CN105636613B - 吡咯并苯并二氮杂卓及其缀合物 - Google Patents
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Abstract
Description
技术领域
背景技术
吡咯并苯并二氮杂
一些吡咯并苯并二氮杂(PBD)具有识别和键合于DNA的特定序列的能力;优选的序列是PuGPu。第一PBD抗肿瘤抗生素,安曲霉素(antramycin),发现于1965年(Leimgruber等,J.Am.Chem.Soc.,87,5793-5795(1965);Leimgruber等,J.Am.Chem.Soc.,87,5791-5793(1965))。自那以后,已报道许多天然存在的PBD,以及已开发用于各种类似物的10种以上的合成路线(Thurston等,Chem.Rev.1994,433-465(1994);Antonow,D.and Thurston,D.E.,Chem.Rev.2011 111(4),2815-2864)。家族成员包括修道院霉素(abbeymycin)(Hochlowski等,J.Antibiotics,40,145-148(1987))、契卡霉素(chicamycin)(Konishi等,J.Antibiotics,37,200-206(1984))、DC-81(日本专利58-180 487;Thurston等,Chem.Brit.,26,767-772(1990);Bose等,Tetrahedron,48,751-758(1992))、甲基氨茴霉素(Kuminoto等,J.Antibiotics,33,665-667(1980))、新茴霉素A和B(Takeuchi等,J.Antibiotics,29,93-96(1976))、porothramycin(Tsunakawa等,J.Antibiotics,41,1366-1373(1988))、prothracarcin(Shimizu,等,J.Antibiotics,29,2492-2503(1982);Langley and Thurston,J.Org.Chem.,52,91-97(1987))、西班米星(DC-102)(Hara等,J.Antibiotics,41,702-704(1988);Itoh等,J.Antibiotics,41,1281-1284(1988))、矛霉素(sibiromycin)(Leber等,J.Am.Chem.Soc.,110,2992-2993(1988))和托马霉素(tomamycin)(Arima等,J.Antibiotics,25,437-444(1972))。PBD具有以下通式结构:
它们的不同之处在于在它们的芳族A环和吡咯并C环中取代基的数量、类型和位置,以及在于C环的饱和度。在B环中,在N10-C11位置,其是负责烷基化DNA的亲电中心,存在亚胺(N=C)、甲醇胺(NH-CH(OH))、或甲醇胺甲基醚(NH-CH(OMe))。所有已知的天然产物在手性C11a位置处具有(S)-构型,当从C环向着A环观看时,其为它们提供右手扭转。这给予它们适当的的三维形状,用于与B型DNA的小沟的同螺旋性(isohelicity),从而导致在结合位点处的滑动配合(snug fit)(Kohn,In Antibiotics III.Springer-Verlag,New York,第3-11页(1975);Hurley and Needham-VanDevanter,Acc.Chem.Res.,19,230-237(1986))。它们在小沟中形成加合物的能力使得它们能够干扰DNA加工,因而使得它们可以用作抗肿瘤剂。
描述了特别有利的吡咯并苯并二氮杂化合物:Gregson等(Chem.Commun.1999,797-798)作为化合物1,以及Gregson等(J.Med.Chem.2001,44,1161-1174)作为化合物4a。此化合物,还被称为SG2000,被示于以下:
WO 2007/085930描述了二聚体PBD化合物的制备,其中所述二聚体PBD化合物具有接头基团,用于连接于细胞结合剂,如抗体。接头存在于连接二聚体的单体PBD单元的桥中。
WO 2011/130598中描述了二聚体PBD化合物,其具有接头基团,用于连接于细胞结合剂,如抗体。这些化合物中的接头连接于可用的N10位置之一,并通常通过在接头基团上的酶的作用被切割。
抗体-药物缀合物
抗体疗法已建立用于靶向治疗患有癌症、免疫疾病和和血管生成疾病的患者(Carter,P.(2006)Nature Reviews Immunology 6:343-357)。抗体-药物缀合物(ADC),即免疫缀合物,用于局部递送细胞毒性剂或细胞抑制剂,即药物以在癌症的治疗中杀死或抑制肿瘤细胞的应用,靶向递送药物部分到肿瘤,以及在其中的细胞内积累,而这些非缀合药剂的全身施用可以导致不可接受水平的对正常细胞的毒性(Xie等(2006)Expert.Opin.Biol.Ther.6(3):281-291;Kovtun等(2006)Cancer Res.66(6):3214-3121;Law等(2006)Cancer Res.66(4):2328-2337;Wu等(2005)Nature Biotech.23(9):1137-1145;Lambert J.(2005)Current Opin.in Pharmacol.5:543-549;Hamann P.(2005)Expert Opin.Ther.Patents 15(9):1087-1103;Payne,G.(2003)Cancer Cell3:207-212;Trail等(2003)Cancer Immunol.Immunother.52:328-337;Syrigos and Epenetos(1999)Anticancer Research 19:605-614)。
因而寻求具有最小毒性的最大疗效。设计和完善ADC的努力已集中于单克隆抗体(mAb)的选择性、药物作用机制、药物连接、药物/抗体比率(负载)、和药物释放性能(Junutula等,2008b Nature Biotech.,26(8):925-932;Dornan等(2009)Blood 114(13):2721-2729;US 7521541;US 7723485;WO2009/052249;McDonagh(2006)ProteinEng.Design&Sel.19(7):299-307;Doronina等(2006)Bioconj.Chem.17:114-124;Erickson等(2006)Cancer Res.66(8):1-8;Sanderson等(2005)Clin.Cancer Res.11:843-852;Jeffrey等(2005)J.Med.Chem.48:1344-1358;Hamblett等(2004)Clin.Cancer Res.10:7063-7070)。通过机制,包括微管蛋白结合、DNA结合、蛋白酶体和/或拓扑异构酶抑制,药物部分可以赋予它们的细胞毒性和细胞抑制效应。当缀合于较大抗体或蛋白质受体配体时,一些细胞毒性药物倾向于是无活性或低活性的。
本发明人已开发了特定的PBD二聚体,其具有连接基团,用于与细胞结合剂形成PBD缀合物,以及尤其是PBD抗体缀合物。
发明内容
在第一方面,本发明提供了化合物A:
及其盐和溶剂化物。
在第二方面,本发明提供了化合物B:
及其盐和溶剂化物。
在第三方面,本发明提供了化合物C:
化合物A、B和C与先前公开的PBD二聚体(含有药物接头,其具有C2-3内双键)的不同之处在于,具有较小的、较少亲脂性的C2取代基,例如4F-苯基、亚丙基。因此,在合成以后,化合物A、B和C的缀合物(见下文)不太可能聚集。可以通过尺寸排阻色谱法(SEC)来测量缀合物的此类聚集。
化合物A和B包含分别用于连接于细胞结合剂的碘乙酰胺和碘溴乙酰胺基团。
化合物C在第二亚胺基团上具有可裂解保护基,该可裂解保护基避免化合物C在合成期间的交叉反应并且在最终产物中避免甲醇胺和甲醇胺甲醚的形成。此保护还避免分子中反应性亚胺基团的存在。
所有三种化合物在每个C环中均具有两个sp2中心,相比于在每个C环中仅具有一个sp2中心的化合物,其可以允许在DNA的小沟中具有更强的结合。
本发明的第四方面提供了式ConjAB:
式ConjC:
的缀合物,
其中CBA表示细胞结合剂。与所示部分的连接是经由在细胞结合剂上的游离S(活性巯基)。
具体实施方式
本发明提供了PBD二聚体,该PBD二聚体具有接头,其是通过在PBD部分之一上的N10位置加以连接,其适合于形成经由接头缀合于细胞结合剂的PBD二聚体。
本发明适用于向受试者的优选部位提供PBD化合物。该缀合物允许释放活性PBD化合物,其并不保留接头的任何部分。不存在可能影响PBD化合物的反应性的残余部分(stub)。因此,ConjAB和ConjC均将释放化合物RelA:
在本发明中,在PBD二聚体和细胞结合剂(例如抗体)之间的指定的连接优选是细胞外稳定的。在转运或递送进入细胞中以前,抗体-药物缀合物(ADC)优选是稳定的并保持完整,即,抗体保持连接于药物部分。接头在靶细胞以外是稳定的并且在细胞内可以以某个有效速率被切割。有效接头将:(i)保持抗体的特异性结合特性;(ii)允许缀合物或药物部分的细胞内递送;(iii)保持稳定和完整,即,不被切割,直到缀合物已被递送或转运它的靶向部位;以及(iv)保持PBD药物部分的细胞毒性、细胞的杀伤效应或细胞抑制效应。可以通过标准分析技术如质谱法、HPLC、和分离/分析技术LC/MS来测量ADC的稳定性。
通过酶(如组织蛋白酶)对连接基团并且特别是对缬氨酸-丙氨酸二肽部分的作用来实现在式ConjAB或ConjC的缀合物的所期望的活化位点上递送化合物RelA。
细胞结合剂
细胞结合剂可以是任何种类,并且包括肽和非肽。它们可以包括抗体或抗体片段,其包含至少一个结合位点,淋巴因子,激素,激素模拟物,维生素,生长因子,营养物输送分子,或任何其他细胞结合分子或物质。
肽
在一个实施方案中,细胞结合剂是线性或环状肽,其包含4-30个,优选6-20个相邻的氨基酸残基。在本实施方案中,优选的是,一种细胞结合剂连接于一种单体或二聚体吡咯并苯并二氮杂化合物。
在一个实施方案中,细胞结合剂包含结合整联蛋白ανβ6的肽。该肽对ανβ6的选择性超出XYS。
在一个实施方案中,细胞结合剂包含A20FMDV-Cys多肽。A20FMDV-Cys具有序列:NAVPNLRGDLQVLAQKVARTC。可替代地,可以使用A20FMDV-Cys序列的变体,其中1、2、3、4、5、6、7、8、9或10个氨基酸残基被另一种氨基酸残基取代。此外,多肽可以具有序列NAVXXXXXXXXXXXXXXXRTC。
抗体
术语“抗体”在本文中是在最广泛的意义上加以使用并且具体地涵盖单克隆抗体、多克隆抗体、二聚体、多聚体、多特异性抗体(例如,双特异性抗体)、和抗体片段,只要它们显示所期望的生物活性(Miller等(2003)Jour.of Immunology 170:4854-4861)。抗体可以是鼠、人、人源化、嵌合抗体,或源于其他物种。抗体是由免疫系统生成的蛋白质,其能够识别和结合于特异性抗原(Janeway,C.,Travers,P.,Walport,M.,Shlomchik(2001)ImmunoBiology,5th Ed.,Garland Publishing,New York)。靶抗原通常具有由在多种抗体上的CDR所识别的许多结合位点,还被称为表位。特异性地结合于不同表位的每种抗体具有不同的结构。因此,一种抗原可以具有多于一种的相应的抗体。抗体包括全长免疫球蛋白分子或全长免疫球蛋白分子的免疫活性部分,即,一种分子,其包含免疫特异性地结合感兴趣的靶的抗原或其部分的抗原结合位点,这样的靶包括但不限于癌细胞或产生与自身免疫疾病相关的自身免疫抗体的细胞。免疫球蛋白可以是任何类型(例如IgG、IgE、IgM、IgD、和IgA)、类(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或免疫球蛋白分子的亚类。免疫球蛋白可以源自任何物种,包括人、鼠、或兔起源。
"抗体片段"包含全长抗体的一部分,通常为其抗原结合或可变区。抗体片段的实例包括Fab、Fab'、F(ab')2、和scFv片段;双体分子;线性抗体;由Fab表达文库产生的片段,抗独特型(抗-Id)抗体,CDR(互补决定区),和任何上述项的表位结合片段,其免疫特异性地结合于癌细胞抗原、病毒抗原或微生物抗原,单链抗体分子;以及形成自抗体片段的多特异性抗体。
如在本文中所使用的,术语“单克隆抗体”是指获自基本上同质性的抗体的群体的抗体,即,除了可少量存在的可以天然发生的突变以外,构成群体的单独抗体是相同的。单克隆抗体是高度特异性的,是针对单一的抗原位点。此外,相对于多克隆抗体制剂,其包括针对不同决定子(表位)的不同抗体,每种单克隆抗体是针对在抗原上的单一决定子。除它们的特异性之外,单克隆抗体也是有利的,因为它们可以被合成而未被其他抗体污染。修饰语“单克隆”表明,抗体的特性是获自抗体的基本同质群体,而并不应当被解释为需要通过任何特定方法来生产抗体。例如,根据本发明使用的单克隆抗体可以通过首先由Kohler等(1975)Nature 256:495描述的杂交瘤方法来制备,或可以通过重组DNA方法来制备(参见,US 4816567)。单克隆抗体还可以分离自噬菌体抗体库,其中利用在Clackson等(1991)Nature,352:624-628、Marks等(1991)J.Mol.Biol.,222:581-597中描述的技术,或者可以分离自携带完全人免疫球蛋白系统的转基因小鼠(Lonberg(2008)Curr.Opinion 20(4):450-459)。
本文中的单克隆抗体特别包括“嵌合”抗体,其中一部分的重和/或轻链相同或同源于在源自特定物种或属于特定抗体类或亚类的抗体中的相应序列,同时链的剩余部分相同于或同源于在源自另一物种或属于另一抗体类或亚类的抗体中的相应序列,以及上述抗体的片段,只要它们显示所期望的生物活性(US 4816567;和Morrison等(1984)Proc.Natl.Acad.Sci.USA,81:6851-6855)。嵌合抗体包括“灵长类化”抗体,其包含源自非人灵长类动物(例如旧大陆猴或猿)的可变区抗原结合序列和人恒定区序列。
本文中的“完整抗体”是这样一种抗体,其包含VL和VH域,以及轻链恒定区(CL)和重链恒定区,CH1、CH2和CH3。恒定区可以是天然序列恒定区(例如人天然序列恒定区)或其氨基酸序列变体。完整抗体可以具有一种或多种“效应子功能”,其是指可归因于抗体的Fc区(天然序列Fc区或氨基酸序列变体Fc区)的那些生物活性。抗体效应子功能的实例包括C1q结合;补体依赖性细胞毒性;Fc受体结合;抗体依赖性细胞介导的细胞毒性(ADCC);吞噬作用;以及细胞表面受体(如B细胞受体和BCR)的下调。
取决于它们的重链的恒定区的氨基酸序列,完整抗体可以被指定为不同的“类”。存在五大类的完整抗体:IgA、IgD、IgE、IgG、和IgM,并且这些的若干种可以进一步分为“亚类”(同种型),例如,IgG1、IgG2、IgG3、IgG4、IgA、和IgA2。对应于不同种类的抗体的重链恒定区分别被称为α、δ、ε、γ、和μ。不同类别的免疫球蛋白的亚基结构和三维构型是众所周知的。
人源化
用于减小非人抗体或抗体片段的体内免疫原性的技术包括那些称作“人源化”的技术。
"人源化抗体"是指一种多肽,其包含人抗体的至少一部分的修饰可变区,其中一部分的可变区,优选基本上小于完整人可变域的部分已被来自非人物种的相应序列所取代,以及其中修饰可变区连接于另一种蛋白的至少另一部分,优选人抗体的恒定区。措辞"人源化抗体"包括人抗体,其中一个或多个互补决定区("CDR")氨基酸残基和/或一个或多个框架区("FW"或"FR")氨基酸残基被来自在啮齿动物或其他非人抗体中的类似位点的氨基酸残基取代。措辞"人源化抗体"还包括免疫球蛋白氨基酸序列变体或其片段,其包含实质上具有人免疫球蛋白的氨基酸序列的FR,以及实质上具有非人免疫球蛋白的氨基酸序列的CDR。
非人(例如,鼠)抗体的"人源化"形式是嵌合抗体,其包含源自非人免疫球蛋白的最小序列。或,以另一种方式看,人源化抗体是人抗体,其还包含来自非人(例如鼠)抗体的选择的序列来代替人序列。人源化抗体可以包括保守氨基酸置换或非天然残基,这些非天然残基来自相同或不同物种,其并不显著改变它的结合和/或生物活性。上述抗体是嵌合抗体,其包含源自非人免疫球蛋白的最小序列。
存在多种人源化技术,包括‘CDR移植’、‘定向选择’、‘去免疫化’、‘镶面(resurfacing)’(还被称为‘饰面(veneering)’)、‘复合抗体’、‘人类序列含量优化(HumanString Content Optimisation)’和框架重排。
CDR移植
在此技术中,人源化抗体是人免疫球蛋白(受体抗体),其中来自受体抗体的互补决定区(CDR)的残基被来自非人物种(供体抗体)如小鼠、大鼠、骆驼、牛、山羊、或兔的CDR的残基所替代,其具有所期望的性能(实际上,非人CDR被‘移植’到人框架上)。在一些情况下,人免疫球蛋白的框架区(FR)残基被相应非人残基替代(当例如特定FR残基对抗原结合具有显著影响时,这可能会发生)。
此外,人源化抗体可以包含这样的残基,其既不存在于受体抗体也不存在于输入的CDR或框架序列中。进行这些修饰以进一步完善和最大化抗体性能。因此,通常,人源化抗体将均包含至少一个,以及在一个方面两个,可变域,其中所有或(基本上)所有的高变环对应于非人免疫球蛋白的那些高变环,以及所有或基本上所有的FR区是人免疫球蛋白序列的那些FR区。人源化抗体可选地还将包含至少一部分的免疫球蛋白恒定区(Fc)、或人免疫球蛋白的免疫球蛋白恒定区。
定向选择
这种方法包括结合对于特定表位具有特异性的给定非人抗体的VH或VL域和人VH或VL文库,并相对于感兴趣的抗原来选择特定人V域。然后这种选择的人VH结合于VL文库产生完全人VHxVL组合。该方法描述于Nature Biotechnology(N.Y.)12,(1994)899-903。
复合抗体
在此方法中,在最终抗体分子内结合来自人抗体的氨基酸序列的两个或更多区段。通过联合地结合多个人VH和VL序列片段,其限制或避免在最终复合抗体V区中的人T细胞表位,来构建它们。在需要时,通过交换有助于或编码T细胞表位的V区区段与避免T细胞表位的替代区段来限制或避免T细胞表位。这种方法描述于US 2008/0206239 A1。
去免疫化
此方法涉及从治疗性抗体(或其他分子)的V区除去人(或其他第二物种)T细胞表位。通过,例如,比较于MHC结合基序的数据库(如"基序"数据库,位于www.wehi.edu.au),来分析治疗性抗体V区序列中MHC类II-结合基序的存在。可替代地,可以利用计算线程方法如由Altuvia等(J.Mol.Biol.249 244-250(1995))所设计的那些方法,来确定MHC类II-结合基序;在这些方法中,测试来自V区序列的连续重叠肽的与MHC II类蛋白的结合能。然后此数据可以结合于关于其他序列特征的信息,其涉及成功呈现的肽,如两亲性、Rothbard基序、和用于组织蛋白酶B和其他加工酶的切割位点。
一旦已确定潜在的第二物种(例如人)T细胞表位,则通过改变一个或多个氨基酸消除它们。修饰氨基酸通常是在T细胞表位本身内,但就蛋白质的一级或二级结构而言也可以是相邻于表位(因此,在一级结构中,可能并不是相邻的)。最典型地,改变是通过置换的方式,但在一些情况下,氨基酸添加或缺失将是更合适的。
可以通过重组DNA技术来完成所有改变,以至通过重组宿主的表达并利用很好建立的方法如定位诱变,来制备最终分子。然而,也可以使用蛋白质化学或分子改变的任何其他方式。
镶面
此方法包括:
(a)通过构建非人抗体可变区的三维模型,确定非人(例如啮齿动物)抗体(或其片段)的可变区的构象结构;
(b)利用来自足够数量的非人和人抗体可变区重和轻链的x射线晶体结构的相对可达性分布,产生序列对比,以给予一组重和轻链框架位置,其中在98%的足够数量的非人抗体重和轻链中序列对比位置是相同的;
(c)利用在步骤(b)中产生的框架位置的组,将非人抗体定义为人源化的、一组重链和轻链的表面暴露氨基酸残基;
(d)依据人抗体氨基酸序列,鉴定一组重链和轻链的表面暴露氨基酸残基,其最密切相同于在步骤(c)中定义的表面暴露的氨基酸残基的组,其中来自人抗体的重链和轻链是或不是天然成对的;
(e)在待人源化的非人抗体的氨基酸序列中,用在步骤(d)中确定的重链和轻链表面暴露的氨基酸残基的组替代在步骤(c)中定义的重链和轻链表面暴露的氨基酸残基的组;
(f)构建产生自在步骤(e)中指定的替代的非人抗体的可变区的三维模型;
(g)通过比较在步骤(a)和(f)中构建的三维模型,并依据在步骤(c)或(d)中确定的组,确定在待人源化的非人抗体的互补决定区的任何残基的任何原子的5埃内的任何氨基酸残基;以及
(h)将在步骤(g)中确定的任何残基从人改变到原来非人氨基酸残基,从而定义表面暴露的氨基酸残基的非人抗体人源化组;前提条件是,无需首先进行步骤(a),但必须在步骤(g)以前进行。
超人源化
该方法比较非人序列与功能性人种系基因库。选择了编码相同或密切相关于非人序列的规范结构的那些人基因。那些选择的在CDR内具有最高同源性的人基因被选作FR供体。最后,将非人CDR移植到这些人FR上。这种方法描述于专利WO 2005/079479 A2。
人类序列含量优化
这种方法比较了非人(例如小鼠)序列与人种系基因库并且差异被评定为人类序列含量(HSC),其在潜在的MHC/T细胞表位的水平量化序列。然后通过最大化它的HSC而不是利用全局同一性措施来人源化靶序列以产生多种不同的人源化变体(描述于MolecularImmunology,44,(2007)1986–1998)。
框架重排
将非人抗体的CDR框内融合于涵盖所有已知的重链和轻链人种系基因框架的cDNA池。然后通过例如淘选噬菌体展示抗体库来选择人源化抗体。这描述于Methods 36,43-60(2005)。
细胞结合剂的实例包括那些描述的用于并入本文中的WO 2007/085930的细胞结合剂。
以下列出用于本发明的实施方案的肿瘤相关抗原和同源抗体。
肿瘤相关抗原和同源抗体
(1)BMPR1B(骨形态发生蛋白受体型IB)
核苷酸
Genbank登录号NM_001203
Genbank版本号NM_001203.2 GI:169790809
Genbank记录更新日期:2012年9月23日下午02:06
多肽
Genbank登录号NP_001194
Genbank版本号NP_001194.1 GI:4502431
Genbank记录更新日期:2012年9月23日下午02:06
交叉参考
ten Dijke,P.等Science 264(5155):101-104(1994),Oncogene 14 10(11):1377-1382(1997));WO2004/063362(权利要求2);WO2003/042661(权利要求12);US2003/134790-A1(页码38-39);WO2002/102235(权利要求13;页码296);WO2003/055443(页码91-92);WO2002/99122(实施例2;页码528-530);WO2003/029421(权利要求6);WO2003/024392(权利要求2;图112);WO2002/98358(权利要求1;页码183);WO2002/54940(页码100-101);WO2002/59377(页码349-350);WO2002/30268(权利要求27;页码376);15WO2001/48204(实施例;图4);NP_001194骨形态发生蛋白受体,型IB/pid=NP_001194.1.;MIM:603248;AY065994。
(2)E16(LAT1,SLC7A5)
核苷酸
Genbank登录号NM_003486
Genbank版本号NM_003486.5 GI:71979931
Genbank记录更新日期:2012年6月27日下午12:06
多肽
Genbank登录号NP_003477
Genbank版本号NP_003477.4 GI:71979932
Genbank记录更新日期:2012年6月27日下午12:06
交叉参考
Biochem.Biophys.Res.
Commun.255(2),283-288(1999),Nature 395(6699):288-291(1998),Gaugitsch,H.W.,et 20 al(1992)J.Biol.Chem.267(16):11267-11273);WO2004/048938(实施例2);WO2004/032842(实施例IV);WO2003/042661(权利要求12);WO2003/016475(权利要求1);WO2002/78524(实施例2);WO2002/99074(权利要求19;页码127-129);WO2002/86443(权利要求27;页码222,393);WO2003/003906(权利要求10;页码293);WO2002/64798(权利要求33;页码93-95);WO2000/14228(权利要求5;页码133-136);US2003/224454(图3);25WO2003/025138(权利要求12;页码150);NP_003477溶质载体家族7(阳离子氨基酸转运蛋白,y+系统),成员5/pid=NP_003477.3-智人;
MIM:600182;;NM_015923。
(3)STEAP1(前列腺的六跨膜上皮抗原)
核苷酸
Genbank登录号NM_012449
Genbank版本号NM_012449.2 GI:22027487
Genbank记录更新日期:2012年9月9日下午02:57
多肽
Genbank登录号NP_036581
Genbank版本号NP_036581.1 GI:9558759
Genbank记录更新日期:2012年9月9日下午02:57
交叉参考
Cancer Res.61(15),5857-5860(2001),Hubert,R.S.等(1999)Proc.Natl.Acad.Sci.U.S.A.96(25):14523-14528);WO2004/065577(权利要求6);WO2004/027049(图1L);EP1394274(实施例11);WO2004/016225(权利要求2);WO2003/042661(权利要求12);US2003/157089(实施例5);US2003/185830(实施例5);US2003/064397(图2);WO2002/89747(实施例5;页码618-619);WO2003/022995(实施例9;图13A,35实施例53;页码173,实施例2;图2A);前列腺的六跨膜上皮抗原;MIM:604415。
(4)0772P(CA125,MUC16)
核苷酸
Genbank登录号AF361486
Genbank版本号AF361486.3 GI:34501466
Genbank记录更新日期:2010年3月11日上午07:56
多肽
Genbank登录号AAK74120
Genbank版本号AAK74120.3 GI:34501467
Genbank记录更新日期:2010年3月11日上午07:56
交叉参考
J.Biol.Chem.276(29):27371-27375(2001));WO2004/045553(权利要求14);WO2002/92836(权利要求6;图12);WO2002/83866(权利要求15;页码116-121);US2003/124140(实施例16);GI:34501467。
(5)MPF(MPF、MSLN、SMR、巨核细胞增效因子、间皮素)
核苷酸
Genbank登录号NM_005823
Genbank版本号NM_005823.5 GI:293651528
Genbank记录更新日期:2012年9月2日下午01:47
多肽
Genbank登录号NP_005814
Genbank版本号NP_005814.2GI:53988378
Genbank记录更新日期:2012年9月2日下午01:47
交叉参考
Yamaguchi,N.等Biol.Chem.269(2),805-808(1994),Proc.Natl.Acad.Sci.U.S.A.96(20):11531-11536(1999),Proc.Natl.Acad.Sci.U.S.A.9310(1):136-140(1996),J.Biol.Chem.270(37):21984-21990(1995));WO2003/101283(权利要求14);(WO2002/102235(权利要求13;页码287-288);WO2002/101075(权利要求4;页码308-309);WO2002/71928(页码320-321);WO94/10312(页码52-57);IM:601051。
(6)Napi3b(NAPI-3B,NPTIIb,SLC34A2,溶质载体家族34(磷酸钠),成员2,II型钠依赖性磷酸转运蛋白3b)
核苷酸
Genbank登录号NM_006424
Genbank版本号NM_006424.2 GI:110611905
Genbank记录更新日期:2012年7月22日下午03:39
多肽
Genbank登录号NP_006415
Genbank版本号NP_006415.2 GI:110611906
Genbank记录更新日期:2012年7月22日下午03:39
交叉参考
J.Biol.Chem.277(22):19665-19672(2002),Genomics 62(2):281-284(1999),Feild,J.A.等(1999)Biochem.Biophys.Res.Commun.258(3):578-582);WO2004/022778(权利要求2);EP1394274(实施例11);WO2002/102235(权利要求13;页码20 326);EP0875569(权利要求1;页码17-19);WO2001/57188(权利要求20;页码329);WO2004/032842(实施例IV);WO2001/75177(权利要求24;页码139-140);MIM:604217。
(7)Sema 5b(FLJ10372,KIAA1445,Mm.42015,SEMA5B,SEMAG,Semaphorin 5bHlog,25sema域,7血小板反应蛋白重复(1型和1型样),跨膜域(TM)和短胞质域(semaphorin5B)
核苷酸
Genbank登录号AB040878
Genbank版本号AB040878.1 GI:7959148
Genbank记录更新日期:2006年8月2日下午05:40
多肽
Genbank登录号BAA95969
Genbank版本号BAA95969.1 GI:7959149
Genbank记录更新日期:2006年8月2日下午05:40
交叉参考
Nagase T.等(2000)DNA Res.7(2):143-150);WO2004/000997(权利要求1);WO2003/003984(权利要求1);WO2002/06339(权利要求1;页码50);WO2001/88133(权利要求1;页码41-43,48-58);WO2003/054152(权利要求20);WO2003/101400(权利要求11);登录号:30Q9P283;Genew;HGNC:10737
(8)PSCA hlg(2700050C12Rik,C530008O16Rik,RIKEN cDNA 2700050C12,RIKENcDNA 2700050C12基因)
核苷酸
Genbank登录号AY358628
Genbank版本号AY358628.1 GI:37182377
Genbank记录更新日期:2009年12月1日上午04:15
多肽
Genbank登录号AAQ88991
Genbank版本号AAQ88991.1 GI:37182378
Genbank记录更新日期:2009年12月1日上午04:15
交叉参考
Ross等(2002)Cancer Res.62:2546-2553;US2003/129192(权利要求2);US2004/044180(权利要求12);US2004/044179 35(权利要求11);US2003/096961(权利要求11);US2003/232056(实施例5);WO2003/10575816(权利要求12);US2003/206918(实施例5);EP1347046(权利要求1);WO2003/025148(权利要求20);GI:37182378。
(9)ETBR(内皮素B型受体)
核苷酸
Genbank登录号AY275463
Genbank版本号AY275463.1 GI:30526094
Genbank记录更新日期:2010年3月11日上午02:26
多肽
Genbank登录号AAP32295
Genbank版本号AAP32295.1 GI:30526095
Genbank记录更新日期:2010年3月11日上午02:26
交叉参考
Nakamuta M.等Biochem.Biophys.Res.Commun.177,34-39,1991;Ogawa Y.等Biochem.Biophys.Res.Commun.178,248-255,1991;Arai H.等Jpn.Circ.J.56,1303-1307,1992;Arai H.等J.Biol.Chem.268,3463-3470,1993;Sakamoto A.,Yanagisawa M.等Biochem.Biophys.Res.Commun.178,656-663,1991;Elshourbagy N.A.等J.Biol.Chem.268,3873-3879,1993;Haendler B.等J.Cardiovasc.Pharmacol.20,s1-S4,1992;Tsutsumi M.等Gene 228,43-49,1999;Strausberg R.L.等Proc.Natl.Acad.Sci.U.S.A.99,16899-16903,2002;Bourgeois C.等J.Clin.Endocrinol.Metab.82,3116-3123,1997;
Okamoto Y.等Biol.Chem.272,21589-21596,1997;Verheij J.B.等Am.J.Med.Genet.108,223-225,2002;Hofstra R.M.W.等Eur.J.Hum.Genet.5,180-185,1997;Puffenberger E.G.等Cell 79,1257-1266,1994;Attie T.,等,Hum.Mol.Genet.4,2407-15 2409,1995;Auricchio A.等Hum.Mol.Genet.5:351-354,1996;Amiel J.等Hum.Mol.
