CN115368461A - 抗trop-2抗体、其抗体-药物偶联物及其医药用途 - Google Patents
抗trop-2抗体、其抗体-药物偶联物及其医药用途 Download PDFInfo
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Abstract
本披露涉及抗TROP‑2抗体、其抗体‑药物偶联物及其医药用途。具体而言,本披露涉及如通式(Pc‑L‑D)所示的抗TROP‑2抗体‑海鞘素类药物偶联物,其中Pc为抗TROP‑2抗体,L和n如说明书中所定义。
Description
技术领域
本披露涉及抗TROP-2抗体、其药物偶联物,及其制备方法,以及所述的抗TROP2抗体或其ADC用于制备治疗疾病或病症的药物中的用途。
背景技术
这里的陈述仅提供与本披露有关的背景信息,而不必然地构成现有技术。
TROP-2是人滋养层细胞表面糖蛋白抗原2,又名肿瘤相关钙离子信号转导子2(TACSTD2)、表皮糖蛋白1(EGP-1)、胃肠肿瘤相关抗原(GA733-1)或表面标志物1(M1S1),是由染色体1p32区域的Tacstd2基因编码表达的细胞表面糖蛋白。TROP-2属GA733蛋白家族,与上皮细胞黏附分子(EpCAM,又称Trop1、TACSTD1)有较高结构序列相似性,同源性达49%。
TROP-2蛋白初级结构是由约323个氨基酸组成的约36KD的多肽,初级结构经N-端糖基化翻译后修饰,形成不同于EpCAM的I型细胞膜糖蛋白,即TROP-2蛋白。TROP-2蛋白横跨细胞膜,N-端为胞外域(TROP2 EC),该胞外域通过一个单向跨膜螺旋(TM)与由26个氨基酸残基构成的疏水性多肽的胞内短尾(TROP2IC)连接,从而固定于胞膜。
目前发现TROP-2在胚胎发育和肿瘤细胞增殖转移的过程中具有重要意义。TROP-2最初发现于滋养层细胞,并作为其表面标志物,滋养细胞源于胚胎外滋养层,TROP-2有助于胚胎着床及胎盘组织形成,并且在胚胎干细胞增殖特性维持以及器官形成发展过程中发挥重要作用。除此之外,TROP-2还是重要的肿瘤发展相关因子,其高表达于多种肿瘤,如胰腺癌、乳腺癌、结肠癌、胃癌、口腔鳞癌、卵巢癌等,可促进肿瘤细胞增殖、侵袭、转移扩散等过程,其高表达与肿瘤受试者生存期缩短及不良预后密切相关,因此以TROP-2为靶点的抗肿瘤药物研究具有重要意义。
抗体-药物偶联物(antibody drug conjugate,ADC),将单克隆抗体或者抗体片段通过接头与具有生物活性的药物相连,充分利用了抗体对正常细胞和肿瘤细胞表面抗原结合的特异性和药物(如细胞毒性剂)的高效性,同时又避免了抗体的疗效偏低和药物的毒副作用过大等缺陷。与以往传统的化疗药物相比,抗体-药物偶联物能更精准地杀伤肿瘤细胞并降低将对正常细胞的影响。
发明内容
本披露涉及抗TROP-2抗体、其ADC,以及其医药用途。更具体的,本披露提供多种序列全新的抗TROP2抗体,以及其与细胞毒性物质(海鞘素类衍生物)偶联的ADC药物。
在一些实施方案中,本披露提供一种抗TROP2抗体,其包含重链可变区和轻链可变区,其中:
所述重链可变区包含:HCDR1,其包含SEQ ID NO:9的氨基酸序列;HCDR2,其包含SEQ ID NO:24的氨基酸序列;和HCDR3,其包含SEQ ID NO:11的氨基酸序列;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:12的氨基酸序列;LCDR2,其包含SEQ ID NO:13的氨基酸序列;和LCDR3,其包含SEQ ID NO:14的氨基酸序列;其中,SEQ IDNO:24如NIDX1X2GDTTYYPDTVKG所示,其中X1为N、Q或S;X2为G或V;
在一些实施方案中,本披露提供一种抗TROP2抗体,其包含重链可变区和轻链可变区,其中:
所述重链可变区包含:HCDR1,其包含SEQ ID NO:15的氨基酸序列;HCDR2,其包含SEQ ID NO:16的氨基酸序列;和LCDR3,其包含SEQ ID NO:17的氨基酸序列;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:18的氨基酸序列;LCDR2,其包含SEQ ID NO:19的氨基酸序列;和LCDR3,其包含SEQ ID NO:20的氨基酸序列。
在一些实施方案中,前述的抗TROP2抗体,其包含重链可变区和轻链可变区,其中:
所述重链可变区包含:HCDR1,其包含SEQ ID NO:9的氨基酸序列;HCDR2,其包含SEQ ID NO:10的氨基酸序列;和HCDR3,其包含SEQ ID NO:11的氨基酸序列;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:12的氨基酸序列;LCDR2,其包含SEQ ID NO:13的氨基酸序列;和LCDR3,其包含SEQ ID NO:14的氨基酸序列。
在一些实施方案中,前述的抗TROP2抗体,其包含重链可变区和轻链可变区,其中:
所述重链可变区包含:HCDR1,其包含SEQ ID NO:9的氨基酸序列;HCDR2,其包含SEQ ID NO:21的氨基酸序列;和HCDR3,其包含SEQ ID NO:11的氨基酸序列;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:12的氨基酸序列;LCDR2,其包含SEQ ID NO:13的氨基酸序列;和LCDR3,其包含SEQ ID NO:14的氨基酸序列。
在一些实施方案中,前述的抗TROP2抗体,其包含重链可变区和轻链可变区,其中:
所述重链可变区包含:HCDR1,其包含SEQ ID NO:9的氨基酸序列;HCDR2,其包含SEQ ID NO:22的氨基酸序列;和HCDR3,其包含SEQ ID NO:11的氨基酸序列;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:12的氨基酸序列;LCDR2,其包含SEQ ID NO:13的氨基酸序列;和LCDR3,其包含SEQ ID NO:14的氨基酸序列。
在一些实施方案中,前述的抗TROP2抗体,其包含重链可变区和轻链可变区,其中:
所述重链可变区包含:HCDR1,其包含SEQ ID NO:9的氨基酸序列;HCDR2,其包含SEQ ID NO:23的氨基酸序列;和HCDR3,其包含SEQ ID NO:11的氨基酸序列;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:12的氨基酸序列;LCDR2,其包含SEQ ID NO:13的氨基酸序列;和LCDR3,其包含SEQ ID NO:14的氨基酸序列。
在一些实施方案中,前述的抗TROP2抗体,其为鼠源抗体、嵌合抗体或人源化抗体。
在一些实施方案中,前述的抗TROP2抗体,其包含人框架,例如人免疫球蛋白框架或人共有框架。
在一个实施方案中,所述的抗TROP2抗体包含重链可变区和轻链可变区,其中:
所述重链可变区包含:HCDR1,其包含SEQ ID NO:9的氨基酸序列;HCDR2,其包含SEQ ID NO:24的氨基酸序列;和HCDR3,其包含SEQ ID NO:11的氨基酸序列;且所述重链可变区的FR包含3K或28S回复突变;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:12的氨基酸序列;LCDR2,其包含SEQ ID NO:13的氨基酸序列;和LCDR3,其包含SEQ ID NO:14的氨基酸序列;且所述轻链可变区的FR包含选自43G、49H、69R和71Y中的一个或多个回复突变。上述的回复突变位点依据Kabat编号规则。
在一个实施方案中,所述的抗TROP2抗体包含重链可变区和轻链可变区,其中:
所述重链可变区包含:HCDR1,其包含SEQ ID NO:9的氨基酸序列;HCDR2,其包含SEQ ID NO:10的氨基酸序列;和HCDR3,其包含SEQ ID NO:11的氨基酸序列;且所述重链可变区的FR包含3K或28S回复突变;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:12的氨基酸序列;LCDR2,其包含SEQ ID NO:13的氨基酸序列;和LCDR3,其包含SEQ ID NO:14的氨基酸序列;且所述轻链可变区的FR包含选自43G、49H、69R和71Y中的一个或多个回复突变。上述的回复突变位点依据Kabat编号规则。
在一个实施方案中,所述的抗TROP2抗体包含重链可变区和轻链可变区,其中:
所述重链可变区包含:HCDR1,其包含SEQ ID NO:9的氨基酸序列;HCDR2,其包含SEQ ID NO:21的氨基酸序列;和HCDR3,其包含SEQ ID NO:11的氨基酸序列;且所述重链可变区的FR包含3K或28S回复突变;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:12的氨基酸序列;LCDR2,其包含SEQ ID NO:13的氨基酸序列;和LCDR3,其包含SEQ ID NO:14的氨基酸序列;且所述轻链可变区的FR包含选自43G、49H、69R和71Y中的一个或多个回复突变。上述的回复突变位点依据Kabat编号规则。
在一个实施方案中,所述的抗TROP2抗体包含重链可变区和轻链可变区,其中:
所述重链可变区包含:HCDR1,其包含SEQ ID NO:9的氨基酸序列;HCDR2,其包含SEQ ID NO:22的氨基酸序列;和HCDR3,其包含SEQ ID NO:11的氨基酸序列;且所述重链可变区的FR包含3K或28S回复突变;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:12的氨基酸序列;LCDR2,其包含SEQ ID NO:13的氨基酸序列;和LCDR3,其包含SEQ ID NO:14的氨基酸序列;且所述轻链可变区的FR包含选自43G、49H、69R和71Y中的一个或多个回复突变。上述的回复突变位点依据Kabat编号规则。
在一个实施方案中,所述的抗TROP2抗体包含重链可变区和轻链可变区,其中:
所述重链可变区包含:HCDR1,其包含SEQ ID NO:9的氨基酸序列;HCDR2,其包含SEQ ID NO:23的氨基酸序列;和HCDR3,其包含SEQ ID NO:11的氨基酸序列;且所述重链可变区的FR包含3K或28S回复突变;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:12的氨基酸序列;LCDR2,其包含SEQ ID NO:13的氨基酸序列;和LCDR3,其包含SEQ ID NO:14的氨基酸序列;且所述轻链可变区的FR包含选自43G、49H、69R和71Y中的一个或多个回复突变。上述的回复突变位点依据Kabat编号规则。
在一个实施方案中,所述的抗TROP2抗体包含重链可变区和轻链可变区,其中:
所述重链可变区包含:HCDR1,其包含SEQ ID NO:15的氨基酸序列;HCDR2,其包含SEQ ID NO:16的氨基酸序列;和HCDR3,其包含SEQ ID NO:17的氨基酸序列;且所述重链可变区的FR包含选自48I、67A、69L和71V中的一个或多个回复突变;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:18的氨基酸序列;LCDR2,其包含SEQ ID NO:19的氨基酸序列;和LCDR3,其包含SEQ ID NO:20的氨基酸序列;且所述轻链可变区的FR包含选自3L、43S和49K中的一个或多个回复突变。上述的回复突变位点依据Kabat编号规则。
在一些实施方案中,前述的抗TROP2抗体,其中:
i)所述重链可变区包含与SEQ ID NO:5、25、26、27、28、29、30、31或32具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列;和/或
所述轻链可变区包含与SEQ ID NO:6、33、34或35具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列;或
ii)所述重链可变区包含与SEQ ID NO:7、36、37、38或39具有至少90%、95%、96%、97%、98%或99%同一性的序列;和/或
所述轻链可变区包含与SEQ ID NO:8、40、41或42具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列。
在一些实施方案中,前述的抗TROP2抗体,其中:
i)所述重链可变区包含与SEQ ID NO:5具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列;和/或
所述轻链可变区包含与SEQ ID NO:6具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列;或
ii)所述重链可变区包含与SEQ ID NO:7具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列;和/或
所述轻链可变区包含与SEQ ID NO:8具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列。
在一些实施方案中,前述的抗TROP2抗体,其中:
i)所述重链可变区包含与SEQ ID NO:25、26、27、28、29、30、31或32任一具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列;和/或
所述轻链可变区包含与SEQ ID NO:33、34或35任一具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列;或
ii)所述重链可变区包含与SEQ ID NO:36、37、38或39任一具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列;和/或
所述轻链可变区包含与SEQ ID NO:40、41或42任一具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列。
在一些实施方案中,前述的抗TROP2抗体,其中:
i)所述重链可变区包含SEQ ID NO:5的序列,和/或所述重链可变区包含SEQ IDNO:6的序列;或
ii)所述重链可变区包含选自SEQ ID NO:25、26、27、28、29、30、31和32中的任一序列,和/或所述轻链可变区包含选自SEQ ID NO:33、34和35中的任一序列;或
iii)所述重链可变区包含SEQ ID NO:7的序列,和/或所述重链可变区包含SEQ IDNO:8的序列;或
ii)所述重链可变区包含选自SEQ ID NO:36、37、38和39中的任一序列,和/或所述轻链可变区包含选自SEQ ID NO:40、41和42中的任一序列。
在一些实施方案中,前述的抗TROP2抗体,其中:
所述重链可变区包含SEQ ID NO:28的序列,和所述轻链可变区包含SEQ ID NO:35的序列;或
所述重链可变区包含SEQ ID NO:36的序列,和所述轻链可变区包含SEQ ID NO:41的序列。
在一些实施方案中,前述的抗TROP2抗体,其包含轻链恒定区和重链恒定区。
在一些实施方案中,前述的抗TROP2抗体,其包含IgG1、IgG2、IgG3或IgG4的恒定区。
在一些实施方案中,前述的抗TROP2抗体,其包含λ链或κ链的恒定区。
在一些实施方案中,前述的抗TROP2抗体,其包含IgG1的重链恒定区和κ链的轻链恒定区。
在一些实施方案中,前述的抗TROP2抗体,所述重链恒定区包含SEQ ID NO:43的序列,和/或轻链恒定区包含SEQ ID NO:44的序列。
在一些实施方案中,前述的抗TROP2抗体,其包含重链和轻链,其中:
所述重链包含与SEQ ID NO:45具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列,和/或所述轻链包含与SEQID NO:46具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列;或
所述重链包含与SEQ ID NO:47具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列,和/或所述轻链包含与SEQID NO:48具有至少85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列。
在一些实施方案中,前述的抗TROP2抗体,所述重链包含SEQ ID NO:45的序列,和/或所述轻链包含SEQ ID NO:46的序列;或
所述重链包含SEQ ID NO:47的序列,和/或所述轻链包含SEQ ID NO:48的序列。
在另一方面,本披露提供一种分离的抗TROP2的抗体,其与前述任一项所述的抗体竞争结合TROP2。
在一些实施方案中,前述的抗TROP2抗体,其中所述抗体具有以下特性中的至少一种:
a)所述抗TROP2抗体以≤1nM的KD值结合人TROP2蛋白,所述KD值通过Biacore测定;
b)所述抗TROP2抗体与表达TROP2的FaDu细胞的结合EC50≤0.4μg/mL,所述EC50通过FACS检测;和
c)所述抗TROP2抗体可被表达TROP2的细胞内吞。
在一些实施方案中,前述的抗TROP2抗体,其中所述的抗TROP2抗体是抗体片段。
在一些实施方案中,前述的抗TROP2抗体,其中所述的抗TROP2抗体是抗体片段,其中所述的抗TROP2抗体片段选自Fab、Fab’、F(ab')2、Fd、Fv、scFv、dsFv和dAb。
在另一方面,本披露提供一种分离的核酸,其编码如前任一项所述的抗TROP2抗体。
在另一方面,本披露提供一种载体,其包含如前所述的核酸。
在又一方面,本披露提供一种宿主细胞,其包含如前所述的载体。
在一个方面,本披露提供一种制备结合TROP2的抗体的方法,其包括在适于表达所述抗体的条件下培养前述的宿主细胞。
在又一个方面,本披露提供一种抗体-药物偶联物或其药学上可接受的盐,其包含如前任一项所述的抗TROP2抗体。
在又一个方面,本披露提供一种抗体-药物偶联物或其药学上可接受的盐,其包含如前任一项所述的抗TROP2抗体和药物,其中所述的药物偶联至所述的抗TROP2抗体。
在一些实施方案中,前述的抗体-药物偶联物或其药学上可接受的盐,其中所述的药物选自细胞毒性剂、放射性标记物、荧光团、发色团、显像剂、免疫调节剂、血管生成抑制剂、细胞增殖抑制剂、促细胞凋亡剂、细胞裂解酶,以及其任何组合。
在一些实施方案中,其中所述的药物是海鞘素Et-743或其衍生物。在一些实施方案中,所述的药物是海鞘素衍生物,如Lubinectedin。
在一些实施方案中,前述的抗体-药物偶联物或其药学上可接受的盐,其具有通式(Pc-L-Da)所示的结构:
其中:Pc为如前任一项所述的抗TROP-2抗体;L为接头;n为1至10。
在一些实施方案中,前述的抗体-药物偶联物或其药学上可接受的盐,其具有通式(Pc-L-D)所示的结构:
其中:Pc为如前任一项所述的抗TROP-2抗体;L为接头;n为1至10。
在一些实施方案中,如前所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,其中n是每个抗体的平均药物模块数,可以是整数或小数。在一些实施方案中,n为1-10,或1-9,或2-10,或2-9,1-8,或2-8,或2-7,或2-4,或1-4,或1-3,或3-8,或3-7,或3-6,或4-7,或4-6,或4-5的平均值;在一些实施方案中,n为1,2,3,4,5,6,7,8,9或10。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,其中接头-L-为-L1-L2-L3-L4-,其中:
L1选自-(琥珀酰亚胺-3-基-N)-W-C(O)-、-CH2-C(O)-NR3-W-C(O)-和-C(O)-W-C(O)-,其中W选自C1-6亚烷基、C1-6亚烷基-C3-6环烷基,其中所述的C1-6亚烷基、C1-6亚烷基-C3-6环烷基各自独立地任选进一步被选自卤素、羟基、氰基、氨基、烷基、氯代烷基、氘代烷基、烷氧基和环烷基的一个或多个取代基所取代;
L2选自-NR4(CH2CH2O)pCH2CH2C(O)-、-NR4(CH2CH2O)pCH2C(O)-、-S(CH2)pC(O)-和化学键,其中p为1至20的整数;
L3为由2至7个氨基酸残基构成的肽残基,其中所述的氨基酸残基选自苯丙氨酸(F)、甘氨酸(G)、缬氨酸(V)、赖氨酸(K)、瓜氨酸、丝氨酸(S)、谷氨酸(E)和天冬氨酸(D)中的氨基酸形成的氨基酸残基,并任选进一步被选自卤素、羟基、氰基、氨基、烷基、氯代烷基、氘代烷基、烷氧基和环烷基中的一个或多个取代基所取代;
L4选自-NR5(CR6R7)t-、-C(O)NR5、-C(O)NR5(CH2)t-和化学键,其中t为1至6的整数;
R3、R4和R5相同或不同,且各自独立地选自氢原子、烷基、卤代烷基、氘代烷基和羟烷基;
R6和R7相同或不同,且各自独立地选自氢原子、卤素、烷基、卤代烷基、氘代烷基和羟烷基。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-Y-D)所示的抗体-药物偶联物或其药学上可接受的盐,其中接头-L-为-L1-L2-L3-L4-,其中:
L2为化学键;
L3为四肽残基;优选地,L3为甘氨酸-甘氨酸-苯丙氨酸-甘氨酸的四肽残基;
L4为-NH(CH2)t-,t为1或2;
其中所述的L1端与Pc相连。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-Y-D)所示的抗体-药物偶联物或其药学上可接受的盐,其中-L-为:
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,所述抗体-药物偶联物具有如下结构:
其中:Pc为如前任一项所述的抗TROP-2抗体;n为1至10。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,所述抗体-药物偶联物具有如下结构:
其中:
n为1至8,优选1-4;
