TWI687436B - 用於肝細胞癌(hcc)和其他癌症免疫治療的新型肽和肽組合物 - Google Patents
用於肝細胞癌(hcc)和其他癌症免疫治療的新型肽和肽組合物 Download PDFInfo
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Abstract
本發明涉及用於免疫治療方法的肽、蛋白質、核酸和細胞。特別是,本發明涉及癌症的免疫療法。本發明進一步涉及單獨使用或與其他腫瘤相關肽(刺激抗腫瘤免疫反應或體外刺激T細胞和轉入患者的疫苗複合體的活性藥物成分)聯合使用的腫瘤相關T細胞(CTL)肽表位。與主要組織相容性複合體(MHC)分子結合的肽或與此同類的肽也可能是抗體、可溶性T細胞受體和其他結合分子的靶標。特別是,本發明涉及數種新型肽序列及其變體,它們源自人腫瘤細胞的HLA-I類和HLA-II類分子,可用于引發抗腫瘤免疫反應的疫苗組合物中或作為開發藥物/免疫活性化合物和細胞的目標。
Description
本案涉及用於免疫治療方法的肽、蛋白質、核酸和細胞。特別是,本發明涉及癌症的免疫療法。本發明進一步涉及單獨使用或與其他腫瘤相關肽(刺激抗腫瘤免疫反應或體外刺激T細胞和轉入患者的疫苗複合體的活性藥物成分)聯合使用的腫瘤相關T細胞(CTL)肽表位。與主要組織相容性複合體(MHC)分子結合的肽或與此同類的肽也可能是抗體、可溶性T細胞受體和其他結合分子的靶標。特別是,本發明涉及數種新型肽序列及其變體,它們源自人腫瘤細胞的HLA-I類和HLA-II類分子,可用于引發抗腫瘤免疫反應的疫苗組合物中或作為開發藥物/免疫活性化合物和細胞的目標。
肝細胞癌(HCC)是世界上最常見的腫瘤之一,占全世界所有確診新發癌症病例的大約6%。2012年,全球大約有782,000例HCC新發病例,使之成為男性中第五位最常見癌症
(554,000例)、女性中第九位常見癌症(228,000例)(http://globocan.iarc.fr)。HCC是最常見的原發性肝惡性腫瘤,占所有成人原發性肝癌80%以上。
HCC的地域分佈不同,發病率取決於性別。男性HCC年齡標準化發病率(ASR)為東亞(31.9)和東南亞(22.2)最高,南歐(9.5)和北美(9.3)中等,北歐(4.6)和中南亞(3.7)最低。女性HCC發病率比男性ASR低。女性最高ASR為東亞(10.2)和西部非洲(8.1),最低為北歐(1.9)和密克羅尼西亞(1.6)。
HCC患者的總體預後較差。HCC的5年相對生存率(5Y-RSR)約為15%,這取決於診斷時的疾病階段。對於癌症仍然局限於肝臟的局部HCC,5Y-RSR約為28%。對於癌症已經發展至附近或遠處的器官區域和遠端HCC,5Y-RSR分別為7%和2%。
HCC的發生與多種危險因素相關,肝硬化是最重要的一種危險因素。肝硬化常因酗酒或HBV或HCV感染所致,但也可能由代謝疾病(如II型糖尿病)引起。因此,健康的肝組織被瘢痕組織取代,這增加了發生癌症的風險。
疾病管理取決於診斷時腫瘤的階段以及肝臟的整體狀況。如有可能,可透過手術切除部分肝臟(肝部分切除術)或整個器官(肝切除)。特別是腫瘤小或腫瘤可完全切除的患者有資格接受肝臟移植。
如果手術不是一種治療選項,可用現有的其他療法。腫瘤消融時,探針被注入肝臟,腫瘤被無線電或微波或冷凍治療破壞。在栓塞程式中,腫瘤的血液供應被機械或化學
方式阻斷。在放射療法中,可用高能量無線電波破壞腫瘤。
HCC的化療包括用於全身治療的多柔比星、5-氟尿嘧啶和順鉑的組合以及用於肝動脈輸注的多柔比星、氟尿苷和絲裂黴素C。但是,大多數HCC病例均於對化療藥物表現出很高的耐藥性(Enguita-German and Fortes,2014)。
晚期不可切除HCC的治療選項僅限於索拉非尼(一種多酪氨酸激酶抑制劑)(Chang et al.,2007;Wilhelm et al.,2004)。索拉非尼是唯一被證實可延長生存期大約3個月的全身藥物,目前是此類患者的唯一實驗性治療方案(Chapiro et al.,2014;Llovet et al.,2008)。
最近,對於HCC進行了少量的免疫療法試驗。細胞因數已被用於啟動免疫細胞的亞群和/或增加腫瘤免疫原性(Reinisch et al.,2002;Sangro et al.,2004)。其他的試驗主要關注腫瘤浸潤性淋巴細胞或活化外周血淋巴細胞的輸注(Shi et al.,2004a;Takayama et al.,1991;Takayama et al.,2000)。
到目前為止,已經進行了少量的治療性疫苗接種試驗。Butterfield等人使用源自甲胎蛋白(AFP)的肽或載有AFP肽的DC進行了兩項體外試驗(Butterfield et al.,2003;Butterfield et al.,2006)。在兩項不同的研究中,自體樹突細胞(DC)用自體腫瘤裂解物(Lee et al.,2005)或肝母細胞瘤細胞系HepG2的裂解物(Palmer et al.,2009)進行體外衝擊。到目前為止,疫苗接種試驗僅顯示臨床結果的有限改善。
在本發明的第一方面,本發明涉及一種肽,包含選
自包括SEQ ID NO:1至SEQ ID NO:300的組的一個氨基酸序列、或該序列的與SEQ ID NO:1至SEQ ID NO:300具有至少80%,較佳至少90%同源(較佳至少80%或至少90%相同)的一種變體序列(其中所述變體與MHC結合和/或誘導T細胞與所述肽發生交叉反應),或其藥用鹽(其中所述肽不是潛在全長多肽)。
本發明進一步涉及本發明的一種肽,包含選自包括SEQ ID NO:1至SEQ ID NO:300的組的一個序列、或與SEQ ID NO:1至SEQ ID NO:300具有至少80%、較佳至少88%同源性的一種變體,其中所述肽或其變體的總長度為8至100個、較佳為8至30個、最較佳為8至14個氨基酸。
下表顯示了根據本發明的肽、它們各自的序列ID號(SEQ ID NO)、以及這些肽的可能源(潛在)基因。表1中所有的肽與HLA-A*02等位基因、表2中的肽與HLA-A*24等位基因結合。表3中的肽之前在大型列表中披露,作為高通量篩查結果,錯誤率高,或使用演算法計算出,但之前與癌症毫無關聯。他們與HLA-A*02結合。表4中的肽是可與本發明其他肽組合使用的其他肽。肽與A*02結合或另有說明時與A*24結合。表5中的肽還可用於診斷和/或治療各種惡性疾病,這些疾病涉及過度表達或過度提呈各潛在多肽。
本發明還一般涉及本發明的肽用於治療增殖性疾病,例如,胰腺癌、結腸癌或直腸癌、腎癌、腦癌和/或白血病。
特別較佳的是本發明的肽(單獨或組合),其選自包括SEQ ID NO:1至SEQ ID NO:300的組。更較佳的是所述肽(單獨或組合)選自包括SEQ ID NO:1至SEQ ID NO:124的組(見表1)較佳為與A*02結合,以及選自包括SEQ ID NO:187至SEQ ID NO:218的組(見表2)較佳為與A*24結合,並且其用於HCC、腦癌、腎癌、胰腺癌、結腸癌或直腸癌或白血病的免疫治療,較佳為HCC的免疫治療。
如示下面的表5A和5B所示,其中本發明的許多肽還可用於其他適應症的免疫治療。該表顯示,對於其他腫瘤類型的選定肽,發現它們過量提呈(特定提呈)於5%以上測定的腫瘤樣本,或提呈於5%以上測定的腫瘤樣本且幾何學平均值腫瘤與正常組織的比值大於3。過度提呈定義為與最高提呈的正常樣本相比,腫瘤樣本中的提呈更高。經過度提呈的正常組織有:脂肪組織、腎上腺、血細胞、血管、骨髓、腦、軟骨、食道、眼、膽囊、心臟、腎、大腸、肝、肺、淋巴結、神經、胰腺、甲狀旁腺、腹膜、垂體、胸膜、唾液腺、骨骼肌、皮膚、小腸、脾、胃、甲狀腺、氣管、輸尿管、膀胱。
NSCLC=非小細胞肺癌,SCLC=小細胞肺癌,RCC=腎癌,CRC=結腸或直腸癌,GC=胃癌,HCC=肝癌,PC=胰腺癌,PrC=攝護腺癌,白血病,BRCA=乳腺癌,MCC=Merkel細胞癌,OC=卵巢癌,NHL=非霍奇金淋巴瘤,AML=急性骨髓性白血病,CLL=慢性淋巴細胞白血病。
因此,本發明的另一個方面涉及根據SEQ序列號1、
14、15、41、43、58、59、60、81、121、135、139、144、176、236、248、275、276、283、286、288、289、290、291、300、302、304、308、313、316、317、325、326、329、331、334、342和343中任一項所述的本發明的至少一種肽與一種較佳實施方案的肽聯合用於治療胰腺癌。
因此,本發明的另一個方面涉及根據SEQ序列號6、15、16、22、26、30、34、36、47、59、65、69、70、77、80、81、88、121、123、125、127、133、137、139、169、172、176、181、186、221、223、229、230、231、232、233、234、236、237、238、244、247、249、250、251、255、260、261、266、269、271、274、275、282、285、289、290、291、293、297、301、302、304、306、310、313、316、317、319、327、328、329、330、331、332、334和342中任一項所述的本發明的至少一種肽與一種較佳實施方案中的肽聯合用於治療結腸癌或腎癌。
因此,本發明的另一個方面涉及根據SEQ序列號10、14、15、22、36、39、54、55、60、72、77、81、90、96、112、116、119、121、133、137、138、148、169、170、172、177、186、187、189、192、197、198、203、206、219、221、229、230、233、234、236、255、260、270、272、275、277、278、279、281、282、285、289、291、292、295、296、297、301、302、305、308、311、313、315、316、319、321、324、328、329、333、334、335、336和346中任一項所述的本發明的至少一種肽與一種較佳實施方案中的肽
聯合用於治療腎癌。
因此,本發明的另一個方面涉及根據SEQ序列號14、15、16、17、36、39、47、51、54、65、88、101、123、125、133、134、135、137、141、147、161、166、169、176、179、184、186、187、189、191、192、193、194、195、196、197、199、203、206、208、214、220、221、224、229、230、231、234、238、239、244、245、250、251、255、258、259、260、268、269、270、271、272、278、279、282、295、297、302、304、305、306、309、310、311、312、313、316、317、319、321、325、327、328、329、330、331、332、333、334、336、337、338、339、340、342、343、344、345和347中任一項所述的本發明的至少一種肽與一種較佳實施方案中的肽聯合用於治療腦癌。
因此,本發明的另一個方面涉及根據序列ID號172、173、240、250、287、299、302、334和335中任一項所述的本發明的至少一種肽與一種較佳實施方案中的肽聯合用於治療CLL。
同樣,上面表5B列出的肽可以與一種較佳實施方案中的肽聯合形成治療適應疾病的基礎。
因此,本發明的另一個方面涉及本發明中肽的用途-較佳聯合用於治療選自HCC、腦癌、腎癌、胰腺癌、結腸癌或直腸癌和白血病組中的增殖性疾病;本發明還涉及本發明的肽,其具有與主要組織相容性複合體(MHC)I或以拉長形式存在的例如長度變化的
-MHC-II類分子結合的能力。
本發明進一步涉及本發明中的肽,其中所述肽(每種肽)系由或基本系由根據SEQ ID NO1至SEQ ID NO300的一個氨基酸序列組成。
本發明進一步涉及本發明的肽,其中所述肽被修飾和/或包含非肽鍵。
本發明進一步涉及本發明的肽,其中所述肽為融合蛋白的一部分,特別是與HLA-DR抗原相關不變鏈(Ii)的N-端氨基酸融合,或與抗體(例如,樹突狀細胞特定抗體)或抗體的序列融合。
本發明進一步涉及一種核酸,其編碼本發明的肽。本發明進一步涉及一種本發明的核酸,為DNA、cDNA、PNA、RNA,也可能為其組合物。
本發明進一步涉及一種能表達和/或表達本發明核酸的表達載體。
本發明進一步涉及本發明的一種肽、本發明的一種核酸或本發明的一種表達載體,其用於治療疾病和用於藥物,特別用於治療包括癌症和自身免疫性/炎症/免疫病理性疾病在內的疾病。
本發明進一步涉及本發明中肽或本發明中所述肽複合體(含有MHC)的抗體以及製造這些抗體的方法。
本發明進一步涉及本發明的T細胞受體(TCR),特別是可溶性TCR(sTCR)和加工為自體或異體T細胞的克隆TCR,以及製造這些TCR的方法和載有所述TCR或所述TCR交叉反
應的NK細胞的製造方法。
抗體和TCR是根據本發明的肽現有免疫治療用途的另外實施方案。
本發明進一步涉及含本發明核酸或前述表達載體的一種宿主細胞。本發明進一步涉及本發明的宿主細胞,其為抗原提呈細胞,較佳為樹突細胞。
本發明進一步涉及配製本發明一種肽的一種方法,所述方法包括培養本發明的宿主細胞和從所述宿主細胞或其培養基中分離肽。
本發明進一步涉及本發明中的所述方法,其中抗原透過與足夠量的含抗原提呈細胞的抗原結合被載入表達於合適抗原提呈細胞或人工抗原呈遞細胞表面的I或II類MHC分子。
本發明進一步涉及本發明的方法,其中抗原提呈細胞由能表達含SEQ ID NO.1至SEQ ID NO.300、較佳為含SEQ ID NO.1至SEQ ID NO.124、以及SEQ ID NO.187至SEQ ID NO.:218所述肽的一個表達載體、或一個變體氨基酸序列組成。
本發明進一步涉及以本發明方法製備的啟動T細胞,其中所述T細胞有選擇性地識別一種細胞,該細胞表達含一種本發明氨基酸序列的多肽。
本發明進一步涉及一種殺傷患者靶細胞的方法,其中患者的靶細胞異常表達含本發明任何氨基酸序列的多肽,該方法包括給予患者按本發明方法製造的有效量T細胞。
本發明進一步涉及任何所述肽、本發明的核酸、本發明的表達載體、本發明的細胞、本發明的作為藥劑或製造藥劑的啟動T淋巴細胞、T細胞受體或抗體或其他肽-和/或肽-MHC結合分子的用途。藥劑較佳為具有抗癌活性。
較佳情況為,所述藥劑為基於可溶性TCR或抗體的細胞治療藥物、疫苗或蛋白質。
本發明進一步涉及一種本發明的用途,其中所述癌細胞為HCC、腦癌、腎癌、胰腺癌、結腸癌或直腸癌或白血病,較佳為HCC細胞。
本發明進一步涉及一種基於本發明肽的特定標誌物蛋白和生物標誌物,在此稱為「靶標」,其可用於診斷和/或判斷HCC的預後。本發明還涉及這些癌症治療中新靶點的用途。
MHC分子有兩類:MHC I類和MHC II類。MHC分子分別由一條α重鏈和β-2-微球蛋白(MHC-I類受體)或一條α和一條β鏈(MHC-II類受體)組成。其三位構造形成一個結合槽,用於與肽進行非共價相互作用。大部分有核細胞上都可發現MHC-I類分子。它們提呈主要為內源性的蛋白、缺陷核糖體產物(DRIP)和較大肽裂解生成的肽。MHC II類分子主要發現於專業抗原提呈細胞(APC)上,並且主要提呈在內吞作用過程中由APC佔據並且隨後被加工的外源性或跨膜蛋白的肽。肽和MHC I類的複合體由負載相應TCR(T細胞受體)的CD8陽性T細胞進行識別,而肽和MHC II類分子的複合體由負載相應TCR的CD4陽性輔助T細胞進行識別。因此,TCR、肽和MHC
按照1:1:1的化學計量呈現,這一點已是共識。
CD4陽性輔助T細胞在誘導和維持CD8陽性細胞毒性T細胞的有效反應中發揮重要作用。腫瘤相關抗原(TAA)衍生的CD4陽性T細胞表位的識別對開發能引發抗腫瘤免疫反應的藥物產品可能非常重要(Gnjatic S,et al.Survey of naturally occurring CD4+ T cell responses against NY-ESO-1 in cancer patients:correlation with antibody responses.Proc Natl Acad Sci USA.2003 Jul22;100(15):8862-7)。在腫瘤部位,T輔助細胞支援毒性T細胞(CTL)友好型細胞因數環境(Mortara L,et al.CIITA-induced MHC class II expression in mammary adenocarcinoma leads to a Th1 polarization of the tumor microenvironment,tumor rejection,and specific antitumor memory.Clin Cancer Res.2006 Jun1;12(11 Pt 1):3435-43)並吸引效應細胞,如CTL、NK細胞、巨噬細胞、粒細胞(Hwang ML,et al.Cognate memory CD4+ T cells generated with dendritic cell priming influence the expansion,trafficking,and differentiation of secondary CD8+ T cells and enhance tumor control.J Immunol.2007 Nov1;179(9):5829-38)。
在沒有炎症的情況下,MHC II類分子的表達主要局限於免疫系統細胞,尤其是專業抗原提呈細胞(APC),例如,單核細胞、單核細胞源性細胞、巨噬細胞、樹突狀細胞。在癌症患者的腫瘤細胞中發現有MHC II類分子的表達(Dengjel J,et al.Unexpected abundance of HLA class II presented peptides in primary renal cell carcinomas.Clin Cancer Res.
2006 Jul 15;12(14Pt1):4163-70)。
本發明的拉長(較長)肽可作為MHC-II類活性表位。MHC-II類表位活化的輔助T細胞在編排抗腫瘤免疫的CTL效應子功能中發揮著重要作用。觸發TH1細胞反應的輔助T細胞表位支援CD8陽性殺傷T細胞的效應子功能,其中包括直接作用於腫瘤細胞的細胞毒性功能(該類腫瘤細胞表面顯示有腫瘤相關肽/MHC複合體)。這樣,腫瘤相關T輔助細胞表位單獨使用或與其他腫瘤相關肽結合使用可作為刺激抗腫瘤免疫反應的疫苗化合物的活性藥物成分。
哺乳動物(如小鼠)模型顯示,即使沒有CD8陽性T淋巴細胞,CD4陽性T細胞也能透過分泌幹擾素-γ(IFNγ)抑制血管生成而足以抑制腫瘤的表現。
已有CD4T細胞作為直接抗腫瘤效應因數的證據(Braumuller et al.,2013;Tran et al.,2014)。
由於HLAII類分子的組成性表達通常僅限於免疫細胞,因此,直接從原發腫瘤中分離II類肽被認為是不可能的事。然而,Dengjel等人成功地在腫瘤中直接識別了多個MHC II類表位(WO 2007/028574,EP 1 760 088 B1)。
腫瘤特異性細胞毒性T淋巴細胞所識別的抗原,即其表位,可以是源自所有蛋白類型的分子,如酶、受體、轉錄因數等,它們在相應腫瘤的細胞中被表達,並且與同源未變的細胞相比,其表達通常上調。
由於CD8依賴型和CD4依賴型這兩種反應共同並協同地促進抗腫瘤作用,因此,確定和表徵由CD8+T細胞(配
體:MHC I類分子+肽表位)或CD4陽性T輔助細胞(配體:MHC II類分子)識別的腫瘤相關抗原對開發腫瘤疫苗非常重要。
對於MHC I類肽觸發(引發)細胞免疫反應,它也必須與MHC分子結合。這一過程依賴於MHC分子的等位基因以及肽氨基酸序列的特異性多態性。MHC-I類-結合肽的長度通常為8-12個氨基酸殘基,並且在其與MHC分子相應結合溝槽相互作用的序列中通常包含兩個保守殘基(「錨」)。這樣,每個MHC的等位基因都有「結合基序」,從而確定哪些肽能與結合溝槽特異性結合。
在MHC-I類依賴性免疫反應中,肽不僅能與腫瘤細胞表達的某些MHC-I類分子結合,而且它們之後還必須能被T細胞負載的特異性T細胞受體(TCR)識別。
目前將腫瘤相關肽分類為以下主要幾組:
a)癌-睾丸抗原:T細胞能夠識別的最先確認的TAA屬於這一類抗原,由於其成員表達於組織學相異的人腫瘤中、正常組織中、僅在睾丸的精母細胞/精原細胞中、偶爾在胎盤中,因此,它最初被稱為癌-睾丸(CT)抗原。由於睾丸細胞不表達HLAI類和II類分子,所以,在正常組織中,這些抗原不能被T細胞識別,因此在免疫學上可考慮為具有腫瘤特異性。CT抗原大家熟知的例子是MAGE家族成員或NY-ESO-1。
b)分化抗原:腫瘤和正常組織(腫瘤源自該組織)都含有TAA,大多數TAA發現于黑色素瘤和正常黑色素細胞中
。許多此類黑色素細胞譜系相關蛋白參與黑色素的生物合成,因此這些蛋白不具有腫瘤特異性,但是仍然被廣泛用於癌症的免疫治療。例子包括,但不僅限於,黑色素瘤的酪氨酸酶和Melan-A/MART-1或攝護腺癌的PSA。
c)過度表達的TAA:在組織學相異的腫瘤中以及許多正常組織中都檢測到了基因編碼被廣泛表達的TAA,一般表達水準較低。有可能許多由正常組織加工和潛在提呈的表位低於T細胞識別的閾值水準,而它們在腫瘤細胞中的過度表達能夠透過打破先前確立的耐受性而引發抗癌反應。這類TAA的典型例子為Her-2/neu、生存素、端粒酶或WT1。
d)腫瘤特異性抗原:這些獨特的TAA產生於正常基因(如β-catenin、CDK4等)的突變。這些分子變化中有一些與致瘤性轉化和/或進展相關。腫瘤特異性抗原一般可在不對正常組織帶來自體免疫反應風險的情況下誘導很強的免疫反應。另一方面,這些TAA在多數情況下只與其上確認了有TAA的確切腫瘤相關,並且通常在許多個體腫瘤之間並不都共用TAA。在含有腫瘤特定(相關)同種型蛋白的情況下,如果肽源自腫瘤(相關)外顯子也可能出現肽腫瘤特異性(或相關性)。
e)由異常翻譯後修飾產生的TAA:此類TAA可能由腫瘤中既不具有特異性也不過度表達的蛋白產生,但其仍然具有腫瘤相關性(該相關性由主要對腫瘤具有活性的翻譯
後加工所致)。此類TAA產生於變糖基化模式的改變,導致腫瘤產生針對MUC1的新型表位或在降解過程中導致諸如蛋白拼接的事件,這可能具有也可能不具有腫瘤特異性。
f)腫瘤病毒蛋白:這些TTA是病毒蛋白,可在致癌過程中發揮關鍵作用,並且由於它們是外源蛋白(非人源蛋白),所以能夠激發T細胞反應。這類蛋白的例子有人乳頭狀瘤16型病毒蛋白、E6和E7,它們在宮頸癌中表達。
對於被細胞毒性T淋巴細胞識別為腫瘤特異性抗原或相關性抗原以及用於治療的蛋白質,必須具備特殊的條件。該抗原應主要由腫瘤細胞表達,而不由正常健康組織表達,或表達數量相對較少。在一個較佳的實施方案中,與正常健康組織相比,所述肽應在腫瘤細胞中過度提呈。更為適宜的情況是,該相應抗原不僅出現於一種腫瘤中,而且濃度(即每個細胞的相應肽拷貝數目)高。腫瘤特異性抗原和腫瘤相關抗原往往是源自直接參與因細胞週期控制或凋亡抑制中的其功能而發生的正常細胞向腫瘤細胞轉化的蛋白。另外,這些直接導致轉化事件的蛋白的下游靶標可能會被上調,因此可能與腫瘤間接相關。這些間接腫瘤相關抗原也可能是預防接種方法的靶標(Singh-Jasuja et al.,2004)。至關重要的是,表位存在於抗原氨基酸序列中,以確保這種肽(「免疫原性肽」)來自腫瘤相關抗原,可導致體外或體內T細胞反應。
基本上,任何能與MHC分子結合的肽都可能充當一個T細胞表位。誘導體外或體內T細胞反應的前提是存在具有
相應TCR的T細胞,並且不存在對該特定表位的免疫耐受性。
因此,TAA是基於T細胞療法(包括但不限於腫瘤疫苗)研發的起點。識別和表徵TAA的方法基於對患者或健康受試者T細胞的使用情況,或基於腫瘤與正常組織肽之間差別轉錄特性或差別表達模式的產生。
然而,對腫瘤組織或人腫瘤細胞株中過度表達或選擇性表達的基因的識別並不提供在免疫療法中使用這些基因所轉錄抗原的準確資訊。這是因為,有著相應TCR的T細胞必須要存在而且對這個特定表位的免疫耐受性必須不存在或為最低水準,因此,這些抗原的表位只有一部分適合這種應用。因此,在本發明的一非常較佳的實施例中,只選擇那些針對可發現功能性和/或增殖性T細胞情況的過量提呈或選擇性提呈肽,這一點非常重要。這種功能性T細胞被定義為在以特異性抗原刺激後能夠克隆地擴展並能夠執行效應子功能(「效應子T細胞」)的T細胞。
在本發明的TCR和抗體下,潛在肽的免疫原性是次要的。對於本發明的TCR和抗體,提呈是決定性因素。
針對其他癌性疾病的治療和診斷用途在本發明肽的基礎蛋白(多肽)的以下更詳細描述中進行披露。
據報告,膀胱癌、橫紋肌樣腫瘤及卵巢癌和基因內的特定多態性的COL18A1差異表達被證明能增加散發性乳房癌的風險(Fang et al.,2013;Gadd et al.,2010;Peters et al.,2005;Lourenco et al.,2006)。
COPA基因表達和RNA編輯的變化被證明與肝細胞
癌相關,實驗研究顯示了COPA在間皮瘤細胞中的抗凋亡作用(Sudo et al.,2010;Qi et al.,2014;Wong et al.,2003)。
CPB2活性被證明在急性早幼粒細胞白血病中顯著降低(Meijers et al.,2000)。
CRP是肝臟中合成的一種急性期蛋白,被證明是多種癌症類型以及腎細胞癌和多發性骨髓瘤的預後標誌物(Ljungberg,2007;Fassas and Tricot,2004)。
CRYZ是腫瘤抑制基因p53的靶基因(Bansal et al.,2011)。其編碼的蛋白ζ晶體被證明可直接與抗凋亡分子bcl-2的mRNA相互作用,並穩定bcl-2在T細胞急性淋巴細胞性白血病中的過度表達(Lapucci et al.,2010)。
CSRP2的過度表達與肝細胞癌的去分化有關(Midorikawa et al.,2002)。
CYB5A編碼一種解毒致癌分子的酶,是胰腺癌的一個預後因素(Blanke et al.,2014;Giovannetti et al.,2014)。
CYP27A1的表達水準增加與子宮內膜癌、乳腺癌和結直腸癌相關(Bergada et al.,2014;Neldon et al.,2013;Matusiak and Benya,2007)。
據報告,CYP2E1在大腸癌中過度表達,特定多態性與膀胱癌、肺癌和乳腺癌細胞相關(Ye et al.,2014;Patel et al.,2014;Deng et al.,2014;Leung et al.,2013)。
CYP2J2是一種酶,其被證明在多種人類癌症中過度表達,包括食道癌、肺癌、乳腺癌、胃癌、肝癌和結腸癌(Jiang et al.,2005;Narjoz et al.,2014)。
CYP4F8被證明在攝護腺癌中高度表達(Vainio et al.,2011)。CYP4F2和CYP4F3均被證明在胰腺導管腺癌中過度表達,而只有CYP4F2在卵巢癌中過度表達(Gandhi et al.,2013;Alexanian et al.,2012)。
CYP4F11的表達被證明被NF-κB和p53調節(Kalsotra et al.,2004;Bell and Strobel,2012;Goldstein et al.,2013)。
CYPAF12的基因變異與胰腺癌患者對吉西他濱響應顯著相關(Goldstein et al.,2013;Harris et al.,2014)。
一方面,高水準DAP3與胃癌對化療更好的反應和乳腺癌更好的臨床結果相關,但另一方面,據報告,DAP3在甲狀腺嗜酸腫瘤和浸潤性成膠質細胞瘤中過度表達(Jia et al.,2014;Wazir et al.,2012;Jacques et al.,2009;Mariani et al.,2001)。
PEX19是過氧化物酶體生物合成所必需的,但也顯示可直接與p19ARF相互作用,最終導致該因數在細胞質中保留並使p53腫瘤抑制功能失活(Sugihara et al.,2001)。
DDX11屬於DNA解旋酶的DEAH家族,在晚期黑素瘤中高度表達(Bhattacharya et al.,2012)。
NME4是一種核苷二磷酸激酶,在結腸癌和胃癌以及骨髓增生異常徵候群中過度表達,在後者的疾病中與不良預後相關(Kracmarova et al.,2008;Seifert et al.,2005)。
DENND5B充當啟動Rab-GTP酶的GDP-GTP交換因數(Yoshimura et al.,2010)。
DIEXF被證明可介導腫瘤抑制基因p53的非蛋白酶
體降解(Tao et al.,2013)。
DOCK7是一種鳥嘌呤核苷酸交換因數,被證明在膠質母細胞瘤中過度表達並可透過啟動Rac-1來增加膠質瘤細胞浸潤以應對HGF(Murray et al.,2014)。
在肝細胞癌細胞株中,DRG2被證明在化療藥物誘導的細胞凋亡期間下調,而DRG2過度表達抑制在這些細胞中阿黴素誘導的細胞凋亡(Chen et al.,2012a)。
DROSHA是微小RNA生物合成中的兩個關鍵酶之一,在許多癌症中過度表達,包括胃腸道腫瘤、乳腺癌和宮頸癌,並且似乎增強增殖、集落形成和腫瘤細胞遷移(Avery-Kiejda et al.,2014;Havens et al.,2014;Zhou et al.,2013b)。
