CN1671412B - 免疫刺激组合物及刺激免疫反应的方法 - Google Patents
免疫刺激组合物及刺激免疫反应的方法 Download PDFInfo
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Abstract
本发明提供包括与抗原部分配对的免疫反应调节剂部分的免疫刺激组合物。
Description
参考相关申请
本申请要求于2002年8月15日提交的美国临时专利申请No.60/403,846的优先权。
发明背景
免疫反应调节剂(“IRM”)包括具有有效免疫调节活性,包括但不限于抗病毒和抗肿瘤活性的化合物。某些IRM调节细胞因子的生产和分泌。例如,有些IRM化合物诱导诸如I型干扰素,TNF-α,IL-1,IL-6,IL-8,IL-10,IL-12,MIP-1,和/或MCP-1的细胞因子的生产和分泌。作为另一例子,有些IRM化合物可抑制某些TH-2细胞因子,诸如IL-4和IL-5的生产和分泌。此外,有些IRM化合物据说抑制IL-1和TNF(美国专利No.6,518,265)。
有些IRM是有机小分子(例如,分子量小于约1000道尔顿,在某些情形下小于约500道尔顿,这与生物大蛋白,肽等相反),诸如在下列美国专利中所公开的:美国专利Nos.4,689,338;4,929,624;4,988,815;5,037,986;5,175,296;5,238,944;5,266,575;5,268,376;5,346,905;5,352,784;5,367,076;5,389,640;5,395,937;5,446,153;5,482,936;5,693,811;5,741,908;5,756,747;5,939,090;6,039,969;6,083,505;6,110,929;6,194,425;6,245,776;6,331,539;6,376,669;6,451,810;6,525,064;6,545,016;6,545,017;6,558,951;和6,573,273;欧洲专利0 394 026;美国专利公布No.2002/0055517;和国际专利公布Nos.WO 01/74343;WO 02/46188;WO 02/46189;WO 02/46190;WO 02/46191;WO 02/46192;WO 02/46193;WO 02/46749WO02/102377;WO 03/020889;WO 03/043572和WO 03/045391。
小分子IRM的其他例子包括某些嘌呤衍生物(诸如公开在美国专利Nos.6,376,501和6,028,076中的那些衍生物),某些咪唑并喹啉酰胺衍生物(诸如公开在美国专利No.6,069,149中的那些衍生物),某些苯并咪唑衍生物(诸如描述在美国专利6,387,938中的那些衍生物),以及某些4-氨基嘧啶与五元含氮杂环稠合的衍生物(诸如描述在美国专利Nos.6,376,501;6,028,076和6,329,381;和WO 02/08595中的腺嘌呤衍生物)。
其他IRM包括诸如寡核苷酸序列的生物大分子。有些IRM寡核苷酸序列含有胞嘧啶-鸟嘌呤二核苷酸(CpG),并且描述在例如,美国专利Nos.6,194,388;6,207,646;6,239,116;6,339,068;和6,406,705中。有些含CpG的寡核苷酸可包括合成的免疫调节结构基元,诸如在美国专利Nos.6,426,334和6,476,000中描述的那些基元。其他IRM核苷酸序列缺乏CpG,并且描述在例如国际专利公布No.WO 00/75304中。
某些IRM可用作Toll样受体(TLR)激动剂。有些小分子IRM可通过TLRs 2,4,6,7和8中的一种或多种生效。CpG可通过TLR 9生效。
通过刺激免疫系统的有些方面,而抑制其他方面(参见,例如,美国专利Nos.6,039,969和6,200,592),IRM可用于治疗许多疾病。例如,小分子IRM咪喹莫特(imiquimod)用于治疗由人乳头瘤病毒导致的外生殖器和肛疣[参见,例如,Tomai等,Antiviral Research 28(3):253-64(1995)]。其他可利用IRM治疗的疾病的例子包括但不限于,基底细胞癌(basal cell carcinoma),湿疹,自发性血小板增生症,乙型肝炎,多发性硬化症,肿瘤病,牛皮癣,类风湿性关节炎,I型单纯疱疹,以及II型单纯疱疹。
IRM化合物也可通过调节B细胞的抗体生产而调节体液免疫。
此外,多种IRM已显示可用作疫苗佐剂(参见,例如,美国专利Nos.6,083,505和6,406,705)。
发明概述
IRM,尤其是小分子IRM和TLR 2,4,6,7和8的激动剂现已发现,当其与抗原通过化学或物理配对形成免疫刺激组合物时,在刺激免疫反应方面是令人惊奇的有效。一具体组合物的免疫刺激作用力于该组合物中同样的抗原和同样或可比的IRM以未配对形式施用的免疫调节作用。
本发明提供免疫刺激组合物,包括与抗原部分配对的免疫反应调节剂(IRM)部分。在有些实施方案中,IRM部分可以是或衍生自Toll样受体2,Toll样受体4,Toll样受体6,Toll样受体7或Toll样受体8的激动剂。在其他实施方案中,IRM部分可包括或衍生自咪唑并喹啉胺;四氢咪唑并喹啉胺;咪唑并吡啶胺;芳基醚取代的咪唑并吡啶胺;1,2-桥连的咪唑并喹啉胺;6,7-稠合的环烷基咪唑并吡啶胺;咪唑并二氮杂萘胺;四氢咪唑并二氮杂萘胺;唑并喹啉胺;噻唑并喹啉胺;唑并吡啶胺;噻唑并吡啶胺;唑并二氮杂萘胺;或噻唑并二氮杂萘胺。在其他实施方案中,IRM部分可包括或衍生自分子量小于约1000道尔顿的有机部分。抗原部分可包括氨基酸序列,核苷酸序列,脂多糖,朊病毒,细菌,病毒或真菌。
在另一方面,本发明提供刺激患者T细胞的方法。所述方法包括提供含有与抗原部分配对的免疫反应调节剂的免疫刺激组合物;让免疫刺激组合物结合至抗原呈递细胞,由此活化抗原呈递细胞;以及使活化的抗原呈递细胞刺激患者的T细胞。患者的T细胞可以在体内或体外进行刺激。
在另一方面,本发明提供刺激抗体生产的细胞的方法。所述方法包括提供含有与抗原部分配对的免疫反应调节剂部分的免疫调节组合物;以及使免疫调节组合物结合至抗体生产的细胞。抗体生产的细胞可在体内或体外进行刺激。
本发明的其他多种特征和优势参照下列详述,实施例,权利要求书和附图应容易变成一目了然。在说明书的若干地方,通过实施例目录而提供指南。在每种情况下,引用目录仅用作代表性基团,不应解释成排他性。
附图简述
图1示出了如实施例4所述的由免疫有卵清蛋白的小鼠生成的卵清蛋白特异性活化的CD8+T细胞的百分比。
图2示出了如实施例4所述的皮下免疫有IRM-卵清蛋白共轭物的小鼠生成的卵清蛋白-特异性活化的CD8+T细胞的百分比。
图3示出了如实施例4所述的腹膜内免疫有IRM-卵清蛋白共轭物的小鼠生成的卵清蛋白-特异性活化的CD8+T细胞的百分比。
图4示出了如实施例5所述的由免疫有卵清蛋白的小鼠诱导产生的干扰素-γ。
图5示出了如实施例5所述的由皮下免疫有IRM-卵清蛋白共轭物的小鼠诱导产生的干扰素-γ。
图6示出了如实施例5所述的由腹膜内免疫有IRM-卵清蛋白共轭物的小鼠诱导产生的干扰素-γ。
图7示出了如实施例6所述的在用IRM-卵清蛋白共轭物提供次级免疫后,抗原-特异性免疫反应的增加。
图8示出了如实施例7所述的在用肿瘤-特异性IRM-抗原共轭物免疫后,肿瘤大小减少。
图9示出了如实施例8所述的在用IRM-肿瘤抗原共轭物免疫后,活化的肿瘤抗原-特异性CD8+T细胞在脾脏中的扩大。
图10示出了如实施例8所述的在用IRM-肿瘤抗原共轭物免疫后,活化的肿瘤抗原-特异性CD8+T细胞在肿瘤中的扩大。
图11示出了如实施例9所述的在用卵清蛋白免疫后,正在呈递Kb/SIINFEKL的抗原呈递细胞的百分比。
