有10%v/v FBS(Gibco,Cat#10099-141)的FreeStyle293培养液(Gibco,Cat#12338-018)中的1.5×103个293F-TROP2细胞(克隆ID#3A8)在96孔平底板(Thermo Fisher Scientific Inc.,Cat#167008)中铺板。将人源化抗体或对照(40nM于含10%v/v FBS的FreeStyle293培养液中)与DT3C蛋白(40nM于含10%v/vFBS的FreeStyle293培养液中)以1∶1体积比混合,室温孵育30分钟,之后梯度稀释于细胞培养液,3倍梯度稀释,起始浓度20nM。结果如图5所示。
根据图5,人源化01-9F-CDR-V11抗体的DT3C偶联物,包括01-9F-CDR-V11-V1-Fc、01-9F-CDR-V11-V9-Fc和01-9F-CDR-V11-V11-Fc,以与对照基准物-DT3C偶联物相似的速率造成靶细胞死亡。
按照以下所述的操作规程以及上述实施例中的操作规程(修改或不做修改),在Biacore、捕获ELISA、间接ELISA、基于细胞的结合FACS、竞争ELISA和蛋白热迁移实验中,进一步测试人源化抗体01-9F-CDR-V11-V11-Fc。
BIAcore测试结果总结于下表6。
对于捕获ELISA,用100μl 2μg/ml亲和纯化F(ab′)2片段山羊抗人IgG,Fcγ片段特异(JacksonImmuno Research,Cat#109-006-008)的PBS液包被96孔板,4℃过夜。板用洗涤缓冲液(PBS+0.05%v/v吐温-20,PBST)冲洗一次,再于37℃用200μl/孔封闭缓冲液(含5%w/v脱脂牛奶的PBST)封闭2小时。板冲洗4次,分别与100μl梯度稀释的本申请TROP2抗体、对照基准物或阴性对照hIgG(静脉注射用人免疫球蛋白(pH4),华兰生物工程有限公司)(5倍稀释于含2.5%w/v脱脂牛奶的PBST,起始浓度66.7nM)于37℃孵育40分钟,然后再次冲洗4次。含有捕获的TROP2抗体的板与生物素标记的人TROP2-his蛋白(内部制备,SEQ ID NO:16,56.7ng/mL于含2.5%w/v脱脂牛奶的PBST中,100μl/孔)37℃孵育40分钟,冲洗4次,与链霉亲和素结合的HRP(1∶10000稀释于PBST,Jackson Immuno Research Laboratories,Inc,Cat#016-030-084,100μl/孔)于37℃孵育40分钟。终洗后,板与100μl/孔ELISA底物TMB(Innoreagents,Cat#TMB-S-002)室温孵育。在室温3-10分钟后用50μl/孔1M H2SO4终止反应,在酶标仪中对各孔的吸光度进行读数,使用双波长模式,450nm用于TMB,630nm作为参照波长。用OD(450-630)值和抗体浓度做图。使用Graphpad Prism软件对数据进行分析,得出EC50值。结果如图6所示。
对于间接ELISA,使用亲和纯化山羊抗人IgG,Fcγ片段特异(JacksonImmunoresearch,Cat#109-005-098),100μl/孔。结果如图7和图8所示。
在基于细胞的结合FACS中,从细胞培养瓶中收集293F-TROP2细胞,洗涤两次,在含2%v/v胎牛血清的磷酸盐缓冲液(PBS)(FACS缓冲液)中重悬。然后,在96孔板中,每孔2×105个293F-TROP2细胞,在冰上,与100μl处于多种浓度的TROP2抗体或对照(起始浓度66.7nM,4倍梯度稀释于FACS缓冲液)孵育40分钟。细胞用FACS缓冲液洗涤两次,并加入100μL/孔R-藻红蛋白亲和纯化山羊抗人IgG,Fcγ片段特异(1:1000稀释于FACS缓冲液,JacksonImmunoresearch,Cat#109-115-098)。4℃避光孵育40分钟后,细胞洗涤2次,并用FACS缓冲液重悬。使用Becton Dickinson FACS CantoII-HTS设备进行荧光测定,用MFI(平均荧光强度)和抗体浓度作图。采用Graphpad Prism软件进行数据分析,得出EC50值。结果如图9所示。
对于表位聚类,使用2μg/mL对照基准物,100μl/孔。用生物素标记的人TROP2-his蛋白(SEQ ID NO:16,8.7ng/mL于含2.5%w/v脱脂牛奶的PBST中)稀释人源化抗体01-9F-CDR-V11-V11或对照,起始浓度66.7nM,5倍梯度稀释,并于室温孵育40分钟。结果如图10所示。
对于热迁移实验,使用蛋白热迁移TM染色试剂盒(Thermo Fisher,Cat#4461146)测定Tm(熔融温度)。简而言之,使GloMeltTM染料融化,达到室温。将装有染料的小瓶进行涡旋振荡和离心。然后,通过向95μL PBS中加入5μL 200×染料,制备10×染料。加入2μL 10×染料和10μg人源化抗体,PBS加至20μL总反应体积。简单地旋转含有染料和抗体的管子,并置于CFX Connect实时PCR检测***(Bio-Rad,Cat#1855201)中。结果如图11A-11C所示。
表6. 01-9F-CDR-V11-V11-Fc的结合亲和力
根据表6,01-9F-CDR-V11-V11-Fc显示出与01-9F和01-9F-CDR-V11-Fc相当的人和猴TROP2结合亲和力,略高于对照基准物。图6至9示出,01-9F-CDR-V11-V11-Fc具有高于对照基准物的人和猴TROP2结合活性。
如图10所示,01-9F-Fc-CDRV11-V11能够阻断BM1-TROP2结合,表明它很可能结合在与BM1相似的表位。
此外,如图11A-11C所示,根据熔融温度,抗体01-9F、01-9F-CDR-V11-Fc和01-9F-CDR-V11-V11-Fc在人体内很可能是稳定的。
尽管本申请已经结合一个或多个实施方式在以上进行了阐述,应当理解的是,本申请不限于那些实施方式,且说明书意在涵盖包括在所附权利要求的宗旨和范围内的所有可选方案、修改和等同物。所有本文中引用的文献进一步通过引用的方式全文并入。
本申请中的序列总结如下。
***
已经在本发明的优选实施方式中进行了具体阐述,应当理解的是,由上述段落定义的本发明不限于在上述描述中列出的特定细节,可以在不脱离本发明宗旨和范围的情况下做出很多明显的变形。
序列表
<110> 博奥信生物技术(南京)有限公司
<120> 结合TROP2的纳米抗体及其用途
<130> 55532 00042
<150> CN202011209105.X
<151> 2020-11-03
<160> 26
<170> PatentIn版本3.5
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 01-9F、01-9F-CDR-V1至01-9F-CDR-V11、
01-9F-CDR-V11-V1至01-9F-CDR-V11-V24的VHH CDR1
<400> 1
Arg Tyr Cys Val Ala
1 5
<210> 2
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 01-9F和01-5A抗体的VHH CDR2
<220>
<221> 其他特征
<222> (5)..(5)
<223> Xaa可以是Asp或Glu
<220>
<221> 其他特征
<222> (6)..(6)
<223> Xaa可以是Gly或Ala
<220>
<221> 其他特征
<222> (12)..(12)
<223> Xaa可以是Asp或Glu
<220>
<221> 其他特征
<222> (13)..(13)
<223> Xaa可以是Ser或Thr
<400> 2
Arg Ile Leu Ser Xaa Xaa Thr Thr Ser Tyr Ser Xaa Xaa Val Lys Gly
1 5 10 15
<210> 3
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 01-9F和01-5A抗体的VHH CDR3
<220>
<221> 其他特征
<222> (10)..(10)
<223> Xaa可以是Asp、Glu或Ile
<220>
<221> 其他特征
<222> (11)..(11)
<223> Xaa可以是Gly或Ala
<400> 3
Glu Ala Phe Arg Pro Phe Thr Pro Ser Xaa Xaa Asp Cys Thr Thr Val
1 5 10 15
Leu Gly Ile Asp Tyr
20
<210> 4
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 01-9F、01-9F-CDR-V1至01-9F-CDR-V3、和01-5A的VHH
<220>
<221> 其他特征
<222> (11)..(11)
