TW201639869A - 來自gpc3之胜肽、使用此胜肽之用於治療或預防癌症之醫藥組成物、免疫誘導劑、及抗原呈現細胞之製造方法 - Google Patents
來自gpc3之胜肽、使用此胜肽之用於治療或預防癌症之醫藥組成物、免疫誘導劑、及抗原呈現細胞之製造方法 Download PDFInfo
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- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
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Abstract
本發明提供一種胜肽，含有序列編號1~11中之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。
Description
本發明係關於來自GPC3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。
活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來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。
為了辨認來自癌細胞的抗原，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1~11中之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方法而受到關注。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。又朝各種免疫療法，尤其朝樹狀細胞療法之應用亦受到預期。
Glypican-3(GPC3)係屬於Glypican家族之蛋白質。Glypican係蛋白多醣(proteoglycan)的一種，已知會和細胞表面之醣苷基-磷脂醯肌醇(glycosyl- phosphatidylinositol)結合。Glypican控制包含Wnts之種種的細胞增殖因子之活性，據認為該作用係因為Glypican會促進或妨礙該等細胞增殖因子與其受體之交互作用。已明瞭尤其GPC3幾乎表現於所有的肝細胞癌(hepatocellular carcinoma (HCC))，另一方面，在正常的肝臟、肝硬變等幾乎不表現。又GPC3已知除了在肝細胞癌以外，在黑色素瘤、卵巢癌等亦會高度表現。 1. “Glypican-3: a marker and a therapeutic target in hepatocellular carcinoma.” Jorge Filmus and Mariana Capurro, FEBS J., 280: 2471-2476, 2013. 2. “Glypican-3: a new target for cancer immunotherapy.” Mitchell Ho and Heungnam Kim, Eur. J. Cancer, 47, 333-338, 2011.
對於肝細胞癌使用來自在肝細胞癌的細胞高度表現的GPC3之胜肽的癌疫苗之臨床研究已在進行，皆有報告其安全性與免疫誘導能力。 3. “Peptide vaccines for hepatocellular carcinoma.” Daisuke Nobuoka, Toshiaki Yoshikawa, Yu Sawada, Toshiyoshi Fujiwara and Tetsuya Nakatsura, Human Vaccines & Immunotherapeutics, 9, 210-212, 2013. 4. “Phase I Trial of a Glypican-3-Derived Peptide Vaccine for Advanced Hepatocellular Carcinoma: Immunologic Evidence and Potential fo Improving Overall Survival.” Yu Sawada, et.al., Clin. Cancer. Res., 18, 3636-3696, 2012.
本發明係與上述臨床研究所報告之胜肽不同之來自GPC3之胜肽，且已鑑定出多數之結合於HLA分子且同時具有免疫誘導能力之胜肽。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＞ 本發明相關之胜肽係含有序列編號1~11中之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1~11之中任一者所示之胺基酸序列構成。本發明之胜肽來自Glypican中之一的GPC3。選擇基於構成GPC3之胺基酸序列，利用使用主動學習(active learning)實驗法(日本特開平8-151396號)而獲得之假說所預測之和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(以下亦有簡單稱為「HLA胜肽」或「免疫原性胜肽」之情況)。在本說明書使用時，「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%之包含日本人之東方人且涵括約55%之西方人，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1~11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1~11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受到消化等變化。因此，本發明之胜肽在抗原呈現細胞攝入前也可以在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1~11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，除了包含天然胺基酸之外，亦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所公知的特性之經化學合成而得之化合物等。作為非天然胺基酸的例子可列舉：α-甲基胺基酸(α-甲基丙胺酸等)、D-胺基酸、類組胺酸胺基酸(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)。