图12示出了如实施例9所述的在用卵清蛋白加上非共轭的IRM免疫后,正在呈递Kb/SIINFEKL的抗原呈递细胞的百分比。
图13示出了如实施例9所述的在用IRM-卵清蛋白共轭物免疫后,正在呈递Kb/SIINFEKL的抗原呈递细胞的百分比。
图14示出了如实施例10所述的在用卵清蛋白-表达的肿瘤细胞攻击后,免疫有卵清蛋白或IRM-卵清蛋白共轭物的小鼠的生存率。
图15示出了如实施例11所述的在用卵清蛋白免疫后,抗原-特异性CD8+T细胞的扩大。
图16示出了如实施例11所述的在用IRM和卵清蛋白的胶状悬浮液免疫后,抗原-特异性CD8+T细胞在一个个体中的扩大。
图17示出了如实施例11所述的在用IRM和卵清蛋白的胶状悬浮液免疫后,抗原-特异性CD8+T细胞在第二个体中的扩大。
图18示出了抗原-特异性CD8+T细胞的扩大,作为利用两个不同IRM以IRM-抗原共轭物免疫的结果。
图19示出了免疫有多种免疫刺激组合物的小鼠在单独用卵清蛋白免疫后的CD8+T细胞的倍增。
本发明例证性实施方案的详述
本发明提供免疫刺激组合物(ISC),制备免疫刺激组合物的方法,利用免疫刺激组合物诱发免疫反应的方法,以及通过将IRM与另一免疫刺激组分(例如,抗原)配对而增强IRM的免疫刺激活性的方法。ISC可设计成引发细胞介导的免疫反应,体液免疫反应,或两者皆有。
如上所述,许多IRM可用作疫苗佐剂,以增加针对同样存在于疫苗中的一种或多种抗原而生成的免疫反应。令人惊奇的是,本发明的某些ISC比含有同样或可比的IRM和同样的抗原,但以未配对形式存在的疫苗可提供甚至更大的免疫反应。在一种情形下,ISC提供的免疫反应比由包括同样抗原和可比IRM的疫苗所生成的免疫反应高大约5倍。
如本发明所用的术语“配对”及其变体是指以某个化学或物理方式相连的组分,以致组分彼此之间不是自由分开的。例如,两个组分可以相互共价结合,以致这两个组分不能单个分离。配对也可通过例如非共价亲和结合,离子结合,亲水或疏水亲和,物理捕获等而实现。配对特异性区分于常规疫苗中抗原和佐剂的简单混合物。在简单混合物中,组分可自由地分散在免疫接种的环境内。如本发明所用,“配对”及其变体的理解是,配对的组分免疫后维持化学或物理连接。
免疫反应调节剂部分可以是或衍生自任何合适的IRM。合适的IRM包括有机小分子,即分子量小于约1000道尔顿的分子,尽管在有些实施方案中,IRM的分子量小于约700道尔顿,而在有些情形下,IRM的分子量为约500道尔顿到约700道尔顿。合适的IRM还包括TLR2,4,6,7,8和9中的一种或多种的激动剂。在有些实施方案中,合适的IRM包括但不限于上述的小分子IRM化合物及其衍生物。合适的小分子IRM具有与五元含氮杂环稠合的2-氨基吡啶,包括但不限于咪唑并喹啉胺,包括但不限于酰胺取代的咪唑并喹啉胺,磺胺取代的咪唑并喹啉胺,尿素取代的咪唑并喹啉胺,芳基醚取代的咪唑并喹啉胺,杂环醚取代的咪唑并喹啉胺,氨基醚取代的咪唑并喹啉胺,亚磺酰氨基醚取代的咪唑并喹啉胺,尿素取代的咪唑并喹啉醚,以及硫醚取代的咪唑并喹啉胺;四氢咪唑并喹啉胺,包括但不限于酰胺取代的四氢咪唑并喹啉胺,磺胺取代的四氢咪唑并喹啉胺,尿素取代的四氢咪唑并喹啉胺,芳基醚取代的四氢咪唑并喹啉胺,杂环醚取代的四氢咪唑并喹啉胺,氨基醚取代的四氢咪唑并喹啉胺,亚磺酰氨基醚取代的四氢咪唑并喹啉胺,尿素取代的四氢咪唑并喹啉醚,以及硫醚取代的四氢咪唑并喹啉胺;咪唑并吡啶胺,包括但不限于酰胺取代的咪唑并吡啶胺,亚磺酰氨基取代的咪唑并吡啶胺,尿素取代的咪唑并吡啶胺;芳基醚取代的咪唑并吡啶胺,杂环醚取代的咪唑并吡啶胺,氨基醚取代的咪唑并吡啶胺,亚磺酰氨基取代的咪唑并吡啶胺,尿素取代的咪唑并吡啶醚,以及硫醚取代的咪唑并吡啶胺;1,2-桥连的咪唑并喹啉胺;6,7-稠合的环烷基咪唑并吡啶胺;咪唑并二氮杂萘胺;四氢咪唑并二氮杂萘胺;唑并喹啉胺;噻唑并喹啉胺;唑并吡啶胺;噻唑并吡啶胺;唑并二氮杂萘胺;以及噻唑并二氮杂萘胺。
其他合适的小分子IRM包括某些嘌呤衍生物,某些咪唑并喹啉酰胺衍生物,某些苯并咪唑衍生物,以及上述4-氨基嘧啶与五元含氮杂环稠合的某些衍生物(如腺嘌呤衍生物)。
其他合适的IRM包括CpG和其他缺乏上述CpG的IRM核苷酸序列。
抗原部分可包括提升细胞介导的免疫反应,体液免疫反应或两者的任何材料。合适的抗原材料包括但不限于肽;多肽;脂质;糖脂;多糖;碳水化合物;多核苷酸;朊病毒s;活的或灭活的细菌,病毒或真菌;以及细菌,病毒,真菌,原生动物,肿瘤衍生或生物体衍生的免疫原,毒素或类毒素。
本发明的免疫刺激组合物可用于治疗的疾病包括但不限于:
(a)病毒性疾病,诸如生殖器疣,流行性疣,脚底疣,乙肝,丙肝,I型和II型单纯疱疹病毒,传染性软疣(molluscum contagiosum),天花,HIV,CMV,VZV,鼻病毒,腺病毒,冠状病毒,流感,副流感;
(b)细菌性疾病,诸如肺结核,鸟分支杆菌(mycobacteriumavium),麻风病;
(c)其他传染性疾病,诸如真菌疾病,衣原体,假丝酵母,曲霉菌,隐球菌性脑膜炎(cryptococcal meningitis),卡氏肺囊虫(pneumocystis carnii),隐孢子虫病(cryptosporidiosis),组织胞浆菌病(histoplasmosis),弓形虫病(toxoplasmosis),锥体虫感染,利什曼病;
(d)瘤性疾病,诸如上皮内瘤形成,宫颈发育不良,光化性角化症(actinic keratosis),基底细胞癌(basal cell carcinoma),鳞状细胞癌,发状细胞白血病(hairy cell leukemia),Karposi氏肉瘤,黑素瘤,肾细胞癌,骨髓性白血病(myelogeous leukemia),多发性骨髓瘤(multiplemyeloma),非Hodgkin氏淋巴瘤,皮肤T-细胞淋巴瘤,以及其他癌症;
(e)TH-2介导的遗传性过敏症和自身免疫疾病,诸如,遗传性过敏皮炎或湿疹,嗜曙红细胞增多,哮喘,过敏,过敏性鼻炎,全身性红斑狼疮,自发性血小板增生症,多发性硬化症,Ommen氏综合症,盘状狼疮,斑秃(alopecia areata),抑制瘢痕瘤形成和其他类型的疤痕,以及增加伤口愈合,包括慢性伤口;以及
(f)作为疫苗佐剂,与任何提升下列体液和/或细胞介导的免疫反应的材料结合使用,诸如活病毒和细菌性免疫原,和灭活病毒,肿瘤衍生的,原生动物,生物体衍生的,真菌和细菌性免疫原,类毒素,毒素,多糖,蛋白,糖蛋白,肽,细胞疫苗,DNA疫苗,重组蛋白,糖蛋白,和肽等与下列病毒组合使用,例如BCG,霍乱,瘟疫,伤寒,甲肝,乙肝和丙肝,流感A和B,副流感,小儿麻痹,狂犬病,麻疹,腮腺炎,风疹,黄热病,破伤风,白喉,B型流感嗜酸杆菌感染,肺结核,脑膜炎球菌疫苗和肺炎球菌疫苗,腺病毒,HIV,水痘,细胞巨化病毒,登革热,猫科白血病,禽流感,HSV-1和HSV-2,猪霍乱,日本脑炎,呼吸道合胞病毒,轮状病毒,乳头瘤病毒,和黄热病。
本发明的免疫刺激组合物包括有效量的生物活性的免疫反应调节剂部分和抗原部分。有效量的生物活性的免疫反应部分(“IRM活性”)包括一种或多种下列活性:增加T细胞产生细胞因子,活化特异于抗原的T细胞,以及活化树突细胞。有效量的生物活性的抗原部分(“抗原活性”)包括一种或多种下列活性:B细胞生成特异于抗原的抗体以及生成呈递抗原的抗原呈递细胞。本发明的免疫刺激组合物可与药用载体,一种或多种赋形剂,或前述化合物相组合从而形成药物组合物。
尽管活性化合物用于本发明药物组合物中的实际量会随本领域专业人员公知的因素而发生变化,这些因素诸如免疫刺激组合物的物理和化学性质,载体的性质,个体免疫系统的性质(例如,抑制,受损,刺激),以及想要的服药方案,可以预期本发明的药物组合物会含有足够的免疫反应调节剂部分以给个体提供剂量为约100ng/kg-约50mg/kg,优选约10μg/kg-约5mg/kg的IRM。