DUSP14基因中的SNP與黑素瘤改變風險相關(Yang et al.,2014a;Liu et al.,2013b)。
整個外顯子測序研究發現胰腺內導管內乳頭狀黏液性腫瘤患者的DYNC1H1基因內有體細胞突變(Furukawa et al.,2011)。
EEF2蛋白被證明在肺癌、食道癌、胰腺癌、乳腺癌、攝護腺癌、多形性膠質母細胞瘤和非霍奇金淋巴瘤過度表達,並在癌細胞生長中發揮致癌作用(Oji et al.,2014;Zhu et al.,2014a)。
EFR3A基因內的突變在結直腸腺瘤樣本中得到鑒定(Bojjireddy et al.,2014;Zhou et al.,2013a)。
EIF2B5編碼翻譯起始因數B的一個亞基。該基因的
單核苷酸多態性被描述與卵巢癌的存活時間相關(Goode et al.,2010)。
EIF3A(真核翻譯起始因數3亞基A)在乳腺癌、肺癌、宮頸癌、食道癌、胃癌和結腸癌中過度表達,並且顯示出參與細胞週期調控(Dong and Zhang,2006)。
EIF4E是在高達30%的人類惡性腫瘤(包括乳腺癌、攝護腺癌、肺癌、頭頸部癌)以及在許多白血病和淋巴瘤中升高的有效癌基因(Carroll and Borden,2013)。
ELOVL2被證明在肝細胞癌中過度表達(Jakobsson et al.,2006;Zekri et al.,2012)。
EPRS編碼多功能氨醯tRNA合成酶,據報告,是結腸癌中腫瘤相關抗原(Line et al.,2002)。
由於DNA低甲基化,EXOSC4啟動子活性在肝細胞癌增加。EXOSC4有效和特異地抑制癌細胞生長和細胞侵入能力(Drazkowska et al.,2013;Stefanska et al.,2014)。
水解酶FUCA2被發現是幽門螺桿菌粘附於人胃癌細胞所必需的(Liu et al.,2009a)。
GABRQ編碼GABAA受體θ亞基。GABA被證明可透過過度表達的GABAA受體θ亞基刺激人肝細胞癌生長(Li et al.,2012)。
據報告,在鱗狀細胞癌中,GALNT2過度表達可透過修改O-糖基化和EGFR的活性來增強腫瘤細胞的侵襲能力(Lin et al.,2014;Hua et al.,2012a;Wu et al.,2011)。
高水準GGH與抗葉酸細胞抗性相關聯,特別是甲氨
蝶呤,同時與侵襲性乳腺癌和肺內分泌腫瘤的不良預後相關(Schneider and Ryan,2006;Shubbar et al.,2013;He et al.,2004)。
GLUL在人乳腺癌細胞和星形細胞瘤中過度表達(Zhuang et al.,2011;Collins et al.,1997;Christa et al.,1994;Cadoret et al.,2002)。
據報告,GNPAT牽涉轉移性黑素瘤中生長抑制和凋亡誘導(Ofman et al.,2001;Qin et al.,2013)。
據報告,GOLGA4染色體區域在宮頸癌中缺失,在骨髓增殖性腫瘤中GOLGA4與PDGFRB結構內mRNA融合(Senchenko et al.,2003;Hidalgo-Curtis et al.,2010)。
GPAM在人乳腺癌中表達,這與在細胞代謝改變和更好的整體存活相關(Brockmoller et al.,2012)。
據報告,GPT高血清水準增加胃腸癌的風險,並且與丙型肝炎病毒誘導的肝細胞癌的發生和復發有關(Kunutsor et al.,2014;Tarao et al.,1997;Tarao et al.,1999)。
GRB14已顯示在乳腺癌中上調,其中高表達與更好的無病生存和總體生存相關(Huang et al.,2013;Balogh et al.,2012)。
據報告,GTF2H4中單核苷酸多態性可增加發生吸煙相關肺癌和乳頭狀瘤病毒誘導的宮頸癌的風險(Mydlikova et al.,2010;Buch et al.,2012;Wang et al.,2010)。
不同的研究表明,HSPA2在宮頸癌、腎細胞癌和膀胱癌的疾病進展中起著重要作用。基因內多態性與胃癌的發
生有關(Singh and Suri,2014;Ferrer-Ferrer et al.,2013;Garg et al.,2010a;Garg et al.,2010b)。
HSPA8被證明在食管鱗狀細胞癌中過度表達。此外,HSPA8在多發性骨髓瘤和結腸癌中過度表達,HSPA8的BCR-ABL1-誘導表達促進慢性髓性白血病細胞的存活(Dadkhah et al.,2013;Wang et al.,2013a;Chatterjee et al.,2013;Kubota et al.,2010;Jose-Eneriz et al.,2008)。
MDN1被描述為一種候選腫瘤抑制基因,在管腔B型乳腺癌中突變(Cornen et al.,2014)。
MIA3,也稱為運輸和高爾基組織蛋白1(TANGO),據報導在結腸和肝細胞癌中下調,在這些實體中發揮腫瘤抑制作用(Arndt and Bosserhoff,2007)。相反,口腔鱗狀細胞癌的一項研究表明,MIA3表達與腫瘤進展、轉移形成和臨床分期相關,指向MIA3的致癌作用(Sasahira et al.,2014)。
CPSF6被認定為「靜止基因盒」中的一種基因,其與幾種類型腫瘤的轉移和侵襲可能的顯著差異相關,如乳腺癌、結腸癌、肝癌、肺癌、食道癌、甲狀腺癌(Yu et al.,2008)。
據報告,MPDZ表達水準低與乳腺癌患者預後不良相關(Martin et al.,2004)。
NAA35(也被稱為MAK10)編碼N(α)-乙醯轉移酶35,NatC輔助亞基。在食管鱗狀細胞癌患者中,檢測到高度癌症富集嵌合體GOLM1-MAK10RNA,其編碼一種分泌的融合蛋白,可能用作分子標誌物(Zhang et al.,2013b)。
NAV2顯示出特異性表達於一組結腸癌中,對含反義寡核苷酸的結腸癌細胞進行NAV2治療誘導細胞凋亡(Ishiguro et al.,2002)。
NCSTN過度表達表明雌激素受體陰性乳腺癌患者的總體生存惡化,在內分泌治療抵抗的乳腺癌細胞中檢測到高水準的Nicastrin和Notch4,它們的啟動最終驅動了侵襲行為(Sarajlic et al.,2014;Lombardo et al.,2014)。
在非小細胞肺癌中NKD1蛋白降低,但NKD1mRNA升高,前者與侵襲能力增加和預後不良相關(Zhang et al.,2011)。NKD1mRNA也被發現在人結腸腫瘤細胞中升高(Yan et al.,2001;Zhang et al.,2011)。
據報告,在食管癌中NUDC與淋巴結轉移相關,而NUDC在攝護腺癌細胞中過度表達導致細胞分裂受阻(Hatakeyama et al.,2006;Lin et al.,2004)。
一項在卵巢癌中調查Notch信號傳導途徑作用的研究報告,與癌症相比,RFNG在腺瘤中表達頻率較高(Guet al.,2012;Hopferet al.,2005)。
RINT1被描述為膠質母細胞瘤的一種癌基因,作為乳腺癌和Lynch徵候群相關癌症中所見的一種適度滲透癌症易感基因(Ngeow and Eng,2014;Quayle et al.,2012)。
RORC的高表達被發現與乳腺癌長期無轉移生存率相關。生長激素腺瘤中RORC表達下降與腫瘤大小增加以及對生長抑素治療臨床反應遲鈍增加相關(Cadenas et al.,2014;Lekva et al.,2013)。
據報告,RPL17可透過抑制藥物誘導的凋亡促進多藥耐藥(Shi et al.,2004b)。
據報告,RPS29在胃癌和結直腸癌中表達增加(Takemasa et al.,2012;Sun et al.,2005)。
SAMM50編碼線粒體外膜的排序和裝配機械(SAM)組分,其在β-桶狀蛋白組裝成線粒體外膜中發揮作用。在乳腺癌和卵巢癌細胞中以及乳腺癌、胃癌、結腸癌、腎癌和子宮癌樣本中檢測到生長促進嵌合體mRNA(SAMM50-PARVB)(Plebani et al.,2012)。
SERPINF2編碼纖溶酶的主要抑制劑,這會降低纖維蛋白和各種其他蛋白。纖溶酶-α2-纖溶酶抑制劑複合體的血漿水準被證明是非小細胞肺癌生存的預測因數,在攝護腺癌患者的血液中觀察到α2-抗纖溶酶活性低(Zietek et al.,1996;Taguchi et al.,1996)。
SF3B3過度表達與雌激素受體陽性乳腺癌中整體存活和內分泌性顯著相關(Gokmen-Polar et al.,2014)。
SHC1的蛋白水準在攝護腺癌、轉移性乳腺癌、卵巢癌和甲狀腺癌和不同的異構體中升高,並且被認為作為主連接蛋白在非基因組水準介導類固醇類的有絲分裂信號(Alam et al.,2009;Rajendran et al.,2010)。
AMACR用作攝護腺癌的生物標誌物,因為它在該實體中高度過表達(Wu et al.,2014)。此外,還用作腎細胞癌診斷的免疫標誌物(Ross et al.,2012)。
實驗資料表明,C1QTNF3表達可能在骨肉瘤腫瘤生
長中發揮作用,與ERK1/2信號途徑活化相關,並且它是一種新型的抗凋亡脂肪因數,可透過PI3K/Akt信號途徑保護充質幹細胞不會發生低氧/血清剝奪誘導的凋亡(Hou et al.,2014;Akiyama et al.,2009)。
大多數肝細胞癌表達GPC3。靶向作用於GPC3的兩種HCC治療方法目前正在II期臨床試驗中進行測試:人源化GPC3單克隆抗體,以及包括兩個GPC3衍生肽的疫苗。後一項研究中使用的肽與本檔中提出的肽不同。在所有卵黃囊腫瘤、一些肺鱗狀細胞癌和卵巢透明細胞癌中也發現有GPC3表達(Filmus and Capurro,2013;Kandil and Cooper,2009)。
MAGEB2被歸類為癌症睾丸抗原,因為它在睾丸和胎盤、很大一部分各種組織學類型腫瘤以及其他多發性骨髓瘤和頭頸部鱗狀細胞癌中表達(Pattani et al.,2012;van et al.,2011)。
MAPKAPK5編碼絲氨酸/蘇氨酸激酶家族的腫瘤抑制物和成員。MAPKAPK5被證明在結直腸癌中低表達,導致myc癌蛋白活性增加並透過抑制造血癌症小鼠模型中致癌ras基因活性而減少癌症形成(Yoshizuka et al.,2012;Kress et al.,2011)。
USP14過度表達與卵巢上皮癌、非小細胞肺癌和結直腸癌中的腫瘤細胞增殖增加和較差預後有關(Wang et al.,2015;Wu et al.,2013a;Shinji et al.,2006)。
C4A被描述為多囊卵巢綜合症和子宮內膜癌的生物標誌物,實驗資料表明,C4可介導癌症生長(Galazis et al.,
2013;Rutkowski et al.,2010)。
據報告,CAPZB在人乳頭瘤病毒18陽性口腔鱗狀細胞癌中過度表達,被確定為攝護腺癌易感基因(Lo et al.,2007;Nwosu et al.,2001)。
CFHR5基因內的單核苷酸多態性與濾泡性淋巴瘤的無事件生存率相關(Charbonneau et al.,2012)。
CLIP1編碼含有連接蛋白1的CAP-GLY域,其把內吞囊泡連接至微管。此基因在霍奇金病和裏德-斯特恩伯格細胞和乳腺癌中高表達,並似乎涉及乳腺癌和胰腺癌細胞的遷移和侵襲(Sun et al.,2013;Suzuki and Takahashi,2008;Li et al.,2014a;Sun et al.,2012)。
CLU可抑制腫瘤進展,而在晚期瘤變中,其可透過抑制許多治療性應激物和提高轉移而帶來腫瘤的顯著生存優勢。CLU已經顯示出在攝護腺癌發病機制中的關鍵作用,透過調節ERK1/2信號和MMP-9表達來調節人腎透明細胞癌細胞的侵襲行為,並形成晚期肺癌治療的抗性(Trougakos,2013;Panico et al.,2009;Takeuchi et al.,2014;Wang et al.,2014)。
融合基因SEC16A-NOTCH1報告為乳腺癌的第一復發融合基因(Edwards and Howarth,2012)。
在SHQ1基因的復發性缺失已在攝護腺癌和宮頸癌中觀察到,提示SHQ1具有腫瘤抑制作用(Krohn et al.,2013;Lando et al.,2013)。
在透明細胞腎細胞癌和膀胱癌中,SLC16A1高表達與預後不良因素相關,並可預測腫瘤的進展。在結直腸癌中
,SLC16A1基因的單核苷酸多態性可影響臨床結果,並且可用來預測對輔助化療的反應(Kim et al.,2015;Fei et al.,2014a;Fei et al.,2014a)。
成膠質細胞瘤已經顯示可釋放高水準的谷氨酸,這可能會刺激腫瘤細胞增殖、促進腫瘤侵襲性,並下調SLC1A2,這與較高的腫瘤分級相關,提示其在神經膠質腫瘤進展中發揮潛在作用。此外,在胃癌中已檢測到SLC1A2與CD44的融合基因,並且該基因可能代表了一類基因融合,其建立了一個有利於腫瘤生長和存活的親致癌代謝環境(Tao et al.,2011;deGroot et al.,2005)。
SLC3A2較高表達與膽道癌患者的腫瘤生長、生物攻擊性和生存相關,並且透過PI3K/Akt途徑促進細胞增殖顯著導致非小細胞肺癌患者的較差預後。此外,SLC3A2與整合素ß1、整合素ß3和Fak過度表達與結直腸癌的進展和肝轉移相關(Kaira et al.,2014;Fei et al.,2014b;Sun et al.,2014)。
SLC9A3R1參與癌症進展的證據存在於肝細胞癌、神經鞘瘤、成膠質細胞瘤、結直腸癌中,尤其在乳腺癌中(Saponaro et al.,2014)。
NFYC已經被報告可促進胃癌和攝護腺癌細胞中癌基因的表達(Zhang et al.,2014a;Gong et al.,2013)。
THY1是鼻咽癌抗侵襲活性的候選抑癌基因(Lung et al.,2010)。
TIMM17A在21T乳腺癌細胞中過度表達,乳腺癌組織中的mRNA表達與腫瘤進展相關(Xu et al.,2010)。
TMEM209在肺癌中廣泛表達(Fujitomo et al.,2012)。
TNK2又稱ACK1酪氨酸激酶,在多種人類癌症中被啟動、擴增或突變。去調節激酶具有致癌性,它的啟動與進展為轉移期相關。ACK1抑制劑在臨床前研究中顯示出良好前景(Mahajan and Mahajan,2013)。
TRIM55編碼RING鋅指蛋白,其在肌肉肌節組裝過程中與微管、肌球蛋白和肌聯蛋白暫態相關,並且還參與肌節到細胞核信號傳導(Pizon et al.,2002)。
Ufd1蛋白的RNA幹擾可以使羥基耐結腸癌細胞株SW1116/HCPT對羥基喜樹堿敏感(Chen et al.,2011a;Chen et al.,2011c)。
在結直腸癌中,UGT1A1基因透過甲基化沉寂,因此被認為是伊立替康(CPT-11)藥物抗性和藥物抗性逆轉控制機制的研究目標靶點(Xie et al.,2014)。
UGT1A10是在胃癌和膽道組織中表達(Strassburg et al.,1997),其過度表達顯著增加了抗腫瘤劑5-二甲基氨基丙基氨基-8-羥基三唑吖啶C-1305的細胞毒性(Pawlowska et al.,2013)。此外,UGT1A10催化外源性化學物質、誘變劑和活性代謝物的葡糖醛酸結合,從而作為間接的抗氧化劑。在UGT1A8、UGT1A9及UGT1A10的啟動子中進行檢測到生物外源性(XRE)和抗氧化劑(ARE)反應元素(Kalthoff et al.,2010)。
UGT1A8主要在胃腸道中表達(Gregory et al.,2003),經化療預防劑萊菔硫烷(SFN)治療後mRNA表達上調(Wang et
al.,2012)。
UGT1A7單倍型與乙肝病毒攜帶者的肝細胞癌風險增加有關(Kong et al.,2008)。
UGT1A6在對甲氨蝶呤抗藥的乳腺癌細胞中過度表達(deAlmagro et al.,2011)並由一種假定的化療預防劑β-萘黃酮誘導(Hanioka et al.,2012)。
UGT1A9主要在肝和腎中表達(Gregory et al.,2003)。UGT1A9生殖多態性是攝護腺切除術後攝護腺癌復發的潛在預測因素(Laverdiere et al.,2014)。
UGT1A4啟動子和編碼區的多態性導致阿那曲唑(乳腺癌患者的一種芳香酶抑制劑)的葡糖醛酸化的變化(Edavana et al.,2013)。
UPF1是無義介導mRNA降解(NMD)機制的一部分,並且可能在攝護腺癌進展和轉移中發揮著功能性作用(Yang et al.,2013)。另外,UPF1RNA監控基因在胰腺癌腺鱗癌中通常突變(Liu et al.,2014)。
UQCRB是線粒體複合體III的一個亞基。腫瘤細胞中UQCRB的抑制阻止缺氧誘導的腫瘤血管生成(Jung et al.,2013)。UQCRB的3'非翻譯區的兩個SNP作為結直腸癌的候選預後標誌物(Lascorz et al.,2012)。
與結節性黑素瘤相比,USO1的拷貝數變化與淺表擴散性黑素瘤差異基因表達相關(Rose et al.,2011)。
在人結腸癌中檢測到USP10和SIRT6蛋白表達顯著減少(Lin et al.,2013)。
UTP18也改變翻譯以促進抗逆性和生長,並經常在癌症中獲得並過度表達(Yang et al.,2014b)。
VARSrs2074511多態性與三陰性型乳腺癌患者的存活相關,因此可被認為是早期乳腺癌患者存活的預後因數(Chae et al.,2011)。
VMP1是一種應激誘發的自噬相關蛋白,也被癌基因KRAS誘發(LoRe et al.,2012)。VMP1在低分化人胰腺癌中過度表達,對化療藥物產生反應(Gilabert et al.,2013)。VMP1在人HCC組織中被發現顯著下調,並與多個腫瘤結節、無包膜形成、靜脈侵犯和HCC預後不良密切相關(Guo et al.,2012)。
WDR26保護心肌細胞免受氧化應激的影響(Feng et al.,2012)。
ZC3H7A是稱為巨噬細胞活化的調節因數CCCH鋅指蛋白家族的一部分(Liang et al.,2008)。ZC3H7A被發現在胰腺導管腺癌轉移性腫瘤中有更高的功能突變等位元基因頻率(Zhou et al.,2012)。
FASN是一種脂肪酸合酶,參與不同類型癌症(包括乳腺癌、胰腺癌、攝護腺癌、肝癌、卵巢癌、結腸癌和子宮內膜癌)的增強脂質合成(Wu et al.,2014;Zhao et al.,2013)。
FGG在肝細胞癌以及攝護腺癌、肺癌和乳腺癌中上調(Vejda et al.,2002;Zhu et al.,2009)。
FMO5是一種單加氧酶,是占主導地位的肝特異性
FMO,並且在雌激素受體α陽性乳腺腫瘤中上調(Bieche et al.,2004;Zhang and Cashman,2006)。
HADHAmRNA隨著HCC(Tanaka et al.,2013)和雌激素受體α陰性乳腺腫瘤(Mamtani and Kulkarni,2012)去分化的進展而下降。
HAL基因的遺傳變異可能在皮膚癌發生中起作用(Welsh et al.,2008)。
HLTF是具有解旋酶和E3泛素連接酶活性的轉錄調節因數SWI/SNF家族中的一員,被發現透過結腸、胃、子宮、膀胱和肺腫瘤的超甲基化而失活(Debauve et al.,2008;Castro et al.,2010;Garcia-Baquero et al.,2014)。
HDAC10是一種組蛋白脫乙醯和轉錄調節因數。與相鄰組織相比,HDAC10的表達在胃癌組織中顯著降低(Jin et al.,2014)。HDAC10在宮頸鱗狀細胞癌人類患者中與淋巴結轉移負相關(Song et al.,2013)。HDAC10在惡性腎上腺皮質腫瘤中超甲基化(Fonseca et al.,2012)。HDAC10水進在慢性淋巴細胞性白血病中增加(Wang et al.,2011)。HDAC10-589C>T啟動子多態性與慢性HBV患者的肝癌發生以及慢性HBV患者的HCC加重顯著相關(Park et al.,2007)。II類組蛋白脫乙醯基因的表達降低與肺癌患者的不良預後有關(Osada et al.,2004)。
HIP1R表達低與彌漫性大B細胞淋巴瘤患者的較差預後密切相關(Wong et al.,2014)。
HM13是一種信號肽肽酶,影響結直腸腺瘤中的細胞活力(Sillars-Hardebol et al.,2012)。
惡性淋巴瘤患者的血清HPR水準比未患病的對照組明顯更高,HPR表達隨著疾病進展而增加(Epelbaum et al.,1998)。HPR表達平行於乳腺癌惡性可能增加,HPR-陽性乳腺癌更有可能在首次切除後復發並與較短的無病間隔相關(Shurbaji et al.,1991)。
HSD11B1基因中的變體(rs932335)與結腸直腸癌和乳腺癌有關(Feigelson et al.,2008;Wang et al.,2013b)。
接受雄激素剝奪治療(ADT)的攝護腺癌患者組織中HSD17B6表達明顯高於未治療患者的組織中表達(Ishizaki et al.,2013)。
HSPE1是一種線粒體伴侶蛋白,在蛋白質折疊和細胞信號傳導(NF-κB和WNT信號傳導)中發揮作用。HSP10水準升高發現於大腸癌、宮頸外口癌、攝護腺癌、套細胞淋巴瘤和漿液性卵巢癌的腫瘤細胞中。在支氣管癌中,報告Hsp10水準下降(David et al.,2013)。
移植到裸鼠側腹並用紫杉醇治療的卵巢癌異種移植物與未治療的異種移植物相比,表現出IDI1表達下降(Bani et al.,2004)。
IGFBPL1是胰島素生長因數的調節因數,因異常超甲基化在乳腺癌細胞系下調。IGFBPL1甲基化與較差的總生存率和無病生存率明顯相關(Smith et al.,2007)。
雄激素敏感微粒相關蛋白IKBKAP調製攝護腺上皮和神經元標誌物的表達,透過雄激素受體依賴性機制減低增殖,並在LNCaP攝護腺腺癌細胞中共同調節雄激素受體介導
的轉錄(Martinez et al.,2011)。
INTS8是標誌物組的一部分,將胃癌與鄰近非癌性組織區分開來(Cheng et al.,2013)。
IRS2衍生肽pIRS-21097-1105在HLA-A2(+)黑色素瘤和乳腺癌、卵巢癌和結直腸癌中提呈(Zarling et al.,2014)。IRS-21057DD基因型和D等位基因與HCC風險顯著相關(Rashad et al.,2014)。
ITGA7是層粘連蛋白-1受體二聚體整合素α-7/β-1的α鏈。ITGA7是一種腫瘤抑制基因,對抑制惡性腫瘤的生長至關重要。突變分析表明,攝護腺癌、肝細胞癌、軟組織肉瘤以及膠質母細胞瘤中存在ITGA7突變。ITGA7在非轉移性攝護腺癌和子宮平滑肌肉瘤中下調(Tan et al.,2013)。
ITIH4在幾種腫瘤組織包括結腸、胃、卵巢、肺、腎、直腸和攝護腺腫瘤中下調(Hamm et al.,2008)。ITIH4低血清水準與HCV相關HCC患者的較短生存期相關(Noh et al.,2014)。ITIH4血清濃度在乳腺癌中觀察到顯著降低,手術後ITIH4血清水準顯著降低(van,I et al.,2010)。
錯義突變在SHKBP1中發現,其作用於FLT3的下游,FLT3在大約30%的AML病例中(一種受體酪氨酸激酶)突變(Greif et al.,2011)。SHKBP1是在疾病不同階段對分化良好的小腸神經內分泌腫瘤(WD-SI-NET)進行分類的幾個候選潛在蛋白質生物標誌物之一(Darmanis et al.,2013)。
與對應的非腫瘤組織相比,KLB表達在HCC組織中升高(Poh et al.,2012)。
LBP多態性rs2232596與中國漢族結直腸癌風險顯著增加相關(Chen et al.,2011b)。LBP是卵巢癌中的一種候選血清生物標誌物(Boylan et al.,2010)。在小細胞肺癌患者中,LBP在化療治療後顯著降低(Staal-van den Brekel AJ et al.,1997)。
LBRmRNA表達與乳腺癌的腫瘤分級和諾丁漢預後指數直接相關(Wazir et al.,2013)。LBR在乳頭狀甲狀腺癌細胞中大量表達,但該蛋白的異常折疊可解釋其缺乏免疫反應性並與核膜反常折疊有關(Recupero et al.,2010)。
LEPR失調已在多種惡性細胞(包括結腸癌、肝癌、子宮內膜癌、甲狀腺癌、乳腺癌和肺癌)中進行了報告(Ntikoudi et al.,2014;Surmacz,2013;Uddinet al.,2011)。
LIG1單核苷酸多態性與肺癌、子宮內膜癌和神經膠質瘤的風險相關(Doherty et al.,2011;Lee et al.,2008;Liu et al.,2009b)。
LRPPRC在胃癌組織中的表達比相應對照組織中顯著較高(Li et al.,2014b)。LRPPRC水準作為攝護腺腺癌(PCA)患者的預後標誌物,LRPPRC水準高的患者手術後的生存時間短於LRPPRC水準低的患者(Jiang et al.,2014)。LRPPRC在各種腫瘤,如肺腺癌、食道鱗狀細胞癌、胃癌、結腸癌、乳腺癌、子宮內膜腺癌和淋巴瘤中大量表達(Tian et al.,2012)。
MANEA在攝護腺癌細胞中的表達受雄激素調節(Romanuik et al.,2009)。
OPLAH在肺、乳腺、腎、結腸和卵巢正常和腫瘤組
織中表達,OPLAH在正常標本中的水準比腫瘤患者中明顯較高(Srivenugopal and Ali-Osman,1997)。
ORM2糖型為區別原發性和繼發性肝癌提供了有價值的資訊(Mackiewicz and Mackiewicz,1995)。與對照組相比,ORM2血漿水準被證實在結直腸癌患者中顯著升高(Zhang et al.,2012)。與對照組相比,岩藻糖形ORM2水準在腺癌肺癌病例中顯著較高(Ahn et al.,2014)。ORM2用於膽管癌早期診斷的一種推定生物標誌物(Rucksaken et al.,2012)。
四氫生物蝶呤水準升高導致人肝癌細胞中的PAH活性和PAH蛋白質增強(McGuire,1991)。
PARP14在骨髓瘤漿細胞高表達,與疾病進展和不良生存期相關。PARP14與JNK2依賴型生存期極度相關。PARP14被發現可透過結合和抑制JNK1促進骨髓瘤細胞的存活(Barbarulo et al.,2013)。
PC水準在肝腫瘤和肺癌中升高(Chang and Morris,1973;Fan et al.,2009)。
PCNT水準升高和中心體異常已在各種惡性血液病和實體瘤(包括AML、CML、套細胞淋巴瘤、乳腺癌和攝護腺癌)中進行了說明(Delaval and Doxsey,2010)。
PIGN是一種癌症染色體不穩定(CIN)-抑制基因,在CIN(+)結直腸癌中發生頻繁的拷貝數損失(Burrell et al.,2013)。
PIPOX表達根據乳腺癌亞型變化,HER-2型腫瘤顯示表達升高,三陰性乳腺癌亞型顯示表達下降。腫瘤PIPOX消極
性與較短的無病生存期相關(Yoon et al.,2014)。PIPOX在攝護腺腫瘤中下降,並透過代謝肌氨酸降低攝護腺細胞的致癌潛力(Khan et al.,2013)。
在結腸癌、骨髓瘤和肝細胞癌中檢測到PSMD4水準升高(Arlt et al.,2009;Midorikawa et al.,2002;Shaughnessy,Jr.et al.,2011)。
與對照組相比,PLIN2在透明細胞和乳頭狀腎細胞癌患者中顯著升高。PLIN2術前尿濃度反映腫瘤大小和分期(Morrissey et al.,2014)。PLIN2在肺腺癌標本中的表達顯著高於正常組織和肺鱗狀細胞癌(Zhang et al.,2014b)。
PLK4在人癌症中經常發生重排或損失,在肝細胞癌中發生率特別高,同時也在結直腸癌、頭頸部癌中發生(Swallow et al.,2005)。PLK4在乳腺癌中過度表達(Marina and Saavedra,2014)。
QARS是氨醯基-tRNA合成酶(ARS)的一員,以穀氨醯胺裝載tRNA。ARS表達和多態性與乳腺癌和成膠質細胞瘤相關(He et al.,2014b;Kim et al.,2012)。
甲基化PMF1基因是膀胱癌患者的診斷和預後生物標誌物(Kandimalla et al.,2013)。
幾種人類腫瘤和血液惡性腫瘤上調PON2,包括甲狀腺、攝護腺、胰腺、睾丸、子宮內膜/子宮、肝、腎、淋巴組織、膀胱腫瘤、ALL和CML,這種過度表達對不同化療藥物(伊馬替尼、多柔比星、星形孢菌素或放線菌素)產生耐藥性(Witte et al.,2011)。
PRKAR2A是蛋白激酶A的一種調節亞基。PRKAR2A顯著增加接受紫杉醇和泰索帝治療的攝護腺癌細胞系的生存期(Zynda et al.,2014)。PRKAR2A在肺腺癌中過度表達(Bidkhori et al.,2013)。
PRPF6是tri-snRNP(小核糖核蛋白)剪接複合體的一員,其透過生長調節相關基因的優先剪接驅動結腸癌增殖(Adler et al.,2014)。PRPF6在肺腺癌中過度表達(Bidkhori et al.,2013)。
與相應的鄰近正常攝護腺組織相比,PSMC4在攝護腺癌細胞中顯著和相干上調(Hellwinkel et al.,2011)。
