TW202022112A - T細胞之活性化/增殖方法 - Google Patents
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Abstract
本發明提供一種T細胞之活性化及/或增殖方法,其包括如下步驟:使包含T細胞之細胞群體與於表面附加有至少一種T細胞活性化配體之核酸傳遞載體接觸;以及一種核酸向T細胞內之傳遞方法及一種含有T細胞而成之醫藥之製造方法等,其包括如下步驟:使包含T細胞之細胞群體與(a)於表面附加有至少一種T細胞活性化配體且於內部包含核酸之核酸傳遞載體接觸,或與(b)至少一種T細胞活性化配體及於內部包含核酸且未於表面附加T細胞活性化配體之核酸傳遞載體同時接觸。
Description
本發明係關於一種於表面附加有T細胞活性化配體之核酸傳遞載體、使用該核酸傳遞載體之T細胞之活性化及/或增殖方法、以及核酸向T細胞內之傳遞方法等。又,本發明係關於一種特徵在於使T細胞活性化配體與核酸傳遞載體同時和T細胞接觸之T細胞之活性化及/或增殖以及核酸向T細胞內之傳遞方法。
(發明之背景)
利用基因導入嵌合抗原受體(CAR)或源自癌抗原特異性殺手T細胞之T細胞受體(TCR)之CAR-T細胞或TCR-T細胞的癌免疫療法之研究、開發正在急速發展。目前之CAR-T細胞療法一般為如下方法:如於美國獲批之Kymriah(商品名)或Yescarta(商品名)般,使用慢病毒載體等病毒載體體外(ex vivo)向自患者採集之T細胞中導入CAR基因而製造CAR-T細胞,對患者投予該CAR-T細胞。然而,該方法必須經過T細胞之活性化/增殖、病毒載體之製備、向T細胞之基因導入等多個階段步驟,週期跨度長,因此細胞培養或病毒載體製備所耗費之成本等導致有製造費用高昂之課題。
作為不使用病毒載體之向T細胞導入CAR之方法,報告有使用專利文獻1、非專利文獻1之奈米粒子或專利文獻2之奈米載體進行之CAR向T細胞之體外(ex vivo)或體內(in vivo)轉染,上述奈米粒子係使編碼CAR之質粒DNA與陽離子性聚合物凝集,再利用複合有抗CD3抗體片段之非陽離子性聚合物被覆該凝集體而成,上述奈米載體係利用表面經抗CD3抗體修飾過之脂質被覆其小孔內封入有編碼CAR之DNA之中孔二氧化矽。
不同於該等,報告有向內部無小孔結構之「脂質奈米粒子(LNP)」內封入目標siRNA(short interfering RNA,短干擾核糖核酸)而向靶細胞傳遞該siRNA之技術,上述脂質奈米粒子(LNP)包含陽離子性脂質與非陽離子性輔助脂質及用以向靶細胞進行傳遞之配體。例如報告有將抗CD4抗體片段作為靶向配體,向T細胞體外或體內轉染針對CD45之siRNA(專利文獻3、非專利文獻2)。
又,專利文獻4中記載有用以向包括T細胞之各種細胞、組織或臟器內導入核酸等活性成分之陽離子性脂質。
另一方面,作為T細胞之活性化/增殖方法,報告有使用固定化有抗CD3/CD28抗體之珠粒或奈米尺寸之基質珠粒,使T細胞活性化及/或增殖之方法(專利文獻5及6)。
然而,迄今為止尚無能夠一步(One Pod)同時進行使T細胞活性化/增殖之步驟與向T細胞之基因導入步驟之技術之相關報告。
[先前技術文獻]
[專利文獻]
專利文獻1:US 2017/0296676
專利文獻2:US 2016/0145348
專利文獻3:WO 2016/189532
專利文獻4:WO 2016/021683
專利文獻5:US 6, 352, 694
專利文獻6:US 2014/0087462
[非專利文獻]
非專利文獻1:Nature Nanotechnology 12, 813-820 (2017)
非專利文獻2:ACS Nano, 2015, 9(7), 6706-6716
[發明所欲解決之問題]
本發明之目的在於縮短、簡化CAR-T療法等之免疫細胞療法劑之製造製程,於短期內提供製造費用較低之免疫細胞療法劑,以及提供一種排除病毒載體之潛在致癌性風險之安全性更高之免疫細胞療法劑之製造製程。
[解決問題之技術手段]
本發明者等人為了達成上述目的,經過銳意研究、不斷努力,最終成功地藉由使用於表面附加有T細胞活性化配體之核酸傳遞載體,一步同時進行使T細胞活性化/增殖之步驟與向T細胞之基因導入步驟。進而亦意外地發現,藉由使T細胞活性化配體與核酸傳遞載體同時和T細胞接觸,效率良好地達成T細胞之活性化/增殖與向T細胞之核酸導入,從而完成本發明。
即,本發明提供以下者。
[1]一種T細胞之活性化及/或增殖方法,其包括如下步驟:使包含T細胞之細胞群體與於表面附加有至少一種T細胞活性化配體之核酸傳遞載體接觸。
[2]如[1]記載之方法,其中上述T細胞活性化配體包含對於CD3之抗體及/或對於CD28之抗體。
[3]如[1]或[2]記載之方法,其中於上述核酸傳遞載體之表面附加有2種以上之T細胞活性化配體。
[4]如[1]至[3]中任一項記載之方法,其中上述核酸傳遞載體為脂質奈米粒子或脂質體。
[5]如[1]至[4]中任一項記載之方法,其中於上述核酸傳遞載體之內部包含抑制T細胞活性化抑制因子之表現之核酸及/或編碼T細胞活性化促進因子之核酸。
[6]如[1]至[5]中任一項記載之方法,其中於上述核酸傳遞載體之內部包含編碼CAR或TCR之核酸。
[7]如[1]至[6]中任一項記載之方法,其係體外進行。
[8]一種核酸向T細胞內之傳遞方法,其包括如下步驟:使包含T細胞之細胞群體與於表面附加有至少一種T細胞活性化配體且於內部包含核酸之核酸傳遞載體接觸。
[9]如[8]記載之方法,其中上述T細胞活性化配體包含對於CD3之抗體及/或對於CD28之抗體。
[10]如[8]或[9]記載之方法,其中於上述核酸傳遞載體之表面附加有2種以上之T細胞活性化配體。
[11]如[8]至[10]中任一項記載之方法,其中上述核酸傳遞載體為脂質奈米粒子或脂質體。
[12]如[8]至[11]中任一項記載之方法,其中上述核酸包含抑制T細胞活性化抑制因子之表現之核酸及/或編碼T細胞活性化促進因子之核酸。
[13]如[8]至[12]中任一項記載之方法,其中上述核酸包含編碼CAR或TCR之核酸。
[14]如[8]至[13]中任一項記載之方法,其係體外進行。
[15]一種核酸向T細胞內之傳遞方法,其包括如下步驟:使包含T細胞之細胞群體同時與至少一種T細胞活性化配體及於內部包含核酸且未於表面附加T細胞活性化配體之核酸傳遞載體接觸。
[16]如[15]記載之方法,其中上述T細胞活性化配體包含對於CD3之抗體及/或對於CD28之抗體。
[17]如[15]或[16]記載之方法,其中使與2種以上之T細胞活性化配體接觸。
[18]如[15]至[17]中任一項記載之方法,其中上述核酸傳遞載體為脂質奈米粒子或脂質體。
[19]如[15]至[18]中任一項記載之方法,其中上述核酸包含抑制T細胞活性化抑制因子之表現之核酸及/或編碼T細胞活性化促進因子之核酸。
[20]如[15]至[19]中任一項記載之方法,其中上述核酸包含編碼CAR或TCR之核酸。
[21]如[15]至[20]中任一項記載之方法,其係體外進行。
[22]一種含有T細胞而成之醫藥之製造方法,其包括如下步驟:使包含T細胞之細胞群體與於表面附加有至少一種T細胞活性化配體且於內部包含核酸之核酸傳遞載體接觸。
[23]如[22]記載之方法,其中上述T細胞活性化配體包含對於CD3之抗體及/或對於CD28之抗體。
[24]如[22]或[23]記載之方法,其中於上述核酸傳遞載體之表面附加有2種以上之T細胞活性化配體。
[25]如[22]至[24]中任一項記載之方法,其中上述核酸傳遞載體為脂質奈米粒子或脂質體。
[26]如[22]至[25]中任一項記載之方法,其中上述核酸包含抑制T細胞活性化抑制因子之表現之核酸及/或編碼T細胞活性化促進因子之核酸。
[27]如[22]至[26]中任一項記載之方法,其中上述核酸包含編碼CAR或TCR之核酸。
[28]如[22]至[27]中任一項記載之方法,其係體外進行。
[29]一種含有T細胞而成之醫藥之製造方法,其包括如下步驟:使包含T細胞之細胞群體同時與至少一種T細胞活性化配體及於內部包含核酸且未於表面附加T細胞活性化配體之核酸傳遞載體接觸。
[30]如[29]記載之方法,其中上述T細胞活性化配體包含對於CD3之抗體及/或對於CD28之抗體。
[31]如[29]或[30]記載之方法,其中使與2種以上之T細胞活性化配體接觸。
[32]如[29]至[31]中任一項記載之方法,其中上述核酸傳遞載體為脂質奈米粒子或脂質體。
[33]如[29]至[32]中任一項記載之方法,其中上述核酸包含抑制T細胞活性化抑制因子之表現之核酸及/或編碼T細胞活性化促進因子之核酸。
[34]如[29]至[33]中任一項記載之方法,其中上述核酸包含編碼CAR或TCR之核酸。
[35]如[29]至[34]中任一項記載之方法,其係體外進行。
[36]一種核酸傳遞載體,其於表面附加有至少一種T細胞活性化配體。
[37]如[36]記載之核酸傳遞載體,其中上述T細胞活性化配體包含對於CD3之抗體及/或對於CD28之抗體。
[38]如[36]或[37]記載之核酸傳遞載體,其中於上述核酸傳遞載體之表面附加有2種以上之T細胞活性化配體。
[39]如[36]至[38]中任一項記載之核酸傳遞載體,其中上述核酸傳遞載體為脂質奈米粒子或脂質體。
[40]如[36]至[39]中任一項記載之核酸傳遞載體,其於內部包含抑制T細胞活性化抑制因子之表現之核酸及/或編碼T細胞活性化促進因子之核酸。
[41]如[36]至[40]中任一項記載之核酸傳遞載體,其於內部包含編碼CAR或TCR之核酸。
[42]一種醫藥,其含有如[36]至[41]中任一項記載之核酸傳遞載體而成。
[43]一種T細胞,其藉由如[15]至[21]中任一項記載之方法向細胞內傳遞有核酸。
[44]一種醫藥,其含有如[43]記載之T細胞而成。
[45]一種細胞培養物,其含有:包含T細胞之細胞群體、與至少一種T細胞活性化配體、未於表面附加T細胞活性化配體之核酸傳遞載體、及培養基。
[46]一種向T細胞之核酸傳遞用組合物,其含有至少一種T細胞活性化配體、及未於表面附加T細胞活性化配體之核酸傳遞載體。
[47]一種向T細胞之核酸傳遞用套組,其含有至少一種T細胞活性化配體、及未於表面附加T細胞活性化配體之核酸傳遞載體。
[48]一種T細胞,其藉由如[8]至[14]中任一項記載之方法向細胞內傳遞有核酸。
[49]一種醫藥,其含有如[48]記載之T細胞而成。
[50]一種細胞培養物,其含有:包含T細胞之細胞群體、與於表面附加有至少一種T細胞活性化配體且於內部包含核酸之核酸傳遞載體、及培養基。
[51]一種向T細胞之核酸傳遞用組合物,其含有於表面附加有至少一種T細胞活性化配體且於內部包含核酸之核酸傳遞載體。
[52]一種向T細胞之核酸傳遞用套組,其含有於表面附加有至少一種T細胞活性化配體且於內部包含核酸之核酸傳遞載體。
[發明之效果]
根據本發明,可於不使用病毒載體之情況下,一步同時進行使T細胞活性化/增殖之步驟與向T細胞之基因導入步驟,因此可於短期內提供製造費用較低之免疫細胞療法劑。
(發明之詳細說明)1. 本發明之核酸傳遞載體
本發明提供一種於表面附加有至少一種T細胞活性化配體之核酸傳遞載體(以下亦稱為「本發明之核酸傳遞載體」)。
此處,所謂「核酸傳遞載體」,意指可載持核酸、且能夠向細胞內傳遞該核酸之載體。所謂「能夠向細胞內傳遞」,意指至少能夠將所載持之核酸傳遞至細胞之細胞質內。
1-1. 核酸傳遞載體
本發明中使用之核酸傳遞載體只要為如上所述可載持核酸、且能夠向細胞內傳遞該核酸者,則其結構、構成分子、核酸之載持形態並無特別限制。作為代表性之核酸之藥物遞送系統(DDS),可列舉利用帶正電之陽離子性脂質體或陽離子性聚合物等作為載體,基於該等與核酸之靜電相互作用而形成之複合體。該複合體與帶負電之細胞膜結合後,藉由吸附性內噬作用被吸入至細胞內。
更具體而言,作為本發明中使用之核酸傳遞載體,例如可列舉:脂質奈米粒子(LNP)、脂質體(例如:陽離子性脂質體、PEG修飾脂質體等)、陽離子性聚合物(例如:聚伸乙基亞胺、聚離胺酸、聚鳥胺酸、聚葡萄胺糖、缺端膠原、魚精蛋白等)、將陽離子性聚合物封入至脂質體中而成者等,但不限定於該等。或亦可使用作為源自生物體之成分的外吐小體。較佳為脂質奈米粒子或脂質體,更佳為脂質奈米粒子。
1-1-1. 脂質奈米粒子 (LNP)
於本說明書中,所謂「脂質奈米粒子(LNP)」,意指於包含陽離子性脂質及非陽離子性脂質之脂質集合體之外殼之內部並無大孔結構(例如脂質體)或小孔結構(例如中孔材料)之平均粒徑未達1 μm之粒子。
以下,對脂質奈米粒子之構成要素進行說明。
(a)陽離子性脂質
於本說明書中,所謂「陽離子性脂質」,意指於生理學pH或內體內等低pH環境下帶淨正電之脂質。本發明中使用之脂質奈米粒子所使用之陽離子性脂質並無特別限定,例如可列舉WO 2016/021683、WO 2015/011633、WO 2011/153493、WO 2013/126803、WO 2010/054401、WO 2010/042877、WO 2016/104580、WO 2015/005253、WO 2014/007398、WO 2017/117528、WO 2017/075531、WO 2017/00414、WO 2015/199952、US 2015/0239834、WO2019/131839等中記載之陽離子性脂質等。
