CN115968377A - 单域抗体及其在癌症治疗中的用途 - Google Patents
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Abstract
本申请涉及完全人源化的抗FGFR4单域抗体(sdAb)及其变体。本发明还涉及包含所述sdAb的功能化药物纳米载体、核酸、载体、宿主细胞、免疫细胞以及包含其的组合物,及其用于治疗的用途。
Description
技术领域
本公开涉及抗FGFR4单域抗体(sdAb)及其在诊断或癌症治疗中的用途。所述抗FGFR4-sdAb还可以进一步包含于嵌合抗原受体中并用于癌症细胞治疗,特别是胞内癌症治疗。
背景技术
成纤维细胞生长因子受体4(FGFR4)属于FGF受体家族,其也包括FGFR1、FGFR2和FGFR3。与FGF受体家族的其他成员一样,跨膜受体FGFR4含有信号肽、胞外配体结合结构域(ECD)、跨膜结构域、胞内蛋白酪氨酸激酶结构域(TKD)和C端磷酸化结构域(KlintP等,1998)。与其他三个FGFR成员相似,FGFR4的胞外区由三个免疫球蛋白样结构域(IgI、IgII和IgIII)组成,其对于特异性配体结合是必需的。
作为肝脏内稳态的重要介质,FGFR4功能是正常饮食条件下维持脂质和葡萄糖代谢所需的,除了其在胆固醇中的确定作用外(Huang X et al.,Diabetes.2007;56:2501–2510)。FGF6/FGFR4途径在成肌细胞分化和肌管再生中也起重要作用(Floss T et al.,Genes Dev.1997;11:2040–2051;Zhao P et al.,Dev.Dyn.2004;229:380-392)。
FGFR4被FGF1、FGF2、FGF4、FGF6、FGF8和FGF9以降低的效率活化(Ornitz等,1996);虽然这些所有也活化其他家族成员,但FGF19对FGFR4具有特异性(Xie等,1999)。经典FGF用肝素/硫酸肝素(HS)结合并活化FGFR4(Lin B.C et al.,J.Biol.Chem.2007;282:27277–27284)。作为FGFR4的特异性配体,FGF19用β-klotho(KLB)共受体结合并活化FGFR4。FGF19作为内分泌配体,对FGFR4比对其他FGFR成员具有更特异性的选择性亲和力(Ornitz D.Met al.,J.Biol.Chem.1996;271:15292–15297;Zhang X et al.,J.Biol.Chem.2006;281:15694–15700)。
已发现成纤维细胞生长因子受体(FGFR)通过增加细胞增殖、转移和存活在肿瘤发生和癌症进展中起重要作用(Babina I.S et al.,Nat.Rev.Cancer.2017;17:318–332;Porta R et al.,Crit.Rev.Oncol./Hematol.2017;113:256–267)。升高的FGFR4已与癌症发展和进展紧密相关,使其成为开发新型和有效的抗癌治疗剂的有吸引力的靶标。最近,一项研究评价了FGFR基因在多种癌症类型中的改变(Helsten T et al.,Clin.CancerRes.2016;22:259–267),并表明FGFR的基因改变发生在4853个实体瘤的7.1%中。尽管基因改变相对较低,但已在许多类型的癌症中进一步报导了FGFR4的过表达。已在三分之一的肝细胞癌(HCC)中和在32%的乳腺癌样品中(Penault-Llorca F et al.,Int.J.Cancer.1995;61:170–176)检测到增加的FGFR4 mRNA的表达(Ho H.K et al.,J.Hepatol.2009;50:118–127)。在64%的口咽鳞状细胞癌和41%的口腔鳞状细胞癌中也观察到FGFR4过表达(Koole K et al.,Pathobiology.2015;82:280–289)。过表达的FGFR4也已在胰腺癌和衍生细胞系中发现,其由肝细胞核因子1α活化的内含增强子介导(Shah R.Net al.,Oncogene.2002;21:8251–8261)。此外,在横纹肌肉瘤中检测到高的FGFR4表达(Taylor J.G et al.,J.Clin.Investig.2009;119:3395–3407,还参见Crose,L.E.S.etal.Clin.Cancer Res.18,3780–3790(2012))。
FGF19基因的扩增发现于肝癌、乳腺癌、肺癌、膀胱癌、头颈部鳞状细胞癌(HNSCC)和食道癌中(Huang X.et al,Proc.Natl.Acad.Sci.USA.2002;99:11369–11374;SaweyE.T.et al.,Cancer Cell.2011;19:347–358;Tiong K.H.et al.,Oncotarget.2016;7:57633;Zhang X.et al.,Thorac.Cancer.2017;8:655–665;Hoover H.et al.,J.ProteomeRes.2015;14:3670–3679)。
机制研究显示磷酸化的FGFR4募集并磷酸化两个重要的细胞内靶标,磷脂酶γ(PLCγ)和FGFR底物2(FRS2)[4]。然后可通过PLCγ用被活化的蛋白激酶C(PKC)刺激MAPK。同时,活化的FRS2通过募集生长因子受体结合2(GRB2)可触发MAPK和PI3K-AKT通路。AKT和ERK1/2的活性上调使得FGF19/FGFR4信号转导活化后HCC中细胞增殖和生存增强。FGF19-FGFR4轴还与转移以及生存较差相关(Touat M.et al.,Clin.Cancer Res.2015;21:2684–2694).
已将努力集中于开发靶向FGFR4的选择性抑制剂,其显示为抗癌单一治疗或辅助治疗的特别的前景。已经着重开发了靶向FGFR4的三种策略,包括中和抗体、反义寡核苷酸和小分子抑制剂。
然而,使用非特异性FGFR抑制剂导致的不可避免的靶上毒性和脱靶活性导致若干副作用(Dieci M.V.et al.,Cancer Discov.2013;3:264–279)。这些缺点最终限制了它们在癌症患者中的应用。
因此,为提供用于诊断和/或治疗用途的其他产品,高度期望具有特异性结合胞外结构域并阻断FGFR4介导的信号转导的高亲和力FGFR4抗体。
因此,本发明潜在的技术问题之一是提供新的FGFR4抗体及其使用方法,其适于诊断、预防和/或治疗与FGFR4表达相关的疾病。特别地,由于单域抗体骨架具有用于治疗的许多优点,诸如更好地穿透组织,在肾脏中更快地清除,高特异性或降低的免疫原性,因此本公开的目的是提供可用于多种治疗和诊断策略的抗FGFR4的高亲和力单域抗体。
嵌合抗原受体T细胞(CAR-T)治疗的过继转移通常是潜在的免疫治疗之一,其在一系列临床试验的显著成功中显示出治疗血液恶性肿瘤的巨大前景。不幸的是,CAR-T细胞治疗在血液恶性肿瘤治疗中的突破仍未在实体瘤中很好地复制(Y.Guo,Y et al.,Chimericantigen receptor-modified T cells for solid tumors:challenges and prospects,JImmunol Res,2016;J.Li et al.,Chimeric antigen receptor T cell(CAR-T)immunotherapy for solid tumors:lessons learned and strategies for movingforward;J Hematol Oncol,11(2018),p.22)。此外,主要用于设计嵌合抗原受体的scFv表现出许多可能对CAR-T的治疗功效产生负面影响的特征。实际上,scFv的显著特征在于表达和稳定性较差,且易于解折叠和聚集。因此,仍需要改进和多样化肿瘤学中的当前治疗工具,使得不仅覆盖患者情况的多样性以及肿瘤的显著可变性。这对于与FGFR4过表达相关的侵袭性肿瘤(诸如横纹肌肉瘤)是特别关键的。
发明简述
本申请现提供了以纳摩尔和皮摩尔范围内的亲和力特异性结合FGFR4的合成人源化单域抗体。这些sdAb已进一步表明具有阻断FGFR4介导的癌细胞(且特别是RMS细胞)中FGFR4下游MAPK通路活化的能力。发明人进一步表明,用所述FGFR4 sdAb功能化的脂质体特异性结合FGFR4阳性的细胞并内化。这些结果提供了强有力的证据,即根据本公开的靶向FGFR4的纳米载体(且特别是脂质体)制剂代表FGFR4过表达癌细胞的特异性药物递送平台,特征在于其快速和特异性的受体介导的细胞内摄取。最后,发明人生产了显示在体外介导针对表达FGFR4的癌细胞的显著抗肿瘤活性的FGFR4-CAR T细胞,因而代表了有前景的靶向治疗选择。
因此,本公开涉及抗FGFR4的单域抗体(sdAb),其中所述人源化抗FGFR4 sdAb具有下式FRW1-CDR1-FRW2-CDR2-FRW3-CDR3-FRW4,且其中所述CDR选自:
-SEQ ID NO:1的CDR1;SEQ ID NO:2的CDR2和SEQ ID NO:3的CDR3,
-SEQ ID NO:4的CDR1;SEQ ID NO:5的CDR2和SEQ ID NO:6的CDR3,
-SEQ ID NO:7的CDR1;SEQ ID NO:8的CDR2和SEQ ID NO:9的CDR3,
-SEQ ID NO:10的CDR1;SEQ ID NO:11的CDR2和SEQ ID NO:12的CDR3,
在一些实施方案中,框架区由以下组成:选自SEQ ID NO:13或SEQ ID NO:17的FRW1,选自SEQ ID NO:14或SEQ ID NO:18的FRW2,选自SEQ ID NO:15或SEQ ID NO:19的FRW3,选自SEQ ID NO:16或SEQ ID NO:20的FRW4,或其功能性变体,其中在FRW1、FRW2、FRW3和FRW4的每一个中具有不超过0、1、2或3个保守氨基酸取。在更具体的实施方案中,框架区由以下组成:SEQ ID NO:13的FRW1、SED ID NO:14的FRW2、SEQ ID NO:15的FRW3和SEQ IDNO:16的FRW4,或者SEQ ID NO:17的FRW1、SED ID NO:18的FRW2、SEQ ID NO:19的FRW3和SEQID NO:20的FRW4,或其功能性变体,其中在FRW1、FRW2、FRW3和FRW4的每一个中具有不超过0、1、2或3个保守氨基酸取代。
在甚至更具体的实施方案中,本公开预期人源化抗FGFR4 sdAb,其具有SEQ IDNO:41、SEQ ID NO:42、SEQ ID NO:43和SEQ ID NO:44中任一个所示的序列。
本公开的人源化抗FGFR4 sdAb可直接或间接、共价或非共价地连接至选自以下的目标化合物:核酸、多肽或蛋白质、病毒、毒素和化学实体。在一些实施方案中,人源化抗FGFR4 sdAb直接或间接、共价或非共价地连接至选自以下的诊断化合物:酶、荧光团、NMR或MRI造影剂、放射性同位素和纳米颗粒。在一些实施方案中,人源化抗FGFR4sdAb直接或间接、共价或非共价地连接至选自以下的化合物:细胞毒性试剂、化疗剂、放射性同位素、靶向抗癌剂、免疫治疗剂(诸如免疫抑制剂或免疫刺激剂)和裂解肽。在一些实施方案中,人源化抗FGFR4sdAb直接或间接、共价或非共价地连接至药物纳米载体,任选地为有机纳米载体。通常地,有机纳米载体可选自聚合物纳米颗粒、脂质体、胶束和基于蛋白质的纳米载体,诸如白蛋白。
FGFR4 sdAb也可与免疫球蛋白结构域融合,特别是Fc结构域。
本公开还涵盖多特异性结合化合物,其包含至少如本文所述的在于FGFR4 sdAb的第一sdAb,且还包含结合第二抗原的另一个sdAb,任选地其中第一sdAb位于第二sdAb的N末端或其中第一sdAb位于第二sdAb的C末端。
本公开还涵盖嵌合抗原受体(CAR),其包含(a)抗原结合结构域,其包含至少如本文所定义的在于FGFR4 sdAb的第一sdAb,和任选地特异性结合第二抗原的第二sdAb,(b)跨膜结构域;和(c)胞内结构域。
通常地,第二抗原选自下组:PSMA、PSCA、BCMA、CS1、GPC3、CSPG4、EGFR、胎儿乙酰胆碱受体γ亚基γ(fAChRγ)、HER3、IgF1R、SLC19A1、ACVR2A、EPHB4、CA125、IL-13R、CD278、CD123、NCAM、5T4、CD2、CD3、CD16(FcγrIII)、CD23、MART-1、L1CAM、MUC16、ROR1、SLAMF7、cKit、CD38、CD53、CD56、CD71、CD74、CD92、CD100、CD123、CD138、CD148、CD150、CD200、CD261、CD262、CD276、CD362、gp100、ROR1、间皮素、CD33/IL3Ra、c-Met、Glycolipid F77、EGFRvIII、GD-2、NKp46受体、NY-ESO-1TCR或MAGE A3 TCR、人端粒酶逆转录酶(hTERT)、生存素、细胞色素P450 1B1(CY1 B)、HER2、Wilm’s肿瘤基因1(WT1)、凋亡抑制因子(livin)、甲胎蛋白(AFP)、癌胚抗原(CEA)、粘蛋白16、MUC1、p53、细胞周期蛋白、免疫检查点靶标或其组合。
跨膜结构域可选自细胞表面靶向蛋白的跨膜结构域,包括CD3ζ跨膜结构域、CD28跨膜结构域、CD8α跨膜结构域、DAP10跨膜结构域或DAP12跨膜结构域。
胞内结构域可包含一个或多个源自CD28、OX40、CD3ζ、4-1BB、DAP10和/或DAP12胞内结构域的结构域。
本公开还涵盖分离的核酸,其包含编码本文所述的人源化抗FGFR4sdAb或CAR的核酸序列,所述序列有利地与异源调控序列连接。
本公开还涵盖包含本文公开的核酸的载体,包含其的宿主细胞,表达人源化抗FGFR4 sdAb的分离的细胞或细胞群,或本文公开的CAR。通常地,所述细胞是同种异体的或自体的细胞,且可选自巨噬细胞、NK细胞和T细胞,尤其是CD4+/CD8+、TIL/肿瘤衍生的CD8 T细胞、中央记忆CD8+T细胞、Treg、MAIT和YδT细胞。
本公开的治疗产品,包括所定义的人源化抗FGFR4 sdAb、CAR、核酸、载体、宿主细胞、分离的细胞或细胞群,可用于治疗,尤其是用于癌症的治疗。其可特别地用于癌症的细胞治疗和/或与其他治疗(尤其是其他癌症治疗,诸如化疗剂,和/或免疫治疗剂,尤其是一种或多种检查点抑制剂)组合。
最后,本公开包括如前所定义的人源化抗FGFR4 sdAb在尤其是用于检测或监测FGFR4介导的癌症的分子成像中的用途。本文特别描述了用于体外或离体诊断或监测受试者中FGFR4介导的癌症的方法,其包括以下步骤:
a)将来自所述受试者的合适的样品与如前定义的诊断剂在体外接触,且
b)测定所述样品中FGFR4的表达。
发明详述
定义:
本文所用的术语仅用于描述特定实施例的目的,而不旨在穷举。必须注意的是,除非上下文另外清楚地指明,如说明书和所附权利要求中所用的单数形式“一个”、“一种”和“该”包括复数指示物。
本文所用的术语“包含”与“包括”或“含有”同义,且是包括性的或开放式的,且不排除其他的、未列举的组成、要素或方法步骤。
除非具体说明或从上下文明显看出,如本文所用,术语“约”应理解为在本领域的正常公差范围内,例如在平均值的2个标准偏差内。约可以理解为在所述值的20%、15%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%、0.1%、0.05%或0.01%内。除非上下文另有明确说明,本文提供的所有数值均由术语约修饰。
如本文所用,术语“分离的”是指这样的物质或实体,其(1)当最初生产时(无论是在自然界中还是在实验环境中)已从与其相关的至少一些组分中分离,和(2)由人工生产、制备和/或制造。分离的物质和/或实体可与它们最初结合的至少约10%、约20%、约30%、约40%、约50%、约60%、约70%、约80%、约90%或更多的其他组分分离。在一些实施方案中,分离的试剂的纯度大于约80%、约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或大于约99%。如本文所用,如果物质基本上不含其他组分,则其为“纯的”。
本公开的“分离的”产物,包括分离的核酸、蛋白质、多肽和抗体不是天然产物(即,“非天然存在的”)。相反,本公开的“分离的”核酸、蛋白质、多肽和抗体是“人造”产品。本公开的“分离的”产物可与天然产物“明显不同”或“显著不同”。作为非限制性实例,分离的核酸可以是纯化的、重组的、合成的、标记的和/或附着于固体基质。这样的核酸可与天然存在的核酸明显不同或显著不同。作为进一步的非限制性实例,本公开的“分离的”蛋白质、多肽和抗体可以是纯化的、重组的、合成的、标记的和/或附着于固体基质。这样的蛋白质、多肽和抗体可以与天然存在的蛋白质、多肽和抗体明显不同或显著不同。
术语“多核苷酸”、“核酸分子”、“核酸”或“核酸序列”是指长度为至少10个碱基的核苷酸的聚合形式。该术语包括DNA分子(例如cDNA或基因组或合成DNA)和RNA分子(例如mRNA或合成RNA),以及含有非天然核苷酸类似物、非天然核苷间键或二者皆有的DNA或RNA类似物。核酸可以是任何拓扑构象。例如,核酸可以是单链的、双链的、三链的、四链的、部分双链的、分支的、发夹的、环状的,或挂锁构象。核酸(也称为多核苷酸)可以包括RNA、cDNA,基因组DNA的正义和反义链,以及上述的合成形式和混合聚合物。本领域技术人员容易理解,它们可以是化学或生物化学修饰的,或者可含有非天然或衍生的核苷酸碱基。此类修饰包括例如标记、甲基化、天然存在的核苷酸和类似物的一个或多个取代、核苷酸间修饰,诸如不带电荷的键(例如,膦酸甲酯、磷酸三酯、氨基磷酸酯、氨基甲酸酯等),带电荷的键(例如,硫代磷酸酯、二硫代磷酸酯等),侧链部分(例如,多肽),嵌入剂(例如,吖啶、补骨脂素等),螯合剂,烷化剂和修饰的键(例如,α异头核酸等)。还包括模拟多核苷酸通过氢键和其他化学相互作用结合指定序列的能力的合成分子。所述分子是本领域已知的,包括例如,其中分子骨架中肽键为磷酸键取代。其他修饰可包括,例如,其中核糖环含有桥连部分或其他结构的类似物,诸如在“锁定”核酸中发现的修饰。
“合成的”RNA、DNA或混合聚合物是在细胞外产生的,例如化学合成的。
如本文所用,术语“核酸片段”是指与全长参照核苷酸序列相比具有缺失,例如5’-端或3’-端缺失的核酸序列。在一个实施方案中,核酸片段是连续序列,其中该片段的核苷酸序列与天然存在序列中的相应位置相同。在一些实施方案中,片段为至少10、15、20或25个核苷酸长,或至少20、30、40、50、60、70、80、90、100、110、120、130、140或150个核苷酸长。在一些实施方案中,核酸序列的片段是开放阅读框序列的片段。在一些实施方案中,这样的片段编码由开放阅读框核苷酸序列编码的蛋白质的多肽片段(如本文所定义)。
核酸可以纯化。优选地,纯化的核酸纯度大于50%、75%、85%、90%、95%、97%、98%或99%。在本发明的上下文中,纯度至少为50%的纯化核酸指含有少于50%其他核酸的纯化核酸样品。例如,如果质粒样品含有少于1%的污染性细菌DNA,则其纯度至少为99%。
在上下文中,术语核酸的“可操作地连接”是指两个或更多个多核苷酸(例如,DNA)片段之间的功能关系。通常,其指转录调节序列与转录序列的功能关系。例如,如果启动子或增强子序列在合适的宿主细胞或其他表达系统中刺激或调节编码序列的转录,则该启动子或增强子序列与编码序列可操作地连接。通常地,可操作地连接于转录序列的启动子转录调节序列与转录序列物理相邻,即它们是顺式作用的。然而,一些转录调节序列,诸如增强子,不需要在物理上与它们增强转录的编码序列相邻或紧密相邻。
术语“多肽”和“蛋白质”在本文中可互换使用,是指氨基酸残基的聚合物。该术语适用于其中一个或多个氨基酸残基是相应天然存在的氨基酸的人工化学模拟物的氨基酸聚合物,以及适用于天然存在的氨基酸聚合物和非天然存在的氨基酸聚合物。除非另有说明,特定的多肽序列还隐含地包括其保守修饰的变体。此外,多肽可包含许多不同的结构域,每个结构域具有一种或多种不同的活性。为了避免疑问,“多肽”可以是两个以上的氨基酸的任何长度。
本文所用的术语“肽”是指短多肽,例如通常含有少于约50个氨基酸,更通常少于约30个氨基酸的多肽。本文所用的术语涵盖模拟结构和生物功能的类似物和模拟物。
术语“分离的蛋白质”或“分离的多肽”是这样的蛋白质或多肽,基于其来源或衍生来源(1)不与以其天然状态伴随其的天然相关组分相关,(2)以自然界中未发现的纯度存在,其中纯度可根据其他细胞物质的存在来判断(例如,不含来自相同物种的其他蛋白质),(3)由来自不同物种的细胞表达,或(4)不在自然界中出现(例如,其为自然界中发现的多肽的片段,或其包括自然界中未发现的氨基酸类似物或衍生物或标准肽键以外的键)。因此,化学合成的或在不同于其天然来源的细胞的细胞系统中合成的多肽,将从其天然相关组分中被“分离”。还可通过使用本领域熟知的蛋白质纯化技术分离使多肽或蛋白质基本上不含天然相关组分。如此定义,“分离的”不一定要求如此描述的蛋白质、多肽、肽或寡肽已经从合成其的细胞中物理地除去。
蛋白质或多肽可纯化。优选地,纯化的蛋白质或多肽的纯度大于50%、75%、85%、90%、95%、97%、98%或99%。在本公开的上下文中,纯度超过50%(等)的纯化蛋白质是指含有少于50%(等)其他蛋白质的纯化蛋白质样品。例如,如果包含的蛋白质样品含有少于1%的污染性宿主细胞蛋白质,则其纯度可以是99%。
如本文所用,术语“多肽片段”是指与全长多肽(诸如天然存在的蛋白质)相比具有缺失(例如氨基末端和/或羧基末端缺失)的多肽。在一个实施方案中,多肽片段是连续序列,其中该片段的氨基酸序列与天然存在序列中的相应位置相同。片段通常为至少5、6、7、8、9或10个氨基酸长,或至少12、14、16或18个氨基酸长,或至少20个氨基酸长,或至少25、30、35、40或45个氨基酸,或至少50或60个氨基酸长,或至少70个氨基酸长,或至少100个氨基酸长。
在上下文中,术语两个或多个核酸或多肽序列的“相同百分比”或“同一性百分比”是指两个或多个序列或亚序列相同的程度。如果两个序列在被比较的区域上具有相同的氨基酸或核苷酸序列,则它们是“相同的”。如果两个序列具有相同的指定百分比的氨基酸残基或核苷酸(即,在指定区域上60%同一性,任选地65%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性,或当未指定时,在整个序列上),当在比较窗口上进行比较和比对以获得最大对应性时,或当使用以下序列比较算法之一或通过手动比对和目视检查测量时,指定区域为“基本上相同的”。任选地,同一性存在于长度为至少约30个核苷酸(或10个氨基酸)的区域上,或更优选地存在于长度为100-500或1000或更多个核苷酸(或20、50、200或更多个氨基酸)的区域上。
