CN113831412A - 靶向cd24的抗体及其制备和用途 - Google Patents
靶向cd24的抗体及其制备和用途 Download PDFInfo
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- CN113831412A CN113831412A CN202111195246.5A CN202111195246A CN113831412A CN 113831412 A CN113831412 A CN 113831412A CN 202111195246 A CN202111195246 A CN 202111195246A CN 113831412 A CN113831412 A CN 113831412A
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Abstract
本申请提供一种与CD24特异结合的单克隆抗体或其抗原结合部分。还提供编码该抗体或其抗原结合部分的核酸分子、包含该核酸分子的表达载体和宿主细胞、制备该抗体或其抗原结合部分的方法,以及使用该抗体或其抗原结合部分来治疗与CD24过表达相关的疾病的方法。
Description
发明领域
本申请涉及一种特异结合CD24的单克隆抗体或其抗原结合部分、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,包括:1)通过高表达膜蛋白CD24,与免疫细胞表面的Siglec-10受体结合,从而抑制免疫激活,来逃避巨噬细胞、T淋巴细胞、B淋巴细胞和自然杀伤细胞的免疫监视;2)通过高表达CD47来逃避巨噬细胞(Mφ)的免疫监视,CD47与巨噬细胞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,该抑制信性号抑制巨噬细胞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,有效杀灭癌细胞的抗癌药物的开发可以针对这些机制。
CD24和Siglec-10
唾液酸结合免疫球蛋白样凝集素(Siglecs)是一种免疫球蛋白样I型跨膜蛋白。在Siglecs家族中,Siglec-10是一种抑制性受体,广泛表达于巨噬细胞、B细胞、NK细胞和活化的T细胞等免疫细胞上。它有五个细胞外Ig样结构域、一个跨膜区和一个胞质尾区。Siglec-10的IgV结构域包含一个关键的精氨酸残基,它与唾液酸的识别有关(Yin,et al.,2020)。已知T细胞上的Siglec-10表达通过抑制T细胞主要组织相容性复合物I类(MHC-I)肽复合物的形成和T细胞受体相关激酶Lck和ZAP-70的磷酸化来干扰T细胞活化(Yin,et al.,2020)。B细胞和NK细胞上表达的Siglec-10能够抑制BCR介导和NK细胞受体介导的信号转导(Yin,et al.,2020)。
CD24是一种糖基-磷脂酰肌醇锚定蛋白,存在于发育中的T淋巴细胞和大多数B淋巴细胞的表面(Yin et al.,2020)。很多癌细胞,包括卵巢癌、乳腺癌、宫颈癌、子宫内膜癌、急性淋巴细胞白血病(ALL)、胆管癌、膀胱癌、胰腺癌、胃腺癌和胶质母细胞瘤,也高表达CD24(Barkal et al.,2019;Liu et al.,2013)。癌细胞上的CD24与免疫细胞上的Siglec-10相互作用,产生“不要吃我”的信号,用于免疫逃避和保护肿瘤细胞免受免疫攻击。
研究表明CD24表达与膀胱肿瘤复发存在相关性(Liu et al.,2013)。在卵巢癌患者中,CD24的表达是总生存期的独立预测因子,并与肿瘤分期、腹膜和淋巴结转移相关;CD24阳性细胞增殖增强,是一种高度侵袭性的表型,并且与卵巢癌细胞的顺铂耐药性相关(Nakamura et al.2017)。
研究表明CD24单克隆抗体能够在膀胱癌和三阴性乳腺癌的小鼠模型中,减少肺部转移并且延长总体存活期。文献还表明,通过抗体阻断CD24-Siglecs 10相互作用能够经巨噬细胞引起肿瘤生长减少,并且延长荷瘤小鼠的生存期(Barkal,et al.,2019;Chan etal.,2019;Overdevest et al.,2011)。
此外,之前的研究表明CD47/CD24双特异性抗体可以有效激活大脑中的髓系免疫(WuH,et al,2021)。CD24抗体和CD47抗体的联合用药可增强对人卵巢癌细胞的吞噬作用(Barkal et al.,2019)。Barakal等人还发现,与单独治疗相比,CD24抗体和西妥昔单抗联合治疗进一步增强了对胰腺癌细胞的吞噬作用,这表明包含CD24中和的联合疗法可能会产生协同抗肿瘤作用。
另有研究表明,CD24上调还与急性移植物抗宿主病(Toubai,T.,et al.,2014)、抗艾滋鸡尾酒疗法引起的炎症反应(包括肝脂肪变性和纤维化、低密度脂蛋白症等)(Tian,R.R.,et al.,2018)、代谢相关脂肪性肝病(Fairbridge,N.A.,et al.,2015)、糖尿病(E1-Mokhtar,M.A.,et al.,2020)、多发性硬化症、风湿性关节炎、系统性红斑狼疮(Tan,Y.,etal.,2016)、败血症(Chen,G.Y.,et al.,2011)等多种疾病有着紧密联系。正在进行的很多临床试验中,也显示了CD24过表达在上述疾病中的作用(参见参考文献8-16)。
领域内需要更多具有所需特性的CD24抗体。
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CD24抗体或其抗原结合部分,其可以结合CD24+细胞,引发对于CD24+细胞的抗体依赖性细胞介导的细胞毒性(ADCC),还具有强劲的体内抗肿瘤效果。特别地,通过施用一定剂量的本申请CD24抗体,可以彻底消除荷肿瘤动物体内的肿瘤。而且,在彻底消除肿瘤后再次植入肿瘤细胞,在不继续给药的情况下,不会成瘤。
因此,在一个方面,本申请涉及一种分离的单克隆抗体、或其抗原结合部分,其与CD24结合,可以含有i)重链可变区,该重链可变区含有VH-CDR1区、VH-CDR2区和VH-CDR3区,其中,VH-CDR1区、VH-CDR2区和VH-CDR3区可以分别包含如SEQ ID NOs:1、2和3所示的氨基酸序列,或与上述序列具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列;和/或ii)轻链可变区,该轻链可变区含有VL-CDR1区、VL-CDR2区和VL-CDR3区,其中,VL-CDR1区、VL-CDR2区和VL-CDR3区可以分别包含如SEQ IDNOs:4、5、和6所示的氨基酸序列,或与上述序列具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。
本申请单克隆抗体或其抗原结合部分的重链可变区可以包含如SEQ IDNOs:7或10所示的氨基酸序列,或与上述序列具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。
本申请的单克隆抗体或其抗原结合部分的轻链可变区可以包含如SEQ ID NOs:8、9或11所示的氨基酸序列,或与上述序列具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列。
在一些实施方式中,本申请单克隆抗体或其抗原结合部分可以包含重链可变区和轻链可变区,其中重链可变区和轻链可变区可以分别包含如(i)SEQ ID NOs:7和8;(ii)SEQID NOs:7和9;或(iii)SEQ ID NOs:10和11所示的氨基酸序列;或与上述具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的氨基酸序列,其中该抗体或其抗原结合部分与CD24结合。
本申请的单克隆抗体或其抗原结合部分可以包含重链恒定区和/或轻链恒定区。重链恒定区可以是IgG1、IgG2或IgG4重链恒定区,具有或经改造具有FcR结合力。在一些实施方式中,重链恒定区可以是人IgG1重链恒定区,具有例如与SEQ ID NO:12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。轻链恒定区可以是κ轻链恒定区,例如人κ恒定区,具有例如与SEQ ID NO:13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,重链恒定区的N端与重链可变区的C端连接,轻链恒定区的N端与轻链可变区的C端连接。
本申请的CD24抗体在一些实施方式中为IgG抗体,包含两条重链和两条轻链,或由两条重链和两条轻链构成,其中各重链包含上述的重链恒定区序列、重链可变区序列或CDR序列,且各轻链包含上述的轻链恒定区序列、轻链可变区序列或CDR序列。本申请的抗体可以是例如IgG4、IgG1、或IgG2的全长抗体。在一些实施方式中,本申请的抗体或其抗原结合部分可以是单链抗体,或由抗体片段构成,例如Fab或F(ab′)2片段。