或可列舉Dong等(Proc Natl Acad Sci U S A. 2014 Apr 15;111(15):5753)中記載之合成陽離子性脂質(例如:K-E12、H-A12、Y-E12、G-O12、K-A12、R-A12、cKK-E12、cPK-E12、PK1K-E12、PK500-E12、cQK-E12、cKK-A12、KK-A12、PK-4K-E12、cWK-E12、PK500-O12、PK1K-O12、cYK-E12、cDK-E12、cSK-E12、cEK-E12、cMK-E12、cKK-O12、cIK-E12、cKK-E10、cKK-E14及cKK-E16,較佳為cKK-E12、cKK-E14),Love KT等(Proc Natl Acad Sci U S A. 2010 May 25;107(21):9915)中記載之合成陽離子性脂質(例如:C14-98、C18-96、C14-113、C14-120、C14-120、C14-110、C16-96及C12-200,較佳為C14-110、C16-96及C12-200)。
於一較佳實施態樣中,可列舉WO 2016/021683中記載之下述通式所表示之陽離子性脂質。
[式中,
W表示式-NR1
R2
或式-N+
R3
R4
R5
(Z-
),
R1
及R2
分別獨立表示C1-4
烷基或氫原子,
R3
、R4
及R5
分別獨立表示C1-4
烷基,
Z-
表示陰離子,
X表示可經取代之C1-6
伸烷基,
YA
、YB
及YC
分別獨立表示可經取代之次甲基,
LA
、LB
及LC
分別獨立表示可經取代之亞甲基或鍵結鍵,
RA1
、RA2
、RB1
、RB2
、RC1
及RC2
分別獨立表示可經取代之C4-10
烷基]
所表示之化合物或其鹽。
可更佳地列舉下述結構式所表示之陽離子性脂質。
以及該等之鹽。
作為上述陽離子性脂質中之更佳者,可列舉下述結構式所表示之陽離子性脂質。
以及該等之鹽。
於另一較佳實施態樣中,可列舉WO2019/131839中記載之下述通式所表示之陽離子性脂質。
[式中,
n表示2~5之整數,
R表示直鏈狀C1-5
烷基、直鏈狀C7-11
烯基或直鏈狀C11
烷二烯基,
波浪線分別獨立表示順型或反型之鍵結]
所表示之化合物或其鹽。
可更佳地列舉下述結構式所表示之陽離子性脂質。
以及該等之鹽。
作為上述陽離子性脂質中之更佳者,可列舉下述結構式所表示之陽離子性脂質。
以及該等之鹽。
於另一較佳實施態樣中,可列舉下述通式(III)所表示之陽離子性脂質。
[式中,
n1表示2~6之整數,
n2表示0~2之整數,
n3表示0~2之整數,
L表示-C(O)O-或-NHC(O)O-,
Ra表示直鏈狀C5-13
烷基、直鏈狀C13-17
烯基或直鏈狀C17
烷二烯基,
Rb表示直鏈狀C2-9
烷基,
Rc表示氫原子或直鏈狀C2-9
烷基,
Rd表示氫原子或直鏈狀C2-9
烷基,
Re表示直鏈狀C2-9
烷基,
Rf表示直鏈狀C2-9
烷基]
所表示之化合物或其鹽。
可更佳地列舉下述結構式所表示之陽離子性脂質。
以及該等之鹽。
作為上述陽離子性脂質中之更佳者,可列舉下述結構式所表示之陽離子性脂質。
以及該等之鹽。
化合物(III)例如可藉由以下之製法製造。尤其於酯化時,藉由使用與目標化合物(III)之結構對應之適當原料,能夠合成所需結構之化合物(I)。又,化合物(III)之鹽可藉由適當地與無機鹼、有機鹼、有機酸、鹼性或酸性胺基酸進行混合而獲得。
上述製造方法中之各步驟中使用之原料或試劑、及所獲得之化合物分別可形成鹽。
於各步驟中獲得之化合物為游離化合物之情形時,可藉由公知方法轉化為目標鹽。反之,於各步驟中獲得之化合物為鹽之情形時,可藉由公知方法轉化為游離體或目標之其他種類之鹽。
各步驟中獲得之化合物可直接將反應液或獲得為粗產物後用於下一反應,或者可將各步驟中獲得之化合物依據常規方法,藉由濃縮、晶化、再結晶、蒸餾、溶劑萃取、分餾、層析等分離方式自反應混合物進行單離及/或純化。
於各步驟之原料或試劑之化合物於市場有售之情形時,可直接使用市售品。
於各步驟之反應中,反應時間可能根據所使用之試劑或溶劑而異,在無特別記載之情況下,通常為1分鐘~48小時,較佳為10分鐘~8小時。
於各步驟之反應中,反應溫度可能根據所使用之試劑或溶劑而異,在無特別記載之情況下,通常為-78℃~300℃,較佳為-78℃~150℃。
於各步驟之反應中,壓力可能根據所使用之試劑或溶劑而異,在無特別記載之情況下,通常為1大氣壓~20大氣壓,較佳為1大氣壓~3大氣壓。
於各步驟之反應中,例如存在使用Biotage公司製造之Initiator等微波合成裝置之情況。反應溫度可能根據所使用之試劑或溶劑而異,在無特別記載之情況下,通常為室溫~300℃,較佳為室溫~250℃,更佳為50℃~250℃。反應時間可能根據所使用之試劑或溶劑而異,在無特別記載之情況下,通常為1分鐘~48小時,較佳為1分鐘~8小時。
於各步驟之反應中,關於試劑,在無特別記載之情況下,相對於基質,使用0.5當量~20當量、較佳為0.8當量~5當量。於使用試劑作為觸媒之情形時,相對於基質,使用0.001當量~1當量、較佳為0.01當量~0.2當量之試劑。於試劑兼作反應溶劑之情形時,試劑係使用溶劑量。
於各步驟之反應中,在無特別記載之情況下,該等反應係於無溶劑之條件下進行、或者溶解或懸浮於適宜溶劑中進行。作為溶劑之具體例,可列舉以下者。
醇類:甲醇、乙醇、異丙醇、異丁醇、第三丁醇、2-甲氧基乙醇等;
醚類:二乙醚、二異丙醚、二苯醚、四氫呋喃、1,2-二甲氧基乙烷等;
芳香族烴類:氯苯、甲苯、二甲苯等;
飽和烴類:環己烷、己烷、庚烷等;
醯胺類:N,N-二甲基甲醯胺、N-甲基吡咯啶酮等;
鹵化烴類:二氯甲烷、四氯化碳等;
腈類:乙腈等;
亞碸類:二甲基亞碸等;
芳香族有機鹼類:吡啶等;
酸酐類:乙酸酐等;
有機酸類:甲酸、乙酸、三氟乙酸等;
無機酸類:鹽酸、硫酸等;
酯類:乙酸乙酯、乙酸異丙酯等;
酮類:丙酮、甲基乙基酮等;
水。
關於上述溶劑,可將兩種以上按適宜比率混合使用。
於各步驟之反應中使用鹼之情形時,例如可使用以下所示之鹼。
無機鹼類:氫氧化鈉、氫氧化鉀、氫氧化鎂等;
鹼性鹽類:碳酸鈉、碳酸鈣、碳酸氫鈉等;
有機鹼類:三乙基胺、二乙基胺、吡啶、4-二甲基胺基吡啶、N,N-二甲基苯胺、1,4-二氮雜雙環[2.2.2]辛烷、1,8-二氮雜雙環[5.4.0]-7-十一烯、咪唑、哌啶等;
金屬烷氧化物類:乙醇鈉、第三丁醇鉀、第三丁醇鈉等;
鹼金屬氫化物類:氫化鈉等;
金屬醯胺類:鈉醯胺、鋰二異丙基醯胺、雙(三甲基矽烷)胺基鋰等;
有機鋰類:正丁基鋰、第二丁基鋰等。
於各步驟之反應中使用酸或酸性觸媒之情形時,例如可使用以下所示之酸或酸性觸媒。
無機酸類:鹽酸、硫酸、硝酸、氫溴酸、磷酸等;
有機酸類:乙酸、三氟乙酸、檸檬酸、對甲苯磺酸、10-樟腦磺酸等;
路易斯酸:三氟化硼二乙醚錯合物、碘化鋅、無水氯化鋁、無水氯化鋅、無水氯化鐵等。
只要無特別記載,各步驟之反應可依據公知方法,例如:第5版實驗化學講座、13卷~19卷(日本化學會(編));新實驗化學講座、14卷~15卷(日本化學會(編));精密有機化學 修訂第2版(L. F. Tietze、Th. Eicher,南江堂);修訂 有機人名反應-機理與要點(東鄉秀雄(著),講談社);ORGANIC SYNTHESES Collective Volume I~VII(John Wiley & SonsInc);Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures(Jie Jack Li(著),OXFORD UNIVERSITY出版);Comprehensive Heterocyclic Chemistry III, Vol.1~Vol.14(Elsevier Japan股份有限公司);從人名反應學習有機合成戰略(富岡清監(譯),化學同人發行);Comprehensive Organic Transformations(VCH Publishers Inc.)1989年刊等中記載之方法進行。
於各步驟中,官能基之保護或脫保護反應可依據公知方法,例如:Wiley-Interscience社2007年刊「Protective Groups in Organic Synthesis, 4thEd.」(Theodora W. Greene、Peter G. M. Wuts(著));Thieme社2004年刊「Protecting Groups 3rdEd.」(P. J. Kocienski(著))等中記載之方法進行。
作為醇等之羥基或酚性羥基之保護基,例如可列舉:甲氧基甲醚、苄醚、對甲氧基苄醚、第三丁基二甲基矽烷醚、第三丁基二苯基矽烷醚、四氫吡喃醚等醚型保護基;乙酸酯等羧酸酯型保護基;甲磺酸酯等磺酸酯型保護基;碳酸第三丁酯等碳酸酯型保護基等。
作為醛之羰基之保護基,例如可列舉:二甲基縮醛等縮醛型保護基;環狀1,3-二㗁烷等環狀縮醛型保護基等。
作為酮之羰基之保護基,例如可列舉:二甲基縮酮等縮酮型保護基;環狀1,3-二㗁烷等環狀縮酮型保護基;O-甲基肟等肟型保護基;N,N-二甲基腙等腙型保護基等。
作為羧基之保護基,例如可列舉:甲酯等酯型保護基;N,N-二甲基醯胺等醯胺型保護基等。
作為硫醇之保護基,例如可列舉:苄硫醚等醚型保護基;硫代乙酸酯、硫代碳酸酯、硫代胺基甲酸酯等酯型保護基等。
作為胺基、或咪唑、吡咯、吲哚等芳香族雜環之保護基,例如可列舉:胺基甲酸苄酯等胺基甲酸酯型保護基;乙醯胺等醯胺型保護基;N-三苯基甲基胺等烷基胺型保護基、甲烷磺醯胺等磺醯胺型保護基等。
保護基之去除可採用公知方法,例如使用酸、鹼、紫外光、肼、苯基肼、N-甲基二硫代胺基甲酸鈉、氟化四丁基銨、乙酸鈀、三烷基鹵矽烷(例如:三甲基碘矽烷、三甲基溴矽烷)之方法或者還原法等進行。
於各步驟中,於進行還原反應之情形時,作為使用之還原劑,可列舉:氫化鋁鋰、三乙醯氧基硼氫化鈉、氰基硼氫化鈉、氫化二異丁基鋁(DIBAL-H)、硼氫化鈉、四甲基三乙醯氧基硼氫化銨等金屬氫化物類;硼烷四氫呋喃錯合物等硼烷類;雷氏鎳;雷氏鈷;氫;甲酸等。例如可於存在氫或甲酸之條件下使用雷氏鎳或雷氏鈷。於還原碳-碳雙鍵或三鍵之情形時,有使用鈀-碳或林德拉(Lindlar)觸媒等觸媒之方法。
於各步驟中,於進行氧化反應之情形時,作為使用之氧化劑,可列舉:間氯過氧苯甲酸(MCPBA)、過氧化氫、第三丁基過氧化氫等過酸類;過氯酸四丁基銨等過氯酸鹽類;氯酸鈉等氯酸鹽類;亞氯酸鈉等亞氯酸鹽類;過碘酸鈉等過碘酸類;氧碘苯等高原子價碘試劑;二氧化錳、過錳酸鉀等含錳試劑;四乙酸鉛等鉛類;氯鉻酸吡啶鎓(PCC)、重鉻酸吡啶鎓(PDC)、瓊斯試劑等含鉻試劑;N-溴琥珀醯亞胺(NBS)等鹵化合物類;氧;臭氧;三氧化硫-吡啶錯合物;四氧化鋨;二氧化硒;2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)等。
於各步驟中,於進行自由基環化反應之情形時,作為使用之自由基起始劑,可列舉:偶氮二異丁腈(AIBN)等偶氮化合物;4-4'-偶氮雙-4-氰基戊酸(ACPA)等水溶性自由基起始劑;空氣條件下或含氧條件下之三乙基硼;過氧化苯甲醯等。又,作為使用之自由基反應試劑,可列舉:三丁基錫烷、三-三甲基矽烷基矽烷、1,1,2,2-四苯基二矽烷、二苯基矽烷、碘化釤等。
於各步驟中,於進行維蒂希(Wittig)反應之情形時,作為使用之維蒂希試劑,可列舉:亞烷基磷烷類等。亞烷基磷烷類可藉由公知方法,例如使鏻鹽與強鹼進行反應而製備。
於各步驟中,於進行霍納爾-埃蒙斯(Horner-Emmons)反應之情形時,作為使用之試劑,可列舉:二甲基膦醯基乙酸甲酯、二乙基膦醯基乙酸乙酯等膦醯基乙酸酯類;鹼金屬氫化物類、有機鋰類等鹼。
於各步驟中,於進行傅里德-克拉夫茨(Friedel-Crafts)反應之情形時,作為使用之試劑,可列舉:路易斯酸、與醯氯或烷化劑(例如:鹵化烷基類、醇、烯烴類等)。或者,亦可使用有機酸或無機酸代替路易斯酸,亦可使用乙酸酐等酸酐代替醯氯。
於各步驟中,於進行芳香族親核取代反應之情形時,作為試劑,可使用親核劑(例如:胺類、咪唑等)與鹼(例如:鹼性鹽類、有機鹼類等)。
於各步驟中,於進行利用碳陰離子之親核加成反應、利用碳陰離子之親核1,4-加成反應(邁克爾(Michael)加成反應)、或利用碳陰離子之親核取代反應之情形時,作為用以產生碳陰離子之鹼,可列舉:有機鋰類、金屬烷氧化物類、無機鹼類、有機鹼類等。
於各步驟中,於進行格林尼亞(Grignard)反應之情形時,作為格林尼亞試劑,可列舉:溴化苯基鎂等鹵化芳基鎂類;溴化甲基鎂、溴化異丙基鎂等鹵化烷基鎂類。格林尼亞試劑可藉由公知方法,例如以醚或四氫呋喃作為溶劑,使鹵化烷基或鹵化芳基與金屬鎂進行反應而製備。
於各步驟中,於進行克腦文蓋爾(Knoevenagel)縮合反應之情形時,作為試劑,可使用被兩個拉電子基夾持之活性亞甲基化合物(例如:丙二酸、丙二酸二乙酯、丙二腈等)及鹼(例如:有機鹼類、金屬烷氧化物類、無機鹼類)。