可采用多种不同的剂型,诸如片剂,锭剂,胶囊,肠胃外制剂,糖浆,乳剂,药膏,气溶胶,经皮贴片,经粘膜贴片等。
本发明的药物组合物在治疗方案中可以单一治疗剂施用,或药物组合物可与另一药物组合物或与其他活性剂,包括其他的免疫反应调节剂,抗病毒素,抗生素,抗体,蛋白,肽,寡核苷酸等组合施用。
在有些实施方案中,免疫刺激免疫反应调节剂部分可共价结合至抗原部分而形成免疫刺激共轭物。如本发明所用,“共价结合”是指专门通过共价键直接或间接偶联两个组分。直接共价偶联可包括免疫反应调节剂部分的原子和抗原部分的原子之间的直接共价结合。此外,共价偶联的发生可通过共价连接至IRM部分,抗原部分或两者的连接基团进行,这促进了IRM部分和抗原部分的共价偶联。非直接共价偶联可包括第三组分,诸如,免疫反应调节剂部分和抗原部分被分开与之共价连接的固相支持物。同样,“共价偶联”与“共价连接”交互使用。
免疫刺激共轭物可包括免疫反应调节剂部分作为IRM部分和含抗原的部分作为抗原部分。当合成免疫刺激共轭物时,免疫反应调节剂部分,连接基团,以及含抗原部分可分别加以选择,从而所得的免疫刺激共轭物具有有效量的IRM活性和有效量的抗原活性。
连接基团可以是任何合适的有机连接基团,只要其能使含抗原部分与免疫反应调节剂部分共价偶联,同时保留有效量的IRM活性和抗原活性。在有些实施方案中,连接基团的选择要考虑到在免疫反应调节剂部分的活性核心与含抗原部分之间有足够的空间,使得含抗原部分不会干扰活性核心和T细胞之间的生物有效相互作用,从而导致IRM活性,诸如细胞因子产生。
连接基团包括能够与抗原反应形成共价键的反应基。合适的反应基包括在下列文献中所述的那些基团:Hermanson,G.(1996),Bioconjugate Techniques,Academic Press,第2章,“反应性官能团的化学(The Chemistry of Reactive Functional Groups)”,137-166。例如,连接基可以与伯胺(例如,N-羟基琥珀酰亚胺基酯(N-hydroxysuccinimidylester)或N-羟基硫代琥珀酰亚胺基酯(N-hydroxysulfosuccinimidyl ester))反应;其可与巯基(例如,马来酰亚胺或碘代乙酰基)反应,或者其可以是光反应基(例如,苯基叠氮化物,包括4-叠氮基苯基,2-羟基-4-叠氮基苯基,2-硝基-4-叠氮基苯基,以及2-硝基-3-叠氮基苯基)。
易与连接基团接近进行共价偶联的化学反应基包括可直接用于共价偶联至连接基团的基团,或者被改性后可用于共价偶联至连接基团的基团。例如,合适的化学反应基包括但不限于伯胺和巯基。由于某些含抗原部分,例如蛋白和其他肽,可包括多个化学反应基,因此本发明的某些ISC可包括多个与特定的含抗原部分共轭的IRM部分。
制备免疫刺激共轭物的方法
本发明的免疫刺激共轭物的通用制备方法如下:将免疫反应调节剂与交联剂反应,然后使所得中间体与抗原反应。许多适于制备生物共轭物的交联剂是公知的,并且许多可商购。参见例如,Hermanson,G.(1996)Bioconjugate Techniques,Academic Press。
本发明的免疫刺激共轭物也可例如,根据反应路线I中所示的方法进行制备,在反应路线I中,含抗原部分通过R1连接至IRM部分。在反应路线I的步骤(1)中,式III化合物与式IV杂双官能交联剂反应生成式II化合物。RA和RB分别含有被选择与其他官能团反应的官能团。例如,如果RA含有伯胺,则可选择杂双官能交联剂,其中RB含有胺反应性官能团,诸如,N-羟基硫代琥珀酰亚胺基酯。可选择RA和RB,它们反应后可在共轭物中提供所需的连接基团。
制备其中RA含有官能团的式III化合物的方法是公知的。参见,例如,U.S.专利Nos.4,689,338;4,929,624;U.S.专利No.5,268,376;5,389,640;5,352,784;5,494,916;4,988,815;5,367,076;5,175,296;5,395,937;5,741,908;5,693,811;6,069,149;6,194,425;和U.S.专利6,331,539以及国际公布WO 00/76505;WO 00/76518;WO 02/46188,WO 02/46189;WO 02/46190;WO 02/46191;WO 02/46192;WO02/46193;和WO 02/46194。
许多杂双官能交联剂是公知的,并且许多是可商购的。参见例如,Hermanson,G.(1996),Bioconjugate Techniques,Academic Press,第5章,“杂双官能交联剂(Heterobifunctional Cross-Linkers)”,229-285。反应的实施通常是将式III化合物的合适溶剂,诸如N,N-二甲基甲酰胺的溶液与式IV杂双官能交联剂的合适溶剂,诸如N,N-二甲基甲酰胺的溶液混合。反应可在室温下进行。接着采用常规技术可对式II产物加以分离。
在反应路线I的步骤(2)中,将含有反应基ZA的式II化合物与抗原发应,以提供式I的免疫刺激共轭物。反应的实施一般是将式II化合物的合适溶剂,诸如二甲基亚砜的溶液与抗原的合适缓冲液,诸如PBS的溶液混合。反应可在室温或低温(约4℃)下进行。如果ZA是光反应基,诸如苯基叠氮化物,则反应混合物将暴露于长波UV光足够长的时间以实现交联(例如,10-20分钟)。每个抗原部分的免疫反应调节剂部分的平均数可通过调节反应中所用的式II化合物的量来进行控制。采用常规技术,式I免疫反应共轭物可加以分离和纯化。
反应路线I
此外,无需利用杂双官能交联剂,可合成式II化合物。只要式II化合物含有反应基ZA,利用上述步骤(2)中的方法,其就可与抗原反应从而提供免疫刺激共轭物。
如本发明所用的术语“烷基”,“烯基”和前缀“烷(烯)”包括直链,支链和环基,即环烷基和环烯基。除非另有说明,这些基团含有1-20个碳原子,而烯基含有2-20个碳原子。优选的基团总共多达10个碳原子。环基可以是单环或多环,以及优选的是具有3-10个环碳原子。示例性环基团包括环丙基,环戊基,环己基,环丙基甲基,以及金刚基(adamantyl)。
术语“卤代烷基”包括被一种或多种卤原子取代的基团,包括全氟化基团。这还适合于包括前缀“卤代”的基团。合适的卤代烷基的例子是氯代甲基,三氟代甲基等。
如本发明所用的术语“芳基”包括碳环形芳香环或环系统。芳基的例子包括苯基,萘基,联苯基,芴基和茚基。术语“杂芳基”包括含有至少一个环杂原子(例如,O,S,N)的芳香环或环系统。合适的杂芳基包括呋喃基,噻吩基,吡啶基,喹啉基,异喹啉基,吲哚基,异吲哚基,三唑基,吡咯基,四唑基,咪唑基,吡唑基,唑基,噻唑基,苯并呋喃基,苯并苯硫基,咔唑基,苯并唑基,嘧啶基,苯并咪唑基,喹喔啉基,苯并噻唑基,二氮杂萘基,异唑基,异噻唑基,嘌呤基,喹唑啉基等。
“杂环基”包括含有至少一个杂原子(例如,O,S,N)的非芳香环或环系统,并且包括上述杂芳基的全部饱和和部分不饱和的衍生物。示例性杂环基包括吡咯烷基,四氢呋喃基,吗啉基,吗啉硫基,哌啶基,哌嗪基,噻唑烷基,异噻唑烷基,以及咪唑烷基。
芳基,杂芳基和杂环基可被一种或多种取代基取代或未取代,所述取代基独立地选自烷基,烷氧基,亚甲基二氧基,亚乙基二氧基,硫烷基,卤代烷基,卤代烷氧基,卤代硫烷基,卤素,硝基,羟基,巯基,氰基,羧基,甲酰基,芳基,芳基氧基,硫芳基,芳基烷氧基,芳基硫烷基,杂芳基,杂芳氧基,杂硫芳基,杂芳基烷氧基,杂芳基硫烷基,氨基,烷基氨基,二烷基氨基,杂环基,杂环烷基,烷基羰基,烯基羰基,烷氧基羰基,卤代烷基羰基,卤代烷氧基羰基,硫烷基羰基,芳基羰基,杂芳基羰基,芳基氧基羰基,杂芳基氧基羰基,硫芳基羰基,杂硫芳基羰基,烷酰氧基,硫烷酰基,烷酰基氨基,芳基羰基氧基,芳基硫羰基,烷基氨基磺酰基,烷基磺酰基,芳基磺酰基,杂芳基磺酰基,芳基二嗪基,烷基磺酰基氨基,芳基磺酰基氨基,芳基烷基磺酰基氨基,烷基羰基氨基,烯基羰基氨基,芳基羰基氨基,芳基烷基羰基氨基,杂芳基羰基氨基,杂芳基烷基羰基氨基,烷基磺酰基氨基,烯基磺酰基氨基,芳基磺酰基氨基,芳基烷基磺酰基氨基,杂芳基磺酰基氨基,杂芳基烷基磺酰基氨基,烷基氨基羰基氨基,烯基氨基羰基氨基,芳基氨基羰基氨基,芳基烷基氨基羰基氨基,杂芳基氨基羰基氨基,杂芳基烷基氨基羰基氨基,以及在杂环基的情形下,为氧代。如果其他基团被描述为“取代的”或“任选取代的”,则这些基团也可以被一种或多种上文列举的取代基取代。
