CN112125929A - 用于偶联的亲水链接体 - Google Patents
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- CN112125929A CN112125929A CN202011053870.7A CN202011053870A CN112125929A CN 112125929 A CN112125929 A CN 112125929A CN 202011053870 A CN202011053870 A CN 202011053870A CN 112125929 A CN112125929 A CN 112125929A
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Abstract
本专利申请提供包含亲水链接体的细胞结合分子‑药物偶联物,以及使用这些链接体和偶联物的方法。
Description
本发明是中国申请号为201580080839.3,发明名称为用于偶联的亲水链接体分案申请。
技术领域
本发明涉及用于将药物,特别是细胞毒性剂或发色团分子偶联至细胞结合分子的亲水性链接体的制备。本发明还涉及制备细胞结合剂-药物(例如细胞毒性剂)共轭体(偶联物)的方法,其包括首先用这些亲水性连接体对药物进行修饰,然后与细胞结合剂反应;或首先用这些亲水性连接子修饰细胞结合剂,随后与药物反应。
背景技术
靶向性的治疗多年来一直是医药研究和开发的重点,是“精准医学”的基石(巴拉克·奥巴马总统,国情咨文,2015年1月20日,www.whitehouse.gov/precisionmedicine)。其是利用人体肿瘤的特定信息来帮助诊断,有计划治疗,寻找治疗效果如何,或做出预测(FS Collins,New Engl.J.Med。2015;372:793-795)。迄今为止,美国食药局(FDA),欧洲药监委(EMA)和中国食药局(CFDA)批准了许多不同的靶向治疗方法用于癌症治疗。这些疗法包括激素疗法,信号转导抑制剂,基因表达调节剂,凋亡诱导剂,血管生成抑制剂,免疫疗法和毒素递送分子。激素疗法通过阻止身体产生激素或通过干扰激素的作用来起作用,其继而可以减缓或停止激素敏感性肿瘤的生长。信号转导抑制剂阻断细胞响应来自其环境的信号,特别是防止癌细胞迅速繁殖并侵入其他组织的能力。基因表达调节剂可以修饰在控制基因表达中起作用的蛋白质的功能。细胞凋亡诱导剂导致癌细胞经受控制细胞死亡的过程。血管生成抑制剂阻断新血管向肿瘤的生长(称为肿瘤血管生成的过程)。免疫疗法引发免疫系统破坏癌细胞。大部分免疫疗法是识别癌细胞表面特异性分子的单克隆抗体。毒素递送分子使用运载体/方法将毒素药物特定性地递送至癌细胞。
过去三十年来广泛研究的比较凑效的方法是毒素的递送分子。有几种全身性递送化疗药物用于肿瘤的靶向治疗:热激活靶向药物递送;使用载体介导的运输系统对癌症进行组织有选择性药物递送;用于靶向递送化疗的肿瘤激活的前药疗法;药物跨血管压力诱导过滤到肿瘤;促进抗癌药物选择性渗透入肿瘤;使用双特异性抗体的两步靶向;抗体偶联物的特异性位点的递送;和大分子的光活化法。许多载体已经以不同的形式或以特殊的配方用于靶向递送抗癌药物的研究,如白蛋白基药物载体;碳水化合物增强性化疗;基于蛋白质和肽的药物载体;作为与活性药物连接的靶向载体的脂肪酸;微球载体;单克隆抗体作为载体;维生素,例如叶酸作为载体;纳米颗粒载体;脂质体载体,如聚乙二醇化脂质体(包封在聚乙二醇双层中);聚乙二醇(PEG)载体;单链抗原结合分子载体;聚合物胶束载体;基于脂蛋白的药物载体;树状大分子;等等。理想的递送载体必须是位点特异性,无毒,生物度相容,非免疫原性的和生物体可降解的(Scott,R。等人,(2008)Expert Opin.Drug Deli.5,459)并且避免被宿主的防御机制所识别(Saltzman,W.(2008).“Drug delivery systems”Access Science.McGraw-Hill Co.)。按此标准,使用单克隆抗体(mAb)作为化疗药物的输送载体则为相当成功。通过将单克隆抗体的独特靶向能力与细胞毒性药物的杀癌能力相结合,抗体-药物偶联物(ADC)可敏感地区分健康和疾病组织(ADC Review,J.Antibody-drugConjugates,-Jun 1,2013)。除了2013年在美国FDA成功上市ado-trastuzumab emtansine(T-DM)和2011年通过美国FDA的Brentuximab vedotin之外,目前在美国临床试验中有超过40种不同的ADC药物(www.clinicaltrials.gov)。但是ADC的发展还存在很多挑战,比如治疗指标改进的链接体选择,链接的单抗(mAb)对目标选择,对作用机制的理解,以及对ADC偏移目标而产生的毒性的管理和理解问题。目前已知输送载体之间的连接体,尤其是抗体和细胞杀伤毒素间的连接体在靶向药物递送系统的发展中起关键作用,因为连接物的性质显着地影响偶联物的活性,选择性和药代动力学(Zhao,R.Y.等人(2011)J.Med.Chem.54,3606;Acchionea,M.等人(2012)mAbs,4,362;Doronina,S.等人,(2006)Bioconjug.Chem,17,114;Hamann,P.等人(2005)Bioconjug.Chem.16,346)。到目前为止,有四种类型的链接体通常用于制备进入临床的细胞结合分子-药物偶联物:(a)酸不稳定链接体,其利用酸性内体和溶酶体细胞内微环境;(b)可被溶酶体蛋白酶切割的链接体;(c)化学稳定的硫醚链接体,其在细胞内的抗体蛋白水解降解后释放赖氨酰加合物;和(d)在暴露于细胞内可被硫醇裂解的含二硫键的链接体(Zhao,R.Y.等人,2011J.Med.Chem.36,5404)。
经由不同类型的连接体的细胞结合剂与药物的偶联物或细胞结合剂与修饰的化学化合物的偶联物已有报道(U.S.Patent Nos.4,680,338,5,122,368,5,141,648,5,208,020,5,416,064;5,475,092,5,543,390,5,563,250 5,585,499,5,880,270,6,214,345,6,436,931,6,372,738,6,340,701,6,989,452,7,129,261,7,375,078,7,498,302,7,507,420,7,691,962,7,910,594,7,968,586,7,989,434,7,994,135,7,999,083,8,153,768,8,236,319,WO2014080251,Zhao,R.;et al,(2011)J.Med.Chem.36,5404;Doronina,S.;etal,(2006)Bioconjug Chem,17,114;Hamann,P.;et al.(2005)Bioconjug Chem.16,346).通常,在这些偶联物中,首先用双功能试剂例如SPDP(N-琥珀酰亚胺基3-(2-吡啶基二硫基)丙酸酯),SMPDP(N-琥珀酰亚胺基4-甲基-4-(2-吡啶基二硫基))戊酸酯),SPDB(4-琥珀酰亚胺基4-(2-吡啶基二硫代)丁酸酯)或SMCC(琥珀酰亚胺基-4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯)以引入活性二硫化物或马来酰亚胺部分。与含巯基的细胞毒性药物的反应得到细胞结合剂如单克隆抗体和药物之间通过二硫键或硫醚键连接的偶联物。
然而,使用细胞结合分子-药物偶联物(例如抗体-药物偶联物(ADC))开发用于各种癌症的疗法已经受限于特定靶向剂(载体)的可用性以及当偶联物载体上的药物的含量(即,药物负载量)增加时导致蛋白质聚集体形成的偶联方法学。通常,当用疏水连接子进行偶联反应时,细胞毒性药物偶联物聚集的趋势尤其成问题。由于较高的载药量增加了偶联物的固有效力,所以希望载足药量载体能同原载体蛋白的亲和力一致。聚集的蛋白质,其可能是非特异性毒性的和免疫原性的,因此必须在治疗应用中除去,使得大规模生产偶联物过程中更加困难并且降低了产品的收率。
我们曾发明了一系列含有次膦酸根,磺酰基和/或亚砜基团的亲水性链接体,其可以用来改善在高载药量下将细胞毒性药物偶联到载体(细胞结合分子)而不出现聚集的方法(PCT/IB2012/056700 and PCT/CN2014/072769)。在这里,我们延续描述亲水链接体,可以进行更好的偶联、有条件性的药物释放,同时每个链接体加载两种不同类型的药物或分子、和/或每个链接体连接一对细胞结合分子的位点得到特定性或更好的偶联。
发明概要
本发明提供了含有磷酰胺,磷酰胺,磺酰胺,磺酰基,磺酰亚胺和/或亚砜基团的亲水性链接体以将药物连接至细胞结合剂(例如抗体)。细胞结合分子-亲水性链接体-药物偶联物(共轭体)的优选配方可以表示为:Cb-(-L-Drug)n,其中Cb是细胞结合剂,L是亲水性链接体,Drug是药物分子,n是1至20的整数。在细胞结合分子-药物偶联物中应用亲水性连接体的优点是:a).减少水基介质中偶联物的聚集;b).能够取得以更高的药物-细胞结合分子比例偶联物,导致更高的效力;c).药物-链接体从偶联物上释放后可滞留在靶细胞内,可抵抗渗透性糖蛋白(Pgp)表达的多药耐药(MDR)细胞;d).允许每个链接体加载两种不同的药物;f).每个链接体偶联一对细胞结合分子的位点。
在本发明的一个方面,亲水性连接基由式(I)表示:其中Y可以与细胞结合剂反应,Z可以与细胞毒性药物反应:
其中:
Y代表能够与细胞结合剂反应的官能团;
Q和T是–X1–P(=O)(OM)-,or X1-S(O2)-,或–X1–S(O)-;或–X1–P(=O)(OM)-X2-,或–X1–P(=O)[X2-R4-Z]-X3-,或–X1–P(=O)[X2-R1-Y]-X3-,或–X1-S(O2)-X2-,或–X1–S(O)-X2-;
X1,X2和X3独立地选自N(R7),O,或S;另外,当X1是N(R7),或O或S时,则X2或X3或另一个X1同–P(=O),-S(O),或-S(O2)连接时,X2或X3或另一个X1可以是CH2;
m和n是从0到5的整数,但不能同时为0;
Z代表一个功能基团,能够通过硫代,硫酯,肽,腙,醚,酯,氨基甲酸酯,碳酸酯,胺(二级,三级或四级),亚胺,环杂烷基,杂芳族基团,烷肟或酰胺键连接一个细胞毒性药物;
R1,R2,R3,R4,R5,R6,和R7是,相同或不同,是H,具有1-6个碳原子的直链烷基,具有3-6个碳原子的支链或环状烷基,直链、支链或环状链烯基或炔基,1-6个碳原子的酯、醚、酰胺,或分子式为(OCH2CH2)p,聚乙烯氧基单元,其中p是0至约1000的整数,或上述组合,
另外,R1,R2,R3和R4分别是选自C、N、O、S、Si和P的原子链,其以共价连接细胞表面结合配体,次膦酸盐或磺酰基团,偶联的药物以及它们之间(R1,R2,R3和R4)连接。用于形成亲水性链接体的原子可以以所有化学相关的方式组合,例如形成烷基、烯、亚烷基,亚烯基、炔基,醚,聚氧化烷基,酯,胺,亚胺,多胺,肼,腙,酰胺,脲,氨基脲,卡巴肼,烷氧基胺,氨基甲酸酯,氨基酸,肽,酰氧基胺,异羟肟酸或其上述的组合。
M是H,或Na,或K,或N+R1R2R3或药用盐。上面已对R1,R2和R3进行了描述。
在另一个实施方案中,当式(I)的亲水性链接体具有两个或更多个Y基团,特别是两个相同的Y基团时,在这种情况下,Q或/和T是-–X1–P(=O)[X2-R1-Y]-X3-,那么式(I)的亲水性链接体可以连接两个或更多个位点,特别是连接到细胞结合分子的一对位点。
在另一个实施方案中,当式(I)的亲水性链接体具有两个或更多个Z基团时,在这种情况下,Q或/和T是–X1–P(=O)[X2-R4-Z]-X3-,那么式(I)的亲水性链接体可连接至两种或更多种药物,特别是两种不同的药物。
另一方面,本发明提供了式(II)的细胞结合剂-药物偶联物,其中细胞结合剂Cb和药物,Drug,已经在亲水性链接体的两端链接:
其中:
Cb代表细胞结合剂;
Drug代表以二硫化物,硫醚,硫酯,肽,腙,醚,酯,氨基甲酸酯,碳酸酯,环杂烷基,杂芳族,烷氧基或酰胺键通过亲水性链接体与细胞结合剂连接的药物;
q是1~20;m,n,R1,R2,R3,R4,R5,R6和M与前述式(I)中的描述相同;
Q和T是–X1–P(=O)(OM)-,或–X1-S(O2)-,或–X1–S(O)-;或–X1–P(=O)(OM)-X2-,或–X1–P(=O)[X2-R4-Drug]-X3-,或–X1–P(=O)[X2-R1-Cb]-X3-,或–X1-S(O2)-X2-,或–X1–S(O)-X2-;
X1,X2和X3独立地选自N(R7),O,或S;另外,当X1是N(R7),或O或S时,则X2或X3或另一个X1同–P(=O),-S(O),或-S(O2)连接时,X2或X3或另一个X1可以是CH2;
另一方面,本发明提供了式(III)的修饰的细胞结合剂,其中细胞结合剂Cb已经与仍具有Z的亲水性链接体反应,该式(III)具有能够与药物进行反应的能力:
其中Cb,Z,m,n,q,R1,R2,R3,R4,R5和R6与式(I)和(II)中的定义相同。
Q和T是–X1–P(=O)(OM)-,或–X1-S(O2)-,或–X1–S(O)-;或–X1–P(=O)(OM)-X2-,或–X1–P(=O)[X2-R4-Z]-X3-,或–X1–P(=O)[X2-R1-Cb]-X3-,或–X1-S(O2)-X2-,or–X1–S(O)-X2-;
X1,X2和X3独立地选自N(R7),O,或S;另外,当X1是N(R7),或O或S时,则连接至–P(=O),-S(O),或–S(O2)的X2,或X3,或另一个X1,可以是CH2。
再一方面,本发明提供了式(IV)的修饰性药物,其中药物,Drug,已经与仍然具有Y的亲水性反应基团,该基团能够与细胞结合分子反应:
其中Y,Drug,m,n,q,R1,R2,R3,R4,R5和R6与式(I)和(II)中的定义相同;
Q和T是–X1–P(=O)(OM)-,或–X1-S(O2)-,或–X1–S(O)-;或–X1–P(=O)(OM)-X2-,或–X1–P(=O)[X2-R4-Drug]-X3-,或–X1–P(=O)[X2-R1-Y]-X3-,或–X1-S(O2)-X2-,或–X1–S(O)-X2-;
X1,X2和X3独立地选自N(R7),O,或S;另外,当X1是N(R7),或O或S时,则连接至–P(=O),-S(O),或–S(O2)的X2,或X3或另一个X1,可以是CH2。
本发明进一步涉及制备式(II)的细胞结合分子-药物偶联物的方法,其中药物通过亲水性链接体与细胞结合剂连接。
本发明还涉及制备式(III)的修饰的细胞结合分子的方法,其中细胞结合分子与亲水性链接体反应。
本发明还涉及制备式(IV)的改性药物的方法,其中药物与亲水性连接体反应。
附图说明
图1显示了含有马来酰亚胺基团的磷酰胺链接体的合成以及这些链接体在抗体与药物偶联中的应用。
图2显示了含有二硫键的磷酰胺链接体的合成以及这些链接体在抗体与药物偶联中的应用。
图3显示了含有马来酰亚胺基团的磷酰胺链接体的合成以及这些链接体在抗体与药物偶联中的应用。
图4显示了含有马来酰亚胺,腙或硫醚基团的磷酰胺链接体的合成以及这些链接体在抗体与药物偶联中的应用。
图5显示了含有马来酰亚胺基团的位阻型磷酰胺链接体的合成以及这些链接体在抗体与药物偶联中的应用。
图6显示了含有二硫化物或肟基团的磷酰胺链接体的合成以及这些链接体在抗体与药物偶联中的应用。
图7显示了含有马来酰亚胺和聚乙二醇基团的磷酰胺链接体的合成以及这些链接体在抗体与药物偶联中的应用。
图8显示了含有马来酰亚胺,聚乙二醇和叠氮基团的磷酰胺链接体的合成以及这些链接体在抗体与两种不同化合物的偶联中的应用。Drug1和Drug2可以是用于治疗应用的细胞毒性剂或用于监测偶联物与靶细胞的相互作用的发色基团化合物。
图9显示含有二硫化物,聚乙二醇或酮基团的磷酰胺链接体的合成,并且这些链接体用于使蛋白质与两种不同化合物偶联。Drug1和Drug2可以是用于治疗应用的细胞毒性剂或用于监测偶联物与靶细胞相互作用的发色团化合物。
图10显示了包含马来酰亚胺基团的磺酰胺和亚磺酰胺连接子的合成以及这些连接子在抗体与细胞毒性药物的偶联中的应用。
图11显示含有二硫化物,聚乙二醇或酮基团的磺酰胺链接体的合成,并且链接体用于使蛋白质与两种不同化合物偶联。Drug1和Drug2可以是用于治疗应用的细胞毒性剂或用于监测偶联物与靶细胞相互作用的发色团化合物。
图12显示了含有硫醚或二硫化物基团的磷酰胺链接体的合成,并且这些链接体用于连接每个链接体的两种药物/化合物。这里的药物可以是用于治疗应用的细胞毒性剂或用于监测偶联物与靶细胞相互作用的发色团化合物。
图13显示了通过含有两个官能团的磷酰胺链接体合成抗体偶联物,其中一个基团连接到细胞毒性剂MMAF用于定向杀伤,另一个连接的荧光染料基团用于监测偶联物与靶细胞的相互作用。
图14显示了含有两个官能团的磷酰胺链接体的合成。
图15显示经由在链接体上含有微管蛋白抑制素类似物和MMAF类似物的磷酰胺链接体的抗体偶联物的合成。
图16显示了含有两种不同细胞毒性药物(PBD二聚体和MMAF类似物)的磷酰胺链接体的合成。
图17显示了通过本专利的磷酰胺链接体合成抗体偶联物。链接体可以每个链接体偶联两种不同的药物(例如PBD类似物和MMAF类似物),或者可以连接到抗体的一对半胱氨酸位点上。
图18显示了含有二硫化物,聚乙二醇,叠氮基或三唑基团的磺酰胺链接体的合成。此链接体用于与两种不同的化合物的偶联。
本发明的详细说明
定义
“烷基”是指在链中有1到8个碳原子的直链或支链的脂肪族烃组。“支链”是指一个或多个较低C数的烷基如甲基、乙基或丙基连接到一个线性烷基链上。烷基实施例包括甲基,乙基,正丙基,异丙基,正丁基,叔丁基,正戊烷基,3-戊烷基,辛烷基,壬烷基,癸烷基,环戊烷基,环己烷基,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,正辛烷基和异辛烷基。C1-C8烷基可以是未被取代或者被以下,但不限于以下的一个或者多个基团取代:C1-C8烷基,C1-C8烷氧基,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',-S(O)2R',-S(O)R',-OH,卤素(-F,-Cl,-Br,或-I),-N3,-NH2,-NH(R'),-N(R')2及-CN;其中R’指各自独立的C1-C8烷基或者芳基。
卤素原子指氟,氯,溴,碘原子,优选氟和氯原子。
"杂烷基"指的是C2-C8烷基,其中一到四碳原子是由O、S和N组成的杂原子独立替换而成的。
"碳环"是指一个饱和或不饱和的环有3到8碳原子作为一个单或7到13碳原子的双环。单碳环有3到6环原子,通常5或6环原子。双环碳环有7到12环原子,组成为双环[4,5],[5,5],[5,6]或[6,6]系统,或9或10环原子组成为双环[5,6]或[6,6]系统。代表C3-C8碳环包括,但不限于,-环丙基,-环丁基,-环戊基,-环己基,-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”指含3-,4-,5-,6-,7-,或8个碳原子的饱和或不饱和的非芳烃环状化合物。C3-C8碳环基团包括非取代或一个或多个取代基包括,但不限于,C1-C8烷基,C1-C8烷氧基,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及-CN;其中R’指各自独立的C1-C8烷基或者芳基。
“烯基”是指含有碳-碳双键的脂族烃基,其可以是在链中具有2-8个碳原子的直链或支链的。烯基实例包括乙烯基,丙烯基,正丁烯基,异丁烯基,3-甲基丁-2-烯基,正戊烯基,己烯基,庚烯基,辛烯基。
“炔基”是指含有碳-碳三键的脂族烃基,其可以是在链中具有2至8个碳原子的直链或支链。实例炔基包括乙炔基,丙炔基,正丁炔基,2-丁炔基,3-甲基丁炔基,5-戊炔基,正戊炔基,己炔基,庚炔基和辛炔基。