於各步驟中,於進行維爾斯邁爾-哈克(Vilsmeier-Haack)反應之情形時,作為試劑,可使用磷醯氯與醯胺衍生物(例如:N,N-二甲基甲醯胺等)。
於各步驟中,於進行醇類、烷基鹵化物類、磺酸酯類之疊氮化反應之情形時,作為所使用之疊氮化劑,可列舉:疊氮磷酸二苯酯(DPPA)、疊氮三甲基矽烷、疊氮化鈉等。例如,於將醇類進行疊氮化之情形時,有使用疊氮磷酸二苯酯與1,8-二氮雜雙環[5,4,0]十一-7-烯(DBU)之方法或使用疊氮三甲基矽烷與路易斯酸之方法等。
於各步驟中,於進行還原性胺基化反應之情形時,作為所使用之還原劑,可列舉:三乙醯氧基硼氫化鈉、氰基硼氫化鈉、氫、甲酸等。於基質為胺化合物之情形時,作為所使用之羰基化合物,可列舉:多聚甲醛及其以外之乙醛等醛類、環己酮等酮類。於基質為羰基化合物之情形時,作為所使用之胺類,可列舉:氨、甲基胺等一級胺;二甲基胺等二級胺等。
於各步驟中,於進行光延反應之情形時,作為試劑,可使用偶氮二羧酸酯類(例如:偶氮二羧酸二乙酯(DEAD)、偶氮二羧酸二異丙酯(DIAD)等)及三苯基膦。
於各步驟中,於進行酯化反應、醯胺化反應或脲化反應之情形時,作為所使用之試劑,可列舉:醯氯、醯溴等鹵化醯體;酸酐、活性酯體、硫酸酯體等經活性化之羧酸類。作為羧酸之活性化劑,可列舉:1-乙基-3-(3-二甲基胺基丙基)碳二醯亞胺鹽酸鹽(WSCD)等碳二醯亞胺系縮合劑;4-(4,6-二甲氧基-1,3,5-三𠯤-2-基)-4-甲基嗎啉鹽酸鹽-n-水合物(DMT-MM)等三𠯤系縮合劑;1,1-羰基二咪唑(CDI)等碳酸酯系縮合劑;疊氮磷酸二苯酯(DPPA);苯并三唑-1-基氧基-三(二甲基胺基)鏻鹽(BOP試劑);碘化2-氯-1-甲基-吡啶鎓(向山試劑);亞硫醯氯;氯甲酸乙酯等鹵甲酸低級烷基酯;六氟磷酸O-(7-氮雜苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓鹽(HATU);硫酸;或該等之組合等。於使用碳二醯亞胺系縮合劑之情形時,可進而於反應中添加1-羥基苯并三唑(HOBt)、N-羥基琥珀醯亞胺(HOSu)、二甲基胺基吡啶(DMAP)等添加劑。
於各步驟中,於進行偶合反應之情形時,作為所使用之金屬觸媒,可列舉:乙酸鈀(II)、四(三苯基膦)鈀(0)、二氯雙(三苯基膦)鈀(II)、二氯雙(三乙基膦)鈀(II)、三(二亞苄基丙酮)二鈀(0)、氯化[1,1'-雙(二苯基膦基)二茂鐵]鈀(II)、乙酸鈀(II)等鈀化合物;四(三苯基膦)鎳(0)等鎳化合物;氯化三(三苯基膦)銠(III)等銠化合物;鈷化合物;氧化銅、碘化銅(I)等銅化合物;鉑化合物等。可進而於反應中添加鹼,作為此種鹼,可列舉:無機鹼類、鹼性鹽類等。
於各步驟中,於進行硫羰基化反應之情形時,作為硫羰基化劑,可代表性地使用五硫化二磷,除五硫化二磷以外,亦可使用2,4-雙(4-甲氧基苯基)-1,3,2,4-二硫二磷雜環丁烷-2,4-二硫醚(勞森(Lowesson)試劑)等具有1,3,2,4-二硫二磷雜環丁烷-2,4-二硫醚結構之試劑。
於各步驟中,於進行沃爾-齊格勒(Wohl-Ziegler)反應之情形時,作為所使用之鹵化劑,可列舉:N-碘琥珀醯亞胺、N-溴琥珀醯亞胺(NBS)、N-氯琥珀醯亞胺(NCS)、溴、磺醯氯等。進而,可藉由在反應中添加熱、光、過氧化苯甲醯、偶氮二異丁腈等自由基起始劑來使反應加速。
於各步驟中,於進行羥基之鹵化反應之情形時,作為所使用之鹵化劑,可列舉氫鹵酸與無機酸之醯鹵化物,具體而言,關於氯化,可列舉:鹽酸、亞硫醯氯、氧氯化磷等,關於溴化,可列舉:48%氫溴酸等。又,亦可採用藉由三苯基膦與四氯化碳或四溴化碳等之作用而由醇獲得鹵化烷基體之方法。或可採用經過將醇轉化為磺酸酯後再與溴化鋰、氯化鋰或碘化鈉反應之類的二段式反應來合成鹵化烷基體之方法。
於各步驟中,於進行阿爾布佐夫(Arbuzov)反應之情形時,作為所使用之試劑,可列舉:溴乙酸乙酯等鹵化烷基類;亞磷酸三乙酯或亞磷酸三(異丙基)酯等亞磷酸酯類。
於各步驟中,於進行磺酯化反應之情形時,作為所使用之磺化劑,可列舉:甲磺醯氯、對甲苯磺醯氯、甲磺酸酐、對甲苯磺酸酐、三氟甲磺酸酐等。
於各步驟中,於進行水解反應之情形時,作為試劑,可使用酸或鹼。又,於進行第三丁酯之酸水解反應之情形時,有為了還原性地捕捉所副生之第三丁基陽離子而添加甲酸或三乙基矽烷等之情況。
於各步驟中,於進行脫水反應之情形時,作為所使用之脫水劑,可列舉:硫酸、五氧化二磷、氧氯化磷、N,N'-二環己基碳二醯亞胺、氧化鋁、多磷酸等。
作為上述各結構式所表示之化合物之鹽,較佳為藥理學上容許之鹽,例如可列舉:與無機鹼之鹽(例如:鈉鹽、鉀鹽等鹼金屬鹽;鈣鹽、鎂鹽等鹼土金屬鹽;鋁鹽、銨鹽);與有機鹼之鹽(例如:與三甲基胺、三乙基胺、吡啶、甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、胺丁三醇[三(羥基甲基)甲基胺]、第三丁基胺、環己基胺、苄基胺、二環己基胺、N,N-二苄基乙二胺之鹽);與無機酸之鹽(例如:與氫氟酸、鹽酸、氫溴酸、氫碘酸、硝酸、硫酸、磷酸之鹽);與有機酸之鹽(與甲酸、乙酸、三氟乙酸、鄰苯二甲酸、反丁烯二酸、草酸、酒石酸、順丁烯二酸、檸檬酸、琥珀酸、蘋果酸、甲磺酸、苯磺酸、對甲苯磺酸之鹽);與鹼性胺基酸之鹽(與精胺酸、離胺酸、鳥胺酸之鹽)或與酸性胺基酸之鹽(與天冬胺酸、麩胺酸之鹽)。
陽離子性脂質於脂質奈米粒子中存在之全部脂質當中所占之比率(莫耳%)例如為約10%~約80%,較佳為約20%~約70%,更佳為約40%~約60%,但不限定於該等。
上述陽離子性脂質可僅使用1種,亦可將2種以上組合使用。於使用複數種之陽離子性脂質之情形時,較佳為以陽離子性脂質整體計為上述比率。
(b)非陽離子性脂質
於本說明書中,所謂「非陽離子性脂質」,意指陽離子性脂質以外之脂質,指於生理學pH等所選擇之pH下不帶淨正電之脂質。作為本發明之脂質奈米粒子所使用之非陽離子性脂質,例如可列舉:磷脂質、類固醇類、PEG脂質等。
作為磷脂質,例如,為了提高核酸向T細胞內之傳遞性,只要為穩定地保持核酸、且不會阻礙與細胞膜(原漿膜及細胞器膜)之融合者則並無特別限定,例如可列舉:磷脂醯膽鹼、磷脂醯乙醇胺、磷脂醯絲胺酸、磷脂醯肌醇、磷脂酸、棕櫚醯油醯磷脂醯膽鹼、溶血磷脂醯膽鹼、溶血磷脂醯乙醇胺、二棕櫚醯磷脂醯膽鹼、二油醯磷脂醯膽鹼、二硬脂醯磷脂醯膽鹼、或二亞麻醯磷脂醯膽鹼等。
作為較佳之磷脂質,可列舉:二硬脂醯磷脂醯膽鹼(DSPC)、二油醯磷脂醯膽鹼(DOPC)、二棕櫚醯磷脂醯膽鹼(DPPC)、二油醯磷脂醯甘油(DOPG)、棕櫚醯油醯磷脂醯甘油(POPG)、二棕櫚醯磷脂醯甘油(DPPG)、二油醯磷脂醯乙醇胺(DOPE)、棕櫚醯油醯磷脂醯膽鹼(POPC)、棕櫚醯油醯磷脂醯乙醇胺(POPE)、及二油醯磷脂醯乙醇胺4-(N-順丁烯二醯亞胺甲基)-環己烷-1-羧酸酯(DOPE-mal),更佳為DOPC、DPPC、POPC及DOPE。
磷脂質於脂質奈米粒子中存在之全部脂質當中所占之比率(莫耳%)例如可為約0%~約90%,較佳為約5%~約30%,更佳為約8%~約15%。
上述磷脂質可僅使用1種,亦可將2種以上組合使用。於使用複數種之磷脂質之情形時,較佳為以磷脂質整體計為上述比率。
作為類固醇類,可列舉:膽固醇、5α-膽固烷醇、5β-腎固醇、膽固醇基-(2'-羥基)-乙醚、膽固醇基-(4'-羥基)-丁醚、6-酮膽固烷醇、5α-膽甾烷、膽甾烯酮、5α-膽固烷酮、5β-膽固烷酮、膽固醇基癸酸酯,較佳為膽固醇。
於存在類固醇類之情形時,其於脂質奈米粒子中存在之全部脂質當中所占之比率(莫耳%)例如可為約10%~約60%,較佳為約12%~約58%,更佳為約20%~約55%。
上述類固醇類可僅使用1種,亦可將2種以上組合使用。於使用複數種之類固醇類之情形時,較佳為以類固醇類整體計為上述比率。
於本說明書中,所謂「PEG脂質」,意指聚乙二醇(PEG)與脂質之任意之複合體。作為PEG脂質,例如,只要為具有能夠抑制脂質奈米粒子凝集之效果者,則並無特別限定,例如可列舉:與二烷氧基丙基鍵結之PEG(PEG-DAA)、與二醯基甘油鍵結之PEG(PEG-DAG)(例如:SUNBRIGHT GM-020(日油))、與磷脂醯乙醇胺等磷脂質鍵結之PEG(PEG-PE)、與腦醯胺複合之PEG(PEG-Cer)、與膽固醇複合之PEG(PEG-cholesterol)或者該等之衍生物或該等之混合物、mPEG2000-1,2-二-O-烷基-sn3-胺甲醯基甘油酯(PEG-C-DOMG)、1-[8'-(1,2-二肉豆蔻醯基-3-丙氧基)-甲醯胺-3',6-二氧雜辛基]胺甲醯基-ω-甲基-聚(乙二醇)(2KPEG-DMG)等。作為較佳之PEG脂質,可列舉:PEG-DGA、PEG-DAA、PEG-PE、PEG-Cer、及該等之混合物,更佳為選自由PEG-二癸氧基丙基複合物、PEG-二月桂氧基丙基複合物、PEG-二肉豆蔻氧基丙基複合物、PEG-二棕櫚氧基丙基複合物、PEG-二硬脂氧基丙基複合物所組成之群中之PEG-DAA複合物、及該等之混合物。
作為PEG之自由末端,除甲氧基以外,亦可使用用以與T細胞活性化配體結合之順丁烯二醯亞胺基或N-羥基丁二醯亞胺基等。作為具有用以與T細胞活性化配體結合之官能基之PEG脂質(於本說明書中有時稱為「末端反應性PEG脂質」),例如可使用SUNBRIGHT DSPE-020MA(日油)。
PEG脂質於本發明之脂質奈米粒子中存在之全部脂質當中所占之比率(莫耳%)例如可為約0%~約20%,較佳為約0.1%~約5%,更佳為約0.7%~約2%。
末端反應性PEG脂質於上述全部PEG脂質當中所占之比率(莫耳%)例如可為約10%~約100%,較佳為約30%~約100%,更佳為約40%~約100%。
上述PEG脂質可僅使用1種,亦可將2種以上組合使用。於使用複數種之PEG脂質之情形時,較佳為以PEG脂質整體計為上述比率。
1-1-2. 脂質體
作為本發明中使用之另一較佳核酸傳遞載體,可列舉脂質體。作為脂質體,可同樣地使用一直以來於核酸向細胞之DDS中所使用者。例如,廣泛使用將作為轉染試劑所開發之各種陽離子性脂質(例如:DOTMA、DOTAP、DDAB、DMRIE等)與促進自內體之釋放之膜融合性之中性脂質(例如:DOPE、膽固醇等)進行混合所製備之脂質體。亦可使用在脂質體之表面附加有PEG、或pH應答性膜融合肽、膜穿透促進肽等功能性分子之脂質體。
1-2.T 細胞活性化配體
本發明之核酸傳遞載體係於上述核酸傳遞載體之表面附加有T細胞活性化配體者。
本發明中使用之T細胞活性化配體只要為與T細胞之表面分子相互作用而促進T細胞之活性化及/或增殖之分子,則並無特別限制。例如可列舉具有和與TCR偶合並負責經由TCR之訊息傳遞之CD3、或和作為T細胞活性化之共刺激因子所知之表面分子CD28、ICOS(inducible T-cell co-stimulator,T細胞可誘導共刺激分子)、CD137、OX40、CD27、GITR(Glucocorticoid-induced TNFR-related protein,糖皮質激素誘導之TNFR相關蛋白)、BAFFR(B-cell-activating factor belonging to the TNF family-receptor,屬於TNF家族之B細胞活化因子之受體)、TACI(transmembrane activator and cyclophilin ligand interactor,跨膜活化因子與親環蛋白配體相互作用因子)、BMCA(B-cell maturation antigen,B細胞成熟抗原)、CD40L等特異性結合而將活性化/增殖訊息或共訊息傳遞至T細胞內或抗原提呈細胞內的功能之分子。作為此種分子,可為針對上述T細胞表面分子之生理性配體(或受體),亦可為具有促效劑活性之非生理性配體(或受體)。作為非生理性配體,可較佳地列舉促效性抗體。
作為本發明中使用之T細胞活性化配體,可更佳地列舉對於CD3之抗體及/或對於CD28之抗體。對於CD3之抗體及對於CD28之抗體只要具有分別與待誘導活性化及/或增殖之目標T細胞上表現之CD3及CD28特異性地結合(例如:於目標T細胞源自人之情形時,對於CD3之抗體及對於CD28之抗體分別較理想為抗人CD3抗體及抗人CD28抗體)並刺激該等T細胞之表面分子來向T細胞內傳遞訊息之能力,則可為完全抗體,亦可為其片段(例如:Fab、F(ab')2
、Fab'、scFv、Fv、還原抗體(rIgG)、dsFv、sFv、雙鏈抗體、三鏈抗體等)。又,抗體之亞型亦無特別限制,較佳為IgG抗體。
於使用對於CD3之抗體或對於CD28之抗體等促效性抗體作為T細胞活性化配體之情形時,若為完全抗體分子,可使用市售之抗CD3抗體、抗CD28抗體等,或可自產生該抗體之細胞之培養液進行單離。另一方面,於該配體為上述任一抗體片段之情形時,可藉由利用還原劑(例如:2-巰基乙醇、二硫蘇糖醇)或肽酶(例如:木瓜酶、胃蛋白酶、無花果酶)對完全抗體進行處理,或藉由與下文記述之取得內包於核酸傳遞載體中之核酸之方法相同之方法,單離編碼抗CD3抗體、抗CD28抗體等之片段之核酸,使用所單離之核酸來重組生產該抗體片段。
