CN116212048A - 纳米颗粒的细胞表面偶联 - Google Patents
纳米颗粒的细胞表面偶联 Download PDFInfo
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Abstract
在一些实施方式中,本发明公开内容涉及包含具有非内化受体的细胞以及用结合所述非内化受体的配体表面修饰的纳米颗粒的方法和组合物。
Description
本申请是申请日为2016年8月12日、申请号为201680059459.6、名称为“纳米颗粒的细胞表面偶联”的专利申请的分案申请。
联邦资助研究
本发明是借助国家健康研究院授予的拨款号No.R01 CA172164的政府支持进行的。政府在本发明中具有一定权利。
相关申请的交叉参考
本申请要求2015年8月12日提交的美国临时专利申请No.62/204,337的优先权和权益,将其完整内容按引用并入本文中。
背景技术
基于纳米结构(例如:纳米颗粒和脂质体)的药物递送策略与基于细胞的治疗的结合已经在研发对于各种疾病的治疗具有提高的功效和降低的毒性的新治疗形态方面产生了许多机会。例如,含有支持性药物(例如,细胞因子)的纳米颗粒可以与治疗性细胞(例如,肿瘤反应性T细胞)偶联以加强基于细胞的治疗(Cancer Res.2007,67,300-308;Nat.Med.2010,16,1035-1041)。或者,某些细胞类型(例如,抗原特异性T细胞、间质干细胞)可以用作载体,以将含药物的纳米颗粒特异性地靶向疾病部位来提高治疗效果(Nat.Med.2005,11,1073-1081;ACS Nano 2011,5,7462-7470)。
发明内容
在一些方面中,本发明公开内容提供了一种有效且稳定地将纳米结构与载体细胞表面(例如,T细胞表面)偶联的方法,其具有最小的细胞内化,从而允许用于各种生物应用(如靶向免疫治疗)的细胞外药物(例如,细胞因子和小分子)的体内递送。通常,颗粒(或纳米结构)与T细胞表面的偶联引发颗粒(或纳米结构)通过例如T细胞受体介导的内吞作用或膜渗透的内化。这样的内化机制阻止了T细胞(其在体内天然归巢(home)于特定组织)用作用于例如治疗剂或诊断剂的递送的载体细胞。出人意料地,本文中提供的实验结果显示,用例如结合CD45的配体(例如,抗-CD45抗体)表面修饰(例如,与其缀合)的纳米结构保持在表达CD45的T细胞的表面。因此,本发明公开内容出乎意料地证明,不是所有T细胞受体促进受体介导的内吞作用。一些分子,如CD45,能够保持颗粒在载体细胞的表面处。还令人惊讶的是证明CD45(特别地,甚至在与内化T细胞受体结合表达时)最小化内化的与细胞表面偶联的颗粒(例如,纳米结构)的结果。
此外,实验结果出乎意料地表明,在进行与载体细胞(例如,T细胞)的偶联反应前将聚阳离子(例如,聚L-赖氨酸)加入到纳米结构的表面时,可以获得例如89.6%的偶联效率。例如,使用本发明公开内容的方法将人IL-15Sa蛋白纳米凝胶与激活的T细胞偶联用于过继性细胞治疗,并且获得了转染T细胞的高效扩增,以及在小鼠中与使用相等剂量的可溶性人IL-15Sa相比显著降低的毒性。这样的结果是出乎意料的,因为细胞毒性已知由使用聚阳离子涂层包被和浓缩的DNA的递送产生。
本文中提供的组合物可用于提高纳米结构与载体细胞表面(例如,T细胞表面)偶联的效率和稳定性,用于各种生物医学和药物应用,如,例如,治疗性和预防性(例如,药物递送)以及诊断性(例如,成像和追踪)应用。
因此,本发明公开内容的一些方面提供了包含具有细胞表面偶联受体的载体细胞和用结合细胞表面偶联受体的配体进行表面修饰的纳米结构的组合物。在某些实施方式中,所述载体细胞是有核载体细胞。在某些实施方式中,所述有核载体细胞归巢于肿瘤。在某些实施方式中,所述组合物包含具有与用结合细胞表面偶联受体的配体表面修饰的纳米结构偶联的细胞表面偶联受体的有核载体细胞。在一些实施方式中,所述配体选自抗体、可溶性蛋白受体、细胞因子、肽、小分子、辅因子、激素和神经递质。
在一些实施方式中,所述细胞表面偶联受体是CD45。
在一些实施方式中,所述配体是抗CD45抗体。在一些实施方式中,所述抗CD45抗体是人抗CD45抗体或人源化抗CD45抗体。在一些实施方式中,所述抗CD45抗体是抗CD45单克隆抗体。在一些实施方式中,所述抗CD45单克隆抗体选自BC8、4B2、9.4和GAP8.3。
在一些实施方式中,所述配体结合细胞表面偶联受体,由此将纳米结构连接或偶联至有核载体细胞。
在一些实施方式中,所述配体结合细胞表面偶联受体。
在一些实施方式中,所述配体结合细胞表面偶联受体并且至少50%(例如,至少60%、至少70%、至少80%、至少90%或至少95%)的配体(例如,抗CD45抗体)保留在细胞表面上至少24小时(例如,至少36小时,或至少48小时)。
在一些实施方式中,所述载体细胞是T细胞、B细胞、自然杀伤(NK)细胞或造血祖细胞。在一些实施方式中,所述载体细胞是T细胞。例如,所述T细胞可以是CD8+T细胞或CD4+T细胞。在一些实施方式中,所述T细胞是过继转移的T细胞。在一些实施方式中,所述T细胞是嵌合抗体受体(CAR)T细胞。
在一些实施方式中,所述纳米结构是纳米颗粒或脂质体。
在一些实施方式中,所述纳米颗粒选自:蛋白质纳米凝胶、核酸纳米凝胶和固化的聚合物。
在一些实施方式中,所述纳米结构是脂质体。在一些实施方式中,所述脂质体是双层间(interbilayer)交联的多层囊泡(ICMV)或单层囊泡。
在一些实施方式中,所述纳米颗粒是蛋白质纳米凝胶。在一些实施方式中,所述蛋白质凝胶是无载体蛋白质纳米凝胶。
在一些实施方式中,所述纳米结构具有1至1000纳米(nm)的直径。例如,所述纳米结构具有50至500nm的直径。
在一些实施方式中,所述配体与纳米结构共价缀合。在一些实施方式中,所述配体经由马来酰亚胺-巯基反应与纳米结构共价缀合。
在一些实施方式中,所述纳米结构包含药剂。在一些实施方式中,所述纳米结构是包含药剂的蛋白质纳米凝胶或脂质体。在一些实施方式中,所述药剂选自治疗剂、预防剂、诊断剂和成像剂。在一些实施方式中,所述药剂选自蛋白质、核酸和小分子药物。在一些实施方式中,所述药剂是生物活性蛋白。例如,所述生物活性蛋白是细胞因子,如IL-2、IL-15或IL-15超激动剂(superagonist)(IL-15超激动剂也称为IL-15Sa或IL-15SA)。
在一些实施方式中,所述纳米结构(例如:蛋白质纳米凝胶)在其表面上包含聚阳离子。在一些实施方式中,所述聚阳离子是聚赖氨酸。在一些实施方式中,所述聚阳离子是聚乙二醇-b-聚赖氨酸或聚乙二醇-g-聚赖氨酸。
在一些实施方式中,所述组合物包含与包含表面聚阳离子的纳米结构共价缀合的有核载体细胞。
本发明公开内容的一些方面提供了组合物,其包含具有CD45受体的T细胞,所述T细胞与包含聚阳离子和结合CD45受体的配体(例如,抗CD45抗体)的蛋白质纳米凝胶偶联。
本发明公开内容的一些方面提供了组合物,其包含具有CD45受体的T细胞,所述T细胞与包含药剂、聚阳离子和结合CD45受体的配体(例如,抗CD45抗体)的蛋白质纳米凝胶偶联。
本发明公开内容的一些方面提供了组合物,其包含具有CD45受体的T细胞,所述T细胞与包含结合CD45受体的配体(例如,抗CD45抗体)的脂质体偶联。
本发明公开内容的一些方面提供了组合物,其包含具有CD45受体的T细胞,所述T细胞与包含药剂和结合CD45受体的配体(例如,抗CD45抗体)的脂质体偶联。
本发明公开内容的一些实施方式提供了包含归巢至肿瘤并且与包含生物活性蛋白的纳米结构偶联的有核载体细胞的组合物,其中所述载体细胞包含CD45受体并与具有结合CD45受体的配体的纳米结构偶联,或所述载体细胞包含带负电荷的细胞膜,而所述纳米结构包含与细胞膜静电地相互作用的聚阳离子表面,并且其中所述纳米结构是蛋白质纳米凝胶或脂质体。
在某些方面中,所述载体细胞包含CD45受体并与具有结合CD45受体的配体的纳米结构偶联。
在某些方面中,所述配体是抗CD45单克隆抗体。
在某些方面中,所述载体细胞包含带负电荷的细胞膜,而所述纳米结构包含与细胞膜通静电相互作用的聚阳离子表面。在某些方面中,所述聚阳离子是聚赖氨酸。在某些方面中,所述聚阳离子是聚乙二醇-b-聚赖氨酸(PEG-PLL)。
在一些实施方式中,所述组合物包含纳米结构,其中所述纳米结构是蛋白质纳米凝胶,并且所述蛋白质纳米凝胶包含通过可降解接头彼此可逆地和共价地交联的多个生物活性蛋白。在一些实施方式中,所述可降解接头是包含二硫键的氧化还原反应性接头。
在一些实施方式中,所述组合物包含纳米结构,其中所述纳米结构是脂质体,并且所述脂质体包含多个生物活性蛋白。在某些方面中,所述脂质体是多层的或双层间交联的多层囊泡。
在一些实施方式中,所述组合物包含载体细胞,其中所述载体细胞是T细胞、B细胞、自然杀伤(NK)细胞或造血祖细胞。在一些方面中,所述载体细胞是T细胞。在一些方面中,所述T细胞是CD8+T细胞或CD4+T细胞。在一些方面中,所述T细胞是过继转移的T细胞。在一些方面中,所述T细胞是嵌合抗原受体(CAR)T细胞。
在一些实施方式中,所述组合物包含含有生物活性蛋白的纳米结构,其中所述生物活性蛋白选自抗体、抗体片段、可溶性蛋白受体和细胞因子。在一些方面中,所述细胞因子是IL-2、IL-7、IL-15(或这些细胞因子的超激动剂/突变体形式,例如:IL-15Sa)、IL-12、IFN-γ、IFN-α、GM-CSF、FLT3-配体。在一些方面中,所述细胞因子是IL-15-Sa。在一些方面中,所述IL-15Sa包括包含二聚IL-15RαSu/Fc和两个IL-15N72D分子的复合物。在一些方面中,所述二聚IL-15RαSu/Fc包含SEQ ID NO:2中所列的氨基酸序列,而IL-15N72D分子包含SEQ ID NO:1中所列的氨基酸序列。
在一些实施方式中,所述组合物包含药物学上可接受的载体。在一些方面中,所述组合物可用作用于将生物活性蛋白递送至患有肿瘤的受试者的药物。
本公开内容的某些方面提供了治疗受试者的癌症的方法,包括将本文中所述的组合物施用于需要的受试者。
本公开内容的某些方面提供了一种包含归巢至肿瘤的有核载体细胞(例如:T细胞)的组合物,所述有核载体细胞与包含生物活性蛋白的纳米结构偶联,其中(a)所述载体细胞包含CD45受体并且与具有结合CD45受体的配体的纳米结构偶联,或(b)所述载体细胞包含带负电荷的细胞膜,而所述纳米结构包含与所述细胞膜通过静电相互作用的聚阳离子表面;或(c)所述载体细胞包含CD45受体并与具有结合CD45受体的配体的纳米结构偶联,并且所述载体细胞包含带负电荷的细胞膜和纳米结构包含与所述细胞膜通过静电相互作用的聚阳离子表面。
本公开内容的某些方面提供了包含含有CD45受体的有核载体细胞(例如:T细胞)和含有生物活性蛋白的纳米结构的组合物,其中所述载体细胞与具有结合CD45受体的配体的纳米结构偶联。
本公开内容的某些方面提供了包含与包含生物活性蛋白的纳米结构偶联的归巢至肿瘤的有核载体细胞(T细胞)的组合物,其中所述载体细胞包含带负电荷的细胞膜,而所述纳米结构包含与所述细胞膜通过静电相互作用的聚阳离子表面。
本公开内容的某些方面提供了包含含有CD45受体的有核载体细胞和蛋白质纳米凝胶的组合物,其中所述载体细胞与具有结合CD45受体的配体的蛋白质纳米凝胶偶联,并且其中所述蛋白质纳米凝胶包含通过可降解接头彼此可逆地和共价地交联的多个生物活性蛋白。
本公开内容的某些方面提供了包含与蛋白质纳米凝胶偶联的归巢至肿瘤的有核载体细胞(T细胞)的组合物,其中所述载体细胞包含带负电荷的细胞膜,而所述蛋白质纳米凝胶包含与所述细胞膜通过静电相互作用的聚阳离子表面,并且其中所述蛋白质纳米凝胶包含通过可降解接头彼此可逆地和共价地交联的多个生物活性蛋白。
本公开内容的某些方面提供了包含含有CD45受体的有核载体细胞(例如,T细胞)和包含多个生物活性蛋白的脂质体的组合物,其中所述载体细胞与具有结合CD45受体的配体的脂质体偶联。
本文中还提供了产生包含与纳米结构偶联的载体细胞的组合物的方法,所述方法包括修饰纳米结构的表面以包含与位于载体细胞表面上的细胞表面偶联受体(例如,CD45)结合的配体(例如,抗CD45抗体);和在导致配体与载体细胞表面上的细胞表面偶联受体结合的条件下将所述纳米结构与包含细胞表面偶联受体的载体细胞组合,由此产生与纳米结构偶联的细胞。
本文中进一步提供了产生包含与纳米结构偶联的载体细胞的组合物的方法,所述方法包括将(a)经表面修饰以含有结合位于载体细胞表面上的细胞表面偶联受体(例如,CD45)的配体(例如,抗CD45抗体)的纳米结构与(b)包含细胞表面偶联受体的载体细胞组合,其中所述纳米结构和载体细胞在导致配体与载体细胞表面上的细胞表面偶联受体结合的条件下组合,由此产生与纳米结构偶联的细胞。
本发明公开内容的一些方面提供了产生包含与纳米结构偶联的载体细胞的组合物的方法,所述方法包括在导致与细胞膜静电相互作用的在其表面上具有正电荷的纳米结构的条件下,将(a)经表面修饰以含有化学接头的纳米结构与(b)聚阳离子组合;将所述纳米结构与细胞共价缀合,由此产生与纳米结构偶联的载体细胞。
本文中还提供了产生包含与纳米结构偶联的载体细胞的组合物的方法,所述方法包括在导致与细胞膜通过静电相互作用的在其表面上具有正电荷的纳米结构的条件下,将经表面修饰以含有化学接头和结合位于载体细胞表面上的细胞表面偶联受体的配体的纳米结构与(b)聚阳离子组合;在导致配体与细胞表面偶联受体结合的条件下,将所述纳米颗粒与包含细胞表面偶联受体的载体细胞组合;和将通过静电与细胞膜相互作用的在其表面上具有正电荷的纳米结构与包含细胞表面偶联受体的载体细胞共价缀合,由此产生与纳米结构偶联的载体细胞。
本公开内容的一个方面提供了通过将包含与包含药剂的纳米结构(例如,纳米颗粒或脂质体)偶联的归巢至肿瘤的有核载体细胞的组合物施用于受试者来递送药剂(例如,生物活性蛋白)的方法,其中所述载体细胞包含细胞表面偶联受体,并且其中所述纳米结构与具有结合细胞表面偶联受体的配体的载体细胞偶联,使得所述药剂在体内从纳米结构释放。
本公开内容的其他方面涉及通过将组合物施用于受试者来递送药剂(例如,生物活性蛋白)的方法,所述组合物包含与包含药剂的纳米结构(例如,纳米颗粒或脂质体)偶联的归巢至肿瘤的有核载体细胞,其中所述纳米结构包含与聚阳离子(例如,聚赖氨酸)结合的表面,使得所述药剂在体内从纳米结构释放。
本公开内容的再另外的方面涉及通过将组合物施用于受试者来递送生物活性蛋白(例如,细胞因子)的方法,所述组合物包含与包含生物活性蛋白的纳米结构(例如,纳米颗粒或脂质体)偶联的归巢至肿瘤的有核载体细胞,其中所述载体细胞包含与具有结合CD45受体的配体的纳米结构偶联的CD45受体,或所述载体细胞包含带负电荷的细胞膜,而所述纳米结构包含与细胞膜通过静电相互作用的聚阳离子表面,并且其中所述纳米结构是蛋白质纳米凝胶或脂质体,使得生物活性蛋白在体内从纳米结构释放。
在其他方面中,所述公开内容提供了通过将组合物施用于受试者来递送免疫刺激细胞因子的方法,所述组合物包含与包含免疫刺激细胞因子的纳米结构偶联的归巢至肿瘤的T细胞,其中所述T细胞包含与具有结合CD45受体的配体的纳米结构偶联的CD45受体,或者所述T细胞包含带负电荷的细胞膜和所述纳米结构包含与细胞膜通过静电相互作用的聚阳离子表面,或者这两者,并且其中所述纳米结构是蛋白质纳米凝胶或脂质体,使得免疫刺激细胞因子在体内从纳米结构释放。
在另一个方面中,所述公开内容提供了用于将免疫刺激细胞因子递送至肿瘤的方法,其包括将与包含免疫刺激细胞因子的纳米凝胶偶联的肿瘤反应性T细胞施用于患有肿瘤的受试者,其中所述T细胞包含与具有结合CD45受体的配体的纳米凝胶偶联的CD45受体,并且其中所述T细胞包含带负电荷的细胞膜,而所述纳米凝胶包含与细胞膜通过静电相互作用的聚阳离子表面,使得免疫刺激细胞因子在体内从纳米结构释放。
在另一个方面中,所述公开内容提供了用于将免疫刺激细胞因子递送至肿瘤的方法,其包括将与包含免疫刺激细胞因子的纳米结构(例如,纳米凝胶或脂质体)偶联的嵌合抗原受体(CAR)T细胞施用于患有肿瘤的受试者,其中所述CAR T细胞包含与具有结合CD45受体的配体的纳米结构偶联的CD45受体,或其中所述CAR T细胞包含带负电荷的细胞膜,和所述纳米结构包含与细胞膜通过静电相互作用的聚阳离子表面,或两者,使得免疫刺激细胞因子在体内从纳米结构释放。
所述公开内容的其他方面提供了用于维持、刺激或增强受试者中的T细胞活性的方法,其包括将包含与包含免疫刺激细胞因子的纳米结构(例如,纳米凝胶或脂质体)偶联的T细胞的组合物施用于受试者,其中所述T细胞包含与纳米结构偶联的CD45受体,所述纳米结构具有结合CD45受体的配体,或其中所述T细胞包含带负电荷的细胞膜,和所述纳米结构包含与所述细胞膜通过静电相互作用的聚阳离子表面,或两者,使得免疫刺激细胞因子在体内从纳米结构释放,并且维持、刺激或增强T细胞的活性。
所述公开内容的更多其他方面涉及用于维持、刺激或增强位于肿瘤环境中的T细胞的活性的方法,其包括将与包含免疫刺激细胞因子的纳米结构(例如,纳米凝胶或脂质体)偶联的归巢至肿瘤的载体T细胞施用于患有肿瘤的受试者,其中所述载体T细胞包含与纳米结构偶联的CD45受体,所述纳米结构具有结合CD45受体的配体,或其中所述载体T细胞包含带负电荷的细胞膜,和所述纳米结构包含与所述细胞膜通过静电相互作用的聚阳离子表面,或两者,并且其中免疫刺激细胞因子从纳米凝胶或脂质体的释放维持、刺激或增强了位于肿瘤环境中的T细胞的活性。
在一些实施方式中,所述受试者患有肿瘤。在相关实施方式中,所述细胞是肿瘤反应性T细胞。在其他相关实施方式中,所述载体细胞归巢至肿瘤或其中存在肿瘤的组织(例如,淋巴组织)。在一些实施方式中,所述肿瘤是淋巴瘤,并且所述药剂是抗体,如抗CD20抗体,或化疗剂,如氟达拉滨。可以替代抗CD20抗体或氟达拉滨,或在抗CD20抗体或氟达拉滨以外,使用对淋巴瘤具有治疗作用的其他药剂。
在一些实施反式中,所述受试者患有自身免疫疾病。在一些实施方式中,所述受试者患有感染。在一些实施方式中,作为例如清髓性(myeloablative)化疗和/或放疗的结果,所述受试者需要造血重建。
在一些实施方式中,所述细胞是肠道特异性T细胞。在一些实施方式中,所述细胞是皮肤特异性T细胞。
在一些实施方式中,所述细胞是受试者自体同源的。在一些实施方式中,在施用于受试者之前,将细胞激活。在一些实施方式中,所述细胞是遗传工程化的,如,例如,嵌合抗原受体(CAR)T细胞。
在一些实施方式中,所述药剂是成像剂。在一些实施方式中,所述药剂是免疫刺激蛋白,如细胞因子。在一些实施方式中,所述细胞因子是IL15SA。在一些实施方式中,所述药剂是抗原。在一些实施方式中,所述药剂是佐剂。在一些实施方式中,所述佐剂是TLR配体。所述TLR配体可以用于刺激抗原特异性免疫应答(通常在外源性或内源性抗原的存在下)和/或抗原非特异性免疫应答。因此,可以在抗原存在或不存在的情况下使用TLR配体。在一些实施方式中,所述药剂是抗体或抗体片段。在一些实施方式中,所述药剂是药物。在一些实施方式中,所述药剂是化合物。在一些实施方式中,所述药剂是核酸。在一些实施方式中,所述核酸是siRNA。
在一些实施方式中,所述药剂是抗癌剂,包括抗癌抗体、癌抗原、抗癌化疗剂等。在各种实施方式中,所述药剂可以以低于全身性给药后在体内获得相同效果所需剂量的剂量来使用。在一些实施方式中,所述剂量比所需全身性剂量低至少2倍、低至少5倍、低至少10倍、低至少20倍、低至少50倍或低至少100倍。
在一些实施方式中,所述细胞与多个纳米结构共价结合。在一些实施方式中,所述多个纳米结构包含相同或不同的药剂。
在一些实施方式中,所述药剂以自分泌的方式起作用(即,其作用于载体细胞自身)。在一些实施方式中,所述药剂以旁分泌的方式起作用(即,其作用于细胞载体以外的细胞,如体内肿瘤部位的细胞)。在再其他实施方式中,所述药剂以自分泌和旁分泌两种方式来起作用。
本文中将更详细地描述这些和其他方面和实施方式。本公开内容在其应用中不是限于以下描述中所列的或附图中所示的构造和/或组成部分排列的细节。
附图说明
没有打算将附图按比例绘制。为了清楚的目的,没有在每张图中标明每个组成部分。
图1A-1C显示了具有表面抗体α-CD2、α-CD8、α-CD11、α-CD45和/或α-Thy1.1的脂质体的内化动力学。
图2显示了用于细胞表面偶联的细胞因子纳米凝胶的制备和表面修饰实例的示意图。
图3A显示了静息和致敏的(primed)CD8+T细胞的细胞表面还原速率。
图3B显示了抗CD45介导的纳米凝胶对T细胞表面的锚定能够产生TCR-反应性蛋白载荷释放。
图4显示了IL-15Sa纳米凝胶在体外促进T细胞扩增。
图5A-5E显示了IL-15Sa纳米凝胶促进了肿瘤中过继转移的T细胞的特异性扩增。具体地,血液(图5A,通过体积标准化)和肿瘤(图5B,通过重量标准化)中的过继转移的(ACT)Thy1.1+CD8+T细胞(方块)和内源性Thy1.1+CD8+T细胞(三角)的计数。图5C-5E显示了T+aCD45/IL-15Sa-NG组中的ACT CD8+T细胞的计数与不同组织中T+游离IL-15Sa的计数(图5C)、通过胞内染色和流式细胞术分析的肿瘤中Ki67+ACT CD8+T细胞的计数(图5D)和通过胞内细胞因子染色的肿瘤中多功能ACT CD8+T细胞的计数(图5E)的比例。
图6A-6E显示了IL-15Sa纳米凝胶增加了ACT过程中佐剂细胞因子递送的治疗窗口,例如,将耐受性提高至80μg,如通过针对第7天标准化的体重(图6A)、血液中细胞因子+内源性CD8+T细胞(图6B)和ACT CD8+T细胞(图6C)的计数以及血清细胞因子水平(TNF-α,图6D;IL-6,图6E)测量的。
图7A-7C显示出TCR信号传导-反应性蛋白纳米凝胶提高了鼠T-细胞和人CAR T细胞治疗的功效。
具体实施方式
在一些方面中,本文中提供了用于将纳米结构有效且稳定地与载体细胞表面偶联的方法和组合物,其具有最小的细胞内化,从而允许例如体内载体细胞药物递送而用于靶向免疫治疗。通常,将纳米结构(例如,合成的纳米颗粒或脂质体)连接或偶联至T细胞的表面例如引发受体介导的胞吞作用。为了最小化或防止纳米结构被载体细胞内吞,纳米结构可以通过共价修饰与载体细胞的表面偶联(参见,例如,US20150110740 A1,按引用并入本文中)。本发明公开内容至少部分是基于以下令人惊讶的结果,其表明通过在细胞表面表达具有延长的停留时间的受体并将同源配体连接到纳米结构促进了纳米结构与细胞表面的偶联。令人惊讶的,某些细胞表面受体(例如,CD45)能够将纳米结构维持在细胞表面处,而不是触发经典的内吞性内化途径。这些细胞表面偶联受体提高了纳米结构至细胞表面的负载和/或偶联效率。这样的细胞表面受体在本文中被称为“细胞表面偶联受体”。这些细胞表面偶联受体具有延长的细胞表面停留时间和/或保持在细胞表面上而具有最小的内化。
因此,在一些方面中,本发明公开内容提供了包含有核载体细胞的组合物,所述有核载体细胞表达至少一种与一个或多个纳米结构偶联的细胞表面偶联受体,所述纳米结构进行修饰以提供结合细胞表面偶联受体的配体。一个这样的实例是表达CD45的T细胞,其经由纳米结构提供的抗CD45抗体与所述纳米结构偶联。
本文中还提供了通过使用聚阳离子提高偶联效率和提高纳米结构(例如:蛋白质纳米凝胶)对载体细胞的负载的组合物,所述聚阳离子在进行偶联反应前添加至纳米结构表面时,起到中和带负电荷的T细胞的作用。实际上,所述聚阳离子作为“磁铁”以在偶联反应过程中将纳米结构(例如:纳米凝胶)带至细胞附近,由此提高偶联反应的效率。
用于与载体细胞偶联的纳米结构
本发明公开内容的纳米结构通常是具有至少一个小于1000nm(例如,小于500,小于250,小于100nm)的维度的微观颗粒。术语“纳米结构”包括本文中所述的脂质体和纳米颗粒。在一些实施方式中,纳米结构是合成的。即,所述纳米结构不是天然存在的。
在一些实施方式中,纳米结构合成为在其外表面上包含一个或多个反应性基团,用于与细胞载体上的反应基团反应。这些纳米结构反应性基团包括,但不限于巯基-反应性马来酰亚胺端基、卤素乙酰基(例如,碘乙酰基)基团、酰亚胺酯基团、N-羟基琥珀酰亚胺酯和吡啶基二硫化物基团。这些反应性基团与载体细胞表面上的基团反应,并且因此提供纳米结构与细胞表面的偶联。应当理解,在以这种方式进行表面修饰时,所述纳米结构意图用于具有“互补的”反应性基团(即,与纳米结构的那些反应性基团反应的反应性基团)的特定载体细胞。在一些实施方式中,所述纳米结构没有整合至构成细胞表面的脂质双层中。
纳米结构可以与载体细胞共价缀合或非共价缀合。将纳米结构与细胞缀合的过程在本文中被称为“偶联反应”。共价缀合通常提供纳米结构和载体细胞之间更稳定(并且因此更长时间的)缔合。在一些实施方式中,共价缀合还可以提供药剂在体内的稳定性并且因此提供更持续的定位药剂递送。非共价缀合包括不限于吸附于细胞表面和/或细胞膜的脂质双层上。
在一些实施方式中,通过马来酰亚胺-巯基反应来实现共价连接,其中存在两步过程,其中载体细胞首先用带有马来酰亚胺的纳米结构孵育以允许与细胞表面缀合,接着用巯基封端的聚乙二醇(PEG)原位PEG化以将颗粒的剩余马来酰亚胺基团加帽并避免细胞的颗粒介导的交联。使用这种方式,相当大数量的100-300nm范围直径的纳米结构与细胞疗法中常用的细胞类型缀合。这种策略允许范围从简单的脂质体(例如,具有加载药物的水性核心)至更复杂的脂质包被的聚合物或基于DNA的纳米结构的颗粒稳定地连接到载体细胞。重要地,连接化学作用是良性的且无毒的,如部分地通过高达139(±29)~200nm直径的脂质包被纳米颗粒与细胞表面缀合而无任何有害影响所证明的(参见美国专利申请公开No.2011/0293705)。
在一些实施方式中,纳米结构是聚合物囊泡(polymersome)。聚合物囊泡是一类可以用于药物递送或作为人工细胞器的人造囊泡。囊泡膜由嵌段共聚物制成。聚合物囊泡具有包裹和运送中央水池中的分子或隔离在其疏水性双层膜中的能力。聚合物囊泡与脂质体不同在于其通常更高度稳定,并且聚合物囊泡的双层膜常常是相对不可渗透的,由此阻碍所包裹的分子的释放。聚合物囊泡可用于包裹和保护敏感性分子,如药物、酶、其他蛋白和肽,以及DNA和RNA片段。聚合物囊泡具有加载亲水性和疏水性分子的能力,使其成为用作药物递送系统的极佳候选物。
在一些实施方式中,纳米结构在所述纳米结构的最外表面包含脂质双层。这种双层可以由一种或多种相同或不同类型的脂质组成。实例包括,但不限于磷脂如磷酸胆碱和磷酸肌醇。特定的实例包括,但不限于DMPC、DOPC、DSPC和各种其它脂质,如以下所述的那些。蛋白质纳米结构的大小可以通过至少有两种途径来测定:基于其“干尺寸”和基于其“流体动力学尺寸”。在某些实施方式中,纳米结构(例如:纳米凝胶)的“干尺寸”是指作为干固体的纳米结构(例如:纳米凝胶)的直径。例如,可以通过透射电子显微镜来测定纳米结构(例如:纳米凝胶)的干尺寸。
在其他实施方式中,纳米结构(例如:脂质体)的“流体动力学尺寸”是指作为水合凝胶(例如,在水性缓冲液中的脂质体)的纳米结构(例如:脂质体)的直径。例如,可以通过动态光散射来测定纳米结构(例如:脂质体)的流体动力学尺寸。通过动态光散射测量纳米结构(例如:脂质体)直径的方法是本领域已知的(参见,例如,在万维网malvern.co.uk上的Malvern Instruments,Ltd.)。
在一些实施方式中,纳米结构的干尺寸小于100nm。在一些实施方式中,纳米结构的干尺寸小于95nm、小于90nm、小于85nm、小于80nm、小于75nm、小于70nm、小于65nm或小于60nm。在一些实施方式中,纳米结构的干尺寸为40至90nm、40至80nm、40至70nm、40至60nm、50至90nm、60至80nm、50至70nm、或50至60nm。在一些实施方式中,纳米结构的干尺寸为40nm、45nm、50nm、55nm、60nm、65nm、70nm、75nm、80nm、85nm、90nm或95nm。
