TW202233246A - 含有抗癌劑之粒線體及其用途 - Google Patents
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Abstract
本發明係關於含有具有抗癌功效之化合物之粒線體及其用途。確認了該粒線體有效地將該化合物遞送至腫瘤,並且確認了含有該化合物之該粒線體的抗癌作用。特定言之,當特異性結合腫瘤之抗體或其片段結合至粒線體表面時,可以將該化合物特異性遞送至該腫瘤。因此,根據本發明含有該化合物之該粒線體可以有效地用於治療癌症,因為該化合物的副作用很少。
Description
發明領域
本發明提供一種能夠修飾粒線體之化合物、含有該化合物之粒線體、以及包含該粒線體作為活性成分之醫藥組成物。
發明背景
粒線體係真核細胞的細胞胞器,參與細胞內能源三磷酸腺苷(ATP)的合成及調節。粒線體與活體內各種代謝途徑相關,例如細胞訊息傳導、細胞分化、細胞死亡,以及細胞週期及細胞生長的控制。粒線體有自己的基因體,且係在細胞能量代謝中起核心作用的胞器。粒線體經由電子傳遞及氧化磷酸化過程產生能量,並在參與細胞凋亡訊息傳導途徑中發揮重要作用。
據報導,由於粒線體功能下降導致的能量產生減少會導致各種疾病。當電子傳遞鏈式反應的功能隨著粒線體基因體及蛋白質體的變化而降低時,就會出現ATP產生減少、活性含氧物產生過多、鈣調節功能降低及其類似現象。在此種情況下,粒線體的膜通透性發生變化,且細胞凋亡的功能可能發生異常,並導致癌症及不可治癒的疾病。
因此,據報導由粒線體功能障礙引起的人類疾病包括粒線體相關遺傳病、糖尿病、心臟病、老年性癡呆,諸如帕金森氏病(Parkinson's disease)或阿茲海默氏症(Alzheimer's disease),以及發生各種癌症及癌症轉移及其類似疾病。此外,在超過200種類型的各種癌症中常見的特徵由細胞凋亡功能受損、發炎反應增加及代謝異常增加組成。所有此等過程均與粒線體功能密切相關,且癌症與粒線體之間的相關性正在引起人們的關注。
另一方面,眾所周知,正常細胞經由電子傳遞系統過程每分子葡萄糖產生36個ATP,但癌細胞與正常細胞不同,其在充足氧氣條件下經由醣解(有氧醣解)每分子葡萄糖產生2個ATP。因此,已知與正常細胞不同,癌細胞使用在能量方面低效的醣解過程來產生快速細胞增殖所必需之胺基酸、脂質、核酸及其類似物。因此,已知癌細胞比正常細胞需要更少的氧氣並產生更大量的乳酸。
因此,由於癌細胞中發生的代謝異常而引起的癌症微環境組成的變化,由粒線體功能障礙引起的細胞凋亡的抑制,發炎反應的增加,以及癌細胞的異常代謝反應在癌症增殖中起著非常重要的作用。因此,利用此等特徵開發代謝相關之抗癌劑可能係解決習知抗癌劑的副作用及經濟問題的好方法。另一方面,最近嘗試將粒線體作為藥物直接投予或開發(韓國專利登記號10-2111321)。
發明概要
技術問題
因此,本發明人藉由在研究粒線體的抗癌活性的過程中確認了粒線體在與習知使用之抗癌劑組合使用時具有優異的抗癌作用,從而完成了本發明。
問題之解決方案
在本發明之一個態樣中,提供了含有抗癌劑之粒線體及包含該粒線體的用於預防或治療癌症之醫藥組成物。
在本發明之另一態樣中,提供了一種製備含有抗癌劑之粒線體之方法,其包含將抗癌劑及經分離粒線體混合。
在本發明之另一態樣中,提供了一種化學結合至TPP的經修飾抗癌劑。
在本發明之另一態樣中,提供了一種預防或治療癌症之方法,其包含向個體投予包含含有抗癌劑之粒線體之醫藥組成物。
本發明之效果
確認了根據本發明之含有具有抗癌功效之化合物之粒線體將化合物有效地遞送至腫瘤,並且確認了含有該化合物之粒線體的抗癌作用。特定言之,當特異性結合腫瘤之抗體或其片段結合至粒線體表面時,可以將化合物特異性遞送至腫瘤。因此,根據本發明之含有化合物之粒線體可以有效地用於治療癌症,因為該化合物的副作用很少。
較佳實施例之詳細說明
含有抗癌劑之粒線體
在本發明之一個態樣中,提供了含有抗癌劑之粒線體。此外,在本發明之另一態樣中,提供一種用於預防或治療癌症之醫藥組成物,其包含含有抗癌劑作為活性成分之粒線體。
如本文所用,術語「粒線體」係真核細胞的細胞胞器,參與細胞內能源三磷酸腺苷(ATP)的合成及調節。粒線體與活體內各種代謝途徑相關,例如細胞訊息傳導、細胞分化、細胞死亡,以及細胞週期及細胞生長的控制。因此,據報導,由於遺傳、環境或未知原因導致之粒線體機能減退或機能障礙與粒線體相關遺傳病、類風濕性關節炎等發炎性疾病、缺血性疾病、傳染病、心臟病、肌肉疾病、帕金森氏病或阿茲海默氏症等退行性疾病及癌形成、癌轉移等各種疾病的發展相關。
粒線體可以自真核生物中獲得,並且可以自哺乳動物或人類中獲得。具體而言,粒線體可以自細胞或組織中分離。舉例而言,粒線體可以自體細胞、生殖細胞或幹細胞中獲得,並且可以自血細胞或血小板中分離。此外,粒線體可以藉由濃縮組織或細胞在破碎後分離,或者可以自冷凍及儲存後解凍的組織或細胞樣品在破碎後分離。
具體而言,體細胞可以係肌肉細胞、肝細胞、神經細胞、纖維母細胞、上皮細胞、脂肪細胞、骨細胞、白血球、淋巴細胞、血小板或黏膜細胞。
此外,幹細胞係能夠分化成各種類型的組織細胞的未分化細胞,且可以係選自由以下組成之群中之任一種:間葉系幹細胞、成體幹細胞、誘導性富潛能幹細胞、胚胎幹細胞、骨髓幹細胞、神經幹細胞、角膜緣幹細胞及組織衍生幹細胞,但不限於此。在此種情況下,間葉系幹細胞可以自選自由以下組成之群中之任一種獲得:臍帶、臍帶血、骨髓、脂肪、肌肉、神經、皮膚、滑液、睾丸、羊膜及胎盤。
此外,粒線體可以藉由在活體外培養細胞或組織來分離,或者可以自冷凍及儲存後解凍的樣品中分離。
此外,粒線體可獲自自體、同種異體或異種個體。具體而言,自體粒線體係指自同一個體的組織或細胞中獲得之粒線體。此外,同種異體粒線體係指自與個體屬於同一物種且對偶基因具有不同基因型的個體獲得之粒線體。此外,異種粒線體係指自屬於與個體不同物種的個體獲得之粒線體。
此外,粒線體可以係自細胞中分離出來之粒線體。此外,粒線體可能係完整的並具有粒線體活性。
另一方面,當自特定細胞中分離粒線體時,可以經由多種改進之方法分離粒線體,包括各種已知之方法,例如,使用特定的緩衝溶液或使用電位差及磁場及類似方法。
在維持粒線體活性方面,可以藉由破壞細胞及離心來獲得粒線體分離。
在此種情況下,抗癌劑可能存在於粒線體的外膜中。具體而言,抗癌劑可以位於外膜及內膜之間。此外,抗癌劑可以位於皺褶中。其亦可能存在於內膜內的基質中。
此外,粒線體可以係經修飾粒線體。在此種情況下,經修飾粒線體可以係其中與腫瘤相關抗原(TAA)特異性結合之抗體或其片段存在於細胞表面上之粒線體。
在此種情況下,腫瘤相關抗原可以係選自由以下組成之群中之任一種:CD19、CD20、黑色素瘤抗原E (MAGE)、NY-ESO-1、癌胚抗原(CEA)、黏蛋白1細胞表面相關蛋白(MUC-1)、前列腺酸性磷酸酶(PAP)、前列腺特異性抗原(PSA)、存活素、酪胺酸相關蛋白1 (tyrp1)、酪胺酸相關蛋白2 (tyrp2)、短尾蛋白(Brachyury)、間皮素、表皮生長因子受體(EGFR)、人類表皮生長因子受體2 (HER-2)、ERBB2、威爾姆斯腫瘤蛋白(Wilms tumor protein,WT1)、FAP、EpCAM、PD-L1、ACPP、CPT1A、IFNG、CD274、FOLR1、EPCAM、ICAM2、NCAM1、LRRC4、UNC5H2、LILRB2、CEACAM、MSLN、連接蛋白-3 (Nectin-3)及其組合,但不限於上述類型。
如本文所用,術語「癌症」被歸類為其中正常組織細胞由於某種原因不受限制地增殖並繼續快速生長而與生物體的生存現象或周圍組織狀況無關的疾病。在本發明中,癌症可以係選自由多種人體癌症組成之群中之任一種癌症,諸如乳癌、肺癌、胰臟癌、神經膠質母細胞瘤、胃癌、肝癌、結腸直腸癌、前列腺癌、卵巢癌、子宮頸癌、甲狀腺癌、喉癌、急性骨髓性白血病、腦瘤、神經母細胞瘤、視網膜母細胞瘤、頭頸癌、唾液腺癌及淋巴瘤,但不限於上述類型。
如本文所用,術語「抗癌劑」係用於抑制癌細胞增殖的藥物。在本發明中,該抗癌劑可以選自由以下組成之群:化學抗癌劑、靶向抗癌劑及驅蟲劑,但不限於此。
具體而言,「化學抗癌劑」可以係選自由以下組成之群中之任一種:烷化劑、微管抑制劑、抗代謝物及拓樸異構酶抑制劑,但不限於此。
烷化劑可以係選自由以下組成之群中之任一種:甲基二(氯乙基)胺(mechlorethamine)、環磷醯胺(cyclophosphamide)、依弗醯胺(ifosfamide)、黴法蘭(melphalan)、氯芥苯丁酸(chlorambucil)、噻替哌(thiotepa)、六甲蜜胺(altretamine)、丙卡巴肼(procarbazine)、硫酸布他卡因(busulfan)、鏈脲佐菌素(streptozocin)、雙氯乙基亞硝脲(carmustine)、洛莫司汀(iomustine)、達卡巴嗪(dacarbazine)、小紅莓、順鉑(cisplatin)、卡鉑(carboplatin)及奧沙利鉑(oxaliplatin),但不限於此。微管抑制劑可以係選自由以下組成之群中之任一種:多西他賽(docetaxel)、長春花鹼(vinblastine)、安可平(oncovin)及長春瑞濱(vinorelbine),但不限於此。抗代謝物質可以係選自由以下組成之群中之任一種:氟尿嘧啶(fluorouracil)、卡培他濱(capecitabine)、阿糖胞苷(cytarabine)、吉西他濱(gemcitabine)、氟達拉濱(fludarabine)、胺甲喋呤(methotrexate)、培美曲塞(pemetrexed)及巰基嘌呤(mercaptopurine),但不限於此。拓樸異構酶抑制劑可以係選自由以下組成之群中之任一種:癌康定(hycamtin)、抗癌妥(camptosar)、依託泊苷(vepesid)、紫杉醇(taxol)、博萊黴素(bleomycin)、阿德力黴素(Adriamycin)及道諾黴素(cerubidine),但不限於此。
此外,「靶向抗癌劑」可以係調節特定目標生物標誌物之化合物。舉例而言,該靶向抗癌劑可以係選自由以下組成之群中之任一種:靶向BTK、Bcr-abl、EGFR、PDGFR/VEGFR/FGFR家族、MEK/RAF、HER2/Neu、CDK、泛蛋白、JAK、MAP2K、ALK、PARP、TGFβRI、蛋白酶體、Bcl-2、Braf、C-Met、VR1、VR2、VR3、c-kit、AXL及RET之化合物。
靶向抗癌劑中之化合物之一個實施例可以係靶向BTK的依魯替尼(ibrutinib)。此外,其可以係靶向Bcr-abl的達沙替尼(dasatinib)、尼羅替尼(nilotinib)、伊馬替尼(imatinib)或波舒替尼(bosutinib)。此外,其可以係靶向EGFR的奧希替尼(osimertinib)、厄洛替尼(erlotinib)或艾瑞莎(gefitinib),但不限於此。此外,其可以係靶向PDGFR/VEGFR/FGFR家族的尼達尼布(nintedanib)、舒尼替尼(sunitinib)、索拉非尼(sorafenib)、卡博替尼(cabozantinib)、樂伐替尼(lenvatinib)、瑞戈非尼(regorafenib)、馬賽替尼(masitinib)、塞馬尼布(semaxanib)、替沃紮尼(tivozanib)、凡德他尼(vandetanib)、阿西替尼(axitinib)或帕唑帕尼(pazopanib),但不限於此。此外,其可以係靶向MEK/RAF的曲美替尼(trametinib)/達拉非尼(dabrafenib),但不限於此。
此外,其可以係靶向HER2/Neu的妥復克(afatinib)、拉帕替尼(lapatinib)或來那替尼(neratinib),但不限於此。此外,其可以係靶向CDK的截癌寧(abemaciclib)或愛乳適(palbociclib),但不限於此。此外,其可以係靶向泛蛋白的來那度胺(lenalidomide),但不限於此。此外,其可以係靶向JAK的魯索利替尼(ruxolitinib)、來他替尼(lestaurtinib)或帕瑞替尼(pacritinib),但不限於此。此外,其可以係靶向MAP2K的考比替尼(cobimethinib)、司美替尼(selumetinib)、曲美替尼(trametinib)或比美替尼(binimetinib),但不限於此。此外,其可以係靶向ALK的艾樂替尼(alectinib)或克唑替尼(crizotinib),但不限於此。此外,其可以係靶向PARP的奧拉帕尼(olaparib),但不限於此。此外,其可以係靶向TGFβRI的加魯色替(galunisertib),但不限於此。此外,其可以係靶向蛋白酶體的依沙米布(ixazomib),但不限於此。此外,其可以係靶向Bcl-2的維奈托克(venetoclax),但不限於此。此外,其可以係靶向Braf的威羅非尼(vemurafenib),但不限於此。
此外,「驅蟲劑」可以係選自由以下組成之群中之任一種:OXPHOS (氧化磷酸化)抑制劑、醣解抑制劑、醣解相關間接抑制劑、PPP(戊醣磷酸途徑)抑制劑及自噬抑制劑,但不限於此。具體而言,該驅蟲劑可以係選自由以下組成之群中之任一種:吡維銨(pyrvinium)、氯硝柳胺(niclosamide)、硝唑尼特(nitazoxanide)、艾弗麥克素(ivermectin)、芬苯達唑(fenbendazole)、硝唑尼特(nitazoxanide)及胺基甲酸甲酯(albendazole),但不限於此。
經修飾粒線體
經修飾粒線體係指異性蛋白與粒線體外膜結合之粒線體。在此種情況下,經修飾粒線體可以在韓國專利申請公開案第10-2019-0048279號中揭示。
如本文所用,術語「異性蛋白」係指包括能夠在細胞內外發揮作用的目標蛋白的蛋白。在此種情況下,異性蛋白係粒線體中不存在的蛋白,且可以係重組蛋白。具體而言,異性蛋白可以包含粒線體錨定肽及目標蛋白。此外,異性蛋白可以係包含粒線體錨定肽及目標蛋白的重組融合蛋白。在此種情況下,異性蛋白可以包含粒線體錨定肽。較佳地,粒線體錨定肽可以係可以位於粒線體外膜上的肽。因此,異性蛋白可能利用粒線體錨定肽與粒線體外膜結合。粒線體錨定肽可以係包含存在於粒線體膜蛋白中之蛋白之N端區域或C端區域以及存在於粒線體蛋白的外膜中之蛋白之N端區域或C端區域的肽可能位於粒線體的外膜上。在此種情況下,錨定肽可以進一步包含粒線體訊息序列。
存在於粒線體膜蛋白中之蛋白質之一個實施例可以係選自由以下組成之群中之任一種:TOM20、TOM70、OM45、TOM5、TOM6、TOM7、TOM22、Fis1、Bcl-2、Bcl-x及VAMP1B。特定言之,當粒線體錨定肽衍生自選自由TOM20、TOM70及OM45組成之群中之任一種時,其可以包含TOM20、TOM70或OM45之N端區域。粒線體錨定肽之一個實施例可以係由SEQ ID NO: 75表示的衍生自酵母之TOM70,或由SEQ ID NO: 76表示的衍生自人類之TOM70。另一個實施例可以係由SEQ ID NO: 77表示的衍生自酵母之TOM20,或由SEQ ID NO: 78表示的衍生自人類之TOM20。另一個實施例可以係由SEQ ID NO: 79表示的衍生自酵母之OM45。
此外,當粒線體錨定肽衍生自選自由TOM5、TOM6、TOM7、TOM22、Fis1、Bcl-2、Bcl-x及VAMP1B組成之群中之任一種時,其可以包含選自由以下組成之群中之任一種的C端區域:TOM5、TOM6、TOM7、TOM22、Fis1、Bcl-2、Bcl-x及VAMP1B。粒線體錨定肽之一個實施例可以係由SEQ ID NO: 80表示的衍生自酵母之TOM5或由SEQ ID NO: 81表示的衍生自人類之TOM5。另一個實施例可以係由SEQ ID NO: 82表示的衍生自酵母之TOM7,或由SEQ ID NO: 83表示的衍生自人類之TOM7。另一個實施例可以係由SEQ ID NO: 84表示的衍生自酵母之TOM22,或由SEQ ID NO: 85表示的衍生自人類之TOM22。另一個實施例可以係由SEQ ID NO: 86表示的衍生自酵母之Fis1,或由SEQ ID NO: 87表示的衍生自人類之Fis1。另一個實施例可以係由SEQ ID NO: 88表示的衍生自人類之Bcl-2α。另一個實施例可以係由SEQ ID NO: 89表示的衍生自酵母之VAMP1,或由SEQ ID NO: 90表示的衍生自人類之VAMP1。
在此種情況下,包括在異性蛋白中之能夠在細胞內外發揮作用的目標蛋白可以係選自由以下組成之群中之任一種:在細胞中表現出活性的活性蛋白、存在於細胞中之蛋白及能夠與細胞膜中存在的配位體或受體結合的蛋白。
活性蛋白或存在於細胞中之蛋白之一實施例可以係選自由以下組成之群中之任一種:p53、顆粒酶B、Bax、Bak、PDCD5、E2F、AP-1 (Jun/Fos)、EGR-1、視網膜母細胞瘤蛋白(RB)、磷酸酶及張力蛋白同源物(PTEN)、E-鈣黏蛋白、神經纖維瘤蛋白-2 (NF-2)、聚[ADP-核糖]合酶1 (PARP-1)、BRCA-1、BRCA-2、腺瘤性結腸瘜肉蛋白(APC)、腫瘤壞死因子受體相關因子(TRAF)、RAF激酶抑制蛋白(RKIP)、p16、KLF-10、LKB1、LHX6、C-RASSF、DKK-3PD1、Oct3/4、Sox2、Klf4及c-Myc。當目標蛋白選自上述群時,目標蛋白可以與包含TOM20、TOM70或OM45之N端區域的錨定肽結合。
此類融合蛋白可以按以下順序結合:
N端-包含TOM20、TOM70或OM45目標蛋白之N端區域的錨定肽-C端。
此外,異性蛋白可以進一步包含由真核細胞中之蛋白水解酶識別之胺基酸序列,或粒線體錨定肽與目標蛋白之間的泛蛋白或其片段。真核細胞中之蛋白水解酶係指降解真核細胞中存在的蛋白的酶。在此種情況下,由於異性蛋白包含被降解該蛋白的酶識別之胺基酸序列,因此與粒線體外膜結合的異性蛋白可以在細胞中分離成錨定肽及目標蛋白。
在此種情況下,泛蛋白片段可以包含SEQ ID NO: 71之胺基酸序列的C端Gly-Gly,並且可以包含自C端連續的3至75個胺基酸。此外,異性蛋白可以進一步包含目標蛋白與泛蛋白或其片段之間的連接子。在此種情況下,連接子可以由1至150個胺基酸構成,或由10至100個胺基酸構成,或由20至50個胺基酸構成,但不限於此。連接子可由自20種胺基酸中適當選擇的胺基酸構成,較佳由甘胺酸及/或絲胺酸構成。連接子之一個實施例可以由5至50個由甘胺酸及絲胺酸組成之胺基酸構成。連接子之一個實施例可以係(G4S)n,其中n係1至10的整數,且n可以係1、2、3、4、5、6、7、8、9或10。
此外,具有與存在於細胞膜中之配位體或受體結合能力的蛋白質可以係存在於腫瘤細胞表面上的配位體或受體。在此種情況下,存在於腫瘤細胞表面的配位體或受體可以係但不限於選自由以下組成之群中之任一種:CD19、CD20、黑色素瘤抗原E (MAGE)、NY-ESO-1、癌胚抗原(CEA)、黏蛋白1細胞表面相關蛋白(MUC-1)、前列腺酸性磷酸酶(PAP)、前列腺特異性抗原(PSA)、存活素、酪胺酸相關蛋白1 (tyrp1)、酪胺酸相關蛋白2 (tyrp2)、短尾蛋白、間皮素、表皮生長因子受體(EGFR)、人類表皮生長因子受體2 (HER-2)、ERBB2、威爾姆斯腫瘤蛋白(WT1)、FAP、EpCAM、PD-L1、ACPP、CPT1A、IFNG、CD274、FOLR1、EPCAM、ICAM2、NCAM1、LRRC4、UNC5H2、LILRB2、CEACAM、連接蛋白-3及其組合。
此外,能夠與細胞膜中存在的配位體或受體結合的蛋白可以係與選自上述群中之任一種結合之抗體或其片段。具體而言,抗體片段係指具有與抗體相同的互補決定區(CDR)的片段。具體而言,其可以係Fab、scFv、F(ab')
2或其組合。
在此種情況下,目標蛋白可以與包含選自由TOM5、TOM6、TOM7、TOM22、Fis1、Bcl-2、Bcl-x及VAMP1B組成之群中之任一種的C端區域的錨定肽結合,並且異性蛋白可以按以下順序結合:
N端-目標蛋白-包含選自由TOM5、TOM6、TOM7、TOM22、Fis1、Bcl-2、Bcl-x及VAMP1B組成之群中之任一種的C端區域的錨定肽-C端。
此外,異性蛋白可以在目標蛋白與選自由TOM5、TOM6、TOM7、TOM22、Fis1、Bcl-2、Bcl-x及VAMP1B組成之群中之任一種的C端區域之間包含連接子。在此種情況下,連接子如上所述。在此種情況下,目標蛋白、活性蛋白、存在於細胞中之蛋白及能夠與細胞膜中存在的配位體或受體結合的蛋白及其類似蛋白如上所述。
在目標蛋白之一個實施例中,靶向特定細胞之抗體或其片段可以呈與錨定肽結合的形式,該錨定肽包含選自由TOM5、TOM6、TOM7、TOM22、Fis1、Bcl-2、Bcl-x及VAMP1B組成之群中之任一種的C端區域。與目標蛋白結合的經修飾粒線體可以容易地引入特定目標中,使得粒線體可以有效地進入特定細胞。
經修飾粒線體之一個實施例可以呈與一或多種目標蛋白結合的形式。具體而言,其可以呈與包含p53的目標蛋白及包含抗HER-2抗體或其片段的目標蛋白結合的形式。此種經修飾粒線體可以有效地將粒線體遞送至表現HER-2的癌細胞中。此外,與經修飾粒線體結合的p53可以有效殺死癌細胞。
根據經修飾粒線體的目的,可以構築包含一或多種活性蛋白的目標蛋白並使其與粒線體結合。此外,靶向細胞的目標蛋白可以根據所靶向的細胞以各種方式構築。
包含粒線體外膜靶向蛋白及目標蛋白的融合蛋白可以稱為修飾粒線體活性的融合蛋白。此類融合蛋白可以具有以下任一結構:
< 結構式1>N端-粒線體外膜錨定肽-目標蛋白-C端
< 結構式2>N端-粒線體外膜錨定肽-泛蛋白或其片段-目標蛋白-C端
< 結構式3>N端-粒線體外膜靶向肽-連接子1-泛蛋白或其片段-目標蛋白-C端
< 結構式4>N端-粒線體外膜錨定肽-泛蛋白或其片段-連接子2-目標蛋白-C端
< 結構式5>N端-粒線體外膜錨定肽-連接子1-泛蛋白或其片段-連接子2-目標蛋白-C端
在上述結構式1至5中,外膜錨定肽可以係選自由TOM20、TOM70及OM45組成之群的蛋白質的末端序列,且目標蛋白可以係選自由以下組成之群中之任一種:p53、顆粒酶B、Bax、Bak、PDCD5、E2F、AP-1 (Jun/Fos)、EGR-1、視網膜母細胞瘤蛋白(RB)、磷酸酶及張力蛋白同源物(PTEN)、E-鈣黏蛋白、神經纖維瘤蛋白-2 (NF-2)、聚[ADP-核糖]合酶1 (PARP-1)、BRCA-1、BRCA-2、腺瘤性結腸瘜肉蛋白(APC)、腫瘤壞死因子受體相關因子(TRAF)、RAF激酶抑制蛋白(RKIP)、p16、KLF-10、LKB1、LHX6、C-RASSF及DKK-3PD1。
在此種情況下,連接子1或2可以係分別由1至100、1至80、1至50或1至30個胺基酸構成的多肽,並且可以較佳地係由1至30個胺基酸構成的多肽,該等胺基酸由絲胺酸、甘胺酸或蘇胺酸單獨或組合組成。另外,連接子1或2可以分別係由5至15個胺基酸構成的多肽,且可以較佳係由5至15個胺基酸構成的多肽,該等胺基酸由絲胺酸、甘胺酸或蘇胺酸單獨或組合構成。連接子之一個實施例可以係(GGGGS)3 (SEQ ID NO: 70)。
< 結構式6>N端-目標蛋白-粒線體外膜錨定肽-C端
< 結構式7>N端-目標蛋白-泛蛋白或其片段-粒線體外膜錨定肽-C端
< 結構式8>N端-目標蛋白-連接子1-泛蛋白或其片段-粒線體外膜錨定肽-C端
< 結構式9>N端-目標蛋白-泛蛋白或其片段-連接子2-粒線體外膜錨定肽-C端
< 結構式10>N端-目標蛋白-連接子1-泛蛋白或其片段-連接子2-粒線體外膜靶向肽-C端
在上述結構式6至10中,外膜錨定肽可以係選自由TOM5、TOM6、TOM7、TOM22、Fis1、Bcl-2、Bcl-X及VAMP1B組成之群的蛋白質的末端序列,且目標蛋白可以係選自由以下組成之群中之任一種:p53、顆粒酶B、Bax、Bak、PDCD5、E2F、AP-1 (Jun/Fos)、EGR-1、視網膜母細胞瘤蛋白(RB)、磷酸酶及張力蛋白同源物(PTEN)、E-鈣黏蛋白、神經纖維瘤蛋白-2 (NF-2)、聚[ADP-核糖]合酶1 (PARP-1)、BRCA-1、BRCA-2、腺瘤性結腸瘜肉蛋白(APC)、腫瘤壞死因子受體相關因子(TRAF)、RAF激酶抑制蛋白(RKIP)、p16、KLF-10、LKB1、LHX6、C-RASSF、DKK-3PD1、Oct3/4、Sox2、Klf4及c-Myc。在此種情況下,連接子1或2如上所述。
對於醫藥組成物,粒線體可以按約0.1 μg/mL至約500 μg/mL、約0.2 μg/mL至約450 μg/mL或約0.5 μg/mL至約400 μg/mL之濃度包括在內,但不限於此。將在上述範圍內之粒線體包括在內可以促進粒線體在投予時的劑量調整,並且可以增強患者疾病症狀的改善程度。在此種情況下,可以經由量化經分離粒線體的膜蛋白來定量粒線體,從而確定粒線體的劑量。具體而言,可以藉由Bradford蛋白分析對經分離粒線體進行量化。
此外,對於醫藥組成物,與粒線體結合之抗癌劑可以按0.1 μg/mL至500 μg/mL、0.2 μg/mL至450 μg/mL或0.5 μg/mL至400 μg/mL之濃度包括在內,但不限於此。將在上述範圍內之抗癌劑包括在內可以促進抗癌劑在投予時的劑量調整,並且可以增強患者疾病症狀的改善程度。
與粒線體結合之抗癌劑可以按每1 μg粒線體約0.01 μg至1 μg、約0.05 μg至0.5 μg或約0.1 μg至0.3 μg的量包括在內。較佳地,其可以按約0.2 μg的量包括在內。
抗癌劑及粒線體可以按適當的比率混合,使得抗癌劑可以包含在粒線體中。舉例而言,基於重量比計,抗癌劑及粒線體的混合比可以係約1:10至約10:1、約1:9至約9:1、約1:8至大約8:1、約1:7至約7:1、約1:6至約6:1、約1:5至約5:1、約1:4至約4:1、約1:3至約3:1、約1:2至約2:1或約1:1的重量比。較佳地,其可以係約1:5。
特定言之,抗癌劑可以係與三苯基鏻(TPP)結合的抗癌劑。
如本文所用,術語「三苯基鏻(TPP)」係一種親脂性陽離子化合物,其可以容易地穿透細胞膜及粒線體膜,並且回應於粒線體膜內部存在的負電壓(-150至-170mV)而被直接吸收至粒線體中。由於此等性質,TPP被用作靶向癌細胞、癌症幹細胞及纖維母細胞的材料,因為與正常細胞相比,TPP在粒線體膜電位差異大的癌細胞或心肌細胞之粒線體中積累更多。
在此種情況下,其中TPP與粒線體結合之抗癌劑可以按每1 μg粒線體約0.01 μg至1 μg、約0.05 μg至0.5 μg或約0.1 μg至0.3 μg的量包括在內。較佳地,其可以按約0.25 μg的量包括在內。
此外,抗癌劑及與TPP結合之粒線體可以按適當的比率混合,使得抗癌劑可以包含在粒線體中。舉例而言,基於重量比計,抗癌劑及與TPP結合之粒線體的混合比可以係約1:10至約10:1、約1:9至約9:1、約1:8至約8:1、約1:7至約7:1、約1:6至約6:1、約1:5至約5:1、約1:4至約4:1、約1:3至約3:1、約1:2至約2:1或約1:1的重量比。較佳地,其可以係約1:4。
在本說明書之一個實施例中,構築了包含TPP-DOX的與抗HER2抗體片段融合之粒線體(TPP-DOX_MT
α-HER2scFv),其中TPP與小紅莓(DOX)結合(圖30至32),及在癌細胞(圖33至43)及使用其之腫瘤小鼠模型(圖65至68)中確認了優異的抗癌活性。
此外,TPP可以包括TPP衍生物。TPP衍生物可以係2-丁烯-1,4-雙-TPP、2-氯苄基-TPP、3-甲基苄基-TPP、2,4-二氯苄基-TPP、1-萘甲基-TPP及對二甲苯雙-TPP及其類似物,但不限於此。此外,TPP衍生物可以進一步包括其衍生物。舉例而言,其可以係2-丁烯-1,4-雙-TPP的衍生物、2-氯苄基-TPP的衍生物、3-甲基苄基-TPP的衍生物、2,4-二氯苄基-TPP的衍生物,1-萘甲基-TPP的衍生物及對二甲苯雙-TPP的衍生物及其類似物,但不限於此。
包含含有本發明之抗癌劑之粒線體之醫藥組成物可以用於預防或治療癌症,及/或可以提高治療效果(功效)。在此種情況下,粒線體及抗癌劑如上所述。
該癌症可以係選自由以下組成之群中之任一種:乳癌、肺癌、胰臟癌、神經膠質母細胞瘤、胃癌、肝癌、結腸直腸癌、前列腺癌、卵巢癌、子宮頸癌、甲狀腺癌、喉癌、急性骨髓性白血病、腦瘤、神經母細胞瘤、視網膜母細胞瘤、頭頸癌、唾液腺癌及淋巴瘤,但不限於此。
如本文所用,術語「預防」係指藉由投予醫藥組成物來抑制或延遲癌症發作的任何作用。此外,「治療」係指藉由投予醫藥組成物來改善或有益地改變癌症症狀的任何作用。
如本文所用,術語「功效」可以由一或多個參數確定,諸如在一段時間,諸如1年、5年或10年內的存活率或無病存活率。此外,該參數可以包括對個體中至少一個腫瘤大小的抑制。
生物可用度等藥物動力學參數及清除率等潛在參數亦可能對功效產生影響。因此,「增強的功效」(例如,功效的提高)可歸因於增強的藥物動力學參數及增強的功效,並且可以藉由比較試驗動物或人類個體中之清除率及腫瘤生長,或藉由比較存活率、復發率或無病存活率等參數來進行量測。
醫藥組成物的較佳劑量根據患者之狀況及體重、疾病之嚴重程度、藥物之形式、投予途徑及持續時間而變化,但一般技術者可以適當選擇。在本發明之用於預防或治療癌症之醫藥組成物中,可以根據用途、配方、組合目的及其類似因素以任何量(有效量)包括活性成分,只要其可以顯示抗癌活性即可。此處,「有效量」係指能夠誘導抗癌作用的活性成分的量。此種有效量可以在一般技術者的普通能力範圍內以實驗方式確定。
本發明之醫藥組成物可以進一步包含醫藥學上可接受之載劑。醫藥學上可接受之載劑可以係任何載劑,只要其係適合遞送給患者的無毒材料即可。蒸餾水、酒精、脂肪、蠟及惰性固體可以作為載劑包括在內。此外,醫藥組成物中可以包括醫藥學上可接受之佐劑(緩衝劑、分散劑)。
具體而言,醫藥組成物可以根據投予途徑利用此項技術中已知的習知方法製備為非經腸調配物,除了活性成分之外亦包括醫藥學上可接受之載劑。此處,「醫藥學上可接受」係指其不抑制活性成分的活性並且不具有超出應用(處方)目標可能適應的毒性。
當本發明之醫藥組成物製備成非經腸調配物時,可以根據此項技術中已知之方法將其與合適的載劑一起調配成注射劑、經皮製劑及鼻吸入劑的形式。當調配成注射劑時,作為適宜的載劑,可以使用無菌水、乙醇、甘油或丙二醇等多元醇、或其混合物,且可以較佳使用林格氏溶液(Ringer's solution)、含有三乙醇胺的磷酸鹽緩衝液(PBS)、或注射用無菌水、諸如5%右旋糖的等張溶液。
本發明之醫藥組成物可以係可注射製劑。因此,根據本發明之醫藥組成物可以藉由使用酸性水溶液或磷酸鹽等緩衝溶液調節pH值而製成物理或化學上非常穩定的注射劑,其可用作注射劑,以便根據規定的注射劑分佈確保產品穩定性。
具體而言,本發明之醫藥組成物可以包含注射用水。注射用水係指為溶解固體注射劑或稀釋水溶性注射劑而製備的蒸餾水。其可以係葡萄糖注射液、木糖醇注射液、D-甘露糖醇注射液、果糖注射液、生理鹽水、葡聚糖40注射液、葡聚糖70注射液、胺基酸注射液、林格氏溶液、乳酸-林格氏溶液或磷酸鹽緩衝溶液或磷酸二氫鈉-檸檬酸鹽緩衝溶液,pH為約3.5至7.5。
另一方面,本發明之醫藥組成物以醫藥學上有效量投予。術語「治療有效量」或「醫藥學上有效量」係指有效預防或治療目標疾病之化合物或組成物的量,其係足以治療疾病、有著合理收益/風險比、適用於醫學治療且不會造成副作用的量。可根據包括患者之健康狀況、疾病之類型及嚴重程度、藥物之活性、對藥物之敏感性、投予方法、投予時間、投予途徑及排泄速率、治療週期、欲組合或同時使用的藥物的因素以及醫學領域熟知的其它因素,確定有效量的位準。在一個實施例中,治療有效量係指有效治療癌症之藥物量。
如本文所用,術語「投予」係指藉由適當之方法將預定物質引入個體,並且組成物的投予途徑可以係經由任何一般途徑,只要其可以到達目標組織即可。其可以係腹腔內投予、靜脈內投予、肌肉內投予、皮下投予、皮內投予、局部投予、鼻內投予、直腸內投予,但不限於此。
本發明之醫藥組成物的較佳劑量可以基於待投予個體的體重按0.01 mg/kg至5 mg/kg、0.1 mg/kg至4 mg/kg或0.25 mg/kg至2.5 mg/kg粒線體的量投予一次,但不限於此。亦即,就細胞活性而言,最佳的是醫藥組成物與含有抗癌劑的經修飾粒線體一起投予,其量基於具有癌組織之個體的體重在上述範圍內。此外,醫藥組成物可以投予1至10次、3至8次或5至6次,較佳5次。在此種情況下,投予間隔時間可以係1至7天或2至5天的間隔時間,較佳3天的間隔時間。此種劑量不應被解釋為在任何態樣限制本發明之範圍。
術語「個體」係指本發明之組成物可以應用(開處)的個體,並且可以係罹患癌症之個體。此外,個體可以係哺乳動物,諸如大鼠、小鼠或家畜,包括人類,且較佳為人類。除了含有抗癌劑之粒線體之外,本發明之組成物亦可以進一步包括已知具有已經驗證的抗癌活性及安全性的任何化合物或天然提取物,用於增強及強化抗癌活性。在此種情況下,該醫藥組成物及具有抗癌活性之化合物或天然提取物可以同時或依次投予。
在本發明之另一態樣中,提供了一種製備含有抗癌劑之粒線體之方法,其包含將抗癌劑及經分離粒線體混合。在此種情況下,抗癌劑及粒線體如上所述。
抗癌劑及粒線體可以按適當的比率混合,使得抗癌劑可以含於粒線體中。舉例而言,抗癌劑及粒線體基於重量比計之混合比可以係約1:10至約10:1、約1:9至約9:1、約1:8至約8:1、約1:7至約7:1、約1:6至約6:1、約1:5至約5:1、約1:4至約4:1、約1:3至約3:1、約1:2至約2:1或約1:1的重量比。較佳地,其可以係約1:5。
在本發明之另一態樣中,提供了一種與TPP化學結合的經修飾抗癌劑。在此種情況下,TPP及抗癌劑如上所述。
在本發明之另一態樣中,提供了一種包含含有抗癌劑之粒線體之醫藥組成物用於預防癌症或增強癌症治療效果的用途。在此種情況下,抗癌劑及粒線體如上所述。
在本發明之另一態樣中,提供了一種治療癌症之方法及/或一種增強治療效果之方法,其包含向個體投予包含含有抗癌劑之粒線體之醫藥組成物。在此種情況下,抗癌劑、粒線體及投予如上所述。個體可以係罹患癌症之個體。此外,個體可以係哺乳動物,較佳人類。
實施本發明之方式
在下文中,將利用以下實例更詳細地描述本發明。然而,以下實例僅用於說明本發明,且本發明之範圍不限於此。
I. 確認結合了靶向蛋白之粒線體的靶向能力 製備實例1. 製備包含與抗HER2scFv 抗體融合之粒線體的HEK293 細胞系
為了將粒線體特異性引入至表現HER2之腫瘤細胞中,構築了其中特異性結合HER2的抗HER2scFv抗體(SEQ ID NO: 98)與粒線體外膜融合之粒線體(圖1及2)。具體的構築方法根據韓國專利申請公開案第10-2019-0124656號中描述之方法進行。
實例1. 確認與抗HER2scFv 抗體融合的粒線體的性質 實例1.1. 分析抗HER2scFv 抗體表現
為了確認包含上述製備實例1中構築的與抗HER2scFv抗體融合之粒線體(MT
α-HER2scFv)的HEK293細胞中抗HER2scFv的表現位準,使用免疫細胞化學染色對細胞進行染色,並使用共焦顯微鏡觀察影像。
具體而言,將HEK293細胞以3×10
4個細胞/孔接種至24孔盤中並培養24小時。培養24小時後,細胞用MitoTracker紅色染色約30分鐘,且用PBS清洗,接著用3.7%甲醛固定。去除甲醛,且將一級抗體,亦即抗myc抗體(Roche,11667149001)在含有1%山羊血清的PBS中以1:1,000稀釋,且用稀釋液處理細胞並反應18小時。反應完成後,藉由用PBS洗滌來去除一級抗體,接著將用Alexa Fluor® 488標記的二級抗體(Invitrogen,11001),亦即抗小鼠IgG抗體,在含0.1% BSA的PBS中以1:500稀釋,且用稀釋液處理細胞並反應約1小時。反應完成後,用PBS清洗細胞,封固,且利用共焦顯微鏡觀察細胞。此時,藉由用DAPI染色來觀察細胞核。
結果,確認了標記粒線體的紅色螢光的位置與標記抗HER2scFv抗體的綠色螢光的位置一致(圖3)。
實例1.2. 確認抗HER2scFv 抗體的表現位置
進行西方墨點法以確認以與上述製備實例1相同方式構築的抗HER2scFv抗體是否在HEK293細胞之粒線體中表現。
具體而言,在將表現抗HER2scFv的細胞破壞之後,藉由離心將細胞提取物分離為粒線體級分及細胞質級分。對每個級分進行電泳並進行西方墨點法。為了鑑別抗HER2scFv、粒線體標誌物及細胞質標誌物蛋白,分別將抗myc抗體(Roche,11667149001)、抗COX4抗體(abcam,33985)及抗β-微管蛋白抗體(Thermo,MA5-16308)用作一級抗體。將抗小鼠IgG HRP或抗兔IgG HRP用作二級抗體。
結果,確認抗HER2scFv抗體與用作粒線體陽性標誌物的COX4一起存在於粒線體級分中,而在存在細胞質陽性標誌物β-微管蛋白的級分中不存在(圖4)。在上述實例中,經由免疫細胞化學染色及西方墨點分析之結果確認了抗HER2scFv抗體在HEK293細胞之粒線體中表現。
實例1.3. 量測與抗HER2scFv 抗體融合之粒線體產生ATP 的能力
為了比較以與上述製備實例1相同方式構築的與抗HER2scFv抗體融合之粒線體與正常粒線體的功能差異,自HEK293細胞(MT
α-HER2scFv) (一種表現與抗HER2scFv抗體融合之粒線體的細胞系)及HEK293細胞中分離粒線體,以比較其產生ATP的能力,產生ATP係粒線體的主要功能之一。
具體而言,藉由用25 μM ADP及100 μL螢光素處理5 μg/100 μL經分離粒線體,並量測粒線體中產生之ATP與螢光素反應所產生的發光值(RLU)來確認產生ATP的能力。結果,MT與MT
α-HER2scFv產生ATP的能力沒有差異(圖5)。
實例1.4. 量測與抗HER2scFv 抗體融合之粒線體的膜電位
為了比較以與上述製備實例1相同方式構築的與抗HER2scFv抗體融合之粒線體與正常粒線體的功能差異,比較了包含與抗HER2scFv抗體融合之粒線體(MT
α-HER2scFv)的HEK293細胞與未經處理的HEK293細胞(MT)的膜電位,膜電位係粒線體的主要特徵之一。
具體而言,將細胞以3×10
4個細胞/孔接種至96孔盤中並培養24小時。24小時後,細胞用DCFDA (Invitrogen,C6827)染料處理並反應1小時。此後,將細胞用PBS洗滌並用Hoechst33242處理以將細胞染色10分鐘。量測DCFDA及Hoechst33242之螢光值,接著藉由計算其比率(DAFDA之螢光值/Hoechst33242之螢光值)確定膜電位。結果,MT及MT
α-HER2scFv的膜電位沒有差異(圖6)。
實例1.5. 量測與抗HER2scFv 抗體融合之粒線體的活性含氧物
為了比較以與上述製備實例1相同方式構築的與抗HER2scFv抗體融合之粒線體與正常粒線體的活性含氧物(ROS)的產生位準,量測了包含與抗HER2scFv抗體融合之粒線體(MT
α-HER2scFv)的HEK293細胞與未經處理的HEK293細胞(MT)中粒線體的活性含氧物。
具體而言,將細胞以3×10
4個細胞/孔接種至96孔盤中並培養24小時。24小時後,每個細胞用TMRE (Invitrogen,T669)染料處理並反應1小時。細胞用PBS洗滌,且接著用Hoechst33242染色10分鐘。量測TMRE及Hoechst33242之螢光值,接著藉由計算其比率(TMRE之螢光值/Hoechst33242之螢光值)來確定活性含氧物的產生量。結果,自細胞中分離的MT及MT
α-HER2scFv的活性含氧物產生量沒有差異(圖7)。
實例2. 分析人類癌細胞系及正常細胞系中之HER2 表現 實例2.1. 經由西方墨點分析確認人類癌細胞系及正常細胞系中之HER2 表現
進行西方墨點法以確認人類乳癌、肺癌、胃癌細胞系及肺纖維母細胞系中HER2之表現位準。
具體而言,將人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)、人類肺癌細胞系(NCI-H1975)、人類胃癌細胞系(MKN-74及NCI-N87)及人類肺纖維母細胞系(WI-38)以約1×10
6個細胞/孔接種至6孔盤中,接著培養24小時。此時,SK-BR-3、BT-474及NCI-N87細胞藉由在含有10% FBS的RPMI-1640培養基中培養來製備,而MDA-MB-231、NCI-H1975、MKN-74及WI-38細胞藉由在含有10% FBS的DMEM培養基中培養來製備。
24小時後,除去培養液,且用PBS洗滌細胞二次,接著直接向細胞中加入100 μL含有蛋白酶抑制劑的RIPA緩衝液。10分鐘後,用刮刀回收細胞,將其轉移至微量離心管中,接著以約12,000×g離心10分鐘。獲得分離的上清液並將其轉移至新的微量離心管中,接著使用BCA分析對蛋白質進行定量。對每個樣品的相同量的蛋白質進行電泳,接著進行西方墨點法。將抗HER2抗體(Cell signaling,29D8)及抗β肌動蛋白抗體(Sigma,A2208)用作一級抗體,且將抗小鼠IgG HRP及抗兔IgG HRP用作二級抗體。
結果,確認SK-BR-3、BT-474及NCI-N87細胞係表現HER2的HER2
+細胞。另一方面,發現MDA-MB-231、NCI-H1975、MKN-74及WI-38細胞幾乎沒有HER2表現,表明其係HER2
-細胞(圖8)。
實例2.2. 經由免疫細胞化學染色確認人類癌細胞系及正常細胞系中之HER2 表現
為了確認HER2在人類乳癌、肺癌、胃癌細胞系及人類肺纖維母細胞系中之表現位準,使用抗HER2抗體進行免疫細胞化學染色。
具體而言,將細胞分別以3×10
4個細胞/孔接種至24孔盤中,且培養24小時。24小時後,用3.7%甲醛固定細胞。去除甲醛,且將一級抗體,亦即抗HER2抗體(Cell Signaling Technology,2165)在含有1%山羊血清的PBS中以1:1,000稀釋,且用稀釋液處理細胞並反應18小時。藉由用PBS洗滌來去除一級抗體,接著將用Alexa Fluor® 488標記的二級抗體(Invitrogen,11008),亦即抗兔IgG抗體在含有0.1% BSA的PBS中以1:500稀釋,接著將細胞用稀釋液處理並反應1小時。反應完成後,用PBS清洗細胞,封固,且利用共焦顯微鏡觀察細胞。此時,藉由用DAPI染色來觀察細胞核。
結果,在作為HER2
+細胞的SK-BR-3、BT-474及NCI-N87細胞的情況下,HER2在細胞表面表現並觀察到綠色螢光,而在作為HER2
-細胞的MDA-MB-231、NCI-H1975、MKN74及CCD-8Lu細胞的情況下,沒有觀察到綠色螢光(圖9)。
實例2.3. 經由流動式細胞測量術確認人類癌細胞系中之HER2 表現
為了確認人類乳癌、肺癌及胃癌細胞系中HER2的表現位準,使用抗HER2抗體進行流動式細胞測量術。
具體而言,人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)、人類胃癌細胞系(NCI-N87及MKN-74)及人類肺癌細胞系(NCI-H1975)分別以約1×10
6個細胞/孔接種至6孔盤中,且培養24小時。24小時後,除去培養液,且用0.05%胰蛋白酶-EDTA處理來收集細胞,且用3.7%甲醛固定。將一級抗體,亦即抗HER2抗體(Cell Signaling Technology,2165),在含有1%山羊血清的PBS中以1:1,000稀釋,且用稀釋液處理細胞並反應18小時。藉由用PBS洗滌來去除一級抗體,接著將用Alexa Fluor® 555標記的二級抗體(Invitrogen,21428),亦即抗兔IgG抗體,在含有0.1% BSA的PBS中以1:500稀釋,接著將細胞用稀釋液處理並反應1小時。反應完成後,用PBS洗滌細胞,且經由流式細胞儀確認HER2的表現。
