TW202404614A - 免疫增強及感染性疾病之治療 - Google Patents
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Abstract
本發明特點在於使用用於雙股DNA (dsDNA)之奈米粒子的方法。該等奈米粒子能夠胞內遞送dsDNA,其中該dsDNA可刺激先天性免疫反應。所描述該等方法之用途包括增強對疫苗之免疫反應及感染性疾病治療。
Description
本發明係關於用於增強免疫反應之方法及治療感染性疾病之方法。所提供之方法可例如與不同類型的針對感染性疾病之治療劑及疫苗組合使用。
感染性疾病係由諸如細菌、病毒、真菌或寄生蟲之病原體所引起之病症。感染性疾病係全世界引起死亡之主要原因,且造成重大的健康、社會及經濟負擔。下呼吸道感染、腹瀉病及結核病位居死亡原因之前10。(Gu等人, Frontiers in Microbiology (2021) 第12卷, article 667561;以及van Seventer及Hochberg International Encyclopedia of Public Health. (2017) 第2版 6:22-39. )
治療由感染性生物體(在本文中亦稱為病原體)引起之疾病的方法包括預防性治療及治療性治療。預防性治療涉及在病原體感染前治療個體。例如,可對一般群體、感染風險較高之個人或感染風險較大之人群進行預防性治療。預防性治療包括使用增強宿主對病原體之免疫反應的疫苗;及使用可增強宿主免疫反應之一或多種組分及/或靶向特定病原體之治療劑。
治療性治療涉及治療感染病原體之個人。例如,可經由使用增強宿主對病原體之免疫反應之治療性疫苗以及經由使用可增強宿主免疫系統之一或多種組分及/或靶向特定病原體之治療劑來進行治療性治療。
不同類型的疫苗,包括治療性疫苗之實例提供於Kutsher等人, (2012) Microbial Biotechnology 5(2), 270-282及由Plotkin等人編輯之Plotkin's Vaccine 第7版 (2018)中。
本發明提供利用奈米粒子遞送雙股DNA (dsDNA)之方法。該等奈米粒子能夠在dsDNA可刺激先天性免疫反應之細胞內遞送dsDNA。所提供之方法可包括使用針對感染性疾病及增強免疫系統之治療劑;及產生針對感染性生物體之免疫的疫苗。
因此,本發明之第一態樣描述一種用於治療之個體中之感染性疾病之方法,其包含向個體投與:(a)包含dsDNA之奈米粒子;及(b)疫苗或治療劑。在一個實施例中,dsDNA包含長度為至少45個鹼基對之dsDNA區。
所提及之「治療(treating)」及「治療(treatment)」包括預防性治療及/或治療患有感染性疾病之個體。
「疫苗」提供免疫反應所針對之抗原。可使用各種不同之疫苗,包括活的減毒、全生物體殺傷、類毒素、次單元(例如經純化之蛋白質、重組蛋白質、多醣及肽)、病毒樣粒子、外膜囊泡、蛋白質-多醣結合物、病毒載體、核酸、細菌引導以及抗原呈現細胞。
「治療劑」提供具有針對感染性疾病之活性之化合物及/或增強宿主針對感染性生物體之免疫反應的一或多種組分。所提及之化合物或藥劑並非對化合物或藥劑之尺寸或複雜度之限制。化合物及藥劑之實例包括小分子及較大分子,諸如抗體及其他蛋白質。
本發明之另一態樣描述一種用於增強個體對疫苗之免疫反應的方法。該方法包含向個體投與(a)包含dsDNA之奈米粒子,及(b)疫苗。在一個實施例中,dsDNA包含長度為至少45個鹼基對之dsDNA區。
其他態樣係關於包含dsDNA之奈米粒子,其係用於本文所描述之方法;及包含dsDNA之奈米粒子之用途,其係用於製備藥劑,較佳用於本文所描述之方法。在一個實施例中,dsDNA包含長度為至少45個鹼基對之dsDNA區。
本發明之其他特徵及優點自本文所提供的包括不同實例之額外描述而顯而易見。所提供的實例說明適用於實踐本發明之不同組分及方法。此類實例不限制所主張之本發明。基於本發明,熟習此項技術者可識別及採用適用於實踐本發明之其他組分及方法。
本發明提供利用奈米粒子遞送dsDNA之方法,其係用於感染性疾病之治療及免疫增強。如下文實例中所說明,dsDNA可刺激先天性免疫反應及提供佐劑活性。儘管不希望受任何理論之束縛,但奈米粒子促進dsDNA之細胞內遞送,其中dsDNA刺激細胞溶質感測cGAS/STING及/或炎性體路徑之先天性免疫反應,從而提供免疫反應。
用於治療感染性疾病之方法涉及使用一或多種具有抗感染性疾病活性之治療劑及/或提供感染性生物體抗原之疫苗。治療劑可例如直接靶向感染性生物體及/或增強宿主免疫系統之一或多種組分。
所提及之「dsDNA」提供形成一或多個雙股DNA區之一或多個聚核苷酸。dsDNA區可由單個聚核苷酸或兩個不同之聚核苷酸形成。dsDNA可含有經修飾之核苷酸,例如,糖修飾(例如2'-甲氧基乙基(2'-MOE)、2'-氟(2'-F)、鎖核酸(LNA)、限制性乙基(cEt)以及三環DNA (tc-DNA))、鹼基修飾(例如經C7修飾之去氮-腺嘌呤(例如甲基、Cl或F)、經C7修飾之去氮-鳥苷(例如甲基、Cl或F)、經C5修飾之胞嘧啶(例如甲基、F或Cl),及經C5修飾之尿苷(例如甲基、F或Cl)),及/或主鏈修飾(例如硫代磷酸酯(Rp及/或Rs)、硫代胺基磷酸酯、二胺基磷酸酯𠰌啉基寡聚物(PMO),以及肽-核酸(PNA))。經修飾之核苷酸之實例提供於例如Adachi等人, (2021) Biomedicines 9, 550;Shen及Corey (2018) Nucleic Acid Research 46: 4, 1584-1600;以及Duffy等人, (2020) 18:112中;其各自以全文引用之方式併入本文中。
所提及之「聚核苷酸」提供一種由天然存在之核苷酸及/或經修飾之核苷酸構成的核酸聚合物。核苷酸可含有糖修飾(例如2'-甲氧基乙基(2'-MOE)、2'-氟(2'-F)、鎖核酸(LNA)、限制性乙基(cEt)以及三環DNA (tc-DNA))、鹼基修飾(例如經C7修飾之去氮-腺嘌呤(例如甲基、Cl或F)、經C7修飾之去氮-鳥苷(例如甲基、Cl或F)、經C5修飾之胞嘧啶(例如甲基、F或Cl),及經C5修飾之尿苷(例如甲基、F或Cl)),及/或主鏈修飾(例如硫代磷酸酯(Rp及/或Rs)、硫代胺基磷酸酯、二胺基磷酸酯𠰌啉基寡聚物(PMO),以及肽-核酸(PNA))。
dsDNA包含dsDNA區且亦可包含額外的區。額外區之實例包括單股區、RNA區、由經修飾之RNA修飾之DNA區以及非核苷酸區。在某些實施例中,dsDNA包含提供具有dsDNA區之結構的連續聚核苷酸股(例如髮夾形環),或包含兩個聚核苷酸股,其中所有該兩個股或其一個區域形成dsDNA區。在不同的實施例中,dsDNA為小型環、奈米質體、開放型線性雙螺旋DNA以及封閉型線性雙螺旋DNA (CELiD/ceDNA/狗骨頭DNA (doggybone DNA))。
可使用不同技術,包括核苷酸聚合物之酶促產生及/或化學修飾來產生dsDNA。用於生產核酸之技術之實例為此項技術中熟知的且包括例如:Kosuri等人, (2014) Nat. Methods. 11(5):499-507;Ducani等人, (2013) Nat. Methods 10, 647-652;Ducani等人, (2014) Nucleic Acids Research, 第42卷, 第16期;以及Sandahl等人, (2021) Nat. Commun. 12, 2760。
在某些實施例中,核苷酸修飾不會顯著降低dsDNA刺激先天性免疫反應之能力。在不同實施例中,與相應未經修飾之dsDNA相比,dsDNA能夠刺激至少50%、至少65%、至少75%、至少85%、至少90%或至少100%之先天性免疫反應,如下文實例中所提供之以IFN-γ及IL-6量測。
「奈米粒子」係指一種小型非病毒粒子,其可與dsDNA一起封裝或與dsDNA結合且促進dsDNA遞送至細胞中。奈米粒子之實例包括脂質奈米粒子(LNP)、聚合奈米粒子、脂質聚合物奈米粒子(LPNP)、基於蛋白及肽之奈米粒子、DNA樹狀體及基於DNA之奈米載體、碳奈米管、微粒子、微膠囊、無機奈米粒子、肽籠狀奈米粒子以及胞泌體。奈米粒子之尺寸在約10 nm至約1000 nm之範圍內。在不同實施例中,奈米粒子為約50 nm至約500 nm,或約50 nm至約200 nm。
所提及之「個體」係指哺乳動物,包括人類;非人類靈長類動物,諸如猿、長臂猿、大猩猩、黑猩猩、紅毛猩猩、短尾猿;家畜,諸如犬及貓;農畜,諸如家禽及鴨、馬、牛、山羊、綿羊及豬;以及實驗動物,諸如小鼠、大鼠、兔及天竺鼠。較佳個體為人類個體。
DNA載體含有可操作地連接至一或多個調節元件之轉殖基因,從而提供自轉殖基因之RNA表現。所產生之RNA可自身為功能性的或可編碼蛋白。一種類型之調節元件為啟動子,其與RNA聚合酶結合且係起始轉錄所必需之轉錄因子。在編碼蛋白時,所產生之RNA序列將亦對編碼序列之末端處之終止序列進行編碼。
術語「可操作地連接」係指單個核酸上之兩個或更多個核酸區段之結合,其中一個區段之功能受另一個區段影響。
所提及之「轉殖基因」係指能夠針對RNA而經表現之DNA區,而不考慮聚核苷酸序列之來源。轉殖基因通常為較長核酸之一部分,其中核酸含有至少一個在自然界中通常不與轉殖基因結合之區域。
除非上下文另有明確指示,否則單數形式「一(a)」、「一(an)」及「該」包括複數個指代物。
如本文所用,在多個所述要素之間的連接性術語「及/或」應理解為涵蓋個別與組合選項。舉例而言,在兩個要素由「及/或」結合時,第一選項係指第一選項在無第二選項之情況下的適用性,第二選項係指第二選項在無第一選項之情況下的適用性,且第三選項係指第一選項及第二選項在一起之適用性。選項中之任一者應理解為屬於含義內,且因此滿足術語「及/或」之要求。選項中之多於一者的並行適用性亦應理解為屬於術語「及/或」之含義內。
除非上下文另有明確指示,否則所採用之術語「或」及「及」具有與「及/或」相同之含義。
所提及之後接不同成員或實例的諸如「包括」、「例如(for example)」、「例如(e.g.)」、「諸如」之術語為開放式描述,其中所列成員或實例係說明性的且可提供或使用其他成員或實例。
術語「多肽」、「蛋白」及「肽」可互換使用以指代胺基酸序列而與功能無關。多肽及肽含有至少兩個胺基酸,而蛋白質含有至少約50個胺基酸。所提供之胺基酸包括天然存在之胺基酸及經修飾之胺基酸,諸如經由細胞修飾而提供之胺基酸。
所提及之相對於一個要素或一組要素使用之「包含(comprise)」及變體,諸如「包含(comprises)」及「包含(comprising)」,係開放式的,且不排除其他未列舉之要素或方法步驟。諸如「包括」、「含有」及「特徵為」之術語與包含同義。在本文所描述之不同態樣及實施例中,所提及之開放式術語,諸如「包含」,可由術語「由……組成」或「基本上由……組成」替換。
所提及之「由……組成」排除所列申請專利範圍要素中未規定的任何要素、步驟或成分,其中此類要素、步驟或成分與所主張之發明相關。
所提及之「基本上由……組成」將申請專利範圍之範疇限於所規定的材料或步驟,以及不會實質性影響所主張之發明之一或多個基本及新型特徵的材料或步驟。
術語「約」係指與基礎參數相差10%以內(亦即,加上或減去10%)之值。例如,「約1:10」包括1.1:10.1或0.9:9.9,且「約5個小時」包括4.5小時或5.5小時。位於一連串的值之開始處的術語「約」將各值修改10%。
除非上下文另有明確指示,否則所有數值或數值範圍包括該等範圍內之整數以及範圍內之值或整數之分數。因此,作為說明,所提及之減少95%或更多包括95%、96%、97%、98%、99%、100%,以及95.1%、95.2%、95.3%、95.4%、95.5%、……、96.1%、96.2%、96.3%、96.4%、96.5%等;所提及之數值範圍,諸如「1至4」包括2、3,以及1.1、1.2、1.3、1.4等;所提及之「1至4週」包括7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27或28天。
所提及之大於(超過)或小於參考數字之整數分別包括大於或小於該參考數字之數字。因此,舉例而言,所提及之大於2包括3、4、5、6、7 、8、9、10、11、12、13、14、15;且投與「兩次或更多次」包括2、3、4、5、6、7、8、9、10、11、12、13、14、15或更多次。
在先前技術及整個本說明書中引用或描述各種參考文獻,包括文章及專利公開案。此等參考文獻中之各者係以全文引用之方式併入本文中。就所揭示或主張之任何發明而言,不承認任何參考文獻為先前技術。在一些情況下,特定參考文獻經指示以引用之方式併入本文中以突顯併入。
本文所提供之定義,包括本章節及本申請案之其他章節中之定義,適用於整個本申請案中。
除非另外定義,否則本文所用之所有技術及科學術語均具有與一般熟習本發明所屬技術者通常所理解相同的含義。
