CN117186238A - 靶向pd-l1和vegf的重组融合蛋白及其制备和用途 - Google Patents
靶向pd-l1和vegf的重组融合蛋白及其制备和用途 Download PDFInfo
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Abstract
本申请提供一种重组融合蛋白,包含1)PD‑L1抗体或其抗体片段,和2)VEGF结合肽,其中该PD‑L1抗体或其抗体片段的至少一个互补位在构成该互补位的重链或轻链的N端通过接头与VEGF结合肽连接。还提供编码该重组融合蛋白的核酸分子、包含该核酸分子的表达载体、制备该重组融合蛋白的方法、以及使用重组融合蛋白来治疗与PD‑L1和/或VEGF通路相关的疾病的方法。
Description
发明领域
本申请涉及一种靶向PD-L1、VEGF和/或FcR的重组融合蛋白、及其制备和用途,特别是其在肿瘤治疗中的用途。
背景技术
癌细胞已经发展出一些逃避宿主免疫监视的机制。例如,很多肿瘤细胞或癌细胞在其表面表达高水平的PD-L1和PD-L2,这两者均能与T细胞表面的PD-1 结合,从而诱导T细胞凋亡。
此外,癌细胞的生长依赖于充分的营养供应。癌细胞自身能够分泌出促进血管生长的因子,例如血管内皮生长因子(VEGF)。抑制VEGF或其受体的活性,将终止对实体瘤的血液供给,从而抑制其生长。
PD-L1和PD-1
PD-1/PD-L1是研究最多的抑制性免疫检查点之一。
PD-L1,又称为程序性死亡配体1或CD274,是一种跨膜蛋白,在一些特定事件例如同种异体组织移植、自免疫疾病和癌症发生中发挥着重要的免疫系统抑制作用。在肿瘤微环境(TME)中,CD4+ Th1辅助细胞和CD8+ T细胞生成干扰素-γ (IFN-γ),这一方面激活巨噬细胞对肿瘤的杀伤,另一方面则诱导巨噬细胞和肿瘤细胞的PD-L1表达。肿瘤特异CD8+ T细胞上PD-1与TME中各细胞表达的PD-L1 结合,引起CD8+ T细胞的失能(Topalian,S.etal.,(2016)Nat Rev Cancer 16(5):275-287)。PD-1还可以与PD-L2结合,下调免疫系统。
对来自肾细胞癌患者的196份肿瘤样本的分析表明,肿瘤高表达PD-L1与肿瘤侵袭性增加以及死亡风险增加4.5倍相关(Thompson RH,et al.,(2004)PNAS. 101(49):17174-17179)。约1/5-1/4患有非小细胞肺癌、黑色素瘤、或肾细胞癌的病人对一种PD-1抗体,BMS-936558,产生了客观性应答(SuzanneL.Topalian,et al., (2012)N Engl J Med 366:2443-2454)。
VEGF和VEGFR
VEGF是在组织/伤口修复程序控制中发挥重要作用的多效生长因子,分为 VEGF-A(又称为VEGF165)、VEGF-B、VEGF-C、VEGF-D、VEGF-E和PIGF。在组织愈伤过程中,VEGF,尤其是VEGF-A,驱使血管的形成和免疫的下调(Canic M,et al.,(2009)J Surg Res.153:347-358;Leung DW,et al.,(1989)Science. 246:1306-1309;Voron T,et al.,(2014)FrontOncol.4:70)。VEGF的这两个特性对于癌变都是很关键的,生成的肿瘤血管可以对癌组织进行血液和营养供给,抑制抗癌免疫可促成癌细胞生长(Hanahan D,Weinberg RA.(2011)Cell.144:646-674)。具体而言,认为VEGF通过三个主要机制发挥免疫抑制作用:抑制树突状细胞(DC) 成熟、减少T细胞肿瘤浸润、以及增加肿瘤微环境中的抑制性细胞。非正常VEGF表达也会促使生成结构异常、易渗漏的新生血管,导致例如糖尿病性视网膜病变、湿性老年性黄斑变性等。贝伐单抗(Avastin),FDA批准的VEGF单抗药物,通过抑制VEGF生物活性来治疗癌症(结肠癌、肺癌)、非鳞状非小细胞肺癌、肾细胞癌、多形性胶质母细胞瘤、卵巢癌、和宫颈癌。另一个靶向VEGF的蛋白药物,阿帕西普(Aflibercept),在美国和欧洲被批准用于治疗湿性黄斑变性(商品名为Eylea)和转移性结直肠癌(Zaltrap)。
VEGF受体(VEGFR)有三个亚型,VEGFR-1、VEGFR-2和VEGFR-3,均具有由7个免疫球蛋白样结构域构成的胞外部分、一个跨膜区域和胞内部分。 VEGFR-2似乎介导几乎所有已知对VEGF的细胞应答,而VEGFR-1阻止VEGF 与VEGFR-2结合,调节VEGFR-2信号通路。VEGF-A,对于人类健康而言最危险的类型,与VEGFR-1和VEGFR-2两者均结合。VEGFR拮抗剂最常用于治疗癌症或癌症治疗研究。乐伐替尼(Lenvima),作为针对VEGFR-1、VEGFR-2和VEGFR-3激酶的多激酶抑制剂,在2015年获批用于分化型甲状腺癌的治疗,2016年获批与依维莫司联合用于晚期肾细胞癌的治疗。
Fc和FcR
可结晶区段(Fc区)是抗体的尾部区,是决定抗体的效应子功能(即,抗体如何与特定细胞受体或其他防御蛋白建立关系)的结构域。
Fc受体(FcR)是在某些细胞,包括B淋巴细胞、滤泡树突状细胞、自然杀伤细胞、巨噬细胞、中性粒细胞、嗜酸粒细胞、嗜碱粒细胞、和肥大细胞等的表面上表达的蛋白。这些细胞有助于免疫系统的保护功能。
Fc区可以与Fc受体以及补体系统的一些蛋白相互作用,激活免疫系统和补体系统。
治疗性双特异性或多特异性融合蛋白/抗体
靶向单一抗原的抗体可能具有有限的疗效。例如,获批的PD-L1抗体, Avelumab总的缓解率仅为33%。
近年来已经开发出双特异性或三特异性融合蛋白,且这些融合蛋白已经在临床前和临床试验中显示出相当不错的效果。
尽管从概念上讲,在传统抗体上附加额外的结合基团不是很复杂的事,然而,这种改造会显著地改变抗体的结构,抗体和额外结合基团间可能会相互影响结合力和/或药效(Wang S et al.,(2021)EMBO Mol Med.13(9):e14291)。为优化体内疗效和药物性质,需要在主次基团(序列)的选择、目标物结合力的平衡、结合位点(重链或轻链的N-或C-端)的选择、结构稳定性、接头长度和序列方面做出精心的设计和改造(Shim H.(2020)Biomolecules.10(3):360)。
对于本申请中任何文件的引用,并不等同于承认这些文件是本申请的现有技术。
发明内容
本申请提供一种新的重组融合蛋白,包含PD-L1抗体和VEGF结合肽。相比于PD-L1抗体和VEGF结合蛋白(包括VEGF抗体),本申请的重组融合蛋白能够以相当的活性结合PD-L1+、VEGF+、和/或PD-L1+VEGF+细胞,对于PD-L1+VEGF+细胞引发相当的抗体依赖性细胞介导的细胞毒效应(ADCC)和抗体依赖性细胞介导的吞噬作用(ADCP),和/或以相当的活性阻断PD-1-PD-L1相互作用以及 VEGF-VEGFR相互作用。此外,本申请的重组融合蛋白在体内实验中显示出比 VEGF结合蛋白与PD-L1抗体联用更好的抗肿瘤效果。
具体地,本申请公开一种重组融合蛋白,其包含1)特异结合PD-L1的PD-L1 抗体或其抗体片段、以及2)特异结合VEGF的VEGF结合肽,其中该VEGF结合肽与该PD-L1抗体或其抗体片段连接。该PD-L1抗体或其抗体片段包含重链可变区、和轻链可变区,重链可变区包含HV-CDR1、HV-CDR2和HV-CDR3,HV-CDR1、 HV-CDR2和HV-CDR3分别包含SEQ ID NOs:1、2和3所示的氨基酸序列,轻链可变区包含LV-CDR1、LV-CDR2和LV-CDR3,LV-CDR1、LV-CDR2和LV-CDR3 分别包含SEQ ID NOs:4、5和6所示的氨基酸序列。该PD-L1抗体或其抗体片段还可以包含重链恒定区,其具有FcR结合力且与重链可变区的C端连接。在某些实施方式中,该PD-L1抗体或其抗体片段包含重链可变区、重链恒定区、和轻链可变区,重链可变区包含HV-CDR1、HV-CDR2和HV-CDR3,HV-CDR1、HV-CDR2 和HV-CDR3分别包含SEQ ID NOs:1、2和3所示的氨基酸序列,轻链可变区包含LV-CDR1、LV-CDR2和LV-CDR3,LV-CDR1、LV-CDR2和LV-CDR3分别包含 SEQ ID NOs:4、5和6所示的氨基酸序列,重链恒定区具有FcR结合力且与重链可变区的C端连接。VEGF结合肽可以与PD-L1抗体或其抗体片段的重链可变区或轻链可变区的N端结合。
VEGF结合肽可以为血管内皮生长因子受体1(VEGFR1)的胞外Ig样结构域。 VEGF结合肽可以为VEGFR1的第二胞外Ig样结构域(VEGFR1D2)。在一些实施方式中,VEGF结合肽包含与SEQ ID NO:11具有至少80%、85%、90%、91%、 92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致度的氨基酸序列。
PD-L1抗体或其抗体片段的重链可变区可以包含与SEQ ID NO:7具有至少 80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致度的氨基酸序列。在一个实施方式中,重链可变区可以包含SEQ ID NO:7所示的氨基酸序列。PD-L1抗体或其抗体片段的轻链可变区可以包含与SEQ ID NO:8 具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致度的氨基酸序列。在一个实施方式中,轻链可变区可以包含SEQ ID NO:8所示的氨基酸序列。在一个实施方式中,PD-L1抗体或其抗体片段的重链可变区和轻链可变区可以包含分别与SEQ ID NOs:7和8具有至少80%、85%、90%、 91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致度的氨基酸序列。在一些实施方式中,PD-L1抗体或其抗体片段的重链可变区和轻链可变区可以分别包含SEQID NOs:7和8所示的氨基酸序列。
具有FcR结合力的重链恒定区可以是天然存在的或经改造的人IgG1、IgG2、 IgG3或IgG4重链恒定区,或其功能片段。在一些实施方式中,具有FcR结合力的重链恒定区是人IgG1重链恒定区,或其功能片段。在一些实施方式中,具有FcR 结合力的重链恒定区可以包含与SEQ ID NO:9具有至少80%、85%、90%、91%、 92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致度的氨基酸序列。
PD-L1抗体或其抗体片段可以包含轻链恒定区,例如人κ轻链恒定区,或其功能片段,与轻链可变区的C端连接。在一些实施方式中,轻链恒定区可以包含与SEQ ID NO:10具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、 97%、98%、99%或100%序列一致度的氨基酸序列。
PD-L1抗体或其抗体片段的重链可以包含与SEQ ID NO:15具有至少80%、 85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致度的氨基酸序列。在一个实施方式中,重链可以包含SEQ ID NO:15所示的氨基酸序列。PD-L1抗体或其抗体片段的轻链可以包含与SEQ ID NO:14具有至少80%、 85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致度的氨基酸序列。在一个实施方式中,轻链可以包含SEQID NO:14所示的氨基酸序列。在一个实施方式中,PD-L1抗体或其抗体片段的重链和轻链可以包含分别与 SEQ ID NOs:15和14具有至少80%、85%、90%、91%、92%、93%、94%、95%、 96%、97%、98%或99%序列一致度的氨基酸序列。在一些实施方式中,PD-L1抗体或其抗体片段的重链和轻链可以分别包含SEQ ID NOs:15和14所示的氨基酸序列。
PD-L1抗体或其抗体片段的至少一个互补位可以在构成该互补位的重链可变区或轻链可变区的N端与VEGF结合肽连接。在一些实施方式中,PD-L1抗体或其抗体片段的各个互补位在构成该互补位的重链可变区或轻链可变区的N端与 VEGF结合肽连接。在一些实施方式中,PD-L1抗体或其抗体片段的各个互补位在构成该互补位的重链可变区的N端与VEGF结合肽连接。在一些实施方式中, PD-L1抗体或其抗体片段的各个互补位在构成该互补位的轻链可变区的N端与 VEGF结合肽连接。
本申请的PD-L1抗体或其抗体片段可以与VEGF结合肽经接头而连接。接头可以是5-30、10-30、10-20、或15个氨基酸长度的肽。接头可以例如为GS接头,如-(Gly-Gly-Gly-Gly-Ser)3-(SEQ ID NO:12)。
本申请的重组融合蛋白可以包含VEGF结合肽-接头-PD-L1抗体重链、和 PD-L1抗体轻链,其中VEGF结合肽-接头-PD-L1抗体重链含有与SEQ ID NO:13 具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或 99%序列一致度的氨基酸序列,PD-L1抗体轻链含有与SEQ ID NO:14具有至少 80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致度的氨基酸序列。在一些实施方式中,本申请的重组融合蛋白可以包含VEGF 结合肽-接头-PD-L1抗体重链、和PD-L1抗体轻链,其中VEGF结合肽-接头-PD-L1 抗体重链含有SEQ ID NO:13所示的氨基酸序列,PD-L1抗体轻链含有SEQ ID NO:14所示的氨基酸序列。SEQ ID NOs:13和14的氨基酸序列可以分别由SEQ ID NOs: 23和24所示的核苷酸序列编码。
在一个实施方式中,本申请的重组融合蛋白包含:
i)第一多肽链,从N端到C端包含VEGF结合肽、接头、特异结合PD-L1 的重链可变区、和重链恒定区;
ii)第二多肽链,从N端到C端包含特异结合PD-L1的轻链可变区、和轻链恒定区;
i)第三多肽链,从N端到C端包含VEGF结合肽、接头、特异结合PD-L1 的重链可变区、和重链恒定区;和
ii)第四多肽链,从N端到C端包含特异结合PD-L1的轻链可变区、和轻链恒定区,
