CN114133454A - 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。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子蛋白的第二抗原结合结构域。在一些实施方案中,本发明的多特异性抗原结合分子可以是能够同时结合靶分子和内化效应子蛋白的双特异性抗体。在本发明的某些实施方案中,靶分子和内化效应子蛋白由本发明的多特异性抗原结合分子同时结合导致减弱靶分子的活性至比靶分子单独结合时更大的程度。在本发明的其他实施方案中,靶分子是肿瘤相关抗原,并且肿瘤相关抗原和内化效应子蛋白由本发明的多特异性抗原结合分子同时结合造成或促进定向杀伤肿瘤细胞。
Description
本申请是CN201380020750.9的分案申请。
技术领域
本发明涉及治疗性蛋白领域,并且尤其涉及能够在体外或在体内失活、阻断、减弱、消除一种或多种靶分子和/或减少其浓度的治疗性蛋白的领域。
背景
治疗性疗法经常需要失活或阻断作用于细胞或在其附近发挥作用的一种或多种靶分子。例如,基于抗体治疗药经常通过与细胞表面上表达的特定抗原或与可溶性配体结合,因而干扰抗原的正常生物学活性来发挥作用。已经显示针对多种细胞因子(例如,IL-1、IL-4、IL-6、IL-13、IL-22、IL-25、IL-33等)或其相应受体的抗体和其他结合构建体例如可用于广泛类型的人类病痛和疾病。这种类型的治疗要一般通过阻断细胞因子和其受体之间的相互作用发挥作用以减弱或抑制细胞信号传导。然而,在某些情况下,以不必要地涉及阻断靶分子与另一种组分物理相互作用的方式失活靶分子或抑制其活性将是治疗性上有益。其中可以实现这类非阻断性减弱靶分子的一种方式将减少靶分子的胞外或细胞表面浓度。虽然用于减少给出靶分子的量或浓度的遗传策略和基于核酸的策略是本领域已知的,但是这类策略经常在治疗性环境下巨大的技术复杂性和未预料的副作用方面令人忧虑。因此,需要替代性策略以促进出于治疗目的失活或减弱各种靶分子。
发明简述
本发明至少部分地基于以下概念:通过促进或造成在靶分子和内化效应子蛋白之间的物理结合减弱或失活靶分子。通过这种类型的分子间物理连接,可以迫使靶分子连同内化效应子蛋白一起内化至细胞中,并且由胞内降解装置加工,或否则减弱、隔绝或失活。这种机制代表一种在不必要阻断靶分子和其结合配偶体之间相互作用的情况下失活或减弱靶分子活性的新颖和创新性策略。
因此,本发明提供能够同时结合靶分子(T)和内化效应子蛋白(E)的多特异性抗原结合分子。更具体地,本发明提供一种多特异性抗原结合分子,所述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T和E由多特异性抗原结合分子同时结合减弱T的活性至比T由D1单独结合时更大的程度。增强的T活性减弱可以归因于T通过其与E物理连接的受迫内化/降解;然而,其他作用机制是可能的并且不从本发明的范围排除。
此外,本发明提供使用多特异性抗原结合分子以失活或减弱靶分子(T)活性的方法。具体而言,本发明提供一种通过以下方式失活或减弱靶分子活性的方法:使T和内化效应子蛋白(E)与多特异性抗原结合分子接触,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);并且其中D1特异性结合T,并且其中D2特异性结合E;并且其中T和E由多特异性抗原结合分子同时结合减弱T的活性至比T由D1单独结合时更大的程度。
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。例如在一些实施方案中,多特异性抗原结合分子可以是双特异性抗体,其中D1包含特异性结合T的抗体重链可变区和轻链可变区对(HCVR/LCVR),并且其中D2包含特异性结合E的HCVR/LCVR对。可选地,D1和/或D2可以包含与靶分子(T)和/或内化效应子蛋白(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,如果内化效应子蛋白是细胞表面内化受体,随后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。在另外的其他实施方案中,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,在任何布局中,最终结果是T和E能够直接地物理连接或通过多特异性抗原结合分子同时结合T和E间接地物理连接。
其他实施方案将从后续详述的回顾中变得显而易见。
附图简述
图1(小图A-D)提供本发明的多特异性抗原结合分子的4种示例性总体作用机制的示意图。在每个所示的布局中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是内化效应子蛋白;和R是结合E时内化的受体。小图A描述其中T和E同时为膜结合的情况。小图B描述其中T为可溶解并且E为膜结合的情况。小图C描述以下情况,其中T是膜结合的并且E是通过E和R的相互作用与细胞相互作用并内化至其中的可溶性蛋白。小图D描述以下情况,其中T是可溶性的并且E是通过E和R的相互作用与细胞相互作用并内化至其中的可溶性蛋白。
图2显示与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,对两个不同细胞(仅表达FcγR1的细胞-1和表达Krm2和FcγR1的细胞-2)进行的免疫沉淀实验的结果。
图3显示在抗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显示以图3中所示实验相同的方式所实施的实验的结果,差异在于CD63表达因针对CD63的siRNA在报道细胞系中显著减少。
图5显示以图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2小时或过夜。上行的柱状图代表在表达正常水平CD63的细胞(“未转染”)中实施的实验的结果,而下行的柱状图代表在CD63表达因针对CD63的siRNA在报道细胞系中显著减少的细胞中实施的实验的结果。
图6显示以图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、30分钟、1小时或2小时。
图7显示其中Stat6-luc报道细胞将在多个稀释度的抗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显示下述实验的结果,其中HEK293细胞将用SOST构建体连同用如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,标记小泡)数目表述。小图A显示在冰上温育3小时后的结果,小图B显示在37℃温育1小时后的结果,并且小图C显示在37℃温育3小时后的结果。
图9显示下述实验的结果,在所述实验中将HEK293细胞用荧光标记的来自大肠杆菌(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,标记小泡)数目表述。
发明详述
在描述本发明之前,应当理解本发明不限于所述的具体方法和实验条件,因为这类方法和条件可以变动。还应当理解本文所用的术语其目的仅在于描述具体实施方案,并且不意图是限制性的,因为本发明的范围将仅由所附的权利要求书限制。
