CN117042809A - 抗her2抗体-免疫激动剂缀合物及其应用 - Google Patents
抗her2抗体-免疫激动剂缀合物及其应用 Download PDFInfo
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Abstract
本公开涉及用于靶向分子‑药物缀合物的连接单元分子以及其相应缀合物、制备和用途,并且具体地,涉及作为一类新颖癌症疗法的抗HER2抗体‑免疫激动剂缀合物(AIAC)。
Description
技术领域
本公开涉及生物医药领域,具体涉及用于靶向分子-免疫激动剂缀合物的连接单元,以及其相应缀合物、制备方法和用途。
背景技术
人表皮生长因子受体2(HER2)是具有酪氨酸激酶活性的表皮生长因子受体家族的成员。在约15-30%的乳腺癌和10-30%的胃/胃食管癌症中出现HER2的扩增或过表达。在如卵巢癌、子宫内膜癌、膀胱癌、肺癌、结肠癌和头颈癌等其它癌症中也见到HER2过表达(Iqbal N.等人,《国际分子生物学(Mol Biol Int.)》2014:852748)。尽管靶向HER2的疗法,如针对HER2的抗体或抗体-药物缀合物(ADC)的功效实质提高了HER2阳性疾病患者的预期寿命,但从本质上讲,与HER2阴性(和HR阳性)疾病患者相比,HER2阳性乳腺癌仍然是一种侵袭性较高的疾病形式,具有不良预后和较差的结果。此外,在其它过表达HER2的癌症中的治疗结果被证实是令人失望的。造成不良结果的多种原因之一是被施用HER2靶向疗法的患者变得具有抗性。肿瘤细胞的免疫逃逸促成这一过程。
免疫疗法是一种新的癌症治疗模式,显示出较高的效力。尽管以CLTA-4和PD-1/L1单克隆抗体为代表的免疫检查点阻断,作为基本上基于T细胞的疗法,已被批准用于多种癌症适应症,仍在努力探索免疫系统对抗癌症的其它机制。靶向骨髓细胞,主要是巨噬细胞、DC,已成为一个颇具前景的方向。利用激动剂或利用巨噬细胞检查点抑制剂激活巨噬细胞和DC不仅增强它们通过吞噬作用清除肿瘤细胞的能力,还增强它们的抗原呈递功能,从而更稳健地激发适应性抗肿瘤免疫。
本发明提供一种针对HER2的抗体-免疫激动剂缀合物(AIAC),这是一种新颖的靶向肿瘤的免疫治疗药物。
发明内容
一方面,提供了一种式(I-1)或(I-2)的化合物:
其中B2是-(CH2)k(CO)-NH-(C2H4-O)j-,k是1至5的整数,j是1至3的整数,PL是连接至所述B2部分的有效载荷(payload),
优选地,PL是瑞喹莫德(Resiquimod)
在又另一方面,提供了一种式(II-1)或式(II-2)的抗体-药物缀合物:
其中B2是-(CH2)k(CO)-NH-(C2H4-O)j-,k是1至5的整数,j是1至3的整数,PL是连接至所述B2部分的有效载荷,
优选地,PL是瑞喹莫德
z是1至4的整数;优选地是1至2的整数;
A是抗体,所述抗体包含具有SEQ ID NO:1的氨基酸序列的轻链和具有SEQ ID NO:2的氨基酸序列的重链。
本发明的抗体-免疫激动剂缀合物(AIAC)提供一类新颖的肿瘤靶向疗法。体外实验证实,与未修饰的裸抗体相比较,AIAC可诱导较高的TNFα产量。AIAC的体内实验显示出抗肿瘤作用。
附图说明
在图7和图8中,在X轴下方的箭头指示施用的时间点。
图1:式(I')的化合物的示例性实例。
图2:式(II')的化合物的示例性实例。
图3:式(III')的化合物示例性实例。
图4:在人PBMC-NCI N87共培养物中缀合物AC102-5-1-1、AC102-6-1-1及其相应未修饰的裸抗体Ab0001(曲妥珠单抗(Trastuzumab)和激动剂瑞喹莫德的TNFα诱导活性。
图5:在PBMC与NCI N87或MDA-MB-468细胞的共培养物中AC102-6-1-1和抗体的TNFα诱导活性。
图6:在PBMC与NCI N87细胞的共培养物中AC102-9-1-1、AC102-12-1-1、AC102-10-1-1、AC102-13-1-1和抗体的TNFα诱导活性。
图7:被给予以下各物的SCID Beige小鼠NCI N87 CDX模型中肿瘤体积随时间的变化:媒剂(PBS pH 6.5)、抗体和测试缀合物(AC102-5-1-1或AC102-6-1-1),5mg/kg。
图8:给予3mg/kg和10mg/kg AC102-6-1-1以及10mg/kg抗体的过表达hHER2的MC38模型中肿瘤体积随时间的变化。
具体实施方式
以下提供具体实施例以说明本公开的技术内容。本领域的技术人员可通过本说明书中所公开的内容,容易地了解本公开的其它优点和作用。本公开也可通过其它不同的具体实施例实施或应用。在不脱离本公开的情况下,本领域的技术人员可以作出各种修改和变化。
定义
除非下文另外定义,否则在此使用的所有技术和科学术语都具有与本领域的技术人员通常所理解相同的含义。本文中使用的技术是指本领域中一般理解的技术,包括本领域的技术人员显而易见的变体和等效取代。尽管相信本领域的技术人员可容易地理解以下术语,但阐述以下定义将更好地说明本公开。当本文中存在商品名时,它是指相应的商品或其活性成分。本文所引用的所有专利、公开的专利申请和出版物都特此以引用的方式并入。
当特定量、浓度或者其它值或参数以范围、优选范围或者优选上限或优选下限的形式阐述时,应理解,它相当于具体地披露通过组合任何上限或优选值与任何下限或优选值所形成的任何范围,不管所述范围是否明确地叙述。除非另外陈述,否则本文中所列的数值范围意图包括该范围的端点以及在该范围内的所有整数和分数(小数)。例如,表述“i是2至20的整数”意思指,i是2至20的任何整数,例如i可以是2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。其它类似的表述也应以类似方式理解。
除非本文中另外陈述,否则单数形式如“一个(种)”和“所述”包括复数形式。表述“一个(种)或多个(种)”或“至少一个(种)”可以指1、2、3、4、5、6、7、8、9个(种)或更多。
术语“约”和“大约”当与数字变量结合使用时,一般意味着该变量的值和该变量的所有值都在实验误差范围内(例如在平均值的95%置信区间内)或在指定值的±10%范围内,或在更宽范围内。
术语“化学计量比”意思指根据以重量计的特定量匹配各种物质。例如,在本公开中,将活性成分与填充剂、粘合剂和润滑剂以指定重量比混合。
术语“可选的”或“任选地”意思指,随后描述的事件可能但未必会发生,并且该描述包括所述事件或情况发生或不发生的情形。
表述“包含”或类似表述“包括”、“含有”和“具有”是开放式的,并且不排除另外未陈述的元件、步骤或成分。表述“由……组成”不包括未指明的任何元件、步骤或成分。表述“基本上由……组成”意思指,范围限于指定元件、步骤或成分,以及任选地存在且大体上不会影响所要求主题的基本和新颖特征的元件、步骤或成分。应理解,表述“包含”涵盖表述“基本上由……组成”和“由……组成”。
术语“靶向分子”是指对特定靶标(例如受体、细胞表面蛋白质、细胞因子等)具有亲和力的分子。靶向分子可通过靶向递送将有效载荷递送至体内特定部位。靶向分子可识别一个或多个靶标。具体靶标位点是由靶向分子所识别的靶标界定。例如,靶向受体的靶向分子可将有效载荷递送至含有大部分受体的位点。靶向分子的实例包括但不限于抗体、抗体片段、针对给定抗原的结合蛋白、抗体模拟物、对给定靶标具有亲和力的支架蛋白、配体等。
如本文所使用,术语“抗体”是以广义方式使用,并且特定地包括完整单克隆抗体、多克隆抗体、单特异性抗体、多特异性抗体(例如双特异性抗体)及抗体片段,只要它们具有所希望的生物活性即可。抗体可以属于任何亚型(如IgG、IgE、IgM、IgD和IgA)或亚类,并且可来源于任何适合的物种。在一些实施例中,抗体是人类或鼠类来源的。抗体还可以是完全人抗体、人源化抗体或通过重组方法制备的嵌合抗体。
