TW201619190A - 來自hsp70之胜肽、使用此胜肽之用於治療或預防癌之醫藥組成物、免疫誘導劑、及抗原呈現細胞之製造方法 - Google Patents
來自hsp70之胜肽、使用此胜肽之用於治療或預防癌之醫藥組成物、免疫誘導劑、及抗原呈現細胞之製造方法 Download PDFInfo
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Abstract
本發明提供含有序列編號1~15之中任一者所示之胺基酸序列中的連續8個以上之胺基酸殘基,且由11個以下之胺基酸殘基構成之胜肽。
Description
本發明係關於來自HSP70之胜肽,更具體而言,係關於藉由和人類白血球抗原的結合而將抗原呈現給T細胞之免疫原性胜肽、使用此胜肽之用於治療或預防癌之醫藥組成物、免疫誘導劑及抗原呈現細胞之製造方法等。
生物體內據認為會隨時偶發地產生癌細胞,但預期通常會引發自然免疫所為之源自癌細胞之專一性癌抗原的排除反應,然後,誘導專一性免疫反應,並引發淋巴細胞等所為之癌細胞的排除反應。
為了辨認源自癌細胞的抗原,存在細胞表面上的人類白血球抗原(HLA)與淋巴細胞必須形成複合體。主要組織相容性抗原即HLA分子大致分為第一型分子(HLA-A型、B型、C型)與第二型分子(HLA-DP型、DQ型、DR型)。細胞傷害性T細胞(CTL)所為之癌細胞的排除反應係藉由癌細胞表面的HLA第一型分子所呈現之由8~11個胺基酸構成的癌抗原(CTL抗原決定位)受到CTL上的T細胞抗原受體(TCR)專一性地辨認而誘導。
目前,期待朝向各種免疫相關疾病的治療或預防之應用,而正在實施免疫原性胜肽的探尋,例如,日本特開平8-151396號公報記載有由特定的胺基酸序列構成之寡胜肽具有HLA結合性之要旨。 [先前技術文獻] [專利文獻]
[專利文獻1]日本特開平8-151396號公報
[發明所欲解決之課題]
已知有許多具有HLA結合性之胜肽,但進一步尋求可使用於各種癌的治療或預防之胜肽。又由於HLA係多型性豐富的基因,故亦要求有關對應於多種HLA型之多型免疫原性胜肽。 [解決課題之手段]
本發明係鑑於上述情事,其目的在於提供:結合於HLA第一型分子的免疫原性胜肽,尤其是能誘導CTL之胜肽、使用此胜肽之用於治療或預防癌之醫藥組成物、免疫誘導劑、及抗原呈現細胞之製造方法等。
亦即,本發明包含以下之發明: (1) 一種胜肽,含有序列編號1~15之中任一者所示之胺基酸序列中的連續8個以上之胺基酸殘基,且由11個以下之胺基酸殘基構成。 (2) 如(1)所記載之胜肽,其中,該胺基酸序列中有1個或數個胺基酸取代、插入、缺失或附加,且具有免疫原性。 (3) 如(2)所記載之胜肽,其中,該胺基酸序列中,第2位之胺基酸以酪胺酸、苯丙胺酸、甲硫胺酸、色胺酸、纈胺酸、白胺酸或麩醯胺酸取代,及/或C端之胺基酸以苯丙胺酸、白胺酸、異白胺酸、色胺酸、甲硫胺酸或纈胺酸取代。 (4) 一種用於治療或預防癌之醫藥組成物,含有如(1)~(3)中任一項所記載之胜肽。 (5) 如(4)所記載之用於治療或預防癌之醫藥組成物,為疫苗之形態。 (6) 如(4)或(5)所記載之用於治療或預防癌之醫藥組成物,其中,該胜肽可與1種或多種類型之HLA分子結合。 (7) 一種免疫誘導劑,包含如(1)~(3)中任一項所記載之胜肽。 (8) 如(7)所記載之免疫誘導劑,用於誘導細胞傷害性T細胞。 (9) 如(7)或(8)所記載之免疫誘導劑,其中,該胜肽可與1種或多種類型之HLA分子結合。 (10) 一種具有CTL誘導活性之抗原呈現細胞之製造方法,包含以下步驟:如(1)~(3)中任一項所記載之胜肽與抗原呈現細胞在試管內(in vitro)接觸。 [發明之效果]
近年,免疫療法作為癌的治療法而受到注目。由於本發明之胜肽與HLA結合性高,且CTL誘導能力亦高,故作為癌疫苗之有效性受到強烈的期待。又,朝向各種免疫療法,尤其樹狀細胞療法之應用亦受到預期。
熱休克蛋白(Heat Shock Protein,HSP)家族作為分子伴護蛋白(molecular chaperone),而與蛋白質的折疊、運送、修飾、或保護等多種的細胞功能相關(Zugel U and Kaufmann SH: Role of heat-shock proteins in protection from and pathogenesis of infectious diseases. Clin Microbiol Rev 12: 19-39, 1999.)。HSP依其分子尺寸之大小而分類成HSP110、HSP90、HSP70、HSP60、HSP40、HSP28、HSP27及HSP25之8個家族。此外,已知HSP與細胞凋亡(apoptosis)相關,而分成抑制細胞凋亡之群組與誘導細胞凋亡之群組兩大類。
HSP70係抑制細胞凋亡之熱休克蛋白,HSP70藉由高度表現而參與例如細胞的癌化等各種狀況下細胞的生存之情事已被闡明。事實上,有報告指出本發明之胜肽的來源即HSP70蛋白質在各種的癌有表現。 (例如: 1. Yoshida et al., Anticancer Res. 2009 Feb;29(2):539-44 2. Ciocca DR, Clark GM, Tandon AK, Fuqua SA, Welch WJ and McGuire WL: Heat-shock protein hsp70 in patients with axillary lymph node-negative breast cancer: prognostic implications. J Natl Cancer Inst 85: 570-574, 1993 3. Kaur J and Ralhan R: Differential expression of 70-kDa heatshock protein in human oral tumorigenesis. Int J Cancer 63: 774-779, 1995 4. Park CS, Joo IS, Song SY, Kim DS, Bae DS and Lee JH: An immunohistochemical analysis of heat-shock protein 70, p53, and estrogen receptor status in carcinoma of the uterine cervix. Gynecol Oncol 74: 53-60, 1999 5. Cornford PA, Dodson AR, Parsons KF, Desmond AD, Woolfenden A, Fordham M, Neoptolemos JP, Ke Y and Foster C: Heat-shock protein expression independently predicts clinical outcome in prostate cancer. Cancer Res 60: 7099-7105, 2000 6. Malusecka E, Zborek A, Krzyzowska-Gruca S and Krawczyk Z: Expression of heat-shock proteins HSP70 and HSP27 in primary non-small cell lung carcinomas. An immunohistochemical study. Anticancer Res 21: 1015-1021, 2001 7. Chuma M, Sakamoto M, Yamazaki K, Ohta T, Ohki M, Asaka M and Hirohashi S: Expression profiling in multistage hepatocarcinogenesis: identification of HSP70 as a molecular marker of early hepatocellular carcinoma. Hepatology 37: 198-207, 2003 8. Castle PE, Ashfaq R, Ansari F and Muller CY: Immunohistochemical evaluation of heat-shock proteins in normal and preinvasive lesions of the cervix. Cancer Lett 229: 245-252, 2005 9. Kurahashi T, Miyake H, Hara I and Fujisawa M: Expression of major heat-shock proteins in prostate cancer: correlation with clinicopathological outcomes in patients undergoing radical prostatectomy. J Urol 177: 757-761, 2007.)