Genet.5,355-357,1996;Hofstra R.M.W.等Nat.Genet.12,445-447,1996;Svensson P.J.等Hum.Genet.103,145-148,1998;Fuchs S.等Mol.Med.7,115-124,2001;Pingault V.等(2002)Hum.Genet.111,198-206;WO2004/045516(权利要求1);WO2004/048938(实施例2);WO2004/040000(权利要求151);WO2003/087768(权利要求1);20WO2003/016475(权利要求1);WO2003/016475(权利要求1);WO2002/61087(图1);WO2003/016494(图6);WO2003/025138(权利要求12;页码144);WO2001/98351(权利要求1;页码124-125);EP0522868(权利要求8;图2);WO2001/77172(权利要求1;页码297-299);US2003/109676;US6518404(图3);US5773223(权利要求1a;Col 31-34);WO2004/001004。
(10)MSG783(RNF124,假定蛋白FLJ20315)
核苷酸
Genbank登录号NM_017763
Genbank版本号NM_017763.4 GI:167830482
Genbank记录更新日期:2012年7月22日上午12:34
多肽
Genbank登录号NP_060233
Genbank版本号NP_060233.3 GI:56711322
Genbank记录更新日期:2012年7月22日上午12:34
交叉参考
WO2003/104275(权利要求1);WO2004/046342(实施例2);WO2003/042661(权利要求12);WO2003/083074(权利要求14;页码61);WO2003/018621(权利要求1);WO2003/024392(权利要求2;图93);WO2001/66689(实施例6);LocusID:54894。
(11)STEAP2(HGNC_8639,IPCA-1,PCANAP1,STAMP1,STEAP2,STMP,前列腺癌相关基因1,前列腺癌相关蛋白1,前列腺的六跨膜上皮抗原2,六跨膜前列腺蛋白)
核苷酸
Genbank登录号AF455138
Genbank版本号AF455138.1 GI:22655487
Genbank记录更新日期:2010年3月11日上午01:54
多肽
Genbank登录号AAN04080
Genbank版本号AAN04080.1 GI:22655488
Genbank记录更新日期:2010年3月11日上午01:54
交叉参考
Lab.Invest.82(11):1573-1582(2002));WO2003/087306;US2003/064397(权利要求1;图1);WO2002/72596(权利要求13;页码54-55);WO2001/72962(权利要求1;图4B);35WO2003/104270(权利要求11);WO2003/104270(权利要求16);US2004/005598(权利要求22);WO2003/042661(权利要求12);US2003/060612(权利要求12;图10);WO2002/26822(权利要求23;图2);WO2002/16429(权利要求12;图10);GI:22655488。
(12)TrpM4(BR22450,FLJ20041,TRPM4,TRPM4B,瞬时受体电位阳离子5通道,亚家族M,成员4)
核苷酸
Genbank登录号NM_017636
Genbank版本号NM_017636.3 GI:304766649
Genbank记录更新日期:2012年6月29日上午11:27
多肽
Genbank登录号NP_060106
Genbank版本号NP_060106.2 GI:21314671
Genbank记录更新日期:2012年6月29日上午11:27
交叉参考
Xu,X.Z.等Proc.Natl.Acad.Sci.U.S.A.98(19):10692-10697(2001),Cell 109(3):397-407(2002),J.Biol.Chem.278(33):30813-30820(2003));US2003/143557(权利要求4);WO2000/40614(权利要求14;页码100-103);WO2002/10382(权利要求1;图9A);WO2003/042661(权利要求12);WO2002/30268(权利要求27;页码391);US2003/219806(权利要求4);WO2001/62794(权利要求10 14;图1A-D);MIM:606936。
(13)CRIPTO(CR,CR1,CRGF,CRIPTO,TDGF1,畸胎癌源性生长因子)
核苷酸
Genbank登录号NM_003212
Genbank版本号NM_003212.3 GI:292494881
Genbank记录更新日期:2012年9月23日下午02:27
多肽
Genbank登录号NP_003203
Genbank版本号NP_003203.1 GI:4507425
Genbank记录更新日期:2012年9月23日下午02:27
交叉参考
Ciccodicola,A.等EMBO J.8(7):1987-1991(1989),Am.J.Hum.Genet.49(3):555-565(1991));US2003/224411(权利要求1);WO2003/083041(实施例1);WO2003/034984(权利要求12);WO2002/88170(权利要求2;页码52-53);WO2003/024392(权利要求2;图58);WO2002/16413(权利要求1;页码94-95,105);WO2002/22808(权利要求2;图1);US5854399(实施例2;Col 17-18);US5792616(图2);MIM:187395。
(14)CD21(CR2(补体受体2)或C3DR(C3d/埃-巴二氏病毒受体(Epstein Barrvirus receptor))或Hs.73792)
核苷酸
Genbank登录号M26004
Genbank版本号M26004.1 GI:181939
Genbank记录更新日期:2010年6月23日上午08:47
多肽
Genbank登录号AAA35786
Genbank版本号AAA35786.1 GI:181940
Genbank记录更新日期:2010年6月23日上午08:47
交叉参考
Fujisaku等(1989)J.Biol.Chem.264(4):2118-2125);Weis J.J.等J.Exp.Med.167,1047-1066,1988;Moore M.等Proc.Natl.Acad.Sci.U.S.A.84,9194-9198,1987;Barel M.等Mol.Immunol.35,1025-1031,1998;Weis J.J.等Proc.Natl.Acad.Sci.U.S.A.83,5639-5643,1986;Sinha S.K.等(1993)J.Immunol.150,5311-5320;WO2004/045520(实施例4);US2004/005538(实施例1);WO2003/062401(权利要求9);WO2004/045520(实施例4);WO91/02536(图9.1-9.9);WO2004/020595(权利要求1);登录号:P20023;Q13866;Q14212;EMBL;M26004;AAA35786.1。
(15)CD79b(CD79B,CD79β,IGb(免疫球蛋白相关β),B29)
核苷酸
Genbank登录号NM_000626
Genbank版本号NM_000626.2 GI:90193589
Genbank记录更新日期:2012年6月26日下午01:53
多肽
Genbank登录号NP_000617
Genbank版本号NP_000617.1 GI:11038674
Genbank记录更新日期:2012年6月26日下午01:53
交叉参考
Proc.Natl.Acad.Sci.U.S.A.(2003)100(7):4126-4131,Blood(2002)100(9):3068-3076,Muller等(1992)Eur.J.Immunol.22(6):1621-1625);WO2004/016225(权利要求2,图140);WO2003/087768,US2004/101874(权利要求1,页码102);WO2003/062401(权利要求9);WO2002/78524(实施例2);US2002/150573(权利要求35 5,页码15);US5644033;WO2003/048202(权利要求1,页码306和309);WO 99/58658,US6534482(权利要求13,图17A/B);WO2000/55351(权利要求11,页码1145-1146);MIM:147245。
(16)FcRH2(IFGP4,IRTA4,SPAP1A(SH2域,包含磷酸酶锚定蛋白51a),SPAP1B,SPAP1C)
核苷酸
Genbank登录号NM_030764
Genbank版本号NM_030764.3 GI:227430280
Genbank记录更新日期:2012年6月30日上午12:30
多肽
Genbank登录号NP_110391
Genbank版本号NP_110391.2 GI:19923629
Genbank记录更新日期:2012年6月30日上午12:30
交叉参考
AY358130);Genome Res.13(10):2265-2270(2003),Immunogenetics 54(2):87-95(2002),Blood 99(8):2662-2669(2002),Proc.Natl.Acad.Sci.U.S.A.98(17):9772-9777(2001),Xu,M.J.等(2001)Biochem.Biophys.Res.Commun.280(3):768-775;WO2004/016225(权利要求2);WO2003/077836;WO2001/38490(权利要求5;图18D-1-18D-2);WO2003/097803(权利要求12);
10 WO2003/089624(权利要求25);MIM:606509。
(17)HER2(ErbB2)
核苷酸
Genbank登录号M11730
Genbank版本号M11730.1 GI:183986
Genbank记录更新日期:2010年6月23日上午08:47
多肽
Genbank登录号AAA75493
Genbank版本号AAA75493.1 GI:306840
Genbank记录更新日期:2010年6月23日上午08:47
交叉参考
Coussens L.等Science(1985)230(4730):1132-1139);Yamamoto T.等Nature319,230-234,1986;Semba K.等Proc.Natl.Acad.Sci.U.S.A.82,6497-6501,1985;SwierczJ.M.等J.Cell Biol.165,869-15 880,2004;Kuhns J.J.等J.Biol.Chem.274,36422-36427,1999;Cho H.-S.等Nature 421,756-760,2003;Ehsani A.等(1993)Genomics 15,426-429;WO2004/048938(实施例2);WO2004/027049(图1I);WO2004/009622;WO2003/081210;
WO2003/089904(权利要求9);WO2003/016475(权利要求1);US2003/118592;WO2003/008537(权利要求1);WO2003/055439(权利要求29;图1A-B);WO2003/025228(权利要求37;图5C);20WO2002/22636(实施例13;页码95-107);WO2002/12341(权利要求68;图7);WO2002/13847(页码71-74);WO2002/14503(页码114-117);WO2001/53463(权利要求2;页码41-46);WO2001/41787(页码15);WO2000/44899(权利要求52;图7);WO2000/20579(权利要求3;图2);US5869445(权利要求3;Col 31-38);WO9630514(权利要求2;页码56-61);EP1439393(权利要求7);WO2004/043361(权利要求7);WO2004/022709;WO2001/00244 25(实施例3;图4);登录号:P04626;EMBL;M11767;AAA35808.1.EMBL;M11761;AAA35808.1。
抗体
Abbott:US20110177095
例如,一种抗体,其包含CDR,所述CDR与具有SEQ ID NO:3(CDR-H1)、SEQ ID NO:4(CDR-H2)、SEQ ID NO:5(CDR-H3)、SEQ ID NO:104和/或SEQ ID NO:6(CDR-L1)、SEQ ID NO:7(CDR-L2)、和SEQ ID NO:8(CDR-L3)的氨基酸序列的CDR具有总体至少80%的序列同一性,其中相比于具有SEQ ID NO:1的VH和SEQ ID NO:2的VL的抗体,抗HER2抗体或抗HER2结合片段具有降低的免疫原性。
Biogen:US20100119511
例如,ATCC登录号:PTA-10355,PTA-10356,PTA-10357,PTA-10358
例如,纯化的抗体分子,该分子结合于HER2,其包含来自抗体的所有6个CDR,所述抗体选自由BIIB71F10(SEQ ID NO:11、13)、BIIB69A09(SEQ ID NO:15、17);BIIB67F10(SEQID NO:19、21);BIIB67F11(SEQ ID NO:23、25)、BIIB66A12(SEQ ID NO:27、29)、BIIB66C01(SEQ ID NO:31、33)、BIIB65C10(SEQ ID NO:35、37)、BIIB65H09(SEQ ID NO:39、41)和BIIB65B03(SEQ ID NO:43、45)组成的组,或与所述CDR相同或与所述CDR没有超过两个的改变。
赫赛汀(Herceptin)(Genentech)-US6,054,297;ATCC登录号CRL-10463(Genentech)
帕妥珠单抗(Pertuzumab)(Genentech)
US20110117097
例如,参见SEQ ID No.15&16、SEQ ID No.17和18、SEQ ID No.23和24以及ATCC登录号HB-12215、HB-12216、CRL 10463、HB-12697。
US20090285837
US20090202546
例如,ATCC登录号:HB-12215、HB-12216、CRL 10463、HB-12698。
US20060088523
-例如,ATCC登录号:HB-12215、HB-12216
-例如,抗体,其包含分别在SEQ ID No.3和4中的可变轻和可变重氨基酸序列。
-例如,抗体,包含轻链氨基酸序列,其选自SEQ ID No.15和23,以及重链氨基酸序列,其选自SEQ ID No.16和24
US20060018899
-例如,ATCC登录号:(7C2)HB-12215、(7F3)HB-12216、(4D5)CRL-10463、(2C4)HB-12697。
-例如,抗体,包含在SEQ ID No.23中的氨基酸序列、或其脱酰胺基和/或氧化变体。
US2011/0159014
-例如,抗体,具有轻链可变域,其包含SEQ ID NO:1”的高变区。
-例如,抗体,具有重链可变域,其包含SEQ ID NO:2的高变区。
US20090187007
Glycotope:TrasGEX抗体http://www.glycotope.com/pipeline
例如,参见International Joint Cancer Institute and Changhai HospitalCancer Cent:HMTI-Fc Ab-Gao J.等BMB Rep.2009年10月31日,42(10):636-41。
Symphogen:US20110217305
Union Stem Cell&Gene Engineering,China-Liu HQ.等Xi Bao Yu Fen Zi MianYi Xue Za Zhi.2010年5月;26(5):456-8。
(18)NCA(CEACAM6)
核苷酸
Genbank登录号M18728
Genbank版本号M18728.1 GI:189084
Genbank记录更新日期:2010年6月23日上午08:48
多肽
Genbank登录号AAA59907
Genbank版本号AAA59907.1 GI:189085
Genbank记录更新日期:2010年6月23日上午08:48
交叉参考
Barnett T.等Genomics 3,59-66,1988;Tawaragi Y.等Biochem.Biophys.Res.Commun.150,89-96,1988;Strausberg R.L.等Proc.Natl.Acad.Sci.U.S.A.99:16899-16903,2002;WO2004/063709;EP1439393(权利要求7);WO2004/044178(实施例4);WO2004/031238;WO2003/042661(权利要求12);WO2002/78524(实施例2);WO2002/86443(权利要求27;页码427);WO2002/60317(权利要求2);登录号:P40199;Q14920;EMBL;M29541;AAA59915.1。
EMBL;M18728。
(19)MDP(DPEP1)
核苷酸
Genbank登录号BC017023
Genbank版本号BC017023.1 GI:16877538
Genbank记录更新日期:2012年3月6日下午01:00
多肽
Genbank登录号AAH17023
Genbank版本号AAH17023.1 GI:16877539
Genbank记录更新日期:2012年3月6日下午01:00
交叉参考
Proc.Natl.Acad.Sci.U.S.A.99(26):16899-16903(2002));WO2003/016475(权利要求1);WO2002/64798(权利要求33;页码85-87);JP05003790(图6-8);WO99/46284(图9);MIM:179780。
(20)IL20R-α(IL20Ra,ZCYTOR7)
核苷酸
Genbank登录号AF184971
Genbank版本号AF184971.1 GI:6013324
Genbank记录更新日期:2010年3月10日下午10:00
多肽
Genbank登录号AAF01320
Genbank版本号AAF01320.1 GI:6013325
Genbank记录更新日期:2010年3月10日下午10:00
交叉参考
Clark H.F.等Genome Res.13,2265-2270,2003;Mungall A.J.等Nature 425,805-811,2003;Blumberg H.等Cell 104,9-19,2001;Dumoutier L.等J.Immunol.167,3545-3549,
2001;Parrish-Novak J.等J.Biol.Chem.277,47517-47523,2002;Pletnev S.等(2003)10Biochemistry 42:12617-12624;Sheikh F.等(2004)J.Immunol.172,2006-2010;EP1394274(实施例11);US2004/005320(实施例5);WO2003/029262(页码74-75);WO2003/002717(权利要求2;页码63);WO2002/22153(页码45-47);US2002/042366(页码20-21);WO2001/46261(页码57-59);WO2001/46232(页码63-65);WO98/37193(权利要求1;页码55-59);登录号:Q9UHF4;Q6UWA9;Q96SH8;EMBL;AF184971;AAF01320.1。
(21)短蛋白聚糖(Brevican)(BCAN,BEHAB)
核苷酸
Genbank登录号AF229053
Genbank版本号AF229053.1 GI:10798902
Genbank记录更新日期:2010年3月11日上午12:58
多肽
Genbank登录号AAG23135
Genbank版本号AAG23135.1 GI:10798903
Genbank记录更新日期:2010年3月11日上午12:58
交叉参考
Gary S.C.等Gene 256,139-147,2000;Clark H.F.等Genome Res.13,2265-2270,2003;Strausberg R.L.等Proc.Natl.Acad.Sci.U.S.A.99,16899-16903,2002;US2003/186372(权利要求11);US2003/186373(权利要求11);US2003/119131(权利要求1;图52);US2003/119122(权利要求1;20图52);US2003/119126(权利要求1);US2003/119121(权利要求1;图52);US2003/119129(权利要求1);US2003/119130(权利要求1);US2003/119128(权利要求1;图52);US2003/119125(权利要求1);WO2003/016475(权利要求1);WO2002/02634(权利要求1)
(22)EphB2R(DRT,ERK,Hek5,EPHT3,Tyro5)
核苷酸
Genbank登录号NM_004442
Genbank版本号NM_004442.6 GI:111118979
Genbank记录更新日期:2012年9月8日下午04:43
多肽
Genbank登录号NP_004433
Genbank版本号NP_004433.2 GI:21396504
Genbank记录更新日期:2012年9月8日下午04:43
交叉参考
Chan,J.and Watt,V.M.,Oncogene 6(6),1057-1061(1991)Oncogene 10(5):897-905(1995),Annu.Rev.Neurosci.21:309-345(1998),Int.Rev.Cytol.196:177-244(2000));WO2003042661(权利要求12);WO200053216(权利要求1;页码41);WO2004065576(权利要求1);WO2004020583(权利要求9);WO2003004529(页码128-132);WO200053216(权利要求1;页码42);MIM:600997。
(23)ASLG659(B7h)
核苷酸
Genbank登录号AX092328
Genbank版本号AX092328.1 GI:13444478
Genbank记录更新日期:2011年1月26日上午07:37
交叉参考
US2004/0101899(权利要求2);WO2003104399(权利要求11);WO2004000221(图3);US2003/165504(权利要求1);US2003/124140(实施例2);US2003/065143(图60);WO2002/102235(权利要求13;页码299);US2003/091580(实施例2);WO2002/10187(权利要求6;图10);WO2001/94641(权利要求12;图7b);WO2002/02624(权利要求13;图1A-1B);US2002/034749(权利要求54;页码45-46);WO2002/06317(实施例2;页码320-321,权利要求34;页码321-322);WO2002/71928(页码468-469);WO2002/02587(实施例1;图1);WO2001/40269(实施例3;页码190-192);WO2000/36107(实施例2;页码205-207);WO2004/053079(权利要求12);WO2003/004989(权利要求1);WO2002/71928(页码233-234,452-453);WO 01/16318。
(24)PSCA(前列腺干细胞抗原前体)
核苷酸
Genbank登录号AJ297436
Genbank版本号AJ297436.1 GI:9367211
Genbank记录更新日期:2011年2月1日上午11:25
多肽
Genbank登录号CAB97347
Genbank版本号CAB97347.1 GI:9367212
Genbank记录更新日期:2011年2月1日上午11:25
交叉参考
Reiter R.E.等Proc.Natl.Acad.Sci.U.S.A.95,1735-1740,1998;Gu Z.等Oncogene 19,
1288-1296,2000;Biochem.Biophys.Res.Commun.(2000)275(3):783-788;WO2004/022709;EP1394274(实施例11);US2004/018553(权利要求17);WO2003/008537(权利要求1);WO2002/81646(权利要求1;页码164);WO2003/003906(权利要求10;页码288);WO2001/40309(实施例1;图17);US2001/055751(实施例1;图1b);WO2000/32752(权利要求18;图1);WO98/51805(权利要求17;页码97);WO98/51824(权利要求10;页码94);WO98/40403(权利要求2;图1B);登录号:O43653;EMBL;AF043498;AAC39607.1
(25)GEDA
核苷酸
Genbank登录号AY260763
Genbank版本号AY260763.1 GI:30102448
Genbank记录更新日期:2010年3月11日上午02:24
多肽
Genbank登录号AAP14954
Genbank版本号AAP14954.1 GI:30102449
Genbank记录更新日期:2010年3月11日上午02:24
交叉参考
AP14954lipoma HMGIC fusion-partnerlike protein/pid=AAP14954.1-智人(人);WO2003/054152(权利要求20);WO2003/000842(权利要求1);WO2003/023013(实施例3,权利要求20);US2003/194704(权利要求45);GI:30102449;
(26)BAFF-R(B细胞活化因子受体,BLyS受体3,BR3)
核苷酸
Genbank登录号AF116456
Genbank版本号AF116456.1 GI:4585274
Genbank记录更新日期:2010年3月10日下午09:44
多肽
Genbank登录号AAD25356
Genbank版本号AAD25356.1 GI:4585275
Genbank记录更新日期:2010年3月10日下午09:44
交叉参考
BAFF受体/pid=NP_443177.1-智人:Thompson,J.S.等Science 293(5537),2108-2111(2001);WO2004/058309;WO2004/011611;WO2003/045422(实施例;页码32-33);WO2003/014294(权利要求35;图6B);WO2003/035846(权利要求70;页码615-616);WO2002/94852(Col 136-137);WO2002/38766 25(权利要求3;页码133);WO2002/24909(实施例3;图3);MIM:606269;NP_443177.1;NM_052945_1;AF132600
(27)CD22(B细胞受体CD22-B同种型,BL-CAM,Lyb-8,Lyb8,SIGLEC-2,FLJ22814)
核苷酸
Genbank登录号AK026467
Genbank版本号AK026467.1 GI:10439337
Genbank记录更新日期:2006年9月11日下午11:24
多肽
Genbank登录号BAB15489
Genbank版本号BAB15489.1 GI:10439338
Genbank记录更新日期:2006年9月11日下午11:24
交叉参考
Wilson等(1991)J.Exp.Med.173:137-146;30 WO2003/072036(权利要求1;图1);IM:107266;NP_001762.1;NM_001771_1。
(27a)CD22(CD22分子)
核苷酸
Genbank登录号X52785
Genbank版本号X52785.1 GI:29778
Genbank记录更新日期:2011年2月2日上午10:09
多肽
Genbank登录号CAA36988
Genbank版本号CAA36988.1 GI:29779
Genbank记录更新日期:2011年2月2日上午10:09
交叉参考
Stamenkovic I.等,Nature 345(6270),74-77(1990)??
其他信息
官方代号:CD22
其他别名:SIGLEC-2,SIGLEC2
其他名称:B细胞受体CD22;B淋巴细胞细胞粘附分子;BL-CAM;CD22抗原;T细胞表面抗原亮氨酸-14;唾液酸结合Ig样凝集素2;唾液酸结合Ig样凝集素2
抗体
G5/44(伊珠单抗,Inotuzumab):DiJoseph JF.等Cancer ImmunolImmunother.2005年1月;54(1):11-24。
依帕珠单抗-Goldenberg DM.等Expert Rev Anticancer Ther.6(10):1341-53,2006。
(28)CD79a(CD79A,CD79α),免疫球蛋白相关的α、B细胞特异性蛋白,其共价相互作用于Igβ(CD79B)并在表面上形成与Ig M 35个分子的复合物,转导涉及B细胞分化的信号,pI:4.84,MW:25028TM:2
[P]基因染色体:19q13.2)。
核苷酸
Genbank登录号NM_001783
Genbank版本号NM_001783.3 GI:90193587
Genbank记录更新日期:2012年6月26日下午01:48
多肽
Genbank登录号NP_001774
Genbank版本号NP_001774.1 GI:4502685
Genbank记录更新日期:2012年6月26日下午01:48
交叉参考
WO2003/088808,US2003/0228319;WO2003/062401(权利要求9);US2002/150573(权利要求4,页码13-14);WO99/58658(权利要求13,图16);WO92/07574(图1);US5644033;Ha等(1992)J.Immunol.148(5):1526-1531;Müller等(1992)Eur.J.Immunol..22:1621-1625;Hashimoto等(1994)Immunogenetics 40(4):287-295;Preud’homme等(1992)Clin.Exp.5Immunol.90(1):141-146;Yu等(1992)J.Immunol.148(2)633-637;Sakaguchi等(1988)
EMBO J.7(11):3457-3464
(29)CXCR5(伯基特淋巴瘤受体1,G蛋白偶联受体,其被CXCL13趋化因子活化,在淋巴细胞迁移和体液性防御中起作用,在HIV-2感染中以及也许在AIDS、淋巴瘤、骨髓瘤、和白血病的发展中起(10)作用);372aa,pI:8.54MW:41959TM:7[P]基因染色体:11q23.3,
核苷酸
Genbank登录号NM_001716
Genbank版本号NM_001716.4 GI:342307092
Genbank记录更新日期:2012年9月30日下午01:49
多肽
Genbank登录号NP_001707
Genbank版本号NP_001707.1 GI:4502415
Genbank记录更新日期:2012年9月30日下午01:49
交叉参考
WO2004/040000;WO2004/015426;US2003/105292(实施例2);US6555339(实施例2);WO2002/61087(图1);WO2001/57188(权利要求20,页码269);WO2001/72830(页码12-13);WO2000/22129(实施例1,页码152-153,15实施例2,页码254-256);WO99/28468(权利要求1,页码38);US5440021(实施例2,col 49-52);WO94/28931(页码56-58);WO92/17497(权利要求7,图5);Dobner等(1992)Eur.J.Immunol.22:2795-2799;Barella等(1995)Biochem.J.309:773-779
(30)HLA-DOB(MHC II类分子的β亚基(Ia抗原),其结合肽并20将它们呈递到CD4+T淋巴细胞);273aa,pI:6.56,MW:30820.TM:1[P]基因染色体:6p21.3)
核苷酸
Genbank登录号NM_002120
Genbank版本号NM_002120.3 GI:118402587
Genbank记录更新日期:2012年9月8日下午04:46
多肽
Genbank登录号NP_002111
Genbank版本号NP_002111.1 GI:4504403
Genbank记录更新日期:2012年9月8日下午04:46
交叉参考
Tonnelle等(1985)EMBO J.4(11):2839-2847;Jonsson等(1989)Immunogenetics29(6):411-413;Beck等(1992)J.Mol.Biol.228:433-441;Strausberg等(2002)Proc.Natl.Acad.Sci USA 99:16899-16903;Servenius等(1987)J.Biol.Chem.262:8759-8766;Beck等(1996)J.Mol.Biol.25 255:1-13;Naruse等(2002)Tissue Antigens 59:512-519;WO99/58658(权利要求13,图15);US6153408(Col 35-38);US5976551(col 168-170);US6011146(col 145-146);Kasahara等(1989)Immunogenetics 30(1):66-68;Larhammar等(1985)J.Biol.Chem.260(26):14111-14119
(31)P2X5(嘌呤能受体P2X配体门控离子通道5,由细胞外ATP门控的离子通道,可能涉及突触传递和神经发生,缺乏可能有助于特发性逼尿肌不稳定的病理生理学);422aa),pI:7.63,MW:47206TM:1[P]基因染色体:17p13.3)。
核苷酸
Genbank登录号NM_002561
Genbank版本号NM_002561.3 GI:325197202
Genbank记录更新日期:2012年6月27日上午12:41
多肽
Genbank登录号NP_002552
Genbank版本号NP_002552.2 GI:28416933
Genbank记录更新日期:2012年6月27日上午12:41
交叉参考
Le等(1997)FEBS Lett.418(1-2):195-199;WO2004/047749;WO2003/072035(权利要求10);Touchman等(2000)Genome Res.10:165-173;WO2002/22660(权利要求20);WO2003/093444(权利要求1);WO2003/087768(权利要求1);WO2003/029277(页码82)
(32)CD72(B细胞分化抗原CD72,Lyb-2);359aa,pI:8.66,MW:40225,TM:1 5[P]基因染色体:9p13.3)。
核苷酸
Genbank登录号NM_001782
Genbank版本号NM_001782.2 GI:194018444
Genbank记录更新日期:2012年6月26日下午01:43
多肽
Genbank登录号NP_001773
Genbank版本号NP_001773.1 GI:4502683
Genbank记录更新日期:2012年6月26日下午01:43
交叉参考
WO2004042346(权利要求65);WO2003/026493(页码51-52,57-58);WO2000/75655(页码105-106);Von Hoegen等(1990)J.Immunol.144(12):4870-4877;Strausberg等(2002)Proc.Natl.Acad.Sci USA 99:16899-16903。
(33)LY64(淋巴细胞抗原64(RP105),富含亮氨酸重复(LRR)家族的I型膜蛋白,调节B细胞活化和细胞凋亡,在患有系统性红斑狼疮的患者中功能的丧失相关于增加的疾病活性);661aa,pI:6.20,MW:74147TM:1[P]基因染色体:5q12)。
核苷酸
Genbank登录号NM_005582
