CN116761824A - 工程化抗-trop2抗体及其抗体-药物偶联物 - Google Patents
工程化抗-trop2抗体及其抗体-药物偶联物 Download PDFInfo
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Abstract
在此提供了一种工程化二聚体抗体,其中各单体包含特异性结合Trop2抗原的Fab结构域和与之操作性相连的工程化铰链区,所述工程化铰链区由截短IgGl铰链区部分和截短IgG4铰链区部分构成,所述工程化二聚体抗体的铰链结构域由此包含至少两个链间二硫键。还提供了一种抗体‑药物偶联物及其制备方法,包含所述抗体‑药物偶联物的组合物及其在治疗癌症中的用途,所述抗体‑药物偶联物包含通过连接子偶联一个或多个药物分子的所述工程化抗体。
Description
技术领域
本发明主要涉及生物制药领域,尤其涉及工程化抗体和抗体-药物偶联物。
背景技术
抗体药物偶联物(ADC)是一种新型靶向药物,由用于靶向的抗体、用于连接药物的连接子和接头以及作为效应物的强效药物载荷构成。抗体或其相关形式在ADC药物中发挥多种作用。抗体通过抗体-抗原相互作用将细胞毒性药物带到表达抗原的细胞。同时,药物与抗体偶联后毒性显著下降。因此,ADC通过降低最小有效剂量(MED)和提高最大耐受剂量(MTD)扩大了治疗窗口。
抗体中的半胱氨酸硫醇(巯基)作为强亲核试剂是理想的偶联反应基团。由于抗体的天然形式中,半胱氨酸残基以二硫键形式存在,因此,抗体轻链与重链之间的二硫键还原为偶联提供了理想的游离半胱氨酸巯基。此处优选部分还原而不是完全还原,因为药物的疏水性和所有半胱氨酸残基连接时的位阻导致ADC药物在血浆中的不稳定性。据报道,因为ADC的药物-抗体比率(DAR)为4时在体内具有最佳的治疗指数,而优选IgG1型抗体部分还原后平均会有四个游离巯基。由于不能很好地区分IgG1抗体中四个二硫键的还原反应性,部分还原后所得ADC的均质性很差。载药量低的ADC物质显示不足的治疗效果,而载药量过高的ADC产物则显示如上所述的不稳定性和毒性。提高ADC的均质性可以解决这个问题。已知的方法是连接子-药物载荷设计、点突变诱导、参与偶联的酶、偶联过程控制。
人源Trop2,也称为肿瘤相关钙信号转导器2(TACSTD2),是一种单程跨膜糖蛋白,具有胞内钙单转导器的功能。Trop2在许多癌症中过度表达,例如乳腺癌、肺癌和胰腺癌。尽管Trop2在许多正常组织中表达,但Trop2在癌症中的过表达水平具有预后意义,从而使Trop2成为癌症治疗的可能靶点之一。在PCT申请号PCT/GB03/00885(公布为WO03/074566)中,靶向Trop2的人RS7抗体被描述为用于疾病治疗的潜在治疗抗体。
抗体-药物偶联物是使用Trop2作为治疗靶点的药物形式之一。Trodevy(戈沙妥组单抗(sacituzumab govitecan-hziy))于2020年获得FDA批准,是市场上第一个抗-Trop2ADC。该ADC使用hRS7作为抗体,并使用CL2A-SN38(参见例如US 9,102,735 B2;以及Oncotarget,6(26):22496-22512,2015年9月01日)作为连接子-药物载荷,用于治疗三阴性乳腺癌(TNBC),DAR接近8.0。其他抗-Trop2抗体-药物偶联物正在开发中。由于Trop2在许多正常组织中表达,因此抗体上连接子-药物载荷的稳定性是抗-Trop2ADC设计的主要因素。
尽管如此,仍有不同ADC产品的需求,例如在DAR值、均质性,稳定性和治疗功效需求方面提升的抗Trop 2ADC。
发明内容
本公开提供了具有工程化铰链结构域的工程化抗-Trop2抗体。令人惊讶地发现,用本发明的工程化抗-Trop2抗体制得的ADC所包含的药物分子大多数在Fab结构域处连接,平均DAR接近或等于4。这些ADC的优势特征在于高稳定性和极佳的治疗功效。
在第一方面,本文提供了一种工程化二聚体抗体,其中各单体包含特异性结合Trop2抗原的Fab结构域和与之操作性相连的工程化铰链区,其中所述工程化铰链区由截短IgGl铰链区部分和截短IgG4铰链区部分构成,所述工程化二聚体抗体的铰链结构域由此包含至少两个链间二硫键。
另一方面,本文提供一种核酸分子或核酸分子组合,所述核酸分子或核酸分子组合编码本发明的工程化抗体。
在另一方面,本文提供了一种抗体-药物偶联物,所述抗体-药物偶联物包含通过连接子偶联一个或多个药物分子的本发明的工程化抗体。
另一方面,本文还提供了一种包含本发明抗体-药物偶联物的混合物或由本发明抗体-药物偶联物的混合物组成的组合物,其中,至少约80%的抗体-药物偶联物的药物/抗体比为4。
另一方面,本文提供了一种药物组合物,包含本发明的抗体-药物偶联物和药学上可接受的载体。
另一方面,本文提供了一种制备本发明的抗体-药物偶联物的方法,其包括通过迈克尔加成反应将部分还原的本发明的抗体与带有马来酰亚胺或卤代乙酰基部分的连接子-药物载荷化合物偶联的步骤。
另一方面,本文提供了一种通过本发明的方法获得的抗体-药物偶联物产品,其包含本发明抗体-药物偶联物的混合物或由本发明抗体-药物偶联物的混合物组成,其中至少约80%的抗体-药物偶联物的药物/抗体比为4。
另一方面,本文提供了一种为有需要的对象治疗癌症的方法,包括给予所述对象治疗有效量的本发明的所述抗体-药物偶联物,其中所述癌症特征为Trop2过表达。
另一方面,本文提供了用于治疗有需要的对象的癌症的本发明的抗体-药物偶联物,其中所述癌症特征为Trop2过表达。
本发明具有多项优势。具体地,对于本发明的工程化抗-Trop2抗体,由于使用天然免疫球蛋白G铰链序列并在其天然结构位置发生了交换而不引入任何全新氨基酸序列,由此所得的工程化抗体在体内引起的免疫原性会更少。而且,对于工程化抗体来说,可以获得相对于它们的IgG1或IgG4对应抗体相当的蛋白质表达滴度。而且,本发明的工程化抗体能够在合适的偶联条件下能够获得高度均质的ADC产品并实现最优的四连接子-药物载荷连接,产品中具有四连接子-药物载荷的ADC呈高百分比,达80%以上。
本发明抗-Trop2抗体-药物偶联物的生产可显著简化,可以是简单的(一锅式)偶联过程,包括:首先用温和还原剂进行部分还原,然后在同一缓冲系中进行偶联。本发明的ADC具有高度的均质性,DAR4产物的百分比可提高至超过80%。进一步地,本发明的抗-Trop2 ADC显示了与Trop2表达相关的细胞毒性。具体地,本发明的ADC对具有高Trop2表达的细胞系显示优异的细胞毒性,而对低表达或不表达Trop2的细胞系显示弱细胞毒性。本发明ADC具有高抗肿瘤功效。以及,本发明ADC具有优异的体外和体内稳定性。
通过以下详细说明,本发明的其他目的、特征和优点将显而易见。然而,应当理解,尽管显示本发明优选实施方式,但具体实施方式和具体实施例仅为示例性描述,因为本领域技术人员能够从这些具体实施方式领会本发明的构思和范围内的各种变化和调整形式。
