CN105377307B - 具有改进的稳定性的抗体-药物缀合物及其用途 - Google Patents
具有改进的稳定性的抗体-药物缀合物及其用途 Download PDFInfo
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- CN105377307B CN105377307B CN201480035895.0A CN201480035895A CN105377307B CN 105377307 B CN105377307 B CN 105377307B CN 201480035895 A CN201480035895 A CN 201480035895A CN 105377307 B CN105377307 B CN 105377307B
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Classifications
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Landscapes
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Abstract
本发明涉及一种抗体‑药物缀合物,其包含与抗体缀合的药物,其制备方法及其用途。
Description
技术领域
本发明涉及包含与抗体的重链或轻链的N-末端氨基酸残基缀合的药物的抗体-药物缀合物,其制备方法及其用途。
背景技术
近年来,已研究了使用抗体诊断或治疗多种疾病的方法。特别是由于抗体的靶物特异性,已开发了多种使用抗体的治疗方法,并且已开发了多种含有抗体的药物,例如,抗体-药物缀合物(ADCs)。因此,已持续进行了研究以增加抗体或抗体-药物缀合物的体内稳定性并使其治疗效果最大化。
其中,抗体-药物缀合物通常具有与天然抗体相比体内稳定性低的缺点,但已进行了开发以通过将它们与药物缀合来克服天然抗体的缺点(低治疗效果)。已开发了多种抗体-药物缀合物,其中将具有某些医药效果的药物(如细胞毒素)缀合于靶物特异性的抗体。特别是,通过缀合于癌细胞特异性抗体的细胞毒素来诱导癌细胞死亡的方法是目前实际上使用的方法。
然而,此类抗体-药物缀合物通常具有与天然抗体相比较低的体内稳定性。此外,如果增加药物抗体比例(DAR)以增加治疗效果,则会有多个技术问题待解决。第一,药物抗体比例的增加不应干扰用于靶物特异性治疗的抗体的抗原结合能力和Fc功能,应导致治疗效果的增加而不应降低抗体-药物缀合物的体内活性(即,血液半寿期)。鉴于上述技术问题,目前抗体-药物缀合物制备领域的目的在于维持尽可能高的抗体药物比例。特别地,考虑到癌细胞表面抗原的表达水平低,应维持尽可能高的药物抗体比例(DAR)以维持高的细胞毒性。然而,如果DAR达到8,则由于缀合于抗体的疏水药物的效果而存在抗体-药物缀合物的血液半寿期降低的问题,因而其毒性可能增加而且其体内功效可能降低。
在此背景下,本发明的发明人已进行了全面的努力以开发能够制备抗体-药物缀合物的技术,所述缀合物维持亲本抗体的抗原-结合活性,呈现优异的抗癌效果,并具有低药物毒性和优异的体内功效。结果,本发明的发明人已发现,当药物缀合于抗体的重链或轻链的N-末端时,所述抗体-药物缀合物具有优异的血液稳定性和抗癌活性,同时与先前报道的抗体-药物缀合物相比具有低的体内毒性,由此完成了本发明。
发明内容
本发明的一个目的是提供抗体-药物缀合物,其包含与抗体的重链或轻链的N-末端氨基酸残基缀合的药物。
本发明的另一个目的是提供用于制备上述抗体-药物缀合物的方法。
本发明的又一个目的是提供包含上述抗体-药物缀合物的组合物。
本发明的再一个目的是提供用于治疗癌症的方法,其包括将上述抗体-药物缀合物施用于怀疑患有癌症的受试者。
本发明的再一个目的是提供用于治疗自身免疫性疾病的方法,其包括将上述抗体-药物缀合物施用于怀疑患有自身免疫性疾病的受试者。
本发明的再一个目的是提供用于筛选适用于制备上述抗体-药物缀合物的抗体的方法。
有利效果
用于根据本发明制备抗体-药物缀合物的方法可制备抗体-药物缀合物,其具有更高的体内功效、稳定性和更低的毒性。
附图简述
图1显示具有连接于末端的醛接头的毒素一甲基阿里他汀F(MMAF)的结构式。
图2为示意图,其显示非遗传修饰的单克隆抗体-细胞毒素缀合物的结构,其中缀合于抗体的细胞毒素部分的数目和位点是同质的(homogeneous)。
图3显示T-N-MMAF的LC/MS谱。
图4显示进行的肽绘图(peptide mapping)的结果,以确定制备的曲妥珠单抗-N-MMAF(T-N-MMAF缀合物)中药物的结合位点。
图5显示制备的T-N-MMAF的SEC-HPLC分析的结果。
图6显示大鼠中总抗体的血液浓度中的时间依赖性变化。
图7显示缀合的抗体的血液浓度中的时间依赖性变化。
图8显示总抗体和缀合的抗体的PK谱在抗体-药物缀合物(ADCs)之间的比较。
图9显示裸大鼠异种移植模型中由HCC1954细胞系形成的肿瘤的生长曲线。
图10显示进行的裸大鼠异种移植模型实验中获得的存活曲线,以测量终点处的肿瘤体积。
图11显示通过施用各抗体-药物缀合物(ADC)的体重上的变化和相对变化。
图12显示检查各ADC的施用是否引起肝毒性的结果。
图13显示通过施用各ADC在中性粒细胞和血小板中的变化。
图14显示T-N-MMAE的LC/MS分析的结果。
图15显示T-N-MMAE的大鼠PK谱。
图16显示布妥昔单抗-N-MMAF(B-N-MMAF)的LC/MS谱。
图17显示分析B-N-MMAF的抗原结合活性的结果。
图18显示Lorvotuzumab-N-MMAF(L-N-MMAF)的缀合谱。
图19显示L-N-MMAF的抗原结合活性。
实施发明的最佳方式
在一个方面,本发明所提供的涉及抗体-药物缀合物,其包含与抗体的重链或轻链的N-末端氨基酸残基缀合的药物。
如本申请使用的,术语“抗体-药物缀合物(ADC)"指药物和抗体化学相互缀合而不降低抗体和药物的生物学活性的形式。在本发明中,术语“抗体-药物缀合物”指其中药物缀合于抗体的重链和/或轻链的N-末端氨基酸残基的形式,特别是,其中药物缀合于抗体的重链和/或轻链的N-末端α-胺基的形式。在本发明中,发现当药物被位点特异性地缀合于抗体的多个区域中重链或轻链的N-末端时,所述抗体-药物缀合物与先前报道的抗体-药物缀合物(包括通过半胱氨酸缀合形成的抗体-药物缀合物,通过巯基(thiol)缀合形成的抗体-药物缀合物,和通过赖氨酸缀合形成的抗体-药物缀合物)相比具有优异的体内功效和稳定性以及低毒性,指示抗体的重链或轻链的N-末端可为在功效、稳定性和低毒性方面有利的位点。根据本发明的抗体-药物缀合物的示意性视图示意性地示于图2。
