CN109310781B - 具有ksp抑制剂和抗-cd123-抗体的特异性抗体-药物-缀合物(adc) - Google Patents
具有ksp抑制剂和抗-cd123-抗体的特异性抗体-药物-缀合物(adc) Download PDFInfo
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Abstract
本发明涉及具有KSP抑制剂和抗‑CD123抗体的特异性抗体‑药物‑缀合物(ADC),这些缀合物用于治疗和/或预防疾病的用途,以及这些缀合物用于制备药物的用途,所述药物用于治疗/或预防疾病,特别是过度增殖和/或血管生成病症,例如癌症疾病。这些治疗可以作为单一疗法进行,或者与其他药物或其他治疗措施组合进行。
Description
简介和现有技术
本发明涉及具有KSP(纺锤体驱动蛋白)抑制剂和抗-CD123-抗体的特异性抗体-药物-缀合物(ADC),涉及这些缀合物用于治疗和/或预防疾病的用途,以及这些缀合物用于制备治疗和/或预防疾病(特别是过度增殖和/或血管生成病症,例如癌症疾病)的药物的用途。这些治疗可以作为单一疗法进行,或者与其他药物或其他治疗措施组合进行。
癌症疾病是最多样化组织不受控制的细胞生长的结果。在许多情况下,新细胞渗透到现有组织中(侵入性生长),或者它们转移到远端器官中。癌症疾病发生在最多样化的器官中,并且通常具有疾病的组织特异性病程。因此,术语癌症作为通用术语描述了一大组的各种器官、组织和细胞类型的确定疾病。
可以通过手术和放射治疗措施去除早期肿瘤。通常,转移性肿瘤只能通过化疗药物进行姑息性治疗。这里的目标是实现改善生活质量和延长寿命的最佳组合。
结合蛋白和抗体与一种或多种活性化合物分子的缀合物是已知的,特别是以抗体药物缀合物(ADC)的形式,其中针对肿瘤相关抗原的内化抗体通过接头与细胞毒性剂共价连接。在将ADC引入肿瘤细胞并随后使缀合物解离后,细胞毒性剂本身或由其形成的细胞毒性代谢物在肿瘤细胞内释放,并可直接和选择性地在其中展开其作用。与常规化学疗法相比,通过这种方式,将对正常组织的损伤控制在明显更窄的范围内[参见,例如,J.M.Lambert,Curr.Opin.Pharmacol.5,543-549(2005);A.M.Wu和P.D.Senter,Nat.Biotechnol.23,1137-1146(2005);P.D.Senter,Curr.Opin.Chem.Biol.13,235-244(2009);L.Ducry和B.Stump,Bioconjugate Chem.21,5-13(2010)]。因此,WO2012/171020描述了其中多个毒性基团分子通过聚合物接头与抗体连接的ADC。作为可能的毒性基团,WO2012/171020尤其提到了物质SB743921、SB715992(伊斯平斯(Ispinesib))、MK-0371、AZD8477、AZ3146和ARRY-520等。
最后提到的物质是纺锤体驱动蛋白抑制剂。纺锤体驱动蛋白(KSP,也称为Eg5、HsEg5、KNSL1或KIF11)是驱动蛋白样的运动蛋白(motorprotein),其对于双极有丝***纺锤体起作用是必需的。KSP的抑制导致有丝***停滞,并且在相对长的时间内导致细胞凋亡(Tao等人,Cancer Cell 2005Jul 8(1),39-59)。在发现第一种细胞穿透性KSP抑制剂Monastrol后,KSP抑制剂本身已成为一类新型化疗药物(Mayer等人,Science 286:971-974,1999),并且它们是许多专利申请的主题(例如WO2006/044825;WO2006/002236;WO2005/051922;WO2006/060737;WO03/060064;WO03/040979和WO03/049527)。然而,由于KSP仅在有丝***期的相对短的时间段内展开其作用,KSP抑制剂必须在这些初始阶段期间以足够高的浓度存在。
在WO2015/096982和WO2014/151030中,抗体药物缀合物(ADC)被描述为纺锤体驱动蛋白抑制剂。
CD123是IL-3受体的α链,且也称为IL3R-α。已知CD123在原发性AML样品上表达,并且已报道在许多恶性细胞上表达。优选的抗-CD123抗体衍生自Sun等人(Sun等人,1996,Blood 87(1):83-92)和Kuo等人(Kuo等人,2009,Bioconjug Chem.20(10):1975-82)公开的抗体。
即使考虑几种已知的抗体-药物-缀合物,仍然存在对新化合物的高需求,所述新化合物增加活性化合物的可用性,与现有技术的化合物相比,所述活性化合物显示出可接受的或甚至更好的性质。
发明概述
在此背景下,本发明的一个目的是提供一些物质,所述物质在以相对低的浓度施用后,发挥凋亡作用并因此可有益于癌症治疗。
现在令人惊讶地发现,具有本文所述的选定药物部分以及本文所述的选定抗体的抗体-药物-缀合物显示出可接受的和显著更好的性质。
这里特别优选的是细胞外癌症靶分子CD123(IL-3Rα)。这种细胞外癌症靶分子也称为IL3RA(白细胞介素3受体亚基α),且具有NCBI基因ID:3563。
对于靶分子CD123,已经发现了提供非常有效和持久的体内抗肿瘤功效的抗体-药物-缀合物。已经发现了针对CD123的其他抗体-药物-缀合物,所述缀合物诱导长期肿瘤抑制,如直到出现肿瘤再生长的时间段所示。
为了实现该目的,本发明进一步提供人源化抗-CD123抗体,所述抗体另外是种系化的,这意味着与人种系的抗体序列相比,它们具有非常小的偏差。特别优选的抗体称为“TPP-8987”,“TPP-9476”,“TPP-8988”和“TPP-9342”。
现在令人惊讶地发现,如下式(I)中定义的抗体(AK)或其功能片段与一种或多种化合物的缀合物显示出优于已知的缀合物:
其中
X是-CH2-或-CH2-CH2-,
L是(-CH2-CH2-O-)m-CH2-CH2-,
m是1-20,
n是1-8,且
AK是抗-CD123抗体或其功能片段,其中所述抗体或其功能片段通过半胱氨酸残基连接,并且所述抗体或其功能片段包含:
可变重链,其包含如SEQ ID NO:122中所示的重链可变CDR1序列,如SEQ ID NO:123中所示的重链可变CDR2序列,和如SEQ ID NO:124中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:126中所示的轻链可变CDR1序列,如SEQ ID NO:127中所示的轻链可变CDR2序列,和如SEQ ID NO:128中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:202中所示的重链可变CDR1序列,如SEQ ID NO:203中所示的重链可变CDR2序列,和如SEQ ID NO:204中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:206中所示的轻链可变CDR1序列,如SEQ ID NO:207中所示的轻链可变CDR2序列,和如SEQ ID NO:208中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:132中所示的重链可变CDR1序列,如SEQ ID NO:133中所示的重链可变CDR2序列,和如SEQ ID NO:134中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:136中所示的轻链可变CDR1序列,如SEQ ID NO:137中所示的轻链可变CDR2序列,和如SEQ ID NO:138中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:192中所示的重链可变CDR1序列,如SEQ ID NO:193中所示的重链可变CDR2序列,和如SEQ ID NO:194中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:196中所示的轻链可变CDR1序列,如SEQ ID NO:197中所示的轻链可变CDR2序列,和如SEQ ID NO:198中所示的轻链可变CDR3序列,
及其盐、溶剂化物、溶剂化物的盐和差向异构体。
附图描述
图1:序列方案。
图2:注释的抗体序列。对于每种抗体或抗体片段,突出显示CDR区(HCDR1、HCDR2、HCDR3、LCDR1、LCDR2、LCDR3)和可变区(VH,VL)。
发明详述和具体实施方式
特别优选的通式(I)化合物是那些化合物,其中:
X是-CH2-,
L是(-CH2-CH2-O-)m-CH2-CH2-,
m是1-20,
n是1-8,且
AK是抗-CD123抗体或其功能片段,其中所述抗体或其功能片段通过半胱氨酸残基连接,并且所述抗体或其功能片段包含:
可变重链,其包含如SEQ ID NO:122中所示的重链可变CDR1序列,如SEQ ID NO:123中所示的重链可变CDR2序列,和如SEQ ID NO:124中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:126中所示的轻链可变CDR1序列,如SEQ ID NO:127中所示的轻链可变CDR2序列,和如SEQ ID NO:128中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:202中所示的重链可变CDR1序列,如SEQ ID NO:203中所示的重链可变CDR2序列,和如SEQ ID NO:204中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:206中所示的轻链可变CDR1序列,如SEQ ID NO:207中所示的轻链可变CDR2序列,和如SEQ ID NO:208中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:132中所示的重链可变CDR1序列,如SEQ ID NO:133中所示的重链可变CDR2序列,和如SEQ ID NO:134中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:136中所示的轻链可变CDR1序列,如SEQ ID NO:137中所示的轻链可变CDR2序列,和如SEQ ID NO:138中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:192中所示的重链可变CDR1序列,如SEQ ID NO:193中所示的重链可变CDR2序列,和如SEQ ID NO:194中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:196中所示的轻链可变CDR1序列,如SEQ ID NO:197中所示的轻链可变CDR2序列,和如SEQ ID NO:198中所示的轻链可变CDR3序列,
及其盐、溶剂化物、溶剂化物的盐和差向异构体。
特别优选的通式(I)化合物是那些化合物,其中:
X是-CH2-,
L是(-CH2-CH2-O-)m-CH2-CH2-,
m是1-20,
n是1-8,且
AK是抗-CD123抗体TPP-8987、TPP-9476、TPP-8988或TPP-9342或其功能片段,其中所述抗体或其功能片段通过半胱氨酸残基连接,及其盐、溶剂化物、溶剂化物的盐和差向异构体。
更特别优选的通式(I)化合物是那些化合物,其中:
X是-CH2-,
L是(-CH2-CH2-O-)m-CH2-CH2-,
m是2-8,
n是1-8,且
AK是抗-CD123抗体或其功能片段,其中所述抗体或其功能片段通过半胱氨酸残基连接,并且所述抗体或其功能片段包含:
可变重链,其包含如SEQ ID NO:122中所示的重链可变CDR1序列,如SEQ ID NO:123中所示的重链可变CDR2序列,和如SEQ ID NO:124中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:126中所示的轻链可变CDR1序列,如SEQ ID NO:127中所示的轻链可变CDR2序列,和如SEQ ID NO:128中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:202中所示的重链可变CDR1序列,如SEQ ID NO:203中所示的重链可变CDR2序列,和如SEQ ID NO:204中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:206中所示的轻链可变CDR1序列,如SEQ ID NO:207中所示的轻链可变CDR2序列,和如SEQ ID NO:208中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:132中所示的重链可变CDR1序列,如SEQ ID NO:133中所示的重链可变CDR2序列,和如SEQ ID NO:134中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:136中所示的轻链可变CDR1序列,如SEQ ID NO:137中所示的轻链可变CDR2序列,和如SEQ ID NO:138中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:192中所示的重链可变CDR1序列,如SEQ ID NO:193中所示的重链可变CDR2序列,和如SEQ ID NO:194中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:196中所示的轻链可变CDR1序列,如SEQ ID NO:197中所示的轻链可变CDR2序列,和如SEQ ID NO:198中所示的轻链可变CDR3序列,
及其盐、溶剂化物、溶剂化物的盐和差向异构体。
更特别优选的通式(I)化合物是那些化合物,其中:
X是-CH2-,
L是(-CH2-CH2-O-)m-CH2-CH2-,
m是2-8,
n是1-8,且
AK是抗-CD123抗体TPP-8987,TPP-9476,TPP-8988或TPP-9342或其功能片段,其中所述抗体或其功能片段通过半胱氨酸连接,
及其盐、溶剂化物、溶剂化物的盐和差向异构体。
更特别优选的通式(I)化合物是:
并且其中
n是1-8,且
AK是抗-CD123抗体或其功能片段,其中所述抗体或其功能片段通过半胱氨酸残基连接,并且所述抗体或其功能片段包含:
可变重链,其包含如SEQ ID NO:122中所示的重链可变CDR1序列,如SEQ ID NO:123中所示的重链可变CDR2序列,和如SEQ ID NO:124中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:126中所示的轻链可变CDR1序列,如SEQ ID NO:127中所示的轻链可变CDR2序列,和如SEQ ID NO:128中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:202中所示的重链可变CDR1序列,如SEQ ID NO:203中所示的重链可变CDR2序列,和如SEQ ID NO:204中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:206中所示的轻链可变CDR1序列,如SEQ ID NO:207中所示的轻链可变CDR2序列,和如SEQ ID NO:208中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:132中所示的重链可变CDR1序列,如SEQ ID NO:133中所示的重链可变CDR2序列,和如SEQ ID NO:134中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:136中所示的轻链可变CDR1序列,如SEQ ID NO:137中所示的轻链可变CDR2序列,和如SEQ ID NO:138中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:192中所示的重链可变CDR1序列,如SEQ ID NO:193中所示的重链可变CDR2序列,和如SEQ ID NO:194中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:196中所示的轻链可变CDR1序列,如SEQ ID NO:197中所示的轻链可变CDR2序列,和如SEQ ID NO:198中所示的轻链可变CDR3序列。
最优选的通式(I)化合物是:
并且其中
n是1-8,且
AK是抗-CD123抗体TPP-8987,TPP-9476,TPP-8988或TPP-9342或其功能片段,其中所述抗体或其功能片段通过半胱氨酸残基连接。
抗-CD123抗体的进一步描述
文献公开了有机分子与抗体的共价偶联(缀合)的各种选择。根据本发明优选的是通过抗体的半胱氨酸残基的一个或多个硫原子和/或通过抗体的赖氨酸残基的一个或多个NH基团将毒性基团与抗体缀合。然而,也可以通过抗体的游离羧基或通过抗体的糖残基将毒性基团与抗体结合。
抗体可以通过键连接到接头。抗体的连接可以通过结合剂的杂原子。根据本发明的可用于连接的抗体的杂原子是硫(在一个实施方案中通过抗体的巯基)、氧(根据本发明通过抗体的羧基或羟基)和氮(在一个实施方案中,通过抗体的伯胺或仲胺基团或酰胺基团)。这些杂原子可以存在于天然抗体中或通过化学方法或分子生物学方法引入。根据本发明,抗体与毒性基团的连接对抗体相对于靶分子的结合活性仅具有较小的影响。在优选的实施方案中,连接对抗体相对于靶分子的结合活性没有影响。
根据本发明,术语“抗体”应以其最广泛的含义理解,并且包括免疫球蛋白分子,例如完整或修饰的单克隆抗体,多克隆抗体或多特异性抗体(例如双特异性抗体)。免疫球蛋白分子优选包含具有四条多肽链(两条重链(H链)和两条轻链(L链))的分子,这些链通常通过二硫桥连接。每条重链包含重链的可变结构域(缩写为VH)和重链的恒定结构域。重链的恒定结构域可以例如包含三个结构域CH1、CH2和CH3。每条轻链包含可变结构域(缩写为VL)和恒定结构域。轻链的恒定结构域包含结构域(缩写为CL)。VH和VL结构域可以进一步细分为具有高可变性的区域(也称为互补决定区(缩写为CDR))和具有低序列可变性的区域(框架区,缩写为FR)。通常,每个VH和VL区由三个CDR和多达四个FR组成。例如,从氨基末端到羧基末端,顺序如下:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。抗体可以从任何合适的物种获得,例如兔、美洲驼、骆驼、小鼠或大鼠。在一个实施方案中,抗体是人或鼠来源的。抗体可以是例如人、人源化或嵌合的。
术语“单克隆”抗体是指从基本上同质的抗体群体获得的抗体,即除了天然存在的突变之外,群体的个体抗体是相同的(其中可能存在少量的天然突变)。单克隆抗体以高特异性识别单个抗原结合位点。术语单克隆抗体不是指特定的制备方法。
术语“完整”抗体是指包含轻链和重链的抗原结合结构域和恒定结构域二者的抗体。恒定结构域可以是天然存在的结构域或其具有许多修饰的氨基酸位置的变体。
术语“修饰的完整”抗体是指通过其氨基末端或羧基末端,借助于共价键(例如肽键)与不源自抗体的其他多肽或蛋白质融合的完整抗体。此外,可以修饰抗体,使得在限定的位置引入反应性半胱氨酸以促进与毒性基团的偶联(参见Junutula等人,Nat Biotechnol.2008,26(8):925-32)。
术语“人”抗体是指可以从人获得的抗体或者是合成的人抗体的抗体。“合成的”人抗体是基于人抗体序列的分析,可部分或完全通过计算机从合成序列获得的抗体。人抗体可以例如通过从人源抗体序列的文库中分离的核酸编码。这种抗体的实例可见于等人,Nature Biotech.2000,18:853-856。
术语“人源化”或“嵌合”抗体描述了由序列的非人和人部分组成的抗体。在这些抗体中,人免疫球蛋白(受体)的部分序列被非人免疫球蛋白(供体)的序列部分取代。在许多情况下,供体是鼠免疫球蛋白。在人源化抗体的情况下,受体CDR的氨基酸被供体的氨基酸取代。有时,框架的氨基酸也被供体的相应氨基酸取代。在一些情况下,人源化抗体含有既不存在于受体中也不存在于供体中的氨基酸,其在抗体优化期间被引入。在嵌合抗体的情况下,供体免疫球蛋白的可变结构域与人抗体的恒定区融合。
如本文所用的术语互补决定区(CDR)是指与抗原结合所需的可变抗体结构域的那些氨基酸。通常,每个可变区具有三个CDR区,称为CDR1、CDR2和CDR3。每个CDR区可以包含根据Kabat定义的氨基酸和/或根据Chotia定义的高变环的氨基酸。根据Kabat的定义包括,例如,来自可变轻链的约氨基酸位置24-34(CDR1)、50-56(CDR2)和89-97(CDR3),和可变重链的31-35(CDR1)、50-65(CDR2)和95-102(CDR3)的区域(Kabat等人,Sequences of Proteinsof Immunological Interest,第五版,Public Health Service,National Institutes ofHealth,Bethesda,MD.(1991))。根据Chotia的定义包括,例如,来自可变轻链的约氨基酸位置26-32(CDR1)、50-52(CDR2)和91-96(CDR3),和可变重链的26-32(CDR1)、53-55(CDR2)和96-101(CDR3)的区域(Chothia和Lesk;J Mol Biol 196:901-917(1987))。在一些情况下,CDR可包含来自根据Kabat和Chotia定义的CDR区的氨基酸。
取决于重链恒定结构域的氨基酸序列,抗体可以分为不同的类别。有五种主要类型的完整抗体:IgA、IgD、IgE、IgG和IgM,并且其中的一些可以分为进一步的亚类(同种型),例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。对应于不同的类型的重链恒定结构域被称为[alpha/α]、[delta/δ]、[epsilon/ε]、[gamma/γ]和[my/μ]。抗体的三维结构和亚基结构都是已知的。
术语抗体/免疫球蛋白的“功能片段”或“抗原结合抗体片段”定义为抗体/免疫球蛋白的片段(例如IgG的可变结构域),其仍包含抗体/免疫球蛋白的抗原结合结构域。抗体的“抗原结合结构域”通常包含抗体的一个或多个高可变区,例如CDR、CDR2和/或CDR3区。然而,抗体的“框架”或“骨架”区也可在抗体与抗原结合期间发挥作用。框架区形成CDR的骨架。优选地,抗原结合结构域至少包含可变轻链的氨基酸4至103和可变重链的氨基酸5至109,更优选可变轻链的氨基酸3至107和可变重链的4至111,特别优选完整的可变轻链和重链,即VL的氨基酸1-109和VH的1-113(根据WO97/08320编号)。
