CN108449940A - 与细胞结合分子的共轭偶联的桥连接体 - Google Patents
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Abstract
本发明涉及一类新型含联胺基团的桥连接体,该连接体通过桥式连接细胞结合分子上的巯基对,把细胞结合分子与小分子药物/细胞毒性剂特异性地共轭偶联。本发明还涉及连接体的制备方法,用此链接体制备均一共轭偶联物,以及用此偶联物应用于治疗癌症、感染和自身免疫性疾病。
Description
技术领域
本发明涉及一类新型桥连接体的制备,该连接体通过与细胞结合分子上的巯基对作用,把细胞结合分子与小分子药物,尤其是细胞毒性剂特异性地共轭偶联。本发明还涉及制备细胞结合剂-药物(细胞毒性剂)共轭偶联物的方法:一种是先用这类连接体修饰药物小分子,再与细胞结合剂反应,另一种是先用这类连接体修饰细胞结合剂,再与药物小分子反应。
技术背景
传统的癌症化疗常伴有病人的全身毒性。单克隆抗体能够通过区分癌细胞上的抗原,提供一种具有肿瘤选择性的靶向治疗方式,但是单独作用时,通常不具备足够的治疗活性。抗体-药物共轭偶联物(ADCs),顾名思义兼具抗体精确的靶向性和化疗药物的细胞毒性,能够靶向传送药物进入癌细胞,并不对正常细胞产生影响,从而提高了化疗试剂的治疗指数。自从美国FDA在2011年批准了Adcetris(brentuximab vedotin),2013年批准了Kadcyla(ado-trastuzumab emtansine)以来,抗体-药物偶联物(ADCs)用作靶向治疗癌症的手段获得了爆发性的发展,几乎所有的大型制药公司和生物技术公司所有涉足其中(Chari,R.et al,Angew.Chem.,Int.Ed.2014,53,3796-3827;Sievers,E.L.et al.AnnuRev Med.2013,64,15-29;Mehrling,T.Future Oncol,2015,11,549)。各家制药公司都有丰富的抗体-药物偶联物管线,相关的交易目前也正处于风头。按照网站www.clinictrails.gov.的统计目前有50多个ADC药物进行到了临床试验阶段,有更多的药物在临床前期或准备进入一期人体临床试验,市场热切地期望更多的ADC药物被监管者批准。
第一代的ADC药物,包括Kadcyla和Adcetris,都是通过非选择性地偶联细胞毒性药物和抗体上天然赖氨酸胺基,或抗体链间半胱氨酸巯基而制备的。由于IgG1抗体上有超过50个暴露在表面的赖氨酸和8个铰链区的半胱氨酸,这种非选择性偶联方式,会导致毒性药物的随机交叉偶联发生在几乎抗体分子的所有区域,尤其是,产生多种多样的具有宽广药物抗体比值(DAR)分布的ADC群体(Wang,L.,et al.Protein Sci.2005,14,2436;Hamblett,K.J.,et al.Clin.Cancer Res.2004,10,7063)。部分不希望产生的ADC亚群具有循环半衰期短、低效、潜在脱靶毒性高以及体内药代动力学(PK)性质不确定等缺陷(Hamblett,K.J.et al,Clin.Cancer Res.2004,10,7063-7070;Adem,Y.T.et al,Bioconjugate Chem.2014,25,656-664;Boylan,N.J.Bioconjugate Chem.,2013,24,1008–1016;Strop,P.,et al Chem.Biol.2013,20,161-167)。此外,这种传统的偶联方式生产的ADC,保持批间一致性非常具有挑战性,需要更高的生产能力(Wakankar,A.mAbs,2011,3,161–172)。
因此,众多生物技术公司和研究机构都致力于开发新型的ADC药物的定点共轭偶联方法。近些年来也有一些定点的ADC药物制备方法(Panowski,S,2014,mAbs 6,34),这些方法包括:在抗体上引入非配对的半胱氨酸,例如Genentech的THIOMAB抗体(Junutula,J.R.,et al Clin.Cancer Res.2010,16,4769;Junutula,J.R.,et al NatBiotechnol.2008 26,925-32;US专利8,309,300;7,855,275;7,521,541;7,723,485;WO2008/141044);或引入谷氨酰胺标签,可以被用茂原轮链丝菌扩增的谷氨酰胺转胺酶(mTG)(Strop,P.,Bioconjugate Chem.,2014,25,855–862;Strop,P.,et al.,Chem.Biol.2013,20,161–167;US专利8,871,908)或由细菌来源的谷氨酰胺转胺酶(MTGase)(Dennler,P.,et al,Bioconjug.Chem.2014,25,569–578;US专利20130189287;7,893,019)所识别;引入巯基-L-岩藻糖(Dennler,P.,et al,Bioconjugate Chemistry2014,25,569;Okeley,N.M.,et alBioconjugate Chem.2013,24,1650);通过诱变引入非天然氨基酸(Axup,J.Y.,et al.,Proc.Natl.Acad.Sci.2012,109,16101–16106;Zimmerman,E.S.,et al.,Bioconjug.Chem.2014,25,351–361;Wu,P.,et al,Proc.Natl.Acad.Sci.2009,106,3000-3005;Rabuka,D.,et al,Nat.Protoc.2012,7,1052-67;美国专利8,778,631;20100184135;WO2010/081110;WO2006/069246,2007/059312,美国专利7,332,571,7,696,312;7,638,299;WO2007/130453,美国专利7,632,492;7,829,659);引入硒代半胱氨酸(Hofer,T.,et al Biochemistry 2009,48,12047–12057;美国专利8,916,159);用甲酰甘氨酸生成酶(FGE)将CXPXR共有序列上的半胱氨酸转化为甲酰甘氨酸(FGly)(Drake,P.M.,et al.,Bioconjug.Chem.2014,25,1331–1341.美国专利7,985,783;8,097,701;8,349,910,美国专利20140141025,20100210543);或用半乳糖或唾液酸转移酶通过糖工程引入唾液酸(Zhou,Q.,et al Bioconjug.Chem.,2014,25,510-520,美国专利20140294867)。用上述的方法可以生产出均一的产品,但是它们都需要抗体工程改造和重新优化细胞培养条件。此外,非天然氨基酸基因编码的表达通常没有希望的那么高(Tian,F.,et al,2014,Proc.Natl.Acad.Sci.U.S.A.111,1766-71),这一点对产品的成本有重要的影响。另外,通过半胱氨酸偶联获得的ADC药物通常在循环系统中的稳定性有限,导致了在抵达肿瘤细胞前,毒性小分子荷载过早的断裂(Junutula,J.R.,et alNat.Biotechnol.2008,26,925-32)。
IgG抗体四种亚型中的二硫键结构在上世纪六十年代就已被人所熟知(MilsteinC.Biochem J 1966,101:338-351;Pink JR,Milstein C.Nature 1967,214:92-94;Frangione B,Milstein C.Nature 1967,216:939-941;Pink JR,Milstein C.Nature1967,216:941-942;Frangione B,et al.Biochem J 1968,106,15–21;Frangione B,Milstein C.J Mol Biol 1968;33:893–906;Edelman GM,et al.Proc Natl Acad Sci USA1969;63:78-85;Frangione B,et al.Nature 196,221:145-148,Spiegelberg,H.L.et alBiochemistry,1975,10,2157-63)。二硫键对于IgG分子的结构、稳定性和生物功能都有很重要的作用。在IgG抗体的四种亚型IgG1,IgG2,IgG3和IgG4中,每个IgG分子含有总共12个链内二硫键;每个二硫键与一个独立的IgG域相关联。两条重链在铰链区通过不同数目的二硫键相连:IgG1和IgG4是2个,IgG24个,IgG311个。在IgG1上,轻链上最后一个半胱氨酸与重链上第5个半胱氨酸形成二硫键而相连。在IgG2,IgG3和IgG4上,轻链上最后一个半胱氨酸与重链上第3个半胱氨酸形成二硫键(Liu,H.and May,K.,2012,mAbs 4,17-23)。通过还原实验、烷基化和LC-MS分析,可以知道人源IgG1抗体上二硫键断裂难易的特性(Liu,H,et alAnal.Chem.,2010,82,5219–5226)。链间二硫键比链内二硫键更易被还原断裂,并且轻重链之间的二硫键比两条重链间的二硫键更易被还原断裂。两条重链上部的链间二硫键比下部的那一条更易断裂。此外,CH2域上的二硫键是最容易被还原的。VL,CL,VH,和CH1域的二硫键具有相似的中等程度的可断裂性,而CH3域的二硫键是最不易被还原的(Liu,H,et alAnal.Chem.,2010,82,5219–5226)。
基于人源IgG1抗体链间二硫键更容易断裂的特点,许多研究所和公司采用化学定点连接的策略,将天然抗体的链间二硫键还原后再搭桥而重新交联在一起,例如使用被称为下一代的马来酰亚胺化合物(NGMs),即溴代物或二溴马来酰亚胺类化合物(Schumacher,F.F.,et al Org.Biomol.Chem.2014,12,7261–7269),使用双烷基化试剂形成一个三碳桥键(Badescu,G.,et al.,Bioconjug.Chem.2014,25,1124–1136,WO2013/190272,WO2014/064424),使用双取代的杂芳基桥键(美国专利2015/0105539),或通过双马来酰亚胺作为桥键(WO2014/114207)。在很长一段时间里,我们同样使用溴代马来酰亚胺和二溴马来酰亚胺作为连接体来偶联药物和抗体(WO2014/009774,PCT/IB2012/053554)。但是,上述的桥连接体的设计是将一个细胞毒性分子和一对二硫键偶联,由于受抗体上可用于共轭偶联的双硫键数目所限(约为2对),大多数情况下生产出的ADCs药物DAR值低于2。
鉴于ADCs药物实现其疗效受限于最终到达肿瘤细胞的毒性小分子数目,为提高ADC治疗指数,其DAR值最好大于3(Epenetos,A.A.et al,Cancer Res.,1986,46,3183–3191;Chari,R.V.Acc.Chem.Res.,2008,41,98-107,Zhao,R.Y.2011J.Med.Chem.54,3606-3623)。本发明中的新型二硫键桥连接体不仅能够在每个连接体上连上2个或更多的小分子药物,实现更高的DAR(≥4),并且为了能够选择性地桥连抗体表面的链间二硫键。这是由于乙炔二羰基中三键伸展的自然特性决定的,当两个毒性小分子连接于伸展的桥连接体两端的时候,能形成大分子(>20间距),其它二硫基团,如重链内部下端二硫基团难以接近。因此本发明的二硫键桥连接体,可以选择性地桥连被TCEP或DTT断裂的抗体链间自由巯基对,从而产生DAR大于4的ADC。其它被还原过头的二硫键由于难以被桥连接体,特别是为含有2个毒性小分子的伸展的桥连接体所接近,可以在偶联完成后用氧化物如脱氢抗坏血酸(DHAA)或Cu(II)重新连接。总之,本发明中的这些桥连接体可以以一种简便的方式产生同质均一的ADC药物。
发明摘要
本发明中连接体含有一个联胺官能团,在一个细胞结合剂(例如抗体)上连接2个小分子药物。细胞结合分子-连接体-药物偶联物可以表示为:其中Cb是细胞结合剂,L是包含联胺官能团的连接体,Drug1和Drug2是药物小分子,n是一个1到20的整数,且2个硫元素桥连Cb于L,每个桥连接体L共价连接2个或更多的药物分子。在细胞小分子-药物偶联物中应用这类连接体的优点有:a).共价交联(重新搭桥)细胞结合剂(如抗体)上还原打开的二硫键巯基的方式,有利于保持偶联物的稳定性;b).可以使毒性小分子/药物连接在细胞结合剂的特定位置,比如IgG抗体的链间位点,从而产生均一的ADC药物。
在一方面,本发明中的连接体结构可以表示为结构式(I)
其中:
Y1和Y2是相同的或不同的,能和细胞结合剂上一对硫原子反应的官能团;Y1和Y2与硫原子对反应生成二硫键、硫醚键或硫酯键。Y1和Y2优选自,但不限于以下官能团:N-羟基琥珀酰亚胺酯、马来酰亚胺、二硫键、卤乙酰、乙烯砜、酰基卤(酸性卤化物)、丙烯酰基和/或酸酐;
Z1和Z2是相同的或不同的能和细胞毒性药物反应的官能团,Z1和Z2与细胞毒性药物反应生成二硫键、醚键、酯键、硫醚键、硫酯键、肽键、腙键、氨基甲酸酯键、碳酸酯键、胺键(二级,三级或四级)、亚胺键、杂环烷基、杂芳基、烷氧肟键或酰胺键;
R1,R2,R3和R4是相同的、不同的或缺省的含1~8个碳原子的直链烷基,3到8个碳原子的支链或环烷基,直链、支链或环烯基或炔基,或1~8个碳原子的酯基、醚基、酰胺基或聚乙氧基(OCH2CH2)p,其中p是0到约1000的整数,或这些基团的组合;
另外,R1,R2,R3和R4是包含C,N,O,S,Si,和P原子的链状结构,最优含0~500个原子,共价连接于Y1或Y2和Z1或Z2;R1,R2,R3和R4中的各个原子以所有可能的化学方式结合,比如形成烷基、亚烷基、亚烯基、亚炔基、醚、聚氧烷基、酯、胺、亚胺、聚胺、肼、腙、酰胺、脲、氨基脲、卡巴肼、烷氧胺、聚氨酯、氨基酸、多肽、酰氧胺、异羟肟酸,或这些基团的组合。
另一方面,本发明中细胞结合剂-药物偶联物可表示为结构式(II),其中细胞结合剂Cb,药物Drug1和Drug2分别与桥连接体两端反应:
其中:Cb为细胞结合剂,最优为抗体;
括号内是通过一对巯基与细胞结合分子偶联的连接体-药物组分。可发生偶联的巯基一般来自细胞结合剂上链间二硫键,被还原剂如DTT和/或TCEP还原生成的巯基对;
Drug1和Drug2为相同的或不同的细胞毒性剂,它们以二硫键、硫醚键、硫酯键、肽键、腙键、醚键、酯键、氨基甲酸酯键、碳酸酯键、环杂烷基、杂芳基、烷氧肟键、酰胺键、亚烷基、亚烯键、亚炔键或芳基与细胞结合剂连接;
n是1~20;R1,R2,R3和R4的定义同结构式(I)。
另一方面,本发明包括一种修饰的细胞结合剂,可表示为结构式(III),其中细胞结合剂Cb已经与桥连接体反应,连接体上包含有能进一步与药物小分子反应的官能团Z1和Z2:
其中Cb,Z1,Z2,n,R1,R2,R3和R4定义同结构式(I)和(II)。
更进一步,本发明包括一种修饰的药物分子,可表示为结构式(IV),其中药物Drug1和Drug2已经与结构式(I)中的连接体反应,仍然保留有能和细胞结合剂上的硫原子对反应的Y1和Y2官能团:
其中Y1,Y2,Drug1,Drug2,R1,R2,R3和R4定义同结构式(I)和(II)。
本发明也包括一种制备如结构式(II)所示的细胞结合分子-药物共轭偶联物的方法,其中药物Drug1和Drug2通过桥连接体和细胞结合剂连接。
本发明也包括一种制备如结构式(III)所示的修饰的细胞结合分子的方法,其中细胞结合分子已与结构式(I)中的桥连接体反应。
本发明还包括一种制备如结构式(IV)所示的修饰的药物小分子的方法,其中药物分子已与结构式(I)中的桥连接体反应。
图例说明
图1桥连接体的合成方法及其应用于抗体和药物的共轭偶联。
图2含有聚乙二醇的桥连接体的合成及通过其中酰胺键和硫醚键共轭偶联抗体和药物。
图3含有聚乙二醇的桥连接体的合成及通过其中酰胺键和硫醚键共轭偶联抗体和药物。
图4桥连接体的合成及通过其中酰胺键和硫醚键共轭偶联抗体和药物。
图5含有多肽的桥连接体的合成及通过其中酰胺键和硫醚键共轭偶联抗体和药物。
图6含有聚乙二醇的桥连接体的合成及通过其中酰胺键和硫醚键共轭偶联抗体和药物。
图7桥连接体(其一含有聚乙二醇)的合成以及应用于每个连接体连接2到4个小分子药物的共轭偶联物的制备(通过酰胺键、肟键或腙键连接药物,通过硫醚键连接抗体)。
图8通过桥连接体连接的抗体-美登素偶联物和抗体-MMAF偶联物的合成。
图9通过桥连接体连接的抗体-美登素偶联物合成(每个桥连接体连接4个美登素分子)。
图10通过桥连接体连接的细胞结合分子-tubulysin同系物的偶联物的合成。
图11每个桥连接体连接4个tubulysin同系物的偶联物的合成,以及含有位阻二硫键连接体的抗体-美登素偶联物的合成。
本发明的详细说明
定义
“烷基”是指在含有1到8个碳原子的直链或支链的脂肪烃。“支链”是指一个或多个较低碳数的烷基如甲基、乙基或丙基连接到一个线性烷基链上。烷基的例子包括甲基,乙基,正丙基,异丙基,正丁基,叔丁基,正戊基,3-戊基,辛基,壬基,癸基,环戊基,环己基,2,2-二甲基丁基,2,3-二甲基丁基,2,2-二甲基戊基,2,3-二甲基戊基,3,3-二甲基戊基,2,3,4–三甲基戊基,3-甲基己基,2,2-二甲基己基,2,4-二甲基己基,2,5-二甲基己基,3,5-二甲基己基,2,4-二甲基戊基,2-甲基庚基,3-甲基庚基,正庚基,异庚基,正辛基,异辛基。一个C1-C8烷基可以是未被取代的或被一个或多个下列基团取代的,包括但不限于-C1-C8烷基,-O-(C1-C8烷基),芳基,-C(O)R',-OC(O)R',-C(O)OR',-C(O)NH2,-C(O)NHR',-C(O)N(R')2,-NHC(O)R',-SR',-S(O)2R',-S(O)R',-OH,卤素,-N3,-NH2,-NH(R'),-N(R')2和–CN;其中每个R'独立选自-C1-C8烷基和芳基。“卤素”指氟、氯、溴、碘原子,优选为氟和氯原子。
“杂烷基”指为C2-C8烷基,其中一至四个碳原子独立地被O,S和N原子所替代。
“碳环”指的是一个饱和或不饱和环,含3至8个碳原子的单环或7至13个碳原子的双环。单环碳环含3至6个原子,典型的是5至6原子。双环碳环含7至12个原子,形成[4,5],[5,5],[5,6]或[6,6]双环系统,或者9至10个原子,形成[5,6]或[6,6]双环系统。典型的C3-C8包括,但不限于环丙基,环丁基,环戊基,环戊二烯基,环己基,环己烯基,1,3-环己二烯基,1,4-环己二烯基,环庚基,1,3-环庚二烯基,1,3,5-环庚三烯基,环辛基和环辛二烯基。
“C3-C8碳环”指的是3,4,5,6,7或8元含有饱和或不饱和的非芳香碳环。一个C3-C8碳环可以是未被取代的或被一个或多个基团取代的,包括但不限于-C1-C8烷基,-O-(C1-C8烷基),芳基,-C(O)R',-OC(O)R',-C(O)OR',-C(O)NH2,-C(O)NHR',-C(O)N(R')2,-NHC(O)R',-SR',-S(O)R',-S(O)2R',-OH,卤素,-N3,-NH2,-NH(R'),-N(R')2和–CN,其中每个R'独立选自-C1-C8烷基和芳基。
“烯基”指的是含有碳碳双键,2至8个碳原子的直链或支链脂肪烃。烯基的例子包括乙烯基,丙烯基,正丁烯基,异丁烯基,3-甲基-2-丁烯基,正戊烯基,己烯基,庚烯基,辛烯基。
“炔基”指的是含有碳碳三键,2至8个碳原子的直链或支链脂肪烃。烯基的例子包括乙炔基,丙炔基,正丁炔基,2-丁炔基,3-甲基丁炔基,5-戊炔基,正戊烯基,己炔基,庚炔基,辛炔基。
“亚烷基”指的是饱和的,1-18个碳原子的支链的或直链或环状烃自由基,包含母系烷烃的同一碳上或不同碳上去除两个氢的得到的两个一价自由基中心。典型的亚烷基包括,但不限于亚甲基(-CH2-),1,2-乙基(-CH2CH2-),1,3-丙基(-CH2CH2CH2-),1,4-丁基(-CH2CH2CH2CH2-)等。
“亚烯基”指的是不饱和的,2-18个碳原子的支链的或直链或环状烃自由基,包含母系烯烃的同一碳上或不同碳上去除两个氢的得到的两个一价自由基中心。典型的亚烯基包括,但不限于1,2-乙烯基(-CH=CH-)。
“亚炔基”指的是不饱和的,2-18个碳原子的支链的或直链或环状烃自由基,包含母系炔烃的同一碳上或不同碳上去除两个氢的得到的两个一价自由基中心。典型的亚炔基包括,但不限于乙炔基,丙炔基和4-戊炔基。
“芳基”或“芳烃基”指芳香族或杂芳基,由一个或几个环组成,包含3至14个碳原子,优先6至10个碳原子。杂芳基指芳环上的一个或多个碳原子(优选1、2、3或4个碳原子)被O,N,Si,Se,P或S取代(优选O,S和N)。“芳基”或Ar也指芳环上的一个或多个氢原子各自独立地被-R’,卤素,-OR’,或-SR’,-NR’R”,-N=NR’,-N=R’,-NR’R”,-NO2,-S(O)R’,-S(O)2R’,-S(O)2OR’,-OS(O)2OR’,-PR’R”,-P(O)R’R”,-P(OR’)(OR”),-P(O)(OR’)(OR”)或-OP(O)(OR’)(OR”)所取代,其中R’,R”是独立的氢,烷基,烯基,炔基,杂烷基,芳基,芳烷基,羰基或药用盐。
“杂环”是一个环系统,其中1至4个原子各自独立地被O,N,S,Se和P等杂原子所取代,优选是O,N和S。“杂环”的定义亦可参考文献The Handbook of Chemistry andPhysics,78th Edition,CRC Press,Inc.,1997-1998,p.225to 226。优选的非芳香类杂环包括,但不限于环氧、乙烯亚氨基、吡咯烷、吡唑烷基,烷基咪唑、环氧乙烷基、四氢呋喃、二氧戊环、吡喃阿霉素,二恶烷基,二氧戊环、呱,哌嗪,吗啉、吡喃、咪唑啉、吡咯啉基、吡唑啉基、噻唑烷基,四氢噻喃,二噻烷,硫吗啉,二氢吡喃、吡喃阿霉素,四氢吡啶、二氢吡啶、四氢嘧啶、二氢噻喃、六亚甲基亚胺以及它们与苯基缩合而产生的结构。
“杂芳基”或芳杂环指的是5至14元,优选5到10元的芳香性杂,单、双或多环,包括吡咯、吡啶、吡唑、嘧啶、吡嗪、四唑基噻吩基、吲哚、喹啉、嘌呤、咪唑基、噻吩、噻唑、苯并噻唑、呋喃、苯并呋喃、1,2,4-三氮唑,异噻唑,三唑,四唑、异喹啉、苯并噻吩、异苯并呋喃、吡唑、咔唑、苯并咪唑、异恶唑,吡啶氮氧化物,以及它们与苯基缩合而产生的环结构。
“烷基”、“环烷基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“杂环”等也指相应的“亚烷基”、“亚环烷基”、“亚烯基”、“亚炔基”、“亚芳基”、“亚杂芳基”和“亚杂环”等去掉两氢原子的基团。
“芳烷基”指的是一个非环状烷烃基自由基,其中一个与碳原子,通常是一个末端或sp3杂化的碳原子,相连的氢原子被芳基取代。典型的芳基烷基包括,但不限于苯基,2-苯基-1-乙基基,2-苯基-1-乙烯基,萘甲基,2-萘基-1-乙基基,2-萘基-1-乙烯基,萘苯基,2-萘苯-1-乙基等。
“杂芳烷基”指一个非环状烷烃基自由基,其中一个与碳原子,通常是一个末端或sp3杂化的碳原子,相连的氢原子被杂芳基取代。典型的杂芳烷基包括,但不限于2-苯并咪唑甲基基,2-呋喃乙基等。
“羟基保护基团”的例子包括,但不限于甲氧甲基醚,2-甲氧乙氧甲基醚,四氢吡喃醚,苄基醚,对甲氧基苄基醚,三甲基硅醚,三乙基硅醚,三异丙基硅基醚,叔丁基二甲基硅醚,三苯基甲基硅醚,乙酰酯,取代乙酰酯,2,2-二甲基丙酸酯,安息香酸酯,苯甲酸酯,甲基磺酸酯和对甲苯磺酸酯。
“离去基团”是指可以被另一个基团取代的官能团。为本领域所熟知的离去基团包括,但不限于卤素(氯,溴,碘),甲磺酰基,对甲苯磺酰基,三氟甲磺酰基,三氟甲磺酸酯。
以下缩写为本发明所采用,其定义为:Boc,叔丁氧羰基;BroP,溴化三(二甲基氨基)膦六氟磷酸;CDI,羰基二咪唑;DCC,二环己基碳二亚胺;DCM,二氯甲烷;DIAD,偶氮二甲酸二异丙酯;DIBAL-H,二异丁基氢化铝;DIPEA,二异丙基乙胺;DEPC,焦碳酸二乙酯;DMA,N,N-二甲基乙酰胺;DMAP,对二甲胺基吡啶;DMF,N,N-二甲基甲酰胺;DMSO,二甲基亚砜;DTT,二硫苏糖醇;EDC,1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐;ESI-MS,电喷雾质谱法;HATU,2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯;HOBt,1-羟基苯并三唑;HPLC,高效液相色谱;NHS,N-羟基琥珀酰亚胺;MMP,4-甲基吗啉;PAB,对氨基苯基;PBS,磷酸缓冲液(pH 7.0~7.5);PEG,聚乙二醇;SEC,分子排阻色谱;TCEP,磷酸三氯乙酯;TFA,三氟乙酸;THF,四氢呋喃;Val,缬氨酸。
“药学上的”或“药学上可接受的”是指在适当的情况下给动物或人类施用后,不会产生有害的、过敏或其他不良反应的分子实体和组合物。
“药学上可接受的溶剂化物”或“溶剂化物”是指所公开的化合物和与它相结合的一个或一个以上的溶剂分子。药学上可接受的溶剂化物中的溶剂包括,但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。
“药用辅料”包括任何载体、稀释剂、助剂或赋形剂,如保护或抗氧化剂,填充剂、崩解剂、润湿剂、乳化剂、悬浮剂、溶剂、分散介质、涂层、抗菌和抗真菌剂、等渗和吸收延缓剂等。在药物活性组分里使用这些介质和试剂在本领域内是众所周知的。任何常规媒介或试剂,除非与活性成分不相容,都可以考虑用在治疗组合物中。辅助活性成分也可加入,成为合适的治疗组合物。
“药用盐”是指所公开的化合物的衍生物,其通过母体化合物与酸或碱作用而成盐。药学上可接受的盐包括常规无毒盐或与母体化合物,例如无毒的无机或有机酸形成的季铵盐。例如,常规的无毒盐包括无机酸的衍生物,如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等;和用有机酸制备的盐,如乙酸、丙酸、丁二酸、酒石酸、柠檬酸、磺酸、苯磺酸、葡萄糖、谷氨酸、苯甲酸、水杨酸、对甲苯磺酸、草酸、琥珀酸,马来有机酸、乳酸等。其它盐包括铵盐,如三甲胺,甲葡胺、吡咯乙醇盐等,和金属盐,如钠、钾、钙、锌和镁盐。