<223> Xaa可以是Ser或Thr
<220>
<221> 其他特征
<222> (13)..(13)
<223> Xaa可以是Gln或Gly
<220>
<221> 其他特征
<222> (107)..(107)
<223> Xaa可以是Asp、Glu或Ile
<220>
<221> 其他特征
<222> (108)..(108)
<223> Xaa可以是Gly或Ala
<220>
<221> 其他特征
<222> (124)..(124)
<223> Xaa可以是Pro或Leu
<400> 4
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Xaa Val Xaa Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Val Ser Gly Leu Pro Tyr Glu Arg Tyr
20 25 30
Cys Val Ala Trp Phe Arg Gln Gly Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Arg Ile Leu Ser Asp Gly Thr Thr Ser Tyr Ser Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Ala Glu Ala Phe Arg Pro Phe Thr Pro Ser Xaa Xaa Asp Cys Thr Thr
100 105 110
Val Leu Gly Ile Asp Tyr Trp Gly Lys Gly Thr Xaa Val Thr Val Ser
115 120 125
Ser
<210> 5
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 01-9F-CDR-V4、01-9F-CDR-V5、01-9F-CDR-V8和01-9F-CDR-V9的VHH
<220>
<221> 其他特征
<222> (54)..(54)
<223> Xaa可以是Glu或Asp
<220>
<221> 其他特征
<222> (55)..(55)
<223> Xaa可以是Gly或Ala
<220>
<221> 其他特征
<222> (61)..(61)
<223> Xaa可以是Asp或Glu
<400> 5
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Val Ser Gly Leu Pro Tyr Glu Arg Tyr
20 25 30
Cys Val Ala Trp Phe Arg Gln Gly Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Arg Ile Leu Ser Xaa Xaa Thr Thr Ser Tyr Ser Xaa Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Ala Glu Ala Phe Arg Pro Phe Thr Pro Ser Glu Gly Asp Cys Thr Thr
100 105 110
Val Leu Gly Ile Asp Tyr Trp Gly Lys Gly Thr Pro Val Thr Val Ser
115 120 125
Ser
<210> 6
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 01-9F-CDR-V6、01-9F-CDR-V7、01-9F-CDR-V10和
01-9F-CDR-V11的VHH
<220>
<221> 其他特征
<222> (54)..(54)
<223> Xaa可以是Asp或Glu
<220>
<221> 其他特征
<222> (55)..(55)
<223> Xaa可以是Gly或Ala
<220>
<221> 其他特征
<222> (62)..(62)
<223> Xaa可以是Ser或Thr
<400> 6
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Val Ser Gly Leu Pro Tyr Glu Arg Tyr
20 25 30
Cys Val Ala Trp Phe Arg Gln Gly Pro Gly Lys Glu Arg Glu Gly Val
35 40 45
Ala Arg Ile Leu Ser Xaa Xaa Thr Thr Ser Tyr Ser Asp Xaa Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Thr Tyr Tyr Cys Ala
85 90 95
Ala Glu Ala Phe Arg Pro Phe Thr Pro Ser Asp Ala Asp Cys Thr Thr
100 105 110
Val Leu Gly Ile Asp Tyr Trp Gly Lys Gly Thr Pro Val Thr Val Ser
115 120 125
Ser
<210> 7
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 01-9F-CDR-V11-V1的VHH
<400> 7
Gln 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 Val Ser Gly Leu Pro Tyr Glu Arg Tyr
20 25 30
Cys Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ala Arg Ile Leu Ser Asp Ala Thr Thr Ser Tyr Ser Asp Thr Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ala Glu Ala Phe Arg Pro Phe Thr Pro Ser Asp Ala Asp Cys Thr Thr
100 105 110
Val Leu Gly Ile Asp Tyr Trp Gly Lys Gly Thr Thr Val Thr Val Ser
115 120 125
Ser
<210> 8
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 01-9F-CDR-V11-V2至01-9F-CDR-V11-V6的VHH
<220>
<221> 其他特征
<222> (27)..(27)
<223> Xaa可以是Phe或Leu
<220>
<221> 其他特征
<222> (29)..(29)
<223> Xaa可以是Tyr或Phe
<220>
<221> 其他特征
<222> (71)..(71)
<223> Xaa可以是Lys或Arg
<220>
<221> 其他特征
<222> (97)..(97)
<223> Xaa可以是Ala或Arg
<400> 8
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 Val Ser Gly Xaa Thr Xaa Ser Arg Tyr
20 25 30
Cys Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ala Arg Ile Leu Ser Asp Ala Thr Thr Ser Tyr Ser Asp Thr Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Xaa Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Xaa Glu Ala Phe Arg Pro Phe Thr Pro Ser Asp Ala Asp Cys Thr Thr
100 105 110
Val Leu Gly Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
115 120 125
Ser
<210> 9
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 01-9F-CDR-V11-V7至01-9F-CDR-V11-V11的VHH
<220>
<221> 其他特征
<222> (27)..(27)
<223> Xaa可以是Phe或Leu
<220>
<221> 其他特征
<222> (29)..(29)
<223> Xaa可以是Tyr或Phe
<220>
<221> 其他特征
<222> (71)..(71)
<223> Xaa可以是Lys或Arg
<220>
<221> 其他特征