某些取代基一般是优选的。例如,优选的R2基团包括氢,1-4个碳原子的烷基(即,甲基,乙基,丙基,异丙基,正丁基,仲丁基,异丁基,叔丁基以及环丙基甲基),以及烷氧基烷基(例如,甲氧基乙基和乙氧基甲基)。优选地,R3和R4独立的是氢或甲基,或者R3和R4合起来形成苯环,吡啶环,6-元饱和环或含有氮原子的6-元饱和环。如果需要,一种或多种这样优选的取代基可以任何组合方式存在于本发明的化合物中。
在有些实施方案中,免疫刺激共轭物可包括固相支持物结构,抗原部分和IRM部分皆可与之连接。在有些实施方案中,利用诸如上述的连接基团,IRM部分,抗原部分或两者可共价连接至固相支持物上。固相支持物可包括例如,琼脂糖珠,金颗粒等。然后,固相支持物可用于将连接的IRM部分和抗原部分共递送到合适的靶细胞群。用于连接生物分子至固相支持物的方法是本领域公知的,而将生物分子固定在固相支持物上的方案也是众所周知的,并且合适的试剂可从商业来源获得。
本发明的免疫刺激组合物除了共价偶联外,还可含有IRM部分和抗原部分之间的化学连接。例如,ISC可包括抗原部分和IRM部分之间的亲和相互作用。亲和素-生物素亲和性代表了非共价相互作用的一个例子,该作用可用于使抗原部分与IRM部分配对。经众多存在于例如,蛋白抗原的氨基酸上的官能团之一(例如,伯胺或巯基),生物素分子可化学连接到抗原。利用相似化学途径,IRM部分可共轭至亲和素分子上。然后,IRM部分与抗原部分由于亲和素-生物素相互作用而配对。用于使蛋白生物素酰化和使化学基团连接到亲和素上的方法是本领域技术人员众所周知的。替代的可用于制备ISC的亲和相互作用包括例如,抗原/抗体相互作用,糖蛋白/凝集素相互作用。
免疫刺激组合物也可通过IRM部分与抗原部分之间的离子相互作用形成。例如,IRM部分,抗原部分或两者可被改性以含有相反的带电组分。相反带电的IRM部分和抗原部分可温育在一起使得两个部分之间发生离子相互作用。接着,所得ISC可施用给个体或细胞群,从而将IRM和抗原共递送到靶细胞上。
如同在共价连接的ISC中的情形一样,其中IRM部分和抗原部分被非共价配对的ISC可包括固相支持物。
利用免疫刺激共轭物引发免疫反应的方法
本发明的免疫刺激组合物可用于在体外或体内引发免疫系统细胞的免疫反应。因此,本发明的ISC作为疫苗的组分或作为T细胞或B细胞的体外细胞培养物中所用的免疫刺激因子可能是有用的。实际上,当IRM作为本发明ISC的部分递送与作为未配对疫苗佐剂递送相比时,其是更有效的免疫刺激因子。当用于体外引发免疫反应时,体外活化的免疫细胞可重新导入患者中。此外,由活化的免疫细胞分泌的因子,例如,抗体,细胞因子等,可加以采集用于研究,诊断和/或治疗应用。
除非另有说明,宿主可以被皮下或腹膜内免疫。在经过足够的时间让宿主对ISC生成免疫反应后,采集合乎免疫部位的免疫细胞。例如,可从已被皮下免疫的宿主中采集淋巴结。从腹膜免疫的宿主采集脾细胞。对于一些宿主而言,细胞采集包括处死宿主。在其他情形下,细胞采集包括对适当组织进行活检或手术分离。
在一个实施方案中,ISC可用于诱导抗原特异的T细胞的增殖。宿主(例如,小鼠)可用包括特定抗原的ISC免疫。在宿主中有足够的温育之后,响应于免疫,某些T细胞(例如,CD8+T细胞)将变成成熟的抗原特异性T细胞。与仅用抗原免疫的宿主相比,用ISC免疫的宿主有更高百分比的T细胞是抗原特异的(图1-3)。通过使IRM部分和抗原部分共价偶联(图1-3),或通过非共价配对,诸如胶状悬浮液(图15-17),ISC可被配对。
如果抗原是蛋白(例如,卵清蛋白),则ISC无需包括整个蛋白。例如,蛋白的免疫显性(immunodominant)肽就是诱导特异于全蛋白抗原的T细胞发育所需的一切。此外,加强免疫,例如初次免疫后15天,可增大诱导抗原特异T细胞(图7)。
以ISC免疫宿主可用于在CD8+胞毒T淋巴细胞(CTL)中引发抗原特异反应。这种反应可针对许多状况,包括但不限于,肿瘤和病毒感染的细胞群。ISC也可预防性施用,以提供带有针对未来肿瘤或病毒感染的保护性CTL免疫的宿主。
在另一实施方案中,ISC可用于诱导抗原特异T细胞体外产生细胞因子。免疫宿主的合适组织可加以采集,并与抗原体外培养,由此诱导产生一种或多种细胞因子(例如,IFN-γ,参见图4-6)。再者,在抗原为蛋白的情形下,抗原蛋白的免疫显性肽就是诱导细胞培养物中的抗原特异T细胞生产和分泌细胞因子所需的一切。
在另一实施方案中,ISC可用于抑制体内肿瘤生长。有肿瘤细胞表达特定抗原的宿主可用含有抗原的ISC免疫。在有些实施方案中,初次免疫可用二次免疫加强。从免疫有含有抗原的ISC宿主中采集的肿瘤一般小于从仅免疫有抗原的宿主中采集的肿瘤(图8)。此外,肿瘤分析表明,从免疫有ISC的宿主中采集的肿瘤比从仅免疫有抗原的宿主中采集的肿瘤含有更高百分比的抗原特异T细胞(图10)。
在另一实施方案中,ISC可用于诱导抗原呈递细胞(APC,例如,树突细胞)以在其细胞表面呈递I型MHC复合物内的抗原肽。宿主可被静脉内免疫以诱导这种类型的反应。通过收集和分析APC呈递抗原/I型MHC复合物的脾细胞,可证实所述反应(图11-13)。
在替代的实施方案中,ISC可用于体外生成抗原特异性T细胞。例如,可从患有表达特定抗原的肿瘤的患者中采集骨髓细胞。采集的细胞可利用含有由肿瘤表达的抗原的ISC体外进行培养。再一次,如果抗原是蛋白,ISC仅需要包括蛋白的免疫显性肽。在与ISC温育的反应中,体外生成的抗原特异T细胞可重新导入患者。
在另一替代的实施方案中,ISC可施用给肿瘤个体以增加存活的可能性,持续时间或两者。给用黑素瘤细胞攻击的小鼠施用包括肿瘤特异性抗原部分的ISC,与仅用肿瘤抗原免疫的小鼠比较,增加了存活率(图14)。
实施例
下列实施例的选择仅为了进一步说明本发明的特征,优点和其他细节。然而应特别理解的是,尽管实施例用作此目的,但所用的具体材料和量以及其他条件和细节不应解释在过分限制本发明范围的内容中。
IRM化合物的制备
IRM化合物1(IRM1):N-[6-({2-[4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基]-1,1-二甲基乙基}氨基)-6-氧代己基]-4-叠氮基-2-羟基苯甲酰胺
A部分
4-氯-3-硝基喹啉(17.3g,83.2mmol)的200ml无水CH2Cl2在N2下的搅拌溶液,用三乙基胺(23.2ml,166.4mmol)和1,2-二氨基-2-甲基丙烷(9.57ml,91.5mmol)处理。搅拌过夜后,反应混合物用800ml CHCl3稀释,并用水(3×300ml)和盐水(300ml)洗涤。有机部分对Na2SO4干燥,并浓缩得到金黄色固体2-甲基-N1-(3-硝基喹啉-4-基)丙烷-1,2-二胺(21.0g)。
B部分
2-甲基-N1-(3-硝基喹啉-4-基)丙烷-1,2-二胺(2.60g,10.0mmol)的50ml四氢呋喃(THF)的溶液在N2下冷却至0℃,并用10ml 1N NaOH溶液处理。然后,将二-叔-丁基二碳酸酯(2.18g,10.0mmol)加入到快速搅拌的溶液中。让反应混合物温热至室温,并搅拌过夜。另加入400mg二-叔-丁基二碳酸酯,继续搅拌3天。用乙酸乙酯(200ml)处理反应液,并用水(2×)和盐水洗涤。有机部分对Na2SO4干燥,浓缩得到黄色固体,并用10%EtOAc/己烷研磨。过滤分离固体,并在真空下干燥过夜,得到黄色粉末叔-丁基1,1-二甲基-2-[(3-硝基喹啉-4-基)氨基]乙基氨基甲酸酯(2.80g)。
