CN113613680A - 用于增强癌症免疫疗法的与免疫检查点抑制剂复合的树枝状聚合物 - Google Patents
用于增强癌症免疫疗法的与免疫检查点抑制剂复合的树枝状聚合物 Download PDFInfo
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Abstract
本文描述了一种纳米颗粒系统,其包括多价纳米颗粒核心,所述多价纳米颗粒核心包含与之缀合的多个免疫检查点抑制剂。还包括药物组合物和制备所述纳米颗粒系统的方法。还包括免疫治疗方法,所述方法包括将所述纳米颗粒系统施用于需要其的受试者,例如人类癌症患者。
Description
相关申请的交叉引用
本申请要求2018年10月29日提交的美国临时申请62/751,831的优先权,其全部内容通过引用的方式并入本文。
技术领域
本公开涉及用免疫检查点抑制剂进行癌症免疫疗法的组合物和方法。
背景技术
肿瘤细胞通过触发免疫检查点调节剂(例如PD-1/PD-L1或CTLA-4/B7)具有免疫逃逸机制。这些相互作用表现出免疫抑制行为,这导致细胞毒性T淋巴细胞凋亡,抑制免疫系统中细胞因子信号分子的释放,并增加免疫功能障碍。这些结果共同促进了肿瘤内微血管的形成和肿瘤细胞的更高的化学抗性。因此,抑制免疫检查点调节剂可以恢复抗原特异性T细胞并抑制肿瘤增殖。
可以通过以下方式来实现免疫检查点抑制:针对T细胞,通过阻断受体如CTLA-4和PD-1;或着针对癌细胞,通过阻断蛋白如PD-L1和PD-L2。PD-1和PD-L1是癌症免疫疗法的靶标,例如,因为它们相互作用的阻断会中止或限制T细胞应答,并导致抗癌免疫活性的重新激活,进而导致肿瘤消退。已开发出几种靶向免疫检查点调节剂的单克隆抗体、肽、蛋白质和其他小分子,例如靶向PD-1的帕博利珠单抗(pembrolizumab)和纳武利尤单抗(novilumab)以及靶向PD-L1的阿替利珠单抗(atezolizumab)、阿维鲁单抗(avelumab)和度伐利尤单抗(durvalumab)。但是,最近发表的此类免疫检查点抑制剂(ICI)分子的临床结果显示出不良的临床疗效,其中多个队列报告的应答率较低。
需要使用ICI进行癌症免疫疗法的新的组合物和方法。
发明内容
在一方面,纳米颗粒系统包括多价纳米颗粒核心,其包含与之缀合的多个免疫检查点抑制剂。
在另一方面,药物组合物包含所述纳米颗粒系统和药学上可接受的赋形剂。
在另一方面,一种制备纳米颗粒系统的方法包括,在足以将多个免疫检查点抑制剂缀合至多价纳米颗粒核心并提供纳米颗粒系统的条件下,使包含多个反应性端基的多价纳米颗粒核心与包含一种或多种免疫检查点抑制剂的组合物接触。
在另一方面,免疫疗法方法包括将所述纳米颗粒系统施用于有需要的受试者。
附图说明
图1是描述通过树枝状聚合物介导的多价结合效应增强癌症免疫疗法的假设的示意图。G7-aPD-L1缀合物和靶标受体(PD-L1)之间增强的结合动力学导致改善了PD-1/PD-L1相互作用的抑制,从而提高了免疫疗法的功效。
图2说明了第7代(G7)聚(氨基胺)(PAMAM)树枝状聚合物和抗PD-L1抗体缀合物(G7-aPD-L1)的合成。用Alexa647标记G7 PAMAM树枝状聚合物,然后使用乙酸酐进行部分乙酰化。然后将剩余的胺端基用琥珀酸酐羧化。使用EDC/NHS(1-乙基-3-(3-二甲基氨基丙基)碳二亚胺/N-羟基琥珀酰亚胺)化学方法激活树枝状聚合物上的羧基端基,并以1:5的摩尔比与aPD-L1抗体缀合。最终的缀合物用100k离心过滤器过滤(三次,每次10分钟)。使用BCA试验测量每个树枝状聚合物分子缀合的抗体的数目。每个树枝状聚合物缀合约3.9±0.6个抗体。
图3示出了使用原子力显微镜(AFM)表征树枝状聚合物缀合物,证实了G7树枝状聚合物与抗体之间的成功缀合。AFM图像表明,与游离抗体(D=12.7±4.4nm;p<0.001)和G7 PAMAM树枝状聚合物(D=16.3±7.3nm;p<0.001)相比,G7-Ab缀合物 的侧向直径(D)和高度(h)均显著增加。
图4示出了图3的AFM表征的量化。
图5A-D示出了G7-aPD-L1缀合物的增强的结合动力学,使用以下方式证实:(A)表面等离子体共振(SPR)、(B)生物层干涉法(BLI)和(C)原子力显微镜(AFM)。图5A和B示出了,与游离aPD-L1相比,G7-aPD-L1缀合物的解离常数(KD)低了高达两个数量级。图5C示出了,如图所示(左图),G7-aPD-L1缀合物与aPD-L1相比倾向于表现出更高的断裂力,并具有多个断裂事件。将不同加载速率下的断裂力直方图拟合到双高斯模型中(中图)。将它们转换成Bell-Evans模型以获得解离速率(右图)。与aPD-L1相比,G7-aPD-L1缀合物的解离率动力学提高了一个数量级。总的来说,图5D显示,G7-aPD-L1表现出比aPD-L1明显更高的结合动力学。
图6(左图)示出了通过western印迹定量的786-O(PD-L1高)和MCF-7(PD-L1低)细胞系的PD-L1表达。右图显示,与MCF-7相比,786-O细胞系中aPD-L1和G7-aPD-L1的表达均明显更高。
图7(左图)显示癌细胞悬浮在用G7-aPD-L1缀合物或aPD-L1官能化的表面上。右图示出,PD-L1高癌细胞在用G7-aPD-L1缀合物以25s-1的剪切速率覆盖的表面上,与用游离抗体的相比,表现出1.4倍(p<0.05)的增强保留。
图8示出了通过评估IL-2的Jurkat T细胞产生,在体外通过G7-aPD-L1缀合物增强对PD-1/PD-L1相互作用的阻断的示意图。
图9示出了,对于图8的试验,通过G7-aPD-L1对PD-1/PD-L1途径的阻断导致T细胞IL-2产生增加1.9倍(p=0.036)。
图10示出了通过测量化学敏感性在体外通过G7-aPD-L1缀合物增强了对PD-1/PD-L1相互作用的阻断的示意图。
图11显示,对于图10的试验,与非ICI处理的细胞相比,通过G7-aPD-L1阻断PD-1/PD-L1途径导致786-O细胞对阿霉素的化学耐药性降低了9%(p=0.002)。
图12显示了G7-aPD-L1的靶特异性,使用小鼠口腔鳞状细胞癌(OSCC)细胞系MOC1(PD-L1高)。上图显示了67nM的浓度的荧光团标记的aPD-L1和G7-aPD-L1在MOC1细胞中均高度表达。但是,当通过用670nM的非荧光aPD-L1预处理细胞来阻断PD-L1配体时,两种抑制剂的表达均显著降低。总的来说,这些结果支持G7-aPD-L1对PD-L1蛋白具有高选择性。