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。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多于1%。例如,如本文所用,表述“约100”包括99和101和之间的全部值(例如,99.1、99.2、99.3、99.4等)。
虽然在本发明的实施或测试中可以使用与本发明中所述相似或等价的任何方法和材料,这里描述了优选的方法和材料。
多特异性抗原结合分子
本发明人令人惊讶地发现,可以通过多特异性抗原结合分子使靶分子与内化效应子蛋白连接减弱靶分子的活性。
因此,本发明提供包含第一抗原结合结构域(在本文中也称作“D1”)和第二抗原结合结构域(在本文中也称作“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作“T”。D2特异性结合“内化效应子蛋白”。内化效应子蛋白在本文中也称作“E”。根据本发明,T和E由多特异性抗原结合分子同时结合减弱T的活性至比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背景下,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)和内化效应子蛋白(E)二者至少一段时间。多特异性抗原结合分子与T和E组分的结合可以是依次的;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失活据信由T内化和及其在细胞内部因与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失活和/或减少靶分子的活性和/或胞外浓度。
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性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特定目的抗原的任何肽、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[见,例如,Boersma和Pluckthun,2011,Curr.Opin.Biotechnol.22:849-857,和其中引用的参考文献])和适配体或其部分。
在其中靶分子或内化效应子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;或如果内化效应子蛋白(E)是转铁蛋白受体,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;或如果内化效应子蛋白(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***(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域(本文中缩写为LCVR或VL)和轻链恒定区。轻链恒定域包含一个结构域(CL1)。VH区和VL区可以进一步再划分为超变区,名为互补性决定区(CDR),其间插有更保守的区域,名为框架区(FR)。每个VH和VL由从氨基端至羧基端按以下顺序:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4排列的3个CDR和4个FR的组成。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、合成性或基因修饰的多肽或糖蛋白。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域和任选地抗体恒定域的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作,例如以将一个或多个可变域和/或恒定域排列成合适布局,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例子包括:(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、纳米体(例如单价纳米体、双价纳米体等)、小模块免疫药物(SMIP)和鲨鱼可变IgNAR域。
抗体的抗原结合片段一般将包含至少一个可变域。可变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可读框的至少一个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。可选地,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域共价连接的至少一个可变域。可以在本发明抗体的抗原结合片段内部存的可变域和恒定域的非限制、示例性布局包括:(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;和(xiv)VL-CL。在可变域和恒定域的任何布局中,包括上文所列的任何示例性布局,可变域和恒定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域和/或恒定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域和恒定域布局的彼此和/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其组成。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从另一个哺乳动物物种(如小鼠)的种系衍生的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其组成。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(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衍生自人种系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子蛋白(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而不限于例如基于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,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域的多肽。多聚化组分的非限制性例子是免疫球蛋白的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其组成的肽或多肽。
