CN107849131A - 多特异性抗原结合分子及其用途 - Google Patents
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Abstract
本发明提供多特异性抗原结合分子及其用途。所述多特异性抗原结合分子包含特异性结合靶分子的第一抗原结合结构域和特异性结合内化效应蛋白的第二抗原结合结构域。本发明的所述多特异性抗原结合分子可以在一些实施方案中是能够结合靶分子和内化效应蛋白两者的双特异性抗体。在本发明的某些实施方案中,本发明的所述多特异性抗原结合分子同时结合所述靶分子和所述内化效应蛋白导致所述靶分子的活性减弱的程度比单独结合所述靶分子时更大。在本发明的其他实施方案中,所述靶分子是肿瘤相关抗原,并且本发明的所述多特异性抗原结合分子同时结合所述肿瘤相关抗原和所述内化效应蛋白导致或促进对肿瘤细胞的靶向杀伤。
Description
技术领域
本发明涉及治疗性蛋白质的领域,并且特别地涉及能够在体外或体内灭活、阻断、减弱、消除和/或降低一种或多种靶分子浓度的治疗性蛋白质领域。
背景技术
治疗性治疗往往需要灭活或阻断作用于细胞或细胞附近的一个或多个靶分子。例如,基于抗体的治疗剂通常通过结合至细胞表面上表达的特定抗原或结合至可溶性配体来起作用,从而干扰抗原的正常生物活性。针对各种细胞因子(例如IL-1、IL-4、IL-6、IL-13、IL-22、IL-25、IL-33等)的抗体和其他结合构建体,或它们各自相应的受体,例如已经显示可用于治疗各种各样的人类病痛和疾病。这种类型的治疗剂通常通过阻断细胞因子与其受体之间的相互作用以减弱或抑制细胞信号传导而起作用。然而,在某些情况下,以不一定涉及阻断靶分子与另一组分的物理相互作用的方式灭活或抑制靶分子的活性是治疗有益的。可以实现对靶分子的这种非阻断性减弱的一种方式是减少靶分子的细胞外或细胞表面浓度。尽管用于减少给定靶分子的量或浓度的基于遗传和核酸的策略是本领域已知的,但是这种策略往往在治疗背景中充满了实质性的技术复杂化和非预期的副作用。因此,需要替代的非阻断性策略来促进各种靶分子的灭活或减弱以用于治疗目的。
发明简述
本发明至少部分地基于以下概念:通过促进或引起靶分子与内化效应蛋白之间的物理连接来减弱或灭活靶分子。通过这种类型的物理分子间连接,可以迫使靶分子与内化效应蛋白一起内化到细胞中,并且通过细胞内降解机制加工,或以其他方式减弱、螯合或灭活。这种机制代表用于灭活或减弱靶分子的活性而不一定阻断靶分子与其结合配偶体之间的相互作用的新颖和创造性策略。
因此,本发明提供了能够同时结合靶分子(T)和内化效应蛋白(E)的多特异性抗原结合分子。更具体地,本发明提供了一种多特异性抗原结合分子,该多特异性抗原结合分子包含第一抗原结合结构域(D1)和第二抗原结合结构域(D2),其中D1特异性结合T,并且D2特异性结合E,并且其中多特异性抗原结合分子同时结合T和E使T的活性比单独由D1结合T减弱更大的程度。T活性的增强减弱可能是由于通过使T与E物理连接而迫使的T内化/降解;然而,其他作用机制是可能的,并且不从本发明的范围中排除。
此外,本发明提供了使用多特异性抗原结合分子来灭活或减弱靶分子(T)的活性的方法。具体地,本发明提供了通过使T和内化效应蛋白(E)与多特异性抗原结合分子接触来灭活或减弱T的活性的方法,其中多特异性抗原结合分子包含第一抗原结合结构域(D1)和第二抗原结合结构域(D2),其中D1特异性结合T,并且其中D2特异性结合E;并且其中多特异性抗原结合分子同时结合T和E使T的活性比单独由D1结合T减弱更大的程度。
在本发明的某些实施方案中,D1和/或D2包含至少一个抗体可变区。例如,多特异性抗原结合分子可以在一些实施方案中是双特异性抗体,其中D1包含特异性结合T的抗体重链和轻链可变区(HCVR/LCVR)对,并且其中D2包含特异性结合E的HCVR/LCVR对。或者,D1和/或D2可以包含与靶分子(T)和/或内化效应蛋白(E)特异性相互作用的肽或多肽。例如,如果靶分子是细胞表面受体,则D1可以包含特异性结合细胞表面受体靶分子的配体的一部分。类似地,如果内化效应蛋白是细胞表面内化受体,则D2可以包含特异性结合细胞表面内化受体的配体的一部分。在某些实施方案中,D1包含特异性结合T的抗体可变区,并且D2包含特异性结合E的肽或多肽。在其他实施方案中,D1包含特异性结合T的肽或多肽,并且D2包含特异性结合E的抗体可变区。然而,在任何配置中,最终结果是T和E能够通过多特异性抗原结合分子同时结合T和E而直接或间接地物理连接。
通过参阅接下来的详细说明,其他实施方案将变得显而易见。
附图简述
图1(小图A至D)提供了本发明的多特异性抗原结合分子的四种一般示例性作用机制的示意图。在每个所示的配置中,D1是第一抗原结合结构域;D2是第二抗原结合结构域;T是靶分子;E是内化效应蛋白;并且R是在结合E时内化的受体。小图A描述了T和E都是膜相关的情况。小图B描述了T是可溶的并且E是膜相关的情况。小图C描述了以下情况,其中T是膜相关的,并且E是通过E与R的相互作用而与细胞相互作用并内化至细胞中的可溶性蛋白。小图D描述了以下情况,其中T是可溶的并且E是通过E与R的相互作用而与细胞相互作用并内化至细胞中的可溶性蛋白。
图2示出了在用DKK1-mFc多特异性抗原结合分子温育不同时间量(0、15、30和60分钟)后,对两种不同细胞(单独表达FcγR1的细胞-1,以及表达Krm2和FcγR1的细胞-2)进行的免疫沉淀实验的结果。
图3示出了在抗IL-4R/抗CD63多特异性抗原结合蛋白(“ab缀合物”)或对照构建体(“对照1”和“对照2”)存在和不存在下在各种浓度的IL-4时,由Stat6-luc报道HEK293细胞产生的IL-4诱导的相对发光。
图4示出了以图3中所示实验相同的方式所进行的实验的结果,差异在于CD63表达因针对CD63的siRNA而在报道细胞系中显著减少。
图5示出了以图3和图4中所示实验相同的方式所进行的实验的结果,差异在于在添加IL-4配体之前,将报道细胞与多特异性抗原结合蛋白(“Ab缀合物”)或对照构建体(“对照1”和“对照2”)在时间零(小图A和小图B)处温育2小时(小图C和小图D)或过夜(小图E和小图F)。上行的柱状图(小图A、小图C和小图E)代表在表达正常水平CD63的细胞(“未转染”)中进行的实验的结果,而底行的柱状图(小图B、小图D和小图F)代表在CD63表达因针对CD63的siRNA在报道细胞系中显著减少的细胞中进行的实验的结果。
图6示出了以图3和图4中所示实验相同的方式所实施的实验的结果,差异在于在添加IL-4配体之前,将报道细胞与抗IL-4R/抗CD63多特异性抗原结合蛋白(“Ab缀合物”)或对照构建体(“对照1”和“对照2”)温育15分钟(小图A)、30分钟(小图B)、1小时(小图C)或2小时(小图D)。
图7示出了其中将Stat6-luc报道细胞在各种稀释度的抗IL-4R x抗CD63双特异性抗体(“双特异性”)或对照构建体(抗IL-4R单特异性,或仅结合IL-4R的模拟双特异性)存在下用10pM IL-4处理的实验的结果。
图8示出了下述实验的结果,其中将HEK293细胞用SOST构建体连同用如图所示的多种单特异性抗体和双特异性抗体处理,所述SOST构建体以myc标签和pH-敏感标记物(其在低pH产生荧光信号)标记。结果根据每细胞的荧光点(即,标记囊泡)数目表述。小图A示出在冰上温育3小时后的结果,小图B示出在37℃温育1小时后的结果,并且小图C示出在37℃温育3小时后的结果。
图9示出了下述实验的结果,在所述实验中将HEK293细胞用荧光标记的来自大肠杆菌(E.coli)(小图A)或明尼苏达沙门氏菌(S.minnesota)(小图B)的脂多糖(LPS)连同抗CD63x抗LPS双特异性抗体、对照抗体或仅LPS一起处理各种时间,随后猝灭未内化(即,表面结合)的荧光团。荧光信号因此反映在所示多种条件下内化的LPS。结果根据每细胞的荧光点(即,标记囊泡)数目表述。
图10示出了来自Alexa488标记的FelD1-mycv-myc-his的任意单位的平均荧光。蓝色直方图描绘细胞表面标记物。红色直方图描绘内化标记物。X轴上的组1表示用抗HLA-B x抗FelD1双特异性抗体处理的细胞;组2表示用抗HLA-B亲本二价单特异性抗体处理的细胞;组3代表用IgG同种型对照进行的处理。小图A示出了不表达MHC1的C1Rneo B-类淋巴母细胞样细胞对FelD1-mmh-488的结合和内化。小图B示出了表达MHC1的C1Rneo B-类淋巴母细胞对FelD1-mmh-488的结合和内化。
图11描绘了通过将细胞从4℃转移至37℃后0至60分钟时测量保留在细胞表面上的PRLR或HER2的量,而得知的催乳素受体(PRLR)和HER2在T47D细胞上的内化。示出了随时间推移剩余的表面受体的百分比。正方形表示PRLR,并且三角形表示HER2。
图12描绘了催乳素受体(PRLR)和HER2与溶酶体在T47D细胞中的共定位。示出了随时间推移与溶酶体相关的受体百分比。正方形表示PRLR,并且三角形表示HER2。
图13示意性地描绘了PRLR和HER2截短物和嵌合体。
图14描绘了表达各种PRLR和HER2构建体和嵌合体的HEK293细胞的荧光显微照片。每个小图中左侧的子小图描绘了内化前4℃时的细胞。每个小图右侧的子小图描绘了在37℃下1小时后的细胞。小图A描绘了表达全长PRLR(PRLR FL)的细胞。小图B描绘了表达全长HER2(PRLR FL)的细胞。小图C描绘了表达PRLRectoHER2cytoTM构建体的细胞。小图D描绘了表达HER2ectoPRLRcytoTM构建体的细胞。
图15描绘了表达各种PRLR构建体和截短物的HEK293细胞的荧光显微照片。小图A描绘了在4℃下1小时后,针对PRLR染色的表达全长PRLR的细胞。小图B描绘了在37℃下1小时后,针对PRLR染色的表达全长PRLR的细胞。小图C描绘了在4℃下1小时后,针对PRLR染色的表达具有胞质结构域的42个残基的截短PRLR的细胞。小图D描绘了在37℃下1小时后,针对PRLR染色的表达具有胞质结构域的42个残基的截短PRLR的细胞。小图E描绘了在4℃下1小时后,针对PRLR染色的表达仅具有胞质结构域的21个残基的截短PRLR的细胞。小图F描绘了在37℃下1小时后,针对PRLR染色的表达仅具有胞质结构域的21个残基的截短PRLR的细胞。
图16描绘了表达全长PRLR的细胞(小图A)、表达保留了胞质结构域的42个残基的截短PRLR的细胞(小图B)、以及表达保留了胞质结构域的21个残基的截短PRLR的细胞(小图C)的细胞裂解物的蛋白质印迹。上部子小图用抗PRLR抗体染色。下部子小图针对β-肌动蛋白染色以用于负载对照。
图17描绘了在用PRLR-DM1或HER2-DM1处理后,早期有丝分裂细胞的百分比对照PRLR或HER2或PRLRectoHER2cytoTM(小图A)、PRLR或HER2ectoPRLRcytoTM(小图B)的表面表达水平。
图18描绘了在CHX处理后0小时和4小时处表达各种PRLR构建体、截短物和置换物的全细胞裂解物的蛋白印迹。上部小图针对PRLR染色,而下部小图针对β-肌动蛋白染色以用于负载对照。
图19描绘了在CHX处理后0小时、1小时、2小时和4小时处经诱导表达全长PRLR的HEK 293细胞的全细胞裂解物的蛋白印迹。上部小图针对HER2染色,而下部小图针对PRLR染色。
图20描绘了在CHX处理后0小时、2小时和4小时处经诱导表达PRLR的细胞质截短形式的HEK 293细胞的全细胞裂解物的蛋白印迹。上部小图针对HER2染色,而下部小图针对PRLR染色。
图21描述了HER2与溶酶体在用HER2xPRLR双特异性抗体处理的T47D细胞中的共定位。示出了随时间推移与HER2受体相关的溶酶体百分比。方块表示用HER2xPRLR双特异性抗体处理的细胞,而三角形表示用非结合对照抗体处理的细胞。
图22是描绘用1nM、10nm或30nM的PRLR-ADC处理(A),用HER2-ADC加HER2xPRLR双特异性抗体处理(B),用单独HER2-ADC处理(C),用非结合对照ADC(D)处理,或不处理(E)的细胞周期停滞的T47D/HER2细胞百分比(Y-轴)的直方图。
图23是描绘表达HER2的活的T47D细胞的百分比对照不断增加量的药物的散点图:PRLR-ADC(A;方块),HER2-ADC加HER2xPRLR双特异性抗体(B;菱形),单独的HER2-ADC(C;正向三角形),非结合型对照ADC(D;圆圈),或非结合型对照ADC加HER2xPRLR双特异性抗体(E;倒三角形)。
图24示出了在用抗HLAB x抗FelD1双特异性抗体、磷酸盐缓冲盐水、抗FelD1二价单特异性抗体和抗HLAB二价单特异性抗体进行处理后不同时间(15分钟、6小时、1天、2天、3天、4天和6天)时用抗FelD1抗体探测的小鼠血清的蛋白印迹图。
图25示出了描绘从小鼠血清清除的高于基线水平并针对初始值归一化的FelD1-Fc的比例(Y轴)的直方图。直方条1描绘用抗HLAB x抗FelD1双特异性抗体进行处理;直方条2描绘用抗FelD1二价单特异性抗体进行处理;并且直方条3描绘用抗HLAB二价单特异性抗体(X轴)进行处理。
图26是描绘到HEK293细胞中的-hHJV-mmh摄取的直方图。Y轴描绘了信号的积分强度(任意单位)。在X轴处,抗Myc::PCSK9描绘了由于无抗体而对HJV摄取的影响(开放条),α-Myc::PCSK9FL(实心填充条),α-Myc::PCSK9LC(水平线填充条),以及α-Myc::PCSK9SC(点画填充条);抗HJV::PCSK9描绘了由于无抗体对HJV摄取的影响(开放条),α-HJV-N::PCSK9FL(实心填充条),α-HJV-N::PCSK9LC(水平线填充条),以及α-HJV-N::PCSK9SC(点画填充条);以及用于背景摄取的无抗体对照。
图27是示出在用抗HJV-阻断二价单特异性抗体(1);抗Myc::PCSK9全长融合蛋白(2);抗HJV-非阻断二价单特异性抗体(3);和抗HJV-非阻断剂::PCSK9全长融合蛋白(4)处理hHLAB转基因小鼠后一周时以微克/分升血清计的血清铁水平(Y轴)的散点图。
发明详述
在描述本发明前,应当理解,本发明不限于所述的特定方法和实验条件,因为这类方法和条件可以变化。还应当理解,本文所用的术语仅用于描述具体实施例的目的,而无意进行限制,因为本发明的范围将仅由所附权利要求书限制。
除非另有定义,否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常所理解的相同含义。如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不大于1%。例如,如本文所用,表述“约100”包括99和101以及它们之间的全部值(例如,99.1、99.2、99.3、99.4等)。
尽管与本文中描述的那些方法和材料类似或等效的任何方法和材料均可用于本发明的实践或检验,但现在描述优选的方法和材料。本说明书中提及的所有专利、申请和非专利出版物全文以引用方式并入本文中。
多特异性抗原结合分子
本发明人已经令人惊讶地发现,可以通过经由多特异性抗原结合分子使靶分子与内化效应蛋白连接来减弱靶分子的活性。
因此,本发明提供包含第一抗原结合结构域(在本文中也称为“D1”)和第二抗原结合结构域(在本文中也称为“D2”)的多特异性抗原结合分子。D1和D2各自结合不同的分子。D1特异性结合“靶分子”。靶分子在本文中也称为“T”。D2特异性结合“内化效应蛋白”。内化效应蛋白在本文中也称为“E”。根据本发明,多特异性抗原结合分子同时结合T和E使T的活性减弱比T由D1单独结合时更大的程度。如本文所用,在多特异性抗原结合分子的情境下,表述“同时结合”意指多特异性抗原结合分子能够在促进T和E之间物理连接的生理相关条件下接触靶分子(T)和内化效应蛋白(E)两者至少一段时间。多特异性抗原结合分子与T和E组分的结合可以是顺序性的;例如,多特异性抗原结合分子可以首先结合T并且随后结合E,或它可以首先结合E并且随后结合T。在任何情况下,只要T和E都由多特异性抗原结合分子结合一段时间(无论结合的依次顺序是什么),出于本公开的目的,多特异性抗原结合分子将视为“同时结合”T和E。不受理论约束,增强的T灭活据信由T内化及T在细胞内部因T与E物理连接而降解性变更途径(rerouting)引起。本发明的多特异性抗原结合分子因此可用于在不直接阻断或拮抗靶分子功能的情况下灭活和/或减少靶分子的活性和/或细胞外浓度。
根据本发明,多特异性抗原结合分子可以是单个多功能多肽,或它可以是彼此共价或非共价结合的两个或更多个多肽的多聚体复合物。如将因本公开而变得明显,将具有同时结合T和E分子的能力的任何抗原结合构建体视为多特异性抗原结合分子。本发明的任何多特异性抗原结合分子或其变体可以使用标准分子生物学技术(例如,重组DNA和蛋白质表达技术)构建,如本领域的普通技术人员将知晓。
抗原结合结构域
本发明的多特异性抗原结合分子包含至少两个独立的抗原结合结构域(D1和D2)。如本文所用,表述“抗原结合结构域”意指能够特异性结合所关注的特定抗原的任何肽、多肽、核酸分子、支架型分子、肽展示分子或含多肽的构建体。如本文所用,术语“特异性结合”等意指抗原结合结构域与以500pM或更小的解离常数(KD)为特征的特定抗原形成复合物,并且在普通测试条件下不结合其他不相关的抗原。“不相关的抗原”是彼此具有小于95%氨基酸同一性的蛋白质、肽或多肽。
可以在本发明上下文中使用的抗原结合结构域的示例性分类包括抗体、抗体的抗原结合部分、与特定抗原特异性相互作用的肽(例如,肽体(peptibody))、与特定抗原特异性相互作用的受体分子,包含特异性结合特定抗原的受体的配体结合部分的蛋白质、抗原结合支架(例如,DARPin、HEAT重复序列蛋白、ARM重复序列蛋白、三角形四肽重复序列蛋白和基于天然存在性重复序列蛋白的其他支架等[参见,例如,Boersma和Pluckthun,2011,Curr.Opin.Biotechnol.22:849-857,和其中引用的参考文献]),以及适配体或其部分。
在其中靶分子或内化效应蛋白是受体分子的某些实施方案中,出于本发明的目的,“抗原结合结构域”可以包含对受体特异的配体或配体部分或由其组成。例如,如果靶分子(T)是IL-4R,则多特异性抗原结合分子的D1组分可以包含能够与IL-4R特异性相互作用的IL-4配体或IL-4配体的一部分;或如果内化效应蛋白(E)是转铁蛋白受体,则多特异性抗原结合分子的D2组分可以包含能够与转铁蛋白受体特异性相互作用的转铁蛋白或转铁蛋白的一部分。
在其中靶分子或内化效应子蛋白是由特定受体特异性识别的配体(例如,可溶性靶分子)的某些实施方案中,出于本发明的目的,“抗原结合结构域”可以包含该受体或该受体的配体结合部分或由其组成。例如,如果靶分子(T)是IL-6,则多特异性抗原结合分子的D1组分可以包含IL-6受体的配体结合结构域;或如果内化效应蛋白(E)是间接内化的蛋白质(如该术语在本文中其他地方定义),则多特异性抗原结合分子的D2组分可以包含对E特异的受体的配体结合结构域。
用于确定两个分子彼此是否特异性结合的方法是本领域熟知的并且例如包括平衡透析法、表面等离子体共振法等。例如,如本发明上下文中所用,抗原结合结构域包括如在表面等离子体共振测定法中所述测量,以小于约500pM、小于约400pM、小于约300pM、小于约200pM、小于约100pM、小于约90pM、小于约80pM、小于约70pM、小于约60pM、小于约50pM、小于约40pM、小于约30pM、小于约20pM、小于约10pM、小于约5pM、小于约4pM、小于约2pM、小于约1pM、小于约0.5pM、小于约0.2pM、小于约0.1pM,或小于约0.05pM的KD结合特定抗原(例如,靶分子[T]或内化效应子蛋白[E])或其部分的多肽。
如本文所用,术语“表面等离子体共振”指允许例如使用BIAcoreTM系统(GEHealthcare的Biacore Life Sciences部门,Piscataway,NJ),通过检测生物传感器基质内部蛋白质浓度的改变来分析实时相互作用的光学现象。
如本文所用,术语“KD”意指特定蛋白质-蛋白质相互作用(例如,抗体-抗原相互作用)的平衡解离常数。除非另外指明,否则本文中公开的KD值指通过表面等离子体共振测定法在25℃确定的KD值。
抗体和抗体的抗原结合片段