图13显示了增强的对G7-aPD-L1的靶向,使用体内小鼠模型。使用从Envigo实验室(Indianapolis,IN)获得的4至6周龄的雌性C57BL/6小鼠进行实验。所有动物程序和维护均根据威斯康星大学的机构指南进行。为了建立体内小鼠肿瘤模型,将大约5×105个MOC1细胞注入小鼠体内。一旦肿瘤达到300mm3,就将50μL 128nM的浓度的G7-aPD-L1或aPD-L1通过荷瘤小鼠的尾静脉注射。体内成像系统(IVIS)分析揭示,与aPD-L1相比,靶向肿瘤的G7-aPD-L1增强了约2倍。
通过以下详细描述、附图和所附权利要求,本领域技术人员将领会和理解上述的和其他特征。
具体实施方式
本文描述了有效抑制免疫检查点的新型纳米颗粒系统,所述系统基于由多支化聚合物介导的多价结合。多种单克隆抗体、肽、蛋白质和小分子已被引入作为免疫治疗检查点抑制剂(ICI),并应用于临床。但是,最近发表的这类抑制剂的临床结果显示出不一致的益处。本文所述的组合物和方法显著改善了ICI的功效。通过使用超支化聚合物、树枝状聚合物、树突(dendron)和胶束的多价结合作用,可以显著增强对这些检查点的抑制作用。树枝状聚合物与ICI之间的缀合物可实现多价抑制,从而提供对靶标受体的增强的选择性、高灵敏度和强大结合亲和力。因此,所述缀合物可显著增加总体结合强度并改善免疫系统过程的调节,最终增强癌症免疫疗法。如本文所用,免疫疗法是使用个体自身的免疫系统来治疗疾病,或使用免疫系统组分来治疗疾病。
不受理论的束缚,据信与多个ICI缀合的多价的例如多支化的纳米颗粒将增强癌症免疫疗法。例如,预计与树枝状聚合物缀合的ICI通过形成多个结合对在配体和受体之间产生更强的结合,这也被称为多价结合效应。多价结合效应增加了细胞内免疫系统信号传导的强度和持续时间,这可以增强对免疫检查点的抑制。图1示出了本公开的实施方案,其中PD-L1抗体缀合的树枝状聚合物可以通过多价结合更有效地抑制PD-1/PD-L1相互作用。
本文所述的纳米颗粒系统的优点包括使用具有高水溶性、生物相容性、可修饰的表面基团和多价的纳米颗粒载体。
在一个实施方案中,纳米颗粒系统包括多价纳米颗粒核心,其包含与之缀合的多个免疫检查点抑制剂。多个ICI可包括缀合至相同纳米颗粒核心的多个相同的ICI或不同的ICI。在具体的实施方案中,所述多价纳米颗粒核心包含超支化聚合物、树枝状聚合物、树突、杂化纳米颗粒或胶束。例如,所述多价纳米颗粒核心的直径可以为3至150nm。
如本文所用,超支化聚合物是多价的颗粒,其在支化和结构方面是多分散的和不规则的。相反,树枝状聚合物具有非常规则的、径向对称的生成结构。树枝状聚合物是单分散的球形聚合物,其与超支化聚合物相比,通常以多步合成的方式制备。树枝状聚合物结构的特征在于代表对称中心的多官能核心、重复单元(代)的各种明确的径向对称层和端基。
超支化聚合物包括聚酯、聚酯酰胺、聚醚、聚酰胺、聚乙烯亚胺、聚甘油、聚乙交酯、聚丙交酯、聚丙交酯-共-乙交酯、聚酒石酸酯和多糖。超支化聚酯包括Perstorp AB的超支化聚酯酰胺包括DSM BV荷兰的聚甘油由Hyperpolymers GmbH生产,并且超支化聚乙烯亚胺包括BASF AG的
超支化聚合物例如超支化聚甘油的制备在本领域中是众所周知的。例如,使缩水甘油进行受控阴离子开环多支化聚合反应,形成超支化聚甘油。然后使超支化聚甘油与琥珀酸酐在吡啶中反应,通过酯键提供羧酸端基。一旦确认了超支化聚甘油上的官能团含量,即可通过以下方案将羟基进一步官能化:在pH8.5的DMSO或DMF中,超支化聚甘油-OH+N-(对-马来酰亚胺基苯基)异氰酸酯(PMPI,10倍摩尔过量),获得超支化聚甘油-马来酰亚胺。因此,超支化聚甘油同时具有羧基和马来酰亚胺官能团,它们可以与相应的交联剂和化学基团反应,或者可以进一步衍生化以适合可用的特定官能团。
两亲性超支化聚合物可以形成胶束状结构。所述超支化聚合物可以是“不完美”的分子,因为它可能包括线性部分,并且可能具有无规或不对称支化的特征。可以对超支化聚合物进行选择性修饰,以在表面上实现多官能度,以及将其与官能组分连接,例如连接碳链以加入疏水性,连接伯胺基团以提供亲水性和活化以进行后续修饰。
超支化聚合物的优点包括较小的单元粒度(直径通常小于60nm)和相对简单的合成步骤。可能的缺点包括宽的粒度分布,以及可能难以控制特定官能性的表面修饰。
本文所用的术语“树枝状聚合物”包括但不限于具有内部核心、内部层(或“代”)和外表面的分子结构,所述内部层(或“代”)是规则地连接至该引发剂核心并从其延伸的重复单元,每一层具有一个或多个支化点,所述外表面是与最外层的代连接的端基。树枝状聚合物具有规则的树枝状或“放射星光状”分子结构。例如,纳米树枝状聚合物的直径通常为3至10nm。
每个连续的树枝状聚合物代可以与前一代共价结合。核心结构的反应性基团的数量决定了n方向性,并限定了可以连接形成下一代的结构的数量。
树枝状结构中的支化数量取决于单体结构单元(包括核心)的支化价。例如,如果所述核心是伯胺,则胺氮将是二价的,从而产生1-2个支化基序。
示例性树枝状聚合物是烷基化树枝状聚合物,如聚(氨基胺)(PAMAM)、聚(乙烯亚胺)(PEI)、聚丙烯亚胺(PPI)、二氨基丁烷胺聚丙烯亚胺四胺(DAB-Am4)、聚丙胺(POPAM)、聚赖氨酸、聚酯、蝶烯(iptycene)、脂族聚(醚)、芳族聚醚树枝状聚合物或包含一种或多种前述物质的组合。
树枝状聚合物可以具有羧基、胺基和羟基末端,并且可以是任何一代,包括但不限于1代树枝状聚合物(G1)、2代树枝状聚合物(G2)、3代树枝状聚合物(G3)、4代树枝状聚合物(G4)、5代树枝状聚合物(G5)、6代树枝状聚合物(G6)、7代树枝状聚合物(G7)、8代树枝状聚合物(G8)、9代树枝状聚合物(G9)或10代树枝状聚合物(G10)。
PAMAM树枝状聚合物含有内部酰胺键,其可以增强其生物降解性,从而提高有关人类治疗应用的耐受性。表面包括极性的高反应性伯胺基团。氨基官能的PAMAM树枝状聚合物的表面是阳离子的,并且可以通过与带负电荷的分子的离子相互作用,或使用许多众所周知的伯胺共价官能化试剂进行衍生化。
当使用PAMAM树枝状聚合物时,通常使用0至7代PAMAM树枝状聚合物。例如,杂化纳米颗粒可以由以下形成:0代PAMAM树枝状聚合物(G0);1代PAMAM树枝状聚合物(G1);2代PAMAM树枝状聚合物(G2);3代PAMAM树枝状聚合物(G3);4代PAMAM树枝状聚合物(G4);5代PAMAM树枝状聚合物(G5);6代PAMAM树枝状聚合物(G6)或7代PAMAM树枝状聚合物(G7)。PAMAM可从多种来源商购获得,包括Sigma-Aldrich(货号597309)。
