CN117355322A - 人源化mAb107 - Google Patents
人源化mAb107 Download PDFInfo
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- CN117355322A CN117355322A CN202280037583.8A CN202280037583A CN117355322A CN 117355322 A CN117355322 A CN 117355322A CN 202280037583 A CN202280037583 A CN 202280037583A CN 117355322 A CN117355322 A CN 117355322A
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Abstract
本文描述了以增强的亲和力与白细胞整合素CD11b/CD18(CD11b、αMβ2、CR3)结合的人源化抗体、及其使用方法。
Description
优先权声明
本申请要求2021年3月26日提交的美国临时专利申请系列号63/166,711的权益。前述文献的完整内容通过引用并入本文。
联邦资助的研究或开发
本发明借助美国政府支持在美国国立卫生研究院授予的授权号DK48549下做出。美国政府享有本发明的一定的权利。
关于序列表的声明
本文件包含序列表,所述序列表已作为命名为序列表的ASCII文本文件电子提交。创建于2022年3月24日的所述ASCII文本文件的大小为21.4千字节。所述ASCII文本文件中的资料以其整体通过引用并入本文。
技术领域
本文描述了以增强的亲和力与白细胞整合素CD11b/CD18(CD11b、αMβ2、CR3)结合的人源化抗体、及其使用方法。
背景技术
白细胞整合素CD11b/CD18(也称为CD11b、αMβ2、CR3,本文中称作CD11b)是在先天免疫细胞上表达的原型先天免疫受体。CD11b结合超过40种配体,由此介导白细胞黏附-依赖性功能,包括归巢、吞噬、黏附-依赖性超氧化物产生、蛋白水解酶和细胞因子产生、抗体-依赖性细胞溶解活性,并增强适应性免疫(Arnaout,F1000Res.2016Oct 4;5:F1000Faculty Rev-2433;van den Elsen等人,Science(2011)332:608-1;Bajic等人,Proc NatlAcad Sci USA.(2013)110:16426-31)。例如ICAM-1、补体iC3b和纤维蛋白原等生理学配体与CD11b的结合诱导CD11b中激活的三级和四级变化,导致促黏附(proadhesive)细胞信号传导。现在确定,使这种激活的促炎状态稳定化的现有抗整合素药剂可以在人体中造成未从啮齿类动物研究中预测到的严重不良后果(Raab-Westphal等人,Cancers(Basel).2017Aug 23;9(9):110)。
发明内容
本文提供了与CD11b结合的抗体或其抗原结合片段、及其使用方法。在一些实施方案中,所述抗体或其抗原结合片段包括包含以下互补决定区(CDR)的氨基酸序列:
1)SEQ ID NO:1的VH的CDR 1,例如,GFNIKD(SEQ ID NO:5);
2)SEQ ID NO:2的VL的CDR 1,例如,SQNLLYSSNQKNY(SEQ ID NO:8);
3)SEQ ID NO:1的VH的CDR 2,例如,PADDKTK(SEQ ID NO:6);
4)SEQ ID NO:2的VL的CDR 2,例如,WASTRESGVPDR(SEQ ID NO:9);
5)SEQ ID NO:1的VH的CDR 3,例如,GHYGYDGYA(SEQ ID NO:7);和
6)SEQ ID NO:2的VL的CDR 3,例如,YYSYPL(SEQ ID NO:10)。
在一些实施方案中,所述抗体或其抗原结合片段包括包含VH CDR 1、2、3的重链可变区和包含VL CDR 1、2、3的轻链可变区,其中所述VH CDR 1、2、3与SEQ ID NO:1中的互补决定区相同,和所述VL CDR 1、2、3与SEQ ID NO:2中的互补决定区的相同。
在一些实施方案中,所述抗体或其抗原结合片段包括包含与选自由以下组成的组中的氨基酸序列为至少95%同一性的氨基酸序列的氨基酸序列:
和
前提是未改变序列的互补决定区。
在一些实施方案中,所述抗体或其抗原结合片段包括单链可变片段(scFv)。在一些实施方案中,所述抗体或其抗原结合片段包括SEQ ID NO:15。
此外,本文提供了包含如本文所述的抗体或其抗原结合片段和药学上可接受的载体的组合物。
本文还提供了用于改善受试者中与缺血再灌注损伤相关的病变的方法。所述方法包括向受试者施用包含治疗有效量的如本文所述的抗体或其抗原结合片段的组合物。
在一些实施方案中,所述病变是缺血后肾纤维化。
在一些实施方案中,所述病变是肾纤维炎性疾病。
在一些实施方案中,所述病变是肺纤维化。
在一些实施方案中,所述病变是心肌梗死后左心室不良重塑。
在一些实施方案中,在缺血再灌注损伤后约5小时内向受试者施用组合物。
在一些实施方案中,在缺血再灌注损伤后约2小时内向受试者施用组合物。
本文还提供了用于治疗患有与器官中缺血再灌注损伤相关的病症或处于发展所述病症的风险的受试者的方法。所述方法包括向受试者施用包含治疗有效量的如本文所述的抗体或其抗原结合片段的组合物。
在一些实施方案中,所述器官是肾脏。在一些实施方案中,所述病症是急性肾损伤。
在一些实施方案中,所述器官是心脏。在一些实施方案中,所述病症是急性冠状动脉综合征。在一些实施方案中,所述病症是急性心肌梗死(MI)。
在一些实施方案中,所述器官是肺。
在一些实施方案中,在缺血再灌注损伤后约5小时内向受试者施用组合物。
在一些实施方案中,在缺血再灌注损伤后约2小时内向受试者施用组合物。
此外,本文提供了用于提供用于移植的器官的方法。所述方法包括向器官供体施用包含如本文所述的抗体或其抗原结合片段的组合物;和从器官供体收获器官。
在一些实施方案中,所述器官是肾脏、心脏或肺。
本文还提供了用于减少器官移植后移植物功能延迟恢复的方法。所述方法包括在移植器官至接受者之前或在移植当日内,向器官接受者施用治疗有效量的包含如本文所述的抗体或其抗原结合片段的组合物,从而减少器官移植后移植物功能延迟恢复。
在一些实施方案中,所述器官是肾脏、心脏或肺。
此外,本文提供了用于在移植至接受者之前处理器官的方法。所述方法包括使器官与包含如本文所述的抗体或其抗原结合片段的组合物接触。
在一些实施方案中,所述器官是肾脏、心脏或肺。
在一些实施方案中,接触步骤包括用包含多肽或抗体的组合物灌注器官,所述多肽或抗体免疫特异性地结合由mab107识别的表位。
此外,本文提供了用于治疗患有自身免疫性疾病的受试者的方法,所述方法包括向受试者施用治疗有效量的包含如本文所述的抗体或其抗原结合片段的组合物。
在一些实施方案中,所述自身免疫性疾病是胞浆抗中性粒细胞胞浆抗体(cANCA)相关性血管炎。
本文还提供了用于治疗患有糖尿病肾病的受试者的方法,所述方法包括向受试者施用治疗有效量的包含如本文所述的抗体或其抗原结合片段的组合物。
本文还提供了用于改善受试者中与化学疗法相关的病变的方法,所述方法包括向受试者施用治疗有效量的包含如本文所述的抗体或抗原结合片段的组合物。在一些实施方案中,所述病变是阿霉素肾病。
除非另有定义,否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常所理解的相同的含义。本文描述了用于本发明的方法和材料;也可以使用本领域已知的其它的合适的方法和材料。材料、方法和实例仅是说明性的,而不旨在进行限制。本文提及的所有出版物、专利申请、专利、序列、数据库条目和其它参考文献都以其整体通过引用并入本文。在冲突的情况下,本说明书(包括定义)将占主导。
本发明的其它特征和优点将从以下详细描述和附图、以及从权利要求显而易见。
附图说明
图1.SDS-PAGE的考马斯(Coomassie)染色,显示出突变成在其CDR2重链中携带新的Asn257/Asp取代的小鼠mAb107和人源化IgG4κmAb107在非还原性(左图)和还原性(右图)条件下的迁移。
图2.SDS-PAGE的考马斯染色,显示出在IgG4的核铰链区中含有野生型Ser228(S)或Pro228(P)的人源化IgG4κmAb107在还原性(左图)或非还原性(右图)条件下的迁移。这种取代减少了对应于已知Fab臂交换(这导致具有未知特异性并因此潜在地降低治疗功效的功能上单价的、双特异性抗体)的条带(Silva等人,J Biol Chem.2015Feb 27;290(9):5462-9)。MW标准品(以kDa计)示于染色凝胶的泳道1。
具体实施方式