又,關於本發明之胜肽中之特定者可與多種HLA型結合。因此,根據本發明之胜肽,能提供涵蓋極廣範圍的癌患者群之癌疫苗、樹狀細胞療法等。
1.免疫原性胜肽 有關本發明之胜肽係含有序列編號1~15之中任一者所示之胺基酸序列中的連續8個以上之胺基酸殘基,且由合計11個以下,宜為10個以下,為9個以下更佳之胺基酸殘基構成之胜肽。本發明之胜肽亦可為由序列編號1~15之中任一者所示之胺基酸序列構成。本發明之胜肽源自熱休克蛋白質之一的HSP70。根據構成HSP70之胺基酸序列,選擇依據使用主動學習(active learning)實驗法(日本特開平8-151396號)而獲得之假說進行預測而得,和HLA分子的結合性換算成-logKd值為3以上之胺基酸序列。
構成本發明之胜肽的胺基酸序列與其和HLA結合之預測分數係如下表1所示: [表1]
本發明之胜肽有HLA結合性,且具有免疫原性(之後也有單獨稱為「HLA胜肽」或「免疫原性胜肽」之情況)。於本說明書使用時,「免疫原性」係意指可誘導免疫反應,例如意指具有CTL誘導活性,進而具有對癌細胞之細胞傷害活性之情事。
理想的態樣中,本發明之胜肽係可與多種HLA-A之基因A之等位基因(allele)型結合之多型HLA胜肽。例如序列編號7之胜肽與HLA-A*24:02基因的產物(HLA-A*24:02分子)、HLA-A*02:01基因的產物(HLA-A*02:01分子)及HLA-A*02:06基因的產物(HLA-A*02:06分子)強結合,同時具有高免疫原性。
能與本發明之胜肽結合的HLA亞型並不限於HLA-A*24:02、HLA-A*02:01及HLA-A*02:06。但是由於該等HLA亞型涵括約85%之包含日本人之東洋人且約55%之西洋人,故據認為本發明之多型HLA胜肽在免疫療法等中具有廣泛的患者涵蓋率。
本發明之胜肽只要能保持免疫原性,亦可將構成序列編號1~15之胺基酸序列之胺基酸殘基或其中一部分進行修飾。雖然希望序列編號1~15所示之胺基酸序列呈現於抗原呈現細胞上之狀態,但將本發明之胜肽直接投予於體內時,依投予途徑有時會因消化器官等而有其末端消化等變化。因此,本發明之胜肽在抗原呈現細胞攝入前也可以N端及/或C端附加1個或多個胺基酸殘基等之前驅體狀態存在,使其在抗原呈現細胞上和預定的HLA第一型分子結合時會保持序列編號1~15所示之胺基酸殘基。
此外,本發明之胜肽只要能具有期望的免疫原性,構成本發明之胜肽的1個或數個胺基酸殘基可取代、插入、缺失或附加、亦或及/或有糖鏈的附加、側鏈的氧化、及/或磷酸化等修飾。本說明書中「胺基酸」使用其最廣的意義,除了天然胺基酸之外,包含人工胺基酸變異體、衍生物。本說明書中胺基酸可列舉:天然蛋白性L-胺基酸;D-胺基酸;胺基酸變異體及衍生物等經化學修飾之胺基酸;正白胺酸、β-丙胺酸、鳥胺酸等天然非蛋白性胺基酸;及具有胺基酸的特徵之發明所屬技術領域中具有通常知識者已知的特性之化學合成而得之化合物等。可列舉α-甲基胺基酸(α-甲基丙胺酸等)、D-胺基酸、組胺酸類胺基酸(β-羥基-組胺酸、高組胺酸(homohistidine)、α-氟甲基-組胺酸及α-甲基-組胺酸等)、側鏈具有額外的亞甲基之胺基酸(「同源」胺基酸)及側鏈中具羧酸官能基之胺基酸被磺酸基取代之胺基酸(半胱胺酸等)作為非天然胺基酸的例子。
關於胺基酸殘基的取代等,考量對HLA展現結合性之胜肽序列的規則性(J. Immunol., 152: p3913, 1994; Immunogenetics, 41: p178, 1995; J. Immunol., 155: p4307, 1994),該技術領域中具有通常知識者可適當地取代構成本發明之胜肽的胺基酸殘基。
更具體而言,為與HLA-A*24:02分子結合之胜肽時,構成胜肽之第2位的胺基酸可用酪胺酸、苯丙胺酸、甲硫胺酸或色胺酸取代,及/或C端之胺基酸亦可用苯丙胺酸、白胺酸、異白胺酸、色胺酸或甲硫胺酸取代。又,為與HLA-A*02:01分子結合之胜肽時,第2位之胺基酸可用白胺酸或甲硫胺酸取代,及/或C端之胺基酸亦可用纈胺酸或白胺酸取代。此外,為與HLA-A*02:06分子結合之胜肽時,第2位之胺基酸可用纈胺酸或麩醯胺酸取代,及/或C端之胺基酸亦可用纈胺酸或白胺酸取代。
本發明之胜肽均能使用該技術領域中具有通常知識者已知的方法製造。例如可利用Fmoc法、tBoc法等固相法或液相法進行人工合成。又,亦可藉由使編碼本發明之胜肽的聚核苷酸或含有該聚核苷酸之重組載體表現而製造期望之胜肽。又,如此而得到的胜肽均能使用該技術領域中具有通常知識者已知的方法鑑定。例如能使用艾德曼降解(Edman degradation)法、質量分析法等鑑定。
2.醫藥組成物 本發明相關之用於治療或預防癌之醫藥組成物含有胜肽作為有效成分,該胜肽例如含有選自於由序列編號1~15構成之群組中1種以上之胺基酸序列中的連續8個以上之胺基酸殘基,且由合計11個以下,宜為10個以下,為9個以下更佳之胺基酸殘基構成。醫藥組成物所含之胜肽亦可由序列編號1~15之中任一者所示之胺基酸序列構成。該胜肽係如上文所定義。
本發明之胜肽係藉由呈現於抗原呈現細胞上而誘導CTL,且該經誘導之CTL會傷害癌細胞。因此,本發明之醫藥組成物的有效成分並不限於本發明之胜肽,亦可為能直接或間接地誘導CTL之成分,例如:編碼該胜肽之聚核苷酸或含有該聚核苷酸之載體、或將該胜肽與HLA分子之複合體呈現在表面之抗原呈現細胞或由抗原呈現細胞所分泌的外泌體(exosomes)、或該等之組合。可列舉巨噬細胞、樹狀細胞等作為本發明所使用的抗原呈現細胞,宜使用CTL誘導能力高的樹狀細胞。本發明之醫藥組成物亦可含有已知使用於癌治療之其他成分,例如:趨化激素(chemokine)、細胞激素(cytokine)、腫瘤壞死因子、化學療法藥劑等。胜肽的用量例如患者為成人時可為1天約1~10mg。但是由於用量因應患者的年齡、體重、投予方法等而變動,故由該技術領域中具有通常知識者做適當地決定。
