TW202106704A - 抗利妥昔單抗嵌合抗原受體及其用途 - Google Patents
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Abstract
本文提供了編碼嵌合抗原受體(CAR)之聚核苷酸,所述嵌合抗原受體包括特異性結合至CD19並對利妥昔單抗結合具有抗性的CD19抗原結合域;及包括此等CD19特異性CAR之免疫細胞,例如CAR-T細胞。亦提供製備及使用此等CD19特異性CAR以及包括此等CD19特異性CAR之免疫細胞之方法。
Description
相關申請之交叉引用
本申請案主張2019年4月26日提交之美國臨時申請案第62/839,455號及2020年4月3日提交之美國臨時申請案第63/005,041號之優先權,其全部內容以全文引用之方式併入本文中。
本揭示案係關於包括結合至CD19之抗原結合分子之嵌合抗原受體(CAR)、編碼所述CAR之聚核苷酸及使用所述CAR治療患者之癌症的方法。
序列表
本申請案含有序列表,所述序列表已以電子方式以ASCII格式提交且以全文引用之方式併入本文中。2020年4月21日創建之所述ASCII複本命名為AT-028_03_SL.txt且大小為80,074個位元組。
經基因修飾以識別惡性病相關之抗原之免疫細胞的授受性轉移顯示出有望作為治療癌症之新穎方法(參見例如Brenner等人,《免疫學新見(Current Opinion in Immunology)》, 22(2):251-257(2010);Rosenberg等人,《癌症自然評論(Nature Reviews Cancer)》, 8(4):299-308 (2008))。免疫細胞可經基因修飾以表現嵌合抗原受體(CAR),由CD19抗原識別部分及T細胞活化域構成之融合蛋白(參見例如Eshhar等人,《美國國家科學院院刊(Proc. Natl. Acad. Sci. USA)》, 90(2):720-724(1993)及Sadelain等人,《免疫學新見(Curr.Opin.Immunol)》,21(2):215-223 (2009))。含有CAR之免疫細胞,例如CAR-T細胞(CAR-T),經工程改造以賦予其抗原特異性,同時保留或增強其識別及殺滅靶細胞的能力。
需要治療涉及CD19表現異常之癌症且尤其惡性病。本文提供解決此需要之方法及組合物。
本文提供包括特異性結合至CD19之CD19抗原結合域之嵌合抗原受體(CAR);編碼此等CAR之聚核苷酸;及表現此等CD19特異性CAR之免疫細胞,例如CAR-T細胞。亦提供製備及使用此等CD19特異性CAR以及包括此等CD19特異性CAR之免疫細胞之方法。
在一個態樣中,本揭示案提供一種經分離之聚核苷酸,其編碼包括與SEQ ID NO:9至少70%一致之抗CD19嵌合抗原受體(CAR)的多肽,其中多肽不包括利妥昔單抗結合位點,且其中聚核苷酸包括能夠在哺乳動物T細胞中表現抗CD19嵌合抗原受體(CAR)之短EF1a啟動子。
在一些實施例中,短EF1a啟動子不包括SEQ ID NO:15之核酸序列內的內含子序列。在一些實施例中,內含子包括SEQ ID NO:39之核酸序列。
在一些實施例中,啟動子包括SEQ ID NO:16之核酸序列。
在一些實施例中,啟動子為包括SEQ ID NO:15之核酸序列的全長EF1a啟動子。
在一些實施例中,啟動子包括SEQ ID NO:15之核酸序列,且聚核苷酸編碼與SEQ ID NO:8-14中之任一者至少約80%、85%、90%、95%、96%、98%、99%或100%一致的多肽。
在一些實施例中,多肽進一步包括安全開關(safety switch)。
在一些實施例中,安全開關使用連接肽連接至CD19 CAR。
在一些實施例中,安全開關使用T2A連接子連接至抗CD19 CAR。
在一些實施例中,安全開關包括抗體結合位點。
在一些實施例中,安全開關包括突變的CD20模擬抗原決定基。
在一些實施例中,多肽進一步包括CD8鉸鏈/跨膜域。
在一些實施例中,多肽包括CD34抗原決定基。
在一些實施例中,CD34抗原決定基為QBEND-10抗原決定基。
在一些實施例中,經分離之聚核苷酸包括與SEQ ID NO:1-7中之任一者至少約80%、85%、90%、95%、96%、98%、99%或100%一致的核酸序列。
在一些實施例中,經分離之聚核苷酸編碼與SEQ ID NO:8-14中之任一者至少約80%、85%、90%、95%、96%、98%、99%或100%一致的多肽。
在另一態樣中,本揭示案提供一種載體,其包括本文所述之經分離之聚核苷酸。
在一些實施例中,載體為反轉錄病毒載體、DNA載體、質體、RNA載體、腺病毒載體、腺病毒相關之載體、慢病毒載體或其任何組合。
在一個態樣中,本揭示案提供一種經工程改造之免疫細胞,其包括本文所述之經分離之聚核苷酸。
在一些實施例中,本揭示案提供包括聚核苷酸之經工程改造之免疫細胞,所述聚核苷酸包括與SEQ ID NO:3至少約80%、85%、90%、95%、96%、98%、99%或100%一致的核酸序列。
在一些實施例中,本揭示案提供包括與如表1中所示之抗CD19 CAR v1.2、v1.3、v1.4、v1.5或v1.6慢病毒構築體至少約80%、85%、90%、95%、96%、98%、99%或100%一致之聚核苷酸的經工程改造之免疫細胞。
在一些實施例中,本揭示案提供包括與如表1中所示之抗CD19 CAR v1.2慢病毒構築體至少約80%、85%、90%、95%、96%、98%、99%或100%一致之聚核苷酸的經工程改造之免疫細胞。
在一些實施例中,本揭示案提供經工程改造之免疫細胞,其包括編碼與具有或不具有信號序列之SEQ ID NO:9或SEQ ID NO:10至少約80%、85%、90%、95%、96%、98%、99%或100%一致之多肽的聚核苷酸。
在一些實施例中,本揭示案提供包括聚核苷酸之經工程改造之免疫細胞,所述聚核苷酸包括由包括SEQ ID NO:16之核酸之EF1a短啟動子驅動之SEQ ID NO:3的核酸序列。
在一些實施例中,本揭示案提供包括聚核苷酸之經工程改造之免疫細胞,所述聚核苷酸編碼由包括SEQ ID NO:16之核酸的EF1a短啟動子驅動之具有或不具有信號序列之SEQ ID NO:9或10的多肽序列。在一些實施例中,啟動子不包括EF1a基因之第一內含子。
在一些實施例中,經工程改造之免疫細胞不包括利妥昔單抗模擬抗原決定基。
在一些實施例中,經工程改造之免疫細胞包括聚核苷酸,所述聚核苷酸包括如圖1中所示之CD19 CAR v1.2慢病毒構築體(亦可稱為ALLO-501A)。
在一些實施例中,經工程改造之免疫細胞包括本文所述之載體。
在一些實施例中,免疫細胞為T細胞、腫瘤浸潤性淋巴細胞(TIL)、NK細胞、TCR表現細胞、樹突狀細胞或NK-T細胞。
在一些實施例中,細胞為自體T細胞。
在一些實施例中,細胞為同種異體T細胞。
在一個態樣中,本揭示案提供本文所描述之經工程改造之免疫細胞,其中細胞對利妥昔單抗具有抗性。
在另一態樣中,本揭示案提供包括本文所述之經工程改造之免疫細胞的醫藥組成物。
在一個態樣中,本揭示案提供一種治療有需要之個體之疾病或病症的方法,其包括向個體投與本文所述之經工程改造之免疫細胞或本文所述之醫藥組成物。
在一些實施例中,疾病或病症為非霍奇金氏淋巴瘤(Non-Hodgkin lymphoma;NHL)。
在一些實施例中,個體已用利妥昔單抗治療或目前正在用利妥昔單抗治療。
在一個態樣中,本揭示案提供一種製品,其包括經工程改造之免疫細胞或醫藥組成物,所述醫藥組成物包括表現本文所述之嵌合抗原受體的經工程改造之免疫細胞。
嵌合抗原受體(CAR)療法為癌症治療之有前景的方法。本文中描述為v1.0之CAR構築體為表現充當安全開關之合成肽RQR8之例示性抗CD19 CAR。RQR8含有兩個利妥昔單抗結合擬抗原決定基。在不良事件之情況下,患者可用利妥昔單抗治療以耗乏循環中之抗CD19 v1.0之含量。利妥昔單抗亦在一些非霍奇金淋巴瘤(NHL)適應症中用作標準治療(standard of care)且在高劑量下投與。歸因於利妥昔單抗之較長半衰期,在循環利妥昔單抗之含量已達至低濃度之前,無法向患者投與抗CD19 v1.0。抗利妥昔單抗CD19 CAR療法將允許先前用利妥昔單抗治療之患者立即接受CAR-T療法,而不必等待利妥昔單抗含量降低且無需對患者進行血球分離術。本文提供抗CD19嵌合抗原受體(CARs),其對CD20結合抗體利妥昔單抗具有抗性。新穎CAR構築體經設計以消除利妥昔單抗結合,同時保持CAR表現及活性。
I.嵌合抗原受體
如本文所使用,嵌合抗原受體(CAR)為特異性識別靶抗原(例如癌細胞上之靶抗原)之蛋白質。當結合至靶抗原時,CAR可活化免疫細胞以攻擊及破壞攜帶所述抗原之細胞(例如癌細胞)。CAR亦可併有共刺激或信號傳導域以提高其效價。參見Krause等人,《實驗醫學雜誌(J . Exp. Med.)》,第188卷,第4號,1998(619-626);Finney等人,《免疫學雜誌(Journal of Immunology
)》1998, 161:2791-2797,Song等人,《血液(Blood)》119:696-706(2012);Kalos等人,《科學轉化醫學(Sci.Transl.Med.
)》3:95(2011);Porter等人,《新英格蘭醫學雜誌(N. Engl. J. Med .
)》365:725-33(2011),及Gross等人,《藥理學與毒理學年刊(Annu. Rev. Pharmacol.Toxicol.
