TW202400801A - 用於克服治療性載體及蛋白質之免疫原性之耐受性免疫修飾奈米粒子 - Google Patents
用於克服治療性載體及蛋白質之免疫原性之耐受性免疫修飾奈米粒子 Download PDFInfo
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Abstract
本申請案大體上有關包含基因療法載體抗原的耐受性免疫介導粒子,其與基因療法方案組合使用,以便降低對該等基因療法載體抗原及/或由該等載體表現之轉殖基因蛋白質產物的免疫原性。
Description
本申請案大體上有關包含基因療法載體抗原的耐受性免疫介導粒子,其與基因療法方案組合使用,以便降低對基因療法載體抗原及/或由該等載體表現之轉殖基因蛋白質產物的免疫原性。
基因遞送載體(例如反轉錄病毒、慢病毒、腺病毒及腺相關病毒(AAV)載體)設計及開發方面的進步使得基因療法成為多種疾病及病況的有吸引力的治療選擇,該等疾病及病況包括罕見及遺傳性基因病症、自體免疫疾病、神經退化性病況及癌症。基因療法依賴於編碼治療蛋白(諸如酶、細胞介素及抗體)之外源DNA之載體介導之遞送。
1 - 6基因療法之目標在於使得治療蛋白能夠持續組織特異性產生以獲得長期治療功效。
除了產生蛋白質及酶以用於治療罕見及遺傳性基因病症(例如血友病、龐培氏病(Pompe Disease)、法布立病(Fabry Disease)及黏多糖病)之外,基因療法載體亦用於自體抗原及致耐受性細胞介素/趨化介素之組織特異性表現以用於治療自體免疫疾病、癌症疫苗,以及產生抗腫瘤蛋白質、細胞介素、趨化介素及抗體以用於治療癌症
3 , 4 , 7。此外,病毒載體(稱作溶瘤病毒)已經工程改造以溶解腫瘤細胞且誘導抗腫瘤免疫反應從而用於治療癌症
8 , 9。
用於基因療法應用的正在使用中及目前處於開發中的基因療法載體通常為天然存在之反轉錄病毒、慢病毒、腺病毒及AAV的經修飾及/或經工程改造之版本
10,文獻中亦描述了若干合成載體
11。為了達成持續的治療功效,必須定期再次投與病毒載體
19 , 20。
基因療法載體以及自載體表現之治療蛋白的免疫原性對持續治療效益所需的週期性再次投與提出重大臨床挑戰,因為載體及載體產生之治療蛋白在投與之後均被快速清除。另外,可能得益於基因療法之相當大一部分患者對基因療法載體表現出預先存在的免疫性,使得其不適合進行治療
12 - 14。無預先存在的中和抗體之患者亦受載體及治療蛋白之免疫原性影響,因為初始載體投與會誘導對載體蛋白之免疫反應,該免疫反應干擾持續治療效益所需的任何再次投與。
旨在預防病毒載體之免疫原性的當前策略依賴於同時投與具有顯著副作用(諸如感染風險增加及甚至死亡)之免疫抑制方案
15。
使用TIMP誘導對基因療法載體及由載體產生之轉殖基因蛋白質產物耐受的抗原特異性T細胞,可潛在地克服與基因療法相關之免疫原性問題,使得能夠再次給藥且引起提高的治療功效。
本發明描述用於誘導對基因療法載體及由載體產生之轉殖基因蛋白質產物的抗原特異性耐受的組合物及方法。本文提供的組合物包含囊封抗原之帶負電荷載體粒子,其中該抗原為一或多種基因療法載體抗原及/或其部分,或基因療法載體抗原或其部分的組合。在各種實施例中,抗原為由基因療法載體產生的治療蛋白及/或其部分或其一或多種抗原表位。在各種實施例中,載體粒子包含聚合物且具有負ζ電位。在各種實施例中,聚合物為生物可降解聚合物。
在各種實施例中,粒子包含選自由以下組成之群的聚合物:聚乙醇酸(PGA)、聚乳酸(PLA)、聚癸二酸(PSA)、聚(乳酸-共-乙醇酸)(PLGA)、聚(乳酸-共-癸二酸)(PLSA)、聚(乙醇酸-共-癸二酸)(PGSA)、聚丙烯硫醚、聚(己內酯)、聚葡萄胺糖、多醣、或脂質、聚苯乙烯、金剛石、脂質體、PEG、環葡聚糖、脂質或金屬,諸如鐵(Fe)、鋅(Zn)、鎘(Cd)、金或銀或其組合。
在各種實施例中,聚合物為共聚物。在各種實施例中,共聚物具有不同莫耳比之組成聚合物。在各種實施例中,莫耳比為25:75、30:70、35:65、40:60、45:55、50:50、55:45、60:40、65:35、70:30、75:25、80:20、81:19、82:18、83:17、84:16、85:15、86:14、87:13、88:12、89:11、90:10、91:9、92:8、93:7、94:6、95:5、96:4、97:3、98:2、99:1或100:0。
在各種實施例中,載體粒子包含聚(乳酸-共-乙醇酸) (PLGA)。在各種實施例中,粒子包含約50:50、約80:20至約100:0聚乳酸:聚乙醇酸或約50:50、約80:20至約100:0聚乙醇酸:聚乳酸。在各種實施例中,粒子包含50:50聚乳酸:聚乙醇酸。在各種實施例中,粒子包含約25:75、30:70、35:65、40:60、45:55、50:50、55:45、60:40、65:35、70:30、75:25、80:20、81:19、82:18、83:17、84:16、85:15、86:14、87:13、88:12、89:11、90:10、91:9、92:8、93:7、94:6、95:5、96:4、97:3、98:2、99:1或100:0聚乳酸:聚乙醇酸,包括全部數值及位於此等數值之間的範圍。
在各種實施例中,粒子具有負ζ電位。在各種實施例中,粒子之ζ電位為約-100 mV至約0 mV、約-100 mV至約-25 mV、約-100至約-30 mV、約-80 mV至約-30 mV、約-75 mV至約-30 mV、約-70 mV至約-30 mV、約-75至約-35 mV、約-70至約-25 mV、約-60 mV至約-30 mV、約-60 mV至約-35 mV或約-50 mV至約-30 mV。在各種實施例中,ζ電位為約-25 mV、-30 mV、-35 mV、-40 mV、-45 mV、-50 mV、-55 mV、-60 mV、-65 mV、-70 mV、-75 mV、-80 mV、-85 mV、-90 mV、-95 mV或-100 mV,包括其中所有數值及範圍。在各種實施例中,載體粒子之負ζ電位在-30 mV至-80 mV之間。在各種實施例中,載體粒子之負ζ電位在-30 mV至-60 mV之間。在各種實施例中,負ζ電位藉由載體粒子之表面官能化來達成。在各種實施例中,表面官能化為羧化。
在各種實施例中,載體粒子之大小或直徑在0.05 µm與約10 µm之間。在各種實施例中,載體粒子之直徑在0.1 µm與約10 µm之間。在各種實施例中,載體粒子之直徑在0.1 µm與約5 µm之間。在各種實施例中,載體粒子之直徑在0.1 µm與約3 µm之間。在各種實施例中,載體粒子之直徑在0.3 µm與約5 µm之間。在各種實施例中,載體粒子之直徑為約0.3 µm至約3 µm。在各種實施例中,載體粒子之直徑在約0.3 µm至約1 µm之間。在各種實施例中,載體粒子之直徑在約0.4 µm至約1 µm之間。在各種實施例中,載體粒子之直徑為約100至10000 nm、約100至5000 nm、約100至3000 nm、約100至2000 nm、約100至1500 nm、約300至5000 nm、約300至3000 nm、約300至1000 nm、約300至800 nm、約400至800 nm或約200至700 nm。在各種實施例中,載體粒子之直徑為約50 nm、100 nm、200 nm、300 nm、400 nm、500 nm、600 nm、700 nm、800 nm、900 nm、1000 nm、1100 nm、1200 nm、1300 nm、1400 nm、1500 nm或2000 nm,包括其中所有數值及範圍。在各種實施例中,帶負電荷粒子之直徑在400 nm與800 nm之間。在各種實施例中,帶負電荷粒子之直徑在350 nm與800 nm之間。
在各種實施例中,載體粒子具有均勻的尺寸分佈。在各種實施例中,載體粒子具有均勻的尺寸分佈,其中至少90%粒子之直徑在0.05 µm與約10 µm之間、在0.1 µm與約10 µm之間、在0.1 µm與約5 µm之間、在0.1 µm與約3 µm之間、在0.3 µm與約5 µm之間、在0.3 µm至約3 µm之間,包括其中所有數值及範圍。在各種實施例中,載體粒子具有均勻的尺寸分佈,其中至少90%粒子之直徑為約100至10000 nm、約100至5000 nm、約100至3000 nm、約100至2000 nm、約300至5000 nm、約300至3000 nm、約300至1000 nm、約300至800 nm、約400至800 nm或約200至700 nm,包括其中所有數值及範圍。在各種實施例中,載體粒子之直徑為約50 nm、100 nm、200 nm、300 nm、400 nm、500 nm、600 nm、700 nm、800 nm、900 nm、1000 nm、1100 nm、1200 nm、1300 nm、1400 nm、1500 nm或2000 nm,包括其中所有數值及範圍。在各種實施例中,載體粒子具有均勻的尺寸分佈,其中至少50%粒子之直徑在約0.05 µm與約10 µm之間、在約0.1 µm與約10 µm之間、在約0.1 µm與約5 µm之間、在約0.1 µm與約3 µm之間、在約0.3 µm與約5 µm之間及在約0.3 µm與約3 µm之間,包括其中所有數值及範圍。在各種實施例中,粒子具有均勻的尺寸分佈,其中至少50%粒子之直徑為約100至10000 nm、約100至5000 nm、約100至3000 nm、約100至2000 nm、約300至5000 nm、約300至3000 nm、約300至1000 nm、約300至800 nm、約400至800 nm或約200至700 nm,包括其中所有數值及範圍。在各種實施例中,載體粒子之直徑為約50 nm、100 nm、200 nm、300 nm、400 nm、500 nm、600 nm、700 nm、800 nm、900 nm、1000 nm、1100 nm、1200 nm、1300 nm、1400 nm、1500 nm或2000 nm,包括其中所有數值及範圍。
在各種實施例中,載體粒子具有均勻的尺寸分佈,其中至少10%粒子之直徑在約0.05 µm與約10 µm之間、在約0.1 µm與約10 µm之間、在約0.1 µm與約5 µm之間、在約0.1 µm與約3 µm之間、在約0.3 µm與約5 µm之間及在約0.3 µm與約3 µm之間,包括其中所有數值及範圍。在各種實施例中,載體粒子具有均勻的尺寸分佈,其中至少10%粒子之直徑為約100至10000 nm、約100至5000 nm、約100至3000 nm、約100至2000 nm、約300至5000 nm、約300至3000 nm、約300至1000 nm、約300至800 nm、約400至800 nm或約200至700 nm,包括其中所有數值及範圍。在各種實施例中,載體粒子之直徑為約50 nm、100 nm、200 nm、300 nm、400 nm、500 nm、600 nm、700 nm、800 nm、900 nm、1000 nm、1100 nm、1200 nm、1300 nm、1400 nm、1500 nm或2000 nm,包括其中所有數值及範圍。
在各種實施例中,粒子囊封抗原,其負ζ電位在-100 mV與0 mV之間,且其中粒子之直徑在100與1000 nm之間。在各種實施例中,粒子囊封包含一或多種基因療法載體抗原、其部分或其組合的一或多種抗原,且其中粒子之尺寸在400與800 nm之間,且粒子之負ζ電位在-30 mV至-80 mV之間。
在各種實施例中,粒子囊封抗原,其負ζ電位在-100 mV與0 mV之間,且其中粒子之直徑在100與1000 nm之間。在各種實施例中,粒子囊封包含一或多種由基因療法載體產生之蛋白治療劑、其部分或組合的一或多種抗原,且其中粒子之尺寸在400與800 nm之間,且粒子之負ζ電位在-30 mV至-80 mV之間。
在各種實施例中,粒子囊封一或多種基因療法載體抗原、其部分或組合,及一或多種由基因療法載體產生之蛋白治療劑、其部分或組合。在各種實施例中,抗原包含一或多種蛋白質、肽或其抗原表位。
本文亦涵蓋一種組合物,其包含囊封一或多種基因療法載體抗原、其部分或組合之脂質體。
在另一實施例中,本發明提供一種組合物,其包含囊封由基因療法載體產生之治療蛋白及/或其部分的脂質體。
在各種實施例中,脂質體帶負電荷。在各種實施例中,脂質體具有負ζ電位。在各種實施例中,負ζ電位在-100 mV至0 mV之間。在各種實施例中,帶負電荷之脂質體之ζ電位為約-100 mV至約0 mV、約-100 mV至約-25 mV、約-100至約-30 mV、約-80 mV至約-30 mV、約-75 mV至約-30 mV、約-70 mV至約-30 mV、約-75至約-35 mV、約-70至約-25 mV、約-60 mV至約-30 mV、約-60 mV至約-35 mV或約-50 mV至約-30 mV。在各種實施例中,ζ電位為約-25 mV、-30 mV、-35 mV、-40 mV、-45 mV、-50 mV、-55 mV、-60 mV、-65 mV、-70 mV、-75 mV、-80 mV、-85 mV、-90 mV、-95 mV或-100 mV,包括其中所有數值及範圍。在各種實施例中,脂質體之負ζ電位在-30 mV至-80 mV之間。在各種實施例中,脂質體之負ζ電位在-30 mV至-60 mV之間。
在各種實施例中,脂質體在100-1000 nm之間、或在300-800 nm之間或在400-800 nm之間。在各種實施例中,脂質體為約100 nm、約200 nm、約300 nm、約400 nm、約500 nm、約600 nm、約700 nm、約800 nm、約900 nm或約1000 nm。
在各種實施例中,抗原包含基因療法載體抗原或其一或多個部分。在各種實施例中,基因療法載體為病毒載體。在各種實施例中,病毒載體係選自由以下組成之群:腺病毒、腺相關病毒(AAV)、單純疱疹病毒、B型肝炎病毒、慢病毒、反轉錄病毒、α病毒、黃病毒、棒狀病毒、麻疹病毒、新城雞瘟病毒(Newcastle disease virus)、科沙奇病毒(Coxsackievirus)、輸血傳播病毒、指環病毒、人類乳突狀瘤病毒、痘病毒、痘瘡病毒、經修飾之安卡拉病毒(modified Ankara virus)、水泡性口炎病毒、小核糖核酸病毒、菸草嵌紋病毒、豇豆嵌紋病毒、豇豆褪綠斑駁病毒、酸漿嵌紋病毒、紅三葉草壞死嵌紋病毒、馬鈴薯病毒x、豇豆花葉病毒、雞貧血病毒或胡瓜嵌紋病毒。在各種實施例中,病毒為溶瘤病毒。在各種實施例中,病毒為嵌合病毒、合成病毒、嵌紋病毒或假型病毒。
在各種實施例中,粒子囊封抗原,其中抗原為一或多種AAV載體、其部分或組合。在各種實施例中,AAV選自由以下組成之群:AAV-1、AAV-2、AAV-3、AAV-4、AAV-5、AAV-6、AAV-7、AAV-8、AAV-9、AAV-10、AAV-12、Anc80、合成AAV、其組合或經工程改造之版本。在各種實施例中,抗原為一或多種AAV衣殼蛋白。在各種實施例中,AAV衣殼蛋白為VP-1、VP-2及VP-3。
在各種實施例中,基因療法載體為細菌、噬菌體、酵母、胞泌體或紅血球。