T細胞活性化配體可僅使用1種,亦可將2種以上組合使用,較佳為組合2種以上。於組合使用2種以上之T細胞活性化配體之情形時,較佳為至少1種為對於CD3之抗體或對於CD28之抗體,更佳為至少1種為對於CD3之抗體。尤佳為同時使用對於CD3之抗體與對於CD28之抗體兩者作為T細胞活性化配體。
於至少將對於CD3之抗體與對於CD28之抗體組合用作T細胞活性化配體之情形時,附加於本發明之核酸傳遞載體之表面之兩者之莫耳比為1:4~4:1,較佳為1:2~2:1。
於組合使用2種以上之T細胞活性化配體之情形時,可將該等T細胞活性化配體分開地附加於核酸傳遞載體之表面,亦可將於保持各自之T細胞活性化活性之限制條件下使該等複合體化而成者附加於核酸傳遞載體之表面。例如,於2種T細胞活性化配體為抗體(例如:對於CD3之抗體與對於CD28之抗體)之情形時,可作為本身公知之雙重特異性抗體來提供。
於本發明之核酸傳遞載體中,T細胞活性化配體只要存在於核酸傳遞載體之表面上,可以任意方式與外殼結合,例如於將包含末端反應性PEG脂質作為非陽離子性脂質之脂質奈米粒子用作核酸傳遞載體之情形時,可附加於PEG之末端。例如,藉由使末端導入有順丁烯二醯亞胺基之PEG脂質(例如:SUNBRIGHT DSPE-020MA)與上述還原抗體之硫醇基進行反應,可製備經配體(抗體)標記之脂質奈米粒子。於使用PEG修飾脂質體作為核酸傳遞載體之情形時,可同樣地於脂質體表面附加T細胞活性化配體。
1-3. 本發明之核酸傳遞載體所含之核酸
本發明之核酸傳遞載體亦可於不含核酸之形態下用於誘導T細胞之活性化及/或增殖,於一較佳實施態樣中,藉由內包核酸,可以一步驟同時進行T細胞之活性化及/或增殖與該核酸向T細胞內之傳遞。因此,於較佳之一實施態樣中,本發明之核酸傳遞載體於其內部進而包含用以向T細胞內傳遞之核酸。
於本發明之核酸傳遞載體在內部包含核酸之情形時,該核酸只要為其本身或其轉錄產物或轉譯產物具有於T細胞內使該T細胞轉變為所需狀態之功能者,則並無特別限制。
1-3-1. 抑制 T 細胞活性化抑制因子之表現之核酸
於一較佳實施態樣中,本發明之核酸傳遞載體於內部包含抑制T細胞活性化抑制因子之表現之核酸。作為成為對象之T細胞活性化抑制因子,只要為抑制T細胞之活性化者則無特別限制,例如可列舉:作為受到抗原提呈細胞或腫瘤細胞之刺激而對T細胞之活性化及/或增殖傳遞負訊息之細胞表面分子的免疫檢查點因子(例如:CTLΑ-4(Cytotoxic T-Lymphocyte-Associated Antigen 4,細胞毒性T淋巴細胞相關蛋白4)、PD-1、TIM(T-cell immunoglobulin and mucin domain-containing molecule,T細胞免疫球蛋白及黏蛋白結構域分子)-3、LAG(Lymphocyte-activation gene,淋巴細胞活化基因)-3、TGIT(T cell immunoglobulin and ITIM domain,T細胞免疫球蛋白與ITIM結構域)、BTLA(B and T lymphocyte attenuator,B與T淋巴細胞衰減蛋白)、VISTA(V domain immunoglobulin suppressor of T cell activation,T細胞活化之免疫球蛋白抑制V型結構域)(PD-1H)等)、CD160、Cbl-b(casitas-B-lineage lymphoma protein-b,卡西塔斯B系淋巴瘤蛋白b)、內源性TCR等。
抑制T細胞活性化抑制因子之表現之核酸可為於編碼該因子之基因之轉錄水平、轉錄後調節之水平、向蛋白質之轉譯水平、轉譯後修飾之水平等某一階段發揮作用者。因此,作為抑制T細胞活性化抑制因子之表現之核酸,例如包括:抑制編碼該因子之基因之轉錄之核酸(例如:反基因)、抑制自初始轉錄產物向mRNA之加工之核酸、抑制自mRNA向蛋白質之轉譯(例如:反義核酸、miRNA(microRNA,小分子核糖核酸))或使mRNA分解(例如:siRNA、核糖核酸酶(ribozyme)、miRNA)之核酸等。可使用於任一階段發揮作用者,較佳為與mRNA互補結合而抑制向蛋白質之轉譯或使mRNA分解之物質。作為該核酸,可列舉:
(a)對編碼該因子之mRNA具有RNAi(RNA interference,RNA干擾)活性之核酸或其前驅物、
(b)對於編碼該因子之mRNA之反義核酸、及
(c)對於編碼該因子之mRNA之核糖核酸酶核酸
等。
編碼各T細胞活性化抑制因子之mRNA(cDNA(complementary DNA,互補DNA))之核苷酸序列為公知,例如可自公共之資料庫(例如:NCBI、EMBL、DDBJ等)獲得序列資訊。
(a)對編碼T細胞活性化抑制因子之mRNA具有RNAi活性之核酸或其前驅物
作為對編碼T細胞活性化抑制因子之mRNA具有RNAi活性之核酸,可列舉包含與目標mRNA互補之寡聚RNA及其互補鏈之雙鏈RNA,即siRNA。siRNA可基於目標基因之cDNA序列資訊,依據例如Elbashir等人(Genes Dev., 15, 188-200 (2001))提倡之規則而設計。又,作為siRNA之前驅物的小髮夾RNA(shRNA)可藉由適當選擇能夠形成環結構之任意連接子序列(例如:5~25鹼基左右),經由該連接子序列將siRNA之正義鏈與反義鏈進行連結而設計。
siRNA及/或shRNA之序列可使用各種web站點上免費提供之檢索軟體進行檢索。作為此種站點,例如可列舉:Dharmacon提供之siDESIGN Center (http: //dharmacon.horizondiscovery.com/ jp/ design- center/?rdr=true&LangType= 1041&pageid=17179928204)、GenScript提供之siRNA Target Finder (https://www.genscript.com/tools/ sirnα- target-finder)等,但並不限定於該等。
於本說明書中,亦將靶向編碼T細胞活性化抑制因子之mRNA之小分子RNA(miRNA)定義為對該mRNA具有RNAi活性之核酸所包含者。miRNA係首先自編碼其之基因轉錄成作為一次轉錄產物之初級小分子RNA(primary-microRNA,pri-miRNA),繼而藉由Drosha加工成具有特徵性髮夾結構之約70鹼基長之前體小分子RNA(precursor-microRNA,pre-miRNA)後,自核向細胞質輸送,進而經過Dicer介導之加工而轉變為成熟型miRNA,結合至RISC而作用於目標mRNA。因此,作為miRNA之前驅物,亦可使用pre-miRNA或pri-miRNA,較佳為使用pre-miRNA。
miRNA可使用各種web站點上免費提供之目標預測軟體進行檢索。作為此種站點,例如可列舉:美國白頭生物研究所公開之TargetScan(http://www.targetscan.0rg/vert_72/)、希臘之亞歷山大·弗萊明生命醫科學研究中心公開之DIANΑ- micro-T-CDS(http://diana.imis.athenα-innovation.gr/DianaTools/index.php?r= microT_CDS/index)等,但並不限定於該等。或者亦可使用CESARE大學・巴斯德研究所等公開之關於已通過實驗證明作用於目標mRNA之miRNA之資料庫TarBase (http: //carolina.imis.athenα-innovation.gr/ diana_tools/web/index.php?r=tarbasev8/index),檢索靶向編碼T細胞活性化抑制因子之mRNA之miRNA。
構成siRNA及/或shRNA、或者miRNA及/或pre-miRNA之核苷酸分子可為天然型之RNA或DNA,為了提高穩定性(化學穩定性及/或對酵素之穩定性)或比活性(與RNA之親和性),可包含自身公知之各種化學修飾。
siRNA可藉由利用DNA/RNA自動合成機分別合成mRNA上之目標序列之正義鏈及反義鏈,於適當之退火緩衝液中在約90~約95℃下進行約1分鐘左右之改性後,在約30~約70℃下進行約1~約8小時之退火而製備。又,亦可藉由合成作為siRNA之前驅物之shRNA,使用dicer將其切斷而製備。miRNA及pre-miRNA可基於該等序列資訊,利用DNA/RNA自動合成機進行合成。
於本說明書中,亦將以能夠於生物體內生成對於編碼T細胞活性化抑制因子之mRNA之siRNA或miRNA之方式設計之核酸定義為對該mRNA具有RNAi活性之核酸所包含者。作為此種核酸,可列舉以表現上述shRNA或siRNA或miRNA或pre-miRNA之方式構建之表現載體等。作為啟動子,亦可使用polII系啟動子(例如:CMV前初始啟動子),為了正確地進行較短RNA之轉錄,一般使用polIII系啟動子。作為polIII系啟動子,可列舉:小鼠及人之U6-snRNA啟動子、人H1-RNase P RNA啟動子、人纈胺酸-tRNA啟動子等。又,作為轉錄終止訊息,可使用4個以上T連續之序列。亦可與shRNA同樣地製作miRNA或pre-miRNA之表現盒。
(b)對於編碼T細胞活性化抑制因子之mRNA之反義核酸
對於編碼T細胞活性化抑制因子之mRNA之反義核酸係包含與該mRNA之核苷酸序列互補之核苷酸序列或其一部分之核酸,具有藉由與目標mRNA結合形成特異性且穩定之雙鏈而抑制蛋白質合成之功能。反義核酸可為DNA,亦可為RNA,或可為DNA/RNA嵌合體。於反義核酸為DNA之情形時,由目標RNA與反義DNA所形成之RNA:DNA雜交體被內源性RNase H(Ribonuclease H,核糖核酸酶H)識別而可引起目標RNA之選擇性分解。關於反義核酸之目標區域,只要為藉由該反義核酸之雜交而結果抑制向蛋白質之轉譯者,則其長度無特別限制,可為編碼蛋白質之mRNA之全序列,亦可為部分序列,短者可列舉約10鹼基左右,長者可列舉mRNA或初始轉錄產物之全序列。又,反義核酸亦可為不僅與目標mRNA或初始轉錄產物雜交而抑制向蛋白質之轉譯,且與作為雙鏈DNA之該等之基因結合形成三鏈(三複合體),從而能夠抑制向RNA之轉錄者(反基因)。
又,為了提高穩定性、比活性等,亦可對構成反義核酸之核苷酸分子進行與上述siRNA等之情形時相同之修飾。
反義寡核苷酸可藉由基於目標基因之cDNA序列或基因組DNA序列而確定mRNA或初始轉錄產物之目標序列,使用市售之DNA/RNA自動合成機來合成與其互補之序列而製備。
於本說明書中,亦將以能夠於生物體內生成對於編碼T細胞活性化抑制因子之mRNA之反義RNA之方式設計之核酸定義為對於該mRNA之反義核酸所包含者。作為此種核酸,可列舉以表現上述反義RNA之方式構建之表現載體等。作為啟動子,可根據轉錄之反義RNA之長度而適當選擇使用polII系啟動子或polIII系啟動子。
(c)對於編碼T細胞活性化抑制因子之mRNA之核糖核酸酶核酸
亦可使用能夠於編碼區域之內部將編碼T細胞活性化抑制因子之mRNA特異性地切斷之核糖核酸酶核酸作為抑制該因子之表現之核酸。所謂「核糖核酸酶」,狹義上指具有將核酸切斷之酵素活性之RNA,於本說明書中係以只要具有序列特異性核酸切斷活性則亦包括DNA在內之概念使用。作為通用性最高之核糖核酸酶核酸,有類病毒(Viroid)或擬病毒(virusoid)等於感染性RNA中發現之自剪接RNA,已知錘頭型或髮夾型等。於將核糖核酸酶以包含編碼其之DNA之表現載體之形態使用之情形時,為了促進轉錄產物向細胞質之轉移,亦可進而與tRNA經改型之序列連結製成雜交核糖核酸酶。
(d)利用基因組編輯來抑制T細胞活性化抑制因子之表現之核酸
作為不同於上述(a)~(c)之另一較佳實施態樣,抑制T細胞活性化抑制因子之表現之核酸可為將編碼該因子之基因失活性化(剔除)之核酸。作為此種核酸,可列舉編碼如下人工核酸酶之核酸,該人工核酸酶包含能夠將該基因中之部分核苷酸序列作為目標進行特異性地識別之核酸序列識別模組(例如:CRISPR/Cas9、ZF結構、TAL(transcription activator-like,轉錄激活物樣)效應器等)、與於目標序列之內部或其附近對該基因導入雙鏈切斷(DSB)之核酸酶。導入DSB後,藉由利用非同源性末端結合(NHEJ)修復錯誤之插入或缺失變異而可剔除該基因。或者亦可藉由與於該基因序列內插入標記基因(例如:螢光蛋白質基因等報導基因、藥劑耐性基因等選擇標記基因)之標靶載體進行組合,進行利用同源性重組(HR)修復之基因剔除。又,亦可於外源性TCR基因藉由HR修復敲入內源性TCR基因。
1-3-2. 編碼 T 細胞活性化促進因子之核酸
於另一較佳實施態樣中,本發明之核酸傳遞載體於內部包含編碼T細胞活性化促進因子之核酸。作為成為對象之T細胞活性化促進因子,例如可列舉:上述T細胞活性化配體與之結合而向T細胞內傳遞活性化及/或增殖訊息之T細胞表面分子(例如:CD28、ICOS、CD137、OX40、CD27、GITR、BAFFR、TACI、BMCA、CD40L等)等。
