CN115197297B - 连接子、缀合物及其应用 - Google Patents
连接子、缀合物及其应用 Download PDFInfo
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- CN115197297B CN115197297B CN202210386199.0A CN202210386199A CN115197297B CN 115197297 B CN115197297 B CN 115197297B CN 202210386199 A CN202210386199 A CN 202210386199A CN 115197297 B CN115197297 B CN 115197297B
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Classifications
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- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
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Abstract
本发明涉及一种靶向分子‑药物缀合物的连接分子、相应的缀合物、其制备方法和用途。
Description
技术领域
本发明涉及生物制药领域,尤其涉及一种用于制备靶向分子-药物缀合物的连接子、相应的缀合物、其制备方法和用途。
背景技术
HER2被发现在几种癌症类型中过度表达,包括乳腺癌和胃癌,并被证明是癌症治疗的一个有希望的靶点。多种HER2靶向治疗方式已获批准,包括HER2酪氨酸激酶抑制剂(拉帕替尼(Lapatinib)、图卡替尼(Tucatinib))、治疗性HER2抗体(赫赛汀(Herceptin)、Perjeta)和HER2靶向ADC(Kadcyla、Enhertu)。这些治疗药物显著提高了HER2阳性乳腺癌和胃癌患者的生存率。特别是,Enhertu不仅在HER2高表达患者中显示出很好的疗效,而且在HER2中/低表达患者中也显示出疗效迹象,这可能使更多HER2表达癌症患者受益。Enhertu虽然疗效显著,但引起了10%以上的间质性肺病,这限制了它在部分患者中的使用。
Enhertu以及其他市售ADC和临床试验中的大多数ADC都是通过化学偶联制备的,使用硫代琥珀酰亚胺结构(硫代琥珀酰亚胺连接)将小分子药物与靶向抗体或蛋白质偶联。硫代琥珀酰亚胺结构由巯基和马来酰亚胺反应形成。然而,硫代琥珀酰亚胺连接并不稳定。在生物体中,逆迈克尔加成或巯基与其他巯基交换导致细胞毒素从ADC脱落,导致脱靶毒性,这降低了安全性并限制了临床应用。
发明内容
在第一方面,本发明提供式(I)的化合物:
其中,
W是氢或LKb;
Y是氢或LKa-LKb;
条件是W和Y不同时为氢;
每个LKa独立选自
opSu为或其混合物;
每个LKb独立选自L2―L1―B;
每个B独立地为末端基团R10或以下1)、2)、3)的组合:1)自切除间隔子Sp1;2)键,或一个二价基团,或两个或更多个的二价基团的组合,其中所述二价基团选自:-CR1R2-、C1-10亚烷基、C4-10亚环烷基、C4-10亚杂环基和-(CO)-;和3)末端基团R10;
R10为氢或与负载物中的基团发生反应时可以离去的基团;
L1是包含可被酶裂解(cleave)的氨基酸序列的可裂解序列1(Cleavablesequence 1),可裂解序列1包含1-10个氨基酸;
L2是键;或C2-20亚烷基,其中亚烷基中的一个或多个-CH2-结构任选地被以下基团代替:-CR3R4-、-O-、-(CO)-、-S(=O)2-、-NR5-、-N⊕R6R7-、C4-10亚环烷基,C4-10亚杂环基、亚苯基;其中,亚环烷基、亚杂环基和亚苯基各自独立地未被取代或被选自卤素、-C1-10烷基、-C1-10卤代烷基、-C1-10亚烷基-NH-R8和-C1-10亚烷基-O-R9的至少一个取代基取代;
Ld2和每个Ld1独立地是键;或选自-NH-C1-20亚烷基-(CO)-、-NH-(PEG)i-(CO)-;或为侧链上各自独立地未取代或被-(PEG)j-R11取代的天然氨基酸或聚合度为2-10的寡聚天然氨基酸;
-(PEG)i-和-(PEG)j-均为PEG片段,包含指定数量的连续-(O-C2H4)-结构单元或连续-(C2H4-O)-结构单元,任选地在一个末端附加C1-10亚烷基;
R1、R2、R3、R4、R5、R6、R7、R8、R9各自独立地选自氢、卤素、-C1-10烷基、-C1-10卤代烷基、C4-10亚环烷基;
R11是C1-10烷基;
n是2-20的任意整数;
d是0,或1-6的任意整数;
每个i独立地为1-100的整数,优选1-20;优选地,每个i独立地为1-12的整数;更优选2-8;特别是4;
每个j独立地为1-100的整数,优选1-20;优选地,每个j独立地为1-12的整数;更优选8-12;特别是8或12。
在第二方面,本发明提供具有式(II)结构的化合物:
其中
Q是氢或LKb―P;
M是氢或LKa-LKb―P;
条件是Q和M不同时为氢;
P是与式(I)化合物的B部分或L1部分连接的负载物;
n、d、Ld1、Ld2、LKa和LKb如式(I)中所定义;
优选地,M是氢或LKa-L2―L1―B―P;其中每个B独立地不存在或为以下1)、2)的组合:1)自切除间隔子Sp1;和2)键,或一个二价基团,或两个或更多个的二价基团的组合,其中所述二价基团选自:-CR1R2-、C1-10亚烷基和-(CO)-;
优选地,Sp1选自PABC、乙缩醛、杂缩醛及其组合;更优选地,Sp1为缩醛、杂缩醛或PABC;进一步优选地,杂缩醛选自N,O-杂缩醛;更优选地,Sp1为-O-CH2-U-或-NH-CH2-U-;其中-O-或-NH-与可裂解序列1相连,U为O、S或NH,优选O或S。
在第三方面,本发明提供具有式(III)结构的缀合物:
其中,
n、d、Ld1、Ld2、LKa和LKb如式(I)中所定义;
Q是氢或LKb―P;
M是氢或LKa-LKb―P;
优选地,M是氢或LKa-L2―L1―B―P;其中
每个B独立地不存在或为以下1)、2)的组合:1)自切除间隔子Sp1;和2)键,或一个二价基团,或两个或更多个的二价基团的组合,其中所述二价基团选自:-CR1R2-、C1-10亚烷基和-(CO)-;优选地,B是-NH-CH2-U-或不存在或-NH-CH2-U-(CH2)g-(CO)-;
条件是Q和M不同时为氢;
P是与式(I)化合物的B部分或L1部分连接的负载物;
A是与式(I)化合物的Gn部分连接的靶向分子;G是甘氨酸;
z是1-20的整数。
在第四方面,本发明提供本发明的缀合物或其药物组合物在制备用于治疗疾病的药物中的用途;其中所述疾病是肿瘤或自身免疫性疾病。
附图说明
图1显示了缀合物和相应负载物在SK-BR-3HER2-高表达细胞系中的效力。
图2显示了缀合物和相应负载物在NCI-N87HER2-高表达细胞系中的效力。
图3显示了缀合物在CFPAC-1HER2-低表达细胞系中的效力。
图4显示了缀合物在NCI-H2110HER2-低表达细胞系中的效力。
图5显示了缀合物在MDA-MB-468HER2阴性细胞系中的效力。
图6显示了在具有JIMT1CDX模型的SCID Beige小鼠中随时间的平均肿瘤体积变化,该模型给药5mg/kg LC1184(8)、LC1184(4)、LC301-2-1(2)、LC302-2-1(4)、LC302-2-4(4)。
图7显示了在具有Capan-1CDX模型的BALB/c裸鼠中随时间的平均肿瘤体积变化,该模型给药5mg/kg LC1184(8)、LC1184(4)、LC301-2-1(2)、LC302-2-1(4)、LC302-2-4(4)。
图8显示了缀合物在混合的人血清中孵育0、24、48和96小时后的离体血清稳定性。
具体实施方式
下面提供具体实施方案来说明本发明的技术内容。本领域技术人员通过说明书中公开的内容可以很容易地理解本发明的其他优点和效果。本发明还可以通过其他不同的具体实施方式来实施或应用。本领域技术人员可以在不脱离本发明的精神的情况下进行各种修改和变化。
定义
除非下文另有定义,本文中使用的所有技术和科学术语与本领域技术人员通常理解的含义相同。本文使用的技术是指本领域通常理解的技术,包括对本领域技术人员显而易见的变体和等效替换。尽管相信以下术语是本领域技术人员容易理解的,但阐述以下定义以更好地说明本发明。当本文出现商品名称时,是指相应的商品或其活性成分。本文引用的所有专利、公开的专利申请和出版物均通过引用并入本文。
当以范围、优选范围或优选上限或优选下限的形式阐述某一量、浓度或其他数值或参数时,应理解为等同于具体揭示通过将任何上限或优选值与任何下限或优选值组合形成的任何范围,无论所述范围是否明确记载。除非另有说明,否则本文列出的数值范围旨在包括范围的端点以及范围内的所有整数和分数(小数)。例如,表述“i是1-20的整数”表示i是1-20的任意整数,例如i可以是1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。其他类似的表述例如j、k和g也应以类似的方式理解。
除非上下文另有明确规定,否则“一种(个)”和“该种(个)”等单数形式包括复数形式。表述“一种(个)或多种(个)”或“至少一种(个)”可表示1、2、3、4、5、6、7、8、9或更多。
术语“约”和“大约”当与数值变量一起使用时,通常意味着变量的值和变量的所有值都在实验误差范围内(例如,在平均值的95%置信区间内)或在指定值的±10%或更宽的范围内。
术语“化学计量比”是指将各种物质按一定的重量配比。例如,在本发明中,活性成分与填充剂、粘合剂和润滑剂以指定的重量比混合。
术语“可选”或“可选地”是指随后描述的事件可能发生但不一定发生,并且描述包括其中所述事件或情况发生或不发生的情况。
表述“包含”、“包括”、“含有”和“具有”是开放式的,并且不排除额外的未列举的元素、步骤或成分。表述“由……组成”不包括未指定的任何元素、步骤或成分。表述“基本上由...组成”是指范围限于指定的元素、步骤或成分,以及任选存在的不会实质性地影响要求保护的主题的基本和新颖特征的元素、步骤或成分。应当理解,表述“包含”包括表述“基本上由……组成”和“由……组成”。
术语“靶向分子”是指对特定靶标(例如,受体、细胞表面蛋白、细胞因子、肿瘤特异性抗原等)具有亲和力的分子。靶向分子可以通过靶向递送将负载物递送至体内特定位点。靶向分子可以识别一个或多个靶标。具体靶点由它识别的靶标定义。例如,靶向受体的靶向分子可以将细胞毒素递送到含有大量受体的位点。靶向分子的实例包括但不限于抗体、抗体片段、给定抗原的结合蛋白、抗体模拟物、对给定靶标具有亲和力的支架蛋白、配体等。
如本文所用,术语“抗体”以广泛的方式使用,特别包括完整的单克隆抗体、多克隆抗体、单特异性抗体、多特异性抗体(例如双特异性抗体)和抗体片段,只要它们具有所需的生物活性。抗体可以是任何亚型(例如IgG、IgE、IgM、IgD和IgA)或亚类,并且可以来源于任何合适的物种。在一些实施方案中,抗体是人或鼠源的。抗体也可以是全人抗体、人源化抗体或通过重组方法制备的嵌合抗体。