“亚烷基”是指具有1-18个碳原子的饱和的支链或直链或环烃基团,并且具有两个通过从原本烷烃的相同或两个不同碳原子上除去两个氢原子而衍生的一价基团烷烃。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-),等等。
“亚烯基”是指具有2-18个碳原子的不饱和的支链或直链或环状烃基,并且具有两个通过从原本烯烃的相同或两个不同碳原子上除去两个氢原子而衍生的一价基团中心烯烃。典型的亚烯基包括但不限于:1,2-亚乙基(-CH=CH-)。
“亚炔基”是指具有2-18个碳原子的不饱和的支链或直链或环状烃基,并且具有两个通过从原本炔烃的相同或两个不同碳原子上除去两个氢原子而衍生的一价基团中心炔。典型的亚炔基包括但不限于:乙炔,炔丙基和4-戊炔基。
“芳基”或Ar是指由一个或几个环组成的芳族或杂芳族基团,其包含三至十四个碳原子,优选六至十个碳原子。所述“杂芳族基团”是指芳族基团上的一个或数个碳,优选地,一个,两个,三个或四个碳原子被O,N,Si,Se,P或S,优选被O,S和N取代。所述芳基或Ar还指芳族基团,其中一个或多个H原子独立地被-R',-卤素,-OR’,-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”)取代,其中R’,R”独立地为H,烷基,烯基,炔基,杂烷基,芳基,芳基烷基,羰基或药用盐。
“杂环”指一环系统,其中环上1至4个碳原子各自独立地被杂元素,如O,N,S,Se和P所取代。优选杂元素为O,N和S。相关杂环的说明亦可参见于The Handbook of Chemistryand Physics,78th Edition,CRC Press,Inc..1997-1998,p.225至226,以及该书引述的文献内。优选的非芳香杂环基包括但不限于环氧基,吖啶基,环硫乙烯基,吡咯烷基,吡唑烷基,咪唑烷基,环氧乙烷基,四氢呋喃基,二氧戊环基,四氢吡喃基,二氧杂环己基,哌啶基,哌嗪基,吗啉基,吡喃基,咪唑啉基,吡咯啉基,吡唑啉基,噻唑烷基,四氢硫吡喃基,二噻烷基,硫吗啉基,二氢吡喃基,四氢吡喃基,四氢吡啶基,二氢吡啶基,四氢嘧啶基,二氢硫吡喃基,氮杂环庚烷基以及他们与苯基生成的稠环。
术语“杂芳基”或芳族杂环是指5至14,优选5至10单元芳族杂环,单环,双环或多环。其例子包含吡咯基,吡啶基,吡唑基,噻吩基,嘧啶基,吡嗪基,四唑基,吲哚基,喹啉基,嘌呤基,咪唑基,噻唑基,苯并噻唑基,呋喃基,苯并呋喃,1,2,4--噻二唑基,异噻唑基,三唑基,四唑基,异喹啉基,吡唑基,噻唑基,苯并噻吩基,异苯并呋喃基,吡唑基,咔唑基,苯并咪唑基,异恶唑基,吡啶基-N-氧化物,以及与苯基缩合得到的嵌合体系。
“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”,“亚炔基”,“亚芳基”,“亚杂芳基”“杂环烯”等是通过除去两个氢原子而形成的。
“芳基烷基”是指无环烷基中与碳原子(通常为末端或sp3碳原子)键合的一氢原子被芳基取代。典型的芳烷基包括但不限于苄基,2-苯基乙烷-1-基,2-苯基乙烯-1-基,萘基甲基,2-萘基乙-1-基,2-萘基乙烯-1-基,萘并-苄基,2-萘酚基乙烷-1-基等。
“杂芳基烷基”是指无环烷基中与碳原子(通常为末端或sp3碳原子)键合的一氢原子被杂芳基取代。典型的杂芳烷基包括但不限于2-苯并咪唑基甲基,2-呋喃基乙基等。
“羟基保护基”的实例包括但不限于甲氧基甲基醚,2-甲氧基乙氧基甲基醚,四氢吡喃基醚,苄基醚,对甲氧基苄基醚,三甲基甲硅烷基醚,三乙基甲硅烷基醚,三异丙基甲硅烷基醚,叔丁基二甲基甲硅烷基醚,三苯基甲基甲硅烷基醚,乙酸酯,取代的乙酸酯,新戊酸酯,苯甲酸酯,甲磺酸酯和对甲苯磺酸酯。
“离去基团”是指可以被另一个功能基团取代的功能基团。这样的离去基团在本领域是众所周知的,其实例包括但不限于卤化物(例如氯化物,溴化物和碘化物),甲磺酰基(mesyl),对甲苯磺酰基(tosyl),三氟甲基磺酰基(三氟甲磺酸酯基)和三氟甲基磺酸酯。
本文可以使用以下缩写并具有指定的定义:Boc,叔丁氧基羰基;BroP,溴代三吡咯烷基鏻六氟磷酸盐;CDI,1,1'-羰基二咪唑;DCC,二环己基碳化二亚胺;DCM,二氯甲烷;DIAD,偶氮二羧酸二异丙酯;DIBAL-H,二异丁基氢化铝;DIPEA,二异丙基乙胺;DEPC,二乙基磷酰氰酸酯;DMA,N,N-二甲基乙酰胺;DMAP,4-(N,N-二甲基氨基)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-乙基碳化二亚胺盐酸盐;ESI-MS,电喷雾质谱;HATU,O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐;HOBt,1-羟基苯并三唑;HPLC,高压液相色谱;NHS,N-羟基琥珀酰亚胺;MMP,4-甲基吗啉;PAB,对氨基苄基;PBS,磷酸盐缓冲盐水(pH7.0~7.5);PEG,聚乙二醇;SEC,分子量排阻色谱法;TCEP,三(2-羧乙基)膦;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”是指当适当地施用于动物或人时不产生不利的,过敏的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”是指一种或多种溶剂分子与公开的化合物的缔合。形成药学上可接受的溶剂化物的溶剂的实例包括但不限于水,异丙醇,乙醇,甲醇,DMSO,乙酸乙酯,乙酸和乙醇胺。
“药学上可接受的赋形剂”包括任何载体,稀释剂,佐剂或赋形剂,如防腐剂或抗氧化剂,填充剂,崩解剂,湿润剂,乳化剂,悬浮剂,溶剂,分散介质,包衣剂,抗细菌剂和抗真菌剂,和吸收延迟剂等。这样的介质和药剂用于药物活性物质的使用在本领域是公知的。除了任何常规的介质或试剂与活性成分不相容之外,其在治疗组合物中的用途也被考虑到。作为合适的治疗组合,还可以将补充的活性成分掺入组合物中。
如本文所用,“药用盐”是指所公开化合物的衍生物,其中母体化合物通过制备其酸或碱盐而被修饰。药学上可接受的盐包括例如由无毒无机酸或有机酸形成的母体化合物的常规无毒盐或季铵盐。例如,这样的常规无毒盐包括衍生自无机酸如盐酸,氢溴酸,硫酸,氨基磺酸,磷酸,硝酸等的那些盐;乙酸,丙酸,琥珀酸,酒石酸,柠檬酸,甲磺酸,苯磺酸,葡糖醛酸,谷氨酸,苯甲酸,水杨酸,甲苯磺酸,草酸,富马酸,马来酸,乳酸等制备的盐。其他加成盐包括铵盐,如氨基丁三醇,葡甲胺,戊二胺等,金属盐如钠,钾,钙,锌或镁。
本发明的药用盐可以通过常规的化学方法由含有碱性或酸性部分的母体化合物合成。一般而言,这些盐可以通过使这些化合物的游离酸性或碱性形式与化学计量量的适当碱或酸在水或有机溶剂中或两者的混合物中反应来制备。通常,非水介质如乙醚,乙酸乙酯,乙醇,异丙醇或乙腈是优选的。可适用的盐列出在Remington's PharmaceuticalSciences,第17版,Mack Publishing Company,Easton,PA,1985,p。1418,其公开内容通过引用结合于此。
本文公开的新型偶联物使用亲水性连接子。图1-17显示了一些合适的连接子及其合成的例子。
亲水链接
图1-18显示了产生亲水连接子的合成途径以及药物与本发明的细胞结合分子的偶联物的制备。亲水性链接体具有三个元件:a)为磷酰胺或次膦酸盐或磺酰胺,或磺酰基,或磺酰胺,和/或亚砜,或这些基团的混合的取代基,b)基团,例如但不限于与能够与细胞结合剂反应的N-羟基琥珀酰亚胺酯基团,马来酰亚胺基团,二硫化物基团,卤代乙酰基团,烷氧基氨基基团和/或酰肼基团,以及c)基团,例如但不限于,能够与药物反应的二硫化物,马来酰亚胺,卤代乙酰基,醛,酮,叠氮化物,胺,烷氧基胺和酰肼。亲水取代基可以通过本文所述的方法引入。例如磷酰胺取代基,它们可以通过氧磷(V)酰氯与图1,2,3,4和5中描述的氨基分子直接缩合而形成。对于混合的次膦酸酯/磷酰胺取代基,它们可以通过首先用迈克尔加成用丙烯酸酯处理市售的次膦酸铵,然后将过量的二溴烷烃取代为次膦酸酯基团,然后与氨基化合物缩合来引入,其例示于图6、7、8、和9。对于例如磺酰胺和亚磺酰胺取代基,可以通过硫酰氯和亚硫酰氯与氨基化合物直接缩合,如图10所示。磺酰基/磺酰胺取代基可以通过缩合例如在图11和18中的一种胺与氯磺酸的反应的例子显示。亲水性连接体的详细合成及其用于制备本发明的细胞结合配体-药物偶联物在图1~18中显示。
优选地,亲水性链接体是下式(I)的化合物:
其中:
Y代表能够与细胞结合剂反应的官能团;
Q和T是–X1–P(=O)(OM)-,or X1-S(O2)-,或–X1–S(O)-;或–X1–P(=O)(OM)-X2-,或–X1–P(=O)[X2-R4-Z]-X3-,或–X1–P(=O)[X2-R1-Y]-X3-,或–X1-S(O2)-X2-,或–X1–S(O)-X2-;
X1,X2和X3独立地选自N(R7),O,或S;另外,当X1是N(R7),或O或S时,则X2或X3或另一个X1同–P(=O),-S(O),或-S(O2)连接时,X2或X3或另一个X1可以是CH2;
m和n是从0到5的整数,但不能同时为0;
Z代表一个功能基团,能够通过硫代,硫酯,肽,腙,醚,酯,氨基甲酸酯,碳酸酯,胺(二级,三级或四级),亚胺,环杂烷基,杂芳族基团,烷肟或酰胺键连接一个细胞毒性药物;
R1,R2,R3,R4,R5,R6,和R7是,相同或不同,是H,具有1-6个碳原子的直链烷基,具有3-6个碳原子的支链或环状烷基,直链、支链或环状链烯基或炔基,1-6个碳原子的酯、醚、酰胺,或分子式为(OCH2CH2)p,聚乙烯氧基单元,其中p是0至约1000的整数,或上述组合;
M是H,或Na,或K,或N+R1R2R3或药用盐。上面已对R1,R2和R3进行了描述。
在另一个实施方案中,R1,R2,R3和R4分别是选自C、N、O、S、Si和P的原子链,其以共价连接细胞表面结合配体,次膦酸盐或磺酰基团,偶联的药物以及它们之间(R1,R2,R3和R4)连接。用于形成亲水性链接体的原子可以以所有化学相关的方式组合,例如形成烷基,烯基,亚烷基,亚烯基和亚炔基,醚,聚氧化烯,酯,胺,亚胺,多胺,肼,腙,酰胺,脲,氨基脲,卡巴肼,烷氧基胺,氨基甲酸酯,氨基酸,酰氧基胺,异羟肟酸和许多其它。另外,形成连接基团(L)的原子既可以是饱和的也可以是不饱和的,或者可以是自由基,或者可以彼此环化形成二价环状结构,包括环烷烃,环醚,环状胺,芳基,杂芳基等。
能够与细胞结合剂反应的官能团Y的例子包括胺反应剂,例如但不限于N-羟基琥珀酰亚胺酯,对硝基苯酯,二硝基苯酯,五氟苯酯;硫醇反应剂,例如但不限于吡啶基二硫化物,硝基吡啶二硫化物,马来酰亚胺,卤代乙酸酯和羧酸氯化物。
能够连接细胞毒性药物的官能团Z的实例包括能够经由二硫化物,硫醚,硫酯,肽,腙,酯,氨基甲酸酯,碳酸酯,烷氧基肟或酰胺键连接的基团。这样的官能团包括但不限于硫醇,二硫化物,氨基,羧基,醛,马来酰亚胺基,卤代乙酰基,肼,烷氧基氨基和/或羟基。
在优选的实施方案中,,R1,R2,R3,和R4,是具有1-6个碳原子的直链烷基或式(OCH2CH2)p,p=1~100,的聚乙烯氧基单元。
在另一个实施方案中,当式(I)的亲水连接基团具有两个或更多个Y基团,特别是两个相同的Y基团时,在这种情况下,Q或/和T是–X1–P(=O)[X2-R1-Y]-X3-,那么式(I)的亲水性连接体可以用于连接两个或更多个位点,特别是连接到一对细胞结合分子的位点。其中X1,X2和X3独立地选自N(R7),O,CH2或S;R1定义如上面。
在另一个实施方案中,当式(I)的亲水性链接体具有两个或更多个Z基团时,在这种情况下,Q或/和T是–X1–P(=O)[X2-R4-Z]-X3-,那么式(I)的亲水性连接体可以用于连接两种或更多个药物,特别是两种不同的药物。其中X1,X2和X3独立地选自N N(R7),O,CH2或S;R4定义如上面。
式(I)的含有2-二硫代-吡啶基的交联链接体的合成例子在图2,6,9,11和12中所示。式(I)的含马来酰亚胺基的交联链接体的合成例子在图1,3,4,5,7,8,10,13和17中所示。式(I)的含硫醚交联链接体的合成例子在图1,3,4,5,7,8,10,12和17中所示。式(I)的含有聚乙二醇的亲水性交联链接体的合成示例子在图7,8,9,11,12,13,14,15,16,17和18中所示。式(I)含有叠氮化物的亲水性交联链接体用于Huisgen 1,3-偶极环加成叠氮化物到炔烃上(也称为点击化学)的合成含有叠氮化物的例子在图8,9,13和18中所示。具有能够通过酸不稳定键连接的酰肼或酮或烷氧基部分的式(I)的亲水性交联链接体的合成例子在图6,9,11,14,15和16中所示。合成可以每个链接体连接两个药物或每个连接物连接两个位点的式(I)的亲水连接体的例子在图1,2,3,4,5,6,7,17和18中显示。合成可以每个链接体连接两个不同化合物/药物的式(I)的亲水连接体的例子在图8,9,11,14,15,16和17中显示。合成可以每个链接体连接一个细胞毒性化合物和一个发色团分子的式(I)的亲水连接体的例子在图13中显示。
细胞结合剂-药物偶联物
本发明的偶联物可以由下式Cb-(-L-Drug)n,表示,其中Cb是细胞结合剂,L是亲水性链接体,Drug是药物分子,n是从1到20的整数。
亲水性连接体L可以含由一种或多种连接体组分。例如的组分包括6-马来酰亚胺己酰基(“MC”),马来酰亚胺丙酰基(“MP”),缬氨酸-瓜氨酸(“val-cit”或“vc”),丙氨酸-苯丙氨酸(“ala-phe”或“af”),4-氨基苄氧羰基(“PAB”),4-硫代戊酸酯(“SPP”),4-(N-马来酰亚胺甲基)环己烷-1羧酸酯(“MCC”),4-乙酰氨基苯甲酸酯(SPO),4-硫代-2-羟基磺酰基-丁酸酯(2-磺基-SPDB),乙烯氧基-–CH2CH2O-作为一个或多个重复单元(“EO”或“PEO”)。其他链接体组件在本领域中是已知的,并且一些链接体组在此进行描述。
这些含有链接体的组分的实例结构是:
优选地,偶联物具有下式(II):
其中:
Cb代表细胞结合剂;
Drug代表药物是依烷基,亚烷基,亚烯基,亚炔基,醚,聚氧化烯,酯,胺,亚胺,多胺,肼,腙,酰胺,尿素,氨基脲,卡巴肼,烷氧基胺,聚氨基甲酸酯,氨基酸,肽,酰氧基胺,异羟肟酸,二硫化物,硫醚,硫酯,氨基甲酸酯,碳酸酯,杂环,杂烷基,杂芳基或烷肟键或它们的组合的键通过亲水性链接体与细胞结合剂连接。
q是1~30;m,n,R1,R2,R3,R4,R5,R6和M与前述式(I)中的描述相同。
Q和T是–X1–P(=O)(OM)-,或–X1-S(O2)-,或–X1–S(O)-;或–X1–P(=O)(OM)-X2-,或–X1–P(=O)[X2-R4-Drug]-X3-,或–X1–P(=O)[X2-R1-Cb]-X3-,或–X1-S(O2)-X2-,或–X1–S(O)-X2-;其中X1,X2和X3与式(I)中所述的相同。
在另一个实施方案中,当式(II)的偶联物具有两个或更多个Cb基团,特别是两个相同的Cb基团时,在这种情况下,Q或/和T是–X1–P(=O)[X2-R1-Cb]-X3-,则式(II)的偶联物连接至两个或更多个位点,特别是一对细胞结合分子的位点。
在另一个实施方案中,当式(II)的偶联物具有两个或更多个Drug基团时,在这种情况下,Q或/和T是–X1–P(=O)[X2-R4-Drug]-X3-,则式(II)的偶联物与两个或更多个药物连接,特别是两个或更多个不同的药物。
如下面更详细描述的,药物可以是许多小分子药物中的任何一种,包括但不限于tubulysins,卡利奇霉素,奥瑞斯他汀,美登素,CC-1065衍生物,吗啉多柔比星,紫杉醇,隐藻菌素,埃博霉素和苯并二氮卓二聚体(如吡咯苯二氮卓二聚体、茅屋霉素二聚体、吲哚啉苯二氮卓二聚体、咪唑苯二氮卓二聚体、恶唑啉苯二氮卓二聚体)类。
为了合成偶联物,细胞结合剂可以首先用本发明的亲水性链接体进行修饰以引入二硫化物,马来酰亚胺基,卤代乙酰基,叠氮化物,1-炔,酮,醛,烷氧基氨基或酰肼的反应性基团。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与含有游离巯基的药物之间的二硫键交换来实现的。通过硫醚连接的细胞结合剂-药物偶联物的合成通过马来酰亚胺基或卤代乙酰基或乙基磺酰基修饰的细胞结合剂与含有游离巯基的药物的反应来实现。带有酸不稳定的腙键的偶联物的合成可以通过本领域已知的方法依羰基与链接体中的酰肼部分的反应来实现(参见例如P.Hamann等人,CancerRes.53,3336-334,1993;B.Laguzza等人,J.Med.Chem.,32;548-555,1959;P.Trail等,Cancer Res.,57;100-105,1997)。
另外,可以用本发明的亲水性连接体对药物进行修饰,以得到具有能够与细胞结合剂反应的功能的式(IV)的修饰药物。例如,含巯基的药物可以与具有马来酰亚胺,卤代乙酰基或乙基磺酰基取代基的式(I)的亲水性连接基在中性pH含水缓冲液中反应,得到依硫醚键连接亲水性链接体连接的药物。含硫醇的药物可以与带有二烷基二硫代部分的亲水性链接体进行二硫化物交换,从而得到通过二硫键与亲水性交联链接体连接的改性药物。具有羟基或巯基的药物可以在温和碱存在下与本发明的带有卤素的亲水性连接物反应,得到带有醚或硫醇醚键的改性药物。含有羟基的药物可以在脱水剂如EDC或DCC的存在下与带有羧基的式(I)的亲水性交联链接体缩合,得到酯键改性药物。含氨基的药物可以类似地与式(I)的亲水性连接体上的羧基进行缩合而得到酰胺键链接。
偶联物可以通过标准的生物化学手段如Sephadex G25或Sephacryl S300柱上的凝胶过滤、吸附层析和离子交换或通过透析来纯化。在某些情况下,与小分子药物偶联的小分子作为细胞结合剂(如叶酸,黑素细胞刺激素,EGF等)可通过色谱如HPLC,中压柱层析或离子交换色谱法来纯化。
修饰的细胞结合剂
通过与本发明的链接体反应而修饰的细胞结合剂优选于式(III)
[01]其中Cb,q,m,n,,R1,R2,R3,R4,R5,R6和Z以及其中的取代基与前述式(I)和(II)中的描述相同。
Q和T是–X1–P(=O)(OM)-,或–X1-S(O2)-,或–X1–S(O)-;或–X1–P(=O)(OM)-X2-,或–X1–P(=O)[X2-R4-Z]-X3-,或–X1–P(=O)[X2-R1-Cb]-X3-,或–X1-S(O2)-X2-,或–X1–S(O)-X2-;
其中X1,X2和X3与式(I)中所述的相同。
在另一个实施方案中,当式(III)的化合物具有两个或更多个Cb基团,特别是两个相同的Cb基团时,在这种情况下,Q或/和T是–X1–P(=O)[X2-R1-Cb]-X3-,那么式(III)的化合物连接两个或更多个位点,特别是一对细胞结合分子的位点。
在另一个实施方案中,当式(III)的化合物具有两个或更多个Z基团时,在这种情况下,Q或/和T是–X1–P(=O)[X2-R4-Z]-X3-,那么式(III)的化合物可用于连接两种或更多种药物,特别是两种不同的药物。
在优选的实施方案中,Z是二硫化物取代基,马来酰亚胺基,卤代乙酰基,烷氧胺基,肼基或N-羟基琥珀酰亚胺酯基基团,并且R1与Cb经硫醚,腙,酰胺,烷肟,氨基甲酸酯或二硫键连接。修饰的细胞结合剂可通过细胞结合剂与亲水性链接体的反应制备。这些方法在本领域其它交联链接体的方法制备中已经知晓(美国专利号5,846,545,5,585,499,5,475,092,5,414,064,5,208,020,and 4,563,304;Carlsson,J.等..Biochem.J.(1978)173,723-737(1978);Goff,D.A.,Bioconj.Chem.(1990),1,381-386;L.Delprino等.J.Pharm.Sci.(1993),82,506-512;S.Arpicco等,Bioconjugate Chem(1997),8,327-337).