<222> (97)..(97)
<223> Xaa可以是Ala或Arg
<400> 9
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 Xaa Pro Xaa Ser Arg Tyr
20 25 30
Cys Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ala Arg Ile Leu Ser Asp Ala Thr Thr Ser Tyr Ser Asp Thr Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Xaa Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Xaa Glu Ala Phe Arg Pro Phe Thr Pro Ser Asp Ala Asp Cys Thr Thr
100 105 110
Val Leu Gly Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
115 120 125
Ser
<210> 10
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 01-9F-CDR-V11-V12至01-9F-CDR-V11-V16的VHH
<220>
<221> 其他特征
<222> (27)..(27)
<223> Xaa可以是Phe或Leu
<220>
<221> 其他特征
<222> (29)..(29)
<223> Xaa可以是Tyr或Phe
<220>
<221> 其他特征
<222> (71)..(71)
<223> Xaa可以是Lys或Arg
<220>
<221> 其他特征
<222> (97)..(97)
<223> Xaa可以是Ala或Arg
<400> 10
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 Xaa Thr Xaa Glu Arg Tyr
20 25 30
Cys Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ala Arg Ile Leu Ser Asp Ala Thr Thr Ser Tyr Ser Asp Thr Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Xaa Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Xaa Glu Ala Phe Arg Pro Phe Thr Pro Ser Asp Ala Asp Cys Thr Thr
100 105 110
Val Leu Gly Ile Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
115 120 125
Ser
<210> 11
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 01-9F-CDR-V11-V17至01-9F-CDR-V11-V21的VHH
<220>
<221> 其他特征
<222> (27)..(27)
<223> Xaa可以是Phe或Leu
<220>
<221> 其他特征
<222> (29)..(29)
<223> Xaa可以是Tyr或Phe
<220>
<221> 其他特征
<222> (71)..(71)
<223> Xaa可以是Lys或Arg
<220>
<221> 其他特征
<222> (97)..(97)
<223> Xaa可以是Ala或Arg
<400> 11
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 Xaa Thr Xaa Ser Arg Tyr
20 25 30
Cys Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val
35 40 45
Ala Arg Ile Leu Ser Asp Ala Thr Thr Ser Tyr Ser Asp Thr Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Xaa Asp Asn Ala Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Xaa Glu Ala Phe Arg Pro Phe Thr Pro Ser Asp Ala Asp Cys Thr Thr
100 105 110
Val Leu Gly Ile Asp Tyr Trp Gly Lys Gly Thr Thr Val Thr Val Ser
115 120 125
Ser
<210> 12
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 01-9F-CDR-V11-V22的VHH
<400> 12
Gln 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 Gly Ser Glu Tyr Arg Tyr
20 25 30
Cys Val Ala Trp Phe Arg Gln Ala Pro Gly Gln Gly Leu Glu Ala Val
35 40 45
Ala Arg Ile Leu Ser Asp Ala Thr Thr Ser Tyr Ser Asp Thr Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Ala Glu Ala Phe Arg Pro Phe Thr Pro Ser Asp Ala Asp Cys Thr Thr
100 105 110
Val Leu Gly Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
115 120 125
Ser
<210> 13
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 01-9F-CDR-V11-V23和01-9F-CDR-V11-V24的VHH
<220>
<221> 其他特征
<222> (37)..(37)
<223> Xaa可以是Val或Phe
<220>
<221> 其他特征
<222> (47)..(47)
<223> Xaa可以是Trp或Gly
<400> 13
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 Val Ser Arg Tyr
20 25 30
Cys Val Ala Trp Xaa Arg Gln Ala Pro Gly Lys Gly Leu Glu Xaa Val
35 40 45
Ser Arg Ile Leu Ser Asp Ala Thr Thr Ser Tyr Ser Asp Thr Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Glu Ala Phe Arg Pro Phe Thr Pro Ser Asp Ala Asp Cys Thr Thr
100 105 110
Val Leu Gly Ile Asp Tyr Trp Gly Lys Gly Thr Thr Val Thr Val Ser
115 120 125
Ser
<210> 14
<211> 232
<212> PRT
<213> 人工序列
<220>
<223> 重链抗体的恒定区
<400> 14
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 15
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> 人TROP2-Fc蛋白
<400> 15
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ser Arg Cys His Thr Ala Ala Gln Asp Asn Cys Thr Cys
20 25 30
Pro Thr Asn Lys Met Thr Val Cys Ser Pro Asp Gly Pro Gly Gly Arg
35 40 45
Cys Gln Cys Arg Ala Leu Gly Ser Gly Met Ala Val Asp Cys Ser Thr
50 55 60
Leu Thr Ser Lys Cys Leu Leu Leu Lys Ala Arg Met Ser Ala Pro Lys
65 70 75 80
