CN108285487A - 抗5t4抗体-药物偶联物及其应用 - Google Patents
抗5t4抗体-药物偶联物及其应用 Download PDFInfo
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- CN108285487A CN108285487A CN201710011890.XA CN201710011890A CN108285487A CN 108285487 A CN108285487 A CN 108285487A CN 201710011890 A CN201710011890 A CN 201710011890A CN 108285487 A CN108285487 A CN 108285487A
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Abstract
本发明提供了抗5T4抗体‑药物偶联物及其应用。具体地,本发明提供了一种抗5T4抗体‑药物偶联物,实验结果表明,所述抗体‑药物偶联物具有显著的抗肿瘤效果。本发明还公开了所述抗5T4抗体‑药物偶联物的制药用途,及其在抑制或预防肿瘤中的作用。
Description
技术领域
本发明属于生物医药领域,具体地说,本发明涉及抗5T4抗体-药物偶联物及其应用。
背景技术
人5T4癌胚抗原是由TPBG基因(滋养层糖蛋白基因)编码的分子量约为72kDa的高度糖基化的跨膜糖蛋白。5T4最早发现于胚胎发育,在胎盘滋养层细胞中高表达,在正常组织中基本不存在,仅在某些特殊的上皮中存在,如基底层复层鳞状上皮,腺体和导管上皮,以及视网膜次级神经元和嗅球。后来相继发现5T4表达于众多癌症类型中,包括卵巢癌、结直肠癌、胃癌、肾癌、***癌等,并且5T4在肿瘤中的过量表达已经与疾病进展关联,其可能发挥的作用是影响肿瘤细胞之间的连接,影响细胞形态、运动和黏附能力,继而促进远端转移,但具体的调控机制尚不完全清楚。但显而易见的是,5T4是癌症靶向治疗的一个非常有吸引力的靶点。几种抗5T4抗体已经得到描述,包括鼠源或人源化单克隆抗体。
5T4用作靶向治疗药物的设计靶点已经提出,如将抗5T4抗体的Fab片段与超抗原融合,利用超抗原激活T细胞产生免疫反应;如将单链抗5T4抗体scFv-Fc与人胰核糖核酸酶融合,利用人胰核糖核酸酶降解RNA,使肿瘤细胞因翻译过程受阻而优先死亡(专利号US2016304617);如CAR-T疗法,将编码靶向5T4的嵌合抗原受体的载体转入患者的T细胞,经过修饰的T细胞能够识别并结合肿瘤细胞上的5T4抗原,进而杀死肿瘤细胞,嵌合抗原受体的胞外配体结合区可以是抗5T4单克隆抗体的scFv(专利号WO2016034666);另外,重组5T4疫苗也被尝试用于治疗癌症。
癌症靶向治疗的发展过程中,另一个成功的策略是利用抗体作为载体,将毒性小分子携带进入癌细胞,然后利用解离下来的小分子来杀死癌细胞。目前已经有两个抗体药物偶联物(Antibody-drug conjugates,ADC)被用于癌症靶向治疗—Adcetris和Kadcyla。靶向5T4的抗体药物偶联物已经得到描述(专利号ZA200702793,US2007231333,US2012251558),如huA1-mcMMAF(US2012251558)是通过传统的抗体二硫键还原的方式将微管蛋白抑制剂MMAF连接到人源化的抗5T4单克隆抗体A1上产生的抗体药物偶联物(一个抗体分子连接2-8个数量不等的MMAF,平均DAR为4),一期临床显示出较好的安全性(2015ASCO)。抗体药物偶联物已经显示出了对肿瘤的显著的治疗效果,在此基础上,本领域技术人员致力于开发新的、更有效的抗体药物偶联物。
发明内容
本发明的目的在于提供一种新型抗5T4抗体药物偶联物及其治疗用途。
本发明的第一方面,提供了一种抗体-药物偶联物或其药学上可接受的盐,所述抗体-药物偶联物包括抗体和偶联于所述抗体的药物,所述抗体包括一重链可变区和一轻链可变区,
其中,所述重链可变区包括三个互补决定区:
CDR1:GFTFSSYE
CDR2:ISSSGSTI和
CDR3:AREMQFGWELLGAFDI;
所述轻链可变区包括三个互补决定区:
CDR1’:QSVSSSY
CDR2’:GAS和
CDR3’:QQYGSS。
在另一优选例中,所述重链可变区的氨基酸序列如SEQ ID NO.7所示。
在另一优选例中,所述轻链可变区的氨基酸序列如SEQ ID NO.8所示。
在另一优选例中,所述抗体包括SEQ ID NO.9所示的重链。
在另一优选例中,所述抗体包括SEQ ID NO.10所示的轻链。
在另一优选例中,所述药物包括选自下组的小分子药物:Duostatin 5、MMAF、Duostatin 14、Duomycin 2、Duomycin 4、Calicheamicin、Amanitine。
在另一优选例中,所述药物为Duostatin 5。
在另一优选例中,所述抗体-药物偶联物结构如式I所示:
Ab-(L-D)n,I
其中,Ab为所述抗体;
L为无或连接所述抗体和所述药物的接头;
D为抑制肿瘤细胞的小分子药物;
n为偶联于所述抗体的所述药物的数量
“-”为键或接头。
在另一优选例中,所述抗体-药物偶联物的轻链恒定区偶联有至少1个药物分子(优选为每条轻链恒定区偶联1个药物分子),并且所述药物分子连接于所述轻链恒定区的赖氨酸位点。
在另一优选例中,所述抗体的轻链恒定区包含EKH基序,并且所述所述药物分子连接于所述基序的赖氨酸(K)位点。
在另一优选例中,所述抗体的轻链恒定区包含YEKHK基序,并且所述药物分子连接于所述基序的第一个赖氨酸(K)位点。
在另一优选例中,所述抗体的轻链恒定区包含ADYEKHK基序,并且所述药物分子连接于所述基序的第一个赖氨酸(K)位点。
在另一优选例中,所述药物分子为抑制肿瘤细胞的小分子药物。