有利的是,因为亲水性链接体上的磷酰胺,次膦酸盐,磺酰胺,磺酰基,磺酰亚胺和/或亚砜基团可溶于水或仅需要小百分比的有机溶剂以维持在水溶液中的溶解度,细胞结合剂和链接体可以在水溶液中进行。将链接体溶解在含少量(通常<10体积%)的可与水混溶的极性有机溶剂(例如不同的醇如甲醇,乙醇和丙醇),丙酮,乙腈,四氢呋喃(THF),1,4-二恶烷,二甲基甲酰胺(DMF),二甲基乙酰胺(DMA)或二甲基亚砜(DMSO)的水缓冲溶液中以达高浓度,如1-100mM,然后加入适当的等分试样细胞结合剂的缓冲水溶液中。合适的等分试样溶液中以每个细胞结合剂引入1-10个链接体基团的,优选地1-6个链接体基团,并且待加入的体积不应超过10%,优选5%,最优选0-3%的细胞结合剂溶液的体积量。细胞结合剂的水溶液被缓冲在pH 6和9之间,优选在6.5和7.5之间,并且可以是含有任何对这些pH范围有用的非亲核性缓冲盐。典型的缓冲剂包括磷酸盐,三乙醇胺HCl,HEPES和MOPS缓冲剂,它们可以含有其他组分,如环糊精,蔗糖和盐份,例如NaCl和KCl。添加后,将反应在4℃至45℃的温度下,优选在环境温度下温育。反应的进程可以通过测量在280或320nm或另一适当波长下的吸收的增加来监测。反应完成后,可以使用常规方式如凝胶过滤色谱或吸附色谱法分离修饰的细胞结合剂。
修饰的程度可以通过测量释放出的N-氧代吡啶硫酮,二硝基吡啶二硫酮,吡啶硫酮,甲酰氨基吡啶二硫酮和二甲酰胺基吡啶二硫酮基团的吸光度来评估。本文描述的亲水性链接体具有不同的官能团,其可以与任何具有合适取代基的细胞结合剂反应。例如带有氨基或羟基取代基的细胞结合剂可以与带有N-羟基琥珀酰亚胺(NHS)酯的交联链接体反应,带有硫醇取代基的细胞结合剂可以与带有马来酰亚胺基或卤代乙酰基的交联链接体反应。另外,带有羰基取代基的细胞结合剂可以与带有酰肼或烷氧基胺的链接体反应。本领域技术人员可以基于细胞结合剂上可用功能基团的已知反应性较容易地确定使用哪个链接体。
修饰细胞毒药物
通过与本发明的交联链接体反应而修饰的细胞毒性药物优选于式(IV):
其中Y,m,n,R1,R2,R3,R4,R5,R6和药物,以及式(IV)中的取代基如同前述式(I)和(II)中所述。
Q和T是–X1–P(=O)(OM)-,或–X1-S(O2)-,或–X1–S(O)-;或–X1–P(=O)(OM)-X2-,或–X1–P(=O)[X2-R4-Drug]-X3-,或–X1–P(=O)[X2-R1-Y]-X3-,或–X1-S(O2)-X2-,或–X1–S(O)-X2-;其中X1,X2和X3与式(I)中所述的相同。
在另一个实施方案中,当式(IV)的化合物中有两个或更多个Y基团,特别是两个相同的Y基团时,在这种情况下,Q或/和T是–X1–P(=O)[X2-R1-Y]-X3-,,则式(IV)的化合物可连接至两个或更多个位点,特别是一对细胞结合分子的位点。
在另一个实施方案中,当式(IV)的化合物具有两个或更多个Drug基团时,在这种情况下,Q或/和T是–X1–P(=O)[X2-R4-Drug]-X3-,则式(II)的化合物与两种或更多种药物连接,特别是连接两种或更多种不同的药物。
在优选的实施方案中,Y是二硫化物取代基,马来酰亚胺基,卤代乙酰基,烷氧基氨基,羧酸或N-羟基琥珀酰亚胺酯。
修饰药物可以通过使药物与本发明的连接体反应来制备,从而得到具有能够与细胞结合剂反应的功能的式(IV)的修饰药物。例如,含巯基的药物可以与具有马来酰亚胺取代基的式(I)的链接体在中性pH下在含水缓冲液中反应,得到通过硫醚键连接至亲水性链接体的药物。含巯基的药物可以与带有二烷基二硫代部分的亲水性链接体进行二硫化物交换,得到通过二硫键与亲水性链接体连接的修饰药物。带有羟基的药物可以在弱碱存在下与带有卤素的连接体反应,得到带有醚键的修饰的药物。在脱水剂如EDC或二环己基碳化二亚胺(DCC)的存在下,含羟基的药物可以与带有羧基的式(I)的连接基缩合,得到酯键。具有巯基的药物可以与带有马来酰亚胺基或乙烯基磺酰基或卤代乙酰基的连接基反应,得到带有硫醚键的修饰的药物。含氨基的药物可以类似地与式(I)的亲水性连接体上的羧基进行缩合而得到酰胺键的修饰的药物。修饰的药物可以通过标准方法如硅胶或氧化铝上的柱色谱,结晶,制备薄层色谱,离子交换色谱或HPLC来纯化。
细胞结合剂
本发明的细胞结合分子构造的偶联物和修饰的细胞结合剂的可以是目前已知的或将知的任何种类的与细胞群的一部分结合,复合或反应的分子,此分子可进行治疗或其他生物学上修饰。
细胞结合剂包括但不限于大分子量蛋白,例如全长抗体(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;诸如Fab,Fab',F(ab')2,Fv,[Parham,J.Immunol.113,2895-2902(1983)]的抗体片段,由Fab表达文库产生的片段,特异性结合癌细胞抗原,病毒抗原,微生物抗原或由免疫系统产生的能够识别,结合的蛋白质的上述任一种的抗独特型(抗-Id)抗体,CDR和表位结合片段(Miller et al(2003)J.of Immunology 170:4854-4861);干扰素(如I,II,III型);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);激素如胰岛素,TRH(促黑激素释放激素),MSH(促黑素细胞激素),类固醇激素如雄激素和雌激素,黑素细胞刺激素(MSH);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)等生长因子和集落刺激因子-I,IGF-II)G-CSF,M-CSF和GM CSF[Burgess,Immunology Today,5,155-158(1984)];牛痘生长因子(VGF);成纤维细胞生长因子(FGF);较小分子量的蛋白质,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-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)等白细胞介素和细胞因子;维生素,如叶酸;脱蛋白和糖蛋白,例如转铁蛋白[O'Keefe等,260J.Biol.Chem。化学。932-937(1985)];糖结合蛋白或脂蛋白,如凝集素;细胞营养传递分子;和诸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的小分子抑制剂(Dhar,等人,Proc.Natl.Acad.Sci.2008,105,17356-61);生物活性树状聚体(Lee,等,Nat.Biotechnol.2005,23,1517-26;Almutairi,等;Proc.Natl.Acad.Sci.2009,106,685-90);纳米颗粒(Liong等,ACS Nano,2008,19,1309-12;Medarova等,Nat.Med.2007,13,372-7;Javier等,Bioconjugate Chem.2008,19,1309-12);脂质体(Medinai等人,Curr.Phar.Des.2004,10,2981-9);病毒衣壳(Flenniken等,Viruses Nanotechnol.2009,327,71-93)。
一般而言,如果适当可选的话,则优选单克隆抗体作为细胞表面结合剂。抗体可以是鼠类,人类,人源化,嵌合或衍生自其他物种的抗体。
用于本发明的抗体的生产涉及体内或体外程序或其组合进行。生产多克隆抗受体肽抗体的方法在本领域是公知的,如美国专利4,493,795(授予Nestor等人)。通常通过将骨髓瘤细胞与来自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.(1975).Nature 256:495-497)。在Harlow和Lane编辑的Cold Spring HarborLaboratory Press,New York(1988)的“Antibodies-A Laboratory Manual”中描述了详细的程序,该文献在此引入作为参考。特别地,单克隆抗体通过用所需研究的抗原如完整的靶细胞,从靶细胞分离的抗原,全病毒,减毒的全病毒和病毒蛋白免疫小鼠,大鼠,仓鼠或任何其他哺乳动物来产生。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)的敏感性选择融合杂交物。产生可用于实施本发明的单克隆抗体的杂交瘤通过其特异性受体免疫反应或抑制靶细胞上的受体活性的能力来鉴定。
用于本发明的单克隆抗体可以通过启动包含含有杂交瘤的营养培养基的单克隆杂交瘤培养物来产生,所述杂交瘤分泌具有适当抗原特异性的抗体分子。在足以使杂交瘤将抗体分子分泌到培养基中的条件下保持培养物。然后收集含抗体的培养基。随后可以通过公知的技术进一步分离抗体分子,例如使用蛋白质-A亲和层析;阴离子,阳离子,疏水性或尺寸排阻色谱(特别是通过蛋白质A之后的特异性抗原的亲和力和尺寸排阻柱色谱法);离心,差异溶解度,或通过用于纯化蛋白质的任何其他标准技术。
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购买获得,包括合成培养基。示例性的合成培养基是Dulbecco's极为必需培养基(DMEM;Dulbecco等,Virol.8,396(1959)补充有4.5g/l葡萄糖,0-20mM谷氨酰胺,0-20%胎牛血清,几个ppm的重金属例如Cu,Mn,Fe或Zn等重金属或/和以其盐形式加入,以及与消泡剂如聚氧乙烯-聚氧丙烯嵌段共聚物的量。
此外,抗体生成细胞系还可以通过融合以外的技术产生,例如用致癌DNA直接转化B淋巴细胞,或者用诸如EB病毒(EBV,也称为人疱疹病毒4(HHV-4))或卡波西肉瘤相关疱疹病毒(KSHV)转染。参见美国专利美国专利号4,341,761;4399121;4427783;4,444,887;4451570;4,466,917;4472500;4491632;4493890。单克隆抗体也可以如本领域公知的那样通过含有羧基末端的抗受体肽或肽产生。参见Niman等人,Proc.Natl.Acad.Sci.USA,80:4949-4953(1983);Geysen等人.,Proc.Natl.Acad.Sci.USA,82:178-182(1985);Lei等人.Biochemistry 34(20):6675-6688,(1995).。通常,抗受体肽或肽类似物单独使用或与免疫原性载体偶联,作为产生抗受体肽单克隆抗体的免疫原。
在本发明中还有许多其他众所周知的用于制备单克隆抗体作为结合分子的技术。特别有用的是制备完全人抗体的方法。一种方法是噬菌体展示技术,其可以用于使用亲和富集的方法来选择与抗原特异性结合的一系列人类抗体。已有文献充分描述了噬菌体展示,并且噬菌体展示文库的构建和筛选在本领域中是公知的,参见例如Dente等人,Gene.148(1):7-13(1994);Little等人,Biotechnol Adv.12(3):539-55(1994);Clackson等人,Nature 352:264-628(1991);Huse等人,Science 246:1275-1281(1989)。
通过杂交瘤技术从人以外的另一物种如小鼠衍生的单克隆抗体可以被人源化以避免人输注时产生的人抗小鼠抗体。抗体人源化的更常见方法是互补决定区移植和表面重建。这些方法已被广泛地描述,参见例如美国专利美国专利号5,859,205和6,797,492;Liu等人,Immunol Rev.222:9-27(2008);Almagro等人,Front Biosci.13:1619-33
(2008);Lazar等人,Mol Immunol.44(8):1986-98(2007);Li等人,Proc.Natl.Acad.Sci.U S A.103(10):3557-62(2006),每一篇均通过其含引用并入本文。完全人抗体也可以通过用免疫原免疫转基因小鼠,兔子,猴子或携带大部分人免疫球蛋白重链和轻链的其它哺乳动物来制备。这种小鼠的例子是:Xenomouse.(Abgenix/Amgen),HuMAb-小鼠(Medarex/BMS),VelociMouse(Regeneron)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中。在对人治疗中,也可以将鼠可变区和人恒定区融合以构建称为“嵌合抗体”的构建体,其在人中的免疫原性比鼠mAb低得多(Kipriyanov等,Mol Biotechnol.26:39-60(2004);Houdebine,Curr Opin Biotechnol.13:625-9(2002),每文在此引入作为参考)。此外,抗体可变区中的定点诱变可导致对其抗原具有更高亲和力和特异性的抗体(Brannigan等人,Nat Rev Mol Cell Biol.3:964-70,(2002));Adams等人,J Immunol Method.231:249-60(1999)),并且交换mAb的恒定区可以改善其介导结合和细胞毒性的效应子功能的能力。
对恶性细胞抗原具有免疫特异性的抗体也可以商业获得或通过本领域技术人员已知的任何方法例如化学合成或重组表达技术来获得。对恶性细胞抗原具有免疫特异性的抗体的核苷酸编码序列可以商业购买获得,例如从GenBank数据库或其类似的数据库,文献出版物,或通过常规克隆和测序获得。
除了抗体之外,能够结合/阻断/靶向或以某种其它方式与靶细胞上的表位或相应受体相互作用的肽或蛋白质可用作结合分子。这些肽或蛋白质可以是对表位或相应受体具有亲和力的任何随机肽或蛋白质,并且它们不一定必须属于免疫球蛋白家族。这些肽可以通过与噬菌体展示抗体相似的技术分离(Szardenings,J Recept Signal TransductRes.2003;23(4):307-49)。来自这种随机肽文库的肽的使用可以类似于抗体和抗体片段。肽或蛋白质的结合分子可以是结合或偶联在大分子或材料上或与大分子或材料上,例如但不限于白蛋白、聚合物、脂质体、纳米颗粒、树状聚体,只要这种结合允许肽或蛋白质保留其抗原结合特异性。
在本发明中用于与药物通过亲水链偶联的,用于治疗癌症、自身免疫性疾病和感染性疾病的抗体举例,但不限于此,如下:3F8(抗GD2抗体),阿巴伏单抗(抗CA-125抗体),阿昔单抗(抗CD41抗体(整合素α-IIB),阿达木单抗(抗-TNF-α抗体),阿德木单抗(抗-EpCAM抗体,CD326),阿非莫单抗(抗-TNF-α);阿夫土珠(抗-CD20抗体),Alacizumab pegol(抗VEGFR2抗体),ALD518(抗-IL-6抗体),阿仑单抗(别名:Campath,MabCampath,坎帕斯,抗CD52抗体),阿妥莫单抗(抗CEA抗体),Anatumomab(抗-TAG-72抗体),Anrukinzumab(别名:IMA-638,抗-IL-13抗体),阿泊珠单抗(抗-HLA-DR抗体),阿西莫单抗(抗CEA抗体),阿塞珠单抗(抗-L-选择素(CD62L)抗体,Atlizumab(别名:托珠单抗,Actemra,RoActemra,抗-IL-6受体抗体),Atorolimumab(抗恒河猴因子抗体),bapineuzumab(抗β-淀粉样蛋白抗体),巴利昔单抗(舒莱,antiCD25(IL-2受体的α链)抗体,巴维昔单抗(抗磷脂酰丝氨酸抗体),贝妥莫单抗(别名:LymphoScan,抗-CD22抗体),贝利木单抗(别名:Benlysta,LymphoStat-B,抗BAFF抗体),Benralizumab(抗CD125抗体),柏替木单抗(抗CCL11(嗜酸性粒细胞趋化因子-1)抗体),贝索单抗(别名:Scintimun,抗CEA-相关抗原抗体),贝伐单抗(别名:阿瓦斯丁,抗VEGF-A抗体)比西单抗(别名:FibriScint,抗血纤维蛋白Ⅱβ链抗体),Bivatuzumab(抗CD44v6抗体),blinatumomab(别名:BiTE,抗CD19抗体),Brentuximab(CAC10,抗-CD30 TNFRSF8抗体),Briakinumab(抗-IL-12,IL-23抗体),康纳单抗(别名:Ilaris,抗-IL-1抗体),Cantuzumab(别名:C242,抗CanAg抗体),卡罗单抗,卡妥索单抗(别名:removab,抗EpCAM,抗-CD3抗体),CC49(抗-TAG-72抗体),Cedelizumab(抗CD4抗体),赛妥珠单抗(别名Cimzia抗TNF-α抗体),西妥昔单抗(别名:爱必妥,IMC-C225,抗-EGFR抗体),西他土珠(抗-EpCAM抗体),Cixutumumab(抗-IGF-1抗体),克立昔单抗(抗CD4抗体),Clivatuzumab(抗MUC1抗体),Conatumumab(抗-TRAIL-R2抗体),CR6261(抗A型流感血凝素抗体),Dacetu-zumab(抗-CD40抗体),达利珠单抗(别名:赛尼哌,抗CD25(IL-2受体的α链)抗体),Daratumumab(抗-CD38(环化ADP核糖水解酶)抗体),,狄诺塞麦(别名:Prolia,抗RANKL抗体),地莫单抗(抗B-淋巴瘤细胞抗体),阿托度单抗,Dorlixizumab,Ecromeximab(抗-GD3神经节苷脂抗体),依库丽单抗(别名:Soliris,抗-C5抗体),埃巴单抗(抗内毒素抗体),依决洛单抗(别名:Panorex,MAb17-1A,抗-EpCAM抗体),依法利珠单抗(别名:Raptiva,抗LFA-1(CD11a)抗体),依芬古单抗(别名:Mycograb,抗Hsp90抗体),Elotuzumab(抗SLAMF7抗体),伊斯利莫(抗IL-6抗体),恩莫单抗(抗ICAM-1(CD54)抗体),Epitumomab(抗episialin抗体),依帕珠单抗(抗-CD22抗体),Erlizumab(抗ITGB2(CD18)抗体),Ertumaxomab(别名:Rexomun,抗HER2/neu,CD3抗体),伊瑞西珠(别名:Abegrin,抗整合素αvβ3抗体),艾韦单抗(抗乙型肝炎表面抗原抗体),Fanolesomab(别名:NeutroSpec,抗CD15抗体),法拉莫单抗(抗干扰素受体抗体),Farletuzumab(抗叶酸受体1抗体),Felvizumab(抗呼吸道合胞病毒抗体),Fezakinumab(抗IL-22抗体),Figitumumab(抗IGF-1受体抗体),Fontolizumab(抗IFN-γ抗体),夫瑞韦如(抗狂犬病毒糖蛋白抗体),Fresolimumab(抗TGF-β抗体),加利昔单抗(抗CD80抗体),Gantenerumab(抗-β淀粉样蛋白抗体),Gavilimomab(抗-CD147(basigin)抗体),吉妥单抗(抗CD33抗体),Girentux-imab(抗碳酸酐酶9抗体),Glembatumumab 5(别名:CR011,抗GPNMB抗体),戈利木单抗(别名:SIMPONI,抗TNF-α抗体),Gomiliximab(抗CD23(IgE受体)抗体),Ibalizumab(抗CD4抗体),替伊莫单抗(抗CD20抗体),伊戈伏单抗(别名:Indimacis-125,抗CA-125抗体),英西单抗(别名:Myoscint,抗心肌肌球蛋白抗体),英夫利昔单抗(别名:英利昔单抗,抗TNF-α抗体),Intetu-mumab(抗CD51抗体),伊诺莫单抗(抗CD25(IL-2受体α链)抗体),Inotu-zumab(抗CD22抗体),易普利姆玛(抗CD152抗体),Iratumumab(抗CD30(TNFRSF8)抗体),Keliximab(抗CD4抗体),Labetuzumab(别名:CEA-Cide,抗CEA抗体),Lebrikizumab(抗IL-13抗体),Lemalesomab(抗NCA-90(粒细胞抗原)抗体),乐德木单抗(抗TGFβ-2抗体),来沙木单抗(抗TRAIL-R2抗体),利韦单抗(抗乙型肝炎表面抗原抗体),林妥珠单抗(抗CD33抗体),Lucatumumab(抗CD40抗体),鲁昔单抗(抗CD23(IgE受体)抗体),Mapa-tumumab(抗TRAIL-R1抗体),马司莫单抗(抗T-细胞受体抗体),马妥珠单抗(抗-EGFR抗体),美泊利单抗(别名:Bosatria,抗IL-5抗体),Metelimumab(抗TGFβ-1抗体),Milatuzumab(抗CD74抗体),Minretumomab(抗TAG-72抗体),米妥莫单抗(别名BEC-2,抗-GD3神经节苷脂抗体),Morolimumab(抗恒河猴因子抗体),莫维珠单抗(别名:NUMAX,抗呼吸道合胞病毒抗体),莫罗单抗-CD3(别名:OKT3 ORTHOCLONE,抗CD3抗体),他那可单抗(抗C242抗体),他那莫单抗(抗5T4抗体),那他珠单抗(别名:Tysabri,抗整合素α4抗体),奈巴库25单抗(抗内毒素抗体),Necitumumab(抗EGFR抗体),Nere-limomab(抗TNF-α抗体),尼妥珠单抗(别名:Theracim,Theraloc,抗EGFR抗体),Nofetumomab,ocrelizumab(抗CD20抗体),奥度莫单抗(别名:Afolimomab,抗LFA-1(CD11A)抗体),木单抗(别名:Arzerra,抗CD20抗体),Olaratumab(抗PDGF-Rα抗体),奥马珠单抗(别名:索雷尔,抗IgE Fc区抗体),Oportuzumab(抗EpCAM抗体),奥戈伏单抗(别名:OvaRex,抗CA-125抗体),Otelixizumab(抗CD3抗体),帕吉昔单抗(抗脂磷壁酸抗体),帕利珠单抗(别名:Synagis,Abbosynagis,抗呼吸道合胞病毒抗体),帕尼单抗(别名:维克替比,ABX-EGF,抗-EGFR抗体),Panobacumab(抗绿脓杆菌抗体),Pasco-lizumab(抗IL-4抗体),Pemtumomab(别名:Theragyn,抗MUC1抗体),帕妥珠单抗(别名:OMNITARG,2C4,抗HER2/neu抗体),培克珠单抗(抗C5抗体),Pintumomab(抗腺癌抗原抗体),普立昔单抗(抗CD4抗体),普托木单抗(抗波形蛋白抗体),PRO140(抗CCR5抗体),Racotumomab(别名:1E10,抗-(N-羟乙酰神经氨酸(NeuGc,NGNA)-神经节苷脂GM3)抗体),瑞非韦鲁(抗狂犬病毒糖蛋白抗体),Ramucirumab(抗VEGFR2抗体),雷珠单抗(别名:Lucentis,抗VEGF-A抗体),瑞西巴库(抗炭疽毒素,保护性抗原抗体),瑞加韦单抗(抗巨细胞病毒的糖蛋白B抗体),Reslizumab(抗IL-5抗体),Rilotumumab(抗HGF抗体),利妥昔单抗(别名:美罗华,Rituxanmab,抗CD20抗体),Robatumumab(抗IGF-1受体抗体),Rontalizumab(抗IFN-α抗体),Rovelizumab(别名:LeukArrest,抗CD11,CD18抗体),Ruplizumab(别名:Antova,抗CD154(CD40L)抗体),沙妥莫单抗(抗TAG-72抗体),司韦单抗(抗巨细胞病毒抗体),Sibrotuzumab(抗FAP抗体),Sifalimumab(抗IFN-α抗体),Siltuximab(抗IL-6抗体),Siplizumab(抗CD2抗体),(Smart)MI95(抗CD33抗体),Solanezumab(抗β-淀粉样蛋白抗体),Sonepcizumab(抗神经鞘氨醇-1-磷酸抗体),索土珠单抗(抗episialin抗体),司他莫鲁(抗肌肉生长抑制素抗体),硫索单抗(别名:LeukoScan,(抗-NCA-90(粒细胞抗原)抗体))),Tacatuzumab(抗α-甲胎蛋白抗体),他度珠单抗(抗整合素αIIbβ3抗体),他利珠单抗(抗IgE抗体),他尼珠(抗NGF抗体),Taplitumomab(抗CD19抗体),Tefibazumab(别名:Aurexis,抗聚集因子A抗体),阿替莫单抗,Tenatumomab(抗固生蛋白C抗体),替奈昔单抗(抗CD40抗体),Teplizumab(抗CD3抗体),TGN1412(抗CD28抗体),Ticilimumab(别名:Tremelimumab(抗CTLA-4抗体),Tigatuzumab(抗TRAIL-R2抗体),TNX-650(抗IL-13抗体),托珠单抗(别名Atlizumab,Actemra,RoActemra,(抗IL-6受体抗体),Toralizumab(抗CD154(CD40L)抗体),托西莫单抗(抗CD20抗体),曲妥珠单抗(赫赛汀,(抗HER2/neu蛋白抗体),Tremelimumab(抗CTLA-4抗体),Tucotuzumab celmoleukin(抗EpCAM抗体),妥韦单抗(抗B型肝炎病毒抗体),Urtoxazumab(抗大肠杆菌抗体),优斯它单抗(别名:Stelara,抗IL-12,IL-23抗体),伐利昔单抗(抗AOC3(VAP-1)抗体),Vedolizumab,(抗整合素α4β7抗体),Veltuzumab(抗CD20抗体),维帕莫单抗(抗AOC3(VAP-1)抗体,Visilizumab(别名:Nuvion,抗CD3抗体),Vitaxin(抗血管整合素avb3抗体),Volociximab(抗整合素α5β1),伏妥莫单抗(别名:HumaSPECT,抗肿瘤抗原CTAA16.88抗体),扎妥木单抗(别名:HUMAX-EGFR,(抗EGFR抗体),Zanolimumab(别名:HUMAX-CD4,抗CD4抗体),Ziralimumab(抗CD147(基础免疫球蛋白)抗体),阿佐莫单抗(抗CD5抗体),依那西普阿法赛特阿巴西普利纳西普(ARCALYST),14F7[抗IRP-2(铁离子调节蛋白2)抗体],14G2a(抗GD2神经节苷脂抗体,治疗黑色素瘤和实体瘤,Nat.cancerinst.),J591(抗PSMA抗体,治疗前列腺癌,威尔康乃尔医学院),225.28S[抗HMW-MAA(高分子量黑色素瘤相关抗原)抗体,索林Radiofarmaci SRL(意大利米兰)治疗黑色素瘤],COL-1(抗CEACAM3抗体,CGM1,Nat.cancer inst.。美国用于治疗大肠癌和胃癌),CYT-356(治疗前列腺癌),HNK20(OraVax公司,用于治疗呼吸道合胞病毒),ImmuRAIT(来自Immunomedics治疗非霍奇金淋巴瘤),Lym-1(抗HLA-DR10抗体,百富勤医药,用于癌症),MAK-195F[抗TNF抗体(又称:肿瘤坏死因子;TNFA,肿瘤坏死因子-α;TNFSF2),阿伯特/诺尔,用于治疗败血症中毒性休克],MEDI-500[别名:T10B9,抗CD3抗体,TRαβ(T细胞受体α/β),复合物,MedImmune公司用于治疗移植物抗宿主病],RING SCAN[抗TAG72(肿瘤相关糖蛋白72抗体),Neoprobe集团,用于治疗乳腺癌、结肠癌和直肠癌。Avicidin(抗-EpCAM抗体(上皮细胞粘附分子),抗TACSTD1抗体(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抗体(上皮糖蛋白2);抗KSA抗体;KS1/4抗原;M4S;肿瘤抗原17-1A;CD326,来自NeoRx公司用于治疗结肠癌,卵巢癌,前列腺癌和非霍奇金淋巴瘤;LymphoCide(IMMUNOMEDICS公司,NJ),smart ID10(Protein Design Labs),Oncolym(Techniclone公司,加利福尼亚州),Allomune(Bio-Transplant,CA),抗VEGF抗体(Genentech公司,CA);CEAcide(IMMUNO-MEDICS公司,NJ),IMC-1C11(ImClone,NJ)和西妥昔单抗(ImClone公司,美国新泽西州)。