Pc为抗TROP-2抗体,其包含SEQ ID NO:45的重链和SEQ ID NO:46的轻链。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,所述抗体-药物偶联物具有如下结构:
其中:
Pc为抗TROP-2抗体,其包含SEQ ID NO:45的重链和SEQ ID NO:46的轻链;n为1-4。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,所述抗体-药物偶联物具有如下结构:
其中:
Pc为抗TROP-2抗体,其包含SEQ ID NO:45的重链和SEQ ID NO:46的轻链;n为1-5。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,所述抗体-药物偶联物具有如下结构:
其中:
Pc为抗TROP-2抗体,其包含SEQ ID NO:45的重链和SEQ ID NO:46的轻链;n为4.19。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,所述抗体-药物偶联物具有如下结构:
其中:
n为2;
Pc为抗TROP-2抗体,其包含SEQ ID NO:45的重链和SEQ ID NO:46的轻链。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,所述抗体-药物偶联物具有如下结构:
其中:
n为1-2;
Pc为抗TROP-2抗体,其包含SEQ ID NO:45的重链和SEQ ID NO:46的轻链。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,所述抗体-药物偶联物具有如下结构:
其中:
n为1至8,优选1至4;
Pc为抗TROP-2抗体,其包含SEQ ID NO:47的重链和SEQ ID NO:48的轻链。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,所述抗体-药物偶联物具有如下结构:
其中:
n为1至5;
Pc为抗TROP-2抗体,其包含SEQ ID NO:47的重链和SEQ ID NO:48的轻链。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,所述抗体-药物偶联物具有如下结构:
其中:
n为4.19;
Pc为抗TROP-2抗体,其包含SEQ ID NO:47的重链和SEQ ID NO:48的轻链。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,所述抗体-药物偶联物具有如下结构:
其中:
n为1至2;
Pc为抗TROP-2抗体,其包含SEQ ID NO:47的重链和SEQ ID NO:48的轻链。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,所述抗体-药物偶联物具有如下结构:
其中:
n为2至3;
Pc为抗TROP-2抗体,其包含SEQ ID NO:47的重链和SEQ ID NO:48的轻链。
在一些实施方案中,如前任一项所述的通式(Pc-L-Da)或(Pc-L-D)所示的抗体-药物偶联物或其药学上可接受的盐,所述抗体-药物偶联物具有如下结构:
其中:
n为2;
Pc为抗TROP-2抗体,其包含SEQ ID NO:47的重链和SEQ ID NO:48的轻链。
本披露进一步提供一种制备抗体-药物偶联物的方法,其包括将如前任一项所述的抗TROP2抗体还原,然后与(L-D)或(L-Da)所示的化合物进行偶联反应,得到本申请所述的抗体偶联药物。
另一方面,本披露提供一种药物组合物,其包含如前任一项所述的抗TROP-2抗体,或如前任一项所述的抗体-药物偶联物或其药学上可接受的盐,以及一种或多种药学上可接受的赋形剂、稀释剂或载体。在一些实施方案中,所述单位剂量的药物组合物中含有0.1-3000mg或1-1000mg如前所述的抗TROP-2抗体或如前所述的抗体-药物偶联物。
另一方面,本披露提供如前任一项所述的抗TROP-2抗体,或如前任一项所述的抗体-药物偶联物或其药学上可接受的盐,或包含其的药物组合物作为药物的用途。
另一方面,本披露提供如前任一项所述的抗TROP-2抗体,或如前任一项所述的抗体-药物偶联物或其药学上可接受的盐,或前述的药物组合物在制备用于治疗TROP-2介导的疾病或病症的药物中的用途。在一些实施方案中,其中所述TROP-2介导的疾病或病症为癌症。在一些实施方案中,其中所述的TROP2介导的疾病或病症为表达TROP2的疾病或病症。
另一方面,本披露提供如前任一项所述的抗TROP-2抗体,或如前任一项所述的抗体-药物偶联物或其药学上可接受的盐,或前述的药物组合物在制备用于治疗或预防肿瘤或癌症的药物中的用途;优选地,其中所述肿瘤或癌症选自:
头和颈鳞状细胞癌、头和颈癌、脑癌、神经胶质瘤、多形性成胶质细胞瘤、神经母细胞瘤、中枢神经系统癌、神经内分泌肿瘤、咽喉癌、咽鳞癌、口腔鳞癌、鼻咽癌、食管癌、甲状腺癌、恶性胸膜间皮瘤、肺癌、乳腺癌、肝癌、肝胆癌、胰腺癌、胃癌、胃肠道癌、肠癌、结肠癌、结肠直肠癌、肾癌、透明细胞肾细胞癌、卵巢癌、子宫内膜癌、子宫颈癌、膀胱癌、前列腺癌、睾丸癌、皮肤癌、黑色素瘤、白血病、淋巴瘤、骨癌、软骨肉瘤、骨髓瘤、多发性骨髓瘤、骨髓异常增生综合征、库肯勃氏瘤、骨髓增生性肿瘤、鳞状细胞癌、尤因氏肉瘤、尿路上皮癌、梅克尔细胞癌、何杰金淋巴瘤、非何杰金淋巴瘤、弥漫性大B-细胞淋巴瘤、滤泡性淋巴瘤、原发性纵隔大B-细胞淋巴瘤、套细胞淋巴瘤、小淋巴细胞性淋巴瘤、富含T-细胞/组织细胞的大B-细胞淋巴瘤、淋巴浆细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、慢性髓细胞样白血病、急性髓细胞样白血病、淋巴细胞白血病、成淋巴细胞性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病和髓样细胞白血病。
另一方面,本披露进一步涉及一种用于治疗和/或预防肿瘤或癌症的方法,该方法包括向需要其的受试者施用治疗有效剂量的如前任一项所述的抗TROP-2抗体,或如前任一项所述的抗体-药物偶联物或其药学上可接受的盐,或前述的药物组合物;优选地,其中所述的肿瘤或癌症为表达TROP-2的肿瘤或癌症。
另一方面,本披露进一步涉及一种用于治疗或预防肿瘤或癌症的方法,该方法包括向需要其的受试者施用治疗有效剂量的如前任一项所述的抗TROP-2抗体,或如前任一项所述的抗体-药物偶联物或其药学上可接受的盐,或前述的药物组合物;其中所述肿瘤或癌症选自:
头和颈鳞状细胞癌、头和颈癌、脑癌、神经胶质瘤、多形性成胶质细胞瘤、神经母细胞瘤、中枢神经系统癌、神经内分泌肿瘤、咽喉癌、咽鳞癌、口腔鳞癌、鼻咽癌、食管癌、甲状腺癌、恶性胸膜间皮瘤、肺癌、乳腺癌、肝癌、肝胆癌、胰腺癌、胃癌、胃肠道癌、肠癌、结肠癌、结肠直肠癌、肾癌、透明细胞肾细胞癌、卵巢癌、子宫内膜癌、子宫颈癌、膀胱癌、前列腺癌、睾丸癌、皮肤癌、黑色素瘤、白血病、淋巴瘤、骨癌、软骨肉瘤、骨髓瘤、多发性骨髓瘤、骨髓异常增生综合征、库肯勃氏瘤、骨髓增生性肿瘤、鳞状细胞癌、尤因氏肉瘤、尿路上皮癌、梅克尔细胞癌、何杰金淋巴瘤、非何杰金淋巴瘤、弥漫性大B-细胞淋巴瘤、滤泡性淋巴瘤、原发性纵隔大B-细胞淋巴瘤、套细胞淋巴瘤、小淋巴细胞性淋巴瘤、富含T-细胞/组织细胞的大B-细胞淋巴瘤、淋巴浆细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、慢性髓细胞样白血病、急性髓细胞样白血病、淋巴细胞白血病、成淋巴细胞性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病和髓样细胞白血病。
另一方面,本披露进一步提供前述的抗TROP-2抗体,或前述的抗体-药物偶联物作为药物,优选作为治疗癌症或肿瘤的药物,更优选作为治疗表达TROP-2的癌症或肿瘤的药物。
本披露提供的抗TROP-2抗体及抗体-药物偶联物与细胞表面抗原具有良好的亲和力,可有效的被表达TROP2的细胞内吞,并具有很强的抑制肿瘤生长的效果,同时具有良好的安全性。
附图说明
图1:DT3C杀伤方法检测抗体被FaDu细胞内吞的实验结果;
图2:pHrodo方法检测抗体被FaDu细胞内吞的实验结果;
图3:给予TROP2-ADC治疗后,裸鼠体内的相对肿瘤体积曲线。
具体实施方式
一.术语
为了更容易理解本披露,以下对某些技术和科学术语进行了描述。除非在本文中另有明确定义,本文使用的全部技术和科学术语具有与本领域的普通技术人员通常所理解的相同含义。
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。
说明书和权利要求书中所用的单数形式“一个”、“一种”和“所述”包括复数指代,除非上下文清楚表明并非如此。
除非上下文另外清楚要求,否则在专利说明书和权利要求书中,应将词语“包含”、“具有”、“包括”等理解为“包括但不仅限于”的意义,而不是排他性或穷举性意义。
术语“和/或”,意指包含“和”与“或”两种含义。例如短语“A、B和/或C”旨在涵盖以下方面中的每一个:A、B和C;A、B或C;A或C;A或B;B或C;A和C;A和B;B和C;A(单独);B(单独);和C(单独)。当本披露中使用商品名时,旨在包括该商品名产品的制剂、该商品名产品的药物和活性药物部分。
本披露所用氨基酸三字母代码和单字母代码如J.biol.chem,243,p3558(1968)中所述。
术语“氨基酸”是指天然存在的和合成的氨基酸,以及以与天然存在的氨基酸类似的方式起作用的氨基酸类似物和氨基酸模拟物。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。氨基酸类似物是指与天然存在的氨基酸具有相同基本化学结构(即与氢、羧基、氨基和R基团结合的α碳)的化合物,例如高丝氨酸、正亮氨酸、甲硫氨酸亚砜、甲硫氨酸甲基锍。此类类似物具有修饰的R基团(例如,正亮氨酸)或修饰的肽骨架,但保留与天然存在的氨基酸相同的基本化学结构。氨基酸模拟物是指具有与氨基酸的一般化学结构不同的结构,但是以与天然存在的氨基酸类似的方式起作用的化学化合物。
术语“氨基酸突变”包括氨基酸取代(也称氨基酸替换)、缺失、插入和修饰。可以进行取代、缺失、插入和修饰的任意组合来实现最终构建体,只要最终构建体拥有期望的特性,例如降低或对Fc受体的结合。氨基酸序列缺失和插入包括在多肽链的氨基端和/或羧基端的缺失和插入。具体的氨基酸突变可以是氨基酸取代。在一个实施方式中,氨基酸突变是非保守性的氨基酸取代,即将一个氨基酸用具有不同结构和/或化学特性的另一种氨基酸替换。氨基酸取代包括由非天然存在的氨基酸或由20种天然氨基酸的衍生物(例如4-羟脯氨酸、3-甲基组氨酸、鸟氨酸、高丝氨酸、5-羟赖氨酸)替换。可以使用本领域中公知的遗传或化学方法生成氨基酸突变。遗传方法可以包括定点诱变、PCR,基因合成等。预计基因工程以外的改变氨基酸侧链基团的方法,如化学修饰也可能是可用的。本文中可使用各种名称来指示同一氨基酸突变。本文中,可采用位置+氨基酸残基的方式表示特定位点的氨基酸残基,例如366W,表示在366位点上的氨基酸残基为W。T366W则表示第366位点上的氨基酸残基由W取代了原来的T。
术语“抗体”以最广义使用,并且涵盖各种抗体结构,包括但不限于单克隆抗体、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)、全长抗体和抗体片段(或抗原结合片段,或抗原结合部分),只要它们展现出期望的抗原结合活性。完整抗体通常包含两条轻链和两条重链构成。从N至C端,每条重链具有一个可变区(VH),又称作可变重域、重链可变区,接着是三个恒定域(CH1、CH2和CH3)。类似地,从N至C端,每条轻链具有一个可变区(VL),又称作可变轻域,或轻链可变域,接着是一个恒定轻域(轻链恒定区、CL)。术语“全长抗体”、“完整抗体”和“全抗体”在本文可互换使用,指具有与天然抗体结构基本类似的结构或具有如本文所限定的Fc区的重链的抗体。天然完整抗体轻链包括轻链可变区VL及恒定区CL,VL处于轻链的氨基末端,轻链恒定区包括κ链及λ链;重链包括可变区VH及恒定区(CH1、CH2及CH3),VH处于重链的氨基末端,恒定区处于羧基末端,其中CH3最接近多肽的羧基末端,重链可属于任何同种型,包括IgG(包括IgG1、IgG2、IgG3及IgG4亚型)、IgA(包括IgA1及IgA2亚型)、IgM及IgE。
术语抗体“可变区”或“可变域”指抗体重链或轻链中涉及抗体结合抗原的域。本文中,抗体重链可变区(VH)和轻链可变区(VL)各包含四个保守的框架区(FR)和三个互补决定区(CDR)。其中,术语“互补决定区”或“CDR”指可变结构域内主要促成与抗原结合的区域;“框架”或“FR”是指除CDR残基之外的可变结构域残基。VH包含3个CDR区:HCDR1、HCDR2和HCDR3;VL包含3个CDR区:LCDR1、LCDR2和LCDR3。每个VH和VL由从氨基末端(也称N末端)排到羧基末端(也称C末端)按以下顺序排列的三个CDR和四个FR构成:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。
可以通过各种公知方案来确定CDR的氨基酸序列边界,例如:“Kabat”编号规则(参见Kabat等(1991),“Sequences of Proteins of Immunological Interest”,第5版,Public Health Service,National Institutes of Health,Bethesda,MD)、“Chothia”编号规则、“ABM”编号规则、“contact”编号规则(参见Martin,ACR.Protein Sequence andStructure Analysis of Antibody Variable Domains[J].2001)和ImMunoGenTics(IMGT)编号规则(Lefranc,M.P.等,Dev.Comp.Immunol.,27,55-77(2003);FrontImmunol.2018Oct 16;9:2278)等;各种编号系统之间的对应关系是本领域技术人员熟知的,示例性的,如下表1中所示。
表1.CDR编号系统之间的关系
CDR | IMGT | Kabat | AbM | Chothia | Contact |
HCDR1 | 27-38 | 31-35 | 26-35 | 26-32 | 30-35 |
HCDR2 | 56-65 | 50-65 | 50-58 | 52-56 | 47-58 |
HCDR3 | 105-117 | 95-102 | 95-102 | 95-102 | 93-101 |
LCDR1 | 27-38 | 24-34 | 24-34 | 24-34 | 30-36 |
LCDR2 | 56-65 | 50-56 | 50-56 | 50-56 | 46-55 |
LCDR3 | 105-117 | 89-97 | 89-97 | 89-97 | 89-96 |
除非另有说明,本披露中的可变区和CDR序列均适用“Kabat”编号规则。
术语“抗体片段”指不同于完整抗体的分子,其包含完整抗体的部分,所述部分与完整抗体所结合的抗原相结合。抗体片段的实例包括但不限于Fv、Fab、Fab’、Fab’-SH、F(ab′)2、单域抗体、单链Fab(scFab)、双抗体、线性抗体、单链抗体分子(例如scFv);以及由抗体片段形成的多特异性抗体。
术语“Fc区”或“片段可结晶区”用于定义抗体重链的C末端区域,包括天然Fc区和改造的Fc区。在一些实施方式中,Fc区包含了相同或不同的两个亚基。在一些实施方式中,人IgG重链的Fc区定义为从Cys226位置处的氨基酸残基或从Pro230延伸至其羧基末端。用于本文所述抗体的合适Fc区包括人IgG1、IgG2(IgG2A、IgG2B)、IgG3和IgG4的Fc区。在一些实施方式中,Fc区的边界还可以变化,例如缺失Fc区的C末端赖氨酸(根据EU编号系统的残基447)或缺失Fc区的C末端甘氨酸和赖氨酸(根据EU编号系统的残基446和447)。除非另有说明,Fc区的编号规则为EU编号系统,又称作EU索引。
术语“嵌合”抗体指抗体中的重和/或轻链的一部分由特定的来源或物种衍生,而重和/或轻链的剩余部分由另外的不同来源或物种衍生的抗体。
术语“人源化”抗体是保留非人抗体的反应性同时在人中具有较低免疫原性的抗体。例如,可以通过保留非人CDR区并用其人对应物(即,恒定区以及可变区的框架区部分)替换抗体的其余部分来实现。
术语“人抗体”、“人源抗体”、“全人抗体”、“完全人抗体”可以互换使用,意指可变区及恒定区是人序列的抗体。该术语涵盖源自人基因但具有,例如,降低可能的免疫原性、增加亲和力、消除可能会引起不期望的折叠的半胱氨酸或糖基化位点等序列已发生改变的抗体。该术语涵盖这些在非人细胞(其可能会赋予不具人细胞特征的糖基化)中重组产生的抗体。该术语亦涵盖已在含有一些或所有人免疫球蛋白重链及轻链基因座的转基因小鼠中饲养的抗体。人抗体的含义明确排除包含非人抗原结合残基的人源化抗体。
术语“亲和力”是指分子(例如,抗体)的单个结合部位与其结合配体(例如,抗原)之间非共价相互作用的总体的强度。除非另外指明,如本文所用,结合“亲和力”是指内部结合亲和力,其反映出结合对(例如,抗体与抗原)的成员之间1:1相互作用。分子X对其配体Y的亲和力通常可以由解离常数(KD)表示。亲和力可以通过本领域已知的常规方法(包括本文所述的那些方法)测量。
如本文所使用的,术语“kassoc”或“ka”指特定抗体-抗原相互作用的缔合速率,术语“kdis”或“kd”指特定抗体-抗原相互作用的解离速率。术语“KD”指解离常数,其获得自kd与ka的比率(即kd/ka)并且表示为摩尔浓度(M)。可以使用本领域公知的方法测定抗体的KD值。例如,使用生物传感系统例如系统测量表面等离子体共振,或通过溶液平衡滴定法(SET)测量溶液中的亲和力。
术语“效应子功能”指那些可归于抗体Fc区(天然序列Fc区或氨基酸序列突变的Fc区)且随抗体同种型而变化的生物学活性。抗体效应子功能的例子包括但不限于:C1q结合和补体依赖性细胞毒性、Fc受体结合、抗体依赖性细胞介导的细胞毒性(ADCC)、吞噬作用、细胞表面受体(例如B细胞受体)下调;和B细胞活化。
术语“单克隆抗体”指基本上均质的抗体的群,即在该群中包含的抗体分子的氨基酸序列是相同的,除了可能少量存在的天然突变以外。相比之下,多克隆抗体制剂通常包含在其可变结构域具有不同氨基酸序列的多种不同抗体,其通常特异性针对不同表位。“单克隆”表示从基本上均质的抗体群体获得的抗体的特征,并且不应解释为要求通过任何特定方法来生产抗体。在一些实施方式中,本披露提供的抗体是单克隆抗体。
术语“抗原”是指能够由诸如抗原结合蛋白(包括例如抗体)的选择性结合剂结合,且另外能够用于动物中以产生能够结合该抗原的抗体的分子或分子部分。抗原可具有一个或多个能够与不同的抗原结合蛋白(例如抗体)相互作用的表位。
术语“表位”指能够与抗体或其抗原结合片段特异性结合的抗原上的区域(area或region)。表位可以由连续氨基酸串(线性表位)形成或包含非连续氨基酸(构象表位),例如因抗原的折叠(即通过蛋白质性质的抗原的三级折叠)而变成空间接近。构象表位和线性表位的差别在于:在变性溶剂的存在下,抗体对构象表位的结合丧失。表位包含处于独特空间构象的至少3,至少4,至少5,至少6,至少7,或8-10个氨基酸。筛选结合特定表位的抗体(即那些结合相同表位的)可以使用本领域例行方法来进行,例如但不限于丙氨酸扫描,肽印迹,肽切割分析,表位切除,表位提取,抗原的化学修饰(见Prot.Sci.9(2000)487-496),和交叉阻断。
术语“抗TROP2抗体”和“结合TROP2的抗体”是指能够以足够的亲和力结合TROP2的抗体。在一个实施例中,抗TROP2抗体与无关蛋白的抗体的结合程度小于该抗体与TROP2结合的约10%,所述结合可通过表面等离子体共振测定法测量。
术语“能够特异性结合”、“特异性结合”或“结合”是指相比其他抗原或表位,抗体能够以更高的亲和力结合至某个抗原或该抗原的表位。通常地,抗体以约1×10-7M或更小(例如约1×10-8M或更小)的平衡解离常数(KD)结合抗原或抗原内的表位。在一些实施方式中,抗体与抗原结合的KD为该抗体结合至非特异性抗原(例如BSA、酪蛋白)的KD的10%或更低(例如1%)。可使用已知的方法来测量KD,例如通过表面等离子体共振测定法所测量的。然而,特异性结合至抗原或抗原内的表位的抗体可能对其它相关的抗原具有交叉反应性,例如,对来自其它物种(同源)(诸如人或猴,例如食蟹猕猴(Macacafascicularis)(cynomolgus,cyno)、黑猩猩(Pan troglodytes)(chimpanzee,chimp))或狨猴(Callithrix jacchus)(commonmarmoset,marmoset)的相应抗原具有交叉反应性。
术语“核酸”在本文中可与术语“多核苷酸”互换使用,并且是指呈单链或双链形式的脱氧核糖核苷酸或核糖核苷酸及其聚合物。所述术语涵盖含有已知核苷酸类似物或修饰的骨架残基或连接的核酸,所述核酸是合成的、天然存在的和非天然存在的,具有与参考核酸相似的结合特性,并且以类似于参考核苷酸的方式代谢。此类类似物的实例包括但不限于硫代磷酸酯、氨基磷酸酯、甲基膦酸酯、手性-甲基膦酸酯、2-O-甲基核糖核苷酸、肽-核酸(PNA)。“分离的”核酸指已经与其天然环境的组分分开的核酸分子。分离的核酸包括在下述细胞中含有的核酸分子,所述细胞通常含有该核酸分子,但该核酸分子存在于染色体外或存在于不同于其天然染色体位置的染色体位置处。编码多肽或融合蛋白的分离的核酸指编码多肽或融合蛋白的一个或更多个核酸分子,包括在单一载体或分开的载体中的这样的一个或更多个核酸分子,和存在于宿主细胞中一个或更多个位置的这样的一个或更多个核酸分子。除非另有说明,否则特定的核酸序列还隐含地涵盖其保守修饰的变体(例如,简并密码子取代)和互补序列以及明确指明的序列。具体地,如下详述,简并密码子取代可以通过产生如下序列而获得,在这些序列中,一个或多个所选的(或全部)密码子的第三位被混合碱基和/或脱氧肌苷残基取代。
术语“多肽”和“蛋白质”在本文中可互换使用,指氨基酸残基的聚合物。该术语适用于氨基酸聚合物,其中一个或多个氨基酸残基是相应天然存在的氨基酸的人工化学模拟物,以及适用于天然存在的氨基酸聚合物和非天然存在的氨基酸聚合物。除非另外说明,否则特定的多肽序列还隐含地涵盖其保守修饰的变体。
