CN113194966A - 抗cd79抗体及其应用 - Google Patents
抗cd79抗体及其应用 Download PDFInfo
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- CN113194966A CN113194966A CN201980058484.6A CN201980058484A CN113194966A CN 113194966 A CN113194966 A CN 113194966A CN 201980058484 A CN201980058484 A CN 201980058484A CN 113194966 A CN113194966 A CN 113194966A
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Abstract
本公开内容提供了以高亲和力特异性结合CD79的人源化和亲和力成熟的抗体(mAb)及其片段。抗CD79mAb及其片段可用于治疗抗体相关病症,包括自身免疫性疾病、过敏、移植排斥或治疗剂的免疫介导排斥,可选地与另外的治疗剂组合。此外,抗CD79mAb及其片段可用于诊断目的,包括检测生物样本中的CD79细胞和诊断B‑细胞相关疾病。
Description
关于联邦资助研究的声明
本发明是在政府机构国家过敏和传染病研究所(National Institute ofAllergy and Infectious Diseases)(NIAID)授予的第1R43AI120433-01号授予的政府支持下完成的。政府拥有本发明的某些权利。
序列表、表格或计算机程序的引用
序列表的正式文本与本说明书同时通过EFS-Web以ASCII格式的文本文件提交,文件名为“PRI01l_ST25.txt”,创建日期为2019年9月30日,大小为73千字节。通过EFS-Web提交的序列表是本说明书的一部分,在此以其全文形式被援引加入本文。
背景技术
B细胞在许多自身免疫性疾病(包括类风湿性关节炎(RA)、系统性红斑狼疮(SLE)、多发性硬化症和I型糖尿病(T1D))的发病机理中起主要作用,正如由针对B细胞的疗法(例如在这些疾病中使用利妥昔单抗)的功效所表明的。遗憾的是,目前的疗法是基于B细胞消耗,从安全的角度来看这是有问题的。由于随之而来的免疫抑制作用,由于长期的严重的B细胞消耗,现有的护理标准疗法会产生不利影响,尤其是机会性感染和潜伏期病毒激活。
CD79(分化簇79)是一种跨膜蛋白,可与B-细胞受体(BCR)形成复合物,并在被BCR识别抗原后产生信号。CD79由两条截然不同的链组成,分别称为CD79A和CD79B(以前称为Ig-α和Ig-β);它们在通过二硫键稳定的B细胞表面上形成异二聚体。CD79a和CD79b都是免疫球蛋白超家族的成员。CD79已用作pan-B细胞标记,并可用于检测B-细胞赘生物/肿瘤。
与抗CD20mAb不同,针对CD79的mAb的保护作用不需要消耗细胞;相反,它们通过诱导可逆的无反应或无变应状态而起作用,因此不参与免疫应答的产生。在动物模型中,抗CD79抗体通过诱导B细胞无反应性提供了免疫抑制并减少了炎症。
发明内容
本公开内容提供了以高亲和力特异性结合CD79的抗体,包括其抗体片段。抗体可以是单克隆抗体,并且可以是嵌合或人源化抗体。包括其片段的嵌合抗CD79抗体可以具有非人(例如鼠)互补决定区(CDR)和非人框架区,以及可选地一个或多个人恒定区。非人、重链和轻链可变区包括SEQ ID NO:1-2。包括其片段的人源化抗CD79抗体可以具有非人(例如鼠)CDR和人框架区,以及可选地与CDR相邻的非人框架氨基酸残基和可选地一个或多个人恒定区。非人CDR包括例如SEQ ID NO:3-5的VH CDR1-3和SEQ ID NO:6-8的VL-CDR1-3。
公开的人源化抗体代表通过将SEQ ID NO:3-8的CDRs移植到重链的人框架和轻链的人框架,连同来自小鼠抗体的选定数量的框架残基来获得抗CD79抗体。可以将用于人源化重链的九个可变区(SEQ ID NO:9-17)和用于人源化轻链的六个可变区(SEQ ID NO:18-23)组合以制备抗CD79人源化抗体。本文公开的抗CD79抗体还包括从由人源化抗CD79抗体制成的亲和力成熟库获得的那些。可以用选自SEQ ID NO:9-17,24-27,32-41,71,72和75-77的重链可变区和选自SEQ ID NO:18-23,28-31,42-56和73-74的轻链可变区来制备抗CD79抗体。抗CD79抗体还可以包括与SEQ ID NO:9-17,24-27,32-41,71,72和75-77中的一个具有99%、95%、90%、80%或70%的序列同一性的重链可变区,以及与SEQ ID NO:18-23,28-31,42-56和73-74中的一个具有99%、95%、90%、80%或70%的序列同一性的轻链可变区。抗CD79抗体可以以2.0-5.1nM、或45nM至300nM、或2.0至300nM的亲和力与CD79结合。抗CD79抗体可以以至少300nM、或至少140nM、或至少100nM、或至少5.1nm、至少3.8nM、或至少2.4nM的亲和力结合。
本文所述的抗CD79抗体可以包括为抗体提供所需特性的修饰。例如,修饰可以增加抗体的血清半衰期,或者修饰可以降低血清半衰期。修饰还可以增加或降低抗体的效应子功能。修饰可以降低免疫原性,或减少由抗CD79抗体引起的其它不想要的副作用或不良事件。
本文所述的抗CD79抗体可在受试者的B-细胞中诱导无反应状态,因此可用于治疗某些自身免疫性疾病。例如,与抗自身抗体反应有关的自身免疫性疾病可以用抗CD79抗体治疗,因为诱导的无反应状态将阻止抗自身抗体的产生。本文所述的抗CD79抗体还可以用于在具有不期望的抗体应答的任何情况下诱导无反应状态。本文所述的抗CD79抗体可用于在B细胞中诱导无反应状态。本文所述的抗CD79抗体可用于抑制B细胞的增殖。本文所述的抗CD79抗体可用于预防由预先存在的抗药物抗体引起的输注反应。本文所述的抗CD79抗体可用于预防生物疗法注射后抗药物抗体的形成。不希望的抗体相关病症可能包括,例如自身免疫性疾病、某些过敏(与抗体相关的过敏)、某些I型糖尿病等。可以用抗CD79抗体治疗的自身免疫性疾病包括,例如系统性红斑狼疮(SLE)、炎性肠病(例如克罗恩病和溃疡性结肠炎)、类风湿性关节炎、多发性硬化症、格雷夫病(Grave’s disease)、CREST综合征、全身性硬化症、腹腔疾病等。其它自身免疫性疾病包括,例如失弛症、爱迪生氏病、成年斯蒂尔氏病、无丙种球蛋白血症、斑秃、淀粉样变性病、强直性脊柱炎、抗GBM/抗TBM肾炎、抗磷脂综合征、自身免疫性血管性水肿、自身免疫性自主神经障碍、自身免疫性脑脊髓炎、自身免疫性肝炎、自身免疫性内耳疾病(AIED)、自身免疫性心肌炎、自身免疫性卵巢炎、自身免疫性睾丸炎、自身免疫性胰腺炎、自身免疫性视网膜病、自身免疫性荨麻疹、轴突和神经元神经病变(AMAN)、Baló病、Behcet’s病、良性粘膜类天疱疮、大疱性类天疱疮、Castleman病(CD)、腹腔疾病、Chagas病、慢性炎症性脱髓鞘性多发性神经炎(CIDP)、慢性复发性多灶性骨髓炎(CRMO)、Churg-Strauss综合征(CSS)或嗜酸性肉芽肿病(EGPA)、瘢痕性类天疱疮、Cogan’s综合症、冷凝集素病、先天性心脏传导阻滞、柯萨奇(Coxsackie)心肌炎、CREST综合征、克罗恩氏(Crohn)病、疱疹样皮炎、皮肌炎、Devic’s病(视神经脊髓炎)、盘状狼疮、Dressler’s综合症、子宫内膜异位症、嗜酸性食管炎(EoE)、嗜酸性筋膜炎、结节性红斑、必要的混合性冷球蛋白血症、Evans综合征、纤维肌痛、纤维化肺泡炎、巨细胞性动脉炎(颞动脉炎)、巨细胞性心肌炎、肾小球肾炎、Goodpasture’s综合征、肉芽肿合并多血管炎、Graves’病、Guillain-Barre综合征、桥本(Hashimoto)甲状腺炎、溶血性贫血、Henoch-Schonlein紫癜(HSP)、妊娠疱疹或妊娠类天疱疮(PG)、化脓性汗腺炎(HS)(反常性痤疮)、低丙球蛋白血症、IgA肾病、与IgG4相关的硬化性疾病、免疫性血小板减少性紫癜(ITP)、包涵体肌炎(IBM)、间质性膀胱炎(IC)、青少年关节炎、青少年糖尿病(1型糖尿病)、青少年肌炎(JM)、川崎(Kawasaki)病,Lambert-Eaton综合征、白细胞碎裂性血管炎、扁平苔癣、硬化苔癣、木样结膜炎、线性IgA病(LAD)、狼疮、慢性莱姆病、Meniere’s病、显微镜下多血管炎(MPA)、混合结缔组织病(MCTD)、Mooren’s溃疡、Mucha-Habermann病、多灶性运动神经病变(MMN)或MMNCB、多发性硬化症、重症肌无力、肌炎、嗜睡症、新生儿狼疮、视神经脊髓炎、中性粒细胞减少症、眼瘢痕性类天疱疮、视神经炎、复发性风湿病(PR)、PANDAS、副肿瘤性小脑变性(PCD)、阵发性睡眠性血红蛋白尿症(PNH)、Parry Romberg综合征、睫状体扁平部炎(周围性葡萄膜炎)、Parsonage-Turner综合征、天疱疮、周围性神经病变、周围性脑脊髓炎、恶性贫血(PA)、POEMS综合征、结节性多发性动脉炎、多腺性综合征(I型、II型、III型)、风湿性多肌痛、多发性肌炎、心肌梗塞后综合征、心包膜切开术后综合征、原发性胆汁性肝硬变、原发性硬化性胆管炎、孕酮性皮炎、牛皮癣、银屑病关节炎、纯红细胞发育不全(PRCA)、坏疽性脓皮病、雷诺(Raynaud)现象、反应性关节炎、反射性交感神经营养不良、复发性多软骨炎、不安腿综合征(RLS)、腹膜后纤维化、风湿热、类风湿性关节炎,结节病、施密特(Schmidt)综合征、巩膜炎、硬皮病、综合症、精子和睾丸自身免疫、僵人综合征(SPS)、亚急性细菌性心内膜炎(SBE)、Susac’s综合征、交感性眼炎(SO)、高安氏(Takayasu)动脉炎、颞动脉炎/巨细胞动脉炎、血小板减少性紫癜(TTP)、Tolosa-Hunt综合征(THS)、横断性脊髓炎、1型糖尿病、溃疡性结肠炎(UC)、未分化结缔组织病(UCTD)、葡萄膜炎、血管炎、白癜风、Vogt-Koyanagi-Harada病。这些不希望的抗体相关病症可以通过将一种或多种本文所述的抗CD79抗体施用至患有不希望的抗体相关病症的受试者来治疗。
本文所述的抗CD79抗体可用于治疗CD79阳性的造血系统癌症,例如淋巴瘤和白血病。它们还可以用于嵌合抗原受体(CAR)中,以制造具有抗CD79CAR的免疫细胞。这些抗CD79CAR免疫细胞包括例如具有抗CD79 CAR的T-细胞或自然杀伤细胞。抗CD79 CAR T-细胞和/或自然杀伤细胞可用于治疗引起疾病的细胞展示CD79的疾病。所述疾病包括例如CD79阳性的造血系统癌症,例如淋巴瘤和白血病。
附图说明
通过参考下面的详细描述,将获得对本公开内容的特征和优点的更好的理解,以下详细描述阐述了本公开内容的说明性实施例以及附图。
图1是示出VH125NOD小鼠中1型糖尿病随时间发展的图。
图2是示出可溶性CD79抗原与表达抗CD79CAR-T构建体的细胞结合的图。
图3a示出了抗体LB517/LB519(hCur14FALA)和Curly-14之间的竞争性结合以结合B细胞。图3b示出了用不同的抗hCD79抗体处理的B-细胞中的PTEN。图3c示出了用不同的抗hCD79抗体处理B-细胞后的B-细胞受体(BCR)表达。
图4a示出了用不同的抗hCD79抗体处理后B-细胞中的钙流入。图4b示出了用不同的抗hCD79抗体处理B-细胞后,B-细胞受体的脱敏作用。
图5示出了在关节炎模型系统中用抗hCD79抗体治疗对关节炎发展的影响。
图6示出了在狼疮模型系统中用抗hCD79抗体治疗对狼疮发展的功效。
图7示出了在MS的模型系统中用抗hCD79抗体治疗对多发性硬化症发展的功效。
具体实施方式
尽管在此描述了本公开内容的各种实施例,但是对于本领域技术人员显而易见的是,这些实施例仅以示例的方式提供。在不脱离本公开内容的情况下,本文描述的实施例的多种修改和改变以及变化和替代对本领域技术人员而言将是显而易见的。应当理解,在实践本发明中可以采用本文描述的实施例的各种替代方案。还应当理解的是,本公开内容的每个实施例可以可选地与在此描述的与该实施例相符的任何一个或多个其它实施例组合。
在元素以列表格式(例如,以马库什(Markush)组)呈现时,应当理解,还公开了元素的每个可能的子组,并且可以从列表或组中移除任何一个或多个元素。
还应当理解的是,除非有明显的相反表示,否则在本文描述或要求保护的包括一个以上动作或步骤的任何方法中,方法的动作或步骤的顺序不必然限于方法的动作或步骤所记载的顺序,而是本公开内容涵盖受此限制的顺序的实施例。
还应当理解的是,一般,在说明书或权利要求书中的实施例被称为包括一个或多个特征的情况下,本公开内容还涵盖由所述的特征组成或基本上由所述的特征组成的实施例。
还应当理解的是,本公开内容的任何实施例,例如在现有技术内发现的任何实施例,可以明确地从权利要求中排除,不管说明书中是否记载了特定的排除。
还应当理解的是,本文中提及的肽、多肽或蛋白质,例如抗体或其片段,包括其药学上可接受的盐,除非另有明确说明或上下文另有清楚表示。这样的盐可以具有正净电荷、负净电荷或没有净电荷。
本文包含标题以供参考并有助于定位某些部分。标题不旨在限制在那些标题下的部分中描述的实施例和概念的范围,并且那些实施例和概念可以贯穿整个公开内容在其它部分中应用。
本文引用的所有专利文献和所有非专利文献都以其全文形式被援引加入本文,其程度与每篇专利文献或非专利文献被具体地和单独地表示为以其全文形式被援引加入本文的程度相同。
定义
除非另有定义或通过在本文中的使用另有明确指出,否则本文使用的所有技术和科学术语具有与本申请所属领域的普通技术人员通常理解的相同含义。
如在说明书和所附权利要求书中所使用的,除非另外明确说明或上下文另外明确指出,否则不定冠词“一个/种(a)”和“一个/种(an)”以及定冠词“该/所述(the)”可以包括复数指代物和单数指代物。
术语“大约(about)”或“近似(approximately)”表示由本领域普通技术人员确定的特定值的可接受误差,其部分取决于如何测量或确定该值。在某些实施例中,术语“大约”或“近似”意指在一个标准偏差之内。在某些实施例中,当没有记载特定的误差范围(例如,图表或数据表中给出的平均值的标准偏差)时,术语“大约”或“近似”表示将涵盖所述值的范围,以及考虑到重要数字,也可以通过向上或向下舍入为所述值来包含的范围。在某些实施例中,术语“大约”或“近似”是指在指定值的±10%、5%、4%、3%、2%或1%之内。每当术语“大约”或“近似”在一系列两个或更多个数值或一系列两个或更多个数值范围中位于第一个数值之前时,术语“大约”或“近似”适用于每个该系列数值或该系列数值范围中的数值。
术语“抗体”是指在功能上被定义为结合蛋白质并且在结构上被定义为包含被公认为源自免疫球蛋白编码基因的框架区的氨基酸序列的蛋白质。抗体可以由基本上由免疫球蛋白基因或免疫球蛋白基因的片段编码的一种或多种多肽组成。公认的免疫球蛋白基因包括κ、λ、α、γ、δ、ε和μ恒定区基因,以及无数的免疫球蛋白可变区基因。轻链被分类为κ或λ。重链被分类为γ、μ、α、δ或ε,其依次定义了免疫球蛋白类别,分别为IgG、IgM、IgA、IgD和IgE。
已知典型的γ免疫球蛋白(抗体)结构单元包含四聚体。每个四聚体由两对相同的多肽链组成,每对具有一条“轻”链(约25kD)和一条“重”链(约50-70kD)。每条链的N-末端定义了约100至110个或更多个氨基酸的可变区,主要负责抗原识别。术语可变轻链(VL)和可变重链(VH)分别是指这些轻链和重链。
抗体以完整的免疫球蛋白或以许多明确表征的片段存在。因此,例如,胃蛋白酶消化铰链区中二硫键下方的抗体以产生F(ab)'2,它是Fab'的二聚体,其本身是自然通过二硫键与VH-CH1-铰链连接的轻链。可以在温和的条件下还原F(ab)'2,以断开铰链区中的二硫键,从而将(Fab')2二聚体转化为Fab'单体。Fab'单体本质上是具有部分铰链区的Fab(参见,Fundamental Immunology,W.E.Paul,ed.,Raven Press,N.Y.(1993),以获得其它抗体片段的更详细描述)。尽管就完整抗体的消化而言定义了各种抗体片段,但是本领域技术人员将理解,片段可以化学地或通过利用重组DNA方法从头合成。因此,如本文所使用的术语抗体还包括通过修饰完整抗体而产生或使用重组DNA方法合成的抗体片段。优选的抗体包括VH-VL二聚体,包括单链抗体(作为单条多肽链存在的抗体),例如单链Fv抗体(sFv或scFv),其中可变重链和可变轻链区(直接或通过肽接头)连接在一起以形成连续的多肽。单链Fv抗体是共价连接的VH-VL异二聚体,其可以从包含直接连接或通过肽编码接头连接的VH-和VL-编码序列的核酸表达(例如,Huston等人,Proc.Nat.Acad.Sci.USA,85:5879-5883,1988,该篇文献以其全文形式被援引加入本文)。尽管VH和VL作为一条多肽链彼此连接,VH和VL结构域非共价结合。可替换地,抗体可以是另一个片段。也可以产生其它片段,包括使用重组技术。例如,如果链中的一条(重链或轻链)与g3衣壳蛋白融合并且互补链以可溶性分子的形式输出到周质中,则Fab分子可以在噬菌体上展示。两条链可以在相同或不同的复制子上编码;每个Fab分子中的两条抗体链会进行翻译后组装,然后通过与g3p的一条链连接而将二聚体掺入噬菌体颗粒中(参见,例如,美国专利号:5,733,743,该专利以其全文形式被援引加入本文)。scFv抗体和多个其它结构将天然聚集的但化学分离的轻和重多肽链从抗体V区转换为折叠成三维结构的分子,该结构基本上类似于抗原结合位点的结构,这对于本领域技术人员而言是已知的(参见例如美国专利号5,091,513、5,132,405和4,956,778,均以其全文形式被援引加入本文)。特别优选的抗体包括所有已经在噬菌体上展示或使用载体通过重组技术产生的那些抗体,其中链以可溶性蛋白的形式分泌,例如scFv、Fv、Fab、(Fab')2。抗体还可以包括双抗(diabody)和微抗体(minibody)。
抗体还包括重链二聚体,例如骆驼科动物的抗体。由于骆驼科动物中的重链二聚体IgG的VH区不必与轻链发生疏水性相互作用,因此通常与轻链接触的重链中的区域变为骆驼科动物中的亲水性氨基酸残基。重链二聚体IgG的VH结构域称为VHH结构域。
在骆驼科动物中,抗体库的多样性取决于VH或VHH区域中的互补决定区(CDR)1、2和3。骆驼VHH区中的CDR3由其相对较长的长度表征,平均为16个氨基酸(Muyldermans等人,1994,Protein Engineering 7(9):1129,该篇文献以其全文形式被援引加入本文)。这与许多其它物种的抗体的CDR3区相反。例如,小鼠VH的CDR3平均具有9个氨基酸。
可以通过例如2005年2月17日公开的美国专利申请公开号US20050037421中公开的方法来制备骆驼科动物来源的抗体可变区的文库,其维持骆驼科动物的可变区的体内多样性,该专利以其全文形式被援引加入本文。
如本文所使用的,抗体的术语“结合特异性”是指抗体结合的抗原的同一性,优选地是指抗体结合的表位的同一性。
如本文所使用的,术语“嵌合多核苷酸”是指多核苷酸包含野生型区域和突变区域。还可能是指多核苷酸包含来自一个多核苷酸的野生型区域和来自另一相关多核苷酸的野生型区域。
如本文所使用的,术语“互补决定区”或“CDR”是指由Kabat和Chothia举例说明的本领域公认的术语。CDR通常也称为高变区或高变环(Chothia和Lesk(1987)JMol.Biol.196:901;Chothia等人,(1989)Nature 342:877;E.A.Kabat等人,Sequences ofProteins of Immunological Interest(National Institutes of Health(美国国立卫生研究院),Bethesda,Md.)(1987);和Tramontano等人,(1990)J Mol.Biol.215:175,均以其全文形式被援引加入本文)。“框架区”或“FR”是指V结构域的CDR侧翼的区域。CDR和框架区的位置可以使用本领域中各种众所周知的定义来确定,例如Kabat,Chothia,International ImMunoGeneTics database(IMGT)和AbM(请参见例如Johnson等人,同上;Chothia&Lesk,1987,Canonical structuresfor the hypervariable regions ofimmunoglobulins.J.Mol.Biol.196,901-917;Chothia C.等人,1989,Conformations ofimmunoglobulin hypervariable regions.Nature 342,877-883;Chothia C.等人,1992,structural repertoire of the human VH segments J.Mol.Biol.227,799-817;Al-Lazikani等人,J.Mol.Biol 1997,273(4))。抗原结合位点的定义还在下述中描述:Ruiz等人,IMGT,the international ImMunoGeneTics database。Nucleic Acids Res.,28,219-221(2000);和Lefranc,M.-P.IMGT,the international ImMunoGeneTicsdatabase.Nucleic Acids Res.,Jan 1;29(l):207-9(2001);MacCallum等人,Antibody-antigen interactions:Contact analysis and binding site topography,J.Mol.Biol.,262(5),732-745(1996);和Martin等人,Proc.Natl Acad.Sci.USA,86,9268-9272(1989);Martin等人,Methods Enzymol.,203,121-153,(1991);Pedersen等人,Immunomethods,1,126,(1992);和Rees等人,In Sternberg M.J.E.(ed.),ProteinStructure Prediction.Oxford University Press,Oxford,141-172,1996,均以其全文形式被援引加入本文)。
