CN111278865A - 新的重组融合蛋白及其制备和用途 - Google Patents
新的重组融合蛋白及其制备和用途 Download PDFInfo
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- CN111278865A CN111278865A CN201880069732.2A CN201880069732A CN111278865A CN 111278865 A CN111278865 A CN 111278865A CN 201880069732 A CN201880069732 A CN 201880069732A CN 111278865 A CN111278865 A CN 111278865A
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- fusion protein
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- recombinant fusion
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Abstract
本发明提供一种重组融合蛋白,其包含PD‑L1抗体,该PD‑L1抗体的至少一个互补位在重链或轻链的N端通过接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接,其中该重组融合蛋白可以同时与CD47、PD‑L1和FcR结合。还提供编码该重组融合蛋白的多核苷酸、包含该多核苷酸的表达载体、制备该重组蛋白的方法、以及使用重组蛋白来治疗由CD47和/或PD‑L1过表达引起的疾病。
Description
发明领域
本发明涉及一种重组融合蛋白、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,包括:1)通过高表达膜蛋白PD-L1和PD-L2来逃避T淋巴细胞的免疫监视,其中膜蛋白PD-L1和PD-L2均与T细胞表面的PD-1结合,引发T细胞凋亡;2)逃避自然杀伤(NK)细胞的免疫监视,NK细胞表面上的NKG2D蛋白,在与癌细胞表面上的MICA/MICB蛋白结合时,可以激活NK细胞来杀死癌细胞,然而,癌细胞已经发展出促进MICA/MICB从癌细胞上脱离的机制,脱离的MICA/MICB与NKG2D结合,阻断其对NK细胞的激活;3)逃避巨噬细胞(Mφ)的免疫监视,几乎所有癌细胞在其表面上表达高水平的CD47,CD47与Mφ表面上的信号调节蛋白α(SIRPα)结合,从而引发抑制性信号的生成,该抑制信性号抑制Mφ对癌细胞的吞噬作用。可以看出,癌细胞相当□聪明□,可以基于它们发展出的逃避机制而迅速增殖。因此,有效杀灭所有癌细胞的抗癌药物的开发需要靶向这些机制。
SIRP和CD47
信号调节蛋白(SIRP)是跨膜糖蛋白,包括三个家族成员,SIRPα(CD172a)、SIRPβ(CD172b)和SIRPγ(CD172g)。这三种蛋白均包含相似的胞外区域,但是具有不同的胞内结构域。胞外区域包含三个免疫球蛋白样结构域,一个Ig-V和两个Ig-C结构域。SIRPα(CD172a)的胞内结构域包含两个抑制性信号转导区域,其可以抑制信号转导以及相应的细胞功能。SIRPβ(CD172b)和SIRPγ(CD172g)的胞内区域非常短,不含信号转导结构域。但是,SIRPβ(CD172b)能够经由衔接蛋白例如DAP12而起到信号转导的功能。SIRP主要表达在巨噬细胞(Mφ)、树突状细胞(DC)和神经元中。
CD47是属于免疫球蛋白超家族的跨膜糖蛋白,在包括红细胞在内的所有细胞类型的表面上表达。CD47的配体包括整联蛋白、血小板反应蛋白-1和SIRP。CD47,通过与SIRPα相互作用发出“不要吃我”的信号,可以抑制巨噬细胞的吞噬作用,并从而保护例如血细胞等的细胞免收巨噬细胞的攻击。
已经有研究表明,很多过表达CD47的肿瘤或癌细胞,通过与巨噬细胞的细胞表面上的SIRPα结合,防止巨噬细胞对癌细胞的吞噬作用。过表达CD47的癌细胞包括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、乳腺癌和胰腺癌细胞。有报道称,向荷肿瘤的小鼠注射阻碍CD47与SIRPα结合的CD47特异性抗体,可以显著地抑制肿瘤生长。当将同一抗体注射到携带人白血病细胞的小鼠中,肿瘤细胞或癌细胞完全消除(Theocharides APA,et al.,2012)。
PD-L1和PD-1
PD-L1,又称为程序性死亡-配体1或CD274,是一种跨膜蛋白,在一些特定情况例如异体组织移植、自身免疫疾病和肿瘤发生的过程中起到抑制免疫系统的重要作用。在癌症中,丧失转录因子例如STAT3与NF-κB之间的反馈限制将引起局部PD-L1表达的增加,这会限制靶向PD-L1的药物的全身性治疗的有效性(Vlahopoulos SA,2017)。对来自肾细胞癌患者的196个肿瘤样本分析发现,肿瘤PD-L1的高表达与增强的肿瘤侵袭性以及增加4.5倍的死亡风险相关(Thompson RH et al.,2004)。
PD-1是长约268个氨基酸的细胞表面受体。当与PD-L1或PD-L2结合时,PD-1可以通过抑制T细胞炎性反应,下调免疫系统,并提高自身耐受性。PD-1对于免疫系统的抑制性作用可防止自身免疫疾病,但也同时阻止免疫系统杀灭癌细胞。一种PD-1抗体,BMS-936558,在大约1/5-1/4的小细胞肺癌、黑色素瘤或肾细胞癌病患中产生客观性缓解(SuzanneL.Topalian et al.,2012)。
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。
治疗性双特异性或多特异性融合蛋白/抗体
靶向单一肿瘤相关抗原的抗体具有有限的疗效。例如,最近批准的PD-L1抗体,Avelumab(BAVENCIO),总的缓解率仅为33%。
因此,已经开发出一些或正在开发一些针对两个或更多个靶点的抗癌药物,但是大多数目前涉及双特异性或多特异性抗体的技术(例如Triomab、CrossMab、DVD-Ig、BiTE、DART和TandAb)有各种缺陷,例如高聚集度、大分子量(>200kDa)和较短的半衰期(<12小时,BiTE、DART和TandAb),从而降低了其疗效。
WO2016/169261公开了一种约90kDa的重组双功能融合蛋白,靶向CD47和FcR,其用于治疗荷HL细胞的Balb/c裸小鼠,且观察到加强的抗肿瘤效果。然而,迄今为止没有报道过任何能够同时精准靶向CD47、PD-L1和FcR且分子量低、半衰期长的单分子药物,而本发明满足该需要。
发明内容
本发明公开一种重组融合蛋白,其包含PD-L1抗体,该PD-L1抗体的至少一个互补位在构成该互补位的重链或轻链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接,其中该蛋白可以同时与CD47、PD-L1以及FcR结合。与癌细胞上的CD47结合,可以阻断CD47与巨噬细胞上SIRP的相互作用,因而解除SIRP介导的抑制信号对巨噬细胞的检查;而与癌细胞上的PD-L1结合,可以解除PD-1介导的抑制信号对T细胞的检查;同时,与NK细胞或巨噬细胞上FcR的结合,可以激活NK细胞或巨噬细胞对癌细胞的靶向杀灭。
在一个实施方式中,PD-L1抗体的一个互补位在构成该互补位的重链或轻链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接。在另一实施方式中,PD-L1抗体的各互补位在构成该互补位的重链或轻链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接。在一个实施方式中,PD-L1抗体的各互补位在构成该互补位的重链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接。在一个实施方式中,PD-L1抗体的各互补位在构成该互补位的轻链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接。在一个实施方式中,PD-L1抗体的一个互补位在构成该互补位的重链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接,该PD-L1抗体的另一互补位在构成该互补位的轻链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接。在一些实施方式中,各互补位在构成该互补位的重链和轻链的N端与多于一个的信号调节蛋白(SIRP)胞外Ig样结构域结合。