在各種實施例中,基因療法載體用於治療癌症、自體免疫疾病、過敏症、心血管疾病、代謝疾病、糖尿病、酶缺乏症、蛋白質缺乏症、囊腫性纖維化、血液病症、β-地中海貧血症、鐮狀細胞疾病、A型血友病、B型血友病、溶素體儲積病、法布立病、高歇氏病(Gaucher disease)、龐培氏病、尼曼-匹克二氏病(Niemann-Pick disease)、泰-薩二氏病(Tay-Sachs disease)、黃斑變性、黏多醣病、靜脈栓塞、馮威里氏病(von Willebrand disease)、猛爆性紫斑、生長激素缺乏症、神經節苷脂症、鹼性低磷酸酶症、膽固醇酯儲積病、高尿酸血症、杜興氏肌肉失養症(Duchenne Muscular Dystrophy)、杭丁頓氏舞蹈症(Huntington's disease)、帕金森氏症(Parkinson's)、阿茲海默氏症(Alzheimer's disease)、無脈絡脈畸型、斯特格氏病(Stargardt Disease)、巴登氏病(Batten disease)、脊髓小腦失調、ALS、額顳葉變性、鳥胺酸胺甲醯基轉移酶缺乏症、色素性視網膜炎、RPE-65突變相關病、大皰性表皮鬆解、隱性營養不良型大皰性表皮鬆解、脊髓性肌萎縮、苯酮尿症(PKU)、X性聯肌小管肌病、克果-納傑氏症候群(Crigler-Najjar syndrome)、兒茶酚胺引發之多型性心室性心搏過速、1型肝醣儲積症、α-甘露糖症、脆弱X染色體症候群、精胺酸酶缺乏症、X性聯慢性肉芽腫病、腺苷去胺酶缺乏症、萊伯氏先天性黑矇(Leber's congenital amaurosis)、脂蛋白脂肪酶缺乏症、大腦型腎上腺腦白質失養症、異染性腦白質失養症、范康尼氏貧血症(Fanconi anemia)、失色症、硬皮病、成骨不全症、冠狀動脈疾病、酪胺酸血症、周邊神經病變、視神經病變、冠狀動脈疾病、呼吸道融合細胞病毒(RSV)介導之下呼吸道疾病、達農病(Danon disease)、嚴重白血球黏附分子缺乏症、丙酮酸激酶缺乏症、恰克-馬利-杜斯氏病(Charcot Marie Tooth disease)、偉-爾二氏症候群(Wiskott Aldrich syndrome)、α-突觸核蛋白tau蛋白病變、心肌缺血引發的難治性絞痛、I型肌強直性營養不良、跛行、周邊動脈疾病、甲基丙二酸血症、蔗糖酶-異麥芽糖酶缺乏症、B型尼曼-匹克二氏病(Niemann-Pick type B disease)、α1-PI缺乏症、遺傳性血管水腫、血纖維蛋白原缺乏症、因子VIIa缺乏症、因子X缺乏症、因子XI缺乏症、因子XII缺乏症、蛋白C缺乏症、抗凝血酶III缺乏症、MPS I、MPS II、MPS III、MPS IV、MPS VI、MPS VII、MPS IX、鈣化/骨化病症、ENPP1缺乏症、ENPP3缺乏症、ABCC6缺乏症、芳族L-胺基酸去羧酶缺乏症、天使症候群(Angelman syndrome)、高苯丙胺酸血症、失智症及雷特氏症候群(Rett syndrome)及尤塞氏症候群(Usher syndrome)。
在各種實施例中,自體免疫性疾病係選自由以下組成之群:多發性硬化症、艾迪森氏病(Addison's disease)、僵直性脊椎炎、禿頭症、骨關節炎、牛皮癬性關節炎、硬皮病、I型糖尿病、類風濕性關節炎、甲狀腺炎、全身性紅斑性狼瘡症、雷諾氏症候群(Reynaud's syndrome)、貝塞特氏症(Behcet's syndrome)、修格蘭氏症候群(Sjorgen's syndrome)、自體免疫葡萄膜炎、伊頓-藍伯疾病(Eaton Lambert's disease)、自體免疫心肌炎、發炎性腸道疾病、肌肉萎縮性側索硬化(ALS)、全身性紅斑狼瘡、視神經脊髓炎、特發性血小板減少性紫癜、血栓性血小板減少性紫斑症、膜性腎病變、類天疱瘡、尋常型天疱瘡、重症肌無力、乳糜瀉、潰瘍性結腸炎、克羅恩氏病(Crohn's disease)、結節性紅斑、絲球體腎炎、古巴士德氏症候群(Goodpasture's syndrome)、肉芽腫病、格雷夫氏病(Grave's disease)、格-巴二氏症候群(Guillain-Barre syndrome)、橋本氏疾病(Hashimoto disease)、溶血性貧血、川崎病(Kawasaki Disease)、混合型結締組織疾病、多病灶性運動神經病變、周邊膽汁性肝硬化、多血管炎重疊症候群、1型硬皮病、硬化性膽管炎、僵體症候群、高安氏動脈炎(Takayasu arteritis)、白斑病或韋格納肉芽腫病(Wegeners granulomatosis)。
在各種實施例中,過敏為食物過敏。在各種實施例中,過敏為環境過敏。在各種實施例中,食物過敏係花生過敏、樹堅果過敏、乳過敏、蛋過敏、魚過敏、小麥過敏、芹菜過敏或桃子過敏。在各種實施例中,環境過敏係花粉過敏、粉塵過敏、寵物皮屑過敏或黴菌過敏。在各種實施例中,寵物過敏係貓過敏或狗過敏。
在各種實施例中,基因療法載體用於治療癌症。在各種實施例中,癌症係選自由以下組成之群:腦癌、皮膚癌、眼癌、乳癌、前列腺癌、肺癌、食道癌、頭頸癌、子宮頸癌、肝癌、大腸癌、骨癌、子宮癌、卵巢癌、膀胱癌、胃癌、口腔癌、甲狀腺癌、腎癌、睪丸癌、白血病、淋巴瘤、黑色素瘤及間皮瘤。
在各種實施例中,由基因療法載體產生之治療劑為蛋白質、多肽或肽。在各種實施例中,蛋白質為細胞介素、趨化介素、激素、生長因子、酶或抗體。
在各種實施例中,抗體為單株抗體。在各種實施例中,抗體為重組單株抗體。在各種實施例中,抗體係選自由以下組成之群:抗體-蛋白質融合物、免疫黏附素、單特異性抗體、雙特異性抗體、三特異性抗體。在各種實施例中,抗體係選自由以下組成之群:抗體片段、抗原結合片段(Fab)、單鏈可變片段(scFv)。在各種實施例中,抗體為單域抗體。在各種實施例中,抗體為IgA、IgD、IgE、IgM及/或其變異體。在各種實施例中,抗體靶向IL-1α、IL-1β、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-12p70、IL-13、IL-14、IL-15、IL-16、IL-17、IL-17、IL-18、IL-20、IL-21、IL-22、IL-23、IL-24、IL-25、IL-26、IL-27、IL-27b、IL-28、IL-29、IL-30、IL-31、IL-32、IL-33、IL-35、IL-36、CCL1、CCL2、CCL3、CCL4、CCL5、CCL6、CCL7、CCL8、CCL9、CCL10、CCL11、CCL12、CCL14、CCL15、CCL16、CCL17、CCL18、CCL19、CCL20、CCL21、CCL22、CCL23、CCL24、CCL25、CCL26、CCL27、CCL28、CXCL1、CXCL2 (MCP-1)、CXCL3 (MIP-1α、CXCL4 (MIP-1β、CXCL5 (RANTES)、CXCL6、CXCL7、CXCL8、CXCL9、CXCL10、CXCL11、CXCL12、CXCL13、CXCL14、CXCL15、CXCL16、CXCL17、GM-CSF、IFN-α、IFN-β、IFN-γ、TNF-α、TNF-a、TNF-β、TGF-β1、TGF-β2、TGF-β3、LT-β、4-1BBL、APRIL、GITRL、LIGHT、OX40L、TALL-1、TRAIL、TWEAK、TRANCE、CD1c、CD2、CD3、CD4、CD5、CD8、CD9、CD10、CD11b、CD11c、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD24、TACI、CD25、CD27、CD28、CD30、CD30L、CD31、CD32、CD32b、CD34、CD33、CD38、CD39、CD40、CD40-L、CD41b、CD42a、CD42b、CD43、CD44、CD45、CD45RA、CD47、CD45RA、CD45RO、CD48、CD52、CD55、CD56、CD58、CD61、CD66b、CD69、CD70、CD72、CD79、CD68、CD84、CD86、CD93、CD94、CD95、CRACC、BLAME、BCMA、CD103、CD107、CD112、CD120a、CD120b、CD123、CD125、CD127、CD134、CD135、CD140a、CD141、CD154、CD155、CD160、CD161、CD163、CD172a、XCR1、CD203c、CD204、CD206、CD207、CD226、CD244、CD267、CD268、CD269、CD355、CD358、CRTH2、NKG2A、NKG2B、NKG2C、NKG2D、NKG2E、NKG2F、NKG2H、KIR2DL1、KIR2DL2、KIR2DL3、KIR2DL5A、KIR2DL5B、KIR3DL1、KIR3DL2、KIR3DL3、KIR3DL4、KIR2DS1、KIR2DS2、KIR2DS3、KIR2DS4、KIR2DS5、DAP12、KIR3DS、NKp44、NKp46、TCR、BCR、整合素、FcβεRI、MHC-I、MHC-II、IL-1R、IL-2Rα、IL-2Rβ、IL-2Rγ、IL-3Rα、CSF2RB、IL-4R、IL-5Rα、CSF2RB、IL-6Rα、gp130、IL-7Rα、IL-9R、IL-10R、IL-12Rβ1、IL-12Rβ2、IL-13Rα1、IL-13Rα2、IL-15Rα、IL-21R、IL-23R、IL-27Rα、IL-31Rα、OSMR、CSF-1R、細胞表面IL-15、IL-10Rα、IL-10Rβ、IL-20Rα、IL-20Rβ、IL-22Rα1、IL-22Rα2、IL-22Rβ、IL-28RA、PD-1、PD-1H、BTLA、CTLA-4、PD-L1、PD-L2、2B4、B7-1、B7-2、B7-H1、B7-H4、B7-DC、DR3、LIGHT、LAIR、LTα1β2、LTβR、TIM-1、TIM-3、TIM-4、TIGIT、LAG-3、ICOS、ICOS-L、SLAM、SLAMF2、OX-40、OX-40L、GITR、GITRL、TL1A、HVEM、41-BB、41BB-L、TL-1A、TRAF1、TRAF2、TRAF3、TRAF5、BAFF、BAFF-R、APRIL、TRAIL、RANK、AITR、TRAMP、CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CCR11、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、CXCR6、CXCR7、CLECL9a、DC-SIGN、IGSF4A、SIGLEC、EGFR、PDGFR、VEGFR、FAP、α-SMA、FAS、FAS-L、FC、ICAM-1、ICAM-2、ICAM-3、ICAM-4、ICAM-5、PECAM-1、MICA、MICB、UL16、ULBP1、ULBP2、ILBP3、ULBP4、ULBP5、ULBP6、MULT1、RAE1 α、β、γ、δ及ε、H60a、H60b、H60c、GPR15、ST2及/或其組合整合素包括α1、α2、αIIb、α3、α4、α5、α6、α7、α8、α9、α10、α11、αD、αE、αL、αM、αV、αX、β1、β2、β3、β4、β5、β6、β7、β8及/或其組合。TCR包括α、β、γ、δ、ε、ζ鏈及/或其組合。
在各種實施例中,抗體靶向一或多種免疫細胞。在各種實施例中,免疫細胞為T細胞、B細胞、NK細胞、NK-T細胞、單核球、巨噬細胞、嗜中性球、粒細胞、樹突狀細胞、肥大細胞、嗜酸性球、嗜鹼性球、TH1細胞、TH2a細胞、Treg細胞、Tr1細胞及Breg細胞。
在各種實施例中,抗體係選自由以下組成之群:阿昔單抗(abciximab)、阿達木單抗(adalimumab)、阿侖單抗(alemtuzumab)、阿維魯單抗(avelumab)、阿替利珠單抗(atezolizumab)、巴利昔單抗(basiliximab)、貝伐單抗(bevacizumab)、貝茨羅特斯單抗(bezlotoxumab)、博納吐單抗(blinatumomab)、康納單抗(canakinumab)、賽妥珠單抗(certolizumab)、西妥昔單抗(cetuximab)、達利珠單抗(daclizumab)、地諾單抗(denosumab)、度伐魯單抗(durvalumab)、艾法珠單抗(efalizumab)、艾美賽珠單抗(emicizumab)、艾托奇單抗(etokimab)、戈利木單抗(golimumab)、伊派利單抗(ipilimumab)、依奇珠單抗(ixekizumab)、英利昔單抗(infliximab)、那他珠單抗(natalizumab)、納武單抗(nivolumab)、奧拉單抗(olaratumab)、奧馬珠單抗(omalizumab)、奧法木單抗(ofatumumab)、帕利珠單抗(palivizumab)、帕尼單抗(panitumumab)、帕博利珠單抗(pembrolizumab)、雷莫蘆單抗(ramucirumab)、利妥昔單抗(rituximab)、托珠單抗(tocilizumab)、曲妥珠單抗(trastuzumab)、曲美木單抗(tremelimumab)、蘇金單抗(secukinumab)、烏司奴單抗(ustekinumab)及維多珠單抗(vedolizumab)。
在各種實施例中,由載體產生之治療劑為細胞介素或趨化介素。在各種實施例中,細胞介素及趨化介素係選自由以下組成之群:IL-1α、IL-1β、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-12p70、IL-13、IL-14、IL-15、IL-16、IL-17、IL-17、IL-18、IL-20、IL-21、IL-22、IL-23、IL-24、IL-25、IL-26、IL-27、IL-27b、IL-28、IL-29、IL-30、IL-31、IL-32、IL-33、IL-35、IL-36、CCL1、CCL2、CCL3、CCL4、CCL5、CCL6、CCL7、CCL8、CCL9、CCL10、CCL11、CCL12、CCL14、CCL15、CCL16、CCL17、CCL18、CCL19、CCL20、CCL21、CCL22、CCL23、CCL24、CCL25、CCL26、CCL27、CCL28、CXCL1、CXCL2 (MCP-1)、CXCL3 (MIP-1α、CXCL4 (MIP-1β、CXCL5 (RANTES)、CXCL6、CXCL7、CXCL8、CXCL9、CXCL10、CXCL11、CXCL12、CXCL13、CXCL14、CXCL15、CXCL16、CXCL17、GM-CSF、IFN-α、IFN-β、IFN-γ、TNF-α、TNF-a、TNF-b、TGF-β1、TGF-β2、TGF-β3、LT-β、4-1BBL、APRIL、GITRL、LIGHT、OX40L、TALL-1、TRAIL、TWEAK及TRANCE.
在各種實施例中,蛋白為選自由以下組成之群的激素:腎上腺素、褪黑激素、去甲腎上腺素(noradrenaline)、正腎上腺素(norepinephrine)、三碘甲狀腺素、甲狀腺素、多巴胺、前列腺素、白三烯、前列腺環素、凝血脂素、澱粉素、抗穆勒氏管激素(Anti-Müllerian hormone)、脂聯素、促腎上腺皮質激素、血管緊縮素原、血管緊張素、抗利尿激素、升壓素、精胺酸升壓素、抑鈣素、膽囊收縮素、促皮質素釋放激素、皮質抑素、腦啡肽、內皮素、紅血球生成素、促濾泡激素、甘丙胺素、胃抑肽、胃泌素、胃內激素、升糖素、類升糖素肽1、促性腺素釋放激素、生長釋放激素、鐵調素(hepcidin)、人類絨毛膜激性腺素、人類胎盤生乳素、生長激素、抑制素、胰島素、似胰島素生長因子、瘦素、促脂素、促黃體素、促黑素細胞素、腸動素、食慾激素受體、骨鈣化素、催產素、胰多肽、副甲狀腺激素、垂體腺苷酸環化酶活化肽、促乳素、促乳素釋放激素、鬆弛素、腎素、胰泌素、生長抑素、血小板生成素、促甲狀腺激素、促甲狀腺素釋放激素、激脈腸肽、鳥苷蛋白、尿鳥苷素、睪固酮、去氫表雄固酮、雄固烯二酮、二氫睪固酮、醛固酮、雌二醇、雌酮、雌三醇、皮質醇、孕酮、促鈣三醇及促鈣二醇。
在各種實施例中,蛋白為選自由以下組成之群的生長因子:腎上腺髓素、血管生成素、自分泌運動性因子、骨形態生成蛋白、睫狀神經營養因子、白血病抑制因子、群落刺激因子、巨噬細胞群落刺激因子、顆粒球群落刺激因子、顆粒球巨噬細胞群落刺激因子、表皮生長因子、ephrin A1、ephrin A2、ephrin A3、ephrin A4、ephrin A5、ephrin B1、ephrin B2、ephrin B3、紅血球生成素、纖維母細胞生長因子、纖維母細胞生長因子1、纖維母細胞生長因子2、纖維母細胞生長因子3、纖維母細胞生長因子4、纖維母細胞生長因子5、纖維母細胞生長因子6、纖維母細胞生長因子7、纖維母細胞生長因子8、纖維母細胞生長因子9、纖維母細胞生長因子10、纖維母細胞生長因子11、纖維母細胞生長因子12、纖維母細胞生長因子13、纖維母細胞生長因子14、纖維母細胞生長因子15、纖維母細胞生長因子16、纖維母細胞生長因子17、纖維母細胞生長因子18、纖維母細胞生長因子19、纖維母細胞生長因子20、纖維母細胞生長因子21、纖維母細胞生長因子22、纖維母細胞生長因子23、胎牛促體素、神經膠質細胞株衍生神經營養因子、神經營養素、珀瑟芬(persephin)、青蒿琥酯、生長分化因子-9、肝細胞生長因子、肝細胞瘤衍生生長因子、似胰島素生長因子-1、似胰島素生長因子-2、角質細胞生長因子、遷移刺激因子、巨噬細胞刺激蛋白、肌肉抑制素、神經調節蛋白1、神經調節蛋白2、神經調節蛋白3、神經調節蛋白4、腦衍生神經營養因子、神經生長因子、神經營養蛋白-3、神經營養蛋白-4、胎盤生長因子、血小板衍生生長因子、腎酶、T細胞生長因子、血小板生成素、轉形生長因子、轉形生長因子α、轉形生長因子β、腫瘤壞死因子-α或血管內皮生長因子。在各種實施例中,細胞介素係選自由以下組成之群:雜項造血素、Epo、Tpo、Flt-3L、SCF、M-CSF及MSP。