編碼各T細胞活性化促進因子之mRNA(cDNA)之核苷酸序列為公知,例如可自公共之資料庫(例如:NCBI、EMBL、DDBJ等)獲得序列資訊。
編碼T細胞活性化促進因子之核酸可以包含mRNA或編碼該因子之DNA之表現載體之形態內包於本發明之核酸傳遞載體。編碼T細胞活性化促進因子之mRNA可使用基於其序列資訊所製作之探針或引子,以自T細胞提取之RNA作為模板,藉由自身公知方法進行單離。所獲得之mRNA可直接內包於本發明之核酸傳遞載體,亦可藉由RT-PCR轉化為cDNA並進行擴增。
所獲得之編碼T細胞活性化促進因子之DNA可直接、或附加適當之連接子及/或核轉移訊息等後,插入至包含在T細胞內發揮功能之啟動子之表現載體,較佳為插入至質粒載體。作為在T細胞內發揮功能之啟動子,可使用哺乳動物細胞中之構成性SRα啟動子、SV40啟動子、LTR(long terminal repeat,長末端重複序列)啟動子、CMV(巨細胞病毒)啟動子、RSV(勞斯肉瘤病毒)啟動子、MoMuLV(莫洛尼鼠白血病病毒)LTR、HSV-TK(單純疱疹病毒胸苷激酶)啟動子等,但不限定於該等。又,亦可使用T細胞特異性地表現之CD3、CD4、CD8等基因啟動子。
編碼T細胞活性化促進因子之mRNA可藉由以包含編碼該因子之DNA之表現載體作為模板,利用自身公知之體外轉錄系統轉錄成mRNA而製備。
1-3-3. 編碼嵌合抗原受體 (CAR) 或外源性 T 細胞受體 (TCR) 之核酸
如上所述,本發明之核酸傳遞載體藉由內包核酸,可以一步驟同時進行T細胞之活性化及/或增殖與該核酸向T細胞內之傳遞。因此,藉由使本發明之核酸傳遞載體內包編碼CAR或TCR之核酸,可一步同時進行使T細胞活性化/增殖之步驟與向T細胞之基因導入步驟。
即,於一較佳實施態樣中,本發明之核酸傳遞載體於內部包含編碼CAR或TCR之核酸。
(a)編碼CAR之核酸
CAR係人工構建之雜交蛋白質,其包含與T細胞訊息傳遞區連結之抗體的抗原結合區(例如:scFv)。關於CAR之特徵,可列舉如下能力:利用單株抗體之抗原結合特性,對於所選擇之目標以非MHC限制性方式轉換T細胞之特異性及反應性。非MHC限制性抗原識別對表現CAR之T細胞賦予與抗原處理無關地識別抗原之能力,藉此繞開腫瘤逃避免疫之主要機制。進而,若於T細胞中表現,則CAR有利的是不與內源性TCR α鏈及β鏈進行二聚物化。
本發明之核酸傳遞載體所內包之CAR包含:能夠對目標T細胞應識別之表面抗原(例如:癌抗原肽、於癌細胞中表現亢進之表面受體等)進行特異性地識別之抗體之抗原結合區、細胞外鉸鏈區、跨膜區及細胞內T細胞訊息傳遞區。
作為抗原結合區所特異性地識別之表面抗原,例如可列舉於各種癌(例如:急性淋巴細胞性癌、腺泡狀橫紋肌肉瘤、膀胱癌、骨癌、腦癌(例如:神經管胚細胞瘤)、乳癌、肛門、肛管或肛門直腸之癌、眼癌、肝內膽管癌、關節癌、頸部、膽囊或胸膜之癌、鼻、鼻腔或中耳之癌、口腔癌、外陰部癌、慢性骨髄性癌、結腸癌、食道癌、宮頸癌、纖維肉瘤、消化道類癌腫瘤、頭頸部癌(例如:頭頸部鱗狀細胞癌)、下嚥癌、腎癌、喉癌、白血病(例如:急性淋巴母細胞性白血病、急性淋巴細胞性白血病、慢性淋巴細胞性白血病、急性骨髄性白血病)、液性腫瘤、肝癌、肺癌(例如:非小細胞肺癌)、淋巴瘤(例如:霍奇金淋巴瘤、非霍奇金淋巴瘤、彌漫性大細胞型B細胞淋巴瘤、濾泡性淋巴瘤)、惡性間皮瘤、肥胖細胞瘤、黑色素瘤、多發性骨髓瘤、鼻咽癌、卵巢癌、胰腺癌;腹膜、網膜及腸系膜之癌;咽癌、前列腺癌、直腸癌、腎癌、皮膚癌、小腸癌、軟組織癌、固體腫瘤、胃癌、睾丸癌、甲狀腺癌、輸尿管癌等)中表現亢進之表面受體,例如:CD(Cluster of Differentiation,分化簇)19、EGF(Epidermal growth factor,表皮生長因子)受體、BCMA(B-cell maturation antigen,B細胞成熟抗原)、CD30、Her2(human epidermal growth factor receptor 2,人類表皮生長因子受體2)、ROR1(Receptor Tyrosine Kinase Like Orphan Receptor 1,Ⅰ型受體酪胺酸激酶樣孤兒受體)、MUC(mucin,黏液素)16、CD20、間皮素(mesothelin)、B細胞突變抗原(B-cell mutation antigen)、CD123、CD3、前列腺特異性膜抗原(prostate specific membrane antigen,PSMA)、CD33、MUC-1、CD138、CD22、GD2(Disialoganglioside,二唾液酸神經節苷脂)、PD-L1(Programmed cell death-ligand 1,細胞程序性死亡-配體1)、CEA(carcinoembryonic antigen,癌胚抗原)、硫酸軟骨蛋白多糖-4(chondroitin sulfate proteoglycan-4)、IL(Interleukin,介白素)-13受體α鏈、IgGκ輕鏈等、或癌抗原肽(例如:源自WT1(Wilm tumor gene 1,威耳姆氏腫瘤基因1)、GPC(Glypican,磷脂肌醇聚糖)3、MART-1(Melanoma Antigen Recognized by T cells 1,T細胞1識別之黑色素瘤抗原)、gp100、NY-ESO-1(New York esophageal squamous cell carcinoma 1,紐約食管鱗狀上皮癌抗原1)、MAGE-A4(melanoma-associated antigen 4,黑色素瘤相關抗原4)等之肽)等,但並不限定於該等。
作為本發明中使用之抗原結合區,只要為能夠特異性地識別目標抗原之抗體片段,則無特別限制,考慮到CAR之易製作性,較理想為將輕鏈可變區與重鏈可變區經由連接子肽連結而成之單鏈抗體(scFv)。關於單鏈抗體中之輕鏈可變區與重鏈可變區之配置,只要兩者能夠重構功能性之抗原結合區,則無特別限定,通常可按照自N末端側起依序為輕鏈可變區-連接子肽-重鏈可變區之順序設計。作為連接子肽,可使用製作單鏈抗體時通常使用之自身公知之連接子肽。編碼輕鏈可變區之DNA、編碼重鏈可變區之DNA例如可分別自抗體產生細胞選殖輕鏈基因、重鏈基因,以該等作為模板進行PCR等而製備,或可根據現有之抗體之序列資訊進行化學合成。將所獲得之各DNA片段與編碼連接子肽之DNA藉由適當方法接合,藉此可取得編碼單鏈抗體之DNA。為了將CAR提呈於T細胞表面,較佳為於抗原結合區之N末端側進而附加前導序列。
作為細胞外鉸鏈區及跨膜區,可適當使用該技術領域中通常使用之源自T細胞表面分子之區域,例如可列舉源自CD8α或CD28之各區,但不限定於該等。
作為細胞內訊息傳遞區,例如可列舉:具有CD3ζ鏈者,於跨膜區與CD3ζ鏈之間進而具有CD28、CD134、CD137、Lck、DAP10、ICOS、4-1BB等共刺激傳遞基序(motif)者,具有2個以上之共刺激傳遞基序者等,但並不限定於該等,可將該技術領域中通常使用之任意區域組合使用。
編碼細胞外鉸鏈區、跨膜區及細胞內訊息傳遞區之核酸序列資訊於該技術領域中周知,業者可基於該等資訊,容易地自T細胞取得編碼各區之DNA片段。
藉由常規方法將如此獲得之分別編碼抗原結合區、細胞外鉸鏈區、跨膜區及細胞內訊息傳遞區之DNA片段進行連結,藉此可取得編碼CAR之DNA。
所獲得之編碼CAR之DNA可直接、或附加適當之連接子及/或核轉移訊息等後,插入至包含在T細胞內發揮功能之啟動子之表現載體,較佳為插入至質粒載體。作為在T細胞內發揮功能之啟動子,可使用哺乳動物細胞中之構成性SRα啟動子、SV40啟動子、LTR啟動子、CMV(巨細胞病毒)啟動子、RSV(勞斯肉瘤病毒)啟動子、MoMuLV(莫洛尼鼠白血病病毒)LTR、HSV-TK(單純疱疹病毒胸苷激酶)啟動子等,但不限定於該等。又,亦可使用T細胞特異性地表現之CD3、CD4、CD8等基因啟動子。
編碼CAR之RNA較佳為mRNA可藉由以上述包含編碼CAR之DNA之表現載體作為模板,利用自身公知之體外轉錄系統轉錄成mRNA而製備。
(b)編碼外源性TCR之核酸
於本說明書中,所謂「T細胞受體(TCR)」,意指由TCR鏈(α鏈、β鏈)之二聚物構成之識別抗原或該抗原-HLA(人白血球型抗原)(MHC:主要組織相容性基因複合體)複合體並向T細胞傳遞刺激訊息之受體。各TCR鏈係由可變區與恆定區構成,可變區存在3個互補性決定區(CDR1、CDR2、CDR3)。又,本發明中使用之TCR不僅指TCR之α鏈與β鏈構成異源二聚物者,亦包括構成同源二聚物者。進而,該TCR亦包括恆定區之一部分或全部缺失者、或者胺基酸序列經重組者、變為可溶性TCR(soluble TCR)者等。
再者,所謂「外源性TCR」,意指對作為本發明之核酸傳遞載體之靶細胞的T細胞而言為外源性。外源性TCR之胺基酸序列與作為本發明之核酸傳遞載體之靶細胞的T細胞所表現之內源性TCR可相同亦可不同。
本發明之核酸傳遞載體所內包之編碼TCR之核酸係編碼能夠對目標T細胞應識別之表面抗原(例如:癌抗原肽等)進行特異性地識別之TCR之α鏈及β鏈之核酸。
該核酸可藉由自身公知方法製備。於目標TCR之胺基酸序列或核酸序列為公知之情形時,基於該序列,例如化學合成DNA鏈或RNA鏈,或者將合成之一部分重疊之寡DNA短鏈利用PCR法或吉布森組裝(Gibson Assembly)法進行連接,藉此能夠構建編碼本發明之TCR之全長或一部分之DNA。
於目標TCR之序列並非公知之情形時,例如可從包含表現目標TCR之T細胞之細胞群體中單離目標T細胞,自該T細胞取得編碼TCR之核酸。具體而言,可自生物體(例如:人)採集含有T細胞之細胞群體(例如:PBMC(peripheral blood mononuclear cell,外周血單個核細胞)),一面於目標TCR所識別之細胞表面抗原之表位之存在下刺激該等細胞群體一面培養,以對於表現該細胞表面抗原之細胞之特異性、與CD8或CD4等細胞表面抗原作為指標,藉由公知方法從該細胞群體中選擇特異性地識別表現該細胞表面抗原之細胞之T細胞。T細胞對表現該表面抗原之細胞之特異性可利用例如Dextramer分析、ELISPOT分析或細胞損傷性分析等進行測定。上述含有T細胞之細胞群體較佳為例如自含有大量表現目標TCR所識別之細胞表面抗原之細胞之生物體(例如:癌等疾病患者、或者與該抗原之表位或經該表位脈衝之樹狀細胞接觸後之含T細胞之細胞群體)採集。
藉由常規方法自上述單離之T細胞提取DNA,以該DNA作為模板,基於TCR之恆定區之核酸序列而擴增TCR基因,進行選殖,藉此獲得本發明之核酸。又,亦可藉由如下方式製備:利用常規方法自細胞提取RNA合成cDNA,將其作為模板,使用與分別編碼TCRα鏈及β鏈之恆定區之核酸互補之反義引子,進行5'-RACE(Rapid amplification of cDNA ends, cDNA末端快速擴增)。5'-RACE藉由公知方法進行即可,例如可使用SMART PCR cDNA Synthesis Kit(Clontech公司製造)之類的市售套組進行。可與上述編碼CAR之DNA同樣地,將所獲得之分別編碼TCR之α鏈及β鏈之DNA插入至適當之表現載體。編碼α鏈之DNA與編碼β鏈之DNA可插入至同一載體,亦可插入至不同載體。於插入同一載體之情形時,該表現載體可多順反子地表現兩鏈,亦可單順反子地表現。於前一種情形時,於編碼兩鏈之DNA之間插入IRES或FMV 2A之類的容許多順反子之表現之中介序列。
又,編碼TCR之各鏈之RNA較佳為mRNA例如可以該表現載體作為模板,與上述編碼CAR之RNA同樣地製備。
1-4. 靶向 T 細胞配體
本發明之核酸傳遞載體較理想為較佳地用於體外使T細胞活性化及/或增殖,但亦包括向對象體內投予之使用態樣。於該情形時,藉由於本發明之核酸傳遞載體之表面進而附加能夠將該核酸傳遞載體靶向T細胞之配體(以下亦稱為「靶向T細胞配體」),可提高向T細胞之靶向效率。
作為靶向T細胞配體,只要為能夠特異性地識別T細胞上特異性地或高表現之表面分子者,則無特別限制,較佳為包含對於CD3、CD4或CD8之抗體之抗原結合區者,作為進而較佳之例,可列舉抗CD3抗體。此處,所謂「抗原結合區」,與上述構成CAR之抗原結合區同義,但CAR由於需以編碼其之核酸之形式製備,故有限制,多數情況下通常使用單鏈抗體,然而,作為靶向T細胞配體之抗原結合區係以蛋白質之狀態包含於本發明之脂質奈米粒子中,因此,不僅為單鏈抗體,亦可較佳地使用例如完全抗體分子、Fab、F(ab')2
、Fab'、Fv、還原抗體(rIgG)、dsFv、sFv、雙鏈抗體、三鏈抗體等其他任意之抗體片段。該等抗體片段可藉由利用還原劑(例如:2-巰基乙醇、二硫蘇糖醇)或肽酶(例如:木瓜酶、胃蛋白酶、無花果酶)對完全抗體(例如:IgG)進行處理,或藉由基因重組操作而製備。
若靶向T細胞配體為完全抗體分子,則亦可使用市售之抗CD3、CD4、CD8抗體等,或可自產生該抗體之細胞之培養液進行單離。另一方面,於該配體為上述任一抗原結合區(抗體片段)之情形時,可藉由與上述取得編碼構成CAR之抗原結合區之核酸之方法相同之方法,單離編碼抗CD3、CD4、CD8抗體等之抗原結合區之核酸,使用其來重組生產該抗原結合區。