在一个实施方式中,重组融合蛋白中的信号调节蛋白可以是SIRPα,且信号调节蛋白的胞外Ig样结构域可以是SIRPα的第一胞外Ig样结构域(SIRPαD1)。信号调节蛋白的胞外Ig样结构域,例如SIRPαD1,可以与例如癌细胞/肿瘤细胞表面的CD47结合,从而阻断CD47与巨噬细胞表面上的SIRP之间的相互作用。
在一个实施方式中,SIRPαD1的核酸序列和氨基酸序列分别如SEQ ID NO:1和SEQID NO:2所示。在一些实施方式中,SIRPαD1可以包含与SEQ ID NO:2至少具有80%、85%、90%、95%、98%或99%同一性的氨基酸序列,其中该SIRPαD1可以与例如癌细胞/肿瘤细胞表面上的CD47结合,阻断CD47与巨噬细胞表面SIRP之间的相互作用。
重组融合蛋白中的接头可以是约5-30氨基酸残基的肽。在一些实施方式中,接头为10-30氨基酸残基的肽。在另一实施方式中,接头是15-30氨基酸残基的肽。在一些实施方式中,接头是-(Gly-Gly-Gly-Gly-Ser)3-(SEQ ID NO:4),其可以由SEQ ID NO:3编码。
PD-L1抗体可以是分离的单克隆抗体,例如Atezolizumab、Avelumab、Durvalumab、以及和Atezolizumab、Avelumab或Durvalumab具有至少80%、85%、90%、95%、98%或99%氨基酸同一性的抗体。
PD-L1抗体可以是分离的单克隆抗体,包含两条重链和两条轻链,各条重链具有SEQ ID NO:6的氨基酸序列,各条轻链具有SEQ ID NO:8的氨基酸序列,这两个氨基酸序列可以分别由SEQ ID NO:5和SEQ ID NO:7的核酸序列编码。PD-L1抗体的抗原结合(Fab)部分(或互补位)可以与癌细胞/肿瘤细胞表面的PD-L1结合,阻断PD-L1与T细胞表面PD-1的相互作用,从而解除PD-1介导的抑制信号对T细胞的检查,而PD-L1抗体的Fc部分可以与NK细胞或巨噬细胞表面上的FcR结合,以激活NK细胞或巨噬细胞对癌细胞的杀灭。在一些实施方式中,重链可以包含与SEQ ID NO:6至少为80%、85%、90%、95%、98%或99%同一性的氨基酸序列,其中PD-L1抗体能够与PD-L1结合并阻断PD-L1与T细胞表面上PD-1之间的相互作用,并且能够与NK细胞或巨噬细胞表面的FcR结合并从而激活NK细胞或巨噬细胞杀灭癌细胞。在一些实施方式中,轻链可以包含与SEQ ID NO:8至少为80%、85%、90%、95%、98%或99%同一性的氨基酸序列,其中,PD-L1抗体能够结合PD-L1并阻断PD-L1与T细胞表面PD-1的相互作用。
SIRPαD1-接头-PD-L1抗体重链可以包含SEQ ID NO:10的氨基酸序列,其可以由SEQ ID NO:9的核酸序列编码。在一些实施方式中,SIRPαD1-接头-PD-L1抗体重链包含与SEQ ID NO:10具有至少80%、85%、90%、95%、98%或99%同一性的氨基酸序列,其中SIRPαD1-接头-PD-L1抗体重链能够与PD-L1抗体轻链一起,与CD47、PD-L1以及FcR结合,i)阻断癌细胞上PD-L1与T细胞上PD-1之间的相互作用;ii)阻断癌细胞上CD47与巨噬细胞上SIRP的相互作用;以及iii)激活NK细胞或巨噬细胞对癌细胞进行灭杀。
本发明还提供编码本发明重组融合蛋白的多核苷酸,以及包含该多核苷酸的表达载体、和包含该表达载体的宿主细胞。
本发明还提供一种使用含上述表达载体的宿主细胞制备重组融合蛋白的方法,包括以下步骤,(i)在宿主细胞中表达重组融合蛋白,以及(ii)从宿主细胞分离重组融合蛋白。
另一方面,本发明提供药物组合物,其包含本发明的重组融合蛋白、以及至少一种药学上可接受的载体。药物组合物还可以包含至少一种佐剂。
另一方面,本发明提供一种用于治疗由过表达CD47和/或PD-L1造成的疾病的方法,包括对有需求的患者或受试者施用治疗有效量的本发明药物组合物。
在一个实施方式中,本发明提供重组融合蛋白在制备用于治疗由过表达CD47和/或PD-L1引起的疾病的药物组合物中的用途。
在一个实施方式中,本发明的方法用于治疗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、胰腺癌和肾细胞癌中的疾病。在一个实施方式中,本发明提供用于治疗克罗恩病、过敏性哮喘或类风湿性关节炎的方法。
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
图1为本发明重组融合蛋白的结构示意图。
图2为本发明重组融合蛋白的作用机制示意图。
图3示出重组融合蛋白IMM2505中PD-L1抗体重链的核酸序列。
图4示出重组融合蛋白IMM2505中PD-L1抗体重链的氨基酸序列。
图5示出重组融合蛋白IMM2505中PD-L1抗体轻链的核酸序列。
图6示出重组融合蛋白IMM2505中PD-L1抗体轻链的氨基酸序列。
图7示出IMM2505对CHO细胞上PD-L1的结合活性。
图8示出IMM2505对Jurkat细胞上CD47的结合活性。
图9示出IMM2505对CHO细胞上PD-L1的阻断。
图10示出IMM2505对Jurkat细胞上CD47的阻断。
图11示出IMM2505的ADCC分析结果。
图12示出IMM2505对Jurkat-CPR的细胞凋亡抑制。
图13示出IMM2505的ADPC分析结果。
图14示出IMM2505在Raji-PD-L1异体移植模型中的疗效。
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混合物。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,患者潜在依从性较差;b)由于药物-药物相互作用,存在可能的不相容性;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,组合中成分的不同药物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化合物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确认更加复杂,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。
经过大量实验,当前的发明人已经发明出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,一种是解除PD-1介导的抑制信号对T细胞的检查或抑制,一种是解除SIRP介导的抑制信号对巨噬细胞的检查,另一种是激活NK细胞和/或巨噬细胞对癌细胞的杀灭。
