CN116234586A - 吡唑并氮呯免疫缀合物及其用途 - Google Patents
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- CN116234586A CN116234586A CN202180056589.5A CN202180056589A CN116234586A CN 116234586 A CN116234586 A CN 116234586A CN 202180056589 A CN202180056589 A CN 202180056589A CN 116234586 A CN116234586 A CN 116234586A
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Abstract
本发明提供了式I的免疫缀合物,所述免疫缀合物包含通过缀合至一个或多个吡唑并氮呯衍生物而连接的抗体。本发明还提供了包含反应性官能团的吡唑并氮呯衍生物中间体组合物。此类中间体组合物是适合用于经由连接子或连接部分形成所述免疫缀合物的基质。本发明进一步提供了用所述免疫缀合物治疗癌症的方法。
Description
相关申请的交叉引用
本非临时申请要求2020年8月13日提交的美国临时申请号63/065,219的优先权益,所述临时申请以全文引用的方式并入。
序列表
本申请包含以ASCII格式用电子方式递交并且特此以全文引用的方式并入的序列表。2021年8月5日创建的所述ASCII拷贝命名为17019_009WO1_SL.txt并且大小为63,469字节。
发明领域
本发明总体上涉及一种免疫缀合物,所述免疫缀合物包含缀合至一个或多个吡唑并氮呯分子的抗体。
发明背景
需要用于递送抗体和免疫佐剂的新组合物和方法,以达到难以接近的肿瘤和/或扩展用于癌症患者和其它受试者的治疗选项。本发明提供了此类组合物和方法。
发明内容
本发明总体上关于免疫缀合物,所述免疫缀合物包含通过缀合而连接至一个或多个吡唑并氮呯衍生物的抗体。本发明进一步关于包含反应性官能团的吡唑并氮呯衍生物中间体组合物。此类中间体组合物是适合用于形成免疫缀合物的基质,其中抗体可以通过连接子L共价结合至具有下式的吡唑并氮呯(PAZ)部分:
其中R1、R2、R3和R4中的一者附接至L。X1、X2和X3以及R1、R2、R3和R4取代基在本文中定义。
本发明进一步关于此种免疫缀合物在治疗疾患,尤其癌症中的用途。
本发明的一个方面是一种免疫缀合物,所述免疫缀合物包含共价附接至连接子的抗体,所述连接子共价附接至一个或多个吡唑并氮呯部分。
本发明的另一个方面是选自式IIa和式IIb的5-氨基吡唑并氮呯-连接子化合物:
其中R1、R2、R3和R4中的一者附接至L。
本发明的另一个方面是一种用于治疗癌症的方法,所述方法包括施用治疗有效量的免疫缀合物,所述免疫缀合物包含通过缀合而连接至一个或多个吡唑并氮呯部分的抗体。
本发明的另一个方面是一种免疫缀合物用于治疗癌症的用途,所述免疫缀合物包含通过缀合而连接至一个或多个吡唑并氮呯部分的抗体。
本发明的另一个方面是一种通过一个或多个吡唑并氮呯部分与抗体缀合来制备免疫缀合物的方法。
附图说明
图1示出了吡唑并氮呯化合物PAZ-2、PAZ-4和PAZ-11对比比较佐剂化合物C-1和C-2在24小时的HEK人类TLR7活性的图。
图2示出了吡唑并氮呯化合物PAZ-2、PAZ-4和PAZ-11对比比较佐剂化合物C-1和C-2在24小时的HEK人类TLR8活性的图。
具体实施方式
现在将详细参考本发明的某些实施方案,其实例以所附结构和化学式说明。虽然将结合所列举的实施方案描述本发明,但应了解,并不意图将本发明限于那些实施方案。相反,本发明意图涵盖可以包括于如权利要求书所界定的本发明范围内的所有替代物、修改和等同物。
本领域技术人员将识别类似或等同于本文所描述的那些的许多方法和材料,其可以用于实施本发明。本发明决不限于所描述的方法和材料。
定义
术语“免疫缀合物”是指经由连接子共价键结至佐剂部分的抗体构建体。术语“佐剂”是指能够在暴露于佐剂的受试者中引发免疫反应的物质。短语“佐剂部分”是指如本文所描述,例如经由连接子共价键结至抗体构建体的佐剂。佐剂部分可以在键结至抗体构建体时或在向受试者施用免疫缀合物后从抗体构建体裂解(例如酶促裂解)之后引发免疫反应。免疫缀合物允许进行活性佐剂部分在结合靶抗原时的靶向递送。
“佐剂”是指能够在暴露于佐剂的受试者中引发免疫反应的物质。短语“佐剂部分”是指如本文所描述,例如经由连接子共价键结至抗体构建体的佐剂。佐剂部分可以在键结至抗体构建体时或在向受试者施用免疫缀合物后从抗体构建体裂解(例如,酶促裂解)之后引发免疫反应。
术语“Toll样受体”和“TLR”是指高度保守的哺乳动物蛋白家族的任何成员,所述成员识别病原体相关的分子模式并且充当先天免疫中的关键信号传导元件。TLR多肽共享特征结构,所述特征结构包括具有富亮氨酸重复的细胞外结构域、跨膜结构域和TLR信号传导中所涉及的细胞内结构域。
术语“Toll样受体7”和“TLR7”是指与公开可用的TLR7序列,例如人类TLR7多肽的GenBank寄存编号AAZ99026或鼠类TLR7多肽的GenBank寄存编号AAK62676共享至少约70%、约80%、约90%、约95%、约96%、约97%、约98%、约99%或更高序列同一性的核酸或多肽。
术语“Toll样受体8”和“TLR8”是指与公开可用的TLR7序列,例如人类TLR8多肽的GenBank寄存编号AAZ95441或鼠类TLR8多肽的GenBank寄存编号AAK62677共享至少约70%、约80%、约90%、约95%、约96%、约97%、约98%、约99%或更高序列同一性的核酸或多肽。
“TLR激动剂”是直接或间接结合至TLR(例如TLR7和/或TLR8)以诱导TLR信号传导的物质。TLR信号传导中任何可检测的差异可以指示激动剂刺激或活化TLR。信号传导差异可以表现为例如以下各者的变化:靶基因的表达、信号转导组分的磷酸化、诸如核因子-κB(NF-κB)的下游元件的细胞内定位、某些组分(诸如IL-1受体相关激酶(IRAK))与其它蛋白质或细胞内结构的缔合,或诸如激酶(诸如有丝分裂原活化蛋白激酶(MAPK))的组分的生物化学活性。
“抗体”是指包含来自免疫球蛋白基因的抗原结合区(包括互补决定区(CDR))的多肽或其片段。术语“抗体”特定涵盖展现所需生物活性的单克隆抗体(包括全长单克隆抗体)、多克隆抗体、多特异性抗体(例如双特异性抗体)和抗体片段。示例性免疫球蛋白(抗体)结构单元包含四聚体。每个四聚体由两对相同多肽链组成,每一对具有由二硫键连接的一条“轻”链(约25kDa)和一条“重”链(约50-70kDa)。每条链由结构域组成,所述结构域称作免疫球蛋白结构域。这些结构域按大小和功能分为不同类别,例如,轻链和重链上的可变结构域或区(分别是VL和VH)以及轻链和重链上的恒定结构域或区(分别是CL和CH)。每条链的N端界定约100至110个或更多个氨基酸的可变区,称作互补位(paratope),其主要负责抗原识别,即,抗原结合结构域。轻链分为κ或λ。重链分为γ、μ、α、δ或ε,其依次分别定义免疫球蛋白种类IgG、IgM、IgA、IgD和IgE。IgG抗体是由四条肽链组成的约150kDa大分子。IgG抗体含有两条约50kDa的相同种类γ重链和两条约25kDa的相同轻链,由此成为四聚四级结构。两条重链由二硫键彼此连接并且各自连接至轻链。所得四聚体具有两个相同半部分,它们一起形成类Y形状。叉形物的每个末端含有相同抗原结合结构域。人类中存在四种IgG子类(IgG1、IgG2、IgG3和IgG4),以它们在血清中的丰度顺序命名(即,IgG1最丰富)。通常,抗体的抗原结合结构域在结合至癌细胞的特异性和亲和力中将最为关键。
靶向特定抗原的抗体包括具有至少一个靶向特定抗原的抗原结合区的双特异性或多特异性抗体。在一些实施方案中,靶向单克隆抗体是具有至少一个靶向肿瘤细胞的抗原结合区的双特异性抗体。此类抗原包括但不限于:间皮素、前列腺特异性膜抗原(PSMA)、HER2、TROP2、CEA、EGFR、5T4、粘连蛋白4(Nectin4)、CD19、CD20、CD22、CD30、CD70、B7H3、B7H4(也称为08E)、蛋白酪氨酸激酶7(PTK7)、磷脂酰肌醇蛋白聚糖-3(glypican-3)、RG1、岩藻糖基-GMl、CTLA-4和CD44(WO 2017/196598)。
“抗体构建体”是指包含(i)抗原结合结构域和(ii)Fc结构域的抗体或融合蛋白。
在一些实施方案中,结合剂是抗原结合抗体“片段”,其为至少包含抗体的抗原结合区的构建体,所述抗原结合区是单独的或与共同构成抗原结合构建体的其它组分一起。许多不同类型的抗体“片段”在本领域中是已知的,包括例如(i)Fab片段,其为由VL、VH、CL和CH1结构域组成的单价片段;(ii)F(ab')2片段,其为包含两个在铰链区由二硫桥连接的Fab片段的二价片段;(iii)Fv片段,其由抗体的单臂的VL和VH结构域组成;(iv)Fab'片段,其通过使用温和还原条件使F(ab')2片段的二硫桥断裂而产生;(v)二硫键稳定的Fv片段(dsFv);以及(vi)单链Fv(scFv),其为由Fv片段的经合成连接子连接的两个结构域(即,VL和VH)组成的单价分子,所述合成连接子使两个结构域能够合成为单一多肽链。
抗体或抗体片段可以是较大构建体的一部分,例如,抗体片段与额外区域的缀合物或融合构建体。举例来说,在一些实施方案中,抗体片段可以融合至如本文所描述的Fc区。在其它实施方案中,抗体片段(例如Fab或scFv)可以是嵌合抗原受体或嵌合T细胞受体的一部分,例如,通过融合至跨膜结构域(任选地具有间插连接子或“茎(stalk)”(例如铰链区))和任选的细胞间信号传导结构域。举例来说,抗体片段可以融合至t细胞受体的γ和/或δ链,以提供结合PD-L1的T细胞受体样构建体。在又一个实施方案中,抗体片段是包含CD1或CD3结合结构域和连接子的双特异性T细胞啮合子(BiTE)的一部分。
“表位”意指与抗原结合结构域结合的抗原的任何抗原决定子或表位决定子(即,在抗原结合结构域的互补位处)。抗原决定子通常由分子的化学活性表面基团,诸如氨基酸或糖侧链组成,并且通常具有特定三维结构特征以及特定电荷特征。
术语“Fc受体”或“FcR”是指结合至抗体的Fc区的受体。存在三个主要种类的Fc受体:(1)结合至IgG的FcγR,(2)结合至IgA的FcαR,以及(3)结合至IgE的FcεR。FcγR家族包括若干成员,诸如FcγI(CD64)、FcγRIIA(CD32A)、FcγRIIB(CD32B)、FcγRIIIA(CD16A)和FcγRIIIB(CD16B)。Fcγ受体对IgG的亲和力不同,并且对IgG子类(例如IgG1、IgG2、IgG3和IgG4)的亲和力也不同。
如本文所提及的核酸或氨基酸序列“同一性”可以通过将所关注的核酸或氨基酸序列与参考核酸或氨基酸序列进行比较来确定。百分比同一性是在最佳比对的所关注序列与参考序列之间相同(即,同一)的核苷酸或氨基酸残基数除以最长序列的长度(即,所关注序列或参考序列任一者的长度,以较长者为准)。序列的比对和百分比同一性的计算可以使用可用的软件程序进行。此类程序的实例包括CLUSTAL-W、T-Coffee和ALIGN(用于核酸和氨基酸序列的比对)、BLAST程序(例如BLAST 2.1、BL2SEQ、BLASTp、BLASTn等等)和FASTA程序(例如FASTA3x、FASTM和SSEARCH)(用于序列比对和序列相似性搜索)。序列比对算法也在以下文献中公开:例如Altschul等,J.Molecular Biol.,215(3):403-410(1990);Beigert等,Proc.Natl.Acad.Sci.USA,106(10):3770-3775(2009);Durbin等编,Biological SequenceAnalysis:Probalistic Models of Proteins and Nucleic Acids,CambridgeUniversity Press,Cambridge,UK(2009);Soding,Bioinformatics,21(7):951-960(2005);Altschul等,Nucleic Acids Res.,25(17):3389-3402(1997);以及Gusfield,Algorithms on Strings,Trees and Sequences,Cambridge University Press,Cambridge UK(1997))。序列的百分比(%)同一性还可以计算为例如100x[(相同位置)/min(TGA、TGB)],其中TGA和TGB是在比对中使TGA和TGB最小化的肽序列A和B中的残基数与内部空位的总和。参见例如Russell等,J.Mol Biol.,244:332-350(1994)。
结合剂包含一起形成抗原结合位点的Ig重链和轻链可变区多肽。重链和轻链可变区中的每一者是包含由构架区连接的三个互补决定区(CDR1、CDR2和CDR3)的多肽。结合剂可以是本领域中已知的包含Ig重链和轻链的多种类型结合剂中的任一者。举例来说,结合剂可以是抗体、抗原结合抗体“片段”或T细胞受体。
“生物类似药(biosimilar)”是指具有类似于以下抗体的活性特性的经核准的抗体构建体:例如,先前经核准的PD-L1靶向抗体构建体,诸如阿特珠单抗(atezolizumab)(TECENTRIQTM,Genentech,Inc.)、得瓦鲁单抗(durvalumab)(IMFINZITM,AstraZeneca)和阿维鲁单抗(avelu mab)(BAVENCIOTM,EMD Serono,Pfizer);先前经核准的HER2靶向抗体构建体,诸如曲妥珠单抗(trastuzumab)(HERCEPTINTM,Gene ntech,Inc.)和帕妥珠单抗(pertuzumab)(PERJETATM,Genentech,In c.);或CEA靶向抗体,诸如拉贝妥珠单抗(labetuzumab)(CEA-CIDE TM,MN-14,hMN14,Immunomedics)CAS登记号219649-07-7)。
“生物改良药(biobetter)”是指经核准的抗体构建体,其为诸如阿特珠单抗、得瓦鲁单抗、阿维鲁单抗、曲妥珠单抗、帕妥珠单抗和拉贝妥珠单抗的先前经核准的抗体构建体的改良。生物改良药相对于先前经核准的抗体构建体可以具有一个或多个修饰(例如改变的聚糖谱,或独特表位)。
“氨基酸”是指可以并入肽、多肽或蛋白质中的任何单体单元。氨基酸包括天然存在的α-氨基酸及其立体异构体,以及非天然(非天然存在的)氨基酸及其立体异构体。给定氨基酸的“立体异构体”是指具有相同分子式和分子内键,但键和原子的三维排列不同的异构体(例如L-氨基酸和对应的D-氨基酸)。氨基酸可以经糖基化(例如N-连接的聚糖、O-连接的聚糖、磷酸聚糖、C-连接的聚糖,或糖基化阳离子(glypication))或去糖基化。氨基酸在本文中可以由通常已知的三字母符号或由IUPAC-IUB生物化学命名委员会推荐的单字母符号来提及。
天然存在的氨基酸是由遗传密码编码的那些氨基酸,以及后来经修饰的那些氨基酸,例如羟脯氨酸、γ-羧基谷氨酸和O-磷酸丝氨酸。天然存在的α-氨基酸包括但不限于丙氨酸(Ala)、半胱氨酸(Cys)、天冬氨酸(Asp)、谷氨酸(Glu)、苯丙氨酸(Phe)、甘氨酸(Gly)、组氨酸(His)、异亮氨酸(Ile)、精氨酸(Arg)、赖氨酸(Lys)、亮氨酸(Leu)、甲硫氨酸(Met)、天冬酰胺(Asn)、脯氨酸(Pro)、谷氨酰胺(Gln)、丝氨酸(Ser)、苏氨酸(Thr)、缬氨酸(Val)、色氨酸(Trp)、酪氨酸(Tyr)和它们的组合。天然存在的α-氨基酸的立体异构体包括但不限于D-丙氨酸(D-Ala)、D-半胱氨酸(D-Cys)、D-天冬氨酸(D-Asp)、D-谷氨酸(D-Glu)、D-苯丙氨酸(D-Phe)、D-组氨酸(D-His)、D-异亮氨酸(D-Ile)、D-精氨酸(D-Arg)、D-赖氨酸(D-Lys)、D-亮氨酸(D-Leu)、D-甲硫氨酸(D-Met)、D-天冬酰胺(D-Asn)、D-脯氨酸(D-Pro)、D-谷氨酰胺(D-Gln)、D-丝氨酸(D-Ser)、D-苏氨酸(D-Thr)、D-缬氨酸(D-Val)、D-色氨酸(D-Trp)、D-酪氨酸(D-Tyr)和它们的组合。
天然存在的氨基酸包括通过转译后修饰在蛋白质中形成的那些氨基酸,诸如瓜氨酸(Cit)。
非天然(非天然存在的)氨基酸包括但不限于氨基酸类似物、氨基酸模拟物、合成氨基酸、N-取代的甘氨酸和呈L-构型或D-构型的N-甲基氨基酸,所述非天然氨基酸以类似于天然存在的氨基酸的方式发挥功能。举例来说,“氨基酸类似物”可以是具有与天然存在的氨基酸相同的基本化学结构(即,键结至氢、羧基、氨基的碳),但具有经修饰的侧链基团或经修饰的肽主链的非天然氨基酸,例如高丝氨酸、正亮氨酸、甲硫氨酸亚砜和甲硫氨酸甲基锍。“氨基酸模拟物”是指具有不同于氨基酸的一般化学结构的结构,但以类似于天然存在的氨基酸的方式发挥功能的化合物。
“连接子”是指共价键结化合物或材料中的两个或更多个部分的官能团。举例来说,连接部分可以用于将佐剂部分共价键结至免疫缀合物中的抗体构建体。
“连接部分”是指共价键结化合物或材料中的两个或更多个部分的官能团。举例来说,连接部分可以用于将佐剂部分共价键结至免疫缀合物中的抗体。可用于将连接部分连接至蛋白质和其它材料的键包括但不限于酰胺、胺、酯、氨基甲酸酯、脲、硫醚、硫代氨基甲酸酯、硫代碳酸酯和硫脲。
“二价”是指含有用于连接两个官能团的两个附接点的化学部分;多价连接部分可以具有用于连接其它官能团的额外附接点。二价基团可以用后缀“二基”表示。举例来说,二价连接部分包括二价聚合物部分,诸如二价聚(乙二醇)、二价环烷基、二价杂环烷基、二价芳基和二价杂芳基。“二价环烷基、杂环烷基、芳基或杂芳基”是指具有用于共价连接分子或材料中的两个部分的两个附接点的环烷基、杂环烷基、芳基或杂芳基。环烷基、杂环烷基、芳基或杂芳基可以经取代或未经取代。环烷基、杂环烷基、芳基或杂芳基可以经一个或多个选自卤基、羟基、氨基、烷基氨基、酰胺基、酰基、硝基、氰基和烷氧基的基团取代。
波形线代表指定化学部分的附接点。如果指定化学部分存在两条波形线那么应了解,可以双向使用所述化学部分,即,从左至右或从右至左读取。在一些实施方案中,存在两条波形线/>的指定部分视为以从左至右读取来使用。
“烷基”是指具有所指示的碳原子数的直链(线性)或支链饱和脂肪族基团。烷基可以包括任何数目的碳,例如一个至十二个。烷基的实例包括但不限于甲基(Me、-CH3)、乙基(Et、-CH2CH3)、1-丙基(n-Pr、正丙基、-CH2CH2CH3)、2-丙基(i-Pr、异丙基、-CH(CH3)2)、1-丁基(n-Bu、正丁基、-CH2CH2CH2CH3)、2-甲基-1-丙基(i-Bu、异丁基、-CH2CH(CH3)2)、2-丁基(s-Bu、仲丁基、-CH(CH3)CH2CH3)、2-甲基-2-丙基(t-Bu、叔丁基、-C(CH3)3)、1-戊基(正戊基、-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、1-己基(-CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)、4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3、1-庚基、1-辛基等。烷基可以经取代或未经取代。“经取代的烷基”基团可以经一个或多个选自卤基、羟基、氨基、氧代(=O)、烷基氨基、酰胺基、酰基、硝基、氰基和烷氧基的基团取代。
术语“烷二基”是指二价烷基。烷二基的实例包括但不限于亚甲基(-CH2-)、亚乙基(-CH2CH2-)、亚丙基(-CH2CH2CH2-)等。烷二基也可以称作“亚烷基”基团。
“烯基”是指具有所指示的碳原子数和至少一个碳碳双键sp2的直链(线性)或支链不饱和脂肪族基团。烯基可以包括两个至约12个或更多个碳原子。烯基是具有“顺式”和“反式”取向或替代地具有“E”和“Z”取向的基团。实例包括但不限于乙烯基(ethylenyl/vinyl)(-CH=CH2)、烯丙基(-CH2CH=CH2)、丁烯基、戊烯基和它们的异构体。烯基可以经取代或未经取代。“经取代的烯基”基团可以经一个或多个选自卤基、羟基、氨基、氧代(=O)、烷基氨基、酰胺基、酰基、硝基、氰基和烷氧基的基团取代。
术语“亚烯基”或“烯二基”是指直链或支链二价烃基。实例包括但不限于亚乙烯基(ethylenylene/vinylene)(-CH=CH-)、烯丙基(-CH2CH=CH-)等。
“炔基”是指具有所指示的碳原子数和至少一个碳碳三键sp的直链(线性)或支链不饱和脂肪族基团。炔基可以包括两个至约12个或更多个碳原子。举例来说,C2-C6炔基包括但不限于乙炔基(-C≡CH)、丙炔基(炔丙基、-CH2C≡CH)、丁炔基、戊炔基、己炔基和它们的异构体。炔基可以经取代或未经取代。“经取代的炔基”基团可以经一个或多个选自卤基、羟基、氨基、氧代(=O)、烷基氨基、酰胺基、酰基、硝基、氰基和烷氧基的基团取代。
术语“亚炔基”或“炔二基”是指二价炔基。
术语“碳环”、“碳环基”、“碳环状环”和“环烷基”是指含有3至12个环原子或所指示的原子数的饱和或部分不饱和单环、稠合双环或桥联多环组合体。饱和单环碳环包括例如环丙基、环丁基、环戊基、环己基和环辛基。饱和双环和多环碳环包括例如降莰烷、[2.2.2]双环辛烷、十氢萘和金刚烷。碳环基团还可以是部分不饱和的,在环中具有一个或多个双键或三键。部分不饱和的代表性碳环基团包括但不限于环丁烯、环戊烯、环己烯、环己二烯(1,3-异构体和1,4-异构体)、环庚烯、环庚二烯、环辛烯、环辛二烯(1,3-异构体、1,4-异构体和1,5-异构体)、降莰烯和降莰二烯。
术语“环烷二基”是指二价环烷基。
“芳基”是指通过从母体芳香族环系统的单个碳原子上去除一个氢原子而得到的6-20个碳原子(C6-C20)的单价芳香族烃基。芳基可以是单环,稠合形成双环或三环基团,或由键连接形成联芳基。代表性芳基包括苯基、萘基和联苯基。其它芳基包括具有亚甲基连接基团的苯甲基。一些芳基具有6至12个环成员,诸如苯基、萘基或联苯基。其它芳基具有6至10个环成员,诸如苯基或萘基。
术语“亚芳基”或“芳二基”意指通过从母体芳香族环系统的两个碳原子上去除两个氢原子而得到的6-20个碳原子(C6-C20)的二价芳香族烃基。一些芳二基在示例性结构中以“Ar”表示。芳二基包括包含稠合至饱和、部分不饱和环或芳香族碳环的芳香族环的双环基团。典型芳二基包括但不限于从苯(苯二基)、经取代的苯、萘、蒽、亚联苯基、亚茚基、亚茚满基、1,2-二氢萘、1,2,3,4-四氢萘基等所得的基团。芳二基也称作“亚芳基”,并且任选地经一个或多个本文所描述的取代基取代。
术语“杂环”、“杂环基”和“杂环状环”在本文中可互换使用并且是指3个至约20个环原子的饱和或部分不饱和(亦即,在环内具有一个或多个双键和/或三键)碳环基团,其中至少一个环原子是选自氮、氧、磷和硫的杂原子,其余环原子是C,其中一个或多个环原子任选地独立地经一个或多个下文所描述的取代基取代。杂环可以是具有3至7个环成员(2至6个碳原子和1至4个选自N、O、P和S的杂原子)的单环或具有7至10个环成员(4至9个碳原子和1至6个选自N、O、P和S的杂原子)的双环,例如:双环[4,5]、[5,5]、[5,6]或[6,6]系统。杂环描述于以下文献中:Paquette,Leo A.;"Principles of Modern HeterocyclicChemistry"(W.A.Benjamin,New York,1968),尤其第1、3、4、6、7和9章;"The Chemistry ofHeterocyclic Compounds,A series of Monographs"(John Wiley&Sons,New York,1950至今),尤其第13、14、16、19和28卷;以及J.Am.Chem.Soc.(1960)82:5566。“杂环基”还包括其中杂环基团与饱和、部分不饱和环或芳香族碳环或杂环稠合的基团。杂环的实例包括但不限于吗啉-4-基、哌啶-1-基、哌嗪基、哌嗪-4-基-2-酮、哌嗪-4-基-3-酮、吡咯烷-1-基、硫代吗啉-4-基、S-二氧代硫代吗啉-4-基、氮杂环辛烷-1-基、氮杂环丁烷-1-基、八氢吡啶并[1,2-a]吡嗪-2-基、[1,4]二氮杂环庚烷-1-基、吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶代、吗啉代、硫代吗啉代、氧硫杂环己烷基、哌嗪基、高哌嗪基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂环庚烷基、二氮杂环庚烷基、硫氮杂环庚烷基、2-吡咯啉基、3-吡咯啉基、吲哚啉基、2H-吡喃基、4H-吡喃基、二噁烷基、1,3-二氧杂环戊烷基、吡唑啉基、二噻烷基、二硫杂环戊烷基、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基咪唑啉基、咪唑烷基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基和N-吡啶基脲。螺杂环基部分也包括于本定义的范围内。螺杂环基部分的实例包括氮杂螺[2.5]辛基和氮杂螺[2.4]庚基。其中2个环原子经氧代(=O)部分取代的杂环基的实例是嘧啶酮基和1,1-二氧代-硫代吗啉基。本文中的杂环基任选地独立地经一个或多个本文所描述的取代基取代。
术语“杂环二基”是指3个至约20个环原子的二价饱和或部分不饱和(亦即,在环内具有一个或多个双键和/或三键)碳环基团,其中至少一个环原子是选自氮、氧、磷和硫的杂原子,其余环原子是C,其中一个或多个环原子任选地独立地经一个或多个所描述的取代基取代。5元和6元杂环二基的实例包括吗啉二基、哌啶二基、哌嗪二基、吡咯烷二基、二噁烷二基、硫代吗啉二基和S-二氧代硫代吗啉二基。
术语“杂芳基”是指5元、6元或7元环的单价芳香族基团,并且包括5-20个原子的稠环系统(其中至少一个环是芳香族的),其含有一个或多个独立地选自氮、氧和硫的杂原子。杂芳基的实例是吡啶基(包括例如2-羟基吡啶基)、咪唑基、咪唑并吡啶基、嘧啶基(包括例如4-羟基嘧啶基)、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁二唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、四氢异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲哚嗪基、酞嗪基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、噻二唑基、呋呫基、苯并呋呫基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基和呋喃并吡啶基。杂芳基任选地独立地经一个或多个本文所描述的取代基取代。
术语“杂芳二基”是指5元、6元或7元环的二价芳香族基团,并且包括5-20个原子的稠环系统(其中至少一个环是芳香族的),其含有一个或多个独立地选自氮、氧和硫的杂原子。5元和6元杂芳二基的实例包括吡啶二基、咪唑二基、嘧啶二基、吡唑二基、三唑二基、吡嗪二基、四唑二基、呋喃二基、噻吩二基、异噁唑二基二基、噻唑二基、噁二唑二基、噁唑二基、异噻唑二基和吡咯二基。
在可能的情况下,杂环或杂芳基可以是碳(碳连接)或氮(氮连接)键结的。举例来说并且不受限制,碳键结的杂环或杂芳基在以下位置处键结:吡啶的2、3、4、5或6位,哒嗪的3、4、5或6位,嘧啶的2、4、5或6位,吡嗪的2、3、5或6位,呋喃、四氢呋喃、硫代呋喃、噻吩、吡咯或四氢吡咯的2、3、4或5位,噁唑、咪唑或噻唑的2、4或5位,异噁唑、吡唑或异噻唑的3、4或5位,氮杂环丙烷的2或3位,氮杂环丁烷的2、3或4位,喹啉的2、3、4、5、6、7或8位,或异喹啉的1、3、4、5、6、7或8位。
举例来说并且不受限制,氮键结的杂环或杂芳基在以下位置处键结:氮杂环丙烷、氮杂环丁烷、吡咯、吡咯烷、2-吡咯啉、3-吡咯啉、咪唑、咪唑烷、2-咪唑啉、3-咪唑啉、吡唑、吡唑啉、2-吡唑啉、3-吡唑啉、哌啶、哌嗪、吲哚、吲哚啉、1H-吲唑的1位,异吲哚或异吲哚啉的2位,吗啉的4位,以及咔唑或β-咔啉的9位。
单独或作为另一取代基的一部分的术语“卤基”和“卤素”是指氟、氯、溴或碘原子。
单独或作为另一取代基的一部分的术语“羰基”是指C(=O)或-C(=O)-,即,碳原子双键键结至氧并且结合至具有羰基的部分中的两个其它基团。
如本文所用的短语“季铵盐”是指已用烷基取代基(例如C1-C4烷基,诸如甲基、乙基、丙基或丁基)季铵化的叔胺。
术语“治疗(treat/treatment/treating)”是指成功治疗或改善损伤、病变、疾患(例如癌症)或症状(例如认知障碍)的任何指标,包括任何客观或主观参数,诸如消除;缓解;减轻症状或使患者更能忍受症状、损伤、病变或疾患;症状进展的速率降低;减少症状或疾患的频率或持续时间;或在一些情况下预防症状发作。症状的治疗或改善可以基于任何客观或主观参数,包括例如身体检查的结果。
术语“癌症”、“赘瘤”和“肿瘤”在本文中用于指展现自主、不受调控的生长的细胞,使得细胞展现以对细胞增殖的控制显著损失为特征的异常生长表型。在本发明的情形中用于检测、分析和/或治疗的所关注细胞包括癌细胞(例如,来自患有癌症的个体的癌细胞)、恶性癌细胞、转移前癌细胞、转移性癌细胞和非转移性癌细胞。几乎每个组织的癌症都是已知的。短语“癌症负担”是指受试者中的癌细胞数量或癌症体积。因此,减少癌症负担是指减小受试者中的癌细胞数目或癌细胞体积。如本文所用的术语“癌细胞”是指成为癌细胞(例如,来自可治疗个体的任何癌症,例如从患有癌症的个体分离)或来源于癌细胞,例如癌细胞克隆体的任何细胞。举例来说,癌细胞可以来自已建立的癌细胞系,可以是从患有癌症的个体分离的初生细胞,可以是来自于从患有癌症的个体分离的初生细胞的子代细胞,等等。在一些实施方案中,这个术语还可以指癌细胞的一部分,诸如癌细胞的亚细胞部分、细胞膜部分或细胞溶解产物。本领域技术人员已知许多类型的癌症,包括实体肿瘤,诸如癌瘤、肉瘤、胶质母细胞瘤、黑色素瘤、淋巴瘤和骨髓瘤,以及循环癌,诸如白血病。
如本文所用的术语“癌症”包括任何形式的癌症,包括但不限于实体肿瘤癌(例如皮肤癌、肺癌、前列腺癌、乳癌、胃癌、膀胱癌、结肠癌、卵巢癌、胰脏癌、肾癌、肝癌、胶质母细胞瘤、髓母细胞瘤、平滑肌肉瘤、头颈部鳞状细胞癌、黑色素瘤和神经内分泌癌)和液体癌(例如血液学癌症);癌瘤;软组织肿瘤;肉瘤;畸胎瘤;黑色素瘤;白血病;淋巴瘤;以及脑癌,包括微小残留病,并且包括原发性和转移性肿瘤。
“PD-L1表达”是指在细胞表面上具有PD-L1受体的细胞。如本文所用的“PD-L1过表达”是指与对应的非癌细胞相比具有更多PD-L1受体的细胞。
“HER2”是指蛋白质人类表皮生长因子受体2。
“HER2表达”是指在细胞表面上具有HER2受体的细胞。举例来说,细胞在细胞表面上可以具有约20,000个至约50,000个HER2受体。如本文所用的“HER2过表达”是指具有超过约50,000个HER2受体的细胞。举例来说,与对应的非癌细胞相比,细胞的HER2受体数目是2、5、10、100、1,000、10,000、100,000或1,000,000倍(例如,约1百万或2百万个HER2受体)。据估计,HER2在约25%至约30%的乳癌中过表达。
癌症的“病变”包括所有损害患者健康的现象。这包括但不限于异常或不可控的细胞生长、转移、干扰邻近细胞正常发挥功能、以异常水平释放细胞因子或其它分泌产物、抑制或加重炎症或免疫反应、赘瘤、癌前病变、恶性病以及侵入周围或远端组织或器官(诸如淋巴结)。
如本文所用的短语“癌症复发”和“肿瘤复发”及其语法变型是指在诊断出癌症之后赘生性细胞或癌细胞的进一步生长。特别地,当癌组织中发生癌细胞进一步生长时可能会发生复发。类似地,当肿瘤细胞播散至局部或远端组织和器官中时发生“肿瘤扩散”,因此,肿瘤扩散涵盖肿瘤转移。当肿瘤生长局部扩散开以通过压缩、破坏或阻止正常器官功能来损害所涉及组织的功能时发生“肿瘤侵入”。
如本文所用的术语“转移”是指癌性肿瘤在器官或身体部分中的生长,所述器官或身体部分不直接连接至原始癌性肿瘤的器官。转移应理解为包括微转移,其为在不直接连接至原始癌性肿瘤的器官的器官或身体部分中存在不可检测量的癌细胞。转移还可以定义为过程的若干步骤,诸如癌细胞从原始肿瘤部位离开以及癌细胞迁移和/或侵入身体的其它部分。
短语“有效量”和“治疗有效量”是指对于施用来说产生治疗作用的物质,诸如免疫缀合物的剂量或量。确切剂量将取决于治疗目的,并且将由本领域技术人员使用已知技术可确定(参见例如Lieberman,Pharmaceutical Dosage Forms(第1-3卷,1992);Lloyd,TheArt,Science and Technology of Pharmaceutical Compounding(1999);Pickar,DosageCalculations(1999);Goodman&Gilman's The Pharmacological Basis ofTherapeutics,第11版(McGraw-Hill,2006);以及Remington:The Science and Practiceof Pharmacy,第22版,(Pharmaceutical Press,London,2012))。在癌症的情况下,治疗有效量的免疫缀合物可以减少癌细胞的数目;减小肿瘤大小;抑制(即,在一定程度上减缓并且优选地停止)癌细胞浸润至周边器官中;抑制(即,在一定程度上减缓并且优选地停止)肿瘤转移;在一定程度上抑制肿瘤生长;和/或在一定程度上缓解一种或多种与癌症相关的症状。在免疫缀合物可以阻止现有癌细胞生长和/或杀死现有癌细胞的程度上,其可能具有细胞生长抑制性和/或细胞毒性。对于癌症疗法,可以例如通过评估疾病进展时间(TTP)和/或确定反应率(RR)来测量功效。
“接受者”、“个体”、“受试者”、“宿主”和“患者”可互换使用并且是指需要诊断、治疗或疗法的任何哺乳动物受试者(例如人类)。用于治疗目的的“哺乳动物”是指归类为哺乳动物的任何动物,包括人类、家养和农场动物以及动物园动物、运动型动物或宠物,诸如犬、马、猫、牛、绵羊、山羊、猪、骆驼等。在某些实施方案中,哺乳动物是人类。
在本发明的情形中,短语“协同佐剂”或“协同组合”包括两种免疫调节剂的组合,诸如受体激动剂、细胞因子和佐剂多肽,所述免疫调节剂以组合形式相对于单独施用的任一者对免疫引发协同作用。特别地,本文所公开的免疫缀合物包含所要求的佐剂与抗体构建体的协同组合。举例来说,相对于在不存在其它部分的情况下施用抗体构建体或佐剂时,这些协同组合在施用后对免疫引发更大作用。此外,与单独施用抗体构建体或佐剂时相比,可以施用减少量的免疫缀合物(如由作为免疫缀合物的一部分施用的抗体构建体的总数或佐剂的总数来测量)。
如本文所用的术语“施用”是指向受试者肠道外、静脉内、腹膜内、肌肉内、肿瘤内、病灶内、鼻内或皮下施用、经口施用、以栓剂施用、局部接触、鞘内施用或植入缓释装置,例如微型渗透泵。
如本文中用于修饰数值的术语“约”和“左右”指示在所述数值周围的接近范围。因此,如果“X”是所述值,那么“约X”或“X左右”指示0.9X至1.1X,例如0.95X至1.05X或0.99X至1.01X的值。提及“约X”或“X左右”特定指示至少值X、0.95X、0.96X、0.97X、0.98X、0.99X、1.01X、1.02X、1.03X、1.04X和1.05X。因此,“约X”和“X左右”意图教示并提供对例如“0.98X”的权利要求限制的书面描述支持。
抗体标靶
