CN111432836A - 治疗性蛋白质组合物及其制备和使用方法 - Google Patents
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Abstract
本文公开了用于蛋白质治疗剂的制备和使用的组合物和方法,并且更具体地涉及具有通过可生物降解的接头可逆地交联的多种治疗性蛋白质单体的蛋白质簇或背包。
Description
相关申请的交叉引用
本申请要求2017年9月5日提交的美国临时申请62/554,058和2019年4月13日提交的美国临时申请62/657,218的优先权权益,两者都通过引用全文纳入本文。
技术领域
本公开总体上涉及用于蛋白质治疗剂的制备和递送的组合物和方法,并且更具体地涉及具有通过可生物降解的接头可逆地交联的多种治疗性蛋白质单体的蛋白质簇或背包。
背景技术
蛋白质治疗剂,例如抗体,细胞因子,生长因子和疫苗,是用于治疗多种疾病的重要治疗剂,所述疾病包括例如癌症,糖尿病和心血管疾病。在最近几年中,这类蛋白质治疗剂在全球制药行业中得到了快速发展。相对于小分子药物,蛋白质治疗剂具有高特异性和强效性的优势。然而,由于其内在的不稳定性、免疫原性和短的半衰期,蛋白质治疗剂的用途受到限制。
为了解决这些限制,通常有两种方法:一种是治疗性蛋白质的基因融合,另一种是使用工程化的运载体来递送蛋白质治疗剂。使用工程化运载体,蛋白质可以通过包封/吸附或偶联来加载。蛋白质在脂质体或纳米颗粒中/上的包封或吸附通常效率低下。蛋白质的偶联通常会降低其生物活性。因此,这两种方法都是有问题的。
因此,迫切需要将治疗剂高效纳入递送系统中的新组合物和方法。
发明内容
本文公开了用于蛋白质治疗剂的改进的方法和组合物。更具体地,本文公开了具有通过可生物降解的接头可逆地交联的多个治疗性蛋白质单体的蛋白质簇或背包,及其制备和使用方法。
一方面,本文公开了一种治疗组合物,其包含:
含有多个彼此可逆交联的治疗性蛋白质单体蛋白质簇,其中所述蛋白质簇的直径通过动态光散射测量为30nm至1000nm;
多种可生物降解的交联剂,每种具有两个、三个或四个能够与治疗性蛋白质单体上的亲核基团反应的官能团,从而将治疗性蛋白质单体交联形成蛋白质簇,其中该交联剂在给予有需要的对象后在生理条件下降解,以从蛋白质簇中释放治疗性蛋白质单体;
药学上可接受的运载体或赋形剂;和
任选地,蛋白质簇上的表面修饰,其中优选地,该表面修饰是聚阳离子。
在一些实施方式中,交联剂具有式A-B-C,其中B是任选的,其中A代表结构模板,B代表聚合物间隔物,C代表可水解的连接键和可以与亲核基团反应的官能团。
在一些实例中,A选自二元醇,三元醇,四元醇,多元醇,二硫醇,三硫醇,四硫醇,聚硫醇,二胺,三胺,四胺或多胺。在一些实施方式中,B可以选自聚乙二醇,糖,多元醇,聚醚,聚硫醚,聚胺,聚酯,烷烃,苯基或氨基酸。在一些实施方式中,C可以是具有式(Ia)的C:
其中:
LG2是离去基团,其选自三氟甲磺酸酯,甲苯磺酰基,Cl,N-羟基琥珀酰亚胺和咪唑啉(imidazolide);
Y2选自O和S;
在每次出现时,X独立地选自O、S和N;
m是选自1-6的整数,优选2。
在某些实施方式中,交联剂具有式(I):
其中:
LG1和LG2各自为离去基团,独立地选自三氟甲磺酸酯,甲苯磺酰基,Cl,N-羟基琥珀酰亚胺和咪唑啉;
Y1和Y2各自独立地选自O和S;
在每次出现时,X独立地选自O、S和N;
在每次出现时,m是选自1-6的整数。
在一些实施方式中,式(I)的交联剂是对称的。
在一些实施方式中,LG1和LG2能够与蛋白质、药物和/或颗粒反应。在一个实例中,LG1和LG2均为咪唑啉。在另一个实例中,LG1和LG2均为N-羟基琥珀酰亚胺。
在一些实施方式中,例如,当一个或多个X为N时,L选自:
(a)–(CH2)n-,其中n是选自0-5的整数;
在一些实施方式中,m是2。
在某些实施方式中,交联剂具有式(II):
其中:
X1和X2各自独立地选自三氟甲磺酸酯,甲苯磺酰基,Cl,N-羟基琥珀酰亚胺和咪唑啉;
A1和A3各自独立地是–(CR1R2)n–;
A2是–(CR1R2)m–;
Y1和Y2各自独立地选自NR3、O和S;
其中每次出现时,R1和R2独立地选自氢,卤素,羟基,C1-12烷基,C2-12烯基,C3-12环烷基,C2-12杂环基;任选地被1个或多个卤素,羟基,C1-6烷基和/或C1-6烷氧基取代的C6-12芳基;和任选地被1个或多个卤素,羟基,C1-6烷基和/或C1-6烷氧基取代的C4-12杂芳基;
其中R3选自氢,C1-12烷基,C2-12烯基,C3-12环烷基,C2-12杂环基;任选地被1个或多个卤素,羟基,C1-6烷基和/或C1-6烷氧基取代的C6-12芳基;和任选地被1个或多个卤素,羟基,C1-6烷基和/或C1-6烷氧基取代的C4-12杂芳基;
在每次出现时,n是独立地选自1-12的整数;并且
m是从0到12的整数。
在一些实施方式中,式(II)的交联剂是对称的。在一些实施方式中,X1和X2各自可以是能够与蛋白质、药物和/或颗粒反应的离去基团。在一个实例中,X1和X2均为咪唑啉。在另一个实例中,X1和X2均为N-羟基琥珀酰亚胺。在一些实施方式中,R1和R2均为氢。在一个实例中,A1和A3均为–(CH2)2-。在一个实施方式中,A2为–(CH2)2-。在一些实施方式中,Y1和Y2均为O。
在一个实施方式中,该交联剂是:
在一些实施方式中,在式(II)的交联剂中,A2是键(例如,当m为0时)。在一个实施方式中,Y1和Y2均为NH。
在一些实施方式中,交联剂是:
在一些实施方式中,该化合物可以用作可降解或可水解的接头。在一些实施方式中,可降解的接头是氧化还原响应性接头。美国公开号2017/0080104,美国专利号9,603,944和美国公开号2014/0081012中公开了制备和使用各种接头(例如,制备纳米凝胶或背包)的方法,其各自通过引用全文纳入本文。
在一些实施方式中,所述组合物还包含优化蛋白质簇形成的试剂。例如,与不含该试剂的组合物相比,该试剂可通过减少未反应的蛋白质来增加蛋白质簇形成的产率。在一些实施方式中,与没有该试剂的组合物相比,该试剂通过减少尺寸大于1000nm的簇的形成来增加蛋白质簇形成的产率。
在一些实施方式中,在本文公开的组合物中,治疗性蛋白质单体包含一种或多种细胞因子分子和/或一种或多种共刺激分子,其中:
(i)一种或多种细胞因子分子选自IL15,IL2,IL7,IL10,IL12,IL18,IL21,IL-23,IL-4,IL1α,IL1β,IL-5,IFNγ,TNFa,IFNα,IFNβ,GM-CSF或GCSF;和
(ii)一种或多种共刺激分子选自CD137,OX40,CD28,GITR,VISTA,抗CD40或CD3。
另一方面涉及用于制备本文公开的任何组合物的方法,该方法包括使多种治疗性蛋白质单体与多种交联剂反应以形成蛋白质簇。在一些实施方式中,反应步骤在约5℃至约40℃的温度下进行。在一些实施方式中,反应步骤进行约1分钟至约8小时。该方法可以进一步包括对蛋白质簇提供表面修饰和/或纯化蛋白质簇。
本文还提供了一种制备细胞疗法组合物的方法,包括:提供本文公开的任何一种组合物;并将蛋白质簇与有核细胞如T和NK细胞一起孵育,优选约30-60分钟。
另一方面涉及细胞疗法组合物,其包含与有核细胞例如T和NK细胞相关的本文公开的任何组合物。
再一方面涉及提供细胞疗法的方法,其包括将本文公开的细胞治疗组合物给予需要其的对象。
附图说明
图1A-1C示出了示例性背包及其制备和使用。
图2:人T细胞上IL-15背包的可滴定加载。
图3:跨多个供体的一致且精确的IL-15背包加载。
图4:从标记的细胞释放IL-15背包驱动细胞扩增。
图5:在间歇洗涤后第14天,与细胞缔合的IL-15背包驱动细胞扩增。
图6A-6C:IL-15背包驱动表达抗EGFR CAR的人CD3 T细胞的扩增。
图7A-7C:在具有完整免疫系统的C57B6小鼠模型中,全身性IL15-Fc和IL-15背包的对比效果。
图8A-8E:收获并表征了来自过程完成的CTL。
图9:给予后第1天和第4天的幼稚小鼠的临床化学参数。HBSS=载剂对照;DP-15PMEL=深IL-15引发的PMEL细胞;D=天。使用ANOVA然后进行Tukey的多重比较测试进行统计学比较。*=p<0.05;**=p<0.01;***=p<0.001;****=p<0.0001。
图10:给予后D1和D4的荷瘤小鼠的临床化学参数。HBSS=载剂对照;DP-15PMEL=深IL-15引发的PMEL细胞;D=天。使用ANOVA然后进行Tukey的多重比较测试进行统计学比较。*=p<0.05;**=p<0.01;***=p<0.001。
图11:ACT后24小时与幼稚小鼠相比,荷瘤小鼠的血清IFN-γ水平。相比于幼稚和荷瘤小鼠中PMEL和DP-15PMEL组,PMEL+IL15-Fc组的血清IFN-γ水平显著升高(Tuway多重比较的双向ANOVA,p<0.001)。ACT=过继细胞转移;DP-15PMEL=深IL-15引发的PMEL细胞。
图12:在幼稚和荷瘤小鼠中,用PMEL+IL15-Fc和深IL-15引发的PMEL细胞处理的小鼠中的IL15-Fc全身暴露。
图13:随时间和在第16天的平均肿瘤体积。在第-5天,第-3天,第0天,第1天,第2天,第4天,第6天,第9天,第10天,第11天,第14天和第16天测量肿瘤体积。数据为平均值±SEM(左图)。右图显示了D16上单个动物的肿瘤体积。使用ANOVA然后进行Tukey的多重比较测试进行统计学比较。*=p<0.05;**=p<0.01;***=p<0.001;****=p<0.0001。星号的颜色代表统计上不同的组。例如,灰色(HBSS)线上方的绿色星号表示HBSS和PMEL细胞之间存在显著差异。HBSS=载剂对照;ACT=过继细胞转移。DP-15PMEL=深IL-15引发的PMEL细胞。
图14:处死时的平均肿瘤重量(n=2-5/组/时间点)。在第1、4、10和16天处死时肿瘤重量(每个时间点n=2-5/组)。使用ANOVA然后进行Tukey的多重比较测试进行统计学比较。*=p<0.05;**=p<0.01;****=p<0.0001。HBSS=载剂对照;DP-15PMEL=深IL-15引发的PMEL细胞。
具体实施方式
癌症免疫疗法,包括过继性T细胞疗法,是治疗癌症的一种有前途的策略,因为它利用对象自身的免疫系统攻击癌细胞。但是,这种方法的主要局限性在于所移植的T淋巴细胞的活力和功能迅速下降。为了在肿瘤中维持大量活的肿瘤特异性细胞毒性T淋巴细胞,免疫刺激剂与转移细胞的共同给予是必要的。当以高剂量全身给予时,这些试剂可以增强转移的(即供体)细胞的体内活力,改善转移的细胞的治疗功能,从而导致总体上提高的抗癌功效;但是,高剂量的此类试剂也可能导致危及生命的副作用。例如,将白介素2(IL-2)用作佐剂极大地支持了黑色素瘤的过继性T细胞疗法,其中IL-2为转移的T细胞提供关键的佐剂信号,但也引起严重的剂量限制性炎性毒性并扩增了调节性T细胞(Treg)。将佐剂活性集中在转移的细胞上的一种方法是对转移的细胞进行基因工程改造以分泌其自身的支持因子。迄今为止,技术难度和挑战以及大规模生产基因工程改造的T淋巴细胞的高成本已大大限制了该方法在临床应用中的潜力。