本申请的抗体可以是例如鼠源、人源、嵌合或人源化抗体。
本申请的抗体或其抗原结合部分可以与人CD24结合,并能够阻断CD24-Siglec-10结合/相互作用,并具有体内抗肿瘤效果。
本申请还提供含有本申请抗体或其抗原结合部分的免疫交联物,该抗体或其抗原结合部分与治疗剂例如细胞毒素或抗癌剂相连接。本申请还提供含有本申请抗体或其抗原结合部分的双特异性分子,该抗体或其抗原结合部分连接有第二功能基团,例如,第二抗体,该第二功能基团具有不同于本申请抗体或其结合部分的结合特异性。在另一方面,本申请的抗体或其抗原结合部分可以是嵌合抗原受体(CAR)或基因改造T细胞受体(TCR)的一部分。本申请还提供具有上述CAR和/或TCR的免疫细胞,包括T细胞、NK细胞等。
本申请还包括编码本申请抗体或其抗原结合部分的核酸分子,以及包含该核酸的表达载体以及包含该表达载体的宿主细胞。本申请还提供使用含有上述表达载体的宿主细胞来制备CD24抗体的方法,包括:(i)在宿主细胞中表达抗体,以及(ii)从宿主细胞或其培养物中分离抗体。
本申请还提供药物组合物,其包含本申请的抗体或其抗原结合部分、免疫交联物、双特异性分子、免疫细胞、核酸分子、表达载体、或宿主细胞,以及药学上可接受的载体。
在一个方面,本申请提供在受试者中治疗或减缓CD24相关的疾病的方法,包括向受试者施用治疗有效量的本申请药物组合物。。
在一些实施方式中,CD24相关的疾病为癌症。癌症可以是实体瘤和血液瘤,包括但不限于,卵巢癌、乳腺癌、宫颈癌、子宫内膜癌、急性淋巴细胞白血病(ALL)、胆管癌、膀胱癌、胰腺癌、胃腺癌、胶质母细胞瘤、和结肠癌。在一些实施方式中,本申请药物组合物可以与至少一种其他抗癌剂一起施用,例如CD47靶向蛋白,如SIRPαD1-Fc蛋白,该蛋白可以具有与SEQ ID NO:19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,在SEQ ID NO:19的第80位具有N80A突变,该位点的突变可实现SIRPαD1去糖基化的效果。
在一些实施方式中,CD24相关的疾病为炎性疾病,包括但不限于急性移植物抗宿主病、抗艾滋鸡尾酒疗法引起的炎症反应(包括肝脂肪变性和纤维化、低密度脂蛋白症等)、风湿性关节炎、和系统性红斑狼疮。
本申请药物组合物可以治疗的其他CD24相关疾病包括但不限于代谢相关脂肪性肝病、糖尿病、多发性硬化症、和败血症。
本申请的抗体还可以用于CD24的体外检测等。
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
详细描述在以下以示例方式给出但不意在将本申请限制于所述具体实施方式,可以结合附图更好地进行理解。
图1是本申请CD24抗体IMM47C、IMM47、和IMM47H的结构示意图。其中IMM47C为IgG抗体,包含鼠源重链可变区、和鼠源轻链可变区,具体包含SEQ ID NO:7的重链可变区、SEQID NO:12的重链恒定区、SEQ ID NO:8的轻链可变区、以及SEQ ID NO:13的轻链恒定区;IMM47为IgG抗体,包含鼠源重链可变区、和人源化轻链可变区,具体包含SEQ ID NO:7的重链可变区、SEQ ID NO:12的重链恒定区、SEQ ID NO:9的轻链可变区、以及SEQ ID NO:13的轻链恒定区;IMM47H为IgG抗体,包含人源化的重链可变区、和人源化的轻链可变区,具体包含SEQ ID NO:10的重链可变区、SEQ ID NO:12的重链恒定区、SEQ ID NO:11的轻链可变区、以及SEQ ID NO:13的轻链恒定区。
图2示出IMM47H与CD24+CD47+MCF-7人乳腺癌细胞的结合活性,hIgG-Fc用作阴性对照。
图3示出IMM47H与CD47+CD24+REH人类急性淋巴瘤细胞的结合活性。IMM01(SIRPαD1-Fc,SEQ ID NO:19)、hIgG-Fc用作对照。
图4示出IMM47C对CD24+CD47+MCF-7人类乳腺癌细胞引发抗体依赖性细胞介导的细胞毒效应(ADCC)的能力,hIgG1-Fc用作阴性对照。
图5示出IMM47C对CD24+CD47+REH人类急性淋巴细胞白血病细胞引发ADCC的能力,具有很低ADCC活性的hIgG1-Fc与IMM01用作对照。
图6示出IMM47对基因改造成表达人类CD24的MC38-hCD24鼠类结肠癌细胞引发ADCC的能力,hIgG1-Fc用作阴性对照。
图7示出IMM47C、以及IMM47C与IMM01组合在携带CD24+CD47+MCF-7人乳腺癌肿瘤的异种移植的CB17-SCID小鼠中的体内抗肿瘤效果。
图8A和8B示出IMM47和IMM47C在B6-Siglec10转基因鼠同源移植MC38-hCD24结肠癌模型中的效用,包括各组的平均肿瘤体积(A)以及个体肿瘤体积(B)。
图9示出IMM47C、IMM47和IMM47H在同源移植MC38-hCD24KI细胞瘤的Siglec10人源化B6小鼠模型中的抗肿瘤效果。
具体实施方式
为更好理解本申请,首先定义一些术语。其他定义则贯穿具体实施方式部分而列出。
本文中的“CD24”是指分化抗原簇蛋白24,又称为热稳定抗原CD24。该术语包括变体、同源物、直向同源物和平行同源物。例如,对人CD24特异的抗体可以在某些情况下与另一物种例如猴的CD24蛋白交叉反应。在其他实施方式中,对人CD24蛋白特异的抗体可以完全地对人CD24蛋白特异而不与其他物种或其他类型的蛋白交叉反应,或者可以与一些其他物种而非所有其他物种的CD24蛋白交叉反应。
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。抗体的重链恒定区可以介导免疫蛋白与宿主组织或因子的结合,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)。特别地,重链恒定区包含Fc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。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/或补体系统。
本文中的术语,抗体的“抗原结合部分”(或简称为抗体部分),是指抗体的保持有特异结合抗原(例如,CD24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“抗原结合部分”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Cm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)。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。
本文所用的术语“分离的抗体”是指基本不含具有不同抗原特异性的其他抗体的抗体。例如,与CD24特异结合的分离抗体基本不含特异结合CD24蛋白之外抗原的抗体。但是,特异结合人CD24蛋白的分离抗体可能对其他抗原例如其他物种的CD24蛋白具有交叉结合性。此外,分离的抗体基本不含其他细胞材料和/或化学物质。
术语“单克隆抗体”或“单抗”或“单克隆抗体组成”是指单一分子组成的抗体分子制品。单克隆抗体组成呈现出对于特定表位的单一结合特异性和亲和力。
术语“小鼠源抗体”是指可变区框架和CDR区得自小鼠种系免疫球蛋白序列的抗体。此外,如果抗体包含恒定区,其也得自小鼠种系免疫球蛋白序列。小鼠源抗体可以包含不由小鼠种系免疫球蛋白序列编码的氨基酸残基,例如通过体外随机突变或点突变或通过体内体细胞突变而导入的突变。然而,术语“鼠源抗体”不包括在小鼠框架序列中插入得自其他哺乳动物物种的CDR序列的抗体。
术语“嵌合抗体”是指通过组合非人源遗传物质与人源遗传物质而得来的抗体。或者更笼统地说,嵌合抗体是指组合有一个物种的遗传物质与另一物种遗传物质的抗体。
术语“人源化抗体”是指来源于非人物种但其蛋白序列已经被修改以增加其与人天然生成抗体的相似度的抗体。
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CD24抗体结合的靶细胞例如癌细胞裂解。
术语“抗体依赖的细胞吞噬”、“抗体依赖性细胞吞噬”或“ADCP”是指抗体如CD70抗体或类抗体蛋白如SIRPα-Fc与免疫细胞如巨噬细胞的FcR结合,引起免疫细胞如巨噬细胞对与抗体如CD70抗体或与SIRPα结合的靶细胞的吞噬,引起靶细胞的内吞和降解。
术语“补体依赖的细胞毒性”、“补体依赖性细胞毒性”或“CDC”是指抗体如CD70抗体或类抗体蛋白如SIRPα-Fc与补体系统蛋白如C1q结合,激发补体通路,对靶细胞进行裂解。
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。
术语“EC50”,又叫半最大效应浓度,是指引起50%最大效应的抗体浓度。
术语“IC50”,又叫半最大抑制浓度,是指引起50%最大抑制效应的抗体浓度。
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。
