TW201803898A - 包含腫瘤相關抗原l6之b細胞抗原決定位之免疫原胜肽 - Google Patents
包含腫瘤相關抗原l6之b細胞抗原決定位之免疫原胜肽 Download PDFInfo
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Landscapes
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Abstract
本揭露關於一種包含序列CLDSLGQWN (SEQ ID NO：2)之免疫原胜肽，以及使用此胜肽治療癌症之方法。
Description
本揭露係關於一種免疫原胜肽，尤指一種包含腫瘤相關抗原L6之B細胞抗原決定位之免疫原胜肽。
腫瘤相關抗原L6(tumor-associated antigen L6，TAL6)是四穿膜超
家族(transmembrane-4 superfamily，TM4SF)的細胞表面蛋白，也稱為TM4SF1。 TM4SF蛋白在不同類型的人類癌症中過度表現，包括肺癌、乳癌、結腸癌、前列腺癌和肝癌。TM4SF1-、TM4SF4-和TM4SF5專一性單株抗體可抑制結腸癌生長，表示TM4SF蛋白是癌症治療的關鍵標的。TAL6在人類肺、乳、結腸和卵巢腫瘤中有超過80％的過度表現，但在正常組織中並無此現象。最近研究發現TAL6在癌細胞移動、侵犯、轉移和血管生成中具關鍵角色。先前研究已證實TAL6的HLA-A2限制性毒殺性T淋巴細胞(cytotoxic T lymphocytes, CTL)抗原決定位A2-5胜肽，能夠誘發 CTL反應，以抑制表現TAL6的癌細胞生長。此外，被誘發的CTL被轉入免疫功能受損小鼠中，可以抑制人類肺癌細胞在免疫功能受損小鼠的生長。
於本揭露的一態樣中，提供一免疫原胜肽，其包含序列CLDSLGQWN (SEQ ID NO：2)，其中，胜肽具有100個或更少之胺基。在一實施例中，胜肽具有序列X1
X2
X3
X4
X5
X6
X7
CLDSLGQWNX8
X9
X10
X11
(SEQ ID NO：3)，其中，X1
至X11
各自為胺基酸(例如，20個標準胺基酸之一)。舉例而言，胜肽可包括序列GLAEGPLCLDSLGQWNYTFA (SEQ ID NO：4)。在一實施例中，胜肽更包括TAL6的細胞毒性T淋巴球(cytotoxic T lymphocyte，CTL)抗原決定位或輔助T細胞(helper T cell，Th)抗原決定位。在另一實施例中，胜肽包含序列AKFVAAWTLKAAAAAALLMLLPAFVAAAGLAEGPLCLDSLGQWNYTFA (SEQ ID NO：9)。
於本揭露的另一態樣中，提供一核酸分子，其包含一序列，其編碼出本文所述免疫原胜肽。
於本揭露的另一態樣中，提供一含有免疫原胜肽之免疫原組合物。免疫原組合物可更包括一佐劑。佐劑可選自由不完全弗氏佐劑(incomplete Freund's adjuvant，IFA)、DOTAP、PELC、及含有非甲基化CpG之去氧寡核苷酸(CpG)所組成之群組。在一實施例中，CpG為類鐸受體9(Toll-like receptor 9，TLR9)之促效劑。在一實施例中，免疫原組合物包括PELC和CpG。
於本揭露的一態樣中，提供一治療所需主體的癌症的方法。此方法包含向主體施用本揭露所述之免疫原組合物。
本揭露的一或多個實施例將以附圖及下文加以說明。實施例的其他特徵、目的及優點，將由下文及圖示、及申請專利範圍更加明瞭。
TAL6意外被發現含有可在體內誘發抗體依賴性細胞毒性(antibody-dependent cellular cytotoxicity ，ADCC)和抗腫瘤作用之B細胞抗原決定位。
以下係為TAL6(SEQ ID NO：1)之胺基酸序列： MCYGKCARCI GHSLVGLALL CIAANILLYF PNGETKYASE NHLSRFVWFF SGIVGGGLLM LLPAFVFIGL EQDDCCGCCG HENCGKRCAM LSSVLAALIG IAGSGYCVIV AALGLAEGPL CLDSLGQWNY TFASTEGQYL LDTSTWSECT EPKHIVEWNV SLFSILLALG GIEFILCLIQ VINGVLGGIC GFCCSHQQQY DC
TAL6 包含兩個細胞外環，例如EL1 (SEQ ID NO： 1之a.a. 31至 a.a. 46 ) 以及 EL2 (SEQ ID NO： 1之a.a. 114至 a.a. 164 )。B細胞抗原決定位位於EL2中。
因此，本揭露提供一種包含抗原決定位的免疫原胜肽，此抗原決定位包含序列CLDSLGQWN(SEQ ID NO：2)。此免疫原胜肽可具有100個或更少之胺基酸(例如，9、10、11、12、13、14、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或100個胺基酸)。
此胜肽可具有序列X1
X2
X3
X4
X5
X6
X7
CLDSLGQWNX8
X9
X10
X11
(SEQ ID NO：3)，其中，X1
至X11
各自為一胺基酸。「胺基酸」一詞係指20個標準胺基酸(即丙胺酸(alanine)、精胺酸(arginine)、天冬醯胺(asparagine)、天冬胺酸(aspartic acid)、半胱胺酸(cysteine)、谷胺醯胺(glutamine)、谷胺酸(glutamic acid)、甘胺酸(glycine)、組胺酸(histidine)、異亮胺酸(isoleucine)、亮胺酸(leucine)、賴胺酸(lysine)、甲硫胺酸(methionine)、苯丙胺酸(phenylanaline)、脯胺酸(praline)、絲胺酸(serine)、蘇胺酸(threonine)、色胺酸(tryptophan)、酪胺酸(tyrosine)和纈胺酸(valine))的任何一個。「胺基酸」一詞還可以指非標準的，非蛋白質的或化學修飾的胺基酸，或胺基酸類似物。
在一實施例中，免疫原胜肽具有序列GLAEGPLCLDSLGQWNYTFA (SEQ ID NO： 4)。
