TW202239768A - 改良之免疫細胞療法 - Google Patents
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Abstract
本發明提供用於治療之經工程改造之人類細胞(例如T細胞)。本發明亦提供用於製造經工程改造之細胞的表現構築體。
Description
在過去二十年間,免疫學及腫瘤生物學之根本進展以及大量腫瘤抗原之鑑別促成基於細胞之免疫療法領域的顯著發展。旨在藉由將自體及離體擴增之T細胞轉移至患者來治療癌症的T細胞療法已引起一些顯著的抗腫瘤反應(Blattman等人,
Science. (2004) 305(5681):200-5)。例如,離體擴增的天然存在之腫瘤浸潤性淋巴球(TIL)的投與介導黑色素瘤患者中50至70%範圍內的客觀反應率,該等患者包括在涉及肝臟、肺、軟組織及腦之多個部位具有大型侵襲性腫瘤的患者(Rosenberg等人,
Nat Rev Cancer. (2008) 8(4):299-308;Dudley等人,
J Clin Oncol. (2005) 23(10):2346-57)。
TIL療法普遍應用的主要限制因素為難以產生具有抗腫瘤潛力之人類T細胞。作為替代方法,可經由T細胞工程改造將外源性高親和力TCR引入患者之普通自體T細胞中。已顯示,將此等細胞授受性轉移至淋巴耗乏患者中介導諸如黑色素瘤、大腸直腸癌及滑膜肉瘤之癌症中的癌症消退(Kunert等人,
Front Immunol. (2013) 4:363;Robbins等人,
Clin Cancer Res. (2015) 21(5):1019-27)。經TCR工程改造之T細胞療法的優勢之一為其可靶向整個系列的潛在細胞內腫瘤特異性蛋白,該等蛋白經加工且經由MHC呈現遞送至細胞表面,且甚至可在較低密度下由抗原特異性細胞毒性T細胞識別(Kunert,見上文)。
已嘗試工程改造具有抗體特異性與T細胞受體效應功能之TCR分子。在此等方法中之一些中,TCR之可變域及恆定域(例如αβ TCR或γδ TCR)經針對腫瘤抗原之抗體的可變域及恆定域置換,從而產生嵌合抗體-TCR,稱為「abTCR」或「caTCR」。參見例如WO 2017/070608及WO 2018/200582,其揭示內容以全文引用之方式併入本文中。在該等方法之一者中,組合使用嵌合刺激受體(CSR)與caTCR以增強經工程改造之T細胞的腫瘤殺滅功效。如同嵌合抗原受體(CAR),CSR具有結合目標配位體(例如腫瘤抗原)之細胞外域及細胞內協同刺激域,但不同於CAR,CSR不具有細胞內初級免疫細胞信號傳導域(其通常為CD3 ζ鏈之細胞內域)或不具有功能性初級免疫細胞信號傳導域。CSR及caTCR結合於不同目標/抗原或相同目標/抗原之不同抗原決定基且協同作用以增強經工程改造之T細胞的細胞毒性。參見例如WO 2018/200583,其揭示內容以全文引用之方式併入本文中。
T細胞療法所面臨之一個挑戰為由於稱為T細胞衰竭之現象而缺乏T細胞活體內持久性。參見例如Fraietta等人,
Nat Med. (2018) 24(5):563-71;Long等人,
Nat Med. (2015) 21(6):581-90;及Eyquem等人,
Nature(2017) 543(7643):113-7。T細胞衰竭之特徵在於代謝功能、轉錄程式中的顯著變化、效應功能缺失(例如降低之細胞介素分泌及細胞毒性)、多種表面抑制性受體之表現及細胞凋亡。T細胞衰竭已歸因於持續抗原暴露,其引起連續TCR信號傳導,或經由T細胞上之經工程改造之抗原受體的組成性(tonic)抗原非依賴性信號傳導(參見例如Long,見上文)。已尋求防止或逆轉T細胞衰竭作為增強T細胞有效性之手段,例如在患有癌症或慢性感染之患者中及在T細胞療法中。參見例如WO 2019/118902,其揭示內容以全文引用之方式併入本文中。
因此,仍需要改良之T細胞療法,其中經工程改造之T細胞具有較高且持續的腫瘤殺滅效力。
本發明提供用於改良免疫細胞療法之組合物及方法。在一態樣中,本發明提供一或多種表現構築體,其包含一或多種用於表現以下之表現卡匣:a)嵌合抗體-T細胞受體(TCR)構築體(caTCR),其包含i)特異性結合於目標抗原之抗原結合模組,及ii) T細胞受體模組(TCRM;例如,源於人類γδ TCR之模組),其包含:包含第一TCR跨膜域(TCRD-TM)之第一TCR域(TCRD),及包含第二TCR-TM之第二TCRD,其中TCRM有助於至少一種TCR相關信號傳導分子的募集;b)嵌合刺激受體(CSR),其包含i)能夠結合目標配位體或與目標配位體相互作用之配位體結合模組,ii)跨膜模組,及iii)能夠提供協同刺激信號至免疫細胞之協同刺激免疫細胞信號傳導模組,其中配位體結合模組及協同刺激免疫細胞信號傳導模組並非源於相同分子,且其中CSR缺乏功能性初級免疫細胞信號傳導域;及c)人類c-Jun多肽。
在一個態樣中,本發明提供一種減少經工程改造之免疫細胞(例如人類免疫細胞;T細胞;及人類T細胞)之衰竭的方法,其包含向經工程改造之免疫細胞中引入增加c-Jun在細胞中之表現的外源核酸分子,其中經工程改造之免疫細胞包含一或多種表現構築體,該一或多種表現構築體包含用於表現以下之一或多種表現卡匣:a) caTCR,其包含i)特異性結合於目標抗原之抗原結合模組,及ii) TCRM (例如,源於人類γδ TCR之TCRM),其包含:包含第一TCR-TM之第一TCRD及包含第二TCR-TM之第二TCRD,其中TCRM有助於至少一種TCR相關信號傳導分子之募集;及b) CSR,其包含i)能夠結合目標配位體或與目標配位體相互作用之配位體結合模組,ii)跨膜模組,及iii)能夠提供協同刺激信號至免疫細胞之協同刺激免疫細胞信號傳導模組,其中配位體結合模組及協同刺激免疫細胞信號傳導模組並非源於相同分子,且其中CSR缺乏功能性初級免疫細胞信號傳導域。
在一些實施例中,c-Jun為野生型人類c-Jun,其視情況包含SEQ ID NO:1。在其他實施例中,c-Jun為突變人類c-Jun,其視情況在其反式活化域或δ域中包含失活突變。在特定實施例中,與野生型c-Jun相比,c-Jun包含(i) S63A及S73A突變或(ii)殘基2與102之間或殘基30與50之間的缺失。
在一些實施例中,CSR中之協同刺激免疫細胞信號傳導模組源於人類CD30且視情況包含SEQ ID NO:21。
在一些實施例中,caTCR之目標抗原為與人類MHC I類分子複合之人類AFP肽。在特定實施例中,目標抗原為與HLA-A2*02:01複合之AFP158。
在一些實施例中,caTCR之抗原結合模組包含(i)免疫球蛋白(Ig)重鏈可變域(VH),其包含SEQ ID NO:2中之HCDR1-3;及(ii) Ig輕鏈可變域(VL),其包含SEQ ID NO:3中之LCDR1-3。在其他實施例中,HCDR1-3分別包含SEQ ID NO:5-7,且LCDR1-3分別包含SEQ ID NO:9-11。在特定實施例中,VH及VL分別包含SEQ ID NO:8及SEQ ID NO:12。在某些實施例中,caTCR為雜二聚體,其分別包含SEQ ID NO:2及SEQ ID NO:3。
在一些實施例中,CSR之目標配位體為人類磷脂肌醇蛋白聚醣3 (glypican 3,GPC3)。在其他實施例中,CSR包含(i) Ig VH,其包含SEQ ID NO:4中之HCDR1-3;及(ii) Ig VL,其包含SEQ ID NO:4中之LCDR1-3。在特定實施例中,CSR中之HCDR1-3分別包含SEQ ID NO:13-15,且CSR中之LCDR1-3分別包含SEQ ID NO:17-19。在某些實施例中,CSR中之VH及VL分別包含SEQ ID NO:16及SEQ ID NO:20。在某些實施例中,CSR包含SEQ ID NO:4。
在一些實施例中,本文中之表現構築體為病毒載體,例如慢病毒載體、腺病毒載體、腺相關病毒載體、牛痘載體、單純疱疹病毒載體及艾-巴二氏(Epstein-Barr)病毒載體。
在一些實施例中,表現構築體包含用於表現雜二聚caTCR、CSR及c-Jun之四順反子表現卡匣。四順反子表現構築體可包含用於表現以下之表現卡匣:a) caTCR,其包含i)特異性結合於與人類MHC I類分子之人類AFP肽複合物(視情況與HLA-A2*02:01複合之AFP158)的抗原結合模組,及ii)源於人類γδ TCR之TCRM;b) CSR,其包含i)配位體結合模組,其能夠與GPC3結合或相互作用,ii)跨膜模組,及iii)協同刺激免疫細胞信號傳導模組,其源於人類CD30之細胞內域;及c)人類c-Jun多肽。在一些實施例中,卡匣包含SEQ ID NO:1之編碼序列、SEQ ID NO:2及SEQ ID NO:3之編碼序列及SEQ ID NO:4之編碼序列,視情況其中編碼序列在框內藉由2A-編碼序列或藉由內部核糖體進入位點(IRES)分隔開。
本文中之表現構築體(例如,諸如慢病毒載體之病毒載體)可包含組成性或誘導性啟動子,視情況,EF-1α啟動子,視情況其中表現構築體為慢病毒載體。
在一個態樣中,本發明提供包含本文中之四順反子表現構築體之重組病毒,視情況其中表現構築體為慢病毒載體。
在另一態樣中,本發明提供一種工程改造免疫細胞之方法,其包含:(a)提供起始細胞群體(例如,人類細胞群體);(b)將本文中之表現構築體或重組病毒引入至起始細胞群體中;(c)視情況選擇表現caTCR、CSR及c-Jun之細胞;及(d)自步驟(b)或(c)之細胞衍生經工程改造之免疫細胞。在一些實施例中,起始細胞群體包含免疫細胞(例如,自體或同種異體T細胞)。在其他實施例中,起始細胞群體包含富潛能或多潛能細胞,且步驟(d)包含將步驟(b)或(c)之細胞分化成免疫細胞,視情況T細胞。
本發明亦提供包含本文中之表現構築體或病毒的人類及/或免疫細胞(例如,T細胞),以及藉由本發明工程改造方法獲得的細胞。在一些實施例中,經工程改造之T細胞包含CD8
+T細胞。在一些實施例中,相比於不過表現c-Jun之對應細胞,經工程改造之細胞表現較低含量(例如,少至少10%、20%、30%、40%、50%、60%或70%)的衰竭標記(例如,為CD39、PD-1、TIM-3或LAG-3),且視情況其中衰竭標記為CD39、PD-1、TIM-3或LAG-3。
本發明亦提供包含本文中之表現構築體、病毒或經工程改造之細胞,及醫藥學上可接受之載劑的醫藥組合物。
在另一態樣中,本發明提供一種殺滅目標細胞之方法,其包含使目標細胞與本文中之經工程改造的免疫細胞在允許藉由免疫細胞殺滅目標細胞之條件下接觸,其中目標細胞表現目標抗原及目標配位體,視情況,其中相比於不包含引起c-Jun過表現之外源核酸分子的對應免疫細胞,免疫細胞在與目標細胞接觸時表現較低含量(例如,少至少10%、20%、30%、40%、50%、60%或70%)的衰竭標記(例如,CD39、PD-1、TIM-3或LAG-3)。在一些實施例中,免疫細胞為T細胞及/或目標細胞為癌細胞。在一些實施例中,CSR中之協同刺激免疫細胞信號傳導模組源於人類CD30,且相比於經工程改造以表現其協同刺激免疫細胞信號傳導模組源於人類CD28之CSR的對應免疫細胞,免疫細胞表現較低含量(例如,少至少10%、20%、30%、40%、50%、60%或70%)之視情況選自CD39、PD-1、TIM-3及LAG-3的衰竭標記。
在一個態樣中,本發明提供一種治療有需要之患者(例如,人類患者)的方法,其包含向患者投與本文中之人類細胞或醫藥組合物。患者可患有例如癌症或腫瘤(例如,實體腫瘤),諸如肝細胞癌或胃癌。
本發明亦提供本文中之表現構築體、病毒或經工程改造之細胞用於製造供治療有需要之患者用之藥劑的用途。進一步提供在如本文所描述之治療方法中用於治療有需要之患者的表現構築體、病毒、細胞或醫藥組合物。
本發明之其他特徵、目標及優勢在以下實施方式中顯而易見。然而,應理解,實施方式雖然指示本發明之實施例及態樣,但僅為了說明而非限制給出。對於熟習此項技術者而言,在本發明之範疇內的各種改變及修改將自實施方式變得顯而易見。
相關申請案之交叉引用
本申請案主張於2021年1月27日申請之美國臨時申請案63/142,486之優先權,其揭示內容以全文引用之方式併入本文中。
本申請案提供經工程改造之人類細胞(例如,諸如T細胞之免疫細胞),其包含用於表現嵌合抗體-T細胞受體(caTCR)、嵌合刺激受體(CSR;本文中亦稱為「嵌合信號傳導受體」)及c-Jun蛋白之構築體。caTCR包含特異性結合於目標抗原之抗原結合模組及能夠募集至少一種TCR相關信號傳導分子之T細胞受體模組(TCRM)。CSR包含特異性結合於目標配位體之配位體結合域及能夠提供刺激信號至免疫細胞之協同刺激免疫細胞信號傳導域,且不包含功能性初級T細胞信號傳導序列。目標抗原及目標配位體為在目標細胞(例如,病變細胞)之細胞表面上表現之不同或相同的蛋白或蛋白複合物。在一些實施例中,目標抗原及目標配位體為相同蛋白或蛋白複合物,但caTCR及CSR結合於相同蛋白或蛋白複合物上之不同區域。在一些實施例中,目標抗原可為蛋白複合物,其包含肽及主要組織相容性複合體(MHC)蛋白,諸如由病變細胞表面上之MHC呈現的疾病相關抗原肽。該疾病可為例如胃癌或肝癌。caTCR藉由控制TCR活化之天然存在的機制調節,而CSR增強由caTCR介導之免疫反應。c-Jun表現有助於藉由例如緩解或防止T細胞衰竭來維持T細胞之活性狀態。
本發明之經工程改造的免疫細胞(諸如T細胞)展現針對攜帶目標的腫瘤細胞之持續強力的細胞毒性。相比於不過表現c-Jun (例如,經由外源引入之c-Jun基因序列)之T細胞,本發明之經工程改造的T細胞展示較少的T細胞衰竭跡象。經工程改造之細胞可具有以下特徵中之一或多者:(i)其隨時間推移不具有增加的衰竭標記PD-1、TIM-3、LAG-3及/或CD39之表現;(ii)具有降低的細胞凋亡速率;(iii)其維持包括分泌包括IL-2、TNF-α、INF-γ及GM-CSF之細胞介素的活性生物狀態;(iv)其具有增加的記憶細胞形成及/或記憶標記(例如CD62L)之維持;(v)其具有增強的細胞毒性;(vi)其展示提高的具有低表面抗原之腫瘤目標之識別;(vii)其具有增強的回應於抗原之增殖;(viii)在重複抗原刺激之後維持存活及功能性;及(ix)其展示提高的腫瘤浸潤能力。
在一些實施例中,CSR包含源於CD30 (例如,人類CD30)之細胞內域的協同刺激免疫細胞信號傳導域。本發明人已意外地發現,c-Jun過表現顯著減少經工程改造以表現caTCR (例如,針對AFP之caTCR)及基於CD30之CSR (例如,靶向GPC3之CSR)的T細胞中之衰竭。當CSR具有源於另一免疫細胞信號傳導域(諸如源於CD28之免疫細胞信號傳導域)的細胞內協同刺激域時,未觀測到此衰竭顯著減少。
I. 免疫細胞來源