附图说明
所述附图属于说明书的一部分,用以进一步说明本发明的相关内容。以下一幅或多幅附图与具体实施方式的详细描述有助于更好地理解本发明。
图1:本发明工程化抗-Trop2抗体的示意图。
图2显示了抗体886-36的结构、与MC-vc-PAB-MMAE偶联的HIC-HPLC的结果和ADC产品的表征。
图3显示了886-36-MMAE的LC-MS表征结果。根据检测到的偶联在轻链上的药物分子的丰度和检测到的偶联在重链上的药物分子的丰度,大部分药物分子载于抗体Fab结构域上。
图4显示了抗体886-37的结构、与MC-vc-PAB-MMAE偶联的HIC-HPLC的结果和ADC产品的表征。
图5显示了886-37-MMAE的LC-MS表征结果。根据检测到的偶联在轻链上的药物分子的丰度和检测到的偶联在重链上的药物分子的丰度,大部分药物分子载于抗体Fab结构域上。
图6显示了hRS-SN38的LC-MS表征结果和ADC产品的表征。
图7显示了hRS-MMAE的HIC-HPLC结果和ADC产品的表征。hRS-MMAE的HIC-HPLC分析显示ADC混合物中偶联物呈正态分布。
图8显示了不同的hRS-SN38-偶联的ADC和MMAE-偶联的ADC对MDA-MB-231细胞、MDA-MB-468细胞、HCC827细胞、BxPC-3细胞和Calu-6细胞的细胞毒性。IC50值表明,MMAE偶联的ADC在Trop2高表达的细胞系中具有高细胞毒性效力,而在Trop2低表达或无表达的细胞系中具有弱生长抑制效力。
图9是实施例5和图8中细胞毒性数据的汇总。
图10显示了不同ADC的细胞培养基稳定性。ADC的DAR通过LC-MS测定。根据孵育过程中DAR的变化,886-36-MMAE和886-37-MMAE在孵育期间具有良好稳定性。
图11:实例抗体的轻链和重链序列,其中工程化铰链区示为斜体。
图12显示了不同ADC的大鼠血浆稳定性。
图13显示了通过FACS检测的不同ADC对MDA-MB-468、HCC827和BxPC-3的结合亲和力。
图14显示了不同ADC在MDA-MB-468、HCC827和BxPC-3中的内化结果。
图15显示了不同ADC对HCC827的体内效力。
图16显示了不同ADC对MDA-MB-468的体内效力。
图17显示了不同ADC对BxPC-3的体内效力。
图18显示了不同ADC的大鼠PK结果。通过ELISA测定总的和各ADC的偶联抗体的浓度。
定义
本文中,“一个”、“一种”和“该/所述”引导的单数形式包括复数含义,除非另作说明。而且,术语“一个(种)”、“一个(种)或多个(种)”和“至少一个(种)”在本文中可以互换使用。
本文中,术语“约”或“大约”指量、水平、值、数目、频率、百分比、维度、尺寸、量、重量或长度相对于参考量、水平、值、数目、频率、百分比、维度、尺寸、量、重量或长度相差至多30%、25%、20%、25%、10%、9%、8%、7%、6%、5%、4%、3%、2%或1%。在特定的实施方式中,术语“约”或“大约”在一个数值前面时表示该值加减15%、10%、5%或1%的范围。
本文中,术语“示例性”表示“用作示例、实例或展示”。本文描述为“示例性”的任何内容不一定解释为比其他方面更优选或有利。
在本文中,术语“包括”、“包含”、“以…为特征”和“具有”,以及它们的语法变体可以互换使用,应理解为包括明示的步骤或元素而不排除任何其他步骤或元素。因此,它们包括由封闭式术语“由…组成”及其语法变体所表示的排他性包含,以及由术语“基本上由…组成”所表示的半封闭式包含,该术语仅对质量和/或数量上不重要的元素是开放式的。
本文中一种实施方式中的一项或多项特征可以与另一实施方式中的一项或多项特征组合,这并不背离本发明的构思和概念。
除非另做定义,本发明使用的所有技术和科学术语其意义与本发明所属领域普通技术人员通常所理解的相同。文中列举的公开文献和专利文献都通过援引纳入本文并适用于各种目的。本说明书引用的文献应视为本领域普通技术人员的技术水平,但这不应理解为承认本发明不可因发明在先而早于这种公开。
本文中,术语“抗体”涵盖任何与一种或多种特定抗原结合的免疫球蛋白、单克隆抗体、多克隆抗体、多特异性抗体或双特异性(二价)抗体。通常,就像天然完整抗体那样,抗体包括两条重链和两条轻链。每条重链包括可变区(“VH”)和第一、第二、第三恒定区(CH1、CH2、CH3)以及条件性的第四恒定区(CH4),如IgM和IgE抗体的情况,而每条轻链由可变区(“VL”)和恒定区(CL)组成。哺乳动物的重链分为α、δ、ε、γ和μ型,而哺乳动物的轻链分为λ和κ型。轻链和重链的可变区负责抗原结合。各可变区通常包含三个高度可变的环,称为“互补决定区(CDR)”。CDR的边界可以通过Kabat、Chothia或Al-Lazikani的规则来定义或鉴定。三个CDR插在与之侧接的框架区(FR)之间,框架区与CDR相比更高度保守并形成支撑高变环的支架。重链和轻链的恒定区不参与抗原结合,但显示多种效应子功能。主要的五类抗体是IgA、IgD、IgE、IgG和IgM,其特征分别在于存在α、δ、ε、γ和μ重链。几个主要的抗体类别被分为亚类,例如IgG1(γ1重链)、IgG2(γ2重链)、IgG3(γ3重链)、IgG4(γ4重链)、IgA1(α1重链)或IgA2(α2重链)。因此,在本发明中,特定的IgG型,例如“IgG1”或“IgG1型”,是指定亚类的各IgG同种型,而不同的IgG型是指不同亚类的IgG同种型。
本文中,就抗体而言的“可变区”指包含一个或多个CDR的抗体可变区或其片段。虽然可变区可以包括完整的可变区(如VH或VL),但也可以包括不够完整但仍保留与抗原结合或形成抗原结合位点的能力的可变区。
抗体可以呈“Y”形,其中的两个臂也称为“抗原结合片段(Fab)”,而茎部包括抗体的铰链结构域和Fc结构域。
本文中,“Fab”、“Fab结构域”和“Fab臂”可互换使用,指沿免疫球蛋白(如抗体)中轻链与重链沿可变区和第一恒定区偶合形成的结构域。通常,Fab结构域可包含一个或多个链间二硫键。在一些实施方式中,轻链和重链的恒定区可以用TCR恒定区代替。Fab结构域负责多种抗原结合活性。
本文中,“Fc区”指重链第二恒定区(CH2)及此后的恒定区组成的片段,或指铰链区的部分、重链的第二恒定区(CH2)及此后的恒定区组成的片段。并且,本文中,二聚体抗体的“Fc结构域”指偶合重链部中各Fc区所在的部分。Fc区具有多种效应子功能,例如ADCC和CDC。
本文中,重链“铰链”或“铰链区”指连接重链CH1区C-末端和CH2区N-末端的区域。铰链区的长度可以是约12-62个氨基酸残基。人IgG1中,铰链区包括第216至230位残基,在人IgG4中包括第219至230位残基,以上按照EU编号。本文中,二聚体抗体的“铰链结构域”指偶合重链中各链铰链区所在的部分。通常,铰链结构域可包含一个、两个或更多个链间二硫键。铰链区是柔性的从而允许两个Fab结构域各自活动。