本专利中的药用盐可以从包含酸或碱的母体,用常规的化学方法合成。一般来说,这种盐可以通过在水中或有机溶剂中或在两种溶剂的混合物中,向母体化合物的自由酸或碱里,加入等当量的合适的碱或酸而形成。一般来说,优选非水介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。适宜的盐的清单可见于Remington's Pharmaceutical Sciences,17thed.,Mack Publishing Company,Easton,PA,1985,p.1418,在此列作参考。
本发明中公开的新型共轭偶联物使用了桥连接体。部分连接体及其合成表示如图1至11。
桥连接体
本专利中的桥连接体的合成,以及药物-细胞结合分子偶联物的制备如图1-11所示。桥连接体含有三个要件:a)相同或不同的,能与细胞结合剂上巯基对反应的两个官能团,包括但不限于:N-羟基琥珀酰亚胺酯、马来酰亚胺,二硫化物、卤代乙酰基,乙烯磺酰基、酰卤、丙烯酰基和/或酸酐基团;b)能连接其它官能团的中间的桥状连接为联胺;c)相同或不同的,能与药物分子反应的两个官能团,包括但不限于二硫化物、马来酰亚胺、卤乙酰基、醛、酮、叠氮、胺、烷氧基胺和肼。包含联胺的桥连接体可以通过联胺和酸,酰卤或酸酐直接缩合,然后引入可以和细胞结合剂和药物分子反应的官能团而制得。这些桥连接体合成的实例可见于图1-11,以及具体实例例。
优选地,桥连接体的结构如(I)所示:
其中:
Y1和Y2是相同的或不同的官能团,可以与细胞结合剂上的一对硫原子反应,形成二硫化物,硫醚或巯酯键。优选的Y1和Y2为,但不限于N-羟基琥珀酰亚胺酯,马来酰亚胺基,二硫化物,卤代乙酰基,酰卤,乙烯磺酰基,丙烯酰基,2-(对甲苯磺酰氧基)乙酰基,2-(甲磺酰氧基)乙酰基,2-(硝基苯氧基)乙酰基,2-(二硝基苯氧基)乙酰基,2-(氟苯氧基)乙酰基,2-(二氟苯氧基)乙酰基,2-(五氟苯氧基)乙酰基,2-(三氟甲磺酸氧基)乙酰基,和/或酸酐基团,其结构如下:
N-羟基琥珀酰亚胺酯;马来酰亚胺基;二硫化物;卤代乙酰基;酰卤或酯;乙烯磺酰基;丙烯酰基;2-(对甲苯磺酰氧基)乙酰基;(甲磺酰氧基)乙酰基;2-(硝基苯氧基)乙酰基;2-(二硝基苯氧基)乙酰基;2-(氟苯氧基)乙酰基;2-(二氟苯氧基)乙酰基;2-(五氟苯氧基)乙酰基;2-(三氟甲磺酸氧基)乙酰基;甲磺酸噁二唑苯基(ODA);酸酐。其中,X1是F,Cl,Br,I或离去基团;X2是O,NH,N(R1)或CH2;R5是R1,芳基,杂芳基或一个或多个H独立地被-R1、卤素、-OR1、-SR1、-NR1R2、-NO2、-S(O)R1、-S(O)2R1或-COOR1所取代的芳基;离去基团包括硝基苯酚、N-羟基琥珀酰亚胺(NHS)、苯酚、二硝基苯酚、五氟苯酚、四氟苯酚、二氟苯酚、单氟苯酚、五氯苯酚、三氟甲基磺酸、咪唑、二氯苯酚、四氯苯酚、1-羟基苯并三氮唑、对甲苯磺酸、甲磺酸、2-乙基-5-苯基异恶唑-3'-磺酸,自我酸酐,或与其他酸酐如乙酰酐、甲酸酐生成的酸酐,或多肽缩合反应或Mitsunobu反应中间体。
Z1和Z2是相同的或不同的能和细胞毒性药物反应的官能团,Z1和Z2与细胞毒性药物反应生成二硫键、醚键、酯键、硫醚键、硫酯键、肽键、腙键、氨基甲酸酯键、碳酸酯键、胺键(二级,三级或四级)、亚胺键、杂环烷基、杂芳基、烷氧肟键或酰胺键。
R1,R2,R3和R4是相同的、不同的或缺省的含1~8个碳原子的直链烷基,3到8个碳原子的支链或环烷基,直链、支链或环烯基或炔基,或1~8个碳原子的酯基、醚基、酰胺基或聚乙氧基(OCH2CH2)p,其中p是0到约1000的整数,或这些基团的组合。
另外,R1,R2,R3和R4是包含C,N,O,S,Si,和P原子的链状结构,最优含0~500个原子,共价连接于Y1或Y2和Z1或Z2;R1,R2,R3和R4中的各个原子以所有可能的化学方式结合,比如形成烷基、亚烷基、亚烯基、亚炔基、醚、聚氧烷基、酯、胺、亚胺、聚胺、肼、腙、酰胺、脲、氨基脲、卡巴肼、烷氧胺、聚氨酯、氨基酸、多肽、酰氧胺、异羟肟酸,或这些基团的组合。
官能团Z1和Z2可以连接细胞毒性药物,可以生成包括二硫键、硫醚、巯基酯、肽、肼、醚、酯、氨基甲酸酯、碳酸酯、肟或酰胺键。此类官能团包括,但不限于巯基,二硫基,氨基,羧基,醛基,羰基,马来酰亚胺基,卤代乙酰基,肼基,烷氧氨基,和/或羟基。
能和药物或细胞毒性分子末端氨基反应的官能团Z1和Z2可以是,但不限于N-羟基琥珀酰亚胺酯,对硝基苯酚酯,二硝基苯酚酯,五氟苯酚酯,或者和四氟苯酚,二氟苯酚,单氟苯酚,五氯苯酚,三氟甲磺酸,咪唑,二氯苯酚,四氯苯酚,1-羟基苯并三氮唑,对甲苯磺酸,甲磺酸,2-乙基-5-苯基异恶唑-3'-磺酸形成的酯;或与乙酰酐,甲酸酐形成的酸酐形;或与多肽缩合剂或Mitsunobu反应形成的中间体。能和末端巯基反应的官能团可以是,但不限于吡啶二硫基,硝基吡啶二硫基,马来酰亚胺基,卤代乙酸酯,羧酸酰氯。能和末端羰基或醛基反应的官能团可以是,但不限于氨基,烷氧氨基,联胺,乙酰氧氨基。能和末端叠氮基反应的官能团可以是,但不限于炔基。
在优选实施例中,官能团Z1和Z2可以和Drug1和Drug2进行酸和氨基缩合反应,形成酰胺键。缩合试剂包括,但不限于:1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC),二环己基碳二亚胺(DCC),N,N'-二异丙基碳二酰亚胺(DIC),1-环已基-2-吗啉乙基碳二亚胺对甲苯磺酸盐(CMC或CME-CDI),羰基二咪唑(CDI),O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸(TBTU),O-苯并三氮唑-四甲基脲六氟磷酸酯(HBTU),苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP),六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBOP),焦碳酸二乙酯(DEPC),N,N,N',N'-四甲基氯甲脒六氟磷酸盐,2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU),1-[(二甲胺)(吗啉基)亚甲基]-1[1,2,3]三唑并[4,5-b]1-吡啶-3-氧六氟磷酸盐(HDMA),2-氯-1,3-二甲基咪唑鎓六氟磷酸盐(CIP),氯代三吡咯烷基鏻六氟磷酸盐(PyClOP),双(四亚甲基)氟代甲酰胺(BTFFH),N,N,N',N'-四甲基-硫-(1-氧代-2-吡啶基)硫脲鎓六氟磷酸盐,2-(2-吡啶酮-1-基)-1,1,3,3-四甲基脲四氟硼酸盐(TPTU),硫-(1-氧代-2-吡啶基)-N,N,N',N'-四甲基硫脲六氟磷酸盐,O-[(乙氧基羰基)氰基甲胺]-N,N,N',N'-四甲基硫脲六氟磷酸盐(HOTU),(1-氰基-2-乙氧基-2-氧代亚乙基氨基氧基)二甲基氨基-吗啉-碳鎓六氟磷酸盐(COMU),(苯并三氮唑-1-基氧基)二吡咯烷碳六氟磷酸盐(HBPyU),N-苄基-N′-环己基碳二亚胺(或荷载在聚合物上),二吡咯烷基(N-琥珀酰亚氨氧基)碳鎓六氟磷酸盐(HSPyU),1-(氯-1-吡咯烷基亚甲基)吡咯烷六氟磷酸盐(PyClU),2-氯-1,3-二甲基咪唑四氟硼酸盐(CIB),(苯并三氮唑-1-基氧基)二哌啶碳六氟磷酸盐(HBPipU),6-氯苯并三氮唑-1,1,3,3-四甲基脲四氟硼酸酯(TCTU),溴化三(二甲基氨基)膦六氟磷酸(BroP),1-正丙基磷酸酐(PPACA,),2-异氰基乙基吗啉(MEI),N,N,N',N'-四甲基脲-氧-(N-琥珀酸亚胺基)六氟磷酸盐(HSTU),2-溴-1-乙基吡啶四氟硼酸盐(BEP),氧-[(乙氧基羰基)氰基甲胺]-N,N,N',N'-四甲基硫尿四氟硼酸盐(TOTU),4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐(MMTM,DMTMM),2-琥珀酰亚胺基-1,1,3,3-四甲基脲四氟硼酸酯(TSTU),N,N,N',N'-四甲基-O-(3,4-二氢-4-氧代-1,2,3-苯并三嗪-3-基)脲四氟硼酸盐(TDBTU),偶氮二甲酰二哌啶(ADD),双(4-氯苄基)偶氮二甲酸酯(DCAD),偶氮二甲酸二叔丁酯(DBAD),偶氮二甲酸二异丙酯(DIAD),偶氮二甲酸二乙酯(DEAD)。
在优选的实施例中,R1,R2,R3和R4是含1~8个碳原子的直链烷基,含二肽、三肽或聚乙氧基(OCH2CH2)p,p=1~100;此外,R1,R2,R3和R4可以被蛋白水解酶切断。
桥连接体合成的具体实例如图1~11。通常桥连接体上的联胺结构可以和连接体组分R1,R2,R3和R4缩合,R1,R2,R3和R4包含有能与药物分子或巯基反应的官能团。
细胞结合剂-药物偶联物
本发明的偶联物可以用下面的结构式表示:其中Cb是细胞结合剂,L是连接体,Drug1和Drug2是药物小分子,n是一个1到20的整数,且2个硫元素桥连Cb于L,每个桥连接体L共价连接2个或更多的药物分子。
桥连接体L可以由一个或者更多的连接体组分构成。典型的连接体组分包括:6-马来酰亚胺己酸(MC),3-马来酰亚胺基丙酸(MP),缬氨酸-瓜氨酸(val-cit或者vc),丙氨酸-苯丙氨酸(ala-phe或者af),对氨基苄氧羰基(PAB),4-硫代戊酸(SPP),4-(N-马来酰亚胺甲基)环正己烷-1-羧酸(MCC),(4-乙酰基)氨基苯甲酸(SIAB),4-硫代丁酸(SPDB),4-硫代-2-羟基磺酰基丁酸(2-Sulfo-SPDB),一个或者多个乙氧基–CH2CH2O—单元(EO orPEO),还包括其他在本领域中众所周知的连接体,部分在这里列出。
包含这些组分的连接体的例子有:
(包含6-马来酰亚胺己酸MC),
(包含3-马来酰亚胺基丙酸MP),
(包含对氨基苄氧羰基PAB),
(包含乙基马来酰亚胺ME),
(包含缬氨酸-瓜氨酸),(包含4-(N-马来酰亚胺甲基)环正己烷-1-羧酸MCC),
(包含(4-乙酰基)氨基苯甲酸),(包含4-硫-2-羟基磺酰基丁酸,2-硫代-SPDB),
优选的偶联物的结构如式(II):
其中:
Cb为细胞结合剂,最优为抗体。
Drug1和Drug2为相同的或不同的细胞毒性剂,它们通过桥连接体以烷基、亚烷基、亚烯基、亚炔基、醚、聚烷氧基、酯、胺,亚胺,聚胺、肼、腙、酰胺、脲、氨基脲、卡巴肼、烷氧基胺、氨基甲酸酯、氨基酸、肽、酰氧胺、异羟肟酸、二硫键、硫醚、硫酯、氨基甲酸酯、碳酸酯、杂环、杂烷基、杂芳基或烷氧肟键及其组合与细胞结合剂连接。
括号内的是连接体-药物组分,它通过一对硫原子和细胞结合剂相偶联。可以进行偶联反应的硫原子对通常是细胞结合剂上双硫键被TCEP或DTT还原所产生。
n是1~20;R1,R2,R3和R4的定义同结构式(I)。
见下文更详细的描述,Drug1和Drug2可以是任何小分子药物,包括但不限于,tubulysin,卡奇霉素、澳瑞他汀,美登素,CC-1065同系物,吗啉代,阿霉素,紫杉烷类,cryptophycins,埃博霉素,苯并二氮卓系列二聚体(例如,吡咯苯并二氮卓(PBD)或托马霉素,吲哚苯并二氮卓,咪唑苯并二氮卓或噁唑苯并二氮卓二聚体)。
以合成共轭偶联物,细胞结合剂上的二硫键首先被还原,产生一对自由巯基,然后与结构式(I)中的桥连接体在pH 5-9的水相中反应,其中可以加入或不加入0-30%的能与水混溶的有机溶剂,如:N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、乙醇、甲醇、丙酮、乙腈、四氢呋喃、异丙醇、二氧六环、丙二醇、或者乙烯二醇,以引入Z1和Z2反应活性基团,可以是二硫键、马来酰亚胺基、卤乙酰基,叠氮化物,1-炔、酮、醛、烷氧基氨基或酰肼。然后,细胞毒性分子的反应基团与被修饰的细胞结合剂反应。例如,通过二硫键连接的细胞结合剂-药物偶联物的合成,是通过修饰的细胞结合剂中的二硫键和含有游离巯基的药物之间的二硫键交换来实现的;通过硫醚键结合的细胞结合子-药物偶联物的合成,是通过经马来酰亚胺基或卤乙酰基或乙基砜修饰的细胞结合剂和含游离巯基的药物反应来实现;合成分子内含酸不稳定的腙的偶联物,可由一个连接体中的酰肼基团和羰基反应来实现,其具体方法为本领域内公知(参考P.Hamann et al.,Hinman,L.M.,et al,Cancer Res.1993,53,3336-334;B.Laguzza et al.,J.Med.Chem.,1959,32;548-555;P.Trail et al.,Cancer Res.,1997,57;100-105);合成含三唑基团的偶联物可以通过一个连接体上的1-炔与含叠氮基团的药物以点击化学反应(偶极环加成)来实现(Lutz,J-F.et al,Adv.Drug Del.Rev.2008,60,958–970;Sletten,E.M.et al Acc.Chem.Research2011,44,666–676)。
或者,药物小分子可以和已经与细胞结合剂偶联,含有反应官能团的,如结构式(III)所示的修饰的细胞结合分子-连接体结构反应。例如,包含巯基的药物可以和结构式(III)中连接体上的马来酰亚胺、卤乙酰基或乙磺酰基,在pH 5.0-9.0的缓冲液中反应,生成硫醚键链接的共轭偶联物。含巯基的药物可以与结构式(III)中连接体上的吡啶二硫片段进行二硫键交换,生成二硫键链接的共轭偶联物。含有羟基或巯基的药物可与结构式(III)中连接体上的卤素,尤其是α卤代羧酸上的卤素,在弱碱条件下,如pH值7.5-9.5,反应得到醚或硫醚键链接的共轭偶联物。含羟基的药物,也可以在EDC或DCC的缩合剂的作用下,和结构式(I)中连接体上的羧基缩合成酯。经药物修饰的桥连接体再与细胞结合分子进行偶联。含有氨基的药物可以和结构式(III)中连接体上的NHS、咪唑、硝基苯酚、N-羟基丁二酰亚胺、苯酚、二硝基苯酚、五氟苯酚、2,3,5,6-四氟苯酚、二氟苯酚、单氟苯酚、五氯苯酚、三氟甲烷磺酸、二氯苯酚、四氯苯酚、1-羟基苯并三唑、甲苯磺酸、甲磺酸、2-乙基-5-苯基异恶唑-3'-磺酸的羧酸酯反应,得到酰胺键链接的共轭偶联物。
偶联物可以通过标准的生化方法纯化,如用Sephadex G25或Sephacryl S300进行凝胶过滤、吸附层析、离子交换或透析。在某些情形,如小分子细胞结合剂(如叶酸、黑素细胞刺激素、EGF等)与小分子药物结合后,可以通过HPLC、中压柱色谱或离子交换色谱等色谱法纯化。
修饰的细胞结合剂/分子
优选的,经本发明中连接体修饰的细胞结合剂的结构如式(III):
其中Cb,Z1,Z2,n,R1,R2,R3和R4与结构式(I)和(II)中定义相同。
在优选实施例中,Z1和Z2是二硫基、马来酰亚胺基、卤乙酰基、烷氧基胺、叠氮、酮、醛、肼、N-羟基琥珀酰亚胺酯或者苯酚、二硝基酚、五氟苯酚、四氟苯酚、二氟苯酚、单氟苯酚、五氯苯酚、三氟甲烷磺酸、咪唑、二氯苯酚、四氯苯酚、1-羟基苯并三唑、甲苯磺酸、甲磺酸、2-乙基-5-苯基异恶唑-3'-磺酸的羧酸酯。Z1和Z2可以与细胞毒性药物反应成硫醚、腙、酰胺、烷肟、氨基甲酸酯、酯、醚或二硫键。如结构式(II)中所述,修饰的细胞结合剂可以通过细胞结合剂与结构式(I)中的描述的桥连接体进行反应制备。
为了实现结构式(I)中桥连接体上官能团Y1和Y2与细胞结合剂,尤其是抗体中游离的一对巯基的高效连接,需要在反应体系中或反应完成后,加入少量有机共溶剂以使得式(III)中的结构在水中良好溶解。在修饰细胞结合剂时,首先把结构式(I)中的交联剂(桥连接体)溶解在可以与水混溶的极性有机溶剂中,例如:各种醇如甲醇、乙醇和丙醇,丙酮,乙腈,四氢呋喃(THF),1,4-二氧六环,二甲基甲酰胺(DMF),二甲基乙酰胺(DMA)或二甲基亚砜(DMSO);溶液浓度略高,如1-500mM。同时将细胞结合剂,如抗体以1~35mg/ml的浓度溶解在pH 5~9.5,最好6~8.5的缓冲液中,与1~20当量的TCEP或者DTT反应20分钟到12小时。还原后,用SEC色谱柱纯化除去DTT,TCEP可以用SEC色谱柱纯化或者不纯化直接进入下一步。此外,用TCEP还原的抗体或其他细胞结合剂可以在结构式(I)桥连接体存在的情形下进行,此时与细胞结合剂的共轭偶联就和TCEP还原同步进行。偶联反应之后,细胞结合剂上过度还原产生的自由巯基可以用DHAA或Cu(II)氧化,重新产生二硫键,或者自由巯基通过与反应基团,如N-乙基马来酰亚胺、碘代乙酸钠、溴代乙酸钠、溴乙酸甲酯等反应而被遮盖。
修饰细胞结合剂的反应一般在pH6至9,优选6.5至7.5的缓冲液里进行,可以是该pH范围内的任何没有亲核性的缓冲盐体系。典型的缓冲液包括磷酸盐、三乙醇胺盐酸盐,HEPES,和MOPS缓冲液,可以包含其它成分,如环糊精,蔗糖和盐,如氯化钠和氯化钾。将结构式(I)中的桥连接体溶液加入到被还原的细胞结合剂溶液中,并在4至45℃,最好是室温孵育,并通过测量溶液在254nm吸光度的下降,或者在280nm吸光度的上升,或者其他合适的波长上吸光度的变化,来监测反应的进程。在反应完成后,可以按照常规方法纯化修饰的细胞结合剂,例如使用凝胶过滤层析或吸附色谱法。
通过测量反应产生的硝基吡啶硫酮、二硝基吡啶二硫酮、吡啶硫酮、甲酰胺吡啶二硫酮和二甲酰胺吡啶二硫酮基团的紫外吸光,可以确定细胞结合剂被修饰的程度。如果偶联物没有发色团,可以用LC-MS或者更优选的UPLC-QTOF质谱,或毛细管电泳质谱(CEMS)来分析确定。本发明中的桥连接体上可以含有不同种类的官能团,与各种药物反应,尤其是具有合适的取代官能团的细胞毒性药物。例如,修饰后含氨基或羟基取代基的细胞结合剂能与含N-羟基琥珀酰亚胺(NHS)酯的药物反应,修饰后含巯基的细胞结合剂能与含马来酰亚胺基或卤素乙酰基的药物反应。此外,修改后含羰基(醛或酮基)的细胞结合剂能与含酰肼或烷氧基胺的药物反应。本领域的技术人员可以很容易地根据其中官能团的反应活性来决定使用怎样的连接体。
修饰的细胞毒性药物
用本发明中的桥连接体修饰的细胞毒性药物结构优选为(IV):
其中Y1,Y2,Drug1,Drug2,R1,R2,R3和R4的定义与式(I)和(II)相同。
在优选的实施例中,Y1和Y2是二硫化物;马来酰亚胺基;卤乙酰基;羧基;酰卤;乙烯磺酰基;丙烯酰基;羧酸酐;N-羟基琥珀酰亚胺酯;或者与苯酚、二硝基酚、五氟苯酚、四氟苯酚、二氟苯酚、单氟苯酚、五氯苯酚、三氟甲烷磺酸、咪唑、二氯苯酚、四氯苯酚、1-羟基苯并三唑、甲苯磺酸、甲磺酸、2-乙基-5-苯基异恶唑-3'-磺酸等形成的酯。
通过药物分子与结构式(I)的连接体反应,得到具有结构(IV)的修饰的药物,其中含有Y1和Y2官能团,能与细胞结合剂上的一对巯基反应。但是对于含有巯基的药物,或者通过含硫醚、硫酯或二硫键连接细胞结合分子的药物,药物Drug1或Drug2最好首先通过硫醚、硫酯或二硫键与R3或R4连接,然后将合成的R3-Drug1或R4-Drug2组分与联胺组装,形成桥连接体修饰的药物(IV)。
例如,含巯基的药物可在中性pH的缓冲液中与R3或R4组分上的马来酰亚胺反应,形成以硫醚键结合的R3-Drug1或R4-Drug2,然后与连接有Y1和Y2官能团的联胺组分缩合,形成如公式(IV)中包含硫醚键的修饰药物。含羟基的药物,在弱碱条件下,可与含有卤素、对甲苯磺酸或甲磺酸酯的R3或R4组分反应,得到以醚键结合R3-Drug1或R4-Drug2,然后与连接有Y1和Y2官能团的联胺组分缩合,形成如公式(IV)中包含硫醚键的修饰药物。含有羟基的药物还可与结构(I)中带有羧基的连接体,在脱水剂如EDC或DCC作用下,缩合得到如结构式(IV)中含酯键的修饰药物。含巯基的药物可与R3或R4组分上的马来酰亚胺、乙烯砜基或卤代乙酰基反应,生成以硫醚键结合的R3-Drug1或R4-Drug2,然后与连接有Y1和Y2官能团的联胺组分缩合,形成如公式(IV)中包含硫醚键的修饰药物。类似地,含氨基的药物也可以与桥连接体(I)上的羧基进行缩合,得到如公式(IV)中含酰胺键的修饰药物。修饰的药物可以用标准的方法纯化,如硅胶或氧化铝柱层析、重结晶、制备薄层色谱、离子交换色谱或高效液相色谱。
细胞结合剂
本发明中的细胞结合剂,包括偶联物内和被修饰的细胞结合剂,可以是目前已知的或即将公开的,能够与具有治疗意义或者被生物学修饰的细胞片段结合,复合或反应的任何种类分子。
细胞结合剂包括,但不仅限于大分子量蛋白质,例如完整抗体(多克隆抗体,单克隆抗体,二聚体,多聚体,多特异性抗体,例如双特异性抗体);单链抗体;抗体片段如Fab,Fab',F(ab')2,Fv(Parham,J.Immunol.1983,131,2895-2902);由Fab表达库产生的片段,抗独特型(抗-Id)抗体;CDR;双价抗体;三价抗体和免疫特异性结合癌细胞抗原的上述任何抗体的表位结合片段;病毒抗原;微生物抗原或由免疫系统产生的蛋白质,能够识别、结合特定抗原或具有期望的生物学活性(Miller et al J.of Immunology 2003,170,4854-4861);干扰素(如I,II,III型);多肽;淋巴因子如IL-2,IL-3,IL-4,IL-5,IL-6,IL-10,GM-CSF,干扰素-γ(IFN-γ);激素例如胰岛素,TRH(促甲状腺激素释放激素),MSH(促黑素细胞激素),类固醇激素如雄激素和雌激素;生长因子和集落刺激因子,如表皮生长因子(EGF),粒细胞巨噬细胞集落刺激因子(GM-CSF),转化生长因子(TGF)如TGFα,TGFβ,胰岛素和胰岛素样生长因子(IGF-I,IGF-II),G-CSF,M-CSF和GM-CSF(Burgess,Immunology Today 1984,5,155-158);牛痘生长因子(VGF);成纤维细胞生长因子(FGF);小分子量的蛋白质;多肽;肽和肽激素,如铃蟾肽,胃泌素,胃泌素释放肽;血小板衍生的生长因子;白细胞介素和细胞因子,例如,白细胞介素-2(IL-2),白细胞介素-6(IL-6),白血病抑制因子,粒细胞巨噬细胞集落刺激因子(GM-CSF);维生素,如叶酸;脱辅基蛋白和糖蛋白,如转铁蛋白(O'Keefe et al,J.Biol.Chem.1985 260932-937);糖结合蛋白或脂蛋白,如凝集素;细胞营养传递分子;小分子抑制剂,如前列腺特异性膜抗原(PSMA)抑制剂和小分子酪氨酸激酶抑制剂(TKI),非肽或任何其它细胞结合分子或物质,如生物活性聚合物(Dhar,et al,Proc.Natl.Acad.Sci.2008,105,17356-61),生物活性树枝状大分子(Lee,et al,Nat.Biotechnol.2005,23,1517-26;Almutairi,et al;Proc.Natl.Acad.Sci.2009,106,685-90),纳米粒子(Liong,et al,ACS Nano,2008,19,1309-12;Medarova,et al,Nat.Med.2007,13,372-7;Javier,et al,Bioconjugate Chem.2008,19,1309-12),脂质体(Medinai,et al,Curr.Phar.Des.2004,10,2981-9)和病毒外壳(Flenniken,et al,Viruses Nanotechnol.2009,327,71-93)。
一般而言,如果适当的单克隆抗体是可用的,则优选单克隆抗体作为细胞表面结合剂。抗体可以是鼠源,人源,人源化,嵌合或源于其他物种。
用于本发明中的抗体的生产包括体内或体外方法或其组合。生产多克隆抗受体肽抗体的方法在本领域是公知的,例如美国专利4,493,795中所述。通常是通过将骨髓瘤细胞,与已经用所需抗原免疫的小鼠的脾细胞融合,来制备单克隆抗体(G.;Milstein,C.Nature 1975,256:495-497)。详细的过程在“Antibodies--A Laboratory Manual,Harlow and Lane,eds.,Cold Spring Harbor Laboratory Press,New York(1988)”中有描述,此处引作参考。具体地,可以用目标抗原,如完整的靶细胞,从靶细胞分离的抗原,完整的病毒,灭活的全病毒和病毒蛋白质,免疫小鼠,大鼠,仓鼠或任何其它哺乳动物。通常使用聚乙二醇(PEG)6000将脾细胞与骨髓瘤细胞融合。通过对HAT(次黄嘌呤-氨基蝶呤-胸腺嘧啶)的敏感性来筛选融合细胞。通过它们免疫反应特异性受体的能力或抑制靶细胞上的受体活性的能力,可以确定实施本发明的单克隆抗体的杂交瘤。
用于本发明中的单克隆抗体的生产在单克隆杂交瘤培养物里进行,其中包含营养培养基和能分泌具有合适抗原特异性的抗体分子的杂交瘤。培养物在合适的条件下保持充足的一段时间,以使杂交瘤将抗体分子分泌到培养基。然后收集含有抗体的培养基。使用通过公知的技术进一步分离抗体分子,如蛋白质A亲和层析,阴离子、阳离子、疏水或体积排阻色谱法(特别是通过蛋白质A亲和层析和体积排阻色谱法),离心,差异溶解度或任何其他纯化蛋白质的标准技术。
可用于制备这些组合物的培养基在本领域中是公知的,并且可商业获得,也包括合成培养基。一个合成的培养基的例子是Dulbecco最少必需培养基(DMEM;Dulbecco etal.,Virol.1959,8,396)补充有4.5g/ml葡萄糖,0-20mM谷氨酰胺,0-20%胎牛血清,几个ppm的Cu,Mn,Fe或Zn等重金属或/和重金属盐,以及消泡剂如聚氧乙烯-聚氧丙烯嵌段共聚物。