在某些方面,本文公开的技术平台允许通过蛋白质,药物或颗粒负载的无载体接头直接化学偶联到细胞的质膜上将生物活性剂(例如药物,蛋白质(例如,佐剂,例如IL-2))或颗粒简单,安全和高效地递送至细胞。在某些实施方式中,这种组合物被称为“纳米凝胶”,“纳米颗粒”或“背包”,这些术语在本文中可互换使用。可以将组合物加载或背负到细胞例如有核细胞上。加载或背负过程也称为“引发(priming)”。背负或引发的细胞可以有许多治疗应用。例如,背负的T细胞可以用于包括ACT(过继细胞疗法)在内的T细胞疗法中。其他重要的免疫细胞类型也可以背负背包,包括例如B细胞,肿瘤浸润淋巴细胞,NK细胞,抗原特异性CD8+T细胞,经遗传工程改造以表达嵌合抗原受体(CAR)的T细胞或CAR-T细胞,经遗传工程改造以表达对肿瘤抗原具有特异性的T细胞受体的T细胞,肿瘤浸润淋巴细胞(TIL),和/或经过抗原训练的T细胞(例如,已经被展示感兴趣的抗原(例如肿瘤相关抗原(TAA))的抗原呈递细胞(APC)“训练”的T细胞)。
除了前述内容之外,本发明还考虑了其他纳米结构,其包括除对过继转移的细胞产生佐剂作用以外的目的的其他蛋白质治疗剂。如本文所提供的,本领域技术人员将容易认识到,本公开具有更广泛的应用。
本公开的各个方面可以单独使用、组合使用、或者以前面描述的实施例中未具体讨论的各种配置使用,因此在其应用上不限于在前面的描述中阐述的或者在附图中示出的部件的细节和布置。例如,一个实施方式中描述的方面可以以任何方式与其它实施方式中描述的方面组合。
定义
方便起见,将说明书、实施例和所附权利要求中使用的特定术语汇集在此。除非另外定义,否则,本文中所使用的所有技术和科学术语都具有本文所属领域普通技术人员通常所理解的含义。
本文使用冠词“一个”和“一种”表示一个或一个以上的(即至少一个)该冠词语法上的宾语。术语“一种”或“一个”当与“包含”在本文中联用时,可表示“一个”,但也与“一个或多个”,“至少一个”和“一个或多于一个”的意思一致。
如本文所用,“约”和“近似”通常表示在考虑测量的性质或精度的情况下测量的量的可接受的误差度。示例性误差度在给定数值范围的20%以内,通常在10%以内,更通常在5%以内。术语“基本上”表示超过50%,更优选超过80%并且最优选超过90%或95%。
如本文所用,术语“包含”或“包括”是指存在于给定实施方式中,但未包含未指定要素的组合物,方法及其各自的组分。
如本文所用,术语“基本上由……组成”是指给定实施方式所需的那些要素。该术语允许存在实质上不影响本公开的该实施方式的基本和新颖的或功能的特征的附加要素。
术语“由……组成”是指本文所述的组合物,方法及其各自的组分,其排除了在该实施方式的描述中未列举的任何要素。
本文所用“多个/多种”表示超过1个/种,例如,2、3、4、、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或更多个/种,例如25、30、40、50、60、70、80、90、100、200、300、400、500或更多个/种,或其间任何整数。
本文使用的术语“治疗物”,“治疗剂”,“活性物”,“活性剂”,“活性药物剂”,“活性药物”或“药物”是指任何活性药物成分(“API”),包括其药学上可接受的盐(例如盐酸盐,氢溴酸盐,氢碘酸盐和糖精盐),以及无水,水合和溶剂化形式,前药形式,以及API各自的光学活性对映体以及API的多晶型物。治疗剂包括药学,化学或生物剂。另外,药学,化学或生物试剂可包括具有期望性质或影响其是否为治疗剂的任何试剂。例如,试剂还包括诊断剂,杀生物剂等。
术语“蛋白质”、“肽”和“多肽”在本文中可互换使用,指任何长度的氨基酸的聚合物。聚合物可以是线性或支化聚合物,可以包含经修饰的氨基酸,并且可间插有非氨基酸。该术语也包括修饰的氨基酸聚合物;例如,二硫键形成、糖基化、脂化、乙酰化、磷酸化或任何其它操作,如与标记组分偶联。多肽可从天然来源分离,可采用重组技术由原核或真核宿主产生,或者可为合成方法的产品。应当理解,术语“蛋白质”包括融合蛋白或嵌合蛋白,以及细胞因子,抗体及其抗原结合片段。
如本文所用的“抗体”或“抗体分子”是指包含至少一种免疫球蛋白可变结构域序列的蛋白质,例如免疫球蛋白链或其片段。抗体分子包括抗体(例如,全长抗体)和抗体片段。在一个实施方式中,抗体分子包含全长抗体或全长免疫球蛋白链的抗原结合或功能片段。例如,全长抗体是天然存在的或通过正常免疫球蛋白基因片段重组过程形成的免疫球蛋白(Ig)分子(例如,IgG)。在实施方式中,抗体分子是指免疫球蛋白分子的免疫活性的抗原结合部分,例如抗体片段。抗体片段(例如功能片段)是抗体的一部分,例如Fab,Fab’,F(ab’)2,F(ab)2,可变片段(Fv),域抗体(dAb)或单链可变片段(scFv)。功能性抗体片段结合与完整(例如,全长)抗体识别的抗原相同的抗原。术语“抗体片段”或“功能片段”还包括由可变区组成的分离的片段,例如由重链和轻链的可变区或其中轻链和重链可变区通过肽接头(“scFv蛋白”)连接的重组单链多肽分子组成的“Fv片段。”在一些实施方式中,抗体片段不包括没有抗原结合活性的抗体部分,例如Fc片段或单氨基酸残基。示例性抗体分子包括全长抗体和抗体片段,例如,dAb(域抗体),单链,Fab,Fab’和F(ab’)2片段以及单链可变片段(scFv)。术语“Fab”和“Fab片段”可互换使用,并且是指包括来自抗体的每个重链和轻链的一个恒定域和一个可变域的区域,即VL,CL,VH,和CH1。
在实施方式中,抗体分子是单特异性的,例如,其包含对单个表位的结合特异性。在一些实施方式中,抗体分子是多特异性的,例如,其包含多个免疫球蛋白可变结构域序列,其中第一免疫球蛋白可变结构域序列对第一表位具有结合特异性,第二免疫球蛋白可变结构域序列对第二表位具有结合特异性。在一些实施方式中,抗体分子是双特异性抗体分子。如本文所用,“双特异性抗体分子”是指对一种以上(例如,两,三,四或更多种)表位和/或抗原具有特异性的抗体分子。
如本文所用,“抗原”(Ag)是指大分子,包括所有蛋白质或肽。在一些实施方式中,抗原是可以引起免疫应答的分子,例如涉及某些免疫细胞的激活和/或抗体产生。抗原不仅参与抗体产生。T细胞受体还识别抗原(尽管其肽或肽片段与MHC分子复合的抗原)。任何大分子,包括几乎所有蛋白质或肽,都可以是抗原。抗原也可以源自基因组重组体或DNA。例如,包含编码能够引发免疫应答的蛋白质的核苷酸序列或部分核苷酸序列的任何DNA都编码“抗原”。在实施方式中,抗原不需要仅由基因的全长核苷酸序列编码,抗原也不需要完全由基因编码。在实施方式中,抗原可以合成或可以衍生自生物学样品,例如组织样品,肿瘤样品,细胞或具有其他生物学组分的流体。如本文所用,“肿瘤抗原”或可互换使用的“癌症抗原”包括存在于癌症,例如,癌症细胞或肿瘤微环境上或与之相关的可以激发免疫应答的任何分子。如本文所用,“免疫细胞抗原”包括存在于免疫细胞上或与之相关的可引起免疫应答的任何分子。
抗体分子的“抗原结合位点”或“抗原结合片段”或“抗原结合部分”(在本文中可互换使用)是指抗体分子,例如免疫球蛋白(Ig)分子,例如IgG参与抗原结合的一部分。在一些实施方式中,抗原结合位点由重(H)链和轻(L)链的可变(V)区的氨基酸残基形成。重链和轻链的可变区域内的三个高度发散的延伸(称为高变区域)位于称为“框架区”(FR)的更为保守的侧翼延伸之间。FR是天然在免疫球蛋白中的高变区之间并与其相邻的氨基酸序列。在实施方式中,在抗体分子中,轻链的三个高变区和重链的三个高变区在三维空间中相对于彼此布置以形成抗原结合表面,其与结合的抗原的三维表面互补。重链和轻链三个高变区中的每一个被称为“互补决定区”或“CDR”。框架区和CDR已经在例如Kabat,E.A.等,(1991)《热门免疫学蛋白质序列》,第五版,美国卫生和人服务部,NIH出版号91-3242,和Chothia,C.等,(1987)J.Mol.Biol.196:901-917中被定义和描述。每条可变链(例如,可变重链和可变轻链)通常由三个CDR和四个FR组成,按照下述氨基酸顺序从氨基端到羧基端排列:FR1,CDR1,FR2,CDR2,FR3,CDR3和FR4。可变轻链(VL)CDR通常定义为包括位置27-32(CDR1),50-56(CDR2)和91-97(CDR3)上的残基。可变重链(VH)CDR通常定义为包括位置27-33(CDR1),52-56(CDR2)和95-102(CDR3)上的残基。本领域普通技术人员将理解,环在抗体之间可以具有不同的长度,并且以诸如Kabat或Chotia的编号系统为准,从而框架在抗体之间具有一致的编号。
在一些实施方式中,抗体的抗原结合片段(例如,当作为融合分子的一部分包括时)可以缺乏或没有完整的Fc结构域。在某些实施方式中,抗体结合片段不包含完整的IgG或完整的Fc,但是可以包含来自轻链和/或重链的一个或多个恒定区(或其片段)。在一些实施方式中,抗原结合片段可以完全不含任何Fc结构域。在一些实施方式中,抗原结合片段可以基本上没有完整的Fc结构域。在一些实施方式中,抗原结合片段可包括完整Fc结构域的一部分(例如,CH2或CH3结构域或其部分)。在一些实施方式中,抗原结合片段可包括完整的Fc结构域。在一些实施方式中,Fc结构域是IgG结构域,例如IgG1,IgG2,IgG3或IgG4Fc结构域。在一些实施方式中,Fc结构域包含CH2结构域和CH3结构域。
如本文所用,“细胞因子”或“细胞因子分子”是指天然存在的野生型细胞因子的全长,片段或变体(包括其具有天然存在的细胞因子分子的至少10%活性的片段和功能变体)。在实施方式中,细胞因子分子具有天然存在的分子至少30%,50%或80%的活性,例如免疫调节活性。在实施方式中,细胞因子分子还包含任选地与免疫球蛋白Fc区偶联的受体结构域,例如细胞因子受体结构域。在其他实施方式中,细胞因子分子与免疫球蛋白Fc区偶联。在其他实施方式中,细胞因子分子与抗体分子(例如,免疫球蛋白Fab或scFv片段,Fab片段,FAB2片段或亲和体片段或衍生物,例如sdAb(纳米抗体)片段,重链抗体片段,单域抗体,双特异性或多特异性抗体),或非抗体支架和抗体模拟物(例如载脂蛋白(例如抗运载蛋白(anticalin)),亲和体,纤连蛋白(例如单抗体(monobody)或阿迪连接素(Adnectin)),结蛋白,锚蛋白重复序列(例如DARPins)和A域(例如avimer)))偶联。
如本文所用“给予”和类似术语是指将组合物递送给正在治疗的个体。优选地,本发明的组合物通过例如肠胃外给予,包括皮下,肌内或优选静脉内途径给予。
本文所用术语“癌症”和“癌的”是指或描述典型特征为细胞生长失控的哺乳动物生理病症。癌症的例子包括但不限于:黑色素瘤,癌,淋巴瘤,母细胞瘤,肉瘤和白血病或淋巴样恶性肿瘤。癌症的更具体的例子包括:鳞状细胞癌(例如上皮鳞状细胞癌),肺癌,包括小细胞肺癌,非小细胞肺癌,肺腺癌和肺鳞状癌,腹膜癌,肝细胞癌,胃癌,包括胃肠道癌,胰腺癌,胶质母细胞瘤,宫颈癌,卵巢癌,肝癌,膀胱癌,肝癌,乳腺癌,结肠癌,直肠癌,结直肠癌,子宫内膜癌或子宫癌,唾液腺癌,肾癌,前列腺癌,外阴癌,甲状腺癌,肝癌,肛门癌,阴茎癌以及头颈癌。
“有核细胞”是含有核的细胞。在一些实施方式中,有核细胞可以是免疫细胞。