二氨基丁烷胺聚丙烯亚胺四胺(DAB Am 4)是一种具有1,4-二氨基丁烷核心(4-碳核心)和4个表面伯氨基团的聚合物。当由DAB-AM 4树枝状聚合物形成杂化纳米颗粒时,通常使用0至7代DAB-AM 4树枝状聚合物。例如,杂化纳米颗粒可以由以下形成:0代DAB-AM 4树枝状聚合物(G0);1代DAB-AM4树枝状聚合物(G1);2代DAB-AM 4树枝状聚合物(G2);3代DAB-AM 4树枝状聚合物(G3);4代DAB-AM 4树枝状聚合物(G4);5代DAB-AM 4树枝状聚合物(G5);6代DAB-AM 4树枝状聚合物(G6)或7代DAB-AM 4树枝状聚合物(G7)。DAB-AM 4可从多种来源商购获得,包括Sigma-Aldrich(货号460699)。
多价纳米颗粒可以由一种或多种不同的树枝状聚合物形成。树枝状聚合物复合物的每个树枝状聚合物可以具有与其他树枝状聚合物相似或不同的化学性质(例如:第一种树枝状聚合物可以是PAMAM树枝状聚合物,而第二种树枝状聚合物可以是POPAM树枝状聚合物)。
树突是在焦点处具有多个端基和单一反应性官能的单分散楔形树枝状聚合物部分。例如,树突可以接枝到一个表面、另一个树突或一个大分子上。双MPA(双二羟甲基丙酸)树突可从Sigma-Aldrich获得。
如本文所用,“胶束”是指两亲性分子在水性介质中的聚集体,其具有内部核心和外表面,其中所述两亲性分子主要根据其形成核心的疏水部分和形成外表面的亲水部分而取向。多种单克隆抗体、肽、蛋白质和小分子可以共价结合到胶束的亲水性头部基团上,用多个缀合的ICI覆盖纳米颗粒,从而具有更强的结合动力学。胶束通常与形成其的两亲性分子或离子形成动态平衡,所述两亲性分子或离子在溶液中以非聚集形式存在。已知许多两亲性化合物和两亲性药物化合物在一定浓度(称为临界胶束浓度或CMC)以上在水性介质中自发形成胶束,所述两亲性化合物包括特别是去污剂、表面活性剂、两亲性聚合物、脂质聚合物(例如PEG-脂质)、胆汁盐、单链磷脂和其他单链两亲物。胶束的两亲性(例如脂质)组分不形成双层相、非双层中间相、各向同性液相或固态非晶型或结晶相。胶束的概念以及形成胶束的方法和条件是本领域技术人员众所周知的。胶束可与脂质颗粒共存于溶液中。
示例性的胶束包括在美国专利号9,212,258中描述的那些,所述专利中包含两亲性树突线圈(dendron-coil)的胶束的公开内容以引用的方式并入本文。每个两亲性树突线圈包括非肽基疏水性核心形成嵌段、聚酯树突和聚乙二醇(PEG)部分。包含两亲性树突线圈的胶束也称为“多价树突缀合物”和“基于树突的纳米胶束(DNM)”。
胶束的疏水性核心形成嵌段是非肽基的,即,疏水性核心形成嵌段不是肽。在一些实施方案中,胶束包含单一类型的两亲性树突线圈(即,所述胶束中的两亲树突线圈都具有相同的三个组成部分)。在一些实施方案中,胶束包含多于一种类型的两亲性树突线圈(即,所述胶束中的两亲树突线圈的三个组成部分不同)。
在一些实施方案中,所述两亲性树突线圈的非肽基疏水性核心形成嵌段包括聚己内酯(PCL)、聚(乳酸)(PLA)、聚(乙醇酸)(PGA)或聚(乳酸-共-乙醇酸)(PLGA)。在一些实施方案中,所述非肽基疏水性核心形成嵌段是PCL。在一些实施方案中,所述PCL是聚(ε-己内酯)。在一些实施方案中,所述非肽基疏水性核心形成嵌段是PLA。在一些实施方案中,所述非肽基疏水性核心形成嵌段是PGA。在一些实施方案中,所述非肽基疏水性核心形成嵌段是PLGA。所述非肽基疏水性核心形成嵌段具有的分子量包括但不限于约0.5kDa至约20kDa的分子量。在一些实施方案中,所述非肽基疏水性核心形成嵌段是分子量为约3.5kDa的聚(ε-己内酯)。在一些实施方案中,所述非肽基疏水性核心形成嵌段是分子量为14kDa的聚(ε-己内酯)。
在一些实施方案中,所述两亲性树突线圈的聚酯树突包括但不限于具有乙炔或羧酸酯核心的3代至5代聚酯树突,即3代(G3)、4代(G4)或5代(G5)。在一些实施方案中,所述聚酯树突为G3树突。在一些实施方案中,所述聚酯树突为G5树突。在一些实施方案中,所述聚酯树突具有乙炔核心。在一些实施方案中,所述聚酯树突为3代聚酯-8-羟基-1-乙炔双-MPA树突。在一些实施方案中,所述聚酯树突具有羧酸酯核心。
在一些实施方案中,所述两亲性树突线圈的PEG部分是甲氧基PEG(mPEG)部分、末端为氨基的PEG(PEG-NH2)部分、乙酰化的PEG(PEG-Ac)部分、羧化的PEG(PEG-COOH)部分、末端为硫醇的PEG(PEG-SH)部分、N-羟基琥珀酰亚胺-PEG(PEG-NHS)部分、NH2-PEG-NH2部分或NH2-PEG-COOH部分。在一些实施方案中,所述PEG部分具有的分子量包括但不限于约0.2kDa至约5kDa的分子量。在一些实施方案中,所述PEG部分是mPEG部分。在一些实施方案中,所述PEG部分是分子量为约2kDa的mPEG部分。在一些实施方案中,所述PEG部分是分子量为约5kDa的mPEG部分。
在一个实施方案中,将聚酯树突用线性疏水性聚合物共价修饰以帮助促进链缠结和分子内相互作用,这有助于核-壳型胶束的自组装并使得疏水性药物分子能够被装载在胶束内。当在体内施用胶束时,PEG部分形成具有无污染性质的亲水性冠部(corona),并提供增加的循环半衰期。
生物学上重要的性质,例如生物降解性、循环半衰期、可靶向性、药代动力学和药物释放,可以通过改变两亲性树突线圈的三个组分(也称为三个聚合物嵌段)来控制。此外,共聚物结构是柔性的,并且易于通过改变每种组分的分子量来操作以微调亲水亲脂平衡(HLB)。例如,多种实施方案采用PCL、聚酯树突和PEG,其分子量分别为0.5-20kDa、G3-G5(约0.9-3.5kDa)和0.2-5kDa。因此,HLB(20MH/(MH+ML),其中MH是亲水性嵌段的质量,ML是亲脂性嵌段的质量)在2.22至19.94之间大范围变化。
当树突在两亲性树突线圈代中与疏水性线性聚合物(例如聚己内酯(PCL)、聚乳酸(PLA)、聚乙醇酸(PGA)和聚乳酸-共-乙醇酸(PLGA))共聚时,锥形的两亲性树突状线圈进而具有有利的结构属性,因为它们形成了自组装的胶束,所述胶束在热力学上是有利的,并且具有高度堆积的PEG表面层,以增加血液循环时间。形成胶束的热力学稳定性以及易于调节的独特结构。
纳米载体系统包括超支化聚合物和其他生物相容性纳米颗粒的杂合物。例如,这样的杂化纳米颗粒包括树枝状聚合物-脂质体、树枝状聚合物-PEG-PLA、树枝状聚合物-外泌体(exosome)杂合物,其结合了树枝状聚合物(直径为2-10nm)和较大的纳米颗粒(50-200nm)的独特优点。
示例性的杂化纳米颗粒(也称为纳米杂合物)包括在美国专利号9,168,225中描述的那些,所述专利中杂化纳米颗粒的公开内容通过引用的方式并入本文。在该实施方案中,杂化纳米颗粒是其中纳米核心被包围或封装在基质或壳中的颗粒。换句话说,较大粒子中具有较小粒子。在某些实施方案中,所述杂化纳米颗粒包含在脂质体内部的纳米核心。在其他实施方案中,所述纳米核心被聚合物基质或壳(例如,聚合物纳米颗粒)包围。