Asn Ala Arg Thr Leu Val Arg Pro Ser Glu His Ala Leu Val Asp Asn
85 90 95
Asp Gly Leu Tyr Asp Pro Asp Cys Asp Pro Glu Gly Arg Phe Lys Ala
100 105 110
Arg Gln Cys Asn Gln Thr Ser Val Cys Trp Cys Val Asn Ser Val Gly
115 120 125
Val Arg Arg Thr Asp Lys Gly Asp Leu Ser Leu Arg Cys Asp Glu Leu
130 135 140
Val Arg Thr His His Ile Leu Ile Asp Leu Arg His Arg Pro Thr Ala
145 150 155 160
Gly Ala Phe Asn His Ser Asp Leu Asp Ala Glu Leu Arg Arg Leu Phe
165 170 175
Arg Glu Arg Tyr Arg Leu His Pro Lys Phe Val Ala Ala Val His Tyr
180 185 190
Glu Gln Pro Thr Ile Gln Ile Glu Leu Arg Gln Asn Thr Ser Gln Lys
195 200 205
Ala Ala Gly Asp Val Asp Ile Gly Asp Ala Ala Tyr Tyr Phe Glu Arg
210 215 220
Asp Ile Lys Gly Glu Ser Leu Phe Gln Gly Arg Gly Gly Leu Asp Leu
225 230 235 240
Arg Val Arg Gly Glu Pro Leu Gln Val Glu Arg Thr Leu Ile Tyr Tyr
245 250 255
Leu Asp Glu Ile Pro Pro Lys Phe Ser Met Lys Arg Leu Thr Glu Pro
260 265 270
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
275 280 285
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
290 295 300
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
305 310 315 320
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
325 330 335
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
340 345 350
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
355 360 365
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
370 375 380
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
385 390 395 400
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
405 410 415
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
420 425 430
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
435 440 445
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
450 455 460
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
465 470 475 480
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
485 490 495
Ser Leu Ser Pro Gly Lys
500
<210> 16
<211> 280
<212> PRT
<213> 人工序列
<220>
<223> 人TROP2-his蛋白
<400> 16
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ser Arg Cys His Thr Ala Ala Gln Asp Asn Cys Thr Cys
20 25 30
Pro Thr Asn Lys Met Thr Val Cys Ser Pro Asp Gly Pro Gly Gly Arg
35 40 45
Cys Gln Cys Arg Ala Leu Gly Ser Gly Met Ala Val Asp Cys Ser Thr
50 55 60
Leu Thr Ser Lys Cys Leu Leu Leu Lys Ala Arg Met Ser Ala Pro Lys
65 70 75 80
Asn Ala Arg Thr Leu Val Arg Pro Ser Glu His Ala Leu Val Asp Asn
85 90 95
Asp Gly Leu Tyr Asp Pro Asp Cys Asp Pro Glu Gly Arg Phe Lys Ala
100 105 110
Arg Gln Cys Asn Gln Thr Ser Val Cys Trp Cys Val Asn Ser Val Gly
115 120 125
Val Arg Arg Thr Asp Lys Gly Asp Leu Ser Leu Arg Cys Asp Glu Leu
130 135 140
Val Arg Thr His His Ile Leu Ile Asp Leu Arg His Arg Pro Thr Ala
145 150 155 160
Gly Ala Phe Asn His Ser Asp Leu Asp Ala Glu Leu Arg Arg Leu Phe
165 170 175
Arg Glu Arg Tyr Arg Leu His Pro Lys Phe Val Ala Ala Val His Tyr
180 185 190
Glu Gln Pro Thr Ile Gln Ile Glu Leu Arg Gln Asn Thr Ser Gln Lys
195 200 205
Ala Ala Gly Asp Val Asp Ile Gly Asp Ala Ala Tyr Tyr Phe Glu Arg
210 215 220
Asp Ile Lys Gly Glu Ser Leu Phe Gln Gly Arg Gly Gly Leu Asp Leu
225 230 235 240
Arg Val Arg Gly Glu Pro Leu Gln Val Glu Arg Thr Leu Ile Tyr Tyr
245 250 255
Leu Asp Glu Ile Pro Pro Lys Phe Ser Met Lys Arg Leu Thr His His
260 265 270
His His His His His His His His
275 280
<210> 17
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> sacituzumab的重链
<400> 17
Ser Val Gln Leu Gln Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Thr Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Ala Asp Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gly Gly Phe Gly Ser Ser Tyr Trp Tyr Phe Asp Val Trp Gly
100 105 110
Gln Gly Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 18
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> sacituzumab的轻链
<400> 18
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp 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 Val Tyr Tyr Cys Gln Gln His Tyr Ile Thr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 19
