TW201438731A - 新穎ctl抗原決定部位5連結肽 - Google Patents
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Abstract
本發明提供一種癌抗原肽,其可在無需HLA型檢查,且不限定於具有特定之HLA型之患者之情況下,作為癌胜肽疫苗而投予廣泛之癌症患者。本發明之CTL抗原決定部位5連結肽係經由連結子將選自報告具有CTL誘導能力之源自腫瘤抗原分子之CTL抗原決定部位肽群中之5個CTL抗原決定部位肽連結而獲得者。
Description
本發明係關於一種作為癌抗原肽有用之新穎肽。更詳細而言,本發明係關於一種將對HLA-A限制性具有CTL誘導能力之5個肽連結而成之新穎癌抗原肽、及利用其之醫藥組合物。
癌症占日本人死亡原因之第1位,一年約有35萬人死亡,目前仍然係嚴重之疾病。作為已確立之癌症治療法,主要有外科切除、抗癌劑治療、及放射線療法。然而,該等療法存在復發、生活品質(Quality of Life,QOL)之降低、進而於無法接受上述治療法之進展期癌症之情形時無治療選項等問題。
癌症免疫療法(癌症疫苗療法)長久以來作為新穎之治療法而備受期待,自可鑑定人類腫瘤抗原中之抗原決定部位肽之1990年起,在全世界範圍內開始了癌胜肽疫苗之臨床研究。但是,基於單獨投予肽或併用療法之臨床研究成果之分析結果,於1,000例以上之投予例中,起效率僅為2.7%(非專利文獻1),而被指摘難以實用化。
另一方面,日本亦長期獨自持續進行使用癌胜肽疫苗之臨床研究,其成果逐漸明確。近年來,作為以提高治療效果為目的之努力之一,亦開始採用投予複數種癌胜肽而非投予一種癌胜肽之策略。例如實施有藉由預先檢查患者之HLA類型及特異性免疫應答而選擇複數種所投予之肽的量身打造型(tailor-made type)癌胜肽疫苗療法,並確認有安全性及抗腫瘤效果。具體而言,藉由單獨投予量身打造型肽疫苗
或與抗癌劑併用,而於腦腫瘤、子宮頸癌、進而攝護腺癌、胰腺癌方面達成了優異之臨床效果及安全性(非專利文獻2、3、4)。
於癌胜肽疫苗療法中,利用被認為是主要效應細胞的抗原決定部位特異性細胞毒殺性T淋巴球(以下,簡稱為CTL)之細胞性免疫為HLA限制性,已實施有僅以具有特定之HLA型、具體而言為對象患者數較多之HLA-A2或HLA-A24之患者作為對象之癌胜肽疫苗開發。
然而,該兩種HLA型之保有率於日本人中分別為約40%、60%(非專利文獻5),而存在具有該兩種以外之HLA型之患者無法得到癌胜肽疫苗之恩惠的問題。並且,於治療開始前需要HLA型檢查,此情況成為延遲治療之開始時期、增大患者負擔之一個原因。據此,業界期待開發/研究出無需HLA型檢查而可適合於所有癌症患者之癌胜肽疫苗。
又,已知於癌胜肽疫苗療法中,除了作為細胞免疫之CTL之活化以外,藉由誘導作為體液性免疫之免疫球蛋白之產生,亦有助於延長壽命效果(非專利文獻6)。
[非專利文獻1]Rosenberg SA et al., Nature Med. 2004, 10(9): 909-15
[非專利文獻2]Terasaki M et al., J Clin Oncol. 2011, 29(3):337-44
[非專利文獻3]Noguchi M et al., Cancer lmmunol. lmmunother. 2010, 59(7):1001-9
[非專利文獻4]Yanagimoto H et al.,Cancer Sci. 2007, 98(4): 605-11
[非專利文獻5]Sette A et al., Immunogenetics. 1999, 50(3-4):201-12
[非專利文獻6]Noguchi M et al., Cancer Biol. Ther. 2011, 10(12):1266-79
本發明之目的在於提供一種癌抗原肽,其可在無需HLA型檢查,且不限定於具有特定之HLA型之患者之情況下,作為癌胜肽疫苗而投予廣泛之癌症患者。
本發明者等人為了解決上述問題進行了努力研究,結果發現:將選自報告有對HLA-A2、HLA-A24、HLA-A26或HLA-A3超型中之任一者、或上述複數種HLA-A限制性具有CTL誘導能力之CTL抗原決定部位肽中之5個肽經由連結子連結而獲得之CTL抗原決定部位5連結肽可在無需HLA型檢查,且不限定於具有特定之HLA型之患者之情況下投予廣泛之癌症患者,進而,藉由投予該CTL抗原決定部位5連結肽,而強烈誘導出對構成該肽之CTL抗原決定部位肽具有特異性之CTL及免疫球蛋白,從而完成本發明。
即,本發明具有以下之特徵。
[1]一種抗原決定部位5連結肽,其係將可重複選自由以下之CTL抗原決定部位肽:序列編號1所表示之肽(PEP])、序列編號2所表示之肽(PEP2)、序列編號3所表示之肽(PEP3)、序列編號4所表示之肽(PEP4)、序列編號5所表示之肽(PEP5)、序列編號6所表示之肽(PEP6)、及序列編號7所表示之肽(PEP7)所組成之群中之5個肽經由連結子分別連結而成者,並且具有選自以下之(1)~(12)中之一個或複數個特徵:(1)包含經由連結子自N末端側起依序使PEP5與PEP2鄰接之序列;(2)包含經由連結子自N末端側起依序使PEP2與PEP4鄰接之序列;(3)包含經由連結子自N末端側起依序使PEP4與PEP6鄰接之序
列;(4)包含經由連結子自N末端側起依序使PEP6與PEP3鄰接之序列;(5)包含經由連結子自N末端側起依序使PEP4與PEP1鄰接之序列;(6)包含經由連結子自N末端側起依序使PEP1與PEP3鄰接之序列;(7)包含經由連結子自N末端側起依序使PEP4與PEP2鄰接之序列;(8)包含經由連結子自N末端側起依序使PEP1與PEP4鄰接之序列;(9)包含經由連結子自N末端側起依序使PEP5與PEP1鄰接之序列;(10)包含經由連結子自N末端側起依序使PEP6與PEP5鄰接之序列;(11)於C末端包含PEP2;以及(12)於C末端包含PEP3。