非决定性地,本发明的“功能片段”或“抗原结合抗体片段”包括Fab、Fab'、F(ab')2和Fv片段、双抗体、单结构域抗体(DAb)、线性抗体、抗体的单个链(单链Fv,缩写为scFv);以及多特异性抗体,例如双和三特异性抗体,例如从抗体片段形成(C.A.K Borrebaeck编辑,(1995)Antibody Engineering(Breakthroughs in Molecular Biology),OxfordUniversity Press;R.Kontermann&S.Duebel编辑,(2001)Antibody Engineering(Springer Laboratory Manual),Springer Verlag)。除“多特异性”或“多功能”抗体之外的抗体是具有相同结合位点的那些抗体。多特异性抗体可以对抗原的不同表位具有特异性,或者可以对多于一种的抗原的表位具有特异性(参见,例如,WO 93/17715;WO 92/08802;WO 91/00360;WO 92/05793;Tutt等人,1991,J.Immunol.147:60 69;美国专利号4,474,893;4,7 14,68 1;4,925,648;5,573,920;5,601,8 19;或Kostelny等人,1992,J.Immunol.148:1547 1553)。可以构建F(ab')2或Fab分子,使得可以减少在Ch1和CL结构域之间发生分子间二硫化物相互作用的数量或完全防止在Ch1和CL结构域之间发生分子间二硫化物相互作用。
“表位”是指能够特异性结合免疫球蛋白或T细胞受体的蛋白质决定簇。表位决定簇通常由分子的化学活性表面基团组成,例如氨基酸或糖侧链或其组合,并且通常具有特定的三维结构特性以及特定的电荷特性。
“功能片段”或“抗原结合抗体片段”可以通过其氨基末端或羧基末端,借助于共价键(例如肽键)与不源自抗体的另一多肽或蛋白质融合。此外,可以通过在限定的位置引入反应性半胱氨酸来修饰抗体和抗原结合片段,以促进与毒性基团的偶联(参见Junutula等人,Nat Biotechnol.2008Aug;26(8):925-32)。
多克隆抗体可通过本领域普通技术人员已知的方法制备。单克隆抗体可通过本领域普通技术人员已知的方法制备(和Milstein,Nature,256,495-497,1975)。人和人源化单克隆抗体可以通过本领域普通技术人员已知的方法制备(Olsson等人,MethEnzymol.92,3-16或Cabilly等人,US 4,816,567或Boss等人,US 4,816,397)。
本领域普通技术人员知道制备人抗体及其片段的多种方法,例如,通过转基因小鼠(N Lonberg和D Huszar,Int Rev Immunol.1995;13(1):65-93)或噬菌体展示技术(Clackson等人,Nature.1991Aug 15;352(6336):624-8)。本发明的抗体可以从重组抗体文库中获得,所述重组抗体文库由例如由大量健康志愿者汇集的多种抗体的氨基酸序列组成。抗体也可以通过已知的重组DNA技术产生。抗体的核酸序列可以通过常规测序获得,或者可从公众可获得的数据库获得。
“分离的”抗体或结合剂已经被纯化以除去细胞的其他成分。可能干扰诊断或治疗用途的细胞污染成分是例如酶,激素或细胞的其他肽或非肽成分。优选的抗体或结合剂是相对于抗体或结合剂,已经纯化至超过95重量%的抗体或结合剂(例如通过Lowry方法,UV-Vis光谱法或通过SDS毛细管凝胶电泳测定)。此外,抗体已经纯化到可以确定氨基末端或内部氨基酸序列的至少15个氨基酸的程度,或已经纯化至同质性,在还原或非还原条件下通过SDS-PAGE确定同质性(检测可以通过考马斯蓝染色或优选通过银染色来确定)。然而,通常通过一个或多个纯化步骤制备抗体。
术语“特异性结合”或“特异地结合”是指结合预定抗原/靶分子的抗体或结合剂。抗体或结合剂的特异性结合通常描述具有至少10-7M的亲和力的抗体或结合剂(作为Kd值; 即优选具有小于10-7M的Kd值的那些),其中抗体或结合剂对于预定抗原/靶分子的亲和力是对于不是预定抗原/靶分子或紧密相关的抗原/靶分子的非特异性抗原/靶分子(例如牛血清白蛋白或酪蛋白)的至少两倍。抗体优选具有至少10-7M的亲和力(作为Kd值;换句话说,优选具有小于10-7M的Kd值的那些),优选至少10-8M,更优选10-9M至10-11M范围的亲和力。Kd值可以例如通过表面等离子体共振光谱法测定。
本发明的抗体-药物缀合物同样显示出在这些范围内的亲和力。亲和力优选基本上不受药物缀合的影响(通常,亲和力降低小于一个数量级,换句话说,例如,最多为10-8M至10-7M)。
优选地,根据本发明使用的抗体值得注意的还在于高选择性。当本发明的抗体显示出对靶蛋白的亲和力是对独立的其它抗原(例如,人血清白蛋白)的亲和力的至少2倍,优选5倍或更优选10倍时,存在高选择性(亲和力可以通过例如表面等离子体共振光谱法测定)。
此外,使用的本发明的抗体优选是交叉反应性的。为了能够促进和更好地解释临床前研究,例如毒理学或活性研究(例如在异种移植小鼠中),如果根据本发明使用的抗体不仅结合人靶蛋白而且还结合用于研究的物种中的物种靶蛋白,则是有利的。在一个实施方案中,除人靶蛋白外,根据本发明使用的抗体与至少一种其他物种的靶蛋白交叉反应。对于毒理学和活性研究,优选使用啮齿动物、狗和非人灵长类动物家族的物种。优选的啮齿动物物种是小鼠和大鼠。优选的非人灵长类动物是恒河猴、黑猩猩和长尾猕猴。
在一个实施方案中,除人靶蛋白外,根据本发明使用的抗体与选自小鼠、大鼠和长尾猕猴(食蟹猴(Macaca fascicularis))物种的至少一种其他物种的靶蛋白交叉反应。特别优选的是根据本发明使用的抗体,其除人靶蛋白外,至少与小鼠靶蛋白交叉反应。优选的是交叉反应性抗体,其对其他非人物种的靶蛋白的亲和力与对人靶蛋白的亲和力相差不超过50倍,更特别地不超过10倍。
针对癌症靶分子的抗体
结合剂(例如抗体或其抗原结合片段)所针对的靶分子优选是癌症靶分子。术语“癌症靶分子”描述了一种靶分子,其在一种或多种癌细胞类型上存在的丰度高于在相同组织类型的非癌细胞。优选地,与相同组织类型的非癌细胞相比,癌症靶分子选择性地存在于一种或多种癌细胞类型上,其中“选择性地”描述与相同组织类型的非癌细胞相比,在癌细胞上至少两倍的富集(“选择性癌症靶分子”)。癌症靶分子的使用允许使用根据本发明的缀合物选择性治疗癌细胞。
在此特别优选的是细胞外癌症靶分子IL-3Rα,即CD123(SEQ ID NO:221)。这种细胞外癌症靶分子也称为IL3RA(白细胞介素3受体亚基α),且具有NCBI基因ID:3563。
功能性白细胞介素3受体是异二聚体,其包含特异性α链(IL-3Rα,CD123)和“通用”IL-3受体β链(βC,CD131),该β链与粒细胞巨噬细胞集落刺激因子(GM-CSF)和白细胞介素5(IL-5)的受体共享。
IL-3Rα,即CD123,是1型跨膜蛋白,具有约41kDa的计算分子量。CD123包含参与IL-3结合的细胞外结构域、跨膜结构域和约50个氨基酸的短细胞质末端。细胞外结构域由两个区域组成:约100个氨基酸的N-末端区域,其与GM-CSF和IL-5受体α链的等同区域具有序列相似性,以及邻近跨膜结构域的区域,该区域包含四个保守的半胱氨酸残基和在细胞因子受体家族中常见的WSXWS基序。
IL-3结合结构域包含约200个氨基酸残基的细胞因子受体基序(CRM),其由两个折叠为Ig样的结构域构成。IL-3Rα的细胞外结构域,即CD123,是高度糖基化的,N-糖基化是配体结合和受体信号转导所必需的。
IL-3Rα,即CD123,在整个造血***中广泛表达,例如在造血前体细胞、肥大细胞、红系细胞、巨核细胞、中性粒细胞、嗜碱性粒细胞和嗜酸性粒细胞、单核细胞/巨噬细胞和CD5+B淋巴细胞上;CD123也在非造血细胞上表达,例如树突细胞、Leydig细胞、内皮细胞和基质细胞。
IL-3Rα,即CD123,也由参与某些疾病的细胞表达;这些疾病包括:骨髓增生异常综合征,白血病(如急性髓性白血病(AML)),淋巴瘤,过敏和自身免疫性病症,如狼疮或硬皮病。
由于这些关系,抗IL-3Rα,抗CD123抗体可以作为裸抗体或偶联抗体(例如ADC)用于治疗。
本发明涉及与特异性结合IL-3Rα,CD123(SEQ ID NO:221)的抗体偶联的化合物。
术语“抗-CD123抗体”涉及特异性地,优选以足以用于诊断和/或治疗应用的亲和力结合癌症靶分子CD123(IL-3Rα,SEQ ID NO:221)的抗体。在一个实施方案中,抗-CD123抗体与CD123不相关的蛋白质的结合小于所述抗体与CD123结合的10%,例如通过表面等离子体共振光谱法测定。在某些实施方案中,所述抗体以≤1μM,≤100nM,≤10nM,≤1nM,≤0.1nM,≤0.01nM,或≤0.001nM的解离常数(KD)结合CD123(IL-3Rα,SEQ ID NO:221)。在某些实施方案中,抗-CD123抗体结合在不同物种之间保守的表位。
结合癌症靶分子的抗体可由本领域普通技术人员使用已知方法制备,例如化学合成或重组表达。用于癌症靶分子的结合剂可以商业获得,或者可以由本领域普通技术人员使用已知方法制备,例如化学合成或重组表达。制备抗体或抗原结合抗体片段的其他方法描述于WO 2007/070538(参见第22页“抗体”)中。本领域技术人员知道如何编制诸如噬菌体展示文库(例如Morphosys HuCAL Gold)的方法,并将其用于发现抗体或抗原结合抗体片段(参见WO 2007/070538,第24页及以后各页和第70页AK实施例1,第72页AK实施例2)。使用来自B细胞的DNA文库制备抗体的其他方法描述于例如第26页(WO 2007/070538)。用于人源化抗体的方法描述于WO2007070538的第30-32页,并且详述于Queen等人,Pros.Natl.Acad.Sci.USA 86:10029-10033,1989或WO 90/0786中。此外,本领域技术人员已知用于一般蛋白质且特别是抗体的重组表达的方法(参见,例如,Berger和Kimrnel(Guide to Molecular Cloning Techniques,Methods in Enzymology,Vo1.152,AcademicPress,Inc.);Sambrook等人,(Molecular Cloning:A Laboratory Manual,(第二版,ColdSpring Harbor Laboratory Press;Cold Spring Harbor,N.Y.;1989)Vol.1-3);CurrentProtocols in Molecular Biology,(F.M.Ausabel等人编辑,Current Protocols,GreenPublishing Associates,Inc./John Wiley&Sons,Inc.);Harlow等人,(MonoclonalAntibodies:A Laboratory Manual,Cold Spring Harbor Laboratory Press(19881,Paul[Ed.]);Fundamental Immunology,(Lippincott Williams&Wilkins(1998));和Harlow等人,(Using Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory Press(1998))。本领域技术人员知道蛋白质/抗体表达所必需的相应载体、启动子和信号肽。常见的方法也在WO 2007/070538第41-45页中描述。制备IgG1抗体的方法描述于例如WO 2007/070538的第74页及以后各页的实施例6中。允许在抗体结合抗原后确定抗体内化的方法是本领域技术人员已知的,并且描述于例如WO 2007/070538第80页。本领域技术人员能够使用WO 2007/070538中描述的方法,其已经用于制备碳酸酐酶IX(Mn)抗体,类似地用于制备具有不同靶分子特异性的抗体。
抗-CD123抗体
根据本发明,使用抗-CD123抗体或其抗原结合片段,优选选自下述那些或通过合适的突变修饰的那些。此外,本领域技术人员熟悉与CD123结合的抗体。
Sun等人(Sun等人,1996,Blood 87(1):83-92)描述了单克隆抗体7G3的产生和性质,其结合IL-3Rα,即CD123的N-末端结构域。美国专利号6,177,078(Lopez)涉及抗-CD123抗体7G3。该抗体的嵌合变体(CSL360)描述于WO2009/070844中,并且人源化形式(CSL362)描述于WO2012/021934中。EP2426148中公开了7G3抗体的序列。
该7G3序列代表人源化和种系化抗体TPP-8987和TPP-9476的起始点。
在细胞表面抗原结合后特别良好地内化的抗体是Kuo等人公开的抗-CD123抗体12F1(Kuo等人,2009,Bioconjug Chem.20(10):1975-82)。抗体12F1以比抗体7G3更高的亲和力结合CD123,并且在细胞表面抗原结合后,内化明显快于7G3。基于12F1的双特异性scFv免疫融合蛋白公开于WO2013/173820中。
该12F1序列代表人源化和种系化抗体TPP-8988和TPP-9342的起始点。
本发明特别涉及具有衍生自小鼠来源的抗体7G3(Sun等人,1996,Blood 87(1):83-92)和12F1(Kuo等人,2009,Bioconjug Chem.20(10):1975-82)的抗体或其抗原结合抗体片段或其变体的缀合物,或具有衍生自小鼠来源的抗体12F1(Kuo等人,2009,BioconjugChem.20(10):1975-82)的抗体或其抗原结合抗体片段或其变体的缀合物。
抗-CD123抗体的产生
基于7G3的可变区(VH和VL)的序列的公开(EP2426148),通过人框架区中的CDR移植和随后的种系优化获得以下抗体序列:TPP-8987和TPP-9476。
基于12F1的可变区(VH和VL)的序列的公开(WO2013/173820),通过人框架区中的CDR移植和随后的种系优化获得以下抗体:TPP-8988和TPP-9342。
抗-CD123抗体的具体实施方案
在本申请中,参考以下优选的本发明的抗-CD123抗体,如下表所示:“TPP-8987”,“TPP-9476”,“TPP-8988”和“TPP-9342”。
TPP-8987和TPP-9476是抗体7G3的人源化和种系化变体。
TPP-8988和TPP-9342是抗体12F1的人源化和种系化变体。
如实施例中所示,本发明的另一个目的是提供7G3和12F1的抗体,其是人源化的并且非常接近人抗体种系序列(种系化)。因此,抗体TPP-8987,TPP-9476,TPP-8988和TPP-9342是本发明的进一步的实施方案。这些抗体的序列如下表所示:
表:用于ADC的优选抗-CD123抗体的表:
对ADC特别优选的是称为“TPP-8987”,“TPP-9476”,“TPP-8988”和“TPP-9342”的抗-CD123抗体。
TPP-8987是抗-CD123抗体,其包含可变重链和可变轻链,所述可变重链包含如SEQID NO:122中所示的重链可变CDR1序列,如SEQ ID NO:123中所示的重链可变CDR2序列,和如SEQ ID NO:124中所示的重链可变CDR3序列,且所述可变轻链包含如SEQ ID NO:126中所示的轻链可变CDR1序列,如SEQ ID NO:127中所示的轻链可变CDR2序列,和如SEQ ID NO:128中所示的轻链可变CDR3序列。
TPP-9476是抗-CD123抗体,其包含可变重链和可变轻链,所述可变重链包含如SEQID NO:202中所示的重链可变CDR1序列,如SEQ ID NO:203中所示的重链可变CDR2序列,和如SEQ ID NO:204中所示的重链可变CDR3序列,且所述可变轻链包含如SEQ ID NO:206中所示的轻链可变CDR1序列,如SEQ ID NO:207中所示的轻链可变CDR2序列,和如SEQ ID NO:208中所示的轻链可变CDR3序列。
TPP-8988是抗-CD123抗体,其包含可变重链和可变轻链,所述可变重链包含如SEQID NO:132中所示的重链可变CDR1序列,如SEQ ID NO:133中所示的重链可变CDR2序列,和如SEQ ID NO:134中所示的重链可变CDR3序列,且所述可变轻链包含如SEQ ID NO:136中所示的轻链可变CDR1序列,如SEQ ID NO:137中所示的轻链可变CDR2序列,和如SEQ ID NO:138中所示的轻链可变CDR3序列。
TPP-9342是抗-CD123抗体,其包含可变重链和可变轻链,所述可变重链包含如SEQID NO:192中所示的重链可变CDR1序列,如SEQ ID NO:193中所示的重链可变CDR2序列,和如SEQ ID NO:194中所示的重链可变CDR3序列,且所述可变轻链包含如SEQ ID NO:196中所示的轻链可变CDR1序列,如SEQ ID NO:197中所示的轻链可变CDR2序列,和如SEQ ID NO:198中所示的轻链可变CDR3序列。
TPP-8987是抗-CD123抗体,其优选包含对应于SEQ ID NO:121的重链可变区和对应于SEQ ID NO:125的轻链可变区。
TPP-9476是抗-CD123抗体,其优选包含对应于SEQ ID NO:201的重链可变区和对应于SEQ ID NO:205的轻链可变区。
TPP-8988是抗-CD123抗体,其优选包含对应于SEQ ID NO:131的重链可变区和对应于SEQ ID NO:135的轻链可变区。
TPP-9342是抗-CD123抗体,其优选包含对应于SEQ ID NO:191的重链可变区和对应于SEQ ID NO:195的轻链可变区。
TPP-8987是抗-CD123抗体,其优选包含对应于SEQ ID NO:129的重链区域和对应于SEQ ID NO:130的轻链区域。
TPP-9476是抗-CD123抗体,其优选包含对应于SEQ ID NO:209的重链区域和对应于SEQ ID NO:210的轻链区域。
TPP-8988是抗-CD123抗体,其包含对应于SEQ ID NO:139的重链区域和优选对应于SEQ ID NO:140的轻链区域。
TPP-9342是抗-CD123抗体,其优选包含对应于SEQ ID NO:199的重链区域和对应于SEQ ID NO:200的轻链区域。
根据本发明,用于与接头和/或毒性基团偶联的抗-CD123抗体的优选实施方案是以下那些:
1.抗体或其与CD123结合的抗原结合片段,包含:
可变重链,其包含如SEQ ID NO:122中所示的重链可变CDR1序列,如SEQ ID NO:123中所示的重链可变CDR2序列,和如SEQ ID NO:124中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:126中所示的轻链可变CDR1序列,如SEQ ID NO:127中所示的轻链可变CDR2序列,和如SEQ ID NO:128中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:202中所示的重链可变CDR1序列,如SEQ ID NO:203中所示的重链可变CDR2序列,和如SEQ ID NO:204中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:206中所示的轻链可变CDR1序列,如SEQ ID NO:207中所示的轻链可变CDR2序列,和如SEQ ID NO:208中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:132中所示的重链可变CDR1序列,如SEQ ID NO:133中所示的重链可变CDR2序列,和如SEQ ID NO:134中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:136中所示的轻链可变CDR1序列,如SEQ ID NO:137中所示的轻链可变CDR2序列,和如SEQ ID NO:138中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:192中所示的重链可变CDR1序列,如SEQ ID NO:193中所示的重链可变CDR2序列,和如SEQ ID NO:194中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:196中所示的轻链可变CDR1序列,如SEQ ID NO:197中所示的轻链可变CDR2序列,和如SEQ ID NO:198中所示的轻链可变CDR3序列。
2.根据实施方案1的抗体或其抗原结合片段,包含:
如SEQ ID NO:121中所示的重链可变序列和如SEQ ID NO:125中所示的轻链可变序列,或
如SEQ ID NO:201中所示的重链可变序列和如SEQ ID NO:205中所示的轻链可变序列,或
如SEQ ID NO:131中所示的重链可变序列和如SEQ ID NO:135中所示的轻链可变序列,或
如SEQ ID NO:191中所示的重链可变序列和如SEQ ID NO:195中所示的轻链可变序列。
3.根据前述实施方案中任一项的抗体,其是IgG抗体。
4.根据前述实施方案中任一项的抗体,其包含:
如SEQ ID NO:129中所示的重链序列和如SEQ ID NO:130中所示的轻链序列,或
如SEQ ID NO:209中所示的重链序列和如SEQ ID NO:210中所示的轻链序列,或
如SEQ ID NO:139中所示的重链序列和如SEQ ID NO:140中所示的轻链序列,或
如SEQ ID NO:199中所示的重链序列和如SEQ ID NO:200中所示的轻链序列。
5.根据前述实施方案中任一项的抗体,其包含:根据前述实施方案中任一项的抗原结合片段或根据前述实施方案中任一项的抗体的抗原结合片段,其是scFv,Fab,Fab'片段或F(ab)2片段。
6.根据前述实施方案中任一项的抗体或抗原结合片段,其是单克隆抗体或其抗原结合片段。
7.根据前述实施方案中任一项的抗体或抗原结合片段,其是人、人源化或嵌合抗体或抗原结合片段。
特别优选的是称为“TPP-8987”,“TPP-9476”,“TPP-8988”和“TPP-9342”的抗-CD123抗体。
本发明的DNA分子
本发明还涉及编码本发明抗体或其抗原结合片段的DNA分子。在某些情况下,这些序列针对哺乳动物表达进行了优化。本发明的DNA分子不限于本文公开的序列,还包括其变体。本发明中的DNA变体可以参考它们在杂交中的物理性质来描述。本领域技术人员将认识到,使用核酸杂交技术,DNA可用于鉴定其互补体,并且因为DNA是双链的,DNA可用于鉴定其等同物或同源物。还将认识到杂交可以以小于100%的互补性发生。然而,在适当选择条件的情况下,杂交技术可用于基于DNA序列与特定探针的结构相关性来区分DNA序列。关于这些条件的指导,参见Sambrook等人,1989如上,和Ausubel等人,1995(Ausubel,F.M.,Brent,R.,Kingston,R.E.,Moore,D.D.,Sedman,J.G.,Smith,J.A.,&Struhl,K.eds.(1995).Current Protocols in Molecular Biology.New York:John Wiley and Sons)。
两个多核苷酸序列之间的结构相似性可以表示为两个序列彼此杂交的条件的“严格性”的函数。如本文所用,术语“严格性”是指条件不利于杂交的程度。严格条件强烈地不利于杂交,并且在这样的条件下,只有结构最相关的分子才会彼此杂交。相反,非-严格的条件有利于分子的杂交,显示出较小程度的结构相关性。因此,杂交严格性与两个核酸序列的结构关系直接相关。