如上文所示,“抗原结合结构域”(D1和/或D2)可以包含抗体或抗体的抗原结合片段或由其组成。如本文所用,术语“抗体”意指包含与特定抗原(例如,T或E)特异性结合或与之相互作用的至少一个互补决定区(CDR)的任何抗原结合分子或分子复合物。术语“抗体”包括包含4条多肽链(由二硫键相互连接的两条重链(H)和两条轻链(L))的免疫球蛋白分子以及其多聚体(例如,IgM)。每条重链包含重链可变区(本文中缩写为HCVR或VH)和重链恒定区。重链恒定区包含3个结构域:CH1、CH2和CH3。每条轻链包含轻链可变区(本文中缩写为LCVR或VL)和轻链恒定区。轻链恒定区包含一个结构域(CL1)。VH区和VL区可以进一步再划分为高变区,称为互补性决定区(CDR),其间插有更保守的区域,称为框架区(FR)。每个VH和VL由从氨基端至羧基端按以下顺序排列的3个CDR和4个FR的组成:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。在本发明的不同实施方案中,本发明抗体的(或其抗原结合部分)的FR可以与人种系序列相同,或可以经天然或人工修饰。可以基于并排分析两个或更多个CDR限定氨基酸共有序列。
本发明的多特异性抗原结合分子的D1和/或D2组分可以包含完整抗体分子的抗原结合片段或由其组成。如本文所用,术语抗体的“抗原结合部分”、抗体的“抗原结合片段”等包括特异性结合抗原以形成复合物的任何天然存在的、酶促可获得的、合成性或基因工程化的多肽或糖蛋白。可以使用任何合适的标准技术如蛋白酶解消化或涉及操作并表达编码抗体可变结构域和任选地抗体恒定结构域的DNA的重组基因工程技术,例如,从完整抗体分子衍生抗体的抗原结合片段。这类DNA是已知的和/或从例如商业来源、DNA文库(包括例如,噬菌体抗体文库)轻易可获得或可以合成。可以对所述DNA测序并化学地或通过使用分子生物学技术操纵,例如以将一个或多个可变结构域和/或恒定结构域排列成合适布局,或以引入密码子、产生半胱氨酸残基、修饰、添加或缺失氨基酸等。
抗原结合片段的非限制性示例包括:(i)Fab片段;(ii)F(ab')2片段;(iii)Fd片段;(iv)Fv片段;(v)单链Fv(scFv)分子;(vi)dAb片段;和(vii)由模拟抗体高变区的氨基酸残基组成的最小识别单位(例如,独立的互补性决定区(CDR),如CDR3肽),或受约束的FR3-CDR3-FR4肽。如本文所用,表述“抗原结合片段”内部也涵盖其他工程化分子,如结构域特异性抗体、单结构域抗体、结构域缺失抗体、嵌合抗体、CDR移植抗体、双体抗体、三体抗体、四体抗体、微型抗体、纳米抗体(例如单价纳米抗体、二价纳米抗体等)、小模块免疫药物(SMIP)和鲨鱼可变IgNAR结构域。
抗体的抗原结合片段一般将包含至少一个可变结构域。可变结构域可以具有任何尺寸或氨基酸组成并且通常将包含与一个或多个框架序列毗邻或符合读框的至少一个CDR。在具有与VL结构域缔合的VH结构域的抗原结合片段中,VH和VL结构域可以按任何合适的排列彼此相对设置。例如,可变区可以是二聚体并含有VH-VH、VH-VL或VL-VL二聚体。或者,抗体的抗原结合片段可以含有单体性VH或VL结构域。
在某些实施方案中,抗体的抗原结合片段可以含有与至少一个恒定结构域共价连接的至少一个可变结构域。可以在本发明抗体的抗原结合片段内部存在的可变结构域和恒定结构域的非限制、示例性配置包括:(i)VH-CH1;(ii)VH-CH2;(iii)VH-CH3;(iv)VH-CH1-CH2;(v)VH-CH1-CH2-CH3;(vi)VH-CH2-CH3;(vii)VH-CL;(viii)VL-CH1;(ix)VL-CH2;(x)VL-CH3;(xi)VL-CH1-CH2;(xii)VL-CH1-CH2-CH3;(xiii)VL-CH2-CH3;以及(xiv)VL-CL。在可变结构域和恒定结构域的任何配置中,包括上文所列的任何示例性配置,可变结构域和恒定结构域可以彼此直接连接或可以由完整或部分的铰链区或接头区连接。铰链区可以由在单个多肽分子中相邻可变结构域和/或恒定结构域之间产生柔性连接或半柔性连接的至少2个(例如,5个、10个、15个、20个、40个、60个或更多个)氨基酸组成。另外,抗原结合片段可以包含具有上文所列的任何可变结构域和恒定结构域配置的彼此和/或与一个或多个单体性VH或VL结构域(例如,通过二硫键))处于非共价缔合的同型二聚体或异质二聚体(或其他多聚体)。
本发明的多特异性抗原结合分子可以包含人抗体和/或重组人抗体或其片段,或由人抗体和/或重组人抗体或其片段组成。如本文所用,术语“人抗体”包括具有源自人种系免疫球蛋白序列的可变区和恒定区的抗体。然而,人抗体可以包括不由人种系免疫球蛋白序列编码的(例如在CDR和尤其CDR3中)的氨基酸残基(例如,通过体外随机诱变或位点特异性诱变或通过体内体细胞突变引入的突变)。然而,如本文所用,术语“人抗体”不意在包括其中已经将源自另一个哺乳动物物种(如小鼠)的种系的CDR序列移植到人框架序列上的抗体。
本发明的多特异性抗原结合分子可以包含重组人抗体或其抗原结合片段,或由重组人抗体或其抗原结合片段组成。如本文所用,术语“重组人抗体”意在包括通过重组手段所制备、表达、产生或分离的全部人抗体,如使用转染至宿主细胞(在下文进一步描述)中的重组表达载体表达的抗体、从重组人抗体组合文库(在下文进一步描述)分离的抗体、从相对于人免疫球蛋白基因而言转基因的动物(例如,小鼠)分离的抗体(参见例如,Taylor等人,(1992)Nucl.Acids Res.20:6287-6295)或通过涉及将人免疫球蛋白基因序列剪接至其他DNA序列的任何其他手段所制备、表达、产生或分离的抗体。此类重组人抗体具有源自人种系免疫球蛋白序列的可变区和恒定区。然而,在某些实施方案中,此类重组人抗体经历体外诱变(或,使用就人Ig序列而言为转基因的动物时,经历体内体细胞诱变)并且因此重组抗体的VH和VL区的氨基酸序列是尽管源自人种系VH和VL序列并且与之相关,但可能在体内人抗体种系库内部不天然存在的序列。
双特异性抗体
根据某些实施方案,本发明的多特异性抗原结合分子是双特异性抗体;例如,包含特异性结合靶分子(T)的抗原结合臂和特异性结合内化效应蛋白(E)的抗原结合臂的双特异性抗体。用于产生双特异性抗体的方法是本领域已知的并且可以用来构建本发明的多特异性抗原结合分子。可以在本发明上下文中使用的示例性双特异性样式包括但不限于例如基于scFv或双体抗体的双特异性样式、IgG-scFv融合物、双可变域(DVD)-Ig、细胞杂交瘤(Quadroma)、结入扣、共同轻链(例如,具有结入扣的共同轻链等)、CrossMab、CrossFab、(SEED)体、亮氨酸拉链、Duobody、IgG1/IgG2、双重作用Fab(DAF)-IgG和Mab2双特异性样式(关于前述样式的综述,参见例如Klein等人,2012,mAbs 4:6,1-11,和其中引用的参考文献)。
多聚化组分
在某些实施方案中,本发明的多特异性抗原结合分子还可以包括一种或多种多聚化组分。多聚化组分可以发挥维持抗原结合结构域(D1和D2)之间缔合的作用。如本文所用,“多聚化组分”是具有与具有相同或相似结构或构造的第二多聚化组分缔合的能力的任何大分子、蛋白质、多肽、肽或氨基酸。例如,多聚化组分可以是包含免疫球蛋白CH3结构域的多肽。多聚化组分的非限制性示例是免疫球蛋白的Fc部分,例如,选自同种型IgG1、IgG2、IgG3和IgG4以及每个同种型组内部任何同种异型的IgG的Fc结构域。在某些实施方案中,多聚化组分是含有至少一个半胱氨酸残基的1至约200个氨基酸长度的Fc片段或氨基酸序列。在其他实施方案中,多聚化组分是半胱氨酸残基或含有半胱氨酸的短肽。其他多聚化结构域包括:包含亮氨酸拉链、螺旋-环基序、或卷曲螺旋基序的肽或多肽,或由亮氨酸拉链、螺旋-环基序、或卷曲螺旋基序组成的肽或多肽。
在某些实施方案中,本发明的多特异性抗原结合分子包含两个多聚化结构域M1和M2,其中D1与M1连接并且D2与M2连接,并且其中M1与M2的缔合促进单个多特异性抗原结合分子中D1与D2的彼此物理连接。在某些实施方案中,M1和M2彼此相同。例如,M1可以是具有特定氨基酸序列的Fc结构域,并且M2是具有与M1相同氨基酸序列的Fc结构域。或者,M1和M2可以在一个或多个氨基酸位置彼此不同。例如,M1可以包含第一免疫球蛋白(Ig)CH3结构域并且M2可以包含第二Ig CH3结构域,其中第一和第二Ig CH3结构域彼此差异至少一个氨基酸,并且其中与具有相同M1和M2序列的参考构建体相比,至少一个氨基酸差异减少靶向构建体与蛋白A的结合。在一个实施方案中,M1的Ig CH3结构域结合蛋白A并且M2的Ig CH3结构域含有减少或消除蛋白A结合作用的突变如H95R修饰(按照IMGT外显子编号;按照EU编号为H435R)。M2的CH3还可以包含Y96F修饰(按照IMGT编号;按照EU编号为Y436F)。可以在M2的CH3中存在的其他修饰包括:在IgG1Fc结构域的情况下D16E、L18M、N44S、K52N、V57M和V82I(按照IMGT编号;按照EU编号为D356E、L358M、N384S、K392N、V397M和V422I);在IgG2Fc结构域的情况下N44S、K52N和V82I(按照IMGT编号;按照EU编号为N384S、K392N和V422I);和在IgG4Fc结构域的情况下Q15R、N44S、K52N、V57M、R69K、E79Q和V82I(按照IMGT编号;按照EU编号为Q355R、N384S、K392N、V397M、R409K、E419Q和V422I)。
内化效应子蛋白(E)
在本发明的上下文中,多特异性抗原结合分子的D2组分特异性结合内化效应蛋白(“E”)。内化效应蛋白是能够内化至细胞中或以其他方式参与或有助于逆梯度膜运输的蛋白质。在一些情况下,内化效应蛋白是经历转胞吞作用的蛋白质;即,蛋白质在细胞的一侧内化并运输至细胞的另一侧(例如,顶端至基底)。在许多实施方案中,内化效应蛋白是细胞表面表达的蛋白质或可溶解的胞外蛋白质。然而,本发明还设想了其中内化效应蛋白表达在胞内隔室如内体、内质网、高尔基体、溶酶体等内部的实施方案。例如,参与逆梯度膜运输(例如,从早期/再循环型内体至反-高尔基体网的途径)的蛋白质可以在本发明的多个实施方案中充当内化效应蛋白。在任何情况下,D2与内化效应蛋白的结合造成整个多特异性抗原结合分子和与之缔合的任何分子(例如,由D1结合的靶分子)也变得内化至细胞中。如下文解释,内化效应蛋白包括直接内化至细胞中的蛋白质,以及间接地内化至细胞中的蛋白质。
直接内化至细胞中的内化效应蛋白包括经历细胞内化并且优选地由胞内降解和/或再循环途径加工的具有至少一个胞外结构域的膜结合分子(例如,跨膜蛋白、GPI-锚定蛋白等)。直接内化至细胞中的内化效应蛋白的具体非限制性示例包括例如CD63、MHC-I(例如,HLA-B27)、Kremen-1、Kremen-2、LRP5、LRP6、LRP8、转铁蛋白受体、LDL-受体、LDL-相关蛋白1受体、ASGR1、ASGR2、淀粉样前体蛋白样蛋白-2(APLP2)、apelin受体(APLNR)、MAL(髓鞘质和淋巴细胞蛋白、又称作VIP17)、IGF2R、液泡型H+ATP酶、白喉毒素受体、叶酸受体、谷氨酸受体、谷胱甘肽受体、瘦蛋白受体、清道夫受体(例如,SCARA1-5、SCARB1-3、CD36)等。
在某些实施方案中,内化效应蛋白是催乳素受体(PRLR)。发现PRLR不仅是某些治疗应用的靶标,而且是基于其高内化速率和翻转率的有效内化效应蛋白。例如,PRLR作为内化效应蛋白的潜力在WO2015/026907中示出,其中尤其证明了抗PRLR抗体在体外被PRLR表达细胞有效内化。
在其中E是直接内化的效应蛋白的实施方案中,多特异性抗原结合分子的D2组分可以例如是特异性结合E的抗体或抗体的抗原结合片段或与效应蛋白特异性相互作用的配体或配体的部分。例如,如果E是Kremen-1或Kremen-2,则D2组分可以包含Kremen配体(例如,DKK1)或其Kremen结合部分,或由Kremen配体或其Kremen结合部分组成。作为另一示例,如果E是受体分子如ASGR1,则D2组分可以包含对该受体特异的配体(例如,脱唾液酸血清类粘蛋白[ASOR]或β-GalNAc)或其受体结合部分,或由对该受体特异的配体或其受体结合部分组成。
间接内化至细胞中的内化效应蛋白包括本身不内化,但与直接内化至细胞中的第二蛋白质或多肽结合或以其他方式缔合后变成内化至细胞中的蛋白质和多肽。间接内化至细胞中的蛋白质包括例如能够与内化性细胞表面表达受体分子结合的可溶性配体。通过可溶性配体与内化性细胞表面表达受体分子相互作用(间接)内化至细胞中的可溶性配体的非限制性示例是转铁蛋白。在其中E是转铁蛋白(或另一种间接内化的蛋白质)的实施方案中,D2与E的结合和E与转铁蛋白受体(或另一种内化细胞表面表达的受体分子)的相互作用,造成整个多特异性抗原结合分子和与之缔合的任何分子(例如,由D1结合的靶分子)变得内化至细胞中,与此同时内化E和其结合配偶体。
在其中E是间接内化的效应子蛋白(如可溶性配体)的实施方案中,多特异性抗原结合分子的D2组分可以是例如特异性结合E的抗体或抗体的抗原结合片段,或与可溶性效应蛋白特异性相互作用的受体或受体的部分。例如,如果E是细胞因子,则D2组分可以包含相应的细胞因子受体或其配体结合部分,或由相应的细胞因子受体或其配体结合部分组成。
靶分子(T)
在本发明的上下文中,多特异性抗原结合分子的D1组分特异性结合靶分子(“T”)。靶分子是需要减弱、减少或消除其活性或胞外浓度的任何蛋白质、多肽或其他大分子。在许多情况中,与D1结合的靶分子是蛋白质或多肽[即,“靶蛋白”];然而,本发明还包括其中靶分子(“T”)是与D1结合的糖、糖蛋白、脂质、脂蛋白、脂多糖或其他非蛋白质聚合物或分子的实施方案。根据本发明,T可以是细胞表面表达的靶蛋白或可溶性靶蛋白。靶由多特异性抗原结合分子结合可以在胞外或细胞表面环境中发生。然而,在某些实施方案中,多特异性抗原结合分子在细胞内部,例如在胞内组分如内质网、高尔基体、内体、溶酶体等中结合靶分子。
细胞表面表达的靶分子的示例包括细胞表面表达的受体、膜结合配体、离子通道和具有与细胞膜连接或缔合的胞外部分的任何其他单聚或多聚多肽组分。可以由本发明的多特异性抗原结合分子靶向的非限制、示例性细胞表面表达的靶分子包括例如细胞因子受体(例如,IL-1、IL-4、IL-6、IL-13、IL-22、IL-25、IL-33等的受体),以及细胞表面靶,包括其他1型跨膜受体如PRLR、G-蛋白偶联受体如GCGR、离子通道如Nav1.7、ASIC1或ASIC2,非受体表面蛋白如MHC-I(例如,HLA-B*27)等。
在其中T是细胞表面表达的靶蛋白的实施方案中,多特异性抗原结合分子的D1组分可以是例如特异性结合T的抗体或抗体的抗原结合片段,或与细胞表面表达的靶蛋白特异性相互作用的配体或配体的部分。例如,如果T是IL-4R,则D1组分可以包含IL-4或其受体结合部分,或由IL-4或其受体结合部分组成。
可溶性靶分子的示例包括细胞因子、生长因子,以及其他配体和信号传导蛋白。可以由本发明的多特异性抗原结合分子靶向的非限制示例性可溶性靶蛋白质包括例如IL-1、IL-4、IL-6、IL-13、IL-22、IL-25、IL-33、SOST、DKK1等。可溶性靶分子还包括例如非人类靶分子如变应原(例如,Fel D1、Betv1、CryJ1)、病原体(例如,白假丝酵母(Candidaalbicans)、金黄色葡萄球菌(S.aureus)等)和致病分子(例如,脂多糖[LPS]、脂磷壁酸[LTA]、蛋白A、毒素等)。在其中T是可溶性靶分子的实施方案中,多特异性抗原结合分子的D1组分可以是例如特异性结合T的抗体或抗体的抗原结合片段,或与可溶性靶分子特异性相互作用的受体或受体的部分。例如,如果T是IL-4,则D1组分可以包含IL-4R或其配体结合部分,或由IL-4R或其配体结合部分组成。
靶分子还包括如本文中他处描述的肿瘤相关抗原。
pH依赖性结合
本发明提供包含第一抗原结合结构域(D1)和第二抗原结合结构域(D2)的多特异性抗原结合分子,其中抗原结合结构域(D1和/或D2)之一或两者以pH依赖性方式结合其抗原(T或E)。例如,与中性pH相比,抗原结合结构域(D1和/或D2)可以在酸性pH显示与其抗原的结合减少。或者,与中性pH相比,抗原结合结构域(D1和/或D2)可以在酸性pH显示与其抗原的结合增强。可以例如,通过就与中性pH相比在酸性pH与特定抗原结合减少(或增强)而筛选抗体群体,来获得具有pH依赖性结合特征的抗原结合结构域。另外,在氨基酸水平修饰抗原结合结构域可以产生具有pH依赖性特征的抗原结合结构域。例如,通过将抗原结合结构域的一个或多个氨基酸(例如,在CDR内部)置换为组氨酸残基,可以获得相对于中性pH在酸性pH时抗原结合作用减少的抗原结合结构域。
在某些实施方案中,本发明包括了包含D1和/或D2组分的多特异性抗原结合分子,其中所述D1和/或D2组分在酸性pH以比D1和/或D2组分在中性pH与其相应抗原结合的KD大至少约3、5、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100倍或更多倍的KD结合其相应抗原(T或E)。pH依赖性结合也可以按照抗原结合结构域与中性pH相比在酸性pH对其抗原的t1/2表述。例如,本发明包括了包含D1和/或D2组分的多特异性抗原结合分子,其中所述D1和/或D2组分在酸性pH以比D1和/或D2组分在中性pH与其相应抗原结合的t1/2短至少约5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60倍或更多倍的t1/2结合其相应抗原(T或E)。
在某些实施方案中,当施用至动物受试者时,与不显示pH依赖性结合特征的类似分子相比,包含与中性pH相比在酸性pH时抗原结合作用减少的D1和/或D2组分的本发明多特异性抗原结合分子可以显示较慢的循环清除率。根据本发明的这个方面,提供了与中性pH相比在酸性pH时对T和/或E的抗原结合作用减少的多特异性抗原结合分子,其中相对于与中性pH相比在酸性pH时不具有减少的抗原结合作用的可比性抗原结合分子,所述多特异性抗原结合分子显示至少慢2倍的循环清除率。清除率可以按照抗体的半寿期表述,其中较慢的清除率与较长的半寿期相关。
如本文所用,表述“酸性pH”意指6.0或更小的pH。表述“酸性pH”包括约6.0、5.95、5.8、5.75、5.7、5.65、5.6、5.55、5.5、5.45、5.4、5.35、5.3、5.25、5.2、5.15、5.1、5.05、5.0或更小的pH值。如本文所用,表述“中性pH”意指约7.0至约7.4的pH。表述“中性pH”包括约7.0、7.05、7.1、7.15、7.2、7.25、7.3、7.35和7.4的pH值。
靶分子活性的减弱
如本文中他处所示并且如通过下文的工作实施例展示,发明人已经发现多特异性抗原结合分子同时结合靶分子(T)和内化效应蛋白(E)使T的活性减弱比T由多特异性抗原结合分子的第一抗原结合结构域(D1)组分单独结合时更大的程度。如本文所用,表述“使T的活性减弱比T由D1单独结合时更大的程度”意指在其中可以使用表达E的细胞测量T活性的测定法中,在多特异性抗原结合分子存在下测量的T活性水平比本身含有D1(即,不与第二抗原结合结构域(D2)物理连接)的对照构建体存在下所测量的T活性水平低至少10%。例如,在多特异性抗原结合分子存在下测量的T活性水平可以比在本身含有D1的对照构建体存在下测量的T活性水平低约10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或100%。
在下文工作实施例1和2中显示用于确定多特异性抗原结合分子是否减弱靶分子的活性至比靶分子由D1结构域单独结合更大程度的非限制、说明性分析模式。在实施例1中,例如,“T”是白介素-4受体(IL-4R)并且“E”是CD63。实施例1的多特异性抗原结合分子是包含通过链霉亲和素/生物素接头与抗CD63mAb连接的抗IL-4R mAb的双抗体缀合物。因此,这个示例性构建体中的“D1”是抗IL-4R抗体的抗原结合结构域(HCVR/LCVR对),并且“D2”是抗CD63抗体的抗原结合结构域(HCVR/LCVR对)。对于实施例1和2的实验,使用基于细胞的分析模式,其中当IL-4R活性受添加外源IL-4配体刺激时,所述分析模式产生报道分子信号。将多特异性抗原结合分子存在下检测到的IL-4诱导的报道分子活性的量与对照构建体存在下检测到的IL-4诱导的报道分子活性的量比较,所述对照构建体含有抗IL-4R抗体与无关对照免疫球蛋白(对照1)连接或与抗CD63抗体(对照2)组合,但是与之不物理连接。对照构建体因此产生其中T由D1单独结合(即,其中D1不是多特异性抗原结合分子本身的部分)的条件。如果在多特异性抗原结合分子存在下观察到的靶分子活性(由报道分子信号代表)的程度比包含不与D2组分物理连接的D1组分的对照构建体(例如,对照1或对照2)存在下观察到的靶分子活性的量小至少10%,则出于本公开的目的,得出结论“多特异性抗原结合分子同时结合T和E使T的活性减弱比T由D1单独结合时更大的程度”。