铰链区是抗体Fab与Fc之间的柔性连接子。IgG亚类IgG1、IgG2、IgG3和IgG4之间,铰链区的长度和柔性差异很大。以最常用作治疗性生物制品的IgG1和IgG4为例,IgG1的铰链区包含15个氨基酸(例如,EPKSCDKTHTCPPCP(SEQ ID NO:5)),很有柔性,IgG4的铰链区较短,仅12个氨基酸(Gestur Vidarsson等,IgG亚类和同种异型:从结构到效应子功能(IgGsubclasses and allotypes:from structure to effector functions,Frontiers inImmunology),2014年10月20日,5:520)。野生型IgG1和IgG4在核心铰链区(EU编号226-229)相差一个氨基酸:IgG1中为Cys-Pro-Pro-Cys而IgG4中为Cys-Pro-Ser-Cys。天然IgG4的核心铰链区存在链间与链内半胱氨酸二硫键之间的平衡,因此会发生重链臂交换和分泌后有IgG4半抗体分子存在。业已证实,IgG4的S228P突变(例如ESKYGPPCPPCP(SEQ ID NO:6))可通过防止自然臂交换来显著稳定IgG4重链之间的共价相互作用,因此已广泛用于IgG4抗体的开发和生产。S228P突变在IgG4铰链中形成多脯氨酸螺旋(PPCPPCP),配合较短的IgG4铰链长度,与IgG1铰链相比会进一步限制其柔性。不同铰链之间的柔性差异对抗体的生物偶联具有重要意义,因为位于柔性铰链片段中的半胱氨酸残基被认为比位于刚性铰链中的半胱氨酸残基更具反应性。有实验表明,S228P IgG4的重链-轻链间二硫键和重链-重链间二硫键均为弱反应性。
本文中,“CH2结构域”指重链分子中如下所述的部分,即按照常规编号方案IgG抗体中约第244位氨基酸至第360位氨基酸所在的部分(按Kabat编号的氨基酸244至360,按EU编号的氨基酸231至340)。
“CH3结构域”从IgG分子的CH2结构域延至C末端,包含大约108个氨基酸。某些免疫球蛋白(例如IgM和IgE)还含有CH4区。
"Fv"、"Fv片段"和"Fv结构域"可以互换使用,指包含抗体完整抗原结合位点的最小结构域。Fv结构域通常包括彼此偶合的轻链可变区(VL)和重链可变区(VH)。
生物序列(包括氨基酸序列和核酸序列)之间的同一性(相同)百分比(%)指待查序列与参考序列按最大匹配比对时两者之间相同残基的百分比。序列同一性(相同性)可以用公共工具来测定,如BLASTN、BLASTp(可见于美国国家生物技术信息中心(NCBI)网站)、ClustalW2(可见于欧洲生物信息学研究所网站),以及ALIGN或Megalign(DNASTAR)软件。
本文中,“特异性结合”或“特异性地结合”指两个分子之间(例如抗体和抗原之间)的非随机结合反应。本发明的工程化抗体特异性结合Trop2抗原的结合亲和力(KD)≤10-6M(例如≤5x10-7 M、≤2x10-7 M、≤10-7M、≤5x10-8 M、≤2x10-8 M、≤10-8M、≤5x10-9 M、≤2x10-9 M、≤10-9M或≤10-10M)。本文中的KD指解离速率与缔合速率之比(koff/kon)。
“操作性地连接/相连”指两个或更多个目标生物序列并置,彼此之间有或没有间隔子或连接子,并置的方式使得它们的关系允许各自以预期方式起作用。用于描述多肽时表示多肽序列相连的连接使得连接产物具有预期的生物功能。例如,抗体可变区可与恒定区操作性连接得到具有抗原结合活性的稳定产物。该术语也可用于描述多核苷酸。例如,当编码多肽的多核苷酸与调控序列(如启动子、增强子、沉默子序列等)操作性相连时表述这些多核苷酸序列的连接方式实现所述多核苷酸受调控地表达多肽。
与参考序列不是100%相同的序列可能在一个或多个位置包含突变,突变可以是取代、添加、缺失或其组合。取代可以是“保守取代”,指用侧链理化性质类似的不同氨基酸进行替换,或在对序列的活性或功能不重要的位点进行取代。例如,保守取代可以是具有非极性侧链的氨基酸(如Met、Ala、Val、Leu和Ile、Pro、Phe、Trp)之间的替换、具有不带电荷的极性侧链的氨基酸(如Cys、Ser、Thr、Asn、Gly和Gln)之间的替换,具有酸性侧链的氨基酸(如Asp、Glu)之间的替换,具有碱性侧链的氨基酸(如His、Lys和Arg)之间的替换,具有β支化侧链的氨基酸(如Thr、Val和Ile)之间的替换,具有含硫侧链的氨基酸(如Cys和Met)之间的替换,或具有芳族侧链的氨基酸(如Trp、Tyr、His和Phe)之间的替换。保守取代不会引起构象结构的显著变化因而能够保留蛋白质的生物活性。
本文中,“对象”指人或非人动物对象。非人动物可以是哺乳动物,例如灵长类动物。非人类哺乳动物对象的例子包括但不限于豢养动物、畜牧动物和动物园动物、竞技动物或宠物,例如犬、猫、豚鼠、兔、大鼠、小鼠、马、猪、牛和熊。优选地,对象是人。“有需要的对象”指有疾病、紊乱或状况需要进行诊断、预后、缓解、预防和/或治疗的对象。
具体实施方式
以下描述仅为说明本文的各种实施方式。因此,在此讨论的具体变化、改换等不应解释为对本文公开范围的限制。对于本领域技术人员来说显而易见的是,在本文公开范围之内,可以得出各种等同形式、调整和改换,应当明白,这些等同实施方式均包括在本文范围之内。本文引用的所有参考文献,包括出版物、专利和专利申请,都通过引用全文方式纳入本文。
在某些实施方式中,本发明工程化抗-Trop2抗体中铰链结构域的工程化造成铰链结构域和Fab结构域之间链间二硫键的还原反应性差异。具体而言,Fab结构域的链间二硫键在温和还原剂部分还原过程中被优先打开,这有利地实现了本发明ADC产品的高均质性。通过优化生产条件,DAR4产物的百分比可以提高到超过80%,其中大部分药物偶联于Fab结构域。得益于偶联过程简单、最终产品均质性高且药物偶联位置确定,本发明抗-Trop2 ADC的CMC(化学、制造与控制)简便易控。并且,本发明的抗-Trop2 ADC具有优异的体外和体内稳定性,在制剂开发和药代动力学特征方面具有潜在优势。并且,本发明的抗-Trop2 ADC表现出与Trop2表达相关的细胞毒性。具体而言,本发明ADC对具有高Trop2表达的细胞系表现出优异的细胞毒性,而对低表达或不表达Trop2的细胞毒性很弱。本发明ADC具有很高的抗肿瘤功效。
工程化抗体
在本公开的一方面中,本文提供了一种工程化二聚体抗体,其中各单体包含特异性结合Trop2抗原的Fab结构域和与之操作性相连的工程化铰链区,其中所述工程化铰链区由截短IgGl铰链区部分和截短IgG4铰链区部分构成,所述工程化二聚体抗体的铰链结构域由此包含至少两个链间二硫键。