对于序列比较,通常一个序列作为参照序列,与测试序列进行比较。当使用序列比较算法时,将测试和参照序列输入计算机,如果需要,指定子序列坐标,并指定序列算法程序参数。可使用默认程序参数,或可指定替代参数。然后序列比较算法基于程序参数计算测试序列相对于参照序列的序列同一性百分比。
如本文所用,“比较窗口”包括对选自下组的连续位置数目的任一个片段的参照:20-600,通常约50-约200,更通常约100-约150,其中在两个序列最佳比对后,可将该序列与相同数目的连续位置的参照序列进行比较。用于比较的序列比对方法是本领域熟知的。用于比较的序列的最佳比对可例如通过Smith和Waterman,Adv.Appl.Math.2:482c(1970)的局部同调算法进行,通过Needleman和Wunsch,J.Mol.Biol.48:443(1970)的同源比对算法进行,通过Pearson和Lipman的Proc.Natl.Acad.Sci.USA 85:2444(1988)的检索相似性方法进行,通过这些算法的计算机化实现(Wisconsin Genetics Software Package,Genetics Computer Group,575Science Dr.,Madison,WI的GAP,BESTFIT,FASTA和TFASTA)的中的GAP,BESTFIT,FASTA和TFASTA),或通过人工比对和视觉检查实现(参见,例如Brentet al.,Current Protocols in Molecular Biology,2003)。
适于确定序列同一性百分比和序列相似性的算法的两个实例是BLAST和BLAST2.0算法,其分别描述于Altschul et al.,Nuc.Acids Res.25:3389-3402,1977;和Altschul et al.,J.Mol.Biol.215:403-410,1990中。用于进行BLAST分析的软件可通过National Center for Biotechnology Information公开获得。该算法包括首先通过鉴定查询序列中长度为W的短字鉴定高得分序列对(HSP),当与数据库序列中相同长度的字比对时,所述短字匹配或满足一些正值阈值得分T。T被称为邻近字分数阈值(Altschul等,同上)。这些初始邻近字命中充当起始搜索以找到含有其的较长HSP的种子。字命中沿着每个序列在两个方向上延伸,直到累积比对分数可以增加。对于核苷酸序列,使用参数M计算累计分数(一对匹配残基的奖励分数;总>0)和N(错配残基的罚分;总<0)。对于氨基酸序列,评分矩阵用于计算累积得分。字在每个方向上的扩展命中在以下情况下停止:累积比对分数从其最大实现值下降数量X;由于一个或多个负评分残基比对的累积,累积得分趋于零或更低;或者到达任一序列的末端。BLAST算法参数W、T和X确定了比对的灵敏度和速度。BLASTN程序(用于核苷酸序列)默认使用11的字长(W),期望值(E)或10,M=5,N=-4和两条链的比较。对于氨基酸序列,BLAS TP程序默认使用字长3,期望值(E)10,和BLOSUM62评分矩阵(参见Henikoff and Henikoff,(1989)Proc.Natl.Acad.Sci.USA 89:10915)的比对(B)为50,期望值(E)为10,M=5,N=-4,并比较两条链。BLAST算法还对两个序列之间的相似性进行统计分析(参见例如Karlin和Altschul,Proc.Natl.Acad.Sci.USA 90:5873-5787,1993)。BLAST算法提供的一种相似性度量是最小总和概率(P(N)),其提供了两个核苷酸或氨基酸序列之间偶然发生匹配的概率的指示。例如,如果测试核酸与参照核酸的比较中最小和概率小于约0.2,更优选小于约0.01,最优选小于约0.001,则认为该核酸与参照序列相似。
也可使用E.Meyers和W.Miller,Comput.Appl.Biosci.4:11-17,1988的算法确定两个氨基酸序列之间的同一性百分比,其已引入入ALIGN程序(version 2.0)中,使用PAM120权重残基表,空位长度罚分为12且空位罚分为4。另外,可使用Needleman和Wunsch,J.Mol.Biol.48:444-453,1970)算法确定两个氨基酸序列之间的同一性百分比,其已引入GCG软件包(可在www.gcg.com获得)中的GAP程序中,使用Blossom62矩阵或PAM250矩阵,且空位权重为16、14、12、10、8、6或4且长度权重为1、2、3、4、5或6。
除了上述的序列同一性百分比之外,两个核酸序列或多肽基本上相同的另一个指征是由第一核酸编码的多肽与针对由第二核酸编码的多肽产生的抗体发生免疫交叉反应,如下所述。因此,多肽通常基本上与第二多肽相同,例如,其中两种肽的区别仅在于保守取代。两个核酸序列基本上相同的另一个指征是两个分子或其的互补物在严格条件下彼此杂交,如下所述。两个核酸序列基本上相同的另一个指征是相同的引物可用于扩增该序列。
如本文所用,“功能性变体”或给定蛋白质包括所述蛋白质的野生型形式、属于同一家族的变体蛋白质、同源蛋白质或截短形式,其保留给定蛋白质的功能。通常,功能变体表现出与给定蛋白质至少70%、75%、80%、85%、90%、95%、97%、98%或99%的氨基酸同一性。
如本文所用,术语“哺乳动物”是指分类学类别中哺乳动物的任何成员,包括胎盘哺乳动物和有袋哺乳动物。因此,“哺乳动物”包括人、灵长类、家畜和实验室哺乳动物。示例性哺乳动物包括啮齿动物、小鼠、大鼠、兔、狗、猫、绵羊、马、山羊、美洲驼、牛、灵长类动物、猪和任何其他哺乳动物。在一些实施方案中,哺乳动物是转基因哺乳动物、基因工程化哺乳动物和克隆哺乳动物中的至少一种。
根据本公开,术语“疾病”是指任何病理状态,包括癌症疾病,特别是本文所述的癌症疾病的形式。
术语“正常”是指健康受试者或组织中的健康状态或病症,即非病理学病症,其中“健康”优选意指非癌性。
术语“恶性肿瘤”是指非良性肿瘤或癌症。如本文所用,术语“癌症”包括以失调或不受控制的细胞生长为特征的恶性肿瘤。
术语“癌症”包括原发性恶性肿瘤(例如,其细胞未迁移至受试者体内除原始肿瘤部位以外的部位)和继发性恶性肿瘤(例如,由肿瘤细胞转移、迁移至不同于原始肿瘤部位的继发性部位引起)。
癌症按类似肿瘤的细胞类型分类,因此,组织假定为肿瘤来源。这些分别是组织学和位置分类。
根据本公开的术语“癌症”尤其包括白血病、精母细胞瘤、黑色素瘤、畸胎瘤、淋巴瘤、成神经细胞瘤、神经胶质瘤以及肉瘤。术语癌症尤其包括直肠癌、子宫内膜癌、肾癌、肾上腺癌、甲状腺癌、血液癌、皮肤癌、脑癌、宫颈癌、肠癌、肝癌、结肠癌、胃癌、肠癌、头颈癌、胃肠癌、淋巴结癌、食道癌、结肠直肠癌、胰腺癌、耳、鼻和喉(ENT)癌、乳腺癌、前列腺癌、子宫癌、卵巢癌和肺癌、软组织肿瘤及其转移。根据本公开的术语癌症还包括癌症转移和癌症复发。
根据本公开的“肿瘤的生长”或“肿瘤生长”涉及肿瘤增加其大小的倾向和/或肿瘤细胞增殖的倾向。
出于本公开的目的,术语“癌症”和“癌症疾病”与术语“肿瘤”和“肿瘤疾病”可互换使用。
“治疗(treat)”意指向受试者施用如本文所述的化合物或组合物,以预防或消除疾病,包括减小受试者中肿瘤的大小或肿瘤的数目;阻止或减缓受试者的疾病;抑制或减缓受试者中新疾病的发展;降低当前患有或曾经患有疾病的受试者的症状和/或复发的频率或严重性;和/或延长,即增加受试者的寿命。特别地,术语“疾病的治疗”包括治愈,缩短持续时间,改善、预防、减缓或抑制疾病或其症状的进展或恶化,或预防或延迟疾病或其症状的发作。
本文所述的治疗活性剂或产品、疫苗和组合物可通过任何常规途径施用,包括通过注射或输注。
本文所述的试剂以有效量施用。“有效量”是指单独或与其他剂量一起实现所需反应或所需效果的量。在治疗特定疾病或特定病症的情况下,所需反应优选涉及抑制疾病过程。这包括减缓疾病的进展,特别是中断或逆转疾病的进展。在疾病或病症的治疗中的所需反应也可以是延迟所述疾病或病症的发作,或预防所述疾病或病症的发作。本文所述的试剂的有效量将取决于待治疗的病症,疾病的严重程度,患者的个体参数,包括年龄、生理状况、大小和体重,治疗的持续时间,伴随治疗的类型(如果存在),具体施用途径和类似因素。因此,本文所述的试剂的施用剂量可取决于若干此类参数。在患者中的反应在初始剂量下不足的情况下,可使用较高剂量(或通过不同的,更局部化的施用途径实现的有效较高剂量)。
本文所述的药物组合物优选是无菌的且含有有效量的治疗活性物质以产生期望的反应或期望的效果。
本文所述的药物组合物通常以药学上相容的量和药学上相容的制剂施用。术语“药学上相容的”是指不与药物组合物的活性组分的作用相互作用的无毒材料。这类制剂通常可含有盐、缓冲物质、防腐剂、载体,补充免疫增强物质,诸如佐剂,例如CpG寡核苷酸、细胞因子、趋化因子、皂苷、GM-CSF和/或RNA以及适当的其他治疗活性化合物。当用于药物中时,盐应当是药学上相容的。
单域抗体及其变体
如本文所用,术语“FGFR4”具有其在本领域中的一般含义且包括人FGFR4(也称为“成纤维细胞生长因子受体4”),特别是人FGFR4的天然序列多肽、同种型、嵌合多肽、所有同源物、片段和前体。天然FGFR4的氨基酸序列包括UniProt reference P22455(FGFR4_HUMAN)。
更具体地,术语“FGFR4”包括以下SEQ ID:45的人FGFR4。
>spots|P22455|FGFR4_HUMAN成纤维细胞生长因子受体4OS=智人OX=9606GN=FGFR4 PE=1SV=2
MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIgGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIgLSYQSAWLTVLPEEDPTWTAAAPEARYTDIILYASGSLALAVLLLLAGLYRGQALHGRHPRPPATVQKLSRFPLARQFSLESGSSGKSSSSLVRGVRLSSSGPALLAGLVSLDLPLDPLWEFPRDRLVLGKPLGEGCFGQVVRAEAFGMDPARPDQASTVAVKMLKDNASDKDLADLVSEMEVMKLIgRHKNIINLLGVCTQEGPLYVIVECAAKGNLREFLRARRPPGPDLSPDGPRSSEGPLSFPVLVSCAYQVARGMQYLESRKCIHRDLAARNVLVTEDNVMKIADFGLARGVHHIDYYKKTSNGRLPVKWMAPEALFDRVYTHQSDVWSFGILLWEIFTLGGSPYPGIPVEELFSLLREGHRMDRPPHCPPELYGLMRECWHAAPSQRPTFKQLVEALDKVLLAVSEEYLDLRLTFGPYSPSGGDASSTCSSSDSVFSHDPLPLGSSSFPFGSGVQT
术语“抗体”广义上是指任何免疫球蛋白(Ig)分子或其抗原结合部分,其由四条多肽链、两条重(H)链和两条轻(L)链、或其任何功能性片段、突变体、变体或衍生物组成,其保留Ig分子的必要表位结合特征。这种突变体、变体或衍生抗体形式是本领域已知的。在全长抗体中,每条重链由重链可变区(本文缩写为HCVR或VH)和重链恒定区组成。重链恒定区由三个结构域CH1、CH2和CH3组成。每条轻链由轻链可变区(本文缩写为LCVR或VL)和轻链恒定区组成。轻链恒定区由一个结构域CL组成。VH和VL区可以进一步细分为超变区,称为互补决定区(CDR),散布有更保守的区域,称为框架区(FR)。每个VH和VL由三个CDR和四个FR组成,从氨基末端到羧基末端按以下顺序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。免疫球蛋白分子可以是任何类型(例如,IgG、IgG、IgM、IgD、IgA和IgY)、类别(例如,IgG1、1gG2、IgG3、1gG4、IgA1和1gA2)或亚类。
抗体片段是抗体的一部分,例如F(ab′)2、Fab、Fv、sFv等。全长抗体的功能片段保留了全长抗体的靶向特异性。因此,重组功能性抗体片段,如Fab(片段、抗体),scFv(单链可变链片段)和单域抗体(dAb)作为基于mAb的治疗剂的替代物,用于开发治疗剂。scFv片段(~25kDa)由两个可变结构域VH和VL组成。自然地,VH和VL结构域通过疏水相互作用非共价结合并倾向于解离。然而,可通过将结构域与亲水性柔性接头连接以产生单链Fv(scFv)来工程化稳定的片段。最小的抗原结合片段是单一可变片段,即VH或VL结构域。靶向结合不需要分别与轻链/重链配偶体结合。这些片段用于单域抗体。因此,单域抗体(~12-15kDa)具有VH或VL结构域。
如本文所用,术语“单域抗体”(sdAb)或(Ablynx的商品名)。具有其在本领域中的一般含义,且是指具有仅12-15kDa分子量的抗体片段,其由来源于重链的单个单体可变抗体结构域组成。这种单域抗体(命名为VHH)可以在骆驼科哺乳动物中发现,且天然缺失轻链。对于(单)域抗体的一般描述,还参考上述现有技术以及EP 0 368 684,Ward等(Nature 1989Oct 12;341(6242):544-6),Holt et al,Trends Biotechnol,2003,21(1l):484-490;和WO 06/030220,WO 06/003388。单域抗体的氨基酸序列和结构可以被认为由四个框架区或“FRW”组成,其在本领域中被分别称为“框架区1”或“FRW1”;“框架区2”或“FRW2”;为“框架区3”或“FRW3”;以及“框架区4”或“FRW4”;框架区被三个互补决定区或“CDR”间隔,在本领域中分别称为“互补决定区1”或“CDR1”;“互补决定区2”或“CDR2”,以及“互补决定区3”或“CDR3”。因此,单域抗体可定义为具有以下一般结构的氨基酸序列:FRW1-CDR1-FRW2-CDR2-FRW3-CDR3-FRW4,其中FRW1-FRW4分别指框架区1-4,且其中CDR1-CDR3指互补决定区1-3。在本公开的上下文中,单域抗体的氨基酸残基根据InternationalImMunoGeneTics information system氨基酸编号(http://imgt.cmes.fr/)给出的VH结构域的通用编号方式进行编号。
如本文所用,“分离的sdAb”是指基本上不含其他抗体,尤其是具有不同抗原特异性的其他sdAb的单域抗体(sdAb)(例如,特异性结合FGFR4的分离的抗体基本上不含有特异性结合除FGFR4外的其他抗原的抗体)。此外,分离的抗体可以基本上不含其他细胞材料和/或化学物质。
如本文所用,术语“合成的”是指这样的抗体,其并非从天然存在的抗体片段获得的抗体,而是从包含人工编码序列的重组核酸产生的。
术语“CDR”是指抗体可变序列内的互补决定区。在重链和轻链的每个可变区中有三个CDR,对每个可变区,称为CDR1、CDR2和CDR3。术语“CDR组”是指存在于能够结合抗原的单一可变区中的一组三个CDR。根据不同的系统,这些CDR的确切边界被不同地定义。本文使用由Kabat描述的系统。术语“Kabat编号”,“Kabat定义”和“Kabat标记”在本文中可互换使用。本领域公认的这些术语是指,在抗体或其抗原结合部分的重链和轻链可变区中比其他氨基酸残基更易变(即,高变)的氨基酸残基的编号系统(Kabat et al.,(1971)Ann.NYAcad.Sci.190:382-391and Kabat,et al.,(1991)Sequences of Proteins ofImmunological Interest,Fifth Edition,U.S.Department of Health and HumanServices,NIH Publication No.91-3242)。
sdAb亲和力是指sdAb通过其抗原结合位点(互补位)与抗原(诸如本公开中的FGFR4)上呈现的表位结合的强度。可基于KD值的评估来评估亲和力。
如本文所用,术语“KD”是指平衡解离常数,其由koff与kon的比例(即koff/kon)获得,并表示为摩尔浓度(M)。KD值涉及抗体的浓度(特定实验所需的抗体量),因此KD值越低(浓度越低),抗体的亲和力越高。抗体的KD值可使用本领域公知的方法测定。用于测定mAb的KD值的方法可见于Harlow et al.,Antibodies:A Laboratory Manual,Cold Spring HarborLaboratory Press,Cold Spring Harbor,N.Y.,1988;Coligan et al.,eds.,CurrentProtocols in Immunology,Greene Publishing Assoc.and Wiley Interscience,N.Y.,1992,1993,以及Muller,Meth.Enzymol.92:589-601,1983,这些参考文献在此全部引入作为参考。用于测定抗体的KD的方法是通过使用表面等离子体共振,或通过使用生物传感器体系如(还参见关于亲和力评估的详细信息,Rich RL et al.,Anal Biochem,2001,以及关于sdAb亲和力测量的具体实施的更多细节,Moutel S et al.,eLife 2016;5:e16228)。亲和力测量通常在25℃下进行。本文所用的术语“kassoc”或“ka”或“kon”是指特定抗体-抗原相互作用的结合速率,而本文所用的术语“kdis”或“kd”或koff是指特定抗体-抗原相互作用的解离速率。简言之,由于sdAb是比其各自的抗原更小的蛋白质,它们可从Biocore生物传感器仪器捕获在传感载体上,而重组抗原(即,通常为rFGFR4)可用作分析物。可在单个循环中以例如3.125nM-50nM的范围内的增加的浓度依次注射分析物,而不在注射中间进行传感载体再生。结合参数可用BIAevaluation软件的1:1的Langmuir结合模型,通过拟合重叠的传感图来获得。
通常地,根据本公开的单域抗体以KD结合亲和力为约10-6M或更小、10-7M或更小、10-8M或更小、10-9M或更小、10-10M或更小,或10-11M或更小的KD结合FGFR4,尤其是如本文定义的人FGFR4。在一些实施方案中,KD结合亲和力在纳摩尔/皮摩尔范围内,尤其是10-7 -10- 12M,尤其是10-8 -10-12,特别地10-8 -10-10。
发明人分离了具有所需的特性,尤其是所需的亲和力的4种参照单域抗体(sdAb),并通过以下序列表征:
表1:sdAb全序列。
因此,本公开包含单域抗体,其具有如表1中定义的4种参照单域抗体之一的至少3个CDR。
在一些实施方案中,根据本公开的sdAb包括与SEQ ID NO:41-44中任一个所示的氨基酸序列具有至少60、70、80、90、95、96、97、98、99或100%同一性的sdAb。
根据本公开的sdAb尤其包括具有与序列SEQ ID NO:13-20中的一个或多个具有至少60、70、80、90、95、96、97、98、99或100%同一性的框架区序列的人源化抗FGFR4 sdAb。
本文公开的人源化抗FGFR4 sdAb的3个CDR区可与表1中定义的参照人源化sdAb(hsdAb)之一的3个CDR区100%相同。或者,在一些实施方案中,根据本公开的hsdAb可具有已通过氨基酸缺失、插入或取代而突变的氨基酸序列,但与表1的sdAb的CDR区相比在CDR区中具有至少60、70、80、90、95、96、97、98、99或100%同一性。通常地,根据本公开,与表1的sdAb的相应CDR序列相比,抗体可在一个或多个CDR中具有1、2、3或4个氨基酸变化(包括缺失、插入或取代)。
在一些实施方案中,本公开的单域抗体是表1的参照单域抗体之一的突变变体,其具有与所述参照sdAb的相应3个CDR区100%相同的3个CDR区,且其中,当与相应参照sdAb的相应框架区相比时,FRW1、FRW2、FRW3和/或FRW4区中的一个或多个中不超过1、2、3、4或5个氨基酸已通过氨基酸缺失、插入或取代而突变。
在一些实施方案中,本公开的sdAb选自与SEQ ID NO.41-44相比具有一个或多个氨基酸取代、缺失、插入或其他修饰的SEQ ID NO.41-44,且其保留单域抗体的生物功能。修饰可包括编码单域抗体或多肽的一个或多个密码子的一个或多个取代、缺失或插入,其导致与参照单域抗体或多肽的序列相比,氨基酸序列的改变。氨基酸取代可以是用具有相似结构和/或化学特性的另一种氨基酸替换其中氨基酸的结果,诸如用丝氨酸替换亮氨酸,即保守氨基酸替换。插入或缺失可任选地在约1-5个氨基酸的范围内。所允许的变化可通过系统地在序列中进行氨基酸的插入、缺失或取代并测试所得变体的全长或成熟天然序列所显示的活性来确定。
在一些实施方案中,修饰是保守序列修饰。如本文所用,术语“保守序列修饰”是指不显著影响或改变含有该氨基酸序列的抗体的结合特性的氨基酸修饰。这种保守修饰包括氨基酸取代、添加和缺失。通过本领域已知的标准技术,诸如定点诱变和PCR介导的诱变,可将修饰引入本文所述的单域抗体中。保守氨基酸取代是其中氨基酸残基被具有相似侧链的氨基酸残基替换的氨基酸取代。具有相似侧链的氨基酸残基家族已在本领域中定义。这些家族包括氨基酸,其具有碱性侧链(例如赖氨酸、精氨酸、组氨酸),酸性侧链(例如天冬氨酸、谷氨酸),不带电荷的极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸),非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸),β-支链侧链(例如苏氨酸、缬氨酸、异亮氨酸)和芳香侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。因此,本公开的单域抗体的CDR区内的一个或多个氨基酸残基可用来自相同侧链家族的其他氨基酸残基替换,且可使用本文所述的功能测定法测试改变的抗体保留的功能(即,上文(c)-(I)中所述的功能)。
在一些实施方案中,单域抗体选自SEQ ID NO.41-44之一,但包含一个或多个氨基酸取代,例如1-20个,诸如1、2、3、4、5、6、7、8、9或10个氨基酸取代。一个或多个氨基酸取代可在一个或多个框架区中。或者,或另外地,一个或多个氨基酸取代可在一个或多个CDR中。在一些实施方案中,氨基酸取代在框架和CDR序列中。
在一些实施方案中,人源化单域抗体是选自具有SEQ ID NO.41-44的单域抗体的变体,其包含一个或多个序列修饰,且与未修饰的单域抗体相比,在一种或多种特性(诸如结合亲和力、特异性、热稳定性、表达水平、效应子功能、糖基化、降低的免疫原性或溶解性方面)具有改进。