免疫原胜肽可為包含前述TAL6的B細胞抗原決定位以及一或多個其他胜肽片段的嵌合肽。例如，嵌合肽可更包含非TAL6抗原抗原決定位或輔助T細胞刺激抗原決定位其中之一或兩者皆有。嵌合肽還可包含TAL6的另一抗原決定位(例如另一B細胞抗原決定位或T細胞抗原決定位)。美國專利第8465756號中描述了TAL6的抗原決定位的例子。
其他可存在於嵌合肽中的胜肽片段，包含一或多個親和標籤(affinity tag，例如FLAG、 poly-His、 Myc、 HA、 CBP、 HBH、 或 V5)、一訊息序列(signal sequence，例如，前導序列或定位訊息)、一標靶胜肽(targeting peptide，用於將嵌合肽標靶至特定細胞、細胞位置或組織)、一配體(例如受體配體)以及治療性胜肽。
在一實施例中，嵌合肽含有SEQ ID NO：2、3或4的序列，以及TAL6的細胞毒性T淋巴球(cytotoxic T lymphocyte，CTL)抗原決定位和輔助T細胞(Th)抗原決定位其中之一或兩者皆有。
CTL抗原決定位可為LLMLLPAFV(SEQ ID NO：5)或RFVWFFSGI(SEQ ID NO：6)。 Th抗原決定位可為PADRE胜肽，例如AKFVAAWTLKAAA(SEQ ID NO：7)、或來自破傷風類毒素的胜肽，例如AQYIKANSKFIGITEL(SEQ ID NO：8)。嵌合肽的例子，可具有序列AKFVAAWTLKAAAAAALLMLLPAFVAAAGLAEGPLCLDSLGQWNYTFA(SEQ ID NO：9)。嵌合肽中的抗原決定位可以以任何順序排列。
連接子，例如包含1、 2、 3、 4、 5、 6、 7、 8、 9、 10、 11、 12、 13、 14、或15個胺基酸的柔性連接子，為可連接嵌合肽中兩相鄰的胜肽片段。本領域中具有通常知識者可設計合適的連接子。
可使用已知方法來製備免疫原胜肽，例如化學合成或重組技術。
免疫原胜肽還可與一或多個非胜肽片段共軛連結，以形成免疫原胜肽複合物。非胜肽片段包括核酸分子、抗體、蛋白質、碳水化合物、可檢測的標記(例如螢光、放射性或酶標記)、小分子藥物、聚合物(例如聚乙二醇)、固體支持物(例如珠或奈米顆粒)、植物萃取物成分和微生物成分。於胜肽合成時還可以進行其他修飾，例如修飾側鏈、胺基酸取代、非天然胺基酸及/或其衍生物的併入，以增加如免疫原胜肽的穩定性及/或在生物體內功效。
由於上述免疫原胜肽包括TAL6的B細胞抗原決定位(一種癌抗原)，因此可用於增強對TAL6陽性癌症(例如肺癌、結腸癌、乳癌、卵巢癌、胃癌、卡波西氏肉瘤、肝癌、胰臟癌、子宮頸癌、子宮內膜癌、頭頸癌、卵巢癌或前列腺癌)的免疫反應(例如抗體依賴性細胞毒性反應)。
免疫原胜肽或能夠表現免疫原胜肽的表現載體可與藥學上可接受的載體混合以形成一免疫原組合物。此組合物可施用於有需要的主體以治療癌症或增強免疫反應。
組合物可以藥學上可接受的載體，如磷酸鹽緩衝液、碳酸氫鹽溶液及/或佐劑配製。合適的藥物載體和稀釋劑以及其使用的藥劑輔料為本領域已知的。組合物可製備成可注射的液體溶液、乳液或其他合適的劑型。
佐劑的例子包括但不限於，明礬沉澱物、弗氏完全佐劑、不完全弗氏佐劑、單磷醯脂質A/海藻糖二霉菌酸酯佐劑(monophosphoryl-lipid A/trehalose dicorynomycolate adjuvant)、含有短棒菌(Corynebacterium parvum)和tRNA的油包水乳劑、以及其他物質，其可藉由模擬特定演化保留分子，包括脂質體、脂多醣(LPS)、抗原分子籠、細菌細胞壁成分和內噬核酸(如雙股RNA、單股DNA和含未甲基化的CpG二核苷酸的DNA)以增加免疫反應的物質。其他例子包括霍亂毒素、大腸桿菌不耐熱腸毒素、脂質體、免疫刺激複合物(immune-stimulating complex、ISCOM)、免疫刺激序列寡脫氧核苷酸(immunostimulatory sequences oligodeoxynucleotide)和氫氧化鋁。組合物還可包括促進體內釋放的聚合物。
在一實施例中，佐劑為不完全弗氏佐劑(IFA)、DOTAP或DOTAP鹽、PELC(為含有生物可再吸收聚合物、Span®
85和角鯊烯的乳劑型佐劑)、或含未甲基化的CpG的寡脫氧核苷酸(unmethylated CpG-containing oligodeoxynucleotide ，CpG )，例如，類鐸受體9(TLR9)促效劑。在免疫原組合物中可包括一或多種佐劑的組合。
TLR9 CpG促效劑包括但不限於5’-tcgtcgttttgtcgttttgtcgtt-3’ (SEQ ID NO： 10)、5’-ggGGGACGATCGTCgggggg-3’ (SEQ ID NO： 11)、5’-gggGACGACGTCGTGgggggg-3’ (SEQ ID NO： 12)、5’-tcgcgacgttcgcccgacgttcggta-3’ (SEQ ID NO： 13)、5’-tcgtcgttttcggcgcgcgccg-3’ (SEQ ID NO： 14)、5’-tcgtcgtcgttcgaacgacgttgat-3’ (SEQ ID NO： 15)、以及 5’-tcgcgaacgttcgccgcgttcgaacgcgg-3’ (SEQ ID NO： 16)。大寫字母的鹼基是磷酸二酯。小寫字母的鹼基是硫代磷酸酯。
有效劑量的免疫原組合物可經腸胃外施用，例如皮下注射或肌內注射。或者，包括栓劑和口服製劑等其他施用方式也是可能的施用方式。對於栓劑、黏合劑和載體可包括，例如聚亞烷基二醇或三酸甘油酯。口服製劑可包括通常使用的初劑(incipient)，例如藥物級糖精、纖維素、碳酸鎂及其相似物。這些組合物為溶液、懸浮液、片劑、丸劑、膠囊、緩釋製劑或粉劑的形式。
下述特定實施例僅為了說明，而不以任何形式限制本揭露的其他部分。雖未進一步說明，本技術領域者仍可依照本文所述，將本揭露做最大的應用。本文所引用的所有文獻均全部併入本揭露以供參酌。
實施例
[用於治療癌症的抗原胜肽]