本发明的重组融合蛋白包含PD-L1抗体,该PD-L1抗体的至少一个互补位在构成该互补位的重链或轻链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接。该重组蛋白可以同时与CD47、PD-L1以及FcR结合,i)阻断癌细胞上PD-L1与T细胞上PD-1之间的相互作用,从而解除PD-1介导的抑制信号对T细胞的检查;ii)阻断癌细胞上CD47与巨噬细胞上SIRP的相互作用,解除SIRP介导的抑制信号对巨噬细胞的检查;以及iii)抗体Fc区与NK细胞或巨噬细胞上FcR结合,激活NK细胞或巨噬细胞对癌细胞的灭杀。在一个实施方式中,PD-L1抗体的一个互补位在构成该互补位的重链或轻链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接。在另一实施方式中,PD-L1抗体的各互补位在构成该互补位的重链或轻链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接。在一个实施方式中,PD-L1抗体的各互补位在构成该互补位的重链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接。在一个实施方式中,PD-L1抗体的各互补位在构成该互补位的轻链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接。在一个实施方式中,PD-L1抗体的一个互补位在构成该互补位的重链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接,该PD-L1抗体的另一互补位在构成该互补位的轻链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接。在一些实施方式中,各互补位在构成该互补位的重链和轻链的N端与多于一个(例如两个)的信号调节蛋白(SIRP)胞外Ig样结构域结合。本发明的重组融合蛋白较小(150-180kDa),且具有5-10天的较长半衰期。
包含在本发明融合蛋白中的三个主要组成部分为信号调节蛋白(SIRP)的胞外Ig样结构域、接头、和PD-L1抗体。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,也可以在本发明中使用其他动物蛋白或肽,可以进行人源化。
能够与CD47结合的任何SIRP(SIRPα、SIRPβ和SIRPγ)的任何胞外Ig样结构域均可以选择用于融合蛋白的构建。在一个实施方式中,重组融合蛋白中的信号调节蛋白是SIRPα,且信号调节蛋白的胞外Ig样结构域为SIRPα的第一胞外Ig样结构域(SIRPαD1)。
在一个实施方式中,重组融合蛋白包含核酸序列和氨基酸序列分别如SEQ ID NO:1和SEQ ID NO:2所示的SIRPαD1。在另一实施方式中,SIRPαD1可以包含与SEQ ID NO:2具有至少80%、85%、90%、95%、98%或99%同一性的氨基酸序列,其中SIRPαD1能够与癌/肿瘤细胞表面的CD47结合并阻断CD47与巨噬细胞表面SIRP的相互作用。
接头主要起到SIRP的胞外Ig样结构域与PD-L1抗体重链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,如本领域技术人员所了解的。在一个实施方式中,5-30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、(Gly)8)、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(Gly-Ser),例如-(Gly-Gly-Gly-Gly-Ser)3-。
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。
任何PD-L1抗体可以用于本发明融合蛋白的形成。PD-L1抗体可以是选自Atezolizumab、Avelumab和Durvalumab的分离单克隆抗体。
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:6的氨基酸序列,各轻链具有SEQ ID NO:8的氨基酸序列,这两个氨基酸序列可以分别由SEQ ID NO:5和SEQ ID NO:7编码。PD-L1抗体的Fab部分(或互补位)可以与癌/肿瘤细胞表面的PD-L1结合,以阻断PD-L1与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,而PD-L1抗体的Fc部分可以与NK细胞和/或巨噬细胞表面的FcR结合,以刺激NK细胞或巨噬细胞对癌细胞的杀灭。在一些实施方式中,重链可包含与SEQ ID NO:6具有至少80%、85%、90%、95%、98%或99%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-L1与T细胞表面PD-1之间的相互作用,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:8具有至少80%、85%、90%、95%、98%或99%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-L1与T细胞表面PD-1之间的相互作用。
同时,本发明提供编码重组融合蛋白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)。
本发明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(Escherichia 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,本发明提供一种药物组合物,其包含本发明的与药学上可接受佐剂配制在一起的融合蛋白。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。本发明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.(Lippincott Williams&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。在本发明的一个实施方式中,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,本发明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,优选为约0.1%-约70%,最优选为约1%-约30%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,更通常地为0.01-10mg/kg。例如,剂量可以为0.3mg/kg体重、1mg/kg体重、3mg/kg体重、5mg/kg体重、或10mg/kg体重,或在1-10mg/kg的范围内。示例性的治疗方案为,每周两次、每周一次、每两周一次、每三周一次、每四周一次、每月一次、每三个月一次、或每三至六个月一次给药。本发明融合蛋白的优选给药方案包括腹膜内给药,3mg/kg体重或6mg/kg体重,使用如下的一种给药时间表:(i)每四周给药六次,之后每三月给药一次;(ii)每三周给药一次;(iii)3mg/kg体重给药一次,之后为1mg/kg体重,每三周一次;(vi)6mg/kg体重,每周一次。在一些方法中,调整剂量以达到约1-1000μg/ml的血浆抗体浓度,在一些方法中为约25-300μg/ml。
“治疗有效量”的本发明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无能。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%。治疗有效量的本发明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,本发明的融合蛋白可以配制成保证合适的体内分布。例如,为保证本发明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。
本发明还涉及体内基因疗法,其中将编码本发明融合蛋白或其衍生物的核酸分子直接引入受试者中。例如,将编码本发明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。
本发明的另一目的是提供制备上述重组融合蛋白以及包含该重组融合蛋白的药物组合物的方法。在一个实施方式中,制备方法包括以下步骤:(1)提供编码蛋白的多核苷酸;(2)构建包含(1)的多核苷酸的表达载体;(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。
本发明的另一目标是提供使用本发明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过表达CD47和/或PD-L1的肿瘤或癌症,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、胰腺癌和肾癌。
