CN107635405A - 抗体药物缀合物 - Google Patents
抗体药物缀合物 Download PDFInfo
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- CN107635405A CN107635405A CN201680009149.3A CN201680009149A CN107635405A CN 107635405 A CN107635405 A CN 107635405A CN 201680009149 A CN201680009149 A CN 201680009149A CN 107635405 A CN107635405 A CN 107635405A
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- antibody
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Abstract
本发明公开了具有蒽环衍生物药物部分的抗体药物缀合物,其提供改善的安全性和细胞杀伤功效,其中蒽环衍生物药物部分用羟甲基酮部分替代酰肼或异羟肟酸酯部分。公开的细胞毒剂(即药物部分)通过Cys或Lys残基与抗体缀合。对于Lys缀合,大部分ADC的DAR(药物抗体比)为2,而当Cys残基发生缀合时,大部分ADC的DAR为4。
Description
技术领域
本公开内容提供了蒽环类衍生物活性剂(药物部分)抗体缀合物(ADC),通过在碱性蒽环类药效团上用羟基甲基酮部分替代酰肼或异羟肟基部分而提供改善的安全性和细胞杀伤效力。所公开的修饰提供经由Cys或Lys与抗体缀合的细胞毒性剂。对于Lys缀合,大部分ADC的DAR(药物抗体比)为2,而当Cys上发生缀合时,大多数缀合物的DAR为4。
背景技术
抗体治疗已经建立以用于癌症、免疫和血管生成障碍患者的靶向治疗(Carter(2006年),自然评论免疫学6:343-357,Carter(2006)Nature Reviews Immunology 6:343-357)。抗体-药物缀合物(ADC)即免疫缀合物用于局部递送细胞毒性或细胞生长抑制剂,即用于杀伤或抑制肿瘤细胞以治疗癌症的药物,药物部分靶向递送至肿瘤和细胞内积累,而这些非缀合药物的全身给药可能导致对正常细胞以及寻求消除的肿瘤细胞的不可接受的毒性水平(Xie等(2006)生物治疗专家意见,6(3):281-291;Kovtun等(2006)癌症研究66(6):3214-3121;Law等(2006)癌症研究,66(4):2328-2337;Wu等(2005)自然生物技术,23(9):1137-1145;Lambert(2005)药理学现代观点5:543-549;Hamann(2005)生物治疗专家意见,15(9):1087-1103;Payne(2003)癌细胞,3:207-212;Trail等(2003)癌症免疫现状52:328-337;Syrigos和Epenetos(1999)抗癌研究,19:605-614)。因此寻求具有最小毒性的最大功效。设计和优化ADC的努力集中在单克隆抗体(mAb)的选择性以及药物作用机制,药物连接,药物/抗体比例(载量)和药物释放性质(McDonagh(2006)蛋白质工程设计与选择;Doronina等(2006)生物缀合化学,17:114-124;Erickson等(2006)癌症研究,66(8):1-8;Sanderson等(2005)临床癌症研究.11:843-852;Jeffrey等(2005)药物化学学报,48:1344-1358;Hamblett等(2004)临床癌症研究,10:7063-7070)。药物部分可以通过包括微管蛋白结合,DNA结合或拓扑异构酶抑制的机制赋予其细胞毒性和细胞抑制作用。当与大抗体或蛋白质受体配体结合时,某些细胞毒性药物往往是无活性的或较不活跃的。蒽环霉素类似物,阿霉素(ADRIAMYCIN)被认为通过插入和抑制解离DNA以便转录的拓扑异构酶II的进展而与DNA相互作用。多柔比星在破坏DNA链进行复制后稳定拓扑异构酶II复合物,防止DNA双螺旋被重新密封,从而停止复制过程。多柔比星和柔红霉素(DAUNOMYCIN)是原型细胞毒性天然产物蒽环霉素化学治疗剂(Sessa等(2007)心血管毒理学,7:75-79)。