本文所用的单克隆抗体是指从基本上同质的抗体群体获得的抗体,即除了少数可能的天然突变外,构成群体的个体抗体是相同的。单克隆抗体对单个抗原位点具有高度特异性。“单克隆”一词是指抗体的特征来源于基本上同质的抗体群体,不应解释为需要一些特定的方法来产生抗体。
完整抗体或全长抗体基本上包含抗原结合可变区以及轻链恒定区(CL)和重链恒定区(CH),其可包括CH1,CH2、CH3和CH4,取决于抗体的亚型。抗原结合可变区(也称为片段可变区,Fv片段)通常包含轻链可变区(VL)和重链可变区(VH)。恒定区可以是具有天然序列的恒定区(例如具有人天然序列的恒定区)或其氨基酸序列变体。可变区识别靶标抗原并与之相互作用。恒定区可以被免疫系统识别并与之相互作用。
抗体片段可包含完整抗体的一部分,优选其抗原结合区或可变区。抗体片段的实例包括Fab、Fab'、F(ab')2、由VH和CH1结构域组成的Fd片段、Fv片段、单结构域抗体(dAb)片段和分离的互补决定区(CDR)。Fab片段是通过木瓜蛋白酶消化全长免疫球蛋白所获得的抗体片段,或通过例如重组表达产生的具有相同结构的片段。Fab片段包含轻链(包含VL和CL)和另一条链,其中所述另一条链包含重链的可变区(VH)和重链的一个恒定区(CH1)。F(ab')2片段是通过在pH 4.0-4.5下用胃蛋白酶消化免疫球蛋白所获得的抗体片段,或者通过例如重组表达产生的具有相同结构的片段。F(ab')2片段基本上包含两个Fab片段,其中每个重链部分包含几个额外的氨基酸,包括形成连接两个片段的二硫键的半胱氨酸。Fab'片段是包含F(ab')2片段的一半(一条重链和一条轻链)的片段。所述抗体片段可以包含连接在一起的多条链,例如通过二硫键和/或通过肽接头连接。抗体片段的实例还包括单链Fv(scFv)、Fv、dsFv、双抗、Fd和Fd'片段,以及其他片段,包括修饰片段。抗体片段通常包含至少或约50个氨基酸,通常至少或约200个氨基酸。抗原结合片段可以包括任何这样的抗体片段:其在被插入抗体框架时(例如,通过置换相应区域)时可以获得免疫特异性结合抗原的抗体。
本发明的抗体可以使用本领域熟知的技术制备,例如以下技术或其组合:重组技术、噬菌体展示技术、合成技术或本领域已知的其他技术。例如,基因工程重组抗体(或抗体模拟物)可以通过合适的培养系统(例如,大肠杆菌(E.Coli)或哺乳动物细胞)表达。所述工程化可以指例如在其末端引入连接酶特异性识别序列。
HER2是指人表皮生长因子受体-2,属于表皮生长因子(EGFR)受体酪氨酸激酶家族。在本申请中,术语ErbB2和HER2具有相同含义并且可以互换使用。
如本文所用,术语“靶向分子-药物缀合物”被称为“缀合物”。缀合物的实例包括但不限于抗体-药物缀合物。
小分子化合物是指大小与通常用于药物的有机分子相当的分子。该术语不涵盖生物大分子(例如蛋白质、核酸等),但涵盖低分子量肽或其衍生物,例如二肽、三肽、四肽、五肽等。通常小分子化合物的分子量例如可以为约100-约2000Da、约200-约1000Da、约200-约900Da、约200-约800Da、约200-约700Da、约200-约600Da、约200-约500Da。
细胞毒素是指抑制或阻止细胞的表达活性、细胞功能,和/或导致细胞破坏的物质。目前在ADC中通常使用的细胞毒素与化疗药物相比毒性更大。细胞毒素的实例包括但不限于靶向以下靶点的药物:微管细胞骨架、DNA、RNA、驱动蛋白介导的蛋白质转运、细胞凋亡的调节。靶向微管细胞骨架的药物例如可以为微管稳定剂或微管蛋白聚合抑制剂。微管稳定剂的实例包括但不限于紫杉烷类。微管蛋白聚合抑制剂的实例包括但不限于美登木素类(maytansinoid)、奥利斯他汀类(auristatin)、长春碱类、秋水仙碱类、海兔毒素类。靶向DNA的药物例如可以为直接破坏DNA结构的药物或拓扑异构酶抑制剂。直接破坏DNA结构的药物的实例包括但不限于DNA双链破坏剂(DNA double strand breaker)、DNA烷化剂、DNA嵌入剂(DNA intercalator)。DNA双链破坏剂例如可以为烯二炔类抗生素,包括但不限于达内霉素、埃斯培拉霉素、新制癌菌素、uncialamycin等。DNA烷化剂例如可以为DNA双烷化剂(bis-alkylator,即DNA交联剂(DNA-cross linker))或DNA单烷化剂(mono-alkylator)。DNA烷化剂的实例包括但不限于吡咯并[2,1-c][1,4]苯二氮类(PBD)二聚体、1-(氯甲基)-2,3-二氢-1H-苯并[e]吲哚(CBI)二聚体、CBI-PBD异二聚体、二氢吲哚并苯二氮(IGN)二聚体、duocarmycin类化合物(duocarmycin-like compound)等。拓扑异构酶抑制剂的实例包括但不限于exatecan及其衍生物(例如DX8951f、DXd-(1)和DXd-(2),其结构如下所述)、喜树碱类和蒽环类。靶向RNA的药物例如可以为抑制剪接的药物,其实例包括但不限于普拉地内酯(pladienolide)。靶向驱动蛋白介导的蛋白质转运的药物例如可以为有丝分裂驱动蛋白抑制剂,包括但不限于纺锤体驱动蛋白(KSP)抑制剂。
“间隔子(spacer)”是指位于不同结构模块之间,可以从空间上将结构模块间隔开的结构。间隔子的定义并不限定是否具有一定的功能,也不限定是否能在体内被切断或降解。间隔子的实例包括但不限于氨基酸和非氨基酸结构,其中非氨基酸结构可以但不限于是氨基酸衍生物或类似物。“间隔序列(Spacer sequence)”是指作为间隔子的氨基酸序列,其实例包括但不限于单个氨基酸、含有多个氨基酸的序列,例如含有两个氨基酸的序列,如GA等,或者例如GGGGS、GGGGSGGGGS、GGGGSGGGGSGGGGS等。自切除间隔子是共价组件,其使得前体中的保护性部分激活后两个化学键相继裂解:保护性部分(例如可切割序列)在激活后被去除,引发级联的分解反应,导致按先后顺序释放较小分子。自切除间隔子的实例包括但不限于PABC(对苄氧基羰基)、缩醛、杂缩醛及其组合。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团,其通过单键与分子的其余部分连接。烷基可以具有1-20个碳原子,指“C1-C20烷基”,例如C1-C4烷基、C1-C3烷基、C1-C2烷基、C3烷基、C4烷基、C3-C6烷基。烷基的非限制性实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基,或者它们的异构体。二价自由基是指由相应的一价自由基的具有自由价电子的碳原子去除一个氢原子从而获得的基团。二价自由基具有两个与分子其余部分相连的连接位点。例如“亚烷基”或“烷基亚基”指饱和的直链或支链的二价烃基。“亚烷基”的实例包括但不限于如亚甲基(-CH2-)、亚乙基(-C2H4-)、亚丙基(-C3H6-)、亚丁基(-C4H8-)、亚戊基(-C5H10-)、亚己基(-C6H12-)、1-甲基亚乙基(-CH(CH3)CH2-)、2-甲基亚乙基(-CH2CH(CH3)-)、甲基亚丙基或乙基亚丙基等。
如本文所用,当基团与另一基团进行组合时,基团之间的连接可以是线性或支化的,前提是形成化学上稳定的结构。通过这样的组合形成的结构可以通过该结构中的任意合适的原子与分子的其他部分连接,优选通过指定的化学键连接。例如,当两个或更多个选自-CR1R2-、C1-10亚烷基、C4-10亚环烷基、C4-10亚杂环基和-(CO)-的二价基团结合在一起形成组合,两个或更多个二价基团可以相互形成线性连接,例如-CR1R2-C1-10亚烷基-(CO)-、-CR1R2-C4-10亚环烷基-(CO)-、-CR1R2-C4-10亚环烷基-C1-10亚烷基-(CO)-、-CR1R2-CR1R2’-(CO)-、-CR1R2-CR1'R2'-CR1”R2”-(CO)-等。得到的二价结构可以进一步连接到分子的其他部分。
如本文所用,表述“抗体-偶联药物”和“抗体-药物缀合物”具有相同的含义。
式(I)的化合物
在第一方面,本发明提供式(I)的化合物:
其中,
W是氢或LKb;
Y是氢或LKa-LKb;
条件是W和Y不同时为氢;
每个LKa独立选自
opSu为或其混合物;
每个LKb独立选自L2―L1―B;
每个B独立地为末端基团R10或以下1)、2)、3)的组合:1)自切除间隔子Sp1;2)键,或一个二价基团,或两个或更多个的二价基团的组合,其中所述二价基团选自:-CR1R2-、C1-10亚烷基、C4-10亚环烷基、C4-10亚杂环基和-(CO)-;和3)末端基团R10;
R10为氢或与负载物中的基团发生反应时可以离去的基团;
L1是包含可被酶裂解的氨基酸序列的可裂解序列1,可裂解序列1包含1-10个氨基酸;
L2是键;或C2-20亚烷基,其中亚烷基中的一个或多个-CH2-结构任选地被以下基团代替:-CR3R4-、-O-、-(CO)-、-S(=O)2-、-NR5-、-N⊕R6R7-、C4-10亚环烷基,C4-10亚杂环基、亚苯基;其中,亚环烷基、亚杂环基和亚苯基各自独立地未被取代或被选自卤素、-C1-10烷基、-C1-10卤代烷基、-C1-10亚烷基-NH-R8和-C1-10亚烷基-O-R9的至少一个取代基取代;
Ld2和每个Ld1独立地是键;或选自-NH-C1-20亚烷基-(CO)-、-NH-(PEG)i-(CO)-;或为侧链上各自独立地未取代或被-(PEG)j-R11取代的天然氨基酸或聚合度为2-10的寡聚天然氨基酸;
-(PEG)i-和-(PEG)j-各自为PEG片段,包含指定数量的连续-(O-C2H4)-结构单元或连续-(C2H4-O)-结构单元,任选地在一个末端附加C1-10亚烷基;
R1、R2、R3、R4、R5、R6、R7、R8、R9各自独立地选自氢、卤素、-C1-10烷基、-C1-10卤代烷基、C4-10亚环烷基;
R11是C1-10烷基;
n是2-20的任意整数;
d是0或1-6的任意整数;
每个i独立地为1-100的整数,优选1-20;优选地,每个i独立地为1-12的整数;更优选2-8;特别是4;
每个j独立地为1-100的整数,优选1-20;优选地,每个j独立地为1-12的整数;更优选8-12;特别是8或12。
在一实施方案中,L2选自:-(CH2)p-(CH2)2(CO)-,p是0或1-5的整数;
b是1-10的整数。
在一实施方案中,上述L2结构中的羰基与L1相连,另一连接位点与opSu相连。
在一实施方案中,p是0-3;优选3。
Ld2和每个Ld1独立选自键,或
每个i、j和k独立选自1-100的整数。
在一实施方案中,每个i、j和k独立选自1-20的整数。在一实施方案中,每个i、j和k独立选自1-12的整数。
在一实施方案中,每个i独立选自2-8的整数;特别是4。
在一实施方案中,每个j独立选自8-12的整数;特别是8或12。
在一实施方案中,每个k独立选自1-7的整数;特别是1或3或5。
在一实施方案中,Ld2和每个Ld1独立选自键;或两端分别带有氨基和羰基的C1-20亚烷基,或两端分别带有氨基和羰基的一定长度的PEG片段(表示为-(PEG)i-),或一个或多个天然氨基酸,所述天然氨基酸侧链上各自独立地未取代或被一定长度的PEG片段(表示为-(PEG)j-)取代。
在一实施方案中,-(PEG)i-包含-(O-C2H4)i-或-(C2H4-O)i-,并且任选地在一个末端附加C1-10亚烷基;-(PEG)j-包含-(O-C2H4)j-或-(C2H4-O)j-,并且任选地在一个末端附加C1-10亚烷基。在一非常具体的实施方案中,-(PEG)i-中包含-C2H4-(O-C2H4)i-或-(C2H4-O)i-C2H4-。
