TWI833056B - 核酸藥物複合體以及其用途 - Google Patents
核酸藥物複合體以及其用途 Download PDFInfo
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- TWI833056B TWI833056B TW109145837A TW109145837A TWI833056B TW I833056 B TWI833056 B TW I833056B TW 109145837 A TW109145837 A TW 109145837A TW 109145837 A TW109145837 A TW 109145837A TW I833056 B TWI833056 B TW I833056B
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Abstract
本揭露提供一種核酸藥物複合體,其包含抗PD-L1適體的核酸序列以及可活化TLR-9的CpG寡核苷酸序列,其中CpG寡核苷酸序列由第一片段以及第二片段所組成,且抗PD-L1適體的核酸序列插入於第一片段以及第二片段之間。
Description
本揭露是關於一種核酸藥物複合體,且特別是關於抗PD-L1適體的核酸藥物複合體以及其用途。
計劃性死亡-1(programmed death-1,PD-1)為活化T細胞表現的共同刺激者,在免疫系統中進行負向調控(negative regulation),可抑制T細胞的活化及增生。PD-L1為PD-1的配體(ligand),PD-L1具有免疫抑制性,PD-L1會表現在一些非淋巴組織的血管內皮系統的抗原表現細胞上,例如樹突細胞(dendritic cell,DC)、巨噬細胞(macrophage)以及B細胞上。再者,由於PD-L1亦表現於許多腫瘤細胞、基質細胞以及免疫細胞上,因此若將PD-1及PD-L1的結合阻斷,可有效強化免疫反應且具有抗腫瘤的效果。以抗PD-1與抗PD-L1抗體調控的免疫檢查點阻斷療法(checkpoint blockade immunotherapy)已應用於臨床治療。
另一方面,CpG寡去氧核苷酸(CpG oligodeoxynucleotide,CpG ODN)為一系列具有強效免疫活化效果的去氧核苷酸,可有效活化多種免疫細胞、引發免疫反應並有
顯著抗癌效果。然而,腫瘤內注射(intratumoral injection,IT)為目前安全且有效給予CpG寡去氧核苷酸的給藥方式,此情形使得CpG寡去氧核苷酸可應用的適應症受到限制。
目前的免疫療法常採用多種藥物併用的方式進行,例如併用抗PD-L1抗體與CpG寡去氧核苷酸,然而,藥物併用可能產生許多潛在的風險,也會造成患者的負擔。因此,發展出具有有效抗癌效果且可單獨給藥的免疫療法仍為醫藥領域致力研究的課題之一。
根據本揭露一些實施例,提供一種核酸藥物複合體,其包含抗PD-L1適體的核酸序列以及可活化TLR-9的CpG寡核苷酸序列,抗PD-L1適體結合至PD-L1,CpG寡核苷酸序列結合至TLR9受體。CpG寡核苷酸序列由第一片段以及第二片段所組成,且抗PD-L1適體的核酸序列插入於第一片段以及第二片段之間。
根據本揭露一些實施例,提供一種前述之核酸藥物複合體的用途,其係用於製備治療癌症的藥物。
根據本揭露一些實施例,提供一種醫藥組合物,包含前述之核酸藥物複合體以及醫藥上可接受之載體。
為讓本揭露之特徵、或優點能更明顯易懂,下文特舉出較佳實施例,並配合所附圖式,作詳細說明如下。
第1A圖顯示根據本揭露一些實施例中,使用流式細胞儀對樣品unstained(負控制組)、AptPDLI-n05、AptPDL1-n07、AptPDL1-1A、AptPDL1-2A及AptPDL1-3A進行PD-L1結合親和性的分析結果;第1B圖顯示根據本揭露一些實施例中,使用流式細胞儀對樣品AptPDL1-A4、AptPDL1-45mer(PBS*)、AptPDL1-45mer(SELEX)(正控制組)、AptPDL1-45mer(SELEX,600nM)(正控制組)及CpG-L0-PS進行PD-L1結合親和性的分析結果;第2圖顯示根據本揭露一些實施例中,第1A圖及第1B圖使用流式細胞儀檢測的實驗結果的量化數據;第3圖顯示根據本揭露一些實施例中,使用ELISA技術對樣品cell only(負控制組)、45mer、n05、n07、1A、2A、3A及A4進行PD-L1結合親和性的分析結果;第4圖顯示根據本揭露一些實施例中,使用HEK293小鼠TLR9報導系統對樣品CpG-L0-PS、ApDC5-PS、ApDC5-7PS、PDL1-CpG30-PS、PDL1-CpG29-9PS及ApDC-A21B進行TLR9活化能力的分析結果;第5圖顯示根據本揭露一些實施例中,使用HEK293小鼠TLR9報導系統對樣品CpG-L0-PS、ApDC5-PS、ApDC-A21B、