如本申请使用的,术语“N-末端”指抗体的重链或轻链的氨基末端(N-末端),其为就本发明而言药物可与之缀合的位点。N-末端的实例包括但不限于,不仅N-末端的远端处的氨基酸残基,还有N-末端附近的氨基酸残基。具体地,术语“N-末端”指抗体的重链或轻链的第一氨基酸残基,而更具体地,指抗体的重链或轻链的第一氨基酸的α-胺基,但不局限于此。
根据本发明的抗体-药物缀合物可具有保证通过抗体和药物之间的位点-特异性缀合或数目-特异性缀合(而得到)的同质性的优势。具体地,通过本发明的优化步骤,可将对应于最佳药物-抗体比例(DAR)的1-8个药物部分缀合于各抗体分子的N-末端氨基酸残基。
如本申请使用的,术语“同质性”指在两种物质的缀合物中两种物质之间缀合的比例和位点是同质的情况。然而,该术语意欲不仅包括其中缀合的比例和位点完全同质的情况,还包括其中特定的缀合比例和位点占优势的情况。当缀合物具有同质性,它是完全同质的,而且其剂量-依赖性的功效能被准确地测量,因而其施用的剂量和数目能被标准化。
如本申请使用的,术语“抗体”意指蛋白质分子,其包含与某种抗原具有免疫反应性的免疫球蛋白分子,且其充当特异性识别所述抗原的受体。该术语意欲涵盖多克隆抗体、单克隆抗体、全长抗体和含有抗原结合域的抗体片段。全长抗体具有两个全长的轻链和两个全长的重链,其中各轻链通过二硫键连接于重链。全长抗体包含IgA、IgD、IgE、IgM和IgG,且IgG的亚型包括IgG1、IgG2、IgG3和IgG4。术语“抗体片段”指具有抗原结合功能的片段,且意欲包括Fab、Fab’、F(ab′)2、scFv和Fv。Fab包含轻链和重链可变区,轻链恒定区,和重链第一恒定域(CH1),并具有一个抗原结合位点。Fab′与Fab区别在于它具有在重链CH1域的C-末端处包括一个或多个半胱氨酸残基的铰链区。F(ab′)2抗体通过Fab′的铰链区的半胱氨酸残基之间的二硫键形成。Fv意指仅具有重链可变区和轻链可变区的最小抗体片段。dsFv具有其中重链可变区和轻链可变区通过二硫键彼此连接的结构,而scFV通常具有其中重链可变区和轻链可变区通过肽接头彼此共价连接的结构。这些抗体片段可使用蛋白酶获得(例如,Fab片段可通过用木瓜蛋白酶消化全长抗体而获得,而F(ab′)2片段可通过用胃蛋白酶消化全长抗体而获得)。优选地,这些抗体片段可通过基因重组技术产生。这些抗体片段可使用蛋白酶获得(例如,用木瓜蛋白酶或胃蛋白酶消化全抗体分别提供Fab或F(ab′)2),并优选可通过基因重组技术来构建。
此外,本发明中使用的抗体可为天然抗体或重组抗体。如本申请使用的,术语“天然抗体”指未经遗传修饰的抗体。不像经体内遗传修饰的抗体,天然抗体可具有显著低的免疫原性风险。如本申请使用的,术语“重组抗体”意指经遗传修饰的抗体,其可具有抗原结合活性或通过遗传修饰赋予的合意的性质。
如本申请使用的,术语“遗传修饰”指改变感兴趣的氨基酸序列的行为,并意欲包括对多肽的修饰,所述多肽具有某种程度不同于编码感兴趣的氨基酸序列的天然序列多肽的氨基酸序列的氨基酸序列。氨基酸序列变体含有在天然氨基酸序列中的一个或多个特定位置具有一个或多个氨基酸残基的取代、缺失或插入的氨基酸序列。
本发明中使用的抗体可为识别细胞表面抗原的抗体,当所述抗原结合于抗体时内化入细胞中。就本发明而言,当抗原通过与抗体结合而内化入细胞时,缀合于抗体的药物(特别是细胞毒性药物)可由于抗体的特征而进入细胞,并由此可呈现高的功效,但不限于此。
此外,本发明中使用的抗体可为特异性结合于癌细胞表面抗原或其中出现了自身免疫性疾病的组织的表面抗原的抗体。
如本申请使用的,术语“癌细胞表面抗原”指不在正常细胞中产生或者不暴露于细胞表面的物质,或特异性地在癌细胞中暴露于细胞表面的物质,或与正常细胞的表面相比在癌细胞的表面上存在更多的物质。当感兴趣的物质被抗体识别时,它称为抗原。
具体地,用于本发明的癌细胞表面抗原可为任何癌细胞表面抗原,其能够被本发明的抗体特异性地识别。癌细胞表面抗原的实例可包括CD19、CD20、CD30、CD33、CD37、CD22、CD56、CD70、CD74、CD138、Muc-16、间皮素、HER2、HER3、GPNMB(糖蛋白NMB)、IGF-1R、BCMA(B细胞成熟抗原)、PSMA(前列腺特异性膜抗原)、EpCAM(上皮细胞粘附分子)和EGFR(表皮生长因子受体)。更具体地,癌细胞表面抗原可为选自下组的任何一个:HER2、CD30、CD56和GPNMB,但不限于此。在本发明的实例中,使用如下作为模型抗体(model antibody):曲妥珠单抗(Trastuzumab),其为一种抗-HER2抗体,Lorvotuzumab,其为一种抗-CD56抗体,布妥昔单抗(Brentuximab),其为一种抗-CD30抗体,和Glembatumumab,其为一种抗-GPNMB抗体,它们识别Her2、CD56和GPNMB。
如本申请使用的,术语“药物”意指具有细胞特异性生物活性的任何物质,并意欲包括化合物、DNA、RNA、肽等。术语“药物”意欲不仅包括含有能够与α-胺基交联的反应性基团的物质,还包括具有接头的物质,所述接头含有能够与α-胺基交联的反应性基团。在此情况中,药物能够通过接头位点特异性地结合于抗体的N-末端氨基酸残基,但不限于此。
术语“接头”指化学基团,其包含允许药物共价结合于抗体的原子链。接头以其结合于药物的状态制备,并且接头的端部具有能够与抗体连接的反应性基团。
能够与α-胺基交联的反应性基团的实例包括本领域已知的任何反应性基团,其能够与抗体的重链或轻链的N-末端α-胺基交联。反应性基团的实例可包括异硫氰酸酯(盐)(isothiocyanate)、异氰酸酯(盐)(isocyanate)、酰叠氮(acyl azide)、NHS酯(NHSester)、磺酰氯(sulfonyl chloride)、醛(aldehyde)、乙二醛(glyoxal)、环氧化物(epoxide)、环氧乙烷(oxirane)、碳酸酯(盐)(carbonate)、芳基卤(aryl halide)、亚氨酸酯(imidoester)、碳二亚胺(carbodiimide)、酐(anhydride)和氟苯酯(fluorophenylester)。更优选地,反应性基团为醛或NHS酯,但不特定地限于此。所述反应性基团能够通过酰基化或烷基化与胺基结合,但不特定地限于此。
