CN115551594A - 经细胞因子修饰的嵌合抗体及其使用方法 - Google Patents
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Abstract
提供了含有超长CDR3的经细胞因子修饰的嵌合抗体,诸如基于牛抗体序列或其人源化序列,其中重链的CDR3的一部分被白细胞介素(IL‑15)或IL‑2替代;以及相关抗体。所提供的抗体包括经IL‑15细胞因子修饰的嵌合抗体分子,其进一步与IL15Rα的细胞外部分诸如IL15Rαsushi结构域连接或复合。还提供了制造和使用所述经细胞因子修饰的嵌合抗体的方法。
Description
相关申请的交叉引用
本申请要求2019年10月24日提交的标题为“经细胞因子修饰的嵌合抗体及其使用方法(CHIMERIC CYTOKINE MODIFIED ANTIBODIES AND METHODS OF USE THEREOF)”的美国临时申请62/925,740的优先权,出于所有目的将所述临时申请的内容通过引用以其整体并入本文。
序列表
本申请是与电子格式的序列表一起提交的。序列表以2020年10月22日创建的名为165772000140SeqList.txt的文件提供,其大小为79,015字节。将在电子格式的序列表中的信息通过引用以其整体并入。
技术领域
本公开文本涉及含有超长CDR3的经细胞因子修饰的嵌合抗体,诸如基于牛抗体序列或其人源化序列,其中重链的CDR3的一部分被白细胞介素(IL-15)或IL-2替代;以及相关抗体。本公开文本的分子包括经IL-15细胞因子修饰的嵌合抗体分子,其进一步与IL15Rα的细胞外部分诸如IL15Rαsushi结构域连接或复合。本公开文本还提供了制造和使用所述经细胞因子修饰的嵌合抗体的方法。
背景技术
抗体是脊椎动物免疫系统响应外来物质(抗原)而形成的天然蛋白质,主要用于防御感染。抗体含有介导与靶抗原的结合的互补决定区(CDR)。与其他脊椎动物相比,一些牛抗体具有异常长的VH CDR3序列,其长度可以高达70个氨基酸。长CDR3可以形成从抗体表面突出的独特结构域,从而允许形成独特的抗体平台。
白细胞介素(IL)15和IL-2是刺激细胞毒性T淋巴细胞和自然杀伤(NK)细胞的增殖和细胞毒性的细胞因子,并且因此是癌症治疗的免疫治疗候选物。然而,此类细胞因子可能难以表达为稳定的可溶性蛋白质并且通常在体外和体内具有短的半衰期。仍然需要改善的细胞因子治疗剂,诸如IL-2或IL-15治疗剂,特别是用于治疗癌症。
发明内容
本文提供了一种经细胞因子修饰的嵌合抗体或抗原结合片段,其包含经修饰的超长CDR3,所述经修饰的超长CDR3包含替代牛抗体或抗原结合片段或其人源化序列的重链的超长CDR3区的至少一部分的白细胞介素-15(IL-15)细胞因子序列或其生物活性部分。
在一些实施方案中,所述IL-15细胞因子序列是人IL-15。在一些实施方案中,所述IL-15细胞因子序列包含与SEQ ID NO:1展现出至少或至少约85%、至少或至少约90%、至少或至少约92%、至少或至少约95%、至少或至少约96%、至少或至少约97%、至少或至少约98%或者至少或至少约99%序列同一性的氨基酸序列。在一些实施方案中,所述IL-15细胞因子序列包含SEQ ID NO:1中所示的氨基酸序列。在一些实施方案中,所述IL-15细胞因子序列由SEQ ID NO:1中所示的氨基酸序列组成。
本文提供了一种经细胞因子修饰的嵌合抗体或抗原结合片段,其包含经修饰的超长CDR3,所述经修饰的超长CDR3包含替代牛抗体或抗原结合片段或其人源化序列的重链的超长CDR3区的至少一部分的白细胞介素-2(IL-2)细胞因子序列或其生物活性部分。
在一些实施方案中,所述IL-2细胞因子序列是人IL-2。在一些实施方案中,所述IL-2细胞因子序列包含与SEQ ID NO:165展现出至少或至少约85%、至少或至少约90%、至少或至少约92%、至少或至少约95%、至少或至少约96%、至少或至少约97%、至少或至少约98%或者至少或至少约99%序列同一性的氨基酸序列。在一些实施方案中,所述IL-2细胞因子序列包含SEQ ID NO:165中所示的氨基酸序列。在一些实施方案中,所述IL-2细胞因子序列由SEQ ID NO:165中所示的氨基酸序列组成。
在任何实施方案中的一些中,所述细胞因子序列替代牛抗体或抗原结合片段的重链的超长CDR3区的至少一部分。在一些实施方案中,所述牛抗体或抗原结合片段是牛抗体BLV1H12或其抗原结合片段。
在一些实施方案中,所述牛抗体或抗原结合片段包含由SEQ ID NO:5中所示序列编码的可变重链氨基酸序列和由SEQ ID NO:8中所示序列编码的可变轻链氨基酸序列。在一些实施方案中,所述牛抗体或抗原结合片段包含由SEQ ID NO:167中所示序列编码的可变重链氨基酸序列和由SEQ ID NO:168中所示序列编码的可变轻链氨基酸序列。
在一些实施方案中,所述牛抗体或抗原结合片段包含SEQ ID NO:26中所示的可变重链和SEQ ID NO:27中所示的可变轻链。
在任何实施方案中的一些中,所述细胞因子序列替代人源化牛抗体或其抗原结合片段的重链的超长CDR3区的至少一部分。在一些实施方案中,所述人源化牛抗体或其抗原结合片段包含作为人重链种系序列或源自人重链种系序列的重链或其一部分和作为人轻链种系序列或源自人轻链种系序列的轻链或其一部分。在一些实施方案中,所述人重链种系序列是VH4-39、VH4-59*03、VH4-34*02或VH4-34*09种系序列或是SEQ ID NO:68-71中任一个所示的序列。
在任何实施方案中的一些中,所述人轻链种系序列是VL1-51种系序列或是基于所述VL1-51种系序列的包含一个或多个突变的序列,任选地其中所述VL1-51种系序列是SEQID NO:156中所示的。在一些实施方案中,所述一个或多个突变选自:基于Kabat编号的氨基酸替代S2A、T5N、P8S、A12G、A13S和P14L中的一个或多个;基于Kabat编号的氨基酸替代S2A、T5N、P8S、A12G、A13S和P14L;CDR1中包含氨基酸替代I29V和N32G的突变;CDR2中包含DNN取代为GDT的突变;CDR2中包含DNNKRP取代为GDTSRA的突变;或任何前项的组合。
在任何实施方案中的一些中,所提供的抗体是包含可变重链和可变轻链的抗原结合片段。在一些实施方案中,所述抗体包含与重链恒定结构域(CH1-CH2-CH3)连接的可变重链和与轻链恒定结构域(CL1)连接的可变轻链。在一些实施方案中,所述重链恒定结构域来自人IgG1。在一些实施方案中,所述轻链恒定结构域是λ轻链区。
在任何实施方案中的一些中,超长CDR3区的所述至少一部分包含杵区,并且所述细胞因子序列存在于所述经修饰的超长CDR3的升茎结构域与降茎结构域之间。在一些实施方案中,所述细胞因子序列经由柔性接头、任选地GGS或GSG接头与所述升茎结构域和/或所述降茎结构域连接。在任何实施方案中的一些中,所述升茎结构域包含SEQ ID NO:158或SEQ ID NO:159中所示的序列。在任何实施方案中的一些中,所述降茎结构域包含SEQ IDNO:161中所示的序列。
在一些实施方案中,所提供的抗体或抗原结合片段包含由SEQ ID NO:7中所示的核苷酸序列或与SEQ ID NO:7中所示的核苷酸序列展现出至少或至少约85%、至少或至少约90%、至少或至少约92%、至少或至少约95%、至少或至少约96%、至少或至少约97%、至少或至少约98%、至少或至少约99%序列同一性的核苷酸序列编码的可变重链序列,其中包含含有IL-15序列的经修饰的超长CDR3。在一些实施方案中,所提供的抗体或抗原结合片段包含由SEQ ID NO:7中所示的核苷酸序列编码的可变重链序列。在一些实施方案中,所提供的抗体或抗原结合片段由以下组成:由SEQ ID NO:7中所示的核苷酸序列编码的可变重链序列。
在任何实施方案中的一些中,所述抗体或抗原结合片段与包括IL15Rαsushi结构域在内的IL15Rα的细胞外结构域复合。在一些实施方案中,包括IL15Rαsushi结构域在内的IL15Rα的所述细胞外结构域与所述IL-15序列非共价缔合。在一些实施方案中,包括IL15Rαsushi结构域在内的IL15Rα的所述细胞外结构域与所述可变轻链连接。在一些实施方案中,包括IL15Rαsushi结构域在内的IL15Rα的所述细胞外结构域经由肽接头与所述可变轻链连接。在任何实施方案中的一些中,所述肽接头是甘氨酸接头或甘氨酸-丝氨酸接头,任选地其中所述接头是GS。
在任何实施方案中的一些中,包括IL15Rαsushi结构域在内的IL15Rα的所述细胞外结构域包含SEQ ID NO:2中所示的序列。在任何实施方案中的一些中,包括IL15Rαsushi结构域在内的IL15Rα的所述细胞外结构域由SEQ ID NO:2中所示的序列组成。
在一些实施方案中,所述可变轻链包含由SEQ ID NO:3编码的氨基酸序列。
本文提供了一种或多种多核苷酸,其编码根据任何前述实施方案所述的经细胞因子修饰的嵌合抗体或抗原结合片段。
本文提供了一种多核苷酸,其编码根据任何前述实施方案所述的经细胞因子修饰的嵌合抗体或抗原结合片段的重链或其可变区。
本文提供了一种多核苷酸,其编码根据任何前述实施方案所述的经细胞因子修饰的嵌合抗体或抗原结合片段的轻链或其可变区。
本文提供了一种表达载体,其包含根据任何前述实施方案所述的多核苷酸。
本文提供了一种宿主细胞,其包含根据任何前述实施方案所述的多核苷酸或表达载体。在任何实施方案中的一些中,所述宿主细胞进一步包含表达包括IL15Rαsushi结构域在内的IL15Rα的细胞外结构域的多核苷酸或载体。在任何实施方案中的一些中,包括IL15Rαsushi结构域在内的IL15Rα的所述细胞外结构域包含SEQ ID NO:2中所示的序列。
本文提供了一种产生经细胞因子修饰的嵌合抗体或抗原结合片段的方法,其包括在根据任何前述实施方案所述的宿主细胞表达所述抗体或抗原结合片段的条件下培养所述细胞,任选地进一步包括回收并纯化所述抗体或抗原结合片段。
本文提供了一种通过根据任何前述实施方案所述的方法产生的经细胞因子修饰的嵌合抗体或抗原结合片段。
本文提供了一种药物组合物,其包含根据任何前述实施方案所述的经细胞因子修饰的嵌合抗体或抗原结合片段。
本文提供了一种治疗受试者的癌症的方法,其包括施用治疗有效量的根据任何前述实施方案所述的经细胞因子修饰的嵌合抗体或抗原结合片段。
本文提供了一种治疗受试者的癌症的方法,其包括施用治疗有效量的任何前述实施方案所述的药物组合物。
附图说明
图1A和图1B描绘了所产生的构建体的示意性图示。图1A示出了BLV1H12的晶体结构,描绘了两条β-链茎如何从牛VH免疫球蛋白结构域突出并且终止于不寻常的三个二硫键连接的杵结构域(左);以及BLV1H12的B15_IL15Rαsushi变体的晶体结构,其中杵区已被IL-15细胞因子结构域替代并且进一步含有IL15Rαsushi结构域(右)。图1B描绘了不同的融合抗体构建体BLV1H12-IL-15(B15)、BLV1H12-IL-15-Rαsushi(B15_Rαsushi)和BLV1H12-IL-15-GS-Rαsushi(B15_GS_Rαsushi)。
图2示出了由HEK 293细胞BLV1H12-IL-15(B15)、BLV1H12-IL-15-Rαsushi(B15_Rαsushi)和BLV1H12-IL-15-GS-Rαsushi(B15_GS_Rαsushi)表达并且通过SDS-PAGE凝胶电泳分析的纯化B15融合抗体构建体的表达。
图3A和图3B描绘了嵌合BLV1H12-IL-15(B15)融合抗体结合IL2/15Rβ受体的能力,如通过ELISA测定所示。图3A描绘了B15抗体与IL2Rα或IL15Rα受体亚基结合的能力。图3B描绘了B15抗体在存在或不存在IL15Rα亚基的情况下结合IL2/15Rβ受体亚基的能力。
图4描绘了嵌合B15分子通过在HEK-Blue IL2报告细胞中诱导和分泌STAT5诱导型碱性磷酸酶(SEAP)报告基因来激活IL2/15Rβ和γc受体和STAT5信号传导。
图5描绘了与IL15Rαsushi结构域缔合的替代嵌合B15分子通过在HEK-Blue IL2报告细胞中诱导和分泌STAT5诱导型碱性磷酸酶(SEAP)报告基因来激活IL2/15Rβ和γc受体和STAT5信号传导。
图6描绘了嵌合B15分子扩增NK-92自然杀伤细胞的能力。将NK-92细胞与2倍连续稀释(从1.33nM至0.005nM)的IL2或IL15单体(R&D Systems)或者嵌合B15、嵌合变体B15_Rαsushi或嵌合B15变体B15_GS_Rαsushi抗体一起孵育,并且通过MTT测定进行分析。
图7描绘了嵌合B15抗体与嵌合B15变体B15-Rαsushi或B15-GS-Rαsushi抗体相比扩增NK-92自然杀伤细胞的能力,如通过MTT测定所示。
图8A和图8B描绘了所产生的构建体的示意性图示。图8A示出了BLV1H12的晶体结构,描绘了两条β-链茎如何从牛VH免疫球蛋白结构域突出并且终止于不寻常的三个二硫键连接的杵结构域(左);以及通过将嵌合B15抗体的IL15区用IL-2替代而产生的嵌合BLV1H12-IL-2(B2)融合抗体的晶体结构(右)。图8B描绘了杵结构域中含有IL-2序列的BLV1H12-IL-2(B2)融合抗体的图示。
图9示出了由HEK 293细胞表达并且通过SDS-PAGE凝胶电泳分析的纯化融合抗体构建体BLV1H12-IL-2(B2)的表达。
图10描绘了嵌合BLV1H12-IL-2(B2)融合抗体结合IL2Rα和IL15Rα的能力,如通过酶联免疫吸附测定(ELISA)所示。
图11描绘了嵌合B2分子通过在HEK-Blue IL2报告细胞中诱导和分泌STAT5诱导型碱性磷酸酶(SEAP)报告基因来激活IL2/15Rβ和γc受体和STAT5信号传导。
图12描绘了嵌合B2分子扩增NK-92自然杀伤细胞的能力。将NK-92细胞与2倍连续稀释(从1.33nM至0.005nM)的IL2单体(R&D Systems)或嵌合B2抗体一起孵育,并且通过MTT测定进行分析。
图13描绘了嵌合B15分子在体外刺激人PBMC中的NK细胞和T细胞的能力。将PBMC与终浓度为250nM至0.016nM的B15和B15_Rαsushi一起孵育,此后将PBMC用抗CD3-FITC(SK7)、抗CD4-PE(OKT4)、抗CD8a-eFluor 450(SK1)和抗CD56-APC(AF12-7H3)染色并且随后使用Novocyte Advanteon流式细胞仪(Agilent,加利福尼亚州圣克拉拉)进行分析。
具体实施方式
本文提供了经细胞因子修饰的嵌合抗体融合分子,其中IL-15或IL-2序列或其生物活性部分替代牛(奶牛)抗体或其人源化序列的重链的超长CDR3区的一部分。在一些实施方案中,超长CDR3区含有升茎区、杵区和降茎区(诸如存在于牛抗体中),其中杵区的全部或一部分被细胞因子序列替代。在一些实施方案中,细胞因子序列是IL-2或其生物活性部分,例如IL-2具有SEQ ID NO:165中所示的序列。在一些实施方案中,细胞因子序列是IL-15或其生物活性部分,例如IL-15具有SEQ ID NO:1中所示的序列。本文还提供了变体经IL-15修饰的嵌合抗体,其包括与IL15Rα的细胞外部分(诸如IL15Rαsushi结构域(例如,SEQ ID NO:2中所示))连接或复合的此类抗体。
IL-15和IL-2是多效性细胞因子,其在先天性免疫和适应性免疫两者中都发挥着重要作用。与IL-2一样,IL-15最初被描述为T细胞生长因子。例如,IL-15参与多个淋巴细胞亚群(包括自然杀伤细胞(NK)、NK-T细胞和记忆CD8T细胞)的产生。IL-15也是针对T细胞的趋化剂,作用于嗜中性粒细胞以诱导形态细胞形状变化,并且刺激IL-8的产生。这两种细胞因子都属于四α-螺旋束家族,并且它们的膜受体共享负责信号转导的两个亚基(IL-2R/IL-15Rβ和γ链)。IL-15通过三聚体IL-15R复合体发挥作用,所示复合体由高亲和力结合α链(IL-15Rα)和常见的IL-2Rβ链和γ链构成。IL-2Rβ/γ复合体是针对两种细胞因子的中间亲和受体,其由大多数NK细胞表达并且可以在体外被纳摩尔浓度的IL-2或IL-15激活。(Wei等人J Immunol.2001,167(1)277-282;Mortier等人J Biol Chem.2006,281(3):1612-1619)。
IL-15Rα和IL-2Rα亚基形成细胞因子受体的亚家族,所述细胞因子受体在其N末端含有细胞外部分(即,所谓的“sushi”结构的结构域)(IL-15Rα中一个以及IL-2Rα中两个),它们也发现于补体或粘附分子中。IL-15RαSushi结构域是蛋白-蛋白相互作用中的常见基序。Sushi结构域也称为短共有重复序列或1型糖蛋白基序。它们已被鉴定在许多蛋白质结合分子上,所述蛋白质结合分子包括补体组分C1r、C1s、因子H和C2m以及非免疫分子因子XIII和β2-糖蛋白。典型的sushi结构域具有与大约60个aa残基并且含有四个半胱氨酸。第一个半胱氨酸与第三个半胱氨酸形成二硫键,并且第二个半胱氨酸与第四个半胱氨酸形成二硫键。这两个二硫键对于维持蛋白质的三级结构至关重要(Kato等人Biochemistry.1991,30:11687;Bottenus等人Biochemistry 1990,29:11195;Ranganathan等人Pac.Symp.Biocomput.2000,00:155)。高亲和力受体α(IL15Rα)参与增加IL15介导的向受体β和γ亚基(IL2/15Rβ和γc)的反式信号传导。
在一些实施方案中,IL-2刺激细胞毒性T淋巴细胞和自然杀伤(NK)细胞的增殖、激活和(在某些情况下)细胞毒性。在一些实施方案中,IL-15刺激细胞毒性T淋巴细胞和自然杀伤(NK)细胞的增殖、激活和(在某些情况下)细胞毒性。IL-15可能是比IL-2更好的候选药物,因为它不会引起血管渗漏综合征或刺激调节性T细胞。尽管这些活性使IL-2和IL-15成为治疗用途所希望的,但IL-2和IL-15难以作为稳定的可溶性蛋白表达并且在体外和体内具有短的半衰期。
所提供的实施方案解决了这些问题。所提供的实施方案包括嵌合抗体,其中IL-2或IL-15细胞因子序列或其生物活性部分替代牛抗体或其人源化变体的杵区的全部或一部分。所提供的含有IL-15细胞因子序列或其生物活性部分的抗体可以进一步与IL15Rα的细胞外部分(诸如IL15Rαsushi结构域)连接或复合,以进一步介导IL15活性。本文发现所提供的嵌合分子(包括嵌合IL2分子(例如,B2)或嵌合IL15分子(例如,B15)及其与IL15Rα的细胞外部分复合或连接的变体)可以类似于典型的人抗体进行表达和纯化,并且展现出对IL2/15Rβ和γc亚基的有效结合和活性。特别地,所提供的分子在体外信号传导分析中的功能类似于各自的IL-2或IL15可溶性单体细胞因子,但可以很容易地在哺乳动物细胞中产生并且具有增加的稳定性。
此类抗体可以用于治疗或预防多种疾病、障碍或病症,包括炎性疾病、障碍或病症,自身免疫疾病、障碍或病症,代谢疾病、障碍或病症,赘生疾病、障碍或病症,和癌症。
本公开文本还提供了用于制备所提供的经细胞因子修饰的嵌合抗体(包括经IL-15修饰的嵌合抗体和经IL-2修饰的嵌合抗体)的方法和材料。
本申请中提及的所有出版物(包括专利文献、科学文章和数据库)出于所有目的通过引用以其整体并入,其并入程度如同将每个单独出版物通过引用单独并入一般。如果本文所述的定义与通过引用并入本文的专利、申请、公开的申请和其他出版物中所述的定义矛盾或以其他方式不一致,则本文所述的定义优先于通过引用并入本文的定义。
本文使用的章节标题仅用于组织目的,而不应解释为限制所描述的主题。
I.定义
除非另有定义,否则本文使用的所有技术术语、符号和其他技术和科学术语或用辞旨在具有与所要求保护的主题所属领域的普通技术人员通常理解的含义相同的含义。在一些情况下,为了清楚和/或为了便于参考而在本文中定义具有通常理解的含义的术语,并且本文中包含的此类定义不应被解释为表示与本领域通常理解的实质性差异。
如本文所用,冠词“一个/种(a)”和“一个/种(an)”是指一个/种或多于一个/种(例如至少一个/种)所述冠词的语法宾语。举例来说,“一个/种要素”意指一个/种要素或多于一个/种要素。
在整个本公开文本中,所要求保护的主题的各个方面以范围形式呈现。应理解,以范围形式描述仅仅是为了方便和简洁,并且不应被解释为对所要求保护的主题的范围的僵硬限制。因此,应当将范围的描述视为已明确公开该范围内所有可能的子范围以及单独数值。例如,在提供值的范围的情况下,应理解,在该范围的上限和下限之间的每个中间值以及在所陈述范围内的任何其他所述值或中间值都涵盖在所要求保护的主题内。这些较小范围的上限和下限可以独立地包括在所述较小范围内,并且也涵盖在所要求保护的主题内,受制于所陈述范围内任何明确排除的限值。在所陈述范围包括一个或两个所述限值的情况下,排除那些所包括限值中的任一个或两个的范围也包括在所要求保护的主题内。无论范围的宽度如何,这都适用。
如本文所用,术语“约”应是本领域普通技术人员所理解的并且将在其使用的上下文中在一定程度上变化。如本文所用,在涉及可测量值(诸如量、持续时间等)时,“约”意在涵盖相对于指定值±20%或±10%、更优选±5%、甚至更优选±1%并且仍然更优选±0.1%的变化,因为此类变化适合于执行所公开的方法。
在本文中可互换使用的“超长CDR3”或“超长CDR3序列”包含并非源自人抗体序列的CDR3或CDR3序列。超长CDR3可以具有35个氨基酸或更长的长度,例如40个氨基酸或更长的长度、45个氨基酸或更长的长度、50个氨基酸或更长的长度、55个氨基酸或更长的长度、或者60个氨基酸或更长的长度。典型地,超长CDR3是重链CDR3(CDR-H3或CDRH3)。超长CDR3H3展现出反刍动物(例如,牛)序列的CDRH3的特征。超长CDR3的长度可以包括非抗体序列,诸如细胞因子序列,例如IL-15。
术语“基本上相似”或“基本上相同”是指两个数值(通常,一个与本文公开的抗体相关并且另一个与参考/比较抗体相关)之间足够高的相似度,使得本领域技术人员将认为这两个值之间的差异在由所述值(例如,Kd值)测量的生物学特征的背景下具有很小或没有生物学和/或统计学显著性。根据参考/比较抗体的值,所述两个值之间的差异优选小于约50%、优选小于约40%、优选小于约30%、优选小于约20%、优选小于约10%。
“结合亲和力”通常是指分子(例如,抗体)的单个结合位点与其结合配偶体(例如,抗原)之间的非共价相互作用的总和的强度。除非另有指示,否则“结合亲和力”是指固有结合亲和力,其反映结合对(例如,抗体和抗原)的成员之间的1:1相互作用。分子X对其配偶体Y的亲和力通常可以表示为解离常数。低亲和力抗体通常缓慢地结合抗原并倾向于易于解离,而高亲和力抗体通常更快地结合抗原并倾向于更长时间地保持结合。测量结合亲和力的多种方法是本领域已知的,其中任何方法都可以用于本公开文本的目的。
关于肽或多肽序列的“氨基酸序列同一性百分比(%)”是指在比对序列和引入缺口(如果需要)以实现最大序列同一性百分比并且不将任何保守取代视为序列同一性的一部分后,候选序列中与特定肽或多肽序列中的氨基酸残基相同的氨基酸残基的百分比。用于确定氨基酸序列同一性百分比的目的的比对可以以本领域熟知的多种方式来实现,例如,使用公众可获得的计算机软件,诸如BLAST、BLAST-2、ALIGN或MegAlign(DNASTAR)软件。本领域技术人员可以确定用于测量比对的适当参数,包括为了在被比较的序列的全长上实现最大比对所需的任何算法。
“多肽”、“肽”、“蛋白质”和“蛋白质片段”可以互换使用以指代氨基酸残基的聚合物。所述术语适用于其中一个或多个氨基酸残基是相应的天然存在的氨基酸的人工化学模拟物的氨基酸聚合物,以及天然存在的氨基酸聚合物和非天然存在的氨基酸聚合物。
“氨基酸”是指天然存在的和合成的氨基酸,以及功能类似于天然存在的氨基酸的氨基酸类似物和氨基酸模拟物。天然存在的氨基酸是由遗传密码编码的氨基酸,以及后来经修饰的氨基酸,例如羟脯氨酸、γ-羧基谷氨酸和O-磷酸丝氨酸。氨基酸类似物是指具有与天然存在的氨基酸相同的基本化学结构(例如,与氢、羧基、氨基和R基团结合的α碳)的化合物,例如高丝氨酸、正亮氨酸、甲硫氨酸亚砜、甲硫氨酸甲基锍。此类类似物可以具有经修饰的R基团(例如,正亮氨酸)或经修饰的肽骨架,但保留与天然存在的氨基酸相同的基本化学结构。氨基酸模拟物是指具有与氨基酸的通用化学结构不同的结构但功能与天然存在的氨基酸类似的化学化合物。
“保守修饰变体”适用于氨基酸和核酸序列两者。“氨基酸变体”是指氨基酸序列。关于特定的核酸序列,保守修饰变体是指编码相同或基本相同的氨基酸序列的那些核酸,或者在核酸不编码氨基酸序列的情况下是指基本相同或相关(例如,天然接连的)序列。由于遗传密码的简并性,大量功能相同的核酸编码大多数蛋白质。例如,密码子GCA、GCC、GCG和GCU都编码氨基酸丙氨酸。因此,在丙氨酸由密码子指定的每个位置处,可以将密码子改变为所描述的对应密码子中的另一个而不改变编码的多肽。此类核酸变异是“沉默变异”,它是一种保守修饰变异。本文中编码多肽的每个核酸序列也描述了核酸的沉默变异。技术人员应认识到,在某些上下文中,核酸中的每个密码子(除了通常是甲硫氨酸的唯一密码子的AUG和通常是色氨酸的唯一密码子的TGG之外)可以被修饰以产生功能相同的分子。因此,编码多肽的核酸的沉默变异隐含在关于表达产物而不是关于实际探针序列的描述序列中。关于氨基酸序列,技术人员应认识到,改变、添加或缺失编码序列中单个氨基酸或小百分比的氨基酸的对核酸、肽、多肽或蛋白质序列的单独取代、缺失或添加是“保守修饰变体”,包括其中所述改变导致氨基酸被化学上相似的氨基酸取代。提供功能相似的氨基酸的保守取代表是本领域熟知的。此类保守修饰变体是对本文公开的多态变体、种间同源物和等位基因的补充并且不排除它们。典型的保守取代包括:1)丙氨酸(A)、甘氨酸(G);2)天冬氨酸(D)、谷氨酸(E);3)天冬酰胺(N)、谷氨酰胺(Q);4)精氨酸(R)、赖氨酸(K);5)异亮氨酸(I)、亮氨酸(L)、甲硫氨酸(M)、缬氨酸(V);6)苯丙氨酸(F)、酪氨酸(Y)、色氨酸(W);7)丝氨酸(S)、苏氨酸(T);和8)半胱氨酸(C)、甲硫氨酸(M)(参见例如,Creighton,Proteins(1984))。
非人(例如,牛)抗体的“人源化”或“人工程化”形式是嵌合抗体,其含有人免疫球蛋白序列中表示的氨基酸,包括例如其中最小序列来源于非人免疫球蛋白。例如,人源化或人工程化抗体可以是非人(例如,牛)抗体,其中一些残基被来自人抗体中类似位点的残基取代(参见例如,美国专利号5,766,886)。人源化抗体任选地也可以包含免疫球蛋白恒定区(Fc)的至少一部分,典型地是人免疫球蛋白恒定区的至少一部分。关于进一步的细节,参见Jones等人,Nature 321:522-525(1986);Riechmann等人,Nature332:323-329(1988);以及Presta,Curr.Op.Struct.Biol.2:593-596(1992)。还参见以下综述文章和其中引用的参考文献:Vaswani和Hamilton,Ann.Allergy,Asthma&Immunol.1:105-115(1998);Harris,Biochem.Soc.Transactions 23:1035-1038(1995);Hurle和Gross,Curr.Op.Biotech.5:428-433(1994)。
关于抗体提及的“可变结构域”是指抗体重链或轻链的特定Ig结构域,其含有因不同抗体而异的氨基酸序列。每条轻链和每条重链具有一个可变区结构域(VL和VH)。可变结构域提供抗原特异性并且因此负责抗原识别。每个可变区含有作为抗原结合位点结构域的一部分的CDR和框架区(FR)。
“恒定区结构域”是指抗体重链或轻链中的结构域,其含有在抗体中比可变区结构域相对更保守的氨基酸序列。每条轻链具有单个轻链恒定区(CL)结构域,并且每条重链包含一个或多个重链恒定区(CH)结构域,其包括CH1、CH2、CH3以及在某些情况下CH4。全长IgA、IgD和IgG同种型含有CH1、CH2CH3和铰链区,而IgE和IgM含有CH1、CH2CH3和CH4。CH1和CL结构域延伸抗体分子的Fab臂,从而有助于与抗原的相互作用和抗体臂的旋转。抗体恒定区可以起到效应子功能,诸如但不限于抗体特异性结合的抗原、病原体和毒素的清除,例如通过与各种细胞、生物分子和组织的相互作用。
关于蛋白质位置的术语“对应于”,如以下叙述:核苷酸或氨基酸位置“对应于”公开序列中的核苷酸或氨基酸位置,如序列表中所述,是指基于结构序列比对或使用标准比对算法(如GAP算法)在与公开序列比对时鉴定的核苷酸或氨基酸位置。例如,相似序列(例如,片段或物种变体)的对应残基可以通过结构比对方法与参考序列比对来确定。通过比对序列,本领域技术人员可以例如使用保守和相同氨基酸残基作为指导来鉴定对应残基。