ApDC-A21A、ApDC-B21B及ApDC-A33B進行TLR9活化能力的分析結果;第6A圖至第6D圖顯示根據本揭露一些實施例中,核酸藥物複合體的二級結構示意圖;第7圖顯示根據本揭露一些實施例中,使用4T1鼠乳腺癌同源腫瘤模型,分析施用樣品Vehicle(負控制組)、PDL1 mAb、AptPDL1+CpG及ApDC5-PS對小鼠的腫瘤體積及存活率的影響;第8圖顯示根據本揭露一些實施例中,使用4T1鼠乳腺癌同源腫瘤模型,分析施用樣品CpG-L0-PS及ApDC-A21B對小鼠的腫瘤體積的影響。
以下針對本揭露實施例的核酸藥物複合體作詳細說明。應了解的是,以下之敘述提供許多不同的實施例或例子,用以實施本揭露一些實施例之不同樣態。以下所述特定的元件及排列方式僅為簡單清楚描述本揭露一些實施例。當然,這些僅用以舉例而非本揭露之限定。
除非另外定義,於本文中使用的全部用語(包含技術及科學用語)具有與本揭露所屬技術領域的技術人員通常理解的相同涵義。能理解的是,這些用語例如在通常使用的字典中定義用語,應被解讀成具有與相關技術及本揭露的背景或上下文一致的意
思,而不應以一理想化或過度正式的方式解讀。為了使本揭露的內容更容易理解,提供以下術語及用詞的定義。
術語「寡核苷酸」、「聚核苷酸」、「核酸」及「核酸分子」在本文中可交替使用,指的是具有任意長度的核苷酸聚合物,可包含單股DNA(ssDNA)、雙股DNA(dsDNA)、單股RNA(ssRNA)及雙股RNA(dsRNA)。核苷酸可為去氧核糖核苷酸、核糖核苷酸、經修飾的核苷酸。核苷由嘌呤(腺嘌呤(A)或鳥嘌呤(G)或其衍生物)或嘧啶(胸腺嘧啶(T)、胞嘧啶(C)或尿嘧啶(U)或其衍生物)鹼基與糖鍵結組成。DNA中的四種核苷單元(或鹼基)稱為去氧腺苷、去氧鳥苷、胸苷及去氧胞苷。RNA中的四種核苷單元(或鹼基)稱為腺苷、鳥苷、尿苷及胞苷。核苷酸為核苷之磷酸酯。
術語「CpG」及「CG」在本文中可交替使用,指的是由磷酸二酯鍵分隔開的胞嘧啶及鳥嘌呤。根據本揭露實施例,寡核苷酸可包含一或多個未經甲基化的CpG二核苷酸。根據本揭露一些實施例,寡核苷酸為寡去氧核苷酸(oligodeoxynucleotide,ODN)。
術語「計劃性死亡配體-1」,亦稱為「PD-L1」、「表面抗原分化叢274(cluster of differentiation 274,CD274)」或「B7同源體-1(B7 homolog-1,B7-H1)」,指的是於人類中由CD274基因編碼的蛋白質。人類PD-L1為40kDa 1型跨膜蛋白,其主要作用於抑制免疫系統。PD-L1結合於經活化的T細胞、B細胞及骨髓細胞上的受體PD-1以調節活化或抑制。PD-L1亦對共刺
激性分子CD80(B7-1)具有顯著親和力。PD-L1與T細胞上的受體PD-1結合可傳遞一種訊號,所述訊號可抑制T細胞受體調控的IL-2產生及T細胞增殖的活化。PD-L1可視為檢查點(checkpoint),且其在腫瘤中的上升表現有助於抑制T細胞調控的抗腫瘤反應。根據本揭露實施例,PD-L1可為源自哺乳類動物的PD-L1,例如,可為源自人類的PD-L1。
術語「癌症」指的是哺乳動物中細胞群體由不受調控的細胞生長表徵的生理學病狀。術語「腫瘤」指的是任何由過度細胞生長或增殖產生的組織塊狀物,包含良性(非癌性)或惡性(癌性)腫瘤,包含癌前病灶。
術語「免疫反應」包含來自先天性免疫系統及後天性免疫系統的反應,其包含細胞調控的免疫反應或體液免疫反應。免疫反應包含T細胞及B細胞反應,以及來自免疫系統的其他細胞例如自然殺手(natural killer,NK)細胞、單核細胞、巨噬細胞等的反應。
再者,術語「治療」指的是使經診斷的病理性病狀或病症治癒、減緩、症狀減輕及/或進程停止的治療性措施,以及預防及/或減緩目標病理性病狀或病症的發展的預防性措施。因此,需要治療的個體可包含已經患有病症者、易患有病症者以及待預防病症者。根據本揭露實施例,若具有癌症或腫瘤的患者顯示以下情況中的一或多者,則代表個體被成功地治療:免疫反應增加、抗腫瘤反應增加、免疫細胞的細胞溶解活性增加、免疫細胞的腫瘤細胞殺
傷增加、癌細胞數目減少或完全不存在;腫瘤尺寸減小;抑制或不存在癌細胞浸潤至周邊器官中;抑制或不存在腫瘤或癌細胞轉移;抑制或不存在癌症生長;緩解一或多種與具體癌症相關的症狀;降低致病率及死亡率;改良生活品質;降低致瘤性;或降低癌症幹細胞的數目或出現頻率等。