每当术语“至少”或“大于”在一系列两个或多个数值中的第一个数值之前时,术语“至少”或“大于”适用于该系列数值中的每个数值。
术语“异源的”是指不是在有关与其相关的氨基酸或核苷酸序列中天然找到的氨基酸或核苷酸序列。
每当术语“不超过”或“小于”在一系列两个或多个数值中的第一个数值之前时,术语“不超过”或“小于”适用于该系列数值中的每个数值。
术语“多核苷酸”是指由核苷酸单元组成的聚合物。多核苷酸包括天然存在的核酸,例如脱氧核糖核酸(“DNA”)和核糖核酸(“RNA”),以及核酸类似物。核酸类似物包括包含非天然存在的碱基、与天然存在的磷酸二酯键以外的其它核苷酸键合的核苷酸、或/和通过磷酸二酯键以外的键合连接的碱基的那些。核苷酸类似物的非限制性实例包括硫代磷酸酯、二硫代磷酸酯、磷酸三酯、磷酰胺、硼酸磷酸酯、甲基膦酸酯、手性甲基膦酸酯、2-O-甲基核糖核苷酸、肽核酸(PNA)等。这样的多核苷酸可以例如使用自动化DNA合成仪合成。术语“核酸分子”通常是指较大的多核苷酸。术语“寡核苷酸”通常是指较短的多核苷酸。在某些实施例中,寡核苷酸包含不超过约50个核苷酸。应当理解,当核苷酸序列由DNA序列(即,A、T、G、C)表示时,其还包括其中“U”代替“T”的RNA序列(即,A、U、G、C)。
术语“多肽”是指由天然或/和非天然氨基酸残基、其天然存在的结构变体或/和其合成的非天然存在的类似物通过肽键连接而组成的聚合物。合成多肽可以例如使用自动化多肽合成仪合成。多肽也可以在表达编码多肽的核酸序列的细胞中重组产生。术语“蛋白质”通常是指较大的多肽。术语“肽”通常是指较短的多肽。在某些实施例中,肽包含不超过约50、40或30个氨基酸残基。多肽包括抗体及其片段。本文使用常规符号来描绘多肽序列:多肽序列的左手端是氨基(N)-末端;多肽序列的右手端是羧基(C)-末端。
多肽可以包括可以在多肽的合成或细胞生产过程中进行的一种或多种修饰,例如一种或多种翻译后修饰,无论一种或多种修饰是否是故意的。修饰可以包括但不限于糖基化(例如,N-连接的糖基化和O-连接的糖基化)、脂化、氧化磷酸化、硫酸化、乙酰化(例如,N-末端的乙酰化)、酰胺化(例如,C-末端的酰胺化)、羟基化、甲基化、分子内或分子间二硫键的形成、两条侧链之间的内酰胺的形成、焦谷氨酸的形成和泛素化。作为另一个实例,多肽可以连接至天然聚合物(例如多糖)或合成聚合物(例如聚乙二醇[PEG])、脂质化(例如用C8-C20酰基酰基化)或用可检测的试剂(例如,放射性核素、荧光染料或酶)标记。聚乙二醇化可以增加蛋白酶的抗性、稳定性和半衰期,增加溶解度并减少多肽的聚集。
术语“保守取代”是指用功能上、结构上或化学上相似的天然或非天然氨基酸取代多肽中的氨基酸。在某些实施例中,以下组各包含彼此保守取代的天然氨基酸:
1)甘氨酸(Gly/G),丙氨酸(Ala/A);
2)异亮氨酸(Ile/I),亮氨酸(Leu/L),蛋氨酸(Met/M),缬氨酸(Val/V);
3)苯丙氨酸(Phe/F),酪氨酸(Tyr/Y),色氨酸(Trp/W);
4)丝氨酸(Ser/S),苏氨酸(Thr/T),半胱氨酸(Cys/C);
5)天冬酰胺(Asn/N),谷氨酰胺(Gln/Q);
6)天冬氨酸(Asp/D),谷氨酸(Glu/E);和
7)精氨酸(Arg/R),赖氨酸(Lys/K),组氨酸(His/H)。
在另外的实施例中,以下组各包含彼此保守取代的天然氨基酸:
1)非极性:Ala,Val,Leu,Ile,Met,Pro(脯氨酸/P),Phe,Trp;
2)疏水性:Val,Leu,Ile,Phe,Tyr,Trp;
3)脂肪族:Ala,Val,Leu,Ile;
4)芳香族:Phe,Tyr,Trp,His;
5)不带电荷的极性或亲水性:Gly,Ala,Pro,Ser,Thr,Cys,Asn,Gln,Tyr(酪氨酸可被视为具有极性侧基的疏水氨基酸);
6)含脂肪族羟基或巯基:Ser,Thr,Cys;
7)含酰胺:Asn,Gln;
8)酸性:Asp,Glu;
9)碱性:Lys,Arg,His;和
10)小的:Gly,Ala,Ser,Cys。
在其它实施例中,氨基酸可如下分组列出:
1)疏水性:Val,Leu,Ile,Met,Phe,Trp,Tyr;
2)芳香族:Phe,Tyr,Trp,His;
3)中性亲水性:Gly,Ala,Pro,Ser,Thr,Cys,Asn,Gln;
4)酸性:Asp,Glu;
5)碱性:Lys,Arg,His;和
6)影响骨架方向的残基:Pro,Gly。
相对于亲本多肽具有一个或多个修饰的多肽可以适当地称为亲本多肽的“类似物”、“衍生物”或“变体”。
本公开内容涵盖多肽的药学上可接受的盐,包括具有正净电荷的那些、具有负净电荷的那些以及没有净电荷的那些。
术语“药学上可接受的”是指适合用于与受试者的组织和器官接触而没有过度刺激、过敏反应、免疫原性和毒性,与合理的收益/风险比相称,并且对于其预期用途有效的物质(例如活性成分或赋形剂)。药物组合物的“药学上可接受的”赋形剂或载体也与组合物的其它成分相容。
术语“严格的杂交条件”是指在42℃的温度下在5XSSC的50%甲酰胺中杂交,并在60℃下在0.2XSSC中洗涤过滤器(1XSSC是0.15M NaCl,0.015M柠檬酸钠)。严格的杂交条件还包括较低的离子强度和较高的洗涤温度,例如50℃下的0.015M氯化钠/0.0015M柠檬酸钠/0.1%十二烷基硫酸钠;与变性剂(例如甲酰胺)杂交,例如42℃下的50%(v/v)甲酰胺与0.1%牛血清白蛋白/0.1%Ficoll/0.1%聚乙烯吡咯烷酮/50mM磷酸钠缓冲液,pH为6.5,与750mM氯化钠、75mM柠檬酸钠;或42℃下的50%甲酰胺、5XSSC(0.75M NaCl、0.075M柠檬酸钠)、50mM磷酸钠(pH 6.8)、0.1%焦磷酸钠、5X Denhardt’s溶液、超声鲑鱼精子DNA(50μg/ml)、0.1%SDS和10%葡聚糖硫酸盐,在42℃下用55℃的0.2XSSC(氯化钠/柠檬酸钠)和50%甲酰胺洗涤,然后在55℃下进行含有含EDTA的0.1XSSC的高严格洗涤。
术语“受试者”是指动物,包括但不限于哺乳动物,例如灵长类动物(例如人、黑猩猩或猴子)、啮齿动物(例如大鼠、小鼠、豚鼠、沙鼠或仓鼠)、兔形动物(例如兔子)、猪(例如猪)、马(例如马)、犬科动物(例如狗)或猫科动物(例如猫)。
在两个多肽或多核苷酸的上下文中,术语“基本上同源”或“基本上相同”是指当使用序列比较算法或通过目视检查测量进行比较和比对以获得最大对应性时,具有至少约50%、60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%或99%的氨基酸或核酸残基同一性的两个或更多个序列或子序列。术语“基本上同源”或“基本上相同”可以表示至少约70%的氨基酸或核酸残基同一性。术语“基本上同源”或“基本上相同”可以表示至少约85%的氨基酸或核酸残基同一性。基本上同源性或同一性可以存在于长度至少约20、30、40、50、100、150或200个残基的序列区域上。在任一或两种比较生物聚合物的全长上,序列可以是基本上同源或相同的。
用于比较的序列的最佳比对可以例如通过Smith和Waterman,Adv.Appl.Math.,2:482(1981)的局部同源性算法;通过Needleman和Wunsch,J.Mol.Biol.,48:443(1970)的同源性比对算法;通过Pearson和Lipman,Proc.Natl.Acad.Sci.USA,85:2444(1988)的相似性寻找方法;通过这些算法的计算机化实现方式(例如,威斯康星州遗传学软件包中的GAP、BESTFIT、FASTA和TFASTA,美国威斯康星州麦迪逊市遗传学计算组);或通过目视检查来进行。
一种有用的算法实例是PILEUP。PILEUP使用渐进的成对比对从一组相关序列中创建多序列比对,以显示关系和百分比序列同一性。它还绘制了树或树状图,显示用于创建比对的聚类关系。PILEUP使用Feng和Doolittle,J.Mol.Evol.,35:351-360(1987)的渐进比对方法的简化。所使用的方法类似于Higgins和Sharp,CABIOS,5:151-153(1989)所描述的方法。该程序可以比对多达约300个序列,每个序列的最大长度为约5,000个核苷酸或氨基酸。多重比对程序从两个最相似序列的成对比对开始,产生两个比对的序列簇。然后将该簇与下一个最相关的序列或比对的序列簇进行比对。通过两个单独序列的成对比对的简单扩展,可以比对两个序列簇。最终的比对通过一系列渐进的成对比对实现。通过为序列比较区域指定特定序列及其氨基酸或核苷酸坐标并通过指定程序参数来运行该程序。例如,可以使用以下参数将参考序列与其它测试序列进行比较,以确定百分比序列同一性关系:默认空位权重(3.00)、默认空位长度权重(0.10)和加权末端空位。对于产生序列的多重比对有用的另一种算法是Clustal W(参见,例如,Thompson等人,Nucleic Acids Research,22:4673-4680[1994])。
适于确定百分比序列同一性和序列相似性的算法的另一实例是BLAST算法,其描述于Altschul等人,J.Mol.Biol.,215:403-410(1990)。可通过国家生物技术信息中心公开获得进行BLAST分析的软件。该算法涉及首先通过识别查询序列中长度为W的短word来识别高分序列对(HSP),这些短word在与数据库序列中相同长度的word比对时匹配或满足一些正值阈值得分T。T称为邻域(neighborhood)word得分阈值(Altschul 1990)。这些最初的邻域word hits(命中)充当启动搜索以找到包含它们的较长HSP的种子(seed)。然后将wordhits沿着每个序列在两个方向上延伸,直到可以增加累积的比对得分。对于核苷酸序列,使用参数M(一对匹配残基的奖励分数;始终>0)和N(错配残基的罚分;始终<0)来计算累积得分。对于氨基酸序列,使用得分矩阵来计算累积得分。在以下情况下,将停止word hits在每个方向上的扩展:累积的比对得分比其最大实现值降低数量X;由于一个或多个负得分残基比对的累积,累积得分变为零或更低;或到达任一序列的末端。BLAST算法参数W、T和X确定比对的灵敏度和速度。BLASTN程序(用于核苷酸序列)使用默认值,例如字长(W)为11,期望(E)为10,M=5,N=-4,和两条链的比较。对于氨基酸序列,BLASTP程序使用默认值,例如字长(W)为3,期望(E)为10,和BLOSUM62得分矩阵(请参见Henikoff和Henikoff,Proc.Natl.Acad.Sci.USA,89:10915[1989])。
除了计算百分比序列同一性外,BLAST算法还对两个序列之间的相似性进行统计分析(参见,例如,Karlin和Altschul,Proc.Natl.Acad.Sci.USA,90:5873-5787[1993])。BLAST算法提供的一种相似性度量是最小总和概率[P(N)],它表示两个核苷酸或氨基酸序列之间偶然发生匹配的概率。在某些实施例中,如果在测试多核苷酸与参考多核苷酸的比较中最小总和概率小于约0.1、0.01或0.001,则认为多核苷酸与参考序列相似。
如果两个多肽仅通过保守氨基酸取代而不同,则该多肽可以与第二多肽基本上同源或相同。如本文所述,如果两个多核苷酸在严格条件下或在高度严格条件下彼此杂交,则两个核酸序列可以是基本上同源或相同的。
术语“治疗有效量”是指化合物的量,当施予受试者时,该量足以防止、降低发展的风险,延缓其发作,减缓发展或引起所治疗的医学病症的消退,或在某种程度上减轻该病症的医学病症或一种或多种症状或并发症。术语“治疗有效量”还指足以引起研究人员、兽医、医生或临床医生所寻求的细胞、组织、器官、系统、动物或人的生物学或医学反应的化合物的量。
术语“治疗”包括减轻、改善或消除医学病症或与该病症有关的一种或多种症状或并发症,以及减轻、改善或消除该病症的一种或多种病因。提及医学病症的“治疗”包括预防病症。术语“预防”包括预防、降低发展的风险和延迟医学病症或与该病症相关的一种或多种症状或并发症的发作。
抗CD79抗体
本文所述的抗体对CD79具有特异性,并包括上述所有形式。可以将抗体工程化以用于特定生物体。生物体可以是人、犬科动物或有商业价值的家畜,例如猪、马、狗、猫、鸡或其它鸟类。抗体的这种工程化改造包括,例如,使用本领域已知的任何库技术或单克隆技术的CDR剪接、人源化、人过程化、嵌合或分离人(或其它生物体)抗体。
抗CD79抗体可以包括选自SEQ ID NO:9-17,24-27和32-41的重链可变区,和选自SEQ ID NO:18-23,28-31和42-56的轻链可变区。例如,可以将具有SEQ ID NO:9的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,71,72,75,76或77的可变区的轻链结合。可以将具有SEQ ID NO:10的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:11的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:12的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:13的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:14的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:15的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:16的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:17的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:24的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:25的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:26的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:27的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:28的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:33的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:34的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:35的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:36的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:37的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:38的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:39的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:40的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:41的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:71的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:72的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:75的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:76的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。可以将具有SEQ ID NO:77的可变区的重链与具有SEQ ID NO:18,19,20,21,22,23,28,29,30,31,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,73或74的可变区的轻链结合。
抗CD79抗体还可以包含与SEQ ID NO:9-17,24-27,32-41,71,72和75-77中之一具有99%、95%、90%、80%或70%的序列同一性的重链可变区,以及选自SEQ ID NO:18-23,28-31,42-56和73-74的轻链可变区。抗CD79抗体还可以包含与SEQ ID NO:9-17,24-28和33-43中之一具有99%、95%、90%、80%或70%的序列同一性的重链可变区,以及与SEQ IDNO:18-23,28-31,42-56和73-74中之一具有99%、95%、90%、80%或70%的序列同一性的轻链可变区。抗CD79抗体还可以包含选自SEQ ID NO:9-17,24-27,32-41,71,72和75-77的重链可变区,以及与SEQ ID NO:18-23,28-31,42-56和73-74中之一具有99%、95%、90%、80%或70%的序列同一性的轻链可变区。抗CD79抗体可以以2.0-5.1nM、或45nM至300nM、或2.0至300nM的亲和力与CD79结合。抗CD79抗体可以以至少300nM、或至少140nM、或至少100nM、或至少5.1nm、至少3.8nM、或至少2.4nM的亲和力结合。
亲和力成熟可以与本文公开的抗体一起使用以获得期望的亲和力的抗CD79抗体。当从动物(例如,携带人抗体库的转基因动物)获得抗CD79抗体时,在转基因动物中制备的抗体可以经历亲和力成熟。可替换地,可以使用链改组方法和/或对编码VH和VL的核酸进行突变,然后通过筛选和/或选择具有更大亲和力的抗体,对来自转基因动物或来自其它技术(例如展示技术)的抗体进行亲和力成熟。
使非人抗体的免疫原性最小化同时保留特异性和亲和力的最广泛使用的方法包括将非人抗体的CDR移植到通常根据其与非人框架的结构同源性选择的人框架上(Jones等人,1986,Nature 321:522-5;美国专利号5,225,539,均以其全文形式在此被援引加入本文)。在框架中关键位置处包含某些非人残基可以改善CDR移植抗体的亲和力(Bajorath等人,1995,J Biol Chem 270:22081-4;Martin等人,1991,Methods Enzymol.203:121-53;Al-Lazikani,1997,J Mol Biol 273:927-48,均以其全文形式在此被援引加入本文)。通过CDR移植来人源化抗体的示例性方法公开于例如美国专利号6,180,370,该专利以其全文形式在此被援引加入本文。
对传统CDR移植方法的改进使用了多种杂交选择方法,其中在连续的几轮选择中,非人抗体的部分已与互补人抗体序列的文库结合,以进行抗原结合,在此过程中,大多数非人序列逐渐被人序列取代。例如,在链改组技术(Marks等人,1992,Biotechnology 10:779-83,该篇文献以其全文形式在此被援引加入本文)中,将非人抗体的一条链与另一条链的天然人源库结合,根本原因是非人链的亲和力将足以约束将人配体(partner)选定在抗原上的相同表位。然后,选定的人配体用于指导选择其余非人链的人对应物(counterpart)。
其它方法包括链置换技术,其中保留非人CDR3,并且仅其余的V区(包括框架和CDR1和2)在依次进行的步骤中被单独置换(例如,美国专利申请号20030166871;Rader等人,Proc Natl Acad Sci USA95:8910-15,1998;Steinberger等人,J.Biol.Chem.275:36073-36078,2000;Rader等人,J.Biol.Chem.275:13668-13676,2000,均以其全文形式在此被援引加入本文)。
通过使用与用于制备用于人类的抗体的CDR移植方法相类似的方法将CDR工程化到受试者物种的框架区中,可以使用这些技术来制备适用于非人受试者的抗体。
可以使用起始抗CD79抗体并将起始抗CD79抗体的可变区(例如CDR)的部分移植到所需的可变域框架中来制备抗CD79抗体。小鼠可变区为:QVQLQQSGPELVKPGASVKISCKASGYAFSYSWMNWVKQRPGKGLEWIGRIYP ENGDTNYNGKFKGKVTLTADKSSSTAYMQLSSLTSEDSAVYFCARWVYGYPHF DYWGQGTTLTVSS(重链可变区,SEQ ID NO:1)
DVVMTQTPLTLSVTIGQPASISCKSSQSLLDSDGKTYLNWLLQRPGQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFPFTFGSGTKL EIK(轻链可变区,SEQ ID NO:2)
例如,使用CDR制备抗CD79人源化抗体:
VHCDR1:YSWMN(SEQ ID NO:3)