另外,生产抗体的细胞系也可以通过融合以外的技术来获得,例如将成瘤DNA转化至B淋巴细胞,或成瘤病毒转染,如爱泼斯坦-巴尔病毒(EBV,也称为人类疱疹病毒4(HHV-4))或卡波西肉瘤相关疱疹病毒(KSHV),见于美国专利4,341,761;4,399,121;4,427,783;4,444,887;4,451,570;4,466,917;4,472,500;4,491,632;4,493,890。单克隆抗体也可以通过含末端羧基的抗受体肽或肽制备,这些都为如本领域所公知,可参考文献Niman etal.,Proc.Natl.Acad.Sci.USA,1983,80:4949-4953;Geysen et al.,Proc.Natl.Acad.Sci.USA,1985,82:178-182;Lei et al.Biochemistry 1995,34(20):6675-6688。通常,抗受体肽或肽同系物作为产生抗受体肽单克隆抗体免疫原,可以单独使用或与免疫原性载体连接。
用作本发明中结合分子的单克隆抗体也可以通过其他本领域已知的技术获得。特别有用的是制造完整人源抗体的方法。一种方法是噬菌体显示技术,它使用亲和富集的方式,可用于选择能与抗原特异性结合的人源抗体。噬菌体展示技术在文献中也有详细描述,噬菌体展示库的构建和筛选在本领域也是众所周知的,可参考文献Dente et al,Gene.1994,148(1):7-13;Little et al,Biotechnol Adv.1994,12(3):539-55;Clacksonet al.,Nature1991,352:264-628;Huse et al.,Science 1989,246:1275-1281。
通过与非人如小鼠细胞融合的杂交瘤产生的单克隆抗体,可以被人源化以避免产生人类抗小鼠抗体。常见的抗体人源化方法是互补决定区移植技术,这些方法也已被详细地描述,如美国专利5,859,205和6,797,492;Liu et al,Immunol Rev.2008,222:9-27;Almagro et al,Front Biosci.2008,13:1619-33;Lazar et al,MolImmunol.2007,44(8):1986-98;Li et al,Proc.Natl.Acad.Sci.U S A.2006,103(10):3557-62,此处引为参考。完整人抗体也可以通过用免疫原免疫携带大部分的人类球蛋白重轻链的转基因小鼠、兔子、猴子或其他哺乳动物来制备。这些老鼠的例子有:Xenomouse(Abgenix/Amgen),HuMAb-Mouse(Medarex/BMS)和VelociMouse(Regeneron),参考美国专利6,596,541,6,207,418,6,150,584,6,111,166,6,075,181,5,922,545,5,661,016,5,545,806,5,436,149和5,569,825。用于人类治疗时,小鼠的可变区域和人的恒定区域也可以被融合,成为“嵌合抗体”,它在人类身上的免疫原性显著低于小鼠单抗(Kipriyanov et al,MolBiotechnol.2004,26:39-60;Houdebine,CurrOpinBiotechnol.2002,13:625-9)。另外,在抗体可变区域的定点诱变能导致抗体具有较高的亲和性和特异性(Brannigan et al,Nat Rev Mol CellBiol.2002,3:964-70;Adams et al,J Immunol Methods.1999,231:249-60),抗体恒定区域的改变可以提高其介导结合和细胞毒性的效应功能。
恶性细胞抗原的免疫特异性抗体也可以从商业途径获得或通过任何已知方法生产,例如化学合成或重组表达技术。对恶性细胞抗原具有免疫特异性的抗体的核苷酸序列编码可以商业获得,例如从GenBank数据库或类似数据库,文献出版物获得,或通过常规克隆和测序得到。
除了抗体之外,与目标细胞上的表位或相应受体相互作用(结合、阻断、靶向或其他类型作用)的一种肽或蛋白质也可以作为结合分子。这些肽或蛋白质可能是任何随机的肽或蛋白质,它们对表位或相应的受体有亲和力,不一定非得是免疫球蛋白家族成员。这些肽可以通过类似噬菌体显示抗体的技术分离出来(Szardenings,J Recept SignalTransduct Res.2003;23(4):307-49)。从随机肽库中获得的肽可以与抗体和抗体片段类似地被使用。肽或蛋白质结合分子可以偶联或链接至大分子或其他物质,包括但不限于白蛋白、聚合物、脂质体、纳米粒子、树形分子,只要这样的链接能保留肽或蛋白质的抗原结合特异性。
在用于治疗癌症、自身免疫性疾病和/或传染性疾病的偶联物上,和药物分子通过本专利的桥连接体连接的抗体的例子包括,但不限于3F8(抗GD2),阿巴单抗(抗CA-125),阿昔单抗(抗CD41(整联蛋白α-IIb),阿达木单抗(抗TNF-α),Adecatumumab(抗EpCAM,CD326),阿非莫单抗(抗TNF-α),Afutuzumab(抗CD20),Alacizumab单抗(抗VEGFR2),ALD518(抗IL-6),Alemtuzumab(Campath,MabCampath,抗CD52),Altumomab(抗CEA),Anatumomab(抗TAG-72),Anrukinzumab(IMA-638,抗-IL-13),Apolizumab(抗-HLA-DR),阿奇单抗(抗-CEA),阿塞珠单抗(抗-L-选择蛋白CD62L),Atlizumab(tocilizumab,Actemra,RoActemra,抗-IL-6受体),Atorolimumab(抗-Rhesus因子),Bapineuzumab(抗-β淀粉样蛋白),Basiliximab(Simulect,抗CD25(IL-2受体的α链)),Bavituximab(抗磷脂酰丝氨酸),Bectumomab(LymphoScan,抗-CD22),贝利单抗(Benlysta,LymphoStat-B,抗BAFF),Benralizumab(抗CD125),Bertilimumab(抗CCL11(eotaxin-1)),Besilesomab(Scintimun,抗CEA相关抗原),贝伐单抗(Avastin,抗VEGF-A),Biciromab(FibriScint,抗纤维蛋白IIβ链),Bivatuzumab(抗-CD44v6),Blinatumomab(BiTE,抗CD19),Brentuximab(cAC10,抗-CD30TNRSF8),Briakinumab(抗IL-12,IL-23),Canakinumab(Ilaris,抗IL-1),Cantuzumab(C242,抗CanAg),Capromab,Catumaxomab(Removab,抗EpCAM,抗CD3),CC49(抗TAG-72),Cedelizumab(抗CD4),Certolizumab单抗(Cimzia抗TNF-α),西妥昔单抗(爱必妥,IMC-C225,抗EGFR),Citatuzumab bogatox(抗EpCAM),Cixutumumab(抗IGF-1),Clenoliximab(抗CD4),Clivatuzu-mab(抗MUC1),Conatumumab(抗TRAIL-R2),CR6261(抗流感A血凝素),Dacetuzumab(抗CD40),Daclizumab(Zenapax,抗CD25(IL-2受体α链)),Daratumumab(抗CD38(环ADP核糖水解酶),Denosumab(Prolia,抗RANKL),Detumomab(抗B淋巴瘤细胞),Dorlimomab,Dorlixizumab,Ecromeximab(抗GD3神经节苷脂),Eculizumab(Soliris,抗-C5),Edobacomab(抗内毒素),Edrecolomab(Panorex,MAb17-1A,抗-EpCAM),Efalizumab(Raptiva,抗LFA-1(CD11a)),Efungumab(Mycograb,抗Hsp90),Elotuzumab(抗SLAMF7),Elsilimomab(抗IL-6),Enlimomab单抗(抗ICAM-1(CD54)),Epitumomab(抗episialin),依他珠单抗(抗-CD22),Erlizumab(抗-ITGB2(CD18)),Ertumaxomab(Rexomun,抗HER2/neu,CD3),依他拉单抗(Abegrin,抗整联蛋白αvβ3),Exbivirumab(抗乙肝表面抗原),Fanolesomab(NeutroSpec,抗CD15),Faralimomab(抗干扰素受体),Farletuzumab(抗叶酸受体1),Felvizumab(抗呼吸道合胞病毒),Fezakinumab(抗-IL-22),Figitumumab(抗-IGF-1受体),Fontolizumab(抗-IFN-γ),Foravirumab(抗狂犬病病毒糖蛋白),Fresolimumab(抗TGF-β),Galiximab(抗CD80),Gantenerumab(抗β淀粉样蛋白),Gavilimomab(抗CD147(basigin)),Gemtuzumab(抗CD33),Girentuximab(抗碳酸酐酶9),Glembatumumab(CR011,抗GPNMB),Golimumab(Simponi,抗-TNF-α),Gomiliximab(抗-CD23(IgE受体)),Ibalizumab(抗-CD4),Ibritumomab(抗CD20),Igovomab(Indimacis-125,抗CA-125),Imciromab(Myoscint,抗心肌肌凝蛋白),Infliximab(Remicade,抗TNF-α),Intetumumab(抗CD51),Inolimomab(抗CD25(IL-2受体α链),伊珠单抗(抗-CD22),Ipilimumab(抗CD152),Iratumumab(抗CD30(TNFRSF8)),Keliximab(抗-CD4),Labetuzumab(CEA-Cide,抗CEA),Lebrikizumab(抗IL-13),Lemalesomab(抗NCA-90(粒细胞抗原)),Lerdelimumab(抗TGFβ2),Lexatumumab(抗TRAIL-R2),Libivirumab(抗乙肝表面抗原),Lintuzumab(抗CD33),鲁米木单抗(抗CD40),鲁米单抗(抗CD23(IgE受体),Mapatumumab(抗TRAIL-R1),马西莫单抗(抗T-细胞受体),马妥珠单抗(抗EGFR),Mepolizumab(Bosatria,抗IL-5),Metelimumab(抗TGFβ1),Milatuzumab(抗CD74),Minretumomab(抗TAG-72),Mitumomab(BEC-2,抗GD3神经节苷脂),Morolimumab(抗恒河猴因子),Motavizumab(Numax,抗呼吸道合胞病毒),Muromonab-CD3(Orthoclone OKT3,抗CD3),Nacolomab(抗C242),Naptumomab(抗5T4),那他珠单抗(Tysabri,抗整联蛋白α4),奈巴单抗(抗内毒素),Necitumumab(抗EGFR),Nerelimomab(抗-TNF-α),Nimotuzumab(Theracim,Theraloc,抗-EGFR),Nofetumomab,Ocrelizumab(抗CD20),奥利木单抗(Afolimomab,抗LFA-1(CD11a)),Ofatumumab(Arzerra,抗CD20),Olaratumab(抗PDGF-Rα),Omalizumab(Xolair,抗IgE Fc区)Oportuzumab(抗EpCAM),Oregovomab(OvaRex,抗CA-125),Otelixizumab(抗CD3),Pagibaximab(抗脂磷壁酸),Palivizumab(Synagis,Abbosynagis,抗呼吸道合胞病毒),帕尼单抗(Vectibix,ABX-EGF,抗EGFR),Panobacumab(抗铜绿假单胞菌(Pseudomonas aeruginosa)),帕考珠单抗(抗IL-4),Pemtumomab(Theragyn,抗MUC1),Pertuzumab(Omnitarg,2C4,抗HER2/neu),Pexelizumab(抗C5),Pintumomab(抗腺癌抗原),Priliximab(抗-D4),Pritumumab(抗波形蛋白),PRO140(抗-CCR5)Racotumomab(1E10,抗-N-羟乙酰神经氨酸(NeuGc,NGNA)-神经节苷脂GM3)),Rafivirumab(抗狂犬病病毒糖蛋白),Ramucirumab(抗VEGFR2),Ranibizumab(Lucentis,抗VEGF-A),Raxibacumab(抗炭疽毒素,保护性抗原),Regavirumab(抗巨细胞病毒糖蛋白B),Reslizumab(抗-IL-5),Rilotumumab(抗-HGF),Rituximab(MabThera,Rituxanmab,抗-CD20),Robatumumab(抗-IGF-1受体),Rontalizumab(抗IFN-α),Rovelizumab(LeukAr-rest,抗CD11,CD18),Ruplizumab(Antova,抗CD154(CD40L)),Satumomab(抗TAG-72),Sevirumab(抗巨细胞病毒),Sibrotuzumab(抗FAP),西法木单抗(抗IFN-α),Siltuximab(抗IL-6),Siplizumab(抗CD2),Smart MI95(抗CD33),Solanezumab(抗β淀粉状蛋白),Sonepcizumab(抗鞘氨醇-1-磷酸),Sontuzumab(抗-episialin),Stamulumab(抗-myostatin),Sulesomab(LeukoScan,抗NCA-90(粒细胞抗原)),Tacatuzumab(抗α甲胎蛋白),Tadocizumab(抗整联蛋白αIIbβ3),Talizumab(抗IgE),Tanezumab(anti-NGF),Taplitumomab(抗CD19),Tefibazumab(Aurexis,(抗凝聚因子A)),Telimomab,Tenatumomab(抗腱生蛋白C),Teneliximab(抗CD40),Teplizumab(抗CD3),TGN1412(抗CD28),Ticilimumab(Tremelimumab,抗-CTLA-4),Tigatuzumab(抗TRAIL-R2),TNX-650(抗IL-13),Tocilizumab(Atlizumab,Actemra,RoActemra,IL-6受体),Toralizumab(抗CD154(CD40L)),Tositumomab(抗CD20),曲妥珠单抗(赫赛汀,抗HER2/neu),Tremelimumab(抗CTLA-4),Tucotuzumab celmoleukin(抗EpCAM),Tuvirumab(抗乙型肝炎病毒),Urtoxazumab(抗大肠杆菌),Ustekinumab(Stelara,抗-IL-12,IL-23),Vapaliximab(抗-AOC3(VAP-1)),维多珠单抗(抗整联蛋白α4β7),维妥珠单抗(抗CD20),Vepalimomab(抗AOC3(VAP-1)),Visilizumab(Nuvion,抗CD3),Vitaxin(抗血管整合素avb3),Volociximab(抗整联蛋白α5β1),Votumumab(HumaSPECT,抗肿瘤抗原CTAA16.88),Zalutumumab(HuMax-EGFR,Zanolimumab(HuMax-CD4,抗-CD4),Ziralimumab(抗-CD147(basigin)),Zolimomab(抗-CD5),依那西普AlefaceptAbataceptRilonacept(Arcalyst),14F7(抗IRP-2(铁调节蛋白2)),14G2a(抗GD2神经节苷脂,源于Nat.Cancer Inst.,治疗黑素瘤和实体瘤),J591(抗-PSMA,源于WeillCornell医学院,治疗前列腺癌),225.28S(抗HMW-MAA(高分子量黑素瘤相关抗原),SorinRadiofarmaci SRL(源于意大利米兰,治疗黑色素瘤),COL-1(抗CEACAM3,CGM1,源于Nat Cancer Inst.治疗结肠直肠癌和胃癌),CYT-356(治疗前列腺癌),HNK20(OraVax Inc.治疗呼吸道合胞病毒感染),ImmuRAIT(源于Immunomedics,治疗NHL),Lym-1(抗HLA-DR10,Peregrine Pharm),MAK-195F(抗TNF(肿瘤坏死因子,TNFA,TNF-α,TNFSF2,源于Abbott/Knoll,治疗脓毒症中毒性休克),MEDI-500(T10B9,抗CD3,TRαβ(T细胞受体α/β),源于MedImmune Inc,用于移植物抗宿主疾病病),RING SCAN(抗TAG 72(肿瘤相关糖蛋白72),源于Neoprobe Corp.,用于乳腺癌,结肠癌和直肠癌),Avicidin(抗EPCAM(上皮细胞粘附分子)),抗-TACSTD1(肿瘤相关钙信号转导1),抗GA733-2(胃肠肿瘤相关蛋白2),抗EGP-2(上皮糖蛋白2),抗KSA,KS1/4抗原,M4S,肿瘤抗原17-1A,CD326(源于NeoRx公司,治疗结肠癌,卵巢癌,前列腺癌和NHL),LymphoCide(源于Immunomedics),Smart ID10(源于ProteinDesign Labs),Oncolym(源于Techniclone Inc),Allomune(源于BioTransplant),抗VEGF(源于Genentech);CEAcide(源于Immunomedics),IMC-1C11(源于ImClone Systems)和Cetuximab(源于ImClone)。
其他可作为细胞结合分子/配体的抗体,包括但不限于,以下抗原的抗体:氨肽酶N(CD13),膜联蛋白A1,B7-H3(CD276,各种癌症),CA125(卵巢癌),CA15-3(各种癌症),CA19-9(各种癌症),L6(各种癌症),路易斯Y(各种癌症),路易斯X(各种癌症),甲胎蛋白(各种癌症),CA242(结直肠癌),胎盘碱性磷酸酶(各种癌症),前列腺特异抗原(前列腺癌),前列腺酸磷酸酶(前列腺癌),表皮生长因子(各种癌症),CD2(霍奇金症,NHL淋巴瘤,多发性骨髓瘤),CD3ε(T细胞淋巴瘤,肺癌,乳腺癌,胃癌,卵巢癌,自身免疫性疾病,恶性腹水),CD19(B细胞恶性肿瘤),CD20(非霍奇金淋巴瘤),CD22(白血病,淋巴瘤,多发性骨髓瘤,SLE),CD30(霍奇金淋巴瘤),CD33(白血病,自身免疫性疾病),CD38(多发性骨髓瘤),CD40(淋巴瘤,多发性骨髓瘤,白血病(CLL)),CD51(转移性黑色素瘤,肉瘤),CD52(白血病),CD56(小细胞肺癌,卵巢癌,梅克细胞癌,以及液体肿瘤,多发性骨髓瘤),CD66e(各种癌症),CD70(转移性肾细胞癌和非霍奇金淋巴瘤),CD74(多发性骨髓瘤),CD80(淋巴瘤),CD98(各种癌症),粘液素(各种癌症),CD221(实体肿瘤)、CD227(乳腺癌、卵巢癌)、CD262(非小细胞肺癌及其他癌症)、CD309(卵巢癌)、CD326(实体肿瘤)、CEACAM3(结肠直肠癌、胃癌)、CEACAM5(癌胚抗原,CEA,CD66e)(乳腺,结直肠癌和肺癌),DLL4,EGFR(表皮生长因子受体,各种癌症),CTLA4(黑色素瘤),CXCR4(CD184,血液肿瘤,实体肿瘤),Endoglin(CD105,实体瘤),EPCAM(上皮细胞粘附分子,膀胱癌,头颈癌,结肠癌,NHL前列腺癌,卵巢癌),ERBB2(表皮生长因子受体2,肺癌,乳腺癌,前列腺癌),FCGR1(自身免疫性疾病),FOLR(叶酸受体,卵巢癌),GD2神经节苷(各种癌症),G-28(细胞表面抗原糖脂质,黑色素瘤),GD3独特型(各自癌症),热休克蛋白(各种癌症),HER1(肺癌,胃癌),HER2(乳腺癌,肺癌和卵巢癌),HLA-DR10(NHL),HLA-DRB(NHL,B细胞白血病),人绒毛膜促性腺激素(各种癌症),IGF1R(类胰岛素生长因子1受体,实体瘤,血癌),IL-2受体(白介素2受体,T细胞白血病和淋巴瘤),IL-6R(白介素6受体,多发性骨髓瘤,风湿性关节炎,Castleman病,白细胞介素6依赖肿瘤),整合蛋白(αvβ3、α5β1、α6β4、αllβ3、α5β5、αvβ5,各种癌症),MAGE-1(各种癌症),MAGE-2(各种癌症),MAGE-3(各种癌症),MAGE 4(各种癌症),抗转铁蛋白受体(各种癌症),p97(黑色素瘤),MS4A1(跨膜4结构域亚家族A成员1,非霍奇金B细胞淋巴瘤,白血病),MUC1或MUC1-KLH(乳腺癌、卵巢癌、子宫颈癌、支气管癌和α胃肠道癌),MUC16(CA125)(卵巢癌),CEA(结直肠癌),gp100(黑色素瘤),MART1(黑色素瘤),MPG(黑素瘤),MS4A1(跨膜4结构域亚家族A成员1,小细胞肺癌,NHL),Nucleolin,Neu癌基因产物(各自癌症),P21(各种癌),抗(N-羟乙酰神经氨酸)抗体结合部位(乳腺癌,黑色素瘤),类PLAP睾丸碱性磷酸酶(卵巢癌、睾丸癌),PSMA(前列腺瘤),PSA(前列腺癌),ROBO4,TAG 72(肿瘤相关糖蛋白72,AML,胃癌、结肠直肠癌、卵巢癌),T细胞跨膜蛋白(各种癌症),Tie(CD202b),TNFRSF10B(肿瘤坏死因子受体超家族成员10B,各种癌症),TNFRSF13B(肿瘤坏死因子受体超家族成员13B,多发性骨髓瘤,NHL,其他癌症,RA和SLE),TPBG(滋养细胞糖蛋白,肾细胞癌),TRAIL-R1(TNF相关坏死诱导配体受体1,淋巴瘤,NHL,结直肠癌,肺癌),VCAM-1(CD106,黑色素瘤),VEGF,VEGF-a,VEGF-2(CD309)(各种癌症)。其它肿瘤相关,可被抗体识别的抗原已被总结和评述(Gerber,et al,mAbs 2009,1:3,247-253;Novellino et al,Cancer ImmunolImmunother.2005,54(3),187-207;Franke,et al,Cancer BiotherRadiopharm.2000,15,459-76)。
细胞结合剂,优选为抗体,可以是任何能够对抗肿瘤细胞,病毒感染细胞,微生物感染细胞,寄生虫感染细胞,自身免疫细胞,活化的细胞,骨髓细胞,激活T细胞,B细胞,或黑色素细胞。