所述纳米核心的最大直径优选为1nm至50nm。更优选地,所述纳米核心的最大直径为1至40nm,最优选其最大直径为3至20nm。可以通过动态光散射和/或扫描电子显微镜分析纳米核心以确定颗粒的粒度。纳米核心可以具有任何形状和形态。纳米核心的实例包括纳米粉末、纳米簇、纳米晶体、纳米球、纳米纤维和纳米管。鉴于其纳米级粒度,纳米核心骨架易于被排出。因此,所采用的纳米核心骨架不必是可生物降解的,但是在特定的实施方案中,所述纳米核心骨架是生物相容的,即对细胞无毒。如果在体外将它们添加到细胞中会导致小于或等于30%、20%、10%、5%或1%的细胞死亡,并且在体内不会引起炎症或其他此类不良影响,那么骨架是“生物相容的”。
示例性的聚合物骨架包括但不限于,聚酰胺、多糖、聚酸酐、聚-L-赖氨酸、聚丙烯酰胺、聚甲基丙烯酸酯、多肽、聚环氧乙烷、聚乙烯亚胺(PEI)或树枝状聚合物(例如聚(氨基胺)(PAMAM)和PAMAM(乙二胺-EDA)树枝状聚合物)或其修饰形式(例如所述聚合物的羟基化、乙酰化或羧化形式)。其他示例性聚合物主链描述于例如WO98/46270(PCT/US98/07171)或WO98/47002(PCT/US98/06963)中。多价聚合物骨架分子可具有选自线性、支化、叉状或星形的构型。
在一些实施方案中,多价聚合物骨架分子的至少一部分可以是疏水的。在一些实施方案中,多价聚合物骨架分子的至少一部分可以是亲水的。在另一个实施方案中,多价聚合物骨架分子的一部分可以是疏水的,并且该分子的不同部分可以是亲水的。在特定的实施方案中,多价聚合物骨架分子是阳离子的。在其他的实施方案中,多价聚合物骨架分子是电中性的。在其他的实施方案中,多价聚合物骨架分子是阴离子的。本领域技术人员将认识到,可以选择多种起始材料以获得表现出所需性质的多价聚合物骨架分子。
在一个实施方案中,壳是由磷脂组成的脂质体,所述磷脂例如卵磷脂酰胆碱、卵磷脂酰乙醇胺、大豆磷脂酰胆碱、卵磷脂、鞘磷脂、合成磷脂酰胆碱、溶血磷脂酰胆碱、磷脂酰甘油、磷脂酸、磷脂酰乙醇胺或磷脂酰丝氨酸,其中所述磷脂可以用长循环剂或冷冻保护剂进行修饰。在另一个实施方案中,壳是由聚合物组成的聚合物纳米颗粒,所述聚合物选自聚(γ-L-谷氨酰基谷氨酰胺)、聚(γ-L-天冬氨酰基谷氨酰胺)、聚-L-乳酸、聚(乳酸-共-乙醇酸)、聚氰基丙烯酸烷基酯、聚酸酐、聚羟基酸、聚丙基延胡索酸酯、聚酰胺、聚缩醛、聚醚、聚酯、聚(原酸酯)、聚氰基丙烯酸酯、[N-(2-羟丙基)甲基丙烯酰胺]共聚物、聚乙烯醇、聚氨酯、聚磷腈、聚丙烯酸酯、聚脲,聚胺、聚ε-己内酯及其共聚物的组,其中所述聚合物被修饰或衍生化以增强蛋白水解抗性、改善循环半衰期、降低抗原性、降低免疫原性、降低毒性、改善溶解度或改善热稳定性或机械稳定性。在特定的实施方案中,壳是可生物降解的。在某些实施方案中,多价聚合物骨架是阳离子的,并且由聚酰胺、多糖、聚酸酐、聚-L-赖氨酸、聚丙烯酰胺、聚甲基丙烯酸酯、多肽、聚环氧乙烷、聚乙烯亚胺、聚(氨基胺)(PAMAM)或PAMAM(乙二胺-EDA)组成。
另一种杂化纳米颗粒是如美国申请序列号16/011,922中所述的树枝状聚合物-外泌体杂合物。树枝状聚合物-外泌体杂合物是装载有一种或多种纳米颗粒树枝状聚合物的外泌体。如本文所用,外泌体是指从多种细胞分泌的具有膜结构的小囊泡。外泌体的直径为约25至约150nm。外泌体可以表达标记物,例如VLA-4、CD162、CXCR4、CD9、CD63、CD81或其组合。在一个实施方案中,外泌体衍生自从受试者例如人类受试者分离的干细胞或肿瘤细胞。
在一个实施方案中,所述外泌体衍生自从受试者例如人类受试者分离的干细胞或肿瘤细胞。
干细胞包括胚胎干细胞或成人干细胞,优选成人干细胞。成人干细胞可以是但不限于间充质干细胞、人类组织来源的间充质基质细胞(间充质基质细胞)、人类组织来源的间充质干细胞、多能干细胞或羊膜上皮细胞,优选间充质干细胞。间充质干细胞可以源自但不限于脐带、脐带血、骨髓、脂肪、肌肉、神经、皮肤、羊膜、胎盘等。
在一个实施方案中,干细胞是间充质干细胞。间充质干细胞(MSC)可以特异性地靶向在癌性区域中常见的炎性区域,即MSC肿瘤归巢。
在另一个实施方案中,外泌体是从肿瘤细胞分离的。肿瘤细胞活跃地产生、释放和利用外泌体来促进肿瘤的生长。
外泌体可通过从受试者分离肿瘤或干细胞、使所述肿瘤或干细胞扩增以提供扩增的细胞群、培养所述扩增的细胞群、并分离从所述扩增的肿瘤或干细胞分泌的外泌体来产生。可以从分离的外泌体中除去内部组分,以提供所谓的外壳(ghost)外泌体,其实质上是用于装载例如纳米颗粒树枝状聚合物的组分的空容器。除上述特征外,源自患者的外泌体还可以为患者提供非免疫原性的纳米载体壳,从而可以选择个性化药物。
为了允许免疫检查点抑制剂的缀合,一方面,通过与烷基环氧化物反应来修饰多价纳米颗粒,其中环氧化物的R基团具有1至30个碳原子。在一些实施方案中,烷基环氧化物与多价纳米颗粒上存在的氨基反应以形成烷基化的多价纳米颗粒。
存在于多价纳米颗粒上的胺基使用偶联接头为多种基于胺的缀合反应提供反应位点,所述偶联接头包括但不限于:二环己基碳化二亚胺、二异丙基碳化二亚胺、N-(3-二甲基氨基丙基)-N'-乙基碳化二亚胺、1,1'-羰基二咪唑、N-琥珀酰亚胺基S-乙酰基硫代乙酸酯、N-琥珀酰亚胺基-S-乙酰硫代丙酸酯、2-巯基乙胺、磺基琥珀酰亚胺基4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯、琥珀酰亚胺基碘乙酸酯、琥珀酰亚胺基3-(2-吡啶基二硫代)丙酸酯。在一些实施方案中,使用反应性酯通过酯键来连接多价纳米颗粒和其他化合物。反应性酯的实例包括但不限于N-羟基琥珀酰亚胺酯、N-羟基磺基琥珀酰亚胺酯、N-γ-马来酰亚胺基丁酰基-氧磺基琥珀酰亚胺酯、硝基苯基酯、四氟苯基酯、五氟苯基酯、硫代吡啶基酯、硫代硝基苯基酯。优选地,反应性酯基是N-羟基琥珀酰亚胺酯。
纳米颗粒系统包括多个缀合的ICI。免疫检查点是指硬连接(hardwire)到免疫系统中的多种抑制途径,这些途径对于维持自我耐受以及调节外周组织中生理免疫应答的持续时间和幅度以将对附带组织的损害最小化至关重要。肿瘤共同选择某些免疫检查点途径作为免疫抵抗的主要机制,特别是针对对肿瘤抗原具有特异性的T细胞。因为许多免疫检查点是由配体-受体相互作用引发的,所以它们很容易被抗体阻断或被重组形式的配体或受体调节。在一个实施方案中,ICI特异性结合CD25、PD-1、PD-L1、PD-L2、CTLA-4、免疫球蛋白受体(KIR)、LAG-3、TIM-3、4-1BB、4-1BBL、GITR、CD40、CD40L、OX40、OX40L、CXCR2、B7-H3、B7-H4、BTLA、HVEM、CD28、A2aR、CD27、CD70、TCR ICOS、CD80、CD86、ICOS-L、CD70、Gal-9、VISTA、CD-137、CD155、CD266、PVR、PVR-2、CD47、CD160、NT5E、CD96、TNFRSF18或包含上述一项或多项的组合。在一个实施方案中,ICI是完整抗体、抗体片段或肽。