单克隆抗体在本文中用于指从大体上同质的抗体群体获得的抗体,即,除了少量可能存在的天然突变外,构成该群体的各个抗体是相同的。单克隆抗体对单一抗原位点具有高度特异性。“单克隆”一词是指抗体的特征是来源于大体上同质的抗体群体,而不应解释为需要一些特定的方法来制备抗体。
完整抗体或全长抗体基本上包含一个或多个抗原结合可变区,以及一个或多个轻链恒定区(CL)和一个或多个重链恒定区(CH),该一个或多个重链恒定区取决于抗体的亚型而可以包括CH1、CH2、CH3和CH4。抗原结合可变区(又称为片段可变区、Fv片段)典型地包含轻链可变区(VL)和重链可变区(VH)。恒定区可以是具有天然序列(如具有人天然序列的恒定区)或其氨基酸序列变体的恒定区。可变区识别靶标抗原并与之相互作用。恒定区可被免疫系统识别并与之相互作用。
抗体片段可包含完整抗体的一部分,优选地其抗原结合区或可变区。抗体片段的实例包括Fab、Fab'、F(ab')2、由VH和CH1结构域组成的Fd片段、Fv片段、单结构域抗体(dAb)片段以及分离的互补决定区(CDR)。Fab片段是通过用木瓜蛋白酶消化全长免疫球蛋白获得的抗体片段,或具有通过例如重组表达产生的相同结构的片段。Fab片段包含轻链(包含VL和CL)和另一条链,其中所述另一条链包含重链的可变结构域(VH)和重链的恒定区结构域(CH1)。F(ab')2片段是通过在pH4.0-4.5下用胃蛋白酶消化免疫球蛋白获得的抗体片段,或具有通过例如重组表达产生的相同结构的片段。F(ab')2片段基本上包含两个Fab片段,其中每个重链部分包含几个另外的氨基酸,包括半胱氨酸,所述半胱氨酸形成连接两个片段的二硫键。Fab'片段是包含F(ab')2片段的一半(一条重链和一条轻链)的片段。抗体片段可包含例如通过二硫键和/或通过肽连接单元接合在一起的多条链。抗体片段的实例还包括单链Fv(scFv)、Fv、dsFv、双功能抗体、Fd和Fd'片段,以及其它片段,包括修饰过的片段。抗体片段典型地包含至少或约50个氨基酸并且典型地包含至少或约200个氨基酸。抗原结合片段可包括当插入抗体构架中(例如通过取代相应区域)时可产生免疫特异性结合至抗原的抗体的任何抗体片段。
根据本公开的抗体可使用本领域中众所周知的技术,如以下技术或其组合制备:重组技术、噬菌体展示技术、合成技术或本领域中已知的其它技术。例如,基因工程化的重组抗体(或抗体模拟物)可利用适合培养系统(例如大肠杆菌或哺乳动物细胞)表达。工程化可以指例如在抗体的末端引入连接酶特异性识别序列。
HER2是指人表皮生长因子受体-2,属于表皮生长因子(EGFR)受体酪氨酸激酶家族。在本申请中,术语ErbB2和HER2具有相同的含义并且可以互换使用。
如本文所使用,术语“靶向分子-药物缀合物”称为“缀合物”。缀合物的实例包括但不限于抗体-药物缀合物。
小分子化合物是指大小与药品中常用有机分子的大小相当的分子。这一术语不包含生物大分子(例如蛋白质、核酸等),但包含低分子量肽或其衍生物,如二肽、三肽、四肽、五肽等。典型地,小分子化合物的分子量可以是例如约100至约2000Da、约200至约1000Da、约200至约900Da、约200至约800Da、约200至约700Da、约200至约600Da、约200至约500Da。
免疫激动剂是指可以如通过激活免疫细胞来诱导或增强针对肿瘤的免疫反应的激动剂,所述免疫细胞包括但不限于DC、B细胞、巨噬细胞、NK细胞和T细胞。本领域中已知免疫激动剂的非限制性实例,如TLR激动剂,包括但不限于TLR7和/或TLR8和/或TLR9的激动剂(例如咪喹莫特(Imiquimod)、瑞喹莫德、852A和VTX-2337)以及STING激动剂(例如ADU-S100和MK-1454)。
连接单元是指共价键接化合物或材料中的两个或更多个部分的官能团。例如,连接单元可用来共价键接一个或多个靶向分子和/或一种或多种有效载荷的辅助部分。
间隔子是位于不同结构模块之间并且能在空间上隔开各结构模块的结构。间隔子的定义不受它是否具有某一功能或它是否能在体内裂解或降解限制。间隔子的实例包括但不限于氨基酸和非氨基酸结构,其中非氨基酸结构可以是但不限于氨基酸衍生物或类似物。“间隔子序列”是指充当间隔子的氨基酸序列,并且其实例包括但不限于单一氨基酸,如Leu、Gln等;含有多个氨基酸的序列,例如含有两个氨基酸如GA的序列等;或例如GGGGS、GGGGSGGGGS、GGGGSGGGGSGGGGS等。间隔子的其它实例包括例如自分解型间隔子,如PABC(对苯甲氧羰基)等。
术语“烷基”是指由碳原子和氢原子组成的直链或支链饱和脂肪烃基,该基团通过单键连接至分子的其余部分。烷基可以含有1至20个碳原子,参考C1-C20烷基,例如C1-C4烷基、C1-C3烷基、C1-C2烷基、C3烷基、C4烷基、C3-C6烷基。烷基的非限制性实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基,或它们的异构体。二价基团是指由相应单价基团,通过从具有自由价电子的碳原子去除一个氢原子获得的基团。二价基团具有两个连接至分子其余部分的连接位点。例如,“亚烷基”或“次烷基”是指直链或支链饱和二价烃基。亚烷基的实例包括但不限于亚甲基(-CH2-)、亚乙基(-C2H4-)、亚丙基(-C3H6-)、亚丁基(-C4H8-)、亚戊基(-C5H10-)、亚己基(-C6H12-)、1-甲基亚乙基(-CH(CH3)CH2-)、2-甲基亚乙基(-CH2CH(CH3)-)、甲基亚丙基、乙基亚丙基等。
如本文所使用,当将一个基团与另一基团组合时,所述基团的连接可以是线性或分支的,只要形成化学上稳定的结构即可。由此类组合形成的结构可通过该结构中的任何适合原子,优选地通过指定化学键连接至分子的其它部分。例如,当描述C1-4亚烷基与包括-CH2-、-NH-、-C(O)-、-NHC(O)-、-C(O)NH-在内的基团中的一者的组合时,C1-4亚烷基可与以上基团形成线性连接,如C1-4亚烷基-CH2-、C1-4亚烷基-NH-、C1-4亚烷基-C(O)-、C1-4亚烷基-NHC(O)-、C1-4亚烷基-C(O)NH-、-CH2-C1-4亚烷基、-NH-C1-4亚烷基、-C(O)-C1-4亚烷基、-NHC(O)-C1-4亚烷基、-C(O)NH-C1-4亚烷基。所得到的二价结构可另外连接至分子的其它部分。
式(I')的化合物
一方面,提供一种式(I')(式(I'-1)或式(I'-2)或其混合物)的化合物:
其中
B2是-(CH2)k1(CO)-NH-(C2H4-O)j-(CH2)k2(CO)-Lys-R3、-(CH2)k(CO)-NH-(C2H4-O)j-H或-(CH2)k(CO)-(NH-CR1R2-(CO))d-R3;
R1是-C1-6烷基;
R2选自氢和C1-6烷基;
R3是当与有效载荷中的基团反应时可离去的基团;
k、k1、k2各自独立地是1至5的整数,j是1至3的整数,d是1或2。
在一个实施例中,式(I'-1)和式(I'-2)中的B2相同。
在一个实施例中,d是1。
在一个实施例中,端基是氢。在一个实施例中,R3是羟基或
在一个实施例中,端基R3表示不会出现在B2与有效载荷反应产生的产物分子中的结构的部分,并因此在连接单元-有效载荷中间体(参见下文)中,对应于B2的结构部分是所述二价基团中的一者或者两者或更多者的组合。
硫代琥珀酰亚胺在生理条件下不稳定并且易于发生反向迈克尔加成(Michaeladdition),导致在缀合位点处裂解。此外,当系统中存在另一种硫醇化合物时,硫代琥珀酰亚胺还可与该另一种硫醇化合物发生硫醇基交换。这些反应都会引起有效载荷的掉落并产生有毒副作用。在本公开中,开环的琥珀酰亚胺结构和/>不再经历反向迈克尔加成或硫醇基交换,并由此使产物更稳定。开环反应的方法可见于WO2015165413A1。
式(I')化合物的具体实施例
