CN110121365A - 制备糖蛋白-药物偶联物的方法 - Google Patents
制备糖蛋白-药物偶联物的方法 Download PDFInfo
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- CN110121365A CN110121365A CN201780081469.4A CN201780081469A CN110121365A CN 110121365 A CN110121365 A CN 110121365A CN 201780081469 A CN201780081469 A CN 201780081469A CN 110121365 A CN110121365 A CN 110121365A
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Abstract
本发明提供一种用于修饰糖蛋白的方法。本发明还提供一种用于制造糖蛋白‑酬载偶联物的方法,以及由此产生的偶联物。
Description
技术领域
本发明涉及一种修饰糖蛋白以使得糖蛋白包含一或多个三甘露糖基核心的方法。本发明还关于糖蛋白-酬载(payload)偶联物,其包含本发明的糖蛋白和相关酬载。
背景技术
治疗性蛋白药物已在临床上广泛使用,且因为其价值高、特异性高和毒性低的优势,所以世界上一些大型医药公司致力于研发此类药物进行临床试验。这些治疗性蛋白中的大部分为单克隆抗体。尽管有一些患者对其临床结果感到满意,但是临床试验数据表明,这些抗体中的一些的治疗效果仍需改良,尤其是在癌症治疗中。为了克服此缺点,科学家开始聚焦于透过一些技术来修饰这些临床抗体,以便增进其在癌症疗法中的功效。在这些技术中,抗体-药物偶联物(antibody-drug conjugate,ADC)因为其对于化学制造管制(chemistry,manufacturing and control,CMC)友善、对用户友善且副作用较低而备受关注。迄今为止,市场上有4种治疗性抗体-药物偶联物可供使用,包括 和还有许多其它药物正在研发当中(库比泽克(Kubizek)F1,艾格里奇(Eggenreich)B1,斯帕杜特(Spadiut)O1.蛋白质和肽快报(Protein Pept Lett.)2017,24(8):686-695;费舍尔(Fischer)E.,罗格希卜利(Roger Schibli)R.抗体(Antibodies)2015,4,197-224;萨普拉(Sapra),P.,霍伯(Hooper),A.,奥唐尼尔(O'Donnell),C.和戈伯(Gerber),H.-P.研究药物专家意见(Expert Opin.Investig.Drugs)2011,20,1131-1180;弗吕加勒(Flygare),J.,皮洛(Pillow),T.和阿里斯托夫(Aristoff),P.,化学生物学与药物设计(Chem.Biol.Drug Des.)2013,81,113-121;帕诺斯基(Panowski),S.;巴克塔(Bhakta),S.;拉布(Raab),H.;波拉吉斯(Polakis),P.和尤努图拉(Junutula),J.R.用于癌症疗法的位点特异性抗体药物结合物(Site-specific antibody drug conjugates forcancer therapy).单克隆抗体(MAbs)2013,6,34-45)。
在这些临床ADC中,Kadcyla和Mylotarg是通过酬载或连接基团与赖氨酸残基的氨基随机偶联所形成,而(维本妥昔单抗(brentuximab vedotin)(cAC10-vcMMAE,SGN-35))则为嵌合抗CD30单克隆抗体,其中融合了鼠抗CD30抗体AC10的可变重链区与轻链区。平均4(2-8)个MMAE分子与SGN-30架构偶联。MMAE的偶联点是通过链间双硫键的温和还原产生的半胱氨酸残基的随机-SH基团。连接基团由硫醇反应性顺丁烯二酰亚胺基己酰基间隔子、二肽缬氨酸-瓜氨酸连接基团和PABC间隔子组成(弗兰斯克(Francisco)JA,科文尼(Cerveny)CG,梅耶(Meyer)DL,米克桑(Mixan)BJ,克拉斯曼(Klussman)K,蔡斯(Chace)DF,雷尼克(Rejniak)SX等人cAC10-vcMMAE.血液(Blood)2003,4,1458-65)。虽然所述技术容易使酬载或连接基团与抗体偶联,但是因为多个赖氨酸序列和抗体中的半胱氨酸残基的最佳还原反应的问题,这两种技术难以控制偶联物的药物抗体比(drug-to-antibody ratio,DAR)。这些现象经常造成抗体产物的异质性且诱发CMC问题。一些文献甚至指出这种类型的第一代非位点特异性ADC具有PK和免疫原性的缺点。
为解决第一代ADC的这些缺点,研发了位点特异性ADC平台,包括SMART标签、非天然氨基酸任何酪氨酸、治疗性转肽酶(sortase)、硫桥(Thio-Bridge)等。正如我们所期望的,这些技术能够通过对亲本抗体中的一些特异性位点或结构域进行工程改造而产生均质ADC产物。举例而言,硫桥技术将连接基团和酬载与抗体的部分还原的双硫键连接。SMART标签是通过使抗体的相邻序列突变为细菌氧化酶的底物序列的技术。所得产物与甲醛一起用作为连接基团与酬载的连接位点。正如预期,这些第二代ADC技术能够产生具有独特的DAR和高均质性的ADC产物。然而,因为天然抗体的突变,ADC产物可能具有PK和免疫原性问题。目前,经由N-糖基化使酬载与抗体偶联吸引了大量关注,这是因为成功研发出了抗体的糖基化工程改造(glycolengineering)。
所有天然存在的IgG和重组抗体均在重链CH2恒定区中的每一个的位置297处具有氨基酸天冬酰氨酸(Asn297),其为一个N-糖基化位点。通过在哺乳动物细胞中的糖基化和后修饰,经由IgG上的N-糖基化形成两个双触状聚糖部分,且双触状聚糖部分各自基本上由具有下式的至少7个糖部分构成:
其中第一GlcNAc(GlcNAc1)分别键结至抗体的Asn297和第二GlcNAc(GlcNAc2),且任选地键结至海藻糖(Fuc);GlcNAc2进一步键结至第一甘露糖(Man1);第二和第三甘露糖(Man2和Man3)分别键结至Man1的α-1,3和α-1,6位置;且另外两个GlcNAc糖(GlcNAc3和GlcNAc4)分别键结至Man2和Man3的β-1,2位置。具有所述聚糖部分与海藻糖的抗体表示为G0F,然而,当海藻糖部分不存在时,抗体为G0。(T.理珊莎拉朱(Shantha Raju)单克隆抗体.2012年5月1日;4(3):385-391)。当GlcNAc3或GlcNAc4键结至额外的半乳糖时,抗体表示为G1F/G1抗体。当抗体的聚糖部分中的末端GlcNAc糖分别键结至两个额外的半乳糖时,抗体表示为G2F/G2抗体。由哺乳动物细胞产生的抗体一般可包括G0F(大于约40%)、G1F(约30%-40%)和G2F(小于1%)以及极少量的连接至唾液酸的G1F/G1和G2F/G2。
因为在N297聚糖中的各分枝位点进行工程改造可维持结构完整且产生一些功能多样性(例如抗体的ADCC、半衰期和CDC),已研发出一些N297糖基化工程改造ADC平台且其中一些产品正处于临床试验阶段。WO 2014/164534 A2、WO 2014/065661 A1、WO 2015/032899 A1、WO 2015/057064 A1、WO 2015/157446 A1、US 8716033 B2、US7416858 B2、EP2753752 B3和综述文章(生物结合物化学(Bioconjug Chem.);2015年11月18日;26(11):2070-5)已公开诸多用于抗体药物偶联的经修饰聚糖部分。然而,在这些技术中无法充分控制抗体-药物偶联中的药物抗体比(DAR)且不能实现酬载多样性,因此在所属领域中需要控制ADC的药物抗体比且提高酬载多样性。本发明满足此需要且提供其它益处。
发明内容
本发明的一个方面提供一种用于制造包含式(1)的结构的糖蛋白-酬载偶联物的方法:
本发明的另一方面提供一种用于制造包含式(5)的结构的糖蛋白-酬载偶联物的方法:
本发明的另一方面提供一种用于制造包含式(7)的结构的糖蛋白-酬载A/B偶联物的方法:
本发明的另一方面提供可通过本发明方法获得的糖蛋白-酬载偶联物。
附图说明
图1显示用于制造三甘露糖基抗体药物偶联物的一步策略和依序策略。
图2显示实例1的折合质量(reduced mass)色谱分析的结果。结果显示,通过β1,4半乳糖苷酶和神经氨糖酸苷酶的处理产生了G0F/G0型贺癌平(Herceptin)。
图3显示实例2的折合质量色谱分析的结果。结果显示,G0F/G0型贺癌平经N-乙酰葡萄糖胺酶S转化为三甘露糖基核心抗体。
图4显示实例3的折合质量色谱分析的结果。结果显示,GlcNAC通过MGAT-1与三甘露糖基贺癌平各位点上的末端甘露糖的一个臂偶联。