本申请的抗体包含与本申请CD24抗体存在一个或多个保守修饰的重链和/或轻链可变区序列或CDR1、CDR2和CDR3序列。本领域知道,一些保守序列修改不会使抗原结合性消失。
本文所用的术语“保守序列修饰”是指不会显著影响或改变抗体结合特性的氨基酸修饰。这样的保守修饰包括氨基酸替换、添加和删除。可以通过领域内已知的标准技术,例如点突变和PCR介导的突变,将修饰引入本申请抗体中。保守氨基酸替换是氨基酸残基用具有相似侧链的氨基酸残基进行替换。具有相似侧链的氨基酸残基组在领域内已知。这些氨基酸残基组包括具有碱性侧链(例如,赖氨酸、精氨酸、组氨酸)、酸性侧链(例如,天冬氨酸、谷氨酸)、不带电极性侧链(例如,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如,丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β-支链侧链(例如,苏氨酸、缬氨酸、异亮氨酸)和芳香族侧链(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。因此,本申请抗体的CDR区中的一个或多个氨基酸残基可以用同侧链组的其他氨基酸残基替换,且得到的抗体可以使用本文所述的功能检测对其进行保留功能(即,上述的功能)的测试。
本申请的抗体可以以具备本申请CD24抗体的一个或多个VH/VL序列的抗体作为起始材料,制备成基因修饰的抗体。抗体可以通过修饰一个或两个可变区(即,VH和/或VL)内(例如,在一个或多个CDR区和/或一个或多个骨架区)的一个或多个残基来进行基因修饰,以改善结合亲和力和/或增加与某些物种天然产生的抗体的相似性。例如,骨架区经修饰成提供人源化的抗体。此外,或者抗体可以通过修饰恒定区中的残基进行基因修饰,例如改变抗体的效应功能。
在某些实施方式中,CDR区植入可以用来基因修饰抗体的可变区。抗体主要通过位于六个重链和轻链互补决定区(CDR)中的氨基酸残基与靶标抗原进行相互作用。出于这个原因,CDR内的氨基酸残基比起CDR外的序列在个体抗体之间更加地多样。因为CDR序列负责主要的抗体-抗原相互作用,可以通过构建含有特定天然抗体的CDR序列植入到不同特性的不同抗体的骨架序列的表达载体,来表达模拟特定天然抗体的特性的重组抗体。
因此,本申请的另一实施方式涉及分离的单克隆抗体或其抗原结合部分,重链可变区包含具有本申请上述序列的CDR1、CDR2和CDR3,轻链可变区包含具有本申请上述序列的CDR1、CDR2和CDR3,而可以含有不同的骨架序列。骨架序列可以从包括种系抗体基因序列的公开DNA数据库或公开参考文献中获得。例如,用于人重链和轻链可变区基因的种系DNA序列可以在例如Vbase人种系序列数据库(www.mrc-cpe.cam.ac.uk/vbase)获得。作为另一实施方式,用于人重链和轻链可变区基因的种系DNA序列可以在Genbank数据库中得到。用于本申请抗体的优选骨架序列是结构上与本申请抗体所用的骨架序列相似的那些。CDR1、CDR2、和CDR3序列可以植入到与得到该骨架序列的种系免疫球蛋白基因具有相同序列的骨架区中,或者CDR序列可以植入到包含有与种系序列相比具有一个或多个突变的骨架区中。例如,在一些情况下,将骨架区中的残基进行突变是有益的,以保持或增强抗体的抗原结合性等。
另一类的可变区修饰是将VH和/或VL CDR1、CDR2和/或CDR3区内的氨基酸残基进行突变,从而改进目标抗体的一种或多种结合特性(例如,亲和力)。可以进行点突变或PCR介导的突变来引入突变,且其对于抗体结合或其他功能特性的影响可以在本领域所知的体外或体内检测中进行评价。优选地,引入本领域所知的保守修饰。突变可以是氨基酸替换、添加或缺失,但优选为替换。此外,通常改变CDR区内的不多于一个、两个、三个、四个或五个的残基。
本申请的基因改造抗体包括在VH和/或VL的骨架残基中做出基因修饰以例如改变抗体特性的那些。通常而言,这些骨架修饰用来降低抗体的免疫原性。例如,一种方法是将一个或多个骨架残基“回复突变”成相应的种系序列。更加具体而言,经历体细胞突变的抗体可能包含不同于得到抗体的种系序列的骨架残基。这些残基可以通过将抗体骨架序列与得到抗体的种系序列相比较而识别出来。
另一类的骨架修饰包括对骨架区的、或者甚至一个或多个CDR区的一个或多个残基进行突变,以去除T细胞表位,从而减少抗体的可能导致的免疫原性。
此外,作为骨架或CDR区内修饰之外的另一种选择,本申请的抗体可以基因改造成在Fc区包括基因修饰,通常来改变抗体的一个或多个功能特性,例如血清半衰期、补体结合、Fc受体结合、和/或抗体依赖的细胞毒性。此外,本申请的抗体可以进行化学修饰(例如,可以向抗体附加一个或多个化学功能基团),或者修饰成改变其糖基化,来改变抗体的一个或多个功能特性。
在一个实施方式中,CH1的铰链区进行修饰,改变,例如增加或减少铰链区的半胱氨酸残基的数量。改变CH1铰链区的半胱氨酸残基,来例如促进重链轻链的组装或增加/降低抗体的稳定性。
在另一个实施方式中,对抗体的Fc铰链区进行突变,以降低抗体的生物半衰期。更加具体地,将一个或多个氨基酸突变引入Fc铰链片段的CH2-CH3连接区,从而抗体相对于天然Fc-铰链结构域SpA结合而言,具有减弱的SpA结合力。
在另一实施方式中,修饰抗体的糖基化。例如,可以制备去糖基化的抗体(即,抗体缺少糖基化)。可以改变糖基化,来例如增加抗体对抗原的亲和性。这样的糖化修饰可以通过例如改变抗体序列中的一个或多个糖基化位点来达成。例如,可以做出一个或多个氨基酸替换,以消除一个或多个可变区骨架糖基化位点,从而消除该位置的糖基化。这样的去糖基化可以增加抗体对抗原的亲和性。此外,可以制备具有改变的糖基化类型的抗体,例如岩藻糖残基量减少的低岩藻糖基抗体,或者具有增加的平分型GlcNac结构的抗体。改变的糖基化形式被证明能增加抗体的ADCC活性。这样的糖化修饰可以通过例如在糖基化系统改变的宿主细胞中表达抗体而进行。具有改变的糖基化系统的细胞在领域中已知,且可以用作表达本申请重组抗体的宿主细胞,以制备具有改变的糖基化的抗体。
本申请的单克隆抗体可以使用Kohler and Milstein(1975)Nature 256:495的体细胞杂交(杂交瘤)技术进行制备。制备单克隆抗体的其他实施方式包括B淋巴细胞的病毒或致癌性转化以及噬菌体展示技术。嵌合或人源化抗体也在领域内熟知。
本申请的抗体还可以使用例如重组DNA技术结合基因转染方法,在宿主细胞转染瘤中生成(例如Morrison,S.(1985)Science 229:1202)。在一个实施方式中,将由标准分子生物技术得到的编码部分或全长轻链和重链的DNA插入一个或多个表达载体中,从而基因与转录和翻译调控序列可操作地连接。在该情况下,术语“可操作地连接”是指抗体基因连接到载体中,从而载体内的转录和翻译控制序列行使它们既定的调控抗体基因转录和翻译的功能。
术语“调控序列”包括控制抗体基因转录或翻译的启动子、增强子和其他表达控制元件(例如,多腺苷酸化信号)。这样的调控序列在例如Goeddel(Gene ExpressionTechnology.Methods in Enzymology 185,Academic Press,San Diego,Calif.(1990))中有过描述。优选的用于哺乳动物宿主细胞表达的调控序列包括引导在哺乳动物细胞中的高水平蛋白表达的病毒元件,例如得自巨细胞病毒(CMV)、猿猴病毒40(SV40)、腺病毒的启动子和/或增强子,如腺病毒主要晚期启动子(AdMLP)和多瘤病毒。或者,可以使用非病毒调控序列,例如泛素启动子或β-珠蛋白启动子。另外,调控元件由不同来源的序列构成,例如SRα启动子系统,其包含来自SV40早期启动子的序列和人T细胞白血病I型病毒的长末端重复(Takebe et al.,(1988)Mol.Cell.Biol.8:466-472)。表达载体和表达控制序列选为与所使用的表达宿主细胞相容。
抗体轻链基因和抗体重链基因可以插入到同一或不同的表达载体中。在优选实施方式中,可变区通过插入到已经编码所需亚型的重链恒定区和轻链恒定区的表达载体中而构建全长抗体基因,从而VH与载体中的CH可操作地连接,VL与载体中的CL可操作地连接。或者,重组表达载体可以编码促进抗体链从宿主细胞分泌的信号肽。抗体链基因可以克隆到载体中,从而信号肽在阅读框内连接到抗体链基因的氨基端。信号肽可以是免疫球蛋白信号肽或异源信号肽(即,来自非免疫球蛋白的信号肽)。
除抗体链基因和调控序列外,本申请的重组表达载体可以携带其他序列,例如调控载体在宿主细胞中复制的序列(例如,复制起始点)和可选择标记物基因。可选择标记物基因可用于选择已导入载体的宿主细胞(参见,例如,美国专利4,399,216;4,634,665和5,179,017)。例如,通常可选择标记物基因赋予已导入载体的宿主细胞以药物抗性,例如G418、潮霉素、或氨甲喋呤抗性。优选的可选择标记物基因包括二氢叶酸还原酶(DHFR)基因(用于dhfr宿主细胞的氨甲喋呤选择/扩增)和neo基因(用于G418选择)。