杂交严格性是许多因素的函数,包括总DNA浓度,离子强度,温度,探针大小和破坏氢键的试剂的存在。促进杂交的因素包括高DNA浓度,高离子强度,低温,较长的探针大小以及不存在破坏氢键的试剂。杂交通常以两个阶段进行:“结合”阶段和“洗涤”阶段。
功能等同的DNA变体
本发明范围内的另一类DNA变体可以参考它们编码的产物描述。这些功能等同的多核苷酸的特征在于以下事实,即由于遗传密码的简并性,它们编码相同的肽序列。
已经认识到,本文提供的DNA分子的变体可以以几种不同的方式构建。例如,它们可以作为完全合成的DNA构建。有效合成寡核苷酸的方法是广泛可用的。参见Ausubel等人,2.11节,补充21(1993)。可以以Khorana等人,J.Mol.Biol.72:209-217(1971)中首次报道的方式,合成和组装重叠寡核苷酸;另见Ausubel等人,同上,8.2节。合成的DNA优选经设计而具有在基因的5'和3'末端工程化的方便的限制性位点,以便于克隆到合适的载体中。
如所指出的,产生变体的方法是从本文公开的DNA之一开始,然后进行定点诱变。参见Ausubel等人,同上,第8章,补充37(1997)。在典型的方法中,将靶DNA克隆到单链DNA噬菌体载体中。分离单链DNA并与含有所需核苷酸改变的寡核苷酸杂交。合成互补链并将双链噬菌体引入宿主中。一些得到的后代将含有所需的突变体,其可以使用DNA测序确认。此外,增加后代噬菌体是所需突变体的可能性的多种方法是可得的。这些方法是本领域技术人员所熟知的,并且产生这种突变体的试剂盒可商购获得。
重组DNA构建体和表达
本发明还提供了重组DNA构建体,其包含一种或多种编码本发明优选抗体的核苷酸序列。本发明的重组构建体可以连同载体一起使用,例如质粒,噬菌粒,噬菌体或病毒载体,其中***了编码本发明的抗体或其抗原结合片段或其变体的DNA分子。
本文提供的抗体、抗原结合部分或其变体可以通过在宿主细胞中重组表达编码轻链和重链或其部分的核酸序列来制备。为了重组表达抗体、抗原结合部分或其变体,可以用一种或多种携带编码轻链和/或重链或其部分的DNA片段的重组表达载体转染宿主细胞,使得轻链和重链在宿主细胞中表达。标准重组DNA方法用于制备和/或获得编码重链和轻链的核酸,将这些核酸并入重组表达载体中并将载体引入宿主细胞,例如Sambrook,Fritsch和Maniatis(编辑),Molecular Cloning;A Laboratory Manual,第二版,Cold SpringHarbor,N.Y.,(1989),Ausubel,F.M.等人(编辑)Current Protocols in MolecularBiology,Greene Publishing Associates,(1989)和Boss等人的美国专利号4,816,397中描述的那些。
另外,编码重链和/或轻链可变区的核酸序列可以转化为例如编码全长抗体链、Fab片段或scFv的核酸序列。编码VL或VH的DNA片段可以与编码例如抗体恒定区或柔性接头的另一DNA片段可操作地连接(使得两个DNA片段编码的氨基酸序列符合读框)。人重链和轻链恒定区的序列是本领域已知的(参见例如Kabat,E.A.等人,(1991)Sequences ofProteins of Immunological Interest,第五版,U.S.Department of Health and HumanServices,NIH公开号91-3242)和包含这些区域的DNA片段可通过标准PCR扩增获得。
为了产生编码scFv的多核苷酸序列,编码VH和VL的核酸可以与编码柔性接头的另一个片段可操作地连接,使得VH和VL序列可以表达为连续的单链蛋白质,其中通过柔性接头连接VL和VH区域(参见例如Bird等人,(1988)Science 242:423-426;Huston等人,(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883;McCafferty等人,Nature(1990)348:552-554)。
为了表达抗体,其抗原结合片段或其变体,可以使用标准的重组DNA表达方法(参见,例如,Goeddel;Gene Expression Technology.Methods in Enzymology 185,AcademicPress,San Diego,Calif.(1990))。例如,可以将编码所需多肽的DNA***表达载体中,然后将其转染到合适的宿主细胞中。合适的宿主细胞是原核细胞和真核细胞。原核宿主细胞的实例是例如细菌,真核宿主细胞的实例是酵母,昆虫和昆虫细胞,植物和植物细胞,转基因动物或哺乳动物细胞。在一些实施方案中,将编码重链和轻链的DNA***分开的载体中。在其他实施方案中,将编码重链和轻链的DNA***相同的载体中。应当理解,表达载体的设计,包括调节序列的选择受诸如宿主细胞的选择、所需蛋白质的表达水平以及表达是组成型还是诱导型等因素的影响。
因此,本发明的一个实施方案也是包含载体或核酸分子的宿主细胞,其中宿主细胞可以是高等真核宿主细胞,例如哺乳动物细胞,低等真核宿主细胞,例如酵母细胞,并且可以是原核细胞,例如细菌细胞。
本发明的另一个实施方案是使用宿主细胞产生抗体和抗原结合片段的方法,包括在合适的条件下培养宿主细胞并回收所述抗体。
因此,本发明的另一个实施方案是用本发明的宿主细胞生产本发明的抗体,并将这些抗体纯化至至少95%重量的同质性。
细菌表达
通过将编码所需蛋白质的DNA序列与在可操作读码段中的合适翻译起始和终止信号一起和功能性启动子***,来构建用于细菌的有用表达载体。载体将包含一种或多种表型选择标记和复制起点,以确保载体的维持,并且如果需要,在宿主内提供扩增。用于转化的合适的原核宿主包括但不限于大肠杆菌(E.coli),枯草芽孢杆菌(Bacillus subtilis),鼠伤寒沙门氏菌(Salmonella typhimurium)和假单胞菌属(Pseudomonas),链霉菌属(Streptomyces)和葡萄球菌属(Staphylococcus)内的各种物种。
细菌载体可以是,例如,基于噬菌体、质粒或噬菌粒的。这些载体可含有选择标记和细菌复制起点,其来自市售质粒,通常含有众所周知的克隆载体pBR322(ATCC 37017)的元件。在将合适的宿主菌株转化并使宿主菌株生长至合适的细胞密度后,通过适当的方法(例如,温度变换或化学诱导)使选择的启动子去抑制/诱导,并将细胞再培养一段时间。通常,通过离心收获细胞,通过物理或化学方法破坏细胞,并保留所得到的粗提取物用于进一步纯化。
在细菌***中,可以有利地选择许多表达载体,这取决于所表达的蛋白质的预期用途。例如,当要产生大量这样的蛋白质时,例如,为了产生抗体或筛选肽文库,可能需要指导高水平的易于纯化的融合蛋白产物表达的载体。
因此,本发明的一个实施方案是表达载体,其包含编码本发明的新抗体的核酸序列。
本发明的抗体或其抗原结合片段或其变体包括天然纯化的产物,化学合成方法的产物,和通过重组技术从原核宿主产生的产物,包括例如大肠杆菌,枯草芽孢杆菌,鼠伤寒沙门氏菌和假单胞菌属、链霉菌属和葡萄球菌属中的各种物种,优选来自大肠杆菌细胞。
哺乳动物表达
用于哺乳动物宿主细胞表达的优选调节序列包括指导哺乳动物细胞中的高水平蛋白质表达的病毒元件,例如源自巨细胞病毒(CMV)(例如CMV启动子/增强子)、猿猴病毒40(SV40)(例如SV40启动子/增强子)、腺病毒(例如,腺病毒主要晚期启动子(AdMLP))和多瘤的启动子和/或增强子。抗体的表达可以是组成型的或受调节的(例如可通过添加或去除小分子诱导物如四环素结合Tet***诱导)。关于病毒调节元件及其序列的进一步描述,参见例如Stinski的US 5,168,062,Bell等人的US 4,510,245和Schaffner等人的U.S.4,968,615。重组表达载体还可以包括复制起点和选择标记(参见例如U.S.4,399,216、4,634,665和U.S.5,179,017)。合适的选择标记包括在已引入载体的宿主细胞上的赋予对药物(例如G418、嘌呤霉素、潮霉素、杀稻瘟素、博来霉素(zeocin/bleomycin)或甲氨蝶呤)的抗性的基因,或利用营养缺陷型的选择标记,例如谷氨酰胺合成酶(Bebbington等人,Biotechnology(N Y).1992Feb;10(2):169-75)。例如,二氢叶酸还原酶(DHFR)基因赋予对甲氨蝶呤的抗性,neo基因赋予对G418的抗性,来自土曲霉(Aspergillus terreus)的bsd基因赋予对杀稻瘟素的抗性,嘌呤霉素N-乙酰转移酶赋予对嘌呤霉素的抗性,Sh ble基因产物赋予对博来霉素的抗性,和大肠杆菌潮霉素抗性基因(hyg或hph)赋予对潮霉素的抗性。选择标记如DHFR或谷氨酰胺合成酶也可用于与MTX和MSX结合的扩增技术。
将表达载体转染到宿主细胞中可以使用标准技术进行,例如电穿孔,核转染,磷酸钙沉淀,脂质转染,基于聚阳离子的转染,例如基于聚乙烯亚胺(PEI)的转染和DEAE-葡聚糖转染。
用于表达本文提供的抗体、其抗原结合片段或其变体的合适的哺乳动物宿主细胞包括中国仓鼠卵巢(CHO细胞),例如CHO-K1,CHO-S,CHO-K1SV[包括dhfr-CHO细胞,描述于Urlaub和Chasin,(1980)Proc.Natl.Acad.Sci.USA 77:4216-4220和Urlaub等人,Cell.1983Jun;33(2):405-12,与DHFR选择标记一起使用,例如,如R.J.Kaufman和P.A.Sharp(1982)Mol.Biol.159:601-621中所述;和Fan等人,BiotechnolBioeng.2012Apr;109(4):1007-15中举例说明的其他敲除细胞],NS0骨髓瘤细胞,COS细胞,HEK293细胞,HKB11细胞,BHK21细胞,CAP细胞,EB66细胞和SP2细胞。
表达***,例如HEK293,HEK293T,HEK293-EBNA,HEK293E,HEK293-6E,HEK293-Freestyle,HKB11,Expi293F,293EBNALT75,CHO Freestyle,CHO-S,CHO-K1,CHO-K1SV,CHOEBNALT85,CHOS-XE,CHO-3E7或CAP-T细胞(例如Durocher等人,Nucleic AcidsRes.2002Jan 15;30(2):E9)中的表达也可能是短暂的或半稳定的。
在一些实施方案中,设计表达载体使得表达的蛋白质分泌到培养宿主细胞的培养基中。可以使用标准蛋白质纯化方法从培养基中回收抗体、其抗原结合片段或其变体。
纯化
可以通过众所周知的方法从重组细胞培养物中回收和纯化本发明的抗体或其抗原结合片段或其变体,包括但不限于硫酸铵或乙醇沉淀,酸提取,蛋白A色谱,蛋白G色谱,阴离子或阳离子交换色谱,磷酸纤维素色谱,疏水相互作用色谱,亲和色谱,羟基磷灰石色谱和凝集素色谱。高效液相色谱(“HPLC”)也可用于纯化。参见,例如Colligan,CurrentProtocols in Immunology,或Current Protocols in Protein Science,John Wiley&Sons,NY,N.Y.,(1997-2001),例如,第1章,第4章,第6章,第8章,第9章,第10章,各自完全通过引用并入本文。
本发明的抗体或其抗原结合片段或其变体包括天然纯化的产物,化学合成方法的产物,和通过重组技术从真核宿主产生的产物,包括例如酵母,高等植物,昆虫和哺乳动物细胞。取决于重组生产方法中使用的宿主,本发明的抗体可以是糖基化的或可以是非糖基化的。许多标准实验室手册中描述了这些方法,例如Sambrook,同上,第17.37-17.42节;Ausubel,同上,第10、12、13、16、18和20章。
在优选的实施方案中,将抗体纯化(1)至大于95%重量的抗体,例如通过Lowry方法,UV-Vis光谱法或通过SDS-毛细管凝胶电泳测定(例如在Caliper LabChip GXII,GX90或Biorad Bioanalyzer装置上),并且在进一步优选的实施方案中,超过99重量%,(2)至足以获得N-末端或内部氨基酸序列的至少15个残基,或(3)至在还原或非还原条件下,使用考马斯蓝或优选银染色,通过SDS-PAGE获得同质性。分离的天然存在抗体包括在重组细胞内的原位的抗体,因为该抗体的天然环境的至少一种组分将不存在。然而,通常分离的抗体将通过至少一个纯化步骤制备。
同位素,盐,溶剂化物,同位素变体
本发明也包括根据本发明的化合物的所有合适的同位素变体。根据本发明的化合物的同位素变体在这里理解为是指这样的化合物:其中在本发明的化合物内至少一个原子已经被替换为相同原子序数的另一原子,但是所述另一原子的原子质量不同于在自然界中通常存在或优势存在的原子质量。可以掺入根据本发明的化合物中的同位素的实例是氢,碳,氮,氧,磷,硫,氟,氯,溴和碘的那些,例如2H(氘)、3H(氚)、13C,14C,15N,17O,18O,32P,33P,33S,34S,35S,36S,18F,36Cl,82Br,123I,124I,129I和131I。根据本发明的化合物的特定同位素变体,特别是其中已掺入了一种或多种放射性同位素的那些,可能是有益的,例如,用于检查体内作用机制或活性化合物分布;由于相对容易的制备性和可检测性,特别是用3H或14C同位素标记的化合物适合于此目的。此外,同位素(例如氘)的掺入由于化合物的更高的代谢稳定性可以导致特定的治疗益处,例如延长体内半衰期或减少所需的活性剂量;因此,在某些情况下,根据本发明的化合物的这些修饰也可构成本发明的优选实施方案。通过本领域技术人员已知的方法,例如通过在下面描述的方法和在工作实施例中描述的方法,通过使用各试剂和/或起始化合物的相应的同位素改性,可以制备根据本发明的化合物的同位素变体。
在本发明上下文中,优选的盐是本发明化合物的生理学可接受的盐。还包括本身不适用于药物应用但可用于例如分离或纯化本发明化合物的盐。
根据本发明的化合物的生理学上可接受的盐包括无机酸、羧酸和磺酸的酸加成盐,例如盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、萘二磺酸、乙酸、三氟乙酸、丙酸、乳酸、酒石酸、苹果酸、柠檬酸、富马酸、马来酸和苯甲酸的盐。
本发明化合物的生理学上可接受的盐还包括常规碱的盐,例如且优选碱金属盐(例如钠和钾盐)、碱土金属盐(例如钙和镁盐)以及衍生自氨或具有1至16个碳原子的有机胺的铵盐,所述有机胺例如且优选乙胺、二乙胺、三乙胺、乙基二异丙胺、单乙醇胺、二乙醇胺、三乙醇胺、二环己胺、二甲基氨基乙醇、普鲁卡因(procaine)、二苄基胺、N-甲基哌啶,N-甲基吗啉、精氨酸、赖氨酸和1,2-乙二胺。
在本发明上下文中,溶剂化物指根据本发明的化合物的这样的形式:其通过与溶剂分子的配位作用形成固体或液体状态的配合物。水合物是与水配位的溶剂化物的特定形式。在本发明的上下文中优选的溶剂化物是水合物。
此外,本发明还包括根据本发明的化合物的前药。术语“前药”在此表示化合物,其本身可以是生物学活性的或无活性的,但在其在体内的停留期间被转化(例如通过代谢或水解方式)为本发明化合物。
本发明的另一个实施方案是如上定义的缀合物,其中抗体或其功能片段结合癌症靶分子。
本发明的另一个实施方案是如上定义的缀合物,其中缀合物具有2至6个缀合位点/抗体或其功能片段。
本发明的另一个实施方案是如上定义的缀合物,其中缀合物具有2个缀合位点/抗体或其功能片段。
本发明的另一个实施方案是如上定义的缀合物,其中缀合物具有4个缀合位点/抗体或其功能片段。
本发明的另一个实施方案是如上定义的缀合物,其中抗体或其功能片段结合细胞外靶分子。
本发明的另一个实施方案是如上定义的缀合物,其中抗体或其功能片段在结合细胞外靶分子后被内化并通过表达靶分子的细胞在细胞内(优选溶酶体)加工。
治疗用途
本文所述的CD123靶向的抗体-药物缀合物可用于治疗表达CD123的病症,例如表达CD123的癌症。通常,此类癌症显示在蛋白质(例如,通过免疫测定)或RNA水平测量的可检测水平的CD123。一些此类癌症相对于相同类型的非癌组织(优选来自同一患者)显示出升高的CD123水平。任选地,在进行治疗之前测量癌症中CD123的水平。
CD123定向的抗体药物缀合物可用于治疗表达CD123的疾病,包括表达CD123的癌症,如造血和淋巴组织的肿瘤或造血和淋巴恶性肿瘤。
与CD123表达相关的癌症的实例包括髓样疾病,例如急性髓性白血病(AML)和骨髓增生异常综合征(MDS)。其他癌症包括B细胞急性淋巴细胞白血病(B-ALL),毛细胞白血病,范可尼贫血,母细胞性浆细胞样树突状细胞肿瘤(BPDCN),霍奇金病,未成熟T细胞急性淋巴细胞白血病(未成熟T-ALL),伯基特淋巴瘤,滤泡性淋巴瘤,慢性淋巴细胞白血病(CLL)或套细胞淋巴瘤。
本发明的方法包括治疗患有表达CD123的癌症的患者,包括给患者施用本发明的抗体-药物缀合物。癌症可以是任何表达CD123的癌症,包括例如AML,MDS,B-ALL,毛细胞白血病,范可尼贫血,BPDCN,霍奇金病,未成熟T-ALL,伯基特氏淋巴瘤,滤泡性淋巴瘤,CLL或套细胞淋巴瘤。
可以使用本发明化合物治疗的过度增殖性疾病尤其包括癌症和肿瘤疾病。在本发明的上下文中,这些被理解为尤其意指以下疾病,但不限于此:乳腺癌和乳腺肿瘤(乳腺癌包括导管和小叶形式,也在原位),呼吸道肿瘤(小细胞和非小细胞癌,支气管癌),脑肿瘤(例如脑干和下丘脑的瘤,星形细胞瘤,室管膜瘤,胶质母细胞瘤,神经胶质瘤,成神经管细胞瘤,脑膜瘤和神经外膜和松果体肿瘤),消化器官肿瘤(食道癌,胃癌,胆囊癌,小肠癌,大肠癌,直肠癌和***癌),肝肿瘤(尤其是肝细胞癌,胆管癌和混合肝细胞胆管癌),头颈部肿瘤(喉、下咽、鼻咽、口咽、嘴唇和口腔癌,口腔黑色素瘤),皮肤肿瘤(基底细胞瘤,脊髓瘤,鳞状细胞癌,卡波西肉瘤,恶性黑色素瘤,非黑色素瘤皮肤癌,Merkel细胞皮肤癌,肥大细胞瘤),软组织肿瘤(尤其是软组织肉瘤,骨肉瘤,恶性纤维组织细胞瘤,软骨肉瘤,纤维肉瘤,血管肉瘤,平滑肌肉瘤,脂肪肉瘤,淋巴肉瘤和横纹肌肉瘤),眼睛肿瘤(尤其是眼内黑色素瘤和视网膜母细胞瘤),内分泌和外分泌腺肿瘤(例如甲状腺和甲状旁腺、胰腺和唾液腺癌,腺癌),泌尿道肿瘤(膀胱、***、肾、肾盂和输尿管的肿瘤)和生殖器官的肿瘤(妇女中的子宫内膜癌,子***,卵巢癌,***癌,外阴癌和子宫癌,男性中的***癌和睾丸癌)。这些还包括血液、淋巴***和脊髓的增殖性血液病(实体形式和作为循环细胞),如白血病,淋巴瘤和骨髓增生性疾病,例如急性髓细胞、急性淋巴细胞、慢性淋巴细胞、慢性髓性和毛细胞白血病,与艾滋病相关的淋巴瘤,霍奇金淋巴瘤,非霍奇金淋巴瘤,皮肤T细胞淋巴瘤,伯基特淋巴瘤和中枢神经***淋巴瘤。
人体中这些充分表征的疾病也可以在其他哺乳动物中以相当的病因发生,并且同样可以用本发明的化合物治疗。
用本发明化合物治疗上述癌症疾病包括治疗实体瘤和治疗其转移或循环形式。
在本发明的上下文中,术语“治疗”以常规意义使用,并且意指出于对抗、减少、减轻或缓解疾病或健康异常和改善由该疾病损害的生活状况的目的,照顾、照护和护理患者,例如,在癌症的情况下。
因此,本发明进一步提供了根据本发明的化合物用于治疗和/或预防病症,特别是上述病症的用途。
本发明进一步提供了本发明化合物在制备用于治疗和/或预防病症,特别是上述病症的药物中的用途。
本发明进一步提供了根据本发明的化合物在治疗和/或预防病症,特别是上述病症的方法中的用途。
本发明进一步提供了使用有效量的至少一种本发明化合物治疗和/或预防病症,特别是上述病症的方法。
根据本发明的化合物可以单独使用或者如果需要,与一种或多种其它药理活性物质组合使用,条件是该组合不会导致不希望的和不可接受的副作用。因此,本发明还提供含有至少一种本发明化合物和一种或多种其它活性化合物的药物,特别是用于治疗和/或预防上述病症。
例如,本发明化合物可与已知的抗过度增殖、细胞抑制或细胞毒性物质组合用于治疗癌症疾病。合适的组合活性化合物的实例包括:131I-chTNT、阿倍瑞克(abarelix)、阿比特龙、阿柔比星、ado-曲妥珠单抗美坦新、阿法替尼、阿柏西普、阿地白介素、阿仑单抗(alemtuzumab)、阿仑膦酸、阿利维A酸(alitretinoin)、六甲蜜胺、氨磷汀、氨鲁米特、氨基乙酰丙酸己酯、氨柔比星、安吖啶、阿那曲唑、安西司亭、茴三硫(anetholedithiolethione)、血管紧张素II、抗凝血酶III、阿瑞吡坦、阿西莫单抗、arglabin、三氧化二砷、门冬酰胺酶、阿西替尼、阿扎胞苷、巴利昔单抗(basiliximab)、贝洛替康(belotecan)、苯达莫司汀、贝利司他、贝伐单抗(bevacizumab)、贝沙罗汀(bexarotene)、比卡鲁胺、比生群、博来霉素、硼替佐米、布舍瑞林、博舒替尼、本妥昔单抗-维汀(vedotin)、白消安、卡巴他赛(cabazitaxel)、卡博替尼、亚叶酸钙、左亚叶酸钙、卡培他滨、卡罗单抗、卡铂、卡菲偌米布、卡莫氟、卡莫司汀、卡妥索单抗(catumaxomab)、西乐葆、西莫白介素、色瑞替尼、西妥昔单抗、苯丁酸氮芥、氯地孕酮、氮芥、西多福韦、西那卡塞、顺铂、克拉屈滨、氯膦酸、氯法拉滨(clofarabine)、copanlisib、克立他酶(crisantaspase)、环磷酰胺、环丙孕酮、阿糖胞苷、达卡巴嗪、放线菌素D、达贝泊汀α(darbepoetin alfa)、达拉非尼、达沙替尼、柔红霉素、地西他滨、地加瑞克、地尼白介素(denileukin diftitox)、地诺塞麦(denosumab)、地普奥肽、地洛瑞林、右丙亚胺、二溴螺氯铵、二去水卫矛醇、双氯芬酸、多西他赛、多拉司琼、去氧氟尿苷、多柔比星、多柔比星+雌酮、屈***酚、依库珠单抗(eculizumab)、依决洛单抗、依利醋铵、伊屈泼帕(eltrombopag)、血管内皮抑素、依诺他滨、恩扎鲁胺、表柔比星、环硫雄醇、依泊汀α、依泊汀β、依泊汀ζ、依他铂、艾日布林(eribulin)、埃洛替尼、埃索美拉唑、***、雌莫司汀、依托泊苷、依维莫司、依西美坦、法屈唑、芬太尼、非格司亭、氟羚甲基***、氟尿苷、氟达拉滨、氟尿嘧啶、氟他胺、亚叶酸、福美坦、福沙吡坦、福莫司汀、氟维司群、钆布醇、加多利道、钆特酸葡甲胺、钆弗塞胺、钆塞酸、硝酸镓、加尼瑞克、吉非替尼、吉西他滨、吉妥单抗(gemtuzumab)、羧肽酶、谷胱甘肽(glutoxim)、GM-CSF、戈舍瑞林、格兰西龙、粒细胞集落刺激因子、二盐酸组胺、组氨瑞林(histrelin)、羟基脲、I-125粒子、兰索拉唑、依班膦酸、替伊莫单抗(ibritumomab tiuxetan)、依鲁替尼、伊达比星、异环磷酰胺、伊马替尼、咪喹莫特、英丙舒凡(improsulfan)、吲地司琼、英卡膦酸、巨大戟醇甲基丁烯酸酯(ingenol