应当理解,当分子中存在两个或更多个Ld1、B、L2或L1结构时,分别独立选择每个Ld1、B、L2或L1的结构。当分子中有两个或更多个Rx(x为1、2、3、4、5、6、7、8、9等)时,每个Rx独立选择。在一些实施方案中,分子中的“x”用或不用额外的单个撇号(’)或多个撇号(例如”、”’、””等)表示,例如R、R1’、R1”、R1”’、R2’、R2”、R2”’等,其中每个带有或不带有额外的单个撇号或多个撇号的Rx,都是独立选择的。其他Rx,如R3、R4、R5、R6、R7、R8、R9和“Ld1”、“B”、“L2”和“L1”,应以类似方式理解。在一些实施方案中,分子中的“i”用或不用附加数字表示,例如i1、i2、i3、i4等,其中数字不表示任何顺序,而仅用于区分“i”。并且每个带有或不带有附加数字的“i”,都是独立选择的。
在一实施方案中,可裂解序列1选自GLy-GLy-Phe-GLy、Phe-Lys、Val-Cit、Val-Lys、GLy-Phe-Leu-Gly、Ala-Leu-Ala-Leu、Ala-Ala-Ala及其组合;优选的可裂解序列1是GLy-GLy-Phe-Gly。
在一实施方案中,W是氢。
在一实施方案中,R11是C1-6烷基,优选甲基。
在一实施方案中,n是2-5的整数,特别是3。
在一实施方案中,d是0,或1-4的任意整数;优选0、1、2或3。
硫代琥珀酰亚胺在生理条件下不稳定,易发生逆迈克尔加成,导致在缀合位点裂解。此外,当系统中存在另一种巯基化合物时,硫代琥珀酰亚胺也可以与另一种巯基化合物进行巯基交换。这两种反应都会导致负载物脱落并产生毒副作用。在本发明中,当应用于连接子时,开环的琥珀酰亚胺结构不再发生逆迈克尔加成或巯基交换,因此产品更加稳定。开环反应的方法可以参见WO2015165413A1。
包含开环琥珀酰亚胺部分的化合物可以通过半制备型/制备型HPLC或其他合适的分离手段纯化以获得高纯度和确定的成分,而不管琥珀酰亚胺开环反应的效率如何。
包含连接酶受体或供体底物的识别序列的部分
在一实施方案中,式(I)化合物的Gn部分是连接酶受体或供体底物的识别序列,其在连接酶的催化下促进式(I)化合物与靶向分子的酶催化偶联。靶向分子任选地被修饰并且包含连接酶受体或供体底物的相应识别序列。
在一实施方案中,连接酶是转肽酶。在一实施方案中,连接酶选自以下组成的组:由天然转肽酶、非天然转肽酶、其变体及其组合。非天然转肽酶可以是但不限于通过工程化天然转肽酶获得的那些。在一优选的实施方案中,连接酶选自以下组成的组:天然Sortase酶、非天然Sortase酶及其组合。天然Sortase酶的种类包括Sortase A、Sortase B、SortaseC、Sortase D、Sortase L.plantarum等(US20110321183A1)。连接酶的类型对应于连接酶识别序列,从而用于实现不同分子或结构片段之间的特异性缀合。
在一些实施方案中,连接酶是Sortase酶,其选自Sortase A、Sortase B、SortaseC、Sortase D和Sortase L.plantarum。在这些实施方案中,连接酶受体底物的识别序列选自由寡聚甘氨酸、寡聚丙氨酸和聚合度为3-10的寡聚甘氨酸/丙氨酸混合物。在一特别的实施方案中,连接酶受体底物的识别序列为Gn,其中G为甘氨酸(Gly),n为2-10的整数。
在另一特别的实施方案中,连接酶是来自金黄色葡萄球菌(Staphylococcusaureus)的Sortase A。因此,连接酶识别序列可以是该酶的典型识别序列LPXTG。在又一特别的实施方案中,连接酶供体底物识别序列为LPXTGJ,连接酶受体底物识别序列为Gn,其中X可以是任何天然的或非天然的单个氨基酸;J不存在,或为包含1-10个氨基酸的氨基酸片段,可以任选地带有标签。在一实施方案中,J不存在。在又一实施方案中,J为包含1-10个氨基酸的氨基酸片段,其中每个氨基酸独立地为任何天然的或非天然的氨基酸。在另一实施方案中,J为Gm,其中m为1-10的整数。在又一特别的实施方案中,连接酶供体底物识别序列为LPETG。在另一特别的实施方案中,连接酶供体底物识别序列为LPETGG。
在一实施方案中,连接酶为来自金黄色葡萄球菌(Staphylococcus aureus)的Sortase B,对应的供体底物识别序列可以是NPQTN。在另一实施方案中,连接酶为来自炭疽杆菌(Bacillus anthracis)的Sortase B,对应的供体底物识别序列可以是NPKTG。
在又一实施方案中,连接酶为来自酿脓链球菌(Streptococcus pyogenes)的Sortase A,对应的供体底物识别序列可以是LPXTGJ,其中J如上文所定义。在另一实施方案中,连接酶为来自天蓝链霉菌(Streptomyces coelicolor)的Sortase subfamily 5,对应的供体底物识别序列可以是LAXTG。
在又一实施方案中,连接酶为来自植物乳杆菌(Lactobacillus plantarum)的Sortase A,对应的供体底物识别序列可以是LPQTSEQ。
连接酶识别序列也可以是人工筛选优化的其他全新的转肽酶识别序列。
包含活性基团部分
用于与负载物连接的活性基团
在一实施方案中,B是末端基团R10,并且L1中的可裂解序列1与负载物相连。在这种情况下,B不存在于可裂解序列1与负载物连接的所得分子中。在一实施方案中,B用于连接到负载物。为了与负载物连接,式(I)化合物包含活性基团。在一实施方案中,式(I)化合物中的B通过酰胺键或酯键或醚键连接至负载物。在一实施方案中,式(I)的B中的活性基团独立地为用于缩合反应、亲核加成或亲电加成的活性基团(例如活性C=O部分、活性C=C-C=O部分、氨基、胺基、羟基或巯基),或用于取代反应的活性基团(例如连接到O、C、N或S原子的离去基团)。在一实施方案中,B中的活性基团独立地选自羧基、活性酯、醛基、氨基、胺基、羟基和巯基。在一具体的实施方案中,B中用于连接负载物的活性基团独立地选自氨基、胺基、羟基、巯基、羧基和活性酯。
在一实施方案中,B中的活性基团独立地为氨基、胺基或羟基,其与负载物中的相应基团(例如羧基、磺酸基、具有游离-OH末端的磷酰基、活性酯、酰氯或异氰酸酯)反应。在另一实施方案中,B中的活性基团独立地为羧基或活性酯,其与负载物中的相应基团(例如氨基、胺基或羟基)反应。
在一实施方案中,B中的活性基团独立地为氨基、羟基或巯基,其与负载物中的相应基团(例如卤素、羟基、醛基)反应。在另一实施方案中,B中的活性基团独立地为羟基,其与负载物中的相应基团(例如卤素或羟基)反应。
在一实施方案中,每个B独立为R10或以下1)、2)、3)的组合:1)自切除间隔子Sp1;2)键,或一个二价基团,或两个或更多个的二价基团的组合,其中所述二价基团选自:-CR1R2-、C1-10亚烷基和-(CO)-;和3)末端基团R10。
在一实施方案中,Sp1选自PABC、缩醛、杂缩醛及其组合。在一实施方案中,Sp1是缩醛、杂缩醛或PABC。在一实施方案中,杂缩醛选自N,O-杂缩醛。在一实施方案中,Sp1是-O-CH2-U-或-NH-CH2-U-,其中-O-或-NH-连接到可裂解序列1。U是O、S或NH,优选O或S。在一实施方案中,U是O、S或N,优选O或S。
在一实施方案中,B是R10或者是-NH-CH2-U-R10或者是-NH-CH2-U-(CH2)g-(CO)-R10。
在一实施方案中,R10是氢、羟基;或在一实施方案中,R10是氢。在一实施方案中,R10是羟基或
在一实施方案中,R10代表不会出现在由B与负载物反应产生的产物分子中的结构部分。
式(I)化合物的具体实施方式
在一实施方案中,W是氢,每个Lka是在一实施方案中,式(I)的化合物具有式(I-1)的结构
在一实施方案中,Ld2是键,d是0。在一实施方案中,式(I-1)的化合物如下:(连接子LA301-1)
在一实施方案中,d是0,Ld2是在一实施方案中,式(I-1)的化合物如下:
(连接子LA301-2)
在一实施方案中,d是1、2或3,Ld2和每个Ld1独立地选自在一实施方案中,式(I-1)的化合物如下:
(连接子LA301-3)
(连接子LA301-4)
或
(连接子LA301-5)
在一实施方案中,Ld2是d是0。在一实施方案中,式(I-1)的化合物如下:
(连接子LA302-1)
在一实施方案中,d是1、2或3,Ld2是并且每个Ld1独立地选自在一实施方案中,式(I-1)的化合物如下:
(连接子LA302-2)
(连接子LA302-3)
或
(连接子LA302-4)
在一实施方案中,n是3,L2是-(CH2)p-(CH2)2(CO)-,p是3,L1是GGFG,B是-NH-CH2-U-R10或-R10或-NH-CH2-U-(CH2)g-(CO)-R10,U是O,g是1。在一实施方案中,连接子LA301-1具有以下结构:
在一实施方案中,连接子LA301-2具有以下结构:
在一实施方案中,连接子LA301-3具有以下结构:
在一实施方案中,连接子LA301-4具有以下结构:
在一实施方案中,连接子LA301-5具有以下结构:
在一实施方案中,连接子LA302-1具有以下结构:
在一实施方案中,连接子LA302-2具有以下结构:
在一实施方案中,连接子LA302-3具有以下结构:
在一实施方案中,连接子LA302-4具有以下结构:
在一实施方案中,i是4,g是1,R11是甲基。
在一实施方案中,连接子LA301-2如下(连接子LA301-2-1至LA301-2-3)所示:
(连接子LA301-2-1)
(连接子LA301-2-2)
(连接子LA301-2-3)
在一实施方案中,i是4,j是8,g是1,R11是甲基。在一实施方案中,连接子LA302-2如下(连接子LA302-2-1至LA302-2-3)所示:
(连接子LA302-2-1)
(连接子LA302-2-2)
(连接子LA302-2-3)
在一实施方案中,i是4,j是12,g是1,R11是甲基。在一实施方案中,连接子LA302-2如下(连接子LA302-2-4至LA302-2-6)所示:
(连接子LA302-2-4)
(连接子LA302-2-5)
(连接子LA302-2-6)
带有负载物的式(I)化合物
B所包含的活性基团与含有另一活性基团的负载物共价缀合,得到带有负载物的式(I)化合物。
在又一方面,本发明提供具有式(II)结构的化合物
其中
Q是氢或LKb―P;
M是氢或LKa-LKb―P;
条件是Q和M不同时为氢;
P是与式(I)化合物的B部分或L1部分连接的负载物;
n、d、Ld1、Ld2、LKa和LKb如式(I)中所定义。
如上文所定义的,式(I)化合物中的每个LKb独立选自L2―L1―B;每个B独立地为末端基团R10或以下1)、2)、3)的组合:1)自切除间隔子Sp1;2)键,或一个二价基团,或两个或更多个的二价基团的组合,其中所述二价基团选自:-CR1R2-、C1-10亚烷基、C4-10亚环烷基、C4-10亚杂环基和-(CO)-;和3)末端基团R10;R10为氢或与负载物中的基团发生反应时可以离去的基团。在一实施方案中,R10代表不会出现在由B与负载物反应产生的产物分子中的结构部分。
在一实施方案中,P与式(I)化合物的B部分连接,形成式(II)化合物。如上所述,式(II)化合物的B―P结构中不会出现R10。