本發明之經工程改造之免疫細胞的來源可為待治療之患者(亦即,自體細胞)或來自並非待治療之患者的供體(例如,同種異體細胞)。在一些實施例中,經工程改造之免疫細胞為經工程改造之T細胞。本文中之經工程改造的T細胞可為CD4
+CD8
-(亦即,CD4單陽性) T細胞、CD4
-CD8
+(亦即,CD8單陽性) T細胞或CD4
+CD8
+(雙陽性) T細胞。功能上,T細胞可為細胞毒性T細胞、輔助T細胞、自然殺手T細胞、抑制T細胞或其混合物。待工程改造之T細胞可為自體或同種異體的。
包括初級T細胞之初級免疫細胞可獲自許多組織來源,其包括周邊血液單核細胞(PBMC)、骨髓、淋巴結組織、臍帶血、胸腺組織、來自感染部位之組織、腹水、肋膜積液、脾臟組織及/或腫瘤組織。包括PBMC之白血球可藉由熟知技術(例如FICOLL™分離及白血球清除)自其他血球分離。白血球清除產物通常含有淋巴球(包括T細胞及B細胞)、單核球、粒細胞及其他有核白血球。T細胞進一步與其他白血球分離,例如藉由經由PERCOLL™梯度進行離心或藉由逆流式離心淘析分離。T細胞之特定亞群,諸如CD3
+、CD25
+、CD28
+、CD4
+、CD8
+、CD45RA
+、GITR
+及CD45RO
+T細胞可藉由正向或負向選擇技術(例如,使用基於螢光或基於磁性之細胞分選)進一步分離。例如,T細胞可藉由與多種可商購的抗體結合珠粒中之任一者(諸如Dynabeads®、CELLection
TM、DETACHaBEAD
TM(Thermo Fisher)或MACS®細胞分離產品(Miltenyi Biotec))一起培育足以正向選擇所要T細胞之時段來分離。
在一些情況下,自體T細胞直接在癌症治療之後獲自癌症患者。已觀測到,在某些癌症治療,尤其損害免疫系統之彼等癌症治療之後,在治療之後不久收集的T細胞之品質可具有提高之離體擴增及/或在離體工程改造之後移植的能力。
不管在基因修飾之前或之後,T細胞可一般使用如例如以下中所描述之方法活化及擴增:美國專利6,352,694;6,534,055;6,905,680;6,692,964;5,858,358;6,887,466;6,905,681;7,144,575;7,067,318;7,172,869;7,232,566;7,175,843;5,883,223;6,905,874;6,797,514;6,867,041;10,786,533;及美國專利公開案20060121005。一般而言,T細胞可藉由與表面接觸而在活體外或離體擴增,該表面附接有刺激CD3/TCR複合物相關信號的試劑及刺激T細胞表面上之協同刺激分子的配位體。尤其,T細胞群體可諸如藉由與抗CD3抗體或其抗原結合片段,或固定於表面上之抗CD3抗體接觸,或藉由與結合鈣離子載體的蛋白激酶C活化因子(例如,苔蘚抑素(bryostatin))接觸而被刺激。對於T細胞表面上輔助分子之共刺激,可使用結合輔助分子之配位體。例如,T細胞群體可與抗CD3抗體及抗CD28抗體在適於刺激T細胞增殖之條件下接觸。為了刺激CD4
+T細胞或CD8
+T細胞之增殖,可採用抗CD3抗體及抗CD28抗體。
細胞培養條件可包括以下中之一或多者:特定培養基、溫度、氧含量、二氧化碳含量、時間、試劑(例如營養素、胺基酸、抗生素、離子及/或刺激因子(諸如細胞介素、趨化激素、抗原、結合搭配物、融合蛋白、重組可溶性受體)),及任何其他經設計以活化細胞之試劑。在一些實施例中,培養條件包括添加IL-2、IL-7及/或IL-15。
在一些實施例中,待工程改造之細胞可為在工程改造之後分化為成熟T細胞的富潛能或多潛能細胞。此等非T細胞可為同種異體的,且可為例如人類胚胎幹細胞、人類誘導富潛能幹細胞或造血幹細胞或祖細胞。為了易於描述,富潛能及多潛能細胞在本文中共同稱為「祖細胞」。
在使用同種異體細胞之情況下,其較佳經工程改造以減少移植物抗宿主排斥反應(例如,藉由基因剔除內源性
B2M及/或
TRAC基因)。
II. 免疫細胞或祖細胞之工程改造
如本文所用,術語「細胞工程改造」或「細胞修飾」(包括其衍生術語)係指細胞(例如本文所揭示之免疫細胞)之靶向修飾。在一些態樣中,細胞工程改造包含病毒基因工程改造、非病毒基因工程改造、引入受體以實現腫瘤特異性靶向(例如,抗AFP caTCR及抗GPC3 CSR)、引入改良T細胞功能之一或多種內源性基因、引入改良免疫細胞(例如T細胞)功能之一或多種合成基因(例如,編碼c-Jun多肽之聚核苷酸,從而使免疫細胞相比於未經修飾之對應細胞展現增加的c-Jun表現),或其任何組合。如本發明中其他地方所進一步描述,在一些態樣中,細胞可經轉錄活化因子(例如,基於CRISPR/Cas系統之轉錄活化因子)工程改造或修飾,其中轉錄活化因子能夠誘導及/或增加所關注之蛋白(例如c-Jun)的內源性表現。
在一些態樣中,本文所描述之細胞業已經轉錄活化因子修飾,該轉錄活化因子能夠誘導及/或增加所關注之蛋白(例如,c-Jun)在細胞中的內源性表現。如本文所用,術語「轉錄活化因子」係指增加基因或一組基因之轉錄(例如,藉由結合至核酸序列之強化子或啟動子近端元件且從而誘導其轉錄)的蛋白。可與本發明一起使用之此類轉錄活化因子的非限制性實例包括:基於轉錄活化因子樣效應物(TALE)之轉錄活化因子、基於鋅指蛋白(ZFP)之轉錄活化因子、基於規律間隔重複短回文序列簇(CRISPR)/CRISPR相關蛋白(Cas)系統之轉錄活化因子或其組合。參見例如Kabadi等人,
Methods(2014) 69(2):188-197,其以全文引用的方式併入本文中。
在一些態樣中,本文所描述之細胞已經基於CRISPR/Cas系統之轉錄活化因子(諸如CRISPR活化(CRISPRa))修飾。參見例如Nissim等人,
Molecular Cell(2014) 54(4):698-710;Perez-Pinera等人,
Nat. Methods(2013) 10(10):973-976;Maeder等人,
Nat. Methods(2013) 10(10):977-979;Cheng等人,
Cell Res. (2013) 23(10):1163-71;Farzadfard等人,
ACS Synth. Biol. (2013) 2(10):604-13;以上所有均以全文引用之方式併入本文中。CRISPRa為一種類型之CRISPR工具,其包含使用缺乏核酸內切酶活性但仍能夠結合至其導引RNA及目標DNA核酸序列的經修飾之Cas蛋白。可用於本發明之此類經修飾之Cas蛋白的非限制性實例為此項技術中已知的。參見例如Pandelakis等人,
Cell Systems(2020) 10(1):1-14,其以全文引用的方式併入本文中。在一些態樣中,經修飾之Cas蛋白包含經修飾之Cas9蛋白(在此項技術中亦稱為「dCas9」)。在一些態樣中,經修飾之Cas蛋白包含經修飾之Cas12a蛋白。在一些態樣中,可用於本發明之經修飾Cas蛋白結合至導引聚核苷酸(例如小導引RNA) (「經修飾之Cas-導引複合物」),其中導引聚核苷酸包含與編碼所關注之蛋白(例如c-Jun)之核酸序列的區域互補的識別序列。在某些態樣中,導引聚核苷酸包含與編碼所關注之蛋白之內源性核酸序列的啟動子區互補的識別序列。在一些態樣中,一或多種轉錄活化因子附接至經修飾之Cas-導引複合物(例如,經修飾之Cas蛋白的N端及/或C端),使得當將經修飾之Cas-導引複合物引入至細胞中時,一或多種轉錄活化因子可結合至內源性基因之調節元件(例如啟動子區)且藉此誘導及/或增加編碼之蛋白(例如c-Jun)之表現。可使用之常見一般活化因子的說明性實例包括RNAP、VP16、VP64及p65之ω子單元(參見例如Kabadi及Gersbach,
Methods(2014) 69(2):188-97)。
在一些態樣中,一或多種轉錄抑制因子(例如,克魯珀相關盒域(Kruppel-associated box domain,KRAB))可附接至經修飾之Cas-導引複合物(例如,經修飾之Cas蛋白的N端及/或C端),使得當引入細胞中時,一或多種轉錄抑制因子可抑制或減少基因之轉錄,例如可干擾c-Jun之表現的彼等基因(例如Bach2)。參見例如US20200030379A1及Yang等人,
J Transl Med. (2021) 19:459,其中之每一者以全文引用之方式併入本文中。在一些態樣中,可用於本發明之經修飾Cas蛋白可附接至一或多種轉錄活化因子及一或多種轉錄抑制因子兩者。
不受任一理論束縛,在一些態樣中,使用此類經修飾之Cas蛋白可實現所關注之基因的條件性轉錄及表現。例如,在一些態樣中,細胞(例如,T細胞)經修飾以包含與蛋白酶(例如,菸草蝕刻病毒(TEV))及靶向c-Jun之啟動子區之單一導引RNA (sgRNA)連接的重組抗原受體(例如,抗AFP caTCR及抗GPC3 CSR)。在一些態樣中,細胞經修飾以進一步包含用於活化T細胞之連接子(LAT),其與經由連接子(例如,TEV可裂解連接子)附接至轉錄活化因子(例如,dCas9-VP64-p65-Rta轉錄活化因子(VPR))的經修飾Cas蛋白複合。在抗原受體活化下,經修飾之Cas蛋白經釋放以核定位且條件性地且可逆地誘導c-Jun之表現。參見例如Yang等人,
J Immunother Cancer(2021) 9(增刊2):A164,其以全文引用之方式併入本文中。
如熟習此項技術者將顯而易見,在一些態樣中,本文所描述之細胞已使用多種方法之組合修飾。例如,在一些態樣中,細胞已經修飾以包含(i)編碼一或多種蛋白(例如,抗AFP caTCR、抗GPC3 CSR及截短EGFR(EGFRt))的外源性核苷酸序列,及(ii)增加內源性蛋白(例如c-Jun)之表現的外源性轉錄活化因子(例如,CRISPRa)。在一些態樣中,細胞已經修飾以包含(i)編碼第一蛋白(例如,抗AFP caTCR)之外源性核苷酸序列,(ii)編碼第二蛋白(例如,抗GPC3 CSR)之外源性核苷酸序列,及(iii)編碼蛋白(例如,c-Jun蛋白)之外源性核苷酸序列。在一些態樣中,經修飾之細胞可進一步包含編碼第三蛋白(例如,EGFRt)之外源核苷酸序列。如本文所描述,在一些態樣中,編碼第一、第二及第三蛋白之外源性核苷酸序列可為單一多順反子載體之部分。
除非另外指明,否則可使用此項技術中已知之任何適合的方法將一或多種外源性核苷酸序列及/或轉錄活化因子引入至細胞中。用於向細胞遞送一或多種外源性核苷酸序列之適合方法的非限制性實例包括:轉染(亦稱為轉型及轉導)、電穿孔、非病毒遞送、病毒轉導、脂質奈米粒子遞送及其組合。
在一些態樣中,細胞已經轉錄活化因子(例如,基於CRISPR/Cas系統之轉錄活化因子,例如CRISPRa)修飾,使得內源性c-Jun蛋白之表現相比於尚未經轉錄活化因子修飾之相應細胞增加。
儘管本文所提供之某些揭示內容大體上關於修飾免疫細胞以包含編碼c-Jun蛋白(野生型c-Jun或其變異體)之外源性核苷酸序列,但熟習此項技術者應顯而易見,可使用其他適合方法誘導及/或增加細胞中之c-Jun蛋白表現(野生型或其變異體)。例如,如本文所描述,在一些態樣中,內源性c-Jun蛋白表現可藉由轉錄活化因子(例如,CRISPRa)增加。除非另外指明,否則使用外源性核苷酸序列之本文所提供的揭示內容同樣適用於本文所提供之誘導及/或增加細胞中的c-Jun蛋白表現的其他方法(例如,轉錄活化因子,例如CRISPRa)。
本文中之免疫細胞(例如,T細胞)或祖細胞可經工程改造以表現caTCR及CSR,且過表現c-Jun (例如,人類c-Jun)。caTCR可特異性結合於腫瘤細胞上之配位體(例如,腫瘤抗原),且CSR可特異性結合於腫瘤細胞上相同或不同的配位體。如本文所用,當結合之K
D≤ 100 nM (例如≤ 10 nM或≤ 1 nM)時,稱受體(例如,caTCR或CSR)特異性結合於配位體(例如,抗原)。K
D結合親和力常數可例如藉由表面電漿子共振(使用例如Biacore™或Octet™系統)量測。
A. caTCR
caTCR為經工程改造之構築體,其包含特異性結合於目標抗原之抗原結合模組及能夠募集至少一種TCR相關信號傳導分子之T細胞受體模組(TCRM)。抗原結合模組可源於免疫球蛋白或抗體之可變域。TCRM可包含:包含第一TCR跨膜域(TCR-TM)之第一TCR域(TCRD)及包含第二TCR-TM之第二TCRD,其中TCRM有助於至少一種TCR相關信號傳導分子之募集。TCR相關信號傳導分子係指具有基於細胞質免疫受體酪胺酸之活化模體(ITAM) (其為TCR-CD3複合物之一部分)的分子。TCR相關信號傳導分子包括CD3γε、CD3δε及ζζ (亦稱為CD3ζ或CD3ζζ)。caTCR進一步包含穩定化模組,該穩定化模組包含第一穩定化域及第二穩定化域,且其中穩定化模組可為免疫球蛋白恆定域,例如選自由以下組成之群:C
H1-C
L模組、C
H2-C
H2模組、C
H3-C
H3模組、C
H4-C
H4模組及TCR恆定區模組,諸如一對γ及δ TCR恆定區。Ig恆定域可來自IgG重鏈同型(例如,IgG
1、IgG
2、IgG
3、IgG
4、IgA、IgE、IgM或IgD)或輕鏈型(κ或λ輕鏈)中之任一者。
在一些實施例中,caTCR為包含源於γδ TCR之TCRM的經工程改造之構築體,其中γ TCR鏈之可變域及恆定域經Ig可變域(V
H)及Ig C
H域(例如C
H1)置換,而δ TCR鏈之可變域及恆定域經Ig可變域(V
L)及Ig C
L域置換。在一些實施例中,caTCR包含源於γδ TCR之TCRM,其中δ TCR鏈之可變域及恆定域經Ig V
H及Ig C
H域(例如C
H1)置換,而γ TCR鏈之可變域及恆定域經Ig V
L及Ig C
L域置換。將caTCR鏈二聚以形成由各別恆定域所支撐之V
H及V
L形成的抗原結合域。TCR之細胞內部分仍能夠募集一或多種CD3鏈以形成功能性TCR複合物(例如CD3δε、CD3γε及CD3ζζ)。本文所描述之caTCR缺乏功能性初級免疫細胞信號傳導序列,諸如包含ITAM (例如CD3ζ之細胞內域)之功能性信號傳導序列。在一些實施例中,caTCR不具有任何初級免疫細胞信號傳導序列。「功能性」初級免疫細胞信號傳導序列為能夠在以可操作方式偶合至適當受體(例如CD3ζ之細胞內域)時轉導免疫細胞活化信號之序列。可包含初級免疫細胞信號傳導序列之片段或變異體的「非功能性」初級免疫細胞信號傳導序列不能轉導免疫細胞活化信號。
caTCR之抗原結合模組可結合於細胞表面抗原,該細胞表面抗原選自例如蛋白、碳水化合物及脂質。在一些實施例中,細胞表面抗原為在病變細胞中表現之疾病相關抗原。在一些實施例中,疾病為癌症且疾病相關抗原為癌細胞中表現之癌症相關抗原,例如癌蛋白。在一些實施例中,疾病為病毒感染且疾病相關抗原為在感染細胞中表現之病毒相關抗原。
在一些實施例中,caTCR特異性結合於選自CD19、CD20、CD22、CD47、GPC-3、ROR1、ROR2、BCMA、GPRC5D或FCRL5 (包括其變異體或突變體)之細胞表面抗原。