术语序列“同一性”指,当对两条序列进行最佳比对时,必要时引入间隙,以获取最大序列同一性百分比,且不将任何保守性取代视为序列同一性的一部分,两条序列的氨基酸/核酸在等价位置相同的程度(百分比)。为测定序列同一性百分比,比对可以通过本领域技术已知的技术来实现,例如使用公开可得到的计算机软件,诸如BLAST、BLAST-2、ALIGN、ALIGN-2或Megalign(DNASTAR)软件。本领域技术人员可确定适用于测量比对的参数,包括在所比较的序列全长上达成最大比对所需的任何算法。
术语“载体”意指能够转运与其连接的另一多核苷酸的多核苷酸分子。一种类型的载体是“质粒”,其是指环状双链DNA环,其中可以连接附加的DNA区段。另一种类型的载体是病毒载体,例如腺相关病毒载体(AAV或AAV2),其中另外的DNA区段可以连接到病毒基因组中。某些载体能够在引入它们的宿主细胞中自主复制(例如,具有细菌复制起点的细菌载体和附加型哺乳动物载体)。其他载体(例如,非附加型哺乳动物载体)可以在引入宿主细胞中后整合到宿主细胞的基因组中,从而与宿主基因组一起复制。术语“表达载体”或“表达构建体”是指可对宿主细胞进行转化,且含有指导和/或控制(连同宿主细胞一起)与其可操作地连接的一个或多个异源编码区的表达的核酸序列的载体。表达构建体可以包括但不限于影响或控制转录、翻译且在存在内含子时影响与其可操作地连接的编码区的RNA剪接的序列。
术语“宿主细胞”、“宿主细胞系”和“宿主细胞培养物”可互换使用,并且指已经导入外源核酸的细胞,包括此类细胞的后代。宿主细胞包括“转化体”和“经转化的细胞”,其包括原代的经转化的细胞及自其衍生的后代,而不考虑传代的次数。后代在核酸内容物上可以与亲本细胞不完全相同,可以含有突变。本文中包括具有与在初始转化细胞中筛选或选择的相同功能或生物学活性的突变体后代。宿主细胞包括原核和真核宿主细胞,其中真核宿主细胞包括但不限于哺乳动物细胞、昆虫细胞系植物细胞和真菌细胞。示例性的宿主细胞如下:中国仓鼠卵巢(CHO)细胞、NSO、SP2细胞、HeLa细胞、幼仓鼠肾(BHK)细胞、猴肾细胞(COS)、人肝细胞癌细胞(例如,HepG2)、A549细胞、3T3细胞和HEK-293细胞、巴氏毕赤酵母(Pichiapastoris)、芬兰毕赤酵母(Pichia finlandica)、白色念珠菌(Candidaalbicans)、黑曲霉(Aspergillus niger)、米曲霉(Aspergillus oryzae)、里氏木霉(Trichoderma reesei)。如在本申请中所使用的,表述“细胞”、“细胞系”和“细胞培养物”可以互换使用,并且所有这样的名称均包括子代。因而,词语“转化体”和“转化的细胞”包括原代受试者细胞和来源于其的培养物,而与传代的次数无关。还应理解的是,由于有意或无意的突变,使得并非所有子代均具有完全相同的DNA内容物。包括与原始转化细胞具有相同功能或生物活性的突变子代。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生的场合。
“抗体-药物偶联物”(antibody drug conjugate,ADC),是将抗体或者抗体片段直接或通过连接单元与具有生物活性的药物相连后得到的。
“药物(缩写:D)”是任何具有生物或可检测活性的物质,例如治疗剂、可检测标记、结合剂等和在体内代谢成活性剂的前药。治疗剂的实例包括细胞毒性剂、化学治疗剂、细胞生长抑制剂和免疫调节剂。化学治疗剂是可用于治疗癌症的化学化合物。代表性治疗剂包括细胞毒素、细胞毒性剂和细胞生长抑制剂。
细胞毒性效应是指缺失、消除和/或杀死目标细胞。细胞毒性剂是指对细胞具有细胞毒性和/或细胞生长抑制效应的药剂。细胞生长抑制效应是指抑制细胞增殖。细胞生长抑制剂是指对细胞具有细胞生长抑制效应、由此抑制细胞的特定亚组的生长和/或扩增的药剂。
额外代表性治疗剂包括放射性同位素、化学治疗剂、免疫调节剂、抗血管生成剂、抗增殖剂、促细胞凋亡剂和细胞裂解酶(例如,RNAse)。这些药物描述词并不互斥,且因此,可使用一个或多个上述术语描述治疗剂。例如,所选放射性同位素也是细胞毒素。治疗剂可制备为上述任一种的药学上可接受的盐、酸或衍生物。通常,具有放射性同位素作为药物的偶联物被称为放射性免疫偶联物,具有化学治疗剂作为药物的那些被称为化学免疫偶联物。
细胞毒性剂的实例包括,但不限于,蒽环霉素、奥里斯他汀、CC-1065、尾海兔素(dolastatin)、多卡米星、烯二炔、格尔德霉素(geldanamycin)、美登素(maytansine)、嘌呤霉素、紫杉烷、长春花生物碱、SN-38、微管溶素(tubulysin)、hemiasterlin、艾日布林、Trabectedin、Lubinectedin和其立体异构体、等排物、类似物或衍生物。也可使用化学治疗剂、植物毒素、其他生物活性蛋白质、酶(即,ADEPT)、放射性同位素、光敏剂(即,用于光动力学治疗)。
尾海兔素和其肽类似物和衍生物奥里斯他汀是高度有效的抗有丝分裂剂,已显示其具有抗癌和抗真菌活性。参见,例如,美国专利号5,663,149和Pettit等人,Antimicrob.Agents Chemother.42:2961-2965,(1998)。示例性尾海兔素和奥里斯他汀包括,但不限于,尾海兔素10、奥里斯他汀E、奥里斯他汀EB(AEB)、奥里斯他汀EFP(AEFP)、MMAD(单甲基奥里斯他汀D或单甲基尾海兔素10)、MMAF(单甲基奥里斯他汀F或N-甲基缬氨酸-缬氨酸-D,L-异亮氨酸(dolaisoleuine)-D,L-脯氨酸(dolaproine)-苯丙氨酸)、MMAE(单甲基奥里斯他汀E或N-甲基缬氨酸-缬氨酸-D,L-异亮氨酸-D,L-脯氨酸-降麻黄碱)、5-苯甲酰基戊酸-AE酯(AEVB)。
术语“标记”当本文中使用时是指直接或间接缀合至抗体以便生成“标记的”抗体的可检测化合物或组合物。标记可以是自身可检测(例如,放射性同位素标记或荧光标记),或在酶促标记的情况下,标记可催化底物化合物或组合物可检测的化学变化。可充当可检测标记的放射性核素包括,例如,I-131、I-123、I-125、Y-90、Re-188、Re-186、At-211、Cu-67、Bi-212、和Pd-109。标记也可以是不可检测的实体,诸如毒素。
放射性同位素或其他标记的实例包括,但不限于,3H、11C、13N、14C、15N、15O、35S、18F、32P、33P、47Sc、51Cr、57Co、58Co、59Fe、62Cu、64Cu、67Cu、67Ga、68Ga、75Se、76Br、77Br、86Y、89Zr、90Y、94Tc、95Ru、97Ru、99Tc、103Ru、105Rh、105Ru、107Hg、109Pd、111Ag、111In、113In、121Te、122Te、123I、124I、125I、125Te、126I、131I、131In、133I、142Pr、143Pr、153Pb、153Sm、161Tb、165Tm、166Dy、166H、167Tm、168Tm、169Yb、177Lu、186Re、188Re、189Re、197Pt、198Au、199Au、201Tl、203Hg、211At、212Bi、212Pb、213Bi、223Ra、224Ac和225Ac。
术语“接头单元”、“接头”、“连接单元”或“连接片段”是指一端与抗体连接而另一端与药物相连的化学结构片段或键,也可以连接其他接头后再与抗体或药物相连。接头附接至抗体可以多种方式完成,诸如经由表面赖氨酸、还原性偶联至氧化碳水化合物、通过还原链间二硫键释放的半胱氨酸残基、在特定位点处改造的反应性半胱氨酸残基、和含有酰基供体谷氨酰胺的标签或通过在转谷氨酰胺酶和胺存在下多肽改造使得具有反应性的内源性谷氨酰胺。多种ADC连接系统是本领域已知的,包括基于腙-、二硫化物-和肽-的连接。
接头可以包含一种或多种接头构件。示例性的接头构件包括6-马来酰亚氨基己酰基(“MC”)、马来酰亚氨基丙酰基(“MP”)、缬氨酸-瓜氨酸(“val-cit”或“vc”)、丙氨酸-苯丙氨酸(“ala-phe”)、对氨基苄氧羰基(“PAB”)、N-琥珀酰亚氨基4-(2-吡啶基硫代)戊酸酯(“SPP”)、N-琥珀酰亚氨基4-(N-马来酰亚氨基甲基)环己烷-1羧酸酯(“SMCC”,在本文中也称作“MCC”)和N-琥珀酰亚氨基(4-碘-乙酰基)氨基苯甲酸酯(“SIAB”)。接头可以选自以下的元件或其组合:延伸物、间隔物和氨基酸单元。可以通过本领域已知方法合成接头,诸如US2005-0238649A1中所记载的。接头可以是便于在细胞中释放药物的“可切割接头”。例如,可使用酸不稳定接头(例如腙)、蛋白酶敏感(例如肽酶敏感)接头、光不稳定接头、二甲基接头、或含二硫化物接头(Chari等,Cancer Research 52:127-131(1992);美国专利No.5,208,020)。
接头元件包括但不限于:
MC=6-马来酰亚氨基己酰基,结构如下:
Val-Cit或“vc”=缬氨酸-瓜氨酸(蛋白酶可切割接头中的示例二肽),
瓜氨酸=2-氨基-5-脲基戊酸,
PAB=对氨基苄氧羰基(“自我牺牲”接头元件的示例),
Me-Val-Cit=N-甲基-缬氨酸-瓜氨酸(其中接头肽键已经修饰以防止其受到组织蛋白酶B的切割),
MC(PEG)6-OH=马来酰亚氨基己酰基-聚乙二醇(可附着于抗体半胱氨酸),
SPP=N-琥珀酰亚氨基4-(2-吡啶基硫代)戊酸酯,
SPDP=N-琥珀酰亚氨基3-(2-吡啶基二硫代)丙酸酯,
SMCC=琥珀酰亚氨基-4-(N-马来酰亚氨基甲基)环己烷-1-羧酸酯,
IT=亚氨基硫烷。
“L-D”是药物(D)连接至接头(L)产生的接头-药物部分。
载药量,也称药物抗体比例(Drug-to-Antibody Ratio,DAR),即ADC中每个抗体所偶联的药物的平均数量。其可在例如每个抗体偶联约1至约10个药物的范围内,并且在某些实施例中,在每个抗体偶联约1至约8个药物的范围内,优选自2-8,2-7,2-6,2-5,2-4,1-3,3-4,3-5,5-6,5-7,5-8和6-8的范围。本披露的ADC通式包括前述一定范围内的抗体药物偶联物的集合。在本披露的实施方式中,载药量可表示为n,是小数或整数。可用常规方法如UV/可见光光谱法,质谱,ELISA试验和RP-HPLC测定载药量。
本披露的一个实施方式中,药物通过连接单元偶联在抗体的巯基上。
可以用以下非限制性方法控制配体细胞毒性药物偶联物的载量,包括:
(1)控制连接试剂和单抗的摩尔比,
(2)控制反应时间和温度,
(3)选择不同的反应试剂。
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷基,更优选为含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基,及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基,非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选独立地任选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“亚烷基”指饱和的直链或支链脂肪族烃基,其为从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基,其为包含1至20个碳原子的直链或支链基团,优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子,更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH2-)、1,1-亚乙基(-CH(CH3)-)、1,2-亚乙基(-CH2CH2)-、1,1-亚丙基(-CH(CH2CH3)-)、1,2-亚丙基(-CH2CH(CH3)-)、1,3-亚丙基(-CH2CH2CH2-)、1,4-亚丁基(-CH2CH2CH2CH2-)等。亚烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选独立地任选选自烯基、炔基、烷氧基、卤代烷氧基、环烷基氧基、杂环基氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基。
术语“烯基”指分子中含有碳碳双键的烷基化合物,其中烷基的定义如上所述。烯基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。
术语“炔基”指分子中含有碳碳三键的烷基化合物,其中烷基的定义如上所述。炔基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,优选包含3至12个碳原子,优选包含3至8个(例如3、4、5、6、7和8个)碳原子,更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等;多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元,单环之间共用一个碳原子(称螺原子)的多环基团,其可以含有一个或多个双键。优选为6至14元,更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基,优选为单螺环烷基和双螺环烷基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括:
术语“稠环烷基”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团,其中一个或多个环可以含有一个或多个双键。优选为6至14元,更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选为双环或三环,更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元的双环烷基。稠环烷基的非限制性实例包括:
术语“桥环烷基”指5至20元,任意两个环共用两个不直接连接的碳原子的全碳多环基团,其可以含有一个或多个双键。优选为6至14元,更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,优选为双环、三环或四环,更优选为双环或三环。桥环烷基的非限制性实例包括:
环烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基),其中烷基或环烷基的定义如上所述。烷氧基的非限制性示例包括:甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“卤代烷基”指烷基上的氢被一个或多个卤素取代,其中烷基如上所定义。
术语“氘代烷基”指烷基上的氢被一个或多个氘原子取代,其中烷基如上所定义。
术语“羟烷基”指烷基上的氢被一个或多个羟基取代,其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH2。
术语“硝基”指-NO2。
术语“氰基”指-CN。
术语“氧代基”或“氧代”指“=O”。
术语“羰基”指C=O。
术语“羧基”指-C(O)OH。
化学式中简称“Me”为甲基。
化学式中简称“Ph”为苯基。
术语“THF”指四氢呋喃。
术语“EtOAc”指乙酸乙酯。
术语“MeOH”指甲醇。
术语“DMF”指N,N-二甲基甲酰胺。
术语“DIPEA”指二异丙基乙胺。
术语“TFA”指三氟乙酸。
术语“MeCN”指乙晴。
术语“DMA”指N,N-二甲基乙酰胺。
术语“Et2O”指乙醚。
术语“DCE”指1,2二氯乙烷。
术语“DIPEA”指N,N-二异丙基乙胺。
术语“NBS”指N-溴代琥珀酰亚胺。
术语“NIS”指N-碘代丁二酰亚胺。
术语“Cbz-Cl”指氯甲酸苄酯。
术语“Pd2(dba)3”指三(二亚苄基丙酮)二钯。
术语“Dppf”指1,1’-双二苯基膦二茂铁。
术语“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。
术语“KHMDS”指六甲基二硅基胺基钾。
术语“LiHMDS”指双三甲基硅基胺基锂。
术语“MeLi”指甲基锂。
术语“n-BuLi”指正丁基锂。
术语“NaBH(OAc)3”指三乙酰氧基硼氢化钠。
术语“DCM”指二氯甲烷。
术语“DMAP”指4-二甲氨基吡啶。
术语“DMBOH”指2,4-二甲氧基苄醇。
术语“EDCI”指1-(3-二甲基氨基丙基)-3-乙基碳二亚胺。
术语“MTBE”指甲基叔丁基醚。
术语“DMF”指N,N-二甲基甲酰胺。
术语“DMTMM”指4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐。
术语“EtOAc”指乙酸乙酯。
术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变,用易于脱去的基团对氨基进行保护。非限制性实施例包含(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。
“取代的”指基团中的一个或多个氢原子,优选为1~5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本披露还包括各种氘化形式的式(Pc-L-Da)或(Pc-L-D)抗体-药物偶联物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(Pc-L-Da)或(Pc-L-D)抗体-药物偶联物。在制备氘代形式的式(Pc-L-Da)或(Pc-L-D)抗体-药物偶联物时可使用市售的氘代起始物质,或它们可使用常规技术采用氘代试剂合成,氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
术语“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
药物组合物可以是无菌注射水溶液形式。可在使用的可接受的溶媒和溶剂中有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射,将注射液或微乳注入受试者的血流中。或者,最好按可保持本披露化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度,可使用连续静脉内递药装置。这种装置的示例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术,用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液,例如1,3-丁二醇中制备的溶液。此外,可方便地用无菌固定油作为溶剂或悬浮介质。为此目的,可使用包括合成甘油单或二酯在内的任何调和固定油。此外,脂肪酸例如油酸也可以制备注射剂。
术语“药学上可接受的盐”或“可药用盐”是指本披露的抗体或抗体-药物偶联物的盐,这类盐用于受试者时具有安全性和有效性,且具有应有的生物活性,本披露抗体、或抗体药物偶联物至少含有一个氨基,因此可以与酸形成盐,可药用盐的非限制性示例包括:盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、柠檬酸盐、乙酸盐、琥珀酸盐、抗坏血酸盐、草酸盐、硝酸盐、梨酸盐、磷酸氢盐、磷酸二氢盐、水杨酸盐、柠檬酸氢盐、酒石酸盐、马来酸盐、富马酸盐、甲酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐。
术语“药学上可接受的载体”指药学配制剂中与活性成分不同的,且对受试者无毒的成分。药学可接受载剂包括但不限于缓冲剂、稳定剂或防腐剂。
术语“赋形剂”是在药物制剂中除主药以外的附加物,也可称为辅料。如片剂中的粘合剂、填充剂、崩解剂、润滑剂;半固体制剂软膏剂、霜剂中的基质部分;液体制剂中的防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等均可称为赋形剂。
术语“稀释剂”又称填充剂,其主要用途是增加片剂的重量和体积。稀释剂的加入不仅保证一定的体积大小,而且减少主要成分的剂量偏差,改善药物的压缩成型性等。当片剂的药物含有油性组分时,需加入吸收剂吸收油性物,使保持“干燥”状态,以利于制成片剂。如淀粉、乳糖、钙的无机盐、微晶纤维素等。
术语“受试者”或“个体”包括人类和非人类动物。非人动物包括所有脊椎动物(例如哺乳动物和非哺乳动物)例如非人灵长类(例如,食蟹猴)、绵羊、狗、牛、鸡、两栖动物和爬行动物。除非指出时,否则所述术语“患者”或“受试者”在本文中可互换地使用。如本文所使用的,术语“食蟹猴(cyno)”或“食蟹猴(cynomolgus)”是指食蟹猴(Macaca fascicularis)。在某些实施方案中,个体或受试者是人。
“施用”或“给予”,当其应用于动物、人、实验受试者、细胞、组织、器官或生物流体时,是指外源性药物、治疗剂、诊断剂或组合物与动物、人、受试者、细胞、组织、器官或生物流体的接触。
术语“样本”是指从受试者分离的类似流体、细胞、或组织的采集物,以及存在于受试者体内的流体、细胞或组织。示例性样本为生物流体,诸如血液、血清和浆膜液、血浆、淋巴液、尿液、唾液、囊液、泪液、排泄物、痰、分泌组织和器官的粘膜分泌物、阴道分泌物、腹水、胸膜、心包、腹膜、腹腔和其它体腔的流体、由支气管灌洗液收集的流体、滑液、与受试者或生物来源接触的液体溶液,例如细胞和器官培养基(包括细胞或器官条件培养基)、灌洗液等,组织活检样本、细针穿刺、手术切除的组织、器官培养物或细胞培养物。
“治疗(treatment或treat)”和“处理”(及其语法变型)指试图改变所治疗个体的天然过程的临床干预,并且可以为了预防或者在临床病理学的过程期间实施。治疗的期望效果包括但不限于预防疾病的发生或再发生,减轻症状,减轻/减少疾病的任何直接或间接病理后果,预防转移,降低疾病进展速率,改善或减轻疾病状态,和消退或改善的预后。在一些实施方案中,使用本披露的抗体来延迟疾病的形成或减缓疾病的进展。
“有效量”一般是足以降低症状的严重程度及/或频率、消除这些症状及/或潜在病因、预防症状及/或其潜在病因出现及/或改良或改善由疾病状态引起或与其相关的损伤(例如肺病)的量。在一些实施例中,有效量是治疗有效量或预防有效量。“治疗有效量”是足以治疗疾病状态或症状、尤其与该疾病状态相关的状态或症状,或者以其他方式预防、阻碍、延迟或逆转该疾病状态或以任何方式与该疾病相关的任何其他不理想症状的进展的量。“预防有效量”是当给予受试者时将具有预定预防效应,例如预防或延迟该疾病状态的发作(或复发),或者降低该疾病状态或相关症状的发作(或复发)可能性的量。完全治疗或预防效未必在给予一个剂量之后便发生,可能在给予一系列剂量之后发生。因而,治疗或预防有效量可以一次或多次给予的方式给予。“治疗有效量”和“预防有效量”可取决于多种因素变化:诸如个体的疾病状态、年龄、性别和体重,以及治疗剂或治疗剂组合在个体中引发期望的应答的能力。有效治疗剂或治疗剂组合的示例性指标包括例如患者改善的健康状况。