以下段落提供了某些定义以提供说明书和权利要求的更清晰和一致的理解。
约:在本文中用于提及数值时,术语“约”是指在所提及的值的语境下相似的值。通常,熟悉该语境的本领域技术人员将理解在该语境中由“约”涵盖的相关变化程度。例如,在一些实施方案中,术语“约”可以涵盖在所提及值的25%、20%、19%、18%、17%、16%、15%、14%、13%、12%、11%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%或更小以内的一系列的值。
施用:如本文所用,术语“施用”通常是指向受试者或系统施用组合物以实现作为组合物的药剂或包含在组合物中的药剂的递送。本领域普通技术人员将知晓在适当的情况下可以用于施用至例如人等受试者的多种途径。例如,在一些实施方案中,施用可以是眼、口、肠胃外、局部的等。在一些具体实施方案中,施用可以是支气管(例如,通过支气管滴注)、颊、皮肤(可以是例如局部至真皮、皮内、皮间、经皮等中的一者或更多者,或包括例如局部至真皮、皮内、皮间、经皮等中的一者或更多者)、肠、动脉内、真皮内、胃内、髓内、肌内、鼻内、腹膜内、鞘内、静脉内、心室内、特定器官内(例如肝内)、粘膜、鼻、口、直肠、皮下、舌下、局部、气管(例如,通过气管内滴注)、阴道、玻璃体的等。在一些实施方案中,施用可以仅涉及单个剂量。在一些实施方案中,施用可以涉及施加固定数量的剂量。在一些实施方案中,施用可以涉及作为间歇性(例如,按时间分隔的多个剂量)和/或周期性(例如,由共同时间段分隔的各个剂量)给药的给药。在一些实施方案中,施用可以涉及连续给药(例如,灌注)持续至少选择的时间段。
亲和力:如本领域已知,“亲和力”是特定配体与其配偶体结合的紧密度的度量。亲和力可以以不同的方式测量。在一些实施方案中,亲和力通过定量测定来测量的。在一些此类实施方案中,结合配偶体浓度可以固定为超过配体浓度,从而模仿生理条件。可选地或另外地,在一些实施方案中,可以改变结合配偶体浓度和/或配体浓度。在一些此类实施方案中,可以将亲和力与类似条件(例如浓度)下的参照相比较。
动物:如本文所用,是指动物界的任何成员。在一些实施方案中,“动物”是指任一性别和处于任何发育阶段的人。在一些实施方案中,“动物”是指处于任何发育阶段的非人动物。在某些实施方案中,非人动物是哺乳动物(例如,啮齿类动物、小鼠、大鼠、兔、猴、犬、猫、羊、牛、灵长类动物、和/或猪)。在一些实施方案中,动物包括但不限于哺乳动物、鸟、爬行类动物、两栖类动物、鱼、昆虫、和/或蠕虫。在一些实施方案中,动物可以是转基因动物、基因工程化动物、和/或克隆。
结合:将理解,如本文所用,术语“结合”通常是指两个或更多个实体之间或其中的非共价缔合。“直接”结合涉及实体或部分之间的物理接触;间接结合涉及借助于与一个或更多个中间实体的物理接触的物理相互作用。两个或更多个实体之间的结合通常可以在任何的各种背景下进行评价-包括单独地研究相互作用的实体或部分、或者在更复杂的系统的背景中(例如,在与载体实体共价或以其它方式结合的同时和/或在生物系统或细胞中)研究相互作用的实体或部分。
CDR:如本文所用,是指抗体可变区内的互补决定区。在重链和轻链的每个可变区中有三个CDR,它们相对于每个可变区被命名为CDR1、CDR2和CDR3。“成套CDR”或“CDR集合”是指一组三个或六个CDR,其出现在能够结合抗原的单一可变区或者能够结合抗原的同源重链和轻链可变区的CDR中。本领域已经发表了限定CDR边界的某些体系(例如,Kabat、Chothia等);本领域技术人员领会这些体系之间和其中的差异,并且能够理解CDR边界至理解和实施要求保护的发明所必需的程度。
表位:如本文所用,包括由免疫球蛋白(例如,抗体或受体)结合组分特异性识别的任何部分。在一些实施方案中,表位由抗原上的多个化学原子或基团构成。在一些实施方案中,当抗原采取相关三维构象时,此类化学原子或基团是表面暴露的。在一些实施方案中,当抗原采取这样的构象时,此类化学原子或基团是空间上彼此物理靠近的。在一些实施方案中,当抗原采取备选构象(alternative conformation)(例如,线性化)时,至少一些此类化学原子是彼此物理上分离的基团。
人源化:如本领域已知,术语“人源化”常用于指代抗体(或抗体组分),其氨基酸序列包含来自在非人物种(例如,小鼠)中生成的参照抗体的VH和VL区序列,但相对于参照抗体,在这些序列中还包括旨在使它们更“像人”、即更类似于人种系可变序列的修饰。在一些实施方案中,“人源化”抗体(或抗体组分)是与感兴趣的抗原免疫特异性结合,并且具有框架(FR)区和互补决定区(CDR)的“人源化”抗体(或抗体组分),其中所述框架区基本上具有如人抗体那样的氨基酸序列,所述互补性决定区基本上具有如非人抗体那样的氨基酸序列。人源化抗体包含基本上全部的至少一个、和通常两个可变结构域(Fab、Fab'、F(ab')2、FabC、Fv),其中全部或基本上全部的CDR区对应于非人免疫球蛋白(即,供者免疫球蛋白)的那些,并且全部或基本上全部的框架区是人免疫球蛋白共有序列的那些。在一些实施方案中,人源化抗体还包括至少一部分的免疫球蛋白恒定区(Fc)、通常是人免疫球蛋白恒定区。在一些实施方案中,人源化抗体包含轻链以及至少重链的可变结构域。抗体还可以包括重链恒定区的CH1、铰链、CH2、CH3、和任选地CH4区。
多肽:如本文所用,术语“多肽”通常具有本领域公认的含义,即至少三个氨基酸的聚合物。本领域普通技术人员将理解,术语“多肽”旨在足够通用以不仅涵盖具有本文引用的完整序列的多肽,还涵盖代表此类完整多肽的功能性片段(即,保留至少一种活性的片段)的多肽。另外,本领域普通技术人员理解,蛋白质序列通常在不破坏活性的情况下容忍一些取代。因此,保留活性并且与同类别的另一多肽共有至少约30-40%总序列同一性,通常大于约50%、60%、70%、或80%,并且通常还在一个或更多个高度保守的区域中包含至少一个同一性高得多的区域,通常大于90%或甚至95%、96%、97%、98%或99%,通常涵盖至少3-4个和往往多达20个或更多个氨基酸的任何多肽,涵盖在如本文所用的相关术语“多肽”内。多肽可以包含L-氨基酸、D-氨基酸或这两者,并且可以包含任何本领域已知的各种氨基酸修饰或类似物。有用的修饰包括例如末端乙酰化、酰胺化、甲基化等。在一些实施方案中,蛋白质可以包括天然氨基酸、非天然氨基酸、合成氨基酸、及其组合。术语“肽”通常用于指代长度小于约100个氨基酸、小于约50个氨基酸、小于20个氨基酸、或小于10个氨基酸的多肽。在一些实施方案中,蛋白质是抗体、抗体片段、其生物学活性部分、和/或其特征性部分。
防止:如本文所用,当与疾病、病症、和/或病况的发生关联使用时,是指降低发展疾病、病症、和/或病况的风险和/或延迟疾病、病症或病况的一个或更多个特征或症状的发作和/或严重程度。在一些实施方案中,防止是以群体为基准进行评价的,使得如果在易感于疾病、病症或病况的群体中观察到该疾病、病症或病况的一个或更多个症状的发展、频率和/或强度的统计学显著的减少,则认为药剂“防止”特定疾病、疾病或病况。
重组:如本文所用,旨在指代通过重组手段设计、工程化、制备、表达、产生、制造和/或分离的多肽,例如使用转染至宿主细胞中的重组表达载体表达的多肽;从重组、组合人多肽文库分离的多肽;从动物(例如,小鼠、兔、羊、鱼等)分离的多肽,所述动物经转基因或以其它方式已被操作以表达一个或更多个基因或基因组分,其编码多肽或其一个或更多个组分、部分、元件、或结构域和/或指导其所述多肽或其一个或更多个组分、部分、元件、或结构域的表达;和/或通过任何其它手段制备、表达、产生或分离的多肽,所述任何其它手段涉及所选核酸序列元件彼此的剪接或连接、化学合成选定的序列元件、和/或以其它方式产生编码多肽或其一个或更多个组分、部分、元件或结构域和/或指导多肽或其一个或更多个组分、部分、元件或结构域的表达的核酸。在一些实施方案中,一个或更多个这样的选定的序列元件在自然界中存在。在一些实施方案中,一个或更多个这样的选定的序列元件是在计算机中设计的。在一些实施方案中,一种或更多个这样的选定的序列元件是由已知序列元件的诱变(例如,在体内或体外)产生的,所述已知序列元件例如来自天然来源或合成来源诸如,例如在感兴趣的来源生物(例如,人,小鼠等)的种系中。
治疗有效量:如本文所用,术语“治疗有效量”是指在根据治疗性给药方案施用至患有或易感于疾病、病症和/或病况的群体时足以治疗所述疾病、病症、和/或病况的量。在一些实施方案中,治疗有效量是减少所述疾病、病症和/或病况的一个或更多个症状的发生率和/或严重程度、使其一个或更多个特征稳定化、和/或延迟其发作的量。本领域普通技术人员将理解,术语“治疗有效量”并不实际上要求应在具体个体中实现成功的治疗。反而,治疗有效量可以是在施用至有此类治疗需要的患者时,在显著数量的受试者中提供特定的期望的药理学应答的量。本领域普通技术人员将理解,在一些实施方案中,治疗有效量可以按单个剂量配制和/或施用。在一些实施方案中,治疗有效量可以按多个剂量配制和/或施用,例如,作为给药方案的一部分。