C部分
叔-丁基1,1-二甲基-2-[(3-硝基喹啉-4-基)氨基]乙基氨基甲酸酯(3.50g,9.72mmol)的150ml甲苯的溶液用0.3g 5%铂碳处理,氢气(3atm,3Kg/cm2)下振荡6小时。溶液通过C盐垫过滤,并浓缩得到3.04g浅橙色泡沫粗叔-丁基2-[(3-氨基喹啉-4-基)-1,1-二甲基乙基氨基甲酸酯。
D部分
叔-丁基2-[(3-氨基喹啉-4-基)-1,1-二甲基乙基氨基甲酸酯(3.04g,9.21mmol)的50ml CH2Cl2的溶液冷却至0℃,并用三乙基胺(1.41ml,10.13mmol)和乙氧基乙酰基氯(1.02ml,10.17mmol)处理。2小时后,反应混合物在减压下浓缩。所得浆液被100ml EtOH吸收,并用4.5ml三乙基胺处理。溶液加热回流过夜。反应混合物浓缩,吸收在100mlCH2Cl2中,并用水(2×)和盐水洗涤。有机部分对Na2SO4干燥且浓缩。所得浆液经柱色谱(SiO2,80%EtOAc/己烷)纯化,得到桃色泡沫叔-丁基2-[2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基]-1,1-二甲基乙基氨基甲酸酯(1.57g)。
E部分
叔-丁基2-[2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基]-1,1-二甲基乙基氨基甲酸酯(1.57g,3.94mmol)的30ml CH2Cl2的溶液用3-氯代过氧苯甲酸(77%,1.01g,4.57mmol)处理。搅拌2小时后,反应混合物另用30ml CH2Cl2处理,并用1%Na2CO3溶液(2×30ml),水和盐水洗涤。有机部分对Na2SO4干燥,浓缩得到浅棕色泡沫叔-丁基2-[2-(2-(乙氧基甲基)-5-氧桥-1H-咪唑并[4,5-c]喹啉-1-基)-1,1-二甲基乙基氨基甲酸酯(1.58g)。
F部分
叔-丁基2-[2-(2-(乙氧基甲基)-5-氧桥-1H-咪唑并[4,5-c]喹啉-1-基)-1,1-二甲基乙基氨基甲酸酯(1.57g,3.79mmol)的20ml 1,2-二氯代乙烷的溶液加热至70℃,并用2ml浓氨水溶液处理。向快速搅拌的溶液中加入固体p-甲苯磺酰基氯(795mg,4.17mmol)。然后,将反应混合物密封在压力容器中,并继续加热2小时。反应混合物冷却,并用50mlCHCl3处理。反应混合物用水,1%Na2CO3溶液(3×)和盐水洗涤。有机部分对Na2SO4干燥,并浓缩得到浅棕色油产物。所得油通过柱色谱(SiO2,2-5%MeOH/CHCl3)纯化,得到浅黄色泡沫叔-丁基2-[4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基]-1,1-二甲基乙基氨基甲酸酯(1.26g)。
G部分
将叔-丁基2-[4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基]-1,1-二甲基乙基氨基甲酸酯(1.26g,3.05mmol)溶解在10ml EtOH中,并用10ml 2M HCl的EtOH处理。加热回流2小时后,反应混合物冷却,并在减压下浓缩。所得黄色固体溶解在50ml水中,并用CHCl3(20ml)萃取。丢弃有机层,加入浓氨水溶液使水相部分变成碱性(pH约12)。然后,用CHCl3(4×20ml)萃取,合并有机部分,用Na2SO4干燥,并浓缩得到浅棕色粉末1-(2-氨基-2-甲基丙基)-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-4-胺(808mg)。m.p.161.0-162.0℃;
MS m/z 314(M+H);
1H NMR(300MHz,d6-DMSO)δ8.30(d,J=7.7Hz,1H),7.59(dd,J=1.2,8.3Hz,1H),7.40(ddd,J=1.0,7.2,8.1Hz,1H),7.21(ddd,J=1.2,7.0,8.2Hz,1H),6.57(s,2H),4.94(br s,2H),4.61(br s,2H),3.52(q,J=7.0Hz,2H),1.61(s,2H),1.31(t,J=7.0Hz,3H),1.07(s,6H);
13C NMR(75MHz,d6-DMSO)δ152.4,151.1,145.7,134.3,126.8,126.7,121.7,120.8,115.7,65.6,65.2,55.8,52.5,29.2,15.4。
C17H23N5O分析计算值:%C,65.15;%H,7.40;%N,22.35。实测值:%C,65.04;%H,7.52;%N,22.07。
H部分
在氮气气氛下,N-羟基硫代琥珀酰基(叠氮基水杨基氨基)己酸酯(100mg,0.204mmol的磺基-LC-NHS-ASA,来自Pierce Biotechnology,Inc,Rockford,IL,USA)的N,N-二甲基甲酰胺DMF(2-4ml)的溶液加入1-(2-氨基-2-甲基丙基)-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-4-胺(63mg,0.201mmol)的DMF(5ml)的溶液中。反应混合物在箔包裹的容器中氮气下搅拌。2天后,另加入50mg N-羟基硫代琥珀酰基(叠氮基水杨基氨基)己酸酯。约1周后,反应混合物在55℃下减压浓缩。残留物分配在含有少量甲醇的二氯甲烷和水之间。分离有机层,并在减压下浓缩。残留物通过闪烁色谱(2×15cm SiO2,用6%甲醇的氯仿洗脱)纯化,得到53mg无色玻璃状产物。利用二氯甲烷将玻璃状产物转移到锥形瓶中,浓缩得到泡沫。泡沫在高真空下干燥过夜,得到48mg白色结晶固体。NMR分析表明存在二氯甲烷,因此此材料先在高真空下干燥过夜,再在真空箱中50℃下干燥5小时。HPLC分析表明纯度>93%。
IRM化合物2(IRM2):N-{6-[(2-{2-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基)氨基]-6-氧代己基}-4-叠氮-2-羟基苯甲酰胺
A部分
2-(2-氨基乙氧基)乙醇(29.0g,0.276mol)的180ml四氢呋喃(THF)的溶液在氮气下冷却至0℃,并用140ml 2N NaOH溶液处理。然后,向快速搅拌的溶液中滴加二-叔-丁基二碳酸酯(60.2g,0.276mol)的180ml THF的溶液,历时1小时以上。反应混合物温热至室温,另搅拌18小时。减压下去除THF,并且加入150ml 1M H2SO4溶液使剩余水浆调整至pH 3。用乙酸乙酯(300ml,100ml)萃取,合并有机层,并经水(2×)和盐水洗涤。有机部分对Na2SO4干燥,并浓缩得到无色油叔-丁基2-(2-羟基乙氧基)乙基氨基甲酸酯(47.1g)。
B部分
叔-丁基2-(2-羟基乙氧基)乙基氨基甲酸酯(47.1g,0.230mol)的1L无水CH2Cl2的快速搅拌溶液氮气下冷却至0℃,并用三乙基胺(48.0ml,0.345mol)处理。然后,滴加甲烷磺酰氯(19.6ml,0.253mol),历时30分钟以上。反应混合物温热至室温,另搅拌22小时。加入500ml饱和NaHCO3溶液猝灭反应,并且分离有机层。接着,用水(3×500ml)和盐水洗涤有机相。有机部分对Na2SO4干燥,并浓缩得到棕色油2-{2-[(叔-丁氧基羰基)氨基]乙氧基}乙基甲烷磺酸酯(63.5g)。
C部分