对于轻链和重链的表达,编码重链和轻链的表达载体通过标准技术转染到宿主细胞中。多个形式的术语“转染”包括多种常用于将外源DNA导入原核或真核宿主细胞的技术,例如,电穿孔、磷酸钙沉淀、DEAE-右旋糖转染等。尽管在原核或真核宿主细胞中表达本申请抗体在理论上是可行的,优选抗体在真核细胞中表达,最优选在哺乳动物宿主细胞中表达,因为真核细胞,特别是哺乳动物细胞,比原核细胞更可能组装并分泌适当折叠且有免疫活性的抗体。
优选的用于表达本申请重组抗体的哺乳动物宿主细胞包括中国仓鼠卵巢(CHO细胞)(包括与DHFR可选择标记物一起施用的dhfr-CHO细胞,在Urlaub and Chasin,(1980)Proc.Natl.Acad.Sci.USA 77:4216-4220中有过描述,DHFR可选择标记物在例如R.J.Kaufman and P.A.Sharp(1982)J.Mol.Biol.159:601-621中描述)、NSO骨髓瘤细胞、COS细胞和SP2细胞。特别在使用NSO骨髓瘤细胞时,另一优选的表达系统是GS基因表达系统。当编码抗体基因的重组表达载体导入哺乳动物宿主细胞时,通过将宿主细胞培养足以使得宿主细胞中抗体表达、或优选地足以使得使抗体分泌到宿主细胞生长的培养基中的一段时间,从而制备抗体。抗体可以使用蛋白纯化方法从培养基中回收。
本申请的抗体或其抗原结合部分可以与治疗剂交联,形成免疫交联物,例如抗体-药物交联物(ADC)。合适的治疗剂包括细胞毒素、烷化剂、DNA小沟结合分子、DNA嵌入剂、DNA交联剂、组蛋白去乙酰化酶抑制剂、核输出抑制剂、蛋白酶体抑制剂、拓扑异构酶I或II的抑制剂、热激蛋白抑制剂、酪氨酸激酶抑制剂、抗生素和抗有丝分裂剂。在ADC中,抗体和治疗剂优选地通过接头交联,该接头可切割,例如肽类接头、二硫类接头或腙类接头。更优选地,接头是肽类接头,例如Val-Cit、Ala-Val、Val-Ala-Val、Lys-Lys、Ala-Asn-Val、Val-Leu-Lys、Ala-Ala-Asn、Cit-Cit、Val-Lys、Lys、Cit、Ser或Glu。
另一方面,本申请涉及包含与至少一个其他功能分子如另一种肽或蛋白(例如,另一抗体或受体配体)相连接的一种或多种本申请抗体或其抗原结合部分的双特异性分子,以生成与至少两个不同结合位点或靶向分子结合的双特异性分子。术语“双特异性分子”包括具有三种或更多种特异性的分子。在一些实施方式中,除Fc结合特异性和CD24结合特异性外,双特异性分子还具有第三特异性。第三特异性可以例如针对CD47,以更好地靶向肿瘤细胞,而免除其他CD24+细胞如免疫细胞。
双特异性分子可以以多种形式和尺寸出现。在尺寸谱的一端,双特异性分子保持传统抗体形式,除其具有两个结合臂且各臂具有不同特异性外,替代具有两个特异性相同的结合臂的情况。在另一极端的是双特异性分子,由两个经肽链连接的单链抗体片段(scFv)构成,称为Bs(scFv)2构建体。中间尺寸的双特异性分子包括由肽类接头连接的两个不同的F(ab)片段。这些和其他形式的双特异性分子可以通过基因改造、体细胞杂交或化学法进行制备。
本申请还提供包含CD24单链抗体scFv的嵌合抗原受体,该scFv包含本申请中所述的重链和轻链CDR、或重链和轻链可变区。CD24嵌合抗原受体可以包含(a)含有CD24 scFv的胞外抗原结合域;(b)跨膜结构域;和(c)胞内信号转导结构域。
在另一方面,本申请提供编码本申请抗体或其抗原结合部分的重链/轻链可变区或CDR的核酸分子。核酸可以存在整细胞中,在细胞裂解液中,或处于部分纯化或基本纯的形式。当通过标准技术从其他细胞组分或其他污染物例如其他细胞核酸或蛋白中纯化出来后,核酸是“分离的”或“基本纯的”。本申请的核酸可以为例如DNA或RNA,且可能包含或可能不包含内含子序列。在优选实施方式中,核酸是cDNA分子。
本申请的核酸可以使用标准的分子生物学技术获得。对于由杂交瘤(例如,由携带人免疫球蛋白基因的转基因小鼠制备的杂交瘤)表达的抗体,编码杂交瘤制备的抗体的轻链和重链的cDNA可以通过标准PCR扩增或cDNA克隆技术获得。对于(例如使用噬菌体展示技术)从免疫球蛋白基因库获得的抗体,编码这类抗体的核酸可以从基因库中收集。
优选的本申请核酸分子包括编码CD24单克隆抗体的VH和VL序列或CDR的那些。一旦获得了编码VH和VL的DNA片段,这些DNA片段可以进一步通过标准的重组DNA技术进行操作,例如将可变区基因转变为全长抗体链基因、Fab片段基因或scFv基因。在这些操作中,编码VH或VL的DNA片段与编码另一蛋白的另一DNA片段,例如抗体恒定区或柔性接头,可操作地连接。术语“可操作地连接”是指两个DNA片段连接在一起,从而两个DNA片段编码的氨基酸序列都在阅读框内。
编码VH区的分离DNA可以通过可操作地连接VH编码DNA与编码重链恒定区(CH1、CH2和CH3)的另一DNA分子而转变成全长重链基因。人重链恒定区基因的序列在领域内已知,且包括这些区域的DNA片段可以通过标准PCR扩增而获得。重链恒定区可以是IgG1、IgG2、IgG3、IgG4、IgA、IgE、IgM或IgD恒定区,但是优选为IgG1或IgG4恒定区。对于Fab片段重链基因,编码VH区的DNA可以可操作地与仅编码重链CH1恒定区的另一DNA分子连接。
编码VL区的分离DNA可以通过可操作地连接VL编码DNA与编码轻链恒定区CL的另一DNA分子而转变成全长轻链基因。人轻链恒定区基因的序列在领域内已知,且包括这些区域的DNA片段可以通过标准PCR扩增而获得。在优选实施方式中,轻链恒定区可以是κ和λ恒定区。
为创建scFv基因,编码VH和VL的DNA片段可以可操作地与编码柔性接头例如5-20氨基酸肽的另一片段连接,从而VH和VL序列可以作为连续的单链蛋白进行表达,其中VH和VL区域通过该柔性接头连接。
在另一方面,本申请提供一种药物组合物,其包含本申请的一种或多种抗体或其抗原结合部分、免疫交联物、免疫细胞、双特异抗体、和/或抗体或其抗原结合部分的编码核酸分子、表达载体或宿主细胞,与药学上可接受的载体配制在一起。组合物可以任选地包含一种或多种其他药学上的有效成分,例如另一抗肿瘤蛋白,如本申请中联用的IMM01,一种SIRPαD1-Fc融合蛋白。
药学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、分散或混悬剂、增溶剂、染色剂、矫味剂、涂层、崩解剂、润滑剂、甜味剂、防腐剂、等渗剂及其组合。
药物组合物可适合于静脉内、肌内、皮下、肠道外、脊柱或表皮施用(例如通过注射或推注)。基于施用途径的不同,有效成分可以包在材料中,以保护其不受酸和可能使其失活的其他自然条件的影响。“肠道外施用”是指不同于肠道和局部外用的方式,通常通过注射进行,包括但不限于静脉内、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、硬脑膜上和胸骨内注射和推注。或者,本申请的抗体可以通过非肠道外路径施用,例如外用、表皮施用或粘膜施用,例如鼻内、经口、阴道、直肠、舌下、或局部外用。
药物组合物可以为无菌水溶液或分散液的形式。它们也可以配制在微乳剂、脂质体或其他适于高浓度药物的有序结构中。
与载体材料一起制备成单剂型的有效成分的量将随着治疗主体和特定施用模式而变,且基本上而言是产生疗效的组合物的量。以百分比计,该量为约0.01-约99%的与药学上可接受载体结合的有效成分。
给药方案经调整提供最佳的所需反应(例如,治疗反应)。例如,可以施用快速灌注剂,可以随时间推移施用多个分剂量,或者剂量可以随治疗情况的危急程度成比例降低或提高。特别有利的是,以方便施用和剂量均匀的剂量单位型配置肠道外组合物。剂量单位型是指物理上分开的单位,适于治疗主体的单次给药;各单位包含计算出来与药学载体一起产生所需疗效的预定量的有效成分。或者,抗体可以以缓释剂施用,这种情况下所需的施用频率降低。
对于抗体的施用,剂量可以为约0.001-100mg/kg宿主体重。
“治疗有效量”的本申请CD24抗体引起疾病症状严重程度的降低、无症状期频率和持续时间的增加。例如,对于带瘤受试者的治疗,“治疗有效量”优选地,与未治疗受试者相比,将肿瘤生长抑制至少约20%、更优选抑制至少约40%,甚至更优选地抑制至少约60%,且更优选地抑制至少约80%。治疗有效量的治疗抗体可以减小肿瘤尺寸,或者减轻受试者的症状,受试者可以是人或另一哺乳动物。
药物组合物可以是缓释试剂,包括植入体、和微胶囊递送系统。可以使用生物可降解、生物相容的聚合物,例如乙烯-醋酸乙烯、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 Drug Delivery Systems,J.R.Robinson,ed.,Marcel Dekker,Inc.,New York,1978。
药学组合物可以经医学设备来给药,例如(1)无针皮下注射设备(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)微量输液泵(美国专利4,487,603);(3)经皮给药设备(美国专利4,486,194);(4)推注设备(美国专利4,447,233和4,447,224);和(5)渗透设备(美国专利4,439,196和4,475,196)。