腫瘤相關抗原L6(tumor-associated antigen L6，TAL6)的B細胞抗原決定位被認為可在生物體內誘發抗體依賴性細胞毒性(antibody-dependent cellular cytotoxicity，ADCC)。將B細胞抗原決定位與細胞毒性T淋巴細胞(CTL)及輔助T細胞(Th)抗原決定位結合以形成嵌合肽。嵌合肽與不同的佐劑配製以免疫HLA-A2基因轉殖小鼠，並評估其免疫性。與乳劑型奈米顆粒(PELC)佐劑和類鐸受體9促效劑(即，含未甲基化的CpG的寡脫氧核苷酸，CpG)配製的嵌合肽，可誘發最大程度的ADCC和CTL反應。被誘發的抗腫瘤免疫反應可抑制TAL6陽性癌細胞的生長。此外，嵌合肽的免疫作用能夠抑制體外癌細胞遷移和體內轉移。這些數據指出，以PELC/CpG佐劑配製的包含TAL6的B和T細胞抗原決定位的嵌合肽可用於癌症免疫治療。
[鑑定TAL6的B細胞抗原決定位]
使用三種純化的抗TAL6單株抗體(1F4、9C7、L6)檢測TAL6在EL-4 (EL-4/L6)細胞表面上的表現。請參考Chang等人，Int J Cancer， 116 (2005) 243-252。連續稀釋的單株抗體可結合EL-4/L6細胞，但無法與負控制組EL-4細胞(數據未顯示)結合，證實這三種單株抗體識別TAL6的細胞外結構域。為了進一步定位抗體結合抗原決定位，使用涵蓋EL1和EL2細胞外環的五種胜肽(EL1和EP1至4)，並以ELISA來確定線性B細胞抗原決定位。請參考圖1A。單株抗體1F4和9C7無法識別這些胜肽。相比之下，EP1胜肽可被L6 mAb測得。請參考圖 1B。
為了測試EP1胜肽是否能產生可結合天然TAL6的抗體，對C57BL/6小鼠施用以IFA/Th配製的EP1胜肽或MCF-7/L6細胞(作為正控制組)。收集來自免疫接種的小鼠的血清，並使用細胞ELISA分析抗TAL6抗體力價。以EP1或MCF-7/L6細胞免疫接種的小鼠血清(1：500)比以載體(PBS)免疫接種的小鼠血清明顯具有更高的抗體量。請參考圖 2A。另外，還研究了EP1免疫作用是否能誘發抗體依賴性細胞毒性(antibody-dependent cellular cytotoxicity，ADCC)。以EP1或MCF-7/L6細胞免疫接種的小鼠血清(1：100)可殺死表現TAL6的EL4(EL4/L6)細胞，但不能殺死EL4母細胞 (61.82％±6.12％ v.s. 0.36％±0.96％和65.54 ％±1.77％ v.s.11.41％±3.094％)。請參考圖2B。為了研究EP1胜肽是否能誘發抗腫瘤活性，以EP1胜肽免疫接種小鼠，而後，在最終免疫接種後第7天用B16-L6細胞(2×104
個/小鼠)進行攻擊。以EP1或MCF-7/L6細胞免疫接種的小鼠明顯抑制腫瘤生長。請參考圖3A。小鼠的存活率如圖3B所示。數據顯示，EP1胜肽係TAL6的線性B細胞抗原決定位，其對表現TAL6癌症細胞具有抗腫瘤活性。
[EP1胜肽在小鼠模型中誘發抗腫瘤作用]
EP1胜肽以不同的佐劑配製成製劑。間隔14天，用50mg製劑對小鼠進行兩次免疫接種。在第二次免疫接種後第7天，皮下注射小鼠2×104
個B16/TAL6細胞。每週監測腫瘤生長2-3次。 EP1顯示出抗腫瘤作用。請參考圖4A。生存率如圖4B所示。
[包含B和T細胞抗原決定位的嵌合肽比單獨只有B或T細胞抗原決定位誘發更大的抗腫瘤活性]
為了研究細胞毒性T細胞(Tc)抗原決定位的併入是否能增強基於B細胞抗原決定位方法的抗腫瘤效果，製備合成肽Th-A2-5、Th-EP1和Th-A2-5-EP1。請參考表1。以不完全弗氏佐劑(IFA)配製胜肽，並用於免疫接種HLA-A2轉殖基因(transgenic ，Tg)小鼠。在最終免疫接種後第7天，皮下注射小鼠2×104
個B16-L6-A2細胞。每週監測腫瘤生長2-3次。用嵌合Th-A2-5-EP1胜肽誘發的免疫作用可強烈抑制腫瘤生長。請參考圖5。使用嵌合肽誘發體液和細胞免疫可協同抗腫瘤活性。
表1. 合成肽
[以PELC/CpG配製的嵌合肽誘發強烈的體液和細胞抗腫瘤免疫反應]
為了研究Th-A2-5-EP1嵌合肽是否能誘發A2-5專一性T細胞反應，進行IFN-γELISPOT和CTL活性測定。施用以不同佐劑配製的Th-A2-5-EP1於HLA-A2基因轉殖小鼠兩次，每次間隔兩週。
使用IFN-γELISPOT測定法測定小鼠的IFN-γ分泌細胞。以PELC/CpG配製的Th-A2-5-EP1比在其他佐劑製劑中的胜肽誘發更多的斑點(368.5±40.42)。請參考圖6A。與控制組小鼠相比，以DOTAP(60.5±7.85)、CpG(107.2±23.89)或DOTAP/CpG(112.5±33.18)配製Th-A2-5-EP1胜肽，可檢測到的斑點數顯著增加，但以PELC(16.7±4.74)或IFA(18±9.75)配製的Th-A2-5-EP1胜肽，檢測到的班點數並沒有顯著增加。我們得出結論，以PELC/CpG配製的Th-A2-5-EP能夠誘發強烈的A2-5專一性T細胞反應。
為了進一步確定PELC/CpG製劑是否能誘發細胞毒活性，故分析CD107a+
CD8+
T細胞的數量。在抗CD107a和抗CD8抗體存在下，用照射的EL4-L6-A2或EL4-L6細胞刺激來自小鼠的脾細胞2小時。以PELC/CpG配製的Th-A2-5-EP1比其他佐劑製劑誘發更多的CD107a+
CD8+
T細胞(6.69±0.49％)。請參考圖6B。這些結果顯示，以PELC/CpG配製的Th-A2-5-EP1可誘發強烈且特定的CTL反應。
用EP1塗覆的96孔ELISA盤測試來自小鼠的抗血清。以含有CpG的PELC配製的Th-A2-5-EP1胜肽，可誘發最多的抗EP1的IgG抗體量(O.D.1.41±0.04)。請參考圖6C。PELC佐劑比IFA佐劑誘發更多的抗體(O.D. 1.01±0.24 v.s. 0.622±0.183)。請參考圖 6C，以DOTAP脂質體配製的C.Th-A2-5-EP1胜肽、DOTAP/CpG、或單獨的CpG產生相似的抗體量(分別為O.D. 0.454±0.025、0.46±0.02和0.54±0.02)。請參考圖6C。與抗體力價數據相反，僅用PELC配製的Th-A2-5-EP1胜肽並未顯著誘發IFN-γ分泌細胞數量。參見圖6B。
用免疫接種的小鼠的血清評估ADCC活性。以PELC/CpG配製的Th-A2-5-EP1胜肽誘發最高程度的ADCC。請參考圖6D。 以PELC佐劑配製的Th-A2-5-EP1胜肽誘發第二高的ADCC活性。這些結果與抗體力價數據相符。