二聚体抗体由两个配对的单体形成,其中各单体包含偶合的重链和轻链。所述工程化抗体可以是IgG型的。单体通过链间键合力(包括链间键和/或链间相互作用)偶合形成二聚体。链间键合的例子包括但不限于二硫键、氢键、静电相互作用、盐桥、疏水-亲水相互作用和杵臼(Knobs-into-Holes)机制。
在某些实施方式中,单体在重链中还包含Fc区,因此工程化抗体具有如图1示意图所示的二聚体结构。工程化抗体可以是同源二聚体抗体。
工程化抗体包含设计的工程化铰链区,其由截短IgGl铰链区部分和截短IgG4铰链区部分构成,所述工程化二聚体抗体的铰链结构域由此包含至少两个链间二硫键。工程化铰链区由天然氨基酸构成,包含用于在重链之间形成至少两个链间二硫键的半胱氨酸残基。本发明工程化二聚体抗体的“铰链结构域”是包括各重链铰链区所在的部分。
IgG1的野生型铰链区包括15个氨基酸(例如EPKSCDKTHTCPPCP(SEQ ID NO:5)),很有柔性,而IgG4的铰链较短,仅有12个氨基酸(同前)。野生型IgG1和IgG4在核心铰链区(EU编号226-229)相差一个氨基酸:IgG1中为Cys-Pro-Pro-Cys而IgG4中为Cys-Pro-Ser-Cys,具有S228P突变的IgG铰链可由序列ESKYGPPCPPCP(SEQ ID NO:6)表示。S228P突变在IgG4铰链中形成多脯氨酸螺旋(PPCPPCP),配合较短的IgG4铰链长度,与IgG1铰链相比进一步限制其柔性。不同铰链之间的柔性差异对抗体的生物偶联具有重要意义,因为位于柔性铰链片段中的半胱氨酸残基被认为比位于刚性铰链中的半胱氨酸残基更具反应性。有实验表明,S228P IgG4的重链-轻链间二硫键和重链-重链间二硫键均为弱反应性。
本发明人惊奇地发现,利用铰链结构域的链间二硫键与Fab结构域的链间二硫键对还原剂的可及性存在差异,本发明的工程化铰链区在生物偶联过程中提供药物载荷-抗体比率(PAR,相当于DAR)改进的。具体而言,如前所述,对于ADC生产和ADC产品本身而言,具有工程化铰链区的工程化抗体具有多项优势,例如改进的DAR和DAR均质性、简化生产、所需药代动力学特性和/或药效动力学特性。
在一些实施方式中,工程化铰链区可包含下式(I)所示的序列:
EPKx1C x2 x3 x4 x5 x6 x7 x8 CPPCP (I)
其中,x1=缺省或S,优选S;x2=缺省或E或S,优选缺省;x3=缺省或S;x4=缺省或K或D;x5=Y或K,优选Y;x6=G或T,优选G;和/或x7x8=PP、PT、HP或HT,优选PP。在一些实施方式中,工程化铰链区包含式EPKSC x2 x3 x4 x5 x6PPCPPCP所示的序列。
工程化铰链区的优选实例包括:
EPKSCESKYGPPCPPCP(SEQ ID NO:1),
EPKSCSKYGPPCPPCP(SEQ ID NO:2),
EPKSCKYGPPCPPCP(SEQ ID NO:3),
EPKSCYGPPCPPCP(SEQ ID NO:4);以及
与上述任一个序列至少85%、优选至少90%和更优选至少95%相同的序列。
在一些实施方式中,工程化铰链区还可包括位于所述铰链区的任一侧或两侧的其他铰链区段(例如上铰链区区段)。
在一些实施方式中,Fab结构域是IgG1抗体的Fab结构域,即IgG1型的Fab结构域。优选地,Fab结构域是人IgG1抗体的Fab结构域。本发明的Fab结构域特异性结合Trop2抗原,优选人Trop2抗原,且可以是任何抗-Trop2抗体的Fab结构域。此类抗体的示例包括但不限于沙西妥珠单抗(Sacituzumab)和Datopotamab。
在一些实施方式中,所述工程化抗体还包含Fc结构域,优选人Fc结构域。优选地,Fc结构域是IgG Fc结构域,即IgG类Fc结构域,更优选地,IgG1或IgG4型的Fc结构域。显然,以上分类方式同样适用于重链的Fc区。
在一个实例中,本发明的工程化抗体包含重链(HC)和轻链(LC),所述重链包含氨基酸序列SEQ ID NO:8或与之至少85%相同的序列,所述轻链包含氨基酸序列SEQ ID NO:7或与之至少85%相同的序列。在另一个实例中,本发明的工程化抗体包含重链和轻链,所述重链包含氨基酸序列SEQ ID NO:10或与之至少85%相同的序列,所述轻链包含氨基酸序列SEQ ID NO:9或与之至少85%相同的序列。
另一方面,本发明提供编码本发明的工程化抗体的核酸分子或核酸分子组合。在一些实施方式中,所述核酸分子或所述组合的各个核酸分子编码SEQ ID NO:7至10中的一个或多个序列或之至少85%相同的序列。一些实施方式中,所述核酸分子可以一个或多个载体,特别是表达载体形式提供。本领域技术人员可以看出,编码重链的核酸和编码轻链的核酸可以分别克隆在分开的表达载体中并共转染到宿主中从而重组表达抗体,也可以将两链的编码序列插入同一表达载体。本领域所知的表达载体和宿主均可用于本发明。例如但不限于质粒、病毒载体、合成载体、细菌宿主、酵母、昆虫细胞和动物细胞,如CHO细胞。在一些实施方式中,所述核酸分子(如载体)或核酸分子组合可以试剂盒形式提供,所述试剂盒可任选地包含使用所述核酸分子或分子重组生产所述抗体的说明。
抗体-药物偶联物
本发明内容之一,本文提供了一种抗体-药物偶联物,包含通过连接子偶联一个或多个药物分子的本发明的工程化抗体上构成抗体-药物偶联物。该工程化抗体的Fab结构域特异性结合Trop2抗原(优选人Trop2抗原),且可以是任何抗-Trop2抗体的Fab结构域。此类抗体的示例包括但不限于沙西妥珠单抗(Sacituzumab)和Datopotamab。
本发明可用的药物(也称为“药物载荷”)没有特别限制。本发明可用的药物包括细胞毒性药物,尤其癌症治疗所用的那些。此类药物包括但不限于DNA损伤剂,DNA结合剂,抗代谢物,酶抑制剂(如胸苷酸合成酶抑制剂和拓扑异构酶抑制剂),微管蛋白抑制剂和毒素(如细菌、真菌、植物或动物来源的毒素)。具体例子包括,例如,紫杉醇,氨甲蝶呤,甲氨喋呤,二氯氨甲蝶呤,5-氟尿嘧啶,6-巯基嘌呤,阿糖胞苷,美法仑,环氧长春碱,长春西定,放线菌素,柔红霉素,多柔比星,丝裂霉素C,丝裂霉素A,洋红霉素,氨基蝶呤,他利霉素,鬼臼及鬼臼衍生物如足叶乙甙或磷酸足叶乙甙,长春花碱,长春新碱,长春地辛,紫杉烷包括紫杉醇,多西他赛视黄酸,丁酸,N8-乙酰基亚精胺,喜树碱,卡奇霉素,埃斯培拉霉素,烯-二炔,多卡霉素A,多卡霉素SA,卡奇霉素,喜树碱,哈米特林,美登木素(包括DM1,DM2,DM3,DM4)和奥瑞他汀类(包括单甲基奥瑞他汀E(MMAE)、单甲基奥瑞他汀F(MMAF)、单甲基奥瑞他汀D(MMAD))。在一些实施方式中,优选奥瑞他汀类,如MMAE。药物可以用任何合适的本领域所知的方法与连接子连接。在一些实施方式中,药物以中间体连接子-药物载荷化合物的形式参与偶联反应,例如"MC-vc-PAB-MMAE"。