<211> 282
<212> PRT
<213> 人工序列
<220>
<223> 猴TROP2-his蛋白
<400> 19
Met Ala Arg Gly Pro Gly Leu Ala Pro Pro Pro Leu Arg Leu Pro Leu
1 5 10 15
Leu Leu Leu Leu Leu Ala Ala Val Thr Gly His Thr Ala Ala Gln Asp
20 25 30
Asn Cys Thr Cys Pro Thr Asn Lys Met Thr Val Cys Ser Pro Asp Gly
35 40 45
Pro Gly Gly Arg Cys Gln Cys Arg Ala Leu Gly Ser Gly Val Ala Val
50 55 60
Asp Cys Ser Thr Leu Thr Ser Lys Cys Leu Leu Leu Lys Ala Arg Met
65 70 75 80
Ser Ala Pro Lys Asn Ala Arg Thr Leu Val Arg Pro Asn Glu His Ala
85 90 95
Leu Val Asp Asn Asp Gly Leu Tyr Asp Pro Asp Cys Asp Pro Glu Gly
100 105 110
Arg Phe Lys Ala Arg Gln Cys Asn Gln Thr Ser Val Cys Trp Cys Val
115 120 125
Asn Ser Val Gly Val Arg Arg Thr Asp Lys Gly Asp Leu Ser Leu Arg
130 135 140
Cys Asp Glu Leu Val Arg Thr His His Ile Leu Ile Asp Leu Arg His
145 150 155 160
Arg Pro Thr Ala Gly Ala Phe Asn His Ser Asp Leu Asp Ala Glu Leu
165 170 175
Arg Arg Leu Phe Arg Glu Arg Tyr Arg Leu His Pro Lys Phe Val Ala
180 185 190
Ala Val His Tyr Glu Gln Pro Thr Ile Gln Ile Glu Leu Arg Gln Asn
195 200 205
Thr Ser Gln Lys Ala Ala Gly Asp Val Asp Ile Gly Asp Ala Ala Tyr
210 215 220
Tyr Phe Glu Arg Asp Val Lys Gly Glu Ser Leu Phe Gln Gly Arg Gly
225 230 235 240
Gly Leu Asp Leu Arg Val Arg Gly Glu Pro Leu Gln Val Glu Arg Thr
245 250 255
Leu Ile Tyr Tyr Leu Asp Glu Ile Pro Pro Lys Phe Ser Met Lys Arg
260 265 270
His His His His His His His His His His
275 280
<210> 20
<211> 336
<212> PRT
<213> 人工序列
<220>
<223> 全长人TROP2
<400> 20
Met Ala Arg Gly Pro Gly Leu Ala Pro Pro Pro Leu Arg Leu Pro Leu
1 5 10 15
Leu Leu Leu Val Leu Ala Ala Val Thr Gly His Thr Ala Ala Gln Asp
20 25 30
Asn Cys Thr Cys Pro Thr Asn Lys Met Thr Val Cys Ser Pro Asp Gly
35 40 45
Pro Gly Gly Arg Cys Gln Cys Arg Ala Leu Gly Ser Gly Met Ala Val
50 55 60
Asp Cys Ser Thr Leu Thr Ser Lys Cys Leu Leu Leu Lys Ala Arg Met
65 70 75 80
Ser Ala Pro Lys Asn Ala Arg Thr Leu Val Arg Pro Ser Glu His Ala
85 90 95
Leu Val Asp Asn Asp Gly Leu Tyr Asp Pro Asp Cys Asp Pro Glu Gly
100 105 110
Arg Phe Lys Ala Arg Gln Cys Asn Gln Thr Ser Val Cys Trp Cys Val
115 120 125
Asn Ser Val Gly Val Arg Arg Thr Asp Lys Gly Asp Leu Ser Leu Arg
130 135 140
Cys Asp Glu Leu Val Arg Thr His His Ile Leu Ile Asp Leu Arg His
145 150 155 160
Arg Pro Thr Ala Gly Ala Phe Asn His Ser Asp Leu Asp Ala Glu Leu
165 170 175
Arg Arg Leu Phe Arg Glu Arg Tyr Arg Leu His Pro Lys Phe Val Ala
180 185 190
Ala Val His Tyr Glu Gln Pro Thr Ile Gln Ile Glu Leu Arg Gln Asn
195 200 205
Thr Ser Gln Lys Ala Ala Gly Asp Val Asp Ile Gly Asp Ala Ala Tyr
210 215 220
Tyr Phe Glu Arg Asp Ile Lys Gly Glu Ser Leu Phe Gln Gly Arg Gly
225 230 235 240
Gly Leu Asp Leu Arg Val Arg Gly Glu Pro Leu Gln Val Glu Arg Thr
245 250 255
Leu Ile Tyr Tyr Leu Asp Glu Ile Pro Pro Lys Phe Ser Met Lys Arg
260 265 270
Leu Thr Ala Gly Leu Ile Ala Val Ile Val Val Val Val Val Ala Leu
275 280 285
Val Ala Gly Met Ala Val Leu Val Ile Thr Asn Arg Arg Lys Ser Gly
290 295 300
Lys Tyr Lys Lys Val Glu Ile Lys Glu Leu Gly Glu Leu Arg Lys Glu
305 310 315 320
Pro Ser Leu Gly Gly Gly Gly Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
325 330 335
<210> 21
<211> 519
<212> PRT
<213> 人工序列
<220>
<223> DTTP-1170蛋白
<400> 21
Met Gly Ala Asp Asp Val Val Asp Ser Ser Lys Ser Phe Val Met Glu
1 5 10 15
Asn Phe Ser Ser Tyr His Gly Thr Lys Pro Gly Tyr Val Asp Ser Ile
20 25 30
Gln Lys Gly Ile Gln Lys Pro Lys Ser Gly Thr Gln Gly Asn Tyr Asp
35 40 45
Asp Asp Trp Lys Gly Phe Tyr Ser Thr Asp Asn Lys Tyr Asp Ala Ala
50 55 60
Gly Tyr Ser Val Asp Asn Glu Asn Pro Leu Ser Gly Lys Ala Gly Gly
65 70 75 80
Val Val Lys Val Thr Tyr Pro Gly Leu Thr Lys Val Leu Ala Leu Lys
85 90 95
Val Asp Asn Ala Glu Thr Ile Lys Lys Glu Leu Gly Leu Ser Leu Thr
100 105 110
Glu Pro Leu Met Glu Gln Val Gly Thr Glu Glu Phe Ile Lys Arg Phe
115 120 125
