TW201908335A - 增強之嵌合抗原受體及其用途 - Google Patents
增強之嵌合抗原受體及其用途Info
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- TW201908335A TW201908335A TW107125720A TW107125720A TW201908335A TW 201908335 A TW201908335 A TW 201908335A TW 107125720 A TW107125720 A TW 107125720A TW 107125720 A TW107125720 A TW 107125720A TW 201908335 A TW201908335 A TW 201908335A
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Abstract
本文提供嵌合抗原受體(chimeric antigen receptor;CAR),其包含該CAR鉸鏈區中之截斷EGFRvIII (Ev3)及/或人類化scFv。本文另外提供表現該等CAR之免疫細胞以及該等細胞用於治療免疫病症之方法。
Description
序列表之併入
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本發明大體上係關於免疫學及分子生物學領域。更特定言之,其係關於增強之嵌合抗原受體(CAR),諸如用於免疫細胞。
儘管可用於診斷患有癌症之患者之診斷及治療選擇存在技術進步,但預後仍通常不佳且許多患者無法治癒。免疫療法有希望向診斷患有各種腫瘤之患者提供強力但靶向之治療,具有根除惡性腫瘤細胞而不破壞正常組織之潛力。理論上,免疫系統之T細胞能夠識別對腫瘤細胞具有特異性之蛋白質圖譜且經由多種效應機制介導其破壞。投與表現嵌合抗原受體(CAR)之免疫細胞,諸如授受性T細胞療法或NK細胞療法為利用及放大患者自身之免疫細胞之腫瘤根除能力,且接著將此等效應子以其有效地消除殘餘腫瘤,然而不破壞健康組織之狀態返還給患者的嘗試。通常,CAR包含對腫瘤相關抗原(TAA)具有特異性之抗體的單鏈可變片段(scFv),該抗原經由鉸鏈及跨膜區耦合至T細胞信號傳導分子之細胞質域。然而,免疫細胞療法之臨床使用中之許多缺點削弱此方法在癌症治療中之充分利用。因此,存在對用於免疫細胞療法之經改進CAR的未滿足需求。
在某些實施例中,本發明提供增強之嵌合抗原受體及使用其治療疾病及病症,包括癌症及自體免疫病症之方法。在一個實施例中,提供截斷之EGFRvIII,稱為Ev3 (或tEv3),其不包括胞內域或功能性EGF結合域。在特定態樣中,Ev3包含EGFR之截斷域1 (L1)、截斷域2 (CR1)、域3 (L2)及域4 (CR2)(如圖2B中所描繪)。在一些態樣中,Ev3可位於CAR之鉸鏈區中且可用於CAR表現細胞之CAR偵測及/或消融。在一些實施例中,CAR包含人類化scFv及Ev3鉸鏈。在另一實施例中,提供CAR之人類化抗原結合域,諸如人類化單鏈可變片段(scFv)。其他實施例提供藉由向受試者投與免疫細胞,諸如T細胞或NK細胞治療免疫相關病症之方法,該等免疫細胞表現實施例之CAR。
在另一實施例中,提供在該CAR之鉸鏈中包含Ev3之嵌合抗原受體(CAR),其中該Ev3鉸鏈連接細胞外域及至少一個細胞內免疫信號傳導域。在一些態樣中,Ev3鉸鏈包含EGFRvIII之跨膜域及非功能胞外域。在特定態樣中,Ev3鉸鏈不包含EGFRvIII胞內域。在一些態樣中,EGFRvIII之非功能胞外域基本上不能夠結合至表皮生長因子(EGF)。
在一些態樣中,Ev3鉸鏈包含與SEQ ID NO: 2具有至少80%,諸如至少81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98或99%序列一致性之胺基酸序列。在一些態樣中,Ev3鉸鏈包含SEQ ID NO: 2之胺基酸序列。
在一些態樣中,Ev3鉸鏈由與SEQ ID NO: 1具有至少80%,諸如至少81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98或99%序列一致性之核苷酸序列編碼。在某些態樣中,Ev3鉸鏈由SEQ ID NO: 1之核苷酸序列編碼。
在某些態樣中,CAR之細胞外域包含選自由F(ab')2、Fab'、Fab、Fv及scFv組成之群的抗原結合域。在一些態樣中,抗原結合域包含scFv。在特定態樣中,scFv另外定義為人類化scFv。在一些態樣中,人類化scFv為根據實施例之scFv。
在一些態樣中,CAR之抗原結合區結合一或多種腫瘤相關抗原。在某些態樣中,一或多種腫瘤相關抗原係選自由以下組成之群:CD19、CD319 (CS1)、ROR1、CD20、癌胚抗原、α胎蛋白、CA-125、MUC-1、上皮腫瘤抗原、黑素瘤相關抗原、突變p53、突變ras、HER2/Neu、ERBB2、葉酸結合蛋白、HIV-1包膜醣蛋白gp120、HIV-1包膜醣蛋白gp41、GD2、CD5、CD123、CD23、CD30、CD56、c-Met、間皮素、GD3、HERV-K、IL-11Rα、κ鏈、λ鏈、CSPG4、ERBB2、WT-1、TRAIL/DR4、VEGFR2、CD33、CLL-1及CD99。在特定態樣中,一或多種腫瘤相關抗原為CD19、CD319、CD123、CD5、ROR1、間皮素、CD33、CLL-1及/或CD99。在一些態樣中,scFv不包含EGFR結合域。
在某些態樣中,至少一個信號傳導域包含CD3ξ、CD28、OX40/CD134、4-1BB/CD137、FcεRIγ、ICOS/CD278、ILRB/CD122、IL-2RG/CD132、DAP12、CD70、CD40或其組合。在特定態樣中,至少一個信號傳導域包含DAP12。在一些態樣中,CAR包含IL-15。在一特定態樣中,CAR包含CD3ζ、CD28、DAP12及IL-15。
在一些態樣中,CAR進一步包含自殺基因。在特定態樣中,自殺基因為誘導性凋亡蛋白酶9。
在一個實施例中,提供包含輕鏈可變區(VL
)及重鏈可變區(VH
)之經分離抗原特異性人類化單鏈可變片段(scFv),其中scFv為: (a) CD19特異性的且其中VL
包含SEQ ID NO: 7之胺基酸序列且VH
包含SEQ ID NO: 8之胺基酸序列; (b) CD123特異性的且其中VL
包含SEQ ID NO: 13之胺基酸序列且VH
包含SEQ ID NO: 14之胺基酸序列; (c)間皮素特異性的且其中VL
包含SEQ ID NO: 19之胺基酸序列且VH
包含SEQ ID NO: 20之胺基酸序列; (d) ROR1特異性的且其中VL
包含SEQ ID NO: 25之胺基酸序列且VH
包含SEQ ID NO: 26之胺基酸序列; (e) CD5特異性的且其中VL
包含SEQ ID NO: 31之胺基酸序列且VH
包含SEQ ID NO: 32之胺基酸序列; (f) CLL-1特異性的且其中VL
包含SEQ ID NO: 59之胺基酸序列且VH
包含SEQ ID NO: 60之胺基酸序列; (g) CD99特異性的且其中VL
包含SEQ ID NO: 63之胺基酸序列且VH
包含SEQ ID NO: 64之胺基酸序列,或 (h)與(a)-(g)中之任一者之構架區具有90%序列一致性之序列。
在一些態樣中,scFv序列包含與SEQ ID NO: 6、12、18、24或30之構架區的91、92、93、94、95、96、97、98或99%序列一致性及與該等序列之CDR的100%序列一致性。在某些態樣中,該等序列之CDR可具有一個、兩個或三個修飾。
在一些態樣中,scFv為CD19特異性的且其中VL
包含SEQ ID NO: 7之胺基酸序列且VH
包含SEQ ID NO: 8之胺基酸序列。在一個特定態樣中,CD19特異性scFv包含SEQ ID NO: 6之胺基酸序列。在某些態樣中,scFv為CD123特異性的且其中VL
包含SEQ ID NO: 13之胺基酸序列且VH
包含SEQ ID NO: 14之胺基酸序列。在特定態樣中,CD123特異性scFv包含SEQ ID NO: 12之胺基酸序列。在一些態樣中,scFv為間皮素特異性的且其中VL
包含SEQ ID NO: 19之胺基酸序列且VH
包含SEQ ID NO: 20之胺基酸序列。在特定態樣中,間皮素特異性scFv包含SEQ ID NO: 18之胺基酸序列。在一些態樣中,scFv為ROR1特異性的且其中VL
包含SEQ ID NO: 25之胺基酸序列且VH
包含SEQ ID NO: 26之胺基酸序列。在特定態樣中,ROR1特異性scFv包含SEQ ID NO: 24之胺基酸序列。在一些態樣中,scFv為CD5特異性的且其中VL
包含SEQ ID NO: 31之胺基酸序列且VH
包含SEQ ID NO: 32之胺基酸序列。在某些態樣中,CD5特異性scFv包含SEQ ID NO: 30之胺基酸序列。
在一些態樣中,scFv包含與SEQ ID NO: 6、12、18、24或30之胺基酸序列之構架區具有至少95%,諸如至少96、97、98或99%序列一致性之胺基酸序列。
本文另外提供編碼以上實施例之經分離scFv之經分離聚核苷酸。在一些態樣中,聚核苷酸包含SEQ ID NO: 3、9、15、21或27。在其他態樣中,聚核苷酸包含與SEQ ID NO: 3、9、15、21或27具有至少90、91、92、93、94、95、96、97、98或99%序列一致性之序列。
本文亦提供包含實施例之經分離核苷酸之表現載體。在一些態樣中,載體另外定義為病毒載體。
本文另外提供經分離核酸,其包含編碼根據本發明實施例中任一者之CAR的核苷酸序列。
本文亦提供宿主細胞,其經工程改造以表現CAR,該CAR包含本發明實施例之人類化scFv及/或該CAR之鉸鏈區中之截斷EGFRvIII (Ev3)。在一些態樣中,CAR係根據本發明實施例中之任一者。在一些態樣中,編碼CAR之DNA整合於細胞之基因組中。
在一些態樣中,宿主細胞另外定義為CAR免疫細胞。在特定態樣中,免疫細胞為T細胞、外周血淋巴細胞、NK細胞、恆定NK細胞、NKT細胞或幹細胞。在特定態樣中,免疫細胞為T細胞或NK細胞。在一些態樣中,幹細胞為間葉系幹細胞(MSC)或誘導多能幹(iPS)細胞。在某些態樣中,免疫細胞衍生自iPS細胞。在一些態樣中,T細胞為CD8+
T細胞、CD4+
T細胞或γ-δ T細胞。在某些態樣中,T細胞為細胞毒性T淋巴細胞(CTL)。在一些態樣中,免疫細胞為同種異體或自體細胞。在一些態樣中,免疫細胞係分離自外周血、臍帶血或骨髓。在某些態樣中,免疫細胞係分離自臍帶血。在特定態樣中,臍帶血彙集自2個或大於2個個體臍帶血單位。
本文另外提供包含根據本發明實施例中之任一者之免疫細胞群體的醫藥組合物。本文亦提供包含本發明實施例中之任一者之免疫細胞群體的組合物,用於治療免疫相關病症。
在另一實施例中,提供一種治療受試者之免疫相關病症之方法,其包含投與有效量的本發明實施例中之任一者之CAR免疫細胞,諸如包含人類化scFv及/或Ev3鉸鏈。
在以上實施例之一些態樣中,免疫相關病症為癌症、自體免疫病症、移植物抗宿主疾病、同種異體移植排斥反應或發炎性病況。在某些態樣中,免疫相關病症為發炎性病況且免疫細胞基本上不表現糖皮質激素受體。在特定態樣中,免疫相關病症為癌症。在一些態樣中,免疫細胞為自體或同種異體細胞。在一些態樣中,癌症為實體癌症或惡性血液病。
在其他態樣中,該方法進一步包含投與至少第二治療劑。在一些態樣中,至少第二治療劑包含化學療法、免疫療法、手術、放射線療法或生物療法。在某些態樣中,免疫細胞及/或至少第二治療劑經靜脈內、腹膜內、氣管內、瘤內、肌肉內、內窺鏡、病灶內、經皮、皮下、局部投與或藉由直接注射或灌注投與。
在一些態樣中,該方法進一步包含投與抗EGFR抗體。在一些態樣中,抗EGFR抗體為單株抗體。在某些態樣中,抗EGFR抗體為西妥昔單抗(cetuximab)或帕尼單抗(panitumumab)。在一些態樣中,抗EGFR抗體經由抗體依賴性細胞介導之細胞毒性(ADCC)選擇性地消融Ev3-CAR免疫細胞。在某些態樣中,抗EGFR抗體融合至可偵測標籤及/或細胞毒性劑。在一些態樣中,該方法進一步包含對可偵測標籤成像,進而偵測Ev3-CAR免疫細胞。在某些態樣中,抗EGFR抗體融合至細胞毒性劑。在一些態樣中,細胞毒性劑在Ev3-CAR免疫細胞中誘導自殺基因之活化。在一些態樣中,細胞毒性劑導致Ev3-CAR免疫細胞之消融。
本發明之其他目的、特徵及優勢將自以下實施方式而變得顯而易知。然而,應理解,實施方式及特定實例雖然指示本發明之較佳實施例,但僅以說明方式給出,因為熟習此項技術者將由此實施方式而變得顯而易知本發明的精神及範疇內的各種改變及修正。
本申請案主張2017年7月25日申請之美國臨時申請案序號62/536,934之優先權,其全部內容特此以引用之方式併入。
基於嵌合抗原受體(CAR)之細胞免疫療法以在癌症治療中顯示顯著功效,尤其就白血病及淋巴瘤治療而言。儘管如此,當前可用之CAR可包含各種設計缺陷。使用CAR重編程免疫細胞以用於靶向癌症免疫療法之新近臨床結果已顯示強力抗腫瘤細胞毒性。由於大部分CAR單鏈可變片段(scFv)模組為鼠類抗體之衍生物,人類抗小鼠免疫反應性損害由此衍生之CAR之功效。
因此,在一些實施例中,本發明提供相對於抗原工程改造人類化CAR (hCAR)之平台技術。抗原可包括CD19 (hCD19CAR)、CD123 (hCD123CAR)、間皮素(hMesoCAR)、ROR1 (hROR1CAR)、CD5 (hCD5CAR)、CLL-1 (hCLL-1CAR)及/或CD99 (hCD99CAR)以及其他可經靶向以治療疾病,諸如癌症或自體免疫病症之抗原。因此,在某些實施例中,本發明另外提供人類化CAR及使用其治療癌症之方法。
在一些實施例中,本發明提供使CAR,特定言之CAR之scFv人類化之平台。方法遵循如實例1中所述之5個模組分量。此等可包括序列分析、3D結構建模、人類構架移植、人類化評分及功能分析。隨後,IgG集中用於人類化方法,利用異型(亦即相同同型之型式)之廣泛序列變化來微調人類構架選擇(圖2)。
在第一步中,人類重鏈及輕鏈之抗體序列可在來自諸如Genbank之來源的本地資料庫中管理。可變域可使用IgBLAST (BLAST之一個版本)比對以根據同源性描繪序列之異型及分類。可隨後識別CDR區且構架序列經編目(圖1A)。可接著進行3D結構建模,諸如使用蛋白質結構同源性建模器(例如SWISS-MODEL)。
在一些實施例中,免疫細胞經工程改造以表現具有本文提供之人類化scFv之CAR。免疫細胞可為NK細胞及/或T細胞,諸如衍生自外周血、臍帶血或骨髓源性浸潤淋巴細胞。具有衍生自本發明人類化平台之scFv的免疫細胞可降低人類抗小鼠抗體(HAMA)產生及遺傳修飾免疫細胞療法產物之相關免疫介導性排斥反應之可能性。
因此,其他實施例提供藉由投與表現具有人類化scFv之CAR的免疫細胞而治療疾病或病症之方法。此等方法可用於降低免疫排斥反應以及延長輸注細胞療法產物之持久性。可治療之例示性受試者包括患有以下各者之癌症患者:CD19+
CLL、ALL及NHL;CD123陽性惡性腫瘤,包括AML、CML、MDS及BPDCN;間皮素陽性癌症,包括子宮頸癌、子宮內膜癌及頭頸癌;ROR1-陽性惡性腫瘤,包括CLL (例如無預先CAR療法或在CD19-CAR與CD19陰性疾病之後復發之患者)、乳房癌、卵巢癌及胰臟癌;CD5陽性惡性腫瘤,包括ALL及NHL以及胸腺癌。
在其他實施例中,本發明提供包含截斷EGFRvIII之CAR,其中受體不包含細胞質胞內域或功能性EGF結合域,在本文中稱為Ev3。EGFRvIII為僅發現於腫瘤細胞(諸如多形性膠質母細胞瘤及肺癌)中,且未發現於正常EGFR表現細胞(諸如上皮細胞)中之EGFR變異體。EGFRvIII具有導致外顯子2-7缺失(相比於野生型之801個鹼基對框內缺失,267個胺基酸缺失)之體細胞突變。EGFRvIII之缺失亦覆蓋大部分域1及2,導致截斷域1及截斷域2。另外,EGFRvIII由於產生額外甘胺酸殘基(胺基酸6-273經甘胺酸殘基置換;亦即LEEKKGNYVVTD)之外顯子1與外顯子8之間的融合而具有特異性抗原決定基,其形成腫瘤特異性抗原,諸如針對多形性膠質母細胞瘤。
本文提供之截斷EGFRvIII (稱為Ev3 (或tEv3))不包含胞內域或功能性EGF結合域。特定言之,Ev3細胞外域可用作CAR莖,排除跨膜域及細胞內信號傳導域,用於a)信號轉導,b)用於分配CAR陽性之細胞標記物,及c)用於經由抗體結合(例如藉由西妥昔單抗(Cetuximab))進行細胞消融之抗原標記物。在特定態樣中,Ev3包含EGFR之截斷域1 (L1)、截斷域2 (CR1)、域3 (L2)及域4 (CR2)(如圖2B中所描繪)。Ev3之例示性序列描繪於圖2C中。本發明Ev3可包含與圖2C中之序列至少90%、95%、96%、97%、98%或99%一致之序列。西妥昔單抗結合位點(域3中)在Ev3及野生型EGFR胞外域兩者中得以保留。除西妥昔單抗(及/或帕尼單抗)結合位點以外,Ev3抗原決定基亦對於其他抗體(例如MR1、mAb 806及DH8.3)呈現額外結合位點。
本文提供之CAR可使用Ev3作為整合信號轉導鉸鏈,其可倍增為抗原安全開關以共價連接scFv (亦即抗原識別域)與信號傳導域(亦即CD28及CD3ζ)。Ev3亦允許在活體外及活體內偵測CAR免疫細胞。另外,Ev3鉸鏈提供遺傳貨物空間保留。
本文提供之Ev3鉸鏈之另一態樣為其藉由諸如MR1之抗體靶向之能力,該等抗體對EGFRvIII具有特異性且將不與存在於其他組織及細胞(諸如上皮細胞)中之EGFR之域III及IV交叉反應。西妥昔單抗及帕尼單抗為臨床上可用之抗體且經FDA批准,其不需要針對具有不同抗原特異性之各CAR之個體基因型抗體,諸如CD19、CD123、CD5、ROR1、CD33、CD99及間皮素獲得監管批准。靶向Ev3-CAR之能力可用於偵測CAR陽性細胞及/或受控細胞消融。細胞消融可在不良事件,諸如細胞介素釋放綜合症、神經毒性及/或中靶或脫靶腫瘤活性之情況下為所需的。由於Ev3不通常表現於免疫細胞,諸如T細胞或NK細胞中,Ev3之強制表現將特異性標記遺傳修飾免疫細胞。最後,Ev3不包含信號傳導胞內域(因為細胞質域經移除)或EGF結合域,包含Ev3之CAR將不與細胞外部或內部之EGF信號傳導路徑(例如AR、ARF4、CAV1、CAV3、CBL、CBLB、CBLC、CD44、CDC25A、CRK、CTNNB1、DCN、EGF、GRB14、Grb2、JAK2、MUC1、NCK1、NCK2、PKCα、PLCG1、PLSCR1、PTPN1、PTPN11、PTPN6、PTPRK、SH2D3A、SH3KBP1、SHC1、SOS1、Src、STAT1、STAT3、STAT3、STAT5A、UBC、WAS)反應或串擾。因此,在特定態樣中,預期此等基因產物中無一者干擾Ev3-CAR之Ev3鉸鏈。
在其他態樣中,Ev3-CAR之功能、功效及細胞持久性可藉由在Ev3-DAP12-CAR中併入DNAX活化蛋白12 (DAP12)信號傳導模組,NK細胞活化中之一種重要元件而進一步增強。