在一个实施例中,在式(I')的化合物中,B2是-(CH2)k1(CO)-NH-(C2H4-O)j-(CH2)k2(CO)-(Lys-OH),k1是5,j是3,k2是1,Lys通过其α氨基连接至B2的其余部分,并且连接单元的结构是以下两种结构的混合物(连接单元LN102-5):
在一个实施例中,在式(I')的化合物中,B2是-(CH2)k(CO)-NH-(C2H4-O)j-H,k是2,j是1,并且连接单元的结构是以下两种结构的混合物(连接单元LN102-6):
在一个实施例中,在式(I')的化合物中,B2是-(CH2)k(CO)-(NH-CR1R2-(CO))d-R3,k是2,d是1,R1是(S)-甲基,R2是氢,并且连接单元的结构是以下两种结构的混合物(连接单元LN102-9):
在一个实施例中,在式(I')的化合物中,B2是-(CH2)k(CO)-(NH-CR1R2-(CO))d-R3,k是2,d是1,R1是(R)-甲基,R2是氢,并且连接单元的结构是以下两种结构的混合物(连接单元LN102-10):
在一个实施例中,在式(I')的化合物中,B2是-(CH2)k(CO)-(NH-CR1R2-(CO))d-R3,k是2,d是2,R1和R2是甲基,R1'是(S)-甲基,R2'是氢,并且连接单元的结构是以下两种结构的混合物(连接单元LN102-12):
在一个实施例中,在式(I')的化合物中,B2是-(CH2)k(CO)-(NH-CR1R2-(CO))d-R3,k是2,d是2,R1和R2是甲基,R1'是(R)-甲基,R2'是氢,并且连接单元的结构是以下两种结构的混合物(连接单元LN102-13):
在一个实施例中,式(I')的化合物是如图1所示的化合物中的一者。
应理解,当在分子中存在两个或更多个-(CH2)kC(O)-基团时,每个k的值是独立选择的。在一些实施例中,分子中的“k”是用或不用另外的数字表示,例如k1、k2、k3等,其中数字不指示任何顺序,而仅用于区别各“k”。其它脚注如g、j、d应以类似方式理解。
应理解,当存在两个或更多个Rx(x是1、2、3、4、5、6、7等)时,每个Rx是独立选择的。在一些实施例中,分子中的“x”是用或不用另外的单撇号(')或多个撇号(如"、"'、""等)表示,例如R、R1'、R1"、R1"'、R2'、R2"、R2"'等。其它Rx如R3应以类似方式理解。
作为连接单元的式(I')的化合物
在一个实施例中,B2所包含的反应性基团可用于与含有另一反应性基团的有效载荷共价缀合,由此使式(I')的化合物携带有效载荷。
在另一实施例中,式(I')所包含的连接酶识别序列GGG(G是甘氨酸)可用于通过连接酶与相应连接酶识别序列LPETGG进行的缀合。
因此,式(I')的化合物可以用作连接单元,该连接单元可连接至靶向分子(如抗体或其抗原结合片段)和/或有效载荷。
本领域的技术人员可通过常规固相或液相方法合成连接单元。
带有效载荷的式(I')化合物
B2所包含的反应性基团与含有另一反应性基团的有效载荷共价缀合,得到带有效载荷的式(I')化合物。
在又另一方面,提供一种具有式(II'-1)或式(II'-2)的结构的化合物
其中
PL是连接至式(I')的化合物的B2部分的有效载荷。
有效载荷
在本公开中,有效载荷可选自小分子化合物、核酸和类似物、示踪分子(包括荧光分子等)、短肽、多肽、拟肽及蛋白质。在一个实施例中,有效载荷选自小分子化合物、核酸分子和示踪分子。在一个优选实施例中,有效载荷选自小分子化合物。在一个更优选的实施例中,有效载荷选自细胞毒素和其片段。在一个更优选的实施例中,有效载荷选自免疫激动剂和其片段。
在一个实施例中,免疫激动剂选自TLR激动剂,如TLR激动剂(例如TLR 7激动剂、TLR 8激动剂、TLR 7/8激动剂);和STING激动剂。在一个实施例中,免疫激动剂选自TLR激动剂。
在一个实施例中,免疫激动剂是瑞喹莫德:
在一个实施例中,连接单元与有效载荷是使用本领域中已知的任何反应,通过如上文所定义的反应性基团连接,所述反应包括但不限于缩合反应、亲核加成、亲电子加成等。
在一个实施例中,有效载荷是免疫激动剂,抗体-免疫激动剂缀合物(编号为LPx)是如下表和图2中所示化合物中的一者。
式(II')的化合物 | 连接单元 | PL(免疫激动剂) |
LP102-4-1 | LN102-5 | 瑞喹莫德 |
LP102-6-1 | LN102-6 | 瑞喹莫德 |
LP102-9-1 | LN102-9 | 瑞喹莫德 |
LP102-12-1 | LN102-12 | 瑞喹莫德 |
LP102-10-1 | LN102-10 | 瑞喹莫德 |
LP102-13-1 | LN102-13 | 瑞喹莫德 |
带有效载荷的式(I')化合物的制备
在一个实施例中,连接单元与有效载荷是使用本领域中已知的任何反应,通过如上文所定义的反应性基团连接,所述反应包括但不限于缩合反应、亲核加成、亲电子加成等。
式(III')的化合物
一方面,提供一种式(III')的化合物:
其中B2如式(I')中所定义。
在一个实施例中,式(III')的化合物可用于通过以下途径制备带有效载荷的式(I')化合物:
将带有效载荷的式(III')化合物转化成带有效载荷的式(I')化合物可使用本领域中或如本文所描述的任何已知方法进行。例如,可进行单步骤或多步骤合成以将结构片段(LU102)引入带有效载荷的式(III')化合物中的顺丁烯二酰亚胺环中,接着所得到的含有琥珀酰亚胺部分的分子可以经历开环反应以打开琥珀酰亚胺环,并获得带有效载荷的式(I')化合物(即,式(II')化合物)。在一个实施例中,将LU102通过式(III')化合物中所包含的顺丁烯二酰亚胺基团与LU102的硫醇基反应而引入带有效载荷的式(III')化合物中。
缀合物及其制备
在又另一方面,提供一种具有式(IV'-1)或式(IV'-2)的结构的缀合物
其中
PL是连接至式(I')的化合物的B2部分的有效载荷;
A是连接至式(I')的化合物的D1或D2部分的靶向分子;
z是1或2。
在一个实施例中,有效载荷是如上文所定义的免疫激动剂。在一个实施例中,缀合物是抗体-免疫激动剂缀合物。
靶向分子
在一个实施例中,靶向分子是抗体或其抗原结合片段。
在本公开的一些实施例中,靶向分子(例如抗体或其抗原结合片段)所识别的靶标包括但不限于CD19、CD22、CD25、CD30/TNFRSF8、CD33、CD37、CD44v6、CD56、CD70、CD71、CD74、CD79b、CD117/KIT、CD123、CD138、CD142、CD174、CD227/MUC1、CD352、CLDN18.2、DLL3、ErbB2/HER2、CN33、GPNMB、ENPP3、粘连蛋白(Nectin)-4、EGFRvIII、SLC44A4/AGS-5、间皮素(mesothelin)、CEACAM5、PSMA、TIM1、LY6E、LIV1、粘连蛋白4、SLITRK6、HGFR/cMet、SLAMF7/CS1、EGFR、BCMA、AXL、NaPi2B、GCC、STEAP1、MUC16、间皮素、ETBR、EphA2、5T4、FOLR1、LAMP1、钙粘蛋白(Cadherin)6、FGFR2、FGFR3、CA6、CanAg、整合素(Integrin)αV、TDGF1、蝶素(Ephrin)A4、Trop2、PTK7、NOTCH3、C4.4A、FLT3。
在一个实施例中,靶向分子是抗人HER2抗体或其抗原结合片段。抗人HER2抗体的实例包括但不限于曲妥珠单抗。曲妥珠单抗结合至HER2的第四细胞外结构域(ECD4)并且被批准用于治疗Her2阳性乳腺癌和胃癌。
在一个优选实施例中,抗人HER2抗体是选自基于曲妥珠单抗的工程化抗HER2抗体中的一者或多者。
在一个优选实施例中,抗人HER2抗体是选自单克隆抗体、嵌合抗体、人源化抗体、抗体片段和抗体模拟物的重组抗体。在一个实施例中,抗体模拟物选自scFv、微型抗体、双功能抗体、纳米抗体。对于与式(I')的化合物缀合,本公开的靶向分子可包含修饰过的部分以与式(I')的化合物连接。此类修饰过的部分的引入位置不受限制,例如,当靶向分子是抗体时,其引入位置可以是但不限于位于抗体重链或轻链的C末端或N末端。