在一个实施方式中,与过表达CD47和/或PD-L1相关的疾病包括但不限于克罗恩病、过敏性哮喘和类风湿性关节炎。
本发明将参照以下非限制性实施例进行进一步说明。
实施例
在以下的实施例中,IMM25是靶向PD-L1的单克隆PD-L1抗体。该抗体具有两条重链和两条轻链,各重链具有SEQ ID NO:6的氨基酸序列,各轻链具有SEQ ID NO:8的氨基酸序列,这两个氨基酸序列可以分别由核酸序列SEQ ID NO:5和SEQ ID NO:7编码。
IMM01是能够结合CD47的融合蛋白,由与Fc片段连接的SIRPαD1构成,其记载在WO2016169261中。该融合蛋白的核酸序列和氨基酸序列分别列于SEQ ID NO:11和SEQ IDNO:12。
IMM2505是重组融合蛋白,包含两个SIRPαD1,各SIRPαD1通过GS接头与IMM25各重链的N端连接,其中SIRPαD1的核酸序列和氨基酸序列分别为SEQ ID NO:1和SEQ ID NO:2,接头的氨基酸序列为SEQ ID NO:4,可以由核酸序列SEQ ID NO:3编码。
实施例1.表达IMM2505的载体的构建
人工设计重组融合蛋白IMM2505的全长编码序列。具体地,对于重链,SIRPα的第一胞外结构域(SIRPαD1)的编码序列(SEQ ID NO:1)通过GS接头(SEQ ID NO:3)与IMM25的重链可变区编码序列(SEQ ID NO:5)的N端连接。将编码小鼠IgG1重链的信号肽的57个核苷酸(SEQ ID NO:13)加到SIRPαD1编码序列的5’端,并将Kozak序列(SEQ ID NO:14)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。对于轻链,使用上述信号肽序列和Kozac序列,但是在所得序列的5’和3’端分别加入HindIII和XbaI限制性酶切位点。两个所得的序列通过Genscript合成(ID#:L31834(重链);M60573(轻链)),并分别克隆到pMac-H和pMac-L载体中。
实施例2.蛋白表达和纯化
为制备重组蛋白IMM2505,将表达载体经电穿孔导入中国仓鼠卵巢(CHO)细胞(ATCC,Cat#CCL-61)中,之后,这些CHO细胞接受几轮的新霉素压力选择。选出的稳定表达细胞在无血清Balan CD CHO生长A培养基(Irvine Scientific,Cat#94120)中适应。对于蛋白表达,将细胞接种到3升生物反应器中并以流加培养法培养。当细胞活力降到~80%时,终止反应器中的反应,收取细胞培养上清液并通过亲和色谱法进行蛋白纯化。重组蛋白的纯度高于95%,且内毒素的量低于0.5U/g。
实施例3.IMM2505与PD-L1或CD47结合
(过表达PD-L1)的CHO-PD-L1细胞或(高表达CD47)的Jurkat细胞在连续稀释的IMM2505或对照中4℃孵育1小时。细胞用冷的PBS清洗两遍,之后用结合FITC的针对人IgG-Fc的二抗(Sigma,Cat#F9512)孵育45分钟。细胞清洗两遍,并重悬浮于200ml的PBS。之后,细胞用流式细胞仪(Merck Millipore, easyCyte 5HT)进行FACS分析。
IMM2505以0.01nM的EC50值与CHO细胞上的PD-L1结合(图7),并以0.04nM的EC50值与Jurkat细胞上的CD47结合(图8),比传统的单抗原靶向抗体略差。
实施例4.IMM2505阻断PD-L1与PD-1的相互作用
生物素-PD1-Fc与连续稀释的IMM2505、IMM25、Atezoliumab或混合,混合物添加到含CHO-PD-L1细胞的96孔板。细胞于4℃孵育45分钟,用PBS洗,并进一步与结合PE的小鼠抗人CD279(BD BioScience,Cat#557946)于4℃孵育45分钟。细胞清洗后重悬于200ml的PBS中,并经FACS分析PD1-Fc对膜上PD-L1的结合亲和力。
如图9所示,IMM2505以0.36nM的IC50值阻断PD1-Fc与PD-L1+细胞的相互作用。
实施例5.IMM2505阻断CD47与SIRPα的相互作用
FITC结合的SIRPα-Fc与连续稀释的IMM2505、IMM01、SIRPα-Fc或混合,混合物添加到含Jurkat细胞的96孔板,细胞于4℃孵育45分钟。细胞用PBS洗,并经FACS分析SIRPα-Fc对膜上CD47的结合亲和力。
如图10所示,IMM2505以83.8nM的IC50值阻断SIRPα-Fc与CD47+细胞的相互作用。
实施例6.IMM2505具有较高的抗体依赖的细胞介导的细胞毒性(ADCC)
CFSE标记的Raji-PD-L1细胞(用作靶向细胞)与稳定表达FcγRIIIa的NK92MI细胞(效应细胞)以1:2混合,且混合的细胞在5%CO2下与连续稀释的IMM2505或IMM25于37℃培养4小时。之后向细胞培养液中加入碘化丙啶(PI)(Sigma,Cat#P4170),浓度5μg/ml,细胞培养液经FACS分析PI信号。由ADCC造成的细胞裂解的百分比基于以下公式进行计算:
%裂解=(%IMM2505或IMM25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
如图11所示,IMM2505具有较高的ADCC活性,几乎是IMM25的5倍。
实施例7.IMM2505抑制Jurkat-CRP的细胞凋亡
E1.形成表达嵌合PD-1受体(CPR)的细胞系
嵌合PD-1受体(CPR)由人PD-1的胞外结构域、人CD8a铰链区、人CD28的跨膜和胞内区、以及人CD3ζ构成。CPR编码序列(SEQ ID NO:15)设计成将人PD-1的胞外结构域编码序列与CD8a铰链区连接,后接人CD28的跨膜和胞内区以及CD3ζ序列。所得的序列通过Convenience Biology合成(ID#:T1509090661-T3970),并克隆到pMac-Fc载体中。
为形成CPR表达细胞系,表达载体经电穿孔导入Jurkat细胞,细胞接受几轮的新霉素压力选择。使用PE小鼠抗人CD279(BD BioScience,Cat#557946)经FACS分析确认所选出的稳定细胞确实稳定表达CPR。
E2.引导CPR表达细胞的细胞凋亡
Jurkat-CPR细胞在96孔板中与Raji-PD-L1细胞以10:1混合,混合的细胞在5%CO2中于37℃培养24小时。之后,将20μl的CCK8(Dojindo,Cat#CK04)加到细胞培养液中,并在细胞培养孵育器中孵育2小时,之后测量450nm波长处的光密度(OD)。
E3.抑制PD-L1诱导的细胞凋亡
Raji-PD-L1细胞在96孔板中与连续稀释的IMM2505、IMM25、Atezoliumab或在5%CO2下37℃培养45分钟,并向板中添加Jurkat-CPR细胞,Jurkat-CPR细胞与Raji-PD-L1细胞的比率为10:1,孵育24小时。向板中加入CCK8,板继续孵育2小时,之后测量450nm波长处的OD值。
由图12可以看出,IMM2505以0.027nM的IC50值抑制Jurkat-CRP的细胞凋亡。
实施例8.IMM2505激活HL-60的胞吞作用
将小鼠巨噬细胞系Ana-1接种到96孔细胞培养板中,每孔1x105个细胞,并于37℃和5%CO2下培养16-18个小时。靶向细胞(HL-60)用CFSE标记,并与连续稀释的IMM2505、IMM01或孵育45分钟。靶向细胞培养液转移到含Ana-1细胞的板中,Ana-1细胞与HL-60细胞的比为1:1。混合物在细胞培养孵育器中培养2小时,之后经FACS分析Ana-1细胞中CFSE的密度。
图13示出,IMM2505能够激活高水平的肿瘤细胞吞噬。
实施例9.IMM2505具有良好的抗肿瘤效果
对四十八只4-6周龄SCID小鼠在右侧腹皮下注射Raji细胞,每只小鼠6x106个细胞。当肿瘤体积达到100-150mm3时,小鼠随机分成6组,每组8只小鼠。小鼠腹膜注射PBS、Rituximab-ADCC+(ADCC加强的Rituximab,2.5mg/kg)、IMM2505(6mg/kg)、IMM25(5mg/kg)、IMM01(0.5mg/kg)、以及IMM01+IMM25(0.5mg.kg+5mg/kg),每周一次,持续4周。每3-4天测量一次肿瘤体积和体重。当PBS组的平均肿瘤体积达到1500mm3时,停止给药,终止实验。