結果,在作為HER2
+細胞的SK-BR-3、BT-474及NCI-N87細胞的情況下,HER2在細胞表面表現並且觀察到螢光值(PE-A)較高,而作為HER2
-細胞的MDA-MB-231、NCI-H1975及MKN-74細胞顯示出比HER2
+細胞低之螢光值(圖10)。
根據以上西方墨點分析、免疫細胞化學染色及流動式細胞測量術之結果,確認SK-BR-3、BT-474及NCI-N87細胞為表現HER2的HER2
+細胞,而MDA-MB-231、NCI-H1975、MKN-74、WI-38細胞及CCD-8Lu細胞係HER2
-細胞。
實例3. 驗證與抗HER2scFv 抗體融合之粒線體的HER2 靶向性
為了確認以與上述製備實例1相同方式構築的與抗HER2scFv抗體融合之粒線體的HER2靶向能力,將與抗HER2scFv抗體融合之粒線體(MT
α-HER2scFv)用共培養之HER2
+細胞及HER2
-細胞處理,接著進行免疫細胞化學染色。
具體而言,將HER2
+細胞及HER2
-細胞以1.5×10
4個細胞/孔一起接種至24孔盤中,且在含有10% FBS的DMEM培養基中共培養24小時。此時,HER2
+細胞SK-BR-3、BT-474及NCI-N87藉由在含有10% FBS的RPMI-1640培養基中培養來製備,而HER2
-細胞MDA-MB-231、NCI-H1975及MKN-74藉由在含有10% FBS的DMEM培養基中培養來製備。藉由分別用MitoTracker紅色處理未經處理的HEK293細胞(MT)及包含與抗HER2scFv抗體融合之粒線體(MT
α-HER2scFv)的HEK293細胞並分離經染色粒線體來製備粒線體。共培養24小時後,用共培養的細胞處理每個經分離粒線體並反應12小時(圖11)。
實例3.1. 確認與抗HER2scFv 抗體融合之粒線體在HER2 陽性及陰性細胞系中之位置
將以與上述實例3相同方式處理的細胞用PBS洗滌一次,且藉由添加3.7%甲醛在室溫下固定30分鐘,接著進行免疫細胞化學染色。此時,將抗HER2抗體(Cell signaling,29D8)用作一級抗體,且將用Alexa Fluor® 488 標記的抗兔IgG抗體(Invitrogen,11008)用作二級抗體。藉由用DAPI染色來觀察細胞核。
結果,如圖12所示,當用未經處理的HEK293細胞衍生之粒線體(MT)處理共培養的SK-BR-3 (HER2
+)及NCI-H1975 (HER2
-)細胞時,在SK-BR-3 (HER2
+)細胞及NCI-H1975 (HER2
-)細胞中同樣觀察到用Mitotracker紅色染色之粒線體(紅色螢光)。另一方面,當細胞用衍生自包含與抗HER2scFv抗體融合之粒線體之HEK293細胞的粒線體(MT
α-HER2scFv)處理時,在HER2
+細胞SK-BR-3細胞中特異性地觀察到了用Mitotracker紅色染色之粒線體。
在共培養的BT-474 (HER2
+)及NCI-H1975 (HER2
-)細胞的情況下,在MT處理組的情況下,在BT-474 (HER2
+)細胞及NCI-H1975 (HER2
-)細胞中同樣觀察到用Mitotracker紅色染色之粒線體,而在MT
α-HER2scFv處理組的情況下,僅在HER2
+細胞BT-474細胞中特異性觀察到該等粒線體(圖13)。
在共培養的NCI-N87 (HER2
+)及MKN-74 (HER2
-)細胞的情況下,在MT處理組的情況下,在NCI-N87 (HER2
+)細胞及MKN-74 (HER2
-)細胞中同樣觀察到用Mitotracker紅色染色之粒線體,而在MT
α-HER2scFv處理組的情況下,僅在HER2
+細胞NCI-N87中特異性觀察到該等粒線體(圖14)。
在共培養的SK-BR-3 (HER2
+)及MDA-MB-231 (HER2
-)細胞的情況下,在MT處理組的情況下,在SK-BR-3 (HER2
+)細胞及MDA-MB-231 (HER2
-)細胞中同樣觀察到用Mitotracker紅色染色之粒線體,而在MT
α-HER2scFv處理組的情況下,僅在HER2
+細胞SK-BR-3細胞中特異性觀察到該等粒線體(圖15)。
在共培養的BT-474 (HER2
+)及MDA-MB-231 (HER2
-)細胞的情況下,在MT處理組的情況下,在BT-474 (HER2
+)細胞及MDA-MB-231 (HER2
-)細胞中同樣觀察到用Mitotracker紅色染色之粒線體,而在MT
α-HER2scFv處理組的情況下,僅在HER2
+細胞BT-474細胞中特異性觀察到該等粒線體(圖16)。
由以上結果確認,與抗HER2scFv抗體融合之粒線體(MT
α-HER2scFv)可以特異性靶向表現HER2抗原的HER2
+細胞。
II. 製備含有抗癌劑並結合靶向蛋白之粒線體,並確認其活性 製備實例2. 製備與抗HER2scFv 抗體融合之粒線體及小紅莓的複合物
包含與抗HER2scFv抗體融合之粒線體的HEK293細胞用MitoTracker綠色處理以染色粒線體(綠色螢光),接著分離粒線體(MT
α-HER2scFv)。將30 µg經分離粒線體與100 μM小紅莓(DOX)在4℃下反應10分鐘,接著以約12,000×g離心10分鐘以去除未反應的小紅莓。此後,將其用500 μL SHE (250 mM蔗糖、20 mM HEPES (pH7.4)、2 mM EGTA)緩衝液洗滌二次,最終獲得包含小紅莓之粒線體(DOX_MT
α-HER2scFv) (圖17)。
實例4. 評估DOX_MT
α-HER2scFv 對癌細胞的抗癌活性 實例4.1. 確認DOX_MT
α-HER2scFv 向癌細胞的遞送性質
用以與上述製備實例2相同的方式獲得的DOX_MT
α-HER2scFv分別處理人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)及人類肺癌細胞系(NCI-H1975),接著利用共焦顯微鏡觀察細胞。此時,藉由用DAPI染色來觀察細胞核。
結果,在細胞質中觀察到經MitoTracker綠色染色之粒線體(MT
α-HER2scFv,綠色螢光),並且在細胞核中觀察到顯示紅色螢光的小紅莓(DOX) (圖18)。由以上結果發現,轉運至細胞內的DOX_MT
α-HER2scFv的小紅莓移動至細胞核,且定位在細胞核內的DNA中。
實例4.2. 確認藉由用DOX_MT
α-HER2scFv 處理引起的癌細胞的形態變化
用以與上述製備實例2相同的方式獲得的DOX_MT
α-HER2scFv分別處理人類乳癌細胞系(SK-BR-3及BT-474)及人類胃癌細胞系(NCI-N87),並且接著藉由共焦顯微鏡觀察癌細胞隨時間的形態變化。此時,藉由用DAPI染色來觀察細胞核。
結果,在用DOX_MT
α-HER2scFv(黃色螢光)處理6小時後,觀察到大部分小紅莓(DOX,紅色螢光)一起存在於粒線體(綠色螢光)中。然而,隨著時間的推移,在細胞核中觀察到小紅莓,並且在用DOX_MT
α-HER2scFv處理72小時後,明顯觀察到細胞的形態變化(圖19)。
實例4.3. 測定結合至MT
α-HER2scFv 的小紅莓之濃度
為了定量以與上述製備實例2相同的方式獲得的結合至DOX_MT
α-HER2scFv的小紅莓之濃度,藉由量測每種濃度的小紅莓的吸光度來製作標準曲線,接著計算結合至DOX_MT
α-HER2scFv的小紅莓之濃度。
具體而言,將各100 μL之濃度為20 μM、10 μM、5 μM、2.5 μM、1.25 μM、0.625 μM及0 μM的小紅莓溶液及在PBS中1/20稀釋之DOX_MT
α-HER2scFv分配至96孔盤中。此後,用多重讀取器(BioTek,Synerge HTX)量測吸光度(發射波長為590 nm)。使用根據小紅莓濃度的吸光度值製作標準曲線,接著藉由代入DOX_MT
α-HER2scFv稀釋溶液的吸光度值來確定結合至DOX_MT
α-HER2scFv的小紅莓之濃度(圖20)。
實例4.4. 確認藉由用每種濃度的DOX_MT
α-HER2scFv 處理產生的癌細胞增殖抑制能力
為了確認使用200 μg MT
α-HER2scFv及100 μM小紅莓(DOX)以與上述製備實例2相同的方式獲得的DOX_MT
α-HER2scFv的抗癌活性,評估用DOX_MT
α-HER2scFv處理人類乳癌、肺癌及胃癌細胞系的細胞增殖抑制作用。
具體而言,將人類乳癌(SK-BR-3、BT-474及MDA-MB-231)、肺癌(NCI-H1975)及胃癌(NCI-N87及MKN-74)細胞系分別以約3×10
3個細胞/孔接種至96孔盤中,且培養24小時。此時SK-BR-3、BT-474及NCI-N87細胞在含有10% FBS的RPMI-1640培養基中培養,且MDA-MB-231、NCI-H1975及MKN-74細胞在含有10% FBS的DMEM培養基中培養。培養24小時後,用濃度為2 μM、1 μM、0.5 μM、0.25 μM、0.1 μM、0.05 μM、0.025 μM及0.01 μM的小紅莓(DOX)或DOX_MT
α-HER2scFv處理每種細胞。樣品處理144小時後,藉由WST-1分析來量測細胞增殖。
結果,如圖21所示,對於未處理組(NC),在僅粒線體處理組(MT)中未觀察到細胞增殖抑制作用。另一方面,在DOX處理組及DOX_MT
α-HER2scFv處理組中,癌細胞增殖以濃度依賴性方式受到抑制。特定言之,確認了當用1 μM DOX_MT
α-HER2scFv處理時,與未處理組相比,取決於癌細胞系,細胞生長被抑制了約60%至90% (圖21)。
實例4.5. 確認藉由用每種濃度的DOX_MT
α-HER2scFv 處理正常細胞產生的增殖抑制能力
200 μg MT
α-HER2scFv及100 μM小紅莓(DOX)以與上述製備實例2相同的方式反應。為了確認獲得的DOX_MT
α-HER2scFv對正常細胞中細胞增殖的影響,評估了用DOX_MT
α-HER2scFv處理人類肺纖維母細胞的細胞增殖抑制作用。
具體而言,將人類肺纖維母細胞系WI-38及CCD-8Lu分別以約3×10
3個細胞/孔接種至96孔盤中,且培養24小時。此時,WI-38及CCD-8Lu在含有10% FBS的DMEM培養基中培養。培養24小時後,用濃度為2 μM、1 μM、0.5 μM、0.25 μM、0.1 μM、0.05 μM、0.025 μM及0.01 μM的小紅莓(DOX)或DOX_MT
α-HER2scFv處理每種細胞。樣品處理144小時後,藉由WST-1分析來量測細胞增殖。
結果,如圖22所示,對於未處理組(NC),在僅粒線體處理組(MT)中未觀察到細胞增殖抑制作用。此外,確認了在DOX處理組及DOX_MT
α-HER2scFv處理組中,細胞增殖抑制能力弱於癌細胞。
實例4.6. 分析用DOX_MT
α-HER2scFv 處理癌細胞及正常細胞的IC
50 值
基於實例4.4及實例4.5中每種濃度的DOX_MT
α-HER2scFv的細胞增殖抑制結果,對每種細胞中之IC
50值進行分析且顯示在圖23中。
實例4.7. 比較藉由用DOX_MT
α-HER2scFv 處理癌細胞及正常細胞產生的增殖抑制能力
200 μg MT
α-HER2scFv及100 μM小紅莓(DOX)以與上述製備實例2相同的方式反應。為了比較獲得的DOX_MT
α-HER2scFv對癌細胞及正常細胞之細胞增殖的影響,用相同濃度的DOX_MT
α-HER2scFv處理人類乳癌、肺癌、胃癌細胞系及肺纖維母細胞系之後,量測細胞增殖抑制能力。
具體而言,人類乳癌(SK-BR-3、BT-474及MDA-MB-231)、肺癌(NCI-H1975)、胃癌(MKN-74及NCI-N87)細胞系及肺纖維母細胞系(CCD-8Lu及WI-38)分別以約3×10
3個細胞/孔接種至96孔盤中,且培養24小時。此時,SK-BR-3、BT-474及NCI-N87細胞在含有10% FBS的RPMI-1640培養基中培養。MDA-MB-231、NCI-H1975、MKN-74、CCD-8Lu及WI-38細胞在含有10% FBS的DMEM培養基中培養。培養24小時後,分別用0.5 μM小紅莓(DOX)或DOX_MT
α-HER2scFv處理細胞,且在144小時後,藉由WST-1分析法評估細胞增殖抑制能力。此時,僅粒線體處理組(MT
α-HER2scFv)用作DOX_MT
α-HER2scFv的陰性對照。使用Graphpad 5.0軟體進行統計處理,並用單因子ANOVA (圖基氏(Turkey's))檢定量測p值(*p<0.05、**p<0.01及***p<0.001)。
結果,如圖24所示,對於癌細胞及正常細胞中之未處理組(NC),在僅粒線體處理組(MT
α-HER2scFv)中未觀察到細胞增殖抑制作用。在DOX處理組及DOX_MT
α-HER2scFv處理組的情況下,與未處理組相比,在癌細胞中顯示出約50%至80%或更高的細胞增殖抑制作用,而在正常細胞中顯示出約25%或更低的細胞增殖抑制作用。
實例4.8. 藉由TUNEL 分析確認藉由用DOX_MT
α-HER2scFv 處理引起的癌細胞凋亡
為了確認以與上述製備實例2相同的方式獲得的DOX_MT
α-HER2scFv在癌細胞中之凋亡誘導活性,在用DOX_MT
α-HER2scFv處理人類乳癌及胃癌細胞系後,進行了TUNEL分析。
具體而言,將人類乳癌細胞系(SK-BR-3及BT-474)及人類胃癌細胞系(NCI-N87)以約3×10
4個細胞/孔接種至24孔盤中,且培養24小時。培養24小時後,用MT
α-HER2scFv或1 μM DOX_MT
α-HER2scFv處理細胞,且48小時後,進行TUNEL分析以確認細胞凋亡。此時,僅粒線體處理組(MT
α-HER2scFv)用作DOX_MT
α-HER2scFv的對照組。藉由用DAPI染色來觀察細胞核。
結果,在僅粒線體處理組(MT
α-HER2scFv)中幾乎沒有觀察到細胞凋亡(綠色螢光)。然而,在DOX_MT
α-HER2scFv處理組的細胞核中觀察到細胞凋亡增加。根據以上結果,確認了DOX_MT
α-HER2scFv處理誘導了細胞凋亡(圖25)。
實例4.9. 經由西方墨點分析確認藉由用DOX_MT
α-HER2scFv 處理引起的癌細胞凋亡
為了確認以與上述製備實例2相同的方式獲得的DOX_MT
α-HER2scFv在癌細胞中之凋亡作用,在人類乳癌細胞系中用DOX_MT
α-HER2scFv處理後,使用抗凋亡標誌物抗體進行西方墨點法。
具體而言,將人類乳癌細胞系(SK-BR-3及BT-474)分別以約5×10
6個細胞/孔接種至6孔盤中,且培養24小時。培養24小時後,分別用MT
α-HER2scFv或DOX_MT
α-HER2scFv處理細胞,且96小時後,裂解細胞,提取蛋白質,且進行西方墨點法。將抗切割PARP抗體(Cell signaling,9541S)、抗切割凋亡蛋白酶3抗體(Cell signaling,9664S)、抗磷酸化p53抗體(ABclonal,AP0762)及抗β肌動蛋白抗體(Sigma,A2228)用作一級抗體。將抗小鼠IgG HRP或抗兔IgG HRP用作二級抗體。經由β肌動蛋白的表現位準校正蛋白質的量。此時,僅粒線體處理組(MT
α-HER2scFv)用作DOX_MT
α-HER2scFv的陰性對照。
結果,在僅粒線體處理組(MT
α-HER2scFv)中,與未處理組(無處理)相似,未觀察到在細胞凋亡過程中觀察到的PARP及凋亡蛋白酶3的切割形式,且p53的磷酸化形式係亦沒有觀察到。另一方面,在DOX_MT
α-HER2scFv處理組中,觀察到磷酸化p53的表現以及PARP及凋亡蛋白酶3的切割形式(圖26)。根據以上結果,確認了DOX_MT
α-HER2scFv處理誘導了細胞凋亡。
實例4.10. 經由流動式細胞測量術確認DOX_MT
α-HER2scFv 引起的癌細胞凋亡
為了確認以與上述製備實例2相同的方式獲得的DOX_MT
α-HER2scFv在癌細胞中之凋亡作用,在用DOX_MT
α-HER2scFv處理人類乳癌及胃癌細胞系後,藉由用磷脂結合蛋白V/PI染色來進行流動式細胞測量術。
具體而言,將人類乳癌細胞系(SK-BR-3及BT-474)及人類胃癌細胞系(NCI-N87)分別以約5×10
6個細胞/孔接種至6孔盤中,且培養24小時。培養24小時後,用MT
α-HER2scFv或1 μM DOX_MT
α-HER2scFv處理細胞。處理96小時後,將細胞用PBS洗滌二次並藉由用0.05%胰蛋白酶-EDTA處理獲得。將獲得的細胞離心,接著用PBS洗滌以除去0.05%胰蛋白酶-EDTA。此後,使用磷脂結合蛋白V/PI染色套組(Roche,11988549001)將細胞染色10分鐘,並使用FACS設備(Beckman Coulter,CytoFLEX)分析染色的細胞。此時,僅粒線體處理組(MT
α-HER2scFv)用作DOX_MT
α-HER2scFv的陰性對照。
結果,對於未處理組(NC),在僅粒線體處理組(MT
α-HER2scFv)中未觀察到磷脂結合蛋白V/PI值的變化。另一方面,磷脂結合蛋白V/PI值在DOX_MT
α-HER2scFv處理組中增加(圖27)。根據以上結果,確認了DOX_MT
α-HER2scFv處理誘導了細胞凋亡。
實例4.11. 評估DOX_MT
α-HER2scFv 對表現HER2 的細胞的選擇性凋亡誘導活性
為了確認以與上述製備實例2相同之方法獲得的DOX_MT
α-HER2scFv的HER2選擇性凋亡誘導作用,將共培養的HER2
+癌細胞及HER2
-正常細胞用DOX_MT
α-HER2scFv處理,接著進行TUNEL分析及免疫細胞化學染色。
具體而言,將人類乳癌細胞系BT-474 (HER2
+)及人類肺纖維母細胞系WI-38 (HER2
-)以3×10
4個細胞/孔一起接種至24孔盤中,並在含有10% FBS的DMEM培養基中共培養24小時。此時,BT-474細胞藉由在含有10% FBS的RPMI-1640培養基中培養來製備,而WI-38細胞藉由在含有10% FBS的DMEM培養基中培養來製備。培養24小時後,共培養的細胞用1 μM DOX_MT
α-HER2scFv處理並再培養48小時。藉由TUNEL分析及免疫細胞化學染色評估細胞凋亡(圖28)。
實例4.12. 藉由TUNEL 分析確認DOX_MT
α-HER2scFv 對表現HER2 的細胞的選擇性凋亡誘導活性
以與上述實例4.11相同的方式處理的細胞用PBS洗滌二次,接著藉由添加3.7%甲醛在室溫下固定30分鐘。此後,將抗HER2抗體(Cell Signaling Technology,2165)用作一級抗體,且將用Alexa Fluor®555標記的抗兔IgG抗體(Invitrogen,21428)用作二級抗體,且HER2
+細胞用紅色螢光標記。之後,用TUNEL溶液染色細胞30分鐘,且將發生凋亡的細胞用綠色螢光標記並封固,且用共焦顯微鏡觀察細胞。此時,藉由用DAPI染色來觀察細胞核。
結果,僅在作為HER2
+癌細胞的BT-474細胞(白色箭頭)中選擇性地觀察到強綠色螢光(圖29)。由以上結果確認,DOX_MT
α-HER2scFv引起的細胞凋亡可以根據HER2表現的有無而被選擇性地誘導。
製備實例3. 製備三苯基鏻- 小紅莓結合之化合物
為了將抗癌藥物小紅莓(DOX)有效地遞送至經分離粒線體中,將能夠靶向粒線體之化合物與小紅莓融合。最具代表的靶向粒線體之化合物係三苯基鏻(TPP),且結合至TPP之抗癌劑使用「Mitochondrial Delivery of Doxorubicin via Triphenylphosphine Modification for Overcoming Drug Resistance in MDA-MB-435/DOX Cells」(Molecular Pharmaceutics, 11 (8), 2640-2649)中已知之方法如圖30所示反應,從而製備TPP-小紅莓(TPP-DOX),並且藉由化合物的MRI分析確認該化合物係TPP-小紅莓(圖31)。
製備實例4. 製備粒線體-TPP 與小紅莓的複合物
用MitoTracker綠色處理表現抗HER2scFv抗體的HEK293細胞以染色粒線體,接著分離粒線體MT
α-HER2scFv。其後,將30 µg與抗HER2scFv抗體融合之粒線體(MT
α-HER2scFv)與100 µM TPP-小紅莓在4℃下反應10分鐘,接著以約12,000×g離心10分鐘以去除未反應的TPP-小紅莓。將反應產物用500 μL SHE (250 mM蔗糖、20 mM HEPES (pH7.4)、2 mM EGTA)緩衝液洗滌二次,最終獲得包含TPP-小紅莓之粒線體(TPP-DOX_MT
α-HER2scFv) (圖32)。
實例5. 評估TPP-DOX_MT
α-HER2scFv 對癌細胞的抗癌活性 實例5.1. 確認TPP-DOX_MT
α-HER2scFv 向癌細胞的遞送性質
用以與上述製備實例4相同的方式獲得的TPP-DOX_MT
α-HER2scFv分別處理人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)及人類肺癌細胞系(NCI-H1975),接著利用共焦顯微鏡觀察細胞。此時,藉由用DAPI染色來觀察細胞核。
結果,在細胞質中之相同位置觀察到經MitoTracker綠色染色之粒線體(MT
α-HER2scFv)及顯示紅色螢光的小紅莓(TPP-DOX) (圖33)。由以上結果確認,由TPP-DOX_MT
α-HER2scFv轉運的TPP-DOX及MT
α-HER2scFv均位於細胞質中。
實例5.2. 確認藉由用TPP-DOX_MT
α-HER2scFv 處理引起的癌細胞的形態變化
用以與上述製備實例4相同的方式獲得的TPP-DOX_MT
α-HER2scFv分別處理人類乳癌細胞系(SK-BR-3及BT-474)及人類胃癌細胞系(NCI-N87),並且接著藉由共焦顯微鏡觀察癌細胞隨時間的形態變化。此時,藉由用DAPI染色來觀察細胞核。
結果,在用TPP-DOX_MT
α-HER2scFv(黃色螢光)處理12小時後,觀察到大部分TPP-DOX (紅色螢光)一起存在於粒線體(綠色螢光)中。然而,隨著時間的推移,在細胞核中觀察到TPP-DOX,並且在用TPP-DOX_MT
α-HER2scFv處理72小時後,明顯觀察到細胞的形態變化(圖34)。
實例5.3. 確認用每種濃度的TPP-DOX_MT
α-HER2scFv 處理癌細胞的增殖抑制能力
為了確認以與上述製備實例4相同的方式獲得的TPP-DOX_MT
α-HER2scFv的抗癌活性,評估用TPP-DOX_MT
α-HER2scFv處理人類乳癌、肺癌及胃癌細胞系的細胞增殖抑制作用。
具體而言,將人類乳癌(SK-BR-3、BT-474及MDA-MB-231)、肺癌(NCI-H1975)及胃癌(NCI-N87及MKN-74)細胞系分別以約3×10
3個細胞/孔接種至96孔盤中,且培養24小時。此時,人類乳癌細胞系(SK-BR-3及BT-474)及人類胃癌細胞系(NCI-N87)在含有10% FBS的RPMI-1640培養基中培養,且人類乳癌細胞系細胞系MDA-MB-231、人類肺癌細胞系NCI-H1975及人類胃癌細胞系MKN-74在含有10% FBS的DMEM培養基中培養。培養24小時後,用濃度為2 μM、1 μM、0.5 μM、0.25 μM、0.1 μM、0.05 μM、0.025 μM及0.01 μM的TPP-DOX或TPP-DOX_MT
α-HER2scFv處理每種細胞。樣品處理144小時後,藉由WST-1分析來量測細胞增殖。此時,僅粒線體處理組(MT,MT
α-HER2scFv)用作TPP-DOX_MT
α-HER2scFv的陰性對照。
結果,如圖35所示,對於未處理組(NC),在僅粒線體處理組(MT)中未觀察到細胞增殖抑制作用。另一方面,在TPP-DOX處理組及TPP-DOX_MT
α-HER2scFv處理組中,癌細胞增殖以濃度依賴性方式受到抑制。特定言之,確認了當用1 μM TPP-DOX_MT
α-HER2scFv處理時,與未處理組相比,取決於癌細胞系,細胞生長被抑制了約60%至70%。
實例5.4. 確認用每種濃度的TPP-DOX_MT
α-HER2scFv 處理正常細胞的增殖抑制能力
為了確認以與上述製備實例4相同的方式獲得的TPP-DOX_MT
α-HER2scFv對正常細胞中之細胞增殖的影響,評估了用TPP-DOX_MT
α-HER2scFv處理人類肺纖維母細胞之後的細胞增殖抑制作用。
具體而言,將人類肺纖維母細胞系WI-38及CCD-8Lu分別以約3×10
3個細胞/孔接種至96孔盤中,且培養24小時。此時,WI-38及CCD-8Lu在含有10% FBS的DMEM培養基中培養。培養24小時後,用濃度為2 μM、1 μM、0.5 μM、0.25 μM、0.1 μM、0.05 μM、0.025 μM及0.01 μM的TPP-DOX或TPP-DOX_MT
α-HER2scFv處理每種細胞。樣品處理144小時後,藉由WST-1分析來量測細胞增殖。此時,僅粒線體處理組(MT,MT
α-HER2scFv)用作TPP-DOX_MT
α-HER2scFv的陰性對照。
結果,如圖36所示,對於未處理組(NC),在僅粒線體處理組(MT)中未觀察到細胞增殖抑制作用。此外,確認了在TPP-DOX處理組及TPP-DOX_MT
α-HER2scFv處理組中,細胞增殖抑制能力弱於癌細胞。
實例5.5. 分析用TPP-DOX_MT
α-HER2scFv 處理癌細胞及正常細胞的IC
50 值
基於實例5.3及實例5.4中每種濃度的TPP-DOX_MT
α-HER2scFv的細胞增殖抑制結果,對每種細胞中之IC
50值進行分析且顯示在圖37中。
實例5.6. 比較用TPP-DOX_MT
α-HER2scFv 處理癌細胞及正常細胞的增殖抑制能力
為了比較以與上述製備實例4相同的方式獲得的TPP-DOX_MT
α-HER2scFv對癌細胞及正常細胞之細胞增殖的影響,用相同濃度的TPP-DOX_MT
α-HER2scFv處理人類乳癌、肺癌、胃癌細胞系及肺纖維母細胞系之後,量測細胞增殖抑制能力。
具體而言,人類乳癌(SK-BR-3、BT-474及MDA-MB-231)、肺癌(NCI-H1975)、胃癌(MKN-74及NCI-N87)細胞系及肺纖維母細胞系(CCD-8Lu及WI-38)分別以約3×10
3個細胞/孔接種至96孔盤中,且培養24小時。此時,SK-BR-3、BT-474及NCI-N87細胞在含有10% FBS的RPMI-1640培養基中培養,且MDA-MB-231、NCI-H1975、MKN-74、CCD-8Lu及WI-38細胞在含有10% FBS的DMEM培養基中培養。培養24小時後,分別用0.5 μM TPP-DOX或TPP-DOX_MT
α-HER2scFv處理細胞,且144小時後,藉由WST-1分析評估細胞增殖抑制能力。此時,僅粒線體處理組(MT
α-HER2scFv)用作TPP-DOX_MT
α-HER2scFv的陰性對照。使用Graphpad 5.0軟體進行統計處理,並用單因子ANOVA (圖基氏)檢定量測p值(*p<0.05,**p<0.01及***p<0.001)。
結果,如圖38所示,對於癌細胞及正常細胞中之未處理組(NC),在僅粒線體處理組(MT
α-HER2scFv)中未觀察到細胞增殖抑制作用。在僅TPP-DOX處理組及TPP-DOX_MT
α-HER2scFv處理組的情況下,與未處理組相比,在癌細胞中顯示出約60%至75%或更高的細胞增殖抑制作用。但是,確認了與在癌細胞中不同,在正常細胞中的增殖抑制能力較弱。
實例5.7. 藉由TUNEL 分析確認TPP-DOX_MT
α-HER2scFv 引起的癌細胞凋亡
為了確認以與上述製備實例4相同的方式獲得的TPP-DOX_MT
α-HER2scFv在癌細胞中之凋亡誘導活性,在用TPP-DOX_MT
α-HER2scFv處理人類乳癌及胃癌細胞系後,進行TUNEL分析。
具體而言,將人類乳癌細胞系(SK-BR-3及BT-474)及人類胃癌細胞系(NCI-N87)分別以約3×10
4個細胞/孔接種至24孔盤中,並進行培養24小時。培養24小時後,用MT
α-HER2scFv或1 μM TPP-DOX_MT
α-HER2scFv處理細胞,且48小時後,進行TUNEL分析以確認細胞凋亡。此時,僅粒線體處理組(MT
α-HER2scFv)用作TPP-DOX_MT
α-HER2scFv的對照組。藉由用DAPI染色來觀察細胞核。
結果,在僅粒線體處理組(MT
α-HER2scFv)中幾乎沒有觀察到細胞凋亡(綠色螢光)。然而,在TPP-DOX_MT
α-HER2scFv處理組的細胞核中觀察到細胞凋亡增加。根據以上結果,確認了藉由TPP-DOX_MT
α-HER2scFv處理誘導了細胞凋亡(圖39)。
實例5.8. 經由西方墨點分析確認藉由用TPP-DOX_MT
α-HER2scFv 處理引起的癌細胞凋亡
為了確認藉由用以與上述製備實例4相同的方式獲得的TPP-DOX_MT
α-HER2scFv處理癌細胞引起的細胞凋亡作用,在用TPP-DOX_MT
α-HER2scFv處理人類乳癌及胃癌細胞系後,使用抗凋亡標誌物之抗體進行西方墨點法。
具體而言,將人類乳癌細胞系(SK-BR-3及BT-474)及人類胃癌細胞系(NCI-N87)分別以約5×10
6個細胞/孔接種至6孔盤中,並培養24小時。培養24小時後,分別用MT
α-HER2scFv或1 μM TPP-DOX_MT
α-HER2scFv處理細胞,且96小時後,破壞細胞,提取蛋白質,且進行西方墨點法。將抗切割PARP抗體(Cell signaling,9541S)、抗切割凋亡蛋白酶3抗體(Cell signaling,9664S)、抗磷酸化p53抗體(ABclonal,AP0762)及抗β肌動蛋白抗體(Sigma,A2228)用作一級抗體。將抗小鼠IgG HRP或抗兔IgG HRP用作二級抗體。經由β肌動蛋白的表現位準校正蛋白質的量。此時,僅粒線體處理組(MT
α-HER2scFv)用作TPP-DOX_MT
α-HER2scFv的對照組。
結果,在僅粒線體處理組(MT
α-HER2scFv)中,與未處理組(無處理)相似,未觀察到在細胞凋亡過程中觀察到的PARP及凋亡蛋白酶3的切割形式,且p53的磷酸化形式亦沒有觀察到。另一方面,在TPP-DOX_MT
α-HER2scFv處理組中,觀察到磷酸化p53的表現以及PARP及凋亡蛋白酶3的裂解形式(圖40)。根據以上結果,確認了用TPP-DOX_MT
α-HER2scFv處理誘導了細胞凋亡。
實例5.9. 經由流動式細胞測量術確認藉由用TPP-DOX_MT
α-HER2scFv 處理引起的癌細胞凋亡
為了確認藉由用以與上述製備實例4相同的方式獲得的TPP-DOX_MT
α-HER2scFv處理癌細胞引起的細胞凋亡作用,在用TPP-DOX_MT
α-HER2scFv處理人類乳癌及胃癌細胞系後,藉由用磷脂結合蛋白V/PI染色進行流動式細胞測量術。
具體而言,將人類乳癌細胞系(SK-BR-3及BT-474)及人類胃癌細胞系(NCI-N87)分別以約5×10
6個細胞/孔接種至6孔盤中,且培養24小時。培養24小時後,用MT
α-HER2scFv或1 μM TPP-DOX_MT
α-HER2scFv處理細胞。96小時後,將細胞用PBS洗滌二次並藉由用0.05%胰蛋白酶-EDTA處理獲得。將獲得的細胞離心,且接著用PBS洗滌以除去0.05%胰蛋白酶-EDTA。此後,使用磷脂結合蛋白V/PI染色套組(Roche,11988549001)將細胞染色10分鐘,並使用FACS設備(Beckman Coulter,CytoFLEX)分析染色的細胞。此時,僅粒線體處理組(MT
α-HER2scFv)用作TPP-DOX_MT
α-HER2scFv的陰性對照。
結果,對於未處理組(NC),在僅粒線體處理組(MT
α-HER2scFv)中未觀察到磷脂結合蛋白V/PI值的變化。另一方面,磷脂結合蛋白V/PI值在TPP-DOX_MT
α-HER2scFv處理組中增加(圖41)。根據以上結果,確認了TPP-DOX_MT
α-HER2scFv處理誘導了細胞凋亡。
實例5.10. 評估TPP-DOX_MT
α-HER2scFv 對表現HER2 的細胞的選擇性凋亡誘導活性
為了確認以與上述製備實例4相同之方法獲得的TPP-DOX_MT
α-HER2scFv的HER2選擇性凋亡誘導作用,將共培養的HER2
+癌細胞及HER2
-正常細胞用TPP-DOX_MT
α-HER2scFv處理,並且接著進行TUNEL分析及免疫細胞化學染色。
具體而言,將人類乳癌細胞系SK-BR-3 (HER2
+)及人類肺纖維母細胞系CCD-8Lu (HER2
-)以3×10
4個細胞/孔一起接種至24孔盤中,並在含有10% FBS的DMEM培養基中共培養24小時。此時,SK-BR-3細胞藉由在含有10% FBS的RPMI-1640培養基中培養來製備,且WI-38細胞藉由在含有10% FBS的DMEM培養基中培養來製備。培養24小時後,共培養的細胞用1 μM TPP-DOX_MT
α-HER2scFv處理,且再培養48小時。藉由TUNEL分析及免疫細胞化學染色評估細胞凋亡(圖42)。
實例5.11. 藉由TUNEL 分析確認TPP-DOX_MT
α-HER2scFv 對表現HER2 的細胞的選擇性凋亡誘導活性
以與上述實例5.10相同的方式處理的細胞用PBS洗滌二次,接著藉由添加3.7%甲醛在室溫下固定30分鐘。此後,將抗HER2抗體(Cell Signaling,29D8)用作一級抗體,且將Alexa Fluor®555 (Invitrogen,21428)用作二級抗體,且HER2
+細胞被紅色螢光標記。之後,用TUNEL溶液染色細胞30分鐘,且將發生凋亡的細胞用綠色螢光標記並封固,用共焦顯微鏡觀察細胞。此時,藉由用DAPI染色來觀察細胞核。
結果,僅在作為HER2
+細胞的SK-BR-3細胞(白色箭頭)中選擇性地觀察到強綠色螢光(圖43)。由以上結果確認,TPP-DOX_MT
α-HER2scFv引起的細胞凋亡可以根據HER2表現的有無而被選擇性地誘導。
製備實例5. 製備包含與抗PDL1scFv 抗體融合之粒線體的HEK293 細胞系
為了將粒線體特異性引入至表現PDL1之腫瘤細胞中,構築了其中特異性結合PDL1的抗PDL1scFv抗體(SEQ ID NO: 94)與粒線體外膜融合之粒線體(圖44及45)。具體的構築方法根據韓國專利申請公開案第10-2019-0124656號中描述之方法進行。
實例6. 經由西方墨點分析對人類癌細胞系中的PDL1 表現進行分析
進行西方墨點法以確認人類胰臟癌細胞系(BXPC-3及CFPAC-1)及人類胃癌細胞系(SNU-216及SNU-484)中PDL1的表現位準。
具體而言,將人類胰臟癌細胞系(BXPC-3及CFPAC-1)及人類胃癌細胞系(SNU-216及SNU-484)以約1×10
6個細胞/孔接種至6孔盤中,接著在含有10% FBS的DMEM培養基中培養24小時。24小時後,除去培養液,且用PBS洗滌細胞二次,接著直接向細胞中加入100 μL含有蛋白酶抑制劑的RIPA緩衝液。10分鐘後,用刮刀回收細胞,將其轉移至微量離心管中,接著以約12,000×g離心10分鐘。獲得分離的上清液並將其轉移至新的微量離心管中,接著使用BCA分析對蛋白質進行定量。對每個樣品的相同量的蛋白質進行電泳,接著進行西方墨點法。將抗PDL1抗體(Cell signaling,13684)及抗β微管蛋白抗體(Thermo Fisher,MA5-16308)用作一級抗體,且將抗小鼠IgG HRP抗體或抗兔IgG HRP抗體用作二級抗體。
結果,如圖46所示,確認BXPC-3及SNU-216細胞係表現PDL1的PDL1
+細胞。另一方面,確認CFPAC-1及SNU-484細胞幾乎沒有顯示PDL1表現,表明其係PDL1
-細胞。
實例7. 驗證與抗PDL1scFv 抗體融合之粒線體的PDL1 靶向性
為了確認以與上述製備實例5中構築的抗PDL1scFv抗體融合之粒線體的PDL1靶向能力,將與抗PDL1scFv抗體融合之粒線體(MT
α-PDL1scFv)用共培養之PDL1
+細胞及PDL1
-細胞處理,接著進行免疫細胞化學染色。
具體而言,將BXPC-3 (PDL1
+)及CFPAC-1 (PDL1
-),或SNU-216 (PDL1
+)及SNU-484 (PDL1
-)以1.5×10
4個細胞/孔一起接種至24孔盤中,且在含有10% FBS的DMEM培養基中共培養24小時。藉由用MitoTracker紅色處理未經處理的HEK293細胞(MT)及包含與抗PDL1scFv抗體融合之粒線體(MT
α-PDL1scFv)的HEK293細胞且接著分離粒線體來製備用作樣品之粒線體。共培養24小時後,用共培養的細胞處理每個經分離粒線體並反應24小時(圖47)。
實例7.1. 確認與抗PDL1scFv 抗體融合之粒線體在PDL1 陽性及陰性細胞系中之位置
將以與上述實例4相同方式處理的細胞用PBS洗滌一次,且藉由添加3.7%甲醛在室溫下固定30分鐘,接著進行免疫細胞化學染色。此時,將抗PDL1抗體(Cell Signaling,86744)用作一級抗體,且將Alexa Fluor 488山羊抗兔IgG (H+L)用作二級抗體。藉由用DAPI染色來觀察細胞核。
結果,如圖48所示,當用未經處理的HEK293細胞衍生之粒線體(MT)處理共培養的BXPC-3 (PDL1
+)及CFPAC-1 (PDL1
-)細胞時,在BXPC-3 (PDL1
+)及CFPAC-1 (PDL1
-)細胞中同樣觀察到用Mitotracker紅色染色之粒線體(紅色螢光)。另一方面,當細胞用衍生自包含與抗PDL1scFv抗體融合之粒線體之HEK293細胞的粒線體(MT
α-PDL1scFv)處理時,在PDL1
+細胞BXPC-3細胞中特異性地觀察到了用Mitotracker紅色染色之粒線體。
此外,同樣地,在共培養的SNU-216 (PDL1
+)及SNU-484 (PDL1
-)細胞的情況下,在MT處理組的情況下,在PDL1
+(SNU-216)及SNU-484 (PDL1
-)細胞中同樣觀察到用Mitotracker紅色染色之粒線體,而在MT
α-PDL1scFv處理組的情況下,僅在PDL1
+細胞SNU-216細胞中特異性觀察該等粒線體。由以上結果可知,與抗PDL1scFv抗體融合之粒線體特異性靶向表現PDL1抗原的細胞。
製備實例6. 製備與抗PDL1scFv 抗體融合之粒線體及小紅莓的複合物
將自包含與抗PDL1scFv抗體融合之粒線體的HEK293細胞中分離出的30 µg粒線體(MT
α-PDL1scFv)與100 μM小紅莓(DOX)在4℃下反應10分鐘,接著以約12,000×g離心10分鐘以去除未反應的小紅莓。此後,將其用500 μL SHE (250 mM蔗糖、20 mM HEPES (pH7.4)、2 mM EGTA)緩衝液洗滌二次,最終獲得包含小紅莓之粒線體(DOX_MT
α-PDL1scFv) (圖49)。
實例8. 評估DOX_MT
α-PDL1scFv 對癌細胞的抗癌活性 實例8.1. 確認藉由用每種濃度的DOX_MT
α-PDL1scFv 處理產生的細胞增殖抑制能力
為了確認以與上述製備實例6相同的方式獲得的DOX_MT
α-PDL1scFv的抗癌活性,在用DOX_MT
α-PDL1scFv處理人類胰臟癌及胃癌細胞系後,評估細胞增殖抑制作用。
具體而言,將人類胰臟癌細胞系(BXPC-3及CFPAC-1)及人類胃癌細胞系(SNU-216及SNU-484)以約5×10
3個細胞/孔接種至96孔盤中並培養24小時。培養24小時後,用濃度為0.01 μM、0.025 μM、0.05 μM、0.1 μM、0.25 μM、0.5 μM及1 μM的DOX_MT
α-PDL1scFv處理每種細胞。每24小時藉由WST-1分析量測細胞增殖,直至樣品處理後168小時。此時,僅粒線體處理組(MT
α-PDL1scFv)用作DOX_MT
α-PDL1scFv的陰性對照。
結果,對於未處理組(NC),在僅粒線體處理組(MT
α-PDL1scFv)中未觀察到細胞增殖抑制作用。另一方面,在DOX_MT
α-PDL1scFv處理組中,癌細胞增殖隨時間以濃度依賴性方式被抑制(圖50)。
實例8.2. 經由西方墨點分析確認DOX_MT
α-PDL1scFv 引起的癌細胞凋亡
為了確認DOX_MT
α-PDL1scFv在癌細胞中之凋亡作用,在人類胰臟癌及胃癌細胞系中用DOX_MT
α-PDL1scFv處理後,使用抗凋亡標誌物之抗體進行西方墨點法。
具體而言,分別以約5×10
6個細胞/孔接種人類胰臟癌細胞系(BXPC-3及CFPAC-1)及人類胃癌細胞系(SNU-216及SNU-484),且培養24小時。
培養24小時後,分別用MT
α-PDL1scFv或DOX_MT
α-PDL1scFv處理細胞,且96小時後,破壞細胞,提取蛋白質,且進行西方墨點法。將抗切割PARP抗體(Cell signaling,9541S)、抗切割凋亡蛋白酶3抗體(Cell signaling,9664)、抗磷酸化p53抗體(ABclonal,AP0762)及抗β肌動蛋白抗體(Sigma,A2228)用作一級抗體,將抗小鼠IgG HRP或抗兔IgG HRP用作二級抗體。經由β肌動蛋白的表現位準校正蛋白質的量。此時,僅粒線體處理組(MT
α-PDL1scFv)用作DOX_MT
α-PDL1scFv的陰性對照。
結果,在僅粒線體處理組(MT
α-PDL1scFv)中,與未處理組(無處理)相似,未觀察到在細胞凋亡過程中觀察到的PARP及凋亡蛋白酶3的切割形式,並且p53的磷酸化形式亦沒有觀察到。另一方面,在DOX_MT
α-PDL1scFv處理組中,觀察到磷酸化p53的表現以及PARP及凋亡蛋白酶3的裂解形式(圖51)。根據以上結果,確認了DOX_MT
α-PDL1scFv處理誘導了細胞凋亡。
製備實例7. 製備包含與抗MSLN scFv 抗體融合之粒線體的HEK293 細胞系
為了將粒線體特異性引入至表現間皮素(MSLN)之腫瘤細胞中,構築了其中特異性結合MSLN的抗MSLNscFv抗體(SEQ ID NO: 102)與粒線體外膜融合之粒線體(圖52及53)。具體的方法根據韓國專利申請公開案第10-2019-0124656號中描述之方法進行。
製備實例8. 製備與抗MSLNscFv 抗體融合之粒線體及去鎂葉綠素酸A 的複合物
將自包含與抗MSLNscFv抗體融合之粒線體的HEK293細胞中分離出的100 µg粒線體(MT
α-MSLNscFv)與100 μM去鎂葉綠素酸A (PBA)在4℃下反應10分鐘,接著以約12,000×g離心10分鐘以去除未反應的去鎂葉綠素酸A。此後,將其用500 μL SHE (250 mM蔗糖、20 mM HEPES (pH7.4)、2 mM EGTA)緩衝液洗滌二次,最終獲得包含去鎂葉綠素酸A之粒線體(PBA_MT
α-MSLNscFv) (圖54)。
實例9. 確認藉由用PBA_MT
α-MSLNscFv 處理產生的細胞增殖抑制能力
為了確認以與上述製備實例8相同的方式獲得的PBA_MT