二、具体实施方式的描述
A.示例性的抗TROP2的抗体
在一个方面中,本披露提供结合TROP2的抗体。在一个方面中,提供结合TROP2的分离的抗体。在一个方面中,本披露提供特异性结合TROP2的抗体。
在某些实施方案中,前述的抗TROP2抗体具有以下特性中的至少一种:
a.对人和食蟹猴的TROP2具有交叉结合活性;
b.与人TROP2结合的KD值≤1nM、≤0.8nM或≤0.5nM;所述的KD值是通过Biacore测定;
c.可被表达TROP2的细胞内吞;
d.具有选择性,对表达TROP2水平不同的细胞,具有不同程度的亲和力;和
e.所述抗体与表达TROP2的FaDu细胞结合的EC50≤0.4μg/mL,所述EC50通过FACS检测。
在一个方面中,本披露提供一种抗TROP2的抗体,其包含选自以下的至少一个、两个、三个、四个、五个或六个CDRs:
(i)HCDR1,其包含SEQ ID NO:9的氨基酸序列;(ii)HCDR2,其包含SEQ ID NO:24的氨基酸序列;(iii)HCDR3,其包含SEQ ID NO:11的氨基酸序列;(iv)LCDR1,其包含SEQ IDNO:12的氨基酸序列;(v)LCDR2,其包含SEQ ID NO:13的氨基酸序列;和(vi)LCDR3,其包含SEQ ID NO:14的氨基酸序列;或
(i)HCDR1,其包含SEQ ID NO:15的氨基酸序列;(ii)HCDR2,其包含SEQ ID NO:16的氨基酸序列;(iii)HCDR3,其包含SEQ ID NO:17的氨基酸序列;(iv)LCDR1,其包含SEQ IDNO:18的氨基酸序列;(v)LCDR2,其包含SEQ ID NO:19的氨基酸序列;和(vi)LCDR3,其包含SEQ ID NO:20的氨基酸序列。
在一个方面中,本披露提供一种抗TROP2的抗体,其包含选自以下的至少一个、两个、三个、四个、五个或六个CDRs:
(i)HCDR1,其包含SEQ ID NO:9的氨基酸序列;(ii)HCDR2,其包含SEQ ID NO:10的氨基酸序列;(iii)HCDR3,其包含SEQ ID NO:11的氨基酸序列;(iv)LCDR1,其包含SEQ IDNO:12的氨基酸序列;(v)LCDR2,其包含SEQ ID NO:13的氨基酸序列;和(vi)LCDR3,其包含SEQ ID NO:14的氨基酸序列;或
(i)HCDR1,其包含SEQ ID NO:9的氨基酸序列;(ii)HCDR2,其包含SEQ ID NO:21的氨基酸序列;(iii)HCDR3,其包含SEQ ID NO:11的氨基酸序列;(iv)LCDR1,其包含SEQ IDNO:12的氨基酸序列;(v)LCDR2,其包含SEQ ID NO:13的氨基酸序列;和(vi)LCDR3,其包含SEQ ID NO:14的氨基酸序列;或
(i)HCDR1,其包含SEQ ID NO:9的氨基酸序列;(ii)HCDR2,其包含SEQ ID NO:22的氨基酸序列;(iii)HCDR3,其包含SEQ ID NO:11的氨基酸序列;(iv)LCDR1,其包含SEQ IDNO:12的氨基酸序列;(v)LCDR2,其包含SEQ ID NO:13的氨基酸序列;和(vi)LCDR3,其包含SEQ ID NO:14的氨基酸序列;或
(i)HCDR1,其包含SEQ ID NO:9的氨基酸序列;(ii)HCDR2,其包含SEQ ID NO:23的氨基酸序列;(iii)HCDR3,其包含SEQ ID NO:11的氨基酸序列;(iv)LCDR1,其包含SEQ IDNO:12的氨基酸序列;(v)LCDR2,其包含SEQ ID NO:13的氨基酸序列;和(vi)LCDR3,其包含SEQ ID NO:14的氨基酸序列。
在一个方面中,本披露提供一种抗TROP2的抗体,其包含SEQ ID NO:5的重链可变区的HCDRs和SEQ ID NO:6的轻链可变区的LCDRs;或
其包含SEQ ID NO:7的重链可变区的HCDRs和SEQ ID NO:8的轻链可变区的LCDRs。
在一些实施方案中,所述的CDRs序列根据本领域内公知的编号方法获得,所述的编号规则包括但不限于Kabat、Chothia、IMGT、AbM和Contact。
在一个方面中,本披露提供一种抗TROP2的抗体,其包含:
HCDR1,其序列如SEQ ID NO:9所示,或与SEQ ID NO:9相比包含3、2或1个氨基酸差异;
HCDR2,其序列如SEQ ID NO:10所示,或与SEQ ID NO:10相比包含3、2或1个氨基酸差异;
HCDR3,其序列如SEQ ID NO:11所示,或与SEQ ID NO:11相比包含3、2或1个氨基酸差异;
LCDR1,其序列如SEQ ID NO:12所示,或与SEQ ID NO:12相比包含3、2或1个氨基酸差异;
LCDR2,其序列如SEQ ID NO:13所示,或与SEQ ID NO:13相比包含3、2或1个氨基酸差异;和
LCDR3,其序列如SEQ ID NO:14所示,或与SEQ ID NO:14相比包含3、2或1个氨基酸差异。
在一个方面中,本披露提供一种抗TROP2的抗体,其包含:
HCDR1,其序列如SEQ ID NO:9所示,或与SEQ ID NO:9相比包含3、2或1个氨基酸差异;
HCDR2,其序列如SEQ ID NO:21所示,或与SEQ ID NO:21相比包含3、2或1个氨基酸差异;
HCDR3,其序列如SEQ ID NO:11所示,或与SEQ ID NO:11相比包含3、2或1个氨基酸差异;
LCDR1,其序列如SEQ ID NO:12所示,或与SEQ ID NO:12相比包含3、2或1个氨基酸差异;
LCDR2,其序列如SEQ ID NO:13所示,或与SEQ ID NO:13相比包含3、2或1个氨基酸差异;和
LCDR3,其序列如SEQ ID NO:14所示,或与SEQ ID NO:14相比包含3、2或1个氨基酸差异。
在一个方面中,本披露提供一种抗TROP2的抗体,其包含:
HCDR1,其序列如SEQ ID NO:9所示,或与SEQ ID NO:9相比包含3、2或1个氨基酸差异;
HCDR2,其序列如SEQ ID NO:22所示,或与SEQ ID NO:22相比包含3、2或1个氨基酸差异;
HCDR3,其序列如SEQ ID NO:11所示,或与SEQ ID NO:11相比包含3、2或1个氨基酸差异;
LCDR1,其序列如SEQ ID NO:12所示,或与SEQ ID NO:12相比包含3、2或1个氨基酸差异;
LCDR2,其序列如SEQ ID NO:13所示,或与SEQ ID NO:13相比包含3、2或1个氨基酸差异;和
LCDR3,其序列如SEQ ID NO:14所示,或与SEQ ID NO:14相比包含3、2或1个氨基酸差异。
在一个方面中,本披露提供一种抗TROP2的抗体,其包含:
HCDR1,其序列如SEQ ID NO:9所示,或与SEQ ID NO:9相比包含3、2或1个氨基酸差异;
HCDR2,其序列如SEQ ID NO:23所示,或与SEQ ID NO:23相比包含3、2或1个氨基酸差异;
HCDR3,其序列如SEQ ID NO:11所示,或与SEQ ID NO:11相比包含3、2或1个氨基酸差异;
LCDR1,其序列如SEQ ID NO:12所示,或与SEQ ID NO:12相比包含3、2或1个氨基酸差异;
LCDR2,其序列如SEQ ID NO:13所示,或与SEQ ID NO:13相比包含3、2或1个氨基酸差异;和
LCDR3,其序列如SEQ ID NO:14所示,或与SEQ ID NO:14相比包含3、2或1个氨基酸差异。
在一个方面中,本披露提供一种抗TROP2的抗体,其包含:
HCDR1,其序列如SEQ ID NO:15所示,或与SEQ ID NO:15相比包含3、2或1个氨基酸差异;
HCDR2,其序列如SEQ ID NO:16所示,或与SEQ ID NO:16相比包含3、2或1个氨基酸差异;
HCDR3,其序列如SEQ ID NO:17所示,或与SEQ ID NO:17相比包含3、2或1个氨基酸差异;
LCDR1,其序列如SEQ ID NO:18所示,或与SEQ ID NO:18相比包含3、2或1个氨基酸差异;
LCDR2,其序列如SEQ ID NO:19所示,或与SEQ ID NO:19相比包含3、2或1个氨基酸差异;和
LCDR3,其序列如SEQ ID NO:20所示,或与SEQ ID NO:20相比包含3、2或1个氨基酸差异。
在一个方面中,本披露提供一种抗TROP2的抗体,其包含重链可变区和轻链可变区,其中:
所述重链可变区包含分别如SEQ ID NO:9、SEQ ID NO:10和SEQ ID NO:11所示的HCDR1、HCDR2和HCDR3;和
所述轻链可变区包含分别如SEQ ID NO:12、SEQ ID NO:13和SEQ ID NO:14所示的LCDR1、LCDR2和LCDR3。
在一个方面中,本披露提供一种抗TROP2的抗体,其包含重链可变区和轻链可变区,其中:
所述重链可变区包含分别如SEQ ID NO:9、SEQ ID NO:21和SEQ ID NO:11所示的HCDR1、HCDR2和HCDR3;和
所述轻链可变区包含分别如SEQ ID NO:12、SEQ ID NO:13和SEQ ID NO:14所示的LCDR1、LCDR2和LCDR3。
在一个方面中,本披露提供一种抗TROP2的抗体,其包含重链可变区和轻链可变区,其中:
所述重链可变区包含分别如SEQ ID NO:9、SEQ ID NO:22和SEQ ID NO:11所示的HCDR1、HCDR2和HCDR3;和
所述轻链可变区包含分别如SEQ ID NO:12、SEQ ID NO:13和SEQ ID NO:14所示的LCDR1、LCDR2和LCDR3。
在一个方面中,本披露提供一种抗TROP2的抗体,其包含重链可变区和轻链可变区,其中:
所述重链可变区包含分别如SEQ ID NO:9、SEQ ID NO:23和SEQ ID NO:11所示的HCDR1、HCDR2和HCDR3;和
所述轻链可变区包含分别如SEQ ID NO:12、SEQ ID NO:13和SEQ ID NO:14所示的LCDR1、LCDR2和LCDR3。
在一个方面中,本披露提供一种抗TROP2的抗体,其包含重链可变区和轻链可变区,其中:
所述重链可变区包含分别如SEQ ID NO:15、SEQ ID NO:16和SEQ ID NO:17所示的HCDR1、HCDR2和HCDR3;和
所述轻链可变区包含分别如SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:20所示的LCDR1、LCDR2和LCDR3。
在另一个方面,抗TROP2抗体的重链可变区包含与SEQ ID NO:5、25、26、27、28、29、30、31或32中的任一氨基酸序列分别具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的序列。在某些实施方案中,具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相对于参考序列的替代(例如保守替代)、插入或缺失,但是包含该序列的抗TROP2抗体保留结合TROP2的能力。在某些实施方案中,替代、插入或缺失发生在CDR以外的区域中(即,FR中)。
在另一个方面,抗TROP2抗体的轻链可变区包含与SEQ ID NO:6、33、34或35中的任一氨基酸序列分别具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的序列。在某些实施方案中,具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相对于参考序列的替代(例如保守替代)、插入或缺失,但是包含该序列的抗TROP2抗体保留结合TROP2的能力。在某些实施方案中,替代、插入或缺失发生在CDR以外的区域中(即,FR中)。
在另一个方面,抗TROP2抗体的重链可变区包含与SEQ ID NO:7、36、37、38或39中的任一氨基酸序列分别具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的序列。在某些实施方案中,具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相对于参考序列的替代(例如保守替代)、插入或缺失,但是包含该序列的抗TROP2抗体保留结合TROP2的能力。在某些实施方案中,替代、插入或缺失发生在CDR以外的区域中(即,FR中)。
在另一个方面,抗TROP2抗体的轻链可变区包含与SEQ ID NO:8、40、41或42中的任一氨基酸序列分别具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%同一性的序列。在某些实施方案中,具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%或99%相对于参考序列的替代(例如保守替代)、插入或缺失,但是包含该序列的抗TROP2抗体保留结合TROP2的能力。在某些实施方案中,替代、插入或缺失发生在CDR以外的区域中(即,FR中)。
在一些实施方案中,前述的抗TROP2抗体包含如SEQ ID NO:5、25、26、27、28、29、30、31或32任一所示的重链可变区,和/或如SEQ ID NO:6、33、34或35任一所示的轻链可变区。
在一些实施方案中,前述的抗TROP2抗体包含如SEQ ID NO:7、36、37、38或39任一所示的重链可变区,和/或如SEQ ID NO:8、40、41或42任一所示的轻链可变区。
在一些实施方案中,前述的抗TROP2抗体包含如SEQ ID NO:5所示的重链可变区,和/或如SEQ ID NO:6任一所示的轻链可变区。
在一些实施方案中,前述的抗TROP2抗体包含如SEQ ID NO:25、26、27、28、29、30、31或32任一所示的重链可变区,和/或如SEQ ID NO:33、34或35任一所示的轻链可变区。
在一些实施方案中,前述的抗TROP2抗体包含如SEQ ID NO:7所示的重链可变区,和/或如SEQ ID NO:8所示的轻链可变区。
在一些实施方案中,前述的抗TROP2抗体包含如SEQ ID NO:36、37、38或39任一所示的重链可变区,和/或如SEQ ID NO:40、41或42任一所示的轻链可变区。
在一些实施方案中,前述的抗TROP2抗体包含如SEQ ID NO:28所示的重链可变区,和如SEQ ID NO:35所示的轻链可变区。
在一些实施方案中,前述的抗TROP2抗体包含如SEQ ID NO:36所示的重链可变区,和如SEQ ID NO:41所示的轻链可变区。
在一些实施方案中,前述的抗TROP2抗体其包含重链恒定区和轻链恒定区。
在一些实施方案中,前述的抗TROP2抗体,其重链恒定区的序列如SEQ ID NO:43所示。
在一些实施方案中,前述的抗TROP2抗体,其轻链恒定区的序列如SEQ ID NO:44所示。
在一些实施方案中,前述的抗TROP2抗体,其包含如SEQ ID NO:45所示的重链,和如SEQ ID NO:46所示的轻链。
在一些实施方案中,前述的抗TROP2抗体,其包含如SEQ ID NO:47所示的重链,和如SEQ ID NO:48所示的轻链。
B.抗体结构
在某些实施方案中,本文中提供的抗体是全长抗体。
在某些实施方案中,本文中提供的抗体是抗体片段。
在一个实施方案中,抗体片段是Fab、Fab'、Fab'-SH或F(ab')2片段,特别是Fab片段。“Fab”,其是由VL、VH、CL和CH1结构域组成的单价片段。“Fab片段”可以是抗体经木瓜蛋白酶裂解产生的。“Fab'”含有VL、CL以及VH和CH1,还含有CH1和CH2结构域之间的区域,以使得在两个Fab'片段的两条重链之间可以形成链间二硫键,以形成F(ab')2分子。“Fab'-SH”是其中恒定区的半胱氨酸残基具有游离巯基的Fab'片段。“F(ab')2”包含在铰链区通过二硫键连接的两个Fab片段的二价片段。
在另一个实施方案中,抗体片段是双抗体,三抗体或四抗体。双抗体是具有两个抗原结合位点的抗体片段,该片段在同一条多肽链(VH-VL)中包含相连的VH和VL。通过使用过短的接头使得同一条链上的两个结构域之间不能配对,迫使这些结构域与另一条链的互补结构域配对,从而产生两个抗原结合位点,两个抗原可以是相同或不同的
在另一个实施方案中,抗体片段是单链Fab片段。“单链Fab片段”或“scFab”是由VH,CH1,VL,CL和接头组成的多肽,其中所述抗体域和所述接头在N端至C端方向具有以下顺序之一:a)VH-CH1-接头-VL-CL,b)VL-CL-接头-VH-CH1,c)VH-CL-接头-VL-CH1或d)VL-CH1-接头-VH-CL。在一个实施方式中,所述接头是具有至少30个氨基酸的多肽。在另一个实施方式中,所述接头是具有32至50个氨基酸之间的多肽。所述单链Fab片段经由CL和CH1之间的天然二硫键而被稳定化。另外,通过插入半胱氨酸残基(例如在重链可变区中的位置44和轻链可变区中的位置100,根据Kabat编号)产生链间二硫键,这些单链Fab分子可以进一步被稳定化。
在另一个实施方案中,抗体片段是单链可变片段(scFv)。“scFv”是包含至少一个含有轻链可变区的抗体片段和至少一个含有重链可变区的抗体片段的融合蛋白,其中轻链可变区和重链可变区通过短的柔性肽接头连续连接,能够表达为单链多肽,并且其中scFv保持其所源自的完整抗体的特异性。除非特别指出,否则在本文中scFv可以以任何一种顺序具有VL和VH可变区,例如相对于多肽的N端和C端,scFv可以包含VL-接头-VH或可以包含VH-接头-VL。
在另一个实施方案中,抗体片段是单域抗体。单域抗体是包含抗体的整个或部分重链可变域或整个或部分轻链可变域的抗体片段。
在某些实施方案中,本文中提供的抗体是嵌合抗体。在一个例子中,嵌合抗体包含非人可变区(例如自小鼠、大鼠、仓鼠、家兔、或非人灵长类,诸如猴衍生的可变区)和人恒定区。在又一个例子中,嵌合抗体是“类转换的”抗体,其中类或亚类已经自亲本抗体的类或亚类改变。
在某些实施方案中,抗体是人源化抗体。通常,将非人抗体通过人源化以降低对人的免疫原性,同时保留亲本非人抗体的特异性和亲和力。一般地,人源化抗体包含一个或多个可变区,其中CDR或其部分衍生自非人抗体,而FR或其部分衍生自人抗体。任选地,人源化抗体还会包含人恒定区的一部分。在一些实施方案中,可将人源化抗体中的一些FR残基用来自非人抗体(例如提供CDR序列的抗体)的相应残基替代。
人源化抗体及其生成方法综述于如Almagro and Fransson,Front.Biosci.13:1619-1633(2008),并且进一步记载于如Riechmann等,Nature 332:323-329(1988);Queen等,Proc.Nat'l Acad.Sci.USA 86:10029-10033(1989);美国专利No.5,821,337,7,527,791,6,982,321和7,087,409;Kashmiri等,Methods 36:25-34(2005)(描述了特异性决定区(SDR)嫁接);Padlan,Mol.Immunol.28:489-498(1991)(描述了“再表面”(resurfuacing));Dall’Acqua等,Methods 36:43-60(2005)(描述了“FR改组”);和Osbourn等,Methods 36:61-68(2005)和Klimka等,Br.J.Cancer 83:252-260(2000)(描述了FR改组的“引导选择”方法)。
可以用于人源化的人框架区包括但不限于:使用“最佳拟合(best-fit)”方法选择的框架区(见例如Sims等,J.Immunol.151:2296(1993));衍生自轻链可变区或重链可变区的特定亚组的人抗体的共有序列的框架区(见例如Carter等Proc.Natl.Acad.Sci.USA,89:4285(1992);和Presta等,J.Immunol.,151:2623(1993));人成熟的(体细胞突变的)框架区或人种系框架区(见例如Almagro and Fransson,Front.Biosci.13:1619-1633(2008));和通过筛选FR文库获得的框架区(见例如Baca等,J.Biol.Chem.272:10678-10684(1997)和Rosok等,J.Biol.Chem.271:22611-22618(1996))。
在某些实施方案中,本文中提供的抗体是多特异性抗体,例如双特异性抗体。多特异性抗体是对至少两种不同位点(即不同抗原上的不同表位或相同抗原上的不同表位)具有结合特异性的单克隆抗体。在某些实施方案中,多特异性抗体具有三种或更多种结合特异性。在某些实施方案中,结合特异性之一针对TROP2,而其它特异性针对任何其它抗原。在某些实施方案中,双特异性抗体可以结合TROP2的两种(或更多种)不同表位。也可以使用多特异性(例如双特异性)抗体来将细胞毒性药剂或细胞定位于表达TROP2的细胞。多特异性抗体可以以全长抗体或抗体片段制备。
用于生成多特异性抗体的技术包括但不限于具有不同特异性的两对免疫球蛋白重链-轻链的重组共表达(见Milstein and Cuello,Nature 305:537(1983)),和“杵臼”工程化(见例如美国专利No.5,731,168和Atwell等,J.Mol.Biol.270:26(1997))。也可以通过用于生成抗体Fc-异二聚体分子的工程化静电操纵效应(见例如WO 2009/089004);交联两种或更多种抗体或片段(见例如美国专利No.4,676,980和Brennan等,Science,229:81(1985));使用亮氨酸拉链来生成双特异性抗体(见例如Kostelny etal.,J.Immunol.,148(5):1547-1553(1992)和WO 2011/034605);使用共同轻链技术来规避轻链错配问题(见例如WO 98/50431);使用用于生成双特异性抗体片段的“双抗体”技术(见例如Hollinger等,Proc.Natl.Acad.Sci.USA,90:6444-6448(1993));和使用单链Fv(sFv)二聚体(参见,例如Gruber等,J.Immunol.,152:5368(1994));和例如Tutt等J.Immunol.147:60(1991)中所描述的,制备三特异性抗体来生成多特异性抗体。