據認為本發明之醫藥組成物係利用以下之作用機制而對癌細胞之殺傷等有效,但目的並非為限定之用。藉由將本發明之醫藥組成物投予於特定之癌患者,醫藥組成物中的胜肽會以和HLA分子結合的狀態呈現在抗原呈現細胞表面。CTL辨認如此之抗原呈現細胞上的胜肽的話就會活性化並增殖而進入體循環。對胜肽有專一性的CTL侵入癌組織的話,就會辨認和源自與癌細胞表面之HLA分子自然地結合之專一性癌抗原相同的胜肽而殺傷該癌細胞。利用該作用可對癌的治療有所貢獻。
本發明之醫藥組成物不僅可使用於癌的治療,亦可使用於癌的預防。例如,藉由將本發明之醫藥組成物投予於健康的人體而誘導CTL,且經誘導之細胞傷害性T細胞會在體內留存,故當特定的癌細胞發生時,即可傷害該癌細胞。同樣地,藉由投予於經癌治療後的人體,亦可預防癌的復發。
預期所有表現HSP70的癌皆可作為受治療或預防的癌。更具體而言可列舉胰臟癌、肝癌、前列腺癌、肺癌、乳癌、大腸癌、血液癌(hematologic cancer)、腦腫瘤、腎臟癌、皮膚癌等作為對象,但目的並非為限定之用。例如本發明之胜肽的來源即HSP70在肝癌會過量表現,故據認為本發明之胜肽尤其在肝癌的治療或預防係為有效。存在多種應予以治療或預防之癌時,可使本發明之醫藥組成物含有多種免疫原性胜肽等有效成分。
本發明之醫藥組成物可溶於水溶性溶劑中,以製藥上允許之鹽的形態進行製劑而投予於患者。可列舉生理上可接受之水溶性的鹽,例如鈉、鉀、鎂、鈣、等鹽的形式且以生理性的pH使其緩衝之形態作為如此之製藥上允許之鹽的形態。又,水溶性溶劑之外,亦可使用非水溶性溶劑,例如可列舉乙醇、丙二醇等醇作為如此之非水溶性溶劑。
又,在含有本實施形態之醫藥組成物的製劑中,亦可含有針對各種目的之藥劑,可列舉例如保藏劑、緩衝劑等作為如此的藥劑。就保藏劑而言可列舉:亞硫酸氫鈉、硫酸氫鈉、硫代硫酸鈉、氯化苯二甲烴銨(benzalkonium chloride)、氯丁醇、硫柳汞(thimerosal)、乙酸苯汞、硝酸苯汞、對羥基苯甲酸甲酯、聚乙烯醇、苯乙醇、氨、二硫蘇糖醇、2-巰基乙醇等。又可列舉碳酸鈉、硼酸鈉、磷酸鈉、乙酸鈉、碳酸氫鈉等作為緩衝劑。該等藥劑能以可將反應系的pH維持在2~9,宜為4~8之間的量而存在。
本發明之醫藥組成物的劑型亦無特別限制,作為疫苗之形態而使用時,其劑型可例示:注射劑(肌肉、皮下、皮內)、經口製劑、點鼻製劑等。本發明之醫藥組成物為疫苗之形態時,亦可為含有多種有效成分之混合雞尾酒疫苗。例如,如此的疫苗係序列編號1~15所示胜肽之中任2個以上,或和其他有效成分的組合且能含有多種有效成分。
又,本發明之疫苗亦可為含有下述成分之含不活性成分之疫苗,該成分係醫藥組成物以外的成分,且該成分本身無活性而具有更進一步提高醫藥組成物作為疫苗之效果的功效。就不活性成分而言可列舉佐劑(adjuvant)、類毒素(toxoid)等。可列舉氫氧化鋁、磷酸鋁、磷酸鈣等沉降性型;弗氏完全佐劑、弗氏不完全佐劑等油性型者作為佐劑的例子,但目的並非為限定之用。
本發明之醫藥組成物以疫苗的形態存在時,宜為利用皮內、皮下、靜脈內、肌肉內投予等所為之注射或輸液、或經皮、或由鼻、咽頭等黏膜吸入等而投予於體內。其一次投予量可設定在能顯著地誘導細胞傷害性T細胞的量至不使顯著數量的非癌細胞受到傷害的量之間。
本發明之醫藥組成物不僅用於對人體之投予,亦可用於體外使用之目的。更具體而言,本發明之醫藥組成物亦可使用於將抗原呈現細胞在試管內或離體(ex vivo)下刺激而增加CTL誘導活性之用。例如以使用於癌樹狀細胞療法時為例進行說明的話,將本發明之醫藥組成物事先與源自有必要進行癌的治療或預防之患者的樹狀細胞等之抗原呈現細胞接觸後,藉由將此抗原呈現細胞回輸至患者體內而能投予於患者。醫藥組成物所含之胜肽例如可利用脂質體轉染法(lipofection)、注射法等導入抗原呈現細胞內。在如此的用途中使用編碼本發明之胜肽的聚核苷酸時,聚核苷酸能利用發明所屬技術領域中具有通常知識者已知的方法導入到抗原呈現細胞。例如亦可利用脂質體轉染法、電穿孔法、顯微注射法、細胞融合法、DEAE葡聚糖法、磷酸鈣法等,在試管內以對象之聚核苷酸或編碼聚核苷酸之載體將源自患者的抗原呈現細胞進行轉型等。
3.免疫誘導劑 本發明相關之免疫誘導劑含有胜肽作為有效成分,該胜肽例如含有選自於由序列編號1~15構成之群組中1種以上之胺基酸序列中的連續8個以上之胺基酸殘基,且由合計11個以下,宜為10個以下,為9個以下更佳之胺基酸殘基構成。免疫誘導劑所含之胜肽亦可由序列編號1~15之中任一者所示之胺基酸序列構成。該胜肽係如上文所定義。
據認為本發明之胜肽係藉由呈現於抗原呈現細胞上而誘導免疫。因此,本發明之免疫誘導劑的有效成分並不限於本發明之胜肽,亦可為能直接或間接地誘導免疫之成分,例如:編碼本發明之胜肽之聚核苷酸或含有該聚核苷酸之表現載體、或將該胜肽與HLA分子的複合體呈現於表面之抗原呈現細胞或由抗原呈現細胞所分泌之外泌體、或該等之組合。可列舉巨噬細胞、樹狀細胞等作為本發明所使用的抗原呈現細胞,宜使用CTL誘導能力高的樹狀細胞。
本發明之免疫誘導劑不僅用於對人體之投予,亦可用於體外使用之目的。具體而言,本發明之免疫誘導劑亦可使用於將抗原呈現細胞在試管內或離體下刺激而增加CTL誘導活性之用。例如以使用於樹狀細胞療法時為例進行說明的話,將本發明之免疫誘導劑事先與源自有必要進行免疫誘導之患者的樹狀細胞等之抗原呈現細胞接觸後,藉由將此抗原呈現細胞回輸至患者體內而能投予於患者。免疫誘導劑所含之胜肽例如可利用脂質體介導之轉染(脂質體轉染法)、注射法等導入到抗原呈現細胞內。在如此的用途中使用編碼本發明之胜肽的聚核苷酸時,聚核苷酸能利用發明所屬技術領域中具有通常知識者已知的方法導入到抗原呈現細胞。例如亦可利用脂質體轉染法、電穿孔法、顯微注射法、細胞融合法、DEAE葡聚糖法、磷酸鈣法等,在試管內以對象之聚核苷酸或表現聚核苷酸之載體將源自患者的抗原呈現細胞進行轉型等。