α-MSLNscFv的抗癌活性,在用PBA_MT
α-MSLNscFv處理人類胰臟癌細胞系後,評估細胞增殖抑制作用。
具體而言,將人類胰臟癌細胞系AsPC-1、Capan-1、Capan-2及Mia PaCa-2以5×10
3個細胞/孔接種至96孔盤中,且培養24小時。此後,用MT
α-MSLNscFv或1 μg PBA-MT
α-MSLNscFv處理細胞並再培養72小時,接著藉由WST-1分析評估細胞增殖。此時,僅粒線體處理組(MT
α-MSLNscFv)用作PBA_MT
α-MSLNscFv的陰性對照。
結果,對於未處理組(CTR),在僅粒線體處理組(MT
α-MSLNscFv)中未觀察到細胞增殖抑制作用。另一方面,確認了在PBA_MT
α-MSLNscFv處理組中,與未處理組相比,細胞生長被抑制了約80%至95% (圖55至58的底部)。
此外,藉由倒置顯微鏡觀察每種胰臟癌細胞系中MT
α-MSLNscFv及PBA_MT
α-MSLNscFv處理後的形態變化。在MT
α-MSLNscFv處理組中,與未處理組相比,幾乎沒有觀察到形態變化,而在PBA_MT
α-MSLNscFv處理組中,確認了所有癌細胞系中之細胞形態發生了改變(圖55至58的頂部)。
製備實例9. 製備與抗MSLNscFv 抗體融合之粒線體及吉西他濱的複合物
將自包含與抗MSLNscFv抗體融合之粒線體的HEK293細胞中分離出的100 µg粒線體與100 μM吉西他濱(Gem)在4℃下反應10分鐘,接著以約12,000×g離心10分鐘以去除未反應的吉西他濱。此後,將其用500 μL SHE (250 mM蔗糖、20 mM HEPES (pH7.4)、2 mM EGTA)緩衝液洗滌二次,最終獲得包含吉西他濱之粒線體(Gem_MT
α-MSLNscFv) (圖59)。
實例10. 確認藉由用Gem_MT
α-MSLNscFv 處理產生的細胞增殖抑制能力
為了確認以與上述製備實例9相同的方式獲得的Gem_MT
α-MSLNscFv的抗癌活性,在用Gem_MT
α-MSLNscFv處理人類胰臟癌細胞系後,評估細胞增殖抑制作用。
具體而言,將人類胰臟癌細胞系AsPC-1、Capan-1、Capan-2及Mia PaCa-2分別以約5×10
3個細胞/孔接種至96孔盤中,且培養24小時。培養24小時後,用MT
α-MSLNscFv或2 μg Gem_MT
α-MSLNscFv處理每種細胞並再培養72小時,接著藉由WST-1分析來量測細胞增殖。此時,僅粒線體處理組(MT
α-MSLNscFv)用作Gem_MT
α-MSLNscFv的陰性對照。
結果,對於未處理組(CTR),在僅粒線體處理組(MT
α-MSLNscFv)中未觀察到細胞增殖抑制作用。另一方面,根據癌細胞系,Gem_MT
α-MSLNscFv處理組與未處理組相比,確認了約20%至30%的細胞增殖抑制作用(圖60)。
製備實例10. 製備與抗MSLNscFv 抗體融合之粒線體及長春瑞濱的複合物
將自包含與抗MSLNscFv抗體融合之粒線體的HEK293細胞中分離出的100 µg粒線體(MT
α-MSLNscFv)與100 μM長春瑞濱(VIBE)在4℃下反應10分鐘,接著以約12,000×g離心10分鐘以去除未反應的長春瑞濱。此後,將其用500 μL SHE (250 mM蔗糖、20 mM HEPES (pH7.4)、2 mM EGTA)緩衝液洗滌二次,最終獲得包含長春瑞濱之粒線體(VIBE_MT
α-MSLNscFv) (圖61)。
實例11. 確認藉由用VIBE_MT
α-MSLNscFv 處理產生的細胞增殖抑制能力
為了確認以與上述製備實例10相同的方式獲得的VIBE_MT
α-MSLNscFv的抗癌活性,在用VIBE_MT
α-MSLNscFv處理人類胰臟癌細胞系後,評估細胞增殖抑制作用。
具體而言,將人類胰臟癌細胞系AsPC-1、Capan-1、Capan-2及MIAPaCa-2分別以約5×10
3個細胞/孔接種至96孔盤中,且培養24小時。培養24小時後,用MT
α-MSLNscFv或2 μg VIBE_MT
α-MSLNscFv處理每種細胞,且再培養72小時,接著藉由WST-1分析來量測細胞增殖。此時,僅粒線體處理組(MT
α-MSLNscFv)用作VIBE_MT
α-MSLNscFv的陰性對照。
結果,對於未處理組(CTR),在僅粒線體處理組(MT
α-MSLNscFv)中未觀察到細胞增殖抑制作用。另一方面,確認了VIBE_MT
α-MSLNscFv處理組與未處理組相比顯示出視癌細胞系而定約50%的細胞增殖抑制作用(圖62)。
實例12. 驗證MT
α-HER2scFv 在異種移植腫瘤小鼠模型中之腫瘤細胞靶向性
5週齡BALB/c雄性裸鼠(初始體重18至20 g) (Nara Biotech)適應1週後,將HER2
+人類胃癌細胞系NCI-N87以1×10
7個細胞/小鼠皮下移植至側腹,從而構築異種移植腫瘤模型小鼠。當腫瘤的平均體積達至50 mm
3或更大時,靜脈內投予20 µg MT
α-HER2scFv。24小時後,提取小鼠組織。使用抗myc抗體藉由免疫組織化學染色分析每個提取的組織以確認MT
α-HER2scFv在小鼠組織中之分佈(圖63)。
實例12.1. 確認MT
α-HER2scFv 在異種移植腫瘤小鼠模型中的腫瘤細胞靶向性
對以與上述實例12相同的方式處理的小鼠的組織進行免疫組織化學染色。將粒線體MT
α-HER2scFv標記的抗myc抗體(Roche,11667149001)用作一級抗體,且將用Alexa Fluor® 488標記的抗小鼠IgG抗體(Invitrogen,11001)用作二級抗體。此時,藉由用DAPI染色來觀察細胞核。
結果,在腎及肝組織中未觀察到MT
α-HER2scFv,但在腫瘤組織中觀察到MT
α-HER2scFv(圖64)。由以上結果確認,注射至小鼠靜脈中之MT
α-HER2scFv特異性靶向皮下移植至小鼠側腹部的NCI-N87 (HER2
+)腫瘤細胞。
實例13. 評估TPP-DOX_MT
α-HER2scFv 在異種移植腫瘤小鼠模型中之抗癌活性
5週齡BALB/c雄性裸鼠(初始體重18至20g) (Nara Biotech)適應1週後,接著將HER2
+人類胃癌細胞系NCI-N87以1×10
7個細胞/小鼠皮下移植至側腹,從而構築異種移植腫瘤模型小鼠。當腫瘤平均體積達至50至100 mm
3時,將小鼠分成3組,每測試組7隻小鼠,且每週一次靜脈內注射4 μg TPP-DOX或TPP-DOX_MT
α-HER2scFv,持續4週,總共7次。每隔2至4天量測腫瘤大小,且自投予開始25天後,取出腫瘤組織,並測定大小及重量(圖65)。
實例13.1. 確認TPP-DOX_MT
α-HER2scFv 在異種移植腫瘤小鼠模型中的腫瘤細胞生長抑制能力
作為經由上述實例13之方法進行的實驗之結果,在TPP-DOX投予組的情況下,與對照組(CTR)相比,直至第30天,腫瘤大小相似。另一方面,TPP-DOX_MT
α-HER2scFv投予組中之腫瘤大小與對照組相比顯著減小(圖66)。此外,TPP-DOX_MT
α-HER2scFv處理組在實驗結束後提取之腫瘤的大小(圖67)及重量(圖68)顯著減小。使用Graphpad 5.0軟體進行統計處理,並用單因子ANOVA (圖基氏)檢定量測p值(*p<0.05)。
實例14. 評估TPP-DOX_MT
α-HER2scFv 在同種異體移植腫瘤小鼠模型中之抗癌活性
將7週齡C57BL/6雌性小鼠(Samtako Bio Korea)適應1週後,將小鼠黑色素瘤細胞系B16F10以約5×10
5個細胞/小鼠皮下移植至小鼠側腹,從而構築同種異體移植腫瘤小鼠。此時,將使用慢病毒過表現人類HER2基因的B16F10細胞用作B16F10細胞。當腫瘤平均體積達至100至200 mm
3時,將小鼠分為4組,每測試組3隻小鼠,且每週3次靜脈內投予MT
α-HER2scFv(20 µg)、TPP-DOX (5µg)或TPP-DOX_MT
α-HER2scFv(TPP-DOX/MT:5 µg/20 µg),持續3週。每週量測3次腫瘤大小,且在實驗結束後(自投予開始3週後),取出小鼠之腫瘤組織,量測大小及重量(圖69)。
實例14.1. 確認TPP-DOX_MT
α-HER2scFv 在同種異體癌細胞移植動物模型中的腫瘤細胞生長抑制能力
作為經由上述實例14之方法進行的實驗之結果,在MT
α-HER2scFv及TPP-DOX投予組的情況下,腫瘤大小與對照組(CTR)相似。另一方面,TPP-DOX_MT
α-HER2scFv投予組中之腫瘤大小與對照組相比顯著減小(圖70)。此外,TPP-DOX_MT
α-HER2scFv處理組在實驗結束後提取之腫瘤的大小(圖71)及重量(圖72)減小。
實例15. 評估DOX_MT
α-HER2scFv 在同種異體移植腫瘤動物模型中之抗癌活性
將7週齡C57BL/6雌性小鼠(Samtako Bio Korea)適應1週後,將小鼠黑色素瘤細胞系B16F10以約5×10
5個細胞/小鼠皮下移植至小鼠側腹,從而構築同種異體移植腫瘤小鼠。此時,將使用慢病毒過表現人類HER2基因的B16F10細胞用作B16F10細胞。當腫瘤平均體積達至100至200 mm
3時,將小鼠分為4組,每測試組3隻小鼠,且每週3次靜脈內投予MT
α-HER2scFv(20 µg)、DOX (4 µg)或DOX_MT
α-HER2scFv(TPP-DOX/MT:4 µg/20 µg),持續3週。每週量測3次腫瘤大小,且在實驗結束後(自投予開始3週後),取出小鼠之腫瘤組織,量測大小及重量(圖73)。
實例15.1. 確認DOX_MT
α-HER2scFv 在同種異體移植腫瘤動物模型中之腫瘤細胞生長抑制能力
作為經由上述實例14之方法進行的實驗之結果,在MT
α-HER2scFv投予組的情況下,腫瘤大小與對照組(CTR)相似。另一方面,與對照組相比,DOX投予組及DOX_MT
α-HER2scFv投予組之腫瘤大小顯著減小。此外,確認了與DOX治療組相比,DOX_MT
α-HER2scFv投予組中之腫瘤大小進一步減小(圖74)。此外,與對照組相比,DOX_MT
α-HER2scFv投予組在實驗結束後提取之腫瘤的大小(圖75)及重量(圖76)減小。
[序列表自由文本]
SEQ ID NO: 1:T2p53引子
SEQ ID NO: 2:Xp53引子
SEQ ID NO: 3:編碼p53之核苷酸序列
SEQ ID NO: 4:NdeUB引子
SEQ ID NO: 5:T2UB引子
SEQ ID NO: 6:編碼UB-p53之核苷酸序列
SEQ ID NO: 7:NdeTOM70引子
SEQ ID NO: 8:TOM70-AS引子
SEQ ID NO: 9:TOM70UB-S引子
SEQ ID NO: 10:T2UB-AS引子
SEQ ID NO: 11:編碼TOM70-UB-p53之核苷酸序列
SEQ ID NO: 12:TOM70 (G)3-AS引子
SEQ ID NO: 13:(G)3UB-S引子
SEQ ID NO: 14:Xp53 (noT)引子
SEQ ID NO: 15:編碼TOM70-(GGGGS)3-UB-p53之核苷酸序列
SEQ ID NO: 16:B (G)3p53
SEQ ID NO: 17:編碼TOM70-(GGGGS)3-p53之核苷酸序列
SEQ ID NO: 18:Xp53 (noT)引子
SEQ ID NO: 19:XTOM7引子
SEQ ID NO: 20:LTOM7引子
SEQ ID NO: 21:編碼UB-p53-TOM7之核苷酸序列
SEQ ID NO: 22:Rp53引子
SEQ ID NO: 23:編碼p53-myc/His之核苷酸序列
SEQ ID NO: 24:T2GZMB引子
SEQ ID NO: 25:XGZMB (noT)引子
SEQ ID NO: 26:編碼顆粒酶B之核苷酸序列
SEQ ID NO: 27:編碼TOM70-(GGGGS)3-UB-顆粒酶B之核苷酸序列
SEQ ID NO: 28:編碼UB-顆粒酶B-TOM7之核苷酸序列
SEQ ID NO: 29:T2RKIP引子
SEQ ID NO: 30:XRKIP (noT)引子
SEQ ID NO: 31:編碼RKIP之核苷酸序列
SEQ ID NO: 32:編碼TOM70-(GGGGS)3-UB-RKIP之核苷酸序列
SEQ ID NO: 33:T2PTEN引子
SEQ ID NO: 34:XPTEN (noT)引子
SEQ ID NO: 35:編碼PTEN之核苷酸序列
SEQ ID NO: 36:編碼TOM70-(GGGGS)3-UB-PTEN之核苷酸序列
SEQ ID NO: 37:編碼scFvHER2之核苷酸序列
SEQ ID NO: 38:編碼UB-scFvHER2-TOM7之核苷酸序列
SEQ ID NO: 39:RscFvHER2引子
SEQ ID NO: 40:XTOM7 (noT)引子
SEQ ID NO: 41:編碼scFvHER2-TOM7-myc/His之核苷酸序列
SEQ ID NO: 42:編碼scFvMEL之核苷酸序列
SEQ ID NO: 43:編碼UB-scFvMEL-TOM7之核苷酸序列
SEQ ID NO: 44:RscFvMEL引子
SEQ ID NO: 45:編碼scFvMEL-TOM7-myc/His之核苷酸序列
SEQ ID NO: 46:編碼scFvPD-L1之核苷酸序列
SEQ ID NO: 47:編碼scFvPD-L1-TOM7-myc/His之核苷酸序列
SEQ ID NO: 48:p53之胺基酸序列
SEQ ID NO: 49:UB-p53之胺基酸序列
SEQ ID NO: 50:TOM70-UB-p53之胺基酸序列
SEQ ID NO: 51:TOM70-(GGGGS)3-UB-p53之胺基酸序列
SEQ ID NO: 52:TOM70-(GGGGS)3-p53之胺基酸序列
SEQ ID NO: 53:UB-p53-TOM7之胺基酸序列
SEQ ID NO: 54:p53-myc/His之胺基酸序列
SEQ ID NO: 55:顆粒酶B之胺基酸序列
SEQ ID NO: 56:TOM70-(GGGGS)3-UB-顆粒酶B之胺基酸序列
SEQ ID NO: 57:UB-顆粒酶B-TOM7之胺基酸序列
SEQ ID NO: 58:RKIP之胺基酸序列
SEQ ID NO: 59:TOM70-(GGGGS)3-UB-RKIP之胺基酸序列
SEQ ID NO: 60:PTEN之胺基酸序列
SEQ ID NO: 61:TOM70-(GGGGS)3-UB-PTEN之胺基酸序列
SEQ ID NO: 62:scFvHER2之胺基酸序列
SEQ ID NO: 63:UB-scFvHER2-TOM7之胺基酸序列
SEQ ID NO: 64:scFvHER2-TOM7-myc/His之胺基酸序列
SEQ ID NO: 65:scFvMEL之胺基酸序列
SEQ ID NO: 66:UB-scFvMEL-TOM7之胺基酸序列
SEQ ID NO: 67:scFvMEL-TOM7-myc/His之胺基酸序列
SEQ ID NO: 68:scFvPD-L1之胺基酸序列
SEQ ID NO: 69:scFvPD-L1-TOM7-myc/His之胺基酸序列
SEQ ID NO: 70:連接子
SEQ ID NO: 71:泛蛋白之胺基酸序列
SEQ ID NO: 72:編碼泛蛋白之核苷酸序列
SEQ ID NO: 73:p53之胺基酸序列
SEQ ID NO: 74:編碼p53之核苷酸序列
SEQ ID NO: 75:釀酒酵母之TOM70
SEQ ID NO: 76:智人之TOM70
SEQ ID NO: 77:釀酒酵母之TOM20
SEQ ID NO: 78:智人之TOM20
SEQ ID NO: 79:釀酒酵母之OM45
SEQ ID NO: 80:釀酒酵母之TOM5
SEQ ID NO: 81:智人之TOM5
SEQ ID NO: 82:釀酒酵母之TOM7
SEQ ID NO: 83:智人之TOM7
SEQ ID NO: 84:釀酒酵母之TOM22
SEQ ID NO: 85:智人之TOM22
SEQ ID NO: 86:釀酒酵母之Fis1
SEQ ID NO: 87:智人之Fis1
SEQ ID NO: 88:智人之Bcl-2α
SEQ ID NO: 89:釀酒酵母之VAMP1
SEQ ID NO: 90:智人之VAMP1
SEQ ID NO: 91:P53-啟動子-S
SEQ ID NO: 92:P53-啟動子-AS
SEQ ID NO: 93:編碼scFvPDL1-myc-TOM7之核苷酸序列
SEQ ID NO: 94:scFvPDL1-myc-TOM7之胺基酸序列
SEQ ID NO: 95:編碼scFvHER2之核苷酸序列
SEQ ID NO: 96:scFvHER2之胺基酸序列
SEQ ID NO: 97:編碼scFvHER2-myc-TOM7之核苷酸序列
SEQ ID NO: 98:scFvHER2-myc-TOM7之胺基酸序列
SEQ ID NO: 99:編碼scFvMSLN之核苷酸序列
SEQ ID NO: 100:scFvMSLN之胺基酸序列
SEQ ID NO: 101:編碼scFvMSLN-myc-TOM7之核苷酸序列
SEQ ID NO: 102:scFvMSLN-myc-TOM7之胺基酸序列
(無)
圖1係示意性地表示用於以與粒線體融合的形式表現抗HER2抗體之單鏈可變區片段的表現載體之視圖。
圖2係顯示藉由西方墨點法確認在人類胚胎腎細胞系(HEK293)中表現的抗HER2抗體之單鏈可變區片段之結果之視圖。
圖3係顯示利用共焦顯微鏡確認在人類胚胎腎細胞系(HEK293)中表現的抗HER2抗體之單鏈可變區片段的細胞內位置之結果之視圖。比例尺代表10 μm。
圖4係顯示藉由西方墨點法確認在人類胚胎腎細胞系(HEK293)中表現的抗HER2抗體之單鏈可變區片段存在於細胞內與粒線體相同位置之結果之視圖。
圖5係顯示自表現抗HER2抗體之單鏈可變區片段的人類胚胎腎細胞系(HEK293)分離之粒線體(MT
α-HER2scFv)中之ATP的量測結果之圖式。在此種情況下,對照組係自不表現抗HER2抗體單鏈可變區片段的HEK293細胞中分離之粒線體。
圖6係顯示自表現抗HER2抗體之單鏈可變區片段的人類胚胎腎細胞系(HEK293)分離之粒線體(MT
α-HER2scFv)中之膜電位的量測結果之圖式。在此種情況下,對照組係自不表現抗HER2抗體單鏈可變區片段的HEK293細胞中分離之粒線體。
圖7係顯示自表現抗HER2抗體之單鏈可變區片段的人類胚胎腎細胞系(HEK293)分離之粒線體(MT
α-HER2scFv)中之活性含氧物(ROS)的量測結果之圖式。在此種情況下,對照組係自不表現抗HER2抗體單鏈可變區片段的HEK293細胞中分離之粒線體。
圖8係顯示藉由西方墨點法確認HER2在人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)、人類肺癌細胞系(NCI-H1975)、肺纖維母細胞系(WI-38)及人類胃癌細胞系(NCI-N87及MKN-74)中之表現的結果之視圖。
圖9係顯示藉由免疫細胞化學染色確認HER2在人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)、人類肺癌細胞系(NCI-H1975)、人類肺纖維母細胞系(WI-38)及人類胃癌細胞系(NCI-N87及MKN-74)中之表現的結果之視圖。
圖10係顯示藉由流動式細胞測量術確認HER2在人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)、人類肺癌細胞系(NCI-H1975)及人類胃癌細胞系(NCI-N87及MKN-74)中之表現的結果之視圖。
圖11係顯示用於驗證自表現抗HER2抗體之單鏈可變區片段的人類胚胎腎細胞系(HEK293)分離之粒線體(MT
α-HER2scFv)的HER2靶向能力的實驗方法之視圖。
圖12係顯示在HER2
+細胞,亦即人類乳癌細胞系SK-BR-3與HER2
-細胞,亦即人類肺癌細胞系NCI-H1975細胞共培養,接著用MT
α-HER2scFv處理培養液之後,藉由免疫細胞化學染色確認HER2及抗HER2抗體之單鏈可變區片段的細胞內表現之結果之視圖。在此種情況下,MT係粒線體,其上沒有融合抗HER2抗體之單鏈可變區片段,係自HEK293細胞中分離出來的。
圖13係顯示在HER2
+細胞,亦即人類乳癌細胞系BT-474與HER2
-細胞,亦即人類肺癌細胞系NCI-H1975細胞共培養,接著用MT
α-HER2scFv處理細胞之後,藉由免疫細胞化學染色確認HER2及抗HER2抗體之單鏈可變區片段的細胞內表現之結果之視圖。在此種情況下,MT係粒線體,其上沒有融合抗HER2抗體之單鏈可變區片段,係自HEK293細胞中分離出來的。
圖14係顯示在HER2
+細胞,亦即人類胃癌細胞系NCI-N87與HER2
-細胞,亦即人類胃癌細胞系MKN-74細胞共培養,接著用MT
α-HER2scFv處理細胞之後,藉由免疫細胞化學染色確認HER2及抗HER2抗體之單鏈可變區片段的細胞內表現之結果之視圖。在此種情況下,MT係粒線體,其上沒有融合抗HER2抗體之單鏈可變區片段,係自HEK293細胞中分離出來的。
圖15係顯示在HER2
+細胞,亦即人類乳癌細胞系SK-BR-3與HER2
-細胞,亦即人類乳癌細胞系MDA-MB-231細胞共培養,接著用MT
α-HER2scFv處理細胞之後,藉由免疫細胞化學染色確認HER2及抗HER2抗體之單鏈可變區片段的細胞內表現之結果之視圖。在此種情況下,MT係粒線體,其上沒有融合抗HER2抗體之單鏈可變區片段,係自HEK293細胞中分離出來的。
圖16係顯示在HER2
+細胞,亦即人類乳癌細胞系BT-474與HER2
-細胞,亦即人類乳癌細胞系MDA-MB-231細胞共培養,接著用MT
α-HER2scFv處理細胞之後,藉由免疫細胞化學染色確認HER2及抗HER2抗體之單鏈可變區片段的細胞內表現之結果之視圖。在此種情況下,MT係粒線體,其上沒有融合抗HER2抗體之單鏈可變區片段,係自HEK293細胞中分離出來的。
圖17係顯示其中經MitoTracker綠色染色的MT
α-HER2scFv與化合物有效負載小紅莓(doxorubicin)結合的DOX_MT
α-HER2scFv的製備方法之視圖。
圖18係顯示在用DOX_MT
α-HER2scFv處理之後,藉由共焦顯微鏡觀察人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)及人類肺癌細胞系(NCI-H1975)的結果之視圖。
圖19係在用DOX_MT
α-HER2scFv處理人類乳癌細胞系(SK-BR-3及BT-474)及人類胃癌細胞(NCI-N87)之後,藉由共焦顯微鏡觀察癌細胞隨時間的形態變化及死亡過程之結果之視圖。
圖20係顯示藉由量測每種濃度的小紅莓的吸光度而得到的標準曲線之圖式。
圖21係顯示藉由用DOX或DOX_MT
α-HER2scFv處理人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)、人類肺癌細胞系(NCI-H1975)及人類胃癌細胞系(NCI-N87及MKN-74)來量測細胞毒性之結果之圖式。在此種情況下,MT係未加載DOX的MT
α-HER2scFv。
圖22係顯示藉由用DOX或DOX_MT
α-HER2scFv處理人類肺纖維母細胞系(WI-38及CCD-8Lu)來量測細胞毒性之結果之圖式。在此種情況下,MT係未加載DOX的MT
α-HER2scFv。
圖23係顯示確認DOX或DOX_MT
α-HER2scFv在人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)、人類肺癌細胞系(NCI-H1975)、人類胃癌細胞系(NCI-N87及MKN-74)及人類肺纖維母細胞系(WI-38及CCD-8Lu)中之IC
50值的結果之視圖。
圖24係顯示藉由用0.5 μM DOX或DOX_MT
α-HER2scFv處理人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)、人類肺癌細胞系(NCI-H1975)、人類胃癌細胞系(NCI-N87及MKN-74)、人類肺纖維母細胞系(WI-38及CCD-8Lu)來量測細胞毒性之結果之圖式。在此種情況下,MT係未加載DOX的MT
α-HER2scFv。
圖25係顯示藉由TUNEL分析確認藉由用MT
α-HER2scFv或DOX_MT
α-HER2scFv處理人類乳癌細胞系(SK-BR-3及BT-474)及人類胃癌細胞系(NCI-N87)引起的細胞凋亡之結果之視圖。
圖26係顯示藉由西方墨點法確認藉由用MT
α-HER2scFv或DOX_MT
α-HER2scFv處理人類乳癌細胞系(SK-BR-3及BT-474)引起的細胞凋亡之結果之視圖。
圖27係顯示藉由流動式細胞測量術確認藉由用MT
α-HER2scFv或DOX_MT
α-HER2scFv處理人類乳癌細胞系(SK-BR-3及BT-474)及人類胃癌細胞系(NCI-N87)引起的細胞凋亡之結果之圖式。在此種情況下,MT係未加載DOX的MT
α-HER2scFv。
圖28係顯示確認DOX_MT
α-HER2scFv對表現HER2的癌細胞的選擇性殺傷作用的實驗方法之視圖。
圖29係顯示藉由TUNEL分析確認藉由將人類乳癌細胞系BT-474 (HER2
+,白色箭頭)與人類肺纖維母細胞系WI-38 (HER2
-)共培養,接著用DOX_MT
α-HER2scFv處理細胞引起的細胞凋亡之結果之視圖。
圖30係顯示三苯基鏻(TPP)-小紅莓(TPP-DOX)的合成過程之視圖。
圖31係顯示TPP-DOX的MRI分析結果之視圖。
圖32係顯示其中經MitoTracker綠色染色的MT
α-HER2scFv與化合物有效負載TPP-DOX結合的TPP-DOX_MT
α-HER2scFv的製備方法之視圖。
圖33係顯示藉由共焦顯微鏡觀察用TPP-DOX_MT
α-HER2scFv處理後的人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)及肺癌細胞系(NCI-H1975)之結果之視圖。
圖34係在用TPP-DOX_MT
α-HER2scFv處理人類乳癌細胞系(SK-BR-3及BT-474)及人類胃癌細胞(NCI-N87)之後,藉由共焦顯微鏡觀察癌細胞隨時間的形態變化及死亡過程之結果之視圖。
圖35係顯示藉由用TPP-DOX及TPP-DOX_MT
α-HER2scFv處理人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)、人類肺癌細胞系(NCI-H1975)及人類胃癌細胞系(NCI-N87及MKN-74)來量測細胞毒性之結果之視圖。在此種情況下,MT係未加載DOX的MT
α-HER2scFv。
圖36係顯示藉由用TPP-DOX及TPP-DOX_MT
α-HER2scFv處理人類肺纖維母細胞系(WI-38及CCD-8Lu)來量測細胞毒性之結果之視圖。在此種情況下,MT係未加載DOX的MT
α-HER2scFv。
圖37係顯示確認TPP-DOX及TPP-DOX_MT
α-HER2scFv在人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)、人類肺癌細胞系(NCI-H1975)、人類胃癌細胞系(NCI-N87及MKN-74)及人類肺纖維母細胞系(WI-38及CCD-8Lu)中之IC
50值的結果之視圖。
圖38係顯示藉由用0.5 μM TPP-DOX或TPP-DOX_MT
α-HER2scFv處理人類乳癌細胞系(SK-BR-3、BT-474及MDA-MB-231)、人類肺癌細胞系(NCI-H1975)、人類胃癌細胞系(NCI-N87及MKN-74)及人類肺纖維母細胞系(WI-38及CCD-8Lu)來量測細胞毒性之結果之視圖。
圖39係顯示藉由TUNEL分析確認藉由用MT
α-HER2scFv或TPP-DOX_MT
α-HER2scFv處理人類乳癌細胞系(SK-BR-3及BT-474及MDA-MB-231)及胃癌細胞系(NCI-N87)引起的細胞凋亡之結果之視圖。
圖40係顯示藉由西方墨點法確認藉由用MT
α-HER2scFv或TPP-DOX_MT
α-HER2scFv處理人類乳癌細胞系(SK-BR-3及BT-474)及人類胃癌細胞系(NCI-N87)引起的細胞凋亡之結果之視圖。
圖41係顯示藉由流動式細胞測量術確認藉由用MT
α-HER2scFv或TPP-DOX_MT
α-HER2scFv處理人類乳癌細胞系(SK-BR-3及BT-474)及胃癌細胞系(NCI-N87)引起的細胞凋亡之結果之圖式。
圖42係顯示確認TPP-DOX_MT
α-HER2scFv對表現HER2的細胞的選擇性殺傷作用的實驗方法之視圖。
圖43係顯示藉由TUNEL分析確認藉由將人類乳癌細胞系SK-BR-3 (HER2
+,白色箭頭)與人類肺纖維母細胞系CCD-8Lu (HER2
-)共培養,接著用TTP-DOX_MT
α-HER2scFv處理細胞引起的細胞凋亡之結果之視圖。
圖44係示意性地表示用於以與粒線體融合的形式表現抗PDL1抗體之單鏈可變區片段的表現載體之視圖。
圖45係顯示藉由西方墨點法確認在人類胚胎腎細胞系(HEK293)中表現的抗PDL1抗體之單鏈可變區片段之結果之視圖。
圖46係顯示藉由西方墨點法確認PD-L1在人類胰臟癌細胞系(BXPC-3及CFPAC-1)及人類胃癌細胞系(SNU-216及SNU-484)中之表現的結果之視圖。
圖47係顯示用於在PDL1
+細胞及PDL1
-細胞共培養,接著用自表現抗PDL1抗體之單鏈可變區片段的人類胚胎腎細胞系(HEK293)分離之粒線體(MT
α-PDL1scFv)處理細胞之後,驗證MT
α-PDL1scFv的PDL1靶向能力的實驗方法之視圖。
圖48係顯示在將人類胃癌細胞系SNU-216 (PDL1
+、白色箭頭)與SNU-484 (PDL1
-)共培養或將人類胰臟癌細胞系BXPC-3 (PDL1
+,白色箭頭)與人類胰臟癌細胞系CFPAC-1 (PDL1
-)共培養,接著用MT
α-PDL1scFv處理細胞之後,藉由免疫細胞化學染色確認抗PDL1抗體之單鏈可變區片段的細胞內表現之結果之視圖。在此種情況下,MT係自HEK293細胞分離的未與抗PDL1抗體之單鏈可變區片段融合之粒線體。
圖49係顯示其中經MitoTracker綠色染色的MT
α-PDL1scFv與化合物有效負載小紅莓(DOX)結合的DOX_MT
α-PDL1scFv的製備方法之視圖。
圖50係顯示藉由用MT
α-PDL1scFv或DOX_MT
α-PDL1scFv處理人類胰臟癌細胞系(BXPC-3及CFPAC-1)及人類胃癌細胞系(SNU-216及SNU-484)來量測細胞毒性之結果之圖式。
圖51係顯示藉由西方墨點法確認藉由用MT
α-PDL1scFv或DOX_MT
α-PDL1scFv處理人類胰臟癌細胞系(BXPC-3及CFPAC-1)及人類胃癌細胞系(SNU-216及SNU-484)引起的細胞凋亡之結果之視圖。
圖52係示意性地表示用於以與粒線體融合的形式表現抗間皮素(MSLN)抗體之單鏈可變區片段的表現載體之視圖。
圖53係顯示藉由西方墨點法確認在人類胚胎腎細胞系(HEK293)中表現的抗MSLN抗體之單鏈可變區片段之結果之視圖。
圖54係顯示其中經MitoTracker綠色染色的MT
α-MSLNscFv與化合物有效負載去鎂葉綠素酸A (PBA)結合的PBA_MT
α-MSLNscFv的製備方法之視圖。
圖55係顯示藉由用MT
α-MSLNscFv或PBA_MT
α-MSLNscFv處理人類胰臟癌細胞系(AsPC-1)來量測細胞毒性之結果之視圖及圖式。MT
α-MSLNscFv係PBA_MT
α-MSLNscFv的陰性對照。
圖56係顯示藉由用MT
α-MSLNscFv或PBA_MT
α-MSLNscFv處理人類胰臟癌細胞系(Capan-1)來量測細胞毒性之結果之視圖及圖式。MT
α-MSLNscFv係PBA_MT
α-MSLNscFv的陰性對照。
圖57係顯示藉由用MT
α-MSLNscFv或PBA_MT
α-MSLNscFv處理人類胰臟癌細胞系(Capan-2)來量測細胞毒性之結果之視圖及圖式。MT
α-MSLNscFv係PBA_MT
α-MSLNscFv的陰性對照。
圖58係顯示藉由用MT
α-MSLNscFv或PBA_MT
α-MSLNscFv處理人類胰臟癌細胞系(Mia PaCa-2)來量測細胞毒性之結果之視圖及圖式。MT
α-MSLNscFv係PBA_MT
α-MSLNscFv的陰性對照。
圖59係顯示其中經MitoTracker綠色染色的MT
α-MSLNscFv與化合物有效負載吉西他濱結合的Gem_MT
α-MSLNscFv的製備方法之視圖。
圖60係顯示藉由用MT
α-MSLNscFv或Gem_MT
α-MSLNscFv處理人類胰臟癌細胞系(AsPC-1、Capan-1、Capan-2及Mia PaCa-2)來量測細胞毒性之結果之視圖及圖式。MT
α-MSLNscFv係Gem_MT
α-MSLNscFv的陰性對照。
圖61係顯示其中經MitoTracker綠色染色的MT
α-MSLNscFv與化合物有效負載長春瑞濱結合的VIBE_MT
α-MSLNscFv的製備方法之示意圖的視圖。
圖62係顯示藉由用MT
α-MSLNscFv或VIBE_MT
α-MSLNscFv處理人類胰臟癌細胞系(AsPC-1、Capan-1、Capan-2及Mia PaCa-2)來量測細胞毒性之結果之圖式。MT
α-MSLNscFv係VIBE_MT
α-MSLNscFv的陰性對照。
圖63係顯示用於在向藉由移植人類胃癌細胞系NCI-N87 (HER2
+)而形成的異種移植小鼠模型投予MT
α-HER2scFv之後驗證MT
α-HER2scFv的HER2靶向能力的實驗方法之視圖。
圖64係顯示在向藉由移植人類胃癌細胞系NCI-N87 (HER2
+)而形成的異種移植小鼠模型投予MT
α-HER2scFv之後觀察到MT
α-HER2scFv位於腫瘤內之結果之視圖。
圖65係顯示用於確認TPP-DOX或TPP-DOX_MT
α-HER2scFv在藉由移植人類胃癌細胞系NCI-N87 (HER2
+)而形成的異種移植小鼠模型中之抗癌功效的實驗方法之視圖。
圖66係顯示在向藉由移植人類胃癌細胞系NCI-N87 (HER2
+)而形成的異種移植小鼠模型投予TPP-DOX或TPP-DOX_MT
α-HER2scFv之後按日期量測腫瘤尺寸(腫瘤體積)之結果之圖式。
圖67係確認在自開始向藉由移植人類胃癌細胞系NCI-N87 (HER2
+)而形成的異種移植小鼠模型投予TPP-DOX或TPP-DOX_MT
α-HER2scFv起25天之後提取之腫瘤的尺寸之視圖。
圖68係顯示在自開始向藉由移植人類胃癌細胞系NCI-N87 (HER2
+)而形成的異種移植小鼠模型投予TPP-DOX或TPP-DOX_MT
α-HER2scFv起25天之後提取之腫瘤重量的量測結果之圖式。
圖69係顯示用於確認MT
α-HER2scFv、TPP-DOX或TPP-DOX_MT
α-HER2scFv在藉由移植過表現人類HER2之小鼠黑色素瘤細胞系B16F10而形成的同種異體移植小鼠模型中之抗癌功效的實驗方法之視圖。
圖70係顯示在向藉由移植過表現人類HER2之小鼠黑色素瘤細胞系B16F10而形成的同種異體移植小鼠模型投予MT
α-HER2scFv、TPP-DOX或TPP-DOX_MT
α-HER2scFv之後按日期量測腫瘤尺寸(腫瘤體積)之結果之圖式。
圖71係確認在自開始向藉由移植過表現人類HER2之小鼠黑色素瘤細胞系B16F10而形成的同種異體移植小鼠模型投予MT
α-HER2scFv、TPP-DOX或TPP-DOX_MT
α-HER2scFv起21天之後提取之腫瘤的尺寸之視圖。
圖72係顯示在自開始向藉由移植過表現人類HER2之小鼠黑色素瘤細胞系B16F10而形成的同種異體移植小鼠模型投予MT
α-HER2scFv、TPP-DOX或TPP-DOX_MT
α-HER2scFv起21天之後提取之腫瘤重量的量測結果之圖式。
圖73係顯示用於確認MT
α-HER2scFv、DOX或DOX_MT
α-HER2scFv在藉由移植過表現人類HER2之小鼠黑色素瘤細胞系B16F10而形成的同種異體移植小鼠模型中之抗癌功效的實驗方法之視圖。
圖74係顯示在向藉由移植過表現人類HER2之小鼠黑色素瘤細胞系B16F10而形成的同種異體移植小鼠模型投予MT
α-HER2scFv、DOX或DOX_MT
α-HER2scFv之後按日期量測腫瘤尺寸之結果之圖式。
圖75係確認在自開始向藉由移植過表現人類HER2之小鼠黑色素瘤細胞系B16F10而形成的同種異體移植小鼠模型投予MT
α-HER2scFv、TPP-DOX或TPP-DOX_MT
α-HER2scFv起21天之後提取之腫瘤的尺寸之視圖。
圖76係顯示在自開始向藉由移植過表現人類HER2之小鼠黑色素瘤細胞系B16F10而形成的同種異體移植小鼠模型投予MT
α-HER2scFv、DOX或DOX_MT
α-HER2scFv起21天之後提取之腫瘤重量的量測結果之圖式。