其中,第一多肽链中特异结合PD-L1的重链可变区和第二多肽链中特异结合 PD-L1的轻链可变区能够结合形成特异结合PD-L1的抗原结合域,第三多肽链中特异结合PD-L1的重链可变区和第四多肽链中特异结合PD-L1的轻链可变区能够结合形成特异结合PD-L1的抗原结合域,且第一多肽链中的重链恒定区与第三多肽链中的重链恒定区能够经例如杵-臼、共价或二硫键等作用结合在一起。
本申请的重组融合蛋白可以包含PD-L1抗体重链、和VEGF结合肽-接头 -PD-L1抗体轻链,其中PD-L1抗体重链含有与SEQ ID NO:15具有至少80%、85%、 90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致度的氨基酸序列,VEGF结合肽-接头-PD-L1抗体轻链含有与SEQ ID NO:16具有至少80%、 85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致度的氨基酸序列。在一些实施方式中,本申请的重组融合蛋白可以包含PD-L1抗体重链、和VEGF结合肽-接头-PD-L1抗体轻链,其中PD-L1抗体重链含有SEQ ID NO: 15所示的氨基酸序列,VEGF结合肽-接头-PD-L1抗体轻链含有SEQ ID NO:16所示的氨基酸序列。SEQ ID NOs:15和16所示的氨基酸序列可以分别由SEQ ID NOs: 25和26所示的核苷酸序列编码。
在一个实施方式中,本申请的重组融合蛋白包含:
i)第一多肽链,从N端到C端包含特异结合PD-L1的重链可变区、和重链恒定区;
ii)第二多肽链,从N端到C端包含VEGF结合肽、接头、特异结合PD-L1 的轻链可变区、和轻链恒定区;
i)第三多肽链,从N端到C端包含特异结合PD-L1的重链可变区、和重链恒定区;和
ii)第四多肽链,从N端到C端包含VEGF结合肽、接头、特异结合PD-L1 的轻链可变区、和轻链恒定区,
其中,第一多肽链中特异结合PD-L1的重链可变区和第二多肽链中特异结合 PD-L1的轻链可变区能够结合形成特异结合PD-L1的抗原结合域,第三多肽链中特异结合PD-L1的重链可变区和第四多肽链中特异结合PD-L1的轻链可变区能够结合形成特异结合PD-L1的抗原结合域,且第一多肽链中的重链恒定区与第三多肽链中的重链恒定区能够经例如杵-臼、共价或二硫键等作用结合在一起。
本申请还保护本申请的PD-L1抗体或其抗原结合部分,其含有重链可变区和轻链可变区,重链可变区包含HV-CDR1、HV-CDR2和HV-CDR3,HV-CDR1、 HV-CDR2和HV-CDR3分别包含SEQ ID NOs:1、2和3所示的氨基酸序列,轻链可变区包含LV-CDR1、LV-CDR2和LV-CDR3,LV-CDR1、LV-CDR2和LV-CDR3 分别包含SEQ ID NOs:4、5和6所示的氨基酸序列。重链可变区可以包含与SEQ ID NO:7具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、 98%、99%或100%序列一致度的氨基酸序列。轻链可变区可以包含与SEQ ID NO: 8具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、 99%或100%序列一致度的氨基酸序列。PD-L1抗体或其抗原结合部分还可以包含重链恒定区和/或轻链恒定区。重链恒定区可以是人IgG1、IgG2、IgG3或IgG4重链恒定区,或其功能片段,与重链可变区的C端连接。在一些实施方式中,重链恒定区是人IgG1重链恒定区,或其功能片段。在一些实施方式中,重链恒定区具有SEQ ID NO:9所示的氨基酸序列。轻链恒定区可以是人κ轻链恒定区,或其功能片段,与轻链可变区的C端连接。在一些实施方式中,轻链恒定区可以包含SEQ ID NO:10所示的氨基酸序列。本申请的PD-L1抗体或其抗原结合部分,与现有技术PD-L1抗体或其抗原结合部分相比,具有相当的PD-L1结合活性/亲和力、以及相当的PD-1-PD-L1阻断活性。本申请的PD-L1抗体或其抗原结合部分还可以引发对于PD-L1+细胞的ADCC和ADCP。
本申请还提供编码本申请重组融合蛋白、PD-L1抗体或其抗原结合部分的核酸分子,以及包含该核酸分子的表达载体、和包含该表达载体的宿主细胞。还提供一种使用本申请的宿主细胞来制备重组融合蛋白、PD-L1抗体或其抗原结合部分的方法,包括(i)在宿主细胞中表达重组融合蛋白、PD-L1抗体或其抗原结合部分,以及(ii)从宿主细胞或其细胞培养物中分离重组融合蛋白、PD-L1抗体或其抗原结合部分。
本申请还提供一种药物组合物,其可以包含本申请的重组融合蛋白、PD-L1 抗体或其抗原结合部分、核酸分子、表达载体或宿主细胞,以及至少一种药学上可接受的载体。在一些实施方式中,药物组合物包含至少一种药学上可接受的佐剂。
本申请的药物组合物可以用于治疗与VEGF和/或PD-L1过表达/通路相关的疾病,或用于制备治疗与VEGF和/或PD-L1过表达/通路相关的疾病的药物。
一方面,本申请提供一种用于在有需求受试者中治疗或减轻与VEGF和/或 PD-L1通路/过表达相关的疾病的方法,包括向该受试者施用治疗有效量的本申请药物组合物。
与VEGF和/或PD-L1通路/过表达相关的疾病可以是急性髓细胞样白血病 (AML)、慢性髓细胞样白血病(CML)、急性淋巴细胞白血病(ALL)、非霍奇金淋巴瘤(NHL)、多发性骨髓瘤(MM)、膀胱癌、卵巢癌、前列腺癌、肺癌、结肠癌、乳腺癌、胰腺癌、肝癌、肾细胞癌、黑色素瘤、多形性胶质母细胞瘤、宫颈癌、老年性黄斑变性(AMD)、糖尿病性视网膜病变、肝纤维化、或血管肉瘤。
基于以下的详细描述和实施例,当前公开的其他特征和有利之处将是非常明晰可见的,详细描述和实施例不应当解读为是限制性的。所有在说明书中引用的文献、Genbank登记号、专利和公开专利申请均通过引用的方式并入本文。
附图说明
以下以示例方式给出但不意在将本发明限制于所述具体实施方式的具体描述,可以结合附图更好地进行理解。
图1是本申请重组融合蛋白IMM2518和IMM2519的结构示意图。结构最上方的圆形结构表示VEGFR1D2,其经接头与PD-L1抗体IMM2515H的重链(左图,IMM2518)或轻链(右图,IMM2519)的N端连接。VEGFR1D2包含SEQ ID NO:11所示的氨基酸序列。接头具有SEQ ID NO:12所示的氨基酸序列。 IMM2515H的重链具有SEQ ID NO:15所示的氨基酸序列,轻链具有SEQ ID NO: 14所示的氨基酸序列。
图2示出IMM2518和IMM2519与VEGF的结合活性。
图3示出IMM2518和IMM2519与PD-L1+CHO的结合活性,IMM2515H用作阳性对照,hIgG1-Fc用作阴性对照。
图4示出IMM2518与PD-L1+CHO的结合活性,IMM2510、IMM2515H和阿替丽珠单抗用作阳性对照,hIgG1-Fc用作阴性对照。
图5示出IMM2518对PD-1与PD-L1+CHO细胞结合的阻断活性,IMM2510、 IMM2515H和阿替丽珠单抗用作阳性对照,hIgG1-Fc用作阴性对照。
图6示出IMM2518对VEGF与VEGFR+Jurkat结合的阻断活性,IMM2510、 VEGFR1-Fc、和贝伐单抗用作阳性对照,hIgG用作阴性对照。
图7示出IMM2518与人PD-L1、大鼠PD-L1、小鼠PD-L1、猴PD-L1、以及人PD-L2的结合活性。
图8A-8C分别示出IMM2518引发对于PD-L1+Raji细胞(A)、RKO细胞(B)、以及HCC827细胞(C)的ADCC的活性,IMM2515H、IMM2510、和阿替丽珠单抗用作阳性对照,hIgG1-Fc用作阴性对照。
图9示出IMM2518引发对于RKO细胞的ADCP的活性,IMM2510、IMM2515H、和阿替丽珠单抗用作阳性对照,hIgG1-Fc用作阴性对照。
图10示出荷肿瘤小鼠施用IMM2518后的肿瘤大小变化,IMM2510、 IMM2515H、VEGFR1D2-Fc、以及IMM2515H+VEGFR1D2-Fc组合用作对照。
具体实施方式
从原理上讲,主要有三种不同的途径来靶向两种或更多种肿瘤生长的药理机制。最常见的,可以给予患者两种或更多种不同药物的组合。尽管这种选择使得对于可能的药物组合和不同剂量有着最大化的灵活度,其面临的问题是:a)由于药物变多且各个药物有不同的剂量安排,患者依从性变差;b)由于药物-药物相互作用,可能存在不相容性;以及c)药物副作用风险增加。这些问题会降低治疗的有效性并妨碍治疗目标的达成,尤其在慢性疾病例如癌症的管理中。
第二个途径是在单剂型中使用多种药物的固定剂量组合。该途径减少药物数量负担,患者依从性改善。固定剂量组合的不利之处主要在于,对于活性成分之间可能的剂量比的选择是有限的,这使得更加难以恰当地针对个体患者将剂量调至最大功效和最小不利作用。此外,组合中不同药物的代谢动力学特性可能在各目标患者中引起复杂的药效时间错位,从而使总的功效折中。
第三个途径是使用在单个分子中结合两种或更多种药理机制的多功能药物。这些多功能分子的设计和鉴定更加复杂,并需要大量的研究来确认分子中靶向活性的最佳比,而联合的药物代谢动力学可能会在分子靶标级别产生匹配的药物代谢动力学活性。多功能分子也可以改造成与其他药物的固定剂量组合,从而在单一的药片中结合三种、甚至四种药理机制,以产生功效的进一步增长。
经过大量的实验,当前的发明人发明出了一种新的重组多功能融合蛋白,其能够通过三种作用机制来攻击肿瘤,一个是解除PD-1介导的抑制信号对免疫细胞如T细胞的检查或抑制,二是抑制肿瘤微环境中新血管的形成并解除免疫抑制,从而限制靶细胞生长,另一个是激活免疫细胞例如NK细胞和巨噬细胞对靶细胞如PD-L1+肿瘤细胞的杀伤。
本申请的重组融合蛋白包含PD-L1抗体或其抗体片段,该PD-L1抗体或其抗体片段的至少一个互补位在构成该互补位的重链或轻链的N端经接头与VEGF结合肽连接。该重组融合蛋白可以同时与VEGF、PD-L1以及FcR结合,i)阻断癌细胞/肿瘤细胞表面的PD-L1与免疫细胞如T细胞表面PD-1的相互作用,从而解除PD-1介导的抑制性信号对T细胞的检查,ii)与免疫细胞例如NK细胞和巨噬细胞表面的FcR结合,以刺激NK细胞或巨噬细胞对靶细胞如PD-L1+肿瘤细胞的杀伤;以及iii)与例如免疫微环境中的VEGF结合,减少肿瘤血管生成,减少对肿瘤细胞的血液和营养供给。
在一个实施方式中,PD-L1抗体或其抗体片段的至少一个互补位在构成该互补位的重链或轻链的N端经接头与VEGF结合肽连接。在另一实施方式中,PD-L1 抗体或其抗体片段的各互补位在构成该互补位的重链或轻链的N端经接头与 VEGF结合肽连接。在一个实施方式中,PD-L1抗体或其抗体片段的各互补位在构成该互补位的重链的N端经接头与VEGF结合肽连接。在一个实施方式中,PD-L1 抗体或其抗体片段的各互补位在构成该互补位的轻链的N端经接头与VEGF结合肽连接。本申请的重组融合蛋白尺寸较小(150-180kDa),具有5-10天的较长半衰期。
包含在本申请重组融合蛋白中的三个主要组成部分为VEGF结合肽、接头、和PD-L1抗体或其抗体片段。本领域技术人员将意识到,对于上述三个组成部分,存在很多种设计选择。优选地,在人癌症治疗中使用人源序列,因为非人动物蛋白或肽的强烈免疫原性可能会引起过敏反应和其他不良反应。然而,基于不同的应用目的,也可以在本申请中使用其他动物蛋白或肽,可以进行人源化。
能够与VEGF,特别是VEGF-A结合的任何VEGFR(VEGFR1、VEGFR2、和VEGFR3)的任何胞外Ig样结构域,可以用于构建本申请的重组融合蛋白。在一个实施方式中,重组蛋白中的VEGFR是VEGFR1,特别是VEGFR1的第二胞外Ig样结构域(VEGFR1D2)。
VEGFR1D2可以包含与SEQ ID NO:11具有至少80%、85%、90%、91%、 92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列,其中 VEGFR1D2可以与靶细胞如癌细胞/肿瘤细胞表达的、或在靶细胞周围的VEGF结合,从而限制靶细胞的生长。在一个实施方式中,VEGFR1D2可以包含SEQ ID NO: 11所示的氨基酸序列。
接头主要起到VEGF结合肽与PD-L1抗体重链或轻链N端之间的间隔的作用。接头可以由肽键连接的氨基酸构成,优选肽键连接的5-30个、10-30个、10-20个、或15个氨基酸,其中氨基酸选自20种天然存在的氨基酸。这些氨基酸中的一个或多个可以糖基化或去糖基化,如本领域技术人员所了解的。在一个实施方式中, 5-30个10-30个、10-20个、或15个氨基酸可以选自甘氨酸、丙氨酸、脯氨酸、天冬酰胺、谷氨酰胺、丝氨酸和赖氨酸。在一个实施方式中,接头由大部分有空键位阻的氨基酸构成,例如甘氨酸和丙氨酸。示例性的接头为多聚甘氨酸(特别是Gly、多聚(Gly-Ala))、以及多聚丙氨酸。以下实施例中示出的示例性合适接头为GS接头,例如-(Gly-Gly-Gly-Gly-Ser)3-(SEQ ID NO:12)。
接头也可以是非肽类接头。例如,可以使用烷基接头,例如-NH-、-(CH2)s-C(O)-,其中s=2-20。这些烷基接头还可以经任何非空间位阻基团例如低级烷基(例如C1-4低级酰基)、卤素(例如Cl、Br)、CN、NH2、苯基等进行取代。
在一些实施方式中,PD-L1抗体是分离的单克隆抗体,包含两条重链和两条轻链,各重链具有SEQ ID NO:15的氨基酸序列,各轻链具有SEQ ID NO:14的氨基酸序列。PD-L1抗体的Fab部分(或互补位)可以与靶细胞例如癌细胞/肿瘤细胞表面的PD-L1结合,阻断PD-L1与免疫细胞如T细胞表面PD-1的相互作用,从而解除PD-1介导的抑制性信号对免疫细胞的检查,而PD-L1抗体的Fc部分可以与免疫细胞例如NK细胞和巨噬细胞表面的FcR结合,以刺激NK细胞或巨噬细胞的靶向细胞杀伤。在一些实施方式中,重链可以包含与SEQ ID NO:15具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列同一性的氨基酸序列,其中该PD-L1抗体能够与PD-L1结合并阻断PD-1-PD-L1 相互作用,并且能够与NK细胞或巨噬细胞表面的FcR结合,以激活NK细胞和/ 或巨噬细胞对癌细胞的杀灭。在一些实施方式中,轻链可以具有与SEQ ID NO:14 具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或 99%序列同一性的氨基酸序列,其中该PD-L1抗体能够与PD-L1结合,并阻断 PD-1-PD-L1相互作用。