QPRT表達隨著腦膠質瘤的惡性程度增加,並在放化療後復發性膠質母細胞瘤中表達增加,QPRT表達與較差預後相關(Sahm et al.,2013)。QPRT是濾泡甲狀腺結節免疫組織化學篩查的潛在標誌物(Hinsch et al.,2009)。
RABGGTB在化療難治性彌漫性大B細胞淋巴瘤中過度表達(Linderoth et al.,2008)。
RAD21在胃腸道腫瘤、結腸直腸癌、晚期子宮內膜癌、攝護腺癌和乳腺癌中過度表達(Atienza et al.,2005;Deb et al.,2014;Porkka et al.,2004;Supernat et al.,2012;Xu et al.,2014)。
RAD23B在乳腺癌進展中發揮著潛在作用(Linge et al.,2014)。單核苷酸多態性RAD23Brs1805329與日本HCV患者的HCC發生和復發有關(Tomoda et al.,2012)。
RASAL2是一種RAS-GTP酶-活化蛋白,在雌激素受
體陽性乳腺癌、卵巢癌和肺癌中具有腫瘤抑制功能(Li and Li,2014;Huang et al.,2014)。與此相反,RASAL2在三陰乳腺癌中具有致癌性,並促進間質浸潤和轉移(Feng et al.,2014a)。
RNMT耗竭在不同類型癌症(包括肝癌)中有效和特異地抑制癌細胞生長和癌症細胞浸潤能力(Stefanska et al.,2014)。
導致激酶活性升高的ROCK1過度表達或ROCK1基因突變已經在數種癌症(包括肺癌、胃癌、CML和AML)中報告(Rath and Olson,2012)。
RPL10A是c-Myc靶基因,可能有助於肝細胞轉化(Hunecke et al.,2012)。
與骨髓性白血病或骨髓增生異常預後特別差相關的INV(3)和t(3;3)中斷點在位於RPN1基因著絲粒和下游的區域簇生(Wieser,2002)。
RRBP1在肺癌和乳腺癌中過度表達(Telikicherla et al.,2012;Tsai et al.,2013)。
SCFD1表達在糜爛性胃炎中增加,這與胃癌相關(Galamb et al.,2008)。
ABCB1編碼在各種器官(如腸、肝、腎、腦和胎盤)正常細胞中表達的P-糖蛋白(P-gp)。P-gp過度表達和基因多態性在結直腸癌以及腎上腺腫瘤、肺癌和ALL中檢測到(Zhang et al.,2013a;Fojo et al.,1987;Gervasini et al.,2006;Jamroziak et al.,2004)。
ABCB10編碼亞家族B的ABC轉運蛋白(MDR/TAP)。
ABCB10被證明參與KCP-4人表皮樣癌細胞的順鉑抗性(Oiso et al.,2014)。
ABCB11的表達被證明在胰腺導管腺癌(最耐藥的癌症之一)中上調。因此,這可能歸因於這種癌症的普遍較差的治療反應(Mohelnikova-Duchonova et al.,2013)。
ABCC2在原發性輸卵管癌中的上調表達與較差預後相關(Halon et al.,2013)。
ABCC6在對姑息化療無應答的結直腸癌中明顯下調(Hlavata et al.,2012)。相反,在耐吉西他濱的人NSCLCA549細胞中上調(Ikeda et al.,2011)。
ACACA的表達被證明在許多人類癌症(如乳腺癌、攝護腺癌和肝癌)中上調,與癌細胞脂肪生成增強有關。各種ACACA抑制劑顯示,透過細胞增殖的抑制對癌細胞系產生治療作用,透過細胞凋亡誘導細胞死亡(Zuet al.,2013)。
ACLY在各種腫瘤(如乳腺癌、肝癌、結腸癌、肺癌和攝護腺癌)中異常表達,與腫瘤分期和分化負相關(Zuet al.,2012)。
ACSL3在肺癌中過度表達,基於臨床前研究,是肺癌治療的有前景的新治療靶標(Pei et al.,2013)。ACSL3上調表達可以作為雌激素受體特異性乳腺癌風險的潛在生物標誌物(Wang et al.,2013c)。
ACSL4在雌激素受體陰性乳腺腫瘤以及在雄激素受體陰性乳腺癌和攝護腺腫瘤中過度表達。類固醇激素敏感性損失與ACSL4表達的誘導有關(Monaco et al.,2010)。研究顯
示,ACSL4上調在從腺瘤向腺癌轉換期間發生(Cao et al.,2001)。
ACSS3的甲基化發現與經典風險因素(即年齡、階段或神經母細胞瘤MYCN狀態)中的至少一種相關(Decock et al.,2012)。
ADSSL1缺失常在致癌物誘導小鼠原發性肺腺癌、小鼠和人肺腺癌細胞系中觀察到,並與在原發性小鼠肺腫瘤更廣泛的染色體不穩定性表型相關(Miller et al.,2009)。
AGFG2被確定為識別可能保持無轉移復發的激素受體陰性或三陰性乳腺癌病例的14種候選預後基因之一(Yau et al.,2010)。
AGT是一種非常有效的抗血管生成因數,其顯示可在體外和體內發揮抗腫瘤效果(Bouquet et al.,2006)。在轉基因小鼠中,人AGT的過度表達顯示可減少血管生成,從而延緩肝癌的進展(Vincent et al.,2009)。
AKR1C4編碼人類醛-酮還原酶家族1成員C4並催化視黃醛還原為視黃醇(Ruiz et al.,2011)。因此,視黃醛耗竭下調視黃酸的生物合成,隨後阻斷類視黃醇信號,這有利於腫瘤進展(Tang and Gudas,2011;Ruiz et al.,2012)。
研究顯示ALDH1L1的表達在HCC和腦膠質瘤中下調。ALDH1L1在上述癌症中的下調與較差的預後和更具侵襲性的表型相關(Rodriguez et al.,2008;Chen et al.,2012b)。
研究顯示ALG3的表達在食管鱗狀細胞癌和宮頸癌中增強(Shi et al.,2014;Choi et al.,2007)。在食管鱗狀細胞癌
中,ALG3表達增加與淋巴結轉移有關(Shi et al.,2014)。
ANKS1A被認定為是Src家族激酶的新靶標,已知涉及某些結直腸癌的發生(Emaduddin et al.,2008)。
APOA1編碼載脂蛋白A-I,該蛋白是高密度脂蛋白(HDL)的主要蛋白成分。在多種動物腫瘤模型中,APOA1在腫瘤發生中顯示出強效的免疫調節作用,並顯示可透過支援先天和適應性免疫過程以抑制腫瘤生長和轉移(Zamanian-Daryoush et al.,2013)。
APOA2被證明在胰腺癌患者中被顯著降低(Hondaet al.,2012)。與此相反,APOA2的表達增加與HCC相關(Liu et al.,2007)。
在甲胎蛋白陰性HBV相關HCC中,APOB被發現是可能與HCC進展相關聯的14個差異表達蛋白質之一(He et al.,2014a)。在晚期乳腺癌中,APOB被發現是可預測新輔助化療反應和患者無復發生存期的6種差異表達蛋白之一(Hyung et al.,2011)。
根據III期結腸直腸癌患者以及在人黑色素瘤細胞中,AQP9與化學抗性增加有關(Dou et al.,2013;Gao et al.,2012)。
ARG1被證明是區分HCC和肝臟其他轉移性腫瘤的一種敏感和特異性標誌物(Sang et al.,2013)。ARG1可能有助於NSCLC的局部免疫抑制(Rotondo et al.,2009)。
與健康供體相比,磷酸化以及活性更高形式的ARSB蛋白被發現在慢性髓性白血病患者外周血白細胞中增加
(Uehara et al.,1983)。
在卵巢癌細胞中,ASNA1的下調被證明可對化療藥物順鉑、卡鉑、奧沙利鉑和亞砷酸鹽的敏感度(Hemmingsson et al.,2009)。
研究顯示,ASPH在各種癌症和癌細胞系中過度表達(Yang et al.,2010)。用ASPH裝載的樹突狀細胞接種產生對抗體外膽管癌細胞的細胞毒性,並顯著抑制肝內腫瘤生長和轉移(Noda et al.,2012)。
ATP1A2被發現是在膠質母細胞瘤中顯著上調的31個蛋白之一(Com et al.,2012)。與此相反,ATP1A2在骨髓浸潤轉移性成神經細胞瘤中下調(Morandi et al.,2012)。
ATP1A3被發現是在膠質母細胞瘤中顯著上調的31個蛋白之一(Com et al.,2012)。
ATP6V1C1可透過溶酶體V-ATP酶活性的調控來促進乳腺癌生長和骨轉移。ATP6V1C1下降明顯抑制小鼠4T1乳腺腫瘤細胞異種移植物腫瘤的生長、轉移以及體內溶骨性病變(Feng et al.,2013)。ATP6V1C1被證明在口腔鱗狀細胞癌中過度表達,並與腫瘤細胞的活動性有關(Otero-Rey et al.,2008)。
ATP7B與抗順鉑(廣泛使用的抗癌藥物)的癌症有關(Dmitriev,2011)。
AXIN2編碼Axin-(軸抑制)相關蛋白2,其可能在Wnt信號通路中對β-連環蛋白的穩定性調節中起著重要作用(Salahshor and Woodgett,2005)。此外,AXIN2被證明壓制癌
基因c-MYC的表達(Rennoll et al.,2014)。
在HCC中,與BAAT較高表達的患者相比,BAAT低表達與較差的生存期相關(Furutani et al.,1996)。
與正常肝組織相比,BHMT和BHMT2轉錄物顯示在HepG2細胞和HCC樣本中急劇下降(Pellanda et al.,2012)。
C12orf44被證明是對自噬是必要的,並以Atg13依賴的方式與ULK1相互作用(Mercer et al.,2009)。自噬在癌症中有雙重角色,透過防止損傷蛋白質和細胞器累積充當腫瘤抑制物,充當能促進已確定腫瘤的生長的細胞存活機制(Yang et al.,2011b)。
C17orf70是範可尼貧血核心複合體成分,對於複合體的穩定性是必不可少的。範可尼貧血核心複合體在DNA損傷應答網路中發揮著中心作用。範可尼貧血核心複合體介導的DNA損傷反應涉及乳腺癌易感基因產物BRCA1和BRCA2(Ling et al.,2007)。
C19orf80編碼肝細胞癌相關基因TD26,並被證明是HCC中甲基化水準最高在對照組織中最低的5個位點之一(Ammerpohl et al.,2012)。
CCT7被發現是一種蛋白質子網路的一部分,該網路可明顯判別晚期人結直腸癌(Nibbe et al.,2009)。
CDK6已顯示可調節腫瘤抑制Rb蛋白的活性。CDK6可透過增強細胞增殖和刺激血管生成發揮其腫瘤促進功能(Kollmann et al.,2013)。CDK6的藥理抑制顯示可抑制異常白血病細胞的生長分化(Placke et al.,2014)。
CFH可能在皮膚鱗狀細胞癌的進展中起著一定的作用(Riihila et al.,2014)。CFH可能在各種癌細胞中補體介導的裂解抗性起著關鍵作用,並顯示出在NSCLC中過度表達,這與預後較差有關(Cui et al.,2011)。
CLPTM1的失活突變在攝護腺癌細胞中被發現(Rossi et al.,2005)。
CMAS編碼胞苷酸N-乙醯神經氨酸合成酶,其催化唾液酸的活化以及其轉化為單磷酸胞苷二酯。活化的唾液酸用於N-糖基化,這是細胞分化過程中一種常見的翻譯後修飾。癌細胞表面上唾液酸糖表達增加是已知的腫瘤特徵之一(Bull et al.,2014)。
TF(轉鐵球蛋白)是使用最廣泛的腫瘤靶向配體之一,因為TF受體(TFR)在惡性細胞上過度表達,並透過與TF相互作用在細胞鐵攝取中起著關鍵作用(Biswas et al.,2013)。TFR的表達水準已表明與腫瘤分期或癌症進展相關(Tortorella and Karagiannis,2014)。
TH1L可能在人乳腺癌細胞增殖和侵襲的調節中起著重要作用,並且可能是人乳腺癌治療的潛在靶點(Zou et al.,2010)。
THTPA水解可能負責NDRG-1的抗增殖作用。NDRG-1已經顯示可減少乳腺癌、結腸癌、攝護腺癌和胰腺癌的侵襲和轉移(Kovacevic et al.,2008)。
SMYD3透過金屬蛋白酶MMP-9的表觀遺傳上調而促進癌浸潤(Medjkane et al.,2012)。SMYD3的表達在許多類
型的人正常組織中檢測不到或非常弱,而SMYD3的過度表達與胃癌、結直腸癌、肝細胞癌、攝護腺癌和乳腺癌的發生和發展相關(Hamamoto et al.,2006;Liuet al.,2014;Liu et al.,2013a)。
在大腦中缺乏STAT2(Yue et al.,2015)或組成性表達IFN-α(Wang et al.,2003)的轉基因小鼠中觀察到了STAT2與腫瘤發生之間的聯繫。
TACC3在許多人類癌症(包括卵巢癌、乳腺癌、鱗狀細胞癌和淋巴瘤)中過度表達(Ma et al.,2003;Jacquemier et al.,2005;Lauffart et al.,2005)。
SPBP還顯示可壓制雌激素受體α(ERα)的轉錄活性。SPBP過度表達抑制Erα依賴性乳腺癌細胞系的增殖(Gburcik et al.,2005)。在細胞核中,SPBP顯示相對低的活動性,並富集在染色質密集區域,這清楚地表明它是一種染色質結合蛋白(Darvekar et al.,2012)。TCF20對於對抗氧化應激的細胞防禦方案中涉及的蛋日質增強誘導很重要(Darvekar et al.,2014)。
C3是炎性腫瘤微環境的一種突出元素(Rutkowski et al.,2010),活化可帶來一種腫瘤生長優勢(Markiewski et al.,2008)。C3的酶裂解導致產生過敏毒素C3a(炎症介質和化學引誘物)和C3b(Sahu et al.,1998)。
CLN3是NT2神經元前體細胞和一些類型癌症的抗凋亡基因(Zhu et al.,2014b)。它參與神經元和非神經元細胞內的細胞內運輸和調節(Rakheja et al.,2008;Getty and Pearce,
2011),它牽涉幾個重要的信號通路(Persaud-Sawin et al.,2002)。在許多癌症細胞系(包括乳腺癌、結腸癌、惡性黑色素瘤、攝護腺癌、卵巢癌、神經母細胞瘤以及膠質母細胞瘤,但不包括肺癌或胰腺癌細胞系)中CLN3mRNA和蛋白過度表達(Rylova et al.,2002)。
SLC13A5是7個CIMP-標記基因之一。腎透明細胞癌(ccRCC)的CIMP(CpG島甲基劑表型)的特點是在CpG島DNA甲基化累積且患者預後較差(Tian et al.,2014;Arai et al.,2012)。
SLC35B2在急性炎症期間唾液酸磺基Lex聚糖生物合成誘導時參與協調轉錄調控(Huopaniemi et al.,2004),並在人結直腸癌細胞系中參與6個磺基乳糖胺表位的硫酸化(Kamiyama et al.,2006)。結直腸癌細胞以及人類結直腸組織表達SLC35B2(Kamiyama et al.,2011)。
PLOD1表達與人類乳腺癌進展相關(Gilkes et al.,2013)。
PRDX5在許多惡性腫瘤中上調(Urig and Becker,2006),抑制PRDX5能阻止腫瘤的發生和進展,表明PRDX5為癌症治療有前景的靶標。其高度親核和易於接近的硒半胱氨酸活性位點可能是藥物設計的主要靶標(Liu et al.,2012)。
PSMD8在周圍肺細胞中表達增加可能對哪些臨界細胞群體參與侵入性癌症發生提供潛在的資訊(Zhou et al.,1996)。
SNRPD1是一個核心剪接蛋白,其在惡性腫瘤中上調
。
SPTBN1表達下降與胰腺癌預後惡化有關(Jiang et al.,2010)。
SQSTM1作為各種信號轉導途徑的信號傳導中心,如NF-κB信號傳導、細胞凋亡和Nrf2活化,其失調與骨佩吉特病和腫瘤發生相關(Komatsu et al.,2012)。
PCNA表達可預測肛腸惡性黑色素瘤的生存期(Ben-Izhak et al.,2002)。PCNA(caPCNA)的癌症相關的同種型被確定其在PCNA內的眾多谷氨酸和天冬氨酸殘基上含有異常模式的甲酯基(Hoelz et al.,2006)。
在一些腫瘤細胞系中消耗SRP54不產生明顯的細胞表型,如生長停滯或死亡,即使在SRP組分穩定還原的選定細胞中也是如此(Ren et al.,2004)。
在分子水準上,STAT1透過其能力增加細胞週期蛋白依賴性激酶抑制劑p21Cip1的表達或降低c-myc的表達來抑制接受IFN-γ治療的小鼠和人腫瘤細胞的增殖(Ramana et al.,2000)。STAT1的抗腫瘤活性透過其抑制小鼠模型中的血管生成和腫瘤轉移的能力進一步得到支援(Huang et al.,2002)。STAT1 mRNA水準增加被證明是分子信號的一部分,與激素受體陰性和三陰性乳腺癌患者的轉移結果預後較好有關(Yau et al.,2010)。
濾泡狀腫瘤的細針穿刺樣本表明,與良性疾病相比,惡性結節過度表達STT3A(Patel et al.,2011)。
一項薈萃分析表明,STXBP4/COX11 rs6504950多態
性與乳腺癌風險顯著相關(Tang et al.,2012)。
由或基本上由本文所指氨基酸序列組成的一種肽可能有一個或兩個非錨定氨基酸(見下麵錨基序相關內容)被交換,而不存在這種情況,即相比於未修飾的肽,與人類主要組織相容性複合體(MHC)-I或-II類分子的能力基本上被改變或受到不利影響。在另一實施方案中,在基本上由本文所述氨基酸序列組成的肽中,一個或兩個氨基酸可與其保守交換夥伴交換(見下文),而不存在這種情況,即相比於未修飾的肽,與人類主要組織相容性複合體(MHC)-I或-II類分子的能力基本上被改變或受到不利影響。
本發明進一步涉及本發明的一種肽,其中所述肽按下文所述被修飾和/或包含非肽鍵。
本發明進一步涉及本發明的一種肽,其中所述肽為融合蛋白的一部分,特別是與HLA-DR抗原相關不變鏈(Ii)的N-端氨基酸融合,或與抗體(例如,樹突狀細胞特定抗體,即與樹突狀細胞結合)或抗體的序列融合。
本發明進一步涉及一種核酸,其編碼本發明的一種肽。本發明進一步涉及一種本發明的核酸,為DNA、cDNA、PNA、RNA,也可能為其組合物。
本發明進一步涉及一種能表達、表達和/或表達本發明核酸的表達載體。
本發明進一步涉及本發明的一種肽、本發明的一種核酸或本發明的一種藥用表達載體。
本發明進一步涉及下文進一步說明的抗體以及製造
抗體的方法。較佳為抗體特定於本發明的肽和/或與MHC結合時特定於本發明的肽。較佳的抗體可以是單克隆的。
本發明進一步涉及T細胞受體(TCR),特別是靶向作用於本發明肽的可溶性TCR(sTCR)和/或肽-其MHC複合體,以及製造它們的方法。
本發明進一步涉及靶向作用於本發明肽的抗體或其他結合分子和/或肽-其MHC複合體,以及製造它們的方法。
本發明進一步涉及含本發明核酸或前述表達載體的一種宿主細胞。本發明進一步涉及為一種抗原提呈細胞的本發明宿主細胞。本發明進一步涉及本發明的宿主細胞,其中抗原提呈細胞為樹突細胞。
本發明還涉及適體。適體(例如,參見WO2014/191359及其中引用的文獻)是短的單鏈核酸或肽分子,其可以折疊為所定義的三維結構並識別特定的靶標結構。它們似乎是開發靶向治療的合適替代方法。適體已顯示可選擇性與具有高親和力和特異性的複合體靶標相結合。
識別細胞表面分子的適體在過去十年內已經確定,並為開發診斷和治療方法提供了手段。由於適體已顯示幾乎無毒性和免疫原性,因此,它們是生物醫學應用中有前景的候選物質。事實上適體,例如攝護腺特異性膜抗原識別適體,已被成功地用於靶向治療並在體內模型的異種移植物中顯示出功能。此外,識別特定腫瘤細胞系的適體也已確定。
可選擇DNA適體來揭示各種癌細胞的廣譜識別屬性,特別是那些來自於實體瘤的細胞,而非致瘤和主要健康細
胞不被識別。如果所識別的適體不僅識別腫瘤特異性子類型,而且與一系列腫瘤相互作用,這使適體適用於作為所謂的廣譜診斷和治療手段。
此外,用流式細胞儀對細胞結合行為的研究顯示,適體在納摩爾範圍內顯示出很好的親和力。
適體用於診斷和治療目的。此外,也可能顯示,一些適體被腫瘤細胞吸取,因而可作為抗癌劑靶向遞送的分子賦形劑,例如siRNA進入腫瘤細胞。
可選擇適體針對複合體的靶標,如細胞和組織以及包含、較佳包括根據任何SEQ ID NO1至SEQ ID NO300的一個序列、根據本發明的肽複合體與MHC分子,使用細胞SELEX(透過指數富集的配體系統進化)技術。
本文所用的「支架」一詞是指與(如抗原)決定因數特異性結合的分子。在一項實施方案中,支架是能夠引導其所連接的實體(例如,(第二)抗原結合部分)至目標靶點,例如,至特定類型的腫瘤細胞或承載抗原決定簇的腫瘤基質(如根據目前應用的肽的複合體)。在另一項實施例中,支架能夠透過其靶抗原(例如T細胞受體複合體抗原)啟動信號通路。支架包括但不限於抗體及其片段,抗體的抗原結合區,其包含抗體重鏈可變區和抗體輕鏈可變區,結合的蛋白包括至少一個錨蛋白重複序列基元和單域抗原結合(SDAB)分子、適體、(可溶)TCR和(經修飾的)細胞,例如同種異體或自體T細胞。
各支架可包括一個標記,其透過確定是否存在或不
存在標籤所提供的信號可檢測到結合支架。例如,該支架可用螢光染料或任何其他適用的細胞標記分子進行標記。此類標記分子是本領域中公知的。例如,透過螢光染料進行的螢光標記可透過螢光或鐳射掃描顯微術或流式細胞術提供結合適體的視覺化。
各支架可與第二個活性分子(例如IL-21、抗CD3、抗CD28)共軛。例如,在WO 2014/071978 A1背景技術部分對多肽支架進行了描述,並作為參考文獻引用。
本發明進一步涉及製備本發明一種肽的一種方法,所述方法包括培養本發明的宿主細胞和從宿主細胞和/或其培養基中分離肽。
本發明進一步涉及一種體外製備啟動的T細胞的方法,該方法包括將T細胞與載有抗原的人I或II類MHC分子進行體外連接,這些分子在合適的抗原提呈細胞表面表達足夠的一段時間從而以抗原特異性方式啟動T細胞,其中所述抗原為本發明的至少一種肽。本發明進一步涉及一種方法,其中抗原透過與足夠量的含抗原提呈細胞的抗原結合被載入表達於合適抗原提呈細胞表面的I或II類MHC分子。
本發明進一步涉及本發明的方法,其中該抗原提呈細胞包括一個表達載體,該載體有能力表達含SEQ ID NO:1至SEQ ID NO:300的肽或其變體氨基酸序列。
本發明進一步涉及以本發明方法製備的啟動T細胞,該方法有選擇性地識別一種細胞,該細胞異常表達含一種本發明氨基酸序列的多肽。
本發明進一步涉及一種殺傷患者靶細胞的方法,其中患者的靶細胞異常表達含本發明任何氨基酸序列的多肽,該方法包括給予患者本發明的有效量T細胞。
本發明進一步涉及任何所述肽、本發明的一種核酸、本發明的一種表達載體、本發明的一種細胞、本發明一種作為藥劑或製造藥劑的啟動T細胞的用途。
本發明進一步涉及一種本發明的用途,其中所述藥劑為一種疫苗,一種細胞,一種細胞群,例如,一個細胞系,sTCR和單克隆抗體。
本發明進一步涉及一種本發明的用途,其中藥劑可有效抗癌。
本發明進一步涉及一種本發明的用途,其中所述癌細胞為HCC細胞。
本發明進一步涉及一種基於本發明肽的特定標誌物蛋白和生物標誌物,其可用於診斷和/或判斷HCC的預後。
此外,本發明涉及這些供癌症治療使用的新靶點。
此外,本發明涉及一種使用預篩選腫瘤相關肽的資料庫(本文中也稱為「存儲庫」)製備個性化抗癌疫苗用於單個患者的方法。
是否能刺激免疫反應取決於是否存在被宿主免疫系統視為異物的抗原。發現腫瘤相關抗原的存在增加了運用宿主免疫系統幹預腫瘤生長的可能性。目前,針對癌症免疫治療,正在探索利用免疫系統的體液和細胞進行免疫的各種機制。
細胞免疫反應的特定元素能特異性地識別和破壞腫瘤細胞。從腫瘤浸潤細胞群或外周血中分離出的T-細胞表明,這些細胞在癌症的天然免疫防禦中發揮了重要作用。特別是CD8陽性T細胞在這種反應中發揮重要作用,TCD8+能識別通常8至10個源自蛋白或位於細胞質的缺損核糖體產物(DRIP)的氨基酸殘基的主要組織相容性複合體(MHC)所載的肽中所含的I類分子。人MHC分子也稱為人白細胞-抗原(HLA)。
本文所用「肽」這一術語,系指一系列氨基酸殘基,通常透過相鄰氨基酸的α-氨基和羰基之間的肽鍵來連接。這些肽的長度較佳為9個氨基酸,但至短可為8個氨基酸長度,至長可為10、11、12或13個氨基酸長度,如果為MHC-II類肽時(本發明肽的拉長變體),至長可為14、15、16、17、18、19或20個氨基酸長度。
因此,「肽」這一術語應包括一系列氨基酸殘基的鹽,通常透過相鄰氨基酸的α-氨基和羰基之間的肽鍵來連接。較佳的情況是,鹽為肽的藥用鹽,例如:氯化物或乙酸(三氟乙酸)鹽。必須注意的是,本發明肽的鹽與其體內狀態的肽基本上不同,因為該不是體內的鹽。
術語「肽」應也包括「寡肽」。本文使用的術語「寡肽」是指一系列氨基酸殘基,通常透過相鄰氨基酸的α-氨基和羰基之間的肽鍵來連接。寡肽的長度對於本發明來說並不十分關鍵,只要在寡肽中保持正確的表位即可。通常,寡肽長度約小於30個氨基酸殘基,約長於15個氨基酸。
「本發明的肽」這一術語應也包括根據SEQ ID NO:1至SEQ ID NO:300的上述肽組成的肽或包含該肽的肽。
「多肽」這一術語是指一系列氨基酸殘基,通常透過相鄰氨基酸的α-氨基和羰基之間的肽鍵來連接。多肽的長度對於本發明來說並不十分關鍵,只要保持正確的表位即可。與術語肽或寡肽相對,多肽這一術語是指包含多於約30個氨基酸殘基的分子。
一種肽、寡肽、蛋白質或編碼該分子的核苷酸如果能誘導免疫反應,則具有「免疫原性」(因此是本發明中的一種「免疫原」)。在本發明的情況下,免疫原性的更具體定義是誘導T細胞反應的能力。因此,「免疫原」是一種能夠誘導免疫反應的分子,並且在本發明的情況下,是一種能誘導T細胞反應的分子。在另一方面,所述免疫原可以是肽,肽與MHC的複合體、和/或用於提高特異性抗體或TCR抗性的蛋白。
I類T細胞「表位」要求的是一種結合至MHC I類受體上的短肽,從而形成一種三元複合體(MHC I類α鏈、β-2-微球蛋白和肽),其可以透過T細胞負載匹配T細胞受體與具有適當親和力的MHC/肽複合體結合來識別。結合至MHC I類分子的肽的典型長度為8-14個氨基酸,最典型為9個氨基酸長度。
在人類中,有三種編碼MHC I類分子的不同基因位點(人MHC分子也是指定的人白細胞抗原(HLA)):HLA-A、HLA-B和HLA-C。HLA-A*01、HLA-A*02和HLA-B*07是可從這些基因位點表達的不同MHC I類等位元基因的實例。
本發明的肽,較佳當如本文描述納入本發明的疫苗時與A*02或A*24結合。疫苗還可能包括泛結合MHC II類肽。因此,本發明的疫苗可用於治療A*02陽性、A*24陽性或A*02和A*24均呈陽性患者中的癌症,但不因為這些肽的廣泛結核性而必須選擇II類MHC同種異型。
一種疫苗中A*02和A*24肽組合具有優勢,即與單獨的MHC I類等位基因相比,可治療更高比例的患者群體。雖然在大多數人群中,低於50%的患者可由單獨的等位基因來解決問題,但是本發明的疫苗可以治療任何相關人群中至少60%的患者。具體來說,各區域中,以下比例的患者這些等位基因中的至少一個有肯定效果:美國61%、西歐62%、中國75%、韓國77%、日本86%(根據www.allelefrequencies.net計算)。
本文提到的DNA序列既包括單鏈DNA也包括雙鏈DNA。因此,除非本文另有所指,否則具體的序列是該序列的單鏈DNA、該序列與其互補序列的雙工(雙鏈DNA)以及該序列的互補序列。「編碼區」這一術語是指在基因的天然基因組環境中天然或正常編碼該基因的表達產物的那部分基因
,即,體內編碼該基因的天然表達產物的區域。
編碼區可來自非突變(「正常」)基因、突變基因或異常基因,甚至還可以來自DNA序列,完全可在實驗室中使用本領域熟知的DNA合成方法合成。
在一項較佳的實施方案中,術語「核苷酸序列」系指去氧核苷酸的雜聚物。
編碼特定肽、寡肽或多肽的核苷酸序列可為天然核苷酸序列,也可為合成核苷酸序列。一般來說,編碼肽、多肽以及本發明蛋白的DNA片段由cDNA片段和短寡核苷酸銜接物,或一系列寡核苷酸組成,以提供一種合成基因,該基因能夠在包含源自微生物或病毒操縱子的調節元素的重組轉錄單元中被表達。
如本文所用的術語「肽的核苷酸編碼」系指對肽進行核苷酸序列編碼,其中該肽包括與將由用於產生TCR的樹突細胞或另一細胞系統所表達該序列的生物系統相容的人工(人造)啟動和停止密碼子。
「表達產物」這一術語是指多肽或蛋白,它是基因和遺傳碼退化並因而編碼同樣的氨基酸所造成的任何核酸序列編碼同等物的翻譯產物。
「片斷」這一術語,當指的是一種編碼序列時,表示包含非完整編碼區的DNA的一部分,其表達產物與完整編碼區表達產物基本上具有相同的生物學功能或活性。
「DNA片段」這一術語是指一種DNA聚合物,以單獨的片段形式或一種較大DNA結構的組分形式存在,它們從
至少分離過一次的DNA中以基本純淨的形式獲得,即不含污染性內源性材料,並且獲得的數量或濃度能夠使用標準生化方法,例如使用克隆載體,進行識別、操縱和回收該片段及其組分核苷酸序列。此類片段以開放閱讀框架(未被內部未翻譯序列打斷)或內含子(通常提呈于真核基因中)的形式存在。未翻譯DNA序列可能存在於開放閱讀框架的下游,在那裏其不會幹預編碼區的操縱或表達。
「引物」這一術語表示一種短核酸序列,其可與一個DNA鏈配對,並在DNA聚合酶開始合成去氧核糖核酸鏈之處提供一個遊離的3'-OH末端。
「啟動子」這一術語表示參與RNA聚合酶的結合從而啟動轉錄的DNA區域。