在一个实施例中,本公开的靶向分子是抗体或其抗原结合片段,其可包含末端修饰。末端修饰是指在抗体重链或轻链的C末端或N末端处的修饰,该修饰例如包含连接酶识别序列。在另一实施例中,末端修饰可进一步包括含2-10个氨基酸的间隔子Sp1,其中抗体、Sp2和连接酶识别序列是依序连接的。在一个特定实施例中,Sp2是选自GA、GGGGS、GGGGSGGGGS和GGGGSGGGGSGGGGS的间隔子序列,尤其是GA。
在一个优选实施例中,抗体或其抗原结合片段的轻链包括3种类型:野生型(LC);C末端修饰的轻链(LCCT),它是通过直接引入连接酶识别序列LPETGG修饰的;以及C末端修饰的轻链(LCCTL),它是通过引入短肽间隔子加连接酶供体底物识别序列LPETGG修饰的。抗体或其抗原结合片段的重链包括3种类型:野生型(HC);C末端修饰的重链(HCCT),它是通过直接引入连接酶识别序列LPETGG修饰的;以及C末端修饰的重链(HCCTL),它是通过引入短肽间隔子加连接酶供体底物识别序列LPETGG修饰的。当式(IV')的化合物中的z是1或2时,以上重链和轻链的组合可形成8种优选的抗体分子,参见氨基酸序列表。
本公开的缀合物还可包含有效载荷。有效载荷如上文所描述。
缀合物的具体实施例
在一个实施例中,在式(IV')中,B2是-(CH2)k1(CO)-NH-(C2H4-O)j-(CH2)k2(CO)-(Lys-OH)-,k1是5,j是3,k2是1,Lys通过其α氨基连接至B2的其余部分,并且缀合物的结构如下(式AC102-5):
在一个实施例中,在式(IV')中,B2是-(CH2)k(CO)-NH-(C2H4-O)j-,k是2,j是1,并且缀合物的结构如下(式AC102-6):
在一个实施例中,在式(IV')中,B2是-(CH2)k(CO)-(NH-CR1R2-(CO))d-,k是2,d是1,R1是(S)-甲基,R2是氢,并且缀合物的结构如下(式AC102-9):
在一个实施例中,在式(IV')中,B2是-(CH2)k(CO)-(NH-CR1R2-(CO))d-,k是2,d是1,R1是(R)-甲基,R2是氢,并且缀合物的结构如下(式AC102-10):
在一个实施例中,在式(IV')中,B2是-(CH2)k(CO)-(NH-CR1R2-(CO))d-,k是2,d是2,R1和R2是甲基,R1'是(S)-甲基,R2'是氢,并且缀合物的结构如下(式AC102-12):
在一个实施例中,在式(IV')中,B2是-(CH2)k(CO)-(NH-CR1R2-(CO))d-,k是2,d是2,R1和R2是甲基,R1'是(R)-甲基,R2'是氢,并且缀合物的结构如下(式AC102-13):
缀合物的制备
本公开的缀合物可以由本领域中已知的任何方法制备。在一些实施例中,缀合物是通过连接酶催化的靶向分子与带有效载荷的式(I')化合物的位点特异性缀合来制备,其中靶向分子被连接酶识别序列修饰。所述方法包含步骤A和步骤B。
步骤A.连接单元-有效载荷中间体的制备
在一个优选实施例中,式(I')的化合物中的B2通过反应性基团共价连接至含有相应反应性基团的有效载荷,其中所述反应性基团分别如上文所定义。
使用本公开的式(I')化合物制备的连接单元-有效载荷中间体具有确定的结构、确定的组成和高纯度,由此使得当与抗体进行缀合反应时,较少的杂质被引入或无其它杂质引入。当使用此类中间体进行连接酶催化的与含有连接酶识别序列的修饰过的抗体的位点特异性缀合时,获得具有高度可控的质量的均质ADC。
步骤B.将靶向分子连接至带有效载荷的式(I')化合物
本公开的靶向分子可通过本领域中已知的任何方法与带有效载荷的式(I')化合物(即,式(II')的化合物)缀合。例如,应用连接酶催化的位点特异性缀合技术,并且靶向分子与带有效载荷的式(I')化合物通过连接酶特异性底物识别序列相互连接。在一个实施例中,靶向分子是具有在轻链和/或重链的C末端处引入的基于识别序列的末端修饰的抗体,并且靶向分子与式(II')的化合物在野生型或优化的工程化连接酶或其任何组合催化下以及在适合催化反应条件下缀合。
在一个具体实施例中,连接酶是分选酶A(Sortase A)并且缀合反应可由以下方案表示:
三角形和五边形分别表示以下中的任一者:抗体的一部分或式(II')化合物的一部分。n分别如上文所定义。当与相应的受体底物识别序列Gn缀合时,在LPETGG序列中甘氨酸上游的肽键被分选酶A裂解,并将由此得到的中间体连接至Gn的游离N末端以产生新肽键。所得到的氨基酸序列是LPETGn。序列Gn和LPETGG如上文所定义。
具体缀合物表
在一个实施例中,有效载荷是免疫激动剂。在一个实施例中,抗体-免疫激动剂缀合物如下表和图3中所示:
药物组合物和药物制剂
本公开的另一目的是提供一种药物组合物,该药物组合物包含预防或治疗有效量的本公开的缀合物,以及至少一种药学上可接受的载体。
本公开的药物组合物可通过任何方式施用,只要它实现预防、缓解、预防或治愈人类或动物的症状的作用即可。例如,可根据施用途径制备各种适合的剂型,尤其是注射剂,如注射用冻干粉、注射液或注射用无菌粉末。
术语“药学上可接受的”意思指当在正常医学判断的范围内与患者的组织接触时,不应产生过度毒性、刺激或过敏反应等,具有合理的优点-缺点比并对预定用途有效。
术语药学上可接受的载体是指药学上可接受的且不会干扰缀合物的生物活性和特性的载体材料。水性载体的实例包括但不限于缓冲盐水等。药学上可接受的载体还包括使组合物接近生理条件的载体材料,如pH调节剂、缓冲剂、毒性调节剂等,以及乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。
在一个实施例中,本公开的药物组合物具有1至20,如1-10、1-8、1-6、1-4、1-3.5、1-3、1-2.5,优选地1-2的整数或非整数药物与抗体比(DAR)。在一个实施例中,本公开的药物组合物具有约1.4至约2,优选地约1.5至约2,更优选地约1.55至约1.95的DAR。在一个实施例中,本公开的药物组合物具有约1.6至约1.8的DAR。
治疗方法和用途
本公开的缀合物可用于治疗肿瘤和/或自身免疫疾病。对缀合物治疗敏感的肿瘤包括以特定肿瘤相关抗原或细胞表面受体为特征的肿瘤,并且这些肿瘤将被缀合物中的靶向分子识别,并且会受到缀合物中激动剂的免疫细胞激活活性影响。
因此,在又另一方面,还提供了本公开的缀合物或本公开的药物组合物在制造用于治疗选自肿瘤或自身免疫疾病的疾病、病症或疾患的药剂中的用途。
另一方面,提供了用于治疗肿瘤或自身免疫疾病的本公开的缀合物或本公开的药物组合物。
在另一方面,提供了一种治疗肿瘤或自身免疫疾病的方法,所述方法包括向有需要的个体施用有效量的本公开的缀合物或本公开的药物组合物。
在一个优选实施例中,通过抗人HER2抗体与有效载荷缀合形成的本公开的缀合物可特异性结合至肿瘤细胞表面上的HER2并选择性杀灭表达HER2的肿瘤细胞。在另一个优选实施例中,提供了本公开的缀合物或本公开的药物组合物在制造用于治疗选自HER2阳性肿瘤的疾病、病症或疾患的药剂中的用途。在一个更优选的实施例中,所述疾病、病症或疾患选自乳腺癌、胃癌、肺癌、卵巢癌、尿道上皮癌等。
施用给受试者的缀合物的剂量可在相当大的范围内调整。剂量可根据特定施用途径和受试者的需要而变化,并且可由健康护理专业人员判断。
有益效果
本公开利用具有独特结构的连接单元并使用连接酶催化抗HER2抗体与激动剂的缀合。本公开的缀合物具有良好均质性、高活性和高选择性。特别地,细胞内代谢物对具有低靶标抗原表达或无靶标抗原表达的细胞显示出明显降低的细胞增殖毒性。此外,连接单元-激动剂中间体的毒性比游离激动剂的毒性低得多,并因此,药物制造过程的危害较小,这将有利于工业生产。
本公开的缀合物实现以下技术作用中的至少一者:
(1)针对靶标细胞的高抑制活性或对靶标细胞的强大杀灭作用。
(2)良好的物理化学特性(例如溶解度、物理和/或化学稳定性)。
(3)良好的药物动力学特性(例如在血浆中良好的稳定性、适当的半衰期和作用持续时间)。
(4)良好的安全性(对非靶标正常细胞或组织的低毒性,和/或较少的副作用、较宽的治疗窗口)等。
药物可预防患者抵抗HER2靶向疗法,并且激活骨髓细胞以增强先天性和适应性免疫反应。它可克服当前针对HER2的疗法的低反应率。
实例
制备实例
为了更清楚地说明目的和技术方案,以下将参照具体实例进一步描述本公开。应理解,这些实例并不打算限制本公开的范围。以下实例中未提到的具体实验方法是根据常规实验方法进行。
仪器、材料和试剂
除非另外陈述,否则实例中使用的仪器和试剂是可商购的。试剂可不经进一步纯化即直接使用。
MS:Thermo Fisher Q Exactive Plus,Water2795-Quattro micro三重四极杆质谱仪
HPLC:Waters 2695、Agilent 1100、Agilent 1200
半制备型HPLC:Lisure HP plus 50D
流式细胞术:CytoFLEX S
HIC-HPLC:Butyl-HIC;流动相A:25mM PB、2M(NH4)2SO4,pH 7.0;流动相B:25mM PB,pH 7.0;流动速率:0.8ml/min;采集时间:25min;注入量:20μg;柱温度:25℃;检测波长:280nm;样品室温度:8℃。
SEC-HPLC:柱:TSK凝胶G3000 SWXL,TOSOH 7.8mm ID×300mm,5μm;流动相:0.2MKH2PO4、0.25M KCl,pH 6.2;流动速率:0.5ml/min;采集时间:30min;注入体积:50μl;柱温度:25℃;检测波长:280nm;样品盘温度:8℃。
CHO获自Thermo Fisher Scientific;pcDNA 3.3获自Life Technology;HEK293F获自Prejin;PEIMAX转染试剂获自Polyscience;MabSelect Sure ProA获自GE;Capto SImpAct获自GE;Rink-酰胺-MBHA树脂和二氯树脂获自Nankai synthesis;HCC1954获自ATCC目录号CRL-2338;SK-BR-3获自ATCC目录号HTB-30;BT474细胞获自ATCC目录号HTB-20;JIMT1细胞获自DSMZ目录号ACC589;Colo205细胞获自ATCC目录号CRL-222;MC38hHER2鼠结直肠癌细胞获自Biocytogen;NUGC4人胃癌细胞获自JCRB目录号JCRB0834;NCI-N87细胞(ATCC目录号CRL-5822);MDA-MB-468获自ATCC目录号HTB-132。
实例1抗体表达载体的构建、抗体表达、纯化和鉴别
1.1修饰过的抗人HER2抗体Ab0001-LCCTL-HC的生产
如下构建抗体Ab0001-LCCTL-HC(轻链:SEQ ID NO:1,重链:SEQ ID NO:2)的表达质粒。抗体Ab0001-LCCTL-HC的序列:基于曲妥珠单抗的氨基酸序列,并将GALPETGG引入轻链的C末端,其中LPETGG是连接酶供体底物的识别序列,并且GA是间隔子序列。将质粒转染至CHO细胞中并建立细胞群,并且筛选高表达的细胞群,将该细胞群在5-10L反应器中参照曲妥珠单抗的培养方法培养,并收集上清液。
1.2抗体Ab0001-LCCTL-HC的纯化
使用MabSelect亲和色谱法和琼脂糖凝胶S阳离子交换色谱法的组合,以标准程序纯化Ab0001-LCCTL-HC,将纯化的产物溶解于原始曲妥珠单抗药物缓冲液(5mM盐酸组氨酸、2%海藻糖、0.009%聚山梨醇酯20,PH 6.0)中,并分数份小等分试样冷冻。
1.3抗体Ab0001-LCCTL-HC的质量控制
经SDS-PAGE确定,以上纯化的抗体Ab0001-LCCTL-HC的纯度是98.5%;经SEC-HPLC确定,样品中高分子量聚合物的含量小于0.4%;内毒素含量小于0.098EU/mg。
1.4其它修饰过的抗人抗体的制备
根据类似方法,将基于连接酶识别序列的末端修饰分别引入曲妥珠单抗轻链和/或重链的C末端,得到修饰过的抗体。
基于Ab0001(曲妥珠单抗)的修饰过的抗人HER2抗体列于表1中。末端修饰序列中的LPETGG是连接酶供体底物的识别序列,并且GA是间隔子序列。
表1修饰过的抗人HER2抗体
*:“-”表示无末端修饰
实例2中间体的制备
2.1连接单元的制备
存在A和Lm的连接单元
通过常规固相多肽合成,使用Rink-酰胺-MBHA树脂或二氯树脂合成含有式(I')的部分A的连接单元片段LU102。使用Fmoc保护连接单元中Lk结构的氨基酸和氨基。缀合试剂选自HOBT、HOAt/DIC、DCC、EDCI或HATU。合成之后,使用三氟乙酸裂解树脂。通过HPLC纯化产物,冻干并储存待用。连接单元片段列于下表中。
表
使上表中的连接单元片段与含有顺丁烯二酰亚胺结构或其衍生物的连接单元片段反应,接着使用如WO2015165413A1中所描述的方法进行开环反应,获得连接单元LN102-5、LN102-6、LN102-9、LN102-10、LN102-12、LN102-13。其结构如上文所示。参见下表:
2.2连接单元-激动剂中间体的制备
2.2.1连接单元-激动剂中间体LP102-6-1的制备
步骤1:将瑞喹莫德(25.0g,79.5mmol)溶解于MeCN(500mL)中,并用Trt-Cl(33.25g,119.3mmol)处理,随后用TEA(20.12mL,20.12mmol)处理。使反应回流2-3小时(TLC)。在真空中浓缩反应混合物。接着,将混合物用AcOEt(700mL)和H2O(400mL)处理,搅拌30分钟并分离。将有机相在真空中浓缩至300mL并用正庚烷(400mL)处理。接着,将混合物搅拌20分钟。在过滤后,将滤饼与EtOH/H2O(1:1,200mL)一起搅动(beat)并过滤。将滤饼真空干燥,获得目标化合物HX20031-a,以白色固体状获得(43.9g,99.1%)。
步骤2:将化合物(HX20031-a)(40.02g,72.9mmol)溶解于DMF(200mL)中并冷却至0-10℃。分批地添加NaH(60%,3.74g,93.4mmol)。在0-10℃下,将悬浮液剧烈搅拌l小时,接着将其升温到20-30℃,搅拌1小时。接着,将混合物冷却至0-10℃并用化合物1186g(20.88g,93.4mmol)一次性处理。将混合物在室温下搅拌过夜,接着用10% NaH2PO4(1L)和AcOEt(1L)的混合物缓慢处理。将反应混合物搅拌3小时并过滤。将有机层浓缩,并通过硅胶柱色谱法(正庚烷至正庚烷/AcOEt=10:1至正庚烷/AcOEt=4:1)来纯化,获得目标化合物HX20031-b(24.89g,46.9%)。
步骤3:将化合物(HX20031-b)(10g,14.3mmol)用TFA(40mL)和H2O(80mL)的混合物处理。在室温下,将反应混合物搅拌24小时。接着,将混合物倒入MTBE(400mL)中并搅拌2小时。在过滤后,将滤饼与MTBE(200mL)一起搅动并过滤。将滤饼真空干燥,获得目标化合物HX20031-c,以白色固体状获得(8.51g,100%)。
步骤4:将化合物HX20031-c(6.0g,10.2mmol)溶解于DMF(50mL)中并用DIPEA(3.5mL,20.4mmol)和N-琥珀酰亚胺基3-顺丁烯二酰亚胺基丙酸酯(3.27g,12.3mmol)处理。在室温下保持反应3小时(HPLC),接着将混合物直接用于下一步骤。