在优选的实施方案中,根据本公开的sdAb对FGFR4具有严格的特异性。通过对FGFR4具有严格特异性,本文意指根据本公开的sdA显示出不可检测的与其他FGFR分子(诸如FGFR1、FGFR2或FGFR3)的结合。如结果所示,可通过检测sdAb与在其表面不表达各种FGFR分子的细胞的结合来进行结合测定。通常,可通过流式细胞术使用标记的(例如FITC-标记的抗-iXHis-tag抗体)检测表面结合的单域抗体来进行测定。
在一些实施方案中,sdAb
通常地,根据本公开的单域抗体对FGFR4具有至少10-7M,尤其是至少10-8M,至少10-9M的亲和力(KD),而对其他FGFR分子(诸如FGFR1、FGFR2和/或FGFR3)不具有亲和力或小于10-3M的非常低的亲和力。在一些实施方案中,对FGFR4具有特异性的sdAb对FGFR1和FGFR3不具有亲和力,而对FGFR2保持高亲和力(1.106 -1.108,尤其是1.106 -1.107)。
在优选的实施方案中,根据本公开的sdAb抑制FGFR4信号转导。该特性的分析可如本文所附结果所示进行。通常,FGFR4活化测定可在Rh30细胞上进行且ERK1:2磷酸化用作读取。因此,可将Rh30细胞与FG19(FGFR4的特异性配体)在有或无待测抗体的情况下孵育。磷光剂ERK1/2水平的增加意味着所测试的抗体按照本公开花火FGFR4下游通路。
技术人员知道有不同的方法来鉴定、获得和优化本文所述的抗原结合分子,包括体外和体内表达文库。可使用本领域已知的优化技术,诸如展示(例如,核糖体和/或噬菌体展示)和/或诱变(例如,易错诱变)。因此,本公开还包括本文所述的单域抗体的序列优化的变体。
在本公开的一些实施方案中,本文所述的分离的人源化单域抗体可以直接或间接、共价或非共价地连接至目标化合物。如上定义的目标物质或化合物可直接和共价或非共价地连接至如本文定义的单域抗体的末端之一(N或C端),或连接至所述单域抗体的氨基酸之一的侧链。目标物质还可通过间隔子(或接头)间接和共价或非共价地连接至所述单域抗体,或连接至所述单域抗体的末端之一,或连接至所述单域抗体的氨基酸之一的侧链。目标物质与肽,特别是抗体的常规连接方法是本领域已知的(例如,参见Ternynck andAvrameas 1987"Techniques immuno enzymatiques"Ed.INSERM,Paris;Hermanson,2010,Bioconjugate Techniques,Academic Press)。
在一些实施例中,如本文所述的单域抗体可以,尤其是,具有式sdAb-(L-(D)m)n的“抗体药物偶联物”的形式,或其药学上可接受的盐;其中sdAb是如前公开的单域抗体;L是接头;D是目标化合物;m为1-8的整数;且n为1-10的整数,通常为3或4。
如本文所用,术语“抗体药物偶联物”是指单域抗体与另一种试剂(诸如化疗剂、毒素、免疫治疗剂、成像探针等)连接。连接可以是共价键,或非共价相互作用,诸如通过静电力。本领域已知的各种接头可用于形成免疫偶联物。接头(L)可以,例如选自下组:可裂解的接头、不可裂解的接头、亲水性接头、带电荷的接头和基于二羧酸的接头。
在一些实施方案中,本公开的单域抗体偶联或共价连接至目标化合物。如本文所用,术语“偶联”具有其在本领域中的一般含义且意指化学偶联或化学交联。许多化学交联方法也是本领域已知的。交联剂可以是同型双功能的(即,具有经历相同反应的两个官能团)或异型双功能的(即,具有两个不同的官能团)。许多交联剂是可商购的。其使用的详细说明可容易地从供应商处获得。关于多肽交联和偶联物制备的一般参考是:WONG,Chemistry of protein conjugation and cross-linking,CRC Press(1991),还参见Arnon et al.,"Monoclonal Antibodies For Immunotargeting Of Drugs In CancerTherapy,"in Monoclonal Antibodies For Immunotargeting Of Drugs In CancerTherapy,"in Monoclonal Antibodies And Cancer Therapy(Reisfeld et al.eds.,AlanR.Liss,Inc.,1985);Hellstrom et al.,"Antibodies For Drug Delivery,"inControlled Drug Delivery(Robinson et al.eds.,Marcel Deiker,Inc.,2nd ed.1987);Thorpe,"Antibody Carriers Of Cytotoxic Agents In Cancer Therapy:A Review,"inMonoclonal Antibodies'84:Biological And Clinical Applications(Pinchera etal.eds.,1985);"Analysis,Results,and Future Prospective of the Therapeutic Useof Radiolabeled Antibody In Cancer Therapy,"in Monoclonal Antibodies ForCancer Detection And Therapy(Baldwin et al.eds.,Academic Press,1985);以及Thorpe et al.,1982,Immunol.Rev.62:119-58.See also,e.g.,PCT publication WO 89/12624.)。通常,核酸分子分别通过N-羟基琥珀酰亚胺酯或马来酰亚胺官能团与抗体上的赖氨酸或半胱氨酸共价连接。已报道了使用工程化半胱氨酸的偶联方法或非天然氨基酸的掺入以改善偶联物的均一性(Axup,J.Y.,Bajjuri,K.M.,Ritland,M.,Hutchins,B.M.,Kim,C.H.,Kazane,S.A.,Haider,R.,Forsyth,J.S.,Santidrian,A.F.,Stafin,K.,et al.(2012).Synthesis of site-specific antibody-drug conjugates using unnaturalamino acids.Proc.Natl.Acad.Sci.USA 109,16101-16106.;Junutula,J.R.,Flagella,K.M.,Graham,R.A.,Parsons,K.L.,Ha,E.,Raab,H.,Bhakta,S.,Nguyen,T.,Dugger,D.L.,Li,G.,et al.(2010)Engineered thio-trastuzumab-DMl conjugate with an improvedtherapeutic index to target human epidermal growth factor receptor 2-positivebreast cancer.Clin.Cancer Res.16,4769-4778.)。Junutula等(2008)开发了称为“THIOMAB”(TDC)的基于半胱氨酸的位点特异性偶联物,其声称显示与常规偶联方法相比的改进治疗指数。特别地,本领域技术人员还可设想用含有酰基供体谷氨酰胺的标签(例如,含有Gln的肽标签或Q标签)或通过多肽工程化(例如,通过多肽上的氨基酸缺失、插入、取代或突变)使之反应的内源谷氨酰胺工程化的多肽。然后转谷氨酰胺酶可与胺供体试剂(例如,包含或连接至反应性胺的小分子)共价交联以形成工程化的含Fc的多肽偶联物的稳定且同质的群体,其中胺供体试剂通过含酰基供体谷氨酰胺的标签或可接近的/暴露的/反应性内源谷氨酰胺位点特异性地偶联至含Fc的多肽(WO2012059882)。与“TGase”或“TG”互换使用的术语“转谷氨酰胺酶”是指能够通过肽结合的谷氨酰胺的γ-甲酰胺基团与赖氨酸的ε-氨基基团或结构相关的伯胺(诸如氨基戊基基团(例如肽结合的赖氨酸))之间的酰基转移反应进行交联蛋白质,以产生ε-(γ-谷氨酰基)赖氨酸异肽键的酶。TGase尤其包括细菌转谷氨酰胺酶(BTG),诸如具有EC参考号EC 2.3.2.13的酶(蛋白质-谷氨酰胺-γ-谷氨酰转移酶)。在一些实施方案中,本公开的单域抗体通过接头分子偶联至异源部分。如本文所用,术语“接头分子”是指连接到本公开的单域抗体的任何分子。连接通常是共价的。在一些实施方案中,接头分子是柔性的且不干扰本公开的单域抗体的结合。
本文预期的目标化合物或物质可以非限制性地选自核酸、多肽或蛋白质、病毒、毒素和化学实体。
在一些实施方案中,目标化合物包括抗原结合结构域试剂,诸如抗体、其变体和片段,尤其是相同或另一种单域抗体、适体或酶。
如上所述,目标化合物或物质可以是治疗或诊断化合物。治疗化合物尤其包括具有抗癌和/或细胞毒性活性的治疗化合物(即细胞毒性化合物),且诊断化合物通常包括成像探针。
化疗药物通常缺乏特异性,也会影响健康组织。为克服该问题,纳米载体可用于将药物主动递送至肿瘤部位。纳米技术在化疗领域中的应用具有通过增加肿瘤部位的药物浓度来改进生物分布和降低对正常细胞的毒性的潜力(参见Ferrari,M.Cancernanotechnology:Opportunities and challenges.Nat.Rev.Cancer 5,161–171(2005);以及Kumari,P.,Ghosh,B.&Biswas,S.Nanocarriers for cancer-targeted drugdelivery.J.Drug Target.24,179–191(2016)详细描述)。
因此,在一些实施方案中,所述目标物质是药物纳米载体,其可以是有机的物质,诸如脂质体或聚合物实体,或包含或包封诊断或治疗化合物的无机的物质(Villaraza etal.2010Chem Rev.,110,2921-2959)。因此,纳米抗体是将毒性货物递送至癌细胞的非常方便的工具,且非常适合于化学偶联至不同的纳米颗粒或纳米载体形式上。有机载体(或货物)可包括脂质颗粒,诸如脂质体或胶束,基于白蛋白的纳米颗粒和包括基于聚合物的聚合物囊泡的聚合物纳米颗粒。无机载体可以包括量子点、碳纳米管、层状双氢氧化物、介孔二氧化硅和磁性纳米颗粒(尤其参见Senapati,S.,Mahanta,A.K.,Kumar,S.etal.Controlled drug delivery vehicles for cancer treatment and theirperformance.Sig Transduct Target Ther 3,7(2018))。
聚合物纳米颗粒是固体的、生物相容的、胶体的且通常是具有纳米级尺寸的生物可降解系统。聚合物纳米颗粒可由合成聚合物制成,例如聚(乳酸)(PLA)、聚(ε-己内酯)(PCL)、聚(乳酸-共-乙醇酸)、N-(2-羟丙基)-甲基丙烯酰胺共聚物(HPMA)和聚(苯乙烯-马来酸酐)共聚物,或由天然聚合物制成,诸如明胶、葡聚糖、瓜尔胶、壳聚糖和胶原。药物可容易地通过在聚合物基质中的分散或与聚合物分子的偶联/附着而被包封,用于它们通过表面或体侵蚀,通过聚合物基质的扩散,溶胀后扩散的受控递送,或作为对局部刺激的响应。
白蛋白是可从多种来源获得的蛋白质,包括卵清(卵清蛋白)、牛血清(牛血清白蛋白、BSA)和人血清(人血清白蛋白、HSA),且可在大豆、牛奶和谷物中获得。基于白蛋白的纳米载体具有若干优点,诸如易于制备,对各种药物的高结合容量,无毒,非免疫原性,生物相容性和生物可降解特性,以及在循环血浆中的半衰期。白蛋白纳米颗粒表面上官能团(氨基和羧基)的存在使其易于结合靶向配体和其他表面修饰。
胶束是通过两亲嵌段共聚物在水溶液中自组装形成的球形或球状胶体纳米级系统,产生疏水核和亲水壳。它们属于在特定浓度(临界胶束浓度;CMC)和温度下的两亲性胶体。疏水性核充当疏水性药物的储存,而亲水性壳使疏水性核稳定并使聚合物和疏水性药物均为水溶性的,从而使颗粒成为静脉注射施用的合适候选物。药物通过物理、化学或静电相互作用引入至聚合物胶束中。
脂质体是小的、球形的、自封闭的结构,在其核心中具有至少一个同心脂质双层和包封的水相。由于它们的生物相容性和生物可降解性,以及它们将亲水试剂(亲水药物、DNA、RNA等)包封在其内部含水核中,并将疏水药物包封在薄层内的独特能力,自从1965年被发现以来,它们已被广泛用作药物递送载体,这使其成为通用的治疗载体。此外,还可使用远程装载方法将两亲性药物装载到脂质体内部水性核心中,诸如用于阿霉素的硫酸铵方法或用于长春新碱的pH梯度方法(参见Bolotin,E.M.et al.Ammonium sulfate gradientsfor efficient and stable remote loading of amphipathic weak bases intoliposomes and ligandoliposomes.J.Liposome.Res.4,455–479(1994),以及Boman,N.L.et al.,Liposomal vincristine which exhibits increased drug retention andincreased circulation longevity cures mice bearing P388 tumors.Cancer Res.54,2830–2833(1994))。已发现配体靶向的脂质体促进脂质体-药物偶联物在体外和体内内化到特定靶细胞中。一些化疗药物的脂质体制剂已被转化到临床中并证明了药物的安全性和改进的药代动力学特性。突出的实例是脂质体阿霉素柔红霉素和VCR 与游离药物相比,它们使得副作用降低(参见O’Brien,M.E.R.et al.,Ann.Oncol.15,440–449(2004);Gill,P.S.et al.,J.Clin.Oncol.14,2353–2364(1996);以及Shah,N.N.et al.,Pediatr.Blood Cancer 63,997–1005(2016))。
关于用于递送治疗化合物的脂质体技术的最近综述,参见Bulbake,Upendra etal.“Liposomal Formulations in Clinical Use:An Updated Review.”Pharmaceuticsvol.9,212.27Mar.2017。靶向脂质体(即如上所述与FGFR4 sdAb结合)的典型实例,特别地描述于结果部分中(但也参见Roveri,M.et al.,Nanomedicine nnm-2017-0430(2017)。示例性的脂质体特别地包含卵神经鞘磷脂、胆固醇、PEG-神经酰胺(典型地,N-棕榈酰-鞘氨醇-1-[琥珀酰[甲氧基PEG-2000]])、DSPE-PEG-马来酰亚胺(典型地,1,2-二硬脂酰-SN-甘油-3-磷酸乙醇胺-N-[马来酰亚胺(聚乙二醇)-2000])(均为Avanti Polar Lipids)和DiR(1,1’-双十八烷基-3,3,3’,3’-四甲基吲哚三碳菁碘化物)(Thermo Fisher Scientific)的组合。所述脂质的有利比例通常分别为49.8:45:4:1:0.2mol%。在脂质膜中达到约70mM的总脂质浓度。
为产生主动靶向脂质体,在远端引入具有反应性马来酰亚胺基团的DSPE-PEG脂质。然后将在C-端具有游离半胱氨酸的单域抗体与脂质体表面偶联。可包封在脂质体中的典型治疗剂包括阿霉素 柔红霉素VCR去甲长春碱(TCL178)。
如下所列的化合物可直接偶联至本文公开的单域抗体或包封在如上所述的载体中。
如本文所用,术语“毒素”、“细胞毒素”或“细胞毒性化合物”是指对细胞的生长和增殖有害,且可用于减少、抑制或破坏细胞或恶性肿瘤的任何试剂。
如本文所用,术语“抗癌化合物”是指可用于治疗细胞增殖性病症诸如癌症的任何试剂,包括但不限于细胞毒性剂、化疗剂、放射性同位素、靶向抗癌剂、免疫治疗剂(诸如免疫抑制剂或免疫刺激剂)和裂解肽。
具有抗癌或细胞毒性活性的治疗化合物例如,可选自下组:V-ATPase抑制剂、促凋亡剂、Bcl2抑制剂、MCL1抑制剂、HSP90抑制剂、IAP抑制剂、mTor抑制剂、微管稳定剂、微管去稳定剂、奥瑞他汀、多拉司他汀、美登素类化合物、MetAP(甲硫氨酸氨肽酶)、蛋白质CRM1的核输出抑制剂、DPPIV抑制剂、蛋白酶体抑制剂、线粒体中的磷酰基转移反应抑制剂、蛋白质合成抑制剂、激酶抑制剂、CDK2抑制剂、CDK9抑制剂、驱动蛋白抑制剂、HDAC抑制剂、DNA损伤剂、DNA烷化剂、DNA嵌入剂、DNA小沟区结合物和DHFR抑制剂。
细胞毒性化合物可以,例如选自下组:紫杉醇;细胞松弛素B;短杆菌肽D;溴化乙锭;依米丁;丝裂霉素;依托泊苷;替尼泊苷;长春新碱;长春碱;秋水仙碱;阿霉素;柔红霉素;dihydroxyanthracindione;微管蛋白抑制剂,诸如美登素或其类似物或衍生物;抗有丝分裂剂,诸如单甲基奥瑞他汀E或F或其类似物或衍生物;多拉司他汀10或15或其类似物;伊立替康或其类似物;米托蒽醌;光神霉素;放线菌素D;1-脱氢睾酮;糖皮质激素;普鲁卡因;丁卡因;利多卡因;普萘洛尔;嘌呤霉素;卡奇霉素或其类似物或衍生物;抗代谢物,诸如甲氨蝶呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、氟达拉滨、5-氟尿嘧啶、地卡巴嗪、羟基脲、天冬酰胺酶、吉西他滨或克拉屈滨;烷化剂,诸如氮芥、塞替派、苯丁酸氮芥、美法仑、卡莫司汀(BSNU)、洛莫司汀(CCNU)、环磷酰胺、白消安、二溴甘露醇、链脲霉素、达卡巴嗪(DTIC)、丙卡巴肼、丝裂霉素C;铂衍生物,诸如顺铂或卡铂;倍癌霉素A、倍癌霉素SA、拉奇霉素(CC-1065)或其类似物或衍生物;抗生素,诸如放线菌素D、博来霉素、柔红霉素、阿霉素、伊达比星、光神霉素、丝裂霉素、米托蒽醌、普卡霉素、氨茴霉素(AMC);吡咯并[2,1-c][1,4]-苯并二氮杂(PDB);白喉毒素和相关分子,诸如白喉A链及其活性片段和杂合分子、蓖麻毒蛋白毒素,诸如蓖麻毒蛋白A或去糖基化的蓖麻毒蛋白A链毒素、霍乱毒素、志贺样毒素,诸如SLT I、SLTII、SLT IIV、LT毒素、C3毒素、志贺菌毒素、百日咳毒素、破伤风毒素、大豆Bowman-Birk蛋白酶抑制物、假单胞菌外毒素、alorin、皂草素、膜联蛋白、gelanin、abrin A链、蒴莲素A链、α-sarin、Aleuritesfordii蛋白、dianthin蛋白、美洲商陆蛋白,诸如PAPI、PAPII和PAP-S、momordicacharantia抑制剂、麻风树毒蛋白、巴豆毒蛋白、肥皂草抑制剂;核糖核酸酶(Rase);DNase I、葡萄球菌肠毒素A;商陆抗病毒蛋白;白喉毒素;和假单胞菌属内毒素。
在一些实施方案中,与本文公开的sdAb偶联或包封在用本文公开的sdAb官能化的纳米载体中的治疗化合物包括奥瑞他汀或其肽类似物、衍生物或前药。奥瑞他汀已显示干扰微管动力学、GTP水解以及核和细胞分裂(Woyke et al(2001)Antimicrob.Agents andChemother.45(12):3580-3584)和具有抗癌(US5663149)和抗真菌活性(Pettit et al,(1998)Antimicrob.Agents and Chemother.42:2961-2965)。例如,奥瑞他汀E可与对乙酰基苯甲酸或苯甲酰戊酸反应以分别产生AEB和AEVB。其他典型的奥瑞他汀衍生物包括AFP、MMAF(单甲基奥瑞他汀F)和MMAE(单甲基奥瑞他汀E)。合适的奥瑞他汀和奥瑞他汀类似物、衍生物和前药以及用于将奥瑞他汀偶联至抗体的合适接头描述于例如美国专利号5,635,483、5,780,588和6,214,345中,以及国际专利申请公开WO02088172、WO2004010957、WO2005081711、WO2005084390、WO2006132670、WO03026577、WO200700860、WO207011968和WO205082023中。
在一些实施方案中,与本文公开的sdAb偶联或包封在用本文公开的sdAb官能化的纳米载体中的治疗化合物包括Mertansine(也称为emtansine或DM1)或其肽类似物、衍生物或前药。Mertansine是微管蛋白抑制剂,表示其通过与微管蛋白结合来抑制微管的组装。
在一些实施方案中,与本文公开的sdAb偶联或包封在用本文公开的sdAb官能化的纳米载体中的治疗化合物包括吡咯并[2,1-c][1,4]-苯并二氮杂(PDB)或其类似物、衍生物或前药。合适的PDB和PDB衍生物以及相关技术描述于,例如Hartley J.A.et al,CancerRes 2010;70(17):6849-6858;Antonow D.et al,Cancer J 2008;14(3):154-169;HowardP.W.et al,Bioorg Med ChemLett 2009;19:6463-6466以及Sagnou et al,Bioorg MedChemLett 2000;10(18):2083-2086中。
在一些实施方案中,与如本文公开的sdAb偶联或包封在用如本文公开的sdAb官能化的纳米载体中的治疗化合物包括下组:蒽环霉素、美登素、卡奇霉素、倍癌霉素、拉奇霉素(CC-1065)、多拉司他汀10、多拉司他汀15、依立替康、单甲基奥瑞他汀E、单甲基奥瑞他汀F、PDB或其任何类似物、衍生物或前药。
在一些实施方案中,与本文公开的sdAb偶联或包封在用本文公开的sdAb官能化的纳米载体中的治疗化合物包括蒽环霉素或其类似物、衍生物或前药。在一些实施方案中,单域抗体与美登素或其类似物、衍生物或前药偶联。在一些实施方案中,单域抗体与卡奇霉素或其类似物、衍生物或前药偶联。在一些实施方案中,单域抗体与倍癌霉素或其类似物、衍生物或前药偶联。在一些实施方案中,单域抗体与拉奇霉素(CC-1065)或其类似物、衍生物或前药偶联。在一些实施方案中,所述抗体与多拉司他汀10或其类似物、衍生物或前药偶联。在一些实施方案中,所述抗体与多拉司他汀15或其类似物、衍生物或前药偶联。在一些实施方案中,抗体与单甲基奥瑞他汀E或其类似物、衍生物或前药偶联。在一些实施方案中,单域抗体与单甲基奥瑞他汀F或其类似物、衍生物或前药偶联。在一些实施方案中,抗体与吡咯并[2,1-c][1,4]-苯并二氮杂或其类似物、衍生物或前药偶联。在一些实施方案中,单域抗体与伊立替康或其类似物、衍生物或前药偶联。