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是与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和D2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。可选地,M1和M2可以在一个或多个种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域和M2可以包含第二IgCH3域,其中第一和第二IgCH3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IgCH3域结合蛋白A并且M2的IgCH3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IgG1 Fc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IgG2 Fc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IgG4 Fc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子蛋白(“E”)。内化效应子蛋白是能够内化至细胞中或否则参与或有助于逆梯度膜运输的蛋白质。在一些情况下,内化效应子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,内化效应子蛋白是细胞表面表达的蛋白质或可溶解的胞外蛋白质。但是,本发明还构思了其中内化效应子蛋白表达在胞内区室如内体、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种实施方案中充当内化效应子蛋白。在任何情况下,D2与内化效应子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,内化效应子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子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子蛋白的具体非限制性例子例如包括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。
在其中E是直接内化的效应子蛋白的实施方案中,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子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结合部分或由其组成。作为另一个例子,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其组成。
间接内化至细胞中的内化效应子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例如包括能够与内化性细胞表面表达受体分子结合的可溶性配体。通过其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例子是转铁蛋白。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组分可以例如是特异性结合E的抗体或抗体的抗原结合片段或与可溶性效应子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其组成。
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下发生。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,例如在胞内区室如内质网、高尔基体、内体、溶酶体等结合靶分子。
细胞表面表达的靶分子的例子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例如包括细胞因子受体(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组分可以例如是特异性结合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,D1组分可以包含IL-4或其受体结合部分或由其组成。
可溶性靶分子的例子包括细胞因子、生长因子和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例如包括IL-1、IL-4、IL-6、IL-13、IL-22、IL-25、IL-33、SOST、DKK1等。可溶性靶分子例如还包括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组分可以例如是特异性结合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其组成。
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。可选地,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,获得具有pH依赖性结合特征的抗原结合结构域。额外地,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,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,发明人已经发现靶分子(T)和内化效应子蛋白(E)由多特异性抗原结合分子同时结合减弱T的活性至比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“减弱T的活性至比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CD63 mAb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),和“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“T和E由多特异性抗原结合分子同时结合减弱T的活性至比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(如在下实施例1的情况,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,T和E由本发明的多特异性抗原结合分子同时结合将减弱T的活性至比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子蛋白的性质,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T和E由多特异性抗原结合分子同时结合是否减弱T的活性至比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结合的内化效应子蛋白“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上。可以靶向本文中他处提到任何内化效应子蛋白用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偏好表达的蛋白质或多肽。