根據本揭露一些實施例,提供一種核酸藥物複合體,其包含結合至PD-L1的抗PD-L1適體(aptamer)的核酸序列以及結合至TLR9(Toll-like receptor 9)受體的CpG寡核苷酸序列,且抗PD-L1適體的核酸序列插入於CpG寡核苷酸序列的第一片段以及第二片段之間。本揭露實施例提供的新型態核酸藥物複合體結合可活化TLR-9的CpG寡核苷酸序列與抗PD-L1適體,其具有腫瘤標靶性以及多重免疫調節活性,可透過靜脈內注射進行全身性給藥,並且可單獨給藥,取代多藥物併用的免疫療法。
根據一些實施例,抗PD-L1適體的核酸序列與序列辨識號:1至9之任一者所示的序列具有至少85%的相似度,例如可具有,86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%的相似度,但不限於此。根據一些實施例,抗PD-L1適體由序列辨識號:1至9之任一者所示之核酸序列所組成。根據一些實施例,抗PD-L1適體的核酸序列中的核苷酸會配對產生特定的二級結構,抗PD-L1適體可藉由此種二級結構與PD-L1結合,阻斷PD-1及PD-L1的結合位,藉此可維持或強化抗腫瘤的免疫反應。
根據一些實施例,核酸藥物複合體包含前述之抗PD-L1適體的核酸序列以及CpG寡核苷酸序列,CpG寡核苷酸序列可結合至TLR9受體,CpG寡核苷酸序列可強烈活化TLR9,促使干擾素(interferon)的產生,誘發抗腫瘤或抗病毒等免疫反應。根據一些實施例,CpG寡核苷酸為寡去氧核苷酸(oligodeoxynucleotide,ODN)。根據一些實施例,CpG寡核苷酸序列與序列辨識號:10至23之任一者所示之核酸序列可具有至少85%的相似度,例如可具有,86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%的相似度,但不限於此。根據一些實施例,CpG寡核苷酸序列可由第一片段以及第二片段所組成。根據一些實施例,CpG寡核苷酸序列之第一片段以及第二片段為擇自由序列辨識號:10至23之任一者所示之核酸序列。
換言之,根據一些實施例,由CpG寡核苷酸序列之第一片段以及第二片段所共同構成的序列與序列辨識號:10至23之任一者所示之核酸序列可具有至少85%的相似度,例如,86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%的相似度,但不限於此。根據一些實施例,CpG寡核苷酸序列之第一片段以及第二片段共同構成了序列辨識號:10至23之任一者所示的核酸序列,亦即,CpG寡核苷酸序列為序列辨識號:10至23之任一者所示的核酸序列。
值得注意的是,根據本揭露實施例,抗PD-L1適體的核酸序列插入於CpG寡核苷酸序列的第一片段以及第二片段之間,使得核酸藥物複合體可同時具有腫瘤標靶性以及多重免疫調節活性。根據一些實施例,抗PD-L1適體的核酸序列以及CpG寡核苷酸序列可透過連接子(linker)進行連接。根據一些實施例,抗PD-L1適體的核酸序列以及CpG寡核苷酸序列亦可不需額外設計連接子進行連接。
根據一些實施例,CpG寡核苷酸序列之第一片段的長度與CpG寡核苷酸序列之第二片段的長度的比例為約1:15至15:1,或約1:10至10:1,例如,CpG寡核苷酸序列之第一片段的長度與CpG寡核苷酸序列之第二片段的長度的比例可為約1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、9:1、8:1、7:1、6:1、5:1、4:1、3:1或2:1,但不限於此。根據一些實施例,CpG寡核苷酸序列的長度(亦即,由第一片段的長度以及第二片段的長度所相加的總長度)範圍約為15個核苷酸至40個核苷酸,或約20個核苷酸至35個核苷酸,或約20個核苷酸至30個核苷酸,例如可為約,21、22、23、24、25、26、27、28或29個核苷酸,但不限於此。
此外,根據一些實施例,CpG寡核苷酸序列可包含一或多個未經甲基化的CpG基序(motif)。根據一些實施例,CpG寡核苷酸序列中的CpG基序可有85%至100%為未經甲基化,例如,可有約88%、90%、92%、95%、98%等為未經甲基化,但不限於此。根據一些實施例,CpG寡核苷酸序列中的CpG基序可全