已经制备和研究了柔红霉素和多柔比星的免疫缀合物和前药(Kratz等(2006)现代药物化学,13:477-523;Jeffrey等(2006)生物有机化学和药物化学通讯,16:358-362;Torgov等(2005)生物缀合化学,16:717-721;Nagy等(2000)Proc.Natl.Acad.Sci.97:829-834;Dubowchik等(2002)生物有机化学和药物化学通讯,12:1529-1532;King等(2002)药物化学学报,45:4336-4343;美国专利6,630,579)。抗体-药物缀合物BR96-多柔比星与肿瘤相关抗原Lewis-Y特异性反应(Tolcher等(1999)临床肿瘤学杂志,17:478-484)。
奈莫柔比星(Nemorubicin)是一种半合成蒽环类衍生物,其比一些常用的蒽环类药物(如多柔比星和伊达比星)显示出更强的细胞杀伤性能。由于其细胞毒性高,目前正在临床评价治疗癌症效果。PNU-159682是肝微粒体中奈莫柔比星的主要代谢产物,其细胞毒性明显多于奈莫柔比星,是抗体靶向癌症治疗的理想活性剂。
通过在糖苷氨基上环化形成的多柔比星和柔红霉素的吗啉代类似物具有更大的效力(Acton等(1984)药物化学学报,638-645;美国专利4,464,529;4,672,057;和5,304,687)。诺霉素是多柔比星与多柔比星的糖苷氨基上的2-甲氧基吗啉基的半合成类似物(Grandi等(1990)癌症治疗综述,17:133;Ripamonti等(1992)英国癌症杂志,65:703)。
奈莫柔比星被命名为(8S,10S)-6,8,11-三羟基-10-((2R,4S,5S,6S)-5-羟基-4-((S)-2-甲氧基吗啉代)-6-甲基四氢-2H-吡喃-2-基氧基)-8-(2-羟基乙酰基)-1-甲氧基-7,8,9,10-四氢四苯-5,12-二酮,CAS登录号为108852-90-0,具有以下结构:
已经表征了几种来自肝微粒体的尼莫尿苷代谢物(MMDX),其中包括PNU(159682)(Quintieri等(2005)临床癌症研究,11(4):1608-1617;Beulz-Riche等(2001)基础与临床药理学,15(6):373-378;EP 0889898;WO2004/082689;and WO2004/082579)。PNU(159682)在体外比尼莫尿苷和多柔比星更具细胞毒性,是有效的体内肿瘤模型。PNU(159682)命名为3’-脱氨基-3“,4’-脱水-[2”(S)-甲氧基-3“(R)-氧基-4”-吗啉基]多柔比星,具有以下结构:
因此,本领域需要进一步合成化合物以寻求该结构的改善的功效特征。本公开内容提供了一系列新的衍生化合物,显示出惊人的改善的功效特征。
概要
本公开内容提供了抗体-药物缀合物(ADC),其包含与药物部分缀合的抗体,其中药物部分是具有式A结构的修饰的三环吗啉代蒽环衍生物,其中Z为O,NH或CH2。在碱性蒽环类药效团上用羟甲基酮替代酰肼或异羟肟酸来修饰药物部分。所公开的修饰提供经由抗体上的Cys或Lys与抗体缀合的细胞毒性剂。对于Lys缀合,大多数缀合物的DAR(药物抗体比)为2,而当在Cys上发生缀合时,大多数缀合物的DAR为4。
本公开内容提供了具有式I结构的抗体药物缀合物(ADC):
或其药学上可接受的盐,
其中:
Ab是抗体;
L1是连接头(connector);
L2是连接基团(linker),其选自:氨基酸,肽,-(CH2)n-,-(CH2CH2O)n-,对氨基苄基(PAB),Val-Cit-PAB,Val-Ala-PAB,Ala-Ala-Asn-PAB及其组合;
D是具有式II结构的活性剂的药物部分:
其中Z=O,NH或CH2,
R1=H,OH或OMe,
R2是C1-C5烷基,
n是1-10的整数。
优选地,对于Cys缀合,-L1-L2选自下组:
优选地,对于Lys缀合,-L1-L2选自下组:
本公开内容进一步提供了用于合成式I的结构或其药学上可接受的盐的合成方法
其中:
Ab是抗体;
L1是连接头;
L2是连接基团,其选自:氨基酸,肽,-(CH2)n-,-(CH2CH2O)n-,对氨基苄基(PAB),Val-Cit-PAB,Val-Ala-PAB,Ala-Ala-Asn-PAB,及其组合;
D是具有式II结构的药物部分:
其中Z=O,NH或CH2,
R1=H,OH或OMe,
R2是C1-C5烷基,
n是1-10的整数
优选地,Ab-L1-L2为
附图简要说明
图1显示ADC 20(抗Her2抗体)在N87异种移植模型中的体内功效。
图2显示在异种移植模型中,ADC 20(抗Her2抗体)在N87细胞中的体内安全性。
图3显示ADC 35(抗Her2抗体)在N87异种移植模型中的体内功效。
图4显示了在N87异种移植模型中ADC 35(抗Her2抗体)的体内安全性。
详细说明
本公开内容提供了以下公开的抗体缀合物的实例,其列举为与抗体上的Lys或抗体上的Cys缀合。
表1.合成的化合物的结构(用于Lys缀合)
表2.合成化合物的结构(用于Cys缀合)
表3.合成的抗体-药物缀合物的结构
Ab优选为IgG类抗体。
定义
如本文所用,常见的有机缩写定义如下:
Ac 乙酰基
aq. 水溶液
BOC或Boc 叔丁氧羰
BrOP 溴三(二甲基氨基)磷六氟磷酸盐
Bu 正丁基
℃ 摄氏度温度
DCM 二氯甲烷
DEPC 磷酸二乙酯
DIC 二异丙基
DIEA 二异丙基乙胺
DMA N,N’-二甲基甲酰胺
DMF N,N’-二甲基甲酰胺
EDC 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺
Et 乙基
EtOAc 乙酸乙酯
Eq 当量
Fmoc 9-芴甲氧羰基
g 克
h 小时(小时)
HATU 2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基尿素六氟磷酸盐
HOBT N-羟基苯并三唑
HOSu N-羟基丁二酰亚胺
HPLC 高效液相色谱
LC/MS 液相色谱-质谱
Me 甲基
MeOH 甲醇
MeCN 乙腈
mL 毫升
MS 质谱
PAB 对氨基苯
RP-HPLC 反相高效液相色谱
rt 室温
t-Bu 叔丁基
TEA 三乙胺
Tert,t 第三的
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层色谱
L 微升
一般程序
从酸形成活化酯(如NHS)。将酸溶于DCM中,如果需要,加入DMF以帮助溶解。加入N-羟基琥珀酰亚胺(1.5当量),然后加入EDC·HCl(1.5当量)。将反应混合物在室温下搅拌1小时,直到大部分酸被消耗。通过RP-HPLC监测反应进程。然后将混合物用DCM稀释并依次用柠檬酸(10%水溶液)和盐水洗涤。将有机层干燥并浓缩至干。粗产物任选地通过RP-HPLC或硅胶柱色谱纯化。
实施例1.化合物2的制备
向化合物41(72mg,0.10mmol)的3mL DMF溶液中加入DIEA(60μL,0.34mmol)和羟胺58(45mg,0.15mmol)。将混合物在室温下搅拌16小时,然后用DCM(30mL)稀释。混合物用盐水洗涤。将有机层干燥并蒸发至干。残余物通过柱(硅胶,DCM:MeOH,9:1)纯化,得到化合物3(46mg,50%)。MS m/z 917.4(M+H)。
实施例2.化合物3的制备
向化合物41(72mg,0.10mmol)在3mL DMF中的溶液中加入DIEA(60μL,0.34mmol)和胺42(42mg,0.10mmol)。将混合物搅拌16小时,然后蒸发并通过柱(硅胶,DCM:MeOH,9:1)纯化,得到化合物3(70mg,68%)。MS m/z 1029.4(M+H)。
实施例3.化合物4的制备
向化合物41(72mg,0.10mmol)的3mL DMF溶液中加入DIEA(60μL,0.34mmol)和酰肼59(43mg,0.15mmol)。将混合物在室温下搅拌16小时,然后用DCM(30mL)稀释。混合物用盐水洗涤。将有机层干燥并蒸发至干。残余物通过柱(硅胶,DCM:MeOH,9:1)纯化,得到化合物4(56mg,62%)。MS m/z 899.4(M+H)。
实施例4.化合物5的制备
向化合物41(72mg,0.10mmol)的3mL DMF溶液中加入DIEA(60μL,0.34mmol)和酰肼60(50mg,0.15mmol)。将混合物在室温下搅拌16小时,然后用DCM(30mL)稀释。混合物用盐水洗涤。将有机层干燥并蒸发至干。残余物通过柱(硅胶,DCM:MeOH,9:1)纯化,得到化合物5(41mg,44%)。MS m/z 942.5(M+H)。