Genbank版本号NM_005582.2 GI:167555126
Genbank记录更新日期:2012年9月2日下午01:50
多肽
Genbank登录号NP_005573
Genbank版本号NP_005573.2 GI:167555127
Genbank记录更新日期:2012年9月2日下午01:50
交叉参考
US2002/193567;WO97/07198(权利要求11,页码39-42);Miura等(1996)15Genomics 38(3):299-304;Miura等(1998)Blood 92:2815-2822;WO2003/083047;WO97/44452(权利要求8,页码57-61);WO2000/12130(页码24-26)。
(34)FcRH1(Fc受体样蛋白1,假定受体,用于免疫球蛋白Fc域,其包含C2型Ig样和ITAM域,在B淋巴细胞(20)分化中可以具有作用);429aa,pI:5.28,MW:46925TM:1[P]基因染色体:1q21-1q22)
核苷酸
Genbank登录号NM_052938
Genbank版本号NM_052938.4 GI:226958543
Genbank记录更新日期:2012年9月2日下午01:43
多肽
Genbank登录号NP_443170
Genbank版本号NP_443170.1 GI:16418419
Genbank记录更新日期:2012年9月2日下午01:43
交叉参考
WO2003/077836;WO2001/38490(权利要求6,图18E-1-18-E-2);Davis等(2001)Proc.Natl.Acad.Sci USA 98(17):9772-9777;WO2003/089624(权利要求8);EP1347046(权利要求1);WO2003/089624(权利要求7)。
(35)IRTA2(免疫球蛋白超家族受体易位相关的2,假定的免疫受体,其在B细胞的发育和淋巴瘤发生中具有可能的作用;在一些B细胞恶性疾病中发生基因的去调节(通过易位));977aa,pI:6.88,MW:106468,TM:1[P]基因染色体:1q21)
核苷酸
Genbank登录号AF343662
Genbank版本号AF343662.1 GI:13591709
Genbank记录更新日期:2010年3月11日上午01:16
多肽
Genbank登录号AAK31325
Genbank版本号AAK31325.1 GI:13591710
Genbank记录更新日期:2010年3月11日上午01:16
交叉参考
AF343663,AF343664,AF343665,AF369794,AF397453,AK090423,AK090475,AL834187,AY358085;小鼠:AK089756,AY158090,AY506558;NP_112571.1;WO2003/024392(权利要求2,图97);Nakayama等(2000)Biochem.Biophys.Res.Commun.277(1):124-127;WO2003/077836;WO2001/38490(权利要求3,图18B-1-18B-2)。
(36)TENB2(TMEFF2,tomoregulin,TPEF,HPP1,TR,推定的跨膜(35)蛋白多糖,涉及到生长因子和卵泡抑素的EGF/调蛋白(heregulin)家族);374aa)
核苷酸
Genbank登录号AF179274
Genbank版本号AF179274.2 GI:12280939
Genbank记录更新日期:2010年3月11日上午01:05
多肽
Genbank登录号AAD55776
Genbank版本号AAD55776.2 GI:12280940
Genbank记录更新日期:2010年3月11日上午01:05
交叉参考
NCBI登录号:AAD55776,AAF91397,AAG49451,NCBI RefSeq:NP_057276;NCBIGene:23671;OMIM:605734;SwissProt Q9UIK5;AY358907,CAF85723,CQ782436;WO2004/074320;JP2004113151;WO2003/042661;WO2003/009814;EP1295944(页码69-70);WO2002/30268(页码329);WO2001/90304;US2004/249130;US2004/022727;WO2004/063355;US2004/197325;US2003/232350;5 US2004/005563;US2003/124579;Horie等(2000)Genomics 67:146-152;Uchida等(1999)Biochem.Biophys.Res.Commun.266:593-602;Liang等(2000)Cancer Res.60:4907-12;Glynne-Jones等(2001)Int J Cancer.10月15日;94(2):178-84。
(37)PSMA–FOLH1(叶酸水解酶(前列腺特异性膜抗原)1)
核苷酸
Genbank登录号M99487
Genbank版本号M99487.1 GI:190663
Genbank记录更新日期:2010年6月23日上午08:48
多肽
Genbank登录号AAA60209
Genbank版本号AAA60209.1 GI:190664
Genbank记录更新日期:2010年6月23日上午08:48
交叉参考
Israeli R.S.等Cancer Res.53(2),227-230(1993)
其他信息
官方代号:FOLH1
其他别名:GIG27、FGCP、FOLH、GCP2、GCPII、NAALAD1、NAALAdase、PSM、PSMA、mGCP
其他名称:N-乙酰化α-连接的酸性二肽酶1;N-乙酰化-α-连接的酸性二肽酶I;NAALADase I;细胞生长抑制基因27蛋白;叶酰多-γ-谷氨酸羧肽酶;谷氨酸羧化酶II;谷氨酸羧肽酶2;谷氨酸羧肽酶II;膜谷氨酸羧肽酶;前列腺特异性膜抗原变体F;蝶酰多-γ-谷氨酸羧肽酶
抗体
US 7,666,425:
抗体是通过杂交瘤所产生,其具有以下ATCC参考:ATCC登录号HB-12101、ATCC登录号HB-12109、ATCC登录号HB-12127和ATCC登录号HB-12126。
Proscan:单克隆抗体,其选自由8H12、3E11、17G1、29B4、30C1和20F2组成的组(US7,811,564;Moffett S.等Hybridoma(Larchmt).2007年12月;26(6):363-72)。
Cytogen:单克隆抗体7E11-C5(ATCC登录号HB 10494)和9H10-A4(ATCC登录号HB11430)–US 5,763,202
GlycoMimetics:NUH2-ATCC登录号HB 9762(US 7,135,301)
人类基因组科学(Human Genome Science):HPRAJ70-ATCC登录号97131(US 6,824,993);由cDNA克隆(HPRAJ70)编码的氨基酸序列,保藏于美国典型培养物保藏中心("ATCC"),保藏号97131
Medarex:抗PSMA抗体,其缺乏岩藻糖基残基-US 7,875,278
小鼠抗PSMA抗体包括3F5.4G6、3D7.1.1、4E10-1.14、3E11、4D8、3E6、3C9、2C7、1G3、3C4、3C6、4D4、1G9、5C8B9、3G6、4C8B9、和单克隆抗体。分泌3F5.4G6、3D7.1.1、4E10-1.14、3E11、4D8、3E6、3C9、2C7、1G3、3C4、3C6、4D4、1G9、5C8B9、3G6或4C8B9的杂交瘤已公开保藏并描述于美国专利号6,159,508。有关的杂交瘤已公开保藏并描述于美国专利号6,107,090。此外,人源化抗PSMA抗体,包括J591的人源化形式,进一步详细描述于PCT申请公开WO 02/098897。
在本领域中已描述了其他小鼠抗人PSMA抗体,如mAb 107-1A4(Wang,S.等(2001)Int.J.Cancer 92:871-876)和mAb 2C9(Kato,K.等(2003)Int.J.Urol.10:439-444)。
人抗PSMA单克隆抗体的实例包括4A3、7F12、8C12、8A11、16F9、2A10、2C6、2F5和1C3抗体,其分离和结构表征最初描述于PCT申请公开WO 01/09192和WO 03/064606以及美国临时申请序列号60/654,125,题为"Human Monoclonal Antibodies to Prostate SpecificMembrane Antigen(PSMA)",于2005年2月18日提交。4A3、7F12、8C12、8A11、16F9、2A10、2C6、2F5和1C3的V.sub.H(重链可变)氨基酸序列分别示于SEQ ID NO:1-9。4A3、7F12、8C12、8A11、16F9、2A10、2C6、2F5和1C3的V.sub.L(轻链可变)氨基酸序列分别示于SEQ ID NO:10-18。
其他人抗PSMA抗体包括在PCT申请公开WO 03/034903和美国申请号2004/0033229中公开的抗体。
NW Biotherapeutics:杂交瘤细胞系选自由ATCC登录号为HB12060的3F5.4G6、ATCC登录号为HB12309的3D7-1.I、ATCC登录号为HB12310的4E10-1.14、3E11(ATCCHB12488)、4D8(ATCC HB12487)、3E6(ATCC HB12486)、3C9(ATCC HB12484)、2C7(ATCCHB12490)、1G3(ATCC HB12489)、3C4(ATCC HB12494)、3C6(ATCC HB12491)、4D4(ATCCHB12493)、1G9(ATCC HB12495)、5C8B9(ATCC HB12492)和3G6(ATCC HB12485)组成的组。参见US 6,150,508。
PSMA Development Company/Progenics/Cytogen–Seattle Genetics:mAb 3.9,其是通过杂交瘤所产生,其中上述杂交瘤保藏为ATCC登录号PTA-3258,或mAb 10.3,其是通过杂交瘤所产生,其中上述杂交瘤保藏为ATCC登录号PTA-3347-US 7,850,971
PSMA Development Company–PSMA抗体的组合物(US 20080286284,表1)
此申请是美国专利申请序列号10/395,894的分案,其于2003年3月21日提交(US7,850,971)
University Hospital Freiburg,德国-mAb 3/A12、3/E7、和3/F11(Wolf P.等Prostate.2010年4月1日;70(5):562-9)
(38)SST(生长抑素受体;注意:存在5种亚型)
(38.1)SSTR2(生长抑素受体2)
核苷酸
Genbank登录号NM_001050
Genbank版本号NM_001050.2 GI:44890054
Genbank记录更新日期:2012年8月19日下午01:37
多肽
Genbank登录号NP_001041
Genbank版本号NP_001041.1 GI:4557859
Genbank记录更新日期:2012年8月19日下午01:37
交叉参考
Yamada Y.等Proc.Natl.Acad.Sci.U.S.A.89(1),251-255(1992);Susini C.等Ann Oncol.2006年12月;17(12):1733-42
其他信息
官方代号:SSTR2
其他名称:SRIF-1;SS2R;生长抑素受体2型
(38.2)SSTR5(生长抑素受体5)
核苷酸
Genbank登录号D16827
Genbank版本号D16827.1 GI:487683
Genbank记录更新日期:2006年8月1日下午12:45
多肽
Genbank登录号BAA04107
Genbank版本号BAA04107.1 GI:487684
Genbank记录更新日期:2006年8月1日下午12:45
交叉参考
Yamada,Y.等Biochem.Biophys.Res.Commun.195(2),844-852(1993)
其他信息
官方代号:SSTR5
其他别名:SS-5-R
其他名称:生长抑素受体亚型5;生长抑素受体类型5
(38.3)SSTR1
(38.4)SSTR3
(38.5)SSTR4
AvB6–两种亚基(39+40)
(39)ITGAV(整联蛋白,αV;
核苷酸
Genbank登录号M14648 J02826 M18365
Genbank版本号M14648.1 GI:340306
Genbank记录更新日期:2010年6月23日上午08:56
多肽
Genbank登录号AAA36808
Genbank版本号AAA36808.1 GI:340307
Genbank记录更新日期:2010年6月23日上午08:56
交叉参考
Suzuki S.等Proc.Natl.Acad.Sci.U.S.A.83(22),8614-8618(1986)
其他信息
官方代号:ITGAV
其他别名:CD51、MSK8、VNRA、VTNR
其他名称:由单克隆抗体L230确定的抗原;整联蛋白α-V;整联蛋白αVβ3;整联蛋白,αV(玻连蛋白受体,α多肽、抗原CD51);玻连蛋白受体亚基α
(40)ITGB6(整联蛋白,β6)
核苷酸
Genbank登录号NM_000888
Genbank版本号NM_000888.3 GI:9966771
Genbank记录更新日期:2012年6月27日上午12:46
多肽
Genbank登录号NP_000879
Genbank版本号NP_000879.2 GI:9625002
Genbank记录更新日期:2012年6月27日上午12:46
交叉参考
Sheppard D.J.等Biol.Chem.265(20),11502-11507(1990)
其他信息
官方代号:ITGB6
其他名称:整联蛋白β-6
抗体
Biogen:US 7,943,742-杂交瘤克隆6.3G9和6.8G6是由ATCC保藏,登录号分别为ATCC PTA-3649和-3645。
Biogen:US7,465,449-在一些实施方案中,抗体包含和由杂交瘤6.1A8、6.3G9、6.8G6、6.2B1、6.2B10、6.2A1、6.2E5、7.1G10、7.7G5、或7.1C5产生的抗体相同的重链和轻链多肽序列。
Centocor(J&J):US7,550,142;US7,163,681
例如在US 7,550,142中,一种抗体,该抗体具有人重链和人轻链可变区,其包含示于SEQ ID NO:7和SEQ ID NO:8中的氨基酸序列。
Seattle Genetics:15H3(Ryan MC.等Cancer Res,2012年4月15日;72(8增刊):4630)
(41)CEACAM5(癌胚抗原相关细胞粘附分子5)
核苷酸
Genbank登录号M17303
Genbank版本号M17303.1 GI:178676
Genbank记录更新日期:2010年6月23日上午08:47
多肽
Genbank登录号AAB59513
Genbank版本号AAB59513.1 GI:178677
Genbank记录更新日期:2010年6月23日上午08:47
交叉参考
Beauchemin N.等Mol.Cell.Biol.7(9),3221-3230(1987)
其他信息
官方代号:CEACAM5
其他别名:CD66e、CEA
其他名称:癌胚抗原100
抗体
AstraZeneca-MedImmune:US 20100330103;US20080057063;US20020142359
-例如一种抗体,该抗体具有互补决定区(CDR),其具有以下序列:重链;CDR1-DNYMH、CDR2-WIDPENGDTE YAPKFRG、CDR3-LIYAGYLAMD Y;以及轻链CDR1-SASSSVTYMH、CDR2-STSNLAS、CDR3-QQRSTYPLT。
-杂交瘤806.077,保藏于欧洲细胞培养物保藏中心(ECACC),保藏号为96022936。
Research Corporation Technologies,Inc:US5,047,507
Bayer Corporation:US6,013,772
BioAlliance:US7,982,017;US7,674,605
·US 7,674,605
-一种抗体,其包含来自SEQ ID NO:1的氨基酸序列的重链可变区序列,以及来自SEQ ID NO:2的氨基酸序列的轻链可变区序列。
-一种抗体,其包含来自SEQ ID NO:5的氨基酸序列的重链可变区序列,以及来自SEQ ID NO:6的氨基酸序列的轻链可变区序列。
Celltech Therapeutics Limited:US5,877,293
Dow Chemical Company:US5,472,693;US6,417,337;US6,333,405
US5,472,693–例如,ATCC号CRL-11215
US6,417,337–例如,ATCC CRL-12208
US6,333,405–例如,ATCC CRL-12208
Immunomedics,Inc:US7,534,431;US7,230,084;US7,300,644;US6,730,300;US20110189085
-一种抗体,具有轻链可变区的CDR,其包括:CDR1,包括KASQDVGTSVA(SEQ ID NO:20);CDR2,包括WTSTRHT(SEQ ID NO:21);以及CDR3,包括QQYSLYRS(SEQ ID NO:22);
以及所述抗CEA抗体的重链可变区的CDR,包含:CDR1,包含TYWMS(SEQ ID NO:23);CDR2,包含EIHPDSSTINYAPSLKD(SEQ ID NO:24);以及CDR3,包含LYFGFPWFAY(SEQ ID NO:25)。
US20100221175;US20090092598;US20070202044;US20110064653;US20090185974;US20080069775。
(42)MET(met原癌基因;肝细胞生长因子受体)
核苷酸
Genbank登录号M35073
Genbank版本号M35073.1 GI:187553
Genbank记录更新日期:2012年3月6日上午11:12
多肽
Genbank登录号AAA59589
Genbank版本号AAA59589.1 GI:553531
Genbank记录更新日期:2012年3月6日上午11:12
交叉参考
Dean M.等Nature 318(6044),385-388(1985)
其他信息
官方代号:MET
其他别名:AUTS9、HGFR、RCCP2、c-Met
其他名称:HGF受体;HGF/SF受体;SF受体;肝细胞生长因子受体;met原癌基因酪氨酸激酶;原癌基因c-Met;分散因子受体;酪氨酸蛋白激酶Met
抗体
Abgenix/Pfizer:US20100040629
例如,由具有美国典型培养物保藏中心(ATCC)登录号PTA-5026的杂交瘤13.3.2产生的抗体;由具有ATCC登录号PTA-5027的杂交瘤9.1.2产生的抗体;由ATCC登录号为PTA-5028的杂交瘤8.70.2产生的抗体;或由ATCC登录号为PTA-5029的杂交瘤6.90.3产生的抗体。
Amgen/Pfizer:US20050054019
例如,一种抗体,该抗体包含重链,其具有在SEQ ID NO:2中展示的氨基酸序列,其中X2是谷氨酸以及X4是丝氨酸,以及轻链,其具有在SEQ ID NO:4中展示的氨基酸序列,其中X8是丙氨酸,没有信号序列;一种抗体,该抗体包含重链,其具有在SEQ ID NO:6中展示的氨基酸序列,以及轻链,其具有在SEQ ID NO:8中展示的氨基酸序列,没有信号序列;一种抗体,该抗体包含重链,其具有在SEQ ID NO:10中展示的氨基酸序列,以及轻链,其具有在SEQID NO:12中展示的氨基酸序列,没有信号序列;或一种抗体,该抗体包含重链,其具有在SEQID NO:14中展示的氨基酸序列,以及轻链,其具有在SEQ ID NO:16中展示的氨基酸序列,没有信号序列。
Agouron Pharmaceuticals(Now Pfizer):US20060035907
Eli Lilly:US20100129369
Genentech:US5,686,292;US20100028337;US20100016241;US20070129301;US20070098707;US20070092520;US20060270594;US20060134104;US20060035278;US20050233960;US20050037431
US 5,686,292–例如,ATCC HB-11894和ATCC HB-11895
US 20100016241–例如,ATCC HB-11894(杂交瘤1A3.3.13)或HB-11895(杂交瘤5D5.11.6)
National Defense Medical Center,Taiwan:Lu RM.等Biomaterials.2011年4月;32(12):3265-74。
Novartis:US20090175860
-例如,一种抗体,该抗体包含重链4687的CDR1、CDR2和CDR3的序列,其中重链4687的CDR1、CDR2、和CDR3的序列分别是SEQ ID NO:58的残基26-35、50-65、和98-102;以及轻链5097的CDR1、CDR2、和CDR3的序列,其中轻链5097的CDR1、CDR2、和CDR3的序列分别是SEQ IDNO:37的残基24-39、55-61、和94-100。
Pharmacia Corporation:US20040166544
Pierre Fabre:US20110239316、US20110097262、US20100115639
Sumsung:US 20110129481–例如产生自登录号为KCLRF-BP-00219或登录号为KCLRF-BP-00223的杂交瘤细胞的单克隆抗体。
Samsung:US 20110104176–例如由登录号为KCLRF-BP-00220的杂交瘤细胞产生的抗体。
University of Turin Medical School:DN-30Pacchiana G.等J BiolChem.2010年11月12日;285(46):36149-57
Van Andel Research Institute:Jiao Y.等Mol Biotechnol.2005年9月;31(1):41-54。
(43)MUC1(粘蛋白1(Mucin 1),细胞表面相关的)
核苷酸
Genbank登录号J05581
Genbank版本号J05581.1 GI:188869
Genbank记录更新日期:2010年6月23日上午08:48
多肽
Genbank登录号AAA59876
Genbank版本号AAA59876.1 GI:188870
Genbank记录更新日期:2010年6月23日上午08:48
交叉参考
Gendler S.J.等J.Biol.Chem.265(25),15286-15293(1990)
其他信息
官方代号:MUC1
其他别名:RP11-263K19.2、CD227、EMA、H23AG、KL-6、MAM6、MUC-1、MUC-1/SEC、MUC-1/X、MUC1/ZD、PEM、PEMT、PUM
其他名称:DF3抗原;H23抗原;乳腺癌相关抗原DF3;癌相关粘蛋白;episialin;krebs von den Lungen-6;粘蛋白1,跨膜;粘蛋白-1;花生反应尿粘蛋白;多形上皮粘蛋白;肿瘤相关的上皮粘蛋白;肿瘤相关上皮膜抗原;肿瘤相关粘蛋白
抗体
AltaRex-Quest Pharma Tech:US 6,716,966–例如由ATCC号为PTA-975的杂交瘤产生的Alt-1抗体。
AltaRex-Quest Pharma Tech:US7,147,850
CRT:5E5-AL.等Glycobiology vol.16 no.2 pp.96–107,2006;HMFG2–Burchell J.等Cancer Res.,47,5476–5482(1987)
Glycotope GT-MAB:GT-MAB 2.5-GEX(网站:http://www.glycotope.com/pipeline/pankomab-gex)
Immunogen:US7,202,346
-例如,抗体MJ-170:杂交瘤细胞系MJ-170 ATCC登录号PTA-5286单克隆抗体MJ-171:杂交瘤细胞系MJ-171 ATCC登录号PTA-5287;单克隆抗体MJ-172:杂交瘤细胞系MJ-172ATCC登录号PTA-5288;或单克隆抗体MJ-173:杂交瘤细胞系MJ-173 ATCC登录号PTA-5302
Immunomedics:US 6,653,104
Ramot Tel Aviv Uni:US7,897,351
Regents Uni.CA:US 7,183,388;US20040005647;US20030077676。
Roche GlycArt:US8,021,856
Russian National Cancer Research Center:Imuteran-Ivanov PK.等Biotechnol J.2007年7月;2(7):863-70
Technische Univ Braunschweig:(IIB6、HT186-B7、HT186-D11、HT186-G2、HT200-3A-C1、HT220-M-D1、HT220-M-G8)-Thie H.等PLoS One.2011年1月14日;6(1):e15921
(44)CA9(碳酸酐酶IX)
核苷酸
Genbank登录号X66839
Genbank版本号X66839.1 GI:1000701
Genbank记录更新日期:2011年2月2日上午10:15
多肽
Genbank登录号CAA47315
Genbank版本号CAA47315.1 GI:1000702
Genbank记录更新日期:2011年2月2日上午10:15
交叉参考
Pastorek J.等Oncogene 9(10),2877-2888(1994)
其他信息
官方代号:CA9
其他别名:CAIX、MN
其他名称:CA-IX;P54/58N;RCC相关抗原G250;RCC相关蛋白G250;碳酸脱水酶IX;碳酸酐酶9;碳酸脱水酶;膜抗原MN;pMW1;肾细胞癌相关抗原G250
抗体
Abgenix/Amgen:US20040018198
Affibody:抗CAIX亲和体(affibody)分子
(http://www.affibody.com/en/Product-Portfolio/Pipeline/)
Bayer:US7,462,696
Bayer/Morphosys:3ee9 mAb-Petrul HM.等Mol Cancer Ther.2012年2月;11(2):340-9
Harvard Medical School:抗体G10、G36、G37、G39、G45、G57、G106、G119、G6、G27、G40和G125。Xu C.等PLoS One.2010年3月10日;5(3):e9625
Institute of Virology,Slovak Academy of Sciences(Bayer)-US5,955,075
-例如,M75-ATCC登录号HB 11128或MN12–ATCC登录号HB 11647
Institute of Virology,Slovak Academy of Sciences:US7,816,493
-例如分泌自杂交瘤VU-M75的M75单克隆抗体,其保藏在美国典型培养物保藏中心,ATCC号为HB 11128;或分泌自杂交瘤V/10-VU的V/10单克隆抗体,其保藏在BelgianCoordinated Collection of Microorganisms(BCCM)的国际保藏机构,在Laboratoriumvoor Moleculaire Bioloqie-Plasmidencollectie(LMBP),在Universeit Gent in Gent,比利时,登录号为LMBP 6009CB。
Institute of Virology,Slovak Academy of Sciences:US20080177046;US20080176310;US20080176258;US20050031623
Novartis:US20090252738
Wilex:US7,691,375-例如由杂交瘤细胞系DSM ASC 2526产生的抗体。
Wilex:US20110123537;Rencarex:Kennett RH.等Curr Opin Mol Ther.2003年2月;5(1):70-5
Xencor:US20090162382
(45)EGFRvIII(表皮生长因子受体(EGFR),转录变体3,
核苷酸
Genbank登录号NM_201283
Genbank版本号NM_201283.1 GI:41327733
Genbank记录更新日期:2012年9月30日下午01:47
多肽
Genbank登录号NP_958440
Genbank版本号NP_958440.1 GI:41327734
Genbank记录更新日期:2012年9月30日下午01:47
交叉参考
Batra SK.等Cell Growth Differ 1995;6:1251–1259。
抗体:
US7,628,986和US7,736,644(Amgen)
例如,重链可变区氨基酸序列,其选自由SEQ ID NO:142和变体组成的组,以及轻链可变区氨基酸序列,其选自由SEQ ID NO:144和变体组成的组。
US20100111979(Amgen)
例如,一种抗体,该抗体包含重链氨基酸序列,其包含:
由序列组成的CDR1,所述序列选自由用于抗体13.1.2(SEQ ID NO:138)、131(SEQID NO:2)、170(SEQ ID NO:4)、150(SEQ ID NO:5)、095(SEQ ID NO:7)、250(SEQ ID NO:9)、139(SEQ ID NO:10)、211(SEQ ID NO:12)、124(SEQ ID NO:13)、318(SEQ ID NO:15)、342(SEQ ID NO:16)、和333(SEQ ID NO:17)的CDR1区的氨基酸序列组成的组;
由序列组成的CDR2,所述序列选自由用于抗体13.1.2(SEQ ID NO:138)、131(SEQID NO:2)、170(SEQ ID NO:4)、150(SEQ ID NO:5)、095(SEQ ID NO:7)、250(SEQ ID NO:9)、139(SEQ ID NO:10)、211(SEQ ID NO:12)、124(SEQ ID NO:13)、318(SEQ ID NO:15)、342(SEQ ID NO:16)、和333(SEQ ID NO:17)的CDR2区的氨基酸序列组成的组;以及
由序列组成的CDR3,所述序列选自由用于抗体13.1.2(SEQ ID NO:138)、131(SEQID NO:2)、170(SEQ ID NO:4)、150(SEQ ID NO:5)、095(SEQ ID NO:7)、250(SEQ ID NO:9)、139(SEQ ID NO:10)、211(SEQ ID NO:12)、124(SEQ ID NO:13)、318(SEQ ID NO:15)、342(SEQ ID NO:16)、和333(SEQ ID NO:17)的CDR3区的氨基酸序列组成的组。
US20090240038(Amgen)
例如,具有重链或轻链多肽的至少之一的抗体包含氨基酸序列,其至少90%相同于选自由SEQ ID NO:2、SEQ ID NO:19、SEQ ID NO:142、SEQ ID NO:144、以及它们的任何组合组成的组的氨基酸序列。
US20090175887(Amgen)
例如,一种抗体,该抗体具有重链氨基酸序列,其选自由抗体13.1.2(SEQ ID NO:138)、131(SEQ ID NO:2)、170(SEQ ID NO:4)、150(SEQ ID NO:5)、095(SEQ ID NO:7)、250(SEQ ID NO:9)、139(SEQ ID NO:10)、211(SEQ ID NO:12)、124(SEQ ID NO:13)、318(SEQID NO:15)、342(SEQ ID NO:16)、和333(SEQ ID NO:17)的重链氨基酸序列组成的组。
US20090156790(Amgen)
例如,具有重链多肽和轻链多肽的抗体,其中重链或轻链多肽的至少之一包含氨基酸序列,其至少90%相同于选自由SEQ ID NO:2、SEQ ID NO:19、SEQ ID NO:142、SEQ IDNO:144、以及它们的任何组合组成的组的氨基酸序列。
US20090155282、US20050059087和US20050053608(Amgen)
例如,抗体重链氨基酸序列,其选自由抗体13.1.2(SEQ ID NO:138)、131(SEQ IDNO:2)、170(SEQ ID NO:4)、150(SEQ ID NO:5)、095(SEQ ID NO:7)、250(SEQ ID NO:9)、139(SEQ ID NO:10)、211(SEQ ID NO:12)、124(SEQ ID NO:13)、318(SEQ ID NO:15)、342(SEQID NO:16)、和333(SEQ ID NO:17)的重链氨基酸序列组成的组。
MR1-1(US7,129,332;Duke)
例如,变体抗体,其具有SEQ ID NO.18的序列,其中具有取代,在CDR3VH中的S98P-T99Y,以及在CDR3VL中的F92W。
L8A4,H10,Y10(Wikstrand CJ.等Cancer Res.1995年7月15日;55(14):3140-8;Duke)
US20090311803(Harvard University)
例如,用于抗体重链可变区的SEQ ID NO:9,以及用于轻链可变区氨基酸序列的SEQ ID NO:3
US20070274991(EMD72000,还被称为马妥珠单抗;Harvard University)
例如,分别用于轻链和重链的SEQ ID NO:3和9
US6,129,915(Schering)
例如,SEQ.ID NO:1、2、3、4、5和6。
mAb CH12-Wang H.等FASEB J.2012年1月;26(1):73-80(上海肿瘤研究所)。
RAbDMvIII-Gupta P.等BMC Biotechnol.2010年10月7日;10:72(StanfordUniversity Medical Center)。
mAb Ua30-Ohman L.等Tumour Biol.2002年3月-4月;23(2):61-9(UppsalaUniversity)。
Han DG.等Nan Fang Yi Ke Da Xue Xue Bao.2010年1月;30(1):25-9(西安交通大学)。
(46)CD33(CD33分子)
核苷酸
Genbank登录号M_23197
Genbank版本号NM_23197.1 GI:180097
Genbank记录更新日期:2010年6月23日上午08:47
多肽
Genbank登录号AAA51948
Genbank版本号AAA51948.1 GI:188098
Genbank记录更新日期:2010年6月23日上午08:47
交叉参考
Simmons D.等J.Immunol.141(8),2797-2800(1988)
其他信息
官方代号:CD33
其他别名:SIGLEC-3、SIGLEC3、p67
其他名称:CD33抗原(gp67);gp67;髓样细胞表面抗原CD33;唾液酸结合Ig样凝集素3;唾液酸结合Ig样凝集素
抗体
H195(林妥珠单抗,Lintuzumab)-Raza A.等Leuk Lymphoma.2009年8月;50(8):1336-44;US6,759,045(Seattle Genetics/Immunomedics)
mAb OKT9:Sutherland,D.R.等Proc Natl Acad Sci USA 78(7):4515-45191981,Schneider,C.等J Biol Chem 257,8516-8522(1982)
mAb E6:Hoogenboom,H.R.等J Immunol 144,3211-3217(1990)
US6,590,088(人类基因组科学(Human Genome Sciences))
例如,SEQ ID NO:1和2以及ATCC登录号97521
US7,557,189(Immunogen)
例如,抗体或其片段,包含重链可变区,其包含具有SEQ ID NO:1-3的氨基酸序列的三个CDR,以及轻链可变区,其包含具有SEQ ID NO:4-6的氨基酸序列的三个CDR。
(47)CD19(CD19分子)
核苷酸
Genbank登录号NM_001178098
Genbank版本号NM_001178098.1 GI:296010920
Genbank记录更新日期:2012年9月10日上午12:43
多肽