在各種實施例中,蛋白為選自由以下組成之群的溶血栓劑:組織纖維蛋白溶酶原活化因子、鏈球菌激酶、尿激酶、阿尼普酶(anistreplase)、瑞替普酶(reteplase)、卡比奇激酶(kabikikinase)、替奈普酶(tenecteplase)及洛激酶(rokinase)。
在各種實施例中,由載體產生之治療劑為酶。在各種實施例中,酶係選自由以下組成之群:基因編輯核酸酶、巨核酸酶、歸巢核酸內切酶、鋅指核酸酶、類轉錄活化子效應子核酸酶(TALEN)、CRISPR相關核酸酶及CRISPR-Cas9。
在各種實施例中,Cas蛋白質係選自由以下組成之群:Cas 3、Cas8a、Cas5、Cas8b、Cas8c、Cas 9、Cas10d、Cse1、Cse2、Csy1、Csy2、Csy3、GSU0054、Cas10、Csm2、Cmr5、Cas10、Csx11、Csx10、Csf1、Cas9、Csn2、Cas4、Cas12、Cas12a、Cas12b、Cas12c、Cas12d、Cas12e、Cas12f、Cas14、C2c10、Cas12g、Cas12h、Cas12i、Cas12k、C2cr4、C2cr8、C2cr9、Cas13、Cas13a、Cas13b、Cas13c、Cas13d。在各種實施例中,TALEN為基於FokI、基於PvuII、基於I-TevI、基於IAniI、基於I-OnuI或基於MutH的TALEN。在各種實施例中,酶為選自由以下組成之群的核酸酶:LAGLIDADG (巨核酸酶)、GIY-YIG、His-Cys匣、H-N-H、PD-(D/E)-xK、Vrs樣、megaTAL。
在各種實施例中,酶係選自由以下組成之群:伊米苷酶(imiglucerase)、他利苷酶α (taliglucerase alfa)、維拉苷酶α (velaglucerase alfa)、β-葡萄糖腦苷酶、阿糖腦苷酶(alglucerase)、阿加糖酶β (agalsidase beta)、阿加糖酶α (agalsidase alpha)、賽貝利酶α (sebelipase alpha)、α-L-艾杜糖醛酸酶(alpha-L-iduronidase)、人類艾杜糖醛酸-2-硫酸酯酶(human iduronate-2-sulfatase)、N-磺基葡萄胺糖磺基水解酶、埃洛磺酶α (elosulfase alpha)、加硫酶(galsulfase)、α-葡萄糖苷酶(GAA)、人類α甘露糖苷酶、因子VIII、因子IX、β-半乳糖苷酶、精胺酸酶、失養性肌強直蛋白質激酶、鳥胺酸胺甲醯基轉移酶、NADPH氧化酶、NADH去氫酶4、腺苷去胺酶、脂蛋白脂肪酶、β-葡萄糖腦苷酶、肌微管素、芳基硫酸酯酶A、DOPA去羧酶、基質金屬肽酶1、延胡索醯乙醯乙酸羥化酶、苯丙胺酸羥化酶、丙酮酸激酶、膽色素原去胺酶、鹼性磷酸酶、蔗糖酶-異麥芽糖酶、酸性鞘磷脂酶、硫酸乙醯肝素硫酸酯酶、N-乙醯半乳胺糖-6-硫酸酯酶、N-乙醯半乳胺糖-4-硫酸酯酶、α-1蛋白酶抑制劑、1-酯酶抑制劑、血纖維蛋白原、因子VIIa、因子X、因子XI、因子XII、蛋白C、抗凝血酶III、外核苷酸焦磷酸酶/磷酸二酯酶1、外核苷酸焦磷酸酶/磷酸二酯酶3及芳族L-胺基酸去羧酶。
在各種實施例中,酶為蛋白酶。在各種實施例中,蛋白酶為天冬胺酸蛋白酶、半胱胺酸蛋白酶、金屬蛋白酶、絲胺酸蛋白酶及/或蘇胺酸蛋白酶。在各種實施例中,蛋白酶係選自由以下組成之群:ADAM1、ADAM2、ADAM7、ADAM8、ADAM9、ADAM10、ADAM11、ADAM12、ADAM15、ADAM17、ADAM18、ADAM19、ADAAM20、ADAM21、ADAM22、ADAM23、ADAM28、ADAM29、ADAM30、ADAM33、肝素酶、MMP1、MMP2、MMP3、MMP7、MMP8、MMP9、MMP10、MMP11、MMP12、MMP13、MMP14、MMP15、MMP16、MMP17、MMP18、MMP19、MMP20、MMP21、MMP23A、MMP23B、MMP24、MMP25、MMP26、MMP27及MMP28。
在各種實施例中,由載體產生之治療劑為蛋白。在各種實施例中,蛋白係選自由以下組成之群:光可活化通道視紫蛋白、腫瘤蛋白53、HIV Gag蛋白、脆弱X染色體智力遲鈍蛋白、β血球蛋白、纖維母細胞生長因子4、人類生長因子、韋-爾二氏症候群(Wisckott Aldrich syndrome)蛋白、存活運動神經元蛋白1、存活運動神經元蛋白2、視網膜色素上皮(RPE) 65、血管內皮生長因子(VEGF)、Rab護航蛋白(REP) 1、腎上腺腦白質營養不良蛋白、范康尼氏貧血互補群A蛋白、ATP結合卡匣轉運蛋白、膠原蛋白VII (COL7)蛋白、I型膠原蛋白、III型及V型膠原蛋白、β2整合素、溶酶體相關膜蛋白、肌萎縮蛋白、微型肌萎縮蛋白、似胰島素生長因子、T細胞免疫調節因子1/ATP酶H+傳輸V0次單元A3胰臟及十二指腸同源匣1、MAF BZIP轉錄因子A、囊性纖維化跨膜傳導調節蛋白、ATP結合卡匣子族C成員6、ATP結合卡匣子族A成員4、血管內皮生長因子A、絲胺酸蛋白酶抑制劑家族A成員1、顆粒蛋白前體、微管相關蛋白tau、C9或f72蛋白及隙型連結b2。
本發明提供使用TIMP囊封抗原來誘導抗原特異性免疫耐受性之方法,該方法包含向個體投與包含囊封抗原之帶負電荷粒子之組合物,其中抗原為一或多種基因療法載體抗原及/或一或多種由基因療法載體產生之轉殖基因蛋白質產物、其部分或其組合。在各種實施例中,抗原為一或多種基因療法載體抗原、其部分或其組合及/或由載體產生之轉殖基因蛋白質、其部分或組合。在各種實施例中,向有需要之個體投與囊封一或多種抗原之TIMP誘導抗原特異性耐受性。
亦提供一種在有需要之個體中誘導耐受性的方法,該方法包含向個體投與包含如本文所描述之脂質體的組合物。
在各種實施例中,向個體投與和囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之TIMP組合的囊封一或多種基因療法載體抗原之TIMP。投與和囊封由基因療法載體產生之轉殖基因蛋白質產物之TIMP組合的囊封基因療法載體抗原之TIMP誘導對基因療法載體抗原及由基因療法載體產生之轉殖基因蛋白質產物兩者的抗原特異性耐受性。在各種實施例中,在向個體投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之TIMP之前、同時或之後向個體投與囊封一或多種基因療法載體抗原之TIMP。
在各種實施例中,囊封一或多種基因療法載體抗原之TIMP在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之TIMP之前5、10、15、30、45或60分鐘投與。在各種實施例中,囊封一或多種基因療法載體抗原之TIMP在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之TIMP之前1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、36、48、72或96小時投與。在各種實施例中,囊封一或多種基因療法載體抗原之TIMP在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之TIMP之前1、2、3、4、5、6或7天投與。在各種實施例中,囊封一或多種基因療法載體抗原之TIMP在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之TIMP之前一週、兩週、三週、四週、1個月、2個月、3個月、4個月、5個月、6個月、7個月、8個月、9個月、10個月、11個月或12個月投與。
在各種實施例中,囊封一或多種基因療法載體抗原之TIMP在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之TIMP之後5、10、15、30、45或60分鐘投與。在各種實施例中,囊封一或多種基因療法載體抗原之TIMP在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之TIMP之後1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、36、48、72或96小時投與。在各種實施例中,囊封一或多種基因療法載體抗原之TIMP在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之TIMP之後1、2、3、4、5、6或7天投與。在各種實施例中,囊封一或多種基因療法載體抗原之TIMP在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之TIMP之後一週、兩週、三週、四週、1個月、2個月、3個月、4個月、5個月、6個月、7個月、8個月、9個月、10個月、11個月或12個月投與。
在各種實施例中,TIMP經靜脈內、皮下、肌肉內、腹膜內、鼻內或經口投與。在各種實施例中,TIMP在投與基因療法載體之前、同時或之後投與。
在各種實施例中,TIMP在投與基因療法載體之前5、10、15、30、45或60分鐘投與。在各種實施例中,TIMP在投與基因療法載體之前1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、36、48、72或96小時投與。在各種實施例中,TIMP在投與基因療法載體之前1、2、3、4、5、6或7天投與。在各種實施例中,TIMP在投與基因療法載體之前一週、兩週、三週、四週、1個月、2個月、3個月、4個月、5個月、6個月、7個月、8個月、9個月、10個月、11個月或12個月投與。
在各種實施例中,TIMP在投與基因療法載體之後5、10、15、30、45或60分鐘投與。在各種實施例中,TIMP在投與基因療法載體之後1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、36、48、72或96小時投與。在各種實施例中,TIMP在投與基因療法載體之後1、2、3、4、5、6或7天投與。在各種實施例中,TIMP在投與基因療法載體之後一週、兩週、三週、四週、1個月、2個月、3個月、4個月、5個月、6個月、7個月、8個月、9個月、10個月、11個月或12個月投與。
在各種實施例中,投與TIMP在有需要之個體中誘導對基因療法載體抗原、其部分或其組合之抗原特異性耐受性。在各種實施例中,投與TIMP在有需要之個體中誘導對轉殖基因蛋白質產物、其部分或組合之抗原特異性耐受性。在各種實施例中,投與TIMP在個體中降低對基因療法載體及/或由載體表現之轉殖基因蛋白質產物的發炎免疫反應。在各種實施例中,投與TIMP在個體中降低對一或多種經囊封之抗原的發炎免疫反應。在各種實施例中,投與TIMP在有需要之個體中降低對未囊封於粒子內之一或多種抗原的發炎反應。此類免疫調節反應在文獻中被稱為『感染性耐受』。在各種實施例中,發炎免疫反應為體液免疫反應及/或適應性免疫反應。在各種實施例中,免疫反應為抗體反應。在各種實施例中,抗體反應為IgA、IgG、IgE或IgM反應。在各種實施例中,抗體反應為中和抗體反應,例如形成針對基因療法載體抗原及/或由載體產生之轉殖基因蛋白質的中和抗體。在各種實施例中,免疫反應為T細胞、B細胞、NK細胞單核球、巨噬細胞、嗜酸性球或嗜鹼性球反應。在各種實施例中,免疫反應為對組織及/或器官之免疫浸潤降低。
在各種實施例中,投與TIMP在有需要之個體中誘導抗原特異性免疫調節因子反應。在各種實施例中,投與TIMP在個體中誘導調節性T細胞、B細胞、單核球及/或巨噬細胞。在各種實施例中,投與TIMP在個體中誘導抗原特異性調節性T細胞(Treg)、Tr1、調節性巨噬細胞(Mreg)及/或調節性B細胞(Breg)細胞。
在各種實施例中,向個體投與和囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之脂質體組合的囊封一或多種基因療法載體抗原之脂質體。投與和囊封由基因療法載體產生之轉殖基因蛋白質產物之脂質體組合的囊封基因療法載體抗原之脂質體誘導對基因療法載體抗原及由基因療法載體產生之轉殖基因蛋白質產物兩者的抗原特異性耐受性。在各種實施例中,在向個體投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之脂質體之前、同時或之後向個體投與囊封一或多種基因療法載體抗原之脂質體。
在各種實施例中,囊封一或多種基因療法載體抗原之脂質體在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之脂質體之前5、10、15、30、45或60分鐘投與。在各種實施例中,囊封一或多種基因療法載體抗原之脂質體在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之脂質體之前1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、36、48、72或96小時投與。在各種實施例中,囊封一或多種基因療法載體抗原之脂質體在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之脂質體之前1、2、3、4、5、6或7天投與。在各種實施例中,囊封一或多種基因療法載體抗原之脂質體在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之脂質體之前一週、兩週、三週、四週、1個月、2個月、3個月、4個月、5個月、6個月、7個月、8個月、9個月、10個月、11個月或12個月投與。
在各種實施例中,囊封一或多種基因療法載體抗原之脂質體在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之脂質體之後5、10、15、30、45或60分鐘投與。在各種實施例中,囊封一或多種基因療法載體抗原之脂質體在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之脂質體之後1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、36、48、72或96小時投與。在各種實施例中,囊封一或多種基因療法載體抗原之脂質體在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之脂質體之後1、2、3、4、5、6或7天投與。在各種實施例中,囊封一或多種基因療法載體抗原之脂質體在投與囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物之脂質體之後一週、兩週、三週、四週、1個月、2個月、3個月、4個月、5個月、6個月、7個月、8個月、9個月、10個月、11個月或12個月投與。
在各種實施例中,脂質體經靜脈內、皮下、肌肉內、腹膜內、鼻內或經口投與。在各種實施例中,脂質體係在投與基因療法載體之前、同時或之後投與。
在各種實施例中,脂質體在投與基因療法載體之前5、10、15、30、45或60分鐘投與。在各種實施例中,脂質體在投與基因療法載體之前1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、36、48、72或96小時投與。在各種實施例中,脂質體在投與基因療法載體之前1、2、3、4、5、6或7天投與。在各種實施例中,脂質體在投與基因療法載體之前一週、兩週、三週、四週、1個月、2個月、3個月、4個月、5個月、6個月、7個月、8個月、9個月、10個月、11個月或12個月投與。
在各種實施例中,脂質體在投與基因療法載體之後5、10、15、30、45或60分鐘投與。在各種實施例中,脂質體在投與基因療法載體之後1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、36、48、72或96小時投與。在各種實施例中,脂質體在投與基因療法載體之後1、2、3、4、5、6或7天投與。在各種實施例中,脂質體在投與基因療法載體之後一週、兩週、三週、四週、1個月、2個月、3個月、4個月、5個月、6個月、7個月、8個月、9個月、10個月、11個月或12個月投與。