C.抗体的修饰
在某些实施方案中,涵盖本文中提供的抗体的氨基酸序列变体。例如,可以期望改善抗体的结合亲和力和/或其它生物学特性。可以通过将合适的修饰引入编码抗体的核苷酸序列中,或者通过肽合成来制备抗体的氨基酸序列变体。此类修饰包括例如对抗体的氨基酸序列内的残基的删除、和/或插入、和/或替代。可以进行删除、插入、和替代的任何组合以得到最终的构建体,只要最终的构建体拥有期望的特征,例如抗原结合。
a)替代、插入、和删除变体
在某些实施方案中,提供了具有一处或多处氨基酸替代的抗体变体。替代诱变感兴趣的位点包括CDR和FR。保守替代在表2中在“优选的替代”的标题下显示。更实质的变化在表2中在“示例性替代”的标题下提供,并且如下文参照氨基酸侧链类别进一步描述的。可以将氨基酸替代引入感兴趣的抗体中,并且对产物筛选期望的活性,例如保留/改善的抗原结合,降低的免疫原性,或改善的ADCC或CDC。
表2
原始残基 | 示例性替代 | 优选的替代 |
Ala(A) | Val;Leu;Ile | Val |
Arg(R) | Lys;Gln;Asn | Lys |
Asn(N) | Gln;His;Asp,Lys;Arg | Gln |
Asp(D) | Glu;Asn | Glu |
Cys(C) | Ser;Ala | Ser |
Gln(Q) | Asn;Glu | Asn |
Glu(E) | Asp;Gln | Asp |
Gly(G) | Ala | Ala |
His(H) | Asn;Gln;Lys;Arg | Arg |
Ile(I) | Leu;Val;Met;Ala;Phe;正亮氨酸 | Leu |
Leu(L) | 正亮氨酸;Ile;Val;Met;Ala;Phe | Ile |
Lys(K) | Arg;Gln;Asn | Arg |
Met(M) | Leu;Phe;Ile | Leu |
Phe(F) | Trp;Leu;Val;Ile;Ala;Tyr | Tyr |
Pro(P) | Ala | Ala |
Ser(S) | Thr | Thr |
Thr(T) | Ser | Ser |
Trp(W) | Tyr;Phe | Tyr |
Tyr(Y) | Trp;Phe;Thr;Ser | Phe |
Val(V) | Ile;Leu;Met;Phe;Ala;正亮氨酸 | Leu |
依照常见的侧链特性,氨基酸可以如下分组:
(1)疏水性的:正亮氨酸,Met,Ala,Val,Leu,Ile;
(2)中性,亲水性的:Cys,Ser,Thr,Asn,Gln;
(3)酸性的:Asp,Glu;
(4)碱性的:His,Lys,Arg;
(5)影响链取向的残基:Gly,Pro;
(6)芳香族的:Trp,Tyr,Phe。
非保守替代会需要用这些类别之一的成员替换另一个类别的成员。
在某些实施方案中,替代、插入或缺失可以在一个或多个CDR内发生,只要此类变化不实质性降低抗体结合抗原的能力。例如,可以对CDR做出保守变化(例如保守替代,如本文中提供的),其不实质性降低结合亲和力。此类变化可以例如在CDR中的抗原接触残基外部。在上文提供的变体VH和VL序列的某些实施方案中,每个CDR是未改变的,或者含有不超过1、2或3处氨基酸替代。
一种可用于鉴定抗体中可以作为诱变靶位的残基或区域的方法称作“丙氨酸扫描诱变”,如由Cunningham and Wells(1989)Science,244:1081-1085所描述的。。在这种方法中,鉴定一个残基或靶残基组(例如带电荷的残基,诸如Arg、Asp、His、Lys和Glu),并且用中性或带负电荷的氨基酸(例如,Ala或聚丙氨酸)替换以确定该抗体与抗原的相互作用是否受影响。可以在对初始替代显示功能敏感性的氨基酸位置引入进一步的替代。此外,可通过研究抗原-抗体复合物的晶体结构来鉴定抗体与抗原间的接触点。这些接触残基及邻近残基可以作为替代候选物被打靶或消除。可以筛选变体以确定它们是否含有期望的特性。
氨基酸序列插入包括长度范围为1个残基至含有100或更多个残基的多肽的氨基和/或羧基端融合,和单个或多个氨基酸残基的序列内插入。末端插入的例子包括具有N端甲硫氨酰基残基的抗体。抗体分子的其它插入变体包括抗体的N或C端与酶或延长抗体的血清半衰期的多肽的融合物。
b)Fc区修饰
在某些实施方案中,可以将一个或多个氨基酸修饰引入本文所提供的抗体的Fc区中。
在一些实施方案中,所述一个或多个氨基酸修饰可减少Fc与Fc受体的结合,例如其与Fcγ受体的结合,并且降低或消除效应子功能。在一些实施方案中,改造的Fc区与天然Fc区相比,对Fc受体的结合亲和力下降50%、80%、90%或95%以上。在一些实施方案中,所述Fc受体是人Fcγ受体,例如FcγRI、FcγRIIa、FcγRIIB、FcγRIIIa。在一些实施方案中,改造的Fc区与天然Fc区相比,对补体,如C1q的结合亲和力也降低。在一些实施方案中,改造的Fc区与天然Fc区相比,对新生儿Fc受体(FcRn)的结合亲和力增强;比如在Fc区引入M252Y/S254T/T256E突变。在一些实施例中,改造的Fc区具有降低的效应子功能,所述降低的效应子功能可以包括但不限于以下中的一个或多个:降低的补体依赖性细胞毒性(CDC)、降低的抗体依赖性细胞介导的细胞毒性(ADCC)、降低的抗体依赖性细胞吞噬(ADCP)、减少的细胞因子分泌、减少的免疫复合物介导的抗原呈递细胞的抗原摄取、减少的与NK细胞的结合、减少的与巨噬细胞的结合、减少的与单核细胞的结合、减少的与多形核细胞的结合、减少的直接信号传导诱导性细胞凋亡、降低的树突细胞成熟或减少的T细胞引发。对于IgG1Fc区,在238、265、269、270、297、327和329等位置的氨基酸残基取代可降低的效应子功能。在一些实施方案中,所述Fc区是人IgG1 Fc区,并且在234和235位置的氨基酸残基为A,编号依据为EU索引。对于IgG4 Fc区,在228等位置的氨基酸残基取代可降低的效应子功能。
在某些实施方案中,抗体包含具有改善ADCC的一处或多处氨基酸替代,例如在Fc区的位置298、333、和/或334(采用EU编号系统)的替代。
在某些实施方案中,本文中的抗体的Fc域包含“杵臼”突变。“杵臼”是一种用于工程化改造抗体重链同二聚体进行异二聚化(例如为了有效生成双特异性抗体,多特异性抗体,或独臂抗体)的设计策略。一般地,此类技术牵涉引入第一多肽(诸如第一抗体重链中的第一CH3域)的界面处的隆起(“杵”)和第二多肽(诸如第二抗体重链中的第二CH3域)的界面中的对应空腔(“臼”),使得隆起能安置在空腔中从而促进异二聚体形成和阻碍同二聚体形成。通过将来自第一多肽(诸如第一抗体重链中的第一CH3域)的界面的较小氨基酸侧链用较大侧链(例如精氨酸,苯丙氨酸,酪氨酸或色氨酸)替换来构建隆起。通过将较大氨基酸侧链用较小侧链(例如丙氨酸,丝氨酸,缬氨酸,或苏氨酸)替换在第二多肽(诸如第二抗体重链中的第二CH3域)的界面中创建与隆起相同或相似尺寸的补偿性空腔。可以通过改变编码多肽的核酸(例如通过位点特异性诱变)或通过肽合成来生成隆起和空腔。在一些实施方案中,杵修饰包含Fc域的两个亚基之一中的氨基酸替代T366W,而臼修饰包含Fc域的两个亚基之中的另一中的氨基酸替代T366S、L368A和Y407V。在一些实施方案中,Fc域的包含杵修饰的亚基另外包含氨基酸替代S354C,而且Fc域的包含臼修饰的亚基另外包含氨基酸替代Y349C。引入这两个半胱氨酸残基导致形成Fc区的两个亚基之间的二硫桥,如此进一步稳定二聚体(Carter,J.Immunol.Methods 248:7-15(2001))。杵臼突变的例示性组合包括但不限于表3中所述。
表3
关于杵臼技术的别的细节描述于例如美国专利No.5,731,168;美国专利No.7,695,936;WO 2009/089004;US 2009/0182127;Marvin and Zhu,Acta PharmacologicaSincia(2005)26(6):649-658;Kontermann,Acta Pharmacologica Sincia(2005)26:1-9;Ridgway等,Prot Eng 9:617-621(1996);和Carter,J Immunol Meth 248:7-15(2001)。
Fc区的C末端可以是以氨基酸残基PGK结束的完整C末端;也可以是缩短的C末端,例如在所述缩短的C末端中已经去除了一个或两个C末端氨基酸残基。在一个优选的方面中,重链的C末端是以PG结束的缩短的C末端。因此,在一些实施方式中,完整抗体的组合物可以包括去除了所有K447残基和/或G446+K447残基的抗体群体。在一些实施方式中,完整抗体的组合物可以包括没有去除K447残基和/或G446+K447残基的抗体群体。在一些实施方式中,完整抗体的组合物具有带有和不带有K447残基和/或G446+K447残基的抗体混合物的抗体群体。
D.重组方法
抗TROP2抗体可以使用重组方法来产生。对于这些方法,提供编码抗体的一个或更多个分离的核酸。
在一个实施方案中,本披露提供了编码如前所述的抗体的分离的核酸。此类核酸可以给自独立的编码前述的任一多肽链。在另一方面中,本披露提供了包含此类核酸的一种或多种载体(例如表达载体)。在另一方面中,本披露提供了包含此类核酸的宿主细胞。在一个实施方案中,提供制备抗TROP2抗体的方法,其中所述方法包括,在适合表达的条件下,培养包含编码所述抗体的核酸的宿主细胞,如上文所提供的,和任选地从宿主细胞(或宿主细胞培养基)回收所述抗体。
为了重组产生抗体,将编码蛋白的核酸分离并插入一个或更多个载体中,用于在宿主细胞中进一步克隆和/或表达。此类核酸可以使用常规程序容易地分离和测序,或者通过重组方法产生或通过化学合成获得。
用于克隆或表达编码抗体的载体的适当宿主细胞包括本文描述的原核或真核细胞。例如,可在细菌中产生,特别是当不需要糖基化和Fc效应子功能时。在表达后,可以在可溶级分中从细菌细胞糊状物分离,并且可进一步纯化。
E.测定
本文提供的TROP2抗体、包含其的抗体-药物偶联物或其药学上可接受的盐可以通过本领域已知的多种测定法对其物理/化学特征和/或生物学活性进行鉴定、筛选或表征。在一个方面中,例如通过已知方法如ELISA、蛋白印迹法等,测试本披露的TROP2抗体、包含其的抗体-药物偶联物或其药学上可接受的盐的活性。
F.治疗方法与施用途径
本文提供的前述任何抗TROP2抗体、包含其的抗体-药物偶联物或其药学上可接受的盐可用于治疗疾病。
在一个方面,本披露提供抗TROP2抗体、包含其的抗体-药物偶联物或其药学上可接受的盐在药物的制造或制备中的用途。在一些实施方案中,本披露提供的抗TROP2抗体、包含其的抗体-药物偶联物或其药学上可接受的盐在制备用于治疗肿瘤或癌症的药物中的用途。在一些实施方案中,其中所述的肿瘤或癌症包括但不限于头和颈鳞状细胞癌、头和颈癌、脑癌、神经胶质瘤、多形性成胶质细胞瘤、神经母细胞瘤、中枢神经系统癌、神经内分泌肿瘤、咽喉癌、咽鳞癌、口腔鳞癌、鼻咽癌、食管癌、甲状腺癌、恶性胸膜间皮瘤、肺癌、乳腺癌、肝癌、肝胆癌、胰腺癌、胃癌、胃肠道癌、肠癌、结肠癌、结肠直肠癌、肾癌、透明细胞肾细胞癌、卵巢癌、子宫内膜癌、子宫颈癌、膀胱癌、前列腺癌、睾丸癌、皮肤癌、黑色素瘤、白血病、淋巴瘤、骨癌、软骨肉瘤、骨髓瘤、多发性骨髓瘤、骨髓异常增生综合征、库肯勃氏瘤、骨髓增生性肿瘤、鳞状细胞癌、尤因氏肉瘤、尿路上皮癌、梅克尔细胞癌和白血病。在一些实施方案中,本披露提供的抗TROP2抗体、包含其的抗体-药物偶联物或其药学上可接受的盐在制备用于治疗TROP2相关的疾病的药物中的用途。在一些实施方案中,本披露提供一种治疗肿瘤或癌症的方法,所述方法包括给予患者治疗有效量的本披露的抗TROP2抗体、包含其的抗体-药物偶联物或其药学上可接受的盐。在一施方案中,所述方法进一步包括向受试者施用有效量的至少一种另外的治疗剂(例如一种、两种、三种、四种、五种或六种另外的治疗剂)。
在又一个的方面,提供包含所述抗TROP2抗体或其药物偶联物或其药学上可接受的盐的药物组合物,例如,其用于以上任何制药用途或治疗方法。在一个实施方案中,药物组合物包含本文提供的任何抗TROP2抗体或其药物偶联物或其药学上可接受的盐和药学上可接受的载体。在另一个实施方案中,药物组合物还包含至少一种另外的治疗剂。在一些实施方案中,所述的另外的治疗剂与本披露的抗TROP2抗体或其药物偶联物或其药学上可接受的盐同时或顺序施用。在一些实施方案中,所述的另外的治疗剂与本披露的抗TROP2抗体或其药物偶联物或其药学上可接受的盐储存在不同的容器中(如药瓶)。
本披露的抗TROP2抗体或其药物偶联物或其药学上可接受的盐可单独使用或与其他试剂联合用于治疗。例如,与至少一种另外的治疗剂共同施用。
本披露的抗TROP2抗体或其药物偶联物或其药学上可接受的盐可通过任何合适的手段施用,包括肠胃外、肺内和鼻内,并且如果需要局部治疗,则病灶内施用。肠胃外输注包括肌肉内、静脉内、动脉内、腹膜内或皮下施用。给药可以通过任何适当的途径,例如,通过注射,诸如静脉内或皮下注射,这部分取决于施用是短期的还是长期的。本文考虑多种给药时间方案,包括但不限于,单次或在多个时间点多次施用,推注施用和脉冲输注。
本披露的抗TROP2抗体或其药物偶联物或其药学上可接受的盐将以符合良好医疗实践的方式配制、给药和施用。在此背景下考虑的因素包括所治疗的具体病症、所治疗的具体哺乳动物、个体患者的临床状况、病症的起因、试剂的递送部位、施用方法、施用时间安排以及医学从业者已知的其他因素。抗TROP2抗体或其药物偶联物可以与或不与目前用于预防或治疗所述病症的一种或更多种试剂一起配制。此类其它试剂的有效量取决于药物组合物中存在的量、病症或治疗的类型以及其它因素。这些通常以与本文所述相同的剂量和施用路径使用,或以本文所述剂量的约1至99%使用,或以其它剂量使用,并通过经验/临床确定为合适的任何途径使用。
为了预防或治疗疾病,本披露的抗TROP2抗体或其药物偶联物或其药学上可接受的盐(当单独使用或与一种或更多种其他另外的治疗剂组合使用时)的适当的剂量将取决于待治疗的疾病的类型,治疗分子的类型,疾病的严重性和病程,是为预防还是治疗目的施用,之前的治疗,患者的临床病史和对治疗分子的响应,和主治医师的判断。治疗分子恰当地以一次或经过一系列治疗施用于患者。
G.制品
在本披露的另一方面中,提供一种制品,所述制品包含可用于治疗、预防和/或诊断病症的材料。该制品包含容器和在容器上或与容器联合的标签或包装插页(packageinsert)。合适的容器包括,例如,瓶子、管形瓶、注射器、IV溶液袋等。容器可以自各种材料诸如玻璃或塑料形成。容器装有单独或与另一种治疗剂合可有效治疗、预防和/或诊断疾患的组合物,并且可具有无菌的存取口(例如,容器可以是具有由皮下注射针可刺穿的塞子的静脉内溶液袋或管形瓶)。组合物中的至少一种活性试剂是本披露的抗TROP2抗体或其药物偶联物或其药学上可接受的盐。标签或包装插页指示使用该组合物是来治疗选择的病况。此外,制品可以包含:(a)其中装有组合物的第一容器,其中所述组合物包含本披露的抗TROP2抗体或其药物偶联物或其药学上可接受的盐;和(b)其中装有组合物的第二容器,其中所述组合物包含另外的细胞毒性剂或其他方面的治疗剂。本披露的实施方案中的制品可进一步包含包装插页,所述包装插页指示所述组合物可以用于治疗特定疾病况。备选地,或另外地,制品可进一步包含第二(或第三)容器,所述第二(或第三)容器包含药学上可接受的缓冲液。从商业和用户立场,它可进一步包括所需的其他材料,包括其他缓冲剂、稀释剂、滤器、针头和注射器。
具体实施方式
以下结合实施例进一步描述本披露,但这些实施例并非限制本发明的范围。
本披露实施例或测试例中未注明具体条件的实验方法,通常按照常规条件,或按照原料或商品制造厂商所建议的条件。参见Sambrook等,分子克隆,实验室手册,冷泉港实验室;当代分子生物学方法,Ausubel等著,Greene出版协会,Wiley Interscience,NY。未注明具体来源的试剂,为市场购买的常规试剂。
一、抗体的制备
实施例1:TROP2重组蛋白和稳定转染的细胞的制备
带His标签的人TROP2蛋白购自北京百普赛斯生物科技股份有限公司(ACRO)。将不带标签的人TROP2基因转染到CHO细胞中,构建表达TROP2蛋白的CHO细胞株,用于后续抗体的筛选和鉴定。相关蛋白氨基酸序列如下:
1、人TROP2-his(huTROP2-His)氨基酸序列(ACRO TR2-H5223):
HTAAQDNCTCPTNKMTVCSPDGPGGRCQCRALGSGMAVDCSTLTSKCLLLKARMSAPKNARTLVRPSEHALVDNDGLYDPDCDPEGRFKARQCNQTSVCWCVNSVGVRRTDKGDLSLRCDELVRTHHILIDLRHRPTAGAFNHSDLDAELRRLFRERYRLHPKFVAAVHYEQPTIQIELRQNTSQKAAGDVDIGDAAYYFERDIKGESLFQGRGGLDLRVRGEPLQVERTLIYYLDEIPPKFSMKRLTHHHHHH
SEQ ID NO:1
2、猴TROP2-his(CynoTROP2-His)氨基酸序列(ACRO TR2-R52H3):
QDNCTCPTNKMTVCSPDGPGGRCQCRALGSGVAVDCSTLTSKCLLLKARMSAPKNARTLVRPNEHALVDNDGLYDPDCDPEGRFKARQCNQTSVCWCVNSVGVRRTDKGDLSLRCDELVRTHHILIDLRHRPTAGAFNHSDLDAELRRLFRERYRLHPKFVAAVHYEQPTIQIELRQNTSQKAAGDVDIGDAAYYFERDVKGESLFQGRGGLDLRVRGEPLQVERTLIYYLDEIPPKFSMKRLTAGLIAVIVVVVVALVAGVAVLVISNRRKSGKYKKVEIKELGELRKEPSLHHHHHH
SEQ ID NO:2
3、鼠TROP2-his(MsTROP2-His)氨基酸序列(ACRO TR2-M52H6):
MARGPGLAPPPLRLPLLLLLLAAVTGHTAAQDNCTCPTNKMTVCSPDGPGGRCQCRALGSGVAVDCSTLTSKCLLLKARMSAPKNARTLVRPNEHALVDNDGLYDPDCDPEGRFKARQCNQTSVCWCVNSVGVRRTDKGDLSLRCDELVRTHHILIDLRHRPTAGAFNHSDLDAELRRLFRERYRLHPKFVAAVHYEQPTIQIELRQNTSQKAAGDVDIGDAAYYFERDVKGESLFQGRGGLDLRVRGEPLQVERTLIYYLDEIPPKFSMKRLTAGLIAVIVVVVVALVAGVAVLVISNRRKSGKYKKVEIKELGELRKEPSLHHHHHH
SEQ ID NO:3
4、CHO细胞表面表达的人TROP2氨基酸序列:
MARGPGLAPPPLRLPLLLLVLAAVTGHTAAQDNCTCPTNKMTVCSPDGPGGRCQCRALGSGMAVDCSTLTSKCLLLKARMSAPKNARTLVRPSEHALVDNDGLYDPDCDPEGRFKARQCNQTSVCWCVNSVGVRRTDKGDLSLRCDELVRTHHILIDLRHRPTAGAFNHSDLDAELRRLFRERYRLHPKFVAAVHYEQPTIQIELRQNTSQKAAGDVDIGDAAYYFERDIKGESLFQGRGGLDLRVRGEPLQVERTLIYYLDEIPPKFSMKRLTAGLIAVIVVVVVALVAGMAVLVITNRRKSGKYKKVEIKELGELRKEPSL
SEQ ID NO:4
高表达huTROP2的CHO-K1细胞株构建
将包含SEQ ID NO:4的pCDH-hTROP2慢病毒表达载体质粒与pVSV-G,pCMV-dR8.91慢病毒包装载体用Lipofectamine 3000转染试剂转染至293T细胞中,收集含有病毒的培养基上清,过滤并进行超高速离心,弃去上清后,用1mL无菌PBS重悬。使用浓缩后的病毒感染中国仓鼠卵巢细胞CHO-K1,经puromycin筛选两至三周,再进行FACS单细胞分选。
挑选出TROP2表达量高的CHO-K1/hTROP2单克隆细胞株。将挑选出的单克隆细胞株扩大培养,冻存,以便后续实验。
实施例2:小鼠抗人TROP2单克隆抗体的制备
1、免疫和融合
单独使用huTROP2-His蛋白或huTROP2-CHO细胞,或huTROP2-His蛋白和huTROP2-CHO-K1细胞进行交叉免疫小鼠。蛋白免疫的用量为第一次免疫用50μg,之后的免疫用25μg,细胞免疫为每次107个细胞,每两周免疫一次。免疫3次后取血测定血清中抗体的效价。选择血清中抗体滴度高并且滴度趋于平台的小鼠进行脾细胞融合,采用PEG介导的融合方法将脾淋巴细胞与骨髓瘤细胞Sp2/0细胞(CRL-8287TM)进行融合,得到杂交瘤细胞。融合好的杂交瘤细胞以0.5-1×106个/mL的密度用MC半固体完全培养基(含20%FBS、1×HAT、1×OPI和2%甲基纤维素的RPMI-1640培养基)重悬,分装于35mm细胞培养皿中,37℃,5%CO2孵育7-9天。融合后第7-9天,根据细胞克隆大小,挑取单细胞克隆至加有200μL/孔的HT完全培养基(含20%FBS、1×HT和1×OPI的RPMI-1640培养基)的96孔细胞培养板中,37℃,5%CO2培养3天进行检测。
2、杂交瘤细胞筛选
根据杂交瘤细胞生长密度,用结合ELISA方法进行杂交瘤培养上清检测。选择与huTROP2-CHO-K1细胞结合能力强,同时与野生型CHO-K1细胞没有结合的孔中的细胞(测试例3),并用ForteBio检测与hu/Cyno/Ms TROP2的亲和力(测试例2),及时进行扩增冻存保种和二到三次亚克隆直至获得单细胞克隆。
3、杂交瘤抗体序列测定
挑选出体外活性好的单克隆杂交瘤细胞株mAb29和mAb53抗体,克隆其中的单克隆抗体序列,再进行人源化,重组表达和活性评价。
从杂交瘤中克隆序列过程如下。收集对数生长期杂交瘤细胞,用Trizol(Invitroge,15596-018)提取RNA(按照试剂盒说明书步骤),反转录(PrimeScriptTMReverse Transcriptase,Takara,cat#2680A)。将反转录得到的cDNA采用mouse Ig-PrimerSet(Novagen,TB326 Rev.B 0503)进行PCR扩增后送测序公司测序。