本文中的术语“抗体”包括例如IgG、IgA、IgD、IgE和IgM的全抗体、及其任意的抗原结合片段(或抗原结合部分)或单链。全抗体是包含至少两条重链和两条轻链的糖蛋白,重链和轻链间经二硫键连接。每一重链包含重链可变区(VH) 和重链恒定区。重链恒定区包含三个结构域,CH1、CH2和CH3。每一轻链包含轻链可变区(VL)和轻链恒定区。轻链恒定区包含一个结构域CL。VH和VL区域还可以再分成高度变化区,即CDR区,CDR区之间分布有较为保守的框架区(FR)。每一VH和VL由三个CDR和四个FR区构成,从氨基端到羧基端以FR1、CDR1、 FR2、CDR2、FR3、CDR3、FR4的顺序排列。重链和轻链的可变区包含与抗原反应的结合域。抗体的恒定区可以介导免疫蛋白与宿主组织或因子,包括多种免疫系统细胞(例如效应细胞)和补体系统第一成分(C1q),的结合。重链恒定区的“功能片段”是指重链恒定区中具备与多种免疫系统细胞(例如效应细胞)和补体系统第一成分(C1q)结合的特性的部分,如Fc区、铰链-Fc区等。
抗体的“抗原结合片段”或“抗原结合部分”,是指抗体的保持有特异结合抗原(例如,PD-L1蛋白)能力的一个或多个片段。已证实,抗体的抗原结合功能可以通过全长抗体的片段来实施。包含在抗体的“抗原结合片段”中的结合片段的例子包括(i)Fab片段,由VL、VH、CL和CH1构成的单价片段;(ii)F(ab′)2片段,包含铰链区二硫桥连接的两个Fab片段的二价片段;(iii)由VH和CH1构成的Fd片段;(iv)由抗体单臂VL和VH构成的Fv片段;(v)由VH构成的dAb 片段(Ward et al.,(1989)Nature 341:544-546);(vi)分离的互补决定区(CDR);以及(vii)纳米抗体,一种包含单可变结构域和两个恒定结构域的重链可变区。此外,尽管Fv片段的两个结构域VL和VH由不同的基因编码,它们可以通过重组法经由使两者成为单蛋白链的合成接头而连接,其中VL和VH区配对形成单价分子(称为单链Fc(scFv);参见例如Bird etal.,(1988)Science 242:423-426;Huston et al.,(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883)。这些单链抗体也意在包括在术语涵义中。这些抗体片段可以通过本领域技术人员已知的常用技术而得到,且片段可以通过与完整抗体相同的方式进行功能筛选。
本文的术语“抗体片段”是指本申请抗体中保持有特异结合抗原(例如PD-L1)、以及任选地结合FcR的能力的部分或片段。
本申请抗体或其抗体片段的重链可变区CDR和轻链可变区CDR通过IMGT 编号系统确定。领域内熟知,重链可变区和轻链可变区CDR可以通过例如Chothia、 Kabat、AbM或Contact编号系统/方法确定。
术语“抗体依赖的细胞毒性”、“抗体依赖的细胞介导的细胞毒性”或“ADCC”是指细胞介导的免疫防御,其中免疫系统效应细胞主动地将细胞膜表面抗原与抗体如PD-L1抗体、或与VEGF结合肽结合的靶细胞例如癌细胞裂解。
术语“抗体依赖性细胞介导的吞噬作用”或“ADCP”,是指抗体经其Fab段与靶细胞上的抗原表位结合,以其Fc段与巨噬细胞或者中性粒细胞的FcR结合,从而促进巨噬细胞或者中性粒细胞对靶细胞的吞噬。
术语“受试者”包括任何人或非人动物。术语“非人动物”包括所有脊椎动物,例如哺乳类和非哺乳类,例如非人灵长类、羊、狗、猫、牛、马、鸡、两栖类、和爬行类,尽管优选哺乳动物,例如非人灵长类、羊、狗、猫、牛和马。
本文中提到的“序列一致度”是指在进行序列比对后,一条序列中与参照序列中核苷酸/氨基酸残基相同的核苷酸/氨基酸百分比,如果需要的话,在序列对比中引入空格来达到两条序列间最大的序列一致性百分比。本领域技术人员可以通过多种方法,例如使用计算机软件,来进行两两序列对比或多序列比对,以确定两条或多条核酸或氨基酸序列之间的序列一致性百分比,此类计算机软件为例如 ClustalOmega、T-coffee、Kalign和MAFFT等。
同时,本申请提供编码重组融合蛋白、PD-L1抗体或其抗原结合部分的多核苷酸和表达重组融合蛋白的表达载体。载体的例子包括但不限于质粒、病毒载体、酵母人工染色体(YAC)、细菌人工染色体(BAC)、可转化人工染色体(TAC)、哺乳动物人工染色体(MAC)和人工附加染色体(HAEC)。
本申请提供包含上述表达载体的宿主细胞。宿主细胞可以用表达载体进行转化或转染。合适的宿主细胞包括大肠杆菌(E.coli)、酵母和其他真核生物。优选地,使用大肠杆菌、酵母或哺乳动物细胞系(例如COS或CHO)。
另一方面,本申请提供一种药物组合物,其包含本申请的与药学上可接受的载体配制在一起的重组融合蛋白、PD-L1抗体或其抗原结合部分。药物组合物可以包含有赋形剂、和/或佐剂。组合物可以任选地包含一种或多种其他药学活性成分,例如另一种抗体或药物。本申请的药物组合物也可以与例如另一种免疫刺激剂、抗癌药物、抗病毒剂或疫苗一起在联合疗法中进行施用。
药物组合物可以包含任何数量的赋形剂。可以使用的赋形剂包括载体、表面活性剂、增稠或乳化剂、固体粘合剂、分散或混悬助剂、稳定剂、着色剂、矫味剂、包衣、崩解剂、润滑剂、甜味剂、防腐剂、等渗剂、及其组合。合适赋形剂的选择和使用在Gennaro,ed.,Remington:The Science and Practice of Pharmacy,20th Ed.(LippincottWilliams&Wilkins 2003)中有过教导,其公开内容通过引用的方式并入本文。
药物组合物中的主要媒介物或载体可以本质上是水性或非水性的。例如,合适的媒介物或载体可以是注射用水、生理盐水或人工脑脊液,可以补充有注射中常见的其他材料。例如,媒介物或载体可以是中性缓冲盐溶液或混有血清白蛋白的盐溶液。其他示例性的药物组合物包含Tris缓冲液、或醋酸盐缓冲液,其还可以包含山梨醇或其合适的替代物。在本申请的一个实施方式中,组合物可以通过混合具有所需纯度的所选组分与任意的配制剂(Remington’s Pharmaceutical Sciences,如上)以冻干或水溶液形式制备而用于储存。此外,治疗组合物可以使用合适的赋形剂例如蔗糖配制为冻干剂。
优选地,药物组合物适用于静脉、肌内、皮下、非肠道、脊柱、或表皮给药 (例如,通过注射或推注)。取决于给药途径的不同,活性分子可以包裹在材料中以保护其免受酸和可能使其失活的其他自然条件的作用。本文所用的术语“非肠道给药”是指除通常通过注射进行的肠道和局部给药外的给药模式,包括而不限于,静脉、肌内、动脉内、膜内、囊内、眶内、心脏内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬脑膜、和胸骨内注射和输注。或者,本申请的抗体可以通过非注射途径给药,例如局部的、表皮的或粘膜的给药模式,例如,鼻内、经口、阴道、直肠、舌下、或局部给药。
药物组合物可以是无菌水溶液或混悬液的形式。它们也可以配制成微乳剂、脂质体、或其他适用于高浓度药物的有序结构。
可以与载体材料结合来制备单剂型的活性成分的量,取决于待治疗的受试者和特定的给药途径而各异,且通常是产生疗效的组合物的量。通常而言,以百分比计,该量为约0.01%-约99%的活性成分,与药学上可接受的载体组合在一起。
给药方案可以调整以达成最优的所需反应(例如,治疗反应)。例如,随着时间的推进施用多个分剂量,或者根据治疗情况的危急程度而成比例地减少或增加剂量。特别有利的是,以剂量单位配制非肠道组合物,以方便给药且有利于剂量的均一性。本文所用的剂量单位型是指适用于待治疗受试者的单次给药的物理上分离的单元;各单元包含事先计算出的与药物载体一起产生所需的疗效的活性化合物的量。或者,融合蛋白可以以持续释放剂型进行给药,在这种情况下,给药的频率降低。
对于融合蛋白的给药,剂量范围为约0.0001-100mg/kg受体体重。示例性的治疗方案为每周两次。
“治疗有效量”的本申请融合蛋白优选地引起疾病症状严重程度的降低、无疾病症状时期的频率和持续时间的上升、或防止由疾病引起的损伤或失能。例如,对于荷肿瘤受试者的治疗,“治疗有效量”是指,相对于未治疗的受试者,优选地,肿瘤生长抑制至少约40%,更优选抑制至少约60%,更优选抑制至少约80%,更优选抑制至少约99%。治疗有效量的本申请融合蛋白可以在受试者(通常为人,或者可以为另一种哺乳动物)中减小肿瘤体积、或者减轻症状。
药物组合物可以是受控的缓释制剂,包括植入体、透皮贴剂、和微囊化递送系统。可以使用可生物降解的生物相容性多聚物,例如乙烯-醋酸乙烯共聚物、聚酸酐、聚乙醇酸、胶原蛋白、聚原酸酯、和聚乳酸。参见,例如Sustained and Controlled Release DrugDelivery Systems,J.R.Robinson,ed.,Marcel Dekker,Inc.,New York, 1978。
药物组合物可以通过以下医疗装置进行施用,例如(1)无针皮下注射装置(例如,美国专利5,399,163、5,383,851、5,312,335、5,064,413、4,941,880、4,790,824、和4,596,556);(2)微输注泵(美国专利4,487,603);(3)透皮装置(美国专利4,486,194);(4)输注装置(美国专利4,447,233和4,447,224);和(5)渗透装置(美国专利4,439,196和4,475,196),以上公开内容通过引用的方式并入本文。
在某些实施方式中,本申请的融合蛋白可以配制成保证合适的体内分布。例如,为保证本申请的治疗融合蛋白跨过血脑屏障,将融合蛋白配制在脂质体中,还可以额外地包含靶向基团以加强对特定细胞或器官的选择性传输。参见,例如,美国专利4,522,811、5,374,548、5,416,016、和5,399,331。
本申请还涉及体内基因疗法,其中将编码本申请融合蛋白或其衍生物的核酸分子直接引入受试者中。例如,将编码本申请重组融合蛋白的核酸序列经由带有或不带有合适递送载体例如腺相关病毒载体的核酸构建体经局部注射而引入目标细胞。其他可供选择的病毒载体包括但不限于逆转录病毒、腺病毒、单纯疱疹病毒、和乳头状瘤病毒载体。病毒载体的体内物理转移可以通过所需核酸构建体或包含所需核酸序列的其他合适递送载体的局部注射、脂质体介导的转移、直接注射(裸露的DNA)、或微粒轰击(基因枪)而实现。
本公开的组合物可以单独使用,或者与其他用于增强其疗效或降低潜在副作用的治疗剂联合使用。
本申请的另一目的是提供制备上述重组融合蛋白、PD-L1抗体或其抗原结合部分的方法。在一个实施方式中,制备方法包括以下步骤:(1)提供编码重组融合蛋白、PD-L1抗体或其抗原结合部分的核酸分子;(2)构建包含(1)的核酸分子的表达载体;(3)用(2)中的表达载体转染或转化合适的宿主细胞并培养这些宿主细胞以表达蛋白;以及(4)纯化蛋白。制备可以由普通技术人员以熟知的技术进行。
本申请的另一目标是提供使用本申请药物组合物来治疗癌症的方法,包括向有该需求的患者或受试者施用有效量的上述药物组合物。在一个实施方式中,药物组合物用于治疗与VEGF和/或PD-L1通路/过表达的疾病,包括但不限于急性髓细胞样白血病(AML)、慢性髓细胞样白血病(CML)、急性淋巴细胞白血病(ALL)、非霍奇金淋巴瘤(NHL)、多发性骨髓瘤(MM)、膀胱癌、卵巢癌、前列腺癌、肺癌、结肠癌、乳腺癌、胰腺癌、肝癌、肾细胞癌、黑色素瘤、多形性胶质母细胞瘤、宫颈癌、老年性黄斑变性(AMD)、糖尿病性视网膜病变、肝纤维化和血管肉瘤。
本申请将参照以下非限制性实施例进行进一步说明。
实施例
本申请的示例性融合蛋白IMM2518和IMM2519,以及对照蛋白的结构简单说明如下。
IMM2515H是特异结合PD-L1的IgG抗体,包含两条重链和两条轻链,其中重链可变区、重链恒定区、轻链可变区和轻链恒定区的氨基酸序列分别如SEQ ID NOs:7、9、8和10所示。重链和轻链的氨基酸序列分别如SEQ ID NOs:15和14 所示。
IMM2518是本申请的示例性重组融合蛋白,包括两个VEGFR1D2(SEQ ID NO:11)经接头(SEQ ID NO:12)与IMM2515H的两条重链的N端连接,如图1所示。即,IMM2518包含两条如SEQ ID NO:13所示的长链,和两条如SEQ ID NO: 14所示的短链。
IMM2519是本申请的示例性重组融合蛋白,包括两个VEGFR1D2(SEQ ID NO: 11)经接头(SEQ ID NO:12)与IMM2515H的两条轻链的N端连接,如图1所示。即,IMM2519包含两条如SEQ ID NO:15所示的长链,和两条如SEQ ID NO: 16所示的短链。
IMM2510是与IMM2518结构相似的重组融合蛋白,区别在于PD-L1抗体不同,具体地包含两条如SEQ ID NO:17所示的长链、两条如SEQ ID NO:18所示的短链。
VEGFR1D2-Fc为VEGFR1D2与Fc的融合蛋白,包含SEQ ID NO:19所示的氨基酸序列。
实施例1.重组融合蛋白的表达载体的构建
1.1IMM2518
人工设计IMM2518的全长编码序列。具体地,对于长链,将编码小鼠IgG1 重链信号肽的57个核苷酸(SEQ ID NO:21)加到VEGF结合肽-接头-PD-L1抗体重链编码序列(SEQ IDNO:23)的5’端,并将Kozak序列(SEQ ID NO:22)加到信号肽序列的5’端。最后,在所得序列的5’和3’端分别加入HindIII和NheI限制性酶切位点。对于短链,将同一信号肽序列和Kozak序列加至PD-L1轻链编码序列(SEQ ID NO:24),在所得序列的5’和3’端分别加入HindIII和XbaI限制性酶切位点。两个所得的序列人工合成,并分别亚克隆到pMac-H和pMac-L载体中。
1.2IMM2519
人工设计IMM2519的全长编码序列。具体地,对于长链,将编码小鼠IgG1 重链信号肽的57个核苷酸(SEQ ID NO:21)加到PD-L1抗体重链编码序列(SEQ ID NO:25)的5’端,并将Kozak序列(SEQ ID NO:22)加到信号肽序列的5’端。最后,在所得序列的5’和3’端分别加入HindIII和NheI限制性酶切位点。对于短链,将同一信号肽序列和Kozak序列加至VEGF结合肽-接头-PD-L1轻链编码序列 (SEQ ID NO:26),在所得序列的5’和3’端分别加入HindIII和XbaI限制性酶切位点。两个所得的序列人工合成,并分别亚克隆到pMac-H和pMac-L载体中。
实施例2.重组融合蛋白的制备和质量分析