其他實施例提供將本文提供之CAR引入至免疫細胞,諸如T細胞及NK細胞之方法。可向受試者投與CAR-T或CAR-NK細胞,諸如用於治療癌症。詳言之,可藉由CAR-T或CAR-NK細胞治療之癌症包括白血病及淋巴瘤,諸如慢性淋巴細胞性白血病(CLL)、急性淋巴細胞性白血病(ALL)及非霍奇金淋巴瘤(NHL)。I. 定義
如本文所用,關於指定組分「基本上不含」在本文中用於意謂指定組分中無一者有目的地調配入組合物中及/或僅作為污染物或以痕量存在。由組合物之任何非預期污染產生的指定組分總量因此遠低於0.05%,較佳低於0.01%。最佳為用標準分析方法未偵測到指定組分之量的組合物。
如本說明書中所用,「一(a/an)」可意謂一或多個。如本文申請專利範圍中所用,當與詞語「包含」結合使用時,詞語「一(a/an)」可意謂一個或多於一個。
儘管本發明支持指僅替代及「及/或」之定義,但除非明確指示為指僅替代或替代相互排斥,否則術語「或」在申請專利範圍中用於意謂「及/或」。如本文所用,「另一」可意謂至少第二個或更多個。
在本申請案通篇,術語「約」用於指示值包括裝置、用以測定該值之方法之誤差的固有偏差或研究受試者當中存在的偏差。
術語「外源」當關於細胞或生物體中之蛋白質、基因、核酸或聚核苷酸使用時,係指已藉由人工或天然方法引入至細胞或生物體中之蛋白質、基因、核酸或聚核苷酸;或當關於細胞使用時,術語係指經分離且隨後藉由人工或天然方法引入至其他細胞或生物體中之細胞。外源核酸可來自不同生物體或細胞,或其可為天然地存在於生物體或細胞內之核酸之一或多個額外複本。外源細胞可來自不同生物體,或其可來自相同生物體。以非限制性實例之方式,外源核酸為染色體位置不同於其在天然細胞中所處之位置,或另外藉由與自然界中所發現不同之核酸序列側接之核酸。
「表現構築體」或「表現卡匣」意謂能夠導引轉錄之核酸分子。表現構築體在最低限度下包括在一或多種所需細胞類型、組織或器官中導引基因表現之一或多種轉錄控制元件(諸如啟動子、增強子或其結構功能等效物)。亦可包括額外元件,諸如轉錄終止信號。
「載體」或「構築體」(有時被稱作基因遞送系統或基因轉移「媒劑」)係指活體外或活體內包含待遞送至宿主細胞之聚核苷酸的大分子或分子複合物。
「質體」,一種常用類型之載體為與能夠獨立於染色體DNA而複製之染色體DNA分離的染色體外DNA分子。在某些情況下,其為環狀及雙鏈的。
如本文所使用,術語「患者」或「受試者」係指活的哺乳動物生物體,諸如人類、猴、母牛、綿羊、山羊、狗、貓、小鼠、大鼠、天竺鼠或其轉殖基因物種。在某些實施例中,患者或受試者為靈長類動物。人類患者之非限制性實例為成年人、青少年、嬰兒及胎兒。
「免疫病症」、「免疫相關病症」或「免疫介導之病症」係指其中免疫反應在疾病之發展或進展中起關鍵作用之病症。免疫介導之病症包括自體免疫病症、同種異體移植排斥反應、移植物抗宿主疾病及發炎性及過敏性病況。
「免疫反應」為免疫系統之細胞,諸如B細胞、或T細胞或固有免疫細胞對刺激之反應。在一個實施例中,反應特異於特定抗原(「抗原特異性反應」)。
術語「腫瘤相關抗原」、「腫瘤抗原」及「癌細胞抗原」在本文中可互換地使用。在各種情況下,術語指代由癌細胞專門或較佳表現之蛋白質、糖蛋白或碳水化合物。
「抗原決定基」為藉由抗體識別之抗原上之位點,該抗體如藉由胺基酸序列之特異性所測定。若兩個抗體各競爭性地抑制(阻斷)另一抗體與抗原之結合(如在競爭性結合檢定中量測),則將其稱為結合至相同抗原決定基。或者,若抗原中減少或消除一種抗體之結合的大部分胺基酸突變減少或消除了另一抗體之結合,則兩個抗體具有相同抗原決定基。若兩個抗體各部分抑制另一抗體與抗原之結合,及/或若減少或消除一種抗體之結合的一些胺基酸突變減少或消除了另一抗體之結合,則將其稱為具有重疊抗原決定基。
「治療(treating/treatment)」疾病或病況係指執行方案,其可包括致力於減輕疾病之跡象或症狀而向患者投與一或多種藥物。所需治療作用包括降低疾病發展速率、改善或減輕疾病病況及緩解或改良預後。緩解可在疾病或病況之跡象或症狀出現之前,以及在其出現之後。因此,「治療」可包括「預防(preventing/prevention)」疾病或非所需病況。另外,「治療」不需要跡象或症狀的完全緩解,不需要治癒,且特定包括僅對患者具有邊際效應之方案。
術語「有效」,如所述術語在說明書及/或申請專利範圍中所用,意謂足以實現所期望、預期或預定的結果。當在以化合物治療患者或受試者之背景中使用時,「有效量」、「治療有效量」或「醫藥學有效量」意謂化合物當投與受試者或患者以治療或預防疾病時之量為足以實現所述疾病之此類治療或預防的量。
「治療」包括(1)抑制經歷或顯示疾病之病理學或症候學之受試者或患者中的疾病(例如遏制病理學及/或症候學進一步發育),(2)改善經歷或顯示疾病之病理學或症候學之受試者或患者中的疾病(例如逆轉病理學及/或症候學)及/或(3)使得經歷或顯示疾病之病理學或症候學之受試者或患者中的疾病出現任何可量測的減弱。
「預防」包括:(1)抑制受試者或患者中之疾病發作,該受試者或患者可有風險及/或易患該疾病但又尚未經歷或顯示該疾病之任何或所有病理學或症候學,及/或(2)減緩受試者或患者中之疾病的病理學或症候學發作,該受試者或患者可有風險及/或易患該疾病但又尚未經歷或顯示該疾病之任何或所有病理學或症候學。
如本文所用,術語「構架區」係指充當CDR之骨架的抗體之可變區之區域。因此,構架區可包含可變輕鏈及可變重鏈之非CDR序列。可變區之CDR可藉由此項技術中已知之方法測定,諸如藉由使用如以全文引用的方式併入本文中之Sela-Culang等人,
2013中所述之Kabat編號系統。由Kabat (CITE)描述之系統不僅提供適用於抗體之任何可變區的明確殘基編號系統,且亦提供界定三種CDR之精確殘基邊界。
如本文一般所用,「醫藥學上可接受」係指在合理的醫學判斷範圍內,適合與人類及動物之組織、器官及/或體液接觸使用而不引起過度毒性、刺激、過敏反應或其他問題或併發症,與合理的益處/風險比相稱的彼等化合物、材料、組合物及/或劑型。
「醫藥學上可接受之鹽」意謂本文所揭示之化合物的鹽,其如上文所定義為醫藥學上可接受的且具有所需藥理學活性。此類鹽包括與無機酸形成之酸加成鹽,無機酸諸如鹽酸、氫溴酸、硫酸、硝酸、磷酸及其類似酸;或與有機酸形成之酸加成鹽,有機酸諸如1,2-乙二磺酸、2-羥基乙磺酸、2-萘磺酸、3-苯基丙酸、4,4'-亞甲基雙(3-羥基-2-烯-1-甲酸)、4-甲基雙環[2.2.2]辛-2-烯-1-甲酸、乙酸、脂族單羧酸及二羧酸、脂族硫酸、芳族硫酸、苯磺酸、苯甲酸、樟腦磺酸、碳酸、肉桂酸、檸檬酸、環戊烷丙酸、乙烷磺酸、反丁烯二酸、葡庚糖酸、葡萄糖酸、麩胺酸、乙醇酸、庚酸、己酸、羥基萘甲酸、乳酸、月桂基硫酸、順丁烯二酸、蘋果酸、丙二酸、杏仁酸、甲烷磺酸、黏康酸(muconic acid)、鄰(4-羥基苯甲醯基)苯甲酸、草酸、對氯苯磺酸、經苯基取代之烷酸、丙酸、對甲苯磺酸、丙酮酸、水楊酸、硬脂酸、丁二酸、酒石酸、第三丁基乙酸、三甲基乙酸及其類似酸。醫藥學上可接受之鹽亦包括可以在存在酸性質子時,能夠與無機或有機鹼反應形成的鹼加成鹽。可接受之無機鹼包括氫氧化鈉、碳酸鈉、氫氧化鉀、氫氧化鋁及氫氧化鈣。可接受之有機鹼包括乙醇胺、二乙醇胺、三乙醇胺、緩血酸胺(tromethamine)、N
-甲基葡糖胺及其類似物。應認識到,形成本發明之任何鹽之一部分的特定陰離子或陽離子並不重要,只要鹽整體上為藥理學上可接受即可。醫藥學上可接受之鹽之其他實例及其製備及使用方法呈現於Handbook of Pharmaceutical Salts: Properties, and Use
(P. H. Stahl及C. G. Wermuth編, Verlag Helvetica Chimica Acta, 2002)中。
「醫藥學上可接受之載劑」、「藥物載劑」或僅「載劑」為與涉及運載、遞送及/或傳輸化學劑之活性成分藥物一起調配的醫藥學上可接受之物質。藥物載劑可用於改良藥物之遞送及有效性,包括例如控制釋放技術以調整藥物生物可用性、減少藥物代謝及/或降低藥物毒性。某些藥物載劑可增加藥物遞送至特定目標位點之有效性。載劑之實例包括:脂質體、微球體(例如由聚(乳酸-共-乙醇酸)製成)、白蛋白微球體、合成聚合物、奈米纖維、蛋白質-DNA複合物、蛋白質結合物、紅血球、病毒顆粒及樹枝狀聚合物。
如本文所用之術語「嵌合抗原受體(CAR)」可指例如人工T細胞受體、嵌合T細胞受體或嵌合免疫受體且涵蓋在特定免疫效應細胞上接枝人工特異性之工程改造受體。可採用在T細胞上賦予單株抗體之特異性之CAR,進而允許產生大量特異性T細胞,例如用於授受性細胞療法。在特定實施例中,例如CAR將細胞之特異性引導至腫瘤相關抗原。在一些實施例中,CAR包含胞內活化域、跨膜域及包含腫瘤相關抗原結合區之細胞外域。在特定態樣中,CAR包含衍生自單株抗體,將跨膜域及胞內域融合至CD3-ζ之單鏈可變片段(scFv)之融合體。其他CAR設計之特異性可衍生自受體(例如肽)之配位體或衍生自圖案識別受體,諸如Dectin。在某些情況下,抗原識別域之間距可經修飾以降低活化誘導之細胞死亡。在某些情況下,CAR包含用於其他共刺激信號傳導之域,諸如CD3ζ、FcR、CD27、CD28、CD137、DAP10及/或OX40。在某些情況下,分子可與CAR共表現,該等分子包括共刺激分子、用於成像(例如用於正電子發射斷層攝影術)之報導基因、在添加前藥時條件性地消融T細胞之基因產物、歸巢受體、趨化激素、趨化細胞素受體、細胞介素及細胞介素受體。
術語「抗原呈遞細胞(APC)」係指能夠呈遞呈可藉由免疫系統之特定效應細胞識別之肽-MHC複合物形式的一或多種抗原,且藉此誘導相對於呈遞之一或多種抗原之有效細胞免疫反應的一類細胞。APC可為完整全細胞,諸如巨噬細胞、B細胞、內皮細胞、活化T細胞及樹突狀細胞;或其他天然存在或合成之分子,諸如與β2-微球蛋白複合之純化MHC I類分子。儘管許多類型之細胞可能能夠在其細胞表面上呈遞抗原用於T細胞識別,但僅樹突狀細胞能夠以有效量呈遞抗原以活化未處理T細胞用於細胞毒性T淋巴細胞(CTL)反應。
術語「培養」係指細胞在適合之培養基中之活體外維持、分化及/或傳播。「富集」意謂包含細胞之組合物以比細胞存在於生物體中之組織中所發現更大的總細胞百分比存在。
「抗癌」試劑能夠不利地影響受試者中之癌細胞/腫瘤,例如藉由促進癌細胞殺滅、誘導癌細胞之細胞凋亡、降低癌細胞增長率、降低轉移瘤之發生率或數目、降低腫瘤尺寸、抑制腫瘤生長、減少對腫瘤或癌症細胞之供應、促進對癌細胞或腫瘤之免疫反應、預防或抑制癌症進展、或提高患有癌症之受試者之使用壽命。
如本文所用之術語「自殺基因」定義為可用於選擇性地靶向細胞以進行殺死之基因。
聚核苷酸或聚核苷酸區(或多肽或多肽區)與另一序列具有一定百分比(例如80%、85%、90%或95%)之「序列一致性」或「同源性」意謂當比對時,在比較兩個序列時彼鹼基(或胺基酸)百分比相同。此比對及百分比同源性或序列一致性可使用此項技術中已知之軟體程式測定,例如CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (F. M. Ausubel等人編, 1987) 增刊30, 第7.7.18章, 表7.7.1中所述之彼等。較佳地,預設參數用於比對。較佳的對準程序係BLAST,使用默認參數。詳言之,較佳程式為使用以下預設參數之BLASTN及BLASTP:遺傳密碼=標準;濾波=無;鏈=兩者;截止值=60;期望值=10;矩陣=BLOSUM62;描述=50個序列;排序方式=HIGH SCORE;資料庫=非冗餘,GenBank+EMBL+DDBJ+PDB+GenBank CDS轉譯+SwissProtein+SPupdate+PIR。II. 免疫細胞
某些本發明之實施例關注表現CAR之免疫細胞,諸如以Ev3作為CAR之鉸鏈及/或以人類化scFv作為CAR之抗原結合域。免疫細胞可為T細胞(例如調節T細胞、CD4+
T細胞、CD8+
T細胞、或γ-δ T細胞)、NK細胞、恆定NK細胞、NKT細胞、幹細胞(例如間充質幹細胞(MSC)或誘導多能幹(iPSC)細胞)。在一些實施例中,細胞為單核球或粒細胞,例如骨髓細胞、巨噬細胞、嗜中性球、樹突狀細胞、肥大細胞、嗜伊紅血球及/或嗜鹼性球。本文亦提供產生及工程改造免疫細胞之方法以及使用及投與細胞用於授受細胞療法之方法,在此情況下,細胞可為自體或同種異體細胞。因此,免疫細胞可用作免疫療法,以便靶向癌細胞。
免疫細胞可分離自受試者,特定言之人類受試者。免疫細胞可獲自所關注之受試者,諸如疑似患有特定疾病或病況之受試者、疑似易患特定疾病或病況之受試者或經歷用於特定疾病或病況之療法的受試者。免疫細胞可收集自免疫細胞駐留於受試者中之任何位置,包括(但不限於)血液、臍帶血、脾臟、胸腺、淋巴結及骨髓。經分離之免疫細胞可直接使用,或其可儲存一段時間,諸如藉由冷凍。
免疫細胞可自其所駐留之任何組織富集/純化,包括(但不限於)血液(包括藉由血庫或臍帶血庫收集之血液)、脾臟、骨髓、在手術程序期間移除及/或暴露之組織及經由活檢程序獲得之組織。富集、分離及/或純化免疫細胞之組織/器官可分離自活受試者及非活受試者兩者,其中非活受試者為器官供體。在特定實施例中,免疫細胞分離自血液,諸如外周血或臍帶血。在一些態樣中,免疫細胞分離自具有增強之免疫調節能力(諸如藉由CD4或CD8陽性T細胞抑制來量測)之臍帶血。在特定態樣中,免疫細胞分離自彙集血液,特定言之彙集臍帶血,以增強免疫調節能力。彙集血液可來自2個或大於2個來源,諸如3、4、5、6、7、8、9、10個或超過10個來源(例如供體受試者)。
免疫細胞群體可獲自需要療法或罹患與降低之免疫細胞活性相關之疾病的受試者。因此,細胞將對於需要療法之受試者為自體的。或者,免疫細胞群體可獲自供體,較佳組織相容性匹配供體。免疫細胞群體可收穫自外周血、臍帶血、骨髓、脾臟或免疫細胞駐留於該受試者或供體中之任何其他器官/組織。免疫細胞可分離自受試者及/或供體之集合,諸如彙集臍帶血。
當免疫細胞群體獲自不同於受試者之供體時,供體較佳為同種異體的,其限制條件為獲得之細胞為受試者相容的以便其可引入至受試者中。同種異體供體細胞可為或可不為人類白血球抗原(HLA)相容的。A. T 細胞
在一些實施例中,免疫細胞為T細胞。過去二十年已描述用於衍生、活化及擴增功能抗腫瘤效應細胞之若干基本方法。此等包括:自體細胞,諸如腫瘤-浸潤淋巴球(TIL);使用自體DC、淋巴球、人工抗原呈現細胞(APC)或包覆有T細胞配位體及活化抗體之珠粒離體活化之T細胞、或憑藉捕集靶細胞膜所分離之細胞;自然表現抗宿主腫瘤T細胞受體(TCR)之同種異體細胞;以及基因重編程或「重新導向」以表現呈現稱為「T-本體」之抗體樣腫瘤識別能力之腫瘤反應性TCR或嵌合TCR分子的非腫瘤特異性自體或同種異體細胞。此等方法已產生可用於本文所描述之方法之T細胞製備及免疫接種的許多方案。
在一些實施例中,T細胞衍生自血液、骨髓、淋巴、臍帶或淋巴器官。在一些態樣中,細胞係人類細胞。細胞通常為初代細胞,諸如直接自受試者分離及/或自受試者分離且冷凍之細胞。在一些實施例中,細胞包括T細胞或其他細胞類型之一或多種亞群,諸如完整T細胞群、CD4+
細胞、CD8+
細胞及其亞群,諸如根據以下所界定之彼等:功能、活化狀態、成熟度、分化潛能、擴增、再循環、位置及/或持久能力、抗原專一性、抗原受體類型、存在於特定器官或區室中、標記物或細胞激素分泌概況及/或分化程度。當提及所治療之受試者時,細胞可為同種異體細胞及/或自體細胞。在一些態樣中,諸如在現成技術中,細胞為多能及/或多潛能細胞,諸如幹細胞,諸如經誘導之多能幹細胞(iPSC)。在一些實施例中,方法包括如本文所述自受試者分離出細胞、對其進行製備、處理、培養及/或工程改造,及低溫保存之前或之後將其再引入同一患者中。
在T細胞的亞型及亞群中(例如CD4+
T細胞及/或CD8+
T細胞)係為未處理T (TN
)細胞、效應子T細胞(TEFF
)、記憶T細胞及其亞型(諸如幹細胞記憶T (TSCM
)、中樞記憶T (TCM
)、效應子記憶T (TEM
)或末期分化效應子記憶T細胞)、腫瘤浸潤性淋巴球(TIL)、不成熟T細胞、成熟T細胞、輔助T細胞、細胞毒性T細胞、黏膜相關恆定T (MAIT)細胞、天然存在及適應性調節T (Treg)細胞、輔助T細胞(諸如TH1細胞、TH2細胞、TH3細胞、TH17細胞、TH9細胞、TH22細胞)、濾泡性輔助T細胞、α/β T細胞及δ/γ T細胞。
在一些實施例中,T細胞群體中之一或多者富含或耗盡對特異性標記(諸如表面標記)呈陽性或對特異性標記呈陰性之細胞。在一些情況下,此類標記不存在於T細胞(例如非記憶細胞)之某些群體上或以相對較低程度表現,但存在於T細胞(例如記憶細胞)之某些其他群體上或以相對較高程度表現。
在一些實施例中,T細胞藉由陰性選擇非T細胞(諸如B細胞、單核球或其他白血球)上所表現之標記物(諸如CD14)而與PBMC樣品分離。在一些態樣中,使用CD4+
或CD8+
選擇步驟分離CD4+
輔助細胞與CD8+
細胞毒性T細胞。此類CD4+
及CD8+
群體可藉由對在一或多種初始、記憶及/或效應T細胞亞群上表現或表現至相對較高程度之標記的陽性或陰性選擇而進一步分選成亞群。
在一些實施例中,CD8+
T細胞諸如藉由基於與各別亞群相關聯之表面抗原的陽性或陰性選擇而相對於未處理、中樞記憶、效應子記憶及/或中樞記憶幹細胞進一步富集或耗盡。在一些實施例中,針對中樞記憶T (TCM
)細胞進行富集以提高功效,諸如在投藥之後改善長期存活率、擴增及/或移植,在一些態樣中,功效在此類亞群中特別穩定。
在一些實施例中,T細胞為自體T細胞。在此方法中,腫瘤樣品獲自患者且獲得單細胞懸浮液。單細胞懸浮液可以任何適合方式獲得,例如以機械方式(使用例如gentleMACS™解離劑、Miltenyi Biotec、Auburn, Calif.解聚腫瘤)或以酶方式(例如膠原蛋白酶或DNA酶)。在介白素-2 (IL-2)中培養腫瘤酶分解物之單細胞懸浮液。
經培養之T細胞可經彙集且快速擴增。快速擴增經約10至約14天之時段提供至少約50倍(例如50、60、70、80、90或100倍或更大)的抗原特異性T細胞數目增加。更佳地,快速擴增經約10至約14天之時段提供至少約200倍(例如200、300、400、500、600、700、800、900倍或更大)之增加。
擴增可藉由如此項技術中已知之多種方法中之任一者實現。舉例而言,T細胞可在飼養淋巴球及介白素-2 (IL-2)或介白素-15 (IL-15)存在下使用非特異性T細胞受體刺激而快速擴增,其中IL-2為較佳的。非特異性T細胞受體刺激物可包括約30 ng/ml OKT3,小鼠單株抗CD3抗體(可購自Ortho-McNeil®, Raritan, N.J.)。或者,T細胞可藉由用一或多種癌症抗原(包括其抗原部分,諸如抗原決定基,或細胞)活體外刺激外周血液單核細胞(PBMC)而快速擴增,該等抗原可視情況在諸如300 IU/ml IL-2或IL-15之T細胞生長因子(其中IL-2較佳)存在下表現自載體,諸如人類白血球抗原A2 (HLA-A2)結合肽。活體外誘導之T細胞係藉由用在HLA-A2表現抗原呈現細胞上脈衝之相同癌症抗原進行再刺激而快速擴增。或者,T細胞可例如藉由經照射之自體淋巴球或藉由經照射之HLA-A2+
同種異體淋巴細胞及IL-2進行再刺激。