為了評估Th-A2-5-EP在不同佐劑製劑中的抗腫瘤效果，用製劑免疫接種HLA-A2轉基因小鼠兩次，每次間隔兩週。在第二次免疫接種後第7天，用B16/L6/A2細胞(2 x 104
)攻擊小鼠。每週監測腫瘤生長2-3次。與其他製劑相比，以PELC/CpG配製的Th-A2-5-EP胜肽顯著抑制腫瘤生長。請參考圖7。以IFA、DOTAP、PELC、CpG、或DOTAP/CpG配製的Th-A2-5-EP胜肽顯示出普通的抗腫瘤活性。請參考圖7。數據顯示，以PELC/CpG配製的含有Th、Tc和B細胞抗原決定位的嵌合肽可強烈誘發對抗癌症的體液和細胞免疫。
[以PELC/CpG配製的嵌合肽Th-A2-5-EP1抑制腫瘤遷移及轉移]
測試Th-A2-5-EP1免疫接種的小鼠的血清是否可以抑制癌細胞遷移。進行腔室傷口測定(chambers wound assay)以評估細胞遷移的抑制。 將B16-L6細胞種在具有Culture-Insert (500 μm)的24孔盤中培養24小時。然後取出Culture-Insert，加入100μl培養基、血清(1：100，v / v)、或正控制組(L6mAb)。在0、24、和48小時獲得的圖像顯示，經過L6或用Th-A2- 5-EP1和PELC/CpG免疫接種小鼠的血清處理後，癌細胞遷移作用受到抑制(數據未顯示)。
在三個獨立的實驗中，無細胞間隙的定量顯示，單獨以CpG(72.97％±5.97)或PELC/CpG(43.04％±15.47)配製的Th-A2-5-EP1所免疫接種的小鼠血清顯著抑制B16-L6細胞遷移。請參考圖 8。而遷移的抑制並不是因為細胞增殖的差異所導致(數據未顯示)。
癌細胞遷移的抑制表示癌細胞轉移也可透過嵌合肽免疫作用來抑制。在B16-L6轉移小鼠模型中檢驗了胜肽的抗轉移活性。以PELC、CpG、或PELC/CpG配製的Th-A2-5-EP1胜肽免疫接種HLA-A2基因轉殖小鼠兩次，每次間隔兩週。第二次免疫接種後第7天，靜脈注射5×105
個B16-L6細胞。細胞接種後22天，犧牲小鼠，收集肺組織進行分析。以PELC、CpG、或PELC / CpG配製的Th-A2-5-EP1顯著降低了肺中的腫瘤結節的形成(數據未顯示)。有趣的是，以PELC/CpG配製的Th-A2-5-EP1胜肽免疫接種的小鼠中幾乎沒有觀察到腫瘤結節。數據顯示，以PELC/CpG配製的Th-A2-5-EP1可抑制癌細胞肺轉移。
[以PELC/CpG配製的嵌合肽Th-A2-5-EP1誘發抗人類癌細胞的抗體介導的細胞毒性]
以不同佐劑配製的Th-A2-5-EP1免疫接種小鼠兩次，每次間隔兩週。6週後收集血清，並以ADCC測定。人類肺癌細胞株H2981、乳癌細胞株MCF7、和MCF7-TAL6為目標細胞。以Cr51
釋放試驗測定TAL6專一性ADCC (TAL6-specific ADCC)。將初始血清中的溶解百分比減去免疫接種血清的溶解百分比來計算溶解百分比。如圖9所示，以PELC/CpG配製的Th-A2-5-EP1對癌細胞具有最強的細胞毒性。
[以丙胺酸掃描法辨識EP1的抗體結合區]
EP1中的胺基酸殘基1至20分別以丙胺酸取代以產生EP1-1至EP1-20胜肽。用單株抗體L6檢測這些胜肽。當用丙胺酸取代時，某些殘基會造成抗體結合減少。請參考圖10。數據顯示，這些殘基對於抗體結合是重要的。
[動物和細胞株]
6週齡的C57BL/6雌性小鼠來自台灣國家實驗動物中心。HLA-A2基因轉殖小鼠係由台灣國立台灣大學陳小梨博士提供，在國家衛生研究院實驗動物中心進行繁殖。所有動物實驗均在國家衛生研究院(NHRI)動物委員會批准的方案下，在無特定病原體(specific pathogen-free，SPF)條件進行。
B16F1細胞穩定表現TAL6(B16-L6)，然後用HLA-A2基因轉染，得到穩定的細胞株B16-L6-A2。將B16-L6-A2和MCF-7-TAL6細胞培養在添加有胎牛血清(FBS ，10%)、青黴素/鏈黴素 (penicillin/streptomycin ，50 units/ mL)、0.5mM丙酮酸鈉、以及20mM HEPES(購自Biological industries，Beit Haemek，Israel)的DMEM培養基中，在37℃、5％CO2
的環境下培養。請參考Tu等人，Journal ofimmunotherapy，35(2012)235-244。將EL4-L6-A2和EL4-L6細胞培養在添加有10％FBS的RPMI-1640培養基中。
[單株抗體的製備]
從美國菌種中心(American Type Culture Collection)取得可產生抗TAL6抗體的融合瘤(L6)。如前所述，用人類TAL6質體DNA免疫接種的BALB/c小鼠可產生1F4和9C7抗TAL6單株抗體。藉由使用如前所述的高鹽條件的蛋白質A親和層析法以純化單株抗體。請參考Chang等人，Int J Cancer，116(2005)243-252。
利用微量BCA蛋白定量分析套組(Micro BCA protein Assay Kit ，購自PIERCE)檢測抗體濃度。
[ELISA]
對於抗體抗原決定位定位，利用ELISA測定L6、9C7和1F4單株抗體。為了要測定專一性抗體的EP1力價，收集用EP1胜肽免疫接種小鼠的抗血清，並藉由ELISA測定專一性抗體的力價。用胜肽(1μg/ ml)或細胞(2×106)塗覆96孔盤。在使用5％BSA-PBS中止後，用5％ BSA-PBS稀釋抗血清(1：1000 v/v)，並將其加入至孔盤中1小時。使用HRP複合的山羊抗小鼠IgG (1：4000 v/v)檢測EP1抗體力價。然後加入TMB過氧化物酶EIA受質，其可用1當量濃度(N)的H2
SO4
終止反應。於450nm測量其吸光度。
[動物實驗]
將以IFA、明礬、DOTAP脂質體、PELC奈米顆粒或TLR9促效劑CpG配製的胜肽皮下注射HLA-A2TG小鼠兩次，每次間隔兩週。第二次免疫接種後第7天，在注射胜肽的另一側位置皮下注射2×104
個B16-L6-A2或B16-L6細胞。每週測量腫瘤大小2-3次。腫瘤體積計算公式為：腫瘤體積=長×寬×寬/ 2。
[抗體依賴性細胞毒性(ADCC)]
在ADCC試驗中，小鼠脾細胞為作用細胞(effector cell)。在LCM培養基中將脾細胞的細胞濃度調整為8 x106