2-{2-[(叔-丁氧基羰基)氨基]乙氧基}乙基甲烷磺酸酯(63.5g,0.224mol)的400ml N,N-二甲基甲酰胺(DMF)的搅拌溶液用NaN3(16.1g,0.247mol)处理,反应混合物在氮气下加热至90℃。5小时后,溶液冷却至室温,并且用500ml冷水处理。然后,反应混合物用Et2O(3×300ml)萃取,合并有机萃取物,用水(4×100ml)和盐水(2×100ml)洗涤。有机部分对MgSO4干燥,并浓缩得到52.0g浅棕色油叔-丁基2-(2-叠氮基乙氧基)乙基氨基甲酸酯。
D部分
叔-丁基2-(2-叠氮基乙氧基)乙基氨基甲酸酯(47.0g,0.204mol)的MeOH溶液用4g 10%铂碳处理,并且在H2(3Kg/cm2)下振荡24小时。然后,通过C盐垫过滤溶液,并且浓缩得到35.3g无色液体粗叔-丁基2-(2-氨基乙氧基)乙基氨基甲酸酯,无需进一步纯化即可使用。
E部分
4-氯-3-硝基喹啉(31.4g,0.151mol)的500ml无水CH2Cl2的搅拌溶液在氮气下用三乙基胺(43ml,0.308mol)和叔-丁基2-(2-氨基乙氧基)乙基氨基甲酸酯(0.151mol)处理。搅拌过夜后,反应混合物用水(2×300ml)和盐水(300ml)洗涤。有机部分对Na2SO4干燥,并浓缩得到金黄色固体。用乙酸乙酯/己烷重结晶得到43.6g金黄色晶体叔-丁基2-{2-[(3-硝基喹啉-4基)氨基]乙氧基}乙基氨基甲酸酯。
F部分
叔-丁基2-{2-[(3-硝基喹啉-4基)氨基]乙氧基}乙基氨基甲酸酯(7.52g,20.0mmol)的甲苯的溶液用1.5g 5%铂碳处理,并且在H2(3Kg/cm2)下振荡24小时。然后,通过C盐垫过滤溶液,并且浓缩得到6.92g黄浆粗叔-丁基2-{2-[(3-氨基喹啉-4-基)氨基]乙氧基}乙基氨基甲酸酯。
G部分
叔-丁基2-{2-[(3-氨基喹啉-4-基)氨基]乙氧基}乙基氨基甲酸酯(10.2g,29.5mmol)的250ml无水CH2Cl2的溶液冷却至0℃,并且用三乙基胺(4.18ml,30.0mmol)处理。然后,滴加甲氧基丙酰基氯(3.30ml,30.3mmol),历时5分钟以上。反应混合物温热至室温,并且继续搅拌1小时。反应混合物减压下浓缩得到橙色固体。将该固体溶解在250ml EtOH中,加入12.5ml三乙基胺。混合物加热至回流,并且在氮气下搅拌过夜。反应液减压下浓缩至干燥,并且用300ml Et2O处理混合物过滤,过滤液减压下浓缩得到棕色固体。固体溶解在200ml热甲醇中,并且用活性碳处理。过滤热溶液,经浓缩得到11.1g黄浆叔-丁基2-{2-[2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基氨基甲酸酯。
H部分
叔-丁基2-{2-[2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基氨基甲酸酯(10.22g,24.7mmol)的250ml CHCl3的溶液用3-氯过苯甲酸(77%,9.12g,40.8mmol)处理。搅拌30分钟后,反应混合物用1%Na2CO3溶液(2×75ml)和盐水洗涤。有机层对Na2SO4干燥,并浓缩得到10.6g橙色泡沫叔-丁基2-{2-[2-(2-甲氧基乙基)-5-氧桥-1H-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基氨基甲酸酯,无需进一步纯化即可使用。
I部分
叔-丁基2-{2-[2-(2-甲氧基乙基)-5-氧桥-1H-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基氨基甲酸酯(10.6g,24.6mmol)的100ml 1,2-二氯乙烷的溶液加热至60℃,并且用10ml浓氨水溶液处理。向快速搅拌的溶液中加入固体p-甲苯磺酰基氯(7.05g,37.0mmol),历时10分钟以上。反应混合物另用1ml浓氨水溶液处理,然后密封在压力容器中,继续加热2小时。接着,反应混合物冷却,并且用100ml CHCl3处理。反应混合物用水,1%Na2CO3溶液(2×)和盐水处理。有机部分对Na2SO4干燥,并且浓缩得到10.6g棕色泡沫叔-丁基2-{2-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基氨基甲酸酯。
J部分
叔-丁基2-{2-[2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基氨基甲酸酯(10.6g,24.6mmol)用75ml 2M HCl的乙醇处理,并且混合物搅拌下加热至回流。1.5小时后,反应混合物冷却,过滤后得到粘性固体。固体用乙醇和Et2O洗涤后,真空干燥,得到浅棕色固体,该产物的盐酸盐。将该盐水盐溶解在50ml水中,并且用10%NaOH溶液处理,从而制成游离碱。然后,水悬浮液浓缩至干燥,残留物用CHCl3处理。通过过滤去除所得盐,过滤液浓缩得到3.82g茶色粉末1-[2-(2-氨基乙氧基)乙基]-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺。
MS 330(M+H)+;
1H NMR(300MHz,DMSO-d6)δ8.10(d,J=8.1Hz,1H);7.66(d,J=8.2Hz,1H);7.40(m,1H);7.25(m,1H);6.88(br s,2H);4.78(t,J=5.4Hz,2H);3.89(t,J=4.8Hz,2H);3.84(t,J=6.9Hz,2H);3.54(t,J=5.4Hz,2H);3.31(s,3H);3.23(t,J=6.6Hz,2H);2.88(t,J=5.3Hz,2H)。
部分K
在氮气气氛下,向1-[2-(2-氨基乙氧基)乙基]-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺(66mg,0.201mmol)的DMF(5ml)溶液中加入N-羟基硫代酰基琥珀酰基(叠氮基水杨基氨基)己酸酯(100mg,0.204mmol磺基-LC-NHS-ASA,来自Pierce Biotechnology,Inc,Rockford,IL,USA)的DMF(2-4ml)的溶液。3.5小时后,HPLC分析显示没有初始材料存在。反应混合物搅拌过夜,并且减压下浓缩。残留物经闪烁色谱(2×15cm SiO2,用8%甲醇的氯仿洗脱)纯化,得到55mg无色玻璃状产物。利用二氯甲烷将玻璃状产物转移至锥形瓶中,浓缩后得到泡沫。泡沫先在高真空下干燥过夜,再在真空箱中50℃下干燥5小时,得到45mg白色蓬松固体产物。HPLC分析显示纯度>95%。
IRM化合物3(IRM3):N-(2-{2-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基)十六烷酰胺
在氮气气氛下,1-[2-(2-氨基乙氧基)乙基]-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺(140.5mg,0.428mmol)在二氯甲烷(3.5ml)和三乙基胺(150μl,1.07mmol)的混合物中的悬浮液冷却至0℃。缓慢加入棕榈酰氯(130μl,0.428mmol)。使反应混合物在0℃下搅拌2小时,此时,薄层色谱分析显示,原料没有留下。反应混合物用二氯甲烷(30ml)稀释,用饱和碳酸氢钠溶液(2×5ml)洗涤,对硫酸镁干燥,然后减压浓缩。所得残留物通过柱色谱(12g硅胶,用2%甲醇的二氯甲烷洗脱)纯化,得到183mg白色粉末N-(2-{2-[4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基]乙氧基}乙基)十六烷酰胺。
C33H53N5O3分析计算值:%C,69.80;%H,9.41;%N,12.33;实测值:%C,69.60;%H,9.28;%N,11.99。