自體T細胞可經修飾以表現促進生長且活化自體T細胞之T細胞生長因子。適合之T細胞生長因子包括例如介白素(IL)-2、IL-7、IL-15、及IL-12。適合之修飾方法為此項技術中已知的。參見例如Sambrook等人,Molecular Cloning: A Laboratory Manual,
第3版, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. 2001;及Ausubel等人,Current Protocols in Molecular Biology
, Greene Publishing Associates and John Wiley & Sons, NY, 1994。在特定態樣中,經修飾自體T細胞以高位準表現T細胞生長因子。T細胞生長因子編碼序列,諸如IL-12之T細胞生長因子編碼序列在此項技術中可容易地用作啟動子,其可操作地連接於T細胞生長因子編碼序列促進高程度表現。B. NK 細胞
在一些實施例中,免疫細胞為自然殺手(NK)細胞。NK細胞為具有針對多種腫瘤細胞、病毒感染細胞及骨髓及胸腺中之一些正常細胞之自發細胞毒性的淋巴細胞亞群。NK細胞在骨髓、淋巴結、脾臟、扁桃體及胸腺中分化及成熟。NK細胞可藉由人體內之特定表面標記物,諸如CD16、CD56及CD8偵測。NK細胞不表現T細胞抗原受體泛T標記物CD3或表面免疫球蛋白B細胞受體。
在某些實施例中,NK細胞係藉由此項技術中熟知之方法衍生自人類外周血液單核細胞(PBMC)、未刺激之白血球清除術產物(PBSC)、人類胚胎幹細胞(hESC)、誘導多能幹細胞(iPSC)、骨髓或臍帶血。特定言之,臍帶CB用於得到NK細胞。在某些態樣中,NK細胞係藉由離體擴增NK細胞之前述方法(Spanholtz等人,
2011;Shah等人,
2013)分離及擴增。在此方法中,CB單核細胞係藉由聚蔗糖密度梯度離心分離且在生物反應器中與IL-2及人工抗原呈遞細胞(aAPC)一起培養。在7天之後,細胞培養物耗盡任何表現細胞之CD3且另外再培養7天。細胞再次耗盡CD3且經表徵以測定CD56+
/CD3-
細胞或NK細胞之百分比。在其他方法中,臍帶CB用於藉由分離CD34+
細胞得到NK細胞且藉由在含有SCF、IL-7、IL-15及IL-2之培養基中培養而分化為CD56+
/CD3-
細胞。C. 幹細胞
在一些實施例中,本發明之免疫細胞可為幹細胞,諸如誘導多能幹細胞(PSC)、間充質幹細胞(MSC)或造血幹細胞(HSC)。
本文所用之多能幹細胞可為誘導多能幹(iPS)細胞,通常縮寫為iPS細胞或iPSC。除胚細胞之外,任何細胞可用作iPSC之起始點。舉例而言,細胞類型可為角質細胞、纖維母細胞、造血細胞、間葉細胞、肝細胞或胃細胞。細胞分化程度或收集細胞之動物的年齡不存在限制;甚至未分化之祖細胞(包括體幹細胞)及最終分化之成熟細胞可用作本文所揭示之方法中之體細胞來源。
體細胞可使用熟習此項技術者已知之方法重編程以產生iPS細胞。一般而言,核重編程因子用於自體細胞產生多能幹細胞。在一些實施例中,利用Klf4、c-Myc、Oct3/4、Sox2、Nanog及Lin28中之至少三者或至少四者。在其他實施例中,利用Oct3/4、Sox2、c-Myc及Klf4或Oct3/4、Sox2、Nanog及Lin28。
一旦衍生,iPSC可在足以維持多能性之培養基中培養。在某些實施例中,可使用不確定條件;舉例而言,多能細胞可在纖維母細胞飼養細胞或已暴露於纖維母細胞飼養細胞以將幹細胞維持於未分化狀態之培養基上培養。在一些實施例中,細胞在用輻射或抗生素處理以終止細胞分裂之小鼠胚胎纖維母細胞(作為飼養細胞)共同存在下培養。或者,多能細胞可使用界定之飼養細胞獨立性培養系統,諸如TESR™培養基或E8™/Essential 8™培養基培養及維持於基本未分化狀態下。III. 增強之嵌合抗原受體 A. 截斷 EGFRvIII ( Ev3 )
在某些實施例中,本發明藉由共價鍵聯抗原結合區與細胞內信號傳導域而提供增強之CAR,其包含Ev3作為CAR之鉸鏈或莖區。抗原結合區可包含衍生自抗抗原結合域之單鏈可變片段(scFv),該結合域衍生自抗體,諸如小鼠抗人類抗體。scFv可靶向任何潛在抗原。scFv可為人類化的,諸如在scFv之構架區中。在特定態樣中,維持與偵測或消融抗體之可接近性(例如經由ADCC)。
Ev3可與SEQ ID NO: 2 LEEKK-GNYVVTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRK-VCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQ-VCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPS (包含部分域1-部分域2-域3-域4)包含或具有至少80%(例如81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%)序列一致性。
在一個實施例中,提供CD19Ev3-CAR,其自N端至C端包含衍生自小鼠抗人類CD19單株抗體之scFv、包括跨膜域之Ev3鉸鏈、CD28胞內域及CD3ζ胞內域。在另一實施例中,CD19Ev3-CAR包含人類化CD19 (hCD19),稱為hCD19Ev3-CAR。CAR可進一步包含DAP12胞內域,諸如在Ev3跨膜域與CD3ζ胞內域之間,諸如CD19Ev3DAP12-CAR或hCD19Ev3DAP12-CAR。
在一個實施例中,提供CD123Ev3-CAR,其自N端至C端包含衍生自小鼠抗人類CD123單株抗體之scFv、包括跨膜域之Ev3鉸鏈、CD28胞內域及CD3ζ胞內域。在另一實施例中,CD123Ev3-CAR包含人類化CD123 (hCD123),稱為hCD123Ev3-CAR。CAR可進一步包含DAP12胞內域,諸如在Ev3跨膜域與CD3ζ胞內域之間,諸如CD123Ev3DAP12-CAR或hCD123Ev3DAP12-CAR。
在一個實施例中,提供MesoEv3-CAR,其自N端至C端包含衍生自小鼠抗人類間皮素單株抗體之scFv、包括跨膜域之Ev3鉸鏈、CD28胞內域及CD3ζ胞內域。在另一實施例中,MesoEv3-CAR包含人類化Meso (hMeso),稱為hMesoEv3-CAR。CAR可進一步包含DAP12胞內域,諸如在Ev3跨膜域與CD3ζ胞內域之間,諸如MesoEv3DAP12-CAR或hMesoEv3DAP12-CAR。
在一個實施例中,提供ROR1-Ev3-CAR,其自N端至C端包含衍生自小鼠抗人類ROR1單株抗體之scFv、包括跨膜域之Ev3鉸鏈、CD28胞內域及CD3ζ胞內域。在另一實施例中,ROR1-Ev3-CAR包含人類化ROR1 (hROR1),稱為hROR1Ev3-CAR。CAR可進一步包含DAP12胞內域,諸如在Ev3跨膜域與CD3ζ胞內域之間,諸如ROR1-Ev3DAP12-CAR或hROR1-Ev3DAP12-CAR。
在一個實施例中,提供CD5Ev3-CAR,其自N端至C端包含衍生自小鼠抗人類CD5單株抗體之scFv、包括跨膜域之Ev3鉸鏈、CD28胞內域及CD3ζ胞內域。在另一實施例中,CD5Ev3-CAR包含人類化CD5 (hCD5),稱為hCD5Ev3-CAR。CAR可進一步包含DAP12胞內域,諸如在Ev3跨膜域與CD3ζ胞內域之間,諸如CD5Ev3DAP12-CAR或hCD5Ev3DAP12-CAR。
在一個實施例中,提供CD99Ev3-CAR,其自N端至C端包含衍生自小鼠抗人類CD99單株抗體之scFv、包括跨膜域之Ev3鉸鏈、CD28胞內域及CD3ζ胞內域。在另一實施例中,CD5Ev3-CAR包含人類化CD99 (hCD99),稱為hCD99Ev3-CAR。CAR可進一步包含DAP12胞內域,諸如在Ev3跨膜域與CD3ζ胞內域之間,諸如CD99Ev3DAP12-CAR或hCD99Ev3DAP12-CAR。
EGFRvIII為EGFR基因之外顯子2-7突變的結果,其使得突變體受體不能結合任何已知配位體,因為受體不具有完整配位體結合域。本發明之截斷EGFRvIII,Ev3進一步包含EGFRvIII之細胞內域或胞內域的缺失。因此,Ev3不包含功能性EGF結合域或EGFRvIII之細胞內信號傳導域。
Ev3鉸鏈可包含SEQ ID NO: 1之核苷酸序列及/或SEQ ID NO: 2之胺基酸序列。在特定實施例中,Ev3鉸鏈與SEQ ID NO: 1或SEQ ID NO: 2具有至少80、85、90、91、92、93、94、95、96、97、98、99或100%序列一致性。Ev3鉸鏈區可包含SEQ ID NO: 2之片段或可在受體片段之N端或C端末端上包含額外胺基酸。Ev3之例示性示意圖描繪於圖2中。
CAR之鉸鏈區中包括截斷EGFRvIII允許遺傳貨物空間保留。Ev3亦可用作安全開關及/或用於活體外或活體內偵測CAR。整合Ev4鉸鏈可藉由抗體,諸如臨床上可獲取之單株抗體(例如西妥昔單抗)識別,用於偵測或細胞消融。另外,Ev3不包含配位體結合域;因此,不存在內源性功能或與其他路徑串擾。Ev3為亦在CAR信號轉導中起作用且為腫瘤特異性的,其可使CAR療法之副作用最小化。B. 抗原
本文提供之CAR可具有適用於治療疾病或病症之任何抗原特異性。本文提供之CAR可包含超過一個抗原,諸如兩個抗原。例示性抗原包括(但不限於)CD19、CD123、間皮素、CD5、CD47、CLL-1、CD33、CD99、CLL-1、U5snRNP200、CD200、CS1、BAFF-R、ROR-1、CD99、間皮素或BCMA。
本文提供之人類化平台可用於開發用於任何給定抗原之人類化CAR。具有人類化CAR之例示性抗原包括(但不限於)CD19、CD123、間皮素、CD5、CD47、CLL-1、CD33、CD99、U5snRNP200、CD200、CS1、BAFF-R、ROR-1或BCMA。
在一個實施例中,編碼之輕鏈可變區包含人類PH0879生殖系序列之一個、兩個、三個或全部四個構架區。hCD19之編碼重鏈可變區可包含人類ACD43442生殖系序列之一個、兩個、三個或全部四個構架區。
在一個實施例中,編碼之抗原結合域為包含胺基酸序列SEQ ID NO: 6、12、18、24、30、58或61之輕鏈及重鏈之scFv。在一個實施例中,抗原結合域(例如scFv)包含:輕鏈可變區,其包含具有本文提供之輕鏈可變區之胺基酸序列之至少一個、兩個或三個修飾(例如取代)但不超過10、20或30個修飾(例如取代)之胺基酸序列,或與胺基酸序列SEQ ID NO: 7、13、19、25、31、59或63具有90-99%一致性之序列;及/或重鏈可變區,其包含具有SEQ ID NO: 8、14、20、26、32、60或64之重鏈可變區之胺基酸序列之至少一個、兩個或三個修飾(例如取代)但不超過10、20或30個修飾(例如取代)之胺基酸序列,或與胺基酸序列SEQ ID NO: 6、12、18、24、30、58或61具有90-99%一致性之序列。
在一些實施例中,本文提供用於CD19之人類化scFv。人類化CD19 (hCD19)scFv可具有可變輕鏈序列SEQ ID NO: 7 (DIQMTQSPSSLSASVGDRVTITCRASQDISKYLN
WYQQKPGKVPKLLIYHTSRLHS
GVPDRFSGSGSGTDFTLTISSLQPEDVATYYCQQGNTLPYT
FGQGTKVEIKR)及可變重鏈SEQ ID NO: 8 (EVQLVESGGGLVQPGGSLRLSCAASGVSLPDYGVS
WVRQAPGKGLEWIGVIWGSETTYYNSALKS
KFIISRDNAKNSLYLQMNSLRAEDTAVYYCARHYYYGGSYAMDY
WGQGTLVTVSS)。在其他態樣中,hCD19 scFv可包含與SEQ ID NO: 7具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之VL
及/或與SEQ ID NO: 8具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之VH
。hCD19 scFv可包含與SEQ ID NO: 6具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之胺基酸序列。hCD19 scFv可藉由與SEQ ID NO: 3具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。hCD19 scFv之VL
可藉由與SEQ ID NO: 4具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。hCD19 scFv之VH
可藉由與SEQ ID NO: 5具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。
在一些實施例中,本文提供用於CD123之人類化scFv。人類化CD123 (hCD123)scFv可具有可變輕鏈序列SEQ ID NO: 13及可變重鏈SEQ ID NO: 14。在其他態樣中,hCD123 scFv可包含與SEQ ID NO: 13具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之VL
及/或與SEQ ID NO: 14具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之VH
。hCD123 scFv可包含與SEQ ID NO: 12具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之胺基酸序列。hCD123 scFv可藉由與SEQ ID NO: 9具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。hCD123 scFv之VL
可藉由與SEQ ID NO: 10具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。hCD123 scFv之VH
可藉由與SEQ ID NO: 11具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。
在一些實施例中,本文提供用於間皮素之人類化scFv。人類化間皮素(hMeso)scFv可具有可變輕鏈sequence SEQ ID NO: 19及可變重鏈SEQ ID NO: 20。在其他態樣中,hMeso scFv可包含與SEQ ID NO: 19具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之VL
及/或與SEQ ID NO: 20具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之VH
。hMeso scFv可包含與SEQ ID NO: 18具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之胺基酸序列。hMeso scFv可藉由與SEQ ID NO: 15具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。hMeso scFv之VL
可藉由與SEQ ID NO: 16具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。hMeso scFv之VH
可藉由與SEQ ID NO: 17具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。
在一些實施例中,本文提供用於ROR1之人類化scFv。人類化ROR1 (hROR1)scFv可具有可變輕鏈序列SEQ ID NO: 25及可變重鏈SEQ ID NO: 26。在其他態樣中,hROR1 scFv可包含與SEQ ID NO: 25具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之VL
及/或與SEQ ID NO: 26具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之VH
。hROR1 scFv可包含與SEQ ID NO: 24具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之胺基酸序列。hROR1 scFv可藉由與SEQ ID NO: 21具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。hROR1 scFv之VL
可藉由與SEQ ID NO: 22具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。hROR1 scFv之VH
可藉由與SEQ ID NO: 23具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。
在一些實施例中,本文提供用於CD5之人類化scFv。人類化CD5 (hCD5)scFv可具有可變輕鏈序列SEQ ID NO: 31及可變重鏈SEQ ID NO: 32。在其他態樣中,hCD5 scFv可包含與SEQ ID NO: 31具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之VL
及/或與SEQ ID NO: 32具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之VH
。hCD5 scFv可包含與SEQ ID NO: 30具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之胺基酸序列。hCD5 scFv可藉由與SEQ ID NO: 27具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。hCD5 scFv之VL
可藉由與SEQ ID NO: 28具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。hCD5 scFv之VH
可藉由與SEQ ID NO: 29具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。
在一些實施例中,本文提供用於CD99之人類化scFv。人類化CD99 (hCD99)scFv可具有可變輕鏈序列SEQ ID NO: 63及可變重鏈SEQ ID NO: 64。在其他態樣中,hCD99 scFv可包含與SEQ ID NO: 63具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之VL
及/或與SEQ ID NO: 64具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之VH