在一些实施方案中,T由D1单独结合可以导致部分减弱T的活性(如在实施例1的情况下,其中相对于未处理的细胞,用抗IL-4R抗体[即,对照1和2]单独处理报道细胞造成低水平的IL-4信号传导减弱)。在其他实施方案中,T由D1单独结合将不导致可检测的T活性减弱;即,T的生物活性可以不受T由D1单独结合影响。然而,在任何情况下,本发明的多特异性抗原结合分子同时结合T和E将使T的活性减弱比T单独由D1结合更大的程度。
考虑到任何给定的多特异性抗原结合分子可能指向的特定靶分子和效应蛋白的性质,替代性分析模式和关于本文中例举的分析模式的变型将是本领域普通技术人员显而易见的。任何的这种样式可以在本发明的上下文中用来确定多特异性抗原结合分子同时结合T和E是否使T的活性减弱比T由D1单独结合时更大的程度。
肿瘤靶向作用
在本发明的另一个方面,多特异性抗原结合分子可用于靶向肿瘤细胞。根据本发明的这个方面,与D1结合的靶分子“T”是肿瘤相关抗原。在某些情况下,肿瘤相关抗原是通常不内化的抗原。与D2结合的内化效应蛋白“E”可以是肿瘤特异的,或它可以表达在个体的肿瘤细胞和非肿瘤细胞两者上。本文中他处提到的任何内化效应蛋白可以靶向于本发明的抗肿瘤应用。
如本文所用,术语“肿瘤相关抗原”包括在肿瘤细胞的表面上优先表达的蛋白质或多肽。如本上下文中所用,表述“优先表达”意指该抗原在肿瘤细胞上以比非肿瘤细胞上该抗原的表达水平高至少10%(例如,10%、20%、30%、40%、50%、60%、70%、80%、90%、100%、110%、150%、200%、400%或更高)的水平表达。在某些实施方案中,靶分子是在选自以下的肿瘤细胞的表面上优先表达的抗原:肾肿瘤细胞、结肠肿瘤细胞、乳腺肿瘤细胞、卵巢肿瘤细胞、皮肤肿瘤细胞、肺肿瘤细胞、前列腺肿瘤细胞、胰腺肿瘤细胞、胶质母细胞瘤细胞、头颈肿瘤细胞和黑色素瘤细胞。特定肿瘤相关抗原的非限制性示例包括例如AFP、ALK、BAGE蛋白、β-联蛋白、brc-abl、BRCA1、BORIS、CA9、碳酸酐酶IX、胱天蛋白酶-8、CD40、CDK4、CEA、CTLA4、细胞周期蛋白-B1、CYP1B1、EGFR、EGFRvIII、ErbB2/Her2、ErbB3、ErbB4、ETV6-AML、EphA2、Fra-1、FOLR1、GAGE蛋白(例如,GAGE-1、GAGE-2)、GD2、GD3、GloboH、磷脂酰肌醇蛋白聚糖-3、GM3、gp100、Her2、HLA/B-raf、HLA/k-ras、HLA/MAGE-A3、hTERT、LMP2、MAGE蛋白(例如,MAGE-1、MAGE-2、MAGE-3、MAGE-4、MAGE-6和MAGE-12)、MART-1、间皮素、ML-IAP、Muc1、Muc16(CA-125)、MUM1、NA17、NY-BR1、NY-BR62、NY-BR85、NY-ESO1、OX40、p15、p53、PAP、PAX3、PAX5、PCTA-1、PLAC1、PRLR、PRAME、PSMA(FOLH1)、RAGE蛋白、Ras、RGS5、Rho、SART-1、SART-3、Steap-1、Steap-2、存活素、TAG-72、TGF-β、TMPRSS2、Tn、TRP-1、TRP-2、酪氨酸酶和尿空斑蛋白-3。
根据本发明的这个方面,多特异性抗原结合分子可以与药物、毒素、放射性同位素或有损细胞生存力的其他物质缀合。或者,药物或毒素可以不直接杀伤细胞,而是使细胞更易遭其他外部物质杀伤的物质。在涉及肿瘤靶向作用的另外的其他实施方案中,本发明的多特异性抗原结合分子本身不与药物、毒素或放射性同位素缀合,但是与对靶(T)特异的第二抗原结合分子(本文中称作“协从分子”)组合施用,其中协从分子与药物、毒素或放射性同位素缀合。在这类实施方案中,多特异性抗原结合分子将优选地与靶分子(T)上与协从分子识别的表位不同和/或不重叠表位结合(即,以允许多特异性抗原结合分子和协从分子与靶同时结合)。
在相关的实施方案中,本发明还包括抗肿瘤组合和治疗方法,包括:(a)毒素或药物缀合的特异性结合肿瘤相关抗原的抗原结合分子;和(b)多特异性抗原结合分子,包含(i)(例如,以低亲和力)特异性结合内化效应子蛋白的第一结合结构域和(ii)特异性结合毒素或药物缀合的抗原结合分子的第二结合结构域。在这个实施方案中,多特异性抗原结合分子发挥使毒素或药物缀合的抗原结合分子连接至内化效应蛋白连接的作用,这因而发挥使肿瘤相关抗原物理连接至内化效应蛋白的作用。毒素标记的抗肿瘤相关抗原抗体通过其与内化效应蛋白的连接而内化因此将导致定向肿瘤细胞杀伤。
根据本发明的肿瘤靶向方面的某些实施方案,多特异性抗原结合分子(或协从抗体)可以与选自以下的一种或多种细胞毒药物缀合:刺孢霉素、埃斯培拉霉素、甲氨蝶呤、多柔比星、美法仑、苯丁酸氮芥、ARA-C、长春地辛、丝裂霉素C、顺铂、依托泊苷、博来霉素、5-氟尿嘧啶、雌氮芥、长春新碱、依托泊苷、多柔比星、紫杉醇、拉洛他赛、替司他赛、奥拉他赛、多西他赛、多拉司他汀10、澳瑞他汀E、澳瑞他汀PHE和基于美登素的化合物(例如,DM1、DM4等)。多特异性抗原结合分子(或协从抗体)还可以或替代地与毒素缀合,如白喉毒素、铜绿假单胞菌(Pseudomonas aeruginosa)外毒素A、蓖麻毒蛋白A链、相思豆毒蛋白A链、蒴莲根毒蛋白A链、α-帚曲菌素、油桐(Aleurites fordii)蛋白、香石竹毒蛋白、垂序商陆(Phytolaca americana)蛋白等。多特异性抗原结合分子(或协从抗体)还可以或替代地与选自以下的一种或多种放射性同位素缀合:225Ac、211At、212Bi、213Bi、186Rh、188Rh、177Lu、90Y、131I、67Cu、125I、123I、77Br、153Sm、166Ho、64Cu、121Pb、224Ra和223Ra。因此,本发明的这个方面包括作为抗体-药物缀合物(ADC)或抗体-放射性同位素缀合物(ARC)的多特异性抗原结合分子。
在肿瘤杀伤应用的情况下,D2组分可以在某些情况下以低亲和力与内化效应蛋白“E”结合。因此,多特异性抗原结合分子将优先地靶向表达肿瘤相关抗原的肿瘤细胞。如本文所用,“低亲和力”结合意指D2组分对内化效应蛋白(E)的结合亲和力比D1组分对靶分子(T)的结合亲和力弱至少10%(例如,弱15%、弱25%、弱50%、弱75%、弱90%等)。在某些实施方案中,“低亲和力”结合意指D2组分以大于约10nM至约1μM的KD与内化效应蛋白(E)相互作用,如表面等离子体共振测定法中在约25℃测量。
多特异性抗原结合分子与内化效应蛋白和肿瘤相关抗原的同时结合将导致多特异性抗原结合分子优先地内化至肿瘤细胞中。如果,例如多特异性抗原结合分子与药物、毒素或放射性同位素缀合(或如果多特异性抗原结合分子与药物、毒素或放射性同位素缀合的协从抗体组合施用),则肿瘤相关抗原通过其与多特异性抗原结合分子的连接定向内化至肿瘤细胞中将导致极端特异的肿瘤细胞杀伤。
药物组合物和施用方法
本发明包括包含多特异性抗原结合分子的药物组合物。本发明的药物组合物可以用合适的载体、赋形剂、和提供改善的转移、递送、耐受性等的其他物质配制。
本发明还包括用于灭活或减弱靶分子(T)活性的方法。本发明的方法包括使靶分子与如本文所述的多特异性抗原结合分子接触。在某些实施方案中,根据本发明这个方面的方法包括施用包含多特异性抗原结合分子的药物组合物至患者,其中对所述患者而言灭活、减弱靶分子或降低其胞外浓度是合乎需要和/或有益的。
多种递送系统是本领域已知的并且可以用来施用本发明的药物组合物至患者。可以在本发明上下文中使用的施用方法包括但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内、硬膜外和口服途径。本发明的药物组合物可以通过任何便利的途径,例如通过输注或快速浓注、通过经上皮衬层或粘膜皮肤衬层(例如,口腔粘膜、直肠和肠道粘膜等)吸收来施用,并且可以与其他生物活性药剂一起施用。施用可以是全身性或局部性的。例如,本发明的药物组合物可以用标准针头和注射器皮下或静脉内递送。此外,就皮下递送而言,笔式递送装置可以用来施用本发明的药物组合物至患者。
实施例
提供以下实施例是为了向本领域普通技术人员提供完整公开内容和描述如何制备和使用本发明的方法和组合物,而非旨在限制发明人所认为的其发明的范围。已努力确保有关所用的数字(例如量、温度等)的准确性,但应考虑某些实验误差和偏差。除非另外指明,否则份数是重量份,分子量是平均分子量,温度是按摄氏度计并且压力是大气压或接近大气压。
实施例1.多特异性抗原结合分子通过与内化效应蛋白的连接诱导细胞表面受体降解的用途
作为初始概念验证实验,产生了能够结合(a)内化性效应分子和(b)细胞表面受体靶分子的多特异性抗原结合分子。在这个实施例中,内化效应蛋白是Kremen-2(Krm2),并且细胞表面受体靶分子是Fc受体(FcγR1[Fc-γ-R1])。
Kremen分子(Krm1和Krm2)是已知通过指导WNT途径信号传导分子LRP5和LRP6内化和降解而介导WNT信号传导的细胞表面蛋白。LRP5/6的内化经由可溶解性相互作用蛋白DKK1完成。具体而言,DKK1使Kremen连接至细胞表面上的LRP5/6,并且因为这种连接,Kremen的内化驱动LRP5和LRP6的内化和降解。(参见Li等人,PLoS One 5(6):e11014)。
发明人力图利用DKK1的Kremen结合特性和Kremen的内化特性来诱导FcγR1的内化。为了促进Kremen介导的FcγR1内化/降解,构建一种多特异性抗原结合分子,该多特异性抗原结合分子由融合于小鼠Fc的DKK1(DKK1-mFc,具有SEQ ID NO:1的氨基酸序列)组成。如本文中他处解释,将多特异性抗原结合分子定义为包含特异性结合靶分子的第一抗原结合结构域(D1)和特异性结合内化效应蛋白的第二抗原结合结构域(D2)的分子。在这个概念验证实施例中,“第一抗原结合结构域”是特异性结合靶分子FcγR1的mFc组分,并且“第二抗原结合结构域”是特异性结合内化效应蛋白Kremen的DKK1组分。
首先进行一项实验以确定DKK1-mFc是否可以按Kremen依赖性方式内吞至细胞中。对于这个实验,使用两个细胞系:细胞-1,经工程化以表达FcγR1但是不表达Kremen-2的HEK293细胞系,和细胞-2,经工程化以同时表达FcγR1和Kremen-2的HEK293细胞系。将1:10稀释的DKK1-mFc条件培养基添加至相应的细胞系并且允许在37℃温育90分钟。在90分钟温育后,将细胞用Alexa-488标记的抗小鼠IgG抗体染色以检测DKK1-mFc分子。使用荧光显微术,观察到实际上无DKK1-mFc定位在细胞-1内部(缺少Kremen);然而,在表达Kremen-2的细胞-2内部检测到了大量的DKK1-mFc。因此,这些结果显示多特异性抗原结合分子DKK1-mFc可以按Kremen依赖性方式内化至细胞中。
接下来,进行一项时程实验以确定DKK1-mFc是否可以按Kremen依赖性方式诱导FcγR1降解。实验方案简述如下:将(仅表达FcγR1的)细胞-1和(表达Kremen-2和FcγR1的)细胞-2用2mg/ml NHS-磺基-生物素在冰上处理15分钟以标记细胞表面表达的全部蛋白质。随后将细胞洗涤并重悬于400μl培养基中并分成4个100μl等分试样,这些等分试样用DKK1-mFc在37℃处理不同的时间量(0分钟、15分钟、30分钟和60分钟)。在DKK1-mFc温育后,将细胞沉淀并用蛋白酶抑制剂处理。来自不同温育时间点的细胞的裂解物经历FcγR1免疫沉淀。对于FcγR1免疫沉淀,将小鼠抗FcγR1抗体添加至细胞裂解物并在4℃温育1小时。随后添加蛋白G珠并且将混合物在4℃温育1小时。随后洗涤所述珠,将蛋白质洗脱并进行SDS-PAGE。将蛋白质转移至膜上并用HRP标记的链霉亲和素探测以揭示每份样品中表面暴露的剩余FcγR1蛋白的相对量。结果在图2中示出。
如图2中所示,表面暴露的FcγR1蛋白在细胞-1样品(表达FcγR1但是不表达Kremen-2)中的量保持相对恒定,无论细胞暴露于DKK1-mFc的时间量是多少。相反,表面暴露的FcγR1蛋白在细胞-2样品(同时表达Kremen-2和FcγR1)中的量随与DKK1-mFc一起温育的时间增加而大幅度减少。因此,这个实验表明DKK1-mFc以Kremen-2依赖性方式诱导细胞表面表达的FcγR1降解。
综上,前述结果显示同时结合细胞表面靶分子(FcγR1)和内化效应蛋白(Kremen-2)的多特异性抗原结合分子可以按效应蛋白依赖性方式诱导靶分子降解。
实施例2.使用对IL-4R和CD63具有特异性的多特异性抗原结合分子减弱IL-4R活性
在又一组概念验证实验中,构建了能够同时结合细胞表面表达的靶分子(即,IL-4R)和细胞表面表达的内化效应蛋白(即,CD63)的多特异性抗原结合分子。这些实验的目的是确定是否可以通过使IL-4R与经内化并靶向在溶酶体内部降解的效应分子(在这种情况下,CD63)物理连接来减弱细胞上的IL-4R活性。换句话讲,将这个实施例设计成检验CD63的正常内化和降解是否可以用来迫使IL-4R在细胞内部的内化和降解性变更途径。
首先,构建能够同时结合IL-4R和CD63的多特异性抗原结合分子。具体而言,将链霉亲和素缀合的抗IL-4R抗体和生物素酰化的抗CD63抗体按1:1比率组合以产生抗IL-4R:抗CD63缀合物(即,同时特异性结合IL-4R和CD63的多特异性抗原结合分子)。此实施例中使用的抗IL-4R抗体是针对IL-4R胞外结构域产生的全人mAb。(抗IL-4R抗体包含具有SEQ IDNO:3的重链可变区和具有SEQ ID NO:4的轻链可变区)。此实施例中使用的抗CD63抗体是从Biolegend公司(San Diego,CA)获得的产品目录号312002的小鼠抗人CD63mAb克隆MEM-259。
还创建了两种对照构建体:对照-1=按1:1比率与生物素酰化对照小鼠IgG1κ抗体组合的链霉亲和素缀合抗IL-4R抗体;并且对照-2=按1:1比率与非生物素酰化抗CD63抗体组合的链霉亲和素缀合抗IL-4R抗体。在这个实施例的实验构建体和对照构建体中使用的抗IL-4R抗体是已知特异性结合IL-4R并仅部分阻断IL-4-介导的信号传导的抗体。
该实施例中使用的实验细胞系是含有STAT6-荧光素酶报道分子构建体和附加STAT6的HEK293细胞系(“HEK293/STAT6-luc细胞”)。在这个实验中使用的细胞在其表面上表达IL-4R和CD63两者。当在任何抑制剂不存在的情况下用IL-4处理时,这个细胞系产生剂量依赖性的可检测化学发光信号,该化学发光信号反映IL-4-介导的信号传导的程度。
在初步实验中,将实验性抗IL-4R/抗CD63多特异性分子或对照构建体添加至HEK293/STAT6-luc细胞,从而培养基中抗IL-4R抗体的最终浓度是12.5nM。在实验构建体和对照构建体存在和不存在下,在IL-4浓度不断增加时测量报道分子信号(图3)。如图3中所见,抗IL-4R/抗CD63多特异性分子(“ab缀合物”)抑制IL-4-介导的信号传导至比任一种对照构建体显著更大的程度。
为了证实图3中观察到的效果依赖于CD63,进行上文描述的相同实验,差异在于使用针对CD63的siRNA时,CD63表达在报道细胞系中显著减少。在CD63表达显著减少时,不再观察到抗IL-4R/抗CD63多特异性分子的增强的抑制活性(图4)。这个结果表明,抗IL-4R/抗CD63多特异性分子减弱IL-4介导的信号传导的能力归因于多特异性分子与IL-4R和CD63同时结合以及随之发生的完整抗体-IL-4R-CD63复合物的内化及降解。
接下来进行相似的实验,其中允许抗IL-4R/抗CD63多特异性分子或对照构建体在添加IL-4之前与HEK293/STAT6-luc报道细胞系温育各种时间量。在第一组这类实验中,允许所述分子在添加50pM IL-4之前与报道细胞系温育0小时(即,与IL-4同时添加)、2小时或过夜。在添加IL-4后六小时测量萤光素酶活性。结果在图5中示出,顶部小图(“未转染”)。在又一组实验中,进行相似方案,差异在于允许实验分子或对照分子在添加50pM IL-4之前与报道细胞系温育15分钟、30分钟、1小时或2小时。结果在图6中示出。
图5和图6中汇总的结果显示,抗IL-4R/抗CD63多特异性分子能够抑制IL-4介导的信号传导,并且这种抑制效果随较长的温育时间增强。与初始实验组一样,使用CD63siRNA证实,抗IL-4R/抗CD63多特异性分子的抑制效果依赖于CD63表达(图5底部小图[“CD63siRNA”])。
总之,这个实施例进一步为通过使用多特异性抗原结合分子抑制靶分子活性提供了概念验证,该多特异性抗原结合分子能够同时结合靶分子(在这种情况下IL-4R)和内化效应蛋白(在这种情况下CD63),因而以引起靶分子在细胞内部内化和降解性变更途径。不同地提到,示例性多特异性抗原结合分子的同时结合IL-4R和CD63使IL-4R活性减弱至比IL-4R由对照构建体单独结合时明显更大的程度(即,>10%)。
实施例3.抗IL-4R x抗CD63双特异性抗体按CD63依赖性方式减弱IL-4R活性
在本文中,实施例2的实验显示抗IL-4R/抗CD63多特异性分子按CD63依赖性方式抑制IL-4介导的信号传导。在那些实验中,多特异性抗原结合分子由通过生物素-链霉亲和素键连接的两种独立单克隆抗体(抗IL-4R和抗CD63)组成。为了证实采用概念验证性多特异性抗原结合分子所观察到的结果可概括其他多特异性抗原结合分子样式,构建了真实的双特异性抗体。
使用标准双特异性抗体技术来构建由对IL-4R特异的第一臂和对CD63特异的第二臂组成的双特异性抗体。IL-4R特异性臂含有与CD63特异性轻链配对的抗IL-4R重链。出于构建便利目的,CD63特异性轻链仅与IL-4R特异性重链配对;然而,抗IL-4R重链与抗CD63轻链的配对保留了针对IL-4R的完整特异性并且不显示与CD63结合。CD63特异性臂含有与抗CD63轻链(与IL-4R臂中使用的轻链相同)配对的抗CD63重链。抗IL-4R重链(包含SEQ IDNO:3)源自如实施例2中使用的完整抗IL-4R抗体;然而,抗CD63重链和轻链源自从开发性研究杂交瘤库(Developmental Studies Hybridoma Bank)(爱荷华大学生物学系,爱荷华市,爱荷华州(University of Iowa Department of Biology,Iowa City,IA))获得的名为H5C6的抗CD63抗体。与实施例2中使用的完整抗IL-4R抗体一样,本实施例中使用的双特异性抗体的抗IL-4R组分本身仅显示中度IL-4R阻断活性。
进行IL-4荧光素酶测定法以评估抗IL-4R x抗CD63双特异性抗体的阻断活性。简而言之,将抗IL-4R x抗CD63双特异性抗体或对照分子的连续稀释物添加至HEK293/STAT6-luc报道细胞(参见实施例2)。在正常条件下,用IL-4处理时,这些细胞产生可检测的荧光素酶信号。对于这个实验,则将10pM IL-4添加至细胞,并且就所用抗体的每种稀释度定量荧光素酶活性。此测定法中使用的对照是:(a)以一条臂结合IL-4R并具有无功能性抗CD63臂的模拟双特异性抗体(即,含有一条抗IL-4R重链和一条抗CD63重链,两者均与抗IL-4R轻链配对);(b)抗IL-4R单特异性抗体;和(c)仅缓冲液(PBS)(在无抗体的情况下)。结果在图7中示出。如图7中所示,对于所用的对照样品,荧光素酶活性甚至在最高抗体浓度时保持相对地高,而对于双特异性抗体,荧光素酶活性随抗体浓度增加显著下降。这些结果证实双特异性抗体同时结合IL-4R和CD63造成对IL-4R活性的明显抑制。
实施例4.使用同时结合SOST和CD63的多特异性抗原结合分子内化SOST
在这个实施例中,评估多特异性抗原结合分子促进可溶性靶分子SOST(硬骨素)内化的能力。对于这些实验,靶分子是由人SOST蛋白组成的融合蛋白,该人SOST蛋白用pHrodoTM部分(生命技术公司,新墨西哥州卡尔斯巴德(Life Technologies,Carlsbad,CA))和myc标签标记。pHrodoTM部分是在中性pH实际上无荧光和在酸性环境如内体中发出明亮荧光的pH敏感性染料。因此,可以使用荧光信号作为SOST融合蛋白的细胞内化的指示剂。用于这些实验的多特异性抗原结合分子是对CD63(内化效应蛋白)和SOST融合蛋白(可溶性靶分子)同时具有结合特异性的双特异性抗体,如下文更详细地描述。