在一些实施方案中,与如本文公开的sdAb偶联或包封在用如本文公开的sdAb官能化的纳米载体中的治疗化合物包括核酸或核酸相关分子。在一个这样的实施方案中,偶联的核酸是细胞毒性核糖核酸酶(RNase)或脱氧核糖核酸酶(例如,DNase I)、反义核酸、抑制性RNA分子(例如,siRNA分子)或免疫刺激性核酸(例如,含有免疫刺激性CpG模体的DNA分子)。在一些实施方案中,抗体与适体或核酶偶联。
在一些实施方案中,如本文公开的偶联至sdAb(例如,为融合蛋白)或包封至如本文公开的sdAb官能化的纳米载体的治疗化合物包括裂解肽,诸如CLIP、蛙皮素2、蜂毒肽、天蚕素和P18。
在一些实施方案中,如本文公开的偶联至sdAb(例如,为融合蛋白)或包封在如本文公开的sdAb官能化的纳米载体的治疗化合物包括细胞因子,诸如IL-2、IL-4、IL-6、IL-7、IL-10、IL-12、IL-13、IL-15、IL-18、IL-23、IL-24、IL-27、IL-28a、IL-28b、IL-29、KGF、IFNα、IFN3、IFNγ、GM-CSF、CD40L、Flt3配体、干细胞因子、安塞司亭和TNFα。
在一些实施方案中,与如本文公开的sdAb偶联或包封在用如本文公开的sdAb官能化的纳米载体中的治疗化合物包括放射性同位素或含放射性同位素的螯合物。例如,所述抗体可偶联至螯合剂接头,例如DOTA、DTPA或tiuxetan,其使得抗体与放射性同位素复合。单域抗体还可以或可替代地包含或偶联至一个或多个放射性标记的氨基酸或其他放射性标记的分子。放射性同位素的非限制性实例包括3H、14C、15N、35S、90Y、"Tc、125I、131I、186Re、213Bi、225Ac和227Th。为治疗目的,可使用发射β或α粒子辐射的放射性同位素,例如131I、90Y、211At、212Bi、67Cu、186Re、188Re和212Pb。
诊断化合物可选自酶、荧光团、NMR或MRI造影剂、放射性同位素或纳米颗粒。例如,诊断化合物可选自下组:
-酶,诸如辣根过氧化物酶、碱性磷酸酶、葡萄糖-6-磷酸酶或β-半乳糖苷酶;
-荧光团,诸如绿色荧光蛋白(GFP),在光谱的紫外(UV)部分中的波长处激发的蓝色荧光染料(例如,AMCA(7-氨基-4-甲基香豆素-3-乙酸);Alexa),由蓝光激发的绿色荧光染料(例如,FITC、Cy2、Alexa),由绿光激发的红色荧光染料(例如,罗丹明、德克萨斯红、Cy3、Alexa Fluro染料546、564和594),或用远红光激发的染料(例如Cy5)以用电子检测器(CCD相机、光电倍增管)可视化;
-放射性同位素,例如可用于PET成像的18F、nC、13N、150、68Ga、82Rb、44Sc、64Cu、86Y、89Zr、124I、152Tb,或可用于SPECT/闪烁照相研究的67Ga、81mKr、99mTc、mIn、123I、125I、13Xe、201T1、155Tb、195mPt,或可用于放射自显影或原位杂交的14C、3H、35S、31P、125I,或可用于标记化合物的At-、Bi-、Br-、Br-、I-、In、177Lu-、212Pb-、186Re-、188Re-、153Sm-、0Y;
-NMR或MRI造影剂,诸如顺磁剂钆(Gd)、镝(Dy)和锰(Mn),和基于氧化铁(诸如MION、SPIO或USPIO)或铂化铁(SIPP)的超顺磁剂,以及X-核,诸如18F、13C、23Na、17O、15N;
-纳米颗粒,诸如金纳米颗粒(B.Van de Broek et al,ACSNano,Vol.5,No.6,4319-4328,2011)或量子点(A.Sukhanova et al,2012Nanomedicine,8516-525)。
当诊断剂用于检测时,其可包含用于闪烁照相研究的放射性原子,例如99Tc或123I,或用于核磁共振(NMR)成像(也称为MRI)的自旋标记,例如13C、9F、Fe、Gd、123I、n1In、Mn、15N或70。
根据本公开的目标物质可以渗透或不渗透哺乳动物或人血脑屏障。
在一些实施方案中,当目标化合物是异源多肽时,本公开的单域抗体可(可选地或另外地)与一个或多个异源多肽融合以形成融合蛋白(在本文中也称为“融合多肽”或“多肽”)。“融合”或“嵌合”蛋白或多肽包含与第二氨基酸序列连接的第一氨基酸序列,其在自然界中并非天然连接的。通常存在于分离的蛋白质中的氨基酸序列可在融合多肽中集合在一起。融合蛋白或多肽例如通过化学合成产生,或通过产生和翻译,多核苷酸,其中多肽区以期望的关联编码。
因此,根据本公开,融合蛋白可包含至少一种根据本公开的分离的人源化单域抗体(hsbAb),其直接或通过间隔子在其C端和/或其N端融合,尤其是在其C端融合至异源多肽的N端,和/或在其N端融合至异源多肽的C端。如本文所用,术语“直接”是指人源化单域抗体末端(N或C端)的(第一个或最后一个)氨基酸与异源多肽末端(N或C端)的(第一个或最后一个)氨基酸融合。换言之,在该实施方案中,所述sdAb的C端的最后一个氨基酸通过共价键与所述异源多肽的N端的第一个氨基酸直接连接,或者所述sdAb的N端的第一个氨基酸通过共价键与所述异源多肽的C端的最后一个氨基酸直接连接。如本文所用,术语“间隔子”也称为“接头”,是指将本公开的sdAb连接至异源多肽的至少一个氨基酸的序列。这种间隔子可用于防止空间位阻。本公开中公开的接头的实例具有以下序列:(Gly3-Ser)4、(Gly3-Ser)、Ser-Gly或(Ala-Ala-Ala)。
在一些实施方案中,目标化合物可以是包含另一个或相同抗原结合结构域的一种或多种多肽。尤其是,目标化合物可以是或不是本文公开的一个或多个单域抗体。所得的包含两个或更多个抗原结合结构域(尤其是包含两个或更多个单域抗体,或基本上由两个或更多个单域抗体组成)的融合蛋白或多肽,在本文中称为“多价”多肽或抗原结合化合物。在一些实施方案中,所述融合蛋白或多肽可包含至少一个具有如本文所述的第一结合结构域的单域抗体和至少一个其他结合结构域(例如抗相同或另一表位、抗原、靶标、蛋白质或多肽),其通常也是单域抗体。“多特异性”(融合)多肽是指包含至少两个不同抗原结合结构域(即靶向不同表位、抗原或靶标)的多肽,其与包含类似抗原结合结构域的多肽相反,尤其是包含相同的单一区域抗体的多肽(“单特异性”(融合)多肽)。
因此,在一些实施方案中,本文所述的融合蛋白还可至少提供针对任何所需蛋白质、多肽、抗原、抗原决定簇或表位的第二抗原结合结构域。所述结合结构域可抗FGFR4,尤其是抗相同或不同的FGFR4表位,或可抗任何其他抗原、多肽或蛋白质。
本公开的“双特异性”融合蛋白是融合多肽,其包含至少一个本文公开的抗第一抗原(即FGFR4)的单域抗体和至少一个抗第二FGFR4表位或抗原(即不同于FGFR4)的另外的结合结构域,而本公开的“三特异性”多肽是包含至少一个本文公开的抗第一抗原(即FGFR4)的单域抗体,至少一个抗第二FGFR4表位或抗原(即不同于FGFR4)的另外的结合结构域和至少一个抗第三FGFR4表位或抗原(即不同于第一和第二抗原)的另外的结合结构域的多肽;等。
FGFR4以外的抗原实例可选自PSMA、PSCA、BCMA、CS1、GPC3、CSPG4、EGFR、胎儿乙酰胆碱受体γ亚基γ(fAChRγ)、HER3、IgF1R、SLC19A1、ACVR2A、EPHB4、CA125、IL-13R、CD278、CD123、NCAM、5T4、CD2、CD3、CD16(FcγrIII)、CD23、MART-1、L1CAM、MUC16、ROR1、SLAMF7、cKit、CD38、CD53、CD56、CD71、CD74、CD92、CD100、CD123、CD138、CD148、CD150、CD200、CD261、CD262、CD276、CD362、gp100、ROR1、间皮素、CD33/IL3Ra、c-Met、Glycolipid F77、EGFRvIII、GD-2、NKp46受体、NY-ESO-1TCR或MAGE A3 TCR、人端粒酶逆转录酶(hTERT)、生存素、细胞色素P450 1B1(CY1 B)、HER2、Wilm’s肿瘤基因1(WT1)、凋亡抑制因子(livin)、甲胎蛋白(AFP)、癌胚抗原(CEA)、粘蛋白16、MUC1、p53、细胞周期蛋白、免疫检查点靶标或其组合。
在一些实施方案中,该多特异性融合多肽的至少一个另外的抗原包含至少一个免疫细胞抗原,诸如一个或多个T细胞抗原,一个或多个巨噬细胞抗原,一个或多个NK细胞抗原,一个或多个嗜中性粒细胞抗原,和/或一个或多个嗜酸性粒细胞抗原,作为双特异性T细胞或NK细胞接合物分子的典型示例(尤其参见Wolf E,Hofmeister R,Kufer P,Schlereth B,Baeuerle PA.“BiTEs:bispecific antibody constructs with uniqueanti-tumor activity”.Drug Discov Today.2005Sep 15;10(18):1237-44.Review)。对于T细胞抗原,可使用CD2和T细胞受体α和β链的框架序列,尤其是CD2或CD3,最特别是CD3复合物的ε链。例如,对于NK细胞,可使用来自FcγrIII和/或来自NKp46受体的抗原片段。
所述多特异性多肽可以以与CAR治疗相同的原理在所使用的免疫细胞中重定向免疫治疗(参见示例性综述Ellwanger K,Reusch U,Fucek I,et al.Redirected optimizedcell killingA highly versatile multispecific fit-for-purposeantibody platform for engaging innate immunity.MAbs.2019;11(5):899–918)。
在一些实施方案中,另外的结合结构域可抗血清蛋白,使得单域抗体的半衰期增加。通常地,所述血清蛋白是白蛋白。
在一些实施方案中,另外的结合结构域可抗血脑屏障的血管内皮上的受体,使得本公开的单域抗体将穿过血脑屏障。靶向受体包括转铁蛋白受体、胰岛素受体、IgF-I和IgF-II受体等。
在一些实施方案中,一个或多个另外的结合结构域可包含常规链抗体(且特别是人抗体)和/或重链抗体的一个或多个部分、片段或结构域。例如,本文定义的单域抗体可任选地通过接头序列与常规(通常地,是人)VH或VL连接。
在一些实施方案中,本公开的多肽或融合蛋白可包含与免疫球蛋白结构域连接的本公开的单域抗体。例如,多肽或融合蛋白包含与Fc部分(诸如人Fc)连接的本公开的单域抗体。所述Fc部分可用于增加本公开的单域抗体的半衰期和甚至生产。例如,Fc部分可结合血清蛋白并从而增加单域抗体的半衰期。在一些实施方案中,至少一个单域抗体还可以任选地通过接头序列与一个或多个(通常是人)铰链和/或CH1和/或CH2和/或CH3结构域连接。例如,与合适的CH1结构域连接的单域抗体可,例如与合适的轻链一起用于产生类似于常规Fab片段或F(ab')2片段的抗体片段/结构,但其中一个或(在F(ab')2片段的情况下)两个常规VH结构域已被本文定义的单域抗体替代。在一些实施方案中,本公开的一个或多个单域抗体可连接(任选地通过合适的接头或铰链区)至一个或多个恒定结构域(例如,可用作Fc部分的一部分/形成Fc部分的2个或3个恒定结构域),Fc部分和/或抗体部分,片段或赋予本公开的多肽一种或多种效应子功能和/或可赋予结合一种或多种Fc受体能力的结构域。例如,为此目的,且不限于此,一个或多个另外的氨基酸序列可包含抗体的一个或多个CH2和/或CH3结构域,诸如来自重链抗体且更典型地来自常规人链抗体的;和/或可形成Fc区,例如来自IgG(例如来自IgG1、IgG2、IgG3或IgG4),来自IgE或来自另一种人Ig如IgA、IgD或IgM。
嵌合抗原受体
本文所用的术语“嵌合抗原受体”或“CAR”或“CARs”是指工程化的受体,其将抗原特异性移植到细胞(例如T细胞,诸如原始T细胞、中央记忆T细胞、效应记忆T细胞或其组合)上,从而将抗原结合结构域的抗原结合特性与T细胞的裂解能力和自我更新相结合。CAR也称为人工T细胞受体、嵌合T细胞受体或嵌合免疫受体。如本文所用,术语“抗原结合结构域或”抗原特异性靶向结构域"是指靶向并结合特异性抗原的CAR区域。当CAR在宿主细胞中表达时,该结构域形成胞外结构域(胞外域)。
本公开的CAR包含以下通式的分子:
sdAb(n)-跨膜结构域-胞内信号转导结构域,
其中n为1或更大。
在一些实施方案中,n为至少2,例如2、3、4或5。sdAb(n)形成抗原结合结构域,且当在细胞中表达时位于细胞外。
通常地,本文所述的CAR优选包含一个或多个,尤其是至少两个抗原结合结构域(每个包含单域抗体),其靶向一个或多个抗原。本公开的CAR的抗原结合结构域可包含均对FGFR4有特异性的两个或至少两个sdAb,从而提供二价结合分子。在一些实施方案中,抗原结合结构域包含两个或至少两个VH单域抗体,其均对FGFR4具有特异性但结合不同表位。换言之,抗原结合结构域包含结合FGFR4的第一表位的第一单域抗体和结合FGFR4的第二表位的第二单域抗体。表位可以重叠。因此,抗原结合结构域是双特异性的。在其他实施方案中,抗原结合结构域包含两个对FGFR4具有特异性且结合相同表位的单域抗体。
在优选的实施方案中,抗原结合结构域包含一个根据本公开的单域抗体,其因此对FGFR4是特异性的,和另一个抗原结合结构域,其对另一种抗原是特异性的,因而提供双特异性抗原结合结构域。换言之,抗原结合结构域包含结合在于FGFR4的第一靶标的第一单域抗体和结合第二靶标的第二单域抗体。因此,在某些实施方案中,本公开涉及双特异性CAR。
如本文所用,术语“双特异性CAR”或“双特异性抗原结合结构域”因此是指对包括FGFR4的两个靶标具有特异性的多肽。因此,本文所述的双特异性结合分子可选择性地和特异性地结合表达(或在其细胞表面上展示)FGFR4和第二靶标的细胞。
在其他实施方案中,所述结合分子包含两个以上的抗原结合结构域,提供多特异性结合分子。因此,除了结合FGFR4之外,本文所述的多特异性抗原结合结构域还可结合一个或多个其他的靶标,即,多特异性多肽可结合至少两个、至少三个、至少四个、至少五个、至少六个或更多个靶标,其中多特异性多肽试剂分别具有至少两个、至少三个、至少四个、至少五个、至少六个或更多个靶标结合位点。
在一些实施方案中,可被根据本公开的多特异性CAR结合的其他抗原包括肿瘤抗原。在一些实施方案中,肿瘤抗原与血液恶性肿瘤或实体瘤相关。例如,肿瘤抗原可选自下组:PSMA、PSCA、BCMA、CS1、GPC3、CSPG4、EGFR、胎儿乙酰胆碱受体γ亚基γ(fAChRγ)、HER3、IgF1R、SLC19A1、ACVR2A、EPHB4、CA125、IL-13R、CD278、CD123、NCAM、5T4、CD2、CD3、CD16(FcγrIII)、CD23、MART-1、L1CAM、MUC16、ROR1、SLAMF7、cKit、CD38、CD53、CD56、CD71、CD74、CD92、CD100、CD123、CD138、CD148、CD150、CD200、CD261、CD262、CD276、CD362、gp100、ROR1、间皮素、CD33/IL3Ra、c-Met、Glycolipid F77、EGFRvIII、GD-2、NKp46受体、NY-ESO-1TCR或MAGE A3 TCR、人端粒酶逆转录酶(hTERT)、生存素、细胞色素P450 1B1(CY1 B)、HER2、Wilm’s肿瘤基因1(WT1)、凋亡抑制因子(livin)、甲胎蛋白(AFP)、癌胚抗原(CEA)、粘蛋白16、MUC1、p53、细胞周期蛋白、免疫检查点靶标或其组合。然而,技术人员可以理解,其他肿瘤抗原也是本公开范围内的靶标。
除以上详细描述的结合结构域之外,本公开的CAR还包含跨膜结构域。如本文所用,“跨膜结构域”(TMD)是指CAR的穿过质膜并与内质网信号转导结构域和抗原结合结构域连接的区域,后者情况下任选通过铰链连接。在一个实施方案中,本公开的CAR的跨膜结构域是跨膜蛋白(例如,I型跨膜蛋白)、人工疏水序列或其组合的跨膜区。在一些实施方案中,跨膜结构域包含CD3ζ结构域、CD28跨膜结构域、CD8α跨膜结构域、DAP10跨膜结构域或DAP12跨膜结构域。其他跨膜结构域对于本领域技术人员而言是显而易见的,且可以与本公开的替代实施方案结合使用。
DAP10和DAP12是与NK细胞中表达的大多数活化NKR和T细胞中表达的所有NKR配对的适配子(参见Chen X,Bai F,Sokol L,et al.A critical role for DAP10 and DAP12in CD8+T cell-mediated tissue damage in large granular lymphocyteleukemia.Blood.2009;113(14):3226-3234)。
在一些实施方案中,胞外结构域与铰链融合,铰链与结合结构域融合。铰链可以是包含2-50个氨基酸的任何接头氨基酸序列,诸如CD8铰链。
本公开的CAR还包含胞内信号转导结构域。“胞内信号转导结构域”、“胞质结构域”或“胞内域”是向T细胞传递活化信号并引导细胞进行其专有功能的结构域。转导效应子功能信号并可根据本公开使用的结构域的实例包括但不限于T细胞受体复合物的ζ链或其任何同源物(例如,η链、FcsRIy链和β链、MB1(IgA)链、B29(Ig)链等),人CD3ζ链,CD3多肽(Δ、δ和ε),Syk家族酪氨酸激酶(Syk、ZAP 70等),src家族酪氨酸激酶(Lck、Fyn、Lyn等)和来自参与T细胞转导的其他分子(例如CD2、CD5、OX40、CD28、DAP10和DAP12)的胞内结构域。其他胞内信号转导结构域对于本领域技术人员而言是显而易见的,且可与本公开的替代实施方案结合使用。在一些实施方案中,该胞内结构域,尤其选自DAP10、DAP12、CD28、4-1BB或人CD3ζ链的胞内结构域。
通常地,根据本公开的CAR可包含CD3ζ链和4-1BB的胞内结构域。
在一些实施方案中,CAR可包含其他的活化结构域(或胞内结构域),其包含至少一个其他的活化结构域的至少50、60、70、80、90、100、110、120、150或200个氨基酸的片段,所述其他的活化结构域选自CD3-ζ链(也简称为ζ)和共刺激受体CD28、4-1BB(CD137)、OX40(CD134)、LAG3、TRIM、HVEM、ICOS、CD27或CD40L的胞质结构域。在多种实施方案中,CAR包含其他活化结构域,所述其他的活化结构域包含至少20、30、40、50、60、70、80、90、100、110、120、150或200个氨基酸的片段,所述片段与上述其他的活化结构域的氨基酸序列享有至少90%以上,优选95%以上,更优选99%以上的同一性。
在一些实施方案中,本公开的CAR还包含一个或多个共刺激结构域以在抗原特异性接合后增强CAR-T细胞活性。在本公开的CAR中包含该结构域增强了记忆细胞的增殖、存活和/或发育。共刺激结构域位于细胞内。共刺激结构域是从选自下组的蛋白质获得的功能性信号转导结构域:CD3ζ、CD28、CD137(4-IBB)、CD134(OX40)、DapIO、CD27、CD2、CD5、ICAM-1、LFA-1(CD11a/CD18)、Lck、TNFR-I、TNFR-II、Fas、CD30、CD40、LAG3、TRIM、HVEM、ICOS、CD40L或其组合。其他共刺激结构域(例如来自其他蛋白质)对于本领域技术人员而言是显而易见的。多个共刺激结构域可包括在单个CAR中以募集多个信号转导途径。在一个实施方案中,共刺激结构域获自4-1BB。术语“4-1BB”是指具有以GenBank登录号AAA62478.2A提供的氨基酸序列的TNFR超家族的成员,或来自非人物种例如啮齿动物(例如小鼠或大鼠)、猴或猿的等同的残基。术语“4-1BB共刺激结构域”指GenBank登录号AAA62478.2的氨基酸残基214-255,或非人物种的等价残基,例如小鼠、啮齿动物、猴、猿等。
在一些实施方案中,本公开的CAR还包含连接胞外抗原结合结构域和跨膜结构域的铰链或间隔子区。该铰链或间隔子区可用于实现所得CAR的不同长度和柔性。可根据本公开使用的铰链或间隔子区的实例包括但不限于,抗体的Fc片段或其片段或衍生物,抗体的铰链区或其片段或衍生物,抗体的CH2区,抗体的CH3区,人工间隔子序列(例如肽序列)或其组合。其他铰链或间隔子区对于本领域技术人员来说是显而易见的,且可以与本公开的替代实施方案结合使用。在一个实施方案中,铰链是IgG4铰链或CD8A铰链。
在一些实施方案中,本公开的CAR还包含连接CAR的不同结构域的“接头结构域”或“接头区”。该结构域包括长度为约1-100个氨基酸的寡肽或多肽区。合适的接头对于本领域技术人员而言是显而易见的,且可与本公开的替代实施方案结合使用。
在一些实施方案中,本公开的CAR还包含“前导序列”。在一个实施方案中,前导序列是CD8A结构域。
本公开的CAR可还包括标记或标签。例如便于成像的标记,诸如荧光标记或其他标记(诸如myc)。这可以例如用于成像肿瘤结合的方法中。标记可与抗原结合区偶联。
本文所述的CAR可作为单个多肽链合成。在该实施方案中,抗原特异性靶向区位于N端,串联排列并被接头肽分开。
CAR设计的实例,尤其在Jaspers JE,Brentjens RJ.“Development of CAR Tcells designed to improve antitumor efficacy and safety”(Pharmacol Ther.2017;178:83–91)中提供。根据本公开的非常适合的CAR设计,尤其包括由Ying,Z.et al.(A safeand potent anti-CD19 CAR T cell therapy.Nat.Med.25,947–953(2019))以及June,C.H.,O’Connor,R.S.,Kawalekar,O.U.,Ghassemi,S.&Milone,M.C.(CAR T cellimmunotherapy for human cancer.Science(80-.).359,1361–1365(2018))所述的内容。根据本公开的其他合适的CAR构建体,尤其公开于WO2019077165中。有利地,根据本公开,其中所述的scFv结合结构域被一种或多种单域抗体替代,且包含至少一种本文所述的抗FGFR4单域抗体。
本文涉及的结果表明,由myc-标记的A8连接CD8α的铰链和跨膜结构域以及4-1BB和CD3ζ的胞内信号转导结构域组成的FGFR4-CAR T细胞在体外介导针对表达FGFR4的RMS细胞的显著抗肿瘤活性,并因此代表有希望的进一步靶向治疗选择。
核酸、载体、宿主细胞
本公开还提供了编码如前所述的单域抗体或其变体,或CAR的分离的核酸,以及包含其的核酸构建体。根据本公开的核酸可通过已知的重组DNA技术和/或化学DNA合成方法获得。与其具有至少60%、70%、80%或90%序列同一性的序列,也在本公开的范围内。
