CN107889491A - 以高亲和性、亲合力及特异性结合转化生长因子‑β1的scFv‑Fc二聚体 - Google Patents
以高亲和性、亲合力及特异性结合转化生长因子‑β1的scFv‑Fc二聚体 Download PDFInfo
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- CN107889491A CN107889491A CN201680025665.5A CN201680025665A CN107889491A CN 107889491 A CN107889491 A CN 107889491A CN 201680025665 A CN201680025665 A CN 201680025665A CN 107889491 A CN107889491 A CN 107889491A
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Abstract
scFv‑Fc二聚体选择性地以高亲和性和亲合力结合并中和TGFβ1。scFv区可以包含与美替木单抗(metelimumab)相同的VH和VL域或CDR区。cFv‑Fc二聚体较小的尺寸,针对TGFβ1的高选择性、效力,以及长的体内半衰期的独特组合使其成为用于治疗应用的理想候选物。
Description
相关申请
本专利申请要求2015年3月4日提交的美国临时专利申请62/128,133的权益,将其通过提述整体并入本文。
发明背景
技术领域
抗原结合的二聚体具有两个多肽单体,其各自包含单链片段可变分子(scFv)、铰链、和Fc分子,所述抗原结合的二聚体展现出对于转化生长因子-β1(TGFβ1)的高亲和性和亲合力,但对于TGFβ2或TGFβ3则无。还提供了包含所述抗原结合的二聚体的组合物和使用该组合物来治疗涉及TGFβ1活性的疾病的方法。
背景
许多严重疾病与TGFβ诱导的信号传输途径机能障碍有关。例如,TGFβ的增加的组织水平被认为是特发性肺纤维化和心肌纤维化进展中的因素。此外,TGFβ的高局部组织水平可以允许一些类型的癌细胞的维持和进展。因此,TGFβ信号传输的下调可以降低此类肿瘤细胞的存活力。
TGFβ同种型是~25kDa同型二聚体分子,其具有相似的结构框架,其中两个单体经二硫桥共价地连接。哺乳动物同种型具有70-82%的序列同一性,但在血管发育和免疫细胞功能调控中具有不重迭的活性。在人中已报道了三个TGFβ同种型:TGFβ1、TGFβ2、和TGFβ3(Swiss Prot登录号分别为P01137、P08112、和P10600)。TGFβ1和TGFβ3在结合至两个跨膜受体(称为TGFβ受体I型和II型)的胞外结构域时触发细胞信号传输级联反应。TGFβ2可以结合至TGFβ受体I型和II型以及TGFβ受体III型。
已针对临床使用测试了能结合人TGFβ1、TGFβ2、和TGFβ3的抗体。例如,Grütter等公开了GC1008(一种人IgG4单克隆抗体(Mab;即GC1008))在临床开发中用于治疗恶性肿瘤和纤维化疾病。Proc.Nat’l Acad.Sci.USA 105(51):20251-56(2008)。GC1008是“泛特异性的”TGFβ中和抗体,因为其能中和所有三种人TGFβ同种型。选择性中和TGFβ1的抗体是公开的,例如在美国专利No.6,492,497和美国专利No.7,151,169中,其在此通过提述并入本文。美替木单抗(metelimumab),又称CAT192(IgG4),是一种选择性中和TGF-β1的人IgG4单克隆抗体。参见例如美国专利No.6,492,497。测试美替木单抗用于治疗弥散性皮肤系统性硬化病(diffuse cutaneous systemic sclerosis),又称硬皮病(scleroderma),但证明其功效不足。
发明概述
本发明提供了结合TGFβ1的scFv-Fc二聚体,其能选择性地中和人TGFβ1。在一个实施方案中,所述scFv-Fc二聚体形式为scFv-Fc融合蛋白,其包含或组成为(comprised of)两个多肽单体,每个单体包含单链Fv区(scFv)、铰链、和Fc区。scFv-Fc二聚体的VH和VL域展现出对TGFβ1较高的亲和性(affinity)和亲合力(avidity),且比以IgG1或IgG4形式使用时更有效地中和TGFβ1。
在一个实施方案中,scFv组分可由与美替木单抗的VH和VL域相同的VH和VL域组成。scFv组分中的可变域可以通过接头,例如[G4S]3-型接头连接在一起。scFv-Fc二聚体的scFv组分的每一个可以经铰链区(例如人IgG1或IgG4铰链区)融合至Fc区。二聚体的单体可以通过铰链区中半胱氨酸残基之间的二硫键共价地连接。在另一个实施方案中,scFv-Fc二聚体可以具有相对于美替木单抗结构上的相异处,最显著的是缺乏CH1和CL域和存在VH和VL域之间的接头。有利的是,scFv-Fc二聚体在A549细胞效力生物测定中对于TGFβ1表现出明显的亲和性,比包含相同VH和VL域的scFv(CAT191(scFv),示于SEQ ID NO:12中)的亲和性高接近两个数量级。进一步地,scFv-Fc二聚体在A549细胞生物测定中表现出对TGFβ1的明显亲和性,比IgG形式化的包含相同VH和VL域的抗体(例如CAT192)的亲和性高超出3个数量级。scFv-Fc二聚体还表现出想要的稳定性和药代动力学特性。由于它们相对小的尺寸和在血清中延长的半衰期,scFv-Fc二聚体对于治疗应用是尤其有用的。
因此,本发明涉及分离的结合蛋白,其包含能结合TGFβ1的可变域,其中如通过表面等离子体共振测得的,所述结合蛋白展现出的针对人TGFβ1的Kd比同一结合蛋白针对人TGFβ2的Kd低至少约50%(所述结合蛋白展现出的针对人TGFβ1的Kd是同一结合蛋白针对人TGFβ2的Kd的至多约1/2)。
在另一个实施方案中,本发明涉及分离的结合蛋白,其包含能结合TGFβ1的可变域,其中如通过表面等离子体共振测得的,所述结合蛋白展现出的针对人TGFβ1的Kd比同一结合蛋白针对人TGFβ3的Kd低至少约50%(所述结合蛋白展现出的针对人TGFβ1的Kd是同一结合蛋白针对人TGFβ3的Kd的至多约1/2)。
在进一步的实施方案中,本发明涉及分离的结合蛋白,其包含能结合TGFβ1的可变域,其中如通过表面等离子体共振测得的,所述结合蛋白展现出的针对人TGFβ1的Kd比同一结合蛋白针对人TGFβ2的Kd低至少约50%且比同一结合蛋白针对人TGFβ3的Kd低至少约50%(所述结合蛋白展现出的针对人TGFβ1的Kd是同一结合蛋白针对人TGFβ2的Kd的至多约1/2且是同一结合蛋白针对人TGFβ3的Kd的至多约1/2)。
在进一步的实施方案中,本发明涉及结合TGFβ1的分离的结合蛋白,其中所述结合蛋白包含第一多肽链和第二多肽链,所述第一和第二多肽链各具有下式:
(VD1)-(接头1)n-(VD2)-(接头2)m-(铰链)p-(Fc区),
其中VD1包含选自下组的第一可变域:分离自能结合TGFβ1的抗体的VL域和分离自能结合TGFβ1的抗体的VH域,而VD2包含选自下组的第二可变域:分离自能结合TGFβ1的抗体的VL域,和分离自能结合TGFβ1的抗体的VH域;且其中,n是0或1,m是0或1,且p是0或1。
在一个实施方案中,本发明涉及一种结合TGFβ1的scFv-Fc二聚体,其选择性地结合TGFβ1。该scFv-Fc二聚体可包含两个多肽单体,其各自从N末端至C末端具有下式:(VH域)-(接头)-(VL域)-(铰链)-(Fc区)。在另一个实施方案中,公开了结合TGFβ1的分离的结合蛋白,其包含第一多肽链和第二多肽链。所述第一和第二多肽链均从N末端至C末端具有下式:(VH域)-(接头1)n-(VL域)-(接头2)m-(铰链)p-(Fc区)。P可以是0或1,n可以是0或1,且m可以是0或1。在一个方面,所述第一和第二多肽链可以是相同的且可以形成二聚体。
在另一个实施方案中,本公开的TGFβ1结合蛋白可以包含多肽链,所述多肽链从N末端至C末端具有下式:(VH域)-(接头1)n-(VL域)-(接头2)m-(铰链)p-(Fc区),其中p可以是0或1,n可以是0或1,且m可以是0或1。
本公开的结合蛋白的VH结构域可以包含可变重链互补决定区1(HCDR1)、可变重链互补决定区2(HCDR2)、及可变重链互补决定区3(HCDR3)。在一个方面,所述HCDR1可以具有SEQ ID NO:22的氨基酸序列,HCDR2可以具有SEQ ID NO:23的氨基酸序列,且HCDR3可以具有选自下组的氨基酸序列:SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、和SEQ ID NO:30。
VH域的框架区可以选自可变重链种系序列。例如,VH域可以选自SEQ ID NO:1或SEQ ID NO:2中所示的人VH域序列,或其在多至4个氨基酸中具有修饰的变体。
本公开的结合蛋白的VL域可以包含可变轻链互补决定区1(LCDR1)、可变轻链互补决定区2(LCDR2)、及可变轻链互补决定区3(LCDR3)。在一个方面,所述LCDR1具有SEQ IDNO:27的氨基酸序列,LCDR2可以具有SEQ ID NO:28的氨基酸序列,且LCDR3可以具有SEQ IDNO:29的氨基酸序列。
VL域的框架区可以选自相同的可变λ或κ种系序列。例如,VL域可以选自例如SEQID NO:5或SEQ ID NO:6中所示的人Vκ域序列,或其具有多至4个氨基酸的修饰的变体。在一个实施方案中,二聚体的各个多肽可以包含SEQ ID NO:1中所示的VH域和SEQ ID NO:5中所示的Vκ域,其分别是美替木单抗中存在的VH和VL域。
在一个实施方案中,scFv组分中的可变域可以通过长度约15个氨基酸的柔性接头连接。此语境中的“约”意指接头的长度能变化在多至±4个氨基酸。对于最佳柔性而言,接头主要由甘氨酸和丝氨酸残基组成。例如,所述接头可以是[G4S]3-型接头。接头可以具有氨基酸序列SGGGSGGGGSGGGGS(SEQ ID NO:3)、氨基酸序列GGGGSGGGGSGGGGS(SEQ ID NO:4),或其具有多至4个氨基酸修饰的变体。就本发明而言,“具有多至x个氨基酸修饰”意指本领域技术人员可以将多至x数目个氨基酸变更为不同的氨基酸,而不显著改变该多核苷酸的结构和功能。
在另一个实施方案中,p是1且scFv组分通过铰链与Fc区连接。所述铰链可以包含来源于人IgG1或IgG4铰链区的氨基酸序列。例如,铰链可以包含氨基酸序列PKSCDKTHTCPPCPAPELLGGP(SEQ ID NO:7),或其具有多至4个氨基酸修饰的变体。在另一个实施方案中,铰链长度可以在3-15个氨基酸变化。当铰链来自人IgG1时,其可以包含氨基酸序列CPPCP(SEQ ID NO:21)。进一步地,SEQ ID NO:7的铰链的变体(其也是人IgG1铰链)可以包含氨基酸序列CPPCP(SEQ ID NO:21)。
在另一个实施方案中,m是1且scFv组分和铰链之间存在接头2。在一个方面,接头2可以包含氨基酸序列GGSG(SEQ ID NO:20),或其具有多至2个氨基酸修饰的变体。
Fc区可以包含两个或三个恒定域,例如CH2域和CH3域。例如,Fc区可以获取自人IgG1、人IgG4、或人IgG1或IgG4的具有多至10个氨基酸修饰的变体。在一个实施方案中,二聚体的各多肽具有SEQ ID NO:9中所示的序列。SEQ ID NO:9的scFv-Fc二聚体的结构示于图2中。所述scFv-Fc二聚体可以选择性结合TGFβ1。该scFv-Fc二聚体可以显示出低于1nM的或甚至低于0.1nM的表观离解参数(apparent dissociation constant)。例如,所述表观离解参数可以通过A549生物测定法或通过表面等离子体共振来测量。
在另一个实施方案中,公开了分离的多核苷酸,其可以包含编码所述scFv-Fc二聚体的核苷酸序列。该分离的多核苷酸可以是cDNA、重组DNA或合成的DNA。宿主细胞可以包含该分离的核酸。所述宿主细胞可以是人细胞,例如人胚肾293(HEK293)细胞及由其衍生的细胞系,或其可以是中国仓鼠卵巢(CHO)细胞。制备所述scFv-Fc二聚体的方法可以包括在适于产生该scFv-Fc二聚体的条件下培养宿主细胞。可以对所述scFv-Fc二聚体进行纯化。纯度可以是90%、95%、99%、99.5%或更高。
本发明的scFv-Fc二聚体可以是组合物的组件。所述组合物可以是药物组合物。所述药物组合物可以包含治疗有效量的scFv-Fc二聚体。组合物还可以包含一个或多个生物活性组分、赋形剂、或稀释剂。
在人中治疗由TGFβ1活性直接或间接导致的疾病或病况的方法可以包括施用药物组合物,所述药物组合物包含治疗有效量的scFv-Fc二聚体。所述疾病或病况可以选自下组:纤维化疾病、癌症、免疫介导的疾病,例如弥散性皮肤系统性硬化病(diffusecutaneous systemic sclerosis)、骨重塑疾病、肾病和/或其组合。scFv-Fc二聚体可以用于制造用于治疗选自下组的疾病或病况的药物中:纤维化疾病、癌症、免疫介导的疾病,例如弥散性皮肤系统性硬化病、骨重塑疾病、肾病和/或其组合。所述疾病或病况的治疗可以包括中和TGFβ1或抑制TGFβ1信号传输。所述疾病或病况的治疗可以包括抑制TGFβ1介导的纤连蛋白产生、血管内皮生长因子(VEGF)产生、上皮细胞增殖、内皮细胞增殖、平滑肌细胞增殖、或免疫抑制。所述疾病或病况的治疗可以包括增加自然杀伤细胞活性。
附图简述及一些观点
本附图在此用于描述的目的,而不用于限制本发明的范围。
图1描绘了多种形式的一般结构。
图2描绘了Biacore TGFβ1结合测定的结果,其显示当scFv(CAT191)转变为全长IgG4(CAT192)分子时亲和性的损失。