VHCDR2:RIYPENGDTNYNGKFKG(SEQ ID NO:4)
VHCDR3:WVYGYPHFDY(SEQ ID NO:5)
VLCDR1:KSSQSLLDSDGKTYLN(SEQ ID NO:6)
VLCDR2:LVSKLDS(SEQ ID NO:7)
VLCDR3:WQGTHFPFT(SEQ ID NO:8)
将三个VH CDR置于人重链可变区的框架序列中以产生VH链:QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRI YPENGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGYP HFDYWGQGTLVTVSS(SEQ ID NO:9)
该VH命名为H1。将取代引入到SEQ ID NO:9的框架区中,以形成两条额外的VH链:
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTADTSISTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:10)
SEQ ID NO:10命名为H2。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWIGRIYPENGDTNYNGKFKGRVTLTADKSISTAYMELSRLRSDDTAVYYCARWVYGYPH FDYWGQGTLVTVSS(SEQ ID NO:11)
SEQ ID NO:11命名为H3。可以在框架区和CDR2中向SEQ ID NO:9引入另外的改变,以增加亲和力和/或稳定抗体抵抗例如氧化、脱氨基和/或蛋白酶切割。这些重链序列的实例是:
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYAGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:12)
SEQ ID NO:12命名为H4。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYAGKFKGRVTMTADTSISTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:13)
SEQ ID NO:13命名为H5。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWIGRIYPENGDTNYAGKFKGRVTLTADKSISTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:14)
SEQ ID NO:14命名为H6。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPESGDTNYAGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:15)
SEQ ID NO:15命名为H7。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPESGDTNYAGKFKGRVTMTADTSISTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:16)
SEQ ID NO:16命名为H8。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWIGRIYPESGDTNYAGKFKGRVTLTADKSISTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:17)
SEQ ID NO:17命名为H9。
将三个VL CDR置于人轻链可变区的框架序列中以产生VL链:DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWFQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:18)
SEQ ID NO:18命名为L1。将取代引入到SEQ ID NO:18的框架区中,以形成额外的VL链:
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:19)
SEQ ID NO:19命名为L2。
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPKRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:20)
SEQ ID NO:20命名为L3。可以在框架区和CDR1中向SEQ ID NO:18引入另外的改变,以增加亲和力和/或稳定抗体抵抗例如氧化、脱氨基和/或蛋白酶切割。这些轻链序列的示例是:
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSSGKTYLNWFQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:21)
SEQ ID NO:21命名为L4。
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSSGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:22)
SEQ ID NO:22命名为L5。
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSSGKTYLNWLQQRPGQSPKRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:23)
SEQ ID NO:23命名为L6。
将三个VH链(H1-H3)与三个VL链(L1-L3)用组合方法组合在一起,重组表达并分离每种抗体。H1-H3和L1-L3抗体链具有相关的框架区,该框架区在几个位置上不同,这可以改善亲和力。测试了这些候选物对CD79的亲和力。候选物结合到具有45nM至300nM范围的Kds的CD79。从这些结果中选择了H1L2(LB495/PRI47,SEQ ID NO:9和19)。
本公开内容涵盖抗CD79抗体的药学上可接受的盐,包括具有正净电荷的那些、具有负净电荷的那些和不具有净电荷的那些,并且包括但不限于在药物组合物中,在其治疗和诊断用途中以及在其生产中的抗CD79抗体(包括其片段)的盐作为化合物。
亲和力成熟
使人源化抗体H1L2(SEQ ID NO:9和19)亲和力成熟。制备了四个噬菌体展示文库,两个来自重链H1(LB495),两个来自轻链L2(PRI47)。对重链(H1)和轻链(L2)的CDR3进行饱和诱变,并且诱变的重链与L2结合,诱变的轻链与H1结合。易错PCR用于随机诱变重链(H1)和轻链(L2),并且诱变的重链与L2结合,诱变的轻链与H1结合。这四个文库以噬菌体展示形式产生,用于进一步筛选。
在包括人源化抗体H1L2在内的竞争性结合中针对CD79淘选每个文库。在竞争性淘选中从文库中选择克隆,在其中加入人源化的H1L2抗体,并将其与基底上的CD79连接,克隆必须与人源化的H1L2抗体竞争。从四个文库的竞争性淘选中获得了三十七(37)个克隆(来自CDR3重链文库的五(5)个,来自CDR3轻链文库的四(4)个,来自重链文库的十一(11)个和来自轻链文库的17个)。来自CDR3重链文库的这5个克隆的序列为:
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARPVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:24)
SEQ ID NO:24命名为LB509-A7。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGLPHFDYWGQGTLVTVSS(SEQ ID NO:25)
SEQ ID NO:25命名为LB509-C2。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVWGYPHFDYWGQGTLVTVSS(SEQ ID NO:26)
SEQ ID NO:26命名为LB509-C10。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGYPHLDYWGQGTLVTVSS(SEQ ID NO:27)
SEQ ID NO:27命名为LB509-G2。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGYPHLDYWGQGTLVTVSS(SEQ ID NO:71)
SEQ ID NO:71也被命名为LB509-H1。
来自CDR3轻链文库的4个克隆的序列为:
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHIPFTFGGGTKVEIK(SEQ ID NO:28)
SEQ ID NO:28命名为LB511-A9。
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHVPFTFGGGTKVEIK(SEQ ID NO:29)
SEQ ID NO:29命名为LB511-B6。
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHLPFTFGGGTKVEIK(SEQ ID NO:30)
SEQ ID NO:30命名为LB511-F6。
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHRPFTFGGGTKVEIK(SEQ ID NO:31)
SEQ ID NO:31命名为LB511-F11。
来自重链文库的11个克隆的序列为:
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:32)
SEQ ID NO:32命名为LB510-B5。
QVQLVQSGAEVKKPGASVKVSCKASGYAFGYSWMNWVRQAPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:33)
SEQ ID NO:33命名为LB510-C7。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRPDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:34)
SEQ ID NO:34命名为LB510-C8。
QVQLVQSGAEVKKPGASVKVSCKASGYAFNYSWMNWVRQVPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:35)
SEQ ID NO:35命名为LB510-F10。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTRDTSINTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:36)
SEQ ID NO:36命名为LB510-G4。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWVNWVRQAPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:37)
SEQ ID NO:37命名为LB510-G5。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTRDTSISTAYMELSGLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:38)
SEQ ID NO:38命名为LB510-G6。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGYPHLDYWGQGTLVTVSS(SEQ ID NO:39)
SEQ ID NO:39命名为LB510-G7。
QVQLVQSGAEVKKPGASVKVSCKASGYAFNYSWVNWVRQAPGQGFEWMGRIYPENGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:72)
SEQ ID NO:72也被命名为LB510-H4。
QVQLVQSGAEVKKPGASVKVSCKASGYAFRYSWMNWVRQAPGQGLEWMGRIYPENGGTNYNGKFKGRVTMTMDTSISTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:40)
SEQ ID NO:40命名为LB510-H7。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYNGKFRGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGYPHFDYWGQGTLVTVSS(SEQ ID NO:41)
SEQ ID NO:41命名为LB510-H11。
来自轻链文库的17个克隆的序列为:
DVVMTQSPLSLPVTLGLPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:42)
SEQ ID NO:42命名为LB512-A7。
DVVMTQSPLSLPVTLGQPASISCKSSKSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:43)
SEQ ID NO:43命名为LB512-A10。
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRIIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:44)
SEQ ID NO:44命名为LB512-B8。
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEADDVGVYYCWQGTHLPFTFGGGTKVEIK(SEQ ID NO:45)
SEQ ID NO:45命名为LB512-B10。
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGFYYCWQGTHLPFTFGGGTKVEIK(SEQ ID NO:46)
SEQ ID NO:46命名为LB512-C2。
DVVMTQSPLSLPVTLGQTASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHLPFTFGGGTKVEIK(SEQ ID NO:47)
SEQ ID NO:47命名为LB512-E2。
DVVMTQSPLSLPVTLGRPASISCKSSQSLLDSGGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:48)
SEQ ID NO:48命名为LB512-E5。
DVVMTQSPLSLPVTLGQPASISCKSSRSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:49)
SEQ ID NO:49命名为LB512-E8。
DVVMTQSPLSLPVTLGLPASISCKSSQSLLDTDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFIGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:50)
SEQ ID NO:50命名为LB512-E10。
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHLPFTFGGGTKVEIK(SEQ ID NO:73)
SEQ ID NO:73也被命名为LB512-F7。
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQPPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:51)
SEQ ID NO:51命名为LB512-F11。
DVVMTQSPLSLPVTLGQPASITCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKPDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:52)
SEQ ID NO:52命名为LB512-G2。
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHLPFTFGGGTKVEIK(SEQ ID NO:74)
SEQ ID NO:74也被命名为LB512-G5。
DVVMTQSPPSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHVPFTFGGGTKVEIK(SEQ ID NO:53)
SEQ ID NO:53命名为LB512-H5。
DVVMTQSPLSLPVTLGQTASISCKSSQSLLDRDGKTYLNWLQQRPGQSPRRIIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:54)
SEQ ID NO:54命名为LB512-H7。
DVVMTQSPLSMPVTLGLPASISCKSSQSLLDSHGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPFTFGGGTKVEIK(SEQ ID NO:55)
SEQ ID NO:55命名为LB512-H8。
DVVMTQSPLSLPVTLGLPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHIPFTFSGGTKVEIK(SEQ ID NO:56)
SEQ ID NO:56命名为LB512-H11。
在竞争性ELISA中筛选了这37个克隆。挑选出比亲本(parent)抗体(H1L2)具有更好结合力的克隆。从竞争性ELISA中获得了九个具有更好亲和力的克隆。两个来自重链CDR3文库(LB509-C2,SEQ ID NO:25;和LB509-G2,SEQ ID NO:27),四个来自轻链CDR3文库(LB511-A9,SEQ ID NO:28;LB511-B6,SEQ ID NO:29;LB511-F6,SEQ ID NO:30;LB511-F11,SEQ ID NO:31),两个来自重链文库(LB510-C7,SEQ ID NO:33;LB510-G5,SEQ ID NO:37),一个来自轻链文库(A7,SEQ ID NO:42)。将这些克隆进行验证性稀释ELISA,并选择表现出更好结合的五个克隆(重链CDR克隆LB509-C2,SEQ ID NO:25;轻链CDR克隆LB511-A9,SEQID NO:28,LB511-B6,SEQ ID NO:29,LB511-F6,SEQ ID NO:30,和LB511-F11,SEQ ID NO:31)。重链CDR克隆C2在CDR3中具有从Y到L的变化,而轻链克隆A9、B6、F6和F11在CDR3中在相同位置具有从F到L、V、I或R的氨基酸变化。制备了两条具有H1序列(SEQ ID NO:10)(命名为LB495),或由Y到L的改变(SEQ ID NO:25)(命名为LB517)的重链,并且制备了五条具有L2序列(SEQ ID NO:19)(命名为PRI47),或L2的CDR3中由F到I(SEQ ID NO:28)(命名为LB518),L2的CDR3中由F到L(SEQ ID NO:30)(命名为LB519),L2的CDR3中由F到R(SEQ ID NO:31)(命名为LB520),或L2的CDR3中由F到V(SEQ ID NO:29)(命名为LB521)的改变的轻链。将两条重链分别与五条轻链用组合方法单独组合,并测试这些抗体的结合动力学。
所有亲和力成熟的抗体组合都比亲本抗体H1L2具有更高的结合CD79的亲和力。亲本抗体对CD79的Kd为5.1nM,而亲和力成熟的抗体对CD79的Kd为3.6nM至2.0nM。
抗CD79抗体修饰
抗CD79抗体可以包括延长抗体的半衰期(T1/2)或/和作用持续时间的部分。该部分可以延长抗体的循环T1/2、血液T1/2、血浆T1/2、血清T1/2、末端T1/2、生物学T1/2、消除T1/2或功能性T1/2、或其任何组合。
抗CD79抗体可以被单个部分修饰。可替换地,抗CD79抗体可以被两个或更多个基本相似或相同的部分或两个或更多个相同类型的部分修饰。抗CD79抗体可以包括两个或更多个不同类型的部分,或者两个或更多个部分的不同类型。两种或多种抗CD79抗体也可以连接到一个部分。抗CD79抗体和该部分之间的连接可以是共价的或非共价的。
可以可选地经由接头将多肽部分重组融合至抗CD79抗体的重链或轻链的N-末端或C-末端。接头可包含约4-30个氨基酸残基。接头可包含从约6或8个氨基酸残基至约20个氨基酸残基,或从约6或8个氨基酸残基至约15个氨基酸残基。
延长部分可以是人血清白蛋白(HSA)或其与新生儿Fc受体(FcRn)结合的部分(例如结构域III)。HSA或其FcRn结合部分可以可选地具有一种或多种赋予有益特性或作用的突变。在某些实施例中,HSA或其FcRn结合部分具有一种或多种突变,所述突变增强pH依赖性的HSA与FcRn的结合或/和增加HSA半衰期,例如K573P或/和E505G/V547A。延长部分可以是非结构化多肽。