术语“核酸”、“多核苷酸”或“核酸分子”是指脱氧核糖核酸(DNA)或核糖核酸(RNA),或DNA或RNA的组合。RNA包括体外转录的RNA或合成的RNA;编码本文所述CAR多肽的mRNA序列。所述核酸还可包含自杀基因。所述构建体可以是质粒、载体、转录物或表达盒的形式。
因此,本公开还提供了包含根据本公开的核酸的重组表达盒,所述核酸在能够使所述核酸在宿主细胞中转录的调节的转录启动子控制下,所述核酸还可与合适的控制序列连接,从而能够调节其在宿主细胞中的翻译。
本公开还提供了包含根据本公开的核酸的重组载体(例如,重组表达载体)。有利地,所述重组载体是包含根据本公开的表达盒的重组表达载体。
如本文所用,术语“载体”是指能够增殖与其连接的另一核酸的核酸分子。该术语包括作为自我复制核酸结构的载体,以及整合到已引入宿主细胞基因组中的载体。某些载体能够引导与其可操作连接的核酸的表达。这些载体在本文中称为“表达载体”。
根据本公开内容的载体优选是适合于稳定基因转移和长期基因表达至哺乳动物细胞中的载体,诸如通过目标序列的复制,该序列的表达,该序列以染色体外形式维持,或整合至宿主的染色体材料中。所述重组载体使用标准重组DNA技术构建并使用本领域已知的常规方法产生。
在一些实施方案中,本公开的载体是整合载体,诸如整合病毒载体,诸如特别是逆转录病毒或AAV载体。优选地,病毒载体是慢病毒载体,最优选地是整合病毒载体。
在本公开的上下文中,“慢病毒载体”是指工程化用于将遗传物质递送至细胞中且需要以反式提供的慢病毒蛋白(例如,Gag、Pol和/或Env)的非复制性非致病性病毒。事实上,慢病毒载体缺乏功能性Gag、Pol和Env蛋白的表达。慢病毒载体有利地是自我失活载体(SIN载体)。慢病毒载体有利地包含中央多嘌呤区/DNA FLAP序列(cPPT-FLAP),和/或绝缘子序列(诸如鸡β-珠蛋白绝缘子序列)以提高目标基因的表达。慢病毒载体有利地用另一种包膜蛋白,优选另一种病毒包膜蛋白,优选水疱性口炎病毒(VSV)糖蛋白进行伪分型。在一些优选的实施方案中,所述慢病毒载体是人免疫缺陷病毒(HIV)载体。
慢病毒载体来源于慢病毒,特别是人免疫缺陷病毒(HIV-1或HIV-2)、猿猴免疫缺陷病毒(SIV)、马传染性脑炎病毒(EIAV)、山羊关节炎脑炎病毒(CAEV)、牛免疫缺陷病毒(BIV)和猫免疫缺陷病毒(FIV),其被修饰以除去参与致病性的基因决定簇并引入用于获得治疗效果的新决定簇。
取决于所述逆转录病毒载体的生产或开发阶段,慢病毒载体可以RNA或DNA分子的形式存在。慢病毒载体可以是重组DNA分子的形式,诸如质粒,或慢病毒载体颗粒的形式(在本公开的上下文中可互换地称为慢病毒颗粒),诸如慢病毒和其他蛋白质的复合物内的RNA分子。
这种载体基于顺式和反式作用序列的分离。为产生复制缺陷型载体,反式作用序列(例如,gag、pol、tat、rev和env基因)可被缺失并用编码转基因的表达盒替换。
在非分裂细胞中的有效整合和复制通常需要在慢病毒基因组的中心存在两个顺式作用序列,即中央多嘌呤区(cPPT)和中央终止序列(CTS)。这些导致形成称为中心DNA“瓣”的三链DNA结构,其作为信号用于在核孔处解除预整合复合物的包被以及将表达盒有效导入非分裂细胞(诸如树突细胞)的核中。在一个实施方案中,本公开包括慢病毒载体,其包含中央多嘌呤区和中央终止序列,称为cPPT/CTS序列,具体如欧洲专利申请EP 2 169073中所述。
其他序列通常以顺式存在,诸如长末端重复序列(LTR),其涉及将载体前病毒DNA序列整合至宿主细胞基因组中。载体可通过例如在所述LTR(AU3)的结构域U3中突变LTR序列而获得(Miyoshi H et al,1998,J Virol.72(10):8150-7;Zufferey et al.,1998,J V/ro/72(12):9873-80)。优选地,所述载体不含有增强子。在一个实施方案中,本公开包括慢病毒载体,其包含LTR序列,优选具有在3’LTR中去除启动子和增强子序列的突变的U3区(AU3)。
包装序列Ψ(psi)也可引入以帮助多核苷酸序列包封至载体颗粒中(Kessler etal.,2007,Leukemia,21(9):1859-74;Paschen et al.,2004,Cancer Immunol Immunother12(6):196-203)。在一个实施方案中,本公开涵盖包含慢病毒包装序列Ψ(psi)的慢病毒载体。
在本公开的慢病毒载体多核苷酸序列中还可有利地包括另外的功能序列,诸如转运RNA结合位点或引物结合位点(PBS)或Woodchuck转录后调控元件(WPRE),以获得转基因在体内更稳定的表达。还可以有利地包括在本公开的慢病毒载体多核苷酸序列中,以获得转基因在体内更稳定的表达。在一些实施方案中,本公开包括包含PBS的慢病毒载体。在一些实施方案中,本公开包括包含WPRE和/或IRES的慢病毒载体。
因此,在一个优选的实施方案中,慢病毒载体包含至少一个cPPT/CTS序列、一个Ψ序列、一个(优选2个)LTR序列和包含在β2ηη或I类MHC启动子的转录控制下的转基因的表达盒。
在本公开的一些实施方案中,本公开的载体(即重组转移载体)是包含用于在宿主细胞中表达靶融合蛋白的适当手段的表达载体。
各种启动子可用于驱动编码靶融合蛋白的核酸序列的高表达。启动子可以是组织特异性的、普遍存在的、组成型的或诱导型的启动子。优选的启动子,尤其在T细胞和/或NK细胞,优选人T细胞和人NK细胞中,具有功能。特别地,优选的启动子能够驱动来自慢病毒载体的靶融合蛋白(尤其是前述定义的CAR)在T细胞或NK细胞(优选人T细胞或NKT细胞)中的高表达。例如,根据本公开的启动子可选自磷酸甘油酸激酶启动子(PGK)、脾病灶形成病毒(SFFV)启动子、延伸因子-1α(EF-1α)启动子,包括所述启动子的短形式(EFS)、病毒启动子诸如巨细胞病毒(CMV)直接早期增强子和启动子、逆转录病毒5’和3’LTR启动子,包括杂合LTR启动子、人泛素启动子、MHC I类启动子、MHC II类启动子和β2微球蛋白(β2ηη)启动子。启动子有利地为人启动子,即来自人细胞或人病毒(诸如脾病灶形成病毒(SFFV))的启动子。更特别优选人泛素启动子、MHC I类启动子、MHC II类启动子和β2微球蛋白(β2ηη)启动子。优选地,MHC I类启动子是HLA-A2启动子、HLA-B7启动子、HLA-Cw5启动子、HLA-F或HLA-E启动子。在一些实施方案中,启动子不是CMV启动子/增强子,或不是dectin-2或MHC II启动子。这种启动子是本领域公知的,其序列可在序列数据库中获得。
通常地,慢病毒颗粒指由遗传物质组成的病毒的细胞外感染形式,所述遗传物质由被称为衣壳的蛋白质外壳包围的DNA或RNA(最优选单链RNA)制成,在一些情况下,被衣壳的脂质包膜包围。因此,慢病毒载体颗粒(或慢病毒颗粒)包含与病毒蛋白结合的前述定义的慢病毒载体。所述载体优选是整合型载体。
慢病毒颗粒的RNA序列可通过从插入宿主细胞基因组的双链DNA序列(前病毒载体DNA)转录获得,或可通过在转化的宿主细胞中瞬时表达质粒DNA(质粒载体DNA)获得。用于设计和制备慢病毒颗粒(特别是用于治疗应用)的合适方法是本领域公知的,例如描述于Merten OW,Hebben M,Bovolenta C.Production of lentiviral vectors.Mol TherMethods Clin Dev.2016Apr 13;3:16017。
优选地,慢病毒颗粒具有整合能力。因此,它们含有功能性整合酶蛋白。非整合载体颗粒具有一个或多个消除慢病毒载体颗粒的大部分或全部整合能力的突变。例如,非整合载体颗粒可能包含由慢病毒pol基因编码的整合酶的突变,其导致整合能力的降低。相反,整合载体颗粒包含功能性整合酶蛋白,其不含有消除慢病毒载体颗粒的大部分或全部整合能力的任何突变。
在一些实施方案中,本公开涵盖包含一种或多种载体的载体系统,所述载体包含:
(a)包含编码如前定义的嵌合抗原受体的核酸序列的核酸,
其中核酸(a)和(b)位于相同或分离的载体上。
优选的核酸(a)已在先前部分中描述。
当该载体系统包含多于一个载体,通常两个或更多个载体时,所述载体通常是相同类型的(例如:慢病毒载体)。在下面的部分中,所述载体也可被认为是“一个或多个载体”或“载体系统”。优选地,本发明包括慢病毒载体系统,尤其是慢病毒颗粒系统。
根据本发明,所述载体可以是表达载体。所述载体可以是质粒载体。
因此,在一个实施方案中,本公开包括载体,尤其是表达载体,最优选慢病毒载体,其包含编码如前定义的CAR蛋白的核酸。
本公开还涵盖病毒颗粒系统,其中一种或多种病毒颗粒包含病毒载体,通常是如前定义的整合病毒载体。优选地,病毒载体是慢病毒载体,病毒颗粒是慢病毒颗粒。
本公开还提供了含有本文公开的核酸构建体,尤其是根据本公开的重组表达盒或重组载体的宿主细胞。宿主细胞是原核或真核宿主细胞。术语“宿主细胞”是指已导入外源核酸的细胞,包括这些细胞的后代。宿主细胞包括“转化体”和“转化细胞”,其包括初级转化细胞和由其衍生的后代,而不考虑传代次数。后代的核酸含量可能与亲代细胞不完全相同,但可能含有突变。本文包括与在原始转化细胞中筛选或选择的具有相同功能或生物活性的突变后代。
本公开还提供了用于在如上定义的宿主细胞中产生多肽的方法,所述多肽由如上定义的单域抗体或CAR组成或包含如上定义的单域抗体或CAR,所述方法包括以下步骤:
-提供含有根据本公开的核酸构建体、重组表达盒或重组载体的宿主细胞,
-培养所述宿主细胞,
-以及任选地纯化本公开的单域抗体或CAR。
纯化多肽的方法是本领域熟知的,诸如色谱法(例如离子交换色谱、凝胶渗透色谱和反相色谱)。
本公开还涵盖包含本文公开的核酸构建体的组合物。
免疫细胞及其获得方法
本公开还提供了分离的细胞、细胞群、细胞系或细胞培养物,其包含如前所述的核酸构建体,尤其是载体,更特别是编码如前所述的至少一种或多种CAR的病毒载体颗粒。
在一个实施方案中,细胞含有整合至细胞基因组中的载体和/或病毒载体颗粒。在一个实施方案中,细胞含有稳定表达CAR的载体。在一个实施方案中,细胞产生编码CAR的慢病毒载体颗粒。
所述细胞优选是哺乳动物细胞,特别是人细胞。特别优选的是人非分裂细胞。优选地,所述细胞是免疫细胞。如本文所用,术语“免疫细胞”包括造血来源的并在免疫应答中起作用的细胞。免疫细胞包括淋巴细胞,诸如B细胞和T细胞、自然杀伤细胞(NK细胞)、骨髓细胞,诸如单核细胞、巨噬细胞、嗜酸性粒细胞、肥大细胞、嗜碱性粒细胞和粒细胞。
如本文所用,术语“T细胞”包括携带T细胞受体(TCR)的细胞,根据本公开的T细胞可选自下组:炎性T淋巴细胞、细胞毒性T淋巴细胞、调节性T淋巴细胞、粘膜相关的不变T细胞(MAIT)、YδT细胞、肿瘤浸润淋巴细胞(TIL)或辅助T淋巴细胞,包括1型和2型辅助T细胞和Th17辅助细胞。在另一个实施方案中,所述细胞可来源于下组:CD4+T淋巴细胞和CD8+T淋巴细胞。
所述免疫细胞可以源自健康供体或源自患有癌症的受试者。
免疫细胞可从血液中提取或源自干细胞。干细胞可以是成体干细胞、胚胎干细胞,更特别是非人干细胞、脐带血干细胞、祖细胞、骨髓干细胞、诱导的多功能干细胞、全能干细胞或造血干细胞。代表性的人细胞是CD34+细胞。
T细胞可从许多非限制性来源获得,包括外周血单核细胞、骨髓、淋巴结组织、脐带血、胸腺组织,来自感染部位的组织、腹水、胸腔积液、脾组织和肿瘤。在某些实施方案中,可使用本领域技术人员已知的任何数量的技术,诸如FICOLLTM分离,从收集自受试者的血液单位获得T细胞。在一个实施方案中,通过单采血液成分术获得来自受试者循环血液的细胞。在某些实施方案中,T细胞分离自PBMC。PBMC可以从通过全血的密度梯度离心获得的血沉棕黄层分离,例如通过LYMPHOPREPTM梯度、PERCOLLTM梯度或FICOLLTM梯度离心。T细胞可通过去除单核细胞从PBMC中分离,例如通过使用CD14在一些实施方案中,可以在密度梯度离心前裂解红细胞。
在另一个实施方案中,所述细胞可来自健康供体,来自诊断患有癌症,尤其是患有尤因肉瘤的受试者。所述细胞可以是自体的或同种异体的。
在异源免疫细胞治疗中,从健康供体而非患者收集免疫细胞。通常,这些是HLA匹配的,以降低移植物抗宿主病的可能性。或者,可能不需要HLA匹配的通用“现成”产品包含经设计以减少移植物抗宿主病的修饰,诸如TCRαβ受体的破坏或移除。参见Graham et al.,Cells.2018Oct;7(10):155的综述。因为单一基因编码α链(TRAC)而非编码β链的两个基因,所以TRAC基因座是去除或破坏TCRαβ受体表达的典型靶标。或者,可表达TCRαβ信号转导的抑制剂,例如CD3ζ的截短形式可充当TCR抑制分子。还使用了I类HLA分子的破坏或去除。例如,Torikai et al.,Blood.2013;122:1341–1349使用ZFN敲除HLA-A基因座,而Ren etal.,Clin.Cancer Res.2017;23:2255–2266敲除HLA I类表达所需的β-2微球蛋白(B2M)。Ren等同时敲除TCRαβ、B2M和免疫检查点PD1。通常,免疫细胞被活化并扩增以用于过继性细胞治疗。本文公开的免疫细胞可在体内或离体扩增。免疫细胞,特别是T细胞通常可用本领域已知的方法活化和扩增。通常,T细胞通过与表面接触而扩增,该表面附着有刺激CD3/TCR复合物相关信号的试剂和刺激T细胞表面上的共刺激分子的配体。
通常地,免疫细胞被修饰以表达本文公开的嵌合抗原受体。多种肿瘤特异性靶标的表达可通过突变或减少靶抗原的表达来减少抗原逃逸的机会。如前所述,本公开的CAR可以是多特异性CAR(即抗多于一种抗原,即抗FGFR4和至少另一种抗原)。此外,或替换地,本文所述的免疫细胞可表达本文定义的一种或多种CAR和靶向一种或多种其他抗原的至少另一种CAR。
可基因修饰免疫细胞以表达重组抗原受体的方法是本领域熟知的。编码抗原受体的核酸分子可以,以例如载体或任何其他合适的核酸构建体的形式导入细胞中。载体及其所需组分是本领域熟知的。编码抗原受体的核酸分子可使用本领域已知的任何方法产生,例如使用PCR的分子克隆。抗原受体序列可用常用方法修饰,诸如定点诱变。
在另一方面,本公开涉及用于产生用于过继性免疫治疗的细胞群的离体方法,其包括用本文所述的CAR转化所述细胞。
本公开的组合物和试剂盒
本公开还包括药物组合物,其包含一种或多种抗FGFR4单域抗体,CAR,编码其的核酸构建体和/或一种或多种包含本文公开的CAR的分离的细胞或细胞群,单独或与至少一种其他试剂(诸如稳定化合物)组合,其可在任何无菌的、生物相容的药物载体中施用且任选地与无菌的药学上可接受的缓冲液、稀释剂和/或赋形剂一起配制。药学上可接受的载体通常增强或稳定组合物,和/或可用于实施组合物的制备。药学上可接受的载体包括溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等,它们是生理上相容的,且在一些实施方案中是药学上惰性的。在一些实施方案中,根据本公开的药物组合物包含与如前公开的药物纳米载体连接的如本文公开的抗FGFR4单域抗体。通常,用本文公开的抗FGFR4sdAb双官能化的所述药物纳米载体包封治疗(例如细胞毒性化合物)或诊断化合物。在特别的实施方案中,所述药物纳米载体是脂质体。
包含本文公开的sdAb的药物组合物的施用可通过口服或胃肠外完成。肠胃外递送的方法包括局部、动脉内(直接至肿瘤)、肌内、脊柱、皮下、髓内、鞘内、心室内、静脉内、腹膜内或鼻内施用。
本公开的基因修饰的细胞或药物组合物可通过任何方便的途径施用,包括肠胃外施用。肠胃外施用包括,例如静脉内、肌内、动脉内、腹膜内、鼻内、直肠、膀胱内、皮内、局部或皮下施用。组合物可采取一个或多个剂量单位的形式。
因此,除了活性成分之外,这些药物组合物可含有合适的药学上可接受的载体,包括赋形剂和助剂,其有助于将活性化合物加工成可药用的制剂。关于制剂和施用技术的更多细节可参考在最新版的Remington's Pharmaceutical Sciences(Ed.Maack PublishingCo,Easton,Pa.)。
根据施用途径,可将单域抗体或其变体包衣在材料中以保护化合物免受酸和其他可使化合物失活的天然条件的作用。
组合物通常是无菌的且优选是流体。例如,通过使用包衣诸如卵磷脂,在分散体的情况下通过维持所需的粒度,和通过使用表面活性剂,可以维持适当的流动性。在许多情况下,组合物中优选包括等渗剂,例如糖、多元醇(诸如甘露醇或山梨醇),和氯化钠。可注射组合物的长期吸收可通过在组合物中包括延迟吸收的试剂(例如单硬脂酸铝或明胶)来实现。
用于口服施用的药物组合物可使用本领域熟知的药学上可接受的载体以适于口服施用的剂量配制。此类载体使得药物组合物能够配制成片剂、丸剂、糖衣丸、胶囊、液体、凝胶、糖浆、浆液、悬浮液等,以供患者服用。
用于口服使用的药物制剂可通过将活性化合物与固体赋形剂组合,任选地研磨所得混合物,且如果需要,在加入合适的辅剂后加工颗粒混合物以获得片剂或糖衣丸芯来获得。合适的赋形剂是碳水化合物或蛋白质填充剂,诸如糖,包括乳糖、蔗糖、甘露醇或山梨醇;来自玉米、小麦、水稻、马铃薯或其他植物的淀粉;纤维素,诸如甲基纤维素、羟丙基甲基纤维素或羧甲基纤维素钠;以及树胶,包括阿拉伯树胶和黄芪胶;以及蛋白质,诸如明胶和胶原。若需要,可加入崩解剂或增溶剂,诸如交联聚乙烯吡咯烷酮、琼脂、海藻酸或其盐,诸如海藻酸钠。
糖衣丸芯具有合适的包衣,诸如浓缩的糖溶液,其还可含有阿拉伯胶、滑石、聚乙烯吡咯烷酮、卡波普凝胶、聚乙二醇和/或二氧化钛、漆溶液和合适的有机溶剂或溶剂混合物。可将染料或颜料加入到片剂或糖衣丸包衣中,用于产品鉴定,或表征活性化合物的量,即剂量。
可口服使用的药物制剂包括由明胶制成的推入配合(push-fit)胶囊,以及由明胶和包衣(诸如甘油或山梨醇)制成的密封软胶囊。推入配合胶囊可含有与填充剂或结合物(诸如乳糖或淀粉),润滑剂(诸如滑石或硬脂酸镁)和任选的稳定剂混合的活性成分。在软胶囊中,活性化合物可溶解或悬浮在合适的液体中,诸如脂肪油、液体石蜡或液体聚乙二醇,有或没有稳定剂。
用于肠胃外施用的药物制剂包括活性化合物的水溶液。对于注射,本公开的药物组合物可配制在水溶液中,优选在生理上相容的缓冲液中,诸如Hank’s溶液、Ringer’s溶液或生理缓冲盐水。水性注射悬浮液可含有增加悬浮液粘度的物质,诸如羧甲基纤维素钠、山梨糖醇或葡聚糖。此外,活性化合物的混悬液可制备为合适的油性注射混悬液。合适的亲脂性溶剂或载体包括脂肪油(诸如芝麻油),或合成脂肪酸酯诸如油酸乙酯或甘油三酯,或脂质体。任选地,悬浮液还可含有合适的稳定剂或增加化合物溶解度以可制备高度浓缩溶液的试剂。
对于局部或鼻部施用,在制剂中使用适于待渗透的特定屏障的渗透剂。这种渗透剂通常是本领域已知的。
本公开的药物组合物可根据本领域熟知和常规实践的方法制备。参见,例如,Remington:The Science and Practice of Pharmacy,Mack Publishing Co.,20th ed.,2000;以及Sustained and Controlled Release Drug Delivery Systems,J R.Robinson,ed.,Marcel Dekker,Inc.,New York,1978.药物组合物优选在GMP条件下制备。
在治疗特定病症或病状中有效/有活性的本公开的药物组合物的量将取决于病症或病状的性质,且可通过标准临床技术来确定。此外,可任选地使用体外或体内测定来帮助确定最佳剂量范围。用于组合物中的精确剂量还将取决于施用途径和疾病或病症的严重性,且应根据从业者的判断和每个患者的情况来决定。
本文公开的组合物包含有效量的本公开的结合分子(例如单域抗体或其变体或嵌合抗原受体),从而获得合适的剂量。化合物的正确剂量将根据具体制剂,施用方式及其具体部位,宿主和所治疗的疾病而变化。其他因素,如年龄、体重、性别、饮食、施用时间、排泄速率、宿主状况、药物组合、反应敏感性和疾病的严重程度应当考虑。施用可在最大耐受剂量内连续或周期性地进行。
通常,该量为,按所述组合物的重量计,至少约0.01%的本公开的结合分子。制备本公开的优选组合物,以使得肠胃外剂量单元含有约0.01重量%-约2重量%的本公开的结合分子。
对于静脉内施用,组合物可通常包含动物体重的约0.1mg/kg至约250mg/kg,优选动物体重的约0.1mg/kg至约20mg/kg,更优选动物体重的约1mg/kg至约10mg/kg。
本发明的组合物可采用合适载体的形式,诸如气雾剂、喷雾剂、混悬剂或任何其他适合使用的形式。合适的药物载体的其他实例描述于E.W.Martin的"Remington'sPharmaceutical Sciences"中。
本文公开的药物组合物可与其他治疗剂供体使用,例如抗癌剂。
医药用途
本公开还涉及本文所述的抗FGFR4单域抗体或其变体,本文所述的抗FGFR4的CAR或其变体,编码所述抗FGFR4单域抗体或CAR的核酸,或包含本文所述的CAR的细胞、细胞系或细胞群,其用于治疗,特别是用于治疗癌症。本公开还涉及本文所述的抗FGFR4单域抗体或其变体,本文所述的抗FGFR4的CAR或其变体,编码所述抗FGFR4单域抗体或CAR的核酸,或包含本文所述的所述CAR的细胞、细胞系或细胞群,其用于制备药物,尤其是用于治疗癌症。
本公开还涵盖用于预防和/或治疗癌症的方法,其包括向受试者施用如本文所述的抗FGFR4单域抗体或其变体,如本文所述的抗FGFR4的CAR或其变体,编码所述抗FGFR4单域抗体或CAR的核酸,或包含如本文所述的CAR的细胞、细胞系或细胞群,所述方法包括向有需要的受试者施用药学活性量的抗FGFR4单域抗体或其变体,CAR,包含如本文所述的CAR的细胞、细胞系或细胞群和/或本公开的药物组合物。该方法可另外包括鉴定患有癌症的受试者的步骤。
本公开还包括抗FGFR4单域抗体或其变体,抗FGFR4的CAR或其变体,编码所述抗FGFR4单域抗体或CAR的核酸,在靶向免疫治疗中的包含如本文所述的CAR的细胞系或细胞群。例如,本公开的sdAb,特别是以进一步靶向免疫细胞抗原的多特异性多肽形式的其变体,和表达CAR的免疫细胞(尤其是CAR T细胞)可用于免疫细胞重定向免疫治疗。
在另一方面,本公开涉及在受试者中刺激响应于靶细胞群或组织的T细胞介导的免疫应答的方法,所述方法包括向受试者施用有效量的表达如本文所述的抗FGFR4的CAR的细胞或细胞群。
在另一方面,本公开涉及在受试者中提供抗肿瘤免疫的方法,所述方法包括向哺乳动物施用有效量的经基因修饰以表达如本文所述的抗FGFR4的CAR的细胞或细胞群,从而在受试者中提供抗肿瘤免疫。
本公开还涉及抗FGFR4单域抗体(包括其变体),如本文所述的抗FGFR4的CAR,或编码所述人源化抗FGFR4 sdAb或CAR的核酸构建体,或如前所定义的表达所述CAR的免疫细胞,其用于受试者中的过继性细胞或CAR-T细胞治疗。通常地,用于本公开的方法的免疫细胞是重定向的T细胞,例如重定向的CD8+和/或CD4+T细胞。