Genbank登录号NP_001171569
Genbank版本号NP_001171569.1 GI:296010921
Genbank记录更新日期:2012年9月10日上午12:43
交叉参考
Tedder TF.等J.Immunol.143(2):712–7(1989)
其他信息
官方代号:CD19
其他别名:B4、CVID3
其他名称:B-淋巴细胞抗原CD19;B淋巴细胞表面抗原B4;T细胞表面抗原亮氨酸-12;分化抗原CD19
抗体
Immunogen:HuB4-Al-Katib AM.等Clin Cancer Res.2009年6月15日;15(12):4038-45。
4G7:Kügler M.等Protein Eng Des Sel.2009年3月;22(3):135-47
例如,在Knappik,A.等J Mol Biol 2000年2月;296(1):57-86的图3中的序列
AstraZeneca/MedImmune:MEDI-551-Herbst R.等J Pharmacol Exp Ther.2010年10月;335(1):213-22
Glenmark Pharmaceuticals:GBR-401-Hou S.等Mol Cancer Ther 2011年11月10(会议摘要补充)C164
US7,109,304(Immunomedics)
例如,一种抗体,其包含hA19Vk(SEQ ID NO:7)的序列和hA19VH(SEQ ID NO:10)的序列
US7,902,338(Immunomedics)
例如,抗体或其抗原结合片段,其包含SEQ ID NO:16(KASQSVDYDGDSYLN)的轻链互补决定区CDR序列CDR1;SEQ ID NO:17(DASNLVS)的CDR2;以及SEQ ID NO:18(QQSTEDPWT)的CDR3,以及SEQ ID NO:19(SYWMN)的重链CDR序列CDR1;SEQ ID NO:20(QIWPGDGDTNYNGKFKG)的CDR2和SEQ ID NO:21(RETTTVGRYYYAMDY)的CDR3,并且还包含人抗体框架(FR)和恒定区序列,其中一个或多个框架区氨基酸残基被亲本鼠抗体的相应的框架区序列所取代,以及其中所述取代的FR残基包含在重链可变区的Kabat残基91处丝氨酸替代苯丙氨酸。
Medarex:MDX-1342-Cardarelli PM.等Cancer Immunol Immunother.2010年2月;59(2):257-65。
MorphoSys/Xencor:MOR-208/XmAb-5574-Zalevsky J.等Blood.2009年4月16日;113(16):3735-43
US7,968,687(Seattle Genetics)
抗体或抗原结合片段,其含有包含SEQ ID NO:9的氨基酸序列的重链可变域和包含SEQ ID NO:24的氨基酸序列的轻链可变域。
4G7 chim-Lang P.等Blood.2004年5月15日;103(10):3982-5(University of Tübingen)
例如,US20120082664的图6和SEQ ID No:80
浙江大学医学院:2E8-Zhang J.等J Drug Target.2010年11月;18(9):675-8
(48)IL2RA(白细胞介素2受体,α);NCBI参考序列:NM_000417.2);
核苷酸
Genbank登录号NM_000417
Genbank版本号NM_000417.2 GI:269973860
Genbank记录更新日期:2012年9月9日下午04:59
多肽
Genbank登录号NP_000408
Genbank版本号NP_000408.1 GI:4557667
Genbank记录更新日期:2012年9月9日下午04:59
交叉参考
Kuziel W.A.等J.Invest.Dermatol.94(6SUPPL),27S-32S(1990)
其他信息
官方代号:IL2RA
其他别名:RP11-536K7.1、CD25、IDDM10、IL2R、TCGFR
其他名称:FIL-2受体亚基α;IL-2-RA;IL-2R亚基α;IL2-RA;TAC抗原;白细胞介素-2受体亚基α;p55
抗体
US6,383,487(Novartis/UCL:Baxilisimab[舒莱(Simulect)])
US6,521,230(Novartis/UCL:Baxilisimab[舒莱])
例如,具有抗原结合位点的抗体包含至少一个域,其包含具有在SEQ.ID.NO:7中的氨基酸序列的CDR1、具有在SEQ.ID.NO:8中的氨基酸序列的CDR2、和具有在SEQ.ID.NO:9中的氨基酸序列的CDR3;或所述CDR1、CDR2和CDR3(按整体序列考虑)包含氨基酸序列,其至少90%相同于SEQ.ID.NO:7、8和9(按整体序列考虑)。
达克珠单抗(Daclizumab)-Rech AJ.等Ann N Y Acad Sci.2009年9月;1174:99-106(Roche)
(49)AXL(AXL受体酪氨酸激酶)
核苷酸
Genbank登录号M76125
Genbank版本号M76125.1 GI:292869
Genbank记录更新日期:2010年6月23日上午08:53
多肽
Genbank登录号AAA61243
Genbank版本号AAA61243.1 GI:29870
Genbank记录更新日期:2010年6月23日上午08:53
交叉参考
O'Bryan J.P.等Mol.Cell.Biol.11(10),5016-5031(1991);Bergsagel P.L.等J.Immunol.148(2),590-596(1992)
其他信息
官方代号:AXL
其他别名:JTK11、UFO
其他名称:AXL癌基因;AXL转化序列/基因;癌基因AXL;酪氨酸蛋白激酶受体UFO
抗体
YW327.6S2-Ye X.等Oncogene.2010年9月23日;29(38):5254-64。(Genentech)
BergenBio:BGB324(http://www.bergenbio.com/BGB324)
(50)CD30-TNFRSF8(肿瘤坏死因子受体超家族,成员8)
核苷酸
Genbank登录号M83554
Genbank版本号M83554.1 GI:180095
Genbank记录更新日期:2010年6月23日上午08:53
多肽
Genbank登录号AAA51947
Genbank版本号AAA51947.1 GI:180096
Genbank记录更新日期:2010年6月23日上午08:53
交叉参考
Durkop H.等Cell 68(3),421-427(1992)
其他信息
官方代号:TNFRSF8
其他别名:CD30、D1S166E、Ki-1
其他名称:CD30L受体;Ki-1抗原;细胞因子受体CD30;淋巴细胞活化抗原CD30;肿瘤坏死因子受体超家族成员8
(51)BCMA(B细胞成熟抗原)-TNFRSF17(肿瘤坏死因子受体超家族,成员17)
核苷酸
Genbank登录号Z29574
Genbank版本号Z29574.1 GI:471244
Genbank记录更新日期:2011年2月2日上午10:40
多肽
Genbank登录号CAA82690
Genbank版本号CAA82690.1 GI:471245
Genbank记录更新日期:2011年2月2日上午10:40
交叉参考
Laabi Y.等Nucleic Acids Res.22(7),1147-1154(1994)
其他信息
官方代号:TNFRSF17
其他别名:BCM、BCMA、CD269
其他名称:B细胞成熟抗原;B细胞成熟因子;B细胞成熟蛋白;肿瘤坏死因子受体超家族成员17
(52)CT Ags–CTA(睾丸癌抗原(Cancer Testis Antigen))
交叉参考
Fratta E.,等Mol Oncol.2011年4月;5(2):164-82;Lim SH.,at al Am J BloodRes.2012;2(1):29-35。
(53)CD174(Lewis Y)-FUT3(岩藻糖基转移酶3(半乳糖苷3(4)-L-岩藻糖基转移酶,路易斯血型)
核苷酸
Genbank登录号NM000149
Genbank版本号NM000149.3 GI:148277008
Genbank记录更新日期:2012年6月26日下午04:49
多肽
Genbank登录号NP_000140
Genbank版本号NP_000140.1 GI:4503809
Genbank记录更新日期:2012年6月26日下午04:49
交叉参考
Kukowska-Latallo,J.F.等Genes Dev.4(8),1288-1303(1990)
其他信息
官方代号:FUT3
其他别名:CD174、FT3B、FucT-III、LE、Les
其他名称:Lewis FT;α-(1,3/1,4)-岩藻糖基转移酶;路易斯血型α-4-岩藻糖基转移酶;岩藻糖基转移酶III;半乳糖苷3(4)-L-岩藻糖基转移酶
(54)CLEC14A(C型凝集素域家族14,成员A;Genbank登录号NM175060)
核苷酸
Genbank登录号NM175060
Genbank版本号NM175060.2 GI:371123930
Genbank记录更新日期:2012年4月1日下午03:34
多肽
Genbank登录号NP_778230
Genbank版本号NP_778230.1 GI:28269707
Genbank记录更新日期:2012年4月1日下午03:34
其他信息
官方代号:CLEC14A
其他别名:UNQ236/PRO269、C14orf27、CEG1、EGFR-5
其他名称:C型凝集素域家族14成员A;含ClECT和EGF样域蛋白质;表皮生长因子受体5
(55)GRP78–HSPA5(热休克70kDa蛋白5(葡萄糖调节蛋白,78kDa)
核苷酸
Genbank登录号NM005347
Genbank版本号NM005347.4 GI:305855105
Genbank记录更新日期:2012年9月30日下午01:42
多肽
Genbank登录号NP_005338
Genbank版本号NP_005338.1 GI:16507237
Genbank记录更新日期:2012年9月30日下午01:42
交叉参考
Ting J.等DNA 7(4),275-286(1988)
其他信息
官方代号:HSPA5
其他别名:BIP、GRP78、MIF2
其他名称:78kDa葡萄糖调节蛋白;内质网腔Ca(2+)-结合蛋白grp78;免疫球蛋白重链-结合蛋白
(56)CD70(CD70分子)L08096
核苷酸
Genbank登录号L08096
Genbank版本号L08096.1 GI:307127
Genbank记录更新日期:2012年6月23日上午08:54
多肽
Genbank登录号AAA36175
Genbank版本号AAA36175.1 GI:307128
Genbank记录更新日期:2012年6月23日上午08:54
交叉参考
Goodwin R.G.等Cell 73(3),447-456(1993)
其他信息
官方代号:CD70
其他别名:CD27L、CD27LG、TNFSF7
其他名称:CD27配体;CD27-L;CD70抗原;Ki-24抗原;表面抗原CD70;肿瘤坏死因子(配体)超家族,成员7;肿瘤坏死因子配体超家族成员7
抗体
MDX-1411,针对CD70(Medarex)
h1F6(Oflazoglu,E.,等,Clin Cancer Res.2008年10月1日;14(19):6171-80;Seattle Genetics)
例如,参见US20060083736 SEQ ID NO:1、2、11和12以及图1。
(57)干细胞特异性抗原。例如:
●5T4(见以下条目(63))
●CD25(见以下条目(48))
●CD32
○多肽
■Genbank登录号ABK42161
■Genbank版本号ABK42161.1 GI:117616286
■Genbank记录更新日期:2007年7月25日下午03:00
●LGR5/GPR49
○核苷酸
■Genbank登录号NM_003667
■Genbank版本号NM_003667.2 GI:24475886
■Genbank记录更新日期:2012年7月22日下午03:38
○多肽
■Genbank登录号NP_003658
■Genbank版本号NP_003658.1 GI:4504379
■Genbank记录更新日期:2012年7月22日下午03:38
●Prominin/CD133
○核苷酸
■Genbank登录号NM_006017
■Genbank版本号NM_006017.2 GI:224994187
■Genbank记录更新日期:2012年9月30日下午01:47
○多肽
■Genbank登录号NP_006008
■Genbank版本号NP_006008.1 GI:5174387
■Genbank记录更新日期:2012年9月30日下午01:47
(58)ASG-5
交叉参考
(Smith L.M.,et.al AACR 2010 Annual Meeting(摘要#2590);Gudas J.M.等AACR 2010Annual Meeting(摘要#4393)
抗体
抗AGS-5抗体;M6.131(Smith,L.M.,et.al AACR 2010Annual Meeting(摘要#2590)
(59)ENPP3(外核苷酸焦磷酸酶/磷酸二酯酶3)
核苷酸
Genbank登录号AF005632
Genbank版本号AF005632.2 GI:4432589
Genbank记录更新日期:2010年3月10日下午09:41
多肽
Genbank登录号AAC51813
Genbank版本号AAC51813.1 GI:2465540
Genbank记录更新日期:2010年3月10日下午09:41
交叉参考
Jin-Hua P.等Genomics 45(2),412-415(1997)
其他信息
官方代号:ENPP3
其他别名:RP5-988G15.3、B10、CD203c、NPP3、PD-IBETA、PDNP3
其他名称:E-NPP 3;dJ1005H11.3(磷酸二酯酶I/核苷酸焦磷酸酶3);dJ914N13.3(磷酸二酯酶I/核苷酸焦磷酸酶3);外核苷酸焦磷酸酶/磷酸二酯酶家族成员3;gp130RB13-6;磷酸二酯酶Iβ;磷酸二酯酶I/核苷酸焦磷酸酶3;磷酸二酯酶-Iβ
(60)PRR4(富含脯氨酸4(泪腺的))
核苷酸
Genbank登录号NM_007244
Genbank版本号NM_007244.2 GI:154448885
Genbank记录更新日期:2012年6月28日下午12:39
多肽
Genbank登录号NP_009175
Genbank版本号NP_009175.2 GI:154448886
Genbank记录更新日期:2012年6月28日下午12:39
交叉参考
Dickinson D.P.等Invest.Ophthalmol.Vis.Sci.36(10),2020-2031(1995)
其他信息
官方代号:PRR4
其他别名:LPRP、PROL4
其他名称:泪腺富含脯氨酸蛋白;鼻咽癌相关富含脯氨酸的蛋白4;富含脯氨酸多肽4;富含脯氨酸蛋白4
(61)GCC–GUCY2C(鸟苷酸环化酶2C(热稳定肠毒素受体)
核苷酸
Genbank登录号NM_004963
Genbank版本号NM_004963.3 GI:222080082
Genbank记录更新日期:2012年9月2日下午01:50
多肽
Genbank登录号NP_004954
Genbank版本号NP_004954.2 GI:222080083
Genbank记录更新日期:2012年9月2日下午01:50
交叉参考
De Sauvage F.J.等J.Biol.Chem.266(27),17912-17918(1991);Singh S.等Biochem.Biophys.Res.Commun.179(3),1455-1463(1991)
其他信息
官方代号:GUCY2C
其他别名:DIAR6、GUC2C、MUCIL、STAR
其他名称:GC-C;STA受体;鸟苷酸环化酶C;hSTAR;热稳定肠毒素受体;肠鸟苷酸环化酶
(62)Liv-1–SLC39A6(溶质载体家族39(锌转运蛋白),成员6)
核苷酸
Genbank登录号U41060
Genbank版本号U41060.2 GI:12711792
Genbank记录更新日期:2009年11月30日下午04:35
多肽
Genbank登录号AAA96258
Genbank版本号AAA96258.2 GI:12711793
Genbank记录更新日期:2009年11月30日下午04:35
交叉参考
Taylor KM.等Biochim Biophys Acta.2003年4月1日;1611(1-2):16-30
其他信息
官方代号:SLC39A6
其他别名:LIV-1
其他名称:LIV-1蛋白,雌激素调节的;ZIP-6;雌激素调节蛋白LIV-1;溶质载体家族39(金属离子转运蛋白),成员6;溶质载体家族39成员6;锌转运蛋白ZIP6;zrt-和Irt-样蛋白6
(63)5T4,滋养层糖蛋白,TPBG–TPBG(滋养层糖蛋白)
核苷酸
Genbank登录号AJ012159
Genbank版本号AJ012159.1 GI:3805946
Genbank记录更新日期:2011年2月1日上午10:27
多肽
Genbank登录号CAA09930
Genbank版本号CAA09930.1 GI:3805947
Genbank记录更新日期:2011年2月1日上午10:27
交叉参考
King K.W.,et al Biochim.Biophys.Acta 1445(3),257-270(1999)
其他信息
·官方代号:TPBG
·其他别名:5T4、5T4AG、M6P1
·其他名称:5T4癌胚抗原;5T4癌胚滋养层糖蛋白;5T4肿瘤滋养层糖蛋白
(64)CD56–NCMA1(神经细胞粘附分子1)
核苷酸
Genbank登录号NM_000615
Genbank版本号NM_000615.6 GI:336285433
Genbank记录更新日期:2012年9月23日下午02:32
多肽
Genbank登录号NP_000606
Genbank版本号NP_000606.3 GI:94420689
Genbank记录更新日期:2012年9月23日下午02:32
交叉参考
Dickson,G.,等,Cell 50(7),1119-1130(1987)
其他信息
官方代号:NCAM1
其他别名:CD56、MSK39、NCAM
其他名称:由单克隆抗体5.1H1 1识别的抗原;神经细胞粘附分子,NCAM
抗体
Immunogen:HuN901(Smith SV.等Curr Opin Mol Ther.2005年8月;7(4):394-401)
例如,参见由鼠N901抗体的人源化。参见Roguska,M.A.,等Proc Natl Acad SciUSA 1994年2月;91:969-973的图1b和1e。
(65)CanAg(肿瘤相关抗原CA242)
交叉参考
Haglund C.等Br J Cancer 60:845-851,1989;Baeckstrom D.等J Biol Chem266:21537-21547,1991
抗体
huC242(Tolcher AW等,J Clin Oncol.2003年1月15日;21(2):211-22;Immunogen)
例如,参见US20080138898A1 SEQ ID NO:1和2
(66)FOLR1(叶酸盐受体1)
核苷酸
Genbank登录号J05013
Genbank版本号J05013.1 GI:182417
Genbank记录更新日期:2010年6月23日上午08:47
多肽
Genbank登录号AAA35823
Genbank版本号AAA35823.1 GI:182418
Genbank记录更新日期:2010年6月23日上午08:47
交叉参考
Elwood P.C.等J.Biol.Chem.264(25),14893-14901(1989)
其他信息
官方代号:FOLR1
其他别名:FBP、FOLR
其他名称:FR-α;KB细胞FBP;成年叶酸结合蛋白;叶酸结合蛋白;叶酸盐受体α;叶酸受体,成年;卵巢肿瘤相关抗原MOv18
抗体
M9346A-Whiteman KR.等Cancer Res 2012年4月15日;72(8 Supplement):4628(Immunogen)
(67)GPNMB(糖蛋白(跨膜)nmb)
核苷酸
Genbank登录号X76534
Genbank版本号X76534.1 GI:666042
Genbank记录更新日期:2011年2月2日上午10:10
多肽
Genbank登录号CAA54044
Genbank版本号CAA54044.1 GI:666043
Genbank记录更新日期:2011年2月2日上午10:10
交叉参考
Weterman M.A.等Int.J.Cancer 60(1),73-81(1995)
其他信息
官方代号:GPNMB
其他别名:UNQ1725/PRO9925、HGFIN、NMB
其他名称:糖蛋白NMB;糖蛋白nmb样蛋白;骨活素(osteoactivin);跨膜糖蛋白HGFIN;跨膜糖蛋白NMB
抗体
Celldex Therapeutics:CR011(Tse KF.等Clin Cancer Res.2006年2月15日;12(4):1373-82)
例如,参见EP1827492B1SEQ ID NO:22、24、26、31、33和35
(68)TIM-1–HAVCR1(甲型肝炎病毒细胞受体1)
核苷酸
Genbank登录号AF043724
Genbank版本号AF043724.1 GI:2827453
Genbank记录更新日期:2010年3月10日下午06:24
多肽
Genbank登录号AAC39862
Genbank版本号AAC39862.1 GI:2827454
Genbank记录更新日期:2010年3月10日下午06:24
交叉参考
Feigelstock D.等J.Virol.72(8),6621-6628(1998)
其他信息
官方代号:HAVCR1
其他别名:HAVCR、HAVCR-1、KIM-1、KIM1、TIM、TIM-1、TIM1、TIMD-1、TIMD1
其他名称:T细胞免疫球蛋白域和粘蛋白域蛋白1;T细胞膜蛋白1;肾损伤分子1
(69)RG-1/前列腺肿瘤靶Mindin–Mindin/RG-1
交叉参考
Parry R.等Cancer Res.2005年9月15日;65(18):8397-405
(70)B7-H4–VTCN1(包含T细胞活化抑制剂的V-set域1
核苷酸
Genbank登录号BX648021
Genbank版本号BX648021.1 GI:34367180
Genbank记录更新日期:2011年2月2日上午08:40
交叉参考
Sica GL.等Immunity.2003年6月;18(6):849-61
其他信息
官方代号:VTCN1
其他别名:RP11-229A19.4、B7-H4、B7H4、B7S1、B7X、B7h.5、PRO1291、VCTN1
其他名称:B7家族成员,H4;B7超家族成员1;T细胞共刺激分子B7x;T细胞共刺激分子B7x;包含T细胞活化抑制剂的V-set域1;免疫共刺激蛋白B7-H4
(71)PTK7(PTK7蛋白酪氨酸激酶7)
核苷酸
Genbank登录号AF447176
Genbank版本号AF447176.1 GI:17432420
Genbank记录更新日期:2008年11月28日下午01:51
多肽
Genbank登录号AAL39062
Genbank版本号AAL39062.1 GI:17432421
Genbank记录更新日期:2008年11月28日下午01:51
交叉参考
Park S.K.等J.Biochem.119(2),235-239(1996)
其他信息
官方代号:PTK7
其他别名:CCK-4、CCK4
其他名称:结肠癌激酶4;失活酪氨酸蛋白激酶7;假酪氨酸激酶受体7;酪氨酸蛋白激酶样7
(72)CD37(CD37分子)
核苷酸
Genbank登录号NM_001040031
Genbank版本号NM_001040031.1 GI:91807109
Genbank记录更新日期:2012年7月29日下午02:08
多肽
Genbank登录号NP_001035120
Genbank版本号NP_001035120.1 GI:91807110
Genbank记录更新日期:2012年7月29日下午02:08
交叉参考
Schwartz-Albiez R.等J.Immunol.140(3),905-914(1988)
其他信息
官方代号:CD37
其他别名:GP52-40、TSPAN26
其他名称:CD37抗原;细胞分化抗原37;白细胞抗原CD37;白细胞表面抗原CD37;四旋蛋白-26(tetraspanin-26);tspan-26
抗体
Boehringer Ingelheim:mAb 37.1(Heider KH.等Blood.2011年10月13日;118(15):4159-68)
Trubion:CD37-SMIP(G28-1 scFv-Ig)((Zhao X.等Blood.2007;110:2569-2577)
例如,参见US20110171208A1 SEQ ID NO:253
Immunogen:K7153A(Deckert J.等Cancer Res,2012年4月15日;72(8增补):4625)
(73)CD138-SDC1(多配体聚糖1(syndecan 1))
核苷酸
Genbank登录号AJ551176
Genbank版本号AJ551176.1 GI:29243141
Genbank记录更新日期:2011年2月1日下午12:09
多肽
Genbank登录号CAD80245
Genbank版本号CAD80245.1 GI:29243142
Genbank记录更新日期:2011年2月1日下午12:09
交叉参考
O'Connell FP.等Am J Clin Pathol.2004年2月;121(2):254-63
其他信息
官方代号:SDC1
其他别名:CD138、SDC、SYND1、多配体聚糖
其他名称:CD138抗原;硫酸乙酰肝素蛋白多糖成纤维细胞生长因子受体;多配体聚糖蛋白多糖1;多配体聚糖-1
抗体
Biotest:嵌合MAb(nBT062)-(Jagannath S.等Poster ASH#3060,2010;WIPO专利申请WO/2010/128087)
例如,参见US20090232810 SEQ ID NO:1和2
Immunogen:B-B4(Tassone P.等Blood 104_3688-3696)
例如,参见US20090175863A1 SEQ ID NO:1和2
(74)CD74(CD74分子,主要组织相容性复合物,II类不变链)
核苷酸
Genbank登录号NM_004355
Genbank版本号NM_004355.1 GI:343403784
Genbank记录更新日期:2012年9月23日下午02:30
多肽
Genbank登录号NP_004346
Genbank版本号NP_004346.1 GI:10835071
Genbank记录更新日期:2012年9月23日下午02:30
交叉参考
Kudo,J.等Nucleic Acids Res.13(24),8827-8841(1985)
其他信息
官方代号:CD74
其他别名:DHLAG、HLADG、II、Ia-GAMMA
其他名称:CD74抗原(主要组织相容性复合物的不变多肽,II类抗原相关的);HLA类II组织相容性抗原γ链;HLA-DR抗原相关的不变链;HLA-DR-γ;Ia-相关的不变链;MHCHLA-DRγ链;II类抗原的γ链;p33
抗体
Immunomedics:hLL1(Milatuzumab,)-Berkova Z.等Expert Opin InvestigDrugs.2010年1月;19(1):141-9)
例如,参见US20040115193 SEQ ID NO:19、20、21、22、23和24
Genmab:HuMax-CD74(参见网站)
(75)Claudins(整合膜连接蛋白)–CLs(Claudins)
交叉参考
Offner S.等Cancer Immunol Immunother.2005年5月;54(5):431-45,Suzuki H.等Ann N Y Acad Sci.2012年7月;1258:65-70)
在人类中,已经描述了家族的24种成员-见交叉参考。
(76)EGFR(表皮生长因子受体)
核苷酸
Genbank登录号NM_005228
Genbank版本号NM_005228.3 GI:41927737
Genbank记录更新日期:2012年9月30日下午01:47
多肽
Genbank登录号NP_005219
Genbank版本号NP_005219.2 GI:29725609
Genbank记录更新日期:2012年9月30日下午01:47
交叉参考
Dhomen NS.等Crit Rev Oncog.2012;17(1):31-50
其他信息
官方代号:EGFR
其他别名:ERBB、ERBB1、HER1、PIG61、mENA
其他名称:禽成红细胞白血病病毒(v-erb-b)癌基因同系物;细胞生长抑制蛋白40;细胞增殖诱导蛋白61;原癌基因c-ErbB-1;受体酪氨酸蛋白激酶erbB-1
抗体
BMS:Cetuximab(Erbitux)-Broadbridge VT.等Expert Rev AnticancerTher.2012年5月;12(5):555-65。
例如,见US6217866–ATTC保藏号9764。
Amgen:帕尼单抗(Panitumumab)(Vectibix)-Argiles G.等Future Oncol.2012年4月;8(4):373-89
例如,见US6235883SEQ ID NO:23-38。
Genmab:扎妥木单抗(Zalutumumab)-Rivera F.等Expert Opin Biol Ther.2009年5月;9(5):667-74。
YM Biosciences:尼妥珠单抗(Nimotuzumab)-Ramakrishnan MS.等MAbs.2009年1月-2月;1(1):41-8。
例如,见US5891996SEQ ID NO:27-34。
(77)Her3(ErbB3)–ERBB3(v-erb-b2成红细胞白血病病毒癌基因同系物3(禽))
核苷酸
Genbank登录号M34309
Genbank版本号M34309.1 GI:183990
Genbank记录更新日期:2010年6月23日下午08:47
多肽
Genbank登录号AAA35979
Genbank版本号AAA35979.1 GI:306841
Genbank记录更新日期:2010年6月23日下午08:47
交叉参考
Plowman,G.D.等,Proc.Natl.Acad.Sci.U.S.A.87(13),4905-4909(1990)
其他信息
官方代号:ERBB3
其他别名:ErbB-3、HER3、LCCS2、MDA-BF-1、c-erbB-3、c-erbB3、erbB3-S、p180-ErbB3、p45-sErbB3、p85-sErbB3
其他名称:原癌基因样蛋白c-ErbB-3;受体酪氨酸蛋白激酶erbB-3;酪氨酸激酶型细胞表面受体HER3
抗体
Merimack Pharma:MM-121(Schoeberl B.等Cancer Res.2010年3月15日;70(6):2485-2494)
例如,见US2011028129SEQ ID NO:1、2、3、4、5、6、7和8。
(78)RON-MST1R(巨噬细胞刺激1受体(c-met相关酪氨酸激酶))
核苷酸
Genbank登录号X70040
Genbank版本号X70040.1 GI:36109
Genbank记录更新日期:2011年2月2日下午10:17
多肽
Genbank登录号CCA49634
Genbank版本号CCA49634.1 GI:36110
Genbank记录更新日期:2011年2月2日下午10:17
交叉参考
Ronsin C.等Oncogene 8(5),1195-1202(1993)
其他信息
官方代号:MST1R
其他别名:CD136、CDw136、PTK8、RON
其他名称:MSP受体;MST1R变体RON30;MST1R变体RON62;PTK8蛋白酪氨酸激酶8;RON变体E2E3;c-met相关酪氨酸激酶;巨噬细胞刺激蛋白受体;p185-Ron;可溶性RON变体1;可溶性RON变体2;可溶性RON变体3;可溶性RON变体4
(79)EPHA2(EPH受体A2)
核苷酸
Genbank登录号BC037166
Genbank版本号BC037166.2 GI:33879863
Genbank记录更新日期:2012年3月6日下午01:59
多肽
Genbank登录号AAH37166
Genbank版本号AAH37166.1 GI:22713539
Genbank记录更新日期:2012年3月6日下午01:59
交叉参考
Strausberg R.L.等Proc.Natl.Acad.Sci.U.S.A.99(26),16899-16903(2002)
其他信息
官方代号:EPHA2
其他别名:ARCC2、CTPA、CTPP1、ECK
其他名称:ephrin A型受体2;上皮细胞受体蛋白酪氨酸激酶;可溶性EPHA2变体1;酪氨酸蛋白激酶受体ECK
抗体
Medimmune:1C1(Lee JW.等Clin Cancer Res.2010年5月1日;16(9):2562-2570)
例如,见US20090304721A1的图7和8。
(80)CD20–MS4A1(跨膜4域,亚家族A,成员1)
核苷酸
Genbank登录号M27394
Genbank版本号M27394.1 GI:179307
Genbank记录更新日期:2009年11月30日上午11:16
多肽
Genbank登录号AAA35581
Genbank版本号AAA35581.1 GI:179308
Genbank记录更新日期:2009年11月30日上午11:16
交叉参考
Tedder T.F.等Proc.Natl.Acad.Sci.U.S.A.85(1),208-212(1988)
其他信息
官方代号:MS4A1
其他别名:B1、Bp35、CD20、CVID5、LEU-16、MS4A2、S7
其他名称:B-淋巴细胞抗原CD20;B淋巴细胞细胞表面抗原B1;CD20抗原;CD20受体;白细胞表面抗原Leu-16
抗体
Genentech/Roche:利妥昔单抗-Abdulla NE.等BioDrugs.2012年4月1日;26(2):71-82。
例如,见US5736137,ATCC保藏号为HB-69119。
GSK/Genmab:奥法木单抗-Nightingale G.等Ann Pharmacother.2011年10月;45(10):1248-55。
例如,见US20090169550A1 SEQ ID NO:2、4和5。
Immunomedics:Veltuzumab-Goldenberg DM.等Leuk Lymphoma.2010年5月;51(5):747-55。
例如,见US7919273B2SEQ ID NO:1、2、3、4、5和6。
(81)腱生蛋白C(肌腱蛋白C,Tenascin C)–TNC(腱生蛋白C)
核苷酸
Genbank登录号NM_002160
Genbank版本号NM_002160.3 GI:340745336
Genbank记录更新日期:2012年9月23日下午02:33
多肽
Genbank登录号NP_002151
Genbank版本号NP_002151.2 GI:153946395
Genbank记录更新日期:2012年9月23日下午02:33
交叉参考
Nies D.E.等J.Biol.Chem.266(5),2818-2823(1991);Siri A.等Nucleic AcidsRes.19(3),525-531(1991)
其他信息
官方代号:TNC
其他别名:150-225、GMEM、GP、HXB、JI、TN、TN-C
其他名称:GP 150-225;肌链抗原(cytotactin);胶质瘤相关细胞外基质抗原;hexabrachion(腱生蛋白);肌腱抗原;神经粘连蛋白;腱生蛋白;腱生蛋白-C同种型14/AD1/16
抗体
Philogen:G11(von Lukowicz T.,等J Nucl Med.2007年4月;48(4):582-7)和F16(Pedretti M.等Lung Cancer.2009年4月;64(1):28-33)
例如,见US7968685SEQ ID NO:29、35、45和47。
(82)FAP(成纤维细胞活化蛋白,α)
核苷酸
Genbank登录号U09278
Genbank版本号U09278.1 GI:1888315
Genbank记录更新日期:2010年6月23日上午09:22
多肽
Genbank登录号AAB49652
Genbank版本号AAB49652.1 GI:1888316
Genbank记录更新日期:2010年6月23日上午09:22
交叉参考