本发明采用的药物可通过连接子与抗体结合。本领域有多种用于ADC的连接子。本发明对于可用的连接子没有特别限制,只要它包含能够与抗体上所含的巯基反应从而与抗体相连的部分。特别适用于本发明的是氨酰亚胺(amleimido)或卤酰基官能化的连接子。例子包括但不限于-MC-vc-PAB-(“MC”:马来酰亚胺-己酰基;“-vc-”:“-Val-Cit-”二肽;“PAB”:对氨基苄基),-MC-GGFG-(“-GGFG-”:“–Gly-Gly-Phe-Gly-”四肽),-MC-vc-,-MC-和-SMCC-(琥珀酰亚胺基-4-(N-马来酰亚胺基甲基)环己烷-1-羧酸酯)。在一些实施方式中,连接子是-MC-vc-PAB-。
一些实施方式中,连接子-药物载荷与通过还原反应而被打开的选定链间二硫键所提供的半胱氨酸残基相连。在一些实施方式中,本发明偶联物的药物/抗体比(DAR)可以是约2至约8,优选约2至6,更优选约4。该比率可以是分子群的平均值,例如ADC群的DAR平均值为DAR4。而且,优选实施方式之一中,偶联物的药物分子大多数结合在Fab结构域,某些情形中,偶联物所含的四个药物分子都结合在Fab结构域。
本文还提供了包含本发明抗体-药物偶联物的混合物或由本发明抗体-药物偶联物的混合物组成的组合物,所述混合物中至少约80%、至少约85%、至少约90%、或至少约95%的DAR为4。在一些情形中,DAR4偶联物中的4个药物分子都连在Fab结构域。
在另一方面,本文提供了一种药物组合物,其包含前文所述的抗体-药物偶联物或其混合物和药学上可接受的载体。
抗体-药物偶联物的制备
本发明的ADC可用本领域所知任何合适的方法制备。本发明中,连接子-药物载荷偶联在经温和还原剂还原后由二硫键释放的半胱氨酸残基处。具体地,本发明的工程化铰链结构域改变了铰链结构域中二硫键的还原反应性,因此,当使用温和还原剂对抗体进行部分还原时会选择性地将Fab结构域的二硫键还原。本发明优势之一在于能够提供高度均质性的产品,其主要包含具有四个连接子-药物载荷的偶联物,所述四个连接子-药物载荷大多连接在Fab结构域。
本文提供了制备本发明抗体-药物偶联物的方法。简言之,所述方法可包括抗体部分还原和部分还原的抗体与连接子-药物载荷的偶联反应。优选地,在还原缓冲剂中进行偶联,所述还原缓冲剂含有作为添加剂的有机溶剂以用于促进连接子-药物载荷的溶解。具体地,该方法可以包括部分还原的本发明抗体与带有马来酰亚胺或卤代乙酰基基团的连接子-药物载荷化合物通过迈克尔加成反应偶联。部分还原的抗体可用温和还原剂对本发明的工程化抗体进行部分还原来生产。一些实施方式中,所述方法可以包括:
用温和还原剂对本发明的工程化抗体进行部分还原,以及
使部分还原的抗体与带有马来酰亚胺或卤代乙酰基基团的连接子-药物载荷化合物通过迈克尔加成反应偶联。
在一些实施方式中,所述温和还原剂是TCEP或DTT。在一些实施方式中,还原剂/抗体比是约1-20,优选约3-10,约3-8,约3-6或约3-5。在一些实施方式中,部分还原在pH约4.0至8.0的条件下进行,优选约5至6。在一些实施方式中,所述部分还原进行约0.5至24小时,优选约1至20小时,约2至16小时或约3至5小时。在一些实施方式中,部分还原在温度4至37℃的条件下进行,优选约4至15℃或约4至10℃。
在一些实施方式中,偶联在pH约4.0至8.0的缓冲液中、可选的在有机添加剂(例如有机溶剂或有机助溶剂)存在的条件下进行,所述有机添加剂的量为约0.0重量%至20.0重量%,优选约5.0重量%至15.0重量%或约10.0重量%至15.0重量%。在一些实施方式中,药物/抗体比可以是约7-20,优选约7-10;反应温度可以是约4至37℃,优选约4至20℃或约4至10℃;和/或反应时间可以是约0.5-4小时,优选约1-3小时。
在一些实施方式中,本发明方法提供包含抗体-偶联物混合物或由抗体-偶联物混合物组成的产品,所述混合物中至少约80%、至少约85%、至少约90%或至少约95%的DAR为4。在一些情况中,DAR为4的偶联物中4个药物分子都连在Fab结构域。
治疗
本发明的抗体-药物偶联物可用于治疗以Trop2过表达为特征的癌症。因此,本文还提供了一种为有需要的对象治疗癌症的方法,包括给予所述对象治疗有效量的本发明的所述抗体-药物偶联物,其中所述癌症特征在于Trop2过表达。本文还提供了用于治疗有需要的对象的癌症的本发明的抗体-药物偶联物,其中所述癌症特征在于Trop2过表达。具体地,所述癌症选自下组:乳腺癌、胰腺癌和肺癌。
缩写
ADC:抗体-药物偶联物
CH:重链恒定区
CMC:化学成分生产和控制
DAR:药物-抗体比
DMA:N,N’-二甲基乙酰胺
DTT:1,4-二硫苏糖醇
EGFR:表皮生长因子受体
Fab:抗原结合片段
Fc:可结晶片段
FDA:食品药品监督管理局
FGE:甲酰甘氨酸生成酶
HIC:疏水相互作用色谱
HPLC:高效液相色谱
IC50:半最大抑制浓度
IgG:免疫球蛋白G
MC:马来酰亚胺-己酰基
MED:最小有效剂量
MMAE:单甲基奥瑞他汀E
MTD:最大耐受剂量
MWCO:截留分子量
NaCl:氯化钠
NNAA:非天然氨基酸
mTG:微生物转谷氨酰胺酶
PAB:对氨基苄基
PAR:药物载荷-抗体之比
RP:反相
SEC:尺寸排阻色谱
TCEP:三(2-羧基乙基)膦
VH:重链可变区
eq:还原剂/抗体摩尔比
实施例
通用方法
抗体的制备
本文中全部抗体分子均进行了灰仓鼠(Cricetulus griseus)密码子优化,按照标准分子生物学方法合成并克隆到生产载体中,然后由TOP10大肠杆菌细胞大量扩增后进行质粒抽提制得。
转染前72小时,将CHO K1宿主细胞按2-4E5个细胞/mL接种在CD CHO培养基中。用Vi-CELL计点宿主细胞计算细胞密度,290g离心7分钟,转染前重悬于预回温的新鲜CD CHO培养基中。使用前,重悬宿主细胞在Kuhner摇床中孵育(36.5℃,75%湿度,6%CO2,120rpm),待用。
将总共4mg编码目标抗体的质粒加至宿主细胞重悬液,然后加12mg聚醚酰亚胺。经转染的培养物在Kuhner摇床中于36.5℃、75%湿度、6% CO2、120rpm培养4小时。添加自有补料培养基,经转染的培养物在Kuhner摇床中于31℃、75%湿度、6%CO2、120rpm培养9-10天。
在收获日,经转染的培养物先1,000g离心10分钟再10,000g离心40分钟澄清化,然后0.22μm过滤器过滤除菌。取上清液用ProA色谱纯化并测定滴度。ProA洗脱物中添加1-2%中和缓冲液(1M Tris-HCl,pH 9.0)进行中和,然后配制在pH 5.5的20mM组氨酸-乙酸盐缓冲液中。