本說明書已分成多個章節及段落,且提供各種實施例。此等分離不應視為一個段落或章節或實施例之主旨與另一段落或章節或實施例之主旨無關聯。所提供之描述具有廣泛應用且涵蓋可考慮之各種章節、段落及句子的所有組合。任何實施例之論述僅意謂為例示性的且並不意欲表明本發明之範疇,包括申請專利範圍(除非申請專利範圍中另有規定)僅限於此等實例。
本文中使用肯定的語言描述本發明之多個實施例來大體揭示本發明。特定言之,本發明亦包括完全或部分排除諸如物質或材料、方法步驟及條件、方案或程序的標的物之實施例。舉例而言,在本發明之某些實施例中,排除材料及/或方法步驟。因此,即使本文中未就本發明不包括的內容來大體表述本發明,但本文中仍揭示了本發明中未明確排除的態樣。
I. 奈米粒子
可採用各種不同之奈米粒子,包括脂質奈米粒子(LNP)、聚合奈米粒子、脂質聚合物奈米粒子(LPNP)、基於蛋白及肽之奈米粒子、DNA樹狀體及基於DNA之奈米載體、碳奈米管、微粒子、微膠囊、無機奈米粒子、肽籠狀奈米粒子以及胞泌體(參見例如Riley及Vermerris, Nanomaterials (2017) 201, 7, 94;Thomas等人, Molecules (2019), 24, 3744;Bochicchio等人, (2021), 13, 198;Munagala等人, Cancer Letters (2021), 505, 58;Fu等人, (2020) NanoImpact 20, 100261;以及Neshat等人, (2020) Current Opin. Biotechnol. 66:1-10)。
若需要,奈米粒子可使用例如識別標靶細胞受體之靶向配體來靶向細胞類型。靶向配體之實例包括碳水化合物(例如半乳糖、甘露糖、葡萄糖及半乳甘露聚糖)、內源性配體(例如葉酸及轉鐵蛋白)、抗體(例如抗HER2抗體及hD1)及蛋白/肽(例如RGD、表皮生長因子及低密度脂蛋白)以及肽(例如Teo等人, Advanced Drug Delivery Reviews (2016), 98, 41)。
本申請案提供奈米粒子遞送dsDNA之用途。在不同實施例中,奈米粒子可遞送額外的治療性化合物;在不同奈米粒子中提供一或多種額外化合物;及在同一奈米粒子中提供dsDNA及一或多種額外化合物。所提及之化合物包括小分子及大分子(例如治療性蛋白及抗體)。
不同奈米粒子之產生以及核酸及其他化合物之併入係此項技術中熟知的,且在整個章節I的論述中藉由不同公開案例示。說明將核酸併入特定奈米粒子,諸如LPNP及LNP中之公開案之實例包括Teo等人, Advanced Drug Delivery Reviews (2016) 98, 41;Bochicchio等人, Pharmaceutics (2021) 13, 198;Mahzabin及Das, IJPSR (2021) 12(1), 65;以及Teixeira等人, (2017) Prog. Lipid Res. Oct;68:1-11 (其各自以全文引用之方式併入本文中)。可能影響小分子併入奈米粒子中之因素包括疏水性及可電離部分之存在(參見例如Nii及Ishii, International Journal of Pharmaceutics (2005) 298, 198;及Chen等人, Journal of Controlled Release (2018) 286, 46)。
I.A. 基於脂質之遞送系統
基於脂質之遞送系統包括使用脂質作為組分。基於脂質之遞送系統之實例包括脂質體、脂質奈米粒子、微胞以及細胞外囊泡。在某些實施例中,脂質奈米粒子包含一或多個內部有序脂質結構,此與例如包含完整脂質雙層及水性核心之脂質體不同。
「脂質奈米粒子」或「LNP」係指可用於遞送核酸分子且具有奈米級尺寸之基於脂質之囊泡。在不同實施例中,奈米粒子為約10 nm至約1000、約50 nm至約500 nm或約50 nm至約200 nm。
DNA為帶負電的。因此,LNP包含陽離子脂質,諸如胺基脂質可能係有利的。例示性胺基脂質描述於美國專利第9,352,042號、第9,220,683號、第9,186,325號、第9,139,554號、第9,126,966號、第9,018,187號、第8,999,351號、第8,722,082號、第8,642,076號、第8,569,256號、第8,466,122號及第7,745,651號,以及美國專利公開案第2016/0213785號、第2016/0199485號、第2015/0265708號、第2014/0288146號、第2013/0123338號、第2013/0116307號、第2013/0064894號、第2012/0172411號以及第2010/0117125號中,其均以全文引用之方式併入本文中。在某些實施例中,LNP包含胺基脂質,諸如WO2013/063468中所描述之任何胺基脂質,其以全文引用之方式併入本文中。
術語「陽離子脂質」及「胺基脂質」在本文中可互換地使用以包括具有一、二、三個或更多個脂肪酸或脂肪烷基鏈及pH可滴定胺基(例如烷基胺基或二烷基胺基)之脂質及其鹽。陽離子脂質通常在低於陽離子脂質之pKa之pH下質子化(亦即,帶正電),且在高於pKa之pH下為實質上中性的。陽離子脂質亦可為可滴定的陽離子脂質。在某些實施例中,陽離子脂質包含可質子化之三級胺(例如pH可滴定的)基團;C18烷基鏈,其中各烷基鏈可獨立地具有一或多個雙鍵、一或多個三鍵;以及頭基與烷基鏈之間的醚、酯或縮酮鍵。
陽離子脂質包括1,2-二亞油氧基-N,N-二甲基胺基丙烷(DLinDMA)、1,2-二次亞麻氧基-N,N-二甲基胺基丙烷(DLenDMA)、1,2-二-γ-亞麻氧基-N,N-二甲基胺基丙烷(γ-DLenDMA)、2,2-二亞油基-4-(2-二甲胺基乙基)-[1,3]-二氧雜環戊烷(DLin-K-C2-DMA,亦稱為DLin-C2K-DMA、XTC2及C2K)、2,2-二亞油基-4-二甲胺基甲基-[1,3]-二氧雜環戊烷(DLin-K-DMA)、二亞油基甲基-3-二甲基胺基丙酸酯(DLin-M-C2-DMA,亦稱為MC2)、4-(二甲胺基)丁酸(6Z,9Z,28Z,31Z)-三十七碳-6,9,28,31-四烯-19-基酯(DLin-M-C3-DMA,亦稱為MC3)、其鹽及其混合物。其他陽離子脂質亦包括1,2-二硬脂基氧基-N,N-二甲基-3-胺基丙烷(DSDMA)、1,2-二油烯基氧基-N,N-二甲基-3-胺基丙烷(DODMA)、2,2-二亞油基-4-(3-二甲基胺基丙基)-[1,3]-二氧雜環戊烷(DLin-K-C3-DMA)、2,2-二亞油基-4-(3-二甲胺基丁基)-[1,3]-二氧雜環戊烷(DLin-K-C4-DMA)、DLen-C2K-DMA、γ-DLen-C2K-DMA以及(DLin-MP-DMA) (亦稱為1-B11)。
其他陽離子脂質包括2,2-二亞油基-5-二甲胺基甲基-[1,3]-二㗁烷(DLin-K6-DMA)、2,2-二亞油基-4-N-甲基哌𠯤并-[1,3]-二氧雜環戊烷(DLin-K-MPZ)、1,2-二亞油基胺甲醯基氧基-3-二甲基胺基丙烷(DLin-C-DAP)、1,2-二亞油基氧基-3-(二甲基胺基)乙醯氧基丙烷(DLin-DAC)、1,2-二亞油基氧基-3-𠰌啉基丙烷(DLin-MA)、1,2-二亞油醯基-3-二甲基胺基丙烷(DLinDAP)、1,2-二亞油基硫基-3-二甲基胺基丙烷(DLin-S-DMA)、1-亞油醯基-2-亞油氧基-3-二甲基胺基丙烷(DLin-2-DMAP)、1,2-二亞油氧基-3-三甲基胺基丙烷氯化物鹽(DLin-TMA.CL)、1,2-二亞油醯基-3-三甲基胺基丙烷氯化物鹽(DLin-TAP.Cl)、1,2-二亞油氧基-3-(N-甲基哌𠯤基)丙烷(DLin-MPZ)、3-(N,N-二亞油基胺基)-1,2-丙二醇(DLinAP)、3-(N,N-二油烯基胺基)-1,2-丙烷二醇(DOAP)、1,2-二亞油基側氧基-3-(2-N, -二甲基胺基)乙氧基丙烷(DLin-Eg-DMA)、N,N-二油烯基-N,N-二甲基銨氯化物(DODAC)、N-(1-(2,3-二油烯基氧基)丙基)-N,N,N-三甲銨氯化物(DOTMA)、N,N-二硬脂基-N,N-二甲銨溴化物(DDAB)、N-(1-(2,3-二油醯氧基)丙基)-N,N,N-三甲銨氯化物(DOTAP)、3-(N-(N',N'-二甲基胺基乙烷)-胺甲醯基)膽固醇(DC-膽固醇)、N-(1,2-二肉豆蔻基氧基丙-3-基)-N,N-二甲基-N-羥基乙銨溴化物(DMRIE)、2,3-二油烯基氧基-N-[2(精胺-甲醯胺基)乙基]-N,N-二甲基-1-丙銨三氟乙酸鹽(DOSPA)、二(十八烷基)醯胺基甘胺醯基精胺(DOGS)、3-二甲胺基-2-(膽固醇-5-烯-3-β-氧基丁-4-氧基)-1-(順,順-9,12-十八碳二烯氧基)丙烷(CLinDMA)、2-[5'-(膽固醇-5-烯-3-β-氧基)-3'-氧雜戊氧基)-3-二甲基-1-(順,順-9',1-2'-十八碳二烯氧基)丙烷(CpLinDMA)、N,N-二甲基-3,4-二油烯基氧基苯甲胺(DMOBA)、1,2-N,N'-二油烯基胺甲醯基-3-二甲基胺基丙烷(DOcarbDAP)、1,2-N,N'-二亞油基胺甲醯基-3-二甲基胺基丙烷(DLincarbDAP)、地塞米松(dexamethasone)-精胺(DS)及經雙取代之精胺(D2S)或其混合物。
可使用多種市售陽離子脂質製劑,諸如LIPOFECTIN® (包括DOTMA及DOPE,可購自GIBCO/BRL),及LIPOFECTAMINE® (包含DOSPA及DOPE,可購自GIBCO/BRL)。
其他可使用之可電離脂質包括C12-200、306Oi10、MC3、CKK-E12、脂質5 (Lipid 5)、脂質9 (Lipid 9)、ATX-002、ATX-003以及Merck-32。美國專利公開案第2017/0367988號描述Merck-32。
在其他實施例中,陽離子脂質可以LNP之約10莫耳%至LNP之約85莫耳%,或LNP之約50莫耳%至LNP之約75莫耳%之量存在。
LNP可包含中性脂質。中性脂質可包含在生理pH下以不帶電或中性兩性離子形式存在之脂質物質。此類脂質包括二醯基磷脂醯膽鹼、二醯基磷脂醯乙醇胺、神經醯胺、神經鞘磷脂、二氫鞘磷脂、腦磷脂及腦苷脂。中性脂質之選擇通常由包括粒徑及穩定性之考慮因素來指導。在某些實施例中,中性脂質組分可為具有兩個醯基之脂質(例如二醯基磷脂醯膽鹼及二醯基磷脂醯乙醇胺)。
可獲得或可分離或合成具有不同鏈長及飽和度之多種醯基鏈基團之脂質。在某些實施例中,可使用含有飽和脂肪酸的脂質,該等飽和脂肪酸之碳鏈長度在C14至C22範圍內。在某些實施例中,使用具有碳鏈長度在C14至C22範圍內之單或雙不飽和脂肪酸的脂質。另外,可使用具有飽和及不飽和脂肪酸鏈之混合物之脂質。例示性中性脂質包括1,2-二油醯基-sn-甘油-3-磷脂醯基-乙醇胺(DOPE)、1,2-二硬脂醯基-sn-甘油-3-磷酸膽鹼(DSPC)、1-軟脂醯基-2-油醯基-sn-甘油-3-磷酸膽鹼(POPC)或磷脂醯膽鹼。中性脂質亦可由神經鞘磷脂、二氫鞘磷脂或具有其他頭基之磷脂(諸如絲胺酸及肌醇)構成。
在其他實施例中,提供中性脂質,該中性脂質可以脂質奈米粒子之約0.1重量%至LNP之約99重量%,或LNP之約5重量%至LNP之約15重量%,例如約1%、約2%、約3%、約4%、約5%、約6%、約7%、約8%、約9%、約10%、約15%、約20%、約25%、約30%、約35%、約40%、約45%、約50%、約55%、60%、約65%、約70%、約75%、約80%、約85%、約90%、約95%或約99%之量存在。
LNP可與諸如固醇及聚乙二醇之額外組分結合。固醇可賦予LNP流動性。如本文中所使用,「固醇」係指植物(植物固醇)或動物(動物固醇)來源之天然存在的固醇以及非天然存在之合成固醇,其特徵均係於固醇A-環之3-位置處具有羥基。適合之固醇包括習知地用於脂質體、脂質囊泡或脂質粒子製備領域之固醇,最普遍者係膽固醇。植物固醇包括菜油固醇、麥固醇及豆固醇。固醇亦包括經固醇修飾之脂質,諸如美國專利申請公開案2011/0177156中所描述之脂質。在所提供固醇之不同實施例中,固醇係以LNP之約1重量%至LNP之約80重量%或LNP之約10重量%至LNP之約25重量%的量存在。
聚乙二醇(PEG)為乙烯PEG重複單元與兩個末端羥基之線性水溶性聚合物。PEG係根據其分子量分類,例如PEG 2000具有約2,000道爾頓之平均分子量,且PEG 5000具有約5,000道爾頓之平均分子量。PEG可自Sigma Chemical Co.及其他公司購得且包括單甲氧基聚乙二醇(MePEG-OH)、單甲氧基聚乙二醇-丁二酸酯(MePEG-S)、單甲氧基聚乙二醇-丁二醯亞胺基丁二酸酯(MePEG-S-NHS)、單甲氧基聚乙二醇-胺(MePEG-NH2)、單甲氧基聚乙二醇-三氟乙磺酸酯(MePEG-TRES)以及單甲氧基聚乙二醇-咪唑基-羰基(MePEG-IM)。
在關於PEG之某些實施例中,PEG具有約550至約10,000道爾頓之平均分子量且視情況經烷基、烷氧基、醯基或芳基取代。在其他實施例中,PEG可在末端羥基位置處經甲基取代。在其他實施例中,PEG可具有約750至約5,000道爾頓,或約1,000至約5,000道爾頓,或約1,500至約3,000道爾頓,或約2,000道爾頓或約750道爾頓之平均分子量。