)》56:59-83(2016);美國專利第7,741,465號及第6,319,494號。
本文所述之嵌合抗原受體包括胞外域、跨膜域及胞內域,其中所述胞外域包括特異性結合至CD19之CD19抗原結合域。在一些實施例中,CD19特異性CAR自5'至3'包括以下元件:信號序列、CD19抗原結合域(例如來源於4G7之scFv)、鉸鏈及跨膜區及一或多個連續信號傳導域。在一些實施例中,抗體結合域結合CD19以治療與CD19表現相關之血液癌。
同種異體抗CD19 CAR v1.0中使用之嵌合抗原受體(CAR)之scFv部分來源於小鼠抗人類CD19抗體純系4G7。4G7為識別CD19之CD19單株抗體。由4G7形成之單鏈可變片段(scFv)包括一些嵌合抗原受體(CAR)之靶向組分(參見WO2014184143A1)。在一些實施例中,來源於CD19單株抗體4G7之scFv包括藉由可撓性連接子連接在一起之CD19單株抗體4G7免疫球蛋白γ1重鏈之一部分(GenBank:CAD88275.1;SEQ ID NO:17)及CD19單株抗體4G7免疫球蛋白κ輕鏈之一部分(GenBank:CAD88204.1;SEQ ID NO:35)。(Peipp M.,D.Saul等人,2004.針對FACS應用之CD抗原之螢光scFv融合蛋白之有效真核表現(Efficient eukaryotic expression of fluorescent scFv fusion proteins directed against CD antigens for FACS applications).《免疫學方法雜誌(J . Immunol .Methods
)》285:265-280)。在一些實施例中,scFv包括藉由可撓性連接子連接在一起之CD19單株抗體4G7免疫球蛋白γ1重鏈的可變片段及CD19單株抗體4G7免疫球蛋白κ輕鏈的可變片段。
CD19單株抗體4G7免疫球蛋白γ1重鏈(信號序列加下劃線)
CD19單株抗體4G7免疫球蛋白κ輕鏈(信號序列加下劃線)
在一些實施例中,scFv包括SEQ ID NO:17及/或SEQ ID NO:18之胺基酸序列的一部分。在一些實施例中,scFv包括與34及/或SEQ ID NO:35之胺基酸序列之可變區至少70%、至少80%、至少90%、至少95%、至少97%或至少99%之序列一致性。本文揭示抗原結合分子,其包含特異性結合至來源於4G7之抗CD19 scFv之抗體,以及包括此等序列之分子及呈現此類分子之細胞。抗原結合分子之人類化形式亦形成為本揭示案之態樣。亦揭示此等抗原結合分子之應用及用途。
a. 抗原結合域
如上文所論述,本文所述之CD19 CAR包括抗原結合域。如本文所用之「抗原結合域」意謂結合指定靶抗原之任何多肽,例如指定靶抗原可為CD19蛋白或其片段。在一些實施例中,抗原結合域結合至腫瘤細胞上之CD19抗原。在一些實施例中,抗原結合域結合至涉及過度增生性疾病之細胞上之CD19抗原。
在一些實施例中,抗原結合域包括可變重鏈、可變輕鏈及/或一或多個CDR。在一些實施例中,抗原結合域為包括輕鏈CDR,CDR1、CDR2及CDR3及重鏈CDR,CDR1、CDR2及CDR3之單鏈可變片段(scFv)。抗原結合域之變異體(例如CDR、VH及/或VL之變異體)亦在本揭示案之範疇內,例如各自具有與本文所描述之抗原結合域序列之胺基酸序列至少70-80%、80-85%、85-90%、90-95%、95-97%、97-99%或高於99%一致之可變輕鏈及/或可變重鏈。在一些情況下,此類分子包含至少一個重鏈及一個輕鏈,而在其他情況下,變異體形式含有兩個可變輕鏈及兩個可變重鏈(或其子部分)。熟習此項技術者將能夠使用熟知技術測定如本文所闡述之抗原結合域之適合變異體。在某些實施例中,本領域中熟習此項技術者可藉由靶向咸信對活性不重要之區域來鑑別分子中可在不破壞活性之情況下進行改變的適合區域。
在某些實施例中,抗原結合域之多肽結構係基於抗體,所述抗體包含但不限於單株抗體、雙特異性抗體、微型抗體、域抗體、合成抗體(有時在本文中稱為「抗體模擬物」)、嵌合抗體、人類化抗體、人類抗體、抗體融合物(有時在本文中稱為「抗體結合物」)及其對應片段。在一些實施例中,抗原結合域包括高親和性多聚體或由高親和性多聚體組成。
當CD19抗原結合域結合至一個目標比其結合至第二目標更緊密時,其稱為「選擇性的」。在一些實施例中,CD19抗原結合域為scFv。
在一些實施例中,本揭示案係關於編碼本文所述之CD19嵌合抗原受體(CAR)中之任一者的經分離之聚核苷酸。在一些實施例中,本揭示案係關於編碼表1中描述之CD19 CAR的經分離之聚核苷酸。本文亦提供包括聚核苷酸之載體及其製造方法。
b.安全開關及單株抗體特異性抗原決定基
安全開關
應瞭解,不良事件可藉由用除利妥昔單抗結合抗原決定基外之自殺基因轉導免疫細胞(含有一或多個CAR)來降至最少。亦可能需要將誘導性「開啟(on)」或「加速(accelerator)」開關併入至免疫細胞中。在用本揭示案之CAR構築體轉導細胞之前、之後或同時,適合技術包含使用誘導性卡斯蛋白酶9(caspase-9)(美國申請案2011/0286980)或胸苷激酶。引入自殺基因及/或「開啟」開關之額外方法包含TALENS、鋅指、RNAi、siRNA、shRNA、反義技術及此項技術中已知之其他技術。
根據本揭示案,本文中可併入開閉(on-off)或其他類型之控制開關技術。此等技術可使用二聚域及視情況存在之此類域二聚作用之活化劑。此等技術包含例如Wu等人, 《科學(Science)》2014 350(6258)中所述在某些細胞中利用FKBP/Rapalog二聚系統之彼等技術,其內容以全文引用之方式併入本文中。額外二聚技術描述於例如Fegan等人,《化學綜述(Chem .Rev.)》2010, 110, 3315-3336以及美國專利第5,830,462號、第5,834,266號、第5,869,337號、及第6,165,787號中,其內容亦以全文引用之方式併入本文中。額外二聚對可包含環孢靈-A/親環蛋白受體、雌激素/雌激素受體(視情況使用他莫昔芬(tamoxifen))、糖皮質激素/糖皮質激素受體、四環素/四環素受體、維生素D/維生素D受體。二聚技術之其他實例可見於例如WO 2014/127261、WO 2015/090229、US 2014/0286987、US 2015/0266973、US 2016/0046700、美國專利第8,486,693號、US 2014/0171649及US 2012/0130076中,其內容進一步以全文引用之方式併入本文中。
在一些實施例中,本揭示案之CAR免疫細胞(例如CAR-T細胞)包括編碼缺乏利妥昔單抗結合之自殺多肽之聚核苷酸。在一些實施例中,自殺肽包括突變的RQR8序列。參見例如WO2013153391A,其以全文引用之方式併入本文中。在包括聚核苷酸之CAR免疫細胞(例如CAR-T細胞)細胞中,自殺多肽表現於CAR免疫細胞(例如CAR-T細胞)之表面處。在一些實施例中,自殺多肽包括SEQ ID NO:19中所示之胺基酸序列。
自殺多肽亦可以在胺基末端包括信號肽,例如,MGTSLCWMALCLLGADHADA(SEQ ID NO:20)。在一些實施例中,自殺多肽包括SEQ ID NO:21中所示之胺基酸序列,其包含SEQ ID NO:20之信號序列。
在某些實施例中,自殺肽包括胺基酸序列,其包括降低或消除利妥昔單抗結合之一或多個突變殘基、插入殘基或缺失殘基。
當自殺多肽表現於CAR免疫細胞(例如CAR-T細胞)之表面時,結合至多肽之自殺基因抗原決定基的抗體引起細胞溶解。CD19特異性CAR免疫細胞(例如CAR-T細胞)之缺失可例如藉由向患者投與自殺劑活體內發生。使所轉移細胞缺失之決定可起因於在患者中偵測到可歸因於所轉移細胞之非所需影響,諸如當偵測到不可接受之毒性水準時。如本文所用,「自殺劑」係指結合至CAR免疫細胞且引起表現CAR之免疫細胞溶解的分子。
在一些實施例中,自殺多肽表現於細胞表面上。在一些實施例中,自殺多肽包含於CAR構築體中。在一些實施例中,自殺多肽並非CD19 CAR構築體之一部分。
在一些實施例中,本文所揭示之CD19特異性CAR中之任一者的胞外域可包括一或多個對單株抗體具有特異性(亦即,由其特異性識別)之抗原決定基。此等抗原決定基在本文中亦稱為mAb特異性抗原決定基。例示性mAb特異性抗原決定基揭示於國際專利公開案第WO 2016/120216號中,其全文併入本文中。在此等實施例中,CAR之胞外域包括特異性結合至CD19之抗原結合域及一或多個結合至一或多種單株抗體(mAb)之抗原決定基。包括mAb特異性抗原決定基之CAR可為單鏈或多鏈。
將對單株抗體具有特異性之抗原決定基納入本文所述CAR之胞外域中允許分選及耗乏表現CAR之經工程改造之免疫細胞。在一些實施例中,此特徵亦促進藉由投與表現CAR之經工程改造之免疫細胞所耗乏之內源CD19表現細胞的恢復。在一些實施例中,在有害影響之情況下,例如在向個體投與後,允許耗乏提供安全開關。
因此,在一些實施例中,本揭示案係關於一種用於分選及/或耗乏具有包括mAb特異性抗原決定基之CAR的經工程改造之免疫細胞之方法及用於促進內源CD19表現細胞恢復之方法。
可使用若干抗原決定基單株抗體偶合產生包括單株抗體特異性抗原決定基之CAR;詳言之,已批准用於醫療用途或供GMP製造之用之彼等者,諸如作為非限制性實例之CD34抗原決定基/QBEND-10。
本揭示案亦涵蓋用於分選具有表現mAb特異性抗原決定基之CD19特異性CAR之經工程改造之免疫細胞的方法及治療方法,其中具有此等CAR之經工程改造之免疫細胞的活化係藉由使用靶向所述CAR之外部配位體結合域之抗體耗乏細胞來調節。表2提供可插入至本揭示案之CAR之胞外域中之例示性模擬抗原決定基序列。
在某些實施例中,CAR包括與表2中闡述之抗原決定基或模擬胺基酸序列至少約75%、至少約80%、至少約85%、至少約90%、至少約95%、至少約96%、至少約97%、至少約98%、至少約99%或100%一致的抗原決定基或模擬抗原決定基胺基酸序列。在某些實施例中,CAR包括不為或不包括SEQ ID NO:22之抗原決定基或模擬抗原決定基胺基酸序列。在某些實施例中,CAR包括抗原決定基或模擬抗原決定基,其包括SEQ ID NO:30之胺基酸序列。
c.鉸鏈域
本揭示案之CAR之胞外域可包括「鉸鏈」域(或鉸鏈區)。術語通常於用以將CAR中之跨膜域連接至CAR中之胞外抗原結合域之任何多肽。特定言之,鉸鏈域可用於為胞外抗原結合域提供更高可撓性及可接近性。
鉸鏈域可包括至多300個胺基酸,在一些實施例中,包括10至100個胺基酸,或在一些實施例中,包括25至50個胺基酸。鉸鏈域可來源於天然存在之分子之全部或一部分,諸如來源於CD8、CD4、CD28、4-1BB或IgG之胞外區之全部或一部分(特定言之,IgG之鉸鏈區;應瞭解,鉸鏈區可含有免疫球蛋白家族之一些或全部成員,諸如IgG1、IgG2、IgG3、IgG4、IgA、IgD、IgE、IgM或其片段),或來源於抗體重鏈恆定區之全部或一部分。或者,鉸鏈域可為對應於天然存在之鉸鏈序列的合成序列,或可為完全合成之鉸鏈序列。在一些實施例中,鉸鏈域為人類CD8α鏈之一部分(例如NP_001139345.1)。在另一特定實施例中,鉸鏈及跨膜域包括人類CD8α鏈之一部分。在一些實施例中,本文所描述之CAR之鉸鏈域包括CD8α、IgG1、IgG4、PD-1或FcγRIIIα之子序列,尤其CD8α、IgG1、IgG4、PD-1或FcγRIIIα中之任一者之鉸鏈區。在一些實施例中,鉸鏈域包括人類CD8α鉸鏈、人類IgG1鉸鏈、人類IgG4、人類PD-1或人類FcγRIIIα鉸鏈。在一些實施例中,本文所揭示之CAR包括scFv、CD8α人類鉸鏈及跨膜域、CD3ζ信號傳導域及4-1BB信號傳導域。表3提供用於本文所提供之例示性鉸鏈之胺基酸序列。
在某些實施例中,鉸鏈區包括與表3中闡述之鉸鏈域胺基酸序列至少約75%、至少約80%、至少約85%、至少約90%、至少約95%、至少約96%、至少約97%、至少約98%、至少約99%或100%一致的胺基酸序列。
d. 跨膜域
本揭示案之CAR設計成具有融合至CAR之胞外域之跨膜域。其可類似地融合至CAR之胞內域。在一些情況下,可以藉由胺基酸取代來選擇或修飾跨膜域,以避免此類域結合至相同或不同表面膜蛋白之跨膜域,從而使與受體複合物中之其他成員的相互作用降至最低。在一些實施例中,短連接子可在CAR之任何或一些胞外域、跨膜域及胞內域之間形成鍵聯。在一些實施例中,連接子包括甘胺酸重複序列。在一些實施例中,連接子包括(GGGGS)n,其中n為1、2、3、4或5(SEQ ID NO:41)。
本文所揭示之CAR的適合跨膜域具有以下能力:(a)在表面表現之免疫細胞,諸如但不限於淋巴球細胞,諸如T輔助(Th
)細胞、細胞毒性T(Tc
)細胞、T調節性(Treg
)細胞或自然殺手(NK)細胞,及/或(b)與胞外抗原結合域及胞內信號傳導域相互作用,以引導免疫細胞針對靶細胞之細胞反應。
跨膜域可來源於天然來源或合成來源。在來源為天然時,域可來源於任何膜結合蛋白或跨膜蛋白。
在本揭示案中特別使用的跨膜區可以源自(包括或對應於)CD28、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程式性死亡1(PD-1) 、誘導性T細胞共刺激因子(ICOS)、淋巴細胞功能相關抗原1(LFA-1、CD1-1a/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7-H3)、LIGHT(TNFSF14)、NKG2C、Igα(CD79a)、DAP-10、Fcγ受體、MHC 1類分子、TNF受體蛋白、免疫球蛋白、細胞介素受體、整合素、信號傳導淋巴細胞活化分子(SLAM蛋白)、活化NK細胞受體、BTLA、鐸配位體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2R β、IL-2Rγ、IL-7R α、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD1 1d、ITGAE、CD103、ITGAL、CD1 1a、LFA-1、ITGAM、CD1 1b、ITGAX、CD1 1c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4(CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRT AM、Ly9(CD229)、CD160 (BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6 (NTB-A、Ly108)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELLPG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、與CD83特異性結合之配位體或其任何組合。