<![CDATA[<110> 南韓商白雁生物技術公司(Paean Biotechnology Inc.)]]> <![CDATA[<120> 含有抗癌劑之粒線體及其用途]]> <![CDATA[<140> TW 110139356]]> <![CDATA[<141> 2021-10-22]]> <![CDATA[<150> KR 10-2020-0137779]]> <![CDATA[<151> 2020-10-22]]> <![CDATA[<160> 102]]> <![CDATA[<170> KoPatentIn 3.0]]> <![CDATA[<210> 1]]> <![CDATA[<211> 39]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> T2p53引子]]> <![CDATA[<400> 1]]> aaaaaaccgc ggtggtgagg agccgcagtc agatcctag 39 <![CDATA[<210> 2]]> <![CDATA[<211> 35]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> Xp53引子]]> <![CDATA[<400> 2]]> aaaaaactcg agtgagtctg agtcaggccc ttctg 35 <![CDATA[<210> 3]]> <![CDATA[<211> 1186]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼p53之核苷酸序列]]> <![CDATA[<400> 3]]> ccgcggtggt gaggagccgc agtcagatcc tagcgtcgag ccccctctga gtcaggaaac 60 attttcagac ctgtggaaac tacttcctga aaacaacgtt ctgtccccct tgccgtccca 120 agcaatggat gatttgatgc tgtccccgga cgatattgaa caatggttca ctgaagaccc 180 aggtccagat gaagctccca gaatgccaga ggctgctccc cgcgtggccc ctgcaccagc 240 agctcctaca ccggcggccc ctgcaccagc cccctcctgg cccctgtcat cttctgtccc 300 ttcccagaaa acctaccagg gcagctacgg tttccgtctg ggcttcttgc attctgggac 360 agccaagtct gtgacttgca cgtactcccc tgccctcaac aagatgtttt gccaactggc 420 caagacctgc cctgtgcagc tgtgggttga ttccacaccc ccgcccggca cccgcgtccg 480 cgccatggcc atctacaagc agtcacagca catgacggag gttgtgaggc gctgccccca 540 ccatgagcgc tgctcagata gcgatggtct ggcccctcct cagcatctta tccgagtgga 600 aggaaatttg cgtgtggagt atttggatga cagaaacact tttcgacata gtgtggtggt 660 gccctatgag ccgcctgagg ttggctctga ctgtaccacc atccactaca actacatgtg 720 taacagttcc tgcatgggcg gcatgaaccg gaggcccatc ctcaccatca tcacactgga 780 agactccagt ggtaatctac tgggacggaa cagctttgag gtgcgtgttt gtgcctgtcc 840 tgggagagac cggcgcacag aggaagagaa tctccgcaag aaaggggagc ctcaccacga 900 gctgccccca gggagcacta agcgagcact gcccaacaac accagctcct ctccccagcc 960 aaagaagaaa ccactggatg gagaatattt cacccttcag atccgtgggc gtgagcgctt 1020 cgagatgttc cgagagctga atgaggcctt ggaactcaag gatgcccagg ctgggaagga 1080 gccagggggg agcagggctc actccagcca cctgaagtcc aaaaagggtc agtctacctc 1140 ccgccataaa aaactcatgt tcaagacaga agggcctgac tcagac 1186 <![CDATA[<210> 4]]> <![CDATA[<211> 35]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> NdeUB引子]]> <![CDATA[<400> 4]]> ggattccata tgcaactttt cgtcaaaact ctaac 35 <![CDATA[<210> 5]]> <![CDATA[<211> 27]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> T2UB引子]]> <![CDATA[<400> 5]]> atgaccaccg cggagtctca acaccaa 27 <![CDATA[<210> 6]]> <![CDATA[<211> 1460]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼UB-p53之核苷酸序列]]> <![CDATA[<400> 6]]> atgggcagca gccatcatca tcatcatcac agcagcggcc tggtgccgcg cggcagccat 60 atgcaaatct tcgtcaaaac tctaacaggg aagactataa ccctagaggt tgaaccatcc 120 gacactattg aaaacgtcaa agctaaaatt caagataaag aaggtatccc tccggatcag 180 cagagattga tttttgctgg taagcaacta gaagatggta gaaccttgtc tgactacaac 240 atccaaaagg aatctactct tcacttggtg ttgagactcc gcggtggtga ggagccgcag 300 tcagatccta gcgtcgagcc ccctctgagt caggaaacat tttcagacct gtggaaacta 360 cttcctgaaa acaacgttct gtcccccttg ccgtcccaag caatggatga tttgatgctg 420 tccccggacg atattgaaca atggttcact gaagacccag gtccagatga agctcccaga 480 atgccagagg ctgctccccg cgtggcccct gcaccagcag ctcctacacc ggcggcccct 540 gcaccagccc cctcctggcc cctgtcatct tctgtccctt cccagaaaac ctaccagggc 600 agctacggtt tccgtctggg cttcttgcat tctgggacag ccaagtctgt gacttgcacg 660 tactcccctg ccctcaacaa gatgttttgc caactggcca agacctgccc tgtgcagctg 720 tgggttgatt ccacaccccc gcccggcacc cgcgtccgcg ccatggccat ctacaagcag 780 tcacagcaca tgacggaggt tgtgaggcgc tgcccccacc atgagcgctg ctcagatagc 840 gatggtctgg cccctcctca gcatcttatc cgagtggaag gaaatttgcg tgtggagtat 900 ttggatgaca gaaacacttt tcgacatagt gtggtggtgc cctatgagcc gcctgaggtt 960 ggctctgact gtaccaccat ccactacaac tacatgtgta acagttcctg catgggcggc 1020 atgaaccgga ggcccatcct caccatcatc acactggaag actccagtgg taatctactg 1080 ggacggaaca gctttgaggt gcgtgtttgt gcctgtcctg ggagagaccg gcgcacagag 1140 gaagagaatc tccgcaagaa aggggagcct caccacgagc tgcccccagg gagcactaag 1200 cgagcactgc ccaacaacac cagctcctct ccccagccaa agaagaaacc actggatgga 1260 gaatatttca cccttcagat ccgtgggcgt gagcgcttcg agatgttccg agagctgaat 1320 gaggccttgg aactcaagga tgcccaggct gggaaggagc caggggggag cagggctcac 1380 tccagccacc tgaagtccaa aaagggtcag tctacctccc gccataaaaa actcatgttc 1440 aagacagaag ggcctgatag 1460 <![CDATA[<210> 7]]> <![CDATA[<211> 59]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> NdeTOM70引子]]> <![CDATA[<400> 7]]> gaattccata tgaaaagttt tataactcgg aataaaactg caattttcgc aactgttgc 59 <![CDATA[<210> 8]]> <![CDATA[<211> 38]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> TOM70-AS引子]]> <![CDATA[<400> 8]]> ggtgcatact actattatca aacttttcgt caaaactc 38 <![CDATA[<210> 9]]> <![CDATA[<211> 36]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> TOM70UB-S引子]]> <![CDATA[<400> 9]]> ggctacgtat ttatttccaa cttttcgtca aaactc 36 <![CDATA[<210> 10]]> <![CDATA[<211> 24]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> T2UB-AS引子]]> <![CDATA[<400> 10]]> ggcaccaccg cggagtctca acac 24 <![CDATA[<210> 11]]> <![CDATA[<211> 1515]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼TOM70-UB-p53之核苷酸序列]]> <![CDATA[<400> 11]]> atgaaaagtt ttataactcg gaataaaact gcaattttcg caactgttgc tgctacggga 60 accgctattg gtgcatacta ctattatcaa atcttcgtca aaactctaac agggaagact 120 ataaccctag aggttgaacc atccgacact attgaaaacg tcaaagctaa aattcaagat 180 aaagaaggta tccctccgga tcagcagaga ttgatttttg ctggtaagca actagaagat 240 ggtagaacct tgtctgacta caacatccaa aaggaatcta ctcttcactt ggtgttgaga 300 ctccgcggtg gtgaggagcc gcagtcagat cctagcgtcg agccccctct gagtcaggaa 360 acattttcag acctgtggaa actacttcct gaaaacaacg ttctgtcccc cttgccgtcc 420 caagcaatgg atgatttgat gctgtccccg gacgatattg aacaatggtt cactgaagac 480 ccaggtccag atgaagctcc cagaatgcca gaggctgctc cccgcgtggc ccctgcacca 540 gcagctccta caccggcggc ccctgcacca gccccctcct ggcccctgtc atcttctgtc 600 ccttcccaga aaacctacca gggcagctac ggtttccgtc tgggcttctt gcattctggg 660 acagccaagt ctgtgacttg cacgtactcc cctgccctca acaagatgtt ttgccaactg 720 gccaagacct gccctgtgca gctgtgggtt gattccacac ccccgcccgg cacccgcgtc 780 cgcgccatgg ccatctacaa gcagtcacag cacatgacgg aggttgtgag gcgctgcccc 840 caccatgagc gctgctcaga tagcgatggt ctggcccctc ctcagcatct tatccgagtg 900 gaaggaaatt tgcgtgtgga gtatttggat gacagaaaca cttttcgaca tagtgtggtg 960 gtgccctatg agccgcctga ggttggctct gactgtacca ccatccacta caactacatg 1020 tgtaacagtt cctgcatggg cggcatgaac cggaggccca tcctcaccat catcacactg 1080 gaagactcca gtggtaatct actgggacgg aacagctttg aggtgcgtgt ttgtgcctgt 1140 cctgggagag accggcgcac agaggaagag aatctccgca agaaagggga gcctcaccac 1200 gagctgcccc cagggagcac taagcgagca ctgcccaaca acaccagctc ctctccccag 1260 ccaaagaaga aaccactgga tggagaatat ttcacccttc agatccgtgg gcgtgagcgc 1320 ttcgagatgt tccgagagct gaatgaggcc ttggaactca aggatgccca ggctgggaag 1380 gagccagggg ggagcagggc tcactccagc cacctgaagt ccaaaaaggg tcagtctacc 1440 tcccgccata aaaaactcat gttcaagaca gaagggcctg actcagacct cgagcaccac 1500 caccaccacc actag 1515 <![CDATA[<210> 12]]> <![CDATA[<211> 59]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> TOM70(G)3-AS引子]]> <![CDATA[<400> 12]]> gcccccggat cctccacccc cgcttccgcc acctccataa tagtagtatg caccaatag 59 <![CDATA[<210> 13]]> <![CDATA[<211> 32]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> (G)3UB-S引子]]> <![CDATA[<400> 13]]> ggtggaggat ccgggggcgc ggaagccaaa tc 32 <![CDATA[<210> 14]]> <![CDATA[<211> 32]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> Xp53(noT)引子]]> <![CDATA[<400> 14]]> aaaaaactcg aggtctgagt caggcccttc tg 32 <![CDATA[<210> 15]]> <![CDATA[<211> 1560]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼TOM70-(GGGGS)3-UB-p53之核苷酸序列]]> <![CDATA[<400> 15]]> atgaaaagtt ttataactcg gaataaaact gcaattttcg caactgttgc tgctacggga 60 accgctattg gtgcatacta ctattatgga ggtggcggaa gcgggggtgg aggatccggg 120 ggcggcggaa gccaaatctt cgtcaaaact ctaacaggga agactataac cctagaggtt 180 gaaccatccg acactattga aaacgtcaaa gctaaaattc aagataaaga aggtatccct 240 ccggatcagc agagattgat ttttgctggt aagcaactag aagatggtag aaccttgtct 300 gactacaaca tccaaaagga atctactctt cacttggtgt tgagactccg cggtggtgag 360 gagccgcagt cagatcctag cgtcgagccc cctctgagtc aggaaacatt ttcagacctg 420 tggaaactac ttcctgaaaa caacgttctg tcccccttgc cgtcccaagc aatggatgat 480 ttgatgctgt ccccggacga tattgaacaa tggttcactg aagacccagg tccagatgaa 540 gctcccagaa tgccagaggc tgctccccgc gtggcccctg caccagcagc tcctacaccg 600 gcggcccctg caccagcccc ctcctggccc ctgtcatctt ctgtcccttc ccagaaaacc 660 taccagggca gctacggttt ccgtctgggc ttcttgcatt ctgggacagc caagtctgtg 720 acttgcacgt actcccctgc cctcaacaag atgttttgcc aactggccaa gacctgccct 780 gtgcagctgt gggttgattc cacacccccg cccggcaccc gcgtccgcgc catggccatc 840 tacaagcagt cacagcacat gacggaggtt gtgaggcgct gcccccacca tgagcgctgc 900 tcagatagcg atggtctggc ccctcctcag catcttatcc gagtggaagg aaatttgcgt 960 gtggagtatt tggatgacag aaacactttt cgacatagtg tggtggtgcc ctatgagccg 1020 cctgaggttg gctctgactg taccaccatc cactacaact acatgtgtaa cagttcctgc 1080 atgggcggca tgaaccggag gcccatcctc accatcatca cactggaaga ctccagtggt 1140 aatctactgg gacggaacag ctttgaggtg cgtgtttgtg cctgtcctgg gagagaccgg 1200 cgcacagagg aagagaatct ccgcaagaaa ggggagcctc accacgagct gcccccaggg 1260 agcactaagc gagcactgcc caacaacacc agctcctctc cccagccaaa gaagaaacca 1320 ctggatggag aatatttcac ccttcagatc cgtgggcgtg agcgcttcga gatgttccga 1380 gagctgaatg aggccttgga actcaaggat gcccaggctg ggaaggagcc aggggggagc 1440 agggctcact ccagccacct gaagtccaaa aagggtcagt ctacctcccg ccataaaaaa 1500 ctcatgttca agacagaagg gcctgactca gacctcgagc accaccacca ccaccactag 1560 1560 <![CDATA[<210> 16]]> <![CDATA[<211> 51]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> B(G)3p53]]> <![CDATA[<400> 16]]> ggtggaggat ccgggggcgg cggaagcgag gagccgcagt cagatcctag c 51 <![CDATA[<210> 17]]> <![CDATA[<211> 1335]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼TOM70-(GGGGS)3-p53之核苷酸序列]]> <![CDATA[<400> 17]]> atgaaaagtt ttataactcg gaataaaact gcaattttcg caactgttgc tgctacggga 60 accgctattg gtgcatacta ctattatgga ggtggcggaa gcgggggtgg aggatccggg 120 ggcggcggaa gcgaggagcc gcagtcagat cctagcgtcg agccccctct gagtcaggaa 180 acattttcag acctgtggaa actacttcct gaaaacaacg ttctgtcccc cttgccgtcc 240 caagcaatgg atgatttgat gctgtccccg gacgatattg aacaatggtt cactgaagac 300 ccaggtccag atgaagctcc cagaatgcca gaggctgctc cccgcgtggc ccctgcacca 360 gcagctccta caccggcggc ccctgcacca gccccctcct ggcccctgtc atcttctgtc 420 ccttcccaga aaacctacca gggcagctac ggtttccgtc tgggcttctt gcattctggg 480 acagccaagt ctgtgacttg cacgtactcc cctgccctca acaagatgtt ttgccaactg 540 gccaagacct gccctgtgca gctgtgggtt gattccacac ccccgcccgg cacccgcgtc 600 cgcgccatgg ccatctacaa gcagtcacag cacatgacgg aggttgtgag gcgctgcccc 660 caccatgagc gctgctcaga tagcgatggt ctggcccctc ctcagcatct tatccgagtg 720 gaaggaaatt tgcgtgtgga gtatttggat gacagaaaca cttttcgaca tagtgtggtg 780 gtgccctatg agccgcctga ggttggctct gactgtacca ccatccacta caactacatg 840 tgtaacagtt cctgcatggg cggcatgaac cggaggccca tcctcaccat catcacactg 900 gaagactcca gtggtaatct actgggacgg aacagctttg aggtgcgtgt ttgtgcctgt 960 cctgggagag accggcgcac agaggaagag aatctccgca agaaagggga gcctcaccac 1020 gagctgcccc cagggagcac taagcgagca ctgcccaaca acaccagctc ctctccccag 1080 ccaaagaaga aaccactgga tggagaatat ttcacccttc agatccgtgg gcgtgagcgc 1140 ttcgagatgt tccgagagct gaatgaggcc ttggaactca aggatgccca ggctgggaag 1200 gagccagggg ggagcagggc tcactccagc cacctgaagt ccaaaaaggg tcagtctacc 1260 tcccgccata aaaaactcat gttcaagaca gaagggcctg actcagacct cgagcaccac 1320 caccaccacc actag 1335 <![CDATA[<210> 18]]> <![CDATA[<211> 32]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> Xp53(noT)引子]]> <![CDATA[<400> 18]]> aaaaaactcg aggtctgagt caggcccttc tg 32 <![CDATA[<210> 19]]> <![CDATA[<211> 36]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> XTOM7引子]]> <![CDATA[<400> 19]]> aaaaaactcg agtttgccat tcgctggggc tttatc 36 <![CDATA[<210> 20]]> <![CDATA[<211> 38]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> LTOM7引子]]> <![CDATA[<400> 20]]> aaaaaagtcg acttatcccc aaagtaggct caaaacag 38 <![CDATA[<210> 21]]> <![CDATA[<211> 1578]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼UB-p53-TOM7之核苷酸序列]]> <![CDATA[<400> 21]]> atgggcagca gccatcatca tcatcatcac agcagcggcc tggtgccgcg cggcagccat 60 atgcaaatct tcgtcaaaac tctaacaggg aagactataa ccctagaggt tgaaccatcc 120 gacactattg aaaacgtcaa agctaaaatt caagataaag aaggtatccc tccggatcag 180 cagagattga tttttgctgg taagcaacta gaagatggta gaaccttgtc tgactacaac 240 atccaaaagg aatctactct tcacttggtg ttgagactcc gcggtggtga ggagccgcag 300 tcagatccta gcgtcgagcc ccctctgagt caggaaacat tttcagacct atggaaacta 360 cttcctgaaa acaacgttct gtcccccttg ccgtcccaag caatggatga tttgatgctg 420 tccccggacg atattgaaca atggttcact gaagacccag gtccagatga agctcccaga 480 atgccagagg ctgctccccg cgtggcccct gcaccagcag ctcctacacc ggcggcccct 540 gcaccagccc cctcctggcc cctgtcatct tctgtccctt cccagaaaac ctaccagggc 600 agctacggtt tccgtctggg cttcttgcat tctgggacag ccaagtctgt gacttgcacg 660 tactcccctg ccctcaacaa gatgttttgc caactggcca agacctgccc tgtgcagctg 720 tgggttgatt ccacaccccc gcccggcacc cgcgtccgcg ccatggccat ctacaagcag 780 tcacagcaca tgacggaggt tgtgaggcgc tgcccccacc atgagcgctg ctcagatagc 840 gatggtctgg cccctcctca gcatcttatc cgagtggaag gaaatttgcg tgtggagtat 900 ttggatgaca gaaacacttt tcgacatagt gtggtggtgc cctatgagcc gcctgaggtt 960 ggctctgact gtaccaccat ccactacaac tacatgtgta acagttcctg catgggcggc 1020 atgaaccgga ggcccatcct caccatcatc acactggaag actccagtgg taatctactg 1080 ggacggaaca gctttgaggt gcatgtttgt gcctgtcctg ggagagaccg gcgcacagag 1140 gaagagaatc tccgcaagaa aggggagcct caccacgagc tgcccccagg gagcactaag 1200 cgagcactgt ccaacaacac cagctcctct ccccagccaa agaagaaacc actggatgga 1260 gaatatttca cccttcagat ccgtgggcgt gagcgcttcg agatgttccg agagctgaat 1320 gaggccttgg aactcaagga tgcccaggct gggaaggagc caggggggag cagggctcac 1380 tccagccacc tgaagtccaa aaagggtcag tctacctccc gccataaaaa actcatgttc 1440 aagacagaag ggcctgactc agacctcgag tttgccattc gctggggctt tatccctctt 1500 gtgatttacc tgggatttaa gaggggtgca gatcccggaa tgcctgaacc aactgttttg 1560 agcctacttt ggggatag 1578 <![CDATA[<210> 22]]> <![CDATA[<211> 35]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> Rp53引子]]> <![CDATA[<400> 22]]> aaaaaagaat tcatggtctg agtcaggccc ttctg 35 <![CDATA[<210> 23]]> <![CDATA[<211> 1266]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼p53-myc/His之核苷酸序列]]> <![CDATA[<400> 23]]> atggaggagc cgcagtcaga tcctagcgtc gagccccctc tgagtcagga aacattttca 60 gacctgtgga aactacttcc tgaaaacaac gttctgtccc ccttgccgtc ccaagcaatg 120 gatgatttga tgctgtcccc ggacgatatt gaacaatggt tcactgaaga cccaggtcca 180 gatgaagctc ccagaatgcc agaggctgct ccccgcgtgg cccctgcacc agcagctcct 240 acaccggcgg cccctgcacc agccccctcc tggcccctgt catcttctgt cccttcccag 300 aaaacctacc agggcagcta cggtttccgt ctgggcttct tgcattctgg gacagccaag 360 tctgtgactt gcacgtactc ccctgccctc aacaagatgt tttgccaact ggccaagacc 420 tgccctgtgc agctgtgggt tgattccaca cccccgcccg gcacccgcgt ccgcgccatg 480 gccatctaca agcagtcaca gcacatgacg gaggttgtga ggcgctgccc ccaccatgag 540 cgctgctcag atagcgatgg tctggcccct cctcagcatc ttatccgagt ggaaggaaat 600 ttgcgtgtgg agtatttgga tgacagaaac acttttcgac atagtgtggt ggtgccctat 660 gagccgcctg aggttggctc tgactgtacc accatccact acaactacat gtgtaacagt 720 tcctgcatgg gcggcatgaa ccggaggccc atcctcacca tcatcacact ggaagactcc 780 agtggtaatc tactgggacg gaacagcttt gaggtgcgtg tttgtgcctg tcctgggaga 840 gaccggcgca cagaggaaga gaatctccgc aagaaagggg agcctcacca cgagctgccc 900 ccagggagca ctaagcgagc actgcccaac aacaccagct cctctcccca gccaaagaag 960 aaaccactgg atggagaata tttcaccctt cagatccgtg ggcgtgagcg cttcgagatg 1020 ttccgagagc tgaatgaggc cttggaactc aaggatgccc aggctgggaa ggagccaggg 1080 gggagcaggg ctcactccag ccacctgaag tccaaaaagg gtcagtctac ctcccgccat 1140 aaaaaactca tgttcaagac agaagggcct gactcagacc tcgagtctag agggcccttc 1200 gaacaaaaac tcatctcaga agaggatctg aatatgcata ccggtcatca tcaccatcac 1260 cattga 1266 <![CDATA[<210> 24]]> <![CDATA[<211> 51]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> T2GZMB引子]]> <![CDATA[<400> 24]]> aaaaaaccgc ggtggtatca tcgggggaca tgaggcacat gaggccaagc c 51 <![CDATA[<210> 25]]> <![CDATA[<211> 38]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> XGZMB(noT)引子]]> <![CDATA[<400> 25]]> aaaaaactcg aggtagcgtt tcatggtttt ctttatcc 38 <![CDATA[<210> 26]]> <![CDATA[<211> 691]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼顆粒酶B之核苷酸序列]]> <![CDATA[<400> 26]]> ccgcggtggt atcatcgggg gacatgaggc caagccccac tcccgcccct acatggctta 60 tcttatgatc tgggatcaga agtctctgaa gaggtgcggt ggcttcctga tacaagacga 120 cttcgtgctg acagctgctc actgttgggg aagctccata aatgtcacct tgggggccca 180 caatatcaaa gaacaggagc cgacccagca gtttatccct gtgaaaagac ccatccccca 240 tccagcctat aatcctaaga acttctccaa cgacatcatg ctactgcagc tggagagaaa 300 ggccaagcgg accagagctg tgcagcccct caggctacct agcaacaagg cccaggtgaa 360 gccagggcag acatgcagtg tggccggctg ggggcagacg gcccccctgg gaaaacactc 420 acacacacta caagaggtga agatgacagt gcaggaagat cgaaagtgcg aatctgactt 480 acgccattat tacgacagta ccattgagtt gtgcgtgggg gacccagaga ttaaaaagac 540 ttcctttaag ggggactctg gaggccctct tgtgtgtaac aaggtggccc agggcattgt 600 ctcctatgga cgaaacaatg gcatgcctcc acgagcctgc accaaagtct caagctttgt 660 acactggata aagaaaacca tgaaacgcta c 691 <![CDATA[<210> 27]]> <![CDATA[<211> 1065]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼TOM70-(GGGGS)3-UB-顆粒酶B之核苷酸序列]]> <![CDATA[<400> 27]]> atgaaaagtt ttataactcg gaataaaact gcaattttcg caactgttgc tgctacggga 60 accgctattg gtgcatacta ctattatgga ggtggcggaa gcgggggtgg aggatccggg 120 ggcggcggaa gccaaatctt cgtcaaaact ctaacaggga agactataac cctagaggtt 180 gaaccatccg acactattga aaacgtcaaa gctaaaattc aagataaaga aggtatccct 240 ccggatcagc agagattgat ttttgctggt aagcaactag aagatggtag aaccttgtct 300 gactacaaca tccaaaagga atctactctt cacttggtgt tgagactccg cggtggtatc 360 atcgggggac atgaggccaa gccccactcc cgcccctaca tggcttatct tatgatctgg 420 gatcagaagt ctctgaagag gtgcggtggc ttcctgatac gagacgactt cgtgctgaca 480 gctgctcact gttggggaag ctccataaat gtcaccttgg gggcccacaa tatcaaagaa 540 caggagccga cccagcagtt tatccctgtg aaaagaccca tcccccatcc agcctataat 600 cctaagaact tctccaacga catcatgcta ctgcagctgg agagaaaggc caagcggacc 660 agagctgtgc agcccctcag gctacctagc aacaaggccc aggtgaagcc agggcagaca 720 tgcagtgtgg ccggctgggg gcagacggcc cccctgggaa aacactcaca cacactacaa 780 gaggtgaaga tgacagtgca ggaagatcga aagtgcgaat ctgacttacg ccattattac 840 gacagtacca ttgagttgtg cgtgggggac ccagagatta aaaagacttc ctttaagggg 900 gactctggag gccctcttgt gtgtaacaag gtggcccagg gcattgtctc ctatggacga 960 aacaatggca tgcctccacg agcctgcacc aaagtctcaa gctttgtaca ctggataaag 1020 aaaaccatga aacgctacct cgagcaccac caccaccacc actag 1065 <![CDATA[<210> 28]]> <![CDATA[<211> 1083]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼UB-顆粒酶B-TOM7之核苷酸序列]]> <![CDATA[<400> 28]]> atgggcagca gccatcatca tcatcatcac agcagcggcc tggtgccgcg cggcagccat 60 atgcaaatct tcgtcaaaac tctaacaggg aagactataa ccctagaggt tgaaccatcc 120 gacactattg aaaacgtcaa agctaaaatt caagataaag aaggtatccc tccggatcag 180 cagagattga tttttgctgg taagcaacta gaagatggta gaaccttgtc tgactacaac 240 atccaaaagg aatctactct tcacttggtg ttgagactcc gcggtggtat catcggggga 300 catgaggcca agccccactc ccgcccctac atggcttatc ttatgatctg ggatcagaag 360 tctctgaaga ggtgcggtgg cttcctgata cgagacgact tcgtgctgac agctgctcac 420 tgttggggaa gctccataaa tgtcaccttg ggggcccaca atatcaaaga acaggagccg 480 acccagcagt ttatccctgt gaaaagaccc atcccccatc cagcctataa tcctaagaac 540 ttctccaacg acatcatgct actgcagctg gagagaaagg ccaagcggac cagagctgtg 600 cagcccctca ggctacctag caacaaggcc caggtgaagc cagggcagac atgcagtgtg 660 gccggctggg ggcagacggc ccccctggga aaacactcac acacactaca agaggtgaag 720 atgacagtgc aggaagatcg aaagtgcgaa tctgacttac gccattatta cgacagtacc 780 attgagttgt gcgtggggga cccagagatt aaaaagactt cctttaaggg ggactctgga 840 ggccctcttg tgtgtaacaa ggtggcccag ggcattgtct cctatggacg aaacaatggc 900 atgcctccac gagcctgcac caaagtctca agctttgtac actggataaa gaaaaccatg 960 aaacgctacc tcgagtttgc cattcgctgg ggctttatcc ctcttgtgat ttacctggga 1020 tttaagaggg gtgcagatcc cggaatgcct gaaccaactg ttttgagcct actttgggga 1080 tag 1083 <![CDATA[<210> 29]]> <![CDATA[<211> 39]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> T2RKIP引子]]> <![CDATA[<400> 29]]> aaaaaaccgc ggtggtccgg tggacctcag caagtggtc 39 <![CDATA[<210> 30]]> <![CDATA[<211> 41]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> XRKIP(noT)引子]]> <![CDATA[<400> 30]]> aaaaaactcg agcttcccag acagctgctc gtacagtttg g 41 <![CDATA[<210> 31]]> <![CDATA[<211> 568]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼RKIP之核苷酸序列]]> <![CDATA[<400> 31]]> ccgcggtggt ccggtggacc tcagcaagtg gtccgggccc ttgagcctgc aagaagtgga 60 cgagcagccg cagcacccac tgcatgtcac ctacgccggg gcggcggtgg acgagctggg 120 caaagtgctg acgcccaccc aggttaagaa tagacccacc agcatttcgt gggatggtct 180 tgattcaggg aagctctaca ccttggtcct gacagacccg gatgctccca gcaggaagga 240 tcccaaatac agagaatggc atcatttcct ggtggtcaac atgaagggca atgacatcag 300 cagtggcaca gtcctctccg attatgtggg ctcggggcct cccaagggca caggcctcca 360 ccgctatgtc tggctggttt acgagcagga caggccgcta aagtgtgacg agcccatcct 420 cagcaaccga tctggagacc accgtggcaa attcaaggtg gcgtccttcc gtaaaaagta 480 tgagctcagg gccccggtgg ctggcacgtg ttaccaggcc gagtgggatg actatgtgcc 540 caaactgtac gagcagctgt ctgggaag 568 <![CDATA[<210> 32]]> <![CDATA[<211> 942]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼TOM70-(GGGGS)3-UB-RKIP之核苷酸序列]]> <![CDATA[<400> 32]]> atgaaaagtt ttataactcg gaataaaact gcaattttcg caactgttgc tgctacggga 60 accgctattg gtgcatacta ctattatgga ggtggcggaa gcgggggtgg aggatccggg 120 ggcggcggaa gccaaatctt cgtcaaaact ctaacaggga agactataac cctagaggtt 180 gaaccatccg acactattga aaacgtcaaa gctaaaattc aagataaaga aggtatccct 240 ccggatcagc agagattgat ttttgctggt