cells/ml。將細胞加入試管中，然後分成等分(在96孔盤中每孔為100μl)。在37℃下，用100 μ Ci之51
C (Na2 51
CrO4
, 購自PerkinElmer, MA)標記EL4-L6或EL-4目標細胞(2 x107
/ml)一小時。將51
Cr標記的EL4-L6或EL4細胞的濃度調整成2×105
cells/ml (在LCM培養基中)，然後加入TAL6抗血清或空白小鼠血清(1：10)。6小時後收集上清液，使用γ計數器測量放射性。在單獨含有目標細胞的孔中測量自發性釋放。 使用Triton X-100(2％)裂解目標細胞以估計最大的釋放量。根據下列公式計算細胞毒性百分比：裂解百分比= 100×(實驗的51
Cr釋放 -自發性51
Cr釋放)/(最大51
Cr釋放 - 自發性51
Cr釋放)。
[ELISPOT試驗]
將脾細胞(5×105
)與10 μg/ ml的指定胜肽混合，並且加至用抗-IFN-γ抗體 (anti-IFN-γ antibody)塗覆的96孔PVDF膜盤 (96-well PVDF-membrane plate)中。然後將孔盤放置在37℃、含有5％ CO2
的濕潤空氣中培養48小時。培養後，用含有tween 20 (0.05% (w/v))的PBS沖洗孔盤6次以移除細胞。在每孔中加入50μl等量的生物素化的二次抗-IFN-γ抗體(R46A2株；購自eBioscience，San Diego，CA)。 2小時後，沖洗孔盤，並且加入鏈黴親和素-HRP(streptavidin-HRP，購自eBioscience)。使用3-胺-9-乙基咔唑(3-amine-9-ethyl carbazole ；購自AEC，Sigma)溶液使斑點呈色。 4-6分鐘後，以自來水清洗孔盤以終止反應。然後使用ELISPOT讀取器(Cellular Technology Ltd.，Shaker Heights，OH)計算斑點。
[CD107a 細胞毒試驗]
在有或沒有CpG ODN (10 μg/mouse)的狀況下，皮下注射在IFA、DOTAP或PELC中乳化的指定胜肽(50 μg/ml)至HLA-A2基因轉殖小鼠兩次。
在第二次免疫接種後第7天，收集脾細胞，然後在96孔圓底盤中將含有10 μg/ml的指定胜肽(50 μg/ml)或細胞(2×106
cell/ ml)、及PE-複合的抗小鼠CD107a抗體(1：100)的培養基中，再懸浮脾細胞至濃度2×107
cell/ ml。在37℃下2小時後，加入布雷非德菌素A (brefeldin A，10μg/ ml)和莫能菌素(monensin ，0.66μg/ ml)放置2-6小時。用含有0.1％FBS的PBS沖洗孔盤，加入抗小鼠Fc抗體(1：100)放置5分鐘，然後加入FITC-複合的抗小鼠CD8抗體(1：100)放置30分鐘。用螢光流式細胞分選儀(FACS calibur，BD Bioscience)分析細胞毒性CD107a+
CD8+
細胞。
[傷口癒合試驗]
使用Culture-Insert(500μm；購自Ibidi)研究傷口癒合。將100 μl在DMEM-10% FBS中的B16-L6細胞懸浮液(5 × 106
cells/ml)種入Culture-Insert的每一孔中。細胞附著24小時後，取出Culture-Insert，並將細胞與抗血清(1：100 v/v)在DMEM-10％FBS中培養。如倒置顯微鏡下所示，於48小時的觀察中，可觀察到細胞遷移到限定的細胞間隙中。對於試驗分析，使用ImageJ programmer 的手動追蹤軟體組件，追蹤細胞。
[數據分析]
使用student t test和ANOVA得到實驗組平均值間的統計學顯著差異。如果P值＜0.05，則差異被認為是統計學顯著性差異。
[其他實施例]
本說明書中公開的所有技術特徵可以任何組合。本說明書中揭露的每個特徵可由可達成相同、等同或相似目的之替代特徵來代替。因此，除非另有明確說明，所揭露的每個特徵僅是等效或相似特徵的通用示範例。
由上述實施例僅，本技術領域者可輕易了解所述實施例的必要特徵，且在不偏離其精神及範圍下，對實施例可作各種的改變及修飾，以適用於各種使用及狀況。因此，其他實施例亦落在申請專利範圍中。
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圖1(A)為涵蓋TAL6細胞外結構域之EL1(SEQ ID NO：1之殘基31至46)、EL2 (SEQ ID NO：1之殘基114至164)、EP1 (SEQ ID NO：4)、EP2 (SEQ ID NO：17、EP3 (SEQ ID NO：18)、以及EP4 (SEQ ID NO：19)之重疊胜肽示意圖；以及(B)為胜肽與抗TAL6抗體結合之圖表。在96孔盤中，將指定之胜肽(10μg/ ml)塗覆於每孔中。 利用三種抗TAL6抗體(1：500)檢測這些胜肽。 CP：對照組胜肽。
圖2為利用EP1胜肽誘發野生型小鼠抗腫瘤免疫反應之系列圖。對小鼠施用以不完全弗氏佐劑(IFA)配製的EP1或正控制組MCF-7/TAL6細胞兩次，每次間隔兩週。(A)為利用細胞ELISA(cell based ELISA)檢測抗TAL6抗體力價。抗原專一性抗體計算方式為：EL4-L6(O.D.)-EL4(O.D.)。(B)為在Cr51
釋放試驗中測定TAL6專一性ADCC。裂解百分比計算方式為：免疫接種的血清(裂解％) - 初始血清(裂解％)。 *** P ＜0.001。
圖3為利用EP1胜肽誘發野生型小鼠抗腫瘤免疫反應之系列圖。向小鼠施用以不完全弗氏佐劑(IFA)配製的EP1或正控制組MCF-7/TAL6細胞兩次，每次間隔兩週。(A)最終免疫接種後第7天，皮下注射B16-L6(2×104
個)細胞。每週監測腫瘤生長2-3次。(B)測定小鼠的存活率。
圖4為以PELC/CpG配製的EP1誘發抗腫瘤作用系列圖。間隔14天，用指定佐劑配製的EP1(50mg)免疫接種小鼠兩次。(A)第二次免疫接種後第7天，皮下注射2×104
個B16/TAL6細胞。每週監測腫瘤生長2-3次。獲得的結果以平均值標準差表示(n = 6)。(B)監測小鼠存活率。結果以平均值±標準差表示(* P ＜0.05，** P ＜0.01)。