特别地,本发明的抗体-药物缀合物可为免疫缀合物,其中连接于具有反应性醛基的接头的药物以位点特异性和数目特异性的方式缀合于抗体的N-末端氨基酸残基。
反应性醛基在将药物位点特异性地缀合于抗体的N-末端氨基酸残基(特别是α-胺基)同时使非特异性反应最小化中是有效的。通过由醛键的还原性烷基化产生的终产物比由酰胺键连接的情况稳定得多。反应性醛基具有在低pH与N-末端α-胺基选择性反应的性质。因此,本发明的缀合物在药物位点特异性地缀合于抗体的N-末端α-胺基方面具有同质性。因此,本发明克服了现有技术中由于常规抗体-药物缀合物中的缀合数目及位点的异质性而造成的药物的一致功效和质量无法保证的问题,但不特定地限于此。
在本发明的一个实例中,本发明的发明人已发现,当缀合反应在6.0或以下的pH进行以使细胞毒性药物位点特异性地缀合于抗体的α-胺基时,细胞毒性药物与赖氨酸残基的ε-胺基的缀合可被最小化。
本发明使用的药物可为能够诱导某些信号传导途径的激活或抑制(包括细胞死亡、细胞增殖、免疫激活和免疫抑制)的任何物质。特别是,药物可为细胞毒性药物或免疫抑制剂。
如本申请使用的,术语“细胞毒性药物”指任何物质,例如化合物,其具有细胞毒性或细胞增殖抑制作用。术语“细胞毒性作用”指抑制或降低细胞的功能以诱导细胞的破坏,而术语“细胞增殖抑制作用”指限制细胞生长功能(如细胞生长或细胞增殖)的作用。
用于本发明的细胞毒性药物的实例包括化学治疗剂,包括微管结构形成抑制剂、减数分裂抑制剂、RNA聚合酶抑制剂、拓扑异构酶抑制剂、DNA嵌入剂、DNA烷化剂和核糖体抑制剂、可作为酶发挥功能的蛋白质毒素和放射性同位素。细胞毒性药物的实例可包括美登木素(maytansinoid)、阿里他汀(auristatin)、多拉司他汀(dolastatin)、tubulysin、卡奇霉素(calicheamicin)、吡咯并苯二氮杂类(pyrrolobenzodiazepines)、阿霉素(doxorubicin)、duocamycin、卡铂(carboplatin)(伯尔定(paraplatin))、顺铂(cisplatin)、环磷酰胺(cyclophosphamide)、异环磷酰胺(ifosfamide)、宁得朗(nidran)、[氮芥(nitrogen mustard)(氮芥HCL(mechlorethamine HCL))]、博莱霉素(bleomycin)、丝裂霉素C(mitomycin C)、阿糖胞苷(cytarabine)、氟尿嘧啶(fluorouracil)、吉西他滨(gemcitabine)、三甲曲沙(trimetrexate)、甲氨蝶呤(methotrexate)、依托泊苷(etoposide)、长春碱(vinblastine)、长春瑞滨(vinorelbine)、力比泰(alimta)、六甲蜜胺(altretamine)、甲基苄肼(procarbazine)、紫杉醇(taxol)、泰索帝(taxotere)、托泊替康(topotecan)、伊立替康(irinotecan)、单端孢霉烯(trichothecene)、CC1065、α-鹅膏蕈碱(alpha-amanitin)、其他烯二炔类抗生素(enediyne antibiotics)、外毒素(exotoxin)和植物毒素(plant toxin)。此外,化合物包括它们的立体异构体和衍生物。此外,用于本发明的阿里他汀可为一甲基阿里他汀E或一甲基阿里他汀F,但不限于此。
术语“免疫抑制剂”指具有减少免疫反应的作用的任何化合物。该术语意指一种物质,其能够拮抗引起免疫的物质或者能够抑制涉及免疫反应的物质(细胞因子如白细胞介素)。
在本发明的一个实例中,将曲妥珠单抗、Lorvotuzumab、布妥昔单抗和Glembatumumab用作模型抗体,并将一甲基阿里他汀E(MMAE)或一甲基阿里他汀F(MMAF)用作要与抗体的N-末端缀合的细胞毒性药物(实施例1和2)。允许曲妥珠单抗在6.0的pH与MMAF或MMAE反应以将药物缀合于抗体的N-末端,由此制备抗体-药物缀合物。在此抗体-药物缀合物的情况中,显示抗体的抗原结合活性和药物的细胞毒性功效甚至在药物缀合后得以维持(实施例3至5)。特别地,此抗体-药物缀合物与具有半胱氨酸或赖氨酸键的另外的抗体-药物缀合物(比较缀合物)相比显示在体外在人血清中优异的稳定性,而且还在使用大鼠进行的优异的药物代谢动力学实验中显示优异的药物代谢动力学(实施例6)。此外,此抗体-药物缀合物在抗癌动物模型中与比较缀合物相比显示优异的抗癌活性,但在体重(weight)、肝毒性、血液等方面显示与对照组类似的低毒性(实施例7和8)。此外,甚至当使用其他药物如MMAE时或当使用其他抗体如Lorvotuzumab、布妥昔单抗和Glembatumumab时,在抗原结合活性、细胞毒性等方面获得了与上述结果类似的结果(实施例9),这指示根据本发明的技术,其中将药物缀合于抗体的重链或轻链的N-末端,能够成为制备抗体-药物缀合物的平台技术。
在另一个方面,本发明涉及制备抗体-药物缀合物的方法。
抗体-药物缀合物及其组分如上所述。
具体地,用于制备抗体-药物缀合物的方法包括允许抗体与药物反应,所述药物含有能够与α-胺基交联的反应性基团,由此将药物缀合于抗体的重链或轻链的N-末端α-胺基。
此外,用于制备抗体-药物缀合物的方法可进一步包括将抗体-药物缀合物从包括抗体和药物的反应产物分离,所述反应产物不形成缀合物。
具体地,在制备方法中,抗体和药物可在4.0-6.5、更具体为5.5-6.5,甚至更具体为6.0的pH相互缀合。如上所述,本发明具有如下优势:药物或其接头中存在的醛基和抗体的N-末端α-胺基之间的特异性缀合能在低pH发生。
分离抗体-药物缀合物的过程可通过本领域已知的多种方法进行。例如,它可通过层析方法(包括大小排阻层析)进行,但不特定地限于此。
在又一个方面,本发明涉及包含抗体-药物缀合物的组合物。
组合物可为用于治疗癌症或自身免疫性疾病的药物组合物的形式,其包含所述抗体-药物缀合物。在此情况中,抗体可为特异性结合于癌细胞表面抗原或其中出现自身免疫性疾病的组织的表面抗原的抗体。本发明的药物组合物可进一步包含药学可接受的载体。
所述的抗体、药物、癌细胞表面抗原和其中出现自身免疫性疾病的组织的表面抗原如上所述。