經PEG修飾之脂質包括美國專利第8,936,942號及第7,803,397號中所描述之PEG-二烷氧基丙基結合物(PEG-DAA)。經PEG修飾之脂質(或脂質-聚氧化乙烯結合物)可具有各種「錨定」脂質部分以將PEG部分固定於脂質囊泡之表面。適合的經PEG修飾之脂質的實例包括經PEG修飾之磷脂醯乙醇胺及磷脂酸;PEG-神經醯胺結合物(例如PEG-CerC14或PEG-CerC20),其描述於美國專利第5,820,873號中;經PEG修飾之二烷基胺及經PEG修飾之1,2-二醯基氧基丙-3-胺。在某些實施例中,經PEG修飾之脂質可為經PEG修飾之二醯基甘油及二烷基甘油。在某些實施例中,PEG的量可為LNP之約0.1重量%至LNP之約50重量%或LNP之約5重量%至LNP之約15重量%。
在關於LNP尺寸之其他實施例中,在囊封前,LNP之尺寸可在約10 nm至500 nm,或約50 nm至約200 nm,或75 nm至約125 nm之範圍內。
在關於LNP之某些實施例中,LNP係由Billingsley等人, Nano Lett. 2020, 20, 1578或Billingsley等人, 國際專利公開案第WO 2021/077066號描述(其均此以全文引用之方式併入本文中)。Billingsley等人及WO 2021/077066描述含有脂質錨定之PEG、膽固醇、磷脂及可電離脂質之LNP。在某些實施例中,LNP含有C14-4多元胺核心及/或具有約70 nm之粒徑。C14-4具有以下結構。
在某些實施例中,LNP由美國專利第10,493,031號、美國專利第10,682,374或WO2021/077066號所描述之陽離子脂質或脂肽構成(其各自以全文引用之方式併入本文中)。在某些實施例中,LNP含有陽離子脂質、基於膽固醇之脂質及/或一或多種經PEG修飾之脂質。在某些實施例中,LNP含有cKK-E12 (Dong等人, PNAS (2014) 111(11), 3955):
在某些實施例中,LNP包含cKK-E12之經修飾之形式(在本文中稱為「bCKK-E12」),其具有以下結構:
在某些實施例中,LNP包含如Sabnis等人, Molecular Therapy 2018, 26:6, 1509-1519 (其以全文引用之方式併入本文中)所描述之脂質1、2、3、4、5、6、7、8、9或10。在某些實施例中,LNP包含Sabnis等人所描述之脂質5、8、9、10或11。
Sabnis等人之脂質5具有以下結構:
Sabnis等人之脂質9具有以下結構:
其他可利用之脂質包括以下所描述之脂質:Roces等人, Pharmaceutics, 2020, 12,1095;Jayaraman等人, Angew. Chem. Int. Ed., 2012, 51, 8529-8533;Maier等人, www.moleculartherapy.org, 2013, 第21卷,第8期, 1570-1578;Liu等人, Adv. Mater. 2019, 31, 1902575,例如BAMEA-O16B;Cheng等人, Adv. Mater., 2018, 30, 1805308,例如5A2-SC8;Hajj及Ball, Small, 2019 15, 1805097,例如306Oi10;Du等人, 美國專利申請公開案第2016/0376224號;及Tanaka等人, Adv. Funct. Mater., 2020, 30, 1910575;其各自以全文引用之方式併入本文中。
在某些實施例中,以莫耳%計,LNP包含以下組分:約20%至65%之一或多種陽離子脂質、約1%至約50%之一或多種磷脂類脂質、約0.1%至10%之一或多種PEG結合之脂質,以及約0%至約70%之膽固醇;約20%至50%之一或多種陽離子脂質、約5%至約20%之一或多種磷脂類脂質、約0.1%至5%之一或多種PEG結合之脂質,以及約20%至約60%之膽固醇;在其他實施例中,磷脂類脂質為中性脂質;且磷脂類脂質為DOPE或DSPC。
在某些實施例中,以莫耳%計,LNP包含以下組分、基本上由以下組分組成或由以下組分組成:(1)約35%之cKK-E12 (進一步描述於上文及Dong等人, PNAS (2014) 111(11), 3955中);約2.5%之C14-PEG2000;約46.5%之膽固醇;及約16%之DOPE;或(2)約50%之脂質9 (進一步描述於上文及Sabnis等人, (2018) Molecular Therapy 26:6, 1509-1519中之脂質9);約1.5%之C14-PEG2000;約38.5%之膽固醇;以及約10%之DSPC。
在某些實施例中,以莫耳%計,LNP包含以下組分、基本上由以下組分組成或由以下組分組成:約35%之bCKK-E12;約2.5%之C14-PEG2000;約46.5%之膽固醇;及約16%之二油醯基磷脂醯乙醇胺(DOPE)。
I.B. 基於聚合物之奈米粒子
基於聚合物之遞送系統可由各種不同天然及合成材料製成。DNA及其他化合物可截留於聚合奈米粒子之聚合基質中或可吸附或結合於奈米粒子之表面上。用於核酸遞送之常用聚合物之實例包括聚(乳酸-共-乙醇酸) (PLGA)、聚乳酸(PLA)、聚(乙烯亞胺) (PEI)及PEI衍生物、聚葡萄胺糖、樹狀體、聚酸酐、聚己內酯、聚甲基丙烯酸酯、聚-L-離胺酸、普魯蘭(pullulan)、聚葡萄糖以及玻尿酸、聚-β-胺基酯(Thomas等人, (2019) Molecules 24, 3744)。
基於聚合物之奈米粒子可具有不同尺寸,其範圍為約1 nm至約1000 nm、約10 nm至約500 nm、約50 nm至約200 nm、約100 nm至約150 nm以及約150 nm或更小。
I.C. 脂質聚合物奈米粒子
脂質聚合物奈米粒子為提供脂質組分及聚合物組分之混合奈米粒子,且因此可視為LNP或LPNP。LPNP組態可提供外部聚合物及內部脂質或外部脂質及內部聚合物。兩種不同類型之材料的存在有助於設計奈米粒子以提供組分之延遲釋放。可視所遞送之材料來選擇不同脂質及聚合物組分(例如參見Teo等人, Advanced Drug Delivery Reviews (2016) 98, 41;Bochicchio等人, Pharmaceutics (2021) 13, 198;Mahzabin及Das, IJPSR (2021) 12(1), 65;以及Teixeira等人, (2017) Prog. Lipid Res. 10月;68:1-11)。
I.D. 基於蛋白及肽之奈米粒子
基於蛋白及肽之系統可採用多種不同蛋白及肽。蛋白之實例包括明膠及彈性蛋白。基於肽之系統可採用例如CPP。
CPP為潛在地能夠細胞內滲透以遞送治療性分子之短肽(6至30個胺基酸殘基)。大多數CPP主要由精胺酸及離胺酸殘基組成,使得其為陽離子性及親水性的,但CPP亦可為兩親媒性、陰離子性或疏水性的。CPP可衍生自天然生物分子(例如Tat,一種HIV-1蛋白),或經由合成方法獲得(例如聚-L-離胺酸、聚精胺酸) (Singh等人, Drug Deliv. 2018;25(1):1996-2006)。CPP之實例包括陽離子CPP (帶大量正電),諸如Tat肽、穿膜肽、魚精蛋白、聚-L-離胺酸及聚精胺酸;兩親媒性CPP (由不同來源構築之嵌合或融合肽,同時含有帶正電及負電之胺基酸序列),諸如運輸蛋白、VT5、牛抗菌肽-7 (Bac7)、富含脯胺酸之肽(PPR)、SAP (VRLPPP)
3、TP10、pep-1及MPG;親膜性CPP (同時呈現疏水性及兩親媒性,且同時包含大型芳族殘基及小型殘基),諸如H625、SPION-PEG-CPP及NP;及疏水性CPP (僅含有非極性模體或殘基),諸如SG3、PFVYLI、pep-7及纖維母細胞生長因子。
蛋白質及肽奈米粒子可以不同尺寸提供,例如範圍為約1 nm至約1000 nm、約10 nm至約500 nm、約50 nm至約200 nm、約100 nm至約150 nm或約150 nm或更小。
I.E. 肽籠狀奈米粒子
基於肽籠之遞送系統可由能夠組裝成形成限制性內部環境之籠狀結構之蛋白質材料產生。肽籠可包含自組裝以形成蛋白質籠之蛋白質殼(例如具有溶劑可天然地進入或可經由改變溶劑濃度、pH或平衡比率而使得溶劑可進入之內部空腔的結構)。蛋白質籠之單體可為天然存在或變異形式,包括胺基酸取代、插入及缺失(例如片段)。
可組裝不同類型之蛋白質「殼」及裝載有不同類型之材料。蛋白質籠可使用一或多種病毒外殼蛋白質(例如來自豇豆褪綠斑點病毒(Cowpea Chlorotic Mottle Virus)蛋白質外殼)以及非病毒蛋白質(例如美國專利第6,180,389號及第6,984,386號、美國專利申請案20040028694以及美國專利申請案20090035389,其各自以全文引用之方式併入本文中)產生。
衍生自非病毒蛋白質之蛋白質籠之實例包括:真核或原核衍生之鐵蛋白及缺鐵基蛋白,諸如12及24次單元鐵蛋白;及熱休克蛋白(HSP),諸如形成內部核心空間之24次單元熱休克蛋白類型、詹氏甲烷球菌(
Methanococcus jannaschii)之小型HSP、大腸桿菌(
E. coli)之十二聚體Dsp HSP;及MrgA蛋白。
蛋白質籠可具有不同核心尺寸,諸如在約1 nm至約1000 nm、約10 nm至約500 nm、約50 nm至約200 nm、約100 nm至約150 nm或約150 nm或更小之範圍內。
I.F. 胞泌體
胞泌體為用於遞送各種運載物(包括小分子、肽、蛋白質及核酸)之小型生物膜囊泡。胞泌體之尺寸通常在約30 nm至100 nm範圍內且可被細胞吸收及遞送其運載物。運載物可與胞泌體表面結構結合或可囊封於胞泌體雙層內。
可對胞泌體進行各種修飾以促進運載物遞送及細胞靶向。用於促進運載物遞送之修飾包括與運載物結合之結構,諸如蛋白質骨架及聚合物。用於細胞靶向之修飾包括靶向配位體及修飾表面電荷。描述用於遞送不同運載物之胞泌體之產生、修飾及使用的公開案包括Munagala等人, Cancer Letters (2021), 505, 58;Fu等人, (2020) NanoImpact 20, 100261;及Dooley等人, (2021) Molecular Therapy 29(5), 1729 (其各自以引用之方式併入本文中)。
II. 感染性疾病治療
感染性疾病治療係關於病原體,諸如病毒、細菌、真菌及寄生蟲。由dsDNA之奈米粒子遞送提供的免疫增強可幫助增強免疫系統以攻擊病原體。在某些實施例中,dsDNA之奈米粒子遞送係與可增強宿主免疫系統之一或多種組分及/或靶向特定病原體之治療劑組合使用;及與疫苗組合使用。
多種治療可用於靶向病原體,包括小分子、蛋白質、多肽、抗體及核酸。核酸治療可包括例如提供編碼抗原、免疫組分、治療蛋白或靶向病原體或病原體組分之功能性核酸的轉殖基因。靶向病原體核酸之功能性核酸之實例包括短髮夾RNA (short hair pin RNA;shRNA)、小型干擾RNA (siRNA)、微型RNA (miRNA)、RNAi、核糖核酸酶、反義RNA、成簇規律間隔短回文重複序列(CRISPR)/Cas9構築體、鋅指核酸酶(ZFN)及/或轉錄活化因子樣效應核酸酶(TALEN)。
II.A. 抗病毒劑
dsDNA之奈米粒子遞送可用於針對不同感染性病毒之治療。在某些實施例中,所治療之病毒係選自由以下組成之群:冠狀病毒(例如229E、NL63、OC43、HKU1、MERS-CoV、SARS-CoV及SARS-CoV-2)、C型肝炎病毒(HCV)、B型肝炎病毒(HBV)、單純疱疹病毒(HSV)、人類免疫缺乏病毒(HIV)、人類乳頭瘤病毒(HPV)、流感病毒、呼吸道融合病毒(RSV)、人類巨細胞病毒(HCMV)以及水痘帶狀疱疹病毒(VZV)。在其他實施例中,dsDNA之奈米粒子遞送係與抗病毒劑組合使用。FDA批准用於治療不同病毒之抗病毒劑之實例提供於Rao等人, (2021) International Journal of Biological Macromolecules 172: 524-541 (其以全文引用之方式併入本文中)中。表1提供可與dsDNA之奈米粒子遞送組合使用的經FDA批准或授權之抗病毒劑之實例。
表1
II.B. 抗細菌劑
病毒 | 抗病毒劑 |
冠狀病毒: 229E NL63 OC43 HKU1 MERS-CoV SARS-CoV SARS-CoV-2 | VEKLURY® (瑞德西韋(remdesivir))、PAXLOVID™ (尼馬瑞韋(nirmatrelvir)及利托那韋(ritonavir)錠劑)、REGEN-COV® (卡斯瑞韋單抗(casirivimab)及依米得韋單抗(imdevimab))、索曲韋單抗(sotrovimab)、巴尼韋單抗(bamlanivimab)、艾特森韋單抗(etesevimab)以及莫那比拉韋(molnupiravir) |