作為非限制性實例,跨膜區可來源於或為T細胞受體(諸如α、β、γ或δ)之一部分;構成CD3複合物之多肽;IL-2受體p55(a鏈)、p75(β鏈)或γ鏈;Fc受體,特定言之,Fcγ受體II或CD蛋白之次單元鏈。或者,跨膜域可為合成的且可主要包括疏水性殘基,諸如白胺酸及纈胺酸。在一些實施例中,跨膜域來源於人類CD8α鏈(例如NP_001139345.1)。
在一些實施例中,本揭示案之CAR中之跨膜域為CD8α跨膜域。在一些實施例中,本揭示案之CAR中之跨膜域為CD8α跨膜域,其包括胺基酸序列IYIWAPLAGTCGVLLLSLVIT(SEQ ID NO:35)。在一些實施例中,CD8α跨膜域包括編碼SEQ ID NO:35之跨膜胺基酸序列的核酸序列。在一些實施例中,本揭示案之CAR中之鉸鏈及跨膜域為包括胺基酸序列TTTPAPRPPTPAPTIAS QPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVIT(SEQ ID NO:36)之CD8α鉸鏈及跨膜域。
e. 胞內域
本揭示案之CAR之胞內(細胞質)域可提供包括CAR之免疫細胞之正常效應功能中之至少一者的活化。T細胞之效應功能例如可指細胞溶解活性或輔助活性,包含分泌細胞介素。
在一些實施例中,用於CAR之活化胞內信號傳導域可以是例如但不限於T細胞受體及共受體之細胞質序列,其協同作用以在抗原受體參與之後啟動信號轉導,以及此等序列之任何衍生物或變異體以及具有相同功能能力之任何合成序列。
應瞭解,合適的(例如,活化的)胞內域包含但不限於源自(或對應於)以下之信號傳導域:CD28、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程式性死亡1(PD-1)、誘導性T細胞共刺激因子(ICOS)、淋巴細胞功能相關抗原1(LFA-1、CD1-1a/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7-H3)、LIGHT (TNFSF14)、NKG2C、Igα(CD79a)、DAP-10、Fcγ受體、MHC 1類分子、TNF受體蛋白、免疫球蛋白、細胞介素受體、整合素、信號傳導淋巴細胞活化分子(SLAM蛋白)、活化NK細胞受體、BTLA、鐸配位體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2R β、IL-2Rγ、IL-7R α、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD1 1d、ITGAE、CD103、ITGAL、CD1 1a、LFA-1、ITGAM、CD1 1b、ITGAX、CD1 1c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4 (CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRT AM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6(NTB-A、Ly108)、SLAM (SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELLPG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、與CD83特異性結合之配位體或其任何組合。
除上述活化域以外,本揭示案CAR之胞內域可併有共刺激信號傳導域(在本文中可互換地稱為共刺激分子)以提高其效價。共刺激域可提供除如本文所述之活化分子所提供之主要信號之外的信號。
應瞭解,在本揭示案範疇內之合適的共刺激域可以衍生自(或對應於)例如CD28、OX40、4-1BB/CD137、CD2、CD3(α、β、δ、ε、γ、ζ)、CD4、CD5、CD7、CD9、CD16、CD22、CD27、CD30、CD 33、CD37、CD40、CD 45、CD64、CD80、CD86、CD134、CD137、CD154、PD-1、ICOS、淋巴細胞功能相關之抗原-1(LFA-1(CD1 1a/CD18))、CD247、CD276(B7-H3)、LIGHT(腫瘤壞死因子超家族成員14;TNFSF14)、NKG2C、Igα(CD79a)、DAP-10、Fcγ受體、MHC I類分子MHC I類分子、TNFR、整合素、信號傳導淋巴球性活化分子、BTLA、鐸配位體受體、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2Rβ、IL-2Rγ、IL-7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD1-1d、ITGAE、CD103、ITGAL、CD1-1a、LFA-1、ITGAM、CD1-1b、ITGAX、CD1-1c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRT AM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A、Ly108)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、CD83配位體或其片段或組合。應瞭解,上文未列出之額外共刺激分子或其片段在本揭示案之範疇內。
在一些實施例中,CAR之胞內/細胞質域可設計成包括41BB/CD137本身本身或與適用於本揭示案之CAR情形的任何其他所需胞內域組合。41BB/CD137之完整原生胺基酸序列描述於NCBI參考序列:NP_001552.2中。完整原生41BB/CD137核酸序列描述於NCBI參考序列:NM_001561.5中。
在一些實施例中,CAR之胞內/細胞質域可設計成包括CD28域本身或與適用於本揭示案CAR之情形下之任何其他所需一或多個胞內域組合。CD28之完整原生胺基酸序列描述於NCBI參考序列:NP_006130.1中。完整原生CD28核酸序列描述於NCBI參考序列:NM_006139.1中。
在一些實施例中,CAR之胞內/細胞質域可設計成包括CD3ζ域本身或與適用於本揭示案CAR之情形下之任何其他所需一或多個胞內域組合。在一些實施例中,CAR之胞內信號傳導域可包括CD3ζ信號傳導域,其具有與SEQ ID NO:38中所示之胺基酸序列至少約70%、至少80%、至少90%、95%、97%或99%序列一致性的胺基酸序列。舉例而言,CAR之胞內域可包括CD3 ζ鏈部分及共刺激信號傳導分子之一部分。在本揭示案之CAR之胞內信號傳導部分內的胞內信號傳導序列可以隨機或指定順序彼此連接。在一些實施例中,胞內域經設計以包括CD3 ζ之活化域及CD28之信號傳導域。
在一些實施例中,本揭示案之CAR之胞內信號傳導域包括共刺激分子之域。在一些實施例中,本揭示案之CAR之胞內信號傳導域包括選自由41BB(基因庫:AAA53133.)及CD28(NP_006130.1)之片段組成之群的共刺激分子之一部分。在一些實施例中,本揭示案之CAR之胞內信號傳導域包括胺基酸序列,其包括與SEQ ID NO:37及SEQ ID NO:38中所示之胺基酸序列至少70%、至少80%、至少90%、95%、97%或99%序列一致性。在一些實施例中,本揭示案之CAR之胞內信號傳導域包括胺基酸序列,其包括與SEQ ID NO:37中所示之胺基酸序列至少70%、至少80%、至少90%、95%、97%或99%之序列一致性及/或與SEQ ID NO:38中所示之胺基酸序列至少70%、至少80%、至少90%、95%、97%或99%之序列一致性。
在例示性實施例中,本揭示案之CAR自N端至C端包括:CD8α信號序列、CD19 scFv、CD8α鉸鏈及跨膜區、41BB細胞質信號傳導域及CD3ζ細胞質信號傳導域。
III. 包括CAR之免疫細胞
a. 免疫細胞
本文提供表現本揭示案CAR之經工程改造之免疫細胞(例如CAR-T細胞)。
在一些實施例中,經工程改造之免疫細胞包括CAR群,各CAR包括不同胞外抗原結合域。在一些實施例中,免疫細胞包括CAR群,各CAR包括相同胞外抗原結合域。
經工程改造之免疫細胞可為同種異體或自體細胞。
在一些實施例中,經工程改造之免疫細胞為T細胞(例如發炎性T淋巴細胞細胞毒性T-淋巴細胞、調節T淋巴細胞、輔助T淋巴細胞、腫瘤浸潤淋巴細胞(TIL))、NK細胞、NK-T細胞、TCR表現細胞、樹突狀細胞、殺手樹突狀細胞、肥大細胞或B細胞。在一些實施例中,細胞可來源於由CD4+T淋巴細胞及CD8+T淋巴細胞組成之群。在一些例示性實施例中,經工程改造之免疫細胞為T細胞。在一些例示性實施例中,經工程改造之免疫細胞為γ δ T細胞。在一些例示性實施例中,經工程改造之免疫細胞為巨噬細胞。
在一些實施例中,經工程改造之免疫細胞可來源於例如但不限於幹細胞。幹細胞可為成體幹細胞、非人類胚胎幹細胞,更特定言之,非人類幹細胞、臍帶血幹細胞、先驅細胞、骨髓幹細胞、誘導性多能幹細胞、分化全能幹細胞或造血幹細胞。
在一些實施例中,細胞係由外周血獲得或製備。在一些實施例中,細胞係由外周血單核細胞(PBMC)獲得或製備。在一些實施例中,細胞係由骨髓獲得或製備。在一些實施例中,細胞係由臍帶血獲得或製備。在一些實施例中,細胞為人類細胞。在一些實施例中,使用選自由以下組成之群的方法藉由核酸載體轉染或轉導細胞:電穿孔、聲致穿孔、基因槍法(例如基因槍(Gene Gun))、脂質轉染、聚合物轉染、奈米粒子、病毒轉染(例如反轉錄病毒、慢病毒、AAV)或聚合複合體。
在一些實施例中,在其細胞表面膜處表現本揭示案之CD19特異性CAR的經工程改造之免疫細胞包含大於10%、20%、30%、40%、50%或60%、70%、80%、90%或100%之百分比之幹細胞記憶及中心記憶細胞。在一些實施例中、在其細胞表面膜處表現之本揭示案之CD19特異性CAR的經工程改造之免疫細胞包含約10%至約100%、約10%至約90%、約10%至約80%、約10%至約70%、約10%至約60%、約10%至約50%、約10%至約40%、約10%至約30%、約10%至約20%、約15%至約100%、約15%至約90%、約15%至約80%、約15%至約70%、約15%至約60%、約15%至約50%、約15%至約40%、約15%至約30%、約20%至約100%、約20%至約90%、約20%至約80%、約20%至約70%、約20%至約60%、約20%至約50%、約20%至約40%、約20%至約30%、約30%至約100%、約30%至約90%、約30%至約80%、約30%至約70%、約30%至約60%、約30%至約50%、約30%至約40%、約40%至約100%、約40%至約90%、約40%至約80%、約40%至約70%、約40%至約60%、約40%至約50%、約50%至約100%、約50%至約90%、約50%至約80%、約50%至約70%、約50%至約60%、約60%至約100%、約60%至約90%、約60%至約80%、約60%至約70%、約70%至約90%、約70%至約80%、約80%至約100%、約80%至約90%、約90%至約100百分比、約25%至約50%、約75%至約100%或約50%至約75%之百分比之幹細胞記憶及中心記憶細胞。
在一些實施例中,免疫細胞為表現本文所述之CAR中之任一者的發炎性T淋巴細胞。在一些實施例中,免疫細胞為表現本文所述之CAR中之任一者的細胞毒性T淋巴細胞。在一些實施例中,免疫細胞為表現本文所述之CAR中之任一者的調節T淋巴細胞。在一些實施例中,免疫細胞為表現本文所述之CAR中之任一者的輔助T淋巴細胞。
擴增及基因修飾之前,細胞源可經由多種非限制性方法由個體獲得。細胞可由多種非限制性來源獲得,包含周邊血液單核細胞、骨髓、淋巴結組織、臍帶血、胸腺組織、幹細胞或iPSC衍生之T細胞或NK細胞、來自感染部位之組織、腹水、肋膜積液、脾臟組織及腫瘤。在一些實施例中,可使用本領域中熟習此項技術者可獲得且已知之任何數目個T細胞株。在一些實施例中,細胞可來源於健康供體、來源於診斷患有癌症之患者或來源於診斷患有感染之患者。在一些實施例中,細胞可為呈現不同表現型特徵之混合細胞群之部分。
本文亦提供根據上述方法中之任一者之由轉型免疫細胞(例如T細胞)獲得之細胞株。本文亦提供對免疫抑制治療具有抗性之經修飾細胞。在一些實施例中,根據本揭示案之經分離細胞包括編碼CAR之聚核苷酸。
本揭示案之免疫細胞可在免疫細胞之基因修飾之前或之後使用如一般已知之方法活化及擴增。一般而言,本揭示案之經工程改造之免疫細胞可例如藉由與刺激T細胞表面上之CD3 TCR複合物及共刺激分子之試劑接觸擴增以產生T細胞之活化信號。舉例而言,可使用化學物質,諸如鈣離子載體A23187、佛波醇12-豆蔻酸酯13-乙酸酯(PMA)或促有絲分裂凝集素(如植物血球凝集素(PHA))來產生T細胞之活化信號。