在一些實施例中,抗原結合模組特異性結合包含肽及MHC蛋白之複合物。肽/MHC複合物包括例如表面呈現的複合物,其包含源於在病變細胞中表現之疾病相關抗原的肽及MHC蛋白。肽可源於例如WT-1、AFP、HPV16-E7、NY-ESO-1、PRAME、EBV-LMP2A、HIV-1、KRAS、組蛋白H3.3及PSA,包括其變異體或突變體。特異性結合於包含肽及MHC蛋白的複合物有時稱為「MHC受限結合」。MHC蛋白可為MHC I類蛋白,諸如HLA-A、HLA-B、HLA-C、HLA-E、HLA-F或HLA-G。在一些實施例中,MHC I類蛋白為HLA-A01、HLA-A02、HLA-A03、HLA-A09、HLA-A10、HLA-A11、HLA-A19、HLA-A23、HLA-A24、HLA-A25、HLA-A26、HLA-A28、HLA-A29、HLA-A30、HLA-A31、HLA-A32、HLA-A33、HLA-A34、HLA-A36、HLA-A43、HLA-A66、HLA-A68、HLA-A69、HLA-A74或HLA-A80。在一些實施例中,MHC I類蛋白為HLA-A02。在一些實施例中,MHC I類蛋白為HLA-A*02:01-555中之任一者,諸如HLA-A*02:01、HLA-A*02:02、HLA-A*02:03、HLA-A*02:04、HLA-A*02:05、HLA-A*02:06、HLA-A*02:07、HLA-A*02:08、HLA-A*02:09、HLA-A*02:10、HLA-A*02:11、HLA-A*02:12、HLA-A*02:13、HLA-A*02:14、HLA-A*02:15、HLA-A*02:16、HLA-A*02:17、HLA-A*02:18、HLA-A*02:19、HLA-A*02:20、HLA-A*02:21、HLA-A*02:22或HLA-A*02:24。在一些實施例中,MHC I類蛋白為HLA-A*02:01。
在一些實施例中,caTCR包含特異性結合於複合物之抗原結合模組,該複合物包含源於疾病相關抗原(諸如腫瘤相關或病毒編碼抗原)之肽及MHC II類蛋白,其中MHC II類蛋白為HLA-DP、HLA-DQ或HLA-DR。在一些實施例中,MHC II類蛋白為HLA-DP。在一些實施例中,MHC II類蛋白為HLA-DQ。在一些實施例中,MHC II類蛋白為HLA-DR。
在特定實施例中,caTCR特異性結合於包含α-胎蛋白(AFP)肽及主要組織相容性複合體(MHC) I類蛋白之複合物。此類caTCR稱為抗AFP caTCR或抗AFP/MHC caTCR。在某些實施例中,caTCR特異性結合於人類AFP之肽片段AFP158肽(FMNKFIYEI;SEQ ID NO:22),其與MHC I之HLA-A*02血清型複合(亦稱為「藉由其呈現」)。在某些實施例中,HLA-A*02具有亞型HLA-A*02:01、HLA-A*02:02、HLA-A*02:03、HLA-A*02:05、HLA-A*02:06、HLA-A*02:07或HLA-A*02:11。例如,抗AFP caTCR具有
圖 1A中所示之結構,其中AFP-結合域由結合於由HLA-A*02:01呈現之AFP158肽之人類抗體的重鏈及輕鏈可變域(V
H及V
L)形成。亦參見WO 2016/161390。在caTCR中,Ig V
H及V
L域分別置換人類γδ TCR之δ及γ鏈的可變域;且人類IgG
1CH
1恆定域及人類Ig κ恆定域分別置換人類γδ TCR之δ及γ鏈的恆定域。
在某些實施例中,caTCR之δ鏈為抗AFP158/HLA-A*02:01-caTCR-1-0 δ且具有以下胺基酸序列,其中Ig V
H域帶下劃線且為粗體字,例示性HCDR呈斜體,IgG
1CH
1域帶雙下劃線,TCR δ細胞內尾區帶點式下劃線,且TCR δ跨膜域加框:
在此等某些實施例中,caTCR之γ鏈為抗AFP158/HLA-A*02:01-caTCR-1-0 γ且具有以下胺基酸序列,其中IgV
L域帶下劃線且為粗體字,例示性LCDR呈斜體,Ig κ C
L域帶雙下劃線,TCR γ細胞外莖區(stem region)帶點式下劃線,TCR γ跨膜域加框,且TCR γ細胞內域帶單下劃線:
caTCR鏈之前驅體可含有信號肽,諸如源於例如鼠類或人類來源的免疫球蛋白κ輕鏈信號肽。
亦可使用作為以上多肽序列之變異體的caTCR鏈,只要其可結合AFP158/HLA-A2複合物且充當嵌合TCR,例如其可募集至少一種TCR相關信號傳導分子,諸如CD3δ、CD3γ、CD3ε及CD3ζ鏈,其可為細胞內源性的或外源性地引入至細胞中。
在一些實施例中,本發明之caTCR包含SEQ ID NO:2及SEQ ID NO:3中之互補決定區(CDR;例如所有六個CDR)。CDR之定界可根據熟知系統中之一者進行。參見例如Kabat等人,
J Biol Chem. (1977) 252:6609-16 (1977);Kabat等人,美國衛生與公眾服務部(U.S. Dept. of Health and Human Services),「Sequences of proteins of immunological interest」(1991);Chothia等人,
J Mol Biol. (1987) 196:901-17;Al-Lazikani等人,
J Mol Biol. (1997) 273:927-48;MacCallum等人,
J Mol Biol. (1996) 262:732-45;Abhinandan及Martin,
Mol Immunol. (2008) 45:3832-9 (2008);Lefranc等人,
Dev Comp Immunol. (2003) 27:55-77 (「IMGT」);及Honegger及Pliickthun,
J Mol Biol. (2001) (「AHo」)。涵蓋如上文所引用之參考文獻中的每一者所定義之CDR的胺基酸殘基闡述於下
表 1中作為比較。CDR預測演算法及介面為此項技術中已知的,包括例如Abhinandan及Martin, 2008,見上文;Ehrenmann等人,
Nucleic Acids Res. (2010) 38:D301-D307;及Adolf-Bryfogle等人,
Nucleic Acids Res. (2015) 43:D432-D438。在特定實施例中,caTCR包含分別包含SEQ ID NO:5-7的HCDR1-3及分別包含SEQ ID NO:9-11的LCDR1-3。
表 1
CDR | Kabat | Chothia | MacCallum | IMGT | AHo |
HCDR1 | 31-35 | 26-32 | 30-35 | 27-38 | 25-40 |
HCDR2 | 50-65 | 53-55 | 47-58 | 56-65 | 58-77 |
HCDR3 | 95-102 | 96-101 | 93-101 | 105-117 | 109-137 |
LCDR1 | 24-34 | 26-32 | 30-36 | 27-38 | 25-40 |
LCDR2 | 50-56 | 50-52 | 46-55 | 56-65 | 58-77 |
LCDR3 | 89-97 | 91-96 | 89-96 | 105-117 | 109-137 |
在一些實施例中,本發明之caTCR分別包含SEQ ID NO:2及SEQ ID NO:3中之V
H及V
L序列(SEQ ID NO:8及SEQ ID NO:12)。
B. CSR
CSR特異性結合於目標配位體(諸如細胞表面抗原或肽/MHC複合體)且能夠在目標配位體結合下刺激其功能性表現於表面上之免疫細胞。CSR包含提供配位體結合特異性之配位體結合模組、跨膜模組及實現刺激免疫細胞之協同刺激免疫細胞信號傳導模組。CSR缺乏功能性初級免疫細胞信號傳導序列。
在一些實施例中,目標配位體為疾病相關配位體,諸如癌症相關配位體或病原體相關配位體(例如,病毒相關配位體)。在一些實施例中,目標配位體為免疫調節分子,例如免疫抑制受體,在此情況下CSR可包含免疫抑制受體之拮抗劑或促效劑的片段。在一些實施例中,目標配位體為免疫檢查點分子、抑制性細胞介素或細胞凋亡分子。
在一些實施例中,CSR中之配位體結合模組為抗體部分。在一些實施例中,配位體結合模組源於受體之細胞外域。
目標配位體可為細胞表面抗原或肽/MHC複合體。在一些實施例中,目標配位體與表現於相同免疫細胞中的caTCR之目標抗原相同或不同。例如,caTCR之目標抗原為呈現於癌細胞上之癌症相關抗原,且目標配位體為表現於癌細胞表面上之普遍存在的分子,諸如整合素。在一些實施例中,目標配位體為疾病相關配位體,例如癌症相關配位體,諸如CD19、CD20、CD22、CD47、IL4、GPC-3、ROR1、ROR2、BCMA、GPRC5D或FCRL5。在一些實施例中,癌症相關配位體為肽/MHC複合體,其包含源於包括WT-1、AFP、HPV16-E7、NY-ESO-1、PRAME、EBV-LMP2A及PSA之蛋白的肽。在一些實施例中,目標配位體為病毒相關配位體。在一些實施例中,目標配位體為免疫檢查點分子,諸如PD-L1、PD-L2、CD80、CD86、ICOSL、B7-H3、B7-H4、HVEM、4-1BBL、OX40L、CD70、CD40及GAL9。在一些實施例中,目標配位體為細胞凋亡分子,諸如FasL、FasR、TNFR1及TNFR2。在一些實施例中,配位體結合模組為(或源於)目標配位體之受體之細胞外域的全部或部分。在一些實施例中,受體包括例如FasR、TNFR1、TNFR2、PD-1、CD28、CTLA-4、ICOS、BTLA、KIR、LAG-3、4-1BB、OX40、CD27及TIM-3。
在一些實施例中,跨膜域包含源於跨膜蛋白之跨膜域,該跨膜蛋白包括例如CD28、CD3.ε、CD3.ζ、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137或CD154。在一些實施例中,CSR包含跨膜蛋白之片段(fTMP)。
在一些實施例中,協同刺激信號傳導域包含免疫細胞協同刺激分子之細胞內域的全部或部分、基本上由其組成或由其組成,該分子包括例如CD27、CD28、4-1BB (CD137)、OX40、CD30、CD40、ICOS、淋巴球功能相關抗原-1 (LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3、與CD83特異性結合之配位體及其類似物。
用於本發明之CSR之協同刺激免疫細胞信號傳導域的實例包括T細胞受體(TCR)之共受體的細胞質序列,其可與caTCR協同作用以在caTCR接觸之後起始信號轉導;以及此等序列之任何衍生物或變異體及具有相同功能能力之任何合成序列。在一些情形下,經由TCR單獨產生之信號不足以完全活化T細胞且亦需要二級或協同刺激信號。因此,在一些實施例中,T細胞活化係由兩種相異類別之細胞內信號傳導序列介導:經由TCR起始抗原依賴性初級活化之彼等序列(在本文中稱為「初級T細胞信號傳導序列」)及以抗原非依賴性方式作用以提供二級或協同刺激信號之彼等序列(在本文中稱為「協同刺激T細胞信號傳導序列」)。
以刺激方式作用之初級免疫細胞信號傳導序列可含有信號傳導模體,其稱為基於免疫受體酪胺酸之活化模體或ITAM。含ITAM之初級免疫細胞信號傳導序列的實例包括源於CD3ζ、CD3γ、CD3δ、CD3ε、FcRγ、FcRβ、CD5、CD22、CD79a、CD79b及CD66d之彼等序列。「功能性」初級免疫細胞信號傳導序列為能夠在以可操作方式偶合至適當受體時轉導免疫細胞活化信號之序列。可包含初級免疫細胞信號傳導序列之片段或變異體的「非功能性」初級免疫細胞信號傳導序列不能轉導免疫細胞活化信號。本文所描述之CSR缺乏功能性初級免疫細胞信號傳導序列,諸如包含ITAM (例如CD3ζ之細胞內域)之功能性信號傳導序列。在一些實施例中,CSR不具有任何初級免疫細胞信號傳導序列。
在一些實施例中,CSR可含有源於來自CD30 (諸如人類CD30)之細胞內域的協同刺激域。在一些實施例中,CD30協同刺激域包含SEQ ID NO:21或其功能等效物(例如與SEQ ID NO:21至少90%、95%、98%或99%同源之序列)。CSR可具有源於CD30、CD8、CD28、41-BB、CD27、OX40或另一細胞表面蛋白之跨膜域的跨膜域。
在其他實施例中,CSR特異性結合於人類磷脂肌醇蛋白聚醣-3 (GPC3)且含有人類CD30協同刺激域。例如,具有人類CD30協同刺激域之抗GPC3 CSR為抗GPC3 scFv CSR7且具有以下序列,其中人類抗GPC3 scFv之Ig V
L及V
H域分別呈斜體且為粗體字,例示性LCDR及HCDR帶點式下劃線,肽連接子加框,CD30序列(表示人類CD30之215至484之胺基酸殘基)帶下劃線,且myc標籤帶雙下劃線:
亦可使用以上多肽序列之變異體,只要其可以結合GPC3且如CD30提供協同刺激即可。
在一些實施例中,本發明之CSR包含SEQ ID NO:4中之CDR,例如所有六個CDR。CDR之定界可根據如上文所揭示之熟知系統中之一者進行。在一些實施例中,CSR包含分別包含SEQ ID NO:13-15的HCDR1-3及分別包含SEQ ID NO:17-19的LCDR1-3。
在一些實施例中,CSR包含SEQ ID NO:4中之V
H及V
L序列(SEQ ID NO:16及SEQ ID NO:20)。
C. c-Jun
在一些實施例中,c-Jun為人類c-Jun,諸如具有以下序列之野生型人類c-Jun (可在GenBank以寄存編號AAA59197.1或在UniProtKB 以寄存編號P05412.2獲得)。
亦參見Hattori等人,
PNAS(1988) 85:9148-52。替代地,c-Jun為突變人類c-Jun,只要突變c-Jun不影響突變體補救異常(衰竭) T細胞之能力即可。在一些實施例中,突變c-Jun包含與野生型c-Jun之C端胺基酸殘基(例如,C端50、75、100、150、200或250或更多個殘基)、C端部分(例如,四分之一、三分之一或二分之一)或C端域(例如ε、bZIP及其C端胺基酸)至少70% (例如,至少75%、80%、85%、90%、95%或99%)之序列一致性。在一些實施例中,野生型c-Jun之N端胺基酸殘基(例如,N端50、75、100或150或更多)、N端部分(例如,四分之一、三分之一或二分之一)或N端域(例如,δ、反式活化域及其N端胺基酸)為缺失、突變或另外失活的。
在一些實施例中,c-Jun在其反式活化域及/或其δ域中包含失活突變(例如,取代、缺失或插入)。在一些實施例中,c-Jun包含S63A及S73A突變中之一或兩者(位置為上文加框處)。在一些實施例中,相比於野生型人類c-Jun,c-Jun在殘基2與102之間或在殘基30與50之間具有缺失。