Scanlan,M.J.,et al Proc.Natl.Acad.Sci.U.S.A.91(12),5657-5661(1994)
其他信息
官方代号:FAP
其他别名:DPPIV、FAPA
其他名称:170kDa黑素瘤膜结合明胶酶;整合膜丝氨酸蛋白酶;透明质酸酶(seprase)
(83)DKK-1(Dickkopf 1同系物(光滑爪蟾,Xenopus laevis))
核苷酸
Genbank登录号NM_012242
Genbank版本号NM_012242.2 GI:61676924
Genbank记录更新日期:2012年9月30日下午01:48
多肽
Genbank登录号NP_036374
Genbank版本号NP_036374.1 GI:7110719
Genbank记录更新日期:2012年9月30日下午01:48
交叉参考
Fedi P.等J.Biol.Chem.274(27),19465-19472(1999)
其他信息
官方代号:DKK1
其他别名:UNQ492/PRO1008、DKK-1、SK
其他名称:dickkopf相关蛋白-1;dickkopf-1样;dickkopf样蛋白1;dickkopf相关蛋白1;hDkk-1
抗体
Novartis:BHQ880(Fulciniti M.等Blood.2009年7月9日;114(2):371-379)
例如,见US20120052070A1SEQ ID NO:100和108。
(84)CD52(CD52分子)
核苷酸
Genbank登录号NM_001803
Genbank版本号NM_001803.2 GI:68342029
Genbank记录更新日期:2012年9月30日下午01:48
多肽
Genbank登录号NP_001794
Genbank版本号NP_001794.2 GI:68342030
Genbank记录更新日期:2012年9月30日下午01:48
交叉参考
Xia M.Q.等Eur.J.Immunol.21(7),1677-1684(1991)
其他信息
官方代号:CD52
其他别名:CDW52
其他名称:CAMPATH-1抗原;CD52抗原(CAMPATH-1抗原);CDW52抗原(CAMPATH-1抗原);剑桥病理1抗原;附睾分泌蛋白E5;he5;人附睾特异蛋白5
抗体
阿仑单抗(Campath)-Skoetz N.等Cochrane Database Syst Rev.2012年2月15日;2:CD008078。
例如,见Drugbank Acc.号DB00087(BIOD00109,BTD00109)
(85)CS1-SLAMF7(SLAM家族成员7)
核苷酸
Genbank登录号NM_021181
Genbank版本号NM_021181.3 GI:1993571
Genbank记录更新日期:2012年6月29日上午11:24
多肽
Genbank登录号NP_067004
Genbank版本号NP_067004.3 GI:19923572
Genbank记录更新日期:2012年6月29日上午11:24
交叉参考
Boles K.S.等Immunogenetics 52(3-4),302-307(2001)
其他信息
官方代号:SLAMF7
其他别名:UNQ576/PRO1138、19A、CD319、CRACC、CS1
其他名称:19A24蛋白;CD2子集(subset)1;CD2样受体活化细胞毒性细胞;CD2样受体活化细胞毒性细胞;膜蛋白FOAP-12;新LY9(淋巴细胞抗原9)样蛋白;蛋白19A
抗体
BMS:elotuzumab/HuLuc63(Benson DM.等J Clin Oncol.2012年6月1日;30(16):2013-2015)
例如,见US20110206701SEQ ID NO:9、10、11、12、13、14、15和16。
(86)Endoglin–ENG(内皮糖蛋白)
核苷酸
Genbank登录号AF035753
Genbank版本号AF035753.1 GI:3452260
Genbank记录更新日期:2010年3月10日下午06:36
多肽
Genbank登录号AAC32802
Genbank版本号AAC32802.1 GI:3452261
Genbank记录更新日期:2010年3月10日下午06:36
交叉参考
Rius C.等Blood 92(12),4677-4690(1998)
官方代号:ENG
其他信息
其他别名:RP11-228B15.2、CD105、END、HHT1、ORW、ORW1
其他名称:CD105抗原
(87)膜联蛋白A1–ANXA1(膜联蛋白A1)
核苷酸
Genbank登录号X05908
Genbank版本号X05908.1 GI:34387
Genbank记录更新日期:2011年2月2日上午10:02
多肽
Genbank登录号CCA29338
Genbank版本号CCA29338.1 GI:34388
Genbank记录更新日期:2011年2月2日上午10:02
交叉参考
Wallner B.P.,et al Nature 320(6057),77-81(1986)
其他信息
官方代号:ANXA1
其他别名:RP11-71A24.1、ANX1、LPC1
其他名称:膜联蛋白I(脂皮质蛋白I);膜联蛋白-1;依钙蛋白II(calpactin II);依钙蛋白-2;嗜铬粒结合蛋白-9;脂皮质蛋白I;p35;磷脂酶A2抑制蛋白
(88)V-CAM(CD106)-VCAM1(血管细胞粘附分子1)
核苷酸
Genbank登录号M60335
Genbank版本号M60335.1 GI:340193
Genbank记录更新日期:2010年6月23日上午08:56
多肽
Genbank登录号AAA61269
Genbank版本号AAA61269.1 GI:340194
Genbank记录更新日期:2010年6月23日上午08:56
交叉参考
Hession C.等J.Biol.Chem.266(11),6682-6685(1991)
其他信息
官方代号VCAM1
其他别名:CD106、INCAM-100
其他名称:CD106抗原;血管细胞粘附蛋白1
抗体序列
抗整联蛋白αvβ6
RHAB6.2
QVQLVQSGSELKKPGASVKISCKASGFAFTDSYMHWVRQAPGQGLEWMGWIDPENGDTEYAPKFQGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCTRGTPTAVPNLRGDLQVLAQKVAGPYPFDYWGQGTLVTVSS
RHCB6.2
QVQLVQSGAEVKKPGASVKVSCKASGYTFIDSYMHWVRQAPGQRLEWMGWIDPENGDTEYAPKFQGRVTITTDTSASTAYMELSSLRSEDTAVYYCARGTPTAVPNLRGDLQVLAQKVAGPYPFDYWGQGTLVTVSS
RHF
QVQLVQSGAEVKKPGASVKVSCKASGFNFIDSYMHWVRQAPGQRLEWMGWIDPENGDTEYAPKFQGRVTFTTDTSASTAYMELSSLRSEDTAVYYCNEGTPTGPYYFDYWGQGTLVTVSS
RHFB6
QVQLVQSGAEVKKPGASVKVSCKASGFNFIDSYMHWVRQAPGQRLEWMGWIDPENGDTEYAPKFQGRVTFTTDTSASTAYMELSSLRSEDTAVYYCNEGTPTAVPNLRGDLQVLAQKVAGPYYFDYWGQGTLVTVSS
RHAY100bP
QVQLVQSGSELKKPGASVKISCKASGFAFTDSYMHWVRQAPGQGLEWMGWIDPENGDTEYAPKFQGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCTRGTPTGPYPFDYWGQGTLVTVSS
RKF
ENVLTQSPGTLSLSPGERATLSCSASSSVSYMHWFQQKPGQAPRLLIYSTSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK
RKFL36L50
ENVLTQSPGTLSLSPGERATLSCSASSSVSYMHWLQQKPGQAPRLLIYLTSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK
RKC
EIVLTQSPGTLSLSPGERATLSCSASSSVSYMHWFQQKPGQAPRLLIYSTSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK
抗CD33
CD33Hum195VH
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYNMHWVRQAPGQGLEWIGYIYPYNGGTGYNQKFKSKATITADESTNTAYMELSSLRSEDTAVYYCARGRPAMDYWGQGTLVTVSS
CD33Hum195VK
DIQMTQSPSSLSASVGDRVTITCRASESVDNYGISFMNWFQQKPGKAPKLLIYAASNQGSGVPSRFSGSGSGTDFTLTISSLQPDDFATYYCQQSKEVPWTFGQGTKVEIK
抗CD19
CD19B4镶面的VH
QVQLVQPGAEVVKPGASVKLSCKTSGYTFTSNWMHWVKQRPGQGLEWIGEIDPSDSYTNYNQNFKGKAKLTVDKSTSTAYMEVSSLRSDDTAVYYCARGSNPYYYAMDYWGQGTSVTVSS
CD19B4镶面的VK
EIVLTQSPAIMSASPGERVTMTCSASSGVNYMHWYQQKPGTSPRRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEPEDAATYYCHQRGSYTFGGGTKLEIK
抗Her2
赫赛汀VH链
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS
赫赛汀VL链
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK
抗CD25
舒莱VK(还被称为巴利昔单抗(Basiliximab))
QIVSTQSPAIMSASPGEKVTMTCSASSSRSYMQWYQQKPGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCHQRSSYTFGGGTKLEIK
舒莱VH
QLQQSGTVLARPGASVKMSCKASGYSFTRYWMHWIKQRPGQGLEWIGAIYPGNSDTSYNQKFEGKAKLTAVTSASTAYMELSSLTHEDSAVYYCSRDYGYYFDFWGQGTTLTVSS
抗PSMA
去免疫VH‘1
EVQLVQSGPEVKKPGATVKISCKTSGYTFTEYTIHWVKQAPGKGLEWIGNINPNNGGTTYNQKFEDKATLTVDKSTDTAYMELSSLRSEDTAVYYCAAGWNFDYWGQGTLLTVSS
去免疫VK‘1
DIQMTQSPSSLSTSVGDRVTLTCKASQDVGTAVDWYQQKPGPSPKLLIYWASTRHTGIPSRFSGSGSGTDFTLTISSLQPEDFADYYCQQYNSYPLTFGPGTKVDIK
去免疫VH1‘5
EVKLVESGGGLVQPGGSMKLSCVASGFTFSNYWMNWVRQAPGKGLEWVAEIRSQSNNFATHYAESVKGRVTISRDDSKSIVYLQMNNLRAEDTGVYYCTRRWNNFWGQGTTVTVSS
去免疫VH2‘5
EVKLVESGGGLVQPGGSLKLSCVASGFTFSNYWMNWVRQAPGKGLEWVAEIRSQSNNFATHYAESVKGRVTISRDDSKSIVYLQMNNLRAEDTAVYYCTRRWNNFWGQGTTVTVSS
去免疫VH3‘5
EVQLVESGGGLVQPGGSLKLSCVASGFTFSNYWMNWVRQAPGKGLEWVAEIRSQSNNFATHYAESVKGRVTISRDDSKSIVYLQMNNLRAEDTAVYYCTRRWNNFWGQGTTVTVSS
去免疫VH4‘5
EVQLVESGGGLVQPGGSLKLSCVASGFTFSNYWMNWVRQAPGKGLEWVAEIRSQSNNFATHYAESVKGRFTISRDDSKSIVYLQMNNLRAEDTAVYYCTRRWNNFWGQGTTVTVSS
去免疫VK1‘5
NIVMTQFPSSMSASVGDRVTITCKASENVGTYVSWYQQKPDQSPKMLIYGASNRFTGVPDRFTGSGSATDFTLTISSLQTEDLADYYCGQSYTFPYTFGQGTKLEMK
去免疫VK2‘5
NIVMTQFPSSMSASVGDRVTITCKASENVGTYVSWYQQKPDQSPKMLIYGASNRFTGVPDRFSGSGSGTDFTLTISSLQAEDLADYYCGQSYTFPYTFGQGTKLEIK
去免疫VK3‘5
NIQMTQFPSAMSASVGDRVTITCKASENVGTYVSWYQQKPDQSPKMLIYGASNRFTGVPDRFSGSGSGTDFTLTISSLQAEDLADYYCGQSYTFPYTFGQGTKLEIK
去免疫VK4‘5
NIQMTQFPSAMSASVGDRVTITCKASENVGTYVSWYQQKPDQSPKMLIYGASNRFTGVPDRFSGSGSGTDFTLTISSLQAEDEADYYCGQSYTFPYTFGQGTKLEIK
去免疫VK DI‘5
NIVMTQFPKSMSASAGERMTLTCKASENVGTYVSWYQQKPTQSPKMLIYGASNRFTGVPDRFSGSGSGTDFILTISSVQAEDLVDYYCGQSYTFPYTFGGGTKLEMK
去免疫VH DI‘5
EVKLEESGGGLVQPGGSMKISCVASGFTFSNYWMNWVRQSPEKGLEWVAEIRSQSNNFATHYAESVKGRVIISRDDSKSSVYLQMNSLRAEDTAVYYCTRRWNNFWGQGTTVTVSS
人源化RHA‘5
EVQLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVGEIRSQSNNFATHYAESVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRRWNNFWGQGTTVTVSS
人源化RHB‘5
EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNFATHYAESVKGRVIISRDDSKNTVYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSS
人源化RHC‘5
EVQLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNFATHYAESVKGRVIISRDDSKNTVYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSS
人源化RHD‘5
EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVGEIRSQSNNFATHYAESVKGRVIISRDDSKNTVYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSS
人源化RHE‘5
EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNFATHYAESVKGRFTISRDDSKNTVYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSS
人源化RHF‘5
EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNFATHYAESVKGRVIISRDDSKNTAYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSS
人源化RHG‘5
EVKLVESGGGLVQPGGSLKLSCAASGFTFSNYWMNWVRQASGKGLEWVAEIRSQSNNFATHYAESVKGRVIISRDDSKNTAYLQMNSLRTEDTAVYYCTRRWNNFWGQGTTVTVSS
人源化RKA‘5
DIQMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKLLIYGASNRFTGVPSRFSGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK
人源化RKB‘5
DIQMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKLLIYGASNRFTGVPSRFSGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK
人源化RKC‘5
DIQMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKMLIYGASNRFTGVPSRFSGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK
人源化RKD‘5
DIQMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKMLIYGASNRFTGVPSRFSGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK
人源化RKE‘5
NIVMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKLLIYGASNRFTGVPDRFTGSGSATDFILTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK
人源化RKF‘5
NIVMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKMLIYGASNRFTGVPSRFSGSGSATDFILTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK
人源化RKG‘5
NIVMTQSPSSVSASVGDRVTITCKASENVGTYVSWYQQKPGTAPKMLIYGASNRFTGVPDRFTGSGSATDFTLTINNLQPEDFATYYCGQSYTFPYTFGQGTKVEIK
亲本抗体还可以是融合蛋白,其包含白蛋白结合肽(ABP)序列(Dennis等(2002)“Albumin Binding As A General Strategy For Improving The Pharmacokinetics OfProteins”J Biol Chem.277:35035-35043;WO 01/45746)。本发明的抗体包括融合蛋白,其具有由下述教导的ABP序列:(i)Dennis等(2002)J Biol Chem.277:35035-35043,表III和IV,35038页;(ii)US 2004/0001827,在[0076]节;以及(iii)WO 01/45746,12-13页,所有上述均以引用方式结合于本文。
在一个实施方案中,抗体已经被提升到针对肿瘤相关抗原ανβ6具有靶特异性。
可以标记细胞结合剂,例如,在加入之前,以辅助检测或纯化作为缀合物或作为缀合物的一部分的细胞结合剂。标记可以是生物素标记。在另一个实施方案中,可以用放射性同位素来标记细胞结合剂。
本发明的实施方案包括ConjA,其中细胞结合剂选自相对于上面讨论的任何抗原的抗体。
本发明的实施方案包括ConjB,其中细胞结合剂选自相对于上面讨论的任何抗原的抗体。
本发明的实施方案包括ConjCD,其中细胞结合剂选自相对于上面讨论的任何抗原的抗体。
本发明的实施方案包括ConjA,其中细胞结合剂选自上面讨论的任何抗体。
本发明的实施方案包括ConjB,其中细胞结合剂选自上面讨论的任何抗体。
本发明的实施方案包括ConjCD,其中细胞结合剂选自上面讨论的任何抗体。
本发明还可以涉及缀合物,其中细胞结合剂选自相对于上面讨论的任何抗原的抗体以及上面讨论的任何抗体连接于不同的药物。
药物负载
药物负载是PBD药物的平均数/细胞结合剂,例如抗体。在本发明的化合物结合于半胱氨酸的情况下,药物负载可以为1至8个药物(D)/细胞结合剂,即其中1、2、3、4、5、6、7、和8个药物部分共价连接于细胞结合剂。缀合物的成分包括细胞结合剂的集合,例如抗体,其缀合于1至8个药物。在本发明的化合物结合于赖氨酸的情况下,药物负载可以为1至80个药物(D)/细胞结合剂,虽然40、20、10或8的上限可以是优选的。缀合物的成分包括细胞结合剂的集合,例如抗体,其缀合于1至80、1至40、1至20、1至10或1至8个药物。
可以通过常规方法如UV、反相HPLC、HIC、质谱法、ELISA测定、和电泳来表征在来自缀合反应的ADC的制剂中的药物/抗体的平均数。还可以确定就p而言ADC的数量分布。通过ELISA,可以确定在ADC的特定制剂中p的平均值(Hamblett等(2004)Clin.Cancer Res.10:7063-7070;Sanderson等(2005)Clin.Cancer Res.11:843-852)。然而,通过ELISA的抗体-抗原结合和检测限,无法辨别p(药物)值的分布。此外,用于检测抗体-药物缀合物的ELISA测定并不确定在何处药物部分连接于抗体,如重链或轻链片段、或特定氨基酸残基。在一些情况下,可以通过方式如反相HPLC或电泳来实现其中p是一定值的均质ADC与具有其他药物负载的ADC的分离、纯化、和表征。这样的技术也适用于其他类型的缀合物。
对于一些抗体-药物缀合物,p可以受限于在抗体上连接位点的数目。例如,抗体可以仅具有一个或数个半胱氨酸巯基,或可以仅具有一个或数个足够反应性巯基,通过其可以连接接头。较高药物负载,例如p>5,可以引起某些抗体-药物缀合物的聚集、不溶性、毒性、或细胞通透性丧失。
通常,在缀合反应期间,将小于理论最大值的药物部分缀合于抗体。抗体可以包含,例如,许多赖氨酸残基,其并不与药物-接头中间体(D-L)或接头试剂反应。仅最具反应性的赖氨酸基团可以与胺-反应性接头试剂反应。同样,仅最具反应性的半胱氨酸巯基反应与巯基-反应性接头试剂可以。通常,抗体并不包含许多(如果有的话)可以连接于药物部分的游离和反应性半胱氨酸巯基。在化合物的抗体中的大多数半胱氨酸巯基残基存在为二硫桥,并且必须在部分或全部还原条件下借助于还原剂如二硫苏糖醇(DTT)或TCEP加以还原。可以以几种不同的方式来控制ADC的负载(药物/抗体比率),包括:(i)限制药物-接头中间体(D-L)或接头试剂相对于抗体的摩尔过量,(ii)限制缀合反应时间或温度,以及(iii)用于半胱氨酸巯基修饰的部分或限制还原条件。
某些抗体具有可还原的链间二硫键,即半胱氨酸桥。通过用还原剂如DTT(二硫苏糖醇)进行处理,可以使抗体对于与接头试剂的缀合具有反应性。因此,理论上,每个半胱氨酸桥将形成两个反应性巯基亲核体。可以通过赖氨酸与2-亚氨基硫杂环戊烷(特劳特试剂(Traut’s reagent))的反应来将另外的亲核基团引入抗体,从而导致将胺转化成硫醇。可以通过设计一个、两个、三个、四个、或更多半胱氨酸残基(例如,制备包含一个或多个非天然半胱氨酸氨基酸残基的突变抗体)来将反应性巯基引入抗体(或其片段)。US 7521541教导了通过引入反应性半胱氨酸氨基酸来设计抗体。
可以在抗体中的反应性位点处设计半胱氨酸氨基酸,并且其并不形成链内或分子间二硫连接(Junutula等,2008b Nature Biotech.,26(8):925-932;Dornan等(2009)Blood114(13):2721-2729;US 7521541;US 7723485;WO2009/052249)。工程半胱氨酸巯基可以与接头试剂或本发明的药物-接头试剂反应,其具有巯基反应性、亲电子基团如马来酰亚胺或α-卤代酰胺,以与半胱氨酸工程抗体和PBD药物部分形成ADC。因此可以设计、控制、和已知药物部分的位置。可以控制药物负载,这是因为工程半胱氨酸巯基通常以高产率与巯基-反应性接头试剂或药物-接头试剂反应。通过在重链或轻链上的单个位点处的替代,设计IgG抗体以引入半胱氨酸氨基酸会产生在对称抗体上的两个新的半胱氨酸。借助于缀合产物ADC的几乎均匀性,可以实现接近2的药物负载。
在抗体的多于一个的亲核或亲电子基团与药物-接头中间体或接头试剂、接着是药物部分试剂反应的情况下,那么得到的产物是ADC化合物与连接于抗体的药物部分的分布的混合物,例如1、2、3等。液相色谱法如聚合物逆相(PLRP)和疏水性相互作用(HIC)可以按照药物负载值来分离在混合物中的化合物。可以分离具有单药物负载值(p)的ADC的制剂,然而,这些单负载值ADC可能仍然是非均匀混合物,这是因为可以经由接头在抗体上的不同位点处连接药物部分。
因此,本发明的抗体-药物缀合物组合物包括抗体-药物缀合物化合物的混合物,其中抗体具有一个或多个PBD药物部分以及其中药物部分可以在不同的氨基酸残基处连接于抗体。
包括其他形式
除非另有规定,在上述中包括这些取代基的众所周知的离子、盐、溶剂化物、和受保护形式。例如,提及羧酸(-COOH)还包括阴离子(羧酸盐)形式(-COO-)、其盐或溶剂化物、以及常规的受保护形式。类似地,提及氨基则包括质子化形式(-N+HR1R2)、氨基的盐或溶剂化物,例如,盐酸盐,以及氨基的常规的受保护形式。类似地,提及羟基还包括阴离子形式(-O-)、其盐或溶剂化物、以及常规的受保护形式。
盐
可以方便或期望的是,制备、纯化、和/或处理活性化合物的相应盐,例如,药用盐。药用盐的实例讨论于Berge等,J.Pharm.Sci.,66,1-19(1977)中。
例如,如果化合物是阴离子的,或具有可以是阴离子的官能团(例如,-COOH可以是-COO-),那么可以与适宜的阳离子形成盐。适宜的无机阳离子的实例包括但不限于碱金属离子如Na+和K+,碱土阳离子如Ca2+和Mg2+,以及其他阳离子如Al+3。适宜的有机阳离子的实例包括但不限于铵离子(即NH4 +)和取代的铵离子(例如NH3R+、NH2R2 +、NHR3 +、NR4 +)。一些适宜的取代的铵离子的实例是那些取代的铵离子,其源自:乙胺、二乙胺、二环己胺、三乙胺、丁胺、乙二胺、乙醇胺、二乙醇胺、哌嗪、苄胺、苯基苄胺、胆碱、葡甲胺(meglumine)、和氨丁三醇(tromethamine)、以及氨基酸,如赖氨酸和精氨酸。常见季铵离子的实例是N(CH3)4 +。
如果化合物是阳离子的,或具有可以是阳离子的官能团(例如-NH2可以是-NH3 +),那么可以与适宜的阴离子形成盐。适宜的无机阴离子的实例包括但不限于那些无机阴离子,其源自以下无机酸:盐酸、氢溴酸、氢碘酸、硫酸、亚硫酸、硝酸、亚硝酸、磷酸、和亚磷酸。
适宜的有机阴离子的实例包括但不限于那些有机阴离子,其源自以下有机酸:2-乙酰氧基苯甲酸、乙酸、抗坏血酸、天冬氨酸、苯甲酸、樟脑磺酸、肉桂酸、柠檬酸、乙二胺四乙酸(edetic)、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖酸(glucheptonic)、葡萄糖酸、谷氨酸、乙醇酸、羟基马来酸、羟基萘羧酸、羟乙磺酸(isethionic)、乳酸、乳糖酸(lactobionic)、月桂酸、马来酸、苹果酸、甲磺酸、粘酸、油酸、酸、棕榈酸、双羟萘酸(pamoic)、泛酸、苯乙酸、苯磺酸、丙酸、丙酮酸、水杨酸、硬脂酸、琥珀酸、磺胺酸(sulfanilic)、酒石酸、甲苯磺酸、三氟乙酸和戊酸。适宜的高分子有机阴离子的实例包括但不限于那些高分子有机阴离子,其源自以下聚合酸:单宁酸(tannic acid)、羧甲基纤维素。
溶剂化物
可以是方便或期望的是,制备、纯化、和/或处理活性化合物的相应溶剂化物。术语“溶剂化物”在本文中在常规意义上用来指溶质(例如活性化合物,活性化合物的盐)和溶剂的复合物。如果溶剂是水,则溶剂化物可以被方便地称为水合物,例如,一水合物、二水合物、三水合物等。
本发明包括这样的化合物,其中溶剂添加在PBD部分的亚胺键,其在下面示出,其中溶剂是水或醇(RAOH,其中RA是C1-4烷基):
这些形式可以被称为PBD的甲醇胺和甲醇胺醚形式(如在相关于上文的R10的部分中所描述的)。这些平衡的协调取决于其中发现化合物的条件、以及部分本身的特性。
可以以固体形式来分离这些特定化合物,例如,通过冷冻干燥。
异构体
本发明的某些化合物可以存在为一种或多种特定几何形状、光学形式、对映体形式、非对映体形式、差向异构形式、阿托形式、立体异构形式、互变异构形式、构象形式、或异头形式(anomeric form),包括但不限于顺式和反式形式;E-和Z-形式;c-、t-、和r-形式;内和外形式;R-、S-、和内消旋(meso)-形式;D-和L-形式;d-和l-形式;(+)和(-)形式;酮-、烯醇-、和烯醇化物-形式;顺式(syn-)和反式(anti-);向斜-(synclinal)和反错-(anticlinal)形式;α-和β-形式;轴向和平伏形式;船-、椅-、扭转-、信封-、和半椅-形式;以及它们的组合,下文统称为“异构体”(或“异构形式”)。
术语“手性”是指这样的分子,其具有镜像配偶体的不可重叠性,而术语“非手性”是指这样的分子,其可重叠于它们的镜像配偶体。
术语“立体异构体”是指这样的化合物,其具有相同的化学组成,但差异在于原子或基团在空间中的排列。
“非对映体”是指具有两个或更多手性中心的立体异构体,以及其分子不是彼此的镜像。非对映体具有不同的物理性能,例如熔点、沸点、光谱特性、和反应性。在高拆分分析操作(如电泳和层析)下,可以分开非对映体的混合物。
“对映体”是指化合物的两种立体异构体,其彼此是不能重叠的镜像。
本文中使用的立体化学定义和惯例通常遵循S.P.Parker,Ed.,McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;以及Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc.,New York,1994。本发明的化合物可以包含不对称或手性中心,因而存在不同的立体异构形式。意图是,本发明的化合物的所有立体异构形式,包括但不限于非对映体、对映体和阻转异构体、以及它们的混合物如外消旋混合物,形成本发明的一部分。许多有机化合物存在旋光形式,即,它们具有旋转平面偏振光的平面的能力。在描述旋光化合物时,前缀D和L、或R和S用来表示分子相对于它的(一个或多个)手性中心的绝对构型。前缀d和l或(+)和(-)用来指定由化合物引起的平面偏振光的旋转符号,其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。对于给定的化学结构,这些立体异构体是相同的,不同之处在于,它们是彼此的镜像。特定立体异构体还可以被称为对映体,并且这样的异构体的混合物通常被称为对映体混合物。对映体的50:50混合物被称为外消旋混合物或外消旋物,在化学反应或过程中不存在立体选择性或立体专一性的情况下其可以发生。术语“外消旋混合物”和“外消旋物”是指两种对映体物质的等摩尔混合物(没有光学活性)。
注意,除了如下面针对互变异构形式所讨论的,如在本文中所使用的,从术语”异构体”特别排除的是结构(或组成)异构体(即这样的异构体,其差别在于在原子之间的连接,而不是仅在于原子在空间中的位置)。例如,提及甲氧基,-OCH3,并不应当被解释为提及它的结构异构体,羟甲基,-CH2OH。类似地,提及邻氯苯基不应当被解释为提及它的结构异构体,间氯苯基。然而,提及一类结构可以良好包括属于上述类的结构异构形式(例如C1-7烷基包括正丙基和异丙基;丁基包括正丁基、异丁基、仲丁基、和叔丁基;甲氧基苯基包括邻甲氧基苯基、间甲氧基苯基、和对甲氧基苯基)。
上述排除不涉及到互变异构形式,例如,酮形式、烯醇形式、和烯醇化物(烯醇盐)形式,如在,例如,以下互变异构对中:酮/烯醇(说明如下)、亚胺/烯胺、酰胺/亚氨基醇、脒/脒、亚硝基/肟、硫酮/烯硫醇、N-亚硝基/羟基偶氮、和硝基/酸式硝基。
术语“互变异构体”或“互变异构形式”是指不同能量的结构异构体,经由低能垒,其是可互相转化的。例如,质子互变异构体(还被称为质子移变互变异构体)包括经由质子迁移的相互转化,如酮-烯醇和亚胺-烯胺异构化。价互变异构体包括相互转化,其中通过一些成键电子的重组。
注意,在术语”异构体”中特别包括的是具有一个或多个同位素替代的化合物。例如,H可以处于任何同位素形式,包括1H、2H(D)、和3H(T);C可以处于任何同位素形式,包括12C、13C、和14C;O可以处于任何同位素形式,包括16O和18O;等等。
可以被加入本发明的化合物的同位素的实例包括氢、碳、氮、氧、磷、氟、和氯的同位素,如但不限于2H(氘,D)、3H(氚)、11C、13C、14C、15N、18F、31P、32P、35S、36Cl、和125I。本发明的各种同位素标记的化合物,例如那些其中加入放射性同位素如3H、13C、和14C的化合物。这样的同位素标记化合物可以用于代谢研究,反应动力学研究,检测或成像技术,如正电子发射断层扫描(PET)或单光子发射计算机断层扫描(SPECT),包括药物或底物组织分布测定法,或用于患者的放射性治疗。本发明的氘标记或取代的治疗性化合物可以具有改善的DMPK(药物代谢和药物动力学)性能,其涉及分布、代谢、和排泄(ADME)。用较重同位素如氘进行的替代可以提供某些治疗优点,其来自更大的代谢稳定性,例如增加的体内半衰期或降低的剂量需要。18F标记化合物可以用于PET或SPECT研究。通常可以通过进行在以下描述的方案中或在实施例中以及在制备中公开的程序来制备本发明的同位素标记化合物以及其前药,其中通过用容易得到的同位素标记试剂取代非同位素标记试剂。另外,用较重同位素,尤其是氘(即,2H或D)进行的替代可以提供某些治疗优点,其来自更大的代谢稳定性,例如增加的体内半衰期或降低的剂量需要或治疗指数的改善。可以理解的是,在此上下文中氘被视为取代基。可以通过同位素富集系数来定义这样的较重同位素(尤其是氘)的浓度。在本发明的化合物中,未特别指定为特定同位素的任何原子旨在表示上述原子的任何稳定的同位素。
除非另有规定,提及特定化合物则包括所有上述异构形式,包括(完全或部分地)它们的外消旋和其他混合物。用于上述异构形式的制备(例如不对称合成)和分离(例如分级结晶和层析方式)的方法是本领域中已知的或以已知的方式通过适应本文教导的方法或已知的方法而容易获得。
生物活性
体外细胞增殖测定
通常,通过以下步骤来测量抗体-药物缀合物(ADC)的细胞毒性或抑制细胞活性:在细胞培养基中,将具有受体蛋白(例如HER2)的哺乳动物细胞暴露于ADC的抗体;培养细胞约6小时至约5天;然后测量细胞生存力(存活力,viability)。基于细胞的体外测定用来测量生存力(增殖)、细胞毒性、和本发明的ADC的细胞凋亡的诱导(半胱天冬酶活化)。
可以通过细胞增殖测定来测量抗体-药物缀合物的体外效力。荧光细胞存活测定(Luminescent Cell Viability Assay)是市售的(Promega Corp.,Madison,WI),基于鞘翅目(Coleoptera)荧光素酶的重组表达的均质测定方法(美国专利号5583024、5674713和5700670)。基于存在的ATP(代谢活性细胞的指标)的定量,这种细胞增殖测定确定在培养物中的活细胞的数目(Crouch等(1993)J.Immunol.Meth.160:81-88;US6602677)。以96孔格式进行测定,从而使它适合于自动化高通量筛选(HTS)(Cree等(1995)AntiCancer Drugs 6:398-404)。均相测定程序涉及将单试剂(试剂)直接加入在补充血清的培养基中培养的细胞。不需要细胞洗涤、除去培养基和多次移液步骤。在加入试剂并混合以后的10分钟内,此系统以384孔格式检测少至15个细胞/孔。可以用ADC来连续处理细胞,或可以处理它们,然后从ADC分离。通常,简短处理(即3小时)的细胞显示和连续处理的细胞相同的效力。
均质“添加-混合-测量”形式导致细胞裂解和产生正比于ATP的存在量的发光信号。ATP的量正比于在培养物中存在的细胞的数目。测定产生“辉光型(glow-type)”发光信号,由荧光素酶反应所产生,其具有通常大于5小时的半衰期,这取决于使用的细胞类型和培养基。以相对发光单位(RLU)来反映活细胞。通过重组萤火虫荧光素酶来氧化地脱羧底物,甲虫荧光素(Beetle Luciferin),同时具有ATP到AMP的伴随转化并生成光子。
还可以通过细胞毒性测定来测量抗体-药物缀合物的体外效力。用PBS洗涤培养的贴壁细胞,用胰蛋白酶解吸,稀释在包含10%FCS的完全培养基中,离心,再悬浮在新鲜培养基中并用血细胞计数器(haemocytometer)计数。直接计数悬浮培养物。适用于计数的单分散细胞悬液可能需要通过反复抽吸来搅拌悬液以打散细胞团块。
将细胞悬液稀释至所期望的接种密度并分配(100μl/孔)到黑色96孔板。温育贴壁细胞系的板过夜以允许贴壁。在接种的当天可以使用悬浮细胞培养物。