在一些实施方式中,多个纳米结构内的纳米结构平均干尺寸小于100nm。在一些实施方式中,这样的多个纳米结构内的纳米结构平均干尺寸变化不超过5%或10%。在一些实施方式中,多个纳米结构内的纳米结构(例如,纳米凝胶)平均干尺寸小于95nm、小于90nm、小于85nm、小于80nm、小于75nm、小于70nm、小于65nm或小于60nm。在一些实施方式中,多个纳米结构内的纳米结构(例如,纳米凝胶)平均干尺寸为40至90nm、40至80nm、40至70nm、40至60nm、50至90nm、60至80nm、50至70nm或50至60nm。在一些实施方式中,纳米结构的干尺寸为40nm、45nm、50nm、55nm、60nm、65nm、70nm、75nm、80nm、85nm、90nm或95nm。
在一些实施方式中,纳米结构的流体动力学尺寸小于100nm。在一些实施方式中,纳米结构的干尺寸小于95nm、小于90nm、小于80nm、小于85nm或小于75nm。在一些实施方式中,纳米结构的流体动力学尺寸为70至90nm、70至85nm、70至80nm、75至90nm、75至85nm、75至80nm、80至90nm、80至85nm或85至90nm。在一些实施方式中,纳米结构的流体动力学尺寸为70nm、75nm、80nm、85nm、90nm或95nm。在一些实施方式中,纳米结构的流体动力学尺寸为80nm、81nm、82nm、83nm、84nm、85nm、86nm、87nm、88nm、89nm或90nm。
在一些实施方式中,多个纳米结构内的纳米结构平均流体动力学尺寸小于100nm。在一些实施方式中,这样的多个纳米结构内的纳米结构平均流体动力学尺寸变化不超过5%或10%。在一些实施方式中,多个纳米结构内的纳米结构平均流体动力学尺寸小于95nm、小于90nm、小于80nm、小于85nm或小于75nm。在一些实施方式中,多个纳米结构内的平均流体动力学尺寸为70至90nm、70至85nm、70至80nm、75至90nm、75至85nm、75至80nm、80至90nm、80至85nm或85至90nm。在一些实施方式中,多个纳米结构内的纳米结构平均流体动力学尺寸为70nm、75nm、80nm、85nm、90nm或95nm。在一些实施方式中,多个纳米结构内的纳米结构平均流体动力学尺寸为80nm、81nm、82nm、83nm、84nm、85nm、86nm、87nm、88nm、89nm或90nm。
在一些实施方式中,以干的固体形式,如冻干形式,来提供纳米结构(例如:蛋白纳米凝胶)。在其他实施方式中,以水合形式,如在水性或其他液体溶液中,来提供纳米结构(例如:脂质体)。
纳米颗粒
术语“纳米颗粒”包括纳米凝胶(例如:蛋白质纳米凝胶和核酸纳米凝胶)、固体胶体纳米颗粒、磁性纳米颗粒、贵金属纳米颗粒、半导体纳米颗粒、多模式(multimodal)纳米颗粒、复合纳米颗粒和其他通常用于生物医学应用的纳米颗粒(参见,例如,Blanco-Andujar等,Annu.Rep.Prog.Chem.,Sect.A,2010,106,553-568,按引用并入本文中)。然而,应当理解术语“纳米颗粒”不包括病毒或者病毒颗粒或脂质体,尽管在一些实施方式中,本文考虑了非传染性病毒样颗粒(VLP),其不含病毒遗传物质。因此,在一些实施方式中,组合物包含与细胞表面偶联的VLP。纳米颗粒与膜或其他结构上分层的聚合物基质区分开来。
在一些实施方式中,纳米颗粒是合成的。即,所述纳米颗粒不是天然存在的。在一些实施方式中,纳米颗粒是生物可降解的,并且因此不是磁性的。生物可降解的纳米颗粒可以使用本领域已知的方法合成,包括,但不限于溶剂蒸发、热熔微包封、溶剂去除和喷雾干燥。用于合成纳米颗粒的示例性方法描述于Bershteyn等,Soft Matter 4:1787-1787,2008和美国专利申请公开No.2008/0014144A1中,将其关于纳米颗粒合成的特定教导按引用并入本文中。
在一些实施方式中,随着其在体内的降解特征,纳米颗粒在许多天中释放其药剂“有效载荷”。性质上是生物可降解的纳米颗粒在水性环境(如在体内存在的)中逐渐降解。如果药剂分散在整个纳米颗粒上,那么随着纳米颗粒的最外层降解或随着纳米颗粒内的孔隙扩大,所述药剂的释放发生。在一些实施方式中,释放动力学研究表明蛋白质和小分子药物可以在范围为1至2周的时间过程中从生物可降解纳米颗粒释放出来。因此,在一些实施方式中,生物可降解纳米颗粒用来将其有效载荷逐渐释放至靶标部位的环境中。
在一些实施方式中,纳米颗粒的直径例如为1-1000纳米(nm)。在一些实施方式中,所述直径为20-750nm、20-500nm或20-250nm。在一些实施方式中,所述直径为50-750nm、50-500nm、50-250nm或100-300nm。在一些实施方式中,所述直径为100nm、150nm、200nm、250nm或300nm。
在一些实施方式中,纳米颗粒由一个或多个以随机方式排列的固化聚合物组成。可以用于形成生物可降解纳米颗粒的示例性合成聚合物包括,但不限于脂肪族聚酯、聚(乳酸)(PLA)、聚(乙醇酸)(PGA)、乳酸和乙醇酸的共聚物(PLGA)、聚己内酯(polycarprolactone)、聚酐、聚(原酸)酯、聚氨酯、聚(丁酸)、聚(戊酸)和聚(丙交酯-共-己内酯),及天然聚合物,如海藻酸盐和其他多糖,包括葡聚糖和纤维素、胶原蛋白、其化学衍生物(包括化学基团(如例如烷基、亚烷基)的取代、添加,羟基化、氧化和本领域技术人员常规进行的其他修饰)、白蛋白和其他亲水性蛋白质、玉米蛋白和其他醇溶谷蛋白以及疏水性蛋白,其共聚物和混合物。通常,这些材料通过在体内酶水解或暴露于水性环境,通过表面或本体溶蚀降解。
聚合物是天然或合成的大分子,或高分子,其由许多重复的、聚合的单体亚基组成。聚合物可以从多达上千个的仅一种单体或单体的组合(共聚物)形成。合成的聚合物包括,但不限于塑料,如聚苯乙烯和聚乙烯。天然聚合物包括,但不限于生物聚合物,如DNA和蛋白质。聚合物相对于小分子化合物的大分子质量产生了独特的物理特性,包括韧性、粘弹性以及形成玻璃和半晶体结构而不是晶体的倾向。
在一些实施方式中,本发明公开内容的蛋白质纳米颗粒(例如,蛋白质纳米凝胶,包括蛋白质-聚合物纳米凝胶)不含载体蛋白或其他载体分子。例如,在一些实施方式中,蛋白质纳米颗粒不含白蛋白(例如,牛血清白蛋白(BSA))。载体蛋白通常有助于不同分子的扩散和/或运送。应当理解,如本文中使用的术语“载体蛋白”是指没有不利地影响蛋白质纳米颗粒的生物活性蛋白的蛋白质。在一些实施方式中,载体蛋白是惰性蛋白。因此,在一些实施方式中,载体蛋白不是生物活性的。在一些实施方式中,本发明公开内容的纳米颗粒不需要载体蛋白或其他载体分子来促进其在体内运送至细胞和组织并进入细胞和组织中。
纳米凝胶
在一些实施方式中,纳米颗粒是纳米凝胶,如蛋白质纳米凝胶或核酸纳米凝胶。例如,纳米凝胶可以由水凝胶组成,所述水凝胶包含通过纳米级尺寸的化学或物理交联的聚合物网络形成的颗粒。在一些实施方式中,纳米凝胶可以由溶胀的纳米级网络组成,所述网络由亲水性或两性的聚合物链组成。在一些实施方式中,纳米凝胶可以由阳离子和中性聚合物的溶胀的化学交联网络组成,所述聚合物例如分支的聚乙烯亚胺(PEI)和聚乙二醇(PEG)(PEG-cl-PEL)。在一些实施方式中,纳米凝胶可以由物理交联的胆固醇修饰的多糖(例如,普鲁兰多糖、甘露聚糖、支链淀粉和葡聚糖)组成。纳米凝胶可以用作用于药物转运的载体,并且可以设计成通过盐键、氢键或疏水相互作用结合生物活性分子。
在一些实施方式中,纳米颗粒是核酸纳米凝胶,其中所述纳米颗粒由核酸内核组成。这样的“DNA纳米颗粒”(或DNA-凝胶纳米颗粒)更详细地描述于美国专利申请公开No.20070148246中。将理解这样的纳米颗粒的核酸核心可以用作用于在体内递送的药剂的支架和/或其自身可以作为药剂。用于合成DNA纳米颗粒的示例性方案提供于美国专利申请公开No.2011/0293705中,其按引用并入本文中。
在一些实施方式中,所述纳米结构(或纳米颗粒)是蛋白质纳米凝胶。蛋白质纳米凝胶是指通过可降解接头彼此交联(例如,可逆且共价地交联)的多个蛋白质(参见,例如,US2015010740A1,按引用并入本文中)。纳米凝胶的蛋白质经由可降解接头(例如,二硫化物接头)可逆地交联,使得在生理条件下,所述接头降解并释放完整的生物活性蛋白。在其他实施方式中,纳米凝胶的蛋白通过可降解接头可逆地连接官能团,使得在生理条件下,所述接头降解并释放完整的生物活性蛋白。在每种情况中,蛋白质被认为是可逆地修饰的,如以下所述。
本文中“可逆地连接另一蛋白质”的蛋白质是指通过可降解接头连接(例如,共价连接)另一蛋白质的蛋白质。这样的蛋白认为是通过可降解接头彼此连接的(例如,交联的)。在一些实施方式中,纳米凝胶含有单一的(例如,单种类型的)生物活性蛋白(例如,IL-2、IL-15、IL-15Sa、IL-2-Fc、IL-15-Fc或IL-15Sa-Fc),而在其他实施方式中,纳米结构含有超过一种(例如,2、3、4、5或更多种)生物活性蛋白(例如,不同蛋白(如IL-2和IL-15(或IL-15SA)的组合)。例如,蛋白质纳米凝胶可以含有蛋白A和蛋白B的组合,其中蛋白A连接于蛋白A,蛋白A连接于蛋白B和/或蛋白B连接于蛋白B。
本文中“可逆地连接官能团”的蛋白质或“可逆地修饰的”蛋白质是指通过可降解接头连接(例如,共价连接)官能团的蛋白质。这样的蛋白质在本文中可被称为“蛋白质缀合物”或“可逆修饰的蛋白质缀合物”-该术语在本文中可互换使用。应当理解蛋白质和聚合物各自含有蛋白质可以经由可逆接头(例如,可降解接头,如二硫化物接头)连接的官能团。如本文中提供的,蛋白质缀合物和可逆修饰的蛋白质的实例包括,但不限于(例如,经由可降解接头)可逆地连接于另一蛋白质的蛋白质、可逆地连接聚合物的蛋白质和可逆地连接另一官能团的蛋白质。应当理解术语“蛋白质”还包括融合蛋白。
在一些实施方式中,本文中提供的可降解接头包括N-羟基琥珀酰亚胺酯,其能够在中性pH(例如,约6至约8,或约7)下与蛋白质反应而不使蛋白质变性。在一些实施方式中,所述可降解接头是“氧化还原反应性”接头,表示它们在生理条件下(例如,20-40℃和/或pH6-8)下在还原剂(例如,谷胱甘肽,GSH)的存在下降解,由此从与其可逆地连接的化合物释放完整蛋白。根据本发明使用的可降解接头的实例如下:
式I的接头含有二硫化物,其在还原剂的存在下切割。例如,在生理条件下,式I的接头的二硫键被谷胱甘肽切割。
蛋白质可以通过任一末端或内部-NH2官能团(例如,赖氨酸的侧链)连接(例如,共价连接)于可降解接头。因此,在具有式I的可降解接头的蛋白质的可逆修饰过程中形成的中间物质如下:
在一些实施方式中,本文提供的可逆修饰的蛋白质可以形成或自装配成各种纳米凝胶,包括,但不限于蛋白质-亲水性聚合物缀合物(例如,用聚乙二醇(PEG)可逆地修饰的)、蛋白质-疏水性聚合物缀合物(例如,用PLA或PLGA可逆地修饰的)、本体(bulk)交联的蛋白质水凝胶、交联的蛋白质纳米凝胶颗粒、具有不同壳材料(例如,二氧化硅)的蛋白质纳米胶囊、蛋白质缀合的纳米结构(例如,脂质体、胶束、聚合物纳米颗粒、无机纳米颗粒)。同样,在一些实施方式中,如本文中提供的彼此交联的蛋白质可以形成或可以自装配成蛋白质纳米颗粒。
在一些实施方式中,考虑了纳米凝胶的蛋白质可以经由不可降解的接头N-羟基磺基琥珀酰亚胺接头不可逆地和共价地交联。
在一些实施方式中,聚合物可以与纳米凝胶的表面交联(例如,与纳米凝胶表面处暴露的蛋白质交联)。在一些实施方式中,蛋白质纳米凝胶被包裹在基于聚合物的或二氧化硅纳纳米壳中。在一些实施方式中,可以通过在催化剂(例如,NaF)的存在下,将蛋白质缀合物的官能团(例如,硅烷)与交联剂(例如,硅烷-PEG-硅烷)聚合来形成纳米壳。
在一些实施方式中,考虑了纳米凝胶的蛋白质可以包含如上文所述的蛋白质药剂。在一些实施方式中,所述蛋白质纳米凝胶可以包含,但不限于选自治疗蛋白、预防蛋白、诊断蛋白和成像蛋白的蛋白质。根据本发明公开内容使用的蛋白质的实例包括,但不限于抗体、单链抗体、抗体片段、酶、融合蛋白、辅因子、受体、配体、转录因子和其他调节因子、一些抗原(如以下讨论的)、细胞因子、趋化因子等。蛋白质可以是或不是天然存在的。考虑其他蛋白并且可以根据所述公开内容使用。这样的纳米凝胶通常不含惰性载体蛋白,如白蛋白。
在一些实施方式中,纳米凝胶的蛋白质是生物活性蛋白,如上文所述的蛋白质药剂。在某些实施方式中,所述蛋白质药剂是如本文中所述的免疫调节蛋白(例如,免疫刺激或免疫抑制蛋白)。在某些方面中,考虑了免疫调节蛋白是程序性死亡-配体1(PD-L1)、细胞毒性T-淋巴细胞相关蛋白4(CTLA-4)、白细胞介素10(IL-10)或转化生长因子β(TGF-β)。
在一些实施方式中,纳米凝胶的蛋白质是与免疫球蛋白Fc结构域融合的生物活性蛋白的融合蛋白,称为Fc融合蛋白(例如,人IgG1Fc融合蛋白)。在一些实施方式中,纳米凝胶的生物活性蛋白是细胞因子,包括,但不限于IL-12、IL-15、IL-15Sa、IL-18、IL-2和CCL5。在一些实施方式中,纳米凝胶的蛋白质是与Fc结构域(例如,人IgG1Fc结构域)融合的细胞因子。
可以在与蛋白质相容的二元溶剂中,对纳米凝胶的蛋白质进行修饰。例如,在一些实施方式中,二元溶剂包括水性缓冲液和水混溶性有机溶剂,如磷酸盐缓冲盐水(PBS)和二甲亚砜(DMSO),并且用于可逆地修饰具有可降解接头的蛋白质。水性缓冲液(例如,PBS)与有机相(例如,DMSO)的比率可以在约50:1至约20:1的范围内。在一些实施方式中,无机相与有机相的比率为约30:1至约20:1,或约25:1(例如,500μL:20μL)。在一些实施方式中,所述有机溶剂低于二元缓冲液或含有二元缓冲液的反应的总体积的5%。
生产蛋白质纳米凝胶的方法描述于US20150110740 A1中,其按引用并入本文中。
脂质体
在一些实施方式中,纳米结构是脂质体。脂质体是包括至少一个脂质双层和内部水性区室的封闭囊泡。脂质体可以是阴离子的、中性的或阳离子的。它们可以是单层的或多层的。脂质体可以包括,但不限于单层囊泡脂质、多层囊泡脂质和挤出脂质,包括DOTMA、DOTAP、DOTIM、DDAB,其单独地或与胆固醇一起以产生DOTMA和胆固醇、DOTAP和胆固醇、DOTIM和胆固醇以及DDAB和胆固醇。用于制备多层囊泡脂质的方法是本领域已知的(参见,例如,美国专利No.6,693,086,将其涉及多层囊泡脂质制备的教导按引用并入本文中)。挤出脂质以相似的方式制备,但随后通过递减尺寸的过滤器挤出,如Templeton等,NatureBiotech,15:647-652,1997中所述的,将其关于挤出脂质制备的教导按引用并入本文中。
脂质体可以在合成过程中或合成后进行表面修饰以包括与载体细胞上的反应性基团互补的反应性基团。这样的反应性基团包括不限于马来酰亚胺基团。作为实例,可以合成脂质体以包括马来酰亚胺缀合的磷脂,如(但不限于)DSPE-MaL-PEG2000。
在一些实施方式中,纳米结构是双层间交联的多层囊泡(ICMV)。ICMV是多层脂质囊泡(MLV)的一种形式。MLV是具有由两个或更多个同心排列的脂质双层组成的外壳的纳米球体或微球体。如本文中使用的,邻近或并列的脂质双层(或脂质双层表面)意指彼此接近但另外是不同的并且通常物理上分离的双层或表面。这个术语通常不表示单个双层的两个单层之间的关系。
与上述的稳定的MLV相似,ICMV是具有由如本文中所述的彼此缀合的两个或更多个同心排列的脂质双层组成的外壳的纳米球体或微球体。稳定的多层囊泡(包括ICMV)中的脂质双层的数量可以从2到30,但更通常在2-15的范围中变化。所述双层通常由具有亲水性头部和疏水性尾部的脂质组成,其以与细胞膜相似的方式排列(即,亲水性头部暴露于通常是水性的环境,而疏水性尾部包埋在双层中)。
ICMV经由其脂质双层之间的交联(例如,共价交联)来稳定,并且因此将其称为“双层间交联的”MLV。如本文中使用的,这表示囊泡外壳中的至少两个脂质双层彼此交联。交联的双层通常是彼此并列或邻近的那些。外壳中的大部分或全部脂质双层可以与外壳中的其并列脂质双层交联。脂质双层之间可以存在一个或多个交联。通常,脂质双层之间可以存在众多交联。这样的交联的排列和定位可以是随机或非随机的。交联的程度(并且因此所获得的囊泡稳定性)可以取决于用于制备囊泡的官能化脂质(或其他脂质双层组分)的比例和交联条件(包括,例如,囊泡与交联剂的孵育时间)。应当理解所有其他因素和参数相同的情况中,囊泡中官能化脂质(或其他脂质双层组分)的比例越高,形成越多的交联。相似地,条件越有利于交联,获得的交联度越高。
产生纳米结构的方法
本文中提供了产生纳米结构的方法。纳米结构的实例是蛋白质纳米凝胶,如含有完整的生物活性蛋白但不含载体(例如,白蛋白、BSA)的蛋白质纳米凝胶。在一些实施方式中,产生无载体的、生物活性蛋白纳米凝胶的方法包括在允许蛋白质通过可降解接头彼此共价交联的条件下将蛋白质接触可降解接头,由此产生无载体的、生物活性蛋白纳米凝胶。在一些实施方式中,方法进一步包括在允许聚合物与蛋白质纳米凝胶的蛋白质交联的条件下将蛋白质凝胶接触聚合物,由此产生无载体的、生物活性蛋白-聚合物纳米凝胶。在一些实施方式中,产生多个蛋白质纳米凝胶或多个蛋白质-聚合物纳米凝胶。
通常,允许蛋白质通过可降解接头彼此可逆共价交联的条件包括在4℃至25℃(例如,4℃、5℃、6℃、7℃、8℃、9℃、10℃、11℃、12℃、13℃、14℃、15℃、16℃、17℃、18℃、19℃、20℃、21℃、22℃、23℃、24℃或25℃)的温度下,将蛋白接触可降解接头。在一些实施方式中,在4℃至25℃的温度(例如,室温)下,在水性缓冲液(例如,PBS)中蛋白质用可降解接头孵育。在一些实施方式中,在不高于30℃的温度下,在水性缓冲液(例如,PBS)中蛋白质用可降解接头孵育。在一些实施方式中,允许蛋白通过可降解接头彼此可逆共价交联的条件包括将蛋白质接触可降解接头30分钟至两小时,或30分钟至一小时(例如,30、35、40、45、50、55或60分钟)。在一些实施方式中,在水性缓冲液(例如,PBS)中,蛋白质用可降解接头孵育30分钟至两小时,或30分钟至一小时。
在一些实施方式中,水性缓冲液中的蛋白质浓度为10mg/mL至50mg/mL。例如,水性缓冲液中的蛋白质浓度可以为10mg/mL,15mg/mL,20mg/mL,25mg/mL,30mg/mL,35mg/mL,40mg/mL,45mg/mL或50mg/mL蛋白质/水性缓冲液)。
在一些实施方式中,无载体的、生物活性蛋白纳米凝胶或蛋白质-聚合物纳米凝胶中的蛋白质的重量百分比为至少75%w/w。例如,所述无载体的、生物活性蛋白质-聚合物纳米凝胶中的蛋白质的重量百分比为至少80%w/w,至少85%w/w,至少90%w/w或至少95%w/w。在一些实施方式中,无载体的、生物活性蛋白纳米凝胶或蛋白质-聚合物纳米凝胶中的蛋白质的重量百分比为75%w/w至90%w/w,80%w/w至90%w/w,或85%w/w至90%w/w。
允许聚合物与蛋白质纳米凝胶的蛋白质交联的条件包括在4℃至25℃(例如,4℃、5℃、6℃、7℃、8℃、9℃、10℃、11℃、12℃、13℃、14℃、15℃、16℃、17℃、18℃、19℃、20℃、21℃、22℃、23℃、24℃或25℃)的温度下,将蛋白质纳米凝胶接触聚合物。在一些实施方式中,在4℃至25℃的温度(例如,室温)下,在水性缓冲液(例如,PBS)中蛋白质纳米凝胶用聚合物孵育。在一些实施方式中,在不高于30℃的温度下,在水性缓冲液(例如,PBS)中蛋白质纳米凝胶用聚合物孵育。在一些实施方式中,允许聚合物与蛋白质纳米凝胶的蛋白质交联的条件包括将蛋白质纳米凝胶接触聚合物30分钟至两小时,或30分钟至一小时(例如,30、35、40、45、50、55或60分钟)。在一些实施方式中,在水性缓冲液(例如,PBS)中,蛋白质纳米凝胶用聚合物孵育30分钟至两小时,或30分钟至一小时。
在一些实施方式中,本发明公开内容的方法特意排除在有机溶剂(例如,醇,如乙醇或异丙醇)的存在下将蛋白质接触可降解接头。在一些实施方式中,本发明公开内容的方法特意排除在有机溶剂(例如,醇,如乙醇或异丙醇)的存在下将蛋白质纳米凝胶接触聚合物。有机溶剂可能不利地影响蛋白的生物活性。
产生本发明公开内容的纳米结构的其他方法可以包括用可降解接头和可聚合官能团修饰蛋白质,并且用交联剂和可溶性氟化物聚合可聚合官能团。
所述公开内容的蛋白质可以用可降解接头修饰,或与可降解接头缀合,所述可降解接头如,例如,氧化还原反应性接头。在一些实施方式中,所述修饰可以是共价修饰。可以在可溶性氟化物催化剂的存在下用交联剂聚合可聚合官能团。在一些实施方式中,所述交联剂是聚合物(例如,硅烷-PEG-硅烷)。在一些实施方式中,所述可溶性氟化物是氟化钠。在一些实施方式中,所述可溶性氟化物是氟化钾。
纳米结构表面包被
用于结合细胞表面偶联受体的配体
配体是结合另一分子如细胞表面受体(例如,细胞表面偶联受体,如CD45)的任何分子。配体的实例包括抗体(也称为免疫球蛋白)、可溶性蛋白受体(例如,CD22;Sgroi等,Proc.Natl.Acad.Sci.USA,92:4026-30,1995)、细胞因子、肽、小分子、辅因子、激素和神经递质。本文中考虑了其他蛋白质结合伴体。配体可以掺入纳米颗粒或脂质体中以促进纳米颗粒或脂质体与载体细胞的偶联。
如本文中使用的术语“抗体”包括通常包含两条大的重链和两条小的轻链的抗体、抗体片段(例如,抗原-结合片段(Fab)和可结晶片段(Fc))和含有抗体片段(例如,抗原结合部分)的重组蛋白,除非另外指出。抗体可以是单克隆抗体或多克隆抗体。在一些实施方式中,抗体是人抗体或人源化抗体。
在一些实施方式中,配体是抗体,如抗CD45抗体。在一些实施方式中,所述抗CD45抗体是人单克隆抗CD45抗体。在一些实施方式中,所述单克隆抗CD45抗体选自BC8(HB-10507TM)、4B2、9.4(/>HB-10508TM)和GAP8.3(/>HB-12TM)。因此,在一些实施方式中,纳米结构(例如,蛋白质纳米凝胶或脂质体)连接抗CD45抗体。在一些实施方式中,包含细胞因子(例如,IL-2、IL-15、IL-15-SA或其组合)的蛋白质纳米凝胶连接抗CD45抗体,并且随后与表达CD45的载体细胞(例如,T细胞)偶联。
在一些实施方式中,纳米结构可以包含10至10000或更多个配体,这部分地取决于纳米结构的尺寸。例如,纳米结构可以包含10至10000、10至1000、10至100个配体、100至10000、100至1000或1000至10000个配体。
在一些实施方式中,配体通过交联反应连接纳米结构。在一些实施方式中,例如,在所述纳米结构是蛋白质纳米凝胶的情况中,用于产生蛋白质纳米凝胶的相同交联剂可以用于并入配体。
在一些实施方式中,用永久性(例如,不可逆)接头将配体连接于纳米结构(例如,抗体,如抗CD45)。在一些实施方式中,所述接头含有两个N-羟基磺基琥珀酰亚胺(磺基-HNS)基团。在一些实施方式中,所述接头含有两个马来酰亚胺基团,或本领域已知的用于将分子与抗体偶联的其他反应性基团。在一些实施方式中,所述接头是可逆接头(例如:在生理条件下还原剂(例如:谷胱甘肽,GSH)的存在下降解的氧化还原反应性接头)。
包含配体的纳米结构可以通过“偶联反应”与载体细胞偶联,如本文中别处所述的,其可以是共价的或非共价的。在一些实施方式中,纳米结构通过游离表面巯基与载体细胞偶联,如,例如美国专利申请公开No.2011/0293705中所述的。
聚阳离子
本发明公开内容的一些方面提供了在其表面上包含聚阳离子的纳米结构(例如:纳米凝胶)。聚阳离子是在几个位点处具有正电荷的分子或化学复合物。通常,聚阳离子具有总体正电荷。根据本发明公开内容使用的聚阳离子的实例包括,但不限于聚赖氨酸(聚-L-赖氨酸和/或聚-D-赖氨酸)、聚(精氨酸甘油琥珀酸酯)(PAGS,基于精氨酸的聚合物)、聚乙烯亚胺、聚组氨酸、聚精氨酸、硫酸鱼精蛋白、聚乙二醇-b-聚赖氨酸(PEG-PLL)或聚乙二醇-g-聚赖氨酸。如本文中提供的,聚阳离子可以用于提高纳米颗粒对载体细胞(例如:T细胞)的粘附,以提高偶联反应的效率。具体地,聚阳离子可以用于提高纳米结构(例如:蛋白质纳米凝胶)至载体细胞的加载。聚阳离子还可以用于提高纳米结构与载体细胞的偶联或偶联效率。据认为聚阳离子增强了细胞膜的负电荷离子与纳米凝胶的正电荷表面离子之间的静电相互作用。
在一些实施方式中,在将纳米凝胶经由细胞表面偶联受体与载体细胞的表面偶联之前,将聚阳离子添加至纳米凝胶的表面。在一些实施方式中,在没有细胞表面偶联受体的情况下将纳米凝胶与细胞表面偶联之前,将聚阳离子(例如,聚乙二醇-b-聚赖氨酸或PEG-PLL)添加至纳米凝胶的表面。在一些实施方式中,所述聚阳离子是聚乙二醇-b-聚赖氨酸。在一些实施方式中,在具有细胞表面偶联受体的情况下将纳米凝胶与载体细胞表面偶联之前,将聚阳离子添加至纳米凝胶。在一些实施方式中,将聚阳离子添加至含或不含抗CD45的纳米凝胶。
在一些实施方式中,将阳离子添加至纳米结构将偶联效率(例如,将纳米凝胶与细胞偶联的效率)提高至至少50%。例如,将阳离子添加至纳米结构可以将偶联效率提高至50%,55%,60%,65%,70%,75%,80%,85%,90%或95%。在一些实施方式中,将阳离子添加至纳米结构将偶联效率提高至60%至90%,70%至90%或80%至90%。
用于载体细胞偶联的细胞表面偶联受体
细胞表面受体(例如,跨膜受体)是介导细胞与其细胞外环境的通讯的蛋白质。细胞外配体,包括细胞因子、生长因子、激素、神经递质和细胞识别分子,结合同源受体,从而引发传导细胞外信号的构象变化,启动细胞内信号传导途径。细胞表面受体调节多种负责生长、分化、增殖和存活的生物途径。T细胞和B细胞都含有负责激活细胞的细胞表面受体。
如上所示,“细胞表面偶联受体”是指位于结合并维持同源配体(例如,连接纳米颗粒的配体)的细胞表面定位的位于细胞(例如:载体细胞)表面处的分子(即:细胞表面受体)。细胞表面偶联受体是稳定地将配体与细胞表面偶联的细胞表面受体,其随着时间具有很少或没有内化。在某些方面中,细胞表面偶联受体呈现延长的细胞表面停留和/或长的细胞表面半衰期。在某些方面中,细胞表面偶联受体是缓慢内化T细胞表面蛋白。在某些方面中,细胞表面偶联受体是缓慢内化的受体。因此,本发明公开内容的各个方面提供了包含经由载体细胞上的细胞表面偶联受体与位于纳米结构上的同源配体之间的结合相互作用连接于载体细胞(例如:有核载体细胞)的表面的纳米结构的组合物。
在一些实施方式中,细胞表面偶联受体(例如,CD45)在结合同源配体(例如,抗CD45抗体)时稳定地将纳米结构与载体细胞偶联。在一些实施方式中,与具有细胞表面偶联受体的载体细胞偶联的纳米结构呈现出延长的表面停留。在一些实施方式中,与具有细胞表面偶联受体的载体细胞偶联的纳米结构呈现出长的细胞表面半衰期。
在一些实施方式中,细胞表面偶联受体(例如,CD45)在结合同源配体(例如,抗CD45抗体)时保留在载体细胞表面上(即,没有内化)至少24小时。例如,结合同源配体的细胞表面偶联受体可以保留在细胞表面上至少30小时,至少36小时,至少42小时,至少48小时,至少54小时,至少60小时,至少66小时,至少72小时。在一些实施方式中,至少50%(例如,至少60%,至少70%,至少80%,至少90%或至少95%)的结合同源配体的细胞表面偶联受体保留在细胞表面上至少24小时(例如,至少30小时、至少36小时、至少42小时、至少48小时、至少54小时、至少60小时、至少66小时、至少72小时)。
细胞表面偶联受体的非限制性实例是CD45。CD45是蛋白酪氨酸磷酸酶(PTP)家族的147kDa单链跨膜成员,其在T细胞和B细胞两者中表达,并且是T细胞和B细胞激活所需的。其含有高度糖基化的胞外结构域、单一跨膜区段和两个串联的细胞内催化结构域。这两个催化结构域参与src和JAK激酶信号传导,并且与抗原受体复合物相互作用。因此,在一些实施方式中,(例如,在其表面处)含有抗CD45抗体的纳米结构连接表达CD45的载体细胞的表面或与其偶联。这样的细胞-表面受体的内化是最小的。在一些实施方式中,50%或更多(或超过50%)的连接表达细胞表面偶联受体(例如,CD45)的载体细胞(例如,T细胞)的脂质体或纳米颗粒(例如:纳米凝胶)保持在细胞表面(即,不内化)至少24小时(例如,24、30、36、42、48、54、60、66、72小时)。例如,超过55%、超过60%、超过65%、超过70%、超过75%、超过80%、超过85%或超过90%的连接表达细胞表面偶联受体的细胞的脂质体或纳米颗粒(例如:纳米凝胶)保持在载体细胞表面上至少24小时。在一些实施方式中,细胞表面偶联受体是人(智人(Homo sapiens))CD45受体。编码人CD45受体的核酸的实例包括,但不限于NCBI参考序列No:NM_080921.3、NM_002838.4、NR_052021.1和NM_001267798.1。