在一些實施例中,T細胞群可活體外如下刺激:藉由與例如抗CD3抗體或其抗原結合片段或固著於表面上之抗CD28抗體接觸,或藉由與蛋白激酶C活化因子(例如苔蘚蟲素)以及鈣離子載體接觸。為了共刺激T細胞表面上之輔助分子,使用結合輔助分子之配位體。舉例而言,可使T細胞群與抗CD3抗體及抗CD28抗體在適於刺激T細胞增殖之條件下接觸。抗CD3抗體及抗CD28抗體可以安置於珠粒或板或其他基板上。適合於T細胞培養之條件包含可含有增殖及存活力所需之因素的合適培養基(例如最低必需培養基或RPMI培養基1640或X-Vivo 15,(Lonza)),其包含血清(例如胎牛或人類血清)、介白素-2(IL-2)、胰島素、IFN-γ、IL-4、IL-7、GM-CSF、IL-10、IL-2、IL-15、TGFβ及TNF或任何其他熟習此項技術者已知之用於細胞生長的添加劑。用於細胞生長之其他添加劑包含但不限於界面活性劑、人血漿蛋白粉,及還原劑,諸如N-乙醯基-半胱胺酸及2-巰基乙醇。培養基可包含具有添加之胺基酸、丙酮酸鈉及維生素之RPMI 1640、A1M-V、DMEM、MEM、a-MEM、F-12、X-Vivo 15及X-Vivo 20、Optimizer,無血清或補充有適量血清(或血漿)或限定激素組,及/或對於T細胞(例如IL7及/或IL-15)之生長及擴增足夠之量的細胞介素。抗生素(例如,青黴素及鏈黴素)僅包含於實驗培養物中,而不在待輸注至個體之細胞培養物中。靶細胞保持於支持生長必需之條件下,例如適當溫度(例如37℃)及氛圍(例如空氣加5% CO2
)。已暴露於變化刺激時間之T細胞可展現不同特徵。
在一些實施例中,本揭示案之細胞可藉由與組織或細胞共培養來擴增。在將細胞投與至個體中後,細胞亦可在活體內,例如在個體之血液中擴增。
在一些實施例中,根據本揭示案之經工程改造之免疫細胞可包括一或多個中斷或不活化之基因。在一些實施例中,根據本揭示案之經工程改造之免疫細胞包括一種選自由以下組成之群的中斷或不活化基因:CD52、CD19、GR、PD-1、CTLA-4、LAG3、TIM3、BTLA、BY55、TIGIT、B7H5、LAIR1、SIGLEC10、2B4、HLA、TCRα及TCRβ,及/或表現CAR、多鏈CAR及/或pTα轉基因。在一些實施例中,經分離細胞包括編碼包括多鏈CAR之多肽的聚核苷酸。在一些實施例中,根據本揭示案之經分離細胞包括兩種選自由以下組成之群的中斷或不活化基因:CD52與GR、CD52與TCRα、CDR52與TCRβ、CD19與CD52、CD19與TCRα、CD19與β、GR與TCRα、GR與TCRβ、TCRα與TCRβ、PD-1與TCRα、PD-1與TCRβ、CTLA-4與TCRα、CTLA-4與TCRβ、LAG3與TCRα、LAG3與TCRβ、TIM3與TCRα、Tim3與TCRβ、BTLA與TCRα、BTLA與TCRβ、BY55與TCRα、BY55與TCRβ、TIGIT與TCRα、TIGIT與TCRβ、B7H5與TCRα、B7H5與TCRβ、LAIR1與TCRα、LAIR1與TCRβ、SIGLEC10與TCRα、SIGLEC10與TCRβ、2B4與TCRα、2B4與TCRβ,及/或表現CAR、多鏈CAR及pTα轉基因。在一些實施例中,所述方法包括藉由將核酸內切酶引入細胞中使一或多種基因中斷或不活化,所述核酸內切酶能夠藉由選擇性DNA裂解使基因選擇性不活化。在一些實施例中,核酸內切酶可為例如鋅指核酸酶(ZFN)、megaTAL核酸酶、巨核酸酶、轉錄活化因子樣效應子核酸酶(TALE核酸酶),或CRISPR(例如Cas9)核酸內切酶。
在一些實施例中,藉由中斷或不活化TCRα基因及/或TCRβ基因來使TCR在根據本揭示案之細胞中失去功能。在一些實施例中,提供用以獲得來源於個體之經修飾細胞之方法,其中細胞可獨立於主要組織相容複合體(major histocompatibility complex;MHC)信號傳導路徑而增殖。本揭示案之範疇涵蓋易於藉由此方法獲得之經修飾細胞,所述經修飾細胞可獨立於MHC信號傳導路徑增殖。本文所揭示之經修飾細胞可用於針對移植物抗宿主(Host versus Graft;HvG)排斥及移植物抗宿主疾病(Graft versus Host Disease;GvHD)治療有需要之患者;因此針對移植物抗宿主(HvG)排斥及移植體對抗宿主疾病(GVHD)治療有需要之患者之方法處於本揭示案之範疇內,所述方法包含藉由向所述患者投與有效量之包括中斷或不活化TCRα及/或TCRβ基因之經修飾細胞來治療所述患者。
在一些實施例中,免疫細胞經工程改造以對一或多種化學療法藥物具有抗性。化學療法藥物可為例如嘌呤核苷酸類似物(PNA),因此製備適用於組合授受性免疫療法及化學療法之癌症治療的免疫細胞。例示性PNA包含例如單獨或組合之氯法拉濱(clofarabine)、氟達拉濱(fludarabine)、環磷醯胺(cyclophosphamide)及阿糖胞苷(cytarabine)。PNA由去氧胞苷激酶(dCK)代謝為單磷酸酯、二磷酸酯及三磷酸酯PNA。其三磷酸酯形式與ATP競爭DNA合成,充當促細胞凋亡劑,且為涉及三核苷酸產生之核糖核苷酸還原酶(RNR)之強抑制劑。本文提供包括中斷或不活化dCK基因之CD19特異性CAR-T細胞。在一些實施例中,dCK基因敲除細胞係利用例如mRNA之電穿孔,藉由使用編碼針對dCK基因之特異性TAL核酸酶之聚核苷酸轉染T細胞製得。dCK基因敲除CD19特異性CAR-T細胞對PNA(包含例如氯法拉濱及/或氟達拉濱)具有抗性,且維持對CD19表現細胞之T細胞細胞毒活性。
在一些實施例中,本揭示案之經分離細胞或細胞株可包括pTα或其功能變異體。在一些實施例中,可進一步藉由中斷或不活化TCRα基因對經分離之細胞或細胞株進行基因修飾。
本揭示案亦提供經工程改造之免疫細胞,其包括本文所述之任何CAR聚核苷酸。
c. 製造方法
本文提供製造本揭示案之CAR及含有免疫細胞之CAR的方法。多種已知技術可用於製備根據本揭示案之聚核苷酸、多肽、載體、抗原結合域、免疫細胞、組合物及其類似者。
聚核苷酸及載體
在一些實施例中,可經由質體載體將CAR引入免疫細胞中作為轉基因。在一些實施例中,質體載體亦可含有例如選擇標記物,所述選擇標記物提供鑑別及/或選擇接收載體之細胞。
在將編碼CAR多肽之聚核苷酸引入細胞中之後,可在細胞中原位合成CAR多肽。或者,CAR多肽可在細胞外部產生,且隨後引入細胞中。將聚核苷酸構築體引入細胞中之方法為此項技術中已知的。在一些實施例中,穩定轉型方法(例如使用慢病毒載體)可用於將聚核苷酸構築體整合至細胞之基因組中。在其他實施例中,可使用短暫轉型方法短暫表現聚核苷酸構築體,且聚核苷酸構築體不整合於細胞之基因組中。在其他實施例中,可使用病毒介導之方法。聚核苷酸可藉由任何適合之方式,諸如重組病毒載體(例如逆轉錄病毒、腺病毒)、脂質體及其類似物引入細胞中。短暫轉型方法包含(例如但不限於)顯微注射、電穿孔或粒子轟擊。聚核苷酸可包含於載體(諸如質體載體或病毒載體)中。
在一些實施例中,提供經分離核酸,其包括啟動子,所述啟動子可操作地連接於編碼CD19抗原結合域、至少一個共刺激分子及活化域之第一聚核苷酸。在一些實施例中,核酸構築體包含於病毒載體內。在一些實施例中,病毒載體係選自由以下組成之群:反轉錄病毒載體、鼠類白血病病毒載體、SFG載體、腺病毒載體、慢病毒載體、腺相關病毒(AAV)載體、疱疹病毒載體及牛痘病毒載體。在一些實施例中,核酸內含於質體內。
在一個態樣中,本揭示案提供一種聚核苷酸序列,其包括能夠在哺乳動物T細胞中表現CAR轉基因之啟動子。在一些實施例中,啟動子為EF1a啟動子。原生EF1a啟動子驅使伸長因子-1複合物之α次單元的表現,所述複合物負責將胺基醯基tRNA酶促遞送至核糖體。EF1a啟動子已廣泛用於哺乳動物表現質體且已顯示有效地自選殖於慢病毒載體中的轉基因驅動CAR表現。參見例如Milone等人,《分子治療(Mol. Ther.)》17(8):1453-1464 (2009)。在一些實施例中,EF1a啟動子包括如SEQ ID NO:15提供之序列。
以上展示之EF1a啟動子序列包括EF1a基因之第一外顯子(粗體)及第一內含子(帶下劃線的,SEQ ID NO:39),隨後為第二外顯子之N端部分。在一些實施例中,本文所提供之聚核苷酸包括短EF1a啟動子。在一些實施例中,本文所提供之聚核苷酸包括比SEQ ID NO:15之核酸序列短的EF1a啟動子。在一些實施例中,本文所提供之聚核苷酸包括EF1a啟動子,其不包括EF1a基因之第一內含子。在一些實施例中,本文所提供之聚核苷酸包括EF1a啟動子,其不包括SEQ ID NO:39之核酸序列。
在本文所述之免疫細胞之活體外操縱或基因修飾之前,可由個體獲得細胞。表現CD19 CAR之細胞可來源於同種異體或自體過程。
源物質
在一些實施例中,免疫細胞包括T細胞。T細胞可由多個來源獲得,包含周邊血液單核細胞(PBMC)、骨髓、淋巴結組織、臍帶血、胸腺組織、來自感染位點之組織、腹水、肋膜積液、脾組織及腫瘤。在某些實施例中,T細胞可使用熟習此項技術者已知之任何數目之技術(諸如FICOLL™分離)由自個體收集之血液單元獲得。
細胞可藉由血球分離術由個體之循環血液獲得。血球分離術產物通常含有淋巴細胞(包含T細胞)、單核球、粒細胞、B細胞、其他成核白血球、紅血球及血小板。在某些實施例中,藉由血球分離術收集之細胞可經洗滌以移除血漿部分,且置於適當緩衝液或培養基中以用於後續處理。
在某些實施例中,T細胞自PBMC藉由裂解紅細胞及耗乏單核細胞,例如藉由使用經由PERCOLL™梯度之離心而分離。特定T細胞亞群(例如CD28+、CD4+、CDS+、CD45RA-及CD45RO+T細胞或CD28+、CD4+、CDS+、CD45RA-、CD45RO+及CD62L+T細胞)可藉由此項技術中已知之正向或負向選擇技術進一步分離。舉例而言,藉由負向選擇富集T細胞群可使用針對負向選擇之細胞所特有之表面標記物的抗體之組合來實現。用於本文中之一種方法為經由負磁性免疫黏附或流式細胞量測術分選及/或選擇細胞,所述負磁性免疫黏附或流式細胞量測術使用針對負選擇細胞上存在之細胞表面標記之單株抗體混合物。舉例而言,為藉由負向選擇富集CD4+細胞,單株抗體混合物通常包含CD14、CD20、CD11b、CD16、HLA-DR及CD8之抗體。流式細胞量測術及細胞分選亦可用於分離用於本揭示案之所關注之細胞群。
PBMC可直接用於使用如本文所描述之方法用免疫細胞(諸如CAR或TCR)進行基因修飾。在某些實施例中,在分離PBMC之後,可進一步分離T淋巴球,且在基因修飾及/或擴增之前或之後,可將細胞毒性與輔助T淋巴球分成初始、記憶及效應T細胞亞群。
在一些實施例中,CD8+細胞藉由鑑別與此等類型之CD8+細胞中之每一者相關之細胞表面抗原而進一步分成初始、幹細胞記憶、中樞記憶及效應細胞。在一些實施例中,中樞記憶T細胞之表現型標記物之表現包含CD45RO、CD62L、CCR7、CD28、CD3及CD127且對於顆粒酶B為陰性的。在一些實施例中,幹細胞記憶T細胞為CD45RO-、CD62L+、CD8+T細胞。在一些實施例中,中樞記憶T細胞為CD45RO+、CD62L+、CD8+T細胞。在一些實施例中,效應T細胞對於CD62L、CCR7、CD28及CD127為陰性的且對於顆粒酶B及穿孔蛋白為陽性的。在某些實施例中,將CD4+T細胞進一步分成亞群。舉例而言,CD4+T輔助細胞可藉由鑑別具有細胞表面抗原之細胞群而分成初始、中樞記憶及效應細胞。
衍生自幹細胞之免疫細胞
在一些實施例中,免疫細胞可衍生自胚胎幹(ES)或誘導多能幹(iPS)細胞。適合之HSC、ES細胞、iPS細胞及其他幹細胞可培養為永生細胞株或自患者直接分離。用於分離、顯影及/或培養幹細胞之各種方法為此項技術中已知的且可用於實踐本發明。
在一些實施例中,免疫細胞為來源於再程式化T細胞之誘導多能幹細胞(iPSC)。在一些實施例中,源物質可為來源於T細胞或非T細胞之誘導多能幹細胞(iPSC)。源物質可為胚胎幹細胞。源物質可為B細胞或來自周邊血液單核細胞分離物、造血先驅細胞、造血幹細胞、間充質幹細胞、脂肪幹細胞或任何其他體細胞類型之任何其他細胞。
經分離細胞之基因修飾
免疫細胞(諸如T細胞)在使用已知方法分離之後進行基因修飾,或免疫細胞在基因修飾之前活體外活化及擴增(或在先驅細胞之情況下分化)。在一些實施例中,經分離免疫細胞經基因修飾以減少或消除內源性TCRα及/或CD52之表現。在一些實施例中,細胞使用基因編輯技術(例如CRISPR/Cas9、鋅指核酸酶(ZFN)、TALEN、MegaTAL、巨核酸酶)基因修飾以減少或消除內源蛋白質(例如TCRα及/或CD52)之表現。在另一實施例中,免疫細胞(諸如T細胞)用本文所描述之嵌合抗原受體進行基因修飾(例如用包括一或多個編碼CAR之核苷酸序列的病毒載體轉導)且隨後活體外活化及/或擴增。用於活化及擴增T細胞之方法在此項技術中已知且描述於例如美國專利第6,905,874號、美國專利第6,867,041號、美國專利第6,797,514號、及PCT WO 2012/079000中,其內容以全文引用之方式併入本文中。一般而言,此類方法包含使PBMC或經分離之T細胞與刺激分子及共刺激分子(諸如抗CD3及抗CD28抗體,一般附著於珠粒或其他表面)在具有適當細胞介素(諸如IL-2)之培養基中接觸。附著於相同珠粒之抗CD3及抗CD28抗體充當「替代」抗原呈現細胞(APC)。一個實例為Dynabeads®系統,一種用於人類T細胞之生理性活化的CD3/CD28活化劑/刺激物系統。在其他實施例中,使用諸如美國專利第6,040,177號、美國專利第5,827,642號及WO2012129514中所描述之彼等方法的方法,利用飼養細胞及適當抗體及細胞介素可活化並刺激T細胞以增殖,其內容以全文引用之方式併入本文中。
用於製備本揭示案之構築體及經工程改造之免疫細胞的某些方法描述於PCT申請案PCT/US15/14520中,其內容以全文引用之方式併入本文中。
應瞭解,PBMC可進一步包含其他細胞毒性淋巴細胞,諸如NK細胞或NKT細胞。可將如本文所揭示之攜帶嵌合受體之編碼序列的表現載體引入人類供體T細胞、NK細胞或NKT細胞的群中。帶有表現載體之成功轉導之T細胞可使用流式細胞量測術分選以分離CD3陽性T細胞,且隨後進一步繁殖以增加除細胞活化外之此等CAR表現T細胞之數目,所述細胞使用抗CD3抗體及IL-2或此項技術中已知之其他方法,如本文中他處所描述。標準程序用於低溫保存表現CAR之T細胞以儲存及/或製備用於人類個體。在一個實施例中,在非人類動物來源之產物,諸如胎牛血清及胎牛血清不存在下進行T細胞之活體外轉導、培養及/或擴增。