Gly Asp Gly Ala Ser Arg Val Val Leu Ser Leu Pro Phe Ala Glu Gly
130 135 140
Ser Ser Ser Val Glu Tyr Ile Asn Asn Trp Glu Gln Ala Lys Ala Leu
145 150 155 160
Ser Val Glu Leu Glu Ile Asn Phe Glu Thr Arg Gly Lys Arg Gly Gln
165 170 175
Asp Ala Met Tyr Glu Tyr Met Ala Gln Ala Cys Ala Gly Asn Arg Val
180 185 190
Arg Arg Ser Val Gly Ser Ser Leu Ser Cys Ile Asn Leu Asp Trp Asp
195 200 205
Val Ile Arg Asp Lys Thr Lys Thr Lys Ile Glu Ser Leu Lys Glu His
210 215 220
Gly Pro Ile Lys Asn Lys Met Ser Glu Ser Pro Asn Lys Thr Val Ser
225 230 235 240
Glu Glu Lys Ala Lys Gln Tyr Leu Glu Glu Phe His Gln Thr Ala Leu
245 250 255
Glu His Pro Glu Leu Ser Glu Leu Lys Thr Val Thr Gly Thr Asn Pro
260 265 270
Val Phe Ala Gly Ala Asn Tyr Ala Ala Trp Ala Val Asn Val Ala Gln
275 280 285
Val Ile Asp Ser Glu Thr Ala Asp Asn Leu Glu Lys Thr Thr Ala Ala
290 295 300
Leu Ser Ile Leu Pro Gly Ile Gly Ser Val Met Gly Ile Ala Asp Gly
305 310 315 320
Ala Val His His Asn Thr Glu Glu Ile Val Ala Gln Ser Ile Ala Leu
325 330 335
Ser Ser Leu Met Val Ala Gln Ala Ile Pro Leu Val Gly Glu Leu Val
340 345 350
Asp Ile Gly Phe Ala Ala Tyr Asn Phe Val Glu Ser Ile Ile Asn Leu
355 360 365
Phe Gln Val Val His Asn Ser Tyr Asn Arg Pro Ala Tyr Ser Pro Gly
370 375 380
His Lys His Gln Val Gln Leu Val Glu Ser Gly Gly Gly Trp Val Gln
385 390 395 400
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
405 410 415
Ser Asp Thr Ala Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Arg
420 425 430
Glu Trp Val Ala Ala Ile Asp Thr Gly Gly Gly Tyr Thr Tyr Tyr Ala
435 440 445
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
450 455 460
Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Arg
465 470 475 480
Tyr Tyr Cys Ala Lys Thr Tyr Ser Gly Asn Tyr Tyr Ser Asn Tyr Thr
485 490 495
Val Ala Asn Tyr Gly Thr Thr Gly Arg Gly Thr Leu Val Thr Val Ser
500 505 510
Ser His His His His His His
515
<210> 22
<211> 624
<212> PRT
<213> 人工序列
<220>
<223> DT3C蛋白
<400> 22
Met Lys Tyr Leu Leu Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu Ala
1 5 10 15
Ala Gln Pro Ala Met Ala Met Gly Ala Asp Asp Val Val Asp Ser Ser
20 25 30
Lys Ser Phe Val Met Glu Asn Phe Ser Ser Tyr His Gly Thr Lys Pro
35 40 45
Gly Tyr Val Asp Ser Ile Gln Lys Gly Ile Gln Lys Pro Lys Ser Gly
50 55 60
Thr Gln Gly Asn Tyr Asp Asp Asp Trp Lys Gly Phe Tyr Ser Thr Asp
65 70 75 80
Asn Lys Tyr Asp Ala Ala Gly Tyr Ser Val Asp Asn Glu Asn Pro Leu
85 90 95
Ser Gly Lys Ala Gly Gly Val Val Lys Val Thr Tyr Pro Gly Leu Thr
100 105 110
Lys Val Leu Ala Leu Lys Val Asp Asn Ala Glu Thr Ile Lys Lys Glu
115 120 125
Leu Gly Leu Ser Leu Thr Glu Pro Leu Met Glu Gln Val Gly Thr Glu
130 135 140
Glu Phe Ile Lys Arg Phe Gly Asp Gly Ala Ser Arg Val Val Leu Ser
145 150 155 160
Leu Pro Phe Ala Glu Gly Ser Ser Ser Val Glu Tyr Ile Asn Asn Trp
165 170 175
Glu Gln Ala Lys Ala Leu Ser Val Glu Leu Glu Ile Asn Phe Glu Thr
180 185 190
Arg Gly Lys Arg Gly Gln Asp Ala Met Tyr Glu Tyr Met Ala Gln Ala
195 200 205
Cys Ala Gly Asn Arg Val Arg Arg Ser Val Gly Ser Ser Leu Ser Cys
210 215 220
Ile Asn Leu Asp Trp Asp Val Ile Arg Asp Lys Thr Lys Thr Lys Ile
225 230 235 240
Glu Ser Leu Lys Glu His Gly Pro Ile Lys Asn Lys Met Ser Glu Ser
245 250 255
Pro Asn Lys Thr Val Ser Glu Glu Lys Ala Lys Gln Tyr Leu Glu Glu
260 265 270
Phe His Gln Thr Ala Leu Glu His Pro Glu Leu Ser Glu Leu Lys Thr
275 280 285
Val Thr Gly Thr Asn Pro Val Phe Ala Gly Ala Asn Tyr Ala Ala Trp
290 295 300
Ala Val Asn Val Ala Gln Val Ile Asp Ser Glu Thr Ala Asp Asn Leu
305 310 315 320
Glu Lys Thr Thr Ala Ala Leu Ser Ile Leu Pro Gly Ile Gly Ser Val
325 330 335
Met Gly Ile Ala Asp Gly Ala Val His His Asn Thr Glu Glu Ile Val
340 345 350
Ala Gln Ser Ile Ala Leu Ser Ser Leu Met Val Ala Gln Ala Ile Pro
355 360 365
Leu Val Gly Glu Leu Val Asp Ile Gly Phe Ala Ala Tyr Asn Phe Val
370 375 380
Glu Ser Ile Ile Asn Leu Phe Gln Val Val His Asn Ser Tyr Asn Arg