图3显示了A549细胞生物测定的结果,该测定比较了多种抗体构建体对TGFβ1刺激的IL-11生产的抑制性作用:scFv双抗体5aa(SEQ ID NO:14);CAT191(scFv)(SEQ ID NO:12);CAT191(scFv-Fc)(SEQ ID NO:9);和CAT192(IgG4)(轻链SEQ ID NO:10和重链SEQ IDNO:11)。
图4描绘了药代动力学测试的结果,以确定CAT191(scFv-Fc)在静脉内(IV)施用后的半衰期。
图5描绘了药代动力学测试的结果,其确定CAT191(scFv-Fc)在腹膜内(IP)施用后的半衰期。
图6显示了制备自CHO细胞的CAT191(scFv-Fc)的TGFβ1特异性的结合结果。
图7显示了制备自CHO细胞的CAT191(scFv-Fc)的基于细胞的效力测定结果。
发明详述
scFv-Fc二聚体以高亲和性和亲合力选择性地结合并中和TGFβ1。scFv区可以由与美替木单抗中相同的VH和VL域组成。scFv-Fc二聚体有利地显示出比所述可变域以其他形式使用时更大的中和TGFβ1的效力。由于其相对小的尺寸和在血清中延长的半衰期,本scFv-Fc二聚体是理想的用于治疗应用的候选物。
如本文所用的,第一组件“和/或”第二组件意指具体公开了分别的第一或第二组件,或所述第一和第二组件的组合。除上下文另有明确说明外,单数形式“一”、“一个”和“该”包括复数指称。
“分离的”多核苷酸(或核酸)或蛋白是使用遗传工程技术自其天然形式移出和/或改变的。“纯化的”核酸或蛋白可以是基本纯的,例如至少90%纯,或是同质形式的。
“选择性结合”或“选择性地结合”至人TGFβ1,意指结合蛋白(例如scFv-Fc二聚体)能够以比结合至人TGFβ2或人TGFβ3更高的亲和性结合人TGFβ1,例如其与人TGFβ1的离解常数比其与TGFβ2或人TGFβ3的离解常数低至少50%(其与人TGFβ1的离解常数为其与TGFβ2或人TGFβ3的离解常数至多1/2),如通过表面等离子体共振测得的。
scFv-Fc二聚体
在一个实施方案中,本scFv-Fc二聚体可变域包含来自美国专利No.6,492,497公开的CDR的互补决定区(CDR)(例如美国专利No.6,492,497的SEQ ID NOs:11-19),其通过提述在此并入。CDR区列于下文:
令人惊奇地揭示了共有的(consensus)HCDR3结合基序,其具有如下序列:
HCDR3 TGX1YSGYDTX2X3X4X5X6 SEQ ID No.30
其中X1可以是任意氨基酸(优选为E或F),或缺失,
X2可以是任意氨基酸(优选为S、D或P),或缺失,
X3可以是任意氨基酸(优选为G、P或A),或缺失,
X4可以是任意氨基酸(优选为V、Q或S),或缺失,
X5可以是任意氨基酸(优选为E、Y或P),或缺失,
X6可以是任意氨基酸(优选为L、S或D),或缺失。
VH域包含SEQ ID No.22的HCDR1、SEQ ID No.23的HCDR2,以及选自下组的HCDR3之一:SEQ ID No.24、SEQ ID No.25、SEQ ID No.26、和SEQ ID No.30。CDR序列可以在任何位置被1至4个框架区分隔,以自N末端:FW1–CDR1–FW2–CDR2–FW3–CDR3–FW4的顺序。VH域的框架区可以选自可变重链种系序列。在一个实施方案中,FW区序列可以选自相同的人可变重链种系序列。VL域包含SEQ ID NO:7的LCDR1、SEQ ID NO:28的LCDR2、和SEQ ID NO:29的LCDR3。VL域的框架区可以选自可变λ或κ种系序列,例如选自相同的人可变λ或κ种系序列。目前,本领域已知约40个可变重链种系序列,如存在40个可变κ种系序列和约30个可变λ种系序列,例如VH3、Vκ1、VH 1-69、和VH 1-e。
在另一个实施方案中,可以通过使用本文公开的CDR序列来生成复合的VH或VL域。例如,VH或VL的晶体结构可以用作引导来生产复合域,所述产生用来自一个抗体的CDR序列和用来自另一抗体的种系FW区来进行。更多细节可见于美国专利申请公开号20020099179;及Homes和Foote,J Immunol.1997Mar 1;158(5):2192-201,其在此通过提述并入本文。
本scFv-Fc二聚体可以由与美替木单抗中相同VH和VL域的组成,其分别具有SEQID NO:1和SEQ ID NO:5中所示序列。所述VH域可以用具有SEQ ID NO:2中所示序列的VH域来替代;所述VL域可以用具有SEQ ID NO:6中所示序列的VL域来替代。这些VH和VL域公开于美国专利No.6,492,497(例如SEQ ID NOS:4、6、8、和10)中,在此通过提述并入。
“可变域”(VD)意指免疫球蛋白的高变结合域,或受体的配体结合域,其涉及抗原/配体结合,正如本领域技术人员所知的。可变域通常根据其在免疫球蛋白内的位置或来源来称呼,例如免疫球蛋白的轻链可变域(VL)、例如免疫球蛋白的重链可变域(VH)、骆驼型免疫球蛋白的重链可变域(VHH)。
“变体”可变域包含与参考序列相比氨基酸添加、取代和/或删除。VH或VL域的“变体”可以具有多至4个此类氨基酸修饰。例如,两个域的一个可以包含氨基酸取代,而另一个域是未修饰的,或两个域都可以包含氨基酸取代。添加或删除氨基酸残基的修饰可以在VH或VL域的N末端或C末端进行。例如,可以删除VH域的N末端残基。
例如,可以进行多至4个氨基酸取代来将scFv-Fc二聚体去免疫化。例如,去免疫化可以根据Harding等(2010)mAbs2:256-265的方法来进行。
例如,可以取代VH和/或VL域的框架残基来增加scFv-Fc二聚体的稳定性和/或降低其聚集的趋势。低稳定性能影响表达scFv-Fc的二聚体在重组表达时适当折迭的能力,导致表达的非功能性的抗体的级分。低稳定性抗体也可能易于形成潜在免疫原性的聚集体或可以具有受损的亲合力或储藏寿命。scFv多肽具体而言可能在细菌和哺乳动物表达系统二者中表现出稳定性、溶解度、表达、聚集、分解产物、和总体可制造性的问题。预期增加稳定性和/或降低VH和/或VL域的聚集趋势的框架氨基酸取代(例如在scFv多肽中)公开于例如WO 2007/109254中。预期本VH和VL域中的相应残基中的取代类似地增加稳定性和/或scFv-Fc二聚体聚集的趋势。
预期能容许的取代包括会用其他人VH或VL域种系序列中出现的相应氨基酸来代替SEQ ID NO:1、2、5、或6的氨基酸的那些。用这些种系序列的任一个中出现的氨基酸对框架氨基酸的取代是可以容许的。例如,SEQ ID NO:1的VH域的残基可以用任何VH种系序列中对应位置中出现的氨基酸来取代,所述VH种系序列例如来自DP-10(VH 1-69)或DP-88(VH 1-e)的种系序列。这种情况中的对应位置是通过不同种系序列之间的序列比对来确定的,所述比对用本领域所熟知的比对技术(例如ClustalW)来进行。
预期容许的额外取代是那些对侧链暴露于溶剂的氨基酸进行的额外取代,如通过分析三个共晶结构所确定的。可以用本领域所熟知的技术来评估残基的溶剂可及的表面积。进一步地,预期对埋藏在可变域内的氨基酸的取代会是更为容许的,如果该氨基酸的侧链不与邻近的残基产生位阻的话。因此,埋藏的氨基酸通常用具有相似或更小的侧链的氨基酸来取代。例如,用Leu、Val、Ala、或Gly对埋藏的Ile残基的取代预期是容许的。可以通过分析所述三个共晶结构来预测可能由取代产生的位阻。预期容许的进一步取代是在可变域内维持现存的静电相互作用(例如偶极-偶极相互作用、诱导的偶极相互作用、氢键、或离子键)的那些。
可变域的额外的氨基酸取代包括预期为抗体或其抗原结合片段带来新的有用特性的那些。例如,可以去除VH和/或VL域中推定的N-糖基化位点以防止或降低N-糖型的形成。可以用Gln来取代氨基末端残基以引起焦谷酰胺化(pyroglutamylation),其能降低电荷变体的数目。例如,氨基酸取代可以用于降低等电点,这能降低IgG多肽抗体的清除率。
例如,可变域的表面残基可以用Cys或Lys残基来取代,然后其能被共价地修饰并偶联至分子,所述分子能为抗体或其抗原结合片段带来有用特性,例如可检测的标记物、毒素、靶向模块、或蛋白。例如,Cys残基能偶联至细胞毒性药物以形成缀合物。Cys残基还能偶联至增加血清半衰期的分子,例如聚乙二醇(PEG)或血清白蛋白。此类氨基酸修饰综述于例如Beck等(2010)Nature 10:345-52中。
可检测标记物包括放射性标记物如131I或99Tc,可以用本领域已知方法将其附接至抗体或其抗原结合片段。标记物也包括酶标记物如辣根过氧化物酶。标记物还包括化学模块如生物素,其可以通过对特异性的同族可检测模块(例如带标记的抗生物素蛋白)的结合来检测。可以附接其他促进纯化的模块。例如,抗体或其抗原结合片段可以用熟知的重组修饰和表达方法加His标签。
scFv-Fc二聚体的VH和VL域通过接头(此处称为接头1)连接在一起。适于制备scFv片段的接头是本领域所熟知的。参见了如Bird等(1988)Science,242:423-426;Huston等(1988)Proc.Nat’l Acad.Sci.USA 85:5879-5883。例如,这可以通过框内融合编码核酸和在合适的宿主细胞中表达融合蛋白来完成。合适的接头包括[G4S]3-型的那些。[G4S]3-型接头由甘氨酸和丝氨酸残基的重复单元组成。例如,此类接头可以具有SGGGSGGGGSGGGGS(SEQID NO:3)或GGGGSGGGGSGGGGS(SEQ ID NO:4)的序列或其具有多至4个氨基酸修饰的变体。修饰可以包括改变接头长度的删除或插入,或氨基酸取代,优选为从Gly至Ser或反之。[G4S]3-型接头已广泛用于连接scFv结构中的可变域,因为该接头是低变应原的且对可变域造成的构象扭曲最小。参见例如Huston等(1988)Proc.Natl.Acad.Sci.USA 85:5879-83。
在scFv-Fc二聚体中,一种短接头序列(此处称为接头2)任选地插入VL域和铰链之间。这种接头序列增加scFv组分相对于Fc组分的柔性。在一个实施方案中,接头2具有GGSG(SEQ ID NO:20)的序列。对GGSG接头的合适修饰包括改变其1至4个氨基酸的长度或取代1至2个氨基酸,优选为从Gly至Ser或反之。
铰链区是柔性域,其将scFv部分与Fc区连接。IgG和IgA分子中铰链区的柔性允许Fab臂采取广范围的角度,允许结合至被可变距离隔开的表位。合适的铰链区包括,例如具有的氨基酸序列PKSCDKTHTCPPCPAPELLGGP(SEQ ID NO:7)的人IgG1铰链区。例如,该序列对应于人IgG1上铰链、中铰链的部分、和CH2域的N末端部分,如美国专利No.8,048,421的图4B中公开的。来自人IgG1的铰链含有两个Cys残基,其能与对应单体上的铰链的Cys残基形成二硫键。形成二硫键的人IgG1铰链部分含有氨基酸序列CPPCP(SEQ ID NO:21)。人IgG1铰链的变体可以包含该序列。
将scFv组分框内融合至Fc区,其形成二聚体的Fc组分。合适的Fc区含有两个或三个恒定区。Fc区包括来自人IgG1的那些(如SEQ ID NO:8所示),或来自IgG4的那些(如SEQID NO:11的CH2和CH3域中所示)。抗体的Fc区介导其血清半衰期和效应子功能,如补体依赖性的细胞毒性(CDC)、抗体依赖性的细胞毒性(ADCC)和抗体依赖性的细胞吞噬作用(ADCP)。
可以对铰链和Fc区进行修饰以改进scFv-Fc二聚体的多种特性。在一个实施方案中,除了对铰链区的修饰外,还可以对天然存在的人Fc区的1、2、3、4、5或多至10个氨基酸进行修饰。例如,可以修饰Fc区以增加scFv-Fc二聚体的血清半衰期。IgG的半衰期取决于其对受体FcRn的pH依赖性结合。FcRn在内皮细胞表面上表达,其以pH依赖性的方式结合IgG并保护其不备降解。例如,已显示定位于CH2和CH3域的界面的突变增加对FcRn的结合亲和性及IgG1的体内半衰期。例如,此类修饰综述于Strohl WR.,2009.Optimization of Fc-mediated effector functions of monoclonal antibodies.CurrOpin Biotechnol.20(6):685-91;及Vaccaro C.等,2005.Engineering the Fc region of immunoglobulin Gto modulate in vivo antibody levels.Nat Biotechnol.23(10):1283-8中。
对铰链和/或Fc区的其他修饰可以增加或降低效应子功能。四个人IgG同种型以不同的亲和性结合激活性的Fcγ受体(FcγRI、FcγRIIa、FcγRIIIa)、抑制性的FcγRIIb受体、及第一补体组份(C1q),导致不同的效应子功能。例如,IgG对FcγRs或C1q的结合取决于定位于IgG铰链区和CH2域中的残基。这些残基的单个或多个氨基酸取代能通过调制IgG与FcγRs或C1q的相互作用影响效应子功能。已知其他取代影响效应子功能。这些修饰综述于例如Strohl(2009)“Optimization of Fc-mediated effector functions of monoclonalantibodies,”Curr.Opin.Biotechnol.20:685-91中。
铰链和/或Fc区的代表性修饰总结于表1中。
表1.代表性的铰链和Fc区修饰
1.Hinton等(2004)J.Biol.Chem.279(8):6213-16.
2.Vaccaro等(2005)Nature Biotechnol.23(10):1283-88.
3.Armour等(1999)Eur.J.Immunol.29(8):2613-24.
4.Shields等(2001)J.Biol.Chem.276(9):6591-604.