在某些实施方式中,本申请的单抗可以经配制,以确保合适的体内分布。例如,为确保本申请的治疗抗体穿越血脑屏障,抗体可以配制在脂质体中,其还可以额外地包含靶向功能基团,以增强对特定细胞或器官的选择性输送。
本申请的药物组合物具有多种体外和外内应用,涉及例如癌症的治疗,或者更笼统地讲,用于癌症疾病患者的免疫增强。抗体可以施用至人受试者,以例如体内抑制肿瘤生长。
考虑到本申请药物组合物的抑制肿瘤细胞增殖和存活的能力,本申请提供抑制受试者中肿瘤细胞生长的方法,包括向该受试者施用本申请的药物组合物,从而在该受试者中肿瘤生长被抑制。可以由本申请抗体治疗的肿瘤的非限制性例子包括但不限于卵巢癌、乳腺癌、宫颈癌、子宫内膜癌、急性淋巴细胞白血病(ALL)、胆管癌、膀胱癌、胰腺癌、胃腺癌、胶质母细胞瘤、和结肠癌,原发或转移的。本申请的药物组合物可以与一种或多种其他抗体或非抗体类治疗剂一起施用,其能有效抑制受试者中的肿瘤生长。在一个实施方式中,本申请提供在受试者中抑制肿瘤生长的方法,包括向受试者施用CD24药物组合物以及IMM01,一种SIRPαD1-Fc融合蛋白。
本申请的药物组合物还可以用于治疗或减缓炎性疾病,例如急性移植物抗宿主病、抗艾滋鸡尾酒疗法引起的炎症反应(包括肝脂肪变性和纤维化、低密度脂蛋白症等)、风湿性关节炎、和系统性红斑狼疮。
本申请的药物组合物还可以用于治疗或减缓的CD24相关疾病包括但不限于代谢相关脂肪性肝病、糖尿病、多发性硬化症、和败血症。
本文讨论的治疗剂的组合可以作为在药学可接受载体中的单一组合物同时施用,或者作为分开的组合物同时施用,其中各药剂处于药学可接受载体中。在另一个实施方式中,治疗剂的组合可以按序施用。
此外,如果进行多次联合疗法施用,且药剂按序施用,则在各时间点的按序施用的次序可以反转或保持相同,按序施用可以与同时施用或其任何组合相结合。
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
图1示出本申请CD24抗体IMM47C、IMM47、和IMM47H的结构。
其中,IMM47C为IgG抗体,包含小鼠源重链可变区、和小鼠源轻链可变区。具体地,IMM47C包含SEQ ID NO:7的重链可变区、SEQ ID NO:12的重链恒定区、SEQ ID NO:8的轻链可变区、以及SEQ ID NO:13的轻链恒定区。
IMM47为IgG抗体,包含小鼠源重链可变区、和人源化轻链可变区。具体地,IMM47包含SEQ ID NO:7的重链可变区、SEQ ID NO:12的重链恒定区、SEQ ID NO:9的轻链可变区、以及SEQ ID NO:13的轻链恒定区。
IMM47H为IgG抗体,包含人源化的重链可变区、和人源化的轻链可变区。具体地,IMM47H包含SEQ ID NO:10的重链可变区、SEQ ID NO:12的重链恒定区、SEQ ID NO:11的轻链可变区、以及SEQ ID NO:13的轻链恒定区。
IMM01为结合CD47的SIRPαD1-Fc融合蛋白,记载于US 2021/0024598A1,包含两个突变SIRPαD1,与Fc二聚体片段连接,其单体含有分别如SEQ ID NO:20和SEQ ID NO:19所示的核酸序列和氨基酸序列。IMM01中的SIRPαD1,相比于野生型SIRPαD1,在SEQ ID NO:19的第80位处存在N80A突变,该位点的突变可实现去糖基化的效果。
实施例1.CD24抗体的生成、人源化、表达载体构建及表达
对小鼠接种人CD24蛋白,取其血清,筛选出滴度高的小鼠。取小鼠脾脏细胞,经杂交瘤技术制备出生产CD24抗体的杂交瘤细胞系,并经CD24结合活性测试筛选出生产CD24结合活性高的单克隆抗体的细胞克隆,包括生产IMM47C的细胞克隆。IMM47C的重链可变区和轻链可变区经测序得知,氨基酸序列分别如SEQ ID NOs:7和8所示。
用CDR移植法对IMM47C进行人源化改造,获得部分人源化(仅轻链可变区人源化)的抗体IMM47、以及完全人源化的抗体IMM47H。其中,IMM47包含SEQ ID NO:7的重链可变区、和SEQ ID NO:9的轻链可变区,IMM47H包含SEQ ID NO:10的重链可变区、和SEQ ID NO:11的轻链可变区。
人工设计出IMM47C、IMM47、和IMM47H的编码序列。
具体地,对于IMM47C的重链,将编码小鼠IgG1重链信号肽的57个核苷酸(SEQ IDNO:21)加至IMM47C重链可变区-恒定区编码序列(SEQ ID NO:14)的5’端,并将Kozak序列(SEQ ID NO:22)加至信号肽序列的5’端。最后,将HindIII和NheI限制性酶切位点分别加至所得序列的5’和3’端。对于IMM47C的轻链,将相同的信号肽序列以及Kozak序列加至IMM47C抗体轻链可变区-恒定区编码序列(SEQ ID NO:15)的5’端,并将HindIII和XbaI限制性酶切位点分别加至所得序列的5’和3’端。所得的序列经金斯瑞生物科技股份有限公司合成,并分别克隆到pMac-H和pMac-L载体中。
对于IMM47的重链,将编码小鼠IgG1重链信号肽的57个核苷酸(SEQ ID NO:21)加至IMM47重链可变区-恒定区编码序列(SEQ ID NO:14)的5’端,并将Kozak序列(SEQ ID NO:22)加至信号肽序列的5’端。最后,将HindIII和NheI限制性酶切位点分别加至所得序列的5’和3’端。对于IMM47的轻链,将相同的信号肽序列以及Kozak序列加至IMM47抗体轻链可变区-恒定区编码序列(SEQ ID NO:16)的5’端,并将HindIII和XbaI限制性酶切位点分别加至所得序列的5’和3’端。所得的序列经金斯瑞生物科技股份有限公司合成,并分别克隆到pMac-H和pMac-L载体中。
对于IMM47H的重链,将编码小鼠IgG1重链信号肽的57个核苷酸(SEQ ID NO:21)加至IMM47H重链可变区-恒定区编码序列(SEQ ID NO:17)的5’端,并将Kozak序列(SEQ IDNO:22)加至信号肽序列的5’端。最后,将HindIII和NheI限制性酶切位点分别加至所得序列的5’和3’端。对于IMM47H的轻链,将相同的信号肽序列以及Kozak序列加至IMM47H抗体轻链可变区-恒定区编码序列(SEQ ID NO:18)的5’端,并将HindIII和XbaI限制性酶切位点分别加至所得序列的5’和3’端。所得的序列经金斯瑞生物科技股份有限公司合成,并分别克隆到pMac-H和pMac-L载体中。
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(MW 40,000聚乙烯亚胺盐酸盐,polysciences)配置成1mg/ml,按照PEI:DNA=4∶1质量比例准备所需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/VDMSO),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Protein A填料进行亲和纯化。
实施例2.CD24抗体与CD24+CD47+MCF-7细胞结合
将CD24+CD47+MCF-7细胞密度调整为1×106/ml,取100μl,分别在100μl起始浓度为30μg/ml、3倍梯度稀释的IMM47H中4℃孵育1小时,hIgG-Fc用作阴性对照。细胞用冷的PBS清洗两遍,之后在100μl FITC标记的针对人IgG-Fc的二抗(Cat#F9512,Sigma)中孵育45分钟。细胞清洗两遍,并重悬浮于200μl PBS。之后,细胞用流式细胞仪(Merck Millipore,easyCyte 5HT)进行FACS分析。
如图2所示,本申请的CD24抗体,包括IMM47H,能够特异地结合CD24+CD47+MCF-7细胞。
实施例3.CD24抗体与CD24+CD47+REH细胞结合
CD24+CD47+REH细胞密度调整为1×106/ml,取100μl,分别在100μl起始浓度为30μg/ml、3倍梯度稀释的IMM47H中4℃孵育1小时,IMM01、hIgG-Fc用作对照。细胞用冷的PBS清洗两遍,之后在100μl FITC标记的针对人IgG-Fc的二抗(Cat#F9512,Sigma)中孵育45分钟。细胞清洗两遍,并重悬浮于200μlPBS。之后,细胞用流式细胞仪(easyCyte 5HT,Merck Millipore)进行FACS分析。
如图3所示,IMM47H与CD24+CD47+REH细胞特异结合,略优于CD47结合蛋白IMM01。
实施例4.CD24抗体针对CD24+CD47+MCF-7细胞引发高水平抗体依赖性细胞介导的
细胞毒性(ADCC)
1mM CFSE(Cat#21888-25mg,Sigma)500倍稀释标记MCF-7细胞。