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-药物处理组肿瘤体积变化/对照组肿瘤体积变化)×100%
表1.IMM2505和其他治疗剂的抗肿瘤效果
第5组的肿瘤抑制率为100.06%,比其他组高得多,如以上表1和图14所示,表明IMM2505的效力比单抗原靶向抗体要好。
尽管本发明已经在以上连同一个或多个实施方式进行了描述,应当理解的是,本发明不限于那些实施方式,且说明意在涵盖可能包括在所附权利要求的宗旨和范围内的所有可变方式、修改方式和等同方式。所有在本文中引用的文献通过引用的方式进一步全部并入本文。
参考文献
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序列表
<110> 宜明昂科生物医药技术(上海)有限公司
<120> 新的重组融合蛋白及其制备和用途
<130> 55525 00022
<150> US 62/577704
<151> 2017-10-26
<160> 15
<170> PatentIn版本3.5
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<223> SIRPα的第一胞外Ig样结构域
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ggagctggac cagcccggga attaatctac aatcaaaaag aaggccactt cccccgggta 180
acaactgttt cagagtccac aaagagagaa aacatggact tttccatcag catcagtgcc 240
atcaccccag cagatgccgg cacctactac tgtgtgaagt tccggaaagg gagccctgac 300
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accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
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tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600
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tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 720
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtatgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacgccacg 900
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aagtgcaagg tctccaacaa agccctccca gcccccatcg ccgcaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga ggagatgacc 1080
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Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
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Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
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ggcaaggcac ctaagctcct gatctactcc gcctccttcc tgtattccgg agtcccctcc 180
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tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
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ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
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<210> 8
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Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
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Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
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Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
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Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
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Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
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Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
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Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
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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> 9
<211> 1767
<212> DNA
<213> 人工序列
<220>
<223> SIRPαD1-接头-PD-L1抗体重链
<400> 9
gaggaggagc tgcaggtgat tcagcctgac aagtccgtat cagttgcagc tggagagtcg 60
gccattctgc actgcactgt gacctccctg atccctgtgg ggcccatcca gtggttcaga 120
ggagctggac cagcccggga attaatctac aatcaaaaag aaggccactt cccccgggta 180
acaactgttt cagagtccac aaagagagaa aacatggact tttccatcag catcagtgcc 240
atcaccccag cagatgccgg cacctactac tgtgtgaagt tccggaaagg gagccctgac 300
acggagttta agtctggagc aggcactgag ctgtctgtgc gtgccaaacc ctctgccccc 360
gtggtatcgg gccctggcgg cggtgggagc ggcggcggtg ggagcggcgg cgggggctcg 420