對於聚核苷酸之選殖,可將載體引入宿主細胞(經分離之宿主細胞)中以允許載體自身複製且從而擴增其中所含之聚核苷酸之複本。選殖載體可含有序列組分,其一般包含但不限於複製起點、啟動子序列、轉錄起始序列、增強子序列及可選標記物。此等元件可視需要由本領域中一般熟習此項技術者選擇。舉例而言,可選擇複製起點以促進載體在宿主細胞中之自主複製。
在某些實施例中,本揭示案提供含有本文所提供之載體之經分離宿主細胞。含有載體之宿主細胞可適用於表現或選殖載體中所含之聚核苷酸。適合宿主細胞可包含但不限於原核細胞、真菌細胞、酵母細胞,或高級真核細胞,諸如哺乳動物細胞。用於此目的之適合原核細胞包含但不限於真細菌,諸如革蘭氏陰性或革蘭氏陽性生物體,例如腸內菌科(Enterobactehaceae),諸如埃希氏桿菌屬(Escherichia),例如大腸桿菌、腸桿菌屬(Enterobacter)、歐文菌屬(Erwinia)、克雷伯氏菌屬(Klebsiella)、變形桿菌屬(Proteus)、沙門氏菌屬(Salmonella),例如鼠傷寒沙門桿菌(Salmonella typhimurium)、沙雷菌屬(Serratia),例如黏質沙雷氏菌(Serratia marcescans)、及志賀桿菌屬(Shigella),以及桿菌(Bacilli),諸如枯草芽孢桿菌(B.subtilis)及地衣芽孢桿菌(B.licheniformis),假單胞菌屬(Pseudomonas),諸如綠膿桿菌(P.aeruginosa)、及鏈黴菌屬(Streptomyces)。
載體可以使用此項技術中已知之任何適合方法引入宿主細胞中,包含但不限於DEAE-葡聚糖介導之遞送、磷酸鈣沈澱法、陽離子性脂質介導之遞送、脂質體介導之轉染、電穿孔、微彈轟擊、受體介導之基因遞送,由聚離胺酸、組蛋白、殼聚糖及肽介導之遞送。用於轉染及轉型細胞以表現所關注載體之標準方法為此項技術中熟知的。在另一實施例中,不同表現載體之混合物可用於基因修飾免疫效應細胞之供體群,其中各載體編碼如本文所揭示之不同CAR。所得經轉導免疫效應細胞形成經工程改造之細胞的混合群,其中一部分經工程改造之細胞表現超過一個不同CAR。
在一些實施例中,載體包括慢病毒載體。包括CAR編碼序列之慢病毒載體可引入至慢病毒包裝細胞株中且藉由包裝細胞株產生之慢病毒可用於轉導T細胞以產生CAR-T細胞。為了製造編碼CAR之慢病毒,可在第0天在6孔板之每孔以0.4萬個細胞/mL於補充有10% FBS (Hyclone或JR Scientific)之2 mL DMEM(Gibco)中接種HEK-293T細胞。第1天,藉由在6孔盤之每孔中,在250 μL Opti-MEM(Gibco)中將慢病毒封裝載體1.5 μg psPAX2、0.5 μg pMD2G及0.5 μg適當轉移CAR載體一起混合來製備慢病毒(「DNA混合物」)。將於250 μL Opti-MEM中之10 μL脂染胺2000(英傑(Invitrogen))在室溫下培育5分鐘且隨後添加至DNA混合物中。在室溫下培育混合物20分鐘且將500 μL總體積緩慢添加至含有HEK-293T之孔的側壁上。含有CAR之慢病毒之產生及轉導的一般方法通常在此項技術中已知,例如參見Milone等人,《白血病(Leukemia)》, 2018, 32:1529-1541;Sanber等人,用於臨床慢病毒載體產生之穩定封裝細胞株之構築(Construction of stable packaging cell lines for clinical lentiviral vector production),《自然(Nature)》2015, DOI:10.1038;Roddie等人,《細胞療法(Cytotherapy)》2019, 21:327-340,其皆以全文引用之方式併入本文中。在一個實施例中,本揭示案提供一種儲存表現靶向CD19蛋白之CAR或TCR的經基因工程改造之細胞的方法。此涉及低溫保存免疫細胞以使得細胞在解凍後保持活力。表現CAR之免疫細胞之一部分可藉由此項技術中已知之方法低溫保存以提供此類細胞之永久來源用於將來治療罹患惡性病之患者。當需要時,冷凍保存之轉型免疫細胞可解凍、生長及擴增更多此類細胞。
在一些實施例中,細胞係如下調配:首先自細胞培養基中收穫細胞,且隨後在適於以治療有效量投與的培養基及容器系統(「醫藥學上可接受之」載劑)中洗滌及濃縮細胞。適合輸注培養基可為任何等張培養基調配物,通常為標準生理鹽水、Normosol™ R(Abbott)或Plasma-Lyte™ A(Baxter),且亦可利用於水或林格氏溶液(Ringer's)乳酸鹽中之5%右旋糖。輸注培養基可補充有人類血清白蛋白。
同種異體CAR T細胞
用於製造同種異體CAR T療法或AlloCARs™之方法涉及自健康供體收集健康的、經選擇之、經篩選之及經測試之T細胞。隨後,T細胞經工程改造以表現CAR,其識別在血液或實體腫瘤中表現之某些細胞表面蛋白質(例如CD19)。設計同種異體T細胞以降低移植物抗宿主疾病(GvHD)風險且預防同種異體排斥反應。T細胞受體基因(例如TCRα、TCRβ)經基因剔除以避免GvHD。CD52基因可經基因剔除以使得CAR T產物對抗CD52抗體治療具有抗性。抗CD52抗體治療可因此用於抑制宿主免疫系統且允許CAR T保持移植以實現完全治療影響。經工程改造之T細胞隨後進行純化步驟且最終低溫保存在小瓶中以遞送至患者。
自體CAR T細胞
自體嵌合抗原受體(CAR)T細胞療法涉及收集患者之自身細胞(例如白血球,包含T細胞)及基因工程改造T細胞以表現識別在一或多個特異性癌細胞及殺滅癌細胞之細胞表面上表現之目標的CAR。隨後低溫保存經工程改造之細胞且隨後向患者投與。
IV. 治療方法
本揭示案包括治療或預防患者中與非所需及/或升高之CD19含量相關之病狀的方法,其包括向有需要之患者投與有效量之至少一種CAR或包括本文所揭示之CAR的免疫細胞。
提供用於治療疾病或病症(包含癌症)之方法。在一些實施例中,本揭示案係關於在個體中產生T細胞介導之免疫反應,其包括向個體投與有效量之本申請案之經工程改造之免疫細胞。在一些實施例中,T細胞介導之免疫反應係針對一或多種靶細胞。在一些實施例中,經工程改造之免疫細胞包括嵌合抗原受體(CAR)。在一些實施例中,靶細胞為腫瘤細胞。在一些態樣中,本揭示案包括一種用於治療或預防惡性病之方法,所述方法包括向有需要之個體投與有效量之至少一種本文所述之經分離之抗原結合域。在一些態樣中,本揭示案包括一種用於治療或預防惡性病之方法,所述方法包括向有需要之個體投與有效量之至少一種免疫細胞,其中所述免疫細胞包括至少一種如本文所描述之嵌合抗原受體、T細胞受體及/或經分離之抗原結合域。
含有本揭示案之免疫細胞的CAR可用於治療涉及CD19之異常表現的惡性病。在一些實施例中,含有本揭示案之免疫細胞的CAR可用於治療癌症。如本文所使用,術語「癌症」包含但不限於實體腫瘤及血源性腫瘤。術語「癌症」係指皮膚組織、器官、血液及血管之疾病,包含但不限於膀胱癌、骨癌或血癌、腦癌、乳癌、子宮頸癌、胸癌、結腸癌、子宮內膜癌、食道癌、眼癌、頭部癌、腎癌、肝癌、淋巴結癌、肺癌、口腔癌、頸部癌、卵巢癌、胰臟癌、前列腺癌、直腸癌、胃癌、睾丸癌、咽喉癌及子宮癌。特定癌症包含但不限於晚期惡性瘤、澱粉樣變性病、神經母細胞瘤、腦膜瘤、血管外皮瘤、多發性腦轉移瘤、多形性神經膠母細胞瘤、神經膠母細胞瘤、腦幹神經膠質瘤、預後不良惡性腦腫瘤、惡性神經膠質瘤、反覆性惡性神經膠質瘤、退行性星形細胞瘤、退行性寡樹突神經膠質瘤、神經內分泌腫瘤、直腸腺癌、杜克氏C期及D期結腸直腸癌(Dukes C&D colorectal cancer)、不可切除性結腸直腸癌、轉移性肝細胞癌、卡波西氏肉瘤(Kaposi's sarcoma)、核型急性骨髓母細胞白血病、霍奇金氏淋巴瘤(Hodgkin lymphoma)、非霍奇金氏淋巴瘤(NHL)、皮膚T細胞淋巴瘤、皮膚B細胞淋巴瘤、彌漫性大B細胞淋巴瘤、低級濾泡性淋巴瘤、惡性黑色素瘤、惡性間皮瘤、惡性肋膜積液間皮瘤症候群、腹膜癌、乳頭狀漿液性癌、婦科肉瘤、軟組織肉瘤、硬皮病、皮膚血管炎、蘭格漢氏細胞組織細胞增多病(Langerhans cell histiocytosis)、平滑肌肉瘤、進行性骨化性纖維發育不良、激素難治性前列腺癌、切除高風險性軟組織肉瘤、不可切除性肝細胞癌、瓦爾登斯特倫氏巨球蛋白血症(Waldenstrom's macroglobulinemia)、和緩性骨髓瘤、惰性骨髓瘤、輸卵管癌、雄激素非依賴性前列腺癌、雄激素依賴性IV期非轉移性前列腺癌、激素不敏感性前列腺癌、化學療法不敏感性前列腺癌、乳頭狀甲狀腺癌、濾泡性甲狀腺癌、髓質性甲狀腺癌及平滑肌瘤。在一個特定實施例中,癌症為轉移性的。在另一個實施例中,癌症為難治性的或對化學療法或放射具有抗性。
在例示性實施例中,將含有CAR之免疫細胞,例如本揭示案之CAR-T細胞用於治療NHL。
亦提供用於減小個體中之腫瘤尺寸的方法,其包括向個體投與本揭示案之經工程改造之細胞至個體,其中所述細胞包括嵌合抗原受體,所述嵌合抗原受體包括CD19抗原結合域且結合至腫瘤上之CD19抗原。
在一些實施例中,個體患有實體腫瘤或血液惡性病,諸如淋巴瘤或白血病。在一些實施例中,將經工程改造之細胞遞送至腫瘤床。在一些實施例中,癌症存在於個體之骨髓中。在一些實施例中,經工程改造之細胞為自體免疫細胞,例如自體T細胞。在一些實施例中,經工程改造之細胞為同種異體免疫細胞,例如同種異體T細胞。在一些實施例中,經工程改造之細胞為異源免疫細胞,例如異源T細胞。在一些實施例中,本申請案之經工程改造之細胞在活體內經轉染或轉導。在其他實施例中,將經工程改造之細胞離體轉染或轉導。如本文所用,術語「活體外細胞」係指離體培養之任何細胞。
治療劑,例如經工程改造之CART細胞之「治療有效量」、「有效劑量」,「有效量」或「治療有效劑量」為單獨或與另一治療劑組合使用時保護個體免於疾病發作或由疾病症狀之嚴重強度降低、無疾病症狀週期之頻率及持續時間增長證明之促進疾病消退,或預防歸因於疾病病痛之損傷或殘疾之任何量。治療劑促進疾病消退之能力可使用熟習此項技術者已知的多種方法評估,諸如在臨床試驗期間在人類個體中評估、在預測人體內之功效的動物模型系統中評估或藉由在活體外分析中分析藥劑活性評估。
術語「患者」及「個體」可互換使用且包含人類及非人類動物個體以及患有經正式診斷之病症之個體、未患有經正式認定之病症之個體、接受醫療照顧之個體、處於罹患病症之風險下之個體等。
術語「治療(treat/treatment)」包含治療性治療、預防性治療及其中降低個體將罹患病症之風險或降低其他風險因素的應用。治療不需要完全治癒病症且涵蓋治療減少症狀或潛在風險因素之實施例。術語「預防」不要求100%消除事件之可能性。確切而言,其表示在化合物或方法存在下,事件發生之可能性已減少。
組合物中所需的細胞治療量一般為至少2個細胞(例如至少1個CD8+中樞記憶T細胞及至少1個CD4+輔助T細胞亞群)或更通常地多於102
個細胞,且至多106
個,至多且包含108
個或109
個細胞,且可為超過1010
個細胞。細胞數目將視預期組合物所需之用途及其中所包含之細胞類型而定。所需細胞之密度通常大於106
個細胞/毫升,且一般大於107
個細胞/毫升,一般108個細胞/毫升或更大。免疫細胞之臨床上相關數目可分為多次灌注,其累積等於或超過105
、106
、107
、108
、109
、1010
、1011
或1012
個細胞。在本揭示案之一些態樣中,尤其因為所有輸注之細胞將再導引至特定靶抗原(CD19),所以可投與在106
/公斤(106
-1011
/患者)範圍內的較低數目之細胞。CAR治療可在此等範圍內之劑量下多次投與。細胞對於經歷療法之患者可為自體、同種異體或異源的。
在一些實施例中,CAR T細胞之治療有效量為約1×105
個細胞/kg、約2×105
個細胞/kg、約3×105
個細胞/kg、約4×105
個細胞/kg、約5×105
個細胞/kg、約6×105
個細胞/kg、約7×105
個細胞/kg、約8×105
個細胞/kg、約9×105
個細胞/kg、2×106
個細胞/kg、約3×106
個細胞/kg、約4×106
個細胞/kg、約5×106
個細胞/kg、約6×106
個細胞/kg、約7×106
個細胞/kg、約8×106
個細胞/kg、約9×106
個細胞/kg、約1×107
個細胞/kg、約2×107
個細胞/kg、約3×107
個細胞/kg、約4×107
個細胞/kgkg、約5×107
個細胞/kg、約6×107
個細胞/kg、約7×107
個細胞/kg、約8×107
個細胞/kg或約9×107
個細胞/kg。
在一些實施例中,CAR+/CAR-T+/TCR+細胞之靶劑量在1×106
-2×108
個細胞/kg,例如2×106
個細胞/kg範圍內。應瞭解,高於及低於此範圍之劑量可適合於某些個體,且適當劑量水準可由醫療保健提供者視需要測定。另外,可根據本揭示案提供多個劑量之細胞。
在一些態樣中,本揭示案包括醫藥組成物,其包括至少一種如本文所描述之抗原結合域及醫藥學上可接受之賦形劑。在一些實施例中,醫藥組成物進一步包括額外活性劑。
本揭示案之表現CAR之細胞群可單獨或以醫藥組成物形式與稀釋劑及/或與其他組分(諸如,IL-2或其他細胞介素或細胞群)組合投與。本揭示案之醫藥組成物可包括如本文所描述之表現CAR或TCR之細胞群,諸如T細胞,以及一或多種醫藥學上或生理學上可接受之載劑、稀釋劑或賦形劑。此類組合物可包括緩衝液,諸如中性緩衝生理食鹽水、磷酸鹽緩衝生理食鹽水及其類似物;碳水化合物,諸如葡萄糖、甘露糖、蔗糖或聚葡萄糖、甘露糖醇;蛋白質;多肽或胺基酸,諸如甘胺酸;抗氧化劑;螯合劑,諸如EDTA或麩胱甘肽;佐劑(例如氫氧化鋁);及防腐劑。本揭示案之組合物較佳調配用於靜脈內投與。
醫藥組成物(溶液,懸浮液等)可包含以下一或多者:無菌稀釋劑,諸如注射用水、鹽溶液,較佳地,生理鹽水、林格氏溶液(Ringer's solution)、等張氯化鈉;非揮發性油,諸如合成單甘油酯或二甘油酯,其可以用作溶劑或懸浮培養基、聚乙二醇、甘油、丙二醇或其他溶劑;抗菌劑,諸如苯甲醇或對羥基苯甲酸甲酯;抗氧化劑,諸如抗壞血酸或亞硫酸氫鈉;螯合劑,諸如乙二胺四乙酸;緩衝液,諸如乙酸鹽,檸檬酸鹽或磷酸鹽,以及用於調節具有滲性的試劑,例如氯化鈉或葡萄糖。非經腸製劑可封裝於由玻璃或塑膠製成之安瓿、拋棄式注射器或多劑量小瓶中。可注射醫藥組成物較佳為無菌的。