[2]如[1]之抗原決定部位5連結肽,其於N末端包含自N末端側起依序使PEP5與PEP2、PEP6與PEP5、或PEP4與PEP6經由連結子而鄰接之序列,及/或於C末端包含自N末端側起依序使PEP7與PEP3、PEP4與PEP3、PEP6與PEP3、PEP1與PEP3、PEP5與PEP2、PEP4與PEP2、或PEP5與PEP3經由連結子而鄰接之序列。
[3]如[2]之抗原決定部位5連結肽,其包含選自以下之(a)~(p)中之序列:(a)PEP5-PEP2-PEP4-PEP7-PEP3;(b)PEP5-PEP2-PEP7-PEP3-PEP4;
(c)PEP4-PEP6-PEP5-PEP7-PEP3;(d)PEP5-PEP2-PEP4-PEP6-PEP3;(e)PEP5-PEP2-PEP4-PEP1-PEP3;(f)PEP4-PEP5-PEP2-PEP7-PEP3;(g)PEP7-PEP3-PEP4-PEP5-PEP2;(h)PEP5-PEP7-PEP3-PEP4-PEP2;(i)PEP6-PEP1-PEP4-PEP5-PEP2;(j)PEP6-PEP5-PEP1-PEP4-PEP2;(k)PEP4-PEP5-PEP1-PEP6-PEP3;(l)PEP7-PEP2-PEP4-PEP5-PEP3;(m)PEP4-PEP2-PEP7-PEP5-PEP3;(n)PEP7-PEP2-PEP5-PEP4-PEP3;(o)PEP5-PEP2-PEP7-PEP4-PEP3;或(p)PEP5-PEP2-PEP4-PEP3-PEP7;再者,式中「-」表示連結子。
[4]如[1]至[3]中任一項之抗原決定部位5連結肽,其中連結子為胺基酸連結子。
[5]如[4]之抗原決定部位5連結肽,其中胺基酸連結子係將2個精胺酸連結而成之精胺酸二聚物。
[6]一種CTL,其係藉由使用如[1]至[5]中任一項之抗原決定部位5連結肽來刺激末梢血液淋巴球而獲得者。
[7]一種醫藥組合物,其用於治療或預防癌症,並且含有如[1]至[5]中任一項之抗原決定部位5連結肽、或如[6]之CTL作為有效成分。
[8]如[7]之醫藥組合物,其係免疫療法劑。
本說明書包含作為本申請案之優先權基礎之日本專利申請案2013-047271號之說明書及/或圖式中所記載之內容。
根據本發明,可提供一種癌抗原肽,其可在無需HLA型檢查,且不限定於具有特定之HLA型之患者之情況下,作為癌胜肽疫苗而投予廣泛之癌症患者。
本發明之CTL抗原決定部位5連結肽可在無需HLA型檢查之情況下投予廣泛之癌症患者,例如HLA-A2陽性患者群、HLA-A24陽性患者群、HLA-A26陽性患者群、HLA-A3超型陽性患者群,可治療及/或預防該患者之癌症或由癌症所引起之疾病。又,構成本發明之CTL抗原決定部位5連結肽之腫瘤抗原於複數個癌種類中可見表現,因此本發明之CTL抗原決定部位5連結肽可用作用於治療或預防多種癌種類之醫藥組合物(更詳細而言為免疫療法劑)。進而,藉由投予本發明之抗原決定部位5連結肽,與將構成其之CTL抗原決定部位肽混合並等量投予之情形相比,可強烈誘導出CTL抗原決定部位肽特異性CTL及免疫球蛋白,可更有效率地使抗腫瘤免疫活化。
圖1表示投予抗原決定部位5連結肽之小鼠模型之抗原決定部位特異性CTL誘導結果(*:表示未研究)。
圖2表示投予抗原決定部位5連結肽之小鼠模型之血清中抗原決定部位特異性IgG抗體效價之測定結果。
以下,更具體地說明本發明。
本發明之「抗原決定部位5連結肽」意指將選自源自相同及/或不同之腫瘤抗原分子之CTL抗原決定部位肽中之5個肽經由連結子連結成直鏈狀而形成1個分子之肽。
「源自腫瘤抗原分子之CTL抗原決定部位肽」係腫瘤抗原於腫瘤
細胞內分解所產生之肽,其可藉由與HLA I型分子結合而呈現於細胞表面,從而被腫瘤特異性之CTL識別,及/或,誘導及/或活化腫瘤特異性之CTL。所謂「誘導腫瘤特異性之CTL」意指於活體外(in vitro)或活體內(in vivo)使特異性地識別源自腫瘤抗原分子之CTL抗原決定部位肽之CTL分化及/或增殖。又,所謂「活化腫瘤特異性之CTL」意指藉由CTL識別利用HLA I型分子所呈現之抗原,而產生干擾素-γ(IFN-γ)。於本說明書中,有時將「源自腫瘤抗原分子之CTL抗原決定部位肽」簡稱為「CTL抗原決定部位肽」。
作為本發明中所使用之CTL抗原決定部位肽,可使用公知者,可列舉以下者:PEP1:KLVERLGAA(序列編號1[WO 01/011044]);PEP2:ASLDSDPWV(序列編號2[WO 02/010369]);PEP3:LLQAEAPRL(序列編號3[WO 00/12701]);PEP4:DYSARWNEI(序列編號4[日本專利特開平11-318455號公報]);PEP5:VYDYNCHVDL(序列編號5[WO 00/12701]);PEP6:LYAWEPSFL(序列編號6[日本專利特開2003-000270號公報]);PEP7:QIRPIFSNR(序列編號7[Cancer lmmunol.lmmunother.2007,56(5),689-698])。
於本說明書中,有時將序列編號1所表示之肽稱為「PEP1」,將序列編號2所表示之肽稱為「PEP2」,將序列編號3所表示之肽稱為「PEP3」,將序列編號4所表示之肽稱為「PEP4」,將序列編號5所表示之肽稱為「PEP5」,將序列編號6所表示之肽稱為「PEP6」,將序列編號7所表示之肽稱為「PEP7」。
於本發明中,具有於PEP1、PEP2、PEP3、PEP4、PEP5、