部皆為未經甲基化。此外,根據一些實施例,CpG寡核苷酸序列包含經修飾的磷酸二酯鍵(phosphodiester bond),例如硫代磷酸酯鍵(phosphorothioate bond),藉此可降低核酸藥物複合體被生物體內的酵素降解的風險,提升核酸藥物複合體的穩定性。根據一些實施例,硫代磷酸酯鍵的數量可佔CpG寡核苷酸序列的磷酸二酯鍵的數量約70%至100%,或約80%至100%,例如可為,85%、90%或95%,但不限於此。根據一些實施例,CpG寡核苷酸序列中的所有磷酸二酯鍵均可被修飾為硫代磷酸酯鍵。
根據一些實施例,核酸藥物複合體的核酸序列與序列辨識號:29至34之任一者所示的序列具有至少85%的相似度,例如可具有86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%的相似度,但不限於此。根據一些實施例,核酸藥物複合體係由序列辨識號:29至34之任一者所示之核酸序列所組成。
詳細而言,序列辨識號:29的核酸序列是由序列辨識號:1的抗PD-L1適體以及序列辨識號:10的CpG寡核苷酸序列組合而成,序列辨識號:1的核酸序列可插入於序列辨識號:10的核酸序列之間,將序列辨識號:10分為具有15個核苷酸的第一片段以及具有15個核苷酸的第二片段,且序列辨識號:10的CpG寡核苷酸序列中的所有磷酸二酯鍵均可被修飾為硫代磷酸酯鍵。
序列辨識號:30的核酸序列是由序列辨識號:2的抗PD-L1適體以及與序列辨識號:10的CpG寡核苷酸序列具有
96%相似度的序列(5端添加2個T,3端的第二個A改為T)組合而成,序列辨識號:2的核酸序列可插入於與序列辨識號:10的CpG寡核苷酸序列具有96%相似度的序列之間,將此序列分為具有17個核苷酸的第一片段以及具有15個核苷酸的第二片段,且此序列中僅位於5端及3端的兩個磷酸二酯鍵可被修飾為硫代磷酸酯鍵。
序列辨識號:31的核酸序列是由序列辨識號:3的抗PD-L1適體以及序列辨識號:10的CpG寡核苷酸序列組合而成,序列辨識號:3的核酸序列可插入於序列辨識號:10的核酸序列之間,將序列辨識號:10分為具有15個核苷酸的第一片段以及具有15個核苷酸的第二片段,且序列辨識號:10的CpG寡核苷酸序列中的所有磷酸二酯鍵均可被修飾為硫代磷酸酯鍵。
序列辨識號:32的核酸序列是由序列辨識號:3的抗PD-L1適體以及序列辨識號:22的CpG寡核苷酸序列組合而成,序列辨識號:3的核酸序列可插入於序列辨識號:22的核酸序列之間,將序列辨識號:22分為具有15個核苷酸的第一片段以及具有15個核苷酸的第二片段,且序列辨識號:22的CpG寡核苷酸序列中的所有磷酸二酯鍵均可被修飾為硫代磷酸酯鍵。
序列辨識號:33的核酸序列是由序列辨識號:3的抗PD-L1適體以及序列辨識號:23的CpG寡核苷酸序列組合而成,序列辨識號:3的核酸序列可插入於序列辨識號:23的核酸序列之間,將序列辨識號:23分為具有15個核苷酸的第一片段以及
具有15個核苷酸的第二片段,且序列辨識號:23的CpG寡核苷酸序列中的所有磷酸二酯鍵均可被修飾為硫代磷酸酯鍵。
序列辨識號:34的核酸序列是由序列辨識號:7的抗PD-L1適體以及序列辨識號:10的CpG寡核苷酸序列組合而成,序列辨識號:7的核酸序列可插入於序列辨識號:10的核酸序列之間,將序列辨識號:10分為具有15個核苷酸的第一片段以及具有15個核苷酸的第二片段,且序列辨識號:10的CpG寡核苷酸序列中的所有磷酸二酯鍵均可被修飾為硫代磷酸酯鍵。
再者,根據一些實施例,前述之核酸藥物複合體可用於製備治療癌症的藥物。此外,根據一些實施例,提供一種醫藥組合物,其包含前述之核酸藥物複合體以及醫藥上可接受之載體,此醫藥組合物可用於治療癌症。例如,根據一些實施例,可將有效量之前述包含核酸藥物複合體的醫藥組合物施用於需要的個體。根據一些實施例,個體可包含哺乳類動物,例如,小鼠、大鼠、天竺鼠、兔子、狗、貓、猴子、猩猩或人類等,但不限於此。根據一些實施例,所述個體可為人類。根據一些實施例,醫藥組合物可藉由靜脈內(intravenous)注射、腫瘤內注射(intratumoral)與皮下注射(subcutaneous)進行給藥,但不限於此。根據一些實施例,所述醫藥組合物可藉由靜脈內(intravenous)注射進行給藥。
根據一些實施例,前述癌症可包含結腸癌、乳癌、肺癌、胰臟癌、肝癌、胃癌、食道癌、頭頸部鱗狀細胞癌、前列腺
癌、膀胱癌、淋巴瘤、膽囊癌、腎癌、血癌、大腸癌、多發性骨髓瘤、卵巢癌、子宮頸癌或神經膠質瘤,但不限於此。
根據一些實施例,醫藥組合物可呈現溶液或懸浮液形式。或者,醫藥組合物可為脫水固體(例如冷凍乾燥或噴霧乾燥的固體)。根據一些實施例,醫藥組合物可為無菌且對個體無毒性的。再者,根據一些實施例,前述醫藥上可接受之載體可包含賦形劑、增溶劑、緩衝劑、穩定劑或防腐劑,但不限於此。