如本文所用,“免疫细胞”是指在免疫系统中起作用,例如保护免受感染和异物侵害的各种细胞中的任何一种。在实施方式中,该术语包括白细胞,例如嗜中性粒细胞,嗜酸性粒细胞,嗜碱性粒细胞,淋巴细胞和单核细胞。术语“免疫细胞”包括本文所述的免疫效应细胞。“免疫细胞”还指参与免疫应答的细胞的修饰形式,例如,修饰的NK细胞,包括NK细胞系NK-92(ATCC目录号CRL-2407),haNK(表达高亲和力Fc受体FcγRIIIa(158V)的NK-92变体)和taNK(靶向的NK-92细胞,其用表达给定肿瘤抗原的CAR的基因转染),例如,如上文Klingemann等所述。
如本文所用的术语“免疫效应细胞”是指参与免疫应答的细胞,例如促进免疫效应应答。免疫效应细胞的示例包括但不限于T细胞,例如CD4+T细胞,CD8+T细胞,αT细胞,βT细胞,γT细胞和δT细胞;B细胞;自然杀伤(NK)细胞;自然杀伤T(NKT)细胞;树突状细胞;和肥大细胞。在一些实施方式中,免疫细胞是免疫细胞(例如,T细胞或NK细胞),其包含,例如,表达嵌合抗原受体(CAR),例如结合癌抗原的CAR。在其他实施方式中,免疫细胞表达外源高亲和力Fc受体。在一些实施方式中,免疫细胞包含,例如表达工程改造的T细胞受体。在一些实施方式中,免疫细胞是肿瘤浸润淋巴细胞。在一些实施方式中,免疫细胞包含免疫细胞群,并且包含已经针对肿瘤相关抗原(TAA)的特异性富集的T细胞,例如,通过分选针对展示感兴趣的TAA(例如MART-1)的MHC具有特异性的T细胞来富集。在一些实施方式中,免疫细胞包括免疫细胞群,并且包括已经被展示感兴趣的TAA肽的抗原呈递细胞(APC),例如,树突状细胞“训练”以具有针对TAA的特异性的T细胞。在一些实施方式中,针对选自MART-1,MAGE-A4,NY-ESO-1,SSX2,生存素或其他中的一种或多种的TAA训练T细胞。在一些实施方式中,免疫细胞包含T细胞群,其已经被展示多个感兴趣的TAA肽的APC,例如,树突状细胞“训练”以对多种TAA具有特异性。在一些实施方式中,免疫细胞是细胞毒性T细胞(例如,CD8+T细胞)。在一些实施方式中,免疫细胞是辅助T细胞,例如CD4+T细胞。
如本文所用的“细胞毒性T淋巴细胞”(CTL)是指具有杀死靶细胞能力的T细胞。当发生以下两个步骤时可以发生CTL活化:1)靶细胞上的抗原结合的MHC分子和CTL上的T细胞受体之间产生相互作用;2)通过T细胞上共刺激分子和靶细胞的接合而产生共刺激信号。然后,CTL识别靶细胞上的特异性抗原并诱导这些靶细胞的破坏,例如通过细胞裂解。在一些实施方式中,CTL表达CAR。在一些实施方式中,CTL表达工程改造的T细胞受体。
如本文所用,“有效量”是指足以以合理的风险/收益比提供期望的局部或全身作用的生物活性剂或诊断剂的量,如将参加任何医学治疗或诊断测试的生物活性剂或诊断剂的量。这将根据患者,疾病,所进行的治疗以及试剂的性质而有所不同。
如本文所用,“药学上可接受的”应指可用于制备基本安全无毒的药物组合物,所述药物组合物既非生物学不利也无其他不利情况,并包括可用于兽医用途以及人类药物用途。“药学上可接受的液体运载体”的实例包括水和有机溶剂。优选的药学上可接受的水性液体包括PBS,盐水和右旋糖溶液等。
术语“治疗”或“处理”表示为了包括如下的目的给予药物:(i)预防疾病或病症,即,导致疾病或病症的临床症状不发展;(ii)抑制疾病或病症,即阻止临床症状的发展;和/或(iii)减轻疾病或病症,即导致临床症状消退。
除非另有说明,否则使用某些化学基团的以下定义。下面列出的关于自由基,取代基和范围的特定和一般值仅作说明之用;它们不排除其他定义的值或在自由基和取代基的定义范围内的其他值。除非另有说明,否则烷基,烷氧基,烯基等表示直链和支链基团。
术语“烷基”是指可以是直链或支链的饱和烃链,其包含所示数目的碳原子。例如,C1-6烷基表示该基团中可以具有1至6个(含)碳原子。任何原子可以任选地被例如一个或多个取代基取代。烷基的实例包括但不限于甲基,乙基,正丙基,异丙基和叔丁基。
如本文所指,术语“烷氧基”是指式-O(烷基)的基团。烷氧基可以是例如甲氧基(—OCH3),乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,仲丁氧基,戊氧基,2-戊氧基,3-戊氧基或己氧基。如本文所用,单独或与其他术语组合使用的术语“羟基”是指式-OH的基团。
术语“烯基”是指含有指定数目的碳原子并具有一个或多个碳-碳双键的直链或支链烃链。任何原子可以任选地被例如一个或多个取代基取代。烯基可包括例如乙烯基,烯丙基,1-丁烯基和2-己烯基。双键碳之一可以任选地是烯基取代基的连接点。
术语“炔基”是指含有指定数目的碳原子并具有一个或多个碳-碳三键的直链或支链烃链。炔基可以任选地被例如一个或多个取代基取代。炔基可包括例如乙炔基,炔丙基和3-己炔基。三键碳原子之一可以任选地是炔基取代基的连接点。
术语“杂环基”是指具有一个或多个独立地选自O,N(应理解,可以存在一个或两个另外的基团以匹配氮价和/或形成盐)或S的构成杂原子的环原子的完全饱和的单环,双环,三环或其他多环系统。杂原子或环碳可以是杂环基取代基与另一个部分的连接点。任何原子可以任选地被例如一个或多个取代基取代。杂环基可包括例如四氢呋喃基,四氢吡喃基,哌啶基(哌啶子基),哌嗪基,吗啉基(吗啉代基),吡咯啉基和吡咯烷基。例如,短语含有“5-6个环原子的杂环,其中1-2个环原子独立地选自N,NH,N(C1-C6烷基),NC(O)(C1-C6烷基),O和S;并且其中所述杂环任选地被1-3个独立选择的Ra取代”将包括(但不限于)四氢呋喃基,四氢吡喃基,哌啶基(哌啶子基),哌嗪基,吗啉基(吗啉代基),吡咯啉基和吡咯烷基。
术语“环烷基”是指完全饱和的单环,双环,三环或其他多环烃基。任何原子可以任选地被例如一个或多个取代基取代。环碳用作环烷基与另一个部分的连接点。环烷基部分可包括例如环丙基,环丁基,环戊基,环己基,环庚基,金刚烷基和降冰片基(双环[2.2.1]庚基)。
术语“芳基”是指芳族单环,双环(2个稠合环)或三环(3个稠合环)或多环(>3个稠合环)烃环系。一个或多个环原子可以任选地被例如一个或多个取代基取代。芳基部分包括例如苯基和萘基。
术语“杂芳基”是指具有一个或多个独立地选自O,N(应理解,可以存在一个或两个另外的基团以匹配氮价和/或形成盐)或S的杂原子的环原子的芳族单环,双环(2个稠合环),三环(3个稠合环)或多环(>3个稠合环)烃基。一个或多个环原子可以任选地被例如一个或多个取代基取代。杂芳基的示例包括但不限于2H-吡咯基,3H-吲哚基,4H-喹啉基,吖啶基,苯并[b]噻吩基,苯并噻唑基,对-咔啉基,咔唑基,香豆基,色烯基,肉桂基,二苯并[b,d]呋喃基,呋咱基,呋喃基,咪唑基,咪二唑基(imidizolyl),吲唑基,吲哚基,异苯并呋喃基,异吲哚基,异喹啉基,异噻唑基,异噁唑基,萘啶基,噁唑基,萘嵌二氮杂苯基(perimidinyl),菲啶基,菲咯啉基(phenanthrolinyl),吩吡嗪基(phenarsazinyl),吩嗪基,吩噻嗪基,吩噁噻基,吩噁嗪基,酞嗪基,蝶啶基,嘌呤基,吡喃基,吡嗪基,吡唑基,哒嗪基,吡啶基,嘧啶基,吡咯基,喹唑啉基,喹啉基,喹喔啉基,噻二唑基,噻蒽基,噻唑基,噻吩基,三唑基和噻吨基。
术语“取代基”是指在该基团的任何原子上“取代”的基团,例如烷基,卤代烷基,环烷基,杂环基,杂环烯基,环烯基,芳基或杂芳基。在一方面,一个基团上的一个或多个取代基独立地是为该取代基描述的任何单个或者两个或多个可允许原子或原子团的任意组合。另一方面,取代基本身可以被上述取代基中的任何一个取代。此外,如本文所用,短语“任选取代的”是指未取代的(例如被H取代)或取代的。如本文所用,术语“取代的”是指氢原子被去除并被取代基取代。可以理解,在给定原子上的取代受价态限制。
下面进一步详细描述本公开的各个方面。在整个说明书中提供了其他定义。
接头
在一些实施方式中,本公开的至少一种药物,蛋白质,聚合物和/或颗粒(统称为“试剂”)通过可降解的接头可逆地彼此连接,使得在生理条件下,该接头降解并释放完整的生物活性剂。在一个实施方式中,蛋白质单体可以被交联在一起以形成包含多个蛋白质单体的簇。在其他实施方式中,各种试剂通过可降解的接头连接至官能团。在各种实施方式中,如下所述,可逆地修饰或链接所述试剂。
如本文所用,“可逆地与另一种试剂连接”的试剂是指通过可降解的接头与另一种药物,蛋白质,聚合物或颗粒连接(例如,共价连接)的药物,蛋白质,聚合物或颗粒。
在本文中“可逆地连接至官能团”的试剂或“可逆地修饰”的试剂是指通过可降解的接头与官能团附连(例如,共价附连)的试剂。这样的试剂在本文中可以被称为“试剂偶联物”或“可逆修饰的试剂偶联物”,这些术语在本文中可以互换使用。应当理解,蛋白质和聚合物(例如,聚乙二醇)各自包含官能团,试剂可以通过可逆接头,例如胺,硅烷,羟基,聚(环氧乙烷),聚乳酸,聚乳酸-羟基乙酸共聚物与之连接。本文提供的试剂偶联物和可逆修饰的蛋白质的实例包括但不限于与另一试剂可逆连接(例如,经由可降解的接头)的试剂,与聚合物可逆连接的试剂,和与另一个官能团可逆连接的蛋白质。应当理解,术语“蛋白质”包括融合蛋白。
在一些实施方式中,交联剂具有式A-B-C,其中B是任选的,其中A代表结构模板,B代表聚合物间隔物,C代表可水解的连接键和可以与亲核基团反应的官能团。
在一些实例中,A选自二元醇,三元醇,四元醇,多元醇,二硫醇,三硫醇,四硫醇,聚硫醇,二胺,三胺,四胺或多胺。在一些实施方式中,B可以选自聚乙二醇,糖,多元醇,聚醚,聚硫醚,聚胺,聚酯,烷烃,苯基或氨基酸。在一些实施方式中,C可以是具有式(Ia)的C:
其中:
LG2是离去基团,其选自三氟甲磺酸酯,甲苯磺酰基,Cl,N-羟基琥珀酰亚胺和咪唑啉;
Y2选自O和S;
在每次出现时,X独立地选自O、S和N;
m是选自1-6的整数,优选2。
根据本公开使用的可降解接头的一个示例由式(I)表示:
其中:
LG1和LG2各自为离去基团,优选独立地选自三氟甲磺酸酯,甲苯磺酰基,Cl,N-羟基琥珀酰亚胺和咪唑啉;
Y1和Y2各自独立地选自O和S;
在每次出现时,X独立地选自O、S和N;
在每次出现时,m是选自1-6的整数。
在一些实施方式中,式(I)所示的交联剂在L是对称的。例如,LG1和LG2可以相同。Y1和Y2可以相同。
在各种实施方式中,LG1和LG2能够与蛋白质,药物和/或颗粒反应。LG1和LG2可均为咪唑啉。在另一个实例中,LG1和LG2均为N-羟基琥珀酰亚胺。
(a)–(CH2)n-,其中n是选自0-5的整数;
根据本公开使用的可降解接头的另一个示例由式(II)表示:
其中:
X1和X2各自独立地选自三氟甲磺酸酯,甲苯磺酰基,Cl,N-羟基琥珀酰亚胺和咪唑啉;
A1和A3各自独立地是–(CR1R2)n–;
A2是–(CR1R2)m–;
Y1和Y2各自独立地选自NR3、O和S;
其中每次出现时,R1和R2独立地选自氢,卤素,羟基,C1-12烷基,C2-12烯基,C3-12环烷基,C2-12杂环基;任选地被1个或多个卤素,羟基,C1-6烷基和/或C1-6烷氧基取代的C6-12芳基;和任选地被1个或多个卤素,羟基,C1-6烷基和/或C1-6烷氧基取代的C4-12杂芳基;