应当理解,当式(I)化合物中的B为末端基团R10时,式(II)化合物中不会出现R10,因此,式(II)化合物的B―P结构中的B相应地不存在。
在一实施方案中,M是氢或LKa-L2―L1―B―P;其中P是与式(I)化合物的B部分或L1部分连接的负载物;每个B独立地为末端基团R10或以下1)、2)、3)的组合:1)自切除间隔子Sp1;2)键,或一个二价基团,或两个或更多个的二价基团的组合,其中所述二价基团选自:-CR1R2-、C1-10亚烷基、C4-10亚环烷基、C4-10亚杂环基和-(CO)-;和3)末端基团R10;R10为氢或与负载物中的基团发生反应时可以离去的基团;R10代表不会出现在由B与负载物反应产生的产物分子中的结构部分。
在一实施方案中,M是氢或LKa-L2―L1―B―P;其中每个B独立地不存在或为以下1)、2)的组合:1)自切除间隔子Sp1;和2)键,或一个二价基团,或两个或更多个的二价基团的组合,其中所述二价基团选自:-CR1R2-、C1-10亚烷基和-(CO)-。在一优选的实施方案中,M是氢或LKa-L2―L1―B―P;其中每个B独立地不存在,或者是-NH-CH2-U-,或者是-NH-CH2-U-(CH2)g-(CO)-。在另一实施方案中,M是LKa-L2―L1―B―P。在一实施方案中,LKa-L2―L1―B―P中的B不存在。在一实施方案中,LKa-L2―L1―B―P中的B为以下1)、2)的组合:1)自切除间隔子Sp1;和2)键,或一个二价基团,或两个或更多个的二价基团的组合,其中所述二价基团选自:-CR1R2-、C1-10亚烷基和-(CO)-。在一实施方案中,LKa-L2―L1―B―P中的B是-NH-CH2-U-或者是-NH-CH2-U-(CH2)g-(CO)-。U是O、S或NH,优选O或S。在一实施方案中,式(I)化合物中的B通过酰胺键或酯键或醚键连接至负载物。
如上所述,当式(I)化合物中的B是末端基团R10,式(II)化合物的B―P结构中的B相应地不存在。此时还可以理解为L1中的可裂解序列1连接到负载物以形成式(II)化合物,其中B不存在于可裂解序列1与负载物连接所得的分子中。因此,在一实施方案中,P与式(I)化合物的L1部分连接,形成式(II)化合物。因此,在一实施方案中,M是LKa-L2―L1―B―P并且B不存在,M还可以表示为LKa-L2―L1―P。
负载物
在本发明中,负载物可以选自由小分子化合物、核酸及核酸类似物、示踪分子(包括荧光分子等)、短肽、多肽、拟肽和蛋白质组成的组。在一实施方案中,负载物选自由小分子化合物、核酸分子、示踪分子组成的组。在一优选的实施方案中,负载物选自小分子化合物。在一更优选的实施方案中,负载物选自由细胞毒素及其片段组成的组。
在一实施方案中,细胞毒素选自由靶向微管细胞骨架的药物组成的组。在一优选的实施方案中,细胞毒素选自由紫杉烷类、美登木素类、奥利斯他汀类、埃博霉素类(epothilones)、康普瑞丁A-4磷酸盐(combretastatin A-4phosphate)、康普瑞丁A-4(combretastatin A-4)及其衍生物、吲哚-磺胺类、长春碱类如长春碱(vinblastine)、长春新碱(vincristine)、长春地辛(vindesine)、长春瑞滨(vinorelbine)、长春氟宁(vinflunine)、长春甘酯(vinglycinate)、脱水长春碱(anhy-drovinblastine)、尾海兔素10(dolastatin 10)及其类似物、软海绵素B、艾瑞布林(eribulin)、吲哚-3-氧乙酰酰胺类、鬼臼毒素类、7-二乙氨基-3-(2'-苯并噁唑基)-香豆素(DBC)、圆皮海绵内酯(discodermolide)、laulimalide组成的组。在另一实施方案中,细胞毒素选自由DNA拓扑异构酶抑制剂如喜树碱类及其衍生物、米托蒽醌、米托胍腙组成的组。在一优选的实施方案中,细胞毒素选自由氮芥类如苯丁酸氮芥、萘氮芥、胆磷酰胺(cholophosphamide)、雌莫司汀、异环磷酰胺、氮芥、盐酸氧化氮芥、美法仑、新氮芥、蛋氨氮芥、苯芥胆甾醇、泼尼莫司汀、曲磷胺、乌拉莫司汀组成的组。在又一优选的实施方案中,细胞毒素选自由亚硝基脲类如卡莫司汀、flubenzuron、福莫特罗、洛莫司汀、尼莫司汀、雷莫司汀组成的组。在一实施方案中,细胞毒素选自由氮杂环丙烷类组成的组。在一优选的实施方案中,细胞毒素选自由苯并多巴、卡波醌、美妥替哌和乌瑞替哌组成的组。在一实施方案中,细胞毒素选自由抗肿瘤抗生素组成的组。在一优选的实施方案中,细胞毒素选自由烯二炔抗生素组成的组。在一更优选的实施方案中,细胞毒素选自由达内霉素(dynemicin)、埃斯培拉霉素(esperamicin)、新制癌菌素、阿克拉霉素组成的组。在另一优选的实施方案中,细胞毒素选自由放线菌素、安曲霉素、博来霉素类、放线菌素C、卡拉比星、洋红霉素、抗癌霉素、洋红霉素、放线菌素D、柔红霉素、地托比星、阿霉素、表柔比星、依索比星、依达比星、麻西罗霉素、丝裂霉素类、诺拉霉素、橄榄霉素、培洛霉素、泊非霉素、嘌罗霉素、铁阿霉素、罗多比星、链黑霉素、链佐星、净司他丁、佐柔比星组成的组。在又一优选的实施方案中,细胞毒素选自由单端孢霉烯类组成的组。在一更优选的实施方案中,细胞毒素选自由T-2毒素、verracurin A、杆孢菌素A和安归啶(anguidine)组成的组。在一实施方案中,细胞毒素选自由抗肿瘤的氨基酸衍生物组成的组。在一优选的实施方案中,细胞毒素选自由乌苯美司、重氮丝氨酸、6-重氮基-5-氧代-L-正亮氨酸组成的组。在另一实施方案中,细胞毒素选自由叶酸类似物组成的组。在一优选的实施方案中,细胞毒素选自由二甲叶酸、甲氨蝶呤、蝶罗呤、三甲曲沙、依达曲沙组成的组。在一实施方案中,细胞毒素选自由嘌呤类似物组成的组。在一优选的实施方案中,细胞毒素选自由氟达拉滨、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤组成的组。在又一实施方案中,细胞毒素选自由嘧啶类似物组成的组。在一优选的实施方案中,细胞毒素选自由安西他滨、吉西他滨、依诺他滨、阿扎胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、二脱氧尿苷、去氧氟尿苷、氟尿苷组成的组。在一实施方案中,细胞毒素选自由雄激素类组成的组。在一优选的实施方案中,细胞毒素选自由卡普睾酮、丙酸屈他雄酮、环硫雄醇、美雄烷、睾内酯组成的组。在另一实施方案中,细胞毒素选自由抗肾上腺类组成的组。在一优选的实施方案中,细胞毒素选自由氨鲁米特、米托坦、曲洛司坦组成的组。在一实施方案中,细胞毒素选自由抗雄激素类组成的组。在一优选的实施方案中,细胞毒素选自由氟他胺、尼鲁米特、比卡鲁胺、醋酸亮丙瑞林和戈舍瑞林组成的组。在又一实施方案中,细胞毒素选自由蛋白激酶抑制剂及蛋白酶体抑制剂组成的组。在另一实施方案中,细胞毒素选自由长春碱类、秋水仙碱类、紫杉烷类、奥利斯他汀类、美登木素类、calicheamicin、doxonubicin、duocarmucin、SN-38、念珠藻素类似物(cryptophycin analog)、deruxtecan、duocarmazine、calicheamicin、centanamycin、dolastansine和pyrrolobenzodiazepine(PBD)组成的组。在一特别的实施方案中,细胞毒素选自由长春碱类、秋水仙碱类、紫杉烷类、奥利斯他汀类和美登木素类组成的组。
在一特别的实施方案中,细胞毒素是exatecan或其衍生物,例如DX8951f等。
在一特别的实施方案中,细胞毒素是美登木素,例如DM1等。应当注意,当使用包含巯基部分的细胞毒素时,巯基部分能够与马来酰亚胺部分反应以形成硫代琥珀酰亚胺,例如美登木素,例如DM1,细胞毒素可以通过硫代琥珀酰亚胺直接连接。在这种情况下,可以理解的是,在一些实施方案中,负载物和巯基部分一起构成细胞毒素,因此在这种情况下,负载物代表除了巯基部分之外的细胞毒素分子的其余部分。
在一特别的实施方案中,细胞毒素是奥利斯他汀(auristatin),例如MMAE(单甲基奥利斯他汀E)、MMAF(单甲基奥利斯他汀F)、MMAD(单甲基奥利斯他汀D)等。奥利斯他汀化合物的合成和结构描述于US20060229253中,其全部公开内容通过引用并入本文。
负载物含有可与式(I)化合物中的活性基团反应并因此将负载物与式(I)化合物共价缀合的活性基团。不含活性基团的化合物需要适当的衍生才能得到负载物。
在一特别的实施方案中,细胞毒素是以下式(i)的化合物
其中,g是1-6的任意整数;
在一实施方案中,g是1-3的任意整数,优选1。
在一实施方案中,细胞毒素选自以下化合物1-14;其中波浪键表示与式(I)化合物连接的连接位点。
在一些实施例中,负载物选自DX8951f(化合物9)、DXd-(1)(化合物10)和DXd-(2)(化合物14),优选DX8951f或DXd-(1),更优选DXd-(1)。
带有负载物的式(I)化合物的制备
在一实施方案中,连接单元和负载物通过如上定义的活性基团使用本领域已知的任何反应连接,包括但不限于缩合反应、亲核加成、亲电加成等。
在一实施方案中,负载物是细胞毒素。在一实施方案中,链接单元-负载物中间体(编号为LBx)如下表所示。
*:对于所有列出的连接子,n是3。
缀合物及其制备
此外,具有包含连接酶识别序列的部分的带有负载物的式(I)化合物可以与包含连接酶识别序列的其他分子缀合,从而可以用于例如靶向分子-药物缀合物的制备,例如抗体-药物缀合物。因此,在又一方面,本发明提供了一种缀合物,其包含式(I)化合物、靶向分子和负载物。
在又一方面,本发明提供具有式(III)结构的缀合物:
其中,
n、d、Ld1和Ld2如式(I)中所定义;
Q是氢或LKb―P;
M是氢或LKa-LKb―P;
条件是Q和M不同时为氢;
P是与式(I)化合物的B部分或L1部分连接的负载物;
A是与式(I)化合物的Gn部分连接的靶向分子;G是甘氨酸;
z是1-20的整数。
在一实施方案中,LKa和LKb如式(I)中所定义。
如上文所定义的,在一实施方案中,式(I)化合物的Gn部分是连接酶受体或供体底物的识别序列,其在连接酶的催化下促进式(I)化合物与靶向分子的酶催化偶联。靶向分子任选地被修饰并且包含连接酶受体或供体底物的相应识别序列。
应当理解,靶向分子A与式(I)化合物的Gn部分在连接酶的催化下缀合时,连接酶受体底物识别序列和连接酶供体底物识别序列反应得到相应的产物序列。
在一实施方案中,靶向分子A包含连接酶的供体底物识别序列LPXTGJ,其中J如上文所定义。当与连接酶的受体底物的相应识别序列Gn缀合时,LPXTGJ序列中甘氨酸的上游肽键被Sortase A裂解,生成的中间体连接到Gn的游离N端生成一个新的肽键。得到的氨基酸序列是LPXTGn。序列Gn和LPXTGJ如上所定义。
在一实施方案中,P与式(I)化合物的B部分或L1部分连接,A与式(I)化合物的Gn部分连接,形成式(III)化合物。
如上所述,式(III)化合物的B―P结构中不会出现R10。如上所述,当式(I)化合物中的B是末端基团R10,式(III)化合物的B―P结构中的B相应地不存在。
如上所述,式(III)化合物的A―Gn结构中,A任选包含连接酶受体底物识别序列和连接酶供体底物识别序列反应得到相应的产物序列。