延长部分可以是衍生自人绒毛膜促性腺激素(hCG)的β-亚基的羧基末端肽(CTP)。在人体中,hCG-β的34个氨基酸的CTP的第四、第五、第七和第八位丝氨酸残基通常与终止于唾液酸残基的O-聚糖连接。
延长部分可以是合成聚合物的1、2、3、4、5或更多个部分。合成聚合物可以是可生物降解的或不可生物降解的。可用作延长部分的可生物降解的聚合物包括但不限于聚(2-甲基丙烯酰氧乙基磷酰胆碱)(PMPC)和聚[低聚(乙二醇)甲基醚甲基丙烯酸酯](POEGMA)。可用作延长部分的不可生物降解的聚合物包括但不限于聚(乙二醇)(PEG)、聚甘油、聚(N-(2-羟丙基)甲基丙烯酰胺)(PHPMA)、聚恶唑啉和聚(N-乙烯基吡咯烷酮)(PVP)。合成聚合物可以是聚乙二醇(PEG)。聚乙二醇化可以通过化学或酶促、位点特异性偶联或通过随机偶联来完成。
一种或多种合成聚合物部分的单个质量(例如平均分子量)或总质量可以为约10-50、10-20、20-30、30-40或40-50kDa,或约10、20、30、40或50kDa。一种或多种合成聚合物部分的单个质量(例如平均MW)或总质量也可以大于约50kDa,例如约50-100、50-60、60-70、70-80、80-90或90-100kDa,或约60、70、80、90或100kDa。而且,单个合成聚合物部分的质量(例如平均MW)可以小于约10kDa,例如约1-5或5-10kDa,或约5kDa。一种或多种合成聚合物(例如PEG)部分的单个质量(例如平均MW)或总质量可以为约20或40kDa。
药物组合物
本公开内容的其它实施例涉及药物组合物,包括抗CD79抗体或其药学上可接受的盐、溶剂化物或水合物,以及一种或多种药学上可接受的赋形剂或载体。组合物可以可选地包含其它治疗剂。一般,药物组合物包含治疗有效量的抗CD79抗体或其片段、一种或多种药学上可接受的赋形剂或载体以及可选地治疗有效量的其它治疗剂,并被配制用于向受试者施用用于治疗用途。
药物组合物一般是根据现行的良好生产规范(GMP)制备的,例如,如联邦食品、药品和化妆品法案§501(a)(2)(B)和国际协调会议Q7指导方针所建议或要求的。
药物组合物/制剂(配方)可以以无菌形式制备。例如,用于通过注射或输注肠胃外施用的药物组合物/制剂一般是无菌的。根据本领域技术人员已知的药物级灭菌标准,例如在美国药典第797、1072和1211章以及21Code of Federal Regulations 211中公开或要求的那些,来合成或制造无菌药物组合物/制剂。
药学上可接受的赋形剂和载体包括药学上可接受的物质、材料和媒介物。赋形剂类型的非限制性实例包括液体和固体填充剂、稀释剂、粘合剂、润滑剂、助流剂、表面活性剂、分散剂、崩解剂、乳化剂、湿润剂、悬浮剂、增稠剂、溶剂、等渗剂、缓冲剂、pH调节剂、吸收延迟剂、稳定剂、抗氧化剂、防腐剂、抗微生物剂、抗菌剂、抗真菌剂、螯合剂、助剂、甜味剂、调味剂、着色剂、包封材料和涂料。此类赋形剂在药物制剂/配方中的使用是本领域已知的。例如,常规的媒介物和载体包括但不限于油(例如植物油,例如橄榄油和芝麻油)、水性溶剂{例如,盐水、缓冲盐水(例如,磷酸盐缓冲盐水[PBS])和等渗溶液(例如,Ringer’s溶液)}和有机溶剂(例如二甲基亚砜[DMSO]和醇[例如乙醇、甘油和丙二醇])。除了在任何常规赋形剂或载体与抗CD79抗体或其片段不相容的范围内之外,本公开内容涵盖常规赋形剂和载体在含有抗CD79抗体或其片段的制剂/配方中的使用。参见,例如,Remington:The Scienceand Practice of Pharmacy,第21版,Lippincott Williams&Wilkins(Philadelphia,Pennsylvania)(2005);Handbook of Pharmaceutical Excipients,第5版,Rowe等任,Eds.,The Pharmaceutical Press and the American Pharmaceutical Association(2005);Handbook of Pharmaceutical Additives,第3版,Ash和Ash,Eds.,GowerPublishing Co.(2007);以及Pharmaceutical Pre-formulation and Formulation,Gibson,Ed.,CRC Press(Boca Raton,Florida)(2004)。
适当的制剂/配方可以取决于多种因素,例如选择的给药途径。包含抗CD79抗体或其片段的药物组合物的潜在给药途径包括但不限于口服、肠胃外(包括皮内、皮下、肌肉内、血管内、静脉内、动脉内、腹膜内、髓内、鞘内和局部)、腔内和局部(包括皮肤/表皮、经皮、粘膜、透粘膜、鼻内(例如,通过鼻喷剂或滴剂)、眼内(例如,通过滴眼剂)、肺部(例如,通过口服或经鼻吸入)、口腔、舌下、直肠[例如,通过栓剂]和阴道[例如,通过栓剂])。可将局部制剂/配方设计成产生局部或全身治疗作用。在某些实施例中,抗CD79抗体或其片段在一段时间内通过注射(例如,作为单次给药剂量)或输注肠胃外(例如,静脉内、皮下、肌肉内或腹膜内)给药。
可用于制备肠胃外制剂的赋形剂和载体包括但不限于溶剂(例如水性溶剂,例如水、盐水、生理盐水、缓冲盐水(例如磷酸盐缓冲盐水)、平衡盐溶液(例如Ringer’s BSS)和右旋糖水溶液)、等渗/等渗剂(例如盐[例如NaCl、KCl和CaCl2]和糖[例如蔗糖])、缓冲剂和pH调节剂(例如磷酸二氢钠[磷酸一钠]/磷酸氢二钠[磷酸二钠]、柠檬酸/柠檬酸钠和L-组氨酸/L-组氨酸HCl)以及乳化剂(例如非离子表面活性剂,例如聚山梨酯[例如聚山梨酯20和80]和泊洛沙姆[例如泊洛沙姆188])。蛋白质制剂和递送系统在例如A.J.Banga,Therapeutic Peptides and Proteins:Formulation,Processing,and DeliverySystems,第3版,CRC Press(Boca Raton,Florida)(2015)中进行了讨论。
赋形剂可以可选地包括一种或多种增加蛋白质稳定性、增加蛋白质溶解度、抑制蛋白质聚集或降低溶液粘度的物质,或其任何组合或全部。此类物质的实例包括但不限于亲水性氨基酸(例如精氨酸和组氨酸)、多元醇(例如myo-肌醇,甘露醇和山梨糖醇)、糖类{例如葡萄糖(包括D-葡萄糖[右旋糖])、乳糖、蔗糖和海藻糖}、渗透剂(例如海藻糖、牛磺酸、氨基酸[例如甘氨酸、肌氨酸、丙氨酸、脯氨酸、丝氨酸、β-丙氨酸和γ-氨基丁酸]和甜菜碱[例如三甲基甘氨酸和三甲胺N-氧化物])和非离子表面活性剂{例如烷基多苷、烷基糖(例如,单糖[例如葡萄糖]或二糖[例如麦芽糖或蔗糖]与长链脂肪酸或相应的长链醇偶联)和聚丙二醇/聚乙二醇嵌段共聚物(例如泊洛沙姆[例如,PluronicTMF-68]和PF-10及其变体)}。由于此类物质增加蛋白质溶解度,因此它们可用于增加制剂/配方中的蛋白质浓度。制剂/配方中较高的蛋白质浓度对于皮下给药是特别有利的,其具有有限量的剂量给药(例如≤约1.5mL)。此外,在冻干蛋白的制备、储存和重构过程中,此类物质可用于稳定蛋白质。
对于肠胃外(例如,静脉内、皮下或肌肉内)给药,可以预先制备抗CD79抗体在含有一种或多种赋形剂的水性溶剂中的无菌溶液或悬浮液,并且可以在例如预填充的注射器中提供。可替换地,可以在冷冻干燥(冷冻-干燥)之前将抗CD79抗体溶解或悬浮在水性溶剂中,该水性溶剂可以可选地包含一种或多种赋形剂。肠胃外给药前不久,可以用例如无菌水重构储存在合适容器(例如小瓶)中的冻干抗CD79抗体,所述无菌水可以可选地包含一种或多种赋形剂。如果抗CD79抗体要通过输注(例如静脉内)给药,则可以将重构的抗CD79抗体的溶液或混悬液添加到含有例如无菌盐水(例如约0.9%NaCl)的输液袋中并稀释。
增强较小蛋白质的透粘膜渗透性的赋形剂包括但不限于环糊精、烷基糖类(例如烷基苷类和烷基麦芽糖苷[例如十四烷基麦芽糖苷])和胆汁酸(例如胆酸、甘氨胆酸、牛磺胆酸、去氧胆酸、脱氧甘胆酸、鹅去氧胆酸和去氢胆酸)。
增强较小蛋白质的经上皮或经皮渗透性的赋形剂包括但不限于化学渗透增强剂(CPE,包括脂肪酸[例如油酸])、细胞穿透肽{CPP,包括富含精氨酸的CPP[例如聚精氨酸,例如R6-R11(例如R6和R9)和与TAT相关的CPP,例如TAT(49-57)]和两亲性CPP[例如Pep-1和渗入剂(penetratin)]}以及渗透皮肤的肽(SPP,例如穿透皮肤和进入细胞的[SPACE]肽)。通过使用物理增强技术,例如离子电渗疗法、空化或非空化超声、电穿孔、热消融、射频、微晶换肤、微针或喷射注射,可以进一步增强较小蛋白质的经皮渗透性。US 2007/0269379提供了广泛的CPE列表。F.Milletti,Drug Discov.Today,17:850-860(2012)是对CPP的综述。R.Ruan等人,Ther.Deliv.,7:89-100(2016)讨论了用于大分子经皮递送的CPP和SPP,M.Prausnitz和R.Langer,Nat.Biotechnol.,26:1261-1268(2008)讨论了各种经皮药物递送方法。
可以从缓释组合物中递送抗CD79抗体。如本文所使用的,术语“缓释组合物”涵盖持续释放、拖延释放(prolonged-release)、延长释放(extended-release)、缓慢释放和控制释放的组合物、系统和装置。蛋白质递送系统在例如Banga(在前)中讨论。缓释组合物可以在延长的时间段内递送治疗有效量的抗CD79抗体。在某些实施例中,缓释组合物在至少约3天、1周、2周、3周、1个月(4周)、6周、2个月、3个月或更长的时间内递送抗CD79抗体。缓释组合物可以例如肠胃外(例如静脉内、皮下或肌肉内)给药。
蛋白质的缓释组合物可以是例如颗粒系统、脂质或油性组合物、或植入物的形式。颗粒系统包括但不限于纳米颗粒、纳米球、纳米胶囊、微粒、微球和微胶囊。纳米颗粒系统一般具有小于约1μm的直径或等效尺寸。在某些实施例中,纳米颗粒、纳米球或纳米胶囊的直径或等效尺寸不超过约500、400或300nm,或不超过约200、150或100nm。在某些实施例中,微粒、微球或微胶囊的直径或等效尺寸为约1-200、100-200或50-150μm,或约1-100、1-50或50-100μm。纳米胶囊或微胶囊通常在中央核心中包含治疗剂,而治疗剂通常分散在整个纳米颗粒或微粒或纳米球或微球中。在某些实施例中,纳米颗粒系统通过静脉内给药,而微粒系统则通过皮下或肌肉内给药。
在某些实施例中,缓释颗粒系统或植入物由生物可降解的聚合物或/和水凝胶制成。在某些实施例中,可生物降解的聚合物包括乳酸或/和羟基乙酸[例如,基于L-乳酸的共聚物,例如聚(L-丙交酯-共-乙交酯)或聚(L-乳酸-共-D,L-2-羟基辛酸)]。可以组成水凝胶的聚合物的非限制性实例包括聚乙烯醇、丙烯酸盐聚合物(例如聚丙烯酸钠)和具有相对大量亲水基团(例如羟基或/和羧酸根基团)的其它均聚物和共聚物。可以选择颗粒系统或植入物的可生物降解的聚合物,使得该聚合物在预计治疗期结束时会基本完全降解,并且使得聚合物降解的副产物(如聚合物)具有生物相容性。
可替换地,蛋白质的缓释组合物可以由不可生物降解的聚合物组成。不可生物降解的聚合物的实例包括但不限于泊洛沙姆(例如泊洛沙姆407)。蛋白质的缓释组合物可以由其它天然或合成物质或材料组成,例如羟磷灰石。
蛋白质的缓释脂质或油性组合物可以是例如脂质体、微胶粒(例如,由可生物降解的天然或/和合成聚合物组成的那些,例如乳糖体(lactosome))和油中的乳剂的形式。
可以将缓释组合物配制成或设计为储库(depot),其可以例如皮下或肌肉内注射或植入。储库可以是例如聚合物颗粒系统、聚合物植入物或脂质或油性组合物的形式。储库制剂可以在生物相容性溶剂系统中包含蛋白质和例如生物可降解聚合物[例如聚(丙交酯-共-乙交酯)]或半生物可降解聚合物(例如乳酸和PEG的嵌段共聚物)的混合物,无论这种混合物是否形成颗粒系统或植入物。
药物组合物可以作为单剂量以单位剂型形式存在,其中所有活性和非活性成分在合适的系统中组合,并且不需要混合组分以形成待施用的组合物。单位剂型一般包含有效剂量的治疗剂。单位剂型的代表性实例是一次性使用注射笔(single-use pen),包括用于胃肠外(例如,静脉内、皮下或肌肉内)注射治疗剂的预填充注射器、针头和针头套。
可替换地,可以将药物组合物作为试剂盒提供,其中将治疗剂、赋形剂和载体(例如溶剂)提供在两个或更多个单独的容器(例如安瓿、小瓶、管、瓶或注射器)中,并且需要组合以形成待施用的组合物。试剂盒可以包含用于储存、制备和施用组合物(例如,要静脉内或皮下注射的溶液)的说明书。
试剂盒可以包含单位剂型形式的所有活性和非活性成分,或者在两个或更多个单独的容器中包含活性成分和非活性成分,并且可以包含用于施用或使用药物组合物来治疗医学病症的说明书。
在某些实施例中,试剂盒包含抗CD79抗体或含有抗CD79抗体的药物组合物,以及用于施用或使用抗CD79抗体或含有抗CD79抗体的药物组合物以治疗抗体相关病症的说明书。
抗CD79抗体的应用
可以将上述抗CD79抗体施用于患有抗体相关病症(例如疾病、病症和/或综合征)的受试者。当受试者是人时,抗CD79抗体可以是嵌合小鼠-人抗体或人源化抗体。此类嵌合或人源化抗体如上所述。抗体相关病症包括例如自身免疫性疾病、某些过敏(与抗体相关的过敏)、某些类型的I型糖尿病等。可以用抗CD79抗体治疗的自身免疫性疾病包括,例如系统性红斑狼疮(SLE)、炎性肠病(例如克罗恩病和溃疡性结肠炎)、类风湿性关节炎、多发性硬化症、格雷夫病、CREST综合征、全身性硬化症、腹腔疾病、失弛症、爱迪生氏病、成年斯蒂尔氏病、无丙种球蛋白血症、斑秃、淀粉样变性病、强直性脊柱炎、抗GBM/抗TBM肾炎、抗磷脂综合征、自身免疫性血管性水肿、自身免疫性自主神经障碍、自身免疫性脑脊髓炎、自身免疫性肝炎、自身免疫性内耳疾病(AIED)、自身免疫性心肌炎、自身免疫性卵巢炎、自身免疫性睾丸炎、自身免疫性胰腺炎、自身免疫性视网膜病、自身免疫性荨麻疹、轴突和神经元神经病变(AMAN)、Baló病、Behcet’s病、良性粘膜类天疱疮、大疱性类天疱疮、Castleman病(CD)、腹腔疾病、Chagas病、慢性炎症性脱髓鞘性多发性神经病变(CIDP)、慢性复发性多灶性骨髓炎(CRMO)、Churg-Strauss综合征(CSS)或嗜酸性肉芽肿病(EGPA)、瘢痕性类天疱疮、Cogan’s综合症、冷凝集素病、先天性心脏传导阻滞、柯萨奇心肌炎、CREST综合征、克罗恩氏病、疱疹样皮炎、皮肌炎、Devic’s病(视神经脊髓炎)、盘状狼疮、Dressler’s综合症、子宫内膜异位症、嗜酸性食管炎(EoE)、嗜酸性筋膜炎、结节性红斑、必要的混合性冷球蛋白血症、Evans综合征、纤维肌痛、纤维化肺泡炎、巨细胞性动脉炎(颞动脉炎)、巨细胞性心肌炎、肾小球肾炎、Goodpasture’s综合征、肉芽肿合并多血管炎、Graves病、Guillain-Barre综合征、Hashimoto甲状腺炎、溶血性贫血、Henoch-Schonlein紫癜(HSP)、妊娠疱疹或妊娠类天疱疮(PG)、化脓性汗腺炎(HS)(反常性痤疮)、低丙球蛋白血症、IgA肾病、与IgG4相关的硬化性疾病、免疫性血小板减少性紫癜(ITP)、包涵体肌炎(IBM)、间质性膀胱炎(IC)、青少年关节炎、青少年糖尿病(1型糖尿病)、青少年肌炎(JM)、川崎病,Lambert-Eaton综合征、白细胞碎裂性血管炎、扁平苔癣、硬化苔癣、木样结膜炎、线性IgA病(LAD)、狼疮、慢性莱姆病、Meniere’s病、显微镜下多血管炎(MPA)、混合结缔组织病(MCTD)、Mooren’s溃疡、Mucha-Habermann病、多灶性运动神经病变(MMN)或MMNCB、多发性硬化症、重症肌无力、肌炎、嗜睡症、新生儿狼疮、视神经脊髓炎、中性粒细胞减少症、眼瘢痕性类天疱疮、视神经炎、复发性风湿病(PR)、PANDAS、副肿瘤性小脑变性(PCD)、阵发性睡眠性血红蛋白尿症(PNH)、Parry Romberg综合征、睫状体扁平部炎(周围性葡萄膜炎)、Parsonage-Turner综合征、天疱疮、周围性神经病变、周围性脑脊髓炎、恶性贫血(PA)、POEMS综合征、结节性多发性动脉炎、多腺性综合征(I型、II型、III型)、风湿性多肌痛、多发性肌炎、心肌梗塞后综合征、心包膜切开术后综合征、原发性胆汁性肝硬变、原发性硬化性胆管炎、孕酮性皮炎、牛皮癣、银屑病关节炎、纯红细胞发育不全(PRCA)、坏疽性脓皮病、Raynaud现象、反应性关节炎、反射性交感神经营养不良、复发性多软骨炎、不安腿综合征(RLS)、腹膜后纤维化、风湿热、类风湿性关节炎,结节病、施密特综合征、巩膜炎、硬皮病、综合症、精子和睾丸自身免疫、僵人综合征(SPS)、亚急性细菌性心内膜炎(SBE)、Susac’s综合征、交感性眼炎(SO)、高安氏动脉炎、颞动脉炎/巨细胞动脉炎、血小板减少性紫癜(TTP)、Tolosa-Hunt综合征(THS)、横断性脊髓炎、1型糖尿病、溃疡性结肠炎(UC)、未分化结缔组织病(UCTD)、葡萄膜炎、血管炎、白癜风、Vogt-Koyanagi-Harada病等。可以用抗CD79抗体治疗的其它抗体相关病症包括,例如过敏(与抗体相关的过敏)、淀粉样变性病、某些形式的移植排斥反应等。这些和其它不希望的抗体相关病症可以通过将一种或多种本文所述的抗CD79抗体施用于患有不希望的抗体相关病症的受试者来治疗。
本文所述的抗CD79抗体可在受试者的B-细胞中诱导无反应状态,因此可用于治疗某些自身免疫性疾病。例如,与抗自身抗体反应有关的自身免疫性疾病可以用抗CD79抗体治疗,因为诱导的无反应状态将阻止抗自身抗体的产生。本文所述的抗CD79抗体还可以用于在具有不希望的抗体应答的任何情况下诱导无反应状态。本文所述的抗CD79抗体可用于在B-细胞中诱导无反应状态。本文所述的抗CD79抗体可用于抑制B-细胞的增殖。
本文所述的抗CD79抗体可用于识别和/或分离样品和/或受试者中的B-细胞。例如,本文所述的抗CD79抗体可用于诊断B-细胞恶性肿瘤或其它淋巴增生性疾病,和/或可用作媒介以选择性地将试剂转运至B-细胞恶性肿瘤。
本文所述的抗CD79抗体可用于直接治疗B-细胞恶性肿瘤,和/或可用于构建表达嵌合T细胞受体(CAR-T)的细胞毒性T细胞,用于治疗CD79阳性的B-细胞恶性肿瘤。可以使用本文所述的抗CD79抗体的抗原结合部分作为CAR的抗原结合结构域/部分来制备嵌合抗原受体(CAR)。这些抗CD79 CAR可放置在免疫细胞(例如T-细胞或自然杀伤细胞)中,并且抗CD79免疫细胞可用于治疗由表达CD79的细胞引起的疾病。这样的疾病包括例如CD79阳性的造血系统癌症(例如,淋巴瘤、白血病、骨髓瘤)。
本文公开的抗CD79抗体治疗抗体相关病症的治疗有效量和给药频率以及用其治疗的时间长短可取决于多种因素,包括病症的性质和严重程度、抗体的效力、给药方式、受试者的年龄、体重、总体健康状况、性别和饮食以及受试者对治疗的反应,并且可以由主治医生确定。用于治疗抗体相关病症的抗体(例如抗CD79抗体LB517/LB519)的治疗有效量可以为从约1、5或10mg至约200mg,从约1、5或10mg至约150mg,从约1、5或10mg至约100mg,或从约1、5或10mg至约50mg,或经主治医生认为适当的量,其可以以单剂量或分剂量给药。抗体的治疗有效量可以是约1-5mg、5-10mg、10-20mg、20-30mg、30-40mg、40-50mg、50-100mg、100-150mg或150-200mg。抗体的治疗有效量可以是约1、5、10、15、20、25、30、40、50、60、70、80、90、100、150或200mg。抗体的治疗有效量可以是约1-5mg、5-10mg或10-50mg。抗体(例如抗CD79抗体LB517/LB519)用于治疗抗体相关病症的治疗有效量可以是约0.01-0.1mg/kg、0.1-0.5mg/kg、0.5-1mg/kg、1-2mg/kg或2-3mg/kg体重,或经主治医生认为适当的量。抗体的治疗有效量可以是约0.01-0.1mg/kg、0.1-0.5mg/kg或0.5-1mg/kg体重。
抗CD79抗体可以以任何合适的频率施用以治疗抗体相关病症。抗体(例如抗CD79抗体LB517/LB519)可以每天一次、每2天一次、每3天一次、每周两次、每周一次、每2周一次、每3周一次、每月一次、每6周一次、每2个月一次或每3个月一次或经主治医生认为适当的频率施用。抗体可以每周一次或每2周一次施用。
同样,抗CD79抗体可以以任何合适的时间长度或以任何合适的剂量总数施用,以治疗与抗体相关病症。抗体(例如抗CD79抗体LB517/LB519)在至少约1周、2周、1个月(4周)、6周、2个月、3个月、6个月、1年、2年、3年或更长的时间段内施用,或者经主治医生认为适当的。抗体相关病症可以是慢性病。慢性病可以存在例如至少约6周或2个月或更长时间。抗体可以在至少约6周、2个月、3个月或6个月的时间内段施用。在整个治疗方案中,可以施用1、2、3、4、5或6剂量的抗体(例如抗CD79抗体LB517/LB519)。在整个治疗方案中,可以施用1、2或3剂量的抗体。
抗CD79抗体(例如抗CD79抗体LB517/LB519)也可以以不定期的方式施用以治疗抗体相关病症。例如,抗体或其片段可以以不定期的方式在1周、2周、3周、1个月、2个月或3个月的时间段内施用1、2、3、4、5或更多次。此外,可以必要时(根据需要)服用抗CD79抗体(例如抗CD79抗体LB517/LB519)来治疗抗体相关病症。例如,抗体可以施用1、2、3、4、5或更多次以治疗高血压,无论以定期或不定期的方式,直到血压降低到一定水平。一旦血压降低到一定水平,就可以选择中止抗体的给药。如果血压达到或超过一定水平,则可以恢复抗体的施用,无论以定期或不定期的方式。抗体的适当剂量、给药频率和治疗时间长度可以由主治医生确定。