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所公知的方法製造。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1~11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1~11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。作為所使用的抗原呈現細胞可列舉巨噬細胞、樹狀細胞等，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，但不限定。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，會活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，會辨認和來自與癌細胞表面之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GPC3的癌皆可作為受治療或預防的癌。更具體而言可列舉肝細胞癌、黑色素瘤等皮膚癌、卵巢癌等作為對象，但不限定。例如，本發明之胜肽的來源即GPC3在肝細胞癌會過量表現，故據認為本發明之胜肽尤其在肝細胞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。作為如此之製藥上允許之鹽的形態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。又，除了使用水溶性溶劑之外，亦可使用非水溶性溶劑，作為如此之非水溶性溶劑可列舉例如乙醇、丙二醇等醇。
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，作為如此的藥劑可列舉例如保存劑、緩衝劑等。作為保存劑可列舉：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。又作為緩衝劑可列舉：碳酸鈉、硼酸鈉、磷酸鈉、乙酸鈉、碳酸氫鈉等。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1~11所示胜肽之中任2個以上，或和其他有效成分的組合，能含有多種有效成分。
又，本發明之疫苗亦可為含有醫藥組成物以外的成分之含不活性成分之疫苗，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。作為不活性成分可列舉佐劑(adjuvant)、類毒素(toxoid)等。作為佐劑之例子可列舉：氫氧化鋁、磷酸鋁、磷酸鈣等沉降性型佐劑；弗氏完全佐劑、弗氏不完全佐劑等油性型佐劑，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來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所公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來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例如含有選自於由序列編號1~11構成之群組中之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的胜肽作為有效成分。免疫誘導劑所含之胜肽亦可由序列編號1~11中之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。作為所使用的抗原呈現細胞可列舉巨噬細胞、樹狀細胞等，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。更具體而言，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來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所公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來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、或使初始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ELISPOT(酵素連結免疫斑點法，Enzyme- Linked ImmunoSpot)法或ELISA(酵素連結免疫吸附法，Enzyme-Linked Immuno Sorbent Assay)法等公知之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游離法等公知的方法測量。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，可評價為免疫或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1~11構成之群組中之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1~11中之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。作為所使用的抗原呈現細胞可列舉巨噬細胞、樹狀細胞等，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來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所公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、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來自患者的抗原呈現細胞進行轉型等。 [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2006/00418 2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1~11所示之胺基酸序列。
＜胜肽合成與純化＞ 具有序列編號1~11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係利用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 Scientific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，瀧口雅文教授所製得之細胞，經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加入到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細胞所相當之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。
在欲測量結合能力之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。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】