如本申请使用的,术语“癌症”无限制地包括各种类型的癌症,而癌症的实例可包括食管癌(esophageal cancer)、胃癌(stomach cancer)、大肠癌(large intestinecancer)、直肠癌(rectal cancer)、口腔癌(oral cancer)、咽癌(pharynx cancer)、喉癌(larynx cancer)、肺癌(lung cancer)、结肠癌(colon cancer)、乳腺癌(breast cancer)、子宫颈癌(uterine cervical cancer)、子宫内膜癌(endometrial cancer)、卵巢癌(ovarian cancer)、前列腺癌(prostate cancer)、睾丸癌(testis cancer)、膀胱癌(bladder cancer)、肾癌(renal cancer)、肝癌(liver cancer)、胰腺症(pancreaticcancer)、骨癌(bone cancer)、结缔组织癌(connective tissue cancer)、皮肤癌(skincancer)、脑癌(brain cancer)、甲状腺癌(thyroid cancer)、白血病(leukemia)、霍奇金病(Hodgkin's disease)、淋巴瘤(lymphoma)和多发性髓样血癌(multiple myeloid bloodcancer)。可选择能够取决于对于癌细胞表面抗原特异的抗原类型而被治疗的癌症。
如本申请使用的,术语“自身免疫性疾病”指由抗体-药物缀合物靶向的任何自身免疫性疾病。自身免疫性疾病的实例包括类风湿性关节炎(rheumatoid arthritis)、系统性硬皮病(systemic scleroderma)、系统性红斑狼疮(systemic lupus erythematosus)、特应性皮炎(atomic dermatitis)、银屑病(psoriasis)、斑秃(alopecia areata)、哮喘(asthma)、克罗恩病(Crohn's disease)、白塞病(Behcet’s disease)、斯耶格伦综合征(syndrome)、格-巴二氏综合征(Guillain-Barre syndrome)、慢性甲状腺炎(chronic thyroiditis)、多发性硬化症(multiple sclerosis)、多肌炎(polymyositis)、强直性脊柱炎(ankylsoing spondylitis)、纤维组织炎(fibrositis)和结节性多动脉炎(polyarteritis nodosa)。
如本申请使用的,术语“药学可接受的载体”指不损害所施用的化合物的生物学活性和特征而不刺激生物体的载体或稀释剂。作为配制为液体溶液的组合物中的药学可接受的载体,使用无菌的且生物相容的载体。药学可接受的载体可为生理盐水、无菌水、林格氏溶液(Ringer’s solution)、缓冲的盐水、白蛋白注射溶液(albumin injectionsolution)、右旋糖溶液、麦芽糊精溶液、甘油、乙醇或它们中的两种或更多种的混合物。此外,本发明的组合物,如果需要的化,可包含其他常规添加剂,包括抗氧化剂、缓冲剂和抑菌剂。
所述载体无特定限制,但对于口服施用,本发明的组合物可包含粘合剂、润滑剂、崩解剂、赋形剂、乳化剂、分散剂、稳定剂、悬浮剂、色素、香料等,对于注射施用,本发明的组合物可包含缓冲剂、防腐剂、镇痛剂、乳化剂、等渗剂、稳定剂等,而对于局部施用,本发明的组合物可包含碱、赋形剂、润滑剂、防腐剂等。
本发明的组合物可用如上所述的药学可接受的载体以多种方式配制。例如,对于口服施用,本发明的组合物可配制为片剂、锭剂、胶囊、酏剂、悬浮剂、糖浆、薄片(wafer)等,而对于注射施用,所述组合物可配制为单位剂量安瓿或多剂量形式。所述组合物还可配制为溶液、悬浮液、片剂、丸剂、胶囊、持续释放制剂等。
同时,适于所述组合物的配制的载体、赋形剂或稀释剂的实例可包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶橡胶(acaciarubber)、海藻酸盐(alginate)、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、硬脂酸镁和矿物油。此外,本发明的组合物可另外含有填充剂、抗聚集剂、润滑剂、润湿剂、香料和防腐剂。
此外,本发明的药物组合物可包括选自下组的根据常规方法的任何一种制剂:片剂、丸剂、粉末、颗粒、胶囊、悬浮剂、内部溶液(internal solutions)、乳剂、糖浆、无菌水溶液、非水性溶剂、悬浮剂、乳剂、冻干剂(lyophilized agents)和栓剂(suppositories)。
此外,缀合物可与多种药学上可接受的载体(如生理盐水或有机溶剂)混合使用。为了增加缀合物的稳定性或吸收性质,可将缀合物与碳水化合物(如葡萄糖、蔗糖或右旋糖酐)、抗氧化剂(如抗坏血酸或谷胱甘肽)、螯合剂、低分子量蛋白质或稳定剂组合使用。
在又一个方面,本发明涉及使用抗体-药物缀合物或组合物治疗癌症或自身免疫性疾病的方法。所述抗体可为特异性结合于癌细胞表面抗原的抗体,而所述药物可为用于治疗癌症的药物。此外,所述抗体可为特异性结合于其中出现自身免疫性疾病的组织的表面抗原的抗体,而所述药物可为用于治疗自身免疫性疾病的药物。
所述的抗体和药物如上所述。
所述方法可为用于治疗癌症或自身免疫性疾病的方法,其包括将所述药物组合物施用于需要治疗的受试者。用于所述方法的抗体-药物缀合物和载体如上所述。
所述组合物可以药学有效量作为单剂或多剂施用。在此情况中,所述组合物可以液体、粉末、气溶胶、胶囊、肠溶片(enteric-coated tablet)或栓剂的形式施用。本发明的组合物可腹膜内、静脉内、肌内、皮下、经皮、口服、局部、鼻内、肺内或直肠内施用,但不限于此。然而,由于口服施用时蛋白质抗体被消化,用于口服施用的组合物中的活性成分应经包覆或经配制,从而保护其免于在胃中降解。此外,所述药物组合物可通过任何装置施用,通过所述装置可将活性成分递送至靶细胞。此外,本发明的药物组合物可单独或与其他治疗剂组合施用,而且可与常规治疗剂顺序或同时施用。
本发明的包含抗体-药物缀合物的组合物以药学有效量施用。如本申请使用的,术语“药学有效量”指足够以适用于医学治疗或预防的合理的益处/风险比例治疗或预防所述疾病的量,而且有效剂量水平可根据如下来确定:疾病的严重性、药物活性、患者的年龄、体重、健康状况、性别和对于药物的敏感性、施用时间、施用路径和排出率、治疗的持续时间、与使用的本发明组合物的组合,或已知要素和其他医药领域中的要素(包括同时使用的药物)。
在另外的方面,本发明涉及筛选适用于制备抗体-药物缀合物的抗体的方法。