图5显示实例4的折合质量色谱分析的结果。结果显示,三甘露糖基贺癌平经MGAT-2和MGAT-1转化为G0/G0F型贺癌平。
图6显示实例6的折合质量色谱分析的结果。结果显示,MGAT-1使UDP-GlcNAz与三甘露糖基贺癌平各位点上的末端甘露糖的一个臂偶联。
图7A显示实例7的折合质量色谱分析的结果;而图7B显示实例7的完整质量(intact mass)色谱分析的结果。结果显示,MGAT-1和MGAT-2使UDP-GlcNAz与三甘露糖基贺癌平偶联而产生G0F/G0型贺癌平,其中4个叠氮基在末端N-乙酰葡萄糖胺中。
图7A和图7B显示实例7的完整质量色谱分析的结果。结果显示,MGAT-1和MGAT-2使UDP-GlcNAz与三甘露糖基贺癌平偶联而产生G0F/G0型贺癌平,其中4个叠氮基在末端N-乙酰葡萄糖胺中。
图8显示实例8的折合质量色谱分析的结果。结果证明,三甘露糖基贺癌平并非用于偶联GlcNAz的MGAT-2的底物。
图9A显示实例9的折合质量色谱分析的结果;而图9B显示实例9的完整质量色谱分析的结果。所述图的结果显示,DBCO-(PEG)4-DM1通过点击化学反应与三甘露糖基贺癌平-4GlcNAz偶联,产生具有DAR4的贺癌平ADC。
图10显示实例10的折合质量色谱分析的结果。所述图的结果显示,第一酬载经MGAT-1和DBCO-(PEG)4-DM1与三甘露糖基-2GlcNAz贺癌平抗体的重链的各臂偶联。
图11显示实例11的折合质量色谱分析的结果。所述图的结果显示,第二GlcNAz使α-6甘露糖经MGAT-2与三甘露糖基贺癌平-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC的重链的各臂偶联。这说明MGAT-2为一种底物非常灵活的酶且将UDP-GlcNAz转化为大官能团抗体,例如三甘露糖基贺癌平-2(GlcNAc-三唑-DBCO-(PEG)4-DM1),产生用于双重酬载ADC产物的中间物。
图12显示实例12的完整质量色谱分析的结果。所述图的结果显示,通过向由实例11的产物产生的中间物三甘露糖基贺癌平-2GlcNAz-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)添加DBCO-(PEG)12-MMAE,产生了在抗体的各臂上具有一个MMAE和一个DM1的DAR4ADC贺癌平产物。
图13显示实例13的完整质量色谱分析的结果。结果显示,通过向由实例11的产物产生的中间物三甘露糖基贺癌平-2GlcNAz-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)添加DBCO-MMAF,产生了在抗体的各臂上具有一个MMAF和一个DM1的DAR4ADC贺癌平产物。
图14显示如实例14中所述的Kadcyla和三甘露糖基贺癌平-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)的结合ELISA。结果指示,Kadcyla与三甘露糖基贺癌平-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)产物之间没有显著的Kd差异。
图15A和图15B显示实例16的三甘露糖基核心曲妥珠单抗(trastuzumab)抗体的折合质量色谱分析的结果。结果显示,透过哺乳动物细胞系产生了三甘露糖基曲妥珠单抗和三甘露糖基抗TMCC3。
图16A、图16B和图16C显示实例17的折合质量色谱分析和完整质量色谱分析的结果。所述图的结果显示,产生三甘露糖基曲妥珠单抗的哺乳动物细胞产生了三甘露糖基曲妥珠单抗-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)。
具体实施方式
除非另外定义,否则本文中所用的所有技术和科学术语具有与本发明所属领域的一般技术者通常所理解相同的含义。虽然可在实施或测试本发明时使用类似于或等效于本文所述的方法和材料的任何方法和材料,但现在描述优选的方法和材料。本文特别提及的所有公开案和专利出于所有目的以引用的方式并入本文中,包括描述和公开公开案中所报导、可联合本发明使用的化学品、细胞系、载体、动物、仪器、统计分析和方法。本说明书中所引用的所有参考文献视为所属领域的技能水平的指示。
缩写
ADC 抗体-药物偶联物
DAR 药物抗体比
Asn 天冬酰氨酸
GlcNAc N-乙酰葡萄糖胺
GlcNAz N-叠氮基乙酰葡萄糖胺
Fuc 海藻糖
Man 甘露糖
MGAT-1;GnT-1 甘露糖基(α-1,3-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶
MGAT-2;GnT-2 甘露糖基(α-1,6-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶
UDP 二磷酸尿苷
DBCO 二苯并环辛炔基
DM1 美登素(mertansine)
PEG 聚乙二醇
MES 4-吗啉乙磺酸
MMAE 单甲基奥瑞他汀E(monomethyl auristatin E)
MMAF 单甲基奥瑞他汀F
TMCC3 d跨om膜ai和n f卷am曲il螺y 3旋)域家族3(transmembraneand coiled-coil
应注意,如本文和随附权利要求书中所用,除非上下文另外清楚地规定,否则单数形式“一(a/an)”和“所述”包括复数个指示物。同样,在本文中,术语“一(a或an)”、“一或多个”和“至少一个”可互换使用。还应注意,术语“包含”、“包括”和“具有”可互换使用。
通常,本文中范围表述为自“约”一个特定值和/或至“约”另一特定值。当表述此类范围时,实施例包括自一个特定值和/或至另一特定值的范围。类似地,当值通过使用词语“约”表述为近似值时,应理解特定值形成另一实施例。将进一步理解,范围中的每一个的端点无论与另一端点相关还是与另一端点无关均为有意义的。如本文所用,术语“约”是指±20%、±15%、±10%、±9%、±8%、±7%、±6%、±5%、±4%、±3%、±2%、±1%、±0.5%或±0.25%。
当提及调配物组分时,例如“药剂”的所用术语意图不仅涵盖特定分子实体,且还涵盖其药学上可接受的类似物,包括(但不限于)盐、酯、酰胺、前药、偶联物、活性代谢物和其它此类衍生物、类似物和相关化合物。
本文所用的通用术语“糖”指示单糖,例如葡萄糖(Glc)、半乳糖(Gal)、甘露糖(Man)和海藻糖(Fuc),以及单糖衍生物,如氨基糖和糖酸,例如葡萄糖胺(GlcN)、半乳糖胺(Galn)、N-乙酰葡萄糖胺(GlcNAc)、N-叠氮基乙酰葡萄糖胺(GlcNAZ)、N-乙酰半乳糖胺(GlaNAc)、N-乙酰神经氨糖酸(NeuNAc)、N-乙酰胞壁酸(MurNAc)、葡萄糖醛酸(GlcA)和艾杜糖醛酸(iduronic acid,IdoA)。
如本文所用,术语“蛋白质”可包括具有天然氨基酸序列的多肽,以及变异体和经修饰形式,不管其来源或制备模式为何。具有天然氨基酸序列的蛋白质为具有如从自然界获得的相同氨基酸序列的蛋白质。所述天然序列蛋白质可从自然界分离或可使用标准重组和/或合成方法制备。天然序列蛋白质明确涵盖天然存在的截短或可溶形式、天然存在的变异体形式(例如交替剪接形式)、天然存在的等位基因变异体和包括翻译后修饰的形式。天然序列蛋白质包括在一些氨基酸残基的翻译后修饰之后的蛋白质,翻译后修饰如糖基化或磷酸化或其它修饰。
如本文所用,术语“糖蛋白”是指包含一或多个共价键结至蛋白质的单糖或寡糖链的蛋白质。聚糖可附接至蛋白质的羟基(O连接型糖基),例如附接至丝氨酸、苏氨酸、酪氨酸、羟基赖氨酸或羟基脯氨酸的羟基,或附接至例如天冬酰氨酸或精氨酸的蛋白质上的酰胺(N-糖蛋白),或附接至例如色氨酸的蛋白质上的碳(C-糖蛋白)。糖蛋白可包含超过一个聚糖,可包含一或多个单糖与一或多个寡糖聚糖的组合,且可包含N连接型、O连接型和C连接型聚糖的组合。糖蛋白的实例包括对细胞表面抗原具有特异性的配体、前列腺特异性膜抗原、南极念珠菌脂肪酶(candida antarctica lipase)、gp41、gp120、红血球生成素(erythropoietin,EPO)、抗冻蛋白和抗体。