在一些实施方案中,本文所述的抗FGFR4单域抗体(包括其变体)和抗FGFR4的CAR以及编码它们的核酸构建体和包含此类CAR的细胞可用于抑制肿瘤生长、诱导分化、减小肿瘤体积和/或减小肿瘤的致瘤性。使用方法可以是体外、离体或体内方法。
在本文所述的医药用途的具体实施方案中,抗FGFR4 sdAb如前所述与药物纳米载体(诸如脂质体)连接。用本文所述的一种或多种抗FGFR4 sdAb官能化的所述药物纳米载体,尤其是这种脂质体,通常包封治疗化合物(诸如细胞毒性化合物)或诊断化合物。
在某些方面,受试者是人,尤其是儿科患者。在某些方面,受试者患有肿瘤或已经切除肿瘤。受试者还可能处于癌症发展期的风险中。
癌症可以是实体癌或液体肿瘤。可通过本文所述的方法、用途和组合物治疗的癌症包括但不限于来自膀胱、血液、骨、骨髓、脑、乳腺、结肠、食道、胃肠道、牙龈、头、肾、肝、肺、鼻咽、颈、卵巢、前列腺、皮肤、胃、睾丸、舌或子宫的癌细胞。此外,癌症可具体为以下组织学类型,但不限于这些:恶性赘生物;癌瘤;癌瘤,未分化的;巨和梭形细胞癌;小细胞癌;乳头状癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母细胞癌;移行细胞癌;乳头状移行细胞癌;腺癌;恶性胃泌素瘤;胆管癌;肝细胞癌;联合肝细胞癌和胆管癌;小梁腺癌;腺样囊性癌;腺瘤性息肉中的腺癌;腺癌,家族性结肠息肉病;实体癌;恶性类癌瘤;鳃-肺泡腺癌;乳头状腺癌;嫌色细胞癌;嗜酸细胞癌;嗜酸性腺癌;嗜碱性细胞癌;透明细胞腺癌;颗粒细胞癌;滤泡性腺癌;乳头状和滤泡性腺癌;非包封硬化癌;肾上腺皮质癌;子宫内膜样癌;皮肤附属器癌;顶泌腺癌;皮脂腺癌;蜡样腺癌;粘液表皮样癌;囊腺癌;乳头状囊腺癌;乳头状浆液性囊腺癌;粘液性囊腺癌;粘液性腺癌;印戒细胞癌;浸润性导管癌;髓样癌;小叶癌;炎性癌;佩吉特氏病,乳腺;腺泡细胞癌;腺鳞癌;腺癌伴鳞状化生;恶性胸腺瘤;卵巢基质瘤,恶性;恶性淋巴瘤;恶性颗粒细胞瘤;恶性,足细胞癌;恶性间质细胞瘤;恶性脂质细胞瘤;恶性副神经节瘤;乳房外副神经节瘤,恶性;嗜铬细胞瘤;血管肉瘤;恶性黑素瘤;无色素性黑素瘤;浅表扩散性黑素瘤;巨大色素性痣中的恶性黑素瘤;上皮样细胞黑素瘤;蓝色痣,恶性;肉瘤;纤维肉瘤;恶性纤维组织细胞瘤;粘液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤(RMS);胚胎性横纹肌肉瘤;肺泡横纹肌肉瘤;基质肉瘤;恶性肿瘤;米勒混合瘤;肾母细胞瘤;肝母细胞瘤;癌肉瘤;间质瘤,恶性的;布伦纳瘤,恶性;叶状肿瘤,恶性;滑膜肉瘤;间皮瘤,恶性;无性细胞瘤;胚胎性癌;畸胎瘤,恶性;卵巢瘤,恶性;绒毛膜癌;中肾瘤,恶性;血管肉瘤;血管内皮瘤,恶性;卡波济肉瘤;恶性血管外皮细胞瘤;淋巴管肉瘤;骨肉瘤;近皮质骨肉瘤;软骨肉瘤;恶性软骨母细胞瘤;间充质软骨肉瘤;骨巨细胞瘤;尤文氏肉瘤;牙源性肿瘤,恶性;成釉细胞的牙肉瘤;恶性成釉细胞瘤;成釉细胞的纤维肉瘤;恶性松果体瘤;脊索瘤;神经胶质瘤,恶性;室管膜瘤;星形细胞瘤;原生质星形细胞瘤;纤维性星形细胞瘤;星形母细胞瘤;胶质母细胞瘤;少突神经胶质瘤;少突胶质细胞瘤;原始神经外胚层;小脑肉瘤;神经节神经母细胞瘤;成神经细胞瘤;成视网膜细胞瘤;嗅觉神经源性肿瘤;恶性脑膜瘤;神经纤维肉瘤;神经鞘瘤,恶性;颗粒细胞瘤,恶性的;恶性淋巴瘤;霍奇金病;霍奇金淋巴瘤;副肉芽肿;恶性淋巴瘤,小淋巴细胞;恶性淋巴瘤,大细胞,弥漫性;恶性淋巴瘤,滤泡性;蕈样肉芽肿病;其他指定的非霍奇金氏淋巴瘤;恶性组织细胞增多症;多发性骨髓瘤;肥大细胞肉瘤;免疫增生性小肠疾病;白血病;淋巴样白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;髓样白血病;嗜碱性白血病;嗜酸性白血病;单核细胞白血病;肥大细胞白血病;巨核细胞白血病;髓样肉瘤;和毛细胞白血病。
可根据本公开治疗和/或预防的更具体的癌症包括FGFR4介导的癌症。通常,FGFR4介导的癌症是FGFR4被表达或过表达的癌症。表达和/或过表达FGFR4的典型癌症包括肝细胞癌(HCC)、乳腺癌、口咽鳞状细胞癌、口腔鳞状细胞癌、胰腺癌和衍生细胞系和横纹肌肉瘤(RMS)。
在一些实施方案中,如上所述的癌症治疗和/或过继性细胞癌症治疗与其他的癌症治疗组合施用。在一些实施方案中,如上所述的癌症治疗和/或过继性细胞癌症治疗与靶向治疗、免疫治疗诸如免疫检查点治疗和免疫检查点抑制剂、共刺激抗体、化疗和/或放疗组合施用。
免疫检查点治疗诸如检查点抑制剂包括但不限于程序性死亡-1(PD-1)抑制剂、程序性死亡配体-1(PD-L1)抑制剂、程序性死亡配体-2(PD-L2)抑制剂、淋巴细胞活化基因3(LAG3)抑制剂、含有蛋白3(TIM-3)的T细胞免疫球蛋白和粘蛋白结构域抑制剂、具有Ig和ITIM结构域(TIGIT)的T细胞免疫受体抑制剂、B-和T-淋巴细胞衰减剂(BTLA)抑制剂、T-细胞活化(VISTA)的V-结构域Ig抑制子抑制剂、细胞毒性T-淋巴细胞相关蛋白4(CTLA4)抑制剂、吲哚胺2,3-双加氧酶(IDO)抑制剂、杀伤免疫球蛋白样受体(KIR)抑制剂、KIR2L3抑制剂、KIR3DL2抑制剂和癌胚抗原相关细胞粘附分子1(CEACAM-1)抑制剂。特别地,检查点抑制剂包括抗体,抗PD1、抗PD-L1、抗CTLA-4、抗TIM-3、抗LAG3。共刺激抗体通过免疫调节受体递送阳性信号,所述免疫调节受体包括但不限于ICOS、CD137、CD27、OX-40和GITR。
抗PD1抗体的实例包括但不限于纳武单抗(nivolumab)、西米普利单抗(cemiplimab)(REGN2810或REGN-2810)、替雷利珠单抗(tisellizumab)(BGB-A317)、替雷利珠单抗、spartalizumab(PDR001或PDR-001)、ABBV-181、JNJ-63723283、BI 754091、MAG012、TSR-042、AGEN2034、pidilizumab、纳武单抗(ONO-4538、BMS-936558、MDX1106、GTPL7300或Opdivo)、帕博利珠单抗(pembrolizumab)(MK-3475、MK03475、lambrolizumab、SCH-900475或Keytruda)和国际专利申请WO2004004771、WO2004056875、WO2006121168、WO2008156712、WO2009014708、WO2009114335、WO2013043569和WO2014047350中描述的抗体。
抗PD-L1抗体的实例包括但不限于LY3300054、阿替利珠单抗(atezolizumab)、度伐利尤单抗(durvalumab)和阿维鲁单抗(avelumab)。
抗CTLA-4抗体的实例包括但不限于伊匹单抗(ipilimumab)(参见例如美国专利US6,984,720和US 8,017,114),替西木单抗(tremelimumab)(参见,例如美国专利US 7,109,003和US 8,143,379),单链抗CTLA-4抗体(参见,例如国际专利申请WO1997020574和WO2007123737)和美国专利US 8,491,895中所述的抗体。
抗VISTA抗体的实例描述于美国专利申请US20130177557中。
LAG3受体抑制剂的实例描述于美国专利US 5,773,578中。
KIR抑制剂的实例是靶向KIR3DL2的IPH4102。
如本文所用,术语“化疗”具有其在本领域中的一般含义且是指包括向患者施用化疗剂的治疗。本文所用的化疗实体是指对细胞具有破坏性的实体,即降低细胞活力的实体。化疗实体可以是细胞毒性药物。化疗剂包括但不限于烷化剂,诸如塞替派和环磷酰胺;烷基磺酸盐,诸如白消安,英丙舒凡和哌泊舒凡;氮丙啶类,诸如苯佐替派、卡波醌、美妥替派和乌瑞替派;乙撑亚胺和甲基蜜胺,包括六甲蜜胺,三乙撑蜜胺,三乙撑磷酰胺、三乙撑硫代磷酰胺和三羟甲蜜胺;番荔枝内酯类(尤其是布拉他辛和布拉他辛酮);喜树碱(包括合成的类似物托泊替康);苔藓抑素;卡利他汀(callystatin);CC-1065(包括其阿多来新、卡折来新和比折来新合成类似物);隐藻素类(特别是隐藻素1和隐藻素8);多拉司他汀;倍癌霉素(包括合成类似物,KW-2189和CB1-TM1);艾榴塞洛素;水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑素;氮芥类,诸如苯丁酸氮芥、萘氮芥、胆磷酰胺、雌莫司汀、异环磷酰胺、双氯乙基甲胺、盐酸氧氮芥、美法仑、新氮芥、苯芥胆甾醇、泼尼莫司汀、曲磷胺、尿嘧啶氮芥;亚硝脲类,诸如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀;抗生素类,诸如烯二炔类抗生素(例如,卡奇霉素,尤其是卡奇霉素γII和卡奇霉素ωII;达内霉素(dynemicin),包括达内霉素A;双膦酸盐,诸如氯膦酸盐;埃斯波霉素;以及新制癌素发色团和相关色蛋白烯二炔类抗生素发色团、阿克拉霉素、放线菌素、氨茴霉素、偶氮丝氨酸、博来霉素、放线菌素C、卡柔比星(carabicin)、洋红霉素、嗜癌霉素、色霉素、放线菌素D、柔红霉素、地托比星、6-二氮-5-氧代-L-正亮氨酸、多柔比星(包括吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯代多柔比星和脱氧多柔比星)、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素,诸如丝裂霉素C、霉酚酸、诺拉霉素、橄榄霉素、培洛霉素、泊非霉素、嘌呤霉素、三铁阿霉素、罗多比星、链黑菌素、链佐星、杀结核菌素、乌苯美司、净司他丁和佐柔比星;抗代谢物诸如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,诸如地诺蝶呤、甲氨蝶呤、蝶罗呤、三甲曲沙;嘌呤类似物如氟达拉滨、6-巯基嘌呤、硫米嘌呤、硫鸟嘌呤;嘧啶类似物,诸如环胞苷、阿扎胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、双脱氧尿苷、去氧氟尿苷、依诺他滨、氟尿苷;雄激素,诸如卡鲁睾酮、丙酸屈他雄酮、环硫雄醇、美匹硫坦、睾内酯;抗肾上腺药物,诸如氨鲁米特、米托坦、曲洛司坦等;叶酸补充剂,诸如亚叶酸;醋格列酮;醛磷酰胺苷;氨基乙酰丙酸;恩尿嘧啶;安吖啶;苯丁酸氮芥;比生群;依达曲沙;地磷酰胺;地美考霉素;二氮喹酮;依美鸟氨酸;依利醋铵;埃坡霉素;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达宁;美登木素生物碱,例如美登素和柄型菌素;米托胍腙;米托蒽醌;单哌潘醇;硝胺;喷司他丁;非那西普;吡柔比星;洛索蒽醌;足叶草酸;2-乙基酰肼;甲基肼衍生物,包括N-甲基肼(MIH)和丙卡巴肼;PSK多糖复合物);雷佐生;根毒素;西佐呋喃;螺锗;替诺唑酸;三氮喹酮;2,2’,2”-三氯三乙胺;单端孢霉烯(尤其是T-2毒素,疣孢菌素A,杆孢菌素A和蛇行菌素);氨酯;长春地辛;达卡巴嗪;甘露莫司汀;二溴甘露醇;二溴卫矛醇;哌泊溴烷;肌肽;阿拉伯糖苷(“Ara-C”);环磷酰胺;噻替派;紫杉烷类,例如紫杉醇和多西他赛;苯丁酸氮芥;吉西他滨;6-硫代鸟嘌呤;巯嘌呤;甲氨蝶呤;铂配位络合物如顺铂,奥沙利铂和卡铂;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨;诺万特龙;替尼泊苷;依达曲沙;道诺霉素;氨基蝶呤;希罗达;伊班膦酸钠;伊立替康(例如,CPT-11);拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(DMFO);类视黄醇,诸如视黄酸;卡培他滨;蒽环类抗生素,亚硝基脲,抗代谢物,表鬼臼毒素,酶如L-天冬酰胺酶;蒽二酮;激素和拮抗剂,包括肾上腺皮质激素拮抗剂,诸如泼尼松和等效物,地塞米松和氨鲁米特;孕激素,诸如己酸羟孕酮,醋酸甲羟孕酮和醋酸甲地孕酮;雌激素如己烯雌酚和乙炔雌二醇等价物;抗雌激素药,诸如他莫昔芬;雄激素,包括丙酸睾酮和氟甲睾酮/等价物;抗雄激素药,诸如氟他胺,促性腺激素释放激素类似物和亮丙立德;以及非甾族抗雄激素药如氟他胺;生物反应调节剂,诸如IFNα、IL-2、G-CSF和GM-CSF;以及任何上述化合物的药学上可接受的盐、酸或衍生物。
放疗的合适实例包括但不限于外束放疗(例如表面X射线治疗、正电压X射线治疗、兆伏电压X射线治疗、放射外科手术、立体定向放射治疗、分割立体定向放射治疗、钴治疗、电子治疗、快中子治疗、中子俘获治疗、质子治疗、强度调制放射治疗(IMRT)、三维适形放射治疗(3D-CRT)等);短距离放射治疗;非密封源放射治疗;断层治疗;等等。γ射线是放射治疗中使用的光子的另一种形式。当某些元素(诸如镭、铀和钴60)在分解或衰变时释放辐射时,自然产生γ射线。在一些实施方案中,放射治疗可以是质子放射治疗或质子微束放射治疗。质子放射治疗是使用质子束的超精确形式的放射治疗(Prezado Y,Jouvion G,Guardiola C,Gonzalez W,Juchaux M,Bergs J,Nauraye C,Labiod D,De Marzi L,Pouzoulet F,Patriarca A,Dendale R.Tumor Control in RG2 Glioma-Bearing Rats:AComparison Between Proton Minibeam Therapy and Standard Proton Therapy.Int JRadiat Oncol Biol Phys.2019Jun 1;104(2):266-271.doi:10.1016/j.ijrobp.2019.01.080;Prezado Y,Jouvion G,Patriarca A,Nauraye C,Guardiola C,Juchaux M,Lamirault C,Labiod D,Jourdain L,Sebrie C,Dendale R,Gonzalez W,Pouzoulet F.Proton minibeam radiation therapy widens the therapeutic indexfor high-grade gliomas.Sci Rep.2018Nov 7;8(1):16479.doi:10.1038/s41598-018-34796-8)。放射治疗也可以是FLASH放射治疗(FLASH-RT)或FLASH质子照射。FLASH放射治疗涉及超快速的放射治疗,剂量率比目前常规临床实践高出几个数量级(超高剂量率)(Favaudon V,Fouillade C,Vozenin MC.The radiotherapy FLASH to save healthytissues.Med Sci(Paris)2015;31:121-123.DOI:10.1051/medsci/20153102002);Patriarca A.,Fouillade C.M.,Martin F.,Pouzoulet F.,Nauraye C.,etal.Experimental set-up for FLASH proton irradiation of small animals using aclinical system.Int J Radiat Oncol Biol Phys,102(2018),pp.619-626.doi:10.1016/j.ijrobp.2018.06.403.Epub2018Jul 11)。
“组合”可指在施用根据本公开的T细胞组合物之前,同时或之后施用其他治疗。
此外,或作为与检查点阻断的组合的替代方案,还可使用包括但不限于TALEN和Crispr/Cas的基因编辑技术基因修饰本公开的T细胞组合物以使它们对免疫检查点具有耐药性。这些方法是本领域已知的,参见例如US20140120622。基因编辑技术可用于预防由T细胞表达的免疫检查点的表达(参见以上列出的检查点抑制剂),且更特别地但不限于PD-1、Lag-3、Tim-3、TIGIT、BTLA CTLA-4及其组合。本文所述的T细胞可通过这些方法中的任一种进行修饰。
根据本公开的T细胞还可被基因修饰以表达增加归巢到肿瘤中和/或将炎性介质递送到肿瘤微环境中的分子,包括但不限于细胞因子、可溶性免疫调节受体和/或配体。
已如此描述了本公开的不同实施例,本领域技术人员应当注意,本文的公开仅是示例性的,且在本公开的范围内可进行各种其他替换、变换和修饰。因此,本公开不限于本文所阐述的具体实施方案。
分子成像和诊断工具
本文公开的纳米抗体在分子成像和诊断(体外和体内)中引起很高的兴趣,通常将成像剂(诸如放射性核素)靶向体内目标细胞。因此,根据本发明,纳米抗体靶向成像可用于多种目的,包括诊断疾病、监测疾病进展和预测对特定治疗剂(特别是对本文公开的抗FGFR4试剂,诸如抗FGFR4 sdAb)的响应。
纳米抗体可以通过检测或定义生物标记而有助于早期诊断和癌症预防。由于其高特异性,纳米抗体可改进基于目前mAb的诊断技术。此外,它们在极端温度、pH或离子强度下的高稳定性确保该应用仍可在苛刻条件下进行。
小尺寸的纳米抗体非常有利,尤其是在分子成像领域,因为其能够实现快速的肿瘤积累和均匀分布以及有效的血液清除,有助于高的肿瘤-背景比。
用于分子成像和/或作为诊断工具的本文所述的纳米抗体可以容易地与几种成像剂偶联,且它们的高特异性使得它们的使用相对安全。
在一些实施方案中,本文公开的纳米抗体可以偶联至放射性核素以用于放射成像。单光子发射计算机断层摄影术(SPECT)基于γ-射线,因此本公开的sdAb可连接至较长寿命的放射性核素,诸如99mTc、177Lu、123I、125I和111In。另一方面,短寿命放射性核素诸如68Ga、124I或89Zr、64Cu、18F或15O可用于正电子发射断层扫描(PET)目的。闪烁显像可以使用与SPECT相同的放射性核素。
可使用的其他成像剂是根据本公开的基于纳米抗体靶向的成像剂,包括吸收小分子染料,金属纳米颗粒(光声成像、PAI),小的合成荧光探针,其常用的成像剂包括近红外荧光团诸如IRDye 800CW、Ag2S量子点和FDA批准的吲哚菁绿,或荧光蛋白表达基因(荧光分子断层摄影术),荧光素酶表达基因(生物发光成像),超顺磁性氧化铁(SPIO),钆-DTPA(磁共振成像),基于纳米颗粒的造影剂(计算机断层摄影术)。
由于它们的小尺寸和快速清除,sdAb在分子成像策略中通常是高度相关的。由于它们的小尺寸和较不复杂的3D结构,其还具有高的耐化学性和耐温性。因此,这有利于分子成像方法以及偶联化学(生产)。
根据本公开的抗FGFR4 sdAb也可用于基于细胞的ELISA测定。为了进行夹心ELISA,使用捕获和检测纳米抗体,优选靶向抗原上的不同表位。
在本公开的一些实施方案中,本文所述的抗FGFR4单域抗体因此可用于检测生物样品中FGFR4的存在。如本文所用,术语“检测”包括定量或定性检测。在某些方面,生物样品包含一种或多种细胞或组织。在某些方面,此类组织包括表达FGFR4(尤其是相对于来自对照受试者或来自对照受试者群体的其他组织或类似组织以更高水平表达FGFR4)的正常和/或癌性组织。
还包括诊断与FGFR4表达增加相关的病症(通常地FGFR4相关癌症或肿瘤)的方法。在某些方面,该方法包括:
-将测试细胞与本公开的抗FGFR4单域抗体接触;
-通过检测所述人源化抗FGFR4 sdAb与HER的结合来测定测试细胞上FGFR4的表达水平(定量或定性);以及
-将测试细胞中FGFR4的表达水平与对照细胞(例如,与测试细胞具有相同组织来源的正常细胞或表达FGFR4水平与正常细胞相当的细胞)中FGFR4的表达水平进行比较,其中与对照细胞相比测试细胞上FGFR4的表达水平较高指示存在与FGFR4表达增加相关的病症。在某些方面,测试细胞获自疑似患有与FGFR4表达增加相关的病症的个体。在某些方面,所述病症是细胞增殖性病症,诸如癌症或肿瘤。
在某些方面,诊断或检测的方法,诸如上述方法,包括检测细胞表面上表达的或从表达FGFR4的细胞表面上获得的膜制剂中表达的抗FGFR4单域抗体的结合。用于检测人源化抗FGFR4 sdAb与细胞表面上表达的FGFR4的结合的示例性测定法是“FACS”测定法。
某些其他方法可用于检测本文公开的人源化抗FGFR4 sdAb与FGFR4的结合。这些方法包括但不限于本领域熟知的抗原结合测定,诸如蛋白质印迹、放射免疫、ELISA(酶联免疫吸附测定)、“三明治”免疫测定、免疫沉淀测定、荧光免疫测定、蛋白A免疫测定和免疫组化(IHC)。有利地,在这些实施方案中,如前所述,本文公开的人源化抗FGFR4 sdAb连接至诊断化合物,特别是可检测标记。
在本文所述方法的一些实施方案中,本文所公开的抗FGFR4 sdAb连接至药物纳米载体,诸如脂质体。通常地,用本文公开的抗FGFR4sdAb官能化的所述药物纳米载体包封诊断化合物。
在下文中,将通过以下实施例和附图说明本发明。
附图说明
图1:噬菌体展示生物筛选和预选FGFR4结合纳米抗体序列的示意性概述。用两种不同的合成纳米抗体噬菌体展示文库对生物素化以及Dynabead结合的FGFR4进行噬菌体展示选择。测试富集的噬菌体克隆与Rh4-FR4wt细胞上的细胞表面FGFR4的结合,得到40种独特的结合物。选择在大肠杆菌中表达的8种纳米抗体,最后4个候选物A8、B1、B5和F8与Rh4-FR4wt结合,但不与Rh4-FR4ko细胞结合。
图2:纳米抗体的体外结合验证。A)通过流式细胞术测试纳米抗体对细胞表面FGFR4的结合选择性。柱状图显示了与Rh4-FR4wt结合的每种纳米相对于Rh4-FR4ko细胞的活单细胞群。二级FITC标记的抗His-tag抗体(2nd)用作背景对照,并且mCherry(mCh)用作阴性对照。用FlowJoTM 10软件测定中值荧光强度(MFI)。B)用重组FGF19与纳米抗体组合进行Rh30细胞中FGFR4的活化测定。将细胞与10μM的纳米抗体(A8、B1、B5、F8、mCh)一起孵育1小时,然后用50nM FGF19刺激FGFR4 10分钟。对照细胞(C)不受刺激或在不存在纳米抗体的情况下用FGF19刺激。用抗磷光剂ERK1/2抗体通过蛋白质印迹分析细胞裂解物。总Erk1/2水平显示为负载对照。
图3:通过表面等离子体共振光谱法测定纳米抗体对重组蛋白的亲和力。通过基于葡聚糖的传感器芯片上的共价胺结合对固定的FGFR4进行单循环动力学分析。以5种不同的浓度注射分析物A8、B1、B5、F8和mCh,随后进入解离阶段。在最后的注射步骤之后加入最后的解离步骤以测定KD计算的Koff速率。黑色曲线代表测量数据,并且红色曲线显示用BIAevaluation软件进行的拟合分析(异质配体模型)。