取50μl密度为6×105/ml的MCF-7细胞(用作靶向细胞),与100μl密度为6×105/ml且稳定表达FcγRIIIa(158V)的NK92MI细胞(效应细胞),按照效靶比2∶1混合,且混合的细胞在5%CO2下分别在50μl起始浓度为1000ng/ml、3倍梯度稀释的IMM47C中于37℃培养4小时,hIgG-Fc用作阴性对照。之后向细胞培养液中加入碘化丙啶(PI)(Cat#P4170,Sigma),浓度5μg/ml,细胞经FACS分析PI信号。由ADCC造成的细胞裂解百分比基于以下公式进行计算:
%裂解=(%IMM47C处理的PI阳性靶细胞-%阴性对照蛋白处理的PI阳性靶细胞)/(100-%阴性对照蛋白处理的PI阳性靶细胞)×100
如图4所示,对于CD24+CD47+MCF-7人类乳腺癌细胞,IMM47C引发了显著水平的ADCC。
实施例5.CD24抗体针对CD24+CD47+REH细胞引发高水平抗体依赖性细胞介导的细
胞毒性(ADCC)
1mM CFSE(Cat#21888-25mg,Sigma)500倍稀释标记REH细胞。
取50μl密度为6×105/ml的REH细胞(用作靶向细胞),与100μl密度为6×105/ml且稳定表达FcγRIIIa(158V)的NK92MI细胞(效应细胞),按照效靶比2∶1混合,且混合的细胞在5%CO2下分别在50μl起始浓度为1000ng/ml、3倍梯度稀释的IMM47C中于37℃培养4小时,hIgG-Fc用作阴性对照。之后向细胞培养液中加入碘化丙啶(PI)(Cat#P4170,Sigma),浓度5μg/ml,细胞经FACS分析PI信号。由ADCC造成的细胞裂解百分比基于以下公式进行计算:
%裂解=(%IMM47C处理的PI阳性靶细胞-%阴性对照蛋白处理的PI阳性靶细胞)/(100-%阴性对照蛋白处理的PI阳性靶细胞)×100
如图5所示,对于CD24+CD47+REH人类急性淋巴细胞白血病细胞,IMM47C引发显著水平的ADCC。
实施例6.CD24抗体针对CD24+MC38-hCD24细胞引发高水平抗体依赖性细胞介导的
细胞毒性(ADCC)
1mM CFSE(Cat#21888-25mg,Sigma)500倍稀释标记MC38-hCD24小鼠结肠癌细胞。
取50μl密度为6×105/ml的MC38-hCD24细胞(用作靶向细胞),与100μl密度为6×105/ml且稳定表达FcγRIIIa的NK92MI细胞(效应细胞),按照效靶比2∶1混合,且混合的细胞在5%CO2下分别与50μl起始浓度为1000ng/ml、3倍梯度稀释的IMM47于37℃培养4小时,hIgG-Fc用作阴性对照。之后向细胞培养液中加入碘化丙啶(PI)(Cat#P4170,Sigma),浓度5μg/ml,细胞经FACS分析PI信号。由ADCC造成的细胞裂解百分比基于以下公式进行计算:
%裂解=(%IMM47处理的PI阳性靶细胞-%阴性对照蛋白处理的PI阳性靶细胞)/(100-%阴性对照蛋白处理的PI阳性靶细胞)×100
如图6所示,对于表达人CD24的MC38-hCD24小鼠结肠癌细胞,IMM47引发显著水平的ADCC。
实施例7.CD24抗体在乳腺癌小鼠异种模型中显示出强劲的体内抗肿瘤活性
40只6-8周龄的SCID小鼠在癌细胞接种前3天,将β-雌二醇缓释药片(0.36mg)接种于每只小鼠的左后背。右前肢腋窝皮下注射MCF-7乳腺癌癌细胞,每只小鼠1x107个细胞。当肿瘤体积达到100-150mm3时,小鼠随机分成5组,每组8只小鼠,分组当天定义为D0。从这一天开始,各组小鼠分别腹膜注射PBS、IMM47C(2.5mg/kg)、IMM01(2.5mg/kg)、和IMM01+IMM47C(2.5mg/kg+2.5mg/kg),持续4周,每周2次。在4周后结束给药,持续观察1周后结束实验。每3-4天测量一次肿瘤体积和小鼠体重。当PBS组肿瘤平均体积达到3000mm3时,所有试验终止。
肿瘤体积(V)计算为(长×宽2)/2。TGI(%)=[1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100%。
测试的方案和结果总结在如下表1中。
表1.IMM47C和其他治疗剂的抗肿瘤效果
开始给药后第28天,溶剂对照组荷瘤鼠的瘤体积达到646.87mm3。与溶剂对照组相比,IMM47C处理组和IMM01处理组均延缓了肿瘤生长,这两组在第28天时的肿瘤体积分别为463.26mm3(T/C=71.60%,TGI=37.30%,p=0.009)和562.24mm3(T/C=86.92%,TGI=17.19%,p=0.375)。而IMM47C+IMM01联合组具有最佳的抑瘤作用,该组在第28天时的肿瘤体积为192.63mm3(T/C=29.81%,TGI=92.22%,p=0.001)。
从表1和图7可以看出,IMM47C和IMM01联合用药时产生协同效应,总体抑瘤效果比单独IMM47C或单独IMM01好得多。
实施例8.CD24抗体在结肠癌小鼠同种模型中显示出强劲的体内抗肿瘤活性
MC38-hCD24细胞培养在37℃、5%CO2的培养箱中,培养基为含10%灭活胎牛血清的DMEM培养基,细胞每隔3至4天长满即分皿传代。取对数生长期MC38-hCD24,重悬于PBS中,进行细胞计数,调整细胞浓度到1.0×107/mL,用1mL注射器将细胞悬液接种于30只B6-Siglec10雄性小鼠(Siglec10人源化B6小鼠)的右侧胁肋部皮下,100μL/只,每只接种约1.0×106个肿瘤细胞。当平均肿瘤体积达到约100mm3时,将动物按肿瘤体积随机分为3组,每组10只。分组日设为D0,从这天开始,对各组小鼠分别腹腔注射IMM47H(10mg/kg)、IMM47C(10mg/kg)和PBS,每周2次。连续给药4次后,每组随机选取7只小鼠于D18再次接种MC38-hCD24肿瘤细胞,用1mL注射器将细胞悬液接种于小鼠的左侧胁肋部皮下,100μL/只,每只接种约1.0×106个肿瘤细胞。一周2次监测前后两次接种肿瘤生长情况。根据动物福利标准,肿瘤超过3000mm3时需要将肿瘤进行安乐死。
肿瘤体积(V)计算为(长×宽2)/2。肿瘤体积抑制率TGI(%)=[1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100%
整个实验方案如图8B和表2所示。
表2.IMM47H和IMM47C治疗后肿瘤大小以及数据分析。
如表2和图8A-8B所示,荷瘤鼠经IMM47H和IMM47C药物给药4次后肿瘤完全清除,而PBS组肿瘤大小为969.92±143.93mm3;在D18再次接种肿瘤细胞后,在不继续给药的情况下,PBS组5/7只小鼠成瘤,IMM47H组和MM47C组未成瘤,空白对照组5只小鼠均成瘤。
以上结果表明,IMM47C和IMM47H在Siglec10人源化B6小鼠同源移植MC38-hCD24KI细胞瘤模型上体现了强大的抑制肿瘤生长,给药组二次接种肿瘤细胞均未有肿瘤形成,提示给药组小鼠可能具有获得性免疫应答。
实施例9.CD24抗体在结肠癌小鼠同种模型中显示出强劲的体内抗肿瘤活性
MC38-hCD24细胞培养在37℃、5%CO2的培养箱中,培养基为含10%灭活胎牛血清的DMEM培养基,细胞每隔3至4天长满即分皿传代。取对数生长期MC38-hCD24,重悬于PBS中,进行细胞计数,调整细胞浓度到1.0×107/mL,用1mL注射器将细胞悬液接种于24只B6-Siglec10雌性小鼠(Siglec10人源化B6小鼠)的右侧胁肋部皮下,100μL/只,每只接种约1.0×106个肿瘤细胞。当平均肿瘤体积达到约100mm3时,将动物按肿瘤体积随机分为4组,每组6只。分组日设为D0,从这天开始,各组小鼠分别腹腔注射IMM47(3mg/kg)、IMM47H(3mg/kg)、IMM47C(3mg/kg)和PBS,每周2次,连续4周。
由于在D21时有小鼠肿瘤大小超过了预设值,因此取D0-D21的数据进行做图和分析。
表3.IMM47、IMM47H和IMM47C治疗后肿瘤大小以及数据分析。
如表2和图9所示,IMM47、IMM47C和IMM47H在Siglec10人源化B6小鼠同源移植MC38-hCD24KI细胞瘤模型上体现了强大的抑制肿瘤生长。具体地,在3mg/kg剂量下,IMM47C处理组6只小鼠肿瘤完全清除,IMM47治疗组4只小鼠肿瘤完全清除,另外2只小鼠肿瘤生长缓慢,IMM47H治疗组5只小鼠肿瘤完全清除,1只小鼠肿瘤持续增长。
本申请的序列信息总结如下。
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。
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27.Orr AW,Pedraza CE,Pallero MA,Elzie CA,Goicoechea S,Strickland DK,Murphy-Ullrich JE.Low density lipoprotein receptor-related protein is acalreticulin coreceptor that signals focal adhesion disassembly.J CellBiol.2003,161:1179-1189.