抗体是由免疫系统所产生,能够识别且结合至特异性抗原的蛋白质。本文中的术语抗体在其最广泛意义上使用且尤其包括单克隆抗体、多株抗体、二聚体、多聚体、多特异性抗体(例如双特异性抗体)、抗体片段和双链与单链抗体。术语“抗体”在本文中还意图包括人类抗体、人类化抗体、嵌合抗体和特异性结合癌症抗原的抗体。术语“抗体”意图包括全抗体,还有抗体片段,例如来自裂解抗体的抗体Fab片段、F(ab')2、Fv片段或Fc片段、scFv-Fc片段、微型抗体、双功能抗体或scFv。此外,所述术语包括抗体的经基因工程改造的衍生物。抗体、抗体片段和经基因工程改造的抗体可通过所属领域中已知的方法获得。合适的可商购抗体包括(但不限于)阿昔单抗(abciximab)、利妥昔单抗(rituximab)、巴利昔单抗(basiliximab)、帕利珠单抗(palivizumab)、英利昔单抗(infliximab)、曲妥珠单抗、阿仑单抗(alemtuzumab)、阿达木单抗(adalimumab)、托西莫单抗(tositumomab)-1131、西妥昔单抗(cetuximab)、替伊莫单抗(ibrituximab tiuxetan)、奥马珠单抗(omalizumab)、贝伐单抗(bevacizumab)、那他珠单抗(natalizumab)、兰尼单抗(ranibizumab)、帕尼单抗(panitumumab)、依库珠单抗(eculizumab)、聚乙二醇化赛妥珠单抗(certolizumabpegol)、戈利木单抗(golimumab)、卡那单抗(canakinumab)、卡妥索单抗(catumaxomab)、优特克单抗(ustekinumab)、托珠单抗(tocilizumab)、奥伐木单抗(ofatumumab)、地诺单抗(denosumab)、贝利单抗(belimumab)、伊匹单抗(ipilimumab)和本妥昔单抗。
可使用多种表达系统(包括原核表达系统和真核表达系统)来产生抗体。在一些实施例中,表达系统为哺乳动物细胞表达系统,如融合瘤;或CHO细胞表达系统。诸多此类系统可广泛地购自商业供货商。在抗体包含VH和VL区的实施例中,VH和VL区可使用单一载体表达,例如以双顺反子表达单元表达;或在不同启动子的控制下表达。在其它实施例中,VH和VL区可使用个别的载体表达。如本文所述的VH和VL区可任选地在N端包含甲硫氨酸。
编码相关抗体的重链和轻链的基因可克隆自细胞,例如,编码单克隆抗体的基因可克隆自融合瘤且用于产生重组单克隆抗体。编码单克隆抗体的重链和轻链的基因库还可由融合瘤或浆细胞制得。重链和轻链基因产物的随机组合产生具有不同抗原特异性的大抗体池。
用于制造单链抗体或重组抗体的技术(美国专利第4,946,778号、美国专利第4,816,567号)可适用于制造本发明多肽的抗体。此外,可使用基因转染小鼠或如其它哺乳动物的其它生物体来表达人类化抗体或人类抗体(参见例如美国专利第5,545,807号;第5,545,806号;第5,569,825号;第5,625,126号;第5,633,425号;第5,661,016号;马克斯(Marks)等人,生物技术(Bio/Technology)10:779-783(1992);龙柏格(Lonberg)等人,自然(Nature)368:856-859(1994);莫里森(Morrison),自然368:812-13(1994);菲什维尔德(Fishwild)等人,自然生物技术(Nature Biotechnology)14:845-51(1996);纽伯格(Neuberger),自然生物技术14:826(1996);以及龙柏格和胡萨尔(Huszar),国际免疫学评论(Intern.Rev.Immunol.)13:65-93(1995))。
如本文所用,“GlcNAc1”、“GlcNAc2”、“GlcNAc3”和“GlcNAc4”分别表示在触状聚糖部分的不同位置处的GlcNAc糖。
如本文所用,表示包含三个甘露糖的三甘露糖基结构,其中第一甘露糖(Man1)连接至GlcNAc糖;而第二和第三甘露糖(Man2和Man3)分别经由α-1,3和α-1,6糖苷键连接至Man1。
如本文所用,“-(Fuc)0-1”表示海藻糖任选地存在,且当存在时,仅有一个海藻糖。
如本文所用,“-(CH2)0-8-”表示-CH2-可存在或可不存在,且当存在时,其可独立地为1、2、3、4、5、6、7或8个-CH2-基团。
本发明的一个方面提供一种用于制造包含式(1)的结构的糖蛋白-酬载偶联物的方法:
所述方法包含以下步骤:
(i)使包含具有式(2)的聚糖的糖蛋白
与β-N-乙酰葡萄糖胺酶反应,产生包含式(3)的三甘露糖基核心的经修饰糖蛋白
(ii)使包含式(3)的三甘露糖基核心的经修饰糖蛋白与UDP-GlcNAc-(CH2)0-8-R在甘露糖基(α-1,3-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶和甘露糖基(α-1,6-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶存在下反应,其中R为叠氮基、酮基或醛,使得两个GlcNAc-(CH2)0-8-R糖分别键结至Man2和Man3各者的β-1,2位置,且借此形成式(4)的聚糖部分
以及
(iii)使两个偶联剂-连接基团-酬载与式(4)的聚糖部分反应,其中两个偶联剂-连接基团-酬载的酬载相同或不同,产生包含式(1)的结构的糖蛋白-酬载偶联物。
在一些实施例中,两个酬载不同,酬载可以随机方式附接至糖蛋白中的四种Man-GlcNAc结构中的任一种。
本发明的另一方面提供一种用于制造包含式(5)的结构的糖蛋白-酬载偶联物的方法:
所述方法包含以下步骤:
(i)使包含如上文所定义的式(3)的三甘露糖基核心的经修饰糖蛋白与UDP-GlcNAc-(CH2)0-8-R在甘露糖基(α-1,3-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶存在下反应,其中R为叠氮基、酮基或醛,使得GlcNAc-(CH2)0-8-R糖键结至Man2的β-1,2位置,且借此形成包含式(6)的聚糖部分的糖蛋白
以及
(ii)使偶联剂-连接基团-酬载与包含式(6)的聚糖部分的糖蛋白反应,产生包含式(5)的结构的糖蛋白-酬载偶联物。
在一些实施例中,为了精确控制酬载所附接的位置,可通过以下步骤产生包含式(7)的结构的糖蛋白-酬载A/B偶联物:
(i)使包含如上文所定义的式(3)的三甘露糖基核心的经修饰糖蛋白与UDP-GlcNAc-(CH2)0-8-R在甘露糖基(α-1,3-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶存在下反应,其中R为叠氮基、酮基或醛,使得GlcNAc-(CH2)0-8-R糖键结至Man2的β-1,2位置,且借此形成包含如上文所定义的式(6)的聚糖部分的糖蛋白;
(ii)使偶联剂-连接基团-酬载A与包含式(6)的聚糖部分的糖蛋白反应,产生包含式(8)的结构的糖蛋白-酬载A偶联物
(iii)使包含式(8)的结构的糖蛋白-酬载A偶联物与UDP-GlcNAc-(CH2)0-8-R在甘露糖基(α-1,6-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶存在下反应,其中R为叠氮基、酮基或醛,使得GlcNAc-(CH2)0-8-R糖键结至Man3的β-1,2位置,且借此形成包含具有式(9)的聚糖-酬载A部分的糖蛋白
以及
(iv)使偶联剂-连接基团-酬载B与包含具有式(9)的聚糖-酬载A部分的糖蛋白反应,产生包含式(7)的结构的糖蛋白-酬载A/B偶联物,
其中所述酬载A与所述酬载B相同或不同。
如本文所用的糖蛋白可例如通过固态肽合成(例如梅里菲尔德固相合成(Merrifield solid phase synthesis))或重组制造获得。关于重组制造,将一或多个编码糖蛋白的聚核苷酸分离且插入载体中以在宿主细胞中进行进一步选殖和/或表达。此类聚核苷酸可使用习知程序容易地分离和定序。可使用所属领域的技术人员熟知的方法来构筑含有糖蛋白的编码序列的表达载体。这些方法包括活体外重组DNA技术、合成技术和活体内重组/基因重组。参见例如曼尼阿提斯(Maniatis)等人,分子克隆:实验室手册(MOLECULARCLONING:A LABORATORY MANUAL),冷泉港实验室(Cold Spring Harbor Laboratory),纽约(N.Y.)(1989);和奥斯贝(Ausubel)等人,分子生物学现代方法(CURRENT PROTOCOLS INMOLECULAR BIOLOGY),格林出版协会和威利国际科学(Greene Publishing Associatesand Wiley Interscience),纽约(1989)中所述的技术。
如本文所用,β-N-乙酰葡萄糖胺酶表示催化来自寡糖的β-N-乙酰葡萄糖胺残基的水解的糖苷酶家族。已发现许多β-N-乙酰基-葡萄糖胺酶都具有催化多种类型的β-糖苷键的水解能力。在一个优选实施例中,β-N-乙酰葡萄糖胺酶可为能够水解位于糖蛋白的末端乙酰葡萄糖胺残基与N-聚糖之间的β1-2键的外切糖苷酶。外切-β-N-乙酰葡萄糖胺酶变异体可自不同来源获得,如链球菌属(Streptococcus spp.)和关刀豆(Canavaliaensiformis)。