在一些實施例中,在投與患者後,在其細胞表面表現本文所述之CD19特異性CAR中之任一者的經工程改造之免疫細胞可以減少、殺滅或溶解患者之內源性CD19表現細胞。在一個實施例中,藉由表現本文所描述之CD19特異性CAR中之任一者的經工程改造之免疫細胞,CD19表現內源性細胞或具有表現CD19之細胞株之細胞的百分比減少或溶解量為至少約或大於10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或95%。在一個實施例中,藉由表現本文所描述之CD19特異性CAR中之任一者的經工程改造之免疫細胞,CD19表現內源性細胞或具有表現CD19之細胞株之細胞的百分比減少或溶解量為約5%至約95%、約10%至約95%、約10%至約90%、約10%至約80%、約10%至約70%、約10%至約60%、約10%至約50%、約10%至約40%、約20%至約90%、約20%至約80%、約20%至約70%、約20%至約60%、約20%至約50%、約25%至約75%或約25%至約60%。在一個實施例中,內源性CD19表現細胞為內源性CD19表現骨髓細胞。
在一個實施例中,藉由在其細胞表面膜表現本揭示案之CD19特異性CAR的經工程改造之免疫細胞,靶細胞(例如,表現CD19之細胞株)之百分比減少或溶解可使用本文所揭示之檢定來量測。
所述方法可進一步包括投與一或多種化學治療劑。在某些實施例中,化學治療劑為淋巴細胞耗乏(預處理)化學治療劑。例如,處理需要T細胞療法之患者的方法包括向患者投與指定的有益劑量的環磷醯胺(200 mg/m2
/天至2000 mg/m2
/天、約100 mg/m2
/天至約2000 mg/m2
/天;例如約100 mg/m2
/天、約200 mg/m2
/天、約300 mg/m2
/天、約400 mg/m2
/天、約500 mg/m2
/天、約600 mg/m2
/天、約700 mg/m2
/天、約800 mg/m2
/天、約900 mg/m2
/天、約1000 mg/m2
/天、約1500 mg/m2
/天或約2000 mg/m2
/天)及特定劑量之氟達拉濱(20 mg/m2
/天至900 mg/m2
/天、約10 mg/m2
/天至900 mg/m2
/天;例如約10 mg/m2
/天、約20 mg/m2
/天、約30 mg/m2
/天、約40 mg/m2
/天、約40 mg/m2
/天、約50 mg/m2
/天、約60 mg/m2
/天、約70 mg/m2
/天、約80 mg/m2
/天、約90 mg/m2
/天、約100 mg/m2
/天、約500 mg/m2
/天或約900 mg/m2
/天)。較佳給藥方案涉及治療患者,其包括在向患者投與治療有效量之經工程改造之T細胞之前,每天向所述患者投與約300 mg/m2
/天的環磷醯胺及約30 mg/m2
/天的氟達拉濱持續三天。
在一些實施例中,淋巴球耗乏進一步包括投與CD52抗體。在一些實施例中,CD52抗體以約13 mg/天IV之劑量投與。
在其他實施例中,抗原結合域,經轉導(或以其他方式工程改造)之細胞及化學治療劑各自以有效治療個體之疾病或病狀之量投與。
在某些實施例中,本文所揭示之包括CAR表現免疫效應細胞之組合物可與多種化學治療劑一起投與。化學治療劑之實例包含烷基化劑,諸如噻替派(thiotepa)及環磷醯胺(CYTOXAN™);磺酸烷基酯,諸如白消安(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶,諸如苯唑多巴(benzodopa)、卡波醌(carboquone)、米特多巴(meturedopa)及尤利多巴(uredopa);伸乙亞胺及甲基三聚氰胺,包括六甲蜜胺(altretamine)、三伸乙基三聚氰胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺及三羥甲基三聚氰胺恢復;氮芥,諸如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、氯磷醯胺(cholophosphamide)、雌莫司汀(estramustine)、異環磷醯胺(ifosfamide)、甲氮芥(mechlorethamine)、氧氮芥鹽酸鹽(mechlorethamine oxide hydrochloride)、美法侖(melphalan)、新氮芥(novembichin)、苯芥膽甾醇(phenesterine)、潑尼氮芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亞硝基脲,諸如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine);抗生素,諸如阿克拉黴素(aclacinomysin)、放射菌素(actinomycin)、安麯黴素(authramycin)、偶氮絲胺酸(azaserine)、博萊黴素、放線菌素C(cactinomycin)、卡奇黴素(calicheamicin)、卡拉比辛(carabicin)、洋紅黴素(carminomycin)、嗜癌菌素(carzinophilin)、色黴素(chromomycins)、放線菌素D(dactinomycin)、道諾黴素、地托比星(detorubicin)、6-重氮基-5-側氧基-L-正白胺酸、小紅莓(doxorubicin)、表柔比星(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(mitomycin)、黴酚酸(mycophenolic acid)、諾加黴素(nogalamycin)、橄欖黴素(olivomycins)、培洛黴素(peplomycin)、潑非黴素(potfiromycin)、嘌呤黴素(puromycin)、奎那黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑菌素(streptonigrin)、鏈脲菌素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)、左柔比星(zorubicin);抗代謝物,諸如甲胺喋呤(methotrexate)及5-氟尿嘧啶(5-fluorouracil,5-FU);葉酸類似物,諸如迪諾特寧(denopterin)、甲胺喋呤、蝶羅呤(pteropterin)、曲美沙特(trimetrexate);嘌呤類似物,諸如氟達拉濱(fludarabine)、6-巰基嘌呤(6-mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鳥嘌呤(thioguanine);嘧啶類似物,諸如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-氮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、雙去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷(floxuridine)、5-FU;雄激素,諸如卡魯睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾內酯(testolactone);抗腎上腺藥,諸如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑,諸如亞葉酸;乙醯葡醛酯(aceglatone);醛磷醯胺糖苷(aldophosphamide glycoside);胺基乙醯丙酸(aminolevulinic acid);安吖啶;貝斯布西(bestrabucil);比生群(bisantrene);艾達曲克(edatraxate);得弗伐胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);艾福米辛(elformithine);依利醋銨(elliptinium acetate);依託格魯(etoglucid);硝酸鎵(gallium nitrate);羥基脲(hydroxyurea);磨菇多糖(lentinan);氯尼達明(lonidamine);丙脒腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidamol);二胺硝吖啶(nitracrine);噴司他丁(pentostatin);凡那明(phenamet);吡柔比星(pirarubicin);鬼臼酸(podophyllinic acid);2-乙基醯肼(2-ethylhydrazide);丙卡巴肼;PSK®;雷佐生(razoxane);西索菲蘭(sizofiran);螺旋鍺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);三亞胺醌(triaziquone);2,2',2''-三氯三乙胺;尿烷(urethan);長春地辛(vindesine);達卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);哌泊溴烷(pipobroman);加西托星(gacytosine);阿拉伯糖苷(arabinoside,「Ara-C」);環磷醯胺;噻替派;紫杉烷類(taxoid), 例如太平洋紫杉醇(TAXOL™,Bristol-Myers Squibb)及多西他賽(doxetaxel)(TAXOTERE®, Rhone-Poulenc Rorer);苯丁酸氮芥;吉西他濱;6-硫代鳥嘌呤;巰嘌呤;甲胺喋呤;鉑類似物,諸如順鉑(cisplatin)及卡鉑(carboplatin);長春鹼;鉑;依託泊苷(VP-16);異環磷醯胺(ifosfamide);絲裂黴素C(mitomycin C);米托蒽醌;長春新鹼;長春瑞賓(vinorelbine);溫諾平(navelbine);諾凡特龍(novantrone);替尼泊苷;道諾黴素;胺基喋呤(aminopterin);希羅達(xeloda);伊班膦酸鹽(ibandronate);CPT-11;拓樸異構酶抑制劑RF S2000;二氟甲基鳥胺酸(difluoromethylomithine,DMFO);視黃酸衍生物,諸如Targretin™(貝瑟羅汀)、Panretin™(阿利維甲酸(alitretinoin));ONTAK™(迪夫托斯地尼白介素(denileukin diftitox));埃斯波黴素(esperamicin);卡培他濱;及以上任一者之醫藥學上可接受之鹽、酸或衍生物。此定義中亦包含用來調控或抑制激素對腫瘤之作用之抗激素劑,諸如抗雌激素,包含例如他莫昔芬(tamoxifen)、雷諾昔酚(raloxifene)、芳香酶抑制4(5)-咪唑、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、雷洛昔芬(keoxifene)、LY117018、奧那司酮(onapristone)及托瑞米芬(toremifene)(法樂通(Fareston));及抗雄激素,諸如氟他胺(flutamide)、尼魯胺(nilutamide)、比卡魯胺(bicalutamide)、亮丙立德(leuprolide)及戈舍瑞林(goserelin);及以上中之任一者之醫藥學上可接受之鹽、酸或衍生物。適當時亦投與化學治療劑之組合,包含但不限於CHOP,亦即環磷醯胺(Cytoxan®)、小紅莓(Doxorubicin)(羥基小紅莓)、長春新鹼(Vincristine) (Oncovin®)及潑尼松(Prednisone)。
在一些實施例中,化學治療劑在投與經工程改造之細胞、多肽或核酸的同時或之後一週內投與。在其他實施例中,化學治療劑在投與經工程改造之細胞、多肽或核酸之後1至4週或1週至1個月、1週至2個月、1週至3個月、1週至6個月、1週至9個月或1週至12個月投與。在其他實施例中,化學治療劑在投與細胞、多肽或核酸之前至少1個月投與。在一些實施例中,方法進一步包括投與兩種或更多種化學治療劑。
各種額外治療劑可與本文所描述之組合物一起使用。舉例而言,可能適用之額外治療劑包含PD-1抑制劑,諸如納武單抗(nivolumab)(Opdivo®)、派立珠單抗(pembrolizumab)(Keytruda®)、派立珠單抗、皮立珠單抗(pidilizumab)及阿特珠單抗。
適用於與本揭示案組合之額外治療劑包含但不限於依魯替尼(ibrutinib,Imbruvica®)、奧伐木單抗(ofatumumab,Arzerra®)、利妥昔單抗(rituximab,Rituxan®)、貝伐單抗(bevacizumab,Avastin®)、曲妥珠單抗(trastuzumab,Herceptin®)、曲妥珠單抗恩他新(trastuzumab emtansine,KADCYLA®)、伊馬替尼(imatinib,Gleevec®)、西妥昔單抗(cetuximab,Erbitux®)、帕尼單抗(panitumumab,Vectibix®)、卡托莫西單抗(catumaxomab)、異貝莫單抗(ibritumomab)、奧伐木單抗(ofatumumab)、托西莫單抗(tositumomab)、貝倫妥單抗(brentuximab)、阿侖單抗(alemtuzumab)、吉妥珠單抗(gemtuzumab)、埃羅替尼(erlotinib)、吉非替尼(gefitinib)、凡德他尼(vandetanib)、阿法替尼(afatinib)、拉帕替尼(lapatinib)、來那替尼(neratinib)、阿西替尼(axitinib)、馬賽替尼(masitinib)、帕佐泮尼(pazopanib)、舒尼替尼(sunitinib)、索拉非尼(sorafenib)、妥賽蘭尼(toceranib)、來他替尼(lestaurtinib)、阿西替尼(axitinib)、西地尼布(cediranib)、樂伐替尼(lenvatinib)、尼達尼布(nintedanib)、帕佐泮尼(pazopanib)、瑞戈非尼(regorafenib)、司馬沙尼(semaxanib)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、替沃紮尼(tivozanib)、妥賽蘭尼(toceranib)、凡德他尼(vandetanib)、恩曲替尼(entrectinib)、卡博替尼(cabozantinib)、伊馬替尼(imatinib)、達沙替尼(dasatinib)、尼羅替尼(nilotinib)、普納替尼(ponatinib)、拉多替尼(radotinib)、伯舒替尼(bosutinib)、來他替尼(lestaurtinib)、盧佐替尼(ruxolitinib)、帕瑞替尼(pacritinib)、考比替尼(cobimetinib)、司美替尼(selumetinib)、曲美替尼(trametinib)、畢尼替尼(binimetinib)、艾樂替尼(alectinib)、色瑞替尼(ceritinib)、克卓替尼(crizotinib)、阿柏西普(aflibercept)、脂肪肽(adipotide)、地尼白介素迪夫托斯(denileukin diftitox)、mTOR抑制劑(諸如依維莫司(Everolimus)及坦羅莫司(Temsirolimus))、豪豬抑制劑(諸如索尼蒂吉伯(sonidegib)及維莫德吉(vismodegib))、CDK抑制劑(諸如CDK抑制劑(帕泊昔布(palbociclib))。