。hCD99 scFv可包含與SEQ ID NO: 61具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之胺基酸序列。hCD99 scFv可藉由與SEQ ID NO: 61具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。
在一些實施例中,本文提供用於CD99之人類化scFv。人類化CD99 (hCD99)scFv可具有可變輕鏈序列SEQ ID NO: 59及可變重鏈SEQ ID NO: 60。在其他態樣中,hCD99 scFv可包含與SEQ ID NO: 59具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之VL
及/或與SEQ ID NO: 60具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%序列一致性之VH
。hCD99 scFv可包含與SEQ ID NO: 58具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之胺基酸序列。hCD99 scFv可藉由與SEQ ID NO: 57具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列一致性之聚核苷酸編碼。
在藉由基因工程改造抗原受體靶向之抗原中包括在經由授受細胞療法靶向之疾病、病況或細胞類型之情況下表現之彼等。在疾病及病況中包括增生性、贅生性及惡性疾病及病症,包括癌症及腫瘤,包括血液癌、免疫系統癌症,諸如淋巴瘤、白血病及/或骨髓瘤,諸如B、T及骨髓白血病、淋巴瘤及多發性骨髓瘤。在一些實施例中,相比於正常或非靶向細胞或組織、與自體免疫或同種免疫病症相關之抗原或病原體特異性抗原,抗原選擇性地表現或過度表現於疾病或病況細胞,例如腫瘤或病原性細胞。在其他實施例中,抗原表現於正常細胞上及/或表現於工程改造細胞上。
任何適合之抗原可用於本發明方法中。例示性抗原包括(但不限於)來自傳染媒介物之抗原分子、自身/自體抗原、腫瘤/癌症相關抗原及腫瘤新抗原。在特定態樣中,抗原包括NY-ESO、EGFRvIII、Muc-1、Her2、CA-125、WT-1、Mage-A3、Mage-A4、Mage-A10、TRAIL/DR4及CEA。
腫瘤相關抗原可衍生自前列腺癌、乳房癌、結腸直腸癌、肺癌、胰臟癌、腎癌、間皮瘤、卵巢癌或黑素瘤。例示性腫瘤相關抗原或腫瘤細胞源性抗原包括MAGE 1、3及MAGE 4;PRAME;BAGE;RAGE、Lage (亦稱為NY ESO 1);SAGE;及HAGE或GAGE。腫瘤抗原之此等非限制性實例表現於大範圍之腫瘤類型,諸如黑素瘤、肺癌、肉瘤及膀胱癌中。前列腺癌腫瘤相關抗原包括例如前列腺特異性膜抗原(PSMA)、前列腺特異性抗原(PSA)、前列腺酸磷酸鹽、NKX3.1及前列腺六次跨膜上皮抗原(STEAP)。
其他腫瘤相關抗原包括Plu-1、HASH-1、HasH-2、Cripto及Criptin。另外,腫瘤抗原可為自身肽激素,諸如全長促性腺激素釋放激素,一種適用於治療許多癌症之長度為10個胺基酸的短肽。
腫瘤抗原包括衍生自藉由腫瘤相關抗原表達,諸如HER-2/neu表達表徵之癌症的腫瘤抗原。所關注之腫瘤相關抗原包括譜系特異性腫瘤抗原,諸如黑色素細胞-黑素瘤譜系抗原MART-1/Melan-A、gp100、gp75、MDA-7、酪胺酸酶及酪胺酸酶相關蛋白。說明性腫瘤相關抗原包括(但不限於)衍生自或包含以下中之任何一或多者之腫瘤抗原:p53、Ras、c-Myc、細胞質絲胺酸/蘇胺酸激酶(例如A-Raf、B-Raf及C-Raf、細胞週期蛋白依賴性激酶)、MAGE-A1、MAGE-A2、MAGE-A3、MAGE-A4、MAGE-A6、MAGE-A10、MAGE-A12、MART-1、BAGE、DAM-6、-10、GAGE-1、-2、-8、GAGE-3、-4、-5、-6、-7B、NA88-A、MART-1、MC1R、Gp100、PSA、PSM、酪胺酸酶、TRP-1、TRP-2、ART-4、CAMEL、CEA、Cyp-B、hTERT、hTRT、iCE、MUC1、MUC2、磷酸肌醇3-激酶(PI3K)、TRK受體、PRAME、P15、RU1、RU2、SART-1、SART-3、威耳姆士腫瘤抗原(Wilms' tumor antigen;WT1)、AFP、-連環蛋白/m、凋亡蛋白酶-8/m、CEA、CDK-4/m、ELF2M、GnT-V、G250、HSP70-2M、HST-2、KIAA0205、MUM-1、MUM-2、MUM-3、肌球蛋白/m、RAGE、SART-2、TRP-2/INT2、707-AP、磷脂結合蛋白II、CDC27/m、TPI/mbcr-abl、BCR-ABL、干擾素調節因子4 (IRF4)、ETV6/AML、LDLR/FUT、Pml/RAR、腫瘤相關鈣信號轉導蛋白1 (TACSTD1)TACSTD2、受體酪胺酸激酶(例如表皮成長因子受體(EGFR)(詳言之,EGFRvIII)、血小板衍生生長因子受體(PDGFR)、血管內皮生長因子受體(VEGFR)、細胞質酪胺酸激酶(例如src-家族、syk-ZAP70家族)、整合素連接激酶(ILK)、轉錄STAT3之信號轉導蛋白及活化因子、STATS及STATE、低氧誘導因子(例如HIF-1及HIF-2)、核因子-κB(NF-B)、Notch受體(例如Notch1-4)、c-Met、雷帕黴素之哺乳動物標靶(mTOR)、WNT、胞外信號調節激酶(ERK)及其調節亞單位、PMSA、PR-3、MDM2、間皮素、腎細胞癌-5T4、SM22-α、碳酸酐酶I (CAI)及IX (CAIX)(亦稱為G250)、STEAD、TEL/AML1、GD2、蛋白酶3、hTERT、肉瘤易位斷點、EphA2、ML-IAP、EpCAM、ERG (TMPRSS2 ETS融合基因)、NA17、PAX3、ALK、雄激素受體、細胞週期蛋白B1、聚唾液酸、MYCN、RhoC、GD3、岩藻糖基GM1、間皮素、PSCA、sLe、PLAC1、GM3、BORIS、Tn、GLoboH、NY-BR-1、RGsS、SART3、STn、PAX5、OY-TES1、精子蛋白17、LCK、HMWMAA、AKAP-4、SSX2、XAGE 1、B7H3、豆莢蛋白、TIE2、Page4、MAD-CT-1、FAP、MAD-CT-2、fos相關抗原1、CBX2、CLDN6、SPANX、TPTE、ACTL8、ANKRD30A、CDKN2A、MAD2L1、CTAG1B、SUNC1、LRRN1及個體基因型。
抗原可包括抗原決定基區域或抗原決定基肽,其衍生自腫瘤細胞中突變之基因或相比於正常細胞在腫瘤細胞中以不同位準經轉錄之基因,諸如端粒酶、存活素、間皮素、突變ras、bcr/abl重排、Her2/neu、突變或野生型p53、細胞色素P450 1B1,及異常表現之內含子序列,諸如N-乙醯胺基葡萄糖轉移酶-V;在骨髓瘤及B細胞淋巴瘤中產生獨特個體基因型之免疫球蛋白基因之純系重排;包括衍生自癌病毒過程之抗原決定基區域或抗原決定基肽之腫瘤抗原,諸如人類乳頭狀瘤病毒蛋白E6及E7;艾巴二氏病毒蛋白(Epstein bar virus protein) LMP2;具有腫瘤選擇性表現之非變異癌胚蛋白,諸如癌胚抗原及α-胎蛋白。
在其他實施例中,抗原獲自或衍生自病原微生物或條件性病原微生物(在本文中亦稱作感染性疾病微生物),諸如病毒、真菌、寄生蟲及細菌。在某些實施例中,衍生自此類微生物之抗原包括全長蛋白。
抗原預期用於本文所述之方法的說明性病原生物體包括人類免疫不全病毒(HIV)、單純疱疹病毒(HSV)、呼吸道融合病毒(RSV)、巨細胞病毒(CMV)、埃-巴二氏病毒(EBV)、A型、B型及C型流感、水泡性口炎病毒(VSV)、水泡性口炎病毒(VSV)、多瘤病毒(例如BK病毒及JC病毒)、腺病毒、包括抗甲氧西林金黃色葡萄球菌(Methicillin-resistant Staphylococcus aureus;MRSA)之葡萄球菌屬物種及包括肺炎鏈球菌(Streptococcus pneumoniae
)之鏈球菌屬物種。如技術人員將理解,用作如本文所述之抗原的衍生自此等及其他病原微生物之蛋白質及編碼該等蛋白質之核苷酸序列可鑑別於出版物及公共資料庫,諸如GENBANK®、Swiss-Prot®及TrEMBL®中。
衍生自人類免疫不全病毒(HIV)之抗原包括以下中之任一者:HIV病毒粒子結構蛋白(例如gp120、gp41、p17、p24)、蛋白酶、逆轉錄酶或由tat、rev、nef、vif、vpr及vpu編碼之HIV蛋白。
衍生自單純疱疹病毒(例如HSV 1及HSV2)之抗原包括(但不限於)表現自HSV晚期基因之蛋白質。晚期基因組主要編碼形成病毒粒子之蛋白質。此類蛋白質包括形成病毒衣殼之來自(UL)之五種蛋白質:UL6、UL18、UL35 UL38及主要衣殼蛋白UL19、UL45及UL27,其各自可用作如本文所述之抗原。預期用作本文中之抗原的其他說明性HSV蛋白包括ICP27 (H1、H2)、醣蛋白B (gB)及醣蛋白D (gD)蛋白。HSV基因組包含至少74個基因,各編碼可潛在地用作抗原之蛋白質。
衍生自巨細胞病毒(CMV)之抗原包括CMV結構蛋白、在病毒複製之即刻早期及早期期間表現之病毒抗原、醣蛋白I及III、衣殼蛋白、外殼蛋白、低基質蛋白pp65 (ppUL83)、p52 (ppUL44)、IE1及1E2 (UL123及UL122)、來自UL128-UL150基因集群之蛋白質產物(Rykman等人, 2006)、包膜醣蛋白B (gB)、gH、gN及pp150。如技術人員將理解,用作本文所述之抗原的CMV蛋白可鑑別於公共資料庫,諸如GenBank®、Swiss-Prot®及TrEMBL®中。
預期用於某些實施例之衍生自艾巴二氏病毒(EBV)之抗原包括EBV溶解蛋白gp350及gp110、在潛伏週期感染期間產生之EBV蛋白,包括艾巴二氏核抗原(EBNA)-1、EBNA-2、EBNA-3A、EBNA-3B、EBNA-3C、EBNA-前導蛋白(EBNA-LP)及潛伏膜蛋白(LMP)-1、LMP-2A及LMP-2B。
預期用於本文中之衍生自呼吸道融合病毒(RSV)之抗原包括由RSV基因組編碼之十一種蛋白質中之任一者,或其抗原片段:NS 1、NS2、N (核衣殼蛋白)、M (基質蛋白)SH、G及F (病毒外殼蛋白)、M2 (第二基質蛋白)、M2-1 (延長因子)、M2-2 (轉錄調節)、RNA聚合酶及磷蛋白P。
預期使用之衍生自水泡性口炎病毒(VSV)之抗原包括由VSV基因組編碼之五種主要蛋白中之任一者及其抗原片段:大蛋白(L)、醣蛋白(G)、核蛋白(N)、磷蛋白(P)及基質蛋白(M)。
預期用於某些實施例之衍生自流感病毒之抗原包括血球凝集素(HA)、神經胺糖酸苷酶(NA)、核蛋白(NP)、基質蛋白M1及M2、NS1、NS2 (NEP)、PA、PB1、PB1-F2及PB2。
例示性病毒抗原亦包括(但不限於)腺病毒多肽、α病毒多肽、杯狀病毒多肽(例如杯狀病毒衣殼抗原)、冠狀病毒多肽、犬瘟熱病毒多肽、伊波拉病毒多肽、腸病毒多肽、黃病毒多肽、肝炎病毒(AE)多肽(B型肝炎核心或表面抗原、C型肝炎病毒E1或E2醣蛋白、核心或非結構蛋白)、疱疹病毒多肽(包括單純疱疹病毒或水痘帶狀皰狀病毒醣蛋白)、感染性腹膜炎病毒多肽、白血病病毒多肽、馬堡病毒(Marburg virus)多肽、正黏液病毒多肽、乳頭瘤病毒多肽、副流感病毒多肽(例如血球凝集素及神經胺糖酸苷酶多肽)、副黏病毒多肽、小病毒多肽、瘟病毒多肽、病毒科病毒多肽(例如脊髓灰白質炎病毒衣殼多肽)、痘病毒多肽(例如牛痘病毒多肽)、狂犬病病毒多肽(例如狂犬病病毒醣蛋白G)、里奧病毒(reovirus)多肽、反轉錄病毒多肽及輪狀病毒多肽。
在某些實施例中,抗原可為細菌抗原。在某些實施例中,所關注之細菌抗原可為分泌多肽。在其他某些實施例中,細菌抗原包括具有暴露於細菌之外細胞表面上之多肽之一或多個部分的抗原。
預期使用之包括抗甲氧西林金黃色葡萄球菌(MRSA)之衍生自葡萄球菌屬物種之抗原包括毒性調節劑,諸如Agr系統、Sar及Sae、Arl系統、Sar同系物(Rot、MgrA、SarS、SarR、SarT、SarU、SarV、SarX、SarZ及TcaR)、Srr系統及TRAP。可充當抗原之其他葡萄球菌屬蛋白質包括Clp蛋白質、HtrA、MsrR、烏頭酸酶、CcpA、SvrA、Msa、CfvA及CfvB (參見例如Staphylococcus
: Molecular Genetics, 2008 Caister Academic Press, Jodi Lindsay編)。金黃色葡萄球菌之兩個物種(N315及Mu50)之基因組已定序且公開可用,例如在PATRIC (PATRIC: The VBI PathoSystems Resource Integration Center, Snyder等人, 2007)。如技術人員將理解,用作抗原之葡萄球菌屬蛋白質亦可鑑別於其他公共資料庫,諸如GenBank®、Swiss-Prot®及TrEMBL®中。
預期用於本文所述之某些實施例的衍生自肺炎鏈球菌之抗原包括肺炎鏈球菌溶血素、PspA、膽鹼-結合蛋白A (CbpA)、NanA、NanB、SpnHL、PavA、LytA、Pht及菌毛蛋白(RrgA;RrgB;RrgC)。肺炎鏈球菌之抗原蛋白質亦為此項技術中已知的且可在一些實施例中用作抗原。肺炎鏈球菌之毒性菌株之完整基因組序列已定序且如技術人員將理解,本文中所用之肺炎鏈球菌蛋白質亦可鑑別於其他公共資料庫,諸如GenBank®、Swiss-Prot®及TrEMBL®中。用於根據本發明之抗原的備受關注之蛋白質包括預測暴露於肺炎球菌表面之毒性因子及蛋白質。
可用作抗原之細菌抗原之實例包括(但不限於)放線菌屬(Actinomyces
)多肽、芽孢桿菌屬(Bacillus
)多肽、擬桿菌屬(Bacteroides
)多肽、鮑特氏菌屬(Bordetella
)多肽、巴爾通體屬(Bartonella
)多肽、疏螺旋體屬(Borrelia
)多肽(例如伯氏疏螺旋體(B. burgdorferi
)OspA)、布氏桿菌屬(Brucella
)多肽、曲狀桿菌屬(Campylobacter
)多肽、二氧化碳嗜纖維菌屬(Capnocytophaga
)多肽、衣原體多肽、棒狀桿菌(Corynebacterium
)多肽、考克斯氏體屬(Coxiella
)多肽、潛蚤屬(Dermatophilus
)多肽、腸球菌屬(Enterococcus
)多肽、艾利希體屬(Ehrlichia
)多肽、埃希氏桿菌屬(Escherichia
)多肽、弗朗西斯氏菌屬(Francisella
)多肽、梭桿菌屬(Fusobacterium
)多肽、血巴爾通氏體屬(Haemobartonella
)多肽、嗜血桿菌屬(Haemophilus
)多肽(例如b型流感嗜血桿菌外膜蛋白)、螺旋桿菌屬(Helicobacter
)多肽、克雷伯氏菌屬(Klebsiella
)多肽、L-形式細菌多肽、鉤端螺旋體屬(Leptospira
)多肽、李斯特菌屬(Listeria
)多肽、分枝桿菌屬(Mycobacteria
)多肽、黴漿菌(Mycoplasma
)多肽、奈瑟氏菌屬(Neisseria
)多肽、新立克次體(Neorickettsia
)多肽、諾卡菌屬(Nocardia
)多肽、巴氏桿菌(Pasteurella
)多肽、消化球菌屬(Peptococcus
)多肽、消化鏈球菌屬(Peptostreptococcus
)多肽、肺炎球菌屬(Pneumococcus
)多肽(亦即,肺炎鏈球菌多肽)(參文中敘述)、變形桿菌屬(Proteus)多肽、假單胞菌屬(Pseudomonas)多肽、立克次體屬(Rickettsia)多肽、羅克利馬體屬(Rochalimaea
)多肽、沙門氏菌屬(Salmonella
)多肽、志賀桿菌屬(Shigella
)多肽、葡萄球菌屬(Staphylococcus
)多肽、A組鏈球菌屬(Streptococcus
)多肽(例如化膿性鏈球菌(S. pyogenes
)M蛋白)、B組鏈球菌屬(無乳鏈球菌(S. agalactiae
))多肽、密螺旋體屬(Treponema
)多肽及耶爾森菌屬(Yersinia
)多肽(例如鼠疫耶爾森菌(Y. pestis
)F1及V抗原)。
真菌抗原之實例包括(但不限於)犁頭黴屬(Absidia
)多肽、枝頂孢屬(Acremonium
)多肽、交鏈孢屬(Alternaria
)多肽、麴菌屬(Aspergillus
)多肽、蛙糞黴菌屬(Basidiobolus
)多肽、平臍蠕孢屬(Bipolaris
)多肽、芽生菌屬(Blastomyces
)多肽、念珠菌屬(Candida
)多肽、粗球菌(Coccidioides
)多肽、耳黴屬(Conidiobolus
)多肽、隱球菌屬(Cryptococcus
)多肽、彎孢黴屬(Curvalaria
)多肽、表皮癬菌(Epidermophyton
)多肽、外瓶黴屬(Exophiala
)多肽、地絲菌(Geotrichum
)多肽、組織漿菌(Histoplasma
)多肽、馬杜拉分支菌屬(Madurella
)多肽、馬拉色氏黴菌屬(Malassezia
)多肽、小芽孢菌(Microsporum
)多肽、小叢梗孢屬(Moniliella
)多肽、被孢黴屬(Mortierella
)多肽、白黴菌屬(Mucor
)多肽、擬青黴菌屬(Paecilomyces
)多肽、青黴菌(Penicillium
)多肽、單胞瓶黴屬(Phialemonium
)多肽、瓶黴屬(Phialophora
)多肽、原壁菌屬(Prototheca
)多肽、假埃希氏菌屬(Pseudallescheria
)多肽、假小托菌屬(Pseudomicrodochium
)多肽、腐黴菌(Pythium
)多肽、鼻孢子蟲屬(Rhinosporidium
)多肽、根黴菌屬(Rhizopus
)多肽、線狀擔子菌屬(Scolecobasidium
)多肽、孢子絲菌屬(Sporothrix
)多肽、匍柄黴屬(Stemphylium
)多肽、發癬菌(Trichophyton
)多肽、毛芽胞酵母(Trichosporon
)多肽及木絲黴屬(Xylohypha
)多肽。
原蟲寄生蟲抗原之實例包括(但不限於)巴倍蟲屬(Babesia
)多肽、腸袋蟲屬(Balantidium
)多肽、貝諾孢子蟲屬(Besnoitia
)多肽、隱胞子蟲屬(Cryptosporidium
)多肽、艾美球蟲屬(Eimeria
)多肽、腦胞內原蟲屬(Encephalitozoon
)多肽、內阿米巴屬(Entamoeba
)多肽、梨形鞭毛蟲屬(Giardia
)多肽、哈蒙德蟲屬(Hammondia
)多肽、肝簇蟲屬(Hepatozoon
)多肽、等孢子球蟲屬(Isospora
)多肽、利什曼原蟲屬(Leishmania
)多肽、微孢子蟲目(Microsporidia
)多肽、新孢子蟲屬(Neospora
)多肽、小孢子蟲屬(Nosema
)多肽、五鞭毛蟲屬(Pentatrichomonas
)多肽、瘧原蟲屬(Plasmodium
)多肽。寄生蠕蟲抗原之實例包括(但不限於)棘唇屬(Acanthocheilonema
)多肽、貓圓線蟲屬(Aelurostrongylus