PEP6、及PEP7之各胺基酸序列中有一個或複數個胺基酸經置換、***、缺失、及/或加成之胺基酸序列,且具有與原本之肽同等或其以上之CTL誘導能力、免疫球蛋白產生誘導能力的肽亦可用作「CTL抗原決定部位肽」。此處,所謂「複數個」係指1~3個,較佳為1~2個。作為此種肽,例如可列舉經具有與原本之胺基酸類似之特性之胺基酸置換(即藉由保守性胺基酸置換而獲得)之肽。
PEP1、PEP2、PEP3、PEP4、及PEP5可被HLA-A2限制,PEP2、PEP4、PEP5、及PEP6可被HLA-A24限制,PEP2、PEP4、PEP5、及PEP7可被HLA-A3超型限制,PEP2及PEP5可被HLA-A26限制,而誘導及/或活化CTL。又,編碼該等CTL抗原決定部位肽之基因於複數個癌症種類中確認有表現(Yang D et al.,Cancer Res.1999,59:4056-63,Harashima N et al.,Eur.J.Immunol.2001,31(2),323-32)。
選自(可重複選擇)PEP1、PEP2、PEP3、PEP4、PEP5、PEP6、及PEP7中之5個肽經由連結子分別連結成直鏈狀。
連結子只要為可於將抗原決定部位5連結肽投予活體時被切斷而使所連結之CTL抗原決定部位肽各自分離者即可,例如可列舉:酯鍵、醚鍵、醯胺鍵、糖鏈連結子、聚乙二醇連結子、胺基酸連結子等。作為可用作胺基酸連結子之胺基酸序列,可例示:精胺酸二聚物、離胺酸二聚物、甘胺酸二聚物、甘胺酸五聚物、甘胺酸六聚物、丙胺酸-丙胺酸-酪胺酸(AAY)、異白胺酸-白胺酸-丙胺酸(ILA)、精胺酸-纈胺酸-離胺酸-精胺酸(RVKR)等,較佳為精胺酸二聚物。
關於所選擇之CTL抗原決定部位肽及其連結順序,可將以特定之組合及特定之連結順序合成之抗原決定部位5連結肽投予人類HLA-A轉基因小鼠,並評價於活體內有無各CTL抗原決定部位肽特異性之CTL誘導而決定。
較佳為本發明之抗原決定部位5連結肽具有選自以下之(1)~(12)
中之一個或複數個特徵:(1)包含經由連結子自N末端側起依序使PEP5與PEP2鄰接之序列;(2)包含經由連結子自N末端側起依序使PEP2與PEP4鄰接之序列;(3)包含經由連結子自N末端側起依序使PEP4與PEP6鄰接之序列;(4)包含經由連結子自N末端側起依序使PEP6與PEP3鄰接之序列;(5)包含經由連結子自N末端側起依序使PEP4與PEP1鄰接之序列;(6)包含經由連結子自N末端側起依序使PEP1與PEP3鄰接之序列;(7)包含經由連結子自N末端側起依序使PEP4與PEP2鄰接之序列;(8)包含經由連結子自N末端側起依序使PEP1與PEP4鄰接之序列;(9)包含經由連結子自N末端側起依序使PEP5與PEP1鄰接之序列;(10)包含經由連結子自N末端側起依序使PEP6與PEP5鄰接之序列;(11)於C末端包含PEP2;以及(12)於C末端包含PEP3。
較佳為本發明之抗原決定部位5連結肽
(I)於N末端包含自N末端側起依序使PEP5與PEP2、
PEP6與PEP5、或PEP4與PEP6經由連結子而鄰接之序列,及/或(II)於C末端包含自N末端側起依序使PEP7與PEP3、PEP4與PEP3、PEP6與PEP3、PEP1與PEP3、PEP5與PEP2、PEP4與PEP2、或PEP5與PEP3經由連結子而鄰接之序列。
進而較佳為本發明之抗原決定部位5連結肽包含選自以下之(a)~(p)中之序列,或者由該序列所構成(式中「-」表示連結子):(a)PEP5-PEP2-PEP4-PEP7-PEP3;(b)PEP5-PEP2-PEP7-PEP3-PEP4;(c)PEP4-PEP6-PEP5-PEP7-PEP3;(d)PEP5-PEP2-PEP4-PEP6-PEP3;(e)PEP5-PEP2-PEP4-PEP1-PEP3;(f)PEP4-PEP5-PEP2-PEP7-PEP3;(g)PEP7-PEP3-PEP4-PEP5-PEP2;(h)PEP5-PEP7-PEP3-PEP4-PEP2;(i)PEP6-PEP1-PEP4-PEP5-PEP2;(j)PEP6-PEP5-PEP1-PEP4-PEP2;(k)PEP4-PEP5-PEP1-PEP6-PEP3;(l)PEP7-PEP2-PEP4-PEP5-PEP3;
(m)PEP4-PEP2-PEP7-PEP5-PEP3;(n)PEP7-PEP2-PEP5-PEP4-PEP3;(o)PEP5-PEP2-PEP7-PEP4-PEP3;或(p)PEP5-PEP2-PEP4-PEP3-PEP7。
本發明之抗原決定部位5連結肽針對所連結之5種CTL抗原決定部位肽中之較佳為2種、進而較佳為3種、更佳為4種、最佳為5種CTL抗原決定部位肽,可誘導及/或活化對各CTL抗原決定部位肽具有特異性之CTL,並且可誘導對各CTL抗原決定部位肽具有特異性之免疫球蛋白之產生。再者,此處所謂「免疫球蛋白」意指IgG、IgM、IgA、IgD。
本發明之抗原決定部位5連結肽可藉由慣用之液相合成法、固相合成法等肽合成法、利用自動肽合成儀之肽合成等而製造(Kelley et al.,Genetics Engineering Principles and Methods,Setlow,J.K.eds.,Plenum Press NY.(1990)Vol.12,p.1-19;S tewart et al.,Solid-Phase Peptide Synthesis(1989)W.H.Freeman Co.;Houghten,Proc.Natl.Acad.Sci.USA(1985)82:p.5132,「新生化學實驗講座1蛋白質IV」(1992)日本生化學會編,東京化學同人)。關於肽合成,準備已將各胺基酸之除了欲結合之α-胺基與α-羧基以外之官能基加以保護之胺基酸類,於各胺基酸之α-胺基與α-羧基之間進行形成肽鍵之反應。通常,預先使位於肽之C末端之胺基酸殘基之羧基經由適當之間隔基或連結子而與固相結合。將上述所獲得之二肽之胺基末端之保護基選擇性地去除,於與下一胺基酸之α-羧基之間形成肽鍵。連續地進行此種操作而製造側基經保護之肽,最後去除所有保護基,並自固相分離。關於保護基之種類或保護方法、形成肽鍵之方法之詳情,詳細地記載於上述文獻中。