歸因於引入外源引入之c-Jun編碼序列,經工程改造之T細胞過表現c-Jun,亦即表現的c-Jun含量高於不具有此序列之T細胞(例如,多至少10%、20%、30%、40%、50%、60%、70%、80%、90%或100%,或多至少2、3、4、5或10倍)。
在某些實施例中,caTCR及/或CSR及/或c-Jun多肽進一步包含可供用於各種用途目的之親和力或純化標籤;例如,其可用於增強目標多肽之純化功效。在一個實施例中,標籤為myc、HIS或HA標籤。
在一些實施例中,如上文所描述,本文中之免疫細胞經工程改造以經由細胞中之內源性c-Jun基因的活化而過表現c-Jun。
D. 核酸
caTCR、CSR及c-Jun可經由一或多種核酸分子(例如,DNA或RNA,諸如mRNA)引入至T細胞或祖細胞中。在一些實施例中,核酸分子可置於一或多種DNA或RNA載體上以引入宿主細胞中。
核酸分子(例如,含有其之DNA或RNA載體)可藉由熟知技術引入至細胞中,該等技術包括但不限於電穿孔、磷酸鈣沈澱、脂質體轉染、粒子轟擊、顯微注射、膠體分散系統(例如,作為大分子複合物、奈米膠囊、微球體及珠粒)及基於脂質之系統(例如,水包油乳液、微胞、混合微胞及脂質體)。替代地,核酸分子可藉由重組病毒之轉導引入至細胞中,該等重組病毒之基因體包含核酸分子。病毒載體之實例包括但不限於衍生自慢病毒、反轉錄病毒、腺病毒、腺相關病毒、單純疱疹病毒、仙台病毒(Sendai virus)及牛痘病毒之載體。
在一些實施例中,caTCR、CSR及c-Jun之兩條多肽鏈的編碼序列可置於單一表現構築體上。四種編碼序列可置於構築體上之一或多個表現卡匣中,各卡匣為其自身的轉錄單元(例如,具有其自身的啟動子及聚腺苷酸化位點及其他轉錄控制元件)。在特定實施例中,四種編碼序列可置於單一表現卡匣(例如四順反子表現卡匣)中,其中四種編碼序列在共同啟動子下轉錄。在多順反子排列中,編碼序列係在同框且藉由自裂解肽(例如,2A自裂解肽,諸如T2A、P2A、E2A或F2A肽)之編碼序列彼此分隔開。替代地,編碼序列可藉由核糖體內部進入位點(IRES)彼此分隔開。因此,多順反子(例如四順反子)表現卡匣轉錄成單一RNA,但最終單一RNA加工且轉譯成不同多肽。
表現卡匣(多順反子或單順反子)可含有在哺乳動物(例如,人類或人類T)細胞中具有組成性活性之啟動子。此類啟動子包括但不限於即刻早期巨細胞病毒(CMV)啟動子、猿猴病毒40 (SV40)早期啟動子、人類免疫缺乏病毒(HIV)長末端重複序列(LTR)啟動子、艾-巴二氏病毒即刻早期啟動子、勞斯氏肉瘤病毒(Rous sarcoma virus)啟動子、伸長因子-1α (EF-1α)啟動子、MND啟動子、肌動蛋白啟動子、肌凝蛋白啟動子、血紅蛋白啟動子及肌酸激酶啟動子。亦考慮源於前述啟動子之核心或最小啟動子。替代地,表現卡匣可包含誘導性啟動子系統。例示性之誘導性啟動子系統包括但不限於激素調節之元件、合成配位體調節之元件、電離輻射調節之元件、四環素(Tet)系統(例如,「Tet-Off」及「Tet-On」系統)及NFAT系統(參見例如Kallunki等人,
Cells(2019) 8(8):796;Uchibori等人,
Mol Ther Oncolytics. (2018) 12:16-25)。
在一些實施例中,表現卡匣亦包括Kozak序列、聚腺苷酸化位點及有助於編碼序列之轉錄及/或轉譯的其他元件。例如,土撥鼠肝炎病毒轉錄後反應元件(WPRE)或其變異體可包括在表現卡匣之3'未轉譯區域處。
在表現卡匣中,轉錄/轉譯調節元件,諸如啟動子、任何強化子及其類似物可操作地連接於編碼序列,以便實現編碼序列之有效表現及RNA轉錄物之有效轉譯。
在某些實施例中,本發明提供包含四順反子表現卡匣之單一載體構築體(例如慢病毒載體),其包含哺乳動物啟動子、c-Jun編碼序列、兩條caTCR鏈之編碼序列、CSR之編碼序列及聚腺苷酸化信號序列。編碼序列係藉由核苷酸連接子連接,該核苷酸連接子可為IRES或自裂解肽(例如,P2A、T2A、E2A、F2A或其功能性等效物)之編碼序列。藉助於實例,
圖 1B繪示此類表現卡匣,其中啟動子為EF-1α啟動子。在其他實施例中,caTCR結合於由HLA-A2呈現之AFP肽,CSR結合於GPC3且含有CD30協同刺激域,且c-Jun為人類c-Jun。
在特定實施例中,表現卡匣編碼包含SEQ ID NO:1的c-Jun、包含分別包含SEQ ID NO:2及SEQ ID NO:3之兩條多肽鏈的caTCR及包含SEQ ID NO:4的CSR。構築體可為重組慢病毒載體且可進一步包含在EF-1α啟動子上游之中心多嘌呤區(central polypurine tract,cPPT),及CSR編碼序列與SV40 EEL聚腺苷酸化信號之間的WPRE序列(參見例如
圖 1C)或用於在哺乳動物細胞中有效轉導及表現的其他序列。
表現卡匣中之編碼序列可經密碼子優化以獲得所關注之宿主細胞(例如,人類細胞)中的最佳表現量。
編碼caTCR、CSR及c-Jun之核酸分子可整合至經工程改造之細胞的基因體中,或保持游離。整合可為經由基因編輯進行的靶向整合(例如,由CRISPR、TALEN、鋅指核酸酶及巨核酸酶介導)。
經工程改造之細胞可藉由正向選擇技術富集。例如,細胞可在例如流式細胞量測分析中針對其結合於目標抗原(AFP或AFP158/HLA-A2)及/或GPC3的能力來選擇。為證實c-Jun表現,可對經工程改造之T細胞進行RT-PCT。正向選擇可引起細胞群體中caTCR
+CSR
+c-Jun
+細胞之富集,其中三陽性T細胞構成總細胞群體之超過30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或95%。可冷凍保存經工程改造之細胞直至使用。
III. 醫藥組合物及用途
本發明提供包含本文所描述之經工程改造之T細胞的醫藥組合物。醫藥組合物可包含醫藥學上可接受之載劑,其適合於在引入患者體內之前維持細胞健康。
在一些實施例中,經工程改造之細胞可自培養基收集,且洗滌及以治療有效量濃縮至載劑中。例示性載劑包括鹽水、緩衝鹽水(例如磷酸鹽緩衝鹽水)、生理鹽水、水、漢克氏溶液(Hanks' solution)、林格氏溶液(Ringer's solution)、Nonnosol-R (Abbott Labs)、Plasma-Lyte A(R) (Baxter Laboratories公司, Morton Grove, IL)、甘油、乙醇及其組合。較佳地,載劑為等張的。在一些實施例中,載劑可補充有成分,諸如人類血清白蛋白(HSA)或其他人類血清組分、5%葡萄糖或右旋糖。額外等張劑包括多元糖醇,其包括三元或更高級糖醇,亦可包括諸如甘油、赤藻糖醇、阿拉伯糖醇(arabitol)、木糖醇(xylitol)、山梨糖醇或甘露糖醇。
可以治療有效量向癌症患者全身性投與(例如,經由靜脈內或門靜脈注射)或局部投與(例如,經由瘤內注射)醫藥T細胞組合物。在一些實施例中,使用諸如靶向AFP之組合物治療患有肝細胞癌(HCC)、胃癌、胰臟癌或生殖系統中之癌症的患者(參見例如Wang及Wang,
Canadian J Gastroent Hep. (2018)文章9049252)。如本文所用,術語「治療(treatment/treating)」係指在所治療之個體中獲得有益或所要結果的方法。此類結果包括但不限於:緩解由疾病(例如,HCC)引起之一或多種症狀、降低疾病程度(例如,減小腫瘤體積)、使疾病穩定化(例如,預防或延緩疾病惡化)、預防或延緩疾病擴散(例如,轉移)、預防或延緩疾病反覆或復發、改善疾病病況、提供疾病之緩和(部分或全部)、減少治療疾病所需要之一或多種其他藥品之劑量、提高生活品質、恢復體重及/或延長存活期(例如總存活期或無進展存活期)。
組合物之治療有效量係指足以實現所要臨床終點之經工程改造之T細胞的數目。在一些實施例中,治療有效量含有超過10
4、10
5、10
6、10
7、10
8或10
9個經工程改造之細胞。
在一些實施例中,醫藥組合物包含可有效治療或預防疾病或病狀之量(諸如治療有效或預防有效量)的細胞。在一些實施例中,治療或預防功效係藉由定期評估所治療之個體來監測。對於歷經數日或更長時間之重複投與,視病狀而定,重複治療直至出現疾病症狀之所要抑制為止。然而,其他給藥方案可為有用的且可加以確定。所要劑量可藉由單次推注投與組合物、藉由多次推注投與組合物或藉由連續輸注投與組合物來遞送。
在某些實施例中,向個體投與約一百萬個至約1000億個範圍內的細胞,諸如100萬個至約500億個細胞(例如,約500萬個細胞、約2500萬個細胞、約5億個細胞、約10億個細胞、約50億個細胞、約200億個細胞、約300億個細胞、約400億個細胞或由前述值中之任兩者定義之範圍);諸如約1000萬至約1000億細胞(例如,約2000萬個細胞、約3000萬個細胞、約4000萬個細胞、約6000萬個細胞、約7000萬個細胞、約8000萬個細胞、約9000萬個細胞、約100億個細胞、約250億個細胞、約500億個細胞、約750億個細胞、約900億個細胞或由前述值中之任兩者定義之範圍);且在一些情況下,約1億個細胞至約500億個細胞(例如,約1.2億個細胞、約2.5億個細胞、約3.5億個細胞、約4.5億個細胞、約6.5億個細胞、約8億個細胞、約9億個細胞、約30億個細胞、約300億個細胞、約450億個細胞)或介於此等範圍之間的任何值。
在一些實施例中,細胞及組合物係使用標準投與技術、調配物及/或裝置投與。提供調配物及用於儲存及投與組合物之裝置,諸如注射器及小瓶。投與可為自體或異源的。例如,免疫反應性細胞或祖細胞可自一個個體獲得且向同一個體或不同的相容個體投與。源於周邊血液之免疫反應性細胞或其後代(例如,活體內、離體或活體外衍生)可經由局部注射投與,其包括導管投與、全身性注射、局部注射、靜脈內注射或非經腸投與。當投與本發明之治療性組合物(例如,含有經基因修飾之細胞的醫藥組合物)時,其將一般調配成單位劑量可注射形式(溶液、懸浮液、乳液)。
在一個態樣中,本發明提供醫藥組合物,其包含用於表現caTCR、CSR及c-Jun之核酸分子。核酸分子可如上文所描述,諸如上文所描述之病毒載體(例如,慢病毒載體)。離體使用醫藥組合物以工程改造T細胞或祖細胞,隨後將其引入至患者中。醫藥組合物包含核酸分子或重組病毒,其基因體包含caTCR、CSR及c-Jun之表現卡匣以及醫藥學上可接受之載劑(諸如緩衝溶液),該載劑視情況包含其他試劑,諸如防腐劑、穩定劑及其類似物。
醫藥組合物可提供為諸如套組之製品,其包括包含生物材料(細胞或核酸分子或重組病毒)之小瓶(例如,單劑量小瓶)及視情況使用說明書。
除非本文中另外定義,否則結合本發明使用之科學與技術術語應具有一般熟習此項技術者通常所瞭解之含義。下文描述例示性方法及材料,但亦可在本發明之實踐或測試中使用類似或等效於本文所描述者之方法及材料。在有矛盾的情況下,將以本說明書(包括定義)為準。一般而言,結合使用之命名法,及本文所描述之免疫學、醫學、藥物及醫藥化學以及細胞生物學之技術為此項技術中熟知且常用的。此外,除非上下文另外要求,否則單數術語應包括複數且複數術語應包括單數。在整個本說明書及實施例中,字組「具有(have)」及「包含(comprise)」或諸如「具有(has/having)」或「包含(comprises/comprising)」之變化形式應理解為暗示包括所陳述整數或整數之群組,但不排除任何其他整數或整數之群組。本文所提及之所有公開案及其他參考文獻均以全文引用之方式併入本文中。儘管本文中引用多個文件,但此引用並不構成此等文件中之任一者形成此項技術中公共常識之一部分的承認。如本文所用,如應用於一或多個所關注值的術語「大致」或「約」係指類似於所陳述參考值的值。在某些實施例中,除非另外說明或另外自上下文顯而易見,否則術語係指在陳述參考值任一方向(大於或小於)上10%、9%、8%、7%、6%、5%、4%、3%、2%、1%或更小範圍內的值。
為了能更好地理解本發明,闡述以下實例。此等實例僅出於說明之目的,且不應理解為以任何方式限制本發明之範疇。
實例
在描述於以下實例中之研究中,細胞株HepG2 (ATCC HB-8065)及SK-Hep-1 (ATCC HTB-52)係獲自美國標準生物品收藏中心(American Type Culture Collection)。HepG2為表現HLA-A2、AFP及GPC3的肝細胞癌細胞株。SK-HEP1為表現HLA-A2但不表現AFP或GPC3的肝腺癌細胞株。在37℃/5% CO
2下,在補充有10% FBS及2 mM麩醯胺酸之RPMI 1640或DMEM中培養細胞株。
構築兩種慢病毒載體。本文中稱為「AFP-caTCR + GPC3-CD30-CSR」或「構築體1」之第一種慢病毒載體含有三順反子表現卡匣,其編碼AFP158/HLA-A*02:01特異性caTCR (SEQ ID NO:2及SEQ ID NO:3)及GPC3-CD30-CSR (SEQ ID NO:4)。本文中稱為「c-Jun + AFP-caTCR + GPC3-CD30-CSR」或「構築體2」之第二種載體含有四順反子表現卡匣,其編碼caTCR、CSR及人類c-Jun (SEQ ID NO:1;置於caTCR及CSR編碼序列之上游)。對於兩種載體,表現卡匣係在EF-1α啟動子之轉錄控制下且不同多肽之編碼序列係藉由2A肽(F2A或P2A)之編碼序列而框內連接。重組病毒係藉由使用已知慢病毒生產方案及封裝系統用編碼構築體之載體轉染293T細胞而產生。
對於活體外研究,初級人類T細胞用於在100 U/ml之介白素-2 (IL-2)存在下使用CD3/CD28珠粒(Dynabeads®,Invitrogen)刺激一天之後的慢病毒轉導。將經濃縮之慢病毒施用於塗佈有Retronectin® (Takara)之6孔盤中的T細胞且培育96小時。轉導效率藉由流式細胞量測術,使用經生物素標記的AFP158/HLA-A*02:01四聚體(「AFP158四聚體」)與PE結合之鏈黴抗生物素蛋白(streptavidin)來評估。對於抗GPC3 CSR,使用抗myc抗體。在第5天及其後每3或4天重複流式細胞量測分析。
藉由Cytox 96®非放射性細胞毒性分析(Promega)分析腫瘤細胞毒性,該分析定量量測乳酸脫氫酶(LDH),一種在細胞溶解時釋放之穩定胞溶質酶。CD3
+T細胞使用EasySep™人類T細胞分離套組(StemCell Technologies)由PBMC富集之全血製備,該套組反向消耗表現CD14、CD16、CD19、CD20、CD36、CD56、CD66b、CD123及血型糖蛋白A (glycophorin A)之細胞。根據製造商之方案藉由CD3/CD28 Dynabeads® (Invitrogen)活化及擴增人類T細胞。活化T細胞(ATC)在具有10% FBS加100 U/ml IL-2之RPMI1640培養基中培養及維持,且在第7至14天使用。活化T細胞及目標細胞以各種效靶比(例如,2.5:1或5:1)共培養16小時且隨後分析細胞毒性。