5.Idusogie等(2000)J.Immunol.164(8):4178-84.
6.Idusogie等(2001)J.Immunol.166(4):2571-75.
7.Lazar等(2006)Proc.Nat’l Acad.Sci.USA 103(11):4005-10.
8.Ryan等(2007)Mol.Cancer Ther.6:3009-18.
9.Datta-Mannan等(2007)Drug Metab.Dispos.35:86-94.
10.Steurer等(1995)J.Immunol.155(3):1165-74.
11.Richards等(2008)Mol.Cancer Ther.7(8):2517-27.
12.Labrijn等(2009)Nature Biotechnol.27(8):767-71.
进一步地,重组氨基酸修饰能用于降低表达的多肽的结构同质性。代表性的例子是Peters等(2012)J.Biol.Chem.287(29):24525-33,其公开了IgG4铰链区中的Cys至Ser取代,其降低二硫键异质性并增加Fab域热稳定性。类似地,Zhang等(2010)Anal.Chem.82:1090-99公开了设计IgG2铰链区以限制治疗应用中二硫键杂乱化(scrambling)和结构异构体的形成。对CH3域的氨基酸修饰也能用于删除羧基末端Lys残基以减少电荷变体的数目。氨基酸修饰也可能用于改进重组抗体或其抗原结合片段的药理学功能。例如,氨基酸修饰能用于提高补体活化、通过增加FcγRIIIA结合或减少FcγRIIIB结合来增强抗体依赖性的细胞毒性(ADCC)、和/或通过增加FcRn结合来增加血清半衰期。例如,此类氨基酸修饰综述于Beck等(2010)Nature 10:345-52中。
核酸和制备scFv-Fc二聚体的方法
本发明进一步的方面提供编码scFv-Fc二聚体的核酸。例如,分离的核酸可以是合成的DNA、非天然存在的mRNA、或cDNA。例子包括编码美国专利No.6,492,497的SEQ ID NOS:3、5、7、和9中所示的VH和VL域的核酸。额外的核酸包括本发明的SEQ ID NO:13中所示序列,其编码SEQ ID NO:14中所示的双抗体-5aa,以及SEQ ID NO:15中所示序列,其编码衍生自亮氨酸拉链肽的二聚体,其具有SEQ ID NO:16中所示的氨基酸序列。额外的核酸包括SEQID NO:17中所示序列,其编码CAT191(scFv-Fc),其具有SEQ ID NO:9中所示的氨基酸序列。可以将核酸插入至质粒、载体、或者转录或表达盒内。可以制备编码scFv-Fc二聚体的核酸,且表达的抗体可以用本领域所熟知的常规技术来测试,例如Borsi等(2002)Int.J.Cancer102:75-85中所公开的。
重组宿主细胞可以包含一个或多个上述构建体。用于制备scFv-Fc二聚体的方法包括在宿主细胞中于产生scFv-Fc二聚体的条件下表达编码核酸,并回收抗体。回收抗体的方法可以包括抗体的分离和/或纯化。生产方法可以包括将抗体配制于组合物中,所述组合物包含至少一个额外的组分,如药学可接受的赋形剂。
本文所用的术语“重组宿主细胞”(或简称“宿主细胞”)意指其中引入了外源DNA的细胞。应当理解此类术语不仅意指具体的细胞本体,还指这种细胞的后代。因为具体的修饰可以发生在随后的数代中,这是由于无论突变或环境影响,实际上这种后代可能与母代细胞不是完全一样的,但同样涵盖在本文所用的术语“宿主细胞”的范围内。优选的是,宿主细胞包括选自生物界任一种的原核和真核细胞。优选的真核细胞包括原生生物、真菌、植物和动物细胞。最优选的是,宿主细胞包括但不限于原核细胞系大肠杆菌(E.Coli);哺乳动物细胞系CHO、HEK 293和COS;昆虫细胞系Sf9;以及真菌细胞酿酒酵母(Saccharomycescerevisiae)。
可以选择或构建合适的包含编码scFv-Fc二聚体的核酸的载体,其包含适当的调控序列,包括启动子序列、终止子序列、多聚腺苷酸化序列、增强子序列、标记基因序列和适当的其他序列。例如,载体可以是质粒、噬菌体、噬菌粒、腺病毒、AAV、慢病毒。用于操作核酸(例如制备核酸构建体、诱变、测序、将DNA引入细胞、和基因表达)的技术和实验方案,是本领域所熟知的。
本文所用的术语“载体”意指能将运输预期连接的另一核酸的核酸分子。一种类型的载体是“质粒”,其意指螺旋双链DNA环,额外的DNA片段可以连接到其中。另一种类型的载体是病毒载体,其中额外的DNA片段可以连接到该病毒基因组中。一些载体能在它们所被引入的宿主细胞(例如具有细菌复制起点的细菌载体和游离体(episomal)哺乳动物载体)中自主复制。其他载体(例如非游离体(non-episomal)哺乳动物载体)在引入宿主细胞中时能整合至宿主细胞的基因组中,并由此与宿主基因组一起复制。此外,一些载体能指导与其可操作地连接的基因的表达。此类载体在此称为“重组表达载体”(或简称“表达载体”)。通常,在重组DNA技术中实用的表达载体常常以质粒的形式。在本说明书中,“质粒”和“载体”可以互换地使用,因为质粒是最常用的载体形式。然而,本发明意在包括这些其他形式的表达载体,如病毒载体(例如复制缺陷逆转录病毒、腺病毒、和腺相关病毒),其发挥等价的功能。
将此类核酸引入宿主细胞可以用本领域所熟知的技术来完成。对于真核细胞而言,合适的技术可以包括例如磷酸钙转染、DEAE-右旋糖酐(DEAE-Dextran)、电穿孔、脂质体介导的转染、和用逆转录病毒或其他病毒转导。对于细菌细胞,合适的技术可以包括氯化钙转化、电穿孔、和用噬菌体转染。引入后可为引起或允许由核酸的表达,例如通过在用于表达基因的条件下培养宿主细胞来进行。在一个实施方案中,本发明的核酸整合至宿主细胞的基因组(例如染色体)中。可以按照标准技术通过包含促进与基因组重组的序列来促进整合。
用于在熟知的多种不同的宿主细胞中克隆和表达多肽的系统。合适的宿主细胞包括细菌、哺乳动物细胞、植物细胞、昆虫细胞、真菌、酵母和转基因植物和动物。本领域中用于表达异源多肽的可用哺乳动物细胞系包括中国仓鼠卵巢(CHO)细胞、HeLa细胞、幼仓鼠肾细胞、小鼠黑色素瘤细胞、大鼠骨髓瘤细胞、人胚肾细胞(例如HEK293细胞)、人胚视网膜细胞、和许多其他细胞系。抗体及其抗体片段在原核细胞(例如大肠杆菌)中的表达是本领域中已发展完善的。综述参见例如Plückthun Bio/Technology9:545-551(1991)。在培养的真核中的表达对于本领域技术人员而言也是可用的,如例如Andersen等(2002)Curr.Opin.Biotechnol.13:117-23中所综述的。
scFv-Fc二聚体可以天然地或是表达宿主(例如CHO、HEK293、或NSO(ECACC85110503)细胞)选择地糖基化,或它们可以是非糖基化的,例如如果通过在原核细胞中表达来产生的话。还可以特意对糖基化进行改变,例如通过抑制岩藻糖基化,从而增加所得scFv-Fc二聚体的ADCC活性。
使用抗体或其抗原结合片段的方法
scFv-Fc二聚体可用于治疗或诊断人或动物身体的方法中,如人患者中的疾病或病症的治疗方法(其可以包括预防性治疗),其包括使用有效量来治疗该患者。可治疗的病况包括TGFβ1起作用的任何病况,例如纤维化疾病、癌症、免疫介导的疾病、和伤口愈合,例如弥散性皮肤系统性硬化病、骨重塑疾病、肾病和/或其组合。
已显示特异性针对人TGFβ1的抗体在动物模型中对于治疗TGFβ1肾小球性肾炎(Border等(1990)Nature 346:371-374)、神经瘢痕形成(Logan等(1994)Eur.J.Neurosci.6:355-363)、真皮瘢痕形成(Shah等(1992)Lancet 339:213-214;Shah等(1994)J.Cell Science 107:1137-1157;Shah等(1995)J.Cell Science 108:985-1002)、及肺纤维化(Giri等(1993)Thorax 48:959-966)是有效的。进一步地,已显示针对TGFβ1、2、和3的抗体在肺纤维化、辐射诱导的纤维化(美国专利No.5,616,561)、骨髓纤维化、烧伤、Dupuytren氏挛缩(Dupuytren’s contracture)、胃溃疡、和类风湿性关节炎模型中是有效的(Wahl等(1993)Exp.Medicine 177:225-230)。
scFv-Fc二聚体对于治疗由TGFβ1活性直接或间接引起的疾病和病况是有用的。scFv-Fc二聚体可以在体外或体内选择性抑制人TGFβ1同种型的活性。TGFβ1同种型的活性包括但不限于:TGFβ介导的信号传输、细胞外基质(ECM)沉积、抑制上皮和内皮细胞增殖、促进平滑肌增殖、诱导III型胶原表达、诱导TGF-β、纤连蛋白、VEGF和IL-11表达、结合潜在相关肽(Latency Associated Peptide)、肿瘤诱导的免疫抑制、促进血管生成、活化成肌纤维细胞、促进转移、和抑制NK细胞活性。例如scFv-Fc二聚体对于治疗局灶性节段性肾小球硬化(FSGS)、肝纤维化(HF)、急性心肌梗死(AMI)、特发性肺纤维化(IPF)、硬皮病(SSc)、和马方综合征(Marfan Syndrome)。
scFv-Fc二聚体对于治疗疾病和病况是有用的,所述疾病和病况包括但不限于纤维化疾病(如肾小球性肾炎、神经瘢痕形成、真皮瘢痕形成、肺纤维化(pulmonaryfibrosis)、肺部纤维化(lung fibrosis)、辐射诱导的纤维化、肝纤维化、骨髓纤维化)、烧伤、免疫介导的疾病、炎症性疾病(包括类风湿性关节炎)、移植排斥、癌症、Dupuytren氏挛缩、和胃溃疡。它们对于治疗、预防肾机能不全或其降低发病风险也是有用的,所述肾机能不全包括但不限于:糖尿病(I型和II型)肾病、辐射诱导的肾病、梗阻性肾病、弥散性系统性硬化病、肺纤维化、同种异体移植物排斥、遗传性肾病(例如多囊性肾病、髓质海绵肾、马蹄肾)、肾小球性肾炎、肾硬化、肾钙质沉着症、系统性红斑狼疮、斯耶格伦氏综合征(Sjogren’s syndrome)、贝格尔氏病(Berger’s disease)、系统性或肾小球性高血压、小球间质性肾病、肾小管性酸中毒、肾结核、及肾梗死。具体而言,当与肾素-血管紧张素-醛固酮系统的拮抗剂组合时,它们是有用的,所述拮抗剂包括但不限于:肾素抑制剂、血管紧张素转化酶(ACE)抑制剂、Ang II受体拮抗剂(也称为“Ang II受体阻断剂”)、和醛固酮拮抗剂。例如,用于组合使用scFv-Fc二聚体与此类拮抗剂的方法示于WO2004/098637中。
scFv-Fc二聚体对于治疗与ECM沉积相关的疾病和病况也是有用的,所述疾病和病况包括系统性硬化病、手术后黏附(postoperative adhesions)、瘢痕疙瘩和肥厚性瘢痕形成、增殖性玻璃体视网膜病变、青光眼引流手术(glaucoma drainage surgery)、角膜损伤、白内障、佩伦涅氏病(Peyronie’s disease)、成人呼吸窘迫综合征、肝硬化、心肌梗死后瘢痕形成、血管成形术后再狭窄(post angioplasty restenosis)、蛛网膜下腔出血后瘢痕形成、多发性硬化、椎板切除术后纤维化、肌腱和其他修复后纤维化、由去除纹身引起的瘢痕形成、胆汁性肝硬化(包括硬化性胆管炎)、心包炎、胸膜炎、气管造口术、渗透性中枢神经系统损伤、嗜曙红细胞肌痛综合征、血管再狭窄、静脉闭塞性病、胰腺炎和牛皮癣性关节病。
scFv-Fc二聚体对于在疾病和病况中促进上皮细胞再形成也是有用的,所述疾病和病况如静脉性溃疡、缺血性溃疡(褥疮)、糖尿病性溃疡、移植部位、移植供体部位、擦伤和烧伤、支气管上皮的疾病,如哮喘、ARDS、肠上皮的疾病,如与细胞毒性治疗相关的粘膜炎、食管溃疡(反流疾病)、胃溃疡、小肠和大肠的病损(炎性肠病)。
scFv-Fc二聚体也用于促进内皮细胞增殖(例如在稳定动脉粥样硬化斑块中)、促进血管吻合术(anastomosis)的伤愈、或抑制平滑肌细胞增殖(例如在动脉疾病、再狭窄、和哮喘中)。
scFv-Fc二聚体对于增强针对巨噬细胞介导的感染的免疫响应而言是有用的。它们对于降低免疫抑制(例如肿瘤、AIDS、或肉芽肿性疾病引起的免疫抑制)也是有用的。scFv-Fc二聚体对于治疗过度增生性疾病是有用的,所述过度增生性疾病如癌症,包括但不限于乳腺、前列腺、卵巢、胃、肾、胰腺、结肠直肠、皮肤、肺、宫颈及膀胱癌、胶质瘤、间皮瘤、以及多种白血病及肉瘤,如卡波西肉瘤(Kaposi’s sarcoma),并且对于治疗或预防此类肿瘤的复发或转移是有用的。本发明的scFv-Fc二聚体还用于抑制环孢菌素(cyclosporin)介导的转移。
在癌症治疗的上下文中,“治疗”包括任何导致肿瘤生长减缓或肿瘤转移减少、以及癌症部分缓解从而延长患者预期寿命的医学干预。
治疗方法包括施用scFv-Fc二聚体或包含scFv-Fc二聚体的药物组合物。scFv-Fc二聚体可用于制造用于施用的药物中。例如,制备药物或药物组合物的方法包括用药学可接受的赋形剂配制scFv-Fc二聚体。组合物可以单独施用或与其他治疗组合施用,所述组合施用或是同时的或是序贯的,取决于其要治疗的病况。
施用优选为以足以对患者显示出益处的“治疗有效量”进行。此类益处可以是具体疾病或病况的至少一个症状的改善。实际的施用量及施用的速率和时间进程会取决于治疗的疾病或病况的性质和严重程度。治疗的处方,例如对剂量等的决定,可以基于临床前和临床研究来确定,对所述研究的设计完全是在本领域技术水平内的。
精确剂量会取决于一些因素,包括scFv-Fc二聚体是用于诊断还是用于治疗、要治疗的部位的大小和位置、以及附接于所述scFv-Fc二聚体的任何可检测标记物或其他分子的性质。例如,scFv-Fc二聚体的典型剂量用于全身应用可以在100μg至1克的范围,而用于局部应用可以为1μg至1mg。用于成人患者单一治疗的剂量可以针对少儿和婴儿进行比例性调整。治疗可以每天一次、每周两次、每周一次、每月一次或根据其他间隔进行重复,由医师斟酌决定。治疗可以是周期性的,并且施用之间的周期为约2周或更多周、优选为约3周或更多周、更优选为4周或更多周,或每周约一次。