另外，序列編號1~11之胺基酸序列係來自登錄於GENBANK之GPC3既定的基因體蛋白質之全長序列(序列編號12)(＞gi|4758462|ref|NP_004475.1| glypican-3 isoform 2 precursor [Homo sapiens])。
＜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) 將利用分離法(pheresis)從已接受針對HSP70之樹狀細胞療法之患者得到的週邊血液單球之中，黏著於培養角瓶之細胞分部(fraction)，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(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) 將誘導後之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1~11)使其濃度成為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-A*24：02用正對照組(EBV LMP2, 419-427:TYGPVFMCL(序列編號13)) HLA-A*24：02用負對照組(HIV env gp160, 584-592:RYLRDQQLL(序列編號14)) HLA-A*02：01用正對照組(Flu A MP, 58-66:GILGFVFTL(序列編號15)) HLA-A*02：01用負對照組(HIV gap p17, 77-85:SLYNTVATL(序列編號16)) HLA-A*02：06用正對照組(EBV LMP2 453-461:LTAGFLIFL(序列編號17)) HLA-A*02：06用負對照組(HIV gap p24 341-349:ATLEEMMTA(序列編號18))
回收樹狀細胞並以充分的量之AIM-CM培養基洗淨3次以上之後進行細胞計數。
(2) CD8T細胞的製備 ･Day0~9 將利用分離法從已用上述疫苗進行2次以上治療後之患者得到的週邊血液單球之中，未黏著於培養角瓶之浮游細胞分部(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) ELISPOT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ELISPOT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ELISPOT用96孔盤在37℃培養。
･Day18 在各孔中加入抗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ELISPOT分析的結果而言，針對HLA型為24：02/24：02之患者的結果如圖1所示，針對02：01/24：02之患者的結果如圖2所示，又，針對02：01/33：03之患者的結果如圖3所示。各圖中係表示每3次分析結果的平均值。
(5) ELISA分析法 ･Day17 將T細胞與上述利用胜肽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ELISA分析的結果而言，針對HLA型為24：02/26：01之患者、24：02/24：02之患者、11：01/24：02之患者、02：01/24：02之患者、02：01/33：03之患者的結果按順序如圖4~8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】圖1係表示以序列編號1之胜肽刺激來自已接受針對HSP70之樹狀細胞療法之患者(HLA型：24：02/24：02)的樣本時之ELISPOT分析的結果(產生IFN-γ的細胞數)。 【圖2】圖2係表示以序列編號1、2或4之胜肽刺激來自已接受針對HSP70之樹狀細胞療法之患者(HLA型：02：01/24：02)的樣本時之ELISPOT分析的結果(產生IFN-γ的細胞數)。 【圖3】圖3係表示以序列編號1、2或4之胜肽刺激來自已接受針對HSP70之樹狀細胞療法之患者(HLA型：02：01/33：03)的樣本時之ELISPOT分析的結果(產生IFN-γ的細胞數)。 【圖4】圖4係表示以序列編號1、2或4之胜肽刺激來自已接受針對HSP70之樹狀細胞療法之患者(HLA型：24：02/26：01)的樣本時之ELISA分析的結果(產生IFN-γ的細胞數)。 【圖5】圖5係表示以序列編號1、2或4之胜肽刺激來自已接受針對HSP70之樹狀細胞療法之患者(HLA型：24：02/24：02)的樣本時之ELISA分析的結果(產生IFN-γ的細胞數)。 【圖6】圖6係表示以序列編號1、2或4之胜肽刺激來自已接受針對HSP70之樹狀細胞療法之患者(HLA型：11：01/24：02)的樣本時之ELISA分析的結果(產生IFN-γ的細胞數)。 【圖7】圖7係表示以序列編號1、2或4之胜肽刺激來自已接受針對HSP70之樹狀細胞療法之患者(HLA型：02：01/24：02)的樣本時之ELISA分析的結果(產生IFN-γ的細胞數)。 【圖8】圖8係表示以序列編號1、2或4之胜肽刺激來自已接受針對HSP70之樹狀細胞療法之患者(HLA型：02：01/33：03)的樣本時之ELISA分析的結果(產生IFN-γ的細胞數)。
＜110＞ 日本電氣股份有限公司 ＜120＞ 來自GPC3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＞ 6470A98014 ＜150＞ JP2015-46463 ＜151＞ 2015-03-09 ＜160＞ 12 ＜170＞ PatentIn version 3.5 ＜210＞ 1 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人(Homo sapiens) ＜400＞ 1 Met Val Asn Glu Leu Phe Asp Ser Leu 1 5 ＜210＞ 2 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 2 Leu Phe Asp Ser Leu Phe Pro Val Ile 1 5 ＜210＞ 3 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 3 Ser Ala Leu Asp Ile Asn Glu Cys Leu 1 5 ＜210＞ 4 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 4 Ser Leu Gln Val Thr Arg Ile Phe Leu 1 5 ＜210＞ 5 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 5 Ser Leu Thr Pro Gln Ala Phe Glu Phe 1 5 ＜210＞ 6 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 6 Gly Tyr Ile Cys Ser His Ser Pro Val 1 5 ＜210＞ 