实施例1:免疫反应调节剂与卵清蛋白的交联
IRM1悬浮在二甲基亚砜(DMSO)中,至10mg/ml。卵清蛋白悬浮在磷酸盐缓冲液(PBS)中,至10mg/ml,以及加入NaOH调节pH>10.0。在12孔组织培养板的单个孔中,500μl卵清蛋白溶液(5mg卵清蛋白)与100μl IRM1溶液(1mg IRM1)混合。将培养板置于冰上,并且将长波长UV光源直接置于板的上方,尽可能靠近含有IRM1/卵清蛋白混合物的孔。照射混合物15分钟。所得共轭物从孔中取出,重新悬浮于PBS中,至终浓度5mg/mL卵清蛋白,0.5mg/ml IRM1,并且对PBS透析以去除任何未共轭的IRM。
实施例2:免疫
C57BL/6小鼠用共轭物(1mg卵清蛋白和200μg IRM1,如实施例1所制备)的200μl PBS或皮下或腹膜内免疫。对照小鼠用1mg卵清蛋白的200μl PBS免疫。对于初级反应分析而言,免疫后5-7天处死小鼠。对次级反应分析而言,小鼠在初始免疫后7-15天加强免疫,并且加强免疫后5-7天被处死。除非另有说明,从皮下免疫小鼠中采集淋巴结用于分析,而从腹膜内免疫小鼠中采集脾细胞用于分析。
实施例3:试剂
荧光染料标记的抗体特异于小鼠CD8,CD11c,和CD44,获自Pharmingen(San Diego,CA)。单克隆抗体25D1.16(Ron Germain博士,NIH)特异于结合至I型MHC分子H-2Kb的卵清蛋白显性肽(SIINFEKL)。Porgador等,Immunity 6:715-26。卵清蛋白获自SigmaChemical Company(St.Louis,MO)。I型MHC分子H-2Kb的四聚体结合至卵清蛋白显性肽SIINFEKL,其制备如Kedl等,J Exp Med,192:1105-13(2000)所述。表达卵清蛋白的黑色瘤细胞系B16ova的制备方法是用编码全长卵清蛋白的质粒脂转染B16-F10细胞系(ATCC#CRL-6475)。参见Kedl等,Proc.Natl.Acad.Sci.USA,98:10811-6。细胞因子捕获和检测试剂来自Miltyeni Biotech(Auburn,CA)。
实施例4:
实验小鼠如实施例2所述用如实施例1制备的共轭物皮下或腹膜内免疫。对照小鼠如实施例2所述用卵清蛋白免疫。7天后,取出淋巴结或脾脏,细胞用特异于CD8,CD44,和H-2Kb/SIINFEKL四聚体的抗体染色,并且通过流式细胞计数仪进行分析。结果示于图1-3。对全部三种标记为阳性染色的细胞鉴定为活化的卵清蛋白特异的CD8+T细胞,其作为免疫的结果而发生。
图1-3分别包括所有受检的CD8+T细胞被鉴定为活化的卵清蛋白特异的CD8+T细胞的百分比。在对照小鼠中,0.07%的CD8+T细胞是活化的卵清蛋白特异的CD8+T细胞。用共轭物皮下免疫生成0.52%活化的卵清蛋白特异的CD8+T细胞。用共轭物腹膜内免疫生成0.92%活化的卵清蛋白特异的CD8+T细胞。
用与IRM1共轭的卵清蛋白优势肽(SIINFEKL)(与200μg IRM1交联的100μg肽)免疫也诱导卵清蛋白-特异的CD8+T细胞的活化。
实施例5
对照小鼠如实施例2所述,用卵清蛋白免疫。实验小鼠如实施例2所述用如实施例1中制备的共轭物或皮下或腹膜内免疫。免疫7天后采集适当的免疫小鼠,并且与SIINFEKL肽体外温育4小时。利用与流式细胞计数仪偶联的IFN-γ捕获和检测分析,鉴定干扰素γ(IFN-γ)-生产的CD8+T细胞。通过用IRM1-卵清蛋白共轭物免疫所生成的CD8+T细胞响应于随后的抗原刺激而产生IFN-γ(图4-6)。
实施例6
如实施例2所述,小鼠用如实施例1中制备的共轭物免疫,然后用等量的共轭物在第15天时加强。加强后7天,对来自加强动物的脾脏和淋巴结细胞进行分析。分析显示,与仅接受初级免疫的小鼠比较,活化的卵清蛋白特异的CD8+T细胞的百分比增加(图7)。
实施例7
小鼠用卵清蛋白表达的黑色瘤细胞系B16ova(1×105细胞)皮内注射。在第7天,小鼠或用1mg卵清蛋白(对照)或用如实施例1制备的共轭物皮下注射。在第14天,小鼠如第7天用卵清蛋白或共轭物皮下加强。在第20天,肿瘤大小用卡尺在两维方向进行测量。与对照比较,用共轭物免疫导致肿瘤大小减小(图8)。
实施例8
小鼠用卵清蛋白表达的黑素瘤细胞系B16ova(1×105细胞)皮内注射。7天和14天后,小鼠或用1mg卵清蛋白(对照)或用如实施例1制备的共轭物腹膜内注射。用黑素瘤细胞系攻击后20天,取出脾脏和肿瘤,并且用特异于CD8和CD44以及H-2Kb/SIINFEKL四聚体的抗体染色各个来源的细胞。流式细胞计数仪分析显示,活化的卵清蛋白特异的CD8+T细胞在脾脏(图9)和肿瘤(图10)内的显著扩大。
实施例9
小鼠用卵清蛋白,卵清蛋白和未配对的IRM1:1-(2-氨基-2-甲基丙基)-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-4-胺(在与连接基团连接之前的IRM1一合成IRM1的G部分产物)或用如实施例1制备的共轭物静脉内免疫。14小时后,取出脾脏,用胶原酶处理,并且细胞用特异于CD8,CD11c和抗体25D1.16的抗体染色,抗体25D1.16特异于复合有I型MHC H-2Kb分子的卵清蛋白肽SIINFEKL。流式细胞计数仪分析显示,用IRM1-卵清蛋白共轭物免疫小鼠(图13)比仅用卵清蛋白免疫小鼠或用未配对的卵清蛋白和IRM1的混合物(图12)免疫小鼠生成了更高百分比的呈递Kb/SIINFEKL的CD11c+,CD8+树突细胞。
实施例10
在第0天,如实施例2所述,小鼠用卵清蛋白(对照)或用如实施例1制备的IRM1共轭物皮下免疫。小鼠在第14天接受加强免疫。然后,小鼠在第28天用卵清蛋白表达的黑素瘤细胞系B16ova(1×105细胞)皮内攻击,并且对肿瘤生长进行监控。在第75天,有80%的免疫有共轭物的小鼠存活并且显示出健康,而仅用卵清蛋白免疫的小鼠全部死亡(图14)。
实施例11
将IRM3溶解于DMSO中至浓度10mg/ml而制备IRM3的储液。卵清蛋白溶解于PBS中至浓度50mg/ml。50μl IRM3储液加入到150μl PBS中,然后通过旋涡振荡混合。50μl卵清蛋白加入到IRM3溶液中,并且通过旋涡振荡混合。结果产生IRM3和卵清蛋白的浑浊胶状悬浮液。
在第0天,如实施例2所述,小鼠或用(a)单独卵清蛋白,或(b)50μl卵清蛋白和IRM3的胶状悬浮液皮下免疫。在第6天,取出引流淋巴结(draining lymph nodes),均质,并且用H-2Kb/SIINFEKL四聚体染色以鉴定卵清蛋白特异的T细胞。图15示出单独用卵清蛋白免疫的对照小鼠的流式细胞仪数据;图16和17示出免疫有胶状悬浮液的两种不同小鼠的数据。
实施例12
如实施例1所述制备IRM2和卵清蛋白的共轭物,除了用IRM2代替IRM1之外。
24只小鼠分成8组,每组3只。其中4组在第0天如实施例2所述皮下免疫,每组接受增量的IRM1-卵清蛋白共轭物。剩余4组在第0天用IRM2-卵清蛋白共轭物进行同样的免疫。在第6天,处死小鼠,取出引流淋巴结,并且用H-2Kb/SIINFEKL四聚体染色以鉴定卵清蛋白特异的T细胞。对每只小鼠计算卵清蛋白特异的T细胞的百分比。图18总结了结果。
实施例13
小鼠用约2×106OT1卵清蛋白-特异的转基因T细胞(The JacksonLaboratory,Bar Harbor,Maine)过继性转移。小鼠在第0天,如实施例2所述,用(a)100μg卵清蛋白,(b)100μg卵清蛋白+50μgCpG(Ova+CpG),(c)100μg卵清蛋白+50μg未配对的IRM1(Ova+IRM),或者(d)100μg与50μg IRM1共轭的卵清蛋白(Ova×IRM)皮下免疫。在第5天,取出引流淋巴结,并且细胞用H-2Kb/SIINFEKL四聚体染色以鉴定卵清蛋白特异的T细胞。图19示出卵清蛋白-特异的T细胞在Ova+CpG,Ova+IRM,和Ova×IRM组比单独用卵清蛋白免疫的小鼠中的倍增。