HBV | 干擾素α-2b (INT2B)、拉米夫定(lamivudine) (3TC)、阿德福韋酯(adefovir dipivoxil) (ADE)、恩替卡韋(entecavir) (ENT)、聚乙二醇化干擾素α-2a (PEG2a)、替比夫定(telbivudine) (LdT)、富馬酸替諾福韋酯(tenofovir disoproxil fumarate) (TDF)以及富馬酸替諾福韋艾拉酚胺(tenofovir alafenamide fumarate) (TAF) |
HCMV | 更昔洛韋鈉(Ganciclovir sodium) (GCV)、膦甲酸鈉(foscarnet sodium) (PFA)、西多福韋(cidofovir) (CID)、福米韋生鈉(fomivirsen sodium) (FMV)、纈更昔洛韋鹽酸鹽(valganciclovir hydrochloride) (VALG)以及萊特莫韋(letermovir) (LET) |
HCV | 司美匹韋(Simeprevir);索非布韋(sofosbuvir);雷迪帕韋(ledipasvir)/索非布韋;達薩布韋(dasabuvir)/奧比他韋(ombitasvir)/帕利瑞韋(paritaprevir)/利托那韋(ritonavir);達卡他韋(daclatasvir)/阿那匹韋(asunaprevir);奧比他韋/帕利瑞韋/利托那韋;達卡他韋/索非布韋;艾爾巴韋(elbasvir)/格佐匹韋(grazoprevir);索非布韋/維帕他韋(valpatasvir);索非布韋/維帕他韋/伏西瑞韋(voxilaprevir);及格卡匹韋(glecaprevir)/匹布他韋(pibrentasvir) |
HIV | 齊多夫定(AZT)、地達諾新(Didanosine) (ddI)、紮西他濱(Zalcitabine) (ddC)、司他夫定(Stavudine) (d4T)、拉米夫定(3TC)、甲磺酸沙奎拉韋(Saquinavir mesylate) (SQV)、硫酸茚地那韋(Indinavir sulfate) (IDV)、利托那韋(RTV)、奈韋拉平(Nevirapine)(NVP)、拉米夫定(3TC)/齊多夫定(AZT)、甲磺酸地拉韋啶(Delavirdine mesylate) (DLV)、甲磺酸奈非那韋(Nelfinavir mesylate) (NFV)、依法韋侖(Efavirenz) (EFV)、硫酸阿巴卡韋(Abacavir sulfate) (ABC)、安普那韋(Amprenavir) (APV)、洛匹那韋(LPV)/利托那韋(RTV)、硫酸阿巴卡韋(ABC)/拉米夫定(3TC)/齊多夫定(AZT)、富馬酸替諾福韋酯(TDF)、恩曲他濱(Emtricitabine) (FTC)、恩夫韋地(Enfuvirtide) (T20)、福沙那偉鈣(Fosamprenavir calcium) (FPV)、硫酸阿紮那韋(Atazanavir sulfate) (ATV)、硫酸阿巴卡韋(ABC)/拉米夫定(3TC)、恩曲他濱(FTC)/富馬酸替諾福韋酯(TDF)、替拉那韋(Tipranavir) (TPV)、依法韋侖(EFV)/恩曲他濱(FTC)/富馬酸替諾福韋酯(TDF)、乙醇化地瑞那韋(Darunavir ethanolate) (DRV)、雷特格韋鉀(Raltegravir potassium) (RAL)、馬拉維若(Maraviroc) (MVC)、依曲韋林(Etravirine) (ETR)、恩曲他濱(FTC)/鹽酸利匹韋林(Rilpivirine hydrochloride) (RPV)、可比司他(COBI)/埃替拉韋(elvitegravir) (EVG)/恩曲他濱(FTC)/富馬酸替諾福韋酯(TDF)、度魯特韋(Dolutegravir)鈉(DTG)、硫酸阿巴卡韋(ABC)/度魯特韋鈉(DTG)/拉米夫定(3TC)、埃替拉韋(EVG)、拉米夫定(3TC)/雷特格韋(RAL)、硫酸阿紮那韋(ATV)/可比司他(COBI)、可比司他(COBI)/埃替拉韋(EVG)/恩曲他濱(FTC)/富馬酸替諾福韋艾拉酚胺(TAF)、可比司他(COBI)/乙醇化地瑞那韋(DRV)、恩曲他濱(FTC)/富馬酸替諾福韋艾拉酚胺(TAF)、恩曲他濱(FTC)/鹽酸利匹韋林(RPV)/富馬酸替諾福韋艾拉酚胺(TAF)、度魯特韋(DTG)/利匹韋林(RPV)、比克替拉韋(Bictegravir;BIC)/恩曲他濱(FTC)/富馬酸替諾福韋艾拉酚胺(TAF)、拉米夫定(3TC)/富馬酸替諾福韋酯(TDF)、多拉韋林(Doravirine) (DOR)/拉米夫定(3TC)/富馬酸替諾福韋酯(TDF)、多拉韋林(DOR)、依法韋侖(EFV)/拉米夫定(3TC)/富馬酸替諾福韋酯(TDF)、依法韋侖(EFV)/拉米夫定(3TC)/富馬酸替諾福韋酯(TDF)、地瑞那韋(DRV)/可比司他(COBI)/恩曲他濱(FTC)/富馬酸替諾福韋艾拉酚胺(TAF)、伊巴珠單抗-uiyk (IBA)以及度魯特韋(DTG)/拉米夫定(3TC) |
HSV | 碘苷(Idoxuridine) (IDU)、阿糖腺苷(Vidarabine) (VDR)、三氟胸苷(Trifluridine) (TFT)、阿昔洛韋(Acyclovir) (ACY)、膦甲酸鈉(PFA)、泛昔洛韋(Famciclovir) (FAM)、鹽酸萬乃洛韋(Valacyclovir hydrochloride) (VAL)、噴昔洛韋(Penciclovir) (PEN)、二十二烷醇(DOC)、溴夫定(Brivudine) (BVDU)以及阿昔洛韋/氫皮質酮(ACY) |
HPV | 干擾素α-2b (INT2B)、干擾素α-N3 (INTN3)、普達非洛(Podofilox) (PDX)、咪喹莫特(Imiquimod) (IMQ)以及賽兒茶素(Sinecatechin) (SIN) |
流感 | 阿曼他丁(Amantadine)、利巴韋林(Ribavirin) (RBV)、金剛烷乙胺(RIM)、紮那米韋(Zanamivir) (ZAN)、奧司他韋(Oseltamivir) (OTV)、辛酸拉尼米韋(Laninamivir) (LO)、帕拉米韋(Peramivir) (PER)、法匹拉韋(Favipiravir)以及巴洛沙韋酯(Baloxavir marboxil;BXM) |
RSV | 利巴韋林(RBV)、RSV-IGIV以及帕利珠單抗(Palivizumab) (PZ) |
VSV | 阿糖腺苷(VDR)、水痘帶狀疱疹免疫球蛋白(VZIG)、阿昔洛韋(ACY)、溴夫定(BVDU)以及水痘帶狀疱疹免疫球蛋白(VariZIG) |
dsDNA之奈米粒子遞送可用於針對不同感染性細菌之治療。在某些實施例中,所治療之細菌或細菌性疾病係選自布氏桿菌病(brucellosis)、曲狀桿菌感染(campylobacter infections)、貓抓病、霍亂、大腸桿菌感染、淋病、克留氏菌(klebsiella)、腸桿菌(enterobacter)及鋸桿菌(serratia)感染、退伍軍人症桿菌感染(legionella infection)、腦膜炎球菌感染、百日咳、瘟疫、假單胞菌屬感染、沙氏桿菌(salmonella)感染、志賀桿菌病(shigellosis)、傷寒熱、兔熱病、炭疽病、白喉症、腸球菌感染、丹毒絲菌病(erysipelothricosis)、李氏菌病(listeriosis)、奴卡菌病(nocardiosis)、肺炎球菌感染、結核病、結核桿菌(
Mycobacterium tuberculosis)、葡萄球菌感染、鏈球菌感染、貝耶病(bejel)、莓疹病(yaws)、品他病(pinta)、勾端螺旋體病(leptospirosis)、萊姆病(lyme disease)、大鼠咬熱、回歸熱、梅毒、放線菌病、類桿菌屬感染、肉毒中毒、梭菌感染以及破傷風。
在其他實施例中,dsDNA之奈米粒子遞送係與一或多種抗菌劑組合使用;且一或多種抗菌劑係選自胺基糖苷類(例如阿米卡星(amikacin)、建它黴素(gentamicin)、康黴素(kanamycin)、新黴素(neomycin)、奈替黴素(netilmicin)、妥布黴素(tobramycin)、巴龍黴素(paromomycin)以及鏈黴素(streptomycin))、安莎黴素(ansamycin) (例如利福昔明(rifaximin))、碳青黴烯(例如厄他培南(ertapenem)、多尼培南(doripenem)、亞胺培南(imipenem)/西司他丁(cilastatin)以及美羅培南(meropenem));頭孢菌素類(例如頭孢卓西(cefadroxil)、頭孢若林(cefazolin)、頭孢拉定(cephradine)、頭孢匹林(cephapirin)、塞吩頭孢菌素(cephalothin)、頭孢胺苄(cefalexin)、頭孢克洛(cefaclor)、頭孢西丁(cefoxitin)、西弗特坦(cefotetan)、頭孢每他唑(cefmetazole)、頭孢尼西(cefonicid)、羅拉碳頭孢(loracarbef)、頭孢丙烯(cefprozil)、頭孢呋辛(cefuroxime)、頭孢克肟(cefixime)、頭孢地尼(cefdinir)、頭孢托侖(cefditoren)、頭孢噻肟(cefotaxime)、頭孢泊肟(cefpodoxime)、頭孢他啶(ceftazidime)、頭孢布烯(ceftibuten)、頭孢唑肟(ceftizoxime)、拉氧頭孢(moxalactam)、頭孢克松(ceftriaxone)、頭孢吡肟(cefepime)、頭孢洛林酯(ceftaroline fosamil)以及頭孢吡普(ceftobiprole));林可醯胺類(例如克林達黴素(clindamycin)及林可黴素(lincomycin)):脂肽類(例如達托黴素(daptomycin));糖肽類(例如萬古黴素(vancomycin)、替考拉寧(teicoplanin)、特拉萬星(telavancin)、達巴萬星(dalbavancin)以及奧利萬星(oritavancin));巨環內酯類(例如亞藥索黴素(azithromycin)、紅黴素(erythromycin)及克拉黴素(clarithromycin)、羅紅黴素(roxithromycin)、泰利黴素(telithromycin)、螺旋黴素(spirmycin)及非達黴素(fidaxomicin));單環內醯胺類(例如胺曲南(aztreonam));硝基呋喃類(例如呋喃唑酮(furazolidone)及呋喃妥因(nitrofurantoin));㗁唑啶酮(利奈唑胺(linezolid)、泊斯唑胺(posizolid)、雷德唑胺(radezolid)及特地唑胺(torezolid))、青黴素類(penicillins)(例如青黴素(penicillin)、阿莫西林(amoxicillin)、安比西林(ampicillin)、氟氯西林(flucloxacillin)、克拉維酸(co-amoxiclav)、氟氯西林以及苯氧基甲基青黴素)、多肽類(例如桿菌素(bacitracin)、黏菌素(colistin)及多黏菌素B (polymyxin B));喹啉酮類及氟喹諾酮類(例如塞普沙星(ciprofloxacin)、依諾沙星(enoxacin)、發替沙星(fatifloxacin)、吉米沙星(gemifloxcin)、洛美沙星(lomefloxacin)、莫西沙星(moxifloxacin)、那氟沙星(nadifloxacin)、㖠啶酮酸(nalidixic acid)、諾氟沙星(norfloxacin)、氧氟沙星(ofloxacin)以及左氧氟沙星(levofloxacin));磺醯胺類(例如磺胺米隆(mafenide)、磺胺醋醯胺(sulfacetamide)、磺胺嘧啶(sulfadiazine)、磺胺二甲氧𠯤(sulfadimethoxine)、磺胺甲基異㗁唑(sulfamethoxazole)、柳氮磺胺吡啶(sulfasalazine)、磺胺異㗁唑(sulfisoxazole)以及三甲氧苄二胺嘧啶(trimethoprim)-磺胺甲基異㗁唑);泰格環黴素(tigecycline);四環素類(例如四環素、去氧羥四環素、去甲基氯四環素、美他環素(metacycline)、米諾四環素(minocycline)、土黴素(oxytetracycline)以及賴甲環素(lymecycline));氯黴素(chloramphenicol)、夫西地酸(fusidic acid)、硝基呋喃妥因(nitrofurantoin)、三甲氧苄二胺嘧啶、克林達黴素、磺醯胺及三甲氧苄二胺嘧啶、甲硝唑(metronidazole)及替硝唑(tinidazole)。可使用各種組合,例如結核病(TB)可使用四藥物組合:1)利福平(rifampin),2)異菸酸酊(isoniazid),3)吡𠯤甲醯胺,及4)乙胺丁醇(ethambutol),或使用貝達喹啉(bedaquiline)、普瑞瑪尼(pretomanid)及利奈唑胺之三藥物方案來治療。