mebutate)、干扰素α、干扰素β、干扰素γ、碘比醇、碘苄胍(123I)、碘美普尔、易普利姆玛(ipilimumab)、伊立替康、伊曲康唑、伊沙匹隆(ixabepilone)、兰瑞肽、拉帕替尼(lapatinib)、Iasocholine、来那度胺(lenalidomide)、来格司亭、蘑菇多糖、来曲唑、亮丙瑞林、左旋四咪唑、左炔诺孕酮、左甲状腺素钠、麦角乙脲、乐铂、环己亚硝脲、氯尼达明、马索罗酚、甲羟孕酮、甲地孕酮、美拉胂醇、苯丙氨酸氮芥、美雄烷、巯基嘌呤、美司钠、***、氨甲喋呤、甲氧沙林、甲基氨基酮戊酸盐、甲基***龙、甲基睾甾酮、甲酪氨酸、米伐木肽(mifamurtide)、米特福辛、米铂(miriplatin)、二溴甘露醇、丙脒腙、二溴卫矛醇、丝裂霉素、米托坦、米托蒽醌、mogamulizumab、莫拉司亭、莫哌达醇、盐酸***、硫酸***、***隆、nabiximols、那法瑞林、纳洛酮+戊唑辛、纳曲酮、那托司亭、奈达铂、奈拉滨(nelarabine)、奈立膦酸、nivolumabpentetreotide、尼洛替尼(nilotinib)、尼鲁米特、尼莫唑、尼妥珠单抗(nimotuzumab)、嘧啶亚硝脲、二胺硝吖啶(nitraerine)、纳武单抗、阿托珠单抗、奥曲肽、奥法木单抗(ofatumumab)、高三尖杉酯碱、奥美拉唑、奥坦西隆、奥普瑞白介素(oprelvekin)、奥古蛋白、orilotimod、奥沙利铂、羟考酮、羟甲烯龙、ozogamicine、p53基因治疗、紫杉醇、palifermin、钯-103粒子、帕洛诺司琼、帕米膦酸、帕尼单抗(panitumumab)、泮托拉唑、帕唑帕尼(pazopanib)、培加帕酶、PEG-倍他依泊汀(甲氧基PEG-倍他依泊汀)、帕母单抗、聚乙二醇非格司亭(pegfilgrastim)、聚乙二醇干扰素α-2b、培美曲唑、镇痛新、喷司他丁、培洛霉素、全氟丁烷、培磷酰胺、帕妥珠单抗、溶链菌制剂(picibanil)、毛果芸香碱、吡柔比星、匹克生琼、普乐沙福(plerixafor)、普卡霉素、聚氨葡糖(poliglusam)、磷酸聚***、聚乙烯吡咯烷酮+透明质酸钠、多糖-K、泊马度胺、帕纳替尼、卟吩姆钠、普拉曲沙(pralatrexate)、松龙苯芥、***、甲基苄肼、丙考达唑、***、喹高利特(quinagolide)、雷贝拉唑、racotumomab、氯化镭223、拉多替尼、雷诺昔酚、雷替曲塞(raltitrexed)、雷莫司琼、雷莫芦单抗、雷莫司汀(ranimustine)、拉布立酶、丙亚胺、refametinib、瑞戈非尼(regorafenib)、利塞膦酸、铼-186依替膦酸盐、利妥昔单抗(rituximab)、罗米地辛(romidepsin)、罗米司亭(romiplostim)、罗莫肽、roniciclib、来昔决南钐(153Sm)、沙莫司亭、沙妥莫单抗、分泌素、sipuleucel-T、西佐喃、索布佐生、甘氨双唑钠(sodium glycididazole)、索拉非尼(sorafenib)、康力龙、链脲霉素、舒尼替尼、他拉泊芬(talaporfin)、他米巴罗汀(tamibarotene)、他莫昔芬、他喷他多、他索纳明(tasonermin)、替西白介素(teceleukin)、锝[99mTc]巯诺莫单抗、99mTc-HYNIC-[Tyr3]-奥曲肽、替加氟、替加氟+吉美嘧啶(gimeracil)+奥替拉西(oteracil)、替莫卟吩、替莫唑胺、西罗莫司(temsirolimus)、表鬼臼毒噻吩糖苷、睾酮、替曲膦(tetrofosmin)、反应停、硫替派、胸腺法新(thymalfasin)、促甲状腺素α、硫鸟嘌呤(tioguanine)、托珠单抗(tocilizumab)、托泊替康、托瑞米芬、托西莫单抗(tositumomab)、曲贝替定(trabectedin)、曲马多、曲妥珠单抗、曲妥珠单抗依酯、曲奥舒凡(treosulfan)、维甲酸、曲氟尿苷+tipiracil、曲洛司坦、曲普瑞林、曲美替尼、氯乙环磷酰胺、促血小板生成素、色氨酸、乌苯美司、瓦他拉尼、戊柔比星(valrubicin)、凡德他尼(vandetanib)、伐普肽、维罗非尼(vemurafenib)、长春碱、长春新碱、长春地辛、长春氟宁、长春瑞宾、维莫德吉、伏立诺他(vorinostat)、伏氯唑、钇-90玻璃微球、净司他丁、净司他丁斯酯、唑来膦酸、佐柔比星。
此外,本发明的化合物可以与例如结合剂组合,结合剂例如可以与下列靶标结合:OX-40,CD137/4-1BB,DR3,IDO1/IDO2,LAG-3,CD40。
另外,根据本发明的化合物也可以与放射疗法和/或外科手术干预联合使用。
通常,本发明化合物与其他抑制细胞生长或细胞毒活性剂的组合可以实现以下目的:
·与用单独的活性化合物治疗相比,改善了减缓肿瘤生长、减小其大小甚至完全消除肿瘤的功效;
·与在单药疗法的情况下相比,以较低剂量使用所用的化学治疗剂的可能性;
·与单独施用相比,具有较少副作用的更耐受的疗法的可能性;
·治疗更广泛的肿瘤疾病的可能性;
·实现对疗法的较高响应率;
·与当今标准疗法相比,患者的存活时间更长。
另外,根据本发明的化合物也可以与放射疗法和/或外科手术干预联合使用。
本发明还提供药物及其用于上述目的的用途,所述药物包含至少一种本发明化合物,通常与一种或多种惰性、无毒、药学上合适的赋形剂一起。
本发明的化合物可以全身和/或局部起作用。为此目的,它们可以以合适的方式施用,例如肠胃外,可能是吸入或作为植入物或支架。
对于这些施用途径,本发明化合物可以以合适的施用形式施用。
肠胃外施用可以绕过吸收步骤(例如静脉内,动脉内,心脏内,脊柱内或腰内)或包括吸收(例如肌内,皮下,皮内,经皮或腹膜内)。适于肠胃外施用的施用形式包括溶液、悬浮液、乳液或冻干物形式的注射和输注制剂。优选肠胃外施用,尤其是静脉内施用。
通常,已发现,在肠胃外施用的情况下,可有利地施用约0.001至1mg/kg、优选约0.01至0.5mg/kg体重的量以实现有效结果。
然而,在适当情况下,可能有必要偏离所述量,尤其根据体重、施用途径、对活性化合物的个体响应、制剂的性质和施用进行的时间或间隔时间而变化。因此,在一些情况下,小于上述最小量可能是足够的,而在其他情况下,必须超过所提及的上限。在施用较大量的情况下,将其分成在一天中的几个单个剂量是可取的。
实施例
下列实施例例示说明本发明。本发明不限于实施例。
除非另有说明,否则以下试验和实施例中的百分比是重量百分比;份数是重量份数。液体/液体溶液的溶剂比、稀释比和浓度数据在各情况下以体积计。
如果在实验描述中没有说明进行反应的温度,则可以假设为室温。
合成路线:
对于工作实施例的示例,下面的方案显示了导致工作实施例的示例性合成路线:
方案1
[a):例如苄基溴,Cs2CO3,DMF,RT;b)例如Pd(dppf)2Cl2,DMF,Na2CO3,85℃;c)例如LiAlH4,THF,0℃;MnO2,DCM,RT;d)例如Ti(iOPr)4,THF,RT;e)例如tBuLi,THF,-78℃;MeOH,NH4Cl;f)例如HCl/1,4-二噁烷]。
方案2:
[a):NaBH(OAc)3,HOAc,二氯甲烷,RT;b)氯乙酰氯,NEt3,DCM,RT;c)L-半胱氨酸,NaHCO3,DBU,异丙醇/Wasser,50℃;d)HATU,DMF,二异丙基乙胺,RT;e)氯化锌,三氟乙醇,50℃;]。
方案3:半胱氨酸连接的ADC的合成
[a):2-5Eq TCEP,PBS pH7.2,在室温下搅拌30分钟;b)在室温下在氩气下搅拌90分钟,然后使用PD10-柱(G-25,GE Healthcare)在pH8下再次缓冲;在室温下在氩气下搅拌过夜,然后通过超速离心浓缩并用PBS缓冲液(pH 7.2)稀释]。
对于工作实施例的示例,下面的方案显示了导致工作实施例的示例性合成路线:
A.实施例
缩写与缩略词:
ABCB1 ATP结合盒亚家族B成员1(P-gp和MDR1的同义词)
ATP 三磷酸腺苷
BCRP 乳腺癌耐药蛋白,外排转运蛋白
BEP 2-溴-1-乙基吡啶鎓四氟硼酸盐
d 双峰(NMR中)
TLC 薄层色谱
DCM 二氯甲烷
DD 双二重峰(NMR中)
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
DPBS,D-PBS, Dulbecco氏磷酸盐缓冲盐溶液
PBS PBS=DPBS=D-PBS,pH7.4,来自Sigma,No D8537
组成:
0.2g KCl
0.2g KH2PO4(无水)
8.0g NaCl
1.15g Na2HPO4(无水)
用H2O制成1升
DTT DL-二硫苏糖醇
EDC N’-(3-二甲基氨基丙基)-N-乙基碳二亚胺盐酸盐
EI 电子碰撞电离(MS中)
ELISA 酶联免疫吸附测定
ESI 电喷雾电离(MS中)
ESI-MicroTofq ESI-MicroTofq(质谱仪名称,其中Tof=飞行时间,q=四极杆)
FCS 胎牛血清
Fmoc (9H-芴-9-基甲氧基)羰基
sat. 饱和的
GTP 鸟苷-5′-三磷酸
h 小时
HATU O-(7-氮杂苯并***-1-基)-N,N,N′N′-四甲基脲鎓六氟磷酸盐
HEPES 4-(2-羟乙基)哌嗪-1-乙磺酸
HPLC 高压,高效液相色谱
IC50 半数最大抑制浓度
i.v. 静脉内,向静脉中施用
KG-1 人肿瘤细胞系
LC-MS 液相色谱-质谱联用
LLC-PK1细胞 Lewis肺瘤猪肾细胞系
L-MDR 人MDR1转染的LLC-PK1细胞
LoVo 人肿瘤细胞系
m 多重峰(NMR中)
MDR1 多药耐药蛋白1
MeCN 乙腈
min 分钟
MOLM-13 人肿瘤细胞系
MS 质谱法
MTT 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-2H-四唑鎓溴化物3
MV-4-11 人肿瘤细胞系
NCI-H292 人肿瘤细胞系
NMR 核磁共振光谱法
NMRI 来自海军医学研究所(Naval Medical Research Institute,NMRI)的小鼠晶系
NB4 人肿瘤细胞系
PBS 磷酸盐缓冲盐溶液
P-gp P-糖蛋白,一种转运蛋白
PNGaseF 用于裂解糖的酶
RT 室温
Rt 保留时间(HPLC中)
s 单峰(NMR中)
SCID小鼠 具有严重联合免疫缺陷的试验小鼠
t 三重峰(NMR中)
TEMPO (2,2,6,6-四甲基哌啶-1-基)氧基
tert 叔
TFA 三氟乙酸
THF 四氢呋喃
THP-1 人肿瘤细胞系
UV 紫外光谱法
Z 苄氧基羰基
HPLC和LC-MS方法:
方法1(LC-MS):
仪器:Waters ACQUITY SQD UPLC***;柱:Waters Acquity UPLC HSS T3 1.8μ50x1mm;流动相A:1升水+0.25毫升99%强度的甲酸,流动相B:1升乙腈+0.25毫升99%强度的甲酸;梯度:0.0分钟90%A→1.2分钟5%A→2.0分钟5%A柱温箱:50℃;流速:0.40毫升/分钟;紫外检测:208-400纳米。
方法2(LC-MS):
MS仪器类型:Waters Synapt G2S;UPLC仪器类型:Waters Acquity I-CLASS;柱:Waters,BEH300,2.1×150mm,C18 1.7μm;流动相A:1升水+0.01%甲酸;流动相B:1升乙腈+0.01%甲酸;梯度:0.0分钟2%B→1.5分钟2%B→8.5分钟95%B→10.0分钟95%B;柱温箱:50℃;流速:0.50毫升/分钟;紫外检测:220纳米。
方法3(LC-MS):
MS仪器:Waters(Micromass)QM;HPLC仪器:Agilent 1100系列;柱:AgilentZORBAX Extend-C18 3.0x50mm 3.5微米;流动相A:1升水+0.01摩尔碳酸铵,流动相B:1升乙腈;梯度:0.0分钟98%A→0.2分钟98%A→3.0分钟5%A→4.5分钟5%A;柱温箱:40℃;流速:1.75毫升/分钟;紫外检测:210纳米。
方法4(LC-MS):
MS仪器类型:Waters Synapt G2S;UPLC仪器类型:Waters Acquity I-CLASS;柱:Waters,HSST3,2.1x50mm,C18 1.8μm;流动相A:1升水+0.01%甲酸;流动相B:1升乙腈+0.01%甲酸;梯度:0.0分钟10%B→0.3分钟10%B→1.7分钟95%B→2.5分钟95%B;柱温箱:50℃;流速:1.20毫升/分钟;紫外检测:210纳米。
方法5(LC-MS):
仪器:Waters ACQUITY SQD UPLC***;柱:Waters Acquity UPLC HSS T3 1.8μ50x1mm;流动相A:1升水+0.25毫升99%强度的甲酸,流动相B:1升乙腈+0.25毫升99%强度的甲酸;梯度:0.0分钟95%A→6.0分钟5%A→7.5分钟5%A;柱温箱:50℃;流速:0.35毫升/分钟;紫外检测:210-400纳米。
方法6(LC-MS):
仪器:Micromass Quattro Premier与Waters UPLC Acquity;柱:ThermoHypersil GOLD 1.9μ50x 1mm;流动相A:1升水+0.5毫升50%强度的甲酸,流动相B:1升乙腈+0.5毫升50%强度的甲酸;梯度:0.0分钟97%A→0.5分钟97%A→3.2分钟5%A→4.0分钟5%A;柱温箱:50℃;流速:0.3毫升/分钟;紫外检测:210纳米。
方法7(LC-MS):
仪器:Agilent MS Quad 6150;HPLC:Agilent 1290;柱:Waters Acquity UPLCHSS T3 1.8μ50x2.1mm;流动相A:1升水+0.25毫升99%强度的甲酸,流动相B:1升乙腈+0.25毫升99%强度的甲酸;梯度:0.0分钟90%A→0.3分钟90%A→1.7分钟5%A→3.0分钟5%A;柱温箱:50℃;流速:1.20毫升/分钟;紫外检测:205-305纳米。
方法8(LC-MS):
MS仪器类型:Waters Synapt G2S;UPLC仪器类型:Waters Acquity I-CLASS;柱:Waters,HSST3,2.1x 50mm,C18 1.8μm;流动相A:1升水+0.01%甲酸;流动相B:1升乙腈+0.01%甲酸;梯度:0.0分钟2%B→2.0分钟2%B→13.0分钟90%B→15.0分钟90%B;柱温箱:50℃;流速:1.20毫升/分钟;紫外检测:210纳米。
方法9:实施例181-191的LC-MS-Prep纯化方法(LIND-LC-MS-制备方法)
MS仪器:Waters,HPLC仪器:Waters(Waters X-Bridge C18柱,19mm x 50mm,5μm,流动相A:水+0.05%氨,流动相B:乙腈(ULC),梯度;流速:40毫升/分钟;紫外检测:DAD;210-400纳米)。
或
MS仪器:Waters,HPLC仪器:Waters(Phenomenex Luna 5μC18(2)100A柱,AXIATech.50×21.2mm,流动相A:水+0.05%甲酸,流动相B:乙腈(ULC),梯度;流速:40毫升/分钟;紫外检测:DAD;210-400纳米)。
方法10:实施例181-191的LC-MS分析方法(LIND_SQD_SB_AQ)
MS仪器:Waters SQD;仪器HPLC:Waters UPLC;柱:Zorbax SB-Aq(Agilent),50mmx 2.1mm,1.8μm;流动相A:水+0.025%甲酸,流动相B:乙腈(ULC)+0.025%甲酸;梯度:0.0分钟98%A-0.9分钟25%A-1.0分钟5%A-1.4分钟5%A-1.41分钟98%A-1.5分钟98%A;柱温箱:40℃;流速:0.600毫升/分钟;紫外检测:DAD;210纳米。
方法11(HPLC):
仪器:HP1100系列
柱:Merck Chromolith SpeedROD RP-18e,50-4.6mm,Cat.No.1.51450.0001,预柱Chromolith Guard Cartridge Kit,RP-18e,5-4.6mm,Cat.No.1.51470.0001
梯度:流速5毫升/分钟
进样体积5μl
溶剂A:HClO4(70%强度)/水(4ml/l)
溶剂B:乙腈
开始20%B
0.50分钟20%B
3.00分钟90%B
3.50分钟90%B
3.51分钟20%B
4.00分钟20%B
柱温:40℃
波长:210纳米。
方法12(LC-MS):
MS仪器类型:Thermo Scientific FT-MS;UHPLC+仪器类型:Thermo ScientificUltiMate 3000;柱:Waters,HSST3,2.1x75mm,C18 1.8μm;流动相A:1升水+0.01%甲酸;流动相B:1升乙腈+0.01%甲酸;梯度:0.0分钟10%B→2.5分钟95%B→3.5分钟95%B;柱温箱:50℃;流速:0.90毫升/分钟;紫外检测:210纳米/最佳积分路径210-300纳米。
方法13:(LC-MS):
MS仪器:Waters(Micromass)Quattro Micro;Instrument Waters UPLC Acquity;柱:Waters BEH C18 1.7μ50x 2.1mm;流动相A:1升水+0.01摩尔甲酸铵,流动相B:1升乙腈;梯度:0.0分钟95%A→0.1分钟95%A→2.0分钟15%A→2.5分钟15%A→2.51分钟10%A→3.0分钟10%A;柱温箱:40℃;流速:0.5毫升/分钟;紫外检测:210纳米。
其制备未在下文中明确描述的所有反应物或试剂均从通常可获得的来源商购。对于其制备同样未在下文中描述且不能商业获得或从通常不可获得的来源获得的所有其他反应物或试剂,给出了描述它们的制备的公开文献作为参考。
原料和中间体:
中间体C52
(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙-1-胺
首先,将10.00g(49.01mmol)4-溴-1H-吡咯-2-甲酸甲酯加入100.0ml DMF中,并加入20.76g(63.72mmol)碳酸铯和9.22g(53.91mmol)苄基溴。将反应混合物在RT搅拌过夜。将反应混合物在水和乙酸乙酯之间分配,且水相用乙酸乙酯萃取。合并的有机相用硫酸镁干燥,并减压蒸发溶剂。用90.0g 4-溴-1H-吡咯-2-甲酸甲酯重复反应。
通过制备型RP-HPLC(柱:Daiso 300x100;10μ,流速:250毫升/分钟,MeCN/水)纯化两个合并的反应物。减压蒸发溶剂,并将残余物在高真空下干燥。这得到125.15g(理论值的87%)的化合物:1-苄基-4-溴-1H-吡咯-2-甲酸甲酯。
LC-MS(方法1):Rt=1.18分钟;MS(ESIpos):m/z=295[M+H]+。
在氩气下,首先,将4.80g(16.32mmol)1-苄基-4-溴-1H-吡咯-2-甲酸甲酯装入DMF中,并加入3.61g(22.85mmol)(2,5-二氟苯基)硼酸、19.20ml饱和碳酸钠溶液和1.33g(1.63mmol)[1,1'-双(二苯基膦基)二茂铁]-二氯化钯(II):二氯甲烷。将该反应混合物在85℃下搅拌过夜。将反应混合物通过硅藻土过滤,并将滤饼用乙酸乙酯洗涤。用水萃取有机相,然后用饱和NaCl溶液洗涤。有机相用硫酸镁干燥,且减压蒸发溶剂。通过硅胶色谱法(流动相:环己烷/乙酸乙酯100:3)纯化残余物。减压蒸发溶剂,并将残余物在高真空下干燥。这得到3.60g(理论值的67%)的化合物:1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-甲酸甲酯。
LC-MS(方法7):Rt=1.59分钟;MS(ESIpos):m/z=328[M+H]+。
首先,将3.60g(11.00mmol)1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-甲酸甲酯装入90.0ml THF中,并且在0℃下加入1.04g(27.50mmol)氢化铝锂(2.4M于THF中)。将反应混合物在0℃下搅拌30分钟。在0℃下,加入饱和酒石酸钾钠溶液,并向反应混合物中加入乙酸乙酯。用饱和酒石酸钾钠溶液萃取有机相三次。用饱和NaCl溶液洗涤有机相一次,并用硫酸镁干燥。减压蒸发溶剂,并将残余物溶于30.0ml二氯甲烷中。加入3.38g(32.99mmol)氧化锰(IV),并将混合物在室温下搅拌48小时。加入另外2.20g(21.47mmol)氧化锰(IV),并将混合物在室温下搅拌过夜。将反应混合物通过硅藻土过滤,并将滤饼用二氯甲烷洗涤。减压蒸发溶剂,并且在下一合成步骤中使用残余物2.80g(1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-甲醛)而无需进一步纯化。
LC-MS(方法7):Rt=1.48分钟;MS(ESIpos):m/z=298[M+H]+。
首先,将28.21g(94.88mmol)1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-甲醛和23.00g(189.77mmol)(R)-2-甲基丙烷-2-亚磺酰胺加入403.0ml无水THF中,并加入67.42g(237.21mmol)异丙醇钛(IV),并将混合物在室温下搅拌过夜。加入500.0ml饱和NaCl溶液和1000.0ml乙酸乙酯,并将混合物在室温下搅拌1小时。将混合物通过硅藻土过滤,并将滤液用饱和NaCl溶液洗涤两次。有机相用硫酸镁干燥,减压蒸发溶剂,并使用Biotage Isolera(硅胶,柱1500+340g SNAP,流速200ml/min,乙酸乙酯/环己烷1∶10)纯化残余物。
LC-MS(方法7):Rt=1.63分钟;MS(ESIpos):m/z=401[M+H]+。
首先,在氩气下将25.00g(62.42mmol)的(R)-N-{(E/Z)-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]亚甲基}-2-甲基丙烷-2-亚磺酰胺加入无水THF中并冷却至-78℃。然后,在-78℃下加入12.00g(187.27mmol)叔丁基锂(1.7M戊烷溶液),并将混合物在该温度下搅拌3小时。在-78℃下,接着依次加入71.4ml甲醇和214.3ml饱和氯化铵溶液,且允许反应混合物温热至室温并在室温下搅拌1小时。将混合物用乙酸乙酯稀释并用水洗涤。有机相用硫酸镁干燥,并减压蒸发溶剂。在合成的下一步骤中使用残余物(R)-N-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2-甲基丙烷-2-亚磺酰胺而无需进一步纯化。
LC-MS(方法6):Rt=2.97分钟;MS(ESIpos):m/z=459[M+H]+。
首先,将28.00g(61.05mmol)(R)-N-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2-甲基丙烷-2-亚磺酰胺加入186.7ml 1,4-二噁烷中,然后加入45.8ml HCl的1,4-二噁烷溶液(4.0M)。将反应混合物在室温下搅拌2小时,且减压蒸发溶剂。通过制备型RP-HPLC(柱:Kinetix 100x30;流速:60毫升/分钟,MeCN/水)纯化残余物。减压蒸发乙腈,且向含水残余物中加入二氯甲烷。用碳酸氢钠溶液洗涤有机相,且用硫酸镁干燥。减压蒸发溶剂,在高真空下干燥残余物。这得到16.2g(理论值的75%)的标题化合物。
LC-MS(方法6):Rt=2.10min;MS(ESIpos):m/z=338[M-NH2]+,709[2M+H]+。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.87(s,9H),1.53(s,2H),3.59(s,1H),5.24(d,2H),6.56(s1H),6.94(m,1H),7.10(d,2H),7.20(m,1H),7.26(m,2H),7.34(m,2H),7.46(m,1H).