(自Invitrogen)購買與FITC或APC結合之針對人類HLA-A02之單株抗體(純系BB7.2)及其同型對照物-與FITC或APC結合之小鼠IgG
2b;及針對人類或小鼠CD3之抗體、人類TCR之各種子單元、3xFLAG標籤、HA標籤、與PE或FITC結合之山羊F(ab)
2抗人類IgG,及螢光結合山羊F(ab')
2抗小鼠免疫球蛋白。研發針對AFP158/HLA-A*02:01特異性抗體之抗個體基因型抗體且內部產生。使用BD FACSCanto II™收集流式細胞量測術資料且使用FlowJo套裝軟體分析。
對於活體內研究,在已建立之HepG2肝癌異種移植模型中測試表現構築體1或構築體2之初級人類T細胞的抗腫瘤活性。在NSG小鼠之右側腹皮下(s.c.)植入HepG2細胞。當腫瘤尺寸達至約200 mm
3時,向小鼠瘤內(i.t.)注射(1) 5×10
6個未轉導供體匹配(模擬)初級人類T細胞;(2) 5×10
6個表現構築體1之初級人類T細胞;或(3) 5×10
6個表現構築體2之初級人類T細胞(n=6隻小鼠/組)。由小鼠中之T細胞輸注產生的健康作用係藉由監測動物之總體外觀、體重及不良反應之其他臨床徵象(包括體溫過低、呼吸困難及後肢麻痹/無力)來評估。
實例 1 : 過表現 c-Jun 的 抗 AFP/MHC+GPC3 CSR T 細胞之增強的長期效力及存活
此實例描述一種研究,其評價c-Jun過表現對經工程改造以表現AFP-caTCR及GPC3-CD30-CSR之人類效應T細胞之細胞毒性及存活的影響。
自健康人類供體分離之初級T細胞用慢病毒構築體1或構築體2轉導7至9天。基於AFP158四聚體染色將效應細胞標準化為30% caTCR
+(使用未轉導/模擬轉導之T細胞,將所有效應細胞樣品調整至T細胞之總數目中相同百分比的受體
+(caTCR
+或CAR
+)細胞)。用於計數效應細胞之基於FACS之分析用於比較轉導細胞之長期殺滅潛力。
用於細胞毒性分析之目標細胞為HepG2細胞(HLA-A2
+AFP
+GPC3
+)。效靶比(E:T比率)為1:1。尤其,50,000個caTCR
+T細胞及50,000個HepG2細胞在各孔中在無細胞介素之RPMI+10% FBS中共同培育。細胞每7天用每孔100,000個HepG2細胞再挑戰。細胞在第14天及第21天再挑戰之前以1:3分割,且在第28天以1:6分割以降低E:T比率且使效應細胞應激。在各目標細胞接觸之後,在選定日定量剩餘目標細胞及caTCR
+T細胞之數目。長期殺滅結果(由相對於與經模擬轉導之T細胞一起培育之目標細胞的剩餘目標細胞的百分比表示)及T細胞存活結果示於
圖 2中。圖之左圖區中的資料顯示表現構築體1之T細胞及表現構築體2之T細胞均有效地介導殺滅幾乎所有最初接觸之目標細胞以及再挑戰之目標細胞。但自第五輪接觸(E5)開始,表現構築體2之T細胞相較於表現構築體1之T細胞殺滅的目標細胞多得多。圖之右圖區中的資料顯示,儘管多輪添加目標細胞且不補充T細胞,但在目標細胞之第三及第四輪接觸之後,表現構築體2之T細胞相較於表現構築體1之T細胞更好地存活及擴增。即使在第五輪目標細胞接觸/添加之後,表現構築體2之T細胞仍比表現構築體1之T細胞存活得更佳。總之,此等結果顯示c-Jun促進延長共表現AFP-caTCR及GPC3-CD30-CSR之T細胞的存活期且維持其長期目標細胞殺滅能力。
實例 2 : 過表現 c-Jun 的 抗 AFP/MHC+GPC3 CSR T 細胞之增強的短期效力
此實例描述一種研究,其關於相比於表現構築體1之T細胞,表現構築體2之T細胞的短期殺滅效率。CD3
+T細胞使用EasySep®人類T細胞分離套組(StemCell Technologies)由PBMC富集之全血製備且用CD3/CD28 Dynabeads®活化。如藉由流式細胞量測術所測定,活化及擴增之細胞群體為>99% CD3
+。初級T細胞經模擬轉導(未添加DNA)或藉由慢病毒構築體1或構築體2轉導7至9天。藉由用經PE標記之AFP158/HLA-A*02:01四聚體(「AFP158四聚體」)染色來測定轉導效率。將T細胞標準化為30% caTCR
+且在如上所描述之基於LDH之分析中測試其殺滅癌細胞之能力。活化T細胞及目標細胞HepG2以2:1之效靶比共培養。抗原陰性目標細胞SK-Hep-1用作陰性對照物,以確認不存在抗原非依賴性殺滅。如
圖 3中所示,經構築體2轉導之T細胞(+cJun)具有比經構築體1轉導之對應T細胞(-cJun)高的活體外腫瘤細胞殺滅功效。
實例 3 : 在與目標細胞共培養之後過表現 c-Jun 的 抗 AFP/MHC+GPC3 CSR T 細胞之表徵
此實例描述在與目標細胞共培養之後表現構築體2之T細胞的表徵。使用Bio-Plex Pro™人類細胞介素8-Plex分析套組(Bio-Rad)藉由Bio-Plex® 200系統(Bio-Rad)量測活體外殺滅實驗之上清液中所釋放之細胞介素的濃度。資料顯示當與HepG2目標細胞共培養時,表現構築體2之T細胞(+cJun)比表現構築體1之T細胞(-cJun)釋放更多細胞介素,其包括IL-2、IFN-γ、TNF-α、GM-CSF (
圖 4)。
為了檢查在抗原刺激時表現於T細胞上之衰竭標記的含量,如上文所描述製備CD3
+T細胞且用CD3/CD28 Dynabeads®活化。藉由流式細胞量測術,活化及擴增之細胞群體為>99% CD3
+。將T細胞用慢病毒構築體1或構築體2轉導7至9天。基於AFP158四聚體染色,將效應細胞標準化為30% caTCR
+。如實例1中所描述培育T細胞且用HepG2細胞再挑戰。caTCR
+CD8
+T細胞上衰竭標記CD39、PD-1、LAG-3及TIM-3的表現量係在各目標細胞接觸之後在選定日藉由流式細胞量測術分析(BioLegend®)。CD39、PD-1、LAG-3及TIM-3為隨T細胞失去功能而積聚於T細胞上的抑制性受體;因此,此等分子用作T細胞衰竭之標記。相對於不表現c-Jun之T細胞,表現c-Jun之T細胞上衰竭標記之表現量(平均螢光強度)的差異倍數示於下
表 2中(E:目標細胞接觸;D:接觸後之天數;n=2 (供體1及供體2))。
表 2具有CD28-CSR或CD30-CSR之T細胞中的衰竭標記表現量
標記 | E0 | E5D7 | ||
CD28-CSR | CD30-CSR | CD28-CSR | CD30-CSR | |
CD39 | 1.01 | 1.11 | 3.85 | 0.57 |
PD-1 | 0.90 | 0.96 | 0.68 | 0.51 |
LAG-3 | 0.92 | 1.02 | 5.69 | 0.96 |
TIM-3 | 0.75 | 0.88 | 2.54 | 0.38 |
如上文所示,在接觸之前,兩組T細胞展示類似含量之衰竭標記(比率接近1)。在第五輪目標細胞接觸之後七天,表現構築體2之T細胞展示衰竭標記CD39、PD-1及TIM-3的含量為表現構築體1之T細胞上之含量的一半或低於一半。此等結果表明c-Jun之過表現產生在長期中顯著更具功能性且耗竭較少之T細胞。
然而,除了CSR含有CD28而非CD30協同刺激域以外,經工程改造以表現相同caTCR及抗GPC3 CSR的T細胞未觀測到此效果。如上
表 2中所示,在E5D7,經CD28-CSR工程改造之T細胞展示相比於不表現c-Jun之T細胞,表現c-Jun之T細胞中之顯著增加的衰竭標記CD39、LAG-3及TIM-3。資料顯示在表現抗AFP/MHC caTCR及抗GPC3-CD28-CSR之T細胞中,c-Jun過表現並不緩解T細胞衰竭。因此,結果表明c-Jun表現對緩解經工程改造以表現caTCR及基於CD30之CSR的T細胞中的T細胞衰竭產生尤其積極的影響。
另外,在各目標細胞接觸之後,在選定日藉由流式細胞量測術分析CD4或CD8單陽性及CD4/CD8雙陽性caTCR
+T細胞之亞群。
表 3中之資料顯示c-Jun過表現產生較高百分比之CD4
-CD8
+T細胞(E:目標細胞接觸;D:接觸後之天數)。
表 3HepG2目標細胞接觸之後
受體
+T細胞中CD4
+及/或CD8
+細胞之百分比
接觸後天數 | 無 cJun | 有cJun |
CD4 +CD8 - | ||
未刺激 | 32.2 | 33.6 |
E4 D3 | 11.3 | 13 |
E4 D5 | 13.3 | 11.2 |
E4 D7 | 11.3 | 11.6 |
E5 D3 | 15 | 8.94 |
E5 D5 | 13.6 | 7.56 |
E5 D7 | 15.9 | 12.6 |
CD4 +CD8 + | ||
未刺激 | 1.18 | 2.59 |
E4 D3 | 22.6 | 7.88 |
E4 D5 | 31.4 | 14.5 |
E4 D7 | 14.5 | 4.78 |
E5 D3 | 13.3 | 3.01 |
E5 D5 | 25.3 | 7.02 |
E5 D7 | 18.6 | 4.1 |
CD4 -CD8 + | ||
未刺激 | 59.6 | 60.3 |
E4 D3 | 61.2 | 75.7 |
E4 D5 | 52.4 | 72.6 |
E4 D7 | 70.9 | 81.9 |
E5 D3 | 67.4 | 84.6 |
E5 D5 | 54.4 | 83.8 |
E5 D7 | 60.3 | 79.9 |
如上表中所示,在E5D7,CD8單陽性群體自總T細胞群體之60.3%擴增至總T細胞群體之79.9%。此等結果表明c-Jun表現促進CD8單陽性T細胞之優先擴增。
實例 4 : 過表現 c-Jun 的 抗 AFP/MHC+GPC3 CSR T 細胞之活體內功效研究
如上文所描述,評估表現構築體1或2之來自供體1之初級人類T細胞的活體內細胞毒素效力。資料顯示,c-Jun過表現顯著增強了「AFP-caTCR + GPC3-CD30-CSR」T細胞之腫瘤殺滅潛力。在注射表現構築體2之T細胞(+cJun)後約第10天,腫瘤開始消退;約60至70天達成腫瘤完全消退(
圖 5A)。相比之下,在注射表現構築體2之T細胞(-cJun)的動物中,腫瘤在約第40天復發(在初始下降後)且持續生長,在約第60天到達峰值(
圖 5A)。資料亦顯示注射表現構築體1之T細胞及表現構築體2之T細胞的動物的體重變化無顯著差異,其表明過表現c-Jun之T細胞在動物中不產生更多不良作用(
圖 5B)。
類似地,當經構築體2轉導且在第17天給藥時,自另一供體(供體2)獲得之T細胞在整個研究期間防止腫瘤復發且維持腫瘤抑制(
圖 6)。但經構築體1轉導之T細胞未長期抑制腫瘤生長;其僅延緩了腫瘤生長(
圖 6)。
有趣地,儘管不太明顯,但亦在表現AFP-caTCR與GPC3-CD28-CSR之T細胞上觀測到c-Jun的增強作用(
圖 7A及
圖 7B)。相比於GPC3-CD28 CSR,c-Jun對GPC3-CD30 CSR提供增加之益處。因此,似乎c-Jun過表現與AFP-caTCR設置中之CD30反式信號傳導起協同作用。
本發明之例示性序列提供於下
表 4中(SEQ:SEQ ID NO)。
表 4
SEQ | 描述 | 胺基酸序列 |
1 | 人類c-Jun | MTAKMETTFY DDALNASFLP SESGPYGYSN PKILKQSMTL NLADPVGSLK PHLRAKNSDL LTSPDVGLLK LASPELERLI IQSSNGHITT TPTPTQFLCP KNVTDEQEGF AEGFVRALAE LHSQNTLPSV TSAAQPVNGA GMVAPAVASV AGGSGSGGFS ASLHSEPPVY ANLSNFNPGA LSSGGGAPSY GAAGLAFPAQ PQQQQQPPHH LPQQMPVQHP RLQALKEEPQ TVPEMPGETP PLSPIDMESQ ERIKAERKRM RNRIAASKCR KRKLERIARL EEKVKTLKAQ NSELASTANM LREQVAQLKQ KVMNHVNSGC QLMLTQQLQT F |
2 | 抗AFP158/HLA-A*02:01-caTCR-1-0 δ | EVQLVQSGAE VKKPGESLTI SCKASGYSFP NYWITWVRQM SGGGLEWMGR IDPGDSYTTY NPSFQGHVTI SIDKSTNTAY LHWNSLKASD TAMYYCARYY VSLVDIWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKRVEPKSC EVKTDSTDHV KPKETENTKQ PSKSCHKPKA IVHTEKVNMM SLTVLGLRML FAKTVAVNFL LTAKLFFL |
3 | 抗AFP158/HLA-A*02:01-caTCR-1-0 γ | QSVLTQPASV SGSPGQSITI SCTGTSSDVG GYNYVSWYQQ HPGKAPKLMI YDVNNRPSEV SNRFSGSKSG NTASLTISGL QAEDEADYYC SSYTTGSRAV FGGGTKLTVL GQPKANPTVT LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADGSPVK AGVETTKPSK QSNNKYAASS YLSLTPEQWK SHRSYSCQVT HEGSTVEKTV APTECSPIKT DVITMDPKDN CSKDANDTLL LQLTNTSAYY MYLLLLLKSV VYFAIITCCL LRRTAFCCNG EKS |
4 | 抗GPC3 scFv CSR7 | QSVLTQPPSV SAAPGQRVTI SCSGTRSNIG SDYVSWYQHL PGTAPKLLVY GDNLRPSGIP DRFSASKSGT SATLGITGLQ TGDEADYYCG TWDYTLNGVV FGGGTKLTVL GSRGGGGSGG GGSGGGGSLE MAQVQLVESG GGLVQPGGSL RLSCAASGFT FSSYAMSWVR QAPGKGLEWV SVIYSGGSST YYADSVKGRF TISRDNSKNT LYLQMNSLRA EDTAVYYCAR TSYLNHGDYW GQGTLVTVSS EQKLISEEDL AAATGAPPLG TQPDCNPTPE NGEAPASTSP TQSLLVDSQA SKTLPIPTSA PVALSSTGKP VLDAGPVLFW VILVLVVVVG SSAFLLCHRR ACRKRIRQKL HLCYPVQTSQ PKLELVDSRP RRSSTQLRSG ASVTEPVAEE RGLMSQPLME TCHSVGAAYL ESLPLQDASP AGGPSSPRDL PEPRVSTEHT NNKIEKIYIM KADTVIVGTV KAELPEGRGL AGPAEPELEE ELEADHTPHY PEQETEPPLG SCSDVMLSVE EEGKEDPLPT AASGK |