更具体地,细胞结合剂可以是任何能够抗下列抗原或受体之一的药物/分子:CD3,CD4,CD5,CD6,CD7,CD8,CD9,CD10,CD11a,CD11b,CD11c,CD12w,CD14,CD15,CD16,CDw17,CD18,CD19,CD20,CD21,CD22,CD23,CD24,CD25,CD26,CD27,CD28,CD29,CD30,CD31,CD32,CD33,CD34,CD35,CD36,CD37,CD38,CD39,CD40,CD41,CD42,CD43,CD44,CD45,CD46,CD47,CD48,CD49b,CD49c,CD51,CD52,CD53,CD54,CD55,CD56,CD58,CD59,CD61,CD62E,CD62L,CD62P,CD63,CD66,CD68,CD69,CD70,CD72,CD74,CD79,CD79a,CD79b,CD80,CD81,CD82,CD83,CD86,CD87,CD88,CD89,CD90,CD91,CD95,CD96,CD98,CD100,CD103,CD105,CD106,CD109,CD117,CD120,CD125,CD126,CD127,CD133,CD134,CD135,CD138,CD141,CD142,CD143,CD144,CD147,CD151,CD147,CD152,CD154,CD156,CD158,CD163,CD166,.CD168,CD174,CD180,CD184,CDw186,CD194,CD195,CD200,CD200a,CD200b,CD209,CD221,CD227,CD235a,CD240,CD262,CD271,CD274,CD276(B7-H3),CD303,CD304,CD309,CD326,4-1BB,5AC,5T4(Trophoblast糖蛋白,TPBG,WNT-活化抑制因子1或WAIF1),腺癌抗原,AGS-5,AGS-22M6,激活素受体激酶1,AFP,AKAP-4,ALK,α整合素,αvβ6,氨基肽酶N,淀粉样蛋白β,雄激素受体,促血管新生蛋白因子2,促血管新生蛋白因子3,膜联蛋白A1,炭疽毒素保护性抗原,抗转移蛋白受体,AOC3(VAP-1),B7-H3,炭疽杆菌,BAFF(B细胞激活因子),B淋巴瘤细胞,bcr-abl,蛙皮素,BORIS,C5,C242抗原,CA125(糖抗原125,MUC16),CA-IX(或CAIX,碳酸酐酶9),CALLA,CanAg,犬红斑狼疮IL31,碳酸酐酶IX,心肌肌凝蛋白,CCL11(C-C片段趋化因子11),CCR4(C-C趋化因子受体4,CD194),CCR5,CD3E(ε),CEA(癌胚抗原),CEACAM3,CEACAM5(癌胚抗原),CFD(因子D),Ch4D5,胆囊收缩素2(CCK2R),CLDN18(Claudin-18),丛生因子A,CRIPTO,FCSF1R(集落刺激因子1受体,CD115),CSF2(集落刺激因子2,粒细胞-巨噬细胞集落刺激因子(GM-CSF)),CTLA4(细胞毒性T淋巴细胞相关蛋白4),CTAA16.88肿瘤抗原,CXCR4(CD184),C-X-C趋化因子受体4,环状ADP核糖核酸酶,细胞周期蛋白B1,CYP1B1,巨细胞病毒,巨细胞病毒糖蛋白B,Dabigatran,DLL4(类Δ配体4),DPP4(双肽-肽酶4),DR5(死亡受体5),大肠杆菌shiga毒素类型-1,大肠杆菌shiga毒素类型-2,ED-B,EGFL7(类EGF结构域蛋白7),EGFR,EGFRII,EGFRvIII,内皮因子(CD105),内皮素B受体,内毒素,EpCAM(上皮细胞粘附分子),EphA2,Episialin,ERBB2(表皮生长因子受体2),ERBB3,ERG(TMPRSS2ETS融合基因),大肠杆菌,ETV6-AML,FAP(成纤维细胞活化蛋白α),FCGR1,甲胎蛋白,纤维蛋白IIβ链,纤连蛋白额外结构域-B,FOLR(叶酸受体),叶酸受体α,叶酸水解酶,Fos相关抗原1,呼吸道合胞病毒的F蛋白,卷曲的受体,岩藻糖GM1,GD2神经节苷脂,G-28(细胞表面抗原糖脂),GD3独特型,GloboH,Glypican 3,N-羟乙酰神经氨酸,GM3,GMCSF受体α链,生长分化因子8,GP100,GPNMB(跨膜糖蛋白NMB),GUCY2C(鸟苷酸环化酶2C),鸟苷酸环化酶C(GC-C),肠鸟苷酸环化酶,鸟苷酸环化酶C受体,热稳定肠毒素受体(hSTAR),热休克蛋白,血凝素,乙肝表面抗原,乙型肝炎病毒,HER1(人类表皮生长因子受体1),HER2,HER2/neu,HER3(ERBB-3),IgG4,HGF/SF(肝细胞生长因子/分散因子),HHGFR,HIV-1,组蛋白复合物,HLA-DR(人类白细胞抗原),HLA-DR10,HLA-DRB,HMWMAA,人类绒毛膜促性腺激素,HNGF,人类分散因子受体激酶,HPVE6/E7,Hsp90,hTERT,ICAM-1(细胞间粘附分子1),独特型,IGF1R(IGF–1,类胰岛素生长因子1受体),IGHE,IFN-γ,流感血凝素,IgE,IgE Fc区,IGHE,IL–1,IL-2R(白介素2受体),IL–4,IL-5,IL–6,IL-6R(白介素6受体),IL-9,IL–10,IL–12,IL-13,IL-17,IL-17A,IL-20,IL-22,IL-23,IL31RA,ILGF2(类胰岛素生长因子2),整合蛋白(α4、αIIbβ3、αvβ3、α4β7、α5β1、α6β4、α7β7、αllβ3、α5β5、αvβ5),干扰素γ诱导蛋白质,ITGA2,ITGB2,KIR2D,LCK,Le,Legumain,Lewis-Y抗原,LFA-1(淋巴细胞功能相关抗原1,CD11a),LHRH,LINGO-1,脂磷壁酸,LIV1A,LMP2,LTA,MAD-CT-1,MAD-CT-2,MAGE-1,MAGE-2,MAGE-3,MAGE A1,MAGE A3,MAGE 4,MART1,MCP-1,MIF(巨噬细胞迁移抑制因子,或糖基抑制因子(GIF)),MS4A1(跨膜4结构域亚家族A成员1),MSLN(间皮素),MUC1(粘蛋白1,细胞表面相关(MUC1)或多态性上皮粘蛋白(PEM)),MUC1-KLH,MUC16(CA125),MCP1(单核细胞趋化蛋白1),MelanA/MART1,ML-IAP,MPG,MS4A1,MYCN,髓磷脂相关糖蛋白,Myostatin,NA17,NARP-1,NCA-90(粒细胞抗原),Nectin-4(ASG-22ME),NGF,神经细胞凋亡调控蛋白酶1,NOGO-A,Notch受体,核仁素,Neu致癌基因产物,NY-BR-1,NY-ESO-1,OX-40,OxLDL(氧化低密度脂蛋白),OY-TES1,P21,p53非突变体,P97,PAP,抗(N-羟乙酰神经氨酸)抗体结合部位,PAX3,PAX5,PCSK9,PDCD1(PD-1、程序性细胞死亡蛋白1,CD279),PDGF-Rα(α血小板源生长因子受体),PDGFR-β,PDL-1,PLAC1,类PLAP睾丸碱性磷酸酶,血小板衍生生长因子受体β,磷酸钠联合转运体,PMEL17,聚唾液酸,蛋白酶3(PR1),前列腺癌,PS(磷脂酰丝氨酸),前列腺癌细胞,铜绿假单胞菌,PSMA,PSA,PSCA,狂犬病病毒糖蛋白,RHD(Rh多肽1(RhPI),CD240),Rhesus因子,RANKL,RhoC,Ras突变,RGS5,ROBO4,呼吸道合胞病毒,RON,肉瘤易位断点,SART3,Sclerostin,SLAMF7(SLAM成员7),Selectin P,SDC1(多配体蛋白聚糖1),系统性红斑狼疮(a),生长调节素C,SIP(1-磷酸鞘氨醇),生长激素抑制素,精子蛋白17,SSX2,STEAP1(6-跨膜上皮前列腺抗原1),STEAP2,STn,TAG-72(肿瘤相关糖蛋白),存活素,T细胞受体,T细胞跨膜蛋白,TEM1(肿瘤血管内皮标记1),TENB2,Tenascin C(TN-C),TGF-α,TGF-β(转化生长因子β),TGF-β1,TGF-β2(转化生长因子2),Tie(CD202b),Tie2,TIM-1(CDX-014),Tn,TNF,TNF-α,TNFRSF8,TNFRSF10B(肿瘤坏死因子受体超家族成员10B),TNFRSF13B(肿瘤坏死因子受体超家族成员13B),TPBG(滋养细胞糖蛋白),TRAIL-R1(TNF相关坏死诱导配体受体1),TRAILR2(死亡受体5(DR5)),肿瘤相关的钙信号传感器2,肿瘤特异糖基化的MUC1,TWEAK受体,TYRP1(糖蛋白75),TRP-2,酪氨酸酶,VCAM-1(CD106),VEGF,VEGF-A,VEGF-2(CD309),VEGFR-1,VEGFR2,vimentin,WT1,XAGE 1,表达任何胰岛素生长因子受体的细胞,或任何表皮生长因子受体。
在另一个具体的实施例中,通过本专利的桥连接体链接的细胞结合剂-药物偶联物,可用于癌症靶向治疗。目标癌症包括但不限于,肾上腺皮质癌、肛门癌、膀胱癌、大脑肿瘤(脑干神经胶质瘤、小脑星形细胞瘤、脑星形细胞瘤、室管膜瘤、成神经管细胞瘤、幕上原始神经外胚层和松果体肿瘤、视觉通路和下丘脑胶质瘤)、乳腺癌、类癌肿瘤、胃肠道癌症、未知小细胞癌、宫颈癌、结肠癌、子宫内膜癌、食道癌、肝外胆管癌、尤因家族肿瘤(PNET)、颅内生殖细胞肿瘤、眼癌、眼内黑色素瘤、胆囊癌、胃癌(胃癌)、性腺外生殖细胞瘤、孕周滋养细胞瘤、头颈癌、下咽癌、胰岛细胞癌、肾癌(肾细胞癌)、喉癌、白血病(急性淋巴细胞,急性髓系,慢性淋巴细胞,慢性粒细胞,毛细胞)、嘴唇和口腔癌症、肝癌、肺癌(非小细胞,小细胞)、淋巴瘤(艾滋病相关,中枢神经系统,皮肤T细胞,霍奇金病,非霍奇金病)、恶性间皮瘤、黑色素瘤、梅克尔细胞癌、转移性鳞状颈癌与隐匿性原发性癌、多发性骨髓瘤和其他浆细胞肿瘤、蕈样肉芽肿、骨髓增生异常综合征、骨髓增生异常、鼻咽癌、神经母细胞瘤、口腔癌、口咽癌、骨肉瘤、卵巢癌(上皮、生殖细胞瘤、低恶性肿瘤)、胰腺癌(外分泌,胰岛细胞癌)、副鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、嗜铬细胞瘤、垂体肿瘤、浆细胞肿瘤、前列腺癌横纹肌肉瘤、直肠癌、肾细胞癌(肾癌)、肾盂和输尿管(移行细胞)、唾腺癌、赛塞里综合症、皮肤癌(皮肤T细胞淋巴瘤,卡波西氏肉瘤,黑色素瘤)、小肠肿瘤、软组织肉瘤、胃癌、睾丸癌、胸腺瘤(恶性)、甲状腺癌、尿道癌症、子宫癌、不寻常的少年癌症、阴道肿瘤、外阴肿瘤和维尔姆斯瘤。
在另一个具体的实施例中,通过本专利的桥连接体链接的细胞结合剂-药物偶联物,可用作治疗或预防自身免疫疾病的成分和方法。自身免疫性疾病包括但不限于,Achlorhydra自身免疫性活动性慢性肝炎,急性播散性脑脊髓炎,急性出血性脑白质炎,艾迪生病,无精症,斑秃,肌萎缩侧索硬化症,强直性脊柱炎,抗GBM/TBM肾炎,抗磷脂综合征,抗异常酶综合征,关节炎,特应性过敏,特应性皮炎,自身免疫性再生障碍性贫血,自身免疫性心肌病,自身免疫性溶血性贫血,自身免疫性肝炎,自身免疫性内耳疾病,自身免疫性淋巴组织增生综合征,自身免疫性周围神经病,自身免疫性胰腺炎,自身免疫性多内分泌综合征I,II和III型,自身免疫性黄体酮皮炎,自身免疫性血小板减少性紫癜,自身免疫性葡萄膜炎,Balo病/Balo同心硬化症,Bechets综合征,Berger氏病,Bickerstaff脑炎,Blau综合征,大疱性类天疱疮,Castleman病,Chagas病,慢性疲劳免疫功能障碍综合征,慢性炎性脱髓鞘性多发性神经病,慢性复发性多灶性骨髓炎,慢性莱姆病,慢性阻塞性肺病,Churg-Strauss综合征,瘢痕性类天疱疮,乳糜泄,Cogan综合征,冷凝集素病,补体成分2缺乏症,颅骨动脉炎,CREST综合征,Crohns病(特发性炎症性肠病),库欣综合征,皮肤白细胞增多性血管炎,德戈氏病,Dercum氏病,疱疹样皮炎,皮肌炎,1型糖尿病,弥漫性皮肤系统性硬化症,Dressler综合征,盘状红斑狼疮,湿疹,子宫内膜异位症,附着点炎相关的关节炎,Eosinophilic筋膜炎,大疱性表皮松解症,结节性红斑,特发性混合性冷球蛋白血症,伊文氏综合征,纤维发育不良性骨化症,纤维肌痛,纤维化性肌炎,纤维性肺泡炎,胃炎,胃肠类天疱疮,巨细胞动脉炎,肾小球肾炎,古德帕斯丘尔综合征,格雷夫斯病,格林-巴利综合征,桥本氏脑炎,桥本氏甲状腺炎,溶血性贫血,过敏性紫癜,妊娠性肝炎,化脓性汗腺炎,休斯综合征(抗磷脂综合征),低丙球蛋白血症,特发性炎性脱髓鞘疾病,特发性肺纤维化,特发性血小板减少性紫癜(自身免疫性血小板减少性紫癜),IgA肾病(伯杰氏病),包涵体肌炎,炎性脱髓鞘性多神经炎,间质性膀胱炎,过敏性肠综合征,少年特发性关节炎,青少年类风湿性关节炎,川崎氏病,朗伯-伊顿重症肌无力综合征,白细胞碎屑性血管炎,扁平苔癣,硬化性硬化症,线状IgA疾病(LAD),Lou Gehrig病(也称肌萎缩侧索硬化症),狼疮性肝炎,红斑狼疮,Majeed综合征,美尼尔氏病,显微镜下多动脉炎,米勒-费希尔综合征,混合性结缔组织病,硬斑病,穆罕默德-哈贝曼病,麦考利综合征,多发性骨髓瘤,多发性硬化症,重症肌无力,肌炎,嗜睡症,视神经脊髓炎(Devic病),神经性肌强直,眼睑瘢痕性类天疱疮,Opsoclonusmyoclonus综合征,Ord甲状腺炎,回文风湿病,PANDAS(与链球菌相关的小儿自身免疫性神经精神病),Paraneoplastic小脑变性,阵发性睡眠性血红蛋白尿症,ParryRomberg综合征,Parsonnage-Turner综合征,睫状体平部炎,天疱疮,寻常型天疱疮,贫血,周围脑脊髓炎,POEMS综合征,结节性多动脉炎,风湿性多肌痛,多发性肌炎,原发性胆汁性肝硬化,原发性硬化性胆管炎,进行性炎症性神经病变,牛皮癣,牛皮癣性关节炎,坏疽性皮肤炎,纯红细胞再生障碍,Rasmussen脑炎,雷诺现象,复发性多软骨炎,赖特综合征,不宁腿综合症,后神经纤维化,类风湿性关节炎,类风湿热,结节病,精神分裂症,施密特综合征,Schnitzler综合征,施尼茨勒综合征,巩膜炎,硬皮病,干燥综合征,脊椎关节病,粘稠血症,Still病,僵人综合征,亚急性细菌性心内膜炎,苏萨克综合征,Sweet综合征,小舞蹈病,交感神经性贫血,Takayasu动脉炎,颞动脉炎(巨细胞动脉炎),Tolosa-Hunt综合征,横贯性脊髓炎,溃疡性结肠炎(特发性炎性肠病),未分化结缔组织病,未分化脊柱关节病,血管炎,白癜风,韦格纳肉芽肿病,威尔逊氏综合征,威斯科特-奥尔德里奇综合征。
在另一个具体的实施例中,在用于治疗或预防自身免疫性疾病的偶联物上,和药物分子通过本专利的桥连接体链接的结合分子,包括但不限于,抗弹性蛋白抗体,Abys抗上皮细胞抗体,抗地下室膜IV型胶原蛋白抗体,抗核抗体,抗ds DNA,抗ss DNA,抗心磷脂抗体IgM,IgG,抗乳糜泻抗体,抗磷脂抗体IgK,IgG,抗SM抗体,抗线粒体抗体,甲状腺抗体,微粒体抗体,T细胞抗体,甲状腺球蛋白抗体,抗SCL-70,抗Jo,抗U.sub.1RNP,抗La/SSB,抗SSA,抗SSB,抗壁细胞抗体,抗组蛋白,抗RNP,C-ANCA,P-ANCA,抗着丝粒,抗纤维蛋白原,抗GBM抗体,抗神经节苷脂抗体,抗Desmogein 3抗体,抗p62抗体,抗sp100抗体,抗线粒体(M2)抗体,类风湿因子抗体,抗MCV抗体,抗拓扑异构酶抗体,抗中性粒细胞胞质(cANCA)抗体。
在某些优选的实施例中,本专利中偶联物上的结合分子,可以与自身免疫性疾病相关的激活淋巴细胞上表达的受体或受体复合物相结合。受体或受体复合物包含,免疫球蛋白基因超家族成员(例如CD2,CD3,CD4,CD8,CD19,CD20,CD22,CD28,CD30,CD33,CD37,CD38,CD56,CD70,CD79,CD79b,CD90,CD125,CD147,CD152/CTLA-4,PD-1或ICOS),TNF受体超家族成员(例如CD27,CD40,CD95/Fas,CD134/OX40,CD137/4-1BB,INF-R1,TNFR-2,RANK,TACI,BCMA,骨保护素,Apo2/TRAIL-R1,TRAIL-R2,TRAIL-R3,TRAIL-R4和APO-3),整合蛋白,细胞因子受体,趋化因子受体,主要组织相容性蛋白,凝集素(C型,S型或I型)或补体控制蛋白。
在另一个具体实施例中,可用的对病毒或微生物抗原具有免疫特异性的细胞结合配体是人源化或人单克隆抗体。“病毒抗原”包括但不限于,任何能够引发免疫应答的病毒肽,多肽蛋白(例如HIV gp120,HIV nef,RSV F糖蛋白,流感病毒神经氨酸苷酶,流感病毒血凝素,HTLV Tax,疱疹单纯疱疹病毒糖蛋白(例如gB,gC,gD和gE)和乙型肝炎表面抗原)。“微生物抗原”包括但不限于,任何能够引发免疫应答的微生物肽,多肽,蛋白质,糖,多糖或脂质分子(例如细菌,真菌,致病原生动物或酵母多肽,包括如LPS和荚膜多糖)。可用于治疗病毒或微生物感染的抗体的实例,包括但不限于:帕利珠单抗,它是用于治疗RSV感染的,人源化抗呼吸道合胞病毒单克隆抗体;PRO542,是一种CD4融合抗体,用于治疗HIV感染;奥斯他韦,是一种用于治疗乙型肝炎病毒的人抗体;PROTVIR,是一种人源化IgG1抗体,用于治疗巨细胞病毒,和抗LPS抗体。
通过本专利的桥连接体制得的细胞结合分子-药物偶联物可用于治疗感染性疾病。这些感染性疾病包括但不限于,不动杆菌属感染,放线菌病,非洲昏睡病(非洲锥虫病),艾滋病(获得性免疫缺陷综合症),阿米巴病,无形体病,炭疽,溶血性耶尔森菌感染,阿根廷出血热,蛔虫病,曲霉病,星状病毒感染,巴贝斯虫病,蜡状芽孢杆菌感染,细菌性肺炎,细菌性阴道炎,类杆菌感染,小袋虫病,蛔虫感染,BK病毒感染,黑色发结节病,人芽囊原虫感染,芽生菌病,玻利维亚出血热,疏螺旋体感染,肉毒中毒(和婴儿肉毒中毒),巴西出血热,布鲁氏杆菌病,伯克霍尔德氏菌感染,布鲁里溃疡,杯状病毒感染(诺如病毒和沙波病毒),弯曲杆菌病,念珠菌病(念珠菌病,鹅口疮),猫抓病,蜂窝组织炎,Chagas病(美洲锥虫病),子囊,水痘,衣原体,肺炎衣原体感染,霍乱,色素母细胞瘤,华支睾吸虫,艰难梭状芽孢杆菌感染,球孢子菌病,科罗拉多蜱热病,普通感冒(急性病毒性鼻咽炎,急性鼻炎),克雅氏病,克里米亚-刚果出血热,隐球菌病,隐孢子虫病,皮肤幼虫迁徙,环孢子虫病,肠杆菌感染,肠道病毒感染,流行性斑疹伤寒,传染性红斑(第五种疾病),急疹,姜片虫病,肝片吸虫病,致命性家族性失眠,丝虫病,产气荚膜梭菌食物中毒,自由活体阿米巴感染,梭杆菌感染,气性坏疽(梭菌性肌坏死),地丝菌病,格斯特曼-斯特拉斯勒-谢克尔病综合征,贾第鞭毛虫病,马鼻疽,淋病,肉芽肿性腹泻(第五性病),A群链球菌感染,B群链球菌感染,流感嗜血杆菌感染,手足口病(HFMD),汉坦病毒肺综合征,幽门螺杆菌感染,溶血性尿毒综合征,肾综合征出血热,甲型肝炎,乙型肝炎,丙型肝炎,丁型肝炎,戊型肝炎,单纯性疱疹,组织胞浆菌病,钩虫感染,人类博卡病毒感染,人类ewingii埃里希体病,人类粒细胞无形体病,人类偏肺病毒感染,人类单核细胞埃里希体病,人乳头瘤病毒感染,人副流感病毒感染,膜壳绦虫病,艾巴氏病毒传染性单核细胞增多症(单),流行性感冒,等孢子虫病,川崎病,角膜炎,金格杆菌感染,库鲁病,拉沙热,军团病(退伍军人症),军团病(庞蒂亚克热),利什曼病,莱姆病,淋巴丝虫病(象皮病),淋巴细胞性脉络丛脑膜炎,疟疾,马尔堡出血热,麻疹,类鼻疽病(惠氏病),脑膜炎,脑膜炎球菌病,后殖吸虫病,微孢子虫病,传染性软疣,腮腺炎,小鼠斑疹伤寒(地方性斑疹伤寒),支原体肺炎,足菌肿,蝇蛆病,新生儿结膜炎(新生儿眼病),变异型克雅氏病(vCJD,nvCJD),诺卡氏菌病,盘尾丝虫病(河盲症),副球孢子菌病(南美芽生菌病),肺吸虫病,巴斯德氏菌病,头虱,体虱,阴虱,盆腔炎,百日咳,鼠疫,肺炎球菌感染,肺孢子虫肺炎,肺炎,脊髓灰质炎,普氏菌感染,原发性阿米巴脑膜脑炎,进行性多灶性白质脑病,鹦鹉热,Q热,狂犬病,鼠咬热,呼吸道合胞病毒感染,鼻孢子虫病,鼻病毒感染,立克次体感染,立克次体痘,裂谷热,落基山斑疹热,轮状病毒感染,风疹,沙门氏菌病,SARS(严重急性呼吸综合征),疥疮,血吸虫病,败血症,志贺氏菌病(Bacillary痢疾),带状疱疹(带状疱疹),天花(天花),孢子丝菌,葡萄球菌食物中毒,感染金黄色葡萄球菌,粪类圆线虫病,梅毒,绦虫病,破伤风,须癣(Barber痒),头皮癣,体癣,股癣,手癣,掌黑癣,足癣(香港脚),甲癣(灰指甲),花斑癣,弓蛔虫病(眼幼虫移行症),弓蛔虫病(内脏幼虫移行症),弓形体病,旋毛虫病,滴虫病,鞭虫病(鞭虫感染),肺结核,兔热病,解脲脲原体感染,委内瑞拉马脑炎,委内瑞拉出血热,病毒性肺炎,西尼罗河热,白毛结节病(白癣),假结核耶尔森氏菌,耶尔森氏鼠疫杆菌肠道病,黄热病,接合菌病。
本发明的细胞结合剂,更优选为抗体,对抗的病原菌株包括但不限于,鲍氏不动杆菌,以色列放线菌,放线菌和丙酸杆菌,布氏锥虫,HIV(人免疫缺陷病毒病毒),溶组织内阿米巴,无形体属,炭疽芽孢杆菌,溶血弧菌,胡宁病毒,蛔虫属,曲霉属,星状病毒科,巴贝虫属,蜡状芽孢杆菌,多种细菌,拟杆菌属,大肠杆菌,蛔虫属,BK病毒,结节菌,人芽囊原虫,皮炎芽生菌,马丘波病毒,疏螺旋体属,肉毒梭菌,清风藤属,布鲁氏菌属,通常为洋葱伯克霍尔德菌和其他伯克霍尔德氏菌种,溃疡分枝杆菌,杯状病毒科,弯曲杆菌属,通常为白色假丝酵母和其他假丝酵母属,汉赛巴尔通体,A群链球菌和葡萄球菌,克氏锥虫,杜克雷嗜血杆菌,VZV,沙眼衣原体,科罗拉多蜱热病毒,鼻病毒,冠状病毒,CJD朊病毒,克里米亚-刚果出血热病毒,新型隐球菌,隐孢子虫属,巴西钩虫,多种寄生虫,环孢子虫,带状绦虫,巨细胞病毒,登革热病毒(DEN-1,DEN-2,DEN-3和DEN-4)-黄病毒,脆弱双歧杆菌,白喉棒状杆菌,裂头绦虫,麦地那龙线虫,埃博拉病毒,棘球绦虫属,埃立克体肠球菌属,肠道病毒属,普氏立克次体,细小病毒B19,人疱疹病毒6和人疱疹病毒7,布氏姜片虫,肝片吸虫和巨大片吸虫,FFI朊病毒,丝虫目超家族,产气荚膜梭菌,梭杆菌属,其他梭状芽孢杆菌,白地霉,GSS朊病毒,肠道贾第虫,伯克霍尔德氏菌,刺孢小芽孢杆菌和革兰氏假丝酵母,淋球菌,肉芽肿克雷伯氏菌,化脓性链球菌,无乳链球菌,流感嗜血杆菌,肠道病毒,主要是柯萨奇A病毒和肠道病毒71,无名病毒,幽门螺旋杆菌,大肠杆菌O157:H7,布尼亚病毒科,甲型肝炎病毒,乙型肝炎病毒,丙型肝炎病毒,丁型肝炎病毒,戊型肝炎病毒,单纯疱疹病毒1,单纯疱疹病毒2,荚膜组织胞浆菌,十二指肠腺瘤和壶腹癌流感嗜血杆菌,人博卡病毒,埃里希体,嗜吞噬细胞无嗜血杆菌,人偏肺病毒,查菲埃里希体,人乳头瘤病毒,人副流感病毒,微小膜壳绦虫和缩小膜壳绦虫,艾巴氏病毒,正粘病毒科家族,贝氏等孢球虫,金格杆菌,肺炎克雷伯菌,克雷伯氏菌,嗜肺军团菌,嗜肺军团菌,嗜肺军团菌,利什曼原虫属,麻风分枝杆菌和结核分枝杆菌,钩端螺旋体属,单核细胞增多性李斯特氏菌,伯氏疏螺旋体和其他疏螺旋体属物种,班氏旋毛虫和马来丝虫,淋巴细胞脉络丛脑膜炎病毒(LCMV)疟原虫属,马尔堡病毒,麻疹病毒,类鼻疽伯克霍尔德氏菌,脑膜炎奈瑟氏球菌,横川后殖吸虫,小孢子虫目门,传染性软疣病毒(MCV),腮腺炎病毒,伤寒立克次氏体,肺炎支原体,多种细菌和真菌寄生双翅蝇幼虫,沙眼衣原体和淋病奈瑟菌,vCJD朊病毒,诺卡氏菌和其他诺卡氏菌属,盘尾丝虫属,盘鲍拟亚科,副龙属西马尼和其他副属,巴斯德氏菌属,头虱,人体虱,百日咳博德特氏菌鼠疫耶尔森氏菌,肺炎链球菌,肺炎球菌,脊髓灰质炎病毒,普雷沃氏菌属,奈氏格氏杆菌,JC病毒,鹦鹉热衣原体,伯氏考克斯体,狂犬病病毒,单链球菌和螺旋菌,呼吸道合胞病毒,鼻孢子菌,鼻病毒,立克次体属,由小株立克次体,裂谷热病毒,立克次体立克次体,轮状病毒,风疹,沙门氏菌属,SARS冠状病毒,人疥螨,血吸虫属,体细胞属,志贺菌属,水痘带状疱疹病毒,天花少校或天花小,申克孢子丝菌,金黄色葡萄球菌属,金黄色葡萄球菌,链球菌化脓,圆线虫,梅毒螺旋体,绦虫属,破伤风,癣属癣音铀,癣属,絮状表皮癣菌,红色毛癣菌,须毛癣菌,红色毛癣菌,威尼克外瓶黴,毛癣菌属属,细胞死亡属,弓箭毒或弓箭毒,刚地弓形虫、旋毛虫,阴道毛滴虫,三丘里三种,结核分枝杆菌,弗朗西拉图拉菌,尿素和马脑炎病毒,委内瑞拉马脑炎病毒,霍乱弧菌,瓜纳里托病毒,西尼罗河病毒,beigelii丝孢,假结核耶尔森氏菌,小肠结肠炎耶尔森氏菌,黄热病病毒,毛霉菌目阶(毛霉菌病)和虫霉目阶(虫霉属真菌病),毛霉菌目绿脓杆菌,弯曲杆菌(弧菌),气单胞菌,艾氏菌,耶尔森氏菌,志贺痢疾杆菌,志贺氏杆菌,志贺氏菌,沙门氏菌,伤寒沙门氏菌,雅司螺旋体,奋森氏螺旋体,伯氏疏螺旋体,细螺旋体,卡氏肺孢子虫,流产布鲁氏菌,布鲁杆菌,布鲁氏菌,支原体属,普氏立克次体,恙虫病立克次氏体,衣原体属,致病性真菌(烟曲霉,白色念珠菌,荚膜组织胞浆菌),原生动物(溶组织内阿米巴,Tenas毛滴虫,Hominis毛滴虫,冈比亚锥虫,罗得西亚锥虫,罗氏利什曼原虫,热带利什曼原虫,巴西利什曼原虫,肺孢子虫肺炎,间日疟原虫,恶性疟原虫,疟原虫疟疾)或Helminiths(日本血吸虫,曼氏血吸虫,埃及血吸虫和钩虫)。
其他用作本专利细胞结合剂,治疗病毒性疾病的抗体,包括但不限于,对下列致病性病毒抗原的抗体:痘病毒;疱疹病毒;腺病毒;小黄病毒;肠病毒;小核糖核酸病毒;细小病毒;呼肠病毒;逆转录病毒;流感病毒;副流感病毒;腮腺炎;麻疹;呼吸道合胞病毒;风疹;虫媒病毒;弹状病毒;沙门氏菌;非a/非b型肝炎病毒;鼻病毒;冠状病毒;罗托病毒;致癌病毒,如HBV(肝细胞癌),人乳头状瘤病毒(宫颈癌,肛门癌),卡波济氏肉瘤相关的疱疹病毒(卡波济氏肉瘤肉瘤)、人类疱疹病毒第四型(鼻咽癌、伯基特淋巴瘤、原发性中枢神经系统淋巴瘤)、瘤病毒(默克尔细胞癌)、SV40(猿猴病毒40)、HCV(肝细胞癌),HTLV-1(成人T细胞白血病/淋巴瘤);免疫紊乱导致病毒,如人类免疫缺陷病毒(艾滋病);中枢神经系统病毒,如JCV(进行性多灶性脑白质病),丙型肝炎病毒(亚急性硬化性全脑炎),LCV(淋巴细胞性脉络丛脑膜炎),亚博病毒脑炎,正粘病毒(脑炎性脑炎),RV(狂犬病),长鼻病毒,疱疹病毒脑膜炎,拉姆齐亨特综合征II型,脊髓灰质炎病毒(脊髓灰质炎病毒,后脊髓灰质炎综合征),HTLV-1(热带麻痹性麻痹));巨细胞病毒(巨细胞病毒视网膜炎,HSV(疱疹性角膜炎);心血管病毒,如CBV(心包炎,心肌炎);呼吸系统/急性病毒性鼻内炎/病毒性肺炎,如爱泼斯坦-巴尔病毒(EBV感染/传染性单核病),巨细胞病毒,非典冠状病毒(严重急性呼吸综合征)或正黏液病毒,流感病毒a/b/c(流感/禽流感),副粘病毒,人类副流感病毒,RSV(人类呼吸道合胞病毒),hMPV;消化系统病毒(腮腺炎病毒,巨细胞病毒(巨细胞病毒食管炎),腺病毒(腺病毒感染),轮状病毒,诺瓦克病毒,星状病毒,冠状病毒,乙型肝炎病毒,CBV,甲型肝炎病毒,丙型肝炎病毒,丁型肝炎病毒,戊型肝炎病毒,HGV);泌尿生殖病毒,如BK病毒,MuV(腮腺炎)。
更进一步,本发明也包括用桥接体连接的共轭偶联物和可接受的载体,稀释剂或辅料构成的组合物,以治疗癌症、感染或自身免疫性疾病。治疗癌症、感染和自身免疫性疾病的方法可以在体外,体内或离体实施。体外用途的实例包括用它处理细胞培养物,以杀死除了不表达靶抗原的变体以外的所有细胞;或者杀死表达不需要的抗原的变体。离体使用的例子包括在进行移植(HSCT)之前对造血干细胞(HSC)进行处理,以杀死患病或恶性细胞。例如,在癌症治疗中的自体移植之前或在自身免疫性疾病的治疗中从骨髓中去除肿瘤细胞或淋巴细胞,或在移植之前为了防止移植物抗宿主疾病从同种异体骨髓或组织中除去T细胞和其他淋巴细胞。这样的临床离体治疗可以按如下步骤进行:从患者或其他个体收获骨髓,然后在含有血清的培养基中约37℃下孵育约30分钟至约48小时,在该培养基中加入本发明的偶联物,浓度范围从约1pM至0.1mM。具体的药物浓度和孵育时间应当由专业临床医师决定。孵育后,用含血清的培养基洗涤骨髓细胞,并按照已知的方法通过静脉注射给患者。若患者在骨髓采集和再输注治疗细胞之间,还接受其它治疗(例如消融化疗或全身辐射疗程)的情况下,应使用标准医疗设备将处理后的骨髓细胞在液氮中冷冻储存。
在临床体内的使用中,可将本专利连接体链接的偶联物作为溶液或冻干固体供应,固体可以被重新溶解在注射用无菌水中。偶联物施用方案的实例如下:偶联物每周一次性静脉注射,连续给予8至20周。在50-500ml生理盐水中给予推注剂量,可以向其中加入人血清白蛋白(例如0.5至5mL的人血清白蛋白的浓缩溶液,100mg/mL)。静脉注射剂量将是约50μg至100mg/kg(体重)每周(每次注射10μg至50mg/kg)。治疗后4~20周,患者可以接受第二疗程治疗。有关施用途径,赋形剂,稀释剂,剂量,次数等的具体临床方案可以由专业临床医生确定。
可用体内或离体方法治疗的医学病症的实例,包括任何类型癌症的恶性肿瘤,自身免疫疾病,移植物排斥和感染(病毒,细菌或寄生虫)。
为达到期望的生物效应所需的偶联物的量将随多种因素而变化,所述因素包括偶联物的化学特性,效力和生物利用度,疾病的类型,患者种族,患者的疾病发展状态,给药途径,所有因素决定了所需剂量、给药方式和给药方案。
一般而言,可将本发明的偶联物配制成含有0.1至10%w/v偶联物的水性生理缓冲溶液中,供注射使用。典型的剂量范围是从1μg/kg至1g/kg(体重),每天1次。优选的剂量范围是每天0.01mg/kg至20mg/kg体重/每天或每周,或幼儿等效剂量。待施用的药物的优选剂量可能取决于诸如疾病或病症的进展的类型和程度,特定患者的总体健康状况,所选化合物的相对生物功效,药物的配方,给药途径(静脉内,肌肉内或其他),药物指定运送途径的药代动力学性质,以及给药速度(推注或连续输注)和给药方案(给定时间内的重复次数)。