在各種實施例中,投與脂質體在有需要之個體中誘導對基因療法載體抗原、其部分或其組合之抗原特異性耐受性。在各種實施例中,投與脂質體在有需要之個體中誘導對轉殖基因蛋白質產物、其部分或組合之抗原特異性耐受性。在各種實施例中,投與在個體中脂質體降低對基因療法載體及/或由載體表現之轉殖基因蛋白質產物的發炎免疫反應。在各種實施例中,投與脂質體在個體中降低對一或多種經囊封之抗原的發炎免疫反應。在各種實施例中,投與脂質體在有需要之個體中降低對未囊封於粒子內之一或多種抗原的發炎反應。此類免疫調節反應在文獻中被稱為『感染性耐受』。在各種實施例中,發炎免疫反應為體液免疫反應及/或適應性免疫反應。在各種實施例中,免疫反應為抗體反應。在各種實施例中,抗體反應為IgA、IgG、IgE或IgM反應。在各種實施例中,抗體反應為中和抗體反應,例如形成針對基因療法載體抗原及/或由載體產生之轉殖基因蛋白質的中和抗體。在各種實施例中,免疫反應為T細胞、B細胞、NK細胞單核球、巨噬細胞、嗜酸性球或嗜鹼性球反應。
在各種實施例中,投與脂質體在有需要之個體中誘導抗原特異性免疫調節因子反應。在各種實施例中,投與脂質體在個體中誘導調節性T細胞、B細胞、單核球及/或巨噬細胞。在各種實施例中,投與TIMP在個體中誘導抗原特異性Treg、Tr1、Mreg及/或Breg細胞。
亦涵蓋本文所描述之組合物,該組合物包含囊封抗原之帶負電荷粒子,其中該抗原為一或多種基因療法載體抗原及/或一或多種由基因療法載體產生之轉殖基因蛋白質產物、其部分或組合,用於在個體中誘導耐受性。
本發明亦提供包含囊封抗原之帶負電荷粒子之本文所描述組合物之用途,其中抗原為一或多種基因療法載體抗原及/或一或多種由基因療法載體產生之轉殖基因蛋白質產物、其部分或組合,其用於製備供在個體中誘導耐受性用的藥劑。
在各種實施例中,帶負電荷粒子為如本文所描述之TIMP或脂質體。
應理解,本文所描述之各特徵或實施例或組合為本發明之態樣中之任一個的非限制性說明性實例,且因此意謂可與本文所描述之任何其他特徵或實施例或組合進行組合。舉例而言,在用諸如「一個實施例」、「一些實施例」、「某些實施例」、「另外的實施例」、「特定例示性實施例」及/或「另一實施例」之語言描述特徵的情況下,此等類型之實施例中之各者為特徵之非限制性實例,該特徵意欲與本文中所描述之任何其他特徵或特徵之組合進行組合而不必列出每一可能組合。此等特徵或特徵組合應用於本發明之態樣中之任一個。在揭示落入範圍內之值之實例的情況下,考慮此等實例中之任一個作為範圍之可能的端點,考慮此等端點之間之任何及所有數值,且設想具有上端點及下端點之任何及所有組合。
本文中之標題係為了方便讀者,且並不意欲為限制性的。根據實施方式及/或附圖及/或申請專利範圍,本發明之其他態樣、實施例及變化形式將為顯而易見的。
相關申請之交叉引用
本申請案主張2022年4月29日申請之美國臨時專利申請案第63/336,754號及2022年5月19日申請之美國臨時專利申請案第63/343,797號之優先權,該等申請案以全文引用的方式併入本文中。
抗原特異性耐受性被描述為克服基因療法載體及由載體產生之蛋白質治療劑之免疫原性的有吸引力的策略。已描述了誘導抗原特異性耐受性之若干方法,但一直難以將其在臨床中進行轉化
16。有必要採取干預措施,使得安全地多次投與治療性病毒載體且克服與載體免疫原性相關之挑戰。
本發明提供囊封一或多種基因療法載體、其部分或組合之帶負電荷粒子的組合物。本發明亦提供囊封一或多種由基因療法載體產生之轉殖基因蛋白質產物、其部分或組合之帶負電荷粒子的組合物。亦包括使用本文所描述之帶負電荷粒子誘導抗原特異性耐受性的方法。
定義
除非另外陳述,否則以下用於本申請案,包括說明書及申請專利範圍之術語具有下文給定之定義。
如本說明書及隨附申請專利範圍中所使用,除非上下文另外明確規定,否則不定冠詞「一(a/an)」以及定冠詞「該(the)」包括複數以及單數指示物。
術語「約」或「大致」意謂如由一般熟習此項技術者所測定的特定值之可接受誤差,其部分視如何量測或測定該值而定。在某些實施例中,術語「約」或「大致」意謂在1、2、3或4個標準差內。在某些實施例中,術語「約」或「大致」意謂在既定值或範圍的30%、25%、20%、15%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%或0.05%內。當術語「約」或「大致」冠於一系列兩個或更多個數值中的第一數值之前時,應理解術語「約」或「大致」適用於該系列中之數值中之各者。
如本文所使用之「粒子」係指任何非組織衍生的物質組成,其可為球體或球體樣實體、珠粒或脂質體。視上下文而定,術語「粒子」、術語「耐受性免疫修飾粒子」、術語「載體粒子」及術語「珠粒」可互換地使用。另外,術語「粒子」可用於涵蓋珠粒及球體。
如本文中所使用之「帶負電荷粒子」係指經修飾以具有小於零之淨表面電荷的粒子。
「羧化粒子」或「羧化珠粒」或「羧化球體」包括已經修飾以在其表面上含有羧基的任何粒子。在一些實施例中,添加羧基增強了吞噬細胞/單核球對來自循環之粒子的吸收,例如經由與諸如MARCO之清除劑受體相互作用。可使用添加羧基之任何化合物達成粒子之羧化,該化合物包括(但不限於)聚(乙烯-順丁烯二酸酐) (PEMA)。
如本文所使用,術語「Th細胞」或「輔助T細胞」係指CD4
+細胞。CD4
+T細胞在免疫過程中輔助其他白血球,包括將B細胞熟化為漿細胞及記憶B細胞,以及活化細胞毒性T細胞及巨噬細胞。當T細胞藉由表現於抗原呈現細胞(APC)之表面上的MHC II類分子呈現肽抗原時,其變得活化。
如本文所使用,術語「Th1細胞」係指產生促發炎介體之Th細胞之子集。Th1細胞分泌細胞介素以促進免疫反應且部分地藉由介導嗜中性球及巨噬細胞向感染組織之募集而在宿主防禦病原體中起一定作用。Th1細胞分泌包括IFN-γ、IL2、IL10及TNF α/β之細胞介素以協調防禦細胞內病原體(諸如病毒及一些細菌)。
如本文所使用,術語「Th2細胞」係指Th細胞之子集,其介導活化及維持針對細胞外寄生蟲、細菌、過敏原及毒素的抗體介導之免疫反應。Th2細胞藉由產生各種細胞介素來介導此等功能,該等細胞介素為諸如IL-4、IL-5、IL-6、IL-9、IL-13及IL-17E (IL-25),其負責產生抗體、活化嗜酸性球及抑制若干巨噬細胞功能,由此提供不依賴吞噬細胞的保護反應。
「多肽」及「蛋白質」係指由經由肽鍵或肽鍵電子等排體連接的胺基酸殘基、相關天然存在之結構變異體及其非天然存在之合成類似物構成的聚合物。合成多肽可例如使用自動化多肽合成器來合成。術語「多肽」及「蛋白質」不限於產物之最小長度。術語「蛋白質」通常係指較大多肽。術語「肽」通常係指較短多肽。因此,肽、寡肽、二聚體、多聚體及類似物包括於定義內。定義涵蓋全長蛋白與其片段。術語「多肽」及「蛋白質」亦包括多肽或蛋白質之表現後修飾,例如醣基化、乙醯化、磷酸化及其類似修飾。此外,出於本發明之目的,「多肽」亦可包括對天然序列之「修飾」,諸如缺失、添加、取代(其在本質上可為保守的或可包括用20個通常存在於人類蛋白質中之胺基酸中之任一者、或任何其他天然或非天然存在或非典型胺基酸取代)及化學改質(例如,添加肽模擬物或用肽模擬物取代)。此等修飾可為有意的,如經由定點誘變或經由胺基酸之化學改質以移除或連接化學部分來進行,或可為偶然的,諸如經由產生蛋白質之宿主細胞所產生之突變或經由宿主細胞轉染之前由PCR擴增引起之誤差來進行。
如本文中所使用之「抗原部分」或「抗原」係指任何由宿主之免疫系統識別之部分,例如肽。抗原部分之實例包括(但不限於)自體抗原、過敏原、酶及/或細菌或病毒蛋白、肽、藥物或組分。
如本文所使用之「基因療法載體抗原」係指引起針對蛋白質或其部分或片段之免疫反應的基因療法載體、或其部分或片段,例如表面蛋白質。基因療法載體抗原可包括全基因療法載體(例如病毒、細菌、噬菌體或其他載體)或基因療法載體之蛋白質部分,諸如病毒衣殼蛋白、包膜蛋白其他與載體相關之蛋白質或部分,其可在接受基因療法載體之個體中引發免疫反應。
「醫藥學上可接受之載劑」係指標準醫藥載劑、緩衝液及其類似物中之任一者,諸如磷酸鹽緩衝鹽水溶液、5%右旋糖水溶液及乳液(例如,油/水或水/油乳液)。賦形劑之非限制性實例包括佐劑、黏合劑、填充劑、稀釋劑、崩解劑、乳化劑、潤濕劑、潤滑劑、助滑劑、甜味劑、調味劑及著色劑。適合的醫藥學載劑、賦形劑及稀釋劑描述於Remington's Pharmaceutical Sciences, 第19版 (Mack Publishing Co., Easton, 1995)中。較佳醫藥載劑視投與活性劑之預期模式而定。典型投藥模式包括經腸(例如,經口)或非經腸(例如,皮下、肌肉內、靜脈內或腹膜內注射;或局部、經皮或經黏膜投藥)或經由吸入。
「醫藥學上可接受的」或「藥理學上可接受的」意謂不為生物學上或以其他方式非所要之物質,亦即可在不導致任何非所要生物效應之情況下或在不以有害方式與含有其之組合物之任何組分或與存在於個體身體之上或之中之任何組分相互作用的情況下向個體投與之物質。
如本文所用,術語「個體」涵蓋哺乳動物及非哺乳動物。哺乳動物之實例包括但不限於哺乳動物類之任何成員:人類、非人類靈長類動物(諸如黑猩猩及其他猿及猴物種);農畜,諸如牛、馬、綿羊、山羊、豬;家畜,諸如兔、狗及貓;實驗室動物,包括嚙齒動物,諸如大鼠、小鼠及天竺鼠以及其類似動物。非哺乳動物之實例包括(但不限於)鳥、魚及其類似動物。該術語不指示具體年齡或性別。
術語「表位」係指能夠在一或多個抗原結合區處由選擇性結合劑識別且結合之任何分子之部分。表位通常由分子之化學活性表面基團(諸如,胺基酸或碳水化合物側鏈)組成,且具有特定三維結構特性以及荷質比特性。如本文中所使用之表位可為相鄰或非相鄰的。此外,表位可為模擬物(擬表位),因為其包含與用於產生抗體之表位一致之三維結構,但不包含或僅包含一些發現於目標中之用於刺激抗體免疫反應之胺基酸殘基。如本文中所使用,擬表位不被視為與由選擇性結合劑結合之表位不同之抗原;選擇性結合劑識別表位及擬表位之相同三維結構。
本文所使用之術語「治療有效量」指示可有效地改善或減輕待治療之疾病之一或多種症狀或徵象的本發明之抗原特異性組合物之量。
如關於本文中之方法所使用之術語「治療(treat/treated/treating/treatment)」係指暫時或永久、部分或完全地消除、減少、抑制或改善事件、疾病或病況之臨床症狀、表現或進展。此類治療未必為絕對有用的。
粒子
先前已描述了包含一或多種抗原之耐受性免疫修飾粒子(TIMP),其用於誘導抗原特異性耐受性以治療發炎病況(例如自體免疫性疾病及過敏)(WO20131319253及WO2015023796,其以引用之方式併入本文中)。在自體免疫疾病及過敏之若干臨床前模型中,TIMP已展現出誘導抗原特異性耐受性及抑制病理性發炎免疫反應之功效。
粒子之尺寸及電荷對耐受性誘導至關重要。雖然粒子將基於囊封於其內之抗原而在尺寸及電荷方面不同,但一般而言,當本文中所描述之粒子在約100奈米與約1500奈米之間且具有在0至約-100 mV之間的電荷時,其在誘導耐受性方面為有效的。在各種實施例中,粒子之直徑為400-800奈米且具有在約-25 mV至-70 mV之間的電荷。在各種實施例中,粒子之直徑為400-800奈米且具有在約-30 mV與-80 mV之間的電荷。在各種實施例中,粒子之直徑為400-800奈米且具有在約-30 mV與-60 mV之間的電荷。粒子之平均粒徑及電荷可在凍乾過程中稍微改變,因此,描述合成後之平均值及凍乾後之平均值。如本文中所使用,術語「合成後之尺寸」及「合成後之電荷」係指粒子在凍乾之前的尺寸及電荷。術語「凍乾後之尺寸」及「凍乾後之電荷」係指粒子在凍乾之後的尺寸及電荷。
在一些實施例中,粒子為非金屬的。在此等實施例中,粒子可由聚合物形成。在一較佳實施例中,粒子可在個體中生物降解。在此實施例中,可在個體中提供跨越多次劑量之粒子,而使個體中不存在粒子積聚。適合的粒子之實例包括聚苯乙烯粒子、PLGA粒子、PLURONICS穩定之聚丙烯硫化物粒子及金剛石粒子。
較佳地,粒子表面由使非特異性或非所需生物相互作用最小化之材料構成。粒子表面與間質之間的相互作用可為在淋巴吸收中起作用之因素。粒子表面可用材料塗佈以防止或減少非特異性相互作用。藉由用親水性層(諸如聚(乙二醇) (PEG)及其共聚物(諸如PLURONICS®) (包括聚(乙二醇)-嵌段-聚(丙二醇)-嵌段-聚(乙二醇)之共聚物))塗佈粒子來達成空間穩定化可減少與間質之蛋白質之非特異性相互作用,以藉由皮下注射之後改良之淋巴吸收所表明。所有此等事實表明粒子在淋巴吸收方面之物理性質之相關性。可生物降解之聚合物可用於製備所有或一些聚合物及/或粒子及/或層。可生物降解之聚合物可例如藉由與溶液中之水反應之官能基引起降解。如本文中所使用之術語「降解」係指藉由減少分子量或藉由將疏水性基團轉化為親水性基團而變得可溶。具有酯基團之聚合物一般經歷自發性水解,例如聚丙交酯及聚乙交酯。
本文中所揭示之粒子亦可含有額外組分。舉例而言,載體可具有併入或結合至載體之顯像劑。具有當前可商購之顯像劑之載劑奈米球之實例為Kodak X-sight奈米球。稱為量子點(QD)之無機量子限制之冷光奈米晶體已作為FRET應用中之理想供體出現:其在單一紫外波長下激發時高量子產率及可調尺寸依賴性之斯托克斯位移(Stokes Shift)准許不同尺寸自藍色至紅外發射。(Bruchez,等人, Science, 1998, 281, 2013;Niemeyer, C. M Angew. Chem. Int. Ed. 2003, 42, 5796;Waggoner, A. Methods Enzymol. 1995, 246, 362;Brus, L. E. J. Chem. Phys. 1993, 79, 5566)。量子點,諸如基於稱為樹枝狀聚合物之一類聚合物之雜交有機/無機量子點,可用於生物標記、成像及光學生物感測系統中。(Lemon等人, J. Am. Chem. Soc. 2000, 122, 12886)。不同於無機量子點之傳統合成,此等雜交量子點奈米粒子之合成不需要高溫或高毒性之不穩定試劑。(Etienne等人, Appl. Phys. Lett. 87, 181913, 2005)。
粒子可由廣泛範圍之材料形成。粒子較佳由適合於生物用途之材料構成。舉例而言,粒子可由玻璃、矽石、羥基羧酸之聚酯、二羧酸之聚酸酐或羥基羧酸及二羧酸之共聚物構成。更一般而言,載體粒子可由以下各者構成:直鏈或分支鏈、經取代或未經取代、飽和或不飽和、直鏈或交聯之烷基、鹵烷基、硫烷基、胺烷基、芳基、芳烷基、烯基、芳烯基、雜芳基或烷氧基羥基酸之聚酯;或直鏈或分支鏈、經取代或未經取代、飽和或不飽和、直鏈或交聯之烷基、鹵烷基、硫烷基、胺烷基、芳基、芳烷基、烯基、芳烯基、雜芳基或烷氧基二羧酸之聚酸酐。另外,載體粒子可為量子點或由量子點構成,諸如量子點聚苯乙烯粒子(Joumaa等人(2006) Langmuir 22: 1810-6)。亦可使用包括酯及酸酐鍵之混合物(例如,乙醇酸及癸二酸之共聚物)的載體粒子。舉例而言,載體粒子可包含包括聚乙醇酸聚合物(PGA)、聚乳酸聚合物(PLA)、聚癸二酸聚合物(PSA)、聚(乳酸-共-乙醇酸)共聚物(PLGA或PLG;術語可互換)、聚(乳酸-共-癸二酸)共聚物(PLSA)、聚(乙醇酸-共-癸二酸)共聚物(PGSA)、聚丙烯硫化物聚合物、聚(己內酯)、聚葡萄胺糖等之材料。其他適用於本發明之生物相容之生物可降解聚合物包括己內酯、碳酸酯、醯胺、胺基酸、原酸酯、縮醛、氰基丙烯酸酯及可降解胺甲酸乙酯之聚合物或共聚物,以及此等與直鏈或分支鏈、經取代或未經取代之烷基、鹵烷基、硫烷基、胺烷基、烯基或芳族羥基羧酸或二羧酸之共聚物。另外,具有反應性側鏈基團之生物學上重要之胺基酸(諸如離胺酸、精胺酸、天冬胺酸、麩胺酸、絲胺酸、蘇胺酸、酪胺酸及半胱胺酸或其鏡像異構物)可包括於與前述物質中之任一者之共聚物中以提供用於結合至抗原肽及蛋白質或結合部分之反應性基團。適用於本發明之可生物降解材料包括金剛石、PLA、PGA、聚丙烯硫化物及PLGA聚合物。生物相容但不可生物降解之材料亦可用於本發明之載體粒子中。舉例而言,可使用丙烯酸酯、乙烯-乙酸乙烯酯、經醯基取代之乙酸纖維素、不可降解之胺基甲酸酯、苯乙烯、氯乙烯、氟乙烯、乙烯基咪唑、氯磺化烯烴、環氧乙烷、乙烯基醇、TEFLON
®(DuPont, Wilmington, Del.)及耐綸之不可生物降解聚合物。