5 | 抗AFP158/HLA-A*02:01-caTCR-1-0 δ HCDR1 | GYSFPNYW |
6 | 抗AFP158/HLA-A*02:01-caTCR-1-0 δ HCDR2 | IDPGDSYT |
7 | 抗AFP158/HLA-A*02:01-caTCR-1-0 δ HCDR3 | ARYYVSLVDI |
8 | 抗AFP158/HLA-A*02:01-caTCR-1-0 δ Ig V H | EVQLVQSGAE VKKPGESLTI SCKASGYSFP NYWITWVRQM SGGGLEWMGR IDPGDSYTTY NPSFQGHVTI SIDKSTNTAY LHWNSLKASD TAMYYCARYY VSLVDIWGQG TLVTVSS |
9 | 抗AFP158/HLA-A*02:01-caTCR-1-0 γ LCDR1 | SSDVGGYNY |
10 | 抗AFP158/HLA-A*02:01-caTCR-1-0 γ LCDR2 | DVN |
11 | 抗AFP158/HLA-A*02:01-caTCR-1-0 γ LCDR3 | SSYTTGSRAV |
12 | 抗AFP158/HLA-A*02:01-caTCR-1-0 γ Ig V L | QSVLTQPASV SGSPGQSITI SCTGTSSDVG GYNYVSWYQQ HPGKAPKLMI YDVNNRPSEV SNRFSGSKSG NTASLTISGL QAEDEADYYC SSYTTGSRAV FGGGTKLTVL |
13 | 抗GPC3 scFv CSR7 HCDR1 | GFTFSSYA |
14 | 抗GPC3 scFv CSR7 HCDR2 | IYSGGSST |
15 | 抗GPC3 scFv CSR7 HCDR3 | ARTSYLNHG DY |
16 | 抗GPC3 scFv CSR7 Ig V H | QVQLVESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSV IYSGGSSTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARTS YLNHGDYWGQ GTLVTVSS |
17 | 抗GPC3 scFv CSR7 LCDR1 | RSNIGSDY |
18 | 抗GPC3 scFv CSR7 LCDR2 | GDN |
19 | 抗GPC3 scFv CSR7 LCDR3 | GTWDYTLNGV V |
20 | 抗GPC3 scFv CSR7 Ig V L | QSVLTQPPSV SAAPGQRVTI SCSGTRSNIG SDYVSWYQHL PGTAPKLLVY GDNLRPSGIP DRFSASKSGT SATLGITGLQ TGDEADYYCG TWDYTLNGVV FGGGTKLTVL G |
21 | 人類CD30協同刺激域 | APPLGTQPDC NPTPENGEAP ASTSPTQSLL VDSQASKTLP IPTSAPVALS STGKPVLDAG PVLFWVILVL VVVVGSSAFL LCHRRACRKR IRQKLHLCYP VQTSQPKLEL VDSRPRRSST QLRSGASVTE PVAEERGLMS QPLMETCHSV GAAYLESLPL QDASPAGGPS SPRDLPEPRV STEHTNNKIE KIYIMKADTV IVGTVKAELP EGRGLAGPAE PELEEELEAD HTPHYPEQET EPPLGSCSDV MLSVEEEGKE DPLPTAASGK |
22 | AFP158肽 | FMNKFIYEI |
圖 1A為caTCR及CSR組合之示意性圖示。
圖 1B為以下之示意性圖示:(i)含有三順反子表現卡匣之慢病毒載體(稱為「構築體1」),該卡匣用於具有γδ TCR模組之抗AFP嵌合抗體-TCR (caTCR)及含有CD30跨膜域及細胞內域之抗GPC3嵌合刺激受體(CSR);及(ii)含有編碼兩條caTCR鏈及CSR以及人類c-Jun之四順反子表現卡匣的慢病毒載體(稱為「構築體2」)。EF1a:EF1a啟動子。
圖 1C為顯示包含[或含有]慢病毒構築體之質體的示意性圖示。
圖 2顯示比較表現AFP-caTCR、GPC3-CD30-CSR及c-Jun之初級T細胞(+cJun)與僅表現AFP-caTCR及GPC3-CD30-CSR但不表現c-Jun之初級T細胞(-cJun)的長期殺滅分析結果。在此分析中,以1:1之效靶比使用HepG2細胞作為目標細胞。藉由FACS染色對T細胞進行計數,且藉由使用結晶紫染料染色對HepG2細胞進行計數。E1至E5:依序第一至第五輪T細胞與HepG2細胞的接觸(添加新鮮HepG2細胞)。各接觸之四個資料點分別代表在各接觸後第0天及第3、5及7天所獲得之資料。
圖 3顯示比較表現AFP-caTCR、GPC3-CD30-CSR及c-Jun之初級效應T細胞(+cJun)與僅表現AFP-caTCR及GPC3-CD30-CSR但不表現c-Jun之初級效應T細胞(-cJun)的短期(隔夜)殺滅分析結果。HepG2細胞用作目標細胞,而SK-Hep-1細胞用作陰性對照物。效靶比為2:1。
圖 4顯示在
圖 3中所示之短期殺滅研究中T細胞的細胞介素IL-2、IFN-γ、TNF-α及GM-CSF分泌。「未刺激」對照組:孔中僅T細胞(無目標細胞)。
圖 5A為顯示如藉由腫瘤體積減少所量測,c-Jun過表現增強「AFP-caTCR + GPC3-CD30-CSR」T細胞活體內之效力的圖。模擬組:注射未經轉導之人類初級T細胞的動物。T細胞自健康人類供體1分離。
圖 5B為顯示相比於不表現c-Jun之T細胞,在
圖 5A之研究中表現c-Jun之T細胞未引起體重減輕的圖。T細胞自供體1分離。
圖 6為顯示注射源於額外人類供體之「AFP-caTCR + GPC3-CD30-CSR」T細胞之小鼠中c-Jun過表現之活體內作用的圖。T細胞自健康人類供體2分離。
圖 7A及
圖 7B為顯示當T細胞經工程改造以表現AFP-caTCR + GPC3-CD28-CSR構築體時,亦觀測到活體內c-Jun作用的圖。在
圖 7A,向動物注射500萬T細胞,而在
圖 7B中,向動物注射250萬T細胞。T細胞自供體1分離。
<![CDATA[<110> 美商萊爾免疫藥物股份有限公司(LYELL IMMUNOPHARMA, INC.)]]> 美商優瑞科生物技術公司(EUREKA THERAPEUTICS, INC.) <![CDATA[<120> 改良之免疫細胞療法]]> <![CDATA[<130> 026225.TW014]]> <![CDATA[<140> TW 111103699]]> <![CDATA[<141> 2022-01-27]]> <![CDATA[<150> US 63/142,486]]> <![CDATA[<151> 2021-01-27]]> <![CDATA[<160> 22 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 331]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 1]]> Met Thr Ala Lys Met Glu Thr Thr Phe Tyr Asp Asp Ala Leu Asn Ala 1 5 10 15 Ser Phe Leu Pro Ser Glu Ser Gly Pro Tyr Gly Tyr Ser Asn Pro Lys 20 25 30 Ile Leu Lys Gln Ser Met Thr Leu Asn Leu Ala Asp Pro Val Gly Ser 35 40 45 Leu Lys Pro His Leu Arg Ala Lys Asn Ser Asp Leu Leu Thr Ser Pro 50 55 60 Asp Val Gly Leu Leu Lys Leu Ala Ser Pro Glu Leu Glu Arg Leu Ile 65 70 75 80 Ile Gln Ser Ser Asn Gly His Ile Thr Thr Thr Pro Thr Pro Thr Gln 85 90 95 Phe Leu Cys Pro Lys Asn Val Thr Asp Glu Gln Glu Gly Phe Ala Glu 100 105 110 Gly Phe Val Arg Ala Leu Ala Glu Leu His Ser Gln Asn Thr Leu Pro 115 120 125 Ser Val Thr Ser Ala Ala Gln Pro Val Asn Gly Ala Gly Met Val Ala 130 135 140 Pro Ala Val Ala Ser Val Ala Gly Gly Ser Gly Ser Gly Gly Phe Ser 145 150 155 160 Ala Ser Leu His Ser Glu Pro Pro Val Tyr Ala Asn Leu Ser Asn Phe 165 170 175 Asn Pro Gly Ala Leu Ser Ser Gly Gly Gly Ala Pro Ser Tyr Gly Ala 180 185 190 Ala Gly Leu Ala Phe Pro Ala Gln Pro Gln Gln Gln Gln Gln Pro Pro 195 200 205 His His Leu Pro Gln Gln Met Pro Val Gln His Pro Arg Leu Gln Ala 210 215 220 Leu Lys Glu Glu Pro Gln Thr Val Pro Glu Met Pro Gly Glu Thr Pro 225 230 235 240 Pro Leu Ser Pro Ile Asp Met Glu Ser Gln Glu Arg Ile Lys Ala Glu 245 250 255 Arg Lys Arg Met Arg Asn Arg Ile Ala Ala Ser Lys Cys Arg Lys Arg 260 265 270 Lys Leu Glu Arg Ile Ala Arg Leu Glu Glu Lys Val Lys Thr Leu Lys 275 280 285 Ala Gln Asn Ser Glu Leu Ala Ser Thr Ala Asn Met Leu Arg Glu Gln 290 295 300 Val Ala Gln Leu Lys Gln Lys Val Met Asn His Val Asn Ser Gly Cys 305 310 315 320 Gln Leu Met Leu Thr Gln Gln Leu Gln Thr Phe 325 330 <![CDATA[<210> 2]]> <![CDATA[<211> 288]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成多肽]]> <![CDATA[<400> 2]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Thr Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asn Tyr 20 25 30 Trp Ile Thr Trp Val Arg Gln Met Ser Gly Gly Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp Pro Gly Asp Ser Tyr Thr Thr Tyr Asn Pro Ser Phe 50 55 60 Gln Gly His Val Thr Ile Ser Ile Asp Lys Ser Thr Asn Thr Ala Tyr 65 70 75 80 Leu His Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Val Ser Leu Val Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Glu Val Lys Thr 210 215 220 Asp Ser Thr Asp His Val Lys Pro Lys Glu Thr Glu Asn Thr Lys Gln 225 230 235 240 Pro Ser Lys Ser Cys His Lys Pro Lys Ala Ile Val His Thr Glu Lys 245 250 255 Val Asn Met Met Ser Leu Thr Val Leu Gly Leu Arg Met Leu Phe Ala 260 265 270 Lys Thr Val Ala Val Asn Phe Leu Leu Thr Ala Lys Leu Phe Phe Leu 275 280 285 <![CDATA[<210> 3]]> <![CDATA[<211> 283]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成多肽]]> <![CDATA[<400> 3]]> Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Glu Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Thr Gly 85 90 95 Ser Arg Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser Pro Ile Lys Thr Asp Val Ile Thr 210 215 220 Met Asp Pro Lys Asp Asn Cys Ser Lys Asp Ala Asn Asp Thr Leu Leu 225 230 235 240 Leu Gln Leu Thr Asn Thr Ser Ala Tyr Tyr Met Tyr Leu