術語「分離」表示一種物質從其原來的環境(例如,如果是天然發生的則是天然環境)中被移走。例如,活體動物中的天然核苷酸或多肽不是分離的,但是,從天然系統中一些或所有共存物質中分離出來的核苷酸或多肽是分離的。此類多核苷酸可能是載體的一部分和/或此類多核苷酸和多肽可能是一種組合物的一部分,並且由於該載體或組合物不是其天然環境的一部分,因此它仍然是分離的。
本發明中披露的多核苷酸和重組或免疫原性多肽也可能以「純化」的形式存在。術語「純化」並非要求絕對的純度;它只是一個相對的定義,可以包括高度純化或部分純化的製劑,相關領域技術人員能理解這些術語。例如,各個從已用傳統方法純化為具有電泳同質性的cDNA庫中分離出
的各種克隆物。明確考慮到將起始材料或天然物質純化至少一個數量級,較佳為兩或三個數量級,更較佳為四或五個數量級。此外,明確考慮到所述多肽的純度較佳為99.999%,或至少為99.99%或99.9%;甚而適宜為以重量計99%或更高。
根據本發明公開的核酸和多肽表達產物,以及包含此類核酸和/或多肽的表達載體可能以「濃縮的形式」存在。本文使用的術語「濃縮」是指材料的濃度至少是其自然濃度的大約2、5、10、100或1000倍,有優勢的是,按重量計為0.01%,較佳為至少0.1%。也明確考慮到,按重量計約為0.5%、1%、5%、10%和20%的濃縮製劑。序列、構型、載體、克隆物以及包含本發明的其他材料可有優勢地以濃縮或分離的形式存在。
「活性片段」這一術語是指產生免疫反應的片段(即具有免疫原性活性),通常是一種肽、多肽或核酸序列的片段,不論是單獨或可選地與合適的佐劑一起或在載體中給予一種動物,比如哺乳動物,例如兔子或小鼠,也包括人;這種免疫反應採用的形式是在接受動物(如:人)體內刺激T細胞反應。或者,「活性片段」也可用於誘導體外T細胞反應。
本文使用的「部分」(portion)、「節段」(segment)、「片段」(fragment)這幾個術語,當與多肽相關地使用時是指殘基的連續序列,比如氨基酸殘基,其序列形成一個較大序列的子集。例如,如果一個多肽以任一種肽鏈內切肽酶(如胰蛋白酶或糜蛋白酶)進行處理,則該處理獲得的寡肽會代表起始多肽的部分、節段或片段。當與多核苷酸相關地使用
時,這些術語系指用任何核酸內切酶處理所述多核苷酸產生的產物。
根據本發明,術語「相同百分比」「等同度百分比」或「等同百分比」,如果指的是序列,則表示在待對比序列(「被對比序列」)與所述序列或請求項的序列(「參考序列」)對準之後將被對比序列與所述序列或請求項的序列進行比較。然後根據下列公式計算等同度百分比:等同度百分比=100[1-(C/R)]
其中C是參考序列與被對比序列之間對準長度上參考序列與被對比序列之間的差異數量,其中(i)參考序列中每個堿基或氨基酸序列在被對比序列中沒有對應的對準堿基或氨基酸;(ii)參考序列中每個空隙,以及(iii)參考序列中每個對準堿基或氨基酸與被比對比序列中對準堿基或氨基酸不同,即構成一個差異以及(iv)必須在對準序列的第1位置開始對準;並且R是參考序列與被對比序列對準長度上在參考序列中產生任何空隙也計算為一個堿基或氨基酸的參考序列中的堿基或氨基酸數目。
如果「被對比序列」和「參考序列」之間存在的一個對準按上述計算的等同度百分比大致等於或大於指定的最低等同度百分比,則被對比序列與參考序列具有指定的最低等同度百分比,雖然可能存在按本文上述計算的等同度百分
比低於指定等同度百分比的對準。
如果無另有說明,那麼本文公開的原始(未修飾)肽可以透過在肽鏈內的不同(可能為選擇性)位點上取代一個或多個殘基而被修飾。較佳情況時,這些取代位於氨基酸鏈的末端。此取代可能是保守性的,例如,其中一個氨基酸被具有類似結構和特點的另一個氨基酸所取代,比如其中一個疏水性氨基酸被另一個疏水性氨基酸取代。更保守的取代是具有相同或類似的大小和化學性質的氨基酸間的取代,例如,亮氨酸被異亮氨酸取代。在天然同源蛋白質家族序列變異的研究中,某些氨基酸的取代往往比其他氨基酸更具有耐受性,這些氨基酸往往表現出與原氨基酸的大小、電荷、極性和疏水性之間的相似性相關,這是確定「保守取代」的基礎。
在本文中,保守取代定義為在以下五種基團之一的內部進行交換:基團1-小脂肪族、非極性或略具極性的殘基(Ala,Ser,Thr,Pro,Gly);基團2一極性、帶負電荷的殘基及其醯胺(Asp,Asn,Glu,Gln);基團3一極性、帶正電荷的殘基(His,Arg,Lys);基團4一大脂肪族非極性殘基(Met,Leu,Ile,Val,Cys)以及基團5一大芳香殘基(Phe,Tyr,Trp)。
較不保守的取代可能涉及一個氨基酸被另一個具有類似特點但在大小上有所不同的氨基酸所取代,如:丙氨酸被異亮氨酸殘基取代。高度不保守的取代可能涉及一個酸性氨基酸被另一個具有極性或甚至具有鹼性性質的氨基酸所取代。然而,這種「激進」取代不能認為是無效的而不予考慮
,因為化學作用是不完全可預測的,激進的取代可能會帶來其簡單化學原理中無法預見的偶然效果。
當然,這種取代可能涉及普通L-氨基酸之外的其他結構。因此,D-氨基酸可能被本發明的抗原肽中常見的L-氨基酸取代,也仍在本公開的範圍之內。此外,具有非標準R基團的氨基酸(即,除了天然蛋白的20個常見氨基酸之外的R基團)也可以用於取代之目的,以生產根據本發明的免疫原和免疫原性多肽。
如果在一個以上位置上的取代發現導致肽的抗原活性基本上等於或大於以下定義值,則對這些取代的組合進行測試,以確定組合的取代是否產生對肽抗原性的疊加或協同效應。肽內被同時取代的位置最多不能超過4個。
本發明的肽可被拉長多達四個氨基酸,即1、2、3或4個氨基酸,可按照4:0與0:4之間的任何組合添加至任意一端。
拉伸/延長的氨基酸可以是所述蛋白或任何其他氨基酸的原序列肽。拉長可用於增強所述肽的穩定性或溶解性。
術語「T細胞反應」是指由一種肽在體外或體內誘導的效應子功能的特異性擴散和啟動。對於MHC I類限制性CTL,效應子功能可能為溶解肽脈衝的、肽前體脈衝的或天然肽提呈的靶細胞、分泌細胞因數,較佳為肽誘導的幹擾素-γ,TNF-α或IL-2,分泌效應分子,較佳為肽誘導的顆粒酶或穿孔素,或脫顆粒。
較佳情況是,當本發明的肽特異性T細胞相比於取代肽受到檢測時,如果取代肽在相對於背景肽溶解度增加達到最大值的一半,則該肽濃度不超過約1mM,較佳為不超過約1μM,更較佳為不超過約1nM,再較佳為不超過約100pM,最較佳為不超過約10pM。也較佳為,取代肽被一個以上的T細胞識別,最少為2個,更較佳為3個。
因此,本發明所述的表位可能與天然腫瘤相關表位或腫瘤特異性表位相同,也可能包括來自參考肽的不超過四個殘基的不同肽,只要它們有基本相同的抗原活性即可。
MHC-I類分子,在細胞核提呈因主要內源性、細胞
質或細胞核蛋白質、DRIPS和較大肽蛋白裂解產生的肽的細胞上都能發現此類分子。然而,源自內體結構或外源性來源的肽也經常在MHC-I類分子上發現。這種I-類分子非經典提呈方式在文獻中被稱為交叉提呈。
由於CD8及CD4依賴型反應共同和協同促進抗腫瘤作用,因此,CD8陽性T細胞(MHC-I分子)或CD4陽性T細胞(MHC-II類分子)對腫瘤相關抗原的識別和鑒定對開發腫瘤疫苗非常重要。因此,提出含有與任一類MHC複合體結合的肽組合物是本發明的一個目標。
考慮到治療癌症相關的嚴重副作用和費用,迫切需要更好的預後和診斷方法。因此,有必要確定代表癌症生物標誌物的其他因數,尤其是HCC。此外,有必要確定可用於治療癌症的因數,尤其是HCC。
本發明提出了有利於治療癌腫/腫瘤,較佳為治療過量提呈或只提呈本發明肽的HCC。這些肽由質譜分析法直接顯示出,而由HLA分子自然提呈于人原發性人HCC樣本中。
與正常組織相比,癌症中高度過度表達肽來源的源基因/蛋白質(也指定為「全長蛋白質」或「潛在蛋白質」)-本發明相關的「正常組織」是健康肝細胞或其他正常組織細胞,這表明腫瘤與這些源基因的高度關聯性(見實施例2)。此外,這些肽本身也在腫瘤組織中過度提呈(本發明相關的「腫瘤組織」是指來自HCC患者的樣本),但不在正常組織中過度提呈(見實施例1)。
HLA結合肽能夠被免疫系統識別,特別是T淋巴細胞
。T細胞可破壞提呈被識別HLA/肽複合體的細胞(如:提呈衍生肽的HCC細胞)。
本發明的所有肽已被證明具有刺激T細胞反應的能力,並過量提呈,因而可用於製備本發明的抗體和/或TCR,特別是sTCR(參見實施例3)。此外,肽與相應的MHC組合時,也可用於製備本發明的抗體和/或TCR,特別是sTCR。各個方法均為技術人員所熟知,並在各個文獻中可找到。因此,本發明的肽可用于在患者中產生免疫反應,從而能夠毀滅腫瘤細胞。患者的免疫反應能夠透過直接給予患者所述肽或前體物質(如,加長肽、蛋白或編碼這些肽的核酸),較理想是與加強免疫原性的製劑相結合,而進行誘導。源自該治療性疫苗的免疫反應預期能夠高度特異性地對抗腫瘤細胞,因為本發明的目標肽在正常組織上提呈的複製數目較少,防止患者發生對抗正常細胞的不良自體免疫反應的風險。
較佳的「藥物組合物」是指較佳適合在醫療機構用於人體的組合物。較佳地,藥物組合物為無菌狀態,並根據GMP指南生產。
藥物組合物包括遊離形式或以一種藥用鹽形式存在的肽(也參見上文)。此處使用的「藥用鹽」系指所公開的肽的一種衍生物,其中該肽由制酸或藥劑的堿鹽進行改性。例如,用與適合的酸反應的遊離堿(通常其中的中性藥物有一個中性-NH2基團)製備酸式鹽。適合製備酸鹽的酸包括有機酸,如:乙酸、丙酸、羥基酸、丙酮酸、草酸、蘋果酸、丙二酸、丁二酸、馬來酸、富馬酸、酒石酸、檸檬酸、苯甲酸
酸、肉桂酸、扁桃酸、甲磺酸、甲磺酸、苯磺酸、水楊酸等等、以及無機酸,如:鹽酸、氫溴酸、硫酸、硝酸和磷酸等。相反,可在一種肽上提呈的酸性基團的堿鹽製劑使用藥用堿基進行製備,如氫氧化鈉、氫氧化鉀、氫氧化銨、氫氧化鈣、三甲胺等等。
在特別較佳的實施例中,藥物組合物包括乙酸(醋酸鹽),三氟乙酸鹽或鹽酸(氯化物)形式的肽。
特別較佳的是一種組合物和/或所述組合物例如以疫苗形式使用,其包括具有SEQ ID NO1、2、7、225、228、301、303和312的肽或具有SEQ ID NO1、2、7、225、228、301、303和312序列的肽反應性支架,及其MHC分子複合體。
本發明的肽除了用於治療癌症,也可用於診斷。由於肽由HCC細胞產生,並且已確定這些肽在正常組織中不存在或水準較低,因此這些肽可用於診斷癌症是否存在。
血液樣本中組織活檢物含請求項的肽,可有助於病理師診斷癌症。用抗體、質譜或其他本領域內已知的方法檢測某些肽可使病理師判斷該組織樣本為惡性的還是炎症或一般病變,也可用作HCC的生物標誌物。肽基團的提呈使得能對病變組織進行分類或進一步分成子類。
對病變標本中肽的檢測使得能對免疫系統治療方法的利益進行判斷,特別是如果T-淋巴細胞已知或預計與作用機制有關。MHC表達的缺失是一種機制,充分說明瞭哪些受感染的惡性細胞逃避了免疫監視。因此,肽的提呈表明,分析過的細胞並沒有利用這種機制。
本發明的肽可用於分析淋巴細胞對肽的反應(如T細胞反應),或抗體對肽或MHC分子絡合的肽發生的反應。這些淋巴細胞反應可以作為預後指標,決定是否採取進一步的治療。這些反應也可以用作免疫療法中的替代指標,旨在以不同方式誘導淋巴細胞反應,如接種蛋白疫苗、核酸、自體材料、淋巴細胞過繼轉移。基因治療中,淋巴細胞對肽發生的反應可以在副作用的評估中考慮。淋巴細胞反應監測也可能成為移植療法隨訪檢查中的一種有價值的工具,如,用於檢測移植物抗宿主和宿主抗移植物疾病。
本發明中的肽可用于生成和開發出針對MHC/肽複合體的特定抗體。這些抗體可用於治療,將毒素或放射性物質靶向病變組織。這些抗體的另一用途是為了成像之目的(如PET)將放射性核素靶向病變組織。這可有助於檢測小轉移灶或確定病變組織的大小和準確位置。
因此,本發明的另一方面是提出產生特異性結合至與HLA限制性抗原絡合的I或II類人主要組織相容性複合體(MHC)的一種重組抗體的方法,該方法包括:用可溶形式的與HLA限制性抗原絡合的(MHC)I或II類分子對包含表達所述主要組織相容性說複合體(MHC)I或II類的基因工程非人哺乳動物進行免疫;將mRNA分子與產生所述非人哺乳動物細胞的抗體分離;產生一個噬菌體顯示庫,顯示由所述mRNA分子編碼的蛋白分子;以及將至少一個噬菌體與所述噬菌體顯示庫分離,所述的至少一個噬菌體顯示所述抗體特異性地結合至與HLA限制性抗原絡合的所述人主要組織相容性說複合體
(MHC)I或II類。
本發明的另一方面提出一種抗體,其特異性結合至與一種HLA限制性抗原絡合的I或II類人主要組織相容性說複合體(MHC),其中該抗體較佳為多克隆抗體、單克隆抗體、雙特異性抗體和/或嵌合抗體。
此外,本發明的另一個方面涉及產生特異性結合至與HLA限制性抗原絡合的I或II類人主要組織相容性複合體(MHC)的一種抗體的方法,該方法包括:用可溶形式的與HLA限制性抗原絡合的(MHC)I或II類分子對包含表達所述主要組織相容性說複合體(MHC)I或II類的基因工程非人哺乳動物進行免疫;將mRNA分子與產生所述非人哺乳動物細胞的抗體分離;產生一個噬菌體顯示庫,顯示由所述mRNA分子編碼的蛋白分子;以及將至少一個噬菌體與所述噬菌體顯示庫分離,所述的至少一個噬菌體顯示所述抗體可特異性地結合至與HLA限制性抗原絡合的所述人主要組織相容性說複合體(MHC)I或II類。產生這種抗體和單鏈I類主要組織相容性複合體的相應方法,以及產生這些抗體的其他工具在WO03/068201、WO2004/084798、WO01/72768、WO03/070752以及Cohen CJ,et al.Recombinant antibodies with MHC-restricted,peptide-specific,T-cell receptor-like specificity:new tools to study antigen presentation and TCR-peptide-MHC interactions.J Mol Recognit.2003 Sep-Oct;16(5):324-32.;Denkberg G,et al.Selective targeting of melanoma and APCs using a recombinant antibody with TCR-like specificity directed
toward a melanoma differentiation antigen.J Immunol.2003 Sep 1;171(5):2197-207;以及Cohen CJ,et al.Direct phenotypic analysis of human MHC class I antigen presentation:visualization,quantitation,and in situ detection of human viral epitopes using peptide-specific,MHC-restricted human recombinant antibodies.J Immunol.2003 Apr 15;170(8):4349-61中進行了披露,為了本發明之目的,所有參考文獻透過引用被完整地併入本文。
較佳地,該抗體與複合體的結合親和力低於20納摩爾,較佳為低於10納摩爾,這在本發明情況下被視為具有揬
本發明的另一方面提出了製備識別特異性肽-MHC複合體的可溶性T細胞受體(sTCR)的一種方法。這種可溶性T細胞受體可從特異性T細胞克隆中產生,並且它們的親和力可以透過互補決定區靶向誘變而增加。為了T細胞受體選擇之目的,可以使用噬菌體展示(美國2010/0113300,Liddy N,et al.Monoclonal TCR-redirected tumor cell killing.Nat Med 2012 Jun;18(6):980-987)。為了在噬菌體展示期間以及實際使用為藥物時穩定T細胞受體之目的,可透過非天然二硫鍵、其他共價鍵(單鏈T細胞受體)或透過二聚化結構域連接α和β鏈(參見Boulter JM,et al.Stable,soluble T-cell receptor molecules for crystallization and therapeutics.Protein Eng 2003 Sep;16(9):707-711.;Card KF,et al.A soluble single-chain T-cell receptor IL-2 fusion protein retains MHC-restricted peptide specificity and IL-2 bioactivity.Cancer Immunol
Immunother 2004 Apr;53(4):345-357;以及Willcox BE,et al.Production of soluble alphabeta T-cell receptor heterodimers suitable for biophysical analysis of ligand binding.Protein Sci 1999 Nov;8(11):2418-2423)。T細胞受體可以連接到毒素、藥物、細胞因數(參見US2013/0115191)、域招募效應細胞,如抗CD3域等,以便對靶細胞執行特定的功能。此外,它可能表達於用於過繼轉移的T細胞。進一步的資訊可在WO2004/033685A1和WO2004/074322A1中找到。sTCR的組合在WO2012/056407A1中進行了描述。WO2013/057586A1中公開了製備的進一步的方法。
此外,可用本發明的肽和/或TCR或抗體或其他結合分子在活檢樣本的基礎上驗證病理師對癌症的診斷。
為了選擇過度提呈的肽,計算了提呈圖,其顯示樣本中位元提呈量以及複製變化。該特點使相關腫瘤實體的樣本與正常組織樣本的基線值並列。透過計算調節線性混合效應模型(J.Pinheiro,et al.The nlme Package:Linear and Nonlinear Mixed Effects Models.2007)的p值可以將以上每個特點併入過度提呈分數中,從而透過假髮現率調整多項檢驗(Y.Benjamini and Y.Hochberg.Controlling the False Discovery Rate:A Practical and Powerful Approach to Multiple Testing.Journal of the Royal Statistical Society.Series B (Methodological),Vol.57(No.1):289-300,1995)。
對於透過質譜法對HLA配體的識別和相對定量,對來自衝擊冷凍組織樣本的HLA分子進行純化並對HLA相關肽
進行分離。分離的肽分開,並透過線上納米-電噴霧-電離(nanoESI)液相色譜-譜(LC-MS)實驗進行鑒定。由此產生的肽序列的驗證方法是,將HCC樣本(N=16個A*02-陽性樣本,包括13個A*02:01-陽性樣本,N=15個A*24-陽性樣本)中記錄的天然TUMAP的片段模式與相同序列相應合成參考肽的片段模式進行比較。由於這些肽被直接鑒定為原發性腫瘤HLA分子的配體,因此這些結果為獲得自31名HCC患者的原發性癌症組織上確定肽的天然加工和提呈提供了直接證據。
發現管道XPRESIDENT® v2.1(例如,參見US 2013-0096016,並在此透過引用將其整體併入本文)考慮到識別和選擇相關過量提呈的候選肽疫苗,這基於與幾種不同的非癌組織和器官相比癌症或其他受感染組織的HLA限制肽水準直接相對定量結果。這透過以下方法實現:使用專有資料分析管道處理的LC-MS採集資料、結合序列識別演算法、譜聚類、計算離子、保留時間調整、充電狀態卷積以及正態化而開發無標記差異化定量方法。
為每種肽和樣本確立了提呈水準,包括誤差估計值。腫瘤組織大量提呈的肽以及腫瘤與非腫瘤組織和器官中過量提呈的肽已經得到確定。
對來自HCC組織樣本的HLA肽複合體進行純化,並且對HLA相關肽使用LC-MS進行分離和分析(見實施例)。本申請中包含的所有TUMAP使用原發性HCC樣本的方法進行鑒定,確認其在原發性HCC上的提呈。
在多個HCC腫瘤和正常組織上確定的TUMAP用無
標記LC-MS資料的離子計數方法進行量化。該方法假定肽的LC-MS信號區域與樣本中其豐度相關。各種LC-MS實驗中肽的所有量化信號在集中趨勢基礎上進行正常化,根據每個樣品進行平均,併合併入柱狀圖(被稱為提呈圖)。提呈圖整合了不同分析方法,如:蛋白資料庫檢索、譜聚類、充電狀態卷積(除電)和保留時間校準和正態化。
本發明涉及一種肽,包含選自SEQ ID NO:1至SEQ ID NO:300的組的一個序列或該序列的與SEQ ID NO:1至SEQ ID NO:300具有90%同源性(較佳為相同)的一種變體,或誘導與所述變異肽發生T細胞交叉反應的一種變體,其中,所述肽不是基本的全長多肽。
本發明進一步涉及一種肽,包含選自SEQ ID NO:1至SEQ ID NO:300的組的一個序列、或與SEQ ID NO:1至SEQ ID NO:300具有至少90%同源性(較佳為相同)的一種變體,其中所述肽或變體的總長度為8至100個、較佳為8至30個、最較佳為8至14個氨基酸。
本發明進一步涉及本發明的肽,其具有與主要組織相容性複合體(MHC)I或II類分子結合的能力。
本發明進一步涉及本發明中的肽,其中肽系由或基本系由根據SEQ ID NO:1至SEQ ID NO:300的一個氨基酸序列組成。
本發明進一步涉及本發明的肽,其中該肽(在化學上)被修飾和/或包含非肽鍵。
本發明進一步涉及本發明的肽,其中該肽為融合蛋
白的一部分,特別包括HLA-DR抗原相關不變鏈(Ii)的N-端氨基酸,或其中該肽與一種抗體(例如,樹突狀細胞特定抗體)融合。
本發明進一步涉及一種核酸,其編碼本發明所述肽,前提是該肽並非完整(完全)的人蛋白。
本發明進一步涉及一種本發明的核酸,為DNA、cDNA、PNA、RNA,也可能為其組合物。
本發明進一步涉及一種能表達本發明核酸的表達載體。
本發明進一步涉及本發明的一種肽、本發明的一種核酸或本發明的一種藥用表達載體,特別是用於治療HCC。
本發明進一步涉及含本發明核酸或本發明表達載體的一種宿主細胞。
本發明進一步涉及本發明的宿主細胞,其為抗原提呈細胞,較佳為樹突細胞。
本發明進一步涉及本發明中的方法,其中抗原透過與足夠量的含抗原提呈細胞的抗原結合被載入表達於合適抗原提呈細胞表面的I或II類MHC分子。
本發明進一步涉及本發明的方法,其中該抗原提呈細胞包括一個表達載體,該載體有能力表達含SEQ ID NO:1至SEQ ID NO:300的肽或所述變體氨基酸序列。
本發明進一步涉及任何所述肽、本發明的一種核酸、本發明的一種表達載體、本發明的一種細胞、本發明一種作為藥劑或製造藥劑的啟動細胞毒性T淋巴細胞的用途。本發
明進一步涉及一種本發明的用途,其中藥劑可有效抗癌。
本發明進一步涉及一種本發明的用途,其中該藥劑為一種疫苗。本發明進一步涉及一種本發明的用途,其中藥劑可有效抗癌。
本發明進一步涉及一種本發明的用途,其中所述癌細胞為HCC細胞或其他實體或血液學腫瘤細胞,例如,胰腺癌、腦癌、腎癌、結腸癌或直腸癌或白血病。
本文中術語「抗體」為廣義上的定義,既包括多克隆也包括單克隆抗體。除了完整或「全部」的免疫球蛋白分子,「抗體」這一術語還包括這些免疫球蛋白分子和人源化免疫球蛋白分子的片段(如,CDR、Fv、Fab和Fc片段)或聚合物,只要它們表現出本發明的任何期望屬性(例如,HCC標誌物多肽的特異性結合、將毒素傳遞給HCC細胞標誌物基因表達水準增加時的HCC細胞和/或抑制HCC標誌物多肽的活性)。
只要有可能,本發明的抗體可從商業來源購買。本發明的抗體也可能使用已知的方法制得。技術人員會瞭解全長HCC標誌物多肽或其片段可用於製備本發明的抗體。用於產生本發明抗體的多肽可部分或全部地由天然源經純化而得,也可利用重組DNA技術生產。
例如,本發明的編碼肽的cDNA,例如,該肽為根據SEQ ID NO:1至SEQ ID NO:30多肽的肽,或其中一個變體或片段,可在原核細胞中(如:細菌)或真核細胞(如:酵母、昆蟲或哺乳動物細胞)中表達,之後,可純化重組蛋白,並用於產生一種特異性結合用於產生本發明抗體的HCC標誌物多肽的單克隆或多克隆抗體製劑。
本領域的技術人員會認識到,兩種或兩種以上不同集合的單克隆抗體或多克隆抗體能最大限度地增加獲得一種含預期用途所需的特異性和親和力(例如,ELISA法、免疫組織化學、體內成像、免疫毒素療法)的抗體的可能性。根據抗體的用途,用已知的方法對其期望活性進行測試(例如,ELISA法、免疫組織化學、免疫治療等;要獲取產生和測試抗體的進一步指導,請參閱,例如,Harlow and Lane,Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,1988,new2nd edition2013)。例如,該抗體可用ELISA法或免疫印跡法、免疫組織化學染色福馬林固定的癌組織或冰凍的組織切片進行檢測。在初次體外表徵後,用於治療或體內診斷用途的抗體根據已知的臨床測試方法進行檢測。
此處使用的術語「單克隆抗體」系指從大量同質抗體中獲得的一種抗體,即,由相同的抗體組成的抗體群,但可能少量提呈的自然突變除外。此處所述的單克隆抗體具體包括「嵌合」抗體,其中一部分重鏈和/或輕鏈與從特定物種中獲得的抗體或屬於特定抗體類型和分類型抗體的相應序列
相同(同質),同時,剩餘鏈與從其他物種中獲得的抗體或屬於特定抗體類型和子類型抗體的相應序列以及這些抗體的片段相同(同質),只要它們表現出預期的拮抗活性(美國4,816,567號專利,其在此以其整體併入)。
本發明的單克隆抗體可能使用雜交瘤方法制得。在雜交瘤方法中,老鼠或其他適當的宿主動物,通常用免疫製劑以引發產生或能產生將特異性結合至免疫製劑的抗體。或者,淋巴細胞可在體外進行免疫。
單克隆抗體也可由DNA重組方法制得,如:美國4,816,567號專利所述。編碼本發明單克隆抗體的DNA可很容易地使用傳統程式進行分離和測序(例如:透過使用能與編碼鼠抗體重鏈和輕鏈的基因特異性結合的寡核苷酸探針)。
體外方法也適用於製備單價抗體。抗體消化以產生抗體的片段,尤其是Fab片段,可以透過使用本領域已知的常規技術完成。例如,可以透過使用木瓜蛋白酶完成消化。木瓜蛋白酶消化的實施例在WO94/29348和美國4,342,566號專利中有描述。抗體的木瓜蛋白酶消化通常產生兩種相同的抗原結合性片段,稱為Fab片段(每個片段都有一個抗原結合點)和殘餘Fc片段。胃蛋白酶處理產生aF(ab')2片段和pFc'片段。
抗體片段,不論其是否附著於其他序列,均可包括特定區域或特定氨基酸殘基的插入、刪除、替換、或其他選擇性修飾,但前提是,片段的活性與非修飾的抗體或抗體片段相比沒有顯著的改變或損害。這些修飾可提供一些額外的
屬性,如:刪除/添加可與二硫鍵結合的氨基酸,以增加其生物壽命、改變其分泌特性等。在任何情況下,抗體片段必須擁有生物活性的特性,如:結合活性、調節結合域的結合力等。抗體的功能性或活性區域可透過蛋白特定區域的基因突變、隨後表達和測試所表達的多肽進行確定。這些方法為本行業技術人員所熟知,可包括編碼抗體片段的核酸的特定位點基因突變。
本發明的抗體可進一步包括人源化抗體或人抗體。非人(如:鼠)抗體的人源化形式為嵌合抗體免疫球蛋白、免疫球蛋白鏈或其片段(如:Fv、Fab、Fab'或抗體的其他抗原結合序列),其中包含從非人免疫球蛋白中獲得的最小序列。人源化抗體包括人免疫球蛋白(受體抗體),其中來自受體互補決定區(CDR)的殘基被來自非人物種(供體抗體)(如具有與其特異性、親和力和能力的小鼠、大鼠或兔子)CDR的殘基取代。在某些情況下,人類免疫球蛋白的Fv框架(FR)殘基被相應的非人殘基取代。人源化抗體可能還包括既非受體抗體、也非輸入CDR或框架序列中發現的殘基。一般來說,人源化抗體將包括幾乎所有的至少一個、通常為二個可變域,其中,全部或幾乎全部的CDR區域均對應於非人免疫球蛋白的區域並且全部或幾乎全部的FR區域均為人免疫球蛋白相同序列的區域。理想情況是,人源化抗體還將包括至少免疫球蛋白恒定區(Fc)的一部分,通常是人免疫球蛋白的恒定區的一部分。
人源化非人抗體的方法為本行業所熟知。一般來說
,人源化抗體具有一個或多個從非人源頭引入的氨基酸殘基。這些非人氨基酸殘基往往被稱為「輸入」殘基,通常從「輸入」可變域中獲得。人源化基本上可以透過將齧齒動物CDR或CDR序列取代為相應的人抗體序列而完成。因此,這種「人源化」抗體為嵌合抗體(美國4,816,567號專利),其中大大少於完整的人可變域被來自於非人物種的相應序列取代。在實踐中,人源化抗體通常為人抗體,其中有些CDR殘基以及可能的一些FR殘基被來自齧齒動物抗體中的類似位點的殘基取代。
可使用免疫後在內源性免疫球蛋白產生缺失時能產生完整人抗體的轉基因動物(如:小鼠)。例如,它被描述為,嵌合和種系突變小鼠中的抗體重鏈連接區域基因的純合性缺失導致內源性抗體生成的完全抑制。在此種系變種小鼠中人種系免疫球蛋白基因陣列的轉移在抗原挑戰後將導致人抗體的生成。人抗體也可在噬菌體展示庫中產生。
本發明的抗體較佳為透過藥用載體的形式給予受試者。通常,在製劑中使用適量的藥用鹽,以使製劑等滲。藥用載體的例子包括生理鹽水、林格氏液和葡萄糖溶液。溶液的pH值較佳為約5至8,更較佳為約7至7.5。此外,載體還包括緩釋製劑,如:含有抗體的固體疏水性聚合物半透性基質,其中基質為有形物品形式,如:薄膜、脂質體或微粒。本行業的技術人員熟知,某些載體可能為更較佳,取決於例如,抗體的給藥途徑和濃度。
該抗體可透過注射(如:靜脈內、腹腔內、皮下、