在一实施方案中,M是氢或LKa-L2―L1―B―P;其中P是与式(I)化合物的B部分或L1部分连接的负载物;每个B独立地为末端基团R10或以下1)、2)、3)的组合:1)自切除间隔子Sp1;2)键,或一个二价基团,或两个或更多个的二价基团的组合,其中所述二价基团选自:-CR1R2-、C1-10亚烷基、C4-10亚环烷基、C4-10亚杂环基和-(CO)-;和3)末端基团R10;R10为氢或与负载物中的基团发生反应时可以离去的基团;R10代表不会出现在由B与负载物反应产生的产物分子中的结构部分。
在一实施方案中,M是氢或LKa-L2―L1―B―P;其中每个B独立地不存在或为以下1)、2)的组合:1)自切除间隔子Sp1;和2)键,或一个二价基团,或两个或更多个的二价基团的组合,其中所述二价基团选自:-CR1R2-、C1-10亚烷基和-(CO)-。在一优选的实施方案中,M是氢或LKa-L2―L1―B―P;其中每个B独立地不存在,或者是-NH-CH2-U-,或者是-NH-CH2-U-(CH2)g-(CO)-。在另一实施方案中,M是LKa-L2―L1―B―P。在一实施方案中,LKa-L2―L1―B―P中的B不存在。在一实施方案中,LKa-L2―L1―B―P中的B为以下1)、2)的组合:1)自切除间隔子Sp1;和2)键,或一个二价基团,或两个或更多个的二价基团的组合,其中所述二价基团选自:-CR1R2-、C1-10亚烷基和-(CO)-。在一实施方案中,LKa-L2―L1―B―P中的B是-NH-CH2-U-或者是-NH-CH2-U-(CH2)g-(CO)-。U是O、S或NH,优选O或S。在一实施方案中,式(I)化合物中的B通过酰胺键或酯键或醚键连接至负载物。在一实施方案中,M是LKa-L2―L1―B―P并且B不存在,M还可以表示为LKa-L2―L1―P。
靶向分子
在一实施方案中,靶向分子是抗体或其抗原结合片段。
在一实施方案中,靶向分子是抗人HER2抗体或其抗原结合片段。抗人HER2抗体的实例包括但不限于帕妥珠单抗(Pertuzumab)和曲妥珠单抗(Trastuzumab)。帕妥珠单抗与HER2的第二个细胞外结构域(ECD2)结合,并被批准用于治疗HER2阳性乳腺癌。曲妥珠单抗与HER2的第四个细胞外结构域(ECD4)结合,被批准用于治疗HER2阳性乳腺癌和胃癌。
在一优选的实施方案中,抗人HER2抗体是一种或多种选自基于曲妥珠单抗的工程化抗HER2抗体。
在一优选的实施方案中,抗人HER2抗体是重组抗体,其选自单克隆抗体、嵌合抗体、人源化抗体、抗体片段和抗体模拟物。在一实施方案中,抗体模拟物选自scFv、微型抗体、双抗、纳米抗体。对于与式(I)化合物的缀合,本发明的靶向分子可包含修饰部分以连接式(I)化合物中的D1或D2。此类修饰部分的引入位置不受限制,例如,当靶向分子为抗体时,其引入位置可以但不限于位于抗体的重链或轻链的C端或N端。
在一可选的实施方案中,用于与式(I)化合物中的D1或D2缀合的修饰部分可以使用例如化学修饰方法在抗体的重链或轻链的非末端位置引入。
在一实施方案中,本发明的靶向分子是抗体或其抗原结合片段,其可以包含末端修饰。末端修饰是指在抗体的重链或轻链的C末端或N末端的修饰,其例如包含连接酶识别序列。在另一实施方案中,末端修饰可以进一步包含包含2-100个氨基酸的间隔子Sp2,其中抗体、Sp2和连接酶识别序列顺序连接。在一优选的实施方案中,Sp2是包含2-20个氨基酸的间隔子序列。在一特别的实施方案中,Sp2是选自GA、GGGGS、GGGGSGGGGS和GGGGSGGGGSGGGGS的间隔子序列,特别是GA。
在一优选的实施方案中,所述抗体或其抗原结合片段的轻链包括3种类型:野生型(LC);通过直接引入连接酶识别序列LPXTG进行修饰的C-端修饰轻链(LCCT)和通过引入短肽间隔子和连接酶供体底物识别序列LPXTG进行修饰的C-末端修饰轻链(LCCTL)。抗体或其抗原结合片段的重链包括3种类型:野生型(HC);通过直接引入连接酶识别序列LPXTG进行修饰的C-端修饰重链(HCCT)和通过引入短肽间隔子和连接酶供体底物识别序列LPXTG进行修饰的C-末端修饰重链(HCCTL)。X可以是任何天然或非天然的单个氨基酸。当式(VII)化合物中的z为1或2时,上述重链和轻链组合可形成8个优选的抗体分子,见氨基酸序列表。
本发明的缀合物可以进一步包含负载物。负载物如上所述。
缀合物具体实施方式
在一实施方案中,Q是氢,每个Lka是在一实施方案中,式(III)的化合物具有式(III-1)的结构:
在一实施方案中,Ld2是键,d是0。在一实施方案中,式(III-1)的化合物如下:
(缀合物LC301-1)
在一实施方案中,d是0,Ld2是在一实施方案中,式(III-1)的化合物如下:
(缀合物LC301-2)
在一实施方案中,d是1、2或3,Ld2和每个Ld1独立地选自在一实施方案中,式(III-1)的化合物如下:
(缀合物LC301-3)
(缀合物LC301-4)
(缀合物LC301-5)
在一实施方案中,Ld2是d是0。在一实施方案中,式(III-1)的化合物如下:
(缀合物LC302-1)
在一实施方案中,d是1、2或3,Ld2是并且每个Ld1独立地选自在一实施方案中,式(III-1)的化合物如下:
(缀合物LC302-2)
(缀合物LC302-3)
(缀合物LC302-4)。
在一实施方案中,z是1-4;在一实施方案中,z是2或4;在一实施方案中,z是2;在一实施方案中,在缀合物LC301-1、LC301-2、LC302-1中,z是2或4。在一实施方案中,在缀合物LC301-3、LC301-4、LC301-5、LC302-2、LC302-3和LC302-4中,z是2。
在一实施方案中,式(I)化合物中的B是末端基团R10,并且L1中的可裂解序列1连接到负载物以形成式(II)化合物,其中B不存在于可裂解序列1与负载物连接所得的分子中。此时也可以理解为M是LKa-L2―L1―B―P并且B不存在。此时,M还可以表示为LKa-L2―L1―P。在一实施方案中,n是3,L2是-(CH2)p-(CH2)2(CO)-,p是3,L1是GGFG,B是-NH-CH2-U-或不存在或-NH-CH2-U-(CH2)g-(CO)-,U是O,g是1。在一实施方案中,缀合物LC301-1具有以下结构:
在一实施方案中,缀合物LC301-2具有以下结构:
在一实施方案中,缀合物LC301-3具有以下结构:
在一实施方案中,缀合物LC301-4具有以下结构:
在一实施方案中,缀合物LC301-5具有以下结构:
在一实施方案中,缀合物LC302-1具有以下结构:
在一实施方案中,缀合物LC302-2具有以下结构:
在一实施方案中,缀合物LC302-3具有以下结构:
在一实施方案中,缀合物LC302-4具有以下结构:
在一实施方案中,i是4,g是1,R11是甲基。
在一实施方案中,缀合物LC301-2如下(缀合物LC301-2-1)所示:
(缀合物LC301-2-1)
在一实施方案中,i是4,j是8,g是1,R11是甲基。在一实施方案中,缀合物LC302-2如下(缀合物LC302-2-1)所示:
(缀合物LC302-2-1)
在一实施方案中,i是4,j是12,g是1,R11是甲基。在一实施方案中,缀合物LC302-2如下(缀合物LC302-2-4)所示:
(缀合物LC302-2-4)
缀合物的制备
本发明的缀合物可以通过本领域已知的任何方法制备。在一些实施方案中,缀合物通过靶向分子和带有负载物的式(I)化合物在连接酶催化下进行位点特异性缀合来制备,其中靶向分子被连接酶识别序列修饰。所述方法包含步骤A和步骤B。
步骤A.连接单元-负载物中间体的制备
在一优选的实施方案中,式(I)化合物中的B通过活性基团共价连接到含有另一活性基团的负载物上。
使用本发明的式(I)化合物制备的连接单元-负载物中间体结构明确、组成明确、纯度高,使得在与抗体进行偶联反应时,引入的杂质较少或没有其他杂质引入。当这样的中间体用于在连接酶催化下与含有连接酶识别序列的修饰抗体进行位点特异性缀合时,获得了具有高度可控质量的同质ADC。
步骤B.将靶向分子连接到带有负载物的式(I)化合物
本发明的靶向分子可以通过本领域已知的任何方法与带有负载物的式(I)化合物(即,式(II)的化合物)缀合。
靶向分子和带有负载物的式(I)化合物通过底物的连接酶特异性识别序列相互连接。识别序列取决于所使用的特定连接酶。在一实施方案中,靶向分子是在轻链和/或重链的C端引入基于识别序列的末端修饰的抗体,并且在野生型或优化的工程连接酶或其任何组合的催化,以及在合适的催化反应条件下靶向分子与式(II)化合物缀合。
在一具体的实施方案中,连接酶是Sortase A,缀合反应可以由以下方案表示:
三角形代表抗体的一部分;并且五边形代表式(II)化合物的一部分。n、X和J分别如上所定义。当与受体底物的相应识别序列Gn缀合时,LPXTGJ序列中甘氨酸的上游肽键被Sortase A裂解,生成的中间体连接到Gn的游离N端生成一个新的肽键。得到的氨基酸序列是LPXTGn。序列Gn和LPXTGJ如上所定义。
缀合物在生理环境中的代谢
当肿瘤细胞中的部分或全部连接子被裂解时,抗肿瘤化合物部分被释放以表现出抗肿瘤化合物的抗肿瘤作用。由于连接子在与药物的连接位置被裂解,抗肿瘤化合物以其固有结构释放以显示其固有的抗肿瘤作用。
在一实施方案中,可裂解序列1(例如GGFG)可以被溶酶体酶(例如组织蛋白酶B和/或组织蛋白酶L)裂解。
在一实施方案中,Sp1包含自切除间隔子。在一实施方案中,Sp1包含PABC、缩醛或杂缩醛。在一实施方案中,L1是GGFG。在一实施方案中,连接子包含-GGFG-NH-CH2-O-。在一实施方案中,-GGFG-NH-CH2-O-代表限制酶位点和自切除间隔子的组合,其将在细胞中裂解并释放目标分子(例如药物)。
具体缀合物表格
在一实施方案中,负载物是细胞毒素或其片段。在一实施方案中,抗体是修饰的曲妥珠单抗,优选Ab0001-LCCTL-HC(轻链SEQ ID NO:1,重链:SEQ ID NO:2)或Ab0001-LCCTL-HCCTL(轻链SEQ ID NO:3,重链:SEQ ID NO:4)。Ab0001-LCCTL-HC和Ab0001-LCCTL-HCCTL的序列均基于Ab0001(曲妥珠单抗)的氨基酸序列,在轻链的C端引入GALPETGG(Ab0001-LCCTL-HC)或在轻链和重链的C端引入GALPETGG(Ab0001-LCCTL-HCCTL),其中LPETGG是连接酶供体底物的识别序列,GA是间隔子序列。在Ab0001-LCCTL-HCCTL中,Ab0001重链C端的赖氨酸可以保持,如SEQ ID NO:4,或可以在引入GALPETGG之前删除(序列列表中未显示结果序列)。在一实施方案中,抗体-药物缀合物如下表所示。
ADC的命名法:括号中的数字表示意图连接到抗体的负载物(药物)分子的数量。
药物组合物和药物制剂
本发明的另一目的是提供一种药物组合物,其包含预防或治疗有效量的本发明的缀合物,以及至少一种药学上可接受的载体。
本发明的药物组合物可以以任何方式给药,只要其达到预防、缓解、预防或治疗人或动物的症状的效果即可。例如,可以根据给药途径制备各种合适的剂型,特别是注射剂如冻干粉针剂、注射剂或无菌注射剂粉剂。
术语“药学上可接受的”是指在正常医学判断范围内与患者组织接触时,不产生不应有的毒性、刺激性或过敏反应等,具有合理的优劣比,对预期用途有效。