mAb29重链可变区:
EVKLVESGGDLVQPGGSLKLSCAASGFSFSDYYMYWVRQTPEKRLEWVANIDNGGDTTYYPDTVKGRFTISRDNAKNTLYLQMSRLKSEDTAMYYCARHDPLTGPPFFAMDYWGQGTSVTVSS
SEQ ID NO:5
mAb29轻链可变区:
DIQMTQSPSSLSASLGGKVTISCKASQGINQYIAWYQLKPGKGPRLLIHYTSTLQPGVPSRFSGSGSGRDYSFSISNLEPEDIASYYCLQYDNLWTFGGGTKLEIK
SEQ ID NO:6
mAb53重链可变区:
QVQLQQPGAELVKPGASVKMSCKASGYTFTSYWITWVKQRPGQGLEWIGNIHPGSSTTNYNEKFKSKATLTVHTSSSTVYMQLTSLTSEDSAVYYCAREVGDYWGQGTSVTVSS
SEQ ID NO:7
mAb53轻链可变区:
DILLTQSPAILSVSPGERASFSCRASQIIGTSIHWYQQRTNGSPRLLIKYVSESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQSHSWPFTFGGGTKL
SEQ ID NO:8
鼠源mAb29和mAb53的CDR序列如表4所述。
表4.鼠源mAb29和mAb53抗体CDR序列
注:VH/VL的CDR的氨基酸由Kabat编号系统确定并注释。
将鼠源抗体与SEQ ID NO:43所示的人IgG1恒定区和SEQ ID NO:44所示的轻链恒定区融合,获得嵌合抗体Ch-29和Ch-53。
实施例3:鼠源抗人TROP2单克隆抗体的人源化和鉴定
通过比对Kabat人类抗体重轻链可变区种系基因数据库,分别挑选同源性高的重、轻链可变区种系基因作为模板,将鼠源抗体的CDR分别graft(嫁接)到相应的人源模板中,形成次序为FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4的可变区序列。
其重链可变区序列分别与SEQ ID NO:43所示的重链恒定区序列组合,获得重链;轻链可变区序列分别与如SEQ ID NO:44所示的轻链恒定区序列组合,获得轻链。
此外,对mAb29的CDR区的某些氨基酸进行突变,获得新的抗TROP2抗体,其CDR的序列见下表。
表5.mAb29突变体的CDR区
表6.mAb29系列抗体的CDR区的通式
其中,X1选自N、Q或S;X2选自G或V。
表7.鼠源mAb29和mAb53抗体的人源化模板及相应点突变
注:N52位是按照Kabat编号的N52A位。
获得的人源化抗体的序列如下:
重链可变区:
mAb29 VH1
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVANIDQGGDTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHDPLTGPPFFAMDYWGQGTTVTVSS
SEQ ID NO:25
mAb29 VH2
mAb29 VH3
mAb29 VH4
mAb29 VH5
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVANIDNGGDTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHDPLTGPPFFAMDYWGQGTTVTVSS
SEQ ID NO:29
mAb29 VH6
mAb29 VH7
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVANIDSGGDTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHDPLTGPPFFAMDYWGQGTTVTVSS
SEQ ID NO:31
mAb29 VH8
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYYMYWVRQAPGKGLEWVANIDNVGDTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHDPLTGPPFFAMDYWGQGTTVTVSS
SEQ ID NO:32
mAb29 VL1
DIQMTQSPSSLSASVGDRVTITCKASQGINQYIAWYQQKPGKAPKLLIYYTSTLQPGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCLQYDNLWTFGGGTKVEIK
SEQ ID NO:33
mAb29 VL2
mAb29 VL3
mAb53 VH1
EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWITWVRQAPGQGLEWMGNIHPGSSTTNYNEKFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAREVGDYWGQGTTVTVSS
SEQ ID NO:36
mAb53 VH2
mAb53 VH3
mAb53 VH4
mAb53 VL1
EIVLTQSPATLSLSPGERATLSCRASQIIGTSIHWYQQKPGQAPRLLIYYVSESISGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSHSWPFTFGGGTKVEIK
SEQ ID NO:40
mAb53 VL2
mAb53 VL3
注:单下划线部分为CDR,双下划线处为回复突变。
示例性的抗体的恒定区如下:
人IgG1的重链恒定区
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:43
κ链恒定区
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:44
示例性的人源化抗体的重、轻链可变区组合如下:
表8.mAb29的人源化抗体
mAb29 | VL1 | VL2 | VL3 |
VH1 | hu29-01 | hu29-02 | hu29-03 |
VH2 | hu29-04 | hu29-05 | hu29-06 |
VH3 | hu29-07 | hu29-08 | hu29-09 |
VH4 | hu29-10 | hu29-11 | hu29-12 |
VH5 | hu29-13 | hu29-14 | hu29-15 |
VH6 | hu29-16 | hu29-17 | hu29-18 |
VH7 | hu29-19 | hu29-20 | hu29-21 |
VH8 | hu29-22 | hu29-23 | hu29-24 |
表9.mAb53的人源化抗体
mAb53 | VL1 | VL2 | VL3 |
VH1 | hu53-01 | hu53-02 | hu53-03 |
VH2 | hu53-04 | hu53-05 | hu53-06 |
VH3 | hu53-07 | hu53-08 | hu53-09 |
VH4 | hu53-10 | hu53-11 | hu53-12 |
分别克隆、表达、纯化上述抗体,经亲和力检测实验(测试例1、2或3)、DT3C内吞杀伤实验(测试例4)、pHrodo内吞检测实验(测试例6)、Biacore(测试例5),最终选出活性较好的人源化抗体。示例性的人源化抗体的序列如下:
hu29-12重链:
EVKLVESGGGLVQPGGSLRLSCAASGFSFSDYYMYWVRQAPGKGLEWVANIDNVGDTTYYPDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHDPLTGPPFFAMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:45
hu29-12轻链:
DIQMTQSPSSLSASVGDRVTITCKASQGINQYIAWYQQKPGKGPKLLIHYTSTLQPGVPSRFSGSGSGRDYTFTISSLQPEDIATYYCLQYDNLWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:46
hu53-02重链:
EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWITWVRQAPGQGLEWMGNIHPGSSTTNYNEKFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCAREVGDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:47
hu53-02轻链:
EIVLTQSPATLSLSPGERATLSCRASQIIGTSIHWYQQKPGQAPRLLIKYVSESISGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSHSWPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:48
本披露中使用的对照分子hRS7参照专利WO03074566构建,TINA抗体参照专利WO2015098099A1构建,其序列分别如下:
hRS7重链:
QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:49
hRS7轻链:
DIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:50
TINA重链:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTTAGMQWVRQAPGQGLEWMGWINTHSGVPKYAEDFKGRVTISADTSTSTAYLQLSSLKSEDTAVYYCARSGFGSSYWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:51
TINA轻链:
DIQMTQSPSSLSASVGDRVTITCKASQDVSTAVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:52
二、化合物的制备
本披露实施例中未注明具体条件的实验方法,通常按照常规条件,或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂,为市场购买的常规试剂。
化合物的结构是通过核磁共振(NMR)或质谱(MS)确定。NMR的测定使用BrukerAVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD),内标为四甲基硅烷(TMS),化学位移是以10-6(ppm)作为单位给出。
MS的测定使用FINNIGAN LCQAd(ESI)质谱仪(Thermo,型号:Finnigan LCQadvantage MAX)。
UPLC的测定使用Waters Acquity UPLC SQD液质联用仪。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
UV-HPLC的测定使用Thermo nanodrop2000紫外分光光度计。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm至0.2mm,薄层层析分离纯化产品采用的规格是0.4mm至0.5mm硅胶板。
柱层析一般使用烟台黄海200~300目硅胶为载体。
本披露的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自ABCR GmbH&Co.KG,Acros Organnics,Aldrich Chemical Company,韶远化学科技(AccelaChemBio Inc)、达瑞化学品等公司。
实施例中如无特殊说明,反应均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空,充入氢气,反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中如无特殊说明,反应中的溶液是指水溶液。
实施例中如无特殊说明,反应的温度为室温,温度范围是20℃至30℃。
实施例中pH=6.5的PBS缓冲液的配制:取KH2PO4 8.5g,K2HPO4.3H2O 8.56g,NaCl5.85g,EDTA 1.5g置于瓶中,定容至2L,超声波使其全部溶解,摇匀即得。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括:A:二氯甲烷和异丙醇体系,B:二氯甲烷和甲醇体系,C:石油醚和乙酸乙酯体系,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。
本披露部分化合物是通过Q-TOF LC/MS来表征的。Q-TOF LC/MS使用安捷伦6530精确质量数四级杆-飞行时间质谱仪和安捷伦1290-Infinity超高效液相色谱仪(安捷伦Poroshell 300SB-C8 5μm,2.1×75mm色谱柱)。
本披露抗体-药物偶联物的药物部分可选择本领域公知的细胞毒性药物,示例性抗体-药物偶联物的合成路线如下。
实施例2-1化合物7的合成
步骤1
将化合物7-1(1.3g,采用WO2013106717公开方法制备而得)溶于50mL乙腈中,依次加入碳酸钾(6.2g)、溴化苄(1.35mL)和四丁基碘化铵(415mg)。室温搅拌,过滤,浓缩,以石油醚/乙酸乙酯为展开剂,用硅胶柱色谱法纯化得化合物7-2。
将化合物7-2(121mg)和7-3(180mg)加入反应瓶中,加入4mL四氢呋喃。氮气氛下,冰水浴降温至0℃左右,加入叔丁醇钾(109mg,0.98mmol),升至室温搅拌40分钟。加入10mL冰水,用乙酸乙酯(20mL×2)和氯仿(10mL×5)萃取,合并有机相并浓缩。所得残余物溶于4mL二氧六环中,加入2mL水,加入碳酸氢钠(49.2mg,0.586mmol)和氯甲酸-9-芴甲酯(126mg,0.49mmol),室温搅拌2小时。加入20mL水,用乙酸乙酯(10mL×3)萃取,有机相用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩。以石油醚/乙酸乙酯为展开剂,用硅胶柱色谱法纯化得到化合物7-4,MS m/z(ESI):515.0[M+1]+。
将化合物7-4(20mg,0.038mmol)溶于4.5mL四氢呋喃和乙酸乙酯(V:V=2:1)混合溶剂中,加入钯碳(12mg,含量10%,干型),氢气置换三次,室温搅拌反应1小时。反应液用硅藻土过滤,滤饼用乙酸乙酯淋洗,滤液浓缩,得到粗品标题化合物7-5(13mg),产品不经纯化直接进行下一步反应。
MS m/z(ESI):424.9[M+1]。
步骤2
将7-5(8.00g,18.9mmol)置于250mL三口瓶中,氮气保护下加入干燥的二氯甲烷(100mL),搅拌溶解并冷至0℃,依次加入4-二甲氨基吡啶(250mg,2.05mmol),2,4-二甲氧基苄醇(4.45g,26.5mmol),1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(5.04g,28.6mmol),保持0℃搅拌反应4小时,加水(50mL)淬灭反应并升至室温,甲基叔丁基醚(100mL)萃取两次,合并有机相,用饱和氯化钠溶液(50mL)洗,无水硫酸钠干燥,减压浓缩至干,得到7-6粗品(13.1g)。
MS Calc:574.2,Found:575.0[M+H]+。
步骤3
将7-6粗品(13.1g)置于500mL反应瓶中,加入DCM(160mL),搅拌溶解,加入二乙胺(80mL),保持室温15~18℃反应3小时,减压浓缩至干,得到粗品,用硅胶柱层析分离,收集所需组分后蒸干(水温<35℃)得到7-7油状物(5.47g),两步收率82.2%。
MS Calc:352.2,Found:353.1[M+H]+。
步骤4
将7-7(4.36g,12.4mmol),7-8(7.03g,14.9mmol,6-(2,5-二氧代-2,5-二氢-1H-吡咯-1-基)己酰基)甘氨酰甘氨酰-L-苯丙氨酸,采用专利申请“EP2907824B”中的实施例73中的方法制备而得)置于250mL反应瓶中,氮气保护下加入干燥的N,N-二甲基甲酰胺(50mL),搅拌溶解并冷至0℃,加入4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐(4.80g,16.3mmol),升温至18℃搅拌反应1小时。冰水浴降温,加水(150mL)淬灭反应,乙酸乙酯(300mL)萃取2次,有机相合并用饱和氯化钠水溶液(50mL)洗一次;无水硫酸钠干燥;过滤,减压浓缩至干,粗品用硅胶柱层析纯化得不纯7-9淡黄色固体(6.02g),将上述固体用甲基叔丁基醚(60mL)打浆纯化,得到7-9(5.08g),类白色固体,收率50.8%。
MS Calc:806.4,Found:807.2[M+H]+。
步骤5
将7-9(150mg,0.186mmol)置于50mL单口瓶中,氮气保护下加入干燥的二氯甲烷(6mL),苯甲醚(60mg,0.558mmol),搅拌并冷至0℃,加入二氯乙酸(0.24mL,2.9mmol),底物溶解,保持0℃搅拌反应3-4小时;在反应液中加入甲基叔丁基醚(18mL),保持0℃打浆搅拌30分钟,过滤抽干,固体加入甲基叔丁基醚(18mL),室温打浆搅拌30分钟,过滤,抽干得到7(120mg,0.183mmol),收率98%。1H NMR(400MHz,DMSO-d6)δ12.56(brs,1H),8.50(t,J=6.8Hz,1H),8.28(t,J=6.0Hz,1H),8.20-8.05(m,2H),8.00(t,J=5.6Hz,1H),7.30-7.15(m,5H),6.99(s,2H),4.65-4.40(m,3H),3.80-3.55(m,7H),3.45(d,J=7.6Hz,2H),3.10-3.00(m,1H),2.85-2.75(m,1H),2.11(t,J=7.6Hz,2H),1.55-1.40(m,4H),1.25-1.15(m,2H),1.05-0.95(m,1H),0.55-0.40(m,2H),0.40-0.30(m,2H).
MS Calc:656.3,Found:679.2[M+Na]+。
实施例2-2化合物8的合成
步骤1
1000mL烧瓶中加入中间体8-1(10.0g,42.9mmol,参考合成方法:TetrahedronLetters,2009,50,75-76.)和MeOH(500mL),加入Pd/C(钯碳催化剂,1.20g,50%wt)。充换氢气三次,室温反应4小时。过滤除去Pd/C,浓缩后得黄色固体中间体8-2(7.20g)。
LCMS(ESI):204.0[M+H]+。
步骤2
1000mL烧瓶中加入中间体8-2(7.20g,35.4mmol)和MeOH(500mL),搅拌状态下加入Boc2O(8.1mL,35.4mmol),室温反应16小时。浓缩后柱层析纯化,得到淡黄色固体中间体8-3(4.62g),LCMS(ESI):304.0[M+H]+。
步骤3
250mL烧瓶中先加入中间体8-3(1000mg,3.30mmol),然后加入四氢铝锂(65.9mL,1M in THF)。氮气保护,油浴50℃加热反应1小时。冰水浴冷却下依次滴加THF(66mL),H2O(2.5mL),15%NaOH水溶液(2.5mL)和H2O(7.5mL),撤去冰水浴,室温搅拌1小时,硅藻土过滤,滤液减压浓缩至干,将粗品8-4与THF(12mL)混合,搅拌状态下加入盐酸水溶液(12mL,6M),室温搅拌反应过夜。将反应液减压浓缩至干,得类白色固体粗品化合物中间体8-4(810mg)。
LCMS(ESI):190.1[M+H]+。
步骤4
室温下将中间体1(80mg,0.12mmol,参照文献J.Am.Chem.Soc.1996,118,9202-9203制备),中间体8-4(160mg,0.61mmol),NaOAc(100mg,1.2mmol)和EtOH(4mL)混合。氮气保护,油浴加热,50℃搅拌反应60分钟。将反应液倒入二氯甲烷(100mL)中,过滤。滤液旋干,柱层析纯化(MeOH/DCM=1/50)得到类白色固体中间体8-5(73mg)。
LCMS(ESI):837.3[M+H]+。
步骤5
向50mL反应瓶中加入中间体8-5(47mg,0.056mmol),THF(6mL)和2N HCl(6mL)。氮气保护,室温搅拌反应24小时。加入饱和NaHCO3淬灭,EA(30mL x3)萃取。合并有机相,干燥,旋干,柱层析纯化(MeOH/DCM=3/100)得到类白色固体中间体8-6(36mg)。
LCMS(ESI):793.2[M+H]+。
步骤6
向20mL反应瓶中加入中间体8-6(36mg,0.045mmol),AgNO3(306mg,1.8mmol),MeCN(3mL)和H2O(2mL)。氮气保护,避光室温搅拌反应10小时。向反应管中加入饱和食盐水(2.5mL)和饱和NaHCO3溶液(2.5mL),搅拌15分钟。混合物倒入H2O(20mL)中,EA(20mLx3)萃取。合并有机相,干燥,旋干,制备HPLC纯化得到化合物类白色固体化合物8(3.9mg)。
LCMS(ESI):784.2[M+H]+。
1H NMR(400MHz,CD3OD)δ7.53(s,1H),7.47–7.42(m,1H),7.21–7.14(m,1H),6.81(s,1H),6.30(s,1H),6.12(s,1H),5.39–5.28(m,3H),4.66–4.63(m,1H),4.35–4.16(m,2H),3.89–3.82(m,1H),3.79(s,3H),3.54–3.43(m,2H),3.06(s,3H),2.94–2.88(m,1H),2.83–2.79(m,1H),2.70(s,3H),2.44(s,3H),2.33–2.25(m,4H),2.22–2.15(m,2H),2.05–2.04(m,3H),1.64–1.55(m,2H).