II.C. 抗真菌劑
dsDNA之奈米粒子遞送可用於針對不同真菌感染之治療。真菌感染之實例包括麴菌病(aspergillosis)、念珠菌病(candidiasis)及白黴菌病(mucormycosis);且可用於治療真菌感染之治療劑之實例包括氟康唑(fluconazole)、伊曲康唑(itraconazole)、伏立康唑(voriconazole)、泊沙康唑(posaconazole)、艾沙康唑(isavuconazole)、卡泊芬淨(caspofungin)、米卡芬淨(micafungin)、阿尼芬淨(anidulafungin)、兩性黴素B (amphotericin B)、氟胞嘧啶(flucytosine)以及阿尼芬淨(參見Houšť等人, (2020) Metabolites 10, no. 3: 106,其以全文引用之方式併入本文中)。
II.D. 抗寄生蟲劑
dsDNA之奈米粒子遞送可用於針對不同寄生蟲感染,諸如原蟲、蠕蟲、線蟲及絛蟲之治療。抗寄生蟲劑之實例及抗寄生蟲劑之用途包括:阿苯達唑(albendazole) (例如治療羅阿絲蟲病(loiasis)、絲蟲病(filariasis)、梨形鞭毛蟲病(giardiasis)、囊蟲病(cysticercosis)、蛔蟲症(toxocariasis)、包蟲病(echinococcosis)以及土壤傳播之蠕蟲病(helminthiases));兩性黴素B (例如治療利什曼體病(leishmaniasis));苄硝唑(benznidazole) (例如治療克氏錐蟲(
Trypanosoma cruzi));二乙碳醯𠯤(diethylcarbamazine )(例如治療淋巴絲蟲病(lymphatic filariasis)、羅阿絲蟲病、熱帶肺嗜酸性球增多症以及蟠尾絲蟲病(onchocerciasis));甲苯達唑(mebendazole) (例如治療包蟲病、蛔蟲症及旋毛蟲病(trichinellosis));甲硝噠唑(metronidazole)(例如治療變形蟲病(amoebiasis)及梨形鞭毛蟲病);米替福新(miltefosine) (例如治療利什曼體病);莫西菌素(moxidectin)(例如治療蟠尾絲蟲病);硝呋替莫(nifurtimox) (例如治療錐蟲病(trypanosomiasis));硝唑尼特(nitazoxanide)(例如治療變形蟲病及梨形鞭毛蟲病);奧沙尼喹(oxamniquine)(例如治療血吸蟲病(schistosomiasis));巴龍黴素(例如治療內臟利什曼體病、梨形鞭毛蟲病、腸變形蟲病(intestinal amebiasis)以及隱孢子蟲病(cryptosporidiosis));噴他脒(pentamidine)(例如治療布氏甘比亞錐蟲(
T. brucei gambiense)及卡氏肺孢子蟲(
Pneumocystis carinii));五價銻(例如治療內臟、皮膚及黏膜皮膚的利什曼體病);吡喹酮(praziquantel) (例如治療血吸蟲病、腸吸蟲感染、肝吸蟲感染、肺吸蟲病(paragonimiasis)及囊蟲病);嘧啶甲胺(pyrimethamine)(例如治療弓蟲病(toxoplasmosis));蘇拉明(surami) (例如治療布氏甘比亞錐蟲HAT);磺胺嘧啶(例如弓蟲病);替硝唑(例如梨形鞭毛蟲病、變形蟲病及滴蟲病(trichomoniasis));以及三氯苯咪唑(triclabendazole)(例如治療片吸蟲病(fascioliasis)及肺吸蟲病) (參見Jatali及Zeitlinger (2020) Clinical Pharmacokinetics 59:827-847,其以全文引用之方式併入本文中)。
II.E. 檢查點抑制劑
免疫細胞上之免疫檢查點分子(諸如PD-1及CTLA4)之上調在急性感染期間發生,削弱宿主免疫系統(Wykes及Lewin (2018) Nat. Rev. Immunol. 18(2): 91-104)。檢查點抑制劑可用於降低入侵生物體下調宿主免疫系統之能力。此外,發現用於癌症治療之檢查點抑制劑在管理病毒感染方面提供益處(Gambichler等人, (2020) J. ImmunoTherapy of Cancer 8;e001145.)。
已批准將不同檢查點抑制劑用於癌症適應症,諸如阿特珠單抗(atezolizumab)、阿維魯單抗(avelumab)、西米普利單抗(cemiplimab)、多塔利單抗(dostarlimab)、度伐魯單抗(durvalumab)、伊匹單抗(ipilimumab)、納武單抗(nivolumab)以及派姆單抗(pembrolizumab)。在某些實施例中,此類抑制劑用於本文所提供之方法中以治療感染性疾病。其他檢查點抑制劑正在進行臨床試驗,且在某些實施例中,用於本文所提供之方法中以治療感染性疾病(參見例如Darvin等人,
Experimental & Molecular Medicine(2018) 50:165,其以全文引用之方式併入本文中)。
在某些實施例中,感染性疾病之治療包含投與檢查點抑制劑作為治療劑。在其他實施例中,感染性疾病係選自冠狀病毒(諸如SARS-CoV-2)、HIV、HBV、SIV、HCV、流感、TB、李氏菌(listeria)、瘧疾、弓形蟲以及利什曼原蟲(leishmania);檢查點抑制劑係靶向PD-1/PD-L1路徑之抗體;檢查點抑制劑係選自阿特珠單抗、阿維魯單抗、西米普利單抗、多塔利單抗、度伐魯單抗、伊匹單抗、納武單抗以及派姆單抗;及/或檢查點抑制劑係與直接靶向感染性生物體之抗感染劑(例如表1)組合使用。
II.F 疫苗
dsDNA之奈米粒子遞送可與靶向感染性疾病之多種不同類型的疫苗組合使用。不同類型之疫苗之實例包括活的減毒、全生物體殺傷、類毒素、次單元(例如經純化之蛋白質、重組蛋白質、多醣及肽)、病毒樣粒子、外膜囊泡、蛋白質-多醣結合物、病毒載體、核酸、細菌引導以及抗原呈現細胞(Pollard及Bijker (2021) Nat Rev Immunol 21, 83-100)。在某些實施例中,與dsDNA之奈米粒子遞送組合使用之疫苗係選自不活化疫苗(例如A型肝炎、流感及狂犬病);減毒活疫苗(例如麻疹、流行性腮腺炎、風疹、輪狀病毒、水痘、帶狀疱疹或黃熱);信使RNA (mRNA)疫苗(例如SARS-CoV-2);次單元、重組型、多醣及結合物疫苗(例如b型流感嗜血桿菌(Haemophilus influenzae type b)、B型肝炎、人類乳頭狀瘤病毒、百日咳(DTaP組合之疫苗之一部分)、肺炎球菌病(例如多醣及經結合之多醣疫苗)、腦膜炎球菌病及帶狀疱疹;類毒素疫苗(亦即,白喉症及破傷風);以及病毒載體疫苗(例如SARS-CoV-2、埃博拉(ebola)、茲卡(Zika)及流感)。其他疫苗以及關於不同疫苗之使用之指導提供於例如Plotkin's Vaccine, 第7版, (2018), Plotkin等人編;以及Epidemiology and Prevention of Vaccine-Preventable Disease (2021) 第14版, hypertext transfer protocol://www.cdc.gov/vaccines/pubs/pinkbook/index.html中,其均以全文引用之方式併入本文中。
在某些實施例中,疫苗為(1)基於肽之疫苗,(2) DNA疫苗,或(3) RNA疫苗。在某些實施例中,dsDNA之奈米粒子遞送係與疫苗組合使用,該疫苗與一或多種抗病毒劑(例如表1中所提供之抗病毒劑)、一或多種抗菌劑(例如提供於上文章節II.B中之抗菌劑)及/或一或多種檢查點抑制劑(例如阿特珠單抗、阿維魯單抗、西米普利單抗、多塔利單抗、度伐魯單抗、伊匹單抗、納武單抗以及派姆單抗)組合。
III. 醫藥組合物
適當的醫藥組合物可基於所投與之化合物及投與途徑來選擇。醫藥組合物含有一或多種活性組分以及醫藥學上可接受之載劑。所提及之「醫藥學」或「醫藥學上可接受」係指適用於投藥及/或儲存之無毒性分子實體。醫藥組合物可包含超過一種治療活性劑。
醫藥學上可接受之載劑之實例包括無毒(以所用量)固體、半固體或液體填充劑、稀釋劑、囊封材料或調配物。關於小分子、疫苗、蛋白質及抗體之調配物的指引可見於例如Remington (2020) The Science and Practice of Pharmacy, 第23版;D'Amico等人, (2021) Drug Deliv. and Transl. Res. 11, 353-372;以及Strickley及Lambert (2021) Journal of Pharmaceutical Sciences 110: 2590-2608中。
醫藥組合物之形式、投與途徑、劑量及方案視所治療之病狀(諸如疾病之嚴重程度)、患者之年齡、體重及性別而定。醫藥組合物可經調配以用於不同投與模式,諸如用於局部、經口、鼻內、非經腸、眼內、靜脈內、肌內或皮下投與。
在一個實施例中,醫藥組合物含有能夠注射至個體中之調配物。可注射調配物組分之實例包括等張、無菌、鹽水溶液(例如,磷酸單鈉或磷酸二鈉、氯化鈉、氯化鉀、氯化鈣或氯化鎂及此類鹽之混合物)、緩衝鹽水、糖(例如,右旋糖)及注射用水。醫藥組合物包括乾燥(例如冷凍乾燥)組合物,其在視情況添加滅菌水或生理鹽水後,實現可注射溶液復原。用於投與之劑量可根據各種參數,諸如投與模式、相關病理學及治療持續時間進行調節。
其他醫藥學上可接受之形式包括用於經口投與之錠劑或其他固體,包括定時釋放膠囊。
IV. 投藥及治療
可基於所選擇之化合物、醫藥組合物及所治療之適應症選擇投與途徑及治療方案。投與途徑包括局部、經口、鼻內、非經腸、眼內、靜脈內、肌內及皮下投與。關於小分子、疫苗、蛋白質及抗體之調配物及投藥的指導可見於例如Remington (2020) The Science and Practice of Pharmacy 第23版;D'Amico等人, (2021) Drug Deliv. and Transl. Res. 11, 353-372;以及Strickley及Lambert (2021) Journal of Pharmaceutical Sciences 110: 2590-2608中。舉例而言,在經批准之治療劑(例如參見表1)的產品說明書中可找到其他指引。
較佳劑量係提供實現可偵測之作用之有效量。一般而言,小分子將以每公斤體重0.0001與10 mg之間或0.001至1 mg之劑量投與。一般而言,大型化合物(諸如抗體及多肽)之劑量可在約10奈克/公斤至約100毫克/公斤體重或約1毫克/公斤/天至10毫克/公斤/天之範圍內變化。
dsDNA之有效劑量足以在宿主免疫系統中提供可偵測之作用且應增強疫苗接種或治療。一般而言,dsDNA係以0.0001 mg/kg至2 mg/kg之範圍投與。在某些實施例中,dsDNA係以0.0001至0.001 mg/kg、0.001至0.01 mg/kg、0.01至0.1 mg/kg或0.1至2 mg/kg之範圍投與。
所提及之「治療(treatment)」或「治療(treat)」係指對患有疾病或病症之患者的預防性治療及治療性治療。預防性治療提供減少的感染疾病或病症之可能性或降低疾病或病症之潛在嚴重程度。治療性治療提供至少一種與疾病或病症相關之症狀或病因的臨床上有意義的改善。
因此,治療可包括向罹患感染疾病或病症之風險的個體、疑似已感染疾病或病症之個體以及患病或已診斷患有疾病或病症之個體投藥。治療病原體之方法能夠減少病原體之擴散、減少病原體之數量、減少感染之可能性、預防感染及疾病及/或抑制病原體生長。疫苗接種方法提供能夠靶向入侵病原體之免疫反應且包括例如降低之病原體感染之可能性或嚴重程度;預防感染及疾病;及/或刺激巨噬細胞、T細胞及/或B細胞(引起包括中和抗體之抗體產生)。
術語「改善(ameliorate)」及「改善(amelioration)」係指疾病或病症症狀或潛在細胞反應之可偵測或可量測之改良。可偵測或可量測之改良包括疾病或病症或由疾病或病症引起或與疾病或病症相關之併發症之發生率、出現率、嚴重程度、進展或持續時間之主觀或客觀減輕、減少、抑制、遏制、限制或控制,或疾病或病症之症狀或潛在病因或結果之改良,或疾病或病症之逆轉。
術語「有效量」及「足夠量」係獲得所需作用所需之量。有效量可以單次或多次劑量形式提供以實現治療性或預防性作用。
有效量可單獨或與另一治療劑、化合物、組合物、治療、方案或治療方案組合投與。該量可例如基於個體之需要、所治療之疾病或病症的類型、狀態及嚴重程度或副作用而按比例增加。
一或多種治療劑及包含dsDNA之奈米粒子之投藥可一起或分開進行。在某些實施例中,治療劑(例如檢查點抑制劑、表1化合物及/或疫苗)及包含dsDNA之奈米粒子係同時投與;在間隔約15分鐘內、在間隔約30分鐘內、在間隔約60分鐘內、在間隔約2小時內、在間隔約4小時內、在間隔約6小時內、在間隔約12小時內、在間隔約一天內、在間隔約2天內、在間隔約3天內、在間隔約4天內、在間隔約5天內、在間隔約一週內或在間隔約2週內投與。在一些情況下,在同時投與之情況下,組合物可包含(i)包含DNA之奈米粒子,及(ii)一或多種治療劑(例如檢查點抑制劑、表1化合物及/或疫苗)兩者;或(i)包含DNA之奈米粒子及(ii)一或多種治療劑(例如檢查點抑制劑、表1化合物及/或疫苗)可以獨立組合物形式提供。