根据本发明,甘露糖基(α-1,3-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶(MGAT1;GnT-I;EC:2.4.1.101)将N-乙酰基-D-葡萄糖胺自UDP-GlcNAc转移至末端甘露糖,末端甘露糖经由α1-3糖苷键连接至另一糖部分或聚糖。通过MGAT1转移的GlcNAc与α3甘露糖的键为β1-2糖苷键。已发现MGAT1普遍在真核生物中表达,因为其在高基体(Golgi)中是杂合和复杂的N-聚糖生物合成所必需的酶。
根据本发明,甘露糖基(α-1,6-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶(MGAT2;GnT-II;EC 2.4.1.143)将N-乙酰基-D-葡萄糖胺自UDP-GlcNAc转移至末端甘露糖,末端甘露糖经由α1-6糖苷键连接至另一糖部分或聚糖。通过MGATII转移的GlcNAc与α6甘露糖的键为β1-2糖苷键。已发现MGAT2普遍在真核生物中表达,因为其在高基体中是复杂的N-聚糖生物合成所必需的酶。
在一些实施例中,包含具有式(2)的聚糖的糖蛋白与β-N-乙酰葡萄糖胺酶之间的反应是在哺乳动物细胞培养物中进行。在哺乳动物细胞培养物中,在适于表达糖蛋白和β-N-乙酰葡萄糖胺酶的条件下将哺乳动物细胞系培育在培养基中,所述哺乳动物细胞系包含:编码包含具有式(2)的聚糖的糖蛋白的第一聚核苷酸和编码β-N-乙酰葡萄糖胺酶的第二聚核苷酸。哺乳动物宿主细胞系的实例包括经SV40转形的猴肾CV1株(COS-7)、人类胚肾株(293或293T细胞)、幼仓鼠肾细胞(baby hamster kidney cell,BHK)、小鼠塞特利氏细胞(mouse sertoli cell)(TM4细胞)、猴肾细胞(CV1)、非洲绿猴肾细胞(VERO-76)、人类宫颈癌细胞(HELA)、犬肾细胞(MDCK)、水牛鼠肝细胞(BRL 3A)、人类肺细胞(W138)、人类肝细胞(Hep G2)、小鼠乳房肿瘤细胞(MMT 060562)、TRI细胞、MRC 5细胞、FS4细胞、中国仓鼠卵巢(Chinese hamster ovary,CHO)细胞和骨髓瘤细胞系,如YO、NS0、P3X63和Sp2/0。
在本发明的一些实施例中,糖蛋白为抗体或其片段。抗体或其片段可为来自裂解抗体的抗体Fab片段、F(ab')2、Fv片段或Fc片段、scFv-Fc片段、微型抗体、双功能抗体或scFv。在一个优选实施例中,抗体为贺癌平、曲妥珠单抗或抗TMCC3抗体。
在本发明的一个实施例中,当R为叠氮基(正常名称是这样吗?)且偶联剂为炔基时,偶联剂-连接基团-酬载与-GlcNAc-(CH2)0-8-R基团经由点击反应而反应形成-GlcNAc-(CH2)0-8-连接基团-酬载(应用化学国际版(Angewandte Chemie InternationalEdition.)40(11):2004-2021;和澳大利亚化学杂志(Australian Journal ofChemistry.)60(6):384-395)。在另一实施例中,当R为酮基或醛且偶联剂为氨基时,偶联剂-连接基团-酬载与-GlcNAc-(CH2)0-8-R基团经由还原胺化而反应形成-GlcNAc-(CH2)0-8-连接基团-酬载(有机化学杂志(J.Org.Chem.),2010,75,5470-5477;和合成(Synthesis),2011,490-496)。在另一实施例中,当R为酮基或醛且偶联剂为β-芳基乙氨基时,偶联剂-连接基团-酬载与-GlcNAc-(CH2)0-8-R基团经由皮克特-施彭格勒反应(Pictet-Spenglerreaction)而反应形成-GlcNAc-(CH2)0-8-连接基团-酬载(生物结合物化学(BioconjugateChem.),2013,24(6),第846-851页)。
在一些实施例中,当使用糖蛋白-酬载偶联物来治疗个体的疾病时,酬载可为治疗剂。治疗剂可为细胞抑制剂或细胞毒性剂或带有相应放射性同位素的同位素螯合剂。细胞抑制剂或细胞毒性剂的实例包括(但不限于)抗代谢物(例如氟尿嘧啶(5-FU)、氟尿苷(5-FUdR)、甲氨喋呤(methotrexate)、甲酰四氢叶酸、羟基尿素、硫鸟嘌呤(6-TG)、巯嘌呤(6-MP)、阿糖胞苷、喷司他汀(pentostatin)、氟达拉滨磷酸盐(fludarabine phosphate)、克拉屈滨(cladribine)(2-CDA)、天冬酰氨酸酶、吉西他滨(gemcitabine)、卡培他滨(capecitibine)、硫唑嘌呤(azathioprine)、胞嘧啶甲氨喋呤、甲氧苄啶(trimethoprim)、乙胺嘧啶(pyrimethamine)或培美曲塞(pemetrexed));烷基化剂(例如美法仑(cmelphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulfan)、噻替派(thiotepa)、异环磷酰胺(ifosfamide)、卡莫司汀(carmustine)、洛莫司汀(lomustine)、司莫司汀(semustine)、链脲佐菌素(streptozocin)、达喀尔巴嗪(dacarbazine)、丝裂霉素C(mitomycin C)、环磷酰胺(cyclophosphamide)、甲基二(氯乙基)胺(mechlorethamine)、乌拉莫司汀(uramustine)、二溴甘露醇(dibromomannitol)、四硝酸酯(tetranitrate)、丙卡巴肼(procarbazine)、六甲蜜胺(altretamine)、米托唑胺(mitozolomide)或替莫唑胺(temozolomide));类烷基化剂(例如顺铂(cisplatin)、卡铂(carboplatin)、奈达铂(nedaplatin)、奥沙利铂(oxaliplatin)、沙铂(satraplatin)或三铂(triplatin));DNA小沟烷基化剂(例如倍癌霉素(duocarmycin),如CC-1065,和其任何类似物或衍生物;吡咯并苯并二氮呯(pyrrolobenzodiazapene)或其任何类似物或衍生物);蒽环霉素(anthracycline)(例如道诺霉素(daunorubicin)、小红莓(doxorubicin)、表柔比星(epirubicin)、埃达霉素(idarubicin)或戊柔比星(valrubicin));抗生素(例如放线菌素D(dactinomycin)、博莱霉素(bleomycin)、光辉霉素(mithramycin)、安曲霉素(anthramycin)、链佐霉素(streptozotocin)、短杆菌素D(gramicidin D)、丝裂霉素(mitomycin)(例如丝裂霉素C));卡奇霉素(calicheamicin);抗有丝分裂剂(包括例如类美登素(maytansinoid)(如DM1、DM3和DM4)、奥瑞他汀(包括例如单甲基奥瑞他汀E(MMAE)和单甲基奥瑞他汀F(MMAF))、尾海兔素(dolastatin)、念珠藻素(cryptophycin)、长春花属生物碱(vinca alkaloid)(例如长春新碱(vincristine)、长春碱(vinblastine)、长春地辛(vindesine)、长春瑞滨(vinorelbine))、紫杉烷(taxane)(例如太平洋紫杉醇(paclitaxel)、多西他赛(docetaxel)或新颖紫杉烷)、特吡莱辛(tubulysin)和秋水仙碱(colchicine));拓朴异构酶抑制剂(topoisomerase inhibitor)(例如,伊立替康(irinotecan)、拓朴替康(topotecan)、喜树碱(camptothecin)、依托泊苷(etoposide)、替尼泊甙(teniposide)、安吖啶(amsacrine)或米托蒽醌(mitoxantrone));HDAC抑制剂(例如,伏立诺他(vorinostat)、罗米地辛(romidepsin)、西达本胺(chidamide)、帕比司他(panobinostat)或贝林诺他(belinostat));蛋白酶体抑制剂(例如,肽基酸);以及放射性同位素,如At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212或213、P32和Lu的放射性同位素,包括Lu177。同位素螯合剂的实例包括(但不限于)乙二胺四乙酸(ethylenediaminetetraaceticacid,EDTA)、二亚乙基三胺-N,N,N',N",N"-五乙酸酯(DTPA)、1,4,7,10-四氮杂环十二烷-N,N',N",N"'-四乙酸酯(DOTA)、1,4,7,10-四(2-羟丙基)-1,4,7,10-四氮杂环十二烷(THP)、三亚乙基四胺-N,N,N',N",N"',N"'-六乙酸酯(TTHA)、1,4,7,10-四氮杂环十二烷-N,N',N",N"'-四(亚甲基膦酸酯)(DOTP)和巯基乙酰基三甘胺酸(MAG3)。