例如,賦形劑可包含溶劑,根據一些實施例,醫藥組合物可包含水性媒劑作為溶劑。水性媒劑例如可包含無菌水、鹽水溶液、磷酸鹽緩衝鹽水或林格氏溶液(Ringer's solution),但不限於此。根據一些實施例,增溶劑為幫助在冷凍或噴霧乾燥期間及/或在儲存期間穩定核酸藥物複合體且防止其降解之保護劑。增溶劑例如可包含糖(單醣、雙醣及多醣),例如蔗糖、乳糖、海藻糖、甘露糖醇、山梨糖醇或葡萄糖,但不限於此。再者,根據一些實施例,緩衝劑可控制pH值以防止核酸藥物複合體在加工、儲存等期間發生降解。緩衝液例如可包含鹽類,例如乙酸鹽、檸檬酸鹽、磷酸鹽或硫酸鹽,但不限於此。緩衝液例如亦可包含胺基酸,例如精胺酸、甘胺酸、組胺酸或離胺酸,但不限於此。根據一些實施例,穩定劑例如可包含右旋糖、甘油、氯化鈉、甘油或甘露糖醇,但不限於此。根據一些實施例,防腐劑例如可包含抗氧化劑或抗微生物劑,但不限於此。
此外,根據本揭露一些實施例,提供一種套組,其包含前述醫藥組合物以及記載使用方法的說明書。包含醫藥組合物的套組係經適當包裝。根據一些實施例,套組可進一步包含用於施用醫藥組合物的裝置(例如,注射器及針頭、噴霧器、或乾燥粉末吸入裝置等)。
為了讓本揭露之上述及其它目的、特徵、及優點能更明顯易懂,下文特舉數實施例以及比較例,作詳細說明如下,然其並非用以限定本揭露之內容。
實施例1:體外的(in vitro)PD-L1結合親和性測試-流式細胞儀分析
使用胰蛋白酶(trypsin)收集表達老鼠PD-L1(mPD-L1)的CT-26細胞以及表達人類PD-L1(hPD-L1)的CHO-K1細胞,沉澱、洗滌並重新懸浮約2×105個細胞於100μL的細胞染色緩衝液(BSA緩衝液,BD)中。接著,加入100nmol的Alexa647標記的抗PD-L1適體樣品(本揭露中所有核酸序列,包含Alexa647標記的適體,均委託Integrated DNA Technologies客製化合成),並將抗PD-L1適體樣品與細胞的懸浮液避光於冰上培養60分鐘,於細胞染色緩衝液中單次洗滌之後,使細胞重新懸浮並且使用FACScan流式細胞儀(Becton Dickinson,Oxford,UK)進行分析。
流式細胞儀的分析結果如第1A圖及第1B圖所示,圖中的樣品unstained代表未經染色的細胞,可作為負控制組
(negative control);圖中的樣品AptPDL1-n05、AptPDL1-n07、AptPDL1-1A、AptPDL1-2A、AptPDL1-3A及AptPDL1-A4分別代表序列辨識號:4、5、6、7、8及9所示之抗PD-L1適體,它們的濃度均為100nM;樣品AptPDL1-45mer(PBS*)代表序列辨識號:24所示之抗PD-L1適體,其並未被配製於細胞染色緩衝液中,而是被配製於經調整的PBS緩衝液(含有鈣離子及鎂離子的DPBS(Dulbecco's Phosphate-Buffered Saline),添加1.33mM的KCl)中,濃度為100nM,並且,AptPDL1-45mer係作為已知的對照序列;樣品AptPDL1-45mer(SELEX)代表藉由SELEX技術篩選得到的序列辨識號:24所示之抗PD-L1適體,濃度為100nM,可作為正控制組(positive control);樣品AptPDL1-45mer(SELEX,600nM)代表藉由SELEX技術篩選得到的序列辨識號:24所示之抗PD-L1適體,可作為正控制組(positive control);樣品CpG-L0-PS代表不與PD-L1親和之核酸序列,可作為負控制組。
如第1A圖及第1B圖所示,樣品AptPDL1-n05、AptPDL1-n07、AptPDL1-1A、AptPDL1-2A、AptPDL1-3A、AptPDL1-A4及AptPDL1-45mer(PBS*、SELEX、600nM)均顯示往右偏移的波峰,表示它們對於PD-L1均具有結合親和性。
請參照第2圖,第2圖顯示第1A圖及第1B圖的流式細胞儀的實驗結果的量化數據,如第2圖所示,相較於CpG-L0-PS(序列辨識號:10),樣品AptPDL1-n05(序列辨識號:
4)、AptPDL1-n07(序列辨識號:5)、AptPDL1-1A(序列辨識號:6)、AptPDL1-2A(序列辨識號:7)、AptPDL1-3A(序列辨識號:8)、AptPDL1-A4(序列辨識號:9)及AptPDL1-45mer(PBS*、SELEX、600nM)(序列辨識號:24)幾乎均顯示提升的PD-L1結合親和性。
實施例2:體外的PD-L1結合親和性測試-細胞結合分析