肌肉內)或透過輸注等其他方法給予受試者、患者或細胞,確保其以有效的形式傳輸到血液中。這些抗體也可以透過瘤內或瘤周途徑給予,從而發揮局部和全身的治療作用。局部或靜脈注射為較佳。
抗體給藥的有效劑量和時間表可根據經驗確定,並且作出此類決定屬本行業的技術範圍內。本行業的技術人員會明白,必須給予的抗體劑量根據以下因素會有所不同,例如:接受抗體的受試者、給藥途徑、使用的抗體以及其他正在使用的藥物的特定類型。單獨使用的抗體的通常日劑量可能為約1μg/kg至最多100mg/kg體重或更多,這取決於上述因素。給予抗體,較佳為治療HCC後,治療抗體的療效可透過技術人員熟知的不同方法評估。例如:接受治療的受試者癌症的大小、數量和/或分佈可使用標準腫瘤成像技術進行監測。因治療而給予的抗體與不給予抗體時的病程相比,可阻止腫瘤生長、導致腫瘤縮小、和/或阻止新腫瘤的發展,這樣的抗體是一種有效治療癌症的抗體。
由於本發明上述表格中提及的肽以及其潛在的多肽在HCC中呈高表達,而在正常細胞中表達極低,抑制選自包括以下基因的蛋白產物的組的一種蛋白:較佳用於抑制和抗體和/或TCR抵抗的是GLUL、GPAM、PLIN2、SLC16A1、SLC9A3R1、PCBD1、SEC16A、AKR1C4、ABCB11、HAL、CYP2E1、C4A、C4B、ALDH1L1、CRP、ACSL4、EEF2、HLTF、FBXO22、GALK1、TMCO1、TMEM33、ZNF318、IPO9、AMACR、C1QTNF3、CYP4F8、CYP4F3、CYP4F11、CYP4F12
、CYP4F2、MOCOS、A1CF、COL18A1、HPR、LBP、C19orf80、CFHR5、ITIH4、TMEM110、LARP4、LMF2、SLC10A5和SLC16A11;進一步較佳用於抑制和抗體和/或TCR抵抗的是ANKFY1、C12orf44、C16orf58、CPSF1、DCAF8、PEX19、DDX11、DDX12P、DECR2、NME4、DENND5B、DYM、EDC4、ERI3、FAM20A、FNDC3A,GPR107、GYG2、HEATR2、IFT81、KCTD3,SHKBP1、KIAA1324L、KLHL24、MARCH6、MBTPS2、MIR1279、CPSF6、NOC4L、NXF1、PANK2、PCNXL3、PIPSL、PSMD4、PSMD14、SLC35B1、TCP11L2、THNSL2、THOC2、TOMM5、TRAPPC6B、TRIM54、TRIM55、TRIM63、UGGT2、URB1、VPS54、WIZ、ZNF451、RFTN2、SCFD1、SERINC5、CCT7P2、CMAS、ANKS1A、C17orf70、CCT7、CDK5RAP2、CLPTM1,最較佳用於抑制和抗體和/或TCR抵抗的是APOB、FASN和/或COPA;這些標誌物的表達或其活性可較佳融入治療或預防HCC的治療策略中。
反義治療的原理是基於這樣的假設:基因表達的序列特異性抑制(透過轉錄或翻譯)可能是透過基因組DNA或mRNA與互補反義種類之間的雜交而實現。這種雜交核酸雙工的形成幹擾目標腫瘤抗原編碼基因組DNA的轉錄,或目標腫瘤抗原mRNA的加工/運輸/翻譯和/或穩定性。
反義核酸可用各種方法傳遞。例如,反義寡核苷酸或反義RNA可以讓腫瘤細胞吸收的方式直接給予(例如,透過靜脈注射)受試者。另外,編碼反義RNA(或RNA片段)的病毒或質粒載體可導入體內細胞。還可透過有義序列誘發
反義效果;然而,表型變化的程度大不相同。透過有效的反義治療誘導的表型變化可根據,例如,靶mRNA水準、靶蛋白水準、和/或靶蛋白活性水準的變化進行評估。
在一個具體的實施例中,可透過直接向受試者給予反義腫瘤標誌物RNA而實現反義基因治療抑制HCC靶標/標誌物。腫瘤標誌物反義RNA可透過任何標準技術製造和分離,但最容易的製造方法是在控制高效啟動子(例如,T7啟動子)的情況下使用腫瘤標誌物反義cDNA經體外轉錄制得。腫瘤標誌物反義RNA給到細胞可透過下文所述的核酸直接給藥方法中的任何一種進行。
用於抑制選自上述蛋白質(最較佳APOB、FASN和/或COPA)組成的組中的蛋白功能的替代策略涉及使用核酸(例如,siRNA或編碼抗蛋白抗體或其部分的核酸,這可被轉入癌細胞或其他細胞,導致細胞內抗體表達和分泌)、蛋白質或小分子、或針對此蛋白的表達、翻譯和/或生物功能的任何其他複合體。
在上述的方法中,其中包括將外源性DNA給入受試者的細胞並被其吸收(即,(即,基因轉導或轉染),本發明的核酸可為裸露DNA形式或核酸可位於載體中將核酸傳遞至細胞以抑制HCC標誌物蛋白的表達。該載體可以是一種市售的製劑,如腺病毒載體(量子生物技術公司,Laval,Quebec,Canada)。核酸或載體可透過多種機制傳遞至細胞中。例如,可使用市售的脂質體,如:Lipofectin、Lipofectamine(GIBCO-25 BRL公司,Gaithersburg,Md.)、Superfect(Qiagen
公司,Hilden,Germany)和Transfectam(Promega Biotec公司,Madison,Wis.,US)以及根據本領域標準程式開發的其他脂質體,透過這些脂質體傳遞。此外,本發明的核酸或載體可透過體內電穿孔傳遞,該技術可從Genetronics公司(San Diego,US)獲得,以及透過Sonoporation機(ImaRx制藥公司,Tucson,Arizona,US)的方式傳遞。
例如,載體可透過病毒系統(如可包裹重組逆轉錄病毒基因組的逆轉錄病毒載體系統)傳遞。重組逆轉錄病毒可用於感染,從而傳遞至抑制選自包括上述蛋白的組的蛋白質表達的受感染細胞反義核酸。當然,將改變的核酸準確地導入至哺乳動物細胞細胞內並不限於使用逆轉錄病毒載體。對於這一程式有廣泛的其他技術可供使用,包括使用腺病毒載體、腺相關病毒(AAV)載體、慢病毒載體、假型逆轉錄病毒載體。也可使用物理轉導技術,如脂質體傳遞和受體介導的及其它內吞作用機制。本發明可與這些技術或其他常用基因轉移方法中的任何方法配合使用。
該抗體也可用於體內診斷實驗。一般來說,抗體用放射性核素標記(如:111In、99Tc、14C、131I、3H、32P或35S),從而可免疫閃爍掃描法使腫瘤局限化。在一實施方案中,其中的抗體或片段與兩個或兩個以上選自包括上述蛋白的組的蛋白質靶標的細胞外域結合,並且親和力值(Kd)低於1x10μM。
診斷用抗體可透過各種影像學方法使用適合檢測的探針進行標記。探針檢測方法包括但不限於,螢光、光、共
聚焦和電鏡方法;磁共振成像和光譜學技術;透視、電腦斷層掃描和正電子發射斷層掃描。合適的探針包括但不限於,螢光素、羅丹明、曙紅及其它螢光團、放射性同位素、黃金、釓和其他稀土、順磁鐵、氟-18和其他正電子發射放射性核素。此外,探針可能是雙功能或多功能的,並且用一種以上的上述方法可進行檢測。這些抗體可用所述的探針直接或間接進行標記。抗體探針的連接,包括探針的共價連接、將探針融合入抗體、以及螯合化合物的共價連接從而結合探針、以及其他本行業熟知的方法。對於免疫組織化學方法,疾病組織樣本可能是新鮮或冷凍或可能包埋於石蠟中以及用福馬林等防腐劑固定。固定或包埋的切片包括與標記一抗和二抗接觸的樣本,其中該抗體用於檢測原位蛋白的表達。
因此,如上所述,本發明提出了一種肽,其包括選自SEQ ID NO:1至SEQ ID NO:300群組的一個序列、或與SEQ ID NO:1至SEQ ID NO:300具有90%同源性的其變體、或誘導與該肽發生T細胞交叉反應的一個變體。本發明所訴的肽具有與主要組織相容性複合體(MHC)I或所述肽拉長版本的II類分子結合的能力。
在本發明中,「同源性」一詞系指兩個氨基酸序列之間的同一度(參見上文的等同度百分比,如肽或多肽序列。前文所述的「同源」是透過將理想條件下調整的兩個序列與待比較序列進行比對後確定的。此類序列同源性可透過使用ClustalW等演算法創建一個排列而進行計算。也可用使用一般序列分析軟體,更具體地說,是Vector NTI、GENETYX或由
公共資料庫提供的其他分析工具。
本領域技術人員能評估特定肽變體誘導的T細胞是否可與該肽本身發生交叉反應(Fong L,et al.Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy.Proc Natl Acad Sci USA.2001 Jul 17;98(15):8809-14;Zaremba S,et al.Identification of an enhancer agonist cytotoxic T lymphocyte peptide from human carcinoembryonic antigen.Cancer Res.1997 Oct 15;57(20):4570-7;Colombetti S,et al.Impact of orthologous melan-A peptide immunizations on the anti-self melan-A/HLA-A2 T cell cross-reactivity.J Immunol.2006 Jun 1;176(11):6560-7;AppayV,et al.Decreased specific CD8+ T cell cross-reactivity of antigen recognition following vaccination with Melan-A peptide.Eur J Immunol.2006 Jul;36(7):1805-14)。
發明人用給定氨基酸序列的「變體」表示,一個或兩個氨基酸殘基等的側鏈透過被另一個天然氨基酸殘基的側鏈或其他側鏈取代而發生改變,這樣,這種肽仍然能夠以含有給定氨基酸序列(由SEQ ID NO:1至SEQ ID NO:300組成)的肽大致同樣的方式與HLA分子結合。例如,一種肽可能被修飾以便至少維持(如沒有提高)其能與HLA-A*02或-DR等合適MHC分子的結合槽相互作用和結合,以及至少維持(如沒有提高)其與啟動T細胞的TCR結合的能力。
隨後,這些T細胞可與細胞和殺傷細胞發生交叉反應
,這些細胞表達多肽(其中包含本發明中定義的同源肽的天然氨基酸序列)。正如科學文獻(Godkin A,et al.Use of eluted peptide sequence data to identify the binding characteristics of peptides to the insulin-dependent diabetes susceptibility allele HLA-DQ8(DQ3.2).Int Immunol.1997 Jun;9(6):905-11)和資料庫(Rammensee H.et al.SYFPEITHI:database for MHC ligands and peptide motifs.Immunogenetics.1999 Nov;50(3-4):213-9)中所述,HLA-A結合肽的某些位點通常為錨定殘基,可形成一種與HLA結合槽的結合模序相稱的核心序列,其定義由構成結合槽的多肽鏈的極性、電物理、疏水性和空間特性確定。因此,本領域技術人員能夠透過保持已知的錨殘基來修飾SEQ ID NO:1至SEQ ID NO:300提出的氨基酸序列,並且能確定這些變體是否保持與MHC I或II類分子結合的能力。本發明的變體保持與啟動T細胞的TCR結合的能力,隨後,這些T細胞可與表達一種包含本發明定義的同源肽的天然氨基酸序列的多肽的細胞發生交叉反應並殺死該等細胞。
這些基本不與T細胞受體互動的氨基酸殘基可透過取代另一個幾乎不影響T細胞反應並不妨礙與相關MHC結合的氨基酸而得到修飾。因此,除了特定限制性條件外,本發明的肽可能為任何包括給定氨基酸序列或部分或其變體的肽(發明人所用的這個術語包括寡肽或多肽)。
這些基本不與TCR體互動的氨基酸殘基可透過取代另一個幾乎不影響T細胞反應並不妨礙與相關MHC結合的氨基酸而得到修飾。因此,除了特定限制性條件外,本發明的
肽可能為任何包括給定氨基酸序列或部分或其變體的肽(發明人所用的這個術語包括寡肽或多肽)。
較長的肽也可能適合。MHC I類表位(通常長度為8
至11個氨基酸)也可能由肽從較長的肽或包含實際表位的蛋白中加工而產生。兩側有實際表位的殘基較佳為在加工過程中幾乎不影響暴露實際表位所需蛋白裂解的殘基。
因此,本發明提出了MHC I類表位的肽和變體,其中所述肽或抗體的總長度為8至100個、較佳為8至30個、最較佳為8至14個氨基酸長度(即10、11、12、13、14個氨基酸,如果為拉長II類結合肽時,長度也可為15、16、17、18、19、20、21或22個氨基酸)。
當然,本發明的肽或變體能與人主要組織相容性複合體(MHC)I或II類分子結合。肽或變體與MHC複合體的結合可用本領域內的已知方法進行測試。
在本發明的一個特別較佳實施方案中,肽系由或基本系由根據SEQ ID NO:1至SEQ ID NO:300所選的氨基酸序列組成。
「基本由...組成」系指本發明的肽,除了根據SEQ ID NO:1至SEQ ID NO:300中的任一序列或其變體組成外,還含有位於其他N和/或C端延伸處的氨基酸,而它們不一定能形成作為MHC分子表位的肽。
但這些延伸區域對有效將本發明中的肽引進細胞具有重要作用。在本發明的一實施例中,該肽為融合蛋白的一部分,含來自NCBI、GenBank登錄號X00497的HLA-DR抗原相關不變鏈(p33,以下稱為「Ii」)的80個N-端氨基酸等。在其他的融合中,本發明的肽可以被融合到本文所述的抗體、或其功能性部分,特別是融合入抗體的序列,以便所述抗體進
行特異性靶向作用,或者,例如進入本文所述的樹突狀細胞特異性抗體。
此外,該肽或變體可進一步修飾以提高穩定性和/或與MHC分子結合,從而引發更強的免疫反應。肽序列的該類優化方法是本領域內所熟知的,包括,例如,反式肽鍵和非肽鍵的引入。
在反式肽鍵氨基酸中,肽(-CO-NH-)並未連接其殘基,但是其肽鍵是反向的。這種逆向反向模擬肽(retro-inverso peptidomimetics)可透過本領域已知的方法製備,例如:Meziere等在《免疫學雜誌》((1997)J.Immunol.159,3230-3237)中所述的方法,以引用的方式併入本文。這種方法涉及製備包含骨架(而並非側鏈)改變的模擬肽。Meziere等人(1997年)的研究顯示,這些類比肽有利於MHC的結合和輔助性T細胞的反應。以NH-CO鍵替代CO-NH肽鍵的逆向反向肽大大地提高了抗水解性能。
非肽鍵為-CH2-NH、-CH2S-、-CH2CH2-、-CH=CH-、-COCH2-、-CH(OH)CH2-和-CH2SO-等。美國4,897,445號專利提出了多肽鏈中非肽鍵(-CH2-NH)的非固相合成法,該方法涉及按標準程式合成的多肽以及透過氨基醛和一種含NaCNBH3的氨基酸相互作用而合成的非肽鍵。
含上述序列的肽可與其氨基和/或羧基末端的其他化學基團進行合成,從而提高肽的穩定性、生物利用度、和/或親和力等。例如,苄氧羰基、丹醯基等疏水基團或叔丁氧羰基團可加入肽的氨基末端。同樣,乙醯基或9-芴甲氧羰基可
能位於肽的氨基末端。此外,疏水基團、叔丁氧羰基團或氨基團都可能被加入肽的羧基末端。
另外,本發明中的所有肽都可能經合成而改變其空間構型。例如,可能使用這些肽的一個或多個氨基酸殘基的右旋體,通常不是其左旋體。更進一步地,本發明中肽的至少一個氨基酸殘基可被熟知的一個非天然氨基酸殘基取代。諸如此類的改變可能有助於增加本發明肽的穩定性、生物利用度和/或結合作用。
同樣,本發明中的肽或變體可在合成肽之前或之後透過特異氨基酸的反應而進行化學修飾。此類修飾的實施例為本領域所熟知,例如,在R.Lundblad所著的《Chemical Reagents for Protein Modification》(3rd ed.CRC Press,2005)中有概述,以參考文獻的方式併入本文。雖然氨基酸的化學修飾方法無限制,但其包括(但不限於)透過以下方法修飾:醯基化、脒基化、賴氨酸吡哆基化、還原烷基化、以2,4,6-三硝基苯磺酸(TNBS)三硝基苯基化氨基團、透過將半胱氨酸過甲酸氧化為磺基丙氨酸而對羧基團和巰基進行氨基修飾、形成易變衍生物、與其他巰基化合物形成混合二硫化合物、與馬來醯亞胺反應,與碘乙酸或碘乙醯胺羧甲基化、在鹼性pH值下與氰酸鹽甲氨醯化。在這方面,技術人員參考了《Current Protocols In Protein Science》(Eds.Coligan et al.(John Wiley and Sons NY 1995-2000))中第15章所述的在蛋白質化學修飾相關的廣泛方法。
簡言之,修飾蛋白質的精氨醯殘基等往往基於於鄰
二羰基化合物(如苯甲醯甲醛、2,3-丁二酮以及1,2-烯巳二酮)的反應而形成加合物。另一個實施例是丙酮醛與精氨酸殘基的反應。半胱氨酸可在賴氨酸和組氨酸等親核位點不作隨同修飾的情況下就得到修飾。因此,有大量試劑可進行半胱氨酸的修飾。Sigma-Aldrich(http://www.sigma-aldrich.com)等公司的網站含有具體試劑的資訊。
蛋白質中二硫鍵的選擇性還原也很普遍。二硫鍵可在生物制藥熱處理中形成和氧化。伍德沃德氏試劑K可用於修飾特定的谷氨酸殘基。N-(3-二甲氨基丙基)-N'-乙基-碳二亞胺可用于形成賴氨酸殘基和谷氨酸殘基的分子內交聯。例如:焦碳酸二乙酯是修飾蛋白質組氨酸殘基的試劑。組氨酸也可使用4-羥基-2-壬烯醛進行修飾。賴氨酸殘基與其他醹-氨基團的反應,例如,有利於肽結合到蛋白/肽的表面或交聯處。賴氨酸聚是多(乙烯)乙二醇的附著點,也是蛋白質糖基化的主要修飾位點。蛋白質的蛋氨酸殘基可透過碘乙醯胺、溴乙胺、氯胺T等被修飾。
四硝基甲烷和N-乙醯基咪唑可用於酪氨酸殘基的修飾。經二酪氨酸形成的交聯可透過過氧化氫/銅離子完成。
對色氨酸修飾的最近研究中使用了N-溴代琥珀醯亞胺、2-羥基-5-硝基苄溴或3-溴-3-甲基-2-(2-硝苯巰基)-3H-吲哚(BPNS-糞臭素)。
當蛋白與戊二醛、聚乙二醇二丙烯酸酯和甲醛的交聯用於配製水凝膠時,治療性蛋白和含聚乙二醇的肽的成功修飾往往可延長迴圈半衰期。針對免疫治療的變態反應原化
學修飾往往透過氰酸鉀的氨基甲醯化實現。
一種肽或變體,其中肽被修飾或含非肽鍵,較佳為本發明的實施例。一般來說,肽和變體(至少含氨基酸殘基之間的肽聯接)可使用Lukas et al.(Solid-phase peptide synthesis under continuous-flow conditions.Proc Natl Acad Sci USA.May 1981;78(5):2791-2795)中以及該文列出的參考文獻所披露的固相肽合成Fmoc-聚醯胺模式進行合成。芴甲氧羰基(Fmoc)團對N-氨基提供臨時保護。使用N,N-二甲基甲醯胺中的20%二甲基呱啶中對這種堿高度敏感的保護基團進行重複分裂。由於它們的丁基醚(在絲氨酸蘇氨酸和酪氨酸的情況下)、丁基酯(在谷氨酸和天門冬氨酸的情況下)、叔丁氧羰基衍生物(在賴氨酸和組氨酸的情況下)、三苯甲基衍生物(在半胱氨酸的情況下)及4-甲氧基-2,3,6-三甲基苯磺醯基衍生物(在精氨酸的情況下),側鏈功能可能會受到保護。只要穀氨醯胺和天冬醯胺為C-末端殘基,側鏈氨基功能保護所使用的是由4,4'-二甲氧基二苯基團。固相支撐基於聚二甲基丙烯醯胺聚合物,其由三個單體二甲基丙烯醯胺(骨架單體)、雙丙烯醯乙烯二胺(交聯劑)和N-丙烯醯肌胺酸甲酯(功能劑)構成。使用的肽-樹脂聯劑為酸敏感的4-羥甲基苯氧乙酸衍生物。所有的氨基酸衍生物均作為其預製對稱酸酐衍生物加入,但是天冬醯胺和穀氨醯胺除外,它們使用被逆轉的N,N-二環己基碳二亞胺/1-羥基苯並三唑介導的耦合程式而加入。所有的耦合和脫保護反應用茚三酮、硝基苯磺酸或isotin測試程式監測。合成完成後,用濃度為95%含50%清道夫混合物的三氟
醋酸,從伴隨去除側鏈保護基團的樹脂支承物中裂解肽。常用的清道夫混合物包括乙二硫醇、苯酚、苯甲醚和水,準確的選擇依據合成肽的氨基酸組成。此外,固相和液相方法結合使用對肽進行合成是可能的(例如,請參閱Bruckdorfer et al.,2004以及本文引用的參考文獻)
三氟乙酸用真空中蒸發、隨後用承載粗肽的二乙基乙醚滴定進行去除。用簡單萃取程式(水相凍幹後,該程式制得不含清道夫混合物的肽)清除任何存在的清道夫混合物。肽合成試劑一般可從Calbiochem-Novabiochem(英國諾丁漢)獲得。
純化可透過以下技術的任何一種或組合方法進行,如:再結晶法、體積排阻色譜法、離子交換色譜法、疏水作用色譜法以及(通常)反相高效液相色譜法(如使用乙腈/水梯度分離)。
可以使用薄層色譜法、電泳特別是毛細管電泳、固相萃取(CSPE)、反相高效液相色譜法、酸解後的氨基酸分析、快原子轟擊(FAB)質譜分析以及MALDI和ESI-Q-TOF質譜分析進行肽分析。
另一方面,本發明提出了一種編碼本發明中肽或肽變體的核酸(如多聚核苷酸)。多聚核苷酸可能為,例如,DNA、cDNA、PNA、RNA或其組合物,它們可為單鏈和/或雙鏈、或多聚核苷酸的原生或穩定形式(如:具有硫代磷酸骨架的多聚核苷酸),並且只要它編碼肽,就可能包含也可能不包含內含子。當然,多聚核苷酸只能編碼加入天然肽鍵並含有天
然氨基酸殘基的肽。另一個方面,本發明提出了一種可根據本發明表達多肽的表達載體。
對於連接多核苷酸,已經開發出多種方法,尤其是針對DNA,可透過向載體補充可連接性末端等方法進行連接。例如,可向DNA片段加入補充性均聚物軌道,之後DNA片段被插入到載體DNA。然後,透過補充性均聚物尾巴的氫鍵結合,將載體和DNA片段結合,從而形成重組DNA分子。
含有一個或多個酶切位點的合成接頭為DNA片段與載體連接提供了另一種方法。含各種限制性核酸內切酶的合成接頭可透過多種管道購得,其中包括從國際生物技術公司(International Biotechnologies Inc,New Haven,CN,美國)購得。
編碼本發明多肽的DNA理想修飾方法是使用Saiki等人所採用的聚合酶鏈反應方法。(Diagnosis of sickle cell anemia and beta-thalassemia with enzymatically amplified DNA and nonradioactive allele-specific oligonucleotide probes.N Engl J Med.1988 Sep 1;319(9):537-41)。此方法可用於將DNA引入合適的載體(例如,透過設計合適的酶切位點),也可用於本領域已知的其他有用方法修飾DNA。如果使用病毒載體,痘病毒載體或腺病毒載體為較佳。
之後,DNA(或在逆轉錄病毒載體情況下,RNA)可能表達於合適的宿主,從而製成含本發明肽或變體的多肽。因此,可根據已知技術使用編碼本發明肽或變體的DNA,用本文所述方法適當修飾後,構建表達載體,然後表達載體
用於轉化合適宿主細胞,從而表達和產生本發明中的多肽。此類技術包括那些公開於,例如,美國專利4,440,859、4,530,901、4,582,800、4,677,063、4,678,751、4,704,362、4,710,463、4,757,006、4,766,075和4,810,648。
編碼含本發明化合物多肽的DNA(或在逆轉錄病毒載體情況下,RNA)可能被加入到其他多種DNA序列,從而引入到合適的宿主中。同伴DNA將取決於宿主的性質、DNA引入宿主的方式、以及是否需要保持為遊離體還是要相互結合。
一般來說,DNA可以適當的方向和正確的表達閱讀框架附著到一種表達載體(如質粒)中。如有必要,該DNA可能與所需宿主所識別的相應轉錄和翻譯調節控制核苷酸序列連接,儘管表達載體中一般存在此類控制功能。然後,該載體透過標準方法被引入宿主。一般來說,並不是所有的宿主都會被載體轉化。因此,有必要選擇轉化過的宿主細胞。選擇方法包括用任何必要的控制元素向表達載體插入一個DNA序列,該序列對轉化細胞中的可選擇性屬性(如抗生素耐藥性)進行編碼。
另外,有這種選擇屬性的基因可在另外一個載體上,該載體用來協同轉化所需的宿主細胞。
然後,本發明中的重組DNA所轉化的宿主細胞在本文中所述本領域技術人員熟悉的合適條件下培養足夠長的時間,從而表達之後可回收的肽。
有許多已知的表達系統,包括細菌(如大腸桿菌和
枯草芽孢桿菌)、酵母(如酵母菌)、絲狀真菌(如曲黴菌)、植物細胞、動物細胞及昆蟲細胞。該系統可較佳為哺乳動物細胞,如來自ATCC細胞生物學庫(Cell Biology Collection)中的CHO細胞。
典型的哺乳動物細胞組成型表達載體質粒包括CMV或含一個合適的多聚A尾巴的SV40啟動子以及抗性標誌物(如新黴素)。一個實例為從Pharmacia公司(Piscataway,新澤西,美國)獲得的pSVL。一種可誘導型哺乳動物表達載體的例子是pMSG,也可以從Pharmacia公司獲得。有用的酵母質粒載體是pRS403-406和pRS413-416,一般可從Stratagene Cloning Systems公司(La Jolla,CA92037,美國)獲得。質粒pRS403、pRS404、pRS405和pRS406是酵母整合型質粒(YIp),並插入了酵母可選擇性標記物HIS3、TRP1、LEU2和URA3。pRS413-416質粒為酵母著絲粒質粒(Ycp)。基於CMV啟動子的載體(如,來自於Sigma-Aldrich公司)提供了暫態或穩定的表達、胞漿表達或分泌,以及FLAG、3xFLAG、c-myc或MATN不同組合物中的N-端或C-端標記。這些融合蛋白可用於檢測、純化及分析重組蛋白。雙標融合為檢測提供了靈活性。
強勁的人巨細胞病毒(CMV)啟動子調控區使得COS細胞中的組成蛋白表達水準高達1mg/L。對於較弱的細胞株,蛋白水準一般低於0.1mg/L。SV40複製原點的出現將導致DNA在SV40複製容納性COS細胞中高水準複製。例如,CMV載體可包含細菌細胞中的pMB1(pBR322的衍生物)複製原點、細菌中進行氨苄青黴素抗性選育的鈣-內醯胺酶基因、hGHpolyA
和f1的原點。含前胰島素原引導(PPT)序列的載體可使用抗FLAG抗體、樹脂和板引導FLAG融合蛋白分泌到進行純化的培養基中。其他與各種宿主細胞一起應用的載體和表達系統是本領域熟知眾所周知的。
在另一個實施方案中,對本發明的兩個或更多的肽或肽變體進行編碼,因此,以一個連續順序(類似於「一串珠子」的構建體)表達。在達到目標,所述肽或肽變體可能透過連接子氨基酸的延伸處(例如LLLLLL)連接或融合一起,也可能它們之間沒有任何附加的肽而被連接。這些構建體也可用於癌症治療,可誘導涉及MHC I和MHC II類分子的免疫應答。
本發明還涉及一種宿主細胞,其以本發明的多核苷酸載體構建轉化而來。宿主細胞可為原核細胞,也可為真核細胞。在有些情況下,細菌細胞為較佳原核宿主細胞,典型為大腸桿菌株,例如,大腸桿菌菌株DH5(從Bethesda Research Laboratories公司(Bethesda,MD,美國)獲得)和RR1(從美國菌種保藏中心(ATCC,Rockville,MD,美國),ATCC編號31343獲得)。首選的真核宿主細胞包括酵母、昆蟲和哺乳動物細胞,較佳為脊椎動物細胞,如:小鼠、大鼠、猴子或人成纖維細胞和結腸癌細胞株中的細胞。酵母宿主細胞包括YPH499、YPH500和YPH501,一般可從Stratagene Cloning Systems公司(La Jolla,CA92037,美國)獲得。首選哺乳動物宿主細胞包括中國倉鼠卵巢(CHO)細胞為ATCC中的CCL61細胞、NIH瑞士小鼠胚胎細胞NIH/3T3為ATCC中的CRL1658細胞
、猴腎源性COS-1細胞為ATCC中的CRL1650細胞以及人胚胎腎細胞的293號細胞。首選昆蟲細胞為Sf9細胞,可用杆狀病毒表達載體轉染。有關針對表達選擇合適宿主細胞的概要,可從教科書(Paulina Balbás and Argelia Lorence《Methods in Molecular Biology Recombinant Gene Expression,Reviews and Protocols》Part One,Second Edition,ISBN 978-1-58829-262-9)和本領域技術人員知道的其他文獻中查到。
含本發明DNA結構的適當宿主細胞的轉化可使用大家熟知的方法完成,通常取決於使用載體的類型。對於原核宿主細胞的轉化,可參閱,如:Cohen等人(1972)在Proc.Natl.Acad.Sci.USA 1972,69,2110中以及Sambrook等人(1989)所著《Molecular Cloning,A Laboratory Manual》Cold Spring Harbor Laboratory,Cold Spring Harbor,NY中使用的方法。酵母細胞的轉化在Sherman等人(1986)在Methods In Yeast Genetics,A Laboratory Manual,Cold Spring Harbor,NY中有描述。Beggs(1978)Nature 275,104-109中所述方法也很有用。對於脊椎動物細胞,轉染這些細胞的試劑等,例如,磷酸鈣和DEAE-葡聚糖或脂質體配方,可從Stratagene Cloning Systems公司或Life Technologies公司(Gaithersburg,MD20877,美國)獲得。電穿孔也可用於轉化和/或轉染細胞,是本領域用於轉化酵母細胞、細菌細胞、昆蟲細胞和脊椎動物細胞大家熟知的方法。