在一些实施例中,当使用糖蛋白-酬载偶联物进行检测时,酬载可为标记。标记包括(但不限于)直接被检测的标记或部分(如荧光标记、发色标记、电子致密标记、化学发光标记和放射性标记),以及例如经由酶促反应或分子相互作用间接被检测的部分,如酶或配体。例示性标记包括(但不限于)放射性同位素P32、C14、I125、H3和I131;荧光团,如稀土螯合物或荧光素(fluorescein)和其衍生物、若丹明(rhodamine)和其衍生物、丹磺酰基(dansyl)、伞酮(umbelliferone);荧光素酶,例如萤火虫荧光素酶和细菌荧光素酶;荧光素(luciferin);2,3-二氢酞嗪二酮;辣根过氧化酶(horseradish peroxidase,HRP);碱性磷酸酶;β-半乳糖苷酶;葡萄糖淀粉酶;溶菌酶;糖氧化酶,例如葡萄糖氧化酶、半乳糖氧化酶和葡萄糖-6-磷酸去氢酶;杂环氧化酶,如尿酸酶和黄嘌呤氧化酶,其与采用过氧化氢来氧化染料前体的酶(如HRP、乳过氧化酶或微过氧化酶)偶合;生物素/抗生物素蛋白;自旋标记;噬菌体标记;稳定自由基和类似标记。在另一实施例中,标记为正电子发射体。正电子发射体包括(但不限于)Ga68、F18、Cu64、Y86、Br76、Zr89和I124。
在一些实施例中,连接基团具有能够与糖蛋白上所存在的亲电子基团反应的官能团。此类亲电子基团的实例包括(但不限于)醛和酮羰基。在一些实施例中,连接基团的反应性官能团的杂原子可与糖蛋白上的亲电子基团反应且与糖蛋白单元形成共价键。此类反应性官能团的非限制性实例包括(但不限于)酰肼、肟、胺基、肼、硫缩胺脲(thiosemicarbazone)、肼羧酸酯和芳基酰肼。
在一些实施例中,偶联剂具有能够与糖蛋白上所存在的亲电子基团反应的官能团。此类亲电子基团的实例包括(但不限于)叠氮基、醛和酮基。在一些实施例中,偶联剂的反应性官能团的杂原子可与糖蛋白上的亲电子基团反应且与糖蛋白单元形成共价键。此类反应性官能团的非限制性实例包括(但不限于)炔烃、二苯并环辛炔、酰肼、肟、胺基、肼、硫缩胺脲、肼羧酸酯和芳基酰肼。
在一些实施例中,连接基团具有能够连接偶联剂和酬载的官能团。此类连接基团的实例包括(但不限于)不可裂解的连接基团和可裂解的连接基团。在一些实施例中,不可裂解的连接基团包括(但不限于)具有2至20个碳原子的直链或分支链烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、烷氧基、酰基、烷基氨基或芳基氨基。在一些实施例中,可裂解的连接基团包括(但不限于)含有双硫键的连接基团、酸不稳定连接基团、光不稳定连接基团、肽酶不稳定连接基团和酯酶不稳定连接基团。
呈现以下实例来说明本发明的某些实施例,但不应将所述实例理解为限制本发明的范围。本发明的范围包括如图1中所示自三甘露糖基核心抗体产生具有一种或两种酬载的均质ADC的一步法或依序法。
实例1.通过使用β1,4-半乳糖苷酶和神经氨糖酸苷酶来制备贺癌平抗体
为了自贺癌平抗体(罗氏公司(Roche Inc))去除N-聚糖的半乳糖和唾液酸部分,将10mg贺癌平抗体在37℃下用20μl β1,4-半乳糖苷酶(NEB,P0745L,8单位/μl)和5μlα2-3,6,8神经氨糖酸苷酶(NEB,P0720L,50单位/μl)在1×糖缓冲剂(GlycoBuffer)1(NEB,总体积1ml)中处理24小时。进一步向反应物添加10μl β1,4-半乳糖苷酶(NEB,P0745L,8单位/μl)且使反应在37℃下再进行24小时以获得G0F/G0抗体样品。通过使用rProtein A SepharoseFast Flow(通用电气医疗集团(GE Healthcare),17-1279-02)纯化抗体样品。在纯化之后,对抗体样品进行折合质量色谱分析。图2中所示的结果揭示,样品中主要量的抗体为G0F(具有分子量50,600Da的重链)且仅少量为G0(无海藻糖;具有分子量50,451Da的重链)。
实例2.贺癌平转化成三甘露糖基核心抗体
将来自实例1的10mg G0F/G0贺癌平抗体在37℃下用20μlβ-N-乙酰葡萄糖胺酶S(NEB,P0744L,4单位/μl)在1×糖缓冲剂1(NEB,总体积1ml)中处理24小时。向反应物添加10μl β-N-乙酰葡萄糖胺酶S(NEB,P0744L,4单位/μl)且使反应在37℃下继续再进行24小时以获得经消化的抗体样品。通过使用rProtein A Sepharose Fast Flow(通用电气医疗集团,17-1279-02)纯化经消化的抗体样品。在纯化之后,对抗体样品进行折合质量色谱分析。图3中所示的结果揭示,获得了具有分子量50,194Da的重链的三甘露糖基核心贺癌平抗体且几乎所有的G0F和G0贺癌平抗体皆被转化为三甘露糖基核心抗体。这说明β-N-乙酰葡萄糖胺酶S能够以高效率将G0F和G0抗体转化为具有三甘露糖基核心的抗体。
实例3.通过甘露糖基(α-1,3-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶(MGAT-1;GnT-1)使GlcNAc与α-3甘露糖在三甘露糖基核心贺癌平抗体的各重链的一个臂中偶联
将来自实例2的三甘露糖基核心贺癌平抗体(40μg)与UDP-GlcNAc(最终浓度2.5mM)(Sigma,U4375)在80μl 1×缓冲剂SP(25mM 4-吗啉乙磺酸(MES),10mM MnCl2,pH6.5)中在MGAT-1(0.15μg;R&D,8334-GT)存在下在37℃下培育16小时。对产物进行折合质量色谱分析。如图4中所示的结果,相比于具有分子量50,195Da的重链的三甘露糖基核心贺癌平抗体,获得了重链另外含有一个GlcNAc(分子量203Da)且分子量为50,398Da的抗体产物。这证明MGAT-1仅将一个N-乙酰葡萄糖胺转移至其底物蛋白。
实例4.通过MGAT-1和甘露糖基(α-1,6-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶(MGAT-2;GnT-2)将三甘露糖基核心贺癌平抗体转化为G0F/G0贺癌平
将来自实例2的三甘露糖基核心贺癌平抗体(40μg)和UDP-GlcNAc(最终浓度2.5mM)(Sigma,U4375)在80μl 1×缓冲剂SP(25mM MES,10mM MnCl2,pH 6.5)中在MGAT-1(0.15μg)和MGAT-2(0.1μg)存在下在37℃下培育16小时。在培育之后,对反应产物进行折合质量色谱分析。如图5中所示的结果,相比于具有分子量50,194Da的重链的三甘露糖基核心贺癌平抗体,获得了带有少量G0的G0F抗体产物,其重链另外含有两个GlcNAc(分子量203Da×2)且分子量为50,600Da。这些结果指示,通过组合MGAT-1、MGAT-2和N-乙酰葡萄糖胺,可将三甘露糖基核心抗体转为G0/G0F抗体。
实例5.三甘露糖基核心贺癌平抗体并非MGAT-2的底物
MGAT-2仅在三甘露糖基核心已具有连接至α(1,3)甘露糖的GlcNAc糖时才将GlcNAc糖自UDP-GlcNAc转移至三甘露糖基核心的α(1,6)甘露糖。换句话说,如果没有GlcNAc糖连接至三甘露糖基核心的α(1,3)甘露糖,那么MGAT-2将不能把GlcNAc糖转移至α(1,3)甘露糖或α(1,6)甘露糖。为了确认以上观察结果,将来自实例2的三甘露糖基核心贺癌平抗体(40μg)与UDP-GlcNAc(2.5mM)在80μl 1×缓冲剂SP(25mM MES,10mM MnCl2,pH6.5)中在MGAT-2(0.1μg)存在下在37℃下培育16小时。对产物进行折合质量色谱分析。在质谱中,三甘露糖基核心抗体的分子量无显著变化(数据未示出)。此结果表明,三甘露糖基核心并非MGAT-2的底物,且MGAT-2需要MGAT-1的转化产物来产生G0F/G0型抗体。
实例6.通过MGAT-1使GlcNAz与三甘露糖基核心贺癌平抗体的各重链的一个臂的末端α-3甘露糖偶联
将来自实例2的三甘露糖基核心贺癌平抗体(40μg)与UDP-GlcNAz(1mM)(R&D,ES104-100)在80μl 1×缓冲剂SP(20mM Tris,10mM MnCl2,pH 6.5)中在MGAT-1(0.25μg;R&D,8334-GT)存在下在37℃下培育16小时。对产物进行折合质量色谱分析。如图6中所示的结果,相比于具有分子量50,195Da的重链的三甘露糖基核心贺癌平抗体,获得了重链另外含有一个GlcNAz(分子量244Da)且分子量为50,438Da的抗体产物。此结果表明,UDP-GlcNAz为MGAT-1的底物之一,且GlcNAz可经由MGAT-1连接至三甘露糖基核心贺癌平抗体的各重链的臂中的α-3甘露糖,形成三甘露糖基贺癌平-2GlcNAz抗体。
实例7.通过MGAT-1和MGAT-2使UDP-GlcNAz与三甘露糖基核心贺癌平抗体偶联产生三甘露糖基贺癌平-4GlcNAz