在某些實施例中,粒子為具有約80:20至約100:0之莫耳比之共聚合物。本發明之免疫修飾粒子之適合的共聚物比可為25:75、30:70、35:65、40:60、45:55、50:50、55:45、60:40、65:35、70:30、75:25、80:20、81:19、82:18、83:17、84:16、85:15、86:14、87:13、88:12、89:11、90:10、91:9、92:8、93:7、94:6、95:5、96:4、97:3、98:2、99:1或100:0。在各種實施例中,粒子為PLURONICS穩定之聚丙烯硫化物粒子、聚乙醇酸粒子(PGA)、聚乳酸粒子(PLA)或聚(乳酸-共-乙醇酸)粒子。在各種實施例中,粒子為羧化PLGA粒子。在各種實施例中,粒子具有聚乳酸/聚乙醇酸80:20、聚乳酸/聚乙醇酸90:10或聚乳酸/聚乙醇酸50:50之共聚物比。在各種實施例中,粒子為聚(乳酸-共-乙醇酸)粒子且具有約50:50聚乳酸:聚乙醇酸之共聚物比。在各種實施例中,粒子包含約50:50、約80:20至約100:0聚乳酸:聚乙醇酸或約50:50、約80:20至約100:0聚乙醇酸:聚乳酸。在各種實施例中,粒子包含50:50聚乳酸:聚乙醇酸。在各種實施例中,粒子包含約99:1至約1:99,例如約99:1、約95:5、約90:10、約85:15、約80:20、約75:25、約70:30、約65:35、約60:40、約55:45、約50:50、約45:55、約40:60、約35:65、約30:70、約25:75、約20:80、約15:85、約10:90、約5:95及約1:99 (包括處於此等值之間的所有值及範圍)之聚乳酸:聚乙醇酸。
經考慮,粒子可進一步包含界面活性劑。界面活性劑可為陰離子性、陽離子性或非離子性的。泊洛沙姆(poloxamer)及泊洛沙胺(poloaxamine)家族中之界面活性劑常用於粒子合成中。可使用之界面活性劑包括(但不限於) PEG、Tween-80、明膠、聚葡萄糖、普朗尼克L-63 (pluronic L-63)、聚乙烯醇(PVA)、聚丙烯酸(PAA)、甲基纖維素、卵磷脂、溴化二(十二烷基)二甲基銨(DMAB)及聚(乙烯-交替-順丁烯二酸酐) (PEMA)。另外,生物可降解及生物相容之界面活性劑包括(但不限於)維生素E TPGS (D-α-生育酚聚乙二醇1000丁二酸酯)、聚胺基酸(例如,離胺酸、精胺酸、天冬胺酸、麩胺酸、絲胺酸、蘇胺酸、酪胺酸及半胱胺酸或其鏡像異構物之聚合物)及硫酸酯聚合物。在一些實施例中,使用兩種界面活性劑。舉例而言,若粒子係藉由雙重乳液方法產生,則兩種界面活性劑可包括用於第一乳液之疏水性界面活性劑及用於第二乳液之疏水性界面活性劑。
在各種實施例中,藉由單乳液方法將多肽抗原囊封於粒子中。在另一實施例中,多肽抗原更具疏水性。有時,雙重乳液方法引起較大粒子之形成,其可引起親水性活性組分之洩漏及低截流效率。聚結及奧斯華熟化(Ostwald ripening)係兩種可使雙重乳液液滴不穩定之機制,且經由親水性活性組分之有機相之擴散為引起低水平之包覆活性組分的主要機制。在一些實施例中,減小奈米粒子尺寸可為有益的。一種實現此目的之策略為應用第二強剪切速率。洩漏效應可藉由使用高聚合物濃度及高聚合物分子量而減少,伴隨著內部水相黏度之增加及界面活性劑分子質量之增加。在某些實施例中,囊封抗原之粒子係藉由奈米沈澱、共沈澱、惰性氣體冷凝、濺鍍、微乳液、溶膠凝膠法、逐層技術或離子膠凝方法製造。若干種用於製造奈米粒子之方法已描述於文獻中且以引用之方式併入本文中
17,18。
在一些實施例中,粒子為脂質體。脂質體可由多種脂質材料製備,包括(但不限於)磷脂醯基膽鹼之脂質、磷脂醯基絲胺酸、磷脂醯基肌醇、磷脂醯基甘油、磷脂醯基乙醇胺、磷脂酸、磷酸二鯨蠟基酯、單唾液酸神經節苷脂、聚乙二醇、硬脂醯基胺、卵磷脂及膽固醇以及此等以不同的化學計量之混合物。如本文所使用之脂質體亦可由非脂質兩性分子形成,諸如聚(氧化乙烯-嵌段-異戊二烯-嵌段-氧化乙烯)之嵌段共聚物及其類似物。在較佳實施例中,脂質體由脂質製備或併入將形成帶負電荷脂質體之脂質,諸如由磷脂醯基絲胺酸、磷酸二鯨蠟基酯及二肉豆蔻醯基磷脂酸產生之脂質體。在各種實施例中,帶負電荷之脂質體之ζ電位為約-100 mV至約0 mV、約-100 mV至約-25 mV、約-100至約-30 mV、約-80 mV至約-30 mV、約-75 mV至約-30 mV、約-70 mV至約-30 mV、約-75至約-35 mV、約-70至約-25 mV、約-60 mV至約-30 mV、約-60 mV至約-35 mV或約-50 mV至約-30 mV。在各種實施例中,ζ電位為約-25 mV、-30 mV、-35 mV、-40 mV、-45 mV、-50 mV、-55 mV、-60 mV、-65 mV、-70 mV、-75 mV、-80 mV、-85 mV、-90 mV、-95 mV或-100 mV,包括其中所有數值及範圍。在各種實施例中,脂質體之負ζ電位在-30 mV至-80 mV之間。在各種實施例中,脂質體之負ζ電位在-30 mV至-60 mV之間。
在各種實施例中,脂質體囊封一或多種基因療法載體抗原及/或其部分,或基因療法載體抗原或其部分之組合。在各種實施例中,脂質體囊封由基因療法載體產生之治療蛋白及/或其片段或部分。在各種實施例中,由基因療法載體產生之治療蛋白為蛋白質、多肽或肽。在各種實施例中,治療蛋白為細胞介素、趨化介素、激素、生長因子、酶或抗體。在各種實施例中,基因療法載體抗原係選自由以下組成之群:腺病毒、腺相關病毒(AAV)、AAV-1、AAV-2、AAV-3、AAV-4、AAV-5、AAV-6、AAV-7、AAV-8、AAV-9、AAV-10、AAV-12、Anc80、合成AAV、其組合或經工程改造之版本、AAV衣殼蛋白VP1、AAV衣殼蛋白VP2、AAV衣殼蛋白VP3、單純疱疹病毒、B型肝炎病毒、慢病毒、反轉錄病毒、α病毒、黃病毒、棒狀病毒、麻疹病毒、新城雞瘟病毒、科沙奇病毒、輸血傳播病毒、指環病毒、人類乳突狀瘤病毒、痘病毒、痘瘡病毒、經修飾之安卡拉病毒、水泡性口炎病毒、小核糖核酸病毒、菸草嵌紋病毒、豇豆嵌紋病毒、豇豆褪綠斑駁病毒、酸漿嵌紋病毒、紅三葉草壞死嵌紋病毒、馬鈴薯病毒x、豇豆花葉病毒、雞貧血病毒、胡瓜嵌紋病毒、溶瘤病毒、嵌合病毒、合成病毒、嵌紋病毒、或假型病毒、細菌、噬菌體、酵母、胞泌體或紅血球。
在各種實施例中,脂質體囊封一或多種基因療法載體抗原,其中該脂質體之尺寸直徑在100與1000 nm之間,且脂質體之負ζ電位在-100 mV與-0 mV之間。在各種實施例中,脂質體囊封一或多種基因療法載體抗原、其部分或其組合,其中該脂質體之尺寸在400與800 nm之間,且該脂質體之負ζ電位在-30 mV與-80 mV之間。
在各種實施例中,脂質體囊封由基因療法載體產生之治療蛋白及/或其片段或部分,其中該脂質體之尺寸在100與1000 nm之間,且該脂質體之負ζ電位在-100 mV與0 mV之間。在各種實施例中,脂質體囊封由基因療法載體產生之治療蛋白及/或其片段或部分,其中該脂質體之尺寸在400與800 nm之間,且該脂質體之負ζ電位在-30 mV與-80 mV之間。在各種實施例中,脂質體用於在有需要之個體中誘導耐受性。在各種實施例中,脂質體經靜脈內投與。
基因療法載體
基因療法載體經設計以將編碼治療性產物之基因傳遞至個體,以緩解疾病(諸如遺傳病症或癌症)之症狀。基因療法載體包括病毒、細菌、噬菌體、酵母、紅血球或胞泌體載體。
常用於人類基因療法之病毒載體包括腺病毒、腺相關病毒(AAV)及反轉錄病毒,諸如慢病毒。
腺病毒載體常衍生自人類血清型HAd2、HAd5、HAd26及HAd35或經工程改造,諸如「高容量」腺病毒載體(HCAd)或溶瘤載體,且亦可衍生自非人類哺乳動物Ad病毒(Bulcha等人, Signal Transduction and Targeted Therapy 第6卷, 文章編號: 53 (2021))。腺病毒表現可誘導針對早期轉錄基因E1 (E1A、E1B)、E2、E3及E4、六鄰體(其為衣殼表面上之最豐富的結構組分)及12個位於衣殼頂點上的五鄰體蛋白之免疫反應,且引起發現於此等病毒上之延伸纖維。考慮包含此等病毒抗原之載體粒子用於誘導對此等基因療法載體抗原之耐受性。
AAV載體為具有主要由三種蛋白VP1、VP2及VP3構成之二十面體衣殼的小病毒載體。已知十二種AAV血清型。(Bulcha等人,
見上文)。用於基因療法之常用血清型包括AAV-1、AAV-2、AAV-5、AAV-9、Anc80,而其他血清型包括AAV-3、AAV-4、AAV-6、AAV-7、AAV-8、AAV-10、AAV-12及合成AAV。原生及經工程改造之衣殼蛋白已用於產生用於在基因療法中投藥之AAV載體。本文考慮包含野生型或經工程改造之AAV病毒衣殼蛋白的載體粒子,用於誘導對此等基因療法載體抗原之耐受性。
慢病毒為具有三個主要基因集合
gag 、 pol及
env基因之包膜病毒,且可具有適用於改良增殖及發病機制之輔助基因(
tat 、 rev 、 vif 、 vpr 、 vpu 及 nef)。Gag基因編碼結構包膜蛋白。然而,經工程改造之慢病毒載體可含有VSV-G蛋白代替包膜蛋白。(Bulcha等人,
見上文)。本文考慮包含野生型或經工程改造之慢病毒蛋白的載體粒子,用於誘導對此等基因療法載體抗原之耐受性。
細菌載體已產生以遞送基因或蛋白質至目標癌細胞(Baban等人, Bioengineered Bugs 1:6, 385-394, 2010),且包括源於沙門桿菌屬(
Salmonella)、志賀桿菌屬(
Shigella)、李氏菌屬(
Listeria)或大腸桿菌(
E. coli)之載體。此等載體已用於表現人類腫瘤抗原、細胞介素、生長因子、酶及治療蛋白。另一種細菌載體之用途為細菌轉染(bactofection),其係指細菌將噬菌體或質體DNA轉移至哺乳動物細胞。本文考慮包含細菌或質體抗原的載體粒子,用於誘導對此等基因療法載體抗原之耐受性。
表現腫瘤或HIV抗原之酵母基因療法載體顯示誘導活體內腫瘤反應性反應。
21胞泌體及聚乙二亞胺基質(EPM)已用於在患者中投與短干擾RNA (siRNA)或質體DNA (pDNA),且胞泌體已用於將CRISPR/Cas9質體遞送至癌細胞。
22,23紅血球,例如紅血球血影(erythrocyte ghost),顯示有效地將質體DNA遞送至細胞
24,或可負載用於活體內遞送之蛋白質。
25抗原
抗原係指可被宿主免疫細胞識別之分子之離散部分,諸如多肽或肽序列、多肽或肽之3D結構形成物、多醣或聚核苷酸。抗原特異性係指個體之宿主細胞識別單獨的抗原或與該抗原極其相似之分子(如表位或擬表位)及產生針對其之免疫反應的能力。
「無反應性」、「耐受性」或「抗原特異性耐受性」係指T細胞對T細胞受體介導之刺激的不敏感性。此類不敏感性一般為抗原特異性的且在停止暴露於抗原肽之後持續存在。舉例而言,T細胞之無反應性的特性在於缺乏細胞介素(例如,IL-2)產生。在T細胞暴露於抗原且在不存在第二信號(協同刺激信號)之情況下接收第一信號(T細胞受體或CD-3介導之信號)時,出現T細胞無反應性。在此等條件下,將細胞再暴露於相同抗原(即使在存在協同刺激分子之情況下進行再暴露)仍無法產生細胞介素且因此無法增殖。因此,無法產生細胞介素會阻礙增殖。然而,若與細胞介素(例如,IL-2)一起培養,則無反應性之T細胞仍可增殖。
經考慮,本文中所描述之耐受性療法為抗原特異性的。舉例而言,作為耐受性療法投與的TIMP囊封與該耐受性療法及所治療之相關疾病或病況相關之一或多種抗原。經考慮,用於耐受性療法之TIMP包含一或多種基因療法載體抗原、其部分或其組合,及/或由基因療法載體產生之轉殖基因蛋白質產物、其部分或其組合。
例示性基因療法載體包括(但不限於)腺病毒、腺相關病毒(AAV)、單純疱疹病毒、B型肝炎病毒、慢病毒、反轉錄病毒、α病毒、黃病毒、棒狀病毒、麻疹病毒、新城雞瘟病毒、科沙奇病毒、輸血傳播病毒、指環病毒、人類乳突狀瘤病毒、痘病毒、痘瘡病毒、經修飾之安卡拉病毒、水泡性口炎病毒、小核糖核酸病毒、菸草嵌紋病毒、豇豆嵌紋病毒、豇豆褪綠斑駁病毒、酸漿嵌紋病毒、紅三葉草壞死嵌紋病毒、馬鈴薯病毒x、豇豆花葉病毒、雞貧血病毒、胡瓜嵌紋病毒、AAV-1、AAV-2、AAV-3、AAV-4、AAV-5、AAV-6、AAV-7、AAV-8、AAV-9、AAV-10、AAV-12、Anc80及合成AAV。經考慮,粒子可囊封病毒載體衣殼或包膜蛋白、其部分或片段或其組合。衣殼蛋白包括例如AAV-Po1 VP1 (UNIPROT ID:C0LA97)、AAV-Po1 VP2 (UNIPROT ID:C0LA98)、AAV-Po1 VP3 (UNIPROT ID:COLA99)、AAV- Po2 VP1 (UNIPROT ID:C0LAA0)、AAV-Po3 (UNIPROT ID:C0LA95)、AAV VP1 (UNIPROT ID:B4Y875)、AAV-1衣殼蛋白(UNIPROT ID:Q9WBP8)、AAV-2 VP1 (UNIPROT ID:P03135)、AAV-3衣殼蛋白(UNIPROT ID:Q65311)、AAV-3B VP1 (UNIPROT ID:O56139)、AAV-4衣殼(UNIPROT ID:O41855)、AAV6 VP1 (UNIPROT ID:O56137)、AAV7衣殼蛋白(UNIPROT ID:Q8JQG0)、AAV8衣殼蛋白(UNIPROT ID:Q8JQF8)、AAV9 VP1 (UNIPROT ID:Q6JC40)、AAV-10衣殼蛋白(UNIPROT ID:Q5Y9B4)、AAV-11衣殼蛋白(UNIPROT ID:Q5Y9B2)、AAV13衣殼蛋白(UNIPROT ID:B5SUY7)及AAV12 VP1 (UNIPROT ID:A9RAI0)。
在某些實施例中,在TIMP中使用一個、兩個、三個或更高數目之抗原或抗原肽。在某些實施例中,一或多種抗原係藉由共價鍵聯至粒子之內表面而囊封於TIMP中(參見例如,美國專利公開案US20190282707,其以引用之方式併入本文中)。在某些實施例中,經考慮,將兩種或更多種抗原之序列連接於融合蛋白中且囊封於本文所描述之TIMP內。用於製備具有連接表位之TIMP之方法描述於美國專利公開案US20190365656中,其以引用之方式併入本文中。
用於治療酶病且由基因療法載體產生之例示性酶包括:伊米苷酶、他利苷酶α、維拉苷酶α、β-葡萄糖腦苷酶、阿糖腦苷酶、阿加糖酶β、阿加糖酶α、賽貝利酶α、α-L-艾杜糖醛酸酶、人類艾杜糖醛-2-硫酸酯酶、N-磺基葡萄胺糖磺基水解酶、埃洛磺酶α、加硫酶、α-葡萄糖苷酶(GAA)、人類α甘露糖苷酶、因子VIII、因子IX、β-半乳糖苷酶、精胺酸酶、失養性肌強直蛋白質激酶、鳥胺酸胺甲醯基轉移酶、NADPH氧化酶、NADH去氫酶4、腺苷去胺酶、脂蛋白脂肪酶、β-葡萄糖腦苷酶、肌微管素、芳基硫酸酯酶A、DOPA去羧酶、基質金屬肽酶1、延胡索醯乙醯乙酸羥化酶、苯丙胺酸羥化酶、丙酮酸激酶、膽色素原去胺酶、鹼性磷酸酶、蔗糖酶-異麥芽糖酶、酸性鞘磷脂酶、硫酸乙醯肝素硫酸酯酶、N-乙醯半乳胺糖-6-硫酸酯酶、N-乙醯半乳胺糖-4-硫酸酯酶、α-1蛋白酶抑制劑、1-酯酶抑制劑、血纖維蛋白原、因子VIIa、因子X、因子XI、因子XII、蛋白C、抗凝血酶III、外核苷酸焦磷酸酶/磷酸二酯酶1、外核苷酸焦磷酸酶/磷酸二酯酶3及芳族L-胺基酸去羧酶。
在某些實施例中,蛋白質治療劑為抗體,例如單株抗體。亦考慮該抗體係單特異性、雙特異性、三特異性或雙特異性T細胞接合分子。在各種實施例中,抗體靶向受體酪胺酸激酶(RTK)、EGFR、VEGF、VEGFR、PDGF、PDGFR、HER2/Neu、ER、PR、TGF-β1、TGF-β2、TGF-β3、SIRP-α、PD-1、PD-L1、CTLA-4、CD3、CD25、CD19、CD20、CD39、CD47、CD73、FAP、IL-1β、IL-12、IL-2R、IL-15、IL-15R、IL-23、IL-33、IL-2R、IL-4Rα、T細胞、B細胞、NK細胞、巨噬細胞、單核球及/或嗜中性球。在各種實施例中,抗體係選自由以下組成之群:阿昔單抗(abciximab)、阿達木單抗(adalimumab)、阿侖單抗(alemtuzumab)、阿維魯單抗(avelumab)、阿替利珠單抗(atezolizumab)、巴利昔單抗(basiliximab)、貝伐單抗(bevacizumab)、貝茨羅特斯單抗(bezlotoxumab)、博納吐單抗(blinatumomab)、康納單抗(canakinumab)、賽妥珠單抗(certolizumab)、西妥昔單抗(cetuximab)、達利珠單抗(daclizumab)、地諾單抗(denosumab)、度伐魯單抗(durvalumab)、艾法珠單抗(efalizumab)、艾美賽珠單抗(emicizumab)、艾托奇單抗(etokimab)、戈利木單抗(golimumab)、伊派利單抗(ipilimumab)、依奇珠單抗(ixekizumab)、英利昔單抗(infliximab)、那他珠單抗(natalizumab)、納武單抗(nivolumab)、奧拉單抗(olaratumab)、奧馬珠單抗(omalizumab)、奧法木單抗(ofatumumab)、帕利珠單抗(palivizumab)、帕尼單抗(panitumumab)、帕博利珠單抗(pembrolizumab)、雷莫蘆單抗(ramucirumab)、利妥昔單抗(rituximab)、托珠單抗(tocilizumab)、曲妥珠單抗(trastuzumab)、曲美木單抗(tremelimumab)、蘇金單抗(secukinumab)、烏司奴單抗(ustekinumab)及維多珠單抗(vedolizumab)。