实验如下进行:简而言之,将HEK293细胞以10,000个细胞/孔接种在聚-D-赖氨酸涂覆的96孔平板(Greiner Bio-One,Monroe,NC)中。在允许细胞静置过夜后,将培养基更换为含有抗体(5μg/ml,如下文描述)、加pHrodoTM-myc标签的SOST(5μg/ml)、肝素(10μg/mL)和Hoechst 33342的培养基。随后将细胞在冰上温育3小时或在37℃温育3小时。将全部细胞在成像之前在PBS中洗涤两次,并且计数每个细胞的荧光点数目及相应的荧光强度,以建立在多种抗体构建体存在下加pHrodo-myc标签的SOST细胞内化的程度。.
这个实施例中使用的抗体如下:(1)抗CD63单特异性抗体(克隆H5C6,开发性研究杂交瘤库(Developmental Studies Hybridoma Bank),爱荷华大学生物学系,爱荷华市,爱荷华州);(2)抗myc抗体(克隆9E10,Schiweck等人,1997,FEBS Lett.414(1):33-38);(3)抗SOST抗体(美国专利号7,592,429中名为“Ab-B”的具有抗体重链可变区和轻链可变区的抗体);(4)抗CD63x抗myc双特异性抗体(即,包含源自抗体H5C6的抗CD63臂和源自9E10的抗myc臂的多特异性抗原结合分子);(5)抗CD63x抗SOST双特异性抗体#1(即,包含源自抗体H5C6的抗CD63臂和源自“Ab-B”的抗SOST臂的多特异性抗原结合分子);和(6)抗CD63x抗SOST双特异性抗体#2(即,包含源自抗体H5C6的抗CD63臂和源自在美国专利No.7,592,429中名为“Ab-20”的抗体的抗SOST臂的多特异性抗原结合分子)。使用所谓“结入扣”方法学(参见,例如,Ridgway等人,1996,Protein Eng.9(7):617-621),来装配在这些实验中使用的双特异性抗体。
图8中示出了内化实验的结果。图8示出了在测试的各种处理条件下,每个细胞的点数(标记囊泡)。综上,这些实验的结果显示(直接或通过myc标签)同时结合CD63和SOST的双特异性构建体造成最大量的SOST内化,如在37℃随时间推移每个细胞的荧光点的荧光强度和数目所反映。因此,该实施例中使用的多特异性抗原结合分子能够有效地指导可溶性靶分子的内化。
实施例5.用结合CD63和SOST的多特异性抗原结合分子处理的小鼠中骨矿物质密度的变化
接下来对如实施例4中所述的抗CD63x抗SOST多特异性抗原结合分子测试其增加小鼠中骨矿物质密度的能力。这些实验中使用五组小鼠(每组约6只小鼠)。处理组如下:(I)未处理的阴性对照小鼠;(II)用本身已知增加骨矿物质密度的阻断性抗SOST单特异性抗体处理的小鼠(阳性对照);(III)用特异性结合CD63和SOST但是本身不抑制SOST活性或本身仅略微抑制SOST活性的双特异性抗体处理的小鼠;(IV)用抗CD63亲本抗体(即,含有与双特异性抗体相同的抗CD63抗原结合结构域的单特异性抗体)处理的小鼠;和(V)用抗SOST亲本抗体(即,含有与双特异性抗体相同的抗SOST抗原结合结构域的单特异性抗体)处理的小鼠。向每个组中小鼠施用的抗体的量是约10至25mg/kg。
预期组III中的小鼠(用抗SOST x抗CD63双特异性抗体处理)将显示与组II小鼠(用已知的阻断性抗SOST抗体处理)中所观察到的骨矿物质密度增加至少相当的骨矿物质密度增加,即便双特异性抗体的抗SOST组分本身不抑制SOST活性(如通过预期不显示骨矿物质密度增加的组V中小鼠所证实)。组III中小鼠中期望的骨矿物质密度增加据信受CD63-介导的SOST内化驱动,如上文实施例4的细胞实验中所观察。
实施例6.由同时结合LPS和CD63的多特异性抗原结合分子介导的脂多糖(LPS)的细胞内化
这个实施例说明本发明的多特异性抗原结合分子指导非蛋白质靶分子即脂多糖(LPS)内化的用途。LPS是革兰氏阴性细菌外膜的组分并且已知有助于败血性休克。已经研究抗LPS抗体作为败血症的可能治疗剂。将本实施例的试验设计成评估多特异性抗原结合分子促进LPS内化的能力。
该实施例中使用的多特异性抗原结合分子是其中一条臂针对LPS(靶)并且另一条臂针对CD63(内化效应子蛋白)的双特异性抗体。抗LPS臂源自称作WN1 222-5的抗体。(DiPadova等人,1993,Infection and Immunity 61(9):3863-3872;Muller-Loennies等人,2003,J.Biol.Chem.278(28):25618-25627;Gomery等人,2012,Proc.Natl.Acad.SciUSA 109(51):20877-20882;US5,858,728)。抗CD63臂源自H5C6抗体(参见实施例4)。使用所谓“结入扣”方法学(参见,例如,Ridgway等人,1996,Protein Eng.9(7):617-621),来装配抗LPS x抗CD63双特异性抗体(即,多特异性抗原结合分子)。
在这些实验中使用两种LPS种类:大肠杆菌LPS和明尼苏达沙门氏菌(Salmonellaminnesota)LPS。两种形式作为荧光标记的分子获得(-488-标记的LPS,生命技术公司,新墨西哥州卡尔斯巴德)。
实验如下进行:将HEK293细胞接种在96孔PDL涂覆的成像平板中。在过夜静置后,将培养基更换为新鲜培养基。将荧光标记的(大肠杆菌来源或明尼苏达沙门氏菌来源的)LPS添加在常规培养基中。接下来,将抗LPS x抗CD63双特异性抗体,或与模拟Fc配对的对照对半抗体添加至样品。在37℃(1小时和3小时)或在冰上(3小时)温育各种时间后,如下加工来自LPS处理的样品的细胞:洗涤–用抗ALEXA--488抗体猝灭–洗涤并固定。抗ALEXA--488抗体猝灭来自未内化(即,表面结合)的荧光团的荧光。因此,在猝灭抗体处理的样品中观察到的任何荧光归因于内化的LPS。测量在各个时间点来自每份样品的荧光水平。
图9按照每个细胞的标记囊泡数目表述这些实验的结果。如图9中所示,仅用抗CD63x抗LPS双特异性抗体处理的细胞显示随时间推移而增加的明显数目的标记囊泡。用标记的LPS和对照抗体处理的细胞未显示可评估数目的荧光囊泡,这表明LPS在这些处理条件下未内化。
这个实施例因此表明抗LPS x抗CD63双特异性抗体造成LPS以需要同时结合LPS和CD63的方式内化至细胞中。因此,这些结果支持本发明的多特异性抗原结合分子促进靶分子如LPS的细胞内化以用于治疗疾病和病症如败血症的用途。
实施例7.由同时结合Her2和PRLR的多特异性抗原结合分子介导的Her2的细胞内化和降解
该实施例包括三个单独的实验,这些实验说明本发明的多特异性抗原结合分子指导肿瘤相关抗原(Her2)的内化和降解的用途。从肿瘤细胞表面消除Her2将是治疗以高Her2表达为特征的某些类型的癌症(例如乳腺癌、胃癌、胃食管癌等)的理想方法。
本实施例的实验中使用的多特异性抗原结合分子是一条臂针对Her2(靶),另一条臂针对PRLR(内化效应蛋白)的双特异性抗体。
实验1
作为初始实验,评价抗Her2x抗PRLR双特异性抗体(本文称为“Her2xPRLR bsAb1”)在T47D乳腺癌细胞中降解内源性Her2的能力。T47D乳腺癌细胞表达低水平的HER2,并且通常对抗HER2治疗顽拗(参见Horwitz等人,“Variant T47D human breast cancer cellswith high progesterone-receptor levels despite estrogen and antiestrogenresistance,”Cell.1982年3月;28(3):633-42)。
抗Her2臂源自称为曲妥单抗的抗体。抗PRLR臂源自完全人抗PRLR抗体。使用所谓“结入扣”方法学(参见例如,Ridgway等人,1996,Protein Eng.9(7):617-621),来装配抗Her2x抗PRLR双特异性抗体(即,多特异性抗原结合分子)。本实验中使用的其他构建体是曲妥单抗(单特异性抗体)、抗PRLR Ab(单特异性抗体,称为H1H6958N2,如美国专利申请公开No.2015/0056221中所述,该专利的公开内容全文以引用方式并入本文)和单特异性对照抗体(针对不相关的非人类抗原)。
对于该实验,表达内源性水平的Her2和PRLR受体的T47D细胞在补充有10%FBS(ATCC,30-2020)、10mM Hepes、1mM丙酮酸钠和10ug/ml胰岛素的RPMI(欧文科技公司(Irvine Scientific),9160)中生长。使用50ug/ml的放线菌酮(CHX)来停止蛋白质合成。将T47D细胞用放线菌酮和曲妥单抗(CHX/曲妥单抗)、放线菌酮和Her2xPRLR bsAb1(CHX/bsAb1)、放线菌酮和PRLR Ab(CHX/PRLR Ab)、放线菌酮和对照Ab(CHX/对照Ab)、或用放线菌酮、PRLR Ab和曲妥单抗处理0、1、2或4小时。
将细胞在冰上于补充有蛋白酶和磷酸酶抑制剂(赛默飞世尔公司(ThermoFisher),1861280)的RIPA缓冲液(100mM Tris-HCl、300mM NaCl、2%NP-40、1%脱氧胆酸钠和0.2%SDS)(波士顿生物试剂公司(Boston BioProducts),BP-116X)中裂解,随后超声处理(Qsonica型号Q55,三次脉冲)。将经超声处理的裂解物用2X SDS样品缓冲液1:1稀释,在95℃加热10分钟,然后在室温下以13,000rpm离心10分钟。将上清液在4至20%的NovexTris-甘氨酸凝胶上分离并印迹到PVDF膜上。
以1:300的Her2抗体(Dako,A0485)或以1:250的PRLR抗体(生命技术公司,35-9200)用于膜的初级标记,然后用1:5000的HRP-缀合的第二抗体用于膜的标记,以及使用ECL(安玛西亚公司(Amersham),RPN2106)进行化学发光检测。通过用CareStream软件(Kodak)计算条带的净强度进行对蛋白印迹的定量。结果在表1中示出。值表示为相对于背景的相对单位。
如表1所示,在用放线菌酮抑制蛋白质合成时,PRLR显示出在所使用的所有处理下经历快速和完全降解;该过程不受任何测试的抗体的影响。相比之下,在放线菌酮存在下,Her2在用Her2xPRLR bsAb1处理的细胞中降解,但在用曲妥单抗和抗PRLR Ab的混合物、单独的PRLR Abs、曲妥单抗或对照抗体处理的细胞中不降解。此结果表明Her2xPRLR bsAb1用于将Her2桥接于细胞表面上的PRLR,随后是Her2-bsAb1-PRLR复合物的降解。
表1
实验2
在第二个实验中,研究了Her2x PRLR多特异性抗原结合蛋白对Her2体外降解的剂量依赖性影响,以及对PRLR水平的潜在影响。在此实验中使用两种不同的Her2x PRLR双特异性抗体(“Her2xPRLR bsAb1”和“Her2xPRLR bsAb2”)。使用“结入扣”方法学构建两种双特异性抗体。抗Her2臂对于两种双特异性抗体是相同的,并且来源于称为曲妥单抗的抗体。Her2xPRLR bsAb1和Her2xPRLR bsAb2的抗PRLR臂来自两种不同的完全人抗PRLR抗体。
对于该实验,表达内源性水平的Her2和PRLR受体的T47D细胞在补充有10%FBS(ATCC,30-2020)、10mM Hepes、1mM丙酮酸钠和10ug/ml胰岛素的RPMI(欧文科技公司(Irvine Scientific),9160)中生长。T47D细胞用bsAb1或bsAb2以10ug/ml、3ug/ml、1μg/ml、0.3μg/ml、0.03μg/ml或0μg/ml处理6小时。
将细胞在冰上于补充有蛋白酶和磷酸酶抑制剂(赛默飞世尔公司(ThermoFisher),1861280)的RIPA缓冲液(100mM Tris-HCl、300mM NaCl、2%NP-40、1%脱氧胆酸钠和0.2%SDS)(波士顿生物试剂公司(Boston BioProducts),BP-116X)中裂解,随后超声处理(Qsonica型号Q55,三次脉冲)。将经超声处理的裂解物用2X SDS样品缓冲液1:1稀释,在95℃加热10分钟,然后在室温下以13,000rpm离心10分钟。将上清液在4至20%的NovexTris-甘氨酸凝胶上分离并印迹到PVDF膜上。
以1:300的Her2抗体(Dako,A0485)、以1:250的PRLR抗体(生命技术公司,35-9200)、或以1:10,000的β-肌动蛋白抗体(Genetex公司,GTX100313)用于膜的初级标记,然后用1:5000的HRP-缀合的第二抗体用于膜的标记,以及使用ECL(安玛西亚公司(Amersham),RPN2106)进行化学发光检测。
通过用CareStream软件(Kodak)计算条带的净强度进行对蛋白印迹的定量。为了用于负载对照,针对肌动蛋白的归一化使用如下:具有最高肌动蛋白净强度的样品用作归一化对照。将每个样品的肌动蛋白净强度除以归一化对照值以获得样品的相对值。将每种靶蛋白(Her2或PRLR)的净强度除以样品的计算的相对肌动蛋白值,以获得归一化的Her2或PRLR值(任意单位)。结果在表2中示出。
如表2所示,Her2xPRLR bsAb1和Her2xPRLR bsAb2均在T47D细胞中以剂量依赖性方式诱导Her2降解。相比之下,PRLR的水平不受双特异性抗体处理的影响。这个结果与PRLR在这些细胞表面上经历组成型表面周转一致。
表2
实验3
前述实验表明由Her2xPRLR双特异性抗体进行的Her2降解需要双特异性抗体同时结合PRLR(内化效应蛋白)和Her2(靶蛋白)。为了证实此原理,进行第三个实验以评估阻断Her2xPRLR bsAb1的PRLR结合臂或Her2结合臂对Her2内化活性的影响。
对于该实验,表达内源性水平的Her2和PRLR受体的T47D细胞在补充有10%FBS(ATCC,30-2020)、10mM Hepes、1mM丙酮酸钠和10ug/ml胰岛素的RPMI(欧文科技公司(Irvine Scientific),9160)中生长。Her2xPRLR bsAb1(10μg/ml)保留未处理(即,双臂未封闭),或在加入到T47D细胞中0、2、4或6小时前与可溶性PRLR蛋白构建体(“PRLR.mmh”用以阻断PRLR结合臂)或可溶性Her2蛋白构建体(“Her2.mmh”用以阻断Her2结合臂)在37℃下温育1小时(1:2摩尔比率)。
在温育期结束时,将细胞在冰上于补充有蛋白酶和磷酸酶抑制剂(赛默飞世尔公司(Thermo Fisher),1861280)的RIPA缓冲液(100mM Tris-HCl、300mM NaCl、2%NP-40、1%脱氧胆酸钠和0.2%SDS)(波士顿生物试剂公司(Boston BioProducts),BP-116X)中裂解,随后超声处理(Qsonica型号Q55,三次脉冲)。将经超声处理的裂解物用2X SDS样品缓冲液1:1稀释,并在95℃加热10分钟,然后在室温下以13,000rpm离心10分钟。将上清液在4至20%的Novex Tris-甘氨酸凝胶上分离并印迹到PVDF膜上。
以1:300的Her2抗体(Dako,A0485)或以1:10,000的β-肌动蛋白抗体(Genetex公司,GTX100313)用于膜的初级标记,然后用1:5000的HRP-缀合的第二抗体用于膜的标记,以及使用ECL(安玛西亚公司(Amersham),RPN2106)进行化学发光检测。
通过用CareStream软件(Kodak)计算条带的净强度进行对蛋白印迹的定量。为了用于负载对照,针对肌动蛋白的归一化使用如下:具有最高肌动蛋白净强度的样品用作归一化对照。将每个样品的肌动蛋白净强度除以归一化对照值以获得样品的相对值。将Her2条带的净强度除以样品的计算的相对肌动蛋白值,以获得归一化的Her2值(任意单位)。结果在表3中示出。
如表3所示,通过阻断Her2xPRLR bsAb1的Her2或PRLR臂,完全阻止了在T47D细胞中Her2xPRLR bsAb1介导的Her2降解,这指示Her2降解通过其与PRLR的物理连接发生,该物理连接由Her2xPRLR bsAb1多特异性抗原结合蛋白与Her2和PRLR的同时结合介导。
实施例8.由同时结合Her2和PRLR的多特异性抗原结合分子介导的曲妥单抗艾美坦辛(Emtansine)的效力增加
此实施例说明了本发明的多特异性抗原结合分子用以增加抗体-药物缀合物(“ADC”)的效力的用途。更具体地,此实施例表明包含针对内化效应蛋白的第一结合结构域和针对肿瘤相关靶抗原的第二结合结构域的多特异性抗原结合分子,联合特异于肿瘤相关抗原靶标的第二抗原结合分子(本文中也称为“协从分子”)的用途,其中协从分子是ADC。在下面本文所述的实验中,内化效应蛋白是催乳素受体(PRLR),肿瘤相关抗原靶标是Her2,并且协从分子是特异于Her2的ADC(即,曲妥单抗美坦辛(T-DM1))。
曲妥单抗是结合Her2的细胞外结构域的重组人源化单克隆抗体。曲妥单抗及其相应的ADC、曲妥单抗-美坦辛或T-DM1已经成功地用于具有强Her2过表达的患者,如通过免疫组织化学(IHC 3+)评估的。然而,目前没有有效的治疗可用于患有Her2IHC2+和Her2IHC1+肿瘤的患者。
表3
在此实施例中,评估了四种不同的抗Her2x抗PRLR双特异性抗体(本文称为“Her2xPRLR bsAb36”、“Her2xPRLR bsAb37”、“Her2xPRLR bsAb42”和“Her2xPRLR bsAb45”)的增加T-DM1对Her2表达细胞的细胞杀伤效力的能力。在此实施例中使用的双特异性抗体由四种不同的抗Her2臂和两种不同的抗PRLR臂构建,如表4中汇总的。
表4
双特异性抗体 | 抗Her2Arm | 抗PRLR Arm |
Her2xPRLR bsAb36 | 抗Her2Ab-1 | 抗PRLR Ab-1 |
Her2xPRLR bsAb37 | 抗Her2Ab-2 | 抗PRLR Ab-1 |
Her2xPRLR bsAb42 | 抗Her2Ab-3 | 抗PRLR Ab-2 |
Her2xPRLR bsAb45 | 抗Her2Ab-4 | 抗PRLR Ab-2 |
使用标准方法构建抗Her2x抗PRLR双特异性抗体(即,多特异性抗原结合分子)。还使用对照ADC(即,包含针对与DM1缀合的不相关非人类蛋白的抗体的抗体-药物缀合物)或抗PRLR-DM1ADC(在US 2015/0056221中称为H1H6958N2的抗体-药物缀合物,该专利的公开内容全文以引用方式并入本文)进行对照实验。
为了评估Her2xPRLR双特异性抗体增强T-DM1的细胞杀伤效果的能力,表达内源性水平的PRLR和过表达Her2至中间水平(T47D/Her2)的T47D细胞首先在补充有10%FBS(ATCC,30-2020)、10mM Hepes、1mM丙酮酸钠和10ug/ml胰岛素的RPMI(欧文科技公司,9160)中生长。然后将细胞以3000个细胞/孔接种在96孔板上。第二天,将细胞保留不进行处理,或用一系列浓度的T-DM1、或对照ADC、或抗PRLR-DM1、或T-DM1与10ug/ml的Her2xPRLRbsAb42、Her2xPRLR bsAb36、Her2xPRLR bsAb37或Her2xPRLR bsAb45的组合一式三份地处理3天。
细胞活力如下评估:处理后3天,用0.25%PFA、0.1%皂苷、2ug/ml Hoechst固定细胞20分钟,在10x的自动显微镜ImageXpressMICRO上获得所有孔的图像,并使用细胞增殖HTMetzxPressTM模块进行分析(核计数)。结果汇总在表5中。
表5
处理 | IC50(nM) |
T-DM1 | 30.0 |
对照ADC | 200.0 |
T-DM1+Her2xPRLR bsAB42 | 2.0 |
对照ADC+Her2xPRLR bsAB42 | 100.0 |
抗PRLR-ADC | 0.9 |
T-DM1+Her2xPRLR bsAB37 | 2.0 |
T-DM1+Her2xPRLR bsAB36 | 2.5 |
T-DM1+Her2xPRLR bsAB45 | 1.0 |
如表5所示,通过本发明的Her2xPRLR双特异性抗体的存在,T-DM1的细胞杀伤效力显著增强。因此,该实施例证明了本发明的多特异性抗原结合蛋白增强针对通常不被细胞以快速方式内化的靶蛋白的免疫缀合物分子的效力和功效的能力。