圖5為T和B細胞抗原決定位的組合，在HLA-A2小鼠中誘發抗腫瘤活性的系列圖。用以不完全弗氏佐劑(IFA)配製的胜肽(50μg/小鼠)免疫接種HLA-A2小鼠兩次，每次間隔兩週。在最終免疫接種後第7天，皮下注射B16/L6/A2細胞(2×104
個)。每週監測腫瘤大小2-3次。腫瘤體積=長x寬x寬/ 2。每張圖中的每一條線對應一隻動物(n = 5-6)。
圖6為用PELC/CpG/Th-A2-5-EP1在HLA-A2小鼠中誘發大量的體液和細胞免疫之系列圖。Th-A2-5-EP1胜肽以不同的佐劑配製。用不同的製劑免疫接種HLA-A2基因轉殖小鼠兩次，每次間隔兩週。(A)使用IFN-γELISpot測定法測定IFN-γ分泌細胞。結果以平均值標準差表示。*** P ＜0.001。(B)在抗CD107a和抗CD8抗體存在下，使用照射的EL4-TAL6-A2或EL4-TAL6細胞(2×104
個)刺激脾細胞(splenocyte)2小時。*** P ＜0.001。(C)將10 mg/ml 的EP1胜肽塗覆在96孔ELISA盤上，加入免疫接種的小鼠的抗血清(1：500)。* P ＜0.05。*** P ＜0.001。(D)以Cr51
釋放測定法測定TAL6專一性ADCC。裂解百分比計算方式為：免疫接種的血清(裂解％) - 初始血清(裂解％)*** P ＜0.001。
圖7為用Th-A2-5-EP1誘發HLA-A2基因轉殖小鼠之抗腫瘤活性免疫反應結果圖。用以不同佐劑配製的Th-A2-5-EP1胜肽免疫接種HLA-A2基因轉殖小鼠兩次，每次間隔兩週。在最終免疫接種後第7天，皮下注射2×104
個B16/TAL6/HLA-A2細胞。每組有6隻小鼠。每週監測腫瘤生長2-3次。結果以平均值標準差表示。
圖8為免疫接種的小鼠血清抑制癌細胞遷移的結果圖。 將B16-L6細胞種在24孔盤中，每孔中含有一個培養小室(Culture-Insert)(500μm)。24小時後，除去Culture-Insert，加入100 ml具有或不具有免疫接種小鼠的抗血清(1：100， v/v)的培養基。在體外0、24和48 小時照相。使用L6 mAb(10mg / ml)作為正控制組。在顯微鏡下，於指定時間觀察遷移到限定的無細胞間隙之細胞遷移。數據以平均值±SD表示(n = 5)。遷移率(%)= 48小時的細胞間隙面積/0小時的細胞間隙面積×100％。 *** P ＜0.001。
圖9為以不同佐劑配製的胜肽，誘發抗人類癌細胞的抗體依賴性細胞毒性(ADCC)之系列圖。用以多種佐劑配製的Th-EP1-A2-5胜肽免疫接種小鼠兩次，每次間隔兩週。6週時收集血清，並進行ADCC測定。(A)使用肺癌細胞株H2981作為目標。(B)使用人類乳癌細胞株MCF7和MCF7-TAL6作為目標。以Cr51
釋放測定法，測定TAL6專一性ADCC。裂解百分比計算方式為：免疫接種的血清(裂解％) - 初始血清(裂解％)*** P ＜0.001。
圖10為使用丙胺酸掃描法檢測對抗體結合重要的EP1殘基的檢測結果圖。EP1中的胺基酸殘基分別被丙胺酸取代，而產生EP1-1至EP1-20胜肽。使用單株抗體L6檢測這些胜肽。EP1是正控制組，EP-3是負控制組。
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＜110＞ National Health Research Institutes ＜120＞ IMMUNOGENIC PEPTIDE CONTAINING A B CELL EPITOPE OF TUMOR ASSOCIATED ANTIGEN L6 ＜130＞ 218384-0004PCT ＜150＞ US 62/331,698 ＜151＞ 2016-05-04 ＜160＞ 22 ＜170＞ PatentIn version 3.5 ＜210＞ 1 ＜211＞ 202 ＜212＞ PRT ＜213＞ Homo sapiens ＜220＞ ＜221＞ MISC_FEATURE ＜222＞ (1)..(202) ＜223＞ TAL6 ＜400＞ 1 Met Cys Tyr Gly Lys Cys Ala Arg Cys Ile Gly His Ser Leu Val Gly 1 5 10 15 Leu Ala Leu Leu Cys Ile Ala Ala Asn Ile Leu Leu Tyr Phe Pro Asn 20 25 30 Gly Glu Thr Lys Tyr Ala Ser Glu Asn His Leu Ser Arg Phe Val Trp 35 40 45 Phe Phe Ser Gly Ile Val Gly Gly Gly Leu Leu Met Leu Leu Pro Ala 50 55 60 Phe Val Phe Ile Gly Leu Glu Gln Asp Asp Cys Cys Gly Cys Cys Gly 65 70 75 80 His Glu Asn Cys Gly Lys Arg Cys Ala Met Leu Ser Ser Val Leu Ala 85 90 95 Ala Leu Ile Gly Ile Ala Gly Ser Gly Tyr Cys Val Ile Val Ala Ala 100 105 110 Leu Gly Leu Ala Glu Gly Pro Leu Cys Leu Asp Ser Leu Gly Gln Trp 115 120 125 Asn Tyr Thr Phe Ala Ser Thr Glu Gly Gln Tyr Leu Leu Asp Thr Ser 130 135 140 Thr Trp Ser Glu Cys Thr Glu Pro Lys His Ile Val Glu Trp Asn Val 145 150 155 160 Ser Leu Phe Ser Ile Leu Leu Ala Leu Gly Gly Ile Glu Phe Ile Leu 165 170 175 Cys Leu Ile Gln Val Ile Asn Gly Val Leu Gly Gly Ile Cys Gly Phe 180 185 190 Cys Cys Ser His Gln Gln Gln Tyr Asp Cys 195 200 ＜210＞ 2 ＜211＞ 9 ＜212＞ PRT ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic polypeptide ＜400＞ 2 Cys Leu Asp Ser Leu Gly Gln Trp Asn 1 5 ＜210＞ 3 ＜211＞ 20 ＜212＞ PRT ＜213＞ Artificial sequence ＜220＞ ＜223＞ Synthetic polypeptide ＜220＞ ＜221＞ misc_feature ＜222＞ (1)..