在本說明書使用時,「免疫誘導」係指誘導免疫反應,例如:使抗原呈現細胞之CTL誘導活性增加,並進一步使CTL之對於癌細胞的細胞傷害活性增加之情事。又,在本說明書使用時,「CTL誘導」係指在試管內或在體內(in vivo),本發明之胜肽藉由呈現於抗原呈現細胞表面上而誘導或增殖專一性地辨認某抗原之CTL、使初始T細胞(naive T cell)朝向具有殺傷癌細胞等標的細胞的能力(細胞傷害活性)之作用細胞(effector cell)分化、及/或使CTL之細胞傷害活性增加之情事。CTL誘導活性可藉由評估源於CTL之細胞激素(例如干擾素(IFN)-γ)的產生而進行測量。例如亦可藉由使用酵素連結免疫斑點法(Enzyme-Linked ImmunoSpot)等已知的高感度免疫分析評估經本發明之胜肽刺激之週邊血液單核細胞(peripheral blood mononuclear cells)等之抗原呈現細胞所致由前驅細胞誘導而成之產生細胞激素的細胞之增加,而測量CTL誘導活性。細胞傷害活性亦可利用51
Cr游離法等已知的方法測量。上述活性與對照組比較有顯著地增加時,例如增加5%以上、10%以上、20%以上、宜為50%以上時,可評估為免疫或CTL受到誘導。
4.抗原呈現細胞之製造方法 本發明相關之抗原呈現細胞之製造方法包含下述步驟:例如使含有選自於由序列編號1~15構成之群組中1種以上之胺基酸序列中的連續8個以上之胺基酸殘基,且由合計11個以下,宜為10個以下,為9以下更佳之胺基酸殘基構成的胜肽與抗原呈現細胞在試管內接觸。本發明之製造方法所使用的胜肽亦可由序列編號1~15之中任一者所示之胺基酸序列構成。該胜肽係如上文所定義。
本發明之製造方法所使用的胜肽據認為會與抗原呈現細胞表面的HLA第一型分子結合,並作為抗原胜肽而呈現給CTL,藉此誘導抗原呈現細胞之CTL活性。因此,和抗原呈現細胞接觸的並不限於本發明之胜肽,亦可為能直接或間接地誘導CTL之成分,例如編碼該胜肽之聚核苷酸或含有該聚核苷酸之載體,或將該胜肽與HLA分子的複合體呈現於表面之抗原呈現細胞或由抗原呈現細胞所分泌之外泌體,或該等之組合。可列舉巨噬細胞、樹狀細胞等作為本發明所使用的抗原呈現細胞,宜使用CTL誘導能力高的樹狀細胞。
利用本發明之製造方法製造的抗原呈現細胞不僅使用作為上述醫藥組成物或免疫誘導劑之有效成分,亦可使用於免疫療法等之用的的目的。例如以使用於癌樹狀細胞療法時為例進行說明的話,將製得的抗原呈現細胞事先與源自有必要進行免疫誘導之患者之CTL誘導能力低的樹狀細胞等之抗原呈現細胞接觸後,藉由將此抗原呈現細胞回輸至患者體內而能投予於患者。本發明之胜肽例如可利用脂質體介導之轉染(脂質體轉染法)、注射法等導入抗原呈現細胞內。在如此的用途中使用編碼本發明之胜肽之聚核苷酸時,聚核苷酸能利用發明所屬技術領域中具有通常知識者已知的方法導入抗原呈現細胞。例如亦可利用脂質體轉染法、電穿孔法、顯微注射法、細胞融合法、二乙氨乙基葡聚糖法、磷酸鈣法等,在試管內以對象之聚核苷酸或編碼聚核苷酸之載體將源自患者的抗原呈現細胞進行轉型。 [實施例1]
以下舉實施例更具體地說明本發明,但本發明並不受限於該等實施例。
具體而言,本實施例中的預測・實驗・評估之程序係基於國際公開2006/004182號小冊所記載之主動學習實驗設計(active learning experiment design)而實施,整體而言重複以下步驟而建構規則。
(1) 實施一次後述之下位學習演算法之試驗。亦即,由累計資料之隨機採樣顯現出多種假設,並選出相對於隨機顯現之問題候選點(胜肽)之預測值的變量最大的點作為應予以實驗之問題點。
(2) 將選出問題點之胜肽利用後述之合成・純化法製造,並利用後述之實驗測量實際的結合能力而加入累計資料中。
藉由實施如此的主動學習法,可減少本來針對由9個胺基酸殘基構成的胜肽有必要實施關於HLA結合性胜肽之所有候選物質5000億(=209
)次以上之結合實驗的數量。
根據如上說明之規則,選出序列編號1~15所示之胺基酸序列。
<胜肽合成與純化> 具有序列編號1~15之胺基酸序列的胜肽係使用Fmoc胺基酸,並以梅里菲爾德(Merrifield)固相法進行人工合成。脱保護之後,使用C18管柱進行逆相HPLC純化並達到95%以上之純度。胜肽之鑑定與純度之確認利用MALDI-TOF質量分析實施(AB SCIEX MALDI-TOF/TOF5800)。胜肽之定量係以BSA作為標準蛋白質利用Micro BCA Assay(Thermo Scienftific公司)實施。
<胜肽結合至HLA-A*24:02分子的實驗> 胜肽結合至HLA-A*24:02基因之產物即HLA-A*24:02分子的能力之測量係使用表現HLA-A*24:02分子之C1R-A24細胞(熊本大學,瀧口雅文教授製得,取得許可而由愛媛大學,安川正貴助教授提供)實施。
首先,將C1R-A24細胞於pH3.3之酸性條件下暴露30秒,將原本結合於HLA-A*24:02分子的內生性胜肽與HLA第一型分子所共通而締合之輕鏈β2m解離並去除。中和後,將純化之β2m加入C1R-A24細胞,並添加至系列稀釋之胜肽中,冰上培養4小時。在此期間使用可辨認再締合而成之HLA-A*24:02分子、胜肽、β2m之3者的締合體(MHC-pep)之螢光標識單株抗體17A12進行染色。