如本文所用,术语“有效量”或“治疗有效量”意指足以显著和积极地改变待治疗的症状和/或病症(例如,提供积极的临床反应)的药物组合物量。用于药物组合物中的活性成分的有效量将随所治疗的具体病症、病症的严重程度、治疗的持续时间、并行疗法的性质、所采用的一种或多种具体活性成分、所使用的特定药学上可接受的一种或多种赋形剂和/或一种或多种载体以及与主治医师的知识和专长类似的因素而变化。
如本文所用,术语“药学上可接受的”是指不消除化合物的生物活性或特性并且相对无毒的材料,诸如载体或稀释剂,即所述材料可以施用于个体而不会引起不希望的生物效应或以有害方式与包含它的组合物的任何组分相互作用。
如本文所用,组合物是指两种或更多种产物、物质或化合物(包括细胞)的任何混合物。它可以是溶液、悬浮剂、液体、散剂、糊剂、水性的、非水性的或其任何组合。
如本文所用,术语“药物组合物”是指至少一种本发明化合物与其他化学组分诸如载体、稳定剂、稀释剂、分散剂、助悬剂、增稠剂和/或赋形剂的混合物。药物组合物有助于将化合物施用于生物体。本领域中存在多种施用化合物的技术,包括但不限于静脉内、口服、气雾剂、肠胃外、眼部、肺部和局部施用。
如本文所用,“疾病或障碍”是指生物体中源自病因或病症(包括但不限于感染、获得性病症、遗传病症)并且特征为可鉴定的症状的病理性状况。
如本文所用,术语“治疗(treat)”、“治疗(treating)”或“治疗(treatment)”是指改善疾病或障碍,例如,减缓或阻止或减少疾病或障碍的发展,例如,障碍的根本原因或其至少一种临床症状。
如本文所用,术语“受试者”是指动物,包括哺乳动物,诸如人。术语受试者和患者可以互换使用。
如本文所用,“任选的”或“任选地”意指随后描述的事件或情形发生或不发生,并且所述描述包括所述事件或情形发生的情况和不发生的情况。例如,任选取代的基团意指所述基团未被取代或被取代。
II.经细胞因子修饰的嵌合抗体
本文提供了经修饰的嵌合抗体,其中细胞因子序列(诸如IL-2序列或其生物活性部分或IL-15序列或其生物活性部分)替代牛(奶牛)抗体或其人源化序列的重链的超长CDR3区的一部分。所提供的经IL-15修饰的嵌合抗体还包括与IL15Rα的细胞外部分(诸如IL15Rαsushi结构域(例如,SEQ ID NO:2中所示))连接或复合的此类抗体。
所提供的抗体展现出牛或奶牛抗体的特征,所述抗体具有独特的重链可变区序列,其含有长度高达70个或更多氨基酸的超长CDR3序列。在牛中鉴定的CDR3序列包括指定为以下的那些:BLV1H12(参见,SEQ ID NO:25)、BLV5B8(参见,SEQ ID NO:30)、BLV5D3(参见,SEQ ID NO:31)和BLV8C1 1(参见,SEQ ID NO:32)(参见例如,Saini等人(1999)Eur.Immunol.29:2420-2426;和Saini and Kaushik(2002)Scand.J.Immunol.55:140-148);BF4E9(参见,SEQ ID NO:33)和BF1H1(参见,SEQ ID NO:34)(参见例如,Saini andKaushik(2002)Scand.J.Immunol.55:140-148);和F18(参见,SEQ ID NO:35)(参见例如,Berens,等人(1997)Int.Immunol.9:189-199)。包含在牛中鉴定的超长CDR3序列的示例性抗体可变区序列包括BLV1H12。在一些实施方案中,BLV1H12超长CDR3序列由SEQ ID NO:25编码。示例性牛抗体包括牛抗体BLVH12(例如,SEQ ID NO:26中所示的重链可变区和SEQ IDNO:27中所示的轻链可变区);和牛抗体BLV5B8(例如,SEQ ID NO:28中所示的重链可变区和SEQ ID NO:29中所示的轻链可变区)。
在奶牛抗体中,超长CDR3序列形成这样的结构,其中具有不寻常结构的亚结构域由以下形成:由两个12残基、逆平行的β链(升链和降链)和39残基构成的“茎”;富含二硫醚的“杵”,其位于茎的顶部,远离典型抗体互补位。长的逆平行β-带用作连接杵结构域与主抗体支架的桥。超长CDR3的独特“茎和杵”结构导致两条逆平行的β链,升茎链和降茎链,其支持二硫醚键合的杵从抗体表面突出以形成微型抗原结合结构域。在一些实施方案中,超长CDR3抗体按顺序包含升茎区、杵区和降茎区。
独特的“茎”和杵结构特征在不同的牛或奶牛超长CDR3序列中是保守的。茎的升链主要包含疏水侧链和在开始升链的基部的相对保守的“T(T/S)VHQ”基序及其变体。这种保守的T(T/S)VHQ基序及其变体典型地发现在各种牛或奶牛序列的可变区序列中的第一个半胱氨酸残基之后。保守的T(T/S)VHQ基序通过可变数量的残基连接至基序(BLV1H12的CPDG),所述基序在每个杵的基部形成β转角。茎可以是可变长度的,并且茎的降链包含交替的芳族化合物,其通过堆叠相互作用形成阶梯,这可能有助于长的溶剂暴露的两股β-带的稳定性(Wang等人Cell.2013,153(6):1379-1393)。
本文提供的嵌合抗体的重链的超长CDR3序列含有茎组分,所述茎组分含有提供杵结构域连接在一起的升链和降链,所述杵结构域含有细胞因子序列,诸如IL-2序列或其生物活性部分或IL-15序列或其生物活性部分。在一些实施方案中,所提供的抗体包含细胞因子(例如,IL-2或IL-15)修饰的超长CDR3融合体,其中抗体序列基于或源自牛或奶牛序列或其人源化序列,其在重链中具有超长CDR3,但其中与抗体序列所来源的超长CDR3相比,所述超长CDR3经修饰以含有非抗体细胞因子序列。在一些实施方案中,非抗体序列是IL-2或其生物活性部分,并且IL-2或其生物活性部分可以插入超长CDR3的一部分中。在一些实施方案中,非抗体序列是IL-15或其生物活性部分,并且IL-15或其生物活性部分可以插入超长CDR3的一部分中。例如,抗体支架可以源自或基于牛抗体序列或其人源化序列,但包含细胞因子序列,例如IL-2序列或其生物活性部分或IL-15序列或其生物活性部分,所述细胞因子序列插入牛抗体序列或其人源化序列的重链的超长CDR3的杵结构域中或替代其一部分。
在一些实施方案中,将IL-15序列或其生物活性部分插入抗体的CDR3序列的杵区中,包括任选地去除CDR3的一部分(例如,CDR3的一个或多个氨基酸)或整个CDR3序列(例如,CDR3的所有或基本上所有氨基酸)。在一些实施方案中,可以将IL-15或其生物活性部分插入超长CDR3的杵结构域中(图1A和图1B)。在一些实施方案中,IL-15或其生物活性部分包含在升茎链与降茎链之间。
在一些实施方案中,将IL-2序列或其生物活性部分插入抗体的CDR3序列的杵区中,包括任选地去除CDR3的一部分(例如,CDR3的一个或多个氨基酸)或整个CDR3序列(例如,CDR3的所有或基本上所有氨基酸)。在一些实施方案中,可以将IL-2或其生物活性部分插入超长CDR3的杵结构域中(图8A和图8B)。在一些实施方案中,IL-2或其生物活性部分包含在升茎链与降茎链之间。
在一些实施方案中,超长CDR3可以具有35个或更多个氨基酸的长度(例如,40或更多、45或更多、50或更多、55或更多、60或更多)。
本文提供的任何实施方案可以含有如PCT/US2013/020910、PCT/US2014/047315或PCT/US2013/020903中描述的任何特征,所有这些专利都通过引用以其整体并入。
A.重链区
在提供的实施方案中,所提供的经细胞因子修饰的嵌合抗体的重链基于或源自具有超长CDR3的框架序列,其中细胞因子序列(例如,IL-2或其生物活性部分或IL-15或其生物活性部分)被插入超长CDR3序列中或替代其至少一部分。抗体框架可以源自牛序列,诸如VH-VL、人种系序列、或经修饰的人种系序列。
在一些实施方案中,所提供的经细胞因子修饰的嵌合抗体的重链基于或源自牛或奶牛框架序列,其中细胞因子序列(例如,IL-2或其生物活性部分或IL-15或其生物活性部分)可以插入牛或奶牛序列的超长CDR3序列中或替代其至少一部分。所述抗体可以包含BLV1H12抗体(包含含有细胞因子序列的超长CDR3融合体)的至少一部分。可替代地或另外,所述抗体包含BLV5D3、BLV8C11、BF1H1、BLV5B8和/或F18抗体(包含含有细胞因子序列的超长CDR3融合体)的至少一部分。在一些实施方案中,IL-15或其生物活性部分可以插入SEQID NO:26或SEQ ID NO:28中所示的序列的超长CDR3中或替代其至少一部分。
在一些实施方案中,所提供的经IL-15修饰的嵌合抗体的重链基于或源自人源化重链框架序列,其与牛或奶牛序列相比人源化的。在一些实施方案中,所提供的经细胞因子修饰的嵌合抗体的重链基于或源自人重链框架序列,其展现出与牛或奶牛序列的序列或结构相似性。在一些情况下,人源化可以包括将源自牛超长CDR3的超长CDR3序列(诸如如上所述的任一种)工程化到人框架中。人框架可以是种系来源的,或可以源自非种系(例如,突变的或亲和力成熟的)序列。可以使用本领域技术人员熟知的基因工程技术(包括如本文所公开的)来产生含有人框架和非人超长CDR3的杂合DNA序列。与可能由源自七个家族之一的V区基因编码的人抗体不同,产生超长CDR3序列的牛抗体似乎利用可能被认为与人VH4家族最同源的单V区家族。在牛源超长CDR3序列将被人源化以产生包含超长CDR3的抗体的特定实施方案中,源自VH4家族的人V区序列可以遗传融合至源自牛的超长CDR3序列。人抗体基因座中的示例性VH4种系基因序列包括但不限于VH4-39、VH4-59*03、VH4-34*02或VH4-34*09人重链种系序列。在一些实施方案中,人重链种系序列是SEQ ID NO:68-71中任一个所示的序列。在一些实施方案中,人重链种系序列是由SEQ ID NO:169-172中任一个所示的序列编码的序列。
在一些实施方案中,细胞因子序列(诸如IL-2或其生物活性部分或IL-15或其生物活性部分)可以插入包含SEQ ID NO:68-71中所示的序列的人种系序列超长CDR3中或替代其至少一部分。
在一些实施方案中,所提供的抗体包含人VH4框架序列与其中杵的至少一部分被IL-15或IL-2或其生物活性部分替代的牛源超长CDR3的融合体。在一些方面,此类融合体可以通过以下步骤产生。首先,鉴定V区基因序列的第二个半胱氨酸以及编码第二个半胱氨酸的核苷酸序列。通常,第二个半胱氨酸标记框架和CDR3的边界,在CDR3上游(N末端)的两个残基。第二,鉴定牛源V区序列中的第二个半胱氨酸,其类似地标记在CDR3上游(N末端)的2个残基。第三,将编码人V区的遗传物质与编码超长CDR3的基因序列组合。因此,可以进行基因融合,其中将超长CDR3序列置于人V区序列的框内。优选地,包含超长CDR3的人源化抗体在氨基酸组成上尽可能接近人。任选地,J区序列可以从牛源序列突变为人序列。还任选地,人源化重链可以与人轻链配对。
在一些实施方案中,所述抗体或其结合片段包含重链可变区,所述重链可变区包含式V1-X-V2的序列,其中重链的V1区包含重链序列部分,所述重链序列部分含有分隔两个CDR区(CDR1和CDR3)的三个框架区(例如,FR-1、FR-2和FR-3),其中X包含超长CDR3序列,其可以包含IL-2序列或其生物活性部分或IL-15序列或其生物活性部分,并且其中V2包含重链部分,其包含FR-4。
在一些实施方案中,V1区包含式FR1-CDR1-FR2-CDR2-FR3。在一些实施方案中,V1区包含选自以下的氨基酸序列:(i)牛重链区,其包含SEQ ID NO:26的氨基酸(由SEQ IDNO:5的核苷酸编码),或(i)人源化重链区,其包含含有SEQ ID NO:12-19的人种系可变区。
在一些实施方案中,X包含超长CDR3序列,其可以包含IL-15序列或其生物活性部分(例如,人IL-15序列或其生物活性部分)。在一些实施方案中,IL-15序列包含SEQ ID NO:1中所示的氨基酸序列或与SEQ ID NO:1中所示的氨基酸序列展现出至少或至少约85%、至少或至少约86%、至少或至少约87%、至少或至少约88%、至少或至少约89%、至少或至少约90%、至少或至少约91%、至少或至少约92%、至少或至少约93%、至少或至少约94%、至少或至少约95%、至少或至少约96%、至少或至少约97%、至少或至少约98%、至少或至少约99%序列同一性的氨基酸序列。在一些实施方案中,IL-15序列包含SEQ ID NO:1中发现的氨基酸序列。
在一些实施方案中,IL-15序列展现出刺激细胞毒性T淋巴细胞和自然杀伤(NK)细胞的增殖、激活或细胞毒性的活性,诸如在体外测定或体内中。在一些实施方案中,IL-15序列展现出与IL2/15Rβ和/或γc亚基的结合,诸如在体外结合测定中。在一些实施方案中,与重组IL-15单体相比,活性或结合相似或保留。
在一些实施方案中,IL-15序列或生物活性部分被插入在升茎区与降茎区之间的超长CDR3的杵中。IL-15序列可以定位在茎区之间,其中IL-15序列直接或间接连接到每个茎区。在一些实施方案中,与一个或两个茎序列的连接是经由接头间接的。接头可以包含氨基酸序列(GGGGS),其中n=1至5。可替代地,接头包含氨基酸序列(GSG)n、GGGSGGGGS或GGGGSGGGS。在一些情况下,接头具有序列GGS或GSG。
在一些实施方案中,X包含超长CDR3序列,其可以包含IL-2序列或其生物活性部分(例如,人IL-2序列或其生物活性部分)。在一些实施方案中,IL-2序列包含SEQ ID NO:165中所示的氨基酸序列或与SEQ ID NO:165中所示的氨基酸序列展现出至少或至少约85%、至少或至少约86%、至少或至少约87%、至少或至少约88%、至少或至少约89%、至少或至少约90%、至少或至少约91%、至少或至少约92%、至少或至少约93%、至少或至少约94%、至少或至少约95%、至少或至少约96%、至少或至少约97%、至少或至少约98%、至少或至少约99%序列同一性的氨基酸序列。在一些实施方案中,IL-2序列包含SEQ ID NO:165中发现的氨基酸序列。
在一些实施方案中,IL-2序列展现出刺激细胞毒性T淋巴细胞和自然杀伤(NK)细胞的增殖、激活或细胞毒性的活性,诸如在体外测定或体内中。在一些实施方案中,IL-2序列展现出与IL2/15Rβ和/或γc亚基的结合,诸如在体外结合测定中。在一些实施方案中,与重组IL-2单体相比,活性或结合相似或保留。
在一些实施方案中,IL-2序列或生物活性部分被插入在升茎区与降茎区之间的超长CDR3的杵中。IL-2序列可以定位在茎区之间,其中IL-2序列直接或间接连接到每个茎区。在一些实施方案中,与一个或两个茎序列的连接是经由接头间接的。接头可以包含氨基酸序列(GGGGS),其中n=1至5。可替代地,接头包含氨基酸序列(GSG)n、GGGSGGGGS或GGGGSGGGS。在一些情况下,接头具有序列GGS或GSG。
超长CDR3可以包含CDR3的杵结构域的至少一部分、CDR3的茎结构域的至少一部分、或其组合。CDR3的杵结构域的部分可以包含一个或多个源自超长CDR3的杵结构域的保守基序。CDR3的茎结构域可以包含一个或多个源自超长CDR3的茎结构域的保守基序。
在以上或以下提及的实施方案的每个或任何方面中,超长CDR3具有35个氨基酸或更长的长度、40个氨基酸或更长的长度、45个氨基酸或更长的长度、50个氨基酸或更长的长度、55个氨基酸或更长的长度或60个氨基酸或更长的长度。在以上或以下提及的每个或任何实施方案中的一些实施方案中,超长CDR3具有35个氨基酸或更长的长度。
在一些实施方案中,重链的包含超长CDR3的X部分包含基序X1X2X3X4X5-[细胞因子序列]-(XaXb)z基序。在一些实施方案中,超长CDR3具有45个氨基酸或更长的长度。在一些实施方案中,X1X2X3X4X5基序与细胞因子序列之间和/或(XaXb)z基序与细胞因子序列之间可以存在一个或多个另外的氨基酸。
在一些实施方案中,X1X2X3X4X5基序是升茎链的全部或一部分。在一些实施方案中,升茎链上的X1X2X3X4X5基序包含选自以下的序列:TTVHQ(SEQ ID NO:36)、TSVHQ(SEQ ID NO:37)、或SEQ ID NO:38-67中的任一个。在一些实施方案中,升茎链包含选自以下的序列:SEQID NO:72-75或SEQ ID NO:158。在一些实施方案中,超长CDR3包含由SEQ ID NO:9、SEQ IDNO:81-121或SEQ ID NO:157编码的升茎区。在一些实施方案中,基序包含N-末端半胱氨酸(Cys或C)残基,诸如CX1X2X3X4X5中所示。例如,在一些情况下,由SEQ ID NO:36-67、72-75或SEQ ID NO:158中的任一个编码的升茎区可以另外含有N-末端Cys残基。此类示例性升茎区是SEQ ID NO:159中所示的。
在一些实施方案中,(XaXb)z基序是降茎链的一部分,其中Xa是任何氨基酸残基,Xb是选自以下的芳族氨基酸:酪氨酸(Y)、苯丙氨酸(F)、色氨酸(W)和组氨酸(H),并且其中z是1-4。在一些实施方案中,降茎链包含交替的芳族化合物,其具有式YXYXYX,其中X是任何氨基酸。在一些实施方案中,降茎链包含SEQ ID NO:76-80或SEQ ID NO:161中所含的序列。在一些实施方案中,超长CDR3包含由SEQ ID NO:10、SEQ ID NO:122-149或SEQ ID NO:160编码的降茎区。
在一些实施方案中,超长CDR3按顺序包含具有由SEQ ID NO:9编码的氨基酸序列的升茎区、SEQ ID NO:1所示的IL15细胞因子序列、和具有由SEQ ID NO:10编码的氨基酸序列的降茎区。在一些实施方案中,超长CDR3按顺序包含具有由SEQ ID NO:157编码的氨基酸序列的升茎区、SEQ ID NO:1所示的IL15细胞因子序列、和具有由SEQ ID NO:160编码的氨基酸序列的降茎区。
在一些实施方案中,超长CDR3按顺序包含具有由SEQ ID NO:9编码的氨基酸序列的升茎区、SEQ ID NO:165所示的IL2细胞因子序列、和具有由SEQ ID NO:10编码的氨基酸序列的降茎区。在一些实施方案中,超长CDR3按顺序包含具有由SEQ ID NO:157编码的氨基酸序列的升茎区、SEQ ID NO:165所示的IL2细胞因子序列、和具有由SEQ ID NO:160编码的氨基酸序列的降茎区。
在一些实施方案中,重链的V2区包含选自以下的氨基酸序列:(i)WGHGTAVTVSS(SEQ ID NO:20),(ii)WGKGTTVTVSS(SEQ ID NO:21),(iii)WGKGTTVTVSS(SEQ ID NO:22),(iv)WGRGTLVTVSS(SEQ ID NO:23),(v)WGKGTTVTVSS(SEQ ID NO:24),和(vi)WGQGLLVTVSS(SEQ ID NO:11)。
在特定实施方案中,本文提供的经IL-15修饰的嵌合抗体或抗原结合片段含有由SEQ ID NO:7中所示的核苷酸序列或与SEQ ID NO:7中所示的核苷酸序列展现出至少或至少约85%、至少或至少约86%、至少或至少约87%、至少或至少约88%、至少或至少约89%、至少或至少约90%、至少或至少约91%、至少或至少约92%、至少或至少约93%、至少或至少约94%、至少或至少约95%、至少或至少约96%、至少或至少约97%、至少或至少约98%、至少或至少约99%序列同一性的核苷酸序列编码的可变重链序列,其中包含含有IL-15序列的经修饰的超长CDR3。在一些实施方案中,本文提供的经IL-15修饰的嵌合抗体或抗原结合片段包含由SEQ ID NO:7中所示的核苷酸序列编码的可变重链序列。在一些实施方案中,本文提供的经IL-15修饰的嵌合抗体或抗原结合片段由以下组成或基本上由以下组成:由SEQ ID NO:7中所示的核苷酸序列编码的可变重链序列。
在一些实施方案中,重链包含如所描述的可变重链,其与人恒定区连接。在一些实施方案中,人恒定区包含CH1-CH2-CH3约束结构域。在一些实施方案中,人恒定区是人IgG1的。
B.轻链区
在一些实施方案中,抗体或抗原结合片段进一步包含轻链可变区。在一些实施方案中,经细胞因子修饰的嵌合抗体可变链基于牛序列并且与牛抗体的可变轻链配对。在另一个实施方案中,本公开文本提供了人源化超长CDR3重链与牛轻链的配对。在特定实施方案中,轻链是λ轻链。
在一些实施方案中,可变轻链是牛抗体的可变轻链,诸如BLVH12、BLV5D3、BLV8C11、BF1H1、BLV5B8和/或F18的可变轻链。在一些实施方案中,轻链可变区可以包含基于或源自多肽序列SEQ ID NO:27或29的序列。在一些实施方案中,轻链多肽序列由基于或源自DNA序列SEQ ID NO:8的DNA序列编码。在一些实施方案中,轻链多肽序列由基于或源自DNA序列SEQ ID NO:168的DNA序列编码。
在一些实施方案中,轻链包含牛抗体的可变轻链,其与人λ轻链恒定区(例如,SEQID NO:155中所示)连接。在一些实施方案中,BLV1H12轻链可变区(例如,SEQ ID NO:8或SEQID NO:168中所示)的一部分与人λ轻链恒定区连接。
在一些实施方案中,轻链是人源化轻链或是人轻链。在实施方案中,本公开文本提供了包含超长CDR3的人源化重链与人轻链配对。在一些实施方案中,轻链是与已知与牛超长CDR3重链配对的牛轻链同源的。几种人VL序列可以用于与上述序列配对,包括VL1-47、VL1-40、VL1-51、VL2-18,其与源自普通牛(Bos Taurus)的λ区同源。在一些实施方案中,轻链可变区是SEQ ID NO:156或173-176中任一个所示的序列。在一些实施方案中,轻链可变序列是由SEQ ID NO:177-180中任一个所示的序列编码的序列。在一些实施方案中,轻链可变区包含SEQ ID NO:156中所示的VL1-51种系序列的可变区。
在一些实施方案中,轻链可变区是含有一个或多个氨基酸修饰的人种系轻链序列,诸如如上所述的任一种。此类修饰可以包括将人轻链中的某些氨基酸残基取代为牛轻链序列中相应位置处的那些残基。经修饰的轻链可以改善包含超长CDR3的抗体的产率和/或增加其结合特异性。在一些实施方案中,修饰包括基于Kabat编号的氨基酸替代S2A、T5N、P8S、A12G、A13S和P14L中的一个或多个。在一些实施方案中,修饰包括基于Kabat编号的氨基酸替代S2A、T5N、P8S、A12G、A13S和P14L。在一些实施方案中,修饰在CDR1中并且包括氨基酸替代I29V和N32G。在一些实施方案中,修饰在CDR2中并且包括DNN取代为GDT。在一些实施方案中,修饰在CDR2中并且包括DNNKRP取代为GDTSRA。在一些实施方案中,修饰包括任何前项的组合。例如,提供的人种系轻链序列的修饰包括基于Kabat编号的氨基酸替代S2A、T5N、P8S、A12G、A13S和P14L以及在CDR2中DNN取代为GDT。
在一些实施方案中,轻链包含如所描述的人源化可变轻链,其与人λ轻链恒定区(例如,SEQ ID NO:155中所示)连接。在一些实施方案中,轻链可变区(诸如经修饰的人种系轻链)的一部分与人λ轻链恒定区连接。
C.IL-15Rαsushi结构域
在一些实施方案中,本文提供的嵌合白细胞介素15抗体分子可以进一步与IL-15高亲和力受体α(IL15Rα)的全部或一部分(诸如IL15Rα的含有细胞外结构域的部分,诸如IL15Rαsushi结构域)连接或复合。在一些实施方案中,IL-15细胞因子序列与IL-15高亲和力受体α(IL15Rα)的全部或一部分连接。在一些实施方案中,表达IL15Rα以增加向受体β和γ亚基(IL2/15Rβ和γc)的反式信号传导。IL-15高亲和力受体包含IL15Rαsushi结构域。在一些实施方案中,IL15Rαsushi结构域包含SEQ ID NO:2中所示的序列。
在一些实施方案中,本文提供了经IL-15修饰的嵌合抗体或抗原结合片段,其中重链或其可变序列包含IL-15序列,其替代超长CDR3的杵的全部或一部分(例如,插入升茎与降茎之间的杵区中),其与IL15Rα的细胞外结构域(诸如IL15Rαsushi结构域)复合。在一些实施方案中,经IL-15修饰的嵌合抗体或抗原结合片段与SEQ ID NO:15中所示的IL15Rαsushi结构域复合。此类抗体分子可以通过在宿主细胞中与重链区和轻链区共表达IL15Rα细胞外结构域(诸如SEQ ID NO:2中所示的,例如,sushi结构域)来产生。
在一些实施方案中,本文提供了经IL-15修饰的嵌合抗体或抗原结合片段,其含有重链或其可变序列,其中IL-15序列替代超长CDR3的杵的全部或一部分(例如,插入升茎与降茎之间的杵区中);以及轻链或其可变序列,其与IL15Rα的细胞外结构域(诸如IL15Rαsushi结构域)连接。在一些实施方案中,经IL-15修饰的嵌合抗体或抗原结合片段与SEQ IDNO:2中所示的IL15Rαsushi结构域连接。IL15Rα的细胞外结构域(例如,IL15Rαsushi结构域,诸如SEQ ID NO:2中所示)之间的连接经由肽接头。在一些实施方案中,接头是柔性接头,诸如甘氨酸接头或甘氨酸-丝氨酸(GS)接头。在一些实施方案中,肽接头是GS接头。示例性GS接头包括但不限于SEQ ID NO:150-154中所示的任何序列或由SEQ ID NO:163或SEQID NO:164中所示的核苷酸序列编码的序列。在一些实施方案中,接头是GS。
在一些实施方案中,本文提供的经IL-15修饰的嵌合抗体或抗原结合片段含有重链或其可变序列,其中IL-15序列替代超长CDR3的杵的全部或一部分(例如,插入升茎与降茎之间的杵区中);以及轻链或其可变序列,其包含由SEQ ID NO:3编码的氨基酸序列。
D.载体、宿主细胞和重组方法
为了重组产生如本文公开的抗体或其片段,分离编码它的核酸,并且将其插入可复制载体,用于进一步克隆(DNA扩增)或表达。使用常规程序(例如,通过使用能够与编码抗体重链和轻链的基因特异性结合的寡核苷酸探针)容易地分离编码抗体的DNA并且测序。在示例性实施方案中,将编码包含超长CDR3的抗体、包含超长CDR3的可变区、或超长CDR3的核酸分离并且插入可复制载体中,用于进一步克隆(DNA扩增)或表达。许多载体是可用的。载体的选择部分取决于要使用的宿主细胞。通常,优选的宿主细胞是原核或真核(通常是哺乳动物)起源的。应理解,任何同种型的恒定区可用于此目的,包括IgG、IgM、IgA、IgD和IgE恒定区,并且此类恒定区可以从任何人或动物物种获得。
含有来自真核病毒的调控元件的表达载体典型地用于真核表达载体,例如,SV40载体、乳头状瘤病毒载体和源自EB病毒(Epstein-Barr virus)的载体。其他示例性真核载体包括pMSG、pAV009/A+、pMTO10/A+、pMAMneo-5、杆状病毒pDSVE和允许在CMV启动子、SV40早期启动子、SV40后期启动子、金属硫蛋白启动子、鼠乳腺肿瘤病毒启动子、劳斯肉瘤(Roussarcoma)病毒启动子、多角体启动子或显示有效用于在真核细胞中表达的其他启动子的指导下表达蛋白质的任何其他载体。
一些表达系统具有提供基因扩增的标记物,诸如胸苷激酶和二氢叶酸还原酶。可替代地,不涉及基因扩增的高产率表达系统也是合适的,诸如在昆虫细胞中使用杆状病毒载体,其中核酸序列在多角体启动子或其他强杆状病毒启动子的指导下编码部分人超长CDR3抗体链。
可以使用标准重组技术来获得编码本文公开的抗体的多肽组分的多核苷酸序列。在一些实施方案中,可以使用核苷酸合成仪或PCR技术合成多核苷酸。一旦获得,将编码多肽的序列插入能够在原核宿主中复制并且表达异源多核苷酸的重组载体中。本领域可获得且已知的许多载体可以用于本公开文本的目的。适当载体的选择将主要取决于要插入载体的核酸的大小和要用载体转化的特定宿主细胞。每种载体含有多种组分,这取决于其功能(异源多核苷酸的扩增或表达或二者)及其与所驻留特定宿主细胞的相容性。载体组分通常包括但不限于:复制起点、选择标记基因、启动子、核糖体结合位点(RBS)、信号序列、异源核酸插入物和转录终止序列。可替代地,包含超长CDR3的V区可以任选地融合至C区以产生包含恒定区的抗体。
通常,含有源自与宿主细胞相容的物种的复制子和控制序列的质粒载体与这些宿主结合使用。载体通常携带复制位点,以及能够在转化细胞中提供表型选择的标记序列。例如,典型地用源自大肠杆菌物种的质粒pBR322来转化大肠杆菌。pBR322含有编码氨苄青霉素(Amp)和四环素(Tet)抗性的基因,并且由此提供轻松鉴定转化细胞的方式。pBR322、其衍生物或其他微生物质粒或噬菌体还可以含有或者被修饰以含有可以由微生物生物体用于表达内源蛋白质的启动子。已描述了用于表达特定抗体的pBR322衍生物的例子(参见例如,美国专利号5,648,237)。
另外,可以使用含有与宿主微生物相容的复制子和控制序列的噬菌体载体作为与这些宿主结合的转化载体。例如,可使用噬菌体诸如λGEMTM-11来构建可以用于转化易感宿主细胞(诸如大肠杆菌LE392)的重组载体。
本文公开的表达载体可以包含两个或更多个启动子-顺反子对,它们编码每一种多肽组分。启动子是位于顺反子上游(5')的非翻译调控序列,它调节所述顺反子的表达。原核启动子典型地分成两类:诱导型和组成型。诱导型启动子是响应于培养条件的变化(例如,营养物的存在或不存在,或者温度变化)而启动受其控制的升高水平的顺反子转录的启动子。