将来自实例2的三甘露糖基核心贺癌平抗体(2mg)与UDP-GlcNAz(1mM)在800μl1×缓冲剂SP(25mM MES,10mM MnCl2,pH 6.5)中在兔MGAT-1(25μg)和大鼠MGAT-2(10μg)存在下在37℃下培育16小时。在培育之后,对反应产物分别进行折合质量色谱分析和完整质量色谱分析。如图7A中所示的折合质量色谱结果,相比于具有分子量50,194Da的重链的三甘露糖基核心贺癌平抗体,获得了三甘露糖基贺癌平-4GlcNAz抗体产物,其中重链含有两个GlcNAz分子(分子量244Da×2=488)且各重链的分子量为50,680Da。此结果表明,GlcNAz经由MGAT-1和MGAT-2与三甘露糖基核心贺癌平抗体的各重链的α-3甘露糖和α-6甘露糖偶联。通过完整质量色谱进一步确认此结果。如图7B中所示的结果,相比于分子量147,237Da的全三甘露糖基核心贺癌平抗体,获得了G0F三甘露糖贺癌平-4GlcNAz抗体产物,其含有四个GlcNAz分子(分子量244Da×4=976Da)且分子量为148,213Da。我们的结果进一步证明,UDP-GlcNAz为MGAT-1和MGAT-2的底物之一,且我们能够成功地以我们的一步法假设来合成中间物四叠氮基抗体。
实例8.三甘露糖基核心贺癌平抗体并非MGAT-2与GlcNAz偶联的底物
将来自实例2的三甘露糖基核心贺癌平抗体(40μg)与UDP-GlcNAz(1mM)(R&DES104-100)在80μl 1×缓冲剂SP(25mM MES,10mM MnCl2,pH 6.5)中在大鼠MGAT-2(0.25μg)存在下在37℃下培育16小时。对产物进行折合质量色谱分析。图8显示,在质谱中,三甘露糖基核心抗体的分子量无显著变化,且表明因为实例5,所以三甘露糖基抗体并非MGAT-2的底物。
实例9.三甘露糖基贺癌平-4GlcNAz抗体与DBCO-(PEG)4-DM1偶联产生具有DAR4的贺癌平ADC
在实例7中,产生在4个末端甘露糖处各自附接4个GlcNAz中的一个的三甘露糖基抗体。为完成本发明的一步法假设,使用DBCO-(PEG)4-DM1将毒性酬载偶合至三甘露糖基贺癌平-4GlcNAz,产生具有DAR4的ADC。在25℃下向含有自实例7获得的5mg/mL三甘露糖基-4GlcNAz贺癌平抗体的50μL缓冲剂(25mM MES;pH 6.5)慢慢添加5μL DBCO-(PEG)4-DM1(10mM,于DMSO中)以进行点击化学反应过夜。在反应之后,经由Amicon Ultra-15离心过滤装置纯化抗体产物,获得三甘露糖基贺癌平-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC。对产物进行折合质量色谱分析。图9A中的结果公开,相比于具有4个GlcNAz的亲本三甘露糖基抗体,反应产物三甘露糖基贺癌平-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)的重链的分子量为53,509Da,此意谓已有两个DBCO-(PEG)4-DM1分子(分子量1,413Da×2=2,826)与抗体的各重链偶联。通过完整质量色谱分析进一步确认此结果。图9B中的结果公开,相比于分子量约148,224Da的三甘露糖基贺癌平-4GlcNAz抗体,获得了三甘露糖基贺癌平-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC产物,其含有四个DBCO-(PEG)4-DM1分子(分子量1,413Da×4=5,652Da)且分子量为153,876Da。实例7和9的结果指示,通过直接组合MGAT-1、MGAT-2和GlcNAz反应与DBCO-(PEG)4-DM1点击化学反应,由三甘露糖基抗体产生了ADC-4DM1产物。因此,我们成功使得本发明中我们的用于产生ADC的一步法假设合理化。
实例10.通过DBCO-(PEG)4-DM1使第一酬载与三甘露糖基贺癌平-2GlcNAz的重链的各臂中的末端GlcNAz偶联
实例4至9证明了本发明中用于产生ADC的一步法产生具有均质DAR 4的位点特异性ADC的可行性。在这些成功结果的基础上进行研究来证明图1中所示的依序法。为合成第一中间产物,使用DBCO-(PEG)4-DM1来偶合酬载,从而连接反应物抗体的重链的各末端GlcNAz。向含有自实例6获得的2mg/mL三甘露糖基贺癌平-2GlcNAz抗体的350μL缓冲剂(25mM MES;pH 6.5)慢慢添加14μL DBCO-(PEG)4-DM1(10mM,于DMSO中)。将反应混合物在氩气下在25℃下搅拌过夜以进行点击化学反应。在反应之后,经由Amicon Ultra-15离心过滤装置过滤抗体产物,获得三甘露糖基贺癌平-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)中间物。对产物进行折合质量色谱分析。如图10中所示的结果,相比于三甘露糖基贺癌平-2GlcNAz抗体,分子量51,852Da的三甘露糖基贺癌平-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)中间物的重链的一个臂含有额外一个分子量1414Da的DBCO-(PEG)4-DM1分子。
实例11.通过MGAT-2使第二GlcNAz与三甘露糖基贺癌平-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC的重链的各臂中的末端α-6甘露糖偶联
将自实例10获得的三甘露糖基贺癌平-2GlcNAz-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)和UDP-GlcNAz(1mM)(R&D ES104-100)在500μl 1×缓冲剂(25mM MES,10mM MnCl2,pH6.5)中在大鼠MGAT-2(15μg)存在下在37℃下培育16小时。在反应之后,经由Amicon Ultra-15离心过滤装置过滤抗体产物,获得三甘露糖基贺癌平-2GlcNAz-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)。对产物进行折合质量色谱分析。如图11中所示的结果,相比于亲本三甘露糖基贺癌平-2(GlcNAc-三唑-DBCO-(PEG)4-DM1),三甘露糖基贺癌平-2GlcNAz-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)的重链各自含有额外一个GlcNAz分子(MW=244),分子量为52,097Da。此结果指示MGAT-2为一种底物非常灵活的酶且将UDP-GlcNAz转化为大官能团抗体,例如三甘露糖基贺癌平-2(GlcNAc-三唑-DBCO-(PEG)4-DM1),产生用于双重酬载ADC产物的中间物。
实例12.构筑抗体的各臂上具有一个MMAE和一个DM1的DAR4ADC贺癌平产物
在实例11中,产生三甘露糖基贺癌平-2GlcNAz-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)中间物。为完成图1中所示的本发明依序法,使用DBCO-(PEG)12-MMAE将毒性酬载偶合至三甘露糖基贺癌平-2GlcNAz 2(GlcNAc-三唑-DBCO-(PEG)4-DM1)且产生具有DAR4和两种酬载的ADC。
向含有自实例11获得的2.5mg/mL三甘露糖基贺癌平-2GlcNAz-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC的76μL 1×缓冲剂(25mM MES,pH 6.5)慢慢添加3.8μL DBCO-(PEG)12-MMAE(10mM,于DMSO中)。将反应混合物在氩气下在25℃下搅拌过夜以进行点击化学反应。在反应之后,经由Amicon Ultra-15离心过滤装置过滤抗体产物,获得三甘露糖基贺癌平-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)-2(GlcNAc-三唑-DBCO-(PEG)12-MMAE)ADC。在纯化之后,随后对产物进行完整质量色谱分析。如图12中所示的结果,相比于分子量151,050kD的亲本三甘露糖基贺癌平-2GlcNAz-2(GlcNAc-三唑-DBCO-(PEG)4-DM1),所获得的三甘露糖基贺癌平-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)-2(GlcNAc-三唑-DBCO-(PEG)12-MMAE)ADC含有额外两个DBCO-(PEG)12-MMAE分子(MW=1648×2=3,296)且分子量为154,345Da。此结果表明,本发明方法可精确控制两个不同酬载(例如DBCO-PEG4-DM1和DBCO-(PEG)12-MMAE)与三甘露糖基贺癌平的偶联。