术语药学上可接受的载体是指那些药学上可接受的并且不干扰缀合物的生物活性和性能的载体材料。水性载体的实例包括但不限于缓冲盐水等。药学上可接受的载体还包括使组合物接近生理条件的载体物质,例如pH调节剂和缓冲剂、毒性调节剂等,乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。
在一实施方案中,本发明的药物组合物的药物/抗体比(DAR)为1-20的整数或非整数,例如约1-约10、约1-约8、约1-约6、约1-约4、约1-3约、约1-约2.5、约1-约2。在一特别的实施方案中,本发明的缀合物的DAR为约2、约4、约6或约8。
治疗方法和用途
本发明的缀合物可用于治疗肿瘤和/或自身免疫疾病。对缀合物治疗敏感的肿瘤包括以特定肿瘤相关抗原或细胞表面受体为特征的肿瘤,这些肿瘤细胞能被缀合物中的靶向分子识别,进而可以被缀合物中的负载物/细胞毒素杀伤。
因此,在又一方面,本发明还提供本发明的缀合物或本发明的药物组合物在制备治疗疾病、病症或病况的药物中的用途,所述疾病、病症或病况选自肿瘤或自身免疫疾病。
在另一方面,本发明提供本发明的缀合物或本发明的药物组合物,用于治疗肿瘤或自身免疫疾病。
在进一步的方面,本发明提供一种治疗肿瘤或自身免疫疾病的方法,所述方法包括向有此需要的个体给药有效量的本发明的缀合物或本发明的药物组合物。
在一优选的实施方案中,本发明提供的抗人HER2抗体与小分子细胞毒素连接形成的缀合物可与肿瘤细胞表面的HER2特异结合,选择性杀伤表达HER2的肿瘤细胞。在另一优选的实施方案中,本发明提供本发明的缀合物或本发明的药物组合物在制备治疗疾病、病症或病况的药物中的用途,所述疾病、病症或病况选自HER2阳性的肿瘤。在一更优选的实施方案中,所述疾病、病症或病状选自由乳腺癌、胃癌、肺癌、卵巢癌和尿路上皮癌等组成的组。
给予受试者的缀合物的剂量可以在相当大的程度上进行调整。剂量可以根据具体的给药途径和受试者的需要而变化,并且可以经过医疗保健专业人员的判断。
如前所述,本发明的实施方案还可以列举如以下[1]至[17]:
[1]一种式(I’)的化合物:
其中,
W是氢或LKb;
Y是氢或LKa-LKb;
条件是W和Y不同时为氢;
每个LKa独立选自
opSu为或其混合物;
每个LKb独立选自L2―L1―B;
每个B独立地为末端基团R10或以下1)、2)、3)的组合:1)自切除间隔子Sp1;2)键,或一个二价基团,或两个或更多个的二价基团的组合,其中所述二价基团选自:-CR1R2-、C1-10亚烷基、C4-10亚环烷基、C4-10亚杂环基和-(CO)-;和3)末端基团R10;
R10为氢或与负载物中的基团发生反应时可以离去的基团;
L1是包含可被酶裂解的氨基酸序列的可裂解序列1,可裂解序列1包含1-10个氨基酸;
L2是键;或C2-20亚烷基,其中亚烷基中的一个或多个-CH2-结构任选地被以下基团代替:-CR3R4-、-O-、-(CO)-、-S(=O)2-、-NR5-、-N⊕R6R7-、C4-10亚环烷基,C4-10亚杂环基、亚苯基;其中,亚环烷基、亚杂环基和亚苯基各自独立地未被取代或被选自卤素、-C1-10烷基、-C1-10卤代烷基、-C1-10亚烷基-NH-R8和-C1-10亚烷基-O-R9的至少一个取代基取代;
Ld2和每个Ld1独立地是键;或选自-NH-C1-20亚烷基-(CO)-、-NH-(PEG)i-(CO)-;或为侧链上各自独立地未取代或被-(PEG)j-R11取代的天然氨基酸或聚合度为2-10的寡聚天然氨基酸;
-(PEG)i-和-(PEG)j-各自为PEG片段,包含指定数量的连续-(O-C2H4)-结构单元或连续-(C2H4-O)-结构单元,任选地在一个末端附加C1-10亚烷基;
R1、R2、R3、R4、R5、R6、R7、R8、R9各自独立地选自氢、卤素、-C1-10烷基、-C1-10卤代烷基、C4-10亚环烷基;
R11是C1-10烷基;
n是2-20的任意整数;
d是0或1-6的任意整数;
每个i独立地为1-100的整数,优选1-20;优选地,每个i独立地为1-12的整数;更优选2-8;特别是4;
每个j独立地为1-100的整数,优选1-20;优选地,每个j独立地为1-12的整数;更优选8-12;特别是8或12。
[2]上述[1]所述的化合物,选自
[3]上述[1]-[2]中任一项所述的化合物,选自
(连接子LA’301-1)
(连接子LA’301-2)
((连接子LA’301-3)
(连接子LA’301-4)
(连接子LA’301-5)
(连接子LA’302-1)
(连接子LA’302-2)
(连接子LA’302-3)
(连接子LA’302-4)
其中,每个i、i1、i2、i3、i4各自独立地为1-100的整数,优选为1-20;优选地,每个i、i1、i2、i3、i4各自独立地为1-12的整数;更优选2-8;特别是4。
[4]上述[1]-[2]中任一项所述的化合物,其中
Ld2和每个Ld1独立选自键,或
每个k独立地为1-100的整数,优选1-20;优选地,每个k独立地为1-12的整数;更优选1-7;特别是1、3或5。
[5]上述[1]-[4]中任一项所述的化合物,其中
可裂解序列1选自GLy-GLy-Phe-GLy、Phe-Lys、Val-Cit、Val-Lys、GLy-Phe-Leu-Gly、ALA’-Leu-ALA’-Leu、ALA’-ALA’-Ala及其组合;优选的可裂解序列1是GLy-GLy-Phe-Gly;
和/或
Sp1选自PABC、乙缩醛、杂缩醛及其组合;优选地,Sp1为缩醛、杂缩醛或PABC;优选地,杂缩醛选自N,O-杂缩醛;优选地,Sp1为-O-CH2-U-或-NH-CH2-U-;其中-O-或-NH-与可裂解序列1相连,U为O、S或N,优选O或S。
[6]上述[1]-[5]中任一项所述的化合物,其中
W是氢;和/或
R10是氢、羟基;或
R11是C1-6烷基,优选甲基;和/或
n是2-5的整数,特别是3;和/或
d是0,或1-4的任意整数;优选0、1、2或3。
[7]上述[1]-[6]中任一项所述的化合物,选自
每个i、i1、i2、i3、i4各自独立为1-100的整数,优选为1-20;优选地,每个i、i1、i2、i3、i4各自独立地为1-12的整数;更优选2-8;特别是4;每个g独立地为1-6的整数,优选1-3;更优选1。
[8]一种具有式(II’)结构的化合物:
其中
Q是氢或LKb―P;
M是氢或LKa-LKb―P;
条件是Q和M不同时为氢;
P是与式(I’)化合物的B部分或L1部分连接的负载物;
n、d、Ld1、Ld2、LKa和LKb上述[1]中所定义。
[9]一种具有式(III’)结构的缀合物:
其中,
n、d、Ld1和Ld2上述[1]中所定义;
Q是氢或LKb―P;
M是氢或LKa-LKb―P;
条件是Q和M不同时为氢;
P是与式(I’)化合物的B部分或L1部分连接的负载物;
A是与式(I’)化合物的Gn部分连接的靶向分子;G是甘氨酸;
z是1-20的整数。
[10]上述[9]所述的缀合物,其中
所述缀合物具有下式(III’-1)的结构:
[11]上述[9]或[10]所述的缀合物,其中
所述缀合物具有以下结构:
(缀合物LC’301-1)
(缀合物LC’301-2)
(缀合物LC’301-3)
(缀合物LC’301-4)
(缀合物LC’301-5)
(缀合物LC’302-1)
(缀合物LC’302-2)
(缀合物LC’302-3)
(缀合物LC’302-4)
优选地,z是1-4;优选2;
每个i、i1、i2、i3、i4各自独立地为1-100的整数,优选为1-20;优选地,每个i、i1、i2、i3、i4各自独立地为1-12的整数;更优选2-8;特别是4;
每个j独立地为1-100的整数,优选1-20;优选地,每个j独立地为1-12的整数;更优选8-12;特别是8或12。
[12]上述[9]-[11]中任一项所述的缀合物,其中
所述靶向分子是抗体或其抗原结合片段;优选修饰所述抗体或抗原结合片段以与式(I’)化合物中的Gn部分连接;
优选地,所述抗体是抗人HER2抗体。
[13]上述[9]-[12]中任一项所述的缀合物,其中
所述负载物是细胞毒素或其片段,具有任选的衍生化以连接到式(I’)化合物中的B部分或L1部分;
优选地,细胞毒素选自由紫杉烷类、美登木素类、奥利斯他汀类、埃博霉素类(epothilones)、康普瑞丁A-4磷酸盐(combretastatin A-4phosphate)、康普瑞丁A-4(combretastatin A-4)及其衍生物、吲哚-磺胺类、长春碱类如长春碱(vinblastine)、长春新碱(vincristine)、长春地辛(vindesine)、长春瑞滨(vinorelbine)、长春氟宁(vinflunine)、长春甘酯(vinglycinate)、脱水长春碱(anhy-drovinblastine)、尾海兔素10(dolastatin 10)及其类似物、软海绵素B、艾瑞布林(eribulin)、吲哚-3-氧乙酰酰胺类、鬼臼毒素类、7-二乙氨基-3-(2'-苯并噁唑基)-香豆素(DBC)、圆皮海绵内酯(discodermolide)、laulimalide、喜树碱类及其衍生物、米托蒽醌、米托胍腙、氮芥类、亚硝基脲类、氮杂环丙烷类、苯并多巴、卡波醌、美妥替哌、乌瑞替哌、达内霉素(dynemicin)、埃斯培拉霉素(esperamicin)、新制癌菌素、阿克拉霉素、放线菌素、安曲霉素、博来霉素、放线菌素C、卡拉比星、洋红霉素、抗癌霉素、洋红霉素、放线菌素D、柔红霉素、地托比星、阿霉素、表柔比星、依索比星、依达比星、麻西罗霉素、丝裂霉素类、诺拉霉素、橄榄霉素、培洛霉素、泊非霉素、嘌罗霉素、铁阿霉素、罗多比星、链黑霉素、链佐星、净司他丁、佐柔比星、单端孢霉烯类、T-2毒素、verracurin A、杆孢菌素A、安归啶(anguidine),乌苯美司、重氮丝氨酸、6-重氮基-5-氧代-L-正亮氨酸,二甲叶酸、甲氨蝶呤、蝶罗呤、三甲曲沙、依达曲沙、氟达拉滨、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤、安西他滨、吉西他滨、依诺他滨、阿扎胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、二脱氧尿苷、去氧氟尿苷、氟尿苷、卡普睾酮、丙酸屈他雄酮、环硫雄醇、美雄烷、睾内酯、氨鲁米特、米托坦、曲洛司坦、氟他胺、尼鲁米特、比卡鲁胺、醋酸亮丙瑞林、蛋白激酶抑制剂和蛋白酶体抑制剂组成的组;和/或
选自长春碱类、秋水仙碱类、紫杉烷类、奥利斯他汀类、美登木素类、calicheamicin、doxonubicin、duocarmucin、SN-38、念珠藻素类似物(cryptophycinanalog)、deruxtecan、duocarmazine、calicheamicin、centanamycin、dolastansine、pyrrolobenzodiazepine和exatecan及其衍生物;和/或
选自奥利斯他汀(auristatin),尤其是MMAE、MMAF或MMAD;和/或
选自exatecan及其衍生物,例如DX8951f;和/或
选自DXd-(1)和DXd-(2);优选DXd-(1)。
[14]上述[9]-[13]中任一项所述的缀合物,其中所述负载物选自
特别是选自
[15]上述[9]-[14]中任一项所述的缀合物,其中
每个g独立为1-6的整数,优选1-3;更优选1。