载体:如本文所用,是指能够运输已经与之连接的另一核酸的核酸分子。一种类型的载体是“质粒”,其是指可以向其连接额外的DNA区段的环状双链DNA环。另一类型的载体是病毒载体,其中可以将额外的DNA区段连接至病毒基因组中。某些载体能够在引入它们的宿主细胞中自主复制(例如,具有细菌复制起点的细菌载体和附加体型(episomal)哺乳动物载体)。其它载体(例如非附加体型哺乳动物载体)可以在引入宿主细胞时整合到宿主细胞的基因组中,从而与宿主基因组一起复制。另外,某些载体能够指导与它们可操作地连接的基因的表达。此类载体在本文中被称作“表达载体”。标准技术可以用于重组DNA、寡核苷酸合成和组织培养和转化(例如,电穿孔、脂质体转染)。酶促反应和纯化技术可以根据生产商的说明书或者如本领域中通常完成的或者如本文所述的那样进行。前述技术和方法通常可以根据本领域熟知的和如本说明书通篇引用和讨论的各种一般参考文献和更具体的参考文献中所述的常规方法进行。参见,例如,Sambrook等人,Molecular Cloning:ALaboratory Manual(第2版,Cold Spring Harbor Laboratory Press,Cold SpringHarbor,N.Y.(1989)),其通过引用并入本文用于任何目的。
本公开的抗体
本公开的抗体包括人源化形式的mAb107,如实施例中所述。在一些实施方案中,本公开的抗体是抗CD11b抗体、或其片段。在一些实施方案中,本公开的抗体是重组抗体。在一些实施方案中,本公开的抗CD11b抗体包括1、2或3个重链CDR序列,所述序列是SEQ ID NOs:5、6、和/或7的序列或者包含SEQ ID NOs:5、6、和/或7的序列。在一些实施方案中,本公开的抗CD11b抗体包括1、2或3个轻链CDR序列,所述序列是SEQ ID NOs:8、9、和/或10的序列或者包含SEQ ID NOs:8、9、和/或10的序列。在一些实施方案中,人源化形式的mAb107或其结合抗原的抗体片段包含一个或更多个包括SEQ ID NOs:1-18的序列。在一些实施方案中,人源化形式的mAb107或其结合抗原的抗体片段包含与SEQ ID NOs:1-18为至少95%、96%、97%、98%、99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%、或99.9%同一性的序列。
本公开的人源化形式的mAb107抗体或抗原结合片段的氨基酸序列可以通过保守取代来取代。本文所用的术语“保守取代”是指其中一个或更多个氨基酸被具有类似生物化学性质的氨基酸取代,从而不造成相应多肽的生物学或生物化学功能的损失的多肽的修饰。本文所用的术语“保守序列变体”或“保守氨基酸取代”是氨基酸残基被具有类似侧链的氨基酸残基取代。本领域定义了具有类似侧链的氨基酸残基。这些残基涵盖具有碱性侧链的氨基酸(例如,赖氨酸、精氨酸和组氨酸)、具有酸性侧链的氨基酸(例如,天冬氨酸和谷氨酸)、具有不带电荷极性侧链的氨基酸(例如,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、和半胱氨酸)、具有非极性侧链的氨基酸(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、和色氨酸)、具有β分支侧链的氨基酸(例如,苏氨酸、缬氨酸和异亮氨酸)和具有芳族侧链的氨基酸(例如,酪氨酸、苯丙氨酸、色氨酸和组氨酸)。因此,预期本发明的抗体可以具有保守氨基酸取代,并且仍确保活性。
在一些实施方案中,本公开提供包含编码人源化形式的mAb107及其片段的核苷酸序列的多核苷酸。因此,可以使用本领域已知的分子生物学方法从核酸分子产生人源化形式的mAb107抗体和片段。本公开的核酸包括例如DNA和/或RNA。
本公开的核酸构建体可以通过本领域已知的方法插入至表达载体或病毒载体中,并且核酸分子可以与表达控制序列可操作地连接。本公开进一步提供包括任何上述核酸分子、或其片段的载体。任何上述核酸分子或其片段可以被克隆至任何合适的载体中,并且可以用于转化或转染任何合适的宿主。载体的选择和构建它们的方法是本领域普通技术人员公知的并且描述于通用技术参考文献(通常参见,"Recombinant DNAPart D,”Methods inEnzymology,第153卷,Wu和Grossman编,Academic Press(1987))。
在一些实施方案中,常规使用的技术,诸如例如电泳、磷酸钙沉淀、DEAE-葡聚糖转染、脂质体转染等可以用于将外来核酸(DNA或RNA)引入至原核或真核宿主细胞。期望地,载体可以包括调控序列,例如转录和翻译起始和终止密码子,根据需要并且考虑载体是否为DNA或RNA,所述调控序列对载体将要引入其中的宿主的类型(例如,细菌、真菌、植物或动物)为特异性的。在一些实施方案中,载体包含对宿主的属(genus)为特异性的调控序列。优选地,载体包含对宿主的物种为特异性的调控序列。
合适的病毒载体包括例如逆转录病毒载体,基于细小病毒的载体,例如基于腺相关病毒(AAV)的载体、AAV-腺病毒嵌合载体、和基于腺病毒的载体,和慢病毒载体,例如基于单纯疱疹(HSV)的载体。这些病毒载体可以使用例如Sambrook等人,Molecular Cloning,aLaboratory Manual,第2版,Cold Spring Harbor Press,Cold Spring Harbor,N.Y.(1989);和Ausubel等人,Current Protocols in Molecular Biology,Greene PublishingAssociates and John Wiley&Sons,New York,N.Y.(1994)中描述的标准重组DNA技术制备。
在一些实施方案中,将核酸分子插入在引入合适的宿主细胞时能够表达人源化mAb107抗体或其片段的载体中。合适的宿主细胞包括但不限于细菌细胞、酵母细胞、昆虫细胞和哺乳动物细胞。示例性宿主细胞包括原核生物(例如,大肠杆菌(E.coli))和真核生物(例如,COS或CHO细胞)。可以使用的哺乳动物宿主细胞包括人Hela 293、Expi293、H9和Jurkat细胞、小鼠NIH3T3和C 127细胞、Cos 1、Cos 7和CV 1、鹌鹑QCl-3细胞、小鼠L细胞和中国仓鼠卵巢(CHO)细胞(例如,DG44细胞)。在一些实施方案中,适于表达抗体的哺乳动物宿主细胞可以是中国仓鼠卵巢(CHO)细胞(例如,包括与DHFR-选择性标记一起使用的DHFR-CHO细胞)、NSO骨髓瘤细胞、COS细胞或SP2细胞。
在一些实施方案中,本公开的核酸和载体可以是分离的和/或纯化的。本公开还提供包含上述分离的或纯化的核酸分子的组合物,任选地以载体的形式。可以使用本领域已知的标准技术制备分离的核酸和载体,所述标准技术包括例如碱/SDS处理、CsCl结合、柱层析、琼脂糖凝胶电泳和本领域熟知的其它技术。组合物可以包括如本文进一步描述的其它组分。
小鼠IgG1 mAb107(mAb107)阻断多配体与CD11b结合,和CD11b介导的跨内皮中性粒细胞/单核细胞迁移和吞噬(Li等人,J Immunol.2002Feb1;168(3):1219-25)。与CD11b复合的小鼠mAb107的晶体结构测定揭示该mAb是配体-模拟物,占据CD11b中的配体结合位点。在细胞整合素中一致的结构的一个非预期的特性是,mAb107的结合将整合素稳定在其无活性非信号传导构象,整合素抑制剂的首个实例(Mahalingam等人,J Immunol.2011Dec15;187(12):6393-401)。最近,mAb107已显示出在非人灵长类动物(NHP)中保护天然肾脏免于由严重缺血再灌注损伤(IRI)导致的不可逆性肾衰竭(Dehnadi等人,Nat Commun.2017Jan10;8:13899)。mAb107在缺血-再灌注的NHP肾中阻断白细胞归巢再灌注的器官、吞噬和产生IL-18、RANTES、C3、IL-6与IFN-γ蛋白。