步骤5-6:将来自步骤4的混合物用连接单元LU102(5.5g,15.3mmol)和H2O(50mL)的溶液处理。使混合物在0-40℃反应0.5-20小时。接着,将反应混合物与适量的Tris碱溶液或促进开环反应的其它溶液混合,并在0-40℃反应0.2-20小时。反应完成之后,通过半制备型/制备型HPLC纯化产物,并冻干,获得连接单元-激动剂LP102-6-1(3.3g,三个步骤30%)。MS m/z 1065.6[M+H]+。
实例3靶向分子-药物缀合物的制备
将连接单元-激动剂中间体分别通过连接酶以位点特异性方式与抗体缀合,形成AIAC。缀合反应的方法可见于WO2015165413A1。所得到的AIAC列于下表中:
效果实例1抗体免疫激动剂缀合物的体外评估
人外周血单核细胞的分离
使用SepMate 50和Lymphoprep(Stem Cell Technologies)从健康血液供体中分离出人外周血单核细胞。对活细胞计数并在含10% FBS的RPMI1640培养基中将细胞浓度调至1.25×106个/毫升。利用胰蛋白酶剥离肿瘤细胞,并将其收集起来。对活细胞计数并在含10% FBS的RPMI1640培养基中将细胞浓度调至2.5×105个/毫升。将12.5×104个人PBMC和2.5×104个肿瘤细胞(PBMC:肿瘤细胞=5:1)添加至96孔板各孔中,接着添加指定浓度的抗体或缀合物。将细胞混合物与药物一起培育18小时,接着收集无细胞上清液用于人TNFαELISA。
为了评价靶向HER2的免疫缀合物的活性,将人PBMC和NCI N87人胃癌细胞以5:1的比率共培养,并添加指定浓度的抗体或测试免疫缀合物(AC102-6-1-1或AC102-5-1-1)。相比抗体Ab0001,AC102-6-1-1诱导较高的TNFα产量,并且AC102-6-1-1的有效浓度比有效载荷瑞喹莫德低得多。与Ab0001相比较,另一种免疫缀合物AC102-5-1-1未显示出明显不同的活性(图4)。在人PBMC和MDA-MB-468HER2阴性细胞的共培养物中未观察到AC102-6-1-1的活性,表明AC102-6-1-1的活性主要取决于靶标肿瘤细胞上HER2的表达(图5)。
在类似实验设置中,评价若干其它缀合物的体外活性(图6)。
效果实例2抗体免疫激动剂缀合物的体内评估
对于体内抗肿瘤功效研究,将1×107个NCI N87人胃癌细胞皮下接种于SCIDBeige小鼠的右侧腹中。6天后,当肿瘤体积达到平均173mm3时,将荷瘤小鼠分组并静脉内施用5mg/kg的Ab0001或测试免疫缀合物(AC102-5-1-1或AC102-6-1-1)。每周两次用测径规测量肿瘤体积。抗体Ab0001本身显示出极其有限的抗肿瘤活性。AC102-5-1-1和AC102-6-1-1在结束时大致治愈肿瘤(图7)。
将5×105个过表达人HER2的MC38hHER2鼠结直肠癌细胞皮下接种于C57BL/6小鼠的右侧腹中。8天之后,当肿瘤体积达到平均90mm3时,将荷瘤小鼠分组并静脉内施用Ab0001或AC102-6-1-1。10mg/kg Ab0001未显示明显抗肿瘤活性。3mg/kg和10mg/kg AC102-6-1-1以剂量依赖性方式抑制肿瘤生长(图8)。
序列表
SEQ ID No.1:Ab0001-LCCTL-HC轻链:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGALPETGG
SEQ ID No.2:Ab0001-LCCTL-HC重链:
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID No.3:Ab0001-LC-HCCT轻链:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID No.4:Ab0001-LC-HCCT重链:
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKLPETGG
SEQ ID No.5:Ab0001-LC-HCCTL轻链:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID No.6:Ab0001-LC-HCCTL重链:
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGALPETGG
SEQ ID No.7:Ab0001-LCCT-HC轻链:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECLPETGG
SEQ ID No.8:Ab0001-LCCT-HC重链:
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID No.9:Ab0001-LCCT-HCCT轻链:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECLPETGG
SEQ ID No.10:Ab0001-LCCT-HCCT重链:
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKLPETGG
SEQ ID No.11:Ab0001-LCCT-HCCTL轻链:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECLPETGG
SEQ ID No.12:Ab0001-LCCT-HCCTL重链:
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGALPETGG
SEQ ID No.13:Ab0001-LCCTL-HCCT轻链:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGALPETGG
SEQ ID No.14:Ab0001-LCCTL-HCCT重链:
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKLPETGG
SEQ ID No.15:Ab0001-LCCTL-HCCTL轻链:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGALPETGG
SEQ ID No.16:Ab0001-LCCTL-HCCTL重链:
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGALPETGG
序列表
<110> 启德医药科技(苏州)有限公司
博瑞生物医药(苏州)股份有限公司
<120> 抗HER2抗体-免疫激动剂缀合物及其应用
<130> P2023TC8448CS
<160> 16
<170> PatentIn version 3.5
<210> 1
<211> 222
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LCCTL-HC Light chain
<400> 1
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 Gln Asp Val Asn Thr 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 Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln 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 Gly Ala Leu Pro Glu Thr Gly Gly
210 215 220
<210> 2
<211> 450
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LCCTL-HC Heavy chain
<400> 2
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 3