实施例5.化合物6的制备
向化合物41(72mg,0.10mmol)的3mL DMF溶液中加入DIEA(60μL,0.34mmol)和酰肼61(87mg,0.15mmol)。将混合物在室温下搅拌16小时,然后用DCM(50mL)稀释。混合物用盐水洗涤。将有机层干燥并蒸发至干。残余物通过柱(硅胶,DCM:MeOH,9:1)纯化,得到化合物6(47mg,40%)。MS m/z 1186.5(M+H)。
实施例6.化合物7的制备
向化合物41(72mg,0.10mmol)的3mL DMF溶液中加入DIEA(60μL,0.34mmol)和酰肼62(30mg,0.15mmol)。将混合物在室温下搅拌16小时,然后用DCM(40mL)稀释。混合物用盐水洗涤。将有机层干燥并蒸发至干。残余物通过柱(硅胶,DCM:MeOH,9:1)纯化,得到化合物7(57mg,56%)。MS m/z 1015.5(M+H)。
实施例7.化合物8的制备
向化合物41(72mg,0.10mmol)在3mL DMF中的溶液中加入DIEA(75μL)和胺.TFA 63(86mg,0.12mmol)。将混合物在室温下搅拌3小时,然后用DCM(40mL)稀释。混合物用盐水洗涤。将有机层干燥并蒸发至干。残余物通过柱(硅胶,DCM:MeOH,9:1)纯化,得到化合物8(63mg,52%)。MS m/z 1214.5(M+H)。
实施例8.化合物9的制备
向化合物44(3.3mg,7.7μmol)的2mL DMF溶液中加入DIEA(2.6μL,15umol),PyBrOP(2.3mg,5μm)和胺43(2.5mg,3μmol)。将混合物搅拌10分钟,然后通过柱(硅胶,DCM:MeOH,95:5)纯化,得到化合物9(2.0mg,54%)。MS m/z 1228.3(M+H)。
实施例9.化合物10的制备
向化合物64(10mg,23μmol)的2mL DMF溶液中加入DIEA(8μL,50umol),PyBrOP(7mg,15μmol)和胺43(8mg,10μmol)。将混合物搅拌10分钟,然后通过柱(硅胶,DCM:MeOH,90:10)纯化,得到化合物10(5.0mg,42%)。MS m/z 1202.3(M+H)。
实施例10.化合物11的制备
化合物47的制备:
向化合物45(17.7mg,28μmol)的2mL DMF溶液中加入DIEA(5μL,30μmol),HATU(11mg,29μmol)和胺46(48mg,28μmol)。将混合物搅拌30分钟,然后加入100μL的哌啶。15分钟后,将混合物蒸发并通过HPLC纯化,得到化合物47(18mg,30%)。MS m/z 1974.7(M+H)。
化合物11的制备:
向化合物48(13.6mg,40μmol)的2mL DCM溶液中加入DIC(2.5mg,20μmol)和胺47(18mg,9μmol)。将混合物搅拌30分钟,然后通过HPLC纯化,得到化合物11(9mg,43%)。MS m/z 2296.8(M+H)。
实施例11.化合物12的制备
向化合物45(45mg,72μmol)的2mL DMF溶液中加入DIEA(13μL,80μmol),HATU(28mg,74μmol)和胺49(36mg,72μmol)。将混合物搅拌30分钟,然后加入100μL的哌啶。15分钟后,将混合物蒸发并通过HPLC纯化,得到化合物50(16mg,25%)。MS m/z 889.4(M+H)。
向化合物48(13.6mg,40μmol)的2mL DCM溶液中加入DIC(2.5mg,20μmol)和胺50(16mg,18μmol)。将混合物搅拌30分钟,然后通过HPLC纯化,得到化合物12(7mg,32%)。MSm/z 1212.3(M+H)。
实施例12.化合物13的制备
向化合物45(45mg,72μmol)的2mL DMF溶液中加入DIEA(13μL,80μmol),HATU(28mg,74μmol)和胺51(49mg,72μmol)。将混合物搅拌30分钟,然后加入100μL的哌啶。15分钟后,将混合物蒸发并通过HPLC纯化,得到化合物52(27mg,35%)。MS m/z 1074.4(M+H)。
向化合物53(15mg,40μmol)的2mL DCM溶液中加入DIC(2.5mg,20μmol)和胺52(21mg,20μmol)。将混合物搅拌30分钟,然后通过HPLC纯化,得到化合物13(13mg,47%)。MSm/z 1416.3(M+H)。