gaggtgcagc tggtcgagtc tggcggcggc ctcgttcaac caggcgggag cctgcggctc 480
agctgcgccg catctggatt caccttttct gattcttgga tccactgggt tcgccaggcc 540
cctggaaagg gactggagtg ggttgcctgg atctccccat atggtggctc gacttattat 600
gccgactctg tgaaaggacg gtttactatc tccgcggaca ctagcaaaaa taccgcatac 660
ctgcagatga actctctccg cgctgaagat acagctgtgt actactgcgc aagacgtcac 720
tggcccggcg gattcgacta ttgggggcag ggcactctgg tcaccgtgtc ctccgctagc 780
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 840
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 900
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 960
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 1020
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 1080
tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 1140
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 1200
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtatgtg 1260
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacgccacg 1320
taccgtgtgg tcagcgtcct caccgtcctg caccaagact ggctgaatgg caaggagtac 1380
aagtgcaagg tctccaacaa agccctccca gcccccatcg ccgcaaccat ctccaaagcc 1440
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga ggagatgacc 1500
aagaaccaag tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1560
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1620
tccgacggct ccttcttcct ctattccaag ctcaccgtgg acaagagcag gtggcagcag 1680
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1740
agcctctccc tgtctccggg caaatga 1767
<210> 10
<211> 588
<212> PRT
<213> 人工序列
<220>
<223> SIRPαD1-接头-PD-L1抗体重链
<400> 10
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Ala
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser
100 105 110
Val Arg Ala Lys Pro Ser Ala Pro Val Val Ser Gly Pro Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
130 135 140
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
145 150 155 160
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser Trp Ile His Trp
165 170 175
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Trp Ile Ser
180 185 190
Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe
195 200 205
Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn
210 215 220
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg His
225 230 235 240
Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
245 250 255
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
260 265 270
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
275 280 285
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
290 295 300
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
305 310 315 320
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
325 330 335
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
340 345 350
Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
355 360 365
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
370 375 380
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
385 390 395 400
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
405 410 415
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
420 425 430
Arg Glu Glu Gln Tyr Asn Ala Thr Tyr Arg Val Val Ser Val Leu Thr
435 440 445
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
450 455 460
Ser Asn Lys Ala Leu Pro Ala Pro Ile Ala Ala Thr Ile Ser Lys Ala
465 470 475 480
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
485 490 495
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
500 505 510
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
515 520 525
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
530 535 540