385 390 395 400
Pro Ala Tyr Ser Pro Gly His Lys His Ile Asp Glu Ile Leu Ala Ala
405 410 415
Leu Pro Lys Thr Asp Thr Tyr Lys Leu Ile Leu Asn Gly Lys Thr Leu
420 425 430
Lys Gly Glu Thr Thr Thr Glu Ala Val Asp Ala Ala Thr Ala Glu Lys
435 440 445
Val Phe Lys Gln Tyr Ala Asn Asp Asn Gly Val Asp Gly Glu Trp Thr
450 455 460
Tyr Asp Asp Ala Thr Lys Thr Phe Thr Val Thr Glu Lys Pro Glu Val
465 470 475 480
Ile Asp Ala Ser Glu Leu Thr Pro Ala Val Thr Thr Tyr Lys Leu Val
485 490 495
Ile Asn Gly Lys Thr Leu Lys Gly Glu Thr Thr Thr Glu Ala Val Asp
500 505 510
Ala Ala Thr Ala Glu Lys Val Phe Lys Gln Tyr Ala Asn Asp Asn Gly
515 520 525
Val Asp Gly Glu Trp Thr Tyr Asp Asp Ala Thr Lys Thr Phe Thr Val
530 535 540
Thr Glu Lys Pro Glu Val Ile Asp Ala Ser Glu Leu Thr Pro Ala Val
545 550 555 560
Thr Thr Tyr Lys Leu Val Ile Asn Gly Lys Thr Leu Lys Gly Glu Thr
565 570 575
Thr Thr Lys Ala Val Asp Ala Glu Thr Ala Glu Lys Ala Phe Lys Gln
580 585 590
Tyr Ala Asn Asp Asn Gly Val Asp Gly Val Trp Thr Tyr Asp Asp Ala
595 600 605
Thr Lys Thr Phe Thr Val Thr Glu Leu Glu His His His His His His
610 615 620
<210> 23
<211> 387
<212> DNA
<213> 人工序列
<220>
<223> 01-9F的VHH
<400> 23
caagtgcaac ttgttgaaag cgggggcggt agcgtacagg cgggagggag cctccgattg 60
agctgcgtgg tcagcgggct gccgtatgag agatactgcg tagcatggtt caggcaaggc 120
ccgggtaaag agcgagaggg agtagctcgg atactttctg acggtactac gtcttatagt 180
gactccgtga aggggcgctt cactattagc aaggataatg cgaaaaacac attgtacctt 240
cagatgaaca gcctgaagag tgaggatacg gctacttatt attgtgcagc ggaagcattc 300
cgcccattca caccctccga cggggattgt accacagtgc ttggtataga ctactgggga 360
aaaggaacgc ctgttactgt gagcagc 387
<210> 24
<211> 387
<212> DNA
<213> 人工序列
<220>
<223> 01-9F-CDR-V11的VHH
<400> 24
caagtgcaac tggtagaatc tggggggggc agtgtacaag ctgggggcag cctgagactg 60
agctgtgtgg tgtctggcct gccctatgag agatactgtg tggcctggtt cagacaaggc 120
cctggcaagg agagagaggg ggtggctaga atcctgtctg atgccaccac aagctactct 180
gacacagtga agggcagatt caccatcagc aaggacaatg ccaagaacac cctgtacctg 240
cagatgaaca gcctgaagtc tgaggacaca gccacctact actgtgctgc tgaggccttc 300
agacccttca ccccctctga tgctgactgc accacagtgc tgggcattga ctactggggc 360
aagggcaccc ctgtgacagt gagctct 387
<210> 25
<211> 387
<212> DNA
<213> 人工序列
<220>
<223> 01-9F-CDR-V11-V11的VHH
<400> 25
gaggtgcagc tcgtggagag cggcgggggc ctggtgcaac ctggcgggag cctgagactg 60
agctgcgccg ctagcggcct gccctacagc agatactgcg tggcctggtt cagacaagcc 120
cccggcaagg gcctggaggg cgtggctaga atcctgagcg acgccaccac aagctacagc 180
gacaccgtga agggcagatt caccatcagc aaggacaacg ccaagaacag cctgtacctg 240
cagatgaaca gcctgagagc cgaggacacc gccgtgtact actgcgccgc cgaggccttc 300
agacccttca cccctagcga cgccgactgc accaccgtgc tgggcatcga ctactggggc 360
caaggcacca ccgtgaccgt gagcagc 387
<210> 26
<211> 699
<212> DNA
<213> 人工序列
<220>
<223> 重链抗体的恒定区
<400> 26
gagcccaaaa gctgtgacaa gacccacacc tgtcccccct gtcctgcccc tgagctcctt 60
gggggcccat ctgtgttcct gttccccccc aagcccaagg acaccctgat gatcagcaga 120
acccctgagg tgacctgtgt ggtggtggat gtgagccatg aggaccctga ggtgaagttc 180
aactggtatg tggatggggt ggaggtgcac aatgccaaga ccaagcctag agaggagcag 240
tacaacagca cctacagagt ggtgtctgtg ctgacagtgc tgcaccaaga ctggctgaat 300
ggcaaggagt acaagtgcaa ggtgagcaac aaggccctgc ctgcccccat tgagaagaca 360
atcagcaagg ccaaggggca gcctagagag ccccaagtgt acaccctgcc ccctagcaga 420
gaggagatga ccaagaacca agtgagcctg acctgcctgg tgaagggctt ctacccctct 480
gacattgctg tggagtggga gagcaatggg cagcctgaga acaactacaa gaccaccccc 540
cctgtgctgg actctgatgg cagcttcttc ctgtacagca agctgacagt ggacaagagc 600
agatggcagc aaggcaatgt gttcagctgc tctgtgatgc atgaggccct gcacaaccac 660
tacacacaga agagcctgag cctgagccct ggcaagtga 699
Claims (15)