如本上下文中所用,表述“偏好表达”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偏好表达的抗原: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、***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例子例如包括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、-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、-2、-3、-4、-6和-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、酪氨酸酶和尿路上皮分化特异糖蛋白(uroplakin)-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。可选地,药物或毒素可以是不直接杀伤细胞,但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子蛋白连接的作用,这因而发挥使肿瘤相关抗原物理连接至内化效应子蛋白的作用。毒素标记的抗肿瘤相关抗原抗体通过其与内化效应子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、埃斯波霉素、甲氨蝶呤、多柔比星、美法仓、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、拉罗他赛、替司他赛、奥他赛(orataxel)、多西紫杉醇、多拉司他汀10、澳瑞司他汀E、澳瑞司他汀PHE和基于美坦辛的化合物(例如,DM1、DM4等)。多特异性抗原结合分子(或协从抗体)还可以或可选地与毒素缀合,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)还可以或可选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子蛋白“E”结合。因此,多特异性抗原结合分子将偏好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组分对内化效应子蛋白(E)的结合亲和力至少10%弱于(例如,15%弱于、25%弱于、50%弱于、75%弱于、90%弱于等)D1组分对靶分子(T)的结合亲和力。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与内化效应子蛋白(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子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偏好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),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。
本发明还包括用于失活或减弱靶分子(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失活、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***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物质一起施用。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
提供以下实施例从而为本领域普通技术人员提供如何产生和使用本发明方法和组合物的完整公开和描述,并且不意图限制本发明人视为其发明的范围。已经作出努力以确保所用数字(例如量、温度等)方面的准确度,但是应当考虑一些实验性误差和偏差。除非另外指明,否则份数是以重量计的份数,分子量是平均分子量,温度是摄氏度,并且压力是在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子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。在这个例子中,内化效应子蛋白是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的内化借助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。(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,其由融合于小鼠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子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子蛋白Kremen的DKK1组分。
首先实施一项实验以确定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(缺少Kremen的)细胞-1内部;然而,在表达Kremen-2的细胞-2内部检测到大量的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,实施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,所述等分试样用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。图2中显示结果。
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)和内化效应子蛋白(Kremen-2)的多特异性抗原结合分子可以按效应子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子蛋白(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与经内化并导引在溶酶体内部降解的效应分子(在这种情况下,CD63)物理连接减弱细胞上的IL-4R活性。换而言之,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)。该实施例中使用的抗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)。该实施例中使用的抗CD63抗体是从Biolegend(San Diego,CA,目录号312002)获得的小鼠抗人CD63 mAb克隆MEM-259。
还产生两种对照构建体: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;和对照-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-萤光素酶报道分子构建体和额外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同时表达IL-4R和CD63。在任何抑制剂不存在的情况下用IL-4处理时,这个细胞系产生反映IL-4-介导的信号传导程度的剂量依赖性可检测化学发光信号。