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
545 550 555 560
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
565 570 575
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
580 585
<210> 11
<211> 1095
<212> DNA
<213> 人工序列
<220>
<223> SIRPαD1-Fc
<400> 11
gaggaggagc tgcaggtgat tcagcctgac aagtccgtat cagttgcagc tggagagtcg 60
gccattctgc actgcactgt gacctccctg atccctgtgg ggcccatcca gtggttcaga 120
ggagctggac cagcccggga attaatctac aatcaaaaag aaggccactt cccccgggta 180
acaactgttt cagagtccac aaagagagaa aacatggact tttccatcag catcagtgcc 240
atcaccccag cagatgccgg cacctactac tgtgtgaagt tccggaaagg gagccctgac 300
acggagttta agtctggagc aggcactgag ctgtctgtgc gtgccaaacc ctctgccccc 360
gtggtatcgg gccctgcggc gagggccaca cctcagcacg agcccaaatc ttgtgacaaa 420
actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 480
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 540
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 600
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 660
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 720
gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 780
ccccgagaac cacaggtgta caccctgccc ccatcccggg atgagctgac caagaaccag 840
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 900
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 960
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1020
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1080
ctgtctccgg gttga 1095
<210> 12
<211> 364
<212> PRT
<213> 人工序列
<220>
<223> SIRPαD1-Fc
<400> 12
Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala
1 5 10 15
Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro
20 25 30
Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu
35 40 45
Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser
50 55 60
Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Ala
65 70 75 80
Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys
85 90 95
Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser
100 105 110
Val Arg Ala Lys Pro Ser Ala Pro Val Val Ser Gly Pro Ala Ala Arg
115 120 125
Ala Thr Pro Gln His Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
130 135 140
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
145 150 155 160
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
165 170 175
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
180 185 190
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
195 200 205
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
210 215 220
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
225 230 235 240
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
245 250 255
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
260 265 270
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
275 280 285
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
290 295 300
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
305 310 315 320
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
325 330 335
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
340 345 350
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
355 360
<210> 13
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 小鼠IgG1重链的信号肽
<400> 13
atgggatggt catgtatcat cctttttctg gtagcaactg caactggagt acattca 57
<210> 14
<211> 10
<212> DNA
<213> 人工序列
<220>
<223> Kozak
<400> 14
gccgccacc 9
<210> 15
<211> 1107
<212> DNA
<213> 人工序列
<220>
<223> 嵌合PD-1受体编码序列
<400> 15
ttagactccc cagacaggcc ctggaacccc cccaccttct ccccagccct gctcgtggtg 60
accgaagggg acaacgccac cttcacctgc agcttctcca acacatcgga gagcttcgtg 120