)多肽、鉤蟲屬(Ancylostoma
)多肽、血管圓線蟲屬(Angiostrongylus
)多肽、蛔蟲屬(Ascaris
)多肽、布魯線蟲屬(Brugia
)多肽、仰口線蟲屬(Bunostomum
)多肽、毛細線蟲屬(Capillaria
)多肽、夏氏線蟲屬(Chabertia
)多肽、古柏線蟲屬(Cooperia
)多肽、環體線蟲屬(Crenosoma
)多肽、網尾線蟲屬(Dictyocaulus
)多肽、膨結線蟲屬(Dioctophyme
)多肽、雙板線蟲屬(Dipetalonema
)多肽、裂頭絛蟲屬(Diphyllobothrium
)多肽、複孔絛蟲屬(Diplydium
)多肽、絲蟲屬(Dirofilaria
)多肽、龍線屬(Dracunculus
)多肽、住腸線蟲屬(Enterobius
)多肽、類絲蟲屬(Filaroides
)多肽、血矛線蟲屬(Haemonchus
)多肽、兔唇蛔屬(Lagochilascaris
)多肽、羅阿線蟲屬(Loa
)多肽、曼森線蟲屬(Mansonella
)多肽、繆勒線蟲屬(Muellerius
)多肽、侏形吸蟲屬(Nanophyetus
)多肽、鉤蟲屬(Necator
)多肽、細頸線蟲屬(Nematodirus
)多肽、結節線蟲屬(Oesophagostomum
)多肽、盤尾絲蟲屬(Onchocerca
)多肽、後睾吸蟲屬(Opisthorchis
)多肽、奧斯特線蟲屬(Ostertagia
)多肽、副絲蟲屬(Parafilaria
)多肽、並殖吸蟲屬(Paragonimus
)多肽、副蛔蟲屬(Parascaris
)多肽、泡翼線蟲屬(Physaloptera
)多肽、原圓屬(Protostrongylus
)多肽、狗尾草屬(Setaria
)多肽、旋尾線蟲屬(Spirocerca
)多肽、迭宮絛蟲屬(Spirometra
)多肽、冠絲蟲屬(Stephanofilaria
)多肽、類圓線蟲屬(Strongyloides
)多肽、圓線蟲(Strongylus
)多肽、吸吮線蟲屬(Thelazia
)多肽、蛔線蟲屬(Toxascaris
)多肽、弓蛔蟲屬(Toxocara
)多肽、旋毛蟲屬(Trichinella
)多肽、毛樣圓蟲屬(Trichostrongylus
)多肽、鞭蟲屬(Trichuris
)多肽、鉤蟲屬(Uncinaria
)多肽及吳策線蟲屬(Wuchereria
)多肽(例如惡性瘧原蟲(P. falciparum
)環子孢子(PfCSP))、子孢子表面蛋白2 (PfSSP2)、肝狀態抗原1之羧基末端(PfLSA1 c-term)及輸出蛋白1(PfExp-1)、肺囊蟲(Pneumocystis
)多肽、肉孢子蟲(Sarcocystis
)多肽、住血吸蟲屬(Schistosoma
)多肽、泰累爾犁漿蟲屬(Theileria
)多肽、弓蟲屬(Toxoplasma
)多肽及錐蟲屬(Trypanosoma
)多肽。
外部寄生蟲抗原之實例包括(但不限於)來自以下各者之多肽(包括抗原以及過敏原):跳蚤;蜱,包括硬蜱及軟蜱;蒼蠅,諸如蠓、蚊子、白蛉、黑蠅、馬蠅、角蠅、鹿蠅、舌蠅、廄螫蠅、引起蠅蛆病之蒼蠅及庫蠓;螞蟻;蜘蛛、虱;蟎;以及蝽,諸如床虱及接吻蟲。C. 嵌合抗原受體
在一些實施例中,CAR含有特異性結合於抗原之細胞外抗原識別域。在一些實施例中,抗原係於細胞之表面上表現之蛋白質。在一些實施例中,CAR係TCR樣CAR且抗原係經處理之肽抗原,諸如胞內蛋白質之肽抗原,其類似TCR,在主要組織相容複合體(MHC)分子之情形下在細胞表面上識別。
在一些實施例中,嵌合抗原受體包含:a)細胞內信號傳導域,b)鉸鏈及跨膜域,諸如Ev3鉸鏈,及c)包含抗原結合區之細胞外域。
在一些實施例中,工程改造抗原受體包括嵌合抗原受體(CAR),包括活化或刺激CAR、共刺激CAR (參見WO2014/055668)及/或抑制CAR (iCAR,參見Fedorov等人, 2013)。CAR一般包括細胞外抗原(或配位體)結合域,其連接至一或多種胞內信號傳導組分,在一些態樣中經由連接子及/或跨膜域。此類分子通常模仿或接近穿過天然抗原受體之信號、穿過此類受體與共刺激受體組合之信號及/或單獨穿過共刺激受體之信號。
本發明之某些實施例關注使用核酸,包括編碼抗原特異性CAR多肽之核酸,包括已經人類化以降低免疫原性之CAR (hCAR),包含細胞內信號傳導域、跨膜域及包含一或多種信號傳導基元之細胞外域。在某些實施例中,CAR可識別包含一或多種抗原之間的共用空間的抗原決定基。在某些實施例中,結合區可包含單株抗體之互補決定區、單株抗體之可變區及/或其抗原結合片段。在另一實施例中,特異性源自結合至受體之肽(例如細胞介素)。
預期人類CAR核酸可為用於增強人類患者之細胞免疫療法的人類基因。在一特定實施例中,本發明包括全長CAR cDNA或編碼區。抗原結合區或域可包含衍生自特定人類單株抗體之單鏈可變片段(scFv)之VH
及VL
鏈的片段,諸如以引用的方式併入本文中之美國專利7,109,304中所述之彼等。片段亦可為人類抗原特異性抗體之任何數目的不同抗原結合域。在更特定實施例中,片段為由序列編碼之抗原特異性scFv,該序列針對用於在人類細胞中表現之人類密碼子使用最佳化。
配置可為多聚的,諸如雙功能抗體或多聚體。多聚體最可能由輕鏈及重鏈之可變部分交叉配對為雙功能抗體形成。構築體之鉸鏈部分可具有多個替代方案,自全部缺失至維持第一半胱胺酸、取代脯胺酸而非絲胺酸、截斷至多第一半胱胺酸。Fc部分可缺失。任何穩定及/或二聚化之蛋白質可供用於此目的。吾人可僅使用Fc域中之一者,例如來自人類免疫球蛋白之CH2或CH3域。吾人亦可使用已經修飾以改良二聚化之人類免疫球蛋白之鉸鏈、CH2及CH3區。吾人亦可僅使用免疫球蛋白之鉸鏈部分。吾人亦可使用CD8α之一部分。
在一些實施例中,CAR核酸包含編碼其他共刺激受體之序列,諸如跨膜域及經修飾之CD28細胞內信號傳導域。其他共刺激受體包括(但不限於)CD28、CD27、OX-40 (CD134)、DAP10、DAP12及4-1BB (CD137)中之一或多者。除藉由CD3ζ引發之初級信號以外,藉由插入於人類CAR中之人類共刺激受體提供之額外信號對於NK細胞之完全活化重要且可幫助改良授受免疫療法之活體內持久性及治療成效。CAR可表現一或多種細胞介素,諸如IL-15。包括一或多種細胞介素可促進活體內持久性。在一些態樣中,CAR包含抗原結合域,諸如人類化scFv、CD3ζ、DAP12及IL-15,視情況與Ev3鉸鏈組合。
在一些實施例中,CAR經構建具有針對特定抗原(或標記物或配位體)之特異性,諸如在授受性療法待靶向之特定細胞類型中表現之抗原,例如癌症標記物;及/或意欲誘導抑制反應之抗原,諸如在正常或非病變細胞類型上表現之抗原。因此,CAR在其細胞外部分中通常包括一或多種抗原結合分子,諸如一或多種抗原結合片段、域、或部分、或一或多種抗體可變域及/或抗體分子。在一些實施例中,CAR包括抗原結合部分或抗體分子部分,諸如衍生自單株抗體(mAb)之可變重鏈(VH)及可變輕鏈(VL)的單鏈抗體片段(scFv)。
在嵌合抗原受體之某些實施例中,受體之抗原特異性部分(其可稱為包含抗原結合區之細胞外域)包含腫瘤相關抗原或病原體特異性抗原結合域。抗原包括藉由模式識別受體,諸如凝集素-1識別之碳水化合物抗原。腫瘤相關抗原可為任何種類,只要其表現於腫瘤細胞之細胞表面上。腫瘤相關抗原之例示性實施例包括CD19、CD319 (CS1)、CD20、癌胚抗原、α胎蛋白、CA-125、MUC-1、CD56、EGFR、c-Met、AKT、Her2、Her3、上皮腫瘤抗原、黑素瘤相關抗原、突變p53、突變ras,諸如此類。在某些實施例中,當存在低量之腫瘤相關抗原時,CAR可與細胞介素共表現以改良持久性。舉例而言,CAR可與IL-15共表現。
編碼嵌合受體之開放閱讀框架之序列可獲自基因組DNA來源、cDNA來源或可合成(例如經由PCR),或其組合。取決於基因組DNA之尺寸及內含子之數目,可能需要使用cDNA或其組合,因為發現內含子使mRNA穩定。另外,可進一步有利地使用內源性或外源性非編碼區來使mRNA穩定。
預期嵌合構築體可以裸DNA形式或在適合之載體中引入至免疫細胞中。使用裸DNA藉由電穿孔穩定轉染細胞之方法為此項技術中已知的。裸DNA一般係指編碼嵌合受體之DNA,該嵌合受體以對於表現恰當之定向包含於質體表現載體中。
或者,病毒載體(例如反轉錄病毒載體、腺病毒載體、腺相關病毒載體或慢病毒載體)可用於將嵌合構築體引入至免疫細胞中。根據本發明方法使用之適合之載體在免疫細胞中為非複製的。已知大量載體係基於病毒,其中維持於細胞中之病毒的複本數足夠低以維持細胞活力,諸如基於HIV、SV40、EBV、HSV或BPV之載體。
在一些態樣中,抗原特異性結合或識別組分連接至一或多個跨膜及細胞內信號傳導域。在一些實施例中,CAR包括融合至CAR之細胞外域之跨膜域。在一個實施例中,使用與CAR中之一個域天然相關之跨膜域。在一些情況下,跨膜域可經選擇或藉由胺基酸取代修飾以避免此類域結合至相同或不同表面膜蛋白質之跨膜域,以使與受體複合物之其他成員的相互作用降至最低。
在一些實施例中,跨膜域來源於天然或合成來源。在天然來源的情況下,在一些態樣中,域來源於任何膜結合蛋白或跨膜蛋白。跨膜區包括衍生自以下各者之彼等跨膜區(亦即包含至少以下各者之一或多個跨膜區):T細胞受體之α鏈、β鏈或ζ鏈、CD28、CD3 ζ、CD3 ε、CD3 γ、CD3 δ、CD45、CD4、CD5、CD8、CD9、CD 16、CD22、CD33、CD37、CD64、CD80、CD86、CD 134、CD137、CD154、ICOS/CD278、GITR/CD357、NKG2D及DAP分子。或者,在一些實施例中,跨膜域為合成的。在一些態樣中,合成性跨膜域主要包含疏水性殘基,諸如白胺酸及纈胺酸。在一些態樣中,將在合成性跨膜域之各端處發現苯丙胺酸、色胺酸及纈胺酸之三聯體。
在某些實施例中,用於遺傳修飾免疫細胞,諸如NK細胞之本文揭示之平台技術包含(i)使用電穿孔裝置(例如核轉染儀)之非病毒基因轉移,(ii)經由胞內域(例如CD28/CD3-ζ、CD137/CD3-ζ或其他組合)傳導信號之CAR,(iii)具有連接抗原識別結構域與細胞表面之胞外域之可變長度的CAR,及在一些情況下,(iv)能夠穩健地且在數值上擴增CAR+
免疫細胞之衍生自K562之人工抗原呈遞細胞(aAPC)(Singh等人, 2008;Singh等人, 2011)。
在一些實施例中,CAR可在細胞中反轉錄轉導。反轉錄病毒載體可為pSFG4載體。反轉錄病毒轉移載體pSFG4包含基於pUC19質體之主鏈(HindIII與EcoRI限制酶位點之間的大片段[2.63kb]),其攜載來自莫洛尼鼠類白血病病毒(Moloney Murine Leukemia Virus;MoMLV)之病毒組分,包括5' LTR、psi包裝序列及3' LTR。LTR為發現於反轉錄病毒原病毒之任一側上之長末端重複序列,且在轉移載體之情況下,囊括所關注之遺傳貨物(在吾人之案例中主要為CAR及相關遺傳組分)。psi包裝序列(其為藉由核衣殼包裝之目標位點)亦以順式併入,包夾於5' LTR與CAR編碼序列之間。因此,pSFG4轉移載體之基本結構可如此概述:pUC19序列-5' LTR-psi包裝序列-所關注之遺傳貨物-3' LTR-pUC19序列。D. 抗原呈遞細胞
抗原呈現細胞包括巨噬細胞、B淋巴球及樹突狀細胞,其藉由其特定MHC分子之表現區分。APC內化抗原且與其外部細胞膜上之MHC分子一起再表現彼抗原之部分。主要組織相容複合體(MHC)係具有多個基因座之大基因複合物。MHC基因座編碼兩個主要類別之MHC膜分子,稱為I類及II類。T輔助淋巴球一般識別與MHC II類分子關聯之抗原,且T細胞毒性淋巴球識別與MHC I類分子關聯之抗原。在人類中,MHC稱為HLA複合物且在小鼠中稱為H-2複合物。
aAPC系統可包含至少一種外源性輔助分子。可採用任何適合之輔助分子之數目及組合。輔助分子可選自諸如共刺激分子及黏附分子之輔助分子。例示性共刺激分子包括CD86、CD64 (FcγRI)、41BB配位體及IL-21。黏附分子可包括諸如選擇素之碳水化合物結合糖蛋白、諸如整合素之跨膜結合糖蛋白、諸如鈣黏素之鈣依賴性蛋白,及諸如細胞間黏附分子(ICAM)之單程跨膜免疫球蛋白(Ig)總科蛋白,其促進例如單元至單元或細胞至基質接觸。例示性黏附分子包括LFA-3及ICAM,諸如ICAM-1。適用於選擇、選殖、製備及表現例示性輔助分子,包括共刺激分子及黏附分子之技術、方法及試劑。IV. 使用方法
在一些實施例中,本發明提供用於免疫療法之方法,其包含投與有效量的表現本發明之CAR (例如具有Ev3鉸鏈及/或人類化scFv之CAR)之免疫細胞。在一個實施例中,係藉由轉遞(transfer)會引發免疫反應之免疫細胞群體來治療醫學疾病或病症。在本發明之某些實施例中,係藉由轉遞會引發免疫反應之免疫細胞群體來治療癌症或感染。本文提供治療或延遲個體中癌症進展之方法,其包含向個體投與有效量的抗原特異性細胞療法。本發明方法可適用於治療免疫病症、實體癌症、血液癌及病毒感染。
在特定實施例中,提供藉由投與表現本文提供之CAR之免疫細胞(諸如NK細胞及/或T細胞)治療癌症患者之方法,本文提供之CAR具有對由該癌症表現之抗原具有特異性之抗原結合域。舉例而言,患有慢性淋巴細胞性白血病(CLL)、B細胞急性淋巴母細胞白血病(ALL)或非霍奇金淋巴瘤(NHL)之受試者可用CD19-Ev3-CAR免疫細胞治療以消融CD19陽性細胞,諸如癌症幹細胞。在其他態樣中,受試者患有急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、骨髓發育不良症候群(MDS)或漿細胞樣樹突狀細胞白血病(PDCL)且用CD123-Ev3-CAR免疫細胞治療。在其他態樣中,受試者患有T細胞白血病及淋巴瘤且用CD5-Ev3-CAR免疫細胞治療。患有CLL、乳癌、胰臟癌或肺癌之受試者可用ROR1-Ev3-CAR免疫細胞治療。患有子宮頸癌、子宮內膜癌或卵巢癌之患者可用Meso-Ev3-CAR免疫細胞治療。
患有多發性骨髓瘤(MM)或其他表現CD319之癌症的受試者可用CD319-CAR免疫細胞治療。在一些態樣中,患有澱粉樣變性病之患者係藉由消融CD319陽性細胞(諸如癌症幹細胞)來治療。在一些態樣中,患有意義不明的單株球蛋白症(monoclonal gammopathy of unknown significance;MGUS)或和緩性骨髓瘤之患者係用CD319-CAR免疫細胞治療。在諸如類風濕性關節炎、SLE或自體免疫溶血性貧血之自體免疫病症中具有CD319陽性細胞之受試者可藉由本發明實施例之免疫細胞治療。在特定態樣中,CD319表現癌係藉由投與表現Ev3-CAR之免疫細胞治療,該Ev3-CAR具有CD319 scFv、CD3ζ、DAP12及IL-15。
在一些實施例中,包含本文提供之Ev3 CAR之細胞可藉由抗EGFR抗體消融及/或偵測。例示性抗EGFR抗體包括(但不限於)西妥昔單抗(艾必妥(Erbitux))及帕尼單抗(維必施(vectibix))以及生物仿製藥。此等抗體均已由FDA批准用於治療結腸直腸癌。在一些實施例中,偵測表現Ev3-CAR之細胞包含投與具有可偵測標籤之抗EGFR抗體。在其他態樣中,表現Ev3-CAR之細胞之消融包含投與誘導ADCC之抗EGFR抗體。在一些態樣中,抗EGFR抗體可融合至前藥或細胞毒性劑,諸如毒素。
本發明治療方法適用之腫瘤包括任何惡性細胞類型,諸如發現於實體腫瘤或血液腫瘤中之彼等。例示性實體腫瘤可包括(但不限於)選自由以下組成之群的器官之腫瘤:胰臟、結腸、盲腸、胃、大腦、頭部、頸部、卵巢、腎、喉、肉瘤、肺、膀胱、前列腺及乳房。例示性血液腫瘤包括骨髓腫瘤、T細胞或B細胞惡性腫瘤、白血病、淋巴瘤、母細胞瘤、骨髓瘤及其類似物。可使用本文所提供之方法治療之癌症的其他實例包括(但不限於)肺癌(包括小細胞肺癌、非小細胞肺癌、肺腺癌及肺鱗狀癌)、腹膜癌、胃癌(包括胃腸癌及胃腸道間質腫瘤)、胰臟癌、子宮頸癌、卵巢癌、肝癌、膀胱癌、乳癌、結腸癌、結腸直腸癌、子宮內膜癌或子宮癌、唾液腺癌、腎癌、前列腺癌、外陰癌、甲狀腺癌、各種類型之頭頸癌及黑素瘤。
癌症可特定為以下組織學類型,儘管其不限於此等:惡性贅瘤;癌瘤;未分化癌瘤;巨細胞及梭形細胞癌;小細胞癌;乳頭狀癌;鱗狀細胞癌;淋巴上皮癌;基底細胞癌;毛母質癌;轉移細胞癌;乳頭狀轉移細胞癌;腺癌;惡性胃泌素瘤;膽管癌;肝細胞癌;組合之肝細胞癌及膽管癌;小梁腺癌;腺樣囊性癌症;腺瘤息肉中之腺癌;家族性結腸息肉病腺癌;實體癌瘤;惡性類癌;細支氣管肺泡腺癌;乳頭狀腺癌;嫌色細胞癌;嗜酸性癌;嗜氧性腺癌;嗜鹼性癌瘤;透明細胞腺癌;粒狀細胞癌;濾泡腺癌;乳頭狀及濾泡腺癌;無包膜硬化性癌;腎上腺皮質癌;子宮內膜樣癌;皮膚附屬器癌;頂泌腺癌;皮脂腺癌;耵聹腺癌;黏液表皮樣癌瘤;囊腺癌;乳頭狀囊腺癌;乳頭狀的漿液性囊腺癌;黏液性囊腺癌;黏液性腺癌;戒環細胞癌;浸潤性導管癌;髓樣癌;小葉癌;炎性癌;乳房佩吉特氏病(paget's disease);腺泡細胞癌;腺鱗癌;腺癌伴鱗狀化生;惡性胸腺瘤;惡性卵巢間質腫瘤;惡性泡膜細胞瘤;惡性粒層細胞瘤;惡性睾丸母細胞瘤;塞特利氏(sertoli)細胞癌;惡性雷迪格細胞瘤;惡性脂質細胞瘤;惡性副神經節瘤;惡性乳腺外副神經節瘤;嗜鉻細胞瘤;血管球肉瘤;惡性黑素瘤;無黑色素性黑素瘤;淺表擴散性黑素瘤;雀斑惡性黑素瘤;肢端雀斑狀黑素瘤;結節性黑素瘤;巨大色素痣內惡性黑素瘤;上皮狀細胞黑素瘤;惡性藍痣;肉瘤;纖維肉瘤;惡性纖維性組織細胞瘤;黏液肉瘤;脂肉瘤;平滑肌肉瘤;橫紋肌肉瘤;胚胎性橫紋肌肉瘤;肺泡橫紋肌肉瘤;基質肉瘤;惡性混合瘤;苗勒混合瘤;腎胚細胞瘤;肝母細胞瘤;癌肉瘤;惡性間葉瘤;惡性布倫納氏瘤(brenner tumor);惡性葉狀腫瘤;滑膜肉瘤;惡性間皮瘤;無性細胞瘤;胚胎性癌;惡性畸胎瘤;惡性卵巢甲狀腺瘤;絨毛膜癌;惡性中腎瘤;血管肉瘤;惡性血管內皮瘤;卡波西氏肉瘤(kaposi's sarcoma);惡性血管外皮瘤;淋巴管肉瘤;骨肉瘤;皮質旁骨肉瘤;軟骨肉瘤;惡性軟骨母細胞瘤;間充質軟骨肉瘤;骨巨細胞瘤;尤文氏肉瘤(ewing's sarcoma);惡性牙源性腫瘤;成釉細胞牙肉瘤;惡性成釉細胞瘤;成釉細胞纖維肉瘤;惡性松果體瘤;脊索瘤;惡性神經膠質瘤;室管膜瘤;星形細胞瘤;原生質星形細胞瘤;纖維型星形細胞瘤;星形母細胞瘤;神經膠母細胞瘤;少突神經膠質瘤;成少突神經膠質細胞瘤;原始神經外胚層;小腦肉瘤;成神經節細胞瘤;成神經細胞瘤;視網膜母細胞瘤;嗅覺神經性腫瘤;惡性腦膜瘤;神經纖維肉瘤;惡性神經鞘瘤;惡性粒狀細胞瘤;惡性淋巴瘤;霍奇金氏病(hodgkin's disease);霍奇金氏;類肉芽腫;小淋巴細胞性惡性淋巴瘤;大細胞彌漫性惡性淋巴瘤;濾泡性惡性淋巴瘤;蕈樣黴菌病;其他指定非霍奇金氏淋巴瘤;B細胞淋巴瘤;低級/濾泡性非霍奇金氏淋巴瘤(NHL);小淋巴細胞性(SL)NHL;中級/濾泡性NHL;中級彌漫性NHL;高級免疫母細胞性NHL;高級淋巴母細胞性NHL;高級小非裂解細胞NHL;巨大腫塊NHL;套細胞淋巴瘤;AIDS相關淋巴瘤;瓦爾登斯特倫氏巨球蛋白血症(Waldenstrom's macroglobulinemia);惡性組織細胞增多病;多發性骨髓瘤;肥大細胞肉瘤;免疫增殖性小腸疾病;白血病;淋巴白血病;漿細胞白血病;紅白血病;淋巴肉瘤細胞白血病;骨髓白血病;嗜鹼性白血病;嗜伊紅血球白血病;單核球性白血病;肥大細胞白血病;巨核母細胞白血病;骨髓肉瘤;毛細胞白血病;慢性淋巴細胞性白血病(CLL);急性淋巴母細胞白血病(ALL);急性骨髓性白血病(AML);及慢性骨髓母細胞白血病。