预期约0.1、0.3、1、3、10、或15毫克每千克患者体重的剂量水平是有用且安全的。例如,大鼠和小鼠中的0.5-5mg/kg在急性病情中是有效的剂量。因此,对于长期给药而言,基于预期的21天半衰期,可以对人施用0.3-10mg/kg。剂量对于功效而言可以是足够的,即使足够低以助于最佳施用。例如,低于50mg的剂量有助于皮下施用。可将静脉内施用用作针对严重疾病的递送途径,其中可能需要高剂量和长给药间隔。皮下注射能增加对于产品的潜在免疫响应。对局部疾病的局部施用能降低施用的产品量并增加作用部位的浓度,其能提高安全性。
本发明的scFv-Fc二聚体可以通过注射施用,例如皮下、静脉内、腔内(例如在肿瘤切除后)、病损内(intralesionally)、腹膜内、或肌内注射。ScFv-Fc二聚体还可以通过吸入或局部地(例如眼内、鼻内、直肠、伤口中、皮肤上)、或口服递送。
scFv-Fc二聚体通常会以药物组合物的形式施用,所述药物组合物可以包含除scFv-Fc二聚体外的至少一个组分。因此药物组合物可以包含药学可接受的赋形剂、载体、缓冲剂、稳定剂或其他本领域技术人员所熟知的材料。此类材料应当是无毒的且应当不干扰活性成分的功效。此类材料可以包括例如任何及全部溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂、和吸收延迟剂。药学可接受的载体的一些例子是水、盐水、磷酸盐缓冲盐水、右旋糖、甘油、乙醇等等,及其组合。在许多情况下,优选在组合物中包括等渗剂,例如糖、多元醇、如甘露醇、山梨醇,或氯化钠。药学可接受的物质的其他例子是润湿剂或辅助物质,如乳化剂、防腐剂、或缓冲剂,其增加储藏期或有效性。
载体或其他材料的准确性质取决于施用途径。对于静脉内注射或在患处的注射而言,活性成分会是非经肠的可接受水溶液形式,其是无热原的且具有合适的pK、等渗性、和稳定性。本领域那些相关技术能很好地制备合适的溶液,例如用等渗介质(如氯化钠注射液、林格氏注射液(Ringer’s injection)、和乳酸林格氏注射液)来制备。可以包括防腐剂、稳定剂、缓冲剂、抗氧化剂和/或其他添加剂。
可以将scFv-Fc二聚体配制于液体、半固体、或固体形式中,如液体溶液(例如可注射和可输注(infusible)溶液)、分散液或悬浮液、粉剂、脂质体、和栓剂。优选的形式取决于意欲施用的模式、治疗应用、分子的理化特性、以及递送途径。配制物可以包括赋形剂、或赋形剂的组合,例如:糖、氨基酸和表面活性剂。液体配制物可以包括广范围的scFv-Fc二聚体浓度和pH。固体配制物可以通过例如冻干法、喷雾干燥、或通过超临界流体技术的干燥来生产。
可以将治疗组合物配制为溶液、微乳液、分散液、脂质体、或其他适于高药物浓度的有序结构。可以通过将scFv-Fc二聚体与上述成分的一个或其组合合并于合适的溶剂中,然后过滤除菌,来制备无菌注射液。通常,通过将活性化合物并入含有基本分散介质和其他来自上述的成分的无菌介质中,来制备分散液。在用于制备无菌注射液的无菌粉末的情况中,优选的制备方法是真空干燥法和冻干法,其得到活性成分加任何额外想要的成分的粉末,所述想要的成分来自其先前经无菌过滤的溶液。例如,可以通过使用包衣(如卵磷脂)、通过维持分散液的粒度、或通过使用表面活性剂来维持溶液的适当流动性。对注射组合物的延长的吸收可以通过将延迟吸收的药剂(例如单硬脂酸盐和明胶)包含于组合物中来实现。
在一些实施方案中,可以将活性化合物与载体一起制备,所述载体会保护scFv-Fc二聚体不被快速释放,如控释制剂,包括移植物、透皮贴片、和微囊化的递送系统。可以使用生物可降解的、生物可相容的聚合物,如乙烯醋酸乙烯酯、聚酐类、聚乙醇酸、胶原、聚原酸酯类、和聚乳酸。许多用于制备此类制剂的方法是获得了专利的或是本领域技术人员普遍知晓的。
使用scFv-Fc二聚体的方法可以包括引起或允许对TGFβ的结合。这种结合可以在体内发生,例如在对患者施用scFv-Fc二聚体后发生,或其可以在体外发生,例如在ELISA、Western印迹、免疫细胞化学法、免疫沉淀法、亲和色谱法、或基于细胞的测定中发生,或在基于离体的治疗方法中发生,例如这样的方法,其中将细胞或体液离体地与scFv-Fc二聚体接触然后施用于患者。
提供了包含scFv-Fc二聚体的套盒。可以对scFv-Fc二聚体进行标记以允许其在要确定的样品中的反应性。例如,可以在诊断分析中采用所述套盒。套盒可以含有用于使用组分的说明。用于帮助此种方法或使其能够实施的辅助材料可以包含在套盒内。
scFv-Fc二聚体在样品中的反应性可以通过任何合适的方法来确定,例如放射免疫测定法(RIA)。可以将带放射性标记的抗原与未标记的抗原(测试样品)混合并允许其结合至scFv-Fc二聚体。将结合的抗原与未结合的抗原物理性地分离,并确定结合至scFv-Fc二聚体的放射性抗原的量。也可以用非放射性抗原来使用竞争性结合测定,其使用连接至报告分子的抗原或类似物。所述报告分子可以是荧光染料、磷光体(phosphor)、或染料。合适的荧光染料包括荧光素、罗丹明、藻红蛋白、和德州红(Texas Red)。合适的发色染料包括二氨基联苯胺。
其他报告子包括大分子胶原颗粒或微粒材料如胶乳球(其是有色的、磁性的或顺磁性的),以及生物或化学活性剂,其能直接或间接引起可检测信号被视觉观察到、电子地检测到,或以其他方式记录到。例如,这些分子可以是催化反应的酶,所述反应显出颜色或改变颜色或是引起电特性的变化。它们可以是分子可激动性的(molecularly excitable),从而能态之间的电子跃迁导致特有的光谱吸收或发射。它们可以包括连同生物传感器一起使用的化学实体。可以采用生物素/抗生物素蛋白或生物素/链霉抗生物素蛋白和碱性磷酸酶检测系统。抗体-报告子缀合物产生的信号可用于产生样品中相关抗体结合的可量化绝对或相对数据。
本发明还提供scFv-Fc二聚体用于测量竞争测定中抗原水平的用途。可以将scFv-Fc二聚体连接至报告子分子,从而在结合时发生例如物理学或光学变化。报告子分子可以直接或间接地产生可检测的,优选为可测量的信号。报告子分子可以直接或间接地、共价地(例如经肽键连接)或非共价地连接。scFv-Fc二聚体和蛋白报告子可以通过肽键连接并重组表达为融合蛋白。
本发明进一步的方面和实施方案根据本公开对于本领域技术人员而言会是明显的,所述公开包括如下实验例示。
实施例
实施例1:scFv和IgG4抗体的亲和性及效力
CAT192(IgG4)(美替木单抗)是选择性中和TGF-β1的人IgG4单克隆抗体。将TGF-β1(20-600RU)用NHS/EDC化学固定化至Biacore上的CM5芯片。将多个量的CAT192(IgG4)注射在表面上,以监测对TGFβ1的结合,其通过表面等离子体共振来确定。用1:1结合模型来分析数据,以确定结合常数。如通过表面等离子体共振所确定的,当与亲本CAT191scFv的结合相比时,发现CAT192(IgG4)以相对低的亲和性结合TGFβ1,如图2中所示。CAT192(IgG4)还在基于A549的效力测定中显示出相对低的效力(IC50=~10nM),所述效力测定测量了对TGFβ1刺激的IL-11生产的抑制。A549测定的代表性结果示于图3中。A549测定是根据Rapoza等(2006)“Development of an in vitro potency assay for therapeutic TGFβantagonists:the A549cell bioassay,”J.Immunol.Methods 316:18-26中公开的步骤进行的。当明显的~10nM的离解常数显示出对TGFβ1的特异性结合,CAT192(IgG4)的治疗应用会从较高的相对效力获益。
实施例2:经修饰的IgG1抗体
CAT192(IgG4)亲和性能被一些变性条件轻微地增强,这说明抗体折迭可能在scFv至IgG4的转换过程中引起了亲和性损失。已有人提出IgG4折迭是独特的(Aalberse和Schuurman“IgG4breaking the rules”,Immunology 105:9-19)。IgG4中的Fab臂交换和Fab与Fc CH2域的相互作用可能解释了这种CAT192(IgG4)的亲和性损失。因此,通过用共有的IgG1序列替换IgG4Fc(CH1、CH2和CH3域),将CAT192重塑以产生IgG1版本。编码CAT192(IgG1)的DNA自GeneArt合成并被亚克隆至表达载体pCEP4(-E+I)Dest中。
从HEK293转染产生CAT192(IgG1)并用Protein A柱将其纯化。然而,将CAT192从IgG4重塑为IgG1未增加其亲和性。产生自IgG1和IgG4的Fab片段也未增加其亲和性。结论为CAT191(scFv)(SEQ ID NO:12)的高亲和性在转换为全长抗体形式的过程中损失了,无论其是IgG1还是IgG4。这是没有预料到的,因为获取自文库的scFv组分通常被工程化为全长IgG形式,用于治疗开发。
实施例3:多种二聚体设计
用表面等离子体共振发现CAT191(scFv)(SEQ ID NO:12)以高亲和性结合TGFβ1,但CAT191(scFv)缺乏TGFβ1的有效中和所需的亲合力。因而,用scFv组分作为基本构件测试了多种其他形式。抗体片段的通用形式(包括测试的形式)示于图1中。
测试的形式包括双抗体、肽衍生的二聚体(例如,亮氨酸拉链肽衍生的二聚体)和scFv-Fc二聚体。scFv CAT191双抗体中以短的5aa接头(GSSGG)(SEQ ID NO:19)替换(Gly4Ser)3-型接头以产生非共价二价结合体(双抗体二聚体)。每个单体具有SEQ ID NO:14中所示序列。亮氨酸拉链肽衍生的二聚体的每个单体具有SEQ ID NO:16中所示序列。最后,scFv-Fc二聚体的每个单体具有SEQ ID NO:9中所示序列。所述双抗体和肽衍生的二聚体表达于大肠杆菌中,并且scFv-Fc表达于HEK293细胞中。
亮氨酸拉链肽衍生的二聚体是难以表达的,并且部分纯化的二聚体仅显示中等亲和性,如表面等离子体共振所测量的。双抗体(scFv 5aa)仅显示中等亲和性,但没有亲合力。相比之下,发现产生自瞬时HEK293转染的scFv-Fc二聚体以高亲和性和亲合力特异性地结合至TGFβ1。通过表面等离子体共振获得的表示为表观离解常数的结合结果概括于下表2中。
表2:scFv-Fc二聚体的结合结果
还在基于A549细胞的生物测定中比较了多种形式的TGFβ1中和效力。图3显示了双抗体(“scFv双抗体5aa”)、CAT191(scFv)(“scFv”)、scFv-Fc二聚体(“CAT191(scFv-Fc”)、和CAT192(IgG4)(“CAT192”)的A549生物测定结果。如图3中所见,scFv-Fc二聚体在此项测定中显示出比CAT192低了超过4个数量级(~10-3nM对~101nM)的表观离解常数。
实施例4:scFv-Fc克隆
在CHO细胞中以较大的规模克隆和产生了CAT191(scFv-Fc)。用基因特异性的正向和反向引物组从基于pCEP4的表达载体来PCR扩增CAT191scFv-Fc编码序列。作为PCR扩增的一部分,将如下变化引入至CAT191scFv-Fc编码序列:1)在5’和3’末端处添加内切核酸酶位点,2)在起始密码子的紧邻上游添加Kozak共有序列,3)将“TAG”终止密码子变为“TAA”,及4)将终止密码子上游的胸腺嘧啶核苷4核苷酸突变为鸟嘌呤核苷,从而消除内源的剪接供体位点。所述剪接供体位点突变未导致氨基酸变化。
将PCR扩增的CAT191编码序列亚克隆至穿梭载体中,以帮助序列验证和分子克隆。在序列验证后,将CAT191编码序列克隆至Genzyme表达载体pGZ600和pGZ620中。两个载体都使用了仓鼠β-肌动蛋白启动子来驱动CAT191转基因的表达。它们还含有DHFR选择标志物,其由单独的启动子(SV40)驱动,从而能够在CHO细胞中进行选择。用pGZ600-CAT191或pGZ620-CAT191表达质粒转染CHO-8D6宿主细胞系。在简短的回收期后,将经转染的细胞置于缺乏核苷酸的用于选择的生长培养基中以产生稳定转染子的汇合物(pools)。在从选择回收汇合物后,在20nM甲氨蝶呤的存在下进行第二轮选择。将以此种方式选出的CHO汇合物按比例增加,并将经调适的培养基用于使用Protein A柱纯化。
CHO细胞产生的蛋白通过SDS-PAGE、Biacore结合、SEC-HPLC及A549细胞效力测定来表征。结果证实了scFv-Fc二聚体具有较高的亲和性和效力,并且其特异性地中和了TGFβ1。所述效力相比于泛特异性的GC1008抗体更有利(图6和图7)。
实施例5:循环半衰期
在小鼠模型中用表3中所示的研究设计测试CAT191(scFv-Fc)的循环半衰期。
表3:scFv-Fc二聚体的循环半衰期
在腹膜内(IP)或静脉内(IV)施用后指定时间从眼球后血管丛(retro-orbitalplexus)采血。收集约60μL的全血于血细胞比容管内并加工为血清。所有样品储存于-80℃直至分析。通过ELISA确定CAT191(scFv-Fc)浓度。此药代动力学研究的结果示于图4和图5中。结果表明了1.5-2.0天的循环半衰期,这比典型的scFv分子要长得多,后者为数小时。
实施例6:scFv-Fc二聚体稳定性
通过SEC-HPLC、Biacore TGFβ1结合、及A549效力测定对储存于-80℃的CAT191(scFv-Fc)的稳定性监测一年。在测试期间对聚集、亲和性、或效力未观察到变化。储存于4℃的材料在一年表现出了轻微但稳定的聚集增加。较小的尺寸、高选择性、针对TGFβ1的效力、及长体内半衰期的独特组合使CAT191(scFv-Fc)成为用于治疗应用的理想候选物。