[16]一种药物组合物,其包含预防或治疗有效量的上述[9]-[15]中任一项所述的缀合物,以及至少一种药学上可接受的载体。
[17]上述[9]-[15]中任一项所述的缀合物或上述[16]所述的药物组合物在制备用于治疗疾病的药物中的用途;其中所述疾病是肿瘤或自身免疫性疾病;优选HER2阳性肿瘤;
优选地,所述HER2阳性肿瘤选自乳腺癌、胃癌、肺癌、卵巢癌和尿路上皮癌。
有益效果
本发明的抗体-药物缀合物使用特别设计的连接子-负载物,更稳定,在较低的DAR下能达到很好的疗效,因此可以减少副作用,提高治疗指数。
本发明利用具有独特结构的连接单元并使用连接酶催化靶向分子与负载物的缀合。本发明的缀合物均质性好、活性高、选择性高。此外,连接单元-负载物中间体的毒性远低于游离负载物,因此药物的制造过程危害较小,有利于工业化生产。
本发明的缀合物实现至少一种以下技术效果:
(1)对靶标细胞有高抑制活性,或对靶细胞有较强杀伤作用。
(2)优异的物理化学性质(例如溶解度、物理和/或化学稳定性)。
(3)优异的药物代谢动力学性质(例如在血浆中良好的稳定性、合适的半衰期和作用持续时间)。
(4)优异的安全性(对非靶标的正常细胞或组织较低的毒性和/或较少的副作用,较宽的治疗窗)等。
(5)高度模块化设计,能简单地组装多种药物。
实施例
制备实施例
为了更清楚地说明本发明的目的和技术方案,下面结合具体实施例对本发明作进一步的说明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未提及的具体实验方法,均按照常规实验方法进行。
仪器、材料与试剂
除非特别说明,实施例中所使用的仪器和试剂均为可商购的。试剂可以不经进一步纯化而直接使用。
MS:Thermo Fisher Q Exactive Plus,Water2795-Quattro微型三重四级杆质谱仪
HPLC:Waters 2695、Agilent 1100、Agilent 1200
半制备HPLC:Lisure HP plus 50D
流式细胞仪CytoFLEX S
HIC-HPLC:Butyl-HIC;流动相A液:25mM PB、2M(NH4)2SO4、pH 7.0;流动相B:25mMPB、pH 7.0;流速:0.8ml/min;采集时间:25min;进样量:20μg;柱温:25℃;检测波长:280nm;样品箱温度:8℃。
SEC-HPLC:色谱柱:TSK-gel G3000SWXL、TOSOH 7.8mm ID×300mm、5μm;流动相:0.2M KH2PO4、0.25M KCl、pH 6.2;流速:0.5ml/min;采集时间:30min;进样体积:50μg;柱温:25℃;检测波长:280nm;样品盘温度:8℃。
CHO细胞获得自Thermo Fisher Scientific;pcDNA3.3获得自Life Technology;HEK293F获得自普瑞金(Prejin);PEIMAX转染试剂获得自Polyscience;MabSelect SureProA获得自GE;Capto S ImpAct获得自GE;Rink-amide-MBHA-树脂及二氯树脂获得自南开合成(Nankai synthesis);HCC1954获得自ATCC CAT#CRL-2338;SK-BR-3获得自ATCC CAT#HTB-30;BT-474获得自ATCC CAT#HTB-20;NCI-N87(ATCC Cat#CRL-5822);MCF7获得自ATCCCAT#HTB-22;MDA-MB-231获得自ATCC CAT#HTB-26;MDA-MB-468获得自ATCC CAT#HTB-132;CFPAC-1获得自ATCC CAT#CRL-1918;NCI-H2110获得自ATCC CAT#CRL-5924;JIMT-1获得自Wuxi Apptech;Capan-1获得自ATCC CAT#CRL-1573;抗体曲妥珠单抗按照已知序列制备;在大肠杆菌(E.coli)中制备源自金黄色葡萄球菌(Staphylococcus aureus)的优化重组酶Sortase A。
实施例1抗体表达载体的构建、抗体表达、纯化及鉴定
1.1修饰的抗人HER2抗体Ab0001-LCCTL-HC的生产
抗体Ab0001-LCCTL-HC(轻链SEQ ID NO:1,重链:SEQ ID NO:2)的表达质粒如下构建。抗体Ab0001-LCCTL-HC的序列:基于曲妥珠单抗的氨基酸序列,在轻链C端引入GALPETGG,其中LPETGG为连接酶供体底物的识别序列,GA为间隔子序列。将质粒转染CHO细胞,建立细胞群并筛选高表达细胞群,参照曲妥珠单抗在5-10L反应器中的培养过程进行培养,收集上清液。
1.2抗体Ab0001-LCCTL-HC的纯化
Ab0001-LCCTL-HC的纯化采用MabSelect亲和层析和Sepharose S阳离子交换层析相结合的标准工艺进行,纯化的产物溶解在原曲妥珠单抗药物缓冲液(5mM组氨酸-HCl、2%海藻糖、0.009%聚山梨醇酯20,PH 6.0),并以小等份冷冻。
1.3抗体Ab0001-LCCTL-HC的质量控制
上述通过SDS-PAGE纯化的抗体Ab0001-LCCTL-HC的纯度为98.5%;SEC-HPLC检测到样品中高分子聚合物的含量小于0.4%;内毒素含量小于0.098EU/mg。
1.4其他修饰抗人抗体的制备
根据类似的方法,在曲妥珠单抗轻链和/或重链的C端分别引入基于连接酶识别序列的末端修饰,得到修饰抗体。
基于Ab0001(曲妥珠单抗)的修饰抗人HER2抗体列于表1。末端修饰序列中的LPETGG是连接酶供体底物的识别序列,GA是间隔子序列。
表1修饰的抗人HER2抗体
序列 | 末端引入的序列 | |
Ab0001-LCCTL-HC轻链 | SEQ ID NO:1 | GALPETGG |
Ab0001-LCCTL-HC重链 | SEQ ID NO:2 | -* |
Ab0001-LCCTL-HCCTL轻链 | SEQ ID NO:3 | GALPETGG |
Ab0001-LCCTL-HCCTL重链 | SEQ ID NO:4 | GALPETGG |
*:“-”表示无末端修饰
实施例2中间体的制备
2.1中间体Mc-GGFG-Dxd(RF1184)的制备
中间体Mc-GGFG-Dxd(RF1184)可商购或按照EP2907824中所述的程序制备。该化合物用于制备连接子-负载物中间体(式(IV)化合物),也用于直接连接(可选修饰的)抗体以制备参考ADC。
2.2连接子-负载物中间体LB301-2-1的制备
步骤1:连接子HX18041的制备
HX18041是通过使用Rink-酰胺-MBHA-树脂的常规固相多肽合成方法合成的。Fmoc用于保护连接单元中的氨基酸。缀合试剂选自HOBT、HOAt/DIC、DCC、EDCI或HATU。合成后,使用三氟乙酸裂解树脂。产物经HPLC纯化,冻干保存备用。理论分子量:538.24,测量值:[M+H]+=539.2。
步骤2:连接子-负载物中间体LB301-2-1的制备
称取HX18041和中间体MC-GGFG-Dxd(摩尔比~1.2:1)分别溶于水和DMF中,充分混合得到混合物,在0-40℃反应0.5-20h。反应完成后,直接向反应混合物中加入适量的Tris碱溶液或其他促进开环反应的溶液,再在0-40℃反应0.2-20h。反应完成后,产物通过半制备型/制备型HPLC纯化并冻干,得到连接子-负载物LB301-2-1。理论质量:1589.65,测量值:[(M+2H)/2]+=796.6。
2.3连接子-负载物中间体LB302-2-1的制备
步骤1:连接子HX20113的制备
HX20113是通过使用Rink-酰胺-MBHA-树脂的常规固相多肽合成方法合成的。Fmoc用于保护连接单元中的氨基酸。缀合试剂选自HOBT、HOAt/DIC、DCC、EDCI或HATU。合成后,使用三氟乙酸裂解树脂。产物经HPLC纯化,冻干保存备用。理论质量:1207.59,测量值:[M-H]-=1206.7。
步骤2:连接子-负载物中间体LB302-2-1的制备
称取HX20113和中间体MC-GGFG-Dxd(摩尔比~1:2)分别溶于水和DMF中,充分混合得到混合物,在0-40℃反应0.5-30h。反应完成后,直接向反应混合物中加入适量的Tris碱溶液或其他促进开环反应的溶液,再在0-40℃反应0.2-20h。反应完成后,产物通过半制备型/制备型HPLC纯化并冻干,得到连接子-负载物中间体LB302-2-1。理论质量:3310.41,测量值:[(M+3H)/3]+=1104.5。
2.4连接子-负载物中间体LB302-2-4的制备
步骤1:连接子HX20111的制备
HX20111是通过使用Rink-酰胺-MBHA-树脂的常规固相多肽合成方法合成的。Fmoc用于保护连接单元中的氨基酸。缀合试剂选自HOBT、HOAt/DIC、DCC、EDCI或HATU。合成后,使用三氟乙酸裂解树脂。产物经HPLC纯化,冻干保存备用。理论质量:1383.70,测量值:[M-H]-=1382.6。
步骤2:连接子-负载物中间体LB302-2-4的制备
称取HX20111和中间体MC-GGFG-Dxd(摩尔比~1:2)分别溶于水和DMF中,充分混合得到混合物,在0-40℃反应0.5-30h。反应完成后,直接向反应混合物中加入适量的Tris碱溶液或其他促进开环反应的溶液,再在0-40℃反应0.2-20h。反应完成后,产物通过半制备型/制备型HPLC纯化并冻干,得到连接子-负载物中间体LB302-2-4。理论质量:3486.52,测量值:[(M+3H)/3]+=1163.3。
实施例3靶向分子-药物缀合物的制备
3.1连接子-负载物中间体分别通过连接酶以位点特异性方式与抗体缀合形成ADC。缀合反应的方法可以在WO2015165413A1中找到。生成的ADC如下表所示:
ADC名称 | 连接子-负载物 | 抗体 |
LC301-2-1(2) | LB301-2-1 | Ab0001-LCCTL-HC |
LC302-2-1(4) | LB302-2-1 | Ab0001-LCCTL-HC |
LC302-2-4(4) | LB302-2-4 | Ab0001-LCCTL-HC |
LC301-2-1(4) | LB301-2-1 | Ab0001-LCCTL-HCCTL |
3.2参考ADCLC1184(8)和LC1184(4)通过将中间体RF1184直接连接到(可选修饰的)抗体(Cys缀合,即通过马来酰亚胺结构与半胱氨酸的巯基基团形成的连接进行缀合)制备。缀合反应的方法是本领域已知的。LC1184(8)通过还原的链间半胱氨酸引入八个RF1184。LC1184(4)通过还原的链间半胱氨酸引入四个RF1184。
效果实施例1靶向HER2的缀合物对细胞增殖的影响
使用HER2高表达癌细胞SK-BR-3(图1)和NCI-N87(图2)、HER2低表达癌细胞CFPAC-1(图3)和NCI-H2110(图4)以及HER2阴性细胞系MDA-MB-468(图5)进行细胞毒性测定,以分析缀合物对肿瘤细胞增殖的影响。测试样品包括缀合物LC302-2-1(4)、LC302-2-4(4)和小分子化合物10(结构如上所述)。简而言之,将3000到5000个细胞铺在96孔板中,细胞能够在生长过夜后贴壁。用不同浓度的指定药物处理细胞120小时。通过Luminescent Cell Viability Assay检查细胞活力,并计算细胞活力百分比。