在根据本发明的抗体-药物缀合物的制备中,可筛选和选择适用于通过将药物缀合于抗体的N-末端(特别是α-胺基)而有效制备抗体-药物缀合物的抗体。
实施例
以下,参考实施例更详细地描述本发明。对于具备本领域普通技术的人,显而易见的是,这些实施例仅是说明目的的,并且不意欲理解为限制本发明的范围。因此,本发明的实质范围由所附权利要求及其等同物限定。
实施例1:模型抗体的选择
在代表本发明的抗体-药物缀合物的抗体-细胞毒素缀合物的制备中,使用抗-HER2抗体曲妥珠单抗、抗-CD56抗体Lorvotuzumab、抗-CD30抗体布妥昔单抗和抗-GPNMB(糖蛋白NMB)抗体Glembatumumab作为模型抗体以检查具有接头的细胞毒素是否位点-选择性地缀合于所述抗体。
使用已知的氨基酸序列信息将上述抗体构建入表达载体,并从CHO细胞系构建稳定的细胞系。或者,将所述抗体瞬时表达、温育和纯化。
实施例2:毒素的合成
合成具有连接于末端的醛接头的一甲基阿里他汀F(MMAF)毒素(LegoChemBiosciences or XcessBioscience)(图1)。此外,为了检查本发明的N-末端缀合方法是否还可适用于除MMAF之外的毒素,合成了一甲基阿里他汀E(MMAE)(XcessBioscience,USA)。
实施例3:单克隆抗体-细胞毒素缀合物的制备
3-1:根据本发明的单克隆抗体-药物缀合物的制备
将抗体稀释于100mM磷酸钾缓冲液(pH 5.49)并浓缩至约7.1mg/ml。接着,将连接有具备醛反应性基团的接头的MMAF(LegoChem Biosciences,Korea)溶解于50%DMSO(二甲亚砜)溶剂至浓度为2.5mg/ml。其后,将制备的抗体溶液和MMAF溶液相互混合以实现如下条件:最终70mM磷酸钾(pH6.0);抗体浓度:5.0mg/ml;14%DMSO;MMAF浓度:0.3mg/ml;和抗体的α-胺基与MMAF之间的摩尔比例:约1:2.3(或抗体与MMAF之间的摩尔比例为1:9)。将NaCNBH3(Sigma,USA)添加至反应溶液至终浓度为20mM,然后在温和搅拌下在4℃反应12小时。为了分离未反应的抗体和未反应的连接有接头的MMAF,使用Sephadex G-25柱(GEHealthcare,USA)或源苯基柱(resource phenyl column)(Resource Phe,GE Healthcare,USA)。根据此过程,制备缀合物,其中每个抗体分子约三个MMAF毒素分子选择性地缀合于抗体的氨基末端(图2)。
3-2:对照抗体-药物缀合物的制备
根据常规技术,通过半胱氨酸缀合(Thiomab(HC-A114C)+Mal-C6-MMAF)、巯基缀合(Mal-C6-MMAF)或赖氨酸缀合(SMCC接头,SH-C6-MMAF)而制备对照抗体-药物缀合物。
为了制备巯基缀合的抗体,将抗体用TCEP在8.0的pH还原,然后将Mal-C4-MMAF添加至其中,并允许在0℃反应3小时。在反应后,将硫醇添加至反应产物,然后其进一步反应。反应终止后,使用G25脱盐柱(GE healthcare,USA)用1X PBS进行更换(replacement)以完成反应。
为了制备半胱氨酸-缀合的抗体,将纯化的抗体中的半胱氨酸活化,然后将Mal-C6-MMAF添加至其中,并根据与巯基-缀合的抗体的制备中所用类似的工艺进行缀合。
参考国际专利公开号WO2005037992(Immunogen)制备包含赖氨酸-缀合的抗体的缀合物。首先,将抗体与SMCC接头反应,并通过缓冲液交换将未反应的SMCC移出。将抗体-SMCC缀合物与含有巯基的SH-C4-MMAF(Concortis bioscience,USA)反应,由此制备抗体-SMCC-MMAF缀合物。
根据本发明通过α-胺基缀合制备的抗体-细胞毒素缀合物总结在下表1中。
表1
分析如上所述制备的四个缀合物以确定DAR(药物抗体比例)和缀合的位点。所述分析通过LC-MS和肽绘图(peptide mapping)进行。
实施例4:物理化学性质和生物学性质
4-1:分子量的分析
通过LC-MS分析确定抗体-药物缀合物(T-N-MMAF)的分子量。使用的药物(MMAF)的理论分子量是824.54Da,而曲妥珠单抗的分子量是145kDa。因此,药物对抗体的缀合和缀合于一个抗体分子的药物部分的数目可通过质谱同时确定。
为了确定实施例3中制备的T-N-MMAF的DAR,通过LC/MS分析了T-N-MMAF的分子量。制备的样品用PNGaseF处理以移出糖链,然后通过ACQUITY UPLC BEH 200 SEC柱分离,此后将样品注射入Waters Synapt G2-S系统以分析质量。分析的结果示于图3。
结果,如图3所示,检测到的化学物质范围从不具有与其缀合的药物部分的化学物质(D0)到具有与其缀合的7个药物部分的化学物质(D7),而且缀合的药物部分的数目基于如下确定:峰之间的分子量差异是否与药物的分子量一致或类似。药物部分的相对强度适于下表2。DAR计算为化学物质的加权平均且为DAR=3.2。
表2
4-2:药物的缀合位点
制备的T-N_MMAF缀合物中药物的缀合位点通过肽绘图确定。实施例3中制备的T-N-MMAF ADC(具有3.2的DAR)用Rapigest(Waters)处理,然后用胰蛋白酶(Roche)处理以制成片段。通过ACQUITY UPLC PST(BEH)C18柱分离反应产物,并将分离的峰通过WatersSynapt G2-S Q/TOF系统进行质谱以确定反应产物的序列。分析的结果示于图4。
结果,如图4所示,在层析图中检测到在非缀合的亲本抗体中未发现的峰。质谱的结果指示所述片段为重链的N-末端、轻链的N-末端、重链的一部分和其他小片段。片段的比例示于下表3。因此可见,75%的药物缀合于N-末端且92%的药物选择性地缀合于N-末端和重链CH2区,其可清楚地限定。
表3
胰蛋白酶片段 | 比例 | |
重链-N-末端 | EVQLVESGGGLVQPGGSLR(SEQ ID NO:1) | 46% |
轻链-N-末端 | DIQMTQSPSSLSASVGDR(SEQ ID NO:2) | 29% |
重链-CH2 | THTCPPCPAPELLGGPSVFLFPPKPKDTLMISR(SEQ ID NO:3) | 17% |
其他 | - | 8% |
4-3:纯度的分析
为了确定制备的T-N-MMAF缀合物的聚集含量(aggregate content),通过SE-HPLC和SDS-PAGE分析进行所述缀合物的纯度分析。将大小排阻层析用于使用PBS作为流动相的TSK-Gel3000SWXL柱中,并使用4-12%NovexNuPAGE凝胶进行SDS-PAGE。层析的结果示于图5。