本文全文引用的所有文献,包括但不限于科学出版物、专利及专利申请出版物,在此通过提述并入本公开,如同其完整内容再现于此。
序列表
SEQ ID No.1:人IgG1VH域克隆SL15(SQN4US6492497)
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTDPQYSWGQGTTVTVSS
SEQ ID No.2:人IgG1VH域克隆JT182(SQN10US6492497)
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTPASPDWGQGTTVTVSS
SEQ ID No.3:合成接头
SGGGSGGGGSGGGGS
SEQ ID No.4:合成接头
GGGGSGGGGSGGGGS
SEQ ID No.5:人IgG1Vκ域克隆SL15A:(SQN6US6492497)
EIVLTQSPSSLSASVGDRVTITCRASQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIK
SEQ ID No.6:人IgG1Vκ域克隆SL15S:(SQN8US6492497)
EIVLTQSPSSLSASVGDRVTITCRSSQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIK
SEQ ID No.7:人IgG1铰链区
PKSCDKTHTCPPCPAPELLGGP
SEQ ID No.8:人IgG1Fc区
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID No.9:CAT191(scFv-Fc)
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTDPQYSWGQGTTVTVSSSGGGSGGGGSGGGGSEIVLTQSPSSLSASVGDRVTITCRSSQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIKGGSGPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID No.10:CAT192(IgG4)轻链
EWLTQSPSSLSASVGDRVTITCRASQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID No.11:CAT192(IgG4)重链
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTDPQYSWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID No.12:CAT191(scFv)
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTDPQYSWGQGTTVTVSSSGGGSGGGGSGGGGSEIVLTQSPSSLSASVGDRVTITCRSSQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIK
SEQ ID No.13:双抗体-5aa编码核酸
Atgaccatgattacgccaagctttggagccttttttttggagattttcaacgtgaaaaaattattattcgcaattcctttagttgttcctttctatgcggcccagccggccatggccgaggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcctctggattcaccttcagtagctatggcatgcactgggtccgccaggctccaggcaaggagctggagtgggtggcagttatatcatatgatggaagtattaaatactatgcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaacagcctgagagctgaggacacggctgtgtattactgtgcgcgaactggtgaatatagtggctacgatacggacccccagtactcctgggggcaagggaccacggtcaccgtctcctcaggttcctctggcggtgaaattgtgctgactcagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccggtcaagtcagggcattggagatgatttgggctggtatcagcagaagccagggaaagcccctatcctcctgatctatggtacatccactttacaaagtggggtcccgtcaaggttcagcggcagtggatctggcacagatttcactctcaccatcaacagcctgcagcctgaagattttgcaacttattactgtctacaagattccaattacccgctcactttcggcggagggacacgactggagattaaacgtgcggccgcacatcatcatcaccatcacggggccgcagaacaaaaactcatctcagaagaggatctgaatggggccgcatagtagctcgagatcaaacgggctagccagccagaactcgccccggaagaccccgaggatgtcgagcaccaccaccaccac
SEQ ID No.14:双抗体-5aa
EVQLVESGGGVVQPGRSLRLSCAASGFTESSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTDPQYSWGQGTTVTVSSGSSGGEIVLTQSPSSLSASVGDRVTITCRSSQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIKRAAAHHHHHHGAAEQKLISEEDLNGAA
SEQ ID No.15:亮氨酸拉链肽衍生的二聚体编码核酸
gaggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcctctggattcaccttcagtagctatggcatgcactgggtccgccaggctccaggcaaggagctggagtgggtggcagttatatcatatgatggaagtattaaatactatgcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaacagcctgagagctgaggacacggctgtgtattactgtgcgcgaactggtgaatatagtggctacgatacggacccccagtactcctgggggcaagggaccacggtcaccgtctcctcaagtggaggcggttcaggcggaggtggcagcggcggtggcggatcggaaattgtgctgactcagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccggtcaagtcagggcattggagatgatttgggctggtatcagcagaagccagggaaagcccctatcctcctgatctatggtacatccactttacaaagtggggtcccgtcaaggttcagcggcagtggatctggcacagatttcactctcaccatcaacagcctgcagcctgaagattttgcaacttattactgtctacaagattccaattacccgctcactttcggcggagggacacgactggagattaaacgtgcggccgcacatcatcatcaccatcacggggccgcagaacaaaaactcatctcagaagaggatctgaatggggccgcacccaagcccagtacccccccaggttcttcaggcgaactggaagaactgctgaaacatctgaaagaactgctgaaaggcccgcgtaaaggcgaactggaagaactgctgaaacatctgaaagaactgctgaaaggcggtgcgccgggcggtcatcatcatcaccatcat
SEQ ID No.16:亮氨酸拉链肽衍生的二聚体
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKELEWVAVISYDGSIKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTGEYSGYDTDPQYSWGQGTTVTVSSSGGGSGGGGSGGGGSEIVLTQSPSSLSASVGDRVTITCRSSQGIGDDLGWYQQKPGKAPILLIYGTSTLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCLQDSNYPLTFGGGTRLEIKRAAAHHHHHHGAAEQKLISEEDLNGAAPKPSTPPGSSGELEELLKHLKELLKGPRKGELEELLKHLKELLKGGAPGGHHHHHH
SEQ ID No.17:CAT191(scFv-Fc)编码核酸
gaggtgcagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcctctggattcaccttcagtagctatggcatgcactgggtccgccaggctccaggcaaggagctggagtgggtggcagttatatcatatgatggaagtattaaatactatgcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaacagcctgagagctgaggacacggctgtgtattactgtgcgcgaactggtgaatatagtggctacgatacggacccccagtactcctgggggcaagggaccacggtcaccgtctcctcaagtggaggcggttcaggcggaggtggcagcggcggtggcggatcggaaattgtgctgactcagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccggtcaagtcagggcattggagatgatttgggctggtatcagcagaagccagggaaagcccctatcctcctgatctatggtacatccactttacaaagtggggtcccgtcaaggttcagcggcagtggatctggcacagatttcactctcaccatcaacagcctgcagcctgaagattttgcaacttattactgtctacaagattccaattacccgctcactttcggcggagggacacgactggagattaaaggtggcagcggacctaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacgtgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcagatggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaatagtag
SEQ ID No.18:人TGFβ1
ALDTNYCFSSTEKNCCVRQLYIDFRKDLGWKWIHEPKGYHANFCLGPCPYIWSLDTQYSKVLALYNQHNPGASAAPCCVPQALEPLPIVYYVGRKPKVEQLSNMIVRSCKCS
SEQ ID No.19
GSSGG
SEQ ID No.20
GGSG
SEQ ID No.21
CPPCP
SEQ ID No.22
SYGMH
SEQ ID No.23
VISYDGSIKYYADSVKG
SEQ ID No.24
TGEYSGYDTSGVEL
SEQ ID No.25
TGEYSGYDTDPQYS
SEQ ID No.26
TGFYSGYDTPASPD
SEQ ID No.27
RASQGIGDDLG
SEQ ID No.28
GTSTLQS
SEQ ID No.29
LQDSNYPLT
SEQ ID No.30
TGX1YSGYDTX2X3X4X5X6
序列表
<110> C·潘
邱华伟
J·博德
<120> 以高亲和力、亲和性及特异性结合转化生长因子-β1的scFv-Fc二聚体
<130> 578962
<150> 62/128133
<151> 2015-03-04
<160> 30
<170> PatentIn 3.5版
<210> 1
<211> 123
<212> PRT
<213> 人(Homo sapiens)
<400> 1
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Glu Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Ile Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Glu Tyr Ser Gly Tyr Asp Thr Asp Pro Gln Tyr Ser
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 2