在一些实施方案中,免疫缀合物的抗体能够结合一个或多个选自以下的标靶(例如,特异性结合至选自以下的标靶):5T4、ABL、ABCF1、ACVR1、ACVR1B、ACVR2、ACVR2B、ACVRL1、ADORA2A、聚集蛋白聚糖(Aggrecan)、AGR2、AICDA、AIF1、AIGI、AKAP1、AKAP2、AMH、AMHR2、ANGPT1、ANGPT2、ANGPTL3、ANGPTL4、ANPEP、APC、APOC1、AR、芳香化酶、ATX、AX1、AZGP1(锌-a-糖蛋白)、B7.1、B7.2、B7-H1、BAD、BAFF、BAG1、BAI1、BCR、BCL2、BCL6、BDNF、BLNK、BLR1(MDR15)、BIyS、BMP1、BMP2、BMP3B(GDFIO)、BMP4、BMP6、BMP8、BMPRTA、BMPR1B、BMPR2、BPAG1(网蛋白(plectin))、BRCA1、C19orflO(IL27w)、C3、C4A、C5、C5R1、CANT1、CAPRIN-1、CASP1、CASP4、CAV1、CCBP2(D6/JAB61)、CCLI(1-309)、CCLI1(嗜酸性粒细胞趋化因子(eotaxin))、CCL13(MCP-4)、CCL15(MIP-Id)、CCL16(HCC-4)、CCL17(TARC)、CCL18(PARC)、CCL19(MIP-3b)、CCL2(MCP-1)、MCAF、CCL20(MIP-3a)、CCL21(MEP-2)、SLC、艾克度司-2(exodus-2)、CCL22(MDC/STC-1)、CCL23(MPIF-I)、CCL24(MPIF-2/嗜酸性粒细胞趋化因子-2)、CCL25(TECK)、CCL26(嗜酸性粒细胞趋化因子-3)、CCL27(CTACK/ILC)、CCL28、CCL3(MIP-Ia)、CCL4(MIPIb)、CCL5(RANTES)、CCL7(MCP-3)、CCL8(mcp-2)、CCNA1、CCNA2、CCND1、CCNE1、CCNE2、CCR1(CKR1/HM145)、CCR2(mcp-IRB/RA)、CCR3(CKR3/CMKBR3)、CCR4、CCR5(CMKBR5/ChemR13)、CCR6(CMKBR6/CKR-L3/STRL22/DRY6)、CCR7(CKR7/EBI1)、CCR8(CMKBR8/TERI/CKR-L1)、CCR9(GPR-9-6)、CCRL1(VSHK1)、CCRL2(L-CCR)、CD164、CD19、CDIC、CD2、CD20、CD21、CD200、CD-22、CD24、CD27、CD28、CD3、CD33、CD35、CD37、CD38、CD3E、CD3G、CD3Z、CD4、CD38、CD40、CD40L、CD44、CD45RB、CD47、CD52、CD69、CD72、CD74、CD79A、CD79B、CD8、CD80、CD81、CD83、CD86、CD137、CD152、CD274、CDH1(E钙粘蛋白(Ecadherin))、CDH1O、CDH12、CDH13、CDH18、CDH19、CDH2O、CDH5、CDH7、CDH8、CDH9、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK9、CDKN1A(p21Wap1/Cip1)、CDKN1B(p27Kip1)、CDKN1C、CDKN2A(p16INK4a)、CDKN2B、CDKN2C、CDKN3、CEBPB、CERI、CHGA、CHGB、几丁质酶(Chitinase)、CHST1O、CKLFSF2、CKLFSF3、CKLFSF4、CKLFSF5、CKLFSF6、CKLFSF7、CKLFSF8、CLDN3、CLDN7(克劳汀蛋白-7(claudin-7))、CLDN18.2(克劳汀蛋白18.2)、CLN3、CLU(簇集蛋白(clusterin))、CMKLR1、CMKOR1(RDC1)、CNR1、COL18A1、COLIA1、COL4A3、COL6A1、CR2、Cripto、CRP、CSF1(M-CSF)、CSF2(GM-CSF)、CSF3(GCSF)、CTL8、CTNNB1(b-连环蛋白(b-catenin))、CTSB(组织蛋白酶B)、CX3CL1(SCYD1)、CX3CR1(V28)、CXCL1(GRO1)、CXCL1O(IP-IO)、CXCLI1(1-TAC/IP-9)、CXCL12(SDF1)、CXCL13、CXCL14、CXCL16、CXCL2(GRO2)、CXCL3(GRO3)、CXCL5(ENA-78/LIX)、CXCL6(GCP-2)、CXCL9(MIG)、CXCR3(GPR9/CKR-L2)、CXCR4、CXCR6(TYMSTR/STRL33/Bonzo)、CYB5、CYC1、CYSLTR1、DAB2IP、DES、DKFZp451J0118、DNCL1、DPP4、E2F1、Engel、Edge、Fennel、EFNA3、EFNB2、EGF、EGFR、ELAC2、ENG、Enola、ENO2、ENO3、EPHA1、EPHA2、EPHA3、EPHA4、EPHA5、EPHA6、EPHA7、EPHA8、EPHA9、EPRA10、EPHB1、EPHB2、EPHB3、EPHB4、EPHB5、EPHB6、EPHRIN-A1、EPHRIN-A2、EPHRINA3、EPHRIN-A4、EPHRIN-A5、EPHRIN-A6、EPHRIN-B1、EPHRIN-B2、EPHRIN-B3、EPHB4、EPG、ERBB2(Her-2)、EREG、ERK8、雌激素受体、Earl、ESR2、F3(TF)、FADD、法尼基转移酶(famesyltransferase)、FasL、FASNf、FCER1A、FCER2、FCGR3A、FGF、FGF1(aFGF)、FGF10、FGF11、FGF12、FGF12B、FGF13、FGF14、FGF16、FGF17、FGF18、FGF19、FGF2(bFGF)、FGF20、FGF21、FGF22、FGF23、FGF3(int-2)、FGF4(HST)、FGF5、FGF6(HST-2)、FGF7(KGF)、FGF8、FGF9、FGFR3、FIGF(VEGFD)、FILI(EPSILON)、FBL1(ZETA)、FLJ12584、FLJ25530、FLRT1(纤维粘连蛋白)、FLT1、FLT-3、FOS、FOSL1(FRA-1)、FY(DARC)、GABRP(GABAa)、GAGEB1、GAGEC1、GALNAC4S-6ST、GATA3、GD2、GDF5、GFI1、GGT1、GM-CSF、GNAS1、GNRH1、GPR2(CCR10)、GPR31、GPR44、GPR81(FKSG80)、GRCC1O(C1O)、GRP、GSN(凝溶胶蛋白(Gelsolin))、GSTP1、HAVCR2、HDAC、HDAC4、HDAC5、HDAC7A、HDAC9、刺猬蛋白(Hedgehog)、HGF、HIF1A、HIP1、组胺和组胺受体、HLA-A、HLA-DRA、HLA-E、HM74、HMOXI、HSP90、HUMCYT2A、ICEBERG、ICOSL、ID2、IFN-a、IFNA1、IFNA2、IFNA4、IFNA5、EFNA6、BFNA7、IFNB1、IFNγ、IFNW1、IGBP1、IGF1、IGFIR、IGF2、IGFBP2、IGFBP3、IGFBP6、DL-1、ILIO、ILIORA、ILIORB、IL-1、IL1R1(CD121a)、IL1R2(CD121b)、IL-IRA、IL-2、IL2RA(CD25)、IL2RB(CD122)、IL2RG(CD132)、IL-4、IL-4R(CD123)、IL-5、IL5RA(CD125)、IL3RB(CD131)、IL-6、IL6RA、(CD126)、IR6RB(CD130)、IL-7、IL7RA(CD127)、IL-8、CXCR1(IL8RA)、CXCR2、(IL8RB/CD128)、IL-9、IL9R(CD129)、IL-10、IL10RA(CD210)、IL10RB(CDW210B)、IL-11、IL11RA、IL-12、IL-12A、IL-12B、IL-12RB1、IL-12RB2、IL-13、IL13RA1、IL13RA2、IL14、IL15、IL15RA、IL16、IL17、IL17A、IL17B、IL17C、IL17R、IL18、IL18BP、IL18R1、IL18RAP、IL19、ILIA、ILIB、ILIF10、ILIF5、IL1F6、ILIF7、IL1F8、DL1F9、ILIHYI、ILIR1、ILIR2、ILIRAP、ILIRAPLI、ILIRAPL2、ILIRL1、IL1RL2、ILIRN、IL2、IL20、IL20RA、IL21R、IL22、IL22R、IL22RA2、IL23、DL24、IL25、IL26、IL27、IL28A、IL28B、IL29、IL2RA、IL2RB、IL2RG、IL3、IL30、IL3RA、IL4、IL4、IL6ST(糖蛋白130)、ILK、INHA、INHBA、INSL3、INSL4、IRAK1、IRAK2、ITGA1、ITGA2、ITGA3、ITGA6(α6整合蛋白)、ITGAV、ITGB3、ITGB4(β4整合蛋白)、JAG1、JAK1、JAK3、JTB、JUN、K6HF、KAI1、KDR、KITLG、KLF5(GC框BP)、KLF6、KLK10、KLK12、KLK13、KLK14、KLK15、KLK3、KLK4、KLK5、KLK6、KLK9、KRT1、KRT19(角蛋白19(Keratin19))、KRT2A、KRTHB6(毛发特异性II型角蛋白)、LAMA5、LEP(瘦素(leptin))、Lingo-p75、Lingo-Troy、LPS、LTA(TNF-b))、LTB、LTB4R(GPR16)、LTB4R2、LTBR、MACMARCKS、MAG或OMgp、MAP2K7(c-Jun)、MCP-1、MDK、MIB1、中期因子(midkine)、MIF、MISRII、MJP-2、MK、MKI67(Ki-67)、MMP2、MMP9、MS4A1、MSMB、MT3(金属硫连接蛋白-UI(metallothionectin-UI))、mTOR、MTSS1、MUC1(粘蛋白(mucin))、MYC、MYD88、NCK2、神经蛋白聚糖(neurocan)、粘连蛋白-4、NFKBI、NFKB2、NGFB(NGF)、NGFR、NgR-Lingo、NgRNogo66、(Nogo)、NgR-p75、NgR-Troy、NMEI(NM23A)、NOTCH、NOTCH1、NOX5、NPPB、NROB1、NROB2、NRID1、NR1D2、NR1H2、NR1H3、NR1H4、NR112、NR113、NR2C1、NR2C2、NR2E1、NR2E3、NR2F1、NR2F2、NR2F6、NR3C1、NR3C2、NR4A1、NR4A2、NR4A3、NR5A1、NR5A2、NR6A1、NRP1、NRP2、NT5E、NTN4、ODZI、OPRDI、P2RX7、PAP、PART1、PATE、PAWR、PCA3、PCDGF、PCNA、PDGFA、PDGFB、PDGFRA、PDGFRB、PECAMI、培门冬酶(peg-asparaginase)、PF4(CXCL4)、PGF、PGR、磷酸蛋白聚糖(phosphacan)、PIAS2、PI3激酶、PIK3CG、PLAU(uPA)、PLG、PLXDCI、PKC、PKC-β、PPBP(CXCL7)、PPID、PR1、PRKCQ、PRKD1、PRL、PROC、PROK2、PSAP、PSCA、PTAFR、PTEN、PTGS2(COX-2)、PIN、RAC2(P21Rac2)、RANK、RANK配体、RARB、RGS1、RGS13、RGS3、RNFI1O(ZNF144)、Ron、ROBO2、RXR、S100A2、SCGB 1D2(亲脂性蛋白B(lipophilin B))、SCGB2A1(乳腺珠蛋白2(mammaglobin 2))、SCGB2A2(乳腺珠蛋白1)、SCYE1(内皮单核细胞活化细胞因子)、SDF2、SERPENA1、SERPINA3、SERPINB5(乳腺丝抑蛋白(maspin))、SERPINEI(PAI-I)、SERPINFI、SHIP-1、SHIP-2、SHB1、SHB2、SHBG、SfcAZ、SLC2A2、SLC33A1、SLC43A1、SLIT2、SPP1、SPRR1B(Spr1)、ST6GAL1、STAB1、STATE、STEAP、STEAP2、TB4R2、TBX21、TCP1O、TDGF1、TEK、TGFA、TGFB1、TGFB1I1、TGFB2、TGFB3、TGFBI、TGEBR1、TGFBR2、TGFBR3、THIL、THBS1(血小板反应蛋白-1(thrombospondin-1))、THBS2、THBS4、THPO、TIE(Tie-1)、TIMP3、组织因子、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TNF、TNF-a、TNFAIP2(B94)、TNFAIP3、TNFRSF11A、TNFRSF1A、TNFRSF1B、TNFRSF21、TNFRSF5、TNFRSF6(Fas)、TNFRSF7、TNFRSF8、TNFRSF9、TNFSF1O(TRAIL)、TNFSF11(TRANCE)、TNFSF12(APO3L)、TNFSF13(April)、TNFSF13B、TNSF14(HVEM-L)、TNFRSF14(HVEM)、TNFSF15(VEGI)、TNFSF18、TNFSF4(OX40配体)、TNFSF5(CD40配体)、TNFSF6(FasL)、TNFSF7(CD27配体)、TNFSF8(CD30配体)、TNFSF9(4-1BB配体)、TOLLIP、Toll样受体、TOP2A(拓扑异构酶1ia)、TP53、TPM1、TPM2、TRADD、TRAF1、TRAF2、TRAF3、TRAF4、TRAF5、TRAF6、TRKA、TREM1、TREM2、TROP2、TRPC6、TSLP、TWEAK、酪氨酸酶、uPAR、VEGF、VEGFB、VEGFC、多能蛋白聚糖(versican)、VHL C5、VLA-4、Wnt-1、XCL1(淋巴细胞趋化因子(tymphotactin))、XCL2(SCM-Ib)、XCRI(GPR5/CCXCR1)、YYI、ZFPM2、CLEC4C(BDCA-2、DLEC、CD303、CLECSF7)、CLEC4D(MCL、CLECSF8)、CLEC4E(敏可素(Mincle))、CLEC6A(达汀素-2(Dectin-2))、CLEC5A(MDL-1、CLECSF5)、CLEC1B(CLEC-2)、CLEC9A(DNGR-1)、CLEC7A(达汀素-1)、PDGFRa、SLAMF7、GP6(GPVI)、LILRA1(CD85I)、LILRA2(CD85H、ILT1)、LILRA4(CD85G、ILT7)、LILRA5(CD85F、ILT11)、LILRA6(CD85b、ILT8)、NCR1(CD335、LY94、NKp46)、NCR3(CD335、LY94、NKp46)、NCR3(CD337、NKp30)、OSCAR、TARM1、CD300C、CD300E、CD300LB(CD300B)、CD300LD(CD300D)、KIR2DL4(CD158D)、KIR2DS、KLRC2(CD159C、NKG2C)、KLRK1(CD314、NKG2D)、NCR2(CD336、NKp44)、PILRB、SIGLEC1(CD169、SN)、SIGLEC14、SIGLEC15(CD33L3)、SIGLEC16、SIRPB1(CD172B)、TREM1(CD354)、TREM2和KLRF1(NKp80)。
在一些实施方案中,抗体结合至FcRγ偶联受体。在一些实施方案中,FcRγ偶联受体选自由GP6(GPVI)、LILRA1(CD85I)、LILRA2(CD85H、ILT1)、LILRA4(CD85G、ILT7)、LILRA5(CD85F、ILT11)、LILRA6(CD85b、ILT8)、NCR1(CD335、LY94、NKp46)、NCR3(CD335、LY94、NKp46)、NCR3(CD337、NKp30)、OSCAR和TARM1组成的组。
在一些实施方案中,抗体结合至DAP12偶联受体。在一些实施方案中,DAP12偶联受体选自由CD300C、CD300E、CD300LB(CD300B)、CD300LD(CD300D)、KIR2DL4(CD158D)、KIR2DS、KLRC2(CD159C、NKG2C)、KLRK1(CD314、NKG2D)、NCR2(CD336、NKp44)、PILRB、SIGLEC1(CD169、SN)、SIGLEC14、SIGLEC15(CD33L3)、SIGLEC16、SIRPB1(CD172B)、TREM1(CD354)和TREM2组成的组。
在一些实施方案中,抗体结合至带有hemITAM的受体。在一些实施方案中,带有hemITAM的受体是KLRF1(NKp80)。
在一些实施方案中,抗体能够结合一个或多个选自以下的标靶:CLEC4C(BDCA-2、DLEC、CD303、CLECSF7)、CLEC4D(MCL、CLECSF8)、CLEC4E(敏可素)、CLEC6A(达汀素-2)、CLEC5A(MDL-1、CLECSF5)、CLEC1B(CLEC-2)、CLEC9A(DNGR-1)和CLEC7A(达汀素-1)。在一些实施方案中,抗体能够结合CLEC6A(达汀素-2)或CLEC5A。在一些实施方案中,抗体能够结合CLEC6A(达汀素-2)。
在一些实施方案中,抗体能够结合一个或多个选自以下的标靶(例如,特异性结合至选自以下的标靶):ATP5I(Q06185)、OAT(P29758)、AIFM1(Q9Z0X1)、AOFA(Q64133)、MTDC(P18155)、CMC1(Q8BH59)、PREP(Q8K411)、YMEL1(O88967)、LPPRC(Q6PB66)、LONM(Q8CGK3)、ACON(Q99KI0)、ODO1(Q60597)、IDHP(P54071)、ALDH2(P47738)、ATPB(P56480)、AATM(P05202)、TMM93(Q9CQW0)、ERGI3(Q9CQE7)、RTN4(Q99P72)、CL041(Q8BQR4)、ERLN2(Q8BFZ9)、TERA(Q01853)、DAD1(P61804)、CALX(P35564)、CALU(O35887)、VAPA (Q9WV55)、MOGS(Q80UM7)、GANAB(Q8BHN3)、ERO1A(Q8R180)、UGGG1(Q6P5E4)、P4HA1(Q60715)、HYEP(Q9D379)、CALR(P14211)、AT2A2(O55143)、PDIA4(P08003)、PDIA1(P09103)、PDIA3(P27773)、PDIA6(Q922R8)、CLH(Q68FD5)、PPIB(P24369)、TCPG(P80318)、MOT4(P57787)、NICA(P57716)、BASI(P18572)、VAPA(Q9WV55)、ENV2(P11370)、VAT1(Q62465)、4F2(P10852)、ENOA(P17182)、ILK(O55222)、GPNMB(Q99P91)、ENV1(P10404)、ERO1A(Q8R180)、CLH、(Q68FD5)、DSG1A(Q61495)、AT1A1(Q8VDN2)、HYOU1(Q9JKR6)、TRAP1(Q9CQN1)、GRP75(P38647)、ENPL(P08113)、CH60(P63038)和CH10(Q64433)。在前述清单中,寄存编号在括号中示出。
在一些实施方案中,抗体结合至选自CDH1、CD19、CD20、CD29、CD30、CD38、CD40、CD47、EpCAM、MUC1、MUC16、EGFR、Her2、SLAMF7和gp75的抗原。在一些实施方案中,抗原选自CD19、CD20、CD47、EpCAM、MUC1、MUC16、EGFR和Her2。在一些实施方案中,抗体结合至选自Tn抗原和汤姆森-弗里德里希抗原(Thomsen-Friedenreich antigen)的抗原。
在一些实施方案中,抗体或Fc融合蛋白选自:阿巴伏单抗(abagovomab)、阿巴西普(abatacept)(也称为)、阿昔单抗(abciximab)(也称为/>c7E3Fab)、阿达木单抗(adalimumab)(也称为/>)、阿德木单抗(adecatumumab)、阿仑单抗(alemtuzumab)(也称为/>MabCampath或Campath-1H)、阿妥莫单抗(altumomab)、阿非莫单抗(afelimomab)、马安那莫单抗(anatumomab mafenatox)、阿尼莫单抗(anetumumab)、安如珠单抗(anrukizumab)、阿泊珠单抗(apolizumab)、阿西莫单抗(arcitumomab)、阿塞珠单抗(aselizumab)、阿利珠单抗(atlizumab)、阿托木单抗(atorolimumab)、巴匹组单抗(bapineuzumab)、巴利昔单抗(basiliximab)(也称为)、巴维昔单抗(bavituximab)、贝妥莫单抗(bectumomab)(也称为)、贝利木单抗(belimumab)(也称为/>)、柏替木单抗(bertilimumab)、贝索单抗(besilesomab)、贝伐珠单抗(bevacizumab)(也称为)、巴比西单抗(biciromab brallobarbital)、莫比伐珠单抗(bivatuzumabmertansine)、坎帕斯(campath)、康纳单抗(canakinumab)(也称为ACZ885)、莫坎妥珠单抗(cantuzumab mertansine)、卡罗单抗(capromab)(也称为/>)、卡妥索单抗(catumaxomab)(也称为/>)、西利珠单抗(cedelizumab)(也称为/>)、培塞利珠单抗(certolizumab pegol)、西妥昔单抗(cetuximab)(也称为/>)、克立昔单抗(clenoliximab)、达西组单抗(dacetuzumab)、达昔单抗(dacliximab)、达克珠单抗(daclizumab)(也称为/>)、地诺单抗(denosumab)(也称为AMG 162)、地莫单抗(detumomab)、阿托度单抗(dorlimomab aritox)、达匹利珠单抗(dorlixizumab)、度妥木单抗(duntumumab)、德里姆单抗(durimulumab)、德木鲁单抗(durmulumab)、依美昔单抗(ecromeximab)、依库珠单抗(eculizumab)(也称为/>)、埃巴单抗(edobacomab)、依决洛单抗(edrecolomab)(也称为Mab17-1A、/>)、依法珠单抗(efalizumab)(也称为/>)、依芬古单抗(efungumab)(也称为/>)、艾西莫单抗(elsilimomab)、培恩莫单抗(enlimomab pegol)、西依匹莫单抗(epitumomab cituxetan)、依法珠单抗、依匹莫单抗(epitumomab)、依帕珠单抗(epratuzumab)、厄利珠单抗(erlizumab)、厄妥索单抗(ertumaxomab)(也称为/>)、依那西普(etanercept)(也称为/>)、埃达组单抗(etaracizumab)(也称为埃妥珠单抗(etaratuzumab)、/>)、艾韦单抗(exbivirumab)、法索单抗(fanolesomab)(也称为/>)、法拉莫单抗(faralimomab)、泛维珠单抗(felvizumab)、芳妥珠单抗(fontolizumab)(也称为/>)、加利昔单抗(galiximab)、更汀芦单抗(gantenerumab)、加维莫单抗(gavilimomab)(也称为)、奥吉妥珠单抗(gemtuzumab ozogamicin)(也称为/>)、戈利木单抗(golimumab)(也称为CNTO 148)、戈利昔单抗(gomiliximab)、伊巴组单抗(ibalizumab)(也称为TNX-355)、替伊莫单抗(ibritumomab tiuxetan)(也称为)、伊戈伏单抗(igovomab)、英西单抗(imciromab)、英夫利昔单抗(infliximab)(也称为/>)、伊诺莫单抗(inolimomab)、奥英妥珠单抗(inotuzumab ozogamicin)、伊匹单抗(ipilimumab)(也称为MDX-010、MDX-101)、伊妥木单抗(iratumumab)、凯利昔单抗(keliximab)、拉贝妥珠单抗、来马索单抗(lemalesomab)、莱布利珠单抗(lebrilizumab)、乐德木单抗(lerdelimumab)、来沙木单抗(lexatumumab)(也称为HGS-ETR2、ETR2-ST01)、雷妥木单抗(lexitumumab)、利韦单抗(libivirumab)、林妥珠单抗(lintuzumab)、卢卡木单抗(lucatumumab)、鲁昔单抗(lumiliximab)、马帕木单抗(mapatumumab)(也称为HGSETR1、TRM-1)、马司莫单抗(maslimomab)、马妥珠单抗(matuzumab)(也称为EMD72000)、美泊利单抗(mepolizumab)(也称为/>)、美替木单抗(metelimumab)、米拉组单抗(milatuzumab)、明瑞莫单抗(minretumomab)、米妥莫单抗(mitumomab)、莫罗木单抗(morolimumab)、莫维珠单抗(motavizwnab)(也称为)、莫罗单抗(muromonab)(也称为OKT3)、他那可单抗(nacolomab tafenatox)、埃托那普妥莫单抗(naptumomab estafenatox)、那他珠单抗(natalizumab)(也称为)、奈巴库单抗(nebacumab)、奈瑞莫单抗(nerelimomab)、尼妥珠单抗(nimotuzumab)(也称为)、莫诺非莫单抗(nofetumomab merpentan)(也称为/>)、奥克立珠单抗(ocrelizumab)、奥度莫单抗(odulimomab)、奥法木单抗(ofatumumab)、奥马珠单抗(omalizumab)(也称为)、奥戈伏单抗(oregovomab)(也称为/>)、奥昔珠单抗(otelixizumab)、帕吉昔单抗(pagibaximab)、帕利珠单抗(palivizumab)(也称为/>)、帕尼单抗(panitumumab)(也称为ABX-EGF、/>)、帕考珠单抗(pascolizumab)、派姆单抗(pemtumomab)(也称为/>)、帕妥珠单抗(也称为2C4、/>)、培克珠单抗(pexelizumab)、平妥莫单抗(pintumomab)、普立昔单抗(priliximab)、普托木单抗(pritumumab)、雷珠单抗(ranibizumab)(也称为/>)、雷昔库单抗(raxibacumab)、瑞加韦单抗(regavirumab)、瑞利珠单抗(reslizumab)、利妥昔单抗(rituximab)(也称为/> )、罗维珠单抗(rovelizumab)、卢利珠单抗(ruplizumab)、沙妥莫单抗(satumomab)、司韦单抗(sevirumab)、西罗珠单抗(sibrotuzumab)、西利珠单抗(siplizumab)(也称为MEDI-507)、索土珠单抗(sontuzumab)、司他芦单抗(stamulumab)(也称为MYO-029)、硫索单抗(sulesomab)(也称为/>)、替他珠单抗(tacatuzumab tetraxetan)、他度珠单抗(tadocizumab)、他利珠单抗(talizumab)、帕他莫单抗(taplitumomab paptox)、替非组单抗(tefibazumab)(也称为/>)、阿替莫单抗(telimomab aritox)、替奈昔单抗(teneliximab)、替利组单抗(teplizumab)、替西木单抗(ticilimumab)、托珠单抗(tocilizumab)(也称为/>)、托拉珠单抗(toralizumab)、托西莫单抗(tositumomab)、曲妥珠单抗(也称为/>)、曲美木单抗(tremelimumab)(也称为CP-675,206)、西莫白介素单抗(tucotuzumab celmoleukin)、妥韦单抗(tuvirumab)、乌珠单抗(urtoxazumab)、乌司奴单抗(ustekinumab)(也称为CNTO 1275)、伐利昔单抗(vapaliximab)、维妥组单抗(veltuzumab)、维帕莫单抗(vepalimomab)、维西珠单抗(visilizumab)(也称为/>)、伏洛昔单抗(volociximab)(也称为M200)、伏妥莫单抗(votumumab)(也称为/>)、扎芦木单抗(zalutumumab)、扎木单抗(zanolimumab)(也称为HuMAX-CD4)、齐拉木单抗(ziralimumab)、阿佐莫单抗(zolimomabaritox)、达雷木单抗(daratumumab)、埃罗妥昔单抗(elotuxumab)、奥比托珠单抗(obintunzumab)、奥拉单抗(olaratumab)、维布妥昔单抗(brentuximab vedotin)、阿波西普(afibercept)、阿巴西普、贝拉西普(belatacept)、阿波西普、依那西普、罗米司亭(romiplostim)、SBT-040(序列在US 2017/0158772中列出)。在一些实施方案中,抗体是利妥昔单抗。
抗体
本发明的免疫缀合物包含抗体。本发明的实施方案的范围内包括本文所描述的抗体构建体或抗原结合结构域的功能变异体。如本文所用的术语“功能变异体”是指具有与亲本抗体构建体或抗原结合结构域具有实质或显著序列同一性或相似性的抗原结合结构域的抗体构建体,所述功能变异体保留作为其变异体的抗体构建体或抗原结合结构域的生物活性。功能变异体涵盖例如本文所描述的抗体构建体或抗原结合结构域(亲本抗体构建体或抗原结合结构域)的那些变异体,所述变异体保留以与亲本抗体构建体或抗原结合结构域相似的程度、相同的程度或更高的程度识别表达例如但不限于PD-L1、HER2、CEA或TROP2的靶细胞的能力。
关于抗体构建体或抗原结合结构域,功能变异体的氨基酸序列与抗体构建体或抗原结合结构域可以例如具有至少约30%、约50%、约75%、约80%、约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高同一性。
功能变异体可以例如包含具有至少一个保守氨基酸取代的亲本抗体构建体或抗原结合结构域的氨基酸序列。替代地或另外,功能变异体可以包含具有至少一个非保守氨基酸取代的亲本抗体构建体或抗原结合结构域的氨基酸序列。在这种情况下,非保守氨基酸取代优选地不干扰或抑制功能变异体的生物活性。非保守氨基酸取代可以增强功能变异体的生物活性,使得功能变异体的生物活性与亲本抗体构建体或抗原结合结构域相比增加。
包含本发明的免疫缀合物的抗体包括Fc工程改造的变异体。在一些实施方案中,在Fc区中调节与一种或多种Fc受体的结合的突变可以包括以下突变中的一者或多者:SD(S239D)、SDIE(S239D/I332E)、SE(S267E)、SELF(S267E/L328F)、SDIE(S239D/I332E)、SDIEAL(S239D/I332E/A330L)、GA(G236A)、ALIE(A330L/I332E)、GASDALIE(G236A/S239D/A330L/I332E)、V9(G237D/P238D/P271G/A330R)和V11(G237D/P238D/H268D/P271G/A330R);和/或以下氨基酸处的一个或多个突变:E345R、E233、G237、P238、H268、P271、L328和A330。用于调节Fc受体结合的额外Fc区修饰在例如US 2016/0145350、US 7416726和US 5624821中描述,所述文献特此以全文引用的方式并入本文中。
包含本发明的免疫缀合物的抗体包括聚糖变异体,诸如去岩藻糖基化。在一些实施方案中,结合剂的Fc区经修饰以与原生未经修饰的Fc区相比具有改变的Fc区糖基化模式。
本发明抗体构建体或抗原结合结构域的氨基酸取代优选地是保守氨基酸取代。保守氨基酸取代在本领域中是已知的,并且包括用一个具有某些物理和/或化学特性的氨基酸交换另一个具有相同或类似化学或物理特性的氨基酸的氨基酸取代。举例来说,保守氨基酸取代可以是酸性/带负电荷极性氨基酸取代另一个酸性/带负电荷极性氨基酸(例如Asp或Glu)、具有非极性侧链的氨基酸取代另一个具有非极性侧链的氨基酸(例如Ala、Gly、Val、Ile、Leu、Met、Phe、Pro、Trp、Cys、Val等)、碱性/带正电荷极性氨基酸取代另一个碱性/带正电荷极性氨基酸(例如Lys、His、Arg等)、具有极性侧链的不带电荷氨基酸取代另一个具有极性侧链的不带电荷氨基酸(例如Asn、Gln、Ser、Thr、Tyr等)、具有β分支侧链的氨基酸取代另一个具有β分支侧链的氨基酸(例如Ile、Thr和Val)、具有芳香族侧链的氨基酸取代另一个具有芳香族侧链的氨基酸(例如His、Phe、Trp和Tyr)等。
抗体构建体或抗原结合结构域可以基本上由本文所描述的一个或多个指定氨基酸序列组成,使得其它组分(例如其它氨基酸)不会本质上改变抗体构建体或抗原结合结构域功能变异体的生物活性。
在一些实施方案中,免疫缀合物中的抗体含有经修饰的Fc区,其中修饰会调节Fc区与一个或多个Fc受体的结合。
在一些实施方案中,与Fc区中缺乏突变的原生抗体相比,免疫缀合物中的抗体(例如,缀合至至少两个佐剂部分的抗体)在Fc区中含有一个或多个修饰(例如,氨基酸插入、缺失和/或取代),从而调节与一个或多个Fc受体(例如,FcγRI(CD64)、FcγRIIA(CD32A)、FcγRIIB(CD32B)、FcγRIIIA(CD16a)和/或FcγRIIIB(CD16b))的结合(例如,结合增加或结合减少)。在一些实施方案中,免疫缀合物中的抗体在Fc区中含有一个或多个修饰(例如,氨基酸插入、缺失和/或取代),从而减少抗体的Fc区与FcγRIIB的结合。在一些实施方案中,与Fc区中缺乏突变的原生抗体相比,免疫缀合物中的抗体在抗体的Fc区中含有一个或多个修饰(例如,氨基酸插入、缺失和/或取代),从而减少抗体与FcγRIIB的结合,同时维持与FcγRI(CD64)、FcγRIIA(CD32A)和/或FcRγIIIA(CD16a)的相同结合或结合增加。在一些实施方案中,免疫缀合物中的抗体在Fc区中含有一个或多个修饰,从而增加抗体的Fc区与FcγRIIB的结合。
在一些实施方案中,经调节的结合是由抗体的Fc区中相对于抗体的原生Fc区的突变来提供。突变可以在CH2结构域、CH3结构域或它们的组合中。“原生Fc区”与“野生型Fc区”同义并且包含与自然界中发现的Fc区的氨基酸序列相同或与原生抗体(例如,西妥昔单抗)中发现的Fc区的氨基酸序列相同的氨基酸序列。原生序列人类Fc区包括原生序列人类IgG1Fc区、原生序列人类IgG2 Fc区、原生序列人类IgG3 Fc区和原生序列人类IgG4 Fc区,以及它们的天然存在的变异体。原生序列Fc包括Fc的各种同种异型(Jefferis等,(2009)mAbs,1(4):332-338)。
在一些实施方案中,免疫缀合物的抗体的Fc区经修饰以与原生未经修饰的Fc区相比具有改变的Fc区糖基化模式。人类免疫球蛋白在每条重链的Cγ2结构域中的Asn297残基处糖基化。这种N-连接的寡糖由核心七糖N-乙酰基葡糖胺4甘露糖3(GlcNAc4Man3)组成。已知用糖苷内切酶或PNGase F去除七糖引起抗体Fc区中的构象变化,这可以显著降低对活化FcγR的抗体结合亲和力并且降低效应子功能。核心七糖通常用半乳糖、平分GlcNAc、岩藻糖或唾液酸装饰,这差异性地影响Fc与活化或抑制性FcγR的结合。另外,已经证明了α2,6-唾液酸化增强体内消炎活性,而去岩藻糖基化会改善FcγRIIIa结合并且使抗体依赖性细胞毒性和抗体依赖性吞噬作用增加10倍。因此,特定糖基化模式可以用于控制炎性效应子功能。
在一些实施方案中,用以改变糖基化模式的修饰是突变。举例来说,在Asn297处取代。在一些实施方案中,使Asn297突变为谷氨酰胺(N297Q)。用调节FcγR调控的信号传导的抗体控制免疫反应的方法描述于例如美国专利7,416,726和美国专利申请公布2007/0014795和2008/0286819中,所述文献特此以全文引用的方式并入。
在一些实施方案中,免疫缀合物的抗体经修饰以含有具有非天然存在的糖基化模式的工程改造的Fab区。举例来说,杂交瘤可以经遗传工程改造以分泌具有能够增加FcRγIIIa结合和效应子功能的特异性突变的无岩藻糖基化mAb、去唾液酸化mAb或去糖基化Fc。在一些实施方案中,将免疫缀合物的抗体工程改造为无岩藻糖基化的。
在一些实施方案中,将免疫缀合物中的抗体的整个Fc区与不同Fc区交换,以使得抗体的Fab区缀合至非原生Fc区。举例来说,通常包含IgG1 Fc区的西妥昔单抗的Fab区可以缀合至IgG2、IgG3、IgG4或IgA,或者通常包含IgG4 Fc区的纳武单抗(nivolumab)的Fab区可以缀合至IgG1、IgG2、IgG3、IgA1或IgG2。在一些实施方案中,具有非原生Fc结构域的Fc修饰的抗体还包含一个或多个氨基酸修饰,诸如IgG4 Fc内的S228P突变,其调节所描述的Fc结构域的稳定性。在一些实施方案中,具有非原生Fc结构域的Fc修饰的抗体还包含本文所描述的一个或多个氨基酸修饰,其调节Fc与FcR的结合。
在一些实施方案中,与原生未经修饰的抗体相比,调节Fc区与FcR的结合的修饰不改变抗体的Fab区与其抗原的结合。在其它实施方案中,与原生未经修饰的抗体相比,调节Fc区与FcR的结合的修饰也增加抗体的Fab区与其抗原的结合。
在一个示例性实施方案中,本发明的免疫缀合物包含抗体构建体,所述抗体构建体包含特异性识别并结合PD-L1的抗原结合结构域。
程序性死亡配体1(PD-L1、分化簇274、CD274、B7-同源物1或B7-H1)属于B7蛋白质超家族,并且是程序性细胞死亡蛋白1(PD-1、PDCD1、分化簇279或CD279)的配体。PD-L1还可以与B7.1(CD80)相互作用,并且据信此种相互作用可以抑制T细胞启动。PD-L1/PD-1轴在抑制适应性免疫反应中起重要作用。更具体来说,据信PD-L1与其受体PD-1的啮合递送抑制T细胞活化和增殖的信号。结合至PD-L1并且阻止配体与PD-1受体结合的剂可以防止这种免疫抑制,并且因此可以在需要时增强免疫反应,诸如用于治疗癌症或感染。PD-L1/PD-1路径还有助于防止自体免疫,并且因此针对PD-L1的激动剂或递送免疫抑制性有效负荷的剂可以帮助治疗自体免疫病症。
已经开发了若干靶向PD-L1的抗体用于治疗癌症,包括阿特珠单抗(TECENTRIQTM)、得瓦鲁单抗(IMFINZITM)和阿维鲁单抗(BAVENCIOTM)。尽管如此,持续需要新的PD-L1结合剂,包括以高亲和力结合PD-L1并且有效防止PD-L1/PD-1信号传导的剂以及可以将治疗性有效负荷递送至PD-L1表达细胞的剂。另外,需要新的PD-L1结合剂以治疗自体免疫病症和感染。
提供了一种将吡唑并氮呯衍生物有效负荷递送至表达PD-L1的细胞的方法,所述方法包括向所述细胞或包含所述细胞的哺乳动物施用免疫缀合物,所述免疫缀合物包含共价附接至连接子的抗PD-L1抗体,所述连接子共价附接至一个或多个吡唑并氮呯部分。
还提供了一种用于增强或减少或抑制哺乳动物的免疫反应的方法和用于治疗对PD-L1抑制有反应的哺乳动物的疾病、病症或疾患的方法,所述方法包括向哺乳动物施用其PD-L1免疫缀合物。
本发明提供了一种PD-L1抗体,所述PD-L1抗体包含免疫球蛋白重链可变区多肽和免疫球蛋白轻链可变区多肽。PD-L1抗体特异性结合PD-L1。所述抗体的结合特异性允许靶向PD-L1表达细胞,例如,以将治疗性有效负荷递送至此类细胞。在一些实施方案中,PD-L1抗体结合至人类PD-L1。然而,还涵盖结合至任何PD-L1片段、同源物或同种同源物的抗体。
在一些实施方案中,PD-L1抗体结合PD-L1,而实质上不抑制或阻止PD-L1与其受体PD-1的结合。然而,在其它实施方案中,PD-L1抗体可以完全或部分阻断(抑制或阻止)PD-L1与其受体PD-1的结合,使得所述抗体可以用于抑制PD-L1/PD-1信号传导(例如用于治疗目的)。抗体或抗原结合抗体片段可以对PD-L1具有单特异性,或可以是双特异性或多特异性的。举例来说,在二价或多价抗体或抗体片段中,结合结构域可以是不同的,其靶向相同抗原的不同表位或靶向不同抗原。构建多价结合构建体的方法在本领域中是已知的。双特异性和多特异性抗体在本领域中是已知的。此外,可以提供双功能抗体、三功能抗体或四功能抗体,其为多肽链的二聚体、三聚体或四聚体,所述多肽链各自包含由肽连接子连接至VL的VH,所述肽连接子过短而不允许同一多肽链上的VH与VL之间配对,从而驱动不同VH-VL多肽链上的互补结构域之间配对,以产生具有两个、三个或四个功能性抗原结合位点的多聚分子。同样,可以产生双scFv片段,所述片段是具有两个不同可变结构域的小scFv片段,以产生能够结合两个不同表位的双特异性双scFv片段。可以使用遗传工程改造方法产生Fab二聚体(Fab2)和Fab三聚体(Fab3),以基于Fab片段创建多特异性构建体。
PD-L1抗体可以是或可以获自人类抗体、非人类抗体、人源化抗体或嵌合抗体或对应的抗体片段。“嵌合”抗体是通常包含人类恒定区和非人类可变区的抗体或其片段。“人源化”抗体是通常包含人类抗体支架,但在至少一个CDR(例如1个、2个、3个、4个、5个或全部六个CDR)中具有非人类来源的氨基酸或序列的单克隆抗体。
PD-L1抗体可以是内化的,如WO 2021/150701中所描述并且以引用的方式并入本文中;或PD-L1抗体可以是非内化的,如WO 2021/150702中所描述并且以引用的方式并入本文中。
在一个示例性实施方案中,本发明的免疫缀合物包含抗体构建体,所述抗体构建体包含特异性识别并结合HER2的抗原结合结构域。
在某些实施方案中,本发明的免疫缀合物包含抗HER2抗体。在本发明的一个实施方案中,本发明的免疫缀合物的抗HER2抗体包含人源化抗HER2抗体,例如huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7和huMAb4D5-8,如US 5821337的表3中所描述,所述文献以引用的方式特别并入本文中。那些抗体含有人类构架区与结合至HER2的鼠类抗体(4D5)的互补决定区。人源化抗体huMAb4D5-8也称作曲妥珠单抗,以商品名HERCEPTINTM(Genentech,Inc.)商购可得。
曲妥珠单抗(CAS 180288-69-1,huMAb4D5-8,rhuMAb HER2,Genentech)是源自DNA的重组IgG1κ单克隆抗体,其为鼠类抗HER2抗体(4D5)的人源化型式,所述人源化型式在基于细胞的测定中以高亲和力(Kd=5nM)选择性结合至HER2的细胞外结构域(US 5677171;US 5821337;US 6054297;US 6165464;US 6339142;US 6407213;US6639055;US 6719971;US 6800738;US7074404;Coussens等(1985)Science 230:1132-9;Slamon等(1989)Science 244:707-12;Slamon等(2001)New Engl.J.Med.344:783-792)。
在本发明的一个实施方案中,抗体构建体或抗原结合结构域包含曲妥珠单抗的CDR区。在本发明的一个实施方案中,抗HER2抗体还包含曲妥珠单抗的构架区。在本发明的一个实施方案中,抗HER2抗体还包含曲妥珠单抗的一个或两个可变区。
在本发明的另一个实施方案中,如US 7862817中所描述,本发明的免疫缀合物的抗HER2抗体包含人源化抗HER2抗体,例如人源化2C4。示例性人源化2C4抗体是帕妥珠单抗(CAS登记号380610-27-5)、PERJETATM(Genentech,Inc.)。帕妥珠单抗是HER二聚抑制剂(HDI)并且发挥功能以抑制HER2与其它HER受体(诸如EGFR/HER1、HER2、HER3和HER4)形成活性异二聚体或同二聚体的能力。参见例如Harari和Yarden,Oncogene 19:6102-14(2000);Yarden和Sliwkowski.Nat Rev Mol Cell Biol 2:127-37(2001);Sliwkowski Nat StructBiol 10:158-9(2003);Cho等Nature 421:756-60(2003);以及Malik等Pro Am Soc CancerRes 44:176-7(2003)。PERJETATM经核准用于治疗乳癌。