其中R3选自氢,C1-12烷基,C2-12烯基,C3-12环烷基,C2-12杂环基;任选地被1个或多个卤素,羟基,C1-6烷基和/或C1-6烷氧基取代的C6-12芳基;和任选地被1个或多个卤素,羟基,C1-6烷基和/或C1-6烷氧基取代的C4-12杂芳基;
在每次出现时,n是独立地选自1-12的整数;并且
m是从0到12的整数。
在一些实施方式中,式(II)的交联剂是对称的。
在一些实施方式中,X1和X2各自是能够与蛋白质、药物和/或颗粒反应的离去基团。在某些实施方式中,X1和X2均为咪唑啉或N-羟基琥珀酰亚胺。
在一些实施方式中,R1和R2均为氢。
在一些实施方式中,A1和A3均为–(CH2)2-。
在某些实施方式中,A2为–(CH2)2-。
在一些实施方式中,Y1和Y2均为O。
在一些实施方式中,该交联剂是:
在一些实施方式中,A2为键。在某些实施方式中,Y1和Y2均为NH。
在一些实施方式中,该交联剂是:
单体
根据本公开使用的蛋白质单体的实例包括但不限于抗体(例如,IgG,Fab,混合的Fc和Fab),单链抗体,抗体片段,工程化的蛋白质,例如Fc融合体,酶,辅因子,受体,配体,转录因子和其他调节因子,细胞因子,趋化因子,人血清白蛋白等。这些蛋白质可能是天然的也可能不是天然的。考虑并且可以根据本公开使用其他蛋白质。如在例如美国公开号2017/0080104,美国专利号9,603,944,美国公开号2014/0081012和2017年6月13日提交的PCT申请号PCT/US17/37249中所公开的,可以通过交联可逆地修饰任何蛋白质以形成簇或纳米凝胶结构,其全部通过引用并入本文。
在各种实施方式中,可以使用本文公开的一种或多种交联剂使治疗性蛋白质单体交联。治疗性蛋白质单体可包含一种或多种细胞因子分子和/或一种或多种共刺激分子。细胞因子分子可以选自IL-15,IL-2,IL-7,IL-10,IL-12,IL-18,IL-21,IL-23,IL-4,IL1α,IL1β,IL-5,IFNγ,TNFa,IFNα,IFNβ,GM-CSF或GCSF。共刺激分子选自CD137,OX40,CD28,GITR,VISTA,抗CD40或CD3。
在一些实施方式中,本公开的蛋白质单体是免疫刺激蛋白质。如本文所用,免疫刺激蛋白是在其被给予的对象中刺激免疫应答(包括增强预先存在的免疫应答)的蛋白质,无论是单独还是与另一种蛋白质或试剂组合。可以根据本公开使用的免疫刺激蛋白的实例包括但不限于抗原,佐剂(例如鞭毛蛋白,胞壁酰二肽),细胞因子包括白介素(例如IL-2,IL-7,IL-15,IL-10,IL-18,IL-21,IL-23(或这些细胞因子的超激动剂/突变形式,例如IL-15SA),IL-12,IFN-γ,IFN-α,GM-CSF,FLT3-配体),和免疫刺激抗体(例如,抗CTLA-4,抗CD28,抗CD3或这些分子的单链/抗体片段)。考虑并且可以根据本公开使用其他免疫刺激蛋白质。在一些实施方式中,免疫刺激蛋白可以是结合免疫抑制剂的抑制剂,例如检查点抑制剂的抑制剂,例如PD-1,PD-L1,LAG-3,TIM-3,CTLA-4,抑制性KIR,CD276,VTCN1,BTLA/HVEM,HAVCR2和ADORA2A的抗体或其抗原结合片段,例如,US2016/0184399中所述的那些,其通过引用并入本文。
在一些实施方式中,本公开的蛋白质单体是抗原。可以根据本公开使用的抗原的实例包括但不限于癌症抗原,自身抗原,微生物抗原,变应原和环境抗原。考虑并且可以根据本公开使用其他蛋白质抗原。
在一些实施方式中,本公开的蛋白质单体是癌症抗原。癌症抗原是优先由癌细胞表达的抗原(即,其在癌细胞中表达的水平高于在非癌细胞上的表达),并且在某些情况下,它仅由癌细胞表达。癌症抗原可以在癌细胞内或在癌细胞表面上表达。可以根据本公开使用的癌症抗原包括但不限于MART-1/Melan-A,gp100,腺苷脱氨酶结合蛋白(ADAbp),FAP,亲环蛋白b,结直肠相关抗原(CRC)-0017-1A/GA733,癌胚抗原(CEA),CAP-1,CAP-2,etv6,AML1,前列腺特异性抗原(PSA),PSA-1,PSA-2,PSA-3,前列腺特异性膜抗原(PSMA),T细胞受体/CD3-ζ链和CD20。癌症抗原可以选自下组:MAGE-A1,MAGE-A2,MAGE-A3,MAGE-A4,MAGE-A5,MAGE-A6,MAGE-A7,MAGE-A8,MAGE-A9,MAGE-A10,MAGE-A11,MAGE-A12,MAGE-Xp2(MAGE-B2),MAGE-Xp3(MAGE-B3),MAGE-Xp4(MAGE-B4),MAGE-C1,MAGE-C2,MAGE-C3,MAGE-C4和MAGE-C5。所述癌症抗原可以选自下组:GAGE-1,GAGE-2,GAGE-3,GAGE-4,GAGE-5,GAGE-6,GAGE-7,GAGE-8和GAGE-9。癌症抗原可以选自下组:BAGE,RAGE,LAGE-1,NAG,GnT-V,MUM-1,CDK4,酪氨酸酶,p53,MUC家族,HER2/neu,p21ras,RCAS1,α-甲胎蛋白,E-钙粘附蛋白,α-连环蛋白,β-连环蛋白,γ-连环蛋白,p120ctn,gp100Pmel117,PRAME,NY-ESO-1,cdc27,腺瘤性息肉病大肠杆菌蛋白(APC),铁蛋白,连接蛋白37,Ig独特型,p15,gp75,GM2神经节苷脂,GD2神经节苷脂,人乳头瘤病毒蛋白,Smad肿瘤抗原家族,Imp-1,P1A,EBV编码的核抗原(EBNA)-1,脑糖原磷酸化酶,SSX-1,SSX-2(HOM-MEL-40),SSX-1,SSX-4,SSX-5,SCP-1和CT-7,CD20和c-erbB-2。考虑并且可以根据本公开使用其他癌症抗原。
在一些实施方式中,本公开内容的蛋白质是抗体或抗体片段,包括但不限于贝伐单抗曲妥珠单抗阿仑单抗(适用于B细胞慢性淋巴细胞性白血病),吉妥单抗(hP67.6,抗CD33,适用于白血病,例如急性髓细胞白血病),利妥昔单抗托西单抗(抗CD20,适用于B细胞恶性肿瘤),MDX-210(同时结合HER-2/neu癌基因蛋白产物和免疫球蛋白G(IgG)(FcγRI)的I型Fc受体的双特异性抗体),奥戈伏单抗(适用于卵巢癌),依决洛单抗达利珠单抗帕利珠单抗(适用于呼吸道疾病,例如RSV感染),替伊莫单抗(适用于非霍奇金淋巴瘤),西妥昔单抗MDX-447,MDX-22,MDX-220(抗TAG-72),IOR-05,IOR-T6(抗CD1),IOR EGF/R3,西洛伐单抗(OV103),依帕妥珠单抗喷突莫单抗和Gliomab-H(适用于脑癌,黑色素瘤)。考虑并且可以根据本公开使用其他抗体和抗体片段。
蛋白质可通过任何末端或内部亲核基团例如-NH2官能团(例如赖氨酸的侧链)连接(例如,共价连接)至可降解的接头。例如,蛋白质可以在允许蛋白质通过可降解的接头彼此可逆的共价交联的条件下与可降解的接头接触。在一些实施方式中,蛋白质可以被交联以形成多个蛋白质纳米凝胶。在一些实施方式中,条件包括使蛋白质与可降解的接头在水性缓冲液中在4℃至25℃的温度下接触。在一些实施方式中,接触步骤可以在水性缓冲液中进行30分钟至一小时。在一些实施方式中,水性缓冲液包含磷酸盐缓冲盐水(PBS)。在一些实施方式中,水性缓冲液中蛋白质的浓度为10mg/mL至50mg/mL(例如10、15、20、25、30、35、40、45或50mg/mL)。
细胞因子
本文所述的方法和组合物,例如接头化合物,可用于交联一种或多种细胞因子分子。在实施方式中,细胞因子分子是细胞因子的全长,片段或变体,例如,包含一个或多个突变的细胞因子。在一些实施方式中,细胞因子分子包含选自以下的细胞因子:白细胞介素-1α(IL-1α),白细胞介素-1β(IL-1β),白细胞介素-2(IL-2),白细胞介素-4(IL-4),白细胞介素-5(IL-5),白细胞介素-6(IL-6),白细胞介素-7(IL-7),白细胞介素-12(IL-12),白细胞介素-15(IL-15),白细胞介素-17(IL-17),白细胞介素-18(IL-18),白细胞介素-21(IL-21),白细胞介素-23(IL-23),干扰素(IFN)α,IFNβ,IFNγ,肿瘤坏死因子α,GM-CSF,GCSF或其片段或变体,或任何上述细胞因子的组合。在其他实施方式中,细胞因子分子选自白细胞介素-2(IL-2),白细胞介素-7(IL-7),白细胞介素-12(IL-12),白细胞介素-15(IL-15),白细胞介素-18(IL-18),白细胞介素-21(IL-21),白细胞介素-23(IL-23)或干扰素γ,或其片段或变体,或任何上述细胞因子的组合。细胞因子分子可以是单体或二聚体。
在实施方式中,细胞因子分子还包含受体结构域,例如细胞因子受体结构域。在一个实施方式中,细胞因子分子包含如本文所述的IL-15受体或其片段(例如,IL-15受体α的胞外IL-15结合结构域)。在一些实施方式中,细胞因子分子是IL-15分子,例如本文所述的IL-15或IL-15超激动剂。如本文所用,与天然存在的细胞因子相比,细胞因子分子的“超激动剂”形式显示增加,例如至少10%,20%,30%的活性。示例性的超激动剂是IL-15SA。在一些实施方式中,IL-15SA包含IL-15和IL-15受体的IL-15结合片段的复合物,例如IL-15受体α或其IL-15结合片段,例如,如本文所述。
在其他实施方式中,细胞因子分子进一步包含抗体分子,例如,免疫球蛋白Fab或scFv片段,Fab片段,FAB2片段或亲和体片段或衍生物,例如,sdAb(纳米抗体)片段,重链抗体片段,例如,Fc区,单结构域抗体,双特异性抗体或多特异性抗体。在一个实施方式中,细胞因子分子还包含免疫球蛋白Fc或Fab。
在一些实施方式中,细胞因子分子是IL-2分子,例如IL-2或IL-2-Fc。在其他实施方式中,细胞因子激动剂可用于本文公开的方法和组合物中。在实施方式中,细胞因子激动剂是细胞因子受体的激动剂,例如针对细胞因子受体的抗体分子(例如,激动性抗体),其引起天然存在的细胞因子的至少一种活性。在实施方式中,细胞因子激动剂是细胞因子受体的激动剂,例如针对选自IL-15Ra或IL-21R的细胞因子受体的抗体分子(例如,激动性抗体)。
在一些实施方式中,细胞因子分子是IL-15分子,例如IL-15(例如人IL-15)的全长、片段或变体。在实施方式中,IL-15分子是野生型人IL-15。在其他实施方式中,IL-15分子是人IL-5的变体,例如,具有一个或多个氨基酸修饰。在一些实施方式中,IL-15分子包含突变,例如N72D点突变。
在其他实施方式中,细胞因子分子还包含任选地与免疫球蛋白Fc或抗体分子偶联的受体结构域,例如IL-15Rα的胞外结构域。在实施方式中,细胞因子分子是如WO 2010/059253中所述的IL-15超激动剂(IL-15SA)。在一些实施方式中,细胞因子分子包含IL-15和与Fc融合的可溶性IL-15受体α结构域(例如,sIL-15Ra-Fc融合蛋白),如Rubinstein等,PNAS 103:24 p.9166-9171(2006)中所述。