在另一优选例中,n为所述抗体-药物偶联物中的药物平均偶联数量,较佳地n为1~4,优选为1.5~3.5,更优选为1.8~2。
在另一优选例中,D选自下组:Duostatin 5、MMAF、Duostatin 14、Duomycin 2、Duomycin 4、Calicheamicin、Amanitine。
在另一优选例中,所述抗体-药物偶联物结构如式III所示:
式III中,所述L1-L2的结构选自下组的L-1、L-2、和L-3:
其中,L21、L22、L23为独立地选自下组的接头-(CH2)n-,-(CH2CH2O)n-,Val-Cit,Ala-Ala-Asn,或其组合;
Ab、D、n如上所述;
波浪线表示与抗体的连接位置。
在另一优选例中,所述抗体-药物偶联物选自下组:
ZV00508、ZV0512、ZV0513、ZV0501、ZV0503、ZV0504、ZV0517、ZV0518、ZV0505、ZV0516、ZV0515、ZV0519
其中,偶联物ZV00508的结构如下:
偶联物ZV0512的结构如下:
偶联物ZV0513的结构如下:
偶联物ZV0501的结构如下:
偶联物ZV0503的结构如下:
偶联物ZV0504的结构如下:
偶联物ZV0517的结构如下:
偶联物ZV0518的结构如下:
偶联物ZV0505的结构如下:
偶联物ZV0516的结构如下:
偶联物ZV0515的结构如下:
偶联物ZV0519的结构如下:
本发明的第二方面,提供了一种药物组合物,所述药物组合物包含本发明第一方面所述的抗体-药物偶联物,以及药学上可接受的载体。
本发明的第三方面,提供了如本发明第一方面所述的抗体-药物偶联物的用途,用于制备抗肿瘤的药物。
在另一优选例中,所述肿瘤为5T4阳性肿瘤,优选地包括乳腺癌、胃癌、卵巢癌、肺癌等。
本发明的第四方面,提供了一种治疗或预防肿瘤的方法,所述方法包括步骤给需要的对象施用本发明第一方面所述的抗体-药物偶联物;
或本发明第二方面所述的药物组合物。
在另一优选例中,所述对象为哺乳动物,包括人。
本发明的第五方面,提供了一种制备本发明第一方面所述的抗体-药物偶联物的方法,所述方法包括步骤:
配置反应体系,所述反应体系中包括抗体和游离的药物分子,然后进行偶联反应,从而制得所述抗体-药物偶联物,
其中,所述药物分子包括接头。
在另一优选例中,所述反应体系的pH为6.5~8.0;优选地pH为6.8~7.8;更优选地pH为7.0~7.5,如7.1、7.2、7.3、7.4。
在另一优选例中,所述药物分子连接于所述抗体的轻链恒定区的赖氨酸位点。
在另一优选例中,反应时间为3h-16h。
在另一优选例中,所述抗体与药物分子的摩尔比为1-2:3-20;优选为1:6-10。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了抗体药物偶联物ZV0508的HIC-HPLC分析结果。
图2显示了抗体药物偶联物ZV0508亲和性未受影响。
图3显示了抗体(ZV05)和ADC(ZV0508)在细胞上具有较强的内吞性。
图4显示了抗体药物偶联物ZV0508使细胞周期停留在G2/M期。
图5显示了ADC治疗小鼠体内MDA-MB-468乳腺癌移植瘤(+++)的疗效。
图6显示了ADC治疗小鼠体内BxPC-3胰腺癌移植瘤(++)的疗效。
图7显示了ADC治疗小鼠体内H1975肺癌移植瘤(+++)的疗效。
图8显示了ADC治疗小鼠体内DU-145***癌移植瘤(+++)的疗效。
图9显示了ADC治疗小鼠体内PA-1卵巢癌移植瘤(+)的疗效。
图10显示了ADC治疗小鼠体内Lovo结肠癌移植瘤(+)的疗效。
具体实施方式
本发明人通过广泛而深入的研究,设计了靶向5T4的抗体药物偶联物,所述抗体-药物偶联物具有显著的抗肿瘤效果。本发明还提供了所述抗5T4抗体-药物偶联物的制药用途,及其在抑制或预防肿瘤中的作用。
在本发明的一个优选的实施方式中,采用的是人源化的抗5T4单克隆抗体(如ZV05抗体),该抗体在5T4抗原以及表达5T4抗原的肿瘤细胞上均表现出较高的亲和力,并且在表达5T4抗原的肿瘤细胞上有较强的内吞性。此外,相较于非人单克隆抗体,免疫原性更低,能够避免HAMA应答,允许实施高剂量和重复剂量达到治疗应答。
可以采用本领域的常规偶联技术对抗体和小分子药物进行偶联,如SeaGen连接方法。优选地采用本发明中的方法对抗体和小分子药物进行偶联,采用本发明的方法通过简单的化学和纯化步骤可实现抗体与药物的定点定量偶联,偶联物的均一性更高。在本发明提供的一系列抗体药物偶联物中,ZV0508表现出更为广谱,更为优越的体内抗肿瘤活性。
本发明采用接头(L)部分,使之能够偶联至抗体恒定区的特定赖氨酸位置,或者偶联至二硫键还原的半胱氨酸上,经过一步疏水纯化(HIC)获得定点定量偶联的抗体偶联药物。
抗体(Ab)通过二硫键还原的半胱氨酸或者恒定区的一个活性赖氨酸经由接头(L,包括L1或者L2)偶联药物模块(D)以形成抗体-药物偶联物:Ab-(L-D)n,其中n为1-4。本发明公开了抗体药物偶联物的偶联方法和治疗用途。
在描述本发明之前,应当理解本发明不限于所述的具体方法和实验条件,因为这类方法和条件可以变动。还应当理解本文所用的术语其目的仅在于描述具体实施方案,并且不意图是限制性的,本发明的范围将仅由所附的权利要求书限制。
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于1%。例如,如本文所用,表述“约100”包括99和101和之间的全部值(例如,99.1、99.2、99.3、99.4等)。
虽然在本发明的实施或测试中可以使用与本发明中所述相似或等价的任何方法和材料,本文在此处例举优选的方法和材料。
本发明提供了两类偶联方法,将毒素小分子通过特定连接物偶联到抗体上,在不改变抗体亲和性的基础上大幅提高抗体对肿瘤细胞的杀伤力。