在本发明的一个实施方案中,抗体构建体或抗原结合结构域包含帕妥珠单抗的CDR区。在本发明的一个实施方案中,抗HER2抗体还包含帕妥珠单抗的构架区。在本发明的一个实施方案中,抗HER2抗体还包含帕妥珠单抗的一个或两个可变区。
在一个示例性实施方案中,本发明的免疫缀合物包含抗体构建体,所述抗体构建体包含特异性识别并结合Caprin-1的抗原结合结构域(Ellis JA,Luzio JP(1995)J BiolChem.270(35):20717-23;Wang B等,(2005)J Immunol.175(7):4274-82;Solomon S等,(2007)Mol Cell Biol.27(6):2324-42)。Caprin-1也称为GPIAP1、GPIP137、GRIP137、M11S1、RNG105、p137GPI和细胞周期相关蛋白1。
细胞质活化/增殖相关蛋白-1(caprin-1)是参与细胞周期控制相关基因的调控的RNA结合蛋白。Caprin-1选择性结合至c-Myc和周期蛋白D2 mRNA,这加速细胞经G1期进展至S期,增强细胞活力并且促进细胞生长,指示其可以在肿瘤形成中起重要作用(Wang B等,(2005)J Immunol.175:4274-4282)。Caprin-1单独或与其它RNA结合蛋白(诸如RasGAP SH3结构域结合蛋白1和脆弱X智能迟缓蛋白)组合起作用。在肿瘤形成过程中,caprin-1主要通过活化细胞增殖并且上调免疫检查点蛋白的表达来发挥功能。经由形成应激颗粒,caprin-1还涉及于肿瘤细胞适应不良条件的过程中,这有助于放射线和化学疗法耐药性。鉴于其在各种临床恶性病中的作用,caprin-1具有用作生物标志物和用于开发新颖治疗剂的标靶的潜力(Yang,Z-S等,(2019)Oncology Letters 18:15-21)。
已描述了用于治疗和检测的靶向caprin-1的抗体(WO 2011/096519;WO 2013/125654;WO 2013/125636;WO 2013/125640;WO 2013/125630;WO 2013/018889;WO 2013/018891;WO 2013/018883;WO 2013/018892;WO 2014/014082;WO 2014/014086;WO 2015/020212;WO 2018/079740)。
在一个示例性实施方案中,本发明的免疫缀合物包含抗体构建体,所述抗体构建体包含特异性识别并结合CEA的抗原结合结构域。癌胚抗原相关细胞粘附分子5(CEACAM5),也称为CD66e(分化簇66e),是癌胚抗原(CEA)基因家族的成员。
癌胚抗原(CEA、CD66e、CEACAM5)的表达升高已牵涉于赘瘤的各种生物方面,尤其肿瘤细胞粘附、转移、阻断细胞免疫机制以及具有抗凋亡功能。CEA还用作许多癌瘤的血液标志物。拉贝妥珠单抗(CEA-CIDETM,Immunomedics,CAS登记号219649-07-7)(也称为MN-14和hMN14)是人源化IgG1单克隆抗体并且已研究用于治疗结肠直肠癌(Blumenthal,R.等(2005)Cancer Immunology Immunother apy 54(4):315-327)。缀合至喜树碱类似物的拉贝妥珠单抗(拉贝妥珠单抗戈维替康(labetuzumab govitecan),IMMU-130)靶向癌胚抗原相关细胞粘附分子5(CEACAM5)并且正在患有复发性或难治性转移性结肠直肠癌的患者中进行研究(Sharkey,R.等,(2018),Molecular Cance r Therapeutics 17(1):196-203;Cardillo,T.等(2018)Molecular Cance r Therapeutics 17(1):150-160)。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含如US6676924中所公开的hMN-14/拉贝妥珠单抗SEQ ID NO.1的可变轻链(VLκ),所述文献出于此目的以引用的方式并入本文中。
DIQLTQSPSSLSASVGDRVTITCKASQDVGTSVAWYQQKPGK APKLLIYWTSTRHTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQ QYSLYRSFGQGTKVEIK SEQ ID NO.1
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含hMN-14/拉贝妥珠单抗的轻链CDR(互补决定区)或轻链构架(LFR)序列SEQ ID NO.2-8(US6676924)。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含如US6676924中所公开的hMN-14/拉贝妥珠单抗的可变重链(VH)SEQ ID NO.9,所述文献出于此目的以引用的方式并入本文中。
EVQLVESGGGVVQPGRSLRLSCSSSGFDFTTYWMSWVRQAP GKGLEWVAEIHPDSSTINYAPSLKDRFTISRDNSKNTLFLQMDSLR PEDTGVYFCASLYFGFPWFAYWGQGTPVTVSS SEQ ID NO.9
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含hMN-14/拉贝妥珠单抗的重链CDR(互补决定区)或重链构架(HFR)序列SEQ ID NO.10-16(US6676924)。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含如US8642742中所公开的hPR1A3的可变轻链(VLκ)SEQ ID NO.17,所述文献出于此目的以引用的方式并入本文中。
DIQMTQSPSSLSASVGDRVTITCKASAAVGTYVAWYQQKPG KAPKLLIYSASYRKRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC HQYYTYPLFTFGQGTKLEIK SEQ ID NO.17
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含hPR1A3的轻链CDR(互补决定区)或轻链构架(LFR)序列SEQ ID NO.18-24(US 8642742)。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含hPR1A3的重链CDR(互补决定区)或重链构架(HFR)序列SEQ ID NO.25-31(US 8642742)。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含如US7232888中所公开的hMFE-23的可变轻链(VLκ)SEQ ID NO.32,所述文献出于此目的以引用的方式并入本文中。
ENVLTQSPSSMSASVGDRVNIACSASSSVSYMHWFQQKPGK SPKLWIYSTSNLASGVPSRFSGSGSGTDYSLTISSMQPEDAATYYC QQRSSYPLTFGGGTKLEIK SEQ ID NO.32
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含hMFE-23的轻链CDR(互补决定区)或轻链构架(LFR)序列SEQ ID NO.33-40(US 7232888)。所述实施方案包括LFR1的两个变异体SEQ ID NO.:33和SEQ ID NO.:34。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含hMFE-23的可变重链(VH)SEQ ID NO.41(US 7232888)。
QVKLEQSGAEVVKPGASVKLSCKASGFNIKDSYMHWLRQGPGQRLEWIGWIDPENGDTEYAPKFQGKATFTTDTSANTAYLGLSSLRPEDTAVYYCNEGTPTGPYYFDYWGQGTLVTVSS SEQ ID NO.41
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含hMFE-23的重链CDR(互补决定区)或重链构架(HFR)序列SEQ ID NO.42-49(US 7232888)。所述实施方案包括HFR1的两个变异体SEQ ID NO.:42和SEQ ID NO.:43。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含SM3E的可变轻链(VLκ)SEQ ID NO.50(US 7232888)。
ENVLTQSPSSMSVSVGDRVTIACSASSSVPYMHWLQQKPGKS PKLLIYLTSNLASGVPSRFSGSGSGTDYSLTISSVQPEDAATYYCQ QRSSYPLTFGGGTKLEIK SEQ ID NO.50
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含SM3E的轻链CDR(互补决定区)或轻链构架(LFR)序列SEQ ID NO.51-56和38-39(US 7232888)。所述实施方案包括LFR1的两个变异体SEQ ID NO.:51和SEQ ID NO.:52。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含NP-4/阿西莫单抗的可变轻链SEQ ID NO.57。
QTVLSQSPAILSASPGEKVTMTCRASSSVTYIHWYQQKPGSSP KSWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQ HWSSKPPTFGGGTKLEIK SEQ ID NO.57
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含NP-4/阿西莫单抗的轻链CDR(互补决定区)或轻链构架(LFR)序列SEQ ID NO.58-64。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含NP-4/阿西莫单抗的可变重链(VH)SEQ ID NO.65。
EVKLVESGGGLVQPGGSLRLSCATSGFTFTDYYMNWVRQPP GKALEWLGFIGNKANGYTTEYSASVKGRFTISRDKSQSILYLQMN TLRAEDSATYYCTRDRGLRFYFDYWGQGTTLTVSS SEQ ID NO.65。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含NP-4的重链CDR(互补决定区)或重链构架(HFR)序列SEQ ID NO.66-72。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含如US7776330中所公开的M5A/hT84.66的可变轻链(VLκ)SEQ ID NO.73,所述文献出于此目的以引用的方式并入本文中。
DIQLTQSPSSLSASVGDRVTITCRAGESVDIFGVGFLHWYQQK PGKAPKLLIYRASNLESGVPSRFSGSGSRTDFTLTISSLQPEDFATY YCQQTNEDPYTFGQGTKVEIK SEQ ID NO.73
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含M5A/hT84.66的轻链CDR(互补决定区)或轻链构架(LFR)序列SEQ ID NO.74-80(US 7776330)。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含M5A/hT84.66的可变重链(VH)SEQ ID NO.81(US 7776330)。
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYMHWVRQAPGKGLEWVARIDPANGNSKYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCAPFGYYVSDYAMAYWGQGTLVTVSS SEQ ID NO.81
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含M5A/hT84.66的重链CDR(互补决定区)或重链构架(HFR)序列SEQ ID NO.82-88(US 7776330)。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含如US9617345中所公开的hAb2-3的可变轻链(VLκ)SEQ ID NO.89,所述文献出于此目的以引用的方式并入本文中。
DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIK SEQ ID NO.89
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含hAb2-3的轻链CDR(互补决定区)或轻链构架(LFR)序列SEQ ID NO.90-96(US 9617345)。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含可变重链(VH)SEQ ID NO.97(US 9617345)。
EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQGTLVTVSS SEQ ID NO.97
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含hAb2-3的重链CDR(互补决定区)或重链构架(HFR)序列SEQ ID NO.98-104。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含如US9982063中所公开的A240VL-B9VH/AMG-211的可变轻链(VLκ)SEQ ID NO.105,所述文献出于此目的以引用的方式并入本文中。
QAVLTQPASLSASPGASASLTCTLRRGINVGAYSIYWYQQKP GSPPQYLLRYKSDSDKQQGSGVSSRFSASKDASANAGILLISGLQS EDEADYYCMIWHSGASAVFGGGTKLTVL SEQ ID NO.105
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含A240VL-B9VH/AMG-211的轻链CDR(互补决定区)或轻链构架(LFR)序列SEQ ID NO.106-112(US 9982063)。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含B9VH的可变重链(VH)SEQ ID NO.113(US 9982063)。
EVQLVESGGGLVQPGRSLRLSCAASGFTVSSYWMHWVRQAPGKGLEWVGFIRNKANGGTTEYAASVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDRGLRFYFDYWGQGTTVTVSS SEQ ID NO.113
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含重链CDR(互补决定区)或重链构架(HFR)序列SEQ ID NO.114-121(US 9982063)。所述实施方案包括CDR-H2的两个变异体SEQ ID NO.:117和SEQ ID NO.:118。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含E12VH的可变重链(VH)SEQ ID NO.122(US9982063)。
EVQLVESGGGLVQPGRSLRLSCAASGFTVSSYWMHWVRQAPGKGLEWVGFILNKANGGTTEYAASVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCARDRGLRFYFDYWGQGTTVTVSS SEQ ID NO.122
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含重链CDR(互补决定区)或重链构架(HFR)序列SEQ ID NO.123-129(US 9982063)。
在本发明的一个实施方案中,靶向CEA的抗体构建体或抗原结合结构域包含PR1A3VH的可变重链(VH)SEQ ID NO.130(US 8642742)。
QVQLVQSGAEVKKPGASVKVSCKASGYTFTEFGMNWVRQAPGQGLEWMGWINTKTGEATYVEEFKGRVTFTTDTSTSTAYMELRSLRSDDTAVYYCARWDFAYYVEAMDYWGQGTTVTVSS SEQ ID NO.130
在一个示例性实施方案中,本发明的免疫缀合物包含抗体构建体,所述抗体构建体包含特异性识别并结合TROP2的抗原结合结构域。肿瘤相关钙信号转导子2(TROP-2)是由TACSTD2基因编码的跨膜糖蛋白(Linnenbach AJ等,(1993)Mol Cell Biol.13(3):1507-15;Calabrese G等,(2001)Cytogenet Cell Genet.92(1-2):164-5)。TROP2是在许多癌症中差异性表达并且向细胞发送自我更新、增殖、侵入和存活信号的细胞内钙信号转导子。TROP2被视为干细胞标志物并且在许多正常组织中表达,但相比之下,在许多癌症中过表达(Ohmachi T等,(2006)Clin.Cancer Res.,12(10),3057-3063;Muhlmann G等,(2009)J.Clin.Pathol.,62(2),152-158;Fong D等,(2008)Br.J.Cancer,99(8),1290-1295;FongD等,(2008)Mod.Pathol.,21(2),186-191;Ning S等,(2013)Neurol.Sci.,34(10),1745-1750)。TROP2的过表达具有预后意义。已经提出了若干配体与TROP2相互作用。TROP2经由不同路径向细胞发信号并且由若干转录因子的复杂网络以转录方式调控。
人类TROP2(TACSTD2:肿瘤相关钙信号转导子2、GA733-1、EGP-1、M1S1;下文中称作hTROP2)是由323个氨基酸残基组成的单次跨膜1型细胞膜蛋白。虽然先前已经提出了免疫抗性中所涉及的细胞膜的存在,这对于人滋养层细胞和癌细胞是常见的(Faulk W P等,Proc.Natl.Acad.Sci.75(4):1947-1951(1978)),但鉴定出由人绒毛膜癌细胞系中针对细胞膜蛋白的单克隆抗体识别的抗原分子并且将TROP2指定为人滋养层细胞中表达的分子之一(Lipinski M等,Proc.Natl.Acad.Sci.78(8),5147-5150(1981))。这种分子也指定为由通过用胃癌细胞系免疫而获得的小鼠单克隆抗体GA733识别的肿瘤抗原GA733-1(Linnenbach AJ等,Proc.Natl.Acad.Sci.86(1),27-31(1989))或由通过用非小细胞肺癌细胞免疫而获得的小鼠单克隆抗体RS7-3G11识别的上皮糖蛋白(EGP-1;Basu A等,Int.J.Cancer,62(4),472-479(1995))。然而,在1995年,克隆了TROP2基因,并且确认了所有这些分子都是相同的分子(Fornaro M等,Int.J.Cancer,62(5),610-618(1995))。hTROP2的DNA序列和氨基酸序列在公共数据库上可用并且可以例如以寄存编号NM_002353和NP_002344(NCBI)提及。
响应于表明与癌症的相关性的此种信息,迄今已经确立了多种抗hTROP2抗体并且研究其抗肿瘤作用。在这些抗体当中,公开了例如在裸小鼠异种移植模型中本身展现抗肿瘤活性的未缀合抗体(WO 2008/144891;WO 2011/145744;WO 2011/155579;WO 2013/077458)以及作为与细胞毒性药物的ADC展现抗肿瘤活性的抗体(WO 2003/074566;WO2011/068845;WO 2013/068946;US 7999083)。然而,其活性的强度或覆盖率仍然不足,并且对于作为治疗标靶的hTROP2存在未满足的医学需要。
癌细胞中的TROP2表达已经与药物抗性相关联。若干策略靶向癌细胞上的TROP2,包括抗体、抗体融合蛋白、化学抑制剂、纳米颗粒等。使用这些不同治疗处理的体外研究和临床前研究已经显著抑制小鼠体外和体内的肿瘤细胞生长。临床研究已经探索了TROP2作为预后生物标志物和作为逆转抗性的治疗标靶的潜在应用。
戈沙妥珠单抗(sacituzumab govitecan)(Immunomedics,IMMU-132),一种连接至拓扑异构酶抑制剂药物的TROP2定向抗体的抗体-药物缀合物,指定用于治疗已经接受至少两种先前疗法的成年患者的转移性三阴性乳癌(mTNBC)。戈沙妥珠单抗中的TROP2抗体缀合至SN-38,伊立替康(irinotecan)的活性代谢物(US 2016/0297890;WO2015/098099)。/>
在本发明的一个实施方案中,靶向TROP2的抗体构建体或抗原结合结构域包含hRS7(人源化RS7)的轻链CDR(互补决定区)序列SEQ ID NO.131-133(US 7238785,以引用的方式并入本文中)。
区域 | CDR序列片段 | SEQ ID NO. |
CDR-L1 | KASQDVSIAVA | 131 |
CDR-L2 | SASYRYT | 132 |
CDR-L3 | QQHYITPLT | 133 |
在本发明的一个实施方案中,靶向TROP2的抗体构建体或抗原结合结构域包含hRS7(人源化RS7)的重链CDR(互补决定区)序列SEQ ID NO.134-136(US 7238785;US9797907;US 9382329;WO 2020/142659,各自以引用的方式并入本文中)。
区域 | CDR序列片段 | SEQ ID NO. |
CDR-H1 | NYGMN | 134 |
CDR-H2 | WINTYTGEPTYTDDFKG | 135 |
CDR-H3 | GGFGSSYWYFDV | 136 |
在本发明的一个实施方案中,靶向TROP2的抗体构建体或抗原结合结构域包含AR47A6.4.2的轻链CDR(互补决定区)序列SEQ ID NO.131-133(US 7420040,以引用的方式并入本文中)。
区域 | CDR序列片段 | SEQ ID NO. |
CDR-L1 | KASQDVSIAVA | 131 |
CDR-L2 | SASYRYT | 132 |
CDR-L3 | QQHYITPLT | 133 |
在本发明的一个实施方案中,靶向TROP2的抗体构建体或抗原结合结构域包含AR47A6.4.2的重链CDR(互补决定区)序列SEQ ID NO.134、137、138(US 7420040,以引用的方式并入本文中)。
区域 | CDR序列片段 | SEQ ID NO. |
CDR-H1 | NYGMN | 134 |
CDR-H2 | WINTKTGEPTYAEEFKG | 137 |
CDR-H3 | GGYGSSYWYFDV | 138 |
在本发明的一个实施方案中,靶向TROP2的抗体构建体或抗原结合结构域包含人源化KM4097的轻链CDR(互补决定区)序列SEQ ID NO.139-141(US 2012/0237518,以引用的方式并入本文中)。
区域 | CDR序列片段 | SEQ ID NO. |
CDR-L1 | KSSQSLLNSGNQQNYLA | 139 |
CDR-L2 | GASTRES | 140 |
CDR-L3 | QSDHIYPYT | 141 |
在本发明的一个实施方案中,靶向TROP2的抗体构建体或抗原结合结构域包含人源化KM4097的重链CDR(互补决定区)序列SEQ ID NO.142-144(US 2012/0237518,以引用的方式并入本文中)。
区域 | CDR序列片段 | SEQ ID NO. |
CDR-H1 | IYWLG | 142 |
CDR-H2 | NIFPGSAYINYNEKFKG | 143 |
CDR-H3 | EGSNSGY | 144 |
在本发明的一个实施方案中,靶向TROP2的抗体构建体或抗原结合结构域包含hTINA1-H1L1的轻链CDR(互补决定区)序列SEQ ID NO.132、133、145(US 10,227,417,以引用的方式并入本文中)。
区域 | CDR序列片段 | SEQ ID NO. |
CDR-L1 | KASQDVSTAVA | 145 |
CDR-L2 | SASYRYT | 132 |
CDR-L3 | QQHYITPLT | 133 |
在本发明的一个实施方案中,靶向TROP2的抗体构建体或抗原结合结构域包含hTINA1-H1L1的重链CDR(互补决定区)序列SEQ ID NO.146-148(US 10,227,417,以引用的方式并入本文中)。
区域 | CDR序列片段 | SEQ ID NO. |
CDR-H1 | TAGMQ | 146 |
CDR-H2 | WINTHSGVPKYAEDFKG | 147 |
CDR-H3 | SGFGSSYWYFDV | 148 |
在本发明的一个实施方案中,靶向TROP2的抗体构建体或抗原结合结构域包含hTINA1-H1L1的轻链CDR(互补决定区)序列SEQ ID NO.149-151(US 8871908,以引用的方式并入本文中)。
在本发明的一个实施方案中,靶向TROP2的抗体构建体或抗原结合结构域包含hTINA1-H1L1的重链CDR(互补决定区)序列SEQ ID NO.152-157(US 8871908,以引用的方式并入本文中)。
在本发明的一个实施方案中,靶向TROP2的抗体构建体或抗原结合结构域包含hTINA1-H1L1的轻链CDR(互补决定区)序列SEQ ID NO.150、151、158(US 8871908,以引用的方式并入本文中)。
区域 | CDR序列片段 | SEQ ID NO. |
CDR-L1 | RASKSVSTSGYSYMH | 158 |
CDR-L2 | LASNLES | 150 |
CDR-L3 | QHSRELPYT | 151 |
在本发明的一个实施方案中,靶向TROP2的抗体构建体或抗原结合结构域包含hTINA1-H1L1的重链CDR(互补决定区)序列SEQ ID NO.152-154、157、159、160(US 8871908,以引用的方式并入本文中)。
区域 | CDR序列片段 | SEQ ID NO. |
CDR-H1 | SYGVH | 152 |
CDR-H1 | GGSISSY | 153 |
CDR-H1 | GGSISSYGVH | 154 |
CDR-H2 | VIWTSGVTDYNSALMG | 159 |
CDR-H2 | WTSGV | 160 |
CDR-H3 | DGDYDRYTMDY | 157 |
在一些实施方案中,抗体构建体还包含Fc结构域。在某些实施方案中,抗体构建体是抗体。在某些实施方案中,抗体构建体是融合蛋白。抗原结合结构域可以是单链可变区片段(scFv)。可以使用常规重组DNA技术工艺产生单链可变区片段(scFv),所述片段是截短的Fab片段,包括经由合成肽连接至轻抗体链的V结构域的抗体重链的可变(V)结构域。类似地,可以通过重组DNA技术制备二硫键稳定的可变区片段(dsFv)。抗体构建体或抗原结合结构域可以包含抗体,诸如抗PD-L1抗体、抗Her2抗体、抗CEA抗体或抗TROP2抗体的抗原结合结构域的一个或多个可变区(例如两个可变区),每个可变区包含CDR1、CDR2和CDR3。
在一些实施方案中,免疫缀合物中的抗体含有经修饰的Fc区,其中修饰调节Fc区与一种或多种Fc受体的结合。
在一些实施方案中,通过包含能够结合TGFβ1的转化生长因子β1(TGFβ1)受体或其片段来修饰Fc区。举例来说,受体可以是TGFβ受体II(TGFβRII)。在一些实施方案中,TGFβ受体是人类TGFβ受体。在一些实施方案中,IgG具有与TGFβRII细胞外结构域(ECD)的C端融合。可以使用“Fc连接子”将IgG附接至TGFβRII细胞外结构域。Fc连接子可以是短柔性肽,其允许分子的适当三维折叠,同时维持与标靶的结合特异性。在一些实施方案中,TGFβ受体的N端融合至抗体构建体的Fc(在存在或不存在Fc连接子的情况下)。在一些实施方案中,抗体构建体重链的C端融合至TGFβ受体(在存在或不存在Fc连接子的情况下)。在一些实施方案中,抗体构建体重链的C端赖氨酸残基突变为丙氨酸。
在一些实施方案中,免疫缀合物中的抗体经糖基化。
在一些实施方案中,免疫缀合物中的抗体是半胱氨酸工程改造的抗体,其经由某些位点处的半胱氨酸取代而提供佐剂、标记或药物部分与抗体的位点特异性缀合,在所述位点处工程改造的半胱氨酸可以用于缀合但不扰乱免疫球蛋白折叠和组装或改变抗原结合和效应功能(Junutula等,2008b Nature Biotech.,26(8):925-932;Dornan等(2009)Blood 114(13):2721-2729;US 7521541;US 7723485;US 2012/0121615;WO 2009/052249)。“半胱氨酸工程改造的抗体”或“半胱氨酸工程改造的抗体变异体”是其中抗体的一个或多个残基经半胱氨酸残基取代的抗体。半胱氨酸工程改造的抗体可以按均匀化学计量(例如,在具有单一工程改造的半胱氨酸位点的抗体中,每个抗体至多两个吡唑并氮呯部分)缀合至呈吡唑并氮呯-连接子化合物的吡唑并氮呯佐剂部分。
在一些实施方案中,用于制备表3的免疫缀合物的半胱氨酸工程改造的抗体具有在轻链的149-赖氨酸位点处引入的半胱氨酸残基(LC K149C)。在其它实施方案中,半胱氨酸工程改造的抗体具有在重链的118-丙氨酸位点(EU编号)处引入的半胱氨酸残基(HCA118C)。或者,这个位点通过依序编号而编号为121或通过Kabat编号而编号为114。在其它实施方案中,半胱氨酸工程改造的抗体具有在轻链中根据Kabat编号的G64C或R142C处或在重链中根据Kabat编号的D101C、V184C或T205C处引入的半胱氨酸残基。
吡唑并氮呯佐剂化合物
本发明的免疫缀合物包含吡唑并氮呯佐剂部分。本文所描述的佐剂部分是引发免疫反应的化合物(即,免疫刺激剂)。一般来说,本文所描述的佐剂部分是TLR激动剂。TLR是负责脊椎动物中先天免疫反应的起始的I型跨膜蛋白。TLR识别来自细菌、病毒和真菌的多种病原体相关分子模式并且充当对抗侵入性病原体的第一道防线。归因于细胞表达和TLR起始的信号传导路径不同,TLR引发重叠但截然不同的生物反应。一旦啮合(例如通过天然刺激或合成性TLR激动剂),TLR起始信号转导级联,从而经由转接蛋白髓样分化初级反应基因88(MyD88)活化核因子-κB(NF-κB)并募集IL-1受体相关激酶(IRAK)。IRAK的磷酸化然后募集TNF受体相关因子6(TRAF6),这引起NF-κB抑制剂I-κB磷酸化。因此,NF-κB进入细胞核并且起始其启动子含有NF-κB结合位点的基因(诸如细胞因子)的转录。用于TLR信号传导的额外调控模式包括含TIR-结构域的转接子诱导干扰素-β(TRIF)依赖性TNF-受体相关因子6(TRAF6)诱导以及经由TRIF和TRAF3活化MyD88非依赖性路径,从而引起干扰素反应因子3(IRF3)的磷酸化。类似地,MyD88依赖性路径还活化若干IRF家族成员,包括IRF5和IRF7,而TRIF依赖性路径还活化NF-κB路径。
通常,本文所描述的佐剂部分是TLR7和/或TLR8激动剂。TLR7和TLR8两者均在单核细胞和树突状细胞中表达。在人类中,TLR7也在浆细胞样树突状细胞(pDC)和B细胞中表达。TLR8主要在髓样来源的细胞,即,单核细胞、粒细胞和髓样树突状细胞中表达。TLR7和TLR8能够检测细胞内“外来”单股RNA的存在,以此作为对病毒侵入作出反应的手段。用TLR8激动剂处理TLR8表达细胞可以产生高水平的IL-12、IFN-γ、IL-1、TNF-α、IL-6和其它炎性细胞因子。类似地,用TLR7激动剂刺激TLR7表达细胞(诸如pDC)可以产生高水平的IFN-α和其它炎性细胞因子。TLR7/TLR8啮合以及所得细胞因子产生可以活化树突状细胞和其它抗原呈递细胞,从而驱动造成肿瘤破坏的各种先天和后天免疫反应机制。
本发明的示例性吡唑并氮呯化合物(PAZ)示于表1中。每种化合物通过质谱法来表征并且显示具有所指示的质量。本发明的吡唑并氮呯化合物包括区域异构体A和B,其中IUPAC位置编号如下所示:
根据实施例202测量针对表达人类TLR7或人类TLR8的HEK293 NFKB报告体细胞的活性。表1的吡唑并氮呯化合物证明TLR8激动剂选择性的令人惊讶并且意想不到的特性,其可以预测可用于治疗癌症和其它病症的治疗活性。
图1示出了吡唑并氮呯化合物PAZ-2、PAZ-4和PAZ-11对比比较佐剂化合物C-1和C-2在24小时的HEK人类TLR7活性的图。PAZ-2和PAZ-11相对于已知的TLR7佐剂C-1具有可比的TLR7活性,而全部具有极为不同的结构和生物物理特征。
图2示出了吡唑并氮呯化合物PAZ-1和PAZ-2对比比较佐剂化合物C-1和C-2在24小时的HEK人类TLR8活性的图。PAZ-11相对于已知的TLR8佐剂C-2具有更好的TLR8效力。另外,其相对于C-2具有改善的亲水性。与增加的TLR8效力相结合的改善的物理化学特性得到更高效的佐剂。
表1:吡唑并氮呯化合物(PAZ)
比较化合物:
吡唑并氮呯-连接子化合物
本发明的免疫缀合物是通过使抗体与吡唑并氮呯-连接子化合物缀合来制备。吡唑并氮呯-连接子化合物包含共价附接至连接子单元的吡唑并氮呯(PAZ)部分。连接子单元包含影响免疫缀合物的稳定性、渗透性、溶解性和其它药物动力学、安全性和功效特性的官能团和亚单元。连接子单元包括反应性官能团,其与抗体的反应性官能团反应,即,缀合。举例来说,抗体的亲核基团,诸如赖氨酸侧链氨基与PAZ-连接子化合物的亲电反应性官能团反应以形成免疫缀合物。同样,举例来说,抗体的半胱氨酸硫醇与PAZ-连接子化合物的马来酰亚胺或溴乙酰胺基团反应以形成免疫缀合物。
关于本发明的免疫缀合物的设计的考虑因素包括:(1)防止在体内循环期间PAZ部分过早释放,以及(2)确保生物活性形式的PAZ部分在所需作用部位以足够的速率释放。免疫缀合物的复杂结构连同其功能特性需要精心设计和选择分子的每个组分,包括抗体、缀合位点、连接子结构和吡唑并氮呯化合物。连接子决定了佐剂释放的机制和速率。
一般来说,连接子单元(L)可以是可裂解的或不可裂解的。可裂解连接子单元可以包括肽序列,所述肽序列是某些蛋白酶,诸如组织蛋白酶的底物,所述组织蛋白酶识别并裂解肽连接子单元,从而使PAZ激动剂与抗体分离(Caculitan NG等,(2017)Cancer Res.77(24):7027-7037)。
可裂解连接子单元可以包括不稳定官能团,诸如酸敏感性二硫化物基团(Kellogg,BA等,(2011)Bioconjugate Chem.22,717-727;Ricart,A.D.等,(2011)Clin.Cancer Res.17,6417-6427;Pillow,T.等,(2017)Chem.Sci.8,366-370;Zhang D等,(2016)ACS Med Chem Lett.7(11):988-993)。
在一些实施方案中,连接子在生理条件下不可裂解。如本文所用,术语“生理条件”是指20-40℃的温度范围、大气压(即,1atm)、约6至约8的pH,以及一种或多种生理酶、蛋白酶、酸和碱。在免疫缀合物中的抗体与PAZ部分之间的不可连接连接子的一个优点是使过早有效负荷释放和相应毒性降至最低。
在一个实施方案中,本发明包括在细胞结合剂与免疫刺激PAZ部分之间的肽连接单元PEP,所述肽连接单元包含基于特定氨基酸残基的线性序列的肽基团,所述肽基团可以由蛋白酶,诸如组织蛋白酶、肿瘤相关弹性蛋白酶或具有类蛋白酶或类弹性蛋白酶活性的酶选择性裂解。肽基团可以为约两个至约十二个氨基酸。肽连接子内键的酶促裂解释放活性形式的免疫刺激PAZ部分。这会增加根据本发明的缀合物的组织特异性并且因此额外减小根据本发明的缀合物在其它组织类型中的毒性。
在一个示例性实施方案中,PEP由选自由以下组成的组的氨基酸的氨基酸残基(AA)组成:
在一个示例性实施方案中,PEP选自由Ala-Pro-Val、Asn-Pro-Val、Ala-Ala-Val、Ala-Ala-Pro-Ala、Ala-Ala-Pro-Val和Ala-Ala-Pro-Nva组成的组。
在一个示例性实施方案中,PEP具有下式:
在一个示例性实施方案中,PEP具有下式:
在一个示例性实施方案中,PEP选自下式:
连接子提供了免疫缀合物在生物介质,例如培养基或血清中的足够稳定性,并且同时由于其特定酶促或水解裂解性的结果而提供了在肿瘤组织内所需的细胞内作用,并释放免疫刺激PAZ部分,即,“有效负荷”。
蛋白酶、组织蛋白酶或弹性蛋白酶的酶促活性可以催化免疫缀合物在生理条件下的共价键裂解。酶促活性是与肿瘤组织相关的细胞的表达产物。在靶向肽的裂解位点上的酶促活性使免疫缀合物转化为不含靶向肽和连接基团的活性免疫刺激药物。裂解位点可以由酶特异性识别。组织蛋白酶或弹性蛋白酶可以催化特定肽的C端氨基酸残基与免疫缀合物的免疫刺激部分之间的特定肽基键裂解。
在一个实施方案中,本发明包括在细胞结合剂与免疫刺激部分之间的连接单元,即,L或连接子,所述连接单元包含葡糖醛酸酶(Jeffrey SC等,(2006)Bioconjug.Chem.17(3):831-40)或硫酸酯酶(Bargh JD等,(2020)Chem Sci.11(9):2375-2380)裂解的底物。特别地,L包括Gluc单元并且包含选自以下的式:
本发明的免疫缀合物的特定裂解利用了免疫系统的肿瘤浸润细胞和白细胞分泌酶的存在,以促进肿瘤部位处抗癌药的活化。
适用于PAZ-连接子化合物的亲电反应性官能团包括但不限于N-羟基琥珀酰亚胺基(NHS)酯和N-羟基磺基琥珀酰亚胺基(磺基-NHS)酯(胺反应性);碳二亚胺(胺和羧基反应性);羟甲基膦(胺反应性);马来酰亚胺(硫醇反应性);卤化乙酰胺,诸如N-碘乙酰胺(硫醇反应性);芳基叠氮化物(伯胺反应性);氟化芳基叠氮化物(经由碳-氢(C-H)插入而具有反应性);五氟苯基(PFP)酯(胺反应性);四氟苯基(TFP)酯(胺反应性);亚胺基酯(胺反应性);异氰酸酯(羟基反应性);乙烯基砜(硫醇、胺和羟基反应性);吡啶基二硫化物(硫醇反应性);以及二苯甲酮衍生物(经由C-H键插入而具有反应性)。其它试剂包括但不限于Hermanson,Bioconjugate Techniques第2版,Academic Press,2008中所描述的那些试剂。
本发明提供了针对免疫缀合物的设计、制备和使用的局限性和挑战的解决方案。一些连接子可能在血流中不稳定,从而在靶细胞中内化之前释放不可接受量的佐剂/药物(Khot,A.等(2015)Bioanalysis7(13):1633-1648)。其它连接子可能在血流中提供稳定性,但细胞内释放有效性可能受负面影响。提供所需细胞内释放的连接子通常在血流中具有较差稳定性。换句话说,血流稳定性与细胞内释放通常呈逆相关。另外,在标准缀合过程中,负载于抗体上的佐剂/药物部分的量(即,药物负荷)、在缀合反应中形成的聚集体的量以及可获得的最终纯化缀合物的产量相互关联。举例来说,聚集体形成一般与缀合至抗体的佐剂/药物部分及其衍生物的当量数呈正相关。在高药物负荷下,必须去除所形成的聚集体以用于治疗应用。因此,药物负荷介导的聚集体形成会降低免疫缀合物产量并且可能使工艺规模扩大变得困难。
示例性实施方案包括式IIa和式IIb的5-氨基吡唑并氮呯-连接子化合物:
其中X1、X2和X3独立地选自由一键、C(=O)、C(=O)N(R5)、O、N(R5)、S、S(O)2和S(O)2N(R5)组成的组;
R1、R2、R3和R4独立地选自由H、C1-C12烷基、C2-C6烯基、C2-C6炔基、C3-C12碳环基、C6-C20芳基、C2-C9杂环基和C1-C20杂芳基组成的组,其中烷基、烯基、炔基、碳环基、芳基、杂环基和杂芳基独立地并且任选地经一个或多个选自以下的基团取代:
-(C1-C12烷二基)-N(R5)-*;
-(C1-C12烷二基)-N(R5)2;
-(C1-C12烷二基)-OR5;
-(C3-C12碳环基);
-(C3-C12碳环基)-*;
-(C3-C12碳环基)-(C1-C12烷二基)-NR5-*;
-(C3-C12碳环基)-(C1-C12烷二基)-N(R5)2;
-(C3-C12碳环基)-NR5-C(=NR5)NR5-*;
-(C6-C20芳基);
-(C6-C20芳二基)-*;
-(C6-C20芳二基)-N(R5)-*;
-(C6-C20芳二基)-(C1-C12烷二基)-N(R5)-*;
-(C6-C20芳二基)-(C1-C12烷二基)-(C2-C20杂环二基)-*;
-(C6-C20芳二基)-(C1-C12烷二基)-N(R5)2;
-(C6-C20芳二基)-(C1-C12烷二基)-NR5-C(=NR5a)N(R5)-*;
-(C2-C20杂环基);
-(C2-C20杂环基)-*;
-(C2-C9杂环基)-(C1-C12烷二基)-NR5-*;
-(C2-C9杂环基)-(C1-C12烷二基)-N(R5)2;
-(C2-C9杂环基)-C(=O)-(C1-C12烷二基)-N(R5)-*;
-(C2-C9杂环基)-NR5-C(=NR5a)NR5-*;
-(C2-C9杂环基)-NR5-(C6-C20芳二基)-(C1-C12烷二基)-N(R5)-*;
-(C2-C9杂环基)-(C6-C20芳二基)-*;
-(C1-C20杂芳基);
-(C1-C20杂芳二基)-*;
-(C1-C20杂芳二基)-(C1-C12烷二基)-N(R5)-*;
-(C1-C20杂芳二基)-(C1-C12烷二基)-N(R5)2;
-(C1-C20杂芳二基)-NR5-C(=NR5a)N(R5)-*;
-(C1-C20杂芳二基)-N(R5)C(=O)-(C1-C12烷二基)-N(R5)-*;
-C(=O)-*;
-C(=O)-(C1-C12烷二基)-N(R5)-*;
-C(=O)-(C2-C20杂环二基)-*;
-C(=O)N(R5)2;
-C(=O)N(R5)-*;
-C(=O)N(R5)-(C1-C12烷二基)-*;
-C(=O)N(R5)-(C1-C12烷二基)-C(=O)N(R5)-*;
-C(=O)N(R5)-(C1-C12烷二基)-N(R5)C(=O)R5;
-C(=O)N(R5)-(C1-C12烷二基)-N(R5)C(=O)N(R5)2;
-C(=O)NR5-(C1-C12烷二基)-N(R5)CO2R5;
-C(=O)NR5-(C1-C12烷二基)-N(R5)C(=NR5a)N(R5)2;
-C(=O)NR5-(C1-C12烷二基)-NR5C(=NR5a)R5;
-C(=O)NR5-(C1-C8烷二基)-NR5(C2-C5杂芳基);
-C(=O)NR5-(C1-C20杂芳二基)-N(R5)-*;
-C(=O)NR5-(C1-C20杂芳二基)-*;
-C(=O)NR5-(C1-C20杂芳二基)-(C1-C12烷二基)-N(R5)2;
-C(=O)NR5-(C1-C20杂芳二基)-(C2-C20杂环二基)-C(=O)NR5-(C1-C12烷二基)-NR5-*;
-N(R5)2;
-N(R5)-*;
-N(R5)C(=O)R5;
-N(R5)C(=O)-*;
-N(R5)C(=O)N(R5)2;
-N(R5)C(=O)N(R5)-*;
-N(R5)CO2R5;
-N(R5)CO2(R5)-*;
-NR5C(=NR5a)N(R5)2;
-NR5C(=NR5a)N(R5)-*;
-NR5C(=NR5a)R5;
-N(R5)C(=O)-(C1-C12烷二基)-N(R5)-*;
-N(R5)-(C2-C5杂芳基);
-N(R5)-S(=O)2-(C1-C12烷基);
-O-(C1-C12烷基);
-O-(C1-C12烷二基)-N(R5)2;
-O-(C1-C12烷二基)-N(R5)-*;
-OC(=O)N(R5)2;
-OC(=O)N(R5)-*;
-S(=O)2-(C2-C20杂环二基)-*;
-S(=O)2-(C2-C20杂环二基)-(C1-C12烷二基)-N(R5)2;
-S(=O)2-(C2-C20杂环二基)-(C1-C12烷二基)-NR5-*;以及
-S(=O)2-(C2-C20杂环二基)-(C1-C12烷二基)-OH;
或R2与R3一起形成5元或6元杂环基环;
R5选自由H、C6-C20芳基、C3-C12碳环基、C2-C20杂环基、C6-C20芳二基、C1-C12烷基和C1-C12烷二基组成的组,或两个R5基团一起形成5元或6元杂环基环;
R5a选自由C6-C20芳基和C1-C20杂芳基组成的组;
其中星号*指示L的附接位点,并且其中R1、R2、R3和R4中的一者附接至L;
L是选自由以下组成的组的连接子:
Q-C(=O)-PEG-;
Q-C(=O)-PEG-C(=O)N(R6)-(C1-C12烷二基)-C(=O)-Gluc-;
Q-C(=O)-PEG-O-;
Q-C(=O)-PEG-O-C(=O)-;
Q-C(=O)-PEG-C(=O)-;
Q-C(=O)-PEG-C(=O)-PEP-;
Q-C(=O)-PEG-N(R6)-;
Q-C(=O)-PEG-N(R6)-C(=O)-;
Q-C(=O)-PEG-N(R6)-PEG-C(=O)-PEP-;
Q-C(=O)-PEG-N+(R6)2-PEG-C(=O)-PEP-;
Q-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷二基)-;
Q-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷二基)N(R6)C(=O)-(C2-C5单杂环二基)-;
Q-C(=O)-PEG-SS-(C1-C12烷二基)-OC(=O)-;
Q-C(=O)-PEG-SS-(C1-C12烷二基)-C(=O)-;
Q-C(=O)-(C1-C12烷二基)-C(=O)-PEP-;
Q-C(=O)-(C1-C12烷二基)-C(=O)-PEP-N(R6)-(C1-C12烷二基)-;
Q-C(=O)-(C1-C12烷二基)-C(=O)-PEP-N(R6)-(C1-C12烷二基)-N(R5)-C(=O);
Q-C(=O)-(C1-C12烷二基)-C(=O)-PEP-N(R6)-(C1-C12烷二基)-N(R6)C(=O)-(C2-C5单杂环二基)-;
Q-(CH2)m-C(=O)N(R6)-PEG-;
Q-(CH2)m-C(=O)N(R6)-PEG-C(=O)N(R6)-(C1-C12烷二基)-C(=O)-Gluc-;
Q-(CH2)m-C(=O)N(R6)-PEG-O-;
Q-(CH2)m-C(=O)N(R6)-PEG-O-C(=O)-;
Q-(CH2)m-C(=O)N(R6)-PEG-C(=O)-;
Q-(CH2)m-C(=O)N(R6)-PEG-N(R5)-;
Q-(CH2)m-C(=O)N(R6)-PEG-N(R5)-C(=O)-;
Q-(CH2)m-C(=O)N(R6)-PEG-C(=O)-PEP-;
Q-(CH2)m-C(=O)N(R6)-PEG-SS-(C1-C12烷二基)-OC(=O)-;
Q-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷二基)-;
Q-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷二基)N(R6)C(=O)-;以及
Q-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷二基)N(R6)C(=O)-(C2-C5单杂环二基)-;
R6独立地是H或C1-C6烷基;
PEG具有下式:-(CH2CH2O)n-(CH2)m-;m是1至5的整数,并且n是2至50的整数;
Gluc具有下式:
PEP具有下式:
其中AA独立地选自天然或非天然氨基酸侧链,或AA中的一者或多者和相邻氮原子形成5元环脯氨酸氨基酸,并且波形线指示附接点;
Cyc选自C6-C20芳二基和C1-C20杂芳二基,任选地经一个或多个选自以下的基团取代:F、Cl、NO2、-OH、-OCH3,以及具有以下结构的葡糖醛酸:
R7选自由-CH(R8)O-、-CH2-、-CH2N(R8)-和-CH(R8)O-C(=O)-组成的组,其中R8选自H、C1-C6烷基、C(=O)-C1-C6烷基和-C(=O)N(R9)2,其中R9独立地选自由H、C1-C12烷基和-(CH2CH2O)n-(CH2)m-OH组成的组,其中m是1至5的整数,并且n是2至50的整数,或两个R9基团一起形成5元或6元杂环基环;
y是2至12的整数;
z是0或1;并且
Q选自由N-羟基琥珀酰亚胺基、N-羟基磺基琥珀酰亚胺基、马来酰亚胺和苯氧基组成的组,经一个或多个独立地选自F、Cl、NO2和SO3 -的基团取代;
其中烷基、烷二基、烯基、烯二基、炔基、炔二基、芳基、芳二基碳环基、碳环二基、杂环基、杂环二基、杂芳基和杂芳二基任选地经一个或多个独立地选自以下的基团取代:F、Cl、Br、I、-CN、-CH3、-CH2CH3、-CH=CH2、-C≡CH、-C≡CCH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2、-CH2OH、-CH2OCH3、-CH2CH2OH、-C(CH3)2OH、-CH(OH)CH(CH3)2、-C(CH3)2CH2OH、-CH2CH2SO2CH3、-CH2OP(O)(OH)2、-CH2F、-CHF2、-CF3、-CH2CF3、-CH2CHF2、-CH(CH3)CN、-C(CH3)2CN、-CH2CN、-CH2NH2、-CH2NHSO2CH3、-CH2NHC H3、-CH2N(CH3)2、-CO2H、-COCH3、-CO2CH3、-CO2C(CH3)3、-CO CH(OH)CH3、-CONH2、-CONHCH3、-CON(CH3)2、-C(CH3)2CONH2、-NH2、-NHCH3、-N(CH3)2、-NHCOCH3、-N(CH3)COCH3、-NHS(O)2CH3、-N(CH3)C(CH3)2CONH2、-N(CH3)CH2CH2S(O)2CH3、-NHC(=NH)H、-NHC(=NH)CH3、-NHC(=NH)NH2、-NHC(=O)NH2、-NO2、=O、-OH、-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2、-O(CH2CH2O)n-(CH2)mCO2H、-O(CH2CH2O)nH、-OP(O)(OH)2、-S(O)2N(CH3)2、-SCH3、-S(O)2CH3和-S(O)3H。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中X1是一键,并且R1是H。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中X2是一键,并且R2是C1-C8烷基。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中X2和X3各自是一键,并且R2和R3独立地选自C1-C8烷基、-O-(C1-C12烷基)、-(C1-C12烷二基)-OR5、-(C1-C8烷二基)-N(R5)CO2R5、-(C1-C12烷基)-OC(O)N(R5)2、-O-(C1-C12烷基)-N(R5)CO2R5和-O-(C1-C12烷基)-OC(O)N(R5)2。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中R2是C1-C8烷基并且R3是-(C1-C8烷二基)-N(R5)CO2R4。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中R2是-CH2CH2CH3并且R3选自-CH2CH2CH2NHCO2(t-Bu)、-OCH2CH2NHCO2(环丁基)和-CH2CH2CH2NHCO2(环丁基)。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中R2和R3各自独立地选自-CH2CH2CH3、-OCH2CH3、-OCH2CF3、-CH2CH2CF3、-OCH2CH2OH和-CH2CH2CH2OH。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中R2和R3各自是-CH2CH2CH3。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中R2是-CH2CH2CH3并且R3是-OCH2CH3。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中X3-R3选自由以下组成的组:
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中R2或R3附接至L。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中X3-R3-L选自由以下组成的组:
其中波形线指示与N的附接点。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中R4是C1-C12烷基。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中R4是-(C1-C12烷二基)-N(R5)-*;其中星号*指示L的附接位点。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中L是-C(=O)-PEG-或-C(=O)-PEG-C(=O)-。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中对于所述PEG,m是1或2,并且n是2至10的整数。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中对于所述PEG,n是10。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中L包含PEP,并且PEP是二肽并具有下式:
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中L包含PEP,并且PEP是三肽并具有下式:
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中L包含PEP,并且PEP是四肽并具有下式:
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中L包含PEP,并且PEP是四肽,其中:
AA1选自由Abu、Ala和Val组成的组;
AA2选自由Nle(O-Bzl)、Oic和Pro组成的组;
AA3选自由Ala和Met(O)2组成的组;并且
AA4选自由Oic、Arg(NO2)、Bpa和Nle(O-Bzl)组成的组。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中PEP具有下式:
其中AA1和AA2独立地选自天然存在的氨基酸的侧链。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中AA1和AA2独立地选自H、-CH3、-CH(CH3)2、-CH2(C6H5)、-CH2CH2CH2CH2NH2、-CH2CH2CH2NHC(NH)NH2、-CHCH(CH3)CH3、-CH2SO3H和-CH2CH2CH2NHC(O)NH2;或AA1和AA2形成5元环脯氨酸氨基酸。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中AA1是-CH(CH3)2,并且AA2是-CH2CH2CH2NHC(O)NH2。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中AA1和AA2独立地选自GlcNAc天冬氨酸、-CH2SO3H和-CH2OPO3H。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中L选自以下结构:
其中波形线指示附接至R1、R2、R3和R4中的一者。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案选自式IIa-IId:
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案选自式IIe-IIl:
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中Q选自:
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中Q是经一个或多个F取代的苯氧基。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中Q是2,3,5,6-四氟苯氧基。
式II的吡唑并氮呯-连接子化合物的一个示例性实施方案包括其中Q是马来酰亚胺。
本发明包括式II实施方案的所有合理组合和特征排列。
吡唑并氮呯-连接子化合物的一个示例性实施方案选自表2a和表2b。每种化合物通过质谱法来表征并且显示具有所指示的质量。表2a和表2b的吡唑并氮呯-连接子化合物证明TLR8激动剂选择性的令人惊讶并且意想不到的特性,其可以预测可用于治疗癌症和其它病症的治疗活性。
表2a吡唑并氮呯-连接子式II化合物(PAZ-L)
表2b吡唑并氮呯-连接子式II化合物(PAZ-L)
免疫缀合物
免疫缀合物的示例性实施方案包含通过连接子共价附接至一个或多个5-氨基吡唑并氮呯(PAZ)部分的抗体,并且具有式I:
Ab-[L-PAZ]p I
或其药学上可接受的盐,
其中:
Ab是所述抗体;
p是1至8的整数;
PAZ是选自式IIa和式IIb的5-氨基吡唑并氮呯部分:
X1、X2和X3独立地选自由一键、C(=O)、C(=O)N(R5)、O、N(R5)、S、S(O)2和S(O)2N(R5)组成的组;
R1、R2、R3和R4独立地选自由H、C1-C12烷基、C2-C6烯基、C2-C6炔基、C3-C12碳环基、C6-C20芳基、C2-C9杂环基和C1-C20杂芳基组成的组,其中烷基、烯基、炔基、碳环基、芳基、杂环基和杂芳基独立地并且任选地经一个或多个选自以下的基团取代:
-(C1-C12烷二基)-N(R5)-*;
-(C1-C12烷二基)-N(R5)2;
-(C1-C12烷二基)-OR5;
-(C3-C12碳环基);
-(C3-C12碳环基)-*;
-(C3-C12碳环基)-(C1-C12烷二基)-NR5-*;
-(C3-C12碳环基)-(C1-C12烷二基)-N(R5)2;
-(C3-C12碳环基)-NR5-C(=NR5)NR5-*;
-(C6-C20芳基);
-(C6-C20芳二基)-*;
-(C6-C20芳二基)-N(R5)-*;
-(C6-C20芳二基)-(C1-C12烷二基)-N(R5)-*;
-(C6-C20芳二基)-(C1-C12烷二基)-(C2-C20杂环二基)-*;
-(C6-C20芳二基)-(C1-C12烷二基)-N(R5)2;
-(C6-C20芳二基)-(C1-C12烷二基)-NR5-C(=NR5a)N(R5)-*;
-(C2-C20杂环基);
-(C2-C20杂环基)-*;
-(C2-C9杂环基)-(C1-C12烷二基)-NR5-*;
-(C2-C9杂环基)-(C1-C12烷二基)-N(R5)2;
-(C2-C9杂环基)-C(=O)-(C1-C12烷二基)-N(R5)-*;
-(C2-C9杂环基)-NR5-C(=NR5a)NR5-*;
-(C2-C9杂环基)-NR5-(C6-C20芳二基)-(C1-C12烷二基)-N(R5)-*;-(C2-C9杂环基)-(C6-C20芳二基)-*;
-(C1-C20杂芳基);
-(C1-C20杂芳二基)-*;
-(C1-C20杂芳二基)-(C1-C12烷二基)-N(R5)-*;
-(C1-C20杂芳二基)-(C1-C12烷二基)-N(R5)2;
-(C1-C20杂芳二基)-NR5-C(=NR5a)N(R5)-*;
-(C1-C20杂芳二基)-N(R5)C(=O)-(C1-C12烷二基)-N(R5)-*;
-C(=O)-*;
-C(=O)-(C1-C12烷二基)-N(R5)-*;
-C(=O)-(C2-C20杂环二基)-*;
-C(=O)N(R5)2;
-C(=O)N(R5)-*;
-C(=O)N(R5)-(C1-C12烷二基)-*;
-C(=O)N(R5)-(C1-C12烷二基)-C(=O)N(R5)-*;
-C(=O)N(R5)-(C1-C12烷二基)-N(R5)C(=O)R5;
-C(=O)N(R5)-(C1-C12烷二基)-N(R5)C(=O)N(R5)2;
-C(=O)NR5-(C1-C12烷二基)-N(R5)CO2R5;
-C(=O)NR5-(C1-C12烷二基)-N(R5)C(=NR5a)N(R5)2;
-C(=O)NR5-(C1-C12烷二基)-NR5C(=NR5a)R5;
-C(=O)NR5-(C1-C8烷二基)-NR5(C2-C5杂芳基);
-C(=O)NR5-(C1-C20杂芳二基)-N(R5)-*;
-C(=O)NR5-(C1-C20杂芳二基)-*;
-C(=O)NR5-(C1-C20杂芳二基)-(C1-C12烷二基)-N(R5)2;
-C(=O)NR5-(C1-C20杂芳二基)-(C2-C20杂环二基)-C(=O)NR5-(C1-C12烷二基)-NR5-*;
-N(R5)2;
-N(R5)-*;
-N(R5)C(=O)R5;
-N(R5)C(=O)-*;
-N(R5)C(=O)N(R5)2;
-N(R5)C(=O)N(R5)-*;
-N(R5)CO2R5;
-N(R5)CO2(R5)-*;
-NR5C(=NR5a)N(R5)2;
-NR5C(=NR5a)N(R5)-*;
-NR5C(=NR5a)R5;
-N(R5)C(=O)-(C1-C12烷二基)-N(R5)-*;
-N(R5)-(C2-C5杂芳基);
-N(R5)-S(=O)2-(C1-C12烷基);
-O-(C1-C12烷基);
-O-(C1-C12烷二基)-N(R5)2;
-O-(C1-C12烷二基)-N(R5)-*;
-OC(=O)N(R5)2;
-OC(=O)N(R5)-*;
-S(=O)2-(C2-C20杂环二基)-*;
-S(=O)2-(C2-C20杂环二基)-(C1-C12烷二基)-N(R5)2;
-S(=O)2-(C2-C20杂环二基)-(C1-C12烷二基)-NR5-*;以及
-S(=O)2-(C2-C20杂环二基)-(C1-C12烷二基)-OH;
或R2与R3一起形成5元或6元杂环基环;
R5选自由H、C6-C20芳基、C3-C12碳环基、C2-C20杂环基、C6-C20芳二基、C1-C12烷基和C1-C12烷二基组成的组,或两个R5基团一起形成5元或6元杂环基环;
R5a选自由C6-C20芳基和C1-C20杂芳基组成的组;
其中星号*指示L的附接位点,并且其中R1、R2、R3和R4中的一者附接至L;
L是选自由以下组成的组的连接子:
-C(=O)-PEG-;
-C(=O)-PEG-C(=O)N(R6)-(C1-C12烷二基)-C(=O)-Gluc-;
-C(=O)-PEG-O-;
-C(=O)-PEG-O-C(=O)-;
-C(=O)-PEG-C(=O)-;
-C(=O)-PEG-C(=O)-PEP-;
-C(=O)-PEG-N(R6)-;
-C(=O)-PEG-N(R6)-C(=O)-;
-C(=O)-PEG-N(R6)-PEG-C(=O)-PEP-;
-C(=O)-PEG-N+(R6)2-PEG-C(=O)-PEP-;
-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷二基)-;
-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷二基)N(R6)C(=O)-(C2-C5单杂环二基)-;
-C(=O)-PEG-SS-(C1-C12烷二基)-OC(=O)-;
-C(=O)-PEG-SS-(C1-C12烷二基)-C(=O)-;
-C(=O)-(C1-C12烷二基)-C(=O)-PEP-;
-C(=O)-(C1-C12烷二基)-C(=O)-PEP-N(R6)-(C1-C12烷二基)-;
-C(=O)-(C1-C12烷二基)-C(=O)-PEP-N(R6)-(C1-C12烷二基)-N(R5)-C(=O);
-C(=O)-(C1-C12烷二基)-C(=O)-PEP-N(R6)-(C1-C12烷二基)-N(R6)C(=O)-(C2-C5单杂环二基)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-C(=O)N(R6)-(C1-C12烷二基)-C(=O)-Gluc-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-O-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-O-C(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-C(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-N(R5)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-N(R5)-C(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-C(=O)-PEP-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-SS-(C1-C12烷二基)-OC(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷二基)-;
-琥珀酰亚胺基-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷二基)N(R6)C(=O)-;以及
-琥珀酰亚胺基-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷二基)N(R6)C(=O)-(C2-C5单杂环二基)-;
R6独立地是H或C1-C6烷基;
PEG具有下式:-(CH2CH2O)n-(CH2)m-;m是1至5的整数,并且n是2至50的整数;
Gluc具有下式:
PEP具有下式:
其中AA独立地选自天然或非天然氨基酸侧链,或AA中的一者或多者和相邻氮原子形成5元环脯氨酸氨基酸,并且波形线指示附接点;
Cyc选自C6-C20芳二基和C1-C20杂芳二基,任选地经一个或多个选自以下的基团取代:F、Cl、NO2、-OH、-OCH3,以及具有以下结构的葡糖醛酸:
R7选自由-CH(R8)O-、-CH2-、-CH2N(R8)-和-CH(R8)O-C(=O)-组成的组,其中R8选自H、C1-C6烷基、C(=O)-C1-C6烷基和-C(=O)N(R9)2,其中R9独立地选自由H、C1-C12烷基和-(CH2CH2O)n-(CH2)m-OH组成的组,其中m是1至5的整数,并且n是2至50的整数,或两个R9基团一起形成5元或6元杂环基环;
y是2至12的整数;
z是0或1;并且
烷基、烷二基、烯基、烯二基、炔基、炔二基、芳基、芳二基、碳环基、碳环二基、杂环基、杂环二基、杂芳基和杂芳二基独立地并且任选地经一个或多个独立地选自以下的基团取代:F、Cl、Br、I、-CN、-CH3、-CH2CH3、-CH=CH2、-C≡CH、-C≡CCH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2、-CH2OH、-CH2OCH3、-CH2CH2OH、-C(CH3)2OH、-CH(OH)CH(CH3)2、-C(CH3)2CH2OH、-CH2CH2SO2CH3、-CH2OP(O)(OH)2、-CH2F、-CHF2、-CF3、-CH2CF3、-CH2CHF2、-CH(CH3)CN、-C(CH3)2CN、-CH2CN、-CH2NH2、-CH2NHSO2CH3、-CH2NHCH3、-CH2N(CH3)2、-CO2H、-COCH3、-CO2CH3、-CO2C(CH3)3、-COCH(OH)CH3、-CONH2、-CONHCH3、-CON(CH3)2、-C(CH3)2CO NH2、-NH2、-NHCH3、-N(CH3)2、-NHCOCH3、-N(CH3)COCH3、-NHS(O)2CH3、-N(CH3)C(CH3)2CONH2、-N(CH3)CH2CH2S(O)2CH3、-NHC(=NH)H、-NHC(=NH)CH3、-NHC(=NH)NH2、-NHC(=O)NH2、-NO2,=O、-OH、-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2、-O(CH2CH2O)n-(CH2)mCO2H、-O(CH2CH2O)nH、-OP(O)(OH)2、-S(O)2N(CH3)2、-SCH3、-S(O)2CH3和-S(O)3H。
式I的免疫缀合物的一个示例性实施方案包括其中所述抗体是具有结合PD-L1的抗原结合结构域的抗体构建体。
式I的免疫缀合物的一个示例性实施方案包括其中所述抗体选自由阿特珠单抗、得瓦鲁单抗和阿维鲁单抗或其生物类似药或生物改良药组成的组。
式I的免疫缀合物的一个示例性实施方案包括其中所述抗体是具有结合HER2的抗原结合结构域的抗体构建体。
式I的免疫缀合物的一个示例性实施方案包括其中所述抗体选自由曲妥珠单抗和帕妥珠单抗或其生物类似药或生物改良药组成的组。
式I的免疫缀合物的一个示例性实施方案包括其中所述抗体是具有结合CEA的抗原结合结构域的抗体构建体。
式I的免疫缀合物的一个示例性实施方案包括其中所述抗体是拉贝妥珠单抗或其生物类似药或生物改良药。
式I的免疫缀合物的一个示例性实施方案包括其中所述抗体是具有结合Caprin-1的抗原结合结构域的抗体构建体。
式I的免疫缀合物的一个示例性实施方案包括其中所述抗体是具有结合TROP2的抗原结合结构域的抗体构建体。
式I的免疫缀合物的一个示例性实施方案包括其中所述抗体是沙西妥珠单抗(sacituzumab)或其生物类似药或生物改良药。
式I的免疫缀合物的一个示例性实施方案包括其中X1是一键,并且R1是H。
式I的免疫缀合物的一个示例性实施方案包括其中X2是一键,并且R2是C1-C8烷基。
式I的免疫缀合物的一个示例性实施方案包括其中X2和X3各自是一键,并且R2和R3独立地选自C1-C8烷基、-O-(C1-C12烷基)、-(C1-C12烷二基)-OR5、-(C1-C8烷二基)-N(R5)CO2R5、-(C1-C12烷基)-OC(O)N(R5)2、-O-(C1-C12烷基)-N(R5)CO2R5和-O-(C1-C12烷基)-OC(O)N(R5)2。
式I的免疫缀合物的一个示例性实施方案包括其中R2是C1-C8烷基并且R3是-(C1-C8烷二基)-N(R5)CO2R4。
式I的免疫缀合物的一个示例性实施方案包括其中R2是-CH2CH2CH3并且R3选自-CH2CH2CH2NHCO2(t-Bu)、-OCH2CH2NHCO2(环丁基)和-CH2CH2CH2NHCO2(环丁基)。
式I的免疫缀合物的一个示例性实施方案包括其中R2和R3各自独立地选自-CH2CH2CH3、-OCH2CH3、-OCH2CF3、-CH2CH2CF3、-OCH2CH2OH和-CH2CH2CH2OH。
式I的免疫缀合物的一个示例性实施方案包括其中R2和R3各自是-CH2CH2CH3。
式I的免疫缀合物的一个示例性实施方案包括其中R2是-CH2CH2CH3并且R3是-OCH2CH3。
式I的免疫缀合物的一个示例性实施方案包括其中X3-R3选自由以下组成的组:
式I的免疫缀合物的一个示例性实施方案包括其中R2或R3附接至L。
式I的免疫缀合物的一个示例性实施方案包括其中X3-R3-L选自由以下组成的组:
其中波形线指示与N的附接点。
式I的免疫缀合物的一个示例性实施方案包括其中R4是C1-C12烷基。
式I的免疫缀合物的一个示例性实施方案包括其中R4是-(C1-C12烷二基)-N(R5)-*;其中星号*指示L的附接位点。
式I的免疫缀合物的一个示例性实施方案包括其中L是-C(=O)-PEG-或-C(=O)-PEG-C(=O)-。
式I的免疫缀合物的一个示例性实施方案包括其中L附接至所述抗体的半胱氨酸硫醇。
式I的免疫缀合物的一个示例性实施方案包括其中对于所述PEG,m是1或2,并且n是2至10的整数。
式I的免疫缀合物的一个示例性实施方案包括其中对于所述PEG,n是10。
式I的免疫缀合物的一个示例性实施方案包括其中L包含PEP,并且PEP是二肽并具有下式:
式I的免疫缀合物的一个示例性实施方案包括其中L包含PEP,并且PEP是三肽并具有下式:
式I的免疫缀合物的一个示例性实施方案包括其中L包含PEP,并且PEP是四肽并具有下式:
式I的免疫缀合物的一个示例性实施方案包括其中PEP具有下式:
其中AA1和AA2独立地选自天然存在的氨基酸的侧链。
式I的免疫缀合物的一个示例性实施方案包括其中AA1和AA2独立地选自H、-CH3、-CH(CH3)2、-CH2(C6H5)、-CH2CH2CH2CH2NH2、-CH2CH2CH2NHC(NH)NH2、-CHCH(CH3)CH3、-CH2SO3H和-CH2CH2CH2NHC(O)NH2;或AA1和AA2形成5元环脯氨酸氨基酸。
式I的免疫缀合物的一个示例性实施方案包括其中AA1是-CH(CH3)2,并且AA2是-CH2CH2CH2NHC(O)NH2。
式I的免疫缀合物的一个示例性实施方案包括其中AA1和AA2独立地选自GlcNAc天冬氨酸、-CH2SO3H和-CH2OPO3H。
式I的免疫缀合物的一个示例性实施方案包括其中
AA1选自由Abu、Ala和Val组成的组;
AA2选自由Nle(O-Bzl)、Oic和Pro组成的组;
AA3选自由Ala和Met(O)2组成的组;并且
AA4选自由Oic、Arg(NO2)、Bpa和Nle(O-Bzl)组成的组。
式I的免疫缀合物的一个示例性实施方案包括其中L选自以下结构:
其中波形线指示附接至R5。
式I的免疫缀合物的一个示例性实施方案选自式Ia-Id:
式I的免疫缀合物的一个示例性实施方案选自式Ie-Il:
本发明包括式I实施方案的所有合理组合和特征排列。
在某些实施方案中,本发明的免疫缀合物化合物包括具有免疫刺激活性的那些化合物。本发明的抗体-药物缀合物选择性地将有效剂量的吡唑并氮呯药物递送至肿瘤组织,从而可以达成相对于未缀合的吡唑并氮呯更大的选择性(即,较低有效剂量),同时增加治疗指数(“治疗窗”)。
药物负荷由p表示,即,式I的免疫缀合物中每个抗体的PAZ部分的数目。药物(PAZ)负荷可以在每个抗体1个至约8个药物部分(D)的范围内。式I的免疫缀合物包括与1个至约8个范围内的药物部分缀合的抗体混合物或集合。在一些实施方案中,可以缀合至抗体的药物部分的数目受反应性或可用氨基酸侧链残基,诸如赖氨酸和半胱氨酸的数目限制。在一些实施方案中,通过本文所描述的方法将游离半胱氨酸残基引入抗体氨基酸序列中。在此类方面,p可以是1、2、3、4、5、6、7或8及其范围,诸如1至8或2至5。在任何此类方面,p和n相等(即,p=n=1、2、3、4、5、6、7或8或介于之间的某个范围)。式I的示例性免疫缀合物包括但不限于具有1、2、3或4个工程改造的半胱氨酸氨基酸的抗体(Lyon,R.等(2012)Methods inEnzym.502:123-138)。在一些实施方案中,在不使用工程改造的情况下形成链内二硫键的抗体中已存在一个或多个游离半胱氨酸残基,在这种情况下可以使用现有游离半胱氨酸残基将抗体缀合至药物。在一些实施方案中,在抗体缀合之前使抗体暴露于还原条件,以产生一个或多个游离半胱氨酸残基。
对于一些免疫缀合物,p可能受抗体上的附接位点的数目限制。举例来说,在附接半胱氨酸硫醇的情况下,如在本文所描述的某些示例性实施方案中,抗体可能仅具有一个或有限数目的半胱氨酸硫醇基团,或可能仅具有一个或有限数目的充分反应性硫醇基团,药物可以附接至所述基团。在其它实施方案中,抗体中的一个或多个赖氨酸氨基对于与式II的PAZ-连接子化合物缀合来说可以是可用的并且具有反应性。在某些实施方案中,较高药物负荷,例如p>5,可能导致某些抗体-药物缀合物的聚集、不溶性、毒性或细胞渗透性损失。在某些实施方案中,免疫缀合物的平均药物负荷在1至约8、约2至约6或约3至约5的范围内。在某些实施方案中,使抗体经受变性条件以显露反应性亲核基团,诸如赖氨酸或半胱氨酸。
免疫缀合物的负荷(药物/抗体比率)可以按不同方式控制,并且例如通过:(i)限制PAZ-连接子中间化合物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)用于优化的抗体反应性的部分或限制性还原变性条件。
应了解,在抗体的多于一个亲核基团与药物反应的情况下,那么所得产物是免疫缀合物化合物的混合物,其具有一个或多个药物部分附接至抗体的分布。可以通过对抗体具有特异性并且对药物具有特异性的双重ELISA抗体测定从混合物计算每个抗体的平均药物数。可以通过质谱法在混合物中鉴定个别免疫缀合物分子,并且通过HPLC,例如疏水相互作用色谱法进行分离(参见例如McDonagh等(2006)Prot.Engr.Design&Selection 19(7):299-307;Hamblett等(2004)Clin.Cancer Res.10:7063-7070;Hamblett,K.J.等"Effectof drug loading on the pharmacology,pharmacokinetics,and toxicity of an anti-CD30antibody-drug conjugate",摘要号624,American Association for CancerResearch,2004Annual Meeting,2004年3月27-31日,Proceedings of the AACR,第45卷,2004年3月;Alley,S.C.等"Controlling the location of drug attachment inantibody-drug conjugates",摘要号627,American Association for Cancer Research,2004Annual Meeting,2004年3月27-31日,Proceedings of the AACR,第45卷,2004年3月)。在某些实施方案中,可以通过电泳或色谱法从缀合混合物中分离具有单一负荷值的均质免疫缀合物。
式I的免疫缀合物的一个示例性实施方案选自表3a和表3b的免疫缀合物。利用实施例203中所描述的方法测试表3a和表3b的免疫缀合物,其中大多数展示出活性。
表3a免疫缀合物(IC)
表3b免疫缀合物(IC)
通过抗HER2抗体曲妥珠单抗与连接子-佐剂化合物缀合来制备比较免疫缀合物A:
免疫缀合物的组合物
本发明提供了一种组合物,例如药学上或药理学上可接受的组合物或制剂,其包含多种如本文所描述的免疫缀合物和其任选的载体,例如药学上或药理学上可接受的载体。免疫缀合物在组成上可以相同或不同,即,组合物可以包含具有连接至抗体构建体上的相同位置的相同数目的佐剂的免疫缀合物和/或具有连接至抗体构建体上的不同位置的相同数目的PAZ佐剂,具有连接至抗体构建体上的相同位置的不同数目的佐剂,或具有连接至抗体构建体上的不同位置的不同数目的佐剂的免疫缀合物。