V
. 套組
本文進一步提供一種套組,其至少在獨立容器中提供:(a)有效量的包含dsDNA之奈米粒子;及(b)有效量的治療劑或疫苗。套組組分進一步描述於例如上文章節I至IV中。套組亦可提供用於根據本文所描述之方法進行投藥之說明書。
VI. 其他態樣及實施例
其他態樣及實施例包括:
第一態樣描述一種治療個體中之感染性疾病的方法,其包含向個體投與:(a)包含雙股DNA (dsDNA)之奈米粒子,其中dsDNA包含雙股區;及(b)疫苗或治療劑。較佳地,dsDNA包含長度為至少45個鹼基對之dsDNA區。
實施例1進一步描述第一態樣,其中個體患有病原性感染。在其他實施例中,感染為細菌感染、病毒感染、真菌感染或寄生蟲感染。
實施例1a進一步描述第一態樣及實施例1,其中(i)該奈米粒子為脂質奈米粒子且該dsDNA為非編碼的;(ii)該奈米粒子為脂質奈米粒子且該dsDNA缺乏可操作地連接至用於該個體中之表現之編碼區的啟動子;(iii)該治療劑為檢查點抑制劑;及/或(iv)提供至少兩種不同之治療劑。
實施例2進一步描述第一態樣以及實施例1及1a,其中該方法包含向個體投與疫苗。在其他實施例中,疫苗為活的減毒、全生物體殺傷、類毒素、次單元(例如經純化之蛋白質、重組蛋白質、多醣及肽)、病毒樣粒子、外膜囊泡、蛋白質-多醣結合物、病毒載體、核酸、細菌引導或抗原呈現細胞;疫苗包含蛋白質抗原;疫苗包含多醣抗原;且疫苗為多醣-多肽結合物疫苗。
所提及之特定實施例包括提及其中所提供之其他實施例。舉例而言,在第二實施例中提及第一實施例提供對第一實施例中所提供之所有實施例,包括其中所提供之其他實施例之參考。
實施例3進一步描述第一態樣以及實施例1、1a及2,其中疫苗係選自A型肝炎、流感及狂犬病不活化疫苗;麻疹、流行性腮腺炎、風疹、輪狀病毒、水痘、帶狀疱疹或黃熱減毒活疫苗;SARS-CoV-2 mRNA疫苗;b型流感嗜血桿菌、B型肝炎、人類乳頭狀瘤病毒、DTaP、腦膜炎球菌病、帶狀疱疹,疫苗(其為次單元、重組型、多醣、多肽或結合物疫苗);白喉及破傷風類毒素疫苗;以及SARS-CoV-2、埃博拉、茲卡及流感病毒載體疫苗。
實施例4進一步描述第一態樣及實施例1至3 (包括1a)中之任一者,其中該方法包含投與治療劑。可投與超過一種類型之治療劑。在其他實施例中,治療劑為小分子、蛋白質、多肽、抗體或核酸。
實施例5進一步描述第一態樣及實施例1至4 (包括1a)中之任一者,其中治療劑為抗病毒劑。在其他實施例中,個體感染引起感染性疾病之病毒,抗病毒感染係如表1中所提供,及/或抗病毒劑係如表1中所提供。
實施例6進一步描述第一態樣及實施例1至4 (包括1a)中之任一者,其中治療劑為抗菌劑。在其他實施例中,個體感染引起感染性疾病之細菌,感染性疾病係如上文章節II.B.中所提供及/或抗菌劑係如上文章節II.B.中所描述。
實施例7進一步描述第一態樣及實施例1至4 (包括1a)中之任一者,其中治療劑為抗真菌劑。在其他實施例中,個體感染引起感染性疾病之真菌,感染性疾病係如上文章節II.C.中所提供及/或抗真菌劑係如上文章節II.C.中所描述。
實施例8進一步描述第一態樣及實施例1至4 (包括1a)中之任一者,其中治療劑為抗寄生蟲劑。在其他實施例中,個體感染引起感染性疾病之寄生蟲,感染性疾病係如上文章節II.D.中所提供及/或抗寄生蟲劑係如上文章節II.D.中所描述。
實施例9進一步描述第一態樣及實施例1至4 (包括1a)中之任一者,其中治療劑為檢查點抑制劑;檢查點抑制劑係選自阿特珠單抗、阿維魯單抗、西米普利單抗、多塔利單抗、度伐魯單抗、納武單抗、伊匹單抗以及派姆單抗;及/或檢查點抑制劑為抗PD-L1抗體或抗PD-1抗體。
實施例10進一步描述第一態樣及實施例1至9 (包括1a)中之任一者,其中投與至少兩種不同的治療劑。在其他實施例中,治療劑中之一者為檢查點抑制劑,且檢查點抑制劑係選自阿特珠單抗、阿維魯單抗、西米普利單抗、多塔利單抗、度伐魯單抗、納武單抗、伊匹單抗以及派姆單抗。
實施例11進一步描述第一態樣及實施例1至10 (包括1a)中之任一者,其中疫苗及/或治療劑係與包含dsDNA之奈米粒子同時或大致同時投與。
第二態樣描述一種用於增強個體對疫苗之免疫反應的方法,其包含向個體投與(a)包含dsDNA之奈米粒子;及(b)疫苗。較佳地,dsDNA包含長度為至少45個鹼基對之dsDNA區,及/或奈米粒子為脂質奈米粒子。
實施例12進一步描述第二態樣,其中免疫反應為T細胞反應。在另一實施例中,T細胞反應為Th1或Th2反應。
實施例13進一步描述第二態樣及實施例11或12,其中疫苗為活的減毒、全生物體殺傷、類毒素、次單元(例如經純化之蛋白質、重組蛋白質、多醣及肽)、病毒樣粒子、外膜囊泡、蛋白質-多醣結合物、病毒載體、核酸、細菌引導或抗原呈現細胞;疫苗包含蛋白質抗原;疫苗包含多醣抗原;及疫苗為多醣-多肽結合物疫苗。
實施例14進一步描述第一態樣及實施例1至13 (包括1a)中之任一者,其中dsDNA包含長度為至少50個鹼基對之dsDNA區。在其他實施例中:(1) dsDNA區之長度為至少100個鹼基對、長度為至少200個鹼基對、長度為至少250個鹼基對、長度為至少300個鹼基對、長度為至少400個鹼基對、長度為至少500個鹼基對、長度為至少600個鹼基對、長度為至少700個鹼基對、長度為至少800個鹼基對、長度為至少900個鹼基對、長度為至少1000個鹼基對、長度為至少1100個鹼基對;長度為至少1200個鹼基對、長度為至少1300個鹼基對、長度為至少1400個鹼基對或長度為至少15,000個鹼基對;及/或具有在(1)中所提及的任意兩者之間的尺寸範圍。
實施例15進一步描述第一及第二態樣以及實施例1至14 (包括1a)中之任一者,其中dsDNA含有6個或更少的CpG、5個或更少的CpG、4個或更少的CpG、3個或更少的CpG、2個CpG、1個或更少的CPG或零個CPG。
實施例16進一步描述第一及第二態樣以及實施例1至15(包括1a)中之任一者,其中dsDNA區及其他核苷酸(若存在)為天然存在及/或經修飾的。在其他實施例中,dsDNA係經修飾的且與相應未經修飾之dsDNA相比,刺激至少50%、至少65%、至少75%、至少85%、至少90%或至少100%之先天性免疫反應,如下文實例中所提供之以IFN-γ及IL-6量測。
實施例17進一步描述第一及第二態樣以及實施例1至16(包括1a)中之任一者,其中構成dsDNA區之核苷酸及其他核苷酸(若存在)為未經修飾的或含有一或多個選自由以下組成之群的經修飾之核苷酸:2'-甲氧基乙基(2'-MOE)、2'-氟(2'-F)、鎖核酸(LNA)、限制性乙基(cEt)、三環DNA (tc-DNA)、經C7修飾之去氮-腺嘌呤(甲基、Cl或F)、經C7修飾之去氮-鳥苷(甲基、Cl或F)、經C5修飾之胞嘧啶(甲基、F或Cl),以及經C5修飾之尿苷(甲基、F或Cl)及/或主鏈修飾(硫代磷酸酯(Rp及/或Rs)、硫代胺基磷酸酯、二胺基磷酸酯𠰌啉基寡聚物(PMO),以及肽-核酸(PNA))。在其他實施例中,一或多個修飾為硫代磷酸酯(Rp及/或Rs)。在其他實施例中,dsDNA係經修飾的且與相應未經修飾之dsDNA相比,刺激至少50%、至少65%、至少75%、至少85%、至少90%或至少100%之先天性免疫反應,如下文實例中所提供之以IFN-γ及IL-6量測。
實施例18進一步描述實施例16及17,其中不超過95%、不超過85%、不超過75%、不超過65%、不超過55%、不超過45%、不超過35%、不超過30%、不超過25%、不超過20%、不超過15%、不超過10%、不超過5%或0%之核苷酸係經修飾的。
實施例19進一步描述實施例16至18,其中dsDNA及/或dsDNA區(1)長度為至少50個鹼基對、長度為至少100個鹼基對、長度為至少200個鹼基對、長度為至少250個鹼基對、長度為至少300個鹼基對、長度為至少400個鹼基對、長度為至少500個鹼基對、長度為至少600個鹼基對、長度為至少700個鹼基對、長度為至少800個鹼基對、長度為至少900個鹼基對、長度為至少1000個鹼基對、長度為至少1100個鹼基對、長度為至少1200個鹼基對、長度為至少1300個鹼基對、長度為至少1400個鹼基對或長度為至少15,000個鹼基對;及/或具有在(1)中所提及的任何兩個尺寸之間的尺寸範圍;其中不超過95%、不超過85%、不超過75%、不超過65%、不超過55%、不超過45%、不超過35%、不超過30%、不超過25%、不超過20%、不超過15%、不超過10%、不超過5%或0%之dsDNA區係經修飾的;其中其餘核苷酸(若存在)可能與(1)中之dsDNA區具有相同的修飾百分比或不同的修飾百分比。在其他實施例中,不超過95%、不超過85%、不超過75%、不超過65%、不超過55%、不超過45%、不超過35%、不超過30%、不超過25%、不超過20%、不超過15%、不超過10%、不超過5%或0%之不屬於(1)中之dsDNA區的核苷酸(若存在)係經修飾的。
實施例20進一步描述第一及第二態樣以及實施例1至19 (包括1a)中之任一者,其中dsDNA區由兩個獨立聚核苷酸或單一聚核苷酸之兩個區形成。
實施例21進一步描述第一及第二態樣以及實施例1至19 (包括1a)中之任一者,其中dsDNA係線性的或環狀的。在其他實施例中,dsDNA係選自由以下組成之群:小型環、質體、開放型線性雙螺旋DNA以及封閉型線性雙螺旋DNA。
實施例22進一步描述第一及第二態樣以及實施例1至21 (包括1a)中之任一者,其中dsDNA為非編碼的,缺乏偶合至用於所治療之個體(例如人類細胞)中之表現的編碼區之啟動子及/或不為包含轉殖基因之DNA載體。所提及之「非編碼」係指dsDNA不編碼個體中之基因(表現基因產物)。
實施例23進一步描述第一及第二態樣以及實施例1至22 (包括1a)中之任一者,其中奈米粒子為脂質奈米粒子、聚合奈米粒子、脂質聚合物奈米粒子(LPNP)、基於蛋白質及肽之奈米粒子、DNA樹狀體或基於DNA之奈米載體、碳奈米管、微粒子、微膠囊、無機奈米粒子或肽籠狀奈米粒子;奈米粒子為LNP或LPNP;或奈米粒子為LNP,且以莫耳%計,LNP包含以下組分、基本上由以下組分組成或由以下組分組成:(1)約35%之cKK-E12、約2.5%之C14-PEG2000、約46.5%之膽固醇及約16%之DOPE;(2)約50%之脂質9、約1.5%之C14-PEG2000、約38.5%之膽固醇及約10%之DSPC;或(3)約35%之bCKK-E12、約2.5%之C14-PEG2000、約46.5%之膽固醇及約16%之二油醯基磷脂醯乙醇胺(DOPE)。
實施例23a進一步描述第一及第二態樣以及實施例1至22 (包括1a)中之任一者,其中以莫耳%計,奈米粒子包含以下組分:(1)約20%至65%之一或多種陽離子脂質、約1%至約50%之一或多種磷脂、約0.1%至約10%之一或多種PEG結合之脂質,以及約0%至約70%之膽固醇;或(2)約20%至約50%之一或多種陽離子脂質、約5%至約20%之一或多種磷脂、約0.1%至約5%之一或多種PEG結合之脂質,以及約20%至約60%之膽固醇;在其他實施例中,磷脂類脂質為中性脂質;且磷脂類脂質為DOPE或DSPC。
實施例24進一步描述第一及第二態樣以及實施例1至23 (包括1a及23a)中之任一者,其中個體為人類個體。
第三態樣描述包含dsDNA之奈米粒子,其係用於第一及第二態樣以及實施例1至24 (包括1a及23a)中之任一者的方法中。較佳地,其中dsDNA包含長度為至少45個鹼基對之雙股區。
第四態樣描述包含dsDNA之奈米粒子之用途,其係用於製備藥劑。在不同實施例中,dsDNA包含長度為至少45個鹼基對之雙股區;及/或該藥劑係用於第一及第二態樣以及實施例1至24 (包括1a及23a)中之任一者之方法中。
實例
下文提供進一步說明本發明之不同特徵之實例及用於實踐本發明之方法。所提供之實例不限制所主張之本發明。
實例 1 : 經奈米粒子調配之 DNA 之免疫刺激特性
使用SARS-CoV-2受體結合蛋白(RBD)評估經脂質奈米粒子調配之DNA (DNA-LNP)之佐劑特性且與不同佐劑(25 µL Adju-Phos及25 µL AddaVax)相比較。DNA係由不提供哺乳動物細胞中之基因表現的不含CpG之質體提供。LNP係由以下構成(以莫耳%計):35%之CKK-E12;2.5%之C14-PEG2000;46.5%之膽固醇;及16%之二油醯基磷脂醯乙醇胺(DOPE)。Adju-Phos描述於Mold等人, (2016) Sci Rep. 8月12日;6:31578中。AddaVax描述於Ott等人, (2000). Methods in Molecular Medicine, 第42卷, 211-228中。RBD係自AcroBiosystems (目錄號:SPD-C52H3)獲得。