为了更快速地建立治疗水平的抗CD79抗体,可以在维持剂量之前施用至少一个负荷剂量的抗体或其片段。可以施用负荷剂量的抗体(例如抗CD79抗体LB517/LB519),然后(i)施用一个或多个额外的负荷剂量,然后再施用一个或多个治疗有效的维持剂量,或(ii)施用一个或多个治疗有效的维持剂量而无额外的负荷剂量,如主治医生认为适当的。药物的负荷剂量可以比随后的维持剂量大(例如,大约1.5、2、3、4或5倍),并且被设计为更快地建立药物的治疗水平。一个或多个治疗有效的维持剂量可以是本文所述的任何治疗有效量。负荷剂量可以比维持剂量大约2倍或3倍。抗体的负荷剂量可以在第1天施用,并且抗体的维持剂量可以之后在治疗期间例如每周一次或每2周一次施用。抗体(例如抗CD79抗体LB517/LB519)可以在第1天以约2-10mg、10-20mg或20-100mg、或约3-15mg、15-30mg或30-150mg的负荷剂量施用,随后在治疗期间(例如,至少约2、3或6个月),每周一次或每2周一次施用约1-5mg、5-10mg或10-50mg的维持剂量,其中负荷剂量比维持剂量大约2倍或3倍,并且抗体或其片段经肠胃外(例如,静脉内、皮下或肌肉内)施用。
可以在维持剂量之前施用两次(或更多次)负荷剂量的抗体。抗体或其片段的第一次负荷剂量可以在第1天施用,第二次负荷剂量可以例如在约1周或2周后施用,并且维持剂量可以之后在治疗期间例如每周一次或每2周一次施用。第一次负荷剂量可以比维持剂量大约3倍或4倍,第二次负荷剂量可以比维持剂量大约2倍。抗体(例如抗CD79抗体LB517/LB519)在第1天可以施用约3-15mg、15-30mg或30-150mg或约4-20mg、20-40mg或40-200mg的第一次负荷剂量,在约1或2周后,施用约2-10mg、10-20mg或20-100mg的第二次负荷剂量,然后在治疗期间(例如,至少约2、3或6个月)每周一次或每2周一次施用约1-5mg、5-10mg或10-50mg的维持剂量,其中第一次负荷剂量可以比维持剂量大约3倍或4倍,第二次负荷剂量可以比维持剂量大约2倍,并且抗体或其片段可以肠道外(例如,静脉内、皮下或肌肉内)施用。
与另外治疗剂的组合疗法
本公开内容提供了一种治疗抗体相关病症的方法,包括向需要治疗的受试者施用治疗有效量的本文所述的抗CD79抗体,可选地与另外的治疗剂组合。本公开内容进一步提供了本文所述的抗CD79抗体,或包含本文所述的抗CD79抗体的组合物,其用作药物,可选地与另外的治疗剂组合。另外,本公开内容提供了本文所述的抗CD79抗体在药物制备中的应用,可选地与另外的治疗剂组合。在某些实施例中,药物用于治疗抗体相关病症。
一种或多种另外的治疗剂可以可选地与抗CD79抗体(例如抗CD79抗体LB517/LB519)组合使用以治疗抗体相关病症。可选的另外的治疗剂可以与抗体同时施用于受试者(例如,在与抗体或其片段相同的组合物中或在单独的组合物中)或循序地(之前或之后)施用于受试者。
可选的另外的治疗剂可以选自免疫抑制剂、抗炎剂、过敏药及其组合。可以将一种或多种免疫抑制剂与抗CD79抗体(例如抗CD79抗体LB517/LB519)组合使用以治疗抗体相关病症。此类免疫抑制剂可包括,例如抗CD20抗体(例如,利妥昔单抗)、钙调磷酸酶抑制剂(例如,他克莫司、环孢霉素等)、抗增殖剂或IDMH抑制剂(例如,霉酚酸酯、霉酚酸钠、咪唑硫嘌呤、来氟米特等)、mTOR抑制剂(例如,雷帕霉素、依维莫司等)、类固醇(例如,皮质类固醇,例如强的松、布地奈德、泼尼松龙等)和生物制剂(例如,阿巴西普(ababatcept)、阿达木单抗(adalimumab)、阿那白滞素(anakinra)、赛妥珠单抗(certolizumab)、依那西普(etanercept)、英夫利昔单抗(infliximab)、ixekizumab、那他珠单抗(natalizumab)、利妥昔单抗(rituximab)、苏金单抗(secukinumab)、托珠单抗(tocilizumab)、uestekinumab、维多珠单抗(vedolizumab)、巴利昔单抗(basiliximab)、达克珠单抗(daclizumab)、莫罗单抗(muromonab)。生物制剂还可包括例如CTLA 4融合蛋白、抗TNFα抗体、IL-1受体拮抗剂蛋白、TNF受体融合蛋白、抗IL17A抗体、抗α4整联蛋白抗体、抗IL6受体抗体、IL12/IL23抗体的抗p40亚基、抗α4β7整联蛋白抗体、抗CD25抗体和抗CD3抗体。
可以将一种或多种抗炎剂与抗CD79抗体(例如抗CD79抗体LB517/LB519)组合使用,以治疗具有炎症成分的抗体相关病症。一种或多种抗炎剂可包括例如促炎性细胞因子的抑制剂或其受体或其产生(例如,TNF-α或/和IL-6或IL-6R)。其它抗炎剂包括例如非甾体类抗炎药(NSAID)、免疫调节剂、免疫抑制剂、抗炎细胞因子和增加其产生的化合物、促炎性细胞因子或其受体的抑制剂、促炎性细胞因子或其受体的产生的抑制剂、促炎性转录因子或其激活或表达的抑制剂、促炎性前列腺素(例如,前列腺素E2[PGE2])或其受体(例如,EP3)或其产生的抑制剂、白三烯或其受体或其产生的抑制剂、磷脂酶A2的抑制剂(例如,分泌的和胞质的PLA2)、C反应蛋白(CRP)活性或水平的阻遏剂、肥大细胞稳定剂、磷酸二酯酶抑制剂、专门的促分解介质(SPM)、其它类型的抗炎剂及其类似物、衍生物、片段和盐。
非甾体类抗炎药(NSAID)包括但不限于:醋酸衍生物、邻氨基苯甲酸衍生物(fenamates)、烯醇酸衍生物(oxicams)、丙酸衍生物、水杨酸盐、COX-2选择性抑制剂、其它种类的NSAID,例如单萜类化合物(例如,桉油精和酚类(例如,香芹酚))、苯胺吡啶羧酸(例如,氯尼辛(clonixin))、磺胺类药物(例如,尼美舒利)以及脂氧合酶(例如,5-LOX)和环加氧酶(例如,COX-2)的双重抑制剂(例如,诃黎勒酸(chebulagic acid)、licofelone、2-(3,4,5-三甲氧苯基)-4-(N-甲基吲哚-3-yl)噻吩和基于二叔丁基苯酚的化合物[例如,DTPBHZ、DTPINH、DTPNHZ和DTPSAL]);及其类似物、衍生物和盐。
皮质类固醇的糖皮质激素类具有抗炎作用和免疫抑制特性。糖皮质激素包括但不限于氢化可的松类型、卤代类固醇、碳酸盐及其类似物、衍生物和盐。
可选的另外的治疗剂可以以任何合适的方式单独施用。潜在的施用方式包括但不限于口服、肠胃外(包括皮内、皮下、肌肉内、血管内、静脉内、动脉内、腹膜内、髓内、鞘内和局部)、腔内和局部(包括皮肤/表皮、经皮、粘膜、透粘膜、鼻内(例如,通过鼻喷剂或滴剂)、眼内(例如,通过滴眼剂)、肺部(例如,通过口服或经鼻吸入)、口腔、舌下、直肠[例如,通过栓剂]和阴道[例如,通过栓剂])。在某些实施例中,可选的另外的治疗剂单独经口服或肠胃外(例如,静脉内、皮下或肌肉内)施用。
可以将一种或多种抗过敏剂与抗CD79抗体(例如抗CD79抗体LB517/LB519)组合使用以治疗抗体相关病症。这样的抗过敏剂可以包括例如抗组胺药(例如,西替利嗪、非索非那定、左旋西替利嗪、氯雷他定、bormpheniramine、扑尔敏、celmastine、苯海拉明、酮替芬、萘甲唑啉、非尼拉敏(pheniramine)、地氯雷他定、氮卓斯汀、依匹斯汀、奥洛他定)、减充血剂(例如,伪麻黄碱、去氧肾上腺素、羟甲唑啉)、类固醇(例如倍氯米松、环索奈德、糠酸氟替卡松、莫米松、布地奈德、曲安奈德、地塞米松、氯替泼诺、prednisone(泼尼松)epocrates)、肥大细胞稳定剂(例如,色甘酸钠、洛度沙胺-氨丁三醇、奈多罗米、吡嘧司特)和白三烯改性剂(例如,孟鲁司特(monteleukast))。
可以将一种或多种用于移植的抗排斥药与抗CD79抗体(例如抗CD79抗体LB517/LB519)组合使用,以在移植程序之后治疗受试者。这样的抗排斥药可以包括例如钙调磷酸酶抑制剂、抗增殖剂或IDMH抑制剂、mTOR抑制剂和类固醇。
可选的另外的治疗剂可以以任何合适的频率单独施用,包括但不限于每天(每天1、2或多次)、每两天或三天、每周两次、每周一次、每两周一次、每三周一次、每月、每两个月或每三个月,或者以不定期的方式或根据需要。给药频率可以取决于例如所选择的施用方式。用可选的另外的治疗剂治疗的时间长度可以由主治医生确定,并且可以独立地为例如至少约1天、2天、3天、4天、1周、2周、3周、4周(1个月)、6周、2个月、3个月、6个月、1年、2年、3年或更长。
抗CD79抗体的诊断应用
本文公开的抗CD79抗体也可用于B-细胞相关疾病的诊断和预后评估。此外,这样的抗体可用于促进治疗决策。
可以使用抗CD79抗体来检测从受试者获得的原始或加工样本中B-细胞谱系细胞的存在。生物样本可以包括例如血液、血浆、血清、尿液、脑脊髓液(CSF)、细胞或组织。样本可以直接分析,在分析之前提取或通过添加合适的溶剂扩大体积。
可以使生物样本与抗CD79抗体接触,并筛选样本以检测抗体或其片段与B-细胞的结合。检测到这种结合表明样本中存在B-细胞。可以用可检测试剂(例如荧光染料)标记抗CD79抗体,从而使抗体与B-细胞的结合引起信号。在引入标记的抗CD79抗体之前,可以将生物样本中的B-细胞固定在表面上(直接测定),相当于与B-细胞结合的标记抗体或其片段的数量的信号量与样本中B-细胞的数量相关。可以通过固定在表面上的未标记的第一抗体捕获生物样本中的B-细胞,然后通过与捕获的B-细胞结合并产生与捕获的B-细胞数量成比例的信号的标记的第二抗体进行检测(夹心测定),其中未标记的第一抗体和标记的第二抗体结合到B-细胞上的不同表位,并且未标记的第一抗体或/和标记的第二抗体独立地可以是本文公开的抗CD79抗体。
生物样本中的B-细胞可以通过竞争性分析来检测。可以将样本(可选地悬浮在缓冲液中)与标记的抗CD79混合。然后可以将所得混合物与B-细胞标记物涂覆的基质接触。样本中B-细胞的数量越多,形成的抗体/B-细胞复合物越多,未结合(游离)的抗体与基质上的B-细胞标记物结合的可能性就越低(“竞争”),因此产生的信号越低。
在上述直接、夹心和竞争性分析中,第一抗CD79抗体可用可检测试剂标记。可替换地,在直接、夹心和竞争性测定中,第一抗CD79抗体可以是未标记的,并且在第一抗体与B-细胞结合后可以被标记的第二抗体(例如,一种与第一抗体的Fc区结合的抗体)结合。如果第二抗体与酶缀合,则酶底物的添加导致酶/底物反应,该反应产生信号(例如发色、荧光或电化学信号)。测量固体支持物(例如板孔或珠子)的吸光度、荧光或电化学信号(例如电流),以确定样本中B-细胞的存在和数量。辣根过氧化物酶(HRP)的底物的非限制性示例包括3-氨基-9-乙基咔唑(AEC)、3,3'-二氨基联苯胺(DAB)和3,3',5,5'-四甲基联苯胺(TMB)、碱性磷酸酶中的那些包括5-溴-4-氯-3-吲哚基磷酸(BCIP),而β-葡萄糖醛酸酶中的那些包括5-溴-4-氯-3-吲哚基-β-D-葡萄糖醛酸(X-Gluc)。这种测定称为酶联免疫吸附测定(ELISA)。
可检测的试剂包括但不限于发色团{例如染料、染色剂、颜料和发色团(例如3-氨基-9-乙基咔唑[AEC]、5-溴-4-氯-3-吲哚基磷酸盐[BCIP]、3,3'-二氨基联苯胺[DAB]和3,3',5,5'-四甲基联苯胺[TMB])}、荧光团/荧光染料(例如荧光染料,例如荧光素、异硫氰酸荧光素和若丹明)、化学发光化合物(例如荧光素和鲁米诺)、放射性同位素(例如3H、14C、32P、35S和125I)、放射性元素(例如锝)、电子致密化合物、磁性物质和颗粒(例如顺磁性和超顺磁性物质和颗粒)、磁共振成像(MRI)造影剂(例如,含钆的造影剂)、酶(例如,辣根过氧化物酶[HRP]、碱性磷酸酶、萤光素酶、β-葡糖醛酸苷酶和β-半乳糖苷酶)、半抗原和毒素。
本文所述的抗CD79抗体可以用于多种免疫测定中。这样的测定包括但不限于发色、荧光、化学发光、光散射、放射性标记、电化学、酶、沉淀、凝集、凝结、蛋白质印迹、网格印迹、组织印迹、斑点印迹、浸量尺和生物传感器测定。参见,例如,Principles and Practiceof Immunoassays,C.Price and D.Newman(Eds.),Stockton Press(1997);以及TheImmunoassay Handbook,2nd Ed.,D.Wild(Ed.),Nature Publishing Group(2001)。此外,抗CD79抗体可以用于成像中,例如通过MRI。
检测和测量生物样本中B-细胞的量可以促进B-细胞相关疾病的诊断、预后和治疗。在一些实施例中,病症与B-细胞水平升高相关,并且与没有病症的其它受试者的相应样本中的B-细胞水平相比,受试者的样本中B-细胞水平升高表示诊断受试者的疾病。用于诊断病症的参考B-细胞水平可以基于例如统计学上或流行病学上数量众多的无疾病的受试者的相应样本中的B-细胞水平与统计学上或流行病学上数量众多的患有疾病的受试者的相应样本中的B-细胞水平的比较来确定。类似地,出于治疗和预后目的,可以将来自受试者的样本中的B-细胞水平与例如与B-细胞相关疾病的严重性相关的B-细胞水平的规模进行比较,以确定疾病的当前严重性并预测疾病的可能病程或结果(例如,进展或消退)。
此外,检测和测量生物样本中B-细胞的数量可以促进治疗决策。在某些实施例中,基于来自受试者的样本中B-细胞的存在、不存在、数量或水平,来维持或调节(增加或减少)向受试者施用的抗CD79抗体的量或/和向受试者施用抗体的频率,或停止向受试者施用抗体或其片段。
在某些实施例中,试剂盒包含可以可选地标记有可检测试剂的抗CD79抗体,以及可选地将抗CD79抗体用于诊断应用(例如,在免疫测定中)的说明书。
抗CD79抗体的产生
本公开内容提供了包括编码本文所述的抗CD79抗体的核酸序列的多核苷酸。多核苷酸可以包括编码抗CD79 mAb的VH结构域或/和VL结构域的核酸序列。多核苷酸可以包括编码抗CD79 mAb的重链或/和轻链的核酸序列。
本公开内容进一步提供了包括编码本文所述的抗Cd79抗体的核酸序列的构建体(也可以称为表达或克隆构建体)。合适的构建体包括但不限于质粒、粘粒、细菌人工染色体、酵母人工染色体、λ噬菌体(例如,删除了溶原基因的那些)和病毒。构建体可以游离存在于细胞中或整合到染色体中(无论哪种方式构建体保留且仍然是构建体、质粒和载体)。
可以采用各种构建体系统。一类构建体利用衍生自动物病毒例如腺病毒、杆状病毒、牛乳头瘤病毒、多瘤病毒、SV40病毒、牛痘病毒和逆转录病毒(例如MMTV、MOMLV和劳斯肉瘤病毒)的DNA元件。另一类构建体利用衍生自RNA病毒例如东部马脑炎病毒、黄病毒和Semliki Forest病毒的RNA元件。
除了编码例如抗Cd79mAb的VH结构域或/和VL结构域、或重链或/和轻链的核酸序列外,构建体还可以包括用于mRNA最佳表达的各种其它元件。例如,构建体可以包含转录启动子、启动子加操纵子、增强子、具有或不具有内含子或/和外显子的开放阅读框、终止信号、剪接信号、分泌信号序列或选择标记(例如,赋予对抗生素或细胞毒剂的抗性的基因)、或其任何组合或全部。
本公开内容还提供了包括或表达编码本文所述的抗CD79抗体的构建体的宿主细胞。合适的宿主细胞包括但不限于真核细胞、哺乳动物细胞(例如,BHK、CHO、COS、HEK293、HeLa、MDCKII和Vero细胞)、昆虫细胞(例如,Sf9细胞)、酵母细胞和细菌细胞(例如,大肠杆菌细胞)。宿主细胞可以是哺乳动物细胞(例如,CHO细胞或HEK293细胞)。
宿主细胞可以包括或表达编码抗CD79mAb的VH结构域或VL结构域、或重链或轻链的构建体。宿主细胞可以包括或表达编码抗CD79 mAb的VH结构域和VL结构域、或重链和轻链的单个构建体。相同的宿主细胞或单独的宿主细胞可以包括或表达编码抗CD79 mAb的VH结构域或重链的构建体,以及编码该mAb的VL结构域或轻链的单独构建体。
可以通过本领域已知的任何方法将构建体转染或引入宿主细胞。转染剂和方法包括但不限于磷酸钙、阳离子聚合物(例如,DEAE-葡聚糖和聚乙二胺)、树状聚合物、fugene、阳离子脂质体、电穿孔、声穿孔、细胞挤压、基因枪、病毒转染和逆转录病毒转导。
培养转染的宿主细胞并回收重组产生的抗CD79抗体的方法和条件是本领域已知的,并且可以根据例如特定的表达载体或/和所使用的宿主细胞进行改变或优化。可以重组产生抗CD79 mAb的VH结构域或/和VL结构域、或重链或/和轻链。重组产生抗CD79完整IgG1、IgG2或IgG4的重链和轻链,或可选的与延长部分融合的抗CD79 Fab片段的重链和轻链。
在本说明书中引用的所有出版物和专利均被援引加入本文,就好像每篇单独的出版物或专利均被具体地和单独地表示为被援引加入本文,并且被援引加入本文以公开和描述与引用的出版物相关的方法和/或材料。
以下实例仅旨在说明本公开内容。其它测定、研究、过程、方案、规程、方法、试剂和条件也可以酌情可替换的使用。
实例
实例1.嵌合抗CD79抗体的产生
由小鼠抗体产生嵌合抗体HcLc,该小鼠抗体以高特异性和高亲和力结合CD79。将小鼠抗体的VH结构域和VL结构域(SEQ ID NO:1和2)分别与人IgG2 CH1、CH2和CH3结构域或人κCL结构域融合。
实例2.人源化抗CD79抗体的产生
结合CD79的小鼠抗体还被人源化。将重链(IgG1)和轻链(κ)SEQ ID NO:3-8的CDR移植到受体人框架序列上。这些CDR中的三个(CDR-L1、CDR-L2和CDR-H2)包含可能不希望出现的氨基酸基序(DG、DS和NG)。不同的CDR-L1用于KSSQSLLDSSGKTYLN(SEQ ID NO:57),两个不同的CDR-H2用于RIYPENGDTNYAGKFKG(SEQ ID NO:58)或RIYPESGDTNYAGKFKG(SEQ ID NO:59)。此外,保留了小鼠抗体的某些框架氨基酸残基,包括在3D免疫球蛋白模型中与CDR序列直接相邻或预测在CDR的约之内的氨基酸,并可能接触抗原并支持CDR与抗原的结合。保留了与CDR相邻的大约三个小鼠框架氨基酸残基。
通过将小鼠框架序列与人框架序列的数据库进行比对来选择人框架序列,以找到每条链的最接近的人同源物(通常约65-70%的序列同一性)。人VH1-2框架被用作人受体框架,它与重链的小鼠框架序列最同源,而VK2-30被用作人受体框架,它与轻链的小鼠框架序列最同源。使用了三种不同的VL-FR2:WFQQRPGQSPRRLIY(SEQ ID NO:60),WLQQRPGQSPRRLIY(SEQ ID NO:61)或WLQQRPGQSPKRLIY(SEQ ID NO:62)。VH-FR1进行了两个氨基酸改变:QVQLVQSGAEVKKPGASVKVSCKASGYAFS(SEQ ID NO:63)。使用了VH-FR2和VH-FR3的三种不同组合:VH-FR2 WVRQAPGQGLEWMG(SEQ ID NO:64)和VH-FR3 RVTMTRDTSISTAYMELSRLRSDDTAVYYCAR(SEQ ID NO:65),VH-FR2 WVRQAPGQGLEWMG(SEQ ID NO:64)和VH-FR3RVTMTADTSISTAYMELSRLRSDDTAVYYCAR(SEQ ID NO:66),以及VH-FR2WVRQAPGQGLEWIG(SEQ ID NO:67)和VH-FR3RVTLTADKSISTAYMELSRLRSDDTAVYYCAR(SEQ ID NO:68)。
制备人源化重链H1-H3(SEQ ID NO:9-11)和L1-L3(SEQ ID NO:18-20)并用组合方法混合和匹配以构建人源化克隆文库(H1-H3与L1-L3用组合方法混合)。分离各成员并测试与CD79的亲和力结合。下表1中列出了获得的结合数据:
加载样本ID | KD(M) | kon(1/Ms) | kdis(1/s) | Full X^2 | Full R^2 |
H1L2 | 4.5E-08 | 9.1E+04 | 4.1E-03 | 0.0208 | 0.9973 |
H2L2 | 4.6E-08 | 1.0E+05 | 4.6E-03 | 0.0315 | 0.9943 |
H1L3 | 4.9E-08 | 8.2E+04 | 4.0E-03 | 0.0264 | 0.9966 |
H1L1 | 5.9E-08 | 9.2E+04 | 5.4E-03 | 0.0408 | 0.9922 |
HcLc | 6.0E-08 | 9.3E+04 | 5.6E-03 | 0.0833 | 0.9857 |
H2L3 | 6.1E-08 | 8.4E+04 | 5.1E-03 | 0.0679 | 0.9869 |
H2L1 | 9.0E-08 | 7.9E+04 | 7.1E-03 | 0.0444 | 0.9895 |
H3L3 | 1.3E-07 | 7.9E+04 | 1.1E-02 | 0.1020 | 0.9611 |
H3L2 | 1.4E-07 | 6.1E+04 | 8.6E-03 | 0.1402 | 0.9726 |
H3L1 | 2.9E-07 | 4.3E+04 | 1.3E-02 | 0.1566 | 0.9472 |
表1.人源化抗体的结合亲和力
选择了导向(lead)抗体H1L2(LB495/PRI47,SEQ ID NO:9和19)。
实例3.人源化抗体H1L2(LB495/PRI47,SEQ ID NO:9和19)的亲和力成熟
使人源化抗体H1L2(SEQ ID NO:9和19)亲和力成熟。制备四个噬菌体展示文库,两个来自重链H1(SEQ ID NO:10),两个来自轻链L2(SEQ ID NO:20)。在CDR3上进行饱和诱变以制备CDR3重链和CDR3轻链文库,并且易错PCR也用于随机诱变H1重链和L2轻链中的每一个,以制备重链文库和轻链文库。将每个重链文库与亲本轻链L2(SEQ ID NO:19)组合,并且将每个轻链文库与亲本重链H1(SEQ ID NO:9)配对,以制备用于亲和力成熟的候选物的噬菌体展示文库。在与亲本H1L2抗体的竞争性分析中针对CD79淘选每个文库,并在ELISA中测试淘选中获得的结合克隆的亲和力。选择在CDR3中具有突变的VH克隆(SEQ ID NO:25),并且选择在CDR3的相同位置处具有突变的VL克隆(SEQ ID NO:28-31)。这些重链和轻链被重新格式化为全长IgG,其由293细胞产生,纯化,然后测试结合。下表2中列出了这些全长IgG的结合数据:
加载样本ID | KD(M) | Kon(1/Ms) | Kdis(1/s) | Full X^2 | Full R^2 |
PRI43/PRI47 | 5.10E-09 | 8.41E+04 | 4.29E-04 | 0.1219 | 0.9989 |
LB517/PRI47 | 3.55E-09 | 8.75E+04 | 3.11E-04 | 0.1046 | 0.9991 |
LB495/518 | 3.64E-09 | 9.12E+04 | 3.32E-04 | 0.0725 | 0.9994 |
LB495/519 | 3.14E-09 | 8.03E+04 | 2.52E-04 | 0.1107 | 0.9989 |
LB495/520 | 3.76E-09 | 9.96E+04 | 3.74E-04 | 0.0723 | 0.9993 |
LB495/521 | 3.65E-09 | 9.91E+04 | 3.62E-04 | 0.0502 | 0.9993 |
LB517/518 | 2.24E-09 | 8.85E+04 | 1.99E-04 | 0.0533 | 0.9994 |
LB517/519 | 2.00E-09 | 7.97E+04 | 1.59E-04 | 0.0834 | 0.9994 |
LB517/520 | 2.40E-09 | 9.78E+04 | 2.34E-04 | 0.0720 | 0.9993 |
LB517/521 | 2.30E-09 | 8.75E+04 | 2.01E-04 | 0.0736 | 0.9992 |
表2.亲和力成熟的抗体的结合亲和力
PRI 47是轻链L2(SEQ ID NO:19),PRI 43和LB495是重链H1(SEQ ID NO:9),LB517是重链LB509-C2(SEQ ID NO:25),LB518是轻链LB511-A9(SEQ ID NO:28),LB519是轻链LB511-F6(SEQ ID NO:30),LB520是轻链LB511-F11(SEQ ID NO:31),并且LB521是轻链LB511-B6(SEQ ID NO:29)。
亲和力成熟的抗体表现出比亲本人源化抗体更高的亲和力。
实例4.抗体细胞系的开发
CHO细胞(Invitrogen)在无血清培养基(CD FortiCHO,Invitrogen)中培养,并使用Freestyle Max转染试剂(Invitrogen)与编码抗CD79抗体的重链和轻链的单独质粒共转染。转染前,将抗体表达质粒通过Sea I进行限制性消化线性化。通过ELISA测量条件培养基中的抗体表达。
用10μg/ml的嘌呤霉素和500μg/ml的G418对转染的细胞进行稳定选择2周。单细胞克隆后,筛选并分离高产CHO细胞克隆。摇瓶培养物中的抗体产生评估为>500mg/L。
实例5.人源化抗CD79抗体的重组产生
HEK293F细胞(Invitrogen)在无血清培养基中培养,并与编码LB517的质粒和编码LB519的质粒或表达其它抗体变体的质粒共转染。转染后第5天,收获细胞培养上清液,并进行蛋白A层析以纯化抗体。
实例6.人CD79a/79b敲入小鼠
C57BL/6胚胎干细胞经工程化改造,以编码人CD79a和人CD79b的核酸取代小鼠CD79a和CD79b基因座。将工程化的C57BL/6ES细胞植入雌性C57BL/6小鼠中,获得人CD79a/b阳性的C57BL/6后代。使用具有抗人CD79抗体的FACS确认了人CD79a和CD79b在B-细胞上的表达。
实例7.抗CD79抗体诱导的人CD79C57BL/6小鼠中的B-细胞无反应
在测定之前,用人源化抗CD79抗体LB517/LB519处理人CD79敲入小鼠18小时。然后,将离体的RBC溶解的脾细胞(1E6/100μL)用抗B220和荧光标记的抗hCD79或PTEN或B细胞受体染色。LB517/LB519(hCur14 FALA)能够结合B细胞并与Curly-14竞争(图3a)。PTEN和细胞表面BCR的细胞内水平也通过用适当的抗体染色来表征。LB517/LB519能够诱导PTEN表达(图3b)并下调BCR表达(图3c)。
通过B-细胞受体激活后,测试这些小鼠的B-细胞的钙通量。将RBC裂解的脾细胞(1E7/mL)用抗B220(B-细胞)染色,并用钙敏感染料(Indo-1 AM)加载1小时,然后进行流量分析。在运行Flow-Jo软件(Tree Star)的FORTESSA(BD Bioscience)中测量,将细胞内Ca2+水平的变化记录为405nm和485nm处的荧光发射。在添加刺激物至100μL培养基中之前,先获取基线钙30秒钟。从刺激后的A.U.C.s减去基础钙测量值,以便产生急性刺激量化。LB517/LB519刺激钙流入(图4a)并使B-细胞受体脱敏(图4b)。
还测试了来自C57BL/6小鼠的B-细胞在B-细胞受体刺激后酪氨酸磷酸化的情况。这些研究表明,用人源化抗CD79抗体LB517/LB519预处理B-细胞会使B-细胞脱敏,使其通过B-细胞受体活化,因为在抗CD79抗体处理过的B-细胞中酪氨酸磷酸化受到抑制。
实例8.I型糖尿病的治疗
获得了在NOD和C57BL/6背景上表达IgM重链转基因VH125和VH281的小鼠。将VH125.C57BL/6小鼠回交到C57BL/6-H2g7(JAX)上以产生VH125.C57BL/6.H2g7。两个连续的血糖读数>250mg/dL(一次触摸)确认了VH125.C57BL/6.H2g7小鼠患有糖尿病。
用抗CD79抗体或生理盐水治疗糖尿病前期(连续血糖读数为>150-<200mg/dL)的VH125NOD小鼠。图1示出了用生理盐水处理的小鼠发展出I型糖尿病(到第5周为80%)。图1还示出了用抗CD79抗体治疗的小鼠发展出较少的I型糖尿病(到第5周为25-30%)。
实例9.用人源化抗CD79抗体LB517/LB519治疗I型糖尿病
根据实例6制备在其B-细胞中表达人CD79a/b的C57BL/6小鼠。hCD79a/b C57BL/6小鼠具有PTPn22 R620W敲入ROSA26基因座,其中具有介于中间的floxed stop cassette(盒)。通过三苯氧胺诱导的PTPn22 R620W自身免疫性风险等位基因(risk allele)的cretam驱动的表达,并结合链脲佐菌素(STZ)处理来破坏胰腺β细胞,在成年小鼠激活疾病。
连续4天给6至8周大的小鼠注射(i.p.)40mg/kg的STZ(Sigma-Aldrich)。在最后一次STZ注射后2周开始,使用Bayer Contour Meter(Bayer)每周两次测量血糖水平。糖尿病是由连续两次测试中葡萄糖水平升高>500mg/dL定义的。
在用STZ治疗小鼠之前/期间/之后,用人源化抗CD79抗体LB517/LB519或盐水治疗PTPn22 R620W hCD79a/b C57BL/6小鼠。通过每周两次的血糖水平监测小鼠。糖尿病是由连续两次测试中葡萄糖水平升高>500mg/dL定义的。
实例10.关节炎的治疗
在第0天,用在弗氏完全佐剂(CFA)中乳化的牛或鸡II型胶原(CII)对C57BL/6小鼠进行免疫。21天后,用在弗氏不完全佐剂(IFA)中乳化的CII对小鼠进行二次免疫。在第0天皮下(s.c.)施用1mg的抗CD79或同种型对照免疫球蛋白。mAb注射后两小时,用胶原蛋白免疫小鼠。如先前所述(Hardy,2014),对各爪进行二次免疫后将评估临床得分,采用得分范围0到4。抗CD79显著抑制了关节炎的发展(图5)。
根据实例6制备在其B-细胞中表达人CD79a/b的hCD79a/b C57BL/6小鼠。在第0天,用在弗氏完全佐剂(CFA)中乳化的牛或鸡II型胶原(CII)对hCD79a/b C57BL/6小鼠进行免疫。21天后,用在弗氏不完全佐剂(IFA)中乳化的CII对小鼠进行二次免疫。
抗小鼠CD79D265A、抗人CD79(人源化抗CD79抗体LB517/LB519)、抗CD20(18B12)或同种型对照免疫球蛋白将在第0天皮下(s.c.)施用。mAb注射后两小时,用胶原免疫小鼠。
如先前所述(Hardy,2014),对各爪进行二次免疫后将评估临床得分,采用得分范围0到4。
实例11.系统性狼疮的治疗
MRL/lpr,MRL/lpr-Thy1.1小鼠每周注射0.5mg抗CD79,持续6-17周。抗CD79减少了肾脏和下颌唾液腺的炎症,并在17周qwk提高了生存率(图6)。
根据实例6制备在其B-细胞中表达人CD79a/b的hCD79a/b C57BL/6小鼠。用急性他莫昔芬处理hCD79a/b C57BL/6小鼠,以删除B-细胞中的含SH2的肌醇脂质磷酸酶(SHIP-1)和/或肌醇脂质磷酸酶PTEN。Getahun等人,J Exp Med.2016May 2;213(5):751-69,该篇文献出于所有目的以其全文形式被援引加入本文。
在他莫昔芬治疗的人CD79C57BL6小鼠中,从8周龄开始(自身抗体出现后)每周一次皮下施用人源化抗CD79抗体LB517/LB519、抗CD20(18B12)或同种型对照免疫球蛋白。将监测抗染色质自身抗体的产生、肾小球沉积和小鼠健康。
实例12.人源化抗CD79抗体的表位定位
抗CD79抗体的结合表位通过CD79抗原的各种片段的竞争和结构分析来定位。
实例13.用于癌症治疗的抗CD79CAR-T的构建
将抗CD79抗体L1H2转换为scFv抗体,并与载体LB586中的跨膜结构域4-1BB和CD3zeta细胞内结构域融合。将质粒LB586转染到CHO细胞中,并选用适当的抗生素2周。用可溶性的生物素化的CD79抗原对稳定细胞进行染色,然后用链霉亲和素PE缀合。通过流式细胞术分析确认了CD79抗原的结合(图2)。抗CD79嵌合抗原受体的核酸序列为:
GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAAGTCAAGTCAGAGCCTCTTAGATAGTGATGGAAAGACATATTTGAATTGGTTACAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATCTGGTGTCTAAACTGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAAGCTGAGGATGTTGGGGTTTATTACTGCTGGCAAGGTACACATCTGCCATTCACGTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGTGGCGGTGGCTCGGGCGGTGGTGGGTCGGGTGGCGGCGGATCTCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACGCATTCAGTTACTCCTGGATGAACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGACGGATTTATCCTGAAAATGGAGATACTAACTACAATGGGAAGTTCAAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGATGGGTCTATGGTCTTCCCCACTTTGACTACTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGATATCTACATCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACTGCAAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTGAGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCGCGTACAAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCCCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGCTGA(SEQ ID NO:69)
抗CD79嵌合抗原受体的氨基酸序列为:
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTDFTLKSRVEAEDVGVYYCWQGTHLPFTFGGGTKVEIKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGLPHFDYWGQGTLVTVSSASTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:70)
抗CD79CAR-T载体用于制备细胞毒性T-细胞,以治疗CD79阳性癌症。
实例14.多发性硬化症的治疗
根据标准程序,使用在200μL弗氏完全佐剂(CFA)中乳化的200μg髓磷脂少突胶质细胞糖蛋白(MOG)35-55对C57BL6/J小鼠进行免疫。在两个部位皮下注射乳化剂,然后两次腹膜内(i.p.)注射在磷酸盐缓冲液(PBS)中的200ng百日咳毒素(PTX),第一次在MOG35-55之后的1-2小时,而第二次在其后的24小时。从第19天开始每周施用1mg的抗CD79。每天评估EAE得分和体重,以评估疾病的严重程度和阶段。抗CD79的治疗减缓了疾病模型的进展(图7)。
实例15亲和力成熟的人源化抗体LB517/519的工程化
VH CDR2(SEQ ID NO:4)中有2个“NG”基序,与高Asn脱酰胺倾向相关导致产生并发症。如果突变不会对抗原相互作用产生负面影响,则可以对Asn残基进行突变以消除脱酰胺风险。第一NG基序被工程化为NS(SEQ ID NO:75),并被克隆到表达载体LB630中。第二NG基序被工程化为NA(SEQ ID NO:76),并被克隆到表达载体LB631中。两个NG基序均被工程化(SEQ ID NO:77),并被克隆到表达载体LB632中。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPESGDTNYNGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGLPHFDYWGQGTLVTVSS(SEQ ID NO:75)
SEQ ID NO:75命名为LB630。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPENGDTNYAGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGLPHFDYWGQGTLVTVSS(SEQ ID NO:76)
SEQ ID NO:76命名为LB631。
QVQLVQSGAEVKKPGASVKVSCKASGYAFSYSWMNWVRQAPGQGLEWMGRIYPESGDTNYAGKFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARWVYGLPHFDYWGQGTLVTVSS(SEQ ID NO:77)
SEQ ID NO:77命名为LB632。
与轻链表达载体LB519配对后,通过瞬时转染从293个细胞产生并纯化工程化的抗体。抗原结合动力学被表征并呈现在下表3中:
加载样本ID | KD(M) | Kon(1/Ms) | Kdis(1/s) | Full X^2 | Full R^2 |
PRI43/PRI47 | 9.22E-09 | 4.17E+04 | 3.84E-04 | 0.8803 | 0.9934 |
LB517/519 | 7.06E-10 | 5.87E+04 | 4.14E-05 | 0.6118 | 0.9964 |
LB630/519 | <1.0E-12 | 5.58E+04 | <1.0E-07 | 0.6271 | 0.9972 |
LB631/519 | 1.04E-09 | 5.86E+04 | 6.10E-05 | 0.3757 | 0.9982 |
LB632/519 | 8.37E-10 | 6.10E+04 | 5.11E-05 | 0.3287 | 0.9983 |
表3.亲和力成熟的抗体的结合亲和力
在3种工程化抗体中,与LB517/519相比,LB631/519和LB632/519的有效结合略少,而LB630/519的抗原结合大大改善。
这些工程化抗体的生物活性与实例7中类似地表征。与LB517/519相比,工程化抗体表现出相似的B-细胞脱敏活性(图3和4)。
应当理解,尽管已经图示和描述了特定实施例,但是可以对其进行各种修改并且在本文中进行了构想。还应理解,本公开内容不受本文提供的具体示例的限制。本文中对本公开内容的实施例和示例的描述和图示不旨在以限制性的意义来解释。还应理解,本公开内容的所有方面不限于本文阐述的具体描述、构造或相对比例,其可以取决于不同条件和变量。本公开内容的实施例和示例的形式和细节上的各种修改和变化对于本领域技术人员将是显而易见的。因此,可以预期的是,本公开内容还涵盖任何和所有这样的修改、变化和等同形式。
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Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
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<212> PRT
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<212> PRT
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Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
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Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
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Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
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Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
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Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
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Thr His Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
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<210> 23
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Humanized antibody light chain (人源化抗体轻链)
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Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
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Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
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Ser Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
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Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
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Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
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Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
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<210> 24
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
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Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