2. 本發明之核酸傳遞載體之製造
以下,作為本發明之核酸傳遞載體之代表例,就使用脂質奈米粒子作為載體之情形時之本發明之核酸傳遞載體(以下亦稱為「本發明之脂質奈米粒子」)之製造例進行說明,於使用脂質體等其他載體之情形時,可根據所使用之載體而施加適當變更,藉此同樣地獲得本發明之核酸傳遞載體。
本發明之脂質奈米粒子例如可藉由如下方式製造:使用US 9,404,127中記載之方法製作脂質奈米粒子後,化學結合T細胞活性化配體。或可藉由如下方式製造:如WO 2016/021683中之記載,例如製備溶解有陽離子性脂質與非陽離子性脂質之有機溶劑溶液,與溶解有欲被脂質奈米粒子內包之核酸之水或緩衝液進行混合,藉此製作脂質奈米粒子後,化學結合T細胞活性化配體(於在體內使用本發明之脂質奈米粒子之情形時,視需要進而選用靶向T細胞配體)。作為陽離子性脂質、磷脂質、膽固醇及PEG脂質之混合比(莫耳比),例如可列舉40~60:0~20:0~50:0~5,但不限定於該等。又,於調配PEG脂質作為非陽離子性脂質、並於PEG之末端附加T細胞活性化配體之情形時,PEG脂質與該配體之調配比(莫耳比)例如可為20:1~1:20。上述PEG脂質中可以約10%~約100%之比率(莫耳%)含有末端反應性PEG。上述混合可使用移液管或微小流體混合系統(例如:Asia microfluidic system(Syrris))進行。可對所獲得之脂質粒子進行利用凝膠過濾之純化、或透析及滅菌過濾。
有機溶劑溶液中之全部脂質成分之濃度較佳為0.5~100 mg/mL。
作為有機溶劑,例如可列舉:甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇、第三丁醇、丙酮、乙腈、N,N-二甲基甲醯胺、二甲基亞碸、或該等之混合物。該有機溶劑亦可含有0~20%之水或緩衝液。作為緩衝液,可列舉:酸性緩衝液(例如:乙酸緩衝液、檸檬酸緩衝液)、或中性緩衝液(例如:4-(2-羥基乙基)-1-哌𠯤乙磺酸(HEPES)緩衝液、三(羥基甲基)胺基甲烷(Tris)緩衝液、磷酸緩衝液、磷酸緩衝生理鹽水(PBS))。
於使用微小流體混合系統進行混合之情形時,較佳為相對於有機溶劑溶液1體積份而混合水或緩衝液1~5體積份。又,於該系統中,混合液(有機溶劑溶液與水或緩衝液之混合液)流速較佳為0.1~10 mL/min,溫度較佳為15~45℃。
於以如上方式製造脂質粒子分散液時,藉由於水或緩衝液中添加欲被脂質奈米粒子內包之核酸,可製造包含陽離子性脂質、非陽離子性脂質、核酸及T細胞活性化配體之分散液。此處,該核酸較佳為以於水或緩衝液中之濃度成為0.05~2.0 mg/mL之方式添加。
又,脂質奈米粒子亦可藉由利用自身公知方法將脂質粒子分散液與該核酸進行混和而製造。
本發明之脂質奈米粒子中之該核酸之含量較佳為1~20重量%。該含量可使用Quant-iTTM
Ribogreen(註冊商標)(Invitrogen)測定。又,本發明之脂質奈米粒子中之該核酸之內封率可基於因有無添加界面活性劑(例如:Triton-X100)引起之螢光強度之差而算出。
可藉由透析將分散介質置換成水或緩衝液。透析係使用區分分子量10~20K之超過濾膜,於4℃~室溫下實施。可反覆進行透析。透析可使用切向流過濾(Tangential Flow Filtration)。
藉由如上方式獲得之本發明之脂質奈米粒子中之核酸與脂質之比率(重量比)為約0.01~約0.2。
本發明之脂質奈米粒子之平均粒徑較佳為10~200 nm。該脂質粒子之平均粒徑例如可藉由使用Zetasizer Nano ZS(Malvern Instruments),進行自相關函數之累積量解析而算出。
3. 使用 T 細胞活性化配體及核酸傳遞載體之 T 細胞之活性化 / 增殖方法、向 T 細胞內之核酸傳遞方法、含有 T 細胞之醫藥之製造方法
又,本發明提供一種使用以如上方式獲得之本發明之核酸傳遞載體的T細胞之活性化及/或增殖方法(以下亦稱為「本發明之活性化/增殖方法」)。該方法包括使包含T細胞之細胞群體與本發明之核酸傳遞載體接觸之步驟。此處,T細胞可為自生物體採集之T細胞(於本說明書中亦稱為「體外T細胞」),亦可為生物體內之T細胞(於本說明書中亦稱為「體內T細胞」),較佳為體外T細胞。
於另一態樣下,於本發明之核酸傳遞載體在內部包含核酸之情形時,藉由實施本發明之活性化/增殖方法,可同時向T細胞內傳遞該核酸。因此,本發明亦提供一種核酸向T細胞內之傳遞方法,其包括使包含T細胞之細胞群體與本發明之核酸傳遞載體接觸之步驟。又,於另一實施態樣中,本發明提供一種核酸向T細胞內之傳遞方法,其包括使包含T細胞之細胞群體同時與至少一種T細胞活性化配體及未於表面附加T細胞活性化配體之上述任一核酸傳遞載體接觸之步驟(以下,包括上述兩實施態樣在內稱為「本發明之核酸傳遞法」)。於本說明書中,於使用未與核酸傳遞載體結合之游離之T細胞活性化配體之情形時,可單獨地使用該配體,亦可以將該配體結合於載體(例如:Dynabeads(R)(Thermo Fisher Scientific公司))而作為複合體使用。又,作為此種複合體,可使用市售品(例如:TransAct(Milteny Biotech公司)、Dynabeads Human T-Activator CD3/CD28(ThermoFisher Scientific公司))。
進而於另一態樣下,可將使用本發明之核酸傳遞載體進行活性化及/或增殖後之T細胞、或者傳遞核酸後之T細胞用作免疫細胞療法劑。因此,本發明亦提供一種含有T細胞之醫藥之製造方法,其包括使包含T細胞之細胞群體與本發明之核酸傳遞載體接觸之步驟。又,於另一實施態樣中,本發明提供一種含有T細胞之醫藥之製造方法,其包括使包含T細胞之細胞群體同時與至少一種T細胞活性化配體及未於表面附加T細胞活性化配體之上述任一核酸傳遞載體接觸之步驟。
作為與本發明之核酸傳遞載體、或與T細胞活性化配體及未於表面附加T細胞活性化配體之核酸傳遞載體接觸的包含T細胞之細胞群體,只要為包含T細胞或其前驅細胞之細胞群體,則可為經單離之T細胞,亦可為例如淋巴細胞或包含多能性細胞之淋巴細胞之前驅細胞之類的不均質細胞群體。於本發明中,所謂「淋巴細胞」,意指脊椎動物之免疫系統中之白血球之亞型之一,作為淋巴細胞,可列舉:T細胞、B細胞、自然殺手細胞(NK細胞)。較佳為經單離純化之T細胞。於本發明中,所謂「T細胞」,意指於淋巴器官或末梢血等中發現之白血球之一種,特徵為主要於胸腺中分化成熟而表現TCR之一類淋巴細胞。作為本發明中可使用之T細胞,例如可列舉:作為CD8陽性細胞之細胞毒殺性T細胞(CTL)、作為CD4陽性細胞之輔助性T細胞、控制性T細胞、效應T細胞等,較佳為細胞毒殺性T細胞。
上述淋巴細胞可自人或非人哺乳動物之例如末梢血、骨髓及臍帶血中採集。於將與本發明之核酸傳遞載體接觸後之體外T細胞用於治療癌等疾病之情形時,該細胞群體較佳為自治療對象本人、或與治療對象之HLA型一致之供體採集。
與本發明之核酸傳遞載體、或與T細胞活性化配體及未於表面附加T細胞活性化配體之核酸傳遞載體接觸的包含T細胞之細胞群體亦可為自包含多能性細胞之淋巴細胞之前驅細胞分化誘導出T細胞之細胞群體。作為包含多能性細胞之淋巴細胞之前驅細胞,例如可列舉:胚性幹細胞(embryonic stem cell:ES細胞)、人工多能性幹細胞(induced pluripotent stem cell:iPS細胞)、胚性腫瘤細胞(EC細胞)、胚性生殖幹細胞(EG細胞)、造血幹細胞、喪失自我複製能力之多能性前驅細胞(multipotent progenitor:MMP)、骨髓淋巴共通前驅細胞(MLP)、骨髓系前驅細胞(MP)、粒細胞單核前驅細胞(GMP)、巨噬細胞-樹狀細胞前驅細胞(MDP)、樹狀細胞前驅細胞(DCP)等。多能性細胞等未分化細胞可藉由自身公知方法分化成T細胞。
使本發明之核酸傳遞載體、或使T細胞活性化配體及未於表面附加T細胞活性化配體之核酸傳遞載體與體外T細胞接觸之方法並無特別限定,例如於通常之T細胞之培養基中添加本發明之核酸傳遞載體、或添加T細胞活性化配體及未於表面附加T細胞活性化配體之核酸傳遞載體即可。因此,於另一態樣下,本發明亦提供一種細胞培養物,其含有包含T細胞之細胞群體、本發明之核酸傳遞載體、及培養基,或含有包含T細胞之細胞群體、至少一種T細胞活性化配體及未於表面附加T細胞活性化配體之核酸傳遞載體、以及培養基。
於本發明之核酸傳遞法中,為了提高核酸之傳遞效率,例如亦可並用磷酸鈣共沈澱法、PEG法、電穿孔法、顯微注射法、脂轉染法等。
於本發明之核酸傳遞法中,於本發明之核酸傳遞載體或未於表面附加T細胞活性化配體之核酸傳遞載體在內部包含尤其是編碼外源性TCR之核酸之情形時,就提昇外源性TCR之表現、抑制錯誤配對之TCR之出現或抑制非自我反應性之觀點而言,可利用siRNA抑制該T細胞原本表現之內源性之TCRα鏈及TCRβ鏈之表現。於該方法中應用上述核酸之情形時,為了避免siRNA對外源性TCR之效果,較佳為將編碼該TCR之核酸之鹼基序列設為與抑制內源性TCRα鏈及TCRβ鏈之表現的siRNA所作用之RNA相應之鹼基序列不同的序列(密碼子轉化型序列)。該等方法例如於WO 2008/153029中有所記載。上述鹼基序列可藉由對天然取得之編碼TCR之核酸導入沉默突變、或化學合成人工設計之核酸而製作。或者為了避免與內源性TCR鏈之錯誤配對,可將編碼外源性TCR之核酸之恆定區之一部分或全部置換成源自人以外之動物、例如小鼠之恆定區。
或者,亦可如上所述般採用基因組編輯技術剔除內源性TCR基因。
4. 將至少一種 T 細胞活性化配體與未於表面附加 T 細胞活性化配體之核酸傳遞載體加以組合而成之核酸傳遞系統
如上所述,藉由使包含T細胞之細胞群體同時與至少一種T細胞活性化配體及未於表面附加T細胞活性化配體之上述任一核酸傳遞載體接觸,可向T細胞內傳遞核酸。因此,本發明亦提供一種將至少一種T細胞活性化配體與未於表面附加T細胞活性化配體之核酸傳遞載體加以組合而成之核酸傳遞系統。於該核酸傳遞系統中,T細胞活性化配體與未於表面附加T細胞活性化配體之核酸傳遞載體可以包含該等兩者而成之組合物之形態提供,或可分別作為分開之構成要素並以套組之形態提供。該核酸傳遞用套組除含有上述兩個構成要素以外,亦可進而含有例如使包含T細胞之細胞群體與該等構成要素接觸時使用之培養基等,但並不限定於此。
5. 含有藉由 T 細胞活性化配體及核酸傳遞載體進行活性化及 / 或增殖後、或傳遞核酸後之體外 T 細胞而成之醫藥
又,本發明提供一種藉由本發明之活性化/增殖方法進行活性化及/或增殖後之體外T細胞、或者藉由本發明之核酸傳遞法傳遞核酸後之體外T細胞(包括進而包含培養基而成之細胞培養物)、以及含有該等而成之醫藥。
藉由本發明之活性化/增殖方法進行活性化及/或增殖後之體外T細胞可特異性地識別表現該T細胞表現之TCR所特異性地識別之表面抗原的細胞並將其殺傷(例如誘導細胞凋亡)。又,藉由本發明之核酸傳遞法傳遞編碼CAR或外源性TCR之核酸後之體外T細胞表現該CAR或外源性TCR,藉此可特異性地識別表現該CAR或外源性TCR所特異性地識別之表面抗原的細胞並將其殺傷(例如誘導細胞凋亡)。因此,表現識別作為表面抗原之於癌細胞等疾病細胞中特異性地表現或表現亢進之表面分子之TCR的T細胞經活性化及/或增殖後之體外T細胞、或者編碼識別該表面分子之CAR或外源性TCR之核酸經傳遞後之體外T細胞可用於預防或治療癌等疾病,可安全地對哺乳動物(人或其他哺乳動物(例如:小鼠、大鼠、倉鼠、兔、貓、狗、牛、羊、猴。較佳為人)進行投予。
於以與本發明之核酸傳遞載體、或與T細胞活性化配體及未於表面附加T細胞活性化配體之核酸傳遞載體接觸後之體外T細胞作為活性成分的醫藥中,對於該T細胞,可於向對象投予前使用適當之培養基進行培養。又,亦可於培養基中添加刺激分子,以維持擴增T細胞之活性化及/或增殖。進而,亦可於培養基中添加血清或血漿。該等於培養基中之添加量並無特別限定,可例示0體積%~20體積%,亦可根據培養階段而變更所使用之血清或血漿之量。例如亦可階段性地降低血清或血漿濃度來使用。作為血清或血漿之來源,可為自己或非己之任意者,就安全性之觀點而言,較佳為自己來源者。
以與本發明之核酸傳遞載體、或與T細胞活性化配體及未於表面附加T細胞活性化配體之核酸傳遞載體接觸後之體外T細胞作為活性成分的醫藥較佳為非經口地向對象投予使用。作為非經口之投予方法,可列舉:靜脈內、動脈內、肌肉內、腹腔內及皮下投予等方法。投予量根據對象之狀態、體重、年齢等適當選擇,一般對於體重60 kg之對象,每次以按細胞數計通常成為1×106
~1×1010
個、較佳成為1×107
~1×109
個、更佳成為5×107
~5×108
個之方式投予。又,可一次投予,亦可複數次投予。以與本發明之核酸傳遞載體接觸後之體外T細胞作為活性成分之醫藥可製成適於非經口投予之公知形態,例如注射或注入劑。該醫藥可適當包含藥理學上容許之賦形劑。作為藥理學上容許之賦形劑,可列舉上文中記載者。為了維持細胞穩定,該醫藥亦可包含生理鹽水、磷酸緩衝生理鹽水(PBS)、培養基等。作為培養基,可列舉:RPMI、AIM-V、X-VIVO10等培養基,但不限定於該等。又,基於穩定化之目的,亦可於該醫藥中添加醫藥學上容許之載體(例如:人血清白蛋白)、保存劑等。