ctaaactggt accgcatgag ccccagcaac cagacggaca agctggccgc cttccccgag 180
gaccgcagcc agcccggcca ggactgccgc ttccgtgtca cacaactgcc caacgggcgt 240
gacttccaca tgagcgtggt cagggcccgg cgcaatgaca gcggcaccta cctctgtggg 300
gccatctccc tggcccccaa ggcgcagatc aaagagagcc tgcgggcaga gctcagggtg 360
acagagagaa gggcagaagt gcccacagcc caccccagcc cctcacccag gccagccggc 420
cagttccaaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 480
cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 540
agggggctgg acttcgcctg tgatttttgg gtgctggtgg tggttggtgg agtcctggct 600
tgctatagct tgctagtaac agtggccttt attattttct gggtgaggag taagaggagc 660
aggctcctgc acagtgacta catgaacatg actccccgcc gccccgggcc cacccgcaag 720
cattaccagc cctatgcccc accacgcgac ttcgcagcct atcgctccag agtgaagttc 780
agcaggagcg cagagccccc cgcgtaccag cagggccaga accagctcta taacgagctc 840
aatctaggac gaagagagga gtacgatgtt ttggacaaga gacgtggccg ggaccctgag 900
atggggggaa agccgagaag gaagaaccct caggaaggcc tgtacaatga actgcagaaa 960
gataagatgg cggaggccta cagtgagatt gggatgaaag gcgagcgccg gaggggcaag 1020
gggcacgatg gcctttacca gggtctcagt acagccacca aggacaccta cgacgccctt 1080
cacatgcagg ccctgccccc tcgctaa 1107
Claims (18)
1.一种重组融合蛋白,包含PD-L1抗体,该PD-L1抗体的至少一个互补位在重链或轻链的N端经接头与信号调节蛋白(SIRP)的胞外Ig样结构域连接,其中该重组融合蛋白能够同时与CD47、PD-L1以及FcR结合。
2.根据权利要求1所述的重组融合蛋白,其中,PD-L1抗体的各互补位在重链或轻链的N端与信号调节蛋白(SIRP)的胞外Ig样结构域连接。
3.根据权利要求2所述的重组融合蛋白,其中PD-L1抗体的各互补位在重链的N端与信号调节蛋白(SIRP)的胞外Ig样结构域连接。
4.根据权利要求1所述的重组融合蛋白,其中信号调节蛋白为SIRPα。
5.根据权利要求1所述的重组融合蛋白,其中信号调节蛋白的胞外Ig样结构域为SIRPαD1。
6.根据权利要求1所述的重组融合蛋白,其中接头为5-30氨基酸残基的短肽。
7.根据权利要求1所述的重组融合蛋白,其中接头为–(Gly-Gly-Gly-Gly-Ser)3-。
8.根据权利要求1所述的重组融合蛋白,其中PD-L1抗体包含两条重链和两条轻链,各重链具有与SEQ ID NO:6具有至少80%、85%、90%、95%、98%或99%同一性的氨基酸序列,各轻链具有与SEQ ID NO:8具有至少80%、85%、90%、95%、98%或99%同一性的氨基酸序列。
9.根据权利要求8所述的重组融合蛋白,其中重链具有SEQ ID NO:6所示的氨基酸序列。
10.根据权利要求8所述的重组融合蛋白,其中轻链具有SEQ ID NO:8所示的氨基酸序列。
11.一种多核苷酸,其编码权利要求1-10中任一项所述的重组融合蛋白。
12.一种表达载体,其包含权利要求11所述的多核苷酸。
13.一种宿主细胞,其包含权利要求12所述的表达载体。
14.一种药物组合物,其包含权利要求1-14中任一项所述的重组融合蛋白、以及至少一种药学上可接受的赋形剂。
15.权利要求14所述的药物组合物,还包含至少一种药学上可接受的佐剂。
16.权利要求1-14中任一项所述的重组融合蛋白或权利要求14或15所述的药物组合物在制备用于治疗由CD47和/或PD-L1过表达引起的疾病的药物中的用途。
17.根据权利要求16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、胰腺癌和肾细胞癌。
18.根据权利要求16所述的用途,其中所述疾病选自克罗恩病、过敏性哮喘和类风湿性关节炎。
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CN112646043A (zh) * | 2020-12-25 | 2021-04-13 | 南京华岩生物技术有限公司 | 一种重组双功能融合蛋白及应用 |
CN112979782A (zh) * | 2021-03-08 | 2021-06-18 | 深圳市乐土生物医药有限公司 | 一种多肽及其用途 |
CN113166258A (zh) * | 2018-12-03 | 2021-07-23 | 宜明昂科生物医药技术(上海)有限公司 | 靶向pd-l1和vegf的重组蛋白 |
CN113321735A (zh) * | 2021-05-20 | 2021-08-31 | 盛禾(中国)生物制药有限公司 | 一种多功能融合蛋白 |
CN113773401A (zh) * | 2021-09-15 | 2021-12-10 | 宜明昂科生物医药技术(上海)有限公司 | 靶向cd47和pd-l1的重组融合蛋白及其制备和用途 |
CN113896802A (zh) * | 2021-10-09 | 2022-01-07 | 宜明昂科生物医药技术(上海)有限公司 | 靶向cd47和cd38的重组融合蛋白及其制备和用途 |
CN113956363A (zh) * | 2021-10-13 | 2022-01-21 | 宜明昂科生物医药技术(上海)有限公司 | 靶向cd47和cd24的重组融合蛋白及其制备和用途 |
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JP7193058B2 (ja) * | 2018-08-08 | 2022-12-20 | イミューンオンコ バイオファーマシューティカルズ (シャンハイ) インコーポレイテッド | Cd47およびher2を標的とする組換え二機能性タンパク質 |
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CN113956363A (zh) * | 2021-10-13 | 2022-01-21 | 宜明昂科生物医药技术(上海)有限公司 | 靶向cd47和cd24的重组融合蛋白及其制备和用途 |
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US10973878B2 (en) | 2021-04-13 |
US20190125834A1 (en) | 2019-05-02 |
WO2019080883A1 (en) | 2019-05-02 |
JP7035299B2 (ja) | 2022-03-15 |
CN117106096A (zh) | 2023-11-24 |
JP2021500042A (ja) | 2021-01-07 |
EP3700938A1 (en) | 2020-09-02 |
CN111278865B (zh) | 2023-04-25 |
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