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LC-HCCT Light chain
<400> 3
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 Gln Asp Val Asn Thr 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 Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln 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> 4
<211> 456
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LC-HCCT Heavy chain
<400> 4
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys Leu Pro Glu Thr Gly Gly
450 455
<210> 5
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LC-HCCTL Light chain
<400> 5
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 Gln Asp Val Asn Thr 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 Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln 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> 6
<211> 458
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LC-HCCTL Heavy chain
<400> 6
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys Gly Ala Leu Pro Glu Thr Gly Gly
450 455
<210> 7
<211> 220
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LCCT-HC Light chain
<400> 7
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 Gln Asp Val Asn Thr 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 Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln 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 Leu Pro Glu Thr Gly Gly
210 215 220
<210> 8
<211> 450
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LCCT-HC Heavy chain
<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 Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 9
<211> 220
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LCCT-HCCT Light chain
<400> 9
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 Gln Asp Val Asn Thr 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 Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln 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 Leu Pro Glu Thr Gly Gly
210 215 220
<210> 10
<211> 456
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LCCT-HCCT Heavy chain
<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 Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys Leu Pro Glu Thr Gly Gly
450 455
<210> 11
<211> 220
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LCCT-HCCTL Light chain
<400> 11
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 Gln Asp Val Asn Thr 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 Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln 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 Leu Pro Glu Thr Gly Gly
210 215 220
<210> 12
<211> 458
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LCCT-HCCTL Heavy chain
<400> 12
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys Gly Ala Leu Pro Glu Thr Gly Gly
450 455
<210> 13
<211> 222
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LCCTL-HCCT Light chain
<400> 13
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 Gln Asp Val Asn Thr 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 Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln 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 Gly Ala Leu Pro Glu Thr Gly Gly
210 215 220
<210> 14
<211> 456
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LCCTL-HCCT Heavy chain
<400> 14
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys Leu Pro Glu Thr Gly Gly
450 455
<210> 15