本发明的偶联物还能够以单位剂量形式给药,其中术语“单位剂量”是指能够给予患者的单次剂量,并且可以很容易地处置和包装,同时活性偶联物本身或如下文所述的药学上可接受的组合物,保持物理和化学上稳定的单位剂量。典型的每日总剂量范围是从0.01至100mg/kg体重。作为一般指导原则,人类的单位剂量其范围为1mg到3000mg每天或者每周,或者2周,3周或者每个月。单位剂量范围优选1至500mg,一周一次至四次,更优选为1mg至100mg,一周一次。本文提供的偶联物可以通过与一种或多种药学上可接受的赋形剂混合而配制成药物组合物。这样的单位剂量组合物可以通过口服给药,如片剂,简单胶囊或软凝胶胶囊的形式的药物;或鼻内给药,如粉剂,滴鼻剂或气雾剂的药物;或皮肤给药,如使用局部用软膏,乳膏,乳液,凝胶或喷雾剂或通过透皮贴剂给药。
药物/细胞毒性剂
可以与本发明中的细胞结合分子偶联的药物是包括细胞毒性剂的小分子药物,可以连接到,或者被修饰后连接到细胞结合剂上。本发明中的“小分子药物”泛指分子量为100至1800,更优120至1400的有机、无机或金属有机化合物。这些小分子药物在本领域文献中已被充分描述,如WO05058367A2和美国专利4,956,303等,此处引作参考。小分子药物包括已知的药物和即将被公开的药物。
已知的药物包括但不限于:
1)化疗剂:a)烷基化剂,如氮芥:氯苯那普,氯普那嗪,环磷酰胺,达卡巴嗪,雌二醇氮芥,异环磷酰胺,氮芥,盐酸二甲氧胺,氧化二氮芥,盐酸氨氯地平,麦考酚酸,卫矛醇,哌泊溴烷,新氮芥,苯芥胆甾醇,松龙苯芥,噻替哌,曲磷胺对,尿嘧啶;CC-1065(包括其阿多来新,卡折来新和比折来新合成同系物);多卡霉素(包括合成同系物KW-2189和CBI-TMI);苯并二氮卓二聚体(例如吡咯并苯二氮卓(PBD)或托美霉素,吲哚并苯并二氮卓,咪唑并苯并噻二氮卓或恶唑烷并苯并二氮卓的二聚体);亚硝基脲(卡莫司汀,洛莫司汀,氯化梭菌素,福莫司汀,尼莫司汀,拉莫司汀);烷基磺酸盐(白消安,硫丹,硫丹和硫磺);三氮烯(达卡巴嗪);含铂化合物(卡铂,顺铂,奥沙利铂);吖丙啶类,如苯并二氢吡喃酮,卡洛酮,美妥替派和乌雷多巴;乙烯亚胺和甲基三聚氰胺,包括六甲蜜胺,三亚乙基三胺,三乙基磷酰胺,三亚乙基硫代磷酰胺和三羟甲基甲基胺;b)植物生物碱:如长春花生物碱(长春新碱,长春碱,长春地辛,长春瑞滨,去甲长春碱);类紫杉醇(紫杉醇,多西紫杉醇)及其同系物;美登素(DM1,DM2,DM3,DM4,美登素和安沙霉素)及其同系物;cryptophycin(特别是cryptophycin 1和cryptophycin 8);埃博霉素,软珊瑚醇,迪莫利德,草苔虫内酯,海兔毒素,奥瑞他汀,tubulysin,cephalostatin,pancratistatin,sarcodictyin,海绵抑制素;c)DNA拓扑异构酶抑制剂,例如依托泊苷替尼(9-氨基喜树碱,喜树碱,克立那托,道诺霉素,依托泊苷,磷酸依托泊苷,伊立替康,米托蒽醌,诺消灵,视黄酸(视黄醇),替尼泊苷,拓扑替康,9-硝基喜树碱(RFS 2000));丝裂霉素(丝裂霉素C);d)抗代谢物,例如抗叶酸剂,DHFR抑制剂(甲氨蝶呤,曲麦克特,二甲叶酸,蝶罗呤,氨喋呤(4-氨基苯甲酸)或其他叶酸同系物);IMP脱氢酶抑制剂(麦考酚酸,噻唑呋林,利巴韦林,EICAR);核糖核苷酸还原酶抑制剂(羟基脲,去铁胺);嘧啶同系物,尿嘧啶同系物(安西他滨,阿扎胞苷,6-氮尿嘧啶,卡培他滨(希罗达),卡莫氟,阿糖胞苷,双脱氧尿苷,去氧氟尿苷,依诺他滨,5-氟尿嘧啶,氟尿苷,ratitrexed(Tomudex);胞嘧啶同系物(阿糖胞苷,胞嘧啶阿拉伯糖苷,氟达拉滨);嘌呤同系物(硫唑嘌呤,氟达拉滨,巯嘌呤,硫胺素,硫鸟嘌呤);叶酸补充剂,如弗洛林酸;e)激素疗法剂,如受体拮抗剂,抗雌激素(甲地孕酮,雷洛昔芬,他莫昔芬),LHRH兴奋剂(戈斯他林,醋酸亮丙瑞林);抗雄激素药(比卡鲁胺,氟他胺,卡鲁司酮,丙酸倍他雄酮,表雄甾醇,戈舍瑞林,亮丙瑞林,美替利定,尼鲁米特,睾内酯,曲洛司坦及其他雄激素抑制剂);维甲类化合物,维生素D3同系物(CB1093,EB1089KH1060,胆钙化醇,麦角钙化甾醇);光动力疗法剂(维替泊芬,酞菁,光敏剂Pc4,去甲氧基-竹红菌素A);细胞因子(干扰素-α,干扰素-γ,肿瘤坏死因子(TNF),含TNF的人蛋白);f)激酶抑制剂,如BIBW 2992(抗-EGFR/Erb2),伊马替尼,吉非替尼,哌加他尼,索拉非尼,达沙替尼,舒尼替尼,厄洛替尼,尼洛替尼,拉帕替尼,阿西替尼,帕唑帕尼,凡德他尼,E7080(抗VEGFR2),mubritinib,普纳替尼(AP24534),bafetinib(INNO-406),bosutinib(SKI-606),卡博替尼,维莫德吉,iniparib,鲁索利替尼,CYT387,阿西替尼,tivozanib,索拉非尼,贝伐单抗,西妥昔单抗,曲妥珠单抗,雷珠单抗,帕尼单抗,伊斯平斯;g)抗生素,如烯二炔类抗生素(加利车霉素,特别是加利车霉素γ1,δ1,α1和β1(参考J.Med.Chem.1996,39(11),2103-2117;Angew Chem Intl.Ed.Engl.1994,33:183-186),达因霉素,包括达因霉素A和脱氧米霉素,埃斯培拉霉素,卡达霉素,C-1027,maduropeptin以及新制癌菌素发色团和相关色蛋白烯二炔抗生素发色团),aclacinomysins,放线菌素,安曲霉素,重氮丝氨酸,博来霉素,卡诺霉素,卡拉霉素,洋红霉素,嗜癌素,阿霉素,阿霉素,吗啉代阿霉素,2-吡咯啉阿霉素和脱氧柔红霉素,表柔比星,阿柔比星,伊达比星,马可霉素,霉素,霉酚酸,洛匹霉素,培洛霉素,培洛霉素,嘌呤霉素,三铁阿霉素,阿霉素,链脲霉素,链脲佐菌素,杀结核菌素,乌苯美司,净司他丁,佐柔比星;h)其他,如聚酮化合物(番荔素),特别是bullatacin和bullatacinone;吉西他滨,环氧酶素(如卡菲偌米布),硼替佐米,沙利度胺,来那度胺,pomalidomide,tosedostat,zybrestat,PLX4032,STA-9090,Stimuvax,allovectin-7,Xegeva,Provenge,Yervoy,异戊二烯化抑制剂(如洛伐他汀),多巴胺能神经毒素(如星形孢菌素),放线菌素(如放线菌素D,更生霉素),博莱霉素(如博来霉素A2,博莱霉素B2,培洛霉素),蒽环类抗生素(如柔红霉素),阿霉素(亚德里亚霉素),伊达比星,表柔比星,吡柔比星,佐柔比星,米托蒽醌,MDR抑制剂(如维拉帕米),Ca2+ATP酶抑制剂(如毒胡萝卜素),组蛋白去乙酰酶抑制剂(伏立诺他,罗米地辛,帕比司他,丙戊酸,Mocetinostat(MGCD0103),Belinostat,PCI-24781,恩替诺特,SB939,Resminostat,Givinostat,AR-42,CUDC-101,萝卜硫素,曲古抑菌素A);塞来昔布,格列酮类,表没食子儿茶素没食子酸酯,双硫仑,Salinosporamide A;抗肾上腺药物,如氨鲁米特,米托坦,曲洛司坦,醋葡醛内酯,醛磷酰胺,氨基乙酰丙酸,安吖啶,阿拉伯糖苷,bestrabucil,比生群,edatraxate,defofamine,美可辛,地吖醌,依氟鸟氨酸(DFMO),elfomithine,依利醋铵,乙基葡糖酸,硝酸镓,胞嘧啶,羟基脲,伊班膦酸盐,香菇多糖,氯尼达明,米托胍腙,米托蒽醌,莫哌达醇,二胺硝吖啶,喷司他丁,蛋氨氮芥,吡柔比星,鬼臼酸,2-乙肼,甲基苄肼;哌嗪二酮丙烷;根霉素;西佐;螺环锗;细格孢氮杂酸;三亚胺醌;三氯三乙胺;单端孢霉烯(特别是T-2毒素,疣孢菌素A,杆孢菌素A和anguidine),聚氨酯,siRNA,反义药物和核酸分解酶。
2)自身免疫疾病药物,包括但不限于,环孢菌素,环孢菌素A,氨基己酸,硫唑嘌呤,溴隐亭,苯丁酸氮芥,氯喹,环磷酰胺,皮质类固醇(例如安西奈德,倍他米松,布地奈德,氢化可的松,氟尼缩松,丙酸氟替卡松,氟可龙达那唑,地塞米松,曲安奈德,二丙酸倍氯米松),DHEA,依那西普,羟基氯喹,英夫利昔单抗,美洛昔康,甲氨蝶呤,麦考酚酸酯,泼尼松,西罗莫司,他克莫司。
3)抗感染性疾病药物,包括但不限于a)氨基糖苷类:阿米卡星,阿司米星,庆大霉素(奈替米星,西索米星,异帕米星),潮霉素B,卡那霉素(阿米卡星,阿贝卡星,氨基去氧卡那霉素,地贝卡星,妥布霉素),新霉素(framycetin,巴龙霉素,核糖霉素),奈替米星,壮观霉素,链霉素,妥布霉素,甲基姿苏霉素;b)酰胺醇类:叠氮氯霉素,氯霉素,氟苯尼考,甲砜霉素;c)安沙霉素:格尔德霉素,除莠霉素;d)碳青霉烯类:比阿培南,多利培南,厄他培南,亚胺培南/西司他丁,美罗培南,帕尼培南;e)头孢烯:碳头孢烯(洛拉卡比),头孢乙腈,氯氨苄青霉素,头孢拉定,头孢羟氨,头孢洛宁,头孢噻啶,头孢噻吩或头孢金素,头孢氨苄,头孢来星,头孢孟多,头孢匹林,羟胺唑头孢菌素,氟唑头孢菌素,孢西酮,唑啉头孢菌素,头孢拉宗,头孢卡品,头孢达肟,头孢吡,头孢克肟,头孢西丁,头孢罗齐,头孢甲氧环烯胺,头孢替唑,头孢呋辛,头孢克肟,头孢地尼,头孢托仑,头孢吡,头孢他美,头孢甲肟,头孢地嗪,头孢尼西,头孢哌酮,头孢雷特,头孢噻肟,噻乙胺唑头孢菌素,头孢唑兰,头孢氨苄,头孢咪唑,头孢匹胺,头孢匹罗,头孢泊肟,头孢罗齐,头孢喹诺,头孢磺啶,头孢他啶,头孢特仑,头孢布腾,头孢噻林,头孢唑肟,头孢吡普,头孢曲松,头孢呋辛,头孢唑南,头霉素(头孢西丁,头孢替坦,头孢氰唑),氧(碳)头孢烯(氟氧头孢,头孢);f)糖肽:博来霉素,万古霉素(奥利万星,特拉万星),替考拉宁(达巴万星),雷莫拉宁,g)甘氨酰环素:如替加环素,h)β-内酰胺酶抑制剂:青霉烷(舒巴坦,他唑巴坦),氧青霉烷(克拉维酸);i)林可酰胺:克林霉素,林可霉素;j)脂肽:达托霉素,A54145,钙依赖性抗生素(CDA);k)大环内酯类:阿奇霉素,克霉素,克拉霉素,地红霉素,红霉素,氟雷霉素,交沙霉素,酮内酯(泰利霉素,塞红霉素),麦迪霉素,米卡霉素,竹桃霉素,利福霉素(异烟肼、利福平,利福布丁,利福喷汀),罗匹霉素,罗红霉素,大观霉素,螺旋霉素,他克莫司(FK506),醋竹桃霉素,泰利霉素;l)单环胺:氨曲南,替吉莫南;m)恶唑烷酮类:利奈唑胺;n)青霉素类:阿莫西林,氨苄青霉素(匹氨西林,海洛西林,巴氨西林,氨苄青霉素,阿霉素),阿替代西林,阿洛西林,苄青霉素,苄星青霉素苄青霉素,苄星青霉素苯氧甲基青霉素,克洛西林,普鲁卡因青霉素(美替西林),美洛西林,甲氧西林,萘夫西林,苯唑西林,醋甲西林,青霉素,非奈西林,苯氧基甲基青霉素,哌拉西林,氨苄西林,磺苯西林,替莫西林,替卡西林;o)多肽:杆菌肽,粘菌素,多粘菌素B,p)喹诺酮类:阿拉曲沙星,巴洛沙星,环丙沙星,克林沙,达氟沙星,二氟沙星,依诺沙星,恩诺沙星,加雷沙星,加替沙星,吉米沙星,格帕沙星,卡诺曲伐沙星,左氧氟沙星,洛美沙星,麻保沙星,莫西沙星,那氟沙星,诺氟沙星,奥比沙星,氧氟沙星,培氟沙星,曲伐沙星,格帕沙星,西他沙星,司帕沙星,替马沙星,托沙星,曲伐沙星;q)链阳性菌素:普那霉素,奎奴普丁/达福普汀,r)磺胺类药物:磺胺类药物:磺胺类药物,磺胺嘧啶,磺胺嘧啶,磺胺嘧啶,柳氮磺胺吡啶,磺胺异恶唑,三苯氧胺,甲氧苄氨嘧啶-磺胺甲恶唑(复方新诺明);s)类固醇抗菌药物:如夫西地酸;t)四环素类:强力霉素,金霉素,氯米西环素,地美环素,雷莫昔林,美西环素,美他环素,米诺环素,土霉素,青霉素V钾哌四环素,吡咯烷甲基四环素,四环素,甘氨酰环素(如替加环素):u)其他类型的抗生素:番荔枝素,胂凡纳明,细菌萜醇抑制剂(杆菌),DANAL/AR抑制剂(环丝氨酸),dictyostatin,圆皮海绵内酯,软珊瑚醇,埃博霉素,乙胺丁醇,依托泊苷,法罗培南,夫西地酸,呋喃唑酮,异烟肼,laulimalide,甲硝唑,莫匹罗星,NAM合成抑制剂(例如磷霉素),呋喃妥因,紫杉醇,普兰西霉素,吡嗪酰胺,奎奴普丁/达福普汀,利福平(利福平),他唑巴坦替硝唑,乌菊花素。
4)抗病毒药物:a)进入/融合抑制剂:阿帕韦洛,马拉韦罗,vicriviroc,gp41(恩夫韦肽),PRO 140,CD4(艾巴利珠单抗);b)整合酶抑制剂:雷特格韦,elvite-gravir,globoidnan A;c)成熟抑制剂:bevirimat,vivecon;d)神经氨酸酶抑制剂:奥司他韦,扎那米韦,帕拉米韦;E)核苷和核苷酸:阿巴卡韦,阿昔单韦,阿德福韦,阿莫西韦,阿昔单抗,溴夫定,西多福韦,克拉夫定,地塞米松,去羟肌苷(ddI),elvucitabine,恩曲他滨(FTC),恩替卡韦,泛昔洛韦,氟拉西林(5-FU),3’-氟取代的2’,3’-脱氧核苷同系物(如3,3’-氟-2′,3′-双脱氧胸苷(FLT)和3’-氟-2’,3’-双脱氧鸟苷(FLG),福米韦生,9-鸟嘌呤,碘苷,拉米夫定(3TC),1-核苷(例如β-1-胸苷和β-1-2'-脱氧胞苷),喷昔洛韦,racivir,利巴韦林,迪替丁,司他夫定(d4T),塔利巴韦林(viramidine),替比夫定,替诺福韦,三氟尿苷伐昔洛韦,缬更昔洛韦,扎西他滨(ddC),齐多夫定(AZT);f)非核苷类:金刚烷胺,阿替吡啶,卡普韦林,二芳基嘧啶(依曲韦林,rilpivirine),地拉夫定,二十二烷醇,乙米韦林,依法韦仑,膦甲酸(磷酰基甲酸),咪喹莫特,聚乙二醇干扰素,洛韦胺,洛德腺苷,甲吲噻腙,奈韦拉平,NOV-205,长效干扰素α,鬼臼毒素,利福平,金刚乙胺,瑞喹莫德(R-848),醋胺金刚烷;g)蛋白酶抑制剂:安普那韦阿扎那韦,boceprevir,darunavir,福沙那韦,印地那韦,洛匹那韦,奈非那韦,普来可那立,利托那韦,沙奎那韦,telaprevir(VX-950),替拉那韦;h)其它类型的抗病毒药物:抗氧化酶,阿比朵尔,卡拉诺莱德,ceragenin,氰维林-n,二芳基嘧啶,表没食子儿茶素没食子酸酯(EGCG),膦甲酸,格里菲辛,taribavirin(viramidine),羟基脲,KP-1461,米替福新,普来可那立,混成抑制剂,利巴韦林,seliciclib。
5)通过本发明的桥连体链接的药物也包括放射性同位素。放射性同位素(放射性核素)的实例有3H,11C,14C,18F,32P,35S,64Cu,68Ga,86Y,99Tc,111In,123I,124I,125I,131I,133Xe,177Lu,211At或213Bi。放射性同位素标记的抗体可用于受体靶向成像实验,或者可用于如本发明的抗体-药物偶联物的靶向治疗(Wu et al Nature Biotechnology 2005,23(9):1137-1146)。细胞结合分子,例如抗体可以通过本专利的连接体链接配体试剂,进行标记。配体可以用文献(Current Protocols in Immunology,Volumes 1and 2,Coligen et al,Ed.Wiley-Interscience,New York,N.Y.,Pubs.(1991))所述的方法与放射性金属结合、螯合或生成复合物。可以络合金属离子的螯合配体包括DOTA,DOTP,DOTMA,DTPA和TETA(Macrocyclics,Dallas,TX)等。
6)上述任何药物的药学上可接受的盐,酸或其衍生物。
在另一个实施例中,结构式(II)和(IV)中的药物可以是发色分子,偶联物可用于检测,监测或研究细胞结合分子与靶细胞的相互作用。发色分子可以吸收一种光,如紫外光,荧光,红外光,近红外光或可见光;发色分子包括黄色素,红细胞,虹彩色素,白细胞,黑色素和蓝绿色素的一类或一个亚类,荧光分子(吸收光后再发光的荧光化学物质)的一类或一个亚类,视觉光转导分子的一类或一个亚类,光子分子的一类或一个亚类,冷光分子的一类或一个亚类和荧光素化合物的一类或一个亚类。
发色分子可选自但不限于,非蛋白质有机荧光团,例如氧杂蒽衍生物(荧光素,罗丹明,俄勒冈绿,伊红和德克萨斯红);花青衍生物(花青,吲哚羰花青,氧杂花青,硫代花青和部花青);方酸衍生物和环取代的方酸,包括Seta,SeTau和Square染料;萘衍生物(丹酰和氟硅酸钠衍生物);香豆素衍生物;恶二唑衍生物(吡啶基恶唑,硝基苯并恶唑和苯并恶二唑);蒽衍生物(蒽醌类,包括DRAQ5,DRAQ7和CyTRAK橙);芘衍生物(级联蓝等);恶嗪衍生物(尼罗红,尼罗蓝,甲酚紫,恶嗪170等);吖啶衍生物(黄醇黄素,吖啶橙,吖啶黄等);芳基甲胺衍生物(金胺,结晶紫,孔雀石绿)和四吡咯衍生物(卟吩,酞菁,胆红素)。
生色分子选自以下荧光化合物的任何同系物和衍生物:CF染料(Biotium),DRAQ和CyTRAK探针(BioS-tatus),BODIPY(Invitrogen),Alexa Fluor(Invitrogen),DyLightFluor(Thermo Scientific,Pierce),Atto和Tracy(Sigma Aldrich),FluoProbes(Interchim),Abberior染料(Abberior),DY和MegaStokes染料(Dyomics),Sulfo Cy染料(Cyandye),HiLyte Fluor(AnaSpec),Seta,SeTau和Square染料(BiosearchTechnologies),SureLight染料(APC,RPEPerCP,Phycobilisomes)(ColumbiaBiosciences),APC,APCXL,RPE,BPE(Phyco-Biotech)。
广泛使用的可与本发明连接体反应或偶联的荧光化合物的实例有:别藻蓝蛋白(APC),氨基胭脂蛋白,APC-Cy7偶联物,BODIPY-FL,Cascade Blue,Cy2,Cy3,Cy3.5,Cy3B,Cy5,Cy5.5,Cy7,荧光素,FluorX,羟基香豆素,丽丝胺罗丹明B,萤光黄,Me-甲氧基香豆素,NBD,Pacific Blue,Pacific Orange,PE-Cy5偶联物,PE-R-藻红蛋白(PE),Red 613,Seta-555-Azide,Seta-555-DBCO,Seta-555-NHS,Seta-580-NHS,Seta-680-NHS,Seta-APC-780,Seta-PerCP-680,Seta-R-PE-670,SeTau-380-NHS,SeTau-405-马来酰亚胺,SeTau-405-NHS,SeTau-425-NHS,SeTau-647-NHS,Texas Red,TRITC,TruRed,X-Rhodamine。
可以与本发明的连接体相连,用于研究核酸或蛋白质的荧光化合物,选自下列化合物或其衍生物:7-AAD(7-氨基放线菌素D,CG-选择性的),吖啶橙,色霉素A3,CyTRAK橙(Biostatus),DAPI,DRAQ5,DRAQ7,溴化乙锭,Hoechst33258,Hoechst33342,LDS 751,光辉霉素,碘化丙啶(PI),SYTOX蓝,SYTOX绿,SYTOX橙,噻唑橙,TO-PRO,菁染料单体,TOTO-1,TO-PRO-1,TOTO-3,TO-PRO-3,YOSeta-1,YOYO-1。可以与本发明的连接体相连,用于研究细胞的荧光化合物,选自下列化合物或其衍生物:DCFH(2',7'-二氯二氢荧光素,氧化形式),DHR(二氢罗丹明123,氧化形式,光催化氧化),Fluo-3(AM酯,pH>6),Fluo-4(AM酯,pH7.2),Indo-1(AM酯,低/高钙(Ca 2+)),SNARF(pH 6/9)。优选的荧光化合物选自:别藻蓝蛋白(APC),AmCyan1(四聚体,Clontech),AsRed2(四聚体,Clontech),蓟绿(单体,MBL),Azurite,B-藻红蛋白(BPE),Cerulean,CyPet,DsRed单体(Clontech),DsRed2(“RFP”,Clontech),EBFP,EBFP2,ECFP,EGFP(弱二聚体,Clontech),Emerald(弱二聚体,Invitrogen),EYFP(弱二聚体,Clontech),GFP(S65A突变),GFP(S65C突变),GFP(S65L突变)GFP(Y66H突变),GFP(Y66W突变),GFPuv,HcRed1,J-Red,Katusha,KusabiraOrange(单聚体,MBL),mCFP,mCherry(单体,MBL),mKate(TagFP635,单体,Evrogen),mKeima-Red(单体,MBL),mKO,mOrange,mPlum,mRaspberry,mRFP1(单体,Tsien实验室),mStrawberry,mTFP1,mTurquoise2,P3(藻胆体复合物),多甲藻黄素-叶绿素-蛋白质复合物(PerCP),R-phycoerythrin(RPE),T-Sapphire,TagCFP(二聚体,Evrogen),TagGFP(二聚体,Evrogen),TagRFP(二聚体,Evrogen),TagYFP(二聚体,Evrogen),tdTomato(串联二聚体),Topaz,TurboFP602(二聚体,Evrogen),TurboFPP635(二聚体,Evrogen),TurboGFP(二聚体,Evrogen),TurboRFP(二聚体,Evrogen),TurboYFP(二聚体,Evrogen),Venus,野生型GFP型,YPet,ZsGreen1(四聚体,Clontech),ZsYellow1(四聚体,Clontech)。
在另一个实施方案中,优选的通过本专利的连接体连接至细胞结合分子的细胞毒剂是tubulysin,美登素,紫杉烷类,CC-1065同系物,柔红霉素和阿霉素化合物,苯并二氮卓二聚体(例如吡咯并苯二氮卓(PBD),托美霉素,吲哚并苯并二氮卓,咪唑并苯并噻二氮卓或恶唑烷并苯并二氮卓的二聚体),卡立霉素类和烯二炔类抗生素,放线菌素,氮丝菌素,博来霉素,表柔比星,他莫昔芬,伊达比星,多拉司他汀,澳瑞他汀(例如MMAE,MMAF,澳瑞他汀PYE,澳瑞他汀TP,澳瑞他汀2-AQ,6-AQ,EB(AEB)和EFP(AEFP)),多卡霉素,噻替派,长春新碱,半米塔林,nazumamide,microginin,radiosumin,alterobactin,microsclerominmin,theonellamide,esperamicin,PNU-159682及其同系物和衍生物。
Tubulysin是优选的用于共轭偶联的细胞毒性剂,可以参考本领域文献,根据已知方法从天然来源分离或合成的方法制备,如Balasubramanian,R.;et al.J.Med.Chem.,2009,52,238–240.Wipf,P.;et al.Org.Lett.,2004,6,4057–4060.Pando,O.;etal.J.Am.Chem.Soc.,2011,133,7692–7695.Reddy,J.A.;et al.Mol.Pharmaceutics,2009,6,1518–1525.Raghavan,B.;et al.J.Med.Chem.,2008,51,1530–1533.Patterson,A.W.;etal.J.Org.Chem.,2008,73,4362–4369.Pando,O.;et al.Org.Lett.,2009,11(24),pp5567–5569.Wipf,P.;et al.Org.Lett.,2007,9(8),1605–1607.Friestad,G.K.;Org.Lett.,2004,6,pp 3249–3252.Hillary M.Peltier,H.M.;et al.J.Am.Chem.Soc.,2006,128,16018–16019.Chandrasekhar,S.;et al.J.Org.Chem.,2009,74,9531–9534.Liu,Y.;et al.Mol.Pharmaceutics,2012,9,168–175.Friestad,G.K.;etal.Org.Lett.,2009,11,1095–1098.Kubicek,K.;et al.,Angew Chem Int Ed Engl,2010.49,4809-12.Chai,Y.;et al.,Chem Biol,2010,17:296-309.Ullrich,A.;et al.,AngewChem Int Ed Engl,2009,48,4422-5.Sani,M.;et al.Angew Chem Int Ed Engl,2007,46,3526-9.Domling,A.;et al.,Angew Chem Int Ed Engl,2006.45,7235-9.专利:Zanda,M.;et al,Can.Pat.Appl.CA 2710693(2011).Chai,Y.;etal.Eur.Pat.Appl.2174947(2010),PCT WO 2010034724.Leamon,C.;et al,PCT WO2010033733,WO 2009002993.Ellman,J.;et al,PCTWO 2009134279;PCT WO 2009012958,US appl.20110263650,20110021568,Matschiner,G.;et al,PCT WO 2009095447.Vlahov,I.;et al,PCT WO 2009055562,WO 2008112873.Low,P.;et al,PCT WO2009026177.Richter,W.,PCT WO 2008138561.Kjems,J.;et al,PCT WO2008125116.Davis,M.;et al,PCT WO 2008076333.Diener,J.;et al,U.S.Pat.Appl.20070041901,WO 2006096754.Matschiner,G.;et al,PCT WO2006056464.Vaghefi,F.;et al,5PCT WO 2006033913.Doemling,A.,Ger.Offen.DE102004030227;PCT WO 2004005327;WO 2004005326;WO2004005269.Stanton,M.;et al,U.S.Pat.Appl.Publ.20040249130.Hoefle,G.;et al,Ger.Offen.DE 10254439;DE10241152;DE 10008089.Leung,D.;et al,WO 2002077036.Reichenbach,H.;et al,Ger.Offen.DE 19638870;Wolfgang,R.;US 20120129779,Chen,H.,US appl.20110027274。在专利PCT/IB2012/053554中描述了与细胞结合分子连接的tubulysin的优选结构。