將表達PD-L1的MDA-MB-231細胞以1×104細胞/100μl/孔的密度接種於96孔盤(Corning)中,並培養48小時。在移除培養基之後,在室溫下以50μl/孔的4%多聚甲醛(paraformaldehyde,PFA)於磷酸鹽緩衝鹽水(phosphate-buffered saline,PBS)中固定細胞10分鐘。在移除PFA之後,將100μl於PBS中的0.1M甘胺酸添加至每個孔中以淬滅(quench)殘留的PFA。之後將96孔盤於室溫下培養10分鐘。接著使用PBS洗滌細胞一次,並在室溫下用Super Block(ScyTek Laboratories Inc)阻斷60分鐘。使用不同濃度的Alexa647標記的抗PD-L1適體樣品(混合在PBS中)於二重複(duplicate)的孔中進行染色,並於37℃下培養45分鐘。之後,使用PBS洗滌細胞四次,並使用酵素免疫分析測讀儀(ELISA plate reader,Tecan,Männedorf,Switzerland)測量螢光強度,激發波長為670nm,發射波長為720nm。
ELISA的分析結果如第3圖所示,圖中的樣品cell only代表未表達PD-L1的細胞,可作為負控制組;圖中的樣品45mer、n05、n07、1A、2A、3A及A4分別代表序列辨識號:24、4、5、6、7、8及9所示之抗PD-L1適體,樣品的濃度均為700nm,均配製於經調整的PBS緩衝液(含有鈣離子及鎂離子的DPBS,添加1.33mM的KCl)中。
如第3圖所示,樣品45mer(AptPDL1-45mer,序列辨識號:24)、n07(AptPDL1-n07,序列辨識號:5)、1A(AptPDL1-1A,序列辨識號:6)、2A(AptPDL1-2A,序列辨識號:7)、3A(AptPDL1-3A,序列辨識號:8)及A4(AptPDL1-A4,序列辨識號:9)均具有高螢光強度,對於PD-L1具有結合親和性。
實施例3:核酸藥物複合體的TLR9的活化能力分析-HEK293小鼠TLR9報導系統
將表達小鼠TLR9的HEK-Blue細胞(InvivoGen)培養於完整的DMEM(Dulbecco's modified Eagle's medium)培養基中,DMEM中補充有100μg/ml的Normocin、30μg/ml的Blasticidin及100μg/ml的Zeocin(均為InvivoGen)。HEK-Blue細胞包含分泌型的胎盤鹼性磷酸酶(secreted alkaline phosphatase,SEAP)報導系統,此系統與TLR9作用後產生色度變化(colorimetric change)。
HEK-Blue檢測混合物(用於SEAP偵測的細胞培養基,InvivoGen)用於檢測SEAP的存在,SEAP與藉由NF-κB活化的TLR9訊號傳導相關。檢測混合物包含用於細胞生長的營養物質及顏色基底,當被SEAP水解時會產生顏色變化。當表達小鼠TLR9的HEK 293細胞(InvivoGen)達到60-80%的匯集(confluency)時,將其收集,離心並重新懸浮於檢測混合物中。將細胞(72 000)接種至96孔盤(180μl)的每個孔中。接著,將細胞與20μl的PBS(未刺激;作為負控制組)、CpG-L0-PS(作為正控制組)或於PBS中的不同濃度的核酸藥物複合體樣品於二重複(duplicate)的孔中組合處理,並在37℃下於5% CO2中培養24小時。使用多功能盤式分析儀(multimode plate reader)(Tecan,InfiniteTMM200 PRO,Männedorf,Switzerland)以分光光度計於620nm至655nm的波長讀取盤。
對TLR9活化能力的分析結果如第4圖所示,圖中的樣品CpG-L0-PS對應於序列辨識號:10(未連接抗PD-L1適體),且CpG寡核苷酸序列中的所有磷酸二酯鍵均被修飾為硫代磷酸酯鍵;樣品ApDC5-PS對應於序列辨識號:25,其表示CpG寡核苷酸序列連接在抗PD-L1適體序列的5端的態樣,且CpG寡核苷酸序列中的所有磷酸二酯鍵均被修飾為硫代磷酸酯鍵,其具有例如第6B圖所示的構型(其中A及B示意地表示CpG寡核苷酸序列的第一片段及第二片段的位置,以方便理解抗PD-L1適體與CpG寡核苷酸序列的位置關係);樣品ApDC5-7PS對應於序列辨識號:
26,其表示CpG寡核苷酸序列連接在抗PD-L1適體序列的5端的態樣,且CpG寡核苷酸序列中僅部分的磷酸二酯鍵被修飾為硫代磷酸酯鍵,其具有例如第6D圖所示的構型;樣品PDL1-CpG30-PS對應於序列辨識號:27,其表示CpG寡核苷酸序列連接在抗PD-L1適體序列的3端的態樣,且CpG寡核苷酸序列中的所有磷酸二酯鍵均被修飾為硫代磷酸酯鍵,其具有例如第6C圖所示的構型;樣品PDL1-CpG29-9PS對應於序列辨識號:28,其表示CpG寡核苷酸序列連接在抗PD-L1適體序列的3端的態樣,且CpG寡核苷酸序列中僅部分的磷酸二酯鍵被修飾為硫代磷酸酯鍵,其具有例如第6D圖所示的構型;樣品ApDC-A21B對應於序列辨識號:31,其表示抗PD-L1適體序列插入於CpG寡核苷酸序列中的態樣,且CpG寡核苷酸序列中的所有磷酸二酯鍵均被修飾為硫代磷酸酯鍵,其具有例如第6A圖所示的構型。
根據第4圖的結果,可得到樣品CpG-L0-PS(序列辨識號:10)的EC50值為2.09nM,樣品ApDC5-PS(序列辨識號:25)的EC50值為2.48nM,樣品ApDC5-7PS(序列辨識號:26)的EC50值為72.23nM,樣品PDL1-CpG30-PS(序列辨識號:27)的EC50值為2.36nM,樣品PDL1-CpG29-9PS(序列辨識號:28)的EC50值為148.82nM,樣品ApDC-A21B(序列辨識號:31)的EC50值為0.77nM。相較於其它樣品,樣品ApDC-A21B(序列辨識號:31)的EC50值最低,具有提升的TLR9活化能力。
由此可知,相較於CpG寡核苷酸序列連接在抗PD-L1適體序列的5端或3端的態樣,抗PD-L1適體序列插入於CpG寡核苷酸序列中的核酸藥物複合體具有較佳的TLR9活化能力。此外,CpG寡核苷酸序列中僅部分的磷酸二酯鍵被修飾為硫代磷酸酯鍵的態樣容易形成互補的雙股結構,此種態樣的核酸藥物複合體的TLR9活化能力會降低。
接著,請參照第5圖,第5圖顯示另一實施例中核酸藥物複合體對TLR9活化能力的分析結果,其實驗內容與第4圖大致相同。第5圖中的樣品CpG-L0-PS對應於序列辨識號:10(未連接抗PD-L1適體),且CpG寡核苷酸序列中的所有磷酸二酯鍵均被修飾為硫代磷酸酯鍵;樣品ApDC5-PS對應於序列辨識號:25,其表示CpG寡核苷酸序列連接在抗PD-L1適體序列的5端的態樣,且CpG寡核苷酸序列中的所有磷酸二酯鍵均被修飾為硫代磷酸酯鍵,其具有例如第6B圖所示的構型;樣品ApDC-A21B對應於序列辨識號:31,其表示抗PD-L1適體序列插入於CpG寡核苷酸序列中的態樣,且CpG寡核苷酸序列中的所有磷酸二酯鍵均被修飾為硫代磷酸酯鍵,其具有例如第6A圖所示的構型;樣品ApDC-A21A對應於序列辨識號:32,其表示抗PD-L1適體序列插入於CpG寡核苷酸序列中的態樣,且CpG寡核苷酸序列中的所有磷酸二酯鍵均被修飾為硫代磷酸酯鍵,其具有類似第6A圖所示的構型,但片段A及片段B的序列相同;樣品ApDC-B21B對應於序列辨識號:33,其表示抗PD-L1適體序列插入於CpG寡核苷
酸序列中的態樣,且CpG寡核苷酸序列中的所有磷酸二酯鍵均被修飾為硫代磷酸酯鍵,其具有類似第6A圖所示的構型,但片段A及片段B的序列相同;樣品ApDC-A33B對應於序列辨識號:30,其表示抗PD-L1適體序列插入於CpG寡核苷酸序列中的態樣,且寡核苷酸序列中僅部分的磷酸二酯鍵被修飾為硫代磷酸酯鍵。
根據第5圖的結果,可得到樣品CpG-L0-PS(序列辨識號:10)的EC50值為2.1nM,樣品ApDC5-PS(序列辨識號:25)的EC50值為5.5nM,樣品ApDC-A21B(序列辨識號:31)的EC50值為1.3nM,樣品ApDC-A21A(序列辨識號:32)的EC50值為0.6nM,樣品ApDC-B21B(序列辨識號:33)的EC50值為0.6nM,樣品ApDC-A33B(序列辨識號:30)的EC50值為16380nM。
相較於樣品ApDC5-PS(序列辨識號:25),抗PD-L1適體序列插入於CpG寡核苷酸序列中的樣品ApDC-A21B(序列辨識號:31)、ApDC-A21A(序列辨識號:32)及ApDC-B21B(序列辨識號:33)具有較低的EC50值,亦即具有改善的TLR9活化能力。此外,相較於CpG寡核苷酸序列中僅部分的磷酸二酯鍵被修飾為硫代磷酸酯鍵的態樣,CpG寡核苷酸序列中的所有磷酸二酯鍵均被修飾為硫代磷酸酯鍵的態樣亦具有較佳的TLR9活化能力。
實施例4:核酸藥物複合體於動物模型體內的(in vivo)抗腫瘤功效分析