在一些实施方式中,细胞表面偶联受体是重组受体(例如,包含获自多个来源的核酸)。
在一些实施方式中,载体细胞表达至少2种(例如,至少3种、至少4种或至少5种)细胞表面偶联受体,包括,例如,CD45。
在一些实施方式中,载体细胞被工程化来表达细胞表面偶联受体(例如,CD45)。例如,如果其含有工程化的核酸,则细胞是工程化的。“工程化核酸”是在自然界中不存在的核酸。然而,应当理解,尽管工程化核酸作为整体不是天然产生的,但其可以包括天然存在的核苷酸序列。在一些实施方式中,工程化核酸包含来自不同生物体(例如,来自不同物种)的核苷酸序列。工程化核酸包括重组核酸和合成核酸。“重组核酸”是通过接合核酸(例如,分离的核酸、合成的核酸或其组合)构建的分子,并且在一些实施方式中,可以在活细胞中复制。“合成核酸”是扩增或者化学地或通过其他方式合成的分子。合成核酸包括化学修饰或以其他方式修饰但可以与天然产生的核酸分子碱基配对的那些。重组核酸和合成核酸还包括从之前任意核酸的复制得到的那些分子。
因此,在一些实施方式中,载体细胞(例如,T细胞)被工程化来表达CD45。例如,载体细胞可以含有编码CD45的工程化核酸。可以使用标准分子生物学方法(参见,例如,Green和Sambrook,Molecular Cloning,A Laboratory Manual,2012,Cold Spring HarborPress)来产生这样的核酸。工程化核酸可以通过常规方法引入细胞中,如,例如,电穿孔(参见,例如,Heiser W.C.Transcription Factor Protocols:Methods in MolecularBiologyTM2000;130:117-134)、化学(例如,磷酸钙或脂质)转染(参见,例如,Lewis W.H.等,Somatic Cell Genet.1980年5月;6(3):333-47;Chen C.等,Mol Cell Biol.1987年8月;7(8):2745–2752)、转导、缀合或将纯化的核酸(例如,DNA)直接微注射至细胞核中(参见,例如,Capecchi M.R.Cell.1980Nov;22(2Pt 2):479-88)。
用于与纳米结构偶联的载体细胞
本发明公开内容的方面提供了包含稳定地结合载体细胞(例如,有核载体细胞)(或更简单地,“细胞”)的纳米结构(例如:蛋白质纳米凝胶或脂质体)的组合物。载体细胞是纳米颗粒与其缀合,并且体内给药时,通常归巢至目标部位的细胞。基于其归巢潜能、其细胞表面表型(用于缀合纳米颗粒)来选择合适的靶细胞。在一些实施方式中,细胞可以是T细胞(也称为T淋巴细胞)、B细胞或自然杀伤(NK)细胞和造血祖细胞,包括,但不限于鼠谱系阴性、Sca-1阳性和c-kit阳性细胞,及其人类对应物。相当水平的游离巯基(-SH)基团存在于T细胞、B细胞和造血祖细胞的表面上,由此促进了纳米结构与这些细胞的缀合。
在一些实施方式中,载体细胞可以从血管渗出(特别是当通过静脉内注射施用时)并且由此进入靶组织或器官。红细胞通常不能离开血流。因此,一种重要的载体细胞类别包括有核载体细胞。因此,在一些实施方式中,载体细胞不是红细胞。在其他实施方式中,载体细胞是红细胞。
本发明公开内容的一些实施方式是指分离的载体细胞。分离的载体细胞是已经从它们天然产生的环境分离的细胞(即,它们在体内不存在)。在体外的T细胞是分离的载体细胞的实例。应当理解载体细胞可以从其体内环境分离,与本发明公开内容的纳米结构缀合,并随后在体内重新引入。这样的载体细胞仍然被认为是分离的细胞。
在一些实施方式中,载体细胞与治疗的受试者是自体同源的。在其他实施方式中,载体细胞是非自体同源的(还优选主要组织相容性复合物(MHC)匹配的细胞)。
载体细胞通常在施用(或在一些情况中再输注)后具有至少48小时、至少3天、至少4天、至少5天、至少6天、至少7天或更长的体内半衰期。
在一些实施方式中,将载体细胞遗传工程化来表达一种或多种因子,包括,但不限于共同刺激分子或受体,包括嵌合受体。在其他实施方式中,载体细胞不是遗传工程化的。在一些实施方式中,载体细胞是分离的并且是天然存在的(即,它们没有遗传工程化或以其他方式工程化)。
根据其性质和功能,在一些实施方式中,载体细胞在与纳米结构缀合前进行操作。然而,载体细胞不必需进行表面修饰以促进纳米结构的缀合。反而,在一些实施方式中,使用正常存在于载体细胞表面上的反应性基团而不是必须将反应性基团或其他实体结合至细胞表面上。因此,为了与纳米结构缀合,这样的载体细胞不需要在其表面上特别地存在外源性实体,如抗体或抗体片段。
这样的操作还可以涉及载体细胞的激活,如常规地对T细胞进行的那样。在一些实施方式中,在与纳米结构混合之前,载体细胞可以在体外扩增和/或激活(或刺激,如这些术语在本文中可互换使用的)。扩增和激活方案可以根据载体细胞类型而改变,但可以包括用一种或多种细胞因子孵育、用一种或多种细胞类型孵育和用一种或多种抗原孵育。如果载体细胞是T细胞,那么可以通过用IL-2、IL-15、IL-15超激动剂(IL-15SA或IL-15Sa)、共同刺激分子(如B7、B7.2、CD40)、各种T细胞表面分子的抗体(包括细胞表面受体的抗体、抗CD3抗体、抗CD28抗体、抗CTLA-4抗体、抗CD40L抗体等)等孵育T细胞来进行激活。在一些实施方式中,载体细胞,并且更特别是T细胞,没有在其细胞表面上用外源性抗体包被(即,在施用之前,细胞在体外没有接触抗体或抗体片段)。
可以通过涉及放射性标记的核苷酸(如氚标记的胸腺嘧啶核苷)掺入的增殖分析来测量扩增。可以通过细胞因子的产生来测量激活,所述细胞因子特别如IL-2、γ-IFN、IL-1、IL-4、IL-6和TNF。测量扩增和激活的其他方式是本领域已知的并且可以根据所述公开内容来使用。
载体细胞可以在施用于受试者之前进行选择,以便富集并且因此在较小体积中施用更高数量的这些细胞和/或从施用的组合物中去除其他的、潜在不需要的细胞。选择可以涉及正向或负向选择,包括,例如,本领域已知的基于柱或平板的富集方案。
载体细胞可以是真核细胞,如哺乳动物细胞(例如,人细胞)。或者,它们可以是非哺乳动物细胞。再在其他实施方式中,所述载体细胞可以是原核细胞(例如,细菌细胞)。几种细菌细胞类型是特别感兴趣的。例如,减毒鼠伤寒沙门氏菌正在作为用于口服疫苗递送的候选载体研究(Xiang等,Immunol Rev 222:117,2008和Iweala等,J Immunol 183(4):2252,2009),而工程化的大肠杆菌已经显示出能够特异性地归巢至不良氧合的肿瘤(Cheong等,Science314(5803):1308,2006)。细菌赋予新的施用方式和组织部位靶向可能性,如口服施用,以及将治疗剂靶向肠道和肠道相关淋巴组织的能力。这样的微生物载体可以在形成现成的即用细胞纳米颗粒系统方面提供相对于自体宿主细胞的优势。可以使用针对哺乳动物细胞所描述的相同的化学策略组来实现颗粒与微生物的缀合。在一些情况中,暂时去除微生物的鞭毛外壳(例如,经由简单的机械剪切,如Rosu等,J Bacteriol 188(14):5196,2006中所述的)可以用于实现颗粒与微生物细胞体的最佳缀合。
T细胞
在一些实施方式中,本发明公开内容的细胞是T细胞。T细胞是通过胸腺产生或加工的类型的淋巴细胞并且积极地参与免疫应答。通过细胞表面上T细胞受体(TCR)的存在,可以将T细胞与其他淋巴细胞(如B细胞和自然杀伤(NK)细胞)区分开来。根据本发明公开内容使用的T细胞的实例包括T辅助细胞(TH细胞,CD4+T细胞)、细胞毒性T细胞(TC细胞、CTL、CD8+T细胞)、记忆T细胞、抑制T细胞和自然杀伤T细胞(NKT细胞)。
T辅助细胞在免疫过程中帮助其他白细胞,包括B细胞成熟成浆细胞和记忆B细胞,以及细胞毒性T细胞和巨噬细胞的激活。它们通过抗原递呈细胞表面上表达的II类MHC分子呈递肽抗原来激活。激活时,T辅助细胞分泌进一步帮助免疫应答的细胞因子。T辅助细胞可以分化成亚型,其分泌不同的细胞因子,从而引起不同的免疫应答。
细胞毒性T细胞通过结合与I类MHC分子相关的抗原识别其靶标,I类MHC分子在所有有核细胞的表面上发现。随后它们破坏病毒感染的细胞或肿瘤细胞。细胞毒性T细胞还涉及移植排斥。IL-10、腺苷和由调节T细胞分泌的其他分子将细胞毒性T细胞保持在无活性的无能状态,从而防止自身免疫疾病。
记忆T细胞,其可以是CD4+或CD8+,在感染消退后持续存在。当重新暴露于其同源抗原时,它们扩增成大量效应T细胞以更有效地消除病原体。抑制T细胞在免疫反应结束时消除T细胞介导的免疫并且抑制逃避脱胸腺中的阴性选择的自身反应性T细胞。与辅助T细胞一起,它们构成调节T细胞。
自然杀伤T细胞(不与以下讨论的自然杀伤细胞混淆)关联适应性和先天性免疫系统。自然杀伤T细胞识别由CD1d呈递的糖脂抗原,而不是由MHC分子呈递的抗原。激活时,自然杀伤T细胞能够产生细胞因子和释放细胞溶解分子。
B细胞
在一些实施方式中,本发明公开内容的细胞是B细胞。B细胞涉及适应性免疫系统中的体液免疫。它们通过其外表面上存在的B细胞受体(BCR)是可区分的。B细胞响应于抗原形成抗体,作为抗原呈递细胞来工作,并且在源于抗原相互作用的激活后发展成记忆B细胞。此外,B细胞分泌用于免疫调节功能中的细胞因子。B细胞在血液和淋巴系统中循环,从而执行免疫监视。它们不产生抗体直至它们完全被激活。B细胞受体(BCR),B细胞表面上存在的膜结合的免疫球蛋白,结合一种特异性抗原。B细胞以T细胞依赖性方式或非T细胞依赖性方式被激活。激活时,B细胞变成浆B细胞或记忆B细胞。B细胞还可以经历中间分化步骤,由此使其免疫球蛋白基因的可变区超突变(hypermutate)并且可能经历类别转换。调节B细胞分泌IL-10和TGF-β,并且涉及通过各种机制的免疫调节。
T细胞和B细胞可以从受试者的外周血采集。
自然杀伤细胞
在一些实施方式中,本发明公开内容的细胞是自然杀伤(NK)细胞。自然杀伤细胞是先天性免疫应答的细胞毒性淋巴细胞。它们常常缺少抗原特异性细胞表面受体,并且能够立即反应而之前没有暴露于病原体。它们含有病毒感染,同时适应性免疫应答产生抗原特异性细胞毒性T细胞来完全清除感染。它们的细胞质中的小颗粒包括穿孔素和颗粒酶,其是蛋白酶。当这些分子在靶细胞附近释放时,穿孔素在靶细胞的细胞膜中形成孔,颗粒酶和其他相关分子通过所述孔可以进入,导致细胞凋亡或渗透性细胞裂解。自然杀伤细胞还分泌α-防御素,这是通过破坏细胞壁直接杀灭细菌的抗微生物分子,与嗜中性粒细胞的作用相似。细胞因子,包括IL-12、IL-15、IL-18、IL-2和CCL5,由细胞响应于病毒感染而释放,并且对NK细胞发出该区域存在病毒病原体的信号。自然杀伤细胞响应于病毒感染分泌IFNγ和TNFα。IFNγ激活巨噬细胞用于吞噬作用和裂解,同时TNFα促进直接的NK肿瘤细胞杀灭。自然杀伤细胞还具有免疫监视功能,并且涉及与树突细胞、巨噬细胞、T细胞和内皮细胞的互惠的相互作用。
造血祖细胞
造血祖细胞可以获自多种来源,包括但不限于脐带血、骨髓、动员的外周血,和在一些情况中,分化的胚胎干细胞。
造血祖细胞在本领域中已经得到了表征。人中的此类细胞通常最少具有CD34+表型,尽管它们也可以是CD59+、Thy1/CD90+、CD38lo/neg、CD33-和/或c-kit/CD117+。它们还被表征为不表达谱系特异性标志物。它们可以使用亲和柱、磁珠、荧光激活的细胞分选(FACS)、其一些组合等从骨髓、脐带血或外周性收获。这些细胞具有在移植时再定殖一个或多个造血谱系的能力。优选地,这些细胞再定殖超过一个谱系,并且甚至更优选地,全部谱系。本文中使用的谱系的再定殖或定殖是指干细胞分化成一个或多个谱系,使得干细胞的后代造成受试者中该谱系的构成。然而,不需要整个谱系区室源自移植的细胞,然而在一些情况中,这可以发生。
可以根据一个或多个标志物,包括但不限于细胞表面标志物,通过异源细胞群体的分级来获得分离的干细胞。
嵌合抗原受体(CAR)T细胞
可以将T细胞工程化来表达嵌合抗原受体(CAR)。在其最简单的形式下,CAR含有与来自CD3ζ链的胞质尾的跨膜结构域和信号传导结构域偶联的抗原结合结构域。存在一些证据表明CD3ζ链不足以完全激活转导的T细胞。因此,CAR优选含有抗原结合结构域、共同刺激结构域和CD3ζ信号传导结构域。使用共同刺激结构域结合CD3ζ信号传导结构域模拟了T细胞激活的两信号模式。例如,本发明公开内容的一些实施方式涉及包含抗原结合结构域、共同刺激结构域(如4-1BB细胞内结构域)和CD3ζ信号传导结构域的嵌合抗原受体。在一些实施方式中,所述抗原结合结构域经由接头(如CD8a铰链和跨膜结构域)与共同刺激结构域和CD3ζ信号传导结构域融合。
在一些实施方式中,将CAR T细胞工程化来表达单克隆抗体或抗体片段的抗原结合结构域,如例如,Fab或scFv。在一些实施方式中,scFv与“BBz”嵌合抗原受体融合,例如,huEGFRscFv-BBz嵌合抗原受体(Johnson等,2015,Sci Transl Med.,7(275);US2014/0271635A1,按引用并入本文中)。huEGFRscFv-BBz嵌合抗原受体是基于EGFR抑制剂西妥昔单抗的重链和轻链设计的融合蛋白。具体地,西妥昔单抗的重链和轻链形成与连接BBz信号传导结构域的人CD8α的细胞外和跨膜结构域的一部分融合的单链可变片段。BBz结构域包括4-1BB和CD3ζ的细胞内结构域。
CAR抗原结合结构域可以是抗体或抗体片段,如,例如,Fab或scFv。抗癌抗体的非限制性实例包括以下,但不限于此:
曲妥珠单抗(Genentech,South San Francisco,Calif.的HERCEPTINTM),其用于治疗HER-2/neu阳性乳腺癌或转移性乳腺癌;
贝伐单抗(Genentech的AVASTINTM),其用于治疗结直肠癌、转移性结肠直肠癌、乳腺癌、转移性乳腺癌、非小细胞肺癌或肾细胞癌;
利妥昔单抗(Genentech的RITUXANTM),其用于治疗非霍奇金淋巴瘤或慢性淋巴细胞性白血病;
帕妥珠单抗(Genentech的OMNITARGTM),其用于治疗乳腺癌、前列腺癌、非小细胞肺癌或卵巢癌;
西妥昔单抗(ImClone Systems Incorporated,New York,N.Y.的ERBITUXTM),其可以用于治疗结肠直肠癌、转移性结肠直肠癌、肺癌、头颈癌、结肠癌、乳腺癌、前列腺癌、胃癌、卵巢癌、脑癌、胰腺癌、食管癌、肾细胞癌、前列腺癌、宫颈癌或膀胱癌;
IMC-1C11(ImClone Systems Incorporated),其用于治疗结肠直肠癌、头颈癌以及其他可能的癌靶标;
托西莫单抗以及托西莫单抗和碘I131(Corixa Corporation,Seattle,Wash.的BEXXARTM),其用于治疗非霍奇金淋巴瘤,该淋巴瘤可以是CD20阳性的、滤泡性的非霍奇金淋巴瘤,有和没有转化,其疾病是利妥昔单抗难治的并且化疗后复发;
In111替伊莫单抗(ibirtumomab tiuxetan);Y90替伊莫单抗;I111替伊莫单抗和Y90替伊莫单抗(Biogen Idec,Cambridge,Mass.的ZEVALINTM),用于治疗淋巴瘤或非霍奇金淋巴瘤,该淋巴瘤可以包括复发的滤泡性淋巴瘤;复发的或难治的、低级或滤泡性非霍奇金淋巴瘤;或转化的B细胞非霍奇金淋巴瘤;
EMD 7200(EMD Pharmaceuticals,Durham,N.C.),其用于治疗非小细胞肺癌或宫颈癌;
SGN-30(Seattle Genetics,Bothell,Wash.的一种遗传工程化的靶向CD30抗原的单克隆抗体),其用于治疗霍奇金淋巴瘤或非霍奇金淋巴瘤;
SGN-15(Seattle Genetics的一种遗传工程化的靶向Lewisγ相关抗原的单克隆抗体,其与阿霉素缀合),其用于治疗非小细胞肺癌;
SGN-33(Seattle Genetics的一种靶向CD33抗原的人源化抗体),其用于治疗急性骨髓性白血病(AML)和骨髓增生异常综合征;
SGN-40(Seattle Genetics的一种靶向CD40抗原的人源化单克隆抗体),其用于治疗多发性骨髓瘤或非霍奇金淋巴瘤;
SGN-35(Seattle Genetics的一种遗传工程化的靶向CD30抗原的单克隆抗体,其与阿里他汀(auristatin)E缀合),其用于治疗非霍奇金淋巴瘤;
SGN-70(Seattle Genetics的一种遗传工程化的靶向CD70抗原的人源化抗体),其用于治疗肾癌和鼻咽癌。
SGN-75(Seattle Genetics的由SGN70抗体和阿里他汀衍生物组成的缀合物);和
SGN-17/19(Seattle Genetics的与美法仑前药缀合的含有抗体和酶的融合蛋白),其用于治疗黑素瘤或转移性黑素瘤。
应当理解本发明方法中使用的治疗抗体不限于上述的那些。
用于纳米结构中的药剂
在一些实施方式中,本发明公开内容提供了用于递送药剂的方法,包括将共价结合包含药剂的纳米结构的载体细胞施用于受试者,其中所述细胞基本上没有将纳米结构内化并且将纳米结构保持在细胞表面上,并且其中所述药剂在体内从纳米结构释放。
本发明公开内容考虑了将药剂递送至特定细胞,并且因此潜在地递送至体内局部化区域或组织。如本文中使用的,“药剂”是可以用于给受试者提供益处(包括但不限于预防或治疗益处)的任何原子或分子或化合物。在一些实施方式中,特别感兴趣的药剂是对靶细胞发挥作用的那些,不管是直接地或间接地发挥作用。一些药剂可以对肿瘤细胞、病原体或病原体感染的细胞发挥作用。药剂的性质取决于特定的应用,这应该是显而易见的。
纳米结构(例如,蛋白质纳米凝胶)可以在内部携带药剂,包括例如在孔隙中或在中空核心中。所述纳米结构可以在内部或在其表面上携带药剂。
本发明公开内容进一步考虑了可以与纳米结构一起使用一种或多种药剂,尽管没有与纳米结构缀合或包封在纳米结构内。例如,所述纳米结构可以与一种或多种药剂一起配制。
所述药剂可以是,但不限于化学实体、蛋白质、多肽、肽、核酸、病毒样颗粒、类固醇、蛋白聚糖、脂质、碳水化合物及其类似物、衍生物、混合物、融合体、组合或缀合物。所述药剂可以是在体内代谢并因此转化成其活性(和/或稳定的)形式的前药。
所述药剂可以是天然产生或非天然产生的。天然产生的药剂包括能够通过将颗粒给药于其的受试者合成的那些。非天然产生的是通常非天然存在的那些,不管是通过植物、动物、微生物或其他活生物体产生的。
可以使用纳米结构以局部化方式递送的一类药剂包括非天然产生的化合物,或不是通过哺乳动物(并且特别是人)细胞天然合成的化合物。
根据本发明公开内容可以递送目前用于治疗目的的各种药剂,并且这些包括但不限于免疫调节剂,如免疫刺激剂、抗原(例如,HPV蛋白)、佐剂、成像剂、抗癌剂、抗感染剂等。
一种特定类别的药剂是免疫抑制的抑制剂。实例包括Shp1/2蛋白酪氨酸磷酸酶(PTPase)抑制剂(NSC-87877;CAS 56932-43-5)、舒尼替尼(sunitinib)或受体酪氨酸激酶的其他抑制剂,或p38 MAPK抑制剂,包括MAPK途径抑制剂。
p38 MAPK途径抑制剂可以是RAF抑制剂,如泛-RAF抑制剂或选择性RAF抑制剂。RAF抑制剂的实例包括RAF265、索拉非尼(sorafenib)、达拉非尼(dabrafenib)(GSK2118436)、SB590885、PLX 4720、PLX4032、GDC-0879和ZM 336372。所述p38 MAPK途径抑制剂可以是MEK抑制剂。MEK抑制剂的实例包括CI-1040/PD184352、AZD6244、PD318088、PD98059、PD334581、RDEA119、6-甲氧基-7-(3-吗啉-4-基-丙氧基)-4-(4-苯氧基-苯基氨基)-喹啉-3-腈和4-[3-氯-4-(1-甲基-1H-咪唑-2-基磺酰基)-苯氨基]-6-甲氧基-7-(3-吗啉-4-基-丙氧基)-喹啉-3-腈、曲美替尼(trametinib)(GSK1120212)和ARRY-438162。
所述p38 MAPK途径抑制剂可以是ERK抑制剂。ERK抑制剂的实例包括VTX11e、AEZS-131、PD98059、FR180204和FR148083。再其他p38 MAPK抑制剂是Tocriset、SB239063、SB203580、pamapimod、dilmapimod和PH797804。
成像剂或诊断剂。如本文中使用的,成像剂是直接或间接发出信号,由此允许其在体内检测的试剂。成像剂,如造影剂和放射性试剂,可以使用医学成像技术如核医学扫描和磁共振成像(MRI)来检测。用于磁共振成像(MRI)的成像剂包括Gd(DOTA)、氧化铁或金纳米颗粒;用于核医学扫描的成像剂包括201T1、γ-发射放射性核素99mTc;用于正电子发射断层扫描(PET)的成像剂包括正电子发射同位素、(18)F-氟脱氧葡萄糖((18)FDG)、(18)F-氟、铜-64、钆双胺(gadoamide)和Pb(II)的放射性同位素,如203Pb,以及11In;用于体内荧光成像的成像剂,如荧光染料或染料缀合的纳米颗粒。在其他实施方式中,待递送的药剂与成像剂缀合,或融合,或混合或组合。
免疫刺激剂。如本文中使用的,免疫刺激剂是刺激给药(不管是单独或结合另一药剂)的受试者的免疫应答(包括增强预先存在的免疫应答)的药剂。实例包括抗原、佐剂(例如,TLR配体,如咪喹莫特(imiquimod)、咪唑喹啉(imidazoquinoline)、包含未甲基化的CpG二核苷酸的核酸、单磷酰基脂质A和其他脂多糖衍生物、单链或双链RNA、鞭毛蛋白、胞壁酰二肽)、包括白细胞介素的细胞因子(例如,IL-12、IL-7、IL-15(或这些细胞因子的超激动剂/突变体形式)、IL-12、IFN-γ、IFN-α、GM-CSF、FLT3-配体等)、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)等。
免疫抑制剂。如本文中使用的,免疫抑制剂是抑制给药的受试者的免疫应答的药剂,不管是单独地或结合另一药剂。实例包括类固醇、视黄酸、地塞米松、环磷酰胺、抗-CD3抗体或抗体片段,和其他免疫抑制剂。
抗癌剂。如本文中使用的,抗癌剂是至少部分地抑制癌症的发生或进展的药剂,包括抑制全部或部分与癌症相关的症状,即使只是短期的。几种抗癌剂可以归类为DNA破坏剂,并且这些包括拓扑异构酶抑制剂(例如,依托泊苷、喜树碱(ramptothecin)、拓扑替康、替尼泊苷、米托蒽醌)、DNA烷化剂(例如,顺铂、氮芥、环磷酰胺、异环磷酰胺、美法仑、苯丁酸氮芥、白消安、噻替哌、卡莫司汀、洛莫司汀、卡铂、氮烯咪胺、甲基苄肼)、DNA链破坏诱导剂(例如,博来霉素、阿霉素、道诺霉素、去甲氧柔红霉素、丝裂霉素C)、抗微管剂(例如,长春新碱、长春碱)、抗代谢剂(例如,阿糖胞苷、氨甲喋呤、羟基脲、5-氟尿嘧啶、氟尿苷、6-硫鸟嘌呤、6-巯基嘌呤、氟达拉滨、喷司他丁、氯脱氧腺苷)、蒽环类、长春花生物碱或表鬼臼毒素。
抗癌剂的实例包括但不限于阿西维辛(Acivicin);阿柔比星(Aclarubicin);盐酸阿考达唑(Acodazole Hydrochloride);阿克罗宁(Acronine);阿多来新(Adozelesin);阿地白介素(Aldesleukin);六甲蜜胺(Altretamine);安波霉素(Ambomycin);醋酸阿美蒽醌(Ametantrone Acetate);阿鲁米特(Aminoglutethimide);安吖啶(Amsacrine);阿那曲唑(Anastrozole);安曲霉素(Anthramycin);天冬酰胺酶;曲林霉素(Asperlin);阿扎胞苷(Azacitidine);阿替派(Azetepa);阿佐霉素(Azotomycin);巴马司他(Batimastat);苯佐替派(Benzodepa);比卡鲁胺(Bicalutamide);盐酸比生群(Bisantrene hydrochloride);二甲磺酸双奈法德(Bisnafide dimesylate);比折来新(Bizelesin);硫酸博来霉素(Bleomycin sulfate);硼替佐米(VELCADE);布喹那钠(Bbrequinar sodium);溴匹立明(Bropirimine);白消安(Busulfan);放线菌素C(Cactinomycin);卡鲁睾酮(Calusterone);卡醋胺(Caracemide);卡贝替姆(Carbetimer);卡铂(Carboplatin)(一种含铂方案);卡莫司汀(Carmustine);盐酸卡柔比星(Carubicin Hydrochloride);卡折来新(Carzelesin);西地芬戈(Cedefingol);苯丁酸氮芥(Chlorambucil);西罗霉素(Cirolemycin);顺铂(Cisplatin)(一种含铂方案);克拉屈滨(Cladribine);甲磺酸克立那托(CrisnatolMesylate);环磷酰胺(Cyclophosphamide);阿糖胞苷(Cytarabine);达卡巴嗪(Dacarbazine);放线菌素D(Dactinomycin);柔红霉素(Daunorubicin);地西他滨(Decitabine);右奥马铂(Dexormaplatin);地扎呱宁(Dezaguanine);地吖醌(Diaziquone);多西他赛(Docetaxel)(TAXOTERE);多柔比星(Doxorubicin);屈洛昔芬(Droloxifene);屈他雄酮(Dromostanolone);达佐霉素(Duazomycin);依达曲沙(Edatrexate);依氟鸟氨酸(Eflornithine);依沙芦星(Elsamitrucin);恩洛铂(Enloplatin);恩普氨酯(Enpromate);依匹哌啶(Epipropidine);表柔比星(Epirubicin);厄布洛唑(Erbulozole);厄洛替尼(Erlotinib)(TARCEVA),依索比星(Esorubicin);雌莫司汀(Estramustine);依他硝唑(Etanidazole);依托泊苷(Etoposide);氯苯乙嘧胺(Etoprine);法倔唑(Fadrozole);法扎拉滨(Fazarabine);芬维A胺(Fenretinide);氟尿苷(Floxuridine);氟达拉滨(Fludarabine);5-氟尿嘧啶(5-Fluorouracil);氟西他滨(Flurocitabine);磷喹酮(Fosquidone);福司曲星(Fostriecin);吉非替尼(Gefitinib)(IRESSA)、吉西他滨(Gemcitabine);羟基脲;伊达比星(Idarubicin);异环磷酰胺(Ifosfamide);伊莫福新(Ilmofosine);甲磺酸伊马替尼(Imatinib mesylate)(GLEEVAC);干扰素α-2a;干扰素α-2b;干扰素α-n1;干扰素α-n3;干扰素β-I a;干扰素γ-I b;异丙铂(Iproplatin);伊立替康(Irinotecan);兰瑞肽(Lanreotide);来那度胺(lenalidomide)(REVLIMID,REVIMID);来曲唑(Letrozole);亮丙立德(Leuprolide);利阿唑(Liarozole);洛美曲索(Lometrexol);洛莫司汀(Lomustine);洛索蒽醌(Losoxantrone);马索罗酚(Masoprocol);美登素(Maytansine);氮芥(Mechlorethamine);甲地孕酮(Megestrol);美仑孕酮(Melengestrol);美法仑(Melphalan);美诺立尔(Menogaril);巯基嘌呤(Mercaptopurine);氨甲蝶呤(Methotrexate);氯苯氨啶(Metoprine);美妥替哌(Meturedepa);米丁度胺(Mitindomide);米托卡星(Mitocarcin);丝裂红素(Mitocromin);米托洁林(Mitogillin);米托马星(Mitomalcin);丝裂霉素(Mitomycin);米托司培(Mitosper);米托坦(Mitotane);米托蒽醌(Mitoxantrone);霉酚酸(Mycophenolic acid);诺考达唑(Nocodazole);诺拉霉素(Nogalamycin);奥马铂(Ormaplatin);奥昔舒仑(Oxisuran);紫杉醇(Paclitaxel);培美曲塞(Pemetrexed)(ALIMTA)、培门冬酶(Pegaspargase);培利霉素(Peliomycin);奈莫司汀(Pentamustine);喷托孟(Pentomone);培洛霉素(Peplomycin);培磷酰胺(Perfosfamide);哌泊溴烷(Pipobroman);哌泊舒凡(Piposulfan);羟乙基磺酸吡曲克辛(Piritrexim isethionate);吡罗蒽醌(Piroxantrone);普卡霉素(Plicamycin);普洛美坦(Plomestane);卟吩姆(Porfimer);紫菜霉素(Porfiromycin);泼尼莫司汀(Prednimustine);丙卡巴肼(Procarbazine);嘌呤霉素(Puromycin);吡唑呋林(Pyrazofurin);利波腺苷(Riboprine);洛太米特(Rogletimide);沙芬戈(Safingol);司莫司汀(Semustine);辛曲秦(Simtrazene);西托糖苷(Sitogluside);磷乙酰天冬氨酸(Sparfosate);司帕霉素(Sparsomycin);锗螺胺(Spirogermanium);螺莫司汀(Spiromustine);螺铂(Spiroplatin);链黑霉素(Streptonigrin);链佐星(Streptozocin);磺氯苯脲(Sulofenur);他利霉素(Talisomycin);坦索罗辛(Tamsulosin);紫杉酚(Taxol);泰索帝(Taxotere);替可加兰(Tecogalan);替加氟(Tegafur);替洛蒽醌(Teloxantrone);替莫泊芬(Temoporfin);替莫唑胺(Temozolomide)(TEMODAR);替尼泊苷(Teniposide);替罗昔隆(Teroxirone);睾内酯(Testolactone);沙利度胺(Thalidomide)(THALOMID)及其衍生物;硫米嘌呤(Thiamiprine);硫鸟嘌呤(Thioguanine);塞替派(Thiotepa);噻唑呋林(Tiazofurin);替拉扎明(Tirapazamine);拓扑替康(Topotecan);托瑞米芬(Toremifene);曲托龙(Trestolone);曲西立滨(Triciribine);三甲曲沙(Trimetrexate);曲普瑞林(Triptorelin);妥布氯唑(Tubulozole);尿嘧啶氮芥(Uracil Mustard);乌瑞替派(Uredepa);伐普肽(Vapreotide);维替泊芬(Verteporfin);长春碱(Vinblastine);长春新碱(Vincristine);长春地辛(Vindesine);长春匹定(Vinepidine);长春甘酯(Vinglycinate);长春罗辛(Vinleurosine);长春瑞滨(Vinorelbine);长春罗定(Vinrosidine);长春利定(Vinzolidine);伏氯唑(Vorozole);折尼铂(Zeniplatin);净司他丁(Zinostatin);佐柔比星(Zorubicin)。