其後,使用螢光細胞分析裝置FACScan(Becton-Dickinson公司)定量測量各個C1R-A24細胞相當之MHC-pep數(和上述螢光抗體之螢光強度成比例)。利用本案發明人於論文(Udaka et al., Immunogenetics, 51, 816-828, 2000)所發表的方法,由每1個細胞之平均螢光強度計算HLA-A*24:02分子與胜肽間的結合解離常數Kd值。
<胜肽結合至HLA-A*02:01分子的實驗> 胜肽結合至HLA-A*02:01基因之產物即HLA-A*02:01分子的能力之測量係使用表現HLA-A*02:01分子之細胞株T2(購自ATCC)實施。
欲測量結合能力的階段系列稀釋之胜肽中加入T2細胞與純化之β2m後,於37℃培養4小時。到達此時間點時使用締合型專一性螢光標識單株抗體BB7.2,將因胜肽之濃度依存性而表現量增加的HLA-A*02:01分子染色。
其後,利用流式細胞儀(flow cytometer)測量每1個細胞之螢光量,並以本案發明人於論文(Udaka et al.,Immunogenetics, 51, 816-828, 2000)所發表的方法計算解離常數Kd值。
<胜肽結合至HLA-A*02:06分子的實驗> 胜肽結合至HLA-A*02:06基因之產物即HLA-A*02:06分子的能力之測量係使用於老鼠之TAP(transporter associated with antigen processing)缺損細胞株即RMAS中導入HLA-A*02:06基因之cDNA的RA2.6細胞(於高知大學新製得之細胞株)實施。
首先將RA2.6細胞於26℃培養隔夜,當細胞表面聚積了未與胜肽結合之HLA-A*02:06分子後加入系列稀釋之胜肽,並於26℃使其結合60分鐘。
其後藉由於35℃培養4小時,未結合胜肽之空的HLA-A*02:06分子會變性並失去立體結構。於此加入專一性地辨認胜肽結合型HLA-A*02:06分子之螢光標識單株抗體BB7.2,並於冰上培養20分鐘,將細胞染色。
其後,利用流式細胞儀測量每1個細胞之螢光量,並以本案發明人於論文(Udaka et al.,Immunogenetics, 51, 816-828, 2000)所發表的方法計算解離常數Kd值。
<結合實驗的評估結果> 其結果得到如下表所示之對於各HLA分子之本發明之胜肽的結合實驗資料。 [表2]
此外,序列編號1~15之胺基酸序列係源自序列編號16所示之HSP70既定的基因體蛋白質之全長序列。
<胜肽之免疫誘導試驗> (1) 胜肽刺激樹狀細胞的製備 ・Day0~9(樹狀細胞的誘導) 按照白血球分離法(leukapheresis)從採取自肝癌患者之週邊血液分離出單核球。將分離出的單核球在添加800U/ml之GM-CSF及500U/ml之IL-4的條件下培養6天。於培養液中再添加300U/ml之TNF-α後培養4天,誘導成成熟樹狀細胞。其後,以電穿孔法導入HSP70 mRNA,製得呈現有源自HSP70之抗原胜肽的樹狀細胞。
將1×107
個或2×107
個或3×107
個已導入HSP70 mRNA之樹狀細胞(HSP70-樹狀細胞)以皮內注射投予至上述肝癌患者的大腿部(HSP70樹狀細胞療法)。每3週重複以相同方法製得的HSP70-樹狀細胞之皮內投予。利用分離法(pheresis)從已用HSP70樹狀細胞療法進行2次以上治療的肝癌患者得到的週邊血液單核球之中,將黏著於培養角瓶(flask)的細胞部分在AIM-CM培養基(Gibco公司製)中,於37℃培養10天。在培養期間之第0天及第3天各別對培養基添加15μl之IL-4、30μl之顆粒球單核球群落刺激因子(granulocyte/monocyte colony stimulating factor,GM-CSF),並於第5天添加15μl之IL-4、30μl之GM-CSF、75μl之腫瘤壞死因子(TNF)-α。
・Day10(胜肽刺激及樹狀細胞的回收) 將自單核球誘導而成的樹狀細胞回收至新的AIM-CM培養基中,並添加本發明之胜肽(序列編號5、6、7、9、10、15)使其濃度為20μg/ml。其後,將含有樹狀細胞之培養基於37℃培養2小時。使用以下的胜肽作為正對照組及負對照組。 HLA-A24:02用正對照組(EBV LMP2, 419-427:TYGPVFMCL(序列編號17)) HLA-A24:02用負對照組(HIV env gp160, 584-592:RYLRDQQLL(序列編號18)) HLA-A02:01用正對照組(Flu A MP, 58-66:GILGFVFTL(序列編號19)) HLA-A02:01用負對照組(HIV gap p17, 77-85:SLYNTVATL(序列編號20)) HLA-A02:06用正對照組(EBV LMP2 453-461:LTAGFLIFL(序列編號21)) HLA-A02:06用負對照組(HIV gap p24 341-349:ATLEEMMTA(序列編號22))
回收樹狀細胞並以充分的量之AIM-CM培養基洗淨3次以上後進行細胞計數。
(2) CD8T細胞的製備 ・Day0~9 利用分離法從已用HSP70樹狀細胞療法進行2次以上治療後之上述肝癌患者得到的週邊血液單核球之中,將未黏著於培養角瓶之浮游細胞部分(包含淋巴細胞)在AIM-CM培養基(Gibco公司製)中,於37℃培養10天。在培養期間之第4天及第6天各別對培養基添加40μl之IL-2。
・Day10 使用CD8負向選擇套組(Miltenyi公司製)從培養基分離CD8T細胞並進行細胞計數。
(3) 共培養 將上述(1)及(2)所得到的樹狀細胞與CD8T細胞在以下的條件於AIM培養基中以37℃共培養。 ・CD8T細胞:5×105
個細胞/孔 ・樹狀細胞:2×105
個細胞/孔