7 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 7 Ala Leu Asn Leu Gly Ile Glu Val Ile 1 5 ＜210＞ 8 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 8 Leu Leu Gln Ser Ala Ser Met Glu Leu 1 5 ＜210＞ 9 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 9 Lys Leu Thr Thr Thr Ile Gly Lys Leu 1 5 ＜210＞ 10 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 10 Gly Met Ile Lys Val Lys Asn Gln Leu 1 5 ＜210＞ 11 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 11 Ala Arg Leu Asn Met Glu Gln Leu Leu 1 5 ＜210＞ 12 ＜211＞ 580 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 12 Met Ala Gly Thr Val Arg Thr Ala Cys Leu Val Val Ala Met Leu Leu 1 5 10 15 Ser Leu Asp Phe Pro Gly Gln Ala Gln Pro Pro Pro Pro Pro Pro Asp 20 25 30 Ala Thr Cys His Gln Val Arg Ser Phe Phe Gln Arg Leu Gln Pro Gly 35 40 45 Leu Lys Trp Val Pro Glu Thr Pro Val Pro Gly Ser Asp Leu Gln Val 50 55 60 Cys Leu Pro Lys Gly Pro Thr Cys Cys Ser Arg Lys Met Glu Glu Lys 65 70 75 80 Tyr Gln Leu Thr Ala Arg Leu Asn Met Glu Gln Leu Leu Gln Ser Ala 85 90 95 Ser Met Glu Leu Lys Phe Leu Ile Ile Gln Asn Ala Ala Val Phe Gln 100 105 110 Glu Ala Phe Glu Ile Val Val Arg His Ala Lys Asn Tyr Thr Asn Ala 115 120 125 Met Phe Lys Asn Asn Tyr Pro Ser Leu Thr Pro Gln Ala Phe Glu Phe 130 135 140 Val Gly Glu Phe Phe Thr Asp Val Ser Leu Tyr Ile Leu Gly Ser Asp 145 150 155 160 Ile Asn Val Asp Asp Met Val Asn Glu Leu Phe Asp Ser Leu Phe Pro 165 170 175 Val Ile Tyr Thr Gln Leu Met Asn Pro Gly Leu Pro Asp Ser Ala Leu 180 185 190 Asp Ile Asn Glu Cys Leu Arg Gly Ala Arg Arg Asp Leu Lys Val Phe 195 200 205 Gly Asn Phe Pro Lys Leu Ile Met Thr Gln Val Ser Lys Ser Leu Gln 210 215 220 Val Thr Arg Ile Phe Leu Gln Ala Leu Asn Leu Gly Ile Glu Val Ile 225 230 235 240 Asn Thr Thr Asp His Leu Lys Phe Ser Lys Asp Cys Gly Arg Met Leu 245 250 255 Thr Arg Met Trp Tyr Cys Ser Tyr Cys Gln Gly Leu Met Met Val Lys 260 265 270 Pro Cys Gly Gly Tyr Cys Asn Val Val Met Gln Gly Cys Met Ala Gly 275 280 285 Val Val Glu Ile Asp Lys Tyr Trp Arg Glu Tyr Ile Leu Ser Leu Glu 290 295 300 Glu Leu Val Asn Gly Met Tyr Arg Ile Tyr Asp Met Glu Asn Val Leu 305 310 315 320 Leu Gly Leu Phe Ser Thr Ile His Asp Ser Ile Gln Tyr Val Gln Lys 325 330 335 Asn Ala Gly Lys Leu Thr Thr Thr Ile Gly Lys Leu Cys Ala His Ser 340 345 350 Gln Gln Arg Gln Tyr Arg Ser Ala Tyr Tyr Pro Glu Asp Leu Phe Ile 355 360 365 Asp Lys Lys Val Leu Lys Val Ala His Val Glu His Glu Glu Thr Leu 370 375 380 Ser Ser Arg Arg Arg Glu Leu Ile Gln Lys Leu Lys Ser Phe Ile Ser 385 390 395 400 Phe Tyr Ser Ala Leu Pro Gly Tyr Ile Cys Ser His Ser Pro Val Ala 405 410 415 Glu Asn Asp Thr Leu Cys Trp Asn Gly Gln Glu Leu Val Glu Arg Tyr 420 425 430 Ser Gln Lys Ala Ala Arg Asn Gly Met Lys Asn Gln Phe Asn Leu His 435 440 445 Glu Leu Lys Met Lys Gly Pro Glu Pro Val Val Ser Gln Ile Ile Asp 450 455 460 Lys Leu Lys His Ile Asn Gln Leu Leu Arg Thr Met Ser Met Pro Lys 465 470 475 480 Gly Arg Val Leu Asp Lys Asn Leu Asp Glu Glu Gly Phe Glu Ser Gly 485 490 495 Asp Cys Gly Asp Asp Glu Asp Glu Cys Ile Gly Gly Ser Gly Asp Gly 500 505 510 Met Ile Lys Val Lys Asn Gln