被多种潜在宿主细胞识别的大量启动子是熟知的。通过经由限制酶消化从来源DNA去除启动子并且将分离的启动子序列插入本文公开的载体中,可以将选择的启动子与编码轻链或重链的顺反子DNA可操作地连接。天然启动子序列和许多异源启动子二者都可以用于引导靶基因的扩增和/或表达。在一些实施方案中,使用异源启动子,因为如与天然靶多肽启动子相比,它们通常允许所表达靶基因的更高转录和更高产量。
适用于原核宿主的启动子包括:ara B启动子、PhoA启动子、β-半乳糖苷酶和乳糖启动子系统、色氨酸(trp)启动子系统和杂合启动子(诸如tac或trc启动子)。然而,在细菌中有功能的其他启动子(诸如其他已知的细菌或噬菌体启动子)也是合适的。它们的核苷酸序列已经发表,由此熟练工作人员能够使用提供任何所需限制位点的接头或衔接头将它们与编码靶轻链和重链的顺反子可操作连接(例如,Siebenlist等人(1980)Cell20:269)。
合适的细菌启动子是本领域中众所周知的并且充分描述在科学文献诸如上述Sambrook and Russell和上述Ausubel等人中。用于表达重组催化多肽的抗体链的细菌表达系统可用于例如大肠杆菌(E.coli)、芽孢杆菌属物种(Bacillus sp.)和沙门氏菌属(Salmonella)(Palva等人,Gene,22:229-235(1983);Mosbach等人,Nature,302:543-545(1983))。
在本文公开的一方面,重组载体内的每个顺反子都包含分泌信号序列组分以引导所表达多肽跨膜易位。通常,信号序列可以是载体的组分,或者它可以是插入载体中的靶多肽DNA的一部分。异源信号序列应是被宿主细胞识别和加工(例如,通过信号肽酶切割)的信号序列。对于不识别和加工异源多肽的天然信号序列的原核宿主细胞,将所述信号序列用所选择的原核信号序列取代,所选择的原核信号序列例如PelB、OmpA、碱性磷酸酶、青霉素酶、Ipp或热稳定的肠毒素II(STII)前导序列、LamB、PhoE和MBP。在本文公开的一个实施方案中,用于表达系统的两个顺反子中的信号序列是STII信号序列或其变体。
在另一方面,根据本公开文本的免疫球蛋白的产生可以在宿主细胞的胞质中进行,并且因此不需要在每个顺反子内存在分泌信号序列。在这方面,在细胞质内表达、折叠和装配免疫球蛋白轻链和重链,以形成功能性免疫球蛋白。某些宿主菌株(例如大肠杆菌trxB菌株)提供有利于二硫键形成的细胞质条件,从而容许所表达蛋白质亚基的正确折叠和装配(参见例如,Proba and Pluckthun Gene,159:203(1995))。
用于克隆或表达编码抗体的载体的合适宿主细胞包括本文所述的原核或真核细胞。在一个实施方案中,宿主细胞是真核的,例如中国仓鼠卵巢(CHO)细胞、人胚肾(HEK)细胞或淋巴细胞(例如,YO、NSO、Sp20细胞)。例如,可以在细菌中产生抗体,特别是当不需要糖基化和Fc效应子功能时。对于抗体片段和多肽在细菌中的表达,参见例如,美国专利号5,648,237、5,789,199和5,840,523。(还参见Charlton,Methods in Molecular Biology,第248卷(B.K.C.Lo编辑,Humana Press,新泽西州托托瓦,2003),第245-254页,描述了抗体片段在大肠杆菌中的表达)。表达后,能以可溶性级分从细菌细胞糊中分离所述抗体,并且可以将其进一步纯化。除原核生物之外,真核微生物(诸如丝状真菌或酵母)也是编码抗体的载体的合适的克隆或表达宿主,包括其糖基化途径已经“人源化”从而产生具有部分或完全人糖基化模式的抗体的真菌和酵母菌株。参见Gemgross,Nat.Biotech.22:1409-1414(2004),和Li等人,Nat.Biotech.24:210-215(2006)。用于表达糖基化抗体的合适宿主细胞也源自多细胞有机体(无脊椎动物和脊椎动物)。无脊椎动物细胞的例子包括植物细胞和昆虫细胞。已经鉴定了可以与昆虫细胞结合使用的许多杆状病毒株,特别是用于草地贪夜蛾(Spodoptera frugiperda)细胞的转染。这些例子是说明性的而非限制性的。用于构建具有限定基因型的任何上述细菌的衍生物的方法是本领域中已知的,并且描述于例如以下文献中:Bass等人,Proteins,8:309-314(1990)。通常需要考虑复制子在细菌细胞中的可复制性来选择适当细菌。例如,在使用熟知质粒(诸如pBR322、pBR325、pACYC177或pKN410)供应复制子时,可以合适地使用大肠杆菌、沙雷菌氏属(Serratia)或沙门氏菌属物种作为宿主。典型地,宿主细胞应分泌最小量的蛋白水解酶,而且可以将另外的蛋白酶抑制剂合意地掺入细胞培养中。
植物细胞培养物也可以用作宿主。参见例如,美国专利号5,959,177、6,040,498、6,420,548、7,125,978和6,417,429(描述了用于在转基因植物中产生抗体的PLANTIBODIESTM技术)。脊椎动物细胞也可以用作宿主。例如,适于悬浮生长的哺乳动物细胞系可以是有用的。有用的哺乳动物宿主细胞系的其他例子是由SV40转化的猴肾CV1系(COS-7);人胚肾系(如所描述的293或293细胞,例如在Graham等人,Gen VlI’0l.36:59(1977)中);乳仓鼠肾细胞(BHK);小鼠塞尔托利细胞(如所描述的TM4细胞,例如在Mather,Biol.Reprod.23:243-251(1980)中);猴肾细胞(CV1);非洲绿猴肾细胞(V ERO-76);人宫颈癌细胞(HELA);犬肾细胞(MDCK);水牛鼠(buffalo rat)肝细胞(BRL 3A);人肺细胞(W138);人肝细胞(Hep G2);小鼠乳腺瘤(MMT 060562);TR1细胞,如例如在Mather等人,AnnalsNI’.Acad.Sci.383:44-68(1982)中所描述的;MRC5细胞;和FS4细胞。其他有用的哺乳动物宿主细胞系包括中国仓鼠卵巢(CHO)细胞,包括DHFR‘CHO细胞(Urlaub等人,Proc.Natl.Acad.Sci.USA 77:4216(1980));和骨髓瘤细胞系,诸如YO、NSO和Sp2/0。关于适用于抗体产生的某些哺乳动物宿主细胞系的综述,参见例如,Yazaki和Wu,Methods inMolecular Biology,第248卷(B.K.C.Lo编辑,Humana Press,新泽西州托托瓦),第255-268页(2003)。
在一个这样的实施方案中,宿主细胞包含以下项(例如,已经被以下项转化):(1)含有编码包含所述抗体的VL的氨基酸序列和包含所述抗体的VH的氨基酸序列的核酸的载体,或(2)含有编码包含所述抗体的VL的氨基酸序列的核酸的第一载体和含有编码包含所述抗体的VH的氨基酸序列的核酸的第二载体。
根据所用宿主细胞,使用对于此类细胞适当的标准技术进行转化。采用氯化钙的钙处理通常用于含有坚固细胞壁屏障的细菌细胞。另一种转化方法采用聚乙二醇/DMSO。所用的又另一种技术是电穿孔。
所表达的本公开文本多肽分泌到宿主细胞的周质中并且从中回收或转运到培养基中。从周质中回收蛋白质典型地涉及破坏微生物,通常通过诸如渗压震扰、超声处理或裂解等方式。一旦细胞遭到破坏,可以通过离心或过滤去除细胞碎片或完整细胞。可以通过例如亲和树脂色谱进一步纯化蛋白质。可替代地,可以从其中分离转运到培养基中的蛋白质。可以从培养物去除细胞,并且将培养物上清液过滤并且浓缩,用于进一步纯化所产生的蛋白质。可以使用公知的方法(诸如聚丙烯酰胺凝胶电泳(PAGE)和蛋白质印迹测定)进一步分离和鉴定所表达的多肽。
可以通过发酵过程大量进行抗体生产。多种大规模补料分批发酵程序可用于产生重组蛋白。大规模发酵具有至少1000升的容量,优选约1,000至100,000升的容量。这些发酵罐使用搅拌器叶轮来分配氧和营养物,尤其是葡萄糖(优选的碳/能源)。小规模发酵通常是指在体积容量不超过大约100升的发酵罐中进行的发酵,并且范围可以是约1升至约100升。
在发酵过程中,典型地在细胞已经在合适的条件下生长至所希望的密度(例如,OD550为约180-220,在此阶段细胞处于早期稳定期)后,启动对蛋白质表达的诱导。如本领域中已知和上文所述,根据所采用的载体构建体,可以使用多种诱导物。可以在诱导前使细胞生长较短的时间。通常将细胞诱导约12-50小时,但是可以使用更长或更短的诱导时间。
为了改善本文公开的多肽的生产产率和品质,可以修改多个发酵条件。例如,为了改善所分泌抗体多肽的正确装配和折叠,可以使用过表达伴侣蛋白(诸如Dsb蛋白(DsbA、DsbB、DsbC、DsbD和或DsbG)或FkpA(具有伴侣活性的肽基脯氨酰-顺式,反式-异构酶))的另外的载体共转化宿主原核细胞。已经证明伴侣蛋白有助于在细菌宿主细胞中产生的异源蛋白质的正确折叠和溶解性。(参见例如,Chen等人(1999)J Bio Chem 274:19601-19605;美国专利号6,083,715;美国专利号6,027,888;Bothmann and Pluckthun(2000)J.Biol.Chem.275:17100-17105;Ramm and Pluckthun(2000)J.Biol.Chem.275:17106-17113;Arie等人(2001)Mol.Microbiol.39:199-210)。
为了将表达的异源蛋白质(尤其是对蛋白水解敏感的那些异源蛋白质)的蛋白水解降至最低,可以将蛋白水解酶缺陷的某些宿主菌株用于本公开文本。例如,可以修饰宿主细胞菌株,以在编码已知细菌蛋白酶(诸如蛋白酶III、OmpT、DegP、Tsp、蛋白酶I、蛋白酶Mi、蛋白酶V、蛋白酶VI及其组合)的基因中实现一个或多个遗传突变。一些大肠杆菌蛋白酶缺陷菌株是可用的(参见例如,Joly等人(1998),上述;美国专利号5,264,365;美国专利号5,508,192;Hara等人,Microbial Drug Resistance,2:63-72(1996))。
可以在本文公开的表达系统中使用蛋白水解酶缺陷并且用过表达一种或多种伴侣蛋白的质粒转化的大肠杆菌菌株作为宿主细胞。
可以采用本领域中已知的标准蛋白质纯化方法。以下程序是合适纯化程序的示例:在免疫亲和或离子交换柱上分级、乙醇沉淀、反相HPLC、二氧化硅或阳离子交换树脂(诸如DEAE)上的色谱、色谱聚焦、SDS-PAGE、硫酸铵沉淀,以及使用例如Sephadex G-75的凝胶过滤。
在一方面,将固定在固相上的蛋白A用于本文公开的全长抗体产物的免疫亲和纯化。蛋白A是来自金黄色葡萄球菌(Staphylococcus aureas)的41kD细胞壁蛋白,其以高亲和力结合至抗体Fc区(参见例如,Lindmark等人(1983)J.Immunol.Meth.62:1-13)。固定有蛋白A的固相优选是包含玻璃或二氧化硅表面的柱、更优选控孔玻璃柱或硅酸柱。在一些应用中,将柱用试剂(诸如甘油)涂覆,以试图防止污染物的非特异性粘附。
作为纯化的第一步骤,将源自如上所述细胞培养物的制剂应用到固定蛋白A的固相上,以允许目的抗体特异性结合至蛋白A。然后将固相洗涤以去除与固相非特异性结合的污染物。最后,通过洗脱从固相回收目的抗体。
III.药物组合物
本文公开的包含超长CDR3的抗体或抗原结合片段、核酸或载体可以配制在组合物、尤其是药物组合物中。具有包含超长CDR3的抗体的此类组合物包含治疗或预防有效量的本文公开的包含超长CDR3的抗体、抗体片段、核酸或载体与合适的载体(例如,药学上可接受的药剂)的混合物。典型地,将本文公开的包含超长CDR3的抗体、抗体片段、核酸或载体针对施用进行充分纯化,然后配制成药物组合物。
用于本发明药物组合物的药学上可接受的药剂包括载体、赋形剂、稀释剂、抗氧化剂、防腐剂、着色剂、调味剂和稀释剂、乳化剂、助悬剂、溶剂、填充剂、增量剂、缓冲液、递送媒介物、张度剂、助溶剂、润湿剂、络合剂、缓冲剂、抗微生物剂和表面活性剂。
中性缓冲盐水或与血清白蛋白混合的盐水是示例性的适当载体。所述药物组合物可以包含抗氧化剂,诸如抗坏血酸;低分子量多肽;蛋白质,诸如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,诸如聚乙烯吡咯烷酮;氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸;单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,诸如EDTA;糖醇,诸如甘露醇或山梨糖醇;成盐抗衡离子,诸如钠;和/或非离子表面活性剂,诸如Tween、普朗尼克类(pluronics)或聚乙二醇(PEG)。还举例来说,合适的张度增强剂包括碱金属卤化物(优选氯化钠或氯化钾)、甘露醇、山梨糖醇等。合适的防腐剂包括苯扎氯铵、硫柳汞、苯乙醇、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、洗必泰、山梨酸等。过氧化氢也可以用作防腐剂。合适的助溶剂包括甘油、丙二醇和PEG。合适的络合剂包括咖啡因、聚乙烯吡咯烷酮、β-环糊精或羟丙基-β-环糊精。合适的表面活性剂或润湿剂包括脱水山梨糖醇酯、聚山梨醇酯诸如聚山梨醇酯80、氨丁三醇、卵磷脂、胆固醇、泰洛沙泊(tyloxapal)等。缓冲液可以是常规缓冲液,诸如乙酸盐、硼酸盐、柠檬酸盐、磷酸盐、碳酸氢盐或Tris-HCl。乙酸盐缓冲液可以是约pH 4-5.5,并且Tris缓冲液可以是约pH 7-8.5。另外的药学药剂阐述在Remington's Pharmaceutical Sciences,第18版,A.R.Gennaro编辑,Mack PublishingCompany,1990中。
所述组合物可以呈液体形式或者呈冻干或冷冻干燥形式,并且可以包括一种或多种冻干保护剂、赋形剂、表面活性剂、高分子量结构添加剂和/或增量剂(参见例如,美国专利号6,685,940、6,566,329和6,372,716)。在一个实施方案中,包括冻干保护剂,其为非还原糖,诸如蔗糖、乳糖或海藻糖。通常包含的冻干保护剂的量使得在重构时,所得配制品将是等渗的,尽管高渗或轻微低渗的配制品也可能是合适的。另外,冻干保护剂的量应足以防止在冻干时不可接受量的蛋白质降解和/或聚集。预冻干配制品中对于糖(例如,蔗糖、乳糖、海藻糖)的示例性冻干保护剂浓度是约10mM至约400mM。在另一个实施方案中,包含表面活性剂,例如像非离子表面活性剂和离子表面活性剂,诸如聚山梨醇酯(例如,聚山梨醇酯20、聚山梨醇酯80);泊洛沙姆(例如,泊洛沙姆188);聚(乙二醇)苯基醚(例如,Triton);十二烷基硫酸钠(SDS);月桂硫酸钠;辛基糖苷钠;月桂基-、肉豆蔻基-、亚油基-或硬脂基-磺基甜菜碱;月桂基-、肉豆蔻基-、亚油基-或硬脂基-肌氨酸;亚油基、肉豆蔻基或鲸蜡基-甜菜碱;月桂酰胺丙基-、椰油酰胺丙基-、亚油酰胺丙基-、肉豆蔻酰胺丙基-、棕榈酰胺丙基-或异硬脂酰胺丙基-甜菜碱(例如,月桂酰胺丙基);肉豆蔻酰胺丙基-、棕榈酰胺丙基-或异硬脂酰胺丙基-二甲胺;甲基椰油酰-牛磺酸钠或甲基油基牛磺酸二钠;和MONAQUATTM系列(Mona Industries,Inc.,新泽西州帕特森)、聚乙二醇、聚丙二醇以及乙二醇和丙二醇的共聚物(例如,Pluronics、PF68等)。可存在于预冻干配制品中的表面活性剂的示例性量是约0.001%-0.5%。高分子量结构添加剂(例如,填充剂、粘合剂)可以包括例如阿拉伯胶、白蛋白、海藻酸、磷酸(二)钙、纤维素、羧甲基纤维素、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、微晶纤维素、葡聚糖、dextrate、蔗糖、tylose、纤维素、预糊化淀粉、硫酸钙、直链淀粉、甘氨酸、膨润土、麦芽糖、山梨糖醇、乙基纤维素、磷酸氢二钠、磷酸二钠、焦亚硫酸二钠、聚乙烯醇、明胶、葡萄糖、瓜尔豆胶、液体葡萄糖、可压缩糖、硅酸铝镁、麦芽糖糊精、聚环氧乙烷、聚甲基丙烯酸酯、聚维酮、海藻酸钠、黄蓍胶微晶纤维素、淀粉和玉米醇溶蛋白。高分子量结构添加剂的示例性浓度是按重量计0.1%至10%。在其他实施方案中,可以包含增量剂(例如,甘露醇、甘氨酸)。
组合物可以适用于肠胃外施用。示例性组合物适用于通过熟练技术人员可用的任何途径(诸如关节内、皮下、静脉内、肌肉内、腹膜内、脑内(脑实质内)、脑室内、肌肉内、眼内、动脉内或病灶内途径)注射或输注到动物中。肠胃外配制品典型地将是无菌、无热原、等渗水溶液,任选地含有药学上可接受的防腐剂。
非水性溶剂的例子是丙二醇、聚乙二醇、植物油(诸如橄榄油)以及可注射的有机酯(诸如油酸乙酯)。水性载体包括水、醇/水溶液、乳液或悬浮液,包括盐水和缓冲介质。肠胃外媒介物包括氯化钠溶液、林格氏右旋糖、右旋糖和氯化钠、乳酸林格氏液或固定油。静脉内媒介物包括流体和营养补充剂、电解质补充剂(诸如基于林格氏右旋糖的那些)等。也可以存在防腐剂和其他添加剂,例如像抗微生物剂、抗氧化剂、螯合剂、惰性气体等。一般参见Remington's Pharmaceutical Science,第16版,Mack编辑,1980。
本文所述的药物组合物可以以在特定局部环境中提供局部浓度的产物(例如,推注、储库效应)和/或增加的稳定性或半衰期的方式被配制用于受控或持续递送。所述组合物可以包含本文公开的包含超长CDR3的抗体、抗体片段、核酸或载体的配制品与诸如聚乳酸、聚乙醇酸等聚合物化合物的微粒制剂以及诸如以下的药剂:可生物降解基质、可注射微球、微囊颗粒、微囊、生物可蚀颗粒珠、脂质体和提供活性剂的受控或缓释的可植入递送装置,其然后可以作为贮库注射剂递送。用于配制此类持续或受控递送手段的技术是已知的,并且已经开发了多种聚合物并且被用于药物的受控释放和递送。此类聚合物典型地是可生物降解的和生物相容的。聚合物水凝胶(包括通过对映体聚合物或多肽片段的络合形成的那些)以及具有温度或pH敏感特性的水凝胶对于提供药物贮库效应可能是希望的,因为在捕获生物活性蛋白药剂(例如,包含超长CDR3的抗体)中涉及温和且水性的条件。参见例如,WO 93/15722中对用于递送药物组合物的控释多孔聚合物微颗粒的描述。
用于此目的的合适材料包括聚丙交酯(参见例如,美国专利号3,773,919)、聚-(a-羟基羧酸)的聚合物诸如聚-D-(-)-3-羟基丁酸(EP 133,988A)、L-谷氨酸和γ-乙基-L-谷氨酸的共聚物(Sidman等人,Biopolymers,22:547-556(1983))、聚(2-羟乙基-甲基丙烯酸酯)(Langer等人,J.Biomed.Mater.Res.,15:167-277(1981),和Langer,Chem.Tech.,12:98-105(1982))、乙烯醋酸乙烯酯、或聚-D(-)-3-羟基丁酸。其他可生物降解聚合物包括聚(内酯)、聚(缩醛)、聚(原酸酯)和聚(原碳酸酯)。缓释组合物还可以包括脂质体,所述脂质体可以通过本领域已知的几种方法中的任何方法来制备(参见例如,Eppstein等人,Proc.Natl.Acad.Sci.USA,82:3688-92(1985))。载体本身或其降解产物在靶组织中应是无毒的并且不应进一步加重病症。这可以通过在目标障碍的动物模型中进行常规筛选来确定,或者如果此类模型不可用,则在正常动物中进行。
用于缓释的重组蛋白的微胶囊化已经成功地用人生长激素(rhGH)、干扰素-(rhIFN-)、白细胞介素-2和MN rgp120进行。Johnson等人,Nat.Med.,2:795-799(1996);Yasuda,Biomed.Ther.,27:1221-1223(1993);Hora等人,Bio/Technology.8:755-758(1990);Cleland,“Design and Production of Single Immunization Vaccines UsingPolylactide Polyglycolide Microsphere Systems,”in Vaccine Design:The Subunitand Adjuvant Approach,Powell和Newman编辑(Plenum Press:纽约,1995),第439-462页;WO 97/03692、WO 96/40072、WO 96/07399和美国专利号5,654,010。由于这些蛋白质的生物相容性和宽范围的可生物降解特性,使用聚-乳酸-共-乙醇酸(PLGA)聚合物开发这些蛋白质的缓释配制品。PLGA、乳酸和乙醇酸的降解产物可以在人体内快速清除。此外,这种聚合物的可降解性可能取决于其分子量和组成。Lewis,“Controlled release of bioactiveagents from lactide/glycolide polymer,”in:M.Chasin和R.Langer(编辑),Biodegradable Polymers as Drug Delivery Systems(Marcel Dekker:纽约,1990),第1-41页。缓释组合物的另外例子包括例如,EP 58,481A、美国专利号3,887,699、EP 158,277A、加拿大专利号1176565、U.Sidman等人,Biopolymers 22,547[1983]、R.Langer等人,Chem.Tech.12,98[1982]、Sinha等人,J.Control.Release 90,261[2003]、Zhu等人,Nat.Biotechnol.18,24[2000]、和Dai等人,Colloids Surf B Biointerfaces 41,117[2005]。
生物粘附聚合物也被考虑用于本公开文本的组合物中或与其一起使用。生物粘附剂是合成和天然存在的材料,其能够粘附在生物基材上持续延长的时间段。例如,卡波姆(Carbopol)和聚卡波非(polycarbophil)都是聚(丙烯酸)的合成交联衍生物。基于天然存在的物质的生物粘附递送系统包括例如透明质酸(hyaluronic acid),也称为玻尿酸(hyaluronan)。透明质酸是一种天然存在的粘多糖,其由D-葡萄糖醛酸和N-乙酰基-D-葡糖胺的残基组成。透明质酸存在于脊椎动物的细胞外组织基质中,包括在结缔组织中以及在滑液中和在眼睛的玻璃体和房水中。透明质酸的酯化衍生物已用于生产用于递送的微球,所述微球具有生物相容性和可生物降解性(参见例如,Cortivo等人,Biomaterials(1991)12:727-730;EP 517,565;WO 96/29998;Illum等人,J.Controlled Rel.(1994)29:133-141)。本公开文本的示例性含有透明质酸的组合物包含透明质酸酯聚合物,其量为包含超长CDR3的抗体占透明质酸聚合物的大约0.1%至约40%(w/w)。
可生物降解聚合物基质和不可生物降解聚合物基质均可以用于递送本公开文本组合物,并且此类聚合物基质可以包含天然或合成聚合物。优选可生物降解基质。发生释放的时间段基于聚合物的选择。典型地,范围在几小时与三至十二个月之间的时间段内释放是最希望的。可用于形成生物可降解递送系统的示例性合成聚合物包括:乳酸和乙醇酸的聚合物、聚酰胺、聚碳酸酯、聚亚烷基、聚亚烷基二醇、聚环氧烷、聚对苯二甲酸亚烷基酯、聚乙烯醇、聚乙烯醚、聚乙烯酯、聚乙烯卤、聚乙烯吡咯烷酮、聚乙交酯、聚硅氧烷、聚酸酐、聚氨酯及其共聚物、聚(丁酸)、聚(戊酸)、烷基纤维素、羟烷基纤维素、纤维素醚、纤维素酯、硝化纤维素、丙烯酸和甲基丙烯酸酯的聚合物、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟丁基甲基纤维素、醋酸纤维素、丙酸纤维素、醋酸丁酸纤维素、醋酸邻苯二甲酸纤维素、羧乙基纤维素、三醋酸纤维素、纤维素硫酸钠盐、聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸乙酯)、聚(甲基丙烯酸丁酯)、聚(甲基丙烯酸异丁酯)、聚(甲基丙烯酸己酯)、聚(甲基丙烯酸异癸酯)、聚(甲基丙烯酸月桂酯)、聚(甲基丙烯酸苯酯)、聚(丙烯酸甲酯)、聚(丙烯酸异丙酯)、聚(丙烯酸异丁酯)、聚(丙烯酸十八酯)、聚乙烯、聚丙烯、聚(乙二醇)、聚(环氧乙烷)、聚(对苯二甲酸乙二醇酯)、聚(乙烯醇)、聚乙酸乙烯酯、聚氯乙烯、聚苯乙烯和聚乙烯吡咯烷酮。示例性天然聚合物包括海藻酸酯和其他多糖,包括葡聚糖和纤维素、胶原、其化学衍生物(取代、化学基团(例如,烷基、亚烷基)的添加、羟基化、氧化和本领域技术人员常规进行的其他修饰)、白蛋白和其他亲水性蛋白质、玉米醇溶蛋白和其他醇溶蛋白和疏水性蛋白质、其共聚物和混合物。通常,这些材料通过酶水解或在体内暴露于水、通过表面或整体侵蚀而降解。聚合物任选地呈水凝胶的形式(参见例如,WO 04/009664、WO 05/087201、Sawhney等人,Macromolecules,1993,26,581-587),所述水凝胶可以吸收高达其重量的约90%的水并且进一步任选地与多价离子或其他聚合物交联。
递送系统还包括非聚合物系统,其为脂质,包括固醇,诸如胆固醇、胆固醇酯和脂肪酸,或中性脂肪,诸如甘油单二酯和甘油三酯;水凝胶释放系统;硅橡胶系统;基于肽的系统;蜡涂层;使用常规粘合剂和赋形剂的压缩片剂;部分融合的植入物;等。具体的例子包括但不限于:(a)产物以在基质中的形式被包含其中的侵蚀系统,诸如美国专利号4,452,775、4,675,189和5,736,152中所述的那些,和(b)产物以受控速率从聚合物中渗透的扩散系统,诸如美国专利号3,854,480、5,133,974和5,407,686中所述的那些。含有产物的脂质体可以通过已知方法的方法制备,例如像(DE 3,218,121;Epstein等人,Proc.Natl.Acad.Sci.USA,82:3688-3692(1985);Hwang等人,Proc.Natl.Acad.Sci.USA,77:4030-4034(1980);EP 52,322;EP 36,676;EP 88,046;EP 143,949;EP 142,641;JP 83-118008;美国专利号4,485,045和4,544,545;和EP 102,324)。
可替代地或另外,所述组合物可以通过其上已吸收或封装本文公开的包含超长CDR3的抗体、抗体片段、核酸或载体的植入膜、海绵或其他适当材料的受影响区域中来局部施用。在使用植入装置的情况下,所述装置可以被植入任何合适的组织或器官中,并且本文公开的包含超长CDR3抗体片段的抗体、核酸或载体的递送可以直接通过所述装置经由推注或经由连续施用或经由导管使用连续输注进行。
可以将包含本文公开的包含超长CDR3的抗体、抗体片段、核酸或载体的药物组合物配制成用于吸入,例如像作为干粉。吸入溶液也可以配制在液化推进剂中用于气雾剂输送。在又另一种配制品中,溶液可以被雾化。用于肺部施用的其他药物组合物包括例如在WO94/20069中描述的那些,所述专利公开了化学修饰蛋白的肺部递送。对于肺部递送,粒度应适合递送至远端肺。例如,粒度可以是1μm至5μm;然而,例如,如果每个颗粒都是相当多孔的,可以使用更大的颗粒。
可以口服施用含有本文公开的包含超长CDR3的抗体、抗体片段、核酸或载体的某些配制品。以这种方式施用的配制品可以用或不用通常在固体剂型(诸如片剂和胶囊)的混配中使用的那些载体来配制。例如,胶囊可以设计为在胃肠道中在生物利用度最大化且前系统性降解最小化时释放配制品的活性部分。可以包含其他药剂以促进选择性结合剂的吸收。还可以采用稀释剂、调味剂、低熔点蜡、植物油、润滑剂、助悬剂、片剂崩解剂和粘合剂。
另一种制剂可以涉及有效量的本文公开的包含超长CDR3的抗体、抗体片段、核酸或载体与适合于制造片剂的无毒赋形剂的混合物。通过将片剂溶解于无菌水或另一种适当媒介物中,可以按单位剂量形式制备溶液。合适的赋形剂包括但不限于惰性稀释剂,诸如碳酸钙、碳酸钠或碳酸氢钠、乳糖或磷酸钙;或者结合剂,诸如淀粉、明胶或阿拉伯胶;或者润滑剂,诸如硬脂酸镁、硬脂酸或滑石。
可以鉴于本公开文本和配制技术的一般知识确定合适的和/或优选的药物配制品,取决于预期的施用途径、递送形式和所希望的剂量。无论施用方式如何,都可以根据患者体重、体表面积或器官大小来计算有效剂量。用于确定涉及本文所述每种配制品的治疗的适当剂量的计算的进一步细化在本领域中常规进行并且在本领域中常规执行的任务的范围内。可以通过使用适当的剂量反应数据来确定适当剂量。
在一些实施方案中,包含超长CDR3的抗体或其片段提供有经修饰的Fc区,其中天然存在的Fc区被修饰以增加抗体或片段在生物环境中的半衰期,例如血清半衰期或通过体外测定测量半衰期。美国专利号6,998,253中也描述了用于改变IgG的Fc区的原始形式的方法。
在某些实施方案中,可能希望修饰抗体或片段以增加其血清半衰期,例如,向抗体片段添加分子诸如PEG或其他水溶性聚合物(包括多糖聚合物)以增加半衰期。这也可以例如通过将补救受体结合表位掺入抗体片段中来实现(例如,通过抗体片段中适当区域的突变或通过将表位掺入肽标签中,所述肽标签然后与抗体片段在任一端或在中间融合,例如通过DNA或肽合成)(参见国际公开号WO 96/32478)。补救受体结合表位是指IgG分子(例如IgG1、IgG2、IgG3、或IgG4)Fc区中负责增加IgG分子体内血清半衰期的表位。