或者,亦可藉由使用編碼本發明之抗原決定部位5連結肽之核酸
的基因重組法或噬菌體展示法等而製造肽。
基因重組法包括:將編碼本發明之抗原決定部位5連結肽之DNA***至適當之表現載體中,將載體導入至適當之宿主細胞中,培養細胞,自細胞內或細胞外液回收目標肽。載體並無限定,例如為質粒、噬菌體、黏接質體、噬菌粒、病毒等載體。供導入載體之宿主細胞為大腸桿菌或枯草桿菌等細菌、酵母細胞、昆蟲細胞、動物細胞(例如哺乳動物細胞)、植物細胞等,向該等細胞之轉形或轉染例如包括磷酸鈣法、電穿孔法、脂轉染法、粒子槍法、PEG法等。培養轉形細胞之方法係依據宿主生物之培養所使用之通常方法而進行。為了使本發明之肽之回收變得容易,較佳為使藉由表現而生成之肽分泌至細胞外。為此,將編碼可實現自該細胞之肽之分泌之肽序列的DNA結合於編碼目標肽之DNA之5'末端側。或者,亦可回收細胞內所蓄積之目標肽。於該情形時,將細胞以物理或化學方式破壞,並使用蛋白質純化技術而回收目標肽。
所製造之肽可藉由常法、例如凝膠過濾層析法、離子交換管柱層析法、親和層析法、逆相管柱層析法、HPLC等層析法、硫酸銨分離、超過濾、免疫吸附法等進行回收或純化。
可使用本發明之抗原決定部位5連結肽,於活體外獲得對CTL抗原決定部位肽具有特異性且毒殺癌細胞之CTL。使用CTL抗原決定部位肽的CTL之活體外之誘導方法為公知方法(例如日本專利特開2006-14637號公報),本發明中亦可利用該等方法。例如於GM-CSF、IL-4等細胞激素之存在下培養源自健康人或癌症患者之末梢血液單細胞(PBMC)中之板貼壁細胞,而誘導樹狀細胞(DC)。對該樹狀細胞脈衝本發明之抗原決定部位5連結肽後,進行X射線照射,藉此製備抗原呈現細胞(刺激物(stimulator))。於無法使用DC之情形時,亦可使用對
源自健康人或相同癌症之患者之末梢血液單核(PBMC)脈衝本發明之抗原決定部位5連結肽後進行X射線照射而成者。其次,添加源自健康人之末梢血液單細胞(PBMC)或源自癌症患者之末梢血液單細胞(PBMC)或局部淋巴結淋巴球(responder),並於IL-2、IL-4、IL-7等細胞激素之存在下進行培養。其後,進而添加如上所述般脈衝本發明之抗原決定部位5連結肽所獲得之抗原呈現細胞而進行再刺激,並於IL-2等細胞激素之存在下進一步加以培養。
作為誘導CTL所使用之細胞培養用培養基,只要使用T淋巴球可生存之任意培養基即可。例如可使用如下者:於RHAMα培養基(Kawai,K.,Sasaki,T.,Saijo-Kurita,K.,Akaza,H.,Koiso,K.,and Ohno,T.,Cancer Immunol.Immunother.35,225-229,1992中所記載之LAK medium)、AIMV培養基(GIBCO BRL,Life Technologies,INC.)、或RPMI1640培養基等中添加有IL-2等各種細胞激素或胎牛血清(FCS)等者。
培養條件只要依據從業者周知之條件即可。例如將培養溫度設為33℃~41℃,較佳為37℃。又,可使用包含空氣或適當濃度之氧氣、及用於將培養基之pH值保持為約7.4的適當濃度之二氧化碳(例如5%CO2)的惰性氣體作為氣相。培養較佳為4~10天,更佳為7天。藉由進行此種培養而誘導之CTL包含針對構成抗原決定部位5連結肽之5個CTL抗原決定部位肽中之較佳為2種、進而較佳為3種、更佳為4種、最佳為5種CTL抗原決定部位肽具有特異性之CTL,可特異性地毒殺癌細胞。
本發明之抗原決定部位5連結肽可用作癌免疫療法所使用之醫藥組合物之有效成分。
於本發明之醫藥組合物中,可含有上述抗原決定部位5連結肽中
之一種或複數種作為有效成分。藉由含有複數種抗原決定部位5連結肽,可獲得更高之效果。
編碼本發明之抗原決定部位5連結肽中所包含之PEP1、PEP2、PEP3、PEP4、PEP5、PEP6、及PEP7的基因於複數種實體癌及血液癌中可見表現。作為實體癌,例如可列舉:腦腫瘤、肺癌、乳癌、甲狀腺癌、子宮頸癌、子宮體癌、卵巢癌、食道癌、胃癌、GIST(gastrointestinal stromal tumor,胃腸道基質瘤)、胰腺癌、大腸癌、直腸癌、肛門癌、腎癌、肝癌、膽道癌、頭頸癌、膀胱癌、攝護腺癌、惡性黑色素瘤、皮膚癌、舌癌、骨肉瘤、軟骨肉瘤、纖維肉瘤、脂肪肉瘤、血管肉瘤、橫紋肌肉瘤、平滑肌肉瘤等。作為血液癌,例如可列舉:白血病、惡性淋巴瘤、骨髓瘤等。因此,本發明之抗原決定部位5連結肽對該等癌症之治療或預防有用。此處,所謂「癌症之治療或預防」意指預防癌症之產生/復發、抑制癌症之進展/惡化、改善癌症之病狀。
本發明之醫藥組合物可含有作為醫藥上容許之製劑素材而慣用之各種有機或無機之載體物質等。作為可利用之醫藥載體,可例示根據製劑之投予形態而通常使用之穩定化劑、殺菌劑、緩衝劑、等張劑、螯合劑、pH值調整劑、界面活性劑、填充劑、增量劑、結合劑、保濕劑、崩解劑、表面活性劑、潤滑劑、舒緩劑、稀釋劑或賦形劑等,較佳為製備為藉由常法添加有該等之複合劑。
又,本發明之醫藥組合物可含有已知於投予疫苗時使用之佐劑。作為佐劑,可列舉:完全弗氏佐劑(CFA,Complete Freund's adjuvant)、不完全弗氏佐劑(IFA,Incomplete Freund's adjuvant)、明礬、脂質A(Lipid A)、單磷醯脂質A、BCG(Bacillus-Calmette-Guerin,卡介苗)等細菌製劑、結核菌素等細菌成分製劑、鑰孔戚血藍素或酵母甘露聚糖等天然高分子物質、胞壁醯三肽或胞壁醯二肽或其等之衍