结果,如图5所示,单体的纯度为98.8%,其适于功效测试,未检测片段化(fragmentation)或交联(cross-linking)。
4-4:抗原结合活性
为了检查甚至在药物缀合于抗体后抗体的抗原结合活性是否维持,通过使用BiacoreTM测量表面等离子体共振的方法测量药物缀合的抗体的抗原结合活性。作为对照抗体,使用天然抗体。使用Biacore T200分析抗原(ErbB2)结合活性,并使用胺偶联试剂盒(amine coupling kit)将每个抗体固定于CM5传感器芯片(GE healthcare,USA)上,其后通过在以50、16.67、5.56、1.85、0.62和0.21nM的浓度并以30uL/min的速率注射ErbB2时测量和分析开关率(on/off rate)来计算kD(M)。
表4
结果,如上表4中所总结的,发现类似于天然抗体的约0.1nM的抗原结合活性得以维持,甚至是在药物缀合后,且无论DAR。
实施例5:体外细胞毒性分析
为了检查制备的抗体-细胞毒素缀合物的体外功效,使用BT474、HCC1954、SKOV-3、JIMT-1细胞系(其为表达HER2的肿瘤细胞系)进行抗-增殖测定法。培养每个细胞系,并将其以1x 105细胞/ml的浓度悬浮,并将100的悬浮液加载入96-孔板的每个孔。将细胞在温育箱中温育3小时,然后将稀释至多种浓度的100的抗体-细胞毒素缀合物添加至板的每个孔,并在温育箱中温育4天。将CCK-8(Dojindo)的1:10稀释物添加至板的每个孔,然后将其覆以金属薄片(foil)并在温育箱中温育2-5小时。接着,使用SpectraMax 190微孔板阅读器(Molecular Device)测量每孔在450nm的吸光度。
表5
结果,如下表5中所示,T-N-MMAF在所有的四个癌细胞系中显示稍微低于T-C-MMAF的细胞毒性,但并没有观察到细胞毒性的显著降低,其可影响体内功效。
实施例6:稳定性测试
6-1:体外人血清中的稳定性
使用实施例3中制备的T-N-MMAF和对照抗体,包括天然抗体、T-C-MMAF和Thiomab-MMAF,进行了体外人血清中的稳定性测试。所述抗体-细胞毒素缀合物用1x PBS缓冲液交换,并浓缩至3.33mg/ml,然后以1:9(v/v)的比例与人血清(Sigma,USA)混合,并允许在37℃静置7天。在7天后,为了移出除样品中所含的抗体-细胞毒素缀合物之外的蛋白质,用MabSelectSure(GE healthcare,USA)处理储存的样品以使LC/MS分析中的干扰最小化。通过LC/MS分析体外人血清中缀合物的稳定性,而且分析的结果示于下表6。
表6
结果,如上表6中可见,储存7天后未观察到T-N-MMAF的含量和DAR与对照天然抗体相比的变化。然而,在T-C-MMAF和Thiomab-MMAF(其为比较的抗体-药物缀合物)的情况中,可观察到总抗体含量和DAR的下降。
6-2:大鼠药物代谢动力学(PK)
通过大鼠药物代谢动力学实验比较和分析了体内稳定性。三种ADC(T-K-MMAF、T-C-MMAF和T-N-MMAF)和曲妥珠单抗的每种以2.5mg/kg的剂量一次静脉内注射至雌性Sprague-Dawley大鼠。在施用所述物质后0.05、0.5、1、6、24、72、168、240和336小时,收集血液。通过ELISA方法进行分析血中所有结合于ErbB2的抗体的总抗体测定法和分析维持药物缀合的抗体的缀合的抗体测定法。
通过ELISA方法分析总抗体含量如下。
将96-孔微孔板用ErbB2(R&D Systems)涂覆,然后将样品添加至所述板并在37℃的温度温育1小时。将板用PBST洗涤以去除所有非-固定的物质,然后使用HRP-缀合的抗-人κ轻链抗体和3,3',5,5'-四甲基联苯胺(TMB,Sigma,T0440)测量板在450nm的吸光度,由此确定样品的总抗体含量。
通过与上述方法类似的方法进行缀合的抗体测定法。具体地,将96-孔微孔板用抗-MMAF抗体(Young In Frontier)涂覆,然后将样品添加至所述板并在在37℃的温度温育1小时。接着将生物素酰化的ErbB2(ACROBIOSYSTEMS,USA)、链霉亲合素-HRP和TMB顺序添加至所述板以显色,然后测量板在450nm的吸光度以确定缀合的抗体的浓度。测量的结果示于图6至8及下表7。
表7
实施例7:测试抗癌模型动物中的抗癌作用
为了检查由不同的技术制备的三种ADC的功效和由药物-抗体比例(DAR)所致的功效差异,使用裸大鼠在乳腺癌(HCC 1954)异种移植物模型中进行了体内功效测试。
将四种ADC(即T-N-M(DAR:约1.6和3.2)、T-C-M(DAR:约3.7)和T-K-M(DAR:约3.9))中的每种以1mg/kg的剂量静脉内一次施用至HCC1954细胞-移植的大鼠,然后比较测试组之间的移植的肿瘤的生长抑制的程度。结果示于图9和10。
结果,如图9和10所示,根据本发明的抗体与对照和比较抗体相比具有优异的抗癌作用。
实施例8:毒性测试
为了检查取决于制备ADC的技术而变化的稳定性是否影响毒性,使用SD大鼠进行了单剂毒性测试。三种ADC中的每种以200mpk的高剂量静脉内一次施用。作为比较组,以200mpk的剂量施用单独抗体和MMAF。从施用测试物质的时间点到测试结束(第12天)的时间过程中每天测量体重。在施用后5天进行血液的生化分析。测量项目为AST和ALT用于确定肝毒性和典型的血液学毒性、中性粒细胞和血小板。
8-1:体重变化
体重变化的测量结果示于图11。如图11所示,T-C-MMAF和T-K-MMAF组显示与T-N-MMAF组和其他组相比体重的明显下降。特别地,在T-C-MMAF施用组的情况中,除了一只动物外所有动物确实在第8天后死亡。
8-2:生化分析(肝毒性)
为了检查ADC是否导致肝毒性,对施用ADC后5天收集的血液进行生化分析。使用Au480临床分析仪(Beckman Coulter,USA)进行分析,并测量指示肝毒性的AST(天冬氨酸氨基转移酶)和ALT(丙氨酸氨基转移酶)的水平。测量的结果示于图12。
结果,如图12所示,可观察到根据本发明的T-N-MMAF组与其他对照组(包括PBS)相比不显示显著差异,这指示它没有引起突然的或严重的肝毒性。然而,在T-C-MMAF和T-K-MMAF组中观察到AST和ALT的显著增加,这指示所述药物的施用引起肝毒性。