如本文所用,术语“抗体”或“免疫球蛋白”是有相同结构特征的约150000道尔顿的异四聚糖蛋白,其由两个相同的轻链(L)和两个相同的重链(H)组成。每条轻链通过一个共价二硫键与重链相连,而不同免疫球蛋白同种型的重链间的二硫键数目不同。每条重链和轻链也有规则间隔的链内二硫键。每条重链的一端有可变区(VH),其后是多个恒定区。每条轻链的一端有可变区(VL),另一端有恒定区;轻链的恒定区与重链的第一个恒定区相对,轻链的可变区与重链的可变区相对。特殊的氨基酸残基在轻链和重链的可变区之间形成界面。
如本文所用,术语“可变”表示抗体中可变区的某些部分在序列上有所不同,它形成了各种特定抗体对其特定抗原的结合和特异性。然而,可变性并不均匀地分布在整个抗体可变区中。它集中于轻链和重链可变区中称为互补决定区(CDR)或超变区中的三个片段中。可变区中较保守的部分称为构架区(FR)。天然重链和轻链的可变区中各自包含四个FR区,它们大致上呈β-折叠构型,由形成连接环的三个CDR相连,在某些情况下可形成部分β折叠结构。每条链中的CDR通过FR区紧密地靠在一起并与另一链的CDR一起形成了抗体的抗原结合部位(参见Kabat等,NIH Publ.No.91-3242,卷I,647-669页(1991))。恒定区不直接参与抗体与抗原的结合,但是它们表现出不同的效应功能,例如参与抗体的依赖于抗体的细胞毒性。
脊椎动物抗体(免疫球蛋白)的“轻链”可根据其恒定区的氨基酸序列归为明显不同的两类(称为κ和λ)中的一类。根据其重链恒定区的氨基酸序列,免疫球蛋白可以分为不同的种类。主要有5类免疫球蛋白:IgA,IgD,IgE,IgG和IgM,其中一些还可进一步分成亚类(同种型),如IgG1,IgG2,IgG3,IgG4,IgA和IgA2。对应于不同类免疫球蛋白的重链恒定区分别称为α、δ、ε、γ、和μ。不同类免疫球蛋白的亚单位结构和三维构型是本领域人员所熟知的。
一般,抗体的抗原结合特性可由位于重链和轻链可变区的3个特定的区域来描述,称为可变区域(CDR),将该段间隔成4个框架区域(FR),4个FR的氨基酸序列相对比较保守,不直接参与结合反应。这些CDR形成环状结构,通过其间的FR形成的β折叠在空间结构上相互靠近,重链上的CDR和相应轻链上的CDR构成了抗体的抗原结合位点。可以通过比较同类型的抗体的氨基酸序列来确定是哪些氨基酸构成了FR或CDR区域。
本发明不仅包括完整的抗体,还包括具有免疫活性的抗体的片段或抗体与其他序列形成的融合蛋白。因此,本发明还包括所述抗体的片段、衍生物和类似物。
如本文所用,术语“片段”、“衍生物”和“类似物”是指基本上保持本发明抗体相同的生物学功能或活性的多肽。本发明的多肽片段、衍生物或类似物可以是(i)有一个或多个保守或非保守性氨基酸残基(优选保守性氨基酸残基)被取代的多肽,而这样的取代的氨基酸残基可以是也可以不是由遗传密码编码的,或(ii)在一个或多个氨基酸残基中具有取代基团的多肽,或(iii)成熟多肽与另一个化合物(比如延长多肽半衰期的化合物,例如聚乙二醇)融合所形成的多肽,或(iv)附加的氨基酸序列融合到此多肽序列而形成的多肽(如前导序列或分泌序列或用来纯化此多肽的序列或蛋白原序列,或与6His标签形成的融合蛋白)。根据本文的教导,这些片段、衍生物和类似物属于本领域熟练技术人员公知的范围。
在本发明中,本发明的抗体还包括其保守性变异体,指与本发明抗体的氨基酸序列相比,有至多10个,较佳地至多8个,更佳地至多5个,最佳地至多3个氨基酸被性质相似或相近的氨基酸所替换而形成多肽。这些保守性变异多肽最好根据表A进行氨基酸替换而产生。
表A
本发明抗体或其片段的DNA分子的序列可以用常规技术,比如利用PCR扩增或基因组文库筛选等方法获得。此外,还可将轻链和重链的编码序列融合在一起,形成单链抗体。
一旦获得了有关的序列,就可以用重组法来大批量地获得有关序列。这通常是将其克隆入载体,再转入细胞,然后通过常规方法从增殖后的宿主细胞中分离得到有关序列。
此外,还可用人工合成的方法来合成有关序列,尤其是片段长度较短时。通常,通过先合成多个小片段,然后再进行连接可获得序列很长的片段。
目前,已经可以完全通过化学合成来得到编码所述的本发明的抗体(或其片段,或其衍生物)的DNA序列。然后可将该DNA序列引入本领域中已知的各种现有的DNA分子(或如载体)和细胞中。此外,还可通过化学合成将突变引入本发明蛋白序列中。
本发明还涉及包含上述的适当DNA序列以及适当启动子或者控制序列的载体。这些载体可以用于转化适当的宿主细胞,以使其能够表达蛋白质。
宿主细胞可以是原核细胞,如细菌细胞;或是低等真核细胞,如酵母细胞;或是高等真核细胞,如哺乳动物细胞。
例如,可通过以下方法来制备本发明的抗体。
首先,提供含有编码本发明抗体的核苷酸序列以及与该序列操作性相连的表达调控序列的表达载体。
本文所用的术语“表达调控序列”通常指参与控制核苷酸序列表达的序列。表达调控序列包括与目标核苷酸序列操作性相连的启动子和终止信号。它们通常还包括核苷酸序列适当翻译所需的序列。“操作性相连”是指线性DNA序列的某些部分能够影响同一线性DNA序列其他部分的活性。例如,如果启动子或增强子增加了编码序列的转录,则它与编码序列是操作性相连的。
编码本发明单克隆抗体的DNA序列可用本领域技术人员熟知的常规手段来制得。例如,可根据本发明公开的序列人工合成或用PCR法扩增得到编码该单克隆抗体重链可变区和轻链可变区的核苷酸序列。然后,用本领域熟知的各种方法通过选择合适的酶切位点将这些核苷酸序列***合适的表达载体中,使它们分别在表达载体所携带的重链恒定区编码序列和轻链恒定区编码序列之前,并使它们在同一阅读框内。本发明中所用的表达载体是本领域技术人员已知的各种市售的表达载体,例如pPIC9K。