抗癌剂可以是酶抑制剂,包括但不限于酪氨酸激酶抑制剂、CDK抑制剂、MAP激酶抑制剂或EGFR抑制剂。酪氨酸激酶抑制剂可以是但不限于染料木黄酮(4’,5,7-三羟基异黄酮)、酪氨酸磷酸化抑制剂(Tyrphostin)25(3,4,5-三羟基苯基),亚甲基]-丙二腈、除锈霉素A、大豆苷元(4’,7-二羟基异黄酮)、AG-126、反式-1-(3’-羧基-4’-羟苯基)-2-(2”,5”-二羟基-苯基)乙烷或HDBA(2-羟基5-(2,5-二羟基苄氨基)-2-羟基苯甲酸。CDK抑制剂可以是但不限于p21、p27、p57、p15、p16、p18或p19。MAP激酶抑制剂可以是但不限于KY12420(C23H24O8)、CNI-1493、PD98059或4-(4-氟苯基)-2-(4-甲基亚磺酰基苯基)-5-(4-吡啶基)1H-咪唑。EGFR抑制剂可以是但不限于厄洛替尼(TARCEVA)、吉非替尼(IRESSA)、WHI-P97(喹唑啉衍生物)、LFM-A12(来氟米特代谢物类似物)、ABX-EGF、拉帕替尼、卡奈替尼、ZD-6474(ZACTIMA)、AEE788和AG1458。
抗癌剂可以是VEGF抑制剂,包括但不限于贝伐单抗(bevacizumab)(AVASTIN)、雷珠单抗(ranibizumab)(LUCENTIS)、培加他尼(pegaptanib)(MACUGEN)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)(SUTENT)、瓦他拉尼(vatalanib)、ZD-6474(ZACTIMA)、阿奈可他(anecortave)(RETAANE)、乳酸角鲨胺和臂板蛋白(semaphorin)。
抗癌剂可以是抗体或抗体片段,包括但不限于抗体或抗体片段,包括但不限于贝伐单抗(AVASTIN)、曲妥单抗(HERCEPTIN)、阿仑单抗(CAMPATH,指示用于B细胞慢性淋巴细胞性白血病)、吉姆单抗(MYLOTARG,hP67.6,抗CD33,指示用于白血病,如急性骨髓性白血病)、利妥昔单抗(RITUXAN)、托西莫单抗(BEXXAR,抗CD20,指示用于B细胞恶性疾病)、MDX-210(同时结合HER-2/neu致癌基因蛋白质产物和免疫球蛋白G(IgG)的1型Fc受体(FcγRI)的双特异性抗体)、奥戈伏单抗(oregovomab)(OVAREX,指示用于卵巢癌)、依决洛单抗(PANOREX)、达克珠单抗(ZENAPAX)、帕利珠单抗(SYNAGIS,指示用于呼吸道病症,如RSV感染)、替伊莫单抗(ZEVALIN,指示用于非霍奇金淋巴瘤)、西妥昔单抗(ERBITUX)、MDX-447、MDX-22、MDX-220(抗TAG-72)、IOR-C5、IOR-T6(抗CD1)、IOR EGF/R3、celogovab(ONCOSCINTOV103)、依帕珠单抗(LYMPHOCIDE)、pemtumomab(THERAGYN)和Gliomab-H(指示用于脑癌、黑素瘤)。
蛋白剂。根据本发明公开内容使用的蛋白剂的实例包括,但不限于抗体、单链抗体、抗体片段、酶、辅因子、受体、配体、转录因子和其他调节因子、一些抗原(如以下讨论的)、细胞因子、趋化因子等。这些蛋白剂可以是或不是天然产生的。考虑了其他蛋白并且可以根据本公开内容来使用。
在一些实施方式中,所述公开内容的蛋白剂是与免疫球蛋白Fc结构域融合的生物活性蛋白的融合蛋白,称为Fc融合蛋白(例如,人IgG1 Fc融合蛋白)。在一些实施方式中,纳米凝胶的生物活性蛋白是细胞因子,包括,但不限于IL-12、IL-15、IL-15-Sa、IL-18、IL-2和CCL5。在一些实施方式中,所述纳米凝胶的蛋白质是与Fc结构域(例如,人IgG1 Fc结构域)融合的细胞因子
在一些实施方式中,所述公开内容的蛋白剂是免疫调节蛋白(例如,免疫刺激或免疫抑制蛋白)。如本文中使用的,免疫调节蛋白是调节(例如,刺激或抑制)给药的受试者的免疫应答的蛋白(包括增强或降低预先存在的免疫应答),不管是单独的或结合另一种蛋白质或药剂。在所述公开内容的某些实施方式中,免疫调节蛋白是PD-L1、CTLA-4、IL-10或TGF-β。
在一些实施方式中,所述公开内容的蛋白剂是免疫刺激蛋白。如本文中使用的,免疫刺激蛋白是刺激给药的受试者的免疫应答的蛋白(包括增强预先存在的免疫应答),不管是单独的或结合另一蛋白质或药剂。根据所述公开内容可以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)、包括白细胞介素的细胞因子(例如,IL-12、IL-7、IL-15(或这些细胞因子的超激动剂/突变形式)、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)。细胞因子是一类由细胞释放的并且经由细胞信号传导影响细胞行为的小分子(~5-20kDa)。细胞因子由各种细胞类型产生,包括,但不限于免疫细胞,如巨噬细胞、B淋巴细胞、T淋巴细胞和肥大细胞,以及内皮细胞、成纤维细胞和各种基质细胞。细胞因子可以通过超过一种细胞类型来产生。细胞因子包括,但不限于趋化因子、干扰素、白细胞介素、淋巴因子和肿瘤坏死因子。考虑了其他免疫刺激蛋白,并且可以根据所述公开内容来使用。
在一些实施方式中,所述免疫刺激蛋白是IL-15SA。人IL-15与可溶性人IL-15Rα的组合产生了称为IL-15超激动剂(IL-15SA)的复合物,其比单独的人IL-15具有更高的生物活性。
可溶性人IL-15Rα,以及胞外结构域的截短形式,现有技术中已经有描述(Wei等,2001J of Immunol.167:277-282)。人IL-15Rα的氨基酸序列列于SEQ ID NO:9中。因此,所述公开内容的一些方面涉及包括人IL-15和可溶性人IL-15Rα分子的复合物的IL-15SA。在所述公开内容的一些方面中,IL-15SA包括人IL-15和含有全部或部分胞外结构域而没有跨膜结构域或胞质结构域的可溶性人IL-15Rα的复合物。在所述公开内容的一些方面中,IL-15SA包括人IL-15和含有完整胞外结构域或保留了IL-15结合活性的截短形式的胞外结构域的可溶性人IL-15Rα的复合物。所述公开内容的一些方面涉及包括人IL-15和含有保留了IL-15结合活性的截短形式的胞外结构域的可溶性人IL-15Rα的复合物,所述截短形式的胞外结构域如人IL-15Rα的氨基酸1-60、1-61、1-62、1-63或1-65。在所述公开内容的一些方面中,IL-15SA包括人IL-15和含有保留了IL-15结合活性的截短形式的胞外结构域的可溶性人IL-15Rα的复合物,所述截短形式的胞外结构域如人IL-15Rα的氨基酸1-80、1-81、1-82、1-83或1-85。在所述公开内容的一些方面中,IL-15SA包括人IL-15和含有保留了IL-15结合活性的截短形式的胞外结构域的可溶性人IL-15Rα的复合物,所述截短形式的胞外结构域如人IL-15Rα的氨基酸1-180、1-181或1-182。
所述公开内容的一些方面涉及包括人IL-15和含有保留了IL-15结合活性并包含Sushi结构域的截短形式的胞外结构域的可溶性人IL-15Rα的复合物的IL-15SA。IL-15Rα的Sushi结构域在现有技术中描述为大约60个氨基酸长并且包含4个半胱氨酸(Wei等,2001)。保留了IL-15活性并包含Sushi结构域的截短形式的可溶性人IL-15Rα在本发明公开内容的IL-15SA中是有用的。
人IL-15的突变体形式是本领域已知的。因此,本发明公开内容提供了之前任一种IL-15SA复合物,其中人IL-15是野生型的或包含一个或多个突变(例如,一个或多个氨基酸置换、添加或删除)的突变IL-15。用于本发明公开内容的IL-15SA中的相对于野生型IL-15具有提高的生物活性的示例性IL-15突变体包括氨基酸72处的天冬酰胺至天冬氨酸置换(N72D)(Zhu等,2009J of Immunol.183:3598)。
在之前任一个实施方式中,本发明公开内容涉及作为与IL-15的融合蛋白表达的包含可溶性人IL-15Rα的复合物,如作为本文中所述的Fc融合体(例如,人IgG1 Fc)。在一些实施方式中,IL-15SA包括与两个人IL-15分子复合的二聚人IL-15RαFc融合蛋白(例如,人IgG1 Fc)。
在一些实施方式中,IL-15SA细胞因子复合物包括包含SEQ ID NO:1、SEQ ID NO:4、SEQ ID NO:5或SEQ ID NO:6中所列氨基酸序列的IL-15分子。在一些实施方式中,IL-15SA细胞因子复合物包括包含SEQ ID NO:3、SEQ ID NO:7或SEQ ID NO:8的序列的可溶性IL-15Rα分子。
在一些实施方式中,所述IL-15SA是包含与两个IL-15分子复合的二聚IL-15RαFc融合蛋白的细胞因子复合物。在一些实施方式中,IL-15SA包括二聚IL-15RαSu(Sushi结构域)/Fc(SEQ ID NO:2)和两个IL-15N72D(SEQ ID NO:1)分子(也称为ALT-803),如US20140134128中所述的,其按引用并入本文中。在一些实施方式中,所述IL-15SA包含二聚IL-15RαSu/Fc分子(SEQ ID NO:2)和两个IL-15分子(SEQ ID NO:4)。在一些实施方式中,所述IL-15SA包含二聚IL-15RαSu/Fc分子(SEQ ID NO:2)和两个IL-15分子(SEQ ID NO:5)。在一些实施方式中,所述IL-15SA包含二聚IL-15RαSu/Fc分子(SEQ ID NO:2)和两个IL-15分子(SEQ ID NO:6)。
在一些实施方式中,所述IL-15SA包含二聚IL-15RαSu/Fc分子(SEQ ID NO:2)和两个包含选自SEQ ID NO:1、4、5和6的序列的IL-15分子。
在一些实施方式中,所述IL-5SA包含可溶性IL-15Rα分子(SEQ ID NO:3)和两个IL-15分子(SEQ ID NO:1)。在一些实施方式中,所述IL-5SA包含可溶性IL-15Rα分子(SEQID NO:3)和两个IL-15分子(SEQ ID NO:4)。在一些实施方式中,所述IL-5SA包含可溶性IL-15Rα分子(SEQ ID NO:3)和两个IL-15分子(SEQ ID NO:5)。在一些实施方式中,所述IL-5SA包含可溶性IL-15Rα分子(SEQ ID NO:3)和两个IL-15分子(SEQ ID NO:6)。
在一些实施方式中,所述IL-5SA包含可溶性IL-15Rα分子(SEQ ID NO:7)和两个IL-15分子(SEQ ID NO:1)。在一些实施方式中,所述IL-5SA包含可溶性IL-15Rα分子(SEQID NO:7)和两个IL-15分子(SEQ ID NO:4)。在一些实施方式中,所述IL-5SA包含可溶性IL-15Rα分子(SEQ ID NO:7)和两个IL-15分子(SEQ ID NO:5)。在一些实施方式中,所述IL-5SA包含可溶性IL-15Rα分子(SEQ ID NO:7)和两个IL-15分子(SEQ ID NO:6)。
在一些实施方式中,所述IL-5SA包含可溶性IL-15Rα分子(SEQ ID NO:8)和两个IL-15分子(SEQ ID NO:1)。在一些实施方式中,所述IL-5SA包含可溶性IL-15Rα分子(SEQID NO:8)和两个IL-15分子(SEQ ID NO:4)。在一些实施方式中,所述IL-5SA包含可溶性IL-15Rα分子(SEQ ID NO:8)和两个IL-15分子(SEQ ID NO:5)。在一些实施方式中,所述IL-5SA包含可溶性IL-15Rα分子(SEQ ID NO:8)和两个IL-15分子(SEQ ID NO:6)。
在一些实施方式中,所述IL-5SA包含二聚IL-15RαSu/Fc(SEQ ID NO:2)分子和两个IL-15分子(SEQ ID NO:5)。在一些实施方式中,所述IL-5SA包含二聚IL-15RαSu/Fc(SEQID NO:2)分子和两个IL-15分子(SEQ ID NO:6)。
在一些实施方式中,所述IL-15SA包含SEQ ID NO:1和SEQ ID NO:3。在一些实施方式中,所述IL-15SA包含SEQ ID NO:4或SEQ ID NO:5。在一些实施方式中,所述IL-15SA包含SEQ ID NO:4和SEQ ID NO:2。在一些实施方式中,所述IL-15SA包含SEQ ID NO:5和SEQ IDNO:2。在一些实施方式中,所述IL-15SA包含SEQ ID NO:6和SEQ ID NO:2。在一些实施方式中,所述IL-15SA包含SEQ ID NO:4和SEQ ID NO:3。在一些实施方式中,所述IL-15SA包含SEQ ID NO:5和SEQ ID NO:3。
在一些实施方式中,所述公开内容的蛋白剂是癌抗原。癌抗原是由癌细胞优先表达的抗原(即,在癌细胞中以高于非癌细胞的水平表达),并且在一些情况中,仅由癌细胞表达。癌抗原可以在癌细胞内或癌细胞表面上表达。根据所述公开内容可以使用的癌抗原包括,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)--C017-1A/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。所述癌抗原可以选自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。所述癌抗原可以选自GAGE-1、GAGE-2、GAGE-3、GAGE-4、GAGE-5、GAGE-6、GAGE-7、GAGE-8和GAGE-9。所述癌抗原可以选自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、腺瘤性结肠息肉病蛋白(APC)、胞衬蛋白、连接蛋白37、Ig-个体基因型、p15、gp75、GM2神经节苷脂、GD2神经节苷脂、人乳头状瘤病毒蛋白、肿瘤抗原的Smad家族、lmp-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。考虑了其他癌抗原并且可以根据所述公开内容来使用。
在一些实施方式中,所述纳米凝胶的蛋白质是人乳头状瘤病毒(HPV)蛋白。
在一些实施方式中,所述公开内容的蛋白剂是抗体或抗体片段,包括,但不限于贝伐单抗曲妥单抗/>阿仑单抗(alemtuzumab)(指示用于B细胞慢性淋巴细胞性白血病)、吉姆单抗(gemtuzumab)(hP67.6,抗-CD33,指示用于白血病,如急性骨髓性白血病)、利妥昔单抗(rituximab)/>托西莫单抗(/>抗-CD20,指示用于B细胞恶性疾病)、MDX-210(同时结合HER-2/neu致癌基因蛋白产物和免疫球蛋白G(IgG)的I型受体(FcγRI)的双特异性抗体)、奥戈伏单抗(/>指示用于卵巢癌)、依决洛单抗/>达克珠单抗/>帕利珠单抗(指示用于呼吸道病症,如RSV感染)、替伊莫单抗(/>指示用于非霍奇金淋巴瘤)、西妥昔单抗/>MDX-447、MDX-22、MDX-220(抗TAG-72)、IOR-C5、IOR-T6(抗CD1)、IOR EGF/R3、celogovab(/>OV103)、依帕珠单抗/>pemtumomab/>和Gliomab-H(指示用于脑癌、黑素瘤)。考虑了其他抗体和抗体片段,并且可以根据所述公开内容来使用。
抗感染剂。该药剂可以是预防剂或抗感染剂,包括但不限于抗细菌剂、抗病毒剂、抗寄生虫剂、抗真菌剂和抗分枝杆菌剂。
抗细菌剂可以是但不限于β内酰胺抗生素、青霉素类(如天然青霉素、氨基青霉素、耐青霉素酶青霉素、羧基青霉素、脲基青霉素)、头孢菌素(第一代、第二代和第三代头孢菌素)、其他β内酰胺(如亚胺培南、单酰胺菌素)、β-内酰胺酶抑制剂、万古霉素、氨基糖苷类和壮观霉素、四环素类、氯霉素、红霉素、林可霉素、克林霉素、利福平、甲硝唑、多粘菌素、磺胺类和甲氧苄啶,或喹啉类。
其他抗细菌剂可以是但不限于乙酰氨苯砜(Acedapsone);磺胺苯砜钠(Acetosulfone Sodium);阿来霉素(Alamecin);阿来西定(Alexidine);阿姆地诺西林(Amdinocillin);阿姆地诺西林双酯(Amdinocillin Pivoxil);阿米环素(Amicycline);氨氟沙星(Amifloxacin);甲磺酸氨氟沙星(Amifloxacin Mesylate);阿米卡星(Amikacin);硫酸阿米卡星(Amikacin Sulfate);氨基水杨酸(Aminosalicylic acid);氨基水杨酸钠(Aminosalicylate sodium);阿莫西林(Amoxicillin);安福霉素(Amphomycin);氨苄青霉素(Ampicillin);氨苄青霉素钠(Ampicillin Sodium);阿帕西林钠(Apalcillin Sodium);安普霉素(Apramycin);天冬菌素(Aspartocin);硫酸阿司米星(Astromicin Sulfate);卑霉素(Avilamycin);阿伏帕星(Avoparcin);阿奇霉素(Azithromycin);阿洛西林(Azlocillin);阿洛西林钠(Azlocillin Sodium);盐酸巴氨西林(BacampicillinHydrochloride);杆菌肽(Bacitracin);亚甲基双水杨酸杆菌肽(Bacitracin MethyleneDisalicylate);杆菌肽锌(Bacitracin Zinc);班贝霉素(Bambermycins);苯沙酸钙(Benzoylpas Calcium);红霉素B(Berythromycin);硫酸倍他霉素(Betamicin Sulfate);比阿培南(Biapenem);比尼拉霉素(Biniramycin);盐酸珍尼柳酯(BiphenamineHydrochloride);Bispyrithione Magsulfex;布替卡星(Butikacin);硫酸丁酰苷菌毒(Butirosin Sulfate);硫酸卷须霉素(Capreomycin Sulfate);卡巴多司(Carbadox);羧苄青霉素二钠(Carbenicillin Disodium);羧苄青霉素茚满基钠(Carbenicillin IndanylSodium);羧苄青霉素苯基钠(Carbenicillin Phenyl Sodium);羧苄青霉素钾(Carbenicillin Potassium);卡鲁莫南钠(Carumonam Sodium);头孢克洛(Cefaclor);头孢羟氨苄(Cefadroxil);头孢孟多(Cefamandole);头孢孟多酯钠(Cefamandole Nafate);头孢孟多钠(Cefamandole Sodium);头孢帕罗(Cefaparole);头孢曲秦(Cefatrizine);头孢氟唑钠(Cefazaflur Sodium);头孢唑林(Cefazolin);头孢唑林钠(Cefazolin Sodium);头孢拉宗(Cefbuperazone);头孢地尼(Cefdinir);头孢吡肟(Cefepime);盐酸头孢吡肟(Cefepime Hydrochloride);头孢替考(Cefetecol);头孢克肟(Cefixime);盐酸头孢甲肟(Cefmenoxime Hydrochloride);头孢美唑(Cefmetazole);头孢美唑钠(CefmetazoleSodium);头孢尼西一钠(Cefonicid Monosodium);头孢尼西钠(Cefonicid Sodium);头孢哌酮钠(Cefoperazone Sodium);头孢雷特(Ceforanide);头孢噻肟钠(CefotaximeSodium);头孢替坦(Cefotetan);头孢替坦二钠(Cefotetan Disodium);盐酸头孢替安(Cefotiam Hydrochloride);头孢西丁(Cefoxitin);头孢西丁钠(Cefoxitin Sodium);头孢咪唑(Cefpimizole);头孢咪唑钠(Cefpimizole Sodium);头孢匹胺(Cefpiramide);头孢匹胺钠(Cefpiramide Sodium);硫酸头孢匹罗(Cefpirome Sulfate);头孢泊肟酯(Cefpodoxime Proxetil);头孢罗齐(Cefprozil);头孢沙定(Cefroxadine);头孢磺啶钠(Cefsulodin Sodium);头孢他啶(Ceftazidime);头孢布烯(Ceftibuten);头孢唑肟钠(Ceftizoxime Sodium);头孢曲松钠(Ceftriaxone Sodium);头孢呋辛(Cefuroxime);头孢呋辛乙酰氧乙酯(Cefuroxime Axetil);头孢呋辛匹赛酯(Cefuroxime Pivoxetil);头孢呋辛钠(Cefuroxime Sodium);头孢钠乙腈(Cephacetrile Sodium);头孢氨苄(Cephalexin);盐酸头孢氨苄(Cephalexin Hydrochloride);头孢甘酸(Cephaloglycin);先锋霉素II(Cephaloridine);头孢噻吩钠(Cephalothin Sodium);头孢匹林钠(Cephapirin Sodium);头孢拉定(Cephradine);盐酸西托环素(Cetocycline Hydrochloride);乙酰霉素(Cetophenicol);氯霉素(Chloramphenicol);棕榈酸氯霉素(ChloramphenicolPalmitate);泛酸氯霉素复合物(Chloramphenicol Pantothenate Complex);氯霉素琥珀酸钠(Chloramphenicol Sodium Succinate);氨基苯磷酸氯己定(ChlorhexidinePhosphanilate);对氯间二甲酚(Chloroxylenol);金霉素硫酸氢盐(ChlortetracyclineBisulfate);盐酸金霉素(Chlortetracycline Hydrochloride);西诺沙星(Cinoxacin);环丙沙星(Ciprofloxacin);盐酸环丙沙星(Ciprofloxacin Hydrochloride);西罗霉素(Cirolemycin);克拉霉素(Clarithromycin);盐酸克林沙星(ClinafloxacinHydrochloride);克林霉素(Clindamycin);盐酸克林霉素(Clindamycin Hydrochloride);棕榈酸盐酸克林霉素(Clindamycin Palmitate Hydrochloride);磷酸克林霉素(Clindamycin Phosphate);氯苯吩嗪(Clofazimine);苄星氯唑西林(CloxacillinBenzathine);氯唑西林钠(Cloxacillin Sodium);氯羟喹(Cloxyquin);磺粘菌素钠(Colistimethate Sodium);硫酸粘菌素(Colistin Sulfate);香豆霉素(Coumermycin);香豆霉素钠(Coumermycin Sodium);环青霉素(Cyclacillin);环丝氨酸(Cycloserine);达福普汀(Dalfopristin);氨苯砜(Dapsone);达托霉素(Daptomycin);地美环素(Demeclocycline);盐酸地美环素(Demeclocycline Hydrochloride);去甲四环素(Demecycline);地奴真菌素(Denofungin);二氨藜芦啶(Diaveridine);双氯青霉素(Dicloxacillin);双氯青霉素钠(Dicloxacillin Sodium);硫酸双氢链霉素(Dihydrostreptomycin Sulfate);双硫氧吡啶(Dipyrithione);地红霉素(Dirithromycin);多西环素(Doxycycline);多西环素钙(Doxycycline Calcium);多西环素磷酸复合物(Doxycycline Fosfatex);盐酸多西环素(Doxycycline Hyclate);屈克沙星钠(Droxacin Sodium);依诺沙星(Enoxacin);依匹西林(Epicillin);盐酸差向四环素(Epitetracycline Hydrochloride);红霉素(Erythromycin);红霉素醋硬脂酸盐(Erythromycin