通过桥连接体连接的抗体-tubulysin偶联物结构的例子如T01,T02,T03,T04,T05,T06和T07:
其中mAb是抗体;Z3和Z3’是H,R1,OP(O)(OM1)(OM2),OCH2OP(O)(OM1)(OM2),OSO3M1或O-糖苷(糖苷,半乳糖苷,甘露糖苷,葡萄糖苷,果糖苷等),NH-糖苷,S-糖苷或CH2-糖苷;M1和M2独立地为H,Na,K,Ca,Mg,NR1R2R3;n是1~20;R1,R2,R3和R4与式(I)中定义相同。
加利车霉素及相关的烯二炔抗生素是优选的细胞毒性剂,可参考文献:Nicolaou,K.C.et al,Science 1992,256,1172-1178;Proc.Natl.Acad.Sci USA.1993,90,5881-5888,和美国专利4,970,198;5,053,394;5,108,912;5,264,586;5,384,412;5,606,040;5,712,374;5,714,586;5,739,116;5,770,701;5,770,710;5,773,001;5,877,296;6,015,562;6,124,310;8,153,768。通过桥连接体连接的抗体-加利车霉素类似物的结构的例子如C01:
其中mAb是抗体;n是1~20;R1,R2,R3和R4与式(I)中定义相同。
美登素是本专利中优选的细胞毒性剂,美登素和其同系物在下列美国专利中有描述:4,256,746;4,361,650;4,307,016;4,294,757;4,294,757;4,371,533;4,424,219;4,331,598;4,450,254;4,364,866;4,313,946;4,315,929;4,362,663;4,322,348;4,371,533;4,424,219;5,208,020;5,416,064;5,208,020;5,416,064;6,333.410;6,441,163;6,716,821,7,276,497;7,301,019;7,303,749;7,368,565;7,411,063;7,851,432和8,163,888。一个抗体-美登素偶联物的例子如M01:
其中mAb是抗体;n是1~20;R1,R2,R3和R4与式(I)中定义相同。
紫杉烷,包括紫杉醇(一种细胞毒性天然产物)和多西紫杉醇(一种半合成衍生物)及其类似物,是本专利优选的细胞毒性分子,在如下文献中有描述:KC.Nicolaou et al.,J.Am.Chem.Soc.1995,117,2409-2420;Ojima et al,J.Med.Chem.1996,39:3889-3896;1997,40,267-278;2002,45,5620-5623;Ojima et al.,Proc.Natl.Acad.Sci.,1999,96:4256-4261;Kim et al.,Bull.Korean Chem.Soc.,1999,20,1389-1390;Miller,etal.J.Med.Chem.,2004,47,4802-4805;美国专利5,475,011 5,728,849,5,811,452;6,340,701;6,372,738;6,391,913,6.436,931;6,589,979;6,596,757;6,706,708;7,008,942;7,186,851;7,217,819;7,276,499;7,598,290和7,667,054。
抗体-紫杉烷经由桥连接体连接的偶联物结构的例子如Tx01,Tx02和Tx03:
其中mAb是抗体;n是1~20;R1,R2,R3和R4定义与式(I)中定义相同。
CC-1065类似物和多卡霉素类似物也是与本专利的桥连接体连接,优选的细胞毒性剂。CC-1065类似物和多卡霉素类似物的实例及其合成可见于:Warpehoski,et al,J.Med.Chem.31:590-603(1988),D.Boger et al.,J.Org.Chem;66;6654-6661,2001;美国专利4169888,4391904,4671958,4816567,4912227,4923990,4952394,4975278,4978757,4994578,5037993,5070092,5084468,5101038,5117006,5137877,5138059,5147786,5187186,5223409,5225539,5288514,5324483,5332740,5332837,5334528,5403484,5427908,5475092,5495009,5530101,5545806,5547667,5569825,5571698,5573922,5580717,5585089,5585499,5587161,5595499,5606017,5622929,5625126,5629430,5633425,5641780,5660829,5661016,5686237,5693762,5703080,5712374,5714586,5739116,5739350,5770429,5773001,5773435,5786377 5786486,5789650,5814318,5846545,5874299,5877296,5877397,5885793,5939598,5962216,5969108,5985908,6060608,6066742,6075181,6103236,6114598,6130237,6132722,6143901,6150584,6162963,6172197,6180370,6194612,6214345,6262271,6281354,6310209,6329497,6342480,6486326,6512101,6521404,6534660,6544731,6548530,6555313,6555693,6566336,6,586,618,6593081,6630579,6,756,397,6759509,6762179,6884869,6897034,6946455,7,049,316,7087600,7091186,7115573,7129261,7214663,7223837,7304032,7329507,7,329,760,7,388,026,7,655,660,7,655,661,7,906,545,和8,012,978。经桥连接体连接的抗体-CC1065类似物结构的实例如CC01、CC02和CC03:
其中mAb是抗体;n是1~20;Z4和Z4’是H,PO(OM1)(OM2),SO3M1,CH2PO(OM1)(OM2),CH3N(CH2CH2)2NC(O)-,O(CH2CH2)2NC(O)-或糖苷;X3和X3’是O,NH,NHR1,NHC(O),OC(O),CO,R1或缺省;M1和M2独立地为H,Na,K,NH4,NR1R2R3R4;R1,R2,R3和R4定义与式(I)中定义相同。
柔红霉素/阿霉素类似物也优选用于通过本专利的桥连接体连接的偶联。优选的结构及其合成可参考文献:Hurwitz,E.,et al.,Cancer Res.1975,35,1175-1181.Yang,H.M.,and Reisfeld,R.A.,Proc.Natl.Acad.Sci.1988,85,1189-1193;Pietersz,C.A.,E.,et al.,E.,et al.,Cancer Res.1988,48,926-9311;Trouet,et al.,1982,79,626-629;Z.Brich et al.,J.Controlled Release,1992,19,245-258;Chen et al.,Syn.Comm.,2003,33,2377-2390;King et al.,Bioconj.Chem.,1999,10,279-288;King et al.,J.Med.Chem.,2002,45,4336-4343;Kratz et al.,J Med Chem.2002,45,5523-33;Kratzet al.,Biol Pharm Bull.Jan.1998,21,56-61;Lau et al.,Bioorg.Med.Chem.1995,3,1305-1312;Scott et al.,Bioorg.Med.l Chem.Lett.1996 6,1491-1496;Watanabe etal.,Tokai J.Experimental Clin.Med.1990,15,327-334;Zhou et al.,J.Am.Chem.Soc.2004,126,15656-7;WO 01/38318;美国专利5,106,951;5,122,368;5,146,064;5,177,016;5,208,323;5,824,805;6,146,658;6,214,345;7569358;7,803,903;8,084,586;8,053,205。通过桥连接体连接的抗体-阿霉素类似物结构的实例如Da01,Da02,Da03和Da04:
其中mAb是抗体;n是1~20;X3和X3’是O,NH,NR1,NHC(O),OC(O)
,C(O),C(O)NR1,C(O)NH,R1或缺省;R1,R2,R3和R4定义与式(I)中相同。
澳瑞他汀和多拉司他汀是优选的和桥连接体连接的细胞毒性剂。澳瑞他汀(如多澳瑞他汀E(AE),澳瑞他汀EB(AEB),澳瑞他汀EFP(AEFP),单甲基澳瑞他汀E(MMAE),单甲基澳瑞他汀F(MMAF),澳瑞他汀F苯二胺(AFP)和MMAE的苯丙氨酸变体)是多拉司他汀的类似物,在如下文献中有描述:Int.J.Oncol.1999,15,367-72;MolecularCancerTherapeutics,2004,3(8),921-932;美国专利申请11134826,20060074008,2006022925,美国专利4414205,4753894,4764368,4816444,4879278,4943628,4978744,5122368,5165923,5169774,5286637,5410024,5521284,5530097,5554725,5585089,5599902,5629197,5635483,5654399,5663149,5665860,5708146,5714586,5741892,5767236,5767237,5780588,5821337,5840699,5965537,6004934,6033876,6034065,6048720,6054297,6054561,6124431,6143721,6162930,6214345,6239104,6323315,6342219,6342221,6407213,6569834,6620911,6639055,6884869,6913748,7090843,7091186,7097840,7098305,7098308,7498298,7375078,7462352,7553816,7659241,7662387,7745394,7754681,7829531,7837980,7837995,7902338,7964566,7964567,7851437,7994135。抗体-澳瑞他汀通过桥连接体连接的偶联物结构的实例如Au01,Au02,Au03,Au04和Au05:
其中mAb是抗体;n为1~20;X3和X3’为独立的CH 2,O,NH,NHC(O),NHC(O)NH,C(O),OC(O)R1或缺省;X4和X4’是独立的CH2,C(O),C(O)NH,C(O)N(R1),R1,NHR1,NR1,C(O)R1或C(O)O;Z3和Z3’是独立的H,R1,OP(O)(OM1)(OM2),OCH2OP(O)(OM1)(OM2),NHR1,OSO3M1,R1或O-糖苷(糖苷,半乳糖苷,甘露糖苷,葡萄糖苷,果糖苷等),NH-糖苷,S-糖苷或CH2-糖苷;M1和M2独立地为H,Na,K,Ca,Mg,NH4,NR1R2R3R4;R1,R2,R3和R4定义与式(I)中相同。
苯并二氮卓二聚体(例如吡咯并苯二氮卓(PBD),托美霉素,吲哚并苯并二氮卓,咪唑并苯并噻二氮卓或恶唑烷并苯并二氮卓的二聚体)是本发明中优选的细胞毒性分子,在本领域的文献中也有描述:美国专利8,163,736;8,153,627;8,034,808;7,834,005;7,741,319;7,704,924;7,691,848;7,678,787;7,612,062;7,608,615;7,557,099;7,528,128;7,528,126;7,511,032;7,429,658;7,407,951;7,326,700;7,312,210;7,265,105;7,202,239;7,189,710;7,173,026;7,109,193;7,067,511;7,064,120;7,056,913;7,049,311;7,022,699;7,015,215;6,979,684;6,951,853;6,884,799;6,800,622;6,747,144;6,660,856;6,608,192;6,562,806;6,977,254;6,951,853;6,909,006;6,344,451;5,880,122;4,935,362;4,764,616;4,761,412;4,723,007;4,723,003;4,683,230;4,663,453;4,508,647;4,464,467;4,427,587;4,000,304;美国专利申请20100203007,20100316656,20030195196。抗体-苯并二氮卓二聚体偶联物结构的实例如PB01,PB02,PB03,PB04,PB05,PB06,PB07,PB08,PB09,PB10和PB11:
其中mAb是抗体;n为1~20;X3和X3’为独立的CH 2,O,NH,NR1,NHC(O),NHC(O)NH,C(O),C(O)R1,OC(O),OC(O)R1,C(O)N(R1),R1或缺省;X4和X4’是独立的CH2,C(O),C(O)NH,C(O)N(R1),C(O)O,R1或缺省;R1,R2,R3和R4定义与式(I)中相同。R3和/或R4也可以缺省。
用于和本发明的桥连接体连接的药物/细胞毒性剂,可以是前文描述的药物/分子的任何类似物和/或衍生物。应当理解,本文所述的每种药物/细胞毒性剂均可以被修饰,所得化合物仍保留相关特异性和/或活性。本领域技术人员还应理解,许多其他化合物也可代替本文所述的药物/细胞毒性剂。因此,本发明的药物/细胞毒剂还包括这些化合物的类似物和衍生物。
在此引用的以及下面的实施例中的全部文献纳入参考。
实施例
本发明用下面的实施例进一步地说明,这些实施例的内容并不旨在限制本发明的范围。在实施例中细胞系,除了特殊说明之外,均是依据美国标准培养物保藏中心(ATCC)、德国菌种保藏中心(DSMZ)或中国科学院上海细胞培养中心规范的条件保存。除了特殊说明外,细胞培养试剂来自于Invitrogen公司。所有的无水试剂均由商业途径获得,并储存于Sure-Seal密封瓶中。其他的试剂和溶剂均按照最高规格购买,使用时未经进一步的处理。Varian Prostar HPLC进行制备HPLC纯化。NMR数据在Varian Mercury 400MHz上获得,化学位移以ppm为单位,四甲基硅烷为参考(0ppm),耦合常数(J)的单位是Hz。质谱数据在WatersXevoQTof质谱仪(连接Waters Acquity UPLC高效液相色谱仪和TUV检测器)上获得。
例1.3-((苄氧基)氨基)丙酸叔丁酯(3)
在O-苄基羟基胺盐酸盐(10.0g,62.7mmol)的THF(100ml)溶液中加入Et3N(15ml)和丙烯酸叔丁酯(12.1g,94.5mmol)。将混合物回流过夜,浓缩后在SiO2柱上纯化,用EtOAc/正己烷(1:4)洗脱,得到标题化合物3(13.08g,83%收率)。1H NMR(CDCl3)7.49~7.25(m,5H),4.75(s,2H),3.20(t,J=6.4Hz,2H),2.54(t,J=6.4Hz,2H),1.49(s,9H);ESIMS m/z+C14H21NNaO3(M+Na),计算值.274.15,实测值274.20。
例2.3-(羟基氨基)丙酸叔丁酯(4)
在氢化反应器中,向化合物3(13.0g,51.76mmol)的甲醇(100ml)溶液中加入Pd/C(0.85g,10%Pd,50%湿)。氢气反应器抽真空后充入2atm氢气,将反应混合物在室温下搅拌过夜。粗反应物通过硅藻土过滤,用乙醇洗涤,浓缩滤液后在SiO2柱上纯化,用MeOH/DCM(1:10~1:5)洗脱,得到标题化合物(7.25g,87%收率)。1H NMR(CDCl3)3.22(t,J=6.4Hz,2H),2.55(t,J=6.4Hz,2H),1.49(s,9H);ESI MS m/z+C7H15NNaO3(M+Na),计算值.184.10,实测值184.30。
例3.3-((甲苯磺酰氧基)氨基)丙酸叔丁酯(5)
在4℃下向化合物4(5.10g,31.65mmol)在DCM(50ml)和吡啶(20ml)的混溶液中加入甲苯磺酰氯(12.05g,63.42mmol)。将混合物在室温下搅拌过夜,浓缩后在SiO2柱上纯化,用EtOAc/DCM(1:10~1:6)洗脱,得到标题化合物(8.58g,86%收率)。1HNMR(CDCl3)7.81(s,2H),7.46(s,2H),3.22(t,J=6.4Hz,2H),2.55(t,J=6.4Hz,2H),2.41(s,3H),1.49(s,9H);ESI MS m/z+C14H21NNaO5S(M+Na),计算值.338.11,实测值338.30。
例4.3,3'-(肼-1,2-二基)二丙酸二叔丁酯(7)
在叔丁基3-氨基丙酸酯6(3.05g,21.01mmol)的THF(80ml)溶液中加入3-((甲苯磺酰氧基)氨基)丙酸叔丁酯5(5.10g,16.18mmol)。将混合物在室温下搅拌1小时,然后在45℃下搅拌6小时。将反应物浓缩并在SiO2柱上纯化,用CH3OH/DCM/Et3N(1:12:0.01~1:8:0.01)洗脱,得到标题化合物(2.89g,62%产率)。ESI MS m/z+C14H28N2NaO4(M+Na),计算值311.20,实测值311.40。
例5.3,3'-(1,2-双(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰基)肼-1,2-二甲酸二叔丁酯-二基)二丙酸酯(13)
向3-马来酰基-丙酸(1.00g,5.91mmol)的DCM(50ml)溶液中加入草酰氯(2.70g,21.25mmol)和DMF(50μL)。将混合物在室温下搅拌2小时,旋干,并与DCM/甲苯共沸旋干,得到3-马来酰基-丙酰氯粗品。向化合物7(0.51g,1.76mmol)的DCM(35ml)溶液中加入3-马来酰基-丙酰氯粗品。将混合物搅拌过夜,浓缩并在SiO2柱上纯化,用EtOAc/DCM(1:15~1:8)洗脱,得到标题化合物13(738mg,71%收率)。ESI MS m/z+C28H38N4NaO10(M+Na),计算值613.26,实测值613.40。
例6.3,3'-(1,2-双(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)丙酰基)-肼-1,2-二基)二丙酸酸(14)
向化合物14(700mg,1.18mmol)的1,4-二氧六环(4ml)溶液中加入浓HCl(1ml),搅拌30分钟后,用乙醇(10mL)和甲苯(10mL)稀释,旋干并与乙醇(10mL)和甲苯(10mL)共沸蒸发,得到标题产物(560mg),粗品直接用于下一步无需进一步纯化。ESIMS m/z-C20H21N4O10(M-H),计算值.477.13,实测值477.20。
例7.双(2,5-二氧代吡咯烷-1-基)-3,3'-(1,2-双(3-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基))丙酰基)肼-1,2-二基)二丙酸酯(79)
向粗产物14(~560mg,~1.17mmol)的DMA(8ml)溶液中加入NHS(400mg,3.47mmol)和EDC(1.01g,5.26mmol)。将混合物搅拌过夜,浓缩后在SiO2柱上纯化,用EtOAc/DCM(1:12~1:7)洗脱,得到标题化合物79(520mg,2步收率65%)。ESI MSm/z+C28H28N6NaO14(M+Na),计算值.695.17,实测值695.40。
例8.3-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)丙酸叔丁酯(84)
搅拌下向350mL无水THF中加入80mg(0.0025mol)的金属钠和三乙二醇84(150.1g,1.00mol)。在钠完全溶解后,加入丙烯酸叔丁酯(24mL,0.33mol)。将该溶液在室温下搅拌20小时,并用8mL的1.0M HCl中和。将溶剂真空除去,残余物用盐水(250mL)稀释,用乙酸乙酯(3×125mL)萃取。用水(100mL)和盐水(100mL)洗涤合并的有机层,用硫酸钠干燥,除去溶剂。将所得无色油状物真空干燥,得到69.78g(产率76%)的产物85。1H NMR:1.41(s,9H),2.49(t,2H,J=6.4Hz),3.59-3.72(m,14H);ESI MS m/z-C13H25O6(M-H),计算值.277.17,实测值277.20。
例9.3-(2-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)乙氧基)丙酸叔丁酯(35)
在85(10.0g,35.95mmol)的乙腈(50.0mL)溶液中加入吡啶(20.0mL),然后在30分钟内通过加料漏斗滴加甲苯磺酰氯(7.12g,37.3mmol)的乙腈(50mL)溶液。5小时后,TLC分析显示反应完成。滤出形成的吡啶盐酸盐,除去滤液中的溶剂,将残余物在硅胶上纯化,用20%乙酸乙酯的正己烷溶液至纯乙酸乙酯洗脱,得到11.2g(76%产率)的化合物86。1HNMR:1.40(s,9H),2.40(s,3H),2.45(t,2H,J=6.4Hz),3.52-3.68(m,14H),4.11(t,2H,J=4.8Hz),7.30(d,2H,J=8.0Hz),7.75(d,2H,J=8.0Hz);ESI MS m/z+C20H33O8S(M+H),计算值433.18,实测值433.30。
例10.3-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)丙酸叔丁酯(87)
搅拌下向50mL DMF中加入3-(2-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)乙氧基)-丙酸叔丁酯86(4.0g,9.25mmol)和叠氮化钠(0.737g,11.3mmol)。将反应液加热至80℃。4小时后,TLC分析显示反应完成。将反应物冷却至室温并用水(25mL)淬灭,用乙酸乙酯(3×35mL)萃取。将合并的有机层用无水硫酸镁干燥,过滤,真空除去溶剂。叠氮化物87粗品(TLC纯度约90%)用于下一步反应,无需进一步纯化。1H NMR(CDCl3)1.40(s,9H),2.45(t,2H,J=6.4Hz),3.33(t,2H,J=5.2Hz),3.53-3.66(m,12H);ESI MS m/z+C13H26N3O8(M+H),计算值304.18,实测值304.20。
例11:13-氨基-4,7,10-三氧杂十二烷酸叔丁酯(88);13-氨基-双(4,7,10-三氧杂十二烷酸叔丁酯)(89)
将叠氮化物87粗品(5.0g,~14.84mmol)溶于乙醇(80mL)中并加入300mg 10%Pd/C。氢气反应器抽真空后充入2atm氢气。然后将反应在室温下搅拌过夜,TLC显示起始物质消失。粗反应物通过硅藻土过滤,用乙醇洗涤,浓缩滤液后在SiO2柱上纯化,使用甲醇(5%至15%)和1%三乙胺的二氯甲烷混合物作为洗脱液,得到13-氨基-4,7,10-三氧杂十二烷酸叔丁酯88(1.83g,产率44%,ESI MS m/z+C13H27NO5(M+H),计算值278.19,实测值278.30)和13-氨基-双(4,7,10-三氧杂十二烷酸叔丁酯)89(2.58g,收率32%,ESIMS m/z+C26H52NO10(M+H),计算值538.35,实测值538.40)。
例12.3-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)丙酸盐酸盐(90)
在搅拌下,向13-氨基-4,7,10-三氧杂十二烷酸叔丁酯88(0.80g,2.89mmol)的1,4-二氧六环(30ml)溶液中加入10ml浓HCl。0.5小时后,TLC分析显示反应完成,将反应混合物浓缩,并与EtOH和EtOH/甲苯共沸旋干,形成HCl盐形式的标题产物(>90%纯度,0.640g,86%收率),无需进一步纯化。ESI MS m/z+C9H20NO5(M+H),计算值222.12,实测值222.20。
例13:13-氨基-双(4,7,10-三氧杂十二烷酸)盐酸盐(91)
在搅拌下,向13-氨基-双(4,7,10-三氧杂十二烷酸叔丁酯)89(1.00g,1.85mmol)的1,4-二氧六环(30ml)溶液中加入10ml浓HCl。0.5小时后,TLC分析显示反应完成,将反应混合物浓缩,并与EtOH和EtOH/甲苯共沸旋干,形成HCl盐形式的标题产物(纯度>90%,0.71g,91%收率),无需进一步纯化。ESI MS m/z+C18H36NO10(M+H),计算值426.22,实测值426.20。