构建好的表达载体利用CHO-S细胞瞬转表达蛋白。大致过程如下:1)瞬转前一天将CHO-S细胞按照1×106个/ml密度接种至含6mM谷氨酰胺的瞬转培养基 (TransFx-CTMCHO瞬转培养基,Hyclone);2)重/轻(长/短)链表达载体质量比为1∶1,按照1μg/ml准备所需DNA,加入至瞬转体积1/20的OPTI-MEM培养基(Gibco);3)PEI(MW40,000聚乙烯亚胺盐酸盐,polysciences)配置成1mg/ml,按照PEI∶DNA=4∶1比例准备所需PEI,加入至瞬转体积1/20的OPTI-MEM培养基 (Gibco);4)将PEI稀释液缓慢加入至DNA稀释液中,混匀,室温孵育20分钟;5)将PEI/DNA混合液加入至细胞液中,并将细胞置于37度5%CO2,转速 110rpm培养箱振荡培养;6)隔天添加转染增强剂(1mM丁酸钠,0.25%V/V DMSO),同时将培养温度降至33度;7)当细胞活率降至50%以下时,3000rpm,离心5 分钟收集上清利用ProteinA填料进行亲和纯化。
经SEC-HPLC图谱显示,IMM2518具有较高的纯度,聚体量和降解量都较低,具体如表1所示。
表1.本申请重组融合蛋白的SEC-HPLC图谱结果
样本 | 聚体(%) | 主峰(%) | 降解度(%) |
IMM2518 | 4.76 | 94.98 | 0.26 |
IMM2519 | 18.72 | 77.55 | 3.73 |
实施例3.重组融合蛋白与VEGF-165结合
对于VEGF结合,在碳酸盐-碳酸氢盐包被缓冲液(Cat#C304l,Sigma-Aldrich) 中配制重组人VEGF-165(Cat#11066-HNAH,Sino Biologicals),并转移到ELISA 板上,50ng/孔,将板置于4℃冰箱过夜。用150μL/孔3%脱脂牛奶,室温封闭2 小时。之后添加100μl梯度稀释的重组融合蛋白,将板于37℃孵育1小时,后用 0.05%吐温20的PBS-T洗5遍。再向板加入HRP-兔抗人IgG Fc(Cat#:309-036-008, Jackson ImmunoResearchLab),且板于37℃孵育1小时。用PBS-T洗板5次后,每孔加入100μL TMB显色液,加入500μL 1N H2SO4停止显色后在酶标仪中读数。
如图2所示,本申请的两种重组融合蛋白具有相似的VAGF-165结合活性。
实施例4.重组融合蛋白与PD-L1结合
对于PD-L1结合的分析,将100μl1×106/ml CHO-PD-L1(Cat#YMAK-C006,ImmuneOnco)分别与100μl梯度稀释的重组融合蛋白以及对照蛋白IMM2515H和 hIgG1-Fc(SEQ ID NO:20)4℃孵育40分钟。在用冷PBS洗涤后,细胞与FITC- 偶联的抗人IgG-Fc抗体(Cat#F9512,Sigma)孵育40分钟。之后,细胞洗涤2 遍,并进行FACS分析。
结果如图3所示,IMM2518和IMM2519的PD-L1+细胞结合活性比单特异性 PD-L1抗体IMM2515H要分别低2.6倍和4.2倍。
同时,也分析了重组融合蛋白以及对照蛋白IMM2515H、IMM2510、阿替丽珠单抗和hIgG1-Fc与CHO-PD-L1的结合,方法步骤同上。
如图4所示,IMM2518的PD-L1+细胞结合活性与IMM2510相近。
实施例5.重组融合蛋白与VEGF以及PD-L1的结合亲和力
在非标记生物分子分析仪(Access Medical Systems,Gator bio)上选择动力学检测(Kinetics Assay)模式,使用Q缓冲液(10mM,PH7.4,PBS+0.02%吐温 +0.2%BSA)作为实验缓冲液,采用人Fc探针作为实验探针,IMM2518起始浓度为10μg/ml,2倍梯度稀释5个浓度,分别以10μg/ml VEGF165(Cat#11066-HNAH,sino Biological)和10μg/ml PD-L1-his(Cat#90251-C08H,sino Biological)作为抗原。最后使用pH 2.0的再生缓冲液(10mM Gly+150mM NaCl,调PH至2.0)对探针再生,仪器设定温度为25℃。
表2.利用BLI技术检测的重组融合蛋白与VEGF以及PD-L1的亲和力
结合靶点 | Koff(1/s) | Kon(1/ms) | KD(M) |
VEGF165 | NA | 1.57E+05 | NA |
PD-L1-his | 0.000218 | 4.94E+05 | 4.41E-10 |
检测结果显示,IMM2518和VEGF165结合后,解离速度非常慢,没有得到具体的解离常数。IMM2518和PD-L1的亲和力为0.441nM。
实施例6.重组融合蛋白对PD-1-PD-L1的阻断活性
对于PD-1-PD-L1阻断活性的分析,将50μl 5×105/ml CHO-PD-L1 (Cat#YMAK-C006,ImmuneOnco)分别与50μl梯度稀释的重组融合蛋白以及对照蛋白IMM2515H、IMM2510、阿替丽珠单抗和hIgG1-Fc于4℃孵育45分钟,再加入50μl的PD1-mFc(宜明昂科内部制备,SEQ ID NO:28),于4℃孵育45分钟,后用冷PBS洗涤后,细胞与PE-偶联的抗鼠IgG-Fc抗体(Biolegend,Cat#405307) 孵育。之后,细胞洗涤2遍,并进行FACS分析。
如图5所示,IMM2518对PD-1蛋白与PD-L1+细胞结合的阻断能力比 IMM2515H以及阿替丽珠单抗要分别低2.2倍和3倍,与IMM2510相近。
实施例7.重组融合蛋白对VEGF活性的阻断
对于VEGF活性的阻断,采用宜明昂科构建的Jurkat-CVR细胞进行评价。CVR (嵌合VEGFR1D2受体)由VEGFR1的膜外端第二结构域、CD8α的绞链区、CD28 的穿膜区及胞内区、以及CD3z的信号传导区等所组成,包含SEQ ID NO:29所示的氨基酸序列。将50μl 5×105/mlJurkat-CVR分别与50μl梯度稀释的重组融合蛋白以及对照蛋白VEGFR1D2-Fc(SEQ ID NO:19)、IMM2510、贝伐单抗和hIgG1-Fc 于37℃孵育45分钟,再加入50μl的VEGF-Fc(宜明昂科内部制备,SEQ ID NO: 27)于37℃孵育过夜,后用冷PBS洗涤后,细胞与PE-偶联的抗人CD69抗体 (Biolegend,Cat#310906)孵育。之后,细胞洗涤2遍,并进行FACS分析。
如图6所示,MM2518对VEGF活性的阻断能力比VEGFR1D2-Fc以及贝伐单抗略低,与IMM2510相近。
实施例8.重组融合蛋白对PD-L1的结合特异性
将人PD-L1(Cat#10084-H08H,sino Biological)、小鼠PD-L1(Cat#50010-M08H,sino Biological)、猴PD-L1(Cat#90251-C08H,sino Biological)、大鼠PD-L1 (Cat#80450-R08H,sino Biological)、和人PD-L2(Cat#10292-H08H,sino Biological) 用碳酸盐-碳酸氢盐包被缓冲液(Cat#C3041,Sigma-Aldrich)置于板中,50ng/孔,将板置于4℃冰箱过夜。用150μL/孔3%脱脂牛奶,室温封闭2小时。之后添加 100μl梯度稀释的重组融合蛋白,将板于37℃孵育1小时,并用0.05%吐温20 的PBS-T洗5遍。向板加入HRP-兔抗人IgG Fc(Cat#:309-036-008,Jackson ImmunoResearchLab),且板于室温孵育1小时。用PBS-T洗板5次后,每孔加入 100μL TMB显色液,加入500μL 1N H2SO4停止显色后在酶标仪中读数。
结果如图7所示,IMM2518与人PD-L1以及猴PD-L1有交叉结合,与大鼠 PD-L1、小鼠PD-L1以及人PD-L2均无交叉结合。
实施例9.重组融合蛋白诱导抗体依赖的细胞介导的细胞毒性(ADCC)
CFSE荧光染料(Cat#21888-25mg,Sigma)标记Raji-PD-L1细胞,6×105/ml, 50μl,与100μl 6×105/ml作为效应细胞的稳定表达FcγRIIIa(158V)的NK92MI 细胞(Cat#CRL-2408,ATCC)以1∶2比率混合,且混合的细胞在5%CO2下与 50μl连续稀释的IMM2518或IMM2515H于37℃培养4小时。之后向细胞培养液中加入碘化丙啶(PI)(Cat#P4170,Sigma),使其终浓度为5μg/ml,细胞培养液经FACS分析CFSE标记靶细胞的PI信号。基于以下公式计算由ADCC造成的细胞裂解百分比:%裂解(或%ADCC)=(%IMM2518或阳性对照处理的PI阳性细胞-%阴性对照蛋白处理的PI阳性细胞)/(100-%阴性对照蛋白处理的PI阳性细胞)*100。
结果如图8A所示。IMM2518针对Raji-PD-L1细胞的ADCC活性比IMM2515H 低近6倍。
胰酶消化处理RKO细胞(Cat#TCHu116,中国科学院细胞库)或HCC827细胞(Cat#TCHu153,中国科学院细胞库),5×105/ml,50μl,与50μl 5×105/ml 作为效应细胞的稳定表达FcγRIIIa(158V)的NK92MI细胞(Cat#CRL-2408,ATCC) 以1∶1比率混合,且混合的细胞在5%CO2下与50μl连续稀释的IMM2518、 IMM2515H、IMM2510、阿替丽珠单抗、或hIgG1-Fc于37℃培养过夜。之后向细胞培养液中加入20μl CCK-8(碧云天,Cat#C0039),培养箱继续孵育3h,在波长450nm下测定吸光度。基于以下公式计算由ADCC造成的细胞裂解百分比:%裂解(或%ADCC)=(阴性对照组的效应细胞和靶细胞的OD450值-IMM2518 或阳性对照处理的效应细胞和靶细胞的OD450值)/(阴性对照组的效应细胞和靶细胞的OD450值-阴性对照的效应细胞的OD450值)*100%。
如图8B、和图8C所示,IMM2518针对RKO细胞以及HCC827细胞的ADCC 活性相对IMM2515H要分别弱6倍和33倍。
实施例10.重组融合蛋白诱导抗体依赖性细胞介导的吞噬作用(ADCP)
2.5×105/ml THP-1(Cat#TCHu 57,中国科学院细胞库),于100μl完全培养基中,接种96孔平底板,含工作浓度200ng/ml PMA(Sigma,Cat#379346-1MG),刺激培养48小时,作为靶细胞的RKO细胞(Cat#TCHu116,中国科学院细胞库) 在胰酶消化处理的同时用CFSE(Cat#21888-25mg,Sigma)标记。CFSE标记的 RKO细胞,5.0×105/ml,100μl与接种至96孔板的效应细胞THP-1按照效靶比1∶ 2比率混合,且混合的细胞在5%CO2下与50μl连续稀释的IMM2518、IMM2515H、 IMM2510、阿替丽珠单抗、或hIgG1-Fc于37℃培养2小时,孵育结束后吸弃上清,同时加入250μl/孔PBS缓冲液清洗5次,将未吸附到板底的靶细胞移除。清洗结束后反复吹吸使THP-1细胞悬浮,经FACS分析THP-1巨噬细胞CFSE信号。
如图9所示,针对RKO肿瘤细胞的吞噬活性,IMM2518、IMM2515H和 IMM2510三者活性相近。
实施例11.重组融合蛋白具有较好的抗肿瘤效果
使用C57BL/6hPD-1人源化小鼠(Gempharmtech)评估本申请重组融合蛋白的体内抗肿瘤效力。小鼠结肠癌细胞系MC38-hPD-L1(药明康德),体外单层培养,一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80%-90%,数量到达要求时,收取细胞,计数。
将含3×105个MC38-hPD-L1细胞的100μL PBS接种于小鼠的右前肢腋窝皮下。选取平均肿瘤体积达到60-90mm3范围内的动物36只,随机分成6组,每组 6只小鼠,这一天设为第0天。从这一天起,小鼠分别腹腔注射DPBS、IMM2510 (6.0mg/kg)、IMM2518(6.0mg/kg)、IMM2515H(5.0mg/kg)、VEGFR1D2-Fc (2.5mg/kg)、以及IMM2515H(5.0mg/kg)+VEGFR1D2-Fc(2.5mg/kg)组合,一周两次,持续4周。测量肿瘤体积和动物体重,一周两次。
肿瘤体积(V)计算为(长×宽2)/2。肿瘤生长抑制率(TGI)用以下公式计算:肿瘤生长抑制率=(1-给药组肿瘤体积变化/对照组肿瘤体积变化)×100%。
结果以均值±S.E.M表示。通过Dunnett’s多重比较进行两组之间的比较,其中认定P<0.05为显著。
如图10所示,与DPBS相比,经单特异性靶向药物、或两种单特异性靶向药物组合处理的小鼠的肿瘤体积生长较慢,而用IMM2510和IMM2518处理的小鼠的肿瘤生长明显更慢。其中,IMM2518的抗肿瘤效率又高于IMM2510,IMM2510 处理的TGI为74.07%,IMM2518处理的TGI为97.47%。
本申请的序列信息总结如下。
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尽管本申请已经结合一个或多个实施方式进行了描述,应当理解的是,本申请并不受限于这些实施方式。本申请中的描述意在涵盖所有变体形式以及等同物,均包含在所附权利要求的主旨和范围内。所有在本文中引用的文献通过引用的方式全部并入本文。
序列表
<110> 宜明昂科生物医药技术(上海)有限公司
<120> 靶向PD-L1和VEGF的重组融合蛋白及其制备和用途
<130> 55525 IMM2518
<160> 29
<170> PatentIn版本3.5
<210> 1
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> IMM2515H的VH-CDR1
<400> 1
Gly Tyr Thr Phe Thr Ser Asn Trp
1 5
<210> 2
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> IMM2515H的VH-CDR2
<400> 2
Ile His Pro Asn Ser Gly Ser Ser
1 5
<210> 3
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> IMM2515H的VH-CDR3
<400> 3
Ala Arg Ser Tyr Tyr Gly Ser Ser Pro Tyr Tyr Phe Asp Tyr
1 5 10
<210> 4