使用方法
本文提供一種對有需要之個體誘導耐受性的方法,其包含向個體投與組合物,該組合物包含囊封抗原之帶負電荷粒子,其中該抗原為一或多種基因療法載體抗原及/或一或多種由基因療法載體產生之轉殖基因蛋白質產物、其部分或組合。
在各種實施例中,個體為已接受基因療法之個體、正在接受基因療法之個體或將接受基因療法之個體。在各種實施例中,個體已接受一次基因療法治療且可進行另一基因療法治療方案,亦即基因療法之再給藥。
在各種實施例中,個體正在接受基因療法以治療癌症、自體免疫疾病、過敏症、心血管疾病、代謝疾病、酶缺乏或蛋白質缺乏。
在各種實施例中,個體患有罕見及遺傳性基因病症,且接受基因療法以得到由載體產生之轉殖基因蛋白質產物,該轉殖基因蛋白質產物為酶。在各種實施例中,個體罹患選自由以下組成之群的罕見及遺傳性基因病症:A型血友病、B型血友病、溶素體儲積病、法布立病、高歇氏病、龐培氏病、尼曼-匹克二氏病、泰-薩二氏病、黃斑變性、黏多醣病、靜脈栓塞、馮威里氏病、猛爆性紫斑、生長激素缺乏症、神經節苷脂症、鹼性低磷酸酶症、膽固醇酯儲積病、高尿酸血症、杜興氏肌肉失養症、杭丁頓氏舞蹈症、帕金森氏症、阿茲海默氏症、無脈絡脈畸型症、斯特格氏病、巴登氏病、脊髓小腦失調、ALS、額顳葉變性、鳥胺酸胺甲醯基轉移酶缺乏症、色素性視網膜炎、RPE-65突變相關病、大皰性表皮鬆解、隱性營養不良型大皰性表皮鬆解、脊髓性肌萎縮、苯酮尿症(PKU)、X性聯肌小管肌病、克果-納傑氏症候群、兒茶酚胺引發之多型性心室性心搏過速、1型肝醣儲積症、α-甘露糖症、脆弱X染色體症候群、精胺酸酶缺乏症、X性聯慢性肉芽腫病、腺苷去胺酶缺乏症、萊伯氏先天性黑矇、脂蛋白脂肪酶缺乏症、大腦型腎上腺腦白質失養症、異染性腦白質失養症、范康尼氏貧血症、失色症、硬皮病、成骨不全症、冠狀動脈疾病、酪胺酸血症、周邊神經病變、視神經病變、冠狀動脈疾病、呼吸道融合細胞病毒(RSV)介導之下呼吸道疾病、達農病、嚴重白血球黏附分子缺乏症、丙酮酸激酶缺乏症、恰克-馬利-杜斯氏病、偉-爾二氏症候群、α-突觸核蛋白tau蛋白病變、心肌缺血引發的難治性絞痛、I型肌強直性營養不良、跛行、周邊動脈疾病、甲基丙二酸血症、MPS I、MPS II、MPS III、MPS IV、MPS VI、MPS VII、MPS IX、鈣化/骨化病症、ENPP1缺乏症、ENPP3缺乏症、ABCC6缺乏症、芳族L-胺基酸去羧酶缺乏症、天使症候群、高苯丙胺酸血症、失智症、雷特氏症候群及尤塞氏症候群。
在各種實施例中,自體免疫疾病係選自由以下組成之群:多發性硬化症、艾迪森氏病、僵直性脊椎炎、禿頭症、骨關節炎、牛皮癬性關節炎、硬皮病、I型糖尿病、類風濕性關節炎、甲狀腺炎、全身性紅斑性狼瘡症、雷諾氏症候群、貝塞特氏症、修格蘭氏症候群、自體免疫葡萄膜炎、伊頓-藍伯疾病、自體免疫心肌炎、發炎性腸道疾病、肌肉萎縮性側索硬化(ALS)、全身性紅斑狼瘡、視神經脊髓炎、特發性血小板減少性紫癜、血栓性血小板減少性紫斑症、膜性腎病變、類天疱瘡、尋常型天疱瘡、重症肌無力、乳糜瀉、潰瘍性結腸炎、克羅恩氏病、結節性紅斑、絲球體腎炎、古巴士德氏症候群、肉芽腫病、格雷夫氏病、格-巴二氏症候群、橋本氏疾病、溶血性貧血、川崎病、混合型結締組織疾病、多病灶性運動神經病變、周邊膽汁性肝硬化、多血管炎重疊症候群、1型硬皮病、硬化性膽管炎、僵體症候群、高安氏動脈炎、白斑病或韋格納肉芽腫病。
在各種實施例中,過敏為食物過敏。在各種實施例中,過敏為環境過敏。在各種實施例中,食物過敏係花生過敏、樹堅果過敏、乳過敏、蛋過敏、魚過敏、小麥過敏、芹菜過敏或桃子過敏。在各種實施例中,環境過敏係花粉過敏、粉塵過敏、寵物皮屑過敏或黴菌過敏。在各種實施例中,寵物過敏係貓過敏或狗過敏。
在各種實施例中,癌症係選自由以下組成之群:腦癌、皮膚癌、眼癌、乳癌、前列腺癌、肺癌、食道癌、頭頸癌、子宮頸癌、肝癌、大腸癌、骨癌、子宮癌、卵巢癌、膀胱癌、胃癌、口腔癌、甲狀腺癌、腎癌、睪丸癌、白血病、淋巴瘤、黑色素瘤及間皮瘤。
在各種實施例中,載體粒子包含一或多種基因療法載體抗原。在各種實施例中,載體粒子包含一或多種由基因療法載體產生之轉殖基因蛋白質產物、其部分、其組合或其一或多種抗原表位。在各種實施例中,載體粒子包含一或多種基因療法載體抗原及轉殖基因蛋白質產物或其一或多種抗原表位。
若包含單一抗原之載體粒子與包含不同抗原之另一載劑粒子或第二藥劑組合投與,則粒子及/或第二藥劑可並行或依序投與。相伴或並行投與兩種治療劑不需要同時或藉由相同途徑投與藥劑,只要藥劑發揮其治療作用的時段存在重疊即可。考慮同時或依序投與,如在不同日或週投與。經進一步考慮,治療劑以單獨調配物形式投與且並行或相伴投與,其中並行係指在彼此相隔30分鐘內給予藥劑。先前投與係指在用載體粒子治療之前一週至投與載體粒子之前30分鐘的範圍內投與治療劑。後續投與意謂描述在治療之後30分鐘至投與之後一週內進行投與。
在各種實施例中,載體粒子以約0.001至約10 mg/kg、約0.005至約12 mg/kg、約0.01至約12 mg/kg、約0.05至約12 mg/kg、約0.1至約12 mg/kg、約0.5至10 mg/kg、約1至8 mg/kg、約1.5至10 mg/kg、約2至12 mg/kg、約2至10 mg/kg、約3至10 mg/kg、約4至10 mg/kg、約4至12mg/kg或約5至12 mg/kg之劑量投與。視情況,載劑粒子以約0.001 mg/kg、約0.0025 mg/kg、約0.005 mg/kg、約0.01 mg/kg、約0.025 mg/kg、約0.05 mg/kg、0.1 mg/kg、0.25、0.5 mg/kg、1.0 mg/kg、2.0 mg/kg、4.0 mg/kg、6 mg/kg、8.0 mg/kg、10 mg/kg或12 mg/kg之劑量投與。替代地,載劑粒子以約0.1 mg、0.25 mg、0.5 mg、1 mg、2 mg、2.5 mg、5 mg、10 mg、25 mg、50 mg、75 mg、100 mg、125 mg、150 mg、175 mg、200 mg、225 mg、250 mg、275 mg、300 mg、325 mg、350 mg、400 mg、425 mg、450 mg、475 mg、500 mg、525 mg、550 mg、575 mg、600 mg、625 mg、650 mg、675 mg、700 mg、725 mg、750 mg、775 mg或800 mg之劑量投與。在另一個實施例中,載體粒子以在約0.0005 mg/mL與約50 mg/mL之間、在約0.05 mg/mL與約50 mg/mL之間的濃度投與,視情況約0.0005 mg/mL、0.001 mg/mL、0.005 mg/mL、0.01 mg/mL、0.05 mg/mL、0.1 mg/mL、0.5 mg/mL、1 mg/mL、2 mg/mL、3 mg/mL、4 mg/mL、5 mg/mL、6 mg/mL、7 mg/mL、8 mg/mL、9 mg/mL、10 mg/mL、11 mg/mL、12.5 mg/mL、15 mg/mL、17.5 mg/mL、20 mg/mL、25 mg/mL、30 mg/mL、40 mg/mL或50 mg/mL。
在一些實施例中,包含一或多種基因療法載體抗原及/或一或多種由基因療法載體產生之轉殖基因蛋白質產物的載體粒子與一或多種治療劑組合投與。在各種實施例中,治療劑為Treg、CAR Treg、TCR Treg之授受性轉移。在各種實施例中,該治療劑阻斷或抑制針對基因療法載體及/或由該基因療法載體產生之轉殖基因蛋白質的先天性免疫反應、補體反應、B細胞反應及/或T細胞反應。
在各種實施例中,治療劑為FcRn抑制劑。在各種實施例中,FcRn抑制劑係選自由以下組成之群:艾加莫德(efgartigimod)、洛利昔珠單抗(rozanoluximumab)、尼卡利單抗(nipocalimab)、巴托利單抗(batoclimab)或奧諾利單抗(orilanolimab)。在各種實施例中,治療劑為免疫抑制劑、補體抑制劑、鈣調神經磷酸酶抑制劑、血漿清除術、IgG蛋白酶、蛋白酶體抑制劑及/或調節性T細胞之誘導劑。在各種實施例中,免疫抑制劑係選自由以下組成之群:皮質類固醇(諸如甲基普賴蘇穠(methylprednisolone)、普賴蘇穠(prednisolone)或普賴蘇(prednisone))、雷帕黴素/西羅莫司或環磷醯胺、黴酚酸嗎啉乙酯。在各種實施例中,補體抑制劑係選自由以下組成之群:C1抑制劑(諸如西瑞茨(Cinryze)、貝裡納特(Berinert)、魯科內斯特(Ruconest)、舒敏單抗(sutimlimab)(Enjaymo)或海加瑞達(Haegarda))、C3抑制劑(諸如培可他普蘭(Pegacetaclplan)(Empaveli)、培可他普蘭注射劑(Syfovre))、C5抑制劑(諸如依庫珠單抗(eculizumab)、雷武珠單抗(ravulizumab)、阿伐可泮(avacopan)、帕澤利單抗(pozelimab)、諾瑪可潘(nomacopan)、齊魯考普(zilucoplan)、韋洛利單抗(vilobelimab)、可伐利單抗(crovalimab)、zimura、森迪西蘭(cemdisiran)、特度魯單抗(tesidolumab)、艾朵利單抗(avdoralimab))、因子D抑制劑(丹尼科潘(danicopan)、維米爾科潘(vemircopan))、或其他補體蛋白質(諸如納索利單抗(narsoplimab)、伊普塔克潘(iptacopan))。在各種實施例中,治療劑為抗CD20 CAR T細胞療法、抗CD19 CAR T細胞療法或抗BCMA CAR T細胞療法。在各種實施例中,治療劑係選自由以下組成之群:抗CD20抗體(例如利妥昔單抗)、抗CD19抗體、抗CD40抗體、CTLA4 Ig (例如,阿巴西普(abatacept))。在各種實施例中,鈣調神經磷酸酶抑制劑為環孢菌素或他克莫司(tacrolimus)。在各種實施例中,蛋白酶體抑制劑係選自由以下組成之群:硼替佐米(bortezomib)、卡非佐米(carfilzomib)、三氧化二砷、羥基氯奎或MnTBAP。在一些實施例中,IgG蛋白酶為IdeZ或IdeS (伊姆利酶(imlifidase))。在各種實施例中,Treg誘導劑為IL2變異體/突變蛋白或CDK8/19抑制劑。
在各種實施例中,治療劑隔離及/或耗乏抗基因療法載體抗體或抗轉殖基因蛋白質產物抗體。在各種實施例中,治療劑為選擇性抗體耗乏複合物。在各種實施例中,治療劑為與基因療法載體或轉殖基因蛋白質產物抗原或表位結合的免疫球蛋白(Ig)、白蛋白或醣蛋白。
在各種實施例中,一或多種治療劑係在投與本文所描述之載體粒子之前、同時或之後投與。在各種實施例中,治療劑在投與載體粒子之前0.5、1、2、4、5、8、10、12、16或24小時投與,包括處於彼等範圍之間的所有範圍及數值。在各種實施例中,治療劑在投與載體粒子之前1、2、3、4、5、6或7天投與。在各種實施例中,治療劑在投與載體粒子之前1、2、3或4週投與。在各種實施例中,治療劑在投與載體粒子之前1、2、3、4、5、6、7、8、9、10、11或12個月投與。在各種實施例中,治療劑在投與載體粒子之前1、2、3、4、5、6、7、8、9、10、11或12年投與。在各種實施例中,治療劑與載體粒子並行投與。在各種實施例中,治療劑在投與載體粒子之後0.5、1、2、4、5、8、10、12、16或24小時投與,包括處於彼等範圍之間的所有範圍及數值。在各種實施例中,治療劑在投與載體粒子之後1、2、3、4、5、6或7天投與。在各種實施例中,治療劑在投與載劑粒子之後1、2、3或4週投與。在各種實施例中,治療劑在投與載體粒子之後1、2、3、4、5、6、7、8、9、10、11或12個月投與。在各種實施例中,治療劑在投與本文所描述之載體粒子之後1、2、3、4、5、6、7、8、9、10、11或12年投與。
篩選方法
經考慮,在已用如本文所描述之載體粒子治療或將要用如本文所描述之載體粒子治療之個體中監測對免疫耐受性之誘導及維持。
在進行如本文所描述之耐受性療法之個體中篩選細胞類型、細胞介素或其他耐受性量度的方法為此項技術中已知的。評定耐受性之方法使用諸如以下技術進行:流式細胞分析技術、質譜流式細胞分析技術(CyTOF)、ELISA、ELISPOT、活體外/離體細胞刺激分析(包括(但不限於)細胞增殖分析、嗜鹼性球活化測試(BAT)、巨噬細胞刺激分析),量測自體抗體或量測Ig血清型,例如藉由ImmunoCap分析進行。
可自生物樣品分析之人類代謝物清單可見於文獻中,該等文獻包括於(Psychogios等人, 2011),(Wishart等人, HMDB: the Human Metabolome Database. Nucleic Acids Res. 2007年1月; 35(Database issue):D521-6, 2007)及the Human Metabalome Database (HMDB)中且以引用之方式併入本文中。
個體之免疫耐受性狀態之一個態樣及免疫標籤藉由分析一或多種來自生物樣品之細胞表面蛋白質測定。在各種實施例中,細胞表面蛋白質包括CD1c、CD2、CD3、CD4、CD5、CD8、CD9、CD10、CD11b、CD11c、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD24、TACI、CD25、CD27、CD28、CD30、CD30L、CD31、CD32、CD32b、CD34、CD33、CD38、CD39、CD40、CD40-L、CD41b、CD42a、CD42b、CD43、CD44、CD45、CD45RA、CD47、CD45RA、CD45RO、CD48、CD52、CD55、CD56、CD58、CD61、CD66b、CD69、CD70、CD72、CD79、CD68、CD84、CD86、CD93、CD94、CD95、CRACC、BLAME、BCMA、CD103、CD107、CD112、CD120a、CD120b、CD123、CD125、CD127、CD134、CD135、CD140a、CD141、CD154、CD155、CD160、CD161、CD163、CD172a、XCR1、CD203c、CD204、CD206、CD207 CD226、CD244、CD267、CD268、CD269、CD355、CD358、CRTH2、NKG2A、NKG2B、NKG2C、NKG2D、NKG2E、NKG2F、NKG2H、KIR2DL1、KIR2DL2、KIR2DL3、KIR2DL5A、KIR2DL5B、KIR3DL1、KIR3DL2、KIR3DL3、KIR3DL4、KIR2DS1、KIR2DS2、KIR2DS3、KIR2DS4、KIR2DS5、DAP12、KIR3DS、NKp44、NKp46、TCR、BCR、整合素、FcβεRI、MHC-I、MHC-II、IL-1R、IL-2Rα、IL-2Rβ、IL-2Rγ、IL-3Rα、CSF2RB、IL-4R、IL-5Rα、CSF2RB、IL-6Rα、gp130、IL-7Rα、IL-9R、IL-10R、IL-12Rβ1、IL-12Rβ2、IL-13Rα1、IL-13Rα2、IL-15Rα、IL-21R、IL-23R、IL-27Rα、IL-31Rα、OSMR、CSF-1R、細胞表面IL-15、IL-10Rα、IL-10Rβ、IL-20Rα、IL-20Rβ、IL-22Rα1、IL-22Rα2、IL-22Rβ、IL-28RA、PD-1、PD-1H、BTLA、CTLA-4、PD-L1、PD-L2、2B4、B7-1、B7-2、B7-H1、B7-H4、B7-DC、DR3、LIGHT、LAIR、LTα1β2、LTβR、TIM-1、TIM-3、TIM-4、TIGIT、LAG-3、ICOS、ICOS-L、SLAM、SLAMF2、OX-40、OX-40L、GITR、GITRL、TL1A、HVEM、41-BB、41BB-L、TL-1A、TRAF1、TRAF2、TRAF3、TRAF5、BAFF、BAFF-R、APRIL、TRAIL、RANK、AITR、TRAMP、CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CCR11、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、CXCR6、CXCR7、CLECL9a、DC-SIGN、IGSF4A、SIGLEC、EGFR、PDGFR、VEGFR、FAP、α-SMA、FAS、FAS-L、FC、ICAM-1、ICAM-2、ICAM-3、ICAM-4、ICAM-5、PECAM-1、MICA、MICB、UL16、ULBP1、ULBP2、ILBP3、ULBP4、ULBP5、ULBP6、MULT1、RAE1 α、β、γ、δ及ε、H60a、H60b、H60c、GPR15、ST2及/或其組合。整合素包括α1、α2、αIIb、α3、α4、α5、α6、α7、α8、α9、α10、α11、αD、αE、αL、αM、αV、αX、β1、β2、β3、β4、β5、β6、β7、β8及/或其組合。TCR包括α、β、γ、δ、ε、ζ鏈及/或其組合。若干種用於分析細胞表面蛋白質表現之方法,包括流式細胞分析技術及質譜流式細胞分析技術(CyTOF)已描述於文獻中。