・Day12或13 於上述培養基中以0.4ml/孔的方式添加含有20U/ml之IL-2的AIM-CM培養基。
(4) 酵素連結免疫斑點分析法 ・Day17 將上述CD8T細胞以每1孔為2×104
個細胞/孔的方式加入固定有抗IFN-γ單株抗體(MABTECH公司製)之酵素連結免疫斑點法用96孔盤(Millipore公司製)。針對各樣本使用3孔以上。各孔中添加100μl之AIM-V(Gibco公司製)。將酵素連結免疫斑點法用96孔盤培養於37℃。
・Day18 各孔中加入抗IFN-γ抗體,再使其與HRP酵素標識的2次抗體反應,利用呈色反應測量產生IFN-γ細胞的數量。就典型的酵素連結免疫斑點分析法之結果而言,針對HLA型為02:01/24:02之患者的結果如圖1所示,針對02:01/33:03之患者的結果如圖2所示,而針對02:06/24:02之患者的結果如圖3所示。各圖中係表示每5次分析結果的平均值。
(5) 酵素連結免疫吸附分析法 ・Day17 將T細胞與上述因胜肽而進行脈衝之樹狀細胞共培養第7天之培養上清液進行1倍、5倍、25倍、125倍之4階段稀釋,並使用Human IFN-γ ELISA MAX Deluxe Set(BioLegend公司製)鑑定落入測量限度內之稀釋階段。其後,以鑑定得到的稀釋階段針對每個樣本實施3次的測量。就典型的酵素連結免疫吸附分析法之結果而言,針對HLA型為24:02/26:01之患者的結果如圖4及圖5所示,針對24:02/24:02之患者的結果按順序如圖6所示。
以上根據實施例說明本發明。該實施例僅為例示,該技術領域中具有通常知識者應理解各種變形例皆為可能,且如此之變形例亦包含在本發明之範圍內。
無
[圖1] 係表示利用序列編號7、9或15之胜肽刺激源自已接受HSP70樹狀細胞療法之肝癌患者(HLA型:02:01/24:02)的樣本時的酵素連結免疫斑點分析法(ELISPOT assay)之結果(產生IFN-γ的細胞數)。 [圖2] 係表示利用序列編號7、9或15之胜肽刺激源自已接受HSP70樹狀細胞療法之肝癌患者(HLA型:02:01/33:03)的樣本時的酵素連結免疫斑點分析法之結果(產生IFN-γ的細胞數)。 [圖3] 係表示利用序列編號7、9或15之胜肽刺激源自已接受HSP70樹狀細胞療法之肝癌患者(HLA型:02:06/24:02)的樣本時的酵素連結免疫斑點分析法之結果(產生IFN-γ的細胞數)。 [圖4] 係表示利用序列編號7、9或15之胜肽刺激源自已接受HSP70樹狀細胞療法之肝癌患者(HLA型:24:02/26:01)的樣本時的酵素連結免疫吸附分析法(ELISA assay)之結果(產生IFN-γ的細胞數)。 [圖5] 係表示利用序列編號5、6、7、9、10或15之胜肽刺激源自已接受HSP70樹狀細胞療法之肝癌患者(HLA型:24:02/26:01)的樣本時的酵素連結免疫吸附分析法之結果(產生IFN-γ的細胞數)。 [圖6] 係表示利用序列編號5、6、7、9或10之胜肽刺激源自已接受HSP70樹狀細胞療法之肝癌患者(HLA型:24:02/24:02)的樣本時的酵素連結免疫吸附分析法之結果(產生IFN-γ的細胞數)。
<110> 日本電氣股份有限公司 <120> 來自HSP70之胜肽、使用此胜肽之用於治療或預防癌之醫藥組成物、免疫誘導劑、及抗原呈現細胞之製造方法 <130> 6470098012 <150> JP2014-206730 <151> 2014-10-07 <160> 22 <170> PatentIn version 3.5 <210> 1 <211> 9 <212> PRT <213> 智人(Homo sapiens) <400> 1 Gly Val Pro Gln Ile Glu Val Thr Phe 1 5 <210> 2 <211> 9 <212> PRT <213> 智人 <400> 2 Thr Phe Asp Val Ser Ile Leu Thr Ile 1 5 <210> 3 <211> 9 <212> PRT <213> 智人 <400> 3 Phe Tyr Pro Glu Glu Ile Ser Ser Met 1 5 <210> 4 <211> 9 <212> PRT <213> 智人 <400> 4 Lys Leu Leu Gln Asp Phe Phe Asn Gly 1 5 <210> 5 <211> 9 <212> PRT <213> 智人 <400> 5 Val Leu Val Gly Gly Ser Thr Arg Ile 1 5 <210> 6 <211> 9 <212> PRT <213> 智人 <400> 6 Met Val Leu Thr Lys Met Lys Glu Ile 1 5 <210> 7 <211> 9 <212> PRT <213> 智人 <400> 7 Tyr Gly Ala Ala Val Gln Ala Ala Ile 1 5 <210> 8 <211> 9 <212> PRT <213> 智人 <400> 8 Leu Leu Leu Asp Val Ala Pro Leu Ser 1 5 <210> 9 <211> 9 <212> PRT <213> 智人 <400> 9 Ala Met Thr Lys Asp Asn Asn Leu Leu 1 5 <210> 10 <211> 9 <212> PRT <213> 智人 <400> 10 Ile Thr Arg Ala Arg Phe Glu Glu Leu 1 5 <210> 11 <211> 9 <212> PRT <213> 智人 <400> 11 Asn Leu Leu Gly Arg Phe Glu Leu Ser 