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> IMM2515H的VL-CDR1
<400> 4
Gln Asp Ile Ile Asn Tyr
1 5
<210> 5
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> IMM2515H的VL-CDR2
<400> 5
Tyr Thr Ser
1
<210> 6
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> IMM2515H的VL-CDR3
<400> 6
Gln Gln Gly Asp Thr Leu Pro Trp Thr
1 5
<210> 7
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> IMM2515H的VH
<400> 7
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 Ser Asn
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Ser 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 Ser Tyr Tyr Gly Ser Ser Pro Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 8
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> IMM2515H的VL
<400> 8
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 Arg Ala Ser Gln Asp Ile Ile Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser 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 Gln Gln Gly Asp Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 9
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 重链恒定区
<400> 9
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
Arg 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 Ala 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 Ala Ala Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met 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> 10
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 轻链恒定区
<400> 10
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> 11
<211> 100
<212> PRT
<213> 人工序列
<220>
<223> VEGF结合肽
<400> 11
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
1 5 10 15
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
20 25 30
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
35 40 45
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
50 55 60
Ile Ile Ser Ala Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
65 70 75 80
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
85 90 95
Gln Thr Asn Thr
100
<210> 12
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 接头
<400> 12
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 13
<211> 566
<212> PRT
<213> 人工序列
<220>
<223> IMM2518的长链
<400> 13
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
1 5 10 15
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
20 25 30
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
35 40 45
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
50 55 60
Ile Ile Ser Ala Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
65 70 75 80
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
85 90 95
Gln Thr Asn Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
100 105 110
Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
115 120 125
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
130 135 140
Thr Ser Asn Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
145 150 155 160
Glu Trp Met Gly Met Ile His Pro Asn Ser Gly Ser Ser Asn Tyr Asn
165 170 175
Glu Lys Phe Lys Ser Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser
180 185 190
Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Ser Tyr Tyr Gly Ser Ser Pro Tyr Tyr Phe Asp
210 215 220
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
225 230 235 240
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
245 250 255
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
260 265 270
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
275 280 285
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
290 295 300
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
305 310 315 320
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro
325 330 335
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
340 345 350
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
355 360 365
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
370 375 380
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
385 390 395 400
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
405 410 415
Ala Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
420 425 430
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
435 440 445
Ala Pro Ile Ala Ala Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
450 455 460
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
465 470 475 480
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
485 490 495
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
500 505 510
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
515 520 525
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
530 535 540
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
545 550 555 560
Ser Leu Ser Pro Gly Lys
565
<210> 14
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> IMM2518的短链
<400> 14
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 Arg Ala Ser Gln Asp Ile Ile Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser 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 Gln Gln Gly Asp Thr Leu Pro Trp
85 90 95
Thr Phe Gly Gln 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> 15
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> IMM2519的长链
<400> 15
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 Ser Asn
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Met Ile His Pro Asn Ser Gly Ser Ser 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 Ser Tyr Tyr Gly Ser Ser Pro Tyr Tyr Phe Asp Tyr 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 Ala 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
Ala Ala 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> 16
<211> 329
<212> PRT
<213> 人工序列
<220>
<223> IMM2519的短链
<400> 16
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
1 5 10 15
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
20 25 30
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
35 40 45
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
50 55 60
Ile Ile Ser Ala Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
65 70 75 80
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
85 90 95
Gln Thr Asn Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
100 105 110
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
115 120 125
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile
130 135 140
Ile Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
145 150 155 160
Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg
165 170 175
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser
180 185 190
Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Thr
195 200 205
Leu Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr
210 215 220
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
225 230 235 240
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
245 250 255
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
260 265 270
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
275 280 285
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
290 295 300
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
305 310 315 320
Thr Lys Ser Phe Asn Arg Gly Glu Cys
325
<210> 17
<211> 563
<212> PRT
<213> 人工序列
<220>
<223> IMM2510的长链
<400> 17
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
1 5 10 15
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
20 25 30
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
35 40 45
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
50 55 60
Ile Ile Ser Ala Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
65 70 75 80
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
85 90 95
Gln Thr Asn Thr Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
100 105 110
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
115 120 125
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
130 135 140
Ser Asp Ser Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
145 150 155 160
Glu Trp Val Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala
165 170 175
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
180 185 190
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
195 200 205
Tyr Tyr Cys Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly
210 215 220
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
225 230 235 240
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
245 250 255
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
260 265 270
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
275 280 285
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
290 295 300
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
305 310 315 320
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
325 330 335
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
340 345 350
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
355 360 365
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
370 375 380
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
385 390 395 400
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ala Thr Tyr
405 410 415
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
420 425 430
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
435 440 445
Ala Ala Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
450 455 460
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
465 470 475 480
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
485 490 495
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
500 505 510
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
515 520 525
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
530 535 540
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
545 550 555 560
Pro Gly Lys
<210> 18
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> IMM2510的短链
<400> 18
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg 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 Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln 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> 19
<211> 334
<212> PRT
<213> 人工序列
<220>
<223> VEGFR1D2-Fc
<400> 19
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
1 5 10 15
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
20 25 30
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
35 40 45
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
50 55 60
Ile Ile Ser Ala Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
65 70 75 80
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
85 90 95
Gln Thr Asn Thr Glu Phe Glu Pro Lys Ser Cys Asp Lys Thr His Thr
100 105 110
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
115 120 125
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
130 135 140
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
145 150 155 160
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
165 170 175
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
180 185 190
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
195 200 205
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
210 215 220
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
225 230 235 240
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
245 250 255
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
260 265 270
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
275 280 285
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
290 295 300
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
305 310 315 320
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 20
<211> 232
<212> PRT
<213> 人工序列
<220>
<223> hIgG1-Fc
<400> 20
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 21
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 小鼠IgG1重链信号肽
<400> 21
atgggatggt catgtatcat cctttttctg gtagcaactg caactggagt acattca 57
<210> 22
<211> 9
<212> DNA
<213> 人工序列
<220>
<223> Kozak序列
<400> 22
gccgccacc 9
<210> 23
<211> 1758
<212> DNA
<213> 人工序列
<220>
<223> IMM2518的长链
<400> 23
atgggatggt catgtatcat cctttttctg gtagcaactg caactggagt acattcaagt 60
gatacaggta gacctttcgt agagatgtac agtgaaatcc ccgaaattat acacatgact 120
gaaggaaggg agctcgtcat tccctgccgg gttacgtcac ctaacatcac tgttacttta 180
aaaaagtttc cacttgacac tttgatccct gatggaaaac gcataatctg ggacagtaga 240
aagggcttca tcatatcagc tgcaacgtac aaagaaatag ggcttctgac ctgtgaagca 300
acagtcaatg ggcatttgta taagacaaac tatctcacac atcgacaaac caatacaggc 360
ggcggtggga gcggcggcgg tgggagcggc ggcgggggct cgcaagtgca gctggtgcag 420
agcggcgccg aggtgaagaa gcctggcgca agcgtgaagg tgagctgcaa ggcaagcggc 480
tacaccttca caagcaactg gatgcactgg gtgagacaag cccctggcca aggcctggag 540
tggatgggca tgatccaccc taacagcggc agcagcaact acaacgagaa gttcaagagc 600
agagtgacca tgacaagaga cacaagcaca agcaccgtgt acatggagct gagcagcctg 660
agaagcgagg acaccgccgt gtactactgc gctagaagct actacggcag cagcccttac 720
tacttcgact actggggcca aggcaccctg gtgaccgtga gcagcgctag caccaagggc 780
ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 840
ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 900
ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 960
agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 1020
aatcacaagc ccagcaacac caaggtggac aagagagttg agcccaaatc ttgtgacaaa 1080
actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 1140
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 1200
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtatgt ggacggcgtg 1260
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacgccac gtaccgtgtg 1320
gtcagcgtcc tcaccgtcct gcaccaagac tggctgaatg gcaaggagta caagtgcaag 1380
gtctccaaca aagccctccc agcccccatc gccgcaacca tctccaaagc caaagggcag 1440
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccaa 1500
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1560
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1620
tccttcttcc tctattccaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1680
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1740
ctgtctccgg gcaaatga 1758
<210> 24
<211> 841
<212> DNA
<213> 人工序列
<220>
<223> IMM2518的短链
<400> 24
atgggatggt catgtatcat cctttttctg gtagcaactg caactggagt acattcagac 60
attcagatga cacagagccc tagcagcctg agcgcaagcg tgggcgacag agtgaccatc 120
acctgcagag caagccaaga catcatcaac tacctgaact ggtatcagca gaagcctggc 180
aaggccccta agctgctgat ctactacaca agcagactgc acagcggcgt gcctagcaga 240
ttcagcggca gcggcagcgg caccgacttc accttcacca tcagcagcct gcagcctgag 300
gacatcgcca cctactactg tcagcaaggc gacaccctgc cttggacctt cggccaaggc 360
accaaggtgg agatcaagcg tgagttctag aggatccatc tgggataagc atgctgtttt 420
ctgtctgtcc ctaacatgcc ctgtgattat ccgcaaacaa cacacccaag ggcagaactt 480
tgttacttaa acaccatcct gtttgcttct ttcctcagga actgtggctg caccatctgt 540
cttcatcttc ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct 600
gctgaataac ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca 660
atcgggtaac tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct 720
cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga 780
agtcacccat cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgtta 840
g 841
<210> 25
<211> 1413
<212> DNA
<213> 人工序列
<220>
<223> IMM2519的长链
<400> 25
atgggatggt catgtatcat cctttttctg gtagcaactg caactggagt acattcacaa 60
gtgcagctgg tgcagagcgg cgccgaggtg aagaagcctg gcgcaagcgt gaaggtgagc 120
tgcaaggcaa gcggctacac cttcacaagc aactggatgc actgggtgag acaagcccct 180
ggccaaggcc tggagtggat gggcatgatc caccctaaca gcggcagcag caactacaac 240
gagaagttca agagcagagt gaccatgaca agagacacaa gcacaagcac cgtgtacatg 300
gagctgagca gcctgagaag cgaggacacc gccgtgtact actgcgctag aagctactac 360
ggcagcagcc cttactactt cgactactgg ggccaaggca ccctggtgac cgtgagcagc 420
gctagcacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 480
ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540
tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 600
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 660
tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 720
aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 780
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 840
gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 900
tatgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 960
gccacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aagactggct gaatggcaag 1020
gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgccgc aaccatctcc 1080
aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1140
atgaccaaga accaagtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1200
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1260
ctggactccg acggctcctt cttcctctat tccaagctca ccgtggacaa gagcaggtgg 1320
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1380
cagaagagcc tctccctgtc tccgggcaaa tga 1413
<210> 26
<211> 1186
<212> DNA
<213> 人工序列
<220>
<223> IMM2519的短链
<400> 26
atgggatggt catgtatcat cctttttctg gtagcaactg caactggagt acattcaagt 60
gatacaggta gacctttcgt agagatgtac agtgaaatcc ccgaaattat acacatgact 120
gaaggaaggg agctcgtcat tccctgccgg gttacgtcac ctaacatcac tgttacttta 180
aaaaagtttc cacttgacac tttgatccct gatggaaaac gcataatctg ggacagtaga 240
aagggcttca tcatatcagc tgcaacgtac aaagaaatag ggcttctgac ctgtgaagca 300
acagtcaatg ggcatttgta taagacaaac tatctcacac atcgacaaac caatacaggc 360
ggcggtggga gcggcggcgg tgggagcggc ggcgggggct cggacattca gatgacacag 420
agccctagca gcctgagcgc aagcgtgggc gacagagtga ccatcacctg cagagcaagc 480
caagacatca tcaactacct gaactggtat cagcagaagc ctggcaaggc ccctaagctg 540
ctgatctact acacaagcag actgcacagc ggcgtgccta gcagattcag cggcagcggc 600
agcggcaccg acttcacctt caccatcagc agcctgcagc ctgaggacat cgccacctac 660
tactgtcagc aaggcgacac cctgccttgg accttcggcc aaggcaccaa ggtggagatc 720
aagcgtgagt tctagaggat ccatctggga taagcatgct gttttctgtc tgtccctaac 780
atgccctgtg attatccgca aacaacacac ccaagggcag aactttgtta cttaaacacc 840
atcctgtttg cttctttcct caggaactgt ggctgcacca tctgtcttca tcttcccgcc 900
atctgatgag cagttgaaat ctggaactgc ctctgttgtg tgcctgctga ataacttcta 960
tcccagagag gccaaagtac agtggaaggt ggataacgcc ctccaatcgg gtaactccca 1020
ggagagtgtc acagagcagg acagcaagga cagcacctac agcctcagca gcaccctgac 1080
gctgagcaaa gcagactacg agaaacacaa agtctacgcc tgcgaagtca cccatcaggg 1140
cctgagctcg cccgtcacaa agagcttcaa caggggagag tgttag 1186
<210> 27
<211> 418
<212> PRT
<213> 人工序列
<220>
<223> VEGF-Fc
<400> 27
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Ala Pro Met Ala Glu Gly Gly Gly Gln Asn His His Glu
20 25 30
Val Val Lys Phe Met Asp Val Tyr Gln Arg Ser Tyr Cys His Pro Ile
35 40 45
Glu Thr Leu Val Asp Ile Phe Gln Glu Tyr Pro Asp Glu Ile Glu Tyr
50 55 60
Ile Phe Lys Pro Ser Cys Val Pro Leu Met Arg Cys Gly Gly Cys Cys
65 70 75 80
Asn Asp Glu Gly Leu Glu Cys Val Pro Thr Glu Glu Ser Asn Ile Thr
85 90 95
Met Gln Ile Met Arg Ile Lys Pro His Gln Gly Gln His Ile Gly Glu
100 105 110
Met Ser Phe Leu Gln His Asn Lys Cys Glu Cys Arg Pro Lys Lys Asp
115 120 125
Arg Ala Arg Gln Glu Asn Pro Cys Gly Pro Cys Ser Glu Arg Arg Lys
130 135 140
His Leu Phe Val Gln Asp Pro Gln Thr Cys Lys Cys Ser Cys Lys Asn
145 150 155 160
Thr Asp Ser Arg Cys Lys Ala Arg Gln Leu Glu Leu Asn Glu Arg Thr
165 170 175
Cys Arg Cys Asp Lys Pro Arg Arg Glu Phe Glu Pro Lys Ser Cys Asp
180 185 190
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
195 200 205
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
210 215 220