IL-15分子可进一步包含多肽,例如细胞因子受体,例如细胞因子受体结构域,和第二异源结构域。在一个实施方式中,异源结构域是免疫球蛋白Fc区。在其他实施方式中,异源结构域是抗体分子,例如,Fab片段,FAB2片段,scFv片段或亲和体片段或衍生物,例如sdAb(纳米抗体)片段,重链抗体片段。在一些实施方式中,多肽还包含第三异源结构域。在一些实施方式中,细胞因子受体结构域是第二结构域的N-末端,并且在其他实施方式中,细胞因子受体结构域是第二结构域的C-末端。
某些细胞因子和抗体公开于例如美国公开号2017/0080104,美国专利号9,603,944,美国公开号2014/0081012和PCT申请号PCT/US2017/037249中(各自通过引用全文纳入本文)。
在一些实施方式中,细胞因子或其他免疫调节剂可以通过融合蛋白靶向受体(例如,在免疫细胞上),例如在PCT申请号PCT/US2018/040777,PCT/US18/40783和PCT/US18/40786(各自通过引用全文纳入本文)。
背包和细胞疗法
可以通过使用本文公开的一种或多种交联剂使各种治疗性蛋白质单体交联来制备背包或纳米颗粒,如图1A所示。尽管该图显示了含二硫化物的接头,但是也可以使用本文公开的其他可生物降解的接头。
在某些实施方式中,背包可以通过使多种治疗性蛋白质单体与多种交联剂反应以形成直径为例如约30nm至1000nm的蛋白质簇而制备。在一些实施方式中,反应可以在约5℃至约40℃的温度下进行。该反应可以进行约1分钟至约8小时。
提供的蛋白质簇可以进行表面修饰,例如聚阳离子。在美国公开号2017/0080104和美国专利号9,603,944中公开了某些表面修饰,两者均通过引用全文纳入本文。实例包括聚赖氨酸(聚K),PEG-聚K和聚精氨酸。
在一些实施方式中,交联反应可以在一种或多种拥挤剂例如聚乙二醇(PEG)和甘油三酯的存在下进行。示例性的PEG包括PEG400,PEG1000,PEG1500,PEG2000,PEG3000和PEG4000。
某些蛋白质溶解性助剂,例如甘油,乙二醇和丙二醇,山梨糖醇和甘露醇也可以提高背包形成的产率。
在某些实施方式中,由于背包中阳离子赖氨酸残基的反应,本发明的某些交联剂将导致背包具有净负电荷,其将抑制细胞附着。这样,首先通过静电相互作用用聚阳离子络合背包驱动细胞附着可能是有用的。例如,背包可以用聚阳离子如聚赖氨酸(聚-L-赖氨酸),聚乙烯亚胺,聚精氨酸,聚组氨酸,聚凝胺(Polybrene)和/或DEAE-右旋糖酐涂覆或表面修饰。聚阳离子可以帮助背包非特异性地结合或吸附在带负电荷的细胞膜上。在一些实施方式中,待包含在混合溶液中的聚阳离子可以是具有阳离子基团或可以变成阳离子基团的基团的聚合化合物,并且游离聚阳离子的水溶液显示碱性。可以变成阳离子基团的基团的实例包括氨基,亚氨基等。聚阳离子的实例包括:聚氨基酸,例如聚赖氨酸,聚鸟氨酸,聚组氨酸,聚精氨酸,聚色氨酸,聚2,4-二氨基丁酸,聚-2,3-二氨基丙酸,鱼精蛋白和多肽链中具有至少一种或多种选自下组的氨基酸残基的多肽:赖氨酸,组氨酸,精氨酸,色氨酸,鸟氨酸,2,4-二氨基丁酸和2,3-二氨基丙酸;聚胺,例如聚烯丙胺,聚乙烯胺,烯丙胺和二烯丙胺的共聚物,以及聚二烯丙胺;和聚亚胺,例如聚乙烯亚胺。
在一些实施方式中,用于促进背包粘附至细胞的聚阳离子涂层或表面修饰剂是PEG-聚赖氨酸的阳离子嵌段共聚物,例如[甲氧基-聚(乙二醇)n-嵌段-聚(L-赖氨酸盐酸盐),PEG-聚赖氨酸](PK30)。该嵌段共聚物可包含约114个PEG单元(MW约5000Da)和30个赖氨酸单元(MW约4900Da)。线性PEG聚合物具有甲氧基端基,聚赖氨酸为盐酸盐形式。PK30是线性两亲嵌段共聚物,其具有聚(L-赖氨酸盐酸盐)嵌段和非反应性PEG嵌段。聚-L-赖氨酸嵌段在生理pH下提供净阳离子电荷,并在缔合后使背包具有净正电荷。PK30结构[甲氧基-聚(乙二醇)n-嵌段-聚(L-赖氨酸盐酸盐)]如下。
在一些实施方式中,背包可以用与免疫细胞表面上的受体结合的抗体或其抗原结合片段包被,从而将背包特异性地靶向免疫细胞。示例性抗体包括本文公开的那些或包含该抗体的融合蛋白。
在一个实例中,如图1B所示,“IL15-Fc”(具有两个缔合的IL-15蛋白的IL15Ra-sushi-结构域-Fc融合同二聚体蛋白)单体可以被交联并用聚阳离子进行表面修饰以形成IL-15背包。然后可以将IL-15背包加载到免疫细胞(例如T细胞)上以形成引发的T细胞。
在一些实施方式中,一旦制备和纯化,背包可以任选地冷冻直到用于细胞疗法,如图1C所示。细胞疗法可选自,例如过继细胞疗法,CAR-T细胞疗法,工程改造的TCR T细胞疗法,肿瘤浸润淋巴细胞疗法,抗原训练的T细胞疗法,或富集的抗原特异性T细胞疗法。
在各种实施方式中,可通过提供本文公开的蛋白质簇或背包组合物,并将蛋白质簇或背包组合物与有核细胞如免疫细胞一起孵育,优选持续约30-60分钟来制备细胞疗法组合物。可以将细胞与背包冷冻保存,直到通过例如输注给予患者。
本文还公开了一种细胞疗法组合物,其包含与有核细胞例如T和NK细胞缔合的本文公开的蛋白质簇或背包组合物。可以将这种细胞疗法组合物给予需要其的对象。给予后,交联剂可在生理条件下降解,从而从蛋白质簇中释放治疗性蛋白质单体。
本文提供了包含背包的组合物,包括药物组合物。组合物可以以药学上可接受的量和药学上可接受的组合物配制。术语“药学上可接受的”是指不干扰活性成分(例如,纳米颗粒的生物活性蛋白)的生物活性的有效性的无毒材料。在一些实施方式中,此类组合物可包含盐,缓冲剂,防腐剂和任选地其他治疗剂。在一些实施方式中,药物组合物还可包含合适的防腐剂。在一些实施方式中,药物组合物可以单位剂型存在,并且可以通过药学领域公知的任何方法制备。在一些实施方式中,适合于肠胃外给予的药物组合物包含纳米颗粒的无菌水性或非水性制剂,在一些实施方式中,其与受体对象的血液等渗。该制剂可以根据已知方法配制。无菌注射制剂也可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液。
背包和包含其的组合物具有多种治疗用途,包括例如癌症、自身免疫疾病和传染病的治疗。本文所述的方法包括通过使用本文所述的背包或背负的细胞治疗对象的癌症。还提供了用于减少或改善对象的癌症症状的方法,以及用于抑制癌症的生长和/或杀死一种或多种癌细胞的方法。在实施方式中,本文描述的方法在给予了本文描述的或本文描述的药物组合物的对象中减小了肿瘤的大小和/或减少了癌细胞的数量。
在实施方式中,癌症是血液癌症。在实施方式中,血液癌症是白血病或淋巴瘤。如本文所用,“血液癌症”是指造血或淋巴组织的肿瘤,例如,影响血液,骨髓或淋巴结的肿瘤。示例性的血液癌症包括,但不限于:白血病(例如,急性淋巴细胞白血病(ALL),急性髓细胞白血病(AML),慢性淋巴细胞白血病(CLL),慢性骨髓性白血病(CML),毛细胞白血病,急性单核细胞白血病(AMoL),慢性髓单核细胞白血病(CMML),青少年髓单核细胞白血病(JMML)或大颗粒性淋巴细胞性白血病),淋巴瘤(例如与AIDS相关的淋巴瘤,皮肤T细胞淋巴瘤,霍奇金淋巴瘤(例如经典霍奇金淋巴瘤或结节性淋巴细胞为主导的霍奇金淋巴瘤),蕈状霉菌病(mycosis fungoides),非霍奇金淋巴瘤(例如B细胞非霍奇金淋巴瘤(例如伯基特淋巴瘤,小淋巴细胞淋巴瘤(CLL/SLL),弥漫性大B细胞淋巴瘤,滤泡性淋巴瘤,免疫母细胞大细胞淋巴瘤,前体B淋巴母细胞淋巴瘤或套细胞淋巴瘤)或T细胞非霍奇金淋巴瘤(蕈状霉菌病,间变性大细胞淋巴瘤或前体T淋巴母细胞淋巴瘤)),原发性中枢神经系统淋巴瘤,Sézary综合征,巨球蛋白血症),慢性骨髓增殖性疾病,朗格汉斯细胞组织细胞增生症,多发性骨髓瘤/浆细胞肿瘤,骨髓增生异常综合征,或骨髓增生异常/骨髓增殖性肿瘤。
在实施方式中,癌症是实体癌。示例性的实体瘤癌包括,但不限于:卵巢癌,直肠癌,胃癌,睾丸癌,肛门区域癌,子宫癌,结肠癌,直肠癌,肾细胞癌,肝癌,肺非小细胞癌,小肠癌,食道癌,黑色素瘤,卡波济肉瘤,内分泌系统癌,甲状腺癌,甲状旁腺癌,肾上腺癌,骨癌,胰腺癌,皮肤癌,头或颈癌,皮肤或眼内恶性黑素瘤,子宫癌,脑干神经胶质瘤,垂体腺瘤,表皮样癌,子宫颈鳞状细胞癌,输卵管癌,子宫内膜癌,阴道癌,软组织肉瘤,尿道癌,外阴癌,阴茎癌,膀胱癌,肾癌或输尿管癌,肾盂癌,脊髓轴肿瘤,中枢神经系统(CNS)肿瘤,原发性CNS淋巴瘤,肿瘤血管生成,所述癌症的转移性病变或其组合。
在实施方式中,以适合于待治疗或预防的疾病的方式给予背包或背负的细胞。通过诸如患者状态这样的因素以及患者疾病的类型和严重程度确定给予的数量和频率。适当的剂量可以通过临床试验确定。例如,当指示“有效量”或“治疗量”时,医师可以考虑对象的肿瘤大小,感染或转移程度,年龄,体重和状况的个体差异来确定要给予的药物组合物(或背包)的精确量。在实施方式中,本文所述的药物组合物可以104至109个细胞/kg体重,例如105至106个细胞/kg体重的剂量给予,包括那些范围内的所有整数值。在实施方式中,本文所述的药物组合物可以这些剂量多次给予。在实施方式中,本文描述的药物组合物可以使用免疫疗法中描述的输注技术给予(参见,例如,Rosenberg等,New Eng.J.Med.319:1676,1988)。
在实施方式中,将背包或背负的细胞肠胃外给予对象。在实施方式中,将细胞静脉内,皮下,肿瘤内,结节内,肌内,皮内或腹膜内给予给对象。在实施方式中,将细胞直接给予(例如注射)到肿瘤或淋巴结中。在实施方式中,以输注(例如,如Rosenberg等,NewEng.J.of Med.319:1676,1988中所述)或静脉内推注方式给予细胞。在实施方式中,细胞以可注射的储库制剂形式给予。
在实施方式中,对象是哺乳动物。在实施方式中,对象是人,猴,猪,狗,猫,牛,绵羊,山羊,兔,大鼠或小鼠。在实施方式中,对象是人。在实施方式中,所述对象是儿科对象,例如小于18岁,例如小于17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2、1岁或以下。在实施方式中,对象是成年人,例如,至少18岁,例如,至少19、20、21、22、23、24、25、25-30、30-35、35-40、40-50、50-60、60-70、70-80或80-90岁。
实施例
实施例1:接头-1的合成
碳酸盐形成
A:2,2'-二硫烷二基二(乙-1-醇)(2.0g,1当量)
B:DSC(N,N′-二琥珀酰亚胺基碳酸酯)(33.2g,10.0当量)
吡啶(11.3mL,10.0当量)
CHCl3,室温(rt),24小时(h)
(1)搅拌在氯仿(333mL,165V)中2,2'-二硫烷二基二(乙-1-醇)(2.0g,12.98mmol,1当量)的溶液
(2)添加DSC(33.2g,12.98mmol,10.0当量)
(3)添加吡啶(11.3mL,12.98mmol,10.0当量)
(4)在室温下搅拌反应混合物24小时(TLC对照)
(5)在减压下浓缩反应混合物以产生半固体
(6)用乙酸乙酯(200mL)稀释半固体并用水洗涤(2x 200mL)
(7)在减压下浓缩有机层以产生白色固体(2.4g,不纯)
(8)通过DCM纯化白色固体以产生产物(60%产率)
HPLC纯度-96.75%。1HNMR含有1.63%DCM