在适当的细胞培养基中制备ADC(20μg/ml)的储备溶液(1ml)。通过连续转移100μl至900μl的细胞培养基,在15ml离心管中进行储备ADC的10倍系列稀释。
在预先平板接种有细胞悬液(100μl)的96孔黑色板中分配每个ADC稀释液(100μl)的四个重复孔,从而导致200μl的最终体积。对照孔接收细胞培养基(100μl)。
如果细胞系的倍增时间大于30小时,则ADC温育是5天,否则进行4天温育。
在温育期结束时,借助于Alamar蓝测定来评估细胞生存力。将AlamarBlue(Invitrogen)分配于整板(20μl/孔)并温育4小时。用Varioskan闪光板(flash plate)阅读器(读取器,reader),在激发570nm、发射585nm下,测量Alamar蓝荧光。细胞存活百分比计算自在ADC处理孔中的平均荧光(相比于在对照孔中的平均荧光)。
体内效力
可以通过在小鼠中的肿瘤异种移植研究来测量本发明的抗体-药物缀合物(ADC)的体内效力。例如,可以通过高表达HER2转基因外植体小鼠模型来测量本发明的抗HER2ADC的体内效力。同种异体移植物增殖自Fo5mmtv转基因小鼠,其并不响应,或较差地响应(赫赛汀)治疗。在一定的剂量水平(mg/kg)和PBD药物暴露(μg/m2)下,用ADC,以及安慰剂缓冲对照(媒介物)治疗受试者一次;然后监测两周或更长时间,以测量至肿瘤倍增、对数细胞杀死、和肿瘤收缩的时间。
用途
本发明的缀合物可以用来在目标位置提供PBD化合物。
目标位置优选是增殖细胞群体。抗体是针对存在于增殖细胞群体上的抗原的抗体。
在一个实施方案中,在非增殖细胞群体中,抗原是不存在的或以降低的水平存在(相比于在增殖细胞群体例如肿瘤细胞群体中存在的抗原量)。
在目标位置处,接头可以被切割以释放化合物RelA或RelB。因此,缀合物可以用来向目标位置选择性地提供化合物RelA或RelB。
可以通过在目标位置处存在的酶来切割接头。
目标位置可以是在体外、体内或离体。
本发明的抗体-药物缀合物(ADC)化合物包括那些具有抗癌活性利用性的化合物。尤其是,上述化合物包括这样的抗体,其缀合于,即通过接头共价连接于,PBD药物部分,即毒素。当药物没有结合于抗体时,PBD药物具有细胞毒性效应。因此,通过缀合于抗体来调节PBD药物部分的生物活性。本发明的抗体-药物缀合物(ADC)向肿瘤组织选择性地递送有效剂量的细胞毒性剂,借此可以实现更大的选择性,即更低有效剂量。
因此,在一个方面,本发明提供了如本文描述的用于治疗的缀合物化合物。
在另一方面,还提供了如本文描述的用于治疗增生性疾病的缀合物化合物。本发明的第二方面提供了缀合物化合物的应用,用于制备用来治疗增生性疾病的药物。
本领域的普通技术人员能够容易地确定候选缀合物是否治疗任何特定细胞类型的增生性病症。例如,可以方便地用来评估由特定化合物提供的活性的测定描述于以下实施例。
术语“增生性疾病”涉及过度或异常细胞的不需要的或不受控制的细胞增殖,其不是所期望的,如,肿瘤或增生性生长(无论是在体外或体内)。
增生性病症的实例包括但不限于良性、恶化前、和恶性细胞增殖,包括但不限于赘生物和肿瘤(例如组织细胞瘤、神经胶质瘤、星形细胞瘤、骨瘤)、癌症(例如肺癌、小细胞肺癌、胃肠癌、肠癌、结肠癌、乳腺癌、卵巢癌、前列腺癌、睾丸癌、肝癌、肾癌、膀胱癌、胰腺癌、脑癌、肉瘤、骨肉瘤、卡波西肉瘤、黑素瘤)、淋巴瘤、白血病、银屑癣、骨疾病、纤维增生性疾病(例如结缔组织的纤维增生性疾病)、和动脉粥样硬化。特别受关注的癌症包括但不限于白血病和卵巢癌。
可以治疗任何类型的细胞,包括但不限于肺、胃肠(包括,例如肠、结肠)、乳腺(乳房)、卵巢、前列腺、肝(肝脏)、肾(肾脏)、膀胱、胰腺、脑、和皮肤(细胞)。
在一个实施方案中,治疗是针对胰腺癌。
在一个实施方案中,治疗是针对在细胞的表面上具有ανβ6整联蛋白的肿瘤。
可以设想,本发明的抗体-药物缀合物(ADC)可以用来治疗各种疾病或病症,例如其特征是肿瘤抗原的过度表达。示例性病症或过度增生性疾病包括良性或恶性肿瘤;白血病、血液和淋巴癌。其他病症或过度增生性疾病包括神经疾病、胶质疾病、星形细胞疾病、下丘脑疾病、腺疾病、巨噬细胞疾病、上皮病症、间质疾病、囊胚腔疾病、炎症性疾病、血管生成和免疫疾病(包括自身免疫性疾病)。
通常,待治疗的疾病或病症是过度增生性疾病如癌症。本文中待治疗的癌症的实例包括但不限于癌、淋巴瘤、母细胞瘤、肉瘤、和白血病或淋巴癌。上述癌症的更具体的实例包括鳞状细胞癌(例如上皮鳞状细胞癌)、肺癌,包括小细胞肺癌、非小细胞肺癌、肺腺癌和肺鳞状癌、腹膜癌、肝细胞癌、胃癌或胃脏癌,包括胃肠癌、胰腺癌、成胶质细胞瘤、子宫颈癌、卵巢癌、肝癌、膀胱癌、肝细胞癌、乳腺癌(乳癌)、结肠癌、直肠癌、结直肠癌、子宫内膜癌或子宫癌、涎腺癌、肾癌或肾脏癌、前列腺癌、外阴癌、甲状腺癌、肝癌、肛门癌、阴茎癌,以及头颈部癌。
ADC化合物可用于治疗的自身免疫病包括风湿性疾病(如,例如,类风湿性关节炎、舍格伦综合征、硬皮病、狼疮如SLE和狼疮肾炎、多肌炎/皮肌炎、冷球蛋白血症、抗磷脂抗体综合征、和银屑病关节炎)、骨关节炎、自身免疫性胃肠和肝脏疾病(如,例如,炎性肠病(例如溃疡性结肠炎和克罗恩病)、自身免疫性胃炎和恶性贫血、自身免疫性肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、和乳糜泻)、血管炎(如,例如,ANCA相关血管炎,包括丘-斯血管炎、韦格纳肉芽肿病和多动脉炎)、自身免疫性神经系统疾病(如,例如,多发性硬化、视性眼阵挛-肌阵挛综合征、重症肌无力、视神经脊髓炎、帕金森病、阿尔茨海默病,和自身免疫性多发性神经病)、肾脏疾病(如,例如,肾小球肾炎、古德帕斯丘综合征和贝尔热病)、自身免疫性皮肤病(如,例如,银屑癣、荨麻疹、荨麻疹、寻常性天疱疮、大疱性类天疱疮、和皮肤红斑狼疮)、血液系统疾病(如,例如,血小板减少性紫癜、血栓性血小板减少性紫癜、输血后紫癜和自身免疫性溶血性贫血)、动脉粥样硬化、葡萄膜炎、自身免疫性听觉疾病(如,例如,内耳疾病和听力丧失)、贝切特氏病(Behcet’s disease)、雷诺综合症、器官移植和自身免疫性内分泌疾病(如,例如,糖尿病相关自身免疫病如胰岛素依赖型糖尿病(IDDM)、艾迪生病和自身免疫性甲状腺病(例如格雷夫斯病和甲状腺炎))。更优选的上述疾病包括,例如,类风湿性关节炎、溃疡性结肠炎、ANCA相关血管炎、狼疮、多发性硬化、舍格伦综合征、格雷夫斯病、IDDM、恶性贫血、甲状腺炎、和肾小球肾炎。
治疗方法
本发明的缀合物可以用于治疗方法。还提供了一种治疗方法,包括将治疗有效量的本发明的缀合物化合物施用给需要治疗的受试者。术语“治疗有效量”是足以对患者显示益处的量。这样的益处可以是至少改善至少一种症状。施用的实际量以及施用的速率和时程将取决于待治疗对象的特性和严重性。治疗处方,例如,对剂量的决定,是在全科医生和其他医生的责任范围内。
可以单独地或连同其他治疗一起来施用本发明的化合物(同时或相继地,其取决于待治疗的病症)。治疗和疗法的实例包括但不限于化疗(施用活性剂,包括,例如药物,如化疗剂);手术;以及放射疗法。
“化疗剂”是可用于治疗癌症的化合物,而不管作用机制。化疗剂的类别包括但不限于:烷基化剂、抗代谢物、纺锤体毒素植物生物碱、细胞毒性/抗肿瘤抗生素、拓扑异构酶抑制剂、抗体、光敏剂、和激酶抑制剂。化疗剂包括在“靶向疗法”和常规化疗中使用的化合物。
化疗剂的实例包括:厄洛替尼(Genentech/OSI Pharm.)、多西他赛(Sanofi-Aventis)、5-FU(氟尿嘧啶,5-氟尿嘧啶,CAS号51-21-8)、吉西他滨(Lilly)、PD-0325901(CAS号391210-10-9,Pfizer)、顺铂(顺式二胺,二氯铂(II),CAS号15663-27-1)、卡铂(CAS号41575-94-4)、紫杉醇(Bristol-MyersSquibb Oncology,Princeton,N.J.)、曲妥单抗(Genentech)、替莫唑胺(4-甲基-5-氧代-2,3,4,6,8-五氮杂双环[4.3.0]壬-2,7,9-三烯-9-咪唑羧酰胺,CAS号85622-93-1,Schering Plough)、他莫昔芬((Z)-2-[4-(1,2-二苯基丁-1-烯基)苯氧基]-N,N-二甲基乙胺, )、多柔比星Akti-1/2、HPPD、和雷帕霉素。
化疗剂的更多实例包括:奥沙利铂(Sanofi)、硼替佐米(Millennium Pharm.)、索坦(sutent)(SU11248,Pfizer)、来曲唑(Novartis)、甲磺酸伊马替尼(Novartis)、XL-518(Mek抑制剂,Exelixis,WO 2007/044515)、ARRY-886(Mek抑制剂,AZD6244,ArrayBioPharma,Astra Zeneca)、SF-1126(PI3K抑制剂,Semafore Pharmaceuticals)、BEZ-235(PI3K抑制剂,Novartis)、XL-147(PI3K抑制剂,Exelixis)、PTK787/ZK 222584(Novartis)、氟维司群(AstraZeneca)、甲酰四氢叶酸(亚叶酸)、雷帕霉素(西罗莫司,Wyeth)、拉帕替尼(GSK572016,Glaxo Smith Kline)、洛那法尼(lonafarnib)(SARASARTM,SCH 66336,Schering Plough)、索拉非尼(BAY43-9006,Bayer Labs)、吉非替尼(AstraZeneca)、伊立替康(CPT-11,Pfizer)、tipifarnib(ZARNESTRATM,Johnson&Johnson)、ABRAXANETM(无聚氧乙烯蓖麻油)、紫杉醇的白蛋白工程纳米颗粒制剂(AmericanPharmaceutical Partners,Schaumberg,II)、凡德他尼(rINN,ZD6474,AstraZeneca)、苯丁酸氮芥(chloranmbucil)、AG1478、AG1571(SU 5271;Sugen)、西罗莫司(Wyeth)、帕唑帕尼(GlaxoSmithKline)、堪佛司非米德(canfosfamide)(Telik)、噻替哌和环磷酰胺烷基磺酸酯如白消安、英丙舒凡和哌泊舒凡;吖丙啶如苯佐替派(benzodopa)、卡波醌、美妥替派(meturedopa)、和乌瑞替派(uredopa);乙烯亚胺和甲基密胺类(methylamelamines),包括六甲蜜胺、曲他胺(triethylenemelamine)、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲密胺;己酸配质(acetogenin)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱(包括合成类似物托泊替康);苔藓抑素;海绵他汀(callystatin);CC-1065(包括它的阿多来新、卡折来新和比折来新合成类似物);自念珠藻环肽类(cryptophycins)(尤其是自念珠藻环肽1和自念珠藻环肽8);多拉司他汀;多卡霉素(duocarmycin)(包括合成类似物,KW-2189和CB1-TM1);艾植塞洛素(eleutherobin);水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);软海绵素(spongistatin);氮芥如苯丁酸氮芥、萘氮芥、氯磷酰胺、雌莫司汀、异环磷酰胺、氮芥、盐酸氧氮芥、美法仑、新氮芥、苯芥胆甾醇、泼尼莫司汀、曲磷胺、乌拉莫司汀;亚硝基脲如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀、和雷莫司汀;抗生素如烯二炔抗生素(例如刺孢霉素、刺孢霉素γ1I、刺孢霉素ωI1(Angew Chem.Intl.Ed.Engl.(1994)33:183-186);达内霉素(dynemicin)、达内霉素A;二膦酸盐,如氯膦酸盐;埃斯波霉素;以及新制癌菌素发色团和相关色素蛋白烯二炔抗生素生色团)、阿克拉霉素、放线菌素、氨茴霉素、重氮丝氨酸、博莱霉素、放线菌素C、卡拉比星(carabicin)、洋红霉素、嗜癌菌素、色霉素、放线菌素D、柔红霉素、地托比星、6-重氮基-5-氧代-L-正亮氨酸、吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉并-多柔比星和脱氧多柔比星)、表柔比星、依索比星、伊达比星、奈莫柔比星、马塞罗霉素、丝裂霉素如丝裂霉素C、菌酚酸、诺加霉素、橄榄霉素、培洛霉素、泊非霉素、嘌呤霉素、三铁阿霉素、罗多比星、链黑菌素、链佐星、杀结核菌素、乌苯美司、净司他丁、佐柔比星;抗代谢物如氨甲蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物如二甲叶酸、氨甲蝶呤、蝶罗呤、三甲曲沙;嘌呤类似物如氟达拉滨、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物如安西他滨、阿扎胞苷、6-氮杂尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、去氧氟尿苷、依诺他滨、氟尿苷;雄激素如卡普睾酮、酸屈他雄酮、环硫雄醇、美雄烷、睾内酯;抗肾上腺如氨鲁米特、米托坦、曲洛司坦;叶酸补充剂如亚叶酸;醋葡醛内酯;醛磷酰胺糖苷;氨基乙酰丙酸;恩尿嘧啶;安吖啶;贝拉布昔(bestrabucil);比生群;依达曲沙;地磷酰胺(defofamine);秋水仙胺;地吖醌;依氟鸟氨酸;依利醋铵;一种大环内酯类抗肿瘤药;依托格鲁;硝酸镓;羟基脲;蘑菇多糖;氯尼达明(lonidainine);美登素如美登素和安丝菌素;米托胍腙;米托蒽醌;莫哌达醇(mopidanmol);尼曲吖啶(nitraerine);喷司他丁;蛋氨氮芥;吡柔比星;洛索蒽醌;鬼臼酸;2-乙基肼;甲基苄肼;多糖复合物(JHS Natural Products,Eugene,OR);雷佐生;根霉素;西佐喃;锗螺胺;细格孢氮杂酸;三亚胺醌;2,2’,2”-三氯三乙胺;单端孢菌素(尤其是T-2毒素、verracurin A、杆孢菌素A和蛇形菌素);乌拉坦;长春地辛;氮烯唑胺;甘露醇氮芥;二溴甘露醇;二溴卫矛醇;哌泊溴烷;gacytosine;阿拉伯糖苷(“Ara-C”);环磷酰胺;噻替哌;6-硫鸟嘌呤;巯基嘌呤;氨甲蝶呤;铂类似物如顺铂和卡铂;长春碱;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨诺消灵;替尼泊苷;依达曲沙;柔红霉素;氨基蝶呤;卡培他滨(Roche);伊班膦酸盐;CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视色素如维甲酸;以及任何前述项的药用盐、酸和衍生物。
在“化疗剂”的定义中还包括:(i)抗激素剂,其用来调节或抑制对肿瘤的激素作用如抗雌激素和选择性雌激素受体调节剂(SERM),包括,例如,他莫昔芬(包括枸橼酸他莫昔芬)、雷洛昔芬、屈洛昔芬、4-羟基他莫昔芬、曲沃昔芬、keoxifene、LY117018、奥那司酮、和(枸橼酸托瑞米芬);(ii)芳香酶抑制剂,它们抑制酶芳香酶,其在肾上腺中调节雌激素的生产,如,例如,4(5)-咪唑、氨鲁米特、(醋酸甲地孕酮)、(依西美坦;Pfizer)、福美坦(formestanie)、法倔唑、(伏氯唑)、(来曲唑;Novartis)、和(阿纳托唑;AstraZeneca);(iii)抗雄激素如氟他胺、尼鲁米特、比卡鲁胺、亮丙立德、和戈舍瑞林;以及曲沙他滨(1,3-二氧代戊环胞嘧啶核苷类似物);(iv)蛋白激酶抑制剂如MEK抑制剂(WO 2007/044515);(v)脂质激酶抑制剂;(vi)反义寡核苷酸,尤其是那些反义寡核苷酸,其在涉及异常细胞增殖的信号通路中抑制基因的表达,例如,PKC-α、Raf和H-Ras,如奥利默森(oblimersen)(Genta Inc.);(vii)核酶如VEGF表达抑制剂(例如,)和HER2表达抑制剂;(viii)疫苗如基因治疗疫苗,例如,和 rIL-2;拓扑异构酶1抑制剂如 rmRH;(ix)抗血管生成剂如贝伐单抗(Genentech);以及任何前述项的药用盐、酸和衍生物。
在“化疗剂”的定义中还包括治疗性抗体如阿仑单抗(Campath)、贝伐单抗(Genentech);西妥昔单抗(Imclone);帕尼单抗(Amgen)、利妥昔单抗(Genentech/Biogen Idec)、奥法木单抗(ofatumumab)(GSK)、帕妥珠单抗(PERJETATM,OMNITARGTM,2C4,Genentech)、曲妥单抗(Genentech)、托西莫单抗(Bexxar,Corixia)、和抗体药物缀合物、吉姆单抗、奥佐米星(Wyeth)。
连同本发明的缀合物一起具有作为化疗剂的治疗潜力的人源化单克隆抗体包括:阿仑单抗、阿泊珠单抗(apolizumab)、阿塞珠单抗(aselizumab)、托珠单抗(atlizumab)、巴匹珠单抗(Bapineuzumab)、贝伐单抗、比伐单抗美坦辛(bivatuzumab mertansine)、美坎珠单抗美坦辛(cantuzumab mertansine)、西利珠单抗、培舍珠单抗(certolizumab pegol)、cidfusituzumab、cidtuzumab、达克珠单抗、依库珠单抗、依法利珠单抗、依帕珠单抗、厄利珠单抗(erlizumab)、非维珠单抗、芳妥珠单抗(fontolizumab)、吉姆单抗奥佐米星、伊珠单抗(inotuzumab)、奥佐米星、伊匹木单抗(ipilimumab)、拉贝珠单抗(labetuzumab)、林妥珠单抗、马妥珠单抗、美泊利单抗、莫他珠单抗(motavizumab)、motovizumab、那他珠单抗、尼妥珠单抗、nolovizumab、numavizumab、奥瑞珠单抗(ocrelizumab)、奥马珠单抗、帕利珠单抗、帕考珠单抗(pascolizumab)、pecfusituzumab、pectuzumab、帕妥珠单抗、培克珠单抗(pexelizumab)、ralivizumab、雷珠单抗(ranibizumab)、瑞利伟珠单抗(reslivizumab)、瑞利珠单抗(reslizumab)、resyvizumab、罗维珠单抗、鲁利单抗、西罗珠单抗、西利珠单抗(siplizumab)、松妥珠单抗(sontuzumab)、他珠单抗(tacatuzumab tetraxetan)、他度珠单抗(tadocizumab)、他利珠单抗(talizumab)、特非珠单抗(tefibazumab)、托珠单抗(tocilizumab)、托利珠单抗(toralizumab)、曲妥单抗、西莫白介素单抗(tucotuzumabcelmoleukin)、tucusituzumab、umavizumab、乌珠单抗(urtoxazumab)和维西珠单抗(visilizumab)。
根据本发明和根据本发明应用的药物组合物,除活性组分(即缀合物化合物)之外,还可以包含药用赋形剂、载体、缓冲剂、稳定剂或其他材料(本领域技术人员众所周知的)。这样的材料应是无毒的并且不应干扰活性组分的功效。载体或其他材料的确切特性将取决于施用途径,其可以是口服、或通过注射,例如皮肤、皮下、或静脉内注射。
用于口服施用的药物组合物可以是片剂、胶囊剂、散剂或液体形式。片剂可以包含固体载体或佐剂。液体药物组合物通常包含液体载体如水、石油、动物或植物油、矿物油或合成油。可以包括生理盐水溶液、葡萄糖或其他糖溶液或二醇类如乙二醇、丙二醇或聚乙二醇。胶囊剂可以包含固体载体如明胶。
对于静脉内、皮肤或皮下注射、或在痛苦部位处的注射,活性组分将具有肠胃外可接受的水溶液的形式,其是无热原的并具有适宜的pH、等渗性和稳定性。利用,例如,等渗媒介物如氯化钠注射液、林格氏注射液、乳酸林格氏注射液,本领域的相关技术人员完全能够制备适宜的溶液。根据需要,可以包括防腐剂、稳定剂、缓冲剂、抗氧化剂和/或其他添加剂。
剂型
虽然可以单独地使用(例如,施用)缀合物化合物,但通常优选的是,它呈现为组合物或制剂。
在一个实施方案中,组合物是药物组合物(例如,配方、制剂、药剂),其包含如本文所描述的缀合物化合物,和药用载体、稀释剂、或赋形剂。
在一个实施方案中,组合物是药物组合物,其包含至少一种缀合物化合物(如本文所描述的),以及一种或多种其他药用成分(本领域技术人员众所周知的),包括但不限于药用载体、稀释剂、赋形剂、佐剂、填充剂、缓冲剂、防腐剂、抗氧化剂、润滑剂、稳定剂、增溶剂、表面活性剂(例如,润湿剂)、掩蔽剂、着色剂、增香剂、和甜味剂。
在一个实施方案中,组合物还包含其他活性剂,例如,其他治疗剂或预防剂。
在标准的制药教科书中可以找到适宜的载体、稀释剂、赋形剂等。见,例如,Handbook of Pharmaceutical Additives,2nd Edition(eds.M.Ash and I.Ash),2001(Synapse Information Resources,Inc.,Endicott,New York,USA),Remington's Pharmaceutical Sciences,20th edition,pub.Lippincott,Williams&Wilkins,2000;以及Handbook of Pharmaceutical Excipients,第2版,1994。
本发明的另一个方面涉及用于制备药物组合物的方法,该方法包括混合至少一种[11C]放射性标记缀合物或结合样化合物(如本文中所定义的)、以及一种或多种其他药用成分(本领域技术人员众所周知的),例如,载体、稀释剂、赋形剂等。如果配制成离散的单位(例如,片剂等),则每个单位含有预定量(剂量)的活性化合物。
如在本文中所使用的,术语“药用”涉及化合物、成分、材料、组合物、剂型等,在合理的医学判断的范围内,其适合与所考虑的受试者(例如,人)的组织接触,而没有过度的毒性、刺激、变态反应、或其他问题或并发症,并与合理的利益/风险比相应。在与制剂的其他成分相容的意义上,载体、稀释剂、赋形剂等各自也必须是“可接受的”。
可以通过药学领域中众所周知的任何方法来制备剂型。这样的方法包括以下步骤:使活性化合物与载体(其构成一种或多种辅助成分)结合在一起。通常,通过使活性化合物与载体(例如,液体载体、细分固体载体等)均匀且紧密地结合在一起,然后将产品成形(如果需要的话),来制备剂型。
可以制备剂型以提供快速或缓慢释放;立即、延迟、定时、或持续释放;或它们的组合。
适用于胃肠外施用(例如,通过注射)的剂型包括水性或非水性的、等渗的、无热原的、无菌液体(例如,溶液、悬浮液),其中溶解、悬浮、或以其他方式(例如,在脂质体或其他微颗粒中)提供活性组分。这样的液体可以另外包含其他药用成分,如抗氧化剂、缓冲剂、防腐剂、稳定剂、抑菌剂、悬浮剂、增稠剂、和溶质,其使制剂与预定接受者的血液(或其他相关体液)等渗。赋形剂的实例包括,例如,水、醇(alcohol)、多元醇、甘油、植物油等。用于上述剂型的适宜的等渗载体的实例包括氯化钠注射液、林格氏液、或乳酸林格氏注射液。通常,在液体中活性组分的浓度为约1ng/ml至约10μg/ml,例如约10ng/ml至约1μg/ml。可以以单位剂量或多剂量密封容器,例如,安瓿和小瓶,来提供剂型,并且可以存储在冷冻干燥(冻干)条件下,从而仅需要在使用前立即添加无菌液体载体,例如注射用水。即时注射溶液和悬浮液可以制备自无菌散剂、颗粒剂、和片剂。
剂量
本领域技术人员将理解的是,缀合物化合物和包含缀合物化合物的组合物的适当剂量可以因患者而异。确定最佳剂量一般将涉及治疗效益水平相对于任何危险或有害副作用的平衡。选择的剂量水平将取决于多种因素,包括但不限于特定化合物的活性,施用途径,施用时间,化合物的排泄速率,治疗的持续时间,联合使用的其他药物、化合物、和/或材料,病症的严重程度,以及患者的物种、性别、年龄、体重、状况、一般健康、和以前的医疗史。化合物的量和施用途径最终将由医师、兽医、或临床医师决定,虽然通常将选择剂量以在作用部位处达到局部浓度,其达到预期的效果而没有引起实质性的有害或有毒的副作用。
在整个治疗过程中,可以以一次剂量、连续或间歇地(例如,以分开的剂量并以适当的间隔)进行施用。用于确定施用的最有效方式和剂量的方法是本领域技术人员众所周知的并且将随用于治疗的剂型、治疗的目的、待治疗的(一个或多个)靶细胞、和待治疗的受试者而变化。借助于由治疗医师、兽医、或临床医师选择的剂量水平和模式可以进行单次或多次施用。
通常,活性化合物的适宜剂量为约100ng至约25mg(更通常地为约1μg至约10mg)/千克受试者体重/天。在活性化合物是盐、酯、酰胺、前药等的情况下,基于母体化合物来计算施用的量,所以按比例增加待使用的实际重量。
在一个实施方案中,按照以下剂量方案:约100mg,每日3次,将活性化合物施用给人患者。
在一个实施方案中,按照以下剂量方案:约150mg,每日2次,将活性化合物施用给人患者。
在一个实施方案中,按照以下剂量方案:约200mg,每日2次,将活性化合物施用给人患者。
然而,在一个实施方案中,按照以下剂量方案:约50或约75mg,每日3或4次,将缀合物化合物施用给人患者。
在一个实施方案中,按照以下剂量方案:约100或约125mg,每日2次,将缀合物化合物施用给人患者。
上文描述的剂量可以适用于缀合物(包括PBD部分和与抗体的接头)或适用于有效量的提供的PBD化合物,例如在接头的切割以后可释放的化合物的量。
对于疾病的预防或治疗,本发明的ADC的适当剂量将取决于待治疗的疾病的类型(如上文所定义的),疾病的严重程度和病程(不管出于预防或治疗的目的来施用分子),以前的治疗,患者的临床病史和对抗体的响应,以及主治医生的判断力。在某个时候或在一系列治疗中,将分子适当地施用给患者。取决于疾病的类型和严重程度,约1μg/kg至15mg/kg(例如0.1-20mg/kg)的分子是用于施用给患者的初始候选剂量,而不论,例如,通过一次或多次单独的施用、或通过连续输注。典型的每日剂量可以为约1μg/kg至100mg/kg或更多,其取决于上述因素。待施用给患者的ADC的示例性剂量为约0.1至约10mg/kg患者体重。对于经数天或更长时间的重复施用,取决于病症,持续治疗直到发生疾病症状的所期望的抑制。示例性剂量方案包括施用约4mg/kg的初始负载剂量,接着每周、两周、或三周另外剂量的ADC。其他剂量方案可以是有用的。通过常规技术和测定,容易监测这种疗法的进展。
治疗
如在本文治疗病症的上下文中所使用的,术语“治疗”一般涉及治疗和疗法,而不论是人或动物(例如,在兽医应用中),其中达到一些所期望的治疗效果,例如,病症的进展的抑制,并且包括进展速率的降低、进展速率的停止、病症的消退、病症的改善、和病症的治愈。还包括作为预防措施(即,防治、预防)的治疗。
如在本文中所使用的,术语“治疗有效量”涉及活性化合物、或材料、组合物或包含活性化合物的剂量(形式)的量,当按照所期望的治疗方案施用时,其可有效地产生一些所期望的治疗效果,并平衡合理的利益/风险比。
类似地,如在本文中所使用的,术语“预防有效量”涉及活性化合物、或材料、组合物或包含活性化合物的剂量(形式)的量,当按照所期望的治疗方案施用时,其可有效地产生一些所期望的预防效果,并平衡合理的利益/风险比。
药物缀合物的制备
可以通过几种途径,采用本领域技术人员已知的有机化学反应、条件、和试剂,包括抗体或细胞结合剂的亲核基团与药物-接头试剂的反应,来制备抗体药物缀合物,以及具有其他细胞结合剂的缀合物。可以借助于各种抗体和细胞结合剂来采用这种方法以制备本发明的抗体-药物缀合物。
在抗体上的亲核基团包括但不限于侧链巯基,例如半胱氨酸。巯基是亲核的并且能够反应以与在接头部分(如本发明的那些接头部分)上的亲电子基团形成共价键。某些抗体具有可还原的链间二硫键,即半胱氨酸桥。通过还原剂如DTT(Cleland试剂,二硫苏糖醇)或TCEP(三(2-羧基乙基)膦盐酸盐;Getz等(1999)Anal.Biochem.Vol 273:73-80;SoltecVentures,Beverly,MA)进行处理,可以使抗体对于与接头试剂缀合具有反应性。因此,理论上,每个半胱氨酸二硫桥将形成两个反应性巯基亲核体。可以通过赖氨酸与2-亚氨基硫杂环戊烷(特劳特试剂)的反应来将另外的亲核基团引入抗体,从而导致胺转化成硫醇(thiol)。
受试者/患者
受试者/患者可以是动物、哺乳动物、胎盘哺乳动物、有袋目哺乳动物(例如,袋鼠、袋熊)、单孔类动物(例如,鸭嘴兽)、啮齿动物(例如,豚鼠、仓鼠、大鼠、小鼠)、鼠(例如,小鼠)、兔类动物(例如,兔)、禽(例如,鸟)、犬科动物(例如,狗)、猫科动物(例如,猫)、马科动物(例如,马)、猪(例如,猪)、绵羊(例如,羊)、牛科动物(例如,奶牛)、灵长目动物、类人猿(例如,猴或猿猴)、猴(例如,绒、狒狒)、猿(例如,大猩猩、黑猩猩、猩猩、长臂猿)、或人。
此外,受试者/患者可以是它的任何发育形式,例如,胎儿。在一个优选的实施方案中,受试者/患者是人。
在一个实施方案中,患者是群体,其中每个患者具有肿瘤,其具有在细胞的表面上的ανβ6整联蛋白。
实施例
用于实施例1和2的一般实验方法
用ADP 220旋光仪(Bellingham Stanley Ltd.)来测量旋光性并以g/100mL为单位来给出浓度(c)。利用数字熔点仪(Electrothermal)来测量熔点。用Perkin-ElmerSpectrum 1000 FT IR光谱仪(Spectrometer)来记录IR谱。在300K下,利用Bruker AvanceNMR分光计并分别在400和100MHz下获得1H和13C NMR谱。相对于TMS(δ=0.0ppm)来报告化学位移,并且信号被指定为s(单峰)、d(双重峰)、t(三重峰)、dt(双三重峰)、dd(双重峰的双重峰)、ddd(双重峰的双双重峰(double doublet of doublets))或m(多重峰),其中以赫兹(Hz)为单位来给出耦合常数。利用耦合于具有Waters 2996 PDA的Waters 2695 HPLC的Waters Micromass ZQ仪器来收集质谱法(MS)数据。使用的Waters Micromass ZQ参数是:毛细管(kV),3.38;锥体(V),35;提取器(V),3.0;源温度(℃),100;去溶剂化温度(℃),200;锥形流动速率(L/h),50;去溶剂化流动速率(L/h),250。用Waters Micromass QTOF Global并以正W模式来记录高分辨率质谱法(HRMS)数据,其中利用金属涂覆的硼硅酸盐玻璃尖端来将样品引入仪器。用硅胶铝板(Merck 60,F254)进行薄层层析(TLC),以及快速层析采用硅胶(Merck 60,230-400目ASTM)。除了HOBt(NovaBiochem)和固体支撑试剂(Argonaut)以外,所有其他化学品和溶剂均购买自Sigma-Aldrich并以所提供的状态加以使用而没有进一步纯化。在干燥氮气气氛下,并在存在适当的干燥剂的条件下,通过蒸馏来制备无水溶剂,然后经分子筛或钠线(sodium wire)加以存储。石油醚是指在40-60℃下沸腾的级分。
一般的LC/MS条件:利用水(A)(甲酸0.1%)和乙腈(B)(甲酸0.1%)的流动相来运行HPLC(Waters Alliance 2695)。梯度:初始组成5%B经1.0分钟,然后5%B至95%B,经2.5分钟。在95%B下保持上述组成0.5分钟,然后在0.1分钟内回到5%B并保持0.9分钟。总梯度运行时间等于5分钟。流动速率3.0mL/分钟,经由通入质谱仪的零死体积丁字管(zero deadvolume tee piece)来分开400μL。波长检测范围:220至400nm。功能类型:二极管阵列(535扫描)。柱:Onyx Monolithic C18 50×4.60mm。
实施例1
(i)(S)-(2-氨基-5-甲氧基-4-((三异丙基甲硅烷基)氧基)苯基)(2-(((叔丁基二
甲基甲硅烷基)氧基)甲基)-4-甲基-2,3-二氢-1H-吡咯-1-基)甲酮(9)
(a)5-甲氧基-2-硝基-4-((三异丙基甲硅烷基)氧基)苯甲醛(2)
将纯三异丙基甲硅烷基氯(56.4mL,262mmol)加入咪唑(48.7g,715.23mmol)和4-羟基-5-甲氧基-2-硝基苯甲醛1(47g,238mmol)(研磨在一起)的混合物。加热混合物直到苯酚和咪唑熔化并进入溶液(100℃)。允许搅拌反应混合物15分钟,然后允许冷却,随后观察到在烧瓶的底部形成固体(咪唑氯)。用5%EtOAc/己烷来稀释反应混合物并直接加载到硅胶上,然后用5%EtOAc/己烷,接着10%EtOAc/己烷,对垫(pad)加以洗脱(由于低过量,在产物中发现很少的未反应的TIPSCl)。用在己烷中的5%乙酸乙酯来洗脱所期望的产物。在减压下通过旋转蒸发来除去过量洗脱液,接着在高真空下干燥以提供结晶光敏感固体(74.4g,88%)。LC/MS满意的纯度(4.22分钟(ES+)m/z(相对强度)353.88([M+H]+.,100));1HNMR(400MHz,CDCl3)δ10.43(s,1H),7.60(s,1H),7.40(s,1H),3.96(s,3H),1.35–1.24(m,3H),1.10(m,18H)。
(b)5-甲氧基-2-硝基-4-((三异丙基甲硅烷基)氧基)苯甲酸(3)
在室温下,将亚氯酸纳(47.3g,523mmol,80%工业级)和磷酸二氢钠(35.2g,293mmol)(NaH2PO4)在水(800mL)中的溶液加入化合物2(74g,209mmol)在四氢呋喃(500mL)中的溶液。将过氧化氢(60%w/w,140mL,2.93mol)立即加入剧烈搅拌的双相混合物。反应混合物逸出气体(氧气),起始材料被溶解,并且反应混合物的温度上升到45℃。在30分钟以后,LC/MS显示反应完成。在冰浴中冷却反应混合物并添加盐酸(1M)以降低pH至3(在许多情况下发现此步骤是不必要的,这是因为在反应结束时pH已经是酸性的;在提取以前,请检查pH)。然后用乙酸乙酯(1L)提取反应混合物并用盐水(2×100mL)洗涤有机相,然后经硫酸镁干燥。过滤有机相,然后在减压下通过旋转蒸发来除去过量溶剂,以提供定量产率的呈黄色固体的产物6。LC/MS(3.93分钟(ES-)m/z(相对强度)367.74([M-H]-.,100));1H NMR(400MHz,CDCl3)δ7.36(s,1H),7.24(s,1H),3.93(s,3H),1.34–1.22(m,3H),1.10(m,18H)。
(c)((2S,4R)-2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-羟基吡咯烷-1-基)(5-甲氧基-2-硝基-4-((三异丙基甲硅烷基)氧基)苯基)甲酮(5)
在0℃下将DCC(29.2g,141mmol,1.2当量)加入酸3(43.5g,117.8mmol,1当量)和羟基苯并三唑水合物(19.8g,129.6mmol,1.1当量)在二氯甲烷(200mL)中的溶液。除去冷浴并在室温下允许反应进行30分钟,此时在-10℃下并在氩气下,快速添加(2S,4R)-2-t-丁基二甲基甲硅氧基甲基-4-羟基吡咯烷4(30g,129.6mmol,1.1当量)和三乙胺(24.66mL,176mmol,1.5当量)在二氯甲烷(100mL)中的溶液(在大规模上,可以通过甚至进一步冷却反应混合物来缩短加入时间)。在室温下允许搅拌反应混合物40分钟至1小时并通过LC/MS和TLC(EtOAc)加以监测。通过经C盐的过滤来除去固体,然后用冷含水0.1M HCl来洗涤有机相,直到pH被测得为4或5。然后用水、接着饱和碳酸氢钠水溶液和盐水来洗涤有机相。经硫酸镁干燥有机层,过滤并在减压下通过旋转蒸发来除去过量溶剂。对残留物进行柱快速层析(硅胶;梯度40/60乙酸乙酯/已烷至80/20乙酸乙酯/已烷)。在减压下通过旋转蒸发来除去过量溶剂,从而得到纯产物13(45.5g的纯产物,66%,以及17g的稍微不纯的产物,总共90%)。LC/MS 4.43分钟(ES+)m/z(相对强度)582.92([M+H]+.,100);1H NMR(400MHz,CDCl3)δ7.66(s,1H),6.74(s,1H),4.54(s,1H),4.40(s,1H),4.13(s,1H),3.86(s,3H),3.77(d,J=9.2Hz,1H),3.36(dd,J=11.3,4.5Hz,1H),3.14–3.02(m,1H),2.38–2.28(m,1H),2.10(ddd,J=13.3,8.4,2.2Hz,1H),1.36–1.19(m,3H),1.15–1.05(m,18H),0.91(s,9H),0.17–0.05(m,6H),(旋转异构体的存在)。
(d)(S)-5-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-(5-甲氧基-2-硝基-4-((三异丙基甲硅烷基)氧基)苯甲酰基)吡咯烷-3-酮(6)