生物、明礬(alum)、非離子性嵌段共聚物等,可使用該等中之1種或組合使用2種以上。佐劑可以與本發明之醫藥組合物之混合狀態、或以乳液之形式同時投予而使用。
進而,本發明之醫藥組合物除了上述抗原決定部位5連結肽以外,亦可含有1種公知之源自腫瘤抗原分子之CTL抗原決定部位肽或含有其之肽、或將其等連結而成之肽(以下記載為「公知之源自腫瘤抗原分子之CTL抗原決定部位肽等」),或組合複數種而含有。作為公知之源自腫瘤抗原分子之CTL抗原決定部位肽,例如可列舉:WT-1 p126-134、modified(M236Y)WT-1 p235-243、NY-ESO-1 p157-165、modified(T210M)gp100 p209-217、survivin-2B p80-88、Her-2/neu p63-71、VEGFR2 p169-177、MART-1 p26-35、Glypican-3 p298-306、SPARC p143-151等,但並不限定於該等。於該情形時,本發明之抗原決定部位5連結肽與公知之源自腫瘤抗原分子之CTL抗原決定部位肽等可為一劑型之製劑形態,亦可使含有本發明之抗原決定部位5連結肽作為有效成分之製劑與含有公知之源自腫瘤抗原分子之CTL抗原決定部位肽等作為有效成分之製劑為分開之製劑形態。
本發明之醫藥組合物可根據投予形態而選擇製劑形態。作為具代表性之製劑形態,可製作溶液劑、乳劑、脂質體製劑、脂肪乳劑、環糊精等之包藏體、懸浮劑、軟膏劑、乳霜劑、經皮吸收劑、經黏膜吸收劑、錠劑、丸劑、膠囊劑、散劑、粉末劑、顆粒劑、細粒劑、糖漿劑等,但並不限定於該等。該等進而可根據投予途徑而分為經口劑、非經口劑、經鼻劑、經***劑、栓劑、舌下劑、吸入劑、滴眼劑、滴耳劑等,各自可依據通常方法進行調配、成形及製備。又,除了可以溶液製劑之形式使用以外,亦可於形成可冷凍乾燥化而保存之狀態後,於使用時利用含有水或生理鹽水等之緩衝液等進行溶解而製備成適當濃度後使用。
又,本發明之醫藥組合物亦可含有使用上述本發明之抗原決定部位5連結肽於活體外所誘導之CTL作為有效成分。此種醫藥組合物較佳為非經口劑之形態。
本發明之醫藥組合物可投予廣泛之癌症患者,例如選自由HLA-A2、HLA-A24、HLA-A26及HLA-A3超型所組成之群中之HLA型陽性患者群,且於治療開始前無需HLA型檢查便可開始治療。
本發明之醫藥組合物藉由投予癌症患者,可誘導及/或活化對構成作為有效成分而含有之抗原決定部位5連結肽之2種以上、較佳為3種以上、更佳為4種以上、進而較佳為5種CTL抗原決定部位肽具有特異性之CTL,並且可誘導對該CTL抗原決定部位肽具有特異性之免疫球蛋白之產生。藉由投予作為有效成分而含有之抗原決定部位5連結肽所進行之免疫球蛋白產生之誘導,顯著高於不使抗原決定部位5連結肽中所包含之CTL抗原決定部位肽連結而各自混合並投予之情形時可見之免疫球蛋白產生之誘導,因此,本發明之抗原決定部位5連結肽可有效率地治療或預防癌症患者之癌症。
本發明之醫藥組合物可藉由經口投予、靜脈投予、動脈投予、肌內投予、皮下投予、皮內投予、舌下投予、腹腔內投予、直腸內投予、經皮投予、經黏膜投予、經鼻投予、經***投予、經眼投予、吸入投予等進行投予。於將含有複數種抗原決定部位5連結肽、及公知之源自腫瘤抗原分子之CTL抗原決定部位肽等作為有效成分之製劑分別製成個別之醫藥組合物之情形時,各醫藥組合物可以相同或不同之投予途徑,同時或非同時地進行投予。
本發明之醫藥組合物之投予量可根據所治療之癌症之狀態/嚴重度、各患者之年齡、體重等要因而適當調整,較佳為將以抗原決定部位5連結肽之量計含有0.0001mg~1000mg、較佳為0.001mg~100
mg、更佳為0.01mg~50mg之醫藥組合物隔數日、數週或數月投予一次並反覆投予。又,於本發明之醫藥組合物含有使用本發明之抗原決定部位5連結肽於活體外所誘導之CTL作為有效成分之情形時,較佳為以1週~2週之間隔每天每1kg體重投予2×106~2×108個CTL。
本發明之醫藥組合物亦可與一般用於癌症化學治療之醫藥品併用而投予癌症患者。例如可列舉:環磷醯胺、替莫唑胺、苯達莫司汀等烷化劑;喃氟啶-尿嘧啶複合劑、喃氟啶-吉莫斯特-奧替拉西鉀複合劑、胺甲喋呤、吉西他濱等代謝拮抗劑;順鉑、奧沙利鉑等鉑製劑;伊立替康、埃立布林、紫杉醇、歐洲紫杉醇、長春新鹼等植物生物鹼製劑;多柔比星、博來黴素、放射菌素D等抗癌性抗生物質;伊馬替尼、舒尼替尼、吉米沙星、索拉非尼、依維莫司、曲妥珠單抗、貝伐單抗、利妥昔單抗、西妥昔單抗、帕尼單抗、莫加木珠單抗(Mogamulizumab)等分子靶向治療劑;比卡魯胺、雌莫司汀、依西美坦等激素療法製劑等。該等醫藥品可以與本發明之醫藥組合物相同或不同之投予途徑,同時或非同時地進行投予。
以下,藉由實施例具體地說明本發明,但本發明不受該等實施例之限定。
CTL抗原決定部位肽、及抗原決定部位5連結肽係使用市售之肽合成儀Prelude(Protein Technologies,Inc.)並藉由固相合成法(Fmoc法)而合成。所獲得之各種合成肽係利用YMC-Pack Pro C18管柱(YMC Co.,Ltd.)及HPLC系統(Gilson)進行純化,於冷凍乾燥後保存於低溫陰暗處,供於以後所示之實施例。
將所合成之CTL抗原決定部位肽之胺基酸序列示於表1,將抗原決定部位5連結肽之胺基酸序列示於表2。
再者,合成WT1(序列編號8)作為與HLA-A2結合之對照肽,合成Her2(序列編號9)作為與HLA-A24結合之對照肽。