使用4T1鼠乳腺癌同源腫瘤模型(syngeneic tumor model)進行體內抗腫瘤療效研究。將4T1(5x105細胞)皮下植入於BALB/c小鼠中。使用卡尺(caliper)測量腫瘤大小,並使用以下公式將其轉換為腫瘤體積;V=LS2/2(其中L為最長直徑,S為最短直徑)。將小鼠隨機分組(n=4~5),且當腫瘤體積達到100~200mm3時進行投藥。每週兩次腹膜內(intraperitoneally)注射抗小鼠PD-L1抗體(PDL1 mAb,InVivoPlus anti-mouse PD-L1,BioXCell)。每週兩次靜脈注射CpG寡核苷酸(序列辨識號:10)以及抗PD-L1適體(序列辨識號:1)(併用形式,標示為AptPDL1+CpG)、以及抗PD-L1適體與CpG寡核苷酸序列共軛連接的核酸藥物複合體(序列辨識號:25)(ApDC5-PS)。由腫瘤生長抑制(tumor growth inhibition,TGI)的百分比判斷抗腫瘤功效。TGI的計算方式為[1-(治療組的最終腫瘤體積-初始腫瘤體積)/(載劑(vehicle)組的最終腫瘤體積-初始腫瘤體積)]×100%。
根據第7圖顯示的結果,經樣品ApDC5-PS(序列辨識號:25)處理的腫瘤體積明顯較低,其抗腫瘤功效比併用CpG寡核苷酸以及抗PD-L1適體(AptPDL1+CpG)的態樣好,也比單獨注射抗小鼠PD-L1抗體(PDL1 mAb)的態樣好。並且,注射樣品ApDC5-PS的小鼠存活率亦明顯提升,於腫瘤細胞接種後的25天後仍有100%的存活率。
再者,第8圖顯示於另一實施例中核酸藥物複合體的抗腫瘤功效分析結果,其實驗內容與第7圖大致相同。第8圖中
的樣品CpG-L0-PS對應於序列辨識號:10(未連接抗PD-L1適體);樣品ApDC-A21B對應於序列辨識號:31,其為抗PD-L1適體序列插入於CpG寡核苷酸序列中的態樣。如第8圖所示,相較於樣品CpG-L0-PS,樣品ApDC-A21B具有較佳的抗腫瘤功效,具有改善的藥效。
承前述,本揭露實施例提供的新型態核酸藥物複合體結合CpG寡核苷酸序列與抗PD-L1適體,其具有腫瘤標靶與免疫檢查點阻斷活性,可增加核酸藥物複合體於腫瘤的累積與腫瘤微環境的免疫細胞毒殺效果,並且具有刺激多種免疫細胞活化的能力,可增加腫瘤微環境的免疫細胞活化與聚集。此外,本揭露實施例提供的核酸藥物複合體具有比單純混用CpG寡核苷酸以及抗PD-L1適體更佳的抗腫瘤藥效。
雖然本揭露的實施例及其優點已揭露如上,但應該瞭解的是,任何所屬技術領域中具有通常知識者,在不脫離本揭露之精神和範圍內,當可作更動、替代與潤飾。再者,每一申請專利範圍構成個別的實施例,且本揭露之保護範圍也包括各個申請專利範圍及實施例的組合。本揭露之保護範圍當視後附之申請專利範圍所界定者為準。
Claims (11)
- 一種核酸藥物複合體,包括:一抗PD-L1適體的核酸序列,其係結合至PD-L1,該抗PD-L1適體的核酸序列係由序列辨識號:1至9之任一者所組成;以及一CpG寡核苷酸序列,其係結合至TLR9受體並用於活化TLR9,該CpG寡核苷酸序列係由序列辨識號:10至23之任一者所組成,其中該CpG寡核苷酸序列由一第一片段以及一第二片段所組成,其中該抗PD-L1適體的核酸序列插入於該CpG寡核苷酸序列之該第一片段以及該第二片段之間,其中該第一片段的長度與該第二片段的長度的比例範圍為1:10至10:1。
- 如請求項1所述之核酸藥物複合體,其中該CpG寡核苷酸序列包括硫代磷酸酯鍵(phosphorothioate bond)。
- 如請求項2所述之核酸藥物複合體,其中該硫代磷酸酯鍵的數量佔該CpG寡核苷酸序列的磷酸二酯鍵的數量的70%至100%。
- 如請求項3所述之核酸藥物複合體,其中該硫代磷酸酯鍵的數量佔該CpG寡核苷酸序列的磷酸二酯鍵的數量的80%至100%。
- 如請求項1所述之核酸藥物複合體,其係由序列辨識號:29及31至34之任一者所示之核酸序列所組成。
- 一種如請求項1至5中任一項所述之核酸藥物複合體的用途,其係用於製備治療癌症的藥物。
- 如請求項6所述之用途,其中該癌症包括結腸癌、乳癌、肺癌、胰臟癌、肝癌、胃癌、食道癌、頭頸部鱗狀細胞癌、前列腺癌、膀胱癌、淋巴瘤、膽囊癌、腎癌、血癌、大腸癌、多發性骨髓瘤、卵巢癌、子宮頸癌或神經膠質瘤。
- 一種醫藥組合物,包括如請求項1至5中任一項所述之核酸藥物複合體以及醫藥上可接受之載體。
- 如請求項8所述之醫藥組合物,其係用於治療癌症。
- 如請求項8所述之醫藥組合物,其係藉由靜脈內(intravenous)注射、腫瘤內注射(intratumoral)或皮下注射(subcutaneous)進行給藥。
- 一種套組,包括如請求項8所述之醫藥組合物。
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