示例性的免疫检查点抑制剂包括:西米普利单抗-rwlc(cemiplimab-rwlc)、纳武利尤单抗(nivolumab)、帕博利珠单抗(pembrolizumab)、匹地利珠单抗(pidilizumab)、MEDI-0680、PDR001、REGN2810、以及BGB-108、AMP-224、免疫粘附素、BMS-936559、阿替利珠单抗(atezolizumab)、YW243.55.S70、MDX-1105、MEDI4736、度伐利尤单抗(durvalumab)、阿维鲁单抗(avelumab)、伊匹单抗(ipilimumab)、曲美木单抗(tremelimumab)、BMS-986016、乌瑞鲁单抗(urelumab)、TRX518、达西珠单抗(dacetuzumab)、卢卡单抗(lucatumumab)、SEA-CD40、CP-870,893、MED16469、MOXR0916、MSB001078C或包含上述一项或多项的组合。
在一个实施方案中,PD-1结合拮抗剂是抗PD-1抗体(例如,人类抗体、人源化抗体或嵌合抗体)。示例性的抗PD-1抗体包括REGN2810(西米普利单抗)、MDX 1106(纳武利尤单抗)、MK-3475(帕博利珠单抗)、CT-011(匹地利珠单抗)、MEDI-0680(AMP-514)、PDR001和BGB-108(替雷利珠单抗)。在一个实施方案中,PD-1结合分子是免疫粘附素(例如,一种免疫粘附素,其包含融合至恒定区(例如,免疫球蛋白序列的Fc区)的PD-L1或PD-L2的细胞外或PD-1结合部分)。在一个实施方案中,PD-1结合分子是AMP-224。AMP-224,也称为B7-DCIg,是在WO2010/027827和WO2011/066342中描述的PD-L2-Fc融合可溶性受体。
MDX-1106,也称为MDX-1106-04、ONO-4538、BMS-936558或纳武利尤单抗,是WO2006/121168中描述的抗PD-1抗体。MK-3475,也称为lambrolizumab(帕博利珠单抗),是WO2009/114335中描述的抗PD-1抗体。CT-011,也称为hBAT、hBAT-1或匹地利珠单抗,是WO2009/101611中描述的抗PD-1抗体。
在一个实施方案中,PD-L1结合拮抗剂是抗PD-L1抗体。示例性的抗PD-L1抗体包括MPDL3280A(阿替利珠单抗)、YW243.55.S70、MDX-1105、MEDI4736(度伐利尤单抗)和MSB0010718C(阿维鲁单抗)。抗体YW243.55.S70是WO2010/077634中描述的抗PD-L1。MDX-1105,也称为BMS-936559,是WO2007/005874中描述的抗PD-L1抗体。MEDI4736是WO2011/066389和US2013/034559中描述的抗PD-L1单克隆抗体。
其他ICI包括伊匹单抗(抗CTLA-4)、曲美木单抗(抗CTLA-4)、BMS-986016(抗LAG-3)、乌瑞鲁单抗(抗4-1BB)、MSB001078C(抗4-1BB)、TRX51(抗GITR)、达西珠单抗(抗CD40)、卢卡单抗(抗CD40)、SEA-CD40(抗CD40)、CP-870,893(抗CD40)、MED16469(OX40)和MOXR0916(OX40)。
多价纳米颗粒核上的大量端基使得能够缀合除ICI外的多种分子。该多价纳米颗粒核心可以与一种或多种治疗、预防或诊断剂关联,例如复合或缀合。诊断剂包括成像剂。
一方面,治疗剂是化疗剂。化疗剂包括但不限于以下类别:烷基化剂、抗代谢药、蒽环类药、植物生物碱、拓扑异构酶抑制剂、单克隆抗体和其他抗肿瘤剂。除了上述化疗药物,即阿霉素、紫杉醇外,其他合适的化疗药物还包括酪氨酸激酶抑制剂甲磺酸伊马替尼(或)、顺铂、卡铂、奥沙利铂、甲氯乙胺、环磷酰胺、苯丁酸氮芥、硫唑嘌呤、巯基嘌呤、嘧啶、长春新碱、长春花碱、长春瑞滨、长春地辛、鬼臼毒素(L01CB)、依托泊苷、多西他赛、拓扑异构酶抑制剂(L01CB和L01XX)、伊立替康、托泊替康、安吖啶、依托泊苷、依托泊苷磷酸酯、替尼泊苷、放线菌素D、氯尼达明、以及单克隆抗体、例如曲妥珠单抗西妥昔单抗、贝伐单抗和利妥昔单抗等。
治疗剂的其他实例包括但不限于抗微生物剂、镇痛剂、抗炎剂及其他。可以将通常用于治疗感染的抗生素(例如万古霉素)掺入颗粒中,所述感染包括由于耐甲氧西林金黄色葡萄球菌(MRSA)引起的感染。颗粒任选地包括环孢菌素,一种作为免疫抑制剂的亲脂性药物,广泛用于同种异体器官移植后,以降低患者免疫系统的活性和器官排斥的风险(由诺华以商标和销售)。包含环孢霉素的颗粒也可以用于局部用乳剂中,以治疗干燥性角膜结膜炎。在这方面,可以设计掺入了此类药物的具有多官能表面结构域的颗粒,以将等剂量的各种药物直接递送至癌细胞,从而潜在地使递送至患者的总量最小化,并使对其他组织的附带损害最小化。
治疗剂还包括治疗性核酸,例如基因沉默剂、基因调节剂、反义剂、肽核酸剂、核酶剂、RNA剂和DNA剂。核酸治疗剂包括能够减少或抑制靶基因或序列的表达的单链或双链RNA或DNA,特别是RNA,例如三链体寡核苷酸、核酶、适体、包括siRNA(短干扰RNA)和shRNA(短发夹RNA)的小干扰RNA,反义RNA、微小RNA(miRNA)或其一部分,或其类似物或模拟物。抑制性核酸可以通过例如介导与干扰RNA序列互补的mRNA的降解或抑制该mRNA的翻译而起作用。
诊断剂是能够对组织或疾病进行检测或成像的试剂。诊断剂的实例包括但不限于放射性标记、荧光团和染料。
成像剂是指附着在本发明的无规共聚物上的用于对受试者的肿瘤、器官或组织进行成像的标记。显像剂的实例包括但不限于放射性核素、荧光团,例如荧光素、若丹明、异硫氰酸酯(TRITC、FITC)、德克萨斯红、Cy2、Cy3、Cy5、APC和(Invitrogen,Carlsbad,Calif.)系列荧光团、抗体、钆、金、纳米材料、辣根过氧化物酶、碱性磷酸酶、其衍生物及其混合物。
放射性标记是指表现出放射性的核素。“核素”是指通过原子序数、原子质量和能态而指定的原子类型,例如碳14(14C)。“放射性”是指由放射性物质发射的辐射,包括α粒子、β粒子、核子、电子、正电子、中微子和伽马射线。
预防剂的施用可以在疾病或病症的特征性症状的表现之前发生,使得疾病或病症发展被预防或者被延缓。