Acistrate);依托红霉素(Erythromycin Estolate);红霉素乙基琥珀酸酯(Erythromycin Ethylsuccinate);葡庚糖酸红霉素(Erythromycin Gluceptate);乳糖酸红霉素(Erythromycin Lactobionate);丙酸红霉素(Erythromycin Propionate);硬脂酸红霉素(Erythromycin Stearate);盐酸乙胺丁醇(Ethambutol Hydrochloride);乙硫异烟胺(Ethionamide);氟罗沙星(Fleroxacin);氟氯青霉素(Floxacillin);氟氘丙氨酸(Fludalanine);氟甲喹(Flumequine);磷霉素(Fosfomycin);磷霉素氨丁三醇(FosfomycinTromethamine);呋莫西林(Fumoxicillin);呋噻咪唑氯(Furazolium Chloride);酒石酸呋噻咪唑(Furazolium Tartrate);夫西地酸钠(Fusidate Sodium);夫西地酸(FusidicAcid);硫酸庆大霉素(Gentamicin Sulfate);格洛莫南(Gloximonam);短杆菌肽(Gramicidin);卤丙炔氧苯(Haloprogin);海他西林(Hetacillin);海他西林钾(Hetacillin Potassium);海克西定(Hexedine);依巴沙星(Ibafloxacin);亚胺培南(Imipenem);异康唑(Isoconazole);异帕米星(Isepamicin);异烟肼(Isoniazid);交沙霉素(Josamycin);硫酸卡那霉素(Kanamycin Sulfate);吉他霉素(Kitasamycin);左旋呋喃唑酮(Levofuraltadone);左普匹西林钾(Levopropylcillin Potassium);来红霉素(Lexithromycin);林可霉素(Lincomycin);盐酸林可霉素(Lincomycin Hydrochloride);罗氟哌酸(Lomefloxacin);盐酸罗氟哌酸(Lomefloxacin Hydrochloride);甲磺酸罗氟哌酸(Lomefloxacin Mesylate);氯碳头孢(Loracarbef);磺胺米隆(Mafenide);甲氯环素(Meclocycline);磺基水杨酸甲氯环素(Meclocycline Sulfosalicylate);巨霉素磷酸钾(Megalomicin Potassium Phosphate);美喹多司(Mequidox);美洛培南(Meropenem);甲烯土霉素(Methacycline);盐酸甲烯土霉素(Methacycline Hydrochloride);乌洛托品(Methenamine);马尿酸乌洛托品(Methenamine Hippurate);扁桃酸乌洛托品(Methenamine Mandelate);甲氧西林钠(Methicillin Sodium);美替普林(Metioprim);盐酸甲硝哒唑(Metronidazole Hydrochloride);磷酸甲硝哒唑(MetronidazolePhosphate);美洛西林(Mezlocillin);美洛西林钠(Mezlocillin Sodium);米诺环素(Minocycline);盐酸米诺环素(Minocycline Hydrochloride);盐酸米林霉素(Mirincamycin Hydrochloride);莫能菌素(Monensin);莫能菌素钠(Monensin Sodium);乙氧萘青霉素钠(Nafcillin Sodium);萘啶酸钠(Nalidixate Sodium);萘啶酸(NalidixicAcid);纳他霉素(Natamycin);尼拉霉素(Nebramycin);棕榈酸新霉素(NeomycinPalmitate);硫酸新霉素(Neomycin Sulfate);十一碳烯酸新霉素(NeomycinUndecylenate);硫酸奈替米星(Netilmicin Sulfate);中性霉素(Neutramycin);硝呋唑烯(Nifuradene);硝呋氨氧腙(Nifuraldezone);硝呋太尔(Nifuratel);硝呋隆(Nifuratrone);硝呋达齐(Nifurdazil);硝呋米特(Nifurimide);硝呋吡醇(Nifurpirinol);呋喃喹唑(Nifurquinazol);硝基噻唑(Nifurthiazole);硝基四环素(Nitrocycline);呋喃妥因(Nitrofurantoin);硝米特(Nitromide);诺氟沙星(Norfloxacin);新生霉素钠(Novobiocin Sodium);氧氟沙星(Ofloxacin);奥美普林(Ormetoprim);苯唑西林钠(Oxacillin Sodium);肟莫南(Oximonam);肟莫南钠(OximonamSodium);噁喹酸(Oxolinic Acid);土霉素(Oxytetracycline);土霉素钙(Oxytetracycline Calcium);盐酸土霉素(Oxytetracycline Hydrochloride);帕地霉素(Paldimycin);对氯苯酚(Parachlorophenol);保洛霉素(Paulomycin);培氟沙星(Pefloxacin);甲磺酸培氟沙星(Pefloxacin Mesylate);培那西林(Penamecillin);苄星青霉素(Penicillin G Benzathine);青霉素G钾(Penicillin G Potassium);鲁卡因青霉素G(Penicillin G Procaine);青霉素G钠(Penicillin G Sodium);青霉素V(PenicillinV);苄星青霉素V(Penicillin V Benzathine);海巴青霉素V(Penicillin VHydrabamine);青霉素V钾(Penicillin V Potassium);戊胺唑酮钠(PentizidoneSodium);对氨基水杨酸苯酯(Phenyl Aminosalicylate);哔哌青霉素钠(PiperacillinSodium);吡苄西林钠(Pirbenicillin Sodium);吡地西林钠(Piridicillin Sodium);盐酸吡利霉素(Pirlimycin Hydrochloride);盐酸匹氨青霉素(PivampicillinHydrochloride);双羟萘酸匹氨青霉素(Pivampicillin Pamoate);丙苯酸匹氨青霉素(Pivampicillin Probenate);硫酸多粘菌素B(Polymyxin B Sulfate);紫菜霉素(Porfiromycin);普匹卡星(Propikacin);吡嗪酰胺(Pyrazinamide);吡啶硫酮锌(Pyrithione Zinc);醋酸喹地卡明(Quindecamine Acetate);喹奴普丁(Quinupristin);消旋甲砜霉素(Racephenicol);雷莫拉宁(Ramoplanin);雷尼霉素(Ranimycin);瑞洛霉素(Relomycin);瑞普米星(Repromicin);利福布丁(Rifabutin);利福美坦(Rifametane);利福克昔(Rifamexil);利福米特(Rifamide);利福平(Rifampin);利福喷丁(Rifapentine);利福昔明(Rifaximin);罗列环素(Rolitetracycline);硝酸罗列环素(RolitetracyclineNitrate);蔷薇霉素(Rosaramicin);丁酸蔷薇霉素(Rosaramicin Butyrate);丙酸蔷薇霉素(Rosaramicin Propionate);蔷薇霉素磷酸钠(Rosaramicin Sodium Phosphate);硬脂酸蔷薇霉素(Rosaramicin Stearate);罗索沙星(Rosoxacin);洛克沙胂(Roxarsone);罗红霉素(Roxithromycin);山环素(Sancycline);山费培南钠(Sanfetrinem Sodium);沙莫西林(Sarmoxicillin);沙匹西林(Sarpicillin);吸水真菌素(Scopafungin);西苏霉素(Sisomicin);硫酸西苏霉素(Sisomicin Sulfate);司氟沙星(Sparfloxacin);盐酸壮观霉素(Spectinomycin Hydrochloride);螺旋霉素(Spiramycin);盐酸司他霉素(StallimycinHydrochloride);司替霉素(Steffimycin);硫酸链霉素(Streptomycin Sulfate);烟肼链霉素(Streptonicozid);磺胺苯(Sulfabenz);磺胺苯酰(Sulfabenzamide);磺胺醋酰(Sulfacetamide);磺胺醋酰钠(Sulfacetamide Sodium);磺胺乙胞嘧啶(Sulfacytine);磺胺嘧啶(Sulfadiazine);磺胺嘧啶钠(Sulfadiazine Sodium);磺胺多辛(Sulfadoxine);磺胺林(Sulfalene);磺胺甲基嘧啶(Sulfamerazine);磺胺对甲氧嘧啶(Sulfameter);磺胺二甲嘧啶(Sulfamethazine);磺胺甲噻二唑(Sulfamethizole);磺胺甲噁唑(Sulfamethoxazole);磺胺间甲氧嘧啶(Sulfamonomethoxine);磺胺二甲唑(Sulfamoxole);磺胺酸锌(Sulfanilate Zinc);磺胺硝苯(Sulfanitran);柳氮磺胺吡啶(Sulfasalazine);磺胺异噻唑(Sulfasomizole);磺胺噻唑(Sulfathiazole);磺胺甲苯吡唑(Sulfazamet);磺胺异噁唑(Sulfisoxazole);乙酰磺胺异噁唑(SulfisoxazoleAcetyl);磺胺异噁唑二乙醇胺(Sulfisoxazole Diolamine);磺粘菌素(Sulfomyxin);硫培南(Sulopenem);舒他西林(Sultamicillin);森西林钠(Suncillin Sodium);盐酸氨苄青霉素酞酯(Talampicillin Hydrochloride);替考拉宁(Teicoplanin);盐酸替马沙星(Temafloxacin Hydrochloride);替莫西林(Temocillin);四环素(Tetracycline);盐酸四环素(Tetracycline Hydrochloride);四环素磷酸盐复合物(Tetracycline PhosphateComplex);四氧普林(Tetroxoprim);甲砜氯霉素(Thiamphenicol);苯硫甲青霉素钾(Thiphencillin Potassium);替卡西林甲苯钠(Ticarcillin Cresyl Sodium);替卡西林二钠(Ticarcillin Disodium);替卡西林一钠(Ticarcillin Monosodium);替克拉酮(Ticlatone);氯化乔多(Tiodonium Chloride);妥布霉素(Tobramycin);硫酸妥布霉素(Tobramycin Sulfate);妥舒沙星(Tosufloxacin);甲氧苄啶(Trimethoprim);硫酸甲氧苄啶(Trimethoprim Sulfate);三重磺胺嘧啶(Trisulfapyrimidines);醋竹桃霉素(Troleandomycin);硫酸醋竹桃霉素(Trospectomycin Sulfate);短杆菌素(Tyrothricin);万古霉素(Vancomycin);盐酸万古霉素(Vancomycin Hydrochloride);维吉霉素(Virginiamycin);或佐尔博霉素(Zorbamycin)。
抗分枝杆菌剂可以是但不限于乙胺丁醇(Myambutol)(盐酸乙胺丁醇)、氨苯砜(Dapsone)(4,4’-二氨基二苯砜)、对氨水杨酸(Paser)颗粒(氨基水杨酸颗粒)、Priftin(利福喷丁(rifapentine))、吡嗪酰胺(Pyrazinamide)、异烟肼(Isoniazid)、Rifadin(利福平(Rifampin))、Rifadin IV、利福平和异烟肼合剂(Rifamate)(利福平和异烟肼)、卫肺特(Rifater)(利福平、异烟肼和吡嗪酰胺)、硫酸链霉素或乙基吡啶碳硫酰胺(Trecator)-SC(乙硫异烟胺)。
抗病毒剂可以是但不限于金刚胺(amantadine)和金刚乙胺(rimantadine)、ribivarin、阿昔洛韦(acyclovir)、阿糖腺苷、三氟胸苷、更昔洛韦(ganciclovir)、齐多呋定(zidovudine)、retinovir和干扰素。
抗病毒剂可以进一步包括,但不限于乙酰吗喃(Acemannan);无环鸟苷(Acyclovir);无环鸟苷钠(Acyclovir Sodium);阿德福韦(Adefovir);阿洛夫定(Alovudine);阿韦舒托(Alvircept Sudotox);盐酸金刚胺(Amantadine Hydrochloride);阿拉诺丁(Aranotin);阿立酮(Arildone);甲磺酸阿的维定(Atevirdine Mesylate);阿夫立定(Avridine);西多福韦(Cidofovir);西潘茶碱(Cipamfylline);盐酸阿糖胞苷(Cytarabine Hydrochloride);甲磺酸地拉夫定(Delavirdine Mesylate);地昔洛韦(Desciclovir);地丹诺辛(Didanosine);二恶沙利(Disoxaril);依度尿苷(Edoxudine);恩韦拉登(Enviradene);恩韦肟(Enviroxime);泛昔洛韦(Famciclovir);盐酸法莫汀(Famotine Hydrochloride);非西他滨(Fiacitabine);非阿尿苷(Fialuridine);膦利脂(Fosarilate);膦甲酸钠(Foscarnet Sodium);膦乙醇钠(Fosfonet Sodium);更昔洛韦(Ganciclovir);更昔洛韦钠(Ganciclovir Sodium);碘苷(Idoxuridine);凯托沙(Kethoxal);拉米夫定(Lamivudine);洛布卡韦(Lobucavir);盐酸美莫汀(MemotineHydrochloride);美替沙腙(Methisazone);奈韦拉平(Nevirapine);喷昔洛韦(Penciclovir);吡罗达韦(Pirodavir);病毒唑(Ribavirin);盐酸金刚烷乙胺(Rimantadine Hydrochloride);甲磺酸沙奎那韦(Saquinavir Mesylate);盐酸索金刚胺(Somantadine Hydrochloride);索利夫定(Sorivudine);维司托隆(Statolon);司他夫定(Stavudine);盐酸替络肟(Tilorone Hydrochloride);曲氟尿苷(Trifluridine);盐酸伐昔洛韦(Valacyclovir Hydrochloride);阿糖腺苷(Vidarabine);磷酸阿糖腺苷(Vidarabine Phosphate);阿糖腺苷磷酸钠(Vidarabine Sodium Phosphate);韦罗肟(Viroxime);扎西他滨(Zalcitabine);齐多夫定(Zidovudine);净韦肟(Zinviroxime)或整合酶抑制剂。
抗真菌剂可以是但不限于咪唑和三唑、多烯大环内酯抗生素、灰黄霉素、两性霉素B和氟胞嘧啶。抗寄生物剂包括重金属、抗疟喹啉、叶酸拮抗剂、硝基咪唑、苯并咪唑、阿维菌素、praxiquantel、鸟氨酸脱羧酶抑制剂、酚类(例如,硫氯酚、氯硝柳胺);合成的生物碱(例如,去氢吐根碱);哌嗪类(例如,乙胺嗪);乙酰苯胺(acetanilide)(例如,糠酸二氯尼特(diloxanide furonate);卤代喹啉类(例如,碘醌醇(二碘氢醌));硝基呋喃类(例如,硝呋噻氧(nifurtimox));二脒类(例如,戊双脒);四氢嘧啶(例如,双羟萘酸噻吩嘧啶);或磺化萘胺(例如,苏拉明(suramin))。
其他抗感染剂可以是但不限于盐酸二氟沙星(Difloxacin Hydrochloride);月桂基异喹啉氮鎓溴化物(Lauryl Isoquinolinium Bromide);拉氧头孢二钠(MoxalactamDisodium);奥硝唑(Ornidazole);喷替米星(Pentisomicin);盐酸沙氟沙星(SarafloxacinHydrochloride);HIV和其他逆转录病毒的蛋白酶抑制剂;HIV和其他逆转录病毒的整合酶抑制剂;头孢克洛(Cefaclor)(Ceclor);无环鸟苷(Acyclovir)(Zovirax);诺氟沙星(Norfloxacin)(Noroxin);头孢西丁(Cefoxitin)(Mefoxin);头孢呋辛酯(Cefuroximeaxetil)(Ceftin);环丙沙星(Ciprofloxacin)(Cipro);盐酸氨吖啶(AminacrineHydrochloride);苄索氯铵(Benzethonium Chloride);硫氯酚钠(Bithionolate Sodium);溴氯唑酮(Bromchlorenone);过氧化脲(Carbamide Peroxide);西他氯铵(CetalkoniumChloride);西吡氯铵(Cetylpyridinium Chloride);盐酸氯已定(ChlorhexidineHydrochloride);氯碘羟喹(Clioquinol);溴化度米芬(Domiphen Bromide);芬替克洛(Fenticlor);氯氟哒唑(Fludazonium Chloride);品红,碱性;呋喃唑酮;龙胆紫(GentianViolet);哈喹诺(Halquinols);六氯酚(Hexachlorophene);过氧化氢;鱼石脂(Ichthammol);咪癸碘(Imidecyl Iodine);碘(Iodine);异丙醇;醋酸磺胺米隆(MafenideAcetate);汞林钠(Meralein Sodium);氯酚汞(Mercufenol Chloride);汞,氨化的;甲苄索氯铵(Methylbenzethonium Chloride);呋喃西林(Nitrofurazone);硝甲酚汞(Nitromersol);盐酸奥替尼啶(Octenidine Hydrochloride);氧氯苯磺酸(Oxychlorosene);氧氯苯磺酸钠(Oxychlorosene Sodium);对氯苯酚,樟脑化的;高锰酸钾;聚维酮-碘(Povidone-Iodine);氯化三苯唑(Sepazonium Chloride);硝酸银;磺胺嘧啶,银;氯氧三嗪;硫汞苯磺钠(Thimerfonate Sodium);硫柳汞(Thimerosal);或曲氯新钾(Troclosene Potassium)。
佐剂。佐剂可以是但不限于明矾(例如,氢氧化铝、磷酸铝);从皂树(Q.saponaria)的树皮纯化的皂素,如QS21(使用HPLC分级,在第21个峰洗脱的糖脂;Antigenics,Inc.,Worcester,Mass.);聚[二(对羧基苯氧(carboxylatophenoxy))磷腈(PCPP聚合物;VirusResearch Institute,USA)、Flt3配体,利士曼原虫延伸因子(纯化的利士曼原虫蛋白;Corixa Corporation,Seattle,Wash.)、ISCOMS(免疫刺激复合物,其含有混合的皂素、脂质并且形成具有可以容纳抗原的孔隙的病毒大小的颗粒;CSL,墨尔本,澳大利亚)、Pam3Cys、SB-AS4(SmithKline Beecham佐剂系统#4,其含有明矾和MPL;SBB,比利时)、形成胶束的非离子嵌段共聚物,如CRL 1005(这些含有疏水性聚氧丙烯的直链,侧翼为聚氧乙烯链,Vaxcel,Inc.,Norcross,Ga.)和Montanide IMS(例如,IMS 1312,与可溶性免疫刺激剂混合的基于水的纳米颗粒,Seppic)。
佐剂可以是Toll-样受体(TLR)配体。通过TLR3作用的佐剂包括但不限于双链RNA。通过TLR4作用的佐剂包括不限于脂多糖的衍生物,如单磷酰基脂质A(MPLA;RibiImmunoChem Research,Inc.,Hamilton,Mont.)和胞壁酰二肽(MDP;Ribi)和苏氨酰-胞壁酰二肽(t-MDP;Ribi);OM-174(与脂质A相关的氨基葡萄糖二糖;OM Pharma SA,Meyrin,Switzerland)。通过TLR5作用的佐剂包括但不限于鞭毛蛋白。通过TLR7和/或TLR8作用的佐剂包括单链RNA、寡核糖核苷酸(ORN)、合成的低分子量化合物,如咪唑并喹啉胺(例如,咪喹莫特、雷西莫特)。通过TLR9作用的佐剂包括病毒或细菌来源的DNA,或合成的寡脱氧核糖核苷酸(ODN),如CpG ODN。另一个佐剂类别是含硫代磷酸酯的分子,如硫代磷酸核苷酸类似物,以及含硫代磷酸酯主链连接的核酸。
组合物和施用方法
本文中提供的化合物包括归巢至肿瘤的并且与包含药剂(例如,生物活性蛋白)的纳米结构(例如,蛋白质纳米凝胶或脂质体)偶联的有核载体细胞,其中所述载体细胞包含细胞表面偶联受体(例如,CD45)并且与具有结合所述载体的配体的纳米结构偶联,或所述载体细胞包含带负电荷的细胞膜,而所述纳米结构包含与细胞膜通过静电相互作用的聚阳离子表面。
在某些方面中,所述组合物包含具有CD45受体的载体细胞,并且所述载体细胞与具有结合CD45受体的配体的纳米结构偶联。在某些方面中,所述配体是抗CD45单克隆抗体。
在某些方面中,所述载体细胞包含带负电荷的细胞膜,而所述纳米结构包含与细胞膜通过静电相互作用的聚阳离子表面。在某些方面中,所述聚阳离子是聚赖氨酸。在某些方面中,所述聚阳离子是聚乙二醇-b-聚赖氨酸(PEG-PLL)。
在一些实施方式中,所述组合物包含蛋白质纳米凝胶。在某些方面中,所述蛋白质纳米凝胶包含多个彼此通过可降解接头可逆且共价交联的生物活性蛋白。在一些实施方式中,所述可降解接头是包括二硫键的氧化还原反应性接头。
在一些实施方式中,所述组合物是脂质体。在某些实施方式中,所述脂质体包含多个生物活性蛋白。在某些方面中,所述脂质体是双层间交联的多层或单层囊泡。
在一些实施方式中,所述组合物包含载体细胞,其中所述载体细胞是T细胞、B细胞、自然杀伤(NK)细胞或干细胞。在一些方面中,所述载体细胞是T细胞。在一些方面中,所述T细胞是CD8+T细胞或CD4+T细胞。在一些方面中,所述T细胞是过继转移的T细胞。在一些方面中,所述T细胞是嵌合抗原受体(CAR)T细胞。
在一些实施方式中,所述组合物包含含有生物活性蛋白的纳米结构,其中所述生物活性蛋白选自抗体、抗体片段、可溶性蛋白受体和细胞因子。在一些方面中,所述细胞因子是IL-2、IL-15或IL-15SA。在一些方面中,所述细胞因子是IL-15-Sa。在一些方面中,所述IL-15Sa包括含有二聚IL-15RαSu/Fc和两个IL-15N72D分子的复合物。在一些方面中,所述二聚IL-15RαSu/Fc包含SEQ ID NO:1中所示的氨基酸序列,而IL-15N72D分子包含SEQ IDNO:2中所示的氨基酸序列。
在一些实施方式中,所述组合物包含药物学上可接受的载体。在一些方面中,所述组合物用作用于将生物活性蛋白递送至患有肿瘤的受试者的药物。
所述公开内容的某些方面提供了治疗受试者的癌症的方法,包括将本文中所述的组合物施用于需要的受试者。
所述公开内容的某些方面提供了包含归巢至肿瘤并与包含生物活性蛋白的纳米结构偶联的有核载体细胞(例如:T细胞)的组合物,其中(a)所述载体细胞包含CD45受体并与具有结合CD45受体的配体的纳米结构偶联,或(b)所述载体细胞包含带负电荷的细胞膜,而所述纳米结构包含与细胞膜通过静电相互作用的聚阳离子表面;或(c)所述载体细胞包含CD45受体并与具有CD45受体的配体的纳米结构偶联,并且所述载体细胞包含带负电荷的细胞膜,而所述纳米结构包含与细胞膜通过静电相互作用的聚阳离子表面。
所述公开内容的某些方面提供了包含含有CD45受体的有核载体细胞(例如:T细胞)和含有生物活性蛋白的纳米结构的组合物,其中载体细胞与具有结合CD45受体的配体的纳米结构偶联。
所述公开内容的某些方面提供了包含归巢至肿瘤并与含有生物活性蛋白的纳米结构偶联的有核载体细胞(例如:T细胞)的组合物,其中所述载体细胞包含带负电荷的细胞膜,而所述纳米结构包含与细胞膜通过静电相互作用的聚阳离子表面。
所述公开内容的某些方面提供了包含含有CD45受体的有核载体细胞和蛋白质纳米凝胶的组合物,其中所述载体细胞与具有结合CD45受体的配体的蛋白质纳米凝胶偶联,和其中所述蛋白质纳米凝胶包含多个彼此通过可降解接头可逆且共价地交联的生物活性蛋白。
所述公开内容的某些方面提供了包含归巢至肿瘤并与蛋白质纳米凝胶偶联的有核载体细胞(例如,T细胞)的组合物,其中所述载体细胞包含带负电荷的细胞膜,而所述蛋白质纳米凝胶包含与细胞膜通过静电相互作用的聚阳离子表面,并且其中所述蛋白质纳米凝胶包含多个彼此通过可降解接头可逆且共价地交联的生物活性蛋白。
所述公开内容的某些方面提供了包含含有CD45受体的有核载体细胞(例如,T细胞)和含有多个生物活性蛋白的脂质体的组合物,其中所述载体细胞与具有结合CD45受体的配体的脂质体偶联。
本文中提供的组合物可以用于各种生物医学和药物应用。在一些实施方式中,所述组合物用于靶向免疫治疗的体内药剂(例如,药物)递送。在一些实施方式中,所述组合物用于过继性细胞治疗。过继性细胞治疗(ACT)是高度个性化的癌症疗法,其通常涉及将具有直接抗癌活性的免疫细胞给予带有癌症的宿主。本发明考虑了将本发明的组合物施用于患有癌症或处于产生癌症风险中的受试者,所述癌症包括例如实体肿瘤癌症。本文中提供了包含蛋白质纳米结构(例如,蛋白质纳米凝胶)的组合物,包括药物组合物。本文中还提供了包含与载体细胞偶联的蛋白质纳米结构(例如,蛋白质纳米凝胶)的组合物,包括药物组合物。组合物可以以药物学上可接受的量并且在药物学上可接受的组合物中施用于受试者。术语“药物学上可接受的”表示不干扰活性成分(例如,所述纳米结构的生物活性蛋白)的生物活性的有效性的无毒物质。在一些实施方式中,这样的组合物可以含有盐、缓冲剂、防腐剂和任选地其他治疗剂。
在一些实施方式中,药物组合物还可以含有合适的防腐剂。
在一些实施方式中,药物组合物可以以单位剂型存在,并且可以通过制药领域中任一种公知方法来制备。
在一些实施方式中,适用于非肠道施用的药物组合物包含纳米结构的无菌水性或非水性制备物,其在一些实施方式中与接受受试者的血液是等渗的。这种制备物可以根据已知方法来配制。无菌可注射制备物也可以是在无毒的肠道外可接受稀释剂或溶剂中的无菌注射溶液或悬浮液。
在一些实施方式中,本发明公开内容的药物组合物可以通过常规途径来施用,所述常规途径包括注射或通过随着时间的逐渐输注。例如,施用可以是口服、静脉内、腹膜内、肌内、腔内、肿瘤内或经皮。
在一些实施方式中,本发明公开内容的药物组合物以有效量施用。“有效量”是本文中提供的任何纳米结构单独或与进一步的剂量和/或其他治疗剂一起产生所需反应(例如,伪自分泌刺激、增强T细胞扩增和最小化佐剂药物在体内的副作用)的量。
在一些实施方式中,本发明公开内容的药物组合物可以是无菌的,并且含有有效量的纳米结构(例如,纳米凝胶)(单独的或结合另一种药剂)用于以适合施用于受试者(例如,人受试者)的单位重量或体积来产生所需反应。例如,可以通过测定所述纳米结构组合物的生理效应来测量所述反应。
可以根据不同的参数,特别是根据所用的给药方式和受试者的状态,来选择施用于受试者的组合物的剂量。其他因素包括所需的治疗时间。在受试者中的反应在所施用初始剂量下不足的情况中,可以使用较高剂量(或通过不同的、更局部化的递送途径效率上更高的剂量)以达到受试者/患者耐受性容许的程度。