中间体C58
(2S)-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(乙醇酰基)氨基]-2-({[2-(三甲基甲硅烷基)乙氧基]羰基}氨基)丁酸
将4.3g(12.2mmol)中间体C52溶于525ml DCM中,并加入3.63g(17.12mmol)三乙酰氧基硼氢化钠和8.4ml乙酸。在室温下搅拌5分钟后,加入溶解在175ml DCM中的8.99g(24.5mmol)中间体L57,并将反应物在室温下再搅拌45分钟。然后,将反应用300ml DCM稀释,并用100ml碳酸氢钠溶液洗涤两次,用饱和NaCl溶液洗涤一次。有机相用硫酸镁干燥,减压蒸发溶剂,并将残余物在高真空下干燥。然后通过制备型RP-HPLC(柱:Chromatorex C18)纯化残余物。合并适当的级分后,减压蒸发溶剂,并将残余物在高真空下干燥。这得到4.6g(理论值的61%)的(2S)-4-({(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}氨基)-2-({[2-(三甲基甲硅烷基)乙氧基]羰基}氨基)丁酸甲酯。
LC-MS(方法12):Rt=1.97min;MS(ESIpos):m/z=614(M+H)+。
首先,将2.06g(3.36mmol)该中间体加入76ml DCM中,并在2.1ml三乙胺存在下用0.81ml(7.17mmol)乙酸2-氯-2-氧代乙酯酰化。在室温下搅拌20小时后,加入0.36ml乙酸2-氯-2-氧代乙酯和0.94ml三乙胺,并将反应在室温下再搅拌15分钟。然后将混合物用500ml乙酸乙酯稀释,并用300ml 5%强度的柠檬酸连续萃取两次,用300ml饱和碳酸氢钠溶液萃取两次,并用100ml饱和氯化钠溶液萃取一次,然后用硫酸镁干燥并且浓缩。在高真空下干燥,得到2.17g(理论值的79%)的受保护的中间体。
LC-MS(方法1):Rt=1.48min;MS(ESIpos):m/z=714(M+H)+。
将2.17mg(2.64mmol)该中间体溶于54ml THF和27ml水中,并加入26ml 2摩尔氢氧化锂溶液。将混合物在室温下搅拌30分钟,然后使用1.4ml TFA将pH调节至3-4。减压浓缩混合物。一旦蒸馏出大部分THF,将水溶液用DCM萃取两次,然后在减压下浓缩至干。通过制备型HPLC(柱:Chromatorex C18)纯化残余物。合并适当的级分后,减压蒸发溶剂,且残余物从乙腈/水冷冻干燥。这得到1.1g(理论值的63%)的标题化合物。
LC-MS(方法1):Rt=1.34min;MS(ESIpos):m/z=656(M-H)-。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.03(s,9H),0.58(m,1H),0.74-0.92(m,11H),1.40(m1H),3.3(m,2H),3,7(m,1H),3.8-4.0(m,2H),4.15(q,2H),4.9and5.2(2d,2H),5.61(s,1H),6.94(m,2H),7.13-7.38(m,7H),7.48(s,1H),7.60(m,1H),12.35(s,1H).
中间体C70
{3-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(氯乙酰基)氨基]丙基}氨基甲酸(2-(三甲基甲硅烷基)乙酯
首先,将990.0mg(2.79mmol)(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙-1-胺(中间体C52)加入15.0ml二氯甲烷中,并加入828.8mg(3.91mmol)三乙酰氧基硼氢化钠和129.9mg(3.21mmol)乙酸,并将混合物在室温下搅拌5分钟。加入溶解在15.0ml二氯甲烷中的698.1mg(3.21mmol)(3-氧代丙基)氨基甲酸2-(三甲基甲硅烷基)乙酯(中间体L58),并将反应混合物在室温下搅拌过夜。将反应混合物用乙酸乙酯稀释,并将有机相用饱和碳酸钠溶液和饱和NaCl溶液洗涤各两次。有机相用硫酸镁干燥,并减压蒸发溶剂。将残余物在硅胶(流动相:二氯甲烷/甲醇=100:2)上纯化。减压蒸发溶剂,并残余物在高真空下干燥。这得到1.25g(理论值的73%)的化合物:[3-({(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}氨基)丙基]氨基甲酸2-(三甲基甲硅烷基)乙酯。
LC-MS(方法1):Rt=1.09min;MS(ESIpos):m/z=556(M+H)+。
首先,将908.1mg(1.63mmol)[3-({(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}氨基)丙基]氨基甲酸2-(三甲基甲硅烷基)乙酯和545.6mg(5.39mmol)三乙胺加入10.0ml二氯甲烷中,并将混合物冷却至0℃。在此温度下,加入590.5mg(5.23mmol)氯乙酰氯,并将混合物在室温下搅拌过夜。反应混合物用乙酸乙酯稀释,并将有机相用饱和碳酸氢钠溶液和饱和氯化铵溶液洗涤各三次。用饱和NaCl溶液洗涤有机相,并用硫酸镁干燥。通过制备型RP-HPLC(柱:Reprosil 250x30;10μ,流速:50毫升/分钟,MeCN/水,0.1%TFA)纯化残余物。减压蒸发溶剂,并将残余物在高真空下干燥。这得到673.8mg(理论值的65%)的标题化合物。
LC-MS(方法1):Rt=1.53min;MS(ESIneg):m/z=676(M+HCOO-)-。
中间体C71
S-(11-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2,2-二甲基-6,12-二氧代-5-氧杂-7,11-二氮杂-2-硅杂十三烷-13-基)-L-半胱氨酸/三氟乙酸(1:1)
将536.6mg(4.43mmol)L-半胱氨酸与531.5mg(6.33mmol)碳酸氢钠一起悬浮在2.5ml水中。加入溶解在25.0ml异丙醇中的400.0mg(0.63mmol){3-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}(氯乙酰基)氨基]丙基}氨基甲酸2-(三甲基甲硅烷基)乙酯(中间体C70)和1.16g(7.59mmol)1,8-二氮杂双环[5.4.0]十一碳-7-烯。将反应混合物在50℃下搅拌1.5小时。向反应混合物中加入乙酸乙酯,有机相用饱和碳酸氢钠溶液反复洗涤,并用饱和NaCl溶液洗涤一次。有机相用硫酸镁干燥,减压蒸发溶剂,并将残余物在高真空下干燥。通过制备型RP-HPLC(柱:Reprosil 250x30;10μ,流速:50毫升/分钟,MeCN/水,0.1%TFA)纯化残余物。减压蒸发溶剂,并将残余物在高真空下干燥。这得到449.5mg(理论值的86%)的标题化合物。
LC-MS(方法1):Rt=1.20min;MS(ESIpos):m/z=717(M+H)+。
中间体C80
S-(11-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2,2-二甲基-6,12-二氧代-5-氧杂-7,11-二氮杂-2-硅杂十三烷-13-基)-N-[15-(甘氨酰基氨基)-4,7,10,13-四氧杂十五烷-1-酰基]-L-半胱氨酸三氟乙酸(1:1)
首先,在氩气下,将43.4mg(95.1μmol)的1-({N-[(苄氧基)羰基]甘氨酰基}氨基)-3,6,9,12-四氧杂十五烷-15-酸(中间体L90)加入2.5ml DMF,加入14.6mg(95.1μmol)1-羟基-1H-苯并***水合物,30.5mg(95.1μmol)(苯并***-1-基氧基)双二甲基氨基碳鎓氟硼酸盐和16.5μl(95.1μmol)N,N-二异丙基乙胺,并将混合物搅拌10分钟。将79.0mg(95.1μmol)S-(11-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2,2-二甲基-6,12-二氧代-5-氧杂-7,11-二氮杂-2-硅杂十三烷-13-基)-L-半胱氨酸三氟乙酸(1:1)(中间体C71)溶于2.5ml DMF中,加入49.5μl(285.3μmol)N,N-二异丙基乙胺,并将混合物加入到反应中。将反应混合物在室温下搅拌2小时,并通过制备型RP-HPLC(柱:Reprosil 125x30;10μ,流速:50毫升/分钟,MeCN/水,0.1%TFA)直接纯化。减压蒸发溶剂,并将残余物在高真空下干燥。这得到44.2mg(理论值的40%)的化合物:S-(11-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2,2-二甲基-6,12-二氧代-5-氧杂-7,11-二氮杂-2-硅杂十三烷-13-基)-N-[15-({N-[(苄氧基)羰基]甘氨酰基}氨基)-4,7,10,13-四氧杂十五烷-1-酰基]-L-半胱氨酸。
LC-MS(方法12):Rt=2.57min;MS(ESIpos):m/z=1156[M+H]+。
将60.2mg(52.1μmol)S-(11-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2,2-二甲基-6,12-二氧代-5-氧杂-7,11-二氮杂-2-硅杂十三烷-13-基)-N-[15-({N-[(苄氧基)羰基]甘氨酰基}氨基)-4,7,10,13-四氧杂十五烷-1-酰基]-L-半胱氨酸悬浮在3.0ml乙醇中,加入6.0mg活性炭载钯(10%),并将混合物在室温和标准压力下用氢气氢化1小时。两次加入6.0mg活性炭载钯(10%)并将混合物在室温和标准压力下用氢气氢化1小时。滤除催化剂,减压从反应混合物除去溶剂,并在高真空下干燥。通过制备型RP-HPLC(柱:Reprosil125x30;10μ,流速:50毫升/分钟,MeCN/水,0.1%TFA)纯化残余物。减压蒸发溶剂,并将残余物在高真空下干燥。这得到29.4mg(理论值的50%)的标题化合物。
LC-MS(方法5):Rt=3.77min;MS(ESIpos):m/z=1021[M+H]+。
中间体L1
三氟乙酸/N-(2-氨基乙基)-2-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙酰胺(1:1)
通过肽化学的经典方法,由市售(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙酸和(2-氨基乙基)氨基甲酸叔丁酯制备标题化合物。
HPLC(方法11):Rt=0.19分钟;
LC-MS(方法1):Rt=0.17min;MS(ESIpos):m/z=198(M+H)+。
中间体L57
(2S)-4-氧代-2-({[2-(三甲基甲硅烷基)乙氧基]羰基}氨基)丁酸甲酯
首先,将500.0mg(2.72mmol)L-天冬酰胺甲酯盐酸盐和706.3mg(2.72mmol)2,5-二氧代吡咯烷-1-甲酸2-(三甲基甲硅烷基)乙酯加入5.0ml 1,4-二噁烷中,并加入826.8mg(8.17mmol)三乙胺。将反应混合物在RT搅拌过夜。通过制备型RP-HPLC(柱:Reprosil250x40;10μ,流速:50毫升/分钟,MeCN/水,0.1%TFA)直接纯化反应混合物。然后减压蒸发溶剂,并且残余物在高真空下干燥。这得到583.9mg(理论值的74%)的化合物:(3S)-4-甲氧基-4-氧代-3-({[2-(三甲基甲硅烷基)乙氧基]羰基}氨基)丁酸。
LC-MS(方法1):Rt=0.89分钟;MS(ESIneg):m/z=290(M-H)-。
首先,将592.9mg(3S)-4-甲氧基-4-氧代-3-({[2-(三甲基甲硅烷基)乙氧基]羰基}氨基)丁酸加入10.0ml 1,2-二甲氧基乙烷中,冷却混合物至-15℃,并加入205.8mg(2.04mmol)4-甲基吗啉和277.9mg(2.04mmol)氯甲酸异丁酯。15分钟后抽滤出沉淀物,并且进行两次,每次用10.0ml 1,2-二甲氧基乙烷。将滤液冷却至-10℃,并在剧烈搅拌下加入溶解在10ml水中的115.5mg(3.05mmol)硼氢化钠。分离各相,并用饱和碳酸氢钠溶液和饱和NaCl溶液洗涤有机相各一次。有机相用硫酸镁干燥,减压蒸发溶剂,并将残余物在高真空下干燥。这得到515.9mg(理论值的91%)的化合物:N-{[2-(三甲基甲硅烷基)乙氧基]羰基}-L-高丝氨酸甲酯。
LC-MS(方法1):Rt=0.87分钟;MS(ESIpos):m/z=278(M+H)+。
首先,将554.9mg(2.00mmol)N-{[2-(三甲基甲硅烷基)乙氧基]羰基}-L-高丝氨酸甲酯加入30.0ml二氯甲烷中,并加入1.27g(3.0mmol)戴斯-马丁氧化剂和474.7mg(6.00mmol)吡啶。将混合物在室温下搅拌过夜。4小时后,将反应用二氯甲烷稀释,有机相用10%强度的Na2S2O3溶液、10%强度的柠檬酸溶液和饱和碳酸氢钠溶液洗涤各三次。有机相用硫酸镁干燥,并减压蒸发溶剂。这得到565.7mg(理论值的97%)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.03(s,9H),0.91(m,2H),2.70-2.79(m,1H),2.88(dd,1H),3.63(s,3H),4.04(m,2H),4.55(m,1H),7.54(d,1H),9.60(t,1H).