治疗性分子、诊断剂和预防剂可以通过化学缀合、物理包封和/或静电相互作用方法与多价纳米颗粒核心组合。
还包括药物组合物,其包含本文所描述的纳米颗粒系统。药物组合物可以进一步包含如上所描述的治疗剂、预防剂或诊断剂。
如本文所用,“药物组合物”是指治疗有效量的纳米颗粒以及药学上可接受的赋形剂,例如稀释剂、防腐剂、增溶剂、乳化剂和佐剂。如本文所用,“药学上可接受的赋形剂”是本领域技术人员众所周知的。
用于口服施用的片剂和胶囊剂可以是单位剂型,并且可以含有常规的赋形剂,例如结合剂,例如糖浆、阿拉伯胶、明胶、山梨糖醇、黄芪胶或聚乙烯吡咯烷酮;填充剂,例如乳糖、糖、玉米淀粉、磷酸钙、山梨糖醇或甘氨酸;压片润滑剂,例如硬脂酸镁、滑石粉、聚乙二醇或二氧化硅;崩解剂,例如马铃薯淀粉,或可接受的润湿剂,例如十二烷基硫酸钠。可以根据常规制药实践中众所周知的方法将所述片剂包衣。用于口服施用的液体制剂可以是例如水性或油性悬浮剂、溶液剂、乳剂、糖浆剂或酏剂的形式,或者可以作为干燥产品存在,以在使用前用水或其他合适的溶媒重构。这样的液体制剂可以含有常规的添加剂,例如悬浮剂,例如山梨糖醇、糖浆、甲基纤维素、葡萄糖浆、明胶氢化的食用脂肪;乳化剂,例如卵磷脂、脱水山梨糖醇单油酸酯或阿拉伯胶;非水性溶媒(可能包括食用油),例如杏仁油、分馏椰子油,油性酯(如甘油、丙二醇或乙醇);防腐剂,例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或山梨酸,以及如果需要的话,常规的调味剂或着色剂。
为了局部施用于皮肤,可以将药物制成乳膏剂、洗剂或软膏剂。可以用于药物的乳膏剂或软膏剂制剂是本领域公知的常规制剂。局部施用包括透皮制剂,例如贴剂。
为了局部施用于眼睛,可以将抑制剂在合适的无菌水性或非水性溶媒中制成溶液或悬浮液。还可以包括添加剂,例如缓冲剂,例如焦亚硫酸钠或乙二胺四乙酸二钠;防腐剂,包括杀菌剂和杀真菌剂,例如乙酸苯汞或硝酸苯汞、苯扎氯铵或洗必泰,以及增稠剂,例如羟丙甲纤维素。
活性成分也可以在无菌介质中,以无菌的可注射的水性或油性悬浮液的形式,通过皮下、或静脉内、或肌肉内、或脑池内、或通过输注技术,肠胃外施用。根据所用的溶媒和浓度,可以将药物悬浮或溶解在溶媒中。有利地,可以将诸如局部麻醉剂、防腐剂和缓冲剂之类的佐剂溶解在溶媒中。
药物组合物可以方便地以单位剂型存在,并且可以通过药学领域公知的任何方法制备。术语“单位剂型”或“单位剂量”是指足以有效治疗指定的活动或状况的预定量的活性成分。制备每种类型的药物组合物包括使活性化合物与载体和一种或多种任选的辅助成分结合的步骤。通常,通过将活性化合物与液体或固体载体均匀且紧密地结合在一起来制备制剂,然后,如果需要,将产品成型为所需的单位剂型。
在一方面,一种制备纳米颗粒系统的方法包括,在足以将多个免疫检查点抑制剂缀合至多价纳米颗粒核心并提供纳米颗粒系统的条件下,使包含多个反应性端基的多价纳米颗粒核心与包含免疫检查点抑制剂的组合物接触。示例性的端基包括偶联接头和反应性环氧化物,例如二环己基碳化二亚胺、二异丙基化碳二亚胺、N-(3-二甲基氨基丙基)-N'-乙基碳化二亚胺、1,1'-羰基二咪唑、N-琥珀酰亚胺基S-乙酰硫代乙酸酯、N-琥珀酰亚胺基-S-乙酰硫代丙酸酯、2-巯基乙胺、磺基琥珀酰亚胺基4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯、琥珀酰亚胺基碘乙酸酯、琥珀酰亚胺基3-(2-吡啶基二硫代)丙酸酯、N-羟基琥珀酰亚胺酯、N-羟基磺基琥珀酰亚胺酯、N-γ-马来酰亚胺基丁酰基-氧磺基琥珀酰亚胺酯、硝基苯基酯、四氟苯基酯、五氟苯基酯、硫代吡啶基酯、硫代硝基苯基酯,以及包含前述至少一项的组合。
在一个实施方案中,多价纳米颗粒核心包含两种或更多种不同类型的反应性端基,以增强核心的反应性和/或特异性。
在另一个实施方案中,免疫疗法方法包括向受试者例如人类受试者施用本文所描述的纳米颗粒系统。示例性的人类受试者包括癌症患者和患有免疫疾病(例如多发性硬化症和类风湿性关节炎)的患者。纳米颗粒可以通过与T细胞、癌细胞和/或抗原呈递细胞相互作用来靶向免疫系统。
本文所描述的组合物和方法适用于所有癌症,包括实体瘤癌症,例如乳腺、前列腺、卵巢、肺和脑的实体瘤癌症,以及液体癌如白血病和淋巴瘤。
本文所描述的方法可以进一步与另外的癌症疗法例如放疗、化疗、手术及其组合相结合。
通过以下非限制性实施例进一步说明本发明。
实施例
实施例1:树枝状聚合物-ICI抗体缀合物的合成
图2展示了聚合物-抑制剂缀合物的示例性合成方法,其包括7代(G7)聚(氨基胺)(PAMAM)树枝状聚合物和四个PD-L1抗体(G7-aPD-L1缀合物)。可以采用多种缀合化学来形成不同的聚合物-抑制剂缀合物。在该实施例中,用Alexa647标记G7 PAMAM树枝状聚合物,然后使用乙酸酐进行部分乙酰化。为了减少空间位阻,将大约90%的胺端基乙酰化。然后通过与琥珀酸酐反应,将剩余的胺端基羧化。使用EDC/NHS化学方法,将树枝状聚合物上的羧基端基与aPD-L1的胺基缀合。每个树枝状聚合物缀合约3.9±0.6个抗体。
图3和4示出了使用AFM表征树枝状聚合物缀合物,证实了G7树枝状聚合物与抗体之间的成功缀合。AFM图像表明,与游离抗体(D=12.7±4.4nm;p<0.001)和G7 PAMAM树枝状聚合物(D=16.3±7.3nm;p<0.001)相比,G7-Ab缀合物 的侧向直径(D)和高度(h)均显著增加。
实施例2:增强结合动力学的确认
图5显示了G7-aPD-L1的结合亲和力的增强,使用以下方式确认:(5A)表面等离子体共振(SPR)、(5B)生物层干涉法(BLI)和(5C)原子力显微镜(AFM):(5A、B),G7-aPD-L1缀合物显示出比游离的aPD-L1低至多两个数量级的解离常数(KD);(5C),如图所示(左图),与aPD-L1相比,G7-aPD-L1缀合物倾向于表现出更高的断裂力,并具有多个断裂事件。将不同加载速率下的断裂力直方图拟合到双高斯模型中(中图)。将它们转换成Bell-Evans模型以获得解离速率(右图)。与aPD-L1相比,G7-aPD-L1缀合物的解离率动力学提高了一个数量级。(5D)。总的来说,G7-aPD-L1表现出比aPD-L1明显更高的结合动力学。
在SPR方法中,将羧甲基化的葡聚糖共价附于金表面。偏振光在界面处撞击导电表面,从而提供反射的电子电荷密度波。反射光的角度随着分子在表面处的结合和解离而改变,并在传感图中记录相互作用曲线。BLI方法是一种无标记的生物传感器方法,其可以对分子相互作用进行实时测量。它可以检测从光纤生物传感器表面反射回的白光干涉图案的变化。x轴是时间(s),y轴是nm。由于没有流动,原始数据显示与生物传感器表面结合的BLI干扰峰(nm)中的波长变化,这是平均光学厚度变化的函数。对于关联,波长实时向右移动。对于解离,波长移回到其原始位置。