被成功轉化的細胞(即含本發明DNA結構的細胞)可用大家熟知的方法(如PCR)進行識別。另外,上清液存在
的蛋白可使用抗體進行檢測。
應瞭解,本發明中的某些宿主細胞用於製備本發明中的肽,例如細菌細胞、酵母細胞和昆蟲細胞。但是,其他宿主細胞可能對某些治療方法有用。例如,抗原提呈細胞(如樹突狀細胞)可用於表達本發明中的肽,使它們可以加載入相應的MHC分子中。因此,本發明提出了含本發明中核酸或表達載體的一種宿主細胞。
在一個較佳實施方案中,宿主細胞為抗原提呈細胞,尤其是樹突狀細胞或抗原提呈細胞。2010年4月29日,美國食品和藥物管理局(FDA)批准載有含攝護腺酸性磷酸酶(PAP)的重組融合蛋白可用於治療無症狀或症狀輕微的轉移性HRPC(Sipuleucel-T)(Small EJ,et al.Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T(APC8015)in patients with metastatic,asymptomatic hormone refractory prostate cancer.J Clin Oncol.2006 Jul 1;24(19):3089-94.Rini et al.Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells(provenge)plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy.Cancer.2006 Jul 1;107(1):67-74)。
另一方面,本發明提出了一種配製一種肽及其變體的方法,該方法包括培養宿主細胞和從宿主細胞或其培養基中分離肽。
在另一個實施方案中,本發明中的肽、核酸或表達
載體用於藥物中。例如,肽或其變體可製備為靜脈(i.v.)注射劑、皮下(s.c.)注射劑、皮內(i.d.)注射劑、腹膜內(i.p.)注射劑、肌肉(i.m.)注射劑。肽注射的較佳方法包括s.c.、i.d.、i.p.、i.m.和i.v.注射。DNA注射的較佳方法為i.d.、i.m.、s.c.、i.p.和i.v.注射。例如,給予50μg至1.5mg,較佳為125μg至500μg的肽或DNA,這取決於具體的肽或DNA。上述劑量範圍在以前的試驗中成功使用(Walter et al Nature Medicine 18,1254-1261(2012))。
本發明的另一方面包括一種體外製備啟動的T細胞的方法,該方法包括將T細胞與載有抗原的人MHC分子進行體外連接,這些分子在合適的抗原提呈細胞表面表達足夠的一段時間從而以抗原特異性方式啟動T細胞,其中所述抗原為根據本發明所述的一種肽。較佳情況是足夠量的抗原與抗原提呈細胞一同使用。
較佳情況是,哺乳動物細胞的TAP肽轉運載體缺乏或水準下降或功能降低。缺乏TAP肽轉運載體的適合細胞包括T2、RMA-S和果蠅細胞。TAP是與抗原加工相關的轉運載體。
人體肽載入的缺陷細胞株T2從屬美國菌種保藏中心(ATCC,12301 Parklawn Drive,Rockville,Maryland 20852,美國)目錄號CRL1992;果蠅細胞株Schneider2號株從屬ATCC目錄CRL19863;小鼠RMA-S細胞株Karre等人描述過。(Ljunggren,H.-G.,and K.Karre.1985.J.Exp.Med.162:1745)。
較佳情況是,宿主細胞在轉染前基本上不表達MHC I類分子。刺激因數細胞還較佳為表達對T細胞共刺激信號起到重要作用的分子,如,B7.1、B7.2、ICAM-1和LFA3中的任一種分子。大量MHC I類分子和共刺激分子的核酸序列可從GenBank和EMBL資料庫中公開獲得。
當MHC I類表位用作一種抗原時,T細胞為CD8陽性T細胞。
如果抗原提呈細胞受到轉染而表達這種表位,則較佳的細胞包括一個表達載體,該載體有能力表達含SEQ ID NO:1至SEQ ID NO:300的肽或變體氨基酸序列。
可使用其他一些方法來體外生成T細胞。例如,自體腫瘤浸潤性淋巴細胞可用于生成CTL。Plebanski等人(Induction of peptide-specific primary cytotoxic T lymphocyte responses from human peripheral blood.Eur J Immunol.1995 Jun;25(6):1783-7)使用自體外周血淋巴細胞(PLB)製備T細胞。另外,也可能用肽或多肽脈衝處理樹突狀細胞或透過與重組病毒感染而製成自體T細胞。此外,B細胞可用於製備自體T細胞。此外,用肽或多肽脈衝處理或用重組病毒感染的巨噬細胞可用於配製自體T細胞。Walter等人在2003(Cutting edge:predetermined avidity of human CD8 T cells expanded on calibrated MHC/anti-CD28-coatedmicrospheres.J Immunol.2003 Nov 15;171(10):4974-8)中描述了透過使用人工抗原提呈細胞(aAPC)體外啟動T細胞,這也是生成作用於所選肽的T細胞的一種合適方法。在本發明中,根據生物素:鏈黴素生
物化學方法透過將預製的MHC:肽複合體耦合到聚苯乙烯顆粒(微球)而生成aAPC。該系統實現了對aAPC上的MHC密度進行精確調節,這使得可以在血液樣本中選擇地引發高或低親合力的高效抗原特異性T細胞反應。除了MHC:肽複合體外,aAPC還應攜運含共刺激活性的其他蛋白,如耦合至表面的抗-CD28抗體。此外,此類基於aAPC的系統往往需要加入適當的可溶性因數,例如,諸如白細胞介素-12的細胞因數。
也可用同種異體細胞制得T細胞,在WO97/26328中詳細描述了一種方法,以參考文獻方式併入本文。例如,除了果蠅細胞和T2細胞,也可用其他細胞來提呈肽,如CHO細胞、杆狀病毒感染的昆蟲細胞、細菌、酵母、牛痘感染的靶細胞。另外,可使用植物病毒(例如,參閱Porta et al.Development of cowpea mosaic virus as a high-yielding system for the presentation of foreign peptides.Virology.1994 Aug 1;202(2):949-55),其中描述了將豇豆花葉病毒開發為一種提呈外來肽的高產系統。
被啟動的T細胞直接針對本發明中的肽,有助於治療。因此,本發明的另一方面提出了用本發明前述方法制得的啟動T細胞。
按上述方法製成的啟動T細胞將會有選擇性地識別異常表達含SEQ ID NO:1至SEQ ID NO300氨基酸序列的多肽。
較佳情況是,T細胞透過與其含HLA/肽複合體的TCR相互作用(如,結合)而識別該細胞。T細胞是殺傷患者
靶細胞方法中有用的細胞,其靶細胞異常表達含本發明中氨基酸序列的多肽。此類患者給予有效量的啟動T細胞。給予患者的T細胞可能源自該患者,並按上述方法啟動(即,它們為自體T細胞)。或者,T細胞不是源自該患者,而是來自另一個人。當然,較佳情況是該供體為健康人。發明人使用「健康個人」系指一個人一般狀況良好,較佳為免疫系統合格,更較佳為無任何可很容易測試或檢測到的疾病。
根據本發明,CD8-陽性T細胞的體內靶細胞可為腫瘤細胞(有時表達MHC-II類抗原)和/或腫瘤周圍的基質細胞(腫瘤細胞)(有時也表達MHC-II類抗原;(Dengjel et al.,2006))。
本發明所述的T細胞可用作治療性組合物中的活性成分。因此,本發明也提出了一種殺傷患者靶細胞的方法,其中患者的靶細胞異常表達含本發明中氨基酸序列的多肽,該方法包括給予患者上述有效量的T細胞。
發明人所用的「異常表達」的意思還包括,與正常表達水準相比,多肽過度表達,或該基因在源自腫瘤的組織中未表達,但是在該腫瘤中卻表達。「過度表達」系指多肽水準至少為正常組織中的1.2倍;較佳為至少為正常組織中的2倍,更較佳為至少5或10倍。
T細胞可用本領域已知的方法制得(如,上述方法)。
T細胞繼轉移方案為本領域所熟知的方案。綜述可發現於:Gattinoni L,et al.Adoptive immunotherapy for cancer:
building on success.Nat Rev Immunol.2006 May;6(5):383-93.Review.以及Morgan RA,et al.Cancer regression in patients after transfer of genetically engineered lymphocytes.Science.2006 Oct 6;314(5796):126-9)。
本發明的任一分子(即肽、核酸、抗體、表達載體、細胞,啟動T細胞、T細胞受體或編碼核酸)都有益於治療疾病,其特點在於細胞逃避免疫反應的打擊。因此,本發明的任一分子都可用作藥劑或用於製造藥劑。這種分子可單獨使用也可與本發明中的其他分子或已知分子聯合使用。
本發明中所述的藥劑較佳為一種疫苗。該疫苗可直接給到患者的受影響器官,也可i.d.、i.m.、s.c.、i.p.和i.v.注射方式全身給藥,或體外應用到來自患者或其細胞株的細胞(隨後再將這些細胞注入到患者中),或體外用於從來自患者的免疫細胞的一個細胞亞群(然後再將細胞重新給予患者)。如果核酸體外注入細胞,可能有益於細胞轉染,以共同表達免疫刺激細胞因數(如白細胞介素-2)。肽可完全單獨給藥,也可與免疫刺激佐劑相結合(見下文)、或與免疫刺激細胞因數聯合使用、或以適當的輸送系統給藥(例如脂質體)。該肽也可共軛形成一種合適的載體(如鑰孔蟲戚血藍蛋白(KLH)或甘露)到合適的載體(例如,參見WO95/18145)。肽也可能被標記,可能是融合蛋白,或可能是雜交分子。在本發明中給出序列的肽預計能刺激CD4或CD8T細胞。然而,在有CD4T-輔助細胞的幫助時,CD8T細胞刺激更加有效。因此,對於刺激CD8T細胞的MHC-I類表位,一種雜合分子的融合夥伴或片
段提供了刺激CD4陽性T細胞的適當表位。CD4-和CD8刺激表位為本領域所熟知、並包括本發明中確定的表位。
一方面,疫苗包括至少含有SEQ ID NO:1至SEQ ID NO:300中提出的一種肽以及至少另外一種肽,較佳為2至50個、更較佳為2至25個、再較佳為2至20個、最較佳為2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18個肽。肽可能從一個或多個特定TAA中衍生,並且可能與MHC I類分子結合。
另一方面,疫苗包括至少含有SEQ ID NO:1至SEQ ID NO:300中提出的一種肽以及至少另外一種肽,較佳為2至50個、更較佳為2至25個、再較佳為2至20個、最較佳為2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18個肽。肽可能從一個或多個特定TAA中衍生,並且可能與MHC I類分子結合。
多聚核苷酸可為基本純化形式,也可包被於載體或輸送系統。核酸可能為DNA、cDNA、PNA、RNA,也可能為其組合物。這種核酸的設計和引入方法為本領域所熟知。例如,下列文獻中有其概述:(Pascolo et al.,Human peripheral blood mononuclear cells transfected with messenger RNA stimulate antigen-specific cytotoxic T-lymphocytes in vitro.Cell Mol Life Sci.2005 Aug;62(15):1755-62)。多核苷酸疫苗很容易製備,但這些載體誘導免疫反應的作用模式尚未完全瞭解。合適的載體和輸送系統包括病毒DNA和/或RNA,如基於腺病毒、牛痘病毒、逆轉錄病毒、皰疹病毒、腺相關病毒
或含一種以上病毒元素的混合病毒的系統。非病毒輸送系統包括陽離子脂質體和陽離子聚合物,是DNA輸送所屬領域內熟知的系統。也可使用物理輸送系統,如透過「基因槍」。肽或核酸編碼的肽可以是一種融合蛋白,例如,含刺激T細胞進行上述CDR的表位。
本發明的藥劑也可能包括一種或多種佐劑。佐劑是那些非特異性地增強或加強免疫反應的物質(例如,透過CD8-陽性T細胞和輔助T(TH)細胞介導的對一種抗原的免疫應答,因此被視為對本發明的藥劑有用。適合的佐劑包括(但不僅限於)1018 ISS、鋁鹽、AMPLIVAX®、AS15、BCG、CP-870,893、CpG7909、CyaA、dSLIM、鞭毛蛋白或鞭毛蛋白衍生的TLR5配體、FLT3配體、GM-CSF、IC30、IC31、咪喹莫特(ALDARA®)、resiquimod、ImuFact IMP321、白細胞介素IL-2、IL-13、IL-21、幹擾素α或β,或其聚乙二醇衍生物、IS Patch、ISS、ISCOMATRIX、ISCOMs、JuvImmune®、LipoVac、MALP2、MF59、單磷醯脂A、Montanide IMS 1312、Montanide ISA 206、Montanide ISA 50V、Montanide ISA-51、水包油和油包水乳狀液、OK-432、OM-174、OM-197-MP-EC、ONTAK、OspA、PepTel®載體系統、基於聚丙交酯複合乙交酯[PLG]和右旋糖苷微粒、重組人乳鐵傳遞蛋白SRL172、病毒顆粒和其他病毒樣顆粒、YF-17D、VEGFtrap、R848、β-葡聚糖、Pam3Cys、源自皂角苷、分支桿菌提取物和細菌細胞壁合成模擬物的Aquila公司的QS21刺激子,以及其他專有佐劑,如:Ribi's Detox、Quil或Superfos。較佳佐劑如:弗氏佐劑或GM-CSF。
前人對一些樹突狀細胞特異性免疫佐劑(如MF59)及其製備方法進行了描述(Allison and Krummel,1995 The Yin and Yang of T cell costimulation.Science.1995 Nov 10;270(5238):932-3)。也可能使用細胞因數。一些細胞因數直接影響樹突狀細胞向淋巴組織遷移(如,TNF-),加速樹突狀細胞成熟為T淋巴細胞的有效抗原提呈細胞(如,GM-CSF、IL-1和IL-4)(美國5,849,589號專利,特別以其完整引用形式併入本文),並充當免疫佐劑(如IL-12、IL-15、IL-23、IL-7、IFN-α、IFN-β)(Gabrilovich,1996 Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells Nat Med.1996 Oct;2(10):1096-103)。
據報告,CpG免疫刺激寡核苷酸可提高佐劑在疫苗中的作用。如果沒有理論的約束,CpG寡核苷酸可透過Toll樣受體(TLR)(主要為TLR9)啟動先天(非適應性)免疫系統從而起作用。CpG引發的TLR9活化作用提高了對各種抗原的抗原特異性體液和細胞反應,這些抗原包括肽或蛋白抗原、活病毒或被殺死的病毒、樹突狀細胞疫苗、自體細胞疫苗以及預防性和治療性疫苗中的多糖結合物。更重要的是,它會增強樹突狀細胞的成熟和分化,導致TH1細胞的活化增強以及細胞毒性T淋巴細胞(CTL)生成加強,甚至CD4T細胞說明的缺失。甚至有疫苗佐劑的存在也能維持TLR9活化作用誘發的TH1偏移,這些佐劑如:正常促進TH2偏移的明礬或弗氏不完全佐劑(IFA)。CpG寡核苷酸與以下其他佐劑或配方一起製備或聯
合給藥時,表現出更強的佐劑活性,如微粒、納米粒子、脂肪乳或類似製劑,當抗原相對較弱時,這些對誘發強反應尤為必要。它們還能加速免疫反應,使抗原劑量減少約兩個數量級,在有些實驗中,對不含CpG的全劑量疫苗也能產生類似的抗體反應(Krieg,2006)。美國6,406,705 B1號專利對CpG寡核苷酸、非核酸佐劑和抗原結合使用促使抗原特異性免疫反應進行了描述。一種CpG TLR9拮抗劑為Mologen公司(德國柏林)的dSLIM(雙幹環免疫調節劑),這是本發明藥物組合物的較佳成分。也可使用其他如TLR結合分子,如:RNA結合TLR7、TLR8和/或TLR9。
其他有用的佐劑例子包括(但不限於)化學修飾性CpG(如CpR、Idera)、dsRNA模擬物,如,Poly(I:C)及其衍生物(如:AmpliGen、Hiltonol、多聚-(ICLC)、多聚(IC-R)、多聚(I:C12U))、非CpG細菌性DNA或RNA以及免疫活性小分子和抗體,如:環磷醯胺、舒尼替單抗、貝伐單抗®、西樂葆、NCX-4016、西地那非、他達拉非、伐地那非、索拉非尼、替莫唑胺、temsirolimus、XL-999、CP-547632、帕唑帕尼、VEGFTrap、ZD2171、AZD2171、抗-CTLA4、免疫系統的其他抗體靶向性主要結構(如:抗-CD40、抗-TGFβ、抗-TNFα受體)和SC58175,這些藥物都可能有治療作用和/或充當佐劑。技術人員無需過度進行不當實驗就很容易確定本發明中有用的佐劑和添加劑的數量和濃度。
首選佐劑是抗-CD40、咪喹莫特、瑞喹莫德、GM-CSF、環磷醯胺、舒尼替尼、貝伐單抗、幹擾素α、CpG寡核苷酸
及衍生物、多聚(I:C)及衍生物、RNA、西地那非和PLG或病毒顆粒的微粒製劑。
本發明藥物組合物的一個較佳實施方案中,佐劑從含集落刺激因數製劑中選擇,如粒細胞巨噬細胞集落刺激因數(GM-CSF,沙格司亭)、環磷醯胺、咪喹莫特、resiquimod和幹擾素-α。
本發明藥物組合物的一個較佳實施方案中,佐劑從含集落刺激因數製劑中選擇,如粒細胞巨噬細胞集落刺激因數(GM-CSF,沙格司亭)、環磷醯胺、咪喹莫特和resimiquimod。在本發明藥物組合物的一個較佳實施方案中,佐劑為環磷醯胺、咪喹莫特或resiquimod。更較佳的佐劑是Montanide IMS 1312、Montanide ISA 206、Montanide ISA 50V、Montanide ISA-51、聚-ICLC(Hiltonol®)和抗CD40mAB或其組合物。
此組合藥物為非腸道注射使用,如皮下、皮內、肌肉注射,也可口服。為此,肽和其他選擇性分子在藥用載體中分解或懸浮,較佳為水載體。此外,組合物可包含輔料,如:緩衝劑、結合劑、衝擊劑、稀釋劑、香料、潤滑劑等。這些肽也可與免疫刺激物質合用,如:細胞因數。可用於此類組合物的更多輔料可在從A.Kibbe所著的Handbook of Pharmaceutical Excipients(第3版,2000年,美國醫藥協會和制藥出版社)等書中獲知。此組合藥物可用於阻止、預防和/或治療腺瘤或癌性疾病。例如,EP2112253中有示例製劑。
本發明提出了一種藥劑,其用於治療癌症,特別是HCC和其他惡性腫瘤。
本發明還涉及一種套組,其包括:(a)一個容器,包含上述溶液或凍乾粉形式的藥物組合物;(b)可選的第二個容器,其含有凍乾粉劑型的稀釋劑或重組溶液;和(c)可選的(i)溶液使用或(ii)重組和/或凍幹製劑使用的說明。
該套組還步包括一個或多個(iii)緩衝劑,(iv)稀釋劑,(v)過濾液,(vi)針,或(v)注射器。容器最好是瓶子、西林瓶、注射器或試管,可以為多用途容器。藥物組合物最好是凍幹的。
本發明中的套組較佳包含一種置於合適容器中的凍幹製劑以及重組和/或使用說明。適當的容器包括,例如瓶子、西林瓶(如雙室瓶)、注射器(如雙室注射器)和試管。該容器可能由多種材料製成,如玻璃或塑膠。試劑盒和/或容器最好有容器或關於容器的說明書,指明重組和/或使用的說明。例如,標籤可能表明凍幹劑型將重組為上述肽濃度。該標籤可進一步表明製劑用於皮下注射。
存放製劑的容器可使用多用途西林瓶,使得可重複給予(例如,2-6次)重組劑型。該套組可進一步包括裝有合適稀釋劑(如碳酸氫鈉溶液)的第二個容器。
稀釋液和凍幹製劑混合後,重組製劑中的肽終濃度較佳為至少0.15mg/mL/肽(=75μg),不超過3mg/mL/肽(=1500μg)。該套組還可包括商業和用戶角度來說可取的其他
材料,包括其他緩衝劑、稀釋劑,過濾液、針頭、注射器和帶有使用說明書的包裝插頁。
本發明中的套組可能有一個單獨的容器,其中包含本發明所述的藥物組合物製劑,該製劑可有其他成分(例如,其他化合物或及其藥物組合物),也可無其他成分,或者每種成分都有其不同容器。
較佳情況是,本發明的套組包括與本發明的一種製劑,包裝後與第二種化合物(如佐劑(例如GM-CSF)、化療藥物、天然產品、激素或拮抗劑、抗血管生成劑或抑制劑、凋亡誘導劑或螯合劑)或其藥物組合物聯合使用。該套組的成分可進行預絡合或每種成分在給予患者之前可放置於單獨的不同容器。該套組的成分可以是一種或多種溶液,較佳為水溶液,更較佳為無菌水溶液。該套組的成分也可為固體形式,加入合適的溶劑後轉換為液體,最好放置於另一個不同的容器中。
治療套組的容器可能為西林瓶、試管、燒瓶、瓶子、注射器、或任何其他盛裝固體或液體的工具。通常,當成分不只一種時,套組將包含第二個西林瓶或其他容器,使之可以單獨定量。該套組還可能包含另一個裝載藥用液體的容器。較佳情況是,治療套組將包含一個裝置(如,一個或多個針頭、注射器、滴眼器、吸液管等),使得可注射本發明的藥物(本套組的組合物)。
本發明的藥物配方適合以任何可接受的途徑進行肽給藥,如口服(腸道)、鼻內、眼內、皮下、皮內、肌內,靜
脈或經皮給藥。較佳為皮下給藥,最較佳為皮內給藥,也可透過輸液泵給藥。
由於本發明的肽從HCC中分離而得,因此,本發明的藥劑較佳用於治療HCC。
本發明進一步包括為個體患者製備個體化藥物的一種方法,其中包括:製造含選自預篩選TUMAP存儲庫至少一種肽的藥物組合物,其中藥物組合物中所用的至少一種肽選擇為適合於個體患者。在一項實施方案中,藥物組合物為一種疫苗。該方法也可以改動以產生下游應用的T細胞克隆物,如:TCR隔離物或可溶性抗體和其他治療選擇。
「個體化藥物」系指專門針對個體患者的治療,將僅用於該等個體患者,包括個體化活性癌症疫苗以及使用自體組織的過繼細胞療法。
如本文所述,「存儲庫」應指已經接受免疫原性預篩查和/或在特定腫瘤類型中過量提呈的一組肽。「存儲庫」一詞並不暗示,疫苗中包括的特定肽已預先製造並儲存於物理設備中,雖然預期有這種可能性。明確預期所述肽可以用於新製造每種個體化疫苗,也可能被預先製造和儲存。存儲庫(例如,資料庫形式)由腫瘤相關肽組成,其在各種HLA-AHLA-B和HLA-C等位基因HCC患者的腫瘤組織中高度過度表達。其可能含有包括MHC I類和MHC II類肽或拉長的MHC I類肽。除了從幾種HCC組織中採集的腫瘤相關肽外,存儲庫還可能包含HLA-A*02和HLA-A*24標記肽。這些肽可對TUMAP誘導的T細胞免疫進行量化比較,從而可得出疫苗抗
腫瘤反應能力的重要結論。其次,在沒有觀察到來自患者「自身」抗原TUMAP的任何疫苗誘導的T細胞反應時,它們可作為來自「非自身」抗原的重要陽性對照肽。第三,它還可對患者的免疫功能狀態得出結論。
存儲庫的TUMAP透過使用一種功能基因組學方法進行鑒定,該方法結合了基因表達分析、質譜法和T細胞免疫學(XPresident®)。該方法確保了只選擇真實存在于高百分比腫瘤但在正常組織中不表達或僅很少量表達的TUMAP用於進一步分析。對於初始肽的選擇,患者的HCC樣本和健康供體的血液以循序漸進的方法進行分析:
1.惡性材料的HLA配體用質譜法確定
2.使用全基因組信使核糖核酸(mRNA)表達分析法用於確定惡性腫瘤組織(HCC)與一系列正常器官和組織相比過度表達的基因。
3.確定的HLA配體與基因表達資料進行比較。腫瘤組織上過度提呈或選擇性提呈的肽,較佳為第2步中檢測到的選擇性表達或過度表達基因所編碼的考慮為多肽疫苗的合適候選TUMAP。
4.文獻檢索以確定更多證據以支持確認為TUMP的肽的相關性
5.過度表達在mRNA水準的相關性由腫瘤組織第3步選定的TUMAP重新檢測而確定,並且在健康組織上缺乏(或不經常)檢測。
6.為了評估透過選定的肽誘導體內T細胞反應是否可行,使用健康供體以及HCC患者的人T細胞進行體外免疫原性測定。
重要的是要認識到,透過本發明的疫苗引發的免疫應答在不同的細胞階段和開發的不同階段攻擊癌症。而且不同的癌症相關信號通路被攻擊。這相對於其他疫苗的優勢,這些疫苗只針對一個或幾個靶標,這可能會導致腫瘤很容易適應於攻擊(腫瘤逃逸)。此外,並非所有的個體腫瘤都表達相同模式的抗原。因此,幾個腫瘤相關肽的組合確保了每個腫瘤都承擔至少一些靶標。該組合物以這樣特別的方式設計,預期每個HLA-A*02和/或HLA-A*24陽性腫瘤可表達幾種抗原並覆蓋腫瘤生長和維持所需要的幾種獨立的途徑。對於特定於兩個HLAI類等位基因(A*02和A*24)的每個肽子集,基於基礎的實驗分析這得到獨立的確保。因此,疫苗可易於「現成的」用於較大患者群體。這意味著,預選擇接受疫苗治療的患者可限制為HLA分型,無需抗原表達的任何額外的生物標誌物評估,但仍然確保多個靶標同時被誘導的免疫應答攻擊,這對於療效很重要(Banchereau et al.,2001;Walter et al.,2012)。
一方面,在將所述肽加入存儲庫之前,對其進行篩查以瞭解免疫原性。舉例來說(但不限於此),納入存儲庫的肽的免疫原性的確定方法包括體外T細胞啟動,具體為:用裝載肽/MHC複合體和抗CD28抗體的人工抗原提呈細胞反復刺激來自健康供體的CD8+T細胞。
這種方法較佳用於罕見癌症以及有罕見表達譜的患者。與含目前開發為固定組分的多肽混合物相反的是,存儲庫可將腫瘤中抗原的實際表達於疫苗進行更高程度的匹配。在多目標方法中,每名患者將使用幾種現成肽的選定單一肽或組合。理論上來說,基於從50抗原肽庫中選擇例如5種不同抗原肽的一種方法可提供大約170萬種可能的藥物產品(DP)組分。
在一方面,選擇所述肽用於疫苗,其基於個體患者的適合性,並使用本發明此處或後文所述的方法。
HLA表型、轉錄和肽組學資料從患者的腫瘤材料和血液樣本中收集,以確定最合適每名患者且含有「存儲庫」和患者獨特(即突變)TUMAP的肽。將選擇的那些肽選擇性地或過度表達于患者腫瘤中,並且可能的情況下,如果用患者個體PBMC進行檢測,則表現出很強的體外免疫原性。
較佳的情況是,疫苗所包括的肽的一種確定方法包括:(a)識別由來自個體患者腫瘤樣本提呈的腫瘤相關肽(TUMAP);(b)將(a)中鑒定的肽與上述肽的存儲庫(資料庫)進行比對;且(c)從與患者中確定的腫瘤相關肽相關的存儲庫(資料庫)中選擇至少一種肽。例如,腫瘤樣本提呈的TUMAP的鑒定方法有:(a1)將來自腫瘤樣本的表達資料與所述腫瘤樣本組織類型相對應的正常組織樣本的表達資料相比對,以識別腫瘤組織中過度表達或異常表達的蛋白;以及(a2)將表達資料與結合到腫瘤樣本中I類MHC和/或II類分子的MHC配體序列想關聯,以確定來源於腫瘤過度表達或異常表達的蛋白質
的MHC配體。較佳情況是,MHC配體的序列的確定方法是:洗脫來自腫瘤樣本分離的MHC分子結合肽,並測序洗脫配體。較佳情況是,腫瘤樣本和正常組織從同一患者獲得。
除了使用存儲庫(資料庫)模型選擇肽以外,或作為一種替代方法,TUMAP可能在新患者中進行重新鑒定,然後列入疫苗中。作為一種實施例,患者中的候選TUMAP可透過以下方法進行鑒定:(a1)將來自腫瘤樣本的表達資料與所述腫瘤樣本組織類型相對應的正常組織樣本的表達資料相比對,以識別腫瘤組織中過度表達或異常表達的蛋白;以及(a2)將表達資料與結合到腫瘤樣本中I類MHC和/或II類分子的MHC配體序列相關聯,以確定來源於腫瘤過度表達或異常表達的蛋白質的MHC配體。作為另一實施例,蛋白的鑒定方法為可包含突變,其對於腫瘤樣本相對于個體患者的相應正常組織是獨特的,並且TUMAP可透過特異性靶向作用於變異來鑒定。例如,腫瘤以及相應正常組織的基因組可透過全基因組測序方法進行測序:為了發現基因蛋白質編碼區域的非同義突變,從腫瘤組織中萃取基因組DNA和RNA,從外周血單核細胞(PBMC)中提取正常非突變基因組種系DNA。運用的NGS方法只限於蛋白編碼區的重測序(外顯子組重測序)。為了這一目的,使用供應商提供的靶序列富集試劑盒來捕獲來自人樣本的外顯子DNA,隨後使用HiSeq2000(Illumina公司)進行測序。此外,對腫瘤的mRNA進行測序,以直接定量基因表達,並確認突變基因在患者腫瘤中表達。得到的數以百萬計的序列讀數透過軟體演算法處理。輸出列表中包含突變
和基因表達。腫瘤特異性體突變透過與PBMC衍生的種系變化比較來確定,並進行優化。然後,為了存儲庫可能測試新確定的肽瞭解如上所述的免疫原性,並且選擇具有合適免疫原性的候選TUMAP用於疫苗。
在一個示範實施方案中,疫苗中所含肽透過以下方法確定:(a)用上述方法識別由來自個體患者腫瘤樣本提呈的腫瘤相關肽(TUMAP);(b)將(a)中鑒定的肽與進行腫瘤(與相應的正常組織相比)免疫原性和過量提呈預篩查肽的存儲庫進行比對;(c)從與患者中確定的腫瘤相關肽相關的存儲庫中選擇至少一種肽;及(d)可選地在(a)中選擇至少一種新確定的肽,確認其免疫原性。
在一個示範實施方案中,疫苗中所含肽透過以下方法確定:(a)識別由來自個體患者腫瘤樣本提呈的腫瘤相關肽(TUMAP);以及(b)在(a)中選擇至少一種新確定的肽,並確認其免疫原性。
一旦選定了用於個體化肽疫苗的肽時,則產生疫苗。該疫苗較佳為一種液體製劑,包括溶解於33%DMSO中的個體肽。