实例13.构筑抗体的各臂上具有一个MMAF和一个DM1的DAR4ADC贺癌平产物
向含有自实例11获得的2.5mg/mL三甘露糖基贺癌平-2GlcNAz-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC的76μL 1×缓冲剂(25mM MES,pH 6.5)慢慢添加3.8μL DBCO-MMAF(10mM,于DMSO中)。将反应混合物在氩气下在25℃下搅拌过夜以进行点击化学反应。在反应之后,经由Amicon Ultra-15离心过滤装置过滤抗体产物,获得三甘露糖基贺癌平-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)-2(GlcNAc-三唑-DBCO-MMAF)ADC。对产物进行完整质量色谱分析。如图13中所示的结果,相比于亲本三甘露糖基贺癌平-2GlcNAz-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC(MW=151,050),所获得的三甘露糖基贺癌平-2(GlcNAc-三唑-DBCO-(PEG)4-DM1)-2(GlcNAc-三唑-DBCO-MMAF)ADC含有额外两个分子量2,038Da的DBCO-MMAF分子且分子量为153,082Da。此结果表明,本发明方法可精确控制不同种的酬载(例如DBCO-(PEG)4-DM1、DBCO-(PEG)12-MMAE和DBCO-MMAF)与三甘露糖基贺癌平的偶联。
总而言之,通过组合MGAT-1、MGAT-2和GlcNAz酶促反应与DBCO-酬载化学反应,我们使得我们的本发明假设合理化。我们能够用我们的一步法产生具有DAR4或DAR2的均质位点特异性ADC产物。另一方面,本发明还适用于通过依序法合成具有两种酬载的均质位点特异性ADC产物。
实例14.三甘露糖基贺癌平-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)的结合亲和力分析
通过以上所述的方法构筑三甘露糖基贺癌平-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC。自(Roche Inc)购得针对Her2/Neu分子的Kadcyla。向NUNC Maxisorp培养板的各孔添加ERBB2-ECD(ebioscience BMS362)(100ng/孔)且将培养板搁置一旁,在4℃下过夜。用1×PBS-T(0.1%)洗涤培养板以去除未涂布的试剂。向培养板的孔添加3%脱脂奶,且将培养板搁置一旁,在室温下历时2小时。将培养板用1×PBS-T(0.1%)洗涤3次,使其干燥,且随后储存于-20℃下供进一步使用。向培养板添加连续稀释度自1×10-6g/mL至1×10-12g/mL的个别抗体,且将培养板在37℃下培育1小时。添加与辣根过氧化酶(HRP)偶联的山羊抗人类IgG,培育1小时,且随后添加3,3',5,5'-四甲基联苯胺(TMB)。读取OD405以计算活性。每个研究重复三次,且数据呈现为平均值±SD。使用Prism软件,使用OD读数和抗体浓度制成多散布图。图14中所示的结果公开,三甘露糖基贺癌平-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC的曲线与阳性对照Kadcyla和三甘露糖基贺癌平-4GlcNAz的曲线几乎相同。阴性对照抗mesothelien显示与Her2/Neu分子无结合亲和力。此结果表明,三甘露糖基贺癌平-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC与Her2/Neu分子的结合亲和力不受所进行的修饰的影响。
实例15.三甘露糖基贺癌平-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC的细胞毒性作用
将Her2/Neu高表达细胞系SK-BR-3、Her2/Neu中等表达细胞系HCC-1954和Her2/Neu低表达细胞系MDA-MB-231稀释至106个细胞/ml。在向96孔板的孔添加100μL经稀释的细胞培养物之后,将细胞在37℃下培育24小时。向各孔添加80μl完全培养基,且随后以不同剂量向不同孔添加20μl三甘露糖基贺癌平-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC。在将培养板在37℃下培育48小时之后,向各孔中添加100μl 试剂。在室温下再培育10分钟之后,用亮度计测量孔的发光(光)。三甘露糖基贺癌平-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC对Her2/Neu高表达细胞系SK-BR-3和Her2/Neu中等表达细胞系HCC-1954的IC50值分别为4.7nM和14nM。IC50值还显示,所有测试抗体对Her2/Neu低表达细胞系MDA-MB-231均无抗增殖作用。此结果表明,就Kadcyla而言,三甘露糖基贺癌平-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC不仅对Her2/Neu高表达细胞有细胞毒性,对Her2/Neu中等表达细胞也有细胞毒性,且三甘露糖基ADC平台对抗体的修饰不影响其生物活性。
实例16.由F293细胞产生三甘露糖基核心曲妥珠单抗抗体和三甘露糖基核心抗TMC33抗体
构筑含有编码β-N-乙酰葡萄糖胺酶S的cDNA的质体pTCAE8.3-exo-Gal且将其共转染至两个F293细胞系中以分别表达三甘露糖基曲妥珠单抗(抗Her2抗体)和三甘露糖基抗跨膜和卷曲螺旋域家族3(TMCC3)抗体。在培育之后,收集两个细胞培养物的上清液且通过使用rProtein A Sepharose Fast Flow(通用电气医疗集团,17-1279-02)分别纯化其中所含的抗体。在纯化之后,对经纯化的抗体样品进行折合质量色谱分析。图15A中所示的结果公开,当与自仅转染曲妥珠单抗基因的F293细胞分离的抗体进行比较时,自同样转染β-N-乙酰葡萄糖胺酶S和曲妥珠单抗基因的相同细胞获得的曲妥珠单抗抗体的重链显示分子量50,195Da的峰,其指示所得曲妥珠单抗抗体为三甘露糖基核心抗体。在转染抗TMCC3抗体基因的相同细胞中见到类似结果(图15B)。结果表明,自商业细胞系大量生产三甘露糖基抗体为可行的且适用于工业CMC扩增。
实例17.通过MGAT-1和MGAT-2使UDP-GlcNAz与细胞表达的三甘露糖基核心曲妥珠单抗抗体偶联产生三甘露糖基贺癌平-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC
根据实例7中所述的方法,将自实例16获得的2mg三甘露糖基核心曲妥珠单抗抗体(由哺乳动物细胞产生)和UDP-GlcNAz(1mM)在800μl 1×缓冲剂SP(25mM MES,10mM MnCl2,pH 6.5)中在兔MGAT-1(25μg)和大鼠MGAT-2(10μg)存在下在37℃下培育16小时。在培育之后,对反应产物进行折合质量色谱分析和完整质量色谱分析。如图16A中所示的折合质量色谱结果,相比于具有分子量50,194Da的重链的三甘露糖基核心曲妥珠单抗抗体,获得了三甘露糖基曲妥珠单抗-4GlcNAz抗体产物,其中重链含有另外两个分子量约244Da×2=488的GlcNAz分子且各重链的分子量为约50,680Da。此结果表明,GlcNAz可经由MGAT-1和MGAT-2与由哺乳动物细胞产生的三甘露糖基核心曲妥珠单抗抗体的各重链的α-3甘露糖和α-6甘露糖偶联。
根据实例9中所述的方法,在25℃下向含有以上所获得的三甘露糖基曲妥珠单抗-4GlcNAz抗体的Tris缓冲剂(pH 7.0)慢慢添加DBCO-(PEG)4-DM1以进行点击化学反应历时16小时。在反应和纯化之后,对产物进行折合质量色谱分析和完整质量色谱分析。图16B中的折合质量色谱分析结果公开,产物重链的分子量为53,509Da,这暗示着两个DBCO-(PEG)4-DM1分子(分子量1,413Da×2=2,826)已与三甘露糖基曲妥珠单抗-4GlcNAz抗体的重链偶联。由图16C中的完整质量色谱分析结果进一步确认此结果。此结果公开,获得了三甘露糖基-4(GlcNAc-三唑-DBCO-(PEG)4-DM1)ADC产物,其含有四个DBCO-(PEG)4-DM1分子(分子量1,413Da×4=5,652Da)且分子量为约153,868Da。
预期所属领域的技术人员能想到如上述例示性实例中所阐述的本发明的诸多修改和变更。因此,本发明应仅受随附权利要求书限制。
Claims (32)
1.一种用于制备包含式(1)的结构的糖蛋白-酬载偶联物的方法,
所述方法包含以下步骤:
(i)使包含具有式(2)的聚糖的糖蛋白
与β-N-乙酰葡萄糖胺酶反应,产生包含式(3)的三甘露糖基核心的经修饰糖蛋白