SPR和BLI结果均表明,G7-aPD-L1缀合物的解离常数(KD)比游离抗体的解离常数低至多两个数量级,这表明缀合物与靶标蛋白的结合更强。
表1:SPR结果
游离抗体 | 缀合物 | |
k<sub>a</sub>(1/Ms) | 7.68×10<sup>4</sup> | 5.53×10<sup>6</sup> |
k<sub>d</sub>(1/s) | 2.83×10<sup>-5</sup> | 2.51×10<sup>-5</sup> |
K<sub>D</sub>(M) | 3.69×10<sup>-10</sup> | 4.54×10<sup>-12</sup> |
·在25μg/mL的浓度下测得的KD值(游离抗体为166.7nM,缀合物为34.5nM)
表2:BLI结果
游离抗体 | 缀合物 | |
k<sub>a</sub>(1/Ms) | 2.38×10<sup>5</sup> | 1.18×10<sup>6</sup> |
k<sub>d</sub>(1/s) | 2.75×10<sup>-4</sup> | 6.79×10<sup>-5</sup> |
K<sub>D</sub>(M) | 1.16×10<sup>-9</sup> | 6.16×10<sup>-11</sup> |
·在25μg/mL的浓度下测得的KD值(游离抗体为166.7nM,缀合物为34.5nM)
实施例3:G7-aPD-L1的靶标特异性和增强的结合动力学
在体外证实了,与aPD-L1相比,G7-aPD-L1的靶标特异性和增强的结合动力学。图6(左图)示出了通过western印迹定量的786-O(PD-L1高)和MCF-7(PD-L1低)细胞系的PD-L1表达。与MCF-7相比,786-O细胞系中aPD-L1和G7-aPD-L1的表达均明显更高。图7显示了通过细胞保留试验在体外验证了增强的结合动力学。在图7中,癌细胞悬浮在用G7-aPD-L1缀合物或aPD-L1官能化的表面上。PD-L1高癌细胞在用G7-aPD-L1缀合物以25s-1的剪切速率覆盖的表面上,与用游离抗体的相比,表现出1.4倍(p<0.05)的增强保留。
实施例4:通过G7-aPD-L1缀合物增强对PD-1/PD-L1相互作用的阻断
通过(图8和9)评估IL-2的Jurkat T细胞产生以及(图10和11)测量化学敏感性,证实了通过G7-aPD-L1缀合物增强了对PD-1/PD-L1相互作用的阻断。与未经ICI处理的细胞相比,通过G7-aPD-L1阻断PD-1/PD-L1途径导致T细胞IL-2产生增加1.9倍(p=0.036),786-O细胞对阿霉素的化学抗性降低9%(p=0.002)。结果优于游离抗体,后者仅显示T细胞IL-2产生增强1.4倍(p=0.004),癌细胞化学抗性降低5%(p=0.020)。需要注意,非靶向树枝状聚合物在阻断PD-1/PD-L1相互作用方面没有显著作用。
实施例5:小鼠研究
如图12和13所示,通过体内小鼠模型研究进一步证实了通过G7-aPD-L1对PD-1/PD-L1相互作用的增强阻断。67nM的浓度的荧光团标记的aPD-L1和G7-aPD-L1在MOC1细胞中均高度表达。但是,当通过用670nM的非荧光aPD-L1预处理细胞来阻断PD-L1配体时,两种抑制剂的表达均显著降低。图13显示了增强的对G7-aPD-L1的靶向,使用体内小鼠模型。使用从Envigo实验室(Indianapolis,IN)获得的4至6周龄的雌性C57BL/6小鼠进行实验。所有动物程序和维护均根据威斯康星大学的机构指南进行。为了建立体内小鼠肿瘤模型,将大约5×105个MOC1细胞注入小鼠体内。一旦肿瘤达到300mm3,就将50μL 128nM的浓度的G7-aPD-L1或aPD-L1通过荷瘤小鼠的尾静脉注射。体内成像系统(IVIS)分析揭示,与aPD-L1相比,靶向肿瘤的G7-aPD-L1增强了约2倍。
除非本文另外指出或与上下文明显矛盾,否则上下文中(特别是在所附权利要求的上下文中)所使用的术语“一(a)”和“一个(an)”以及“该(the)”和类似的附图标记应被解释为涵盖单数和复数。这里使用的术语第一、第二等并不意味着表示任何特定的顺序,而仅仅是为了方便表示多个例如层。除非另有说明,否则术语“包含”、“具有”、“包括”和“含有”应被解释为开放式术语(即,意思是“包括但不限于”)。除非另有说明,否则数值范围的列举仅旨在用作分别指代落入该范围内的每个单独值的简写方法,并且每个单独值都被并入说明书中,就如同在此单独列举一样。所有范围的端点都包含在该范围内并且可以独立组合。除非本文另外指出或与上下文明显矛盾,否则本文描述的所有方法可以以合适的顺序执行。除非另外要求,否则所使用的任何示例和所有示例或示例性语言(例如“诸如”)仅旨在更好地说明本发明,并且不对本发明的范围构成限制。说明书中的任何语言都不应被解释为表示任何未要求保护的要素对于如本文所使用的本发明的实施是必不可少的。
虽然已经参考示例性实施方案描述了本发明,但是本领域技术人员将理解,可以进行各种改变,并且可以在不脱离本发明范围的情况下用等同物代替其要素。另外,在不脱离本发明的实质范围的情况下,可以做出许多修改以使特定情况或材料适应本发明的教导。因此,意图是本发明不限于作为预期用于实现本发明的最佳模式而公开的特定实施方案,而是本发明将包括落入所附权利要求的范围内的所有实施方案。除非本文另外指出或上下文明显矛盾,否则本发明涵盖上述元素在其所有可能的变化中的任何组合。
Claims (31)
1.一种纳米颗粒系统,其包含
多价纳米颗粒核心,所述多价纳米颗粒核心包含与之缀合的多个免疫检查点抑制剂。
2.根据权利要求1所述的纳米颗粒系统,其中所述多价纳米颗粒核心包含超支化聚合物、树枝状聚合物、树突、杂化纳米颗粒或胶束。
3.根据权利要求2所述的纳米颗粒系统,其中所述胶束包含两亲性树突线圈。
4.根据权利要求2所述的纳米颗粒系统,其中所述杂化纳米颗粒包含树枝状聚合物-外泌体杂合物。
5.根据权利要求2所述的纳米颗粒系统,其中所述杂化纳米颗粒包含:多价聚合物骨架纳米颗粒核心,其上共价连接了免疫检查点抑制剂;以及包封所述聚合物骨架纳米颗粒核心的外壳,其中所述外壳包括脂质体或聚合物壳。
6.根据权利要求2所述的纳米颗粒系统,其中所述树枝状聚合物是聚(氨基胺)(PAMAM)树枝状聚合物、聚酯树枝状聚合物、聚丙烯亚胺(PPI)树枝状聚合物、二氨基丁烷胺聚丙烯亚胺四胺(DAB-Am 4)树枝状聚合物、聚丙基胺(POPAM)树枝状聚合物、聚赖氨酸树枝状聚合物、聚酯树枝状聚合物、蝶烯树枝状聚合物、脂肪族聚(醚)树枝状聚合物、芳族聚醚树枝状聚合物或包含一种或多种前述物质的组合。