补救受体结合表位可以包含这样的区域,其中来自Fc结构域的一个或两个环的任何一个或多个氨基酸残基被转移到抗体片段的类似位置。甚至更优选地,转移来自Fc结构域的一个或两个环的三个或更多个残基。再更优选地,表位取自zxs区(例如,IgG的zxs区)的CH2结构域并且转移到抗体的CH1、CH3或VH区或多于一个这样的区域。可替代地,表位取自Fc区的CH2结构域并且转移到抗体片段的CL区或VL区或两者。还参见WO 97/34631和WO96/32478,其描述了Fc变体以及其与补救受体的相互作用。
IV.治疗方法和用途
本文提供了含有经细胞因子修饰的嵌合抗体或抗原结合片段的组合物用于治疗疾病或病症的使用方法和用途。在特定实施方案中,所述疾病或病症是可用嵌合分子中存在的细胞因子治疗的疾病或病症。例如,所述疾病或病症可用IL-2或IL-15治疗。在一些实施方案中,所提供的经细胞因子修饰的嵌合抗体或抗原结合片段特别适合用作免疫疗法。在特定方面,所提供的经细胞因子修饰的嵌合抗体或抗原结合片段或其组合物通过促进T细胞激活和/或增殖而在许多肿瘤学应用(诸如癌症)中具有用途。在一些实施方案中,所提供的经细胞因子修饰的嵌合抗体或抗原结合片段用于治疗有需要的受试者的癌症。
此类方法和用途包括治疗性方法和用途,例如,涉及将分子施用于患有疾病、病症或障碍(诸如癌症)的受试者,以实现疾病或障碍的治疗。用途包括组合物在此类方法和治疗中的用途以及此类组合物在制备实施此类治疗性方法的药剂中的用途。在一些实施方案中,所述方法和用途从而治疗受试者的疾病或病症或障碍,诸如肿瘤或癌症。
在一些实施方案中,所述癌症是头颈癌、乳腺癌、肝癌、结肠癌、卵巢癌、前列腺癌、胰腺癌、脑癌、宫颈癌、骨癌、皮肤癌、肺癌或血液癌。在一些实施方案中,癌症可以包括以异常或不受控制的细胞生长为特征的恶性肿瘤。可能与癌症相关的其他特征包括转移、干扰邻近细胞的正常功能、释放异常水平的细胞因子或其他分泌产物以及抑制或加重炎性或免疫反应、侵袭周围或远处的组织或器官,诸如淋巴结等。转移性疾病可以指癌细胞已经离开原始肿瘤部位并且迁移到身体的其他部位,例如经由血流或淋巴系统。
在一些实施方案中,所提供的方法导致疾病或病症(诸如癌症)的改善和或治疗。在一些方面,所提供的方法导致疾病的一种或多种改善,诸如赘生细胞数量的减少、赘生细胞死亡的增加、赘生细胞存活的抑制、肿瘤生长的抑制(即,在一定程度上减缓或停止)、患者存活率的增加和/或与疾病或病症相关的一种或多种症状的一些缓解。
在所提供的方法的方面,可以使用特定于疾病或病症的标准来评估或确定反应。在一些实施方案中,可以使用筛选技术(诸如磁共振成像(MRI)扫描、X射线照相成像、计算机断层成像(CT)扫描、骨扫描成像、内窥镜检查、和肿瘤活检取样,包括骨髓抽吸(BMA)和循环中肿瘤细胞的计数)来评估肿瘤反应以了解肿瘤形态的变化(即,总体肿瘤负荷、肿瘤大小)。
所提供的方法涉及将治疗有效量的本文提供的组合物施用于有需要的受试者,诸如癌症受试者。治疗有效量可以多种因素而变化,所述因素诸如个体的疾病状态、年龄、性别和体重以及药剂在个体中引发所希望的反应的能力。治疗有效量也是治疗有益作用超过抗体或抗体片段部分的任何毒性或有害作用的量。在一些情况下,肿瘤或癌症疗法的治疗有效量也可以通过其稳定疾病进展的能力来测量。可以在预测人类肿瘤中的功效的动物模型系统中评价所提供的抗体或抗原结合片段抑制癌症的能力。
可替代地,可以通过经由熟练从业者已知的体外测定检查抗体或抗原结合片段抑制细胞生长或诱导细胞凋亡的能力来评价组合物的这种特性。治疗有效量的治疗性化合物可以减小受试者的肿瘤大小或以其他方式改善症状。本领域普通技术人员将能够基于此类因素(诸如受试者的体型、受试者症状的严重程度以及所选择的施用的特定组合物或途径)来确定此类量。
在一些实施方案中,所提供的抗体或抗原结合片段可以根据需要以单剂量或数个剂量施用以获得所希望的反应。在一些实施方案中,有效量取决于应用的来源、正在治疗的受试者、正在治疗的病症的严重程度和类型以及施用方式。
可以调节剂量方案以提供最佳的希望反应(例如,治疗反应)。例如,可以施用单次推注,可以随时间施用几个分开的剂量,或者可以如根据治疗情况的紧急程度指示的按比例减少或增加剂量。肠胃外组合物可以配制成剂量单位形式以易于施用和剂量的一致性。如本文所用的剂量单位形式是指适合作为待治疗受试者的单位剂量的物理上离散的单位;每个单位含有经计算与所希望的药物载体联合产生所希望的治疗作用的预定量的活性化合物。
在一些实施方案中,治疗有效量在等于或约0.1至100mg/kg之间或任何前项之间的任何值。
V.示例性实施方案
所提供的实施方案包括:
1.一种经细胞因子修饰的嵌合抗体或抗原结合片段,其包含经修饰的超长CDR3,所述经修饰的超长CDR3包含替代牛抗体或抗原结合片段或其人源化序列的重链的超长CDR3区的至少一部分的白细胞介素-15(IL-15)细胞因子序列或其生物活性部分。
2.根据实施方案1所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述IL-15细胞因子序列是人IL-15。
3.根据实施方案1或实施方案2所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述IL-15细胞因子序列包含与SEQ ID NO:1展现出至少或至少约85%、至少或至少约90%、至少或至少约92%、至少或至少约95%、至少或至少约96%、至少或至少约97%、至少或至少约98%或者至少或至少约99%序列同一性的氨基酸序列。
4.根据实施方案1-3中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述IL-15细胞因子序列包含SEQ ID NO:1中所示的氨基酸序列。
5.一种经细胞因子修饰的嵌合抗体或抗原结合片段,其包含经修饰的超长CDR3,所述经修饰的超长CDR3包含替代牛抗体或抗原结合片段或其人源化序列的重链的超长CDR3区的至少一部分的白细胞介素-2(IL-2)细胞因子序列或其生物活性部分。
6.根据实施方案5所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述IL-2细胞因子序列是人IL-2。
7.根据实施方案5或实施方案6所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述IL-2细胞因子序列包含与SEQ ID NO:165展现出至少或至少约85%、至少或至少约90%、至少或至少约92%、至少或至少约95%、至少或至少约96%、至少或至少约97%、至少或至少约98%或者至少或至少约99%序列同一性的氨基酸序列。
8.根据实施方案5-7中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述IL-2细胞因子序列包含SEQ ID NO:165中所示的氨基酸序列。
9.根据实施方案1-8中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述细胞因子序列替代牛抗体或抗原结合片段的重链的超长CDR3区的至少一部分。
10.根据实施方案9所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述牛抗体或抗原结合片段是牛抗体BLV1H12或其抗原结合片段。
11.根据实施方案9或实施方案10所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述牛抗体或抗原结合片段包含由SEQ ID NO:5中所示序列编码的可变重链氨基酸序列和由SEQ ID NO:8中所示序列编码的可变轻链氨基酸序列。
12.根据实施方案9或实施方案10所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述牛抗体或抗原结合片段包含由SEQ ID NO:167中所示序列编码的可变重链氨基酸序列和由SEQ ID NO:168中所示序列编码的可变轻链氨基酸序列。
13.根据实施方案9或实施方案10所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述牛抗体或抗原结合片段包含SEQ ID NO:26中所示的可变重链和SEQ ID NO:27中所示的可变轻链。
14.根据实施方案1-8中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述细胞因子序列替代人源化牛抗体或其抗原结合片段的重链的超长CDR3区的至少一部分。
15.根据实施方案14所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述人源化牛抗体或其抗原结合片段包含作为人重链种系序列或源自人重链种系序列的重链或其一部分和作为人轻链种系序列或源自人轻链种系序列的轻链或其一部分。
16.根据实施方案15所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述人重链种系序列是VH4-39、VH4-59*03、VH4-34*02或VH4-34*09种系序列或是SEQ ID NO:68-71中任一个所示的序列。
17.根据实施方案15或实施方案16所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述人轻链种系序列是VL1-51种系序列或是基于所述VL1-51种系序列的包含一个或多个突变的序列,任选地其中所述VL1-51种系序列是SEQ ID NO:156中所示的。
18.根据实施方案17所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述一个或多个突变选自:
基于Kabat编号的氨基酸替代S2A、T5N、P8S、A12G、A13S和P14L中的一个或多个;
基于Kabat编号的氨基酸替代S2A、T5N、P8S、A12G、A13S和P14L;
CDR1中包含氨基酸替代I29V和N32G的突变;
CDR2中包含DNN取代为GDT的突变;
CDR2中包含DNNKRP取代为GDTSRA的突变;
或任何前项的组合。
19.根据实施方案1-18中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述抗体是包含可变重链和可变轻链的抗原结合片段。
20.根据实施方案1-19中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述抗体包含与重链恒定结构域(CH1-CH2-CH3)连接的可变重链和与轻链恒定结构域(CL1)连接的可变轻链。
21.根据实施方案20所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述重链恒定结构域来自人IgG1。
22.根据实施方案20或实施方案21所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述轻链恒定结构域是λ轻链区。
23.根据实施方案1-22中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中超长CDR3区的所述至少一部分包含杵区,并且所述细胞因子序列存在于所述经修饰的超长CDR3的升茎结构域与降茎结构域之间。
24.根据实施方案23所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述细胞因子序列经由柔性接头、任选地GGS或GSG接头与所述升茎结构域和/或所述降茎结构域连接。
25.根据实施方案23或实施方案24所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述升茎结构域包含SEQ ID NO:158或SEQ ID NO:159中所示的序列。
26.根据实施方案23-25中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述降茎结构域包含SEQ ID NO:161中所示的序列。
27.根据实施方案1-4和9-26中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述抗体或抗原结合片段包含由SEQ ID NO:7中所示的核苷酸序列或与SEQID NO:7中所示的核苷酸序列展现出至少或至少约85%、至少或至少约90%、至少或至少约92%、至少或至少约95%、至少或至少约96%、至少或至少约97%、至少或至少约98%、至少或至少约99%序列同一性的核苷酸序列编码的可变重链序列,其中包含含有IL-15序列的经修饰的超长CDR3。
28.根据实施方案1-4和9-27中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述抗体或抗原结合片段与包括IL15Rαsushi结构域在内的IL15Rα的细胞外结构域复合。
29.根据实施方案28所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中包括IL15Rαsushi结构域在内的IL15Rα的所述细胞外结构域与所述IL-15序列非共价缔合。
30.根据实施方案28所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中包括IL15Rαsushi结构域在内的IL15Rα的所述细胞外结构域与所述可变轻链连接。
31.根据实施方案30所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其经由肽接头连接。
32.根据实施方案31所述的经细胞因子修饰的嵌合抗体,其中所述肽接头是甘氨酸接头或甘氨酸-丝氨酸接头,任选地其中所述接头是GS。
33.根据实施方案28-32中任一项所述的经细胞因子修饰的嵌合抗体,其中包括IL15Rαsushi结构域在内的IL15Rα的所述细胞外结构域包含SEQ ID NO:2中所示的序列。
34.根据实施方案30-33中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述可变轻链包含由SEQ ID NO:3编码的氨基酸序列。
35.一种或多种多核苷酸,其编码根据实施方案1-34中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段。
36.一种多核苷酸,其编码根据实施方案1-34中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段的重链或其可变区。
37.一种多核苷酸,其编码根据实施方案1-34中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段的轻链或其可变区。
38.一种表达载体,其包含根据实施方案35-37中任一项所述的多核苷酸。
39.一种宿主细胞,其包含根据实施方案35-37中任一项所述的多核苷酸或根据实施方案38所述的表达载体。
40.根据实施方案39所述的宿主细胞,其进一步包含表达包括IL15Rαsushi结构域在内的IL15Rα的细胞外结构域的多核苷酸或载体。
41.根据实施方案40所述的宿主细胞,其中包括IL15Rαsushi结构域在内的IL15Rα的所述细胞外结构域包含SEQ ID NO:2中所示的序列。
42.一种产生经细胞因子修饰的嵌合抗体或抗原结合片段的方法,其包括在根据实施方案39-41中任一项所述的宿主细胞表达所述抗体或抗原结合片段的条件下培养所述细胞,任选地进一步包括回收并纯化所述抗体或抗原结合片段。
43.一种通过根据实施方案42所述的方法产生的经细胞因子修饰的嵌合抗体或抗原结合片段。
44.一种药物组合物,其包含根据实施方案1-34或43中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段。
45.一种治疗受试者的癌症的方法,其包括施用治疗有效量的根据实施方案1-34或43中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段。
46.一种治疗受试者的癌症的方法,其包括施用治疗有效量的根据实施方案44所述的药物组合物。
VI.实施例
包括以下实施例仅出于说明性目的,并且不旨在限制本发明的范围。
实施例1嵌合白细胞介素15融合抗体的产生。
产生嵌合BLV1H12-IL-15(B15)融合抗体,其中通过将牛BLV1H12抗体的杵区用白细胞介素(IL)-15替代来工程化BLV1H12的超长CDR3区。
将来自嵌合BLV1H12牛重链序列(SEQ ID NO:167)的可变重链(VH)区通过PCR扩增,并且在信号序列与编码人lgG1的CH1-CH2-CH3的核苷酸序列之间框内亚克隆以产生SEQID NO:6中所示的序列。嵌合超长牛重链序列(SEQ ID NO:167)含有来自BLV1H12的重链的茎序列,其中升茎链中的最后一个丝氨酸为了克隆目的被改变为苏氨酸;并且含有来自牛抗HIV抗体的杵。为了将IL-15细胞因子序列(SEQ ID NO:1中所示)插入嵌合BLV1H12重链的CDR3中,通过以下方式设计编码整个B15可变区及其信号肽的序列(SEQ ID NO:7):将杵序列(SEQ ID NO:162)用IL-15序列连同编码N-末端GGS接头的序列(SEQ ID NO:163)和编码C-末端GSG接头的序列(SEQ ID NO:164)替代,其中IL-15与升茎(SEQ ID NO:157,编码SEQID NO:159中所示的序列)和降茎(SEQ ID NO:160,编码SEQ ID NO:161中所示的序列)连接。此序列是用5'EcoRI位点化学合成的,并且由GenScript,Inc.克隆到pUC57载体中。合成序列中已经存在3'端NheI位点。使用EcoRI和NheI限制酶将合成序列(SEQ ID NO:6)亚克隆到BLV1H12表达载体中。
然后将编码每条重链的表达载体与编码牛轻链BLV1H12(SEQ ID NO:168)的pFUSE表达载体平行共转染到自由式HEK 293细胞(ThermoScientific)中。允许细胞在37℃、8%CO2下生长,并且将表达的嵌合BLV1H12-IL-15(B15)融合抗体分泌到培养基中,并且在转染后96小时收获。通过CaptureSelect CH1-XL亲和基质(ThermoScientific)纯化嵌合融合抗体,然后浓缩并且使用Amicon Ultra-4离心过滤器(截留MW=10,000kDa,MilliporeSigma)经缓冲液交换到磷酸盐缓冲盐水(PBS)中。基于分子量和消光系数,使用Nanodrop对它们进行量化。
为了评估IL-15是否可能需要其高亲和力受体α(IL15Rα)来增加向受体β和γ亚基(IL2/15Rβ和γc)的反式信号传导,通过共表达IL-15嵌合融合抗体与IL15Rα的sushi结构域产生两种另外的分子。通过在自由式HEK 293细胞中共表达IL15Rαsushi结构域(SEQ IDNO:2)与嵌合IgG(B15_Rαsushi)或将IL15Rαsushi结构域经由GS接头与轻链融合(SEQ IDNO:3)(B15_GS_Rαsushi)来产生两种另外的变体分子。
图1A和图1B阐述了所产生的构建体的示意性描绘。
通过SDS-PAGE凝胶分析B15融合抗体。图2示出了由HEK 293细胞表达的纯化B15融合抗体构建体BLV1H12-IL-15(B15)、BLV1H12-IL-15-Rαsushi(B15_Rαsushi)和BLV1H12-IL-15-GS-Rαsushi(B15_GS_Rαsushi)的SDS-PAGE凝胶。这些结果证明嵌合B15抗体或含有IL15-Rαsushi结构域的变体可以与典型的人抗体类似地表达和纯化。
实施例2嵌合B15融合抗体-受体结合测定。
在酶联免疫吸附测定(ELISA)中评价嵌合BLV1H12-IL-15(B15)融合抗体与IL2受体α(IL2Rα)和IL15Rα的结合。在96孔高结合板中在4℃下每孔包被50ng IL2Rα或100ngIL15Rα蛋白(R&D systems)过夜。将板用含有0.1%Tween 20的tris缓冲盐水(TBS)(TBST)洗涤三次。将板上的未结合位点在室温下用在TBST中制备的1%牛血清白蛋白(BSA)封闭1小时。每孔添加10皮摩尔B15(稀释在TBST中的1%BSA中),并且还设置仅添加BSA的阴性对照孔。将板在室温下孵育1小时,然后将其用TBST洗涤四次以去除未结合的B15。使用的检测抗体是辣根过氧化物酶缀合的山羊抗人λ(Southern Biotech),将其1比5000稀释在TBST中的1%BSA中,并且每孔添加50ul稀释液。与第二抗体孵育30分钟后,将板用TBST洗涤五次以去除未结合的第二抗体。每孔添加50ul TMB底物(TheromoScientific),并且辣根过氧化物酶-TMB反应运行1分30秒,并且然后通过每孔添加50ul 1.0标准硫酸使其停止。在Tecan读板器中在450nm处读取板,并且绘制的值是三个重复孔的平均值,其中扣除背景读数。
在ELISA测定中评价嵌合BLV1H12-IL-15(B15)融合抗体与IL2/15Rβ受体的结合。将板在4℃下用每孔50ng IL2/15Rβ蛋白(R&D systems)包被过夜。将板用含有0.1%Tween20的tris缓冲盐水(TBS)(TBST)洗涤三次。将板上的未结合位点在室温下用在TBST中制备的1%牛血清白蛋白(BSA)封闭1小时。每孔添加10皮摩尔B15或预混的等摩尔B15和IL15Rα-Fc(R&D systems),并且还设置仅添加BSA的阴性对照孔。将板在室温下孵育1小时,并且然后将其用TBST洗涤四次以去除未结合的B15或预混的B15和IL15Rα-Fc。使用的检测抗体是辣根过氧化物酶缀合的山羊抗人λ(Southern Biotech),将其1比5000稀释在TBST中的1%BSA中,并且每孔添加50ul稀释液。与第二抗体孵育30分钟后,将板用TBST洗涤五次以去除未结合的第二抗体。每孔添加50ul TMB底物(TheromoScientific),并且过氧化物酶-TMB反应运行3分钟,并且然后通过每孔添加50ul 1.0标准硫酸使其停止。在Tecan读板器中在450nm处读取板,并且绘制的值是三个重复孔的平均值,其中扣除背景读数。
如图3A和图3B所示,嵌合B15可以结合至IL15Rα和IL2/15Rβ亚基两者,并且IL15Rαsushi结构域亚基可以改善B15与IL2/15Rβ亚基的结合。未检测到B15与IL2Rα之间的结合。这些结果证明,IL15Rα或其sushi结构域参与了与IL2/15Rβ和γc亚基的有效结合。
实施例3嵌合B15融合抗体诱导的受体激活和信号传导。
使用HEK-Blue IL2报告细胞(InvivoGen)测试由如实施例1中所述产生的嵌合B15分子引起的IL2/15Rβ和γc受体激活和STAT5信号传导,并且通过STAT5诱导型碱性磷酸酶(SEAP)报告基因的诱导和分泌进行分析。
由于在HEK-Blue IL2报告细胞中没有表达IL15Rα亚基,因此将IL15Rα-Fc(R&DSystems)与IL15(或B15)混合以增加其与IL2/15Rβ和γc亚基的结合。首先,通过以下方式将HEK-Blue IL2报告细胞制备成悬浮液:将细胞用预温热的磷酸盐缓冲盐水(PBS)轻轻冲洗两次,通过使用细胞刮刀在PBS的存在下分离细胞,并且将细胞重悬在新鲜的预温热的测试培养基(含高葡萄糖和10%热灭活FBS的DMEM)至每ml约280,000个细胞。将与半摩尔IL15Rα-Fc一起孵育的IL15单体(在4℃下过夜(预混的IL15和IL15Rα)或就在测定开始之前(新混合的IL15和IL15Rα))或者就在测定开始之前与等摩尔IL15Rα-Fc混合的嵌合B15(新混合的B15和IL15Rα)进行在PBS中从64nM至0.25nM的4倍连续稀释,并且每孔将20ul每个细胞因子稀释液添加到96孔组织培养处理的板中,其中每个稀释度三个重复。然后将50,000个细胞添加到每个孔中,并且在37℃、5%CO2下培养20小时。由于嵌合B15抗体是二价的,因此与IL15单体相比,仅使用半摩尔浓度。将来自每个含有分泌的SEAP的孔的20ul细胞培养上清液与180ul Quanti-Blue底物溶液在37℃下混合30分钟,使用Tecan读板器在590nm处测量颜色变化(对应于分泌的SEAP的量)。
如图4所示,体外STAT5信号传导测定表明嵌合B15抗体可以以比IL15单体快得多地与IL2/15Rβ受体缔合。
然后使用HEK-Blue IL2报告细胞在与IL15Rαsushi结构域缔合的替代嵌合B15分子的存在下评估受体激活和STAT5信号传导。与上面相同地制备HEK-Blue IL2报告细胞,并且与单独的4倍连续稀释(从64nM至0.25nM)的嵌合B15抗体、就在测定开始之前与IL15Rα-Fc混合的嵌合B15抗体(新混合的B15和IL15Rα)、嵌合B15变体B15_Rαsushi、或嵌合B15变体B15_GS_Rαsushi抗体共培养。如图5所示,表达有IL15Rαsushi结构域的嵌合B15变体实现了与预混的B15和IL15Rα-Fc相同的信号传导效力,它们在不存在IL15Rα亚基的情况下均好于嵌合B15抗体。
实施例4通过扩增NK-92细胞评估嵌合B15融合抗体的活性。
如实施例1所述产生的嵌合B15分子的活性通过其扩增NK-92自然杀伤细胞的能力来评估。NK-92细胞表达IL2Rα、IL15Rα、IL2/15Rβ和γc亚基,并且其生长和增殖依赖于外源性添加IL2或IL15以结合和激活受体。
将NK-92细胞维持在提供有200U/ml IL2的生长培养基中。在扩增测定之前,将NK-92细胞用不含IL2的生长培养基洗涤两次,以去除任何残留的细胞结合的IL2,并且在组织培养处理的96孔板中每孔接种10,000个细胞。将这些细胞与2倍连续稀释(从1.33nM至0.005nM)的IL2或IL15单体(R&D Systems)或者嵌合B15、嵌合变体B15_Rαsushi或嵌合B15变体B15_GS_Rαsushi抗体在37℃、5%CO2下一起孵育48小时。对于嵌合B15抗体及其变体,与IL2和IL15单体相比,仅使用半摩尔浓度。通过在代谢活性氧化还原酶(MTT测定试剂盒,Promega)的存在下将四唑鎓染料MTT还原为其不溶性甲臜来评估每孔的最终NK92细胞数量。
如图6所示,所有B15构建体都能够扩增NK-92细胞,尽管程度低于IL2或IL15单体。尚不知嵌合B15或具有IL15Rαsushi的其变体为何在扩增NK-92细胞中效力较低。不希望受理论束缚,一个假设是尽管嵌合B15或其变体是二价的,但它们只能单价结合在NK-92细胞上,而这些测定仅使用半摩尔浓度的嵌合B15或其变体。第二个假设是嵌合B15及其变体在HEK细胞中产生并且与大肠杆菌产生的IL2和IL15单体(R&D systems)相比是天然糖基化的,并且IL15的糖基化可能对其与NK-92细胞上的IL15受体的结合具有负面影响。第三个假设是嵌合B15或其变体的大小大于IL2或IL15单体,因为它与抗体结构融合,这从而稳定了IL15,但降低了其对NK-92细胞上IL15受体的可及性。
然后使用NK-92细胞的扩增来评估嵌合B15抗体与嵌合B15变体B15-Rαsushi或B15-GS-Rαsushi抗体相比的活性差异。实验的设置方式与图6相同。如图7所示,IL15Rαsushi结构域的存在改善了嵌合B15抗体扩增NK-92细胞的能力。
实施例5嵌合白细胞介素2融合抗体的产生。
通过将上述嵌合B15抗体的IL15区用IL-2(SEQ ID NO:165)替代产生嵌合BLV1H12-IL-2(B2)融合抗体。
由GenScript Inc.化学合成具有5’端GGS接头编码序列(SEQ ID NO:163)和3’端GSG接头编码序列(SEQ ID NO:164)的IL2编码序列(SEQ ID NO:166)。还添加5’端AgeI位点和3’端BamHI位点。由GenScript,Inc.将合成序列克隆到pUC57载体中,并且使用AgeI和BamHI限制酶亚克隆到嵌合B15重链可变区(SEQ ID NO:7)中。
然后将编码重链的表达载体与编码牛轻链BLV1H12(SEQ ID NO:168)的pFUSE表达载体平行共转染到自由式HEK 293细胞(ThermoScientific)中。允许细胞在37℃、8%CO2下生长,并且将表达的嵌合BLV1H12-IL-2(B2)融合抗体分泌到培养基中,并且在转染后96小时收获。通过CaptureSelect CH1-XL亲和基质(ThermoScientific)纯化嵌合B2融合抗体,然后浓缩并且使用Amicon Ultra-4离心过滤器(截留MW=10,000kDa,Millipore Sigma)经缓冲液交换到磷酸盐缓冲盐水(PBS)中。基于分子量和消光系数,使用Nanodrop对它们进行量化。
图8A和图8B阐述了所产生的构建体的示意性描绘。