实施例13.化合物14的制备
向化合物50(18mg,0.02mmol)在DCM(2mL)中的溶液中加入化合物65(15mg),然后加入DIEA(5μL)。将混合物在室温下搅拌10分钟。然后将反应用DCM(30mL)稀释并用水性饱和NaHCO3洗涤。将有机层浓缩,通过RP-HPLC纯化残余物,得到冷冻干燥后为红色固体的化合物14(7mg,29%)。MS m/z 1231.3(M+H)。
实施例14.化合物15的制备
向化合物55(9mg,20μmol)的2mL DCM中加入PyBrOP(9mg,20μmol),DIEA(8μL,80μmol)和胺54(15mg,20μmol)。将混合物搅拌30分钟,然后蒸发并通过HPLC纯化,得到化合物15(9mg,37%)。MS m/z 1253.2(M+H)。
实施例15.化合物16的制备
向化合物55(9mg,20μmol)的2mL DCM溶液中加入PyBrOP(9mg,20μmol),DIEA(8μL,80μmol)和胺56(15mg,20μmol)。将混合物搅拌30分钟,然后蒸发并通过HPLC纯化,得到化合物16(8mg,33%)。MS m/z 1196.2(M+H)。
实施例16.化合物17的制备
向化合物57(12mg,20μmol)的2mL DCM中加入PyBrOP(9mg,20μmol),DIEA(8μL,80μmol)和胺54(15mg,20μmol)。将混合物搅拌30分钟,然后蒸发并通过HPLC纯化,得到化合物17(13mg,47%)。MS m/z 1419.3(M+H)。
实施例17.化合物18的制备
向化合物45(63mg,0.1mmol)的DMF(3mL)溶液中加入化合物66(75mg,0.1mmol),然后加入DIEA(70μL)和HATU(40mg)。将混合物在室温下搅拌5分钟,然后用DCM(50mL)稀释。混合物用水性饱和NaHCO3和盐水洗涤。将有机层干燥并浓缩。粗产物通过柱色谱(硅胶,MeOH/DCM:1/19,/v/v)纯化,得到化合物67,为红色固体(81mg,61%)。
将化合物67(66mg,0.05mmol)溶于DMF(2mL)中。加入哌啶(100L)。将混合物在室温下搅拌30分钟,然后在减压下浓缩至干。将残余物再溶于DCM(3mL)中。加入酐65(42mg),然后加入DIEA(18μL)。30分钟后,将反应浓缩,粗产物通过RP-HPLC纯化,得到化合物18,为红色固体(52mg,72%)。MS m/z 1444.5(M+H)。
实施例18
本实施例提供了在特定细胞中体外测定指定药物缀合抗体的EC50测定的结果。作为比较,从缀合有抗Her 2抗体的未修饰的PNU-159682(WO2010/009124 A2)合成ADC 70。本文公开的大多数ADC显示出很大的改善的安全特性(ADC 21-29,31和35),并且一些ADC显示出改善的细胞杀伤功效(ADC 26,30,31和34)。
实施例19
该实施例显示ADC 20(抗Her2抗体缀合物)在皮下N87异种移植模型中的体内功效。图1显示通过静脉内给药施用于BALB/c裸鼠的单剂量的缀合物20。每组8只小鼠,共3组小鼠进行研究:一组小鼠注射T-DM1(曲妥珠单抗-DM1结合物),一组小鼠注射ADC20,和一运载体对照组。所有药物以相同的方式施用(单次剂量)。单次剂量的以1mg/kg静脉内给予的ADC-20效果优于2mg/kg的T-DM1,并且完全抑制肿瘤生长达58天。
实施例20
该实施例显示在皮下N87异种移植模型中ADC 20(抗Her2抗体缀合物)的体内安全性。图2显示通过静脉内给药施用于BALB/c裸鼠的单剂量的缀合物20。每组8只小鼠,共3组小鼠进行研究:一组小鼠注射T-DM1(曲妥珠单抗-DM1结合物),一组小鼠注射ADC 20,和一运载体对照组。所有药物以相同的方式施用(单次剂量)。单次剂量的以1mg/kg静脉内给予的ADC-20不妨碍小鼠体重增加,其与T-DM1的功效相当。
实施例21
该实施例显示ADC 35(抗Her2抗体缀合物)在皮下N87异种移植模型中的体内功效。图3显示通过静脉内给药施用于BALB/c裸鼠的单剂量的缀合物30。每组8只小鼠,共3只小鼠进行研究:一组小鼠注射T-DM1(曲妥珠单抗-DM1结合物),一组小鼠注射ADC 20,和一运载体对照组。所有药物以相同的方式施用(单次剂量)。单剂量的以1mg/kg静脉内给予的ADC-35优于2mg/kg的T-DM1,并且完全抑制肿瘤生长达58天。