实施例2:接头-2的合成
步骤:1(酯形成)
A:琥珀酸(5.0g,1当量)
B:一乙二醇(10V)
H2SO4(35滴)
80℃,18小时
(1)在室温下向琥珀酸(A)(5.0g,42.34mmol,1当量)
(2)添加一乙二醇(B)(50mL)
(3)添加H2SO4(35滴)
(4)加热所得反应混合物至80℃持续18小时(TLC对照)
(5)冷却至室温
(6)用碳酸氢钠中和(pH约7-8)
(7)通过柱层析纯化粗材料;用乙酸乙酯稀释所需化合物
(8)所得是无色液体C:(双(2-羟乙基)丁二酸)(3.96g,45.36%产率)
步骤:2(碳酸酯形成)
C:双(2-羟乙基)丁二酸酯(1.5g,1当量)
D:DSC(18.66g,10当量)
吡啶(5.76g,10当量)
CHCl3,室温,20小时
(1)搅拌在CHCl3(150mL,100V)中双(2-羟乙基)丁二酸酯(C)(1.5g,1当量,7.2mmol)的溶液
(2)添加DSC(D)(18.66g,72.74mmol,10当量)
(3)添加吡啶(5.76g,72.74mmol,10当量)
(4)在室温下搅拌反应混合物20小时(TLC对照)
(5)在减压下浓缩反应混合物
(6)用DCM洗脱并用水洗涤(2x 300mL)
(7)分离有机层并在无水硫酸钠上干燥
(8)在减压下浓缩以产生1.9g灰白色半固体,
(9)冻干
(10)用DCM:甲醇研磨1.9g(不纯)化合物以得到1.06g的灰白色固体
实施例3:免疫细胞的背负
目的:可以用HBSS中5种浓度的IL15背包以50M/mL的细胞浓度标记人类细胞(例如T细胞,CAR-T,NK细胞,其他免疫细胞)。标记后,可以测试细胞:
a.通过FACS测量的7-AAD染色的活力
b.通过FACS测量的计数珠的培养中扩增
c.通过针对IL15和人类抗IgG的抗体对背包表面进行标记
IL15背包的解冻:
使用前,应将背包保存于-80℃。解冻后的背包可以重新冷冻,最多可以重复使用3次或更多次的冷冻/解冻周期。
从冰柜中取出背包等份试样,然后在冰上解冻。
1.将BP溶液解冻后,在进行细胞标记实验前15分钟将其温热至室温。
2.用HBSS调整BP母液至3mg/mL的最终工作溶液
背包稀释和细胞标记:
总共7个反应:1个仅PBS的对照,1个可溶性IL15恒定对照(接种后添加到细胞中),和5个背包样品(一式三份)(总共21个样品)。背包样品为:
a.BP-剂量1:3mg/mL
b.BP-剂量2:1.5mg/mL
c.BP-剂量3:0.75mg/mL
d.BP-剂量4:0.375mg/mL
e.BP-剂量5:0.1875mg/mL
1.用圆底96孔板对背包进行系列稀释:
2.将上述每孔的10ul稀释背包分配到一个圆底96孔板中的三个孔中(一式三份背负),总共21孔。
注意:圆底板比V底板好,因为它们限制了背包的毒性
细胞洗涤和背负:
以下步骤中使用的缓冲液,PBS和培养基应预热至37℃。
1.从培养物中收集30x106个细胞,并以500g沉淀它们5分钟。
2.抽吸除去细胞上清液。
3.通过将沉淀物重悬于10mL预热(37℃)HBSS缓冲液中洗涤细胞,然后用Cellometer(含AOPI染料)或台盼蓝计数。
4.以500g离心5分钟。
5.吸出上清液并将细胞沉淀物悬浮在预热的(37℃)HBSS中,使其浓度为100x106/mL细胞(约300ul缓冲液)。
6.将10ul细胞吸取到具有背包或HBSS的每个孔中,并通过吹打轻轻混合它们。
7.用微膜覆盖板以防止蒸发,然后在细胞培养箱中孵育(通常在37℃与5%CO2条件下或最适合培养的条件下)。
8.在37℃下孵育细胞一小时。
9.向每个孔中添加180uL预热的完全细胞培养基(含血清)。
10.以500g沉淀细胞5分钟,并用多孔歧管抽吸培养基。
11.按照步骤9和步骤10用200uL完全培养基再洗涤细胞两次,沉淀细胞和吸出上清液。
12.第三次洗涤后,将每个样品中的细胞重悬于200uL完全培养基中。细胞的密度应约为5x106个细胞/mL,在铺板过程中需要进一步以1:10稀释。
13.通过将20ul细胞悬液从96孔U底转移到96孔平底组织培养板中然后添加180ul细胞培养基(不添加细胞因子)以1:10的比例稀释细胞,以达到5x105个细胞/mL的最终铺板密度。
14.在三个单独的96孔平底板中,将步骤13再重复3次(总共4个板:第0天,第1天,第3天,第X天,以分裂用于将来的时间点)。
注意:
a.通常将细胞的几个“分裂(split)”铺板到多个96孔板中,这样可以在不同时间点分析单个分裂,同时允许在其他板中继续繁殖,因此有第0天,第1天,第3天,第X天的4个板。
b.当细胞生长至过度融合时,在第X天时,需要对其进行传代。我们建议通过直接培养基稀释来传代细胞。例如,在第X天时,将96孔板从培养箱中取出。通过上下吹打将细胞重悬于培养基中。将40uL细胞溶液转移到新的96孔平底板中,向每个孔中加入160uL新鲜、温热的培养基,以进行1:5分裂。
15.将可溶性IL15单体添加到每个板的可溶性IL15恒定对照孔中。
细胞计数和活力测试:
在流式细胞仪上使用7-AAD和CountBright计数珠对细胞进行计数。
1.在每个时间点,从培养箱中取出一个96孔平底板,通过上下吹打将细胞重悬于培养基中。
2.将20uL细胞溶液转移到96孔V型底平板上。
3.向每个孔中添加20uL的“CountBright珠溶液”。
CountBright珠溶液包含(下面列出了标记1个孔的体积):
a.19.6ul CountBright珠母液
b.0.4ul的100x 7AAD(7-AAD,生命技术公司(LifeTech),A1310,10ug/mL是100x)
4.在培养后第1、3和X天重复这些步骤以评估活力和扩增。
通过表面染色的BP加载效率测试:
在第0天和第1天使用抗IL15和抗人IgG抗体通过流式细胞术分析IL-15背包的表面水平。
1.从培养箱中取出96孔平底板,通过上下吹打将细胞重悬于培养基中。
2.将100uL细胞溶液转移到新的V型底96孔板中(应包含约50000个细胞)。
3.沉淀细胞(500g,5分钟)并吸出上清液。
4.将细胞重悬于40uL“抗体细胞表面染色液”中。
抗体染色溶液(下面列出了用于标记1个孔的体积):
a.0.4uL的小鼠抗-人IgG BV421–白乐津公司目录号409318,1:100稀释
b.0.4uL的抗-IL15 PE:R&D系统公司目录号IC2471IP,1:100稀释
c.0.4ul的100x 7AAD(7-AAD,生命技术公司(LifeTech),A1310,10ug/mL是100x)
d.38.8uL的MaCS缓冲液
5.在室温下孵育细胞10分钟。
6.向每个孔中加入160uL冷MACS缓冲液,以500g沉淀细胞5分钟,吸出。
7.再用200uL冷MACS缓冲液洗涤细胞一次。
8.重悬于30μL/孔的MACS缓冲液中,并在流式细胞仪上分析(HTS模式)。
使用的试剂:
汉克斯平衡盐溶液(HBSS,吉布可公司(Gibco),含钙和镁,目录号14025-092)
磷酸盐缓冲盐水(PBS,吉布可公司,无钙,无镁,目录号10010-023)
圆底96孔平板(Granier-Bio,透明,无菌,聚丙烯平板,目录号650261)
V型底96孔平板(任选但推荐):Costar 3894
平底96孔平板(FisherSci,目录号353072)
计数珠(生命技术公司,CountBright绝对计数珠,目录号C36950)
7-氨基放线菌素-D(7-AAD,生命技术公司,目录号A1310)
人IL-15PE-偶联的抗体(R&D系统公司,目录号IC2471P)
小鼠抗-人IgG,BV421(白乐津公司,目录号409318)
替代性抗体:小鼠抗-人IgG,APC(白乐津公司,目录号409306)
替代性抗体:驴抗-人IgG(H+L),DyLight 650(赛默飞世尔(ThermoFisher),目录号SA5-10129)
MACS缓冲液(任选的):
EDTA:生命技术公司,15575-038
磷酸盐缓冲盐水,pH 7.4(与上述相同)
牛血清白蛋白(BSA):美国生物公司(AmericanBio,Inc.),目录号AB01243-00050
实施例4:在IL-15的受控浓缩释放驱动的过继转移后,IL-15背包提供T细胞的自分泌刺激和扩增
白介素15是CD8和NK细胞扩增的强大刺激剂,能够驱动过继转移的T细胞的抗肿瘤活性。但是,全身递送不能安全地提供足够的剂量来驱动T细胞扩增植入和抗肿瘤活性。
我们启动白介素15背包(IL-15背包)项目的目的是,通过向转移的T细胞加载细胞因子的自分泌来源来提供安全有效剂量的白介素15(IL-15)(Stephan等,用表面偶联的合成纳米颗粒的治疗性细胞工程改造(Therapeutic cell engineering with surface-conjugated synthetic nanoparticles),Nat.Med.(2010)16(9):1035-1041)。癌症患者血液中高水平的IL-15与成功的临床反应相关(Kochenderfer等,由抗CD19嵌合抗原受体T细胞引起的淋巴瘤缓解与高血清白介素15水平相关(Lymphoma remissions caused byanti-CD19 chimeric antigen receptor T cells are associated with high seruminterleukin-15levels),J.Clinical Oncology(2017)35(16):1803-1813)。
本文公开的由IL-15背包引发的T细胞是携带严格控制剂量的IL-15的自体T细胞,其在7-14天的时间内缓慢释放以使输注的T细胞的定向自分泌激活而不影响内源性T细胞。
一个例子是IL-15背包引发的细胞毒性T细胞(CTL),其是使用新型树突细胞引发序列引发的肿瘤抗原。我们已经开发出一种完全封闭的生产工艺,以生产自体T细胞,以高产量的反应性细胞严格控制IL-15背包在这些细胞上的负载,每次单采血细胞数超过10亿。
如图2所示,使用健康的人CD8 T细胞在细胞标记反应中滴定含荧光团的IL-15背包。荧光直方图(LHS)和MFI定量(RHS)表明,IL-15背包加载程度随IL-15背包加载浓度的增加而增加。
图3显示了来自四个健康供体的经dynabead激活的人CD3 T细胞用三种不同浓度的IL-15背包标记。通过定量标记反应中剩余的IL-15背包并从反应中添加的IL-15背包总量中减去该数量,评估细胞缔合的IL-15背包加载。
图4显示在培养7天之前,用或不用IL-15背包处理dynabead激活的人CD3细胞。通过ELISA评估培养上清液中的IL-15水平。通过流式细胞术评估扩增。
图5显示将IL-15背包标记的人CD3 T细胞培养14天。在第1天,第2天,第3天或第4天进行培养基交换,以去除分泌的IL-15。
图6A显示通过流式细胞术测量的±IL-15背包加载的CAR-T细胞的体外细胞扩增。图6B显示了在注射入带NSCLC肿瘤的NSG小鼠后,流式细胞术测量的CAR-T细胞的血清水平。图6C显示了肿瘤大小的PET成像。