28.Overdevest,J.B.,Thomas,S.,Kristiansen,G.,Hansel,D.E.,Smith,S.C.,and Theodorescu,D.(2011).CD24 offers a therapeutic target for control ofbladder cancer metastasis based on a requirement for lungcolonization.CancerRes 71(11),3802-11.
序列表
<110> 宜明昂科生物医药技术(上海)有限公司
<120> 靶向CD24的抗体及其制备和用途
<130> 55525 00044
<160> 23
<170> PatentIn版本3.5
<210> 1
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> IMM47C、IMM47和IMM47H抗体重链HV-CDR-1
<400> 1
Gly Tyr Ser Ile Thr Ser Gly Tyr Ser
1 5
<210> 2
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> IMM47C、IMM47和IMM47H抗体重链HV-CDR-2
<400> 2
Ile His Tyr Ser Gly Ser Thr
1 5
<210> 3
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> IMM47C、IMM47和IMM47H抗体重链HV-CDR-3
<400> 3
Ala Arg Gly Ala Asp Tyr Ala Leu Asp Tyr
1 5 10
<210> 4
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> IMM47C、IMM47和IMM47H抗体轻链LV-CDR-1
<400> 4
Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr
1 5 10
<210> 5
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> IMM47C、IMM47和IMM47H抗体轻链LV-CDR-2
<400> 5
Trp Ala Ser
1
<210> 6
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> IMM47C、IMM47和IMM47H抗体轻链LV-CDR-3
<400> 6
Gln Gln Asn Phe Ile Tyr Pro Leu Thr
1 5
<210> 7
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> IMM47C和IMM47抗体重链可变区
<400> 7
Asp Val Gln Leu Gln Glu Ser Gly Pro Asp Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Gly
20 25 30
Tyr Ser Trp His Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile His Tyr Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Gly Ala Asp Tyr Ala Leu Asp Tyr Trp Gly Gln Arg Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 8
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> IMM47C抗体轻链可变区
<400> 8
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly His
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Asn Phe Ile Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 9
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> IMM47抗体轻链可变区
<400> 9
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 Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Asn Phe Ile Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Leu
100 105 110
Lys
<210> 10
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> IMM47H抗体重链可变区
<400> 10
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Gly
20 25 30
Tyr Ser Trp His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile His Tyr Ser Gly Ser Thr Lys Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Asp Tyr Ala Leu Asp Tyr Trp Gly Gln Arg Thr Ser
100 105 110
Val Thr Val Ser Ser
115
<210> 11
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> IMM47H抗体轻链可变区
<400> 11
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Asn Phe Ile Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Leu
100 105 110
Lys
<210> 12
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 重链恒定区
<400> 12
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> 13
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 轻链恒定区
<400> 13
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> 14
<211> 1398
<212> DNA
<213> 人工序列
<220>
<223> IMM47C和IMM47抗体重链的核酸序列
<400> 14
atgagagtgc tgattctttt gtgcctgttc acagcctttc ctggtatcct gtctgatgtg 60
cagcttcagg agtcaggacc tgacctggtg aaaccttctc agtcactttc actcacctgc 120
actgtcactg gctactccat caccagtggt tatagctggc actggatccg gcagtttcca 180
ggaaacaaac tggaatggat gggctacata cactatagtg gtagcactaa gtacaaccca 240
tctctcaaaa gtcgaatctc tatcactcga gacacatcca agaaccagtt cttcctgcag 300
ttgaattctg tgactactga ggacacagcc acatatttct gtgcaagagg cgcggactat 360
gctttggact actggggtca acgaacctca gtcaccgtct cctcagctag caccaagggc 420
ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 480
ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 540
ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 600
agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 660
aatcacaagc ccagcaacac caaggtggac aagagagttg agcccaaatc ttgtgacaaa 720
actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 780
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 840
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtatgt ggacggcgtg 900
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacgccac gtaccgtgtg 960
gtcagcgtcc tcaccgtcct gcaccaagac tggctgaatg gcaaggagta caagtgcaag 1020
gtctccaaca aagccctccc agcccccatc gccgcaacca tctccaaagc caaagggcag 1080
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccaa 1140
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1200
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1260
tccttcttcc tctattccaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1320
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1380
ctgtctccgg gcaaatga 1398
<210> 15
<211> 862
<212> DNA
<213> 人工序列
<220>
<223> IMM47C抗体轻链的核酸序列
<400> 15
atggattcac aggcccaggt tcttatgtta ctgctgctat gggtatctgg tacctgtggg 60
gacattgtga tgtcacagtc tccatcctcc ctagctgtgt cagttggaga gaaggttact 120
atgagctgca agtccagtca gagcctttta tatagtagca atcaaaagaa ctacttggcc 180
tggtaccagc agaaaccagg gcactctcct aaactgctga tttactgggc atccactagg 240
gaatctgggg tccctgatcg cttcacaggc agtggatctg ggacagattt cactctcacc 300
atcagcagtg tgaaggctga agacctggca gtttattact gtcagcaaaa ttttatctat 360
ccgctcacgt tcggtgctgg gaccaagctg gagctgaaac gtgagttcta gaggatccat 420
ctgggataag catgctgttt tctgtctgtc cctaacatgc cctgtgatta tccgcaaaca 480
acacacccaa gggcagaact ttgttactta aacaccatcc tgtttgcttc tttcctcagg 540
aactgtggct gcaccatctg tcttcatctt cccgccatct gatgagcagt tgaaatctgg 600
aactgcctct gttgtgtgcc tgctgaataa cttctatccc agagaggcca aagtacagtg 660
gaaggtggat aacgccctcc aatcgggtaa ctcccaggag agtgtcacag agcaggacag 720
caaggacagc acctacagcc tcagcagcac cctgacgctg agcaaagcag actacgagaa 780
acacaaagtc tacgcctgcg aagtcaccca tcagggcctg agctcgcccg tcacaaagag 840
cttcaacagg ggagagtgtt ag 862
<210> 16
<211> 859
<212> DNA
<213> 人工序列
<220>
<223> IMM47抗体轻链的核酸序列
<400> 16
atgggatggt catgtatcat cctttttctg gtagcaactg caactggagt acattcagac 60
attcagatga cacagagccc tagcagcctg agcgcctccg tgggcgacag agtgaccatc 120
acctgcaaga gcagccaaag cctgctgtac agcagcaatc agaagaacta cctggcctgg 180
tatcagcaga agcctggcaa ggcccctaag ctgctgatct actgggcctc cacaagagag 240
agcggcgtgc ctagcagatt cagcggcagc ggcagcggca ccgacttcac cctgaccatc 300
agcagcctgc agcctgagga cttcgccacc tactactgtc agcagaactt catctaccct 360
ctgaccttcg gcggaggcac caaggtggag ctgaagcgtg agttctagag gatccatctg 420
ggataagcat gctgttttct gtctgtccct aacatgccct gtgattatcc gcaaacaaca 480
cacccaaggg cagaactttg ttacttaaac accatcctgt ttgcttcttt cctcaggaac 540
tgtggctgca ccatctgtct tcatcttccc gccatctgat gagcagttga aatctggaac 600
tgcctctgtt gtgtgcctgc tgaataactt ctatcccaga gaggccaaag tacagtggaa 660
ggtggataac gccctccaat cgggtaactc ccaggagagt gtcacagagc aggacagcaa 720
ggacagcacc tacagcctca gcagcaccct gacgctgagc aaagcagact acgagaaaca 780