随后,用上述获得的表达载体转化合适的宿主细胞。“宿主细胞”一般包括原核细胞和真核细胞。常用的原核宿主细胞的例子包括大肠杆菌、枯草杆菌等。常用的真核宿主细胞包括酵母细胞,昆虫细胞、和哺乳动物细胞。在本发明中,优选哺乳动物细胞。通常用哺乳动物细胞系来作为表达真核细胞衍生多肽的宿主细胞。哺乳动物细胞在培养物中的繁殖是本领域熟知的。见《组织培养》,Academic Press,Kruse and Patterson编辑(1973),该文纳入本文作为参考。较佳的哺乳动物细胞是许多可购得的无限增殖细胞系。这些无限增殖细胞系包括但不局限于,中国仓鼠卵巢(CHO)细胞、Vero细胞、海拉细胞、幼仓鼠肾(BHK)细胞、猴肾细胞(COS)、人肝细胞癌细胞(如Hep G2)和其它许多细胞系。它们为蛋白质分子提供了翻译后修饰,包括正确的折叠、正确的二硫键形成以及正确位点的糖基化。尽管在下文实施例中,本发明仅列举了以CHO细胞作为宿主细胞的例子,但是本领域技术人员在阅读了本发明的详细描述和具体实施例可以知道,本发明也能采用上述这些细胞系。
用表达载体转化宿主细胞的方法有很多种,所用的转化程序取决于待转化的宿主。将异源多核苷酸导入哺乳动物细胞中的方法是本领域所知的,其包括葡聚糖介导的转染、磷酸钙沉淀、Polybrene(1,5-二甲基-1,5-二氮十一亚甲基聚甲溴化物)介导转染、原生质体融合、电穿孔、脂质体介导转染以及将DNA直接显微注射到胞核中。在本发明中,较佳的方法是电穿孔法或脂质体介导法等。例如可采用Invitrogen公司的脂质体法试剂盒来转染诸如CHO细胞等宿主细胞。
然后,在适合本发明抗体表达的条件下,培养转化所得的宿主细胞。然后用常规的免疫球蛋白纯化步骤,如蛋白A-Sepharose、羟基磷灰石层析、凝胶电泳、透析、离子交换层析、疏水层析、分子筛层析或亲和层析等本领域技术人员熟知的常规分离纯化手段纯化得到本发明的抗体。
所得单克隆抗体可用常规手段来鉴定。比如,单克隆抗体的结合特异性可用免疫沉淀或体外结合试验(如放射性免疫测定(RIA)或酶联免疫吸附测定(ELISA))来测定。单克隆抗体的结合亲和力例如可用Munson等,Anal.Biochem.,107:220(1980)的Scatchard分析来测定。
本发明的抗体可在细胞内、或在细胞膜上表达、或分泌到细胞外。如果需要,可利用其物理的、化学的和其它特性通过各种分离方法分离和纯化重组的蛋白。这些方法是本领域技术人员所熟知的。这些方法的例子包括但并不限于:常规的复性处理、用蛋白沉淀剂处理(盐析方法)、离心、渗透破菌、超声处理、超离心、分子筛层析(凝胶过滤)、吸附层析、离子交换层析、高效液相层析(HPLC)和其它各种液相层析技术及这些方法的结合。
在本发明的一个优选地实施方式中,所述抗5T4抗体的重链可变区包括三个互补决定区:
CDR1:GFTFSSYE(SEQ ID NO.1)
CDR2:ISSSGSTI(SEQ ID NO.2)和
CDR3:AREMQFGWELLGAFDI(SEQ ID NO.3)。
在本发明的另一个优选地实施方式中,所述抗5T4抗体的所述轻链可变区包括三个互补决定区:
CDR1’:QSVSSSY(SEQ ID NO.4)
CDR2’:GAS(SEQ ID NO.5)和
CDR3’:QQYGSS(SEQ ID NO.6)。
在另一优选例中,所述重链可变区的氨基酸序列如下:
MDWTWRFLFVVAAATGVQSQVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYEMNWVRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREMQFGWELLGAFDIWGQGTMVTVSS(SEQ IDNO.7)。
在另一优选例中,所述轻链可变区的氨基酸序列如下:
MDMRVPAQLLGLLLLWLSGARCEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSFGQGTKLEIK(SEQ ID NO.8)。
在另一优选例中,所述抗体的重链如下:
MDWTWRFLFVVAAATGVQSQVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYEMNWVRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREMQFGWELLGAFDIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO.9)。
在另一优选例中,所述抗体的轻链如下:
MDMRVPAQLLGLLLLWLSGARCEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO.10)。
在本发明的一个优选地实施方式中,所述抗体-药物偶联物结构如式II所示:
Ab-(L-D)n,II
其中,Ab为抗体;
D为抑制肿瘤细胞的小分子药物;
L为连接所述抗体和所述药物的接头。
在另一优选例中,n为1~8,优选为整数。
在另一优选例中,D选自下组:
Duostatin 5:
MMAF:
Duostatin 14:
Duomycin 2:
Duomycin 4:
Calicheamicinγ1:
α-Amanitine:
在本发明的一个优选地实施方式中,所述抗体-药物偶联物结构如式IV所示(即,L包括L1-L2):
式IV中,所述L1-L2的结构选自下组:
其中,L2为选自下组的接头-(CH2)n-,-(CH2CH2O)n-,Val-Cit,Ala-Ala-Asn,或其组合;
Ab、D、n如上所述;
波浪线表示与抗体的连接位置。
在另一优选例中,所述抗体-药物偶联物选自下组:
ZV00508、ZV0512、ZV0513、ZV0501、ZV0503、ZV0504、ZV0517、ZV0518、ZV0505、ZV0516、ZV0515、ZV0519