Leu Leu Leu 245 250 255 Leu Lys Ser Val Val Tyr Phe Ala Ile Ile Thr Cys Cys Leu Leu Arg 260 265 270 Arg Thr Ala Phe Cys Cys Asn Gly Glu Lys Ser 275 280 <![CDATA[<210> 4]]> <![CDATA[<211> 535]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成多肽]]> <![CDATA[<400> 4]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn Ile Gly Ser Asp 20 25 30 Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Thr Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Ser 100 105 110 Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Leu Glu Met Ala Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 130 135 140 Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr 145 150 155 160 Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly 165 170 175 Leu Glu Trp Val Ser Val Ile Tyr Ser Gly Gly Ser Ser Thr Tyr Tyr 180 185 190 Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys 195 200 205 Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala 210 215 220 Val Tyr Tyr Cys Ala Arg Thr Ser Tyr Leu Asn His Gly Asp Tyr Trp 225 230 235 240 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Glu Gln Lys Leu Ile Ser 245 250 255 Glu Glu Asp Leu Ala Ala Ala Thr Gly Ala Pro Pro Leu Gly Thr Gln 260 265 270 Pro Asp Cys Asn Pro Thr Pro Glu Asn Gly Glu Ala Pro Ala Ser Thr 275 280 285 Ser Pro Thr Gln Ser Leu Leu Val Asp Ser Gln Ala Ser Lys Thr Leu 290 295 300 Pro Ile Pro Thr Ser Ala Pro Val Ala Leu Ser Ser Thr Gly Lys Pro 305 310 315 320 Val Leu Asp Ala Gly Pro Val Leu Phe Trp Val Ile Leu Val Leu Val 325 330 335 Val Val Val Gly Ser Ser Ala Phe Leu Leu Cys His Arg Arg Ala Cys 340 345 350 Arg Lys Arg Ile Arg Gln Lys Leu His Leu Cys Tyr Pro Val Gln Thr 355 360 365 Ser Gln Pro Lys Leu Glu Leu Val Asp Ser Arg Pro Arg Arg Ser Ser 370 375 380 Thr Gln Leu Arg Ser Gly Ala Ser Val Thr Glu Pro Val Ala Glu Glu 385 390 395 400 Arg Gly Leu Met Ser Gln Pro Leu Met Glu Thr Cys His Ser Val Gly 405 410 415 Ala Ala Tyr Leu Glu Ser Leu Pro Leu Gln Asp Ala Ser Pro Ala Gly 420 425 430 Gly Pro Ser Ser Pro Arg Asp Leu Pro Glu Pro Arg Val Ser Thr Glu 435 440 445 His Thr Asn Asn Lys Ile Glu Lys Ile Tyr Ile Met Lys Ala Asp Thr 450 455 460 Val Ile Val Gly Thr Val Lys Ala Glu Leu Pro Glu Gly Arg Gly Leu 465 470 475 480 Ala Gly Pro Ala Glu Pro Glu Leu Glu Glu Glu Leu Glu Ala Asp His 485 490 495 Thr Pro His Tyr Pro Glu Gln Glu Thr Glu Pro Pro Leu Gly Ser Cys 500 505 510 Ser Asp Val Met Leu Ser Val Glu Glu Glu Gly Lys Glu Asp Pro Leu 515 520 525 Pro Thr Ala Ala Ser Gly Lys 530 535 <![CDATA[<210> 5]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成肽]]> <![CDATA[<400> 5]]> Gly Tyr Ser Phe Pro Asn Tyr Trp 1 5 <![CDATA[<210> 6]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成肽]]> <![CDATA[<400> 6]]> Ile Asp Pro Gly Asp Ser Tyr Thr 1 5 <![CDATA[<210> 7]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成肽]]> <![CDATA[<400> 7]]> Ala Arg Tyr Tyr Val Ser Leu Val Asp Ile 1 5 10 <![CDATA[<210> 8]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成多肽]]> <![CDATA[<400> 8]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Thr Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Pro Asn Tyr 20 25 30 Trp Ile Thr Trp Val Arg Gln Met Ser Gly Gly Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp Pro Gly Asp Ser Tyr Thr Thr Tyr Asn Pro Ser Phe 50 55 60 Gln Gly His Val Thr Ile Ser Ile Asp Lys Ser Thr Asn Thr Ala Tyr 65 70 75 80 Leu His Trp Asn Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Tyr Tyr Val Ser Leu Val Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 9]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成肽]]> <![CDATA[<400> 9]]> Ser Ser Asp Val Gly Gly Tyr Asn Tyr 1 5 <![CDATA[<210> 10]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成肽]]> <![CDATA[<400> 10]]> Asp Val Asn 1 <![CDATA[<210> 11]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成肽]]> <![CDATA[<400> 11]]> Ser Ser Tyr Thr Thr Gly Ser Arg Ala Val 1 5 10 <![CDATA[<210> 12]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成多肽]]> <![CDATA[<400> 12]]> Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Glu Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Thr Gly 85 90 95 Ser Arg Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 13]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成肽]]> <![CDATA[<400> 13]]> Gly Phe Thr Phe Ser Ser Tyr Ala 1 5 <![CDATA[<210> 14]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成肽]]> <![CDATA[<400> 14]]> Ile Tyr Ser Gly Gly Ser Ser Thr 1 5 <![CDATA[<210> 15]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成肽]]> <![CDATA[<400> 15]]> Ala Arg Thr Ser Tyr Leu Asn His Gly Asp Tyr 1 5 10 <![CDATA[<210> 16]]> <![CDATA[<211> 118]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成多肽]]> <![CDATA[<400> 16]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Tyr Ser Gly Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Ser Tyr Leu Asn His Gly Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 17]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成肽]]> <![CDATA[<400> 17]]> Arg Ser Asn Ile Gly Ser Asp Tyr 1 5 <![CDATA[<210> 18]]> <![CDATA[<211> 3]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成肽]]> <![CDATA[<400> 18]]> Gly Asp Asn 1 <![CDATA[<210> 19]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成肽]]> <![CDATA[<400> 19]]> Gly Thr Trp Asp Tyr Thr Leu Asn Gly Val Val 1 5 10 <![CDATA[<210> 20]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人工序列之描述:合成多肽]]> <![CDATA[<400> 20]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Thr Arg Ser Asn Ile Gly Ser Asp 20 25 30 Tyr Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Val Tyr Gly Asp Asn Leu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Ala Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Tyr Thr Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <![CDATA[<210> 21]]> <![CDATA[<211> 270]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 21]]> Ala Pro Pro Leu Gly Thr Gln Pro Asp Cys Asn Pro Thr Pro Glu Asn 1 5 10 15 Gly Glu Ala Pro Ala Ser Thr Ser Pro Thr Gln Ser Leu Leu Val Asp 20 25 30 Ser Gln Ala Ser Lys Thr Leu Pro Ile Pro Thr Ser Ala Pro Val Ala 35 40 45 Leu Ser Ser Thr Gly Lys Pro Val Leu Asp Ala Gly Pro Val Leu Phe 50 55 60 Trp Val Ile Leu Val Leu Val Val Val Val Gly Ser Ser Ala Phe Leu 65 70 75 80 Leu Cys His Arg Arg Ala Cys Arg Lys Arg Ile Arg Gln Lys Leu His 85 90 95 Leu Cys Tyr Pro Val Gln Thr Ser Gln Pro Lys Leu Glu Leu Val Asp 100 105 110 Ser Arg Pro Arg Arg Ser Ser Thr Gln Leu Arg Ser Gly Ala Ser Val 115 120 125 Thr Glu Pro Val Ala Glu Glu Arg Gly Leu Met Ser Gln Pro Leu Met 130 135 140 Glu Thr Cys His Ser Val Gly Ala Ala Tyr Leu Glu Ser Leu Pro Leu 145 150 155 160 Gln Asp Ala Ser Pro Ala Gly Gly Pro Ser Ser Pro Arg Asp Leu Pro 165 170 175 Glu Pro Arg Val Ser Thr Glu His Thr Asn Asn Lys Ile Glu Lys Ile 180 185 190 Tyr Ile Met Lys Ala Asp Thr Val Ile Val Gly Thr Val Lys Ala Glu 195 200 205 Leu Pro Glu Gly Arg Gly Leu Ala Gly Pro Ala Glu Pro Glu Leu Glu 210 215 220 Glu Glu Leu Glu Ala Asp His Thr Pro His Tyr Pro Glu Gln Glu Thr 225 230 235 240 Glu Pro Pro Leu Gly Ser Cys Ser Asp Val Met Leu Ser Val Glu Glu 245 250 255 Glu Gly Lys Glu Asp Pro Leu Pro Thr Ala Ala Ser Gly Lys 260 265 270 <![CDATA[<210> 22]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 22]]> Phe Met Asn Lys Phe Ile Tyr Glu Ile 1 5