以與本發明之核酸傳遞載體、或與T細胞活性化配體及未於表面附加T細胞活性化配體之核酸傳遞載體接觸後之體外T細胞作為活性成分的醫藥可為癌之預防或治療藥。成為本發明之醫藥之適用對象的癌並無特別限制,例如可列舉:急性淋巴細胞性癌、腺泡狀橫紋肌肉瘤、膀胱癌、骨癌、腦癌(例如:神經管胚細胞瘤)、乳癌、肛門、肛管或肛門直腸之癌、眼癌、肝內膽管癌、關節癌、頸部、膽囊或胸膜之癌、鼻、鼻腔或中耳之癌、口腔癌、外陰部癌、慢性骨髄性癌、結腸癌、食道癌、宮頸癌、纖維肉瘤、消化道類癌腫瘤、頭頸部癌(例如:頭頸部鱗狀細胞癌)、下嚥癌、腎癌、喉癌、白血病(例如:急性淋巴母細胞性白血病、急性淋巴細胞性白血病、慢性淋巴細胞性白血病、急性骨髄性白血病)、液性腫瘤、肝癌、肺癌(例如:非小細胞肺癌)、淋巴瘤(例如:霍奇金淋巴瘤、非霍奇金淋巴瘤、彌漫性大細胞型B細胞淋巴瘤、濾泡性淋巴瘤)、惡性間皮瘤、肥胖細胞瘤、黑色素瘤、多發性骨髓瘤、鼻咽癌、卵巢癌、胰腺癌;腹膜、網膜及腸系膜之癌;咽癌、前列腺癌、直腸癌、腎癌、皮膚癌、小腸癌、軟組織癌、固體腫瘤、胃癌、睾丸癌、甲狀腺癌、輸尿管癌等,但並不限定於該等。
6. 含有本發明之核酸傳遞載體而成之醫藥
本發明之核酸傳遞載體藉由對人等哺乳動物進行體內投予,可誘導生物體內之T細胞之活性化及/或增殖。又,於內部包含編碼CAR或外源性TCR之核酸的本發明之核酸傳遞載體藉由對人等哺乳動物進行體內投予,可向生物體內之T細胞內傳遞該核酸並使其表現,藉此對該T細胞賦予特異性地識別表現該CAR或外源性TCR所特異性地識別之表面抗原(例如:癌抗原)之細胞(例如:癌細胞)並將其殺傷(例如誘導細胞凋亡)之能力。因此,本發明亦提供一種含有本發明之核酸傳遞載體而成之醫藥。
含有本發明之核酸傳遞載體而成之醫藥較佳為將該核酸傳遞載體與藥學上容許之公知載體(包括賦形劑、稀釋劑、增量劑、結合劑、潤滑劑、流動助劑、崩解劑、界面活性劑等)或慣用添加劑等進行混合而以醫藥組合物之形式製備。賦形劑為業者熟知,例如可列舉:磷酸緩衝生理鹽水(例如:0.01M磷酸鹽、0.138M NaCl、0.0027M KCl,pH值7.4)、含有鹽酸鹽、氫溴酸鹽、磷酸鹽、硫酸鹽等礦酸鹽之水溶液、生理鹽水、乙二醇或乙醇等溶液及乙酸鹽、丙酸鹽、丙二酸鹽、苯甲酸鹽等有機酸之鹽等。又,亦可使用濕潤劑或乳化劑等輔助劑、及pH緩衝劑。進而,亦可使用懸浮化劑、保存劑、穩定化劑及分散劑等製劑輔助劑等。又,上述醫藥組合物亦可為用以於使用前藉由適當之無菌液體來再構成之乾燥形態。該醫藥組合物可根據製備形態(錠劑、丸劑、膠囊劑、散劑、顆粒劑、糖漿劑、乳劑、懸浮液等經口投予劑;注射劑、點滴劑、外用劑、栓劑等非經口投予劑)等,經口投予或非經口地於全身或局部投予。於非經口投予之情形時,可進行靜脈投予、皮內投予、皮下投予、直腸投予、經皮投予等。又,於以注射劑型使用之情形時,亦可添加容許之緩衝劑、溶解輔助劑、等張劑等。
作為含有本發明之核酸傳遞載體而成之醫藥之投予量,例如按編碼CAR或外源性TCR之核酸量計,每次平均1 kg體重於0.001 mg~10 mg之範圍內投予。例如於對人患者進行投予之情形時,對於體重60 kg之患者,於0.001~50 mg之範圍內投予。上述投予量為例示,可根據所使用之核酸之種類或投予路徑、投予對象或患者之年齢、體重、症狀等來適當選擇投予量。
含有本發明之核酸傳遞載體而成之醫藥藉由對哺乳動物(人或其他哺乳動物(例如:小鼠、大鼠、倉鼠、兔、貓、狗、牛、羊、猴)。較佳為人)進行投予,可於該動物體內之T細胞(體內T細胞)中誘導CAR或外源性TCR之表現,該體內T細胞殺傷表現CAR或外源性TCR所靶向之表面抗原之癌細胞等疾病細胞,藉此表現出對該疾病之預防或治療效果。
含有本發明之核酸傳遞載體而成之醫藥可為癌之預防或治療藥。成為本發明之醫藥之適用對象的癌並無特別限制,例如可列舉:急性淋巴細胞性癌、腺泡狀橫紋肌肉瘤、膀胱癌、骨癌、腦癌(例如:神經管胚細胞瘤)、乳癌、肛門、肛管或肛門直腸之癌、眼癌、肝內膽管癌、關節癌、頸部、膽囊或胸膜之癌、鼻、鼻腔或中耳之癌、口腔癌、外陰部癌、慢性骨髄性癌、結腸癌、食道癌、宮頸癌、纖維肉瘤、消化道類癌腫瘤、頭頸部癌(例如:頭頸部鱗狀細胞癌)、下嚥癌、腎癌、喉癌、白血病(例如:急性淋巴母細胞性白血病、急性淋巴細胞性白血病、慢性淋巴細胞性白血病、急性骨髄性白血病)、液性腫瘤、肝癌、肺癌(例如:非小細胞肺癌)、淋巴瘤(例如:霍奇金淋巴瘤、非霍奇金淋巴瘤、彌漫性大細胞型B細胞淋巴瘤、濾泡性淋巴瘤)、惡性間皮瘤、肥胖細胞瘤、黑色素瘤、多發性骨髓瘤、鼻咽癌、卵巢癌、胰腺癌;腹膜、網膜及腸系膜之癌;咽癌、前列腺癌、直腸癌、腎癌、皮膚癌、小腸癌、軟組織癌、固體腫瘤、胃癌、睾丸癌、甲狀腺癌、輸尿管癌等,但並不限定於該等。
以下,列舉實施例來更具體地說明本發明,但該等僅為例示,本發明並不限定於該等。
[實施例]
1. 抗體之還原處理
於9.21 mg/ml之抗CD3抗體及抗CD28抗體(Bio X Cell公司)溶液各111 μl中混合10 mM之DTT(Dithiothreitol,二硫蘇糖醇)水溶液12.3 μl。利用vortex將各抗體與DTT之混合液進行混合,於室溫下進行30分鐘反應。藉由HPLC(high performance liquid chromatography,高效液相層析法)(管柱:TSKgel G2000SWXL 7.8 mm×30 cm,TOSOH公司,流動相:PBS)對反應液進行分提,獲得包含還原抗體之分取液。使用Amicon 0.5 ml-10K對分取液進行超濃縮。濃縮液中之抗體蛋白濃度及硫醇基濃度分別藉由230 nm之吸光度及使用N-(7-二甲基胺基-4-甲基香豆素-3-基)順丁烯二醯亞胺(DACM)之螢光呈色反應進行測定。
2. 順丁烯二醯亞胺 (Maleimide)- 脂質奈米粒子之製備
使包含化合物7、11、12、21、31或35作為陽離子性脂質之脂質混合物(陽離子性脂質:DPPC:膽固醇(Cholesterol):SUNBRIGHT GM-020:SUNBRIGHT DSPE-020MA=60:10.6:28:1.4:1,莫耳比)溶解於90%EtOH、10%水,獲得7.0 mg/ml之脂質溶液。另一方面,使螢光素酶(luciferase)mRNA(TriLink公司)溶解於pH值5.0之2-嗎啉乙磺酸(2-morpholinoethanesulfonic acid,MES)緩衝液而獲得0.2 mg/ml之mRNA溶液。將所獲得之脂質溶液及mRNA溶液於室溫下利用NanoAssemblr裝置(Precision Nanosystems公司)以流速比3 ml/min:6 ml/min進行混合,而獲得包含組合物之分散液。針對所獲得之分散液,使用Slyde-Α-Lyzer(20k之區分分子量,Thermo Scientific公司),對水於室溫下進行1小時透析、對PBS於4℃下進行48小時透析。繼而,使用0.2 μm之針筒過濾器(syringe filter)(Iwaki)進行過濾,於4℃下保存。
3. 還原抗體與順丁烯二醯亞胺 - 脂質奈米粒子之結合反應
以還原抗體相對於順丁烯二醯亞胺之莫耳濃度成為1/20之方式於順丁烯二醯亞胺-脂質奈米粒子分散液中混合還原抗體溶液,於室溫下靜置4小時。其後,於4℃下保管直至純化步驟。
4. 抗體 - 脂質奈米粒子之凝膠過濾純化
將還原抗體與順丁烯二醯亞胺-脂質奈米粒子之反應液載入至凝膠過濾管柱Sepharose CL-4B(Cat No.17-0150-01 / GE Healthcare),以D-PBS(-)作為流動相進行分提。繼而,測定各組分之蛋白濃度,藉此鑑定包含目標抗體-脂質奈米粒子之組分,而獲得抗體-脂質奈米粒子原液。利用0.2 μm之針筒過濾器對抗體-脂質奈米粒子進行過濾,於4℃下保存。
5. 抗體 - 脂質奈米粒子之粒徑測定
向抗體-脂質奈米粒子原液1 μl中添加99 μl之磷酸鹽緩衝生理鹽水(phosphate buffered saline)(137 mM NaCl、7.99 mM Na2
HPO4
、2.7 mM KCl、1.47 mM KH2
PO4
,pH值7.4)。將所獲得之分散液供於使用Zetasizer Nano ZS(Malvern instruments)之動態光散射測定,進行自相關函數之累積量解析,測定Z平均粒徑及多分散性指數(polydispersity index,PDI)。
6. 抗體 - 脂質奈米粒子之 ζ 電位測定
向抗體-脂質奈米粒子原液50 μl中添加700 μl之HEPES緩衝液(10 mM HEPES-NaOH,pH值7.3)。將所獲得之分散液供於使用Zetasizer Nano ZS(Malvern instruments)之電泳光散射測定,測定ζ電位。
7. 抗體 - 脂質奈米粒子之 mRNA 內封率・濃度測定
利用TE緩衝液稀釋抗體-脂質奈米粒子原液,將mRNA濃度調整為約4 μg/ml。又,作為mRNA濃度基準液,利用TE緩衝液將裸mRNA(naked mRNA)稀釋成4 μg/ml。向經稀釋之抗體-脂質奈米粒子及裸mRNA濃度基準液各60 μl中分別混合60 μl之TE緩衝液或包含2%Triton-X100之TE緩衝液。於室溫下靜置5分鐘後,混合120 μl之Quant-iTTM
RiboGreen(註冊商標),進而靜置5分鐘。混合液之螢光強度測定係使用Envision微盤讀取器(Perkin-Elmer公司)進行。藉由下式算出mRNA內封率及mRNA濃度。
% mRNA內封率=(1-FTE
/FTriton
)×100
mRNA濃度=(FTriton
-b)×d/m
(其中,FTE
表示與TE緩衝液混合後之脂質奈米粒子之RiboGreen螢光強度,FTriton
表示與包含2%Triton-X100之TE緩衝液混合後之脂質奈米粒子之RiboGreen螢光強度。b與m表示根據濃度基準siRNA之校準曲線獲得之y截距與斜率。d表示脂質奈米粒子之稀釋率)
將所製備之抗體-脂質奈米粒子之分析結果一覽示於下表。
8. 利用結合有抗 CD3 抗體之脂質奈米粒子進行之向人初代培養 T 細胞之 mRNA 轉染
於圓底96孔盤(96-well plate)(Corning公司)以1×105
cells/well之細胞密度接種人末梢血CD3陽性泛T細胞(Precision Bioservices公司)。培養基係使用添加有30 ng/ml之重組IL-2(Thermo Fisher Scientific公司)之無血清造血細胞培養基X-VIVO10(Lonza公司)。繼而,以培養基中螢光素酶mRNA濃度成為1 μg/ml之方式向培養基中添加內封螢光素酶mRNA(TriLink公司)之抗CD3抗體結合脂質奈米粒子,於37℃之5%CO2
培養箱內靜置72小時。使用Bright-Glo螢光素酶檢測系統(Bright-Glo Luciferase Assay System)套組(Promega公司)測定於T細胞表現之螢光素酶。將添加有各抗CD3抗體-脂質奈米粒子之T細胞之相對螢光素酶發光強度示於圖1。
9. 利用結合有抗 CD3 抗體及 / 或抗 CD28 抗體之脂質奈米粒子進行之向人初代培養 T 細胞之 mRNA 轉染
於圓底96孔盤(Corning公司)以1×105
cells/well之細胞密度接種人末梢血CD3陽性泛T細胞(Precision Bioservices公司)。培養基係使用添加有30 ng/ml之重組IL-2(Thermo Fisher Scientific公司)之無血清造血細胞培養基X-VIVO10(Lonza公司)。繼而,以培養基中螢光素酶mRNA濃度成為1 μg/ml之方式向培養基中添加內封螢光素酶mRNA(TriLink公司)之抗CD3抗體結合脂質奈米粒子、抗CD28抗體結合脂質奈米粒子、抗CD3抗體結合脂質奈米粒子與抗CD28抗體結合脂質奈米粒子之混合物、及抗CD3抗體與抗CD28抗體混合結合脂質奈米粒子,於37℃之5%CO2
培養箱內靜置72小時。使用Bright-Glo螢光素酶檢測系統套組(Promega公司)測定於T細胞表現之螢光素酶。將添加有各抗體-脂質奈米粒子之T細胞之相對螢光素酶發光強度示於圖2。
10. 利用結合有抗 CD3/ 抗 CD28 抗體之脂質奈米粒子進行之向人初代培養 T 細胞之 mRNA 轉染與 T 細胞活性化刺激
於圓底96孔盤(Corning公司)以1×105
cells/well之細胞密度接種人末梢血CD3陽性泛T細胞(Precision Bioservices公司)。培養基係使用添加有30 ng/ml之重組IL-2(Thermo Fisher Scientific公司)之無血清造血細胞培養基X-VIVO10(Lonza公司)。繼而,以培養基中螢光素酶mRNA濃度成為0.3及1 μg/ml之方式向培養基中添加內封螢光素酶mRNA(TriLink公司)之結合有抗CD3抗體及抗CD28抗體之脂質奈米粒子,於37℃之5%CO2