通过SDS-PAGE凝胶分析B2融合抗体。图9示出了由HEK 293细胞表达的纯化融合抗体构建体BLV1H12-IL-2(B2)的SDS-PAGE凝胶。结果证明嵌合B2抗体可以与典型的人抗体类似地表达和纯化。
实施例6嵌合B2融合抗体-受体结合测定。
在酶联免疫吸附测定(ELISA)中评价嵌合BLV1H12-IL-2(B2)融合抗体与IL2Rα和IL15Rα的结合。在96孔高结合板中在4℃下每孔包被50ng IL2Rα或100ng IL15Rα蛋白(R&Dsystems)过夜。第二天,将板用含有0.1%Tween 20的tris缓冲盐水(TBS)(TBST)洗涤三次。将板上的未结合位点在室温下用在TBST中制备的1%牛血清白蛋白(BSA)封闭1小时。每孔添加10皮摩尔B2(稀释在TBST中的1%BSA中),并且还设置仅添加BSA的阴性对照孔。将板在室温下孵育1小时,并且然后将其用TBST洗涤四次以去除未结合的B2抗体。使用的检测抗体是辣根过氧化物酶缀合的山羊抗人λ(Southern Biotech),将其1比5000稀释在TBST中的1%BSA中,并且每孔添加50ul稀释液。与第二抗体孵育30分钟后,将板用TBST洗涤五次以去除未结合的第二抗体。每孔添加50ul TMB底物(TheromoScientific),并且辣根过氧化物酶-TMB反应运行1分30秒,并且然后通过每孔添加50ul 1.0标准硫酸使其停止。在Tecan读板器中在450nm处读取板,并且绘制的值是三个重复孔的平均值,其中扣除背景读数。
如图10所示,嵌合B2可以结合至IL2Rα但不结合IL15Rα。
实施例7嵌合B2融合抗体诱导的受体激活和信号传导。
使用HEK-Blue IL2报告细胞(InvivoGen)对IL2单体(R&D systems和MilliporeSigma)测试由如实施例5中所述产生的嵌合B2分子引起的IL2/15Rβ和γc受体激活和STAT5信号传导,并且通过STAT5诱导型碱性磷酸酶(SEAP)报告基因的诱导和分泌进行分析。
首先,通过以下方式将HEK-Blue IL2报告细胞制备成悬浮液:将细胞用预温热的磷酸盐缓冲盐水(PBS)轻轻冲洗两次,通过使用细胞刮刀在PBS的存在下分离细胞,并且将细胞重悬在新鲜的预温热的测试培养基(含高葡萄糖和10%热灭活FBS的DMEM)至每ml约280,000个细胞。将IL2单体或嵌合B2抗体进行在PBS中从64nM至0.25nM的4倍连续稀释,并且每孔将20ul每个细胞因子稀释液添加到96孔组织培养处理的板中,其中每个稀释度三个重复。然后将50,000个细胞添加到每个孔中,并且在37℃、5%CO2下培养20小时。由于嵌合B2抗体是二价的,因此与IL2单体相比,仅使用半摩尔浓度。将来自每个含有分泌的SEAP的孔的20ul细胞培养上清液与180ul Quanti-Blue底物溶液在37℃下混合30分钟,使用Tecan读板器在590nm处测量颜色变化(对应于分泌的SEAP的量)。
如图11所示,体外STAT5信号传导测定表明嵌合B2抗体表现地类似于源自大肠杆菌的IL2单体(R&D systems和Millipore Sigma)。
实施例8通过扩增NK-92细胞评估嵌合融合B2抗体的活性。
如实施例5所述产生的嵌合B2分子的活性通过其扩增NK-92自然杀伤细胞的能力来评估。NK-92细胞表达IL2Rα、IL15Rα、IL2/15Rβ和γc亚基,并且其生长和增殖依赖于外源性添加IL2或IL15以结合和激活受体。
将NK-92细胞维持在提供有200U/ml IL2的生长培养基中。在扩增测定之前,将NK-92细胞用不含IL2的生长培养基洗涤两次,以去除任何残留的细胞结合的IL2,并且在组织培养处理的96孔板中每孔接种10,000个细胞。将这些细胞与2倍连续稀释(从1.33nM至0.005nM)的IL2单体(R&D Systems)或者嵌合B2抗体在37℃、5%CO2下一起孵育48小时。对于嵌合B2抗体,与IL2单体相比,仅使用半摩尔浓度。通过在代谢活性氧化还原酶(MTT测定试剂盒,Promega)的存在下将四唑鎓染料MTT还原为其不溶性甲臜来评估每孔的最终NK92细胞数量。
如图12所示,在NK-92细胞扩增中嵌合B2抗体几乎比IL2单体好两倍。
实施例9嵌合B15融合抗体在人PBMC中的体外活性的评估。
如实施例1所述产生的嵌合B15分子的活性通过其在体外刺激人PBMC中的NK细胞和T细胞的能力来评估。NK细胞和T细胞均表达IL15Rα、IL2/15Rβ和γc亚基,并且其生长和增殖依赖于内源性或外源性IL15结合和激活受体。
将人PBMC在PBS中洗涤两次,使用血细胞计数器计数并且重悬于含10%FBS的RPMI1640培养基中。将100μl中的100,000个细胞每孔接种在组织培养处理的96孔平底或U形底(促进细胞接触)板中。将B15和B15_Rαsushi进行在相同的培养基中从500nM至0.032nM的5倍连续稀释,并且将100μl的每种稀释液添加到相应的细胞中以达到从250nM至0.016nM的最终浓度。还设置了没有添加任何B15或B15_Rαsushi的对照。将细胞在37℃、5%CO2下孵育96小时。处理后,将PBMC用抗CD3-FITC(SK7)、抗CD4-PE(OKT4)、抗CD8a-eFluor 450(SK1)和抗CD56-APC(AF12-7H3)染色以对以下细胞类型进行门控:CD3+CD4+T细胞、CD3+CD8+T细胞和NK细胞(CD3-CD56+)。按照制造商的方案,使用抗Ki67-PE-Cy7(20Raj1)和Foxp3/转录因子染色缓冲液组(Thermo Fisher Scientific)对作为细胞增殖标记物的细胞内Ki67进行染色。随后使用Novocyte Advanteon流式细胞仪(Agilent,加利福尼亚州圣克拉拉)分析染色样品。
如图13所示,B15和B15_15Rα均在体外诱导CD8+T细胞和NK细胞的有效力的增殖并且在小得多的程度上诱导CD4+T细胞。增殖与所使用的不同类型的96孔板无关(平底与U形底),这表明增殖仅由B15或B15_15Rα诱导,并且细胞间接触的影响最小。在这些实验中,B15_15Rα在较低浓度下在诱导T细胞和NK细胞增殖方面的表现略好于B15,表明IL15Rα在低浓度下可以增强IL15的功能。B15和B15_15Rα诱导的NK细胞增殖在0.4nM时达到平台,而CD8+T细胞的增殖在10nM时达到平台,表明B15和B15_15Rα对NK细胞的亲和力高于CD8+T细胞。
本发明在范围上不旨在限于具体公开的实施方案,提供具体公开的实施方案例如是为了说明本发明的各个方面。根据本文的描述和传授,对所述组合物和方法的各种修改将变得清楚。可以在不背离本公开文本的真实范围和精神的情况下实践此类变化,并且此类变化旨在落入本公开文本的范围内。
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<110> 米诺陶治疗公司
<120> 经细胞因子修饰的嵌合抗体及其使用方法
<130> 165772000140
<150> 62/925,740
<151> 2019-10-24
<160> 180
<170> PatentIn 3.5版
<210> 1
<211> 114
<212> PRT
<213> 智人(Homo sapiens)
<220>
<221> 尚未归类的特征
<223> IL-15
<400> 1
Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile
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Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln
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Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu
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Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val
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Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile
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Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn
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Thr Ser
<210> 2
<211> 77
<212> PRT
<213> 人工序列
<220>
<223> IL15-Rαsushi
<400> 2
Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val
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Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly
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Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro
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<210> 3
<211> 912
<212> DNA
<213> 人工序列
<220>
<223> IL-15 Rαsushi_GS接头_BLV1H12轻链
<400> 3
atcacctgcc cacctccaat gagcgtggag cacgcagaca tctgggtgaa gtcttacagc 60
ctgtattccc gggagagata catctgcaac tctggcttca agcggaaggc cggcaccagc 120
tccctgacag agtgcgtgct gaacaaggcc accaatgtgg cccactggac aactccttcc 180
ctgaaatgta ttagagaccc cgccctggtg catcagagac ctgccccccc tggtggaggc 240
ggttcaggcg gaggtggatc ccaggccgtc ctgaaccagc caagcagcgt ctccgggtct 300
ctggggcagc gggtctcaat cacctgtagc gggtcttcct ccaatgtcgg caacggctac 360
gtgtcttggt atcagctgat ccctggcagt gccccacgaa ccctgatcta cggcgacaca 420
tccagagctt ctggggtccc cgatcggttc tcagggagca gatccggaaa cacagctact 480
ctgaccatca gctccctgca ggctgaggac gaagcagatt atttctgcgc atctgccgag 540
gactctagtt caaatgccgt gtttggaagc ggcaccacac tgacagtcct aggtcagccc 600
aaggctgccc cctcggtcac tctgttcccg ccctcctctg aggagcttca agccaacaag 660
gccacactgg tgtgtctcat aagtgacttc tacccgggag ccgtgacagt ggcctggaag 720
gcagatagca gccccgtcaa ggcgggagtg gagaccacca caccctccaa acaaagcaac 780
aacaagtacg cggccagcag ctatctgagc ctgacgcctg agcagtggaa gtcccacaga 840
agctacagct gccaggtcac gcatgaaggg agcaccgtgg agaagacagt ggcccctaca 900
gaatgttcat aa 912
<210> 4
<211> 524
<212> PRT
<213> 人工序列
<220>
<223> IL2受体亚基β
<400> 4
Val Asn Gly Thr Ser Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala Asn
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Ile Ser Cys Val Trp Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser Cys
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Gln Val His Ala Trp Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys Glu
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Leu Leu Pro Val Ser Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu Gly
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Ala Pro Asp Ser Gln Lys Leu Thr Thr Val Asp Ile Val Thr Leu Arg
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Val Leu Cys Arg Glu Gly Val Arg Trp Arg Val Met Ala Ile Gln Asp
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Val Val His Val Glu Thr His Arg Cys Asn Ile Ser Trp Glu Ile Ser
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Gln Ala Ser His Tyr Phe Glu Arg His Leu Glu Phe Glu Ala Arg Thr
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Leu Ser Pro Gly His Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu Lys
145 150 155 160
Gln Lys Gln Glu Trp Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr Gln
165 170 175
Tyr Glu Phe Gln Val Arg Val Lys Pro Leu Gln Gly Glu Phe Thr Thr
180 185 190
Trp Ser Pro Trp Ser Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala Ala
195 200 205
Leu Gly Lys Asp Thr Ile Pro Trp Leu Gly His Leu Leu Val Gly Leu
210 215 220
Ser Gly Ala Phe Gly Phe Ile Ile Leu Val Tyr Leu Leu Ile Asn Cys
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Arg Asn Thr Gly Pro Trp Leu Lys Lys Val Leu Lys Cys Asn Thr Pro
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Asp Pro Ser Lys Phe Phe Ser Gln Leu Ser Ser Glu His Gly Gly Asp
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Val Gln Lys Trp Leu Ser Ser Pro Phe Pro Ser Ser Ser Phe Ser Pro
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Gly Gly Leu Ala Pro Glu Ile Ser Pro Leu Glu Val Leu Glu Arg Asp
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Lys Val Thr Gln Leu Leu Leu Gln Gln Asp Lys Val Pro Glu Pro Ala
305 310 315 320
Ser Leu Ser Ser Asn His Ser Leu Thr Ser Cys Phe Thr Asn Gln Gly
325 330 335
Tyr Phe Phe Phe His Leu Pro Asp Ala Leu Glu Ile Glu Ala Cys Gln
340 345 350
Val Tyr Phe Thr Tyr Asp Pro Tyr Ser Glu Glu Asp Pro Asp Glu Gly
355 360 365
Val Ala Gly Ala Pro Thr Gly Ser Ser Pro Gln Pro Leu Gln Pro Leu
370 375 380
Ser Gly Glu Asp Asp Ala Tyr Cys Thr Phe Pro Ser Arg Asp Asp Leu
385 390 395 400
Leu Leu Phe Ser Pro Ser Leu Leu Gly Gly Pro Ser Pro Pro Ser Thr
405 410 415
Ala Pro Gly Gly Ser Gly Ala Gly Glu Glu Arg Met Pro Pro Ser Leu
420 425 430
Gln Glu Arg Val Pro Arg Asp Trp Asp Pro Gln Pro Leu Gly Pro Pro
435 440 445
Thr Pro Gly Val Pro Asp Leu Val Asp Phe Gln Pro Pro Pro Glu Leu
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Val Leu Arg Glu Ala Gly Glu Glu Val Pro Asp Ala Gly Pro Arg Glu
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Gly Val Ser Phe Pro Trp Ser Arg Pro Pro Gly Gln Gly Glu Phe Arg
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Ala Leu Asn Ala Arg Leu Pro Leu Asn Thr Asp Ala Tyr Leu Ser Leu
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Gln Glu Leu Gln Gly Gln Asp Pro Thr His Leu Val
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<210> 5
<211> 513
<212> DNA
<213> 人工序列
<220>
<223> BLV1H 12重链
<400> 5
caggtccagc tgagagagag cggcccttca ctggtcaagc catcccagac actgagcctg 60
acatgcacag caagcgggtt ttcactgagc gacaaggcag tgggatgggt ccgacaggca 120
ccaggaaaag ccctggaatg gctgggcagc atcgataccg gcgggaacac agggtacaat 180
cccggactga agagcagact gtccattacc aaggacaact ctaaaagtca ggtgtcactg 240
agcgtgagct ccgtcaccac agaggatagt gcaacttact attgcacctc tgtgcaccag 300
gaaactaaga aataccagag ctgtcctgac ggctatcggg agagatctga ttgcagtaat 360
aggccagctt gtggcacatc cgactgctgt cgcgtgtctg tcttcgggaa ctgcctgact 420
accctgcctg tgtcctactc ttatacctac aattatgaat ggcatgtgga tgtctgggga 480
cagggcctgc tggtgacagt ctctagtgct agc 513
<210> 6
<211> 1557
<212> DNA
<213> 人工序列
<220>
<223> (信号序列 - V区 - CH1CH2CH3) 基于人IgG的BLV1H12 V
<400> 6
atgggatggt catgtatcat cctttttcta gtagcaactg caaccggtgt acattcccag 60
gtgcagctgc gggagtcggg ccccagcctg atgaagccgt cacagaccct ctccctcacc 120
tgcacggtct ctggatcttc attgaacgac aagtctgtag gctgggtccg ccaggctcca 180
gggaaggcgc tgcagtggct cggtagtgtg gacactagtg gaaacacaga ctataaccca 240
ggcctgaaat cccggctcag catcaccaag gacaactcca agagccgaat ctctcttaca 300
gtgactggca tgacaactga agactcggcc acatactact gtacttctgt gcaccaggaa 360
acaaaaaaat accaaagttg tccggaggat tatacttata atccacgttg ccctcagcag 420
tatggttgga gtgactgtga ttgtatgggc gataggtttg ggggttactg tcgacaggat 480
ggttgtagta attatagtta tacttacaat tacgaatggc acgtcgatgt ctggggccaa 540
ggactcctgg tcaccgtctc ctcagctagc accaagggcc catcggtctt ccccctggca 600
ccctcctcca agagcacctc tgggggcaca gcggccctgg gctgcctggt caaggactac 660
ttccccgaac ctgtgacggt ctcgtggaac tcaggcgccc tgaccagcgg cgtgcacacc 720
ttcccggctg tcctacagtc ctcaggactc tactccctca gcagcgtggt gaccgtgccc 780
tccagcagct tgggcaccca gacctacatc tgcaacgtga atcacaagcc cagcaacacc 840
aaggtggaca agagagttga gcccaaatct tgtgacaaaa ctcacacatg cccaccgtgc 900
ccagcacctg aactcctggg gggaccgtca gtcttcctct tccccccaaa acccaaggac 960
accctcatga tctcccggac ccctgaggtc acatgcgtgg tggtggacgt gagccacgaa 1020
gaccctgagg tcaagttcaa ctggtacgtg gacggcgtgg aggtgcataa tgccaagaca 1080
aagccgcggg aggagcagta caacagcacg taccgtgtgg tcagcgtcct caccgtcctg 1140
caccaggact ggctgaatgg caaggagtac aagtgcaagg tctccaacaa agccctccca 1200
gcccccatcg agaaaaccat ctccaaagcc aaagggcagc cccgagaacc acaggtgtac 1260
accctgcccc catcccggga ggagatgacc aagaaccagg tcagcctgac ctgcctggtc 1320
aaaggcttct atcccagcga catcgccgtg gagtgggaga gcaatgggca gccggagaac 1380
aactacaaga ccacgcctcc cgtgctggac tccgacggct ccttcttcct ctatagcaag 1440
ctcaccgtgg acaagagcag gtggcagcag gggaacgtct tctcatgctc cgtgatgcat 1500
gaggctctgc acaaccacta cacgcagaag agcctctccc tgtccccggg taaatga 1557
<210> 7
<211> 823
<212> DNA
<213> 人工序列
<220>
<223> B15可变区+信号肽
<400> 7
gaattccacc atgggatggt catgtatcat cctttttcta gtagcaactg caaccggagt 60
acattcccag gtgcagctgc gcgagtcggg ccccagcctg gtgaagccgt cacagaccct 120
ctcgctcacc tgcacggcct ctggattctc attgagcgac aaggctgtag gctgggtccg 180
ccaggctcca gggaaggcgc tggagtggct cggtagtata gacactggtg gaaacacagg 240
ctataaccca ggcctgaaat cccggctcag catcaccaag gacaactcca agagtcaagt 300
ctctctgtca gtgagcagcg tgacaactga ggactcggcc acatactact gtacttctgt 360
gcaccaggaa acaaaaaaat accaaaccgg tggatcaaac tgggtgaatg taataagtga 420
tttgaaaaaa attgaagatc ttattcaatc tatgcatatt gatgctactt tatatacgga 480
aagtgatgtt caccccagtt gcaaagtaac agcaatgaag tgctttctct tggagttaca 540
agttatttca cttgagtccg gagatgcaag tattcatgat acagtagaaa atctgatcat 600
cctagcaaac aacagtttgt cttctaatgg gaatgtaaca gaatctggat gcaaagaatg 660
tgaggaactg gaggaaaaaa atattaaaga atttttgcag agttttgtac atattgtcca 720
aatgttcatc aacacttctg gttcaggatc ctatacttac aattacgaat ggcacgtcga 780
tgtctggggc caaggactcc tggtcaccgt ctcctcagct agc 823
<210> 8
<211> 672
<212> DNA
<213> 人工序列
<220>
<223> BLV1H12轻链
<400> 8
tcacgaattc gcaggccgtc ctgaaccagc caagcagcgt ctccgggtct ctggggcagc 60
gggtctcaat cacctgtagc gggtcttcct ccaatgtcgg caacggctac gtgtcttggt 120