其中,偶联物ZV0508的结构如下:
偶联物ZV0512的结构如下:
偶联物ZV0513的结构如下:
偶联物ZV0501的结构如下:
偶联物ZV0503的结构如下:
偶联物ZV0504的结构如下:
偶联物ZV0517的结构如下:
偶联物ZV0518的结构如下:
偶联物ZV0505的结构如下:
偶联物ZV0516的结构如下:
偶联物ZV0515的结构如下:
偶联物ZV0519的结构如下:
在本发明的一个优选的实施方式中,制备所述抗体-药物偶联物的偶联方式,有K-Lock和C-Lock两种偶联方式。在K-Lock偶联方式中,药物分子偶联于抗体序列中赖氨酸(K)残基,在C-Lock偶联方式中,药物分子偶联于抗体序列中的半胱氨酸残基(C)以下概述本发明的抗体-药物偶联物的偶联方法。
K-Lock方法:抗体可以在温和的溶液体系中直接和L1-D连接。例如,在室温用6-10倍过量的L1-D和抗体反应3-16h,超滤去掉过量的小分子L1-D。将抗体-药物偶联物加载至疏水层析柱(HIC),纯化获得偶联数量为2的抗5T4抗体-药物偶联物。
C-Lock方法:抗体经过TCEP还原后在温和的溶液体系中直接和L2-D连接。例如,抗体在室温用5-10倍过量的TCEP还原,超滤去掉过量的TCEP。将5-10倍的L2-D加入到还原后的抗体溶液中反应,超滤去掉过量的小分子L2-D。将抗体-药物偶联物加载至疏水层析柱(HIC),纯化获得偶联数量为4的抗5T4抗体-药物偶联物。
本发明还提供了所述抗体-药物偶联物在制备抗肿瘤药物中的应用。
所述抗肿瘤药物包括有效量的根据本发明的抗体-药物偶联物,以及至少一种药学上可接受的载体、稀释剂或赋形剂。制备时,通常将活性成分与赋形剂混合,或用赋形剂稀释,或包在可以胶囊或药囊形式存在的载体中。当赋形剂起稀释剂作用时,它可采用固体、半固体或液体材料作为赋形剂、载体或活性成分的介质。因此,组合物可以是片剂、丸剂、粉剂、溶液剂、糖浆剂、灭菌注射溶液等。
合适的赋形剂包括:乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水等;制剂还可包括:湿润剂、乳化剂、防腐剂(如羟基苯甲酸甲酯和丙酯)、甜味剂等。所述抗肿瘤药物可制成单元或多元剂型,各剂型包含为了产生所期望的疗效而计算出预定量的所述抗5T4抗体-海兔毒素偶联物,以及合适的药剂学赋形剂。
所述的抗肿瘤药物可以通过常规途径进行给药,包括(但并不限于):肌内、腹膜内、静脉内、皮下、皮内、局部给药等。
使用该药物时,是将安全有效量的所述抗体-药物偶联物施用于人,其中该安全有效量的范围优选为0.5~50毫克/千克体重,更优选为1~10毫克/千克体重。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是在熟练医师技能范围之内的。
此外,本发明的偶联物还可与其他治疗药物联用,其中包括(但并不限于):各种细胞因子,如TNF、IFN、IL-2等;各种肿瘤化疗药物,如5-FU、氨甲喋呤等影响核酸生物合成的药物;氮芥、环磷酰胺等烷化剂类药物;阿霉素、放线菌素D等干扰转录过程阻止RNA合成的药物;长春新碱、喜树碱类等影响蛋白质合成的药物及某些激素类药物,等等。
与现有技术相比,本发明的有益效果为:
(1)本发明的靶向5T4的抗体药物偶联物,具有显著的抗肿瘤效果;
(2)根据本发明的抗体-药物偶联物,在5T4抗原以及表达5T4抗原的肿瘤细胞上均表现出较高的亲和力,并且在表达5T4抗原的肿瘤细胞上有较强的内吞性。
下面结合具体实施例,进一步详陈本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明详细条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
通用合成步骤 从一种带羧基的化合物合成其活性酯的方法(比如NHS)
将羧基化合物溶解于二氯甲烷或N,N-二甲基甲酰胺中,加入1.5当量的N-羟基琥珀酰亚胺,1.5当量的EDCI。反应液在室温搅拌1个小时,直到羧基化合物消耗完毕。反应过程由RP-HPLC监控。用二氯甲烷稀释反应液,并用柠檬酸(aq.10%)和饱和食盐水洗有机相。分离并干燥有机相,用HPLC或者中压正相硅胶色谱纯化,得到相应的活性酯。
实施例中所用的对照抗体(人源化的A1抗体)重链氨基酸序列如下:
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNFGMNWVRQAPGKGLEWVAWINTNTGEPRYAEEFKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDWDGAYFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ IDNO.11);
轻链氨基酸序列如下:
DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYFATNRYTGVPSRFSGSGYGTDFTLTISSLQPEDFATYYCQQDYSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO.12)
实施例1小分子药物的合成
Calicheamicin小分子的合成线路:
(9H-fluoren-9-yl)methyl(2-chloro-2-oxoethyl)carbamate(256mg,0.81mmol)和二异丙基乙基胺(DIEA,173μL,1mmol)加到卡其美素γ1(1,880mg,0.54mmol,溶在25mLDMF中)。该混合物在搅拌2小时,然后移去溶液,经HPLC纯化得到化合物2(300mg).MS m/z1647.3(M+H).