在一些實施例中,包括含CAR免疫細胞之組合物可與預防細胞介素釋放症候群(CRS)或神經毒性之治療方案一起投與。預防細胞介素釋放症候群(CRS)或神經毒性之治療方案可包含朗齊魯單抗(lenzilumab)、妥珠單抗(tocilizumab)、心房利尿鈉肽(ANP)、阿那白滯素(anakinra)、iNOS抑制劑(例如L-NIL或1400W)。在其他實施例中,包括含CAR免疫細胞之組合物可與消炎劑一起投與。消炎劑或藥物包含但不限於類固醇及糖皮質激素(包含倍他米松(betamethasone)、布地奈德(budesonide)、地塞米松(dexamethasone)、乙酸氫化可體松(hydrocortisone acetate)、氫化可體松、氫化可體松、甲基潑尼龍(methylprednisolone)、潑尼龍(prednisolone)、潑尼松(prednisone)、曲安西龍(triamcinolone));非類固醇消炎藥(NSAIDS),包含阿司匹林(aspirin)、布洛芬(ibuprofen)、萘普生(naproxen)、甲胺喋呤、柳氮磺胺吡啶(sulfasalazine)、來氟米特(leflunomide)、抗TNF藥物、環磷醯胺及黴酚酸酯(mycophenolate)。例示性NSAID包含布洛芬、萘普生、萘普生鈉、Cox-2抑制劑及唾液酸化物。例示性鎮痛劑包含乙醯胺苯酚、羥考酮(oxycodone)、鹽酸丙氧芬(proporxyphene hydrochloride)之曲馬多(tramadol)。例示性糖皮質激素包含可的松(cortisone)、地塞米松、氫皮質酮、甲基潑尼龍、潑尼龍或潑尼松。例示性生物反應修飾劑包含針對細胞表面標記物之分子(例如CD4、CD5等)、細胞介素抑制劑,諸如TNF拮抗劑(例如依那西普(etanercept,ENBREL®
)、阿達木單抗(adalimumab,HUMIRA®
)及英利昔單抗(infliximab,REMICADE®
)、趨化介素抑制劑及黏附分子抑制劑。生物反應修飾劑包含單株抗體以及分子之重組形式。例示性DMARD包含硫唑嘌呤(azathioprine)、環磷醯胺、環孢靈、甲胺喋呤、青黴胺(penicillamine)、來氟米特、柳氮磺胺吡啶、羥基氯奎(hydroxychloroquine)、金製劑(Gold)(經口(金諾芬(auranofin))及肌肉內)及二甲胺四環素(minocycline)。
在某些實施例中,本文中所述之組合物與細胞介素結合投與。細胞介素之實例為淋巴介質、單核球激素及傳統多肽激素。細胞介素中包含生長激素,諸如人類生長激素、N-甲硫胺醯基人類生長激素及牛類生長激素;副甲狀腺激素;甲狀腺素;胰島素;胰島素原;鬆弛素;鬆弛素原;醣蛋白激素,諸如濾泡刺激激素(FSH)、促甲狀腺激素(TSH)及促黃體激素(LH);肝生長因子(HGF);纖維母細胞生長因子(FGF);促乳素;胎盤催乳激素;苗勒氏管抑制物質;小鼠促性腺激素相關肽;抑制素;活化素;血管內皮生長因子;整合素;血小板生成素(TPO);神經生長因子(NGF),諸如NGF-β;血小板生長因子;轉型生長因子(TGF),諸如TGF-α及TGF-β;胰島素樣生長因子-I及胰島素樣生長因子-II;紅血球生成素(EPO);骨性誘導因子;干擾素,諸如干擾素-α、干擾素-β及干擾素-γ;群落刺激因子(CSF),諸如巨噬細胞-CSF(M-CSF);粒細胞-巨噬細胞-CSF(GM-CSF);及粒細胞-CSF(G-CSF);介白素(IL),諸如IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-15、IL-21腫瘤壞死因子,諸如TNF-α或TNF-β;及其他多肽因子,包含LIF及kit配位體(KL)。如本文所用,術語細胞介素包含來自天然來源或來自重組細胞培養物之蛋白質及原生序列細胞介素之生物活性等效物。
V.分選及耗乏之方法
在一些實施例中,提供用於活體外分選免疫細胞群之方法,其中免疫細胞群之子集包括表現CD19特異性CAR中之任一者的經工程改造之免疫細胞,所述CD19特異性CAR包括對單株抗體具有特異性之抗原決定基(例如例示性模擬抗原決定基序列)。所述方法包括使免疫細胞群與對抗原決定基具有特異性之單株抗體接觸及選擇結合至單株抗體之免疫細胞以獲得富含表現CD19特異性CAR之經工程改造之免疫細胞的細胞群。
在一些實施例中,對所述抗原決定基具有特異性之所述單株抗體視情況與螢光團結合。在此實施例中,選擇結合至單株抗體之細胞的步驟可藉由螢光活化細胞分選(FACS)進行。
在一些實施例中,對所述抗原決定基具有特異性之所述單株抗體視情況與磁性顆粒結合。在此實施例中,選擇結合至單株抗體之細胞之步驟可藉由磁活化細胞分選(MACS)進行。
在一些實施例中,用於分選表現CAR之免疫細胞之方法中所用的mAb係選自阿侖單抗(alemtuzumab)、替伊莫單抗(ibritumomab tiuxetan)、莫羅單抗-CD3(muromonab-CD3)、托西莫單抗(tositumomab)、阿昔單抗(abciximab)、巴利昔單抗(basiliximab)、貝倫妥單抗維多汀(brentuximab vedotin)、西妥昔單抗、英利昔單抗(infliximab)、利妥昔單抗(rituximab)、貝伐單抗(bevacizumab)、聚乙二醇化賽妥珠單抗(certolizumab pegol)、達利珠單抗(daclizumab)、艾庫組單抗(eculizumab)、艾法珠單抗(efalizumab)、吉妥珠單抗(gemtuzumab)、那他珠單抗(natalizumab)、奧馬珠單抗(omalizumab)、帕利珠單抗(palivizumab)、蘭尼單抗(ranibizumab)、托西利單抗(tocilizumab)、曲妥珠單抗(trastuzumab)、維多珠單抗(vedolizumab)、阿達木單抗(adalimumab)、貝利單抗(belimumab)、康納單抗(canakinumab)、地諾單抗(denosumab)、戈利木單抗(golimumab)、伊匹利單抗(ipilimumab)、奧伐木單抗(ofatumumab)、帕尼單抗(panitumumab)、QBEND-10及/或優特克單抗(ustekinumab)。在一些實施例中,所述mAb為利妥昔單抗。在另一實施例中,所述mAb為QBEND-10。
在一些實施例中,當使用活體外分選上文所描述之CAR表現免疫細胞之方法時獲得的CAR表現免疫細胞群包括至少70%、75%、80%、85%、90%、95%之CAR表現免疫細胞。在一些實施例中,當使用活體外分選CAR表現免疫細胞之方法時獲得的CAR表現免疫細胞群包括至少85%之CAR表現免疫細胞。
在一些實施例中,相較於初始(非分選)細胞群,當使用活體外分選上文所描述之CAR表現免疫細胞之方法時獲得的CAR表現免疫細胞群展示增加之活體外細胞毒活性。在一些實施例中,所述活體外細胞毒活性增加10%、20%、30%或50%。在一些實施例中,免疫細胞為T細胞。
在一些實施例中,mAb先前結合至支撐物或表面上。固體支撐物之非限制性實例可包含珠粒、瓊脂糖珠粒、磁性珠粒、塑膠孔板、玻璃孔板、陶瓷孔板、管柱或細胞培養袋。
待投與至接受者之CAR表現免疫細胞可在活體外自來源群富集。擴增源種群之方法可包含使用密度離心、免疫磁珠純化、親和性層析法及螢光活化細胞分選之組合選擇表現諸如CD34抗原之抗原的細胞。
可使用流式細胞量測術對細胞群內之特異性細胞類型進行定量。一般而言,流式細胞量測術為主要藉由光學手段對細胞之組分或結構特徵定量之方法。因為不同細胞型可藉由定量結構特徵區分,所以可使用流式細胞量測術及細胞分選計數及分選混合物中具有不同表現型之細胞。
流式細胞量測術分析涉及兩個主要步驟:1)用一或多種經標記標記物標記所選擇細胞類型,及T)測定相對於群中之細胞總數的經標記細胞數目。在一些實施例中,標記細胞類型之方法包含將經標記之抗體結合至由特異性細胞類型表現之標記物。抗體可為使用螢光化合物直接標記或使用例如識別第一抗體之經螢光標記之第二抗體間接標記。
在一些實施例中,用於分選表現CAR之T細胞的方法為磁活化細胞分選(MACS)。磁活化細胞分選(MACS)為藉由使用超順磁奈米顆粒及管柱分離各種細胞群之方法,此視其表面抗原(CD分子)而定。MACS可用於獲得純細胞群。單細胞懸浮液中之細胞可以磁性方式用微珠粒標記。將樣品塗覆於由鐵磁性球體構成之管柱,所述球體覆蓋有允許快速且溫和地分離細胞之細胞友好型塗層。未標記之細胞通過,而經磁性標記之細胞保留在管柱內。可收集流過物作為未標記之細胞溶離份。在洗滌步驟之後,自分離器移除管柱,且自管柱溶離經磁性標記之細胞。
用於純化特定細胞群(諸如T細胞)之詳細方案可見於Basu S等人(2010)(Basu S, Campbell HM, Dittel BN, Ray A. 藉由螢光活化細胞分選(FACS)純化特定細胞群. J Vis Exp.(41):1546)。
在一些態樣中,本揭示案提供一種藉由活體內耗乏耗盡CD19特異性CAR表現免疫細胞之方法。活體內耗盡可包含向旨在藉由抑制或消除阻止CAR表現免疫細胞之增殖的哺乳動物生物體投與治療(例如結合CAR上之抗原決定基的分子)。
本發明之一個態樣係關於一種活體內耗盡表現包括mAb特異性抗原決定基之CD19 CAR之經工程改造之免疫細胞的方法,其包括使所述經工程改造之免疫細胞或所述CAR表現免疫細胞與至少一種抗原決定基特異性mAb接觸。本發明之另一態樣係關於一種活體內耗盡CAR表現免疫細胞之方法,其包括藉由使所述經工程改造之免疫細胞與抗原決定基特異性抗體接觸之嵌合scFv(例如藉由插入mAb特異性抗原決定基形成)。在一些實施例中,免疫細胞為T細胞及/或抗體為單株抗體。
根據一個實施例,對經工程改造之免疫細胞執行經工程改造之免疫細胞的活體內耗乏,所述經工程改造之免疫細胞先前已使用本發明之活體外方法分選。在此情況下,可使用相同輸注之mAb。在一些實施例中,mAb特異性抗原為CD20抗原且抗原決定基特異性mAb為利妥昔單抗。在一些實施例中,本發明係關於一種活體內耗盡患者中之表現包括mAb特異性抗原決定基之CAR的經工程改造之免疫細胞CAR表現免疫細胞)的方法,其包括使所述CAR表現免疫細胞與至少一種抗原決定基特異性mAb接觸。
在一些實施例中,使所述經工程改造之免疫細胞或所述CAR表現免疫細胞與至少一種抗原決定基特異性mAb接觸之步驟包括向患者輸注抗原決定基特異性mAb(例如利妥昔單抗)。在一些實施例中,向患者投與之抗原決定基特異性mAb之量足以消除患者中至少20%、30%、40%、50%、60%、70%、80%或90% CAR表現免疫細胞。
在一些實施例中,使所述經工程改造之免疫細胞或所述CAR表現免疫細胞與至少一種抗原決定基特異性mAb接觸的步驟包括向患者輸注375 mg/m2
利妥昔單抗一次或若干次。在一些實施例中,每週一次投與mAb(例如利妥昔單抗)。
在一些實施例中,當在補體依賴性細胞毒性(CDC)分析中使用抗原決定基特異性mAb耗乏表現包括mAb特異性抗原決定基之CAR之免疫細胞時,可存活的CAR表現免疫細胞之量減少。在一些實施例中,可存活的CAR表現免疫細胞之量減少至少10%、20%、30%、40%、50%、60%、70%、80%或90%。在一些實施例中,所述mAb特異性抗原決定基為CD20抗原決定基或模擬抗原決定基及/或抗原決定基特異性mAb為利妥昔單抗。
在某些實施例中,經CAR工程改造之免疫細胞的活體內耗乏係藉由輸注雙特異性抗體進行。根據定義,雙特異性單株抗體(BsAb)為由兩種不同單株抗體之片段構成之人工蛋白質且因此結合至兩種不同類型之抗原。此等BsAb及其在免疫療法中之用途已綜述於Muller D及Kontermann R.E.(2010)癌症免疫療法的雙特異性抗體,《生物藥物(BioDrugs)》24(2):89-98。
根據另一特定實施例,輸注之雙特異性mAb能夠結合表現嵌合scFv之經工程改造之免疫細胞上所承載之mAb特異性抗原決定基及效應細胞及細胞毒性細胞(例如免疫細胞,諸如淋巴細胞、巨噬細胞、樹突狀細胞、自然殺手細胞(NK細胞)、細胞毒性T淋巴細胞(CTL))上之表面抗原。藉此,由BsAb觸發之經工程改造之免疫細胞的耗乏可經由抗體依賴性細胞之細胞毒性(ADCC)發生。(Deo Y M, Sundarapandiyan K, Keler T, Wallace PK及Graziano RF,(2000), 《免疫學雜誌》, 165(10):5954-5961])。
在一些實施例中,細胞毒性藥物與可用於耗盡CAR表現免疫細胞之抗原決定基特異性mAb偶合。相較於使用單獨的藥物,藉由將單株抗體之靶向能力與細胞毒性藥物之癌症殺滅能力組合,抗體-藥物結合物(ADC)允許靈敏地辨別健康組織與病變組織。若干種ADC已獲准市售;其製備技術,特定言之,經連接子製備其的技術,描述於(Payne,G.(2003)《癌細胞(Cancer Cell)》3:207-212;Trail等人(2003)《癌症免疫療法(Cancer Immunol.Immunother.)》52:328-337;Syrigos及Epenetos(1999)《抗癌研究(Anticancer Research)》19:605-614; Niculescu-Duvaz及Springer(1997) 《先進藥物遞送綜述(Adv. Drug Del.Rev.)》26:151-172;美國專利第4,975,278號)。