施用方法
所述公开内容还提供了将包含与纳米结构偶联的载体细胞的组合物体内施用于受试者的方法。所述公开内容的方法可以在很可能得益于本文中所述的药剂(例如,生物活性蛋白)的递送的受试者中实施。在一些实施方式中,人受试者是优选的受试者。受试者还包括动物,如家养宠物(例如,狗、猫、兔子、雪貂)、牲畜或农场动物(例如,奶牛、马、猪、绵羊、鸡和其他家禽)、实验室动物(例如,小鼠、大鼠、兔子)等。受试者还包括鱼和其他水生物种。
对其递送组合物的受试者可以是正常的或健康的受试者。或者,他们可能患有从本文中公开的一种或多种药剂的递送可以诊断或可以得益的病症或可能处于产生所述病症的风险中。这样的病症包括癌症(例如,实体肿瘤癌症)、自身免疫障碍、过敏或过敏性病症、哮喘、移植排斥等。
用于诊断本发明公开内容包括的各种病症的测试是本领域已知的,并且是普通医学从业者熟悉的。这些实验室测试包括但不限于显微镜分析、培养依赖性测试(如培养物)和核酸检测测试。这些包括湿涂片、染色增强的显微镜检查、免疫显微镜检查(例如,FISH)、杂交显微镜检查、颗粒聚集、酶联免疫吸附分析、尿筛查测试、DNA探针杂交、血清学测试等。除了运行上述实验室测试外,医学从业者通常还将获取全部病史并进行完整的身体检查。
患有癌症的受试者是具有可检测的癌细胞的受试者。处于产生癌症的风险中的受试者是具有高于正常产生癌症概率的受试者。这些受试者包括,例如,具有已经证明与产生癌症的较高可能性相关的遗传异常的受试者、具有家族性癌症倾向的受试者、暴露于癌症诱发剂(例如,致癌物)(如烟草、石棉和其他化学毒素)的受试者以及之前针对癌症治疗过并在明显缓解中的受试者。
患有感染的受试者是呈现其症状的那些,包括但不限于发烧、冷颤、肌痛、畏光、咽炎、急性淋巴结肿大、脾肿大、胃肠不适、白细胞增多或白细胞减少,和/或其中可以检测到传染性病原体或其副产物的那些。
处于产生感染风险中的受试者是处于暴露于传染性病原体的风险中的受试者。这样的受试者包括生活在其中已知存在此类病原体并且其中这样的感染常见的地区中的那些受试者。这些受试者还包括从事高风险活动的那些,如共用针具、进行未受保护的性行为、日常接触受受试者的感染样品(例如,医学从业者)、经历了外科手术的人,包括但不限于腹部手术,等。
受试者可以患有感染或处于产生感染的风险中,如细菌感染、病毒感染、真菌感染、寄生虫感染或分枝杆菌感染。在这些实施方式中,所述纳米结构可以包含抗微生物剂,如抗细菌剂、抗病毒剂、抗真菌剂、抗寄生虫剂或抗分枝杆菌剂,并且所述细胞载体(例如,T细胞)可以进行遗传工程化以产生在刺激对抗感染的免疫应答中有用的或潜在治疗所述感染的另一种药剂。
在一些情况中,施用组合物的受试者需要造血重建。这样的受试者可能已经暴露于蓄意或偶然的清髓性事件,包括但不限于清髓性化疗和/或全身放疗,如可能作为针对非实体癌症或转移性癌症的治疗方案的部分给予的。所述公开内容提供了将与包含能够刺激祖细胞增殖的药剂的纳米结构缀合的造血祖细胞施用于这样的受试者。在一些情况中,所述药剂还可以是分化剂(即,驱动祖细胞及其后代分化的药剂,任选地朝向所有谱系或谱系子集)。在其他情况中,所述药剂可以是自我更新剂(即,驱动祖细胞自我更新的药剂)。还在其他情况中,所述载体细胞可以与包含两种类型的药剂的纳米结构缀合,不管这样的药剂是在相同或不同纳米结构中。此外,所述公开内容提供了受试者对于这些不同药剂的暴露可以错开(例如,暴露于自我更新剂可以在暴露于分化剂之前进行)。
治疗方法
治疗癌症的方法
所述公开内容提供了将本文中所述的组合物施用于患有癌症或处于产生癌症风险中的受试者,所述癌症包括例如实体肿瘤癌症。所述癌症可以是癌瘤(carcinoma)、肉瘤或黑素瘤。癌瘤包括但不限于基细胞癌瘤、胆管癌、膀胱癌、乳腺癌、宫颈癌、绒毛膜癌、CNS癌、结肠和直肠癌、肾或肾细胞癌、咽癌、肝癌、小细胞肺癌、非小细胞肺癌(NSCLC,包括腺癌、巨(或燕麦)细胞癌和鳞状细胞癌)、口腔癌、卵巢癌、胰腺癌、前列腺癌、皮肤癌(包括基细胞癌和鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、直肠癌、呼吸系统的癌症和泌尿系统的癌症。
肉瘤是在骨(骨肉瘤)和软组织(纤维肉瘤)中产生的罕见间充质肿瘤。肉瘤包括但不限于脂肪肉瘤(包括粘液样脂肪肉瘤和多形性脂肪肉瘤)、平滑肌肉瘤、横纹肌肉瘤、恶性外周神经鞘肿瘤(也称为恶性神经鞘瘤、神经纤维肉瘤或神经源性肉瘤)、Ewing’s肿瘤(包括骨的Ewing’s肉瘤、骨外(即,非骨)Ewing’s肉瘤和原发性神经外胚层肿瘤)、滑膜肉瘤、血管肉瘤(angiosarcomas)、血管肉瘤(hemangiosarcomas)、淋巴管肉瘤(lymphangiosarcomas)、Kaposi’s肉瘤、血管内皮瘤、硬纤维瘤(也称为侵袭性纤维瘤病)、隆突性皮肤纤维肉瘤(DFSP)、恶性纤维组织细胞瘤(MFH)、血管外皮细胞瘤、恶性间质瘤、肺泡状软组织肉瘤、上皮样肉瘤、透明细胞肉瘤、促纤维性小细胞瘤、胃肠道间质瘤(GIST)(也称为GI间质肉瘤)和软骨肉瘤。
黑素瘤是从皮肤和其他器官的黑色素细胞系统产生的肿瘤。黑素瘤的实例包括但不限于恶性雀斑痣黑色素瘤、浅表扩散性黑素瘤、结节性黑素瘤和肢端黑素瘤。
所述癌症可以是实体肿瘤淋巴瘤。实例包括霍奇金淋巴瘤、非霍奇金淋巴瘤和B细胞淋巴瘤。
所述癌症可以是但不限于骨癌、脑癌、乳腺癌、结直肠癌、结缔组织癌、消化系统的癌症、子宫内膜癌、食道癌、眼癌、头颈癌、胃癌、上皮内肿瘤、黑色素瘤神经母细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌、前列腺癌、视网膜母细胞瘤或横纹肌肉瘤。
治疗感染的方法
所述公开内容还提供了将本文中所述的组合物施用于患有感染或处于产生感染的风险中的受试者的方法,所述感染如细菌感染、病毒感染、真菌感染、寄生虫感染或分枝杆菌感染。所述细菌感染可以是但不限于大肠杆菌感染、葡萄球菌感染、链球菌感染、假单胞菌感染、艰难梭菌感染、军团菌感染、肺炎球菌感染、嗜血杆菌感染、克雷伯氏菌感染、肠杆菌感染、柠檬酸杆菌感染、奈瑟氏菌感染、志贺氏菌感染、沙门氏菌感染、李斯特氏菌感染、巴斯德氏菌感染、链杆菌感染、螺旋菌感染、密螺旋体感染、放线菌感染、疏螺旋体感染、棒杆菌感染、诺卡氏菌感染、加德纳菌感染、弯曲菌感染、螺旋体感染、变形杆菌(Proteus)感染、拟杆菌(Bacteriode)感染、幽门螺旋杆菌感染或炭疽菌感染。
分枝杆菌感染可以是但不限于分别由结核分枝杆菌和麻风分枝杆菌种引起的肺结核或麻风病。
病毒感染可以是但不限于单纯疱疹病毒1感染、单纯疱疹病毒2感染、巨细胞病毒感染、甲肝病毒感染、乙肝病毒感染、丙肝病毒感染、人乳头状瘤病毒感染、EB病毒感染、轮状病毒感染、腺病毒感染、甲流病毒感染、H1N1(猪流感)感染、呼吸道合胞体病毒感染、水痘-带状疱疹病毒感染、小痘感染、猴痘感染、SARS感染或禽流感感染。
真菌感染可以是但不限于念珠菌病、藓菌病、组织胞浆菌病、芽生菌病、副球孢子菌病、隐球菌病、曲霉病、着色真菌病、足菌病感染、假性阿利什利菌病或花斑癣感染。
寄生虫感染可以是但不限于阿米巴病、克氏锥虫感染、片形吸虫病、利什曼病、疟原虫感染、盘尾丝虫病、肺吸虫病、布氏锥虫感染、肺囊虫感染、阴道滴虫感染、绦虫感染、膜壳绦虫感染、棘球绦虫感染、血吸虫病、脑囊虫病、美洲钩虫感染或毛首鞭虫感染。
治疗过敏和哮喘的方法
所述公开内容进一步提供了将本文中所述的组合物施用于患有或处于产生过敏或哮喘的风险中的受试者。过敏是对过敏原的获得性超敏反应。过敏性病症包括但不限于湿疹、过敏性鼻炎或鼻炎、枯草热、支气管哮喘、荨麻疹(hives)和食物过敏,以及其他特应性病症。过敏通常是由对抗有害过敏原的IgE抗体产生引起的。哮喘是呼吸系统的障碍,其特征在于发炎、气道狭窄和提高的气道对吸入物质的反应。哮喘常常(尽管不是专门地)与特应性或过敏性症状相关。根据所述公开内容,Th1细胞因子(如IL-12和IFN-γ)的施用可以用于治疗过敏或哮喘。
治疗自身免疫疾病的方法
所述公开内容提供了将本文中所述的组合物施用于患有或处于产生自身免疫疾病风险中的受试者。自身免疫疾病是其中患者自身的抗体与宿主组织反应或其中免疫效应T细胞对内源性自身肽是自身反应性的并且引起组织破坏的一类疾病。因此,免疫反应对抗受试者自身的抗原(称为自身抗原)而产生。自身免疫疾病通常被认为是Th1偏倚的(Th1biased)。因此,引入Th2免疫反应或Th2样细胞因子可能是有益的。这样的细胞因子包括IL-4、IL-5和IL-10。
自身免疫疾病包括但不限于类风湿性关节炎、节段性回肠炎、多发性硬化、全身性红斑狼疮(SLE)、自身免疫性脑脊髓炎、重症肌无力(MG)、桥本甲状腺炎、Goodpasture’s综合征、天疱疮(例如,寻常型天疱疮)、Grave’s病、自身免疫性溶血性贫血、自身免疫性血小板减少性紫癜、具有抗胶原蛋白抗体的硬皮病、混合型结缔组织病、多肌炎、恶性贫血、特发性爱迪生病、自身免疫相关的不育、肾小球肾炎(例如,新月体性肾小球肾炎、增殖性肾小球肾炎)、大疱性类天疱疮、综合征、胰岛素抵抗和自身免疫性糖尿病。
移植疗法
本文中提供的方法还可以用于调节移植治疗后的免疫反应。移植成功常常受限于移植的组织受到身体免疫系统的排斥。因此,为了允许移植的组织存活,移植物接受者常常是长时间免疫抑制的。所述公开内容提供了免疫调节剂并且特别地免疫抑制剂定位递送至移植部位以最小化移植物排斥。因此,所述公开内容提供了将组合物施用于正准备经历、正在经历或已经经历了移植的受试者。以上列表不打算是穷举性的,而是示例性的。本领域普通技术人员将确定适合使用所述公开内容的方法预防和治疗的各种病症类型的其他实例。
有效量、方案、制剂
将本文中所述的组合物以有效量来施用。有效量是足以提供医学上所需结果的药剂剂量。有效量将随着所治疗的特定病症、待治疗受试者的年龄和身体状况、病症的严重程度、治疗的持续时间、同时或联合治疗(如果有的话)的性质、特定的施用途径以及健康从业者的知识和技能内的类似因素而改变。通常优选可以使用最大剂量,即,根据合理医学判断的最高安全剂量。
例如,如果受试者患有肿瘤,有效量可以是减小肿瘤体积或载荷(例如通过将肿瘤成像测定的)的量。还可以通过血液或其他体液或组织(例如,活检样品)中癌细胞的存在和/或频率来评估有效量。如果肿瘤正影响组织或器官的正常功能,那么可以通过测量组织或器官的正常功能来评估有效量。
所述公开内容提供了药物组合物。药物组合物是包括细胞、纳米结构和/或药剂(优选在药物学上可接受的载体中)的无菌组合物。术语“药物学上可接受的载体”表示一种或多种相容的固体或液体填充剂、稀释剂或包封物质,其适合施用于人或本文中所述的其他受试者。术语“载体”表示细胞、纳米结构和药剂与其组合以有助于施用的有机或无机成分(天然或合成的)。以排除将实质性地损害所需药物功效的相互作用的方式来混合所述药物组合物的组分。
期望全身性递送时,组合物可以配制用于通过注射(例如,通过浓注或连续输注)的非肠道施用。可以以单位剂型,例如,在安瓿或多剂量容器中,来提供用于注射的制剂。非肠道药物制剂包括成分的水溶液。含水注射悬浮液可以含有提高悬浮液粘度的物质,如羧甲基纤维素钠、山梨糖醇或葡聚糖。或者,成分的悬浮液可以制成油基悬浮液。合适的亲脂性溶剂或载体包括脂肪油,如芝麻油,或合成的脂肪酸酯,如油酸乙酯或甘油三酯,或脂质体。
其他实施方式
在第一方面中,本发明公开内容提供了包含归巢至肿瘤并且与包含药剂的纳米结构偶联的有核载体细胞的组合物,其中所述载体细胞包括细胞表面偶联受体,并且其中所述纳米结构与具有结合细胞表面偶联受体的配体的载体细胞偶联。在所述第一方面的一些实施方式中,所述配体选自抗体、抗体片段、可溶性蛋白质受体、细胞因子、肽、小分子、辅因子、激素和神经递质。在一些实施方式中,所述细胞表面受体是CD45,如结合抗CD45单克隆抗体(例如,人抗CD45抗体或人源化抗CD45抗体)或被抗CD45单克隆抗体(例如,人抗CD45抗体或人源化抗CD45抗体)结合的受体。在一些实施方式中,所述抗CD45单克隆抗体选自BC8、4B2、9.4和GAP8.3。在所述第一方面的上述任一实施方式中,所述载体细胞是T细胞、B细胞或自然杀伤(NK)细胞。在一些实施方式中,所述载体细胞是T细胞,如CD8+T细胞或CD4+T细胞。在一些实施方式中,所述T细胞是过继转移的T细胞。在一些实施方式中,所述T细胞是嵌合抗原受体(CAR)T细胞。
在所述第一方面的上述任一实施方式中,所述纳米结构选自:脂质体、蛋白质纳米凝胶、核酸纳米凝胶和固化聚合物。在一些实施方式中,所述纳米结构是脂质体。在一些实施方式中,所述脂质体是双层间交联的多层囊泡(ICMV)。在一些实施方式中,所述纳米结构是蛋白质纳米凝胶。在所述第一方面的上述任一实施方式中,所述纳米结构具有1至1000纳米(nm)的直径。在一些实施方式中,所述纳米结构具有50至500nm的直径。在所述第一方面的上述任一实施方式中,所述配体与所述纳米结构共价缀合。在一些实施方式中,所述配体经由马来酰亚胺-巯基相互作用与纳米结构共价缀合。
在所述第一方面的上述任一实施方式中,所述药剂选自治疗剂、预防剂和成像剂。在一些实施方式中,所述药剂选自蛋白质、核酸和小分子药物。在一些实施方式中,所述药剂是蛋白质。在一些实施方式中,所述蛋白质是细胞因子。在一些实施方式中,所述细胞因子是IL-2、IL-15或IL-15-Sa。在所述第一方面的上述任一实施方式中,所述纳米结构在其表面上包含聚阳离子。在一些实施方式中,所述聚阳离子是聚赖氨酸。在一些实施方式中,所述聚阳离子是聚乙二醇-b-聚赖氨酸(PEG-PLL)。
在第二方面中,本发明公开内容提供了包含与包含药剂的纳米结构偶联的归巢至肿瘤的有核载体细胞的组合物,其中所述纳米结构包含与聚阳离子结合的表面。在一些实施方式中,所述载体细胞是T细胞、B细胞或自然杀伤(NK)细胞。在一些实施方式中,所述载体细胞是T细胞。在一些实施方式中,所述T细胞是CD8+T细胞或CD4+T细胞。在一些实施方式中,所述T细胞是过继转移的T细胞。在一些实施方式中,所述T细胞是嵌合抗原受体(CAR)T细胞。在第二方面的上述任一实施方式中,所述纳米结构选自:脂质体、蛋白质纳米凝胶、核酸纳米凝胶和固化聚合物。在一些实施方式中,所述纳米结构是脂质体。在一些实施方式中,所述脂质体是双层间交联的多层囊泡(ICMV)。在一些实施方式中,所述纳米结构是蛋白质纳米凝胶。在一些实施方式中,所述纳米结构具有1至1000纳米(nm)的直径。在一些实施方式中,所述纳米结构具有50至500nm的直径。在所述第二方面的上述任一实施方式中,所述载体细胞经由马来酰亚胺-巯基相互作用与纳米结构共价缀合。
在所述第二方面的上述任一实施方式中,所述药剂选自治疗剂、预防剂和成像剂。在一些实施方式中,所述药剂选自蛋白质、核酸和小分子药物。在一些实施方式中,所述药剂是蛋白质。在一些实施方式中,所述蛋白质是细胞因子。在一些实施方式中,所述细胞因子是IL-2、IL-15或IL-15-Sa。在所述第二方面的上述任一实施方式中,所述聚阳离子是聚赖氨酸。在一些实施方式中,所述聚阳离子是聚乙二醇-b-聚赖氨酸(PEG-PLL)。
在第三方面中,本发明公开内容提供了包含与包含聚阳离子的蛋白质纳米凝胶偶联的具有CD45受体的T细胞的组合物,其中所述T细胞与具有结合CD45受体的配体的蛋白质纳米凝胶偶联。在一些实施方式中,所述配体选自抗体、可溶性蛋白质受体、细胞因子、肽、小分子、辅因子、激素和神经递质。在一些实施方式中,所述配体是抗CD45单克隆抗体,如人抗CD45抗体或人源化抗CD45抗体。在一些实施方式中,所述抗CD45单克隆抗体选自BC8、4B2、9.4和GAP8.3。在所述第三方面的上述任一实施方式中,所述T细胞是CD8+T细胞或CD4+T细胞。在一些实施方式中,所述T细胞是过继转移的T细胞。在一些实施方式中,所述T细胞是嵌合抗原受体(CAR)T细胞。在所述第三方面的上述任一实施方式中,所述蛋白质纳米凝胶具有1至1000纳米(nm)的直径。在一些实施方式中,所述蛋白质纳米凝胶具有50至500nm的直径。在所述第三方面的上述任一实施方式中,所述配体与蛋白质纳米凝胶共价缀合。在一些实施方式中,所述抗CD45抗体经由含有两个N-羟基硫代琥珀酰亚胺基团的接头与蛋白质纳米凝胶共价缀合。
在所述第三方面的上述任一实施方式中,所述蛋白质纳米凝胶包含选自治疗蛋白、预防蛋白、诊断蛋白和成像蛋白的蛋白质。在一些实施方式中,所述蛋白质纳米凝胶包含细胞因子。在一些实施方式中,所述细胞因子是IL-2、IL-15或IL-15-Sa。在所述第三方面的上述任一实施方式中,所述聚阳离子是聚赖氨酸。在一些实施方式中,所述聚阳离子是聚乙二醇-b-聚赖氨酸(PEG-PLL)。
通过以下实施例进一步说明本发明,所述实施例绝不应当解释为进一步的限制。将贯穿本申请中引用的所有参考文献(包括文献参考、授权的专利、公开的专利申请和共同未决的专利申请)的完整内容特意按引用并入本文,特别是针对本文中参考的教导。
序列表格A:
*Su,是指sushi结构域。
实施例
尽管许多接近细胞表面的纳米结构经由胞吞作用或被动膜渗透被快速内化,但一些可以在细胞表面上保持较长时间段。内化动力学差异的原因仍然是难以捉摸的。因此,研究被纳米结构结合的缓慢内化细胞表面蛋白质提供了关于设计具有长时间表面停留的纳米结构的深入了解。目前,大部分尝试致力于设计内化药物缀合物以递送胞内药物。然而,如果可以使用具有最少内化的细胞表面受体来设计具有延长的稳定性和细胞表面上的停留时间的新结构,那么可以将扩展的药物库(例如:细胞外药物,如细胞因子和小分子药物)递送至细胞。在细胞表面上纳米结构的延长的稳定性和维持还提高了用于药物递送、成像、追踪和诊断目的的纳米结构的功效和效率。
实施例1.CD45作为用于最大化脂质体加载的稳定细胞表面锚的鉴定
双层间交联的多层囊泡(ICMV)(Nature Mater.2011,10,243-251)是可以在细胞表面(例如,T细胞表面)上保留超过四天的一种颗粒类型。通过最丰富结合的总表面蛋白ICMV的质谱分析获得了缓慢内化受体的候选池。通过使用与抗前面的候选表面受体(如CD2、CD11和CD45)的抗体表面偶联的脂质体进行了ICMV长时间表面停留的主要因素的筛选。抗体缀合的脂质体与载体细胞偶联。
脂质体合成
通过水合含有2.5% PEG-马来酰亚胺和1%生物素头基的干燥高-TM磷脂膜来产生抗体缀合的脂质体。具体地,将由2.5/27/68/1.5摩尔比的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(马来酰亚胺-PEG2000-DSPE)/胆固醇/氢化大豆L-α-磷脂酰胆碱(HSPC)/1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-N-[生物素基(聚乙二醇)-2000(生物素-PEG2000-DSPE)组成的真空干燥磷脂膜(Avanti Polar Lipids,Alabaster,AL,USA)与1%荧光亲脂性示踪染料DiD在250μL 50-mM 4-(2-羟乙基)-1-哌嗪乙磺酸(HEPES)/150-mM NaCl-缓冲液(pH 6.5)中再水合。将脂质在62℃下每10min涡旋,持续1h,以形成囊泡并通过聚碳酸酯膜(0.2μm)尺寸挤出。在过量PBS中洗涤并在110,000×g下超离心旋转4h后,将脂质体重悬浮于100μl PBS/1.4mg脂质中。为了与脂质体的马来酰亚胺基团偶联,在10mM EDTA的存在下,在25℃下,用1.8mM二硫苏糖醇(DTT)处理抗体、细胞因子和不同摩尔比(2-5mg/mL)的抗体/细胞因子混合物20min以暴露铰链区游离巯基。随后通过使用Zeba脱盐柱除去DTT,接着与PBS中带有马来酰亚胺的脂质体混合(对于蛋白质/脂质,1/1wt./wt.)。在旋转器上在25℃下孵育18h后,通过在过量PBS中的超离心除去过量蛋白质。将未结合的脂质体洗掉,接着在37℃下,在Roswell Park Memorial Institute(RPMI)培养基中孵育T细胞。
通过DTT还原对抗表面受体CD2、CD11、CD45的抗体(Ab)或对抗两种表面标志物(例如,CD2/CD45或CD11/CD45)的1:1比率的抗体混合物以暴露铰链区游离巯基,并且随后经由马来酰亚胺-巯基反应与脂质体表面偶联,如上所述。抗体获自BioXcell(West Lebanon,NH,USA),包括抗小鼠CD45抗体,克隆号:MB23G2。
脂质体与载体细胞偶联
100μL PBS中的抗体缀合的脂质体(0.7mg脂质)在37℃下,在0.5ml补充了10%胎牛血清(FCS)的完全RPMI中用20×106个激活的(primed)pmel-1Thy1.1+CD8+T细胞孵育30min,每15min温和搅动。用PBS洗涤缀合的T细胞(20mL×2)以除去未结合的脂质体并且用重组IL-7(1.5ng/mL)和10% FCS在RPMI培养基中以0.5×106细胞/mL在37℃下孵育。
脂质体表征
将未结合的脂质体洗掉,并且将细胞在完全RPMI中在37℃下孵育。通过抗生物素蛋白链菌素-荧光团将细胞染色,并在缀合后零(0)时(hr)、6hr、24hr和48hr(图1A)或在缀合后零(0)hr、19hr、45hr和69hr(图1B和1C)通过流式细胞仪分析。将荧光标记的细胞的百分比随着时间作图。只有具有表面脂质体的T细胞被荧光标记,因为内化的脂质体不能接近抗生物素蛋白链菌素-染料。48hr后,几乎100%的细胞仍然具有锚定在其表面上的抗CD45(α-CD45)抗体装饰的脂质体,而表面抗CD11(α-CD11)抗体和抗CD2(α-CD2)抗体脂质体分别只在30%和70%细胞上发现(图1A)。出乎预料地,CD45比更快内化的受体CD11和CD2呈现出延长的细胞表面停留时间。在将α-CD45与α-CD2或α-CD11结合用来表面装饰脂质体时,CD45和CD2(或CD45和CD11)两者上锚定的脂质体在两天后仍然保留在100%细胞上,无论是否与较快内化受体CD2和CD11结合(图1A)。抗CD45脂质体呈现出延长的细胞表面保留,不仅与CD2和CD11相比,而且与CD8和Thy1.1相比(图1B)。
为了进一步证实CD45在脂质体上的非内化特性,将CD45与公知的内化IL-2受体和同源标志物Thy1一起测试。如上所述,将对抗Thy1的抗体(α-Thy1.1)或由与小鼠Fc抗体框架融合的IL-2组成的工程化IL-2-Fc蛋白(按照之前所述的来制备,J Controlled Release2013,172,426-435)与脂质体表面偶联。也使用了含有固定量的不同摩尔比的α-Thy1.1和α-CD45(或IL-2-Fc和α-CD45)的配体混合物来装饰脂质体表面。与激活的CD8+T细胞缀合后,95%的IL-2-Fc脂质体和70%的α-Thy1.1脂质体分别在20小时内内化(图1C)。配体混合物中只有1mol%的α-CD45确保了67%的细胞甚至在70小时后在表面上具有α-Thy1.1/α-CD45脂质体,且5%的α-CD45确保了几乎100%的细胞在3天后具有表面脂质体。相似地,5%的α-CD45逆转了IL-2受体的快速内化并且在3天后几乎90%的细胞具有表面保留的IL-2-Fc/α-CD45脂质体。在使用10%α-CD45时,100%的细胞在表面上具有IL-2-Fc/α-CD45脂质体(图1C)。令人惊讶地,CD45的结合对T细胞是安全的,尽管事实上CD45是淋巴样细胞上最丰富的糖蛋白之一。当用IL-2-Fc脂质体孵育T细胞时,α-CD45脂质体(0.2μg/ml)的存在没有改变IL-2信号传导或影响T细胞存活和增殖(数据未显示)。
实施例2.用于有效和稳定的T细胞表面偶联的细胞因子纳米凝胶的制备和表面修饰
按照2015年4月2日公布的国际公开号WO 2015/048498 A2(按引用并入本文中)中所述的制备了细胞因子纳米凝胶(NG)。按照本文中所述的,我们对细胞因子纳米凝胶进行了进一步多修饰。一般地,将细胞因子与可逆接头(NHS-SS-NHS)化学交联以形成蛋白质的交联纳米结构,称为蛋白质纳米凝胶(NG,图2)。完成细胞因子的交联反应后,原位添加抗CD45抗体和/或聚阳离子用于修饰NG表面(图2)。合成后,对纳米凝胶进行表征,并如下进一步所述的,与载体细胞偶联。
纳米凝胶的合成
NHS-SS-NHS交联剂的合成:在125mL圆底烧瓶中,将2-羟乙基二硫化物(1.54g,10mmol)溶解于四氢呋喃中(THF,30mL,无水)中,并逐滴加入光气溶液(15mL,甲苯中15wt%,22mmol)中。将混合物在25℃下搅拌10h,接着在真空下除去溶剂。将N-羟基琥珀酰亚胺(NHS)(2.3g,22mmol)溶解于THF中(30mL,无水),并且作为一个部分加入,并随后注入无水三乙胺(1.57mL,11mmol)。将反应在40℃下进行16h。在真空下除去溶剂,并且将混合物过滤以除去沉淀物。将粗产物通过硅胶柱色谱纯化(二氯甲烷/甲醇=10/1)并用冰己烷(80mL)重结晶。将所得到的白色固体在真空下干燥(3.1g,产率71%)。1H-NMR(CDCl3,500MHz):δ4.58(t,4H),3.05(t,4H),2.84(s,8H).13C-NMR(CDCl3,500MHz):δ168.77,151.66,68.84,36.68,25.69.ESI(m/z):C14H16N2O10S2计算值,436.4[M];实测值,459.0[M+Na]+。
纳米凝胶装配
人IL-15Sa纳米凝胶:将NHS-SS-NHS(93.5μg,0.214μmol)溶解于9.35μL DMSO中,加入IL-15Sa(ALT-803(1320μg,0.0143μmol),Altor BioScience Corporation(Miramar,FL,USA.)。还参见US2014/0134128和Cytokine 2011,56,804-810)溶液中。将混合物在25℃下旋转30min,接着添加1188μL PBS缓冲液。对于并入CD45靶向抗体的纳米凝胶,31.7μlPBS缓冲液中的抗-CD45(215μg,0.0014μmol)然后添加到稀释的溶液中。使用抗小鼠CD45RB(克隆:MB23G2:购自BioXCell(West Lebanon,NH,USA))或抗人CD45(克隆:MEM-28,购自Abcam(剑桥,英国))。将反应混合物在25℃下再旋转30min。不含抗CD45的IL-15Sa-NG的制备是相似的,除了抗CD45由35.8μL PBS缓冲液中的永久性接头NH2-PEG10k-NH2(715μg,0.0715μmol)(Laysan Bio:Arab,AL,USA)替代。替代NHS-SS-NHS,使用永久性接头双(磺基琥珀酰亚胺基)基质(Thermo Fisher Scientific,Waltham,MA,USA)制备不可降解的NG(例如,aCD45/IL-15Sa-NG(不可降解的))。
其他蛋白质纳米凝胶:使用相似的蛋白质浓度和相同的交联剂/蛋白质摩尔比来制备IL-2-Fc蛋白质NG。IL-2-Fc是与小鼠IgG2a骨架连接的鼠野生型IL-2的C-末端的二价融合蛋白。按照之前所述的(J Controlled Release 2013,172,426-435)制备了IL-2Fc。还如上所述使用相似的蛋白质浓度和相同的交联剂/蛋白质摩尔比,制备了牛血清白蛋白(BSA)(Sigma-Aldrich,St Louis,MO,USA)和人IgG(Jackson Immuno Research Labs,WestGrove,PA,USA)纳米凝胶对照。随后在Amicon离心过滤器(分子量截留=100kDa,Millipore,Billerica,MA,USA)中用PBS(1.5mL×3)洗涤所得到的NG。例如,在小鼠IL-2Fc纳米凝胶的制备中,将溶解于10.8μL DMSO中的可逆二硫化物交联剂(107.9μg,0.247μmol)加入165μL PBS缓冲液中的IL-2-Fc(1650μg,0.0165μmol)溶液中。将混合物在室温(rt)下旋转30min,接着加入1485μL PBS缓冲液。然后将43μL PBS缓冲液中的抗CD45(247.5μg,0.0016μmol)加入稀释的溶液中。将反应混合物在室温下再旋转30min。用MilliporeAmocin超离心过滤器(分子量截留=100,000Da)收集所得到的IL-2-Fc NG,并用PBS洗涤(1.5mL×3)。用Nanodrop(A280)测定了IL-2-Fc NG的终浓度。在使用前,将纯化的IL-2-FcNG在4℃下储存在PBS中。不含抗CD45的IL-2Fc纳米凝胶的制备是相似的,除了抗CD45由35.8μL PBS缓冲液中的永久性接头NH2-PEG10k-NH2(715μg,0.0715μmol)(Laysan Bio:Arab,AL,USA)替代。