在一个示例性实施方案中,包含免疫缀合物化合物的组合物包含免疫缀合物化合物的混合物,其中免疫缀合物化合物的混合物中每个抗体的平均药物(PAZ)负荷为约2至约5。
本发明的免疫缀合物的组合物可以具有约0.4至约10的平均佐剂与抗体构建体比率(DAR)。技术人员将认识到,在包含本发明的多种免疫缀合物的组合物中,缀合至抗体构建体的吡唑并氮呯佐剂的数目可能随着免疫缀合物的不同而变化,并且因此,可以用平均值测量佐剂与抗体构建体(例如抗体)比率,这可以称作药物与抗体比率(DAR)。佐剂与抗体构建体(例如抗体)比率可以通过任何适合的手段来评估,其中许多手段在本领域中是已知的。
在从缀合反应制备免疫缀合物中每个抗体的佐剂部分的平均数目(DAR)可以通过常规手段,诸如质谱法、ELISA测定和HPLC来表征。还可以确定免疫缀合物在组合物中的定量分布,以p表示。在一些情况下,可以通过诸如反相HPLC或电泳的手段,从具有其它药物负荷的免疫缀合物中分离、纯化和表征其中p是一定值的均质免疫缀合物。
在一些实施方案中,组合物还包含一种或多种药学上或药理学上可接受的赋形剂。举例来说,本发明的免疫缀合物可以经配制用于肠道外施用,诸如静脉内施用或向器官的体腔或内腔中施用。或者,可以肿瘤内注射免疫缀合物。注射用组合物通常将包含免疫缀合物溶解于药学上可接受的载体中的溶液。可以采用的可接受媒剂和溶剂是水和一种或多种盐的等张溶液,诸如氯化钠,例如林格氏溶液(Ringer'ssolution)。另外,无菌非挥发性油可以常规地用作溶剂或悬浮介质。出于此目的,可以采用任何温和的非挥发性油,包括合成单酸甘油酯或二酸甘油酯。另外,诸如油酸的脂肪酸同样可以用于可注射剂的制备中。这些组合物理想地是无菌的并且一般不含非所需的物质。这些组合物可以通过常规的熟知灭菌技术进行灭菌。组合物可以含有接近生理条件所需的药学上可接受的辅助物质,诸如pH调节剂和缓冲剂、毒性调节剂,例如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等等。
组合物可以含有任何适合浓度的免疫缀合物。组合物中免疫缀合物的浓度可以广泛变化,并且将根据所选特定施用模式和患者需要,主要基于流体体积、粘度、体重等等来选择。在某些实施方案中,注射用溶液制剂中免疫缀合物的浓度将在约0.1%(w/w)至约10%(w/w)的范围内。
用免疫缀合物治疗癌症的方法
本发明提供了一种用于治疗癌症的方法。所述方法包括向有需要的受试者,例如患有癌症并且需要治疗癌症的受试者施用治疗有效量的如本文所描述的免疫缀合物(例如,如本文所描述的组合物)。所述方法包括施用治疗有效量的选自表3a和3b的免疫缀合物(IC)。
预期本发明的免疫缀合物可以用于治疗各种过度增生性疾病或病症,例如以肿瘤抗原的过表达为特征。示例性过度增生性病症包括良性或恶性实体肿瘤和血液学病症,诸如白血病和淋巴样恶性病。
在另一个方面,提供了一种用作药剂的免疫缀合物。在某些实施方案中,本发明提供了一种用于治疗受试者的方法中的免疫缀合物,所述方法包括向受试者施用有效量的免疫缀合物。在一个此类实施方案中,所述方法还包括向受试者施用有效量的至少一种额外治疗剂,例如,如本文所描述。
在另一个方面,本发明提供了免疫缀合物在药剂制造或制备中的用途。在一个实施方案中,药剂用于治疗癌症,所述方法包括向患有癌症的受试者施用有效量的药剂。在一个此类实施方案中,所述方法还包括向受试者施用有效量的至少一种额外治疗剂,例如,如本文所描述。
癌瘤是起源于上皮组织的恶性病。上皮细胞覆盖身体的外表面,内衬于内腔,并且形成腺组织的衬里。癌瘤的实例包括但不限于腺癌(始于腺(分泌)细胞的癌症,诸如乳癌、胰脏癌、肺癌、前列腺癌、胃癌、胃食管连接部癌症和结肠癌);肾上腺皮质癌;肝细胞癌;肾细胞癌;卵巢癌;原位癌;导管癌;乳癌;基底细胞癌;鳞状细胞癌;移行细胞癌;结肠癌;鼻咽癌;多房囊性肾细胞癌;燕麦细胞癌;大细胞肺癌;小细胞肺癌;非小细胞肺癌;等等。在前列腺、胰脏、结肠、脑(通常是继发性转移)、肺、乳房和皮肤中可以发现癌瘤。在一些实施方案中,用于治疗非小细胞肺癌的方法包括施用含有能够结合PD-L1的抗体构建体(例如阿特珠单抗、得瓦鲁单抗、阿维鲁单抗、其生物类似药或其生物改良药)的免疫缀合物。在一些实施方案中,用于治疗乳癌的方法包括施用含有能够结合PD-L1的抗体构建体(例如阿特珠单抗、得瓦鲁单抗、阿维鲁单抗、其生物类似药或其生物改良药)的免疫缀合物。在一些实施方案中,用于治疗三阴性乳癌的方法包括施用含有能够结合PD-L1的抗体构建体(例如阿特珠单抗、得瓦鲁单抗、阿维鲁单抗、其生物类似药或其生物改良药)的免疫缀合物。
软组织肿瘤是来源于结缔组织的罕见肿瘤的高度多样化群组。软组织肿瘤的实例包括但不限于肺泡状软组织肉瘤;血管瘤样纤维组织细胞瘤;软骨粘液样纤维瘤;骨骼软骨肉瘤;骨骼外粘液样软骨肉瘤;透明细胞肉瘤;促结缔组织增生性小圆细胞瘤;隆突性皮肤纤维肉瘤;子宫内膜间质瘤;尤因氏肉瘤(Ewing's sarcoma);纤维瘤病(硬纤维);婴儿纤维肉瘤;胃肠道间质瘤;骨巨细胞瘤;腱鞘巨细胞瘤;炎性肌纤维母细胞瘤;子宫平滑肌瘤;平滑肌肉瘤;脂肪母细胞瘤;典型脂肪瘤;梭形细胞或多形性脂肪瘤;非典型脂肪瘤;软骨样脂肪瘤;高分化脂肪肉瘤;粘液样/圆形细胞脂肪肉瘤;多形性脂肪肉瘤;粘液样恶性纤维组织细胞瘤;高度恶性纤维组织细胞瘤;粘液性纤维肉瘤;恶性周边神经鞘瘤;间皮瘤;神经母细胞瘤;骨软骨瘤;骨肉瘤;原始神经外胚层肿瘤;肺泡状横纹肌肉瘤;胚胎横纹肌肉瘤;良性或恶性神经鞘瘤;滑膜肉瘤;埃文氏肿瘤(Evan's tumor);结节性筋膜炎;硬纤维型纤维瘤病;孤立性纤维瘤;隆突性皮肤纤维肉瘤(DFSP);血管肉瘤;上皮样血管内皮瘤;腱鞘巨细胞瘤(TGCT);色素绒毛结节性滑膜炎(PVNS);纤维性发育不良;粘液性纤维肉瘤;纤维肉瘤;滑膜肉瘤;恶性周边神经鞘瘤;神经纤维瘤;软组织多形性腺瘤;以及来源于纤维母细胞、肌纤维母细胞、组织细胞、血管细胞/内皮细胞和神经鞘细胞的赘瘤。
肉瘤是罕见类型的癌症,其出现于间叶来源的细胞中,例如身体的骨骼中或软组织中,所述软组织包括软骨、脂肪、肌肉、血管、纤维组织或其它结缔组织或支持组织。不同类型的肉瘤基于癌症形成的部位。举例来说,骨肉瘤在骨骼中形成,脂肪肉瘤在脂肪中形成,并且横纹肌肉瘤在肌肉中形成。肉瘤的实例包括但不限于阿斯金氏肿瘤(askin'stumor);葡萄状肉瘤;软骨肉瘤;尤因氏肉瘤;恶性血管内皮瘤;恶性神经鞘瘤;骨肉瘤;以及软组织肉瘤(例如肺泡状软组织肉瘤;血管肉瘤;叶状囊性肉瘤;隆突性皮肤纤维肉瘤(DFSP);硬纤维瘤;促结缔组织增生性小圆细胞瘤;上皮样肉瘤;骨骼外软骨肉瘤;骨骼外骨肉瘤;纤维肉瘤;胃肠道间质瘤(GIST);血管外皮细胞瘤;血管肉瘤(hemangiosarcoma)(更常称作“血管肉瘤(angiosarcoma)”);卡波西氏肉瘤(kaposi's sarcoma);平滑肌肉瘤;脂肪肉瘤;淋巴管肉瘤;恶性周边神经鞘瘤(MPNST);神经纤维肉瘤;滑膜肉瘤;以及未分化多形性肉瘤)。
畸胎瘤是一种类型的生殖细胞肿瘤,其可以含有若干不同类型的组织(例如可以包括来源于以下三个胚层中的任一者和/或全部的组织:内胚层、中胚层和外胚层),包括例如毛发、肌肉和骨骼。畸胎瘤最常出现于女性的卵巢、男性的睪丸和儿童的尾骨中。
黑色素瘤是始于黑色素细胞(制造黑色素的细胞)的癌症形式。黑色素瘤可以始于黑痣(皮肤黑色素瘤),但也可以始于其它有色素组织,诸如眼中或肠中。
默克尔细胞癌(Merkel cell carcinoma)是一种罕见类型的皮肤癌,其通常以肉色或蓝红色结节出现于面部、头部或颈部。默克尔细胞癌也称为皮肤神经内分泌癌。在一些实施方案中,用于治疗默克尔细胞癌的方法包括施用含有能够结合PD-L1的抗体构建体(例如阿特珠单抗、得瓦鲁单抗、阿维鲁单抗、其生物类似药或其生物改良药)的免疫缀合物。在一些实施方案中,当进行施用时默克尔细胞癌已转移。
白血病是始于血液形成组织(诸如骨髓)的癌症,并且导致大量异常血细胞产生并且进入血流。举例来说,白血病可以起源于通常在血流中成熟的骨髓源性细胞。白血病以疾病发展及进展的速度(例如急性对比慢性)和受影响的白血球类型(例如髓样对比淋巴样)而命名。髓样白血病也称为骨髓性或骨髓母细胞性白血病。淋巴样白血病也称为淋巴母细胞性或淋巴细胞性白血病。淋巴样白血病细胞可聚集于淋巴结中,从而淋巴结可变得肿胀。白血病的实例包括但不限于急性髓样白血病(AML)、急性淋巴母细胞性白血病(ALL)、慢性髓样白血病(CML)和慢性淋巴细胞性白血病(CLL)。
淋巴瘤是始于免疫系统细胞的癌症。举例来说,淋巴瘤可以起源于通常在淋巴系统中成熟的骨髓源性细胞。淋巴瘤存在两种基本类别。一种类别的淋巴瘤是霍奇金淋巴瘤(Hodgkin lymphoma,HL),其以称为里-斯二氏细胞(Reed-Sternberg cell)的细胞类型的存在为标志。当前存在6种公认的HL类型。霍奇金淋巴瘤的实例包括结节性硬化经典型霍奇金淋巴瘤(CHL)、混合细胞型CHL、淋巴细胞耗竭型CHL、富淋巴细胞型CHL和结节性淋巴细胞为主型HL。
另一种类别的淋巴瘤是非霍奇金淋巴瘤(non-Hodgkin lymphoma,NHL),其包括免疫系统细胞癌的大型多样化群组。非霍奇金淋巴瘤可以进一步分为具有无痛性(缓慢生长)病程的癌症和具有侵袭性(快速生长)病程的癌症。当前存在61种公认的NHL类型。非霍奇金淋巴瘤的实例包括但不限于AIDS相关淋巴瘤、退行性大细胞淋巴瘤、血管免疫母细胞性淋巴瘤、母细胞性NK细胞淋巴瘤、伯基特氏淋巴瘤(Burkitt's lymphoma)、伯基特样淋巴瘤(Burkitt-like lymphoma)(小无裂细胞淋巴瘤)、慢性淋巴细胞性白血病/小淋巴细胞性淋巴瘤、皮肤性T细胞淋巴瘤、弥漫性大B细胞淋巴瘤、肠病型T细胞淋巴瘤、滤泡性淋巴瘤、肝脾γ-δT细胞淋巴瘤、T细胞白血病、淋巴母细胞性淋巴瘤、套细胞淋巴瘤、边缘区淋巴瘤、鼻部T细胞淋巴瘤、小儿淋巴瘤、周边T细胞淋巴瘤、原发性中枢神经系统淋巴瘤、转化性淋巴瘤、治疗相关T细胞淋巴瘤和瓦尔登斯特伦氏巨球蛋白血症(Waldenstrom'smacroglobulinemia)。
脑癌包括脑组织的任何癌症。脑癌的实例包括但不限于神经胶质瘤(例如胶质母细胞瘤、星形细胞瘤、寡树突神经胶质瘤、室管膜瘤和类似癌症)、脑膜瘤、垂体腺瘤和前庭神经鞘瘤、原始神经外胚层肿瘤(髓母细胞瘤)。
本发明的免疫缀合物可以单独或与其它剂组合用于疗法中。举例来说,免疫缀合物可以与至少一种额外治疗剂,诸如化学治疗剂共同施用。此类组合疗法涵盖组合施用(其中两种或更多种治疗剂包括于相同或独立制剂中);以及独立施用,在这种情况下,免疫缀合物的施用可以在额外治疗剂和/或佐剂施用之前、同时和/或之后进行。免疫缀合物还可以与放射线疗法组合使用。
本发明的免疫缀合物(和任何额外治疗剂)可以通过任何适合的手段施用,包括肠道外、肺内和鼻内,并且必要时对于局部治疗,病灶内施用。肠道外输注包括肌肉内、静脉内、动脉内、腹膜内或皮下施用。给药可以通过任何适合的途径进行,例如通过注射,诸如静脉内或皮下注射,在部分程度上取决于施用是短暂的还是长期的。本文预期各种给药方案,包括但不限于单次施用或经多个时间点的多次施用、推注施用和脉冲输注。
已知阿特珠单抗、得瓦鲁单抗、阿维鲁单抗、其生物类似药及其生物改良药可以用于治疗癌症,特别是乳癌,尤其三阴性(对雌激素受体、黄体酮受体和过量HER2蛋白质测试呈阴性)乳癌、膀胱癌和默克尔细胞癌。本文所描述的免疫缀合物与阿特珠单抗、得瓦鲁单抗、阿维鲁单抗、其生物类似药及其生物改良药可以用于治疗相同类型的癌症,特别是乳癌,尤其三阴性(对雌激素受体、黄体酮受体和过量HER2蛋白质测试呈阴性)乳癌、膀胱癌和默克尔细胞癌。
使用任何适合的给药方案,诸如用于阿特珠单抗、得瓦鲁单抗、阿维鲁单抗、其生物类似药及其生物改良药的给药方案,以任何治疗有效量向有需要的受试者施用免疫缀合物。举例来说,所述方法可以包括施用免疫缀合物以向受试者提供约100ng/kg至约50mg/kg的剂量。免疫缀合物剂量可以在约5mg/kg至约50mg/kg、约10μg/kg至约5mg/kg、或约100μg/kg至约1mg/kg的范围内。免疫缀合物剂量可以为约100、200、300、400或500μg/kg。免疫缀合物剂量可以为约1、2、3、4、5、6、7、8、9或10mg/kg。取决于特定缀合物以及所治疗的癌症的类型和严重性,免疫缀合物剂量也可以在这些范围外。施用频率可以在每周单次给药至多次给药的范围内,或更高频率。在一些实施方案中,每月约一次至每周约五次施用免疫缀合物。在一些实施方案中,每周一次施用免疫缀合物。
在另一个方面,本发明提供了一种用于预防癌症的方法。所述方法包括向受试者施用治疗有效量的免疫缀合物(例如,如上文所描述的组合物)。在某些实施方案中,受试者易患某种有待预防的癌症。举例来说,所述方法可以包括施用免疫缀合物以向受试者提供约100ng/kg至约50mg/kg的剂量。免疫缀合物剂量可以在约5mg/kg至约50mg/kg、约10μg/kg至约5mg/kg、或约100μg/kg至约1mg/kg的范围内。免疫缀合物剂量可以为约100、200、300、400或500μg/kg。免疫缀合物剂量可以为约1、2、3、4、5、6、7、8、9或10mg/kg。取决于特定缀合物以及所治疗的癌症的类型和严重性,免疫缀合物剂量也可以在这些范围外。施用频率可以在每周单次给药至多次给药的范围内,或更高频率。在一些实施方案中,每月约一次至每周约五次施用免疫缀合物。在一些实施方案中,每周一次施用免疫缀合物。
本发明的一些实施方案提供用于治疗如上文所描述的癌症的方法,其中所述癌症是乳癌。乳癌可以起源于乳房的不同区域,并且许多不同类型的乳癌已表征。举例来说,本发明的免疫缀合物可以用于治疗原位导管癌;浸润性导管癌(例如小管癌;髓质癌;粘液癌;乳突癌;或乳房筛状癌);原位小叶癌;浸润性小叶癌;炎性乳癌;以及其它形式的乳癌,诸如三阴性(对雌激素受体、黄体酮受体和过量HER2蛋白质测试呈阴性)乳癌。在一些实施方案中,用于治疗乳癌的方法包括施用含有能够结合HER2的抗体构建体(例如曲妥珠单抗、帕妥珠单抗、其生物类似药或生物改良药)和能够结合PD-L1的抗体构建体(例如阿特珠单抗、得瓦鲁单抗、阿维鲁单抗、其生物类似药或生物改良药)的免疫缀合物。在一些实施方案中,用于治疗结肠癌、肺癌、肾癌、胰脏癌、胃癌和食管癌的方法包括施用含有能够结合CEA或过表达CEA的肿瘤的抗体构建体(例如拉贝妥珠单抗、其生物类似药或生物改良药)的免疫缀合物。
在一些实施方案中,癌症容易发生由TLR7和/或TLR8诱导的促炎反应。
在一些实施方案中,向需要治疗癌症的患者施用治疗有效量的免疫缀合物,其中所述癌症表达PD-L1、HER2、CEA或TROP2。
在一些实施方案中,向需要治疗宫颈癌、子宫内膜癌、卵巢癌、前列腺癌、胰腺癌、食道癌、膀胱癌、尿道癌、尿路上皮癌、肺癌、非小细胞肺癌、梅克尔细胞癌、结肠癌、结肠直肠癌、胃癌或乳癌的患者施用治疗有效量的免疫缀合物。梅克尔细胞癌可以是转移性梅克尔细胞癌。乳癌可以是三阴性乳癌。食道癌可以是胃食管连接部腺癌。
实施例
制备吡唑并氮呯化合物(PAZ)和中间体
实施例1合成5-氨基-1-甲基-N,N-二丙基-1,6-二氢吡唑并[4,3-b]氮呯-7-甲酰胺,PAZ-1
制备4-(叔丁氧基羰基氨基)-2-甲基-吡唑-3-甲酸甲酯,1b
向4-氨基-2-甲基-吡唑-3-甲酸甲酯1a(1g,6.45mmol,1当量)于DCM(25mL)中的混合物中添加TEA(1.96g,19.3mmol,2.69mL,3当量)、DMAP(78.7mg,644umol(微摩尔),0.1当量)和(Boc)2O(2.81g,12.9mmol,2.96mL,2当量),然后在15℃下搅拌10小时。浓缩混合物并且通过柱色谱法(SiO2,石油醚/乙酸乙酯=1:0至1:1)纯化,得到呈黄色油状的1b(1g,3.92mmol,产率60.78%)。
制备N-[5-(羟甲基)-1-甲基-吡唑-4-基]氨基甲酸叔丁酯,1c
在0℃下向1b(800mg,3.13mmol,1当量)于DCM(5mL)中的混合物中添加DIBAL-H(1M,12.5mL,4当量),并且在15℃下搅拌10小时。用水(0.5mL)淬灭反应混合物,然后经Na2SO4干燥,并且经硅藻土过滤,并且浓缩滤液,得到呈黄色油状的1c(400mg,1.76mmol,产率56.2%)。LC/MS[M+H]228.1(计算值);LC/MS[M+H]228.0(观测值)。
制备N-(5-甲酰基-1-甲基-吡唑-4-基)氨基甲酸叔丁酯,1d
在45℃下将1c(300mg,1.32mmol,1当量)和MnO2(1.15g,13.2mmol,10当量)于DCM(10mL)中的混合物搅拌23小时。经硅藻土过滤混合物,并且浓缩滤液,得到呈黄色油状的1d(297mg,1.32mmol,产率99.9%)。1H NMR(400MHz,CDCl3)δ10.01(s,1H),8.28(s,1H),8.04(s,1H),4.11(s,3H),1.53(s,9H)
制备(E)-3-(4-((叔丁氧基羰基)氨基)-1-甲基-1H-吡唑-5-基)-2-(氰基甲基)丙烯酸乙酯,1e
在80℃下将1d(270mg,1.20mmol,1当量)和3-氰基-2-(三苯基-亚膦基)丙酸乙酯(650mg,1.68mmol,1.4当量)于甲苯(10mL)中的混合物搅拌10小时。浓缩混合物并且通过柱色谱法(SiO2,石油醚/乙酸乙酯=1:0-1:2)纯化粗物质,得到呈黄色油状的1e(300mg,897.21umol,产率74.9%)。LC/MS[M+H]335.2(计算值);LC/MS[M+H]335.2(观测值)。
制备5-氨基-1-甲基-6H-吡唑并[4,3-b]氮呯-7-甲酸乙酯,1f
在15℃下将1e(280mg,837umol,1当量)于HCl/EtOAc(4M,5mL)中的混合物搅拌10分钟。浓缩混合物,得到呈黄色固体状的1f(120mg,512umol,产率61.17%)。
制备5-氨基-1-甲基-6H-吡唑并[4,3-b]氮呯-7-甲酸,1g
向1f(120mg,512umol,1当量)于EtOH(5mL)和H2O(1mL)中的混合物中添加LiOH.H2O(43mg,1.02mmol,2当量),并且在25℃下搅拌10小时。通过制备型HPLC(HCl条件:柱:WatersXbridge BEH C18 100*30mm*10um;流动相:[水(0.04%HCl)-ACN];B%:1%-20%,9分钟)纯化混合物,得到呈黄色固体状的1g(90mg,436umol,产率85.2%)。LC/MS[M+H]207.1(计算值);LC/MS[M+H]207.1(观测值)。
制备5-氨基-1-甲基-6H-吡唑并[4,3-b]氮呯-7-甲酸,PAZ-1
向5-氨基-1-甲基-6H-吡唑并[4,3-b]氮呯-7-甲酸(60mg,291umol,1当量)于DMF(1mL)中的混合物中添加六氟磷酸1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物,六氟磷酸氮杂苯并三唑四甲基脲鎓HATU(133mg,349umol,1.2当量)和DIEA(188mg,1.45mmol,253uL,5当量)。然后将N-丙基丙-1-胺(147mg,1.45mmol,201uL,5当量)添加至混合物中,并且在15℃下搅拌10小时。浓缩混合物,然后通过制备型HPLC(TFA条件:柱:Phenomenex Synergi C18 150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:15%-40%,10分钟)纯化,得到呈白色固体状的5-氨基-1-甲基-N,N-二丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺(14mg,48.4umol,产率16.6%)。1H NMR(400MHz,MeOD-d4)δ7.61(s,1H),7.11(s,1H),3.51-3.35(m,4H),3.34(s,2H),1.73-1.64(m,4H),1.02-0.85(m,6H)。LC/MS[M+H]290.2(计算值);LC/MS[M+H]290.2(观测值)。
实施例2合成5-氨基-1-(5-氨基戊基)-N,N-二丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺,PAZ-2
通过实施例4的程序制备N-[5-[5-氨基-7-(二丙基氨甲酰基)-6H-吡唑并[4,3-b]氮呯-1-基]戊基]氨基甲酸叔丁酯PAZ-4。向PAZ-4(30mg,65.1umol,1.0当量)于EtOAc(1mL)中的溶液中添加HCl/EtOAc(4M,5mL),然后在20℃下搅拌0.5小时。在真空中浓缩混合物,得到呈白色固体状的5-氨基-1-(5-氨基戊基)-N,N-二丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺(14.2mg,35.2umol,产率54.09%,纯度98.48%,HCl)。1H NMR(MeOD,400MHz)δ7.66(s,1H),7.14(s,1H),4.27(t,J=7.2Hz,2H),3.46-3.42(m,4H),3.38(s,2H),2.90(t,J=8.0Hz,2H),1.89-1.86(m,2H),1.72-1.66(m,6H),1.40-1.38(m,2H),0.96-0.89(m,6H)。LC/MS[M+H]361.3(计算值);LC/MS[M+H]361.2(观测值)。
实施例4合成N-[5-[5-氨基-7-(二丙基氨甲酰基)-6H-吡唑并[4,3-b]氮呯-1-基]戊基]氨基甲酸叔丁酯,PAZ-4
制备2-[5-(叔丁氧基羰基氨基)戊基]-4-硝基-吡唑-3-甲酸甲酯,4b
在25℃下于N2下向4-硝基-1H-吡唑-5-甲酸甲酯4a(5g,29.2mmol,1.0当量)于DMF(50mL)中的溶液中添加K2CO3(20.2g,146mmol,5.0当量)和4-甲基苯磺酸5-(叔丁氧基羰基氨基)戊酯(10.5g,29.2mmol,1.0当量)。在60℃下搅拌混合物3h(小时)。然后通过添加H2O(200mL)淬灭并且用乙酸乙酯(200mL x 3)萃取。用盐水(100mL)洗涤合并的有机相,经无水Na2SO4干燥,过滤并且在真空中浓缩。通过硅胶色谱法(柱高度:250mm,直径:100mm,100-200目硅胶,石油醚/乙酸乙酯=50/1,0/1)纯化残余物,得到呈黄色油状的4b(4.1g,粗物质)和呈黄色油状的区域异构体1-[5-(叔丁氧基羰基氨基)戊基]-4-硝基-吡唑-3-甲酸甲酯(6.1g,粗物质)。1H NMR(CDCl3,400MHz)δ8.03(s,1H),4.26(t,J=7.2Hz,2H),4.03(s,3H),3.11(q,J=6.8Hz,2H),1.94-1.86(m,2H),1.53-1.44(m,2H),1.44(s,9H),1.34-1.33(m,2H)。
制备N-[5-[5-(羟甲基)-4-硝基-吡唑-1-基]戊基]氨基甲酸叔丁酯,4c
在0℃下将4b(3.6g,10.1mmol,1.0当量)于DCM(36mL)中的溶液添加至DIBAL-H(1M,40.4mL,4.0当量)中,然后在0℃下搅拌0.5小时。用2mL H2O淬灭混合物并且搅拌10分钟,然后经Na2SO4干燥,用乙酸乙酯(50mL x 4)洗涤,过滤并且在压力下浓缩。通过硅胶色谱法(柱高度:250mm,直径:100mm,100-200目硅胶,石油醚/乙酸乙酯=100/1至0/1)纯化残余物,得到呈黄色油状的4c(2.4g,7.31mmol,产率72.35%)。1H NMR(CDCl3,400MHz)δ8.09(s,1H),4.98(d,J=7.2Hz,2H),4.59(s,1H),4.24(t,J=7.2Hz,2H),3.32(t,J=6.8Hz,1H),3.12(q,J=6.8Hz,2H),1.96-1.92(m,2H),1.53-1.49(m,2H),1.44(s,9H),1.38-1.34(m,2H)。
制备N-[5-(5-甲酰基-4-硝基-吡唑-1-基)戊基]氨基甲酸叔丁酯,4d
向4c(2.4g,7.31mmol,1.0当量)于DCM(24mL)中的溶液中添加MnO2(6.35g,73.1mmol,10.0当量),然后在50℃下搅拌12小时。过滤混合物并且在压力下浓缩。通过硅胶色谱法(柱高度:250mm,直径:100mm,100-200目硅胶,石油醚/乙酸乙酯=100/1至0/1)纯化残余物,得到呈黄色油状的2d(0.93g,2.85mmol,产率38.99%)。1H NMR(CDCl3,400MHz)δ10.51(s,1H),8.13(s,1H),4.56(t,J=7.6Hz,2H),3.13-3.10(m,2H),1.91-1.84(m,2H),1.53-1.51(m,2H),1.45(s,9H),1.43-1.36(m,2H)。
制备(E)-3-(1-(5-((叔丁氧基羰基)氨基)戊基)-4-硝基-1H-吡唑-5-基)-2-(氰基甲基)丙烯酸乙酯,4e
向3-氰基-2-(三苯基-λ5-亚膦基)丙酸乙酯(1.21g,3.13mmol,1.10当量)于甲苯(10mL)中的溶液中添加2d(0.93g,2.85mmol,1.0当量),然后在70℃下于N2下搅拌3小时。此后,将其浓缩以去除甲苯(10mL)。通过硅胶色谱法(柱高度:250mm,直径:100mm,100-200目硅胶,石油醚/乙酸乙酯=100/1至0/1至乙酸乙酯/MeOH=100/1至10/1)纯化残余物,获得呈黄色油状的4e(1.2g,2.76mmol,产率96.70%)。1H NMR(CDCl3,400MHz)δ8.22(s,1H),7.63(s,1H),4.58(s,1H),4.45-4.40(m,2H),4.10-4.07(m,2H),3.41(s,2H),3.11(q,J=6.4Hz,2H),1.93-1.89(m,2H),1.54-1.50(m,2H),1.45-1.42(m,12H),1.34-1.32(m,2H)
制备5-氨基-1-[5-(叔丁氧基羰基氨基)戊基]-6H-吡唑并[4,3-b]氮呯-7-甲酸乙酯,4f
向4e(600mg,1.38mmol,1.0当量)于AcOH(6mL)中的溶液中添加Fe(385mg,6.89mmol,5.0当量),然后在70℃下搅拌3小时。过滤混合物并浓缩以去除AcOH,然后添加5mL H2O,用乙酸乙酯(10mL x 5)萃取。用盐水(5mL)洗涤合并的有机相,经无水Na2SO4干燥,过滤并且在真空中浓缩。通过硅胶色谱法(柱高度:250mm,直径:100mm,100-200目硅胶,石油醚/乙酸乙酯=50/1至0/1至乙酸乙酯/MeOH=50/1至1/1)纯化残余物,得到呈黄色油状的4f(150mg,369.92umol,产率26.85%)。1H NMR(CDCl3,400MHz)δ7.69(s,1H),7.58(s,1H),4.36-4.31(m,2H),4.20-4.16(m,2H),3.13(s,2H),3.10-3.09(m,2H),1.89-1.84(m,2H),1.52-1.49(m,2H),1.44(s,9H),1.39(t,J=7.2Hz,3H),1.32-1.31(m,2H)。
制备5-氨基-1-[5-(叔丁氧基羰基氨基)戊基]-6H-吡唑并[4,3-b]氮呯-7-甲酸,4g
向4f(130mg,321umol,1.0当量)于EtOH(0.5mL)中的溶液中添加LiOH.H2O(53.8mg,1.28mmol,4.0当量)于H2O(0.5mL)中的溶液,然后在20℃下搅拌3小时。用HCl(4M)将混合物的pH调节至约7,然后用DCM/i-PrOH(3/1,10mL x 3)萃取。经无水Na2SO4干燥合并的有机相,过滤并且在真空中浓缩,得到呈黄色油状的4g(121mg,320.58umol,产率99.99%)。1H NMR(MeOD,400MHz)δ7.66(s,1H),7.56(s,1H),4.23(t,J=7.2Hz,2H),3.41(s,2H),2.99(t,J=6.8Hz,2H),1.86-1.82(m,2H),1.48-1.45(m,2H),1.41(s,9H),1.29-1.26(m,2H)
制备N-[5-[5-氨基-7-(二丙基氨甲酰基)-6H-吡唑并[4,3-b]氮呯-1-基]戊基]氨基甲酸叔丁酯,PAZ-4
向4g(100mg,265umol,1.0当量)于DMF(0.5mL)中的溶液中添加HATU(106mg,278umol,1.05当量)、DIEA(103mg,795umol,3.0当量)和N-丙基丙-1-胺(40.2mg,397umol,1.50当量)。在20℃下搅拌混合物0.5小时。然后将其过滤并且通过制备型HPLC(柱:Phenomenex Synergi C18 150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:20%-45%,9分钟)纯化,获得呈白色固体状的PAZ-4(105mg,218.98umol,产率82.65%,纯度96.06%)。1H NMR(MeOD,400MHz)δ7.63(s,1H),7.14(s,1H),4.25(t,J=7.2Hz,2H),3.46-3.45(m,4H),3.37(s,2H),2.98(t,J=6.4Hz,2H),1.84-1.83(m,2H),1.73-1.67(m,4H),1.45-1.44(m,2H),1.42(s,9H),1.31-1.27(m,2H),0.96-0.89(m,6H)。LC/MS[M+H]461.3(计算值);LC/MS[M+H]461.3(观测值)。
实施例6合成5-氨基-2-甲基-N,N-二丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺,PAZ-6
制备(1-甲基-4-硝基-吡唑-3-基)甲醇,6b
在0℃下于N2下向1-甲基-4-硝基-吡唑-3-甲酸甲酯6a(4.00g,21.6mmol,1.0当量)于DCM(40mL)中的溶液中逐滴添加DIBAL-H(1M,64.8mL,3.0当量),然后在0℃下搅拌1小时。用水(1.2mL)淬灭反应混合物并过滤,然后在真空中浓缩滤液。通过硅胶色谱法(柱高度:250mm,直径:100mm,100-200目硅胶,石油醚/乙酸乙酯=10/1,1/2)纯化残余物,得到呈白色固体状的6b(2.20g,14.0mmol,产率64.8%)。1H NMR(400MHz,CDCl3)δ8.07(s,1H),4.84(d,J=5.6Hz,2H),3.87(s,3H),2.77(t,J=5.6Hz,1H)。
制备1-甲基-4-硝基-吡唑-3-甲醛,6c
在20℃下于N2下向6b(2.20g,14.0mmol,1.0当量)于DCM(20mL)中的溶液中一次性添加MnO2(6.09g,70.0mmol,5.0当量),然后在40℃下搅拌10小时。过滤反应混合物并且在真空中浓缩滤液。通过硅胶色谱法(柱高度:250mm,直径:100mm,100-200目硅胶,石油醚/乙酸乙酯=10/1,1/4)纯化残余物,得到呈黄色固体状的6c(1.00g,6.45mmol,产率46.0%)。1H NMR(400MHz,CDCl3)δ10.38(s,1H),8.15(s,1H),4.01(s,3H)。
制备(E)-2-(氰基甲基)-3-(1-甲基-4-硝基-1H-吡唑-3-基)丙烯酸乙酯,6d
在20℃下于N2下一次性添加6c(1.00g,6.45mmol,1.0当量)和3-氰基-2-(三苯基-λ5-亚膦基)丙酸乙酯(3.25g,8.38mmol,1.3当量)于甲苯(10mL)中的混合物,并且在75℃下搅拌10小时。在真空中浓缩反应混合物。通过硅胶色谱法(柱高度:250mm,直径:100mm,100-200目硅胶,石油醚/乙酸乙酯=10/1,1/1)纯化残余物,得到呈黄色固体状的6d(1.10g,4.16mmol,产率64.5%)。1H NMR(400MHz,CDCl3)δ8.27(s,1H),8.17(s,1H),4.30(q,J=7.2Hz,2H),3.98(s,3H),3.95(s,2H),1.33(t,J=7.2Hz,3H)。
制备5-氨基-2-甲基-6H-吡唑并[4,3-b]氮呯-7-甲酸乙酯,6e
在20℃下于N2下向6d(900mg,3.41mmol,1.0当量)于AcOH(18mL)中的溶液中一次性添加Fe(951mg,17.0mmol,5.0当量),然后在60℃下搅拌10小时。在真空中浓缩反应混合物。通过硅胶色谱法(柱高度:250mm,直径:100mm,100-200目硅胶,石油醚/乙酸乙酯=10/1,0/1继之以乙酸乙酯/甲醇=1/0,6/1)纯化残余物,得到呈黄色固体状的6e(270mg,1.15mmol,产率33.8%)。
制备5-氨基-2-甲基-6H-吡唑并[4,3-b]氮呯-7-甲酸,6f
在20℃下于N2下向PAZ-6e(120mg,512umol,1.0当量)于EtOH(10mL)和H2O(2mL)中的溶液中一次性添加LiOH·H2O(107mg,2.56mmol,5.0当量),然后在20℃下搅拌10小时。向反应混合物中添加水(5mL)并且用HCl(4M)将pH调节至约7,然后在真空中浓缩混合物,过滤并干燥滤饼,得到呈浅黄色固体状的6f(70.0mg,339umol,产率66.2%)。1H NMR(400MHz,DMSO-d6)δ7.56(s,1H),7.19(br s,1H),3.86(s,3H),3.07(s,2H)。
制备5-氨基-2-甲基-N,N-二丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺,PAZ-6
在20℃下于N2下向6f(60.0mg,291umol,1.0当量)于DMF(1mL)中的溶液中添加HATU(99.5mg,261umol,0.9当量)和DIEA(112mg,873umol,152uL,3.0当量)。10分钟后,添加N-丙基丙-1-胺(58.9mg,582umol,80.2uL,2.0当量),并且在20℃下再搅拌0.5小时。过滤反应混合物并且通过制备型HPLC(柱:Phenomenex Luna C18 150*30mm*5um;流动相:[水(0.1%TFA)-ACN];B%:5%-40%,12分钟)纯化滤液,得到呈黄色固体状的PAZ-6(25.6mg,86.7umol,产率29.8%,纯度98.0%)。1H NMR(400MHz,MeOD-d4)δ7.86(s,1H),6.96(s,1H),3.99(s,3H),3.50-3.42(m,4H),3.41(s,2H),1.75-1.64(m,4H),0.98-0.92(m,6H)。LC/MS[M+H]290.2(计算值);LC/MS[M+H]290.2(观测值)。
实施例7合成5-氨基-1-(5-氨基戊基)-N-[3-(3,3-二甲基丁酰基氨基)丙基]-N-丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺,PAZ-7
向PAZ-8(80mg,139umol,1.0当量)于EtOAc(2mL)中的溶液中添加HCl/EtOAc(4M,1.05mL,30.0当量),然后在20℃下搅拌混合物0.5小时。在压力下浓缩混合物,获得黄色固体(75mg,146umol,产率98%,PAZ-7,2HCl)。1H NMR(MeOD,400MHz)δ7.67(s,1H),7.18(s,1H),4.28(t,J=7.2Hz,2H),3.52(t,J=6.8Hz,2H),3.45-3.41(m,4H),3.32(d,J=2.4Hz,2H),2.91(t,J=7.6Hz,2H),2.07-2.04(m,2H),1.90-1.85(m,4H),1.69-1.66(m,4H),1.40-1.36(m,2H),1.02(s,9H),0.97-0.87(m,3H)。LC/MS[M+H]474.3(计算值);LC/MS[M+H]474.3(观测值)。
实施例8合成N-[5-[5-氨基-7-[3-(3,3-二甲基丁酰基氨基)丙基-丙基-氨甲酰基]-6H-吡唑并[4,3-b]氮呯-1-基]戊基]氨基甲酸叔丁酯,PAZ-8
在20℃下向8a(250mg,662umol,1.0当量)于DMF(3mL)中的溶液中添加HATU(252mg,662umol,1.0当量)、DIEA(257mg,1.99mmol,346uL,3.0当量)和3,3-二甲基-N-[3-(丙基氨基)丙基]丁酰胺(149mg,695umol,1.05当量),并且搅拌0.5小时。过滤混合物并且通过制备型HPLC(柱:Phenomenex Synergi C18 150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:15%-45%,10分钟)纯化,得到呈白色固体状的PAZ-8(120mg,195umol,产率29.44%,纯度93.23%)。1H NMR(MeOD,400MHz)δ7.64(s,1H),7.17(s,1H),4.25(t,J=7.2Hz,2H),3.52(t,J=7.2Hz,2H),3.46-3.40(m,4H),3.22(d,J=1.6Hz,2H),3.00-2.97(m,2H),2.06(s,2H),1.88-1.83(m,4H),1.70-1.68(m,2H),1.47-1.45(m,2H),1.42-1.41(m,11H),1.28-1.27(m,2H),1.02(s,9H),0.93(s,3H)。LC/MS[M+H]574.4(计算值);LC/MS[M+H]574.4(观测值)。
实施例9合成5-氨基-2-(5-氨基戊基)-N-[3-(3,3-二甲基丁酰基氨基)丙基]-N-丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺,PAZ-9
向来自实施例10的N-[5-[5-氨基-7-[3-(3,3-二甲基丁酰基氨基)丙基-丙基-氨甲酰基]-6H-吡唑并[4,3-b]氮呯-2-基]戊基]氨基甲酸叔丁酯PAZ-10(80.0mg,139umol,1当量)于EtOAc(2mL)中的溶液中添加HCl/EtOAc(4M,2mL,57.0当量),并且在20℃下搅拌1小时。浓缩混合物,得到呈浅黄色固体状的PAZ-9(70mg,128umol,产率91.85%,2HCl)。1H NMR(MeOD-d4,400MHz)δ7.93(s,1H),6.97(s,1H),4.25(t,J=6.8Hz,2H),3.52(br t,J=7.2Hz,2H),3.47-3.39(m,4H),3.27-3.16(m,2H),2.92(br t,J=7.2Hz,2H),2.08-2.01(m,2H),1.99-1.91(m,2H),1.90-1.80(m,2H),1.75-1.63(m,4H),1.44-1.40(m,2H),1.01(brs,9H),0.94-0.90(m,3H)。LC/MS[M+H]474.4(计算值);LC/MS[M+H]474.3(观测值)。
实施例10合成N-[5-[5-氨基-7-[3-(3,3-二甲基丁酰基氨基)丙基-丙基-氨甲酰基]-6H-吡唑并[4,3-b]氮呯-2-基]戊基]氨基甲酸叔丁酯,PAZ-10
向5-氨基-2-[5-(叔丁氧基羰基氨基)戊基]-6H-吡唑并[4,3-b]氮呯-7-甲酸10a(250mg,662umol,1当量)于DMF(5mL)中的溶液中添加HATU(252mg,662umol,1当量)、DIEA(257mg,2.00mmol,346uL,3当量)和3,3-二甲基-N-[3-(丙基氨基)丙基]丁酰胺(664mg,2.70mmol,4当量,HCl),然后在20℃下搅拌1小时。用水(30mL)稀释混合物并且用EtOAc(30mL x 3)萃取。用盐水(20mL)洗涤有机层,经Na2SO4干燥,过滤并浓缩。通过制备型HPLC(柱:Phenomenex Synergi C18 150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:15%-45%,8分钟)纯化残余物,得到呈浅黄色固体状的PAZ-10(90mg,131umol,产率19.76%,TFA)。1H NMR(MeOD-d4,400MHz)δ7.88(s,1H),6.98(s,1H),4.22(t,J=7.2Hz,2H),3.52(brt,J=7.2Hz,2H),3.48-3.38(m,4H),3.26-3.15(m,2H),3.02(t,J=6.8Hz,2H),2.10-1.99(m,2H),1.96-1.79(m,4H),1.72-1.62(m,2H),1.54-1.47(m,2H),1.42(s,9H),1.37-1.28(m,2H),1.01(s,9H),0.95-0.86(m,3H)。LC/MS[M+H]574.4(计算值);LC/MS[M+H]574.4(观测值)。