已知T-DM1对表达高水平HER2的肿瘤具有活性,而表达低和中等水平的HER2的那些细胞保持对T-DM1治疗的抗性。相比之下,抗PRLR-ADC能够诱导对表达低水平PRLR的乳腺肿瘤细胞的稳健杀伤。抗PRLR-ADC和T-DM1之间的杀伤效率的差异可能是由于内化速率差异和它们靶向各自相应靶标的溶酶体运输的差异。比较PRLR和HER2的细胞内运输。
在表达低表面水平的PRLR和HER2的那些细胞中,观察到PRLR经历快速组成性溶酶体运输和降解,该快速组成性溶酶体运输和降解在很大程度上独立于催乳素配体。然而,HER2没有经历快速组成性溶酶体运输和降解。例如,表达低水平的PRLR和HER2的T47D细胞在60分钟内内化80%的PRLR,而HER不被内化(图11)。在这些实验中,将T47D细胞与CFTM594标记的抗PRLR一抗或CFTM594标记的抗HER2一抗在冰上温育。通过向细胞中加入预热(37℃)的培养基来开始内化过程。在指定的时间,用4%多聚甲醛固定细胞以停止内化,并用第二Alexa488缀合的山羊抗人Fab染色以检测保留在细胞表面上的非内化抗体(黄色)。针对共焦堆叠的所有部分在逐像素基础上量化共定位。结果描绘于图11中)
同样,观察到PRLR,而不是HER2被快速内化到T47D细胞的溶酶体隔室中。将CFTM594标记的抗PRLR抗体或CFTM594标记的抗HER2抗体加入到用荧光素-3kDa葡聚糖预标记的T47D细胞中。允许抗体-受体复合物在37℃下内化指定的时间(图12的X轴),然后用4%多聚甲醛固定。测定内化抗体与葡聚糖标记的溶酶体的共定位。结果描绘于图12中,并且基本上与图11的内化数据一致。
控制PRLR的组成型周转的序列基序被映射到受体胞质结构域中的21个氨基酸区域;PRLR周转使得能够进行有效的ADC介导的细胞周期停滞和细胞杀伤。图13描绘了在以下实验中使用的各种PRLR和HER2构建体,包括:(1)全长PRLR(PRLR FL),(2)全长HER2(HER2FL),(3)PRLR的与HER2的跨膜(TM)和细胞质(Cyto)部分融合的细胞外(Ecto)结构域(PRLRectoHER2cytoTM),(4)HER2的与PRLR的跨膜(TM)和细胞质(Cyto)部分融合的细胞外(Ecto)结构域(HER2ectoPRLRcytoTM),(5)缺失氨基酸301至622(如用具有保留信号肽的未加工蛋白质测量的)的PRLR(PRLR Cyto42),以及(6)缺失氨基酸280至622(如用具有保留信号肽的未加工蛋白质测量的)的PRLR(PRLR Cyto21)。
为了将PRLR的内化效应序列映射到其结构域中的一个(细胞外、跨膜、细胞质)结构域,将HEK293细胞在24孔光学板中生长,并用编码PRLR、HER2、HER2ectoPRLRcytoTM或PRLRectoHER2cytoTM的哺乳动物表达载体瞬时转染24小时。然后将转染的细胞在CFTM594标记的一抗的存在下在冰上温育,然后加温至37℃并温育另外1小时。图14描绘了当构建体预期不被内化时,在4℃下修饰的细胞,并且在37℃后,能够快速内化的那些构建体将被内化。小图A描绘了在37℃下内化的PRLR FL构建体。小图B描述了HER2FL构建体,其基本上不能在37℃下在一个小时内内化。小图C描述了PRLRecto-HER2cyto/TM构建体,其也基本上不能在37℃下在一个小时内内化。小图D描述了在37℃下内化的HER2ectoPRLRcyto/TM构建体。这些结果表明PRLR的胞质结构域提供内化效应序列。
内化效应序列进一步映射到约280个至约300个的PRLR氨基酸残基(例如,SEQ IDNO:11的残基280至300;残基DAHLLEKGKSEELLSALGCQD[SEQ ID NO:12])(又称为PRLRCyto21-42)。如上所述对HEK293细胞进行标记抗体-冰至37℃实验。图15描绘了含有PRLR的整个胞质结构域的那些构建体(PRLR FL)的细胞摄取(小图A和小图B),含有PRLR的膜近端42个氨基酸的那些构建体(PRLR Cyto42)的细胞摄取(小图C和小图D),以及含有PRLR的膜近端21个氨基酸的那些构建体(PRLR Cyto21)的细胞摄取(小图D和小图E)。当PRLR Cyto42构建体被快速内化时,PRLR Cyto21构建体未被内化。这表明在质膜附近的21个氨基酸与42个氨基酸之间的PRLR胞质结构域区域(Cyto21-42)含有PRLR的内化和降解所必需的信息。
为了确定内化的PRLR构建体是否降解(即,靶向溶酶体),在加温后的不同时间(0小时、2小时、4小时、6小时)用放线菌酮(CHX)处理经转染的HEK293细胞以停滞蛋白质生产。如通过总细胞裂解物的蛋白印迹所证明的(图16),PRLR FL和PRLR Cyto42迅速降解,而几乎没有检测到PRLR Cyto21降解。
在经转染的HEK293细胞上测试PRLR跨膜和胞质结构域作为内化效应子用于递送作为抗体药物缀合物(ADC)的抗细胞增殖药物的有效性。将HEK293细胞以四环素控制的方式(例如,使用Lenti-XTMTet-系统,Clontech公司,加州山景城(Mountain View,CA))工程化以表达PRLR、HER2或PRLRectoHER2cyto/TM。用0.01μg/ml或0.003μg/ml或0.7μg/ml强力霉素诱导转染的细胞24小时,以实现受体的不同表达水平,表达水平通过流式细胞术测定。将与mertansine(又称为DM1,又称为美坦辛)缀合的PRLR(1ηM)(小图A,图17)或与HER2-DM1缀合的PRLR(1ηM)(小图B,图17)分别加入到转染的细胞中,将这些细胞温育另外24小时。使用磷酸化组蛋白H3(Ser10)抗体进行细胞周期分析以检测早期有丝分裂细胞。结果描绘于图17中,其证明PRLR的跨膜/胞质结构域有效地介导药物到细胞中的递送。
进行胞质结构域,特别是Cyto21-24结构域的丙氨酸诱变,以帮助映射内化所必需的残基。包含在Cyto21-42序列中的两个二亮氨酸的定点诱变抑制转染的HEK293细胞上PRLR Cyto42的周转。将T-RExTMHEK293细胞(即,稳定的Tet-On表达细胞,赛默飞世尔科技公司(ThermoFisher Scientific),马塞诸塞州沃尔瑟姆(Waltham MA))工程化,以用四环素控制的方式(使用例如Jump-InTM细胞工程化平台,赛默飞世尔科技公司,马塞诸塞州沃尔瑟姆)表达PRLR Cyto42、PRLR Cyto21、PRLR Cyto42L283A L284A、PRLR Cyto42L292A L293A、或PRLR Cyto42L283A L284A L292A L293A(又称为4LA),用强力霉素(0.7μg/ml)诱导24小时并用CHX(50μg/ml)处理0或4小时。结果描绘于图18的蛋白印迹中,图18示出了缺乏Cyto21-42或二亮氨酸重复片段的那些构建体的蛋白质降解的减少。结果支持了这些残基对于溶酶体靶向重要的结论。
另外的实验证明,当两种受体使用HER2(T)xPRLR双特异性抗体桥接时,由PRLR的胞质结构域介导的PRLR周转是指导HER2至溶酶体降解的驱动力。(HER2(T)代表曲妥单抗臂。)首先评估双特异性抗体及其亲本单特异性抗体的动力学结合参数。双特异性抗体显示与作为其亲本抗体的HER2和PRLR的细胞外结构域类似的结合动力学(表6)。
为了证明PRLR的胞质结构域是HER2(T)xPRLR bsAb介导的内源性HER2降解所必需的,将T-RExTMHEK293细胞工程化以表达全长PRLR,或缺少整个胞质结构域的截短PRLR(下部小图)。使用Jump-InTM细胞工程化平台(赛默飞世尔科技公司,马塞诸塞州沃尔瑟姆)以四环素控制的方式表达蛋白质。用0.7μg/ml强力霉素诱导细胞24小时,随后用CHX与指定抗体(表6)的组合温育不同时间、裂解、并加工以用于蛋白印迹。
表6
图19描绘了来自表达全长PRLR构建体的细胞的裂解物的蛋白印迹。注意,HER2(T)x PRLR双特异性抗体有效地将HER2靶向溶酶体,而抗HER2(T)抗体则不靶向,这表明PRLR作为低表达HER2的内化效应子的有效性。图20描绘了来自表达细胞质截短的PRLR构建体的细胞的裂解物的蛋白印迹。在此,在任何处理下没有观察到PRLR或HER2的降解,因此证明了PRLR的胞质结构域对将该受体及其分子货物(molecular cargo)靶向到溶酶体的必要性。
HER2xPRLR双特异性抗体诱导HER2的溶酶体运输、增强HER2-ADC诱导的细胞周期停滞,并促进T47D细胞中的细胞杀伤。为了确定溶酶体靶向,用非结合对照抗体或HER2xPRLR双特异性抗体处理T47D细胞,并进行冰至37℃内吞测定。对溶酶体和HER2染色,并测定HER2像素占据溶酶体标记物像素的百分比。结果描绘于图21中,图21示出了在加热60分钟内HER2x PRLR双特异性抗体将大于50%至60%的HER2靶向溶酶体,相比之下对照中少于25%。
为了确定HER2x PRLR双特异性抗体增强HER2-DM1介导的细胞周期停滞,将表达HER2的T47D细胞用1nM、10nM或30nM的PRLR-ADC处理(A)、用HER2-ADC加HER2x PRLR双特异性抗体处理(B)、用单独的HER2-ADC处理(C)、用非结合型对照ADC(D)处理,或不处理(E)。通过用抗磷酸化组蛋白(Ser10)抗体(细胞周期停滞的指示物)染色来测定早期有丝分裂细胞的百分比。结果描绘于图22中,图22示出了HER2-ADC加HER2x PRLR双特异性抗体(B)比单独的HER2-ADC更有效地停滞细胞(C)。
为了确定HER2x PRLR双特异性抗体增强HER2-DM1介导的细胞杀伤,用药物处理表达HER2的T47D细胞,如图23所示:PRLR-ADC(A)、HER2-ADC加HER2x PRLR双特异性抗体(B)、单独的HER2-ADC(C)、非结合型对照ADC(D)、或非结合型对照ADC加HER2x PRLR双特异性抗体(E)。图23描绘了结果,并且显示HER2x PRLR双特异性抗体显著降低HER2-ADC的IC 50。
实施例9.使用hMHC-1内化剂的高靶周转率和靶降解
高周转蛋白用于降解可溶性和跨膜靶标。设计多特异性抗原结合蛋白(例如双特异性抗体)以将靶分子与“破坏者”蛋白连接,该“驱逐器”蛋白(i)已知快速周转,(ii)表现出靶介导的高二价抗体清除,和(iii)已知运输到或来自溶酶体。为了便于设计和制造,双特异性抗体被制备成含有共同轻链、针对“破坏者”蛋白的重链、以及针对靶的重链。重链中的一条重链含有H95R修饰。
在该实施例中,所选择的破坏者分子是主要组织相容性复合物I MHC-1,更具体地,为I类,B同种型(又称为HLA-B)。HLA的紧密结合单克隆抗体被快速清除,这是“破坏者”分子的标志。作为示例性可溶性靶分子,选择过敏原FelD1作为靶分子。FelD1是包含两个二硫键连接的异源二聚体的四聚体糖蛋白。构建并测试了两种形式的可溶性FelD1,一种FelD1-myc-myc-his融合蛋白(FelD1-mmh)和一种FelD1-Fc融合蛋白。
在一组实验中,用Alexa 488标记FelD1-mmh以帮助跟踪靶的内化。使用包含HLA-B特异性臂(结合破坏者)和FelD1特异性臂(结合靶)的双特异性抗体(α-HLAB27·α-FelD1)作为多特异性抗原结合蛋白。将表达HLA-B的C1Rneo B类淋巴母细胞用10μg/ml FelD1-mmh-Alexa 488和10μg/mlα-HLAB27·α-FelD1温育。将细胞温育过夜以允许FelD1靶蛋白有时间进行内化。然后用抗Alexa488抗体(Alexa-Fluor-488-抗体-多克隆/A-11094,赛默飞世尔科技公司,马塞诸塞州沃尔瑟姆)染色细胞,该抗体淬灭Alexa488的荧光。抗Alexa488抗体不会淬灭已被内化的标记靶,因此内化靶标可以与与细胞表面相关的靶标区分开。在此,通过FACs定量荧光。
图10描述了MHC1阴性细胞(作为对照)和MHC1阳性细胞的表面结合靶标和内化靶标的平均荧光(通过FACS定量的任意单位)。所使用的双特异性抗体是α-HLAB27·α-FelD1。使用亲本α-HLAB27·α-HLAB27二价抗体和非特异性IgG同种型作为对照。对于表达MHC1(破坏者)的那些细胞,与α-HLAB27·α-FelD1接触的细胞表现出相对于表面缔合靶分子大约四倍增加的内化靶分子。对于对照基本上没有检测到效果。结果描绘于图10和下表7中。
评估了α-HLAB27·α-FelD1介导的从表达人HLA-B等位基因的小鼠的血清中的FelD1-Fc清除。通过皮下注射(10mg/kg)将双特异性抗体α-HLAB27·α-FelD1和对照(PBS,抗FelD1二价单特异性,和抗HLAB27二价单特异性)施用于表达人HLA-B等位基因的小鼠。第二天,通过尾静脉注射施用1.6mg/kg的FelD1-Fc。(使用3:1的抗体:靶比率。)从在15分钟,6小时,1天,2天,3天,4天,6天和8天取得的尾部血获得血清样品。使用抗FelD1抗体,通过蛋白印迹法检测和定量FelD1水平。α-HLAB27·α-FelD1双特异性处理显示快速的FelD1清除,具有的t1/2<30小时,类似于在不存在FelD1的情况下抗HLAB27的清除率(即33小时的t1/2),并且是在不存在FelD1的情况下α-HLAB27·α-FelD1的清除率(即,65小时的t1/2)的大于两倍。抗FelD1的施用不影响MHC1介导的清除,但是观察到一些中度清除,这归因于Fc受体。结果描绘于图11和图12中。
表7:平均荧光单位(FelD1-mmh-Alexa288)
实施例10.使用APLP2/PCSK9系统降解靶标
为了评估前蛋白转化酶枯草杆菌蛋白酶/kexin 9型(PCSK9)及其细胞表面伴侣(例如LDLR和APLP2;参见DeVay等人,“Characterization of proprotein convertasesubtilisin/kexin type 9(PCSK9)trafficking reveals a novel lysosomal targetingmechanism via amyloid precursor-like protein 2(APLP2)”,288(15)J.Biol.Chem.10805-18(2013年4月12日))可以用作抗体介导的靶标破坏的效应物,制成抗靶标PCSK9融合蛋白。融合蛋白可以被认为是掺入抗PSCK9或抗APLP2结合臂代替PCSK9融合体的双特异性抗体的模型。
对于这些实验,使用铁调素调节蛋白(HJV)作为模型靶,这部分是因为体内功效读数,即在治疗开始后一周测量血清铁的增加,是容易和可靠的。HJV是骨形态发生蛋白6(BMP6)的共受体。阻断HJV抑制BMP6信号传导并降低铁调素水平,这继而抑制铁转运蛋白铁蛋白。最终,阻断HJV增加血清铁。(参见Core等人,“Hemojuvelin and bone morphogeneticprotein(BMP)signaling in iron homeostasis,”5Front.Pharmacol.104(1-9),2014年5月13日。)
产生六种抗体::PCSK9融合分子,每种包含在hIgG1骨架中的抗HJV非阻断抗体(α-HJV-n)或抗Myc抗体(α-Myc),该hIgG1骨架通过3xGGGS接头(SEQ ID NO:6)融合到三种不同的PCSK9(例如,SEQ ID NO:5)变体中的一种。第一种变体是没有信号序列但包括pro结构域的全长PCSK9(全长[“PCSK9FL”];SEQ ID NO:7)。第二种变体是仅C末端结构域,包括PCSK9的催化和C端结构域之间的一些内部接头序列(长C末端[“PCSK9LC”];SEQ ID NO:8)。第三种变体是不包括该内部接头序列的C末端结构域的短变体(短C末端[“PCSK9SC”];SEQ IDNO:9)。预期C末端变体仅结合APLP2而不结合LDL受体。
抗体::PCSK9融合体在CHO细胞中表达并由CHO细胞分泌。将含有重链PCSK9融合体和相关抗体的同源轻链的质粒共转染到10cm或15cm培养皿中的CHO-K1细胞中。然后将细胞温育4-5天以允许产生和分泌抗体::PCSK9,之后收获上清液并通过0.2微米过滤器过滤灭菌。随后测试含有融合蛋白的CHO细胞上清液在体外内化可溶性HJV蛋白的能力。
用荧光团pHrodo标记的可溶性HJV如下制备。通过GPG接头融合到myc-myc-6xhis(mmh)标签的HJV ecto结构域(SEQ ID NO:10)在CHO sups中表达并纯化。随后使用N-羟基硫代琥珀酰亚胺(NHS)化学用(赛默飞世尔科技公司,沃尔瑟姆)标记纯化的蛋白质。
将HepG2细胞用溶液温育,该溶液含有50%的含抗体::PCSK9的CHO上清液、具有5%脂蛋白缺陷血清和1μg/ml标记的hHJV-mmh的50%的HepG2培养基。HepG2细胞是方便的模型,因为它们表达LDLR和APLP2两者,LDLR和APLP2是已知内化PCSK9的关键蛋白。然而,为了评估PCSK9融合多特异性抗原结合蛋白,技术人员将理解PCSK9被内化(包括通过除LDLR和APLP2之外的结合配偶体)的任何细胞系(天然的、诱导的、异位转化的等)可以潜在地用于该测定。在测定前一天将细胞以1.5×105个细胞/mL接种,并在37℃温育。通过在高内涵成像仪(分子仪器公司,加利福尼亚州森尼韦尔市(Sunnyvale,CA))上成像来监测内化24小时,其中24小时时间点显示出构建体和对照之间的最大差异最可能是由于-HJV-mmh在整个测定中积聚于细胞中。使用软件(分子仪器公司(Molecular Devices))定量内化荧光。
使用α-HJV-N::PCSK9FL和α-Myc::PCSK9FL温育相对于无抗体对照增加了标记的HJV-mmh蛋白的内化。由于pHrodo标记的HJV-mmh含有两个myc标签,α-Myc::PCSK9FL预期在该测定中与α-HJV-N::PCSK9FL类似地起作用。有趣的是,含有PCSK9C末端结构域(即α-HJV-N::PCSK9LC和α-HJV-N::PCSK9SC)的融合蛋白未能内化标记的HJV蛋白,可能是由于减弱的LDLR结合。结果描绘于图26中。
实施例11.使用APLP2/PCSK9系统在体内降解靶标
测试亲本α-HJV-N二价单特异性抗体(其不阻断BMP与HJV的结合)、α-HJV-B二价单特异性抗体(其阻断BMP与HJV的结合)、α-HJV-N::PCSK9FL融合蛋白和α-Myc::PCSK9FL融合蛋白在体内阻断HJV信号传导的能力。通过流体动力学递送(HDD)向小鼠施用分子。一周后采集血清样品。由于内源性HJV不具有myc-myc-his标签,α-Myc::PCSK9FL融合蛋白在体内作为阴性对照。如所预期的,α-HJV-N二价多特异性抗体(阳性对照)的HDD导致血清铁相对于阴性对照显著增加。α-HJV-N::PCSK9FL(测试分子)的HDD也导致与阻断抗体相似量级的血清铁的显著增加,这表明该分子在体内有效内化和螯合或破坏HJV(图27)。
本发明的范围不受本文所述的特定实施方案限制。实际上,除了本文中所述的那些内容之外,所属领域的技术人员根据前述说明和附图将显而易知本发明的各种修改。希望这些修改属于所附权利要求书的范围内。
序列表
<110> Regeneron Pharmaceuticals, Inc.
<120> 多特异性抗原结合分子及其用途
<130> 10172WO01
<141> 2016-07-06
<150> US 62/188,860
<151> 2015-07-06
<150> US 62/328,900
<151> 2016-04-28
<150> US 62/347,179
<151> 2016-06-08
<160> 12
<170> SIPOSequenceListing 1.0
<210> 1
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 1
Met Met Ala Leu Gly Ala Ala Gly Ala Thr Arg Val Phe Val Ala Met
1 5 10 15
Val Ala Ala Ala Leu Gly Gly His Pro Leu Leu Gly Val Ser Ala Thr
20 25 30
Leu Asn Ser Val Leu Asn Ser Asn Ala Ile Lys Asn Leu Pro Pro Pro
35 40 45
Leu Gly Gly Ala Ala Gly His Pro Gly Ser Ala Val Ser Ala Ala Pro
50 55 60