培養箱內靜置72小時。再者,作為T細胞活性化刺激之對照樣本,亦製備添加有TransAct(Miltenyi Biotec公司)之T細胞及添加有Dynabeads(Thermo Fisher Scientific公司)之T細胞。使用Bright-Glo螢光素酶檢測系統套組(Promega公司)測定於T細胞表現之螢光素酶。又,使用CellTiter-Glo套組(Promega公司)測定T細胞之存活細胞數。將螢光素酶之表現量示於圖3(I),將T細胞之存活數示於圖3(II)及(III)。
11.Luc mRNA 內封脂質奈米粒子之製備
使包含化合物35作為陽離子性脂質之脂質混合物(化合物35:DPPC:膽固醇:SUNBRIGHT GM-020:SUNBRIGHT=60:10.6:28:1.4,莫耳比)溶解於90%EtOH、10%水,獲得8.1 mg/ml之脂質溶液。另一方面,使螢光素酶mRNA(Luc mRNA)(TriLink公司)溶解於pH值5.0之2-嗎啉乙磺酸(MES)緩衝液而獲得0.18 mg/ml之mRNA溶液。將所獲得之脂質溶液及mRNA溶液於室溫下利用NanoAssemblr裝置(Precision Nanosystems公司)以流速比3 ml/min:6 ml/min進行混合,而獲得Luc mRNA內封脂質奈米粒子之分散液。針對所獲得之分散液,使用Slyde-Α-Lyzer(20k之區分分子量,Thermo Scientific公司),對水於室溫下進行1小時透析、對PBS於4℃下進行48小時透析。繼而,使用0.2 μm之針筒過濾器(Iwaki)進行過濾,於4℃下保存。
12.Luc mRNA 內封脂質奈米粒子之粒徑測定
向Luc mRNA內封脂質奈米粒子原液1 μl中添加99 μl之磷酸鹽緩衝生理鹽水(137 mM NaCl、7.99 mM Na2
HPO4
、2.7 mM KCl、1.47 mM KH2
PO4
,pH值7.4)。將所獲得之分散液供於使用Zetasizer Nano ZS(Malvern instruments)之動態光散射測定,進行自相關函數之累積量解析,測定Z平均粒徑及多分散性指數。
13.Luc mRNA 內封脂質奈米粒子之 ζ 電位測定
向Luc mRNA內封脂質奈米粒子原液50 μl中添加700 μl之HEPES緩衝液(10 mM HEPES-NaOH,pH值7.3)。將所獲得之分散液供於使用Zetasizer Nano ZS(Malvern instruments)之電泳光散射測定,測定ζ電位。
14.Luc mRNA 內封脂質奈米粒子之 mRNA 內封率・濃度測定
利用TE緩衝液稀釋Luc mRNA內封脂質奈米粒子原液,將mRNA濃度調整為約4 μg/ml。又,作為mRNA濃度基準液,利用TE緩衝液將裸mRNA稀釋成4 μg/ml。向經稀釋之Luc mRNA內封脂質奈米粒子及裸mRNA濃度基準液各60 μl中分別混合60 μl之TE緩衝液或包含2%Triton-X100之TE緩衝液。於室溫下靜置5分鐘後,混合120 μl之Quant-iTTM RiboGreen(註冊商標),進而靜置5分鐘。混合液之螢光強度測定係使用Envision微盤讀取器(Perkin-Elmer公司)進行。藉由下式算出mRNA內封率及mRNA濃度。
% mRNA內封率=(1-FTE
/FTriton
)×100
mRNA濃度=(FTriton
-b)×d/m
(其中,FTE
表示與TE緩衝液混合後之脂質奈米粒子之RiboGreen螢光強度,FTriton
表示與包含2%Triton-X100之TE緩衝液混合後之脂質奈米粒子之RiboGreen螢光強度。b與m表示根據濃度基準siRNA之校準曲線獲得之y截距與斜率。d表示脂質奈米粒子之稀釋率)
將Luc mRNA內封脂質奈米粒子之分析結果示於表2。
15. 藉由活性化刺激劑與脂質奈米粒子之共添加而進行之向人末梢血 CD3 陽性泛 T 細胞之高效率之螢光素酶 mRNA 轉染
於圓底96孔盤(Corning公司)以1×105
cells/well之細胞密度接種人末梢血CD3陽性泛T細胞(Precision Bioservices公司)。培養基係使用添加有30 ng/ml之重組IL-2(Thermo Fisher Scientific公司)、及按照各製造商之推薦方案添加有對T細胞賦予活性化刺激之TransAct(Milteny Biotech公司)或Dynabeads Human T-Activator CD3/CD28(ThermoFisher Scientific公司)之無血清造血細胞培養基X-VIVO10(Lonza公司)。繼而,以培養基中螢光素酶mRNA濃度成為0.1、0.3、1 μg/ml之方式向培養基中添加內封螢光素酶mRNA(TriLink公司)之脂質奈米粒子化合物35-螢光素酶mRNA,於37℃之5%CO2
培養箱內靜置72小時。使用Bright-Glo螢光素酶檢測系統套組(Promega公司)測定於T細胞表現之螢光素酶。使用CellTiter-Glo發光法細胞活力檢測(CellTiter-Glo Luminescent Cell Viability Assay)套組(Promega公司)測定T細胞之存活及增殖率。將所獲得之結果示於圖4及5。顯示藉由對活性化刺激下之T細胞添加內封有Luc mRNA之脂質奈米粒子,轉染活性顯著提昇(圖4)。又,T細胞之存活及增殖率得以高水準維持(圖5)。
16. 藉由活性化刺激劑與脂質奈米粒子之共添加而進行之向人 CD4/CD8 陽性 T 細胞之高效率之螢光素酶 mRNA 轉染
利用LOVO細胞處理系統(LOVO Cell Processing System)(Fresenius公司)清洗人末梢血白血球組分Leukopak(HemaCare公司),藉由細胞處理系統CliniMACS(Milteny Biotec公司)回收CD4及CD8陽性細胞。於平底96孔盤(Corning公司)以1×105
cells/well之細胞密度接種所獲得之CD4/CD8陽性細胞。再者,細胞之培養係使用於OPTmizer CTS T細胞擴增基礎培養基(OPTmizer CTS T-Cell Expansion Basal Medium)每1 L中含有26 mL之OPTmizer CTS T細胞擴增添加物(OPTmizer CTS T-cell Expansion Supplement)、20 mL之CTS Immune SR、10 mL之L-麩醯胺酸(L-Glutamine)200 mM(以上ThermoFischer Scientific公司)、10 mL之硫酸鏈黴素(Streptomycin Sulfate)10 mg/ml(MEIJI公司)、4.2 ng/ml之MACS GMP重組人IL-2(MACS GMP Recombinant Human IL-2)(Milteny Biotec公司)之培養基。又,作為T細胞之活性化刺激劑,按照製造商之推薦方案添加TransAct(Milteny Biotech公司)。繼而,以培養基中螢光素酶mRNA濃度成為1、3、10 μg/ml之方式向培養基中添加內封螢光素酶mRNA(TriLink公司)之脂質奈米粒子化合物35-螢光素酶mRNA,於37℃之5%CO2
培養箱內靜置72小時。使用Bright-Glo螢光素酶檢測系統套組(Promega公司)測定於T細胞表現之螢光素酶。使用CellTiter-Glo發光法細胞活力檢測套組(Promega公司)測定T細胞之存活及增殖率。將所獲得之結果示於圖6。顯示藉由對活性化刺激下之T細胞添加內封有Luc mRNA之脂質奈米粒子,轉染活性顯著提昇。又,T細胞之存活及增殖率得以高水準維持。
[產業上之可利用性]
藉由使用本發明之核酸傳遞載體或本發明之核酸傳遞方法,能夠一步同時進行使T細胞活性化/增殖之步驟與向T細胞之基因導入步驟,因此在能夠於短期內製造製造費用較低之免疫細胞療法劑,能夠提供更廉價之免疫細胞療法之方面極其有用。
本申請案係基於2018年10月18日提出申請之日本專利特願2018-197069及2019年7月3日提出申請之日本專利特願2019-124629,於此申明該等之內容全部包含於本說明書中。
圖1係表示各種包含陽離子性脂質(化合物7、11、12、21、31及35)且於表面附加有抗CD3抗體之脂質奈米粒子的向T細胞之基因導入效率之比較之圖。
圖2係表示於表面附加有抗CD3抗體及/或抗CD28抗體之脂質奈米粒子的向T細胞之基因導入效率之比較之圖。
圖3係表示藉由於表面附加有抗CD3抗體及抗CD28抗體之脂質奈米粒子同時達成向T細胞之基因導入(I)與T細胞之活性化(II)之圖。於(I)及(II)中,上一行數值表示內封之mRNA(messenger RNA,信使核糖核酸)濃度(μg/ml),下一行數值表示抗體濃度(μg/ml)。(III)係為了進行比較而示出先前公知之於表面附加有抗CD3抗體及抗CD28抗體之珠粒之T細胞活性化效率。
圖4係表示藉由共添加活性化刺激劑與脂質奈米粒子而向人末梢血CD3陽性泛T細胞效率良好地導入螢光素酶mRNA(luc mRNA)之圖。
圖5係表示藉由脂質奈米粒子轉染螢光素酶mRNA後之T細胞之存活及增殖率之圖。
圖6係表示藉由共添加活性化刺激劑與脂質奈米粒子而向人CD4/CD8陽性T細胞效率良好地導入螢光素酶mRNA(左圖)、及以較高水準維持T細胞之存活及增殖率(右圖)之圖。
Claims (32)
- 一種T細胞之活性化及/或增殖方法,其包括如下步驟:使包含T細胞之細胞群體與於表面附加有至少一種T細胞活性化配體之核酸傳遞載體接觸。
- 如請求項1之方法,其中上述T細胞活性化配體包含對於CD3之抗體及/或對於CD28之抗體。
- 如請求項1之方法,其中於上述核酸傳遞載體之表面附加有2種以上之T細胞活性化配體。
- 如請求項1之方法,其中上述核酸傳遞載體為脂質奈米粒子或脂質體。
- 如請求項1之方法,其中於上述核酸傳遞載體之內部包含抑制T細胞活性化抑制因子之表現之核酸及/或編碼T細胞活性化促進因子之核酸。
- 如請求項1之方法,其中於上述核酸傳遞載體之內部包含編碼CAR或TCR之核酸。
- 如請求項1之方法,其係體外進行。
- 一種核酸向T細胞內之傳遞方法,其包括如下步驟:使包含T細胞之細胞群體與於表面附加有至少一種T細胞活性化配體且於內部包含核酸之核酸傳遞載體接觸,並且該核酸不含編碼CAR或TCR之核酸。
- 如請求項8之方法,其中上述T細胞活性化配體包含對於CD3之抗體及/或對於CD28之抗體。
- 如請求項8之方法,其中於上述核酸傳遞載體之表面附加有2種以上之T細胞活性化配體。
- 如請求項8之方法,其中上述核酸傳遞載體為脂質奈米粒子或脂質體。
- 如請求項8之方法,其中上述核酸包含抑制T細胞活性化抑制因子之表現之核酸及/或編碼T細胞活性化促進因子之核酸。
- 如請求項8之方法,其係體外進行。
- 一種核酸向T細胞內之傳遞方法,其包括如下步驟:使包含T細胞之細胞群體同時與至少一種T細胞活性化配體及於內部包含核酸且未於表面附加T細胞活性化配體之核酸傳遞載體接觸。
- 如請求項14之方法,其中上述T細胞活性化配體包含對於CD3之抗體及/或對於CD28之抗體。
- 如請求項14之方法,其中使與2種以上之T細胞活性化配體接觸。
- 如請求項14之方法,其中上述核酸傳遞載體為脂質奈米粒子或脂質體。
- 如請求項14之方法,其中上述核酸包含抑制T細胞活性化抑制因子之表現之核酸及/或編碼T細胞活性化促進因子之核酸。
- 如請求項14之方法,其中上述核酸包含編碼CAR或TCR之核酸。
- 如請求項14之方法,其係體外進行。
- 一種含有T細胞而成之醫藥之製造方法,其包括如下步驟:使包含T細胞之細胞群體同時與至少一種T細胞活性化配體及於內部包含核酸且未於表面附加T細胞活性化配體之核酸傳遞載體接觸。
- 如請求項21之方法,其中上述T細胞活性化配體包含對於CD3之抗體及/或對於CD28之抗體。
- 如請求項21之方法,其中使與2種以上之T細胞活性化配體接觸。
- 如請求項21之方法,其中上述核酸傳遞載體為脂質奈米粒子或脂質體。
- 如請求項21之方法,其中上述核酸包含抑制T細胞活性化抑制因子之表現之核酸及/或編碼T細胞活性化促進因子之核酸。
- 如請求項21之方法,其中上述核酸包含編碼CAR或TCR之核酸。
- 如請求項21之方法,其係體外進行。
- 一種T細胞,其藉由如請求項14之方法向細胞內傳遞核酸。
- 一種醫藥,其係含有如請求項28之T細胞而成。
- 一種細胞培養物,其含有包含T細胞之細胞群體、與至少一種T細胞活性化配體、未於表面附加T細胞活性化配體之核酸傳遞載體、及培養基。
- 一種向T細胞之核酸傳遞用組合物,其含有至少一種T細胞活性化配體、及未於表面附加T細胞活性化配體之核酸傳遞載體。
- 一種向T細胞之核酸傳遞用套組,其含有至少一種T細胞活性化配體、及未於表面附加T細胞活性化配體之核酸傳遞載體。
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