偶联之前所有蛋白质均经过质控检测,包括还原和非还原SDS-PAGE、SEC-HPLC、通过LAL凝胶法(LAL gel clot assay)检测内毒素,并通过质谱进行分子鉴定。
ADC的制备
向pH4.0-8.0缓冲液例如组氨酸-乙酸盐存储液配制的浓度1mg/ml至20mg/ml的抗体溶液中添加1至20eq(例如,有些实施方式中是3-10eq)还原剂(例如TCEP或DTT)。在4-37℃温和振荡或搅拌反应0.5至24小时。不纯化,在部分还原的抗体中加入有机助溶剂(例如DMA)至浓度为0%至20%,马来酰亚胺或卤代乙酰基官能化的连接子-药物载荷7-20eq。在4-37℃温和振荡或搅拌进行偶联0.5至24小时。最终的偶联产物特征鉴定包括UV-vis测定浓度,HIC-HPLC测定偶联物分布和DAR,RP-HPLC测定轻链上和重链上的药物加载以及游离药物残留,SEC-HPLC测定聚集体和纯度,动力学比浊法测内毒素水平。
HIC-HPLC
SEC-HPLC
RP-HPLC测药物负载
过程:将20μl ADC样品与75μl 8M盐酸胍和5μl Tris-HCl混合,pH 8.0。向混合物中添加1μl的0.5M TCEP溶液。37℃反应30分钟(min),然后用RP-HPLC测定抗体上的药物负载。
RP-HLPC测定游离药物
过程:85μl ADC溶液与15μl DMA混合,然后用100μl沉淀缓冲液(NaCl饱和的37.5%v/v甲醇/乙腈溶液)沉淀蛋白质,22℃以1400rpm漩涡搅拌10分钟(min)。
样品以16000rpf离心10分钟。取上清液与标准样品一起进行RP-HPLC检测以测定游离药物。
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LC-MS测定DAR
过程:85μl ADC溶液与15μl 50mM TCEP混合,然后在22℃孵育30分钟。样品用LC-MS测定DAR。
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以下实施例仅用于本发明展示,不对本发明范围构成限制。
实施例1
用包含SEQ ID NO:2序列的工程化铰链结构域构建抗-Trop2抗体886-36,图11中也称为“WBP886-36”。该抗体具有SEQ ID NO:7所示的轻链(LC)序列和SEQ ID NO:8所示的重链(HC)序列。可变区VH和VL具有如PCT/GB03/00885所公开的RS7抗体的序列。该抗体按通用方法部分所述重组生产。
将抗体溶于20mM组氨酸-乙酸盐缓冲液(pH 5.5),浓度为7.2mg/ml。向抗体溶液添加5eq的TCEP,混合物于4℃孵育2小时。向还原抗体添加DMA至浓度为10%,然后添加10eq的MC-vc-PAB-MMAE(Levena Biopharma,SET0201)。偶联反应在4℃进行1小时。偶联产物用40KD MWCO脱盐柱纯化,于pH5.5的20mM组氨酸-乙酸盐缓冲液中保存。进行最终产物表征,包括HIC-HPLC测定DAR和药物分布,SEC-HPLC测定纯度和聚集体水平,LC-MS测定药物负载,RP-HPLC测定游离药物残留量,动态比浊法测定内毒素水平(图2和图3)。结果显示,该产品高度均质,主要包含DAR4产物,百分比高达82.3%。此外,LC-MS的结果显示,药物分子大多载于Fab结构域。以及,产品表征表明编为“886-36-MMAE”的ADC可用于体外和体内研究。DAR和药物分布的HIC-HPLC结果:
实施例2
用包含SEQ ID NO:2序列的工程化铰链结构域构建抗-Trop2抗体886-37,图11中也称为“WBP886-37”。该抗体具有SEQ ID NO:9所示的轻链(LC)序列和SEQ ID NO:10所述的重链(HC)序列。可变区VH和VL具有如PCT/GB03/00885所公开的另一RS7抗体的序列。该抗体按通用方法部分所述重组生产。
将抗体溶于20mM组氨酸-乙酸盐缓冲液(pH 5.5),浓度为6.9mg/ml。向抗体溶液添加3.5eq的TCEP,混合物于4℃孵育2小时。向还原抗体添加DMA至浓度为10%,然后添加8eq的MC-vc-PAB-MMAE。偶联反应在4℃进行1小时。偶联产物用40KD MWCO脱盐柱纯化,于pH5.5的20mM组氨酸-乙酸盐缓冲液中保存。进行最终产物表征,包括HIC-HPLC测定DAR和药物分布,SEC-HPLC测定纯度和聚集体水平,LC-MS测定药物加载,RP-HPLC测定游离药物残留量,动态比浊法测定内毒素水平(图4和图5)。结果显示,该产品高度均质,主要包含DAR4产物,百分比高达82.0%。此外,LC-MS的结果显示,药物分子大多载于Fab结构域。以及,产品表征表明编为“886-37-MMAE”的ADC可用于体外和体内研究。
DAR和药物分布的HIC-HPLC结果:
实施例3
将抗-Trop2抗体沙西妥珠单抗(hRS7)溶于20mM组氨酸-乙酸盐缓冲液(pH 5.5),浓度为5.0mg/ml。向抗体溶液添加8.0eq的TCEP,混合物于37℃孵育3小时。向还原抗体添加DMA至浓度为10%,然后添加14eq的CL2A-SN38(Levena Biopharma,SET0217)。偶联反应在4℃进行1小时。偶联产物用40KD MWCO脱盐柱纯化,于pH5.5的20mM组氨酸-乙酸盐缓冲液中保存。进行最终产物"hRS7-SN38"表征,LC-MS测定DAR,SEC-HPLC测定纯度和聚集体水平,RP-HPLC测定游离药物残留量,动态比浊法测定内毒素水平(图6)。
偶联结果:
实施例4
将抗-Trop2抗体沙西妥珠单抗(hRS7)溶于20mM组氨酸-乙酸盐缓冲液(pH 5.5),浓度为8.0mg/ml。向抗体溶液添加2.1eq的TCEP,混合物于37℃孵育3小时。向还原抗体添加DMA至浓度为10%,然后添加7eq的MC-vc-PAB-MMAE。偶联反应在4℃进行1小时。偶联产物用40KD MWCO脱盐柱纯化,于pH5.5的20mM组氨酸-乙酸盐缓冲液中保存。对最终产物“hRS7-MMAE”进行表征,包括HIC-HPLC测定DAR和药物分布,SEC-HPLC测定纯度和聚集体水平,LC-MS测定药物负载,RP-HPLC测定游离药物残留量,动态比浊法测定内毒素水平(图7)。
DAR和药物分布的HIC-HPLC结果:
实施例5
体外细胞毒性实验:测试了靶向Trop2的抗体-药物偶联物对人乳腺癌细胞系MDA-MB-231(Trop2低表达)和MDA-MB-468(Trop2高表达)、人非小细胞肺癌细胞系HCC827(Trop2高表达)、胰腺癌细胞系BxPC-3(Trop2高表达)和人肺腺癌细胞系Calu-6(Trop2低表达)的细胞毒性。