特定實施例關注白血病治療方法。白血病為血液或骨髓癌症且特徵在於血細胞、通常白血細胞(白血球)之異常增殖(增殖產生)。其為稱作血液贅瘤之廣泛疾病組的一部分。白血病為廣義術語,涵蓋一系列疾病。白血病在臨床上及病理上分成其急性及慢性形式。
在本發明之某些實施例中,免疫細胞遞送至有需要之個人,諸如患有癌症或感染之個體。細胞接著增強個體之免疫系統以攻擊各別癌症或病原細胞。在一些情況下,個體提供有一或多個劑量之免疫細胞。在個體提供有兩個或超過兩個劑量之免疫細胞的情況下,投與之間的持續時間應足以允許在個體中傳播之時間,且在特定實施例中,劑量之間的持續時間為1、2、3、4、5、6、7天或更多天。
本發明之某些實施例提供治療或預防免疫介導之病症之方法。在一個實施例中,受試者患有自體免疫疾病。自體免疫疾病之非限制性實例包括:斑禿、僵直性脊椎炎、抗磷脂症候群、自體免疫性艾迪森氏病(Addison's disease)、腎上腺之自體免疫疾病、自體免疫性溶血性貧血、自體免疫性肝炎、自體免疫性卵巢炎及睾丸炎、自體免疫性血小板減少症、白塞氏病(Behcet's disease)、大皰性類天疱瘡、心肌病、口炎性腹瀉-皮炎、慢性疲勞免疫功能障礙症候群(CFIDS)、慢性發炎性脫髓鞘性多發性神經病、徹奇-斯全司症候群(Churg-Strauss syndrome)、瘢痕性類天疱瘡、CREST症候群、冷凝集素病、克羅恩氏病(Crohn's disease)、盤狀狼瘡、特發性混合型冷球蛋白血症、纖維肌痛-纖維肌炎、絲球體腎炎、格雷夫斯氏病(Graves' disease)、格林-巴利(Guillain-Barre)、橋本氏甲狀腺炎(Hashimoto's thyroiditis)、特發性肺部纖維化、特發性血小板減少性紫癜(ITP)、IgA神經病變、幼年期關節炎、扁平苔癬、紅斑狼瘡、梅尼爾氏病(Meniere's disease)、混合性結締組織病、多發性硬化症、1型或免疫介導糖尿病、重症肌無力、腎病症候群(諸如微小病變疾病、局灶性腎小球硬化或膜性腎病)、尋常天疱瘡、惡性貧血、結節性多動脈炎、多軟骨炎、多腺症候群、風濕性多肌痛、多發性肌炎及皮肌炎、原發性無γ球蛋白血症、原發性膽汁性肝硬化、牛皮癬、牛皮癬性關節炎、雷諾氏現象(Raynauld's phenomenon)、萊特氏症候群(Reiter's syndrome)、類風濕性關節炎、類肉瘤病、硬皮病、休格連氏症候群(Sjogren's syndrome)、僵人症候群、全身性紅斑性狼瘡症、紅斑狼瘡、潰瘍性結腸炎、葡萄膜炎、血管炎(諸如結節性多動脈炎、高安氏動脈炎(takayasu arteritis)、顳動脈炎/巨細胞動脈炎或疱疹樣皮炎血管炎)、白斑病及韋格納氏肉芽腫病(Wegener's granulomatosis)。因此,可使用本文所揭示之方法治療之自體免疫疾病之一些實例包括(但不限於)多發性硬化症、類風濕性關節炎、全身性紅斑狼瘡、I型糖尿病、克羅恩氏病、潰瘍性結腸炎、重症肌無力、絲球體腎炎、僵直性脊椎炎、血管炎或牛皮癬。受試者亦可具有過敏性病症,諸如哮喘。
在另一實施例中,受試者為移植器官之受體或幹細胞及免疫細胞用來預防及/或治療排斥反應。在特定實施例中,受試者患有移植物抗宿主疾病或處於罹患移植物抗宿主疾病之風險下。GVHD為使用或含有來自相關或無關供體之幹細胞之任何移植體的可能併發症。存在兩種類型之GVHD,急性及慢性。急性GVHD在移植後前三個月內出現。急性GVHD之病徵包括手部及足部上之微紅皮疹,其可擴散且變得更嚴重,伴以脫皮或皮膚起皰。急性GVHD亦可影響胃及腸,在此情況下存在痙攣、噁心及腹瀉。皮膚及眼睛發黃(黃疸)指示急性GVHD已影響肝臟。慢性GVHD係基於其嚴重度分級:階段/級別1為輕度;階段/級別4為嚴重。慢性GVHD在移植後三個月或更晚產生。慢性GVHD之症狀與急性GVHD之症狀類似,但另外,慢性GVHD亦可影響眼睛中之黏液腺、口腔中之唾液腺及潤滑胃黏膜及腸之腺體。可利用本文揭示之免疫細胞群體中之任一者。移植器官之實例包括實體器官移植體,諸如腎、肝、皮膚、胰臟、肺及/或心臟,或細胞移植體,諸如胰島、肝細胞、肌母細胞、骨髓或造血或其他幹細胞。移植體可為複合移植體,諸如面部組織。免疫細胞可在移植之前、與移植同時或在移植之後投與。在一些實施例中,免疫細胞在移植之前,諸如在移植之前至少1小時、至少12小時、至少1天、至少2天、至少3天、至少4天、至少5天、至少6天、至少1週、至少2週、至少3週、至少4週或至少1個月投與。在一個特定非限制性實例中,投與治療有效量之免疫細胞在移植之前3-5天進行。
在一些實施例中,可在免疫細胞療法之前向受試者投與非清髓性淋巴細胞耗盡化學療法。非清髓性淋巴細胞耗盡化學療法可為任何適合之此類療法,其可藉由任何適合之途徑投與。非清髓性淋巴細胞耗盡化學療法包含例如投與環磷醯胺及氟達拉賓,尤其若癌症係為轉移性之黑素瘤時。投與環磷醯胺及氟達拉賓之例示性途徑係靜脈內。同樣地,可投與任何適合劑量之環磷醯胺及氟達拉賓。在特定態樣中,持續兩天投與約60 mg/kg環磷醯胺,其後持續五天投與約25 mg/m2
氟達拉賓。
在某些實施例中,與免疫細胞同時或在免疫細胞之後向受試者投與促進免疫細胞生長及活化之生長因子。免疫細胞生長因子可為促進免疫細胞生長及活化之任何適合之生長因子。適合之免疫細胞生長因子之實例包括介白素(IL)-2、IL-7、IL-15及IL-12,其可單獨或以各種組合使用,諸如IL-2及IL-7;IL-2及IL-15;IL-7及IL-15;IL-2、IL-7及IL-15;IL-12及IL-7;IL-12及IL-15;或IL-12及IL2。
治療有效量之免疫細胞可藉由多種途徑投與,包括非經腸投藥,例如靜脈內、腹膜內、肌肉內、胸骨內或關節內注射或輸注。
用於授受細胞療法之免疫細胞之治療有效量為在治療之受試者中實現所需效應之該量。舉例而言,此可為抑制自體免疫或同種免疫疾病進展,或使其消退必需之免疫細胞之量,或其能夠緩解由自體免疫疾病引起之症狀,諸如疼痛及發炎。其可為緩解與發炎相關之症狀,諸如疼痛、水腫及高溫必需之量。其亦可為減輕或預防移植器官之排斥反應必需之量。
免疫細胞群體可以與疾病一致之治療方案投與,例如經一天至數天之單一劑量或若干劑量,以經延長時間改善疾病狀態或週期劑量,以抑制疾病進展及預防疾病復發。待用於調配物中之精確劑量亦將視投藥途徑及疾病或病症之嚴重性而定,且應根據醫師之判斷及各患者之情況來決定。免疫細胞之治療有效量將依賴於治療之受試者、病痛之嚴重度及類型以及投與方式。在一些實施例中,人類受試者治療中可使用之劑量在至少3.8×104
、至少3.8×105
、至少3.8×106
、至少3.8×107
、至少3.8×108
、至少3.8×109
或至少3.8×1010
個免疫細胞/m2
範圍內。在某一實施例中,用於人類受試者治療之劑量在約3.8×109
至約3.8×1010
個免疫細胞/m2
範圍內。在額外實施例中,免疫細胞之治療有效量可在每公斤體重約5×106
個細胞至每公斤體重約7.5×108
個細胞,諸如每公斤體重約2×107
個細胞至約5×108
個細胞,或每公斤體重約5×107
個細胞至約2×108
個細胞範圍內變化。免疫細胞之準確量易於由熟習此項技術者基於受試者之年齡、體重、性別及生理條件而確定。有效劑量可自來源於活體外或動物模型測試系統之劑量反應曲線外推得到。
免疫細胞可與一或多種其他治療劑組合投與以治療免疫介導之病症。組合療法可包括(但不限於)一或多種抗微生物劑(例如抗生素、抗病毒劑及抗真菌劑)、抗腫瘤劑(例如氟尿嘧啶、甲胺喋呤、太平洋紫杉醇、氟達拉賓(fludarabine)、依託泊苷(etoposide)、小紅莓或長春新鹼)、免疫耗乏劑(例如氟達拉賓、依託泊苷、小紅莓或長春新鹼)、免疫抑制劑(例如硫唑嘌呤或糖皮質激素,諸如地塞米松(dexamethasone)或強的松(prednisone))、消炎劑(例如糖皮質激素,諸如氫皮質酮、地塞米松或強的松,或非類固醇消炎劑,諸如乙醯水楊酸、布洛芬(ibuprofen)或萘普生鈉)、細胞介素(例如介白素-10或轉化生長因子-β)、激素(例如雌激素)或疫苗。另外,可投與免疫抑制劑或耐受劑,包括(但不限於)鈣調神經磷酸酶抑制劑(例如環孢素及他克莫司(tacrolimus));mTOR抑制劑(例如雷帕黴素(Rapamycin));黴酚酸嗎啉乙酯抗體(例如識別CD3、CD4、CD40、CD154、CD45、IVIG或B細胞);化學治療劑(例如甲胺喋呤、曲奧舒凡(Treosulfan)、白消安);照射;或趨化因子、介白素或其抑制劑(例如BAFF、IL-2、抗IL-2R、IL-4、JAK激酶抑制劑)。此類其他藥劑可取決於所需效應而在投與免疫細胞之前、期間或之後投與。細胞及藥劑之此投與可藉由相同途徑或藉由不同途徑,且在相同位點或在不同位點。B. 醫藥組合物
本文亦提供包含免疫細胞(例如T細胞或NK細胞)及醫藥學上可接受之載劑之醫藥組合物及調配物。
如本文所述之醫藥組合物及調配物可藉由以下製備:混合具有所需純度之活性成分(諸如抗體或多肽)與一或多種視情況選用之醫藥學上可接受之載劑(Remington's Pharmaceutical Sciences 第22版, 2012),呈凍乾調配物或水溶液形式。醫藥學上可接受之載劑在採用之劑量及濃度下一般對受體無毒性,且包括(但不限於):緩衝劑,諸如磷酸鹽、檸檬酸鹽及其他有機酸;抗氧化劑,包括抗壞血酸及甲硫胺酸;防腐劑(諸如十八烷基二甲基苯甲基氯化銨;氯化六羥季銨;苯紮氯銨;苄索氯銨;丁基苯酚或苯甲醇;對羥基苯甲酸烷基酯,諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯;兒茶酚;間苯二酚;環己醇;3-戊醇;及間甲酚);低分子量(小於約10個殘基)多肽;蛋白質,諸如血清白蛋白、明膠或免疫球蛋白;親水性聚合物,諸如聚乙烯吡咯啶酮;胺基酸,諸如甘胺酸、麩醯胺酸、天冬醯胺、組胺酸、精胺酸或離胺酸;單醣、雙醣及其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合劑,諸如EDTA;糖,諸如蔗糖、甘露醇、海藻糖或山梨醇;成鹽抗衡離子,諸如鈉;金屬錯合物(例如Zn-蛋白質錯合物);及/或非離子界面活性劑,諸如聚乙二醇(PEG)。C. 組合療法
在某些實施例中,本發明實施例之組合物及方法涉及與至少一種其他療法組合之免疫細胞群體。其他療法可為輻射療法、手術(例如乳房腫瘤切除術及乳房切除術)、化學療法、基因療法、DNA療法、病毒療法、RNA療法、免疫療法、骨髓移植、奈米療法、單株抗體療法或前述各者之組合。其他療法可呈輔助或新輔助療法形式。
在一些實施例中,其他療法為投與小分子酶抑制劑或抗轉移性藥劑。在一些實施例中,其他療法為投與副作用限制劑(例如意欲減少治療之副作用出現及/或嚴重程度的藥劑,諸如抗噁心劑等)。在一些實施例中,其他療法為放射療法。在一些實施例中,其他療法為手術。在一些實施例中,其他療法為輻射療法與手術之組合。在一些實施例中,其他療法為γ輻射。在一些實施例中,其他療法係靶向PBK/AKT/mTOR路徑、HSP90抑制劑、微管蛋白抑制劑、細胞凋亡抑制劑及/或化學預防劑之療法。其他療法可為此項技術中已知之化學治療劑中之一或多者。
免疫細胞療法相對於其他癌症療法,諸如免疫檢查點療法可在其之前、期間、之後或以各種組合投與。投藥可呈在同時至數分鐘至數天至數週範圍內之間隔。在其中免疫細胞療法與另一種治療劑分別提供於患者之實施例中,一般將保證在每一次遞送之時間段之間未停用大量時間,使得兩種化合物將仍能夠對患者發揮有利的組合效果。在此類情況下,預期吾人可向患者提供彼此在約12至24或72 h內,且更特定言之,彼此在約6-12 h內之抗體療法及抗癌療法。在某些情況下,可能需要延長時段以進行顯著治療,其中在各別投藥之間會流逝若干天(2、3、4、5、6或7)至若干週(1、2、3、4、5、6、7或8)。
可採用各種組合。對於以下實例,CAR免疫細胞療法為「A」且抗癌療法為「B」:
向患者投與本發明實施例之任何化合物或療法將遵循用於投與此類化合物之一般方案,考慮試劑之毒性(若存在)。因此,在一些實施例中,存在監測由於組合療法而引起之毒性。1. 化學療法
各種化學治療劑可用於本發明實施例。術語「化學療法」指代使用藥物治療癌症。「化學治療劑」用於意味著在治療癌症中投與之化合物或組合物。此等藥劑或藥物藉由其在細胞內之活性模式分類,例如其是否且在哪一階段影響細胞週期。或者,一種藥劑可基於其直接與DNA交聯、嵌入DNA中或藉由影響核酸合成來誘導染色體及有絲分裂失常之能力表徵。
化學治療劑之實例包括烷基化劑,諸如噻替派及環磷醯胺;烷基磺酸酯,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、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甲基三聚氰胺;多聚乙醯(尤其布拉他辛(bullatacin)及布拉他辛酮(bullatacinone));喜樹鹼(包括合成模擬拓朴替康(topotecan));苔蘚蟲素;海洋抑素;CC-1065 (包括其阿多來新(adozelesin)、卡折來新(carzelesin)及比折來新(bizelesin)合成類似物);隱藻素(尤其克瑞托欣1 (cryptophycin 1)及克瑞托欣8 (cryptophycin8));海兔毒素;倍癌黴素(包括合成類似物,KW-2189及CB1 TM1);艾榴塞洛素(eleutherobin);盤克斯塔叮(pancratistatin);匍枝珊瑚醇;海綿抑素;氮芥,諸如氯芥苯丁酸、萘氮芥、氯磷醯胺、雌氮芥、異環磷醯胺、氮芥、氮芥氧化物氫氯化物、美法侖、新氮芥、苯芥膽甾醇、潑尼氮芥(prednimustine)、曲磷胺及尿嘧啶氮芥;亞硝基脲,諸如卡莫司汀(carmustine)、氯脲菌素、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)及雷莫司汀(ranimnustine);抗生素,諸如烯二炔抗生素(例如卡奇黴素(calicheamicin),尤其卡奇黴素γII及卡奇黴素φI1);達米辛(dynemicin),包括達米辛A;雙膦酸鹽,諸如氯屈膦酸鹽;埃斯培拉黴素(esperamicin);以及新抑癌蛋白發色團及相關色蛋白烯二炔抗生素發色團、阿克拉黴素(aclacinomysins)、放射菌素、奧納黴素(authrarnycin)、偶氮絲胺酸、博萊黴素(bleomycins)、放線菌素C、卡拉比辛(carabicin)、洋紅黴素、嗜癌菌素、色黴素、放線菌素d、道諾黴素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-側氧基-L-正白胺酸、小紅莓(包括嗎啉基-小紅莓、氰基-N-嗎啉基-小紅莓、2-吡咯啉基-小紅莓及去氧小紅莓)、表柔比星(epirubicin)、依索比星(esorubicin)、艾達黴素(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(諸如絲裂黴素C)、黴酚酸、諾加黴素(nogalarnycin)、橄欖黴素、培洛黴素(peplomycin)、潑非黴素(potfiromycin)、嘌呤黴素、奎那黴素(奎那黴素)、羅多比星(rodorubicin)、鏈黑菌素、鏈脲菌素、殺結核菌素、烏苯美司(ubenimex)、淨司他丁(zinostatin)及左柔比星(zorubicin);抗代謝物,諸如甲胺喋呤及5-氟尿嘧啶(5-FU);葉酸類似物,諸如迪諾特寧(denopterin)、蝶羅呤及曲美沙特(trimetrexate);嘌呤類似物,諸如氟達拉賓、6-巰基嘌呤、硫咪嘌呤及硫鳥嘌呤;嘧啶類似物,諸如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷、雙去氧尿苷、去氧氟尿苷、依諾他濱(enocitabine)及氟尿苷;雄激素,諸如卡魯睾酮、屈他雄酮丙酸酯、環硫雄醇、美雄烷及睾內酯;抗腎上腺素,諸如米托坦(mitotane)及曲洛司坦(trilostane);葉酸補充劑,諸如亞葉酸;醋葡醛內酯;醛磷醯胺糖苷;胺基乙醯丙酸;恩尿嘧啶;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;艾福米辛(elformithine);依利醋銨;埃坡黴素;依託格魯(etoglucid);硝酸鎵;羥基尿素;磨菇多糖;氯尼達明(lonidainine);類美登素(maytansinoids),諸如美登素(maytansine)及安絲菌素;丙脒腙;米托蒽醌(mitoxantrone);莫比達摩(mopidanmol);二胺硝吖啶;噴司他丁(pentostatin);苯來美特(phenamet);吡柔比星(pirarubicin);洛索蒽醌;鬼臼酸;2-乙基醯肼;丙卡巴肼;PSK多糖複合物;雷佐生(razoxane);根瘤菌素;西索菲蘭(sizofiran);螺旋鍺;細交鏈孢菌酮酸;三亞胺醌;2,2',2''-三氯三乙胺;單端孢黴烯(尤其T-2毒素、弗納庫林A (verracurin A)、桿孢菌素A及胺癸叮);尿烷;長春地辛;達卡巴嗪(dacarbazine);甘露醇氮芥;二溴甘露醇;二溴衛矛醇;哌泊溴烷;加西托星(gacytosine);阿拉伯糖苷(arabinoside)(「Ara-C」);環磷醯胺;類紫杉醇,例如太平洋紫杉醇及多西他賽吉西他濱;6-硫代鳥嘌呤;巰基嘌呤;鉑協調複合物,諸如順鉑、奧沙利鉑(oxaliplatin)及卡鉑;長春鹼;鉑;依託泊苷(VP-16);異環磷醯胺;米托蒽醌;長春新鹼;長春瑞濱(vinorelbine);米托蒽醌;替尼泊甙(teniposide);依達曲沙(edatrexate);柔紅黴素;胺基喋呤;希羅達(xeloda);伊班膦酸鹽;伊立替康(irinotecan)(例如CPT-11);拓樸異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(DMFO);類視黃素,諸如視黃酸;卡培他濱(capecitabine);卡鉑、丙卡巴肼、光輝黴素、吉西他濱(gemcitabien)、溫諾平(navelbine)、法呢基-蛋白質轉移酶抑制劑、反鉑及以上各者中之任一者的醫藥學上可接受之鹽、酸或衍生物。2. 放射線療法
造成DNA破壞且已廣泛使用之其他因素包括通常稱為γ-射線、X射線及/或將放射性同位素定向遞送至腫瘤細胞之彼等。亦涵蓋其他形式之DNA破壞因子,諸如微波、質子束照射及UV照射。最可能之情形為,所有此等因素對DNA、DNA之前驅物、DNA之複製及修復,及染色體之組裝及維持造成多種破壞。X射線之劑量範圍在延長之時間段(3至4週)期間50至200倫琴日劑量至2000至6000倫琴之單次劑量範圍內。放射性同位素之劑量範圍變化極大,且視同位素之半衰期、所發出之輻射強度及類型,及贅生性細胞之吸收情況而定。3. 免疫療法