图7A-7B显示了PMEL T细胞,其被抗CD3/抗CD28包被的平板离体激活,并且被注射,用IL-15背包(“IL-15 BP”)引发或与IL15-Fc单体共同给予到B16-F10荷瘤C57B6小鼠中。在第1、4、10和16天处死小鼠以收集血液和组织。在2、24、48和96小时抽血以定量IL15-Fc(ELISA)和IFN-γ(Luminex)(图7A),以及枚举CD8,NK和PMEL细胞(图7B,流式细胞术)。图7C显示在不存在PMEL T细胞注射的情况下,将IL15-Fc或IL-15背包注射到非荷瘤C56BL6小鼠中。抽取血液以定量IFN-γ,并枚举活化的(CD25+)CD4,CD8和NK细胞。
新的,封闭的,半自动化的细胞生产工艺,其产量高达数十亿个针对可定制组的肿瘤相关抗原(TAA)靶向的细胞毒性T淋巴细胞(CTL)。在最后一步中,将抗原引导的CTL加载IL-15背包,以产生TRQ15-01细胞产物。
图8A-8E显示收获并针对以下表征了来自过程完成的CTL:(A)产物TAA特异性细胞计数和反应性(肽刺激后的细胞内细胞因子染色);(B)将TRQ15-01 CTL产物与其来料单采血(incoming apheresis)进行比较的TCR测序,以及(C)基于流的免疫细胞组成。D)用带有抗原肽之一的MHC四聚体标记TAA训练的CTL;(E)将CTL±IL-15背包注射到NSG小鼠中,并在第1、4、8、10天抽血。通过流式细胞术测量细胞扩增。
综上所述,IL-15背包细胞加载稳定且可调,从而使每个细胞的IL-15剂量受到控制。我们的IL-15背包技术的设计提供了缓慢且可控的IL-15释放,从而导致过继T细胞疗法中的自分泌刺激和持续的细胞扩增。与全身递送的IL-15相反,由于缺乏全身暴露,IL-15背包引发诱导的全身IFNg水平,内源性CD8和NK细胞扩增降低了几个数量级。尽管超低频率(<1%)前体,一个完全封闭的半自动化细胞过程仍可从健康供体中产生数十亿个抗原导向的人CTL,反应性约为20%,T细胞纯度为95%。人CTL高度依赖IL-15背包引发技术来实现体内细胞存活和扩增。
实施例5:深IL-15引发的PMEL T细胞的药理活性
深IL-15(Deep IL-15)是指具有两个缔合的IL-15分子的人IL-15受体α-sushi-结构域-Fc融合同源二聚体(IL15-Fc)的多聚体,通过可裂解的交联剂(接头-2)连接,且非共价包被有聚乙二醇(PEG)-聚赖氨酸30嵌段共聚物(PK30)。具体而言,深IL-15是指人IL15-Fc单体的多聚体,通过可水解的交联剂(CL17)连接,且非共价包覆有聚乙二醇(PEG)-聚赖氨酸30嵌段共聚物(PK30)。IL15-Fc单体由两个亚基组成,每个亚基由与非共价结合至IL-15分子的IL-15受体α-sushi-结构域融合的效应子减毒IgG2 Fc变体组成。深IL-15引发的T细胞是通过加载过程生成的,在该过程中,靶细胞与高浓度的深IL-15共孵育。通过此过程,深IL-15通过静电相互作用与细胞缔合,并被内化以产生深IL-15的细胞内储库。从这些储库中,深IL-15通过交联剂的水解缓慢释放生物活性IL15-Fc。IL15-Fc的这种延长释放促进了深IL-15引发的T细胞的增殖和存活,从而提供了靶向的,可控制的和时间依赖性的免疫刺激。
这项研究的目的是测试在有或没有原位放置B16-F10黑色素瘤的C57BL/6J小鼠中深IL-15引发的PMEL T细胞的药理活性。对照组包括载剂对照,单独的PMEL细胞和PMEL细胞+IL15-Fc,分别注射给予(10μg,最大耐受剂量,MTD)。
材料和方法
B16-F10肿瘤建立和肿瘤测量
在研究第-12天,将B16-F10黑色素瘤肿瘤细胞(0.2x106)皮内注射到雌性C57BL/6小鼠(杰克逊实验室)的剃毛的右胁腹中。记录体重并每周用卡尺测量肿瘤尺寸(在缩写列表中定义的长度[L]和宽度[W])2至3次。使用以下公式计算肿瘤体积:W2 x L xπ/6。
PEML细胞的分离和扩增
从14只雌性转基因PMEL小鼠(杰克逊实验室,缅因州巴港)的脾脏和淋巴结(腹膜,腋窝和宫颈)中分离出PMEL细胞。用GentleMACS Octo Dissociator(美天旎生物技术公司(Miltenyi Biotech),加利福尼亚州奥本)处理脾脏和淋巴结,并通过40μm过滤器。离心洗涤细胞,并使用IMACS幼稚CD8a+分离试剂盒(美天旎生物技术公司)和MultiMACS细胞24块(美天旎生物技术公司)和带有18根柱的分离器(美天旎生物技术公司)按照制造商的操作规程纯化CD8a+细胞。通过亲和柱除去非CD8a+细胞,并在柱洗脱液中收集CD8a+T细胞。通过流式细胞术确认了CD8a+细胞的纯度。
分离后(D0),将来自PMEL小鼠的纯化的CD8a+细胞以5x106个细胞/孔的密度接种到十个包被有抗CD3和抗CD28的6孔组织培养板中,并在37℃和5%二氧化碳下孵育24小时。接种后24小时(D1)加入鼠IL-2(20ng/mL)和鼠IL-7(0.5ng/mL)。在第2天和第3天,对细胞计数并用含有鼠IL-21(10ng/mL)的新鲜培养基稀释至0.2×106个细胞/mL的浓度。在第4天收集细胞以在28mL载剂对照中获得总计100x106个PMEL细胞/mL。
深IL-15引发的PMEL T细胞的制备
将5mL PMEL细胞(100x106个细胞/mL)与5.5mL的深IL-15(1.36mg/ml)混合,并在37℃旋转孵育1小时,以产生深IL-15引发的PMEL细胞。通过离心(500g)洗涤深IL-15引发的PMEL细胞(3X,首先用培养基,然后用HBSS洗涤两次)并计数。将深IL-15引发的PMEL细胞以50x106个细胞/mL的浓度重悬。给5A和5B组的小鼠注射200μL的这种制剂,每只小鼠总共10x106个深IL-15引发的PMEL细胞。将PMEL细胞(15mL以100x106个细胞/mL)与15mL HBSS混合,在37℃旋转孵育1小时,通过离心(500g)洗涤(3X,先用培养基,然后再用HBSS洗涤2次)并计数。将PMEL细胞以50x106个细胞/mL的浓度重悬。给2A和2B组的小鼠静脉内注射200μL的这种制剂,每只小鼠总共10x106个PMEL细胞。给3A和3B组的小鼠静脉内注射200μL的这种制剂,每只小鼠总共10x106个PMEL细胞,并接受眶后注射IL15-Fc(每只小鼠在50μl HBSS中10μg/小鼠;批号TS0)。基于39%的平均加载效率,与10x106个PMEL细胞缔合的IL15-Fc总量为58.5μg,这比3A和3B组中通过注射IL15-Fc(10μg)全身递送的量高5.85倍。
Fc-IL-15 ELISA
Fc-IL15酶联免疫吸附测定(ELISA)用于确定给予后2小时,第1天,第2天,第4天和第10天收集的样品中IL15 Fc的浓度。ELISA板在4℃下用山羊抗人IgG Fc捕获抗体包被过夜。洗涤板,并在30℃下用试剂稀释剂封闭至少2小时。洗涤板,向孔中加入样品(在试剂稀释剂中稀释)和IL15-Fc标准品(一式两份,在试剂稀释剂中31至2000pg/mL),并将板在37℃下孵育1小时。洗涤板,然后加入生物素-抗IL15检测抗体并在37℃下孵育1小时。将板洗涤并在37℃下与链霉亲和素-HRP孵育20分钟。洗涤板,然后添加3,3',5,5'-四甲基联苯胺(TMB)底物溶液并在黑暗中于室温下孵育20分钟,直到反应停止。在酶标仪(450nm)上读板。
该测定进行两次。对于第一次运行,以以下稀释度对样品进行评估:2小时时间点为1:20000,第1天时间点为1:5000,并且第2天,第4天和第10天时间点为1:250。对于第二次运行,将来自3A和3B组的样品在第1天时间点按1:5000稀释,在第2天时间点按1:250稀释,并在第4天和第10天时间点按1:25稀释。在所有分析的时间点,将来自1A和1B,2A和2B和5A和5B组的样品按1:25稀释。报告第二次运行的数据。但是,由于第二次运行中2小时时间点的样品已消耗尽,并且考虑到两次运行中3A和3B组在24小时时IL15-Fc的浓度相似,因此包含了第一次运行的2小时值与来自第二次运行的其他数据点一起用于计算药代动力学(PK)参数。
1:20000稀释中血液的定量下限(LLOQ)为310ng/ml,1:5000稀释中为77.5ng/ml,1:250稀释中为3.875ng/ml,而1:25稀释中为0.3875ng/ml。
来自小鼠的血清中的血清细胞因子水平
根据制造商的方案,使用ThermoFisher ProcartaPlex小鼠高灵敏度面板5plex目录号EPXS0S0-22199-901试剂盒,并在Bio-Plex 200系统上分析样品。将血清在冰上解冻,并测试20μL血清的IFN-γ,TNF-α,IL-2,IL-4和IL-6水平。在一些样品中,无法获得20μL的血清,因此使用了较小的体积。调节稀释因子,以根据标准曲线计算浓度。统计分析在GraphPad Prism中进行。
结果
临床化学
在血清样品上测量临床化学参数。图9显示了临床化学参数,其中在给予后第1天和第4天观察到幼稚小鼠的统计学显著变化。给予后第1天,相对于深IL-15引发的PMEL组,观察到PMEL+IL15-Fc组的白蛋白水平显著降低(p<0.05),以及与载剂对照和深IL-15引发的PMEL相比,血尿素氮(BUN)水平也显著降低(两者均p<0.05)。给予后第4天,PMEL+IL15-Fc组显示显著降低的白蛋白(与所有其他治疗组相比,p<0.05),总蛋白(与载剂对照相比,p<0.05),葡萄糖(与深IL-15引发的PMEL相比p<0.05),白蛋白/球蛋白(ALB/GLOB)比率(与载剂对照相比p<0.05,并且与PMEL和深IL-15引发的PMEL相比p<0.01)。此外,PMEL+IL15-Fc组胆固醇水平显著增加(与载剂对照和深IL-15引发的PMEL相比,p<0.05)。与载剂对照相比,所有治疗组均表现出钙水平降低的趋势,这在PMEL组中是统计学显著的(p<0.05)。深IL-15引发的PMEL组在总胆红素(与载剂对照和PMEL相比,p<0.05)和磷(与PMEL相比,p<0.05)上显示出统计学显著的变化。
图10显示了临床化学参数,其中在给予后第1天和第4天观察到荷瘤小鼠的统计学显著变化。给予后第1天,在临床化学上唯一的统计学显著变化是胆红素–偶联物的减少,在PMEL+IL15-Fc和深IL-15引发的PMEL组中均观察到(与载剂对照相比,两者均p<0.05)。在给予后第4天,PMEL组的白蛋白(与载剂对照相比,p<0.05),总蛋白(与载剂对照相比,p<0.01)和碳酸氢盐TCO2(与载剂对照相比,p<0.05)在统计学上显著增加。此外,PMEL组(与载剂对照相比p<0.001;与DP-15PMEL相比p<0.05)和PMEL+IL15-Fc组(与载剂对照相比,P<0.05)观察到球蛋白的统计学显著增加。
全身细胞因子释放
使用Luminex 5-plex试剂盒,在给予后2小时,24小时和96小时测量血清细胞因子(IFN-γ,IL-2,IL-4,IL-6和TNFα)。在幼稚非荷瘤小鼠中,PMEL+IL15-Fc组中的IFN-γ水平为12.8±3.7pg/mL,而在深IL-15引发的PMEL组中,IFN-γ低于定量下限(LLOQ=0.06pg/mL)(图11)。在荷瘤小鼠中,与深IL-15引发的PMEL组(0.5±0.1pg/mL)相比,PMEL+IL15-Fc组(20.5±0.5pg/mL)中的IFN-γ浓度平均高41倍。与其他组相比,PMEL+IL15-Fc组也观察到更高水平的IL-2,IL-6和TNFα。