其它与配体结合的抗体,此抗体具有抗下述抗原(但不仅限于此):氨肽酶N(CD13),膜联蛋白A1,B7-H3(CD276,各种癌症),CA125,CA15-3(癌),CA19-9(癌),L6(癌),Lewis Y(癌),Lewis X(癌),甲胎蛋白(癌),CA242,胎盘碱性磷酸酶(癌),前列腺特异性抗原(前列腺癌),前列腺酸性磷酸酶(前列腺),表皮生长因子(癌),CD2(霍奇金病,非霍奇金淋巴瘤的淋巴瘤,多发性骨髓瘤),CD3的ε(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,系统性红斑狼疮),CD30(霍奇金淋巴瘤),CD33(白血病,自体免疫疾病),CD38(多发性骨髓瘤),CD40(淋巴瘤,多发性骨髓瘤,白血病),CD51(转移性黑素瘤,肉瘤),CD52(白血病),CD56(小细胞肺癌癌,卵巢癌,Merkel细胞癌,以及液体肿瘤,多发性骨髓瘤),CD66e(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(癌症),粘蛋白(癌),CD221(实体瘤),CD227(乳腺癌,卵巢癌),CD262(非小细胞肺癌和其他癌),CD309(卵巢癌),CD326(实体瘤),CEACAM3(大肠癌,胃癌),CEACAM5(癌胚抗原;CEA,CD66e)(乳腺癌,结肠直肠癌和肺癌),DLL4(Δ状-4),EGFR(表皮生长因子受体,各种癌症),CTLA4(黑色素瘤),CXCR4(CD184,血红素肿瘤,实体肿瘤),内皮糖蛋白(CD105,实体瘤),EPCAM(上皮细胞粘附分子,膀胱癌,头,颈,结肠,前列腺非霍奇金淋巴瘤,和卵巢癌),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神经节苷脂(癌症),G-28(一种细胞表面抗原glyvolipid,黑素瘤),独特型GD3(癌症),热休克蛋白(癌症),HER1(肺,胃癌),HER2(乳腺癌,肺癌和卵巢癌),HLA-DR10(NHL),HLA-DRB(非霍奇金淋巴瘤,B细胞白血病),人绒毛膜促性腺激素(癌),IGF1R(胰岛素样生长因子1受体,实体瘤,血液癌症),IL-2受体(白细胞介素2受体,T-细胞白血病和淋巴瘤),IL-6R(白细胞介素6受体,多发性骨髓瘤,类风湿性关节炎,Castleman病,IL6依赖性肿瘤),整合素(αvβ3,α5β1,α6β4,αllβ3,α5β5,αvβ5细胞附着因子,对各种癌症),MAGE-1(癌),MAGE-2(癌),MAGE-3(癌),MAGE 4(癌),抗转铁蛋白受体(癌),P97(黑色素瘤),MS4A1(跨膜域4亚科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,支气管和胃肠道癌症),MUC16(CA125)(卵巢癌),CEA(大肠),GP100(黑色素瘤),MART1(黑色素瘤)MPG(黑色素瘤),MS4A1(跨膜域4蛋白A,小细胞肺癌,非霍奇金淋巴瘤),核仁,神经癌基因产物(癌),P21(癌),抗(N-羟乙酰神经氨酸,乳腺癌,黑色素瘤的癌症),PLAP样睾丸碱性磷酸酶(卵巢癌,睾丸癌),PSMA(前列腺肿瘤),PSA(前列腺),ROBO4,TAG 72(肿瘤相关糖蛋白72,白血病,胃癌,结肠直肠癌,卵巢癌)中,T细胞的跨膜蛋白(癌症),Tie(CD202b),TNFRSF10B(肿瘤坏死因子受体超家族成员10B,癌症),TNFRSF13B(肿瘤坏死因子受体超家族成员13B,多发性骨髓瘤,非霍奇金淋巴瘤,以及其他癌症,类风湿性关节炎和系统性红斑狼疮),TPBG(滋养层糖蛋白,肾细胞癌),TRAIL-R1(肿瘤坏死凋亡诱导配体受体1,淋巴瘤,非霍奇金淋巴瘤,大肠癌,肺癌),VCAM-1(CD106,黑色素瘤),血管内皮生长因子,血管内皮生长因子-A,VEGF-2(CD309)(各种癌症)。通过抗体识别的一些其他的肿瘤相关抗原已审阅(Gerber等,mAbs 1:3,247-253(2009);Novellino等人,Cancer Immunol Immunother.54(3),187-207(2005)Franke等人,CancerBiother.Radiopharm.2000,15,459-76)。
细胞结合剂,更优选的抗体,可以是能够抗肿瘤细胞,病毒感染的细胞,微生物感染的细胞,寄生虫感染的细胞,自身免疫细胞,活化的细胞,骨髓细胞,活化的T细胞,B细胞,或黑素细胞。更具体地,细胞结合剂可以是能够抵抗以下抗原或受体中的任何一种的任何试剂/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 glycoprote-in,TPBG,5T4,Wnt-ActivatedInhibitory Factor 1or WAIF1),
细胞结合剂,更优选的抗体,可以是能够抗肿瘤细胞,病毒感染的细胞,微生物感染的细胞,寄生虫感染的细胞,自身免疫细胞,活化的细胞,骨髓细胞,活化的T细胞,B细胞,或黑素细胞。更具体地,细胞结合剂可以是能够抵抗以下抗原或受体中的任何一种的任何试剂/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(滋养层细胞糖蛋白,TPBG,5T4,Wnt激活抑制因子1或WAIF1),腺癌抗原,AGS-5,AGS-22M6,激活素受体样激酶1,AFP,AKAP-4,ALK,α整合素,αvβ6,氨基肽酶N,淀粉状蛋白β,雄激素受体,血管生成素2,促血管生成素3,膜联蛋白A1,炭疽毒素保护性抗原,抗转铁蛋白受体AOC3(VAP-1),B7-H3,炭疽杆菌炭疽菌,细胞激活因子),B-淋巴瘤细胞,bcr-abl,铃蟾肽,BORIS,C5,C242抗原,CA125(碳水化合物抗原125,MUC16),CA-IX(或CAIX,碳酸酐酶9),CALLA,CanAg,家族性狼疮家族IL31,碳酸酐酶IX,Cardi-ac肌球蛋白,CCL11(CC基序趋化因子11),CCR4(CC趋化因子受体4型,CD194),CCR5,CD3E(ε),CEA(癌胚抗原),CEACAM3,CAM5(癌胚抗原),CFD(因子D),Ch4D5,胆囊收缩素2(CCK2R),CLDN18(紧密连接蛋白18),凝聚因子A,CRIPTO,FCSF1R(集落刺激因子1受体,CD115)(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型,环状ADP核糖水解酶,细胞周期蛋白B1,CYP1B1,巨细胞病毒,巨细胞病毒糖蛋白B,达比加群,DLL4(δ样配体4),DPP4(二肽基肽酶4),DR5(死亡受体5)大肠杆菌志贺毒素-1型,大肠杆菌志贺毒素-2型,ED-B,EGFL7(EGF样结构域蛋白7),EGFR,EGFRII,EGFRvIII,内皮糖蛋白(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,α-胎蛋白,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.F呼吸蛋白合胞体病毒,卷曲蛋白受体,岩藻糖基GM1,GD2神经节苷脂,G-28(细胞表面抗原glyvolipid),GD3独特型,GloboH,磷脂酰肌醇蛋白聚糖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-C),肠道鸟苷酸环化酶,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,乙型肝炎表面抗原,乙型肝炎病毒,HER1(人表皮生长因子受体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(人白细胞抗原)HLA-DRB,HMW-MAA,人绒毛膜促性腺激素,HNGF,人分散因子受体激酶,HPV E6/E7,Hsp90,hTERT,ICAM-1(细胞间粘附分子1),个体基因型,IGF1R(IGF-1,胰岛素样生长因子1受体),IGHE,IFN-γ,流感血凝素,IgE,IgE Fc区,IGHE,IL-1,IL-2受体(白细胞介素2受体),IL-4,IL-5,IL-6,IL-6R(白细胞介素6受体),IL-9,IL-10,IL-12,IL-13,IL-17,IL-17A,IL-20,IL-22,IL-23,IL31RA,ILGF2(胰岛素样生长因子2),整联蛋白(α4,αIIbβ3,αvβ3,α4β7,α5β1,α6β4,α7β7,αllβ3,α5β5,αvβ5),干扰素γ诱导蛋白,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,脂胞壁酸质,LIV1A,LMP2,LTA,MAD-CT-1,MAD-CT-2,MAGE-1,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化抑制因子(GIF)),MS4A1(跨膜4结构域亚家族A成员1),MSLN(间皮素),MUC1(粘蛋白1,细胞表面缔合(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),Mela-nA/MART1,ML-IAP,MPG,MS4A1(跨膜4-结构域亚家族A),MYCN,髓鞘相关糖蛋白,肌肉生长抑制素,NA17,NARP-1,NCA-90(粒细胞抗原),Nectin-4(ASG-22M E),NGF,神经凋亡调节蛋白酶1,NOGO-A,Notch受体,核仁素,Neu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 nonmutant,P97,Page4,PAP,Paratope of anti-(N-glycolylneuraminicacid),PAX3,PAX5,PCSK9,PDCD1(PD-1,程序性细胞死亡蛋白1,CD279),PDGF-Rα,PY1,PY1,P13,P53,非变异型P97,PAP,Paratope,抗PAA3,PAX5,PCSK9,PDCD1(α型血小板衍生生长因子受体),PDGFR-β,PDL-1,PLAC1,PLAP样睾丸碱性磷酸酶,血小板衍生生长因子受体β,磷酸钠共转运蛋白,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),恒河猴因子,RANKL,RhoC,Ras突变体,RGS5,ROBO4,呼吸道合胞病毒,RON,肉瘤易位断点,SART3,硬化蛋白,SLAMF7(SLAM家族成员7),选择蛋白P,SDC1(Syndecan1),sLe(a),生长调节蛋白C,SIP(1-磷酸-鞘氨醇),生长抑素,精子蛋白17,SSX2,STEAP1(前列腺1的六跨膜上皮抗原),STEAP2,STn,TAG-72(肿瘤相关糖蛋白72),存活蛋白,T细胞受体,T细胞跨膜蛋白,TEM1(肿瘤内皮标记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β2),Tie2(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(滋养层糖蛋白),TRAIL-R1(肿瘤坏死性凋亡诱导配体受体1),TRAILR2(死亡受体5(DR5)),肿瘤相关钙信号转导子2,MUC1的肿瘤特异性糖基化,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或波形蛋白,WT1,XAGE1或任何表达胰岛素生长因子受体的细胞,或任何表皮生长因子受体表皮生长因子受体的细胞。
在另一个具体的实施方案中,经由本发明的亲水链接体的细胞结合配体-药物偶联物用于癌症的靶向治疗。靶向癌症包括但不限于肾上腺皮质癌,肛门癌,膀胱癌,脑肿瘤(成人,脑干胶质瘤,儿童期,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,视觉神经胶质瘤),乳腺癌,类癌瘤,胃肠道癌,不明原发性癌,宫颈癌,结肠癌,子宫内膜癌,食管癌,肝外胆管癌,尤文氏家族肿瘤(PNET),颅外生殖细胞肿瘤,眼癌症,眼内黑色素瘤,胆囊癌,胃癌(胃),生殖细胞瘤,胚外,妊娠滋养细胞肿瘤,头颈部癌,下咽癌,胰岛细胞癌,肾癌(肾细胞癌),喉癌,白血病(急性淋巴细胞性,急性骨髓性,慢性淋巴细胞性,慢性粒细胞性,毛细胞),唇和口腔癌,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,黑素瘤,默克尔细胞癌,隐匿性原发性,多发性骨髓瘤,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(上皮细胞瘤,生殖细胞瘤,低恶性潜能肿瘤),胰腺癌(外分泌细胞瘤,胰岛细胞癌),鼻窦癌,鼻窦癌,甲状旁腺癌,阴茎癌,嗜铬细胞瘤癌,垂体癌,浆细胞瘤,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)癌,唾液腺癌,塞扎里综合征,皮肤癌,皮肤癌(皮肤T细胞淋巴瘤,卡波西肉瘤,黑色素瘤),小肠癌,软组织肉瘤,胃癌,睾丸癌,胸腺瘤(恶性),甲状腺癌,尿道癌,子宫癌(肉瘤),不寻常的儿童癌症,阴道癌,外阴癌,肾母细胞瘤。
在另一具体实施例中,本发明采用亲水链接体的细胞结合分子-药物共轭体通过其组分和方法可以用来治疗或预防自身免疫疾病。自身免疫疾病包括,但不限于,胃酸缺乏自身免疫性慢性活动性肝炎,急性播散性脑脊髓炎,急性出血性脑白质炎,阿狄森氏病,丙种球蛋白血症,斑秃,肌萎缩性侧索硬化症,强直性脊柱炎,抗肾小球基底膜/肾小管基底膜肾炎,抗磷脂综合征,抗合成酶综合征,关节炎,异位性过敏症,过敏性皮炎,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,自身免疫性内耳病,自身免疫性淋巴组织增生综合征,自身免疫性周围神经系统疾病,自身免疫性胰腺炎自体免疫多内分泌症I,II,III型,自身免疫性孕酮皮炎,自身免疫性血小板减少性紫癜,自身免疫性色素层炎,巴洛病/巴洛同心性硬化,黑奇特综合征,Berger病,Bickerstaff脑干脑炎,Blau综合征,大苞性类天苞疮,巨淋巴结增生,美洲锥虫病,慢性疲劳免疫功能紊乱综合征,慢性炎症性脱髓鞘性多发神经病,慢性复发性多病灶性骨髓炎,慢性莱姆病,慢性阻塞性肺疾病,变应性肉芽肿性血管炎,瘢痕性类天疱疮,腹部疾病,耳蜗前庭综合征,冷凝集素病,补体C2缺乏症,颅动脉炎,肢端硬皮综合征,克隆氏病(一种特发性炎症性肠病),柯兴氏症,皮肤白细胞碎裂性血管炎,恶性萎缩性丘疹病,痛性肥胖病,疱疹样皮炎,皮肌炎,1型糖尿病,弥漫性皮肤硬皮病,心肌梗塞后综合征,盘状红斑狼疮,湿疹,子宫内膜异位症,幼年特发性关节炎,嗜酸细胞性筋膜炎,嗜酸细胞性筋膜炎,结节性红斑,特发性混合性冷球蛋白血症,埃文斯综合征,渐进性骨化性纤维组织结构不良,纤维肌痛,纤维肌炎,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,肺出血肾炎综合征,格雷夫斯氏病,格林-巴利神经根炎,桥本脑炎,淋巴瘤性甲状腺肿,溶血性贫血,过敏性紫癜多,妊娠期疱疹,化脓性汗腺炎,休斯综合症(抗磷脂抗体综合征),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(Berger病),包涵体肌炎,发炎性脱髓鞘病变,间质性膀胱炎,肠易激综合征,幼年特发性关节炎,幼儿型类风湿性关节炎,皮肤粘膜淋巴结综合征,兰伯特肌无力综合征,白细胞分裂性血管炎,扁平苔藓,硬化性苔藓,线状IgA病(LAD),肌萎缩性侧索硬化症,狼疮样肝炎,红斑狼疮,马吉德综合征,美尼尔氏综合症,显微镜下多血管炎,米勒·费希尔综合征,混合性结缔组织病,硬斑病,穆哈二氏病,韦尔斯综合征,多发性骨髓瘤,多发性硬化症,重症肌无力,肌炎,发作性睡病,视神经脊髓炎(德维克病),神经性肌强直,眼部瘢痕性类天疱疮,眼阵挛-肌阵挛综合征,奥德氏甲状腺炎,复发性风湿病,熊猫症候群(合并链球菌感染的儿童自体免疫神经精神异常),类肿瘤性小脑变性,阵发性睡眠性血红蛋白尿症,进行性一侧面萎缩,巴-特二氏综合征,睫状体扁平部炎,天疱疮,寻常型天疱疮,恶性贫血,静脉周围炎,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,进行性炎性神经病变,银屑病,银屑病关节炎,坏疽性脓皮,纯红细胞再生障碍性贫血,罗斯默森氏脑炎,雷诺病,复发性多软骨炎,莱特尔综合征,腿多动综合征,腹膜后纤维化,类风湿关节炎,类风湿发热,结节病,精神分裂症,施密特综合征,施尼茨勒综合征,巩膜炎,硬皮病,干燥综合征,脊椎关节病,粘血综合征,斯蒂尔病,僵人综合征,亚急性细菌性心内膜炎,Susac氏综合征,急性热性嗜中性皮肤病,西德纳姆舞蹈病,交感性眼炎,高安氏动脉炎,颞动脉炎(巨细胞动脉炎),痛性眼肌麻痹综合征,横贯性脊髓炎,溃疡性结肠炎(一种特发性炎症性肠疾病),未分化的结缔组织病,未分化脊柱关节病,血管炎,白癜风,韦格纳氏肉芽肿病,威尔逊氏综合征,威斯科特-奥尔德里奇综合征。
在另一具体实施方案中,通过本发明的亲水链接体链接的用于治疗或预防自身免疫疾病的细胞结合分子包括,但不限于:抗弹性蛋白抗体;Abys抗上皮细胞抗体;抗基底膜IV型胶原蛋白抗体;抗核抗体;抗双链DNA抗体;抗单链DNA抗体,抗心肌磷脂抗体IgM,IgG;抗celiac抗体;抗磷脂抗体IgK,IgG;抗核糖蛋白抗体;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,抗硬皮病-70抗体(anti-SCL-70);人抗Jo抗体;抗系统性红斑狼疮患者自身抗体;抗干燥综合症抗体(Anti-La/SSB);抗系统性红斑狼疮抗体;抗壁细胞抗体;抗组蛋白抗体;抗核糖核蛋白抗体(anti-RNP);中性粒细胞胞质抗体(C-ANCA);细胞核周围抗中性粒细胞抗体(P-ANCA);抗着丝粒抗体;抗核纤维蛋白抗体,以及抗肾小球基底膜抗体(GBM)抗体,抗神经节苷脂抗体;抗桥粒芯糖蛋白3抗体(anti-Desmogein3);抗人P62抗体;抗人sp100抗体;抗线粒体M2抗体;类风湿因子抗体;抗突变型瓜氨酸波形蛋白抗体(anti-MCV);抗拓扑异构酶抗体;抗中性粒细胞胞浆(CANCA)抗体。
在某些优选的实施方案中,本发明中用于共轭偶联的结合分子,可以与自身免疫性疾病相关的活化淋巴细胞表达的受体或受体复合物结合。包括免疫球蛋白基因超家族成员(如CD2,CD3,CD4,CD8,CD19,CD20,CD22,CD28,CD30,CD37,CD38,CD56,CD70,CD79,CD90,CD125,CD152/CTLA-4,PD-1,PDL-1,或ICOS),TNF受体超家族成员(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,APO-3),整联蛋白,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)或补体调控蛋白。
在另一特定实施方案中,对病毒性或细菌性抗原具有免疫特异性的有用的结合体是人源化的或人源单克隆抗体。本文所用术语“病毒性抗原”包括,但不限于:任何能诱发免疫反应的病毒肽段,多肽蛋白(例如,HIVgp120,HIV nef,RSV F糖蛋白,流感病毒神经氨酸酶,流感病毒血凝素,人类T淋巴细胞病毒感染调节因子tax,单疱疹病毒糖蛋白(例如,gB,gC,gD和gE)和乙型肝炎表面抗原)。本文所用的术语“细菌性抗原”包括,但不限于:任何能诱发免疫反应的微生物肽段,多肽蛋白,糖类,多糖,脂质分子(例如,细菌,真菌,致病性原生动物,酵母多肽包括,例如,脂多糖和荚膜多糖5/8)。可用于治疗病毒性或细菌性感染的抗体包括,但不限于:帕利珠单抗,一种用于治疗RSV感染的人源的抗呼吸道合胞体病毒单克隆抗体;PRO542,一种用于治疗HIV感染的CD4融合抗体;Ostavir,一种治疗乙肝病毒人源性抗体;PROTVIR,一种用于治疗巨细胞病毒人源化免疫球蛋白亚型I抗体,还有抗脂多糖(anti-LPS)抗体。
通过本发明亲水连接体的制备的细胞结合分子-药物共轭体可以用于治疗传染性疾病。这些传染病包括,但不限于:不动杆菌感染,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,微粒孢子虫病,炭疽,溶血隐秘杆菌感染,阿根廷出血热,蛔虫病,曲霉菌病,星状病毒感染,巴贝虫病,蜡样芽胞杆菌感染,细菌性肺炎,细菌性阴道病,类杆菌感染,小袋虫病,贝利蛔线虫感染,BK病毒感染,黑色发结节病,人芽囊原虫感染,芽生菌,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,布氏杆菌病,伯霍尔德杆菌感染,布鲁里溃疡,感染杯状病毒(诺罗病毒和札幌病毒),弯曲菌病,念珠菌感染(念珠菌病,鹅口疮),猫抓病,蜂窝组织炎,查格斯病(美洲锥虫病),软下疳,水痘,衣原体,肺炎衣原体感染,霍乱,着色真菌病,肝吸虫病,难辨梭状芽孢杆菌感染,球孢子菌病,科罗拉多蜱热,普通感冒(急性病毒鼻咽炎;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,皮肤幼虫移行症,环孢子虫感染,囊虫病,巨细胞病毒感染,登革热,双核阿米巴病,白喉,裂头绦虫,龙线虫病,埃博拉出血热,包虫病,埃里希体病,蛲虫病(蛲虫感染),肠球菌感染,肠病毒感染,流行性斑疹伤寒,传染性红斑(第五病),幼儿急疹,姜片虫病,家族致命性失眠症,丝虫病,产气荚膜梭菌引起的食物中毒,非寄生阿米巴感染,梭杆菌感染,气性坏疽(梭菌性肌坏死),地丝菌病,吉斯特曼-施特劳斯综合征,贾第虫病,马鼻疽,腭口线虫病,淋病,腹股沟肉芽肿,A组链球菌感染,B组链球菌感染,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,出血热肾病综合征,甲型肝炎,乙型肝炎,丙型肝炎,丁型肝炎,戊型肝炎,单纯疱疹,组织胞浆菌病,钩虫感染,人鲍坎病毒感染,人埃文氏埃立克体病,人粒细胞无形体病,人类偏肺病毒感染,人体单核细胞埃立克体病,人乳头状瘤病毒感染,人副流感病毒感染,膜壳绦虫病,爱泼斯坦-巴尔病毒传染性单核细胞增多症(单一),流感,等孢子球虫病,川崎病,角膜炎,金氏金氏杆菌感染,库鲁病,拉沙热,军团杆菌病(退伍军人协会会员病),军团杆菌病(庞蒂亚克热),利什曼病,麻风病,钩端螺旋体病,李氏杆菌病,莱姆病(莱姆疏螺旋体病),淋巴丝虫病(象皮肿),淋巴细胞性脉络丛脑膜炎,疟疾,马尔堡出血热,麻疹,类鼻疽(惠特莫尔氏病),脑膜炎,脑膜炎球菌病,后殖吸虫病,微孢子虫病,传染性软疣,流行性腮腺炎,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(新生儿眼炎),克—亚综合征(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,巴氏杆菌病,头虱病(头虱),体虱病(体虱),阴虱病(阴虱),盆腔炎,百日咳,鼠疫,肺炎球菌感染,肺孢子虫性肺炎,肺炎,脊髓灰质炎,普氏菌感染,原发性阿米巴脑膜脑炎,进行性多病灶脑白质病,鹦鹉热,Q热,狂犬病,鼠咬热,呼吸道合胞病毒感染,鼻孢子菌病,鼻病毒感染,立克次体感染,立克次氏体,裂谷热,洛矶山斑疹热,轮状病毒感染,风疹,沙门氏菌病,SARS(严重急性呼吸系统综合症),疥疮,血吸虫病,败血症,痢疾(菌痢),带状疱疹(带状疱疹),天花(天花),孢子丝菌病,葡萄球菌食物中毒,葡萄球菌感染,线虫,梅毒,绦虫病,破伤风(牙关紧闭症),须癣,头癣,体癣,股癣,手癣,黑糠疹,足癣,甲癣,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,尿素分解尿素支原体感染,委内瑞拉马脑炎,委内瑞拉出血热,病毒性肺炎,西尼罗热,白色毛结节菌病(白色毛结节菌病),假结核菌感染,耶尔森菌病,黄热病,接合菌病。