熟練技術人員應瞭解,其他免疫療法可與實施例之方法或結合。在癌症治療之情形下,免疫治療劑一般依賴於使用免疫效應細胞及分子靶向及摧毀癌細胞。利妥昔單抗(Rituximab)(RITUXAN®)為此類實例。免疫效應子可為例如對腫瘤細胞表面上之一些標記物具有特異性之抗體。單獨的抗體可充當療法之效應子或其可募集其他細胞以實際上影響細胞殺滅。抗體亦可與藥物或毒素(化學治療劑、放射性核種、蓖麻毒素A鏈、霍亂毒素、百日咳毒素等)結合且用作靶向劑。或者,效應子可為攜帶直接或間接與腫瘤細胞標靶相互作用之表面分子的淋巴細胞。各種效應細胞包括細胞毒性T細胞及NK細胞。
抗體-藥物結合物(ADC)包含共價連接至細胞殺死藥物之單株抗體(mAb)且可用於組合療法。此方法組合MAb對其抗原標靶之高特異性與高度有效之細胞毒性藥物,導致將有效負載物(藥物)遞送至具有富集含量之抗原之腫瘤細胞的「武裝」MAb。藥物之靶向遞送亦將其在正常組織中之暴露量減到最少,其導致毒性降低且提高治療指數。例示性ADC藥物包括ADCETRIS® (本妥昔單抗維多汀(brentuximab vedotin))及KADCYLA® (曲妥珠單抗恩他新(trastuzumab emtansine)或T-DM1)。
在免疫療法之一個態樣中,腫瘤細胞必須攜帶一些適合於靶向,亦即大多數其他細胞上不存在之標記物。存在許多腫瘤標記物且此等標記物中之任一者可適用於在本發明實施例之情形下靶向。常見腫瘤標記物包括CD20、癌胚抗原、酪胺酸酶(p97)、gp68、TAG-72、HMFG、Sialyl Lewis抗原、MucA、MucB、PLAP、層黏連蛋白受體、erb B及p155。免疫療法之替代態樣為組合抗癌作用與免疫刺激作用。亦存在免疫刺激分子,包括:細胞介素,諸如IL-2、IL-4、IL-12、GM-CSF、γ-IFN;趨化激素,諸如MIP-1、MCP-1、IL-8及生長因子,諸如FLT3配位體。
免疫療法之實例包括免疫佐劑,例如牛分支桿菌、惡性瘧原蟲、二硝基氯苯及芳族化合物);細胞介素療法,例如干擾素α、β及γ、IL-1、GM-CSF及TNF;基因療法,例如TNF、IL-1、IL-2及p53;及單株抗體,例如抗CD20、抗神經節苷脂GM2及抗p185。預期一或多種抗癌療法可與本文所描述之抗體療法一起使用。
在一些實施例中,免疫療法可為免疫檢查點抑制劑。免疫檢查點增強信號(例如共刺激分子)或減弱信號。可由免疫檢查點阻斷靶向之抑制性免疫檢查點包括腺苷A2A受體(A2AR)、B7-H3 (亦稱為CD276)、B及T淋巴細胞弱化子(BTLA)、細胞毒性T淋巴細胞相關蛋白質4 (CTLA-4,亦稱為CD152)、吲哚胺2,3-二氧酶(IDO)、殺手細胞免疫球蛋白(KIR)、淋巴細胞活化基因-3 (LAG3)、程式化死亡1 (PD-1)、T細胞免疫球蛋白域及黏蛋白域3 (TIM-3)及T細胞活化之V域Ig抑制因子(VISTA)。詳言之,免疫檢查點抑制劑靶向PD-1軸及/或CTLA-4。
免疫檢查點抑制劑可為藥物,諸如小分子、重組形式之配位體或受體,或尤其為抗體,諸如人類抗體。可使用免疫檢查點蛋白或其類似物之已知抑制劑,尤其可使用抗體之嵌合、人類化或人類形式。如熟練人員將知曉,替代及/或等效名稱可用於在本發明中提及之某些抗體。此類替代及/或等效名稱在本案揭示內容之情形下可互換。舉例而言,已知拉立珠單抗(lambrolizumab)亦以替代及等效名稱MK-3475及派立珠單抗(pembrolizumab)已知。
在一些實施例中,PD-1結合拮抗劑為抑制PD-1與其配位體結合搭配物結合之分子。在一特定態樣中,PD-1配位體結合搭配物為PDL1及/或PDL2。在另一實施例中,PDL1結合拮抗劑為抑制PDL1與其結合搭配物結合之分子。在一特定態樣中,PDL1結合搭配物為PD-1及/或B7-1。在另一實施例中,PDL2結合拮抗劑為抑制PDL2與其結合搭配物結合之分子。在一特定態樣中,PDL2結合搭配物為PD-1。拮抗劑可為抗體、其抗原結合片段、免疫黏附素、融合蛋白或寡肽。
在一些實施例中,PD-1結合拮抗劑為抗PD-1抗體(例如人類抗體、人類化抗體或嵌合抗體)。在一些實施例中,抗PD-1抗體選自由納武單抗(nivolumab)、派立珠單抗(pembrolizumab)及CT-011組成之群。在一些實施例中,PD-1結合拮抗劑為免疫黏附素(例如包含融合至恆定區(例如免疫球蛋白序列之Fc區)之PDL1或PDL2之細胞外或PD-1結合部分的免疫黏附素)。在一些實施例中,PD-1結合拮抗劑為AMP-224。納武單抗(亦稱為MDX-1106-04、MDX-1106、ONO-4538、BMS-936558及OPDIVO®
)為可使用之抗PD-1抗體。派立珠單抗(亦稱為MK-3475、Merck 3475、拉立珠單抗、KEYTRUDA®
及SCH-900475)為例示性抗PD-1抗體。CT-011 (亦稱為hBAT或hBAT-1)亦為抗PD-1抗體。AMP-224 (亦稱為B7-DCIg)為PDL2-Fc融合可溶受體。
可在本文中提供之方法中靶向之其他免疫檢查點為細胞毒性T淋巴細胞相關蛋白4 (CTLA-4),亦稱為CD152。人類CTLA-4之完整cDNA序列具有GenBank寄存編號L15006。CTLA-4發現於T細胞之表面上且結合於抗原呈現細胞之表面上之CD80或CD86時充當「閉合」開關。CTLA4係表現於輔助T細胞之表面上之免疫球蛋白總科的成員且將抑制信號傳輸至T細胞。CTLA4類似於T細胞共刺激蛋白質CD28,且兩種分子均結合於抗原呈現細胞上之亦分別稱為B7-1及B7-2的CD80及CD86。CTLA4將抑制信號傳輸至T細胞,而CD28傳輸刺激信號。胞內CTLA4亦發現於調節T細胞中且對其功能可為重要的。經由T細胞受體及CD28之T細胞活化導致B7分子之抑制性受體CTLA-4之表現提高。
在一些實施例中,免疫檢查點抑制劑為抗CTLA-4抗體(例如人類抗體、人類化抗體或嵌合抗體)、其抗原結合片段、免疫黏附素、融合蛋白或寡肽。
適用於本發明方法之抗人類-CTLA-4抗體(或自其衍生之VH及/或VL域)可使用此項技術中熟知之方法產生。或者,可使用此項技術公認之抗CTLA-4抗體。例示性抗CTLA-4抗體為伊匹單抗(ipilimumab)(亦稱為10D1、MDX-010、MDX-101及Yervoy®)或其抗原結合片段及變異體。在其他實施例中,抗體包含伊匹單抗之重鏈及輕鏈CDR或VR。因此,在一個實施例中,抗體包含伊匹單抗之VH區之CDR1、CDR2及CDR3域,及伊匹單抗之VL區之CDR1、CDR2及CDR3域。在另一實施例中,抗體競爭與與上文所提及之抗體相同之CTLA-4上的表位結合及/或結合於與上文所提及之抗體相同之CTLA-4上的表位。在另一實施例中,抗體與上文所提及之抗體具有至少約90%可變區胺基酸序列一致性(例如與伊匹單抗之至少約90%、95%或99%可變區一致性)。4. 手術
約60%患有癌症的人將經歷一些類型之手術,其包括預防性、診斷或分期、治癒性及姑息性手術。治癒性手術包括切除,其中所有或一部分癌症組織經物理移除、切除及/或破壞,且可與其他療法結合使用,諸如本發明實施例之治療、化學療法、放射線療法、激素療法、基因療法、免疫療法及/或替代療法。腫瘤切除係指物理移除腫瘤之至少一部分。除腫瘤切除以外,手術治療包括雷射手術、冷凍手術、電手術及顯微鏡控制手術(莫氏手術(Mohs'surgery))。
在切除一部分或所有癌細胞、組織或腫瘤後,可在體內形成空腔。治療可藉由用額外抗癌療法對該區域灌注、直接注射或局部施用而實現。可例如每1天、2天、3天、4天、5天、6天或7天、或每1週、2週、3週、4週及5週或每1個月、2個月、3個月、4個月、5個月、6個月、7個月、8個月、9個月、10個月、11個月、或12個月重複此類治療。此等治療亦可具有不同劑量。5. 其他藥劑
預期其他試劑可與本發明實施例之某些態樣組合使用以改善治療之治療功效。此等其他試劑包括影響細胞表面受體及GAP連接之上調之試劑、細胞生長抑制劑及分化劑、細胞黏附抑制劑、提高過度增殖細胞對細胞凋亡誘導物之靈敏度之試劑或其他生物試劑。藉由升高GAP連接之數目增加細胞間信號傳導將增加對相鄰過度增殖性細胞群體之抗過度增殖性效應。在其他實施例中,細胞生長抑制劑或分化劑可與本發明實施例之某些態樣組合使用以改善治療之抗過度增殖性功效。涵蓋細胞黏附抑制劑以改善本發明實施例之功效。細胞黏附抑制劑之實例為局部黏著斑激酶(FAK)抑制劑及洛伐他汀(Lovastatin)。另外預期增加過度增殖性細胞對細胞凋亡之敏感度的其他試劑,諸如抗體c225可與本發明實施例之某些態樣組合使用以改善治療功效。V. 製品或套組
本文亦提供包含免疫細胞之製品或套組。製品或套組可進一步包含藥品說明書,該藥品說明書包含使用免疫細胞治療受試者中之癌症或延遲癌症進展或提高具有癌症之受試者之免疫功能的說明。本文中描述之抗原特異性免疫細胞中之任一者可包括於製品或套組中。適合之容器包括例如瓶子、小瓶、袋及注射器。容器可由多種材料形成,諸如玻璃、塑膠(諸如聚氯乙烯或聚烯烴)或金屬合金(諸如不鏽鋼或赫史特合金)。在一些實施例中,容器裝有調配物,及容器上或與容器系連之標籤可指示使用說明。製品或套組可進一步包括自商業及使用者觀點來看所需之其他材料,包括具有使用說明書之其他緩衝劑、稀釋劑、過濾器、針、注射器及封裝插件。在一些實施例中,製品進一步包含一或多種另一藥劑(例如化學治療劑及抗贅生劑)。用於一或多種藥劑之適合容器包括例如瓶、小瓶、袋及注射器。VI. 實例
包括以下實例以表明本發明之較佳實施例。本領域中熟習此項技術者應瞭解,以下實例中所揭示之技術代表本發明人所發現之在本發明實施中起良好作用之技術,且因此可視為構成其較佳實施方式。然而,根據本發明,熟習此項技術者應瞭解,在不背離本發明之精神及範疇的情況下可對所揭示之特定實施例作出許多改變且仍獲得相同或類似結果。實例 1 - 產生 截斷 EGFRvIII ( Ev3 ) CAR
Ev3-CAR經設計,其中Ev3莖充當整合結構以自抗原結合轉導信號,諸如藉由scFv,以及「閉合」開關,意謂其可藉由臨床上可獲得之抗體(諸如西妥昔單抗)識別以消融CAR陽性免疫細胞(圖1A)。Ev3-CAR可進一步包含DAP12信號傳導域且稱為Ev3-DAP12-CAR。描繪Ev3相比於包含胞內域及EGF結合域之EGFR的示意圖顯示於圖2中。
如圖3A至3D中所描繪地產生編碼具有各種抗原結合域之Ev3-CAR或Ev3-DAP12-CAR的反轉錄病毒載體。抗原結合域為衍生自小鼠抗人類抗體之scFv以及人類化scFv。載體包含CD28及CD3ζ信號傳導域及視情況存在之DAP12。載體亦包含自殺基因,誘導性卡斯蛋白酶9。
包括CAR19.Ev3.CD28.CD3ζ、CAR19.Ev3.DAP12.CD3ζ或人類化CAR19.Ev3.CD3ζ之CD19特異性CAR經轉導至NK細胞中(圖4A)。測試CAR-NK細胞殺死CD19+
Raji或K562細胞之功效(圖4B)。觀察到CAR19-Ev3-CD28-DAP12-CARNK細胞具有最高細胞毒性。因此,與DAP12胞內域組合使用CAR之鉸鏈區中之Ev3產生針對靶細胞具高度細胞毒性之CAR。實例 2 - 產生 人類化 CAR
開發平台以產生人類化scFv,用於產生人類化CAR。由於結構限制,一些殘基更多地促進抗原結合,因此3-D建模用於鑑別對產生人類化CAR潛在重要的相互作用。下文詳述之逐步方法可迭代地重複以在先前循環上改良。
本文提供之CAR人類化工作流包含如下文詳述及圖5A中描繪之5個基本過程模組。
模組I包含單株抗體(mAb)序列分析。BLAST程序用於檢索免疫球蛋白(IG)序列以相對於起始查詢,諸如鼠類mAb序列(圖5B)最佳匹配。BLAST可連續(逐個)或並行(分批)地分析核苷酸及胺基酸序列,以及同時針對生殖系基因資料庫,包括管理之序列資料庫進行檢索,因此使獲得最佳匹配變數之機率最大化(V基因。關於參考序列,生殖系可變(V)、多樣性(D)及連接(J)基因之資料庫用於描繪IG V域構架區(FR1-4s)及互補決定區(CDR)。對於各抗體,分析可變域之輕鏈及重鏈,其各自由多個基因編碼,包括基因V、D及J基因。此研究之焦點主要在於V基因以比較在界定區域之情況下的變化,發現各FR及CDR區之邊界及相比於資料庫中之其他IG序列。
由於基因組序列內之個體差異(亦即以每1,000 bp DNA序列1個單核苷酸多形性估計),生殖系IG序列包含數千個異型(亦即基因之對偶基因或型式)(圖6)。產生人類異型之資料庫且用於CAR人類化。
舉例而言,人類化域係使用特定人類異型,藉由CDR移植轉化來自小鼠抗體(純系FMC63)之抗人類CD19結合域VL及VH序列而衍生(圖7A)。CDR區在圖7A中加底線。
構架序列來源係藉由圖7B中示出之BLAST (Altshul等人, 1997)分析來確認。另外,序列同源性及一致性易於定量且概述於圖7C中。作為比較,重新產生之序列相比於先前可用之序列且在胺基酸及核苷酸層級偵測到重大且可易於辨別之差異。
模組II包含3D結構建模。為了鑑別抗原結合之重要殘基,構建3D結構以評估構築體。SWISS-MODEL為用於製造人類化mAb之3維模型的蛋白質結構同源性建模器。從SAbDab (結構抗體資料庫)中取出結構檔案作為同源性建模的模板。作為表徵VL及VH域之CDR區之3D構形的實例,採用同源性建模,其使用具有以下一級胺基酸序列之SWISS-MODEL (Arnold等人,
2006;Benkert等人,
2011)算法:
SWISS-MODEL模板文庫(SMTL版本2017-06-28,PDB發佈2017-06-23)係用BLAST (Altschul等人, 1997)及HHBlits (Remmert等人,
2012)搜尋匹配靶序列hCD19 VL
及hCD19 VH
之進化相關結構。
總體而言,對於hCD19 VL
發現13,535個模板,其中2fgw.1.A顯示最好擬合(圖8A)且用於另外的分析。用BLAST相對於SMTL中所含之一級胺基酸序列搜尋靶序列(hCD19 VL
)。總共發現761個模板。已使用由Remmert等人概述之程序構建初始HHblits特徵曲線,接著相對於NR20進行HHblits之1個迭代。接著相對於SMTL之所有概況搜尋因此獲得之特徵曲線。總共發現12,946個模板。
總體而言,對於hCD19 VH
發現14,631個模板,其中4uv7.1.B顯示最好擬合(圖8A)且用於另外的分析。用BLAST相對於SMTL中所含之一級胺基酸序列搜尋靶序列(hCD19 VL
)。總共發現755個模板。已使用由Remmert等人概述之程序構建初始HHblits特徵曲線,接著相對於NR20進行HHblits之1個迭代。接著相對於SMTL之所有概況搜尋因此獲得之特徵曲線。總共發現13,964個模板。
模板選擇:
對於各鑑別之模板,已自目標-模板比對之特徵預測模板之品質。接著選擇具有最高品質之模板用於建模。
建模:
使用ProMod3.座標基於目標-模板比對構建模型,該等座標在目標與模板之間保守,自模板複製至模型。使用片段文庫重塑插入及缺失。接著重建側鏈。最後,藉由使用力場來使所得模型之幾何結構規則化。倘若用ProMod3環區建模失敗,則用PROMOD-II (Geux等人,
1997)構建替代模型。
模型品質評估 :
已使用QMEAN評分函數(Benkert等人,
2011)評估全局及每殘餘(per-residue)模型品質。為了提高效能,已特定針對SWISS-MODEL訓練個別QMEAN項之權重。
hCD19 VL
及hCD19 VH
之3維模型顯示CDR殘基暴露水相且能夠形成原位旁表面,與其抗原結合特性一致。
模組III包含人類構架移植。作為合成性CAR構建方法之一部分,穩固且可靠的CDR移植技術包含於平台技術中。使用定製分析算法(傳統Kabat/IMGT及新穎方法之組合)將抗原結合序列(CDR)自抗體可變域鑑別及剪接至選擇性人類構架序列(基於關鍵殘基之同源性及位置的小心管理之定製資料庫)中,以產生一組全長人類化scFv用於穩固表現。
全人類化scFv為將mAb之抗原結合域併入至CAR中用於臨床應用之方法中之必需步驟,而降低人類抗小鼠反應性之可能性確保了CAR修飾之治療細胞之持久性及活力。本發明CAR人類化平台之功效係藉由重新產生一組至少5個高品質、全長、人類化CAR用於表現表徵、功能驗證及臨床前測試來顯示。
模組IV包含人類化評分。評分量度用於定量及客觀評估合成構築體作為CAR人類化方法之一部分。T201
評分算法施加至如圖10B中所列之一系列市售及FDA批准之單株抗體(mAb)以測試其效用。如所預期,VL
及VH
(圖10C)序列隨著增加人類化程度而得分更高。有趣的是,相比於配對之VH
序列,VL
序列在T20評分中之趨勢更高。
作為相關分析,評估關於FDA批准之抗體療法的資訊且自公共領域中之處方資訊觀測患者之所報導免疫原性水準。如圖10E中所概述,較高人類化水準傾向於與患者中減少之所報導免疫毒性情況相關。
作為人類化評分之實例,在人類化方法之前及之後對於mCD19CAR相對於hCD19CAR評估VL
及VH
序列之T20評分(圖10F-G)。實際上,對於兩個經處理片段(人類化VL
及VH
)均觀測到較高T20評分。由於工作流可迭代,CAR人類化方法可用於產生具有較低免疫原性、較好持久性及穩固功能之CAR。 * * *
本文中所揭示及主張之所有方法可在無根據本發明不當之實驗的情況下進行及執行。雖然已根據較佳實施例描述本發明之組合物及方法,但熟習此項技術者應清楚變化可在不背離本發明之概念、精神及範疇的情況下應用於本文所述之方法中及方法之步驟或步驟順序中。更特定言之,顯而易知在化學上及生理上相關之某些藥劑可取代本文所描述之藥劑,同時獲得相同或類似結果。對熟習此項技術者顯而易見的所有此類類似取代及修改視為在由隨附申請專利範圍所定義之本發明之精神、範疇及概念內。參考文獻
以下參考文獻特定地以引用的方式併入本文中,以致其對本文所闡述之彼等提供例示性程序或其他細節補充。 Altschul, S.F.,et al., Nucleic Acids Res
, 25, 3389-3402, 1997. Arnold, K.,et al., Bioinformatics
, 22, 195-201, 2006. Benkert, P.,et al., Bioinformatics
, 27, 343-350, 2011. Fedorovet al
.,Sci. Transl. Medicine
, 5(215), 2013. Gao SH,et al., BMC Biotechnology
. 13:55, 2013. Guex, N.et al., Electrophoresis
, 18, 2714-2723, 1997. Marco Biasiniet al., Nucleic Acids Research
, 42 (W1): W252-W258, 2014. Remmert, M.,et al., Nat Methods
, 9, 173-175, 2012. Sela-Culanget al., Frontiers in Immunology
, 4:302, 2013. Shahet al.