图4:负载长春新碱的靶向脂质体的表征。A)通过动态光散射测量纳米抗体包被的脂质体的尺寸分布。B)偶联纳米抗体的蛋白质印迹分析。在用于凝胶电泳的还原和变性条件下加样等量于100ng纳米抗体的脂质体悬浮液(L)。加样100和50ng未偶联蛋白作为对照。用抗His6-tag抗体检测纳米抗体。
图5:FGFR4靶向脂质体的体外结合验证。通过流式细胞术测试用靶向FGFR4的纳米抗体A8、B1、B5和F8或mCh阴性对照修饰的脂质体对于细胞表面FGFR4的结合选择性。将贴壁细胞与0.5mM总脂质浓度在37℃和5% CO2下孵育2h。柱状图显示了结合Rh4-FR4wtvs.Rh4-FR4ko细胞的脂质体的活单细胞群。未处理的细胞代表对照群体。用FlowJoTM10软件测定中值荧光强度(MFI)。
图6:FGFR4靶向脂质体的内化。用纳米抗体包被的荧光脂质体在37℃和5% CO2下孵育Rh4-FR4wt细胞2小时的共聚焦显微镜分析。总脂质浓度为3mM。细胞用含有DAPI的培养基清洗、固定和安装。
图7:FGFR4-CAR T细胞对RMS细胞的细胞毒性。A)CAR-VHHaFR4构建体的示意图。CAR由具有CD8α单肽序列和C端myc-tag的纳米抗体A8和CD8α的铰链和跨膜(TM)结构域组成。胞内信号转导结构域是4-1BB和CD3ζ且随后是链霉亲和素结合肽(SBP)。B)供体A和B的CD8+T细胞转导效率如下测定:BFP信号的流式细胞分析。C)Rh4细胞与供体A和b的效应T细胞共培养72小时,通过荧光素酶活性测定细胞毒性。在两种供体中,Rh4-FR4wt细胞与FGFR4-CAR T细胞在指定的效应:靶(E:T)细胞比例下培养时,相对细胞死亡率最高。在Rh4-FR4ko细胞中,观察到所有CAR T细胞和非转导CD8+T细胞共培养的非特异性细胞杀伤。D)使用xCELLigence RTCA DP对与来自供体B的效应T细胞共培养的Rh4细胞的实时细胞死亡分析。与非特异性CD19-CAR T细胞或非转导的CD8+T细胞相比,FGFR4-CAR T细胞在Rh4-FR4wt中E:T细胞比例下显示出更高的杀伤活性。在Rh4-FR4ko细胞中未观察到特异性细胞毒性。星号表示添加效应T细胞的时间。
具体实施方式
材料和方法
质粒和克隆
对于重组蛋白表达,将pHEN2噬菌粒载体上的纳米抗体编码序列用SapI引入引物进行PCR扩增,用于将FX克隆54导入pSB_init(由M.Seeger lab,University of Zurich提供)。表达载体含有ccdB自杀盒、C端半胱氨酸和6xHis-tag。成功克隆的纳米抗体序列取代ccdB,并且将构建体在大肠杆菌MC1061中扩增。用A8纳米抗体序列产生CAR T细胞构建体,并连接至pTRIP-BFP-2a-scFvCD19-myc-41BB-CD3ζ-SBP进行克隆,用A8(pTRIP-BFP-2a-vHH-FGFR4-myc-41BB-CD3ζ-SBP)取代scFvCD19。pTRIP-BFP-2a-scFvCD19-myc-41BB-CD3ζ-SBP先前通过由以下组成的序列的基因合成产生:单肽CD8α-单链可变片段抗CD19-myctag-CD8α的铰链和跨膜结构域-刺激结构域4-1BB和CD3ζ结构域-链霉亲和素结合肽(SBP)。将该基因克隆到由Nicolas Manel(Institut Curie,Paris55)提供的pTRIP-SFFV-tagBFP-2A.ape中。
细胞系
将细胞系Rh4(Peter Houghton,Research Institute at Nationwide Children’s Hospital,Columbus,OH,提供)、Rh30、HEK293ft HEK293T(购自ATCC,LGC Promochem)在37℃下,5% CO2中维持在补充有10% FBS(均为Sigma-Aldrich)、2mM L-谷氨酰胺和100U/ml青霉素/链霉素(均为Thermo Fisher Scientific)的DMEM中。RMS细胞系在2014/2015年通过细胞系分型分析(STR分析)进行测定和鉴别,且匹配阳性48。所有细胞系的支原体检测结果均为阴性。
CRISPR/Cas9 FGFR4敲除细胞的产生
通过CRISPR/Cas9技术产生Rh4 FGFR4敲除克隆。将用于FGFR4敲除的互补单链寡核苷酸编码sgRNA序列(TTGCACATAGGGGAAACCGT)退火并经由Esp3I(ER0451,Thermo FisherScientific)限制和T4连接(15224017,Thermo Fisher Scientific)克隆至lentiCRISPRv2puro载体(#98290,Addgene)中。慢病毒载体在HEK293T细胞中产生。使用JetPrime(Polyplus Transfection)用pMDL、pREV、pVSV-G和lentiCRISPRv2-sgFR4Ex14瞬时转染细胞。24小时后,更换培养基,再过48小时后收获病毒上清液。将上清液过滤,浓缩20倍(Amicon Ultra15,Merck Millipore,4000g,15min)并储存在-80℃。在10μg/ml聚凝胺(Merck Millipore)存在下用浓缩的病毒上清液进行RMS细胞的转导。24小时后更换培养基,72小时后开始1μg/ml的嘌呤霉素筛选并进行7天。用选择的细胞在96孔板上进行单细胞克隆,且通过蛋白质印迹在蛋白质水平上证实FGFR4敲除。所有实验均用敲除克隆#8进行。
用于CAR T细胞构建的慢病毒载体的生产
通过使用聚乙烯亚胺(PEI)沉淀方案将含有目的基因的质粒(BFP-2a-scFvCD19/sdAB-FGFR4-myc-41BB-CD3ζ-SBP),包装质粒psPAX2和包膜质粒pVSVG共转染到HEK293ft中来产生慢病毒颗粒。将细胞在37℃,5% CO2下孵育,48小时后收获上清液并保存,然后加入新鲜培养基再进行24小时的慢病毒生产。72小时后,将上清液合并在一起并使用0.2μm孔径的过滤器过滤。为浓缩慢病毒颗粒,将含20%蔗糖的PBS应用于过滤的上清液,然后在4℃下以100,000g离心1.5h。将沉淀回收在1mL冷冻培养基(DMEM完全培养基+0.1mMβ-巯基乙醇(Gibco)和1mM HEPES(GIBCO))中并储存在-80℃下待用。通过转导后72小时检测HEK293ft细胞中的荧光蛋白(mtag BFP),使用流式细胞术测定慢病毒效价。
T细胞分离和转导
使用密度梯度Lymphoprep(StemCells)回收外周血单核细胞(PBMC)。根据CD8+T细胞人分离试剂盒(Miltenyi)的说明,使用含有针对CD4、CD15、CD16、CD19、CD34、CD36、CD56、CD123、TCRγ/δ和CD235a(血型糖蛋白A)的抗体的混合物,通过负筛选分离CD8+T细胞。然后将分离的CD8+T细胞在补充有50μMβ-巯基乙醇(Merck Millipore)和5%人血清(MerckMillipore)的X-VIVO培养基(Lonza)中培养,并按照制造说明使用人T-活化剂CD3/CD28Dynabeads(Gibco)活化。T细胞活化约24小时后,用与4μg/mL聚凝胺(MerckMillipore)混合的慢病毒颗粒以大约或高于5的MOI转导T细胞。2天后,用补充有5ng/mL重组人白介素-2(IL2;R&D Biosystem)的新鲜培养基交换和替换培养基。在转导后第6或7天,通过使用流式细胞术检测mtagBFP表达细胞来评估转导效率。
健康的成年人血液供体(Saint-Louis Etablissementdu sang(EPS)or Saint-Antoine Crozatier EFS at Paris,France)同意提供他们的血液用于研究目的。
噬菌体展示选择
使用由3×109个合成的人源化sdAb组成的Nali-H1文库24和由1.6×109个合成的完全人源化sdAb组成的Gimli文库,在如描述的天然条件下用生物素化的胞外FGFR4(G&PBiosciences)进行FGFR4的筛选56。
蛋白质表达和纯化
在含有pSB_init载体的大肠杆菌MC1061中进行纳米抗体的周质表达,从而促使含有C端半胱氨酸和6xHis-tag的蛋白质生成。将在Terrific Broth培养基(25μg/ml氯霉素)中生长的20ml过夜预培养物在2000ml新鲜培养基中稀释并在37℃生长2小时。然后将温度降低至25℃,并且1小时后用0.02% L-阿拉伯糖诱导蛋白质表达。细菌培养物在25℃下生长过夜,并通过离心(12000g,15分钟)收获细胞。用渗透压休克法进行周质蛋白提取。将细胞用50ml裂解缓冲液1(50mM Tris/HCl,pH 8.0,20%蔗糖,0.5mM EDTA,5μg/ml溶菌酶,2mMDTT)重悬并在冰上孵育30min。加入冰冷的裂解缓冲液2(PBS,pH7.5,1mM MgCl2,2mM DTT)后,通过离心(3800g,15分钟)收集细胞碎片,并向含有蛋白的上清液中补充终浓度为10mM的咪唑。用洗涤缓冲液(PBS,pH7.5,30mM咪唑,2mM DTT)洗涤10ml Co2+-磁珠浆料(HisPur钴树脂,Thermo Fisher Scientific),并将上清液加入磁珠中。在4℃下孵育1小时后,用20ml洗涤缓冲液洗涤磁珠,并用20ml洗脱缓冲液(PBS,pH 7.5,300mM咪唑,2mM DTT)洗脱结合的蛋白质。在尺寸排阻层析(SEC)之前,将蛋白质洗脱物在PBS,pH 7.5,2mM DTT中透析过夜,并通过旋转过滤离心(Amicon Ultra 15,3kDa,Merck Millipore)浓缩。
流式细胞术
在Rh4-FR4wt和Rh4-FR4ko细胞上进行所选噬菌体、重组纳米抗体的结合验证。通过流式细胞术在96孔板(Becton Dickinson)中测定所选的噬菌体克隆结合FGFR4的特异性。在冰上在补充有1% FBS的PBS中进行Rh4-FR4wt或Rh4-FR4ko细胞的细胞表面染色。在冰上,将80μL噬菌体+20μL PBS/1%牛奶在1x105个细胞上孵育1小时。在PBS中洗涤2次后,通过1:250稀释的抗M13抗体(27-9420-01;GE healthcare)在冰上放置1小时,然后用1:400稀释的A488-缀合的抗小鼠抗体(715-545-151;Jackson Immunoresearc,Europe Ltd)处理45分钟。洗涤两次后,在MACSQuant细胞计数器(Miltenyi)上通过流式细胞术分析样品,且结果用FlowJo软件(BD Biosciences,France)分析。噬菌体展示的抗mCherry纳米抗体用作阴性对照24,我们使用抗FGFR4抗体(BT53,由J.Khan lab,NCI,Bethesda,MD提供)用作阳性对照。对于重组纳米抗体的结合试验,用Accutase(Stemcell Technologies)分离细胞并用PBS洗涤。所有以下步骤在冰上进行:将4×105个细胞与30μg/ml浓度的纳米抗体一起孵育1小时,用PBS洗涤一次,并与抗His-tag FITC标记的抗体(LSC-57341,LS Bioscience,1:10稀释)一起再孵育30分钟。将细胞用PBS再洗涤一次并分析。将细胞用PBS洗涤两次并用Accutase分离。用Fortessa流式细胞术(BD Biosciences)进行所有流式细胞术测量,并使用FlowJoTM 10.4.1软件分析数据。
受体活化测定
为测试纳米抗体对FGFR4活化的影响,将6×104个Rh30-FR4wt和Rh30-FR4ko细胞置于24孔板上。第二天,将纳米抗体以10μM浓度添加到无FBS培养基中的细胞中,并在37℃下孵育1小时,然后用50nM重组人FGF19(Peprotech)刺激10分钟。立即用冰冷的PBS洗涤细胞并在Tris/RIPA缓冲液(50mM Tris HCl,pH 7.5,150mM氯化钠,1%NP40,0.5% NA-脱氧胆酸盐,0.1% SDS,1mM EGTA,具有标准蛋白酶和磷酸酶抑制剂)中裂解。然后通过蛋白质印迹分析总细胞提取物。
蛋白质印迹
在4-12% NuPAGE Bis-Tris凝胶(Thermo Fisher Scientific)上分离SDS-PAGE样品,并在Trans-Blot Turbo Transfer Blot膜(Biorad)上印迹。在室温下用封闭缓冲液(5%牛奶/TBST)封闭膜1小时后,以1:1000稀释度加入一抗并在4℃下孵育过夜。将HRP-偶联的二抗在封闭缓冲液中以1:10,000稀释,并在室温下加入到洗涤的膜中1小时。并在孵育后用AmershamTM ECLTM检测试剂(GE Healthcare)或SuperSignalTM West Femto MaximumSensitivity Substrate(Thermo Fisher Scientific)在ChemiDocTM Touch Imaging系统(Biorad)中检测化学荧光。使用的一抗是磷酸-p44/42MAPK Thr202/Tyr204(#9101)、β-微管蛋白D3U1W(#86298)、FGF受体1D8E4(#9740)(均来自Cell Signaling Technology)、FGF受体2C-17(sc-122)、FGF受体3B9(sc-13121)和FGF受体4A-10(sc-136988)(均来自SantaCruz Biotechnology)。二抗是抗兔IgG(#7074,Cell Signaling Technology)和抗小鼠IgG(#7076,Cell Signaling Technology)。
表面等离子体共振光谱法
用BIAcore T200仪器(GE Healthcare)在用300mM NHS(N-羟基琥珀酰亚胺)和50mM EDC(N-乙基-N’-(二甲基氨基丙基)碳二亚胺)的混合物活化的CMD200M传感器芯片(XanTec bioanalytics GmbH)上进行单循环动力学分析。将重组FGFR1、FGFR2、FGFR3和FGFR4(G&PBiosciences)固定在活化的生物传感器(800-12’000RU;1RU=1pg/mm2),随后用1M乙醇胺进行封闭步骤。每个芯片使用一个流动通道作为参照以提供背景校正。以5种不同浓度注射纳米抗体,随后进行解离阶段。从最后一次注射后的最后解离步骤测定koff速率。由于与表面的强结合和不完全解离,对新鲜固定的蛋白质上的每种纳米抗体进行FGFR4测量。固定化流速为5μl/min,并且结合研究以30μl/min进行。用BIAevaluation软件的异质配体模型拟合确定结合参数。黑色曲线代表测量数据,并且红色曲线显示进行的拟合分析。
荧光标记的装载VCR的脂质体的制备
脂质体的产生和长春新碱装样如描述的进行23,稍加修改。分别以49.8:45:4:1:0.2mol%的比例,用卵鞘磷脂(Lipoid GmbH)、胆固醇(Sigma Aldrich)、PEG-神经酰胺(N-棕榈酰-鞘氨醇-1-[琥珀酰[甲氧基PEG-2000]])、DSPE-PEG-马来酰亚胺(1,2-二硬脂酰-Sn-甘油-3-磷酸乙醇胺-N-[马来酰亚胺(聚乙二醇)-2000])(均为Avanti Polar Lipids)和DiR(1,1’-双十八烷基-3,3,3’,3’-四甲基吲哚三碳菁碘化物)(Thermo FisherScientific),用膜水合/挤压方法制备脂质体。脂质膜用柠檬酸盐缓冲液(250mM,pH 3)水合,产生70mM的总脂质浓度。然后,用Thermobarrel extruder(EvonikNutrition and Care GmbH)和100nm孔径聚碳酸酯膜(Whatman)进行6次冻融循环和10次挤压步骤。用PD MiniTrapTM Sephadex G-25柱(GE Healthcare Lifesciences)通过凝胶排阻层析产生跨膜pH梯度。柱用偶联缓冲液(PBS,pH 7.0)调节,并且将洗脱的脂质体悬浮液(14mM)用于长春新碱包封。对于0.05的药物:脂质摩尔比,将1ml脂质体与稀释在偶联缓冲液中的1ml的0.7mM VCR(长春新碱,Teva pharma AG)混合并在65℃下孵育1小时。通过旋转过滤离心(Amicon Ultra 0.5,100kDa,Merck Millipore)除去未包封的VCR,并将包封反应浓缩成11.2mM悬浮液。
纳米抗体修饰脂质体
为将纳米抗体偶联至脂质体表面,用PD MiniTrapTM Sephadex G-25柱(GEHealthcare Lifesciences)将蛋白质缓冲交换到偶联缓冲液(PBS,pH 7.0)中。选择0.4nmol/μmol的纳米抗体与脂质的比例用于反应45,得到每个脂质体约30个纳米抗体。将反应在4℃下孵育过夜,并通过旋转过滤离心(Amicon Ultra 0.5,100kDa,Merck Millipore)洗涤和过滤两个步骤除去未偶联的纳米抗体。通过动态光散射(Litesizer 500,Antonpaar)测量脂质体的平均直径和多分散性指数(PDI)。为估算偶联至脂质体的纳米抗体的量,在变性和还原条件下用标记的脂质体和确定量的相应纳米抗体进行凝胶电泳。如上所述,用抗His-tag抗体(ab18184,Abcam)进行样品分离、蛋白质印迹和成像。
VCR量化
长春新碱浓度的定量通过HPLC(Ultimate 3000HPLC system,Thermo FisherScientific)用RP-18(5μm,4.6×250mm)100柱(Merck)进行。制备范围为890μg/ml至13.9μg/ml的长春新碱的校准曲线,并用甲醇破坏脂质体样品用于分析。将阿霉素与所有样品混合,作为内标。使用磷酸二钾缓冲液(50mM,pH 3.2)与乙腈/UPW 90/10(v/v;32%)的混合物作为流动相(68%)30分钟,流速为1.5ml/min。注射20μl各样品,用UV-VIS检测器在230nm进行检测。通过分析旋转过滤器纯化的脂质体悬浮液和水流中的长春新碱浓度来测定载药效率。包封效率表示与来自过滤的脂质体和流过物的组合的量相比,脂质体悬浮液中长春新碱的百分比。
共聚焦显微术
通过共聚焦激光扫描显微镜(CLSM-Leica SP8反向)在Rh4野生型和Rh4-FGFR4敲除细胞上进行荧光脂质体的细胞结合和内化的检测。将40’000个细胞接种在四孔显微镜载玻片(FalconTM Chambered Cell Culture Slides,Fisher Scientific)上。第二天,将靶向或对照脂质体以3mM的最终脂质浓度加入到细胞中,并在37℃和5% CO2下孵育2小时。然后用PBS洗涤孔两次,用4%甲醛溶液固定细胞15分钟。在用PBS进一步进行两个洗涤步骤后,将载玻片从室盒中分离并用含有DAPI的培养基(具有鬼笔环肽的Hardset Antifade Mounting培养基,Vector Laboratories)封固。显微镜成像用63x物镜(HC PL APO CS2 63x/1.30)和激光Diode405和Diode638分别进行DAPI和DiR激发。所有图像用ImageJ处理。
CAR T细胞的细胞毒性测定
使用两种方法评价T细胞对RMS细胞的细胞毒性。对于生物发光测定,用慢病毒颗粒转导Rh4-FR4wt和Rh4-FR4ko细胞以共同表达三种蛋白作为操纵子(P2A)、mtag BFP、RedFirefly荧光素酶和嘌呤霉素抗性基因(BFP-P2A-荧光素酶-P2A-嘌呤霉素)。简言之,将靶细胞接种(4000个细胞/孔)在DMEM完全培养基中的96孔ViewPlate Black(Perkin-Elmer)中,第二天在X-ViVO培养基(与DMEM相比2倍体积)中以指定的效应物:靶标(E:T)比例加入效应细胞(CD8+T细胞)。在37℃和5% CO2下孵育约72小时后,用PBS洗涤孔两次,且在用FLUOstar OPTIMA(BMG LabTech)测量荧光之前,将1-2mg/mL在PBS中的荧光素底物(PerkinElmer)添加10分钟(37℃)。通过取每个点的荧光值并将其除以获得的最高发光值来计算细胞存活百分比。用xCELL Igence实时分析仪系统(ACEA Biosciences)进行实时细胞死亡测量。简言之,将靶细胞接种(10’000细胞/孔)在16孔E-板(ACEA Biosciences)中的DMEM完全培养基中,第二天在X-Vivo培养基(与DMEM相比2倍体积)中以指定的E:T比例加入效应细胞。在37℃和5%CO2下每15分钟实时监测细胞指数(相对阻抗)约四天。曲线内的水平线表示测定过程中使用的重复两孔的SD。
结果
FGFR4特异性纳米抗体的噬菌体展示选择
在两个合成噬菌体展示文库,人源化sdAb文库NaLi-H124和完全人源化sdAb文库Gimli上进行FGFR4结合纳米抗体的筛选。我们用三轮抗重组FGFR4的生物筛选进行了两次独立的噬菌体展示选择(图1)。为验证对FGFR4的结合特异性,我们通过CRISPR/Cas9生成FGFR4敲除细胞RMS细胞,并测试来自每次筛选的80个噬菌体克隆对Rh4FGFR4野生型细胞(Rh4-FR4wt)和Rh4 FGFR4敲除细胞(Rh4-FR4ko)的结合。流式细胞术分析显示24个NaLi-H1文库和来自Gimli文库的55个噬菌体克隆仅与Rh4-FR4wt细胞结合。79个噬菌体克隆的Sanger测序证实了来自NaLi-H1的12个独特的纳米抗体和来自Gimli文库的28个。然后,来自每个文库的显示对Rh4-FR4wt的最佳结合的四个噬菌体克隆(即NaLi-H1:A8、B1、B5、C3;Gimli:A4、F8、F11、H2)通过流式细胞术(数据未显示)被重组表达。作为阴性对照,我们表达了抗mCherry纳米抗体(mCh)24。将约17kDa的重组纳米抗体工程化以使用C端Myc/6xHis-tag和额外的半胱氨酸表达,用于将马来酰亚胺偶联至脂质体表面。6xHis-tag纯化和尺寸排阻层析产生高纯度的蛋白(附图2),产率为每升细菌培养物3-16mg。
选择的纳米抗体结合RMS细胞并抑制受体信号转导
通过流式细胞术用Rh4-FR4wt和Rh4-FR4ko细胞进行重组纳米抗体与细胞表面表达的FGFR4的结合的验证。FITC标记的抗6XHis-tag抗体用于检测表面结合的纳米抗体。所测试的四个重组纳米抗体显示与Rh4-FR4wt细胞没有显著的结合(C3、A4、F11、H2,数据未显示),而重组纳米抗体A8、B1、B5和F8显示与Rh4-FR4wt细胞的特异性结合而不与Rh4-FR4ko细胞结合(图2A)。如所预期,抗mCherry阴性对照纳米抗体既不结合Rh4-FR4wt也不结合Rh4-FR4ko细胞。与Rh4-FR4wt细胞孵育的四种FGFR4结合物的中值荧光强度(MFI)在400的范围内,但抗mCherry阴性对照或抗-6xHis-tag抗体仅显示200的MFI(图2B),类似于与Rh4-FR4ko细胞的结合,其中对于B5候选物具有略高的值。