在本专利中被描述的细胞结合分子主要倾向为抗体。这些抗体可用来对抗致病菌。所对抗的致病菌包括,但不限于:鲍曼不动杆菌,以色列放线菌,戈氏放线菌和丙酸丙酸盐杆菌,布氏锥虫,HIV(人类免疫缺陷病毒),溶组织内阿米巴,无形体属,炭疽杆菌,溶血隐秘杆菌,胡宁病毒,蛔虫,曲霉属,星状病毒家庭,巴贝斯虫属,蜡样芽胞杆菌,多杆菌,类杆菌属,结肠小袋纤毛虫,贝利蛔线虫属,BK病毒,何德毛结节菌,人芽囊原虫,皮炎芽生菌,沙粒病毒,疏螺旋体属,肉毒梭菌,清风藤,布鲁菌属,通常洋葱伯克霍尔德菌和其他伯克霍尔德杆菌种,溃疡分枝杆菌,杯状病毒科家族,弯曲杆菌属,通常是白色念珠菌和其他念珠菌属,巴尔通体,A组链球菌和葡萄球菌,克氏锥虫,杜克雷嗜血杆菌,水痘带状疱疹病毒(VZV),沙眼衣原体,肺炎衣原体,霍乱弧菌,裴氏着色霉,华支睾吸虫,难辨梭状芽孢杆菌,粗球孢子菌和Cocci-dioides posadasii,科罗拉多蜱热病毒,鼻病毒,冠状病毒,朊病毒克雅氏病,克里米亚-刚果出血热病毒,新型隐球菌,隐孢子虫属,猫钩虫;multipleparasites,环孢子,猪带绦虫,巨细胞病毒,登革热病毒(DEN-1,DEN-2,DEN-3和DEN-4)虫媒病毒,脆弱双核阿米巴,白喉棒状杆菌,裂头属,麦地那龙线虫,埃博拉病毒,棘球属,埃立克体属,蛲虫,肠球菌属,肠道病毒属,普氏立克次体,细小病毒B19,人类疱疹病毒6型和人类疱疹病毒7型,布氏姜片吸虫,肝片吸虫和大片吸虫,FFI朊病毒,丝虫目超家族,产气荚膜杆菌,梭杆菌属,产气荚膜梭菌,其他梭菌属,白地霉,GSS朊病毒,肠贾第鞭毛虫,鼻疽伯克霍尔德氏菌,棘颚口线虫和刚棘颚口虫,淋病奈瑟菌,肉芽肿杆菌,化脓性链球菌,无乳链球菌,流感嗜血杆菌,肠道病毒,大多数柯萨奇A病毒和肠病毒71型,辛诺瓦病毒,幽门螺旋杆菌,大肠杆菌O157:H7,布尼亚病毒科家族,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型,单纯疱疹病毒2型,组织胞浆菌,十二指肠钩虫和美洲板口线虫,流感嗜血杆菌,人类博卡病毒,埃文氏埃立克体,无形体科,人类偏肺病毒,沙费埃里希体,人乳头瘤病毒,人副流感病毒,微小膜壳绦虫和缩小包膜绦虫,EB病毒,正粘病毒科,贝利等孢球虫,金氏金氏杆菌,肺炎克雷伯菌,Klebsiella ozaenas,库鲁病朊病毒,拉沙病毒,嗜肺军团菌,嗜肺军团菌,利什曼原虫属,麻风分枝杆菌和弥漫型痳疯分枝杆菌,钩端螺旋体属,李斯特菌,博氏包柔螺旋体和其他疏螺旋体属,班氏丝虫和马来丝虫,淋巴细胞性脉络丛脑膜炎病毒(LCMV),疟原虫属,马尔堡病毒,麻疹病毒,类鼻疽伯克氏菌,脑膜炎奈瑟菌,横川后殖吸虫,微孢子虫门,传染性软疣病毒(MCV),腮腺炎病毒,立克次体杆菌,肺炎支原体,多种细菌(马杜拉分枝菌病)和真菌(马杜拉分枝菌病),寄生双翅目蝇蛆,沙眼衣原体和淋球菌,vCJD朊病毒,星状诺卡氏菌和其他诺卡氏菌属物种,旋盘尾丝虫,巴西芽生菌,卫氏并殖吸虫和其他并殖吸虫属,巴斯德氏菌属,虱头癣,体虱,阴虱,百日咳博德特氏菌,鼠疫耶尔森氏菌,肺炎链球菌,卡氏肺囊虫,脊髓灰质炎病毒,普雷沃氏菌属,福氏耐格里阿米巴,JC病毒,鹦鹉热衣原体,立克次体,狂犬病毒,念珠状链杆菌和鼠咬热螺旋体,呼吸道合胞病毒,西伯鼻孢子虫,鼻病毒,立克次体属,螨立克次体,立夫特山谷热病毒,立氏立克次体,轮状病毒,风疹病毒,沙门氏菌属,非典型肺炎冠状病毒,疥螨,血吸虫属,志贺氏菌属,水痘带状疱疹病毒,重型天花或类天花,申克孢子丝菌,葡萄球菌属,金黄色葡萄球菌,化脓性链球菌,粪类圆线虫,梅毒螺旋体,绦虫属,破伤风梭菌,毛癣菌属,断发毛癣菌,发癣菌属,絮状表皮癣菌,红色毛癣菌和须癣毛癣菌,威尼克外瓶霉,毛癣菌属,马拉色菌属,犬弓首蛔虫或猫弓蛔虫,弓形虫,旋毛虫,阴道毛滴虫,鞭虫,结核杆菌,土拉热弗朗西丝菌,解脲支原体,委内瑞拉马脑炎病毒,霍乱弧菌,瓜纳瑞托病毒,西尼罗病毒,白色毛孢子菌,假结核耶尔森菌,小肠结肠炎耶尔森菌,黄热病毒,毛霉目(毛霉菌病)和虫霉目(虫霉菌病),铜绿假单胞菌,胎儿弯曲杆菌(弧菌),嗜水气单胞菌,迟缓爱德华氏菌,耶尔森菌,志贺痢疾杆菌,福氏痢疾杆菌,宋内志贺氏菌,鼠伤寒沙门氏菌,雅司螺旋体,Treponemacarateneum,奋森疏螺旋体,博氏包柔螺旋体,出血性黄疸钩端螺旋体,卡氏肺囊虫,布鲁氏菌,猪布鲁氏菌,布氏杆菌,支原体属,斑疹伤寒病原体,Rickettsia tsutsugumushi,披衣菌属;病原真菌(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,阴道毛滴虫,人毛滴虫,Tryoanosoma gambiense,罗得西亚锥虫,杜氏利什曼原虫,热带利什曼原虫,巴西利什曼原虫,肺囊虫肺炎,间日疟原虫,恶性疟原虫,恶性疟疾)或蠕虫(日本血吸虫,曼氏血吸虫,埃及血吸虫和钩虫)。
其他作为细胞结合配体的抗体在本发明中用于治疗多种病毒性疾病包括,但不限于:抗体作用于病原病毒的抗原包括以下例子但不限于:天花病毒,疱疹病毒,腺病毒,乳多空病毒科,肠道病毒科,细小RNA病毒科,细小病毒科,呼肠孤病毒,逆转录病毒科,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,沙粒病毒科,Non-A/Non-B肝炎病毒,鼻病毒,冠状病毒,轮状病毒科,肿瘤病毒[例如,乙型肝炎病毒(肝细胞癌),人乳头状瘤病毒(宫颈癌,肛门癌),卡波西肉瘤相关疱疹病毒(卡波济氏肉瘤),EB病毒(鼻咽癌,伯基特淋巴瘤,原发性中枢神经系统淋巴瘤),MCPyV(梅克尔细胞癌),SV40(猿猴病毒40),丙型肝炎病毒(肝癌),人类嗜T淋巴细胞病毒1型(成人T细胞白血病/淋巴瘤),免疫失调引起病毒:[如人类免疫缺陷病毒(艾滋病)];中枢神经系统病毒:[如,JCV(进行性多病灶脑白质病),MeV(亚急性硬化性全脑炎),LCV(淋巴细胞性脉络丛脑膜炎),虫媒病毒性脑炎,正粘病毒科(可能的)(昏睡性脑炎),RV(狂犬病),水疱性口炎-印度病毒属,疹病毒性脑膜炎,拉姆齐·亨特综合征II型;脊髓灰质炎(小儿麻痹症,后小儿麻痹症候群),人类嗜T淋巴细胞病毒1型(热带痉挛性截瘫)];巨细胞病毒(巨细胞病毒性视网膜炎,HSV(疱疹性角膜炎));心血管病病毒[如柯萨奇病毒(心包炎,心肌炎)];呼吸系统/急性鼻咽炎病毒/病毒性肺炎:[非洲淋巴细胞瘤病毒(疱疹病毒4型感染/传染性单核细胞增多),巨细胞病毒;SARS冠状病毒(严重急性呼吸器官综合征)正粘病毒:流感病毒A/B/C(流感/禽流感),副粘病毒:人类副流感病毒(副流感),呼吸道合胞病毒(人类呼吸道合胞病毒),肺病毒];消化系统病毒[MUV(腮腺炎),巨细胞病毒(巨细胞病毒性食管炎);腺病毒(腺病毒感染);轮状病毒,诺如病毒,星状病毒,冠状病毒;HBV(乙肝病毒),柯萨奇病毒,甲型肝炎(甲肝病毒),HCV(丙型肝炎病毒),HDV(丁型肝炎病毒),HEV(戊型肝炎病毒),HGV(庚型肝炎病毒)];泌尿生殖系统的病毒[如,BK病毒,MUV(腮腺炎)]。
按照更进一步的目标,由本发明的亲水链连接的共轭体包含药学上可接受的载体组分共同用来治疗癌症或自身免疫疾病。治疗癌症和自身免疫疾病的方法包括体外,体内或离体疗法。体外疗法应用实例,包括药物处理体外培养细胞,杀死除了没有表达目标抗原的细胞以外的所有细胞;或者杀死表达非想要的抗原的细胞。作为离体疗法的治疗方法的一个示例:在体外处理造血干细胞,杀死患病或恶性细胞后输回原患者体内。例如,临床上先通过间接体内治疗除去骨髓中的肿瘤细胞或淋巴细胞然后输回原患者来治疗癌症和自体免疫疾病,或者在移植前去除骨髓中的T细胞和其它淋巴细胞以防止对移植物的免疫拮抗反应。实施方法如下:从病人或其他个体获取骨髓细胞,然后在加入本发明共轭药物的含血清培养基中37℃培养,药物浓度范围为1pM到0.1mM,培养时间为30分钟左右到48小时左右。药物具体浓度和培养时间由经验丰富的临床医生决定。培养结束后,骨髓细胞用含血清培养基洗涤后,按照已知方法通过静脉注射输回人体内。如果病人在获取骨髓细胞和回输处理前需要接受其它治疗,比如烧蚀化疗或全身放射疗法的情况下,处理后的骨髓细胞可以保存在合格的液氮医疗设备中。
用于体内临床应用时,由本发明的链接体连接的共轭体药物将以溶液或能被无菌水溶解后注射的冻干固体的形式提供。合适的共轭药物给药方法实施例如下:共轭药物每星期通过静脉注射一次,持续8星期。单次剂量通过溶解于50到500毫升的生理盐水,生理盐水可以加入人血清白蛋白(例如,0.5到1毫升的100mg/ml的浓缩人血清白蛋白)。药物剂量大概在50μg到20mg每千克体重每星期,静脉注射(每次注射10ug到200mg/kg体重)。8周的治疗结束后,病人可以再接受新一轮的治疗。详细的治疗方法包括给药途径,赋形剂,稀释剂,药物剂量,治疗时间等等可以由有经验的临床医生决定。
可以通过体内或离体的方法选择性杀死细胞群来治疗疾病的例子包括任何种类的恶性肿瘤,自体免疫疾病,移植排斥和感染(包括病毒,细菌或寄生虫)疾病。
达到理想的生物学效果而需要的共轭药物的量,将因多个因素而各异,这些因素包括化合物的性质特点,疗效和共轭药物的生物利用度,疾病的类型,病人的种族,病人患病的状态,给药的途径,所有这些因素共同决定给药时间表和给药方式。
概括的说,通过本发明中的链连接的共轭药物可以通过以0.1到10%质量体积比溶解在生理缓冲液中用于非肠道给药。典型的药物剂量范围从1ug到0.1g每千克体重每天;推荐的药物剂量范围从0.01mg到20mg每千克体重每天或者等效剂量的儿童用量。推荐的给药量取决于多个变量,包括疾病或功能紊乱的类型,病人个体的整体的健康状态,偶联药物的相对生物学活性,化合物的剂型,给药的方式(静脉注射,肌肉注射,或其它),在选中给药方式下的药物动力学特性,以及给药的速度(单次注射或者连续滴注)和给药的时间表(在一定时间内重复给药的次数)。
由本发明的链连接的共轭药物同样可以以单位剂量的形式给药,这里的“单位剂量”是指一个病人一次给药的剂量,单位剂量的药物可以简单方便地包装和使用,单位剂量的药物是保持物理和化学稳定的活性共轭药物本身,或者是像以下介绍的药学上可接受的混合物。典型的一天的剂量范围从0.01mg到100mg每千克体重。一般而言,人每天,或每周,或每两周,或每月的单位剂量范围从1mg到3000mg。推荐的单位剂量范围是1mg到500mg,每天给药一到四次,或者更理想的10mg到600mg,每天一次。本发明的共轭药物可以通过加入一种或多种药学上可接受的辅料,制成药物制剂给药。此单位剂量的药物也可以用于口服给药,比如是片剂,简单的胶囊或软胶囊;或鼻内给药,比如粉末状,滴鼻剂,或喷雾剂;或者通过皮肤给药,比如局部软膏剂,乳膏剂,洗液,凝胶剂或喷雾剂或皮肤贴片。
药物/细胞毒素分子
药物是指可以直接或修饰后通过本发明连接到细胞结合分子上的小分子药物包括细胞毒素。这里的“小分子药物”广泛的指分子量在100到1800的有机的,无机的或者有机金属的化合物,更适当的分子量是120到1400.对于小分子药物的更好的定义可以参见WO05058367A2和美国专利No.4,956,303,以及其它的文献,这里小分子药物的定义包含所有参考文献对小分子药物的定义。这里的药物包括所有已知的药物以及所有可能成为药物的药物。
已知的药物包括,但不限于,
1).化学治疗药物试剂a).烷基化试剂:比如氮芥类:苯丁酸氮芥,萘氮芥,环磷酰胺,达卡巴嗪,雌氮芥,异环磷酰胺,二氯甲基二乙胺,盐酸甲氧氮芥,甘露醇氮芥,二溴甘露醇,美法仑,二溴卫矛醇,哌血生,新恩比兴,苯芥胆甾醇,泼尼氮芥,噻替派,曲洛磷胺,尿嘧啶氮芥;CC-1065(包括它的阿多来星、卡折来星、比折来新合成类似物);倍癌霉素(包括合成类似物KW-2189和CBI-TMI);苯二氮卓二聚体(比如吡咯并苯二氮卓(PBD),或托马霉素,吲哚啉并苯二氮卓,咪唑并苯二氮卓,或者恶唑烷并苯二氮卓的二聚体);亚硝基脲:(卡莫司汀,洛莫司汀,氯脲霉素,福莫司汀,尼莫司汀,雷莫司汀);磺酸烷酯:(白消安,苏消安,英丙舒凡和嗪消安);三氮烯类:(达卡巴嗪);含铂化合物:(卡铂,顺铂,奥沙利铂);氮丙啶类:如苯佐替派,卡波醌,美妥替哌和乌瑞替派;乙撑亚胺和甲基三聚氰胺类,包括六甲蜜胺,三乙撑蜜胺,三甘醇磷酰胺,三乙基硫代磷酰胺和三羟甲基三聚氰胺];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,异长春花碱);紫杉烷类化合物:(紫杉醇,多西紫杉醇)及其类似物,美登木素生物碱(DM1,DM2,DM3,DM4,美登素和安丝菌素)及其类似物,隐藻素(特别是隐藻素1和隐藻素8);埃博霉素,艾榴塞洛素,圆皮海绵内酯,草苔虫素,多罗斯他丁,阿里他汀,tubulysins,Cephalostatins;水鬼蕉碱;珊瑚素A;海绵抑制素;c).DNA拓扑异构酶抑制剂:如[epipodophyllins:(9-氨基喜树碱,喜树碱,克立那托,柔红霉素,依托泊苷,磷酸依托泊苷,伊立替康,米托蒽醌,盐酸米托蒽醌,视黄酸(视黄醇),替尼泊苷,拓扑替康,9-硝基喜树碱(RFS2000));丝裂霉素:(丝裂霉素C)];d).抗代谢药物:如{[抗叶酸:二氢叶酸还原酶抑制剂(氨甲喋呤,三甲曲沙,二甲叶酸,蝶罗呤,氨基蝶呤(4—氨基蝶酸)或其他叶酸类似物);IMP脱氢酶抑制剂:(霉酚酸,甲酰胺基噻唑,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:(环胞苷,阿扎胞苷,6—氮杂尿苷,卡培他滨(希罗达),卡莫氟,阿糖胞苷,二脱氧尿苷,去氧氟尿苷,散瘤星,5-氟尿嘧啶,氟尿苷,拉泰曲克(雷替曲塞));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,巯基嘌呤,硫唑嘌呤胺,硫鸟嘌呤)];叶酸补充剂,如亚叶酸};e).激素疗法:如{受体拮抗剂:[抗雌激素:(甲地孕酮,雷洛昔芬,他莫昔芬);LHRH激动剂:(戈舍瑞林,醋酸亮丙瑞林);抗雄激素:(比卡鲁胺,氟他胺,二甲睾酮,丙酸甲雄烷酮,环硫,戈舍瑞林,醋酸亮丙瑞林,美雄烷,尼鲁米特,曲洛司坦和其它雄激素睾内酯,抑制剂)];维甲酸/三角肌:[维生素D3类似物(CB 1093,EB1089KH 1060,胆钙化醇,维生素D2);光动力疗法:(维替泊芬,酞菁,光敏剂PC4,去甲氧基竹红菌甲素);细胞因子(干扰素-α,干扰素-γ,肿瘤坏死因子(TNFs)),含TNF域的人类的蛋白质)};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,尼罗替尼,拉帕替尼,阿西替尼,帕唑帕尼,凡德他尼,E7080(抗VEGFR2),莫立替尼,普纳替尼(AP24534),巴非替尼(INNO-406),波舒替尼(SKI-606),卡博替尼,维莫德吉,Iniparib,星熠艾克,CYT387,阿西替尼,替伏扎尼,索拉非尼,贝伐单抗,西妥昔单抗,曲妥珠单抗,兰尼单抗,帕尼单抗,伊匹尼塞;g).抗生素,如烯二炔类抗生素(如刺孢霉素,尤其是卡奇霉素γ1,δ1,α1和β1,见例,J.Med.Chem.,39(11),2103–
2117(1996),Angew Chem Intl.Ed.Engl.33:183-186(1994);蒽环类抗生素dynemicin,包括dynemicin A和deoxydynemicin,埃斯培拉霉素,卡达西叮,C-1027,maduropeptin,以及新抑癌蛋白发色团和其相应的色蛋白烯二炔类抗生素chromomophores),aclacinomysins,放线菌素,authramycin,重氮丝氨酸,平阳霉素,放线菌素C,carabicin,洋红霉素,嗜癌素;色霉素,更生霉素,柔毛霉素,地托比星,6-重氮-5-氧代-L-正亮氨酸,阿霉素,吗啉阿霉素,氰基吗啉阿霉素,2-吡咯啉阿霉素和去氧阿霉素,表柔比星,依索比星,伊达比星,麻西罗霉素,丝裂霉素,霉酚酸,诺加霉素,橄榄霉素,培洛霉素,potfiromycin,嘌呤霉素,三铁阿霉素,罗多比星,链黑菌素,链脲菌素,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(乙酰配基类),特别是布拉它辛和布拉它辛酮;吉西他滨,epoxomicins(卡菲佐米),硼替佐米,沙利度胺,lenalidomide,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1-甲基-4-苯基吡啶离子),细胞周期抑制剂(如星形孢菌素),放线菌素(如放线菌素D,放线菌素),平阳霉素(如博莱霉素博莱霉素A2,B2,培洛霉素),蒽环类药物(如柔红霉素,阿霉素(亚德里亚霉素),伊达比星,表阿霉素,吡柔比星,柔红霉素苯腙,mtoxantrone,MDR抑制剂(如维拉帕米),Ca2+ATP酶抑制剂(如毒胡萝卜素),组蛋白去乙酰化酶抑制剂(vorinostat,罗米地辛,帕比司他,丙戊酸,mocetinostat(MGCD0103),belinostat,PCI-24781,entinostat,SB939,resminostat,givinostat,AR-42,CUDC-10,萝卜硫素,曲古抑菌素A);毒胡萝卜素,塞来昔布,格列酮类,表没食子儿茶素没食子酸酯,双硫仑,salinosporamideA.;antiadrenals,如氨鲁米特,米托坦,曲洛司坦;酰葡醛内酯;醛磷酰胺糖苷;乙酰丙酸;吖啶;阿糖胞苷,bestrabucil;比生群,edatraxate;defofamine;秋水仙碱;二氮化合物;依氟鸟氨酸(DFMO),elfomithine;依利醋铵,乙环氧啶;硝酸镓;gacytosine,羟基脲;伊班磷酸钠,香菇多糖;氯尼达明;丙脒腙;米托蒽醌;单哌潘生丁;
(特别是T-2毒素,单端孢疣孢菌素A,roridina A和anguidine);尿烷类,siRNA,反义药物,和溶核酶。
2).一种抗自身免疫病剂包括,但不限于,环孢素,环孢素A,硫唑嘌呤,氨基己酸,溴隐亭,苯丁酸氮芥,氯喹,环磷酰胺,糖皮质激素(如激素类药,倍他米松,布地奈德,氟尼缩松,氢化可的松,丙酸氟替卡松,氟考龙,地塞米松,曲安奈德,丙酸倍氯米松),脱氢表雄酮,enanercept,羟氯喹,英夫利昔单抗,美洛昔康,甲氨蝶呤,吗替麦考酚酯,西罗莫司,他克莫司,强的松。
3).抗传染病剂包括,但不限于,a).氨基糖苷类:丁胺卡那霉素,武夷霉素,庆大霉素(奈替米星,西索米星,异帕米星),潮霉素B,卡那霉素(阿贝卡星,阿米卡星,卡那霉素B,地贝卡星,妥布霉素),新霉素,(巴龙霉素,新霉素b,核糖霉素),乙基西梭霉素,大观霉素,链霉素,妥布霉素,甲基姿苏霉素;b).氯霉素类抗生素类:
叠氮氯霉素,氯霉素,氟苯尼考,甲砜霉素;c).安莎类抗生素类:格尔德霉素,除莠霉素;d).碳青霉烯类抗生素类:比阿培南,多尼培南,厄他培南,亚胺培南/西司他丁,美罗培南,帕尼培南;e).头孢类:碳头孢烯(氯碳头孢),头孢乙腈,头孢克罗,头孢拉定,头孢羟氨,头孢洛宁,头孢噻啶,先锋霉素Ⅰ或头孢噻吩,头孢氨苄,头孢来星,头孢羟唑,头孢匹林,头孢曲嗪,头孢氮氟,头孢西酮,头孢唑啉,头孢拉宗,头孢卡品,头孢达肟,头孢吡肟,头孢米诺,头孢西丁,头孢丙烯,头孢沙定,头孢替唑,头孢呋辛,头孢克肟,头孢地尼,头孢妥仑,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,头孢替安,头孢唑兰,头孢咪唑,头孢匹胺,头孢匹罗,头孢泊肟,头孢喹肟,头孢磺啶,头孢他啶,头孢特仑,头孢布烯,头孢噻林,头孢唑肟,头孢吡普,头孢曲松,头孢唑喃,头霉素(头孢西丁,头孢替坦,头孢美唑),氧头孢烯(氟氧头孢,拉氧头孢);f).糖肽类:万古霉素(博莱霉素,奥利万星,特拉万星),替考拉宁(达巴万星),雷莫拉宁;g).甘氨酰环类:如替加环素;h).β-内酰胺酶抑制剂类:青霉烷(舒巴坦,他唑巴坦),clavam(克拉维酸);i).林可酰胺类: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).大环内酯类抗生素红霉素,阿奇霉素,克拉霉素,地红霉素,红霉素,罗红霉素,交沙霉素,酮内酯(泰利霉素,喹红霉素),麦迪霉素,美地霉素,竹桃霉素,利福霉素(利福平,利福布丁,利福喷丁),罗他霉素,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β-内酰胺类:氨曲南,tigemonam,m).恶唑烷酮类:利奈唑胺;n).青霉素类抗生素:阿莫西林,氨比西林(匹氨西林,海他西林,巴氨西林,美坦西林,酞氨西林),叠氮西林,阿洛西林,青霉素G,苄星青霉素,苄星青霉素,苄星苯氧甲基青霉素,氯甲西林,普鲁卡因苄青霉素,羧苄青霉素(卡茚西林),氯唑西林,双氯西林,依匹西林,氟氯西林,美西林(匹美西林),美洛西林,甲氧西林,萘夫西林,苯唑西林,培那西林,盘尼西林,非奈西林,青霉素V,哌拉西林,丙匹西林,磺苄西林,替莫西林,替卡西林;o).多肽类:杆菌肽,粘杆菌素,多粘菌素B;p).喹诺酮类:阿拉沙星,巴洛沙星,环丙沙星,克林沙星,依诺沙星,恩诺沙星,达氟沙星,二氟沙星,氧氟沙星,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,那氟沙星,莫西沙星,奥比沙星,诺氟沙星,氧氟沙星,培氟沙星,曲伐沙星,西他沙星,司帕沙星,格帕沙星,替马沙星,托氟沙星,曲伐沙星;q).阳菌素类:普那霉素,奎奴普丁/达福普汀)r).磺胺类:磺胺米隆,偶氮磺胺,磺胺醋酰,磺胺甲二唑,柳氮磺胺吡啶,磺胺异恶唑,甲氧苄啶,磺胺甲恶唑(复方新诺明);s).甾体类抗菌药:例如,夫西地酸;t).四环素类抗生素:多西环素,氯羟四环素,氯四环素,赖甲环素,去甲金霉素,土霉素,米诺环素,氯甲烯土霉素,氧四环素,青哌环素,吡甲四环素,四环素,甘氨酰(例如替加环素);u).其他的类型的抗生素:番荔枝素,砷凡纳明,细菌萜醇抑制剂(杆菌肽),DADAL/AR抑制剂(环丝氨酸),dictyostatin,圆皮海绵内酯,艾榴塞洛素,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,mycolactone,NAM合成抑制剂(如磷霉素),硝基呋喃妥因,紫杉醇,平板霉素,吡嗪酰胺,奎奴普丁/达福普汀,利福平(甲哌利福霉素),他唑巴坦磺甲硝咪唑,番荔枝内酯;
4).抗病毒药物:a).输入/融合抑制剂:aplaviroc,maraviroc,Vicriviroc,gp41(恩夫韦肽),PRO 140,CD4(ibalizumab);b).整合酶抑制剂:雷特格韦,埃替拉韦,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).核苷及核苷酸:阿巴卡韦,阿昔洛韦,阿德福韦酯,氨多索韦,阿普瑞西他滨,溴夫定,西多福韦,右艾夫他滨,克拉夫定,地达诺新(DDI),艾夫他滨,恩曲他滨(FTC),恩替卡韦,泛昔洛韦,氟二氧嘧啶(5-FU),3’-氟-取代的2’,3’-二脱氧核苷类似物,(例如,3’-氟-2’,3’-二脱氧胸苷(FLT),3’-氟-2’,3’-双脱氧鸟苷(FLG),福米韦生,更昔洛韦,碘苷,拉米夫定(3TC),1-核苷(比如.β-l-胸苷和β-l-2’-脱氧胞苷)喷昔洛韦,racivir,利巴韦林,stampidine,司他夫定(d4T),tarib avirin(viramidine),替比夫定,替诺福韦,三伐昔洛韦,缬更昔洛韦,扎西他滨(DD C),齐多夫定(AZT);f).非核苷类药物:金刚烷胺,ateviridine,卡普韦林,二芳基嘧啶类化合物(依曲韦林,利匹韦林),地拉韦啶,廿二醇,乙米韦林,依法韦仑,膦甲酸(膦甲酸),咪喹莫特,alfa-干扰素,洛韦胺,洛德腺苷,甲吲噻腙,奈韦拉平,nov-205,聚乙二醇干扰素alfa,足叶草毒素,利福平,金刚烷乙胺,瑞喹莫德(R-84
8),g).蛋白酶抑制剂:安普那韦,阿扎那韦,博赛泼维,地瑞纳韦,福沙那韦,茚地那韦,洛匹那韦,奈非那韦,利托那韦,普拉康纳利,沙奎那韦,特拉匹韦(VX-950),替拉那韦;h).其他类型抗病毒药物:抗体酶,阿比朵尔,胡桐内酯A,ceragenin,蓝藻抗病毒蛋白N,二芳基嘧啶类化合物,表没食子儿茶素没食子酸酯(EGCG),膦甲酸,griffithsin,塔利韦林(viramidine),羟基脲,kp-1461,米替福新,普拉康纳利,portm anteau inhibitors,利巴韦林,Seliciclib。
5).本发明中通过亲水连接体链接的的药物还包括下列放射性同位素。例放射性同位素(放射性核素)是3H,11C,14C,18F,32P,35S,64Cu,68Ga,86Y,99Tc,111In,123I,124I,125I,131I,133Xe,177Lu,211At,和213Bi。放射性同位素标记的抗体在受体靶向成像实验中非常有用或可直接用于有针对性的靶向治疗,如抗体药物缀合物的发明(Wu et al(2005)NatureBiotechnology 23(9):1137-1146)。细胞结合的分子,如抗体,前面描述的那样:可以通过本专利亲水链接体结合、螯合或形成其他复杂的放射性同位素金属结合作用来被标记,此标记技术描述于Current Protocols in Immunology,Volumes 1and 2,Coligen et al,Ed.Wiley-Interscience,New York,N.Y.,Pubs.(1991)。能生成复杂金属络合物的螯合剂包括DOTA,DOTP,DOTMA,DTPA和TETA(Macrocyclics,Dallas,Tex.).