中间体L58
(3-氧代丙基)氨基甲酸2-(三甲基甲硅烷基)乙酯
将434.4mg(5.78mmol)3-氨基-1-丙醇和1.50g(5.78mmol)2,5-二氧代吡咯烷-1-甲酸2-(三甲基甲硅烷基)乙酯溶于10.0ml二氯甲烷中,加入585.3mg(5.78mmol)三乙胺,并将混合物在室温下搅拌过夜。将反应混合物用二氯甲烷稀释,将有机相用水和饱和碳酸氢钠溶液洗涤,然后用硫酸镁干燥。减压蒸发溶剂。将残余物(3-羟丙基)氨基甲酸2-(三甲基甲硅烷基)乙酯(996.4mg,理论值的79%)在高真空下干燥,并在下一步合成中使用而无需进一步纯化。
首先,将807.0mg(3.68mmol)(3-羟丙基)氨基甲酸2-(三甲基甲硅烷基)乙酯加入15.0ml氯仿和15.0ml 0.05N碳酸钾/0.05N碳酸氢钠溶液(1∶1)中。然后加入102.2mg(0.37mmol)氯化四正丁基铵、736.9mg(5.52mmol)N-氯代琥珀酰亚胺和57.5mg(0.37mmol)TEMPO,并将反应混合物在室温下剧烈搅拌过夜。将反应混合物用二氯甲烷稀释,且有机相用水和饱和NaCl溶液洗涤。有机相用硫酸镁干燥,且减压蒸发溶剂。将残余物在高真空下干燥,并在下一步合成中使用而无需进一步纯化(890.3mg)。
中间体L74
3-[2-[2-[2-[2-[[2-(2,5-二氧代吡咯-1-基)乙酰基]氨基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸
将107mg(0.335mmol)3-[2-[2-[2-(2-氨基乙氧基)乙氧基]乙氧基]乙氧基]丙酸叔丁酯和93mg(0.369mmol)2-(2,5-二氧代吡咯-1-基)乙酸(2,5-二氧代吡咯烷-1-基)酯溶于5ml二甲基甲酰胺中,并加入0.074ml(0.671mmol)N-甲基吗啉。将反应混合物在RT搅拌过夜。加入0.048ml(0.838mmol)乙酸,并通过制备型RP-HPLC(柱:Reprosil 125x30;10μ,流速:50毫升/分钟,MeCN/水/0.1%TFA)直接纯化反应混合物。减压蒸发溶剂,并将残余物在高真空下干燥。这得到133mg(86%,纯度100%)的3-[2-[2-[2-[2-[[2-(2,5-二氧代吡咯-1-基)乙酰基]氨基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯。
LC-MS(方法1):Rt=0.82分钟;MS(ESIpos):m/z=459(M+H)+。
将0.5ml TFA加入到3-[2-[2-[2-[2-[[2-(2,5-二氧代吡咯-1-基)乙酰基]氨基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯(130mg,0.284mmol)在5ml二氯甲烷中的溶液中。将反应混合物在RT搅拌过夜。减压浓缩反应混合物,并将残余物溶于水中并冻干。将残余物不经进一步纯化继续使用。这得到102mg(90%,纯度100%)的标题化合物。
LC-MS(方法1):Rt=0.52分钟;MS(ESIpos):m/z=402(M+H)+。
中间体L90
1-({N-[(苄氧基)羰基]甘氨酰基}氨基)-3,6,9,12-四氧杂十五烷-15-酸
首先,将118mg(566μmol)N-[(苄氧基)羰基]甘氨酸加入5.0ml DMF中,加入200mg(622μmol)1-氨基-3,6,9,12-四氧杂十五烷-15-酸叔丁酯、130mg(849μmol)1-羟基-1H-苯并***水合物和130mg(679μmol)的1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐,并将混合物在室温下搅拌1小时。加入乙酸乙酯,并将混合物用5%强度的柠檬酸溶液和饱和碳酸氢钠溶液萃取两次。将有机相用饱和氯化钠溶液洗涤两次并用硫酸镁干燥。减压蒸发溶剂,并将残余物在高真空下干燥。这得到274mg(理论值的95%)1-({N-[(苄氧基)羰基]甘氨酰基}氨基)-3,6,9,12-四氧杂十五烷-15-酸叔丁酯。
LC-MS(方法12):Rt=1.69分钟;MS(ESIpos):m/z=513(M+H)+。
将820μl(11mmol)TFA加入到274mg(535μmol)1-({N-[(苄氧基)羰基]甘氨酰基}氨基)-3,6,9,12-四氧杂十五烷-15-酸叔丁酯在5.0ml二氯甲烷中的溶液中。将反应混合物在室温下搅拌3小时。减压浓缩反应混合物,并将残余物溶于水中并冻干。这得到262mg(理论值的100%)的标题化合物。
LC-MS(方法12):Rt=1.12分钟;MS(ESIpos):m/z=457(M+H)+。
中间体F104
三氟乙酸/(2S)-2-氨基-4-[{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基(乙醇酰基)氨基]-N-(2-{[(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙酰基]氨基}乙基)丁酰胺(1:1)
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首先,在13mg(0.034mmol)HATU和10μl N,N-二异丙基乙胺的存在下,使15mg(0.023mmol)中间体C58与11mg(0.036mmol)中间体L1反应。在室温下搅拌60分钟后,浓缩混合物并通过制备型HPLC纯化残余物。这得到12.3mg(理论值的63%)的受保护的中间体。
LC-MS(方法1):Rt=1.3分钟;MS(EIpos):m/z=837[M+H]+。
在第二步中,将该中间体溶于3ml 2,2,2-三氟乙醇中。加入12mg(0.088mmol)氯化锌,并将反应在50℃下搅拌2小时。然后加入26mg(0.088mmol)乙二胺-N,N,N',N'-四乙酸和2ml 0.1%强度的三氟乙酸水溶液。通过制备型HPLC纯化反应。浓缩合适的级分并将残余物从乙腈/水中冷冻干燥,得到8.1mg(理论值的68%)的标题化合物。
LC-MS(方法1):Rt=0.89分钟;MS(ESIpos):m/z=693(M+H)+。
中间体F257
R-{2-[(3-氨基丙基){(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}氨基]-2-氧代乙基}-N-[18-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-17-氧代-4,7,10,13-四氧杂-16-氮杂十八烷-1-酰基]-L-半胱氨酸/三氟乙酸(1:1)
将50.0mg(0.06mmol)R-(11-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2,2-二甲基-6,12-二氧代-5-氧杂-7,11-二氮杂-2-硅杂十三烷-13-基)-L-半胱氨酸/三氟乙酸(1:1)(中间体C71)和29mg(0.07mmol)3-[2-[2-[2-[2-[[2-(2,5-二氧代吡咯-1-基)乙酰基]氨基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸(中间体L74)溶于3.0ml DMF中,并加入27.3mg(0.07mmol)HATU和23.3mg(0.18mmol)N,N-二异丙基乙胺。将反应混合物在室温下搅拌2小时。通过制备型RP-HPLC(柱:Reprosil 125x30;10μ,流速:50毫升/分钟,MeCN/水/0.1%TFA)直接纯化反应混合物。减压蒸发溶剂,并将残余物在高真空下干燥。这得到17.4mg(26%)化合物R-(11-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2,2-二甲基-6,12-二氧代-5-氧杂-7,11-二氮杂-2-硅杂十三烷-13-基)-N-[18-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-17-氧代-4,7,10,13-四氧杂-16-氮杂十八烷-1-酰基]-L-半胱氨酸。
LC-MS(方法6):Rt=1.34分钟;MS(ESIpos):m/z=1101(M+H)+。
将17mg(0.02mmol)R-(11-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2,2-二甲基-6,12-二氧代-5-氧杂-7,11-二氮杂-2-硅杂十三烷-13-基)-N-[18-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-17-氧代-4,7,10,13-四氧杂-16-氮杂十八烷-1-酰基]-L-半胱氨酸溶于1.0ml三氟乙醇中,并加入6.3mg(0.05mmol)二氯化锌。将该反应混合物在50℃下搅拌过夜。加入13.5mg(0.05mmol)乙二胺-N,N,N',N'-四乙酸,将反应混合物搅拌10分钟,然后加入水(0.1%TFA)。通过制备型RP-HPLC(柱:Reprosil 125x30;10μ,流速:50毫升/分钟,MeCN/水,0.1%TFA)直接进行纯化。减压蒸发溶剂,并将残余物在高真空下干燥。这得到7.6mg(46%)的标题化合物。
LC-MS(方法1):Rt=0.91分钟;MS(ESIpos):m/z=957(M+H)+。
B:抗体药物缀合物(ADC)的制备
B-1.产生抗-CD123抗体的一般方法
通过CDR移植获得抗-CD123抗体。7G3抗体的序列(EP2426148)代表人源化抗体例如TPP-5969,TPP-8987和TPP-9476的起始点。基于12F1的双特异性scFv免疫融合蛋白公开于WO2013/173820中。基于12F1的可变区(VH和VL)的序列的公开(WO2013/173820),通过供体免疫球蛋白的可变结构域(VH和VL)与人抗体恒定区的融合获得以下抗体序列。产生12F1的嵌合变体。通过CDR移植获得人源化抗-CD123抗体,其代表人源化抗体例如TPP-8988和TPP-9342的起始点。
人源化
通过将CDR转移到人抗体骨架中来人源化7G3抗体的鼠抗体序列。有关根据Kabat的CDR的定义,请参阅Andre C.R.Martin,“Protein sequence and structure analysisof antibody variable domains”in Antibody Engineering(Springer Lab Manuals),Eds.:Duebel,S.和Kontermann,R.,Springer-Verlag,Heidelberg。在将鼠框架序列(没有CDR)与人种系序列进行比较后,选择了类似的频率出现的人框架序列。在这种情况下,它是具有J序列IGHJ4-03的重链IGHV1-46-01和具有J区段IGKJ2的轻链IGKV4-1-01。种系序列源于VBASE2数据库(Retter I,Althaus HH,Münch R,Müller W:VBASE2,an integrative Vgene database.Nucleic Acids Res.2005Jan 1;33(Database issue):D671-4)。使用IMGT***命名序列(Lefranc,M.-P.,Giudicelli,V.,Ginestoux,C.,Jabado-Michaloud,J.,Folch,G.,Bellahcene,F.,Wu,Y.,Gemrot,E.,Brochet,X.,Lane,J.,Regnier,L.,Ehrenmann,F.,Lefranc,G.和Duroux,P.the international ImMunoGeneTicsinformation />Nucl.Acids Res,37,D1006-D1012(2009);doi:10.1093/nar/gkn838)。本文所述的抗体变体TPP-5969、TPP-8987和TPP-9476携带不同于人种系序列的各种点突变,这可能影响它们的性质。除了嵌合抗体TPP-6013,人源化抗体通过将CDR转移到人抗体骨架中而获得,如TPP-8988和TPP-9342。
B-2.在哺乳动物细胞中表达抗-CD123抗体的一般方法
抗体,例如TPP-6013、TPP-5969、TPP-8987、TPP-8988、TPP-9476和TPP-9342是在哺乳动物细胞的瞬时培养物中产生的,如Tom等人,在Methods Express:ExpressionSystems,Micheal R.Dyson和Yves Durocher编辑,第12章,Scion Publishing Ltd,2007中所述。
B-3.从细胞上清液中纯化抗体的一般方法
从细胞培养上清液中获得抗体,例如TPP-8987和TPP-8988。通过离心细胞澄清细胞上清液。然后在MabSelect Sure(GE Healthcare)色谱柱上通过亲和色谱法纯化细胞上清液。为此,将柱在DPBS pH 7.4(Sigma/Aldrich)中平衡,施加细胞上清液并用约10倍柱体积的DPBS pH 7.4+500mM氯化钠洗涤柱。将抗体在50mM乙酸钠pH 3.5+500mM氯化钠中洗脱,然后在Superdex 200柱(GE Healthcare)上DPBS pH 7.4中通过凝胶过滤色谱进一步纯化。
此外,抗体的特征在于它们通过BIAcore分析的对可溶性IL3Rα(从R&D Systems获得)的结合亲和力。为了确定抗-CD123抗体的细胞结合特征,通过流式细胞术在CD123阳性癌细胞系MOLM-13上测量结合。
B-4.偶联到半胱氨酸侧链的一般方法
以下抗体用于偶联反应:
TPP-5969
TPP-6013
TPP-8987
TPP-8988
TPP-9476
偶联反应通常在氩气下进行。
将溶解在PBS缓冲液中的2至5当量的三(2-羧乙基)膦盐酸盐(TCEP)加入到适当抗体在PBS缓冲液中的溶液中(浓度范围为1mg/ml至20mg/ml,优选在约10mg/ml至15mg/ml的范围内),并将混合物在室温下搅拌30分钟。为此目的,所用各抗体的溶液可以以工作实施例中所述的浓度使用,或者也可以任选地用PBS缓冲液稀释至所述起始浓度的约一半,以达到优选的浓度范围。随后,取决于预期的载量,将2至12当量,优选约5-10当量的待偶联的马来酰亚胺前体化合物作为在DMSO中的溶液加入。这里,DMSO的量不应超过总体积的10%。将反应在室温下搅拌60-240分钟,然后用预先调节至pH8的PBS缓冲液稀释。然后将溶液应用于PBS pH8-平衡的PD10柱(G-25,GE Healthcare)并用PBS pH 8缓冲液洗脱。可以用pH8的PBS缓冲液稀释洗脱液。将该溶液在室温和氩气下搅拌过夜。然后将溶液重新缓冲至pH 7.2。然后通过超速离心浓缩样品,并任选地用PBS缓冲液重新稀释。如果需要,为了更好地除去低分子量组分,在用PBS缓冲液重新稀释后重复超滤浓缩。对于生物学测试,如果需要,通过重新稀释任选地将最终ADC样品的浓度调节至0.5-15mg/ml的范围。确定了ADC溶液的工作实施例中所述的对应蛋白浓度。此外,使用B-7中描述的方法测定抗体载量(药物/mAb比率)。
实施例中显示的ADC也可以以与抗体连接的封闭的琥珀酰胺的形式,以更低或更高的程度存在。
在所示的结构式中,AKTPP-XXXX或AK具有以下含义
AK=抗-CD123抗体(部分还原)-S§1
AKTPP5969=抗-CD123 TPP5969(部分还原)-S§1
AKTPP6013=抗-CD123 TPP6013(部分还原)-S§1
AKTPP8987=抗-CD123 TPP8987(部分还原)-S§1
AKTPP8988=抗-CD123 TPP8988(部分还原)-S§1
AKTPP9476=抗-CD123 TPP9476(部分还原)-S§1
其中
§1表示与琥珀酰亚胺基团或与任何异构水解开链琥珀酰胺或由其产生的亚烷基的键连(linkage),
和
S代表部分还原的抗体的半胱氨酸残基的硫原子。
B-6a.制备异构开放琥珀酰胺-半胱氨酸加合物的一般方法:
在一个示例性实施方案中,将68μmol上述马来酰亚胺前体化合物溶于15ml DMF中,并添加36mg(136μmol)N-{[2-(三甲基甲硅烷基)乙氧基]羰基}-L-半胱氨酸。将反应混合物在室温下搅拌~20小时,然后在减压下浓缩,然后通过制备型HPLC纯化。合并合适的级分,减压蒸发溶剂,然后将残余物溶于15ml THF/水(1:1)中。加入131μl 2M氢氧化锂水溶液,且将反应在室温下搅拌1小时。然后用1M盐酸中和反应,减压蒸发溶剂,且将残余物用制备型HPLC纯化。这得到理论值的约50%的为无色泡沫的区域异构保护的中间体。
在最后一步中,将0.023mmol的这些区域异构水解产物溶解在3ml的2,2,2-三氟乙醇中。加入12.5mg(0.092mmol)氯化锌,并将反应在50℃下搅拌4小时。然后加入27mg(0.092mmol)乙二胺-N,N,N',N'-四乙酸,且减压蒸发溶剂。通过制备型HPLC纯化残余物。浓缩合适的级分并将残余物从乙腈/水中冷冻干燥,得到为区域异构体混合物的水解的开环巯基琥珀酰胺(sulphanylsuccinamide)。
根据本发明的缀合物的进一步纯化和表征
在反应之后,在一些情况下,将反应混合物浓缩,例如通过超滤,然后脱盐并通过色谱法纯化,例如使用G-25柱。例如,用磷酸盐缓冲盐水(PBS)进行洗脱。然后将溶液无菌过滤并冷冻。或者,可以将缀合物冻干。
B-7.测定抗体、毒性基团载量和开放半胱氨酸加合物的比例
对于在去糖基化和/或变性后的分子量测定之外的蛋白质鉴定,进行胰蛋白酶消化,其在变性、还原和衍生化后,通过发现的胰蛋白酶肽确认蛋白质的特性。
由工作实施例中描述的缀合物获得的PBS缓冲溶液的毒性基团载量如下测定:
通过质谱法测定单个缀合物种类的分子量,进行赖氨酸连接的ADC的毒性基团载量的测定。此处,首先,用PNGaseF将抗体缀合物去糖基化,并将样品酸化,在HPLC分离/脱盐后,使用ESI-MicroTofQ(Bruker Daltonik)通过质谱法分析。添加TIC(总离子色谱图)中信号的所有光谱,并基于MaxEnt去卷积计算不同缀合物种类的分子量。然后在不同种类的信号积分后计算DAR(=药物/抗体比率)。
通过还原和变性的ADC的反相色谱法测定半胱氨酸连接的缀合物的毒性基团载量。将盐酸胍(GuHCl)(28.6mg)和DL-二硫苏糖醇(DTT)溶液(500mM,3μl)加入到ADC溶液(1mg/ml,50μl)中。将混合物在55℃下温育1小时,并通过HPLC分析。
HPLC分析在Agilent 1260HPLC***上进行,检测波长为220nm。使用PolymerLaboratories PLRP-S聚合物反相柱(目录号PL1912-3802)(2.1×150mm,8μm粒径, ),以1ml/min的流速以及以下梯度:0分钟,25%B;3分钟,25%B;28分钟,50%B。流动相A由0.05%三氟乙酸(TFA)/水组成,流动相B由0.05%三氟乙酸/乙腈组成。
通过与未缀合抗体的轻链(L0)和重链(H0)的保留时间比较来指定检测到的峰。仅在缀合样品中检测到的峰被指定为具有一个毒性基团的轻链(L1)和具有一个、两个和三个毒性基团的重链(H1,H2,H3)。
由通过积分确定的峰面积计算具有毒性基团的抗体的平均载量,其为HC载量和LC载量之和的两倍,其中LC载量由所有LC峰的毒性基团数均加权积分结果的总和除以所有LC峰的单个加权积分结果的总和计算,并且其中HC载量由所有HC峰的毒性基团数均加权积分结果的总和除以所有HC峰的单个加权积分结果的总和计算。在个别情况下,由于某些峰的共洗脱,可能无法准确地确定毒性基团载荷。
在通过HPLC不能充分分离轻链和重链的情况下,通过质谱法测定轻链和重链上各个缀合物种类的分子量,进行半胱氨酸连接的缀合物的毒性基团载量的测定。
将盐酸胍(GuHCl)(28.6mg)和DL-二硫苏糖醇(DTT)溶液(500mM,3μl)加入到ADC溶液(1mg/ml,50μl)中。将混合物在55℃温育1小时,并在使用ESI-MicroTofQ(BrukerDaltonik)在线脱盐后通过质谱法分析。
对于DAR测定,将所有光谱添加到TIC(总离子色谱图)中的信号上,并且基于MaxEnt去卷积计算轻链和重链上的不同缀合物种类的分子量。由通过积分确定的峰面积计算具有毒性基团的抗体的平均载量,其为HC载量和LC载量之和的两倍,其中LC载量由所有LC峰的毒性基团数均加权积分结果的总和除以所有LC峰的单个加权积分结果的总和计算,并且其中HC载量由所有HC峰的毒性基团数均加权积分结果的总和除以所有HC峰的单个加权积分结果的总和计算。
为了确定开放半胱氨酸加合物的比例,测定所有单缀合的轻链和重链变体的闭合半胱氨酸加合物与开放半胱氨酸加合物(分子量Δ18道尔顿)的分子量面积比。所有变体的平均值产生开放半胱氨酸加合物的比例。
B-8.检查ADC的抗原结合
在偶联发生后检查结合剂与靶分子结合的能力。本领域技术人员熟悉可用于此目的的各种方法;例如,可以使用ELISA技术或表面等离子体共振分析(BIAcoreTM测量)检查缀合物的亲和力。缀合物浓度可由本领域技术人员使用常规方法测量,例如通过蛋白质测定法测定抗体缀合物。(也参见Doronina等人,Nature Biotechnol.2003;21:778-784和Polson等人,Blood 2007;1102:616-623)。
代谢物实施方案
实施例M20
(1R,4R,27R,33R)-1-氨基-32-(3-氨基丙基)-33-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-34,34-二甲基-6,9,25,31-四氧代-13,16,19,22-四氧杂-3,29-二硫杂-7,10,26,32-四氮杂三十五烷-1,4,27-三甲酸/三氟乙酸酸(1:2)
首先,在N,N-二异丙基乙胺存在下,用DMF中的1-({[2-(三甲基甲硅烷基)乙氧基]羰基}氧基)吡咯烷-2,5-二酮,将L-半胱氨酸甲酯盐酸盐(1:1)转化为N-{[2-(三甲基甲硅烷基)乙氧基]羰基}-L-半胱氨酸甲酯。
将408mg(1.93mmol)市售3-溴-4-甲氧基-4-氧代丁酸和180mg(0.644mmol)N-{[2-(三甲基甲硅烷基)乙氧基]羰基}-L-半胱氨酸甲酯溶解于8ml DMF中,并加入147mg(0.97mmol)1,8-二氮杂双环[5.4.0]十一碳-7-烯。在室温下搅拌18小时后,加入另外136mg(0.64mmol)的3-溴-4-甲氧基-4-氧代丁酸和147mg(0.97mmol)的1,8-二氮杂双环[5.4.0]十一碳-7-烯,并将混合物在室温下再搅拌12小时,然后减压浓缩。通过制备型HPLC纯化残余物。合适的级分的合并和减压蒸发溶剂得到151mg(理论值的57%)的4-甲氧基-3-{[(2R)-3-甲氧基-3-氧代-2-({[2-(三甲基甲硅烷基)乙氧基]羰基}氨基)丙基]硫基}-4-氧代丁酸。
LC-MS(方法12):Rt=1.74分钟;MS(ESIneg):m/z=408(M-H)-。
在3.66mg(8.93μmol)HATU和1.6μl(15μmol)4-甲基吗啉的存在下,将3.66mg(8.93μmol)4-甲氧基-3-{[(2R)-3-甲氧基-3-氧代-2-({[2-(三甲基甲硅烷基)乙氧基]羰基}氨基)丙基]硫基}-4-氧代丁酸与13.0mg(7.44μmol)S-(11-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2,2-二甲基-6,12-二氧代-5-氧杂-7,11-二氮杂-2-硅杂十三烷-13-基)-N-[15-(甘氨酰基氨基)-4,7,10,13-四氧杂十五烷-1-酰基]-L-半胱氨酸/三氟乙酸(1:1)(中间体C80)偶联,在HPLC纯化后得到3.9mg(理论值的37%)的完全保护的中间体S-(11-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2,2-二甲基-6,12-二氧代-5-氧杂-7,11-二氮杂-2-硅杂十三烷-13-基)-N-[15-({N-[(8R,11R)-8,11-二(甲氧羰基)-2,2-二甲基-6,13-二氧代-5-氧杂-10-硫杂-7-氮杂-2-硅杂十三烷-13-基]甘氨酰基}氨基)-4,7,10,13-四氧杂十五烷-1-酰基]-L-半胱氨酸。