列入產品的每種肽都溶於DMSO中。單個肽溶液濃度的選擇取決於要列入產品中的肽的數量。單肽-DMSO溶液均等混合,以實現一種溶液中包含所有的肽,且濃度為每肽~2.5mg/ml。然後該混合溶液按照1:3比例用注射用水進行稀釋,以達到在33%DMSO中每肽0.826mg/ml的濃度。稀釋的溶液透過0.22μm無菌篩檢程式進行過濾。從而獲得最終本體溶
液。
最終本體溶液填充到小瓶中,在使用前儲存於-20℃下。一個小瓶包含700μL溶液,其中每種肽含有0.578mg。其中的500μL(每種肽約400μg)將用於皮內注射。
下列描述較佳方案的實施例將對本發明進行說明(但是不僅限於此)。考慮到本發明的目的,文中引用的所有參考文獻透過引用的方式併入在本文中。
在圖中,圖1顯示了正常組織(暗灰色)和HCC(淺灰色)中各種肽的過量提呈。圖1A)APOB,肽:ALVDTLKFV(A*02)(SEQ ID NO:7),從左至右的組織;1脂肪組織,3腎上腺,2動脈,2骨髓,7大腦,3乳房,13結腸,4食管,2膽囊,3胃腸道,3心臟,16腎臟,4白細胞樣本,45肺,1淋巴結,1卵巢,7胰腺,1周圍神經,1腦垂體,3胸膜,1攝護腺,6直肌,3骨骼肌肉,1漿膜,3皮膚,4脾臟,7胃,1睾丸,2胸腺,3甲狀腺2子宮,2靜脈,以及20肝臟;圖1B)ALDH1L1,肽:KLQAGTVFV(A*02)(SEQ ID NO:2),從左至右的組織:1脂肪組織,3腎上腺,2動脈,2骨髓,7大腦,3乳房,13結腸,4食管,2膽囊,3胃腸道,3心臟,16腎臟,4白細胞樣本,45肺,1淋巴結,1卵巢,7胰腺,1周圍神經,1腦垂體,3胸膜,1攝護腺,6直肌,3骨骼肌肉,1漿膜,3皮膚,4脾臟,7胃,1睾丸,2胸腺,3甲狀腺2子宮,2靜脈,以及20肝臟;圖1C)C8B,肽:AYLLQPSQF(A*24)(SEQ ID NO:200),從左至右
的組織:包括2腎上腺,1動脈,4大腦,1乳腺,5結腸,1心臟,13腎臟,9肺,3胰腺,2直肌,3皮膚,1脾臟,12胃,1胸腺,2子宮和9肝臟;圖1D)RAD23B肽:KIDEKNFVV(SEQ ID NO:63),1漿膜,1脂肪組織,3腎上腺,2動脈,2骨髓,7大腦,3乳房,13結腸,2膽囊,3胃腸道,3心臟,12腎臟,4白細胞,19肺,43肺,1淋巴結,1卵巢,6胰腺,1周圍神經,1腦垂體,3胸膜,1攝護腺,6直肌,3骨骼肌肉,3皮膚,4脾臟,5胃,1睾丸,2胸腺,3甲狀腺2子宮,2靜脈,4食管;圖1E)RAD23B,肽:KIDEKNFVV(SEQ ID NO:63),顯示的僅是上面提呈肽的樣本:5細胞系,1正常組織(1腎上腺),16癌組織(2腦癌,4肝癌,5肺癌,1直腸癌,1膀胱癌,3子宮癌)(從左至右);圖1F)RFNGRLPPDTLLQQV(SEQ ID NO:92),顯示的僅是上面提呈肽的樣本:1漿膜,1脂肪組織,3腎上腺,2動脈,2骨髓,7大腦,3乳房,13結腸,2膽囊,3胃腸道,3心臟,12腎臟,4白細胞,19肺,43肺,1淋巴結,1卵巢,6胰腺,1周圍神經,1腦垂體,3胸膜,1攝護腺,6直肌,3骨骼肌肉,3皮膚,4脾臟,5胃,1睾丸,2胸腺,3甲狀腺2子宮,2靜脈,4食管;圖1G)RFNG,肽:RLPPDTLLQQV(SEQ ID NO:92),顯示的僅是上面提呈肽的樣本:2細胞系,2正常組織(2腎上腺),17癌組織(1腦癌,1乳房癌,1食道癌,5肝癌,4肺癌,1卵巢癌,1攝護腺癌,2膀胱癌,1子宮癌)(從左至右);圖1H)FLVCR1,肽:SVWFGPKEV(SEQ ID NO:104),1漿膜,1脂肪組織,3腎上腺,2動脈,2骨髓,7大腦,3乳房,13結腸,2膽囊,3胃腸
道,3心臟,12腎臟,4白細胞,19肺,43肺,1淋巴結,1卵巢,6胰腺,1周圍神經,1腦垂體,3胸膜,1攝護腺,6直肌,3骨骼肌肉,3皮膚,4脾臟,5胃,1睾丸,2胸腺,3甲狀腺2子宮,2靜脈,4食管;圖1I)FLVCR1,肽:SVWFGPKEV(SEQ ID NO:104),顯示的僅是上面提呈肽的樣本:9細胞系,1正常組織(1小腸),16癌組織(1腦癌,1乳腺癌,5肝癌,5肺癌,1皮膚癌,1胃癌,1膀胱癌,1子宮癌)(從左至右);圖1J)IKBKAP,肽:LLFPHPVNQV(SEQ ID NO:156),1漿膜,1脂肪組織,3腎上腺,2動脈,2骨髓,7大腦,3乳房,13結腸,2膽囊,3胃腸道,3心臟,12腎臟,4白細胞,19肺,43肺,1淋巴結,1卵巢,6胰腺,1周圍神經,1腦垂體,3胸膜,1攝護腺,6直肌,3骨骼肌肉,3皮膚,4脾臟,5胃,1睾丸,2胸腺,3甲狀腺2子宮,2靜脈,4食管;圖1K)IKBKAP,肽:LLFPHPVNQV(SEQ ID NO:156),顯示的僅是上面提呈肽的樣本:7細胞系,2原代培養物,1正常組織(1結腸),34癌組織(1骨髓癌,1乳腺癌,1結腸癌,2食道癌,2白細胞白血病癌症,4肝癌,11肺癌,3淋巴結癌,5卵巢癌,4膀胱癌)(從左至右);圖1L)NKD1,肽:FLDTPIAKV(SEQ ID NO:47),1漿膜,1脂肪組織,3腎上腺,2動脈,2骨髓,7大腦,3乳房,13結腸,2膽囊,3胃腸道,3心臟,12腎臟,4白細胞,19肺,43肺,1淋巴結,1卵巢,6胰腺,1周圍神經,1腦垂體,3胸膜,1攝護腺,6直肌,3骨骼肌肉,3皮膚,4脾臟,5胃,1睾丸,2胸腺,3甲狀腺2子宮,2靜脈,4食管;圖1M)NKD1,肽:FLDTPIAKV(SEQ ID NO:47),顯示的僅是
上面提呈肽的樣本:1其他疾病(腦膨出),2正常組織(1肺,1脾),35癌組織(5腦癌,6結腸癌,1食道癌,6肝癌,9肺癌,1卵巢癌,1攝護腺癌,4直腸癌,2胃癌)(從左至右)。
圖2顯示了本發明的源基因的代表性表達特徵(與正常腎臟相比的相對表達),這些基因在一系列正常組織(深灰色)HCC中以及12份HCC樣本(灰色)中高度過度表達或專門表達。圖2A)APOB,從左到右的組織:1腎上腺,1動脈,1骨髓,1腦(全),1乳腺,1結腸,1食道,1心臟,3腎臟,1白細胞樣本,1肝臟,1肺,1淋巴結,1卵巢,1胰腺,1胎盤,1攝護腺,1唾液腺,1骨骼肌,1皮膚,1小腸,1脾臟,1胃,1睾丸,1胸腺,1甲狀腺,1膀胱,1子宮頸,1子宮,1靜脈;圖2B)AMACR,從左到右的組織:1腎上腺,1動脈,1骨髓,1腦(全),1乳腺,1結腸,1食道,1心臟,3腎臟,1白細胞樣本,1肝臟,1肺,1淋巴結,1卵巢,1胰腺,1胎盤,1攝護腺,1唾液腺,1骨骼肌,1皮膚,1小腸,1脾臟,1胃,1睾丸,1胸腺,1甲狀腺,1膀胱,1子宮頸,1子宮,1靜脈;圖2C)ALDH1L1,從左到右的組織:1腎上腺,1動脈,1骨髓,1腦(全),1乳腺,1結腸,1食道,1心臟,3腎臟,1白細胞樣本,1肝臟,1肺,1淋巴結,1卵巢,1胰腺,1胎盤,1攝護腺,1唾液腺,1骨骼肌,1皮膚,1小腸,1脾臟,1胃,1睾丸,1胸腺,1甲狀腺,1膀胱,1子宮頸,1子宮,1靜脈;圖2D)FGG,從左到右的組織:1腎上腺,1動脈,1骨髓,1腦(全),1乳腺,1結腸,1食道,1心臟,3腎臟,1白細胞樣本,1肝臟,1肺,1淋巴結,1卵巢,1胰腺,1胎盤,1攝護腺,1唾
液腺,1骨骼肌,1皮膚,1小腸,1脾臟,1胃,1睾丸,1胸腺,1甲狀腺,1膀胱,1子宮頸,1子宮,1靜脈;圖2E)C8B,從左到右的組織:1腎上腺,1動脈,1骨髓,1腦(全),1乳腺,1結腸,1食道,1心臟,3腎臟,1白細胞樣本,1肝臟,1肺,1淋巴結,1卵巢,1胰腺,1胎盤,1攝護腺,1唾液腺,1骨骼肌,1皮膚,1小腸,1脾臟,1胃,1睾丸,1胸腺,1甲狀腺,1膀胱,1子宮頸,1子宮,1靜脈;和圖2F)HSD17B6,從左到右的組織:包括1腎上腺,1動脈,1骨髓,1腦(全),1乳腺,1結腸,1食道,1心臟,3腎臟,1白細胞樣本,1肝臟,1肺,1淋巴結,1卵巢,1胰腺,1胎盤,1攝護腺,1唾液腺,1骨骼肌,1皮膚,1小腸,1脾臟,1胃,1睾丸,1胸腺,1甲狀腺,1膀胱,1子宮頸,1子宮,1靜脈。
圖3顯示肽特定多聚體染色後實例性流式細胞儀結果。進一步的解釋見實施例4。
圖4顯示肽特定多聚體染色後實例性流式細胞儀結果。進一步的解釋見實施例4。
實施例
實施例1:細胞表面提呈的腫瘤相關肽的識別和定量
組織樣本
患者的腫瘤組織獲得自Universitätsklinik für Allgemeine,Viszeral-und Transplantationschirurgie,圖賓根,德國;Istituto Nazionale Tumori "Pascale"。分子生物學與病毒腫瘤單元,Via Mariano,那不勒斯,義大利;Bio-Options Inc.
,Brea,CA,美國;ProteoGenex Inc.,Culver City,加州,美國;Asterand Europe,Royston Herts,英國。所有患者在手術前都獲得了書面知情同意。手術後組織立即進行激凍處理,在分離TUMAP前儲存於-70℃或以下。
從組織樣本中分離HLA肽
根據方案(Falk,K.,1991;Seeger,F.H.T.,1999)略加修改,使用HLA-A*02-特異性抗體BB7.2、HLA-A、HLA-B、HLA-C特異性抗體W6/32、CNBr活化的瓊脂糖凝膠、酸處理和超濾方法以固體組織的免疫沉澱法獲得了激凍組織樣本的HLA肽庫。
質譜分析
獲得的HLA肽庫根據其疏水性用反相色譜(nanoAcquity UPLC system,Waters)分離,洗脫肽用裝有電噴霧源的LTQ-velos融合雜交質譜(ThermoElectron)進行了分析。肽庫被直接載入填充有1.7μmC18反相材料(Waters)的分析用熔煉石英微毛細管柱(75μm內徑x250mm),應用流速為400nL每分鐘。隨後,使用來自流速為300nL每分鐘、濃度為10%至33%溶劑B中的兩步180分鐘二元梯度法對肽進行分離。梯度由溶劑A(含0.1%甲酸的水)和溶劑B(含0.1%甲酸的乙腈)。金鍍膜玻璃毛細管(PicoTip,New Objective)用於引入到納升電噴霧源。使用前5(TOP5)策略在資料依賴模式下操作LTQ-Orbitrap質譜儀。簡言之,首先以高精確品質完全掃描在orbitrap開始一個掃描週期(R=30000),之後用先前選定離子的動態排除技術在orbitrap中對5種含量最為豐富的前體離子進
行MS/MS掃描(R=7500)。串聯質譜以SEQUEST和另一種手動控制器進行解讀。生成的自然肽碎片模式與合成序列相同參考肽的碎片模式進行比較後,確保了被識別的肽序列。
無標記相對LC-MS定量透過離子計數(即透過LC-MS功能提取和分析)來進行(Mueller et al.2007a)。該方法假定肽的LC-MS信號區域與樣本中其豐度相關。提取的特徵透過充電狀態去卷積和保留時間校準進行進一步處理(Mueller et al.2007b;Sturm et al.2008)。最後,所有的LC-MS特徵與序列鑒定結果交叉引用,以將不同樣本和組織的定量資料與肽呈遞特徵結合。定量資料根據集中資料以兩層方式進行正態化處理,以說明技術和生物學複製變異。因此,每個被識別的肽均可與定量資料相關,從而可得出樣本和組織之間的相對定量。此外,對候選肽獲得的所有定量資料進行手動檢查,以確保資料的一致性,並驗證自動化分析的準確度。對於每種肽,計算了提呈圖,其顯示樣本平均提呈量以及複製變化。這些特徵使HCC樣本與正常組織樣本的基線值並列。
示範性過度提呈肽的提呈譜示於圖1中。示範性肽的提呈分數見表8。
實施例2
編碼本發明肽的基因的表達譜
與正常細胞相比在腫瘤細胞上一種肽過度提呈或特定提呈足夠其在免疫治療中有效使用,一些肽為腫瘤特異性的,儘管存在其源蛋白也存在于正常組織中。但是,mRNA表達譜增加了免疫治療目標肽選擇中其他級別的安全性。特別是對於具有高安全性風險的治療選擇,諸如親和力成熟的TCR,理想的目標肽將來源於對該腫瘤獨一無二且不出現于正常組織中的蛋白。
RNA來源與製備
手術切除組織標本按如上所述(參見實施例1)在獲得每名患者的書面知情同意後提供。手術後立即速凍腫瘤組織標本,之後在液態氮中用杵臼勻漿。使用TRI試劑(Ambion公司,Darmstadt,德國)之後用RNeasy(QIAGEN公司,Hilden,德國)清理從這些樣本中製備總RNA;這兩種方法都根據
製造商的方案進行。
健康人體組織中的總RNA從商業途徑獲得(Ambion公司,Huntingdon,英國;Clontech公司,海德堡,德國;Stratagene公司,阿姆斯特丹,荷蘭;BioChain公司,Hayward,CA,美國)。混合數個人(2至123個人)的RNA,從而使每個人的RNA得到等加權。
所有RNA樣本的品質和數量都在Agilent 2100 Bioanalyzer分析儀(Agilent公司,Waldbronn,德國)上使用RNA 6000 Pico LabChip Kit試劑盒(Agilent公司)進行評估。
微陣列實驗
所有腫瘤和正常組織的RNA樣本都使用Affymetrix Human Genome(HG)U133A或HG-U133 Plus 2.0 Affymetrix寡核苷酸晶片(Affymetrix公司,SantaClara,CA,美國)進行基因表達分析。所有步驟都根據Affymetrix手冊進行。簡言之,如手冊中所述,使用SuperScript RTII(Invitrogen公司)以及oligo-dT-T7引物(MWG Biotech公司,Ebersberg,德國)從5-8μgRNA中合成雙鏈cDNA。用BioArray HighYield RNA Transcript Labelling Kit(ENZO Diagnostics公司,Farmingdale,NY,美國)進行U133A測定或用GeneChip IVT Labelling Kit(Affymetrix公司)進行U133 Plus 2.0測定,之後用鏈黴親和素-藻紅蛋白和生物素化抗鏈黴素蛋白抗體(Molecular Probes公司,Leiden,荷蘭)進行破碎、雜交和染色,這樣完成體外轉錄。用Agilent 2500A GeneArray Scanner(U133A)或
Affymetrix Gene-Chip Scanner 3000(U133 Plus 2.0)對圖像進行掃描,用GCOS軟體(Affymetrix公司)在所有參數默認設置情況下對資料進行分析。為了實現標準化,使用了Affymetrix公司提供的100種管家基因(housekeeping gene)。相對表達值用軟體給定的signal log ratio進行計算,正常腎組織樣本的值任意設置為1.0。本發明的代表性源基因在HCC中高度過度表達的表達譜如圖2所示。進一步代表性基因的表達分數見表9。
實施例3:與HLA-A*02和HLA-A*24結合的UV配體交換/肽
本發明基於T細胞療法的候選肽進一步測試其MHC結合能力(親和性)。單個肽-MHC複合體透過UV-配體交換產生,其中,紫外線敏感肽經紫外線照射後裂解,與分析的相關肽交換。只有能夠有效地結合並穩定肽接受MHC分子的候選肽才能阻止MHC複合體的解離。為了確定交換反應的產率,將基於穩定MHC複合體輕鏈(β2m)的檢測結果進行ELISA測定。檢測總體上按照Rodenko等人描述的方法進行。(Rodenko B,Toebes M,Hadrup SR,van Esch WJ,Molenaar AM,
Schumacher TN,Ovaa H.Generation of peptide-MHC class I complexes through UV-mediated ligand exchange.Nat Protoc.2006;1(3):1120-32.)。
96孔Maxisorp板(NUNC)在室溫下在PBS中以2ug/ml鏈黴親和素包被過夜,用4倍洗滌並在37℃下在含封閉緩衝液的2%BSA中封閉1小時。複性的HLA-A*0201/MLA-001單體作為標準品,涵蓋15-500ng/ml的範圍。紫外線交換反應的肽-MHC單體在封閉緩衝液中稀釋100倍。樣本在37℃下孵育1小時,洗滌四次,在37℃下以2ug/mlHRP綴合抗-β2m溫育1小時,再次洗滌,並以NH2SO4封堵的TMB溶液進行檢測。在450nm處測量吸收。在生成和產生抗體或其片段時和/或T細胞受體或其片段時,通常較佳顯示為高交換產率(較佳為高於50%,最較佳為高於75%)的候選肽,這是因為它們對MHC分子表現出足夠的親合力,並能防止MHC複合體的解離。
實施例4
MHC-I類提呈肽的體外免疫原性
為了獲得關於本發明TUMAP的免疫原性資訊,發明人使用體外T細胞擴增分析方法進行了研究,其中該分析方法基於使用裝載肽/MHC複合體和抗CD28抗體的人工抗原提呈細胞(aAPC)進行反復刺激。用這種方法,發明人可顯示出本發明目前為止22種HLA-A*0201限制TUMAP具有免疫原性,這表明這些肽為對抗人CD8+前體T細胞的T細胞表位(表11)。
CD8+T細胞體外啟動
為了用載有肽-MHC複合體(pMHC)和抗CD28抗體的人工抗原提呈細胞進行體外刺激,發明人首先從德國曼海姆大學診所在知情同意後獲取健康供體的新鮮HLA-A*02白細胞清除術後產物,使用CD8微珠(Miltenyi Biotec,Bergisch-Gladbach,Germany)透過積極選擇分離出CD8+T細胞。
PBMC和分離出的CD8+淋巴細胞使用前在T細胞培養基(TCM)中培養,培養基包括RPMI-Glutamax(Invitrogen公司,Karlsruhe,德國)並補充10%熱滅活人AB血清(
PAN-Biotech公司,Aidenbach,德國)、100U/ml青黴素/100μg/ml鏈黴素(Cambrex公司,Cologne,德國),1mM丙酮酸鈉(CCPro公司,Oberdorla,德國)和20μg/ml慶大黴素(Cambrex公司)。在此步驟,2.5ng/ml的IL-7(PromoCell公司,Heidelberg,德國)和10U/ml的IL-2(NovartisPharma公司,Nürnberg,德國)也加入TCM。
對於pMHC/抗-CD28塗層珠的生成、T細胞的刺激和讀出,使用每刺激條件四個不同pMHC分子以及每個讀出條件8個不同的pMHC分子在高度限定的體外系統中進行。
純化的共刺激小鼠IgG2a抗人CD28抗體9.3(Jung et al.,1987)使用製造商(Perbio公司,波恩,德國)推薦的N-羥基琥珀醯亞胺生物素進行化學生物素化處理。所用珠為5.6μm的鏈黴抗生物素蛋白包裹的多聚苯乙烯顆粒(Bangs Laboratories,伊利諾州,美國)。
用於陽性和陰性對照刺激物的pMHC分別為A*0201/MLA-001(從Melan-A/MART-1中修飾制得的肽ELAGIGILTV)和A*0201/DDX5-001(從DDX5中獲得的YLLPAIVHI)。
800.000珠/200μl包裹於含有4x12.5ng不同生物素-pMHC的96孔板、進行洗滌,隨後加入體積為200μl的600ng生物素抗-CD28。在37℃下,在含5ng/mlIL-12(PromoCell)的200μlTCM中共培養1x106CD8+T細胞與2x105的清洗塗層珠3天,從而啟動刺激。之後,一半培養基與補充80U/mlIL-2的新鮮TCM進行交換,並且培養在37℃下持續4天。這種刺激性週
期總共進行3次。對於使用每條件8種不同pMHC分子的pMHC多聚體讀出,二維組合編碼方法如前述使用(Andersen et al.,2012),稍作修飾,涵蓋耦合至5種不同的螢光染料。最後,用Live/dead near IR染料(Invitrogen公司,Karlsruhe,德國)、CD8-FITC抗體克隆SK1(BD公司,Heidelberg,德國)和螢光pMHC多聚體而執行多聚體分析。對於分析,使用了配有合適鐳射儀和篩檢程式的BDLSRIISORP細胞儀。肽特異性細胞以占總CD8+細胞的百分比形式進行計算。多聚體分析結果使用FlowJo軟體(Tree Star公司,Oregon,美國)進行評估。特定多聚體+CD8+淋巴細胞的體外填裝用與陰性對照刺激組比較而進行檢測。如果健康供體中的至少一個可評價的體外刺激孔在體外刺激後發現含有特異性CD8+T細胞株(即該孔包含至少1%特定多聚體+CD8+T細胞,並且特定多聚體+的百分比至少為陰性對照刺激中位數的10倍),則檢測給定抗原的免疫原性。
HCC肽體外免疫原性
對於受到測試的HLA-I類肽,可透過肽特異性T細胞株的生成證明其體外免疫原性。TUMAP特異性多聚體對本發明的三種肽染色後流式細胞儀檢測的典型結果如圖3和圖4所示,同時也含有相應的陰性對照資訊。本發明22種肽的結果匯總於表11A。
健康HLA-A*02+供體的肽特異性CD8+T細胞體外反應的示例性結果(圖3)
CD8+T細胞製備的方法為:使用抗CD28mAb和HLA-A*02塗層的人工APC分別與IMA-APOB-002(序列號7)肽(A,右圖)或IMA-APOB-003(B,右圖,序列號1)或IMA-ALDH1L1-001(C,右圖,序列號2)合成。經過3個週期的刺激後,用A*02/APOB-002(A)或A*02/APOB-003(B)或A*02/ALDH1L1-001進行2D多聚體染色檢測肽反應性細胞。左圖(A,B,C)顯示不相關A*02/肽複合體刺激的細胞的對照染色。活單細胞在CD8+淋巴細胞上得到門控。Boolean門控幫助排除用不同肽特定的多聚體檢測的假陽性事件。提示了特異性多聚體+細胞和CD8+淋巴細胞的頻率。
健康HLA-A*24+供體的肽特異性CD8+T細胞體外反應的示例性結果(圖4)
CD8+T細胞製備的方法為:使用抗CD28mAb和HLA-A*24塗層的人工APC分別與IMA-KLHL24-001(序列號
190)肽(A,右圖)或IMA-APOB-006(B,右圖,序列號218)合成。經過3個週期的刺激後,用A*24/KLHL24-001(A)或A*24/APOB-006(B)的2D多聚體染色法對肽反應性細胞進行檢測。左圖(A和B)顯示用不相關A*24/肽複合體刺激的細胞對照染色。活單細胞在CD8+淋巴細胞上得到門控。Boolean門控幫助排除用不同肽特定的多聚體檢測的假陽性事件。提示了特異性多聚體+細胞和CD8+淋巴細胞的頻率。
實施例5:肽的合成
所有的肽透過使用Fmoc策略以標準、廣為接受的固相肽合成法合成。每個肽的身份和純度已使用質譜和RP-HPLC分析法確定。用凍幹法(三氟乙酸鹽)獲得白色至類白色的肽,純度為>50%。所有的TUMAP較佳作為三氟乙酸鹽或乙酸鹽進行給藥,其他鹽形式也可以。
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<212> PRT
<213> Homo sapiens
<210> 63
<211> 9
<212> PRT
<213> Homo sapiens
<210> 64
<211> 9
<212> PRT
<213> Homo sapiens
<210> 65
<211> 11
<212> PRT
<213> Homo sapiens
<210> 66
<211> 9
<212> PRT
<213> Homo sapiens
<210> 67
<211> 9
<212> PRT
<213> Homo sapiens
<210> 68
<211> 10
<212> PRT
<213> Homo sapiens
<210> 69
<211> 11
<212> PRT
<213> Homo sapiens
<210> 70
<211> 12
<212> PRT
<213> Homo sapiens
<210> 71
<211> 9
<212> PRT
<213> Homo sapiens
<210> 72
<211> 9
<212> PRT
<213> Homo sapiens
<210> 73
<211> 9
<212> PRT
<213> Homo sapiens
<210> 74
<211> 9
<212> PRT
<213> Homo sapiens
<210> 75
<211> 9
<212> PRT
<213> Homo sapiens
<210> 76
<211> 12
<212> PRT
<213> Homo sapiens
<210> 77
<211> 9
<212> PRT
<213> Homo sapiens
<210> 78
<211> 9
<212> PRT
<213> Homo sapiens
<210> 79
<211> 9
<212> PRT
<213> Homo sapiens
<210> 80
<211> 9
<212> PRT
<213> Homo sapiens
<210> 81
<211> 11
<212> PRT
<213> Homo sapiens
<210> 82
<211> 9
<212> PRT
<213> Homo sapiens
<210> 83
<211> 9
<212> PRT
<213> Homo sapiens
<210> 84
<211> 9
<212> PRT
<213> Homo sapiens
<210> 85
<211> 9
<212> PRT
<213> Homo sapiens
<210> 86
<211> 9
<212> PRT
<213> Homo sapiens
<210> 87
<211> 10
<212> PRT
<213> Homo sapiens
<210> 88
<211> 9
<212> PRT
<213> Homo sapiens
<210> 89
<211> 9
<212> PRT
<213> Homo sapiens
<210> 90
<211> 10
<212> PRT
<213> Homo sapiens
<210> 91
<211> 10
<212> PRT
<213> Homo sapiens
<210> 92
<211> 11
<212> PRT
<213> Homo sapiens
<210> 93
<211> 10
<212> PRT
<213> Homo sapiens
<210> 94
<211> 9
<212> PRT
<213> Homo sapiens
<210> 95
<211> 9
<212> PRT
<213> Homo sapiens
<210> 96
<211> 11
<212> PRT
<213> Homo sapiens
<210> 97
<211> 9
<212> PRT
<213> Homo sapiens
<210> 98
<211> 11
<212> PRT
<213> Homo sapiens
<210> 99
<211> 9
<212> PRT
<213> Homo sapiens
<210> 100
<211> 11
<212> PRT
<213> Homo sapiens
<210> 101
<211> 10
<212> PRT
<213> Homo sapiens
<210> 102
<211> 9
<212> PRT
<213> Homo sapiens
<210> 103
<211> 9
<212> PRT
<213> Homo sapiens
<210> 104
<211> 9
<212> PRT
<213> Homo sapiens
<210> 105
<211> 9
<212> PRT
<213> Homo sapiens
<210> 106
<211> 9
<212> PRT
<213> Homo sapiens
<210> 107
<211> 9
<212> PRT
<213> Homo sapiens
<210> 108
<211> 9
<212> PRT
<213> Homo sapiens
<210> 109
<211> 9
<212> PRT
<213> Homo sapiens
<210> 110
<211> 11
<212> PRT
<213> Homo sapiens
<210> 111
<211> 13
<212> PRT
<213> Homo sapiens
<210> 112
<211> 9
<212> PRT
<213> Homo sapiens
<210> 113
<211> 9
<212> PRT
<213> Homo sapiens
<210> 114
<211> 9
<212> PRT
<213> Homo sapiens
<210> 115
<211> 10
<212> PRT
<213> Homo sapiens
<210> 116
<211> 9
<212> PRT
<213> Homo sapiens
<210> 117
<211> 9
<212> PRT
<213> Homo sapiens
<210> 118
<211> 10
<212> PRT
<213> Homo sapiens
<210> 119
<211> 10
<212> PRT
<213> Homo sapiens
<210> 120
<211> 9
<212> PRT
<213> Homo sapiens
<210> 121
<211> 10
<212> PRT
<213> Homo sapiens
<210> 122
<211> 12
<212> PRT
<213> Homo sapiens
<210> 123
<211> 12
<212> PRT
<213> Homo sapiens
<210> 124
<211> 9