Gly Ile Leu Tyr Pro Gly Gly Asn Lys Tyr Gln Thr Ile Asp Asn Tyr
65 70 75 80
Gln Pro Tyr Pro Cys Ala Glu Asp Glu Glu Cys Gly Thr Asp Glu Tyr
85 90 95
Cys Ala Ser Pro Thr Arg Gly Gly Asp Ala Gly Val Gln Ile Cys Leu
100 105 110
Ala Cys Arg Lys Arg Arg Lys Arg Cys Met Arg His Ala Met Cys Cys
115 120 125
Pro Gly Asn Tyr Cys Lys Asn Gly Ile Cys Val Ser Ser Asp Gln Asn
130 135 140
His Phe Arg Gly Glu Ile Glu Glu Thr Ile Thr Glu Ser Phe Gly Asn
145 150 155 160
Asp His Ser Thr Leu Asp Gly Tyr Ser Arg Arg Thr Thr Leu Ser Ser
165 170 175
Lys Met Tyr His Thr Lys Gly Gln Glu Gly Ser Val Cys Leu Arg Ser
180 185 190
Ser Asp Cys Ala Ser Gly Leu Cys Cys Ala Arg His Phe Trp Ser Lys
195 200 205
Ile Cys Lys Pro Val Leu Lys Glu Gly Gln Val Cys Thr Lys His Arg
210 215 220
Arg Lys Gly Ser His Gly Leu Glu Ile Phe Gln Arg Cys Tyr Cys Gly
225 230 235 240
Glu Gly Leu Ser Cys Arg Ile Gln Lys Asp His His Gln Ala Ser Asn
245 250 255
Ser Ser Arg Leu His Thr Cys Gln Arg His Gly Pro Gly Glu Pro Arg
260 265 270
Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn
275 280 285
Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp
290 295 300
Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp
305 310 315 320
Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn
325 330 335
Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn
340 345 350
Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp
355 360 365
Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro
370 375 380
Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala
385 390 395 400
Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys
405 410 415
Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile
420 425 430
Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn
435 440 445
Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys
450 455 460
Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys
465 470 475 480
Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe
485 490 495
Ser Arg Thr Pro Gly Lys
500
<210> 2
<211> 496
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 2
Met Met Ala Leu Gly Ala Ala Gly Ala Thr Arg Val Phe Val Ala Met
1 5 10 15
Val Ala Ala Ala Leu Gly Gly His Pro Leu Leu Gly Val Ser Ala Thr
20 25 30
Leu Asn Ser Val Leu Asn Ser Asn Ala Ile Lys Asn Leu Pro Pro Pro
35 40 45
Leu Gly Gly Ala Ala Gly His Pro Gly Ser Ala Val Ser Ala Ala Pro
50 55 60
Gly Ile Leu Tyr Pro Gly Gly Asn Lys Tyr Gln Thr Ile Asp Asn Tyr
65 70 75 80
Gln Pro Tyr Pro Cys Ala Glu Asp Glu Glu Cys Gly Thr Asp Glu Tyr
85 90 95
Cys Ala Ser Pro Thr Arg Gly Gly Asp Ala Gly Val Gln Ile Cys Leu
100 105 110
Ala Cys Arg Lys Arg Arg Lys Arg Cys Met Arg His Ala Met Cys Cys
115 120 125
Pro Gly Asn Tyr Cys Lys Asn Gly Ile Cys Val Ser Ser Asp Gln Asn
130 135 140
His Phe Arg Gly Glu Ile Glu Glu Thr Ile Thr Glu Ser Phe Gly Asn
145 150 155 160
Asp His Ser Thr Leu Asp Gly Tyr Ser Arg Arg Thr Thr Leu Ser Ser
165 170 175
Lys Met Tyr His Thr Lys Gly Gln Glu Gly Ser Val Cys Leu Arg Ser
180 185 190
Ser Asp Cys Ala Ser Gly Leu Cys Cys Ala Arg His Phe Trp Ser Lys
195 200 205
Ile Cys Lys Pro Val Leu Lys Glu Gly Gln Val Cys Thr Lys His Arg
210 215 220
Arg Lys Gly Ser His Gly Leu Glu Ile Phe Gln Arg Cys Tyr Cys Gly
225 230 235 240
Glu Gly Leu Ser Cys Arg Ile Gln Lys Asp His His Gln Ala Ser Asn
245 250 255
Ser Ser Arg Leu His Thr Cys Gln Arg His Gly Pro Gly Asp Lys Thr
260 265 270
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
275 280 285
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
290 295 300
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
305 310 315 320
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
325 330 335
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
340 345 350
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
355 360 365
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
370 375 380
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
385 390 395 400
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
405 410 415
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
420 425 430
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
435 440 445
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
450 455 460
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
465 470 475 480
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
485 490 495
<210> 3
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 3
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 Val Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Ile Lys Tyr Phe Arg 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 Val Glu Asp Thr Ala His Tyr Tyr Cys
85 90 95
Ala Lys Glu Ser Ser Ser Trp Tyr Phe Tyr His Gly Leu Asp Val Trp
100 105 110
Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 4
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 4
Glu Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Asn Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Asn Tyr Leu Ala Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro His Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Gly Asp Val Gly Thr Tyr Phe Cys Met Gln Ser
85 90 95
Leu Gln Ala Pro Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Glu Ile
100 105 110
Lys Arg
<210> 5
<211> 692
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 5
Met Gly Thr Val Ser Ser Arg Arg Ser Trp Trp Pro Leu Pro Leu Leu
1 5 10 15
Leu Leu Leu Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Gln Glu
20 25 30
Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg Ser Glu
35 40 45
Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala Thr Phe
50 55 60
His Arg Cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr Val Val
65 70 75 80
Val Leu Lys Glu Glu Thr His Leu Ser Gln Ser Glu Arg Thr Ala Arg
85 90 95
Arg Leu Gln Ala Gln Ala Ala Arg Arg Gly Tyr Leu Thr Lys Ile Leu
100 105 110
His Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met Ser Gly
115 120 125
Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr Ile Glu
130 135 140
Glu Asp Ser Ser Val Phe Ala Gln Ser Ile Pro Trp Asn Leu Glu Arg
145 150 155 160
Ile Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gln Pro Pro Asp Gly
165 170 175
Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser Ile Gln Ser Asp
180 185 190
His Arg Glu Ile Glu Gly Arg Val Met Val Thr Asp Phe Glu Asn Val
195 200 205
Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gln Ala Ser Lys Cys Asp
210 215 220
Ser His Gly Thr His Leu Ala Gly Val Val Ser Gly Arg Asp Ala Gly
225 230 235 240
Val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn Cys Gln
245 250 255
Gly Lys Gly Thr Val Ser Gly Thr Leu Ile Gly Leu Glu Phe Ile Arg
260 265 270
Lys Ser Gln Leu Val Gln Pro Val Gly Pro Leu Val Val Leu Leu Pro
275 280 285
Leu Ala Gly Gly Tyr Ser Arg Val Leu Asn Ala Ala Cys Gln Arg Leu
290 295 300
Ala Arg Ala Gly Val Val Leu Val Thr Ala Ala Gly Asn Phe Arg Asp
305 310 315 320
Asp Ala Cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu Val Ile Thr Val
325 330 335
Gly Ala Thr Asn Ala Gln Asp Gln Pro Val Thr Leu Gly Thr Leu Gly
340 345 350
Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Glu Asp Ile
355 360 365
Ile Gly Ala Ser Ser Asp Cys Ser Thr Cys Phe Val Ser Gln Ser Gly
370 375 380
Thr Ser Gln Ala Ala Ala His Val Ala Gly Ile Ala Ala Met Met Leu
385 390 395 400
Ser Ala Glu Pro Glu Leu Thr Leu Ala Glu Leu Arg Gln Arg Leu Ile
405 410 415
His Phe Ser Ala Lys Asp Val Ile Asn Glu Ala Trp Phe Pro Glu Asp
420 425 430
Gln Arg Val Leu Thr Pro Asn Leu Val Ala Ala Leu Pro Pro Ser Thr
435 440 445
His Gly Ala Gly Trp Gln Leu Phe Cys Arg Thr Val Trp Ser Ala His
450 455 460
Ser Gly Pro Thr Arg Met Ala Thr Ala Val Ala Arg Cys Ala Pro Asp
465 470 475 480
Glu Glu Leu Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys Arg Arg
485 490 495
Gly Glu Arg Met Glu Ala Gln Gly Gly Lys Leu Val Cys Arg Ala His
500 505 510
Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala Ile Ala Arg Cys Cys Leu
515 520 525
Leu Pro Gln Ala Asn Cys Ser Val His Thr Ala Pro Pro Ala Glu Ala
530 535 540
Ser Met Gly Thr Arg Val His Cys His Gln Gln Gly His Val Leu Thr
545 550 555 560
Gly Cys Ser Ser His Trp Glu Val Glu Asp Leu Gly Thr His Lys Pro
565 570 575
Pro Val Leu Arg Pro Arg Gly Gln Pro Asn Gln Cys Val Gly His Arg
580 585 590
Glu Ala Ser Ile His Ala Ser Cys Cys His Ala Pro Gly Leu Glu Cys
595 600 605
Lys Val Lys Glu His Gly Ile Pro Ala Pro Gln Glu Gln Val Thr Val
610 615 620
Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu Pro Gly
625 630 635 640
Thr Ser His Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys Val Val
645 650 655
Arg Ser Arg Asp Val Ser Thr Thr Gly Ser Thr Ser Glu Gly Ala Val
660 665 670
Thr Ala Val Ala Ile Cys Cys Arg Ser Arg His Leu Ala Gln Ala Ser
675 680 685
Gln Glu Leu Gln
690
<210> 6
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 6
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 7
<211> 662
<212> PRT
<213> 智人
<400> 7
Gln Glu Asp Glu Asp Gly Asp Tyr Glu Glu Leu Val Leu Ala Leu Arg