IRI是由再灌注后浸润缺血器官的激活的先天免疫细胞介导的常见急性炎症反应。它构成包括心脏、脑和肾脏在内的多器官的缺血后衰竭的原因。它也是移植物功能延迟恢复和原发性同种异体移植物无功能的原因,已广泛公认这二者不利地影响移植物生存、初始住院时间、医疗费用和死亡率(iedlecki等人,Kidney Int.2011Aug;80(3):263-71;Menke等人,Curr Opin Organ Transplant.2014Aug;19(4):395-400;Cooper等人,CurrOpin Nephrol Hypertens.2013Nov;22(6):698-703;Renders和Heeman,Curr Opin OrganTransplant.2012Dec;17(6):634-9)。主要在啮齿类动物中实施的限制IRI的先前的努力已经瞄准各促炎介质并且在啮齿类动物中显示出有前景,但这种方法在大动物中不太有效并且在人体试验中无效(Cerda等人,Clin J Am Soc Nephrol.2015Oct 7;10(10):1859-67;Molitoris等人,Clin.J.Am.Soc.Nephrol.7,842–843(2012);Anderson等人,Cold SpringHarb Perspect Med.2013Sep1;3(9):a015503;Gallagher等人,Expert Opin InvestigDrugs.2017Feb;26(2):141-154;Benoit等人,Pediatr Nephrol.2018May;33(5):779-787)。促成因素可能包括啮齿类动物与灵长类动物之间的免疫应答的显著物种差异(Seok等人,Proc Natl Acad Sci U S A.2013Feb 26;110(9):3507-12)、灵长类动物中免疫细胞群体的异质性、和免疫细胞不仅在组织损伤中并且还在组织修复中的双重作用,这使得靶标选择和干预的时机变得复杂。因此,mAb107在防止非人灵长类动物中缺血后肾衰竭方面的令人印象深刻的成功是主要进展,形成令人信服的理由用于测试其在人类中的实用性。本文描述了结合CD11b的抗体或其抗原结合片段,其包括人源化抗体和诱变的抗体或其抗原结合片段。
如本文所用,术语“抗体”是指包含至少一个(例如,1、2、3、4、5或6个)互补决定区(CDR)(例如,来自免疫球蛋白轻链的三个CDR中的任何或来自免疫球蛋白重链的三个CDR中的任何)并且能够与表位特异性结合的任何抗原结合分子。抗体的非限制性实例包括:单克隆抗体、多克隆抗体、多特异性抗体(例如,双特异性抗体)、单链抗体、嵌合抗体、人抗体和人源化抗体。在一些实施方案中,抗体可以包含人抗体的Fc区。该术语抗体还包括衍生物,例如,由抗体片段形成的双特异性抗体、单链抗体、双体抗体(diabodies)、线性抗体和多特异性抗体。
如本文所用,术语“抗体”不仅涵盖完整的多克隆或单克隆抗体,还涵盖其任何抗原结合片段(即,“抗原结合部分”)或单链、包含抗体的融合蛋白、和包含抗原识别位点的免疫球蛋白分子的任何其它修饰的构型。抗体包括任何类别的抗体,例如IgG、IgA或IgM(或其亚类),并且抗体不必是任何特定类别。取决于其重链的恒定区的抗体氨基酸序列,免疫球蛋白可以分为不同的类别。免疫球蛋白有五种主要类别:IgA、IgD、IgE、IgG和IgM,并且这些中的几个可以进一步分为亚类(同种型),例如,IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。对应于不同类别的免疫球蛋白的重链恒定区分别称作α、δ、ε、γ和μ。不同类别的免疫球蛋白的亚基结构和三维构型是熟知的。示例性抗体和抗体片段包括但不限于单克隆抗体(包括全长单克隆抗体)、多克隆抗体、由至少两个不同的表位结合片段形成的多特异性抗体(例如,双特异性抗体)、骆驼科抗体、嵌合抗体、单链可变片段(scFv)、单链抗体、单结构域抗体、结构域抗体、Fab片段、F(ab')2片段、显示期望的生物学活性的抗体片段(例如抗原结合部分)、二硫键连接的Fvs(dsFv)、和抗独特型(抗Id)抗体(包括例如针对本发明的抗体的抗Id抗体)、胞内抗体、和前述中的任何的表位结合片段。
Fv片段是包含完整抗原识别和结合位点的抗体片段。该区域由紧密结合的一个重链可变结构域和一个轻链可变结构域的二聚体组成,所述紧密结合在本质上可以是共价的,例如在scFv中。在这种构型中,每个可变结构域的三个CDR相互作用以定义VH-VL二聚体的表面上的抗原结合位点。共同地,六个CDR或其亚类赋予抗体抗原结合特异性。然而,甚至单个可变结构域(或仅包含对抗原为特异性的三个CDR的一半的Fv)可以具有识别和结合抗原的能力,尽管通常是以比完整结合位点更低的亲和力。
单链Fv或(scFv)抗体片段包括抗体的VH和VL结构域,其中这些结构域存在于单个多肽链中。通常,Fv多肽进一步包括VH和VL结构域之间的多肽接头,所述多肽接头能够使scFv形成所需的结构用于抗原结合。一个示例性scFV示于SEQ ID NO:15。该scFV包括人源化VH区段、人源化VL区段、和这两个区段之间的接头。
Fab片段包含轻链的可变结构域和恒定结构域、以及重链的可变结构域和第一恒定结构域(CH1)。F(ab')2抗体片段包含一对Fab片段,所述Fab片段通常通过它们之间的铰链半胱氨酸在其羧基末端附近共价连接。本领域也已知抗体片段的其它化学偶联。
双体抗体是具有两个抗原结合位点的小抗体片段,所述片段包含在相同多肽链(VH和VL)中与VL连接的VH。通过使用太短而不能允许相同链上的两个结构域之间配对的接头,所述结构域被迫与另一条链的互补结构域配对,产生两个抗原结合位点。
线性抗体包含一对串联的Fd区段(VH-CH1-VH-CH1),所述区段与互补轻链多肽一起形成一对抗原结合区。线性抗体可以是双特异或单特异的。本公开的抗体和抗体片段可以在Fc区内被修饰,以提供期望的效应子功能或血清半衰期。
在一些实施方案中,Fc区可以缀合至PEG或白蛋白以增加血清半衰期,或导致期望的效果的一些其它缀合。可选地,在期望消除或减少效应子功能,从而最小化副作用或治疗并发症的情况下,可以使用某些其它Fc区。
使用方法
本公开提供治疗方法,所述方法包括向受试者施用本文公开的组合物。
如本文所用,术语“受试者”是指任何动物。在一些实施方案中,受试者是哺乳动物。在一些实施方案中,如本文所用,术语“受试者”是指人(例如,男性、女性或儿童)。用于所述方法的样品可以包括血清样品,例如从选定的受试者获得的。
在一些实施方案中,受试者选择可以包括从受试者(例如,候选受试者)获得样品,并且对样品测试受试者适合选择的指标。在一些实施方案中,可以例如由卫生保健专业人员确认或鉴定受试者已经患有病况或疾病或者正患有病况或疾病。在一些实施方案中,对病况或疾病的正向反应的表现,可以根据患者记录、家族史和/或检测到正向反应的指标来做出。在一些实施方案中,受试者选择中可以包括多方。例如,第一方可以从候选受试者获得样品,并且第二方可以检验样品。在一些实施方案中,受试者可以由医疗执业者(例如,全科医生)选择和/或转诊(referred)。在一些实施方案中,受试者选择可以包括从选定的受试者获得样品,并且贮存样品和/或用于本文公开的方法中。样品可以包括例如细胞或细胞群体。
本文所述的抗体可以施用至已遭受急性心肌梗死的患者,以期防止由于缺血再灌注损伤导致的损害。在一些实施方案中,心肌梗死病况是心肌梗死后左心室不良重塑。在一些实施方案中,心肌梗死病况包括心肌顿抑。在一些实施方案中,心肌梗死病况包括微血管功能障碍。在一些实施方案中,在缺血再灌注损伤约5小时内向具有该损伤的受试者施用本公开的抗CD11b抗体。在一些实施方案中,在缺血再灌注损伤约2小时内向具有该损伤的受试者施用本公开的抗CD11b抗体。在一些实施方案中,在缺血性再灌注损伤之前施用本公开的抗CD11b抗体。目前估计在美国每年860,000位心肌梗死患者中超过30%遭受由于再灌注损伤导致的并发症,并且它是不良后果的主要原因。
本文所述的抗体也可以用于防止由于缺血再灌注损伤导致的急性肾损伤(AKI),所述急性肾损伤使多达30-40%的患者从心脏手术的恢复变得复杂,总计在美国每年估计有180万名患者,对美国卫生系统造成的年度费用约为100亿美元。肾替代疗法(透析)存在于2-5%的此类患者中,并且与50%死亡率以及增加的长期死亡率的风险相关(HR,1.31;95% CI,1.16-1.47;p<0.00001),没有有效的预防性疗法。在选择性、常见性、造成相对标准化的损伤并且其中可进行密切监测方面,这种临床环境类似于肾缺血/再灌注损伤的非人类灵长类动物模型中的结果并且得到其支持(Dehnadi等人,Nat Commun.2017Jan10;8:13899)。在一些实施方案中,肾损伤包括肾纤维炎性疾病。在一些实施方案中,肾损伤包括缺血后肾纤维化。在一些实施方案中,在缺血再灌注损伤约5小时内向具有该损伤的受试者施用本公开的抗CD11b抗体。在一些实施方案中,在缺血再灌注损伤约2小时内向具有该损伤的受试者施用本公开的抗CD11b抗体。在一些实施方案中,在缺血性再灌注损伤之前施用本公开的抗CD11b抗体。