例14.(S)-2-(甲氨基)丙酸美登醇酯
将美登醇(200mg,0.354mmol)溶于DMF(5ml)和THF(3ml)中,冰水浴冷却,加入DIPEA(0.3ml),三氟甲磺酸锌(380mg,1.05mmol)和3,4-二甲基恶唑烷-2,5-二酮(92mg,0.71mmol)。将反应混合物在室温氩气下搅拌过夜,用EtOAc(20mL)稀释,用1:1盐水/饱和碳酸氢钠溶液(8mL)洗涤。水相中滤出白色沉淀,将得到的溶液用EtOAc(2×10mL)萃取。合并有机层,用盐水洗涤,浓缩后在C-18制备HPLC上纯化,用MeOH/水(在45分钟内10%至65%MeOH,Φ50mmx250mm,v=80ml/min)洗脱,得到标题化合物(156mg,产率68%)。ESI MS m/z+C32H45ClN3O9(M+H),计算值650.28,实测值650.20。
例15.(2S,2'S)-2,2'-((3,3'-(1,2-双(3-(马来酰亚胺基)丙酰基)肼-1,2-二基)双(丙酰基))双甲基二烷二基))二丙酸二美登醇酯(108)
向(S)-2-(甲基氨基)丙酸美登醇酯(150mg,0.231mmol)和3,3'-(1,2-双(马来酰基)丙酰基)-肼-1,2-二基)二丙酸14(50mg,0.104mmol)的DMA(10ml)溶液中加入EDC(300mg,1.56mmol)。将混合物搅拌过夜,浓缩后在C-18制备HPLC上纯化,用MeOH/水(在45分钟内10%至85%MeOH,Φ20mm×250mm,v=20ml/min)洗脱,得到标题化合物108(115mg,收率63%)。ESI MS m/z+C84H107Cl2N10O26(M+H),计算值1741.67,实测值1741.90。
例16.3,3'-(1,2-双(3-(马来酰亚胺基)丙酰基)肼-1,2-二基)二(N-MMAF丙酰胺)
向搅拌的3,3'-(1,2-双(马来酰基)丙酰基)-肼-1,2-二基)二-丙酸14(50mg,0.104mmol)的DCM(4ml)溶液中加入草酰氯(0.4ml,2M DCM溶液,0.8mmol)和DMF(10μl)中。将混合物在室温下搅拌2小时,旋干,并与DCM/甲苯共沸旋干,获得3,3'-(1,2-双(马来酰基)丙酰基)-肼-1,2-二基)二丙酸酰氯107粗品。向MMAF 110(160mg,0.219mmol)的DCM(5ml)溶液中加入酰氯107粗品,将混合物搅拌过夜,浓缩后用C-18制备HPLC纯化,用MeOH/水(45分钟内10%至85%MeOH,Φ20mm×250mm,v=20ml/分钟)洗脱,得到标题化合物111(98mg,49%收率)。ESI MS m/z+C98H149Cl2N14O24(M+H),计算值1906.08,实测值1906.50。
例17:3,3'-(1,2-双(3-(马来酰亚胺基)丙酰基)肼-1,2-二基)双(N-微管蛋白类似物的丙酰胺)(119)
向搅拌的3,3'-(1,2-双(马来酰基)丙酰基)-肼-1,2-二基)二-丙酸14(50mg,0.104mmol)的DCM(4ml)溶液中加入草酰氯(0.4ml,2M DCM溶液,0.8mmol)和DMF(10μLl)中。将混合物在室温下搅拌2小时,旋干并与DCM/甲苯共沸旋干,获得2,3'-(1,2-双(马来酰基)丙酰基)-肼-1,2-二基)二丙酸酰氯107粗品。向(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶戊酰氨基)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(3-氨基-4-羟基苯基)-2-甲基戊酸118((Huang Y.et al,Med Chem.#44,249th ACS NationalMeeting,Denver,CO,Mar.22~26,2015;WO2014009774)(172mg,0.226mmol)的DCM(5ml)溶液中加入酰氯107粗品。将混合物搅拌过夜后浓缩,在C-18制备HPLC上纯化,用MeOH/水(在45分钟内10%至80%MeOH,Φ20mm×250mm,v=20ml/min)洗脱,得到标题化合物119(106mg,产率52%)。ESI MS m/z+C97H139Cl2N16O24S2(M+H),计算值.1975.95,实测值1976.50。
例15.化合物108,111或119和抗体共轭偶联得109,112或120
向赫赛汀溶液(2.0mL 10mg/ml pH7.0-8.0)中加入pH 6.5-7.5缓冲液(0.70-2.0mL100mM NaH2PO4),TCEP(28μL,20mM水溶液)和化合物108,111或119(14μL,20mMDMA溶液)。将混合物在室温温育2-16小时,然后加入DHAA(135μL,50mM)。在室温下温育过夜后,将混合物在G-25柱上纯化,用100mM NaH2PO4,50mM NaCl pH6.0~7.5的缓冲液洗脱,得到结合物化合物109,112或120(13.0~15.6ml缓冲液中)。用UPLC-QTof质谱确定药物/抗体比率(DAR)。SEC HPLC(Tosoh Bioscience,TskgelG3000SW,7.8mm ID x 30cm,0.5ml/min,100min)分析显示95~99%单体含量,并且SDS-PAGE凝胶测量显示单一条带。
偶联物109,15.8mg(产率79%),DAR 3.90,95%单体;偶联物112,16.7mg(83%产率),DAR 3.95,96%单体;偶联物120,16.3mg(产率81%),DAR 3.96,97%单体。
例18.偶联物109,112和120的体外细胞毒性评估(对比T-DM1):
细胞毒性实验中使用的细胞系包括HL-60,一种人类早幼粒细胞白血病细胞系,NCI-N87,一种人类胃癌细胞系,BT-474,为一种人浸润性导管癌细胞系,和SKOV3,为一种人类卵巢癌细胞系。对于HL-60,NCI-N87和BT-474细胞,这些细胞生长在含10%FBS的RPMI–1640培养基。对于SKOV3细胞,细胞生长在含10%FBS的McCoy 5A培养基。运行试验时,细胞(180μl,6000细胞)被添加到96孔板并且在37oC和5%二氧化碳的环境中孵育24小时,之后用不同浓度的化合物(20μL)来处理这些细胞(总体积0.2mL)。对照孔包含细胞和培养基,无测试化合物。孔板在37oC和5%的二氧化碳的环境中孵育120小时后,向其中加入MTT(5mg/mL),在37℃孵化1.5小时。小心的去除培养基后加入DMSO(180μL),震荡15分钟,用620nm参比滤器在490nm和570nm测量吸光度。依照以下公式计算抑制率:
抑制率%=[1-(分析值-空白对照值)/(控制值-空白对照值)]×100%
细胞毒性结果:
所有三种偶联物都比T-DM1更有效。偶联物109对N87细胞的特异性超过93,对SK-OV-3细胞超过127;偶联物112对N87细胞的特异性超过99,对SK-OV-3细胞超过113;偶联物120对N87细胞的特异性超过105,SK-OV-3细胞超过136;偶联物T-DM1对N87细胞的特异性超过56,对SK-OV-3细胞超过84。
Claims (29)
1.结构如(I)所示的桥连接体,用于制备细胞结合剂和细胞毒性剂的偶联物:
其中:
Y1和Y2是相同的或不同的官能团,可以与细胞结合剂上的一对硫原子反应,形成二硫化物,硫醚或巯酯键。优选的Y1和Y2为,但不限于N-羟基琥珀酰亚胺酯,马来酰亚胺基,二硫化物,卤代乙酰基,酰卤,乙烯磺酰基,丙烯酰基,2-(对甲苯磺酰氧基)乙酰基,2-(甲磺酰氧基)乙酰基,2-(硝基苯氧基)乙酰基,2-(二硝基苯氧基)乙酰基,2-(氟苯氧基)乙酰基,2-(二氟苯氧基)乙酰基,2-(五氟苯氧基)乙酰基,2-(三氟甲磺酸氧基)乙酰基,和/或酸酐基团,其结构如下:
N-羟基琥珀酰亚胺酯;马来酰亚胺基;二硫化物;卤代乙酰基;酰卤或酯;乙烯磺酰基;丙烯酰基;2-(对甲苯磺酰氧基)乙酰基;2-(甲磺酰氧基)乙酰基;2-(硝基苯氧基)乙酰基;2-(二硝基苯氧基)乙酰基;2-(氟苯氧基)乙酰基;2-(二氟苯氧基)乙酰基;2-(五氟苯氧基)乙酰基;2-(三氟甲磺酸氧基)乙酰基;甲磺酸噁二唑苯基(ODA);酸酐。其中,X1是F,Cl,Br,I或离去基团;X2是O,NH,N(R1)或CH2;R5是R1,芳基,杂芳基或一个或多个H独立地被-R1、卤素、-OR1、-SR1、-NR1R2、-NO2、-S(O)R1、-S(O)2R1或-COOR1所取代的芳基;离去基团包括硝基苯酚、N-羟基琥珀酰亚胺(NHS)、苯酚、二硝基苯酚、五氟苯酚、四氟苯酚、二氟苯酚、单氟苯酚、五氯苯酚、三氟甲基磺酸、咪唑、二氯苯酚、四氯苯酚、1-羟基苯并三氮唑、对甲苯磺酸、甲磺酸、2-乙基-5-苯基异恶唑-3'-磺酸,自我酸酐,或与其他酸酐如乙酰酐、甲酸酐生成的酸酐,或多肽缩合反应或Mitsunobu反应中间体。
Z1和Z2是相同的或不同的能和细胞毒性药物反应的官能团,Z1和Z2与细胞毒性药物反应生成二硫键、醚键、酯键、硫醚键、硫酯键、肽键、腙键、氨基甲酸酯键、碳酸酯键、胺键(二级,三级或四级)、亚胺键、杂环烷基、杂芳基、烷氧肟键或酰胺键;此类官能团包括巯基,二硫基,氨基,羧基,醛基,羰基,马来酰亚胺基,卤代乙酰基,肼基,烷氧氨基,和/或羟基。能和药物或细胞毒性分子末端氨基反应的官能团Z1和Z2独立选自:羧基卤化物(酰卤),N-羟基琥珀酰亚胺酯,对硝基苯酚酯,二硝基苯酚酯,五氟苯酚酯,或者和四氟苯酚,二氟苯酚,单氟苯酚,五氯苯酚,三氟甲磺酸,咪唑,二氯苯酚,四氯苯酚,1-羟基苯并三氮唑,对甲苯磺酸,甲磺酸,2-乙基-5-苯基异恶唑-3'-磺酸形成的酯;或与乙酰酐,甲酸酐形成的酸酐形;或与多肽缩合剂或Mitsunobu反应形成的中间体。能和末端巯基反应的官能团可选自吡啶二硫基,硝基吡啶二硫基,马来酰亚胺基,卤代乙酸酯,羧酸酰氯。能和末端羰基或醛基反应的官能团选自氨基,烷氧氨基,联胺,乙酰氧氨基。能和末端叠氮基反应的官能团选自炔基。
R1,R2,R3和R4是相同的、不同的或缺省的含1~8个碳原子的直链烷基,3到8个碳原子的支链或环烷基,直链、支链或环烯基或炔基,或1~8个碳原子的酯基、醚基、酰胺基或聚乙氧基(OCH2CH2)p,其中p是0到约1000的整数,或这些基团的组合。
另外,R1,R2,R3和R4是包含C,N,O,S,Si,和P原子的链状结构,最优含0~500个原子,共价连接于Y1或Y2和Z1或Z2;R1,R2,R3和R4中的各个原子以所有可能的化学方式结合,比如形成烷基、亚烷基、亚烯基、亚炔基、醚、聚氧烷基、酯、胺、亚胺、聚胺、肼、腙、酰胺、脲、氨基脲、卡巴肼、烷氧胺、聚氨酯、氨基酸、多肽、酰氧胺、异羟肟酸,或这些基团的组合。
2.结构如式(II)的细胞结合剂-药物偶联物:
其中:
Cb为细胞结合剂,最优为抗体。
Drug1和Drug2为相同的或不同的细胞毒性剂,它们通过桥连接体以烷基、亚烷基、亚烯基、亚炔基、醚、聚烷氧基、酯、胺,亚胺,聚胺、肼、腙、酰胺、脲、氨基脲、卡巴肼、烷氧基胺、氨基甲酸酯、氨基酸、肽、酰氧胺、异羟肟酸、二硫键、硫醚、硫酯、氨基甲酸酯、碳酸酯、杂环、杂烷基、杂芳基或烷氧肟键及其组合与细胞结合剂连接。
括号内的是连接体-药物组分,它通过一对硫原子(巯基)和细胞结合剂相偶联。可以进行偶联反应的硫原子对通常是细胞结合剂上双硫键被TCEP或DTT还原所产生。
n是1~20;R1,R2,R3和R4的定义同权利要求1。
3.结构如式(III)的化合物:
其中Cb,Z1,Z2,n,R1,R2,R3和R4的定义同权利要求1和2。
4.结构如式(IV)的化合物:
其中Y1,Y2,Drug1,Drug2,R1,R2,R3和R4的定义同权利要求1和2。
5.权利要求1中结构如式(I)的桥连接体,其中联胺组分通过联胺和酸、酰卤或酸酐反应得到,然后再引入能与细胞结合剂和药物分子反应的官能团。通常联胺上的取代基都可以和连接体组分R1,R2,R3和R4缩合,其上连接官能团Y1,Y2,Z1或Z2,与巯基和/或药物分子反应。
6.在权利要求2和4中,公式(II)和(IV)里的Drug1和Drug2相同或各自独立选自:
1)化疗剂:a)烷基化剂,如氮芥:氯苯那普,氯普那嗪,环磷酰胺,达卡巴嗪,雌二醇氮芥,异环磷酰胺,氮芥,盐酸二甲氧胺,氧化二氮芥,盐酸氨氯地平,麦考酚酸,卫矛醇,哌泊溴烷,新氮芥,苯芥胆甾醇,松龙苯芥,噻替哌,曲磷胺对,尿嘧啶;CC-1065(包括其阿多来新,卡折来新和比折来新合成类似物);多卡霉素(包括合成类似物KW-2189和CBI-TMI);苯并二氮卓二聚体(例如吡咯并苯二氮卓(PBD)或托美霉素,吲哚并苯并二氮卓,咪唑并苯并噻二氮卓或恶唑烷并苯并二氮卓的二聚体);亚硝基脲(卡莫司汀,洛莫司汀,氯化梭菌素,福莫司汀,尼莫司汀,拉莫司汀);烷基磺酸盐(白消安,硫丹,硫丹和硫磺);三氮烯(达卡巴嗪);含铂化合物(卡铂,顺铂,奥沙利铂);吖丙啶类,如苯并二氢吡喃酮,卡洛酮,美妥替派和乌雷多巴;乙烯亚胺和甲基三聚氰胺,包括六甲蜜胺,三亚乙基三胺,三乙基磷酰胺,三亚乙基硫代磷酰胺和三羟甲基甲基胺;b)植物生物碱,如长春花生物碱(长春新碱,长春碱,长春地辛,长春瑞滨,去甲长春碱);类紫杉醇(紫杉醇,多西紫杉醇)及其类似物;美登素生物碱(DM1,DM2,DM3,DM4,美登素和安沙霉素)及其类似物;cryptophycin(特别是cryptophycin 1和cryptophycin 8);埃博霉素,软珊瑚醇,迪莫利德,草苔虫内酯,海兔毒素,奥瑞他汀,tubulysin,cephalostatin,pancratistatin,sarcodictyin,海绵抑制素;c)DNA拓扑异构酶抑制剂,例如依托泊苷替尼(9-氨基喜树碱,喜树碱,克立那托,道诺霉素,依托泊苷,磷酸依托泊苷,伊立替康,米托蒽醌,诺消灵,视黄酸(视黄醇),替尼泊苷,拓扑替康,9-硝基喜树碱(RFS 2000));丝裂霉素(丝裂霉素C);d)抗代谢物,例如抗叶酸剂,DHFR抑制剂(甲氨蝶呤,曲麦克特,二甲叶酸,蝶罗呤,氨喋呤(4-氨基苯甲酸)或其他叶酸类似物);IMP脱氢酶抑制剂(麦考酚酸,噻唑呋林,利巴韦林,EICAR);核糖核苷酸还原酶抑制剂(羟基脲,去铁胺);嘧啶类似物,尿嘧啶类似物(安西他滨,阿扎胞苷,6-氮尿嘧啶,卡培他滨(希罗达),卡莫氟,阿糖胞苷,双脱氧尿苷,去氧氟尿苷,依诺他滨,5-氟尿嘧啶,氟尿苷,ratitrexed(Tomudex);胞嘧啶类似物(阿糖胞苷,胞嘧啶阿拉伯糖苷,氟达拉滨);嘌呤类似物(硫唑嘌呤,氟达拉滨,巯嘌呤,硫胺素,硫鸟嘌呤);叶酸补充剂,如弗洛林酸;e)激素疗法剂,如受体拮抗剂,抗雌激素(甲地孕酮,雷洛昔芬,他莫昔芬),LHRH兴奋剂(戈斯他林,醋酸亮丙瑞林);抗雄激素药(比卡鲁胺,氟他胺,卡鲁司酮,丙酸倍他雄酮,表雄甾醇,戈舍瑞林,亮丙瑞林,美替利定,尼鲁米特,睾内酯,曲洛司坦及其他雄激素抑制剂);维甲类化合物,维生素D3类似物(CB1093,EB1089KH1060,胆钙化醇,麦角钙化甾醇);光动力疗法剂(维替泊芬,酞菁,光敏剂Pc4,去甲氧基-竹红菌素A);细胞因子(干扰素-α,干扰素-γ,肿瘤坏死因子(TNF),含TNF的人蛋白);f)激酶抑制剂,如BIBW 2992(抗-EGFR/Erb2),伊马替尼,吉非替尼,哌加他尼,索拉非尼,达沙替尼,舒尼替尼,厄洛替尼,尼洛替尼,拉帕替尼,阿西替尼,帕唑帕尼,凡德他尼,E7080(抗VEGFR2),mubritinib,普纳替尼(AP24534),bafetinib(INNO-406),bosutinib(SKI-606),卡博替尼,维莫德吉,iniparib,鲁索利替尼,CYT387,阿西替尼,tivozanib,索拉非尼,贝伐单抗,西妥昔单抗,曲妥珠单抗,雷珠单抗,帕尼单抗,伊斯平斯;g)抗生素,如烯二炔类抗生素(加利车霉素,特别是加利车霉素γ1,δ1,α1和β1(参考J.Med.Chem.1996,39(11),2103-2117;Angew Chem Intl.Ed.Engl.1994,33:183-186),达因霉素,包括达因霉素A和脱氧米霉素,埃斯培拉霉素,卡达霉素,C-1027,maduropeptin以及新制癌菌素发色团和相关色蛋白烯二炔抗生素发色团),aclacinomysins,放线菌素,安曲霉素,重氮丝氨酸,博来霉素,卡诺霉素,卡拉霉素,洋红霉素,嗜癌素,阿霉素,阿霉素,吗啉代阿霉素,2-吡咯啉阿霉素和脱氧柔红霉素,表柔比星,阿柔比星,伊达比星,马可霉素,霉素,霉酚酸,洛匹霉素,培洛霉素,培洛霉素,嘌呤霉素,三铁阿霉素,阿霉素,链脲霉素,链脲佐菌素,杀结核菌素,乌苯美司,净司他丁,佐柔比星;h)其他,如聚酮化合物(番荔素),特别是bullatacin和bullatacinone;吉西他滨,环氧酶素(如卡菲偌米布),硼替佐米,沙利度胺,来那度胺,pomalidomide,tosedostat,zybrestat,PLX4032,STA-9090,Stimuvax,allovectin-7,Xegeva,Provenge,Yervoy,异戊二烯化抑制剂(如洛伐他汀),多巴胺能神经毒素(如星形孢菌素),放线菌素(如放线菌素D,更生霉素),博莱霉素(如博来霉素A2,博莱霉素B2,培洛霉素),蒽环类抗生素(如柔红霉素),阿霉素(亚德里亚霉素),伊达比星,表柔比星,吡柔比星,佐柔比星,米托蒽醌,MDR抑制剂(如维拉帕米),Ca2+ATP酶抑制剂(如毒胡萝卜素),组蛋白去乙酰酶抑制剂(伏立诺他,罗米地辛,帕比司他,丙戊酸,Mocetinostat(MGCD0103),Belinostat,PCI-24781,恩替诺特,SB939,Resminostat,Givinostat,AR-42,CUDC-101,萝卜硫素,曲古抑菌素A);塞来昔布,格列酮类,表没食子儿茶素没食子酸酯,双硫仑,Salinosporamide A;抗肾上腺药物,如氨鲁米特,米托坦,曲洛司坦,醋葡醛内酯,醛磷酰胺,氨基乙酰丙酸,安吖啶,阿拉伯糖苷,bestrabucil,比生群,edatraxate,defofamine,美可辛,地吖醌,依氟鸟氨酸(DFMO),elfomithine,依利醋铵,乙基葡糖酸,硝酸镓,胞嘧啶,羟基脲,伊班膦酸盐,香菇多糖,氯尼达明,米托胍腙,米托蒽醌,莫哌达醇,二胺硝吖啶,喷司他丁,蛋氨氮芥,吡柔比星,鬼臼酸,2-乙肼,甲基苄肼;哌嗪二酮丙烷;根霉素;西佐;螺环锗;细格孢氮杂酸;三亚胺醌;三氯三乙胺;单端孢霉烯(特别是T-2毒素,疣孢菌素A,杆孢菌素A和anguidine),聚氨酯,siRNA和反义药物。
2)自身免疫疾病药物:环孢菌素,环孢菌素A,氨基己酸,硫唑嘌呤,溴隐亭,苯丁酸氮芥,氯喹,环磷酰胺,皮质类固醇(例如安西奈德,倍他米松,布地奈德,氢化可的松,氟尼缩松,丙酸氟替卡松,氟可龙达那唑,地塞米松,曲安奈德,二丙酸倍氯米松),DHEA,依那西普,羟基氯喹,英夫利昔单抗,美洛昔康,甲氨蝶呤,麦考酚酸酯,泼尼松,西罗莫司,他克莫司。
3)抗感染性疾病药物:a)氨基糖苷类:阿米卡星,阿司米星,庆大霉素(奈替米星,西索米星,异帕米星),潮霉素B,卡那霉素(阿米卡星,阿贝卡星,氨基去氧卡那霉素,地贝卡星,妥布霉素),新霉素(framycetin,巴龙霉素,核糖霉素),奈替米星,壮观霉素,链霉素,妥布霉素,甲基姿苏霉素;b)酰胺醇类:叠氮氯霉素,氯霉素,氟苯尼考,甲砜霉素;c)安沙霉素:格尔德霉素,除莠霉素;d)碳青霉烯类:比阿培南,多利培南,厄他培南,亚胺培南/西司他丁,美罗培南,帕尼培南;e)头孢烯:碳头孢烯(洛拉卡比),头孢乙腈,氯氨苄青霉素,头孢拉定,头孢羟氨,头孢洛宁,头孢噻啶,头孢噻吩或头孢金素,头孢氨苄,头孢来星,头孢孟多,头孢匹林,羟胺唑头孢菌素,氟唑头孢菌素,孢西酮,唑啉头孢菌素,头孢拉宗,头孢卡品,头孢达肟,头孢吡,头孢克肟,头孢西丁,头孢罗齐,头孢甲氧环烯胺,头孢替唑,头孢呋辛,头孢克肟,头孢地尼,头孢托仑,头孢吡,头孢他美,头孢甲肟,头孢地嗪,头孢尼西,头孢哌酮,头孢雷特,头孢噻肟,噻乙胺唑头孢菌素,头孢唑兰,头孢氨苄,头孢咪唑,头孢匹胺,头孢匹罗,头孢泊肟,头孢罗齐,头孢喹诺,头孢磺啶,头孢他啶,头孢特仑,头孢布腾,头孢噻林,头孢唑肟,头孢吡普,头孢曲松,头孢呋辛,头孢唑南,头霉素(头孢西丁,头孢替坦,头孢氰唑),氧(碳)头孢烯(氟氧头孢,头孢);f)糖肽:博来霉素,万古霉素(奥利万星,特拉万星),替考拉宁(达巴万星),雷莫拉宁,g)甘氨酰环素:如替加环素,h)β-内酰胺酶抑制剂:青霉烷(舒巴坦,他唑巴坦),氧青霉烷(克拉维酸);i)林可酰胺:克林霉素,林可霉素;j)脂肽:达托霉素,A54145,钙依赖性抗生素(CDA);k)大环内酯类:阿奇霉素,克霉素,克拉霉素,地红霉素,红霉素,氟雷霉素,交沙霉素,酮内酯(泰利霉素,塞红霉素),麦迪霉素,米卡霉素,竹桃霉素,利福霉素(异烟肼、利福平,利福布丁,利福喷汀),罗匹霉素,罗红霉素,大观霉素,螺旋霉素,他克莫司(FK506),醋竹桃霉素,泰利霉素;l)单环胺:氨曲南,替吉莫南;m)恶唑烷酮类:利奈唑胺;n)青霉素类:阿莫西林,氨苄青霉素(匹氨西林,海洛西林,巴氨西林,氨苄青霉素,阿霉素),阿替代西林,阿洛西林,苄青霉素,苄星青霉素苄青霉素,苄星青霉素苯氧甲基青霉素,克洛西林,普鲁卡因青霉素(美替西林),美洛西林,甲氧西林,萘夫西林,苯唑西林,醋甲西林,青霉素,非奈西林,苯氧基甲基青霉素,哌拉西林,氨苄西林,磺苯西林,替莫西林,替卡西林;o)多肽:杆菌肽,粘菌素,多粘菌素B,p)喹诺酮类:阿拉曲沙星,巴洛沙星,环丙沙星,克林沙,达氟沙星,二氟沙星,依诺沙星,恩诺沙星,加雷沙星,加替沙星,吉米沙星,格帕沙星,卡诺曲伐沙星,左氧氟沙星,洛美沙星,麻保沙星,莫西沙星,那氟沙星,诺氟沙星,奥比沙星,氧氟沙星,培氟沙星,曲伐沙星,格帕沙星,西他沙星,司帕沙星,替马沙星,托沙星,曲伐沙星;q)链阳性菌素:普那霉素,奎奴普丁/达福普汀,r)磺胺类药物:磺胺类药物:磺胺类药物,磺胺嘧啶,磺胺嘧啶,磺胺嘧啶,柳氮磺胺吡啶,磺胺异恶唑,三苯氧胺,甲氧苄氨嘧啶-磺胺甲恶唑(复方新诺明);s)类固醇抗菌药物:如夫西地酸;t)四环素类:强力霉素,金霉素,氯米西环素,地美环素,雷莫昔林,美西环素,美他环素,米诺环素,土霉素,青霉素V钾哌四环素,吡咯烷甲基四环素,四环素,甘氨酰环素(如替加环素):u)其他类型的抗生素:番荔枝素,胂凡纳明,细菌萜醇抑制剂(杆菌),DANAL/AR抑制剂(环丝氨酸),dictyostatin,圆皮海绵内酯,软珊瑚醇,埃博霉素,乙胺丁醇,依托泊苷,法罗培南,夫西地酸,呋喃唑酮,异烟肼,laulimalide,甲硝唑,莫匹罗星,NAM合成抑制剂(例如磷霉素),呋喃妥因,紫杉醇,普兰西霉素,吡嗪酰胺,奎奴普丁/达福普汀,利福平(利福平),他唑巴坦替硝唑,乌菊花素。
4)抗病毒药物:a)进入/融合抑制剂:阿帕韦洛,马拉韦罗,vicriviroc,gp41((恩夫韦肽),PRO 140,CD4(艾巴利珠单抗);b)整合酶抑制剂:雷特格韦,elvite-gravir,globoidnan A;c)成熟抑制剂:bevirimat,vivecon;d)神经氨酸酶抑制剂:奥司他韦,扎那米韦,帕拉米韦;E)核苷和核苷酸:阿巴卡韦,阿昔单韦,阿德福韦,阿莫西韦,阿昔单抗,溴夫定,西多福韦,克拉夫定,地塞米松,去羟肌苷(ddI),elvucitabine,恩曲他滨(FTC),恩替卡韦,泛昔洛韦,氟拉西林(5-FU),3’-氟取代的2’,3’-脱氧核苷类似物(如3,3’-氟-2′,3′-双脱氧胸苷(FLT)和3’-氟-2’,3’-双脱氧鸟苷(FLG),福米韦生,9-鸟嘌呤,碘苷,拉米夫定(3TC),1-核苷(例如β-1-胸苷和β-1-2'-脱氧胞苷),喷昔洛韦,racivir,利巴韦林,迪替丁,司他夫定(d4T),塔利巴韦林(viramidine),替比夫定,替诺福韦,三氟尿苷伐昔洛韦,缬更昔洛韦,扎西他滨(ddC),齐多夫定(AZT);f)非核苷类:金刚烷胺,阿替吡啶,卡普韦林,二芳基嘧啶(依曲韦林,rilpivirine),地拉夫定,二十二烷醇,乙米韦林,依法韦仑,膦甲酸(磷酰基甲酸),咪喹莫特,聚乙二醇干扰素,洛韦胺,洛德腺苷,甲吲噻腙,奈韦拉平,NOV-205,长效干扰素α,鬼臼毒素,利福平,金刚乙胺,瑞喹莫德(R-848),醋胺金刚烷;g)蛋白酶抑制剂:安普那韦阿扎那韦,boceprevir,darunavir,福沙那韦,印地那韦,洛匹那韦,奈非那韦,普来可那立,利托那韦,沙奎那韦,telaprevir(VX-950),替拉那韦;h)其它类型的抗病毒药物:抗氧化酶,阿比朵尔,卡拉诺莱德,ceragenin,氰维林-n,二芳基嘧啶,表没食子儿茶素没食子酸酯(EGCG),膦甲酸,格里菲辛,taribavirin(viramidine),羟基脲,KP-1461,米替福新,普来可那立,混成抑制剂,利巴韦林,seliciclib。
5)放射性同位素(放射性核素),选自3H,11C,14C,18F,32P,35S,64Cu,68Ga,86Y,99Tc,111In,123I,124I,125I,131I,133Xe,177Lu,211At或213Bi。