將抗原決定部位5連結肽利用大塚蒸餾水(大塚製藥工廠)製備成2mg/mL或4mg/mL,並填充至B Braun Injekt注射器中。於另一注射器中填充等量之不完全弗氏佐劑(IFA)後,利用GP注射器連接器將兩注射器連接,並使抗原決定部位5連結肽溶液與IFA充分混合,藉此製備乳液。將其於小鼠(HLA-A2.1 transgenic,HLA-A24 transgenic(Taconic))之尾根部周邊每次100μL每週1次共計投予2次。於最終投予1週後,自小鼠回收鼠蹊部淋巴結。將淋巴結細胞懸浮液利用完全培養基(Complete Medium)(RPMI-1640、10%熱滅活之FBS、100U/mL之青黴素(Penicillin)、100μg/mL之鏈黴素(Streptomycin)、50μM之2-巰基乙醇)製備成5×106cells/mL,分別添加標靶CTL抗原決定部位肽(最終濃度10μg/mL)、小鼠重組IL-15(最終濃度100ng/mL)、小鼠重組IL-21(最終濃度100ng/mL)並以1mL/well接種至24孔板(well plate)後,於37℃、5%CO2培養箱內培養8天。8天後,回收細胞並以1×105cells/well接種至Murine IFN-γ ELISpot Kit(GEN-PROBE)隨附之anti IFN-γ抗體固相化板。繼而,將由同系小鼠脾臟製備並照射30Gy之X射線後之脾臟細胞作為抗原呈現細胞以1×105cells/well接種至同一孔後,添加標靶CTL抗原決定部位肽或陰性對照肽(最終濃度10μg/mL),並於37℃、5%CO2培養箱內培養一晚。次日,依據套組之隨附資料,使IFN-γ產生細胞點顯色。IFN-γ產生細胞點數係利用ELISPOT分析儀(Immunospot S6,Cellular Technology Ltd.)進行定量。關於CTL抗原決定部位肽特異性CTL之誘導,於藉由該試驗所獲得之標靶CTL抗原決定部位肽添加孔之IFN-γ產生細胞點數與陰性對照肽添加孔之IFN-γ產生細胞點數相比明顯較高(Student's t-test,p<
0.05)之情形時,判斷為陽性。再者,陰性對照肽係使用WT1或Her2。進而,為了使CTL誘導強度可視化,於設為(標靶CTL抗原決定部位肽添加孔之平均IFN-γ產生細胞點數)-(陰性對照肽添加孔之平均IFN-γ產生細胞點數)=△時,將10≦△<100之情形表示為陽性,將100≦△<200之情形表示為中陽性,將200≦△之情形表示為強陽性。
將CTL抗原決定部位肽特異性CTL誘導之研究結果示於圖1。如圖1所示,抗原決定部位5連結肽中之任一序列為PEP5-RR-PEP2或PEP4-RR-PEP2、或者抗原決定部位5連結肽之C末端為PEP3的抗原決定部位5連結肽顯示出至少3種以上之CTL誘導。另一方面,於如TPV18之連結順序之5連結體中未顯示出2種以上之CTL誘導。
由以上之結果明確,即便對小鼠投予將已知之CTL抗原決定部位肽經由精胺酸二聚物連結而成之抗原決定部位5連結肽,亦並非對所有CTL抗原決定部位肽必定可誘導抗原決定部位特異性CTL。
根據以下之順序,將肽固相化於xMAP Multi-Analyte COOH Microspheres(Luminex corporation,以下稱為珠粒)上。利用MES緩衝液(0.1M之MES-NaOH,pH值7.0)清洗珠粒後,藉由離心分離而去除上清液。重複兩次上述操作後,使珠粒懸浮於75μL之MES緩衝液中。向其中添加製備成1mg/mL之CTL抗原決定部位肽溶液100μL,進而添加10mg/mL之EDC(1-乙基-3-(3-二甲胺基丙基)碳二亞胺鹽酸鹽)5μL並充分混合後,於30℃下、陰暗處反應一晚。次日,藉由離心分離而去除上清液後,添加1M之Tris-HCl 125μL,並於30℃下、陰暗處培養30分鐘。去除上清液後,利用洗滌緩衝液(PBS(-),0.05% Tween20)清洗兩次後,懸浮於Immunoblock(DS Pharma Biomedical)中,藉此完成CTL抗原決定部位肽之固相化。
將本發明之抗原決定部位5連結肽利用大塚蒸餾水(大塚製藥工廠)製備成2mg/mL,並填充至B Braun Injekt注射器中。於另一注射器中填充等量之IFA後,利用GP注射器連接器將兩注射器連接,並使該抗原決定部位5連結肽溶液與IFA充分混合,藉此製備乳液。將其於CBF1小鼠(C57BL/6×Balb/c F1)之尾根部周邊每次100μL每週1次共計投予3次。於最終投予1週後,自小鼠採血而獲得血清樣品。作為對照群,使用PEP2、PEP3、PEP4、PEP5、PEP7之各肽混合物(各1mg/mL)而製備乳液,並以與抗原決定部位5連結肽相同之排程進行投予(混合物投予群)。
於96孔濾板中分注利用Immunoblock進行稀釋之固相化有CTL抗原決定部位肽之珠粒,並利用洗滌緩衝液進行清洗後,以100μL/well添加利用Immunoblock稀釋200倍之小鼠血清樣品。將板於30℃培養箱中一面以600rpm攪拌,一面培養90分鐘。利用洗滌緩衝液清洗3次後,以100μL/well添加利用Immunoblock稀釋500倍之生物素化抗小鼠IgG(H+L)(Vector Labolatories),並於30℃、600rpm之攪拌條件下培養60分鐘。利用洗滌緩衝液清洗3次後,以100μL/well添加利用Immunoblock稀釋500倍之卵白素R-藻紅素複合物(Invitrogen),並於30℃、600rpm之攪拌條件下培養30分鐘。利用洗滌緩衝液清洗3次後,以100μL/well添加洗滌緩衝液而使珠粒懸浮,其後利用Bio-Plex懸浮陣列系統(BIO-RAD)測定各珠粒特異性地結合之PE色素之平均螢光強度。