1 5 10 15
Ser Glu Glu Asp Gly Leu Ala Glu Ala Pro Glu His Gly Thr Thr Ala
20 25 30
Thr Phe His Arg Cys Ala Lys Asp Pro Trp Arg Leu Pro Gly Thr Tyr
35 40 45
Val Val Val Leu Lys Glu Glu Thr His Leu Ser Gln Ser Glu Arg Thr
50 55 60
Ala Arg Arg Leu Gln Ala Gln Ala Ala Arg Arg Gly Tyr Leu Thr Lys
65 70 75 80
Ile Leu His Val Phe His Gly Leu Leu Pro Gly Phe Leu Val Lys Met
85 90 95
Ser Gly Asp Leu Leu Glu Leu Ala Leu Lys Leu Pro His Val Asp Tyr
100 105 110
Ile Glu Glu Asp Ser Ser Val Phe Ala Gln Ser Ile Pro Trp Asn Leu
115 120 125
Glu Arg Ile Thr Pro Pro Arg Tyr Arg Ala Asp Glu Tyr Gln Pro Pro
130 135 140
Asp Gly Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser Ile Gln
145 150 155 160
Ser Asp His Arg Glu Ile Glu Gly Arg Val Met Val Thr Asp Phe Glu
165 170 175
Asn Val Pro Glu Glu Asp Gly Thr Arg Phe His Arg Gln Ala Ser Lys
180 185 190
Cys Asp Ser His Gly Thr His Leu Ala Gly Val Val Ser Gly Arg Asp
195 200 205
Ala Gly Val Ala Lys Gly Ala Ser Met Arg Ser Leu Arg Val Leu Asn
210 215 220
Cys Gln Gly Lys Gly Thr Val Ser Gly Thr Leu Ile Gly Leu Glu Phe
225 230 235 240
Ile Arg Lys Ser Gln Leu Val Gln Pro Val Gly Pro Leu Val Val Leu
245 250 255
Leu Pro Leu Ala Gly Gly Tyr Ser Arg Val Leu Asn Ala Ala Cys Gln
260 265 270
Arg Leu Ala Arg Ala Gly Val Val Leu Val Thr Ala Ala Gly Asn Phe
275 280 285
Arg Asp Asp Ala Cys Leu Tyr Ser Pro Ala Ser Ala Pro Glu Val Ile
290 295 300
Thr Val Gly Ala Thr Asn Ala Gln Asp Gln Pro Val Thr Leu Gly Thr
305 310 315 320
Leu Gly Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Glu
325 330 335
Asp Ile Ile Gly Ala Ser Ser Asp Cys Ser Thr Cys Phe Val Ser Gln
340 345 350
Ser Gly Thr Ser Gln Ala Ala Ala His Val Ala Gly Ile Ala Ala Met
355 360 365
Met Leu Ser Ala Glu Pro Glu Leu Thr Leu Ala Glu Leu Arg Gln Arg
370 375 380
Leu Ile His Phe Ser Ala Lys Asp Val Ile Asn Glu Ala Trp Phe Pro
385 390 395 400
Glu Asp Gln Arg Val Leu Thr Pro Asn Leu Val Ala Ala Leu Pro Pro
405 410 415
Ser Thr His Gly Ala Gly Trp Gln Leu Phe Cys Arg Thr Val Trp Ser
420 425 430
Ala His Ser Gly Pro Thr Arg Met Ala Thr Ala Val Ala Arg Cys Ala
435 440 445
Pro Asp Glu Glu Leu Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys
450 455 460
Arg Arg Gly Glu Arg Met Glu Ala Gln Gly Gly Lys Leu Val Cys Arg
465 470 475 480
Ala His Asn Ala Phe Gly Gly Glu Gly Val Tyr Ala Ile Ala Arg Cys
485 490 495
Cys Leu Leu Pro Gln Ala Asn Cys Ser Val His Thr Ala Pro Pro Ala
500 505 510
Glu Ala Ser Met Gly Thr Arg Val His Cys His Gln Gln Gly His Val
515 520 525
Leu Thr Gly Cys Ser Ser His Trp Glu Val Glu Asp Leu Gly Thr His
530 535 540
Lys Pro Pro Val Leu Arg Pro Arg Gly Gln Pro Asn Gln Cys Val Gly
545 550 555 560
His Arg Glu Ala Ser Ile His Ala Ser Cys Cys His Ala Pro Gly Leu
565 570 575
Glu Cys Lys Val Lys Glu His Gly Ile Pro Ala Pro Gln Glu Gln Val
580 585 590
Thr Val Ala Cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu
595 600 605
Pro Gly Thr Ser His Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys
610 615 620
Val Val Arg Ser Arg Asp Val Ser Thr Thr Gly Ser Thr Ser Glu Gly
625 630 635 640
Ala Val Thr Ala Val Ala Ile Cys Cys Arg Ser Arg His Leu Ala Gln
645 650 655
Ala Ser Gln Glu Leu Gln
660
<210> 8
<211> 267
<212> PRT
<213> 智人
<400> 8
Glu Ala Trp Phe Pro Glu Asp Gln Arg Val Leu Thr Pro Asn Leu Val
1 5 10 15
Ala Ala Leu Pro Pro Ser Thr His Gly Ala Gly Trp Gln Leu Phe Cys
20 25 30
Arg Thr Val Trp Ser Ala His Ser Gly Pro Thr Arg Met Ala Thr Ala
35 40 45
Val Ala Arg Cys Ala Pro Asp Glu Glu Leu Leu Ser Cys Ser Ser Phe
50 55 60
Ser Arg Ser Gly Lys Arg Arg Gly Glu Arg Met Glu Ala Gln Gly Gly
65 70 75 80
Lys Leu Val Cys Arg Ala His Asn Ala Phe Gly Gly Glu Gly Val Tyr
85 90 95
Ala Ile Ala Arg Cys Cys Leu Leu Pro Gln Ala Asn Cys Ser Val His
100 105 110
Thr Ala Pro Pro Ala Glu Ala Ser Met Gly Thr Arg Val His Cys His
115 120 125
Gln Gln Gly His Val Leu Thr Gly Cys Ser Ser His Trp Glu Val Glu
130 135 140
Asp Leu Gly Thr His Lys Pro Pro Val Leu Arg Pro Arg Gly Gln Pro
145 150 155 160
Asn Gln Cys Val Gly His Arg Glu Ala Ser Ile His Ala Ser Cys Cys
165 170 175
His Ala Pro Gly Leu Glu Cys Lys Val Lys Glu His Gly Ile Pro Ala
180 185 190
Pro Gln Glu Gln Val Thr Val Ala Cys Glu Glu Gly Trp Thr Leu Thr
195 200 205
Gly Cys Ser Ala Leu Pro Gly Thr Ser His Val Leu Gly Ala Tyr Ala
210 215 220
Val Asp Asn Thr Cys Val Val Arg Ser Arg Asp Val Ser Thr Thr Gly
225 230 235 240
Ser Thr Ser Glu Gly Ala Val Thr Ala Val Ala Ile Cys Cys Arg Ser
245 250 255
Arg His Leu Ala Gln Ala Ser Gln Glu Leu Gln
260 265
<210> 9
<211> 243
<212> PRT
<213> 智人
<400> 9
Gly Ala Gly Trp Gln Leu Phe Cys Arg Thr Val Trp Ser Ala His Ser
1 5 10 15
Gly Pro Thr Arg Met Ala Thr Ala Val Ala Arg Cys Ala Pro Asp Glu
20 25 30
Glu Leu Leu Ser Cys Ser Ser Phe Ser Arg Ser Gly Lys Arg Arg Gly
35 40 45
Glu Arg Met Glu Ala Gln Gly Gly Lys Leu Val Cys Arg Ala His Asn
50 55 60
Ala Phe Gly Gly Glu Gly Val Tyr Ala Ile Ala Arg Cys Cys Leu Leu
65 70 75 80
Pro Gln Ala Asn Cys Ser Val His Thr Ala Pro Pro Ala Glu Ala Ser
85 90 95
Met Gly Thr Arg Val His Cys His Gln Gln Gly His Val Leu Thr Gly
100 105 110
Cys Ser Ser His Trp Glu Val Glu Asp Leu Gly Thr His Lys Pro Pro
115 120 125
Val Leu Arg Pro Arg Gly Gln Pro Asn Gln Cys Val Gly His Arg Glu
130 135 140
Ala Ser Ile His Ala Ser Cys Cys His Ala Pro Gly Leu Glu Cys Lys
145 150 155 160
Val Lys Glu His Gly Ile Pro Ala Pro Gln Glu Gln Val Thr Val Ala
165 170 175
Cys Glu Glu Gly Trp Thr Leu Thr Gly Cys Ser Ala Leu Pro Gly Thr
180 185 190
Ser His Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys Val Val Arg
195 200 205
Ser Arg Asp Val Ser Thr Thr Gly Ser Thr Ser Glu Gly Ala Val Thr
210 215 220
Ala Val Ala Ile Cys Cys Arg Ser Arg His Leu Ala Gln Ala Ser Gln
225 230 235 240
Glu Leu Gln
<210> 10
<211> 399
<212> PRT
<213> 智人
<400> 10
Met Gly Glu Pro Gly Gln Ser Pro Ser Pro Arg Ser Ser His Gly Ser
1 5 10 15
Pro Pro Thr Leu Ser Thr Leu Thr Leu Leu Leu Leu Leu Cys Gly His
20 25 30
Ala His Ser Gln Cys Lys Ile Leu Arg Cys Asn Ala Glu Tyr Val Ser
35 40 45
Ser Thr Leu Ser Leu Arg Gly Gly Gly Ser Ser Gly Ala Leu Arg Gly
50 55 60
Gly Gly Gly Gly Gly Arg Gly Gly Gly Val Gly Ser Gly Gly Leu Cys
65 70 75 80
Arg Ala Leu Arg Ser Tyr Ala Leu Cys Thr Arg Arg Thr Ala Arg Thr
85 90 95
Cys Arg Gly Asp Leu Ala Phe His Ser Ala Val His Gly Ile Glu Asp
100 105 110
Leu Met Ile Gln His Asn Cys Ser Arg Gln Gly Pro Thr Ala Pro Pro
115 120 125
Pro Pro Arg Gly Pro Ala Leu Pro Gly Ala Gly Ser Gly Leu Pro Ala
130 135 140
Pro Asp Pro Cys Asp Tyr Glu Gly Arg Phe Ser Arg Leu His Gly Arg
145 150 155 160
Pro Pro Gly Phe Leu His Cys Ala Ser Phe Gly Asp Pro His Val Arg
165 170 175
Ser Phe His His His Phe His Thr Cys Arg Val Gln Gly Ala Trp Pro
180 185 190
Leu Leu Asp Asn Asp Phe Leu Phe Val Gln Ala Thr Ser Ser Pro Met
195 200 205
Ala Leu Gly Ala Asn Ala Thr Ala Thr Arg Lys Leu Thr Ile Ile Phe
210 215 220
Lys Asn Met Gln Glu Cys Ile Asp Gln Lys Val Tyr Gln Ala Glu Val
225 230 235 240
Asp Asn Leu Pro Val Ala Phe Glu Asp Gly Ser Ile Asn Gly Gly Asp
245 250 255
Arg Pro Gly Gly Ser Ser Leu Ser Ile Gln Thr Ala Asn Pro Gly Asn
260 265 270
His Val Glu Ile Gln Ala Ala Tyr Ile Gly Thr Thr Ile Ile Ile Arg
275 280 285
Gln Thr Ala Gly Gln Leu Ser Phe Ser Ile Lys Val Ala Glu Asp Val
290 295 300
Ala Met Ala Phe Ser Ala Glu Gln Asp Leu Gln Leu Cys Val Gly Gly
305 310 315 320
Cys Pro Pro Ser Gln Arg Leu Ser Arg Ser Glu Arg Asn Arg Arg Gly
325 330 335
Ala Ile Thr Ile Asp Thr Ala Arg Arg Leu Cys Lys Glu Gly Leu Pro
340 345 350
Val Glu Asp Ala Tyr Phe His Ser Cys Val Phe Asp Val Leu Ile Ser
355 360 365
Gly Asp Pro Asn Phe Thr Val Ala Ala Gln Ala Ala Leu Glu Asp Ala
370 375 380
Arg Ala Phe Leu Pro Asp Leu Glu Lys Leu His Leu Phe Pro Ser
385 390 395
<210> 11
<211> 622
<212> PRT
<213> 智人
<400> 11
Met Lys Glu Asn Val Ala Ser Ala Thr Val Phe Thr Leu Leu Leu Phe
1 5 10 15
Leu Asn Thr Cys Leu Leu Asn Gly Gln Leu Pro Pro Gly Lys Pro Glu
20 25 30
Ile Phe Lys Cys Arg Ser Pro Asn Lys Glu Thr Phe Thr Cys Trp Trp
35 40 45
Arg Pro Gly Thr Asp Gly Gly Leu Pro Thr Asn Tyr Ser Leu Thr Tyr
50 55 60
His Arg Glu Gly Glu Thr Leu Met His Glu Cys Pro Asp Tyr Ile Thr
65 70 75 80
Gly Gly Pro Asn Ser Cys His Phe Gly Lys Gln Tyr Thr Ser Met Trp
85 90 95
Arg Thr Tyr Ile Met Met Val Asn Ala Thr Asn Gln Met Gly Ser Ser
100 105 110
Phe Ser Asp Glu Leu Tyr Val Asp Val Thr Tyr Ile Val Gln Pro Asp
115 120 125
Pro Pro Leu Glu Leu Ala Val Glu Val Lys Gln Pro Glu Asp Arg Lys
130 135 140
Pro Tyr Leu Trp Ile Lys Trp Ser Pro Pro Thr Leu Ile Asp Leu Lys
145 150 155 160
Thr Gly Trp Phe Thr Leu Leu Tyr Glu Ile Arg Leu Lys Pro Glu Lys
165 170 175
Ala Ala Glu Trp Glu Ile His Phe Ala Gly Gln Gln Thr Glu Phe Lys
180 185 190
Ile Leu Ser Leu His Pro Gly Gln Lys Tyr Leu Val Gln Val Arg Cys
195 200 205
Lys Pro Asp His Gly Tyr Trp Ser Ala Trp Ser Pro Ala Thr Phe Ile
210 215 220
Gln Ile Pro Ser Asp Phe Thr Met Asn Asp Thr Thr Val Trp Ile Ser
225 230 235 240
Val Ala Val Leu Ser Ala Val Ile Cys Leu Ile Ile Val Trp Ala Val