6)发色分子,可以吸收一种光,如紫外光,荧光,红外光,近红外光或可见光;黄色素,红细胞,虹彩色素,白细胞,黑色素和蓝绿色素的一类或一个亚类,荧光分子(吸收光后再发光的荧光化学物质)的一类或一个亚类,视觉光转导分子,光子分子,冷光分子和荧光素化合物;非蛋白质有机荧光团,例如氧杂蒽衍生物(荧光素,罗丹明,俄勒冈绿,伊红和德克萨斯红);花青衍生物(花青,吲哚羰花青,氧杂花青,硫代花青和部花青);方酸衍生物和环取代的方酸,包括Seta,SeTau和Square染料;萘衍生物(丹酰和氟硅酸钠衍生物);香豆素衍生物;恶二唑衍生物(吡啶基恶唑,硝基苯并恶唑和苯并恶二唑);蒽衍生物(蒽醌类,包括DRAQ5,DRAQ7和CyTRAK橙);芘衍生物(级联蓝等);恶嗪衍生物(尼罗红,尼罗蓝,甲酚紫,恶嗪170等);吖啶衍生物(黄醇黄素,吖啶橙,吖啶黄等);芳基甲胺衍生物(金胺,结晶紫,孔雀石绿)和四吡咯衍生物(卟吩,酞菁,胆红素);下列荧光化合物的类似物和衍生物:CF染料(Biotium),DRAQ和CyTRAK探针(BioS-tatus),BODIPY(Invitrogen),Alexa Fluor(Invitrogen),DyLight Fluor(Thermo Scientific,Pierce),Atto和Tracy(SigmaAldrich),FluoProbes(Interchim),Abberior染料(Abberior),DY和MegaStokes染料(Dyomics),Sulfo Cy染料(Cyandye),HiLyte Fluor(AnaSpec),Seta,SeTau和Square染料(Biosearch Technologies),SureLight染料(APC,RPEPerCP,Phycobilisomes)(ColumbiaBiosciences),APC,APCXL,RPE,BPE(Phyco-Biotech),别藻蓝蛋白(APC),氨基胭脂蛋白,APC-Cy7偶联物,BODIPY-FL,Cascade Blue,Cy2,Cy3,Cy3.5,Cy3B,Cy5,Cy5.5,Cy7,荧光素,FluorX,羟基香豆素,丽丝胺罗丹明B,萤光黄,Me-甲氧基香豆素,NBD,Pacific Blue,Pacific Orange,PE-Cy5偶联物,PE-R-藻红蛋白(PE),Red 613,Seta-555-Azide,Seta-555-DBCO,Seta-555-NHS,Seta-580-NHS,Seta-680-NHS,Seta-APC-780,Seta-PerCP-680,Seta-R-PE-670,SeTau-380-NHS,SeTau-405-马来酰亚胺,SeTau-405-NHS,SeTau-425-NHS,SeTau-647-NHS,Texas Red,TRITC,TruRed,X-Rhodamine,7-AAD(7-氨基放线菌素D,CG-选择性的),吖啶橙,色霉素A3,CyTRAK橙(Biostatus),DAPI,DRAQ5,DRAQ7,溴化乙锭,Hoechst33258,Hoechst33342,LDS 751,光辉霉素,碘化丙啶(PI),SYTOX蓝,SYTOX绿,SYTOX橙,噻唑橙,TO-PRO,菁染料单体,TOTO-1,TO-PRO-1,TOTO-3,TO-PRO-3,YOSeta-1,YOYO-1。可以与本发明的连接体相连,用于研究细胞的荧光化合物,选自下列化合物或其衍生物:DCFH(2',7'-二氯二氢荧光素,氧化形式),DHR(二氢罗丹明123,氧化形式,光催化氧化),Fluo-3(AM酯,pH>6),Fluo-4(AM酯,pH7.2),Indo-1(AM酯,低/高钙(Ca 2+)),SNARF(pH 6/9)。优选的荧光化合物选自:别藻蓝蛋白(APC),AmCyan1(四聚体,Clontech),AsRed2(四聚体,Clontech),蓟绿(单体,MBL),Azurite,B-藻红蛋白(BPE),Cerulean,CyPet,DsRed单体(Clontech),DsRed2(“RFP”,Clontech),EBFP,EBFP2,ECFP,EGFP(弱二聚体,Clontech),Emerald(弱二聚体,Invitrogen),EYFP(弱二聚体,Clontech),GFP(S65A突变),GFP(S65C突变),GFP(S65L突变)GFP(Y66H突变),GFP(Y66W突变),GFPuv,HcRed1,J-Red,Katusha,Kusabira Orange(单聚体,MBL),mCFP,mCherry(单体,MBL),mKate(TagFP635,单体,Evrogen),mKeima-Red(单体,MBL),mKO,mOrange,mPlum,mRaspberry,mRFP1(单体,Tsien实验室),mStrawberry,mTFP1,mTurquoise2,P3(藻胆体复合物),多甲藻黄素-叶绿素-蛋白质复合物(PerCP),R-phycoerythrin(RPE),T-Sapphire,TagCFP(二聚体,Evrogen),TagGFP(二聚体,Evrogen),TagRFP(二聚体,Evrogen),TagYFP(二聚体,Evrogen),tdTomato(串联二聚体),Topaz,TurboFP602(二聚体,Evrogen),TurboFPP635(二聚体,Evrogen),TurboGFP(二聚体,Evrogen),TurboRFP(二聚体,Evrogen),TurboYFP(二聚体,Evrogen),Venus,野生型GFP型,YPet,ZsGreen1(四聚体,Clontech),ZsYellow1(四聚体,Clontech)。
7)上述药物的药学上可接受的盐、酸或其衍生物。
7.在权利要求2和4中,公式(II)和(IV)里的Drug1和Drug2为发色分子,结构式为(II)和(IV)的偶联物可用于检测,监测或研究细胞结合分子的功能,与靶细胞的相互作用,和/或偶联物与目标物,特别是靶细胞的相互作用。
8.在权利要求2和4中,Drug1和Drug2优选自tubulysin,卡奇霉素,澳瑞他汀,美登素生物碱,CC-1065类似物,柔红霉素和阿霉素化合物,紫杉烷类(紫杉烷类),cryptophycin,埃博霉素,苯并二氮卓二聚体(例如吡咯并苯二氮卓(PBD),托美霉素,安曲霉素,吲哚并苯并二氮卓,咪唑并苯并噻二氮卓或恶唑烷并苯并二氮卓的二聚体),卡立霉素类和烯二炔类抗生素,放线菌素,氮丝菌素,博来霉素,表柔比星,他莫昔芬,伊达比星,多拉司他汀/澳瑞他汀(例如MMAE,MMAF,澳瑞他汀PYE,澳瑞他汀TP,澳瑞他汀2-AQ,6-AQ,EB(AEB)和EFP(AEFP)),多卡霉素,噻替派,长春新碱,半米塔林,nazumamide,microginin,radiosumin,alterobactin,microsclerominmin,theonellamide,esperamicin,siRNA,溶核酶和/或其药学上可接受的盐、酸和/或上述分子的同系物和衍生物。
9.权利要求2和3中的细胞结合剂/分子选自抗体、蛋白、维生素(如叶酸)、肽、聚合物胶束、脂质体、脂蛋白为基础的药物载体、纳米颗粒药物载体、树状分子和涂覆了细胞结合配体的上述分子或其组合物。
10.权利要求2、3和9中的细胞结合剂/分子优选为,抗体,完整抗体(多克隆抗体,单克隆抗体,二聚体,多聚体,多特异性抗体,例如双特异性抗体);单链抗体;结合靶细胞的抗体片段、单克隆抗体,单链单克隆抗体或结合靶细胞的单克隆抗体片段,嵌合抗体、结合靶细胞的嵌合抗体片段,单域抗体,结合靶细胞的单域抗体片段,表面修饰抗体,单链表面修饰抗体,或结合靶细胞的表面修饰抗体片段,人源化抗体,单链人源化抗体,或结合靶细胞的人源化抗体片段,淋巴因子,激素,维生素,生长因子,一个集落刺激因子或营养转运分子。
11.权利要求2、3和9中的细胞结合剂/分子可以是任何能够靶向下列细胞的试剂:肿瘤细胞、病毒感染的细胞、微生物感染的细胞,寄生虫感染的细胞,自身免疫性疾病的细胞,激活的肿瘤细胞,骨髓细胞,活化的T细胞,B细胞,或黑素细胞。
12.权利要求2、3和9中的细胞结合剂/分子可以是任何能够抗下列抗原或受体之一的药物/分子:CD3,CD4,CD5,CD6,CD7,CD8,CD9,CD10,CD11a,CD11b,CD11c,CD12w,CD14,CD15,CD16,CDw17,CD18,CD19,CD20,CD21,CD22,CD23,CD24,CD25,CD26,CD27,CD28,CD29,CD30,CD31,CD32,CD33,CD34,CD35,CD36,CD37,CD38,CD39,CD40,CD41,CD42,CD43,CD44,CD45,CD46,CD47,CD48,CD49b,CD49c,CD51,CD52,CD53,CD54,CD55,CD56,CD58,CD59,CD61,CD62E,CD62L,CD62P,CD63,CD66,CD68,CD69,CD70,CD72,CD74,CD79,CD79a,CD79b,CD80,CD81,CD82,CD83,CD86,CD87,CD88,CD89,CD90,CD91,CD95,CD96,CD98,CD100,CD103,CD105,CD106,CD109,CD117,CD120,CD125,CD126,CD127,CD133,CD134,CD135,CD138,CD141,CD142,CD143,CD144,CD147,CD151,CD147,CD152,CD154,CD156,CD158,CD163,CD166,.CD168,CD174,CD180,CD184,CDw186,CD194,CD195,CD200,CD200a,CD200b,CD209,CD221,CD227,CD235a,CD240,CD262,CD271,CD274,CD276(B7-H3),CD303,CD304,CD309,CD326,4-1BB,5AC,5T4(Trophoblast糖蛋白,TPBG,5T4,WNT-活化抑制因子1或WAIF1),腺癌抗原,AGS-5,AGS-22M6,激活素受体激酶1,AFP,AKAP-4,ALK,α整合素,αvβ6,氨基肽酶N,淀粉样蛋白β,雄激素受体,促血管新生蛋白因子2,促血管新生蛋白因子3,膜联蛋白A1,炭疽毒素保护性抗原,抗转移蛋白受体,AOC3(VAP-1),B7-H3,炭疽杆菌,BAFF(B细胞激活因子),B淋巴瘤细胞,bcr-abl,蛙皮素,BORIS,C5,C242抗原,CA125(糖抗原125,MUC16),CA-IX(或CAIX,碳酸酐酶9),CALLA,CanAg,犬红斑狼疮IL31,碳酸酐酶IX,心肌肌凝蛋白,CCL11(C-C片段趋化因子11),CCR4(C-C趋化因子受体4,CD194),CCR5,CD3E(ε),CEA(癌胚抗原),CEACAM3,CEACAM5(癌胚抗原),CFD(因子D),Ch4D5,胆囊收缩素2(CCK2R),CLDN18(Claudin-18),丛生因子A,CRIPTO,FCSF1R(集落刺激因子1受体,CD115),CSF2(集落刺激因子2,粒细胞-巨噬细胞集落刺激因子(GM-CSF)),CTLA4(细胞毒性T淋巴细胞相关蛋白4),CTAA16.88肿瘤抗原,CXCR4(CD184),C-X-C趋化因子受体4,环状ADP核糖核酸酶,细胞周期蛋白B1,CYP1B1,巨细胞病毒,巨细胞病毒糖蛋白B,Dabigatran,DLL4(类Δ配体4),DPP4(双肽-肽酶4),DR5(死亡受体5),大肠杆菌shiga毒素类型-1,大肠杆菌shiga毒素type-2,ED-B,EGFL7(类EGF结构域蛋白7),EGFR,EGFRII,EGFRvIII,内皮因子(CD105),内皮素B受体,内毒素,EpCAM(上皮细胞粘附分子),EphA2,Episialin,ERBB2(表皮生长因子受体2),ERBB3,ERG(TMPRSS2 ETS融合基因),大肠杆菌,ETV6-AML,FAP(成纤维细胞活化蛋白α),FCGR1,甲胎蛋白,纤维蛋白IIβ链,纤连蛋白额外结构域-B,FOLR(叶酸受体),叶酸受体α,叶酸水解酶,Fos相关抗原1,呼吸道合胞病毒的F蛋白,卷曲的受体,岩藻糖GM1,GD2神经节苷脂,G-28(细胞表面抗原糖脂),GD3独特型,GloboH,Glypican 3,N-羟乙酰神经氨酸,GM3,GMCSF受体α链,生长分化因子8,GP100,GPNMB(跨膜糖蛋白NMB),GUCY2C(鸟苷酸环化酶2C),鸟苷酸环化酶C(GC-C),肠鸟苷酸环化酶,鸟苷酸环化酶C受体,热稳定肠毒素受体(hSTAR),热休克蛋白,血凝素,乙肝表面抗原,乙型肝炎病毒,HER1(人类表皮生长因子受体1),HER2,HER2/neu,HER3(ERBB-3),IgG4,HGF/SF(肝细胞生长因子/分散因子),HHGFR,HIV-1,组蛋白复合物,HLA-DR(人类白细胞抗原),HLA-DR10,HLA-DRB,HMWMAA,人类绒毛膜促性腺激素,HNGF,人类分散因子受体激酶,HPV E6/E7,Hsp90,hTERT,ICAM-1(细胞间粘附分子1),独特型,IGF1R(IGF–1,类胰岛素生长因子1受体),IGHE,IFN-γ,流感血凝素,IgE,IgE Fc区,IGHE,IL–1,IL-2R(白介素2受体),IL–4,IL-5,IL–6,IL-6R(白介素6受体),IL-9,IL–10,IL–12,IL-13,IL-17,IL-17A,IL-20,IL-22,IL-23,IL31RA,ILGF2(类胰岛素生长因子2),整合蛋白(α4、αIIbβ3、αvβ3、α4β7、α5β1、α6β4、α7β7、αllβ3、α5β5、αvβ5),干扰素γ诱导蛋白质,ITGA2,ITGB2,KIR2D,LCK,Le,Legumain,Lewis-Y抗原,LFA-1(淋巴细胞功能相关抗原1,CD11a),LHRH,LINGO-1,脂磷壁酸,LIV1A,LMP2,LTA,MAD-CT-1,MAD-CT-2,MAGE-1,MAGE-2,MAGE-3,MAGE A1,MAGEA3,MAGE 4,MART1,MCP-1,MIF(巨噬细胞迁移抑制因子,或糖基抑制因子(GIF)),MS4A1(跨膜4结构域亚家族A成员1),MSLN(间皮素),MUC1(粘蛋白1,细胞表面相关(MUC1)或多态性上皮粘蛋白(PEM)),MUC1-KLH,MUC16(CA125),MCP1(单核细胞趋化蛋白1),MelanA/MART1,ML-IAP,MPG,MS4A1,MYCN,髓磷脂相关糖蛋白,Myostatin,NA17,NARP-1,NCA-90(粒细胞抗原),Nectin-4(ASG-22ME),NGF,神经细胞凋亡调控蛋白酶1,NOGO-A,Notch受体,核仁素,Neu致癌基因产物,NY-BR-1,NY-ESO-1,OX-40,OxLDL(氧化低密度脂蛋白),OY-TES1,P21,p53非突变体,P97,PAP,抗(N-羟乙酰神经氨酸)抗体结合部位,PAX3,PAX5,PCSK9,PDCD1(PD-1、程序性细胞死亡蛋白1,CD279),PDGF-Rα(α血小板源生长因子受体),PDGFR-β,PDL-1,PLAC1,类PLAP睾丸碱性磷酸酶,血小板衍生生长因子受体β,磷酸钠联合转运体,PMEL 17,聚唾液酸,蛋白酶3(PR1),前列腺癌,PS(磷脂酰丝氨酸),前列腺癌细胞,铜绿假单胞菌,PSMA,PSA,PSCA,狂犬病病毒糖蛋白,RHD(Rh多肽1(RhPI),CD240),Rhesus因子,RANKL,RhoC,Ras突变,RGS5,ROBO4,呼吸道合胞病毒,RON,肉瘤易位断点,SART3,Sclerostin,SLAMF7(SLAM成员7),Selectin P,SDC1(多配体蛋白聚糖1),系统性红斑狼疮(a),生长调节素C,SIP(1-磷酸鞘氨醇),生长激素抑制素,精子蛋白17,SSX2,STEAP1(6-跨膜上皮前列腺抗原1),STEAP2,STn,TAG-72(肿瘤相关糖蛋白),存活素,T细胞受体,T细胞跨膜蛋白,TEM1(肿瘤血管内皮标记1),TENB2,Tenascin C(TN-C),TGF-α,TGF-β(转化生长因子β),TGF-β1,TGF-β2(转化生长因子2),Tie(CD202b),Tie2,TIM-1(CDX-014),Tn,TNF,TNF-α,TNFRSF8,TNFRSF10B(肿瘤坏死因子受体超家族成员10B),TNFRSF13B(肿瘤坏死因子受体超家族成员13B),TPBG(滋养细胞糖蛋白),TRAIL-R1(TNF相关坏死诱导配体受体1),TRAILR2(死亡受体5(DR5)),肿瘤相关的钙信号传感器2,肿瘤特异糖基化的MUC1,TWEAK受体,TYRP1(糖蛋白75),TRP-2,酪氨酸酶,VCAM-1(CD106),VEGF,VEGF-A,VEGF-2(CD309),VEGFR-1,VEGFR2,vimentin,WT1,XAGE1,表达任何胰岛素生长因子受体的细胞,或任何表皮生长因子受体。
13.权利要求11中的肿瘤细胞选自淋巴瘤细胞、骨髓瘤细胞、肾细胞癌细胞、乳腺癌细胞、前列腺癌细胞、卵巢癌细胞、结肠癌细胞、胃癌细胞、鳞状细胞癌、小细胞肺癌、非小细胞肺癌细胞、睾丸癌细胞,或任何不受控、加速生长、分化而致癌的细胞。
14.权利要求1,2,3和4中的连接体组分R1,R2,R3和/或R4可以由一个或者多个的连接体组分构成:6-马来酰亚胺己酸(MC),3-马来酰亚胺基丙酸(MP),缬氨酸-瓜氨酸(val-cit),丙氨酸-苯丙氨酸(ala-phe),对氨基苄氧羰基(PAB),4-硫代戊酸(SPP),4-(N-马来酰亚胺甲基)环己烷-1-羧酸(MCC),4-硫代丁酸(SPDB),乙基马来酰亚胺(ME),4-硫代-2-羟基磺基丁酸(2-Sulfo-SPDB),吡啶二硫醇(PySS),烷氧基氨基(AOA),乙烯氧基(EO),4-甲基-4-二硫-戊酸(MPDP),叠氮(N3),炔,二硫代,肽,和/或(4-乙酰基)氨基苯甲酸酯(SIAB)。
15.权利要求2中,Drug1和Drug2为Tubulysin同系物,具有结构通式(II)的优选的偶联物T01,T02,T03,T04,T05,T06和T07:
其中mAb是抗体;Z3和Z3’是H,R1,OP(O)(OM1)(OM2),OCH2OP(O)(OM1)(OM2),OSO3M1或O-糖苷(糖苷,半乳糖苷,甘露糖苷,葡萄糖苷,果糖苷等),NH-糖苷,S-糖苷或CH2-糖苷;M1和M2独立地为H,Na,K,Ca,Mg,NR1R2R3;n是1~20;R1,R2,R3和R4定义与权利要求1相同。
16.权利要求2中,Drug1和Drug2为加利车霉素同系物,具有结构通式(II)的优选的偶联物C01:
其中mAb是抗体;n是1~20;R1,R2,R3和R4与权利要求1中定义相同。
17.权利要求2中,Drug1和Drug2为美登素生物碱同系物,具有结构通式(II)的优选的偶联物M01:
其中mAb是抗体;n是1~20;R1,R2,R3和42与权利要求1中定义相同。
18.权利要求2中,Drug1和Drug2为紫杉烷同系物,具有结构通式(II)的优选的偶联物Tx01,Tx02和Tx03:
其中mAb是抗体;n是1~20;R1,R2,R3和R4与权利要求1中定义相同。
19.权利要求2中,Drug1和Drug2为CC-1065同系物和/或多卡霉素类似物,具有结构通式(II)的优选的偶联物CC01,CC02,CC03:
其中mAb是抗体;n是1~20;Z4和Z4’是H,PO(OM1)(OM2),SO3M1,CH2PO(OM1)(OM2),CH3N(CH2CH2)2NC(O)-,O(CH2CH2)2NC(O)-或糖苷;X3和X3’是O,NH,NHR1,NHC(O),OC(O),CO,R1或缺省;M1和M2独立地为H,Na,K,NH4,NR1R2R3R4;R1,R2,R3和R4定义与权利要求1中相同。
20.权利要求2中,Drug1和Drug2为柔红霉素/阿霉素同系物,具有结构通式(II)的优选的偶联物Da01,Da02,Da03和Da04:
其中mAb是抗体;n是1~20;X3和X3’是O,NH,NR1,NHC(O),OC(O),C(O),C(O)NR1,C(O)NH,R1或缺省;R1,R2,R3和R4定义同权利要求1。
21.权利要求2中,Drug1和Drug2为澳瑞他汀同系物,具有结构通式(II)的优选的偶联物Au01,Au02,Au03,Au04和Au05:
其中mAb是抗体;n为1~20;X3和X3’为独立的CH 2,O,NH,NR1,NHC(O),NHC(O)NH,C(O),OC(O),R1或缺省;X4和X4’是独立的CH2,C(O),C(O)NH,C(O)N(R1),R1或C(O)O;Z3和Z3’是独立的H,R1,OP(O)(OM1)(OM2),OCH2OP(O)(OM1)(OM2),OSO3M1或O-糖苷(糖苷,半乳糖苷,甘露糖苷,葡萄糖苷,果糖苷等),NH-糖苷,S-糖苷或CH2-糖苷;M1和M2独立地为H,Na,K,Ca,Mg,NH4,NR1R2R3R4;R1,R2,R3和R4定义同权利要求1。
22.权利要求2中,Drug1和Drug2为苯并二氮卓二聚体同系物,具有结构通式(II)的优选的偶联物PB01,PB02,PB03,PB04,PB05,PB06,PB07,PB08,PB09,PB10和PB11:
其中mAb是抗体;n为1~20;X3和X3’为独立的CH2,O,NH,NR1,NHC(O),NHC(O)NH,C(O),C(O)R1,OC(O),C(O)NR1,R1或缺省;X4和X4’是独立的CH2,C(O),C(O)NH,C(O)N(R1),C(O)O,R1或缺省;R1,R2,R3和/或R4定义同权利要求1。另外,R3和/或R4可以缺省。
23.一种用于癌症、自身免疫性疾病或传染病的治疗或预防的药物组合物,包含治疗有效剂量的权利要求2,15,16,17,18,19,20,21和/或22中的偶联物,和其药学可接受的盐、载体、稀释剂或赋形剂或其组合。
24.权利要求2,15,16,17,18,19,20,21,22和23中的偶联物,具有体外,体内或离体活性。
25.权利要求2,15,16,17,18,19,20,21或22中的偶联物,其中连接体组分R1,R2,R3和/或R4包含一个1~20天然或非天然氨基酸单元的肽,氨基苄单元,6-马来酰亚胺己酰基单元,二硫化物,硫醚单元,腙单元、三唑单元,或烷氧肟单元。
26.权利要求2,15,16,17,18,19,20,21或22中的连接体组分R1,R2,R3和/或R4可以被蛋白酶所切断。
27.权利要求2,15,16,17,18,19,20,21或22中的偶联物,其中的硫原子对优选来自抗体上链间二硫键被TCEP和或DTT还原产生的一对巯基。
28.一种药物组合物,包含治疗有效量的权利要求2,15,16,17,18,19,20,21,22和/或23中的偶联物,与其它治疗剂如化疗药物、放射治疗、免疫治疗剂,自身免疫性疾病药物、抗感染药物或其他偶联物同时使用,协同有效治疗或预防癌症、自身免疫性疾病或传染病。
29.权利要求28中的协同剂优选自下列药物中的一种或几种:阿巴西普,醋酸阿比特龙,对乙酰氨基酚/氢可酮,阿达木单抗,阿法替尼马来酸盐,阿仑单抗,阿利维A酸,曲妥珠单抗,苯丙胺混合盐(苯丙胺/右苯丙胺)阿那曲唑,阿立哌唑,阿扎那韦,Atezolizumab,阿托伐他汀,阿昔替尼,贝林,贝伐单抗,卡巴他赛,卡博替,贝沙罗汀,blinatumomab,硼替佐米,波舒替尼,brentuximab vedotin,布地奈德,布地奈德/福莫特罗,丁丙诺啡,卡培他滨,卡非佐米,塞来考昔,ceritinib,西妥昔单抗,环孢素,西那卡塞,克里唑替尼,达比加群,达拉菲尼,阿法达贝汀,地瑞那韦,甲磺酸伊马替尼,达沙替尼,地尼白介素,狄诺塞麦,双丙戊酸钠,右兰索拉唑,右哌甲酯,Dinutuximab,多西环素,度洛西汀,恩曲他滨/利匹韦林/替诺福韦地索普西富马酸盐,恩曲他滨/替诺福韦/依法韦仑,依诺肝素,恩杂鲁胺,阿法依泊汀,厄洛替尼,埃索美拉唑,依折麦布,依折麦布/辛伐他汀,非诺贝特,非格司亭,芬戈莫德,丙酸氟替卡松,氟替卡松/沙美特罗,氟维司群,吉非替尼,格拉替雷,醋酸戈舍瑞林,伊马替尼,替伊莫单抗,依鲁替尼,胰岛素门冬胰岛素,地特胰岛素,甘精胰岛素,赖脯胰岛素,干扰素β1a,干扰素β1b,拉帕替尼,Ipilimumab,异丙托溴铵/沙丁胺醇,醋酸兰乐肽,来那度胺,联合二甲苯磺酸盐,来曲唑,左甲状腺素,左旋甲状腺素,利多卡因,利奈唑胺,利拉鲁肽,MEDI4736,美金刚,哌醋甲酯,美托洛尔,莫达非尼,莫米松,尼罗替尼,Nivolumab,奥法木单抗,奥立他珠单抗,帕唑帕尼,派姆单抗,培美曲塞,帕妥珠单抗,肺炎球菌结合疫苗,泊马度胺,普瑞巴林,喹硫平,雷贝拉唑氯化镭223,雷洛昔芬,拉替拉韦,雷莫瑞单抗,雷珠单抗,瑞格菲尼,利妥昔单抗,利伐沙班,罗米地辛,罗苏伐他汀,鲁索替尼磷酸盐,沙丁胺醇,司维拉明,西地那非,siltuximab,西他列汀,西他列汀/二甲双胍,索非那新,索拉非尼,舒尼替尼,他达拉非,他莫昔芬,替拉普韦,替西罗莫司,替诺福韦/恩曲他滨,睾酮凝胶,沙利度胺(Talidex),噻托溴铵,托瑞米芬,曲美替尼,曲妥珠单抗,Tretinoin,尤特克单抗,缬沙坦,凡德他尼,维罗非尼,伏立诺他,阿柏西普,Zostavax及其同系物、衍生物、药学上可接受的盐、载体、稀释剂或赋形剂,或其组合。
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ZA201800825B (en) | 2019-05-29 |
CA2991973A1 (en) | 2015-10-08 |
JP6759326B2 (ja) | 2020-09-23 |
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AU2021202467A1 (en) | 2021-05-20 |
WO2015151081A3 (en) | 2016-06-02 |
AU2015242213A1 (en) | 2018-03-08 |
EP3319936A2 (en) | 2018-05-16 |
WO2015151081A2 (en) | 2015-10-08 |
CA2991973C (en) | 2021-12-07 |
JP2018524377A (ja) | 2018-08-30 |
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AU2021202467B2 (en) | 2022-07-21 |
EP3319936A4 (en) | 2019-02-06 |
CN108449940B (zh) | 2021-06-08 |
PH12018500285A1 (en) | 2018-08-29 |
AU2022206809A1 (en) | 2022-08-18 |
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