6).药学上上述任何化合物可接受的盐、酸以及上述任何药物的衍生物。
本专利优选的通过此亲水链接体共轭连接到细胞结合分子的细胞毒性药物是tubulysins,美登素类,taxanoids(紫杉醇),CC-1065类似物,柔红霉素和阿霉素的化合物,苯二氮卓类二聚体(例如,吡咯并苯二氮卓(PBD)二聚体,托马霉素二聚体,氨茴霉素二聚体,吲哚啉并苯二氮卓二聚体,咪唑并苯二氮卓二聚体,或者恶唑烷并苯二氮卓的二聚体),刺孢霉素和烯二炔类抗生素,放线菌素,重氮丝氨酸(azaserines),博莱霉素,表柔比星(表阿霉素),他莫昔芬,伊达比星,海兔毒素(多拉司他汀)/奥瑞斯他汀(如单甲基奥瑞斯他汀E,MMAE,MMAF,奥瑞斯他汀PYE,奥瑞斯他汀TP,奥瑞斯他汀2-AQ,6-AQ,EB(AEB),和EFP(AEFP)),多卡米星,塞替派,长春新碱,hemiasterlins,esperamicins,以及它们的类似物和衍生物。
在另一个实施方案中,式(II)和(IV)中的药物可以是发色团分子,其结合物可用于检测,监测或研究细胞结合分子与靶细胞的相互作用。发色团分子是具有吸收一种光的能力的化合物,如紫外光,荧光,红外光,近红外光,可见光;色素分子包括黄色素,红细胞生物,虹膜色素,白细胞,黑素细胞和蓝细胞的类别或亚类;荧光团分子的类别或子类别,其是荧光化学化合物在光下重新发光;视觉光转导分子的类别或亚类;发光光子分子的一类或亚类;冷发光分子的一类或亚类;和荧光素化合物的类别或亚类。
发色团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);方酸菁衍生物和环取代的方酸菁,包括Seta,SeTau和Square染料;萘衍生物(丹酰和prodan衍生物);香豆素衍生物;恶二唑衍生物(吡啶并恶唑,硝基苯并恶二唑和苯并恶二唑);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(二氨基吖啶黄素,吖啶橙,吖啶黄等);芳基甲胺衍生物(金胺,结晶紫,孔雀石绿);四吡咯衍生物(卟吩,酞菁,胆红素);或生色团分子可以选自以下荧光团化合物的任何类似物和衍生物:CF染料(Biotium),DRAQ和CyTRAK探针(BioStatus),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),磺基Cy染料(Cyandye),HiLyte Fluor(AnaSpec),Seta,SeTau和Square染料(SETA BioMedicals),Quasar和Cal Fluor染料(生物研发技术公司),SureLight染料(APC,RPEPerCP,Phycobilisomes)(哥伦比亚生物科学公司),APC,APCXL,RPE,BPE(Phyco-Biotech);
与本发明的链接体反应或可偶联的荧光团化合物的实例是别藻蓝蛋白(APC),氨基香豆素,APC-Cy7偶联物,BODIPY-FL,Cascade蓝,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,Methoxycoumarin,NBD,太平洋蓝,太平洋橙,PE-Cy5偶联物,PE-Cy7偶联物,PerCP,R-藻红蛋白(PE),Red 613,Seta-555-叠氮,Seta-555-DBCO,Seta-555-N-羟基琥珀酰亚胺,Seta-580-N-羟基琥珀酰亚胺,Seta-680-N-羟基琥珀酰亚胺,Seta-780-N-羟基琥珀酰亚胺,Seta--APC-780,Seta-PerCP-680,Seta-R-PE-670,SeTau-380-N-羟基琥珀酰亚胺,SeTau-405-马来酰亚胺,SeTau-405-N-羟基琥珀酰亚胺,SeTau-425-N-羟基琥珀酰亚胺,SeTau-647-N-羟基琥珀酰亚胺,Texas Red,TRITC,TruRed,X-若丹明。
可以与本发明的链接体连接的用于研究核酸或蛋白质的荧光团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,色素-A3,CyTRAK橙(Biostatus,红色激发黑),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:花青单体,TOTO-1,TO-PRO-1,TOTO-3,TO-PRO-3,YOSeta-1,YOYO-1。可以与本发明的链接体连接的用于研究细胞的荧光团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,轻质催化剂氧化),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)。可以与本发明的链接体连接的用于研究蛋白质/抗体的荧光团化合物选自下列化合物或其衍生物:别藻蓝蛋白(APC),AmCyan1(四聚体,Clontech),AsRed2(四聚体,Clontech),Azami Green(单聚体,MBL),Azurite,B-phycoerythrin(BPE),Cerulean,CyPet,DsRed monomer(Clontech),DsRed2("RFP",Clontech),EBFP,EBFP2,ECFP,EGFP(弱二聚体,Clontech),Emerald公司(Emerald公司),萤光素B(藻红蛋白)弱二聚体,Invitrogen),EYFP(弱二聚体,Clontech),绿色荧光蛋白(S65A突变),绿色荧光蛋白(S65C突变),绿色荧光蛋白(S65L突变),绿色荧光蛋白(S65T突变),绿色荧光蛋白(Y66F突变),绿色荧光蛋白(Y66H突变),绿色荧光蛋白(Y66W突变),绿色荧光蛋白uv,HcRed1,J-Red,卡图沙,卡图沙黄(单体,MBL),mCFP,mCher-ry,mCitrine,Midoriishi青色(二聚体,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(藻胆体复合体),Peridinin叶绿素(PerCP),R-藻红蛋白(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),TurboFP635(二聚体,Evrogen),TurboGFP(二聚体,Evrogen),TurboRFP(二聚体,Evrogen),TurboYFP(二聚体,Evrogen),Venus,野生型GFP,YPet,ZsGreen1(四聚体,Clontech),ZsYellow1(四聚体,Clontech)。
在另一个实施方案中,通过本专利的亲水性链接体偶联至细胞结合分子的优选细胞毒性剂是tubulysins,美登木素生物碱,紫杉烷类(紫杉烷),CC-1065类似物,柔红霉素和阿霉素化合物,苯二氮卓类二聚体(例如吡咯苯二氮卓二聚体、茅屋霉素二聚体、安曲霉素二聚体、吲哚啉苯二氮卓二聚体、咪唑苯二氮卓二聚体、恶唑啉苯二氮卓二聚体),加利车霉素和烯二炔抗生素,放线菌素,重氮丝氨酸,博来霉素,表柔比星,他莫昔芬,伊达比星,多拉司他汀,奥瑞斯他汀(例如单甲基奥瑞他汀E,MMAE,MMAF,奥瑞他汀PYE,奥瑞他汀TP,奥瑞他汀2-AQ,6-AQ,EB(AEB)和EFP(AEFP)),杜卡霉素,噻替派,长春新碱,半米塔林,nazumamides,微麦球蛋白,radiosumins,alterobactins,microsclerominmins,theonellamides,esperamicins,PNU-159682及其类似物和及其衍生物。
本发明中偶联优选的Tubulysins是本领域公知的并且可以根据已知方法从天然来源分离或者根据已知方法合成制备(例如,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:p.4809-12.Chai,Y.;et al.,Chem Biol,2010,17:296-309.Ullrich,A.;et al.,Angew Chem 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.Patentapplications: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,PCT WO 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.优先的用于偶联细胞结合分子的Tubulysin结构已在专利申请PCT/IB2012/053554中描述。
关于本专利的细胞结合分子-药物偶联物优选的加利车霉素及其相关烯二炔抗生素描述于:Nicolaou,K.C.等人,Science 1992,256,1172-1178;Proc.Natl.Acad.SciUSA.1993,90,5881-5888),U.S.Patent Nos.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.
应用于本专利的优选的美登木素包括美登木素生物碱和美登木素生物碱类似物描述于美国专利号: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.
细胞毒性天然产物紫杉醇烷包括紫杉醇(泰素)和半合成的多西紫杉醇(泰索帝)及其类似物优选地通过本专利的亲水性连接子进行制备偶联。其例如在:K C.Nicolaou等人,J.Am.Chem.Soc.117,2409-2420,(1995);Ojima等人,J.Med.Chem.39:3889-3896(1996);40:267-278(1997);45,5620-5623(2002);Ojima等人,Proc.Natl.Acad.Sci.,96:4256-4261(1999;Kim等人,Bull.Korean Chem.Soc.,20,1389-1390(1999);Miller,等人,J.Med.Chem.,47,4802-4805(2004);美国专利号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;and 7,667,054.
CC-1065类似物和杜卡霉类似物优选地通过本专利的亲水性连接子进行制备偶联。CC-1065类似物和杜卡霉类似物例子和它们的合成描述如下:Warpehoski et al,J.Med.Chem.31:590-603(1988),D.Boger et al.,J.Org.Chem;66;6654-6661,2001;U.S.Patent Nos: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,and8,012,978.
柔红霉素/多柔比星类似物也优选用于通过本专利的亲水性连接体进行偶联。其优选的结构及其合成例子如下:Hurwitz,E.,et al.,Cancer Res.35,1175-1181(1975).Yang,H.M.,and Reisfeld,R.A.,Proc.Natl.Acad.Sci.85,1189-1193(1988);Pietersz,C.A.,E.,et al.,E.,et al.,"Cancer Res.48,926-9311(1988);Trouet,et al.,79,626-629(1982);Z.Brich et al.,J.Controlled Release,19,245-258(1992);Chen et al.,Syn.Comm.,33,2377-2390,2003;King et al.,Bioconj.Chem.,10,279-288,1999;King etal.,J.Med.Chem.,45,4336-4343,2002;Kratz et al.,J Med Chem.45,5523-33.2002;Kratz et al.,Biol Pharm Bull.Jan.21,56-61,1998;Lau et al.,Bioorg.Med.Chem.3,1305-1312,1995;Scott et al.,Bioorg.Med.l Chem.Lett.6,1491-1496;1996;Watanabeet al.,Tokai J.Experimental Clin.Med.15,327-334,1990;Zhou et al.,J.Am.Chem.Soc.126,15656-7,2004;WO 01/38318;U.S.Patent No.).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.
奥瑞斯他汀和多拉司他汀也优选用于通过本专利的亲水性连接体进行偶联。奥瑞斯他汀(例如单甲基奥瑞他汀E(MMAE),单甲基奥瑞他汀(MMAF),奥瑞他汀PYE,奥瑞他汀TP,奥瑞他汀2-AQ,6-AQ,EB(AEB)和EFP(AEFP)
奥瑞斯他汀和多拉司他汀也优选用于通过本专利的亲水性连接体进行偶联。奥瑞斯他汀(例如奥瑞斯他汀E(AE),奥瑞斯他汀EB(AEB),奥瑞斯他汀EFP(AEFP),单甲基奥瑞他汀E(MMAE),单甲基奥瑞他汀(MMAF),奥瑞斯他汀F苯二胺(AFP)和MMAE苯丙氨酸变异体)是多拉司他汀类似物,在下面文献已报道:Int.J.Oncol.15:367-72(1999);MolecularCancer Therapeutics,vol.3,No.8,pp.921-932(2004);美国专利申请号11134826,20060074008,2006022925.美国专利号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.
苯二氮卓类二聚体(例如吡咯苯二氮卓二聚体、茅屋霉素二聚体、安曲霉素二聚体、吲哚啉苯二氮卓二聚体、咪唑苯二氮卓二聚体、或恶唑啉苯二氮卓二聚体)是本发明优选的细胞毒性剂的二聚体,其示例:美国专利号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;US patent appl.20100203007,20100316656,20030195196.
本发明专利中,所描述的细胞毒性药物/药剂的类似物及衍生物可以通过本发明亲水性链接体试剂进行偶联。在本行业领域中,熟练技术人员通常知道对细胞毒性药物/试剂用什么方式进行修饰并能够在保持每一种细胞毒性药物/试剂起始的特异性/活性。同样,熟练技术人员通常知道很多化合物可以被用于替代本发明专利中所描述的细胞毒性药物/药剂。因此,本发明专利中的药物/药剂包括了这里所述化合物的类似物及衍生物。
本发明专利中所引用的文献以及实例都明确地并入例子里进行了说明。
实例
本发明专利用下面的实例进行了进一步的说明,这些实例的内容不限制本发明专利的范围。在实例中所描述的细胞系的培养条件,除了特殊说明之外,均是依据美国菌种保藏中心(ATCC)或者德国菌种保藏中心(DSMZ)或中国上海细胞培养研究所指定的条件下培养。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,并储存于充氮密封瓶中。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。制备型HPLC分离在Varain PreStar HPLC进行。核磁共振谱图在Varian Mercury400MHz仪器上检测得出,化学位移以ppm为单位,四甲基硅烷为标准,耦合常数(J)的单位是Hz。质谱数据由Waters Acquity UPLC分离模块和Acquity TUV检测器在Waters Xevo Qtof质谱上获取
实施例1:3-(((2-(2,5-二氧-2,5-二氢-1H-吡咯-1-基)乙基)氨基)(羟基)磷酰基)氨基)丙酸(4)
在-78℃冷却的N-2-乙基-酰亚胺盐酸盐(1.0g,5.66mmol)的THF(50ml)溶液中加入三氯化磷酰(0.86g,5.66mmol)。在-78℃下搅拌2小时以形成(2-(2,5-二氧-2,5-二氢-1H-吡咯-1-基)乙基)氨基磷酰二氯(2),将3-氨基丙酸(0.51g,5.70毫摩尔)在THF/H2O(2:1,30毫升)溶液中和三乙胺(1.0克,9.90毫摩尔)加入到混合物溶液中。混合物在室温下搅拌3小时,真空浓缩并在用H2O/CH3CN(1:20~1:10)洗脱溶剂在SiO2柱上纯化,得到标题化合物4(1.28g,78%产率)。ESI MS m/z-C9H13N3O6P(M-H),计算值290.06,找到值290.10。
实施例2:3-((((2-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙基)氨基)(羟基)磷酰基)氨基)丙酸N-羟基琥珀酰亚胺酯。
3-((((2-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙基)氨基)(羟基)-磷酰基)氨基)丙酸(4)(0.50g,1.72mmol)的DMA(30ml)溶液中加入NHS(0.20g,1.74mmol)和EDC(0.81g,4.22mmol)。将混合物在Ar下搅拌过夜,蒸发并用丙酮/CH2Cl2(1:10~1:3)洗脱剂在SiO2色谱上纯化。合并含有产物的收集液,蒸发,在C2H5OH二氧六环/己烷中固化,得到标题化合物(392mg,58%收率)。ESI MS m/z-C13H16N4O8P(M-H),计算值387.08,找到387.20。
实施例3:3-((二((2-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙基)氨基)-磷酰基)-氨基)丙酸(8)。
在-78℃下冷却的N-2-乙基-马来酰亚胺盐酸盐(2.0g,11.32mmol)的THF(100ml)溶液中加入三氯化磷酰(0.86g,5.66mmol)。在-78℃下搅拌1小时后,向混合物中加入三乙胺(1.0g,9.90mmol),并将所得溶液在室温下搅拌3小时以产生双(2-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙基)-氨基磷酰氯(7)。然后将3-氨基丙酸(0.51g,5.70mmol)在THF/H2O(2:1,30ml)和三乙胺(1.51g,14.90mmol)的混合物中加入到溶液中。将所得混合物在35℃下搅拌3小时,真空浓缩,用H2O/CH3CN(1:20~1:10)洗脱剂在SiO2柱上纯化,得到标题化合物8(1.47g,63%收率)。ESI MS m/z-C15H19N5O7P(M-H),计算值412.11,找到412.20。
实施例4:3-((双((2-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙基)氨基)磷酰基)氨基)丙酸N-羟基琥珀酰亚胺酯(9)。
3-((双((2-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙基)氨基)磷酰基)氨基)-丙酸(8)(0.55g,1.33mmol)在DMA(30ml)中的溶液中加入NHS(0.20g,1.74mmol)和EDC(0.78g,4.06mmol)。将混合物在Ar下搅拌过夜,蒸发并在短SiO2色谱柱上纯化,用EtOAc/CH2Cl2(1:3~1:1)洗脱。合并含有产物的收集液,真空蒸发得到标题化合物(536mg,产率79%)。ESI MSm/z+C19H23N6NaO9P(M+Na),计算值533.13,发现533.20。
实施例5:3-((羟基((2-(吡啶-2-基二硫烷基)乙基)氨基)磷酰基)氨基)丙酸(15)。
(吡啶-2-基二硫烷基)乙胺盐酸盐(1.40g,7.52mmol)的THF(60ml)溶液中加入三氯化磷(1.15g,7.56mmol)。在-78℃下搅拌2小时以形成(2-(吡啶-2-基二硫烷基)乙基)氨基磷酰二氯(14)后,3-氨基丙酸(0.67g,7.52mmol),30ml)在THF/H2O(2:1,30ml)溶液中和三乙胺(20g,19.80mmol)加入到上面混合溶液中。所得混合物在室温下搅拌3小时,真空浓缩并在SiO2柱上用H2O/CH3CN(1:20~1:10)洗脱纯化,得到标题化合物15(1.69g,66%产率)。ESI MS m/z-C10H15N3O4PS(M-H),计算值336.03,找到336.20。
实施例6:3-((((2-(吡啶-2-基二硫烷基)乙基)氨基)-(羟基)磷酰基)氨基)丙酸N-羟基琥珀酰亚胺酯(16)。
3-((((2-(吡啶-2-基二硫烷基)乙基)氨基)(羟基)-磷酰基)氨基)丙酸(15)(0.60g,1.78mmol)在DMA(30ml)溶液中加入NHS(0.22g,1.91mmol)和EDC(0.81g,4.22mmol)。将混合物在Ar下搅拌过夜,蒸发并在4℃用短C-18色谱上依水/二恶烷洗脱进行纯化。合并含有产物的收集液,在-78℃冷冻,冻干,得到标题化合物16(477mg,61%收率)。ESI MS m/z-C14H19N4O6PS2(M-H),计算值433.05,找到433.20。
实施例7:3-((双((2-(吡啶-2-基二硫烷基)乙基)氨基)磷酰基)氨基)-丙酸(18)。
(吡啶-2-基二硫烷基)乙胺盐酸盐(2.10g,11.29mmol)的THF(100ml)溶液中加入三氯化磷酰(0.85g,5.59mmol)。在-78℃搅拌1小时后,向混合物中加入三乙胺(1.0g,9.90mmol),并将所得溶液在室温下搅拌3小时以产生双(2-(吡啶-2-基二硫烷基)乙基)-氨基磷酰二氯(17)。然后将3-氨基丙酸(0.61g,6.85mmol)在THF/H2O(2:1,30ml)溶剂中和三乙胺(1.80g,17.82mmol)加入到混合溶液中。将所得混合物在35℃下搅拌3小时,真空浓缩并在用H2O/CH3CN(1:20~1:10)洗脱的SiO2柱上纯化,得到标题化合物18(1.47g,63%收率)。ESI MS m/z-C17H23N5O3PS(M-H),计算值504.05,发现504.20。
实施例8.3-((双((2-(吡啶-2-基二硫烷基)乙基)-氨基)磷酰基)氨基)2,5-二氧代吡咯烷-1-基丙酸酯(19)。
3-((二((2-(吡啶-2-基二硫烷基)乙基)氨基)磷酰基)氨基)丙酸(18)(0.52g,1.03mmol)在DMA(30ml)溶液中加入NHS(0.20g,1.74mmol)和EDC(0.80g,4.16mmol)。将混合物在Ar下搅拌过夜,蒸发并在短SiO2色谱上用EtOAc/CH2Cl2(1:4~1:1)洗脱纯化。合并含有产物的收集液,真空蒸发,得到标题化合物19(536mg,79%收率)。ESI MS m/z+C21H27N6NaO5PS4(M+Na),计算值625.06,找到625.20。
实施例9.1-(2-(甲基氨基)乙基)-1H-吡咯-2,5-二酮(43)
在0℃下将N1-甲基乙烷-1,2-二胺(10.23g,138.08mmol)的DMA(150ml)溶液中加入琥珀酸酐(13.82g,138.08mmol)。在Ar于0℃下搅拌1小时,然后室温搅拌4小时,蒸发混合物,再溶于乙酸(100ml,98%)和Ac2O(0.5ml)中,然后在80℃加热8小时。浓缩混合物,在用水/CH3OH(100%水至含有0.3%HCl的60%水)洗脱的C-18快速层析纯化,得到盐酸盐形式的标题化合物。(13.68g,收率52%)。ESI MS m/z+155.10(M+H).