FGFR4的胞外结构域与FGFR1、2和3具有高氨基酸同源性。为最佳靶向RMS肿瘤,我们旨在鉴定仅对FGFR4具有特异性的结合物。Rh4-FR4wt和Rh4-FR4ko细胞均表达FGFR1和FGFR2,尽管Rh4-FR4ko水平略低于Rh4-FR4wt(附图1),我们推断纳米抗体对FGFR4是特异性的且不结合FGFR1或FGFR2。总之,纳米抗体在RMS细胞上的结合验证揭示了四个靶向FGFR4的纳米抗体候选物。
异常的FGFR信号转导涉及各种类型的癌症。在RMS中,除过度表达外,FGFR4已显示在超过6%的所有肿瘤中具有活化突变,导致细胞内组成型肿瘤促进信号转导3,32。FGFR4启动四个主要信号转导通路:RAS-MAPK、PI3K-AKT、PLCγ和STAT33。因此,我们测试了所选纳米抗体对FGFR4活化和下游信号转导的作用。我们在Rh30细胞上进行FGFR4活化测定,并将ERK1/2磷酸化用作读数。预先添加或不添加纳米抗体下(图2C),我们将Rh30细胞与FGF19(FGFR4的特异性配体)一起孵育。如所预期,FGF19导致磷光剂-ERK1/2水平的急剧增加。值得注意的是,当Rh30细胞与所选择的纳米抗体预孵育时不存在激酶活化,而阴性对照抗mCherry不阻断ERK1/2磷酸化。这些数据表明所选择的纳米抗体具有阻断RMS细胞中FGFR4下游MAPK通路的活化的能力。
纳米抗体与FGFR4的高亲和力结合
为测定纳米抗体对FGFR4的结合亲和力,我们用重组FGFR4进行了表面等离子体共振(SPR)光谱。如上所述,将FGFR1和FGFR2在Rh4-FR4ko细胞上表达,并且流式细胞术分析表明纳米抗体不与细胞结合。为进一步证实FGFR4特异性,我们还包括使用重组FGFR1、FGFR2和FGFR3的亲和力测量。将纳米抗体A8、B1、B5、F8和mCh以五种不同的浓度注射至FGFR包被的芯片上。除阴性对照mCh外,FGFR4结合的计算的KD值在纳摩尔和皮摩尔范围内(图3;表2)。亲和力参数不能用1:1结合模型拟合,用BIAevaluation软件的异质配体模型得到最佳拟合,得到每个候选物的两个KD值。如所预期,对受体家族同种型FGFR1和FGFR3的亲和力的测量表明没有分析物的结合。SPR数据证实了所有候选物与FGFR4的强结合,表明B1和F8具有严格的FGFR4特异性。
表2:纳米抗体对FGFR4的结合亲和力的表面等离子体共振光谱法测定。用异质配体模型拟合测量数据,并揭示用于解离平衡常数KD(koff/kon)计算亲和力的结合常数和解离常数(kon和koff)。对于测定的KD,最大分析物结合信号Rmax以RU表示,并且类似于它们在总结合纳米抗体的量中的分数。
装载VCR的靶向脂质体的制备和表征
在以前的研究中,我们已优化了脂质体VCR23的制剂。这里,为生产主动靶向脂质体,我们在远端引入了具有反应性马来酰亚胺基团的DSPE-PEG脂质。然后将在C端具有游离半胱氨酸的纳米抗体偶联至脂质体表面。通过膜水合/挤压法,随后VCR包封和纳米抗体偶联制备由卵鞘磷脂、胆固醇、PEG-神经酰胺、DSPE-PEG-马来酰亚胺和DiR(49.8:45:4:1:0.2mol%)组成的荧光脂质体。修饰的脂质体L-A8、L-B1、L-B5、L-F8和L-mCh的动态光散射测量显示约120-135nm的流体动力学直径和0.03-0.13的低PDI值(图4A;表2)。
通过用抗-6xHis-tag抗体的蛋白质印迹分析与脂质体偶联的纳米抗体。以理论纳米抗体量100ng的制备脂质体悬浮液样品。为估算偶联效率,我们将100ng和50ng相应的重组纳米抗体加载到蛋白质印迹凝胶上(图4B)。所有脂质体悬浮液显示以25kDa的表观尺寸运行的主要级分,对应于与DSPE-PEG-马来酰亚胺(2.9kDa)结合的一个纳米抗体分子(17kDa)。另外两条带以更大的尺寸出现,表明每个纳米抗体形成两个或三个脂质分子的复合物。除了C端半胱氨酸之外,纳米抗体还具有两个形成分子内二硫键并代表马来酰亚胺基团的可能反应位点的半胱氨酸。值得注意的是,在所有脂质体样品中仅存在对应于游离纳米抗体的微弱条带。
为确定VCR的包封效率,我们用VCR包封反应和它们最终纯化后的所有靶向脂质体进行HPLC分析。VCR包封效率高,其中97.8%的药物包埋在纳米囊泡中,并且靶向脂质体的VCR浓度在250-320μg/ml的范围内(表3)。
总之,我们能够生产在样品中具有相似药物浓度和尺寸分布的荧光标记的装载VCR的和纳米抗体包被的脂质体。
表3:靶向FGFR4和装载VCR的脂质体的表征。动态光散射显示由PDI表示的脂质体的流体动力学直径和尺寸分布。通过HPLC确定五种制剂的VCR终浓度。
FGFR4靶向脂质体特异性结合FGFR4阳性的RMS细胞并内化
我们接着想要测试脂质体表面上的纳米抗体是否仍可结合表达FGFR4的RMS细胞。在正常细胞培养条件下,将Rh4-FR4wt和Rh4-FR4ko细胞与FGFR4靶向脂质体或靶向mCherry的对照脂质体一起孵育2小时。随后通过流式细胞术分析DiR荧光(图5)。与FGFR4靶向脂质体孵育的Rh4-FR4wt显示增加的荧光信号,表明与FGFR4结合,而在与FGFR4靶向脂质体孵育的Rh4-FR4ko细胞中未观察到荧光增加。与对照mCherry靶向脂质体孵育的Rh4-FR4wt具有低于50的与未处理细胞相似的MFI。在FGFR4靶向脂质体中,L-A8、L-B1、L-B5和L-F8的MFI值分别在300、600、1700和1400之间,因此比L-mCh的MFI值增加6、12、34和28倍。这些结果表明,当偶联至装载VCR的脂质体表面时,纳米抗体仍然能够特异性结合Rh4-FR4wt,但是四种纳米抗体之间的结合强度不同。
众所周知的现象是装载药物的脂质体的受体介导的内化增加细胞内药物量并因此增强其治疗效果34。因此,我们通过共聚焦显微镜研究了FGFR4靶向脂质体的内化。将脂质体在Rh4-FR4wt和Rh4-FR4ko细胞上孵育2小时。随后,固定细胞的图像显示清楚的所有包被有FGFR4靶向纳米抗体的脂质体的细胞内摄取。值得注意的是,当Rh4-FR4wt细胞与L-mCh孵育时没有检测到荧光信号(图6)。与流式细胞术数据一致,L-A8和L-B1显示较弱的细胞内荧光。值得注意的是,在Rh4-FR4ko细胞中没有观察到荧光,支持其对FGFR4的特异性(附图4)。因此,FGFR4靶向脂质体制剂代表FGFR4过表达RMS肿瘤细胞的特异性药物递送平台,特征在于它们的快速和特异性的受体介导的细胞内摄取。
RMS细胞的FGFR4-CAR T细胞靶向
为研究选择的纳米抗体的治疗潜力,我们生成嵌合抗原受体(CAR)以产生抗FGFR4的T细胞。A8纳米抗体用于替代目前用于血液癌症治疗的CD19-CAR T构建体(Celgene,JunoTherapeutics and Kymriad,Novartis)中的靶向CD19的单链抗体片段(scFv)25,35。得到的CAR(CAR-sdAbaFGFR4)由myc标记的A8,随后是CD8α的铰链和跨膜结构域以及4-1BB和CD3ζ的胞内信号结构域组成(图7A)。从四个健康供体(供体A、B、C和D)分离CD8+T细胞,并用靶向FGFR4或CD19的CAR转导。通过mtagBFP表达测量转导效率,其显示约80% FGFR4-CAR和60%CD19-CAR阳性细胞(图7B,附图5A)。为评估CAR T细胞针对Rh4-FR4wt和Rh4-FR4ko细胞的细胞毒性效力,我们应用生物荧光和实时细胞死亡测定(图7C、D)。将RMS细胞与CAR T细胞以不同比例(E:T-效应T细胞比靶向RMS细胞)共培养,且作为另外的对照,我们使用非转导的CD8+T细胞。用来自供体A和供体B的T细胞进行生物荧光测定,并揭示FGFR4-CAR T细胞对Rh4-FR4wt的特异性杀伤(图7C)。来自供体B的T细胞显示出更高的细胞毒性效率,在最低的E:T比例4:1下具有几乎100%死细胞。通过比较T细胞在E:T比例为32:1的细胞死亡,我们可证实具有几乎100%死亡细胞的FGFR4-CAR T细胞的选择性细胞毒性作用。CD19-CART细胞和CD8+对照T细胞仅达到约20-35%死细胞的值。对于CAR和CD8+对照T细胞的T细胞介导的毒性和对Rh4-FR4ko细胞的相似。使用来自供体B、C和D的CAR的细胞死亡的实时分析显示类似的结果,其中通过FGFR4-CAR T对Rh4-FR4wt的选择性细胞杀伤,但在Rh4-FR4ko细胞中不存在细胞毒性或降低(图7D、附图5B)。总之,这些数据显示所选择的纳米抗体A8可产生FGFR4-CART细胞,其在体外介导针对表达FGFR4的RMS细胞的显著抗肿瘤活性,并因此代表有前景的进一步靶向治疗选项。
讨论
我们在此报道了通过用纳米抗体靶向FGFR4开发两种对RMS的治疗策略,并在RMS细胞上验证。我们选择了四种FGFR4结合纳米抗体并在体外测试它们用于活性药物递送和细胞介导的免疫治疗。当与RMS细胞孵育时,装载VCR的荧光标记的FGFR4靶向脂质体显示选择性结合和内化。此外,我们能够产生具有一种纳米抗体候选物的FGFR4-CAR T细胞,从而导致针对表达FGFR4的RMS细胞的特异性细胞毒性。
四种选择的纳米抗体A8、B1、B5和F8不仅结合表达FGFR4的RMS细胞,而且还能够阻断FGFR4-FGF19 MAPK信号转导轴。尽管我们的目的是选择纳米抗体以靶向FGFR4用于活性药物递送而非其功能,但值得注意的是受体信号转导也可代表RMS中的治疗靶标32,36。在ARMS中,FGFR4是融合蛋白PAX3-FOXO1的直接靶基因37,而在ERMS中,FGFR4通常扩增有12%的肿瘤携带受体的激活突变38-40。此外,FGFR4不仅涉及RMS肿瘤发生。FGFR4在表达FGF19的肝细胞癌和头颈鳞状细胞癌中驱动肿瘤进展41-43,且据估计所有肿瘤中的0.5%在FGFR444中显示异常。因此,所选择的纳米抗体也可以用作其他癌症的可能治疗方法。
与FGFR4结合的纳米抗体的表面等离子体共振光谱显示出纳米级至皮摩尔级的强亲和力。测量数据不能用1:1结合模型拟合。用异质配体模型获得最佳拟合,表明纳米抗体对FGFR4的两个单独的结合亲和力参数。我们必须通过胺基结合将重组FGFR4直接固定至传感器芯片上的活化羧基,因为其他方法与我们的测量不兼容。因此,FGFR4与传感器芯片的非定向结合可能已导致纳米抗体结合位点的完全或部分的空间位阻,从而导致异质结合参数。当比较代表最大纳米抗体结合信号的Rmax值时,这是显而易见的:对于A8的亲和力测量,我们可以将800RU FGFR4固定到传感器芯片上。对于40kDa的配体和17kDa的纳米抗体的大概分子量,我们预期Rmax为340RU((MWFGFR4/MWNB)*800RU),但实际上仅达到44RU的值。由于我们在纳米抗体结合后不能完全再生流动细胞,用新鲜固定的FGFR4对每种纳米抗体进行所有测量。这产生不同量的固定化FGFR4。用大约800RU的FGFR4进行A8、B1和B5分析,而对于F8和mCh,我们分别固定9000和12’000RU。对这种高配体密度的阴性对照mCh的测量迫使在高纳米抗体浓度下的非特异性相互作用。这导致与纳米抗体候选物相比低的计算的亲和力。
游离纳米抗体和脂质体偶联的纳米抗体均与Rh4-FR4wt细胞特异性结合,且不与Rh4-FR4ko结合。
通过引入1mol%的DSPE-PEG-马来酰亚胺来修饰脂质体VCR的制剂。我们能够生产质量、尺寸和载药效率与上述相当的脂质体23。如Oliveira及同事45所述用0.4nmol纳米抗体/μmol总脂质进行纳米抗体与表面的偶联,并使得高偶联效率。我们还测试了偶联反应中纳米抗体与脂质的较高比例,但这导致脂质体沉淀。脂质体悬浮液中的未偶联纳米抗体的小部分是可忽略的且不干扰我们对细胞的结合验证。
荧光FGFR4靶向脂质体通过共聚焦显微镜显示在Rh4-FR4wt细胞中由点样结构表示的非常特异性的内化,而Rh4-FR4ko细胞内不存在。孵育2小时后拍摄的图像表明相当快速的内化过程,这对于药物递送平台至高度血管化的肿瘤是有利的。
体外细胞测定不适于预测和比较依赖于增强的渗透和保留作用的载药纳米微球的治疗效果13。我们已经用递增浓度的靶向脂质体和L-mCh孵育了RMSRh4-FR4wt和Rh4-FR4ko细胞,但在脂质体和细胞系之间的细胞毒性作用中不能看到显著差异(数据未显示)。甚至在脂质体在附着的细胞上孵育1小时或2小时并随后洗掉以防止在培养的三天内脂质体的非特异性摄取或药物释放之后,也获得这些结果。脂质体与细胞培养板的非特异性结合可能是对此的解释。因此,将FGFR4靶向药物递送至RMS的治疗潜力需进一步体内研究。
我们能够验证基于纳米抗体的FGFR4-CART细胞对Rh4-FR4wt的选择性细胞介导的细胞毒性。尽管我们看到三个CD8+T细胞供体A、B和C之间的杀伤效率的一些差异,但是所有FGFR4-CAR T显示相同的特异性趋势。实时细胞分析代表监测CAR T的细胞毒性潜力的良好工具,且显示FGFR4-CART细胞对Rh4-FR4ko的作用没有或降低,与CD19-CAR T细胞的作用相当。我们相信用FGFR4-CAR T细胞对RMS的基于免疫的治疗具有很好的潜力,因为RMS肿瘤与健康组织相比显示异常高的FGFR4表达39。已表明,有效的CAR T细胞活化需要高于某一阈值水平的高抗原密度,且允许RMS治疗的治疗窗口46,47。
由于鉴定了RMS中异常的FGFR4表达和信号转导,已将其研究为可能的治疗靶标。已报道用小分子抑制剂PD173074靶向受体在携带ARMS的小鼠中诱导肿瘤消退,但伴随着毒性副作用48。Li和同事研究了多激酶抑制剂ponatinib36的治疗效果。用ERMS和ARMS的体外实验显示细胞对抑制剂的高敏感性,其中IC50值在低纳摩尔范围内。此外,它们能够显示抑制剂仅在携带具有FGFR4突变的RMS的小鼠中延迟肿瘤生长。在进一步的研究中,FGFR4下游信号转导途径PI3K-AKT-mTOR和RAS-MEK-ERK在RMS中被同时靶向并在体外和体内显示出协同效应49。已研究了基于FGFR4抗体的RMS治疗的很好的结果,其或作为抗体药物偶联物(ADC)50-52或具有移植在嵌合抗原受体(CAR)上的抗原结合结构域以产生CAR T细胞53。通过我们的工作,我们在此显示了通过活性药物递送和T细胞募集的基于纳米抗体的FGFR4靶向的新的很好的策略。
总之,我们筛选了对受体信号转导具有抑制作用的FGFR4特异性纳米抗体。此外,我们开发了通过靶向脂质体VCR用于RMS治疗的有效药物递送平台,且可在体外用FGFR4-CAR T细胞显示有效的细胞介导的细胞毒性。肿瘤靶向方法需要在RMS体内模型中测试,且可进一步应用于其他表达FGFR4的肿瘤。
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Claims (29)
1.抗FGFR4的人源化合成单域抗体(sdAb),其中所述抗FGFR4 sdAB具有下式:FRW1-CDR1-FRW2-CDR2-FRW3-CDR3-FRW4,且其中所述CDR选自:
-SEQ ID NO:1的CDR1;SEQ ID NO:2的CDR2和SEQ ID NO:3的CDR3,
-SEQ ID NO:4的CDR1;SEQ ID NO:5的CDR2和SEQ ID NO:6的CDR3,
-SEQ ID NO:7的CDR1;SEQ ID NO:8的CDR2和SEQ ID NO:9的CDR3,
-SEQ ID NO:10的CDR1;SEQ ID NO:11的CDR2和SEQ ID NO:12的CDR3。
2.根据权利要求1所述的人源化抗FGFR4 sdAb,其中所述框架区由以下组成:
-选自SEQ ID NO:13或SEQ ID NO:17的FRW1,
-选自SEQ ID NO:14或SEQ ID NO:18的FRW2,
-选自SEQ ID NO:15或SEQ ID NO:19的FRW3,
-选自SEQ ID NO:16或SEQ ID NO:20的FRW4,
或其功能性变体,其中在FRW1、FRW2、FRW3和FRW4的每一个中具有不超过0、1、2或3个保守氨基酸取代。
3.根据权利要求2所述的人源化抗FGFR4 sdAb,其具有SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43和SEQ ID NO:44中任一个所示的序列。
4.根据权利要求1-3中任一项所述的人源化抗FGFR4 sdAb,其与选自核酸、多肽或蛋白质、病毒、毒素和化学实体的目标化合物直接或间接、共价或非共价地连接。
5.根据权利要求4所述的人源化抗FGFR4 sdAb,其中所述抗体与选自酶、荧光团、NMR或MRI造影剂、放射性同位素和纳米颗粒的诊断化合物直接或间接、共价或非共价地连接。
6.根据权利要求4所述的人源化抗FGFR4 sdAb,其中所述抗体与选自细胞毒性试剂、化疗剂、放射性同位素、靶向抗癌剂、免疫治疗剂(诸如免疫抑制剂或免疫刺激剂)和裂解肽的治疗化合物直接或间接、共价或非共价地连接。
7.根据权利要求1-4中任一项所述的FGFR4 sdAB,其直接或间接、共价或非共价地连接至药物纳米载体,任选地有机纳米载体。
8.根据权利要求1-4中任一项所述的FGFR4 sdAB,其中所述有机纳米载体选自聚合物纳米颗粒、脂质体、胶束和基于蛋白质的纳米载体诸如白蛋白,任选地其中所述有机纳米载体是脂质体。
9.根据权利要求7或8中任一项所述的FGFR4 sdAB,其中,包封至所述纳米载体中的药物包括治疗化合物或诊断化合物,任选地其中所述治疗化合物是细胞毒性化合物。
10.根据权利要求1-4中任一项所述的FGFR4 sdAb,其与免疫球蛋白结构域融合,任选地,其与Fc结构域融合。
11.多特异性结合化合物,其包含至少如权利要求1-10中任一项所定义的FGFR4 sdAb的第一sdAb,且还包含结合第二抗原的另一个sdAb,任选地其中所述第一sdAb位于所述第二sdAb的N端,或其中所述第一sdAb位于所述第二sdAb的C端。
12.嵌合抗原受体(CAR),其包含(a)抗原结合结构域,其包含至少如权利要求1-4中任一项所定义的抗FGFR4 sdAb的第一sdAb,和任选地,特异性结合第二抗原的第二sdAb,(b)跨膜结构域;和(c)胞内结构域。
13.根据权利要求12所述的CAR,其中所述跨膜结构域选自CD3ζ结构域的跨膜结构域、CD28跨膜结构域、CD8α跨膜结构域、DAP10跨膜结构域,或DAP12跨膜结构域。
14.根据权利要求12-13中任一项所述的CAR,其中所述胞内结构域包含源自CD28、OX40、CD3ζ、4-1BB、DAP10和/或DAP12的胞内结构域的一个或多个结构域,任选地其中所述胞内结构域包含CD3ζ和4-1BB胞内结构域。
15.根据权利要求12-14中任一项所述的CAR,其中所述跨膜结构域是CD8α的跨膜结构域,且所述胞内结构域包含CD3ζ和4-1BB胞内结构域。
16.根据权利要求12-15中任一项所述的CAR,其进一步包含位于胞外抗原结合结构域的C端结构域和跨膜结构域的N端之间的间隔子和/或铰链结构域,任选地其中铰链是CD8α的铰链。
17.根据权利要求12-16中任一项所述的CAR,其进一步包含位于多肽的N端的信号肽。
18.分离的核酸,其包含编码根据权利要求1-17中任一项所述的人源化抗FGFR4 sdAb或CAR的核酸序列。
19.根据权利要求18所述的分离的核酸,其中所述人源化抗FGFR4 sdAb或CAR与异源调控序列连接。
20.载体,其包含权利要求18或19中任一项所述的核酸。
21.宿主细胞,其包含根据权利要求18或19所述的核酸或根据权利要求20所述的载体。
22.分离的细胞或细胞群,其表达根据权利要求1-17中任一项所述的人源化抗FGFR4sdAb或CAR。
23.根据权利要求22所述的分离的细胞或细胞群,其中所述细胞是选自巨噬细胞、NK细胞、CD4+/CD8+、TIL/肿瘤衍生的CD8 T细胞、中央记忆CD8+T细胞、Treg、MAIT和YδT细胞的同种异体或自体细胞。
24.如权利要求1-23中任一项所定义的人源化抗FGFR4 sdAb、CAR、核酸、载体、宿主细胞、分离的细胞或细胞群,其用于治疗。
25.如权利要求1-23中任一项所定义的人源化抗FGFR4 sdAb、CAR、核酸、载体、宿主细胞、分离的细胞或细胞群,其用于在有需要的受试者中治疗癌症。
26.根据权利要求22或23所述的分离的细胞或细胞群,其用于癌症的细胞治疗。
27.如权利要求1-23中任一项所定义的人源化抗FGFR4 sdAb、CAR、核酸、载体、宿主细胞、分离的细胞或细胞群,用于根据权利要求24-27所述的治疗,其中所述人源化抗FGFR4sdAb、CAR、核酸、载体、宿主细胞、分离的细胞或细胞群与至少一种另外的治疗剂组合使用,其中所述至少一种另外的治疗剂是抗癌剂,任选地化疗剂,或免疫治疗剂,任选地检查点抑制剂。
28.权利要求4、5或9所述的人源化抗FGFR4 sdAb用于检测或监测FGFR4介导的癌症的用途。
29.用于诊断或监测受试者中FGFR4介导的癌症的体外或离体方法,其包括以下步骤:
a)将来自所述受试者的合适的样品与如权利要求5或9所定义的诊断试剂在体外接触,且
b)测定所述样品中FGFR4的表达。
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WO2023212587A1 (en) * | 2022-04-28 | 2023-11-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Recombinant polypeptides comprising single-domain antibodies targeting herv-k subtype hml-2 |
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EP4153628A1 (en) | 2023-03-29 |
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CA3182333A1 (en) | 2021-11-25 |
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US20230302050A1 (en) | 2023-09-28 |
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