实施例22
该实施例显示在皮下N87异种移植模型中ADC 35(抗Her2抗体缀合物)的体内安全性。图4显示通过静脉内给药施用于BALB/c裸鼠的单剂量的缀合物30。每组8只小鼠,共3组小鼠进行研究:一组小鼠注射T-DM1(曲妥珠单抗-DM1结合物),一组小鼠注射ADC 20,和一运载体对照组。所有药物以相同的方式施用(单次剂量)。单次剂量的以1mg/kg静脉内给予的ADC-35不妨碍小鼠体重增加,其与T-DM1的功效相当。
实施例23
该实施例显示了用于合成抗体药物缀合物19、20、21、22、23、24和25(上述表3)的通用缀合方法。以部分或连续流动的方式向在含0-30%有机溶剂的pH6.0-9.0的缓冲液中的0.5-50mg/mL抗体加入0.1-10当量的活化药物连接基团缀合物(2,或3,或4,或5,或6,或7,或8)。在轻微搅拌或摇动下,在0-40℃下反应0.5-50小时,用HIC-HPLC监测。所得到的粗ADC产物经历了必要的下游步骤,其中使用最先进的方法进行脱盐,自动更换/配制,以及任选的纯化。ADC产物通过HIC-HPLC,SEC,RP-HPLC和任选的LC-MS表征。
实施例24
该实施例显示了合成抗体药物缀合物26、27、28、29、30、31、32、33、34和35(上述表3)的一般缀合方法。在pH 5.0-9.0的某些缓冲溶液(例如PBS)中向0.5-50mg/mL的抗体溶液中加入0.5-100当量的还原剂,例如TCEP和DTT。在轻微搅拌或摇动下,在0-40℃下还原0.5-40小时,然后通过柱或超滤除去还原剂。向含有0-30%的有机共溶剂,如DMA的pH 5.0-9.0的某些缓冲溶液(例如PBS)配制的还原抗体(0.5-50mg/mL)中加入0.5-10当量的药物-连接基团反应物(选自化合物9)。反应在0-40℃下进行0.5-40小时,同时温和搅拌或摇动,通过HIC-HPLC监测。所得到的粗ADC产物经历了必要的下游步骤,其中使用最先进的方法进行脱盐,自动更换/配制,以及任选的纯化。最终的ADC产品通过HIC-HPLC,SEC,RP-HPLC和任选的LC-MS表征。
Claims (2)
1.一种具有式I结构的抗体药物缀合物(ADC)或其药学上可接受的盐,
其中:
Ab是抗体;
L1是连接头;
L2是连接基团,其选自氨基酸,肽,-(CH2)n-,-(CH2CH2O)n-,PAB,Val-Cit-PAB,Val-Ala-PAB,Ala-Ala-Asn-PAB及其组合;
其中-L1-L2选自下组:
D是具有式II结构的药物部分
其中Z=O,NH或CH2,
R1=H,OH或OMe,和
R2是C1-C5烷基,
n是1-10的整数。
2.如权利要求1所述的ADC,其中式I为选自下组的组合物
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EP4137159A1 (en) | 2015-01-28 | 2023-02-22 | Sorrento Therapeutics, Inc. | Antibody drug conjugates |
CN108369229A (zh) * | 2015-07-17 | 2018-08-03 | 奥菲迪亚有限公司 | 用于处理基底表面的连接分子 |
KR20190074310A (ko) | 2016-11-08 | 2019-06-27 | 리제너론 파마슈티칼스 인코포레이티드 | 스테로이드 및 이의 단백질-접합체 |
CN108285487B (zh) * | 2017-01-08 | 2021-02-19 | 浙江昭华生物医药有限公司 | 抗5t4抗体-药物偶联物及其应用 |
AU2018270784B2 (en) * | 2017-05-18 | 2024-05-16 | Regeneron Pharmaceuticals, Inc. | Cyclodextrin protein drug conjugates |
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