在某些實施例中,個體之耐受性狀態係藉由分析來自生物樣品之核酸來測定。在各種實施例中,核酸為DNA及/或RNA,包括(但不限於)單股DNA、雙股DNA、mRNA、rRNA、tRNA、siRNA、miRNA、長非編碼RNA (長ncRNA、lncRNA)及非編碼RNA (ncRNA)、粒線體RNA。在各種實施例中,個體之免疫耐受性狀態係藉由分析來自生物樣品之基因表現來測定。在各種實施例中,免疫耐受性狀態係藉由分析與免疫功能、抗體、異物反應、代謝、細胞凋亡、細胞死亡、壞死、鐵死亡、自體吞噬、細胞遷移、內飲作用、吞噬作用、胞飲作用、緊密接合調節、細胞黏附、分化及/或其組合相關之基因表現來測定。在各種實施例中,免疫耐受性狀態係藉由分析與免疫抑制相關之基因表現來測定。在各種實施例中,免疫耐受性狀態係藉由分析與免疫活化相關之基因表現來測定。在各種實施例中,免疫耐受性狀態係藉由分析與免疫調節功能相關之基因表現來測定。在各種實施例中,核酸分析用於產生免疫耐受性標籤。在針對高通量基因表現分析之文獻中已描述了若干方法,該等方法包括RNA定序(RNA-seq)、單細胞RNA定序(scRNA-seq)、外顯子體定序及基於微陣列之分析。
視情況在用一或多種刺激物(諸如抗原、過敏原及一或多種活化劑)活體內及/或離體刺激之後分析生物樣品。經考慮,用於分析之T細胞、B細胞及免疫球蛋白為抗原特異性的。例示性T細胞包括效應記憶T細胞、抗原特異性T細胞、活化抗原特異性T細胞、Th1細胞、病原性Th2a+細胞、Th17細胞、T濾泡性輔助細胞(TFH)細胞、TH0細胞或其他抗原特異性T細胞。B細胞包括效應B細胞、記憶B細胞、漿細胞及調節性B (Breg)細胞。
在各種實施例中,個體之免疫耐受性狀態係藉由在第一次投與TIMP當天(第1天)之給藥前及在投與後之某天自個體獲得的一或多份樣品(例如全血)來測定。隨後全血可經處理以分離周邊血液單核細胞(PBMC)、嗜鹼性球、嗜中性球、血漿及血清,用於下游分析。對自個體收集及經分析之一或多份樣品分離之細胞進行分析。
醫藥調配物
含有本文中所描述之TIMP及抗原之本發明之醫藥組合物可含有醫藥學上可接受之載劑或添加劑,視投藥途徑而定。此等載劑或添加劑之實例包括水、醫藥學上可接受之有機溶劑、膠原蛋白、聚乙烯醇、聚乙烯吡咯啶酮、羧基乙烯基聚合物、羧甲基纖維素鈉、聚丙烯酸鈉、海藻酸鈉、水溶性聚葡萄糖、羧甲基澱粉鈉、果膠、甲基纖維素、乙基纖維素、三仙膠、阿拉伯膠、酪蛋白、明膠、瓊脂、二甘油、甘油、丙二醇、聚乙二醇、Vaseline®、石蠟、硬脂醇、硬脂酸、人類血清白蛋白(human serum albumin,HSA)、甘露糖醇、山梨糖醇、乳糖、醫藥學上可接受之界面活性劑以及其類似物。視本發明之劑型而定,所使用之添加劑按需要選自(但不限於)上文或其組合。
醫藥組合物之調配將根據所選投與途徑(例如,溶液、乳液)變化。包含所投與之治療劑之適當組合物可以生理學上可接受之媒劑或載劑形式製備。對於溶液或乳液,適合之載劑包括例如水性或醇/水溶液、乳液或懸浮液,包括鹽水及緩衝介質。非經腸媒劑可包括氯化鈉溶液、林格氏右旋糖(Ringer's dextrose)、右旋糖及氯化鈉、乳酸化林格氏溶液或不揮發性油。靜脈內媒劑可包括各種添加劑、防腐劑或流體、營養或電解質補充劑。
存在各種水性載劑,例如無菌磷酸鹽緩衝鹽水溶液、抑菌水、水、緩衝水、0.4%生理鹽水、0.3%甘胺酸及其類似物,且可包括用於增強穩定性之其他蛋白質,諸如白蛋白、脂蛋白、球蛋白等,其經歷輕度化學改質或其類似方法。
藉由將具有所需純度之抑制劑與視情況選用之生理學上可接受之載劑、賦形劑或穩定劑混合來製備呈凍乾調配物或水溶液形式的抑制劑之治療調配物以用於儲存(Remington's Pharmaceutical Sciences第16版, Osol, A.編(1980))。可接受之載劑、賦形劑或穩定劑在所使用之劑量及濃度下對接受者為無毒性的,且包括緩衝液,諸如磷酸鹽、檸檬酸鹽及其他有機酸;抗氧化劑,包括抗壞血酸及甲硫胺酸;防腐劑(諸如氯化十八烷基二甲基苯甲基銨;氯化六羥季銨;氯化苄烷銨、氯化苯索寧;苯酚、丁醇或苄醇;對羥基苯甲酸烷基酯,諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯;兒茶酚;間苯二酚;環己醇;3-戊醇;及間甲酚);低分子量(少於約10個殘基)多肽;蛋白質,諸如血清白蛋白、明膠或免疫球蛋白;親水性聚合物,諸如聚乙烯吡咯啶酮;胺基酸,諸如甘胺酸、麩醯胺酸、天冬醯胺、組胺酸、精胺酸或離胺酸;單醣、雙醣及其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合劑,諸如EDTA;糖,諸如蔗糖、甘露醇、海藻糖或山梨醇;成鹽相對離子,諸如鈉;金屬錯合物(例如,Zn-蛋白質錯合物)及/或非離子性界面活性劑,諸如TWEEN™、PLURONICS™或聚乙二醇(PEG)。
用於活體內投藥之調配物必須為無菌的。此容易藉由無菌過濾膜過濾來完成。
水性懸浮液可含有與適用於製造水性懸浮液之賦形劑混合之活性化合物。此類賦形劑為懸浮劑,例如羧甲基纖維素鈉、甲基纖維素、羥基丙基甲基纖維素、海藻酸鈉、聚乙烯吡咯啶酮、黃蓍膠及阿拉伯膠;分散劑或濕潤劑可為天然存在之磷脂,例如卵磷脂,或環氧烷與脂肪酸之縮合產物,例如聚氧乙烯硬脂酸酯,或環氧乙烷與長鏈脂族醇之縮合產物,例如十七伸乙基氧基十六醇,或環氧乙烷與衍生自脂肪酸及己糖醇之偏酯的縮合產物,諸如聚氧乙烯山梨醇單油酸酯,或環氧乙烷與衍生自脂肪酸及己糖醇酐之偏酯的縮合產物,例如聚乙烯脫水山梨醇單油酸酯。水性懸浮液亦可含有一或多種防腐劑,例如對羥基苯甲酸乙酯或對羥基苯甲酸正丙酯。
本文中所描述之TIMP可凍乾儲存且在使用之前在適合之載劑中復原。
用於經口投與之固體劑型包括膠囊、錠劑、丸劑、散劑及顆粒劑。在此類固體劑型中,將經修飾之粒子與以下混合:至少一種惰性、醫藥學上可接受之賦形劑或載劑(諸如檸檬酸鈉或磷酸二鈣)及/或a)填充劑或增量劑,諸如澱粉、乳糖、蔗糖、葡萄糖、甘露糖醇及矽酸;b)黏合劑,諸如羧甲基纖維素、海藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖及阿拉伯膠;c)保濕劑,諸如甘油;d)崩解劑,諸如瓊脂-瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、海藻酸、某些矽酸鹽及碳酸鈉;e)溶液阻滯劑,諸如石蠟;f)吸收促進劑,諸如四級銨化合物;g)濕潤劑,諸如鯨蠟醇及丙三醇單硬脂酸酯;h)吸附劑,諸如高嶺土(kaolin)及膨潤土(bentonite clay),以及i)潤滑劑,諸如滑石、硬脂酸鈣、硬脂酸鎂、固態聚乙二醇、月桂基硫酸鈉及其混合物。在膠囊、錠劑及丸劑之情況下,該劑型亦可包含緩衝劑。
套組
本發明亦提供套組,其包含以有助於其用於實踐本發明之方法之方式封裝的一或多種化合物或組合物。在一個實施例中,此類套組包括封裝於容器(諸如密封瓶或容器)中之本文所描述之化合物或組合物(例如,包含單獨或與另一藥劑組合之TIMP的組合物),其中標籤貼附於容器上或包括於封裝中,描述化合物或組合物在實踐方法中之用途。較佳地,以單位劑型封裝化合物或組合物。套組可進一步包括適用於根據特定投藥途徑投與組合物或適用於實踐篩檢分析法之裝置。較佳地,套組含有描述粒子組合物之用途的標籤。
本發明之額外態樣及細節將自以下實例顯而易知,該等實例旨在說明性而非限制性的。
實例
實例1-TIMP在提高AAV8-GFP投與之後的表現及能夠實現AAV8-GFP再給藥方面的功效
檢測囊封重組eGFP (CNP-GFP)及AAV8 VP1衣殼蛋白(CNP-VP1) (CNP-GFP+CNP-VP1)之TIMP在初始投與時及在用rAAV8-GFP載體再給藥後在誘導抗原特異性耐受性及提高轉殖基因表現方面的功效。
用於此研究中之粒子之平均直徑為400-800 nm且ζ電位在-30與-80 mV之間。
在第-7天及第0天,向雌性BALB/c小鼠(6-8週齡,每組n=10)靜脈內注射CNP-GFP (1.25 mg/小鼠)及CNP-VP1 (1.25 mg/小鼠)或未負載CNP (對照組)。在第0天,在左四頭肌經由肌肉內注射向小鼠投與rAAV8-eGFP。藉由經皮螢光光譜分析,在第0天、第3天、第7天、第14天、第21天及第28天,監測小鼠之預致敏左四頭肌中之轉殖基因eGFP表現。如
圖 1中所示,當與對照組相比時,用CNP-GFP+CNP-VP1處理引起顯著較高的GFP表現(*p<0.05;***p<0.001;****p<0.0001)。
在第28天,在對側右四頭肌處向小鼠肌肉內再給藥AAV8-GFP (各組N=5)。再給藥之後七天(第35天),處死小鼠且採集右四頭肌及左四頭肌以用於分析。AAV8-VP1及GFP特異性CD8
+T細胞之頻率及總細胞計數係使用四聚體染色藉由流式細胞分析技術來評估。如
圖 2中所示,用CNP-GFP+CNP-VP1處理導致投與AAV8-GFP之初始組織(左四頭肌)及再給藥AAV8-GFP之組織(右四頭肌)兩者中之VP1及GFP特異性CD8+T細胞的數目顯著減少(*p<0.05;**p<0.01)。
在第35天,在對側右四頭肌處向各處理組剩餘小鼠(每組N=5)肌肉內再給藥AAV8-GFP,且藉由經皮螢光光譜分析監測右四頭肌中之eGFP表現。如
圖 3中所示,當與對照組相比時,再給藥AAV8-GFP之後14天及21天,經CNP-GFP+CNP-VP1處理之小鼠顯示右四頭肌中之eGFP表現顯著較高(**p<0.01;****p<0.0001)。相對於對照處理,CNP-GFP+CNP-VP1處理引起第14天至第21天GFP表現增加58%。
基於此等結果,用CNP-GFP+CNP-VP1之治療可抑制抗VP1及抗GFP抗體之產生。使用ELISA自血液量測對抗體反應之抑制。
此研究之結果證明囊封AAV8 VP1衣殼蛋白及轉殖基因產物之TIMP能有效地誘導抗原特異性耐受性,引起提高的轉殖基因表現且能夠再給藥AAV8-GFP。
實例2-靜脈內投與囊封AAV8-GFP之TIMP引起全身耐受性
檢測囊封重組eGFP (CNP-GFP)及AAV8 VP1衣殼蛋白(CNP-VP1)之TIMP在治療性小鼠模型中靜脈內投與後在誘導抗原特異性耐受性方面的功效。
用於此研究中之粒子之平均直徑為400-800 nm且ζ電位在-30與-80 mV之間。
在第0天,用PBS或空AAV8衣殼預致敏C57BL/6小鼠(6-8週齡,n=5)。在第14天及第21天,向小鼠投與2個靜脈內劑量之CNP-GFP (1.25 mg/小鼠)+CNP-VP1 (1.25 mg/小鼠)。在第28天藉由靜脈內投與AAV8-GFP來攻擊小鼠。在第53天,處死小鼠且獲取最終讀數。
與對照組小鼠相比,經CNP處理之小鼠之心臟中之免疫浸潤減少(圖4A)。
如圖4B中所示,自經CNP處理之小鼠獲得的CD4+ T細胞顯示脾臟、肝臟及心臟中之調節性表現型增加(圖4B)。當與對照處理之小鼠相比時,經CNP處理之小鼠之脾臟及肝臟中之表現調節性標記物的CD4+T細胞(Foxp3+及Ctla4+)數目增加。接受CNP療法之小鼠之脾臟中之表現調節性細胞介素IL-10+及CD44hi記憶標記物的CD4+T細胞數目亦增加(圖4B)。經CNP處理之小鼠之心臟中之具有記憶表現型的CD4+T細胞增加(CD44hi,CD44hi IFN-γ+及CD44hi IFN-γ-)且調節性細胞(CD4+Foxp3+、CD4+PD-1+、CD4+CTLA4+、CD4+IL-10+)增加。(*p<0.05;**p<0.01)。
如圖4C中所示,當與對照處理之小鼠相比時,經CNP治療及用AAV再給藥之小鼠之浸潤心臟的效應CD8+T細胞(CD8+顆粒酶+、CD8+PD-1+、CD8+CD69+)數目減少(圖4C)。(*p<0.05;**p<0.01;***p<0.001)。
本文所論述及引用之所有出版物、專利及專利申請案均特此以引用之方式整體併入。應瞭解,所揭示之發明不侷限於所描述之特定方法、方案及材料,因為該等可以變化。亦應瞭解,本文中所用之術語僅出於描述特定實施例之目的且並不意欲限制所附申請專利範圍之範疇。
熟習此項技術者將認識到或能夠確定本文中所描述之本發明之特定實施例的許多等效物。該等等效物欲由隨附申請專利範圍所涵蓋。
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圖 1 : 在經由肌肉內注射初始投與 AAV8 - GFP 後 CNP-GFP+ CNP - VP1 處理對 GFP 表現之作用。在第-7天及第0天,向雌性BALB/c小鼠(6-8週齡,每組n=10)靜脈內注射CNP-GFP (1.25 mg/小鼠)及CNP-VP1 (1.25 mg/小鼠)或未負載CNP (對照組)。在第0天,在左四頭肌經由肌肉內注射向小鼠投與rAAV8-eGFP。藉由經皮螢光光譜分析,在第0天、第3天、第7天、第14天、第21天及第28天,監測小鼠之預致敏左四頭肌中之轉殖基因eGFP表現。當與對照組相比時,用CNP-GFP+CNP-VP1處理引起顯著較高的GFP表現(*p<0.05;***p<0.001;****p<0.0001)。
圖 2A - 圖 2D : 在經由肌肉內注射初始投與及再給藥 AAV8 - GFP 後 CNP - GFP + CNP - VP1 處理對抗原特異性 CD8 T 細胞之作用。在第-7天及第0天,向雌性BALB/c小鼠(6-8週齡,每組n=10)靜脈內注射CNP-GFP (1.25 mg/小鼠)及CNP-VP1 (1.25 mg/小鼠)或未負載CNP (對照組)。在第0天,在左四頭肌經由肌肉內注射向小鼠投與rAAV8-eGFP。在第28天,在對側右四頭肌處向小鼠肌肉內再給藥AAV8-GFP (各組N=5)。再給藥之後七天(第35天),處死小鼠且採集右四頭肌及左四頭肌以用於分析。AAV8-VP1及GFP特異性CD8
+T細胞之頻率及總細胞計數係使用四聚體染色藉由流式細胞分析技術來評估。用CNP-GFP+CNP-VP1處理導致投與AAV8-GFP之初始組織(左四頭肌) (圖2A,圖2B)及再給藥AAV8-GFP之組織(右四頭肌) (圖2C,圖2D)兩者中之VP1及GFP特異性CD8+ T細胞的數目顯著減少(*p<0.05;**p<0.01)。
圖 3 : 在經由肌肉內注射 再給藥 AAV8 - GFP 後 CNP - GFP + CNP - VP1 處理對 GFP 表現之作用。在第-7天及第0天,向雌性BALB/c小鼠(6-8週齡,每組n=10)靜脈內注射CNP-GFP (1.25 mg/小鼠)及CNP-VP1 (1.25 mg/小鼠)或未負載CNP (對照組)。在第0天,在左四頭肌經由肌肉內注射向小鼠投與rAAV8-eGFP。在第35天,在對側右四頭肌處向各處理組小鼠(每組N=5)肌肉內再給藥AAV8-eGFP,且藉由經皮螢光光譜分析監測右四頭肌中之eGFP表現。當與對照組相比時,再給藥AAV8-GFP之後14天及21天,經CNP-GFP+CNP-VP1處理之小鼠顯示右四頭肌中之eGFP表現顯著較高(**p<0.01;****p<0.0001)。相對於對照處理,CNP-GFP+CNP-VP1處理引起第14天至第21天GFP表現增加58%。
圖 4A 至圖 4C : 全身投與囊封 AAV8 - GFP 之 TIMP 引起致耐受性表現型。在第0天,用PBS或空AAV8衣殼預致敏C57BL/6小鼠(6-8週齡,n=5)。在第14天及第21天,向小鼠投與2個靜脈內劑量之CNP-GFP (1.25 mg/小鼠)+CNP-VP1 (1.25 mg/小鼠)。在第28天,藉由IV投與用AAV8-eGFP攻擊小鼠。在第53天,處死小鼠且獲取最終讀數。與對照組小鼠相比,經CNP處理之小鼠之心臟中之白血球減少(圖4A)。CD4+T細胞顯示脾臟、肝臟及心臟中之調節性表現型增加(圖4B)。當與對照處理(PBS)之小鼠相比時,經CNP處理之小鼠之脾臟及肝臟中之調節性T細胞(CD4+Foxp3+及CD4+Ctla4+)增加(圖4B)。接受CNP療法之小鼠之脾臟中之表現調節性細胞介素IL-10+及CD44