atcagctgat ccctggcagt gccccacgaa ccctgatcta cggcgacaca tccagagctt 180
ctggggtccc cgatcggttc tcagggagca gatccggaaa cacagctact ctgaccatca 240
gctccctgca ggctgaggac gaagcagatt atttctgcgc atctgccgag gactctagtt 300
caaatgccgt gtttggaagc ggcaccacac tgacagtcct ggggcagccc aagagtcccc 360
cttcagtgac tctgttccca ccctctaccg aggaactgaa cggaaacaag gccacactgg 420
tgtgtctgat cagcgacttt taccctggat ccgtcactgt ggtctggaag gcagatggca 480
gcacaattac taggaacgtg gaaactaccc gcgcctccaa gcagtctaat agtaaatacg 540
ccgccagctc ctatctgagc ctgacctcta gtgattggaa gtccaaaggg tcatatagct 600
gcgaagtgac ccatgaaggc tcaaccgtga ctaagactgt gaaaccatcc gagtgctcct 660
aggctagctg gc 672
<210> 9
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> BLV1H 12升茎区
<400> 9
Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser
1 5 10
<210> 10
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> BLV1H 12降茎区
<400> 10
Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val
1 5 10
<210> 11
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> V2替代序列
<400> 11
Trp Gly Gln Gly Leu Leu Val Thr Val Ser Ser
1 5 10
<210> 12
<211> 95
<212> PRT
<213> 人工序列
<220>
<223> VH4-34_Q5RQ6E的V1替代B序列
<400> 12
Gln Val Gln Leu Arg Glu Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
<210> 13
<211> 95
<212> PRT
<213> 人工序列
<220>
<223> VH4-34_CDR1-G31DY32K_Q5RQ6E的V1替代B序列
<400> 13
Gln Val Gln Leu Arg Glu Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Lys
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
<210> 14
<211> 95
<212> PRT
<213> 人工序列
<220>
<223> VH4-34_CDR2-E50S_Q5RQ6E的V1替代B序列
<400> 14
Gln Val Gln Leu Arg Glu Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ser Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
<210> 15
<211> 95
<212> PRT
<213> 人工序列
<220>
<223> 合成:VH4-34_CDR1-G31DY32K_CDR2-E50S_Q5RQ6E
的V1替代B序列
<400> 15
Gln Val Gln Leu Arg Glu Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Asp Lys
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ser Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
<210> 16
<211> 95
<212> PRT
<213> 人工序列
<220>
<223> 合成:VH4-34_CDR1-奶牛_Q5RQ6E的V1替代B序列
<400> 16
Gln Val Gln Leu Arg Glu Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys
20 25 30
Ala Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
<210> 17
<211> 95
<212> PRT
<213> 人工序列
<220>
<223> 合成:VH4-34_CDR2-奶牛_Q5RQ6E的V1替代B序列
<400> 17
Gln Val Gln Leu Arg Glu Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Leu Gly Ser Ile Asp
20 25 30
Thr Gly Gly Asn Thr Gly Ser Phe Ser Gly Tyr Tyr Trp Ser Trp Ile
35 40 45
Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
<210> 18
<211> 95
<212> PRT
<213> 人工序列
<220>
<223> 合成:VH4-34_CDR1-奶牛_CDR2-E50S_Q5RQ6E
的V1替代B序列
<400> 18
Gln Val Gln Leu Arg Glu Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys
20 25 30
Ala Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Ser Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
<210> 19
<211> 95
<212> PRT
<213> 人工序列
<220>
<223> 合成:VH4-34_CDR1-奶牛_CDR2-奶牛_Q5RQ6E
的V1替代N序列
<400> 19
Gln Val Gln Leu Arg Glu Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys
20 25 30
Ala Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
<210> 20
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> V2替代序列
<400> 20
Trp Gly His Gly Thr Ala Val Thr Val Ser Ser
1 5 10
<210> 21
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> V2替代序列
<400> 21
Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 22
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> V2替代序列
<400> 22
Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 23
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> V2替代序列
<400> 23
Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 24
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> V2替代序列
<400> 24
Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 25
<211> 61
<212> PRT
<213> 人工序列
<220>
<223> 合成:超长CDR3序列(BLV1H12)
<400> 25
Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Cys Pro Asp Gly Tyr
1 5 10 15
Arg Glu Arg Ser Asp Cys Ser Asn Arg Pro Ala Cys Gly Thr Ser Asp
20 25 30
Cys Cys Arg Val Ser Val Phe Gly Asn Cys Leu Thr Thr Leu Pro Val
35 40 45
Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp
50 55 60
<210> 26
<211> 274
<212> PRT
<213> 人工序列
<220>
<223> BLV1H12重链
<400> 26
Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys
20 25 30
Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Ser Ile Asp Thr Gly Gly Asn Thr Gly Tyr Asn Pro Gly Leu Lys
50 55 60
Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr
85 90 95
Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Cys Pro Asp Gly Tyr
100 105 110
Arg Glu Arg Ser Asp Cys Ser Asn Arg Pro Ala Cys Gly Thr Ser Asp
115 120 125
Cys Cys Arg Val Ser Val Phe Gly Asn Cys Leu Thr Thr Leu Pro Val
130 135 140
Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp Gly
145 150 155 160
Gln Gly Leu Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Lys
165 170 175
Val Tyr Pro Leu Ser Ser Cys Cys Gly Asp Lys Ser Ser Ser Thr Val
180 185 190
Thr Leu Gly Cys Leu Val Ser Ser Tyr Met Pro Glu Pro Val Thr Val
195 200 205
Thr Trp Asn Ser Gly Ala Leu Lys Ser Gly Val His Thr Phe Pro Ala
210 215 220
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val
225 230 235 240
Pro Gly Ser Thr Ser Gly Gln Thr Phe Thr Cys Asn Val Ala His Pro
245 250 255
Ala Ser Ser Thr Lys Val Asp Lys Ala Val Glu Pro Lys Ser Cys Asp
260 265 270
Gly Ser
<210> 27
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> BLV1H12轻链
<400> 27
Gln Ala Val Leu Asn Gln Pro Ser Ser Val Ser Gly Ser Leu Gly Gln
1 5 10 15
Arg Val Ser Ile Thr Cys Ser Gly Ser Ser Ser Asn Val Gly Asn Gly
20 25 30
Tyr Val Ser Trp Tyr Gln Leu Ile Pro Gly Ser Ala Pro Arg Thr Leu
35 40 45
Ile Tyr Gly Asp Thr Ser Arg Ala Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Arg Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ala Ser Ala Glu Asp Ser Ser
85 90 95
Ser Asn Ala Val Phe Gly Ser Gly Thr Thr Leu Thr Val Leu Gly Gln
100 105 110
Pro Lys Ser Pro Pro Ser Val Thr Leu Phe Pro Pro Ser Thr Glu Glu
115 120 125
Leu Asn Gly Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ser Val Thr Val Val Trp Lys Ala Asp Gly Ser Thr Ile Thr
145 150 155 160
Arg Asn Val Glu Thr Thr Arg Ala Ser Lys Gln Ser Asn Ser Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Ser Ser Asp Trp Lys Ser Lys
180 185 190
Gly Ser Tyr Ser Cys Glu Val Thr His Glu Gly Ser Thr Val Thr Lys
195 200 205
Thr Val Lys Pro Ser Glu Cys Ser
210 215
<210> 28
<211> 269
<212> PRT
<213> 人工序列
<220>
<223> BLV5B8重链
<400> 28
Gln Val Gln Leu Arg Glu Ser Gly Pro Ser Leu Val Gln Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Asp Lys
20 25 30
Ala Val Gly Trp Val Arg Gln Ala Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Ser Ile Asp Thr Gly Gly Ser Thr Gly Tyr Asn Pro Gly Leu Lys
50 55 60
Ser Arg Leu Ser Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Ser Val Ser Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Thr
85 90 95
Thr Val His Gln Glu Thr Arg Lys Thr Cys Ser Asp Gly Tyr Ile Ala
100 105 110
Val Asp Ser Cys Gly Arg Gly Gln Ser Asp Gly Cys Val Asn Asp Cys
115 120 125
Asn Ser Cys Tyr Tyr Gly Trp Arg Asn Cys Arg Arg Gln Pro Ala Ile
130 135 140
His Ser Tyr Glu Phe His Val Asp Ala Trp Gly Arg Gly Leu Leu Val
145 150 155 160
Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Lys Val Tyr Pro Leu Ser
165 170 175
Ser Cys Cys Gly Asp Lys Ser Ser Ser Thr Val Thr Leu Gly Cys Leu
180 185 190
Val Ser Ser Tyr Met Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly
195 200 205
Ala Leu Lys Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
210 215 220
Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val Pro Gly Ser Thr Ser
225 230 235 240
Gly Gln Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys
245 250 255
Val Asp Lys Ala Val Glu Pro Lys Ser Cys Asp Gly Ser
260 265
<210> 29
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> BLV5B8轻链
<400> 29
Gln Ala Val Leu Asn Gln Pro Ser Ser Val Ser Gly Ser Leu Gly Gln
1 5 10 15
Arg Val Ser Ile Thr Cys Ser Gly Ser Ser Ser Asn Val Gly Asn Gly
20 25 30
Tyr Val Ser Trp Tyr Gln Leu Ile Pro Gly Ser Ala Pro Arg Thr Leu
35 40 45
Ile Tyr Gly Asp Thr Ser Arg Ala Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Arg Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Ala Glu Asp Glu Ala Asp Tyr Phe Cys Ala Ser Ala Glu Asp Ser Ser
85 90 95
Ser Asn Ala Val Phe Gly Ser Gly Thr Thr Leu Thr Val Leu Gly Gln
100 105 110
Pro Lys Ser Pro Pro Ser Val Thr Leu Phe Pro Pro Ser Thr Glu Glu
115 120 125
Leu Asn Gly Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ser Val Thr Val Val Trp Lys Ala Asp Gly Ser Thr Ile Thr
145 150 155 160
Arg Asn Val Glu Thr Thr Arg Ala Ser Lys Gln Ser Asn Ser Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Ser Ser Asp Trp Lys Ser Lys
180 185 190
Gly Ser Tyr Ser Cys Glu Val Thr His Glu Gly Ser Thr Val Thr Lys
195 200 205
Thr Val Lys Pro Ser Glu Cys Ser
210 215
<210> 30
<211> 56
<212> PRT
<213> 人工序列
<220>
<223> BLV5B8 CDR3
<400> 30
Thr Val His Gln Glu Thr Arg Lys Thr Cys Ser Asp Gly Tyr Ile Ala
1 5 10 15
Val Asp Ser Cys Gly Arg Gly Gln Ser Asp Gly Cys Val Asn Asp Cys
20 25 30
Asn Ser Cys Tyr Tyr Gly Trp Arg Asn Cys Arg Arg Gln Pro Ala Ile
35 40 45
His Ser Tyr Glu Phe His Val Asp
50 55
<210> 31
<211> 57
<212> PRT
<213> 人工序列
<220>
<223> BLV5D3 CDR3
<400> 31
Ser Val Thr Gln Arg Thr His Val Ser Arg Ser Cys Pro Asp Gly Cys
1 5 10 15
Ser Asp Gly Asp Gly Cys Val Asp Gly Cys Cys Cys Ser Ala Tyr Arg
20 25 30
Cys Tyr Thr Pro Gly Val Arg Asp Leu Ser Cys Thr Ser Tyr Ser Ile
35 40 45
Thr Tyr Thr Tyr Glu Trp Asn Val Asp
50 55
<210> 32
<211> 58
<212> PRT
<213> 人工序列
<220>
<223> BLV8C11 CDR3
<400> 32
Thr Val His Gln Lys Thr Thr Arg Lys Thr Cys Cys Ser Asp Ala Tyr
1 5 10 15
Arg Tyr Asp Ser Gly Cys Gly Ser Gly Cys Asp Cys Cys Gly Ala Asp
20 25 30
Cys Tyr Val Phe Gly Ala Cys Thr Phe Gly Leu Asp Ser Ser Tyr Ser
35 40 45
Tyr Ile Tyr Ile Tyr Gln Trp Tyr Val Asp
50 55
<210> 33
<211> 56
<212> PRT
<213> 人工序列
<220>
<223> BF4E9 CDR3
<400> 33
Thr Val His Gln Ile Phe Cys Pro Asp Gly Tyr Ser Tyr Gly Tyr Gly
1 5 10 15
Cys Gly Tyr Gly Tyr Gly Cys Ser Gly Tyr Asp Cys Tyr Gly Tyr Gly
20 25 30
Gly Tyr Gly Tyr Gly Gly Tyr Gly Gly Tyr Ser Ser Tyr Ser Tyr Ser
35 40 45
Tyr Ser Tyr Glu Tyr Tyr Gly Asp
50 55
<210> 34
<211> 48
<212> PRT
<213> 人工序列
<220>
<223> BF1H1 CDR3
<400> 34
Thr Val His Pro Ser Pro Asp Gly Tyr Ser Tyr Gly Tyr Gly Cys Gly
1 5 10 15
Tyr Gly Tyr Gly Cys Ser Gly Tyr Asp Cys Tyr Gly Tyr Gly Gly Tyr
20 25 30
Gly Tyr Gly Gly Tyr Gly Gly Tyr Ser Ser Tyr Ser Tyr Ser Tyr Ser
35 40 45
<210> 35
<211> 48
<212> PRT
<213> 人工序列
<220>
<223> F18 CDR3
<400> 35
Thr Val His Gln Ile Arg Cys Pro Asp Gly Tyr Gly Tyr Gly Tyr Gly
1 5 10 15
Cys Gly Tyr Gly Ser Tyr Gly Tyr Ser Gly Tyr Asp Cys Tyr Gly Tyr
20 25 30
Gly Gly Tyr Gly Gly Tyr Gly Gly Tyr Gly Gly Tyr Ser Ser Tyr Ser
35 40 45
<210> 36
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 36
Thr Thr Val His Gln
1 5
<210> 37
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 37
Thr Ser Val His Gln
1 5
<210> 38
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 38
Ser Ser Val Thr Gln
1 5
<210> 39
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 39
Ser Thr Val His Gln
1 5
<210> 40
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 40
Ala Thr Val Arg Gln
1 5
<210> 41
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 41
Thr Thr Val Tyr Gln
1 5
<210> 42
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 42
Ser Pro Val His Gln
1 5
<210> 43
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 43
Ala Thr Val Tyr Gln
1 5
<210> 44
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 44
Ala Ser Cys Glu Asn Asp Ile Asn Gly Ser Thr Ala Leu Lys Ser Thr
1 5 10 15
Arg Ala Asn Asp
20
<210> 45
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 45
Thr Asn Val His Gln
1 5
<210> 46
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 46
Ala Thr Val His Gln
1 5
<210> 47
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 47
Ser Thr Val Tyr Gln
1 5
<210> 48
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 48
Thr Ile Val His Gln
1 5
<210> 49
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 49
Ala Ile Val Tyr Gln
1 5
<210> 50
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 50
Thr Thr Val Phe Gln
1 5
<210> 51
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 51
Ala Ala Val Phe Gln
1 5
<210> 52
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 52
Gly Thr Val His Gln
1 5
<210> 53
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 53
Ala Ser Val His Gln
1 5
<210> 54
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 54
Thr Ala Val Phe Gln
1 5
<210> 55
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 55