在第0天、第15天及第30天向BALB/c雄性小鼠肌內給藥(50毫升/動物,四次)。表2說明研究設計(「DNA-NP」表示經LNP調配之DNA)。
表
2
組 | n | 抗原 | 佐劑 | ||
1 | 5 | - | - | - | - |
2 | 5 | RBD蛋白 | 1 μg | - | - |
3 | 5 | - | - | DNA-NP | 1 μg |
4 | 5 | RBD蛋白 | 1 μg | Adju-Phos | |
5 | 5 | AddaVax | |||
6 | 5 | DNA-NP | 0.1 μg | ||
7 | 5 | 1 μg | |||
8 | 5 | DNA | 0.1 μg | ||
9 | 5 | 1 μg | |||
10 | 5 | RBD蛋白 | 0.1 μg | Adju-Phos | |
11 | 5 | AddaVax | |||
12 | 5 | DNA-NP | 0.1 μg | ||
13 | 5 | 1 μg | |||
14 | 5 | DNA | 0.1 μg | ||
15 | 5 | 1 μg |
圖1A及圖1B繪示給藥後6小時小鼠中之細胞介素反應。圖1A顯示IFN-γ水平且圖1B顯示IL-6水平。
圖2繪示在投與COVID-19受體蛋白(RBD)、DNA-LNP及不同佐劑(Adju-Phos及AddaVax)後第38天小鼠中之IgG抗體效價。使用抗RBD ELISA量測抗體效價。
圖3A及圖3B繪示在投與COVID-19受體蛋白(RBD)、DNA-LNP及不同佐劑(Adju-Phos及AddaVax)後第38天小鼠中之IgG亞型。
DNA-LNP在血液中誘導顯著更高的IFN-γ及IL-6水平。DNA-NP及AddaVax兩者均顯示顯著的佐劑效能。小鼠中之IgG同型定量為Th1或Th2免疫反應之代用量測(Rostamian等人, (2017) (50) 160-166)。DNA-LNP誘導不同於AddaVax之Th1反應。Th1反應對於在免疫反應中產生B細胞(用於預防感染)及T細胞(用於在發生感染後對抗感染)之預防性疫苗為有利的。
實例
2
:
DNA-LNP
之免疫刺激特性
使用腺相關病毒粒子(AAV)作為抗原評估DNA-LNP之佐劑特性。DNA係由不提供哺乳動物細胞中之基因表現的約1.3 kb質體提供。LNP係由以下構成(以莫耳%計):35%之bCKK-E12;2.5%之C14-PEG2000;46.5%之膽固醇;及16%之二油醯基磷脂醯乙醇胺(DOPE)。
在第0天以1×10
12個載體基因體(vg)/動物向C57BL/6雌性小鼠靜脈內投與AAV。一些小鼠靜脈內接受與DNA-LNP (5 µg)混合之AAV或與「空」LNP (無DNA)混合之AAV (劑量等效於5 µg DNA-LNP中之LNP的量)。收集血漿以分析抗AAV IgG及細胞介素水平。
圖4繪示在投與AAV、AAV與「空」LNP (無DNA)之混合物或使用DNA-LNP作為佐劑之AAV後兩週時小鼠中之抗AAV抗體水平。與DNA-LNP混合之AAV增加了血漿中之抗AAV IgG水平。
表3說明在投與AAV、與「空」LNP混合之AAV或與DNA-LNP混合之AAV後4小時血漿中之細胞介素水平。細胞介素水平由於與DNA-LNP混合之AAV之投藥而增加。細胞介素水平由於與DNA-LNP混合之AAV之投藥而增加。AAV及空LNP未顯示佐劑作用。
表
3
AAV | AAV + LNP | AAV + DNA-LNP | ||||
pg/mL | 平均值 | SD | 平均值 | SD | 平均值 | SD |
IFN- α | 20.9 | 0.0 | 20.9 | 0.0 | 5601.1 | 1079.5 |
IFN-ß | 40.0 | 0.0 | 40.0 | 0.0 | 10282.7 | 6611.9 |
IFN-γ | 5.5 | 0.0 | 10.8 | 10.5 | 2616.3 | 1686.1 |
IL-6 | 27.3 | 0.0 | 35.0 | 15.4 | 43880.1 | 29590.4 |
KC/GRO | 8.1 | 0.0 | 10.3 | 4.4 | 1281.6 | 339.1 |
MCP-1 | 60.1 | 0.0 | 60.1 | 0.0 | 12815.8 | 1927.0 |
MIP-1ß | 5.8 | 1.0 | 10.5 | 4.4 | 3074.7 | 2346.3 |
TNF- α | 14.3 | 0.0 | 15.2 | 1.9 | 1364.1 | 1810.5 |
IL-18 | 149.8 | 0.0 | 264.7 | 101.4 | 4445.9 | 844.8 |
實例
3
:
免疫信號傳導路徑
在缺乏不同免疫信號傳導路徑之C57BL/6基因剔除(KO)小鼠中評估DNA-LNP投藥之後的細胞介素水平。DNA-LNP組合物係如實例1中所提供。向小鼠靜脈內投與DNA-LNP (5 µg)。在投與DNA-LNP之後3或4小時收集血漿以用於細胞介素分析。
結果說明免疫信號傳導路徑有助於在投與DNA-LNP後誘導之細胞介素水平。比較野生型小鼠(黑線)及多個KO小鼠(灰線)中之細胞介素水平:cGAS KO (表4)、STING KO (表4)、TLR9 KO (表5)、IFNAR KO (表5);AIM2 KO (表6)、MyD88 KO (表6);RIG-I KO (表7)、NLRP3 KO (表8)、凋亡蛋白酶1 KO (表9);及消皮素D KO (表10)。cGAS及STING有助於細胞介素水平但不影響IL-18水平,IL-18為由炎性體路徑誘導之細胞介素。基因剔除小鼠之結果表明炎性體介體(諸如AIM2、凋亡蛋白酶1及消皮素D)有助於誘導由DNA-LNP投藥產生之IL-18及IFN-γ。
表
4
基線 | 野生型 | cGAS KO | STING KO | ||||
pg/mL | 值 | 平均值 | SD | 平均值 | SD | 平均值 | SD |
IFN- α | 154.0 | 27059.0 | 13071.3 | 154.3 | 0.0 | 154.3 | 0.0 |
IFN-ß | 4.2 | 2453.6 | 1295.4 | 4.2 | 0.0 | 4.2 | 0.0 |
IFN-γ | 0.5 | 1580.4 | 941.5 | 20.0 | 10.6 | 15.8 | 3.2 |
IL-6 | 49.4 | 21944.3 | 11713.9 | 206.1 | 146.6 | 532.5 | 205.1 |
KC/GRO | 189.0 | 838.2 | 328.3 | 1223.2 | 644.0 | 2025.8 | 548.6 |
MCP-1 | 32.7 | 11304.9 | 4582.1 | 433.3 | 277.8 | 455.6 | 234.0 |
MIP-1ß | 52.7 | 14661.8 | 6071.5 | 156.3 | 62.8 | 204.9 | 84.7 |
TNF- α | 14.0 | 635.9 | 266.2 | 10.9 | 2.0 | 12.6 | 1.4 |
IL-18 | 354.2 | 1929.8 | 1284.9 | 2801.8 | 1954.1 | 3316.2 | 941.8 |
表
5
基線 | 野生型 | TLR9 KO | IFNAR KO | ||||
pg/mL | 值 | 平均值 | SD | 平均值 | SD | 平均值 | SD |
IFN- α | 154.0 | 27059.0 | 13071.3 | 27624.7 | 5894.4 | 6783.6 | 1688.4 |
IFN-ß | 4.2 | 2453.6 | 1295.4 | 3486.7 | 3012.2 | 2960.9 | 321.1 |
IFN-γ | 0.5 | 1580.4 | 941.5 | 2701.4 | 599.7 | 36.7 | 8.2 |
IL-6 | 49.4 | 21944.3 | 11713.9 | 42228.5 | 34135.1 | 3942.7 | 1573.2 |
KC/GRO | 189.0 | 838.2 | 328.3 | 1741.6 | 1451.8 | 3815.3 | 1082.6 |
MCP-1 | 32.7 | 11304.9 | 4582.1 | 13632.2 | 1437.9 | 4349.4 | 559.7 |
MIP-1ß | 52.7 | 14661.8 | 6071.5 | 19373.4 | 11452.1 | 4871.8 | 755.8 |
TNF- α | 14.0 | 635.9 | 266.2 | 1037.9 | 796.2 | 298.7 | 53.2 |
IL-18 | 354.2 | 1929.8 | 1284.9 | 2387.6 | 546.0 | 1804.4 | 413.2 |
表
6
基線 | 野生型 | AIM2 KO | MyD88 KO | ||||
pg/mL | 值 | 平均值 | SD | 平均值 | SD | 平均值 | SD |
IFN-α | 222.3 | 53705.6 | 3425.7 | 50028.9 | 4976.0 | 41330.1 | 6665.1 |
IFN-β | 6.3 | 2537.0 | 549.6 | 1329.2 | 276.6 | 3219.8 | 1271.9 |
IFN-γ | 0.8 | 10027.0 | 2488.5 | 91.0 | 17.8 | 113.4 | 67.7 |
IL-6 | 7.8 | 73633.5 | 13288.7 | 12108.4 | 1407.4 | 16502.9 | 4903.1 |
KC/GRO | 132.8 | 2289.6 | 537.1 | 1846.8 | 217.4 | 556.4 | 141.5 |
MCP-1 | 23.5 | 19668.0 | 408.3 | 16421.8 | 1655.6 | 19033.1 | 1449.9 |
MIP-1β | 31.5 | 9849.5 | 760.0 | 7828.3 | 1657.6 | 10205.5 | 2389.7 |
TNF-α | 9.1 | 996.7 | 363.3 | 464.0 | 36.1 | 829.5 | 301.0 |
IL-18 | 144.4 | 6176.9 | 3101.5 | 330.5 | 51.0 | 5538.7 | 1046.6 |
表
7
基線 | 野生型 | RIG-I KO | |||
pg/mL | 值 | 平均值 | SD | 平均值 | SD |
IFN-α | 338.4 | 36868.1 | 7154.2 | 23474.2 | 7908.4 |
IFN-β | 7.6 | 3627.3 | 757.9 | 1761.8 | 542.6 |
IFN-γ | 1.1 | 2112.2 | 705.4 | 694.1 | 527.1 |
IL-6 | 14.2 | 40576.2 | 7257.5 | 16861.5 | 9217.0 |
KC/GRO | 99.7 | 1627.9 | 597.6 | 1287.9 | 586.4 |
MCP-1 | 28.5 | 3050.0 | 0.0 | 3050.0 | 0.0 |
MIP-1β | 43.1 | 15910.6 | 801.1 | 11644.2 | 951.4 |
TNF-α | 7.0 | 723.7 | 151.2 | 644.9 | 139.4 |
IL-18 | 156.4 | 3294.6 | 776.9 | 1482.3 | 730.4 |
表
8
基線 | 野生型 | NLRP3 KO | |||
pg/mL | 值 | 平均值 | SD | 平均值 | SD |
IFN-α | 397.3 | 44955.5 | 4375.7 | 24106.3 | 6717.5 |
IFN-β | 15.1 | 4891.2 | 1266.8 | 1642.8 | 717.7 |
IFN-γ | 1.4 | 2839.4 | 1228.8 | 1130.3 | 812.8 |
IL-6 | 16.4 | 36661.8 | 6388.4 | 14871.4 | 4497.6 |
KC/GRO | 145.2 | 2979.1 | 962.3 | 1617.0 | 698.1 |
MCP-1 | 41.4 | 9.8 | 0.0 | 9.8 | 0.0 |
MIP-1β | 65.2 | 17504.6 | 1436.7 | 9050.1 | 2434.4 |
TNF-α | 8.3 | 1637.1 | 146.4 | 659.4 | 231.4 |
IL-18 | 216.2 | 3954.5 | 1078.1 | 2448.1 | 880.7 |
表
9
基線 | 野生型 | 凋亡蛋白酶 -1 KO | |||