CTL抗原決定部位特異性IgG抗體效價之測定結果如圖2所示。再者,圖2中表示與陰性對照群(以下簡稱為IFA群)之血清中CTL抗原決定部位特異性IgG抗體效價測定結果相比,誘導出多少倍之該IgG抗體之產生,該陰性對照群係製備將IFA與大塚蒸餾水(大塚製藥工廠)等量混合而成之乳液,並以與CTL抗原決定部位肽混合物或抗原決定部
位5連結肽相同之排程投予小鼠。
如圖2所示,混合物投予群與IFA群相比,未見CTL抗原決定部位特異性IgG抗體產生之誘導。另一方面,判明於投予抗原決定部位5連結肽之情形時可見高頻度且較強之CTL抗原決定部位特異性IgG抗體產生之誘導,進而,該IgG之產生量根據所投予之抗原決定部位5連結肽而被顯著誘導至數十倍至百倍以上。另一方面,對於如TPV17之連結順序之5連結體,未見複數種CTL抗原決定部位特異性IgG抗體產生之誘導。
以上之結果顯示,藉由投予抗原決定部位5連結肽,與將構成該抗原決定部位5連結肽之CTL抗原決定部位肽混合並投予之情形相比,抗腫瘤免疫被較強地活化。
接受癌胜肽疫苗治療之癌症患者之CTL抗原決定部位肽特異性IgG產生之誘導與抗原決定部位肽特異性CTL之誘導共同有助於延長壽命效果。因此,本發明與如包含已知之CTL抗原決定部位肽或其混合物之癌胜肽疫苗療法相比可產生優異之延長壽命效果。因此,本發明之抗原決定部位5連結肽與如包含已知之CTL抗原決定部位肽或其混合物之癌胜肽疫苗療法相比可提高治療效果,可適宜地用作癌症或由癌症引起之疾病之治療劑及/或預防劑、癌胜肽疫苗。
將本說明書中所引用之所有出版物、專利及專利申請直接作為參考而併入本說明書中。
<110> 日本大鵬藥品工業股份有限公司
<120> 新穎CTL抗原決定部位5連結肽
<130> PH-5795TW
<150> JP 2013-047271
<151> 2013-03-08
<160> 27
<170> PatentIn第3.5版
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Claims (8)
- 一種抗原決定部位5連結肽,其係經由連結子將可重複選自由以下之CTL抗原決定部位肽:序列編號1所表示之肽(PEP1)、序列編號2所表示之肽(PEP2)、序列編號3所表示之肽(PEP3)、序列編號4所表示之肽(PEP4)、序列編號5所表示之肽(PEP5)、序列編號6所表示之肽(PEP6)、及序列編號7所表示之肽(PEP7)所組成之群中之5個肽分別連結而成者,並且具有選自以下之(1)~(12)中之一個或複數個特徵:(1)包含經由連結子自N末端側起依序使PEP5與PEP2鄰接之序列;(2)包含經由連結子自N末端側起依序使PEP2與PEP4鄰接之序列;(3)包含經由連結子自N末端側起依序使PEP4與PEP6鄰接之序列;(4)包含經由連結子自N末端側起依序使PEP6與PEP3鄰接之序列;(5)包含經由連結子自N末端側起依序使PEP4與PEP1鄰接之序列;(6)包含經由連結子自N末端側起依序使PEP1與PEP3鄰接之序列;(7)包含經由連結子自N末端側起依序使PEP4與PEP2鄰接之序列;(8)包含經由連結子自N末端側起依序使PEP1與PEP4鄰接之序列;(9)包含經由連結子自N末端側起依序使PEP5與PEP1鄰接之序 列;(10)包含經由連結子自N末端側起依序使PEP6與PEP5鄰接之序列;(11)於C末端包含PEP2;以及(12)於C末端包含PEP3。
- 如請求項1之抗原決定部位5連結肽,其於N末端包含自N末端側起依序使PEP5與PEP2、PEP6與PEP5、或PEP4與PEP6經由連結子而鄰接之序列,及/或於C末端包含自N末端側起依序使PEP7與PEP3、PEP4與PEP3、PEP6與PEP3、PEP1與PEP3、PEP5與PEP2、PEP4與PEP2、或PEP5與PEP3經由連結子而鄰接之序列。
- 如請求項2之抗原決定部位5連結肽,其包含選自以下之(a)~(p)中之序列:(a)PEP5-PEP2-PEP4-PEP7-PEP3;(b)PEP5-PEP2-PEP7-PEP3-PEP4;(c)PEP4-PEP6-PEP5-PEP7-PEP3;(d)PEP5-PEP2-PEP4-PEP6-PEP3;(e)PEP5-PEP2-PEP4-PEP1-PEP3;(f)PEP4-PEP5-PEP2-PEP7-PEP3;(g)PEP7-PEP3-PEP4-PEP5-PEP2;(h)PEP5-PEP7-PEP3-PEP4-PEP2;(i)PEP6-PEP1-PEP4-PEP5-PEP2;(j)PEP6-PEP5-PEP1-PEP4-PEP2;(k)PEP4-PEP5-PEP1-PEP6-PEP3;(l)PEP7-PEP2-PEP4-PEP5-PEP3;(m)PEP4-PEP2-PEP7-PEP5-PEP3;(n)PEP7-PEP2-PEP5-PEP4-PEP3; (o)PEP5-PEP2-PEP7-PEP4-PEP3;或(p)PEP5-PEP2-PEP4-PEP3-PEP7;再者,式中「-」表示連結子。
- 如請求項1至3中任一項之抗原決定部位5連結肽,其中連結子為胺基酸連結子。
- 如請求項4之抗原決定部位5連結肽,其中胺基酸連結子係將2個精胺酸連結而成之精胺酸二聚物。
- 一種CTL,其係藉由使用如請求項1至5中任一項之抗原決定部位5連結肽來刺激末梢血液淋巴球而獲得者。
- 一種醫藥組合物,其用於治療或預防癌症,並且含有如請求項1至5中任一項之抗原決定部位5連結肽、或如請求項6之CTL作為有效成分。
- 如請求項7之醫藥組合物,其係免疫療法劑。
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US20080286228A1 (en) | 1995-10-20 | 2008-11-20 | Tarantolo Stefano R | Compositions and methods for enhancing immune responses mediated by antigen-presenting cells |