实施例11合成N-[5-[5-氨基-7-[乙氧基(丙基)氨甲酰基]-6H-吡唑并[4,3-b]氮呯-1-基]戊基]氨基甲酸叔丁酯,PAZ-11
向5-氨基-1-[5-(叔丁氧基羰基氨基)戊基]-6H-吡唑并[4,3-b]氮呯-7-甲酸4g(220mg,582umol,1当量)和N-乙氧基丙-1-胺(122mg,874umol,1.5当量,HCl)于DCM(5mL)和二甲基乙酰胺DMA(5mL)中的溶液中添加1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐EDCI(447mg,2.33mmol,4当量),然后在20℃下搅拌1小时。过滤反应混合物并且在减压下浓缩。通过制备型HPLC(TFA条件:柱:Phenomenex Gemini-NX 150*30mm*5um;流动相:[水(0.1%TFA)-ACN];B%:25%-55%,9分钟)纯化残余物,得到呈白色固体状的PAZ-11(135mg,234.13umol,产率40.17%,TFA)。1H NMR(MeOD-d4,400MHz)δ7.64(s,1H),7.48(s,1H),4.25(t,J=6.8Hz,2H),3.96(q,J=7.2Hz,2H),3.74(t,J=7.2Hz,2H),3.43(s,2H),2.99(t,J=6.8Hz,2H),1.90-1.71(m,4H),1.51-1.37(m,11H),1.33-1.23(m,2H),1.19(t,J=7.2Hz,3H),1.00(t,J=7.2Hz,3H)。LC/MS[M+H]463.3(计算值);LC/MS[M+H]463.3(观测值)。
实施例12合成5-氨基-1-(5-氨基戊基)-N-乙氧基-N-丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺,PAZ-12
向PAZ-11(123mg,265.90umol,1当量)于EtOAc(1mL)中的溶液中添加HCl/EtOAc(4M,10mL,150当量),并且在20℃下搅拌0.5小时。在减压下浓缩反应混合物,得到呈浅黄色固体状的PAZ-12(100.5mg,230.83umol,产率86.81%,2HCl)。1H NMR(MeOD-d4,400MHz)δ7.66(s,1H),7.46(s,1H),4.28(t,J=7.2Hz,2H),3.95(q,J=7.2Hz,2H),3.74(t,J=7.2Hz,2H),3.43(s,2H),2.91(t,J=7.6Hz,2H),1.95-1.84(m,2H),1.83-1.73(m,2H),1.70-1.64(m,2H),1.45-1.34(m,2H),1.18(t,J=7.2Hz,3H),1.00(t,J=7.2Hz,3H)。LC/MS[M+H]363.2(计算值);LC/MS[M+H]363.1(观测值)。
实施例13合成N-[[4-[[5-氨基-7-(二丙基氨甲酰基)-6H-吡唑并[4,3-b]氮呯-1-基]甲基]苯基]甲基]氨基甲酸叔丁酯,PAZ-13
制备2-[[4-[(叔丁氧基羰基氨基)甲基]苯基]甲基]-4-硝基-吡唑-3-甲酸甲酯,13b
在20℃下于N2下向4-硝基-1H-吡唑-5-甲酸甲酯13a(200mg,1.17mmol,1.0当量)和N-[[4-(溴甲基)苯基]甲基]氨基甲酸叔丁酯(350mg,1.17mmol,1.0当量)于DMF(5mL)中的混合物中一次性添加K2CO3(323mg,2.34mmol,2.0当量),然后在20℃下搅拌2小时。添加水(20mL)并且用乙酸乙酯(10mL x 3)萃取水相,用盐水(20mL)洗涤合并的有机相,经无水Na2SO4干燥,过滤并且在真空中浓缩。通过硅胶色谱法(柱高度:250mm,直径:100mm,100-200目硅胶,石油醚/乙酸乙酯=1/0,2/1)纯化残余物,得到呈白色固体状的13b(100mg,256umol,产率21.9%)。1H NMR(400MHz,MeOD-d4)δ8.18(s,1H),7.32-7.21(m,4H),5.50(s,2H),4.23(s,2H),3.92(s,3H),1.46(s,9H)。
制备N-[[4-[[5-(羟甲基)-4-硝基-吡唑-1-基]甲基]苯基]甲基]氨基甲酸叔丁酯,13c
在0℃下于N2下向13b(1.50g,3.84mmol,1.0当量)于DCM(20mL)中的溶液中逐滴添加DIBAL-H(1M,15.3mL,4.0当量),在0℃下搅拌混合物2小时。用冰水(3mL)淬灭反应混合物,然后过滤混合物并且浓缩滤液。通过硅胶色谱法(柱高度:250mm,直径:100mm,100-200目硅胶,石油醚/乙酸乙酯=1/0,1/1)纯化残余物,得到呈黄色油状的13c(600mg,1.66mmol,产率43.1%)。1H NMR(400MHz,CDCl3-d)δ8.05(s,1H),7.23-7.20(m,2H),7.14-7.11(m,2H),5.36(s,2H),4.85(d,J=6.8Hz,2H),4.22(d,J=6.0Hz,2H),1.38(s,9H)。
制备N-[[4-[(5-甲酰基-4-硝基-吡唑-1-基)甲基]苯基]甲基]氨基甲酸叔丁酯,13d
在20℃下于N2下向13c(600mg,1.66mmol,1.0当量)于DCM(10mL)中的溶液中一次性添加MnO2(1.44g,16.5mmol,10当量),然后在45℃下搅拌混合物48小时。过滤反应混合物并且在真空中浓缩滤液。通过硅胶色谱法(柱高度:250mm,直径:100mm,100-200目硅胶,石油醚/乙酸乙酯=1/0,2/1)纯化残余物,得到呈黄色固体状的13d(500mg,1.39mmol,产率83.8%)。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.53(s,1H),7.25(s,4H),5.72(s,2H),4.14(d,J=6.0Hz,2H),1.43(s,9H)。
制备(E)-3-[2-[[4-[(叔丁氧基羰基氨基)甲基]苯基]甲基]-4-硝基-吡唑-3-基]-2-(氰基甲基)丙-2-烯酸乙酯,13e
在75℃下将PAZ-13d(380mg,1.05mmol,1.0当量)和3-氰基-2-(三苯基-λ5-亚膦基)丙酸乙酯(449mg,1.16mmol,1.1当量)于甲苯(10mL)中的混合物搅拌3小时。在真空中浓缩反应混合物,然后通过硅胶色谱法(柱高度:250mm,直径:100mm,100-200目硅胶,石油醚/乙酸乙酯=10/1,2/1)纯化残余物,得到呈棕色固体状的13e(370mg,788umol,产率74.7%)。
制备5-氨基-1-[[4-[(叔丁氧基羰基氨基)甲基]苯基]甲基]-6H-吡唑并[4,3-b]氮呯-7-甲酸乙酯,13f
在20℃下于N2下向13e(370mg,788umol,1.0当量)于AcOH(7mL)中的溶液中一次性添加Fe(220mg,3.94mmol,5.0当量),然后在65℃下搅拌10小时。用乙酸乙酯稀释反应混合物,然后过滤。在真空中浓缩滤液。通过制备型HPLC(柱:Phenomenex luna C18100*40mm*5um;流动相:[水(0.1%TFA)-ACN];B%:15%-40%,8分钟)纯化残余物,得到呈黄色固体状的13f(180mg,409umol,产率51.9%)。1H NMR(400MHz,MeOD)δ7.73(s,1H),7.48(s,1H),7.24(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2H),5.44(s,2H),4.28(q,J=7.2Hz,2H),4.21(s,2H),3.05(s,2H),1.45(s,9H),1.34(t,J=7.2Hz,3H)。
制备5-氨基-1-[[4-[(叔丁氧基羰基氨基)甲基]苯基]甲基]-6H-吡唑并[4,3-b]氮呯-7-甲酸,13g
在20℃下于N2下向PAZ-13f(160mg,364umol,1.0当量)于EtOH(4mL)和H2O(4mL)中的溶液中一次性添加LiOH·H2O(61.1mg,1.46mmol,4.0当量),且在20℃下搅拌3小时。用HCl(4M)淬灭反应混合物直至pH=7,然后在真空中浓缩以去除EtOH。过滤沉淀物,得到呈灰色固体状的13g(120mg,291umol,产率80.1%)。1H NMR(400MHz,DMSO-d6)δ7.66(s,1H),7.39(s,1H),7.18(d,J=8.0Hz,2H),7.04(d,J=8.0Hz,2H),5.39(s,2H),4.09(d,J=6.0Hz,2H),2.90(s,2H),1.39(s,9H)。
制备PAZ-13
在20℃下于N2下向13g(150mg,364umol,1.0当量)于DMF(2mL)中的溶液中一次性添加HATU(138mg,364umol,1.0当量)和Et3N(110mg,1.09mmol,152uL,3.0当量)。10分钟后,添加N-丙基丙-1-胺(110mg,1.09mmol,150uL,3.0当量),并且在20℃下搅拌1小时。过滤反应混合物并且通过制备型HPLC(柱:Phenomenex Synergi C18 150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:10%-40%,10分钟)纯化滤液,得到呈白色固体状的PAZ-13(110mg,221umol,产率60.8%,纯度99.7%)。1H NMR(400MHz,MeOD)δ7.71(s,1H),7.26(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2H),7.02(s,1H),5.51(s,2H),4.20(s,2H),3.38-3.34(m,4H),3.30(s,2H),1.55-1.50(m,4H),1.45(s,9H),1.04-0.66(m,6H)。LC/MS[M+H]495.3(计算值);LC/MS[M+H]495.2(观测值)。
实施例14合成5-氨基-1-[[4-(氨基甲基)苯基]甲基]-N,N-二丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺,PAZ-14
在20℃下于N2下向N-[[4-[[5-氨基-7-(二丙基氨甲酰基)-6H-吡唑并[4,3-b]氮呯-1-基]甲基]苯基]甲基]氨基甲酸叔丁酯PAZ-13(100mg,202umol,1.0当量)于EtOAc(2mL)中的溶液中一次性添加HCl/EtOAc(4M,2.53mL,50当量),然后在20℃下搅拌混合物1小时。在真空中浓缩反应混合物,得到呈棕色油状的PAZ-14(87.0mg,196umol,产率97.1%,纯度97.2%,HCl)。1H NMR(400MHz,MeOD)δ7.74(s,1H),7.46(d,J=8.0Hz,2H),7.25(d,J=8.0Hz,2H),7.06(s,1H),5.56(s,2H),4.11(s,2H),3.35(s,2H),3.33-3.31(m,4H),1.72-1.54(m,4H),1.01-0.71(m,6H)。LC/MS[M+H]395.2(计算值);LC/MS[M+H]395.1(观测值)。
实施例15合成(3-(5-氨基-1-(5-氨基戊基)-N-丙基-1,6-二氢吡唑并[4,3-b]氮呯-7-甲酰胺基)丙基)氨基甲酸环丁酯,PAZ-15
向PAZ-16(200mg,349umol,1当量)于EtOAc(3mL)中的溶液中添加HCl/EtOAc(4M,10mL),然后在25℃下搅拌1小时。在减压下浓缩混合物,得到呈黄色固体状的PAZ-15(170mg,333umol,产率95.61%,HCl)。1H NMR(MeOD-d4,400MHz)δ7.67(s,1H),7.17(br s,1H),4.85-4.80(m,1H),4.28(t,J=7.2Hz,2H),3.51(br t,J=7.2Hz,2H),3.47-3.36(m,4H),3.19-3.02(m,2H),2.91(br t,J=7.6Hz,2H),2.32-2.20(m,2H),2.04-1.92(m,2H),1.90-1.82(m,4H),1.77-1.57(m,6H),1.45-1.31(m,2H),0.98-0.84(m,3H)。LC/MS[M+H]474.3(计算值);LC/MS[M+H]474.1(观测值)。
实施例16合成(5-(5-氨基-7-((3-((环丁氧基羰基)氨基)丙基)(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-1(6H)-基)戊基)氨基甲酸叔丁酯,PAZ-16
向5-氨基-1-[5-(叔丁氧基羰基氨基)戊基]-6H-吡唑并[4,3-b]氮呯-7-甲酸4g(250mg,662umol,1当量)于DMF(0.5mL)中的溶液中添加HATU(277mg,729umol,1.1当量)和DIEA(428mg,3.3mmol,577uL,5当量),然后添加N-[3-(丙基氨基)丙基]氨基甲酸环丁酯(166mg,662umol,1当量,HCl),并且在25℃下搅拌0.5小时。过滤混合物并且通过制备型HPLC(TFA条件;柱:Phenomenex Gemini-NX C18 75*30mm*3um;流动相:[水(0.1%TFA)-ACN];B%:30%-50%,8分钟)纯化,得到呈黄色固体状的PAZ-16(200mg,348.6umol,产率52.63%)。1H NMR(MeOD-d4,400MHz)δ7.42(s,1H),6.95(s,1H),4.84-4.77(m,1H),4.17(t,J=7.2Hz,2H),3.48(br t,J=7.2Hz,2H),3.42-3.37(m,2H),3.30(br s,2H),3.12-3.02(m,2H),2.98(t,J=6.8Hz,2H),2.27(br s,2H),2.07-1.93(m,2H),1.83-1.75(m,4H),1.71-1.55(m,4H),1.47-1.39(m,11H),1.29-1.22(m,2H),0.97-0.86(m,3H)。LC/MS[M+H]574.4(计算值);LC/MS[M+H]574.4(观测值)。
实施例L-1合成3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[5-氨基-7-(二丙基氨甲酰基)-6H-吡唑并[4,3-b]氮呯-1-基]戊基-甲基-氨基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸(2,3,5,6-四氟苯基)酯,PAZ-L-1
制备3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[5-氨基-7-(二丙基氨甲酰基)-6H-吡唑并[4,3-b]氮呯-1-基]戊基-甲基-氨基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯,L-1a
向5-氨基-1-(5-氨基戊基)-N,N-二丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺PAZ-2(57mg,143.59umol,1.0当量,HCl)于MeOH(2mL)中的溶液中添加3-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-侧氧基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯(218mg,373umol,2.60当量)和NaBH3CN(27.0mg,431umol,3.0当量),并且在20℃下搅拌混合物12小时,然后添加HCHO(23.3mg,287umol,21.3uL,纯度37%,2.0当量),并且在20℃下再搅拌1小时。过滤反应物并且通过制备型HPLC(柱:PhenomenexSynergi C18 150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:25%-35%,10分钟)纯化,获得呈黄色油状的L-1a(100mg,106.02umol,产率73.83%)。1H NMR(MeOD,400MHz)δ7.67(s,1H),7.13(s,1H),4.30-4.28(m,2H),3.84-3.83(m,2H),3.71-3.59(m,40H),3.47-3.44(m,6H),3.38(s,2H),2.91(s,3H),2.47(t,J=6.0Hz,2H),2.03(s,3H),1.94-1.91(m,2H),1.82-1.63(m,6H),1.45(s,9H),1.39-1.37(m,2H),0.96-0.91(m,6H)。
制备3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[5-氨基-7-(二丙基氨甲酰基)-6H-吡唑并[4,3-b]氮呯-1-基]戊基-甲基-氨基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸,L-1b
向L-1a(90mg,95.42umol,1.0当量)于H2O(0.2mL)中的溶液中添加HCl(12M,159uL,20.0当量),并且在80℃下搅拌1小时。在压力下浓缩混合物,得到呈黄色油状的L-1b(60mg,67.64umol,产率70.88%)。
制备PAZ-L-1
向L-1b(55mg,62.0umol,1.0当量)于DMA(0.1mL)和DCM(1mL)中的溶液中添加2,3,5,6-四氟苯酚(82.5mg,496umol,8当量)和EDCI(119mg,620umol,10.0当量),然后在20℃下搅拌0.5小时。在25℃下浓缩混合物并且通过(柱:Phenomenex Synergi C18150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:20%-50%,8分钟)纯化,获得呈浅黄色油状的PAZ-L-1(31.5mg,24.94umol,产率40.22%,2TFA)。1H NMR(MeOD,400MHz)δ7.67(s,1H),7.47-7.42(m,1H),7.13(s,1H),4.28(t,J=7.2Hz,2H),3.87-3.85(m,2H),3.84-3.82(m,2H),3.71-3.57(m,38H),3.53-3.40(m,6H),3.41(s,2H),2.98(t,J=6.0Hz,2H),2.91(s,3H),1.90-1.89(m,2H),1.77-1.76(m,2H),1.71-1.66(m,4H),1.38-1.34(m,2H),0.96-0.92(m,6H)。LC/MS[M+H]1035.6(计算值);LC/MS[M+H]1035.6(观测值)。
实施例L-4合成39-(5-氨基-7-((3-(3,3-二甲基丁酰胺基)丙基)(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-1(6H)-基)-34-甲基-4,7,10,13,16,19,22,25,28,31-十氧杂-34-氮杂三十九烷酸2,3,5,6-四氟苯酯,PAZ-L-4
制备3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[5-氨基-7-[3-(3,3-二甲基丁酰基氨基)丙基-丙基-氨甲酰基]-6H-吡唑并[4,3-b]氮呯-1-基]戊基-甲基-氨基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯,L-4a
在25℃下向PAZ-7(90mg,165umol,1.0当量,2HCl)于MeOH(4mL)中的混合物中一次性添加3-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-侧氧基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯(96.3mg,165umol,1.0当量)和NaBH3CN(20.7mg,329.3umol,2.0当量)。在25℃下搅拌混合物12小时。然后添加甲醛HCHO(66.81mg,823umol,纯度37%,5当量)和氰基硼氢化钠NaBH3CN(20.7mg,329umol,2当量),并且在25℃下再搅拌2小时。浓缩反应混合物并且通过制备型HPLC(柱:PhenomenexGemini-NX 150*30mm*5um;流动相:[水(0.1% TFA)-ACN];B%:20%-50%,9分钟)纯化,得到呈黄色油状的L-4a(80mg,75.73umol,产率45.99%)。
制备3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[5-氨基-7-[3-(3,3-二甲基丁酰基氨基)丙基-丙基-氨甲酰基]-6H-吡唑并[4,3-b]氮呯-1-基]戊基-甲基-氨基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸,L-4b
在25℃下向L-4a(75mg,71.0umol,1.0当量)于H2O(2mL)和CH3CN(0.5mL)中的混合物中一次性添加HCl(12M,148uL,25当量)。在80℃下搅拌混合物1小时,然后浓缩,获得呈黄色油状的L-4b(60mg,粗物质,HCl)。
制备PAZ-L-4
在25℃下向L-4b(55mg,54.9umol,1.0当量,HCl)于DCM(2mL)和DMA(0.4mL)中的混合物中一次性添加2,3,5,6-四氟苯酚(91.3mg,550umol,10当量)和EDCI(105mg,550umol,10当量)。在25℃下搅拌混合物1小时,然后浓缩并且通过制备型HPLC(柱:PhenomenexSynergi C18 150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:20%-50%,8分钟)纯化,得到呈黄色油状的PAZ-L-4(39.4mg,34.31umol,产率62.40%)。1H NMR(MeOD,400MHz)δ7.67(s,1H),7.47-7.42(m,1H),7.17(s,1H),4.28(t,J=7.2Hz,2H),3.87(t,J=6.0Hz,2H),3.84-3.51(m,2H),3.71-3.57(m,38H),3.53-3.41(m,8H),3.17-3.05(m,2H),2.98(t,J=5.6Hz,2H),2.91(s,3H),2.10-2.06(m,2H),1.96-1.82(m,4H),1.82-1.73(m,2H),1.73-1.62(m,2H),1.39-1.37(m,2H),1.02(s,9H),0.95-0.88(m,3H)。LC/MS[M+H]1148.6(计算值);LC/MS[M+H]1148.7(观测值)。
实施例L-5合成39-(5-氨基-7-((3-(3,3-二甲基丁酰胺基)丙基)(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-2(6H)-基)-34-甲基-4,7,10,13,16,19,22,25,28,31-十氧杂-34-氮杂三十九烷酸2,3,5,6-四氟苯酯,PAZ-L-5
制备3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[5-氨基-7-[3-(3,3-二甲基丁酰基氨基)丙基-丙基-氨甲酰基]-6H-吡唑并[4,3-b]氮呯-2-基]戊基-甲基-氨基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯,L-5a
向5-氨基-2-(5-氨基戊基)-N-[3-(3,3-二甲基丁酰基氨基)丙基]-N-丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺PAZ-9(55.0mg,101umol,1当量,2HCl)于MeOH(1mL)中的溶液中添加3-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-侧氧基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯(88.0mg,151umol,1.5当量)和NaBH3CN(10.00mg,151.00umol,1.5当量),然后搅拌23小时。此后,将HCHO(50.00mg,503.00umol,46.00uL,纯度30%,5当量)和NaBH3CN(10.00mg,151.00umol,1.5当量)添加至混合物中,并且在25℃下再搅拌1小时。过滤混合物并浓缩。通过制备型HPLC(柱:Phenomenex Synergi C18 150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:15%-45%,8分钟)纯化残余物,得到呈无色油状的L-5a(70mg,59.81umol,产率59.44%,TFA)。LC/MS[M+H]1056.7(计算值);LC/MS[M+H]1056.6(观测值)。
制备39-(5-氨基-7-((3-(3,3-二甲基丁酰胺基)丙基)(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-2(6H)-基)-34-甲基-4,7,10,13,16,19,22,25,28,31-十氧杂-34-氮杂三十九烷酸,L-5b
在20℃下向L-5a(70.0mg,60.0umol,1当量,TFA)于H2O(1mL)中的溶液中添加HCl(12M,75.0uL,15当量),然后在80℃下搅拌1小时。浓缩混合物,得到呈浅黄色固体状的L-5b(50mg,48.2umol,产率80.64%,HCl)。LC/MS[M+H]1000.7(计算值);LC/MS[M+H]1000.6(观测值)。
制备PAZ-L-5
向L-5b(45.0mg,43.0umol,1当量,HCl)于DCM(2mL)和DMA(0.1mL)中的溶液中添加2,3,5,6-四氟苯酚(58.0mg,347umol,8当量)和EDCI(83.0mg,434umol,10当量)。在20℃下搅拌混合物1小时,然后浓缩并过滤。通过制备型HPLC(柱:Phenomenex Synergi C18150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:20%-50%,8分钟)纯化残余物,得到呈浅黄色油状的PAZ-L-5(22mg,17.43umol,产率40.15%,TFA)。1H NMR(MeOD-d4,400MHz)δ7.92(s,1H),7.50-7.42(m,1H),6.98(s,1H),4.26(t,J=6.8Hz,2H),3.87(t,J=6.0Hz,2H),3.85-3.80(m,2H),3.71-3.60(m,38H),3.52(br t,J=7.2Hz,2H),3.49-3.35(m,6H),3.26-3.07(m,4H),2.98(t,J=6.0Hz,2H),2.91(s,3H),2.10-1.92(m,4H),1.89-1.75(m,4H),1.69-1.65(m,2H),1.47-1.36(m,2H),1.02(br s,9H),0.96-0.86(m,3H)。LC/MS[M+H]1148.6(计算值);LC/MS[M+H]1148.5(观测值)。
实施例L-6合成43-(5-氨基-7-(乙氧基(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-1(6H)-基)-37-侧氧基-4,7,10,13,16,19,22,25,28,31,34-十一氧杂-38-氮杂四十三烷酸2,3,5,6-四氟苯酯,PAZ-L-6
制备43-(5-氨基-7-(乙氧基(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-1(6H)-基)-37-侧氧基-4,7,10,13,16,19,22,25,28,31,34-十一氧杂-38-氮杂四十三烷酸叔丁酯,L-6a
向2,2-二甲基-4-侧氧基-3,7,10,13,16,19,22,25,28,31,34,37-十二氧杂四十烷-40-酸(54.5mg,82.7umol,1.2当量)于DMF(0.5mL)中的溶液中添加HATU(28.8mg,75.8umol,1.1当量)和DIPEA(44.5mg,344umol,5当量)。5分钟后,将5-氨基-1-(5-氨基戊基)-N-乙氧基-N-丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺PAZ-12(30mg,68.90umol,1当量,2HCl)添加至反应混合物中,并且在15℃下搅拌25分钟。过滤反应混合物并且在减压下浓缩。通过制备型HPLC(TFA条件:柱:Phenomenex Synergi C18 150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:15%-45%,10分钟)纯化残余物,得到呈浅黄色油状的L-6a(40mg,35.80umol,产率51.96%,TFA)。LC/MS[M+H]1003.6(计算值);LC/MS[M+H]1003.8(观测值)。
制备43-(5-氨基-7-(乙氧基(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-1(6H)-基)-37-侧氧基-4,7,10,13,16,19,22,25,28,31,34-十一氧杂-38-氮杂四十三烷酸,L-6b
向L-6a(40mg,35.8umol,1当量,TFA)于H2O(3mL)中的溶液中添加HCl(12M,20当量),并且在80℃下搅拌混合物0.5小时。在减压下浓缩反应混合物,得到呈浅黄色油状的L-6b(40mg,粗物质,HCl)。LC/MS[M+H]947.6(计算值);LC/MS[M+H]947.7(观测值)。
制备PAZ-L-6
向L-6b(30mg,30.5umol,1当量,HCl)和2,3,5,6-四氟苯酚(50.6mg,305umol,10当量)于DMA(0.2mL)和DCM(1mL)中的溶液中添加EDCI(58.5mg,305umol,10当量),并且在15℃下搅拌1小时。在减压下浓缩反应混合物。通过制备型HPLC(TFA条件:柱:PhenomenexSynergi C18 150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:25%-50%,8分钟)纯化残余物,得到呈浅黄色油状的PAZ-L-6(13mg,10.75umol,产率35.25%,TFA)。1H NMR(MeOD-d4,400MHz)δ7.66(s,1H),7.48(s,1H),7.47-7.38(m,1H),4.26(t,J=6.8Hz,2H),3.97(q,J=6.8Hz,2H),3.88(t,J=6.0Hz,2H),3.77-3.67(m,4H),3.66-3.64(m,4H),3.64-3.58(m,36H),3.43(s,2H),3.35(s,2H),3.14(t,J=6.8Hz,2H),2.98(t,J=6.0Hz,2H),2.40(t,J=6.0Hz,2H),1.91-1.70(m,4H),1.52-1.46(m,2H),1.34-1.24(m,2H),1.20(t,J=7.2Hz,3H),1.00(t,J=7.2Hz,3H)。LC/MS[M+H]1095.5(计算值);LC/MS[M+H]1095.4(观测值)。
实施例L-7合成39-(5-氨基-7-(乙氧基(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-1(6H)-基)-34-甲基-4,7,10,13,16,19,22,25,28,31-十氧杂-34-氮杂三十九烷酸2,3,5,6-四氟苯酯,PAZ-L-7
制备3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[5-氨基-7-[乙氧基(丙基)氨甲酰基]-6H-吡唑并[4,3-b]氮呯-1-基]戊基-甲基-氨基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯,L-7a
在15℃下向5-氨基-1-(5-氨基戊基)-N-乙氧基-N-丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺PAZ-12(30mg,68.9umol,1当量,2HCl)于MeOH(10mL)中的溶液中添加TEA(13.9mg,137umol,2当量)和3-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-侧氧基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯(80.6mg,138umol,2当量)。30分钟后,在15℃下添加NaBH3CN(8.66mg,137.81umol,2当量),并且在此温度下搅拌所得混合物12小时。在15℃下将HCHO(41.38mg,413.42umol,37.97uL,纯度30%,6当量)和NaBH3CN(8.66mg,137.81umol,2当量)添加至混合物中,并且在15℃下搅拌2小时。在减压下浓缩反应混合物。通过制备型HPLC(TFA条件:柱:Phenomenex Synergi C18 150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:25%-43%,8分钟)纯化残余物,得到呈浅黄色油状的L-7a(45mg,38.36umol,产率55.67%,2TFA)。LC/MS[M+H]945.6(计算值);LC/MS[M+H]945.5(观测值)。
制备3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[5-[5-氨基-7-[乙氧基(丙基)氨甲酰基]-6H-吡唑并[4,3-b]氮呯-1-基]戊基-甲基-氨基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸,L-7b
向L-7a(45mg,38.36umol,1当量,2TFA)于H2O(3mL)中的溶液中添加HCl(12M,63.9uL,20当量),然后在80℃下搅拌混合物1小时。在减压下浓缩反应混合物,得到呈浅黄色油状的L-7b(40mg,粗物质,2HCl)。LC/MS[M+H]889.5(计算值);LC/MS[M+H]889.6(观测值)。
制备PAZ-L-7
向L-7b(40mg,41.58umol,1当量,2HCl)和2,3,5,6-四氟苯酚(69.0mg,416umol,10当量)于DCM(3mL)和DMA(0.3mL)中的溶液中添加EDCI(79.7mg,415umol,10当量),然后在15℃下搅拌1小时。在减压下浓缩反应混合物。通过制备型HPLC(TFA条件:柱:PhenomenexSynergi C18 150*25*10um;流动相:[水(0.1%TFA)-ACN];B%:25%-50%,8分钟)纯化残余物,得到呈浅黄色油状的PAZ-L-7(19.5mg,15.41umol,产率37.07%,2TFA)。1H NMR(MeOD-d4,400MHz)δ7.67(s,1H),7.46(s,1H),7.45-7.38(m,1H),4.29(t,J=6.8Hz,2H),3.95(q,J=7.2Hz,2H),3.88(t,J=6.0Hz,2H),3.82(br d,J=3.6Hz,2H),3.74(t,J=7.2Hz,2H),3.71-3.55(m,38H),3.43(s,2H),3.26-3.03(m,2H),2.98(t,J=6.0Hz,2H),2.91(s,3H),1.97-1.87(m,2H),1.78-1.74(m,4H),1.44-1.32(m,2H),1.18(t,J=7.2Hz,3H),1.00(t,J=7.6Hz,3H)。LC/MS[M+H]1037.5(计算值);LC/MS[M+H]1037.4(观测值)。
实施例L-8合成43-(5-氨基-7-((3-((环丁氧基羰基)氨基)丙基)(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-1(6H)-基)-37-侧氧基-4,7,10,13,16,19,22,25,28,31,34-十一氧杂-38-氮杂四十三烷酸2,3,5,6-四氟苯酯,PAZ-L-8
制备43-(5-氨基-7-((3-((环丁氧基羰基)氨基)丙基)(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-1(6H)-基)-37-侧氧基-4,7,10,13,16,19,22,25,28,31,34-十一氧杂-38-氮杂四十三烷酸叔丁酯,L-8a
向2,2-二甲基-4-侧氧基-3,7,10,13,16,19,22,25,28,31,34,37-十二氧杂四十烷-40-酸(77.5mg,117umol,1当量)于DMF(0.5mL)中的溶液中添加HATU(49.2mg,129umol,1.1当量)和DIEA(76.0mg,588umol,102uL,5当量),然后添加(3-(5-氨基-1-(5-氨基戊基)-N-丙基-1,6-二氢吡唑并[4,3-b]氮呯-7-甲酰胺基)丙基)氨基甲酸环丁酯PAZ-15(60mg,117.6umol,1当量,HCl)。在25℃下搅拌混合物0.5小时。过滤残余物并且在减压下浓缩,然后通过制备型HPLC(TFA条件;柱:Phenomenex luna C18 100*40mm*5um;流动相:[水(0.1%TFA)-ACN];B%:10%-45%,8分钟)纯化,得到呈黄色油状的L-8a(90mg,73.3umol,产率62.29%,TFA)。1H NMR(MeOD-d4,400MHz)δ7.66(s,1H),7.16(br s,1H),4.90-4.89(m,1H),4.26(t,J=7.2Hz,2H),3.72-3.68(m,4H),3.65-3.57(m,44H),3.55-3.43(m,4H),3.39(brs,2H),3.17-3.11(m,2H),2.47(t,J=6.4Hz,2H),2.40(t,J=6.0Hz,2H),2.29-2.23(m,2H),2.05-1.99(m,2H),1.90-1.80(m,4H),1.77-1.56(m,4H),1.53-1.41(m,12H),1.32-1.25(m,2H),0.98-0.89(m,3H)
制备43-(5-氨基-7-((3-((环丁氧基羰基)氨基)丙基)(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-1(6H)-基)-37-侧氧基-4,7,10,13,16,19,22,25,28,31,34-十一氧杂-38-氮杂四十三烷酸,L-8b
向L-8a(50mg,44.9umol,1当量,TFA)于水(2mL)中的溶液中添加HCl(12M,74.8uL,20当量),然后在80℃下搅拌混合物0.5小时。在减压下浓缩混合物,得到呈无色油状的L-8b(40mg,37.8umol,产率84.24%)。
制备PAZ-L-8.