aagcaactag aagatggtag aaccttgtct 300 gactacaaca tccaaaagga atctactctt cacttggtgt tgagactccg cggtggtccg 360 gtggacctca gcaagtggtc cgggcccttg agcctgcaag aagtggacga gcagccgcag 420 cacccactgc atgtcaccta cgccggggcg gcggtggacg agctgggcaa agtgctgacg 480 cccacccagg ttaagaatag acccaccagc atttcgtggg atggtcttga ttcagggaag 540 ctctacacct tggtcctgac agacccggat gctcccagca ggaaggatcc caaatacaga 600 gaatggcatc atttcctggt ggtcaacatg aagggcaatg acatcagcag tggcacagtc 660 ctctccgatt atgtgggctc ggggcctccc aagggcacag gcctccaccg ctatgtctgg 720 ctggtttacg agcaggacag gccgctaaag tgtgacgagc ccatcctcag caaccgatct 780 ggagaccacc gtggcaaatt caaggtggcg tccttccgta aaaagtatga gctcagggcc 840 ccggtggctg gcacgtgtta ccaggccgag tgggatgact atgtgcccaa actgtacgag 900 cagctgtctg ggaagctcga gcaccaccac caccaccact ag 942 <![CDATA[<210> 33]]> <![CDATA[<211> 42]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> T2PTEN引子]]> <![CDATA[<400> 33]]> aaaaaaccgc ggtggtacag ccatcatcaa agagatcgtt ag 42 <![CDATA[<210> 34]]> <![CDATA[<211> 36]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> XPTEN(noT)引子]]> <![CDATA[<400> 34]]> aaaaaactcg aggacttttg taatttgtgt atgctg 36 <![CDATA[<210> 35]]> <![CDATA[<211> 1216]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼PTEN之核苷酸序列]]> <![CDATA[<400> 35]]> ccgcggtggt acagccatca tcaaagagat cgttagcaga aacaaaagga gatatcaaga 60 ggatggattc gacttagact tgacctatat ttatccaaac attattgcta tgggatttcc 120 tgcagaaaga cttgaaggcg tatacaggaa caatattgat gatgtagtaa ggtttttgga 180 ttcaaagcat aaaaaccatt acaagatata caatctttgt gctgaaagac attatgacac 240 cgccaaattt aattgcagag ttgcacaata tccttttgaa gaccataacc caccacagct 300 agaacttatc aaaccctttt gtgaagatct tgaccaatgg ctaagtgaag atgacaatca 360 tgttgcagca attcactgta aagctggaaa gggacgaact ggtgtaatga tatgtgcata 420 tttattacat cggggcaaat ttttaaaggc acaagaggcc ctagatttct atggggaagt 480 aaggaccaga gacaaaaagg gagtaactat tcccagtcag aggcgctatg tgtattatta 540 tagctacctg ttaaagaatc atctggatta tagaccagtg gcactgttgt ttcacaagat 600 gatgtttgaa actattccaa tgttcagtgg cggaacttgc aatcctcagt ttgtggtctg 660 ccagctaaag gtgaagatat attcctccaa ttcaggaccc acacgacggg aagacaagtt 720 catgtacttt gagttccctc agccgttacc tgtgtgtggt gatatcaaag tagagttctt 780 ccacaaacag aacaagatgc taaaaaagga caaaatgttt cacttttggg taaatacatt 840 cttcatacca ggaccagagg aaacctcaga aaaagtagaa aatggaagtc tatgtgatca 900 agaaatcgat agcatttgca gtatagagcg tgcagataat gacaaggaat atctagtact 960 tactttaaca aaaaatgatc ttgacaaagc aaataaagac aaagccaacc gatacttttc 1020 tccaaatttt aaggtgaagc tgtacttcac aaaaacagta gaggagccgt caaatccaga 1080 ggctagcagt tcaacttctg taacaccaga tgttagtgac aatgaacctg atcattatag 1140 atattctgac accactgact ctgatccaga gaatgaacct tttgatgaag atcagcatac 1200 acaaattaca aaagtc 1216 <![CDATA[<210> 36]]> <![CDATA[<211> 1590]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼TOM70-(GGGGS)3-UB-PTEN之核苷酸序列]]> <![CDATA[<400> 36]]> atgaaaagtt ttataactcg gaataaaact gcaattttcg caactgttgc tgctacggga 60 accgctattg gtgcatacta ctattatgga ggtggcggaa gcgggggtgg aggatccggg 120 ggcggcggaa gccaaatctt cgtcaaaact ctaacaggga agactataac cctagaggtt 180 gaaccatccg acactattga aaacgtcaaa gctaaaattc aagataaaga aggtatccct 240 ccggatcagc agagattgat ttttgctggt aagcaactag aagatggtag aaccttgtct 300 gactacaaca tccaaaagga atctactctt cacttggtgt tgagactccg cggtggtaca 360 gccatcatca aagagatcgt tagcagaaac aaaaggagat atcaagagga tggattcgac 420 ttagacttga cctatattta tccaaacatt attgctatgg gatttcctgc agaaagactt 480 gaaggcgtat acaggaacaa tattgatgat gtagtaaggt ttttggattc aaagcataaa 540 aaccattaca agatatacaa tctttgtgct gaaagacatt atgacaccgc caaatttaat 600 tgcagagttg cacaatatcc ttttgaagac cataacccac cacagctaga acttatcaaa 660 cccttttgtg aagatcttga ccaatggcta agtgaagatg acaatcatgt tgcagcaatt 720 cactgtaaag ctggaaaggg acgaactggt gtaatgatat gtgcatattt attacatcgg 780 ggcaaatttt taaaggcaca agaggcccta gatttctatg gggaagtaag gaccagagac 840 aaaaagggag taactattcc cagtcagagg cgctatgtgt attattatag ctacctgtta 900 aagaatcatc tggattatag accagtggca ctgttgtttc acaagatgat gtttgaaact 960 attccaatgt tcagtggcgg aacttgcaat cctcagtttg tggtctgcca gctaaaggtg 1020 aagatatatt cctccaattc aggacccaca cgacgggaag acaagttcat gtactttgag 1080 ttccctcagc cgttacctgt gtgtggtgat atcaaagtag agttcttcca caaacagaac 1140 aagatgctaa aaaaggacaa aatgtttcac ttttgggtaa atacattctt cataccagga 1200 ccagaggaaa cctcagaaaa agtagaaaat ggaagtctat gtgatcaaga aatcgatagc 1260 atttgcagta tagagcgtgc agataatgac aaggaatatc tagtacttac tttaacaaaa 1320 aatgatcttg acaaagcaaa taaagacaaa gccaaccgat acttttctcc aaattttaag 1380 gtgaagctgt acttcacaaa aacagtagag gagccgtcaa atccagaggc tagcagttca 1440 acttctgtaa caccagatgt tagtgacaat gaacctgatc attatagata ttctgacacc 1500 actgactctg atccagagaa tgaacctttt gatgaagatc agcatacaca aattacaaaa 1560 gtcctcgagc accaccacca ccaccactag 1590 <![CDATA[<210> 37]]> <![CDATA[<211> 739]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼scFvHER2之核苷酸序列]]> <![CDATA[<400> 37]]> ccgcggtggt gaagtgcaac ttgttgagag tggcggagga ctggtccaac cgggcggttc 60 acttaggctc tcatgtgcag cttcagggtt cacgttcacg gactatacaa tggactgggt 120 gaggcaagcc cctggtaagg gactggagtg ggttgctgac gttaacccta attccggtgg 180 gtccatctac aaccagcgat tcaagggacg atttactctt tcagtcgaca gaagcaaaaa 240 caccctctac ctccagatga actccttgcg ggcagaggat acagcggtct actattgcgc 300 gagaaacttg ggaccaagct tctacttcga ctactggggg caaggaacgc ttgttacggt 360 ttcaagcgga ggtggaggaa gtggaggtgg cggttccggc ggtggcggtt cagatataca 420 gatgacccaa tcacccagtt ctcttagcgc gtctgtaggc gacagggtaa ccataacctg 480 caaggcgtcc caggacgtgt caattggagt tgcctggtat cagcaaaaac ctgggaaagc 540 tccgaagctc ctgatttaca gcgcatctta ccgatatact ggtgtccctt caaggttcag 600 tggcagtgga tctgggacag actttacgct tactatcagc agtctgcaac ctgaggattt 660 cgcgacctac tactgtcagc agtattacat ctatccgtac acgttcggtc aaggtacaaa 720 ggtagaaata aaacgcact 739 <![CDATA[<210> 38]]> <![CDATA[<211> 1125]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼UB-scFvHER2-TOM7之核苷酸序列]]> <![CDATA[<400> 38]]> atgggcagca gccatcatca tcatcatcac agcagcggcc tggtgccgcg cggcagccat 60 atgcaaatct tcgtcaaaac tctaacaggg aagactataa ccctagaggt tgaaccatcc 120 gacactattg aaaacgtcaa agctaaaatt caagataaag aaggtatccc tccggatcag 180 cagagattga tttttgctgg taagcaacta gaagatggta gaaccttgtc tgactacaac 240 atccaaaagg aatctactct tcacttggtg ttgagactcc gcggtggtga agtgcaactt 300 gttgagagtg gcggaggact ggtccaaccg ggcggttcac ttaggctctc atgtgcagct 360 tcagggttca cgttcacgga ctatacaatg gactgggtga ggcaagcccc tggtaaggga 420 ctggagtggg ttgctgacgt taaccctaat tccggtgggt ccatctacaa ccagcgattc 480 aagggacgat ttactctttc agtcgacaga agcaaaaaca ccctctacct ccagatgaac 540 tccttgcggg cagaggatac agcggtctac tattgcgcga gaaacttggg accaagcttc 600 tacttcgact actgggggca aggaacgctt gttacggttt caagcggagg tggaggaagt 660 ggaggtggcg gttccggcgg tggcggttca gatatacaga tgacccaatc acccagttct 720 cttagcgcgt ctgtaggcga cagggtaacc ataacctgca aggcgtccca ggacgtgtca 780 attggagttg cctggtatca gcaaaaacct gggaaagctc cgaagctcct gatttacagc 840 gcatcttacc gatatactgg tgtcccttca aggttcagtg gcagtggatc tgggacagac 900 tttacgctta ctatcagcag tctgcaacct gaggatttcg cgacctacta ctgtcagcag 960 tattacatct atccgtacac gttcggtcaa ggtacaaagg tagaaataaa acgcactttt 1020 gccattcgct ggggctttat ccctcttgtg atttacctgg gatttaagag gggtgcagat 1080 cccggaatgc ctgaaccaac tgttttgagc ctactttggg gatag 1125 <![CDATA[<210> 39]]> <![CDATA[<211> 38]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> RscFvHER2引子]]> <![CDATA[<400> 39]]> aaaaaagaat tcatggaagt gcaacttgtt gagagtgg 38 <![CDATA[<210> 40]]> <![CDATA[<211> 35]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> XTOM7(noT)引子]]> <![CDATA[<400> 40]]> aaaaaactcg agtccccaaa gtaggctcaa aacag 35 <![CDATA[<210> 41]]> <![CDATA[<211> 924]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼scFvHER2-TOM7-myc/His之核苷酸序列]]> <![CDATA[<400> 41]]> atggaagtgc aacttgttga gagtggcgga ggactggtcc aaccgggcgg ttcacttagg 60 ctctcatgtg cagcttcagg gttcacgttc acggactata caatggactg ggtgaggcaa 120 gcccctggta agggactgga gtgggttgct gacgttaacc ctaattccgg tgggtccatc 180 tacaaccagc gattcaaggg acgatttact ctttcagtcg acagaagcaa aaacaccctc 240 tacctccaga tgaactcctt gcgggcagag gatacagcgg tctactattg cgcgagaaac 300 ttgggaccaa gcttctactt cgactactgg gggcaaggaa cgcttgttac ggtttcaagc 360 ggaggtggag gaagtggagg tggcggttcc ggcggtggcg gttcagatat acagatgacc 420 caatcaccca gttctcttag cgcgtctgta ggcgacaggg taaccataac ctgcaaggcg 480 tcccaggacg tgtcaattgg agttgcctgg tatcagcaaa aacctgggaa agctccgaag 540 ctcctgattt acagcgcatc ttaccgatat actggtgtcc cttcaaggtt cagtggcagt 600 ggatctggga cagactttac gcttactatc agcagtctgc aacctgagga tttcgcgacc 660 tactactgtc agcagtatta catctatccg tacacgttcg gtcaaggtac aaaggtagaa 720 ataaaacgca cttttgccat tcgctggggc tttatccctc ttgtgattta cctgggattt 780 aagaggggtg cagatcccgg aatgcctgaa ccaactgttt tgagcctact ttggggactc 840 gagtctagag ggcccttcga acaaaaactc atctcagaag aggatctgaa tatgcatacc 900 ggtcatcatc accatcacca ttga 924 <![CDATA[<210> 42]]> <![CDATA[<211> 760]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼scFvMEL之核苷酸序列]]> <![CDATA[<400> 42]]> ccgcggtggt acggacattg tgatgaccca gtctcaaaaa ttcatgtcca catcagtagg 60 agacagggtc agcgtcacct gcaaggccag tcagaatgtg gatactaatg tagcctggta 120 tcaacaaaaa ccagggcaat ctcctgaacc actgcttttc tcggcatcct accgttacac 180 tggagtccct gatcgcttca caggcagtgg atctgggaca gatttcactc tcaccatcag 240 caatgtgcag tctgaagact tggcagagta tttctgtcag caatataaca gctatcctct 300 gacgttcggt ggaggcacca agctggagat caaaggctcc accagcggca gcggtaagcc 360 aggctccggc gaaggcagca ccaaaggcga agtgaaggtt gaggagtctg gaggaggctt 420 ggtgcaacct ggaggatcca tgaaactctc ctgtgttgtc tctggattca ctttcggtaa 480 ttactggatg aactgggtcc gccagtctcc agagaagggg cttgagtgga ttgcagaaat 540 tagattgaaa tccaataatt ttgcaagata ttatgcggag tctgtgaaag ggaggttcac 600 catctcaaga gatgattcca aaagtagtgt ctacctgcaa atgatcaacc taagagctga 660 agatactggc atttattact gtaccagtta tggtaactac gttgggcact attttgacca 720 ctggggccaa ggcaccactc tcaccgtctc cctttgggga 760 <![CDATA[<210> 43]]> <![CDATA[<211> 1137]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼UB-scFvMEL-TOM7之核苷酸序列]]> <![CDATA[<400> 43]]> atgggcagca gccatcatca tcatcatcac agcagcggcc tggtgccgcg cggcagccat 60 atgcaaatct tcgtcaaaac tctaacaggg aagactataa ccctagaggt tgaaccatcc 120 gacactattg aaaacgtcaa agctaaaatt caagataaag aaggtatccc tccggatcag 180 cagagattga tttttgctgg taagcaacta gaagatggta gaaccttgtc tgactacaac 240 atccaaaagg aatctactct tcacttggtg ttgagactcc gcggtggtac ggacattgtg 300 atgacccagt ctcaaaaatt catgtccaca tcagtaggag acagggtcag cgtcacctgc 360 aaggccagtc agaatgtgga tactaatgta gcctggtatc aacaaaaacc agggcaatct 420 cctgaaccac tgcttttctc ggcatcctac cgttacactg gagtccctga tcgcttcaca 480 ggcagtggat ctgggacaga tttcactctc accatcagca atgtgcagtc tgaagacttg 540 gcagagtatt tctgtcagca atataacagc tatcctctga cgttcggtgg aggcaccaag 600 ctggagatca aaggctccac cagcggcagc ggtaagccag gctccggcga aggcagcacc 660 aaaggcgaag tgaaggttga ggagtctgga ggaggcttgg tgcaacctgg aggatccatg 720 aaactctcct gtgttgtctc tggattcact ttcggtaatt actggatgaa ctgggtccgc 780 cagtctccag agaaggggct tgagtggatt gcagaaatta gattgaaatc caataatttt 840 gcaagatatt atgcggagtc tgtgaaaggg aggttcacca tctcaagaga tgattccaaa 900 agtagtgtct acctgcaaat gatcaaccta agagctgaag atactggcat ttattactgt 960 accagttatg gtaactacgt tgggcactat tttgaccact ggggccaagg caccactctc 1020 accgtctcct catttgccat tcgctggggc tttatccctc ttgtgattta cctgggattt 1080 aagaggggtg cagatcccgg aatgcctgaa ccaactgttt tgagcctact ttgggga 1137 <![CDATA[<210> 44]]> <![CDATA[<211> 36]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> RscFvMEL引子]]> <![CDATA[<400> 44]]> aaaaaagaat tcatgaaaac aagtaaccca ggagtg 36 <![CDATA[<210> 45]]> <![CDATA[<211> 939]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼scFvMEL-TOM7-myc/His之核苷酸序列]]> <![CDATA[<400> 45]]> atgacggaca ttgtgatgac ccagtctcaa aaattcatgt ccacatcagt aggagacagg 60 gtcagcgtca cctgcaaggc cagtcagaat gtggatacta atgtagcctg gtatcaacaa 120 aaaccagggc aatctcctga accactgctt ttctcggcat cctaccgtta cactggagtc 180 cctgatcgct tcacaggcag tggatctggg acagatttca ctctcaccat cagcaatgtg 240 cagtctgaag acttggcaga gtatttctgt cagcaatata acagctatcc tctgacgttc 300 ggtggaggca ccaagctgga gatcaaaggc tccaccagcg gcagcggtaa gccaggctcc 360 ggcgaaggca gcaccaaagg cgaagtgaag gttgaggagt ctggaggagg cttggtgcaa 420 cctggaggat ccatgaaact ctcctgtgtt gtctctggat tcactttcgg taattactgg 480 atgaactggg tccgccagtc tccagagaag gggcttgagt ggattgcaga aattagattg 540 aaatccaata attttgcaag atattatgcg gagtctgtga aagggaggtt caccatctca 600 agagatgatt ccaaaagtag tgtctacctg caaatgatca acctaagagc tgaagatact 660 ggcatttatt actgtaccag ttatggtaac tacgttgggc actattttga ccactggggc 720 caaggcacca ctctcaccgt ctcctcattt gccattcgct ggggctttat ccctcttgtg 780 atttacctgg gatttaagag gggtgcagat cccggaatgc ctgaaccaac tgttttgagc 840 ctactttggg gactcgagtc tagagggccc ttcgaacaaa aactcatctc agaagaggat 900 ctgaatatgc ataccggtca tcatcaccat caccattga 939 <![CDATA[<210> 46]]> <![CDATA[<211> 750]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼scFvPD-L1之核苷酸序列]]> <![CDATA[<400> 46]]> atggacatcg tgatgagcca gtctcccagc agcctggctg tgtctgctgg ggagaaggtg 60 accatgtcct gcaagagctc ccagtccctg ctgaacagcc gcaccaggaa gaactacctg 120 gcctggtacc agcagaagcc aggccagagc cccaagctcc tcatctactg ggccagcacc 180 cgggagagcg gggtgcctga ccgcttcact ggaagtggca gcggcacaga cttcaccctg 240 accatcagct ctgtgcaggc cgaggacctg gcagtgtact actgccagca aagctatgat 300 gtggtgacat ttggagctgg caccaagctg gagctgaagg gaggtggcgg aagcgggggt 360 ggaggatccg ggggcggcgg aagccaggtc caggtgcagc agagcggggc tgagctggcc 420 gagcccgggg cctctgtgaa gatgagctgc aaggcttctg gctacatctt caccagctac 480 tggatgcact ggctcaagca gaggcctggg caggggctgg agtggatcgg ctatatcaac 540 cccagcagtg actacaatga atattctgag aagttcatgg acaaagccac cctgactgct 600 gacaaggcca gcaccaccgc ctacatgcag ctgatcagcc tgacctcaga ggacagcgct 660 gtgtactact gtgcccggag cggctggctg gtgcacgggg actattattt tgattattgg 720 ggccagggca ccacactgac agtgagcagc 750 <![CDATA[<210> 47]]> <![CDATA[<211> 948]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼scFvPD-L1-TOM7-myc/His之核苷酸序列]]> <![CDATA[<400> 47]]> atggacatcg tgatgagcca gtctcccagc agcctggctg tgtctgctgg ggagaaggtg 60 accatgtcct gcaagagctc ccagtccctg ctgaacagcc gcaccaggaa gaactacctg 120 gcctggtacc agcagaagcc aggccagagc cccaagctcc tcatctactg ggccagcacc 180 cgggagagcg gggtgcctga ccgcttcact ggaagtggca gcggcacaga cttcaccctg 240 accatcagct ctgtgcaggc cgaggacctg gcagtgtact actgccagca aagctatgat 300 gtggtgacat ttggagctgg caccaagctg gagctgaagg gaggtggcgg aagcgggggt 360 ggaggatccg ggggcggcgg aagccaggtc caggtgcagc agagcggggc tgagctggcc 420 gagcccgggg cctctgtgaa gatgagctgc aaggcttctg gctacatctt caccagctac 480 tggatgcact ggctcaagca gaggcctggg caggggctgg agtggatcgg ctatatcaac 540 cccagcagtg actacaatga atattctgag aagttcatgg acaaagccac cctgactgct 600 gacaaggcca gcaccaccgc ctacatgcag ctgatcagcc tgacctcaga ggacagcgct 660 gtgtactact gtgcccggag cggctggctg gtgcacgggg actattattt tgattattgg 720 ggccagggca ccacactgac agtgagcagc ctcgagtttg ccattcgctg gggctttatc 780 cctcttgtga tttacctggg atttaagagg ggtgcagatc ccggaatgcc tgaaccaact 840 gttttgagcc tactttgggg actcgagtct agagggccct tcgaacaaaa actcatctca 900 gaagaggatc tgaatatgca taccggtcat catcaccatc accattga 948 <![CDATA[<210> 48]]> <![CDATA[<211> 395]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> p53之胺基酸序列]]> <![CDATA[<400> 48]]> Arg Gly Gly Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu 1 5 10 15 Ser Gln Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn 20 25 30 Val Leu Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser 35 40 45 Pro Asp Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu 50 55 60 Ala Pro Arg Met Pro Glu Ala Ala Pro Arg Val Ala Pro Ala Pro Ala 65 70 75 80 Ala Pro Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser 85 90 95 Ser Ser Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg 100 105 110 Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr 115 120 125 Ser Pro Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro 130 135 140 Val Gln Leu Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg 145 150 155 160 Ala Met Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg 165 170 175 Arg Cys Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro 180 185 190 Pro Gln His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu 195 200 205 Asp Asp Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro 210 215 220 Pro Glu Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys 225 230 235 240 Asn Ser Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile 245 250 255 Ile Thr Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe 260 265 270 Glu Val Arg Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu 275 280 285 Glu Asn Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly 290 295 300 Ser Thr Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro 305 310 315 320 Lys Lys Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly 325 330 335 Arg Glu Arg Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu 340 345 350 Lys Asp Ala Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His Ser 355 360 365 Ser His Leu Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys 370 375 380 Leu Met Phe Lys Thr Glu Gly Pro Asp Ser Asp 385 390 395 <![CDATA[<210> 49]]> <![CDATA[<211> 488]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> UB-p53之胺基酸序列]]> <![CDATA[<400> 49]]> Met Gly Ser Ser His His His His His His Ser Ser Gly Leu Val Pro 1 5 10 15 Arg Gly Ser His Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr 20 25 30 Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala 35 40 45 Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile 50 55 60 Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn 65 70 75 80 Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly 85 90 95 Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln Glu 100 105 110 Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu Ser 115 120 125 Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp Asp 130 135 140 Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro Arg 145 150 155 160 Met Pro Glu Ala Ala Pro Arg Val Ala Pro Ala Pro Ala Ala Pro Thr 165 170 175 Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser Val 180 185 190 Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly Phe 195 200 205 Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro Ala 210 215 220 Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln Leu 225 230 235 240 Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met Ala 245 250 255 Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys Pro 260 265 270 His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln His 275 280 285 Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg 290 295 300 Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu Val 305 310 315 320 Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser Ser 325 330 335 Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu 340 345 350 Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val