纳米凝胶的聚赖氨酸修饰
为了将更多的NG富集至T细胞表面上,在载体细胞偶联前,将聚阳离子(例如,聚乙二醇-b-聚赖氨酸(PEG-PLL))原位加入一些样品中。例如,将新制得的抗CD45/IL-15Sa-NG溶液稀释至1μg/μL,接着在以下所述的T细胞偶联前,加入43.6μL PBS中的聚乙二醇-b-聚赖氨酸(PEG5K-PLKC200,19μg,0.0005μmol,或者43.6μg,0.0011μmol)(Alamanda Polymers,Huntsville,AL,USA)。然后将混合物在25℃下旋转30min,并且无进一步纯化而使用。
NG的荧光和生物素标记
为了制备荧光标记的NG,用Alexa Fluor 647NHS酯(Thermo Fisher Scientific)将细胞因子载荷进行荧光标记,并用Amicon超离心过滤器(分子量截留50kDa)纯化。按照以上所述的相同程序,将荧光细胞因子与未标记的细胞因子混合(10mol%标记的细胞因子)用于制备荧光NG。对于生物素化NG的制备,将溶解于9.35μL DMSO中的NHS-SS-NHS(93.5μg,0.214μmol)加入132μL PBS缓冲液中的IL-15Sa(1320μg,0.0143μmol)溶液中。将混合物在25℃下旋转20min,接着加入7.5μL DMSO中的EZ-Link NHS-LC-LC-生物素(40.6μg,0.072μmol,Thermo Fisher Scientific)。将混合物在25℃下再旋转20min,并且随后用1188μLPBS缓冲液稀释,接着加入31.7μL PBS缓冲液中的抗CD45(215μg,0.0014μmol)。其余的程序与以上所述的相同。
NG与载体细胞的偶联
在典型的实验中,将950μL PBS中用Alexa Fluor 647标记的aCD45/IL-15Sa-NG(950μg,0.010μmol)加入475μL HBSS中的小鼠CD8+T细胞(95×106)中,接着在37℃下孵育1h。通过在800×g下离心5min收集具有表面偶联的NG的T细胞,用PBS洗涤(1.0mL×2),并以所需浓度重悬浮于缓冲液或培养基中用于体外或体内研究。对于总NG偶联的测量,将荧光标记的NG与T细胞偶联,并且收集上清液,并使用平板阅读器(TecanM1000PRO),在640/680的激发/发射波长下测量荧光强度。使用从NG储液连续稀释制得的标准曲线,将荧光读数转化成NG浓度。通过从总的添加量中减去未结合的NG来计算偶联的NG的量。通过改变用于偶联的加入细胞中的NG质量来控制每细胞的NG加载量。对于缺少抗CD45的NG与T细胞的缀合,首先用磺基琥珀酰亚胺4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯(218μg,0.50μmol)或双(磺基琥珀酰亚胺)基质(286μg,0.50μmol)激活PBS(950μL)中的IL-15Sa-NG(950μg,0.010μmol),用Amicon超离心过滤器(分子量截留50kDa)收集并用PBS洗涤(1.5mL×3),并随后加入475μL HBSS中的CD8+T细胞(95×106)中,接着在37℃下孵育1hr。相似地洗涤并收集细胞。如上所述相似地测定了缀合NG的量。含有或不含抗人CD45的NG与人CD8+T细胞的偶联按照以上所述的相似程序。使用从外周血单核细胞分离的抗CD3/CD28激活的人CD8+T细胞进行了相似的分析。
与未修饰的NG相比,修饰的细胞因子NG对于T细胞偶联显示出较高的效率(表1-3)。滴定偶联反应中添加的PEG-PLL的量,并且发现随着添加的PEG-PLL的量增加,偶联效率提高的趋势(表1)。出乎预料地,当仅0.05当量PEG-PLL加入具有略有增加的颗粒大小(180.0±2.8nm)的IL-2-Fc NG时,与未修饰的NG的13.2%的偶联效率相比,与T细胞的偶联效率可以提高至40.4%。4.04μg/1×106细胞的NG的表面密度是容易获得的,这允许细胞因子药物对过继转移的T细胞的高负载而用于延长的扩增和抗癌活性。由于不同的偶联效率,获得了具有不同的IL-2-Fc NG表面密度的T细胞,这用流式细胞术得到了证实(数据未显示)。使用人IL-15Sa NG进行了相似的研究。当将0.05当量PEG-PLL加入人IL-15Sa NG时,获得了77.0%的偶联效率(表2)。也获得了具有不同人IL-15Sa NG表面密度的T细胞,并用流式细胞术得到了证实(数据未显示)。
表1.聚阳离子提高了小鼠IL-2-Fc纳米凝胶在T细胞表面上的偶联效率。纳米凝胶含有固定量的CD45与IL-2Fc(1:10摩尔)。[a]就在偶联反应前,将不同量的PEG-PLL与小鼠IL-2-Fc纳米凝胶混合;[b]添加PEG-PLL后,用动态光散射测量了纳米凝胶的大小;[c]偶联效率=缀合的纳米凝胶/添加到T细胞的总纳米凝胶;[d]基于纳米凝胶的进料量(5μg/100,000个细胞)和偶联效率计算表面结合的纳米凝胶的量。
表2.聚阳离子提高了人IL-15Sa纳米凝胶在T细胞表面上的偶联效率。纳米凝胶含有固定量的CD45与IL-15Sa(1:10摩尔)。[a]就在结合反应前,将不同量的PEG-PLL与人IL-15Sa纳米凝胶混合;[b]添加PEG-PLL后,用动态光散射测量纳米凝胶的大小;[c]偶联效率=缀合的纳米凝胶/添加至T细胞的总纳米凝胶;[d]基于纳米凝胶的进料量(5μg/100,000个细胞)和偶联效率,计算表面结合的纳米凝胶的量。
表3.用抗CD45和PEG-PLL表面修饰之前和之后IL-15Sa-NG的流体动力学大小和ξ-电位。
为了评价静止在激活的小鼠T细胞上的蛋白质纳米凝胶的TCR信号传导反应性,我们使用以下实验方案进行分离。将来自C57Bl/6或pmel-1Thy1.1+小鼠(JacksonLaboratory)的脾通过70-μm细胞研磨器研磨,并通过用ACK裂解缓冲液(2mL/脾)在25℃下孵育5min除去红细胞。分别使用EasySepTM小鼠CD4+或CD8+T细胞富集试剂盒(StemcellTechnologies,温哥华,加拿大)通过磁性负向选择直接从脾细胞分离静息CD4+或CD8+T细胞。对于激活的CD8+T细胞,用PBS洗涤脾细胞,随后在含有10% FCS、con-A(2μg/mL)和IL-7(1ng/mL)的RPMI 1640培养基中在37℃下培养用于激活。孵育2天后,通过Ficoll-PaguePlus梯度分离除去死细胞,并使用EasySepTM小鼠CD8+T细胞富集试剂盒分离CD8+T细胞。将纯化的CD8+T细胞以1.5×106/mL重悬浮于含有10ng/mL重组鼠IL-2的RPMI中。24h后,将细胞在PBS中洗涤3次,并重悬浮于缓冲液或培养基中用于体外和体内研究。
还分离了人CD8+T细胞用于平行实验。总的外周血单核细胞(PBMC)获自健康供体(New York Blood Center,Long Island City,NY,USA)。使用RosetteSepTM人CD8+T细胞富集混合物(Stemcell)直接分离静息CD8+T细胞。在人IL-2(50UI/mL)的存在下,在抗人CD3(2.5μg/mL)和抗人CD28(1.0μg/mL)涂覆的非组织培养平板中激活人CD8+T细胞2天。将细胞在PBS中洗涤3次,并重悬浮于缓冲液或培养基中用于体外研究。
使用含有WST-1和电子耦合试剂的商业WST-1分析试剂盒(Roche,巴塞尔,瑞士)测定了T细胞表面还原活性。将来自C57Bl/6小鼠的静息或伴刀豆球蛋白A(con-A)激活的CD8+T细胞以1×106/mL悬浮于Hnak’s平衡盐溶液(HBSS)中。将商业WST-1试剂混合物(10μL)加入T细胞悬浮液中(200μL)。将细胞在37℃下孵育1h。在孵育过程中,针对450nm下提高的吸光度,用平板阅读器(TecanM1000PRO,Tecan,/>瑞士)测量了WST-1甲臜产生率。对于响应于TCR触发的细胞表面还原的测量,静息或con-A激活的CD8+T细胞在IL-7(1ng/mL)的存在下用抗CD3/CD28包被的珠(1:1细胞:珠比例)或gp100肽(10μg/mL)在37℃下孵育24h。将细胞洗涤并重悬浮于HBSS中(1×106/mL),并在37℃下孵育1h后,用相同的商业WST-1试剂混合物测量表面还原。
与静息T细胞相比,激活的CD8+T细胞显示出明显升高的细胞表面还原率,如通过WST-1分析测量的(图3A)。用抗原或抗CD3/CD28包被的珠刺激后,T细胞表面氧化还原活性进一步提高。我们推断使用与T细胞质膜结合的还原反应性纳米颗粒,T细胞表面处提高的氧化还原活性可以用于获得抗原触发的佐剂蛋白释放。因此,设计了二硫化物交联剂以响应于T细胞表面处的还原条件而切割,接着通过自分解(self-immolative)反应释放未加合(un-adducted)的蛋白质载荷。我们聚焦于有前景的治疗性细胞因子载荷。将激活的pmel-sCD8+T细胞与抗CD45/细胞因子-或仅细胞因子-生物素化NG缀合,孵育所示的时间段,接着用抗生物素蛋白链菌素染色用于通过流式细胞术的细胞表面NG的分析。使用纳米凝胶表面上的抗CD45,IL-2-Fc NG和IL-15Sa NG显示出T细胞表面上提高的偶联。从纳米凝胶的细胞因子释放也在预期分子量下发生,表示没有残余化学基团的完整细胞因子。
此外,用抗CD3/CD28珠刺激细胞时,与人激活T细胞偶联的抗CD45 NG也快得多地释放蛋白质(图3B)。结果令人惊讶地显示出表面修饰的抗CD45和聚阳离子,细胞因子NG可以有效地与T细胞表面偶联并稳定地锚定在T细胞表面上,使得能够在体外实现TCR反应性的蛋白质载荷释放。
实施例3.细胞因子纳米凝胶在体外和体内促进效应T细胞扩增
进行了T细胞的体外增殖分析以确定抗CD45对T细胞扩增的作用。用羧基荧光素琥珀酰亚胺酯(CFSE)标记天然pmel-1CD8+T细胞,并随后如上所述分别与aCD45/IL-15Sa-NG、IL-15Sa-NG或aCD45/IL-15Sa-NG(非降解的)缀合。在除去未结合的NG后,将T细胞重悬浮于含有10% FCS的RPMI中(5.0×105/mL)并以1:2珠:T细胞比率加入抗CD3/CD28包被的珠中。在对照组中,以等同剂量将游离IL-15Sa加入细胞中(脉冲的或连续的)。每3天替换细胞培养基,并且在连续处理组中补充游离IL-15Sa。在选定的时间点,与计数的珠一起加入重复的T细胞,并用流式细胞分析缓冲液(含有2%FCS的PBS)洗涤,接着aqua活/死染色。使用抗体针对表面标志物(CD8、CD122)将细胞染色,接着用胞内固定&透化缓冲剂套盒(eBioscience)固定和透化。细胞随后针对pSTAT5和Ki67进行细胞内染色,并用流式细胞仪(BD Canto,BD Biosciences)分析。
与用抗CD3/CD28珠刺激的T细胞偶联的抗CD45/IL-15Sa-NG的大量增殖,在5天中扩增了~100倍,比用相同总量的游离IL-15Sa脉冲1hr的T细胞多得多。NG偶联的T细胞也比用游离IL-15Sa连续培养的细胞更多地扩增,表明NG的细胞表面定位增强了受体啮合(图4)。纳米凝胶与T细胞共价连接而不是通过抗CD45(IL-15Sa-NG)连接,并且用非降解交联剂形成的NG(aCD45/IL-15Sa-NG(非降解的))比氧化还原反应性的aCD45/IL-15Sa-NG刺激较弱的T细胞扩增(图4);因此,延长的细胞表面保留以及细胞因子从NG的释放对于最大刺激都是重要的。在低至~30ng IL-15Sa/106细胞的剂量下,NG增强了T细胞对抗CD3/CD28珠的增殖性反应。IL-15Sa-偶联的T细胞维持IL-15Rβ(CD122)的大致恒定的水平,并且在培养物中维持T细胞的刺激至少一周,如通过9天中升高的pSTAT5和Ki67水平所证明的。CD45抑制剂的添加没有改变对NG的增殖性反应,暗示NG锚定没有触发抑制性CD45磷酸酶活性。因此,IL-15Sa NG背包(backpack)在TCR激活的存在下提供了持续且有效的T细胞刺激。
这可能是由于以下的综合效应:(1)IL-15Sa/α-CD45 NG的延长的表面保留,因此在内化之前释放更多的IL-15Sa,和(2)增强的细胞因子纳米凝胶在细胞表面的负载,因此细胞表面上增强的IL-15Sa载荷,因为额外的锚CD45促进了IL-15Sa/α-CD45 NG的结合。
为了测定IL-Sa/抗CD45 NG对带有肿瘤的小鼠中的T细胞扩增的体内作用,使用了同系B16F10黑素瘤小鼠模型(Proc.Natl.Acad.Sci.U.S.A.,2004,101,1969-1974)。在第0天在C57Bl/6小鼠的侧腹中皮下(s.c.)注射B16F10黑素瘤细胞(美国组织培养物保藏中心(Manassas,VA,USA))(5×105)。肿瘤接种后6天,动物通过全身照射(5Gy)亚致死地消耗淋巴细胞。在第7天,静脉内(i.v.)单独地或与表面结合的NG一起施用200μl PBS中激活的pmel-1CD8+T细胞(1.0×107)。处理组包括单独的T细胞、T细胞接着全身性注射游离IL-15Sa(40ug)和与抗CD45IL-15Sa-NG(40ug)偶联的T细胞。每两天测量肿瘤面积(2个测量的正交直径的乘积)和体重。为了监控体内T细胞扩增和功能,在第14天处死小鼠用于尸检和流式细胞术分析,除非体重减轻超过给药前体重的20%,或肿瘤面积达到150mm2(作为预定终点),或动物在小鼠安乐死的时间点已经变得奄奄一息。
将腹股沟淋巴结(远端或肿瘤引流淋巴结)和脾通过70μm细胞筛研磨。然后用ACK裂解缓冲液(2mL/脾)在25℃下裂解脾细胞5min以除去红细胞。用ACK裂解缓冲液(1mL×2)在25℃下裂解血液样品(200μL)5min。将肿瘤称重并通过70μm细胞筛研磨。所有细胞与计数的珠一起加入并用流式细胞术缓冲液(含有2% FCS的PBS)洗涤,接着aqua活/死染色。细胞使用抗体针对表面标志物(CD8、Thy1.1、CD4、NK1.1)进行染色,接着用Cytofix/Cytoperm(BD Biosciences)固定和透化。随后将细胞针对Ki67进行细胞内染色。用FACS缓冲液洗涤后,将细胞重悬浮于FACS缓冲液中,并通过流式细胞术分析。对于细胞内细胞因子染色,用gp100肽(10μg/mL)在37℃下孵育单细胞悬浮液中的样品2h,接着添加布雷菲德菌素(brefledin)A(eBioscience,San Diego,CA,USA),并再孵育4h。如上所述表面染色后,以相同的方式将样品固定和透化,并且用抗IFN-γ、TNF-α和IL-2的抗体染色。使用BD Fortessa(BD Biosciences)进行了流式细胞术分析,并且使用FlowJo软件(Tree Star,Oregon,USA)进行了数据分析。
通过游离全身性IL-15Sa辅助的ACT导致血液中转移的pmel-1T-细胞和内源性T细胞的实质性扩增(图5A),以及全身性循环中扩增的NK细胞和CD4+T细胞。全身性IL-15Sa还扩增了肿瘤引流淋巴结(TDLN)和肿瘤中的内源性T细胞(数据未显示)(图5B)。相反,作为背包递送的IL-15Sa扩增了转移的CD8+T细胞,但没有在任何区室中扩增内源性T细胞(图5A-5B)。在肿瘤中,我们预期抗原识别加速IL-15Sa从NG释放的情况中,在可溶性IL-15Sa辅助的组中,IL-15Sa-偶联的T细胞比pmel-1细胞扩增多16倍,比没有细胞因子支持的T细胞多1000倍(图5B)。按预期递增的抗原浓度的顺序(血液<远端LN<TDLN<肿瘤)将组织分级,我们观察到了在NG组vs.游离IL-15Sa辅助的组中的ACT细胞的相应增加的ACT T细胞计数的比率(图5C)。肿瘤中背包的T细胞也增殖并且产生效应细胞因子(图5D-5E)。即使在高剂量的IL-15Sa/抗CD45 NG下,仍然没有造成毒性(例如:57ug/小鼠),而全身性IL15Sa引起了体重的明显下降(18%)。纳米凝胶IL-15Sa递送因此将细胞因子作用集中于转移的T细胞上,并且优先在体内带有抗原的微环境中而没有毒性作用。
实施例4.通过纳米凝胶背包的细胞因子递送扩大了用于辅助细胞因子疗法的治疗窗口
使用了上述的同系B16F10黑素瘤小鼠模型,然而处理组如下。动物接受了PBS、仅T细胞、T细胞接着不同剂量的作为单剂量(过继性转移后立即)或分成多个剂量(第7、10、13和16天)的iv.注射的游离IL-15Sa或与不同剂量的抗CD45/IL-15Sa NG偶联的T细胞的假注射。随着时间分析体重和全身性细胞因子、趋化因子和肝酶水平。将相对体重针对第7天的体重标准化。在第14天,通过细胞内细胞因子染色和流式细胞术分析了血液中的细胞因子+内源性CD8+T细胞和ACT CD8+T细胞的计数。从第17天收集的样品测量了血清细胞因子水平和肝酶,或在由于毒性将动物安乐死时测量。使用细胞计数珠阵列(CBA)小鼠炎症试剂盒(BD Biosciences)测量了细胞因子水平。还将血清样品发送至IDEXX Reference实验室用于丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)的分析。数据表示平均±s.e.m.(n=5/组)并且与对照组(仅T细胞)比较用于统计学分析。通过One-Way ANOVA和Tukey’s检验,*,p<0.05;**,p<0.01;***,p<0.001;n.s.,没有显著性;n.d.,不可检测。
接受游离高剂量IL-15Sa的动物在治疗后失去了相当多的体重,这提示我们随剂量和递送方式来评价IL-15Sa的毒性。接受>10μg游离IL-15Sa的动物稳定地失去体重并且最终死于致命的免疫毒性,与给药方案无关,从而在这个模型中设定最大耐受剂量(MTD)为10μg(图6A)。相反,当以T细胞结合的NG形式施用时,直到最大可获得的IL-15Sa载荷/细胞(80μg IL-15Sa/10×6T细胞,图6A),也没有观察到明显的毒性。游离IL-15Sa刺激了血液中的pmel-1和内源性T细胞的细胞因子产生,这与通过NG递送的IL-15Sa相反,其中大部分背包的和内源性T细胞在全身性循环中保持静态(图6B和6C)。在淋巴细胞充足(lymphoreplete)的动物中,>10μg的游离IL-15Sa没有引发高水平的血清细胞因子诱导(Biomaterials 2012,33,5776-5787)。然而,在这种淋巴细胞消耗的情况中,ACT与>10μg的游离IL-15Sa诱导了全身性的TNF-a(图6D)、IL-6(图6E)和IL-10(数据未显示)的细胞因子释放,以及升高的肝酶、ALT和AST(数据未显示)。相反,背包的T细胞(蛋白质纳米凝胶偶联的T细胞)直至最大可施用剂量引发基础水平的这些生物标志物。因此,T细胞结合的NG限制了全身性循环中淋巴细胞的刺激,使得能够实现显著更高的IL-15Sa给药。
为了确定由IL-15Sa-NG提供的扩大的治疗窗口的影响,按照以上相同的处理方案,我们比较了ACT与仅T细胞、T细胞和游离IL-15Sa(10μg的MTD下)或NG背包的T细胞的抗肿瘤功效。与T细胞和相同剂量的游离IL-15Sa支持相比,10μg IL-15Sa-NG组中的肿瘤生长明显延迟。然而,通过提高细胞因子-NG剂量,肿瘤抑制得到进一步实质性地增强,其中相对于用游离IL-15Sa的MTD治疗的动物,用最大80μg剂量治疗的动物显示出中值存活提高1.7倍,是这个挑战性肿瘤模型中令人印象深刻的反应。值得注意的是,尽管使用了异种(人)IL-15Sa细胞因子,在任何NG-背包-处理组中,处理后血清中没有检测到高于背景的抗-hIL-15Sa抗体。
实施例6.TCR信号传导反应性细胞因子纳米凝胶提高了人CAR T细胞疗法的功效。
作为临床中T细胞治疗的重要方式,我们验证了NG递送的细胞因子是否还可以积极地影响CAR T-细胞的功能。为此,我们在免疫缺陷NSG小鼠中的荧光素酶表达人成胶质细胞瘤模型中利用了靶向EGFR的人CAR T-细胞。使用基于西妥昔单抗的重链和轻链形成单链可变片段而设计的huEGFRscFv-BBz嵌合抗原受体(Johnson等,2015,Sci Transl Med.,7(275);US2014/0271635A1)制备CAR T-细胞,所述可变片段与人CD8α的胞外和跨膜结构域的一部分融合,接着与4-1BB和CD3ζ的胞内结构域融合。双顺反子载体还编码截短的人CD19作为选择标记,并且放置在T2A核糖体跳跃序列后面。合成编码huEGFRscFv-BBz-CAR的质粒,并且通过VectorBuilder产生慢病毒包装。分离的T细胞源自购买的白细胞分离产品,所述产品依据IRB-批准的实验方案获自去识别的健康供体。在3:1的珠-细胞比率下,用Dynabeads人T激活剂CD3/CD28(Life Technologies)刺激T细胞。将T细胞在补充了10%胎牛血清、Hepes缓冲剂(20mM)、青霉素和链霉素(1%)以及IL-2(20IU/mL)的RPMI 1640培养基中培养。珠刺激一天后,用CAR慢病毒转导T细胞(TDN)和或保持未转导(UTD),并且随后将T细胞扩增10天,并冷藏保存直至使用。证实了CAR的表面表达,并且用生物素化的人EGFR蛋白(ACRO Biosystems)定量。
为了测试NG递送的细胞因子提高CAR T-细胞功能的能力,在NSG小鼠(n=5/组)中s.c.注射表达荧光素酶的U-87MG人胶质母细胞瘤细胞(美国组织培养物保藏中心,Manassas,VA,USA)(1×106)。在第7天动物接受了人T细胞的i.v.过继性转移(2.6×106总细胞,38%用EGFR-靶向CAR(1.0×106CAR-T细胞)转导))。动物用假盐水注射、单独的CAR-T、CAR-T接着13.8μg游离IL-15Sa,或与aCD45/IL-15Sa-NG(13.8μg)偶联的CAR-T细胞处理。还测量了随着时间表达荧光素酶的U-87MG肿瘤的体内生物发光成像。产生了处理组的个体肿瘤生长曲线和存活曲线。对于肿瘤生长数据使用Two-Way ANOVA检验进行统计学分析,而对于存活曲线,使用了Log-秩检验。数据表示平均±s.e.m。*,p<0.05;**,p<0.01;***,p<0.001;n.s.,没有显著性。
与具有相同剂量的游离IL-15Sa支持的T细胞相比,10μg IL-15Sa-NG组中的肿瘤生长显著延迟(图7A)。然而,通过提高细胞因子-NG剂量,肿瘤抑制得到进一步的实质性增强(图7A),相对于用游离MTD的IL-15Sa处理的动物,用最大80μg剂量处理的动物显示出中值存活提高1.7倍。将与aCD45/IL-15Sa-NG偶联的CAR T细胞与单独的CAR T细胞或补充有等同全身剂量的游离IL-15Sa的T细胞相比。单独的106CAR-T细胞的转移对肿瘤生长和存活具有小的影响,其没有达到统计学显著性;通过添加游离IL-15Sa,反应边际性地提高(图7B和7C)。相反,NG偶联的CAR T细胞根除了5只动物中4只的肿瘤并且提高了动物存活(图7C)。因此,显示出细胞因子的aCD45/IL-15Sa-NG递送增强CAR T-细胞疗法。
为了测量血清抗体,在ACT后30天,从不同组中的处理小鼠收集血清样品。通过用单克隆抗人IL-15抗体(eBioscience)校准的标准ELISA程序测量了抗IL-15-Sa抗体的血清浓度。
*****
尽管本文中已经描述和说明了几个实施方式,但本领域普通技术人员将容易地想到用于执行所述功能和/或获得本文中所述的结果和/或一个或多个优势的各种其他装置和/或结构,并且认为每个这样的变化和/或改变在本文中所述的本发明的实施方式的范围内。更一般地,本领域技术人员将容易地认识到本文中所述的所有参数、尺寸、材料和构造表示是示例性的并且实际参数、尺寸、材料和/或构造将取决于针对其使用所述教导的特定的一种或多种应用。本领域技术人员使用不超过常规的实验将认识到或能够确定本文中所述的特定的本发明实施方式的等价方式。因此,将理解之前的实施方式只是通过举例的方式来呈现的并且在所附权利要求及其等同物的范围内,所述实施方式可以除了如特意描述和要求保护的以外实施。本发明公开内容的实施方式针对本文中所述的每个单独的特征、系统、物体、材料、试剂盒和/或方法。此外,如果这样的特征、系统、物体、材料、试剂盒和/或方法不是互相矛盾的,那么两个或多个这样的特征、系统、物体、材料、试剂盒和/或方法的任意组合包括在本发明公开内容的发明范围内。
所有定义,如本文中限定和使用的,应当理解为优先于字典定义、按引用并入的文献中的定义和/或所限定术语的普通含义。
本文中公开的所有参考文献、专利和专利申请关于每篇引用的主题按引用并入,其在一些情况中可以包括文献的全部内容。
如本文在说明书和权利要求中使用的不定冠词“一(a)”和“一个(an)”,除非明确表示相反,否则应当理解为表示“至少一个”。
如本文在说明书和权利要求中使用的短语“和/或”应当理解为如此连结的要素的“任一或两者”,即,在一些情况中结合地存在和在其他情况中分离地存在。用“和/或”列出的多种要素应当以相同方式来解释,即,如此连结的要素的“一种或多种”。除了通过“和/或”从句特意指定的要素,其他要素可以任选存在。因此,作为非限制性实例,“A和/或B”的指代结合开放式语言(如,“包含(comprising)”)使用时,在一个实施方式中,可以指仅A(任选包括除了B以外的其他要素);在另一个实施方式中,可以指仅B(任选包括除了A以外的其他要素);在再另一个实施方式中,可以指A和B两者(任选地包括其他要素);等等。
如本文在说明书和权利要求中使用的,短语“至少一个”,涉及一个或多个要素的列表,应当理解为表示选自要素列表中的任何一个或多个要素的至少一个要素,但不必定包括要素列表内特意列出的各个和每个要素中的至少一个且不排除要素列表中的任意要素组合。这一定义还允许,可以任选地存在除了短语“至少一个”所指要素列表内特意确定的要素外的要素,不管与特意确定的那些要素相关或不相关。因此,作为非限制性实例,“A和B中的至少一个”(或等同地,“A或B中的至少一个”,或等同地“A和/或B中的至少一个”)在一个实施方式中可以是指至少一个,任选包括超过一个A,不存在B(和任选包括除了B以外的要素);在另一个实施方式中,是指至少一个,任选包括超过一个B,不存在A(和任选包括除了A以外的要素);在再另一个实施方式中,是指至少一个,任选包括超过一个A,和至少一个B,任选超过一个B(和任选包括其他要素);等等。
还应当理解,除了明确相反指出,在本文中要求保护的包括超过一个步骤或行为的任何方法中,所述方法的步骤或行为的顺序不必定限于其中描述方法的步骤或行为的顺序。
在权利要求中,以及在以上的说明书中,所有连接词(transitional phrases),如“包含(comprising)”、“包括(including)”、“携带(carrying)”、“具有(having)”、“含有(containing)”、“涉及(involving)”、“容纳(holding)”、“组成(composed of)”等理解为开放式的,即,表示包括但不限于。只有转折词“由……组成(consisting of)”和“基本上由……组成(consisting essentially of)”应当分别是封闭或半封闭的连接词,如美国专利局专利审查程序指南(United States Patent Office Manual of Patent ExaminingProcedures),2111.03部分中所示的。
Claims (26)