<211> 123
<212> PRT
<213> 人(Homo sapiens)
<400> 2
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Glu Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Ile Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Glu Tyr Ser Gly Tyr Asp Thr Pro Ala Ser Pro Asp
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 3
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 3
Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 4
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 4
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 5
<211> 107
<212> PRT
<213> 人(Homo sapiens)
<400> 5
Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Asp Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Ile Leu Leu Ile
35 40 45
Tyr Gly Thr Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Ser Asn Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 6
<211> 107
<212> PRT
<213> 人(Homo sapiens)
<400> 6
Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Gly Ile Gly Asp Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Ile Leu Leu Ile
35 40 45
Tyr Gly Thr Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Ser Asn Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 7
<211> 22
<212> PRT
<213> 人(Homo sapiens)
<400> 7
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
1 5 10 15
Glu Leu Leu Gly Gly Pro
20
<210> 8
<211> 209
<212> PRT
<213> 人(Homo sapiens)
<400> 8
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
1 5 10 15
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
20 25 30
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
35 40 45
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
50 55 60
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
65 70 75 80
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
85 90 95
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
100 105 110
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
115 120 125
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
130 135 140
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
145 150 155 160
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
165 170 175
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
180 185 190
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
195 200 205
Lys
<210> 9
<211> 480
<212> PRT
<213> 人(Homo sapiens)
<400> 9
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Glu Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Ile Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Glu Tyr Ser Gly Tyr Asp Thr Asp Pro Gln Tyr Ser
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ser Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln
130 135 140
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ser Ser Gln Gly Ile Gly Asp Asp Leu Gly Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Ile Leu Leu Ile Tyr Gly Thr Ser Thr Leu
180 185 190
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
Tyr Cys Leu Gln Asp Ser Asn Tyr Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
Arg Leu Glu Ile Lys Gly Gly Ser Gly Pro Lys Ser Cys Asp Lys Thr
245 250 255
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
260 265 270
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
275 280 285
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
290 295 300
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
305 310 315 320
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
325 330 335
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
340 345 350
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
355 360 365
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
370 375 380
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
385 390 395 400
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
405 410 415
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
420 425 430
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
435 440 445
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
450 455 460
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475 480
<210> 10
<211> 213
<212> PRT
<213> 人(Homo sapiens)
<400> 10
Glu Trp Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
1 5 10 15
Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Gly Asp Asp Leu
20 25 30
Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Ile Leu Leu Ile Tyr
35 40 45
Gly Thr Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Ser Asn Tyr Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 11
<211> 450
<212> PRT
<213> 人(Homo sapiens)
<400> 11
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Glu Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Ile Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Glu Tyr Ser Gly Tyr Asp Thr Asp Pro Gln Tyr Ser
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
260 265 270
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
435 440 445
Gly Lys
450
<210> 12
<211> 245
<212> PRT
<213> 人(Homo sapiens)
<400> 12
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Glu Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Ile Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Glu Tyr Ser Gly Tyr Asp Thr Asp Pro Gln Tyr Ser
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ser Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln
130 135 140
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ser Ser Gln Gly Ile Gly Asp Asp Leu Gly Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Ile Leu Leu Ile Tyr Gly Thr Ser Thr Leu
180 185 190
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
Tyr Cys Leu Gln Asp Ser Asn Tyr Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
Arg Leu Glu Ile Lys
245
<210> 13
<211> 984
<212> DNA
<213> 人(Homo sapiens)
<400> 13
atgaccatga ttacgccaag ctttggagcc ttttttttgg agattttcaa cgtgaaaaaa 60
ttattattcg caattccttt agttgttcct ttctatgcgg cccagccggc catggccgag 120
gtgcagctgg tggagtctgg gggaggcgtg gtccagcctg ggaggtccct gagactctcc 180
tgtgcagcct ctggattcac cttcagtagc tatggcatgc actgggtccg ccaggctcca 240
ggcaaggagc tggagtgggt ggcagttata tcatatgatg gaagtattaa atactatgca 300
gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctg 360
caaatgaaca gcctgagagc tgaggacacg gctgtgtatt actgtgcgcg aactggtgaa 420
tatagtggct acgatacgga cccccagtac tcctgggggc aagggaccac ggtcaccgtc 480
tcctcaggtt cctctggcgg tgaaattgtg ctgactcagt ctccatcctc cctgtctgca 540
tctgtaggag acagagtcac catcacttgc cggtcaagtc agggcattgg agatgatttg 600
ggctggtatc agcagaagcc agggaaagcc cctatcctcc tgatctatgg tacatccact 660
ttacaaagtg gggtcccgtc aaggttcagc ggcagtggat ctggcacaga tttcactctc 720
accatcaaca gcctgcagcc tgaagatttt gcaacttatt actgtctaca agattccaat 780
tacccgctca ctttcggcgg agggacacga ctggagatta aacgtgcggc cgcacatcat 840
catcaccatc acggggccgc agaacaaaaa ctcatctcag aagaggatct gaatggggcc 900
gcatagtagc tcgagatcaa acgggctagc cagccagaac tcgccccgga agaccccgag 960
gatgtcgagc accaccacca ccac 984
<210> 14
<211> 262
<212> PRT
<213> 人(Homo sapiens)
<400> 14
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Glu Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Glu Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Ile Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Glu Tyr Ser Gly Tyr Asp Thr Asp Pro Gln Tyr Ser
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Ser Ser Gly Gly
115 120 125
Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
130 135 140
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Gly Ile Gly Asp Asp
145 150 155 160
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Ile Leu Leu Ile
165 170 175
Tyr Gly Thr Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
180 185 190
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro
195 200 205
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Asp Ser Asn Tyr Pro Leu
210 215 220
Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys Arg Ala Ala Ala His
225 230 235 240
His His His His His Gly Ala Ala Glu Gln Lys Leu Ile Ser Glu Glu
245 250 255
Asp Leu Asn Gly Ala Ala
260
<210> 15
<211> 984
<212> DNA
<213> 人(Homo sapiens)
<400> 15
gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg agctggagtg ggtggcagtt atatcatatg atggaagtat taaatactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gcgaactggt 300
gaatatagtg gctacgatac ggacccccag tactcctggg ggcaagggac cacggtcacc 360
gtctcctcaa gtggaggcgg ttcaggcgga ggtggcagcg gcggtggcgg atcggaaatt 420
gtgctgactc agtctccatc ctccctgtct gcatctgtag gagacagagt caccatcact 480
tgccggtcaa gtcagggcat tggagatgat ttgggctggt atcagcagaa gccagggaaa 540
gcccctatcc tcctgatcta tggtacatcc actttacaaa gtggggtccc gtcaaggttc 600
agcggcagtg gatctggcac agatttcact ctcaccatca acagcctgca gcctgaagat 660
tttgcaactt attactgtct acaagattcc aattacccgc tcactttcgg cggagggaca 720
cgactggaga ttaaacgtgc ggccgcacat catcatcacc atcacggggc cgcagaacaa 780
aaactcatct cagaagagga tctgaatggg gccgcaccca agcccagtac ccccccaggt 840
tcttcaggcg aactggaaga actgctgaaa catctgaaag aactgctgaa aggcccgcgt 900
aaaggcgaac tggaagaact gctgaaacat ctgaaagaac tgctgaaagg cggtgcgccg 960
ggcggtcatc atcatcacca tcat 984
<210> 16
<211> 328
<212> PRT
<213> 人(Homo sapiens)
<400> 16
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Glu Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Ile Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Glu Tyr Ser Gly Tyr Asp Thr Asp Pro Gln Tyr Ser
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ser Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln
130 135 140
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ser Ser Gln Gly Ile Gly Asp Asp Leu Gly Trp Tyr Gln Gln
165 170 175
Lys Pro Gly Lys Ala Pro Ile Leu Leu Ile Tyr Gly Thr Ser Thr Leu
180 185 190
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
195 200 205
Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
210 215 220
Tyr Cys Leu Gln Asp Ser Asn Tyr Pro Leu Thr Phe Gly Gly Gly Thr
225 230 235 240
Arg Leu Glu Ile Lys Arg Ala Ala Ala His His His His His His Gly
245 250 255
Ala Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Asn Gly Ala Ala
260 265 270
Pro Lys Pro Ser Thr Pro Pro Gly Ser Ser Gly Glu Leu Glu Glu Leu
275 280 285
Leu Lys His Leu Lys Glu Leu Leu Lys Gly Pro Arg Lys Gly Glu Leu
290 295 300
Glu Glu Leu Leu Lys His Leu Lys Glu Leu Leu Lys Gly Gly Ala Pro
305 310 315 320
Gly Gly His His His His His His
325
<210> 17
<211> 1446
<212> DNA
<213> 人(Homo sapiens)
<400> 17
gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120
ccaggcaagg agctggagtg ggtggcagtt atatcatatg atggaagtat taaatactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gcgaactggt 300
gaatatagtg gctacgatac ggacccccag tactcctggg ggcaagggac cacggtcacc 360
gtctcctcaa gtggaggcgg ttcaggcgga ggtggcagcg gcggtggcgg atcggaaatt 420
gtgctgactc agtctccatc ctccctgtct gcatctgtag gagacagagt caccatcact 480
tgccggtcaa gtcagggcat tggagatgat ttgggctggt atcagcagaa gccagggaaa 540
gcccctatcc tcctgatcta tggtacatcc actttacaaa gtggggtccc gtcaaggttc 600
agcggcagtg gatctggcac agatttcact ctcaccatca acagcctgca gcctgaagat 660
tttgcaactt attactgtct acaagattcc aattacccgc tcactttcgg cggagggaca 720
cgactggaga ttaaaggtgg cagcggacct aaatcttgtg acaaaactca cacatgccca 780
ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 840
aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 900
cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 960
aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 1020
gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 1080
ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 1140
gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacgtgc 1200
ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 1260
gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 1320
agcaagctca ccgtggacaa gagcagatgg cagcagggga acgtcttctc atgctccgtg 1380
atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 1440
tagtag 1446
<210> 18
<211> 112
<212> PRT
<213> 人(Homo sapiens)
<400> 18
Ala Leu Asp Thr Asn Tyr Cys Phe Ser Ser Thr Glu Lys Asn Cys Cys
1 5 10 15
Val Arg Gln Leu Tyr Ile Asp Phe Arg Lys Asp Leu Gly Trp Lys Trp
20 25 30
Ile His Glu Pro Lys Gly Tyr His Ala Asn Phe Cys Leu Gly Pro Cys