8-3:血液学分析(中性粒细胞减少症(Neutropenia)和血小板减少症)
因为目前批准的ADC的主要临床毒性指示血液学性质,使用Hemavet 950 FS血液学分析仪(Drew Scientific Inc.,USA)对施用ADC后5天收集的血液进行血液学分析。分析仪的结果示于图13。
结果,如图13所示,T-N-MMAF组与对照组(包括PBS)相比不显示中性粒细胞数目的显著变化,这表明T-N-MMAF不引起突然的或严重的血液学毒性。然而,T-C-MMAF组显示中性粒细胞数目的显著减少,而T-K-MMAF组显示中性粒细胞数目的显著增加,其在施用后立即减少然后增加。因此,对于这两组,可得出如下结论:突然的血液学毒性是由所述药物的施用引起的。
T-N-MMAF组中血小板的数目明显小于其他对照组(包括PBS)中的情况。然而,T-C-MMAF和T-K-MMAF组显示血小板数目的显著减少,这指示突然的毒性是由所述药物的施用引起的。
实施例9:平台功能的检查
检查了根据本发明制备抗体-药物缀合物的方法是否能应用于多种抗体-药物缀合物。为此,将所述方法应用于多种药物或抗体和多种抗体形式以检查其功能。
9-1:根据药物类型检查功能
为了确定根据本发明制备抗体-药物缀合物的方法是否能应用于多种药物,使用曲妥珠单抗作为模型抗体进行了多种药物的N-末端缀合。具体地,使用了两种药物(MMAF和MMAE),且使用MMAF获得的结果如上述实施例中所述。根据实施例1中所述方法制备抗体-药物缀合物,并根据上述实施例中所述的方法对制备的抗体-药物缀合物进行DAR分析、体外稳定性和大鼠PK。
9-1-1:T-N-MMAE的制备
根据上述制备了MMAE(XcessBioscience,USA)和抗体之间的缀合物。为了确定缀合物的DAR,通过LC/MS分析缀合物的分子量,且分析的结果示于图14和下表8。
表8
9-1-2:人血清中T-N-MMAE的稳定性分析
根据实施例6的方法,评价了血清中T-N-MMAE ADC的稳定性。使用ELISA通过总抗体测定法测量了每个样品中ADC的浓度,并通过LC/MS测量了DAR的变化。
表9
μg/ml | % | DAR | % | |
第0天 | 364.8 | 100% | 3.17 | 100% |
第3天 | 346.9 | 95% | 3.33 | 105% |
第7天 | 294.8 | 81% | 3.28 | 103% |
9-1-3:T-N-MMAE的大鼠PK
为了评价制备的MMAE缀合物的体内稳定性,根据与实施例6类似的方法进行了SD大鼠中的PK研究。不久(shortly),将2.5mg/pk的ADC施用于雌性SD大鼠。在施用ADC后12分钟、30分钟、1小时、6小时、24小时、3天、7天、10天、14天、17天和21天从大鼠收集血液,并使用ELISA技术根据上述方法测量血液中总蛋白和缀合的抗体的浓度。
表10
结果,如图15和上表10所示,T-N-MMAE显示总抗体和缀合抗体的概貌(profile),其与亲本抗体的情况没有显著区别,这表明使用MMAE制备的抗体-药物缀合物具有与使用MMAF制备的抗体-药物缀合物类似的稳定性。
9-1-4:T-N-MMAE的活性
为了确定制备的MMAE缀合物的生物活性,使用四种不同的肿瘤细胞系测量其活性。测量的结果示于下表11。使用的方法类似于实施例5中所用的方法。
表11
结果,测量的IC50范围为0.33-3.76nM,其类似于文献中报道的BT474细胞系针对曲妥珠单抗/MMAE硫醇缀合物的活性(0.47nM)。这表明根据本发明用于选择性缀合于N-末端α-胺基的方法也可应用于其他类型的药物。
9-2:根据抗体类型检查功能
为了检查根据本发明的制备抗体-药物缀合物的方法是否能够应用于不同的抗体,进行了对于三种抗癌抗体(布妥昔单抗、Lorvotuzumab、Glembatumumab)的N-末端缀合,并测量了所述缀合物的DAR和体外稳定性。
9-2-1:布妥昔单抗
9-2-1-1:布妥昔单抗-N-MMAF的制备
使用从CHO细胞系表达的布妥昔单抗,根据实施例3的方法制备布妥昔单抗-N-MMAF(B-N-MMAF)。制备的ADC显示示于图16和下表12的LC/MS谱。在ADC中,检测到范围从D0至D6的化学物质,且DAR计算为2.90。
表12
结合的药物的数目 | 质量(Da) | 相对含量(%) | Δ质量(Da) |
D0 | 145208.6 | 3.1 | |
D1 | 146034.9 | 14 | 826.3 |
D2 | 146863.3 | 24.4 | 828.4 |
D3 | 147692 | 26.4 | 828.7 |
D4 | 148520.7 | 18.2 | 828.7 |
D5 | 149349.7 | 9.3 | 829 |
D6 | 150177.5 | 4.7 | 827.8 |
DAR | 2.90 |
9-2-1-2:配体结合测定法
为了确定所述抗体的性质是否由于缀合而变化,通过ELISA技术测量了抗体对抗原的结合活性。具体地,将100μg的抗原CD30(R&D Systems)涂覆于96-孔微孔板上,然后用1%BSA在37℃封闭1小时。在移出封闭溶液后,将样品添加至板,并在37℃温育1小时。将板用PBST(PBS+0.05%Tween 20)洗涤五次,然后将HRP-缀合的抗-人κ轻链抗体的1000-倍稀释物添加至板并在37℃温育1小时。将板用PBST洗涤五次,再将TMB(Sigma)添加至板,然后将其进行显色10分钟。将1N H2SO4添加至板以停止反应,然后测量板在450nm的吸光度。测量的结果示于图17。在图17中,以O指示的线指示非缀合的布妥昔单抗的结果,以◇指示的线指示具有2.90的DAR的B-N-MMAF的结果,而以△指示的线指示具有4.22的DAR的B-N-MMAF的结果。如从结果可见,抗体对抗原的结合活性甚至在缀合后没有变化,无论DAR值为何。
9-2-1-3:体外细胞毒性
为了确定制备的抗体-细胞毒素缀合物的体外功效,使用Karpas-299和L-540细胞系(其为表达CD30的细胞系)进行抗-增殖测定法。
具体地,培养每个细胞系并将其以1x 105细胞/ml的浓度悬浮,并将100的悬浮液加载入96-孔板的每孔。将细胞在温育箱中温育3小时,然后将稀释至不同浓度的100的抗体-细胞毒素缀合物添加至板的每孔,然后将其在温育箱中温育4天。将1:10稀释的CCK-8(Dojindo)添加至板的每孔,然后其覆以金属薄片并在温育箱中温育2-5小时。接着,使用SpectraMax 190微孔板阅读器测量每孔在450nm的吸光度。测量的结果示于下表13。