hi記憶標記物的CD4+細胞數目亦增加(圖4B)。經CNP處理之小鼠之心臟中之記憶CD4+ T細胞(CD44hi IFN-γ-)增加且調節性細胞(CD4+Foxp3+、CD4+PD-1+、CD4+Ctla4+、CD4+IL-10+)增加(圖4B)。與經CNP處理之小鼠之心臟相比,CD8+T細胞之效應子表現型減少(CD8+顆粒酶+、CD8+PD-1+、CD8+CD69+) (圖4C)。(*p<0.05;**p<0.01;***p<0.001)。
Claims (65)
- 一種組合物,其包含囊封抗原之帶負電荷粒子,其中該抗原為一或多種基因療法載體抗原、其部分或其組合及/或一或多種由基因療法載體產生之轉殖基因蛋白質產物、其部分或其組合。
- 如請求項1之組合物,其中該粒子包含聚(丙交酯-共-乙交酯) (PLG)、聚乳酸(PLA)、PLG及PLA之共聚物(PLGA)、聚己內酯(PCL)、聚苯乙烯、聚乙二醇(PEG)、聚葡萄胺糖、多醣、一或多種脂質、鐵、鋅、鎘、金或銀。
- 如請求項1或2之組合物,其中該粒子之ζ電位在0 mV與-100 mV之間。
- 如請求項3之組合物,其中該粒子之ζ電位在-30與-80 mV之間。
- 如請求項1至4中任一項之組合物,其中該粒子的尺寸在100 nm與1000 nm之間。
- 如請求項5之組合物,其中該粒子的尺寸在400至800 nm之間。
- 如請求項1至5中任一項之組合物,其中該抗原包含一或多種蛋白質、肽或其抗原表位。
- 如請求項1至7中任一項之組合物,其中該基因療法載體為病毒載體。
- 如8之組合物,其中該病毒載體為腺病毒、腺相關病毒(AAV)、單純疱疹病毒、B型肝炎病毒、慢病毒、反轉錄病毒、α病毒、黃病毒、棒狀病毒、麻疹病毒、新城雞瘟病毒(Newcastle disease virus)、科沙奇病毒(coxsackievirus)、輸血傳播病毒、指環體、人類乳突狀瘤病毒、痘病毒、痘瘡病毒、經修飾之安卡拉病毒(modified Ankara virus)、水泡性口炎病毒、小核糖核酸病毒、菸草嵌紋病毒、豇豆嵌紋病毒、豇豆褪綠斑駁病毒、酸漿嵌紋病毒、紅三葉草壞死嵌紋病毒、馬鈴薯病毒x、豇豆花葉病毒、雞貧血病毒或胡瓜嵌紋病毒。
- 如請求項9之組合物,其中該AAV為AAV-1、AAV-2、AAV-3、AAV-4、AAV-5、AAV-6、AAV-7、AAV-8、AAV-9、AAV-10、AAV-12、Anc80、合成AAV、其組合、經工程改造或經修飾之版本。
- 如請求項1至10中任一項之組合物,其中該抗原與一或多種病毒載體衣殼蛋白、肽及/或其抗原表位相關。
- 如請求項11之組合物,其中該衣殼蛋白為VP-1、VP-2、VP-3、其組合或部分。
- 如請求項1至12中任一項之組合物,其中該轉殖基因蛋白質產物為細胞介素、趨化介素、激素、生長因子、酶或抗體。
- 如請求項13之組合物,其中該抗體為單株抗體。
- 一種對有需要之個體誘導耐受性的方法,其包含向個體投與組合物,該組合物包含囊封抗原之帶負電荷粒子,其中該抗原為一或多種基因療法載體抗原及/或一或多種由該(等)基因療法載體產生之轉殖基因蛋白質產物、其部分或組合。
- 如請求項15之方法,其中囊封一或多種基因療法載體抗原之該等帶負電荷粒子與囊封一或多種由該(等)基因療法載體產生之轉殖基因蛋白質產物之帶負電荷粒子組合投與。
- 如請求項16之方法,其中囊封一或多種基因療法載體抗原之該等帶負電荷粒子係在投與囊封一或多種由該(等)基因療法載體產生之轉殖基因蛋白質產物之帶負電荷粒子之前、同時或之後投與。
- 如請求項15至17中任一項之方法,其中該粒子包含聚(丙交酯-共-乙交酯) (PLG)、聚乳酸(PLA)、PLG及PLA之共聚物(PLGA)、聚己內酯(PCL)、聚乙二醇(PEG)、聚苯乙烯、聚葡萄胺糖、多醣或一或多種脂質、鐵、鋅、鎘、金或銀。
- 如請求項15至18中任一項之方法,其中粒子具有負ζ電位。
- 如請求項15至19中任一項之方法,其中該粒子之ζ電位在0 mV與-100 mV之間。
- 如請求項15至20中任一項之方法,其中該粒子之ζ電位在-30 mV與-100 mV之間。
- 如請求項15至21中任一項之方法,其中該粒子之尺寸在100 nm與1000 nm之間。
- 如請求項15至22中任一項之方法,其中該粒子之尺寸在400 nm與800 nm之間。
- 如請求項15至23中任一項之方法,其中該抗原包含蛋白質、肽或其一或多種抗原表位。
- 如請求項15至24中任一項之方法,其中該基因療法載體為病毒載體。
- 如請求項25之方法,其中該病毒載體為腺病毒、腺相關病毒(AAV)、單純疱疹病毒、B型肝炎病毒、慢病毒、反轉錄病毒、α病毒、黃病毒、棒狀病毒、麻疹病毒、新城雞瘟病毒、科沙奇病毒、輸血傳播病毒、指環體、人類乳突狀瘤病毒、痘病毒、痘瘡病毒、經修飾之安卡拉病毒、水泡性口炎病毒、小核糖核酸病毒、菸草嵌紋病毒、豇豆嵌紋病毒、豇豆褪綠斑駁病毒、酸漿嵌紋病毒、紅三葉草壞死嵌紋病毒、馬鈴薯病毒x、豇豆花葉病毒、雞貧血病毒或胡瓜嵌紋病毒。
- 如請求項26之方法,其中該AAV係選自由以下組成之群:AAV-1、AAV-2、AAV-3、AAV-4、AAV-5、AAV-6、AAV-7、AAV-8、AAV-9、AAV-10、AAV-12、Anc80、合成AAV、其組合或經工程改造之版本。
- 如請求項15至27中任一項之方法,其中該抗原與一或多種病毒載體衣殼蛋白質、肽及/或其抗原表位相關。
- 如請求項28之方法,其中該衣殼蛋白質為VP-1、VP-2、VP-3、其組合或部分。
- 如請求項15至29中任一項之方法,其中該個體患有癌症、自體免疫疾病、過敏症、心血管疾病、代謝疾病、糖尿病、酶缺乏症、蛋白質缺乏症、囊腫性纖維化、血液病症、β-地中海貧血症、鐮狀細胞疾病、A型血友病、B型血友病、溶素體儲積病、法布立病(Fabry disease)、高歇氏病(Gaucher disease)、龐培氏病(Pompe disease)、尼曼-匹克二氏病(Niemann-Pick disease)、泰-薩二氏病(Tay-Sachs disease)、黃斑變性、黏多醣病、靜脈栓塞、馮威里氏病(von Willebrand disease)、猛爆性紫斑、生長激素缺乏症、神經節苷脂症、鹼性低磷酸酶症、膽固醇酯儲積病、高尿酸血症、杜興氏肌肉失養症(Duchenne Muscular Dystrophy)、杭丁頓氏舞蹈症(Huntington's disease)、帕金森氏症(Parkinson's)、阿茲海默氏症(Alzheimer's disease)、無脈絡脈畸型症、斯特格氏病(Stargardt Disease)、巴登氏病(Batten disease)、脊髓小腦失調、ALS、額顳葉變性、鳥胺酸胺甲醯基轉移酶缺乏症、色素性視網膜炎、RPE-65突變相關病、大皰性表皮鬆解、隱性營養不良型大皰性表皮鬆解、脊髓性肌萎縮、苯酮尿症(PKU)、X性聯肌小管肌病、克果-納傑氏症候群(Crigler-Najjar syndrome)、兒茶酚胺引發之多型性心室性心搏過速、1型肝醣儲積症、α-甘露糖症、脆弱X染色體症候群、精胺酸酶缺乏症、X性聯慢性肉芽腫病、腺苷去胺酶缺乏症、萊伯氏先天性黑矇(Leber's congenital amaurosis)、脂蛋白脂肪酶缺乏症、大腦型腎上腺腦白質失養症、異染性腦白質失養症、范康尼氏貧血症(Fanconi anemia)、失色症、硬皮病、成骨不全症、冠狀動脈疾病、酪胺酸血症、周邊神經病變、視神經病變、冠狀動脈疾病、呼吸道融合細胞病毒(RSV)介導之下呼吸道疾病、達農病(Danon disease)、嚴重白血球黏附分子缺乏症、丙酮酸激酶缺乏症、恰克-馬利-杜斯氏病(Charcot Marie Tooth disease)、偉-爾二氏症候群(Wiskott Aldrich syndrome)、α-突觸核蛋白tau蛋白病變、心肌缺血引發的難治性絞痛、I型肌強直性營養不良、跛行、周邊動脈疾病、甲基丙二酸血症、蔗糖酶-異麥芽糖酶缺乏症、B型尼曼-匹克二氏病(Niemann-Pick type B disease)、α1-PI缺乏症、遺傳性血管水腫、血纖維蛋白原缺乏症、因子VIIa缺乏症、因子X缺乏症、因子XI缺乏症、因子XII缺乏症、蛋白C缺乏症、抗凝血酶III缺乏症、MPS I、MPS II、MPS III、MPS IV、MPS VI、MPS VII、MPS IX、鈣化/骨化病症、ENPP1缺乏症、ENPP3缺乏症、ABCC6缺乏症、芳族L-胺基酸去羧酶缺乏症、天使症候群(Angelman syndrome)、高苯丙胺酸血症、失智症、雷特氏症候群(Rett syndrome)及尤塞氏症候群(Usher syndrome)。
- 如請求項30之方法,其中該個體患有選自由以下組成之群的癌症:腦癌、皮膚癌、眼癌、乳癌、前列腺癌、肺癌、食道癌、頭頸癌、子宮頸癌、肝癌、大腸癌、骨癌、子宮癌、卵巢癌、膀胱癌、胃癌、口腔癌、甲狀腺癌、腎癌、睪丸癌、白血病、淋巴瘤、黑色素瘤及間皮瘤。
- 如請求項30之方法,其中該個體患有選自由以下組成之群的自體免疫疾病:多發性硬化症、艾迪森氏病(Addison's disease)、僵直性脊椎炎、禿頭症、骨關節炎、牛皮癬性關節炎、硬皮病、I型糖尿病、類風濕性關節炎、甲狀腺炎、全身性紅斑性狼瘡症、雷諾氏症候群(Reynaud's syndrome)、貝塞特氏症(Behcet's syndrome)、修格蘭氏症候群(Sjorgen's syndrome)、自體免疫葡萄膜炎、伊頓-藍伯疾病(Eaton Lambert's disease)、自體免疫心肌炎、發炎性腸道疾病、肌肉萎縮性側索硬化(ALS)、全身性紅斑狼瘡、視神經脊髓炎、特發性血小板減少性紫癜、血栓性血小板減少性紫斑症、膜性腎病變、類天疱瘡、尋常型天疱瘡、重症肌無力、乳糜瀉、潰瘍性結腸炎、克羅恩氏病(Crohn's disease)、結節性紅斑、絲球體腎炎、古巴士德氏症候群(Goodpasture's syndrome)、肉芽腫病、格雷夫氏病(Grave's disease)、格-巴二氏症候群(Guillain-Barre syndrome)、橋本氏疾病(Hashimoto disease)、溶血性貧血、川崎病(Kawasaki Disease)、混合型結締組織疾病、多病灶性運動神經病變、周邊膽汁性肝硬化、多血管炎重疊症候群、1型硬皮病、硬化性膽管炎、僵體症候群、高安氏動脈炎(Takayasu arteritis)、白斑病或韋格納肉芽腫病(Wegeners granulomatosis)。
- 如請求項30之方法,其中該個體患有選自由以下組成之群的過敏:花生過敏、樹堅果過敏、乳過敏、蛋過敏、魚過敏、小麥過敏、芹菜過敏或桃子過敏;在各種實施例中,環境過敏係花粉過敏、粉塵過敏、寵物皮屑過敏或黴菌過敏。
- 如請求項15至33中任一項之方法,其中該組合物在該基因療法載體之前、之後或同時投與。
- 如請求項15至34中任一項之方法,其中投與該組合物降低對該基因療法載體及/或由該載體產生之該轉殖基因蛋白質產物的免疫反應。
- 如請求項35之方法,其中該免疫反應為發炎免疫反應。
- 如請求項35至36中任一項之方法,其中該免疫反應為體液免疫反應。
- 如請求項35至36中任一項之方法,其中該免疫反應為適應性免疫反應。
- 如請求項35至36中任一項之方法,其中該免疫反應為先天性免疫反應。
- 如請求項35至39中任一項之方法,其中該免疫反應為T細胞、B細胞、單核球、巨噬細胞、嗜中性球、嗜鹼性球或嗜酸性球反應。
- 如請求項35至40中任一項之方法,其中該免疫反應為抗體反應。
- 如請求項41之方法,其中該抗體反應為形成針對該基因療法載體及/或由該載體產生之該轉殖基因蛋白質的中和抗體。
- 如請求項15至42中任一項之方法,其中投與該組合物誘導針對該基因療法載體及/或由該載體產生之該轉殖基因蛋白質產物的免疫調節反應。
- 如請求項43之方法,其中該免疫調節反應為調節性T細胞、B細胞、單核球及/或巨噬細胞。
- 如請求項43之方法,其中該免疫調節反應為抗原特異性Treg、Tr1、Mreg及/或Breg細胞。
- 如請求項15至45中任一項之方法,其中該組合物經靜脈內、肌肉內、經眼、腹膜內、經皮、經鼻、經口及/或皮下投與。
- 一種組合物,其包含囊封一或多種基因療法載體抗原、其部分或組合之脂質體。
- 一種組合物,其包含囊封由該基因療法載體產生之治療蛋白及/或其部分的脂質體。
- 如請求項47至48中任一項之組合物,其中該脂質體具有負ζ電位。
- 如請求項49之組合物,其中該負ζ電位在-100 mV至0 mV之間。
- 如請求項50之組合物,其中該負ζ電位在-80 mV至-30 mV之間。
- 如請求項47至51中任一項之組合物,其中該基因療法載體抗原係選自由以下組成之群:腺病毒、腺相關病毒(AAV)、AAV-1、AAV-2、AAV-3、AAV-4、AAV-5、AAV-6、AAV-7、AAV-8、AAV-9、AAV-10、AAV-12、Anc80、合成AAV、其組合或經工程改造之版本、AAV衣殼蛋白VP1、AAV衣殼蛋白VP2、AAV衣殼蛋白VP3、單純疱疹病毒、B型肝炎病毒、慢病毒、反轉錄病毒、α病毒、黃病毒、棒狀病毒、麻疹病毒、新城雞瘟病毒、科沙奇病毒、輸血傳播病毒、指環病毒、人類乳突狀瘤病毒、痘病毒、痘瘡病毒、經修飾之安卡拉病毒、水泡性口炎病毒、小核糖核酸病毒、菸草嵌紋病毒、豇豆嵌紋病毒、豇豆褪綠斑駁病毒、酸漿嵌紋病毒、紅三葉草壞死嵌紋病毒、馬鈴薯病毒x、豇豆花葉病毒、雞貧血病毒、胡瓜嵌紋病毒、溶瘤病毒、嵌合病毒、合成病毒、嵌紋病毒、假型病毒、細菌、噬菌體、酵母、胞泌體或紅血球。
- 如請求項47至52中任一項之組合物,其中由該基因療法載體產生之該治療蛋白及/或其部分係選自由以下組成之群:細胞介素、趨化介素、激素、生長因子、酶或抗體。
- 如請求項47至53中任一項之組合物,其中該脂質體在100至1000 nm之間。
- 一種在有需要之個體中誘導耐受性的方法,其包含向該個體投與如請求項47至54中任一項之組合物。
- 如請求項1至14或47至54中任一項之組合物,其包含囊封抗原之帶負電荷粒子,其中該抗原為一或多種基因療法載體抗原及/或一或多種由該(等)基因療法載體產生之轉殖基因蛋白質產物、其部分或組合,用於在個體中誘導耐受性。
- 一種如請求項1至14或47至54中任一項之組合物之用途,該組合物包含囊封抗原之帶負電荷粒子,其中該抗原為一或多種基因療法載體抗原及/或一或多種由該(等)基因療法載體產生之轉殖基因蛋白質產物、其部分或組合,該組合物用於製備供在個體中誘導耐受性用的藥物。
- 一種對有需要之個體誘導耐受性的方法,其包含向個體投與和一或多種治療劑組合的如請求項1至14或47至54中任一項之組合物,該組合物包含囊封抗原之帶負電荷粒子,其中該抗原為一或多種基因療法載體抗原及/或一或多種由該(等)基因療法載體產生之轉殖基因蛋白質產物、其部分或組合。
- 如請求項58之方法,其中該治療劑阻斷或抑制針對該基因療法載體及/或由該基因療法載體產生之轉殖基因蛋白質的先天性免疫反應、補體反應、B細胞反應及/或T細胞反應。
- 如請求項58或59之方法,其中該治療劑係選自由以下組成之群:免疫抑制劑、補體抑制劑、鈣調神經磷酸酶抑制劑、血漿去除法、IgG蛋白酶、蛋白酶體抑制劑及/或調節T細胞之誘導劑。
- 如請求項58至60中任一項之方法,其中該治療劑為FcRn抑制劑。
- 如請求項58至60中任一項之方法,其中該治療劑為皮質類固醇、雷帕黴素(rapamycin)/西羅莫司(sirolimus)、環磷醯胺或黴酚酸嗎啉乙酯。
- 如請求項58至60中任一項之方法,其中該治療劑為抗CD20 CAR T細胞療法、抗CD19 CAR T細胞療法或抗BCMA CAR T細胞療法。
- 如請求項58至60中任一項之方法,其中該治療劑為抗CD20抗體、抗CD19抗體、抗CD40抗體或CTLA4 Ig。
- 如請求項58至64中任一項之方法,其中該一或多種治療劑在投與如請求項1至14或47至54中任一項之組合物之前、同時或之後投與,該組合物包含囊封抗原之帶負電荷粒子,其中該抗原為一或多種基因療法載體抗原及/或一或多種由該(等)基因療法載體產生之轉殖基因蛋白質產物、其部分或組合。
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