ATE406913T1 (de) * | 1996-03-10 | 2008-09-15 | Meiji Dairies Corp | Auf peptiden basierendes immunotherapeutisches mittel gegen allergien |
JP4138073B2 (ja) | 1998-05-08 | 2008-08-20 | 株式会社グリーンペプタイド | ヒト癌退縮抗原タンパク質 |
WO2000012701A1 (fr) | 1998-08-28 | 2000-03-09 | Sumitomo Pharmaceuticals Company, Limited | Nouvelle proteine d'antigene tumoral sart-3 et peptide d'antigene tumoral de celle-ci |
US6667037B1 (en) * | 1998-10-09 | 2003-12-23 | Ludwig Institute For Cancer Research | Isolated peptides which bind to HLA-B35 molecules, larger peptides which contain these, nucleic acid molecules encoding peptides, and uses thereof |
US6660843B1 (en) | 1998-10-23 | 2003-12-09 | Amgen Inc. | Modified peptides as therapeutic agents |
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WO2001011044A1 (en) | 1999-08-05 | 2001-02-15 | Kyogo Itoh | Tumor antigen |
KR20020047249A (ko) | 1999-10-19 | 2002-06-21 | 에드워드 에이. 맥더모트, 주니어 | Mage-a12 항원성 펩티드 및 그의 용도 |
CA2393730A1 (en) * | 1999-12-13 | 2001-06-14 | Epimmune Inc. | Hla class i a2 tumor associated antigen peptides and vaccine compositions |
JP2002008491A (ja) * | 2000-06-27 | 2002-01-11 | Matsushita Electric Works Ltd | スイッチ装置 |
ES2304398T3 (es) | 2000-07-31 | 2008-10-16 | Green Peptide Co., Ltd. | Antigeno de tumores. |
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ATE441713T1 (de) | 2002-09-27 | 2009-09-15 | Dainippon Sumitomo Pharma Co | Tumorantigenprotein und dessen verwendung |
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CA2804127A1 (en) | 2010-07-07 | 2012-01-12 | Green Peptide Co., Ltd. | Cancer peptide vaccine |
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CN105008399B (zh) | 2018-09-28 |
JPWO2014136814A1 (ja) | 2017-02-16 |
KR101851666B1 (ko) | 2018-04-24 |
RU2015142659A (ru) | 2017-04-13 |
CA2901984A1 (en) | 2014-09-12 |
RU2627175C2 (ru) | 2017-08-03 |
EP2966092A4 (en) | 2016-11-16 |
MX2015011257A (es) | 2015-11-16 |
US20160017014A1 (en) | 2016-01-21 |
KR20150125652A (ko) | 2015-11-09 |
AU2014227019A1 (en) | 2015-09-03 |
WO2014136814A1 (ja) | 2014-09-12 |
AU2014227019B2 (en) | 2016-10-27 |
JP6077641B2 (ja) | 2017-02-08 |
EP2966092A1 (en) | 2016-01-13 |
BR112015021162A2 (pt) | 2017-10-10 |
HK1215440A1 (zh) | 2016-08-26 |
US9701729B2 (en) | 2017-07-11 |
TWI561243B (zh) | 2016-12-11 |
CN105008399A (zh) | 2015-10-28 |
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