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浓度渐增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,实施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表达显著减少的同时,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同时结合和完整抗体-IL-4R-CD63复合物的后续内化及降解。
接下来实施相似的实验,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6小时测量萤光素酶活性。图5中显示结果,顶部小图(“未转染”)。在又一组实验中,实施相似方案,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。图6中显示结果。
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CD63 siRNA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概念验证,其中所述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)和内化效应子蛋白(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,IL-4R和CD63由示例性多特异性抗原结合分子的同时结合减弱IL-4R活性至比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
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)衍生自如实施例2中使用的完整抗IL-4R抗体;但是,抗CD63重链和轻链衍生自从开发性研究杂交瘤库(Developmental Studies Hybridoma Bank)(爱荷华大学生物学系,IowaCity,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。
实施IL-4萤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(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萤光素酶信号。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萤光素酶活性。这个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,二者均与抗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)。图7中显示结果。如图7中所示,对于所用的对照样品,萤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,萤光素酶活性随抗体浓度增加显著下降。这些结果证实IL-4R和CD63由双特异性抗体同时结合造成明显抑制IL-4R活性。
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
在这个例子中,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,所述人SOST蛋白用pHrodoTM部分(Life Technologies,Carlsbad,CA)和myc标签加标签。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结合特异性CD63(内化效应子蛋白)和SOST融合蛋白(可溶性靶分子)同时具有的双特异性抗体,如下文更详细地描述。
实验如下实施:简而言之,将HEK293细胞以10,000个细胞/孔铺种在聚-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2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,Iowa City,IA);(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,包含从抗体H5C6衍生的抗CD63臂和从9E10衍生的抗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,包含从抗体H5C6衍生的抗CD63臂和从“Ab-B”衍生的抗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,包含从抗体H5C6衍生的抗CD63臂和从美国专利号7,592,429中名为“Ab-20”的抗体衍生的抗SOST臂的多特异性抗原结合分子)。使用所谓“结入扣”方法学(见,例如,Ridgway等人,1996,Protein Eng.9(7):617-621),装配在这些实验中使用的双特异性抗体。
图8中显示内化实验的结果。图8显示在测试的各种处理条件下每个细胞的荧光点数(标记小泡)。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5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)将显示至少与组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类似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
这个实施例显示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脓毒性休克。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臂是源自称作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;US 5,858,728)。抗CD63臂源自H5C6抗体(见实施例4)。使用所谓“结入扣”方法学(见,例如,Ridgway等人,1996,Protein Eng.9(7):617-621),装配抗LPSx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个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,Life Technologies,Carlsbad,CA)。