实施例2-3化合物9的合成
步骤1
称取中间体9-1(即实施2-2中的化合物8-6,5.0mg,6.3μmol),(S)-2-环丙基-2-羟基乙酸(3.66mg,31.5μmol),HATU(3.57mg,9.5μmol),加入到10mL反应管,依次加入DMF(1mL),DIPEA(8.13mg,63.0μmol),氩气保护,然后室温搅拌反应18小时。向反应液中加入乙酸乙酯(20mL),用饱和碳酸氢钠溶液洗涤(10mLx2),饱和氯化钠溶液洗涤(5mL),有机相干燥、过滤、旋干,prep-TLC纯化(PE/EA=4/1)得到白色固体中间体9-2(6mg)。LCMS(ESI):891.3[M+H]+。
步骤2
称取中间体9-2(6.0mg,6.3μmol),加入到10mL反应管,依次加入乙腈(0.6mL),水(0.4mL),室温搅拌下加入AgNO3(42.0mg,252μmol),然后室温搅拌。室温搅拌3小时。向反应液中加入乙酸乙酯(20mL),加入氯化钠溶液(2mL)、饱和碳酸氢钠溶液(2mL),分出有机相,水相再用乙酸乙酯(10mL)萃取,合并有机相干燥、过滤、旋干,得到粗品,制备HPLC纯化得到化合物9(1.9mg)。
LCMS(ESI):864.3[M-OH]+。
1H NMR(400MHz,DMSO-d6)δ7.45-7.30(m,2H),7.02(d,J=8.0Hz,1H),6.74(s,1H),6.27(s,1H),6.20(s,1H),5.15(d,J=11.2Hz,1H),4.89(d,J=2.8Hz,1H),4.80-4.70(m,1H),4.70-4.65(m,1H),4.55-4.40(brm,1H),4.22(d,J=10.8Hz,1H),3.92(d,J=9.2Hz,1H),3.80-3.70(m,1H),3.70(s,3H),3.40-3.35(m,3H),3.30-3.15(m,3H),3.15(s,3H),3.15-3.05(m,2H),2.90-2.75(m,2H),2.75-2.65(m,1H),2.65-2.55(m,1H),2.35(s,3H),2.29(s,3H),1.98(s,3H),0.95-0.85(m,1H),0.30-0.15(m,2H),0.10-0.00(m,1H),-0.15--0.25(m,1H).
实施例2-4L-9的合成
步骤1
称取化合物8-6(50mg,0.063mmol),7(85mg,0.13mmol)于反应瓶中,将体系用氮气保护。加入N-甲基咪唑(21mg,0.25mmol)的干燥的MeCN(4mL)溶液。将体系用冰水浴冷却,然后滴加入TCFH(45mg,0.16mmol,N,N,N',N'-四甲基氯甲脒六氟磷酸盐)的干燥的MeOH(1mL)溶液。冰水浴中反应80min,取样LCMS检测原料消耗完全。反应液用砂芯漏斗抽滤。滤饼用干燥的MeCN洗涤。合并滤液,减压浓缩得到粗品经过柱层析(甲醇/二氯甲烷=1:25)得到白色固体L-8-6约83mg,收率:92.22%。
MS Calc:1430.6,Found:1431.4[M+H]。
步骤2
称取化合物L-8-6(81mg,0.057mmol),溶于干燥的MeCN(7mL)中。加入AgNO3(781mg,4.60mmol)的水(4.7mL)溶液。氮气保护,避光室温反应21h,取样LCMS检测原料消耗完全。向反应液中加入饱和NaHCO3水溶液(11.7mL)和饱和NaCl溶液(11.7mL),剧烈搅拌30分钟,硅藻土过滤。滤液用(MeOH/CHCl3=1/10,20mL×3)萃取。合并有机相,加入Na2SO4干燥,过滤,减压浓缩至干得粗品,用prep-HPLC纯化,得到白色固体L-9约52mg,收率:64.6%。
1H NMR(400MHz,CD3OD)δ7.32-7.18(m,7H),6.97(d,J=8.4Hz,1H),6.75(s,2H),6.66(s,1H),6.25(s,1H),6.07(s,1H),5.23(d,J=11.2Hz,1H),4.77(s,1H),4.62-4.56(m,4H),4.50(dd,J=6.0,8.4Hz,1H),4.41(s,1H),4.18(d,J=10.8Hz,1H),3.87-3.55(m,12H),3.45(t,J=6.8Hz,2H),3.27(s,3H),3.22-3.17(m,2H),3.05-2.88(m,3H),2.79(d,J=15.2Hz,1H),2.65-2.59(m,2H),2.39(s,3H),2.37(s,3H),2.29(s,3H),2.24(t,J=7.6Hz,2H),2.12(d,J=15.9Hz,1H),2.03(s,4H),1.63-1.50(m,4H),1.31-1.23(m,2H),1.01-0.95(m,1H),0.44-0.22(m,3H),-0.09--0.14(m,1H).
三、ADC的制备
实施例3-1.ADC-1的合成
在37℃条件下,向抗体hRS7的PBS缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;10.0mg/mL,2.2mL,148.6nmol)加入配置好的三(2-羧乙基)膦(TCEP盐酸盐)的水溶液(10mM,38.6μL,386nmol),置于水浴振荡器,于37℃下振荡反应3小时,停止反应。将反应液用水浴降温至25℃。
将化合物L-9(2.11mg,1484nmol)溶解于100μLDMSO中,加入到上述反应液中,置于水浴振荡器,于25℃下振荡反应3小时,停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相:pH为6.5的0.05M的PBS缓冲水溶液),得到标题产物ADC-1的PBS缓冲液(1.57mg/mL,14.2mL),于4℃储存。
RP-HPLC计算平均值:n=3.86。
实施例3-2.ADC-2的制备
在37℃条件下,向抗体hu29-12的PBS缓冲水溶液(pH=6.5的0.05M的PBS缓冲水溶液;10.0mg/mL,3.0mL,202.7nmol)加入配置好的三(2-羧乙基)膦(TCEP盐酸盐)的水溶液(10mM,54.7μL,547nmol),置于水浴振荡器,于37℃下振荡反应3小时,停止反应。将反应液用水浴降温至25℃。
将化合物L-9(2.88mg,2025nmol)溶解于150μLDMSO中,加入到上述反应液中,置于水浴振荡器,于25℃下振荡反应3小时,停止反应。将反应液用Sephadex G25凝胶柱脱盐纯化(洗脱相:pH为6.5的0.05M的PBS缓冲水溶液),得到标题产物ADC-2的PBS缓冲液(2.06mg/mL,15.0mL),于4℃储存。
RP-HPLC计算平均值:n=4.19。
ADC原液药物载量分析
ADC是一种抗体交联物类药物,其治疗疾病的机理是依赖抗体的靶向性将药物运送到细胞中,进而将细胞杀死或抑制细胞生长。药物的载量对药效起着决定性的作用。本披露采用RP-HPLC法分析药物载量,过程基本如下:
试剂和仪器:
三氟乙酸(TFA),sigma生产,100mL/瓶;乙腈,LC grade,4L/瓶,Fisher生产;DTT(0.25M),1g/瓶,sigma生产。
高效液相色谱仪:Agilent 1200
溶液配制:
0.25M DTT溶液:取DTT 5.78mg,加入150μL纯化水充分溶解后,配得0.25MDTT溶液,-20℃保存。
流动相A(0.1%TFA水溶液):量筒量取1000mL纯化水,加入1mL TFA,充分混匀后使用,2-8℃保存14天。
流动相B(0.1%TFA乙腈溶液):量筒量取1000mL乙腈,加入1mL TFA,充分混匀后使用,2-8℃保存14天。
裸抗和供测试样品(浓度为1mg/mL,约200μL),加入4μLDDT还原,37℃水浴1h,结束后取出到内插管中,待进样使用。
色谱条件:
色谱柱:Agilent PLRP-S 1000A 8μm 4.6*250mm;柱温:80℃;
DAD检测器:检测波长280nm;
样品室温度:4℃;
流速:1mL/分钟;进样量为:40μL;
色谱梯度:B%(起始20%-5min36%-32min60%)
数据分析:
通过样品与裸抗的谱图比对,区分出轻重链的位置,然后对检测样品的谱图进行积分,计算出DAR值。
计算公式如下:
LC:0(连接药物数)、LC+1:2(连接药物数)、HC:0(连接药物数)、HC+1:2(连接药物数)、HC+2:4(连接药物数)、HC+3:6(连接药物数)。
LC峰面积总和=LC峰面积+LC+1峰面积;
HC峰面积总和=HC峰面积+HC+1峰面积+HC+2峰面积+HC+3峰面积;
LC DAR=Σ(连接药物数*峰面积百分比)/LC峰面积总和;
HC DAR=Σ(连接药物数*峰面积百分比)/HC峰面积总和;
DAR=LC DAR+HC DAR
以下用生化测试方法验证本披露的抗体及ADC的活性
测试例1:细胞水平的ELISA结合实验
将huTROP-2 CHO-K1和CHO-K1 WT(野生型)细胞制备成2×104细胞/mL细胞悬液,以100μL/孔加入细胞培养板中,5%二氧化碳37℃培养24小时后,弃去上清,加入50μL/孔4%多聚甲醛水溶液固定细胞,室温1小时后,以PBST(0.1%吐温,PBS)洗涤3次,加入M-PBS(5%牛奶+PBS),37℃孵育3小时,以PBST洗涤3次备用。
50μL/孔加入用M-PBS(5%脱脂牛奶PBS)1:1稀释的不同待测抗体至之前准备好的huTROP-2 CHO-K1或CHO-K1 WT细胞板中,37℃孵育2小时。用PBST洗涤3次,加入工作浓度的羊抗-鼠IgG(H+L)-HRP(Jackson)抗体,37℃孵育1小时。用PBST洗涤3次,50μL/孔加入显色底物TMB(KPL 52-00-03),室温避光孵育10分钟后在酶标仪(PE Victor 3)上OD450读数。结果见表10。
结果显示:mAb29、mAb53两个鼠源抗体对huTROP2在细胞水平具有优异的结合能力
表10.鼠源mAb29和mAb53抗体细胞水平的ELISA结合结果
测试例2:ForteBio检测抗TROP2抗体亲和力
将人TROP2-his、食蟹猴TROP2-his和鼠TROP2-his用PBST(PBS pH7.4+0.02%吐温20)制备成100nM溶液。在ForteBio Octet HTX中使用Biosensor/Protein A(ForteBio18-5010)固化待测抗体60秒,在PBST溶液中平衡120秒后,移至各种抗原蛋白PBST溶液中检测结合曲线,最后换至PBST溶液中检测解离曲线,并计算KD、Ka、Kd。结果见下表。
表11.鼠源mAb29和mAb53抗体与不同种属TROP2的亲和力
结果显示:mAb29、mAb53鼠源抗体对人TROP2和食蟹猴TROP2有优异的亲和力,对鼠TROP2无交叉结合。
表12.抗体对huTROP2蛋白的亲和力
结果显示:TROP2抗体均可特异性结合huTROP2,亲和力优于TINA。
测试例3:抗体细胞水平FACS结合实验
将高表达huTROP2的FaDu细胞(ATCC,货号HTB-43TM)和低表达TROP2的SK-OV-3(ATCC,货号:HTB-77)细胞用FACS缓冲液(2%胎牛血清(Gibco,10099141)和pH7.4 PBS(pH7.4源培,B320))制备成1×106/mL的细胞悬液,100μL/孔加入96孔圆底板(Corning,3795)中。离心去除上清后加入50μL/孔用FACS缓冲液稀释的不同浓度待测抗体,放于4℃冰箱中避光孵育1小时。300g离心洗涤3次后,加入工作浓度的Alexa Fluor 488Goat anti-Human IgG(H+L)(invitrogen,A-11013),放于4℃冰箱中避光孵育40分钟。300g离心洗涤3次后,在BD FACSCantoII流式细胞仪上检测几何平均数荧光强度,计算抗体对表达TROP2的细胞的结合EC50值。
表13.抗体细胞水平结合活性
结果显示,本披露中示例性的抗体hu29-12和hu53-02均可特异性结合表达TROP2的细胞。
测试例4:抗体DT3C内吞杀伤实验
DT3C是重组表达的融合蛋白,由白喉毒素的Fragment A(仅毒素部分)和G群链球菌的3C片段(IgG结合部分)融合而成,该蛋白能够与抗体的IgG部分高度亲和,在抗体发生内吞时一同进入细胞,在胞内弗林蛋白酶的作用下,释放出具有毒性的DT,DT能够抑制EF2-ADP核糖基化的活性,阻断蛋白翻译过程,最终导致细胞死亡。而未进入细胞的DT3C则不具有杀伤细胞的活性。根据细胞杀伤情况来评价抗体的内吞活性。
用含20%low IgG FBS的新鲜细胞培养基制取FaDu细胞悬液,细胞密度为2×104细胞/mL,以50μL/孔加入细胞培养板3903中,5%二氧化碳37℃培养16小时。
用无血清培养基配制成4×浓度的DT3C,0.22μm小滤器过滤成无菌溶液。用无血清培养基配制4×浓度的抗体,将80μL DT3C和80μL抗体按照1:1的体积混匀,室温下静置孵育30分钟。取50μL稀释好的抗体加入50μL的细胞中,培养箱中孵育三天。每孔加入50μL CTG(Promega G7573),室温下避光孵育10分钟,在Victor3上读取化学发光。结果见图1和下表14。
表14.抗体内吞后对FaDu细胞的杀伤结果
抗体 | IC50(nM) | Imax(%) |
hRS7 | 0.069 | 97.65 |
hu29-12 | 0.0094 | 100 |
hu53-02 | 0.0643 | 97.45 |
结果显示,本披露中示例性的抗体hu29-12和hu53-02均可被表达TROP2的细胞内吞,其中hu29-12抗体比阳性对照抗体hRS7具有更强的内吞杀伤作用。
测试例5:Biacore抗体亲和力测定
用Protein A生物传感芯片亲和捕获待测抗体(4μg/mL,24s),然后于芯片表面流经某一浓度huTROP2-his(ACRO)180秒,之后解离900秒,用Biacore T200仪器实时检测反应信号获得结合和解离曲线。在每个实验循环解离完成后,用10mM Gly-HCl pH 1.5将生物传感芯片洗净再生。采用1:1Model模型拟合数据得到亲和力参数,结果见表15。
表15.人源化抗体huTROP2亲和力
抗体 | hu29-12 | hu53-02 | TINA |
KD(M) | 2.02E-10 | 6.91E-10 | 1.70E-08 |
结果显示:hu29-12和hu53-02比阳性对照抗体TINA具有更高的亲和力。
测试例6:pHrodo检测TROP2抗体的内吞活性测定
本实验的目的是根据pHrodo iFL染料在中性pH值时几乎不发荧光,该染料能够与抗体的IgG部分高度亲和,随着染料被内化且pH降低,Red(红色)或Green(绿色)荧光信号会逐渐增强。而荧光信号的增强则可用于检测胞吞途径的过程。
用含20%FBS的新鲜细胞培养基制取FaDu细胞悬液,细胞密度为4×105细胞/mL,以50μL/孔加入细胞培养板3903中,5%二氧化碳37℃的条件下培养24小时。用无血清培养基配制成4×浓度的pHrodo iFL染料。用无血清培养基配制4×浓度的抗体,将80μL pHrodoiFL染料和80μL抗体按照1:1的体积混匀,室温下静置孵育10分钟。取100μL混合物加入50μL的细胞中,培养箱中孵育。内吞24h后,吸出培养基。每孔加入50μL胰酶,消化2分钟。用100μL新鲜培养基终止消化。将细胞转到3788圆底孔。洗涤3次后,使用FACS检测荧光信号,结果见图2。
结果显示:hu29-12和hu53-02均可被细胞内吞。
体内活性生物学评价
测试例7:Fadu细胞CDX小鼠模型体内药效评价
将Fadu细胞(3×106个)接种于Balb/c裸鼠右肋部皮下,接种10天后,待肿瘤体积在~245mm3后去除体重、肿瘤过大和过小的,按肿瘤体积将小鼠随机分为3组,每组8只.