然后,将3.90mg(2.76μmol)该中间体在室温下与35μl的2M氢氧化锂溶液在1.0mlTHF/水3:1中一起搅拌15分钟,导致两个甲酯基团的裂解。通过HPLC纯化,得到3.60mg(理论值的94%)的二羧酸衍生物。
LC-MS(方法5):Rt=4.83分钟;MS(ESIpos):m/z=1385[M+H]+。
最后,如上所述,用三氟乙醇中的氯化锌,将3.6mg(2.6μmol)该中间体完全脱保护。通过制备型HPLC纯化残余物。浓缩合适的级分并将残余物从乙腈/水中冷冻干燥,得到1.92mg(理论值的55%)的标题化合物。
LC-MS(方法5):Rt=2.72分钟;MS(ESIneg):m/z=1094[MH]-。
实施例M21
(2R,24S,27R)-27-氨基-2-[({2-[(3-氨基丙基){(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}氨基]-2-氧代乙基}硫基)甲基]-24-(羧甲基)-4,20,23-三氧代-7,10,13,16-四氧杂-25-硫杂-3,19,22-三氮杂二十八烷-1,28-二酸/三氟乙酸(1:2)
将742.8mg(3.3mmol)市售的2-溴-4-乙氧基-4-氧代丁酸和802mg(2.87mmol)的N-{[2-(三甲基甲硅烷基)乙氧基]羰基}-L-半胱氨酸甲酯溶解于32ml DMF,并加入655.4mg(4.31mmol)1,8-二氮杂双环[5.4.0]十一碳-7-烯。在室温下搅拌20小时后,将反应减压浓缩,并将残余物通过制备型HPLC纯化。合适的级分的合并和减压蒸发溶剂得到521mg(理论值的43%)的4-乙氧基-2-{[(2R)-3-甲氧基-3-氧代-2-({[2-(三甲基甲硅烷基)乙氧基]羰基}氨基)丙基]硫基}-4-氧代丁酸。
LC-MS(方法5):Rt=3.13分钟;MS(ESIpos):m/z=424(M+H)+。
在3.92mg(10.3μmol)HATU和1.9μl(17μmol)4-甲基吗啉的存在下,将4.36mg(10.3μmol)的4-乙氧基-2-{[(2R)-3-甲氧基-3-氧代-2-({[2-(三甲基甲硅烷基)乙氧基]羰基}氨基)丙基]硫基}-4-氧代丁酸与15.0mg(8.59μmol)S-(11-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2,2-二甲基-6,12-二氧代-5-氧杂-7,11-二氮杂-2-硅杂十三烷-13-基)-N-[15-(甘氨酰基氨基)-4,7,10,13-四氧杂十五烷-1-酰基]-L-半胱氨酸/三氟乙酸(1:1)(中间体C80)偶联,在HPLC纯化后得到3.6mg(理论值的26%)的完全保护的中间体S-(11-{(1R)-1-[1-苄基-4-(2,5-二氟苯基)-1H-吡咯-2-基]-2,2-二甲基丙基}-2,2-二甲基-6,12-二氧代-5-氧杂-7,11-二氮杂-2-硅杂十三烷-13-基)-N-[15-({N-[(8R,11S)-11-(2-乙氧基-2-氧代乙基)-8-(甲氧基羰基)-2,2-二甲基-6,12-二氧代-5-氧杂-10-硫杂-7-氮杂-2-硅杂十二烷-12-基]甘氨酰基}氨基)-4,7,10,13-四氧杂十五烷-1-酰基]-L-半胱氨酸。
然后,将6.20mg(2.82μmol)该中间体在室温下与35μl的2M氢氧化锂溶液在1.0mlTHF/水(1:1)中一起搅拌15分钟,导致两个酯基团的裂解。通过HPLC酸化和纯化,得到3.60mg(理论值的92%)的二羧酸衍生物。
LC-MS(方法5):Rt=4.71分钟;MS(ESIpos):m/z=1385[M+H]+。
最后,如上所述,用三氟乙醇中的氯化锌,将3.60mg(1.69μmol)该中间体完全脱保护。通过制备型HPLC纯化残余物。浓缩合适的级分并将残余物从乙腈/水中冷冻干燥,得到0.88mg(理论值的39%)的标题化合物。
LC-MS(方法5):Rt=2.72分钟;MS(ESIneg):m/z=1094[MH]-。
工作实施例ADC
取决于接头和偶联程序,在工作实施例的结构式中显示的ADC(其通过马来酰亚胺基团与抗体的半胱氨酸侧链偶联)主要以每种情况下显示的开环形式存在。然而,制剂可包含一小部分闭环形式。
闭环形式是:
Ref 208m1
在氩气下,将1.4mg TCEP在0.83ml PBS缓冲液中的溶液加入到21.7ml PBS中的250mg抗-CD123 TPP-5969(c=11.5mg/ml)中。将反应物在室温下搅拌30分钟,然后加入溶解在2500μl DMSO中的10.76mg(0.0133mmol)中间体F104。在室温下再搅拌90分钟后,使用PD-10柱(G-25,GE Healthcare),将反应物再缓冲至pH8。将洗脱液在室温下在氩气下搅拌过夜,然后使用PD-10柱重新缓冲至pH 7.2。然后,用PBS缓冲液(pH7.2)将洗脱液稀释至125ml,通过超速离心浓缩,用PBS缓冲液(pH7.2)重新稀释并再次再浓缩。获得的ADC批次的特征如下:
蛋白质浓度:9.79mg/ml
药物/mAb比率:2.9。
Ref 208m3
在氩气下,将1.4mg TCEP在0.83ml PBS缓冲液中的溶液加入到21.7ml PBS中的250mg抗-CD123 TPP-6013(c=11.5mg/ml)中。将反应物在室温下搅拌30分钟,然后加入溶解在2500μl DMSO中的10.76mg(0.0133mmol)中间体F104。在室温下再搅拌90分钟后,使用PD-10柱(G-25,GE Healthcare),将反应物再缓冲至pH8。将洗脱液在室温下在氩气下搅拌过夜,然后使用PD-10柱重新缓冲至pH 7.2。然后,用PBS缓冲液(pH7.2)将洗脱液稀释至125ml,通过超速离心浓缩,用PBS缓冲液(pH7.2)重新稀释并再次再浓缩。获得的ADC批次的特征如下:
蛋白质浓度:11.06mg/ml
药物/mAb比率:3.4。
Ref 257m1
在氩气下,将1.4mg TCEP在0.83ml PBS缓冲液中的溶液加入到21.7ml PBS中的250mg抗-CD123 TPP-5969(c=11.5mg/ml)中。将反应物在室温下搅拌30分钟,然后加入溶解在2500μl DMSO中的8.92mg(0.0083mmol)中间体F257。在室温下再搅拌90分钟后,使用PD-10柱(G-25,GE Healthcare),将反应物再缓冲至pH8。将洗脱液在室温下在氩气下搅拌过夜,然后使用PD-10柱重新缓冲至pH 7.2。然后,用PBS缓冲液(pH7.2)将洗脱液稀释至125ml,通过超速离心浓缩,用PBS缓冲液(pH7.2)重新稀释并再次再浓缩。获得的ADC批次的特征如下:
蛋白质浓度:11.27mg/ml
药物/mAb比率:3.6。
Ref 257m3
在氩气下,将1.4mg TCEP在0.83ml PBS缓冲液中的溶液加入到21.7ml PBS中的250mg抗-CD123 TPP-6013(c=11.5mg/ml)中。将反应物在室温下搅拌30分钟,然后加入溶解在2500μl DMSO中的8.92mg(0.0083mmol)中间体F257。在室温下再搅拌90分钟后,使用PD-10柱(G-25,GE Healthcare),将反应物再缓冲至pH8。将洗脱液在室温下在氩气下搅拌过夜,然后使用PD-10柱重新缓冲至pH 7.2。然后,用PBS缓冲液(pH7.2)将洗脱液稀释至125ml,通过超速离心浓缩,用PBS缓冲液(pH7.2)重新稀释并再次再浓缩。获得的ADC批次的特征如下:
蛋白质浓度:13.36mg/ml
药物/mAb比率:3.3。
实施例1a
在氩气下,将0.057mg TCEP在100μl PBS缓冲液中的溶液加入到900μl PBS中的10mg抗-CD123 TPP-8987(c=11.11mg/ml)中。将反应物在室温下搅拌30分钟。然后加入溶解在100μl DMSO中的0.357mg(0.00033mmol)中间体F257。在室温下再搅拌90分钟后,使用PD-10柱(G-25,GE Healthcare),将反应物再缓冲至pH8。将洗脱液在室温下在氩气下搅拌过夜,然后使用PD-10柱重新缓冲至pH 7.2。然后,用PBS缓冲液(pH7.2)将洗脱液稀释至14ml,通过超速离心浓缩,用PBS缓冲液(pH7.2)重新稀释并再次再浓缩。获得的ADC批次的特征如下:
蛋白质浓度:6.30mg/ml
药物/mAb比率:3.1。
实施例1b
在氩气下,将0.143mg TCEP在250μl PBS缓冲液中的溶液加入到2500μl PBS中的25mg抗-CD123 TPP-8988(c=10.0mg/ml)中。将反应物在室温下搅拌30分钟。然后加入溶解在250μl DMSO中的0.893mg(0.00083mmol)中间体F257。在室温下再搅拌90分钟后,使用PD-10柱(G-25,GE Healthcare),将反应物再缓冲至pH8。将洗脱液在室温下在氩气下搅拌过夜,然后使用PD-10柱重新缓冲至pH 7.2。然后,用PBS缓冲液(pH7.2)将洗脱液稀释至14ml,通过超速离心浓缩,用PBS缓冲液(pH7.2)重新稀释并再次再浓缩。获得的ADC批次的特征如下:
蛋白质浓度:10.43mg/ml
药物/mAb比率:4.3。
实施例1c
在氩气下,将0.172mg TCEP在300μl PBS缓冲液中的溶液加入到3000μl PBS中的30mg抗-CD123 TPP-9476(c=10.0mg/ml)中。将反应物在室温下搅拌30分钟。然后加入溶解在300μl DMSO中的1.071mg(0.001mmol)中间体F257。在室温下再搅拌90分钟后,使用PD-10柱(G-25,GE Healthcare),将反应物再缓冲至pH8。将洗脱液在室温下在氩气下搅拌过夜,然后使用PD-10柱重新缓冲至pH 7.2。然后,用PBS缓冲液(pH7.2)将洗脱液稀释至14ml,通过超速离心浓缩,用PBS缓冲液(pH7.2)重新稀释并再次再浓缩。获得的ADC批次的特征如下:
蛋白质浓度:11.04mg/ml
药物/mAb比率:4.4。
C:生物功效的评估
根据本发明的化合物的生物活性可以在下述测定中显示:
C-1a测定ADC针对CD123的细胞毒性作用
抗-CD123 ADC和相应代谢物的细胞毒性作用的分析使用各种细胞系进行:
NCI-H292:人粘液表皮样肺癌细胞,ATCC-CRL-1848,标准培养基:RPMI 1640(Biochrom;#FG1215,稳定的谷氨酰胺)+10%FCS(Biochrom;#S0415)。
MOLM-13:从外周血获得的人急性单核细胞白血病细胞(AML-M5a),DSMZ,No.ACC554,标准培养基:RPMI 1640(Gibco;#21875-059,稳定的L-谷氨酰胺)+20%热灭活FCS(Gibco,No.10500-064);CD123阳性。
THP-1:从外周血获得的人单核细胞白血病细胞,ATCC,No.TIB-202,标准培养基:RPMI 1640(Gibco;#21875--059,稳定的L-谷氨酰胺)+10%热灭活的FCS(Gibco,No.10500-064)+2.5g葡萄糖(20%葡萄糖溶液,Gibco,No.19002);CD123阳性。
MV-4-11:从外周血获得的人双表型B骨髓单核细胞白血病细胞,ATCC-CRL-9591,标准培养基:IMDM(ATCC:30-2005),+10%热灭活FCS(Gibco,No.10500-064);CD123阳性。
KG-1:从骨髓获得的人急性髓细胞白血病细胞,DSMZ,No.ACC 14,标准培养基:RPMI 1640(Gibco;#21875-059,稳定的L-谷氨酰胺)+10%热灭活的FCS(Gibco,No.10500-064)+2.5g葡萄糖(20%葡萄糖溶液,Gibco,No.19002);CD123阳性。
NB4:从骨髓获得的人急性早幼粒细胞白血病细胞,DSMZ,No.ACC 207,标准培养基:RPMI 1640+GlutaMAX I(Invitrogen 61870)+10%热灭活FCS(Gibco,No.10500-064)+2.5g葡萄糖(20%葡萄糖溶液,Gibco,No.19002)+10mM Hepes(Invitrogen 15630)+1mM丙酮酸钠(Invitrogen 11360);CD123阴性。
通过美国组织培养物保藏中心(American Tissue Culture Collection,ATCC)或莱布尼茨研究所DSMZ-德国微生物和细胞培养物保藏中心(Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH,DSMZ)所述的用于所讨论的细胞系的标准方法培养细胞。
MTT测定
使用C-1中列出的生长培养基,根据标准方法培养细胞。测试通过如下进行:用Accutase在PBS中的溶液(Biochrom AG#L2143;在贴壁细胞的情况下)分离细胞,沉淀,重悬于培养基中,计数并接种到具有白底的96孔培养板(Costar#3610)(NCI H292:2500个细胞/孔;MOLM-13:2000个细胞/孔;THP-1:8000个细胞/孔;NB4:7000个细胞/孔;KG-1:5000细胞/孔,MV-4-11:5000个细胞/孔,总体积为100μl)中。然后,将细胞在37℃和5%二氧化碳下在培养箱中温育。6小时或48小时(贴壁细胞)后,更换培养基。然后,将10μl培养基中浓度为10-5M至10-13M的抗体药物缀合物或代谢物移液至细胞(一式三份),然后将测定在37℃和5%二氧化碳下在培养箱中培养。96小时后,使用MTT测定法(ATCC,Manassas,Virginia,USA,目录号30-1010K)检测细胞增殖。为此,将MTT试剂与细胞一起温育4小时,然后通过加入去污剂将细胞裂解过夜。在570nm处检测形成的染料(Infinite M1000 pro,Tecan)。使用DRC(剂量响应曲线),将测量数据用于计算生长抑制的IC50。未用测试物质处理但在其他方面相同处理的细胞的增殖定义为100%数字。
下表1列出了来自该测定的不同抗-CD123抗体的代表性工作实施例的IC50值:
表1:
报告的活性数据涉及本实验部分中描述的工作实施例,其中显示了药物/mAB比率。对于不同的药物/mAB比率,这些值可能会有所偏差。IC50值是几个独立实验或个体值的平均值。CD123抗体药物缀合物的作用对包含各接头和毒性基团的各同种型具有选择性。
C-1b通过选择的实施例测定纺锤体驱动蛋白KSP/Eg5的抑制
将人纺锤体驱动蛋白KSP/Eg5(tebu-bio/Cytoskeleton Inc,No.027EG01-XL)的运动结构域以10nM的浓度与用50μg/ml紫杉醇(Sigma No.T7191-5MG)稳定的微管(牛或猪的,tebu-bio/Cytoskeleton Inc)一起在室温下在15mM PIPES,pH 6.8(5mM MgCl2和10mMDTT,Sigma)中温育5分钟。将新制备的混合物等分到384MTP(Greiner bio-one REF781096)中。然后,加入浓度为1.0×10-6M至1.0×10-13M的待检测抑制剂和ATP(终浓度500μM,Sigma)。在室温下温育2小时。通过检测使用孔雀石绿(Biomol)形成的无机磷酸盐,来检测ATP酶活性。在添加试剂后,将测定在室温下温育50分钟,然后检测波长为620nm的吸收。使用的阳性对照是monastrol(Sigma,M8515-1mg)和伊斯平斯(AdooQ BioscienceA10486)。剂量-活性曲线的个体数据是八倍测定。IC50值是两次独立实验的平均值。100%对照是未用抑制剂处理的样品。
下表2列出了来自所述测定的代表性工作实施例的IC50值和相应的细胞毒性数据(MTT测定)。
表2
报告的活性数据涉及本实验部分中描述的工作实施例。
C-2a内化测定内化是能够通过抗体药物缀合物(ADC)在表达抗原的癌细胞中特异性和有效地提供细胞毒性有效负载的关键过程。通过特异性CD123抗体的荧光标记和用pH敏感性荧光团标记的同种型对照抗体来监测该过程。首先,荧光染料与抗体的赖氨酸缀合。使用两倍摩尔过量的CypHer 5E单NHS酯(批号357392,GE Healthcare)在pH 8.3下进行缀合。偶联后,将反应混合物通过凝胶色谱法纯化(Zeba Spin脱盐柱,40K,ThermoScientific,No.87768;洗脱缓冲液:DULBECCO's PBS,Sigma-Aldrich,编号D8537),以消除过量的染料并调节pH值。使用VIVASPIN 500柱(Sartorius stedim biotec VS0131)浓缩蛋白质溶液。通过分光光度分析(NanoDrop)测定抗体的染料载量,并使用以下等式进行后续计算:D:P=A染料ε蛋白:(A280-0.16A染料)ε染料。此处检测的CD123抗体和同种型对照的染料载量具有相当的量级。在细胞结合测定中,证实缀合没有导致抗体亲和力的变化。待检查的抗原由造血悬浮细胞表达,因此在基于FACS的内化测定中检查标记的CD123抗体的内化。为此,选择并测试具有不同受体表达水平的细胞系。将细胞(5×104/孔)接种在96-MTP中,总体积为100μl(Greiner bio-one,CELLSTAR,650 180,U-底)。在以10μg/ml的终浓度添加待检测的抗-CD123抗体后,将细胞批次在37℃下培养不同时间(1小时,2小时,6小时,一式三份)。将相同的处理方案应用于标记的同种型对照(阴性对照)。同时,在4℃下处理相同的测试批次(阴性对照)。然后,使用Guava流式细胞仪(Millipore)进行FACS分析。通过使用guavaSoft2.6软件(Millipore)测量荧光强度进行动力学评估。在各种癌细胞系(MOLM-13,THP-1,KG-1)中观察到靶向介导的抗-CD123抗体的特异性内化,而同种型对照和4℃批次未显示内化。
C-2b确定内化的CD123抗体在溶酶体中的共定位由于选择的接头,抗体药物缀合物的毒性活性化合物在溶酶体中释放。因此,抗体向该细胞器的转运至关重要。通过将抗体与对溶酶体特异的标记蛋白(例如表面蛋白或小GTPasen)共定位,可以鉴定具有合适谱的抗体。为此,首先,将100μl培养基中的CD123阳性细胞(5×104/孔)接种到96-MTP(Greinerbio-one,CELLSTAR,650 180,U-底)中。加入CypHer5E标记的抗-CD123抗体(终浓度20μg/ml)后,将批次在37℃下温育6小时,一式两份。在每种情况下,在温育时间结束前30分钟,将溶酶体特异性活染料加入样品中。使用CytoPainter LysoGreen指示剂试剂(最终浓度1:2000;abcam,ab176826)染色溶酶体。温育后,将200μl冰冷的FACS缓冲液(DULBECCO′S PBS,Sigma-Aldrich,No.D8537+3%FBS热灭活的FBS,Gibco,No.10500-064)移液到批次中,并且细胞悬浮液在400×g和4℃下离心5分钟。然后,将沉淀重悬于300μl冰冷的FACS缓冲液中并再次离心(4分钟,4℃下400×g)。离心后,弃去上清液,并将沉淀物溶于30μl冰冷的FACS缓冲液中。立即对以这种方式制备的样品进行FACS/图像分析(FlowSight amnis,Millipore)。使用特定的共定位软件IDEAS Application v6.1评估共定位。表3总结了来自该测定的检测的抗-CD123抗体的数据。
表3
实施例 | 共定位[%] |
TPP-6013 | 43.5 |
TPP-5969 | 26.0 |
TPP-8987 | 28.0 |
TPP-8988 | 41.0 |
TPP-9476 | 29.0 |
7G3 | 10.0 |
同种型对照 | 0.2 |
。
与鼠抗体相比,不同的抗体显示出改善的特异性内化效力和共定位。
C-3用于确定细胞渗透性的体外试验
可以通过使用Caco-2细胞的通量测定中的体外测试来研究物质的细胞渗透性[M.D.Troutman和D.R.Thakker,Pharm.Res.20(8),1210-1224(2003)]。为此目的,将细胞在24孔滤板上培养15-16天。为了测定渗透,将各测试物质在HEPES缓冲液中施用于细胞顶部(A)或基部(B),并温育2小时。0小时后和2小时后,从顺式和反式隔室中取样。使用反相柱,通过HPLC(Agilent 1200,Germany)分离样品。HPLC***通过Turbo离子喷雾接口与Triple Quadropol质谱仪API 4000(AB SCIEX Deutschland GmbH,Darmstadt,Germany)联接。基于Papp值评估渗透性,所述Papp值使用Schwab等人公布的公式计算[D.Schwab等人,J.Med.Chem.46,1716-1725(2003)]。当Papp(B-A)/Papp(A-B)的比率(流出率)>2或<0.5时,将物质分类为主动转运的。
对细胞内释放的毒性基团至关重要的是从B到A的渗透性[Papp(B-A)]和Papp(B-A)/Papp(A-B)的比率(流出率):这种渗透性越低,物质通过单层Caco-2细胞的主动和被动转运过程越慢。另外,如果流出率不表明任何主动转运,则在细胞内释放后,该物质可在细胞中保持更长时间。因此,还有更多的时间可用于与生化目标(在这种情况下:纺锤体驱动蛋白,KSP/Eg5)相互作用。
下表4列出了来自该测定的代表性工作实施例的渗透性数据:
表4
C-4用于测定P-糖蛋白(P-gp)底物特性的体外试验
许多肿瘤细胞表达药物的转运蛋白,这经常伴随着对细胞抑制剂的抗性的发展。因此,不是这种转运蛋白的底物的物质,例如P-糖蛋白(P-gp)或BCRP,可以表现出改善的活性谱。
通过使用过表达P-gp的LLC-PK1细胞(L-MDR1细胞)的通量测定来确定P-gp(ABCB1)物质的底物特性[A.H.Schinkel等人,J.Clin.Invest.96,1698-1705(1995)]。为此目的,将LLC-PK1细胞或L-MDR1细胞在96孔滤板上培养3-4天。为了测定渗透,将单独或在抑制剂(例如伊维菌素或维拉帕米)存在下的各测试物质在HEPES缓冲液中施用于细胞顶部(A)或基部(B),并温育2小时。0小时后和2小时后,从顺式和反式隔室中取样。使用反相柱,通过HPLC分离样品。HPLC***通过Turbo离子喷雾接口与Triple Quadropol质谱仪API3000(Applied Biosystems Applera,Darmstadt,Germany)联接。基于Papp值评估渗透性,Papp值使用Schwab等人公布的公式计算[D.Schwab等人,J.Med.Chem.46,1716-1725(2003)]。当Papp(B-A)/Papp(A-B)的流出率>2时,将物质分类为P-gp底物。
作为评估P-gp底物性质的另一标准,可以比较L-MDR1和LLC-PK1细胞中的流出率或存在或不存在抑制剂时的流出率。如果这些值相差超过2倍,则所讨论的物质是P-gp底物。
C-5药代动力学
C5a:体外内化后鉴定ADC代谢物
方法描述:
进行使用免疫缀合物的内化研究以分析细胞内形成的代谢物。为此,将人肺肿瘤细胞NCI H292(3×105/孔)接种在6孔板中并温育过夜(37℃,5%CO2)。用10μg/ml(66nM)待检查的ADC处理细胞。内化在37℃和5%CO2下进行。在不同的时间点(0,4,24,48,72小时),取细胞样品用于进一步分析。首先,收获上清液(约5ml),并且在离心(2分钟,室温,1000rpmHeraeus Variofuge 3.0R)后,储存在-80℃。用PBS洗涤细胞并用Accutase分离,并测定细胞数。再次洗涤后,用100ml裂解缓冲液(哺乳动物细胞裂解试剂盒(Sigma MCL1))处理确定数量的细胞(2×105)并在蛋白质LoBind管(Eppendorf Cat.No.0030 108.116)中在连续摇动(Thermomixer,15分钟,4℃,650rpm)下温育。温育后,将裂解物离心(10分钟,4℃,12000g,Eppendorf 5415R)并收获上清液。将获得的上清液储存在-80℃。然后如下分析所有样品。
在将蛋白质用甲醇或乙腈沉淀后,通过与三重四极杆质谱仪(MS)联接的高压液相色谱(HPLC)进行培养物上清液或细胞裂解物中化合物的测量。
为了后处理50μl培养物上清液/细胞裂解物,加入150μl沉淀试剂(通常为乙腈)并将混合物振荡10秒。沉淀试剂含有合适浓度的内标(ISTD)(通常在20-100ng/ml范围内)。在16000g离心3分钟后,将上清液转移到自动进样器小瓶中,用500μl适合于流动相的缓冲液补足并再次摇动。
然后,使用来自AB SCIEX Deutschland GmbH的HPLC联接的三重四极杆质谱仪API6500测量两种基质样品。
为了校准,将0.5-2000μg/l的浓度添加到浆样品中。检测限(LOQ)约为2μg/l。线性范围从2到1000μg/l。
为了校准肿瘤样品,将0.5-200μg/l的浓度添加到未处理的肿瘤的上清液中。检测限为4μg/l。线性范围从4到200μg/l。
测试有效性的质量对照包含5和50μg/l。
C5b:在体内ADC代谢物的鉴定
静脉施用3-30mg/kg不同的ADC后,可以测量ADC和产生的任何代谢物的血浆和肿瘤浓度,并且可以计算药代动力学参数,如清除率(CL),曲线下面积(AUC)和半衰期(t1/2)。
产生的任何代谢物的量化分析
在用甲醇或乙腈沉淀蛋白质后,通过与三重四极杆质谱仪(MS)联接的高压液相色谱(HPLC),进行血浆和肿瘤中化合物的测量。
为了后处理50μl血浆,加入250μl沉淀试剂(通常为乙腈)并将混合物摇动10秒。沉淀试剂含有合适浓度的内标(ISTD)(通常在20-100ng/ml范围内)。在16000g离心3分钟后,将上清液转移到自动进样器小瓶中,用500μl适合于流动相的缓冲液补足并再次摇动。
在肿瘤的后处理期间,肿瘤用3倍量的提取缓冲液处理。提取缓冲液含有50ml组织蛋白质提取试剂(Pierce,Rockford,IL),两粒完全蛋白酶抑制剂混合物(RocheDiagnostics GmbH,Mannheim,Germany)和苯甲基磺酰氟(Sigma,St.Louis,MO),最终浓度为1mM。将样品在Tissuelyser II(Qiagen)中以最大冲程数匀化两次,持续20分钟。将50μl匀浆转移到自动进样器小瓶中,并用150μl甲醇(包括ISTD)补足。在16000g离心3分钟后,用180μl适合于流动相的缓冲液补足10μl上清液并再次摇动。然后肿瘤样品准备好进行测量。
然后,使用来自AB SCIEX Deutschland GmbH的HPLC联接的三重四极杆质谱仪API6500测量两种基质样品。
为了校准,将0.5-2000μg/l的浓度添加到血浆样品中。检测限(LOQ)约为2μg/l。线性范围从2到1000μg/l。
为了校准肿瘤样品,将0.5-200μg/l的浓度添加到未处理的肿瘤的上清液中。检测限为5μg/l。线性范围从5到200μg/l。
用于测试有效性的质量对照包含5和50μg/l,血浆中另外包含500μg/l。
所用抗体的定量分析
使用配体结合测定(ELISA),将ADC的抗体部分作为血浆样品和肿瘤裂解物中的总IgG浓度测量。这里,使用夹心ELISA形式。该ELISA已被准予并验证用于血浆和肿瘤样品中的测定。用抗人山羊IgG Fc抗体包被ELISA板。与样品一起温育后,洗涤板并与猿猴抗人IgG(H+L)抗体和辣根过氧化物酶(HRP)的检测缀合物一起温育。在进一步洗涤步骤后,将HRP底物加入到OPD中,并通过在490nm处的吸收监测显色。使用4-参数方程拟合具有已知IgG浓度的标准样品。在较低(LLOQ)和较高(ULOQ)定量限度内,通过内插法确定未知浓度。
C-6体内功效测试已经在肿瘤异种移植模型中测试了本发明的缀合物的体内功效。专家熟悉现有技术中可以测试本发明化合物有效性的方法(参见例如WO 2005/081711;Polson等人,Cancer Res 2009Mar 15;69(6):2358-64)。
例如,在啮齿动物(例如小鼠)中植入表达抗体靶分子的肿瘤细胞系。然后,将本发明的缀合物、同种型缀合物、对照抗体或等渗盐水(媒介物)施用于植入的动物。在数天的温育期后,在缀合物处理的动物与对照组(对照缀合物和/或载体)中测定肿瘤大小。缀合物处理的动物显示肿瘤尺寸减小。
C-6a.小鼠中实验性肿瘤的生长抑制
将表达抗体-药物缀合物的靶抗原的人肿瘤细胞皮下接种到免疫受损小鼠(例如:NMRI裸鼠或SCID小鼠)的侧腹中。从细胞培养物中分离出100-1000万个细胞,离心并用培养基或培养基/Matrigel重悬。将细胞悬浮液皮下注射到小鼠中。在肿瘤建立(肿瘤大小大约为40mm2)后,开始治疗(ip施用,体积为5mL/kg;给药方案显示在表x中)。
默认情况下,每个治疗组使用8只动物。除了接受活性物质的组外,一组仅用载体治疗。在实验期间,定期用卡尺在二个维度(长度/宽度)测量肿瘤区域。肿瘤面积由长度x宽度确定。治疗组的平均肿瘤面积与对照组的比较表示为T/C面积。
C-6b.根据本发明的化合物在人AML异种移植模型中的功效用抗CD123抗体-药物缀合物治疗导致显著且持久的肿瘤生长抑制。表5总结了代表性工作实施例的体内功效。初步读出是治疗对比载体组的肿瘤生长抑制,如T/C值所示(在载体组达到>200mm2的肿瘤大小并且由于德国动物保护法必须处死之前的最后测量时间点确定)。作为第二读出,表5还表示直到治疗组显示肿瘤再生长并且研究终止的时间段。
实验1显示通过在THP-1AML异种移植模型中的肿瘤生长抑制测量的ref 257m1相对208m1的强效和明显优势(T/C 0.46vs.0.92)。
也已在另外的AML异种移植模型中评估了ref 257m1的功效。实验2基于肿瘤生长抑制确认了ref 257m1相对208m1的优势(T/C 0.25vs 0.42),并且还强烈减少MOLM 13AML异种移植模型中肿瘤再生长的时间(34天vs 24天)。实施例1a、1b、1c在两种AML模型(实验3和实验4)中显示出强效力。所有描述的实施例都显示出优于ref 208m1(例如1a vs 208m1-T/C 0.32vs 0,42)。
具有所示方案(Q7dx2)的相应同种型-ADC对照与载体对照相当。
表5
抗-CD123抗体的工作实施例
除非在此详细描述,否则所有实施例均使用本领域技术人员已知的标准方法进行。以下实施例的分子生物学的常规方法可以如标准实验室教科书中所述进行,例如Sambrook等人,Molecular Cloning:a Laboratory Manual,第二版;Cold Spring HarborLaboratory Press,Cold Spring Harbor,N.Y.,1989。
人源化抗-CD123抗体的产生和优化
本文描述的抗体基于文献(EP2426148;WO2013/173820)中描述的两个鼠抗体克隆7G3和12F1。简而言之,如O’Brien和Jones,(Humanizing Antibodies by CDR Grafting,第40章,579页,表4)以及Hwang等人(Methods 36(2005)p35-42)所述,将鼠CDR移植到人框架中。有关根据Kabat的CDR的定义,请参阅Andre C.R.Martin,“Protein sequence andstructure analysis of antibody variable domains”in Antibody Engineering(Springer Lab Manuals),Eds.:Duebel,S.和Kontermann,R.,Springer-Verlag,Heidelberg。在将鼠框架序列(没有CDR)与人种系序列进行比较后,选择了类似的频率出现的人框架序列。使用IMGT***命名序列(Lefranc,M.-P.,Giudicelli,V.,Ginestoux,C.,Jabado-Michaloud,J.,Folch,G.,Bellahcene,F.,Wu,Y.,Gemrot,E.,Brochet,X.,Lane,J.,Regnier,L.,Ehrenmann,F.,Lefranc,G.和Duroux,P.the internationalImMunoGeneTics information/>Nucl.Acids Res,37,D1006-D1012(2009);doi:10.1093/nar/gkn838)。
人源化变体在HEK293细胞中瞬时表达。在SPR和FACS中测试上清液与抗原和细胞的结合。为了降低免疫原性并优化结合特性,在CDR和框架中引入单个或多个突变。测试了100多种变体,以生成和选择最终的主要候选物。本文所述的抗体变体携带与人种系序列不同的各种点突变,这可能影响它们的性质。
第一组工作基于鼠抗体克隆12F1(WO2013/173820)。CDR的移植不是简单的,并且必须在几个人框架骨架上进行测试才能成功。最佳移植形式被鉴定为TPP-8988,其中轻链CDR被移植到人框架骨架IGKV3-20中,重链CDR被移植到人框架骨架IGHV3-66中。相比之下,鼠CDR的移植在其他情况下失败,例如对于显示降低的FACS结合的TPP-8613。在该变体中,轻链CDR被移植到人框架骨架IGKV4-1中,重链CDR被移植到人框架骨架IGHV3-66中。另一个不能作为移植形式产生足够表达的实例是TPP-8617,其中轻链CDR被移植到人框架骨架IGKV4-1中,重链CDR被移植到人框架骨架IGHV5-51中。
为了进一步使TPP-8988去免疫,将单个和重组的非种系残基交换到人种系,并测试66个变体的表达和结合。测试的最佳重组变体是TPP-9342。其他变体,例如TPP-9075、TPP-9078、TPP-9104、TPP-9129或TPP-9130,尽管与TPP-8988/TPP9342共享相似的序列,但在SPR测量中显示低表达和/或不期望的多相行为。
第二组工作基于鼠抗体克隆7G3(EP2426148)。基于人类种系IGKV4-1和IGHV1-69,如上所述产生人源化形式TPP-5969。它可以作为CSL(EP2606069)生成的人源化形式CSL-362(TPP-5709)的替代方案。
不幸的是,TPP-5969在SPR分析中显示出不希望的多相结合行为。为了消除这种多相结合并使TPP-5969去免疫,将单个和重组的非种系残基交换到人种系,并测试53个变体的表达和结合。大多数变体,例如TPP-8465、TPP-8467、TPP-8468或TPP-9479在SPR测量中显示低表达和多相行为以及减少的FACS结合,尽管它们与人源化形式TPP-5969和/或最终候选物TPP-8987或TPP-9476共享相似的序列。
只有与TPP-5969相比在重链中含有三个突变(N61A、K65Q和Q67R)的变体(例如TPP-8695)在FACS结合中显示单位数纳摩尔级的EC50值,同时在低表达的SPR中以多相方式结合。出乎意料的是,TPP8987中轻链CDR2中单点突变的引入(V29L)消除了不希望的多相结合特性。由于TPP-8987的表达率相当低,因此产生了不同的重链变体以发现允许合理表达以及非多相SPR结合特性和阳性FACS结果的突变的重组。TPP-9476代表了这些有利特性,其与TPP-8987的差别仅在于R67Q回复突变,但10倍表达,同时保留其有利的结合特征。
通过表面等离子体共振测定抗体的结合亲和力:
使用Biacore T200仪器(GE Healthcare Biacore,Inc.)进行用于定量结合分析的表面等离子体共振实验。在此,借助于与传感器芯片表面胺偶联的抗人Fc抗体(“人抗体捕获试剂盒”,BR-1008-39,GE Healthcare Biacore,Inc.)固定待检测的抗体。根据制造商的说明,使用1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)、N-羟基琥珀酰亚胺(NHS)和pH8.5的乙醇胺盐酸盐(“Amine Coupling Kit”BR-1000-50,GE HealthcareBiacore,Inc.)进行胺偶联。对于分析,将S系列传感器芯片CM5(GE Healthcare Biacore,Inc.)与移动缓冲液HBS-EP+(10mM HEPES pH 7.4,150mM NaCl,3mM EDTA,0.05%表面活性剂P20)一起使用。所有实验步骤均在25℃下进行。在固定待检测的抗-CD123抗体后,进行浓度为100nM的IL3Rα细胞外结构域(分析物,R&D Systems)的注射,并且在每次抗原注射后,用pH2.0的甘氨酸HCl再生传感器表面。在另一次分析物注射之前,在每种情况下,在相同条件下,如上固定抗体。对于所有测量,仅含有固定的胺偶联的抗人Fc抗体的上游流动池用作参考池。在双参考(减去参考流动池信号和缓冲液注射)后,在Biacore T200评估软件(GEHealthcare Biacore,Inc.)的帮助下,通过基于1:1朗缪尔结合模型的全局拟合进行获得的传感图的评估。
表6a:用于亲和力测定的重组抗原(IL3R3α/CD123)
命名 | 描述 | 来源 | Cat.No.(R&D) |
TPP-5521 | IL3Ra aa20-305 | 鼠 | 203-IL。 |
。
表6b:使用IL3Ra蛋白(TPP-5521作为分析物)用Biacore测定的抗-CD123抗体的单价KD值
抗-CD123抗体与各种表达抗原的癌细胞系的结合
使用人血液细胞系MOLM-13,通过流式细胞术检查抗-CD123抗体的结合。为此,将细胞(5×105细胞/孔)在FACS缓冲液(PBS,不含Ca/Mg,3%FCS,Biochrom)中与10μg/ml一抗溶液(起始浓度)在冰上避光温育30-45分钟。绘制剂量活性曲线(1:5稀释)。温育后,使用移液管加入200μl冰冷的FACS缓冲液,并将细胞悬浮液在4℃、400g离心4分钟。用300μl冰冷的FACS缓冲液洗涤细胞沉淀,然后将获得的沉淀重悬于100μl FACS缓冲液中,并与1:10稀释的二抗(单克隆抗κ轻链-FITC抗体,Sigma,No.SAB4700605)一起在冰上再次温育30分钟。然后,用冰冷的FACS缓冲液洗涤细胞,并在使用Guava流式细胞仪(Millipore)进行流式细胞术之前,将细胞浓度调节至0.5×106细胞/ml。碘化丙啶(终浓度1μg/ml)用于活染色。结果显示为基于剂量响应曲线和与最大结合相比的功效确定的EC50值。令人惊讶的是,TPP-8988与TPP-5969相比,以及TPP-8988与TPP-6013相比,可以检测到显著改善的结合行为(表7A)。TPP-5969的大多数人源化变体显示与靶标(7B)无结合或不充分结合,TPP-6013的人源化变体也是如此(7C;参见生成和优化)。
表7:FACS分析:抗-CD123抗体与MOLM-13癌细胞系的结合。A:改进的人源化抗-CD123抗体;B:TPP-5963变体;C:TPP-6013变体
A
B
C
表:序列表
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Claims (21)
1.如下式(I)中定义的缀合物:
其中
X是-CH2-或-CH2-CH2-,
L是(-CH2-CH2-O-)m-CH2-CH2-,
m是1-20,
n是1-8,且
AK是抗-CD123抗体或其功能片段,其中所述抗体或其功能片段通过半胱氨酸残基连接,并且所述抗体或其功能片段包含:
可变重链,其包含如SEQ ID NO:122中所示的重链可变CDR1序列,如SEQ ID NO:123中所示的重链可变CDR2序列,和如SEQ ID NO:124中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:126中所示的轻链可变CDR1序列,如SEQ ID NO:127中所示的轻链可变CDR2序列,和如SEQ ID NO:128中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:202中所示的重链可变CDR1序列,如SEQ ID NO:203中所示的重链可变CDR2序列,和如SEQ ID NO:204中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:206中所示的轻链可变CDR1序列,如SEQ ID NO:207中所示的轻链可变CDR2序列,和如SEQ ID NO:208中所示的轻链可变CDR3序列;
及其盐。
2.根据权利要求1的缀合物,其中
X是-CH2-,
L是(-CH2-CH2-O-)m-CH2-CH2-,
m是1-20,
n是1-8,且
AK是抗-CD123抗体或其功能片段,其中所述抗体或其功能片段通过半胱氨酸残基连接,并且所述抗体或其功能片段包含:
可变重链,其包含如SEQ ID NO:122中所示的重链可变CDR1序列,如SEQ ID NO:123中所示的重链可变CDR2序列,和如SEQ ID NO:124中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:126中所示的轻链可变CDR1序列,如SEQ ID NO:127中所示的轻链可变CDR2序列,和如SEQ ID NO:128中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:202中所示的重链可变CDR1序列,如SEQ ID NO:203中所示的重链可变CDR2序列,和如SEQ ID NO:204中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:206中所示的轻链可变CDR1序列,如SEQ ID NO:207中所示的轻链可变CDR2序列,和如SEQ ID NO:208中所示的轻链可变CDR3序列;
及其盐。
3.根据权利要求1或2的缀合物,其中:
X是-CH2-,
L是(-CH2-CH2-O-)m-CH2-CH2-,
m是2-8,且
n是1-8,且
AK是抗-CD123抗体或其功能片段,其中所述抗体或其功能片段通过半胱氨酸残基连接,并且所述抗体或其功能片段包含:
可变重链,其包含如SEQ ID NO:122中所示的重链可变CDR1序列,如SEQ ID NO:123中所示的重链可变CDR2序列,和如SEQ ID NO:124中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:126中所示的轻链可变CDR1序列,如SEQ ID NO:127中所示的轻链可变CDR2序列,和如SEQ ID NO:128中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:202中所示的重链可变CDR1序列,如SEQ ID NO:203中所示的重链可变CDR2序列,和如SEQ ID NO:204中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:206中所示的轻链可变CDR1序列,如SEQ ID NO:207中所示的轻链可变CDR2序列,和如SEQ ID NO:208中所示的轻链可变CDR3序列;
及其盐。
4.根据权利要求1或2的缀合物,其是:
其中
n是1-8,且
AK是抗-CD123抗体或其功能片段,其中所述抗体或其功能片段通过半胱氨酸残基连接,并且所述抗体或其功能片段包含:
可变重链,其包含如SEQ ID NO:122中所示的重链可变CDR1序列,如SEQ ID NO:123中所示的重链可变CDR2序列,和如SEQ ID NO:124中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:126中所示的轻链可变CDR1序列,如SEQ ID NO:127中所示的轻链可变CDR2序列,和如SEQ ID NO:128中所示的轻链可变CDR3序列;或
可变重链,其包含如SEQ ID NO:202中所示的重链可变CDR1序列,如SEQ ID NO:203中所示的重链可变CDR2序列,和如SEQ ID NO:204中所示的重链可变CDR3序列,和
可变轻链,其包含如SEQ ID NO:206中所示的轻链可变CDR1序列,如SEQ ID NO:207中所示的轻链可变CDR2序列,和如SEQ ID NO:208中所示的轻链可变CDR3序列。
5.根据权利要求1或2的缀合物,其中n为2-6。
6.根据权利要求1或2的缀合物,其中所述抗-CD123抗体或其功能片段包含:
如SEQ ID NO:121中所示的重链可变序列和如SEQ ID NO:125中所示的轻链可变序列,或
如SEQ ID NO:201中所示的重链可变序列和如SEQ ID NO:205中所示的轻链可变序列。
7.根据权利要求1或2的缀合物,其中所述抗-CD123抗体是IgG抗体,并且其中其功能片段是scFv、Fab、Fab'片段或F(ab)2片段。
8.根据权利要求1或2的缀合物,其中所述抗-CD123抗体包含:
如SEQ ID NO:129中所示的重链序列和如SEQ ID NO:130中所示的轻链序列,或
如SEQ ID NO:209中所示的重链序列和如SEQ ID NO:210中所示的轻链序列。
9.药物组合物,其包含根据权利要求1-8中任一项的缀合物以及惰性无毒的药学上合适的辅助剂。
10.至少一种根据权利要求1-8中任一项的缀合物在制备用于治疗白血病的药物中的用途。
11.与CD123结合的抗体或抗原结合抗体片段,其包含可变重链,其包含如SEQ ID NO:202中所示的重链可变CDR1序列,如SEQ ID NO:203中所示的重链可变CDR2序列,和如SEQID NO:204中所示的重链可变CDR3序列;和可变轻链,其包含如SEQ ID NO:206中所示的轻链可变CDR1序列,如SEQ ID NO:207中所示的轻链可变CDR2序列,和如SEQ ID NO:208中所示的轻链可变CDR3序列。
12.根据权利要求11所述的抗体或抗原结合抗体片段,其中所述可变重链包含SEQ IDNO:201所示的序列。
13.根据权利要求11或12所述的抗体或抗原结合抗体片段,其中所述可变轻链包含SEQID NO:205所示的序列。
14.根据权利要求11或12所述的抗体或抗原结合抗体片段,其包含重链,所述重链包含SEQ ID NO:209所示的序列。
15.根据权利要求11或12所述的抗体或抗原结合抗体片段,其包含轻链,所述轻链包含SEQ ID NO:210所示的序列。
16.包含根据权利要求11-15中任一项的抗体或抗原结合抗体片段以及式(I)中定义的一种或多种化合物的缀合物或其盐:
其中
X是-CH2-或-CH2-CH2-,
L是(-CH2-CH2-O-)m-CH2-CH2-,
m是1-20,
n是1-8,且
AK是所述抗体或抗原结合抗体片段,其中所述抗体或抗原结合抗体片段通过半胱氨酸残基连接。
17.根据权利要求16所述的缀合物,其中X为-CH2-。
18.根据权利要求16或17所述的缀合物,其中m是2至8。
19.根据权利要求16或17所述的缀合物,其中所述缀合物具有如下结构:
其中n是1至8,并且AK为所述抗体或者抗原结合抗体片段,其中所述抗体或抗原结合抗体片段通过所述抗体或抗原结合抗体片段的半胱氨酸残基连接。
20.根据权利要求16或17所述的缀合物,其中n是2至6。
21.根据权利要求16至20中任一项所述的缀合物在制备用于治疗白血病的药物中的用途。
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