,PLoS One
, 8:e776781, 2013. Singhet al.
,Cancer Research
, 68:2961-2971, 2008. Singhet al.
,Cancer Research
, 71:3516-3527, 2011. U.S. Patent 7,109,304
以下圖式形成本說明書之一部分且包括在此以進一步展示本發明之某些態樣。參照此等圖式中之一或多者,結合本文中呈現之特定實施例之詳細描述,可更好地理解本發明。
圖1A-1B:當前CAR與Ev3-CAR設計之間的比較。(A) Ev3莖充當整合結構以自抗原結合轉導信號,諸如藉由scFv,以及「閉合」開關,使得其可藉由臨床上可獲得之抗體(諸如西妥昔單抗)識別以消融CAR陽性免疫細胞。(B)作為相對於CAR,諸如T細胞使用之增強,DAP12可用作Ev3-DAP12 CAR中之信號增強器以提高NK細胞中之CAR功能的功效。
圖2A-2C:(A)描繪Ev3相比於包含胞內域及EGF結合域之EGFR的示意圖。(B)描繪EGFR變異體及片段之示意圖。(C)僅包含胞外域之Ev3的序列。
圖3A-3F:抗原CD19 (A)、hCD19 (B)、CD123 (C)、hCD123 (D)及CD99 (E)之反轉錄病毒載體之圖式。(F)使用人類化scFv相對於CD19 (其可經其他scFv替換)之CAR 2.0之構築圖。
圖4A-4B:(A) Ev3抗體識別CAR19.Ev3.CD28.CD3ζ、CAR19.Ev3.DAP12.CD3ζ或人類化CAR19.Ev3.CD3ζ轉導之NK細胞。(B)在評估CAR.19轉導之NK細胞針對CD19+
Raji腫瘤標靶之殺死活性的鉻釋放分析中,顯示CAR19.Ev3.CD28.DAP12 NK細胞在以多個效應:目標比殺死CD19+
Raji細胞中與CAR19.IgG1.CD28.CD3z轉導之NK細胞一樣有效。
圖5A-5B:(A)描繪CAR人類化平台之示意圖。(B)單株抗體序列分析。
圖6:描繪抗體之同型、異型及個體基因型之示意圖。描繪抗體之結構決定子以界定分離之要素且用於分析及後續CDR/構架移植。如所指示地進一步細分人類免疫球蛋白之5種主要同型(IgG1、2、3、4、IgA1、2)。
圖7A-7C:(A)包括VL
及VH
之hCD19 scFv及mCD19 scFv之胺基酸序列。對CDR區加底線。(B)對hCD19 scFv及mCD19 scFv之BLAST分析以藉由序列一致性或同源性驗證其各別物種起源。(C)比較mCD19 scFv相對於人類化CD19 scFv之分析的概述。
圖8A-8D:(A)描繪3D結構建模之示意圖。(B-D)人類CD19可變輕鏈之3D結構建模。使用SWISS-MODEL*,一種完全自動化蛋白質結構同源性建模器,產生人類化VL及VH域之3維模型(抗CD19作為示出之特定實例)。從SAbDab (結構抗體資料庫)中取出結構檔案作為同源性建模的模板,以及使用自動存入SWISS-MODEL之PDB結構檔案。
圖9A-9C:人類CD19可變重鏈之3D結構建模。對於hCD19VL
域之特定實例,(A)在SWISS-MODEL中根據評分(GMQE)及匹配方法(BLAST或HHblits)產生最佳匹配(結構上同源)結構之清單。(B-C)最佳評分結構(2fgw)接著與hCD19VL
域(「標靶」)比對,如下部圖中所示。
圖10A-10G:(A)描繪人類構架移植之示意圖,其顯示自小鼠抗體鑑別及分離CDR區(左上圖)、蒸餾人類構架區(右圖)及人類構架/鼠類CDR移植(左下圖)。自如上文所述之序列分析搜集CDR及構架區。(B)使用T20評分系統(Gao等人, 2013)進行單株抗體之基線人類化評分以列舉特定Ig域之『人類化』。作為對照,從抗體中取出VL
及VH
域,該等抗體當前在市面上用於評分及比較。對於VL
及VH
域列出指定抗體之人類化評分(最右欄)。(C)批准用於商業市場之早期治療抗體為鼠類或嵌合抗體(可變小鼠區+人類恆定區),而後續批准傾向於為人類化或人類抗體。人類化評分傾向於針對相同類型之抗體(鼠類、嵌合、人類化或人類)叢集,且與人類含量相關之人類化評分增加。(D)抗體經FDA批准之年份的可變重鏈之人類化評分。人類化評分傾向於針對相同類型之抗體(鼠類、嵌合、人類化或人類)叢集,且與人類含量相關之人類化評分增加。由於VH
域之較大尺寸,人類化評分傾向於較低(相比於VL
)。(E)指定抗體之人類化評分。抗治療抗體反應之頻率顯示為%且所評估患者組之大小以括號給出。大體而言,抗體愈人類或人類化,臨床使用中報導之免疫原性愈少。(F)hCD19-CAR (SEQ ID NO: 1)及mCD19-CAR (SEQ ID NO: 3)之可變輕鏈的人類化評分。(G) hCD19-CAR (SEQ ID NO: 2)及mCD19-CAR (SEQ ID NO: 4)之可變重鏈的人類化評分。
圖11A-11E:(A) CD19-CAR及hCD19-CAR構築體之示意圖。(B) CAR之轉導效率。(C)不同CAR構築體針對K562細胞之細胞毒性。(D)不同CAR構築體針對Raji細胞之細胞毒性。(E)在指定效應:目標比下具有對照CD3ζ/IgG1 CAR或人類化CD3ζ/IgG1 CAR之細胞相對於K562或Raji細胞之細胞毒性分析。
圖12A-12I:(A) CD319-CAR NK轉導。(B) NK細胞之生長曲線。(C)細胞株內之CD319表現。(D-F) CD319-CAR NK細胞毒性分析。(G) CD319-CAR NK細胞相對於指定細胞類型(包括K562、MM、1S及OPM2)之細胞毒性分析。(H-I) CD319-CAR NK細胞具有效應表現型。
Claims (82)
- 一種嵌合抗原受體(CAR),其包含該CAR鉸鏈區中之截斷EGFRvIII (Ev3),其中該Ev3鉸鏈連接細胞外域及至少一個細胞內信號傳導域。
- 如請求項1之CAR,其中該Ev3鉸鏈包含EGFRvIII之跨膜域及非功能胞外域。
- 如請求項1之CAR,其中該Ev3鉸鏈不包含EGFRvIII胞內域。
- 如請求項2之CAR,其中該EGFRvIII之非功能胞外域基本上不結合至表皮生長因子(EGF)。
- 如請求項1至4中任一項之CAR,其中該Ev3鉸鏈包含EGFR之截斷域1、截斷域2、域3及域4。
- 如請求項5之CAR,其中該EGFR之域3及域4未經截斷。
- 如請求項1至4中任一項之CAR,其中該Ev3鉸鏈包含與SEQ ID NO: 2具有至少80%序列一致性之胺基酸序列。
- 如請求項1至4中任一項之CAR,其中該Ev3鉸鏈包含與SEQ ID NO: 2具有至少95%序列一致性之胺基酸序列。
- 如請求項1至4中任一項之CAR,其中該Ev3鉸鏈包含SEQ ID NO: 2之胺基酸序列。
- 如請求項1至4中任一項之CAR,其中該Ev3鉸鏈係由與SEQ ID NO: 1具有至少80%序列一致性之核苷酸序列編碼。
- 如請求項1至4中任一項之CAR,其中該Ev3鉸鏈係由與SEQ ID NO: 1具有至少95%序列一致性之核苷酸序列編碼。
- 如請求項1至4中任一項之CAR,其中該Ev3鉸鏈係由SEQ ID NO: 1之核苷酸序列編碼。
- 如請求項1之CAR,其中該CAR之細胞外域包含選自由F(ab')2、Fab'、Fab、Fv及scFv組成之群的抗原結合域。
- 如請求項13之CAR,其中該抗原結合域包含scFv。
- 如請求項14之CAR,其中該scFv進一步定義為人類化scFv。
- 如請求項13至15中任一項之CAR,其中該CAR之抗原結合區結合一或多種腫瘤相關抗原。
- 如請求項16之CAR,其中該一或多種腫瘤相關抗原係選自由以下組成之群:CD19、CD319 (CS1)、ROR1、CD20、癌胚抗原、α胎蛋白、CA-125、MUC-1、上皮腫瘤抗原、黑素瘤相關抗原、突變p53、突變ras、HER2/Neu、ERBB2、葉酸結合蛋白、HIV-1包膜醣蛋白gp120、HIV-1包膜醣蛋白gp41、GD2、CD5、CD123、CD23、CD30、CD56、c-Met、間皮素、GD3、HERV-K、IL-11Rα、κ鏈、λ鏈、CSPG4、ERBB2、WT-1、TRAIL/DR4、VEGFR2、CD33、CD47、CLL-1、U5snRNP200、CD200、BAFF-R、BCMA及CD99。
- 如請求項16之CAR,其中該一或多種腫瘤相關抗原為CD19、CD319、CD123、CD5、ROR1、CD33、CD99及/或間皮素。
- 如請求項13至15中任一項之CAR,其中該scFv不包含EGFR結合域。
- 如請求項1之CAR,其中該至少一個信號傳導域包含CD3ξ、CD28、OX40/CD134、4-1BB/CD137、FcεRIγ、ICOS/CD278、ILRB/CD122、IL-2RG/CD132、DAP12、CD70、CD40或其組合。
- 如請求項1之CAR,其中該至少一個信號傳導域包含DAP12。
- 如請求項1之CAR,其中該CAR包含IL-15。
- 如請求項1之CAR,其中該CAR包含CD3ζ、CD28、DAP12及IL-15。
- 如請求項1之CAR,其中該CAR進一步包含自殺基因。
- 如請求項24之CAR,其中該自殺基因為誘導性凋亡蛋白酶9。
- 一種經分離之抗原特異性人類化單鏈可變片段(scFv),其包含輕鏈可變區(VL )及重鏈可變區(VH ),其中該scFv為: (a) CD19特異性的,且其中該VL 包含SEQ ID NO: 7之胺基酸序列及該VH 包含SEQ ID NO: 8之胺基酸序列; (b) CD123特異性的,且其中該VL 包含SEQ ID NO: 13之胺基酸序列及該VH 包含SEQ ID NO: 14之胺基酸序列; (c)間皮素特異性的,且其中該VL 包含SEQ ID NO: 19之胺基酸序列及該VH 包含SEQ ID NO: 20之胺基酸序列; (d) ROR1特異性的,且其中該VL 包含SEQ ID NO: 25之胺基酸序列及該VH 包含SEQ ID NO: 26之胺基酸序列; (e) CD5特異性的,且其中該VL 包含SEQ ID NO: 31之胺基酸序列及該VH 包含SEQ ID NO: 32之胺基酸序列; (f) CLL-1特異性的,且其中該VL 包含SEQ ID NO: 59之胺基酸序列及該VH 包含SEQ ID NO: 60之胺基酸序列; (g) CD99特異性的,且其中該VL 包含SEQ ID NO: 63之胺基酸序列及該VH 包含SEQ ID NO: 64之胺基酸序列,或 (h)與(a)至(g)中之任一者之構架區具有90%序列一致性之序列。
- 如請求項26之人類化scFv,其中該scFv為CD19特異性的,且其中該VL 包含SEQ ID NO: 7之胺基酸序列及該VH 包含SEQ ID NO: 8之胺基酸序列。
- 如請求項27之人類化scFv,其中該CD19特異性scFv包含SEQ ID NO: 6之胺基酸序列。
- 如請求項26之人類化scFv,其中該scFv為CD123特異性的,且其中該VL 包含SEQ ID NO: 13之胺基酸序列及該VH 包含SEQ ID NO: 14之胺基酸序列。
- 如請求項29之人類化scFv,其中該CD123特異性scFv包含SEQ ID NO: 12之胺基酸序列。
- 如請求項26之人類化scFv,其中該scFv為間皮素特異性的,且其中該VL 包含SEQ ID NO: 19之胺基酸序列及該VH 包含SEQ ID NO: 20之胺基酸序列。
- 如請求項31之人類化scFv,其中該間皮素特異性scFv包含SEQ ID NO: 18之胺基酸序列。
- 如請求項26之人類化scFv,其中該scFv為ROR1特異性的,且其中該VL 包含SEQ ID NO: 25之胺基酸序列及該VH 包含SEQ ID NO: 26之胺基酸序列。
- 如請求項33之人類化scFv,其中該ROR1特異性scFv包含SEQ ID NO: 24之胺基酸序列。
- 如請求項26之人類化scFv,其中該scFv為CD5特異性的,且其中該VL 包含SEQ ID NO: 31之胺基酸序列及該VH 包含SEQ ID NO: 32之胺基酸序列。
- 如請求項35之人類化scFv,其中該CD5特異性scFv包含SEQ ID NO: 30之胺基酸序列。
- 如請求項26之人類化scFv,其中該scFv為CD99特異性的,且其中該VL 包含SEQ ID NO: 63之胺基酸序列及該VH 包含SEQ ID NO: 64之胺基酸序列。
- 如請求項35之人類化scFv,其中該CD99特異性scFv包含SEQ ID NO: 62之胺基酸序列。
- 如請求項26至38中任一項之人類化scFv,其中該scFv包含與SEQ ID NO: 6、12、18、24或30之胺基酸序列之構架區具有至少95%序列一致性之胺基酸序列。
- 如請求項26至38中任一項之人類化scFv,其中該scFv包含與SEQ ID NO: 6、12、18、24或30之胺基酸序列之構架區具有至少98%序列一致性之胺基酸序列。
- 一種經分離聚核苷酸,其編碼如請求項26至38中任一項之經分離人類化scFv。
- 如請求項41之經分離聚核苷酸,其中該聚核苷酸包含SEQ ID NO: 3、9、15、21或27。
- 一種表現載體,其包含如請求項41之經分離聚核苷酸。
- 如請求項43之載體,其中該載體進一步定義為病毒載體。
- 如請求項15之CAR,其中該人類化scFv為如請求項26至38中任一項之scFv。
- 一種經分離核酸,其包含編碼如請求項1至25及45之CAR的核苷酸序列。
- 一種宿主細胞,其經工程改造以表現CAR,該CAR包含如請求項26至38中任一項之人類化scFv及/或該CAR鉸鏈區中之截斷EGFRvIII (Ev3)。
- 如請求項47之細胞,其中該CAR係如請求項1至25中任一項所述。
- 如請求項47之細胞,其中該宿主細胞進一步定義為CAR免疫細胞。
- 如請求項49之細胞,其中該免疫細胞為T細胞、外周血淋巴細胞、NK細胞、恆定NK細胞、NKT細胞或幹細胞。
- 如請求項49之細胞,其中該免疫細胞為T細胞或NK細胞。
- 如請求項50之細胞,其中該幹細胞為間葉系幹細胞(MSC)或誘導多能幹(iPS)細胞。
- 如請求項49之細胞,其中該免疫細胞係衍生自iPS細胞。
- 如請求項50之細胞,其中該T細胞為CD8+ T細胞、CD4+ T細胞或γ-δ T細胞。
- 如請求項50之細胞,其中該T細胞為細胞毒性T淋巴細胞(CTL)。
- 如請求項49之細胞,其中該免疫細胞為同種異體細胞。
- 如請求項49之細胞,其中該免疫細胞為自體細胞。
- 如請求項49之細胞,其中該免疫細胞分離自外周血、臍帶血或骨髓。
- 如請求項49之細胞,其中該免疫細胞分離自臍帶血。
- 如請求項59之細胞,其中該臍帶血彙集自2個或大於2個個體臍帶血單位。
- 如請求項47之細胞,其中編碼該CAR之DNA係整合至該細胞之基因組中。
- 一種醫藥組合物,其包含如請求項47至61中任一項之細胞群體。
- 一種包含如請求項47至61中任一項之細胞群體之組合物,其用於治療免疫相關病症。
- 一種治療受試者中免疫相關病症之方法,其包含向該受試者投與有效量的如請求項47至61中任一項之細胞。
- 如請求項64之方法,其中該免疫相關病症為癌症、自體免疫病症、移植物抗宿主疾病、同種異體移植排斥反應或發炎性病況。
- 如請求項64之方法,其中該免疫相關病症為發炎性病況,且該等免疫細胞基本上不表現糖皮質激素受體。
- 如請求項64之方法,其中該等免疫細胞為自體細胞。
- 如請求項64之方法,其中該等免疫細胞為同種異體細胞。
- 如請求項64之方法,其中該免疫相關病症為癌症。
- 如請求項69之方法,其中該癌症為實體癌症或惡性血液病。
- 如請求項64之方法,其進一步包含投與至少第二治療劑。
- 如請求項71之方法,其中該至少第二治療劑包含化學療法、免疫療法、手術、放射線療法或生物療法。
- 如請求項71之方法,其中該等免疫細胞及/或該至少第二治療劑係以靜脈內、腹膜內、氣管內、瘤內、肌肉內、內窺鏡、病灶內、經皮、皮下、局部方式投與或藉由直接注射或灌注投與。
- 如請求項64之方法,其進一步包含投與抗EGFR抗體。
- 如請求項74之方法,其中該抗EGFR抗體為單株抗體。
- 如請求項75之方法,其中該抗EGFR抗體為西妥昔單抗(cetuximab)或帕尼單抗(panitumumab)。
- 如請求項74至76中任一項之方法,其中該抗EGFR抗體經由抗體依賴性細胞介導之細胞毒性(ADCC)選擇性地消融Ev3-CAR免疫細胞。
- 如請求項74至76中任一項之方法,其中該抗EGFR抗體係融合至可偵測標籤及/或細胞毒性劑。
- 如請求項78之方法,其進一步包含使該可偵測標籤成像,進而偵測該等Ev3-CAR免疫細胞。
- 如請求項74至76中任一項之方法,其中該抗EGFR抗體係融合至細胞毒性劑。
- 如請求項79之方法,其中該細胞毒性劑在該等Ev3-CAR免疫細胞中誘導該自殺基因之活化。
- 如請求項78之方法,其中該細胞毒性劑導致Ev3-CAR免疫細胞之消融。
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PT2496698T (pt) * | 2009-11-03 | 2019-04-18 | Hope City | Recetor de fator de crescimento epidermal truncado (egfrt) para seleção de células t transduzidas |
MX370265B (es) * | 2012-05-25 | 2019-12-09 | Cellectis | Métodos para manipular por ingeniería genética célula t alogénica y resistente a inmunosupresores para inmunoterapia. |
PL2958943T3 (pl) * | 2013-02-20 | 2020-04-30 | The Trustees Of The University Of Pennsylvania | Leczenie nowotworu złośliwego za pomocą humanizowanego chimerycznego receptora antygenowego anty-egfrviii |
KR102329836B1 (ko) * | 2015-01-26 | 2021-11-19 | 셀렉티스 | 암 면역치료를 위한 항-CLL1 특이적 단일-체인 키메라 항원 수용체들(scCARS) |
AU2016363025B2 (en) * | 2015-12-03 | 2021-04-08 | Juno Therapeutics, Inc. | Modified chimeric receptors and related compositions and methods |
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2018
- 2018-07-25 EP EP18838056.2A patent/EP3658163A4/en active Pending
- 2018-07-25 CN CN202410061631.8A patent/CN118206655A/zh active Pending
- 2018-07-25 CA CA3070998A patent/CA3070998A1/en active Pending
- 2018-07-25 TW TW107125720A patent/TW201908335A/zh unknown
- 2018-07-25 AU AU2018306307A patent/AU2018306307A1/en active Pending
- 2018-07-25 KR KR1020207005375A patent/KR20200032174A/ko not_active Application Discontinuation
- 2018-07-25 WO PCT/US2018/043779 patent/WO2019023396A1/en unknown
- 2018-07-25 CN CN201880058794.3A patent/CN111432823A/zh active Pending
- 2018-07-25 JP JP2020503988A patent/JP2020530989A/ja not_active Withdrawn
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2023
- 2023-07-19 JP JP2023117421A patent/JP2023134735A/ja active Pending
Also Published As
Publication number | Publication date |
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CN118206655A (zh) | 2024-06-18 |
JP2023134735A (ja) | 2023-09-27 |
WO2019023396A1 (en) | 2019-01-31 |
EP3658163A4 (en) | 2021-08-04 |
CA3070998A1 (en) | 2019-01-31 |
CN111432823A (zh) | 2020-07-17 |
EP3658163A1 (en) | 2020-06-03 |
KR20200032174A (ko) | 2020-03-25 |
JP2020530989A (ja) | 2020-11-05 |
AU2018306307A1 (en) | 2020-02-20 |
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