五种细胞系均培养在补充了10%胎牛血清的RPMI-1640培养基中。五种细胞系均以3000个细胞/孔铺板于96孔板中,并在细胞铺板后24小时用ADC处理。在37℃下用ADC处理5天后分析细胞的活力。计算抑制百分比和最大抑制百分比(图8)。数据进一步汇总于图9。
结果显示,本发明ADC对Trop2高表达细胞系具有高细胞毒性效力,而对Trop2低表达细胞系仅有弱生长抑制效力。
实施例6
hRS7-SN38、hRS7-MMAE、886-36-MMAE和886-37-MMAE以0.5mg/mL在RPMI-1640培养基中37℃孵育。分别在第0天、第1天、第3天和第5天取样。用LC-MS的解卷积结果确定各个时间点样品的DAR(图10)。
据孵育过程中DAR的变化,886-36-MMAE和886-37-MMAE在孵育期间具有良好稳定性。
实施例7
hRS7-SN38、hRS7-MMAE、886-36-MMAE和886-37-MMAE以0.5mg/mL与大鼠血浆在37℃孵育。分别在6小时、24小时、72小时、120小时和240小时取样。通过LC-MS测定的ADC的DAR的解卷积结果与其原始值相比,确定每个时间点样品中剩余药物的百分比(%)(图12)。
根据孵育过程中剩余药物百分比的变化,886-36-MMAE和886-37-MMAE在孵育期间具有良好的大鼠血浆稳定性。
实施例8
用FACS检测ADC与人Trop2的结合。检测当日,将肿瘤细胞(1×105个细胞/孔)与系列稀释的ADC和抗体在4℃下孵育1-2小时。人IgG型抗体用作阴性对照。阴性对照1是886-36的同型对照,阴性对照2是886-37的同型对照。阴性对照分别与测试抗体共有相同的Fc区,但不结合任何抗原。用FACS染色缓冲液清洗细胞后,将Alexa647偶联的山羊抗-人IgG Fc作为二抗用FACS染色缓冲液稀释后加入细胞。将板在4℃避光孵育20-60分钟。通过流式细胞仪测量细胞的荧光强度并用FlowJo软件进行分析。用GraphPad Prism软件计算EC50值(图13)。
根据EC50,886-36和886-37、hRS7-SN38、hRS7-MMAE、886-36-MMAE和886-37-MMAE与hRS7抗体的结合亲和力相似。
实施例9
用Fab-ZAP检测测定抗体内化。肿瘤细胞系MDA-MB-468、HCC827和BxPC-3细胞按常规培养在RPMI1640培养基中。检测日的前一日,将肿瘤细胞按适宜的细胞密度接种到96孔板上的培养基中。第二天,将抗体与在细胞培养基中系列稀释的Fab-ZAP混合,然后添加到预先铺有肿瘤细胞的96孔板中。人IgG型抗体用作阴性对照。阴性对照1是886-36的同型对照,阴性对照2是886-37的同型对照。阴性对照与测试抗体的Fc区相同,但不结合任何抗原。将板放置在设定为37℃、5% CO2的培养箱中3-6天。孵育后,用CellTiter-Glo测定细胞活力。用GraphPad Prism软件计算IC50值(图14)。
根据IC50,886-36和886-37与hRS7抗体具有相似的内化效率。
实施例10
肿瘤细胞(HCC827)在体外维持并常规每周传代培养两次。收获指数生长期的细胞并计数用于肿瘤接种。Balb/c裸鼠,雌性,6-8周,体重约18-22g,在右胁腹皮下接种0.2mlPBS和Matrigel(1:1)中的MDA-MB-468肿瘤细胞(10x 106)任肿瘤发展。当目测肿瘤体积平均达到约150-200mm3时,对所有动物进行称重并测量各肿瘤体积。然后将所有小鼠随机分组并分别注射3mg/kg的hRS7-MMAE、886-36-MMAE或886-37-MMAE。每3-4天记录体重和肿瘤大小(图15)。
结果显示,本发明的ADC在HCC827 CDX模型中具有高肿瘤抑制功效。
实施例11
肿瘤细胞(MDA-MB-468)在体外维持,并每周常规传代培养两次。收获指数生长期的细胞并计数用于肿瘤接种。Balb/c裸鼠,雌性,6-8周,体重约18-22g,在右胁腹皮下接种0.2ml PBS和Matrigel(1:1)中的HCC827肿瘤细胞(1x 106)任肿瘤发展。当目测肿瘤体积平均达到约150-200mm3时,对所有动物进行称重并测量个体肿瘤体积。然后将所有小鼠随机分组并分别注射3mg/kg的hRS7-MMAE、886-36-MMAE或886-37-MMAE。每3-4天记录体重和肿瘤大小(图16)。
结果显示,本发明的ADC在MDA-MB-468CDX模型中具有高肿瘤抑制功效。
实施例12
肿瘤细胞(BxPC-3)在体外维持并常规每周传代培养两次。收获指数生长期的细胞并计数以用于肿瘤接种。Balb/c裸鼠,雌性,6-8周,体重约18-22g,在右胁腹皮下接种0.1ml的PBS中的BxPC-3肿瘤细胞(5x 106)任肿瘤发展。当目视检查肿瘤体积平均达到约150-200mm3时,对所有动物进行称重并测量个体肿瘤体积。然后将所有小鼠随机分组并分别注射3mg/kg的hRS7-MMAE、886-36-MMAE或886-37-MMAE。每3-4天记录体重和肿瘤大小(图17)。
结果显示,本发明的ADC在BxPC-3CDX模型中具有高肿瘤抑制功效。
实施例13
将7-10周龄的幼年雄性Sprague-Dawley大鼠随机分组,并分别单次静脉推注10mg/kg hRS7-MMAE、886-36-MMAE或886-37-MMAE。分别在0.083、6、24、48、72和144小时采集每个时间点的约0.25mL的血样,并转移至预冷的EDTA-K2管中并置于湿冰上直至离心。离心后收集血浆样品并在干冰上快速冷冻直至进行ELISA分析。
总抗体ELISA。Nunc MaxiSorp 96孔板用人Trop2蛋白质包被,4℃孵育过夜,用0.05% Tween-20的PBS缓冲液(pH 7.4)洗涤5次。在孔内添加稀释的标准品和ADC血浆样品,并在37℃下孵育1小时。将板洗涤6次,并将检测抗体即辣根过氧化物酶偶联的山羊抗-人κ抗体添加到孔中,并在37℃下孵育1小时。洗板6次并使用TMB过氧化物酶底物显色。ADC的测定范围为0.32768-1250μg/mL,最小稀释度为1:2.5。
偶联抗体ELISA。Nunc MaxiSorp 96孔板用抗-MMAE抗体包被,并在4℃下孵育过夜。用含0.05% Tween-20的PBS缓冲液(pH7.4)洗板5次。将稀释的标准品和ADC血浆样品添加到孔中,并在37℃下孵育1小时。将板洗涤6次,并添加检测抗体即与辣根过氧化物酶偶联的山羊抗-人κ抗体,在37℃下孵育1小时。所有板均使用TMB过氧化物酶底物显色。ADC的测定范围为0.3-600μg/mL,最小稀释度为1:1.5(图18)。
结果显示,与hRS7-MMAE相比,本发明的ADC在总抗体方面具有相似的PK稳定性,并且在偶联抗体方面具有明显更好的稳定性。
序列表
<110> 上海药明合联生物技术有限公司 (WUXI XDC (SHANGHAI) CO., LTD.)