(7) ＜223＞ Xaa can be any naturally occurring amino acid ＜220＞ ＜221＞ misc_feature ＜222＞ (17)..(20) ＜223＞ Xaa can be any naturally occurring amino acid ＜400＞ 3 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Cys Leu Asp Ser Leu Gly Gln Trp Asn 1 5 10 15 Xaa Xaa Xaa Xaa 20 ＜210＞ 4 ＜211＞ 20 ＜212＞ PRT ＜213＞ Artificial sequence ＜220＞ ＜223＞ Synthetic polypeptide ＜400＞ 4 Gly Leu Ala Glu Gly Pro Leu Cys Leu Asp Ser Leu Gly Gln Trp Asn 1 5 10 15 Tyr Thr Phe Ala 20 ＜210＞ 5 ＜211＞ 9 ＜212＞ PRT ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic polypeptide ＜400＞ 5 Leu Leu Met Leu Leu Pro Ala Phe Val 1 5 ＜210＞ 6 ＜211＞ 9 ＜212＞ PRT ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic polypeptide ＜400＞ 6 Arg Phe Val Trp Phe Phe Ser Gly Ile 1 5 ＜210＞ 7 ＜211＞ 13 ＜212＞ PRT ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic polypeptide ＜400＞ 7 Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala 1 5 10 ＜210＞ 8 ＜211＞ 16 ＜212＞ PRT ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic polypeptide ＜400＞ 8 Ala Gln Tyr Ile Lys Ala Asn Ser Lys Phe Ile Gly Ile Thr Glu Leu 1 5 10 15 ＜210＞ 9 ＜211＞ 48 ＜212＞ PRT ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic polypeptide ＜400＞ 9 Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala Ala Ala Ala 1 5 10 15 Leu Leu Met Leu Leu Pro Ala Phe Val Ala Ala Ala Gly Leu Ala Glu 20 25 30 Gly Pro Leu Cys Leu Asp Ser Leu Gly Gln Trp Asn Tyr Thr Phe Ala 35 40 45 ＜210＞ 10 ＜211＞ 24 ＜212＞ DNA ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic oligonucleotide ＜400＞ 10 tcgtcgtttt gtcgttttgt cgtt 24 ＜210＞ 11 ＜211＞ 20 ＜212＞ DNA ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic oligonucleotide ＜400＞ 11 gggggacgat cgtcgggggg 20 ＜210＞ 12 ＜211＞ 21 ＜212＞ DNA ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic oligonucleotide ＜400＞ 12 ggggacgacg tcgtgggggg g 21 ＜210＞ 13 ＜211＞ 26 ＜212＞ DNA ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic oligonucleotide ＜400＞ 13 tcgcgacgtt cgcccgacgt tcggta 26 ＜210＞ 14 ＜211＞ 22 ＜212＞ DNA ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic oligonucleotide ＜400＞ 14 tcgtcgtttt cggcgcgcgc cg 22 ＜210＞ 15 ＜211＞ 25 ＜212＞ DNA ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic oligonucleotide ＜400＞ 15 tcgtcgtcgt tcgaacgacg ttgat 25 ＜210＞ 16 ＜211＞ 29 ＜212＞ DNA ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic oligonucleotide ＜400＞ 16 tcgcgaacgt