向L-8b(40mg,34.0umol,1当量,TFA)于DCM(1mL)和DMA(0.1mL)中的溶液中添加2,3,5,6-四氟苯酚(45.3mg,273umol,8当量)和EDCI(65.4mg,341umol,10当量),并且在25℃下搅拌0.5小时。过滤残余物并且在减压下浓缩,然后通过制备型HPLC(TFA条件;柱:Phenomenex Synergi C18 150*30mm*4um;流动相:[水(0.1%TFA)-ACN];B%:25%-50%,8分钟)纯化,得到呈黄色固体状的PAZ-L-8(30mg,22.7umol,产率66.65%,TFA)。1H NMR(甲醇-d4,400MHz)δ7.65(s,1H),7.49-7.38(m,1H),7.16(s,1H),4.90-4.89(m,1H),4.25(t,J=6.8Hz,2H),3.88(t,J=6.0Hz,2H),3.72-3.55(m,44H),3.54-3.44(m,4H),3.38(br s,2H),3.18-3.12(m,2H),2.98(t,J=6.0Hz,2H),2.40(t,J=6.0Hz,2H),2.32-2.24(m,2H),2.04-1.98(m,2H),1.89-1.80(m,4H),1.80-1.56(m,4H),1.55-1.42(m,2H),1.32-1.26(m,2H),0.96-0.89(m,3H)。LC/MS[M+H]1206.6(计算值);LC/MS[M+H]1206.6(观测值)。
实施例L-9合成39-(5-氨基-7-((3-((环丁氧基羰基)氨基)丙基)(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-1(6H)-基)-34-甲基-4,7,10,13,16,19,22,25,28,31-十氧杂-34-氮杂三十九烷酸2,3,5,6-四氟苯酯,PAZ-L-9
制备39-(5-氨基-7-((3-((环丁氧基羰基)氨基)丙基)(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-1(6H)-基)-34-甲基-4,7,10,13,16,19,22,25,28,31-十氧杂-34-氮杂三十九烷酸叔丁酯,L-9a
向(3-(5-氨基-1-(5-氨基戊基)-N-丙基-1,6-二氢吡唑并[4,3-b]氮呯-7-甲酰胺基)丙基)氨基甲酸环丁酯PAZ-15(70mg,137umol,1当量,HCl)和1-侧氧基-3,6,9,12,15,18,21,24,27,30-十氧杂三十三烷-33-酸叔丁酯(185mg,316umol,2.3当量)于MeOH(2mL)中的溶液中添加NaBH3CN(17.3mg,274.5umol,2当量)和Et3N(13.9mg,137umol,1当量),并且在25℃下搅拌16小时。然后将甲醛(22.3mg,274.5umol,20.4uL,纯度37%,2当量)和NaBH3CN(17.3mg,274.5umol,2当量)添加至混合物中,并且在25℃下再搅拌0.5小时。过滤残余物并且在减压下浓缩,然后通过制备型HPLC(TFA条件;柱:Phenomenex Gemini-NX C18 75*30mm*3um;流动相:[水(0.1%TFA)-ACN];B%:20%-40%,8分钟)纯化,得到呈黄色油状的L-9a(90mg,76.90umol,产率56.03%,TFA)。
制备39-(5-氨基-7-((3-((环丁氧基羰基)氨基)丙基)(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-1(6H)-基)-34-甲基-4,7,10,13,16,19,22,25,28,31-十氧杂-34-氮杂三十九烷酸,L-9b
向L-9a(90mg,76.9umol,1当量,TFA)于水(2mL)中的溶液中添加HCl(12M,128uL,20当量),并且在80℃下搅拌混合物0.5小时。在减压下浓缩混合物,得到呈无色油状的L-9b(70mg,67.5umol,产率87.81%,HCl)。
制备PAZ-L-9
向L-9b(70mg,62.8umol,1当量,TFA)于DCM(2mL)和DMA(0.1mL)中的溶液中添加2,3,5,6-四氟苯酚(83.5mg,503umol,8当量)和EDCI(120mg,628umol,10当量),然后在25℃下搅拌混合物0.5小时。过滤残余物并且在减压下浓缩,然后通过制备型HPLC(TFA条件;柱:Phenomenex Synergi C18 150*30mm*4um;流动相:[水(0.1%TFA)-ACN];B%:25%-50%,8分钟)纯化,得到呈黄色固体状的PAZ-L-9(40mg,31.69umol,产率50.44%,TFA)。1H NMR(MeOD-d4,400MHz)δ7.68(s,1H),7.50-7.39(m,1H),7.16(br s,1H),4.80-4.76(m,1H),4.29(t,J=6.8Hz,2H),3.88(t,J=6.0Hz,2H),3.83(br s,2H),3.69-3.61(m,38H),3.53-3.48(m,2H),3.44(br d,J=7.2Hz,2H),3.38(br s,2H),3.29-3.19(m,2H),3.16-3.05(m,2H),2.99(t,J=6.0Hz,2H),2.91(s,3H),2.28-2.24(m,2H),2.04-1.98(m,2H),1.96-1.90(m,2H),1.89-1.72(m,6H),1.71-1.62(m,2H),1.42-1.36(m,2H),0.96-0.93(m,3H)。LC/MS[M+H]1148.6(计算值);LC/MS[M+H]1148.6(观测值)。
实施例L-27合成5-氨基-1-(1-(2,5-二侧氧基-2,5-二氢-1H-吡咯-1-基)-2,36-二侧氧基-6,9,12,15,18,21,24,27,30,33-十氧杂-3,37-二氮杂四十二烷-42-基)-N-乙氧基-N-丙基-1,6-二氢吡唑并[4,3-b]氮呯-7-甲酰胺,PAZ-L-27
制备3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(对甲苯基磺酰氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯,L-27b
在0℃下于N2下向3-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-羟基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯L-27a(100g,170mmol,1当量)、TEA(43.1g,426mmol,59.3mL,2.5当量)和DMAP(2.08g,17.0mmol,0.1当量)于DCM(1000mL)中的溶液中添加TosCl(48.7g,255mmol,1.5当量),然后在15℃下搅拌12小时。在0℃下通过添加H2O(2000mL)淬灭反应混合物,然后用DCM(1000mL x 3)萃取。用盐水(300mL)洗涤合并的有机层,经Na2SO4干燥,过滤并且在减压下浓缩。通过柱色谱法(SiO2,石油醚:乙酸乙酯=1:0至0:1)继之以(SiO2,EtOAc:MeOH=1:0至10:1)纯化残余物,得到呈浅黄色油状的L-27b(187.4g,粗物质)。1H NMR(CDCl3,400MHz)δ7.81(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),4.17(t,J=4.8Hz,2H),3.74-3.57(m,40H),2.51(t,J=6.4Hz,2H),2.46(s,3H),1.45(s,9H)。
制备3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(1,3-二侧氧基异吲哚啉-2-基)乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯,L-27c
在25℃下向L-27b(127g,171mmol,1当量)于DMF(1000mL)中的溶液中添加(1,3-二侧氧基异吲哚啉-2-基)钾(41.3g,223mmol,1.3当量),然后在50℃下搅拌12小时。将反应混合物倾倒至冰水(3000mL)中,然后用EtOAc(800mL x 6)萃取。用盐水(300mL x 3)洗涤合并的有机层,经Na2SO4干燥,过滤并且在减压下浓缩。通过柱色谱法(SiO2,石油醚:乙酸乙酯=1:0至0:1)继之以(SiO2,EtOAc:MeOH=1:0至10:1)纯化残余物,得到呈黄色油状的L-27c(142g,粗物质)。1H NMR(CDCl3,400MHz)δ7.85(dd,J=3.2,5.6Hz,2H),7.72(dd,J=3.2,5.6Hz,2H),3.96-3.86(m,2H),3.76-3.69(m,4H),3.68-3.55(m,36H),2.51(t,J=6.8Hz,2H),1.45(s,9H)。
制备3-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-氨基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯,L-27d
在25℃下向L-27c(100g,140mmol,1当量)于MeOH(1000mL)中的溶液中添加NH2NH2.H2O(28.54g,559mmol,27.71mL,纯度98%,4当量),然后在50℃下搅拌8小时。将反应混合物冷却至25℃,然后过滤并且在减压下浓缩滤液。在25℃下用MTBE(500mL x 3)进一步湿磨粗产物30分钟,然后过滤并且在减压下浓缩,得到呈浅黄色油状的L-27d(113.7g,粗物质)。1H NMR(CDCl3,400MHz)δ3.74-3.58(m,38H),3.51(t,J=5.2Hz,2H),2.86(t,J=5.2Hz,2H),2.50(t,J=6.8Hz,2H),1.45(s,9H)。LC/MS[M+H]586.4(计算值);LC/MS[M+H]586.4(观测值)
制备3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-(2,5-二侧氧基吡咯-1-基)乙酰基]氨基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸叔丁酯,L-27e
在0℃下向L-27d(11.3g,19.3mmol,1当量)、2-(2,5-二侧氧基吡咯-1-基)乙酸(3g,19.3mmol,1当量)和二异丙基乙胺DIPEA(10.0g,77.4mmol,13.5mL,4当量)于DCM(100mL)中的溶液中添加HATU(8.09g,21.3mmol,1.1当量),然后在0℃下搅拌30分钟。在减压下浓缩反应混合物。通过制备型HPLC(TFA条件;柱:Phenomenex luna c18 250mm*100mm*10um;流动相:[水(0.1%TFA)-ACN];B%:25%-55%,25分钟)纯化残余物,得到呈黄色油状的L-27e(4.5g,6.23mmol,产率32.2%)。1H NMR(CDCl3,400MHz)δ6.88-6.80(m,1H),6.78(s,2H),4.22(s,2H),3.77-3.54(m,40H),3.47(q,J=5.2Hz,2H),2.51(t,J=6.4Hz,2H),1.46(s,9H)
制备3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-(2,5-二侧氧基吡咯-1-基)乙酰基]氨基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]丙酸,L-27f
向L-27e(4.5g,6.23mmol,1当量)于CH3CN(25mL)和H2O(25mL)中的溶液中添加TFA(5.68g,49.8mmol,3.69mL,8当量),然后在80℃下搅拌1小时。在减压下浓缩反应混合物以去除CH3CN。用MTBE(10mL x 3)萃取残余物并弃去。在减压下浓缩水相,得到残余物。通过制备型HPLC(TFA条件;柱:Phenomenex luna c18250mm*100mm*10um;流动相:[水(0.1%TFA)-ACN];B%:0%-25%,24分钟)纯化残余物,得到呈浅黄色油状的L-27f(1.6g,2.40mmol,产率38.6%)。1H NMR(CDCl3,400MHz)δ6.95(br s,1H),6.78(s,2H),4.22(s,2H),3.78(t,J=6.4Hz,2H),3.70-3.63(m,36H),3.60-3.54(m,2H),3.46(q,J=5.2Hz,2H),2.61(t,J=6.0Hz,2H)。LC/MS[M+H]667.3(计算值);LC/MS[M+H]667.2(观测值)。
制备PAZ-L-27
在25℃下向L-27f(79.0mg,119umol(微摩尔),1.0当量)于DMF(0.5mL)中的混合物中添加HATU(45.1mg,119umol,1.0当量)、DIEA(61.3mg,474umol,82.6uL(微升),4.0当量)和5-氨基-1-(5-氨基戊基)-N-乙氧基-N-丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺PAZ-12(70.0mg,119umol,1.0当量,2TFA),然后在此温度下搅拌0.5小时。通过制备型HPLC(柱:Phenomenex Luna 80*30mm*3um;流动相:[水(TFA)-ACN];B%:5%-30%,8分钟)纯化混合物,得到呈浅黄色油状的PAZ-L-27(40.4mg,39.95umol,产率33.70%)。1H NMR(MeOD,400MHz)δ7.66(s,1H),7.48(s,1H),6.90(s,2H),4.26(t,J=6.8Hz,2H),4.17(s,2H),3.97(q,J=7.2Hz,2H),3.74(t,J=7.2Hz,2H),3.69(t,J=6.0Hz,2H),3.66-3.55(m,38H),3.44(s,2H),3.40-3.35(m,2H),3.14(t,J=6.8Hz,2H),2.40(t,J=6.0Hz,2H),1.90-1.71(m,4H),1.56-1.45(m,2H),1.34-1.24(m,2H),1.20(t,J=7.2Hz,3H),1.00(t,J=7.6Hz,3H)。LC/MS[M+H]1011.6(计算值);LC/MS[M+H]1011.5(观测值)。
实施例L-28合成(5-(5-氨基-7-(乙氧基(丙基)氨甲酰基)吡唑并[4,3-b]氮呯-1(6H)-基)戊基)氨基甲酸1-(2,5-二侧氧基-2,5-二氢-1H-吡咯-1-基)-2-侧氧基-6,9,12,15,18,21,24,27,30,33-十氧杂-3-氮杂三十五烷-35-基酯,PAZ-L-28
制备2-(2,5-二侧氧基-2,5-二氢-1H-吡咯-1-基)-N-(32-羟基-3,6,9,12,15,18,21,24,27,30-十氧杂三十二烷基)乙酰胺,L-28b
在0℃下于N2下向2-(2,5-二侧氧基吡咯-1-基)乙酸(309mg,1.99mmol,1当量)和2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-氨基乙氧基)乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙氧基]乙醇L-28a(1g,1.99mmol,1当量)于DCM(5mL)中的混合物中添加HATU(796mg,2.09mmol,1.05当量)和Et3N(302mg,2.99mmol,416uL,1.5当量),然后在0℃下搅拌1小时。用H2O(20mL*2)洗涤反应混合物,经无水Na2SO4干燥有机相,过滤并且在真空中浓缩,得到呈无色油状的L-28b。1H NMR(CDCl3,400MHz)δ6.78(s,2H),6.71-6.76(m,1H),4.21(s,2H),3.55-3.79(m,42H),3.60-3.45(m,2H)。
制备碳酸1-(2,5-二侧氧基-2,5-二氢-1H-吡咯-1-基)-2-侧氧基-6,9,12,15,18,21,24,27,30,33-十氧杂-3-氮杂三十五烷-35-基酯(4-硝基苯基)酯,L-28c
在25℃下于N2下向L-28b(1g,1.57mmol,1当量)和氯甲酸(4-硝基苯基)酯(473mg,2.35mmol,1.5当量)于DCM(20mL)中的混合物中添加吡啶Py(247mg,3.13mmol,252uL,2当量),然后在25℃下搅拌2小时。用H2O(20mL)洗涤混合物,然后用盐水(20mL)洗涤,经无水Na2SO4干燥有机相,过滤并且在真空中浓缩。通过硅胶色谱法(柱高度:250mm,直径:100mm,100-200目硅胶,石油醚/乙酸乙酯=1/1,0/1至EtOAc/MeOH=10/1)纯化残余物,得到呈浅黄色油状的L-28c(750mg,933.07umol,产率59.59%)。1H NMR(CDCl3,400MHz)δ8.23-8.33(m,2H),7.37-7.45(m,2H),6.78(s,2H),6.62-6.69(m,1H),4.41-4.48(m,2H),4.21(s,2H),3.79-3.87(m,2H),3.62-3.73(m,36H),3.56-3.61(m,2H),3.43-3.49(m,2H)。
制备PAZ-L-28
在25℃下向5-氨基-1-(5-氨基戊基)-N-乙氧基-N-丙基-6H-吡唑并[4,3-b]氮呯-7-甲酰胺PAZ-12(70mg,119umol,1.0当量,2TFA)和L-28c(95.2mg,118umol,1当量)于DMF(0.5mL)中的混合物中一次性添加DIEA(61.3mg,474umol,82.6uL,4.0当量),然后在25℃下搅拌0.5小时。过滤混合物,通过制备型HPLC(柱:Phenomenex Luna 80*30mm*3um;流动相:[水(TFA)-ACN];B%:5%-30%,8分钟)纯化滤液,得到呈浅黄色油状的PAZ-L-28(23.1mg,22.4umol,产率18.9%)。1H NMR(MeOD,400MHz)δ7.66(s,1H),7.49(s,1H),6.90(s,2H),4.26(t,J=6.8Hz,2H),4.17(s,2H),4.14-4.09(m,2H),3.97(q,J=7.2Hz,2H),3.74(t,J=7.2Hz,2H),3.67-3.60(m,38H),3.55(t,J=5.6Hz,2H),3.44(s,2H),3.40-3.35(m,2H),3.05(t,J=6.8Hz,2H),1.91-1.72(m,4H),1.55-1.41(m,2H),1.34-1.23(m,2H),1.20(t,J=7.2Hz,3H),1.00(t,J=7.6Hz,3H)。LC/MS[M+H]1027.6(计算值);LC/MS[M+H]1027.5(观测值)。
实施例201制备免疫缀合物(IC)
在一种示例性程序中,为了制备基于赖氨酸的缀合,使用ZebaTM自旋脱盐柱(Thermo Fisher Scientific)将抗体进行缓冲液交换成含有100mM硼酸盐、50mM氯化钠、1mM乙二胺四乙酸的缀合缓冲液(pH 8.3)。使用缀合缓冲液将缓冲液交换的抗体的浓度调节至约5-25mg/ml并且进行无菌过滤。将吡唑并氮呯-连接子式II化合物(PAZ-L)溶解于二甲亚砜(DMSO)或二甲基乙酰胺(DMA)中以达到5-20mM的浓度。为了进行缀合,将抗体与4-20摩尔当量的PAZ-L混合。在一些情况下,添加至多20%(v/v)的额外DMA或DMSO以提高缀合缓冲液中PAZ-L的溶解度。使反应在20℃或30℃或37℃下进行约30分钟至4小时。使用两个连续ZebaTM自旋脱盐柱纯化所得缀合物以去除未反应的PAZ-L。将所述柱用磷酸盐缓冲盐水(PBS)pH 7.2预平衡。通过在连接至XEVOTM G2-XS TOF质谱仪(Waters Corporation)的ACQUITYTM UPLC H级(Waters Corporation,Milford,MA)上使用C4反相柱进行液相色谱质谱分析来估计佐剂与抗体的比率(DAR)。
在一种示例性程序中,为了制备基于半胱氨酸的缀合,使用ZebaTM自旋脱盐柱(Thermo Fisher Scientific)将抗体进行缓冲液交换成含有PBS(pH 7.2)和2mM EDTA的缀合缓冲液。在37℃下使用2-4摩尔当量的Tris(2-羧乙基)膦(TCEP)或二硫苏糖醇(DTT)还原链间二硫化物,持续30分钟至2小时。使用缀合缓冲液预平衡的ZebaTM自旋脱盐柱去除过量的TCEP或DTT。使用缀合缓冲液将缓冲液交换的抗体的浓度调节至约5-20mg/ml并且进行无菌过滤。将PAZ-L溶解于二甲亚砜(DMSO)或二甲基乙酰胺(DMA)中以达到5-20mM的浓度。为了进行缀合,将抗体与10-20摩尔当量的PAZ-L混合。在一些情况下,添加至多20%(v/v)的额外DMA或DMSO以提高缀合缓冲液中PAZ-L的溶解度。使反应在20℃下进行约30分钟至4小时。使用两个连续ZebaTM自旋脱盐柱纯化所得缀合物以去除未反应的PAZ-L。将所述柱用磷酸盐缓冲盐水(PBS)pH 7.2预平衡。通过在连接至XEVOTM G2-XS TOF质谱仪(WatersCorporation)的ACQUITYTM UPLC H级(Waters Corporation,Milford,MA)上使用C4反相柱进行液相色谱质谱分析来估计佐剂与抗体的比率(DAR)。
缀合后,为了潜在地去除未反应的PAZ-L和/或较高分子量的聚集体,可以使用尺寸排阻色谱法、疏水相互作用色谱法、离子交换色谱法、色谱聚焦、超滤、离心超滤、切向流过滤和它们的组合进一步纯化缀合物。
在另一种示例性程序中,使用G-25SEPHADEXTM脱盐柱(Sigma-Aldrich,St.Louis,MO)将抗体进行缓冲液交换成含有100mM硼酸、50mM氯化钠、1mM乙二胺四乙酸的缀合缓冲液(pH 8.3)。然后使用缓冲液将洗脱液各自调节至约1-10mg/ml的浓度,然后进行无菌过滤。将抗体预热至20-30℃并且与2-20(例如7-10)摩尔当量的PAZ-L快速混合。使反应在30℃下进行约16小时,并且通过在pH 7.2磷酸盐缓冲盐水(PBS)中平衡的两个连续G-25脱盐柱上过柱而使免疫缀合物(IC)与反应物分离,以提供表2的免疫缀合物(IC)。通过在连接至XEVOTM G2-XS TOF质谱仪(Waters Corporation)的ACQUITYTM UPLC H级(WatersCorporation,Milford,MA)上使用C4反相柱进行液相色谱质谱分析来确定佐剂-抗体比率(DAR)。
为了进行缀合,可以将抗体溶解于本领域中已知的水性缓冲系统中,所述水性缓冲系统不会不利地影响抗体的稳定性或抗原结合特异性。可以使用磷酸盐缓冲盐水。将PAZ-L溶解于包含如本文别处所描述的至少一种极性非质子性溶剂的溶剂系统中。在一些此类方面,将PAZ-L以约5mM、约10mM、约20mM、约30mM、约40mM或约50mM及其范围,诸如约5mM至约50mM或约10mM至约30mM的浓度溶解于pH 8Tris缓冲液(例如50mM Tris)中。在一些方面,将PAZ-L溶解于DMSO(二甲亚砜)、DMA(二甲基乙酰胺)或乙腈或另一种适合的偶极非质子性溶剂中。
或者,在缀合反应中,可以稀释当量过量的PAZ-L溶液并且与抗体溶液合并。可以用至少一种极性非质子性溶剂和至少一种极性质子性溶剂(其实例包括水、甲醇、乙醇、正丙醇和乙酸)适当稀释PAZ-L溶液。PAZ-L与抗体的摩尔当量可以为约1.5:1、约3:1、约5:1、约10:1、约15:1或约20:1及其范围,诸如约1.5:1至约20:1、约1.5:1至约15:1、约1.5:1至约10:1、约3:1至约15:1、约3:1至约10:1、约5:1至约15:1或约5:1至约10:1。可以通过本领域中已知的方法,诸如LC-MS适当监测反应的完成。缀合反应通常在约1小时至约16小时的范围内完成。反应完成后,可以将试剂添加至反应混合物中以淬灭反应物。如果抗体硫醇基与硫醇反应基,诸如PAZ-L的马来酰亚胺反应,那么未反应的抗体硫醇基可以与封端试剂反应。适合封端试剂的实例是乙基马来酰亚胺。
缀合后,可以通过本领域中已知的纯化方法纯化免疫缀合物并且与未缀合的反应物和/或缀合物聚集体分离,所述纯化方法诸如并且不限于尺寸排阻色谱法、疏水相互作用色谱法、离子交换色谱法、色谱聚焦、超滤、离心超滤、切向流过滤和它们的组合。举例来说,在纯化之前可以稀释免疫缀合物,诸如在20mM琥珀酸钠(pH 5)中。将经稀释的溶液施加至阳离子交换柱,继而用例如至少10柱体积的20mM琥珀酸钠(pH 5)洗涤。可以用诸如PBS的缓冲液适当洗脱缀合物。
实施例202HEK报告体测定
表达人类TLR7或人类TLR8的HEK293报告体细胞购自Invivogen,并且对于细胞繁殖和实验遵循供货商方案。简单地说,在5%CO2下于补充有10%FBS、吉欧霉素(Zeocin)和杀稻瘟菌素(Blasticidin)的DMEM中使细胞生长至80-85%汇合。然后将细胞以4x104个细胞/孔与含有HEK检测介质和免疫刺激分子的基质一起接种于96孔平板中。在620-655nm波长下使用板读取器测量活性。
实施例203体外免疫缀合物活性的评估
本实施例显示本发明的免疫缀合物有效引发髓样活化,诸如树突状细胞中的髓样活化,并且因此可用于治疗癌症。
人类常规树突状细胞的分离:通过密度梯度离心从获自健康血液供体(StanfordBlood Center,Palo Alto,California)的人类周边血液中阴性选择人类常规树突状细胞(cDC)。简单地说,首先通过使用ROSETTESEPTM人类CD3耗竭混合液(Stem CellTechnologies,Vancouver,Canada)以从细胞制剂中去除T细胞来富集细胞。然后经由使用EASYSEPTM人类髓样DC富集试剂盒(Stem Cell Technologies)进行阴性选择来进一步富集cDC。
cDC活化测定:将8x 104个APC与表达ISAC靶抗原的肿瘤细胞以10:1效应子(cDC)与标靶(肿瘤细胞)比率共同培养。在含有补充有10% FBS的RPMI-1640培养基并且在指定情况下含有各种浓度的本发明的指定免疫缀合物(如根据上述实施例制备)的96孔板(Corning,Corning,NY)中孵育细胞。过夜孵育约18小时后,收集无细胞上清液并且使用BioLegend LEGENDPLEX细胞因子珠粒阵列来分析细胞因子分泌(包括TNFα)。
可以使用除所描述的测定(其中利用不同髓样群体)以外的各种筛选测定来测量髓样细胞类型的活化。这些类型可以包括以下:从健康供体血液分离的单核细胞、M-CSF分化的巨噬细胞、GM-CSF分化的巨噬细胞、源自GM-CSF+IL-4单核细胞的树突状细胞、从健康供体血液分离的常规树突状细胞(cDC),以及极化成免疫抑制状态的髓样细胞(也称作髓源性抑制细胞或MDSC)。MDSC极化细胞的实例包括向免疫抑制状态分化的单核细胞,诸如M2aMΦ(IL4/IL13)、M2cMΦ(IL10/TGFb)、GM-CSF/IL6 MDSC和肿瘤驯化的单核细胞(TEM)。可以使用肿瘤条件培养基(例如786.O、MDA-MB-231、HCC1954)进行TEM分化。初级肿瘤相关髓样细胞还可以包括存在于离解的肿瘤细胞悬浮液(Discovery Life Sciences)中的初级细胞。
可以作为单一培养物或作为与表达所关注抗原的细胞的共同培养物进行所描述的髓样细胞群体活化的评估,ISAC可以经由抗体的CDR区结合至所述抗原。孵育18-48小时后,可以通过使用流式细胞术或通过测量分泌的促炎性细胞因子上调细胞表面共刺激分子来评估活化。为了进行细胞因子测量,收集无细胞上清液并且通过细胞因子珠粒阵列(例如来自Biolegend的LegendPlex)使用流式细胞术进行分析。
本文引用的所有参考文献,包括公布、专利申请和专利,特此以引用的方式并入,其程度如同每个参考文献个别地和特定地指示以引用的方式并入并且在本文中以全文阐述一样。
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<110> 博尔特生物治疗药物有限公司
<120> 吡唑并氮呯免疫缀合物及其用途
<130> 17019.009WO1
<140>
<141>
<150> 63/065,219
<151> 2020-08-13
<160> 160
<170> PatentIn version 3.5
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
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Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
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Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Ala Ala Val Gly Thr Tyr
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Lys Arg Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Tyr Tyr Thr Tyr Pro Leu
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 18
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 18
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys
20
<210> 19
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 19
Lys Ala Ser Ala Ala Val Gly Thr Tyr Val Ala
1 5 10
<210> 20
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 20
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 21
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 21
Ser Ala Ser Tyr Arg Lys Arg
1 5
<210> 22
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 22
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25 30
<210> 23
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 23
His Gln Tyr Tyr Thr Tyr Pro Leu Phe Thr
1 5 10
<210> 24
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 24
Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 25
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 25
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
20 25 30
<210> 26
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 26
Glu Phe Gly Met Asn
1 5
<210> 27
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 27
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 28
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 28
Trp Ile Asn Thr Lys Thr Gly Glu Ala Thr Tyr Val Glu Glu Phe Lys
1 5 10 15
Gly
<210> 29
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 29
Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 30
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 30
Trp Asp Phe Ala Tyr Tyr Val Glu Ala Met Asp Tyr
1 5 10
<210> 31
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 31
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 32
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 32
Glu Asn Val Leu Thr Gln Ser Pro Ser Ser Met Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Asn Ile Ala Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Trp Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Ser Met Gln Pro Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Ser Tyr Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 33
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 33
Glu Asn Val Leu Thr Gln Ser Pro Ser Ser Met Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Asn Ile Ala Cys
20
<210> 34
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 34
Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Met Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Asn Ile Ala Cys
20
<210> 35
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 35
Ser Ala Ser Ser Ser Val Ser Tyr Met His
1 5 10
<210> 36
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 36
Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Trp Ile Tyr
1 5 10 15
<210> 37
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 37
Ser Thr Ser Asn Leu Ala Ser
1 5
<210> 38
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 38
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser
1 5 10 15
Leu Thr Ile Ser Ser Met Gln Pro Glu Asp Ala Ala Thr Tyr Tyr Cys
20 25 30
<210> 39
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 39
Gln Gln Arg Ser Ser Tyr Pro Leu Thr
1 5
<210> 40
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 40
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 41
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 41
Gln Val Lys Leu Glu Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Ser
20 25 30
Tyr Met His Trp Leu Arg Gln Gly Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Phe Thr Thr Asp Thr Ser Ala Asn Thr Ala Tyr
65 70 75 80
Leu Gly Leu Ser Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Asn Glu Gly Thr Pro Thr Gly Pro Tyr Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 42
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 42
Gln Val Lys Leu Glu Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys
20 25 30
<210> 43
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 43
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys
20 25 30
<210> 44
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 44
Asp Ser Tyr Met His
1 5
<210> 45
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 45
Trp Leu Arg Gln Gly Pro Gly Gln Arg Leu Glu Trp Ile Gly
1 5 10
<210> 46
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 46
Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Pro Lys Phe Gln
1 5 10 15
Gly
<210> 47
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 47
Lys Ala Thr Phe Thr Thr Asp Thr Ser Ala Asn Thr Ala Tyr Leu Gly
1 5 10 15
Leu Ser Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Glu
20 25 30
<210> 48
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 48
Gly Thr Pro Thr Gly Pro Tyr Tyr Phe Asp Tyr
1 5 10
<210> 49
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 49
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 50
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 50
Glu Asn Val Leu Thr Gln Ser Pro Ser Ser Met Ser Val Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Ala Cys Ser Ala Ser Ser Ser Val Pro Tyr Met
20 25 30
His Trp Leu Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile Tyr
35 40 45
Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Ser Val Gln Pro Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Ser Tyr Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 51
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 51
Glu Asn Val Leu Thr Gln Ser Pro Ser Ser Met Ser Val Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Ala Cys
20
<210> 52
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 52
Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Met Ser Val Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Ala Cys
20
<210> 53
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 53
Ser Ala Ser Ser Ser Val Pro Tyr Met His
1 5 10
<210> 54
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 54
Trp Leu Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 55
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 55
Leu Thr Ser Asn Leu Ala Ser
1 5
<210> 56
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 56
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser
1 5 10 15
Leu Thr Ile Ser Ser Val Gln Pro Glu Asp Ala Ala Thr Tyr Tyr Cys
20 25 30
<210> 57
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 57
Gln Thr Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Thr Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Ser Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln His Trp Ser Ser Lys Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 58
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 58
Gln Thr Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys
20
<210> 59
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 59
Arg Ala Ser Ser Ser Val Thr Tyr Ile His
1 5 10
<210> 60
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 60
Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Ser Trp Ile Tyr
1 5 10 15
<210> 61
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 61
Ala Thr Ser Asn Leu Ala Ser
1 5
<210> 62
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 62
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
1 5 10 15
Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
20 25 30
<210> 63
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 63
Gln His Trp Ser Ser Lys Pro Pro Thr
1 5
<210> 64
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 64
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 65
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 65
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Phe Ile Gly Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Lys Ser Gln Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Ser Ala Thr Tyr
85 90 95
Tyr Cys Thr Arg Asp Arg Gly Leu Arg Phe Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 66
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 66
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr
20 25 30
<210> 67
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 67
Asp Tyr Tyr Met Asn
1 5
<210> 68
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 68
Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu Gly
1 5 10
<210> 69
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 69
Phe Ile Gly Asn Lys Ala Asn Gly Tyr Thr Thr Glu Tyr Ser Ala Ser
1 5 10 15
Val Lys Gly
<210> 70
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 70
Arg Phe Thr Ile Ser Arg Asp Lys Ser Gln Ser Ile Leu Tyr Leu Gln
1 5 10 15
Met Asn Thr Leu Arg Ala Glu Asp Ser Ala Thr Tyr Tyr Cys Thr Arg
20 25 30
<210> 71
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 71
Asp Arg Gly Leu Arg Phe Tyr Phe Asp Tyr
1 5 10
<210> 72
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 72
Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
1 5 10
<210> 73
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 73
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Gly Glu Ser Val Asp Ile Phe
20 25 30
Gly Val Gly Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Asn
85 90 95
Glu Asp Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 74
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 74
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys
20
<210> 75
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 75
Arg Ala Gly Glu Ser Val Asp Ile Phe Gly Val Gly Phe Leu His
1 5 10 15
<210> 76
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 76
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 77
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 77
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 78
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 78
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25 30
<210> 79
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 79
Gln Gln Thr Asn Glu Asp Pro Tyr Thr
1 5
<210> 80
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 80
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 81
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 81
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Asp Pro Ala Asn Gly Asn Ser Lys Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Pro Phe Gly Tyr Tyr Val Ser Asp Tyr Ala Met Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 82
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 82
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys
20 25 30
<210> 83
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 83
Asp Thr Tyr Met His
1 5
<210> 84
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 84
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala
1 5 10
<210> 85
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 85
Arg Ile Asp Pro Ala Asn Gly Asn Ser Lys Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 86
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 86
Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Pro
20 25 30
<210> 87
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 87
Phe Gly Tyr Tyr Val Ser Asp Tyr Ala Met Ala Tyr
1 5 10
<210> 88
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 88
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 89
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 89
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Phe Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Val
35 40 45
Tyr Asn Thr Arg Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 90
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 90
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys
20
<210> 91
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 91
Arg Ala Ser Glu Asn Ile Phe Ser Tyr Leu Ala
1 5 10
<210> 92
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 92
Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Val Tyr
1 5 10 15
<210> 93
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 93
Asn Thr Arg Thr Leu Ala Glu
1 5
<210> 94
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 94
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25 30
<210> 95
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 95
Gln His His Tyr Gly Thr Pro Phe Thr
1 5
<210> 96
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 96
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 97
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 97
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Thr Pro Glu Arg Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Gly Gly Ile Thr Tyr Ala Pro Ser Thr Val
50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 98
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 98
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser
20 25 30
<210> 99
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 99
Ser Tyr Asp Met Ser
1 5
<210> 100
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 100
Trp Val Arg Gln Thr Pro Glu Arg Gly Leu Glu Trp Val Ala
1 5 10
<210> 101
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 101
Tyr Ile Ser Ser Gly Gly Gly Ile Thr Tyr Ala Pro Ser Thr Val Lys
1 5 10 15
Gly
<210> 102
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 102
Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala
20 25 30
<210> 103
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 103
His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr
1 5 10
<210> 104
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 104
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 105
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 105
Gln Ala Val Leu Thr Gln Pro Ala Ser Leu Ser Ala Ser Pro Gly Ala
1 5 10 15
Ser Ala Ser Leu Thr Cys Thr Leu Arg Arg Gly Ile Asn Val Gly Ala
20 25 30
Tyr Ser Ile Tyr Trp Tyr Gln Gln Lys Pro Gly Ser Pro Pro Gln Tyr
35 40 45
Leu Leu Arg Tyr Lys Ser Asp Ser Asp Lys Gln Gln Gly Ser Gly Val
50 55 60
Ser Ser Arg Phe Ser Ala Ser Lys Asp Ala Ser Ala Asn Ala Gly Ile
65 70 75 80
Leu Leu Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys
85 90 95
Met Ile Trp His Ser Gly Ala Ser Ala Val Phe Gly Gly Gly Thr Lys
100 105 110
Leu Thr Val Leu
115
<210> 106
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 106
Gln Ala Val Leu Thr Gln Pro Ala Ser Leu Ser Ala Ser Pro Gly Ala
1 5 10 15
Ser Ala Ser Leu Thr Cys
20
<210> 107
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 107
Thr Leu Arg Arg Gly Ile Asn Val Gly Ala Tyr Ser Ile Tyr
1 5 10
<210> 108
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 108
Trp Tyr Gln Gln Lys Pro Gly Ser Pro Pro Gln Tyr Leu Leu Arg
1 5 10 15
<210> 109
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 109
Tyr Lys Ser Asp Ser Asp Lys Gln Gln Gly Ser
1 5 10
<210> 110
<211> 34
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 110
Gly Val Ser Ser Arg Phe Ser Ala Ser Lys Asp Ala Ser Ala Asn Ala
1 5 10 15
Gly Ile Leu Leu Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr
20 25 30
Tyr Cys
<210> 111
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 111
Met Ile Trp His Ser Gly Ala Ser Ala Val
1 5 10
<210> 112
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 112
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
1 5 10
<210> 113
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 113
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Phe Ile Arg Asn Lys Ala Asn Gly Gly Thr Thr Glu Tyr Ala Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Arg Gly Leu Arg Phe Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 114
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 114
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser
20 25 30
<210> 115
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 115
Ser Tyr Trp Met His
1 5
<210> 116
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 116
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly
1 5 10
<210> 117
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 117
Phe Ile Arg Asn Lys Ala Asn Gly Gly Thr Thr Glu Tyr Ala Ala Ser