<120> 工程化抗-TROP2抗体及其抗体-药物偶联物
<130> 219837 1PCWO
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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> 8
<211> 452
<212> PRT
<213> 人工序列
<220>
<223> 抗体886-36的重链的氨基酸序列
<400> 8
Gln 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
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Leu Gly Lys
450
<210> 9
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗体886-37的轻链的氨基酸序列
<400> 9
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> 10
<211> 452
<212> PRT
<213> 人工序列
<220>
<223> 抗体886-37的重链的氨基酸序列
<400> 10
Gln 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
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
Claims (20)
1.一种工程化二聚体抗体,其中各单体包含特异性结合Trop2抗原的Fab结构域和与之操作性相连的工程化铰链区,其中所述工程化铰链区由截短IgGl铰链区部分和截短IgG4铰链区部分构成,所述工程化二聚体抗体的铰链结构域由此包含至少两个链间二硫键。
2.如权利要求1所述的工程化抗体,其中所述工程化铰链区包含下式所示的序列:
EPKx1C x2 x3 x4 x5 x6 x7 x8 CPPCP(I)
其中,x1=缺省或S;x2=缺省或E或S,优选缺省;x3=缺省或S;x4=缺省或K或D;x5=Y或K;x6=G或T;和/或x7x8=PP、PT、HP或HT。
3.如权利要求1所述的工程化抗体,其中,所述工程化铰链区包含(a)EPKSCESKYGPPCPPCP(SEQ ID NO:1)、EPKSCSKYGPPCPPCP(SEQ ID NO:2)、EPKSCKYGPPCPPCP(SEQ ID NO:3)或EPKSCYGPPCPPCP(SEQ ID NO:4)所示的序列;或(b)与(a)至少85%相同的序列。
4.如权利要求1所述的工程化抗体,其中,所述Fab结构域为IgG1型,优选人IgG1型。
5.如权利要求1所述的工程化抗体,其中,各单体还包含IgG类Fc区,优选IgG1型或IgG4型的Fc区;并且,所述Fc区优选人Fc区。
6.如权利要求1所述的工程化抗体,其中,各单体包含,
(a)重链和轻链,所述重链包含氨基酸序列SEQ ID NO:8或与之至少85%相同的序列,所述轻链包含氨基酸序列SEQ ID NO:7或与之至少85%相同的序列;或
(b)重链和轻链,所述重链包含氨基酸序列SEQ ID NO:10或与之至少85%相同的序列,所述轻链包含氨基酸序列SEQ ID NO:9或与之至少85%相同的序列。
7.一种核酸分子或核酸分子组合,所述核酸分子或核酸分子组合编码权利要求1所述的工程化抗体。
8.如权利要求7所述的核酸分子或核酸分子组合,其中,所述核酸分子或所述组合的各个核酸分子编码SEQ ID NO:7至10中的一个或多个序列或与之至少85%相同的序列。
9.如权利要求7所述的核酸分子或核酸分子组合,其中所述核酸分子或所述组合中的各核酸分子是载体。
10.一种试剂盒,其包含如权利要求7所述的核酸分子或核酸分子组合。
11.一种抗体-药物偶联物,其包含通过连接子偶联一个或多个药物分子的权利要求1所述工程化抗体。
12.如权利要求11所述的抗体-药物偶联物,具有一项或多项以下特征:
其中,所述连接子是-MC-vc-PAB-;
其中,所述药物是MMAE;
其中,所述偶联物的药物/抗体比为2-8,优选4;且/或
其中,所述偶联物所具有的4个药物分子全都连在所述抗体的Fab结构域处。
13.一种组合物,包含权利要求11所述抗体-药物偶联物的混合物或由权利要求11所述抗体-药物偶联物的混合物组成,其中,至少80%的所述抗体-药物偶联物其药物/抗体比为4。
14.一种药物组合物,其包含权利要求11所述的抗体-药物偶联物和药学上可接受的载体。
15.一种制备权利要求11所述抗体-药物偶联物的方法,其包括部分还原的权利要求1所述抗体与带有马来酰亚胺或卤代乙酰基部分的连接子-药物载荷化合物通过迈克尔加成反应偶联。
16.如权利要求15所述的方法,还包括用温和还原剂对权利要求1所述的工程化抗体进行部分还原以提供所述部分还原的抗体。
17.如权利要求16所述的方法,具有一项或多项以下特征:
其中,所述温和还原剂是TCEP或DTT;
其中,还原剂/抗体比为1至20,优选3至10;
其中,所述部分还原步骤的pH为4.0至8.0,优选5至6;
其中,所述部分还原步骤进行0.5至24小时,优选1至20小时;且/或
其中,所述部分还原步骤的温度为4至37℃,优选4至15℃。
18.一种用权利要求15所述方法获得的抗体-药物偶联物产品,其包含权利要求11所述抗体-药物偶联物的混合物或由权利要求11所述抗体-药物偶联物的混合物组成,其中,至少80%的所述抗体-药物偶联物的药物/抗体比为4。
19.一种为有需要的对象治疗癌症的方法,包括给予所述对象治疗有效量的权利要求11所述抗体-药物偶联物,其中所述癌症的特征在于Trop2过表达。
20.如权利要求19所述的方法,其中所述癌症选自下组:乳腺癌、胰腺癌和肺癌。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013124450A1 (en) * | 2012-02-22 | 2013-08-29 | Ucb Pharma S.A. | Sequence symmetric modified igg4 bispecific antibodies |
WO2015177360A1 (en) * | 2014-05-22 | 2015-11-26 | Synthon Biopharmaceuticals B.V. | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
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 |
CN110575547A (zh) * | 2018-06-07 | 2019-12-17 | 中国科学院上海药物研究所 | 靶向于tf的抗体-药物偶联物及其制法和用途 |
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 |
CN112175082A (zh) * | 2020-09-29 | 2021-01-05 | 姚雪英 | 抗叶酸受体α抗体、其缀合物及其用途 |
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WO2015012904A2 (en) * | 2012-12-13 | 2015-01-29 | Immunomedics, Inc. | Antibody-sn-38 immunoconjugates with a cl2a linker |
SI3088419T1 (sl) * | 2013-12-25 | 2019-01-31 | Daiichi Sankyo Company | Zdravilni konjugat anti trop2 protitelesa |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013124450A1 (en) * | 2012-02-22 | 2013-08-29 | Ucb Pharma S.A. | Sequence symmetric modified igg4 bispecific antibodies |
WO2015177360A1 (en) * | 2014-05-22 | 2015-11-26 | Synthon Biopharmaceuticals B.V. | Site-specific conjugation of linker drugs to antibodies and resulting adcs |
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 |
CN110575547A (zh) * | 2018-06-07 | 2019-12-17 | 中国科学院上海药物研究所 | 靶向于tf的抗体-药物偶联物及其制法和用途 |
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 |
CN112175082A (zh) * | 2020-09-29 | 2021-01-05 | 姚雪英 | 抗叶酸受体α抗体、其缀合物及其用途 |
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