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Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
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Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
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Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Pro Val Tyr Gly Tyr Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 25
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
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Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
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Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
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Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Leu Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 26
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 26
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Trp Gly Tyr Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 27
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 27
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Tyr Pro His Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 28
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 28
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Ile Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 29
<211> 112
<212> PRT
<213> Artificial SEQUENCE (人工序列)
<220>
<223> aFFINITY MATURED ANTIBODY LIGHT CHAIN (亲和力成熟的抗体轻链)
<400> 29
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Val Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 30
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 30
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Leu Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 31
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 31
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Arg Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 32
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 32
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Tyr Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 33
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 33
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Gly Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Tyr Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 34
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 34
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Pro Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Tyr Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 35
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 35
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Asn Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Val Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Tyr Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 36
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 36
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Tyr Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 37
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 37
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Val Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Tyr Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 38
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 38
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Gly Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Tyr Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 39
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 39
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Asn Tyr Ser
20 25 30
Trp Val Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Phe Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Tyr Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 40
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 40
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Arg Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Gly Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Met Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Tyr Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 41
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 41
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Arg Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Tyr Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 42
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 42
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Leu Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 43
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 43
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Lys Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 44
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 44
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Ile Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 45
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 45
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Asp Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Leu Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 46
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 46
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Leu Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 47
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 47
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Thr Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Leu Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 48
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 48
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Arg Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Gly Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 49
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 49
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Arg Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 50
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 50
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Leu Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Thr
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 51
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 51
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Pro
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 52
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 52
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Pro Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 53
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 53
Asp Val Val Met Thr Gln Ser Pro Pro Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Val Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 54
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 54
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Thr Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Arg
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Ile Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 55
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 55
Asp Val Val Met Thr Gln Ser Pro Leu Ser Met Pro Val Thr Leu Gly
1 5 10 15
Leu Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
His Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 56
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 56
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Leu Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Ile Pro Phe Thr Phe Ser Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 57
<211> 16
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Antibody light chain CDR1 (抗体轻链CDR1)
<400> 57
Lys Ser Ser Gln Ser Leu Leu Asp Ser Ser Gly Lys Thr Tyr Leu Asn
1 5 10 15
<210> 58
<211> 17
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Antibody heavy chain CDR2 (抗体重链CDR2)
<400> 58
Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Ala Gly Lys Phe Lys
1 5 10 15
Gly
<210> 59
<211> 17
<212> PRT
<213> Articial Sequence (人工序列)
<220>
<223> Antibody heavy chain CDR2 (抗体重链CDR2)
<400> 59
Arg Ile Tyr Pro Glu Ser Gly Asp Thr Asn Tyr Ala Gly Lys Phe Lys
1 5 10 15
Gly
<210> 60
<211> 15
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Antibody light chain FR2 (抗体轻链FR2)
<400> 60
Trp Phe Gln Gln Arg Pro Gly Gln Ser Pro Arg Arg Leu Ile Tyr
1 5 10 15
<210> 61
<211> 15
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Antibody light chain FR2 (抗体轻链FR2)
<400> 61
Trp Leu Gln Gln Arg Pro Gly Gln Ser Pro Arg Arg Leu Ile Tyr
1 5 10 15
<210> 62
<211> 15
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Antibody light chain FR2 (抗体轻链FR2)
<400> 62
Trp Leu Gln Gln Arg Pro Gly Gln Ser Pro Lys Arg Leu Ile Tyr
1 5 10 15
<210> 63
<211> 30
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Antibody heavy chain FR1 (抗体重链FR1)
<400> 63
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser
20 25 30
<210> 64
<211> 14
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Antibody heavy chain FR2 (抗体重链FR2)
<400> 64
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 65
<211> 32
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Antibody heavy chain FR3 (抗体重链FR3)
<400> 65
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 66
<211> 32
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Antibody heavy chain FR3 (抗体重链FR3)
<400> 66
Arg Val Thr Met Thr Ala Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 67
<211> 14
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Antibody heavy chain FR2 (抗体重链FR2)
<400> 67
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10
<210> 68
<211> 32
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Antibody heavy chain FR3 (抗体重链FR3)