Arg 355 360 365 Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu 370 375 380 Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr Lys 385 390 395 400 Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys 405 410 415 Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu Arg 420 425 430 Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp Ala 435 440 445 Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His Leu 450 455 460 Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met Phe 465 470 475 480 Lys Thr Glu Gly Pro Asp Ser Asp 485 <![CDATA[<210> 50]]> <![CDATA[<211> 504]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> TOM70-UB-p53之胺基酸序列]]> <![CDATA[<400> 50]]> Met Lys Ser Phe Ile Thr Arg Asn Lys Thr Ala Ile Phe Ala Thr Val 1 5 10 15 Ala Ala Thr Gly Thr Ala Ile Gly Ala Tyr Tyr Tyr Tyr Gln Ile Phe 20 25 30 Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser 35 40 45 Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile 50 55 60 Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp 65 70 75 80 Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His 85 90 95 Leu Val Leu Arg Leu Arg Gly Gly Glu Glu Pro Gln Ser Asp Pro Ser 100 105 110 Val Glu Pro Pro Leu Ser Gln Glu Thr Phe Ser Asp Leu Trp Lys Leu 115 120 125 Leu Pro Glu Asn Asn Val Leu Ser Pro Leu Pro Ser Gln Ala Met Asp 130 135 140 Asp Leu Met Leu Ser Pro Asp Asp Ile Glu Gln Trp Phe Thr Glu Asp 145 150 155 160 Pro Gly Pro Asp Glu Ala Pro Arg Met Pro Glu Ala Ala Pro Arg Val 165 170 175 Ala Pro Ala Pro Ala Ala Pro Thr Pro Ala Ala Pro Ala Pro Ala Pro 180 185 190 Ser Trp Pro Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr Gln Gly 195 200 205 Ser Tyr Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser 210 215 220 Val Thr Cys Thr Tyr Ser Pro Ala Leu Asn Lys Met Phe Cys Gln Leu 225 230 235 240 Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp Ser Thr Pro Pro Pro 245 250 255 Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys Gln Ser Gln His Met 260 265 270 Thr Glu Val Val Arg Arg Cys Pro His His Glu Arg Cys Ser Asp Ser 275 280 285 Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg Val Glu Gly Asn Leu 290 295 300 Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe Arg His Ser Val Val 305 310 315 320 Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp Cys Thr Thr Ile His 325 330 335 Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly Gly Met Asn Arg Arg 340 345 350 Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser Ser Gly Asn Leu Leu 355 360 365 Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala Cys Pro Gly Arg Asp 370 375 380 Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys Gly Glu Pro His His 385 390 395 400 Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu Pro Asn Asn Thr Ser 405 410 415 Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp Gly Glu Tyr Phe Thr 420 425 430 Leu Gln Ile Arg Gly Arg Glu Arg Phe Glu Met Phe Arg Glu Leu Asn 435 440 445 Glu Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly Lys Glu Pro Gly Gly 450 455 460 Ser Arg Ala His Ser Ser His Leu Lys Ser Lys Lys Gly Gln Ser Thr 465 470 475 480 Ser Arg His Lys Lys Leu Met Phe Lys Thr Glu Gly Pro Asp Ser Asp 485 490 495 Leu Glu His His His His His His 500 <![CDATA[<210> 51]]> <![CDATA[<211> 519]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> TOM70-(GGGGS)3-UB-p53之胺基酸序列]]> <![CDATA[<400> 51]]> Met Lys Ser Phe Ile Thr Arg Asn Lys Thr Ala Ile Phe Ala Thr Val 1 5 10 15 Ala Ala Thr Gly Thr Ala Ile Gly Ala Tyr Tyr Tyr Tyr Gly Gly Gly 20 25 30 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Phe Val 35 40 45 Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp 50 55 60 Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro 65 70 75 80 Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly 85 90 95 Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu 100 105 110 Val Leu Arg Leu Arg Gly Gly Glu Glu Pro Gln Ser Asp Pro Ser Val 115 120 125 Glu Pro Pro Leu Ser Gln Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu 130 135 140 Pro Glu Asn Asn Val Leu Ser Pro Leu Pro Ser Gln Ala Met Asp Asp 145 150 155 160 Leu Met Leu Ser Pro Asp Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro 165 170 175 Gly Pro Asp Glu Ala Pro Arg Met Pro Glu Ala Ala Pro Arg Val Ala 180 185 190 Pro Ala Pro Ala Ala Pro Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser 195 200 205 Trp Pro Leu Ser Ser Ser Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser 210 215 220 Tyr Gly Phe Arg Leu Gly Phe Leu His Ser Gly Thr Ala Lys Ser Val 225 230 235 240 Thr Cys Thr Tyr Ser Pro Ala Leu Asn Lys Met Phe Cys Gln Leu Ala 245 250 255 Lys Thr Cys Pro Val Gln Leu Trp Val Asp Ser Thr Pro Pro Pro Gly 260 265 270 Thr Arg Val Arg Ala Met Ala Ile Tyr Lys Gln Ser Gln His Met Thr 275 280 285 Glu Val Val Arg Arg Cys Pro His His Glu Arg Cys Ser Asp Ser Asp 290 295 300 Gly Leu Ala Pro Pro Gln His Leu Ile Arg Val Glu Gly Asn Leu Arg 305 310 315 320 Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe Arg His Ser Val Val Val 325 330 335 Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp Cys Thr Thr Ile His Tyr 340 345 350 Asn Tyr Met Cys Asn Ser Ser Cys Met Gly Gly Met Asn Arg Arg Pro 355 360 365 Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly 370 375 380 Arg Asn Ser Phe Glu Val Arg Val Cys Ala Cys Pro Gly Arg Asp Arg 385 390 395 400 Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys Gly Glu Pro His His Glu 405 410 415 Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser 420 425 430 Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu 435 440 445 Gln Ile Arg Gly Arg Glu Arg Phe Glu Met Phe Arg Glu Leu Asn Glu 450 455 460 Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly Lys Glu Pro Gly Gly Ser 465 470 475 480 Arg Ala His Ser Ser His Leu Lys Ser Lys Lys Gly Gln Ser Thr Ser 485 490 495 Arg His Lys Lys Leu Met Phe Lys Thr Glu Gly Pro Asp Ser Asp Leu 500 505 510 Glu His His His His His His 515 <![CDATA[<210> 52]]> <![CDATA[<211> 444]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> TOM70-(GGGGS)3-p53之胺基酸序列]]> <![CDATA[<400> 52]]> Met Lys Ser Phe Ile Thr Arg Asn Lys Thr Ala Ile Phe Ala Thr Val 1 5 10 15 Ala Ala Thr Gly Thr Ala Ile Gly Ala Tyr Tyr Tyr Tyr Gly Gly Gly 20 25 30 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Glu Pro Gln 35 40 45 Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln Glu Thr Phe Ser Asp 50 55 60 Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu Ser Pro Leu Pro Ser 65 70 75 80 Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp Asp Ile Glu Gln Trp 85 90 95 Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro Arg Met Pro Glu Ala 100 105 110 Ala Pro Arg Val Ala Pro Ala Pro Ala Ala Pro Thr Pro Ala Ala Pro 115 120 125 Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser Val Pro Ser Gln Lys 130 135 140 Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly Phe Leu His Ser Gly 145 150 155 160 Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro Ala Leu Asn Lys Met 165 170 175 Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln Leu Trp Val Asp Ser 180 185 190 Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met Ala Ile Tyr Lys Gln 195 200 205 Ser Gln His Met Thr Glu Val Val Arg Arg Cys Pro His His Glu Arg 210 215 220 Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln His Leu Ile Arg Val 225 230 235 240 Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg Asn Thr Phe Arg 245 250 255 His Ser Val Val Val Pro Tyr Glu Pro Pro Glu Val Gly Ser Asp Cys 260 265 270 Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser Ser Cys Met Gly Gly 275 280 285 Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu Glu Asp Ser Ser 290 295 300 Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val Arg Val Cys Ala Cys 305 310 315 320 Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu Arg Lys Lys Gly 325 330 335 Glu Pro His His Glu Leu Pro Pro Gly Ser Thr Lys Arg Ala Leu Pro 340 345 350 Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys Pro Leu Asp Gly 355 360 365 Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu Arg Phe Glu Met Phe 370 375 380 Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp Ala Gln Ala Gly Lys 385 390 395 400 Glu Pro Gly Gly Ser Arg Ala His Ser Ser His Leu Lys Ser Lys Lys 405 410 415 Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met Phe Lys Thr Glu Gly 420 425 430 Pro Asp Ser Asp Leu Glu His His His His His His 435 440 <![CDATA[<210> 53]]> <![CDATA[<211> 525]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> UB-p53-TOM7之胺基酸序列]]> <![CDATA[<400> 53]]> Met Gly Ser Ser His His His His His His Ser Ser Gly Leu Val Pro 1 5 10 15 Arg Gly Ser His Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr 20 25 30 Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala 35 40 45 Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile 50 55 60 Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn 65 70 75 80 Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly 85 90 95 Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln Glu 100 105 110 Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu Ser 115 120 125 Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp Asp 130 135 140 Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro Arg 145 150 155 160 Met Pro Glu Ala Ala Pro Arg Val Ala Pro Ala Pro Ala Ala Pro Thr 165 170 175 Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser Val 180 185 190 Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly Phe 195 200 205 Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro Ala 210 215 220 Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln Leu 225 230 235 240 Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met Ala 245 250 255 Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys Pro 260 265 270 His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln His 275 280 285 Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg 290 295 300 Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu Val 305 310 315 320 Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser Ser 325 330 335 Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu 340 345 350 Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val His 355 360 365 Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu 370 375 380 Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr Lys 385 390 395 400 Arg Ala Leu Ser Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys 405 410 415 Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu Arg 420 425 430 Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp Ala 435 440 445 Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His Leu 450 455 460 Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met Phe 465 470 475 480 Lys Thr Glu Gly Pro Asp Ser Asp Leu Glu Phe Ala Ile Arg Trp Gly 485 490 495 Phe Ile Pro Leu Val Ile Tyr Leu Gly Phe Lys Arg Gly Ala Asp Pro 500 505 510 Gly Met Pro Glu Pro Thr Val Leu Ser Leu Leu Trp Gly 515 520 525 <![CDATA[<210> 54]]> <![CDATA[<211> 421]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> p53-myc/His之胺基酸序列]]> <![CDATA[<400> 54]]> Met Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln 1 5 10 15 Glu Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu 20 25 30 Ser Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp 35 40 45 Asp Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro 50 55 60 Arg Met Pro Glu Ala Ala Pro Arg Val Ala Pro Ala Pro Ala Ala Pro 65 70 75 80 Thr Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser 85 90 95 Val Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly 100 105 110 Phe Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro 115 120 125 Ala Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln 130 135 140 Leu Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met 145 150 155 160 Ala Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys 165 170 175 Pro His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln 180 185 190 His Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp 195 200 205 Arg Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu 210 215 220 Val Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser 225 230 235 240 Ser Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr 245 250 255 Leu Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val 260 265 270 Arg Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn 275 280 285 Leu Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr 290 295 300 Lys Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys 305 310 315 320 Lys Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu 325 330 335 Arg Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp 340 345 350 Ala Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His 355 360 365 Leu Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met 370 375 380 Phe Lys Thr Glu Gly Pro Asp Ser Asp Leu Glu Ser Arg Gly Pro Phe 385 390 395 400 Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Asn Met His Thr Gly His 405 410 415 His His His His His 420 <![CDATA[<210> 55]]> <![CDATA[<211> 230]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 顆粒酶B之胺基酸序列]]> <![CDATA[<400> 55]]> Arg Gly Gly Ile Ile Gly Gly His Glu Ala Lys Pro His Ser Arg Pro 1 5 10 15 Tyr Met Ala Tyr Leu Met Ile Trp Asp Gln Lys Ser Leu Lys Arg Cys 20 25 30 Gly Gly Phe Leu Ile Gln Asp Asp Phe Val Leu Thr Ala Ala His Cys 35 40 45 Trp Gly Ser Ser Ile Asn Val Thr Leu Gly Ala His Asn Ile Lys Glu 50 55 60 Gln Glu Pro Thr Gln Gln Phe Ile Pro Val Lys Arg Pro Ile Pro His 65 70 75 80 Pro Ala Tyr Asn Pro Lys Asn Phe Ser Asn Asp Ile Met Leu Leu Gln 85 90 95 Leu Glu Arg Lys Ala Lys Arg Thr Arg Ala Val Gln Pro Leu Arg Leu 100 105 110 Pro Ser Asn Lys Ala Gln Val Lys Pro Gly Gln Thr Cys Ser Val Ala 115 120 125 Gly Trp Gly Gln Thr Ala Pro Leu Gly Lys His Ser His Thr Leu Gln 130 135 140 Glu Val Lys Met Thr Val Gln Glu Asp Arg Lys Cys Glu Ser Asp Leu 145 150 155 160 Arg His Tyr Tyr Asp Ser Thr Ile Glu Leu Cys Val Gly Asp Pro Glu 165 170 175 Ile Lys Lys Thr Ser Phe Lys Gly Asp Ser Gly Gly Pro Leu Val Cys 180 185 190 Asn Lys Val Ala Gln Gly Ile Val Ser Tyr Gly Arg Asn Asn Gly Met 195 200 205 Pro Pro Arg Ala Cys Thr Lys Val Ser Ser Phe Val His Trp Ile Lys 210 215 220 Lys Thr Met Lys Arg Tyr 225 230 <![CDATA[<210> 56]]> <![CDATA[<211> 354]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> TOM70-(GGGGS)3-UB-顆粒酶B之胺基酸序列]]> <![CDATA[<400> 56]]> Met Lys Ser Phe Ile Thr Arg Asn Lys Thr Ala Ile Phe Ala Thr Val 1 5 10 15 Ala Ala Thr Gly Thr Ala Ile Gly Ala Tyr Tyr Tyr Tyr Gly Gly Gly 20 25 30 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Phe Val 35 40 45 Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp 50 55 60 Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro 65 70 75 80 Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly 85 90 95 Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu 100 105 110 Val Leu Arg Leu Arg Gly Gly Ile Ile Gly Gly His Glu Ala Lys Pro 115 120 125 His Ser Arg Pro Tyr Met Ala Tyr Leu Met Ile Trp Asp Gln Lys Ser 130 135 140 Leu Lys Arg Cys Gly Gly Phe Leu Ile Arg Asp Asp Phe Val Leu Thr 145 150 155 160 Ala Ala His Cys Trp Gly Ser Ser Ile Asn Val Thr Leu Gly Ala His 165 170 175 Asn Ile Lys Glu Gln Glu Pro Thr Gln Gln Phe Ile Pro Val Lys Arg 180 185 190 Pro Ile Pro His Pro Ala Tyr Asn Pro Lys Asn Phe Ser Asn Asp Ile 195 200 205 Met Leu Leu Gln Leu Glu Arg Lys Ala Lys Arg Thr Arg Ala Val Gln 210 215 220 Pro Leu Arg Leu Pro Ser Asn Lys Ala Gln Val Lys Pro Gly Gln Thr 225 230 235 240 Cys Ser Val Ala Gly Trp Gly Gln Thr Ala Pro Leu Gly Lys His Ser 245 250 255 His Thr Leu Gln Glu Val Lys Met Thr Val Gln Glu Asp Arg Lys Cys 260 265 270 Glu Ser Asp Leu Arg His Tyr Tyr Asp Ser Thr Ile Glu Leu Cys Val 275 280 285 Gly Asp Pro Glu Ile Lys Lys Thr Ser Phe Lys Gly Asp Ser Gly Gly 290 295 300 Pro Leu Val Cys Asn Lys Val Ala Gln Gly Ile Val Ser Tyr Gly Arg 305 310 315 320 Asn Asn Gly Met Pro Pro Arg Ala Cys Thr Lys Val Ser Ser Phe Val 325 330 335 His Trp Ile Lys Lys Thr Met Lys Arg Tyr Leu Glu His His His His 340 345 350 His His <![CDATA[<210> 57]]> <![CDATA[<211> 360]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> UB-顆粒酶B-TOM7之胺基酸序列]]> <![CDATA[<400> 57]]> Met Gly Ser Ser His His His His His His Ser Ser Gly Leu Val Pro 1 5 10 15 Arg Gly Ser His Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr 20 25 30 Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala 35 40 45 Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile 50 55 60 Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn 65 70 75 80 Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly 85 90 95 Ile Ile Gly Gly His Glu Ala Lys Pro His Ser Arg Pro Tyr Met Ala 100 105 110 Tyr Leu Met Ile Trp Asp Gln Lys Ser Leu Lys Arg Cys Gly Gly Phe 115 120 125 Leu Ile Arg Asp Asp Phe Val Leu Thr Ala Ala His Cys Trp Gly Ser 130 135 140 Ser Ile Asn Val Thr Leu Gly Ala His Asn Ile Lys Glu Gln Glu Pro 145 150 155 160 Thr Gln Gln Phe Ile Pro Val Lys Arg Pro Ile Pro His Pro Ala Tyr 165 170 175 Asn Pro Lys Asn Phe Ser Asn Asp Ile Met Leu Leu Gln Leu Glu Arg 180 185 190 Lys Ala Lys Arg Thr Arg Ala Val Gln Pro Leu Arg Leu Pro Ser Asn 195 200 205 Lys Ala Gln Val Lys Pro Gly Gln Thr Cys Ser Val Ala Gly Trp Gly 210 215 220 Gln Thr Ala Pro Leu Gly Lys His Ser His Thr Leu Gln Glu Val Lys 225 230 235 240 Met Thr Val Gln Glu Asp Arg Lys Cys Glu Ser Asp Leu Arg His Tyr 245 250 255 Tyr Asp Ser Thr Ile Glu Leu Cys Val Gly Asp Pro Glu Ile Lys Lys 260 265 270 Thr Ser Phe Lys Gly Asp Ser Gly Gly Pro Leu Val Cys Asn Lys Val 275 280 285 Ala Gln Gly Ile Val Ser Tyr Gly Arg Asn Asn Gly Met Pro Pro Arg 290 295 300 Ala Cys Thr Lys Val Ser Ser Phe Val His Trp Ile Lys Lys Thr Met 305 310 315 320 Lys Arg Tyr Leu Glu Phe Ala Ile Arg Trp Gly Phe Ile Pro Leu Val 325 330 335 Ile Tyr Leu Gly Phe Lys Arg Gly Ala Asp Pro Gly Met Pro Glu Pro 340 345 350 Thr Val Leu Ser Leu Leu Trp Gly 355 360 <![CDATA[<210> 58]]> <![CDATA[<211> 189]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> RKIP之胺基酸序列]]> <![CDATA[<400> 58]]> Arg Gly Gly Pro Val Asp Leu Ser Lys Trp Ser Gly Pro Leu Ser Leu 1 5 10 15 Gln Glu Val Asp Glu Gln Pro Gln His Pro Leu His Val Thr Tyr Ala 20 25 30 Gly Ala Ala Val Asp Glu Leu Gly Lys Val Leu Thr Pro Thr Gln Val 35 40 45 Lys Asn Arg Pro Thr Ser Ile Ser Trp Asp Gly Leu Asp Ser Gly Lys 50 55 60 Leu Tyr Thr Leu Val Leu Thr Asp Pro Asp Ala Pro Ser Arg Lys Asp 65 70 75 80 Pro Lys Tyr Arg Glu Trp His His Phe Leu Val Val Asn Met Lys Gly 85 90 95 Asn Asp Ile Ser Ser Gly Thr Val Leu Ser Asp Tyr Val Gly Ser Gly 100 105 110 Pro Pro Lys Gly Thr Gly Leu His Arg Tyr Val Trp Leu Val Tyr Glu 115 120 125 Gln Asp Arg Pro Leu Lys Cys Asp Glu Pro Ile Leu Ser Asn Arg Ser 130 135 140 Gly Asp His Arg Gly Lys Phe Lys Val Ala Ser Phe Arg Lys Lys Tyr 145 150 155 160 Glu Leu Arg Ala Pro Val Ala Gly Thr Cys Tyr Gln Ala