在HER2高表达SK-BR-3和NCI-N87中,缀合物LC302-2-1(4)、LC302-2-4(4)表现出相似的效力。LC302-2-1(4)和LC302-2-4(4)的IC50值低于小分子负载物Dxd。在HER2低表达和阴性细胞中,缀合物LC302-2-1(4)和LC302-2-4(4)表现出最小的效力。
效果实施例2:缀合物体内评估
对于体内抗肿瘤效力研究,在SCID Beige小鼠的右腹皮下接种x106JIMT-1人乳腺癌细胞(HER2培养基)。7天后,当肿瘤体积平均达到142mm3时,分配荷瘤小鼠并以5mg/kg静脉内给药LC1184(8)和其他五种不同的缀合物。每周两次用卡尺测量肿瘤体积。LC1184(8)显示出比LC1184(4)更好的效力,这表明使用相同的负载物时,更高的DAR将带来更好的效力。LC302-2-1(4)和LC302-2-4(4)的效力优于LC1184(8)。LC301-2-1(4)表现出与LC1184(8)相当的效力,而LC301-2-1(2)表现出与LC1184(4)相当的效力(图6)。本发明的缀合物在较低DAR取得良好的效力。
在BALB/c裸鼠的右腹皮下接种5x106Capan-1人胰腺癌细胞(HER2低表达)以制备移植瘤模型。8天后,当肿瘤体积平均达到178mm3时,荷瘤小鼠以5mg/kg静脉内给药LC1184(8)和其他五种不同的缀合物。每周两次用卡尺测量肿瘤体积。LC1184(8)的效力优于LC1184(4)。LC302-2-1(4)、LC302-2-4(4)和LC301-2-1(4)表现出与LC1184(8)相当的效力,而LC301-2-1(2)表现出与LC1184(4)相当的效力(图7)。
效果实施例3:缀合物的离体血清稳定性
对于离体血清稳定性研究,将缀合物LC302-2-1(4)、LC302-2-4(4)和LC1184(8)分别接种于37℃的混合人血清中。在0、24、48和96小时,用抗原捕获缀合物,然后用糖苷酶去糖基化并用酸解离。收集上清液并离心,然后通过高分辨率LC-MS检测以确定DAR。
LC302-2-1(4)和LC302-2-4(4)在血清中孵育96小时后非常稳定。孵育96小时后,LC302-2-1(4)和LC302-2-4(4)的DAR没有明显降低。然而,LC1184(8)的DAR在孵育96小时后从7.8下降到2.6(图8)。连接子的稳定性表明更多负载物递送至靶向的肿瘤,而脱靶游离负载物释放减少,从而提高了治疗指数。
序列表
SEQ ID No.1:Ab0001-LCCTL-HC轻链:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGALPETGG
SEQ ID No.2:Ab0001-LCCTL-HC重链:
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID No.3:Ab0001-LCCTL-HCCTL轻链:
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGALPETGG
SEQ ID No.4:Ab0001-LCCTL-HCCTL重链:
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGALPETGG
序列表
<110> 启德医药科技(苏州)有限公司
<120> 连接子、缀合物及其应用
<130> I2022TC6727C
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Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys Gly Ala Leu Pro Glu Thr Gly Gly
450 455
Claims (31)
1.化合物,选自
其中,
opSu为或其混合物;
R10为氢或与负载物中的基团发生反应时可以离去的基团;每个i各自独立为1-20的整数;
j为1-20的整数;
每个g独立地为1-6的整数。
2.如权利要求1所述的化合物,其中R10是氢、羟基;或
3.如权利要求1所述的化合物,其中
每个i各自独立地为1-12的整数。
4.如权利要求3所述的化合物,其中
每个i各自独立地为2-8的整数。
5.如权利要求4所述的化合物,其中每个i为4。
6.如权利要求1-5中任一项所述的化合物,其中j为1-12的整数。
7.如权利要求6所述的化合物,其中j为8-12的整数。
8.如权利要求7所述的化合物,其中j为8或12。
9.如权利要求1-5中任一项所述的化合物,其中每个g独立地为1-3的整数。
10.如权利要求9所述的化合物,其中每个g为1。
11.化合物,选自:
其中,
opSu为或其混合物。
12.如权利要求11所述的化合物,选自:
13.缀合物,选自:
其中,
opSu为或其混合物;每个i各自独立地为1-20的整数;
j为1-20的整数;
每个g独立为1-6的整数;
A是抗体或其抗原结合片段;
z是1-4的整数。
14.如权利要求13所述的缀合物,其中
所述抗体是抗人HER2抗体。
15.如权利要求13-14中任一项所述的缀合物,其中
所述抗体选自基于曲妥珠单抗的工程化抗HER2抗体。
16.如权利要求13所述的缀合物,其中
所述抗体或其抗原结合片段包含末端修饰,末端修饰是指在抗体的重链或轻链的C末端的修饰,其包含连接酶识别序列,进一步包含间隔子Sp2,其中抗体、Sp2和连接酶识别序列顺序连接;
其中,连接酶识别序列是LPETGG,Sp2是GA。
17.如权利要求13-14中任一项所述的缀合物,其中
所述抗体是Ab0001-LCCTL-HC,其轻链的氨基酸序列如SEQ ID NO:1所示,重链的氨基酸序列如SEQ ID NO:2所示;或者是Ab0001-LCCTL-HCCTL,其轻链的氨基酸序列如SEQ ID NO:3所示,重链的氨基酸序列如SEQ ID NO:4所示。
18.如权利要求13-14中任一项所述的化合物,其中
每个i各自独立地为1-12的整数。
19.如权利要求18所述的化合物,其中
每个i各自独立地为2-8的整数。
20.如权利要求19所述的化合物,其中
每个i为4。
21.如权利要求13-14中任一项所述的化合物,其中
j为1-12的整数。
22.如权利要求21所述的化合物,其中
j为8-12的整数。
23.如权利要求22所述的化合物,其中
j为8或12。
24.如权利要求13-14中任一项所述的化合物,其中
每个g独立地为1-3的整数。
25.如权利要求24所述的化合物,其中
每个g为1。
26.如权利要求13-14中任一项所述的化合物,其中
z是2。
27.一种药物组合物,其包含预防或治疗有效量的如权利要求13-26中任一项所述的缀合物,以及至少一种药学上可接受的载体。
28.如权利要求13-26中任一项所述的缀合物或如权利要求27所述的药物组合物在制备用于治疗疾病的药物中的用途;其中所述疾病是肿瘤或自身免疫性疾病。
29.如权利要求28所述的用途;其中所述疾病是HER2阳性肿瘤。
30.如权利要求29所述的用途;其中所述HER2阳性肿瘤选自乳腺癌、胃癌、肺癌、卵巢癌和尿路上皮癌。
31.一种具有以下结构的化合物:
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US11814394B2 (en) * | 2021-11-16 | 2023-11-14 | Genequantum Healthcare (Suzhou) Co., Ltd. | Exatecan derivatives, linker-payloads, and conjugates and thereof |
WO2024002154A1 (en) * | 2022-06-28 | 2024-01-04 | Genequantum Healthcare (Suzhou) Co., Ltd. | Anti-fgfr3 antibody conjugate and medical use thereof |
WO2024012569A1 (en) * | 2022-07-15 | 2024-01-18 | Genequantum Healthcare (Suzhou) Co., Ltd. | Linkers, conjugates and applications thereof |
WO2024207177A1 (en) * | 2023-04-04 | 2024-10-10 | Genequantum Healthcare (Suzhou) Co., Ltd. | Antibody, linkers, payload, conjugates and applications thereof |
WO2024041587A1 (zh) * | 2022-08-25 | 2024-02-29 | 启德医药科技(苏州)有限公司 | 抗体偶联药物的药物组合物 |
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EP2276506A4 (en) | 2008-04-30 | 2014-05-07 | Immunogen Inc | EFFICIENT CONJUGATES AND HYDROPHILIC BINDER |
US9504756B2 (en) | 2012-05-15 | 2016-11-29 | Seattle Genetics, Inc. | Self-stabilizing linker conjugates |
AU2013326881B2 (en) | 2012-10-04 | 2018-08-02 | Immunogen, Inc. | Use of a PVDF membrane to purify cell-binding agent cytotoxic agent conjugates |
CN115960111A (zh) * | 2012-10-11 | 2023-04-14 | 第一三共株式会社 | 抗体-药物偶联物 |
EP2777714A1 (en) | 2013-03-15 | 2014-09-17 | NBE-Therapeutics LLC | Method of producing an immunoligand/payload conjugate by means of a sequence-specific transpeptidase enzyme |
JP2016520574A (ja) * | 2013-04-28 | 2016-07-14 | 秦剛 | 新規リンカー、その製造方法およびその応用 |
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US20220395581A1 (en) | 2022-12-15 |
JP2024514174A (ja) | 2024-03-28 |
CN115197297A (zh) | 2022-10-18 |
KR20230170769A (ko) | 2023-12-19 |
AU2022259314A1 (en) | 2023-11-30 |
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