本文所述的抗体也可以用于防止(降低其风险)由于肾移植物的缺血再灌注损伤导致的移植物功能延迟恢复(DGF,FDA批准的孤儿药命名)。这是肾移植中常见的且主要的并发症,在2015年升高至接受来自已故供体的同种异体移植物的患者的31%。在2016年,仅在美国进行的19,060例肾移植中,70.5%(每年约13,437例)来自已故供体,在欧洲联盟(EU),每年约14,000例。没有获批的疗法。再次,临床环境在此类似于非人类灵长类动物模型中的实验设置(Dehnadi等人,Nat Commun.2017Jan 10;8:13899)。DGF增加术后成本超过4,000美元,增加移植后住院时间(通常5-10天)多达75%,并且在移植后五年,DGF患者具有显著更高的透析次数、移植排异和死亡率。用于DGF的mAb107可能实现逾3亿美元年收益,其中小于三分之一的移植物渗透进行住院治疗,三分之一的那些转向居家治疗。
在与抗CD40抗体联合递送时,本公开的抗体也可以用于改善异种移植物的接受度和对同种异体移植物的耐受诱导。使用抗CD11b抗体的治疗在动物模型中减轻早期异种移植物排异,并且抗CD40/CD11b疗法在统计学上类似于用于防止异种移植排异的抗CD154抗体治疗(Liu和Ford,Am J Transplant.2020;20:2216-2225;D.A.Faber等人,“CombinedCD11b/CD40 Blockade is Superior to CD40 Blockade Alone in Prolonging Survivalin Pig-to-Nonhuman Primate Renal Xenotransplantation”,2021American TransplantCongress摘要2)。
本公开的抗体也可以施用至具有肺的再灌注损伤的受试者。例如,本公开的抗体可以施用至具有肺纤维化的受试者。在一些实施方案中,在再灌注损伤约5小时内向具有该损伤的受试者施用本公开的抗CD11b抗体。在一些实施方案中,在再灌注损伤约2小时内向具有该损伤的受试者施用本公开的抗CD11b抗体。在一些实施方案中,在再灌注损伤之前施用本公开的抗CD11b抗体。
本公开的抗体也可以施用至患有自身免疫性疾病的受试者,所述自身免疫性疾病例如胞浆抗中性粒细胞胞浆抗体(cANCA)相关性血管炎或糖尿病肾病。另外,本公开的抗体也可以施用至正经历或已经经历化学疗法的受试者。
本公开的抗体也可以施用至患有或诊断患有干眼病的受试者。在一些实施方案中,本公开的抗体可以局部地施用。在一些实施方案中,本公开的抗体可以施用至角膜。在一些实施方案中,本公开的抗体可以施用至结膜上皮。部分通过CD11b阻断白细胞归巢的risuteganib的局部施用减少炎症并改善干眼病的体征和症状。(Donnenfeld等人,“Prospective,Randomized,Double-Masked,Vehicle-Controlled,Safety and EfficacyStudy of Topical Risuteganib in Treating Dry Eye Disease”,ASCRS2021年会议,论文77664)。
本公开的抗体也可以施用至患有或诊断患有阿尔茨海默病的受试者。在一些实施方案中,本公开的抗体可以与其它组分或不与其它组分一起施用以减少小胶质细胞激活。小胶质细胞激活在阿尔茨海默小鼠模型中介导早期神经元突触损失。(Hong等人,Science.2016May 6.352:6286;Merlini等人,Neuron.2019March 20.101:1099-1108)。因此,通过施用本公开的抗CD11b抗体阻断或减弱小胶质细胞激活可以用于治疗患有或诊断患有阿尔茨海默病的受试者。
本文所述的抗体包括人源化形式的mAb107,基于我们的晶体结构,其可以包括一个或更多个氨基酸取代,包括相对于小鼠形式而言提高人源化mAb107对CD11b的亲和力的那些。
还参见,US2018/0244782、US 7,323,552、US 7,998,738和10,738,121,其完整公开内容通过引用并入本文。
药物组合物和施用方法
本文所述的方法包括使用包含本文所述的抗体或其抗原结合片段作为活性成分的药物组合物。
药物组合物通常包含药学上可接受的载体。如本文所用,措辞“药学上可接受的载体”包括与药物施用相容的盐水、溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂等。
通常将药物组合物配制成与其预期施用途径相容。施用途径的实例包括肠胃外,例如静脉内、皮内、皮下、口服(例如吸入)、经皮(局部)、经粘膜和直肠施用。
配制合适的药物组合物的方法是本领域已知的,参见,例如Remington:TheScience and Practice of Pharmacy,第21版,2005;和Drugs and the PharmaceuticalSciences:a Series of Textbooks and Monographs(Dekker,NY)系列丛书。例如,用于肠胃外、皮内或皮下施用的溶液或悬浮液可以包含以下组分:无菌稀释剂,例如注射用水、盐水溶液、固定油(fixed oils)、聚乙二醇、甘油、丙二醇或其它合成溶剂;抗细菌剂,例如苯甲醇或对羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸;缓冲剂,例如乙酸盐、柠檬酸盐或磷酸盐,和用于调节张力的试剂如氯化钠或右旋糖。可以用例如盐酸或氢氧化钠等酸或碱调节pH。可以将肠胃外制剂封装在由玻璃或塑料制成的安瓿、一次性注射器或更多剂量小瓶中。
适用于可注射用途的药物组合物可以包括无菌水溶液(其中为水溶性的)或用于临时配制无菌可注射溶液或分散液的分散体和无菌粉末。对于静脉内施用,合适的载体包括生理盐水、抑菌水、Cremophor ELTM(BASF,Parsippany,NJ)或磷酸盐缓冲盐水(PBS)。在所有情况中,组合物必须是无菌的,并且应当是达到容易注射的程度的流体。它在制造和储存条件下应当是稳定的,并且必须保存免于例如细菌和真菌等微生物的污染作用。载体可以是溶剂或分散介质,其包括例如水、乙醇、多元醇(例如,甘油、丙二醇和液态聚乙二醇等)、及其合适的混合物。可以维持适当的流动性,例如通过使用诸如卵磷脂等包衣、通过在分散的情况下保持所需的颗粒尺寸和通过使用表面活性剂。可以通过例如对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸和硫柳汞等各种抗细菌和抗真菌剂来实现防止微生物的作用。在许多情况下,组合物中优选包含等渗剂,例如糖、多元醇如甘露醇、山梨醇、氯化钠。可注射组合物的延长吸收可以通过在组合物中包含例如单硬脂酸铝和明胶等延迟吸收的试剂来实现。
无菌可注射溶液可以通过将所需量的活性化合物与上述枚举的一种成分或更多种成分的组合根据需要混入适当的溶剂中、然后过滤除菌来制备。通常,分散体是通过将活性化合物混入无菌溶媒来制备的,所述无菌溶媒包含基础分散介质和所需的来自上述枚举的那些的其它成分。在用于制备无菌可注射溶液的无菌粉末情况下,优选的制备方法是真空干燥和冷冻干燥,其从先前无菌过滤的溶液中产生活性成分和任何附加的所需成分的粉末。
口服组合物通常包括惰性稀释剂或可食用载体。出于口服治疗施用的目的,活性化合物可以与赋形剂混合,并以片剂、锭剂、或胶囊剂如明胶胶囊的形式使用。口服组合物也可以使用用作漱口剂的流体载体制备。可以包含药学上相容的粘合剂、和/或佐剂材料作为组合物的一部分。片剂、丸剂、胶囊剂和锭剂等可以含有任何以下成分、或类似性质的化合物:粘合剂,例如微晶纤维素、黄蓍胶或明胶;赋形剂,例如淀粉或乳糖,崩解剂,例如海藻酸、Primogel或玉米淀粉;润滑剂,例如硬脂酸镁或Sterote;助流剂,例如胶体二氧化硅;甜味剂,例如蔗糖或糖精;或矫味剂,例如薄荷、水杨酸甲酯或柑橘调味料。
对于通过吸入施用,所述化合物可以以来自含有适当的推进剂如气体如二氧化碳的压力容器或分配器、或喷雾器的气溶胶喷雾剂的形式递送。这样的方法包括美国专利号6,468,798中描述的那些。
如本文所述的治疗性化合物的全身施用也可以通过经粘膜或经皮方法。对于经粘膜或经皮施用,将适于要渗透的屏障的渗透剂用于制剂中。这样的渗透剂在本领域通常是已知的并且包括,例如对于透粘膜施用,洗涤剂、胆盐和夫西地酸衍生物。经粘膜施用可以通过使用鼻喷雾剂或栓剂来完成。对于经皮施用,将活性化合物配制成软膏剂、药膏、凝胶剂或霜剂,如本领域中通常已知的。
药物组合物也可以制备成栓剂(例如,用例如可可脂和其它甘油酯等常规栓剂基质)或保留灌肠剂的形式用于直肠施用。
在一个实施方案中,将治疗性化合物用将所述保护治疗性化合物免于从身体快速消除的载体制备,例如控释制剂,包括植入物和微胶囊化递送系统。可以使用可生物降解的生物相容的聚合物,例如乙烯乙酸乙烯酯、聚酸酐、聚乙醇酸、胶原蛋白、聚原酸酯和聚乳酸。这样的制剂可以使用标准技术制备或市售可得,例如来自Alza Corporation和NovaPharmaceuticals,Inc.。脂质体悬液(包括具有针对细胞抗原的单克隆抗体的靶向所选细胞的脂质体)也可以用作药学上可接受的载体。这些可以根据本领域技术人员已知的方法制备,例如,如美国专利号4,522,811中所述。