ADC腹腔注射,于0天和第8天共给药2次,每只按体重注射10g/0.1mL,给药量1mg/kg,共计给药3mg/kg。每周测量2次瘤体积和体重,记录数据,共记录21天。
使用Excel统计软件记录数据:平均值以avg计算;SD值以STDEV计算;SEM值以STDEV/SQRT(每组动物数)计算;采用GraphPad Prism软件作图,采用Two-way ANOVA或One-way ANOVA对数据进行统计学分析。
肿瘤体积(V)计算公式为:V=1/2×L长×L短 2
相对肿瘤增殖率T/C(%)=(T-T0)/(C-C0)×100%,其中T、C为实验结束时治疗组和对照组的肿瘤体积;T0、C0为实验开始时的肿瘤体积。
抑瘤率TGI(%)=1-T/C(%)。
结果见表16和图3,表明在3mpk剂量下,ADC-2对FaDu移植瘤有较强的抑瘤效果。
表16.ADC对荷瘤裸鼠FaDu移植瘤的疗效
序列表
<110> 江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
<120> 抗TROP-2抗体、其抗体-药物偶联物及其医药用途
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<170> SIPOSequenceListing 1.0
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<212> PRT
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<221> PEPTIDE
<223> huTROP2-His
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His Thr Ala Ala Gln Asp Asn Cys Thr Cys Pro Thr Asn Lys Met Thr
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Val Cys Ser Pro Asp Gly Pro Gly Gly Arg Cys Gln Cys Arg Ala Leu
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Gly Ser Gly Met Ala Val Asp Cys Ser Thr Leu Thr Ser Lys Cys Leu
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Leu Leu Lys Ala Arg Met Ser Ala Pro Lys Asn Ala Arg Thr Leu Val
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Arg Pro Ser Glu His Ala Leu Val Asp Asn Asp Gly Leu Tyr Asp Pro
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Ser Val Cys Trp Cys Val Asn Ser Val Gly Val Arg Arg Thr Asp Lys
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Gly Asp Leu Ser Leu Arg Cys Asp Glu Leu Val Arg Thr His His Ile
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Leu Ile Asp Leu Arg His Arg Pro Thr Ala Gly Ala Phe Asn His Ser
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Asp Leu Asp Ala Glu Leu Arg Arg Leu Phe Arg Glu Arg Tyr Arg Leu
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His Pro Lys Phe Val Ala Ala Val His Tyr Glu Gln Pro Thr Ile Gln
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Gln Asp Asn Cys Thr Cys Pro Thr Asn Lys Met Thr Val Cys Ser Pro
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Asp Gly Pro Gly Gly Arg Cys Gln Cys Arg Ala Leu Gly Ser Gly Val
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Ala Val Asp Cys Ser Thr Leu Thr Ser Lys Cys Leu Leu Leu Lys Ala
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Arg Met Ser Ala Pro Lys Asn Ala Arg Thr Leu Val Arg Pro Asn Glu
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His Ala Leu Val Asp Asn Asp Gly Leu Tyr Asp Pro Asp Cys Asp Pro
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Glu Gly Arg Phe Lys Ala Arg Gln Cys Asn Gln Thr Ser Val Cys Trp
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Cys Val Asn Ser Val Gly Val Arg Arg Thr Asp Lys Gly Asp Leu Ser
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Leu Arg Cys Asp Glu Leu Val Arg Thr His His Ile Leu Ile Asp Leu
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Arg His Arg Pro Thr Ala Gly Ala Phe Asn His Ser Asp Leu Asp Ala
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Val Ala Ala Val His Tyr Glu Gln Pro Thr Ile Gln Ile Glu Leu Arg
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Arg Phe Lys Ala Arg Gln Cys Asn Gln Thr Ser Val Cys Trp Cys Val
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Asn Ser Val Gly Val Arg Arg Thr Asp Lys Gly Asp Leu Ser Leu Arg
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Arg Pro Thr Ala Gly Ala Phe Asn His Ser Asp Leu Asp Ala Glu Leu
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Arg Arg Leu Phe Arg Glu Arg Tyr Arg Leu His Pro Lys Phe Val Ala
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Ala Val His Tyr Glu Gln Pro Thr Ile Gln Ile Glu Leu Arg Gln Asn
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Thr Ser Gln Lys Ala Ala Gly Asp Val Asp Ile Gly Asp Ala Ala Tyr
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Tyr Phe Glu Arg Asp Val Lys Gly Glu Ser Leu Phe Gln Gly Arg Gly
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Gly Leu Asp Leu Arg Val Arg Gly Glu Pro Leu Gln Val Glu Arg Thr
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Leu Ile Tyr Tyr Leu Asp Glu Ile Pro Pro Lys Phe Ser Met Lys Arg
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Met Ala Arg Gly Pro Gly Leu Ala Pro Pro Pro Leu Arg Leu Pro Leu
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Asn Cys Thr Cys Pro Thr Asn Lys Met Thr Val Cys Ser Pro Asp Gly
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Pro Gly Gly Arg Cys Gln Cys Arg Ala Leu Gly Ser Gly Met Ala Val
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Asp Cys Ser Thr Leu Thr Ser Lys Cys Leu Leu Leu Lys Ala Arg Met
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Ser Ala Pro Lys Asn Ala Arg Thr Leu Val Arg Pro Ser Glu His Ala
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Leu Val Asp Asn Asp Gly Leu Tyr Asp Pro Asp Cys Asp Pro Glu Gly
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Arg Phe Lys Ala Arg Gln Cys Asn Gln Thr Ser Val Cys Trp Cys Val
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Arg Pro Thr Ala Gly Ala Phe Asn His Ser Asp Leu Asp Ala Glu Leu
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Arg Arg Leu Phe Arg Glu Arg Tyr Arg Leu His Pro Lys Phe Val Ala
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Ala Val His Tyr Glu Gln Pro Thr Ile Gln Ile Glu Leu Arg Gln Asn
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Val Ala Gly Met Ala Val Leu Val Ile Thr Asn Arg Arg Lys Ser Gly
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Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
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<212> PRT
<213> Mus musculus
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Gly Asn Ile His Pro Gly Ser Ser Thr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Lys Ala Thr Leu Thr Val His Thr Ser Ser Ser Thr Val Tyr
65 70 75 80
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85 90 95
Ala Arg Glu Val Gly Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
100 105 110
Ser Ser
<210> 8
<211> 104
<212> PRT
<213> Mus musculus
<220>
<221> DOMAIN
<223> mAb53轻链可变区
<400> 8
Asp Ile Leu Leu Thr Gln Ser Pro Ala Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Ser Phe Ser Cys Arg Ala Ser Gln Ile Ile Gly Thr Ser
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Val Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Ser His Ser Trp Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu
100
<210> 9
<211> 5
<212> PRT
<213> Mus musculus
<220>
<221> DOMAIN
<223> mAb29 HCDR1
<400> 9
Asp Tyr Tyr Met Tyr
1 5
<210> 10
<211> 17
<212> PRT
<213> Mus musculus
<220>
<221> DOMAIN
<223> mAb29 HCDR2
<400> 10
Asn Ile Asp Asn Gly Gly Asp Thr Thr Tyr Tyr Pro Asp Thr Val Lys
1 5 10 15
Gly
<210> 11
<211> 14
<212> PRT
<213> Mus musculus
<220>
<221> DOMAIN
<223> mAb29 HCDR3
<400> 11
His Asp Pro Leu Thr Gly Pro Pro Phe Phe Ala Met Asp Tyr
1 5 10
<210> 12
<211> 11
<212> PRT
<213> Mus musculus
<220>
<221> DOMAIN
<223> mAb29 LCDR1
<400> 12
Lys Ala Ser Gln Gly Ile Asn Gln Tyr Ile Ala
1 5 10
<210> 13
<211> 7
<212> PRT
<213> Mus musculus
<220>
<221> DOMAIN
<223> mAb29 LCDR2
<400> 13
Tyr Thr Ser Thr Leu Gln Pro
1 5
<210> 14
<211> 8
<212> PRT
<213> Mus musculus
<220>
<221> DOMAIN
<223> mAb29 LCDR3
<400> 14
Leu Gln Tyr Asp Asn Leu Trp Thr
1 5
<210> 15
<211> 5
<212> PRT
<213> Mus musculus
<220>
<221> DOMAIN
<223> mAb53 HCDR1
<400> 15
Ser Tyr Trp Ile Thr
1 5
<210> 16
<211> 17
<212> PRT
<213> Mus musculus
<220>
<221> DOMAIN
<223> mAb53 HCDR2
<400> 16
Asn Ile His Pro Gly Ser Ser Thr Thr Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Ser
<210> 17
<211> 5
<212> PRT
<213> Mus musculus
<220>
<221> DOMAIN
<223> mAb53 HCDR3
<400> 17
Glu Val Gly Asp Tyr
1 5
<210> 18
<211> 11
<212> PRT
<213> Mus musculus
<220>
<221> DOMAIN
<223> mAb53 LCDR1
<400> 18
Arg Ala Ser Gln Ile Ile Gly Thr Ser Ile His
1 5 10
<210> 19
<211> 7
<212> PRT
<213> Mus musculus
<220>
<221> DOMAIN
<223> mAb53 LCDR2
<400> 19
Tyr Val Ser Glu Ser Ile Ser
1 5
<210> 20
<211> 9
<212> PRT
<213> Mus musculus
<220>
<221> DOMAIN
<223> mAb53 LCDR3
<400> 20
Gln Gln Ser His Ser Trp Pro Phe Thr
1 5
<210> 21
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb29-a HCDR2
<400> 21
Asn Ile Asp Gln Gly Gly Asp Thr Thr Tyr Tyr Pro Asp Thr Val Lys
1 5 10 15
Gly
<210> 22
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb29-b HCDR2
<400> 22
Asn Ile Asp Ser Gly Gly Asp Thr Thr Tyr Tyr Pro Asp Thr Val Lys
1 5 10 15
Gly
<210> 23
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb29-c HCDR2
<400> 23
Asn Ile Asp Asn Val Gly Asp Thr Thr Tyr Tyr Pro Asp Thr Val Lys
1 5 10 15
Gly
<210> 24
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<222> (4)..(4)
<223> Xaa选自Asn,Gln或Ser。
<220>
<221> UNSURE
<222> (5)..(5)
<223> Xaa选自Gly或Val。
<400> 24
Asn Ile Asp Xaa Xaa Gly Asp Thr Thr Tyr Tyr Pro Asp Thr Val Lys
1 5 10 15
Gly
<210> 25
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb29 VH1
<400> 25
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 Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asp Gln Gly Gly Asp Thr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu 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 Arg His Asp Pro Leu Thr Gly Pro Pro Phe Phe Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 26
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb29 VH2
<400> 26
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 Ala Ser Gly Phe Ser Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asp Gln Gly Gly Asp Thr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu 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 Arg His Asp Pro Leu Thr Gly Pro Pro Phe Phe Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 27
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb29 VH3
<400> 27
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 Ala Ser Gly Phe Ser Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asp Ser Gly Gly Asp Thr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu 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 Arg His Asp Pro Leu Thr Gly Pro Pro Phe Phe Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 28
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb29 VH4
<400> 28
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 Ala Ser Gly Phe Ser Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asp Asn Val Gly Asp Thr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu 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 Arg His Asp Pro Leu Thr Gly Pro Pro Phe Phe Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 29
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb29 VH5
<400> 29
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 Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asp Asn Gly Gly Asp Thr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu 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 Arg His Asp Pro Leu Thr Gly Pro Pro Phe Phe Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 30
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb29 VH6
<400> 30
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 Ala Ser Gly Phe Ser Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asp Asn Gly Gly Asp Thr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu 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 Arg His Asp Pro Leu Thr Gly Pro Pro Phe Phe Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 31
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb29 VH7
<400> 31
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 Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asp Ser Gly Gly Asp Thr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu 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 Arg His Asp Pro Leu Thr Gly Pro Pro Phe Phe Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 32
<211> 123
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb29 VH8
<400> 32
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 Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asp Asn Val Gly Asp Thr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu 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 Arg His Asp Pro Leu Thr Gly Pro Pro Phe Phe Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 33
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb29 VL1
<400> 33
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 Lys Ala Ser Gln Gly Ile Asn Gln Tyr
20 25 30
Ile Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Thr Leu Gln Pro Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 34
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb29 VL2
<400> 34
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 Lys Ala Ser Gln Gly Ile Asn Gln Tyr
20 25 30
Ile Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
His Tyr Thr Ser Thr Leu Gln Pro Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Arg Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 35
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb29 VL3
<400> 35
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 Lys Ala Ser Gln Gly Ile Asn Gln Tyr
20 25 30
Ile Ala Trp Tyr Gln Gln Lys Pro Gly Lys Gly Pro Lys Leu Leu Ile
35 40 45
His Tyr Thr Ser Thr Leu Gln Pro Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Arg Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 36
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb53 VH1
<400> 36
Glu 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 Ser Tyr
20 25 30
Trp Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile His Pro Gly Ser Ser Thr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Val Gly Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 37
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb53 VH2
<400> 37
Glu 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 Ser Tyr
20 25 30
Trp Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile His Pro Gly Ser Ser Thr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Arg Val Thr Met Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Val Gly Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 38
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb53 VH3
<400> 38
Glu 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 Ser Tyr
20 25 30
Trp Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile His Pro Gly Ser Ser Thr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Arg Val Thr Leu Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Val Gly Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 39
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb53 VH4
<400> 39
Glu 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 Ser Tyr
20 25 30
Trp Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile His Pro Gly Ser Ser Thr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Arg Ala Thr Leu Thr Val Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Val Gly Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 40
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb53 VL1
<400> 40
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ile Ile Gly Thr Ser
20 25 30
Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Tyr Val Ser Glu Ser Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser His Ser Trp Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 41
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb53 VL2
<400> 41
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ile Ile Gly Thr Ser
20 25 30
Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Val Ser Glu Ser Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser His Ser Trp Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 42
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> mAb53 VL3
<400> 42
Glu Ile Leu Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ile Ile Gly Thr Ser
20 25 30
Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Val Ser Glu Ser Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser His Ser Trp Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 43
<211> 330
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> 人IgG1的重链恒定区
<400> 43
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 44
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> κ链恒定区
<400> 44
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 45
<211> 453
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> CHAIN
<223> hu29-12重链
<400> 45
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 Ala Ser Gly Phe Ser Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Asp Asn Val Gly Asp Thr Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu 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 Arg His Asp Pro Leu Thr Gly Pro Pro Phe Phe Ala Met Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Lys
450
<210> 46
<211> 213
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> CHAIN
<223> hu29-12轻链
<400> 46
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 Lys Ala Ser Gln Gly Ile Asn Gln Tyr
20 25 30
Ile Ala Trp Tyr Gln Gln Lys Pro Gly Lys Gly Pro Lys Leu Leu Ile
35 40 45
His Tyr Thr Ser Thr Leu Gln Pro Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Arg Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Asn Leu Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 47
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> CHAIN
<223> hu53-02重链
<400> 47
Glu 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 Ser Tyr
20 25 30
Trp Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Asn Ile His Pro Gly Ser Ser Thr Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Ser Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Val Gly Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 48
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> CHAIN
<223> hu53-02轻链
<400> 48
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ile Ile Gly Thr Ser
20 25 30
Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Val Ser Glu Ser Ile Ser Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser His Ser Trp Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 49
<211> 451
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> CHAIN
<223> hRS7重链
<400> 49
Gln Val Gln Leu Gln Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Thr Asp Asp Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Ala Asp Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gly Gly Phe Gly Ser Ser Tyr Trp Tyr Phe Asp Val Trp Gly
100 105 110
Gln Gly Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 50
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> CHAIN
<223> hRS7轻链
<400> 50
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Ala
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 Tyr Thr Gly Val Pro Asp 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 Val Tyr Tyr Cys Gln Gln His Tyr Ile Thr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 51
<211> 451
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> DOMAIN
<223> TINA重链
<400> 51
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 Thr Ala
20 25 30
Gly Met Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr His Ser Gly Val Pro Lys Tyr Ala Glu Asp Phe
50 55 60
Lys Gly Arg Val Thr Ile Ser Ala Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Gln Leu Ser Ser Leu Lys Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Phe Gly Ser Ser Tyr Trp Tyr Phe Asp Val Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 52
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> CHAIN
<223> TINA轻链
<400> 52
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 Lys Ala Ser Gln Asp Val Ser Thr Ala
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 Tyr Thr 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 Val Tyr Tyr Cys Gln Gln His Tyr Ile Thr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
Claims (24)
1.一种抗TROP2抗体,其包含重链可变区和轻链可变区,其中:
i)所述重链可变区包含:HCDR1,其包含SEQ ID NO:9的氨基酸序列;HCDR2,其包含SEQID NO:24的氨基酸序列;和HCDR3,其包含SEQ ID NO:11的氨基酸序列;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:12的氨基酸序列;LCDR2,其包含SEQID NO:13的氨基酸序列;和LCDR3,其包含SEQ ID NO:14的氨基酸序列;
或
ii)所述重链可变区包含:HCDR1,其包含SEQ ID NO:15的氨基酸序列;HCDR2,其包含SEQ ID NO:16的氨基酸序列;和HCDR3,其包含SEQ ID NO:17的氨基酸序列;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:18的氨基酸序列;LCDR2,其包含SEQID NO:19的氨基酸序列;和LCDR3,其包含SEQ ID NO:20的氨基酸序列。
2.根据权利要求1所述的抗TROP2抗体,其中:
所述重链可变区包含:HCDR1,其包含SEQ ID NO:9的氨基酸序列;HCDR2,其包含SEQ IDNO:23、10、21或22的氨基酸序列;和HCDR3,其包含SEQ ID NO:11的氨基酸序列;和
所述轻链可变区包含:LCDR1,其包含SEQ ID NO:12的氨基酸序列;LCDR2,其包含SEQID NO:13的氨基酸序列;和LCDR3,其包含SEQ ID NO:14的氨基酸序列。
3.根据权利要求1或2所述的抗TROP2抗体,其为鼠源抗体、嵌合抗体或人源化抗体。
4.根据权利要求1至3中任一项所述的抗TROP2抗体,其中:
i)所述重链可变区包含与SEQ ID NO:28、5、25、26、27、29、30、31或32具有至少90%同一性的氨基酸序列;和/或
所述轻链可变区包含与SEQ ID NO:35、6、33或34具有至少90%同一性的氨基酸序列;或
ii)所述重链可变区包含与SEQ ID NO:36、7、37、38或39具有至少90%同一性的氨基酸序列;和/或
所述轻链可变区包含与SEQ ID NO:41、8、40或42具有至少90%同一性的氨基酸序列;
优选地,
i)所述重链可变区包含SEQ ID NO:5的氨基酸序列,和/或所述轻链可变区包含SEQ IDNO:6的氨基酸序列;或
ii)所述重链可变区包含选自SEQ ID NO:28、25、26、27、29、30、31和32中的任一氨基酸序列,和/或所述轻链可变区包含选自SEQ ID NO:35、33或34中的任一氨基酸序列;或
iii)所述重链可变区包含SEQ ID NO:7的氨基酸序列,和/或所述轻链可变区包含SEQID NO:8的氨基酸序列;或
iv)所述重链可变区包含选自SEQ ID NO:36、37、38和39中的任一氨基酸序列,和/或所述轻链可变区包含选自SEQ ID NO:41、40和42中的任一氨基酸序列;
更优选地,
所述重链可变区包含SEQ ID NO:28的氨基酸序列,和所述轻链可变区包含SEQ ID NO:35的氨基酸序列;或
所述重链可变区包含SEQ ID NO:36的氨基酸序列,和所述轻链可变区包含SEQ ID NO:41的氨基酸序列。
5.根据权利要求1至4中任一项所述的抗TROP2抗体,其中所述的抗TROP2抗体是抗体片段;优选地,其中所述的抗体片段为Fab、Fab’、F(ab')2、Fd、Fv、scFv、dsFv或dAb。
6.根据权利要求1至4中任一项所述的抗TROP2抗体,其包含重链恒定区和轻链恒定区;优选地,所述重链恒定区包含SEQ ID NO:43的氨基酸序列,和/或所述轻链恒定区包含SEQID NO:44的氨基酸序列。
7.根据权利要求6所述的抗TROP2抗体,其包含重链和轻链,其中:
所述重链包含与SEQ ID NO:45具有至少85%同一性的氨基酸序列,和/或所述轻链包含与SEQ ID NO:46具有至少85%同一性的氨基酸序列;或
所述重链包含与SEQ ID NO:47具有至少85%同一性的氨基酸序列,和/或所述轻链包含与SEQ ID NO:48具有至少85%同一性的氨基酸序列;
优选地:
所述重链包含SEQ ID NO:45的氨基酸序列,和/或所述轻链包含SEQ ID NO:46的氨基酸序列;或
所述重链包含SEQ ID NO:47的氨基酸序列,和/或所述轻链包含SEQ ID NO:48的氨基酸序列。
8.一种分离的抗TROP2抗体,其与权利要求1至7中任一项所述的抗体竞争结合TROP2。
9.根据权利要求1至8中任一项所述的抗TROP2抗体,其具有以下特性中的至少一种:
a)所述抗TROP2抗体以≤1nM的KD值结合人TROP2,所述KD值通过Biacore测定;
b)所述抗TROP2抗体与表达TROP2的FaDu细胞结合的EC50≤0.4μg/mL,所述EC50通过FACS检测;和
c)所述抗TROP2抗体可被表达TROP2的细胞内吞。
10.分离的核酸,其编码权利要求1至9中任一项所述的抗TROP2抗体。
11.载体,其包含权利要求10所述的分离的核酸。
12.一种宿主细胞,其包含权利要求11所述的载体。
13.一种制备抗TROP2抗体的方法,其包括在适于表达所述抗TROP2抗体的条件下培养权利要求12所述的宿主细胞。
14.一种抗体-药物偶联物或其药学上可接受的盐,其包含权利要求1至9中任一项所述的抗TROP2抗体和药物;优选地,其中所述的药物选自:细胞毒性剂、放射性标记物、荧光团、发色团、显像剂、免疫调节剂、血管生成抑制剂、细胞增殖抑制剂、促细胞凋亡剂、细胞裂解酶,以及其任何组合。
17.根据权利要求15或16所述的抗体-药物偶联物或其药学上可接受的盐,其中所述的接头-L-为-L1-L2-L3-L4-,其中:
L1选自-(琥珀酰亚胺-3-基-N)-W-C(O)-、-CH2-C(O)-NR3-W-C(O)-和-C(O)-W-C(O)-,其中W选自C1-6亚烷基、C1-6亚烷基-C3-6环烷基,其中所述的C1-6亚烷基、C1-6亚烷基-C3-6环烷基各自独立地任选进一步被选自卤素、羟基、氰基、氨基、烷基、氯代烷基、氘代烷基、烷氧基和环烷基的一个或多个取代基所取代;
L2选自-NR4(CH2CH2O)pCH2CH2C(O)-、-NR4(CH2CH2O)pCH2C(O)-、-S(CH2)pC(O)-和化学键,其中p为1至20的整数;
L3为由2至7个氨基酸残基构成的肽残基,其中所述的氨基酸残基选自苯丙氨酸(F)、甘氨酸(G)、缬氨酸(V)、赖氨酸(K)、瓜氨酸、丝氨酸(S)、谷氨酸(E)和天冬氨酸(D)中的氨基酸形成的氨基酸残基,并任选进一步被选自卤素、羟基、氰基、氨基、烷基、氯代烷基、氘代烷基、烷氧基和环烷基中的一个或多个取代基所取代;
L4选自-NR5(CR6R7)t-、-C(O)NR5、-C(O)NR5(CH2)t-和化学键,其中t为1至6的整数;
R3、R4和R5相同或不同,且各自独立地选自氢原子、烷基、卤代烷基、氘代烷基和羟烷基;
R6和R7相同或不同,且各自独立地选自氢原子、卤素、烷基、卤代烷基、氘代烷基和羟烷基。
22.一种药物组合物,其包含权利要求1至9中任一项所述的抗TROP-2抗体,或权利要求14至21中任一项所述的抗体-药物偶联物或其药学上可接受的盐,以及一种或多种药学上可接受的赋形剂、稀释剂或载体。
23.根据权利要求1至9中任一项所述的抗TROP-2抗体,或权利要求14至21中任一项所述的抗体-药物偶联物或其药学上可接受的盐,或权利要求22所述的药物组合物在制备用于治疗TROP-2介导的疾病或病症的药物中的用途。
24.根据权利要求1至9中任一项所述的抗TROP-2抗体,或权利要求14至21中任一项所述的抗体-药物偶联物或其药学上可接受的盐,或权利要求22所述的药物组合物在制备用于治疗肿瘤或癌症的药物中的用途;优选地,其中所述肿瘤或癌症选自:
头和颈鳞状细胞癌、头和颈癌、脑癌、神经胶质瘤、多形性成胶质细胞瘤、神经母细胞瘤、中枢神经系统癌、神经内分泌肿瘤、咽喉癌、咽鳞癌、口腔鳞癌、鼻咽癌、食管癌、甲状腺癌、恶性胸膜间皮瘤、肺癌、乳腺癌、肝癌、肝胆癌、胰腺癌、胃癌、胃肠道癌、肠癌、结肠癌、结肠直肠癌、肾癌、透明细胞肾细胞癌、卵巢癌、子宫内膜癌、子宫颈癌、膀胱癌、前列腺癌、睾丸癌、皮肤癌、黑色素瘤、白血病、淋巴瘤、骨癌、软骨肉瘤、骨髓瘤、多发性骨髓瘤、骨髓异常增生综合征、库肯勃氏瘤、骨髓增生性肿瘤、鳞状细胞癌、尤因氏肉瘤、尿路上皮癌、梅克尔细胞癌、何杰金淋巴瘤、非何杰金淋巴瘤、弥漫性大B-细胞淋巴瘤、滤泡性淋巴瘤、原发性纵隔大B-细胞淋巴瘤、套细胞淋巴瘤、小淋巴细胞性淋巴瘤、富含T-细胞/组织细胞的大B-细胞淋巴瘤、淋巴浆细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、慢性髓细胞样白血病、急性髓细胞样白血病、淋巴细胞白血病、成淋巴细胞性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病和髓样细胞白血病。
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