Ala Thr Val Phe Gln
1 5
<210> 56
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 56
Ala Ala Ala His Gln
1 5
<210> 57
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 57
Val Trp Tyr Gln
1
<210> 58
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 58
Gly Thr Val Phe Gln
1 5
<210> 59
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 59
Thr Ala Val His Gln
1 5
<210> 60
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 60
Ile Thr Val His Gln
1 5
<210> 61
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 61
Ile Thr Ala His Gln
1 5
<210> 62
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 62
Val Thr Val His Gln
1 5
<210> 63
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 63
Ala Ala Val His Gln
1 5
<210> 64
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 64
Gly Thr Val Tyr Gln
1 5
<210> 65
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 65
Thr Thr Val Leu Gln
1 5
<210> 66
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 66
Thr Thr Thr His Gln
1 5
<210> 67
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 67
Thr Thr Asp Tyr Gln
1 5
<210> 68
<211> 99
<212> PRT
<213> 人工序列
<220>
<223> 人重链可变区序列VH4-39
<400> 68
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg
<210> 69
<211> 96
<212> PRT
<213> 人工序列
<220>
<223> 人重链可变区序列4-59*03
<400> 69
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
<210> 70
<211> 97
<212> PRT
<213> 人工序列
<220>
<223> 人重链可变区序列4-34*02
<400> 70
Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg
<210> 71
<211> 97
<212> PRT
<213> 人工序列
<220>
<223> 人重链可变区序列4-34*09
<400> 71
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg
<210> 72
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 72
Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln
1 5 10
<210> 73
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 73
Val His Gln Glu Thr Lys Lys Tyr Gln
1 5
<210> 74
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 74
Ile His Ser Tyr Glu Phe
1 5
<210> 75
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 75
Ser Tyr Glu Phe
1
<210> 76
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 76
Tyr Thr Tyr Asn Tyr Glu
1 5
<210> 77
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 77
Tyr Thr Tyr Asn Tyr Glu Trp
1 5
<210> 78
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 78
Ser Tyr Thr Tyr Asn Tyr Glu Trp
1 5
<210> 79
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 79
Thr Tyr Asn Tyr Glu Trp
1 5
<210> 80
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 80
Ser Tyr Thr Tyr
1
<210> 81
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 81
Gly Ser Lys His Arg Leu Arg Asp Tyr Phe Leu Tyr Asn Glu
1 5 10
<210> 82
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 82
Gly Ser Lys His Arg Leu Arg Asp Tyr Phe Leu Tyr Asn
1 5 10
<210> 83
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 83
Gly Ser Lys His Arg Leu Arg Asp Tyr Phe Leu Tyr
1 5 10
<210> 84
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 84
Gly Ser Lys His Arg Leu Arg Asp Tyr Phe Leu
1 5 10
<210> 85
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 85
Gly Ser Lys His Arg Leu Arg Asp Tyr Phe
1 5 10
<210> 86
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 86
Gly Ser Lys His Arg Leu Arg Asp Tyr
1 5
<210> 87
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 87
Gly Ser Lys His Arg Leu Arg Asp
1 5
<210> 88
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 88
Glu Ala Gly Gly Pro Asp Tyr Arg Asn Gly Tyr Asn Tyr
1 5 10
<210> 89
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 89
Glu Ala Gly Gly Pro Asp Tyr Arg Asn Gly Tyr Asn
1 5 10
<210> 90
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 90
Glu Ala Gly Gly Pro Asp Tyr Arg Asn Gly Tyr
1 5 10
<210> 91
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 91
Glu Ala Gly Gly Pro Asp Tyr Arg Asn Gly
1 5 10
<210> 92
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 92
Glu Ala Gly Gly Pro Asp Tyr Arg Asn
1 5
<210> 93
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 93
Glu Ala Gly Gly Pro Asp Tyr Arg
1 5
<210> 94
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 94
Glu Ala Gly Gly Pro Asp Tyr
1 5
<210> 95
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 95
Glu Ala Gly Gly Pro Asp
1 5
<210> 96
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 96
Glu Ala Gly Gly Pro Ile Trp His Asp Asp Val Lys Tyr
1 5 10
<210> 97
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 97
Glu Ala Gly Gly Pro Ile Trp His Asp Asp Val Lys
1 5 10
<210> 98
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 98
Glu Ala Gly Gly Pro Ile Trp His Asp Asp Val
1 5 10
<210> 99
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 99
Glu Ala Gly Gly Pro Ile Trp His Asp Asp
1 5 10
<210> 100
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 100
Glu Ala Gly Gly Pro Ile Trp His Asp
1 5
<210> 101
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 101
Glu Ala Gly Gly Pro Ile Trp His
1 5
<210> 102
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 102
Glu Ala Gly Gly Pro Ile Trp
1 5
<210> 103
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 103
Glu Ala Gly Gly Pro Ile
1 5
<210> 104
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 104
Gly Thr Asp Tyr Thr Ile Asp Asp Gln Gly Ile
1 5 10
<210> 105
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 105
Gly Thr Asp Tyr Thr Ile Asp Asp Gln Gly
1 5 10
<210> 106
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 106
Gly Thr Asp Tyr Thr Ile Asp Asp Gln
1 5
<210> 107
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 107
Gly Thr Asp Tyr Thr Ile Asp Asp
1 5
<210> 108
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 108
Gly Thr Asp Tyr Thr Ile Asp
1 5
<210> 109
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 109
Gly Thr Asp Tyr Thr Ile
1 5
<210> 110
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 110
Asp Lys Gly Asp Ser Asp Tyr Asp Tyr Asn Leu
1 5 10
<210> 111
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 111
Asp Lys Gly Asp Ser Asp Tyr Asp Tyr Asn
1 5 10
<210> 112
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 112
Asp Lys Gly Asp Ser Asp Tyr Asp Tyr
1 5
<210> 113
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 113
Asp Lys Gly Asp Ser Asp Tyr Asp
1 5
<210> 114
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 114
Asp Lys Gly Asp Ser Asp Tyr
1 5
<210> 115
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 115
Asp Lys Gly Asp Ser Asp
1 5
<210> 116
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 116
Tyr Gly Pro Asn Tyr Glu Glu Trp Gly Asp Tyr Leu Ala Thr Leu Asp
1 5 10 15
Val
<210> 117
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 117
Gly Pro Asn Tyr Glu Glu Trp Gly Asp Tyr Leu Ala Thr Leu Asp Val
1 5 10 15
<210> 118
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 118
Pro Asn Tyr Glu Glu Trp Gly Asp Tyr Leu Ala Thr Leu Asp Val
1 5 10 15
<210> 119
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 119
Asn Tyr Glu Glu Trp Gly Asp Tyr Leu Ala Thr Leu Asp Val
1 5 10
<210> 120
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 120
Tyr Glu Glu Trp Gly Asp Tyr Leu Ala Thr Leu Asp Val
1 5 10
<210> 121
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 升茎链
<400> 121
Glu Glu Trp Gly Asp Tyr Leu Ala Thr Leu Asp Val
1 5 10
<210> 122
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 122
Tyr Asp Phe Tyr Asp Gly Tyr Tyr Asn Tyr His Tyr Met Asp Val
1 5 10 15
<210> 123
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 123
Asp Phe Tyr Asp Gly Tyr Tyr Asn Tyr His Tyr Met Asp Val
1 5 10
<210> 124
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 124
Phe Tyr Asp Gly Tyr Tyr Asn Tyr His Tyr Met Asp Val
1 5 10
<210> 125
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 125
Tyr Asp Gly Tyr Tyr Asn Tyr His Tyr Met Asp Val
1 5 10
<210> 126
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 126
Asp Gly Tyr Tyr Asn Tyr His Tyr Met Asp Val
1 5 10
<210> 127
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 127
Gly Tyr Tyr Asn Tyr His Tyr Met Asp Val
1 5 10
<210> 128
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 128
Tyr Tyr Asn Tyr His Tyr Met Asp Val
1 5
<210> 129
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 129
Tyr Asp Phe Asn Asp Gly Tyr Tyr Asn Tyr His Tyr Met Asp Val
1 5 10 15
<210> 130
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 130
Asp Phe Tyr Asp Gly Tyr Tyr Asn Tyr His Tyr Met Asp Val
1 5 10
<210> 131
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 131
Phe Tyr Asp Gly Tyr Tyr Asn Tyr His Tyr Met Asp Val
1 5 10
<210> 132
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 132
Tyr Asp Gly Tyr Tyr Asn Tyr His Tyr Met Asp Val
1 5 10
<210> 133
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 133
Asp Gly Tyr Tyr Asn Tyr His Tyr Met Asp Val
1 5 10
<210> 134
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 134
Gly Tyr Tyr Asn Tyr His Tyr Met Asp Val
1 5 10
<210> 135
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 135
Gln Gly Ile Arg Tyr Gln Gly Ser Gly Thr Phe Trp Tyr Phe Asp Val
1 5 10 15
<210> 136
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 136
Gly Ile Arg Tyr Gln Gly Ser Gly Thr Phe Trp Tyr Phe Asp Val
1 5 10 15
<210> 137
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 137
Ile Arg Tyr Gln Gly Ser Gly Thr Phe Trp Tyr Phe Asp Val
1 5 10
<210> 138
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 138
Arg Tyr Gln Gly Ser Gly Thr Phe Trp Tyr Phe Asp Val
1 5 10
<210> 139
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 139
Tyr Gln Gly Ser Gly Thr Phe Trp Tyr Phe Asp Val
1 5 10
<210> 140
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 140
Gln Gly Ser Gly Thr Phe Trp Tyr Phe Asp Val
1 5 10
<210> 141
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 141
Gly Ser Gly Thr Phe Trp Tyr Phe Asp Val
1 5 10
<210> 142
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 142
Ser Gly Thr Phe Trp Tyr Phe Asp Val
1 5
<210> 143
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 143
Gly Thr Phe Trp Tyr Phe Asp Val
1 5
<210> 144
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 144
Tyr Asn Leu Gly Tyr Ser Tyr Phe Tyr Tyr Met Asp Gly
1 5 10
<210> 145
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 145
Asn Leu Gly Tyr Ser Tyr Phe Tyr Tyr Met Asp Gly
1 5 10
<210> 146
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 146
Leu Gly Tyr Ser Tyr Phe Tyr Tyr Met Asp Gly
1 5 10
<210> 147
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 147
Gly Tyr Ser Tyr Phe Tyr Tyr Met Asp Gly
1 5 10
<210> 148
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 148
Tyr Ser Tyr Phe Tyr Tyr Met Asp Gly
1 5
<210> 149
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 降茎链
<400> 149
Ser Tyr Phe Tyr Tyr Met Asp Gly
1 5
<210> 150
<211> 2
<212> PRT
<213> 人工序列
<220>
<223> 接头
<400> 150
Gly Ser
1
<210> 151
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 接头
<400> 151
Gly Gly Ser
1
<210> 152
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 接头
<400> 152
Gly Gly Ser Gly Gly Ser
1 5
<210> 153
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 接头
<400> 153
Gly Gly Ser Gly Gly Ser Gly Gly Ser
1 5
<210> 154
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 接头
<400> 154
Gly Gly Gly Gly Ser
1 5
<210> 155
<211> 662
<212> DNA
<213> 人工序列
<220>
<223> 人轻链λ区
<400> 155
tcacgaattc gcaggccgtc ctgaaccagc caagcagcgt ctccgggtct ctggggcagc 60
gggtctcaat cacctgtagc gggtcttcct ccaatgtcgg caacggctac gtgtcttggt 120
atcagctgat ccctggcagt gccccacgaa ccctgatcta cggcgacaca tccagagctt 180
ctggggtccc cgatcggttc tcagggagca gatccggaaa cacagctact ctgaccatca 240
gctccctgca ggctgaggac gaagcagatt atttctgcgc atctgccgag gactctagtt 300
caaatgccgt gtttggaagc ggcaccacac tgacagtcct aggtcagccc aaggctgccc 360
cctcggtcac tctgttcccg ccctcctctg aggagcttca agccaacaag gccacactgg 420
tgtgtctcat aagtgacttc tacccgggag ccgtgacagt ggcctggaag gcagatagca 480
gccccgtcaa ggcgggagtg gagaccacca caccctccaa acaaagcaac aacaagtacg 540
cggccagcag ctatctgagc ctgacgcctg agcagtggaa gtcccacaga agctacagct 600
gccaggtcac gcatgaaggg agcaccgtgg agaagacagt ggcccctaca gaatgttcat 660
aa 662
<210> 156
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> 人VL1-51
<400> 156
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln
65 70 75 80
Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Ala Glu Asp Ser Ser
85 90 95
Ser Asn Ala Val Phe Gly Ser Gly Thr Thr Leu Thr Val Leu Gly Gln
100 105 110
Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210> 157
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> BLV1H12升茎区
<400> 157
tgtacttctg tgcaccagga aacaaaaaaa taccaaacc 39
<210> 158
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> BLV1H12升茎区