pg/mL | 值 | 平均值 | SD | 平均值 | SD |
IFN-α | 338.4 | 34184.2 | 3665.9 | 26776.1 | 3453.3 |
IFN-β | 7.6 | 2357.2 | 327.3 | 1458.4 | 159.0 |
IFN-γ | 1.1 | 2381.7 | 510.0 | 31.5 | 8.9 |
IL-6 | 14.2 | 41571.1 | 6226.1 | 8470.7 | 2255.2 |
KC/GRO | 99.7 | 1510.2 | 391.7 | 795.0 | 54.5 |
MCP-1 | 28.5 | 3050.0 | 0.0 | 3050.0 | 0.0 |
MIP-1β | 43.1 | 12779.5 | 698.4 | 10320.8 | 1394.6 |
TNF-α | 7.0 | 709.7 | 114.6 | 438.9 | 63.7 |
IL-18 | 128.8 | 3275.8 | 590.8 | 128.0 | 0.0 |
表
10
基線 | 野生型 | GSDMD KO | |||
pg/mL | 值 | 平均值 | SD | 平均值 | SD |
IFN-α | 316.0 | 72389.8 | 9211.6 | 51409.0 | 5402.2 |
IFN-β | 33.3 | 8332.0 | 3978.6 | 5926.1 | 2222.9 |
IFN-γ | 5.1 | 4569.5 | 2115.7 | 222.6 | 121.2 |
IL-6 | 15.0 | 53000.0 | 0.0 | 27457.0 | 13392.6 |
KC/GRO | 193.2 | 4406.2 | 1487.4 | 1439.2 | 999.5 |
MCP-1 | 21.5 | 2975.0 | 0.0 | 2975.0 | 0.0 |
MIP-1β | 52.7 | 38571.6 | 12349.6 | 26922.1 | 3292.6 |
TNF-α | 6.7 | 2125.7 | 2005.9 | 941.5 | 170.3 |
IL-18 | 148.9 | 2796.8 | 409.4 | 187.6 | 68.6 |
實例
4
:
dsDNA
與
不同
LNP
之組合之免疫刺激特性
在C57BL/6小鼠中評估DNA-LNP投藥後之細胞介素水平。靜脈內投與包含不同LNP之DNA-LNP (25 µg)。DNA係由不提供哺乳動物細胞中之基因表現的不含CpG之質體提供。LNP1係由以下構成(以莫耳%計):35%之bCKK-E12;2.5%之C14-PEG2000;46.5%之膽固醇;及16%之二油醯基磷脂醯乙醇胺(DOPE)。LNP2係由以下構成(以莫耳%計):約50%之脂質9 (脂質9進一步描述於上文章節I.A.及Sabnis等人, (2018) Molecular Therapy 26:6, 1509-1519中);約1.5%之C14-PEG2000;約38.5%之膽固醇;及約10%之二硬脂醯基磷脂醯膽鹼(DSPC)。LNP3為GenVoy-ILMTM LNP (Precision NanoSystems)。Roces等人, Pharmaceutics, 2020, 12,1095指示GenVoy-ILM
TMLNP含有:約50%之可電離脂質;約10%之DSPC;約37.5%之膽固醇;以及約2.5%之穩定劑(PEG-脂質)。
表11提供在各種DNA-LNP投藥後4小時所誘導之細胞介素水平的結果。
表
11
基線 | DNA-LNP1 | DNA-LNP2 | DNA-LNP3 | ||||
pg/mL | 值 | 平均值 | SD | 平均值 | SD | 平均值 | SD |
IFN-α | 822.6 | 62884.5 | 10799.3 | 86183.9 | 21185.1 | 4519.6 | 3110.0 |
IFN-β | 29.8 | 3545.8 | 1618.2 | 3593.5 | 1449.8 | 287.4 | 151.8 |
IFN-γ | 4.0 | 13912.3 | 5516.9 | 9831.0 | 2563.8 | 279.3 | 174.3 |
IL-6 | 83.4 | 163879.4 | 25922.0 | 175874.9 | 12047.8 | 124430.2 | 32827.0 |
KC/GRO | 446.9 | 14887.4 | 5575.6 | 21600.0 | 0.0 | 21600.0 | 0.0 |
MCP-1 | 167.3 | 12200.0 | 0.0 | 12200.0 | 0.0 | 10163.5 | 1316.5 |
MIP-1β | 196.3 | 22750.6 | 7330.8 | 36731.4 | 11319.8 | 7318.7 | 3296.3 |
TNF-α | 14.1 | 1051.5 | 142.9 | 1131.7 | 282.6 | 210.8 | 56.3 |
IL-18 | 1280.0 | 7813.3 | 1533.3 | 10088.3 | 2030.8 | 50000.0 | 0.0 |
在整個申請案中已描述本發明之許多不同態樣及實施例。然而,熟習此項技術者在不背離本發明之精神及範疇的情況下可對本發明作出各種改變及修改以使其適應各種用途及條件。
圖1A及圖1B繪示在投與SARS-CoV-2受體蛋白(RBD)、DNA-LNP (標記為「DNA-NP」)及不同佐劑(Adju-Phos及AddaVax)後6小時小鼠中之細胞介素反應。圖1A顯示血清IFN-γ水平且圖1B顯示血清IL-6水平。「LLOQ」係指定量之下限。
圖2繪示在投與SARS-CoV-2病毒受體蛋白(RBD)、DNA-LNP (標記為「DNA-NP」)及不同佐劑(Adju-Phos及AddaVax)後第38天小鼠中之抗RBD IgG抗體效價。「ULOD」係指偵測之上限。「LLOD」係指偵測之下限。
圖3A及圖3B分別繪示在投與SARS-CoV-2病毒受體蛋白(RBD)、DNA-LNP (標記為「DNA-NP」)及不同佐劑(Adju-Phos及AddaVax)後第38天小鼠中之抗RBD IgG亞型及其比率。「ULOD」係指偵測之上限。「LLOD」係指偵測之下限。
圖4繪示在投與AAV、AAV與「空」(無DNA)LNP之混合物以及使用DNA-LNP作為佐劑之AAV後兩週時血漿中之抗AAV抗體水平。所提及之***係指P值<0.001,且所提及之****係指P值<0.0001。
Claims (36)
- 一種治療個體中感染性疾病之方法,該方法包含向該個體投與: a) 包含雙股DNA (dsDNA)之奈米粒子,其中該dsDNA包含長度為至少45個鹼基對之雙股區;及 b)疫苗或治療劑; 其中(i)該奈米粒子為脂質奈米粒子且該dsDNA為非編碼的;(ii)該奈米粒子為脂質奈米粒子且該dsDNA缺乏可操作地連接至用於在該個體中表現之編碼區的啟動子;(iii)該治療劑為檢查點抑制劑;及/或(iv)提供至少兩種不同之治療劑。
- 如請求項1之方法,其中該奈米粒子為脂質奈米粒子且該dsDNA為非編碼的。
- 如請求項1之方法,其中該奈米粒子為脂質奈米粒子且該dsDNA缺乏可操作地連接至用於在該個體中表現之編碼區的啟動子。
- 如請求項1至3中任一項之方法,其中該治療劑為檢查點抑制劑。
- 如請求項4之方法,其中該檢查點抑制劑為抗PD-L1抗體或抗PD-1抗體。
- 如請求項5之方法,其中該檢查點抑制劑係選自由以下組成之群:阿特珠單抗(atezolizumab)、阿維魯單抗(avelumab)、西米普利單抗(cemiplimab)、多塔利單抗(dostarlimab)、度伐魯單抗(durvalumab)、納武單抗(nivolumab)、伊匹單抗(ipilimumab)以及派姆單抗(pembrolizumab)。
- 如請求項1至3中任一項之方法,其中該方法包含投與該治療劑且該治療劑為抗病毒劑、抗菌劑、抗真菌劑或抗寄生蟲劑。
- 如請求項1至7中任一項之方法,其中該方法包含投與該疫苗,其中該疫苗包含多肽抗原、多醣抗原或為經結合之多醣-多肽。
- 如請求項1至8中任一項之方法,其中該個體患有病原性感染。
- 如請求項1至9中任一項之方法,其中投與至少兩種不同之治療劑。
- 如請求項10之方法,其中該兩種不同之治療劑包含選自表1中所提供之抗病毒劑的第一治療劑及選自以下之第二治療劑:阿特珠單抗、阿維魯單抗、西米普利單抗、多塔利單抗、度伐魯單抗、納武單抗、伊匹單抗以及派姆單抗。
- 如請求項1至11中任一項之方法,其中該疫苗及/或治療劑係與該dsDNA同時或大約同時投與。
- 一種用於增強個體對疫苗之免疫反應的方法,其包含向該個體投與: a) 包含雙股DNA (dsDNA)奈米粒子,其中該dsDNA包含長度為至少45個鹼基對之雙股區,及 b)該疫苗,其中該奈米粒子為脂質奈米粒子。
- 如請求項13之方法,其中該免疫反應為T細胞反應。
- 如請求項14之方法,其中該T細胞反應為Th1或Th2反應。
- 如請求項13至15中任一項之方法,其中該疫苗包含多肽抗原、多醣抗原或為經結合之多醣-肽。
- 如請求項1至16中任一項之方法,其中該dsDNA區長度為至少50個鹼基對。
- 如請求項17之方法,其中該dsDNA區長度為至少100個鹼基對。
- 如請求項18之方法,其中該dsDNA長度為至少200個鹼基對。
- 如請求項1至19中任一項之方法,其中該dsDNA未經修飾。
- 如請求項1至20中任一項之方法,其中該dsDNA係線性的或環狀的。
- 如請求項1至20中任一項之方法,其中該dsDNA係選自由以下組成之群:小型環、質體、開放型線性雙螺旋DNA以及封閉型線性雙螺旋DNA。
- 如請求項1至20中任一項之方法,其中該dsDNA區係由聚核苷酸之兩個區提供且該聚核苷酸包含環形區。
- 如請求項13至23中任一項之方法,其中該dsDNA為非編碼的或缺乏可操作地連接至用於在該個體中表現之編碼區的啟動子。
- 如請求項1至24中任一項之方法,其中以莫耳%計,該奈米粒子包含約20%至約50%之一或多種陽離子脂質、約5%至約20%之一或多種磷脂、約0.1%至約5%之一或多種PEG結合之脂質,以及約20%至約60%之膽固醇。
- 如請求項1至24中任一項之方法,其中以莫耳%計,該奈米粒子包含約20%至約65%之一或多種陽離子脂質、約1%至約50%之一或多種磷脂、約0.1%至約10%之一或多種PEG結合之脂質,以及約0%至約70%之膽固醇。
- 如請求項25或26之方法,其中該磷脂類脂質為1,2-二油醯基-sn-甘油-3-磷脂醯基-乙醇胺或1,2-二硬脂醯基-sn-甘油-3-磷酸膽鹼。
- 如請求項25之方法,其中以莫耳%計,該奈米粒子包含(1)約35%之cKK-E12、約2.5%之C14-PEG2000、約46.5%之膽固醇及約16%之1,2-二油醯基-sn-甘油-3-磷脂醯基-乙醇胺(DOPE);或(2)約50%之脂質9 (Lipid 9)、約1.5%之C14-PEG2000、約38.5%之膽固醇及約10%之1,2-二硬脂醯基-sn-甘油-3-磷酸膽鹼(DSPC)。
- 如請求項1至3或13至15中任一項之方法,其中以莫耳%計,該奈米粒子包含約20%至約50%之一或多種陽離子脂質、約5%至約20%之一或多種磷脂、約0.1%至約5%之一或多種PEG結合之脂質,以及約20%至約60%之膽固醇。
- 如請求項1至3或13至15中任一項之方法,其中以莫耳%計,該奈米粒子包含約20%至約65%之一或多種陽離子脂質、約1%至約50%之一或多種磷脂類脂質、約0.1%至約10%之一或多種PEG結合之脂質,以及約0%至約70%之膽固醇。
- 如請求項30之方法,其中該磷脂類脂質為1,2-二油醯基-sn-甘油-3-磷脂醯基-乙醇胺或1,2-二硬脂醯基-sn-甘油-3-磷酸膽鹼。
- 如請求項30之方法,其中該磷脂類脂質為1,2-二油醯基-sn-甘油-3-磷脂醯基-乙醇胺或1,2-二硬脂醯基-sn-甘油-3-磷酸膽鹼。
- 如請求項1至3或13至15中任一項之方法,其中以莫耳%計,該奈米粒子包含(1)約35%之cKK-E12、約2.5%之C14-PEG2000、約46.5%之膽固醇及約16%之1,2-二油醯基-sn-甘油-3-磷脂醯基-乙醇胺(DOPE);或(2)約50%之脂質9、約1.5%之C14-PEG2000、約38.5%之膽固醇及約10%之1,2-二硬脂醯基-sn-甘油-3-磷酸膽鹼(DSPC)。
- 如請求項1至33中任一項之方法,其中該個體為人類。
- 一種包含dsDNA的奈米粒子,其係用於如請求項1至34中任一項之方法,其中該dsDNA包含長度為至少45個鹼基對之雙股區。
- 一種包含dsDNA之奈米粒子之用途,其係用於製備藥劑、用於如請求項1至34中任一項之方法,其中該dsDNA包含長度為至少45個鹼基對之雙股區。
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