药物组合物可以与施用说明书一起包含在容器、包装或分配器中。
实施例
在以下实施例中进一步描述了本发明,所述实施例不限制权利要求中描述的本发明的范围。
实施例1.使mAb107人源化
简要方法
设计:将小鼠mAb107的每条可变重链和轻链中的三个CDR侧翼的序列改变成人免疫球蛋白序列。另外,我们在可变重链的CDR2中引入变化,用天冬氨酸(D)替代天冬酰胺(N)以改善亲和力。商业地制得cDNA。
克隆:使用在线程序对我们设计的编码人源化mAb107的可变重链和轻链的cDNA的可变区进行逆翻译,并且由IDT合成。在每条链的5’-端添加分泌信号序列。使用QuikChangeII XL定点诱变试剂盒(Agilent)向重链引入N/D突变。通过重叠PCR将重链的可变区与人IgG4κ恒定区连接,并使用XbaI和XhoI限制性位点,将其克隆至pcDNA3.4。类似地,将轻链可变区与人κ轻链恒定区融合。
生产、纯化和评价:Expi293细胞(Thermo Fisher)用于产生重组抗体。细胞在轨道式摇床(125rpm)上、在Expi293表达培养基(Thermo Fisher)中、在37℃下、在5% CO2中生长。使用制造商的方案,用1:1重链和轻链质粒瞬时转染Expi293细胞。一周后收获培养上清液,并且使用蛋白G琼脂糖珠(Thermo Scientific)纯化IgG。我们常规地获得每100ml的细胞培养物1-3mg的纯化IgG。在SDSPAGE上确认IgG的重链和轻链的蛋白质大小和纯度。使用CD11b的A结构域作为配体、通过生物膜干涉技术(BLI)、使用Octet测定体系,测定人源化mAb107相对于小鼠mAb107的亲和力。
结果
人源化N55D取代的mAb107的重链和轻链的优化氨基酸序列如下:
A)人源化重链(CDR1、2和3为粗体;CDR2中的N57D取代以小写字母表示)。
B)人源化轻链(CDR1、2和3为粗体)
人源化mAb107 IgG4κ的序列
重(H)链(CDR为粗体;CDR2中的N57D取代以小写字母表示;恒定区为斜体)。CDR3中的小写字母“d”是在MIDAS结合金属离子的D残基。
mAB107 IgG1是
轻(L)链(CDR为粗体;恒定区为斜体)
在SDSPAGE上确认IgG的重链和轻链的蛋白质大小和纯度,并且观察到预期的大小(图1)。
通过BLI测定对CD11b A结构域的亲和力。亲本抗体即小鼠mAb107的亲和力是1-5nM。人源化humAb107的亲和力是5-9nM。
实施例2.人源化诱变的抗体CD11b
IgG4铰链区(VESKYGPPCPPCPAPEFLGG)中位置[228]处S至P突变(SEQ ID NO:12中的斜体)减少Fab臂交换,如图2中所示。
人源化诱变的mAb107 IgG4k重链V5的DNA序列-亲和力5-9nM
蛋白质翻译:
前导序列:METDTLLLWVLLLWVPGSTGD(SEQ ID NO:13)
CDR2H中的N至D取代:粗体(以增强亲和力)[107Fab/CD11bA结构域复合体的晶体结构中的N57]。
S至P取代:粗体(以防止Fab臂交换[JBC,第290卷,第9期,第5462-5469页,2015年2月27日])。
人源化mAb107 IgG4k轻链的DNA序列
蛋白质翻译:
MW=24,569
前导序列:METDTLLLWVLLLWVPGSTGD(SEQ ID NO:13)scFv形式的人源化突变的mAB107
特征:
两个外来氨基酸:EF
GS接头:GGGGSGGGGSGGGGS(SEQ ID NO:16)
重链和轻链的CDR1-3为粗体
其它实施方案
应理解,尽管已结合本发明的详细说明描述了本发明,但前述描述旨在进行说明而非限制本发明的范围,本发明的范围由所附权利要求的范围限定。其它方面、优点和修改在所附权利要求的范围内。
序列表
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atggagacag acacactcct gctatgggta ctgctgctct gggttccagg ttccactggt 60
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tatgatccga aatttcaggg ccgcgcgacc attaccgcgg ataccagcgc gagcaccgcg 300
tatctggaac tgagcagcct gcgcagcgaa gataccgcgg tgtattattg cgcgagcgaa 360
ggccattatg gctatgatgg ctatgcgatg gattattggg gccagggcac caccgtgacc 420
gtgagcagcg ctagcaccaa gggcccatcc gtcttccccc tggcgccctg ctccaggagc 480
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acggtgtcgt ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta 600
cagtcctcag gactctactc cctcagcagc gtggtgaccg tgccctccag cagcttgggc 660
acgaagacct acacctgcaa cgtagatcac aagcccagca acaccaaggt ggacaagaga 720
gttgagtcca aatatggtcc cccatgccca ccatgcccag cacctgagtt cctgggggga 780
ccatcagtct tcctgttccc cccaaaaccc aaggacactc tcatgatctc ccggacccct 840
gaggtcacgt gcgtggtggt ggacgtgagc caggaagacc ccgaggtcca gttcaactgg 900
tacgtggatg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagttcaac 960
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaacggcaag 1020
gagtacaagt gcaaggtctc caacaaaggc ctcccgtcct ccatcgagaa aaccatctcc 1080
aaagccaaag ggcagccccg agagccacag gtgtacaccc tgcccccatc ccaggaggag 1140
atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctaccc cagcgacatc 1200
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1260
ctggactccg acggctcctt cttcctctac agcaggctaa ccgtggacaa gagcaggtgg 1320
caggagggga atgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacaca 1380
cagaagagcc tctccctgtc tctgggtaaa tga 1413
<210> 12
<211> 470
<212> PRT
<213> 人工
<220>
<223> 人源化诱变的mAB 107 IgG4kappa重链V5
<400> 12
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
20 25 30
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Pro Ser Gly Phe
35 40 45
Asn Ile Lys Asp Ile Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Gln
50 55 60
Arg Leu Glu Trp Ile Gly Arg Ile Asp Pro Ala Asp Asp Lys Thr Lys
65 70 75 80
Tyr Asp Pro Lys Phe Gln Gly Arg Ala Thr Ile Thr Ala Asp Thr Ser
85 90 95