35 40 45
Pro Tyr Ile Trp Ser Leu Asp Thr Gln Tyr Ser Lys Val Leu Ala Leu
50 55 60
Tyr Asn Gln His Asn Pro Gly Ala Ser Ala Ala Pro Cys Cys Val Pro
65 70 75 80
Gln Ala Leu Glu Pro Leu Pro Ile Val Tyr Tyr Val Gly Arg Lys Pro
85 90 95
Lys Val Glu Gln Leu Ser Asn Met Ile Val Arg Ser Cys Lys Cys Ser
100 105 110
<210> 19
<211> 5
<212> PRT
<213> 人(Homo sapiens)
<400> 19
Gly Ser Ser Gly Gly
1 5
<210> 20
<211> 4
<212> PRT
<213> 人(Homo sapiens)
<400> 20
Gly Gly Ser Gly
1
<210> 21
<211> 5
<212> PRT
<213> 人(Homo sapiens)
<400> 21
Cys Pro Pro Cys Pro
1 5
<210> 22
<211> 5
<212> PRT
<213> 人(Homo sapiens)
<400> 22
Ser Tyr Gly Met His
1 5
<210> 23
<211> 17
<212> PRT
<213> 人(Homo sapiens)
<400> 23
Val Ile Ser Tyr Asp Gly Ser Ile Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 24
<211> 14
<212> PRT
<213> 人(Homo sapiens)
<400> 24
Thr Gly Glu Tyr Ser Gly Tyr Asp Thr Ser Gly Val Glu Leu
1 5 10
<210> 25
<211> 14
<212> PRT
<213> 人(Homo sapiens)
<400> 25
Thr Gly Glu Tyr Ser Gly Tyr Asp Thr Asp Pro Gln Tyr Ser
1 5 10
<210> 26
<211> 14
<212> PRT
<213> 人(Homo sapiens)
<400> 26
Thr Gly Phe Tyr Ser Gly Tyr Asp Thr Pro Ala Ser Pro Asp
1 5 10
<210> 27
<211> 11
<212> PRT
<213> 人(Homo sapiens)
<400> 27
Arg Ala Ser Gln Gly Ile Gly Asp Asp Leu Gly
1 5 10
<210> 28
<211> 7
<212> PRT
<213> 人(Homo sapiens)
<400> 28
Gly Thr Ser Thr Leu Gln Ser
1 5
<210> 29
<211> 9
<212> PRT
<213> 人(Homo sapiens)
<400> 29
Leu Gln Asp Ser Asn Tyr Pro Leu Thr
1 5
<210> 30
<211> 14
<212> PRT
<213> 人(Homo sapiens)
<220>
<221> misc_feature
<222> (3)..(3)
<223> Xaa可以为任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (10)..(14)
<223> Xaa可以为任何天然存在的氨基酸
<400> 30
Thr Gly Xaa Tyr Ser Gly Tyr Asp Thr Xaa Xaa Xaa Xaa Xaa
1 5 10
Claims (42)
1.一种结合TGFβ1的分离的结合蛋白,其中所述结合蛋白包含第一多肽链和第二多肽链,所述第一和第二多肽链均从N末端至C末端具有下式:
(VH域)-(接头1)n-(VL域)-(接头2)m-(铰链)p-(Fc区),
其中所述第一和第二多肽链中每一个的VH域包含可变重链互补决定区1(HCDR1)、可变重链互补决定区2(HCDR2)、及可变重链互补决定区3(HCDR3),所述HCDR1包含SEQ ID NO:22的氨基酸序列;所述HCDR2包含SEQ ID NO:23的氨基酸序列;且所述HCDR3包含选自下组的氨基酸序列:SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、和SEQ ID NO:30;
其中所述第一和第二多肽链中每一个的VL域包含可变轻链互补决定区1(LCDR1)、可变轻链互补决定区2(LCDR2)、及可变轻链互补决定区3(LCDR3),所述LCDR1包含SEQ ID NO:27的氨基酸序列,所述LCDR2包含SEQ ID NO:28的氨基酸序列,且所述LCDR3包含SEQ ID NO:29的氨基酸序列;且
其中p是0或1,n是0或1,且m是0或1。
2.权利要求1的结合蛋白,其中所述第一和第二多肽链是相同的且形成二聚体。
3.权利要求1-2任一项的结合蛋白,其中所述第一或第二多肽链的VH域的框架区选自相同的可变重链种系序列,且同一多肽链的VL域的框架区选自相同的可变λ或κ种系序列。
4.权利要求1-3任一项的结合蛋白,其中所述第一或第二多肽链的VH域包含SEQ IDNO:1或SEQ ID NO:2中所示的人VH域序列,或其具有多至4个氨基酸修饰的变体;且
其中同一多肽链的VL域包含SEQ ID NO:5或SEQ ID NO:6中所示的人Vκ域序列,或其具有多至4个氨基酸修饰的变体
5.权利要求1-4任一项的结合蛋白,其中所述第一或第二多肽链的VH域包含SEQ IDNO:1中所示的序列,并且同一多肽链的VL域包含SEQ ID NO:5中所示的序列。
6.权利要求1-5任一项的结合蛋白,其中所述第一多肽链或第二多肽链包含SEQ IDNO:9中所示的序列。
7.权利要求1-6任一项的结合蛋白,其中所述结合蛋白选择性地结合TGFβ1。
8.权利要求1-7任一项的结合蛋白,其中所述结合蛋白在A549生物测定中具有针对人TGFβ1的低于1nM的IC50。
9.权利要求1-8任一项的结合蛋白,其中所述结合蛋白在A549生物测定中具有针对人TGFβ1的低于0.1nM的IC50。
10.权利要求1-9任一项的结合蛋白,其中n是1且所述接头1长度是约15个氨基酸。
11.权利要求1-10任一项的结合蛋白,其中n是1且接头1包含氨基酸序列SGGGSGGGGSGGGGS(SEQ ID NO:3)、氨基酸序列GGGGSGGGGSGGGGS(SEQ ID NO:4)、或其具有多至4个氨基酸修饰的变体。
12.权利要求1-11任一项的结合蛋白,其中p是1,且所述铰链包含来自人IgG1或IgG4铰链区的氨基酸序列。
13.权利要求1-12任一项的结合蛋白,其中所述铰链包含氨基酸序列PKSCDKTHTCPPCPAPELLGGP(SEQ ID NO:7),或其具有多至4个氨基酸修饰的变体。
14.权利要求1-12任一项的结合蛋白,其中所述铰链包含氨基酸序列CPPCP(SEQ IDNO:21)。
15.权利要求1-14任一项的结合蛋白,其中m是1且所述接头2包含氨基酸序列GGSG(SEQID NO:20),或其具有多至2个氨基酸修饰的变体。
16.权利要求1-15任一项的结合蛋白,其中所述Fc区包含恒定域CH2和CH3。
17.权利要求1-16任一项的结合蛋白,其中所述Fc区来源于人IgG1、人IgG4、或人IgG1或IgG4的变体,其中多至10个氨基酸可以是经修饰的。
18.一种结合TGFβ1的分离的结合蛋白,其中所述结合蛋白包含多肽链,所述多肽链从N末端至C末端具有下式:
(VH域)-(接头1)n-(VL域)-(接头2)m-(铰链)p-(Fc区),
其中所述VH域包含可变重链互补决定区1(HCDR1)、可变重链互补决定区2(HCDR2)、及可变重链互补决定区3(HCDR3),所述HCDR1具有SEQ ID NO:22的氨基酸序列;所述HCDR2具有SEQ ID NO:23的氨基酸序列;且所述HCDR3具有选自下组的氨基酸序列:SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26、和SEQ ID NO:30;
其中所述VL域包含可变轻链互补决定区1(LCDR1)、可变轻链互补决定区2(LCDR2)、及可变轻链互补决定区3(LCDR3),所述LCDR1具有SEQ ID NO:27的氨基酸序列,所述LCDR2具有SEQ ID NO:28的氨基酸序列,且所述LCDR3具有SEQ ID NO:29的氨基酸序列;且
其中p是0或1,n是0或1,且m是0或1。
19.一种分离的结合蛋白,其包含能结合TGFβ1的可变域,其中通过表面等离子体共振测得所述结合蛋白展现出的针对人TGFβ1的Kd比所述结合蛋白针对人TGFβ2的Kd低至少约50%。
20.一种分离的结合蛋白,其包含能结合TGFβ1的可变域,其中通过表面等离子体共振测得所述结合蛋白展现出的针对人TGFβ1的Kd比所述结合蛋白针对人TGFβ3的Kd低至少约50%。
21.一种分离的结合蛋白,其包含能结合TGFβ1的可变域,其中通过表面等离子体共振测得所述结合蛋白展现出的针对人TGFβ1的Kd比所述结合蛋白针对人TGFβ2的Kd低至少约50%且比所述结合蛋白针对人TGFβ3的Kd低至少约50%。
22.一种结合TGFβ1的分离的结合蛋白,其中所述结合蛋白包含第一多肽链和第二多肽链,所述第一和第二多肽链各具有下式:
(VD1)-(接头1)n-(VD2)-(接头2)m-(铰链)p-(Fc区),
其中VD1包含选自下组的第一可变域:分离自能结合TGFβ1的抗体的VL域,和分离自能结合TGFβ1的抗体的VH域,而VD2包含选自下组的第二可变域:分离自能结合TGFβ1的抗体的VL域,和分离自能结合TGFβ1的抗体的VH域;且
其中,n是0或1,m是0或1,且p是0或1。
23.一种结合TGFβ1的分离的结合蛋白,其中所述结合蛋白包含第一多肽链和第二多肽链,所述第一和第二多肽链均从N末端至C末端具有下式:
(VH域)-(接头1)n-(VL域)-(接头2)m-(铰链)p-(Fc区),
其中p是0或1,n是0或1,且m是0或1,且其中所述结合蛋白选择性地结合TGFβ1。
24.一种分离的多核苷酸,其包含编码权利要求1-23任一项的结合蛋白的核苷酸序列。
25.权利要求24的分离的多核苷酸,其包含SEQ ID NO:17中所示的核苷酸序列。
26.一种载体,其包含权利要求24-25任一项的多核苷酸。
27.一种宿主细胞,其包含权利要求24-25任一项的多核苷酸。
28.权利要求27的宿主细胞,其中所述宿主细胞是人细胞。
29.权利要求27-28任一项的宿主细胞,其中所述宿主细胞是人胚肾293(HEK293)细胞。
30.权利要求27的宿主细胞,其中所述宿主细胞是中国仓鼠卵巢细胞。
31.一种制备权利要求1-23任一项的结合蛋白的方法,包括在适于产生所述结合蛋白的条件下培养权利要求27所述的宿主细胞。
32.权利要求31的方法,其还包括纯化所述结合蛋白。
33.一种组合物,其包含权利要求1-23任一项的结合蛋白。
34.权利要求33的组合物,其中所述组合物是包含治疗有效量的所述结合蛋白的药物组合物。
35.权利要求33-34任一项的组合物,其还包含一个或多个生物活性组分、赋形剂、或稀释剂。
36.一种在人中治疗由TGFβ1活性直接或间接导致的疾病或病况的方法,包括对人施用药物组合物,所述药物组合物包含治疗有效量的权利要求1-23任一项的结合蛋白。
37.权利要求36的方法,其中所述疾病或病况选自下组:纤维化疾病、癌症、免疫介导的疾病,及其组合。
38.权利要求36-37任一项的方法,其中所述疾病是弥散性皮肤系统性硬化病(diffusecutaneous systemic sclerosis)。
39.权利要求1-23任一项的结合蛋白在制造用于治疗选自下组的疾病或病况的药物中的用途:纤维化疾病、癌症、免疫介导的疾病,及其组合。
40.权利要求39的用途,其中所述疾病是弥散性皮肤系统性硬化病。
41.权利要求39的用途,其中所述疾病是骨重塑疾病。
42.权利要求39的用途,其中所述疾病是肾病。
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US20200131258A1 (en) | 2020-04-30 |
KR20170120173A (ko) | 2017-10-30 |
AU2016226097A1 (en) | 2017-10-26 |
US11325971B2 (en) | 2022-05-10 |
RU2017134042A (ru) | 2019-04-05 |
CN107889491B (zh) | 2022-01-07 |
US20180222970A1 (en) | 2018-08-09 |
SG10201912449UA (en) | 2020-02-27 |
JP6845802B2 (ja) | 2021-03-24 |
KR102598790B1 (ko) | 2023-11-07 |
JP2018508218A (ja) | 2018-03-29 |
US11976112B2 (en) | 2024-05-07 |
CA2978459A1 (en) | 2016-09-09 |
IL254238A0 (en) | 2017-10-31 |
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