血液中IL15-Fc的药代动力学
夹心ELISA(抗Fc捕获抗体,然后抗IL15检测抗体)用于测量注射PMEL+IL15-Fc(10μg)和深IL-15引发的PMEL(携带58.5ug的IL15-Fc)的小鼠血液中的IL15-Fc。
对于幼稚和荷瘤小鼠,确定了复合动物的单次剂量给予深IL-15引发的PMEL和PMEL+IL15-Fc的药代动力学(PK)。对于PMEL+IL15-Fc组,在幼稚和荷瘤小鼠中,给予后2小时均达到最大浓度(Cmax)。在深IL-15引发的PMEL组中,首次测量的浓度在24小时(最初以非最佳稀释度测量2小时样品,未检测到IL15-Fc,并且没有足够的样品供用理想稀释度重复测量)。荷瘤小鼠达到比幼稚小鼠略低的浓度。在荷瘤小鼠和非荷瘤小鼠中,PMEL+IL15-Fc组中IL15-Fc的计算平均值t1/2分别为28.9小时和7.12小时。
比较了PMEL+IL15-Fc和深IL-15引发的PMEL组在24小时时间点的IL15-Fc浓度。PMEL+IL15-Fc(10μg)组中的总IL15-Fc浓度高于深IL-15引发的PMEL组(58.5ug的IL15-Fc),在幼稚小鼠约高3488倍,并且在荷瘤小鼠中高3299倍。表1总结了复合IL15-Fc PK参数,图12描绘了平均(SD)IL15-Fc PK曲线。
表1:在幼稚和荷瘤小鼠中PMEL+IL15-Fc组的复合IL15-Fc PK参数(10ug剂量的IL15-Fc)
肿瘤生长的抑制
在第0天(给予当天),肿瘤已达到约140mm3的平均体积。与载剂对照相比,在所有治疗组中,在给予后第4天观察到对肿瘤生长的统计学显著抑制(p<0.0001),并且这种差异随着时间的推移变得更加明显(图13,左图)。在研究第16天,在载剂对照组中仅剩余2/5的动物(由于广泛的肿瘤负担而处死了其他动物),但是在每个治疗组中剩余4/5的动物。载剂对照组中的肿瘤体积与所有其他组均显著(p<0.0001)不同。PMEL组的肿瘤体积显著(p<0.05)大于深IL-15引发的PMEL和PMEL+IL15-Fc组的肿瘤体积。在第16天,PMEL+IL15-Fc和深IL-15引发的PMEL组中肿瘤生长的抑制作用彼此不同(图13,左图和右图)。在给予后第1、4、10和16天,在处死后(n=2-5,每个组,每个时间点)称量肿瘤。肿瘤重量示于图14。
在研究指定的终点之前,发现一些动物濒死或死亡。这些包括在载剂对照(共4只:第9天1只,第10天1只,第14天2只),PMEL组(共2只:第2天1只,第6天1只),PMEL+IL15-Fc组(共2只:第9天1只,第11天1只)和深IL-15引发的PMEL组(共2只:第9天1只,第16天1只)中的小鼠。这些不被认为与治疗有关,因为它们在组间分布,并在载剂对照中具有最高数量(n=4)。最后,与PMEL相比,深IL-15引发的PMEL组相关的濒死或死亡的动物没有差异。
结论
该研究的主要发现总结如下。
1.深IL-15引发的PMEL细胞在10x106个细胞的给予剂量下具有良好的耐受性。
2.与载剂对照相比,PMEL,PMEL+IL15-Fc和深IL-15引发的PMEL细胞均导致肿瘤生长抑制。与PMEL相比,PMEL+IL15-Fc和深IL-15引发的PMEL细胞的抑制作用更高。
3.使用PMEL或深IL-15引发的PMEL细胞均未观察到毒理学相关的临床化学参数变化。用PMEL+IL-15Fc观察到一些变化。
4.在任何时间点,使用PMEL或深IL-15引发的PMEL细胞均未检测到血清IFN-γ,TNF-α或IL-6的变化。使用PMEL+IL15-Fc在24小时观察到血清IFN-γ和TNF-α的显著变化。在2小时(仅非荷瘤(幼稚)小鼠)和24小时,PMEL+IL15-Fc使IL-6升高。
5.与在PMEL+IL15-Fc组中检测到的水平相比,深IL-15引发的PMEL组中的IL15-Fc血清水平低3000倍以上,对应于与PMEL+IL15-Fc组相比,无体重减轻,CBC和内源性免疫细胞(CD8+,NK1.1+和CD4+细胞)无明显变化,降低的IFN-γ血清水平和相关药理变化。
对本公开所述方法和组合物的改进和变动对本领域技术人员是显而易见的,而不偏离本公开的范围和精神。虽然已结合具体的优选实施方案对本公开作了描述,但应了解,如权利要求所述,本公开不应过分地受限于这些具体实施方案。实际上,本公开所属领域的相关领域的技术人员意图和理解对所描述的用于实施本公开的方式的各种修改,这些修改落入由所附权利要求所表示的本公开的范围内。
通过引用纳入
本说明书中提到的所有专利和公开通过引用纳入本文,就好像将各篇单独的专利或公开专门和单独地通过引用纳入本文那样。
Claims (33)
1.一种治疗性组合物,其包含:
包含多个彼此可逆交联的治疗性蛋白质单体的蛋白质簇,其中所述蛋白质簇的直径通过动态光散射测量为30nm至1000nm;
多种可生物降解的交联剂,每种具有两个、三个或四个能够与治疗性蛋白质单体上的亲核基团反应的官能团,从而将治疗性蛋白质单体交联形成蛋白质簇,其中所述交联剂在给予有需要的对象后在生理条件下降解,以从蛋白质簇中释放治疗性蛋白质单体;
药学上可接受的运载体或赋形剂;和
任选地,蛋白质簇上的表面修饰,其中优选地,所述表面修饰是聚阳离子。
2.如权利要求1所述的组合物,其中所述交联剂具有式A-B-C,其中B是任选的,其中A代表结构模板,B代表聚合物间隔物,C代表可水解的连接键和可以与亲核基团反应的官能团。
5.如权利要求4所述的组合物,其中所述交联剂是对称的。
6.如权利要求4所述的组合物,其中LG1和LG2能够与蛋白质、药物和/或颗粒反应。
7.如权利要求4-6中任一项所述的化合物,其中LG1和LG2均为咪唑啉或N-羟基琥珀酰亚胺。
10.如权利要求1-3中任一项所述的组合物,其中所述交联剂具有式(II):
其中:
X1和X2各自独立地选自三氟甲磺酸酯,甲苯磺酰基,Cl,N-羟基琥珀酰亚胺和咪唑啉;
A1和A3各自独立地是–(CR1R2)n–;
A2是–(CR1R2)m–;
Y1和Y2各自独立地选自NR3、O和S;
其中每次出现时,R1和R2独立地选自氢,卤素,羟基,C1-12烷基,C2-12烯基,C3-12环烷基,C2-12杂环基;任选地被1个或多个卤素,羟基,C1-6烷基和/或C1-6烷氧基取代的C6-12芳基;和任选地被1个或多个卤素,羟基,C1-6烷基和/或C1-6烷氧基取代的C4-12杂芳基;
其中R3选自氢,C1-12烷基,C2-12烯基,C3-12环烷基,C2-12杂环基;任选地被1个或多个卤素,羟基,C1-6烷基和/或C1-6烷氧基取代的C6-12芳基;和任选地被1个或多个卤素,羟基,C1-6烷基和/或C1-6烷氧基取代的C4-12杂芳基;
在每次出现时,n是独立地选自1-12的整数;并且
m是从0到12的整数。
11.如权利要求10所述的组合物,其中所述交联剂是对称的。
12.如权利要求10或11所述的组合物,其中X1和X2各自是能够与蛋白质、药物和/或颗粒反应的离去基团。
13.如权利要求12所述的组合物,其中X1和X2均为咪唑啉或N-羟基琥珀酰亚胺。
14.如权利要求10或11所述的组合物,其中R1和R2都是氢。
15.如权利要求14所述的组合物,其中A1和A3均为–(CH2)2-。
16.如权利要求10、11、13和15中任一项所述的组合物,其中A2是–(CH2)2-。
17.如权利要求10-16中任一项所述的组合物,其中Y1和Y2均为O。
19.如权利要求10、11、13和15中任一项所述的组合物,其中A2是键。
20.如权利要求19所述的组合物,其中Y1和Y2均为NH。
22.如前述权利要求中任一项所述的组合物,还包括优化所述蛋白质簇形成的试剂。
23.如权利要求22所述的组合物,其中与不含所述试剂的组合物相比,所述试剂通过减少未反应的蛋白质来增加蛋白质簇形成的产率。
24.如权利要求22所述的组合物,其中与不含所述试剂的组合物相比,所述试剂通过减少尺寸大于1000nm的簇的形成来增加蛋白质簇形成的产率。
25.如前述权利要求中任一项所述的组合物,其中所述治疗性蛋白质单体包含一种或多种细胞因子分子和/或一种或多种共刺激分子,其中:
(iii)所述一种或多种细胞因子分子选自IL15,IL2,IL7,IL10,IL12,IL18,IL21,IL-23,IL-4,IL1α,IL1β,IL-5,IFNγ,TNFα,IFNα,IFNβ,GM-CSF或GCSF;和/或
(iv)一种或多种共刺激分子选自CD137,OX40,CD28,GITR,VISTA,抗CD40或CD3。
26.一种制备如权利要求1-25中任一项所述的组合物的方法,包括使所述多种治疗性蛋白质单体与所述多种交联剂反应以形成所述蛋白质簇。
27.如权利要求26所述的方法,其中反应步骤在约5℃至约40℃的温度下进行。
28.如权利要求26或27所述的方法,其中反应步骤进行约1分钟至约8小时。
29.如权利要求26-28中任一项所述的方法,还包括向所述蛋白质簇提供表面修饰。
30.如权利要求26-29中任一项所述的方法,还包括纯化所述蛋白质簇。
31.一种制备细胞疗法组合物的方法,包括:
提供如权利要求1-25中任一项所述的组合物;和
孵育所述蛋白质簇与有核细胞如T和NK细胞,优选持续约30-60分钟。
32.一种细胞疗法组合物,包括与有核细胞如T和NK细胞缔合的如权利要求1-25中任一项所述的组合物。
33.一种提供细胞疗法的方法,包括向有需要的对象给予如权利要求32所述的细胞疗法组合物。
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CN112891556A (zh) * | 2021-02-01 | 2021-06-04 | 浙江大学医学院附属第一医院 | 一种单抗类药物口服纳米凝胶及其制备方法 |
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CA3074826A1 (en) | 2019-03-14 |
US20230233609A1 (en) | 2023-07-27 |
AU2018328209A1 (en) | 2020-04-23 |
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US11524033B2 (en) | 2022-12-13 |
KR20210032924A (ko) | 2021-03-25 |
WO2019050978A1 (en) | 2019-03-14 |
US20210060065A1 (en) | 2021-03-04 |
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JP2020532568A (ja) | 2020-11-12 |
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