caaagtctac gcctgcgaag tcacccatca gggcctgagc tcgcccgtca caaagagctt 840
caacagggga gagtgttag 859
<210> 17
<211> 1401
<212> DNA
<213> 人工序列
<220>
<223> IMM47H抗体重链的核酸序列
<400> 17
atgggatggt catgtatcat cctttttctg gtagcaactg caactggagt acattcagac 60
gtgcagctgc aagagagcgg ccctggcctg gtgaagccta gcgagaccct gagcctgacc 120
tgcaccgtgt ccggctacag catcacaagc ggctacagct ggcactggat cagacagcct 180
cctggcaagg gcctggagtg gatcggctac atccactaca gcggcagcac caagtacaac 240
cctagcctga agagcagagt gaccatcagc gtggacacaa gcaagaatca gttcagcctg 300
aagctgagca gcgtgaccgc cgccgacacc gccgtgtact actgcgctag aggcgccgac 360
tacgccctgg actactgggg acagagaaca agcgtgaccg tgagcagcgc tagcaccaag 420
ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg cacagcggcc 480
ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 540
gccctgacca gcggcgtgca caccttcccg gctgtcctac agtcctcagg actctactcc 600
ctcagcagcg tggtgaccgt gccctccagc agcttgggca cccagaccta catctgcaac 660
gtgaatcaca agcccagcaa caccaaggtg gacaagagag ttgagcccaa atcttgtgac 720
aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 780
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 840
gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta tgtggacggc 900
gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacgc cacgtaccgt 960
gtggtcagcg tcctcaccgt cctgcaccaa gactggctga atggcaagga gtacaagtgc 1020
aaggtctcca acaaagccct cccagccccc atcgccgcaa ccatctccaa agccaaaggg 1080
cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 1140
caagtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 1200
gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 1260
ggctccttct tcctctattc caagctcacc gtggacaaga gcaggtggca gcaggggaac 1320
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1380
tccctgtctc cgggcaaatg a 1401
<210> 18
<211> 859
<212> DNA
<213> 人工序列
<220>
<223> IMM47H抗体轻的核酸序列
<400> 18
atgggatggt catgtatcat cctttttctg gtagcaactg caactggagt acattcagac 60
atcgtgatga cacagagccc tgacagcctg gccgtgagcc tgggcgagag agccaccatc 120
aactgcaaga gctctcagag cctgctgtac agcagcaatc agaagaacta cctggcctgg 180
tatcagcaga agcctggaca gcctcctaag ctgctgatct actgggcaag cacaagagag 240
agcggcgtgc ctgacagatt cagcggcagc ggcagcggca ccgacttcac cctgaccatc 300
agcagcctgc aagccgagga cgtggccgtg tactactgtc agcagaactt catctaccct 360
ctgaccttcg gcggcggcac caaggtggag ctgaagcgtg agttctagag gatccatctg 420
ggataagcat gctgttttct gtctgtccct aacatgccct gtgattatcc gcaaacaaca 480
cacccaaggg cagaactttg ttacttaaac accatcctgt ttgcttcttt cctcaggaac 540
tgtggctgca ccatctgtct tcatcttccc gccatctgat gagcagttga aatctggaac 600
tgcctctgtt gtgtgcctgc tgaataactt ctatcccaga gaggccaaag tacagtggaa 660
ggtggataac gccctccaat cgggtaactc ccaggagagt gtcacagagc aggacagcaa 720
ggacagcacc tacagcctca gcagcaccct gacgctgagc aaagcagact acgagaaaca 780
caaagtctac gcctgcgaag tcacccatca gggcctgagc tcgcccgtca caaagagctt 840
caacagggga gagtgttag 859
<210> 19
<211> 364
<212> PRT
<213> 人工序列
<220>
<223> SIRPαD1突变体-Fc(IMM01)
<400> 19
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> 20
<211> 1095
<212> DNA
<213> 人工序列
<220>
<223> SIRPαD1突变体-Fc(IMM01)
<400> 20
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> 21
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 小鼠IgG1重链信号肽的核酸序列
<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> 597
<212> PRT
<213> 人工序列
<220>
<223> 人SIRPα-鼠IgG1 Fc
<400> 23
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
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Val His Ser Ser Cys Ala Trp Ser Gly Val Ala Gly Glu Glu Glu Leu
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Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala Ala Gly Glu Ser
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Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro Val Gly Pro Ile
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Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu Ile Tyr Asn Gln
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Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys Gly Ser Pro Asp
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Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser Val Arg Ala Lys
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Pro Ser Ala Pro Val Val Ser Gly Pro Ala Ala Arg Ala Thr Pro Gln
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His Thr Val Ser Phe Thr Cys Glu Ser His Gly Phe Ser Pro Arg Asp
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Ile Thr Leu Lys Trp Phe Lys Asn Gly Asn Glu Leu Ser Asp Phe Gln
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Thr Asn Val Asp Pro Val Gly Glu Ser Val Ser Tyr Ser Ile His Ser
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Gln Gln Pro Val Arg Ala Glu Asn Gln Val Asn Val Thr Cys Gln Val
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His Ser Pro Gly Lys
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Claims (14)
1.一种分离的单克隆抗体或其抗原结合部分,与CD24结合,包含重链可变区和轻链可变区,该重链可变区包含HV-CDR1区、HV-CDR2区和HV-CDR3区,该轻链可变区包含LV-CDR1区、LV-CDR2区和LV-CDR3区,其中HV-CDR1区、HV-CDR2区、HV-CDR3区、LV-CDR1区、LV-CDR2区和LV-CDR3区的氨基酸序列分别如SEQ ID NOs:1、2、3、4、5和6所示。
2.根据权利要求1所述的分离的单克隆抗体或其抗原结合部分,其中所述重链可变区包含SEQ ID NOs:7或10所示的氨基酸序列。
3.根据权利要求1所述的分离的单克隆抗体或其抗原结合部分,其中所述轻链可变区包含SEQ ID NOs:8、9或11所示的氨基酸序列。
4.根据权利要求2所述的分离的单克隆抗体或其抗原结合部分,其中所述重链可变区和所述轻链可变区分别包含i)SEQ ID NOs:7和8;ii)SEQ ID NOs:7和9;或iii)SEQ IDNOs:10和11所示的氨基酸序列。
5.根据权利要求1所述的分离的单克隆抗体或其抗原结合部分,其为IgG1、IgG2、或IgG4亚型。
6.根据权利要求1所述的分离的单克隆抗体或其抗原结合部分,包含重链恒定区和轻链恒定区,其中所述重链恒定区和轻链恒定区分别包含如SEQ ID NOs:12和13所示的氨基酸序列。
7.根据权利要求1所述的分离的单克隆抗体或其抗原结合部分,其为鼠源、嵌合或人源化抗体。
8.一种核酸分子,其编码权利要求1-7中任一项所述的分离的单克隆抗体或其抗原结合部分。
9.一种表达载体,其包含权利要求8所述的核酸分子。
10.一种宿主细胞,其包含权利要求9所述的表达载体。
11.一种药物组合物,其包含权利要求1-7中任一项所述的分离的单克隆抗体或其抗原结合部分、权利要求8所述的核酸分子、权利要求9所述的表达载体、或权利要求10所述的宿主细胞,以及至少一种药学上可接受的载体。
12.权利要求11所述的药物组合物在制备用于治疗与CD24过表达相关的疾病的药物中的用途。
13.根据权利要求12所述的用途,其中所述疾病选自卵巢癌、乳腺癌、宫颈癌、子宫内膜癌、急性淋巴细胞白血病(ALL)、胆管癌、膀胱癌、胰腺癌、胃腺癌、胶质母细胞瘤、和结肠癌。
14.根据权利要求12所述的用途,其中所述疾病选自急性移植物抗宿主病、抗艾滋鸡尾酒疗法引起的炎症、风湿性关节炎、系统性红斑狼疮、代谢相关脂肪性肝病、糖尿病、多发性硬化症、和败血症。
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CN202111195246.5A CN113831412B (zh) | 2021-10-13 | 2021-10-13 | 靶向cd24的抗体及其制备和用途 |
JP2022019864A JP7355977B2 (ja) | 2021-10-13 | 2022-02-10 | Cd24に結合する抗体、その調製および使用 |
EP22156295.2A EP4166196A1 (en) | 2021-10-13 | 2022-02-11 | Antibodies binding cd24, preparation and use thereof |
US17/685,530 US11926675B2 (en) | 2021-10-13 | 2022-03-03 | Antibodies binding CD24, preparation and use thereof |
PCT/CN2022/114945 WO2023061064A1 (zh) | 2021-10-13 | 2022-08-25 | 靶向cd24的抗体及其制备和用途 |
KR1020247015860A KR20240082409A (ko) | 2021-10-13 | 2022-08-25 | Cd24를 표적화하는 항체와 이의 제조 및 용도 |
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US11926675B2 (en) | 2024-03-12 |
US20230110607A1 (en) | 2023-04-13 |
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