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
225 230 235 240
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
245 250 255
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
260 265 270
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
275 280 285
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
290 295 300
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
305 310 315 320
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
325 330 335
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
340 345 350
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
355 360 365
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
370 375 380
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
385 390 395 400
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
405 410 415
Gly Lys
<210> 28
<211> 391
<212> PRT
<213> 人工序列
<220>
<223> PD1-mFc
<400> 28
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr Phe
20 25 30
Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Ala Ala Thr Phe Thr
35 40 45
Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr Arg
50 55 60
Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu Asp
65 70 75 80
Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu Pro
85 90 95
Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn Asp
100 105 110
Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala Gln
115 120 125
Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg Ala
130 135 140
Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly Gln
145 150 155 160
Phe Gln Glu Phe Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys
165 170 175
Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys
180 185 190
Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val
195 200 205
Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp
210 215 220
Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe
225 230 235 240
Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp
245 250 255
Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe
260 265 270
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys
275 280 285
Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys
290 295 300
Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp
305 310 315 320
Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys
325 330 335
Asn Thr Gln Pro Ile Met Asn Thr Asn Gly Ser Tyr Phe Val Tyr Ser
340 345 350
Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr
355 360 365
Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser
370 375 380
Leu Ser His Ser Pro Gly Lys
385 390
<210> 29
<211> 344
<212> PRT
<213> 人工序列
<220>
<223> CVR
<400> 29
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu
20 25 30
Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro
35 40 45
Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro
50 55 60
Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg
65 70 75 80
Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu
85 90 95
Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu
100 105 110
Thr His Arg Gln Thr Asn Thr Thr Thr Thr Pro Ala Pro Arg Pro Pro
115 120 125
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
130 135 140
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
145 150 155 160
Phe Ala Cys Asp Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala
165 170 175
Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val Arg
180 185 190
Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro
195 200 205
Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro
210 215 220
Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala
225 230 235 240
Glu Pro Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu
245 250 255
Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly
260 265 270
Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu
275 280 285
Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser
290 295 300
Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly
305 310 315 320
Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu
325 330 335
His Met Gln Ala Leu Pro Pro Arg
340
Claims (15)
1.一种重组融合蛋白,包含PD-L1抗体或其抗体片段、以及VEGF结合肽,
所述PD-L1抗体或其抗体片段包含重链可变区、和轻链可变区,重链可变区包含氨基酸序列分别如SEQ ID NOs:1、2和3所示的HV-CDR1、HV-CDR2、和HV-CDR3,轻链可变区包含氨基酸序列分别如SEQ ID NOs:4、5和6所示的LV-CDR1、LV-CDR2、和LV-CDR3,
所述VEGF结合肽包含血管内皮生长因子受体1(VEGFR1)的第二胞外Ig样结构域(VEGFR1D2),
所述PD-L1抗体或其抗体片段的各互补位与所述VEGF结合肽在构成该互补位的重链可变区或轻链可变区的N端连接。
2.根据权利要求1所述的重组融合蛋白,其中VEGF结合肽包含SEQ ID NO:11所示的氨基酸序列。
3.根据权利要求1所述的重组融合蛋白,其中重链可变区包含SEQ ID NO:7所示的氨基酸序列,轻链可变区包含SEQ ID NO:8所示的氨基酸序列。
4.根据权利要求1所述的重组融合蛋白,其中所述PD-L1抗体或其抗体片段的各互补位与所述VEGF结合肽在构成该互补位的重链可变区的N端连接。
5.根据权利要求1所述的重组融合蛋白,还包含重链恒定区,与重链可变区的C端连接,其包含SEQ ID NO:9所示的氨基酸序列。
6.根据权利要求1所述的重组融合蛋白,其中所述PD-L1抗体或其抗体片段经接头与所述VEGF结合肽连接。
7.根据权利要求6所述的重组融合蛋白,其中接头为-(Gly-Gly-Gly-Gly-Ser)3-(SEQID NO:12)。
8.根据权利要求1所述的重组融合蛋白,还包含轻链恒定区,所述轻链恒定区包含SEQID NO:10所述的氨基酸序列,且与所述轻链可变区的C端连接。
9.根据权利要求1所述的重组融合蛋白,包含:
i)具有SEQ ID NO:13所示的氨基酸序列的VEGF结合肽-接头-PD-L1抗体重链可变区-重链恒定区、以及具有SEQ ID NO:14所示的氨基酸序列的PD-L1抗体轻链可变区-轻链恒定区;或
ii)具有SEQ ID NO:15所示的氨基酸序列的PD-L1抗体重链可变区-重链恒定区、以及具有SEQ ID NO:16所示的氨基酸序列的VEGF结合肽-接头-PD-L1抗体轻链可变区-轻链恒定区。
10.一种核酸分子,其编码权利要求1-9中任一项所述的重组融合蛋白。
11.一种表达载体,其包含权利要求10所述的核酸分子。
12.一种宿主细胞,其包含权利要求11所述的表达载体。
13.一种药物组合物,其包含权利要求1-9中任一项所述的重组融合蛋白、权利要求10所述的核酸分子、权利要求11所述的表达载体、或权利要求12所述的宿主细胞,以及至少一种药学上可接受的载体。
14.权利要求13所述的药物组合物在制备用于治疗与PD-L1和/或VEGF通路相关的疾病的药物中的用途。
15.根据权利要求14所述的用途,其中所述疾病选自急性髓细胞样白血病(AML)、慢性髓细胞样白血病(CML)、急性淋巴细胞白血病(ALL)、非霍奇金淋巴瘤(NHL)、多发性骨髓瘤(MM)、膀胱癌、卵巢癌、前列腺癌、肺癌、结肠癌、乳腺癌、胰腺癌、肝癌、肾细胞癌、黑色素瘤、多形性胶质母细胞瘤、宫颈癌、老年性黄斑变性(AMD)、糖尿病性视网膜病变、肝纤维化和血管肉瘤。
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CN109575140B (zh) * | 2017-09-29 | 2021-02-23 | 北京比洋生物技术有限公司 | 靶向pd-1或pd-l1且靶向vegf家族的双靶向融合蛋白及其用途 |
CN113166258B (zh) * | 2018-12-03 | 2023-06-20 | 宜明昂科生物医药技术(上海)股份有限公司 | 靶向pd-l1和vegf的重组蛋白 |
CN114106190A (zh) * | 2020-08-31 | 2022-03-01 | 普米斯生物技术(珠海)有限公司 | 一种抗vegf/pd-l1双特异性抗体及其用途 |
WO2022068894A1 (zh) * | 2020-09-30 | 2022-04-07 | 上海齐鲁制药研究中心有限公司 | 同时靶向pd-l1和vegf的双功能分子及其医药用途 |
CN113773401B (zh) * | 2021-09-15 | 2023-06-20 | 宜明昂科生物医药技术(上海)股份有限公司 | 靶向cd47和pd-l1的重组融合蛋白及其制备和用途 |
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2022
- 2022-05-31 CN CN202210639281.XA patent/CN117186238A/zh active Pending
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2023
- 2023-05-30 WO PCT/CN2023/097088 patent/WO2023232022A1/zh unknown
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