在一些實施例中,待輸注之抗原決定基特異性mAb預先與能夠促進補體依賴性細胞毒性(CDC)之分子結合。因此,補體系統有助於或補充抗體自生物體清除病原體之能力。當受到刺激時,活化級聯隨反應之大規模擴增及細胞殺滅攻膜複合物之活化而被觸發。可使用不同分子來結合mAb,諸如聚醣[[Courtois, A, Gac-Breton, S., Berthou, C, Guezennec, J., Bordron, A.及Boisset, C.(2012),治療性抗體片段之補體依賴性細胞毒活性可藉由免疫原性聚醣偶合獲取,生物技術ISSN之電子期刊:0717-3458;http://www.ejbiotechnology.info DOI:10.2225/voll5-issue5)。
VI. 套組及製品
本申請案提供包括含有CAR之CD19或含有本文所述之免疫細胞之CD19 CAR中之任一者的套組及其醫藥組成物。在一些例示性實施例中,本揭示案之套組包括含有同種異體CD19之T細胞及用於向個體投與淋巴細胞耗乏方案及CAR-T方案之CD52抗體。
本申請案亦提供包括本文所描述之治療性組合物或套組中之任一者的製品。製品之實例包含小瓶(例如密封小瓶)。
實例
實例1:產生抗利妥昔單抗CD19 CAR免疫細胞
產生如圖1及表4中所示之不表現利妥昔單抗結合位點之抗利妥昔單抗抗CD19嵌合抗原受體構築體。將慢病毒載體構築體引入病毒包裝細胞株中且在同種異體基因產生含有抗CD19 CAR之慢病毒。
將來自四個人類供體(541、604、410及2593)之Pan T細胞解凍且在IL-2(100 IU/ml)存在下以1.5×106
個細胞/毫升用大規模T細胞TransAct™(1:15比率)活化。在2天之後,用包括表4中描述之載體的2 ml新鮮慢病毒轉導1.5×106
個細胞(於3 ml中)。經修飾之載體之示意圖展示於圖1中。在第0、2、5、7、9和12天添加IL-2(100 IU/ml)。在第5天將6×106
個總細胞轉移至6孔G-Rex培養盤,且在第9及12天進行培養基交換。在第13天將細胞冷凍。
對在淋巴細胞、存活CD3+、CAR+、CD4/CD8及下游標記物上閘控之轉導細胞進行流式細胞量測術實驗。在第5天及第13天使用一組CD3、CD4、CD8、存活率、CD34及針對抗CD19 CAR(4G7抗Id)之抗體之抗個體基因型進行人類轉導檢查及CD34小組。圖2A及2B顯示使用抗CD19 CAR抗Id抗體,展現來自用表4中所示之CAR表現載體轉導之Pan T細胞在第5天之CAR表現之流式細胞量測術曲線圖。
在第9及13天進行具有人類表現型及活化小組之流式細胞量測術。小組包含CD3、CD4、CD8、存活率、CD45RO、CD62L、CD25、4-1BB、PD-1、針對抗CD19 CAR之抗體之抗個體基因型及TIM3。在第13天,針對細胞擴增及來自所有四名供體之最終CAR表現對細胞進行標準化(圖3)。圖3中之資料顯示,與例如v1.0及v1.1相比,雖然v1.2展現更高轉導速率(%CAR+),但v1.2轉導之細胞展現更低CAR表現(CAR MFI)。隨時間推移監測來自用抗利妥昔單抗CAR表現載體轉導之供體541(圖4A)、604(圖4B)、410(圖4C)、2593(圖4D)之Pan T細胞之細胞擴增及CAR表現。
在第5、9及13天量測來自用抗利妥昔單抗CAR表現載體轉導之供體541(圖5A)、604(圖5B)、410(圖5C)、2593(圖5D)之Pan T細胞的CD4/CD8比率。圖6A-6D顯示來自用抗利妥昔單抗CAR表現載體轉導之供體541(圖6A)、604(圖6B)、410(圖6C)、2593(圖6D)之Pan T細胞在第9天之表現型及活化。圖7顯示第9天自所有四名供體平均化的使用TIM3及PD1染色量測之表現型、活化%CD8+及T細胞無反應性。在來自用抗利妥昔單抗CAR表現載體轉導之供體541(圖8A)、604(圖8B)、410(圖8C)、2593(圖8D)之Pan T細胞之第13天量測表現型及活化。圖9顯示第13天自所有四名供體使用TIM3及PD1染色量測之表現型、活化%CD8+及T細胞無反應性。
實例2:短期及長期體外殺滅分析
測試來自實例1之經轉導CAR細胞之短期及長期殺滅能力。製備具有拉吉細胞(2:1 E比T)之CAR T細胞共培養物用於後流式螢光檢測術分析。測定各CAR構築體使用拉吉細胞作為靶細胞之平均短期(24小時)殺滅分析(圖10)。圖11A-11D顯示使用A549-CD19+細胞作為各CAR構築體之靶細胞之平均長期殺滅分析,其中E:T為8:1(圖11A)、4:1(圖11B)、2:1(圖11C)及1:1(圖11D)。
分析殺滅分析結果與表現型特徵之相關性。以1:1之E比T的第7天殺滅百分比與AR+CD4+41BB+、CAR+CD4+Tim3+(p=0.0352)、CAR+CD4+TEM
+(p=0.0328)、CAR+CD8+PD-1+(p=0.0269)及第13天之CAR表現%(p=0.0245)負相關。以1:1之E比T的第7天殺滅百分比與CAR+CD8+TSCM
+正相關。以1:1之E比T的第9天殺滅百分比與CAR+CD4+Tim3+、CAR+CD4+TEM
+(p=0.0031)、CAR+CD8+Tcm
+(p=0.0182)及第13天之CAR表現%(p=0.0469)負相關。以1:1之E比T的第9天殺滅百分比與CAR+CD8+TSCM
+, CAR+CD8+Tim3-PD-1-(p
=0.0318)及CAR+CD4+TSCM
+(p
=0.0289)正相關。
實例3:含有不同慢病毒構築體之慢病毒效價分析
在此實驗中,將慢病毒載體構築體引入病毒封裝細胞株中且產生含有抗CD19 CAR之慢病毒且在與實例1類似之方案下在Lentigen(馬里蘭州蓋瑟斯堡(Gaithersberg,MD))下測定效價。
藉由量測病毒蛋白p24之水準之物理效價或藉由量測轉導效價來評估對慢病毒效價。意外地發現,當自慢病毒構築體v1.0移除安全開關RQR8時,病毒效價顯著降低(比較表5中之v1.0與v1.1)。當在v1.1中之EF1a啟動子經如在v1.2(「EF1a(短)啟動子」)中之較短或截短之EF1a啟動子替代時,效價得到改進。
為分析抗CD19 CAR v1.0、v1.2及v1.3之慢病毒製劑之穩固性,進行病毒滴定分析。在pan T細胞轉導後第5天,針對% CAR+T細胞分析v1.0、v1.2及v1.3之慢病毒製劑之連續體積稀釋液。結果顯示,在低稀釋度(例如10% v/v)下,所有三個構築體均展現類似可接受之轉導效率。然而,在提高稀釋度(例如,3.3%、1.1% v/v)時,相較於其他抗利妥昔單抗抗CD19 CAR構築體v1.2,抗利妥昔單抗抗CD19 CAR構築體v1.3之轉導效率更顯著下降。參見圖12。選擇構築體v1.2用於活體內分析。
實例4:活體內效價分析
在此實驗中,在小鼠腫瘤模型中,相較於ALLO-501v1.0分析ALLO-501v1.2之活體內抗腫瘤效價。將攜帶螢光素酶報導基因之CD19陽性拉吉細胞注射至NSG小鼠中。將含有v1.0或v1.2慢病毒構築體之慢病毒轉導至兩個供體541及604之panT細胞中。經由尾靜脈注射100,000螢光素酶拉吉細胞接種NSG小鼠。在接種後第4天,向攜帶拉吉細胞之NSG小鼠投與指定劑量之CAR構築體。藉由腹膜內注射螢光素酶底物,隨後量測累積螢光素酶信號來評估拉吉細胞移植及進展。結果展示於圖13A(供體541)及圖13B(供體604)中。
[圖1]顯示抗利妥昔單抗CD19嵌合抗原受體之示意性圖示。
[圖2A及2B]顯示來自用抗利妥昔單抗CAR表現載體轉導之Pan T細胞在第5天之CAR表現之流式細胞測量術圖。圖2A顯示來自供體541及604之細胞上之CAR表現。圖2B顯示來自供體410之細胞上之CAR及CD34表現。在供體2593下觀察到類似概況(資料未顯示)。
[圖3]顯示第13天所有四名供體之標準化細胞擴增及最終CAR表現。
[圖4A-4D]顯示來自用抗利妥昔單抗CAR表現載體轉導之供體541(圖4A)、604(圖4B)、410(圖4C)、2593(圖4D)之Pan T細胞隨時間推移之細胞擴增及CAR表現。
[圖5A-5D]顯示來自用抗利妥昔單抗CAR表現載體轉導之供體541(圖5A)、604(圖5B)、410(圖5C)、2593(圖5D)之Pan T細胞在第5、9及13天之CD4/CD8比率。
[圖6A-6D]顯示來自用抗利妥昔單抗CAR表現載體轉導之供體541(圖6A)、604(圖6B)、410(圖6C)、2593(圖6D)之Pan T細胞在第9天之表現型及活化。
[圖7]顯示第9天自所有四名供體平均化的使用TIM3及PD1染色量測之表現型、活化%CD8+及無反應性。
[圖8A-8D]顯示來自用抗利妥昔單抗CAR表現載體轉導之供體541(圖8A)、604(圖8B)、410(圖8C)、2593(圖8D)之Pan T細胞在第13天之表現型及活化。
[圖9]顯示第13天自所有四名供體使用TIM3及PD1染色量測之表現型、活化%CD8+及無反應性。
[圖10]顯示使用拉吉細胞(Raji cell)作為各CAR構築體之靶細胞的平均短期(24小時)殺滅分析。
[圖11A-11D]顯示使用A549-CD19+細胞作為各CAR構築體之靶細胞之平均長期殺滅分析,其中E:T為8:1(圖11A)、4:1(圖11B)、2:1(圖11C)及1:1(圖11D)。
[圖12]顯示在用連續稀釋之抗利妥昔單抗慢病毒構築體(ALLO-501v1.2及v1.3)或抗利妥昔單抗慢病毒構築體(ALLO-501v1.0)之慢病毒製劑轉導Pan T細胞之後第5天時之CAR+T細胞%的含量。
[圖13A-B]顯示當在攜帶拉吉細胞之NSG小鼠腫瘤模型中測試時,來自用抗利妥昔單抗CAR表現載體(ALLO-501v1.2)或抗利妥昔單抗CAR表現載體(ALLO-501v1.0)轉導之供體541(圖13A)及604(圖13B)之pan T細胞的活體內功效。
Claims (27)
- 一種經分離之聚核苷酸,其編碼包括與SEQ ID NO:9至少70%一致之抗CD19嵌合抗原受體(CAR)之多肽,其中所述多肽不包括利妥昔單抗結合位點,及 其中所述聚核苷酸包括能夠在哺乳動物T細胞中表現所述抗CD19嵌合抗原受體(CAR)之短EF1a啟動子。
- 如請求項1之經分離之聚核苷酸,其中所述短EF1a啟動子不包括SEQ ID NO:15所包括的內含子。
- 如請求項2之經分離之聚核苷酸,其中所述內含子包括SEQ ID NO:39之核酸序列。
- 如前述請求項中任一項之經分離之聚核苷酸,其中所述啟動子包括SEQ ID NO:16之核酸序列。
- 如前述請求項中任一項之經分離之聚核苷酸,其中所述多肽進一步包括安全開關(safety switch)。
- 如請求項5之經分離之聚核苷酸,其中所述安全開關使用連接肽連接至CD19 CAR。
- 如請求項5之經分離之聚核苷酸,其中所述安全開關使用T2A連接子連接至所述抗CD19 CAR。
- 如請求項5至7中任一項之經分離之聚核苷酸,其中所述安全開關包括抗體結合位點。
- 如請求項5至7中任一項之經分離之聚核苷酸,其中所述安全開關包括突變的CD20模擬抗原決定基。
- 如請求項5至9中任一項之經分離之聚核苷酸,其中所述多肽包括CD34抗原決定基。
- 如請求項10之經分離之聚核苷酸,其中所述CD34抗原決定基為QBEND-10抗原決定基。
- 如請求項5至11中任一項之經分離之聚核苷酸,其中所述多肽進一步包括CD8鉸鏈/跨膜域。如前述請求項中任一項之經分離之聚核苷酸,其包括與SEQ ID NO:1-7中之任一者至少約80%、85%、90%、95%、96%、98%、99%或100%一致的核酸序列。
- 如前述請求項中任一項之經分離之聚核苷酸,其編碼與SEQ ID NO:8-14中之任一者至少約80%、85%、90%、95%、96%、98%、99%或100%一致的多肽。
- 一種載體,其包括如前述請求項中任一項之經分離之聚核苷酸。
- 如請求項15之載體,其中所述載體為逆轉錄病毒載體、DNA載體、質體、RNA載體、腺病毒載體、腺病毒相關載體、慢病毒載體或其任何組合。
- 一種經工程改造之免疫細胞,其包括如請求項1至14中任一項之經分離之聚核苷酸,其中所述經工程改造之免疫細胞不表現利妥昔單抗結合位點。
- 一種經工程改造之免疫細胞,其包括如請求項14或16之載體,其中所述經工程改造之免疫細胞不表現利妥昔單抗結合位點。
- 如請求項17或18中任一項之經工程改造之免疫細胞,其中免疫細胞為T細胞、腫瘤浸潤性淋巴細胞(TIL)、NK細胞、TCR表現細胞、樹突狀細胞或NK-T細胞。
- 如請求項19之經工程改造之免疫細胞,其中細胞為自體T細胞。
- 如請求項19之經工程改造之免疫細胞,其中細胞為同種異體T細胞。
- 如請求項17至21中任一項之經工程改造之免疫細胞,其中所述細胞包括與SEQ ID NO:3之核酸序列至少80%、85%、90%、95%、96%、98%、99%或100%一致的聚核苷酸。
- 如請求項17至22中任一項之經工程改造之免疫細胞,其中所述細胞對利妥昔單抗具有抗性
- 一種醫藥組成物,其包括如請求項17至23中任一項之經工程改造之免疫細胞。
- 一種治療有需要之個體之疾病或病症的方法,其包括向所述個體投與如請求項17至23中任一項之經工程改造之免疫細胞或如請求項24所述之醫藥組成物。
- 如請求項25之方法,其中所述疾病或病症為非霍奇金氏淋巴瘤(Non-Hodgkin lymphoma,NHL)。
- 如請求項25或26之方法,其中所述個體已用利妥昔單抗治療或目前正在用利妥昔單抗治療。
- 一種製品,其包括如請求項17至23中任一項之經工程改造之免疫細胞或如請求項24之醫藥組成物。
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