1 5 10 15
Val Lys Gly
<210> 118
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 118
Phe Ile Arg Asn Lys Ala Asn Ser Gly Thr Thr Glu Tyr Ala Ala Ser
1 5 10 15
Val Lys Gly
<210> 119
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 119
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 120
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 120
Asp Arg Gly Leu Arg Phe Tyr Phe Asp Tyr
1 5 10
<210> 121
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 121
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 122
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 122
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Tyr
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Phe Ile Leu Asn Lys Ala Asn Gly Gly Thr Thr Glu Tyr Ala Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Asp Arg Gly Leu Arg Phe Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 123
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 123
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser
20 25 30
<210> 124
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 124
Ser Tyr Trp Met His
1 5
<210> 125
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 125
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly
1 5 10
<210> 126
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 126
Phe Ile Leu Asn Lys Ala Asn Gly Gly Thr Thr Glu Tyr Ala Ala Ser
1 5 10 15
Val Lys Gly
<210> 127
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 127
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr Leu Gln
1 5 10 15
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 128
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 128
Asp Arg Gly Leu Arg Phe Tyr Phe Asp Tyr
1 5 10
<210> 129
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 129
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 130
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成多肽"
<400> 130
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Phe
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Lys Thr Gly Glu Ala Thr Tyr Val Glu Glu Phe
50 55 60
Lys Gly Arg Val Thr Phe Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Phe Ala Tyr Tyr Val Glu Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 131
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 131
Lys Ala Ser Gln Asp Val Ser Ile Ala Val Ala
1 5 10
<210> 132
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 132
Ser Ala Ser Tyr Arg Tyr Thr
1 5
<210> 133
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 133
Gln Gln His Tyr Ile Thr Pro Leu Thr
1 5
<210> 134
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 134
Asn Tyr Gly Met Asn
1 5
<210> 135
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 135
Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Thr Asp Asp Phe Lys
1 5 10 15
Gly
<210> 136
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 136
Gly Gly Phe Gly Ser Ser Tyr Trp Tyr Phe Asp Val
1 5 10
<210> 137
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 137
Trp Ile Asn Thr Lys Thr Gly Glu Pro Thr Tyr Ala Glu Glu Phe Lys
1 5 10 15
Gly
<210> 138
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 138
Gly Gly Tyr Gly Ser Ser Tyr Trp Tyr Phe Asp Val
1 5 10
<210> 139
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 139
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Gln Asn Tyr Leu
1 5 10 15
Ala
<210> 140
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 140
Gly Ala Ser Thr Arg Glu Ser
1 5
<210> 141
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 141
Gln Ser Asp His Ile Tyr Pro Tyr Thr
1 5
<210> 142
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 142
Ile Tyr Trp Leu Gly
1 5
<210> 143
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 143
Asn Ile Phe Pro Gly Ser Ala Tyr Ile Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 144
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 144
Glu Gly Ser Asn Ser Gly Tyr
1 5
<210> 145
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 145
Lys Ala Ser Gln Asp Val Ser Thr Ala Val Ala
1 5 10
<210> 146
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 146
Thr Ala Gly Met Gln
1 5
<210> 147
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 147
Trp Ile Asn Thr His Ser Gly Val Pro Lys Tyr Ala Glu Asp Phe Lys
1 5 10 15
Gly
<210> 148
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 148
Ser Gly Phe Gly Ser Ser Tyr Trp Tyr Phe Asp Val
1 5 10
<210> 149
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<220>
<221> 变异体
<222> (10)..(10)
<223> /置换="Leu"或"Asn"
<220>
<221> 位点
<222> (1)..(15)
<223> /注释="序列中给出的变异残基关于变异位置的标注中的那些没有偏好"
<400> 149
Arg Ala Ser Lys Ser Val Ser Thr Ser Gly Tyr Ser Tyr Met His
1 5 10 15
<210> 150
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 150
Leu Ala Ser Asn Leu Glu Ser
1 5
<210> 151
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 151
Gln His Ser Arg Glu Leu Pro Tyr Thr
1 5
<210> 152
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 152
Ser Tyr Gly Val His
1 5
<210> 153
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 153
Gly Gly Ser Ile Ser Ser Tyr
1 5
<210> 154
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 154
Gly Gly Ser Ile Ser Ser Tyr Gly Val His
1 5 10
<210> 155
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<220>
<221> 变异体
<222> (5)..(5)
<223> /置换="Ser"
<220>
<221> 变异体
<222> (7)..(7)
<223> /置换="Val"
<220>
<221> 变异体
<222> (16)..(16)
<223> /置换="Gly"
<220>
<221> 位点
<222> (1)..(16)
<223> /注释="序列中给出的变异残基关于变异位置的标注中的那些没有偏好"
<400> 155
Val Ile Trp Thr Gly Gly Ser Thr Asp Tyr Asn Ser Ala Leu Met Ser
1 5 10 15
<210> 156
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<220>
<221> 变异体
<222> (3)..(3)
<223> /置换="Ser"
<220>
<221> 变异体
<222> (5)..(5)
<223> /置换="Val"
<220>
<221> 位点
<222> (1)..(5)
<223> /注释="序列中给出的变异残基关于变异位置的标注中的那些没有偏好"
<400> 156
Trp Thr Gly Gly Ser
1 5
<210> 157
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 157
Asp Gly Asp Tyr Asp Arg Tyr Thr Met Asp Tyr
1 5 10
<210> 158
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 158
Arg Ala Ser Lys Ser Val Ser Thr Ser Gly Tyr Ser Tyr Met His
1 5 10 15
<210> 159
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 159
Val Ile Trp Thr Ser Gly Val Thr Asp Tyr Asn Ser Ala Leu Met Gly
1 5 10 15
<210> 160
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> 来源
<223> /注释="人工序列的描述:合成肽"
<400> 160
Trp Thr Ser Gly Val
1 5
Claims (89)
1.一种免疫缀合物,所述免疫缀合物包含通过连接子共价附接至一个或多个5-氨基吡唑并氮呯部分的抗体,并且具有式I:
Ab-[L-PAZ]p I
或其药学上可接受的盐,
其中:
Ab是所述抗体;
p是1至8的整数;
PAZ是选自式IIa和式IIb的5-氨基吡唑并氮呯部分:
X1、X2和X3独立地选自由一键、C(=O)、C(=O)N(R5)、O、N(R5)、S、S(O)2和S(O)2N(R5)组成的组;
R1、R2、R3和R4独立地选自由H、C1-C12烷基、C2-C6烯基、C2-C6炔基、C3-C12碳环基、C6-C20芳基、C2-C9杂环基和C1-C20杂芳基组成的组,其中烷基、烯基、炔基、碳环基、芳基、杂环基和杂芳基独立地并且任选地经一个或多个选自以下的基团取代:
-(C1-C12烷二基)-N(R5)-*;
-(C1-C12烷二基)-N(R5)2;
-(C1-C12烷二基)-OR5;
-(C3-C12碳环基);
-(C3-C12碳环基)-*;
-(C3-C12碳环基)-(C1-C12烷二基)-NR5-*;
-(C3-C12碳环基)-(C1-C12烷二基)-N(R5)2;
-(C3-C12碳环基)-NR5-C(=NR5)NR5-*;
-(C6-C20芳基);
-(C6-C20芳二基)-*;
-(C6-C20芳二基)-N(R5)-*;
-(C6-C20芳二基)-(C1-C12烷二基)-N(R5)-*;
-(C6-C20芳二基)-(C1-C12烷二基)-(C2-C20杂环二基)-*;
-(C6-C20芳二基)-(C1-C12烷二基)-N(R5)2;
-(C6-C20芳二基)-(C1-C12烷二基)-NR5-C(=NR5a)N(R5)-*;-(C2-C20杂环基);
-(C2-C20杂环基)-*;
-(C2-C9杂环基)-(C1-C12烷二基)-NR5-*;
-(C2-C9杂环基)-(C1-C12烷二基)-N(R5)2;
-(C2-C9杂环基)-C(=O)-(C1-C12烷二基)-N(R5)-*;
-(C2-C9杂环基)-NR5-C(=NR5a)NR5-*;
-(C2-C9杂环基)-NR5-(C6-C20芳二基)-(C1-C12烷二基)-N(R5)-*;-(C2-C9杂环基)-(C6-C20芳二基)-*;
-(C1-C20杂芳基);
-(C1-C20杂芳二基)-*;
-(C1-C20杂芳二基)-(C1-C12烷二基)-N(R5)-*;
-(C1-C20杂芳二基)-(C1-C12烷二基)-N(R5)2;
-(C1-C20杂芳二基)-NR5-C(=NR5a)N(R5)-*;
-(C1-C20杂芳二基)-N(R5)C(=O)-(C1-C12烷二基)-N(R5)-*;
-C(=O)-*;
-C(=O)-(C1-C12烷二基)-N(R5)-*;
-C(=O)-(C2-C20杂环二基)-*;
-C(=O)N(R5)2;
-C(=O)N(R5)-*;
-C(=O)N(R5)-(C1-C12烷二基)-*;
-C(=O)N(R5)-(C1-C12烷二基)-C(=O)N(R5)-*;
-C(=O)N(R5)-(C1-C12烷二基)-N(R5)C(=O)R5;
-C(=O)N(R5)-(C1-C12烷二基)-N(R5)C(=O)N(R5)2;
-C(=O)NR5-(C1-C12烷二基)-N(R5)CO2R5;
-C(=O)NR5-(C1-C12烷二基)-N(R5)C(=NR5a)N(R5)2;
-C(=O)NR5-(C1-C12烷二基)-NR5C(=NR5a)R5;
-C(=O)NR5-(C1-C8烷二基)-NR5(C2-C5杂芳基);
-C(=O)NR5-(C1-C20杂芳二基)-N(R5)-*;
-C(=O)NR5-(C1-C20杂芳二基)-*;
-C(=O)NR5-(C1-C20杂芳二基)-(C1-C12烷二基)-N(R5)2;
-C(=O)NR5-(C1-C20杂芳二基)-(C2-C20杂环二基)-C(=O)NR5-(C1-C12烷二基)-NR5-*;
-N(R5)2;
-N(R5)-*;
-N(R5)C(=O)R5;
-N(R5)C(=O)-*;
-N(R5)C(=O)N(R5)2;
-N(R5)C(=O)N(R5)-*;
-N(R5)CO2R5;
-N(R5)CO2(R5)-*;
-NR5C(=NR5a)N(R5)2;
-NR5C(=NR5a)N(R5)-*;
-NR5C(=NR5a)R5;
-N(R5)C(=O)-(C1-C12烷二基)-N(R5)-*;
-N(R5)-(C2-C5杂芳基);
-N(R5)-S(=O)2-(C1-C12烷基);
-O-(C1-C12烷基);
-O-(C1-C12烷二基)-N(R5)2;
-O-(C1-C12烷二基)-N(R5)-*;
-OC(=O)N(R5)2;
-OC(=O)N(R5)-*;
-S(=O)2-(C2-C20杂环二基)-*;
-S(=O)2-(C2-C20杂环二基)-(C1-C12烷二基)-N(R5)2;
-S(=O)2-(C2-C20杂环二基)-(C1-C12烷二基)-NR5-*;以及
-S(=O)2-(C2-C20杂环二基)-(C1-C12烷二基)-OH;
或R2与R3一起形成5元或6元杂环基环;
R5选自由H、C6-C20芳基、C3-C12碳环基、C2-C20杂环基、C6-C20芳二基、C1-C12烷基和C1-C12烷二基组成的组,或两个R5基团一起形成5元或6元杂环基环;
R5a选自由C6-C20芳基和C1-C20杂芳基组成的组;
其中星号*指示L的附接位点,并且其中R1、R2、R3和R4中的一者附接至L;
L是选自由以下组成的组的连接子:
-C(=O)-PEG-;
-C(=O)-PEG-C(=O)N(R6)-(C1-C12烷二基)-C(=O)-Gluc-;
-C(=O)-PEG-O-;
-C(=O)-PEG-O-C(=O)-;
-C(=O)-PEG-C(=O)-;
-C(=O)-PEG-C(=O)-PEP-;
-C(=O)-PEG-N(R6)-;
-C(=O)-PEG-N(R6)-C(=O)-;
-C(=O)-PEG-N(R6)-PEG-C(=O)-PEP-;
-C(=O)-PEG-N+(R6)2-PEG-C(=O)-PEP-;
-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷二基)-;
-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷二基)N(R6)C(=O)-(C2-C5单杂环二基)-;
-C(=O)-PEG-SS-(C1-C12烷二基)-OC(=O)-;
-C(=O)-PEG-SS-(C1-C12烷二基)-C(=O)-;
-C(=O)-(C1-C12烷二基)-C(=O)-PEP-;
-C(=O)-(C1-C12烷二基)-C(=O)-PEP-N(R6)-(C1-C12烷二基)-;
-C(=O)-(C1-C12烷二基)-C(=O)-PEP-N(R6)-(C1-C12烷二基)-N(R5)-C(=O);
-C(=O)-(C1-C12烷二基)-C(=O)-PEP-N(R6)-(C1-C12烷二基)-N(R6)C(=O)-(C2-C5单杂环二基)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-C(=O)N(R6)-(C1-C12烷二基)-C(=O)-Gluc-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-O-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-O-C(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-C(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-N(R5)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-N(R5)-C(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-C(=O)-PEP-;
-琥珀酰亚胺基-(CH2)m-C(=O)N(R6)-PEG-SS-(C1-C12烷二基)-OC(=O)-;
-琥珀酰亚胺基-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷二基)-;
-琥珀酰亚胺基-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷二基)N(R6)C(=O)-;以及
-琥珀酰亚胺基-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷二基)N(R6)C(=O)-(C2-C5单杂环二基)-;
R6独立地是H或C1-C6烷基;
PEG具有下式:-(CH2CH2O)n-(CH2)m-;m是1至5的整数,并且n是2至50的整数;
Gluc具有下式:
PEP具有下式:
其中AA独立地选自天然或非天然氨基酸侧链,或AA中的一者或多者和相邻氮原子形成5元环脯氨酸氨基酸,并且波形线指示附接点;
Cyc选自C6-C20芳二基和C1-C20杂芳二基,任选地经一个或多个选自以下的基团取代:F、Cl、NO2、-OH、-OCH3,以及具有以下结构的葡糖醛酸:
R7选自由-CH(R8)O-、-CH2-、-CH2N(R8)-和-CH(R8)O-C(=O)-组成的组,其中R8选自H、C1-C6烷基、C(=O)-C1-C6烷基和-C(=O)N(R9)2,其中R9独立地选自由H、C1-C12烷基和-(CH2CH2O)n-(CH2)m-OH组成的组,其中m是1至5的整数,并且n是2至50的整数,或两个R9基团一起形成5元或6元杂环基环;
y是2至12的整数;
z是0或1;并且
烷基、烷二基、烯基、烯二基、炔基、炔二基、芳基、芳二基、碳环基、碳环二基、杂环基、杂环二基、杂芳基和杂芳二基独立地并且任选地经一个或多个独立地选自以下的基团取代:F、Cl、Br、I、-CN、-CH3、-CH2CH3、-CH=CH2、-C≡CH、-C≡CCH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2、-CH2OH、-CH2OCH3、-CH2CH2OH、-C(CH3)2OH、-CH(OH)CH(CH3)2、-C(CH3)2CH2OH、-CH2CH2SO2CH3、-CH2OP(O)(OH)2、-CH2F、-CHF2、-CF3、-CH2CF3、-CH2CHF2、-CH(CH3)CN、-C(CH3)2CN、-CH2CN、-CH2NH2、-CH2NHSO2CH3、-CH2NHCH3、-CH2N(CH3)2、-CO2H、-COCH3、-CO2CH3、-CO2C(CH3)3、-COCH(OH)CH3、-CONH2、-CONHCH3、-CON(CH3)2、-C(CH3)2CONH2、-NH2、-NHCH3、-N(CH3)2、-NHCOCH3、-N(CH3)COCH3、-NHS(O)2CH3、-N(CH3)C(CH3)2CONH2、-N(CH3)CH2CH2S(O)2CH3、-NHC(=NH)H、-NHC(=NH)CH3、-NHC(=NH)NH2、-NHC(=O)NH2、-NO2、=O、-OH、-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2、-O(CH2CH2O)n-(CH2)mCO2H、-O(CH2CH2O)nH、-OP(O)(OH)2、-S(O)2N(CH3)2、-SCH3、-S(O)2CH3和-S(O)3H。
2.如权利要求1所述的免疫缀合物,其中所述抗体是具有结合PD-L1的抗原结合结构域的抗体构建体。
3.如权利要求2所述的免疫缀合物,其中所述抗体选自由阿特珠单抗、得瓦鲁单抗和阿维鲁单抗或其生物类似药或生物改良药组成的组。
4.如权利要求1所述的免疫缀合物,其中所述抗体是具有结合HER2的抗原结合结构域的抗体构建体。
5.如权利要求4所述的免疫缀合物,其中所述抗体选自由曲妥珠单抗和帕妥珠单抗或其生物类似药或生物改良药组成的组。
6.如权利要求1所述的免疫缀合物,其中所述抗体是具有结合CEA的抗原结合结构域的抗体构建体。
7.如权利要求6所述的免疫缀合物,其中所述抗体是拉贝妥珠单抗或其生物类似药或生物改良药。
8.如权利要求1所述的免疫缀合物,其中所述抗体是具有结合TROP2的抗原结合结构域的抗体构建体。
9.如权利要求8所述的免疫缀合物,其中所述抗体是沙西妥珠单抗或其生物类似药或生物改良药。
10.如权利要求1至9中任一项所述的免疫缀合物,其中X1是一键,并且R1是H。
11.如权利要求1至9中任一项所述的免疫缀合物,其中X2是一键,并且R2是C1-C8烷基。
12.如权利要求1至9中任一项所述的免疫缀合物,其中X2和X3各自是一键,并且R2和R3独立地选自C1-C8烷基、-O-(C1-C12烷基)、-(C1-C12烷二基)-OR5、-(C1-C8烷二基)-N(R5)CO2R5、-(C1-C12烷基)-OC(O)N(R5)2、-O-(C1-C12烷基)-N(R5)CO2R5和-O-(C1-C12烷基)-OC(O)N(R5)2。
13.如权利要求12所述的免疫缀合物,其中R2是C1-C8烷基并且R3是-(C1-C8烷二基)-N(R5)CO2R4。
14.如权利要求12所述的免疫缀合物,其中R2是-CH2CH2CH3并且R3选自-CH2CH2CH2NHCO2(t-Bu)、-OCH2CH2NHCO2(环丁基)和-CH2CH2CH2NHCO2(环丁基)。
15.如权利要求12所述的免疫缀合物,其中R2和R3各自独立地选自-CH2CH2CH3、-OCH2CH3、-OCH2CF3、-CH2CH2CF3、-OCH2CH2OH和-CH2CH2CH2OH。
16.如权利要求12所述的免疫缀合物,其中R2和R3各自是-CH2CH2CH3。
17.如权利要求12所述的免疫缀合物,其中R2是-CH2CH2CH3并且R3是-OCH2CH3。
19.如权利要求1至9中任一项所述的免疫缀合物,其中R2或R3附接至L。
21.如权利要求1至9中任一项所述的免疫缀合物,其中R4是C1-C12烷基。
22.如权利要求1至9中任一项所述的免疫缀合物,其中R4是-(C1-C12烷二基)-N(R5)-*;其中星号*指示L的附接位点。
23.如权利要求1至9中任一项所述的免疫缀合物,其中L是-C(=O)-PEG-或-C(=O)-PEG-C(=O)-。
24.如权利要求1至9中任一项所述的免疫缀合物,其中L附接至所述抗体的半胱氨酸硫醇。
25.如权利要求1至9中任一项所述的免疫缀合物,其中对于所述PEG,m是1或2,并且n是2至10的整数。
26.如权利要求25所述的免疫缀合物,其中n是10。
28.如权利要求27所述的免疫缀合物,其中AA1和AA2独立地选自H、-CH3、-CH(CH3)2、-CH2(C6H5)、-CH2CH2CH2CH2NH2、-CH2CH2CH2NHC(NH)NH2、-CHCH(CH3)CH3、-CH2SO3H和-CH2CH2CH2NHC(O)NH2;或AA1和AA2形成5元环脯氨酸氨基酸。
29.如权利要求27所述的免疫缀合物,其中AA1是-CH(CH3)2,并且AA2是-CH2CH2CH2NHC(O)NH2。
30.如权利要求27所述的免疫缀合物,其中AA1和AA2独立地选自GlcNAc天冬氨酸、-CH2SO3H和-CH2OPO3H。
34.如权利要求33所述的免疫缀合物,其中
AA1选自由Abu、Ala和Val组成的组;
AA2选自由Nle(O-Bzl)、Oic和Pro组成的组;
AA3选自由Ala和Met(O)2组成的组;并且
AA4选自由Oic、Arg(NO2)、Bpa和Nle(O-Bzl)组成的组。
35.如权利要求1至9中任一项所述的免疫缀合物,其中L包含PEP,并且PEP选自由Ala-Pro-Val、Asn-Pro-Val、Ala-Ala-Val、Ala-Ala-Pro-Ala、Ala-Ala-Pro-Val和Ala-Ala-Pro-Nva组成的组。
40.一种5-氨基吡唑并氮呯-连接子化合物,所述化合物选自式IIa和式IIb:
其中X1、X2和X3独立地选自由一键、C(=O)、C(=O)N(R5)、O、N(R5)、S、S(O)2和S(O)2N(R5)组成的组;
R1、R2、R3和R4独立地选自由H、C1-C12烷基、C2-C6烯基、C2-C6炔基、C3-C12碳环基、C6-C20芳基、C2-C9杂环基和C1-C20杂芳基组成的组,其中烷基、烯基、炔基、碳环基、芳基、杂环基和杂芳基独立地并且任选地经一个或多个选自以下的基团取代:
-(C1-C12烷二基)-N(R5)-*;
-(C1-C12烷二基)-N(R5)2;
-(C1-C12烷二基)-OR5;
-(C3-C12碳环基);
-(C3-C12碳环基)-*;
-(C3-C12碳环基)-(C1-C12烷二基)-NR5-*;
-(C3-C12碳环基)-(C1-C12烷二基)-N(R5)2;
-(C3-C12碳环基)-NR5-C(=NR5)NR5-*;
-(C6-C20芳基);
-(C6-C20芳二基)-*;
-(C6-C20芳二基)-N(R5)-*;
-(C6-C20芳二基)-(C1-C12烷二基)-N(R5)-*;
-(C6-C20芳二基)-(C1-C12烷二基)-(C2-C20杂环二基)-*;
-(C6-C20芳二基)-(C1-C12烷二基)-N(R5)2;
-(C6-C20芳二基)-(C1-C12烷二基)-NR5-C(=NR5a)N(R5)-*;
-(C2-C20杂环基);
-(C2-C20杂环基)-*;
-(C2-C9杂环基)-(C1-C12烷二基)-NR5-*;
-(C2-C9杂环基)-(C1-C12烷二基)-N(R5)2;
-(C2-C9杂环基)-C(=O)-(C1-C12烷二基)-N(R5)-*;
-(C2-C9杂环基)-NR5-C(=NR5a)NR5-*;
-(C2-C9杂环基)-NR5-(C6-C20芳二基)-(C1-C12烷二基)-N(R5)-*;-(C2-C9杂环基)-(C6-C20芳二基)-*;
-(C1-C20杂芳基);
-(C1-C20杂芳二基)-*;
-(C1-C20杂芳二基)-(C1-C12烷二基)-N(R5)-*;
-(C1-C20杂芳二基)-(C1-C12烷二基)-N(R5)2;
-(C1-C20杂芳二基)-NR5-C(=NR5a)N(R5)-*;
-(C1-C20杂芳二基)-N(R5)C(=O)-(C1-C12烷二基)-N(R5)-*;
-C(=O)-*;
-C(=O)-(C1-C12烷二基)-N(R5)-*;
-C(=O)-(C2-C20杂环二基)-*;
-C(=O)N(R5)2;
-C(=O)N(R5)-*;
-C(=O)N(R5)-(C1-C12烷二基)-*;
-C(=O)N(R5)-(C1-C12烷二基)-C(=O)N(R5)-*;
-C(=O)N(R5)-(C1-C12烷二基)-N(R5)C(=O)R5;
-C(=O)N(R5)-(C1-C12烷二基)-N(R5)C(=O)N(R5)2;
-C(=O)NR5-(C1-C12烷二基)-N(R5)CO2R5;
-C(=O)NR5-(C1-C12烷二基)-N(R5)C(=NR5a)N(R5)2;
-C(=O)NR5-(C1-C12烷二基)-NR5C(=NR5a)R5;
-C(=O)NR5-(C1-C8烷二基)-NR5(C2-C5杂芳基);
-C(=O)NR5-(C1-C20杂芳二基)-N(R5)-*;
-C(=O)NR5-(C1-C20杂芳二基)-*;
-C(=O)NR5-(C1-C20杂芳二基)-(C1-C12烷二基)-N(R5)2;
-C(=O)NR5-(C1-C20杂芳二基)-(C2-C20杂环二基)-C(=O)NR5-(C1-C12烷二基)-NR5-*;
-N(R5)2;
-N(R5)-*;
-N(R5)C(=O)R5;
-N(R5)C(=O)-*;
-N(R5)C(=O)N(R5)2;
-N(R5)C(=O)N(R5)-*;
-N(R5)CO2R5;
-N(R5)CO2(R5)-*;
-NR5C(=NR5a)N(R5)2;
-NR5C(=NR5a)N(R5)-*;
-NR5C(=NR5a)R5;
-N(R5)C(=O)-(C1-C12烷二基)-N(R5)-*;
-N(R5)-(C2-C5杂芳基);
-N(R5)-S(=O)2-(C1-C12烷基);
-O-(C1-C12烷基);
-O-(C1-C12烷二基)-N(R5)2;
-O-(C1-C12烷二基)-N(R5)-*;
-OC(=O)N(R5)2;
-OC(=O)N(R5)-*;
-S(=O)2-(C2-C20杂环二基)-*;
-S(=O)2-(C2-C20杂环二基)-(C1-C12烷二基)-N(R5)2;
-S(=O)2-(C2-C20杂环二基)-(C1-C12烷二基)-NR5-*;以及
-S(=O)2-(C2-C20杂环二基)-(C1-C12烷二基)-OH;
或R2与R3一起形成5元或6元杂环基环;
R5选自由H、C6-C20芳基、C3-C12碳环基、C2-C20杂环基、C6-C20芳二基、C1-C12烷基和C1-C12烷二基组成的组,或两个R5基团一起形成5元或6元杂环基环;
R5a选自由C6-C20芳基和C1-C20杂芳基组成的组;
其中星号*指示L的附接位点,并且其中R1、R2、R3和R4中的一者附接至L;
L是选自由以下组成的组的连接子:
Q-C(=O)-PEG-;
Q-C(=O)-PEG-C(=O)N(R6)-(C1-C12烷二基)-C(=O)-Gluc-;
Q-C(=O)-PEG-O-;
Q-C(=O)-PEG-O-C(=O)-;
Q-C(=O)-PEG-C(=O)-;
Q-C(=O)-PEG-C(=O)-PEP-;
Q-C(=O)-PEG-N(R6)-;
Q-C(=O)-PEG-N(R6)-C(=O)-;
Q-C(=O)-PEG-N(R6)-PEG-C(=O)-PEP-;
Q-C(=O)-PEG-N+(R6)2-PEG-C(=O)-PEP-;
Q-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷二基)-;
Q-C(=O)-PEG-C(=O)-PEP-N(R6)-(C1-C12烷二基)N(R6)C(=O)-(C2-
C5单杂环二基)-;
Q-C(=O)-PEG-SS-(C1-C12烷二基)-OC(=O)-;
Q-C(=O)-PEG-SS-(C1-C12烷二基)-C(=O)-;
Q-C(=O)-(C1-C12烷二基)-C(=O)-PEP-;
Q-C(=O)-(C1-C12烷二基)-C(=O)-PEP-N(R6)-(C1-C12烷二基)-;
Q-C(=O)-(C1-C12烷二基)-C(=O)-PEP-N(R6)-(C1-C12烷二基)-N(R5)-C(=O);
Q-C(=O)-(C1-C12烷二基)-C(=O)-PEP-N(R6)-(C1-C12烷二基)-N(R6)C(=O)-(C2-C5单杂环二基)-;
Q-(CH2)m-C(=O)N(R6)-PEG-;
Q-(CH2)m-C(=O)N(R6)-PEG-C(=O)N(R6)-(C1-C12烷二基)-C(=O)-G
luc-;
Q-(CH2)m-C(=O)N(R6)-PEG-O-;
Q-(CH2)m-C(=O)N(R6)-PEG-O-C(=O)-;
Q-(CH2)m-C(=O)N(R6)-PEG-C(=O)-;
Q-(CH2)m-C(=O)N(R6)-PEG-N(R5)-;
Q-(CH2)m-C(=O)N(R6)-PEG-N(R5)-C(=O)-;
Q-(CH2)m-C(=O)N(R6)-PEG-C(=O)-PEP-;
Q-(CH2)m-C(=O)N(R6)-PEG-SS-(C1-C12烷二基)-OC(=O)-;
Q-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷二基)-;
Q-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷二基)N(R6)C(=O)-;以及
Q-(CH2)m-C(=O)-PEP-N(R6)-(C1-C12烷二基)N(R6)C(=O)-(C2-C5单
杂环二基)-;
R6独立地是H或C1-C6烷基;
PEG具有下式:-(CH2CH2O)n-(CH2)m-;m是1至5的整数,并且n是2至50的整数;
Gluc具有下式:
PEP具有下式:
其中AA独立地选自天然或非天然氨基酸侧链,或AA中的一者或多者和相邻氮原子形成5元环脯氨酸氨基酸,并且波形线指示附接点;
Cyc选自C6-C20芳二基和C1-C20杂芳二基,任选地经一个或多个选自以下的基团取代:F、Cl、NO2、-OH、-OCH3,以及具有以下结构的葡糖醛酸:
R7选自由-CH(R8)O-、-CH2-、-CH2N(R8)-和-CH(R8)O-C(=O)-组成的组,其中R8选自H、C1-C6烷基、C(=O)-C1-C6烷基和-C(=O)N(R9)2,其中R9独立地选自由H、C1-C12烷基和-(CH2CH2O)n-(CH2)m-OH组成的组,其中m是1至5的整数,并且n是2至50的整数,或两个R9基团一起形成5元或6元杂环基环;
y是2至12的整数;
z是0或1;并且
Q选自由N-羟基琥珀酰亚胺基、N-羟基磺基琥珀酰亚胺基、马来酰亚胺和苯氧基组成的组,经一个或多个独立地选自F、Cl、NO2和SO3 -的基团取代;
其中烷基、烷二基、烯基、烯二基、炔基、炔二基、芳基、芳二基碳环基、碳环二基、杂环基、杂环二基、杂芳基和杂芳二基任选地经一个或多个独立地选自以下的基团取代:F、Cl、Br、I、-CN、-CH3、-CH2CH3、-CH=CH2、-C≡CH、-C≡CCH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2、-CH2OH、-CH2OCH3、-CH2CH2OH、-C(CH3)2OH、-CH(OH)CH(CH3)2、-C(CH3)2CH2OH、-CH2CH2SO2CH3、-CH2OP(O)(OH)2、-CH2F、-CHF2、-CF3、-CH2CF3、-CH2CHF2、-CH(CH3)CN、-C(CH3)2CN、-CH2CN、-CH2NH2、-CH2NHSO2CH3、-CH2NHCH3、-CH2N(CH3)2、-CO2H、-COCH3、-CO2CH3、-CO2C(CH3)3、-COCH(OH)CH3、-CONH2、-CONHCH3、-CON(CH3)2、-C(CH3)2CONH2、-NH2、-NHCH3、-N(CH3)2、-NHCOCH3、-N(CH3)COCH3、-NHS(O)2CH3、-N(CH3)C(CH3)2CONH2、-N(CH3)CH2CH2S(O)2CH3、-NHC(=NH)H、-NHC(=NH)CH3、-NHC(=NH)NH2、-NHC(=O)NH2、-NO2、=O、-OH、-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OH、-OCH2CH2N(CH3)2、-O(CH2CH2O)n-(CH2)mCO2H、-O(CH2CH2O)nH、-OP(O)(OH)2、-S(O)2N(CH3)2、-SCH3、-S(O)2CH3和-S(O)3H。
41.如权利要求40所述的5-氨基-吡唑并氮呯-连接子化合物,其中X1是一键,并且R1是H。
42.如权利要求40所述的5-氨基-吡唑并氮呯-连接子化合物,其中X2是一键,并且R2是C1-C8烷基。
43.如权利要求40所述的5-氨基-吡唑并氮呯-连接子化合物,其中X2和X3各自是一键,并且R2和R3独立地选自C1-C8烷基、-O-(C1-C12烷基)、-(C1-C12烷二基)-OR5、-(C1-C8烷二基)-N(R5)CO2R5、-(C1-C12烷基)-OC(O)N(R5)2、-O-(C1-C12烷基)-N(R5)CO2R5和-O-(C1-C12烷基)-OC(O)N(R5)2。
44.如权利要求43所述的5-氨基-吡唑并氮呯-连接子化合物,其中R2是C1-C8烷基并且R3是-(C1-C8烷二基)-N(R5)CO2R4。
45.如权利要求43所述的5-氨基-吡唑并氮呯-连接子化合物,其中R2是-CH2CH2CH3并且R3选自-CH2CH2CH2NHCO2(t-Bu)、-OCH2CH2NHCO2(环丁基)和-CH2CH2CH2NHCO2(环丁基)。
46.如权利要求43所述的5-氨基-吡唑并氮呯-连接子化合物,其中R2和R3各自独立地选自-CH2CH2CH3、-OCH2CH3、-OCH2CF3、-CH2CH2CF3、-OCH2CH2OH和-CH2CH2CH2OH。
47.如权利要求43所述的5-氨基-吡唑并氮呯-连接子化合物,其中R2和R3各自是-CH2CH2CH3。
48.如权利要求43所述的5-氨基-吡唑并氮呯-连接子化合物,其中R2是-CH2CH2CH3并且R3是-OCH2CH3。
50.如权利要求40所述的5-氨基-吡唑并氮呯-连接子化合物,其中R2或R3附接至L。
52.如权利要求40所述的5-氨基-吡唑并氮呯-连接子化合物,其中R4是C1-C12烷基。
53.如权利要求40所述的5-氨基-吡唑并氮呯-连接子化合物,其中R4是-(C1-C12烷二基)-N(R5)-*;其中星号*指示L的附接位点。
54.如权利要求40所述的5-氨基-吡唑并氮呯-连接子化合物,其中L是-C(=O)-PEG-或-C(=O)-PEG-C(=O)-。
55.如权利要求40所述的5-氨基-吡唑并氮呯-连接子化合物,其中对于所述PEG,m是1或2,并且n是2至10的整数。
56.如权利要求55所述的5-氨基-吡唑并氮呯-连接子化合物,其中n是10。
58.如权利要求57所述的5-氨基-吡唑并氮呯-连接子化合物,其中AA1和AA2独立地选自H、-CH3、-CH(CH3)2、-CH2(C6H5)、-CH2CH2CH2CH2NH2、-CH2CH2CH2NHC(NH)NH2、-CHCH(CH3)CH3、-CH2SO3H和-CH2CH2CH2NHC(O)NH2;或AA1和AA2形成5元环脯氨酸氨基酸。
59.如权利要求58所述的5-氨基-吡唑并氮呯-连接子化合物,其中AA1是-CH(CH3)2,并且AA2是-CH2CH2CH2NHC(O)NH2。
60.如权利要求57所述的5-氨基-吡唑并氮呯-连接子化合物,其中AA1和AA2独立地选自GlcNAc天冬氨酸、-CH2SO3H和-CH2OPO3H。
64.如权利要求63所述的5-氨基-吡唑并氮呯-连接子化合物,其中
AA1选自由Abu、Ala和Val组成的组;
AA2选自由Nle(O-Bzl)、Oic和Pro组成的组;
AA3选自由Ala和Met(O)2组成的组;并且
AA4选自由Oic、Arg(NO2)、Bpa和Nle(O-Bzl)组成的组。
65.如权利要求40所述的5-氨基-吡唑并氮呯-连接子化合物,其中L包含PEP,并且PEP选自由Ala-Pro-Val、Asn-Pro-Val、Ala-Ala-Val、Ala-Ala-Pro-Ala、Ala-Ala-Pro-Val和Ala-Ala-Pro-Nva组成的组。
71.如权利要求70所述的5-氨基-吡唑并氮呯-连接子化合物,其中Q是经一个或多个F取代的苯氧基。
72.如权利要求71所述的5-氨基-吡唑并氮呯-连接子化合物,其中Q是2,3,5,6-四氟苯氧基。
73.如权利要求70所述的5-氨基-吡唑并氮呯-连接子化合物,其中Q是马来酰亚胺。
74.如权利要求40所述的5-氨基-吡唑并氮呯-连接子化合物,所述化合物选自表2a和表2b。
75.一种免疫缀合物,所述免疫缀合物是通过使抗体与权利要求40所述的5-氨基-吡唑并氮呯-连接子化合物缀合来制备。
76.一种药物组合物,所述药物组合物包含治疗有效量的根据权利要求1至39中任一项所述的免疫缀合物和一种或多种药学上可接受的稀释剂、媒剂、载体或赋形剂。
77.一种用于治疗癌症的方法,所述方法包括向有需要的患者施用治疗有效量的根据权利要求1至39中任一项所述的免疫缀合物。
78.如权利要求77所述的方法,其中所述癌症容易发生由TLR7和/或TLR8促效作用诱导的促炎反应。
79.如权利要求77所述的方法,其中所述癌症是表达PD-L1的癌症。
80.如权利要求77所述的方法,其中所述癌症是表达HER2的癌症。
81.如权利要求77所述的方法,其中所述癌症是表达CEA的癌症。
82.如权利要求77所述的方法,其中所述癌症是表达TROP2的癌症。
83.如权利要求77至82中任一项所述的方法,其中所述癌症选自宫颈癌、子宫内膜癌、卵巢癌、前列腺癌、胰腺癌、食道癌、膀胱癌、尿道癌、尿路上皮癌、肺癌、非小细胞肺癌、梅克尔细胞癌、结肠癌、结肠直肠癌、胃癌和乳癌。
84.如权利要求83所述的方法,其中所述乳癌是三阴性乳癌。
85.如权利要求83所述的方法,其中所述梅克尔细胞癌是转移性梅克尔细胞癌。
86.如权利要求83所述的方法,其中所述胃癌是过表达HER2的胃癌。
87.如权利要求83所述的方法,其中所述癌症是胃食管连接部腺癌。
88.一种根据权利要求1至36中任一项所述的免疫缀合物的用途,其用于治疗癌症。
89.一种制备权利要求1所述的式I免疫缀合物的方法,其中使权利要求40所述的式II的5-氨基-吡唑并氮呯-连接子化合物与所述抗体缀合。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023076599A1 (en) * | 2021-10-29 | 2023-05-04 | Bolt Biotherapeutics, Inc. | Tlr agonist immunoconjugates with cysteine-mutant antibodies, and uses thereof |
Family Cites Families (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1988007089A1 (en) | 1987-03-18 | 1988-09-22 | Medical Research Council | Altered antibodies |
JP3040121B2 (ja) | 1988-01-12 | 2000-05-08 | ジェネンテク,インコーポレイテッド | 増殖因子レセプターの機能を阻害することにより腫瘍細胞を処置する方法 |
CA2103059C (en) | 1991-06-14 | 2005-03-22 | Paul J. Carter | Method for making humanized antibodies |
US6800738B1 (en) | 1991-06-14 | 2004-10-05 | Genentech, Inc. | Method for making humanized antibodies |
WO1994004679A1 (en) | 1991-06-14 | 1994-03-03 | Genentech, Inc. | Method for making humanized antibodies |
US5874540A (en) | 1994-10-05 | 1999-02-23 | Immunomedics, Inc. | CDR-grafted type III anti-CEA humanized mouse monoclonal antibodies |
SI1308455T1 (sl) | 1998-05-06 | 2006-08-31 | Genentech Inc | Sestavek, ki obsega protitelesa anti-HER2 |
US6949245B1 (en) | 1999-06-25 | 2005-09-27 | Genentech, Inc. | Humanized anti-ErbB2 antibodies and treatment with anti-ErbB2 antibodies |
US7416726B2 (en) | 2000-04-13 | 2008-08-26 | The Rockefeller University | Enhancement of antibody-mediated immune responses |
AU2003209447B8 (en) | 2002-03-01 | 2008-10-23 | Immunomedics, Inc. | RS7 antibodies |
US7232888B2 (en) | 2002-07-01 | 2007-06-19 | Massachusetts Institute Of Technology | Antibodies against tumor surface antigens |
US7273608B2 (en) | 2004-03-11 | 2007-09-25 | City Of Hope | Humanized anti-CEA T84.66 antibody and uses thereof |
WO2006034488A2 (en) | 2004-09-23 | 2006-03-30 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
EP1835935A4 (en) | 2004-12-30 | 2009-06-17 | Univ Rockefeller | COMPOSITIONS AND METHODS FOR IMPROVED DENDRITIC CELL REPRODUCTION AND FUNCTION |
WO2007055916A2 (en) | 2005-11-07 | 2007-05-18 | The Rockefeller University | Reagents, methods and systems for selecting a cytotoxic antibody or variant thereof |
US8394926B2 (en) | 2005-12-21 | 2013-03-12 | Micromet Ag | Pharmaceutical compositions with resistance to soluble CEA |
US7420040B2 (en) | 2006-02-24 | 2008-09-02 | Arius Research Inc. | Cytotoxicity mediation of cells evidencing surface expression of TROP-2 |
US20080131428A1 (en) | 2006-02-24 | 2008-06-05 | Arius Research, Inc. | Cytotoxicity mediation of cells evidencing surface expression of TROP-2 |
PE20090245A1 (es) | 2007-05-08 | 2009-03-17 | Genentech Inc | Anticuerpos anti-muc16 disenados con cisteina y conjugados de anticuerpos y farmacos |
WO2009052249A1 (en) | 2007-10-19 | 2009-04-23 | Genentech, Inc. | Cysteine engineered anti-tenb2 antibodies and antibody drug conjugates |
CN102448494B (zh) | 2009-02-13 | 2016-02-03 | 免疫医疗公司 | 具有胞内可裂解的键的免疫共轭物 |
CA2782194C (en) | 2009-12-02 | 2018-01-16 | Immunomedics, Inc. | Combination of radiolabelled antibodies (rait) and antibody-drug conjugates (adc) for treatment of pancreatic cancer |
PT2532680E (pt) | 2010-02-04 | 2015-09-14 | Toray Industries | Composição medicinal para tratar e/ou prevenir o cancro |
EA201500220A1 (ru) | 2010-05-17 | 2015-10-30 | Ливтех, Инк. | Антитело против trop-2 человека, обладающее противоопухолевой активностью in vivo |
JPWO2011155579A1 (ja) | 2010-06-10 | 2013-08-15 | 北海道公立大学法人 札幌医科大学 | 抗Trop−2抗体 |
ES2544608T3 (es) | 2010-11-17 | 2015-09-02 | Genentech, Inc. | Conjugados de anticuerpo y de alaninil-maitansinol |
EA029300B1 (ru) | 2011-03-02 | 2018-03-30 | Роше Гликарт Аг | Антитело к связанному с мембраной человеческому карциноэмбриональному антигену, его получение и применение |
HUE039219T2 (hu) | 2011-08-04 | 2018-12-28 | Toray Industries | Gyógyászati készítmény rák kezelésére és/vagy megelõzésére |
PT2740795T (pt) | 2011-08-04 | 2017-01-09 | Toray Industries | Composição de fármaco para o tratamento e/ou a prevenção de cancro |
AU2012290955B2 (en) | 2011-08-04 | 2017-04-27 | Toray Industries, Inc. | Drug composition for cancer treatment and/or prevention |
US9180188B2 (en) | 2011-08-04 | 2015-11-10 | Toray Industries, Inc. | Pharmaceutical composition for treatment and/or prophylaxis of cancer |
CN104053672A (zh) | 2011-11-11 | 2014-09-17 | 瑞纳神经科学公司 | Trop-2特异性抗体及其用途 |
US9427464B2 (en) | 2011-11-22 | 2016-08-30 | Chiome Bioscience Inc. | Anti-human TROP-2 antibody having an antitumor activity in vivo |
EP2818481B1 (en) | 2012-02-21 | 2019-08-07 | Toray Industries, Inc. | Pharmaceutical composition for treatment and/or prevention of cancer |
JP6187255B2 (ja) | 2012-02-21 | 2017-08-30 | 東レ株式会社 | 癌の治療及び/又は予防用医薬組成物 |
KR102005786B1 (ko) | 2012-02-21 | 2019-07-31 | 도레이 카부시키가이샤 | 암의 치료 및/또는 예방용 의약 조성물 |
CA2865020C (en) | 2012-02-21 | 2021-01-26 | Toray Industries, Inc. | Pharmaceutical composition for treatment and/or prevention of cancer |
EP2876447B1 (en) | 2012-07-19 | 2019-11-20 | Toray Industries, Inc. | Method for detecting cancer |
CN104471403B (zh) | 2012-07-19 | 2017-03-01 | 东丽株式会社 | 癌的检测方法 |
US9382329B2 (en) | 2012-08-14 | 2016-07-05 | Ibc Pharmaceuticals, Inc. | Disease therapy by inducing immune response to Trop-2 expressing cells |
SI3199552T1 (sl) | 2012-11-20 | 2020-06-30 | Sanofi | Protitelesa proti-CEACAM5 in njihove uporabe |
MX360671B (es) | 2013-08-09 | 2018-11-13 | Toray Industries | Composición farmacéutica para el tratamiento y/o prevención del cáncer. |
EP3088419B1 (en) | 2013-12-25 | 2018-10-10 | Daiichi Sankyo Company, Limited | Anti-trop2 antibody-drug conjugate |
HUE050596T2 (hu) | 2014-11-21 | 2020-12-28 | Bristol Myers Squibb Co | Antitestek CD73 ellen és azok felhasználásai |
JP6746845B2 (ja) | 2015-04-22 | 2020-08-26 | イミューノメディクス、インコーポレイテッドImmunomedics, Inc. | 循環trop−2陽性癌細胞の単離、検出、診断及び/または特徴付け |
US20170158772A1 (en) | 2015-12-07 | 2017-06-08 | Opi Vi - Ip Holdco Llc | Compositions of antibody construct - agonist conjugates and methods of use thereof |
CN109069665A (zh) | 2016-05-10 | 2018-12-21 | 百时美施贵宝公司 | 具有增强的稳定性的微管溶素类似物的抗体-药物缀合物 |
KR20230149857A (ko) * | 2016-07-07 | 2023-10-27 | 더 보드 어브 트러스티스 어브 더 리랜드 스탠포드 주니어 유니버시티 | 항체-애쥬번트 접합체 |
BR112019008335A2 (pt) | 2016-10-28 | 2020-01-28 | Toray Industries | conjugado de um anticorpo, composição farmacêutica e método para o tratamento e/ou a prevenção de um câncer |
WO2018112108A1 (en) * | 2016-12-13 | 2018-06-21 | Bolt Biotherapeutics, Inc. | Antibody adjuvant conjugates |
CA3049791A1 (en) * | 2017-01-27 | 2018-08-02 | Silverback Therapeutics, Inc. | Tumor targeting conjugates and methods of use thereof |
SG10202110183VA (en) * | 2017-03-15 | 2021-10-28 | Silverback Therapeutics Inc | Benzazepine compounds, conjugates, and uses thereof |
EP3724222A1 (en) * | 2017-12-15 | 2020-10-21 | Silverback Therapeutics, Inc. | Antibody construct-drug conjugate for the treatment of hepatitis |
WO2019222676A1 (en) * | 2018-05-17 | 2019-11-21 | Bolt Biotherapeutics, Inc. | Immunoconjugates |
AU2020205100A1 (en) | 2019-01-04 | 2021-08-19 | Trio Pharmaceuticals, Inc. | Multi-specific protein molecules and uses thereof |
MX2021015221A (es) * | 2019-06-13 | 2022-03-17 | Bolt Biotherapeutics Inc | Compuestos de aminobenzazepina, inmunoconjugados y usos de estos. |
CA3143156A1 (en) * | 2019-06-13 | 2020-12-17 | Bolt Biotherapeutics, Inc. | Macromolecule-supported aminobenzazepine compounds |
WO2021081407A1 (en) * | 2019-10-25 | 2021-04-29 | Bolt Biotherapeutics, Inc. | Thienoazepine immunoconjugates, and uses thereof |
JP2022554094A (ja) * | 2019-10-25 | 2022-12-28 | ボルト バイオセラピューティクス、インコーポレーテッド | 高分子支持チエノアゼピン化合物、及びそれらの使用 |
AU2021211669A1 (en) | 2020-01-21 | 2022-08-25 | Bolt Biotherapeutics, Inc. | Anti-PD-L1 antibodies |
US20230069055A1 (en) | 2020-01-21 | 2023-03-02 | Bolt Biotherapeutics, Inc | Anti-pd-l1 antibodies |
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WO2022036101A1 (en) | 2022-02-17 |
AU2021326516A1 (en) | 2023-04-13 |
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