Claims (38)
- 一或多種表現構築體,其包含一或多種用於表現以下之表現卡匣: a) 嵌合抗體-T細胞受體(TCR)構築體(caTCR),其包含: i) 抗原結合模組,其特異性結合於目標抗原;及 ii) T細胞受體模組(T cell receptor module;TCRM),其包含:包含第一TCR跨膜域(TCR-TM)之第一TCR域(TCR domain;TCRD)及包含第二TCR-TM之第二TCRD,其中該TCRM有助於至少一種TCR相關信號傳導分子之募集; b) 嵌合刺激受體(chimeric stimulating receptor;CSR),其包含: i) 配位體結合模組,其能夠與目標配位體結合或相互作用; ii) 跨膜模組;及 iii) 協同刺激免疫細胞信號傳導模組,其能夠提供協同刺激信號至免疫細胞,其中該配位體結合模組及該協同刺激免疫細胞信號傳導模組非源於相同分子,且其中該CSR缺乏功能性初級免疫細胞信號傳導域;及 c) 人類c-Jun多肽。
- 一種減少經工程改造之免疫細胞之衰竭的方法,其包含向該經工程改造之免疫細胞中引入增加c-Jun在細胞中表現的外源核酸分子,其中該經工程改造之免疫細胞包含一或多種表現構築體,該一或多種表現構築體包含用於表現以下之一或多種表現卡匣: a) 嵌合抗體-T細胞受體(TCR)構築體(caTCR),其包含: i) 抗原結合模組,其特異性結合於目標抗原;及 ii) T細胞受體模組(TCRM),其包含:包含第一TCR跨膜域(TCR-TM)之第一TCR域(TCRD)及包含第二TCR-TM之第二TCRD,其中該TCRM有助於至少一種TCR相關信號傳導分子之募集;及 b) 嵌合刺激受體(CSR),其包含: i) 配位體結合模組,其能夠與目標配位體結合或相互作用; ii) 跨膜模組;及 iii) 協同刺激免疫細胞信號傳導模組,其能夠提供協同刺激信號至該免疫細胞,其中該配位體結合模組及該協同刺激免疫細胞信號傳導模組非源於相同分子,且其中該CSR缺乏功能性初級免疫細胞信號傳導域, 視情況其中該免疫細胞為T細胞。
- 如請求項1或2之表現構築體或方法,其中該c-Jun為野生型人類c-Jun,其視情況包含SEQ ID NO:1。
- 如請求項1或2之表現構築體或方法,其中該c-Jun為突變人類c-Jun,其視情況在其反式活化域或δ域中包含失活突變。
- 如請求項4之表現構築體或方法,其中與野生型c-Jun相比,該c-Jun包含(i) S63A及S73A突變或(ii)殘基2與102之間或殘基30與50之間的缺失。
- 如前述請求項中任一項之表現構築體或方法,其中該協同刺激免疫細胞信號傳導模組源於人類CD30且視情況包含SEQ ID NO:21。
- 如前述請求項中任一項之表現構築體或方法,其中該目標抗原為與人類MHC I類分子複合之人類AFP肽。
- 如請求項7之表現構築體或方法,其中該目標抗原為與HLA-A2*02:01複合之AFP158。
- 如前述請求項中任一項之表現構築體或方法,其中該TCRM源於人類γδ TCR。
- 如前述請求項中任一項之表現構築體或方法,其中該抗原結合模組包含(i)免疫球蛋白(Ig)重鏈可變域(V H),其包含SEQ ID NO:2中之HCDR1-3;及(ii) Ig輕鏈可變域(V L),其包含SEQ ID NO:3中之LCDR1-3。
- 如請求項10之表現構築體或方法,其中該等HCDR1-3分別包含SEQ ID NO:5-7,且該等LCDR1-3分別包含SEQ ID NO:9-11。
- 如請求項11之表現構築體或方法,其中該V H及該V L分別包含SEQ ID NO:8及SEQ ID NO:12。
- 如請求項12之表現構築體或方法,其中該caTCR為雜二聚體,其分別包含SEQ ID NO:2及SEQ ID NO:3。
- 如前述請求項中任一項之表現構築體或方法,其中該目標配位體為人類磷脂肌醇蛋白聚醣3 (glypican 3,GPC3)。
- 如請求項14之表現構築體或方法,其中該CSR包含(i) Ig V H,其包含SEQ ID NO:4中之HCDR1-3;及(ii) Ig V L,其包含SEQ ID NO:4中之LCDR1-3。
- 如請求項15之表現構築體或方法,其中該CSR中之該等HCDR1-3分別包含SEQ ID NO:13-15,且該CSR中之該等LCDR1-3分別包含SEQ ID NO:17-19。
- 如請求項16之表現構築體或方法,其中該CSR中之該V H及該V L分別包含SEQ ID NO:16及SEQ ID NO:20。
- 如請求項17之表現構築體或方法,其中該CSR包含SEQ ID NO:4。
- 如前述請求項中任一項之表現構築體或方法,其中該(等)構築體為病毒載體,視情況選自慢病毒載體、腺病毒載體、腺相關病毒載體、牛痘載體、單純疱疹病毒載體及艾-巴二氏(Epstein-Barr)病毒載體。
- 如前述請求項中任一項之表現構築體或方法,其中該表現構築體包含用於表現該caTCR、該CSR及該c-Jun之四順反子表現卡匣(quad-cistronic expression cassette)。
- 一種四順反子表現構築體,其包含用於表現以下之表現卡匣: a) 嵌合抗體-T細胞受體(TCR)構築體(caTCR),其包含: i) 抗原結合模組,其特異性結合於與人類MHC I類分子之人類AFP肽複合物,視情況與HLA-A2*02:01複合之AFP158;及 ii) T細胞受體模組(TCRM),其源於人類γδ TCR; b) 嵌合刺激受體(CSR),其包含: i) 配位體結合模組,其能夠與GPC3結合或相互作用; ii) 跨膜模組;及 iii) 協同刺激免疫細胞信號傳導模組,其源於人類CD30之細胞內域;及 c) 人類c-Jun多肽。
- 如請求項21之表現構築體,其中該表現卡匣包含SEQ ID NO:1之編碼序列、SEQ ID NO:2及SEQ ID NO:3之編碼序列及SEQ ID NO:4之編碼序列,視情況其中該等編碼序列係藉由2A-編碼序列或藉由內部核糖體進入位點(internal ribosomal entry site;IRES)以同框方式分隔開。
- 如前述請求項中任一項之表現構築體或方法,其中該(等)表現卡匣包含組成性或誘導性啟動子,視情況EF-1α啟動子,視情況其中該(等)表現構築體為慢病毒載體。
- 一種重組病毒,其包含如請求項21至23之四順反子表現構築體,視情況其中該表現構築體為慢病毒載體。
- 一種工程改造免疫細胞之方法,其包含: (a) 提供起始細胞群體, (b) 將如請求項1及3至23中任一項之表現構築體或如請求項24之重組病毒引入至該起始細胞群體中, (c) 視情況選擇表現該caTCR、該CSR及該c-Jun之細胞,及 (d) 自步驟(b)或(c)之該等細胞衍生經工程改造之免疫細胞, 視情況其中該等免疫細胞為人類細胞。
- 如請求項25之方法,其中該起始細胞群體包含免疫細胞,視情況自體或同種異體T細胞。
- 如請求項25之方法,其中該起始細胞群體包含富潛能或多潛能細胞且步驟(d)包含將步驟(b)或(c)之該等細胞分化成免疫細胞,視情況T細胞。
- 一種人類細胞群體,其包含如請求項1及3至23中任一項之表現構築體或如請求項24之重組病毒,視情況其中該等人類細胞為免疫細胞。
- 一種免疫細胞群體,其藉由如請求項2至20及25至27中任一項之方法獲得,視情況其中該等免疫細胞為人類細胞。
- 如請求項28或29之細胞,其中該等細胞為T細胞,視情況CD8 +T細胞。
- 如請求項28至30中任一項之細胞,其中相比於不會過表現c-Jun之相應細胞,該等細胞表現較低含量之衰竭標記,且視情況其中該衰竭標記為CD39、PD-1、TIM-3或LAG-3。
- 一種醫藥組合物,其包含如請求項1及3至23中任一項之表現構築體、如請求項24之重組病毒或如請求項28至31中任一項之細胞及醫藥學上可接受之載劑。
- 一種殺滅目標細胞之方法,其包含使該等目標細胞與如請求項28至31中任一項之免疫細胞或如請求項32之醫藥組合物在允許藉由該等免疫細胞殺滅該等目標細胞之條件下接觸, 其中該等目標細胞表現該目標抗原及該目標配位體, 視情況,其中相比於未包含引起c-Jun過表現之外源核酸分子的對應免疫細胞,該等免疫細胞在與該等目標細胞接觸時表現較低含量之衰竭標記,視情況其中該衰竭標記為CD39、PD-1、TIM-3或LAG-3,及 視情況其中該等免疫細胞包含T細胞,視情況CD8 +T細胞,及/或該等目標細胞為癌細胞。
- 如請求項33之方法,其中該CSR中之該協同刺激免疫細胞信號傳導模組源於人類CD30,且相比於經工程改造以表現其協同刺激免疫細胞信號傳導模組源於人類CD28之CSR的對應免疫細胞,該等免疫細胞表現較低含量之視情況選自CD39、PD-1、TIM-3及LAG3的衰竭標記。
- 一種治療有需要之患者的方法,其包含向該患者投與如請求項28至31中任一項之人類細胞或如請求項32之醫藥組合物。
- 如請求項35之方法,其中該患者患有癌症,視情況肝細胞癌或胃癌。
- 一種如請求項1及3至23中任一項之表現構築體、如請求項24之重組病毒或如請求項28至31中任一項之人類細胞的用途,其用於製造在如請求項33至36中任一項之方法中供治療有需要之患者用之藥劑。
- 如請求項1及3至23中任一項之表現構築體、如請求項24之重組病毒、如請求項28至31中任一項之人類細胞或如請求項32之醫藥組合物,其用於在如請求項33至36中任一項之方法中治療有需要之患者。
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US6534055B1 (en) | 1988-11-23 | 2003-03-18 | Genetics Institute, Inc. | Methods for selectively stimulating proliferation of T cells |
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US6352694B1 (en) | 1994-06-03 | 2002-03-05 | Genetics Institute, Inc. | Methods for inducing a population of T cells to proliferate using agents which recognize TCR/CD3 and ligands which stimulate an accessory molecule on the surface of the T cells |
US7175843B2 (en) | 1994-06-03 | 2007-02-13 | Genetics Institute, Llc | Methods for selectively stimulating proliferation of T cells |
US6692964B1 (en) | 1995-05-04 | 2004-02-17 | The United States Of America As Represented By The Secretary Of The Navy | Methods for transfecting T cells |
US7067318B2 (en) | 1995-06-07 | 2006-06-27 | The Regents Of The University Of Michigan | Methods for transfecting T cells |
US6867041B2 (en) | 2000-02-24 | 2005-03-15 | Xcyte Therapies, Inc. | Simultaneous stimulation and concentration of cells |
US7572631B2 (en) | 2000-02-24 | 2009-08-11 | Invitrogen Corporation | Activation and expansion of T cells |
US6797514B2 (en) | 2000-02-24 | 2004-09-28 | Xcyte Therapies, Inc. | Simultaneous stimulation and concentration of cells |
AU4328801A (en) | 2000-02-24 | 2001-09-03 | Xcyte Therapies Inc | Simultaneous stimulation and concentration of cells |
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