实施例10.3-((双((2-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙基)(甲基)-氨基)磷酰基)(甲基)氨基)丙酸(50)
在-78℃冷却的1-(2-(甲基氨基)乙基)-1H-吡咯-2,5-二酮盐酸盐(43)(4.05g,21.00mmol)的THF(100ml)溶液中加入三氯化磷酰(1.59g,10.50mmol)。在-78℃搅拌1小时后,向混合物中加入三乙胺(1.2g,11.88mmol),将所得溶液在室温下搅拌3小时,产生双(2-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙基(甲基))-氨基磷酰氯(49)。然后将3-(甲基氨基)丙酸(1.21g,11.73mmol)在THF(30ml)和三乙胺(1.20g,11.88mmol)的混合物中加入到该溶液中。将所得混合物在45℃下搅拌3小时,真空浓缩并在用H2O/CH3CN(1:20~1:10)洗脱的SiO2柱上纯化,得到标题化合物50(2.44g,51%收率)。ESI MS m/z-C18H25N5O7P(M-H),计算值.454.16,找到454.20。
实施例11.3-((双((2-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)乙基)(甲基)氨基)磷酰基)(甲基)氨基)2,5-二氧代吡咯烷-1-基丙酸乙酯(51)
在DMA(40ml)中的化合物50(1.10g,2.41mmol)中加入NHS(0.40g,3.48mmol)和EDC(1.80g,9.37mmol)。将混合物在Ar下搅拌过夜,蒸发并在短SiO2色谱柱上用丙酮/CH2Cl2(1:6~1:2)洗脱纯化。合并含有产物的收集液,真空蒸发,得到标题化合物51(971mg,产率73%)。ESI MS m/z+C22H29N6NaO9P(M+Na),计算值575.17,找到575.20。
实施例12.每个链接体有两个DM1与抗体的偶联(52a)。
将化合物51(在DMA中20mM,35μL),缓冲液(60μL,100mM NaH2PO4,pH5.0~7.0)和DM1(在DMA中20mM,85μL)在15~30℃温育20分钟~2.5小时。然后将混合物加入2.0mL10mg/ml抗-Her2抗体的pH 6.5~8.0PBS缓冲液,1.0~2.0mL100mM NaH2PO4,pH7.5缓冲液。将标题混合物溶液在室温孵育2~24小时,用100mM NaH2PO4,50mM NaCl pH 5.5~7.5缓冲液洗脱液在G-25柱上纯化,得到16.5~18.3mg化合物52a在11.6~14.2ml缓冲液中(~86%产率)。根据参考文献(Zhao,R.Y.等人,J.Med.Chem.2011,54,3606)计算DM1/抗体比率为6.8~7.8。通过SEC HPLC(Tosoh Bioscience,Tskgel G3000SW,7.8mm ID x 30cm,0.5ml/min,100min)分析为95-99%单体,
或者,将化合物51(在DMA中20mM,35μL)加入2.0mL 10mg/ml抗-Her2抗体的pH 6.5~8.0PBS缓冲液和0.5~1.7mL的100mM NaH2PO4,pH6.5~8.0缓冲液的混合液。在RT孵育2h后,混合物在G-25柱上纯化,用100mM NaH2PO4,50mM NaCl pH 5.5~7.5缓冲液洗脱。然后向收集的受试者溶液(4.5~6.5ml)中加入DM1(70μL,2在DMA中20mM)和DMA(0.1~0.5ml)。随后将混合物在RT温育2-16小时,在G-25柱上纯化,用100mM NaH2PO4,50mM NaCl pH 5.5~7.5缓冲液洗脱,得到15.8~17.3mg化合物52a(~81%产率)15.5~17.4ml缓冲液。DM1/抗体比率为7.1~7.7(其根据参考文献(Zhao,R.Y.等人,J.Med.Chem。2011,54,3606)计算)。通过SEC HPLC(Tosoh Biosciences,Tskgel G3000SW,7.8mm ID×30cm,0.5ml/min,100min)分析为95-99%单体。
实施例13.携带本发明的亲水性链接体与tubulysin类似物偶联的化合物147a。
化合物51(120mg,0.217mmol)的THF(3.0ml)溶液中加入化合物146a(Huang Y.等人,药物化学第44篇,第249届美国化学学会年会,科罗拉多州丹佛市,2015年3月22日至26日;世界知识产权专利申请WO2014009774)(151mg,0.199mmol)的THF(3.0ml)和缓冲液(5ml,100mM Na2HPO4,pH 7.2)中。在室温搅拌4小时后,浓缩混合物并用C-18制备型HPLC(长250mm×内径30mm)纯化,流动相为水/乙醇(35分钟内由90%水至50%水,流速65毫升/分钟)。合并含有产物的收集组份液,浓缩并用EtOH/己烷结晶,得到标题化合物(159mg,67%收率)。ESI MS m/z+C56H82N11NaO14PS(M+Na),计算值1218.35,找到1218.40。
实施例14.化合物147a与抗体偶联得到148a。
向2.0mL浓度为10mg/ml抗-Her2抗体(pH6.0~8.0)的混合物中加入0.70~2.0mLPBS缓冲液(100mM NaH2PO4,pH 6.5~7.5),TCEP(28μL,20mM水溶液)的和化合物147a(35μL,20mM于DMA中)。将混合物在RT温育2-16小时,然后加入DHAA(135μL,50mM)。在室温下连续温育过夜后,将混合物用100mM NaH2PO4,50mM NaCl,pH6.0~7.5的缓冲液作为洗脱液在G-25柱上纯化,得到16.8~17.9mg在13.1~14.9ml缓冲液中的偶联物化合物148a(~87%收率)。经UPLC-Qtof质谱测定药物/抗体比(DAR)为2.8~3.7。通过SEC HPLC(TosohBiosciences,Tskgel G3000SW,7.8mm ID x 30cm,0.5ml/min,100min)分析为96-99%单体,并通过SDS-PAGE凝胶测量为单一条带。
另外实验,将pH为6.0~8.0的PBS缓冲液中的2.0mL的10mg/ml的抗Her2抗体,pH6.0~8.0,100mM NaH2PO4的缓冲液0.50~1.5mL,以及DTT(30μL,20mM的水溶液)在15~37℃孵育1~5h,然后用100mM NaH2PO4,50mM NaCl,pH6.0~8.0的缓冲液作为洗脱液在G-25柱上纯化。将合并含有产物的收集组份液(3.8-5.8ml)加入0.2-0.6mL DMA和化合物147a(35μL,20mM的DMA溶液),在RT下温育4-12小时。加入DHAA(135μL,50mM)并在RT下连续温育过夜后,将混合物在G-25柱上纯化,用100mM NaH2PO4,50mM NaCl pH7.5缓冲液洗脱,得到15.5~16.8mg结合物化合物148a(~80%产率)的13.8~15.9ml缓冲液。通过UPLC-QTOF质谱测定药物/抗体比(DAR)为2.6~3.8。由SEC HPLC(Tosoh Biosciences,Tskgel G3000SW,7.8mmID×30cm,0.5ml/min,100min)分析为96-98%单体,并通过SDS-PAGE凝胶测量单一谱带。
实施例15.偶联物52a和148a的体外细胞毒性评估:
将靶细胞(例如N-87,SKOV3和HL60细胞,6000个细胞)在不同浓度的抗Her2抗体偶联物52a和148a的存在下培养96小时,然后使用Becton Dickinson FACSort(BectonDickinson,Franklin Lakes,NJ)流式细胞仪通过碘化丙啶排阻测量细胞活力。激发的细胞的红色荧光强度(在FL2通道中在617nm发射)在488nm下测量。另外使用细胞的正向光散射和直角光散射性质来设置活细胞的区域。活细胞的丧失是由定义存活细胞的门控区域内细胞的损失决定的。平均活细胞数由每6个重复培养物计算而得。绘制存活分数对偶联物浓度以确定偶联物52a和148a的IC50值(50%细胞杀死浓度)。
细胞毒性结果:
偶联物52a对N87细胞的特异性超过1850(IC50>50/IC50=0.027),对SK-OV-3细胞超过2380。
偶联物148a对N87细胞的特异性超过1315(IC50>50/IC50=0.038),对SK-OV-3细胞超过1560。
偶联物52a和偶联物148a都是非常高活性的并且具有非常特异性的靶向抗原阳性肿瘤细胞。
Claims (31)
1.式(I)的亲水性连接基团化合物:
其中:
Y表示能够与细胞结合剂反应的官能团,Y选自硫醇,二硫化物取代基,马来酰亚胺基,卤代乙酰基,炔基,烷氧基氨基,羧酸,羧酸卤化物,硝基苯酯,二硝基苯酯,三氟苯基酯或N-羟基琥珀酰亚胺酯;
Q和T是–X1–P(=O)(OM)-,或–X1-S(O2)-,或–X1–S(O)-;或–X1–P(=O)(OM)-X2-,或–X1–P(=O)[X2-R4-Z]-X3-,或–X1–P(=O)[X2-R1-Y]-X3-,或–X1-S(O2)-X2-,或–X1–S(O)-X2-;
X1,X2和X3独立地选自N(R7),O,或S;另外,当X1是N(R7),或O或S时,则X2或X3或另一个X1同–P(=O),-S(O),或-S(O2)连接时,X2或X3或另一个X1可以是CH2;
m和n是从0到5的整数,但不能同时为0;
Z代表一个功能基团,能够通过硫代,硫酯,肽,腙,醚,酯,氨基甲酸酯,碳酸酯,胺(二级,三级或四级),亚胺,环杂烷基,杂芳族基团,烷肟或酰胺键连接一个细胞毒性药物;
R1,R2,R3,R4,R5,R6,和R7是,相同或不同,是H,具有1-6个碳原子的直链烷基,具有3-6个碳原子的支链或环状烷基,直链、支链或环状链烯基或炔基,1-6个碳原子的酯、醚、酰胺,或分子式为(OCH2CH2)p,聚乙烯氧基单元,其中p是0至约1000的整数,或上述组合;
M是H,或Na,或K,或N+R1R2R3或药用盐。上面已对R1,R2和R3进行了描述。
5.权利要求1的式(I)化合物,其中Q或/和T是–X1–P(=O)[X1-R1-Y]-X3-,因此式(I)化合物包含两个或更多个Y基团可以用于连接两个或更多个位点,或者一对细胞结合分子的位点;
其中的X1,X2和X3独立地选自N(R7),O,CH2,或S;Y,R1和R7如权利要求1所定义。
6.权利要求1的式(I)化合物,其中Q或/和T是–X1–P(=O)[X2-R4-Z]-X3-,因此式(I)化合物包含两个或更多个Z基团可以用于连接两个或更多个药物;
其中的X1,X2和X3独立地选自N(R7),O,CH2,或S;Z,R4和R7如权利要求1所定义。
7.权利要求2的式(II)偶联化合物,其中Q或/和T是–X1–P(=O)[X1-R1-Cb]-X3-,因此式(II)化合物包含两个或更多个Cb基团连接两个或更多个位点,或者一对细胞结合分子的位点;
其中的X1,X2和X3独立地选自N(R7),O,CH2,或S;Y,R1和R7如权利要求1所定义;Cb定义如同权利要求2中定义。
8.权利要求2的式(II)偶联化合物,其中Q或/和T是–X1–P(=O)[X2-R4-Drug]-X3-,因此式(II)化合物包含两个或更多“Drug”即连接两个或更多相同或不同的药物;
其中的X1,X2和X3独立地选自N(R7),O,CH2,或S;Y,R4和R7如权利要求1所定义;“Drug”定义如同权利要求2中定义。
9.权利要求3的式(III)化合物,其中Q或/和T是–X1–P(=O)[X2-R1-Cb]-X3-,因此式(III)化合物包含两个或更多个Cb基团即连接两个或更多个位点,或者一对细胞结合分子的位点;
其中的X1,X2和X3独立地选自N(R7),O,CH2,或S;R1和R7如权利要求1所定义;Cb定义如同权利要求2中定义。
10.权利要求3的式(III)化合物,其中Q或/和T是T is–X1–P(=O)[X2-R4-Z]-X3-,因此式(III)化合物包含两个或更多个Z基团可以用于连接两个或更多相同或不同的药物;
其中的X1,X2和X3独立地选自N(R7),O,CH2,或S;R4和R7如权利要求1所定义。
11.权利要求4的式(IV)化合物,其中Q或/和T是–X1–P(=O)[X2-R1-Y]-X3-,因此式(IV)化合物包含两个或更多个Y基团可以用于连接两个或更多个位点,或者一对细胞结合分子的位点;
其中的X1,X2和X3独立地选自N(R7),O,CH2,或S;R1和R7如权利要求1所定义。
12.权利要求4的式(IV)化合物,其中Q或/和T是–X1–P(=O)[X2-R4-Drug]-X3-,因此式(IV)化合物包含两个或更多“Drug”即连接两个或更多相同或不同的药物;
其中的X1,X2和X3独立地选自N(R7),O,CH2,或S;Y,R4和R7如权利要求1所定义;“Drug”定义如同权利要求2中定义。
13.根据权利要求2,4,8或12的化合物,其中“Drug”选自于:
1).化疗药物:
a).烷基化试剂:苯丁酸氮芥,氯萘甲唑啉,环磷酰胺,达卡巴嗪,雌莫司汀,异环磷酰胺,氮芥,盐酸甲氧氮芥,甘露醇氮芥,二溴甘露醇,美法仑,二溴卫矛醇,哌血生,新恩比兴,苯芥胆甾醇,泼尼氮芥,噻替派,曲洛磷胺,尿嘧啶氮芥;CC-1065及其阿多来星、卡折来星、比折来星合成类似物;倍癌霉素及其合成类似物KW-2189和CBI-TMI;吡咯并苯二氮卓,托马霉素,吲哚啉并苯二氮卓、咪唑并苯二氮卓或恶唑烷并苯二氮卓的二聚体;卡莫司汀,洛莫司汀,氯脲霉素,福莫司汀,尼莫司汀,雷莫司汀;白消安,苏消安,英丙舒凡和嗪消安;达卡巴嗪;卡铂,顺铂,奥沙利铂;苯佐替派,卡波醌,美妥替哌和乌瑞替派;六甲蜜胺,三乙撑蜜胺,三甘醇磷酰胺,三乙基硫代磷酰胺和三羟甲基三聚氰胺;
b).植物生物碱:长春新碱,长春碱,长春地辛,长春瑞滨,异长春花碱;紫杉醇,多西紫杉醇及其类似物,美登木素生物碱及其类似物,隐藻素1和隐藻素8;埃博霉素,艾榴塞洛素,圆皮海绵内酯,草苔虫素,多罗斯他丁,阿里他汀,tubulysins,Cephalostatins;水鬼蕉碱;珊瑚素A;spongistatin;
c).DNA拓扑异构酶抑制剂:9-氨基喜树碱,喜树碱,克立那托,柔红霉素,依托泊苷,磷酸依托泊苷,伊立替康,米托蒽醌,盐酸米托蒽醌,视黄酸,视黄醇,替尼泊苷,拓扑替康,9-硝基喜树碱;丝裂霉素C;
d).抗代谢药物:氨甲喋呤,三甲曲沙,二甲叶酸,蝶罗呤,氨基蝶呤或其他叶酸类似物;霉酚酸,甲酰胺基噻唑,利巴韦林,EICAR;羟基脲,去铁胺;环胞苷,阿扎胞苷,6—氮杂尿苷,卡培他滨,卡莫氟,阿糖胞苷,二脱氧尿苷,去氧氟尿苷,散瘤星,5-氟尿嘧啶,氟尿苷,拉泰曲克;阿糖胞苷,胞嘧啶阿拉伯糖苷,氟达拉滨;硫唑嘌呤,氟达拉滨,巯基嘌呤,硫唑嘌呤胺,硫鸟嘌呤;亚叶酸;
e).激素疗法:甲地孕酮,雷洛昔芬,他莫昔芬;戈舍瑞林,醋酸亮丙瑞林;比卡鲁胺,氟他胺,二甲睾酮,丙酸甲雄烷酮,环硫,戈舍瑞林,醋酸亮丙瑞林,美雄烷,尼鲁米特和曲洛司坦;CB1093,EB1089KH1060,胆钙化醇,维生素D2;维替泊芬,酞菁,光敏剂PC4,去甲氧基竹红菌甲素;α-干扰素,慢性支气管炎肿瘤坏死因子,人类的蛋白质含TNF域;
f).激酶抑制剂:bibw2992,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,尼罗替尼,拉帕替尼,阿西替尼,帕唑帕尼,凡德他尼,e7080,莫立替尼,普纳替尼,巴非替尼,波舒替尼,卡博替尼,维莫德吉,Iniparib,星熠艾克,CYT387,阿西替尼,替伏扎尼,贝伐单抗,索拉非尼,曲妥珠单抗,西妥昔单抗,兰尼单抗,帕尼单抗,伊匹尼塞;
g).抗生素:刺孢霉素,卡奇霉素γ1、δ1、α1和β1,dynemicin A和deoxydynemicin,esperamicin,卡达西叮,C-1027,maduropeptin,以及新抑癌蛋白发色团和其相应的色蛋白烯二炔类抗生素chromomophores,aclacinomysins,放线菌素,authramycin,重氮丝氨酸,平阳霉素,放线菌素C,carabicin,洋红霉素,嗜癌素;色霉素,更生霉素,柔毛霉素,地托比星,6-重氮-5-氧代-L-正亮氨酸,阿霉素,吗啉阿霉素,氰基吗啉阿霉素,2-吡咯啉阿霉素和去氧阿霉素,表柔比星,依索比星,伊达比星,麻西罗霉素,丝裂霉素,霉酚酸,诺加霉素,橄榄霉素,培洛霉素,potfiromycin,嘌呤霉素,三铁阿霉素,罗多比星,链黑菌素,链脲菌素,杀结核菌素,乌苯美司,净司他丁,佐柔比星;
h).其他:布拉它辛和布拉它辛酮;吉西他滨,卡菲佐米,硼替佐米,沙利度胺,lenalidomide,pomalidomide,tosedostat,zybrestat,PLX4032,STA-9090,Stimuvax,allovectin-7,Xegeva,Provenge,Yervoy,洛伐他汀,1-甲基-4-苯基吡啶离子,星形孢菌素,放线菌素D,放线菌素,博莱霉素博莱霉素A2,B2,培洛霉素,柔红霉素,阿霉素,伊达比星,表阿霉素,吡柔比星,柔红霉素苯腙,mtoxantrone,维拉帕米,毒胡萝卜素,vorinostat,罗米地辛,帕比司他,丙戊酸,mocetinostat,belinostat,PCI-24781,entinostat,SB939,resminostat,givinostat,AR-42,CUDC-10,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.;氨鲁米特,米托坦,曲洛司坦;酰葡醛内酯;醛磷酰胺糖苷;氨基酮戊酸;安吖啶;阿糖胞苷bestrabucil;比生群edatraxate;defofamine;秋水仙碱;二氮化合物;依氟鸟氨酸,elfomithine;依利醋铵,乙环氧啶;硝酸镓;gacytosine,羟基脲;伊班膦酸钠,香菇多糖;氯尼达明;丙脒腙;米托蒽醌;单哌潘生丁;nitracrine;喷司他丁;蛋氨氮芥;吡柔比星;鬼臼酸;乙肼;甲基苄肼;丙亚胺;根瘤菌素;西佐喃;螺旋锗;细格孢氮杂酸;三乙撑亚胺苯醌;2,2’2”-三氯三乙胺;T-2毒素,单端孢菌,疣孢菌素A,杆孢菌素A和anguidine;尿烷,干扰性小核糖核酸(siRNA),反义药物;
2).抗自身免疫性疾病药物:环孢素,环孢素A,氨基己酸,硫唑嘌呤,溴隐亭,苯丁酸氮芥,氯喹,环磷酰胺,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,氟考龙,达那唑,地塞米松,曲安奈德,丙酸倍氯米松,脱氢表雄酮,依那西普,羟氯喹,英夫利昔单抗,美洛昔康,甲氨蝶呤,骁悉,麦考酚酯,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,阿奇霉素,奈替米星,西索米星,异帕米星,潮霉素B,丁胺卡那霉素,阿贝卡星,卡那霉素B,地贝卡星,妥布霉素,新霉素B,巴龙霉素,核糖霉素,奈替米星,大观霉素,链霉素,妥布霉素,威达米星;
b).氯霉素类抗生素类:叠氮氯霉素,氯霉素,氟苯尼考,甲砜霉素;
c).安莎类抗生素类:格尔德霉素,除莠霉素;
d).碳青霉烯类抗生素类:比阿培南,多尼培南,厄他培南,亚胺培南,西司他丁,美罗培南,帕尼培南;
e).头孢类:碳头孢烯,头孢乙腈,头孢克罗,头孢拉定,头孢羟氨,头孢洛宁,头孢噻啶,先锋霉素Ⅰ或头孢噻吩,头孢氨苄,头孢来星,头孢羟唑,头孢匹林,头孢曲嗪,头孢氮氟,头孢西酮,头孢唑啉,头孢拉宗,头孢卡品,头孢达肟,头孢吡肟,头孢米诺,头孢西丁,头孢丙烯,头孢沙定,头孢替唑,头孢呋辛,头孢克肟头孢地尼,头孢妥仑,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,头孢替安,头孢唑兰,头孢咪唑,头孢匹胺,头孢匹罗头孢泊肟,头孢喹肟,头孢磺啶,头孢他啶,头孢特仑,头孢布烯,头孢噻林,头孢唑肟,头孢吡普,头孢曲松,头孢唑喃,头孢西丁,头孢替坦,头孢美唑,氟氧头孢,拉氧头孢;
f).糖肽类:博莱霉素,奥利万星,特拉万星,替考拉宁,雷莫拉宁;
g).甘氨酰环类:替加环素;
h).β-内酰胺酶抑制剂类:青霉烷,舒巴坦,他唑巴坦,克拉维酸;
i).林可酰胺类:克林霉素,林可霉素;
j).脂肽:达托霉素,A54145,钙依赖性抗生素;
k).大环内酯类抗生素:红霉素,阿奇霉素,克拉霉素,地红霉素,红霉素,罗红霉素,交沙霉素,泰利霉素,喹红霉素,麦迪霉素,美地霉素,竹桃霉素,利福平,利福布丁,利福喷丁,罗他霉素,罗红霉素,大观霉素,螺旋霉素,他克莫司,醋竹桃霉素,泰利霉素;
l).单环β-内酰胺类:氨曲南,替吉莫南;
m).恶唑烷酮类:利奈唑胺;
n).青霉素类抗生素:阿莫西林,匹氨西林,海他西林,巴氨西林,美坦西林,酞氨西林,叠氮西林,阿洛西林,青霉素G,苄星青霉素,苄星青霉素,苄星苯氧甲基青霉素,氯甲西林,普鲁卡因苄青霉素,羧苄青霉素,氯唑西林,双氯西林,依匹西林,氟氯西林,美西林,美洛西林,甲氧西林,萘夫西林,苯唑西林,培那西林,盘尼西林,非奈西林,青霉素V,哌拉西林,丙匹西林,磺苄西林,替莫西林,替卡西林;
o).多肽类:杆菌肽,粘杆菌素,多粘菌素B;
p).喹诺酮类:阿拉沙星,巴洛沙星,环丙沙星,克林沙星,依诺沙星,恩诺沙星,达氟沙星,二氟沙星,氧氟沙星,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,那氟沙星,莫西沙星,奥比沙星,诺氟沙星,氧氟沙星,培氟沙星,曲伐沙星,西他沙星,司帕沙星,格帕沙星,替马沙星,托氟沙星,曲伐沙星;
q).阳菌素类:普那霉素,奎奴普丁,达福普汀
r).磺胺类:磺胺米隆,偶氮磺胺,磺胺醋酰,磺胺甲二唑,柳氮磺胺吡啶,磺胺异恶唑,甲氧苄啶,磺胺甲恶唑;
s).甾体类抗菌药:夫西地酸;
t).四环素类抗生素:多西环素,氯羟四环素,氯四环素,赖甲环素,去甲金霉素,土霉素,米诺环素,氯甲烯土霉素,氧四环素,青哌环素,吡甲四环素,四环素,替加环素;
u).其他的类型的抗生素:番荔枝素,砷凡纳明,杆菌肽,环丝氨酸,圆皮海绵内酯,艾榴塞洛素,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,细菌内酯,磷霉素,硝基呋喃妥因,紫杉醇,平板霉素,吡嗪酰胺,奎奴普丁/达福普汀,利福平,他唑巴坦磺甲硝咪唑,番荔枝内酯;
4).抗病毒药物:
a).输入/融合抑制剂:阿普拉韦罗,马拉韦罗,vicriviroc,恩夫韦肽,PRO140,依巴里足单抗ibalizumab;
b).整合酶抑制剂:雷特格韦,埃替拉韦,globoidnanA;
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).核苷及核苷酸:阿巴卡韦,阿昔洛韦,阿德福韦酯,氨多索韦,阿普瑞西他滨,溴夫定,西多福韦,右艾夫他滨,克拉夫定,地达诺新,艾夫他滨,恩曲他滨,恩替卡韦,泛昔洛韦,氟二氧嘧啶,3’-氟-2’,3’-二脱氧胸苷,3’-氟-2’,3’-双脱氧鸟苷,福米韦生,更昔洛韦,疱疹净,拉米夫定,β-1-胸苷和β-1-2’-脱氧胞苷,喷昔洛韦,racivir,利巴韦林,stampidine,司他夫定,taribavirin,替比夫定,替诺福韦,三伐昔洛韦,缬更昔洛韦,扎西他滨,齐多夫定;
f).非核苷类药物:金刚烷胺,ateviridine,卡普韦林,依曲韦林,利匹韦林,地拉韦啶,廿二醇,乙米韦林,依法韦仑,膦甲酸,咪喹莫特,·-干扰素,洛韦胺,洛德腺苷,甲吲噻腙,奈韦拉平,NOV-205,聚乙二醇干扰素·,足叶草毒素,利福平,金刚烷乙胺,瑞喹莫德;
g).蛋白酶抑制剂:安普那韦,阿扎那韦,博赛泼维,地瑞纳韦,福沙那韦,茚地那韦,洛匹那韦,奈非那韦,利托那韦,普拉康纳利,沙奎那韦,特拉匹韦,替拉那韦;
h).其他类型抗病毒药物:抗体酶,阿比朵尔,胡桐内酯A,ceragenin,蓝藻抗病毒蛋白N,二芳基嘧啶类化合物,表没食子儿茶素没食子酸酯,膦甲酸,griffithsin,塔利韦林,羟基脲,KP-1461,米替福新,普拉康纳利,利巴韦林,Seliciclib。
5).放射性同位素可以选自(放射性核素)3H,11C,14C,18F,32P,35S,64Cu,68Ga,86Y, 99Tc,111In,123I,124I,125I,131I,133Xe,177Lu,211At,或213Bi.