tcgccgcgtt cgaacgcgg 29 ＜210＞ 17 ＜211＞ 20 ＜212＞ PRT ＜213＞ Artificial Sequence ＜220＞ 223＞ Synthetic polypeptide ＜400＞ 17 Ser Leu Gly Gln Trp Asn Tyr Thr Phe Ala Ser Thr Glu Gly Gln Tyr 1 5 10 15 Leu Leu Asp Thr 20 ＜210＞ 18 ＜211＞ 20 ＜212＞ PRT ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic polypeptide ＜400＞ 18 Ser Thr Glu Gly Gln Tyr Leu Leu Asp Thr Ser Thr Trp Ser Glu Cys 1 5 10 15 Thr Glu Pro Lys 20 ＜210＞ 19 ＜211＞ 21 ＜212＞ PRT ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic polypeptide ＜400＞ 19 Ser Thr Trp Ser Glu Cys Thr Glu Pro Lys His Ile Val Glu Trp Asn 1 5 10 15 Val Ser Leu Phe Ser 20 ＜210＞ 20 ＜211＞ 25 ＜212＞ PRT ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic polypeptide ＜400＞ 20 Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala Ala Ala Ala 1 5 10 15 Leu Leu Met Leu Leu Pro Ala Phe Val 20 25 ＜210＞ 21 ＜211＞ 36 ＜212＞ PRT ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic polypeptide ＜400＞ 21 Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala Ala Ala Ala 1 5 10 15 Gly Leu Ala Glu Gly Pro Leu Cys Leu Asp Ser Leu Gly Gln Trp Asn 20 25 30 Tyr Thr Phe Ala 35 ＜210＞ 22 ＜211＞ 24 ＜212＞ PRT ＜213＞ Artificial Sequence ＜220＞ ＜223＞ Synthetic polypeptide ＜400＞ 22 Ala Lys Phe Val Ala Ala Trp Thr Leu Lys Ala Ala Ala Ser Ser Cys 1 5 10 15 Ser Ser Cys Pro Leu Ser Lys Ile 20
Claims (21)
- 一種免疫原胜肽，包含序列CLDSLGQWN，其中，該胜肽具有100個或更少之胺基。
- 如申請專利範圍第1項所述之胜肽，其中，該胜肽具有一序列X1 X2 X3 X4 X5 X6 X7 CLDSLGQWNX8 X9 X10 X11 ，其中，X1 至X11 各自係為胺基酸。
- 如申請專利範圍第2項所述之胜肽，其中，X6 係為脯胺酸(proline)。
- 如申請專利範圍第2或3項所述之胜肽，其中，X8 係為蘇胺酸(threonine)。
- 如申請專利範圍第3或4項所述之胜肽，其中，該胜肽包含一序列GLAEGPLCLDSLGQWNYTFA。
- 如申請專利範圍第1至5項任一項所述之胜肽，更包含(i) 一TAL6的細胞毒性T淋巴球(cytotoxic T lymphocyte，CTL)抗原決定位，及/或(ii) 一輔助T細胞(helper T cell，Th)抗原決定位。
- 如申請專利範圍第6項所述之胜肽，其中，該CTL抗原決定位係為LLMLLPAFV或RFVWFFSGI。
- 如申請專利範圍第6或7項所述之胜肽，其中，該Th抗原決定位係為AKFVAAWTLKAAA或QYIKANSKFIGITEL。
- 如申請專利範圍第6至8項任一項所述之胜肽，更包含一連接序列(linker sequence)，位於兩個抗原決定位之間。
- 如申請專利範圍第9項所述之胜肽，其中，該胜肽包含一序列AKFVAAWTLKAAAAAALLMLLPAFVAAAGLAEGPLCLDSLGQWNYTFA。
- 一種核酸分子，包含一序列，該序列編碼出如申請專利範圍第1至10項任一項所述之免疫原胜肽。
- 如申請專利範圍第11項所述之核酸分子，其中，該核酸分子係一種可表現該胜肽之表現載體(expression vector)。
- 一種免疫原組合物，包含如申請專利範圍第1至10項任一項所述之該胜肽。
- 如申請專利範圍第13項所述之免疫原組合物，更包含一佐劑。
- 如申請專利範圍第14項所述之免疫原組合物，其中，該佐劑係選自由不完全弗氏佐劑(incomplete Freund's adjuvant，IFA)、DOTAP、PELC、及含有非甲基化CpG之去氧寡核苷酸(CpG)所組成之群組。
- 如申請專利範圍第15項所述之免疫原組合物，其中，該組合物包含PELC以及CpG，且該胜肽具有一序列AKFVAAWTLKAAAAAALLMLLPAFVAAAGLAEGPLCLDSLGQWNYTFA。
- 一種免疫原組合物，其中，包含如申請專利範圍第11或12項所述之該核酸分子。
- 如申請專利範圍第17項所述之免疫原組合物，更包含一佐劑。
- 一種治療一主體的癌症之方法，包括提供如申請專利範圍第13至18項任一項所述之免疫原組合物至一所需主體。
- 如申請專利範圍第19項所述之方法，其中，該癌症具有表現TAL6之細胞。
- 如申請專利範圍第20項所述之方法，其中，該癌症係肺癌、結腸癌、乳癌、卵巢癌、胃癌、卡波西氏肉瘤、肝癌、胰臟癌、子宮頸癌、子宮內膜癌、頭頸癌、卵巢癌或前列腺癌。
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