245 250 255
Ala Leu Lys Gly Tyr Ser Met Val Thr Cys Ile Phe Pro Pro Val Pro
260 265 270
Gly Pro Lys Ile Lys Gly Phe Asp Ala His Leu Leu Glu Lys Gly Lys
275 280 285
Ser Glu Glu Leu Leu Ser Ala Leu Gly Cys Gln Asp Phe Pro Pro Thr
290 295 300
Ser Asp Tyr Glu Asp Leu Leu Val Glu Tyr Leu Glu Val Asp Asp Ser
305 310 315 320
Glu Asp Gln His Leu Met Ser Val His Ser Lys Glu His Pro Ser Gln
325 330 335
Gly Met Lys Pro Thr Tyr Leu Asp Pro Asp Thr Asp Ser Gly Arg Gly
340 345 350
Ser Cys Asp Ser Pro Ser Leu Leu Ser Glu Lys Cys Glu Glu Pro Gln
355 360 365
Ala Asn Pro Ser Thr Phe Tyr Asp Pro Glu Val Ile Glu Lys Pro Glu
370 375 380
Asn Pro Glu Thr Thr His Thr Trp Asp Pro Gln Cys Ile Ser Met Glu
385 390 395 400
Gly Lys Ile Pro Tyr Phe His Ala Gly Gly Ser Lys Cys Ser Thr Trp
405 410 415
Pro Leu Pro Gln Pro Ser Gln His Asn Pro Arg Ser Ser Tyr His Asn
420 425 430
Ile Thr Asp Val Cys Glu Leu Ala Val Gly Pro Ala Gly Ala Pro Ala
435 440 445
Thr Leu Leu Asn Glu Ala Gly Lys Asp Ala Leu Lys Ser Ser Gln Thr
450 455 460
Ile Lys Ser Arg Glu Glu Gly Lys Ala Thr Gln Gln Arg Glu Val Glu
465 470 475 480
Ser Phe His Ser Glu Thr Asp Gln Asp Thr Pro Trp Leu Leu Pro Gln
485 490 495
Glu Lys Thr Pro Phe Gly Ser Ala Lys Pro Leu Asp Tyr Val Glu Ile
500 505 510
His Lys Val Asn Lys Asp Gly Ala Leu Ser Leu Leu Pro Lys Gln Arg
515 520 525
Glu Asn Ser Gly Lys Pro Lys Lys Pro Gly Thr Pro Glu Asn Asn Lys
530 535 540
Glu Tyr Ala Lys Val Ser Gly Val Met Asp Asn Asn Ile Leu Val Leu
545 550 555 560
Val Pro Asp Pro His Ala Lys Asn Val Ala Cys Phe Glu Glu Ser Ala
565 570 575
Lys Glu Ala Pro Pro Ser Leu Glu Gln Asn Gln Ala Glu Lys Ala Leu
580 585 590
Ala Asn Phe Thr Ala Thr Ser Ser Lys Cys Arg Leu Gln Leu Gly Gly
595 600 605
Leu Asp Tyr Leu Asp Pro Ala Cys Phe Thr His Ser Phe His
610 615 620
<210> 12
<211> 21
<212> PRT
<213> 智人
<400> 12
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权利要求书(按照条约第19条的修改)
1.一种抑制肿瘤细胞生长或促进对肿瘤细胞的杀伤的方法,所述方法包括使肿瘤细胞与多特异性抗原结合蛋白接触,其中:
(a)所述多特异性抗原结合蛋白包含特异性结合肿瘤靶标(T)的第一抗原结合结构域和特异性结合内化效应蛋白(E)的第二抗原结合结构域;
(b)所述肿瘤细胞表达T和E两者;
(c)所述T和所述E各自在所述细胞上以低水平表达;
(d)在所述多特异性抗原结合蛋白不存在的情况下,所述T不经历快速溶酶体运输;
(e)在所述多特异性抗原结合蛋白不存在的情况下,所述E经历快速溶酶体运输;并且
(f)在所述多特异性抗原结合蛋白存在的情况下,所述T经历快速溶酶体靶向和降解。
2.根据权利要求1所述的方法,其进一步包括使所述肿瘤细胞与细胞毒剂接触。
3.根据权利要求2所述的方法,其中所述细胞毒剂是抗体药物缀合物(ADC),所述ADC包含与特异性结合所述T的抗原结合蛋白缀合的药物、毒素或放射性同位素。
4.根据权利要求3所述的方法,其中所述ADC的所述抗原结合部分结合不与由所述多特异性抗原结合结构域的所述第一抗原结合结构域识别的T上表位重叠的T上表位。
5.根据权利要求3或4所述的方法,其中所述ADC的所述抗原结合蛋白是抗体。
6.根据权利要求2所述的方法,其中所述细胞毒剂是放射性同位素、毒素或药物。
7.根据权利要求3至6中任一项所述的方法,其中所述药物选自由刺孢霉素、澳瑞他汀或基于美登素的药物组成的组。
8.根据权利要求1至7中任一项所述的方法,其中所述多特异性抗原结合蛋白对E的结合亲和力小于所述多特异性抗原结合蛋白对T的结合亲和力。
9.根据权利要求1至8中任一项所述的方法,其中所述靶分子是膜蛋白或可溶性蛋白。
10.根据权利要求1至9中任一项所述的方法,其中所述多特异性抗原结合蛋白是双特异性抗体。
11.根据权利要求1至10中任一项所述的方法,其中所述靶分子选自由以下各项组成的组:过敏原、过敏原结合蛋白、细胞因子、细胞因子结合蛋白,细胞因子受体、wnt蛋白、wnt结合蛋白、卷曲蛋白、生长因子、生长因子结合蛋白、生长因子受体、G蛋白偶联受体、脂蛋白、脂蛋白结合蛋白、脂蛋白受体、激素、激素结合蛋白、激素受体、膜通道、配体门控离子通道、电压门控离子通道、病原体或其片段、以及GPI连接的蛋白质。
12.根据权利要求1至11中任一项所述的方法,其中所述靶分子是选自由以下各项组成的组的肿瘤相关靶标:AFP、ALK、BAGE蛋白、β-联蛋白、brc-abl、BRCA1、BORIS、CA9、碳酸酐酶IX、胱天蛋白酶-8、CD40、CDK4、CEA、CTLA4、细胞周期蛋白-B1、CYP1B1、EGFR、EGFRvl l l、ErbB2/Her2、ErbB3、ErbB4、ETV6-AML、EphA2、Fra-1、FOLR1、GAGE蛋白(例如,GAGE-1、GAGE-2)、GD2、GD3、GloboH、磷脂酰肌醇蛋白聚糖-3、GM3、gp100、Her2、HLA/B-raf、HLA/k-ras、HLA/MAG E-A3、hTERT、LMP2、MAGE蛋白(例如,MAGE-1、MAGE-2、MAGE-3、MAGE-4、MAGE-6和MAGE-12)、MART-1、间皮素、ML-IAP、Mud、Muc16(CA-125)、MUM 1、NA17、NY-BR1、NY-BR62、NY-BR85、NY-ES01、OX40、p15、p53、PAP、PAX3、PAX5、PCTA-1、PLAC1、PRLR、PRAME、PSMA(FOLH 1)、RAGE蛋白、Ras、RGS5、Rho、SART-1、SART-3、Steap-1、Steap-2、存活素、TAG-72、TGF-β、TMPRSS2、Tn、TRP-1、TRP-2、酪氨酸酶和尿空斑蛋白-3。
13.根据权利要求1至12中任一项所述的方法,其中所述内化效应子包含含有一个或多个二亮氨酸基序的胞质结构域。
14.根据权利要求13所述的方法,其中所述内化效应子包含含有SEQ ID NO:12的氨基酸序列的胞质结构域。
15.根据权利要求13或14所述的方法,其中所述内化效应子是催乳素受体(PRLR)。
16.根据权利要求15所述的方法,其中所述靶分子是受体酪氨酸-蛋白激酶。
17.根据权利要求16所述的方法,其中所述靶分子是HER2。
18.根据权利要求16所述的方法,其中所述多特异性抗原结合蛋白是抗HER2x PRLR双特异性抗体。
19.根据权利要求1至18中任一项所述的方法,其中所述ADC包含与抗HER2二价单特异性抗体或抗PRLR二价单特异性抗体缀合的基于美登素的药物。
20.根据权利要求1至19中任一项所述的方法,其中所述肿瘤细胞是乳腺癌细胞。
21.根据权利要求20所述的方法,其中所述乳腺癌细胞是T47D细胞。
22.一种药物组合物,其包含:
(a)与(i)快速内化的细胞表面受体和(ii)缓慢内化的细胞表面受体结合的多特异性抗原结合蛋白,其中所述快速内化的细胞表面受体和所述缓慢内化的细胞表面受体在同一细胞上表达;以及
(b)细胞毒剂。
23.根据权利要求22所述的药物组合物,其中所述多特异性抗原结合蛋白是双特异性抗体。
24.根据权利要求22或23所述的药物组合物,其中所述快速内化的细胞表面受体包含含有一个或多个二亮氨酸基序的胞质结构域。
25.根据权利要求24所述的药物组合物,其中所述快速内化的细胞表面受体包含含有SEQ ID NO:12的氨基酸序列的胞质结构域。
26.根据权利要求25所述的药物组合物,其中所述快速内化的细胞表面受体是催乳素受体(PRLR)。
27.根据权利要求22至26中任一项所述的药物组合物,其中所述缓慢内化的细胞表面受体是受体酪氨酸-蛋白激酶。
28.根据权利要求27所述的药物组合物,其中所述受体酪氨酸-蛋白激酶是HER2。
29.根据权利要求28所述的药物组合物,其中所述多特异性抗原结合蛋白是抗HER2xPRLR双特异性抗体。
30.根据权利要求22至29中任一项所述的药物组合物,其中所述细胞毒剂包含与抗HER2二价单特异性抗体或抗PRLR二价单特异性抗体缀合的基于美登素类化合物的药物。
Claims (58)
1.一种在癌症患者中抑制肿瘤生长或促进肿瘤消退的方法,所述方法包括对所述患者施用抗体药物缀合物(ADC)和多特异性抗原结合蛋白,其中所述ADC包含与特异性结合肿瘤靶标(T)的抗原结合蛋白缀合的药物、毒素或放射性同位素,并且其中所述多特异性抗原结合蛋白包含特异性结合T的第一抗原结合结构域和特异性结合内化效应蛋白(E)的第二抗原结合结构域;其中所述患者患有包含表达T和E两者的细胞的肿瘤。
2.根据权利要求1所述的方法,其中所述ADC的所述抗原结合部分结合不与由所述多特异性抗原结合结构域的所述第一抗原结合结构域识别的T上表位重叠的T上表位。
3.根据权利要求1或2所述的方法,其中所述多特异性抗原结合蛋白对E的结合亲和力小于所述多特异性抗原结合蛋白对T的结合亲和力。
4.一种降解靶分子的方法,包括使所述靶分子和破坏者分子与至少一种多特异性抗原结合蛋白接触的步骤,其中所述多特异性抗原结合蛋白、所述靶分子和所述破坏者分子随后被转运至细胞内的溶酶体并且所述靶分子被降解。
5.根据权利要求4所述的方法,其中所述多特异性抗原结合蛋白包含在第一表位处结合所述靶分子的第一互补位;和在第二表位处结合所述破坏者分子的第二互补位。
6.根据权利要求4或5所述的方法,其中(i)所述多特异性抗原结合蛋白在所述靶分子不存在的情况下以低亲和力与所述破坏者分子结合,并且(ii)所述多特异性抗原结合蛋白在所述靶分子存在的情况下以高亲和力与所述破坏者分子结合。
7.根据权利要求4所述的方法,其中所述破坏者分子是快速内化的膜蛋白,或结合快速内化的膜蛋白的可溶性蛋白。
8.根据权利要求7所述的方法,其中所述破坏者分子选自由HLA、APLP2、LDLR、PCSK9和CD63组成的组。
9.根据权利要求4或5所述的方法,其中所述靶分子包含至少两个相同的亚基。
10.根据权利要求4或5所述的方法,其还包括使所述靶分子与第二多特异性抗原结合蛋白接触的步骤,其中所述第二多特异性抗原结合蛋白包含所述第二互补位和结合第三表位的第三互补位,并且所述靶标包含结合所述第三互补位的第三表位。
11.根据权利要求4或5所述的方法,其中所述靶分子是膜蛋白或可溶性蛋白。
12.根据权利要求11所述的方法,其中所述靶分子结合靶分子配体。
13.根据权利要求12所述的方法,其中所述靶分子配体被降解。
14.根据权利要求4或5所述的方法,其中所述多特异性抗原结合蛋白是双特异性抗体。
15.根据权利要求10所述的方法,其中所述第二多特异性抗原结合蛋白是双特异性抗体。
16.根据权利要求4或5所述的方法,其中所述靶分子选自由以下各项组成的组:过敏原、过敏原结合蛋白、细胞因子、细胞因子结合蛋白,细胞因子受体、wnt蛋白、wnt结合蛋白、卷曲蛋白、生长因子、生长因子结合蛋白、生长因子受体、G蛋白偶联受体、脂蛋白、脂蛋白结合蛋白、脂蛋白受体、激素、激素结合蛋白、激素受体、膜通道、配体门控离子通道、电压门控离子通道、病原体或其片段、以及GPI连接的蛋白质。
17.根据权利要求16所述的方法,其中所述靶分子选自由以下各项组成的组:IL-1、IL-1受体、IL-4、IL-4受体、VEGF、VEGF受体、RSV、NGF、NGF受体、程序性细胞死亡蛋白-1(PD1)、程序性细胞死亡蛋白配体-1(PD-L1)、PD-L2、PDGF、PDGF受体、促血管生成素-2(Ang2)、Ang2受体、肌肉生长抑制素(GDF8)、GDF8受体、CD3和CD20。
18.根据权利要求4或5所述的方法,其中所述破坏者分子是人分子。
19.根据权利要求18所述的方法,其中所述细胞在体内。
20.一种多特异性抗原结合蛋白,其包含结合靶分子的第一表位的第一互补位和结合破坏者分子的第二表位的第二互补位。
21.根据权利要求20所述的多特异性抗原结合蛋白,其中所述多特异性抗原结合蛋白是包含与抗体重链的C末端连接的配体或可溶性受体片段的融合蛋白,其中所述抗体包含所述第一互补位并且所述配体或可溶性受体包含所述第二互补位。
22.根据权利要求21所述的多特异性抗原结合蛋白,其中所述配体或可溶性受体包含PCSK9分子或其片段,并且所述破坏者分子是LDLR或APLP2。
23.根据权利要求21或22所述的多特异性抗原结合蛋白,其中所述靶分子包含至少两个第一表位。
24.根据权利要求21至23中任一项所述的多特异性抗原结合蛋白,其中所述破坏者分子是快速周转的细胞表面分子。
25.根据权利要求24所述的多特异性抗原结合蛋白,其中所述破坏者分子选自由HLA、APLP2、LDLR、PCSK9和CD63组成的组。
26.一种包含第一多特异性抗原结合蛋白和第二多特异性抗原结合蛋白的组合物,其中(a)所述第一多特异性抗原结合蛋白包含(i)结合靶分子的第一表位的第一互补位,和(ii)结合破坏者分子的第二表位的第二互补位;并且(b)所述第二多特异性抗原结合蛋白包含(i)结合所述靶分子的第三表位的第三互补位,和(ii)结合所述破坏者分子的所述第二表位的所述第二互补位。
27.根据权利要求26所述的组合物,其中所述第一多特异性抗原结合蛋白是双特异性抗体,所述双特异性抗体的一个臂包含所述第一互补位,并且所述双特异性抗体的另一个臂包含所述第二互补位。
28.根据权利要求26或27所述的组合物,其中所述第二多特异性抗原结合蛋白是双特异性抗体,所述双特异性抗体的一个臂包含所述第三互补位,并且所述双特异性抗体的另一个臂包含所述第二互补位。
29.根据权利要求26所述的组合物,其中所述破坏者分子是快速周转的细胞表面分子。
30.根据权利要求29所述的组合物,其中所述破坏者分子选自由HLA、APLP2、LDLR、PCSK9和CD63组成的组。
31.一种治疗患者的方法,其包括向患者施用根据权利要求26所述的组合物,其中治疗性靶分子从所述患者的血清中被快速清除。
32.根据权利要求31所述的方法,其中在将所述多特异性抗原结合蛋白施用于所述患者8天后,在从所述患者采集的血清中未检测到所述治疗性靶分子,其中所述检测通过蛋白质印迹分析进行。
33.一种杀伤细胞的方法,包括使细胞上的靶分子和内化效应子与至少一种多特异性抗原结合蛋白和细胞毒剂接触的步骤,其中所述多特异性抗原结合蛋白、所述靶分子、所述内化效应子和所述细胞毒剂随后被转运至所述细胞内的溶酶体;并且所述药物被释放到所述细胞的细胞质中。
34.根据权利要求33所述的方法,其中所述细胞毒剂与所述多特异性抗原结合蛋白或另一抗原结合剂缀合。
35.根据权利要求34所述的方法,其中所述细胞毒剂是放射性同位素、毒素或药物。
36.根据权利要求34或35所述的方法,其中所述细胞毒剂是刺孢霉素、澳瑞他汀或基于美登素的细胞毒剂。
37.根据权利要求33至35中任一项所述的方法,其中所述内化效应子被快速内化。
38.根据权利要求37所述的方法,其中所述内化效应子包含含有一个或多个二亮氨酸基序的胞质结构域。
39.根据权利要求38所述的方法,其中所述内化效应子包含含有SEQ ID NO:12的氨基酸序列的胞质结构域。
40.根据权利要求38或39所述的方法,其中所述内化效应子是催乳素受体(PRLR)。
41.根据权利要求37所述的方法,其中所述靶分子是受体酪氨酸-蛋白激酶。
42.根据权利要求41所述的方法,其中所述靶分子是HER2。
43.根据权利要求42所述的方法,其中所述多特异性抗原结合蛋白是抗HER2x PRLR双特异性抗体。
44.根据权利要求43所述的方法,其中所述细胞毒剂包含与所述抗HER2x PRLR双特异性抗体缀合的基于美登素类化合物的毒素。
45.根据权利要求43所述的方法,其中所述细胞毒剂包含与抗HER2二价单特异性抗体缀合的基于美登素类化合物的毒素。
46.根据权利要求33至35中任一项所述的方法,其中所述细胞是癌细胞。
47.根据权利要求40至45和46中任一项所述的方法,其中所述细胞是乳腺癌细胞。
48.一种包含多特异性抗原结合蛋白和细胞毒剂的药物组合物。
49.根据权利要求48所述的药物组合物,其中所述多特异性抗原结合蛋白是双特异性抗体。
50.根据权利要求48或49所述的药物组合物,其中所述多特异性抗原结合蛋白与迅速内化的细胞表面受体结合并且与缓慢内化的细胞表面受体结合。
51.根据权利要求50所述的药物组合物,其中所述快速内化的细胞表面受体包含含有一个或多个二亮氨酸基序的胞质结构域。
52.根据权利要求51所述的药物组合物,其中所述快速内化的细胞表面受体包含含有SEQ ID NO:12的氨基酸序列的胞质结构域。
53.根据权利要求52所述的药物组合物,其中所述快速内化的细胞表面受体是催乳素受体(PRLR)。
54.根据权利要求50所述的药物组合物,其中所述缓慢内化的细胞表面受体是受体酪氨酸-蛋白激酶。
55.根据权利要求54所述的药物组合物,其中所述受体酪氨酸-蛋白激酶是HER2。
56.根据权利要求53或55所述的药物组合物,其中所述多特异性抗原结合蛋白是抗HER2x PRLR双特异性抗体。
57.根据权利要求56所述的药物组合物,其中所述细胞毒剂包含与所述多特异性抗原结合蛋白缀合的基于美登素类化合物的毒素。
58.根据权利要求57所述的药物组合物,其中所述细胞毒剂包含与抗HER2二价单特异性抗体缀合的基于美登素类化合物的毒素。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
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US201562188860P | 2015-07-06 | 2015-07-06 | |
US62/188,860 | 2015-07-06 | ||
US201662328900P | 2016-04-28 | 2016-04-28 | |
US62/328,900 | 2016-04-28 | ||
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CN116789843A (zh) * | 2022-03-16 | 2023-09-22 | 伯桢生物科技(杭州)有限公司 | Wnt重组蛋白及其应用 |
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