6).发色团分子:选自紫外光、荧光灯、红外光、近红外光、可见光、一种或多种黄色素、红细胞、虹彩色、隐色、黑色素、氰基、荧光化合物,光再发光、视觉光转导分子、发光分子、荧光素化合物;非蛋白质有机荧光团选自:黄种人,红细胞体,红细胞色素,白细胞,mel-anophores,氰基团,荧光化合物荧光化合物,光再发光,视觉光转导分子,发光团分子,发光分子,荧光素化合物;氧杂蒽衍生物(荧光素,罗丹明,俄勒冈绿,曙红和德克萨斯红);花菁衍生物(花菁,吲哚羰花青,氧杂花青,硫代花青和部花菁);方酸菁衍生物和环取代的方酸菁(包括Seta,SeTau和Square染料);萘衍生物(丹酰和prodan衍生物);香豆素衍生物;恶二唑衍生物(吡啶并恶唑,硝基苯并恶二唑和苯并恶二唑);蒽衍生物(蒽醌类,包括DRAQ5,DRAQ7和CyTRAK橙);芘衍生物(级联蓝色);恶嗪衍生物(尼罗红,尼罗蓝,甲酚紫,恶嗪170);吖啶衍生物(二氨基吖啶黄素,吖啶橙,吖啶黄);芳基甲胺衍生物(金胺,结晶紫,孔雀石绿);四吡咯衍生物(卟吩,酞菁,胆红素);以下荧光团化合物的任何类似物和衍生物:CF染料(Biotium),DRAQ和CyTRAK探针,BODIPY,Alexa Fluor,DyLight Fluor,Atto和TracyAb),DY和MegaStokes Dyes,Sulfo Cy染料(Cyandye),HiLyte Fluor,Se-ta,SeTau和Square Dyes(SETA BioMedicals),Quasar(APC),APC,APCXL,RPE,BPE(藻类生物技术),别藻蓝蛋白(APC),氨基香豆素,APC-Cy7偶联物,BODIPY-FL,Cascade Blue,Cy2,Cy3,Cy3.5,Cy3B,Cy5,Cy5.5,Cy7,Fluoresce-in,FluorX,羟基香豆素,丽丝胺罗丹明B,萤光黄,Methoxycoumarin,NBD,太平洋蓝,太平洋橙,PE-Cy5偶联物,PE-Cy7偶联物,PerCP,R-藻红蛋白(PE),Red 613,Seta-555-叠氮,Seta-555-DBCO,Seta-555-N-羟基琥珀酰亚胺,Seta-580-N-羟基琥珀酰亚胺,Seta-680-N-羟基琥珀酰亚胺,Seta-780-N-羟基琥珀酰亚胺,Seta--APC-780,Seta-PerCP-680,Seta-R-PE-670,SeTau-380-N-羟基琥珀酰亚胺,SeTau-405-马来酰亚胺,SeTau-405-N-羟基琥珀酰亚胺,SeTau-425-N-羟基琥珀酰亚胺,SeTau-647-N-羟基琥珀酰亚胺,Texas Red,TRITC,TruRed,X-若丹明,7-AAD(7-氨基放线菌素D,CG-选择性),吖啶橙,ChromomycinA3,CyTRAK橙(Biostatus,红色激发黑),DAPI,DRAQ5,DRAQ7,溴化乙锭,Hoechst33258,Hoechst33342,LDS751,Mith-雷霉素,碘化丙啶(PI),SYTOX蓝,SYTOXGreen,SYTOX橙,噻唑Or-ange,TO-PRO:花青单体,TOTO-1,TO-PRO-1,TOTO-3,TO-PRO-3,YOSeta-1,YOYO-1。可以与本发明的用于研究细胞的连接子连接的荧光团化合物选自下列化合物或其衍生物:DCFH(2'7'Dichorodihydro-fluorescein,氧化形式),DHR(二氢罗丹明123,氧化形式,轻质催化剂氧化),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)别藻蓝蛋白(APC),AmCyan1(四聚体,Clontech),AsRed2(四聚体,Clontech),Azami Green(单聚体,MBL),Azurite,B-phycoerythrin(BPE),Cerulean,CyPet,DsRed monomer(Clontech),DsRed2("RFP",Clontech),EBFP,EBFP2,ECFP,EGFP(弱二聚体,Clontech),Emerald公司(Emerald公司),萤光素B(藻红蛋白)弱二聚体,Invitrogen),EYFP(弱二聚体,Clontech),绿色荧光蛋白(S65A突变),绿色荧光蛋白(S65C突变),绿色荧光蛋白(S65L突变),绿色荧光蛋白(S65T突变),绿色荧光蛋白(Y66F突变),绿色荧光蛋白(Y66H突变),绿色荧光蛋白(Y66W突变),绿色荧光蛋白uv,HcRed1,J-Red,卡图沙,卡图沙黄(单体,MBL),mCFP,mCherry,mCitrine,Midoriishi青色(二聚体,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(藻胆体复合体),Peridinin叶绿素(PerCP),R-藻红蛋白(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),TurboFP635(二聚体,Evrogen),TurboGFP(二聚体,Evrogen),TurboRFP(二聚体,Evrogen),TurboYFP(二聚体,Evrogen),Venus,野生型GFP,YPet,ZsGreen1(四聚体,Clontech),ZsYellow1(四聚体,Clontech)
7).上述任何药物的药学上可接受的盐,酸或衍生物。
14.T如权利要求2,4,8或12所述的化合物,其中“Drug”是发色团分子时,用于检测、监测或研究细胞结合分子、和/或偶联物与靶标或靶细胞之间的相互作用或功能。
15.权利要求2,4,8或12的化合物,其中“药物”选自tubulysins,卡利奇霉素,奥瑞斯他汀,美登素,CC-1065衍生物,阿霉素,紫杉醇,埃博霉素和苯并二氮卓二聚体、吡咯苯二氮卓二聚体、茅屋霉素二聚体、安曲霉素二聚体、吲哚啉苯二氮卓二聚体、咪唑苯二氮卓二聚体、恶唑啉苯二氮卓二聚体,siRNA或其组合,和/或任何一种上述分子的药学上可接受的盐,酸或衍生物。
16.权利要求2,3,7或9的化合物,其中所述细胞结合剂/分子选自抗体,蛋白质,维生素(叶酸),肽,聚合物胶束,脂质体,基于脂蛋白的药物载体,纳米颗粒药物载体,树枝状聚合物以及上述任何一种的组合。
17.根据权利要求2,3,7,9或16中任一项所述的细胞结合分子/药剂,选自为抗体,单链抗体,与靶细胞结合的抗体片段,单克隆抗体,单链单克隆抗体或与靶细胞结合的单克隆抗体片段,嵌合抗体,与靶细胞结合的嵌合抗体片段,结构域抗体,结合靶细胞的结构域抗体片段,表面重构抗体,表面重构的单链抗体或与靶细胞结合的表面重构的抗体片段,人源化抗体或表面重构抗体,人源化单链抗体或结合靶细胞的人源化抗体片段,淋巴因子,维生素,生长因子,集落刺激因子或营养转运分子。
18.根据权利要求2,3,7,9或16中任一项所述的细胞结合分子/药剂可以是能够针对肿瘤细胞,病毒感染的细胞,微生物感染的细胞,寄生虫感染的细胞,自身免疫疾病细胞,活化的肿瘤细胞,骨髓细胞,活化的T细胞,感染B细胞或黑素细胞。
19.根据权利要求2,3,7,9或16中任一项所述的细胞结合分子/剂可以是能够针对以下任一种抗原或受体的任何分子: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(滋养层糖蛋白,TPBG,5T4,Wnt信号活化抑制因子1或WAIF1),腺癌抗原,AGS-5,AGS-22M6,激活素受体样激酶1,AFP,AKAP-4,ALK,阿尔法整合素,阿尔法v beta6,氨基肽酶N,β淀粉样蛋白,雄激素受体,血管生成素2,血管生成素3,膜联蛋白A1,炭疽毒素的保护性抗原,抗运铁蛋白受体,AOC3(VAP-1),B7-H3,炭疽芽孢杆菌炭疽,BAFF(B-细胞活化因子),B淋巴瘤细胞,BCR-ABL,蛙皮素,BORIS,C5,C242抗原,CA125(碳水化合物抗原125,MUC16),CAIX(或CAIX,碳酸酐酶9),CALLA,CanAg的,狼家族性IL31,碳酸酐酶IX,心脏肌球蛋白CCL11(CC基序趋化因子11),CCR4(CC趋化因子受体4型,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(密蛋白-18),凝聚因子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),CXC化学-CYP1B1,巨细胞病毒,巨细胞病毒糖蛋白B,达比加群,DLL3(δ-样配体3),DPP4-1,大肠杆菌志贺毒素-2型,ED-B,EGFL7(EGF样结构域蛋白7),EGFR,EGFRII,EGFRvIII,内皮糖蛋白(CD105),内皮素B受体,内毒素,EpCAM(上皮细胞粘附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,α-胎蛋白,β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.F蛋白的呼吸系统核糖体GM1,GD2神经节苷脂,G-28(细胞表面抗原glyvolipid),GD3独特型,GloboH,磷脂酰肌醇蛋白聚糖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),肠道鸟苷酸环化酶,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,肝炎B表面抗原,乙型肝炎病毒,HER1(人表皮生长因子受体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(人白细胞抗原),HLA-DR10,HLA-DRB,HMWMAA,人绒毛膜促性腺激素,HNGF,人散射因子受体激酶,HPVE6/E7,Hsp90的催化亚基,ICAM-1(细胞间粘附分子1),独特型,IGF1R(IGF-1,胰岛素样生长因子1受体),IGHE,IFN-γ,流感血凝素,Ig E,IgE Fc区,IGHE,IL-1,IL-2受体(白介素2受体),IL-4,IL-5,IL-6,IL-6R(白细胞介素6受体),IL-9,IL-(胰岛素样生长因子2),整联蛋白(α4,αIIbβ3,αvβ3,α4β7),IL-12,IL-13,IL-17,IL-,干扰素γ诱导蛋白ITGA2,ITGB2,KIR2D,LCK,Le,Legumain,Lewis-Y抗原,LFA-1(淋巴细胞功能相关抗原1,CD11a),α5β1,α6β4,α7β7,α11β3,α5β5,αvβ5,,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(巨噬细胞移动抑制因子或gly-cosylation-inhibiting factor(GIF)),MS4A1(跨膜4结构域亚家族A成员1),MSLN(间皮素),MUC1(粘蛋白1,细胞表面相关联的(MUC1)或polymor-PHIC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(跨膜4结构域亚家族A),MYC N,髓鞘相关糖蛋白,Myostatin,NA17,NARP-1,NCA-90(粒细胞抗原),Nectin-4(ASG-22ME),NGF,神经凋亡调节蛋白酶1,NOGO-A,Notch受体,Nucleolin,Neu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 nonmutant,P97,Page4, PAP,Paratope of anti-(N-glycolylneuraminicacid),PAX3,PAX5,PCSK9,PDCD1(PD-1,程序性细胞死亡蛋白1,CD279),PDGF,PDX1,PAX5,PCSK9,PDCD1的互补位(paratope of anti-N-glycolylneuraminic ac-(α型血小板衍生生长因子受体),PDGFR-β,PDL-1,PLAC1,PLAP样睾丸碱性磷酸酶,血小板衍生生长因子受体β,磷酸钠共转运蛋白,PMEL17,聚唾液酸(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),恒河猴因子,RANKL,RhoC,Ras突变体,RGS5,ROBO4,呼吸道合胞病毒,RON,肉瘤易位断点,SART3,硬化蛋白,SLAMF7(SLAM家族成员7),Selectin P,SDC1(Syndecan 1),sLe(a),Somatomedin C,SIP生长抑素,精子蛋白17,SSX2,STEAP1(前列腺1的六跨膜上皮抗原),STEAP2,STn,TAG-72(肿瘤相关的甘氨酸T细胞受体,T细胞跨膜蛋白,TEM1(肿瘤内皮标志物1),TENB2,TenascinC(TN-C),TGF-α,TGF-β(转化生长因子β)TGF-β1,转化生长因子β2,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(滋养层糖蛋白),TRAIL-R1(肿瘤坏死脱辅基诱导配体受体1),TRAILR2(死亡受体5(DR5)(catenin)信号转导2,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-VEGFR2或波形蛋白,WT1,XAGE1或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。
20.根据权利要求18的肿瘤细胞选自淋巴瘤细胞,骨髓瘤细胞,肾细胞,乳腺癌细胞,前列腺癌细胞,卵巢癌细胞,结肠直肠癌细胞,胃癌细胞,鳞状细胞癌细胞,小细胞肺癌细胞,非小细胞肺癌细胞,睾丸癌细胞,或以不能调节、快速的速度生长和分裂而以引起癌症的任何细胞。
21.一种药物组合物包含有效治疗剂量的权利要求2和/或8的偶联化合物和药学上可接受的盐、载体、稀释剂或赋形剂,用于治疗或预防癌症,或自身免疫性疾病或传染病。
22.根据权利要求2,4,8或12中任一项所述的偶联物或化合物,其中“Drug”选自毒素,化学治疗剂,药物分子,抗生素,放射性同位素,核酸分解酶和/或发色基团分子。
23.根据权利要求1,5或6中任一项所述的偶联物或化合物,其中所述;链接体可以含由以下组分:6-马来酰亚胺己酰基(MC),马来酰亚胺丙酰基(MP),缬氨酸-瓜氨酸(val-cit),丙氨酸-苯丙氨酸(ala-phe),赖氨酸-苯丙氨酸(lys-phe),对氨基苄氧羰基(PAB),4-硫代戊酸酯(SPP),4-(N-马来酰亚胺甲基)-环己烷-1-羧酸酯MCC),4-硫代丁酸酯(SPDB),马来酰亚胺乙基(ME),4-硫代-2-羟基磺酰基丁酸酯(2-磺基-SPDB),吡啶基二硫醇(PySS),烷氧基氨基(AOA),乙炔基氧(EO),4-甲基-4-二硫代戊酸(MPDP),叠氮基(N3),炔基,二硫基,肽和/或(4-乙酰基)氨基苯甲酸酯(SIAB)。
24.根据权利要求2,8或22中任一项的偶联物或化合物,其中“Drug”选自tubulysins,美登木素生物碱,类紫杉醇(紫杉烷),CC-1065类似物,柔红霉素和阿霉素化合物,苯并二氮卓二聚体(选自为吡咯并苯二氮卓二聚体、托马霉素二聚体、吲哚啉并苯二氮卓二聚体、咪唑并苯二氮卓或恶唑烷并苯二氮卓二聚体),加利霉素和烯二炔抗生素,放线菌素,azaserines,博来霉素,表柔比星,他莫昔芬,伊达比星,多拉司他汀/奥瑞斯他汀(选自单甲基奥瑞斯他汀E,奥瑞斯他汀MMAE,奥瑞斯他汀MMAF,奥瑞斯他汀PYE,auristatin TP,奥瑞斯他汀2-AQ,奥瑞斯他汀6-AQ,奥瑞斯他汀EB(AEB)和奥瑞斯他汀EFP(AEFP)),多卡米星,噻替派,长春新碱,hemiasterlins,nazumamides,microginins,radiosumins,alterobactins,microsclerominmins,theonellamides,esperamicins,类似物和衍生物。
25.根据权利要求1或4的化合物,其含有能够与细胞结合剂反应的官能团,包含如下式5,9,16,19,27,29,30,33,35,40,47,50,51,53,62,63,65,68,69,74,75,77,84,85,88,89,94,95,99,100,108,109,114,115,121,123,124,135,136,141,142,144,147a,147b,147c,147d,153,158,172,173,174,182,183,193,194,195,202,203,204,207,208,或209所示:
其中m1,m2和m3独立地为0~24,X为卤素,R1和Drug的定义与权利要求1,2,13,或14中的相同。
27.根据权利要求2,7,或8中任一项所述的偶联物,其具有体外,体内或离体细胞杀伤活性。
28.如权利要求2,7和/或8中任一项所述的偶联化合物,其可以包含1~20个单位的天然或非天然氨基酸的肽,或者对氨基苄基单元或者6-马来酰亚胺基己酰基单元,或者二硫化物单元,或硫醚单元,或腙单元,或三唑单元,或烷肟单元。
29.根据权利要求2,7或8中任一项所述的偶联化合物,其中本发明的连接组分可以被蛋白酶裂解。
30.包含有效治疗剂量的权利要求2,7或/和8的偶联化合物的药物组合物,用于与选自化疗试剂,放射疗法,免疫治疗剂,自身免疫病症试剂,抗感染试剂或其他偶联物协同有效治疗或预防癌症、或自身免疫疾病、或传染病。
31.根据权利要求30的协同剂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,阿法替尼二马来酸盐,阿仑单抗,阿利维A酸,爱都曲妥单抗美登素,阿米珠单抗,安非他明混合盐(安非他明/右旋安非他命),阿那曲唑,阿立哌唑,阿扎那韦,阿特珠单抗,阿托伐他汀,阿昔替尼,贝利司他,贝伐珠单抗,卡巴它赛,卡博替尼,蓓萨罗丁,博纳吐单抗,硼替佐米,博舒替尼,本妥昔单抗,布地奈德,布地奈德/福莫特罗,丁丙诺啡,卡培他滨,卡非佐米,塞来昔布,赛立替尼,西妥昔单抗,环孢素,西那卡塞,克唑替尼,达比加群,达拉菲尼,达比泊汀阿尔珐,达芦那韦,甲磺酸伊马替尼,达沙替尼,地尼白介素-2白喉毒素,地诺单抗,双丙戊酸钠,地塞米松,右兰索拉唑,右哌甲酯,地努妥昔单抗,多西环素,度洛西汀,恩曲他滨/利匹韦林/富马酸替诺福韦二吡呋酯,恩曲他滨/替诺福韦/依法韦仑,依诺肝素,恩佐鲁胺,依泊汀α,厄洛替尼,埃索美拉唑,艾司佐匹克隆,依那西普,依维莫司,依西美坦,依折替米贝,依折替米贝/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,伊曲替尼,伊布替莫单抗逖携坦,依鲁替尼,艾代拉利司,英夫利昔单抗,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,易普利姆玛,异丙托溴铵/沙丁胺醇,醋酸兰纳肽,来那度胺,甲磺酸莱那替林,来曲唑,左旋甲状腺素,利多卡因,利奈唑胺,利拉鲁肽,二甲磺酸赖右苯丙胺,MEDI4736,美金刚胺,利他灵,美托洛尔,莫达非尼,莫米松,尼罗替尼,纳武单抗,奥法木单抗,奥滨尤妥珠单抗,奥拉帕尼,奥美沙坦,奥美沙坦/氢氯噻嗪,奥马珠单抗,欧米伽-3脂肪酸乙酯,奥司他韦,羟考酮,帕博西尼,帕利珠单抗,帕尼单抗,帕比司他,帕唑帕尼,派姆单抗,培美曲塞,帕妥珠单抗,肺炎链球菌疫苗,泊马度胺,普瑞巴林,喹硫平,雷贝拉唑,镭223氯化物,雷洛昔芬,拉替拉韦,雷莫卢单抗,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,磷酸鲁索利替尼,沙丁胺醇,司维拉姆,西地那非,司妥昔单抗,西他列汀,西他列汀/二甲双胍,索利那新,索拉非尼,舒尼替尼,他达拉非,他莫昔芬,特拉匹韦,替西罗莫司,替诺福韦/恩曲他滨,睾酮凝胶,沙利度胺(依缪普林),噻托溴铵,托瑞米芬,曲美替尼,曲妥珠单抗,维生素A酸,优特克单抗,缬沙坦,凡德他尼,威罗菲尼,伏瑞斯特,阿柏西普,带状疱疹疫苗,及其类似物、衍生物、药学上可接受的盐、载体或赋形剂,或上述的组合。
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CN108026123A (zh) | 2018-05-11 |
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CA2989269A1 (en) | 2015-10-08 |
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