在0℃下将TCCA(8.82g,40mmol,0.7当量)加入5(31.7g,54mmol,1当量)和TEMPO(0.85g,5.4mmol,0.1当量)在无水二氯甲烷(250mL)中的搅拌溶液。剧烈搅拌反应混合物20分钟,此时TLC(50/50乙酸乙酯/已烷)揭示起始材料的完全消耗。通过C盐(celite)来过滤反应混合物,并用水饱和碳酸氢钠(100mL)、硫代硫酸钠(9g,在300mL中)、盐水(100mL)来洗涤滤液,然后经硫酸镁干燥。在减压下的旋转蒸发得到定量产率的产物6。LC/MS 4.52分钟(ES+)m/z(相对强度)581.08([M+H]+.,100);1H NMR(400MHz,CDCl3)δ7.78–7.60(m,1H),6.85–6.62(m,1H),4.94(dd,J=30.8,7.8Hz,1H),4.50–4.16(m,1H),3.99–3.82(m,3H),3.80–3.34(m,3H),2.92–2.17(m,2H),1.40–1.18(m,3H),1.11(t,J=6.2Hz,18H),0.97–0.75(m,9H),0.15–-0.06(m,6H),(旋转异构体的存在)。
(e)(S)-5-(((叔丁基二甲基甲硅烷基)氧基)甲基)-1-(5-甲氧基-2-硝基-4-((三异丙基甲硅烷基)氧基)苯甲酰基)-4,5-二氢-1H-吡咯-3-基三氟甲磺酸酯(7)
在-50℃(丙酮/干冰浴)下,在存在2,6-二甲基吡啶(25.6mL,23.5g,220mmol,4当量,经分子筛干燥)的情况下,将三氟甲磺酸酐(27.7mL,46.4g,165mmol,3当量)注入(温度受控)酮6(31.9g,55mmol,1当量)在无水二氯甲烷(900mL)中的剧烈搅拌悬浮液。允许搅拌反应混合物1.5小时,其时LC/MS,在小型后处理(水/二氯甲烷)以后,揭示了反应完成。将水加入依然冷的反应混合物并分离有机层,然后用饱和碳酸氢钠、盐水和硫酸镁加以洗涤。过滤有机相并在减压下通过旋转蒸发来除去过量溶剂。对残留物进行柱快速层析(硅胶;10/90v/v乙酸乙酯/已烷),除去过量洗脱液,从而得到产物7(37.6g,96%)。LC/MS,方法2,4.32分钟(ES+)m/z(相对强度)712.89([M+H]+.,100);1H NMR(400MHz,CDCl3)δ7.71(s,1H),6.75(s,1H),6.05(d,J=1.8Hz,1H),4.78(dd,J=9.8,5.5Hz,1H),4.15–3.75(m,5H),3.17(ddd,J=16.2,10.4,2.3Hz,1H),2.99(ddd,J=16.3,4.0,1.6Hz,1H),1.45–1.19(m,3H),1.15–1.08(m,18H),1.05(s,6H),0.95–0.87(m,9H),0.15–0.08(m,6H)。
(f)(S)-(2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-甲基-2,3-二氢-1H-吡咯-1-基)(5-甲氧基)2-硝基-4-((三异丙基甲硅烷基)氧基)苯基)甲酮(8)
在氩气氛下,将三苯胂(1.71g,5.60mmol,0.4当量)加入三氟甲磺酸酯7(10.00g,14mmol,1当量)、甲基硼酸(2.94g,49.1mmol,3.5当量)、氧化银(13g,56mmol,4当量)和磷酸钾(17.8g,84mmol,6当量)在无水二氧杂环己烷(80mL)中的混合物。用氩气冲洗反应3次,然后添加二(苄腈)钯(II)氯化物(540mg,1.40mmol,0.1当量)。在被立即升温到110℃(在加入烧瓶以前,drysyn加热块被预先加热到110℃)以前,用氩气再冲洗反应3次。在10分钟以后,将反应冷却至室温,然后通过C盐垫加以过滤。在减压下,通过旋转蒸发来除去溶剂。对得到的残留物进行柱快速层析(硅胶;10%乙酸乙酯/已烷)。在减压下通过旋转蒸发来除去溶剂。对得到的残留物进行柱快速层析(硅胶;10%乙酸乙酯/已烷)。收集并合并纯级分,然后在减压下通过旋转蒸发来除去过量洗脱液,从而得到产物8(4.5g,55%)。LC/MS,4.27分钟(ES+)m/z(相对强度)579.18([M+H]+.,100);1H NMR(400MHz,CDCl3)δ7.70(s,1H),6.77(s,1H),5.51(d,J=1.7Hz,1H),4.77–4.59(m,1H),3.89(s,3H),2.92–2.65(m,1H),2.55(d,J=14.8Hz,1H),1.62(d,J=1.1Hz,3H),1.40–1.18(m,3H),1.11(s,9H),1.10(s,9H),0.90(s,9H),0.11(d,J=2.3Hz,6H)。
(g)(S)-(2-氨基-5-甲氧基-4-((三异丙基甲硅烷基)氧基)苯基)(2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-甲基-2,3-二氢-1H-吡咯-1-基)甲酮(9)
在约15℃下,将锌粉(28g,430mmol,37当量)加入在5%甲酸中的化合物8(6.7g,11.58mmol)在乙醇v/v(70mL)中的溶液。利用冰浴来控制产生的放热以保持反应混合物的温度低于30℃。在30分钟以后,通过C盐垫来过滤反应混合物。用乙酸乙酯来稀释滤液并用水、饱和碳酸氢钠水溶液和盐水来洗涤有机相。经硫酸镁干燥有机相,过滤,然后在减压下通过旋转蒸发来除去过量溶剂。对产生的残留物进行快速柱层析(硅胶;10%乙酸乙酯,在己烷中)。收集并合并纯级分并在减压下通过旋转蒸发来除去过量溶剂,以提供产物9(5.1g,80%)。LC/MS,4.23分钟(ES+)m/z(相对强度)550.21([M+H]+.,100);1H NMR(400MHz,CDCl3)δ7.28(s,1H),6.67(s,1H),6.19(s,1H),4.64–4.53(m,J=4.1Hz,1H),4.17(s,1H),3.87(s,1H),3.77–3.69(m,1H),3.66(s,3H),2.71–2.60(m,1H),2.53–2.43(m,1H),2.04–1.97(m,J=11.9Hz,1H),1.62(s,3H),1.26–1.13(m,3H),1.08–0.99(m,18H),0.82(s,9H),0.03–-0.03(m,J=6.2Hz,6H)。
(ii)(11S,11aS)-烯丙基11-((叔丁基二甲基甲硅烷基)氧基)-8-((5-碘代戊基)
氧基)-7-甲氧基-2-甲基-5-氧代-11,11a-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂
-10(5H)-羧酸酯
(a)(S)-烯丙基(2-(2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-甲基-2,3-二氢-1H-吡咯-1-羰基)-4-甲氧基-5-((三异丙基甲硅烷基)氧基)苯基)氨基甲酸酯(10)
在-78℃(丙酮/干冰浴)下,在存在无水吡啶(dry pyridine)(0.48mL,6.00mmol,2.2当量)的情况下,将氯甲酸烯丙酯(0.30mL,3.00mmol,1.1当量)加入胺9(1.5g,2.73mmol)在无水二氯甲烷(20mL)中的溶液。在30分钟以后,除去浴并允许反应混合物升温至室温。用二氯甲烷稀释反应混合物并添加饱和硫酸铜水溶液。然后依次用饱和碳酸氢钠水溶液和盐水来洗涤有机层。经硫酸镁干燥有机相,过滤,然后在减压下通过旋转蒸发来除去过量溶剂,以提供产物10,其直接用于下一反应。LC/MS,4.45分钟(ES+)m/z(相对强度)632.91([M+H]+.,100)
(b)(S)-烯丙基(2-(2-(羟甲基)-4-甲基-2,3-二氢-1H-吡咯-1-羰基)-4-甲氧基-5-((三异丙基甲硅烷基)氧基)苯基)氨基甲酸酯(11)
将粗10溶解于乙酸/甲醇/四氢呋喃/水(28:4:4:8mL)的7:1:1:2混合物并允许在室温下搅拌。在3小时以后,通过LC/MS,观察到起始材料的完全消失。用乙酸乙酯稀释反应混合物,然后依次用水(2×500mL)、饱和碳酸氢钠水溶液(200mL)和盐水加以洗涤。经硫酸镁干燥有机相,过滤并在减压下通过旋转蒸发来除去多余的乙酸乙酯。对产生的残留物进行快速柱层析(硅胶,25%乙酸乙酯,在己烷中)。收集并合并纯级分并在减压下通过旋转蒸发来除去过量洗脱液,以提供所期望的产物11(1g,71%)。LC/MS,3.70分钟(ES+)m/z(相对强度)519.13([M+H]+.,95);1H NMR(400MHz,CDCl3)δ8.34(s,1H),7.69(s,1H),6.78(s,1H),6.15(s,1H),5.95(ddt,J=17.2,10.5,5.7Hz,1H),5.33(dq,J=17.2,1.5Hz,1H),5.23(ddd,J=10.4,2.6,1.3Hz,1H),4.73(tt,J=7.8,4.8Hz,1H),4.63(dt,J=5.7,1.4Hz,2H),4.54(s,1H),3.89–3.70(m,5H),2.87(dd,J=16.5,10.5Hz,1H),2.19(dd,J=16.8,4.6Hz,1H),1.70(d,J=1.3Hz,3H),1.38–1.23(m,3H),1.12(s,10H),1.10(s,8H)。
(c)(11S,11aS)-烯丙基11-羟基-7-甲氧基-2-甲基-5-氧代-8-((三异丙基甲硅烷基)氧基)-11,11a-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯(12)
在-78℃(干冰/丙酮浴)下,在氩气气氛下,将二甲亚砜(0.35mL,4.83mmol,2.5当量)逐滴加入草酰氯(0.2mL,2.32mmol,1.2当量)在无水二氯甲烷(10mL)中的溶液。在10分钟以后,缓慢添加11(1g,1.93mmol)在无水二氯甲烷(8mL)中的溶液,其中温度仍然在-78℃下。在15分钟以后,滴加三乙胺(1.35mL,经分子筛干燥,9.65mmol,5当量),然后除去干冰/丙酮浴。允许反应混合物达到室温,然后用冷盐酸(0.1M)、饱和碳酸氢钠水溶液和盐水加以提取。经硫酸镁干燥有机相,过滤,然后在减压下通过旋转蒸发来除去多余的二氯甲烷,以提供产物12(658mg,66%)。LC/MS,3.52分钟(ES+)m/z(相对强度)517.14([M+H]+.,100);1H NMR(400MHz,CDCl3)δ7.20(s,1H),6.75–6.63(m,J=8.8,4.0Hz,2H),5.89–5.64(m,J=9.6,4.1Hz,2H),5.23–5.03(m,2H),4.68–4.38(m,2H),3.84(s,3H),3.83–3.77(m,1H),3.40(s,1H),3.05–2.83(m,1H),2.59(d,J=17.1Hz,1H),1.78(d,J=1.3Hz,3H),1.33–1.16(m,3H),1.09(d,J=2.2Hz,9H),1.07(d,J=2.1Hz,9H)。
(d)(11S,11aS)-烯丙基11-((叔丁基二甲基甲硅烷基)氧基)-7-甲氧基-2-甲基-5-氧代-8-((三异丙基甲硅烷基)氧基)-11,11a-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯(13)
在0℃并在氩气下,将叔丁基二甲基甲硅烷基三氟甲磺酸酯(0.70mL,3.00mmol,3当量)加入化合物12(520mg,1.00mmol)和2,6-二甲基吡啶(0.46mL,4.00mmol,4当量)在无水二氯甲烷(40mL)中的溶液。在10分钟以后,除去冷浴并在室温下搅拌反应混合物1小时。用水、饱和碳酸氢钠水溶液和盐水来提取反应混合物。经硫酸镁干燥有机相,过滤并在减压下通过旋转蒸发来除去过量。对产生的残留物进行快速柱层析(硅胶;梯度,在己烷中的10%乙酸乙酯至在己烷中的20%乙酸乙酯)。收集并合并纯级分并在减压下通过旋转蒸发来除去过量洗脱液,以得到产物13(540mg,85%)。LC/MS,4.42分钟(ES+)m/z(相对强度)653.14([M+Na]+.,100);1H NMR(400MHz,CDCl3)δ7.20(s,1H),6.71–6.64(m,J=5.5Hz,2H),5.83(d,J=9.0Hz,1H),5.80–5.68(m,J=5.9Hz,1H),5.14–5.06(m,2H),4.58(dd,J=13.2,5.2Hz,1H),4.36(dd,J=13.3,5.5Hz,1H),3.84(s,3H),3.71(td,J=10.1,3.8Hz,1H),2.91(dd,J=16.9,10.3Hz,1H),2.36(d,J=16.8Hz,1H),1.75(s,3H),1.31–1.16(m,3H),1.12–1.01(m,J=7.4,2.1Hz,18H),0.89–0.81(m,9H),0.25(s,3H),0.19(s,3H)。
(e)(11S,11aS)-烯丙基11-((叔丁基二甲基甲硅烷基)氧基)-8-羟基-7-甲氧基-2-甲基-5-氧代-11,11a-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯(14)
将乙酸锂(87mg,0.85mmol)加入化合物13(540mg,0.85mmol)在湿二甲基甲酰胺(6mL,50:1DMF/水)的溶液。在4小时以后,反应完成并用乙酸乙酯(25mL)稀释反应混合物,然后用柠檬酸水溶液(pH~3)、水和盐水加以洗涤。经硫酸镁干燥有机层,过滤并在减压下通过旋转蒸发来除去多余的乙酸乙酯。对产生的残留物进行快速柱层析(硅胶;梯度,25%至75%乙酸乙酯,在己烷中)。收集并合并纯级分并在减压下通过旋转蒸发来除去过量洗脱液,以得到产物14(400mg,定量的)。LC/MS,(3.33分钟(ES+)m/z(相对强度)475.26([M+H]+,100)。
(f)(11S,11aS)-烯丙基11-((叔丁基二甲基甲硅烷基)氧基)-8-((5-碘代戊基)氧基)-7-甲氧基-2-甲基-5-氧代-11,11a-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂10(5H)-羧酸酯(15)
将二碘代戊烷(0.63mL,4.21mmol,5当量)和碳酸钾(116mg,0.84mmol,1当量)加入苯酚14(400mg,0.84mmol)在丙酮(4mL,经分子筛干燥)中的溶液。然后加热反应混合物至60℃并搅拌6小时。在减压下通过旋转蒸发来除去丙酮。对产生的残留物进行快速柱层析(硅胶;50/50,v/v,己烷/乙酸乙酯)。收集并合并纯级分并除去过量洗脱液,以提供产率为90%的15。LC/MS,3.90分钟(ES+)m/z(相对强度)670.91([M]+,100).1H NMR(400MHz,CDCl3)δ7.23(s,1H),6.69(s,1H),6.60(s,1H),5.87(d,J=8.8Hz,1H),5.83–5.68(m,J=5.6Hz,1H),5.15–5.01(m,2H),4.67–4.58(m,1H),4.45–4.35(m,1H),4.04–3.93(m,2H),3.91(s,3H),3.73(td,J=10.0,3.8Hz,1H),3.25–3.14(m,J=8.5,7.0Hz,2H),2.92(dd,J=16.8,10.3Hz,1H),2.38(d,J=16.8Hz,1H),1.95–1.81(m,4H),1.77(s,3H),1.64–1.49(m,2H),0.88(s,9H),0.25(s,3H),0.23(s,3H)。
(iii)(11S,11aS)-4-(2-(1-((1-(烯丙氧基)-4-甲基-1,2-二氧代戊-3-基)氨
基)-1-氧代丙-2-基)肼基)苄基11-((叔丁基二甲基甲硅烷基)氧基)-8-羟基-7-甲氧基-2-
甲基-5-氧代-11,11a-二氢-1H-苯并[e]吡并[1,2-a][1,4]二氮杂
-10(5H)-羧酸酯(20)
(a)3-(2-(2-(4-((((2-((S)-2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-甲基-2,3-二氢-1H-吡咯-1-羰基)-4-甲氧基-5-((三异丙基甲硅烷基)氧基)苯基)氨基甲酰基)氧基)甲基)苯基)肼基)丙酰胺基)-4-甲基-2-氧代戊酸烯丙酯(16)
在5℃(冰浴)下,将三乙胺(2.23mL,18.04mmol,2.2当量)加入胺9(4g,8.20mmol)和三光气(778mg,2.95mmol,0.36当量)在无水四氢呋喃(40mL)中的搅拌溶液。通过从反应混合物定期取出等分试样,用甲醇骤冷并进行LC/MS分析,来监测异氰酸酯反应的进展。一旦完成异氰酸酯形成以后,通过注射,将alloc-Val-Ala-PABOH(4.12g,12.30mmol,1.5当量)和三乙胺(1.52mL,12.30mmol,1.5当量)在无水四氢呋喃(40mL)的溶液快速加入新鲜制备的异氰酸酯。允许在40℃下搅拌反应混合物4小时。在减压下通过旋转蒸发来除去过量溶剂。对产生的残留物进行快速柱层析(硅胶;梯度,1%甲醇至5%甲醇,在二氯甲烷中)。(利用EtOAc和己烷的可替代层析条件也已是成功的)。收集并合并纯级分并在减压下通过旋转蒸发来除去过量洗脱液,以得到产物16(3.9g,50%)。LC/MS,4.23分钟(ES+)m/z(相对强度)952.36([M+H]+.,100);1H NMR(400MHz,CDCl3)δ8.62(br s,1H),8.46(s,1H),7.77(br s,1H),7.53(d,J=8.4Hz,2H),7.32(d,J=8.5Hz,2H),6.76(s,1H),6.57(d,J=7.6Hz,1H),6.17(s,1H),6.03–5.83(m,1H),5.26(dd,J=33.8,13.5Hz,3H),5.10(s,2H),4.70–4.60(m,2H),4.58(dd,J=5.7,1.3Hz,2H),4.06–3.99(m,1H),3.92(s,1H),3.82–3.71(m,1H),3.75(s,3H),2.79–2.64(m,1H),2.54(d,J=12.9Hz,1H),2.16(dq,J=13.5,6.7Hz,1H),1.67(s,3H),1.46(d,J=7.0Hz,3H),1.35–1.24(m,3H),1.12(s,9H),1.10(s,9H),0.97(d,J=6.8Hz,3H),0.94(d,J=6.8Hz,3H),0.87(s,9H),0.07–-0.02(m,6H)。
(b)3-(2-(2-(4-((((2-((S)-2-(羟甲基)-4-甲基-2,3-二氢-1H-吡咯-1-羰基)-4-甲氧基-5-((三异丙基甲硅烷基)氧基)苯基)氨基甲酰基)氧基)甲基)苯基)肼基)丙酰胺基)-4-甲基-2-氧代戊酸烯丙酯(17)
将TBS醚16(1.32g,1.38mmol)溶解于乙酸/甲醇/四氢呋喃/水(14:2:2:4mL)的7:1:1:2混合物并允许在室温下搅拌。在3小时以后,通过LC/MS,观察不到更多的起始材料。用乙酸乙酯(25mL)稀释反应混合物,然后依次用水、饱和碳酸氢钠水溶液和盐水加以洗涤。经硫酸镁干燥有机相,过滤,然后在减压下通过旋转蒸发来除去多余的乙酸乙酯。对产生的残留物进行快速柱层析(硅胶,2%甲醇,在二氯甲烷中)。收集并合并纯级分并在减压下通过旋转蒸发来除去过量洗脱液,以提供所期望的产物17(920mg,80%)。LC/MS,3.60分钟(ES+)m/z(相对强度)838.18([M+H]+.,100).1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.35(s,1H),7.68(s,1H),7.52(d,J=8.1Hz,2H),7.31(d,J=8.4Hz,2H),6.77(s,1H),6.71(d,J=7.5Hz,1H),6.13(s,1H),5.97–5.82(m,J=5.7Hz,1H),5.41–5.15(m,3H),5.10(d,J=3.5Hz,2H),4.76–4.42(m,5H),4.03(t,J=6.6Hz,1H),3.77(s,5H),2.84(dd,J=16.7,10.4Hz,1H),2.26–2.08(m,2H),1.68(s,3H),1.44(d,J=7.0Hz,3H),1.30(dt,J=14.7,7.4Hz,3H),1.12(s,9H),1.10(s,9H),0.96(d,J=6.8Hz,3H),0.93(d,J=6.8Hz,3H)。
(c)(11S,11aS)-4-(2-(1-((1-(烯丙氧基)-4-甲基-1,2-二氧代戊-3-基)氨基)-1-氧代丙-2-基)肼基)苄基11-羟基-7-甲氧基-2-甲基-5-氧代-8-((三异丙基甲硅烷基)氧基)-11,11a-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯(18)
在-78℃(干冰/丙酮浴)和氩气气氛下,将二甲亚砜(0.2mL,2.75mmol,2.5当量)逐滴加入草酰氯(0.11mL,1.32mmol,1.2当量)在无水二氯甲烷(7mL)中的溶液。在10分钟以后,缓慢添加17(920mg,1.10mmol)在无水二氯甲烷(5mL)中的溶液,其中温度仍然在-78℃下。在15分钟以后,滴加三乙胺(0.77mL,经分子筛干燥,5.50mmol,5当量)并除去干冰/丙酮浴。允许反应混合物达到室温并用冷盐酸(0.1M)、饱和碳酸氢钠水溶液和盐水加以提取。经硫酸镁干燥有机相,过滤,然后在减压下通过旋转蒸发来除去多余的二氯甲烷。对产生的残留物进行柱快速层析(硅胶;梯度2%甲醇至5%甲醇,在二氯甲烷中)。收集并合并纯级分,然后在减压下通过旋转蒸发来除去过量洗脱液,以得到产物18(550mg,60%)。LC/MS,3.43分钟(ES+)m/z(相对强度)836.01([M]+.,100).1H NMR(400MHz,CDCl3)δ8.39(s,1H),7.52–7.40(m,2H),7.21–7.08(m,J=11.5Hz,2H),6.67(s,1H),6.60–6.47(m,J=7.4Hz,1H),5.97–5.83(m,1H),5.79–5.66(m,1H),5.38–4.90(m,6H),4.68–4.52(m,J=18.4,5.5Hz,4H),4.04–3.94(m,J=6.5Hz,1H),3.87–3.76(m,5H),3.00–2.88(m,1H),2.66–2.49(m,2H),2.21–2.08(m,2H),1.76(s,3H),1.45(d,J=7.0Hz,3H),1.09–0.98(m,J=8.9Hz,18H),0.96(d,J=6.7Hz,3H),0.93(d,J=6.9Hz,3H)。
(d)(11S,11aS)-4-(2-(1-((1-(烯丙氧基)-4-甲基-1,2-二氧代戊-3-基)氨基)-1-氧代丙-2-基)肼基)苄基11-((叔丁基二甲基甲硅烷基)氧基)-7-甲氧基-2-甲基-5-氧代-8-((三异丙基甲硅烷基)氧基)-11,11a-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂10(5H)-羧酸酯(19)
在0℃和氩气下,将叔丁基二甲基甲硅烷基三氟甲磺酸酯(0.38mL,1.62mmol,3当量)加入化合物18(450mg,0.54mmol)和2,6-二甲基吡啶(0.25mL,2.16mmol,4当量)在无水二氯甲烷(5mL)中的溶液。在10分钟以后,除去冷浴并在室温下搅拌反应混合物1小时。用水、饱和碳酸氢钠水溶液和盐水来提取反应混合物。经硫酸镁干燥有机相,过滤,然后在减压下通过旋转蒸发来除去过量溶剂。对产生的残留物进行柱快速层析(硅胶;50/50v/v己烷/乙酸乙酯)。收集并合并纯级分并在减压下通过旋转蒸发来除去过量洗脱液,以得到产物19(334mg,65%)。LC/MS,4.18分钟(ES+)m/z(相对强度)950.50([M]+.,100).1H NMR(400MHz,CDCl3)δ8.53(s,1H),8.02(s,1H),7.44(d,J=7.6Hz,2H),7.21(s,1H),7.08(d,J=8.2Hz,2H),6.72–6.61(m,J=8.9Hz,2H),6.16(s,1H),5.97–5.79(m,J=24.4,7.5Hz,2H),5.41–5.08(m,5H),4.86(d,J=12.5Hz,1H),4.69–4.60(m,1H),4.57(s,1H),4.03(t,J=6.7Hz,1H),3.87(s,3H),3.74(td,J=9.6,3.6Hz,1H),2.43–2.09(m,J=34.8,19.4,11.7Hz,3H),1.76(s,3H),1.43(d,J=6.9Hz,3H),1.30–1.21(m,3H),0.97(d,J=6.7Hz,3H),0.92(t,J=8.4Hz,3H),0.84(s,9H),0.23(s,3H),0.12(s,3H)。
(e)(11S,11aS)-4-(2-(1-((1-(烯丙氧基)-4-甲基-1,2-二氧代戊-3-基)氨基)-1-氧代丙-2-基)肼基)苄基11-((叔丁基二甲基甲硅烷基)氧基)-8-羟基-7-甲氧基-2-甲基-5-氧代-11,11a-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-羧酸酯(20)
将乙酸锂(50mg,0.49mmol)加入化合物19(470mg,0.49mmol)在湿二甲基甲酰胺(4mL,50:1DMF/水)中的溶液。在4小时以后,反应完成并用乙酸乙酯稀释反应混合物,然后用柠檬酸(pH~3)、水和盐水加以洗涤。经硫酸镁干燥有机层,过滤并在减压下通过旋转蒸发来除去多余的乙酸乙酯。对产生的残留物进行柱快速层析(硅胶;梯度,50/50至25/75v/v己烷/乙酸乙酯)。收集并合并纯级分并在减压下通过旋转蒸发来除去过量洗脱液,以得到产物20(400mg,定量的)。LC/MS,3.32分钟(ES+)m/z(相对强度)794.18([M+H]+.,100).1HNMR(400MHz,CDCl3)δ8.53(s,1H),8.02(s,1H),7.44(d,J=7.6Hz,2H),7.21(s,1H),7.08(d,J=8.2Hz,2H),6.72–6.61(m,J=8.9Hz,2H),6.16(s,1H),5.97–5.79(m,J=24.4,7.5Hz,2H),5.41–5.08(m,5H),4.86(d,J=12.5Hz,1H),4.69–4.60(m,1H),4.57(s,1H),4.03(t,J=6.7Hz,1H),3.87(s,3H),3.74(td,J=9.6,3.6Hz,1H),2.43–2.09(m,J=34.8,19.4,11.7Hz,3H),1.76(s,3H),1.43(d,J=6.9Hz,3H),1.30–1.21(m,3H),0.97(d,J=6.7Hz,3H),0.92(t,J=8.4Hz,3H),0.84(s,9H),0.23(s,3H),0.12(s,3H)。
(iv)(11S)-4-(2-(1-((1-氨基-3-甲基-1-氧代丁-2-基)氨基)-1-氧代丙-2-基)
肼基)苄基11-羟基-7-甲氧基-8-((5-((7-甲氧基-2-甲基-5-氧代-5,11a-二氢-1H-苯并
[e]吡咯并[1,2-a][1,4]二氮杂
-8-基)氧基)戊基)氧基)-2-甲基-5-氧代-11,11a-二
氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂
-10(5H)-羧酸酯(23)
将氟化四正丁基铵(1M,0.34mL,0.34mmol,2当量)加入21(230mg,0.172mmol)在无水四氢呋喃(3mL)中的溶液。在10分钟以后,起始材料被完全消耗。用乙酸乙酯(30mL)稀释反应混合物并
[M+H]+。1H NMR(400MHz,CDCl3)δ7.04(br s,1H),3.78(t,J=6.0Hz,2H,),3.74(s,2H),3.68–3.64(m,28H),3.60–3.56(m,2H),3.46(dd,J=10.2Hz,5.3Hz,2H),2.61(t,J=6.0Hz,2H)。
(b)1-溴-2-氧代-6,9,12,15-八氧杂-3-氮杂三十烷-30-酸(26)
将溴乙酸酐(0.065g,0.249mmol,1.1当量)在无水DCM(1mL)中的溶液加入在DCM(1mL)中的氨基-PEG(8)-酸24(0.100g,0.226mmol,1.0当量)。在黑暗中并在室温下搅拌混合物4小时。用5%柠檬酸、水来洗涤反应混合物,经MgSO4干燥,过滤并在减压下浓缩。通过快速层析(硅胶,3%MeOH和0.1%甲酸,在氯仿中,至10%MeOH和0.1%甲酸,在氯仿中)来纯化残留物,以得到得到产物,作为浅橙色油(0.050g,39%)。LC/MS(1.08分钟(ES+))(体系1),m/z:562.20[M]+564.15[M+2]+。1H NMR(400MHz,CDCl3)δ7.28(br s,1H),3.87(s,2H),3.76(t,J=6.1Hz,2H),3.68–3.60(m,28H),3.60–3.56(m,2H),3.47(dd,J=10.3Hz,5.2Hz,2H),2.59(t,J=6.1Hz,2H)。
用于步骤(vi)和(vii)的一般实验方法
利用具有Shimadzu LCMS-2020四极MS的Shimadzu Nexera系列LC/MS,并借助于电喷射离子化,来获得LC/MS数据。流动相A-0.1%甲酸,在水中。流动相B-0.1%甲酸,在乙腈中。流动速率为0.80ml/min。梯度,经2.00分钟,从5%B上升到100%B,保持在100%B下,时间为0.50分钟,然后经0.05分钟回落到5%B(保持0.45分钟)。总运行时间是3分钟。柱:Waters,Aquity UPLC BEH Shield RP18 1.7μm,2.1×50mm;(体系1)。
或者,梯度,经10.00分钟,从5%B上升到100%B,保持在100%B下2.00分钟,然后经0.10分钟回落到5%B(保持2.90分钟)。总运行时间是15分钟。柱:Phenomenex,Gemini-NX3u C18 110A,100×2.00mm;(体系2)。
层析图基于在254nm处的UV检测。利用MS并以正模式来获得质谱。
在具有UV/VIS检测器(SPD-20A)和级分收集器(FRC-10A)的HPLC系统(ShimadzuProminence系列)上进行HPLC分析。流动相A-0.1%甲酸,在水中。流动相B-0.1%甲酸,在乙腈中。梯度(适用于分析型系统和制备型系统)经15.00分钟,从0%B上升到100%B,保持在100%B下,时间为2.00分钟,然后经1.10分钟回落到13%B。分析型分析,柱:Phenomenex,Gemini-NX 5μC18 110A,150×4.60mm并且流速为1.00ml/min(体系3)。制备型分析,柱:Phenomenex,Gemini-NX 5μC18 110A,150×21.20mm并且流速为20.00ml/min(体系4)。
(vi)(11S,11aS)-4-((32S,35S)-1-碘-32-异丙基-35-甲基-2,30,33-三氧代-6,
9,12,15-八氧杂-3,31,34-三氮杂三十六烷酰胺基)苄基11-羟基-7-甲氧基-8-((5-(((S)-
7-甲氧基-2-甲基-5-氧代-5,11a-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂
-8-基)
氧基)戊基)氧基)-2-甲基-5-氧代-11,11a-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂
-10(5H)-羧酸酯(27,A)
将N,N′-二异丙基碳二亚胺(DIC,9.22μL,0.059mmol,1.1当量)加入胺23(0.054mmol,1.1当量)和碘-(PEG)8-酸25(39.6mg,0.065mmol,1.2当量)在无水二氯甲烷(5mL)中的溶液。搅拌反应过夜直至通过LC/MS不再观察到起始材料的存在。用二氯甲烷稀释反应并依次用水和盐水加以洗涤。经硫酸镁干燥有机相,过滤,并在减压下通过旋转蒸发来除去多余的二氯甲烷。对产生的残留物进行快速柱层析(硅胶;100%氯仿至5%甲醇,在氯仿中)。收集并合并含有产物的级分并且在减压下通过旋转蒸发来除去过量洗脱液,然后将其用反相制备型HPLC(体系4)进行进一步纯化。将纯级分用收集器收集,合并,并冻干所需的产物,得到27,A(15.8mg,19%,历经3个步骤)。LC-MS,体系1,1.44分钟(ES+)m/z1513.60[M+H]+。1H NMR(400MHz,CDCl3)δ8.82(s,1H),7.92–7.78(m,1H),7.64(d,J=7.0Hz,2H),7.50(s,1H),7.23–6.98(m,6H),6.81(s,1H),6.75(s,1H),6.69(s,1H),6.46(s,1H),5.76(d,J=8.3Hz,1H),5.32(m,1H),4.73(d,J=11.3Hz,1H),4.67–4.54(m,1H),4.42(brs,1H),4.32–4.19(m,2H),4.18–3.99(m,4H),3.91(s,3H),3.87(s,3H),3.84–3.76(m,3H),3.71(s,2H),3.70–3.58(m,28H),3.56(dd,J=10.1,5.1Hz,2H),3.43(dd,J=10.0,5.1Hz,1H),3.25–3.12(m,1H),3.06–2.87(m,2H),2.73-2.41(m,4H),2.33–1.97(m,3H),1.96–1.71(m,4H),1.84(s,3H),1.78(s,3H),1.71–1.51(m,2H),1.49–1.22(m,3H),1.07–0.85(m,6H)。
(vii)(11S,11aS)-4-((32S,35S)-1-溴-32-异丙基-35-甲基-2,30,33-三氧代-6,
9,12,15-八氧杂-3,31,34-三氮杂三十六烷酰胺基)苄基11-羟基-7-甲氧基-8-((5-(((S)-
7-甲氧基-2-甲基-5-氧代-5,11a-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂
-8-基)
氧基)戊基)氧基)-2-甲基-5-氧代-11,11a-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂
-10(5H)-羧酸酯(28,B)
将N,N′-二异丙基碳二亚胺(DIC,9.22μL,0.059mmol,1.1当量)加入胺23(0.054mmol,1.1当量)和溴-(PEG)8-酸26(36.5mg,0.065mmol,1.2当量)在无水二氯甲烷(5mL)中的溶液。搅拌反应过夜直至通过LC/MS不再观察到起始材料的存在。用二氯甲烷稀释反应并依次用水和盐水加以洗涤。经硫酸镁干燥有机相,过滤,并在减压下通过旋转蒸发来除去多余的二氯甲烷。用反相制备型HPLC(体系4)纯化产生的残留物。将纯级分用收集器收集,合并,并冻干所需的产物,得到28,D(26.6mg,33%,历经3个步骤)。LC-MS,体系1,1.44分钟(ES+)m/z 1466.85[M]+。1H NMR(400MHz,CDCl3)δ8.82(s,1H),7.87(s,1H),7.64(d,J=7.0Hz,2H),7.50(s,1H),7.23–6.98(m,6H),6.81(s,1H),6.74(s,1H),6.69(s,1H),6.45(s,1H),5.75(d,J=9.2Hz,1H),5.32(d,J=11.2Hz,1H),4.72(d,J=11.7Hz,1H),4.68–4.52(m,1H),4.35(br s,1H),4.32–4.17(m,2H),4.17–3.99(m,4H),3.90(s,3H),3.87(s,3H),3.84–3.74(m,3H),3.72–3.58(m,32H),3.46(dd,J=10.1,5.1Hz,2H),3.25–3.09(m,1H),3.05–2.84(m,2H),2.75–2.40(m,3H),2.34–1.98(m,3H),1.96–1.71(m,4H),1.83(s,3H),1.77(s,3H),1.67–1.52(m,2H),1.48–1.20(m,3H),1.09–0.88(m,6H)。
用于实施例2的一般实验方法
通过薄层层析(TLC)来监测反应进展,其中利用Merck Kieselgel 60 F254硅胶,并借助于在铝板上的荧光指示剂。除非另有说明,借助于UV光或碘蒸气来实现TLC的可视化。利用Merck Kieselgel 60 F254硅胶来进行快速层析。购买和使用来自FisherScientific,U.K.的提取和层析溶剂而没有进一步纯化。所有化学品均购买自Aldrich、Lancaster或BDH。
在δ规模上,在400MHz处,利用Bruker AV400,来测量质子NMR化学位移值。使用了以下缩写:s,单峰;d,双重峰;t,三重峰;q,四重峰;quin,五重峰;m,多重峰;br,宽。以Hz为单位来报告耦合常数。除非另有说明,用Merck Kieselgel二氧化硅(Art.9385)进行柱层析(通过快速程序)。利用耦合于Waters 2795 HPLC分离模块的Waters Micromass LCT仪器来收集质谱法(MS)数据。用硅胶铝板(Merck 60,F254)进行薄层层析(TLC)。所有其他化学品和溶剂以所提供的状态加以使用而没有进一步纯化。
利用具有Shimadzu LCMS-2020四极MS的Shimadzu Nexera系列LC/MS,并借助于电喷射离子化,来获得LCMS数据。流动相A-0.1%甲酸,在水中。流动相B-0.1%甲酸,在乙腈中。流动速率为0.80ml/分钟。梯度,经2.00分钟,从5%B上升到100%B,保持在100%B下,时间为0.50分钟,然后经0.05分钟回落到5%B(保持0.45分钟)。总运行时间是3分钟。柱:Waters Aquity UPLC BEH Shield RP18 1.7μm,2.1×50mm;(体系1)。