Ala Ser Thr Ala Tyr Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Ser Glu Gly His Tyr Gly Tyr Asp Gly Tyr
115 120 125
Ala Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala
130 135 140
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser
145 150 155 160
Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
165 170 175
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
180 185 190
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
195 200 205
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr
210 215 220
Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg
225 230 235 240
Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
340 345 350
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Leu Gly Lys
465 470
<210> 13
<211> 21
<212> PRT
<213> 人工
<220>
<223> 前导序列
<400> 13
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp
20
<210> 14
<211> 726
<212> DNA
<213> 人工
<220>
<223> 人源化mAb107 IgG4 kappa轻链
<400> 14
atggagacag acacactcct gctatgggta ctgctgctct gggttccagg ttccactggt 60
gacgatattg tgatgaccca gagcccggat agcctggcgg tgagcctggg cgaacgcgcg 120
accattaact gcaaaagcag ccagaacctg ctgtatagca gcaaccagaa aaactatctg 180
gcgtggtatc agcagaaacc gggccagccg ccgaaactgc tgatttattg ggcgagcacc 240
cgcgaaagcg gcgtgccgga tcgctttagc ggcagcggca gcggcaccga ttttaccctg 300
accattagca gcctgcaggc ggaagatgtg gcggtgtatt attgccagca gtattatagc 360
tatccgctga cctttggcca gggcaccaaa ctggaaatta aacgtacggt ggctgcacca 420
tctgtcttca tcttcccgcc atctgatgag cagttgaaat ctggaactgc ctctgttgtg 480
tgcctgctga ataacttcta tcccagagag gccaaagtac agtggaaggt ggataacgcc 540
ctccaatcgg gtaactccca ggagagtgtc acagagcagg acagcaagga cagcacctac 600
agcctcagca gcaccctgac gctgagcaaa gcagactacg agaaacacaa agtctacgcc 660
tgcgaagtca cccatcaggg cctgagctca cccgtcacaa agagcttcaa caggggagag 720
tgttag 726
<210> 15
<211> 260
<212> PRT
<213> 人工
<220>
<223> 人源化突变的mAb107的scFv
<400> 15
Glu Phe Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
1 5 10 15
Gly Ala Ser Val Lys Val Ser Cys Lys Pro Ser Gly Phe Asn Ile Lys
20 25 30
Asp Ile Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu
35 40 45
Trp Ile Gly Arg Ile Asp Pro Ala Asp Asp Lys Thr Lys Tyr Asp Pro
50 55 60
Lys Phe Gln Gly Arg Ala Thr Ile Thr Ala Asp Thr Ser Ala Ser Thr
65 70 75 80
Ala Tyr Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Ser Glu Gly His Tyr Gly Tyr Asp Gly Tyr Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr
130 135 140
Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile
145 150 155 160
Asn Cys Lys Ser Ser Gln Asn Leu Leu Tyr Ser Ser Asn Gln Lys Asn
165 170 175
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu
180 185 190
Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser
195 200 205
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
210 215 220
Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Ser Tyr Pro
225 230 235 240
Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Glu Asn Leu Tyr
245 250 255
Phe Gln Gly Ser
260
<210> 16
<211> 15
<212> PRT
<213> 人工
<220>
<223> GS接头
<400> 16
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 17
<211> 225
<212> PRT
<213> 人工
<220>
<223> mAb107 IgG1
<400> 17
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 Pro Ser Gly Phe Asn Ile Lys Asp Ile
20 25 30
Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asp Asp Lys Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Ile Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Glu Gly His Tyr Gly Tyr Asp Gly Tyr Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys
225
<210> 18
<211> 241
<212> PRT
<213> 人工
<220>
<223> 具有前导序列的人源化轻链mAb107 IgG4kappa
<400> 18
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu
20 25 30
Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln
35 40 45
Asn Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln
50 55 60
Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr
65 70 75 80
Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val
100 105 110
Tyr Tyr Cys Gln Gln Tyr Tyr Ser Tyr Pro Leu Thr Phe Gly Gln Gly
115 120 125
Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
130 135 140
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
165 170 175
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
180 185 190
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
210 215 220
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
225 230 235 240
Cys
Claims (39)
1.一种抗体或其抗原结合片段,其包括包含以下互补决定区(CDR)的氨基酸序列:
1)SEQ ID NO:1的VH的CDR 1,其包含SEQ ID NO:5的序列;
2)SEQ ID NO:2的VL的CDR 1,其包含SEQ ID NO:8的序列;
3)SEQ ID NO:1的VH的CDR 2,其包含SEQ ID NO:6的序列;
4)SEQ ID NO:2的VL的CDR 2,其包含SEQ ID NO:9的序列;
5)SEQ ID NO:1的VH的CDR 3,其包含SEQ ID NO:7的序列;和
6)SEQ ID NO:2的VL的CDR 3,其包含SEQ ID NO:10的序列。
2.一种抗体或其抗原结合片段,其包括包含VH CDR 1、2、3的重链可变区和包含VL CDR1、2、3的轻链可变区,其中
所述VH CDR 1、2、3与SEQ ID NO:1中的互补决定区相同;和
所述VL CDR 1、2、3与SEQ ID NO:2中的互补决定区相同。
3.一种抗体或其抗原结合片段2,其包括包含与选自由以下组成的组中的氨基酸序列为至少95%同一性的氨基酸序列的氨基酸序列:
和
前提是未改变序列的互补决定区。
4.根据权利要求1所述的抗体或其抗原结合片段,其中所述抗原结合片段是单链可变片段(scFv)。
5.根据权利要求6所述的抗体或其抗原结合片段,其包括SEQ ID NO:15。
6.一种改善受试者中与缺血再灌注损伤相关的病变的方法,所述方法包括向受试者施用包含治疗有效量的根据权利要求1至5所述的抗体或其抗原结合片段的组合物。
7.根据权利要求6所述的方法,其中所述病变是缺血后肾纤维化。
8.根据权利要求6所述的方法,其中所述病变是肾纤维炎性疾病。
9.根据权利要求6所述的方法,其中所述病变是肺纤维化。
10.根据权利要求6所述的方法,其中所述病变是心肌梗死后左心室不良重塑。
11.根据权利要求6所述的方法,其中在缺血再灌注损伤后约5小时内向受试者施用组合物。
12.根据权利要求6所述的方法,其中在缺血再灌注损伤后约2小时内向受试者施用组合物。
13.一种治疗患有与器官中缺血再灌注损伤相关的病症或处于发展所述病症的风险的受试者的方法,所述方法包括:
向受试者施用包含治疗有效量的根据权利要求1至5所述的抗体或其抗原结合片段的组合物。
14.根据权利要求13所述的方法,其中所述器官是肾脏。
15.根据权利要求14所述的方法,其中所述病症是急性肾损伤。
16.根据权利要求13所述的方法,其中所述器官是心脏。
17.根据权利要求16所述的方法,其中所述病症是急性冠状动脉综合征。
18.根据权利要求16所述的方法,其中所述病症是急性心肌梗死(MI)。
19.根据权利要求13所述的方法,其中所述器官是肺。
20.根据权利要求13所述的方法,其中在缺血再灌注损伤后约5小时内向受试者施用组合物。
21.根据权利要求13所述的方法,其中在缺血再灌注损伤后约2小时内向受试者施用组合物。
22.一种提供用于移植的器官的方法,所述方法包括:
向器官供体施用包含根据权利要求1至5所述的抗体或其抗原结合片段的组合物;和
从所述器官供体收获器官。
23.根据权利要求22所述的方法,其中所述器官是肾脏、心脏或肺。
24.一种减少器官移植后移植物功能延迟恢复的方法,所述方法包括:
在移植器官至接受者之前或在移植当日内,向器官接受者施用治疗有效量的包含根据权利要求1至5所述的抗体或其抗原结合片段的组合物,
从而减少器官移植后移植物功能延迟恢复。
25.根据权利要求24所述的方法,其中所述器官是肾脏、心脏或肺。
26.一种在移植至接受者之前处理器官的方法,所述方法包括:
使器官与包含根据权利要求1至5所述的抗体或其抗原结合片段的组合物接触。
27.根据权利要求26所述的方法,其中所述器官是肾脏、心脏或肺。
28.根据权利要求26所述的方法,其中接触步骤包括用包含多肽或抗体的组合物灌注器官,所述多肽或抗体免疫特异性地结合由mab107识别的表位。
29.一种治疗患有自身免疫性疾病的受试者的方法,所述方法包括向受试者施用治疗有效量的包含根据权利要求1至5所述的抗体或其抗原结合片段的组合物。
30.根据权利要求29所述的方法,其中所述自身免疫性疾病是胞浆抗中性粒细胞胞浆抗体(cANCA)相关性血管炎。
31.一种治疗患有糖尿病肾病的受试者的方法,所述方法包括向受试者施用治疗有效量的包含根据权利要求1至5所述的抗体或其抗原结合片段的组合物。
32.一种改善受试者中与化学疗法相关的病变的方法,所述方法包括向受试者施用治疗有效量的包含根据权利要求1至5所述的抗体或其抗原结合片段的组合物。
33.根据权利要求32所述的方法,其中所述病变是阿霉素肾病。
34.一种组合物,其包含根据权利要求1至5所述的抗体或其抗原结合片段和药学上可接受的载体。
35.一种核酸分子,其编码根据权利要求1至5中任一项所述的人源化mAb107抗体或抗原结合片段。
36.一种重组载体,其包含根据权利要求35所述的核酸分子。
37.一种宿主细胞,其包含根据权利要求36所述的重组载体和或根据权利要求35所述的核酸分子。
38.根据权利要求37所述的宿主细胞,其中所述宿主细胞选自由大肠杆菌、巴斯德毕赤酵母、Sf9、COS、HEK293和CHO组成的组。
39.一种药物组合物,其包含:
(a)根据权利要求35所述的核酸分子、根据权利要求36所述的重组载体或根据权利要求37至38所述的宿主细胞中的一者或更多者;和
(b)药学上可接受的载体。
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US202163166711P | 2021-03-26 | 2021-03-26 | |
US63/166,711 | 2021-03-26 | ||
PCT/US2022/021950 WO2022204516A1 (en) | 2021-03-26 | 2022-03-25 | Humanized mab107 |
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EP (1) | EP4313112A1 (zh) |
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PT3283524T (pt) * | 2015-04-17 | 2023-06-05 | Amgen Res Munich Gmbh | Construções de anticorpos biespecíficos para cdh3 e cd3 |
RU2757489C2 (ru) * | 2015-06-12 | 2021-10-18 | Маккэй Медикл Фаундэйшн Зе Пресбайтериэн Чёч Ин Тайвэнь Маккэй Мемориал Хоспитэл | Способы и антитела для модуляции иммунного ответа |
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- 2022-03-25 US US18/283,927 patent/US20240158511A1/en active Pending
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AU2022243562A1 (en) | 2023-10-12 |
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