实验如下实施:将HEK293细胞铺种在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(大肠杆菌衍生或明尼苏达沙门氏菌衍生的)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-488抗体猝灭–洗涤并固定。抗-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小泡数目表述这些实验的结果。如9图中所示,仅用抗CD63x抗LPS双特异性抗体处理的细胞展示明显数目随时间而推移增加标记小泡。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小泡,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的细胞内化用于治疗疾病和病症如败血症的用途。
本发明在范围方面不受本文中描述的具体实施方案限制。实际上,除了本文描述的那些修改之外,本发明的各种修改将因前文描述和附图是本领域技术人员显见的。这类修改意在落入所附权利要求的范围内。
本发明包括以下实施方案:
1.一种多特异性抗原结合分子,其包含:
第一抗原结合结构域(D1);和
第二抗原结合结构域(D2);并且
其中D1特异性结合靶分子(T);并且
其中D2特异性结合内化效应子蛋白(E);
其中T和E由多特异性抗原结合分子同时结合减弱T的活性至比T由D1单独结合时更大的程度。
2.根据实施方案1所述的多特异性抗原结合分子,其中E是直接内化至细胞中的细胞表面表达的分子。
3.根据实施方案2所述的多特异性抗原结合分子,其中E选自CD63、MHC-I、Kremen-1、Kremen-2、LRP5、LRP6、转铁蛋白受体、LDLr、MAL、V-ATP酶和ASGR。
4.根据实施方案2所述的多特异性抗原结合分子,其中D2包含特异性结合E的配体或配体的部分。
5.根据实施方案1所述的多特异性抗原结合分子,其中E是通过E和内化性细胞表面表达的受体分子之间的相互作用内化至细胞中的可溶性配体。
6.根据实施方案5所述的多特异性抗原结合分子,其中E是能够与膜表达的转铁蛋白受体结合的转铁蛋白或其部分。
7.根据实施方案5所述的多特异性抗原结合分子,其中D2包含特异性结合E的受体或受体的配体结合部分。
8.根据实施方案1所述的多特异性抗原结合分子,其中T是细胞表面表达的靶分子。
9.根据实施方案8所述的多特异性抗原结合分子,其中T选自IL-4R、IL-6R、PRLR、Nav1.7、GCGR和HLA-B27。
10.根据实施方案8所述的多特异性抗原结合分子,其中D1包含特异性结合T的配体或配体的部分。
11.根据实施方案1所述的多特异性抗原结合分子,其中T是分泌型或跨膜蛋白的胞内前体。
12.根据实施方案1所述的多特异性抗原结合分子,其中T是可溶性靶分子。
13.根据实施方案12所述的多特异性抗原结合分子,其中T选自IL-4、IL-6、IL-13、SOST和DKK1。
14.根据实施方案12所述的多特异性抗原结合分子,其中D1包含特异性结合T的受体或受体的配体结合部分。
15.根据实施方案1所述的多特异性抗原结合分子,其中D1和/或D2显示pH依赖性结合其抗原。
16.根据实施方案15所述的多特异性抗原结合分子,其中D1与中性pH相比在酸性pH以较低亲和力结合T;和/或其中D2与中性pH相比在酸性pH以较低亲和力结合E。
17.根据实施方案1所述的多特异性抗原结合分子,其中D1和/或D2包含至少一个抗体可变区。
18.根据实施方案17所述的多特异性抗原结合分子,其中D1和/或D2包含重链可变区(HCVR)和轻链可变区(LCVR)。
19.根据实施方案18所述的多特异性抗原结合分子,其中多特异性抗原结合分子是双特异性抗体。
20.根据实施方案1所述的多特异性抗原结合分子,其中D1衍生自结合但是基本上不使其自身上的T失活的抗原结合分子。
21.一种用于失活或减弱靶分子(T)活性的方法,所述方法包括使T和内化效应子蛋白(E)与多特异性抗原结合分子接触,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);并且其中D1特异性结合T,其中D2特异性结合E;并且其中T和E由多特异性抗原结合分子同时结合造成T失活至比T由D1单独结合时更大的程度。
22.根据实施方案21所述的方法,其中E是直接内化至细胞中的细胞表面表达的分子。
23.根据实施方案21所述的方法,其中E是通过E和内化性细胞表面表达的受体分子之间的相互作用内化至细胞中的可溶性配体。
24.根据实施方案21所述的方法,其中T是细胞表面表达的靶分子。
25.根据实施方案21所述的方法,其中T是可溶性靶分子。
26.根据实施方案1所述的多特异性抗原结合分子,其中D2包含抗CD63抗体的抗原结合部分。
27.根据实施方案26所述的多特异性抗原结合分子,其中D1包含抗IL-4R抗体的抗原结合部分。
28.根据实施方案26所述的多特异性抗原结合分子,其中D1包含抗SOST抗体的抗原结合部分。
29.一种多特异性抗原结合分子,其包含:
第一抗原结合结构域(D1);和
第二抗原结合结构域(D2);并且
其中D1特异性结合靶分子(T);
其中D2结合内化效应子蛋白(E);
其中T是肿瘤相关抗原;
并且其中T和E由多特异性抗原结合分子同时结合造成多特异性抗原结合分子内化至肿瘤细胞中。
30.根据实施方案29所述的多特异性抗原结合分子,其中多特异性抗原结合分子与药物、毒素或放射性同位素缀合。
31.根据实施方案29所述的多特异性抗原结合分子,其中D2以低亲和力结合E。
32.一种靶向受试者中肿瘤的方法,所述方法包括向受试者施用根据实施方案29所述的多特异性抗原结合分子和在与D1结合的表位不重叠的表位处特异性结合T的第二抗原结合蛋白。
33.根据实施方案32所述的方法,其中第二抗原结合蛋白与药物、毒素或放射性同位素缀合。
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Claims (10)
1.一种多特异性抗原结合分子,其包含:
第一抗原结合结构域(D1);和
第二抗原结合结构域(D2);并且
其中D1特异性结合靶分子(T);并且
其中D2特异性结合内化效应子蛋白(E);
其中T和E由多特异性抗原结合分子同时结合减弱T的活性至比T由D1单独结合时更大的程度。
2.根据权利要求1所述的多特异性抗原结合分子,其中E是直接内化至细胞中的细胞表面表达的分子。
3.根据权利要求2所述的多特异性抗原结合分子,其中E选自CD63、MHC-I、Kremen-1、Kremen-2、LRP5、LRP6、转铁蛋白受体、LDLr、MAL、V-ATP酶和ASGR。
4.根据权利要求2所述的多特异性抗原结合分子,其中D2包含特异性结合E的配体或配体的部分。
5.根据权利要求1所述的多特异性抗原结合分子,其中E是通过E和内化性细胞表面表达的受体分子之间的相互作用内化至细胞中的可溶性配体。
6.根据权利要求5所述的多特异性抗原结合分子,其中E是能够与膜表达的转铁蛋白受体结合的转铁蛋白或其部分。
7.根据权利要求5所述的多特异性抗原结合分子,其中D2包含特异性结合E的受体或受体的配体结合部分。
8.根据权利要求1所述的多特异性抗原结合分子,其中T是细胞表面表达的靶分子。
9.根据权利要求8所述的多特异性抗原结合分子,其中T选自IL-4R、IL-6R、PRLR、Nav1.7、GCGR和HLA-B27。
10.根据权利要求8所述的多特异性抗原结合分子,其中D1包含特异性结合T的配体或配体的部分。
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