表13
细胞系 | IC<sub>50</sub>(pM) |
Karpas-299 | 32.2 |
L-540 | 37.1 |
结果,在所有两个细胞系(Karpas-299和L-540)中观察到低于40pM的细胞毒性。
9-2-2:Lorvotuzumab
9-2-2-1:Lorvotuzumab-N-MMAF的制备
使用从CHO细胞瞬时表达的Lorvotuzumab,根据实施例3的方法制备Lorvotuzumab-N-MMAF(L-N-MMAF)。结果,制备的ADC显示示于图18和下表14的缀合谱。且缀合物的DAR确定为3.33。
表14
结合的药物的数目 | 质量(Da) | 相对含量(%) | Δ质量(Da) |
D0 | 147001.5 | 3.3 | |
D1 | 147830.8 | 10.8 | 829.3 |
D2 | 148657.9 | 18.6 | 827.1 |
D3 | 149486.6 | 22.7 | 828.7 |
D4 | 150315.4 | 20.1 | 828.8 |
D5 | 151144.7 | 13.7 | 829.3 |
D6 | 151973.5 | 7 | 828.8 |
D7 | 152803 | 3.7 | 829.5 |
DAR | 3.329 |
9-2-2-2:配体结合测定法
为了确定所述抗体的性质是否由于缀合而变化,通过ELISA技术测量了缀合之前和之后抗体对抗原的结合活性。具体地,将100μg的抗原CD30(R&D Systems,2408-NC-050)以1μg/ml的浓度涂覆于96-孔微孔板上,然后用1%BSA在37℃封闭1小时。在移出封闭溶液后,将测试样品添加至板,并在37℃温育1小时。将板用PBST(PBS+0.05%Tween 20)洗涤五次,然后将HRP-缀合的抗-人κ轻链抗体的1000-倍稀释物添加至板并在37℃温育1小时。将板用PBST洗涤五次,再将TMB(Sigma)添加至板,然后将其进行显色10分钟。将1N H2SO4添加至板以停止反应,然后测量板在450nm的吸光度。测量的结果示于图19。在图19中,以○指示的线指示未缀合于药物的抗体的结果,以△指示的线指示具有2.5的DAR的L-N-MMAF的结果,而以◇指示的线指示具有3.3的DAR的L-N-MMAF的结果。如从结果可见,抗体对抗原的结合活性得到维持,而无论DAR值为何。
9-2-2-2:体外细胞毒性
为了确定制备的抗体-细胞毒素缀合物的体外功效,使用OPM-2细胞系进行抗-增殖测定法。具体地,培养所述细胞系并将其以1x 105细胞/ml的浓度悬浮,并将100的悬浮液加载入96-孔板的每孔。将细胞在温育箱中温育3小时,然后将稀释至不同浓度的100的抗体-细胞毒素缀合物添加至板的每孔,然后将其在温育箱中温育4天。将1:10稀释的CCK-8(Dojindo)添加至板的每孔,然后其覆以金属薄片并在温育箱中温育2-5小时。接着,使用SpectraMax 190微孔板阅读器测量每孔在450nm的吸光度。测量的结果示于下表15。
表15
如上表15中可见,根据本发明的L-N-MMAF抗体显示约42-53nM的细胞毒性。
9-2-3:Glembatumumab
9-2-3-1:体外细胞毒性
为了确定制备的抗体-细胞毒素缀合物的体外功效,使用SK-MEL-2细胞系(其为皮肤癌细胞系)进行抗-增殖测定法。具体地,培养所述细胞系并将其以1x 105细胞/ml的浓度悬浮,并将100的悬浮液加载入96-孔板的每孔。将细胞在温育箱中温育3小时,然后将稀释至不同浓度的100的抗体-细胞毒素缀合物添加至板的每孔,然后将其在温育箱中温育4天。将1:10稀释的CCK-8(Dojindo)添加至板的每孔,然后其覆以金属薄片并在温育箱中温育2-5小时。接着,使用SpectraMax 190微孔板阅读器测量每孔在450nm的吸光度。测量的结果示于下表16。
表16
SK-MEL-2 | IC<sub>50</sub>(nM) |
G-N-MMAF DAR 2.2 | 5.47 |
G-N-MMAF DAR 3.4 | 3.36 |
如上表16中可见,根据本发明的G-N-MMAF抗体显示约3-5nM的细胞毒性。
上述结果表明,通过将药物位点特异性地缀合于抗体的重链或轻链的N-末端氨基酸残基制备的抗体-药物缀合物的新的平台不显示所述抗体的靶物特异性的降低,同时具有高稳定性,还表明所述抗体的治疗效果能够通过与其缀合的药物而加倍。
本方面所属领域的技术人员根据前述会理解的是:可在其他具体实施方案中实施本发明而不改变其技术精神或必要特征。在这方面,应该理解的是上述实施例在所有方面都是说明性的,而非限制性的。本发明的范围应理解为包括所附权利要求的涵义和范围以及由其等同概念得到的所有改变和修饰形式,而非仅限于本详细说明。
Claims (7)
1.一种抗体-药物缀合物,其包含与抗体的重链或轻链的氨基酸残基的N-末端α-胺基缀合的细胞毒性药物,其中所述细胞毒性药物为一甲基阿里他汀F或一甲基阿里他汀E;其中所述抗体为曲妥珠单抗、Lorvotuzumab、布妥昔单抗或Glembatumumab;且其中所述细胞毒性药物缀合于抗体的重链或轻链的第一氨基酸残基的N-末端α-胺基,以及所述细胞毒性药物通过具有反应性醛基团的接头经由所述醛基团的还原性烷基化缀合于所述抗体。
2.权利要求1的抗体-药物缀合物,其中所述抗体包括全长抗体或含有抗原结合域的抗体片段。
3.权利要求2的抗体-药物缀合物,其中所述抗体选自下组:IgG、scFv、Fv、Fab、Fab'和F(ab')2。
4.一种用于制备权利要求1-3中任一项的抗体-药物缀合物的方法,所述方法包括将细胞毒性药物一甲基阿里他汀F或一甲基阿里他汀E通过使抗体曲妥珠单抗、Lorvotuzumab、布妥昔单抗或Glembatumumab与含有能够与α-胺基交联的反应性基团的细胞毒性药物反应而缀合于所述抗体的重链或轻链的第一氨基酸残基的N-末端α-胺基。
5.权利要求4的方法,其进一步包括:将所述抗体-药物缀合物与包括抗体和细胞毒性药物的反应产物分离,在所述反应产物中不形成所述缀合物。
6.一种用于治疗癌症的药物组合物,其包含权利要求1-3中任一项的抗体-药物缀合物。
7.权利要求1-3中任一项的抗体-药物缀合物在制备药物中的用途,所述药物用于在怀疑患有癌症的受试者中治疗癌症。
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