在此引用的专利,专利文献和公布的全部内容以其全文引作参考,就如同分别单个引入一样。在存在冲突的情况下,以本说明书,包括定义为准。
在无需背离本发明的范围和实质的情况下,本领域技术人员可对本发明有多种修饰和改变是一目了然的。例证性实施方案和实施例仅仅以例子提供,并非旨在限制本发明的范围。本发明的保护范围仅受随附的权利要求限制。
Claims (11)
1.一种免疫刺激组合物,包括:
与抗原部分配对的免疫反应调节剂部分。
2.权利要求1的免疫刺激组合物,其中免疫反应调节剂部分是Toll样受体2,Toll样受体4,Toll样受体6,Toll样受体7,或Toll样受体8的激动剂。
3.权利要求1的免疫刺激组合物,其中免疫反应调节剂部分包括咪唑并喹啉胺;四氢咪唑并喹啉胺;咪唑并吡啶胺;芳基醚取代的咪唑并吡啶胺;1,2-桥连的咪唑并喹啉胺;6,7-稠合的环烷基咪唑并吡啶胺;咪唑并二氮杂萘胺;四氢咪唑并二氮杂萘胺;唑并喹啉胺;噻唑并喹啉胺;唑并吡啶胺;噻唑并吡啶胺;唑并二氮杂萘胺;或噻唑并二氮杂萘胺。
4.权利要求1的免疫刺激组合物,其中免疫反应调节剂部分和抗原部分是共价偶联的。
5.权利要求1的免疫刺激组合物,其中免疫反应调节剂部分和抗原部分除了共价偶联外,是通过物理或化学结合而配对的,所述共价偶联限制了免疫反应调节剂部分相对于抗原部分的独立扩散。
6.权利要求1的免疫刺激组合物,其中所述组合物包括胶状悬浮液。
7.权利要求1的免疫刺激组合物,其中抗原部分包括氨基酸序列,核苷酸序列,脂多糖,朊病毒,细菌,病毒或真菌。
8.权利要求1的免疫刺激组合物,其中免疫反应调节剂部分为下式的化合物:
其中;
R1为连接基团;
R2选自:
-氢;
-烷基;
-烯基;
-芳基;
-取代的芳基;
-杂芳基;
-取代的杂芳基;
-烷基-O-烷基;
-烷基-S-烷基;
-烷基-O-芳基;
-烷基-S-芳基;
-烷基-O-烯基;
-烷基-S-烯基;以及
-被一种或多种选自下列基团的取代基取代的烷基或烯基:
-OH;
-卤素;
-N(R5)2;
-CO-N(R5)2;
-CS-N(R5)2;
-SOx-N(R5)2;
-NR5-CO-C1-10烷基;
-NR5-CS-C1-10烷基;
-NR5-SO2-C1-10烷基;
-CO-C1-10烷基;
-CO-O-C1-10烷基;
-N3;
-芳基;
-取代的芳基;
-杂芳基;
-取代的杂芳基;
-杂环基;
-取代的杂环基;
-CO-芳基;
-CO-(取代的芳基);
-CO-杂芳基;以及
-CO-(取代的杂芳基);
R3和R4各自独立是:
-氢;
-卤素;
-烷基;
-烯基;
-O-烷基;
-S-烷基;以及
-N(R5)2;
或者当合起来时,R3和R4形成任选被一种或多种选自下列基团的取代基取代的稠合的芳基或杂芳基:
-卤素;
-烷基;
-烯基;
-O-烷基;
-S-烷基;以及
-N(R5)2;
或者当合起来时,R3和R4形成稠合的5-7元饱和环,任选含有一种或多种杂原子,以及任选被一种或多种选自下列基团的取代基取代:
-卤素;
-烷基;
-烯基;
-O-烷基;
-S-烷基;以及
-N(R5)2;以及
各个R5独立地为氢或C1-10烷基。
9.下式的免疫刺激共轭物或其可药用盐:
其中:
R1为连接基团;
R2选自:
-氢;
-烷基;
-烯基;
-芳基;
-取代的芳基;
-杂芳基;
-取代的杂芳基;
-烷基-O-烷基;
-烷基-S-烷基;
-烷基-O-芳基;
-烷基-S-芳基;
-烷基-O-烯基;
-烷基-S-烯基;以及
-被一种或多种选自下列基团的取代基取代的烷基或烯基:
-OH;
-卤素;
-N(R5)2;
-CO-N(R5)2;
-CS-N(R5)2;
-SO2-N(R5)2;
-NR5-CO-C1-10烷基;
-NR5-CS-C1-10烷基;
-NR5-SO2-C1-10烷基;
-CO-C1-10烷基;
-CO-O-C1-10烷基;
-N3;
-芳基;
-取代的芳基;
-杂芳基;
-取代的杂芳基;
-杂环基;
-取代的杂环基;
-CO-芳基;
-CO-(取代的芳基);
-CO-杂芳基;以及
-CO-(取代的杂芳基);
R3和R4各自独立是:
-氢;
-卤素;
-烷基;
-烯基;
-O-烷基;
-S-烷基;以及
-N(R5)2;
或者当合起来时,R3和R4形成任选被一种或多种选自下列基团的取代基取代的稠合的芳基或杂芳基:
-卤素;
-烷基;
-烯基;
-O-烷基;
-S-烷基;以及
-N(R5)2;
或者当合起来时,R3和R4形成稠合的5-7元饱和环,任选含有一种或多种杂原子,以及任选被一种或多种选自下列基团的取代基取代:
-卤素;
-烷基;
-烯基;
-O-烷基;
-S-烷基;以及
-N(R5)2;以及
各个R5独立地为氢或C1-10烷基;以及
n为1-10。
10.一种刺激产生抗体的细胞的方法,所述方法包括:
a)提供包含与抗原部分配对的免疫反应调节剂部分的免疫刺激组合物;以及
b)让免疫刺激组合物与产生抗体的细胞结合。
11.包含与抗原部分配对的免疫反应调节剂部分的免疫刺激组合物在制备用于诱导生物体针对抗原部分的免疫反应的药物中的应用。
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EP1545597A2 (en) | 2005-06-29 |
KR20050026709A (ko) | 2005-03-15 |
EP2269632B1 (en) | 2014-01-01 |
AU2003299863A2 (en) | 2004-05-04 |
EP1545597B1 (en) | 2010-11-17 |
AU2003299863A1 (en) | 2004-05-04 |
CN1671412A (zh) | 2005-09-21 |
BR0313587A (pt) | 2006-06-13 |
AU2003299863B2 (en) | 2009-09-24 |
JP4860923B2 (ja) | 2012-01-25 |
DE60335010D1 (de) | 2010-12-30 |
MXPA05001647A (es) | 2005-04-19 |
EP2269632A3 (en) | 2012-10-24 |
EP2269632A2 (en) | 2011-01-05 |
JP5491364B2 (ja) | 2014-05-14 |
ATE488246T1 (de) | 2010-12-15 |
KR101088615B1 (ko) | 2011-11-30 |
WO2004032829A3 (en) | 2004-12-09 |
DK1545597T3 (da) | 2011-01-31 |
US7427629B2 (en) | 2008-09-23 |
NZ538812A (en) | 2009-02-28 |
ES2355819T3 (es) | 2011-03-31 |
JP2006507265A (ja) | 2006-03-02 |
PT1545597E (pt) | 2010-12-29 |
US20040091491A1 (en) | 2004-05-13 |
JP2011057699A (ja) | 2011-03-24 |
EP1545597A4 (en) | 2006-08-30 |
WO2004032829A2 (en) | 2004-04-22 |
CA2495570A1 (en) | 2004-04-22 |
CA2495570C (en) | 2012-12-04 |
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