1 5 <210> 12 <211> 9 <212> PRT <213> 智人 <400> 12 Ala Gln Ile His Asp Leu Val Leu Val 1 5 <210> 13 <211> 9 <212> PRT <213> 智人 <400> 13 Tyr Ala Phe Asn Met Lys Ser Ala Val 1 5 <210> 14 <211> 9 <212> PRT <213> 智人 <400> 14 Asn Gln Pro Gly Val Leu Ile Gln Val 1 5 <210> 15 <211> 9 <212> PRT <213> 智人 <400> 15 Ser Val Thr Asn Ala Val Ile Thr Val 1 5 <210> 16 <211> 641 <212> PRT <213> 智人 <400> 16 Met Ala Lys Ala Ala Ala Val Gly Ile Asp Leu Gly Thr Thr Tyr Ser 1 5 10 15 Cys Val Gly Val Phe Gln His Gly Lys Val Glu Ile Ile Ala Asn Asp 20 25 30 Gln Gly Asn Arg Thr Thr Pro Ser Tyr Val Ala Phe Thr Asp Thr Glu 35 40 45 Arg Leu Ile Gly Asp Ala Ala Lys Asn Gln Val Ala Leu Asn Pro Gln 50 55 60 Asn Thr Val Phe Asp Ala Lys Arg Leu Ile Gly Arg Lys Phe Gly Asp 65 70 75 80 Pro Val Val Gln Ser Asp Met Lys His Trp Pro Phe Gln Val Ile Asn 85 90 95 Asp Gly Asp Lys Pro Lys Val Gln Val Ser Tyr Lys Gly Glu Thr Lys 100 105 110 Ala Phe Tyr Pro Glu Glu Ile Ser Ser Met Val Leu Thr Lys Met Lys 115 120 125 Glu Ile Ala Glu Ala Tyr Leu Gly Tyr Ser Val Thr Asn Ala Val Ile 130 135 140 Thr Val Pro Ala Tyr Phe Asn Asp Ser Gln Arg Gln Ala Thr Lys Asp 145 150 155 160 Ala Gly Val Ile Ala Gly Leu Asn Val Leu Arg Ile Ile Asn Glu Pro 165 170 175 Thr Ala Ala Ala Ile Ala Tyr Gly Leu Asp Arg Thr Gly Lys Gly Glu 180 185 190 Arg Asn Val Leu Ile Phe Asp Leu Gly Gly Gly Thr Phe Asp Val Ser 195 200 205 Ile Leu Thr Ile Asp Asp Gly Ile Phe Glu Val Lys Ala Thr Ala Gly 210 215 220 Asp Thr His Leu Gly Gly Glu Asp Phe Asp Asn Arg Leu Val Asn His 225 230 235 240 Phe Val Glu Glu Phe Lys Arg Lys His Lys Lys Asp Ile Ser Gln Asn 245 250 255 Lys Arg Ala Val Arg Arg Leu Arg Thr Ala Cys Glu Arg Ala Lys Arg 260 265 270 Thr Leu Ser Ser Ser Thr Gln Ala Ser Leu Glu Ile Asp Ser Leu Phe 275 280 285 Glu Gly Ile Asp Phe Tyr Thr Ser Ile Thr Arg Ala Arg Phe Glu Glu 290 295 300 Leu Cys Ser Asp Leu Phe Arg Ser Thr Leu Glu Pro Val Glu Lys Ala 305 310 315 320 Leu Arg Asp Ala Lys Leu Asp Lys Ala Gln Ile His Asp Leu Val Leu 325 330 335 Val Gly Gly Ser Thr Arg Ile Pro Lys Val Gln Lys Leu Leu Gln Asp 340 345 350 Phe Phe Asn Gly Arg Asp Leu Asn Lys Ser Ile Asn Pro Asp Glu Ala 355 360 365 Val Ala Tyr Gly Ala Ala Val Gln Ala Ala Ile Leu Met Gly Asp Lys 370 375 380 Ser Glu Asn Val Gln Asp Leu Leu Leu Leu Asp Val Ala Pro Leu Ser 385 390 395 400 Leu Gly Leu Glu Thr Ala Gly Gly Val Met Thr Ala Leu Ile Lys Arg 405 410 415 Asn Ser Thr Ile Pro Thr Lys Gln Thr Gln Ile Phe Thr Thr Tyr Ser 420 