Leu Arg Phe Leu Ala Glu Leu Ala Tyr 515 520 525 Asp Leu Asp Val Asp Asp Ala Pro Gly Asn Ser Gln Gln Ala Thr Pro 530 535 540 Lys Asp Asn Glu Ile Ser Thr Phe His Asn Leu Gly Asn Val His Ser 545 550 555 560 Pro Leu Lys Leu Leu Thr Ser Met Ala Ile Ser Val Val Cys Phe Phe 565 570 575 Phe Leu Val His 580 ＜210＞ 14 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 14 Thr Tyr Gly Pro Val Phe Met Cys Leu 1 5 ＜210＞ 15 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 15 Arg Tyr Leu Arg Asp Gln Gln Leu Leu 1 5 ＜210＞ 16 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 16 Gly Ile Leu Gly Phe Val Phe Thr Leu 1 5 ＜210＞ 17 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 17 Ser Leu Tyr Asn Thr Val Ala Thr Leu 1 5 ＜210＞ 18 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 18 Leu Thr Ala Gly Phe Leu Ile Phe Leu 1 5 ＜210＞ 19 ＜211＞ 9 ＜212＞ PRT ＜213＞ 智人 ＜400＞ 19 Ala Thr Leu Glu Glu Met Met Thr Ala 1 5
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Claims (10)
- 一種胜肽，含有序列編號1~11中之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：將如申請專利範圍第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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| SG11201506727RA (en) | 2013-03-01 | 2015-09-29 | Astex Pharmaceuticals Inc | Drug combinations |
| US10682400B2 (en) | 2014-04-30 | 2020-06-16 | President And Fellows Of Harvard College | Combination vaccine devices and methods of killing cancer cells |
| ES2882827T3 (es) | 2014-10-07 | 2021-12-02 | Cytlimic Inc | Péptido inductor de inmunidad derivado de HSP70 |
| BR112017018703A2 (pt) | 2015-03-09 | 2018-04-17 | Cytlimic Inc. | peptídeo derivado de gpc3, composição farmacêutica para tratamento ou prevenção de câncer usando o mesmo, indutor de imunidade, e método para produzir células de apresentação de antígeno |
| JP6311094B2 (ja) | 2015-04-07 | 2018-04-18 | サイトリミック株式会社 | 医薬 |
| US11291718B2 (en) * | 2016-10-11 | 2022-04-05 | Cytlimic Inc. | Method for treating cancer by administering a toll-like receptor agonist and LAG-3 IgG fusion protein |
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| RU2017135038A (ru) | 2019-04-08 |
| US10526388B2 (en) | 2020-01-07 |
| US20180105567A1 (en) | 2018-04-19 |
| TWI714558B (zh) | 2021-01-01 |
| CN113388021A (zh) | 2021-09-14 |
| ES2805829T3 (es) | 2021-02-15 |
| US20200157163A1 (en) | 2020-05-21 |
| US20190062389A1 (en) | 2019-02-28 |
| CA2979168A1 (en) | 2016-09-15 |
| CN107428815B (zh) | 2021-07-09 |
| BR112017018703A2 (pt) | 2018-04-17 |
| EP3269733A4 (en) | 2018-08-01 |
| AU2016230125A1 (en) | 2017-09-21 |
| AU2016230125B2 (en) | 2020-07-16 |
| DK3269733T3 (da) | 2020-07-27 |
| EP3269733A1 (en) | 2018-01-17 |
| RU2714117C2 (ru) | 2020-02-11 |
| TW202115102A (zh) | 2021-04-16 |
| US10590179B2 (en) | 2020-03-17 |
| JP6898225B2 (ja) | 2021-07-07 |
| CN107428815A (zh) | 2017-12-01 |
| RU2017135038A3 (zh) | 2019-08-30 |
| JPWO2016143816A1 (ja) | 2018-03-01 |
| WO2016143816A1 (ja) | 2016-09-15 |
| US10875900B2 (en) | 2020-12-29 |
| EP3269733B1 (en) | 2020-06-17 |
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