制备化合物8:
化合物2(100mg,0.06mmol)溶于4mL乙腈和0.3mL二甲基甲酰胺(DMF)然后向其中加入化合物3(75mg,0.24mmol)。反应在搅拌下持续16小时,然后加入120μL哌啶。30分钟后,经HPLC纯化得到化合物4(60mg).MS m/z 1654.4(M+H)。
向化合物4(20mg,12μmol,溶于2mL二甲基甲酰胺DMF中)加入化合物5(11mg,14μmol)、N-Hydroxybenzotriazole(HOBt,2mg)和5μL二异丙基乙基胺(DIEA)。将反应混合物搅拌一小时,然后加入40μL哌啶。10分钟后,该混合物经HPLC纯化得到化合物6(21mg).MS m/z2059.6(M+H).
向化合物6(21mg,10μmol,溶于2mL二氯甲烷DCM中)加入化合物7(13mg,13μmol)及3μL二异丙基乙基胺(DIEA)。该反应混合液在搅拌20后,移除溶剂并在HPLC上纯化得到化合物8(11mg).MS m/z 2558.6(M+H).
Duostatin5小分子的合成线路:
制备化合物25:
化合物19的TFA盐(1mmol)、化合物24(1eq.)、HOAt(3eq.)、二氯甲烷DCM(20mL)、二异丙基乙基胺(DIEA6eq.)及DIC(2eq.)置于圆底瓶中。经16小时搅拌后,将反应液用20mL二氯甲烷稀释,并用20mL水洗。有机相在用硫酸钠干燥后,减压移去溶剂,所得玻璃状固体直接用于下一步反应。将所得固体溶于10mL二氯甲烷(DCM)、10mL三氟乙酸(TFA)和1mL三异丙基硅烷并搅拌一小时。经真空移除溶剂后,用HPLC纯化获得化合物6.MS m/z 1351.5(M+H).
制备化合物26:
化合物25(0.5mmol)、乙腈20mL、水5mL和饱和碳酸氢钠10mL水溶液置于圆底瓶中,然后加入硫代硫酸钠Na2S2O4(4eq.)并继续搅拌20分钟。经HPLC纯化得到化合物7.MS m/z1321.7(M+H).
制备化合物27:
化合物26(0.4mmol)溶于10mL乙腈,然后加入1,4-dibromo-2,3-butanedione(3eq.)。20搅拌后,经HPLC纯化得到化合物27.MS m/z 1527.6(M+H).
实施例2抗体的制备
通过化学合成获得抗体(抗5T4抗体和对照抗体A1)重链和轻链的可变区基因序列,对获得抗体(抗5T4抗体和对照抗体A1)重链和轻链的恒定区基因序列进行PCR扩增。通过酶切连接,将重链的可变区和恒定区组装至表达载体;通过类似的方法将轻链的可变区和恒定区组装至另一个表达载体;再通过酶切连接,将重链可变区和恒定区表达载体和轻链可变区和恒定区表达载体组装在一起,即得到抗体的重组表达载体。将抗体的表达载体转化CHO细胞进行表达。收集表达上清,通过protein A纯化获得高纯度的抗体,利用超滤或者脱盐柱将抗体置换至适合偶联的缓冲液体系。
5T4-抗体在37℃下用15x摩尔当量的TCEP(在水中制备)在C-Lock缓冲液(50mM磷酸钠,4mM EDTA,pH7.0)中还原3小时或在室温下过夜。
通过PD-10凝胶过滤柱或通过Amicon旋转浓缩器进行缓冲液调换纯化完全还原的抗体以除去TCEP。
使用分光光度计对412nm吸光度和280nm吸光度进行测量,以便对抗体的游离硫醇进行定量。应该从3个二硫键产生大约6个游离硫醇。在TCEP去除后,使用分光光度计在280nm吸光度对抗体浓度进行定量。
实施例3抗体-药物偶联物制备
K-Lock方法以ZV0512为例:抗体(如具有SEQ ID NO.10所示的轻链和SEQ ID NO.9所示的的重链)可以在温和的溶液体系中直接和药物分子连接。
在室温25℃(范围可以是4-37℃),10mg/ml抗体(溶于磷酸盐缓冲液PBS,浓度范围5-30mg/ml)中加入6-10倍摩尔量于抗体的药物分子(溶于DMA,体积不超过PBS的10%)反应3-16h,超滤去掉过量的药物分子。将抗体-药物偶联物加载至疏水层析柱(HIC),用0.75-1M的硫酸铵溶液平衡后再用25mM的硫酸铵溶液洗脱,合并偶联数量为2的洗脱液并用PBS置换,获得偶联数量为2的抗5T4抗体-药物偶联物。
本发明人发现,在偶联抗体和药物的过程中,pH对偶联反应具有显著影响,较佳的偶联pH为6.5~8.0;优选地偶联pH为6.8~7.8;更优选地偶联pH为7.0~7.5,如7.1、7.2、7.3、7.4。
实验结果表明,在pH6以下抗体几乎不和药物分子发生偶联反应,在PH7.8时原抗体还有部分剩余,DAR数量为1的占很大比例,而pH在约7.0的时候DAR2的占主要部分,因此pH为约7.0时反应效率更好。
C-Lock方法以ZV0508为例:
A.偶联
将待偶联药物(Duostatin 5)溶解在60%乙腈/水中以制备10mM储备溶液。
每5分钟加入0.5x摩尔当量的药物到还原的5T4抗体中,直到4.5x最终药物当量。将反应在室温下在旋转器上混合。
在HIC-HPLC上进行反应以分析缀合曲线。未结合的抗体应为0%,DAR 4峰≥70%
B.纯化
如果ADC产物留作含有DAR 2-4的异质混合物,则通过使用Amicon旋转浓缩器的缓冲液交换来除去游离药物。缓冲液是50mM磷酸钠+30%丙二醇。
如果需要均相的DAR 3峰,则产物将在疏水作用柱上纯化以除去不需要的DAR。
将抗体-药物偶联物加载至疏水层析柱(HIC),纯化获得偶联数量为4的抗5T4抗体-药物偶联物。
本实施中制备的抗体-药物偶联物的结构如下表所示。
表1抗体-药物偶联物结构
取代表性的1个抗体偶联药物进行HIC-HPLC分析,操作步骤如下:
使用TSKgel Butyl-NPR柱(4.6mmIDx3.5cm,2.5mm,Tosoh Bioscience,Montgomeryville,PA),流动相分别为1.5M硫酸铵加0.025M磷酸钠缓冲液(pH7)和75%0.025M磷酸钠缓冲加25%异丙醇(PH7.0),梯度洗脱:10%B-70%B,10min;70%B-100%B,5min;100%B-10%B,2min。
图1显示了根据本发明的抗体药物偶联物ZV0508的HIC分析结果,结果表明。
实施例4亲和性检测
亲和性检测的实验步骤如下:
将ZV05和ZV0508稀释至10μg/ml,然后按3倍的梯度稀释,浓度分别为10、3.3、1.1、0.33μg/ml,分别加入至含有3.0×105个MDA-MB-468细胞的EP管中,4℃条件下孵育30min。离心沉淀细胞,加PBS洗一次。然后加入600μl FITC标记的二抗稀释液,4℃条件下避光孵育30min。离心沉淀细胞,PBS洗两次,最后加入500μl PBS悬匀细胞,用流式细胞仪检测平均荧光强度值。
检测结果如下:
对本发明制备的抗5T4抗体偶联物偶联前后的亲和性比较,代表性的抗体药物偶联物ZV0508亲和性检测结果如图2所示,从图中可以看出偶联前后抗体亲和性基本未改变。
实施例5细胞内吞性检测
细胞内吞性的实验步骤如下:
将ZV05和ZV0508稀释至10μg/ml,分别加入至含有3.0×105个MDA-MB-468细胞的EP管中,4℃条件下孵育30min。离心沉淀细胞,加PBS洗一次。每个EP管中细胞分成等量的两份,一份置于4℃孵育2h,一份置于37℃孵育2h。离心沉淀细胞,加PBS洗1次。然后每个EP管中加入600μl FITC标记的二抗稀释液,4℃条件下避光孵育30min。离心沉淀细胞,PBS洗两次,最后加入500μlPBS悬匀细胞,用流式细胞仪检测平均荧光强度值。内吞率计算公式:内吞率(%)=(MFI4℃-MFI37℃)/MFI4℃。检测结果如下:
代表性的抗体药物偶联物ZV0508内吞性检测结果如图3所示,从图中可以看出抗体(ZV05)和ADC(ZV0508)在细胞上具有较强的内吞性。
实施例6肿瘤细胞的细胞周期抑制实验
本实施例检测了本发明的抗体-药物偶联物对5T4阳性细胞的细胞周期抑制效果。本实施例中的肿瘤细胞株均购自美国ATCC。
实验步骤如下:
MDA-MB-468细胞以5.0×104个/孔接种至6孔板中,37℃细胞培养箱中培养,待细胞贴壁后,将ZV05和ZV0508稀释至5μg/ml,分别加入6孔板中,继续培养48h~72h后,采用碧云天的细胞周期检测试剂盒,根据说明书操作步骤,用流式细胞仪测定DNA含量,分析细胞周期。
实验结果表明,在药物作用下抗体药物偶联物ZV0508使细胞周期停留在G2/M期,结果如图4所示,图4中ZV05为没有偶联药物的抗体对照。
实施例7体内抗肿瘤活性
抗5T4抗体-药物偶联物的体内抗肿瘤活性检测步骤如下:
肿瘤细胞接种于裸鼠或Scid鼠腋下,等肿瘤体积长到100-300mm3时开始尾静脉给药,OE19分三次给药,三天一次,其余模型都为单次给药,给药后定时测量肿瘤大小,测量瘤块的长径(a)、短径(b),肿瘤体积(tumor volume,TV)计算公式为:TV=1/2×a×b2。
实验结果表明,本发明的抗5T4抗体(ZV05)-药物偶联物,对体内肿瘤具有显著的抑制作用,体内肿瘤抑制活性显著优于对照抗体(人源化的A1抗体)以上。
图5显示了ADC治疗小鼠体内MDA-MB-468乳腺癌移植瘤(+++)的疗效。
图6显示了ADC治疗小鼠体内BxPC-3胰腺癌移植瘤(++)的疗效。
图7显示了ADC治疗小鼠体内H1975肺癌移植瘤(+++)的疗效。
图8显示了ADC治疗小鼠体内DU-145***癌移植瘤(+++)的疗效。
图9显示了ADC治疗小鼠体内PA-1卵巢癌移植瘤(+)的疗效。
图10显示了ADC治疗小鼠体内Lovo结肠癌移植瘤(+)的疗效。其中,作为对照的抗体药物偶联物(A1-MMAF)的肿瘤抑制效果显著低于本发明的抗体药物偶联物。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 浙江昭华生物医药有限公司
<120> 抗5T4抗体-药物偶联物及其应用
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Claims (10)
1.一种抗体-药物偶联物或其药学上可接受的盐,其特征在于,所述抗体-药物偶联物包括抗体和偶联于所述抗体的药物,所述抗体包括一重链可变区和一轻链可变区,
其中,所述重链可变区包括三个互补决定区:
CDR1:GFTFSSYE
CDR2:ISSSGSTI和
CDR3:AREMQFGWELLGAFDI;
所述轻链可变区包括三个互补决定区:
CDR1’:QSVSSSY
CDR2’:GAS和
CDR3’:QQYGSS。
2.如权利要求1所述的抗体-药物偶联物或其药学上可接受的盐,其特征在于,所述重链可变区的氨基酸序列如SEQ ID NO.7所示。
3.如权利要求1所述的抗体-药物偶联物或其药学上可接受的盐,其特征在于,所述轻链可变区的氨基酸序列如SEQ ID NO.8所示。
4.如权利要求1所述的抗体-药物偶联物或其药学上可接受的盐,其特征在于,所述抗体包括SEQ ID NO.9所示的重链。
5.如权利要求1所述的抗体-药物偶联物或其药学上可接受的盐,其特征在于,所述抗体包括SEQ ID NO.10所示的轻链。
6.如权利要求1所述的抗体-药物偶联物或其药学上可接受的盐,其特征在于,所述药物包括选自下组的小分子药物:Duostatin 5、MMAF、Duostatin 14、Duomycin 2、Duomycin4、Calicheamicin、Amanitine。
7.一种药物组合物,其特征在于,所述药物组合物包含权利要求1所述的抗体-药物偶联物,以及药学上可接受的载体。
8.如权利要求1所述的抗体-药物偶联物的用途,用于制备抗肿瘤的药物。
9.一种治疗或预防肿瘤的方法,其特征在于,所述方法包括步骤给需要的对象施用权利要求1所述的抗体-药物偶联物;
10.一种制备权利要求1所述的抗体-药物偶联物的方法,所述方法包括步骤:
配置反应体系,所述反应体系中包括所述抗体和游离的药物分子,然后进行偶联反应,从而制得所述抗体-药物偶联物,
其中,所述药物分子包括接头。
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710011890.XA CN108285487B (zh) | 2017-01-08 | 2017-01-08 | 抗5t4抗体-药物偶联物及其应用 |
EP18736750.3A EP3599249A4 (en) | 2017-01-08 | 2018-01-08 | ANTI-5T4-DRUG ANTIBODY CONJUGATE AND ITS USE |
JP2019537114A JP6944526B2 (ja) | 2017-01-08 | 2018-01-08 | 抗5t4抗体−薬物複合体およびその使用 |