<212> PRT
<213> Homo sapiens
<210> 125
<211> 9
<212> PRT
<213> Homo sapiens
<210> 126
<211> 9
<212> PRT
<213> Homo sapiens
<210> 127
<211> 9
<212> PRT
<213> Homo sapiens
<210> 128
<211> 9
<212> PRT
<213> Homo sapiens
<210> 129
<211> 9
<212> PRT
<213> Homo sapiens
<210> 130
<211> 10
<212> PRT
<213> Homo sapiens
<210> 131
<211> 10
<212> PRT
<213> Homo sapiens
<210> 132
<211> 9
<212> PRT
<213> Homo sapiens
<210> 133
<211> 9
<212> PRT
<213> Homo sapiens
<210> 134
<211> 10
<212> PRT
<213> Homo sapiens
<210> 135
<211> 9
<212> PRT
<213> Homo sapiens
<210> 136
<211> 9
<212> PRT
<213> Homo sapiens
<210> 137
<211> 9
<212> PRT
<213> Homo sapiens
<210> 138
<211> 9
<212> PRT
<213> Homo sapiens
<210> 139
<211> 9
<212> PRT
<213> Homo sapiens
<210> 140
<211> 9
<212> PRT
<213> Homo sapiens
<210> 141
<211> 9
<212> PRT
<213> Homo sapiens
<210> 142
<211> 9
<212> PRT
<213> Homo sapiens
<210> 143
<211> 12
<212> PRT
<213> Homo sapiens
<210> 144
<211> 8
<212> PRT
<213> Homo sapiens
<210> 145
<211> 10
<212> PRT
<213> Homo sapiens
<210> 146
<211> 10
<212> PRT
<213> Homo sapiens
<210> 147
<211> 10
<212> PRT
<213> Homo sapiens
<210> 148
<211> 9
<212> PRT
<213> Homo sapiens
<210> 149
<211> 11
<212> PRT
<213> Homo sapiens
<210> 150
<211> 10
<212> PRT
<213> Homo sapiens
<210> 151
<211> 9
<212> PRT
<213> Homo sapiens
<210> 152
<211> 9
<212> PRT
<213> Homo sapiens
<210> 153
<211> 9
<212> PRT
<213> Homo sapiens
<210> 154
<211> 9
<212> PRT
<213> Homo sapiens
<210> 155
<211> 11
<212> PRT
<213> Homo sapiens
<210> 156
<211> 10
<212> PRT
<213> Homo sapiens
<210> 157
<211> 9
<212> PRT
<213> Homo sapiens
<210> 158
<211> 9
<212> PRT
<213> Homo sapiens
<210> 159
<211> 10
<212> PRT
<213> Homo sapiens
<210> 160
<211> 9
<212> PRT
<213> Homo sapiens
<210> 161
<211> 9
<212> PRT
<213> Homo sapiens
<210> 162
<211> 9
<212> PRT
<213> Homo sapiens
<210> 163
<211> 9
<212> PRT
<213> Homo sapiens
<210> 164
<211> 9
<212> PRT
<213> Homo sapiens
<210> 165
<211> 9
<212> PRT
<213> Homo sapiens
<210> 166
<211> 9
<212> PRT
<213> Homo sapiens
<210> 167
<211> 9
<212> PRT
<213> Homo sapiens
<210> 168
<211> 9
<212> PRT
<213> Homo sapiens
<210> 169
<211> 9
<212> PRT
<213> Homo sapiens
<210> 170
<211> 9
<212> PRT
<213> Homo sapiens
<210> 171
<211> 9
<212> PRT
<213> Homo sapiens
<210> 172
<211> 9
<212> PRT
<213> Homo sapiens
<210> 173
<211> 9
<212> PRT
<213> Homo sapiens
<210> 174
<211> 10
<212> PRT
<213> Homo sapiens
<210> 175
<211> 9
<212> PRT
<213> Homo sapiens
<210> 176
<211> 8
<212> PRT
<213> Homo sapiens
<210> 177
<211> 9
<212> PRT
<213> Homo sapiens
<210> 178
<211> 9
<212> PRT
<213> Homo sapiens
<210> 179
<211> 9
<212> PRT
<213> Homo sapiens
<210> 180
<211> 11
<212> PRT
<213> Homo sapiens
<210> 181
<211> 9
<212> PRT
<213> Homo sapiens
<210> 182
<211> 9
<212> PRT
<213> Homo sapiens
<210> 183
<211> 11
<212> PRT
<213> Homo sapiens
<210> 184
<211> 11
<212> PRT
<213> Homo sapiens
<210> 185
<211> 13
<212> PRT
<213> Homo sapiens
<210> 186
<211> 9
<212> PRT
<213> Homo sapiens
<210> 187
<211> 9
<212> PRT
<213> Homo sapiens
<210> 188
<211> 10
<212> PRT
<213> Homo sapiens
<210> 189
<211> 11
<212> PRT
<213> Homo sapiens
<210> 190
<211> 9
<212> PRT
<213> Homo sapiens
<210> 191
<211> 9
<212> PRT
<213> Homo sapiens
<210> 192
<211> 9
<212> PRT
<213> Homo sapiens
<210> 193
<211> 9
<212> PRT
<213> Homo sapiens
<210> 194
<211> 9
<212> PRT
<213> Homo sapiens
<210> 195
<211> 11
<212> PRT
<213> Homo sapiens
<210> 196
<211> 9
<212> PRT
<213> Homo sapiens
<210> 197
<211> 9
<212> PRT
<213> Homo sapiens
<210> 198
<211> 9
<212> PRT
<213> Homo sapiens
<210> 199
<211> 9
<212> PRT
<213> Homo sapiens
<210> 200
<211> 9
<212> PRT
<213> Homo sapiens
<210> 201
<211> 9
<212> PRT
<213> Homo sapiens
<210> 202
<211> 9
<212> PRT
<213> Homo sapiens
<210> 203
<211> 9
<212> PRT
<213> Homo sapiens
<210> 204
<211> 9
<212> PRT
<213> Homo sapiens
<210> 205
<211> 9
<212> PRT
<213> Homo sapiens
<210> 206
<211> 9
<212> PRT
<213> Homo sapiens
<210> 207
<211> 9
<212> PRT
<213> Homo sapiens
<210> 208
<211> 11
<212> PRT
<213> Homo sapiens
<210> 209
<211> 9
<212> PRT
<213> Homo sapiens
<210> 210
<211> 9
<212> PRT
<213> Homo sapiens
<210> 211
<211> 9
<212> PRT
<213> Homo sapiens
<210> 212
<211> 9
<212> PRT
<213> Homo sapiens
<210> 213
<211> 9
<212> PRT
<213> Homo sapiens
<210> 214
<211> 9
<212> PRT
<213> Homo sapiens
<210> 215
<211> 9
<212> PRT
<213> Homo sapiens
<210> 216
<211> 9
<212> PRT
<213> Homo sapiens
<210> 217
<211> 9
<212> PRT
<213> Homo sapiens
<210> 218
<211> 9
<212> PRT
<213> Homo sapiens
<210> 219
<211> 10
<212> PRT
<213> Homo sapiens
<210> 220
<211> 10
<212> PRT
<213> Homo sapiens
<210> 221
<211> 10
<212> PRT
<213> Homo sapiens
<210> 222
<211> 8
<212> PRT
<213> Homo sapiens
<210> 223
<211> 11
<212> PRT
<213> Homo sapiens
<210> 224
<211> 9
<212> PRT
<213> Homo sapiens
<210> 225
<211> 9
<212> PRT
<213> Homo sapiens
<210> 226
<211> 11
<212> PRT
<213> Homo sapiens
<210> 227
<211> 9
<212> PRT
<213> Homo sapiens
<210> 228
<211> 9
<212> PRT
<213> Homo sapiens
<210> 229
<211> 10
<212> PRT
<213> Homo sapiens
<210> 230
<211> 9
<212> PRT
<213> Homo sapiens
<210> 231
<211> 10
<212> PRT
<213> Homo sapiens
<210> 232
<211> 9
<212> PRT
<213> Homo sapiens
<210> 233
<211> 9
<212> PRT
<213> Homo sapiens
<210> 234
<211> 9
<212> PRT
<213> Homo sapiens
<210> 235
<211> 9
<212> PRT
<213> Homo sapiens
<210> 236
<211> 11
<212> PRT
<213> Homo sapiens
<210> 237
<211> 9
<212> PRT
<213> Homo sapiens
<210> 238
<211> 10
<212> PRT
<213> Homo sapiens
<210> 239
<211> 10
<212> PRT
<213> Homo sapiens
<210> 240
<211> 10
<212> PRT
<213> Homo sapiens
<210> 241
<211> 11
<212> PRT
<213> Homo sapiens
<210> 242
<211> 9
<212> PRT
<213> Homo sapiens
<210> 243
<211> 10
<212> PRT
<213> Homo sapiens
<210> 244
<211> 9
<212> PRT
<213> Homo sapiens
<210> 245
<211> 9
<212> PRT
<213> Homo sapiens
<210> 246
<211> 9
<212> PRT
<213> Homo sapiens
<210> 247
<211> 11
<212> PRT
<213> Homo sapiens
<210> 248
<211> 9
<212> PRT
<213> Homo sapiens
<210> 249
<211> 9
<212> PRT
<213> Homo sapiens
<210> 250
<211> 9
<212> PRT
<213> Homo sapiens
<210> 251
<211> 10
<212> PRT
<213> Homo sapiens
<210> 252
<211> 9
<212> PRT
<213> Homo sapiens
<210> 253
<211> 9
<212> PRT
<213> Homo sapiens
<210> 254
<211> 9
<212> PRT
<213> Homo sapiens
<210> 255
<211> 10
<212> PRT
<213> Homo sapiens
<210> 256
<211> 11
<212> PRT
<213> Homo sapiens
<210> 257
<211> 10
<212> PRT
<213> Homo sapiens
<210> 258
<211> 10
<212> PRT
<213> Homo sapiens
<210> 259
<211> 10
<212> PRT
<213> Homo sapiens
<210> 260
<211> 10
<212> PRT
<213> Homo sapiens
<210> 261
<211> 10
<212> PRT
<213> Homo sapiens
<210> 262
<211> 10
<212> PRT
<213> Homo sapiens
<210> 263
<211> 9
<212> PRT
<213> Homo sapiens
<210> 264
<211> 11
<212> PRT
<213> Homo sapiens
<210> 265
<211> 11
<212> PRT
<213> Homo sapiens
<210> 266
<211> 11
<212> PRT
<213> Homo sapiens
<210> 267
<211> 9
<212> PRT
<213> Homo sapiens
<210> 268
<211> 11
<212> PRT
<213> Homo sapiens
<210> 269
<211> 10
<212> PRT
<213> Homo sapiens
<210> 270
<211> 9
<212> PRT
<213> Homo sapiens
<210> 271
<211> 9
<212> PRT
<213> Homo sapiens
<210> 272
<211> 11
<212> PRT
<213> Homo sapiens
<210> 273
<211> 10
<212> PRT
<213> Homo sapiens
<210> 274
<211> 9
<212> PRT
<213> Homo sapiens
<210> 275
<211> 10
<212> PRT
<213> Homo sapiens
<210> 276
<211> 11
<212> PRT
<213> Homo sapiens
<210> 277
<211> 11
<212> PRT
<213> Homo sapiens
<210> 278
<211> 9
<212> PRT
<213> Homo sapiens
<210> 279
<211> 9
<212> PRT
<213> Homo sapiens
<210> 280
<211> 9
<212> PRT
<213> Homo sapiens
<210> 281
<211> 11
<212> PRT
<213> Homo sapiens
<210> 282
<211> 10
<212> PRT
<213> Homo sapiens
<210> 283
<211> 10
<212> PRT
<213> Homo sapiens
<210> 284
<211> 9
<212> PRT
<213> Homo sapiens
<210> 285
<211> 11
<212> PRT
<213> Homo sapiens
<210> 286
<211> 9
<212> PRT
<213> Homo sapiens
<210> 287
<211> 9
<212> PRT
<213> Homo sapiens
<210> 288
<211> 9
<212> PRT
<213> Homo sapiens
<210> 289
<211> 11
<212> PRT
<213> Homo sapiens
<210> 290
<211> 10
<212> PRT
<213> Homo sapiens
<210> 291
<211> 9
<212> PRT
<213> Homo sapiens
<210> 292
<211> 9
<212> PRT
<213> Homo sapiens
<210> 293
<211> 11
<212> PRT
<213> Homo sapiens
<210> 294
<211> 9
<212> PRT
<213> Homo sapiens
<210> 295
<211> 9
<212> PRT
<213> Homo sapiens
<210> 296
<211> 10
<212> PRT
<213> Homo sapiens
<210> 297
<211> 9
<212> PRT
<213> Homo sapiens
<210> 298
<211> 11
<212> PRT
<213> Homo sapiens
<210> 299
<211> 9
<212> PRT
<213> Homo sapiens
<210> 300
<211> 9
<212> PRT
<213> Homo sapiens
<210> 301
<211> 9
<212> PRT
<213> Homo sapiens
<210> 302
<211> 9
<212> PRT
<213> Homo sapiens
<210> 303
<211> 10
<212> PRT
<213> Homo sapiens
<210> 304
<211> 9
<212> PRT
<213> Homo sapiens
<210> 305
<211> 9
<212> PRT
<213> Homo sapiens
<210> 306
<211> 10
<212> PRT
<213> Homo sapiens
<210> 307
<211> 9
<212> PRT
<213> Homo sapiens
<210> 308
<211> 9
<212> PRT
<213> Homo sapiens
<210> 309
<211> 9
<212> PRT
<213> Homo sapiens
<210> 310
<211> 9
<212> PRT
<213> Homo sapiens
<210> 311
<211> 9
<212> PRT
<213> Homo sapiens
<210> 312
<211> 9
<212> PRT
<213> Homo sapiens
<210> 313
<211> 11
<212> PRT
<213> Homo sapiens
<210> 314
<211> 9
<212> PRT
<213> Homo sapiens
<210> 315
<211> 10
<212> PRT
<213> Homo sapiens
<210> 316
<211> 9
<212> PRT
<213> Homo sapiens
<210> 317
<211> 9
<212> PRT
<213> Homo sapiens
<210> 318
<211> 9
<212> PRT
<213> Homo sapiens
<210> 319
<211> 9
<212> PRT
<213> Homo sapiens
<210> 320
<211> 11
<212> PRT
<213> Homo sapiens
<210> 321
<211> 10
<212> PRT
<213> Homo sapiens
<210> 322
<211> 10
<212> PRT
<213> Homo sapiens
<210> 323
<211> 11
<212> PRT
<213> Homo sapiens
<210> 324
<211> 10
<212> PRT
<213> Homo sapiens
<210> 325
<211> 9
<212> PRT
<213> Homo sapiens
<210> 326
<211> 9
<212> PRT
<213> Homo sapiens
<210> 327
<211> 9
<212> PRT
<213> Homo sapiens
<210> 328
<211> 11
<212> PRT
<213> Homo sapiens
<210> 329
<211> 9
<212> PRT
<213> Homo sapiens
<210> 330
<211> 9
<212> PRT
<213> Homo sapiens
<210> 331
<211> 11
<212> PRT
<213> Homo sapiens
<210> 332
<211> 9
<212> PRT
<213> Homo sapiens
<210> 333
<211> 11
<212> PRT
<213> Homo sapiens
<210> 334
<211> 12
<212> PRT
<213> Homo sapiens
<210> 335
<211> 11
<212> PRT
<213> Homo sapiens
<210> 336
<211> 9
<212> PRT
<213> Homo sapiens
<210> 337
<211> 11
<212> PRT
<213> Homo sapiens
<210> 338
<211> 12
<212> PRT
<213> Homo sapiens
<210> 339
<211> 9
<212> PRT
<213> Homo sapiens
<210> 340
<211> 9
<212> PRT
<213> Homo sapiens
<210> 341
<211> 9
<212> PRT
<213> Homo sapiens
<210> 342
<211> 9
<212> PRT
<213> Homo sapiens
<210> 343
<211> 9
<212> PRT
<213> Homo sapiens
<210> 344
<211> 9
<212> PRT
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<213> Homo sapiens
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Claims (27)
- 一種肽,包括SEQ ID NO.6的氨基酸序列,或其藥用鹽,其中所述肽的總長度為9至30個氨基酸,其中所述肽有能力與人類主要組織相容性複合體(MHC)-I類分子結合,且其中所述肽與MHC結合時能夠被CD8 T細胞識別。
- 根據請求項1所述的肽,其中所述肽的總長度為9至16個氨基酸。
- 根據請求項2所述的肽,其中該肽由根據SEQ ID NO.6的氨基酸序列組成。
- 根據請求項1至3中任一項所述的肽,其中該肽包含非肽鍵,及/或其中所述肽為一融合蛋白的一部分,該融合蛋白包含HLA-DR抗原相關不變鏈(Ii)的N-端氨基酸。
- 一種可溶性或膜結合之抗體,其特異性地識別根據請求項1至4中任一項的肽。
- 根據請求項5所述的抗體,其特異性地識別與MHC分子結合時之根據請求項1至4中任一項的肽。
- 一種可溶性或膜結合之T細胞受體(TCR),其能與HLA配體反應,其中該配體與根據SEQ ID No.6之氨基酸序列具有 至少88%的等同度(identity)或由根據SEQ ID No.6之氨基酸序列構成。
- 根據請求項7所述的T細胞受體(TCR),其中所述RCT作為可溶性分子提供且進一步具有效應子功能(effector function)。
- 根據請求項8所述的T細胞受體(TCR),其中該效應子功能係一免疫刺激域或毒素。
- 一種核酸,該核酸編碼根據請求項1至4中任一項所述之肽、根據請求項5或6所述之抗體,或根據請求項7至9中任一項所述之TCR。
- 一種表達載體,其表達根據請求項10所述的核酸。
- 一種宿主細胞,包含根據請求項1至4中任一項所述之肽、根據請求項10所述之核酸,或根據請求項11所述的表達載體。
- 根據請求項12所述的宿主細胞,其中該宿主細胞係一抗原提呈細胞。
- 根據請求項13所述的宿主細胞,其中該抗原提呈細胞係 一樹突細胞、一T細胞或NK細胞。
- 一種製備根據請求項1至4中任一項所述的肽、根據請求項5或6所述的抗體或根據請求項7至9中任一項所述的TCR之方法,該方法包括培養根據請求項12至14中任一項所述的宿主細胞,該宿主細胞提呈根據請求項1至4中任一項所述的肽或表達根據請求項10所述的核酸或根據請求項11所述的表達載體,以及從該宿主細胞及/或其培養基中分離出所述肽、所述抗體或所述TCR。
- 一種體外製備啟動的T淋巴細胞的方法,該方法包括將T細胞與在一合適之抗原提呈細胞或仿照抗原提呈細胞之一人造結構之表面上表達之載有抗原的人I類MHC分子進行體外接觸達足夠的一段時間,從而以抗原特異性方式啟動所述T細胞,其中所述抗原為根據請求項1至4中任一項所述的肽。
- 一種根據請求項16所述的方法製成的啟動T細胞,其有選擇性地識別提呈一多肽之一細胞,該多肽包含請求項1至4中任一項給定之一氨基酸序列。
- 一種藥物組合物,其包含至少一種活性成分及一藥用載體,該至少一種活性成分選自由根據請求項1至4中任一項所述之肽、根據請求項5或6所述之抗體、根據請求項7至9 中任一項所述之TCR、根據請求項10所述之核酸、根據請求項11所述之表達載體、根據請求項12至14中任一項所述之宿主細胞、根據請求項17所述之啟動T細胞所組成之群組。
- 根據請求項18所述的藥物組合物,進一步包含藥用賦形劑及/或穩定劑。
- 一種根據請求項1至4中任一項所述之肽、根據請求項5或6所述之抗體、根據請求項7至9中任一項所述之TCR、根據請求項10所述之核酸、根據請求項11所述之表達載體、根據請求項12至14中任一項所述之宿主細胞、根據請求項17所述之啟動T細胞,或根據請求項18或19所述之藥物組合物用於製造一藥劑之用途。
- 根據請求項20所述之用途,其中該藥劑係用於治療癌症。
- 根據請求項21所述之用途,其中所述癌症係選自由HCC、腦癌、腎癌、胰腺癌、結腸癌或直腸癌、白血病及顯示出AXIN2之過度表達的其他腫瘤所組成之群組。
- 一種套組,包含:(a)一容器,包含呈溶液或凍乾粉形式之根據請求項18的藥物組合物。
- 根據請求項23所述的套組,進一步包含:(b)第二容器,其含有用於凍乾粉劑型之一稀釋劑或重組溶液。
- 根據請求項23所述的套組,進一步包含:(c)至少一種額外肽,其選自由SEQ ID No.1至SEQ ID No.5及SEQ ID No.7至SEQ ID No.346所組成之群組。
- 根據請求項24所述的套組,進一步包含:(d)針對(i)該溶液之用途或(ii)重組及/或凍乾粉劑型之用途的說明書。
- 根據請求項23至26中任一項所述的套組,進一步包含以下一或多者:(iii)一緩衝劑、(iv)一稀釋劑、(v)一過濾劑、(vi)一針,或(v)一注射器。
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