<211> 222
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LCCTL-HCCTL Light chain
<400> 15
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 Gln Asp Val Asn Thr 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 Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln 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 Gly Ala Leu Pro Glu Thr Gly Gly
210 215 220
<210> 16
<211> 458
<212> PRT
<213> Artificial Sequence
<220>
<223> Ab0001-LCCTL-HCCTL Heavy chain
<400> 16
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys Gly Ala Leu Pro Glu Thr Gly Gly
450 455
Claims (8)
1.一种式(I-1)或式(I-2)的化合物:
其中B2是-(CH2)k(CO)-NH-(C2H4-O)j-,k是1至5的整数,j是1至3的整数,
PL是连接至所述B2部分的有效载荷,
优选地,PL是瑞喹莫德
2.根据权利要求1所述的化合物,其中,k是2。
3.根据权利要求1或2所述的化合物,其中,j是1。
4.根据权利要求1至3中任一项所述的化合物,所述化合物选自以下结构:
5.一种式(II-1)或式(II-2)的抗体-药物缀合物:
其中B2是-(CH2)k(CO)-NH-(C2H4-O)j-,k是1至5的整数,j是1至3的整数,
PL是连接至所述B2部分的有效载荷,
优选地,PL是瑞喹莫德
z是1至4的整数;优选地是1至2的整数;
A是抗体,所述抗体包含具有SEQ ID NO:1的氨基酸序列的轻链和具有SEQID NO:2的氨基酸序列的重链。
6.根据权利要求5所述的抗体-药物缀合物,其中,k是2。
7.根据权利要求6所述的抗体-药物缀合物,其中,j是1。
8.根据权利要求5至7中任一项所述的抗体-药物缀合物,所述缀合物选自以下结构:
z是1至4的整数;优选地是1至2的整数;
A是抗体,所述抗体包含具有SEQ ID NO:1的氨基酸序列的轻链和具有SEQ ID NO:2的氨基酸序列的重链。
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CN2021079611 | 2021-03-08 | ||
CNPCT/CN2021/079611 | 2021-03-08 | ||
PCT/CN2022/079531 WO2022188743A1 (en) | 2021-03-08 | 2022-03-07 | Anti-her2 antibody-immune agonist conjugate and applications thereof |
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US (1) | US20240181072A1 (zh) |
EP (1) | EP4304661A1 (zh) |
JP (1) | JP2024509891A (zh) |
KR (1) | KR20230157385A (zh) |
CN (1) | CN117042809A (zh) |
AU (1) | AU2022232674A1 (zh) |
WO (1) | WO2022188743A1 (zh) |
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US11814394B2 (en) | 2021-11-16 | 2023-11-14 | Genequantum Healthcare (Suzhou) Co., Ltd. | Exatecan derivatives, linker-payloads, and conjugates and thereof |
WO2024051747A1 (en) * | 2022-09-06 | 2024-03-14 | Genequantum Healthcare (Suzhou) Co., Ltd. | A pharmaceutical composition of anti-her2 antibody-immune agonist conjugate and applications thereof |
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CN102993265B (zh) * | 2012-10-10 | 2015-05-13 | 深圳大学 | 免疫受体调节剂偶联体及其制备方法和应用、制备其的偶联前体以及合成偶联前体的化合物 |
RU2016129517A (ru) * | 2013-12-20 | 2018-01-25 | Ф. Хоффманн-Ля Рош Аг | Биспецифические антитела к her2 и способы применения |
WO2015165413A1 (zh) * | 2014-04-29 | 2015-11-05 | 秦刚 | 一种新型的稳定型抗体药物耦联物及其制备方法和用途 |
US20220323596A1 (en) * | 2018-09-12 | 2022-10-13 | Silverback Therapeutics, Inc. | Antibody conjugates of toll-like receptor agonists |
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- 2022-03-07 WO PCT/CN2022/079531 patent/WO2022188743A1/en active Application Filing
- 2022-03-07 CN CN202280020319.3A patent/CN117042809A/zh active Pending
- 2022-03-07 AU AU2022232674A patent/AU2022232674A1/en active Pending
- 2022-03-07 EP EP22766266.5A patent/EP4304661A1/en active Pending
- 2022-03-07 US US18/549,446 patent/US20240181072A1/en active Pending
- 2022-03-07 KR KR1020237034299A patent/KR20230157385A/ko unknown
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AU2022232674A9 (en) | 2023-10-26 |
AU2022232674A1 (en) | 2023-10-12 |
JP2024509891A (ja) | 2024-03-05 |
US20240181072A1 (en) | 2024-06-06 |
EP4304661A1 (en) | 2024-01-17 |
KR20230157385A (ko) | 2023-11-16 |
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