或,梯度,经10.00分钟,从5%B上升到100%B,保持在100%B下2.00分钟,然后经0.10分钟回落到5%B(保持2.90分钟)。总运行时间是15分钟。柱:Gemini-NX 3u C18 110A,100×2.00mm;(体系2)。
层析图基于在254nm处的UV检测。利用MS并以正模式来获得质谱。
实施例2
(i)(S)-((戊烷-1,5-二基双(氧基))双(2-氨基-5-甲氧基-4,1-亚苯基))双
(((S)-2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-甲基-2,3-二氢-1H-吡咯-1-基)甲酮)
(35)
(a)(S,R)-((戊烷-1,5-二基双(氧基))双(5-甲氧基-2-硝基-4,1-亚苯基))双(((2S,4R)-2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-羟基吡咯烷-1-基)甲酮)(31)
将无水DMF(大约0.5mL)逐滴加入4,4'-(戊烷-1,5-二基双(氧基))双(5-甲氧基-2-硝基苯甲酸)(29)(36.64g,74.0mmol)和草酰氯(18.79mL,0.222mol,3.0当量)在无水DCM(450mL)中的搅拌悬浮液直至发生剧烈起泡然,后保持搅拌反应混合物过夜。蒸发反应混合物至干燥,并用乙醚加以研磨。在-40℃下,从溶液过滤产生的黄色沉淀,用乙醚(100mL)加以洗涤并立即加入(3R,5S)-5-((叔丁基二甲基甲硅烷基氧基)甲基)吡咯烷-3-醇(30)(39.40g,0.170mol,2.3当量)和无水三乙胺(82.63mL,0.592mol,8当量)在无水DCM(400mL)中的溶液。允许反应混合物缓慢升温至室温(经2.5小时),其后,LCMS分析表明完全反应。添加DCM(250mL)并将混合物转移到分液漏斗。相继用0.1M HCl(2×800mL)、饱和NaHCO3(500mL)和盐水(300mL)洗涤有机层。在经MgSO4干燥和过滤以后,溶剂的蒸发留下产物,呈黄色泡沫(62.8g,92%)。LC/MS,体系1:RT 1.96分钟;MS(ES+)m/z(相对强度)921.45([M+H]+,100)。
(b)(5S,5'S)-1,1'-(4,4'-(戊烷-1,5-二基双(氧基))双(5-甲氧基-2-硝基苯甲酰基))双(5-(((叔丁基二甲基甲硅烷基)氧基)甲基)吡咯烷-3-酮)(32)
在氩气气氛和0℃下,将三氯异氰脲酸(21.86g,94.07mmol,1.4当量)一次性加入加入二醇31(61.90g,67.20mmol)和TEMPO(2.10g,13.44mmol,0.2当量)在无水DCM(500mL)中的溶液。在0℃下,搅拌反应混合物20分钟,其后,反应混合物的LCMS分析显示完全反应。用DCM(400mL)稀释反应混合物,并用饱和碳酸氢钠(500mL)、0.2M硫代硫酸钠溶液(600mL)、盐水(400mL)加以洗涤,然后干燥(MgSO4)。溶剂的蒸发产生粗制产物。快速层析[梯度洗脱80%正己烷/20%乙酸乙酯至100%乙酸乙酯]产生纯32,呈黄色固体(49.30g,80%)。LC/MS,体系1:RT 2.03分钟;MS(ES+)m/z(相对强度)917.55([M+H]+,100)。
(c)(5S,5'S)-1,1'-(4,4'-(戊烷-1,5-二基双(氧基))双(5-甲氧基-2-硝基苯甲酰基))双(5-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4,5-二氢-1H-吡咯-3,1-二基)双(三氟甲磺酸酯)(33)
在-40℃下,将三氟甲磺酸酐(24.19mL,0.144mol,6.0当量)逐滴加入双酮32(21.98g,23.96mmol)在无水DCM(400mL)(包含2,6-二甲基吡啶(22.33mL,0.192mol,8.0当量))中的剧烈搅拌溶液。在-40℃下,搅拌反应混合物30分钟,其后,LCMS分析表明完全反应。用DCM(500mL)快速稀释反应混合物并用冰冷水(600mL)、冰冷饱和碳酸氢钠(400mL)和盐水(500mL)加以洗涤,经MgSO4干燥,过滤并蒸发,以留下粗制棕色油。快速层析[梯度洗脱80%正己烷/20%乙酸乙酯至66%正己烷/33%乙酸乙酯]得到纯33,呈棕色泡沫(16.40g,58%)。LC/MS,体系1:RT 2.28分钟;MS(ES+)m/z(相对强度),无数据。
(d)(S)-((戊烷-1,5-二基双(氧基))双(5-甲氧基-2-硝基-4,1-亚苯基))双(((S)-2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-甲基-2,3-二氢-1H-吡咯-1-基)甲酮(34)
将三氟甲磺酸酯33(5.06g,4.29mmol)、甲基硼酸(1.80g,30.00mmol,7当量)和三苯胂(1.05g,3.43mmol,0.8当量)溶解于无水二氧杂环己烷并在氩气下搅拌。然后添加Pd(II)二苄腈氯化物并快速加热反应混合物至80℃,时间为20分钟。冷却反应混合物,通过C盐过滤(通过用乙酸乙酯加以洗涤),用水(500mL)、盐水(500mL)来洗涤滤液,经MgSO4干燥,过滤和蒸发。快速层析[梯度洗脱50%正己烷/50%乙酸乙酯]得到纯34,呈棕色泡沫(4.31g,59%)。LC/MS,体系1:RT 2.23分钟;MS(ES+)m/z(相对强度)913.50([M+H]+,100)。
(e)(S)-((戊烷-1,5-二基双(氧基))双(2-氨基-5-甲氧基-4,1-亚苯基))双(((S)-2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-甲基-2,3-二氢-1H-吡咯-1-基)甲酮)(35)
以1份将锌粉(26.48g,0.405mol,36.0当量)加入二硝基化合物34(10.26g,11.24mmol)在5%甲酸/甲醇(200mL)中的溶液,同时借助于冷水浴将温度保持为25-30℃。在30℃下搅拌反应20分钟,其后,LCMS显示完全反应。通过C盐来过滤反应混合物以除去过量的锌,用乙酸乙酯(600mL)对其加以洗涤。用水(500mL)、饱和碳酸氢钠(500mL)和盐水(400mL)来洗涤有机级分,经MgSO4干燥并蒸发。快速层析[梯度洗脱100%氯仿至99%氯仿/1%甲醇]得到纯35,呈橙色泡沫(6.22g,65%)。LC/MS,体系1:RT 2.20分钟;MS(ES+)m/z(相对强度)853.50([M+H]+,100)。
(ii)4-((R)-2-((R)-2-(((烯丙氧基)羰基)氨基)-3-甲基丁酰胺基)丙酰胺基)苄
基4-((10R,13R)-10-异丙基-13-甲基-8,11-二氧代-2,5-二氧杂-9,12-二氮杂十四烷酰胺
基)苄基((S)-(戊烷-1,5-二基双(氧基))双(2-((S)-2-(羟基甲基)-4-甲基-2,3-二氢-1H-
吡咯-1-羰基)-4-甲氧基-5,1-亚苯基))二氨基甲酸酯(40)
(a)(5-((5-(5-氨基-4-((S)-2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-甲基-2,3-二氢-1H-吡咯-1-羰基)-2-甲氧基苯氧基)戊基)氧基)-2-((S)-2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-甲基-2,3-二氢-1H-吡咯-1-羰基)-4-甲氧基苯基)氨基甲酸烯丙酯(36)
在-78℃和氩气气氛下,将吡啶(1.156mL,14.30mmol,1.5当量)加入双苯胺35(8.14g,9.54mmol)在无水DCM(350mL)中的溶液。在5分钟以后,添加氯甲酸烯丙酯(0.911mL,8.58mmol,0.9当量)并允许反应混合物升温至室温。用DCM(250mL)稀释反应混合物,用饱和CuSO4溶液(400mL)、饱和碳酸氢钠(400mL)和盐水(400mL)加以洗涤,经MgSO4干燥。快速层析[梯度洗脱66%正己烷/33%乙酸乙酯至33%正己烷/66%乙酸乙酯]得到纯36,呈橙色泡沫(3.88g,43%)。LC/MS,体系1:RT 2.27分钟;MS(ES+)m/z(相对强度)937.55([M+H]+,100)。
(b)4-((10S,13S)-10-异丙基-13-甲基-8,11-二氧代-2,5-二氧杂-9,12-二氮杂十四烷酰胺基)苄基((S)-(戊烷-1,5-二基双(氧基))双(2-((S)-2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-甲基-2,3-二氢-1H-吡咯-1-羰基)-4-甲氧基-5,1-亚苯基))二氨基甲酸烯丙酯(37)
在氩气和0℃下,将三乙胺(0.854mL,6.14mmol,2.2当量)加入苯胺36(2.62g,2.79mmol)和三光气(0.30g,1.00mmol,0.36当量)在无水THF(50mL)中的搅拌溶液。在室温下搅拌反应混合物5分钟。对用甲醇加以骤冷的等分试样进行的LCMS分析显示形成异氰酸酯。将mPEG2-Val-Ala-PAB-OH(1.54g,3.63mmol,1.3当量)和三乙胺(0.583mL,4.19mmol,1.5当量)在无水THF(50mL)中的溶液一次性加入,并在40℃下将产生的混合物搅拌过夜。将反应混合物的溶剂蒸发,留下粗制产物。快速层析[梯度洗脱100%氯仿至98%氯仿/2%甲醇]产生纯37,呈淡橙色固体(2.38g,62%)。LC/MS,体系1:RT 2.29分钟;MS(ES+)m/z(相对强度)无数据。
(c)4-((10S,13S)-10-异丙基-13-甲基-8,11-二氧代-2,5-二氧杂-9,12-二氮杂十四烷酰胺基)苄基(5-((5-(5-氨基-4-((S)-2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-甲基-2,3-二氢-1H-吡咯-1-羰基)-2-甲氧基苯氧基)戊基)氧基)-2-((S)-2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-甲基-2,3-二氢-1H-吡咯-1-羰基)-4-甲氧基苯基)氨基甲酸酯(38)
在氩气和室温下,将四(三苯基膦)钯(39mg,0.034mmol,0.02当量)加入37(2.35g,1.69mmol)和吡咯烷(0.35mL,4.24mmol,2.5当量)在无水DCM(25mL)中的搅拌溶液。允许搅拌反应混合物45分钟,然后用DCM(100mL)稀释,用饱和氯化铵溶液(100mL)、盐水(100mL)洗涤,经MgSO4干燥,过滤并蒸发。快速层析[梯度洗脱100%氯仿至95%氯仿/5%甲醇]产生纯38,呈黄色固体(1.81g,82%)。LC/MS,体系1:RT 2.21分钟;MS(ES+)m/z(相对强度)1303.65([M+H]+,100)。
(d)4-((R)-2-((R)-2-(((烯丙氧基)羰基)氨基)-3-甲基丁酰胺基)丙酰胺基)苄基4-((10R,13R)-10-异丙基-13-甲基-8,11-二氧代-2,5-二氧杂-9,12-二氮杂十四烷酰胺基)苄基((S)-(戊烷-1,5-二基双(氧基))双(2-((S)-2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-4-甲基-2,3-二氢-1H-吡咯-1-羰基)-4-甲氧基-5,1-亚苯基))二氨基甲酸酯(39)
在氩气和0℃下,将三乙胺(0.419mL,3.01mmol,2.2当量)加入苯胺38(1.78g,1.37mmol)和三光气(0.15g,0.49mmol,0.36当量)在无水THF(50mL)中的搅拌溶液。在室温下搅拌反应混合物5分钟。对用甲醇加以骤冷的等分试样进行的LCMS分析显示形成异氰酸酯。将Alloc-Val-Ala-PAB-OH(0.67g,1.78mmol,1.3当量)和三乙胺(0.29mL,2.05mmol,1.5当量)在无水THF(45mL)中的溶液一次性加入,并在40℃下将产生的混合物搅拌过夜。将反应混合物的溶剂蒸发,留下粗制产物。快速层析[梯度洗脱100%乙酸乙酯至97%乙酸乙酯/3%甲醇]产生纯39,呈浅黄色固体(1.33g,57%)。LC/MS,体系1:RT 2.21分钟;MS(ES+)m/z(相对强度)无数据。
(e)4-((R)-2-((R)-2-(((烯丙氧基)羰基)氨基)-3-甲基丁酰胺基)丙酰胺基)苄基4-((10R,13R)-10-异丙基-13-甲基-8,11-二氧代-2,5-二氧杂-9,12-二氮杂十四烷酰胺基)苄基((S)-(戊烷-1,5-二基双(氧基))双(2-((S)-2-(羟基甲基)-4-甲基-2,3-二氢-1H-吡咯-1-羰基)-4-甲氧基-5,1-亚苯基))二氨基甲酸酯(40)
将四正丁基氟化铵(1M,1.52mL,1.52mmol,2.0当量)加入TBS被保护的化合物39(1.30g,0.76mmol)在无水THF(15mL)中的溶液。在室温下将反应混合物搅拌4小时。将反应混合物用氯仿(100mL)稀释,并依序用水(40mL)和饱和盐水(40mL)洗涤。将有机相经MgSO4干燥并蒸发以留下黄色固体。快速层析[梯度洗脱95%乙酸乙酯/5%甲醇至90%乙酸乙酯/10%甲醇]产生纯40,呈浅黄色固体(1.00g,89%)。LC/MS,体系1:RT 1.60分钟;MS(ES+)m/z(相对强度)1478.45(100)。
(iii)(11S,11aS)-4-((2R,5R)-37-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-5-异
丙基-2-甲基-4,7,35-三氧代-10,13,16,19,22,25,28,31-八氧杂-3,6,34-三氮杂三十七
烷酰胺基)苄基11-羟基-8-((5-(((11S,11aS)-11-羟基-10-(((4-((10R,13R)-10-异丙基-
13-甲基-8,11-二氧代-2,5-二氧杂-9,12-二氮杂十四烷酰胺基)苄基)氧基)羰基)-7-甲氧
基-2-甲基-5-氧代-5,10,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂
-8-基)氧
基)戊基)氧基)-7-甲氧基-2-甲基-5-氧代-11,11a-二氢-1H-吡咯并[2,1-c][1,4]苯并二
氮杂
-10(5H)-羧酸酯(43)
(a)(11S,11aS)-4-((R)-2-((R)-2-(((烯丙氧基)羰基)氨基)-3-甲基丁酰胺基)丙酰胺基)苄基11-羟基-8-((5-(((11S,11aS)-11-羟基-10-(((4-((10R,13R)-10-异丙基-13-甲基-8,11-二氧代-2,5-二氧杂-9,12-二氮杂十四烷酰胺基)苄基)氧基)羰基)-7-甲氧基-2-甲基-5-氧代-5,10,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-8-基)氧基)戊基)氧基)-7-甲氧基-2-甲基-5-氧代-11,11a-二氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-10(5H)-羧酸酯(41)
在氩气和室温下,将戴斯-马丁氧化剂(Dess-Martin periodinane)(0.59g,1.38mmol,2.1当量)加入40(0.97g,0.66mmol)在无水DCM中的搅拌溶液。允许搅拌反应混合物4小时。将反应混合物用DCM(100mL)稀释,用饱和碳酸氢钠溶液(3×100mL)、水(100mL)、盐水(100mL)洗涤,经MgSO4干燥,过滤并蒸发。快速层析[梯度洗脱100%氯仿至95%氯仿/5%甲醇]产生纯41,呈浅黄色固体(0.88g,90%)。LC/MS,体系1:RT 1.57分钟;MS(ES+)m/z(相对强度)1473.35(100)。
(b)(11S,11aS)-4-((R)-2-((R)-2-氨基-3-甲基丁酰胺基)丙酰胺基)苄基11-羟基-8-((5-(((11S,11aS)-11-羟基-10-(((4-((10R,13R)-10-异丙基-13-甲基-8,11-二氧代-2,5-二氧杂-9,12-二氮杂十四烷酰胺基)苄基)氧基)羰基)-7-甲氧基-2-甲基-5-氧代-5,10,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂-8-基)氧基)戊基)氧基)-7-甲氧基-2-甲基-5-氧代-11,11a-二氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯(42)
将四(三苯基膦)钯(5mg,0.004mmol,0.06当量)加入41(105mg,0.071mmol)和吡咯烷(7μL,0.086mmol,1.2当量)在无水DCM(5mL)中的溶液。将反应混合物搅拌15分钟,然后用氯仿(50mL)稀释并依序用饱和氯化铵水溶液(30mL)和盐水(30mL)洗涤。经硫酸镁干燥有机相,过滤并蒸发。快速层析[梯度洗脱100%氯仿至90%氯仿/10%甲醇]产生纯42,呈浅黄色固体(54mg,55%)。LC/MS,体系1:RT 1.21分钟;MS(ES+)m/z(相对强度)1389.50(100)。
(c)(11S,11aS)-4-((2R,5R)-37-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)-5-异丙基-2-甲基-4,7,35-三氧代-10,13,16,19,22,25,28,31-八氧杂-3,6,34-三氮杂三十七烷酰胺基)苄基11-羟基-8-((5-(((11S,11aS)-11-羟基-10-(((4-((10R,13R)-10-异丙基-13-甲基-8,11-二氧代-2,5-二氧杂-9,12-二氮杂十四烷酰胺基)苄基)氧基)羰基)-7-甲氧基-2-甲基-5-氧代-5,10,11,11a-四氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂8-基)氧基)戊基)氧基)-7-甲氧基-2-甲基-5-氧代-11,11a-二氢-1H-吡咯并[2,1-c][1,4]苯并二氮杂10(5H)-羧酸酯(43)
将N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺(28mg,0.146mmol,1当量)加入42(203mg,0.146mmol)和马来酰亚胺-PEG8酸(87mg,0.146mmol)在氯仿(5mL)中的溶液。将反应搅拌1.5h,然后用氯仿(50mL)稀释,用水(50mL)、盐水(30mL)洗涤,经硫酸镁干燥,过滤并蒸发。快速层析[梯度洗脱100%DCM至90%DCM/10%甲醇]产生43,呈浅黄色固体(205mg,72%)。LC/MS,体系1:RT 5.75分钟;MS(ES+)m/z(相对强度)982.90(100),1963.70(5)。
实施例3:所释放化合物的活性
K562测定
在37℃下并在包含5%CO2的加湿气氛中,将K562人慢性髓性白血病细胞维持在补充有10%胎牛血清和2mM谷氨酰胺的RPM1 1640培养基中,并在37℃下和在黑暗中用特定剂量的药物温育1小时或96小时。通过离心(5分钟,300g)来终止温育,并用无药物培养基洗涤细胞一次。在适当的药物处理以后,将细胞转移到96孔微量滴定板(104个细胞/孔,8孔/样品)。然后在37℃下在包含5%CO2的加湿气氛中将滴定板保持在黑暗中。上述测定是基于活细胞将黄色可溶性四唑盐,3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-2H-溴化四唑(MTT,Aldrich-Sigma),还原成不溶性紫色甲臜沉淀的能力。在温育滴定板4天(以允许对照细胞的数目增加约10倍)以后,将20μL的MTT溶液(5mg/mL,在磷酸盐缓冲盐水中)加入每个孔并进一步温育滴定板5小时。然后在300g下离心滴定板5分钟并且培养基的大部分吸移自细胞沉淀,从而留下10–20μL/孔。将DMSO(200μL)加入每个孔并搅拌样品以确保完全混合。然后用Titertek Multiscan ELISA平板读数器在550nm的波长处读出光密度,并构建剂量反应曲线(剂量响应曲线)。对于每个曲线,IC50值读为将最终光密度减小至对照值的50%所需要的剂量。
在此测定中,化合物RelA具有0.425nM的IC50。
实施例4:缀合物的形成
ADC1A
将抗体1(15.0mg,100纳摩尔)稀释进入13mL的还原缓冲液,其包含10mM硼酸钠(pH8.4)、2.5mM EDTA和1.1mg/mL的最终抗体浓度。添加TCEP的10mM溶液(2摩尔当量/抗体,200纳摩尔,20.0μL)并在加热块中在+37℃下加热还原混合物2小时。在冷却至室温以后,添加化合物A作为DMSO溶液(15摩尔当量/抗体,1.5微摩尔,在1.5mL DMSO中)。在室温下混合溶液过夜(17小时),然后通过添加N-乙酰半胱氨酸(1.5微摩尔,15μL,100mM)使缀合物骤冷,然后注入AKTATMFPLC,其中使用填充有Superdex 200 PG的GE Healthcare XK26/100柱,用4.5mL/min的无菌过滤磷酸盐缓冲盐水(PBS)进行洗脱。将对应于ADC1A单体峰的级分汇集,使用15mL Amicon Ultracell 50KDa MWCO自旋过滤器浓缩,进行分析并无菌过滤。BCA测定给出最终ADC1A的浓度为在8.7mL中的1.36mg/mL,并且获得的ADC1A质量是11.8mg(79%产率)。
通过Shimadzu Prominence系统,使用Phenomenex Aeris 3.6u XB-C18 150×2.1mm柱(用水和乙腈的梯度进行洗脱)对ADC1A的还原样品在280nm和330nm处(化合物A特异性)进行的UHPLC分析表明,连接于化合物A的若干分子的轻链和重链的混合物与2.6个化合物A分子/抗体的药物/抗体比率(DAR)一致。
通过Shimadzu Prominence系统,使用Waters Acquity UPLC BEH200 SEC 1.7um4.6×150mm柱(用含有5%异丙醇(v/v)无菌过滤的磷酸盐缓冲盐水(PBS)进行洗脱)对ADC1A的样品在280nm处的UHPLC分析显示98.7%的单体纯度。
ADC2B
将抗体2(5.0mg,33.3纳摩尔)稀释到4.5mL的还原缓冲液,其包含73硼酸钠(pH8.4)、1.0mM EDTA和1.0mg/mL的最终抗体浓度。添加TCEP的10mM溶液(2摩尔当量/抗体,67纳摩尔,6.6μL)并在加热块中在+37℃下加热还原混合物2.5小时。在冷却至室温以后,添加化合物B作为DMSO溶液(13.3摩尔当量/抗体,444微摩尔,在0.5mL DMSO中)。在室温下混合溶液过夜(17小时),然后注入AKTATMFPLC,其中使用填充有Superdex 200 PG的GEHealthcare XK26/600柱,用2.5mL/min的无菌过滤磷酸盐缓冲盐水(PBS)进行洗脱。将对应于ADC2B单体峰的级分汇集,使用15mL Amicon Ultracell 50KDa MWCO自旋过滤器浓缩,进行分析并无菌过滤。BCA测定给出最终ADC2B的浓度为在3.2mL中的0.80mg/mL,并且获得的ADC2B质量是2.54mg(52%产率)。
通过Shimadzu Prominence系统,使用Phenomenex Aeris 3.6u XB-C18 150×2.1mm柱(用水和乙腈的梯度进行洗脱)对ADC2B的还原样品在280nm和330nm处(化合物B特异性)进行的UHPLC分析表明,连接于化合物B的若干分子的轻链和重链的混合物与2.3个化合物B分子/抗体的药物/抗体比率(DAR)一致。
通过Shimadzu Prominence系统,使用Waters Acquity UPLC BEH200 SEC 1.7um4.6×150mm柱(用含有5%异丙醇(v/v)无菌过滤的磷酸盐缓冲盐水(PBS)进行洗脱)对ADC2B的样品在280nm处的UHPLC分析显示99.4%的单体纯度。
ADC1C
将抗体1(12.0mg,80.0纳摩尔)稀释到8.5mL的还原缓冲液,其包含10mM硼酸钠(pH8.4)、2.5mM EDTA和1.3mg/mL的最终抗体浓度。添加TCEP的10mM溶液(2摩尔当量/抗体,160纳摩尔,16.0μL)并在加热块中在+37℃下加热还原混合物2.5小时。在冷却至室温以后,添加化合物C作为DMSO溶液(10摩尔当量/抗体,800微摩尔,在1.0mL DMSO中)。在室温下混合溶液3小时,然后通过添加N-乙酰半胱氨酸(1600纳摩尔,16μL,100mM)使缀合物骤冷,然后注入AKTATMFPLC,其中使用填充有Superdex 200 PG的GE Healthcare XK26/100柱,用4.5mL/min的无菌过滤磷酸盐缓冲盐水(PBS)进行洗脱。将对应于ADC1C单体峰的级分汇集,使用15mL Amicon Ultracell 50KDa MWCO自旋过滤器浓缩,进行分析并无菌过滤。BCA测定给出最终ADC1C的浓度为在13.4mL中的0.61mg/mL,并且获得的ADC1C质量是8.14mg(68产率)。
通过Shimadzu Prominence系统,使用Phenomenex Aeris 3.6u XB-C18 150×2.1mm柱(用水和乙腈的梯度进行洗脱)对ADC1C的还原样品在280nm和330nm处(化合物C特异性)进行的UHPLC分析表明,连接于化合物C的若干分子的轻链和重链的混合物与2.3个化合物C分子/抗体的药物/抗体比率(DAR)一致。
通过Shimadzu Prominence系统,使用Waters Acquity UPLC BEH200 SEC 1.7um4.6×150mm柱(用含有5%异丙醇(v/v)无菌过滤的磷酸盐缓冲盐水(PBS)进行洗脱)对ADC1C的样品在280nm处的UHPLC分析显示97.8%的单体纯度。
ADC1C-2
将抗体1(15.0mg,100纳摩尔)稀释到13.5mL的10mM硼酸钠(pH 8.4)、1mM EDTA溶液,其中最终抗体浓度为1.1mg/mL。添加TCEP的2mM溶液(1.6摩尔当量/抗体,160纳摩尔,80μL)并在恒温箱中在+37℃下加热还原混合物90分钟。在冷却至室温以后,添加化合物C作为DMSO溶液(10.0摩尔当量/抗体,10000微摩尔,在1.5mL DMSO中)。在室温下混合溶液1.5小时,然后通过添加N-乙酰半胱氨酸(4微摩尔,400μL,10mM)使缀合物骤冷,然后注入AKTATMPure FPLC,其中使用填充有Superdex 200 PG的GE Healthcare HiLoadTM 26/600柱,用2.6mL/min的无菌过滤磷酸盐缓冲盐水(PBS)进行洗脱。将对应于ADC1C-2单体峰的级分汇集,使用15mL Amicon Ultracell 50KDa MWCO自旋过滤器浓缩,进行分析并无菌过滤。
通过Shimadzu Prominence系统,使用Phenomenex Aeris 3.6u XB-C18 150×2.1mm柱(用水和乙腈的梯度进行洗脱)对ADC1C-2的还原样品在280nm和330nm处(化合物C特异性)进行的UHPLC分析表明,连接于化合物C的若干分子的轻链和重链的混合物与2.39个化合物C分子/抗体的药物/抗体比率(DAR)一致。
通过Shimadzu Prominence系统,使用Phenomenex Yarra 3u SEC-3000300x4.60mm(用含有200mM磷酸钾pH 6.95、250mM氯化钾和10%异丙醇(v/v)的无菌过滤SEC缓冲液进行洗脱)对ADC1C-2的样品在280nm处的UHPLC分析显示超过99.8%的纯度,含有0.2%二聚体。HPLC浓度测定给出最终ADC1C-2的浓度为在7.72mL中的0.98mg/mL,并且获得的ADC1C-2质量是7.5mg(50%产率)。
上述抗体1为赫赛汀。
实施例5:体外ADC效力研究
ADC1A
在上述细胞毒性测定中对ADC1A的细胞毒性进行测定。结果在图1中示出。实线表示抗原表达细胞系(AECL),虚线表示抗原非表达细胞系(ANECL),误差条指示±标准偏差。
上述AECL为BT474,并且ANECL为MDAMB468。
实施例6:体内ADC效力研究
对8-12周龄的CB.17SCID小鼠的胁腹皮下注射1mm3肿瘤片段。当肿瘤达到100-150mg的平均尺寸时,开始治疗。每周称重小鼠两次。每周测量肿瘤尺寸两次。单独地监测动物。实验的终点是肿瘤体积达到1000mm3或67天,以先到者为准。可以随访响应者更长时间。
对10只异种移植小鼠的组静脉注射0.2ml的抗体药物缀合物(ADC),或在磷酸盐缓冲盐水(媒介物)中的裸抗体,或注射单独的0.2ml媒介物。调节ADC的浓度以单剂量产生,例如,0.3或1.0mg ADC/kg体重。可以以例如1周的间隔将三个相同的剂量施用给每只小鼠。
图2示出在10只小鼠的组中ADC1A剂量为0.3(实线)或1.0mg/kg(虚线)时与媒介物(虚线)对照相比对平均肿瘤体积的影响。
图3示出示出在10只小鼠的组中ADC1C剂量为0.3(实线)或1.0mg/kg(虚线)时与媒介物(虚线)对照相比对平均肿瘤体积的影响。
图2和图3中报道的研究中的肿瘤均为BT474肿瘤。
上文提及的所有文献和其他参考文献均以引用方式结合于本文。
缩略语
Ac 乙酰基
Acm 乙酰胺基甲基
Alloc 烯丙氧基羰基
Boc 二碳酸二叔丁酯
t-Bu 叔丁基
Bzl 苄基,其中Bzl-OMe是甲氧基苄基以及Bzl-Me是甲苯
Cbz或Z 苄氧基-羰基,其中Z-Cl和Z-Br分别是氯-和溴苄氧基羰基
DMF N,N-二甲基甲酰胺
Dnp 二硝基苯基
DTT 二硫苏糖醇
Fmoc 9H-芴-9-基甲氧基羰基
imp N-10亚胺保护基:3-(2-甲氧基乙氧基)丙酸酯-Val-Ala-PAB
MC-OSu 马来酰亚氨基己酰基-O-N-琥珀酰亚胺
Moc 甲氧基羰基
MP 马来酰亚氨基丙酰胺
Mtr 4-甲氧基-2,3,6-三甲基苯磺酰基
PAB 对氨基苄氧基羰基
PEG 乙烯氧基
PNZ 氨基甲酸对硝基苄酯
Psec 2-(苯基磺酰基)乙氧基羰基
TBDMS 叔丁基二甲基甲硅烷基
TBDPS 叔丁基二苯基甲硅烷基
Teoc 2-(三甲基甲硅烷基)乙氧基羰基
Tos 甲苯磺酰基
Troc 2,2,2-三氯乙氧基羰基氯化物
Trt 三苯甲基
Xan 呫吨基
Claims (21)
3.根据权利要求2所述的缀合物,其中所述细胞结合剂是抗体或其活性片段。
4.根据权利要求3所述的缀合物,其中所述抗体或抗体片段是针对肿瘤相关抗原的抗体或抗体片段。
5.根据权利要求3所述的缀合物,其中所述抗体或抗体片段是抗体,所述抗体结合于一种或多种肿瘤相关抗原或细胞表面受体,所述肿瘤相关抗原或细胞表面受体选自(1)-(88):
(1)BMPR1B;
(2)E16;
(3)STEAP1;
(4)0772P;
(5)MPF;
(6)Napi3b;
(7)Sema 5b;
(8)PSCA hlg;
(9)ETBR;
(10)MSG783;
(11)STEAP2;
(12)TrpM4;
(13)CRIPTO;
(14)CD21;
(15)CD79b;
(16)FcRH2;
(17)HER2;
(18)NCA;
(19)MDP;
(20)IL20R-α;
(21)短蛋白聚糖;
(22)EphB2R;
(23)ASLG659;
(24)PSCA;
(25)GEDA;
(26)BAFF-R;
(27)CD22;
(28)CD79a;
(29)CXCR5;
(30)HLA-DOB;
(31)P2X5;
(32)CD72;
(33)LY64;
(34)FcRH1;
(35)IRTA2;
(36)TENB2;
(37)PSMA–FOLH1;
(38)SST;
(38.1)SSTR2;
(38.2)SSTR5;
(38.3)SSTR1;
(38.4)SSTR3;
(38.5)SSTR4;
(39)ITGAV;
(40)ITGB6;
(41)CEACAM5;
(42)MET;
(43)MUC1;
(44)CA9;
(45)EGFRvIII;
(46)CD33;
(47)CD19;
(48)IL2RA;
(49)AXL;
(50)CD30-TNFRSF8;
(51)BCMA-TNFRSF17;
(52)CT Ags–CTA;
(53)CD174(Lewis Y)-FUT3;
(54)CLEC14A;
(55)GRP78–HSPA5;
(56)CD70;
(57)干细胞特异性抗原;
(58)ASG-5;
(59)ENPP3;
(60)PRR4;
(61)GCC–GUCY2C;
(62)Liv-1–SLC39A6;
(63)5T4;
(64)CD56–NCMA1;
(65)CanAg;
(66)FOLR1;
(67)GPNMB;
(68)TIM-1–HAVCR1;
(69)RG-1/前列腺肿瘤靶Mindin–Mindin/RG-1;
(70)B7-H4–VTCN1;
(71)PTK7;
(72)CD37;
(73)CD138–SDC1;
(74)CD74;
(75)Claudins–CLs;
(76)EGFR;
(77)Her3;
(78)RON-MST1R;
(79)EPHA2;
(80)CD20–MS4A1;
(81)腱生蛋白C–TNC;
(82)FAP;
(83)DKK-1;
(84)CD52;
(85)CS1-SLAMF7;
(86)内皮糖蛋白–ENG;
(87)膜联蛋白A1–ANXA1;
(88)V-CAM(CD106)-VCAM1。
6.根据权利要求3至5中任一项所述的缀合物,其中所述抗体或抗体片段是半胱氨酸工程抗体。
7.根据权利要求3至5中任一项所述的缀合物,其中PBD二聚体药物(D)对抗体(Ab)的药物负载(p)是1至8的整数。
8.根据权利要求7所述的缀合物,其中p是1、2、3、或4。
9.一种组合物,其包含根据权利要求3至8中任一项所述的缀合物的混合物,其中在所述缀合物的混合物中PBD二聚体药物对抗体的平均药物负载(p)为1至8。
10.根据权利要求2至8中任一项所述的缀合物或根据权利要求9所述的组合物,其用于在治疗中使用。
11.根据权利要求2至8中任一项所述的缀合物或根据权利要求9所述的组合物,其用于在治疗受试者的增生性疾病中使用。
12.根据权利要求11所述的缀合物或组合物,其中所述疾病是癌症。
13.一种药物组合物,其包含根据权利要求2至8中任一项所述的缀合物或根据权利要求9所述的组合物以及药用载体或赋形剂。
14.根据权利要求13所述的药物组合物,其包含药用稀释剂。
15.根据权利要求13或14所述的药物组合物,其还包含治疗有效量的化疗剂。
16.根据权利要求2至8中任一项所述的缀合物或根据权利要求9所述的组合物在制备用于治疗受试者的癌症的药剂中的用途。
17.根据权利要求16所述的用途,其中所述癌症是乳腺癌。
18.权利要求15所述的药物组合物在制备用于在患者中治疗癌症的药物中的用途。
19.根据权利要求18所述的用途,其中所述癌症是乳腺癌。
20.根据权利要求18所述的用途,其中连同所述缀合物一起,将化疗剂施用给所述患者。
21.一种制备根据权利要求2至8中任一项所述的缀合物或根据权利要求9所述的组合物的方法,所述方法包括以下步骤:使细胞结合剂与如权利要求1中所限定的化合物C反应。
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ES2728869T3 (es) | 2019-10-29 |
KR20160068787A (ko) | 2016-06-15 |
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AU2014333763A1 (en) | 2018-04-19 |
BR112016008033A2 (zh) | 2017-10-03 |
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BR112016008033B1 (pt) | 2022-08-02 |
MX2016004467A (es) | 2016-12-09 |
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KR102052244B1 (ko) | 2019-12-04 |
US20160250345A1 (en) | 2016-09-01 |
CA2926876A1 (en) | 2015-04-16 |
TW201602111A (zh) | 2016-01-16 |
CN105636613A (zh) | 2016-06-01 |
JP6448632B2 (ja) | 2019-01-09 |
NZ718826A (en) | 2019-10-25 |
GB201317982D0 (en) | 2013-11-27 |
EP3054990B1 (en) | 2019-03-27 |
TWI716343B (zh) | 2021-01-21 |
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