7.根据权利要求2所述的纳米颗粒系统,其中所述树枝状聚合物是PAMAM树枝状聚合物。
8.根据权利要求1所述的纳米颗粒系统,其中所述免疫检查点抑制剂特异性结合CD25、PD-1、PD-L1、PD-L2、CTLA-4、免疫球蛋白受体(KIR)、LAG-3、TIM-3、4-1BB、4-1BBL、GITR、CD40、CD40L、OX40、OX40L、CXCR2、B7-H3、B7-H4、BTLA、HVEM、CD28、A2aR、CD27、CD70、TCRICOS、CD80、CD86、ICOS-L、CD70、Gal-9、VISTA、CD-137、CD155、CD266、PVR、PVR-2、CD47、CD160、NT5E、CD96或TNFRSF18。
9.根据权利要求8所述的纳米颗粒系统,其中所述免疫检查点抑制剂是完整抗体、抗体片段或肽。
10.根据权利要求8所述的纳米颗粒系统,其中所述免疫检查点抑制剂包括:西米普利单抗-rwlc、纳武利尤单抗、帕博利珠单抗、匹地利珠单抗、MEDI-0680、PDR001、REGN2810、以及BGB-108、AMP-224、免疫粘附素、BMS-936559、阿替利珠单抗、YW243.55.S70、MDX-1105、MEDI4736、度伐利尤单抗、阿维鲁单抗、伊匹单抗、曲美木单抗、BMS-986016、乌瑞鲁单抗、TRX518、达西珠单抗、卢卡单抗、SEA-CD40、CP-870,893、MED16469、MOXR0916或MSB001078C。
11.根据权利要求1所述的纳米颗粒系统,其中所述纳米颗粒系统进一步与治疗剂、预防剂或诊断剂相关联。
12.根据权利要求11所述的纳米颗粒系统,其中所述治疗剂是化疗剂或治疗性核酸。
13.根据权利要求11所述的纳米颗粒系统,其中所述诊断剂是成像剂。
14.一种药物组合物,其包含如权利要求1-13的任一项所述的纳米颗粒系统和药学上可接受的赋形剂。
15.根据权利要求14所述的药物组合物,其还包含治疗剂、预防剂或诊断剂。
16.一种制备纳米颗粒系统的方法,所述方法包括:
在足以将多个免疫检查点抑制剂缀合至多价纳米颗粒核心并提供纳米颗粒系统的条件下,使包含多个反应性端基的多价纳米颗粒核心与包含一种或多种免疫检查点抑制剂的组合物接触。
17.根据权利要求16所述的方法,其中所述反应性端基包括二环己基碳化二亚胺、二异丙基化碳二亚胺、N-(3-二甲基氨基丙基)-N'-乙基碳化二亚胺、1,1'-羰基二咪唑、N-琥珀酰亚胺基S-乙酰硫代乙酸酯、N-琥珀酰亚胺基-S-乙酰硫代丙酸酯、2-巯基乙胺、磺基琥珀酰亚胺基4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯、琥珀酰亚胺基碘乙酸酯、琥珀酰亚胺基3-(2-吡啶基二硫代)丙酸酯、N-羟基琥珀酰亚胺酯、N-羟基磺基琥珀酰亚胺酯、N-γ-马来酰亚胺基丁酰基-氧磺基琥珀酰亚胺酯、硝基苯基酯、四氟苯基酯、五氟苯基酯、硫代吡啶基酯、硫代硝基苯基酯,以及包含前述至少一项的组合。
18.根据权利要求16所述的方法,其中所述多价纳米颗粒核心包含两种或更多种不同的反应性端基。
19.根据权利要求16所述的方法,其还包括使包含多个反应性端基的多价纳米颗粒核与治疗剂、预防剂或诊断剂接触。
20.根据权利要求16所述的方法,其中所述多价纳米颗粒核心包含超支化聚合物、树枝状聚合物、树突、杂化纳米颗粒或胶束。
21.根据权利要求20所述的方法,其中所述胶束包含两亲性树突线圈。
22.根据权利要求20所述的方法,其中所述杂化纳米颗粒包含树枝状聚合物-外泌体杂合物。
23.根据权利要求20所述的方法,其中所述杂化纳米颗粒包含:多价聚合物骨架纳米颗粒核心,其上共价连接了免疫检查点抑制剂;以及包封所述聚合物骨架纳米颗粒核心的外壳,其中所述外壳包括脂质体或聚合物壳。
24.根据权利要求20所述的方法,其中所述树枝状聚合物是聚(氨基胺)
(PAMAM)树枝状聚合物、聚酯树枝状聚合物、聚丙烯亚胺(PPI)树枝状聚合物、二氨基丁烷胺聚丙烯亚胺四胺(DAB-Am 4)树枝状聚合物、聚丙基胺(POPAM)树枝状聚合物、聚赖氨酸树枝状聚合物、聚酯树枝状聚合物、蝶烯树枝状聚合物、脂肪族聚(醚)树枝状聚合物、芳族聚醚树枝状聚合物或包含一种或多种前述物质的组合。
25.根据权利要求20所述的方法,其中所述树枝状聚合物是PAMAM树枝状聚合物。
26.根据权利要求20所述的方法,其中所述免疫检查点抑制剂特异性结合CD25、PD-1、PD-L1、PD-L2、CTLA-4、免疫球蛋白受体(KIR)、LAG-3、TIM-3、4-1BB、4-1BBL、GITR、CD40、CD40L、OX40、OX40L、CXCR2、B7-H3、B7-H4、BTLA、HVEM、CD28、A2aR、CD27、CD70、TCR ICOS、CD80、CD86、ICOS-L、CD70、Gal-9、VISTA、CD-137、CD155、CD266、PVR、PVR-2、CD47、CD160、NT5E、CD96或TNFRSF18。
27.根据权利要求20所述的方法,其中所述免疫检查点抑制剂是完整抗体、抗体片段或肽。
28.根据权利要求20所述的方法,其中所述免疫检查点抑制剂包括:西米普利单抗-rwlc、纳武利尤单抗、帕博利珠单抗、匹地利珠单抗、MEDI-0680、PDR001、REGN2810、以及BGB-108、AMP-224、免疫粘附素、BMS-936559、阿替利珠单抗、YW243.55.S70、MDX-1105、MEDI4736、度伐利尤单抗、阿维鲁单抗、伊匹单抗、曲美木单抗、BMS-986016、乌瑞鲁单抗、TRX518、达西珠单抗、卢卡单抗、SEA-CD40、CP-870,893、MED16469、MOXR0916或MSB001078C。
29.一种免疫治疗方法,其包括对有需要的受试者施用权利要求1-13的任一项所述的纳米颗粒系统。
30.根据权利要求29所述的免疫治疗方法,其中所述受试者是人类癌症患者或患有免疫疾病的人类患者。
31.根据权利要求29所述的免疫治疗方法,其还包括施用放疗、化疗、外科手术或包含前述至少一种的组合。
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WO2020092304A9 (en) | 2021-07-22 |
US20210393799A1 (en) | 2021-12-23 |
KR20210084552A (ko) | 2021-07-07 |
WO2020092304A1 (en) | 2020-05-07 |
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