1.一种包含归巢至肿瘤并且与包含生物活性蛋白的纳米结构偶联的有核载体细胞的组合物,其中所述载体细胞包含CD45受体并与具有结合所述CD45受体的配体的纳米结构偶联,或所述载体细胞包含带负电荷的细胞膜和所述纳米结构包含与所述细胞膜通过静电相互作用的聚阳离子表面,并且其中所述纳米结构是蛋白质纳米凝胶或脂质体。
2.权利要求1的组合物,其中所述载体细胞包含CD45受体并且与具有结合所述CD45受体的配体的纳米结构偶联。
3.权利要求2的组合物,其中所述配体是抗CD45单克隆抗体。
4.权利要求1-3任一项的组合物,其中所述载体细胞包含带负电荷的细胞膜,而所述纳米结构包含与细胞膜通过静电相互作用的聚阳离子表面。
5.权利要求4的组合物,其中所述聚阳离子是聚赖氨酸。
6.权利要求4的组合物,其中所述聚阳离子是聚乙二醇-b-聚赖氨酸(PEG-PLL)。
7.权利要求1-6任一项的组合物,其中所述纳米结构是蛋白质纳米凝胶,并且所述蛋白质纳米凝胶包含多个通过可降解接头彼此可逆地和共价地交联的生物活性蛋白。
8.权利要求7的组合物,其中所述可降解接头是包含二硫键的氧化还原反应性接头。
9.权利要求1-6任一项的组合物,其中所述纳米结构是脂质体,并且所述脂质体包含多个生物活性蛋白。
10.权利要求9的组合物,其中所述脂质体是双层间交联的多层囊泡(ICMV)或单层囊泡。
11.权利要求1-10任一项的组合物,其中所述载体细胞是T细胞、B细胞、自然杀伤(NK)细胞或造血祖细胞。
12.权利要求11的组合物,其中所述载体细胞是T细胞。
13.权利要求12的组合物,其中所述T细胞是CD8+T细胞或CD4+T细胞。
14.权利要求12的组合物,其中所述T细胞是过继转移的T细胞。
15.权利要求12的组合物,其中所述T细胞是嵌合抗原受体(CAR)T细胞。
16.权利要求1-15任一项的组合物,其中所述生物活性蛋白是抗体或细胞因子。
17.权利要求16的组合物,其中所述生物活性蛋白是抗体。
18.权利要求16的组合物,其中所述生物活性蛋白是细胞因子。
19.权利要求18的组合物,其中所述细胞因子是IL-2、IL-15或IL-15-Sa。
20.权利要求18的组合物,其中所述细胞因子是IL-15-Sa。
21.权利要求20的组合物,其中所述IL-15-Sa包括包含二聚IL-15RαSu/Fc和两个IL-15N72D分子的复合物。
22.权利要求21的组合物,其中所述二聚IL-15RαSu/Fc包含SEQ ID NO:2中列出的氨基酸序列,并且所述IL-15N72D分子包含SEQ IDNO:1中列出的氨基酸序列。
23.根据之前权利要求任一项的组合物,进一步包含药物学上可接受的载体。
24.根据之前权利要求任一项的组合物,其用作用于将生物活性蛋白递送至患有肿瘤的受试者的药物。
25.权利要求24的组合物,其中所述肿瘤是实体肿瘤。
26.一种治疗受试者的癌症的方法,包括将之前权利要求任一项的组合物施用于需要的受试者。
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WO2019084273A1 (en) | 2017-10-25 | 2019-05-02 | Actinium Pharmaceuticals, Inc. | METHODS OF ANTI-CD45-BASED LYMPHODEPPLICATION AND USES THEREOF IN COMBINATION WITH ACT-BASED ANTICANCER THERAPIES |
LU100795B1 (en) * | 2018-05-14 | 2019-11-14 | Diatron MI PLC | Immunoassay for whole blood samples |
TW202026423A (zh) * | 2018-08-24 | 2020-07-16 | 法商賽諾菲公司 | 用於實體瘤癌症的治療性rna |
JP2022500034A (ja) | 2018-09-10 | 2022-01-04 | トルク セラピューティクス, インコーポレイテッド | 抗原特異的tリンパ球ならびに抗原特異的tリンパ球を作製および使用する方法 |
KR102257394B1 (ko) * | 2019-01-16 | 2021-05-27 | 서울대학교산학협력단 | 약물 전달 시스템 및 방법 |
BR112021019471A2 (pt) * | 2019-03-29 | 2022-04-26 | Torque Therapeutics Inc | Composições imunoterapêuticas e uso das mesmas |
JP7479399B2 (ja) | 2019-05-06 | 2024-05-08 | マルコム,トーマス | 癌腫瘍に対するテーラード低免疫ナノ小胞送達系 |
KR102657743B1 (ko) * | 2019-12-30 | 2024-04-22 | (주) 테라베스트 | 나노 구조체가 부착된 면역세포 |
WO2021137611A1 (ko) * | 2019-12-30 | 2021-07-08 | (주)테라베스트 | 나노 구조체가 부착된 면역세포 |
CN112807289B (zh) * | 2021-02-09 | 2022-12-06 | 中国医学科学院生物医学工程研究所 | 基于纳米颗粒的活细胞表面改造方法及其使用的纳米颗粒 |
CN116236461A (zh) * | 2021-12-08 | 2023-06-09 | 深圳先进技术研究院 | 一种氧化还原型纳米颗粒和活细胞载体及其应用 |
US20240159764A1 (en) * | 2022-11-12 | 2024-05-16 | OneCell Diagnostics, Inc. | Compositions and methods for selective capture, purification, release and isolation of single cells |
Family Cites Families (68)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE147633T1 (de) | 1988-10-27 | 1997-02-15 | Univ Minnesota | Immunhilfsmittel aus liposome enthaltend lymphokin il -2 |
JPH03244601A (ja) | 1990-02-22 | 1991-10-31 | Masuko Suzuki | マンナンと癌細胞分化誘導体の複合体、その製法及び抗癌剤 |
US5453491A (en) | 1990-09-11 | 1995-09-26 | Kiyoshi Takatsu | Murine interleukin-5 receptor |
US6197298B1 (en) | 1991-04-19 | 2001-03-06 | Tanox, Inc. | Modified binding molecules specific for T lymphocytes and their use as in vivo immune modulators in animals |
CA2065658A1 (en) | 1991-04-19 | 1992-10-20 | Tse-Wen Chang | Conjugates of liposomes or microbeads and antibodies specific for t lymphocytes and their use in vivo immune modulators |
US5753261A (en) | 1993-02-12 | 1998-05-19 | Access Pharmaceuticals, Inc. | Lipid-coated condensed-phase microparticle composition |
US6180134B1 (en) | 1993-03-23 | 2001-01-30 | Sequus Pharmaceuticals, Inc. | Enhanced ciruclation effector composition and method |
US5464629A (en) | 1993-11-16 | 1995-11-07 | Georgetown University | Method of forming hydrogel particles having a controlled size using liposomes |
ES2267100T5 (es) | 1994-07-15 | 2011-04-08 | The University Of Iowa Research Foundation | Oligonucleótidos inmunomoduladores. |
US6056973A (en) | 1996-10-11 | 2000-05-02 | Sequus Pharmaceuticals, Inc. | Therapeutic liposome composition and method of preparation |
IN184589B (zh) | 1996-10-16 | 2000-09-09 | Alza Corp | |
US6120751A (en) | 1997-03-21 | 2000-09-19 | Imarx Pharmaceutical Corp. | Charged lipids and uses for the same |
IN190388B (zh) | 1997-10-01 | 2003-07-26 | Biomira Usa Inc | |
US6787132B1 (en) | 1997-12-04 | 2004-09-07 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Combined chemo-immunotherapy with liposomal drugs and cytokines |
US6693086B1 (en) | 1998-06-25 | 2004-02-17 | National Jewish Medical And Research Center | Systemic immune activation method using nucleic acid-lipid complexes |
US6319715B1 (en) | 2000-04-21 | 2001-11-20 | Cornell Research Foundation, Inc. | Method of enhancing the delivery of nucleic acids using silica nanoparticles |
US20020151004A1 (en) | 2000-07-24 | 2002-10-17 | Roger Craig | Delivery vehicles and methods for using the same |
WO2002076428A1 (en) | 2001-03-26 | 2002-10-03 | Alza Corporation | Liposome composition for improved intracellular delivery of a therapeutic agent |
US20030235619A1 (en) | 2001-12-21 | 2003-12-25 | Christine Allen | Polymer-lipid delivery vehicles |
ATE457733T1 (de) | 2002-05-09 | 2010-03-15 | Oncothyreon Inc | Lipid-a- und andere kohlenhydrat-liganden-analoga |
WO2004032970A2 (en) | 2002-10-10 | 2004-04-22 | Samir Mitragotri | Carriers attached to blood cells |
US8192485B2 (en) | 2002-11-13 | 2012-06-05 | The United States of America, as represented by the Department of Veterens Affairs | Reversible hydrogel systems and methods therefor |
US7435592B2 (en) | 2003-05-13 | 2008-10-14 | Immunovative Therapies, Ltd. | Compositions for allogeneic cell therapy |
US7402431B2 (en) | 2004-03-01 | 2008-07-22 | Immunovative Therapies, Ltd. | T-cell therapy formulation |
US20040247624A1 (en) | 2003-06-05 | 2004-12-09 | Unger Evan Charles | Methods of making pharmaceutical formulations for the delivery of drugs having low aqueous solubility |
US7223544B2 (en) | 2003-06-27 | 2007-05-29 | Cornell Research Foundation, Inc. | Nucleic acid-engineered materials |
US20050042298A1 (en) | 2003-08-20 | 2005-02-24 | Pardridge William M. | Immunonanoparticles |
EP1550458A1 (en) | 2003-12-23 | 2005-07-06 | Vectron Therapeutics AG | Synergistic liposomal adjuvants |
CN101031287A (zh) | 2004-03-02 | 2007-09-05 | 麻省理工学院 | 纳米细胞药物递送系统 |
AU2005326322B2 (en) | 2004-07-01 | 2009-02-05 | Yale University | Targeted and high density drug loaded polymeric materials |
TW200616604A (en) | 2004-08-26 | 2006-06-01 | Nicholas Piramal India Ltd | Nitric oxide releasing prodrugs containing bio-cleavable linker |
DE102004054536A1 (de) | 2004-11-06 | 2006-05-11 | Capsulution Nanoscience Ag | Multimodal veränderte Zellen als zellulare Darreichungsformen für aktive Substanzen und als diagnostische Zellpartikel |
US8246995B2 (en) | 2005-05-10 | 2012-08-21 | The Board Of Trustees Of The Leland Stanford Junior University | Hydrophobic nanotubes and nanoparticles as transporters for the delivery of drugs into cells |
CA2608474C (en) | 2005-05-17 | 2019-11-12 | University Of Connecticut | Compositions and methods for immunomodulation in an organism |
US20070148246A1 (en) | 2005-08-11 | 2007-06-28 | Dan Luo | Nucleic Acid-Based Matrixes |
WO2007022152A2 (en) | 2005-08-15 | 2007-02-22 | The Research Foundation Of State University Of New York | Lipid nano particulates containing antigens as cancer vaccines |
US20080267876A1 (en) | 2005-09-20 | 2008-10-30 | Yissum Research Development Company | Nanoparticles for Targeted Delivery of Active Agent |
KR101152557B1 (ko) | 2005-12-12 | 2012-09-07 | 에이씨 이뮨 에스.에이. | 치료 백신 |
US20120121688A1 (en) | 2006-01-13 | 2012-05-17 | Rinken | Preventative or therapeutic agent and method for immune disease |
BRPI0708299A2 (pt) | 2006-02-27 | 2011-05-24 | Univ Leland Stanford Junior | composições e métodos para o transporte de moléculas com propriedades melhoradas de liberação através de barreiras biológicas |
US20110177156A1 (en) | 2007-11-14 | 2011-07-21 | Szoka Jr Francis C | Sterol-Modified Amphiphilic Lipids |
JP2009149526A (ja) | 2007-12-18 | 2009-07-09 | Tokyo Medical & Dental Univ | サイトカイン−ナノゲル複合体を含む皮下注射又は筋肉内注射徐放製剤 |
WO2009134866A2 (en) | 2008-04-29 | 2009-11-05 | The Brigham And Women's Hospital, Inc. | Cell membrane engineering |
EP3936122A1 (en) | 2008-11-24 | 2022-01-12 | Massachusetts Institute Of Technology | Methods and compositions for localized agent delivery |
KR20110126166A (ko) | 2009-03-09 | 2011-11-22 | 더 리전츠 오브 더 유니버시티 오브 캘리포니아 | 장기 효과를 갖는 단백질 전달을 위한 단일 단백질 나노캡슐 |
EP2405758B1 (en) | 2009-03-09 | 2016-04-27 | Molecular Express, Inc. | Methods and compositions for liposomal formulation of antigens and uses thereof |
EA022699B1 (ru) | 2009-05-27 | 2016-02-29 | Селекта Байосайенсиз, Инк. | НАЦЕЛЕННЫЕ СИНТЕТИЧЕСКИЕ НАНОНОСИТЕЛИ С pH-ЧУВСТВИТЕЛЬНЫМ ВЫСВОБОЖДЕНИЕМ ИММУНОМОДУЛИРУЮЩИХ СРЕДСТВ |
US20100323018A1 (en) | 2009-06-17 | 2010-12-23 | Massachusetts Institute Of Technology | Branched DNA/RNA monomers and uses thereof |
US20100324124A1 (en) | 2009-06-17 | 2010-12-23 | Massachusetts Institute Of Technology | Compositions and methods relating to DNA-based particles |
BR112012011943A2 (pt) | 2009-11-18 | 2018-09-11 | Nektar Therapeutics | formas de sais de ácidos de conjugados de polímero-fármaco e métodos de alcoxilação |
US20110229556A1 (en) | 2010-03-19 | 2011-09-22 | Massachusetts Institute Of Technology | Lipid-coated polymer particles for immune stimulation |
WO2011115684A2 (en) | 2010-03-19 | 2011-09-22 | Massachusetts Institute Of Technology | Lipid vesicle compositions and methods of use |
US9149432B2 (en) | 2010-03-19 | 2015-10-06 | Massachusetts Institute Of Technology | Lipid vesicle compositions and methods of use |
US9289505B2 (en) * | 2010-08-17 | 2016-03-22 | Rutgers, The State University Of New Jersey | Compositions and methods for delivering nucleic acid molecules and treating cancer |
US20130203675A1 (en) | 2010-09-16 | 2013-08-08 | Joseph M. DeSimone | Asymmetric biofunctional silyl monomers and particles thereof as prodrugs and delivery vehicles for pharmaceutical, chemical and biological agents |
DK3327040T3 (da) * | 2010-09-21 | 2021-09-20 | Altor Bioscience Corp | Multimeriske opløselige il-15-fusionsmolekyler og fremgangsmåder til at fremstille og anvende samme |
WO2012112689A1 (en) | 2011-02-15 | 2012-08-23 | The University Of North Carolina At Chapel Hill | Nanoparticle, liposomes, polymers, agents and proteins modified with reversible linkers |
US20140037748A1 (en) | 2011-04-15 | 2014-02-06 | The Regents Of The University Of California | Redox responsive polymeric nanocapsules for protein delivery |
US9090640B2 (en) | 2011-09-02 | 2015-07-28 | Ulrich Bierbach | Targeted delivery and prodrug designs for platinum-acridine anti-cancer compounds and methods thereof |
JP2013173689A (ja) | 2012-02-24 | 2013-09-05 | Univ Of Tsukuba | 高分子化ニトロキシドラジカル化合物と非ステロイド性抗炎症薬の複合体 |
US20130337471A1 (en) * | 2012-06-14 | 2013-12-19 | Emory University | Cell identification with nanoparticles, compositions and methods related thereto |
US9149535B2 (en) | 2012-06-28 | 2015-10-06 | University Of South Carolina | Polymers and the preparation of nanogel drug cocktails |
UY35468A (es) | 2013-03-16 | 2014-10-31 | Novartis Ag | Tratamiento de cáncer utilizando un receptor quimérico de antígeno anti-cd19 |
FR3004106B1 (fr) | 2013-04-05 | 2016-08-05 | Oreal | Composition contenant des particules composites filtrant les radiations uv de taille moyenne superieure a 0,1μm et des particules d'aerogel de silice hydrophobes |
WO2014204762A1 (en) | 2013-06-19 | 2014-12-24 | Massachusetts Institute Of Technology | In vivo targeting of cells with ligand-conjugated particles |
CA2925304C (en) * | 2013-09-27 | 2023-04-18 | Massachusetts Institute Of Technology | Carrier-free biologically-active protein nanostructures |
WO2017027843A1 (en) | 2015-08-12 | 2017-02-16 | Massachusetts Institute Of Technology | Cell surface coupling of nanoparticles |
EP3468581A1 (en) * | 2016-06-13 | 2019-04-17 | Torque Therapeutics, Inc. | Methods and compositions for promoting immune cell function |
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