US16/476,487 US11679162B2 (en) | 2017-01-08 | 2018-01-08 | Anti-5T4 antibody-drug conjugate and use thereof |
PCT/CN2018/071774 WO2018127175A1 (zh) | 2017-01-08 | 2018-01-08 | 抗5t4抗体-药物偶联物及其应用 |
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Cited By (8)
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WO2022233262A1 (zh) * | 2021-05-07 | 2022-11-10 | 四川科伦博泰生物医药股份有限公司 | 抗体药物偶联物治疗癌症的方法及用途 |
CN116715773A (zh) * | 2023-02-28 | 2023-09-08 | 星奕昂(上海)生物科技有限公司 | 一种靶向5t4的抗体及其应用 |
CN117903034A (zh) * | 2024-01-15 | 2024-04-19 | 南京联宁生物制药有限公司 | DUO-5重要构成片段Boc-Dap-Tra单晶及其制备方法和应用 |
WO2024140904A1 (zh) * | 2022-12-30 | 2024-07-04 | 英百瑞(杭州)生物医药有限公司 | 抗5t4抗体-自然杀伤细胞偶联物及其用途 |
WO2024140450A1 (zh) * | 2022-12-29 | 2024-07-04 | 杭州爱科瑞思生物医药有限公司 | N-烷氧烷基取代的喜树碱衍生物的抗体偶联药物 |
WO2024140447A1 (zh) * | 2022-12-29 | 2024-07-04 | 杭州爱科瑞思生物医药有限公司 | N-卤代烷基取代的喜树碱衍生物的抗体偶联药物 |
WO2024140443A1 (zh) * | 2022-12-29 | 2024-07-04 | 杭州爱科瑞思生物医药有限公司 | N-叠氮烷基取代的喜树碱衍生物的抗体偶联药物 |
WO2024140449A1 (zh) * | 2022-12-29 | 2024-07-04 | 杭州爱科瑞思生物医药有限公司 | N-氧杂环烷基取代的喜树碱衍生物的抗体偶联药物 |
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MA52152A (fr) | 2018-03-12 | 2021-01-20 | Genmab As | Anticorps |
WO2023155925A1 (en) * | 2022-02-21 | 2023-08-24 | Concept To Medicine Biotech Co., Ltd. | Anti-5t4 antibodies and uses thereof |
TW202400247A (zh) * | 2022-05-10 | 2024-01-01 | 美商索倫多醫療公司 | 包含抗folr1抗體之抗體藥物結合物 |
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Cited By (9)
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WO2022233262A1 (zh) * | 2021-05-07 | 2022-11-10 | 四川科伦博泰生物医药股份有限公司 | 抗体药物偶联物治疗癌症的方法及用途 |
WO2024140450A1 (zh) * | 2022-12-29 | 2024-07-04 | 杭州爱科瑞思生物医药有限公司 | N-烷氧烷基取代的喜树碱衍生物的抗体偶联药物 |
WO2024140447A1 (zh) * | 2022-12-29 | 2024-07-04 | 杭州爱科瑞思生物医药有限公司 | N-卤代烷基取代的喜树碱衍生物的抗体偶联药物 |
WO2024140443A1 (zh) * | 2022-12-29 | 2024-07-04 | 杭州爱科瑞思生物医药有限公司 | N-叠氮烷基取代的喜树碱衍生物的抗体偶联药物 |
WO2024140449A1 (zh) * | 2022-12-29 | 2024-07-04 | 杭州爱科瑞思生物医药有限公司 | N-氧杂环烷基取代的喜树碱衍生物的抗体偶联药物 |
WO2024140904A1 (zh) * | 2022-12-30 | 2024-07-04 | 英百瑞(杭州)生物医药有限公司 | 抗5t4抗体-自然杀伤细胞偶联物及其用途 |
CN116715773A (zh) * | 2023-02-28 | 2023-09-08 | 星奕昂(上海)生物科技有限公司 | 一种靶向5t4的抗体及其应用 |
CN116715773B (zh) * | 2023-02-28 | 2024-03-01 | 星奕昂(上海)生物科技有限公司 | 一种靶向5t4的抗体及其应用 |
CN117903034A (zh) * | 2024-01-15 | 2024-04-19 | 南京联宁生物制药有限公司 | DUO-5重要构成片段Boc-Dap-Tra单晶及其制备方法和应用 |
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CN108285487B (zh) | 2021-02-19 |
US11679162B2 (en) | 2023-06-20 |
JP6944526B2 (ja) | 2021-10-06 |
EP3599249A4 (en) | 2021-04-21 |
US20190374651A1 (en) | 2019-12-12 |
JP2020514302A (ja) | 2020-05-21 |
WO2018127175A1 (zh) | 2018-07-12 |
EP3599249A1 (en) | 2020-01-29 |
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