<400> 158
Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Thr
1 5 10
<210> 159
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> BLV1H12升茎区
<400> 159
Cys Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Thr
1 5 10
<210> 160
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> 降茎区
<400> 160
tcctatactt acaattacga atggcacgtc gatgtctgg 39
<210> 161
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 降茎区
<400> 161
Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp
1 5 10
<210> 162
<211> 117
<212> DNA
<213> 人工序列
<220>
<223> BLV1H12杵序列
<400> 162
tgtccggagg attatactta taatccacgt tgccctcagc agtatggttg gagtgactgt 60
gattgtatgg gcgataggtt tgggggttac tgtcgacagg atggttgtag taattat 117
<210> 163
<211> 9
<212> DNA
<213> 人工序列
<220>
<223> N-末端GGS接头的编码序列
<400> 163
ggtggatca 9
<210> 164
<211> 9
<212> DNA
<213> 人工序列
<220>
<223> C-末端GSG接头的编码序列
<400> 164
ggttcagga 9
<210> 165
<211> 133
<212> PRT
<213> 智人(Homo sapiens)
<220>
<221> 尚未归类的特征
<223> IL2
<400> 165
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 166
<211> 399
<212> DNA
<213> 人工序列
<220>
<223> IL2编码序列
<400> 166
gcacctactt caagttctac aaagaaaaca cagctacaac tggagcattt actgctggat 60
ttacagatga ttttgaatgg aattaataat tacaagaatc ccaaactcac caggatgctc 120
acatttaagt tttacatgcc caagaaggcc acagaactga aacatcttca gtgtctagaa 180
gaagaactca aacctctgga ggaagtgcta aatttagctc aaagcaaaaa ctttcactta 240
agacccaggg acttaatcag caatatcaac gtaatagttc tggaactaaa gggatctgaa 300
acaacattca tgtgtgaata tgctgatgag acagcaacca ttgtagaatt tctgaacaga 360
tggattacct tttgtcaaag catcatctca acactgact 399
<210> 167
<211> 513
<212> DNA
<213> 人工序列
<220>
<223> 嵌合超长牛重链序列
<400> 167
caggtgcagc tgcgggagtc gggccccagc ctgatgaagc cgtcacagac cctctccctc 60
acctgcacgg tctctggatc ttcattgaac gacaagtctg taggctgggt ccgccaggct 120
ccagggaagg cgctgcagtg gctcggtagt gtggacacta gtggaaacac agactataac 180
ccaggcctga aatcccggct cagcatcacc aaggacaact ccaagagccg aatctctctt 240
acagtgactg gcatgacaac tgaagactcg gccacatact actgtacttc tgtgcaccag 300
gaaacaaaaa aataccaaag ttgtccggag gattatactt ataatccacg ttgccctcag 360
cagtatggtt ggagtgactg tgattgtatg ggcgataggt ttgggggtta ctgtcgacag 420
gatggttgta gtaattatag ttatacttac aattacgaat ggcacgtcga tgtctggggc 480
caaggactcc tggtcaccgt ctcctcagct agc 513
<210> 168
<211> 651
<212> DNA
<213> 人工序列
<220>
<223> BLV1H12轻链-
<400> 168
caggccgtcc tgaaccagcc aagcagcgtc tccgggtctc tggggcagcg ggtctcaatc 60
acctgtagcg ggtcttcctc caatgtcggc aacggctacg tgtcttggta tcagctgatc 120
cctggcagtg ccccacgaac cctgatctac ggcgacacat ccagagcttc tggggtcccc 180
gatcggttct cagggagcag atccggaaac acagctactc tgaccatcag ctccctgcag 240
gctgaggacg aagcagatta tttctgcgca tctgccgagg actctagttc aaatgccgtg 300
tttggaagcg gcaccacact gacagtccta ggtcagccca aggctgcccc ctcggtcact 360
ctgttcccgc cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata 420
agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag ccccgtcaag 480
gcgggagtgg agaccaccac accctccaaa caaagcaaca acaagtacgc ggccagcagc 540
tatctgagcc tgacgcctga gcagtggaag tcccacagaa gctacagctg ccaggtcacg 600
catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgttcata a 651
<210> 169
<211> 311
<212> DNA
<213> 人工序列
<220>
<223> 人重链可变区序列4-39
<400> 169
cagctgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcagc agtagtagtt actactgggg ctggatccgc 120
cagcccccag ggaaggggct ggagtggatt gggagtatct attatagtgg gagcacctac 180
tacaacccgt ccctcaagag tcgagtcacc atatccgtag acacgtccaa gaaccagttc 240
tccctgaagc tgagctctgt gaccgccgca gacacggctg tgtattactg tgcgagacac 300
acagtgaggg g 311
<210> 170
<211> 288
<212> DNA
<213> 人工序列
<220>
<223> 人重链可变区序列4-59*03
<400> 170
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcagt agttactact ggagctggat ccggcagccc 120
ccagggaagg gactggagtg gattgggtat atctattaca gtgggagcac caactacaac 180
ccctccctca agagtcgagt caccatatca gtagacacgt ccaagaacca attctccctg 240
aagctgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcg 288
<210> 171
<211> 291
<212> DNA
<213> 人工序列
<220>
<223> 人重链可变区序列4-34*09
<400> 171
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcgctg tctatggtgg gtccttcagt ggttactact ggagctggat ccgccagccc 120
ccagggaagg gactggagtg gattggggaa atcaatcata gtggaagcac caactacaac 180
ccgtccctca agagtcgagt taccatatca gtagacacgt ctaagaacca gttctccctg 240
aagctgagct ctgtgactgc cgcggacacg gccgtgtatt actgtgcgag a 291
<210> 172
<211> 290
<212> DNA
<213> 人工序列
<220>
<223> 人重链可变区序列4-34*02
<400> 172
caggtgcagc tacaacagtg gggcgcagga ctgttgaagc cttcggagac cctgtccctc 60
acctgcgctg tctatggtgg gtccttcagt ggttactact ggagctggat ccgccagccc 120
ccagggaagg ggctggagtg gattggggaa atcaatcata gtggaagcac caactacaac 180
ccgtccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240
aagctgagct ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgag 290
<210> 173
<211> 98
<212> PRT
<213> 人工序列
<220>
<223> 人种系轻链可变区序列VL1-47
<400> 173
Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu
85 90 95
Ser Gly
<210> 174
<211> 99
<212> PRT
<213> 人工序列
<220>
<223> 人种系轻链可变区序列VL1-40*1
<400> 174
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
85 90 95
Leu Ser Gly
<210> 175
<211> 98
<212> PRT
<213> 人工序列
<220>
<223> 人种系轻链可变区序列VL1-51*01
<400> 175
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln
1 5 10 15
Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn
20 25 30
Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln
65 70 75 80
Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu
85 90 95
Ser Ala
<210> 176
<211> 99
<212> PRT
<213> 人工序列
<220>
<223> 人种系轻链可变区序列VL2-18*02
<400> 176
Gln Ser Ala Leu Thr Gln Pro Pro Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr
20 25 30
Asn Arg Val Ser Trp Tyr Gln Gln Pro Pro Gly Thr Ala Pro Lys Leu
35 40 45
Met Ile Tyr Glu Val Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Phe
<210> 177
<211> 296
<212> DNA
<213> 人工序列
<220>
<223> 人种系轻链可变区序列VL1-47
<400> 177
cagtctgtgc tgactcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60
tcttgttctg gaagcagctc caacatcgga agtaattatg tatactggta ccagcagctc 120
ccaggaacgg cccccaaact cctcatctat aggaataatc agcggccctc aggggtccct 180
gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccgg 240
tccgaggatg aggctgatta ttactgtgca gcatgggatg acagcctgag tggtcc 296
<210> 178
<211> 299
<212> DNA
<213> 人工序列
<220>
<223> 人种系轻链可变区序列VL1-40*1
<400> 178
cagtctgtgc tgacgcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc 60
tcctgcactg ggagcagctc caacatcggg gcaggttatg atgtacactg gtaccagcag 120
cttccaggaa cagcccccaa actcctcatc tatggtaaca gcaatcggcc ctcaggggtc 180
cctgaccgat tctctggctc caagtctggc acctcagcct ccctggccat cactgggctc 240
caggctgagg atgaggctga ttattactgc cagtcctatg acagcagcct gagtggttc 299
<210> 179
<211> 296
<212> DNA
<213> 人工序列
<220>
<223> 人种系轻链可变区序列VL1-51*01
<400> 179
cagtctgtgt tgacgcagcc gccctcagtg tctgcggccc caggacagaa ggtcaccatc 60
tcctgctctg gaagcagctc caacattggg aataattatg tatcctggta ccagcagctc 120
ccaggaacag cccccaaact cctcatttat gacaataata agcgaccctc agggattcct 180
gaccgattct ctggctccaa gtctggcacg tcagccaccc tgggcatcac cggactccag 240
actggggacg aggccgatta ttactgcgga acatgggata gcagcctgag tgctgg 296
<210> 180
<211> 297
<212> DNA
<213> 人工序列
<220>
<223> 人种系轻链可变区序列VL2-18*02
<400> 180
cagtctgccc tgactcagcc tccctccgtg tccgggtctc ctggacagtc agtcaccatc 60
tcctgcactg gaaccagcag tgacgttggt agttataacc gtgtctcctg gtaccagcag 120
cccccaggca cagcccccaa actcatgatt tatgaggtca gtaatcggcc ctcaggggtc 180
cctgatcgct tctctgggtc caagtctggc aacacggcct ccctgaccat ctctgggctc 240
caggctgagg acgaggctga ttattactgc agctcatata caagcagcag cactttc 297
Claims (46)
1.一种经细胞因子修饰的嵌合抗体或抗原结合片段,其包含经修饰的超长CDR3,所述经修饰的超长CDR3包含替代牛抗体或抗原结合片段或其人源化序列的重链的超长CDR3区的至少一部分的白细胞介素-15(IL-15)细胞因子序列或其生物活性部分。
2.根据权利要求1所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述IL-15细胞因子序列是人IL-15。
3.根据权利要求1或权利要求2所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述IL-15细胞因子序列包含与SEQ ID NO:1展现出至少或至少约85%、至少或至少约90%、至少或至少约92%、至少或至少约95%、至少或至少约96%、至少或至少约97%、至少或至少约98%或者至少或至少约99%序列同一性的氨基酸序列。
4.根据权利要求1-3中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述IL-15细胞因子序列包含SEQ ID NO:1中所示的氨基酸序列。
5.一种经细胞因子修饰的嵌合抗体或抗原结合片段,其包含经修饰的超长CDR3,所述经修饰的超长CDR3包含替代牛抗体或抗原结合片段或其人源化序列的重链的超长CDR3区的至少一部分的白细胞介素-2(IL-2)细胞因子序列或其生物活性部分。
6.根据权利要求5所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述IL-2细胞因子序列是人IL-2。
7.根据权利要求5或权利要求6所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述IL-2细胞因子序列包含与SEQ ID NO:165展现出至少或至少约85%、至少或至少约90%、至少或至少约92%、至少或至少约95%、至少或至少约96%、至少或至少约97%、至少或至少约98%或者至少或至少约99%序列同一性的氨基酸序列。
8.根据权利要求5-7中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述IL-2细胞因子序列包含SEQ ID NO:165中所示的氨基酸序列。
9.根据权利要求1-8中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述细胞因子序列替代牛抗体或抗原结合片段的重链的超长CDR3区的至少一部分。
10.根据权利要求9所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述牛抗体或抗原结合片段是牛抗体BLV1H12或其抗原结合片段。
11.根据权利要求9或权利要求10所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述牛抗体或抗原结合片段包含由SEQ ID NO:5中所示序列编码的可变重链氨基酸序列和由SEQ ID NO:8中所示序列编码的可变轻链氨基酸序列。
12.根据权利要求9或权利要求10所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述牛抗体或抗原结合片段包含由SEQ ID NO:167中所示序列编码的可变重链氨基酸序列和由SEQ ID NO:168中所示序列编码的可变轻链氨基酸序列。
13.根据权利要求9或权利要求10所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述牛抗体或抗原结合片段包含SEQ ID NO:26中所示的可变重链和SEQ ID NO:27中所示的可变轻链。
14.根据权利要求1-8中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述细胞因子序列替代人源化牛抗体或其抗原结合片段的重链的超长CDR3区的至少一部分。
15.根据权利要求14所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述人源化牛抗体或其抗原结合片段包含作为人重链种系序列或源自人重链种系序列的重链或其一部分和作为人轻链种系序列或源自人轻链种系序列的轻链或其一部分。
16.根据权利要求15所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述人重链种系序列是VH4-39、VH4-59*03、VH4-34*02或VH4-34*09种系序列或是SEQ ID NO:68-71中任一个所示的序列。
17.根据权利要求15或权利要求16所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述人轻链种系序列是VL1-51种系序列或是基于所述VL1-51种系序列的包含一个或多个突变的序列,任选地其中所述VL1-51种系序列是SEQ ID NO:156中所示的。
18.根据权利要求17所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述一个或多个突变选自:
基于Kabat编号的氨基酸替代S2A、T5N、P8S、A12G、A13S和P14L中的一个或多个;
基于Kabat编号的氨基酸替代S2A、T5N、P8S、A12G、A13S和P14L;
CDR1中包含氨基酸替代I29V和N32G的突变;
CDR2中包含DNN取代为GDT的突变;
CDR2中包含DNNKRP取代为GDTSRA的突变;
或任何前项的组合。
19.根据权利要求1-18中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述抗体是包含可变重链和可变轻链的抗原结合片段。
20.根据权利要求1-19中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述抗体包含与重链恒定结构域(CH1-CH2-CH3)连接的可变重链和与轻链恒定结构域(CL1)连接的可变轻链。
21.根据权利要求20所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述重链恒定结构域来自人IgG1。
22.根据权利要求20或权利要求21所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述轻链恒定结构域是λ轻链区。
23.根据权利要求1-22中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中超长CDR3区的所述至少一部分包含杵区,并且所述细胞因子序列存在于所述经修饰的超长CDR3的升茎结构域与降茎结构域之间。
24.根据权利要求23所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述细胞因子序列经由柔性接头、任选地GGS或GSG接头与所述升茎结构域和/或所述降茎结构域连接。
25.根据权利要求23或权利要求24所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述升茎结构域包含SEQ ID NO:158或SEQ ID NO:159中所示的序列。
26.根据权利要求23-25中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述降茎结构域包含SEQ ID NO:161中所示的序列。
27.根据权利要求1-4和9-26中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述抗体或抗原结合片段包含由SEQ ID NO:7中所示的核苷酸序列或与SEQ IDNO:7中所示的核苷酸序列展现出至少或至少约85%、至少或至少约90%、至少或至少约92%、至少或至少约95%、至少或至少约96%、至少或至少约97%、至少或至少约98%、至少或至少约99%序列同一性的核苷酸序列编码的可变重链序列,其中包含含有IL-15序列的经修饰的超长CDR3。
28.根据权利要求1-4和9-27中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述抗体或抗原结合片段与包括IL15Rαsushi结构域在内的IL15Rα的细胞外结构域复合。
29.根据权利要求28所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中包括IL15Rαsushi结构域在内的IL15Rα的所述细胞外结构域与所述IL-15序列非共价缔合。
30.根据权利要求28所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中包括IL15Rαsushi结构域在内的IL15Rα的所述细胞外结构域与所述可变轻链连接。
31.根据权利要求30所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其经由肽接头连接。
32.根据权利要求31所述的经细胞因子修饰的嵌合抗体,其中所述肽接头是甘氨酸接头或甘氨酸-丝氨酸接头,任选地其中所述接头是GS。
33.根据权利要求28-32中任一项所述的经细胞因子修饰的嵌合抗体,其中包括IL15Rαsushi结构域在内的IL15Rα的所述细胞外结构域包含SEQ ID NO:2中所示的序列。
34.根据权利要求30-33中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段,其中所述可变轻链包含由SEQ ID NO:3编码的氨基酸序列。
35.一种或多种多核苷酸,其编码根据权利要求1-34中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段。
36.一种多核苷酸,其编码根据权利要求1-34中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段的重链或其可变区。
37.一种多核苷酸,其编码根据权利要求1-34中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段的轻链或其可变区。
38.一种表达载体,其包含根据权利要求35-37中任一项所述的多核苷酸。
39.一种宿主细胞,其包含根据权利要求35-37中任一项所述的多核苷酸或根据权利要求37所述的表达载体。
40.根据权利要求39所述的宿主细胞,其进一步包含表达包括IL15Rαsushi结构域在内的IL15Rα的细胞外结构域的多核苷酸或载体。
41.根据权利要求40所述的宿主细胞,其中包括IL15Rαsushi结构域在内的IL15Rα的所述细胞外结构域包含SEQ ID NO:2中所示的序列。
42.一种产生经细胞因子修饰的嵌合抗体或抗原结合片段的方法,其包括在根据权利要求39-41中任一项所述的宿主细胞表达所述抗体或抗原结合片段的条件下培养所述细胞,任选地进一步包括回收并纯化所述抗体或抗原结合片段。
43.一种通过根据权利要求42所述的方法产生的经细胞因子修饰的嵌合抗体或抗原结合片段。
44.一种药物组合物,其包含根据权利要求1-34或43中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段。
45.一种治疗受试者的癌症的方法,其包括施用治疗有效量的根据权利要求1-34或43中任一项所述的经细胞因子修饰的嵌合抗体或抗原结合片段。
46.一种治疗受试者的癌症的方法,其包括施用治疗有效量的根据权利要求44所述的药物组合物。
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