(ii)使包含式(3)的三甘露糖基核心的经修饰糖蛋白与UDP-GlcNAc-(CH2)0-8-R在甘露糖基(α-1,3-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶和甘露糖基(α-1,6-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶存在下反应,其中R为叠氮基、酮基或醛,使得两个GlcNAc-(CH2)0-8-R糖分别键结至Man2和Man3各自的β-1,2位置,且借此形成式(4)的聚糖部分
以及
(iii)使两个偶联剂-连接基团-酬载与式(4)的聚糖部分反应,其中所述两个偶联剂-连接基团-酬载的所述酬载相同或不同,产生包含式(1)的结构的糖蛋白-酬载偶联物。
2.根据权利要求1所述的方法,其中步骤(i)中的所述包含具有式(2)的聚糖的糖蛋白和所述β-N-乙酰葡萄糖胺酶是由哺乳动物细胞系产生。
3.根据权利要求2所述的方法,所述哺乳动物细胞系为经SV40转形的猴肾CV1株(COS-7)、人类胚肾株(293或293T细胞)、幼仓鼠肾细胞(baby hamster kidney cell,BHK)、小鼠塞特利氏细胞(mouse sertoli cell)(TM4细胞)、猴肾细胞(CV1)、非洲绿猴肾细胞(VERO-76)、人类宫颈癌细胞(HELA)、犬肾细胞(MDCK)、水牛鼠肝细胞(BRL 3A)、人类肺细胞(W138)、人类肝细胞(Hep G2)、小鼠乳房肿瘤细胞(MMT 060562)、TRI细胞、MRC 5细胞、FS4细胞、中国仓鼠卵巢(Chinese hamster ovary,CHO)细胞或骨髓瘤细胞系。
4.根据权利要求1所述的方法,其中所述糖蛋白为抗体或其片段,例如来自裂解抗体的抗体Fab片段、F(ab')2、Fv片段或Fc片段、scFv-Fc片段、微型抗体、双功能抗体或scFv。
5.根据权利要求1所述的方法,其中R为叠氮基,所述偶联剂为炔基,且步骤(iii)中进行的反应为点击反应(click reaction)。
6.根据权利要求1所述的方法,其中R为酮基或醛,所述偶联剂为氨基,且步骤(iii)中进行的反应为还原胺化。
7.根据权利要求1所述的方法,其中R为酮基或醛,所述偶联剂为β-芳基乙氨基,且步骤(iii)中进行的反应为皮克特-施彭格勒反应(Pictet-Spengler reaction)。
8.根据权利要求1所述的方法,其中所述连接基团为选自具有2至20个碳原子的直链或分支链烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、烷氧基、酰基、烷基氨基或芳基氨基、含有双硫键的连接基团、酸不稳定连接基团、光不稳定连接基团、肽酶不稳定连接基团和酯酶不稳定连接基团。
9.根据权利要求1所述的方法,其中所述酬载独立地选自治疗剂和标记。
10.根据权利要求9所述的方法,其中所述治疗剂选自抗代谢物、烷基化剂、类烷基化剂、DNA小沟烷基化剂、蒽环霉素(anthracycline)、抗生素、卡奇霉素(calicheamicin)、抗有丝分裂剂、拓朴异构酶抑制剂(topoisomerase inhibitor)、蛋白酶体抑制剂和放射性同位素。
11.根据权利要求9所述的方法,其中所述标记为荧光标记、发色标记、电子致密标记、化学发光标记、放射性标记、酶标记或正电子发射体。
12.一种糖蛋白-酬载偶联物,其包含如权利要求1中所定义的式(1)的结构。
13.一种用于制造包含式(5)的结构的糖蛋白-酬载偶联物的方法,
所述方法包含以下步骤:
(i)使包含如权利要求1中所定义的式(3)的三甘露糖基核心的经修饰糖蛋白与UDP-GlcNAc-(CH2)0-8-R在甘露糖基(α-1,3-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶存在下反应,其中R为叠氮基、酮基或醛,使得GlcNAc-(CH2)0-8-R糖键结至Man2的β-1,2位置,且借此形成包含式(6)的聚糖部分的糖蛋白
以及
(ii)使偶联剂-连接基团-酬载与包含式(6)的聚糖部分的糖蛋白反应,产生包含式(5)的结构的糖蛋白-酬载偶联物。
14.根据权利要求13所述的方法,其中所述糖蛋白为抗体或其片段,例如来自裂解抗体的抗体Fab片段、F(ab')2、Fv片段或Fc片段、scFv-Fc片段、微型抗体、双功能抗体或scFv。
15.根据权利要求13所述的方法,其中R为叠氮基,所述偶联剂为炔基,且步骤(ii)中进行的反应为点击反应。
16.根据权利要求13所述的方法,其中R为酮基或醛,所述偶联剂为氨基,且步骤(ii)中进行的反应为还原胺化。
17.根据权利要求13所述的方法,其中R为酮基或醛,所述偶联剂为β-芳基乙氨基,且步骤(ii)中进行的反应为皮克特-施彭格勒反应。
18.根据权利要求13所述的方法,其中所述连接基团选自具有2至20个碳原子的直链或分支链烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、烷氧基、酰基、烷基氨基或芳基氨基、含有双硫键的连接基团、酸不稳定连接基团、光不稳定连接基团、肽酶不稳定连接基团和酯酶不稳定连接基团。
19.根据权利要求13所述的方法,其中所述酬载为治疗剂或标记。
20.根据权利要求19所述的方法,其中所述治疗剂选自抗代谢物、烷基化剂、类烷基化剂、DNA小沟烷基化剂、蒽环霉素、抗生素、卡奇霉素、抗有丝分裂剂、拓朴异构酶抑制剂、蛋白酶体抑制剂和放射性同位素。
21.根据权利要求19所述的方法,其中所述标记为荧光标记、发色标记、电子致密标记、化学发光标记、放射性标记、酶标记或正电子发射体。
22.一种糖蛋白-酬载偶联物,其包含如权利要求13中所定义的式(5)的结构。
23.一种用于制造包含式(7)的结构的糖蛋白-酬载A/B偶联物的方法,
所述方法包含以下步骤:
(i)使包含如权利要求1中所定义的式(3)的三甘露糖基核心的经修饰糖蛋白与UDP-GlcNAc-(CH2)0-8-R在甘露糖基(α-1,3-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶存在下反应,其中R为叠氮基、酮基或醛,使得GlcNAc-(CH2)0-8-R糖键结至Man2的β-1,2位置,且借此形成包含如权利要求13中所定义的式(6)的聚糖部分的糖蛋白;
(ii)使偶联剂-连接基团-酬载A与包含式(6)的聚糖部分的糖蛋白反应,产生包含式(8)的结构的糖蛋白-酬载A偶联物
(iii)使包含式(8)的结构的糖蛋白-酬载A偶联物与UDP-GlcNAc-(CH2)0-8-R在甘露糖基(α-1,6-)-糖蛋白β-1,2-N-乙酰葡萄糖氨基转移酶存在下反应,其中R为叠氮基、酮基或醛,使得GlcNAc-(CH2)0-8-R糖键结至Man3的β-1,2位置,且借此形成包含具有式(9)的聚糖-酬载A部分的糖蛋白
以及
(iv)使偶联剂-连接基团-酬载B与包含具有式(9)的聚糖-酬载A部分的糖蛋白反应,产生包含式(7)的结构的糖蛋白-酬载A/B偶联物,
其中所述酬载A与所述酬载B相同或不同。
24.根据权利要求23所述的方法,其中所述糖蛋白为抗体或其片段,例如来自裂解抗体的抗体Fab片段、F(ab')2、Fv片段或Fc片段、scFv-Fc片段、微型抗体、双功能抗体或scFv。
25.根据权利要求23所述的方法,其中R为叠氮基,所述偶联剂为炔基,且步骤(ii)/(iv)中进行的反应为点击反应。
26.根据权利要求23所述的方法,其中R为酮基或醛,所述偶联剂为胺基,且步骤(ii)/(iv)中进行的反应为还原胺化。
27.根据权利要求23所述的方法,其中R为酮基或醛,所述偶联剂为β-芳基乙胺基,且步骤(ii)/(iv)中进行的反应为皮克特-施彭格勒反应。
28.根据权利要求23所述的方法,其中所述连接基团选自具有2至20个碳原子的直链或分支链烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、烷氧基、酰基、烷基氨基或芳基氨基、含有双硫键的连接基团、酸不稳定连接基团、光不稳定连接基团、肽酶不稳定连接基团和酯酶不稳定连接基团。
29.根据权利要求23所述的方法,其中所述酬载A和所述酬载B独立地选自治疗剂和标记。
30.根据权利要求29所述的方法,其中所述治疗剂选自抗代谢物、烷基化剂、类烷基化剂、DNA小沟烷基化剂、蒽环霉素、抗生素、卡奇霉素、抗有丝分裂剂、拓朴异构酶抑制剂、蛋白酶体抑制剂和放射性同位素。
31.根据权利要求29所述的方法,其中所述标记为荧光标记、发色标记、电子致密标记、化学发光标记、放射性标记、酶标记或正电子发射体。
32.一种糖蛋白-酬载A/B偶联物,其包含如权利要求23中所定义的式(7)的结构。
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