<400> 68
Arg Val Thr Leu Thr Ala Asp Lys Ser Ile Ser Thr Ala Tyr Met Glu
1 5 10 15
Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
20 25 30
<210> 69
<211> 1415
<212> DNA
<213> Artificial Sequence (人工序列)
<220>
<223> Chimeric antigen receptor (嵌合抗原受体)
<400> 69
gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60
atctcctgca agtcaagtca gagcctctta gatagtgatg gaaagacata tttgaattgg 120
ttacagcaga ggccaggcca atctccaagg cgcctaattt atctggtgtc taaactggac 180
tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240
agcagggtgg aagctgagga tgttggggtt tattactgct ggcaaggtac acatctgcca 300
ttcacgttcg gcggagggac caaggtggag atcaaaggtg gcggtggctc gggcggtggt 360
gggtcgggtg gcggcggatc tcaggtgcag ctggtgcagt ctggggctga ggtgaagaag 420
cctggggcct cagtgaaggt ctcctgcaag gcttctggat acgcattcag ttactcctgg 480
atgaactggg tgcgacaggc ccctggacaa gggcttgagt ggatgggacg gatttatcct 540
gaaaatggag atactaacta caatgggaag ttcaagggca gggtcaccat gaccagggac 600
acgtccatca gcacagccta catggagctg agcaggctga gatctgacga cacggccgtg 660
tattactgtg cgagatgggt ctatggtctt ccccactttg actactgggg ccaaggaacc 720
ctggtcaccg tctcctcagc tagcaccacg acgccagcgc cgcgaccacc aacaccggcg 780
cccaccatcg cgtcgcagcc cctgtccctg cgcccagagg cgtgccggcc agcggcgggg 840
ggcgcagtgc acacgagggg gctggacttc gcctgtgata tctacatctg ggcgcccttg 900
gccgggactt gtggggtcct tctcctgtca ctggttatca ccctttactg caaacggggc 960
agaaagaaac tcctgtatat attcaaacaa ccatttatga gaccagtaca aactactcaa 1020
gaggaagatg gctgtagctg ccgatttcca gaagaagaag aaggaggatg tgaactgaga 1080
gtgaagttca gcaggagcgc agacgccccg cgtacaagca gggccagaac cagctctata 1140
acgagctcaa tctaggacga agagaggagt acgatgtttt ggacaagaga cgtggccggg 1200
accctgagat ggggggaaag ccgagaagga agaaccccca ggaaggcctg tacaatgaac 1260
tgcagaaaga taagatggcg gaggcctaca gtgagattgg gatgaaaggc gagcgccgga 1320
ggggcaaggg gcacgatggc ctttaccagg gtctcagtac agccaccaag gacacctacg 1380
acgcccttca catgcaggcc ctgccccctc gctga 1415
<210> 70
<211> 470
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Chimeric antigen receptor (嵌合抗原受体)
<400> 70
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ser
65 70 75 80
Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly Thr
85 90 95
His Leu Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val
115 120 125
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val
130 135 140
Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met
145 150 155 160
Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg
165 170 175
Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe Lys Gly
180 185 190
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met Glu
195 200 205
Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg
210 215 220
Trp Val Tyr Gly Leu Pro His Phe Asp Tyr Trp Gly Gln Gly Thr Leu
225 230 235 240
Val Thr Val Ser Ser Ala Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro
245 250 255
Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu
260 265 270
Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
275 280 285
Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly
290 295 300
Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg
305 310 315 320
Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln
325 330 335
Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu
340 345 350
Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala
355 360 365
Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu
370 375 380
Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp
385 390 395 400
Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu
405 410 415
Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile
420 425 430
Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr
435 440 445
Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met
450 455 460
Gln Ala Leu Pro Pro Arg
465 470
<210> 71
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 71
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Asn Tyr Ser
20 25 30
Trp Val Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Phe Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Tyr Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 72
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 72
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Asn Tyr Ser
20 25 30
Trp Val Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Phe Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Tyr Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 73
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 73
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Leu Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 74
<211> 112
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody light chain (亲和力成熟的抗体轻链)
<400> 74
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly
85 90 95
Thr His Leu Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 75
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Affinity matured antibody heavy chain (亲和力成熟的抗体重链)
<400> 75
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Ser Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Leu Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 76
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Antibody heavy chain (抗体重链)
<400> 76
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Asn Gly Asp Thr Asn Tyr Ala Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Leu Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 77
<211> 119
<212> PRT
<213> Artificial Sequence (人工序列)
<220>
<223> Antibody heavy chain (抗体重链)
<400> 77
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Tyr Pro Glu Ser Gly Asp Thr Asn Tyr Ala Gly Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Val Tyr Gly Leu Pro His Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
Claims (36)
1.一种抗CD79抗体,包括具有选自由SEQ ID NO:9-17,24-27,32-41,71,72和75-77组成的组的可变区的重链,和具有选自由SEQ ID NO:18-23,28-31,42-56和73-74组成的组的可变区的轻链。
2.根据权利要求1所述的抗CD79抗体,其中重链的可变区选自由SEQ ID NO:24-27和75-77组成的组,而轻链的可变区选自由SEQ ID NO:28-31组成的组。
3.根据权利要求2所述的抗CD79抗体,其中重链的可变区是SEQ ID NO:25,而轻链的可变区是SEQ ID NO:30。
4.根据权利要求2所述的抗CD79抗体,其中重链的可变区是SEQ ID NO:75,而轻链的可变区是SEQ ID NO:30。
5.根据权利要求2所述的抗CD79抗体,其中重链的可变区是SEQ ID NO:76,而轻链的可变区是SEQ ID NO:30。
6.根据权利要求2所述的抗CD79抗体,其中重链的可变区是SEQ ID NO:77,而轻链的可变区是SEQ ID NO:30。
7.一种抗CD79抗体,包括具有选自由SEQ ID NO:9-17组成的组的可变区的重链和具有选自由SEQ ID NO:18-23组成的组的可变区的轻链。
8.一种治疗关节炎的方法,包括以下步骤:提供哺乳动物,其中所述哺乳动物患有关节炎,以及向所述哺乳动物施用权利要求1-7中任一项所述的抗CD79抗体。
9.根据权利要求8所述的方法,其中重链的可变区是SEQ ID NO:25,而轻链的可变区是SEQ ID NO:30。
10.根据权利要求8所述的方法,其中重链的可变区是SEQ ID NO:75,而轻链的可变区是SEQ ID NO:30。
11.根据权利要求8所述的方法,其中重链的可变区是SEQ ID NO:76,而轻链的可变区是SEQ ID NO:30。
12.根据权利要求8所述的方法,其中重链的可变区是SEQ ID NO:77,而轻链的可变区是SEQ ID NO:30。
13.一种治疗系统性狼疮的方法,包括以下步骤:提供哺乳动物,其中所述哺乳动物患有系统性狼疮,以及向所述哺乳动物施用权利要求1-7中任一项所述的抗CD79抗体。
14.根据权利要求13所述的方法,其中重链的可变区是SEQ ID NO:25,而轻链的可变区是SEQ ID NO:30。
15.根据权利要求13所述的方法,其中重链的可变区是SEQ ID NO:75,而轻链的可变区是SEQ ID NO:30。
16.根据权利要求13所述的方法,其中重链的可变区是SEQ ID NO:76,而轻链的可变区是SEQ ID NO:30。
17.根据权利要求13所述的方法,其中重链的可变区是SEQ ID NO:77,而轻链的可变区是SEQ ID NO:30。
18.一种治疗1型糖尿病的方法,包括以下步骤:提供哺乳动物,其中所述哺乳动物患有1型糖尿病,向所述哺乳动物施用权利要求1-7中任一项所述的抗CD79抗体。
19.根据权利要求18所述的方法,其中重链的可变区是SEQ ID NO:25,而轻链的可变区是SEQ ID NO:30。
20.根据权利要求18所述的方法,其中重链的可变区是SEQ ID NO:75,而轻链的可变区是SEQ ID NO:30。
21.根据权利要求18所述的方法,其中重链的可变区是SEQ ID NO:76,而轻链的可变区是SEQ ID NO:30。
22.根据权利要求18所述的方法,其中重链的可变区是SEQ ID NO:77,而轻链的可变区是SEQ ID NO:30。
23.一种治疗多发性硬化症的方法,包括以下步骤:提供哺乳动物,其中所述哺乳动物患有多发性硬化症,向所述哺乳动物施用权利要求1-7中任一项所述的抗CD79抗体。
24.根据权利要求23所述的方法,其中重链的可变区是SEQ ID NO:25,而轻链的可变区是SEQ ID NO:30。
25.根据权利要求23所述的方法,其中重链的可变区是SEQ ID NO:75,而轻链的可变区是SEQ ID NO:30。
26.根据权利要求23所述的方法,其中重链的可变区是SEQ ID NO:76,而轻链的可变区是SEQ ID NO:30。
27.根据权利要求23所述的方法,其中重链的可变区是SEQ ID NO:77,而轻链的可变区是SEQ ID NO:30。
28.一种治疗自身免疫性疾病的方法,包括以下步骤:提供哺乳动物,其中所述哺乳动物患有自身免疫性疾病,以及向所述哺乳动物施用权利要求1-7中任一项所述的抗CD79抗体。
29.根据权利要求28所述的方法,其中自身免疫性疾病涉及B细胞。
30.一种治疗过敏的方法,包括以下步骤:提供哺乳动物,其中所述哺乳动物患有过敏,向所述哺乳动物施用权利要求1-7中任一项所述的抗CD79抗体。
31.一种防止移植排斥反应的方法,包括以下步骤:提供哺乳动物,其中所述哺乳动物已经接受了移植的器官,向所述哺乳动物施用权利要求1-7中任一项所述的抗CD79抗体。
32.一种预防对治疗剂的免疫应答的方法,包括以下步骤:提供哺乳动物,其中所述哺乳动物已经接受了治疗剂,向所述哺乳动物施用权利要求1-7中任一项所述的抗CD79抗体。
33.一种T-细胞,包括:嵌合抗原受体,其中嵌合抗原受体具有抗原结合部分,所述抗原结合部分包括选自由SEQ ID NO:9-17,24-27,32-41,71,72和75-77组成的组的重链可变区和具有选自由SEQ ID NO:18-23,28-31,42-56和73-74组成的组的可变区的轻链。
34.根据权利要求33所述的T-细胞,其中嵌合抗原受体是SEQ ID NO:70。
35.一种用于治疗患有CD79阳性癌症的受试者的方法,包括以下步骤:向受试者施用权利要求33所述的T-细胞,从而治疗CD79阳性癌症。
36.根据权利要求35的方法,其中T-细胞中的嵌合抗原受体是SEQ ID NO:70。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201862740655P | 2018-10-03 | 2018-10-03 | |
US62/740,655 | 2018-10-03 | ||
PCT/US2019/054372 WO2020072705A1 (en) | 2018-10-03 | 2019-10-03 | Anti-cd79 antibodies and their uses |
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CN113194966A true CN113194966A (zh) | 2021-07-30 |
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US (2) | US11078276B2 (zh) |
EP (1) | EP3829606A4 (zh) |
JP (1) | JP2022513338A (zh) |
KR (1) | KR20210071987A (zh) |
CN (1) | CN113194966A (zh) |
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WO2023011338A1 (zh) * | 2021-08-02 | 2023-02-09 | 信达生物制药(苏州)有限公司 | 抗CD79b×CD3双特异性抗体及其用途 |
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EP3829606A4 (en) * | 2018-10-03 | 2022-07-06 | Nepenthe Bioscience, LLC | ANTI-CD79 ANTIBODIES AND THEIR USES |
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US20200109198A1 (en) | 2020-04-09 |
EP3829606A4 (en) | 2022-07-06 |
KR20210071987A (ko) | 2021-06-16 |
JP2022513338A (ja) | 2022-02-07 |
EP3829606A1 (en) | 2021-06-09 |
US20210355214A1 (en) | 2021-11-18 |
AU2019355115A1 (en) | 2021-03-04 |
US11078276B2 (en) | 2021-08-03 |
WO2020072705A1 (en) | 2020-04-09 |
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