425 430 Asp Asn Gln Pro Gly Val Leu Ile Gln Val Tyr Glu Gly Glu Arg Ala 435 440 445 Met Thr Lys Asp Asn Asn Leu Leu Gly Arg Phe Glu Leu Ser Gly Ile 450 455 460 Pro Pro Ala Pro Arg Gly Val Pro Gln Ile Glu Val Thr Phe Asp Ile 465 470 475 480 Asp Ala Asn Gly Ile Leu Asn Val Thr Ala Thr Asp Lys Ser Thr Gly 485 490 495 Lys Ala Asn Lys Ile Thr Ile Thr Asn Asp Lys Gly Arg Leu Ser Lys 500 505 510 Glu Glu Ile Glu Arg Met Val Gln Glu Ala Glu Lys Tyr Lys Ala Glu 515 520 525 Asp Glu Val Gln Arg Glu Arg Val Ser Ala Lys Asn Ala Leu Glu Ser 530 535 540 Tyr Ala Phe Asn Met Lys Ser Ala Val Glu Asp Glu Gly Leu Lys Gly 545 550 555 560 Lys Ile Ser Glu Ala Asp Lys Lys Lys Val Leu Asp Lys Cys Gln Glu 565 570 575 Val Ile Ser Trp Leu Asp Ala Asn Thr Leu Ala Glu Lys Asp Glu Phe 580 585 590 Glu His Lys Arg Lys Glu Leu Glu Gln Val Cys Asn Pro Ile Ile Ser 595 600 605 Gly Leu Tyr Gln Gly Ala Gly Gly Pro Gly Pro Gly Gly Phe Gly Ala 610 615 620 Gln Gly Pro Lys Gly Gly Ser Gly Ser Gly Pro Pro Ile Glu Glu Val 625 630 635 640 <210> 17 <211> 9 <212> PRT <213> 智人 <400> 17 Thr Tyr Gly Pro Val Phe Met Cys Leu 1 5 <210> 18 <211> 9 <212> PRT <213> 智人 <400> 18 Arg Tyr Leu Arg Asp Gln Gln Leu Leu 1 5 <210> 19 <211> 9 <212> PRT <213> 智人 <400> 19 Gly Ile Leu Gly Phe Val Phe Thr Leu 1 5 <210> 20 <211> 9 <212> PRT <213> 智人 <400> 20 Ser Leu Tyr Asn Thr Val Ala Thr Leu 1 5 <210> 21 <211> 9 <212> PRT <213> 智人 <400> 21 Leu Thr Ala Gly Phe Leu Ile Phe Leu 1 5 <210> 22 <211> 9 <212> PRT <213> 智人 <400> 22 Ala Thr Leu Glu Glu Met Met Thr Ala 1 5
無
Claims (10)
- 一種胜肽,含有序列編號1~15之中任一者所示之胺基酸序列中的連續8個以上之胺基酸殘基,且由11個以下之胺基酸殘基構成。
- 如申請專利範圍第1項之胜肽,其中,該胺基酸序列中有1個或數個胺基酸取代、插入、缺失或附加,且具有免疫原性。
- 如申請專利範圍第2項之胜肽,其中,該胺基酸序列中,第2位之胺基酸以酪胺酸、苯丙胺酸、甲硫胺酸、色胺酸、纈胺酸、白胺酸或麩醯胺酸取代,及/或C端之胺基酸以苯丙胺酸、白胺酸、異白胺酸、色胺酸、甲硫胺酸或纈胺酸取代。
- 一種用於治療或預防癌之醫藥組成物,含有如申請專利範圍第1至3項中任一項之胜肽。
- 如申請專利範圍第4項之用於治療或預防癌之醫藥組成物,為疫苗之形態。
- 如申請專利範圍第4或5項之用於治療或預防癌之醫藥組成物,其中,該胜肽可與1種或多種類型之HLA分子結合。
- 一種免疫誘導劑,包含如申請專利範圍第1至3項中任一項之胜肽。
- 如申請專利範圍第7項之免疫誘導劑,用於誘導細胞傷害性T細胞。
- 如申請專利範圍第7或8項之免疫誘導劑,其中,該胜肽可與1種或多種類型之HLA分子結合。
- 一種具有CTL誘導活性之抗原呈現細胞之製造方法,包含以下步驟: 如申請專利範圍第1至3項中任一項之胜肽與抗原呈現細胞在試管內(in vitro)接觸。
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CN107428815B (zh) | 2015-03-09 | 2021-07-09 | Cytlimic公司 | 源于gpc3的肽、使用其的用于治疗或预防癌症的医药组合物、免疫诱导剂、及抗原呈递细胞的制造方法 |
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WO2023163094A1 (ja) * | 2022-02-25 | 2023-08-31 | 日本電気株式会社 | 成人t細胞白血病の治療又は予防のための医薬組成物 |
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