1.一种重链抗体或其抗原结合部分,其与TROP2结合,包含可变区,所述可变区包含CDR1区、CDR2区和CDR3区,其中所述CDR1区、CDR2区和CDR3区分别包含与(1)SEQ ID NOs:1、2(x1=D、X2=G、X3=D、X4=S)和3(X1=D、X2=G);(2)SEQ ID NOs:1、2(X1=D、X2=G、X3=D、X4=S)和3(X1=E、X2=G);(3)SEQ ID NOs:1、2(X1=D、X2=G、X3=D、X4=S)和3(X1=D、X2=A);(4)SEQ ID NOs:1、2(X1=D、X2=G、X3=D、X4=S)和3(X1=I、X2=G);(5)SEQ IDNOs:1、2(X1=E、X2=G、X3=D、X4=S)和3(X1=E、X2=G);(6)SEQ ID NOs:1、2(X1=D、X2=A、X3=D、X4=S)和3(X1=E、X2=G);(7)SEQ ID NOs:1、2(X1=E、X2=G、X3=D、X4=S)和3(X1=D、X2=A);(8)SEQ ID NOs:1、2(X1=D、X2=A、X3=D、X4=S)和3(X1=D、X2=A);(9)SEQ ID NOs:1、2(X1=E、X2=G、X3=E、X4=S)和3(X1=E、X2=G);(10)SEQ ID NOs:1、2(X1=D、X2=A、X3=E、X4=S)和3(X1=E、X2=G);(11)SEQ ID NOs:1、2(X1=E、X2=G、X3=D、X4=T)和3(X1=D、X2=A);或(12)SEQ ID NOs:1、2(X1=D、X2=A、X3=D、X4=T)和3(X1=D、X2=A)具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。
2.如权利要求1所述的重链抗体或其抗原结合部分,其中所述可变区包含与SEQ IDNOs:4(X1=S、X2=Q、X3=D、X4=G、X5=P;X1=S、X2=Q、X3=E、X4=G、X5=P;X1=S、X2=Q、X3=D、X4=A、X5=P;X1=S、X2=Q、X3=I、X4=G、X5=P;或X1=T、X2=G、X3=D、X4=G、X5=L)、5(X1=E、X2=G、X3=D;X1=D、X2=A、X3=D;X1=E、X2=G、X3=E;或X1=D、X2=A、X3=E);6(X1=E、X2=G、X3=S;X1=D、X2=A、X3=S;X1=E、X2=G、X3=T;或X1=D、X2=A、X3=T)、7、8(X1=F、X2=Y、X3=K、X4=A;X1=L、X2=F、X3=K、X4=A;X1=L、X2=Y、X3=R、X4=A;X1=L、X2=Y、X3=K、X4=R;或X1=L、X2=Y、X3=K、X4=A)、9(X1=F、X2=Y、X3=K、X4=A;X1=L、X2=F、X3=K、X4=A;X1=L、X2=Y、X3=R、X4=A;X1=L、X2=Y、X3=K、X4=R;或X1=L、X2=Y、X3=K、X4=A)、10(X1=F、X2=Y、X3=K、X4=A;X1=L、X2=F、X3=K、X4=A;X1=L、X2=Y、X3=R、X4=A;X1=L、X2=Y、X3=K、X4=R;或X1=L、X2=Y、X3=K、X4=A);11(X1=F、X2=Y、X3=K、X4=A;X1=L、X2=F、X3=K、X4=A;X1=L、X2=Y、X3=R、X4=A;X1=L、X2=Y、X3=K、X4=R;或X1=L、X2=Y、X3=K、X4=A)、12、或13(X1=V、X2=W;或X1=F、X2=G)具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的氨基酸序列。
3.如权利要求1所述的重链抗体或其抗原结合部分,其包含恒定区,与所述可变区相连,所述恒定区具有SEQ ID NO:14所示的氨基酸序列。
4.如权利要求1所述的重链抗体或其抗原结合部分,其(a)结合人TROP2;(b)结合猴TROP2;和/或(c)由TROP2+细胞内化。
5.如权利要求1所述的重链抗体或其抗原结合部分,其为骆驼源、嵌合或人源化的。
6.一种免疫偶联物,其包含权利要求1所述的重链抗体或其抗原结合部分,与毒素或放射性同位素连接。
7.如权利要求6所述的免疫偶联物,其中所述毒素为包含SEQ ID NO:22所示氨基酸序列的重组蛋白。
8.一种核酸分子,其编码权利要求1至5中任一项所述的重链抗体或其抗原结合部分、或权利要求6或7中所述的免疫偶联物。
9.一种表达载体,其包含权利要求8所述的核酸分子。
10.一种宿主细胞,其包含权利要求9所述的表达载体。
11.一种药物组合物,其包含权利要求1至5中任一项所述的重链抗体或其抗原结合部分、权利要求6或7所述的免疫偶联物、权利要求8所述的核酸分子、权利要求9所述的表达载体、或权利要求10所述的宿主细胞,以及药学上可接受的载体。
12.如权利要求11所述的药物组合物,还包含抗肿瘤剂。
13.一种用于在有需求受试者中治疗与TROP2相关疾病的方法,包括向受试者施用治疗有效量的权利要求11或12所述的药物组合物。
14.如权利要求13所述的方法,其中该疾病是选自乳癌、结直肠癌、胃腺癌、食管癌、肝细胞癌、非小细胞肺癌、小细胞肺癌、卵巢上皮癌、***癌、胰腺导管腺癌、头颈癌、鳞状细胞癌、肾细胞癌、***、***、子宫内膜癌、滤泡状甲状腺癌、和多形性胶质母细胞瘤的癌症。
15.一种用于在有需求受试者中进行癌症成像的方法,包括向受试者施用权利要求1至5中任一项所述的重链抗体或其抗原结合部分,其中该重链抗体或其抗原结合部分经放射性标记。
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US11957693B2 (en) | 2021-06-11 | 2024-04-16 | Gilead Sciences, Inc. | Combination MCL-1 inhibitors with anti-cancer agents |
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CN107446050A (zh) * | 2017-08-11 | 2017-12-08 | 百奥泰生物科技(广州)有限公司 | Trop2阳性疾病治疗的化合物及方法 |
TW202016148A (zh) * | 2018-07-09 | 2020-05-01 | 大陸商艾比瑪特生物醫藥(上海)有限公司 | 滋養層抗原2(trop2)特異性抗體 |
WO2020191092A1 (en) * | 2019-03-19 | 2020-09-24 | Cspc Dophen Corporation | Anti-trophoblast cell surface antigen 2 (trop2) antibodies and antibody drug conjugates comprising same |
CN113527496B (zh) * | 2020-04-16 | 2022-03-04 | 上海洛启生物医药技术有限公司 | 抗Trop2纳米抗体及其应用 |
CN112321715B (zh) * | 2020-11-03 | 2022-05-10 | 博奥信生物技术(南京)有限公司 | 抗trop2纳米抗体及其制备方法和应用 |
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2020
- 2020-11-03 CN CN202011209105.XA patent/CN112321715B/zh active Active
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2021
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- 2021-11-02 EP EP21888548.1A patent/EP4240773A1/en active Pending
- 2021-11-02 US US18/250,800 patent/US20230383007A1/en active Pending
- 2021-11-02 WO PCT/CN2021/128204 patent/WO2022095851A1/en active Application Filing
- 2021-11-02 KR KR1020237018679A patent/KR20230097165A/ko unknown
- 2021-11-02 CN CN202180073913.4A patent/CN116406424A/zh active Pending
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CN112321715B (zh) | 2022-05-10 |
KR20230097165A (ko) | 2023-06-30 |
JP2023547254A (ja) | 2023-11-09 |
EP4240773A1 (en) | 2023-09-13 |
US20230383007A1 (en) | 2023-11-30 |
CN112321715A (zh) | 2021-02-05 |
WO2022095851A1 (en) | 2022-05-12 |
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