Glu Trp Asp 165 170 175 Asp Tyr Val Pro Lys Leu Tyr Glu Gln Leu Ser Gly Lys 180 185 <![CDATA[<210> 59]]> <![CDATA[<211> 313]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> TOM70-(GGGGS)3-UB-RKIP之胺基酸序列]]> <![CDATA[<400> 59]]> Met Lys Ser Phe Ile Thr Arg Asn Lys Thr Ala Ile Phe Ala Thr Val 1 5 10 15 Ala Ala Thr Gly Thr Ala Ile Gly Ala Tyr Tyr Tyr Tyr Gly Gly Gly 20 25 30 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Phe Val 35 40 45 Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp 50 55 60 Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro 65 70 75 80 Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly 85 90 95 Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu 100 105 110 Val Leu Arg Leu Arg Gly Gly Pro Val Asp Leu Ser Lys Trp Ser Gly 115 120 125 Pro Leu Ser Leu Gln Glu Val Asp Glu Gln Pro Gln His Pro Leu His 130 135 140 Val Thr Tyr Ala Gly Ala Ala Val Asp Glu Leu Gly Lys Val Leu Thr 145 150 155 160 Pro Thr Gln Val Lys Asn Arg Pro Thr Ser Ile Ser Trp Asp Gly Leu 165 170 175 Asp Ser Gly Lys Leu Tyr Thr Leu Val Leu Thr Asp Pro Asp Ala Pro 180 185 190 Ser Arg Lys Asp Pro Lys Tyr Arg Glu Trp His His Phe Leu Val Val 195 200 205 Asn Met Lys Gly Asn Asp Ile Ser Ser Gly Thr Val Leu Ser Asp Tyr 210 215 220 Val Gly Ser Gly Pro Pro Lys Gly Thr Gly Leu His Arg Tyr Val Trp 225 230 235 240 Leu Val Tyr Glu Gln Asp Arg Pro Leu Lys Cys Asp Glu Pro Ile Leu 245 250 255 Ser Asn Arg Ser Gly Asp His Arg Gly Lys Phe Lys Val Ala Ser Phe 260 265 270 Arg Lys Lys Tyr Glu Leu Arg Ala Pro Val Ala Gly Thr Cys Tyr Gln 275 280 285 Ala Glu Trp Asp Asp Tyr Val Pro Lys Leu Tyr Glu Gln Leu Ser Gly 290 295 300 Lys Leu Glu His His His His His His 305 310 <![CDATA[<210> 60]]> <![CDATA[<211> 405]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> PTEN之胺基酸序列]]> <![CDATA[<400> 60]]> Arg Gly Gly Thr Ala Ile Ile Lys Glu Ile Val Ser Arg Asn Lys Arg 1 5 10 15 Arg Tyr Gln Glu Asp Gly Phe Asp Leu Asp Leu Thr Tyr Ile Tyr Pro 20 25 30 Asn Ile Ile Ala Met Gly Phe Pro Ala Glu Arg Leu Glu Gly Val Tyr 35 40 45 Arg Asn Asn Ile Asp Asp Val Val Arg Phe Leu Asp Ser Lys His Lys 50 55 60 Asn His Tyr Lys Ile Tyr Asn Leu Cys Ala Glu Arg His Tyr Asp Thr 65 70 75 80 Ala Lys Phe Asn Cys Arg Val Ala Gln Tyr Pro Phe Glu Asp His Asn 85 90 95 Pro Pro Gln Leu Glu Leu Ile Lys Pro Phe Cys Glu Asp Leu Asp Gln 100 105 110 Trp Leu Ser Glu Asp Asp Asn His Val Ala Ala Ile His Cys Lys Ala 115 120 125 Gly Lys Gly Arg Thr Gly Val Met Ile Cys Ala Tyr Leu Leu His Arg 130 135 140 Gly Lys Phe Leu Lys Ala Gln Glu Ala Leu Asp Phe Tyr Gly Glu Val 145 150 155 160 Arg Thr Arg Asp Lys Lys Gly Val Thr Ile Pro Ser Gln Arg Arg Tyr 165 170 175 Val Tyr Tyr Tyr Ser Tyr Leu Leu Lys Asn His Leu Asp Tyr Arg Pro 180 185 190 Val Ala Leu Leu Phe His Lys Met Met Phe Glu Thr Ile Pro Met Phe 195 200 205 Ser Gly Gly Thr Cys Asn Pro Gln Phe Val Val Cys Gln Leu Lys Val 210 215 220 Lys Ile Tyr Ser Ser Asn Ser Gly Pro Thr Arg Arg Glu Asp Lys Phe 225 230 235 240 Met Tyr Phe Glu Phe Pro Gln Pro Leu Pro Val Cys Gly Asp Ile Lys 245 250 255 Val Glu Phe Phe His Lys Gln Asn Lys Met Leu Lys Lys Asp Lys Met 260 265 270 Phe His Phe Trp Val Asn Thr Phe Phe Ile Pro Gly Pro Glu Glu Thr 275 280 285 Ser Glu Lys Val Glu Asn Gly Ser Leu Cys Asp Gln Glu Ile Asp Ser 290 295 300 Ile Cys Ser Ile Glu Arg Ala Asp Asn Asp Lys Glu Tyr Leu Val Leu 305 310 315 320 Thr Leu Thr Lys Asn Asp Leu Asp Lys Ala Asn Lys Asp Lys Ala Asn 325 330 335 Arg Tyr Phe Ser Pro Asn Phe Lys Val Lys Leu Tyr Phe Thr Lys Thr 340 345 350 Val Glu Glu Pro Ser Asn Pro Glu Ala Ser Ser Ser Thr Ser Val Thr 355 360 365 Pro Asp Val Ser Asp Asn Glu Pro Asp His Tyr Arg Tyr Ser Asp Thr 370 375 380 Thr Asp Ser Asp Pro Glu Asn Glu Pro Phe Asp Glu Asp Gln His Thr 385 390 395 400 Gln Ile Thr Lys Val 405 <![CDATA[<210> 61]]> <![CDATA[<211> 529]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> TOM70-(GGGGS)3-UB-PTEN之胺基酸序列]]> <![CDATA[<400> 61]]> Met Lys Ser Phe Ile Thr Arg Asn Lys Thr Ala Ile Phe Ala Thr Val 1 5 10 15 Ala Ala Thr Gly Thr Ala Ile Gly Ala Tyr Tyr Tyr Tyr Gly Gly Gly 20 25 30 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Phe Val 35 40 45 Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu Val Glu Pro Ser Asp 50 55 60 Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp Lys Glu Gly Ile Pro 65 70 75 80 Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln Leu Glu Asp Gly 85 90 95 Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser Thr Leu His Leu 100 105 110 Val Leu Arg Leu Arg Gly Gly Thr Ala Ile Ile Lys Glu Ile Val Ser 115 120 125 Arg Asn Lys Arg Arg Tyr Gln Glu Asp Gly Phe Asp Leu Asp Leu Thr 130 135 140 Tyr Ile Tyr Pro Asn Ile Ile Ala Met Gly Phe Pro Ala Glu Arg Leu 145 150 155 160 Glu Gly Val Tyr Arg Asn Asn Ile Asp Asp Val Val Arg Phe Leu Asp 165 170 175 Ser Lys His Lys Asn His Tyr Lys Ile Tyr Asn Leu Cys Ala Glu Arg 180 185 190 His Tyr Asp Thr Ala Lys Phe Asn Cys Arg Val Ala Gln Tyr Pro Phe 195 200 205 Glu Asp His Asn Pro Pro Gln Leu Glu Leu Ile Lys Pro Phe Cys Glu 210 215 220 Asp Leu Asp Gln Trp Leu Ser Glu Asp Asp Asn His Val Ala Ala Ile 225 230 235 240 His Cys Lys Ala Gly Lys Gly Arg Thr Gly Val Met Ile Cys Ala Tyr 245 250 255 Leu Leu His Arg Gly Lys Phe Leu Lys Ala Gln Glu Ala Leu Asp Phe 260 265 270 Tyr Gly Glu Val Arg Thr Arg Asp Lys Lys Gly Val Thr Ile Pro Ser 275 280 285 Gln Arg Arg Tyr Val Tyr Tyr Tyr Ser Tyr Leu Leu Lys Asn His Leu 290 295 300 Asp Tyr Arg Pro Val Ala Leu Leu Phe His Lys Met Met Phe Glu Thr 305 310 315 320 Ile Pro Met Phe Ser Gly Gly Thr Cys Asn Pro Gln Phe Val Val Cys 325 330 335 Gln Leu Lys Val Lys Ile Tyr Ser Ser Asn Ser Gly Pro Thr Arg Arg 340 345 350 Glu Asp Lys Phe Met Tyr Phe Glu Phe Pro Gln Pro Leu Pro Val Cys 355 360 365 Gly Asp Ile Lys Val Glu Phe Phe His Lys Gln Asn Lys Met Leu Lys 370 375 380 Lys Asp Lys Met Phe His Phe Trp Val Asn Thr Phe Phe Ile Pro Gly 385 390 395 400 Pro Glu Glu Thr Ser Glu Lys Val Glu Asn Gly Ser Leu Cys Asp Gln 405 410 415 Glu Ile Asp Ser Ile Cys Ser Ile Glu Arg Ala Asp Asn Asp Lys Glu 420 425 430 Tyr Leu Val Leu Thr Leu Thr Lys Asn Asp Leu Asp Lys Ala Asn Lys 435 440 445 Asp Lys Ala Asn Arg Tyr Phe Ser Pro Asn Phe Lys Val Lys Leu Tyr 450 455 460 Phe Thr Lys Thr Val Glu Glu Pro Ser Asn Pro Glu Ala Ser Ser Ser 465 470 475 480 Thr Ser Val Thr Pro Asp Val Ser Asp Asn Glu Pro Asp His Tyr Arg 485 490 495 Tyr Ser Asp Thr Thr Asp Ser Asp Pro Glu Asn Glu Pro Phe Asp Glu 500 505 510 Asp Gln His Thr Gln Ile Thr Lys Val Leu Glu His His His His His 515 520 525 His <![CDATA[<210> 62]]> <![CDATA[<211> 246]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> scFvHER2之胺基酸序列]]> <![CDATA[<400> 62]]> Arg Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 1 5 10 15 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 20 25 30 Thr Asp Tyr Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 35 40 45 Glu Trp Val Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn 50 55 60 Gln Arg Phe Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn 65 70 75 80 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 85 90 95 Tyr Tyr Cys Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Lys Ala Ser Gln Asp Val Ser Ile Gly Val Ala Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr 180 185 190 Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 210 215 220 Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys 225 230 235 240 Val Glu Ile Lys Arg Thr 245 <![CDATA[<210> 63]]> <![CDATA[<211> 374]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> UB-scFvHER2-TOM7之胺基酸序列]]> <![CDATA[<400> 63]]> Met Gly Ser Ser His His His His His His Ser Ser Gly Leu Val Pro 1 5 10 15 Arg Gly Ser His Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr 20 25 30 Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala 35 40 45 Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile 50 55 60 Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn 65 70 75 80 Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly 85 90 95 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 100 105 110 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 115 120 125 Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 130 135 140 Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe 145 150 155 160 Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr 165 170 175 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 180 185 190 Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly 195 200 205 Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 210 215 220 Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 225 230 235 240 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser 245 250 255 Gln Asp Val Ser Ile Gly Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys 260 265 270 Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val 275 280 285 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 290 295 300 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 305 310 315 320 Tyr Tyr Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 325 330 335 Lys Arg Thr Phe Ala Ile Arg Trp Gly Phe Ile Pro Leu Val Ile Tyr 340 345 350 Leu Gly Phe Lys Arg Gly Ala Asp Pro Gly Met Pro Glu Pro Thr Val 355 360 365 Leu Ser Leu Leu Trp Gly 370 <![CDATA[<210> 64]]> <![CDATA[<211> 307]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> scFvHER2-TOM7-myc/His之胺基酸序列]]> <![CDATA[<400> 64]]> Met Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 1 5 10 15 Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp 20 25 30 Tyr Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45 Val Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg 50 55 60 Phe Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu 65 70 75 80 Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 130 135 140 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala 145 150 155 160 Ser Gln Asp Val Ser Ile Gly Val Ala Trp Tyr Gln Gln Lys Pro Gly 165 170 175 Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly 180 185 190 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln 210 215 220 Gln Tyr Tyr Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu 225 230 235 240 Ile Lys Arg Thr Phe Ala Ile Arg Trp Gly Phe Ile Pro Leu Val Ile 245 250 255 Tyr Leu Gly Phe Lys Arg Gly Ala Asp Pro Gly Met Pro Glu Pro Thr 260 265 270 Val Leu Ser Leu Leu Trp Gly Leu Glu Ser Arg Gly Pro Phe Glu Gln 275 280 285 Lys Leu Ile Ser Glu Glu Asp Leu Asn Met His Thr Gly His His His 290 295 300 His His His 305 <![CDATA[<210> 65]]> <![CDATA[<211> 251]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> scFvMEL之胺基酸序列]]> <![CDATA[<400> 65]]> Arg Gly Gly Thr Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser 1 5 10 15 Thr Ser Val Gly Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn 20 25 30 Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro 35 40 45 Glu Pro Leu Leu Phe Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp 50 55 60 Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 65 70 75 80 Asn Val Gln Ser Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn 85 90 95 Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly 100 105 110 Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys 115 120 125 Gly Glu Val Lys Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 130 135 140 Gly Ser Met Lys Leu Ser Cys Val Val Ser Gly Phe Thr Phe Gly Asn 145 150 155 160 Tyr Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp 165 170 175 Ile Ala Glu Ile Arg Leu Lys Ser Asn Asn Phe Ala Arg Tyr Tyr Ala 180 185 190 Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser 195 200 205 Ser Val Tyr Leu Gln Met Ile Asn Leu Arg Ala Glu Asp Thr Gly Ile 210 215 220 Tyr Tyr Cys Thr Ser Tyr Gly Asn Tyr Val Gly His Tyr Phe Asp His 225 230 235 240 Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser 245 250 <![CDATA[<210> 66]]> <![CDATA[<211> 378]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> UB-scFvMEL-TOM7之胺基酸序列]]> <![CDATA[<400> 66]]> Met Gly Ser Ser His His His His His His Ser Ser Gly Leu Val Pro 1 5 10 15 Arg Gly Ser His Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr 20 25 30 Ile Thr Leu Glu Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala 35 40 45 Lys Ile Gln Asp Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile 50 55 60 Phe Ala Gly Lys Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn 65 70 75 80 Ile Gln Lys Glu Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly 85 90 95 Thr Asp Ile Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly 100 105 110 Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Asp Thr Asn 115 120 125 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Glu Pro Leu Leu 130 135 140 Phe Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 145 150 155 160 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser 165 170 175 Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu 180 185 190 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Ser Thr Ser Gly 195 200 205 Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val Lys 210 215 220 Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Met Lys 225 230 235 240 Leu Ser Cys Val Val Ser Gly Phe Thr Phe Gly Asn Tyr Trp Met Asn 245 250 255 Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Ile Ala Glu Ile 260 265 270 Arg Leu Lys Ser Asn Asn Phe Ala Arg Tyr Tyr Ala Glu Ser Val Lys 275 280 285 Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser Val Tyr Leu 290 295 300 Gln Met Ile Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr Tyr Cys Thr 305 310 315 320 Ser Tyr Gly Asn Tyr Val Gly His Tyr Phe Asp His Trp Gly Gln Gly 325 330 335 Thr Thr Leu Thr Val Ser Ser Phe Ala Ile Arg Trp Gly Phe Ile Pro 340 345 350 Leu Val Ile Tyr Leu Gly Phe Lys Arg Gly Ala Asp Pro Gly Met Pro 355 360 365 Glu Pro Thr Val Leu Ser Leu Leu Trp Gly 370 375 <![CDATA[<210> 67]]> <![CDATA[<211> 312]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> scFvMEL-TOM7-myc/His之胺基酸序列]]> <![CDATA[<400> 67]]> Met Thr Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser 1 5 10 15 Val Gly Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Asp 20 25 30 Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Glu Pro 35 40 45 Leu Leu Phe Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe 50 55 60 Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val 65 70 75 80 Gln Ser Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr 85 90 95 Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Ser Thr 100 105 110 Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu 115 120 125 Val Lys Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser 130 135 140 Met Lys Leu Ser Cys Val Val Ser Gly Phe Thr Phe Gly Asn Tyr Trp 145 150 155 160 Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Ile Ala 165 170 175 Glu Ile Arg Leu Lys Ser Asn Asn Phe Ala Arg Tyr Tyr Ala Glu Ser 180 185 190 Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser Val 195 200 205 Tyr Leu Gln Met Ile Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr Tyr 210 215 220 Cys Thr Ser Tyr Gly Asn Tyr Val Gly His Tyr Phe Asp His Trp Gly 225 230 235 240 Gln Gly Thr Thr Leu Thr Val Ser Ser Phe Ala Ile Arg Trp Gly Phe 245 250 255 Ile Pro Leu Val Ile Tyr Leu Gly Phe Lys Arg Gly Ala Asp Pro Gly 260 265 270 Met Pro Glu Pro Thr Val Leu Ser Leu Leu Trp Gly Leu Glu Ser Arg 275 280 285 Gly Pro Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Asn Met His 290 295 300 Thr Gly His His His His His His 305 310 <![CDATA[<210> 68]]> <![CDATA[<211> 250]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> scFvPD-L1之胺基酸序列]]> <![CDATA[<400> 68]]> Met Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala 1 5 10 15 Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn 20 25 30 Ser Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly 35 40 45 Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly 50 55 60 Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 65 70 75 80 Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln 85 90 95 Gln Ser Tyr Asp Val Val Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 100 105 110 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gln Val Gln Val Gln Gln Ser Gly Ala Glu Leu Ala Glu Pro Gly Ala 130 135 140 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Ser Tyr 145 150 155 160 Trp Met His Trp Leu Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 165 170 175 Gly Tyr Ile Asn Pro Ser Ser Asp Tyr Asn Glu Tyr Ser Glu Lys Phe 180 185 190 Met Asp Lys Ala Thr Leu Thr Ala Asp Lys Ala Ser Thr Thr Ala Tyr 195 200 205 Met Gln Leu Ile Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 210 215 220 Ala Arg Ser Gly Trp Leu Val His Gly Asp Tyr Tyr Phe Asp Tyr Trp 225 230 235 240 Gly Gln Gly Thr Thr Leu Thr Val Ser Ser 245 250 <![CDATA[<210> 69]]> <![CDATA[<211> 315]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> scFvPD-L1-TOM7-myc/His之胺基酸序列]]> <![CDATA[<400> 69]]> Met Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala 1 5 10 15 Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn 20 25 30 Ser Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly 35 40 45 Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly 50 55 60 Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 65 70 75 80 Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln 85 90 95 Gln Ser Tyr Asp Val Val Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 100 105 110 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gln Val Gln Val Gln Gln Ser Gly Ala Glu Leu Ala Glu Pro Gly Ala 130 135 140 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Ser Tyr 145 150 155 160 Trp Met His Trp Leu Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 165 170 175 Gly Tyr Ile Asn Pro Ser Ser Asp Tyr Asn Glu Tyr Ser Glu Lys Phe 180 185 190 Met Asp Lys Ala Thr Leu Thr Ala Asp Lys Ala Ser Thr Thr Ala Tyr 195 200 205 Met Gln Leu Ile Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 210 215 220 Ala Arg Ser Gly Trp Leu Val His Gly Asp Tyr Tyr Phe Asp Tyr Trp 225 230 235 240 Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Leu Glu Phe Ala Ile Arg 245 250 255 Trp Gly Phe Ile Pro Leu Val Ile Tyr Leu Gly Phe Lys Arg Gly Ala 260 265 270 Asp Pro Gly Met Pro Glu Pro Thr Val Leu Ser Leu Leu Trp Gly Leu 275 280 285 Glu Ser Arg Gly Pro Phe Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu 290 295 300 Asn Met His Thr Gly His His His His His His 305 310 315 <![CDATA[<210> 70]]> <![CDATA[<211> 15]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 連接子]]> <![CDATA[<400> 70]]> ggggsggggs ggggs 15 <![CDATA[<210> 71]]> <![CDATA[<211> 75]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 泛蛋白之胺基酸序列]]> <![CDATA[<400> 71]]> Gln Leu Phe Val Lys Thr Leu Thr Gly Lys Thr Val Thr Leu Glu Val 1 5 10 15 Glu Ser Ser Asp Thr Ile Asp Asn Val Lys Ser Lys Ile Gln Asp Lys 20 25 30 Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys Gln 35 40 45 Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu Ser 50 55 60 Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly 65 70 75 <![CDATA[<210> 72]]> <![CDATA[<211> 225]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼泛蛋白之核苷酸序列]]> <![CDATA[<400> 72]]> caacttttcg tcaaaactct aacagggaag actgtaaccc tagaggttga atcttccgac 60 actattgaca acgtcaaaag taaaattcaa gataaagaag gtatccctcc ggatcagcag 120 agattgattt ttgctggtaa gcaactagaa gatggtagaa ccttgtctga ctacaacatc 180 caaaaggaat ctactcttca cttggtgttg agactccgcg gtggt 225 <![CDATA[<210> 73]]> <![CDATA[<211> 400]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> p53之胺基酸序列]]> <![CDATA[<400> 73]]> Glu Glu Pro Gln Ser Asp Pro Ser Val Glu Pro Pro Leu Ser Gln Glu 1 5 10 15 Thr Phe Ser Asp Leu Trp Lys Leu Leu Pro Glu Asn Asn Val Leu Ser 20 25 30 Pro Leu Pro Ser Gln Ala Met Asp Asp Leu Met Leu Ser Pro Asp Asp 35 40 45 Ile Glu Gln Trp Phe Thr Glu Asp Pro Gly Pro Asp Glu Ala Pro Arg 50 55 60 Met Pro Glu Ala Ala Pro Arg Val Ala Pro Ala Pro Ala Ala Pro Thr 65 70 75 80 Pro Ala Ala Pro Ala Pro Ala Pro Ser Trp Pro Leu Ser Ser Ser Val 85 90 95 Pro Ser Gln Lys Thr Tyr Gln Gly Ser Tyr Gly Phe Arg Leu Gly Phe 100 105 110 Leu His Ser Gly Thr Ala Lys Ser Val Thr Cys Thr Tyr Ser Pro Ala 115 120 125 Leu Asn Lys Met Phe Cys Gln Leu Ala Lys Thr Cys Pro Val Gln Leu 130 135 140 Trp Val Asp Ser Thr Pro Pro Pro Gly Thr Arg Val Arg Ala Met Ala 145 150 155 160 Ile Tyr Lys Gln Ser Gln His Met Thr Glu Val Val Arg Arg Cys Pro 165 170 175 His His Glu Arg Cys Ser Asp Ser Asp Gly Leu Ala Pro Pro Gln His 180 185 190 Leu Ile Arg Val Glu Gly Asn Leu Arg Val Glu Tyr Leu Asp Asp Arg 195 200 205 Asn Thr Phe Arg His Ser Val Val Val Pro Tyr Glu Pro Pro Glu Val 210 215 220 Gly Ser Asp Cys Thr Thr Ile His Tyr Asn Tyr Met Cys Asn Ser Ser 225 230 235 240 Cys Met Gly Gly Met Asn Arg Arg Pro Ile Leu Thr Ile Ile Thr Leu 245 250 255 Glu Asp Ser Ser Gly Asn Leu Leu Gly Arg Asn Ser Phe Glu Val Arg 260 265 270 Val Cys Ala Cys Pro Gly Arg Asp Arg Arg Thr Glu Glu Glu Asn Leu 275 280 285 Arg Lys Lys Gly Glu Pro His His Glu Leu Pro Pro Gly Ser Thr Lys 290 295 300 Arg Ala Leu Pro Asn Asn Thr Ser Ser Ser Pro Gln Pro Lys Lys Lys 305 310 315 320 Pro Leu Asp Gly Glu Tyr Phe Thr Leu Gln Ile Arg Gly Arg Glu Arg 325 330 335 Phe Glu Met Phe Arg Glu Leu Asn Glu Ala Leu Glu Leu Lys Asp Ala 340 345 350 Gln Ala Gly Lys Glu Pro Gly Gly Ser Arg Ala His Ser Ser His Leu 355 360 365 Lys Ser Lys Lys Gly Gln Ser Thr Ser Arg His Lys Lys Leu Met Phe 370 375 380 Lys Thr Glu Gly Pro Asp Ser Asp Leu Glu His His His His His His 385 390 395 400 <![CDATA[<210> 74]]> <![CDATA[<211> 1203]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼p53之核苷酸序列]]> <![CDATA[<400> 74]]> gaggagccgc agtcagatcc tagcgtcgag ccccctctga gtcaggaaac attttcagac 60 ctgtggaaac tacttcctga aaacaacgtt ctgtccccct tgccgtccca agcaatggat 120 gatttgatgc tgtccccgga cgatattgaa caatggttca ctgaagaccc aggtccagat 180 gaagctccca gaatgccaga ggctgctccc cgcgtggccc ctgcaccagc agctcctaca 240 ccggcggccc ctgcaccagc cccctcctgg cccctgtcat cttctgtccc ttcccagaaa 300 acctaccagg gcagctacgg tttccgtctg ggcttcttgc attctgggac agccaagtct 360 gtgacttgca cgtactcccc tgccctcaac aagatgtttt gccaactggc caagacctgc 420 cctgtgcagc tgtgggttga ttccacaccc ccgcccggca cccgcgtccg cgccatggcc 480 atctacaagc agtcacagca catgacggag gttgtgaggc gctgccccca ccatgagcgc 540 tgctcagata gcgatggtct ggcccctcct cagcatctta tccgagtgga aggaaatttg 600 cgtgtggagt atttggatga cagaaacact tttcgacata gtgtggtggt gccctatgag 660 ccgcctgagg ttggctctga ctgtaccacc atccactaca actacatgtg taacagttcc 720 tgcatgggcg gcatgaaccg gaggcccatc ctcaccatca tcacactgga agactccagt 780 ggtaatctac tgggacggaa cagctttgag gtgcgtgttt gtgcctgtcc tgggagagac 840 cggcgcacag aggaagagaa tctccgcaag aaaggggagc ctcaccacga gctgccccca 900 gggagcacta agcgagcact gcccaacaac accagctcct ctccccagcc aaagaagaaa 960 ccactggatg gagaatattt cacccttcag atccgtgggc gtgagcgctt cgagatgttc 1020 cgagagctga atgaggcctt ggaactcaag gatgcccagg ctgggaagga gccagggggg 1080 agcagggctc actccagcca cctgaagtcc aaaaagggtc agtctacctc ccgccataaa 1140 aaactcatgt tcaagacaga agggcctgac tcagacctcg agcaccacca ccaccaccac 1200 tag 1203 <![CDATA[<210> 75]]> <![CDATA[<211> 29]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 釀酒酵母之TOM70]]> <![CDATA[<400> 75]]> Met Lys Ser Phe Ile Thr Arg Asn Lys Thr Ala Ile Phe Ala Thr Val 1 5 10 15 Ala Ala Thr Gly Thr Ala Ile Gly Ala Tyr Tyr Tyr Tyr 20 25 <![CDATA[<210> 76]]> <![CDATA[<211> 60]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 智人之TOM70]]> <![CDATA[<400> 76]]> Met Ala Ala Ser Lys Pro Val Glu Ala Ala Val Val Ala Ala Ala Val 1 5 10 15 Pro Ser Ser Gly Ser Gly Val Gly Gly Gly Gly Thr Ala Gly Pro Gly 20 25 30 Thr Gly Gly Leu Pro Arg Trp Gln Leu Ala Leu Ala Val Gly Ala Pro 35 40 45 Leu Leu Leu Gly Ala Gly Ala Ile Tyr Leu Trp Ser 50 55 60 <![CDATA[<210> 77]]> <![CDATA[<211> 29]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 釀酒酵母之TOM20]]> <![CDATA[<400> 77]]> Met Ser Gln Ser Asn Pro Ile Leu Arg Gly Leu Ala Ile Thr Thr Ala 1 5 10 15 Ile Ala Ala Leu Ser Ala Thr Gly Tyr Ala Ile Tyr Phe 20 25 <![CDATA[<210> 78]]> <![CDATA[<211> 24]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 智人之TOM20]]> <![CDATA[<400> 78]]> Met Val Gly Arg Asn Ser Ala Ile Ala Ala Gly Val Cys Gly Ala Leu 1 5 10 15 Phe Ile Gly Tyr Cys Ile Tyr Phe 20 <![CDATA[<210> 79]]> <![CDATA[<211> 22]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 釀酒酵母之OM45]]> <![CDATA[<400> 79]]> Met Ser Ser Arg Ile Ile Val Gly Ser Ala Ala Leu Ala Ala Ala Ile 1 5 10 15 Thr Ala Ser Ile Met Val 20 <![CDATA[<210> 80]]> <![CDATA[<211> 23]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 釀酒酵母之TOM5]]> <![CDATA[<400> 80]]> Ala Ala Tyr Val Ala Ala Phe Leu Trp Val Ser Pro Met Ile Trp His 1 5 10 15 Leu Val Lys Lys Gln Trp Lys 20 <![CDATA[<210> 81]]> <![CDATA[<211> 24]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 智人之TOM5]]> <![CDATA[<400> 81]]> Ile Arg Asn Phe Leu Ile Tyr Val Ala Leu Leu Arg Val Thr Pro Phe 1 5 10 15 Ile Leu Lys Lys Leu Asp Ser Ile 20 <![CDATA[<210> 82]]> <![CDATA[<211> 41]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 釀酒酵母之TOM7]]> <![CDATA[<400> 82]]> Ile Leu Thr Leu Thr His Asn Val Ala His Tyr Gly Trp Ile Pro Phe 1 5 10 15 Val Leu Tyr Leu Gly Trp Ala His Thr Ser Asn Arg Pro Asn Phe Leu 20 25 30 Asn Leu Leu Ser Pro Leu Pro Ser Val 35 40 <![CDATA[<210> 83]]> <![CDATA[<211> 35]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 智人之TOM7]]> <![CDATA[<400> 83]]> Phe Ala Ile Arg Trp Gly Phe Ile Pro Leu Val Ile Tyr Leu Gly Phe 1 5 10 15 Lys Arg Gly Ala Asp Pro Gly Met Pro Glu Pro Thr Val Leu Ser Leu 20 25 30 Leu Trp Gly 35 <![CDATA[<210> 84]]> <![CDATA[<211> 55]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 釀酒酵母之TOM22]]> <![CDATA[<400> 84]]> Leu Ala Trp Thr Leu Thr Thr Thr Ala Leu Leu Leu Gly Val Pro Leu 1 5 10 15 Ser Leu Ser Ile Leu Ala Glu Gln Gln Leu Ile Glu Met Glu Lys Thr 20 25 30 Phe Asp Leu Gln Ser Asp Ala Asn Asn Ile Leu Ala Gln Gly Glu Lys 35 40 45 Asp Ala Ala Ala Thr Ala Asn 50 55 <![CDATA[<210> 85]]> <![CDATA[<211> 60]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 智人之TOM22]]> <![CDATA[<400> 85]]> Ala Ala Leu Trp Ile Gly Thr Thr Ser Phe Met Ile Leu Val Leu Pro 1 5 10 15 Val Val Phe Glu Thr Glu Lys Leu Gln Met Glu Gln Gln Gln Gln Leu 20 25 30 Gln Gln Arg Gln Ile Leu Leu Gly Pro Asn Thr Gly Leu Ser Gly Gly 35 40 45 Met Pro Gly Ala Leu Pro Ser Leu Pro Gly Lys Ile 50 55 60 <![CDATA[<210> 86]]> <![CDATA[<211> 25]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 釀酒酵母之Fis1]]> <![CDATA[<400> 86]]> Gly Val Val Val Ala Gly Gly Val Leu Ala Gly Ala Val Ala Val Ala 1 5 10 15 Ser Phe Phe Leu Arg Asn Lys Arg Arg 20 25 <![CDATA[<210> 87]]> <![CDATA[<211> 31]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 智人之Fis1]]> <![CDATA[<400> 87]]> Gly Leu Val Gly Met Ala Ile Val Gly Gly Met Ala Leu Gly Val Ala 1 5 10 15 Gly Leu Ala Gly Leu Ile Gly Leu Ala Val Ser Lys Ser Lys Ser 20 25 30 <![CDATA[<210> 88]]> <![CDATA[<211> 25]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 智人之Bcl-2α]]> <![CDATA[<400> 88]]> Leu Ser Leu Lys Thr Leu Leu Ser Leu Ala Leu Val Gly Ala Cys Ile 1 5 10 15 Thr Leu Gly Ala Tyr Leu Gly His Lys 20 25 <![CDATA[<210> 89]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 釀酒酵母之VAMP1]]> <![CDATA[<400> 89]]> Met Ile Met Leu Gly Ala Ile Cys Ala Ile Ile Val Val Val Ile Val 1 5 10 15 Arg Arg Asp <![CDATA[<210> 90]]> <![CDATA[<211> 22]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 智人之VAMP1]]> <![CDATA[<400> 90]]> Met Met Ile Met Leu Gly Ala Ile Cys Ala Ile Ile Val Val Val Ile 1 5 10 15 Val Ile Tyr Phe Phe Thr 20 <![CDATA[<210> 91]]> <![CDATA[<211> 60]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> P53-啟動子-S]]> <![CDATA[<400> 91]]> gggcatgctc gggcatgccc gggcatgctc gggcatgccc gggcatgctc gggcatgccc 60 60 <![CDATA[<210> 92]]> <![CDATA[<211> 60]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> P53-啟動子-AS]]> <![CDATA[<400> 92]]> gggcatgccc gagcatgccc gggcatgccc gagcatgccc gggcatgccc gagcatgccc 60 60 <![CDATA[<210> 93]]> <![CDATA[<211> 945]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼scFvPDL1-myc-TOM7之核苷酸序列]]> <![CDATA[<400> 93]]> atggacatcg tgatgagcca gtctcccagc agcctggctg tgtctgctgg ggagaaggtg 60 accatgtcct gcaagagctc ccagtccctg ctgaacagcc gcaccaggaa gaactacctg 120 gcctggtacc agcagaagcc aggccagagc cccaagctcc tcatctactg ggccagcacc 180 cgggagagcg gggtgcctga ccgcttcact ggaagtggca gcggcacaga cttcaccctg 240 accatcagct ctgtgcaggc cgaggacctg gcagtgtact actgccagca aagctatgat 300 gtggtgacat ttggagctgg caccaagctg gagctgaagg gaggtggcgg aagcgggggt 360 ggaggatccg ggggcggcgg aagccaggtc caggtgcagc agagcggggc tgagctggcc 420 gagcccgggg cctctgtgaa gatgagctgc aaggcttctg gctacatctt caccagctac 480 tggatgcact ggctcaagca gaggcctggg caggggctgg agtggatcgg ctatatcaac 540 cccagcagtg actacaatga atattctgag aagttcatgg acaaagccac cctgactgct 600 gacaaggcca gcaccaccgc ctacatgcag ctgatcagcc tgacctcaga ggacagcgct 660 gtgtactact gtgcccggag cggctggctg gtgcacgggg actattattt tgattattgg 720 ggccagggca ccacactgac agtgagcagc gaacaaaaac tcatctcaga agaggatctg 780 gtgaagctga gcaaagaggc caagcagaga ctacagcagc tcttcaaggg gagccagttt 840 gccattcgct ggggctttat ccctcttgtg atttacctgg gatttaagag gggtgcagat 900 cccggaatgc ctgaaccaac tgttttgagc ctactttggg gataa 945 <![CDATA[<210> 94]]> <![CDATA[<211> 314]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> scFvPDL1-myc-TOM7之胺基酸序列]]> <![CDATA[<400> 94]]> Met Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala 1 5 10 15 Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn 20 25 30 Ser Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly 35 40 45 Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly 50 55 60 Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 65 70 75 80 Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln 85 90 95 Gln Ser Tyr Asp Val Val Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 100 105 110 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gln Val Gln Val Gln Gln Ser Gly Ala Glu Leu Ala Glu Pro Gly Ala 130 135 140 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Ser Tyr 145 150 155 160 Trp Met His Trp Leu Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 165 170 175 Gly Tyr Ile Asn Pro Ser Ser Asp Tyr Asn Glu Tyr Ser Glu Lys Phe 180 185 190 Met Asp Lys Ala Thr Leu Thr Ala Asp Lys Ala Ser Thr Thr Ala Tyr 195 200 205 Met Gln Leu Ile Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 210 215 220 Ala Arg Ser Gly Trp Leu Val His Gly Asp Tyr Tyr Phe Asp Tyr Trp 225 230 235 240 Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Glu Gln Lys Leu Ile Ser 245 250 255 Glu Glu Asp Leu Val Lys Leu Ser Lys Glu Ala Lys Gln Arg Leu Gln 260 265 270 Gln Leu Phe Lys Gly Ser Gln Phe Ala Ile Arg Trp Gly Phe Ile Pro 275 280 285 Leu Val Ile Tyr Leu Gly Phe Lys Arg Gly Ala Asp Pro Gly Met Pro 290 295 300 Glu Pro Thr Val Leu Ser Leu Leu Trp Gly 305 310 <![CDATA[<210> 95]]> <![CDATA[<211> 732]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼scFvHER2之核苷酸序列]]> <![CDATA[<400> 95]]> atggaagtgc aacttgttga gagtggcgga ggactggtcc aaccgggcgg ttcacttagg 60 ctctcatgtg cagcttcagg gttcacgttc acggactata caatggactg ggtgaggcaa 120 gcccctggta agggactgga gtgggttgct gacgttaacc ctaattccgg tgggtccatc 180 tacaaccagc gattcaaggg acgatttact ctttcagtcg acagaagcaa aaacaccctc 240 tacctccaga tgaactcctt gcgggcagag gatacagcgg tctactattg cgcgagaaac 300 ttgggaccaa gcttctactt cgactactgg gggcaaggaa cgcttgttac ggtttcaagc 360 ggaggtggag gaagtggagg tggcggttcc ggcggtggcg gttcagatat acagatgacc 420 caatcaccca gttctcttag cgcgtctgta ggcgacaggg taaccataac ctgcaaggcg 480 tcccaggacg tgtcaattgg agttgcctgg tatcagcaaa aacctgggaa agctccgaag 540 ctcctgattt acagcgcatc ttaccgatat actggtgtcc cttcaaggtt cagtggcagt 600 ggatctggga cagactttac gcttactatc agcagtctgc aacctgagga tttcgcgacc 660 tactactgtc agcagtatta catctatccg tacacgttcg gtcaaggtac aaaggtagaa 720 ataaaacgca ct 732 <![CDATA[<210> 96]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> scFvHER2之胺基酸序列]]> <![CDATA[<400> 96]]> Met Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 1 5 10 15 Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp 20 25 30 Tyr Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45 Val Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg 50 55 60 Phe Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu 65 70 75 80 Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 130 135 140 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala 145 150 155 160 Ser Gln Asp Val Ser Ile Gly Val Ala Trp Tyr Gln Gln Lys Pro Gly 165 170 175 Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly 180 185 190 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln 210 215 220 Gln Tyr Tyr Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu 225 230 235 240 Ile Lys Arg Thr <![CDATA[<210> 97]]> <![CDATA[<211> 927]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼scFvHER2-myc-TOM7之核苷酸序列]]> <![CDATA[<400> 97]]> atggaagtgc aacttgttga gagtggcgga ggactggtcc aaccgggcgg ttcacttagg 60 ctctcatgtg cagcttcagg gttcacgttc acggactata caatggactg ggtgaggcaa 120 gcccctggta agggactgga gtgggttgct gacgttaacc ctaattccgg tgggtccatc 180 tacaaccagc gattcaaggg acgatttact ctttcagtcg acagaagcaa aaacaccctc 240 tacctccaga tgaactcctt gcgggcagag gatacagcgg tctactattg cgcgagaaac 300 ttgggaccaa gcttctactt cgactactgg gggcaaggaa cgcttgttac ggtttcaagc 360 ggaggtggag gaagtggagg tggcggttcc ggcggtggcg gttcagatat acagatgacc 420 caatcaccca gttctcttag cgcgtctgta ggcgacaggg taaccataac ctgcaaggcg 480 tcccaggacg tgtcaattgg agttgcctgg tatcagcaaa aacctgggaa agctccgaag 540 ctcctgattt acagcgcatc ttaccgatat actggtgtcc cttcaaggtt cagtggcagt 600 ggatctggga cagactttac gcttactatc agcagtctgc aacctgagga tttcgcgacc 660 tactactgtc agcagtatta catctatccg tacacgttcg gtcaaggtac aaaggtagaa 720 ataaaacgca ctgaacaaaa actcatctca gaagaggatc tggtgaagct gagcaaagag 780 gccaagcaga gactacagca gctcttcaag gggagccagt ttgccattcg ctggggcttt 840 atccctcttg tgatttacct gggatttaag aggggtgcag atcccggaat gcctgaacca 900 actgttttga gcctactttg gggataa 927 <![CDATA[<210> 98]]> <![CDATA[<211> 308]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> scFvHER2-myc-TOM7之胺基酸序列]]> <![CDATA[<400> 98]]> Met Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 1 5 10 15 Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp 20 25 30 Tyr Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45 Val Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg 50 55 60 Phe Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu 65 70 75 80 Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 130 135 140 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala 145 150 155 160 Ser Gln Asp Val Ser Ile Gly Val Ala Trp Tyr Gln Gln Lys Pro Gly 165 170 175 Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly 180 185 190 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln 210 215 220 Gln Tyr Tyr Ile Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu 225 230 235 240 Ile Lys Arg Thr Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Val Lys 245 250 255 Leu Ser Lys Glu Ala Lys Gln Arg Leu Gln Gln Leu Phe Lys Gly Ser 260 265 270 Gln Phe Ala Ile Arg Trp Gly Phe Ile Pro Leu Val Ile Tyr Leu Gly 275 280 285 Phe Lys Arg Gly Ala Asp Pro Gly Met Pro Glu Pro Thr Val Leu Ser 290 295 300 Leu Leu Trp Gly 305 <![CDATA[<210> 99]]> <![CDATA[<211> 726]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼scFvMSLN之核苷酸序列]]> <![CDATA[<400> 99]]> atgcaagtgc agctcgtcca gtctggggct gaggtgaaga ggcctggagc cagtgttcag 60 gtgtcctgcc gggcctctgg ctacagcatc aacacctact atatgcagtg ggtgcggcag 120 gcccctgggg ccggcctgga gtggatgggc gtcatcaatc ccagcggggt gacctcctat 180 gcccagaagt tccagggccg cgtgactctc accaatgaca ccagcaccaa cacagtctac 240 atgcagctga acagcctcac ttcagctgac acagctgtgt actactgtgc ccgctgggcc 300 ctgtggggag actttggcat ggatgtgtgg ggcaagggca ctctggtgac agtgagcagt 360 ggagggggcg gcagcggtgg cggtggaagt ggcggaggag gcagtgacat ccagatgacc 420 cagagcccct ccacactgtc tgcttccatc ggggacagag tcaccatcac ctgccgcgcc 480 agcgagggca tctaccactg gctggcctgg taccagcaga aaccaggaaa agcccccaag 540 ctgctgattt acaaggcctc ctccctggct tcaggcgccc caagccgctt cagcggctcc 600 ggctctggaa cagacttcac cctgacaatc agcagcctgc agccagatga ttttgccacc 660 tattactgcc agcagtactc caactacccc ctgaccttcg gcgggggcac caagttggag 720 atcaag 726 <![CDATA[<210> 100]]> <![CDATA[<211> 242]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> scFvMSLN之胺基酸序列]]> <![CDATA[<400> 100]]> Met Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Arg Pro Gly 1 5 10 15 Ala Ser Val Gln Val Ser Cys Arg Ala Ser Gly Tyr Ser Ile Asn Thr 20 25 30 Tyr Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Ala Gly Leu Glu Trp 35 40 45 Met Gly Val Ile Asn Pro Ser Gly Val Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Leu Thr Asn Asp Thr Ser Thr Asn Thr Val Tyr 65 70 75 80 Met Gln Leu Asn Ser Leu Thr Ser Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Ala Leu Trp Gly Asp Phe Gly Met Asp Val Trp Gly Lys 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 130 135 140 Thr Leu Ser Ala Ser Ile Gly Asp Arg Val Thr Ile Thr Cys Arg Ala 145 150 155 160 Ser Glu Gly Ile Tyr His Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly 165 170 175 Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Ser Leu Ala Ser Gly 180 185 190 Ala Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln 210 215 220 Gln Tyr Ser Asn Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu 225 230 235 240 Ile Lys <![CDATA[<210> 101]]> <![CDATA[<211> 921]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼scFvMSLN-myc-TOM7之核苷酸序列]]> <![CDATA[<400> 101]]> atgcaagtgc agctcgtcca gtctggggct gaggtgaaga ggcctggagc cagtgttcag 60 gtgtcctgcc gggcctctgg ctacagcatc aacacctact atatgcagtg ggtgcggcag 120 gcccctgggg ccggcctgga gtggatgggc gtcatcaatc ccagcggggt gacctcctat 180 gcccagaagt tccagggccg cgtgactctc accaatgaca ccagcaccaa cacagtctac 240 atgcagctga acagcctcac ttcagctgac acagctgtgt actactgtgc ccgctgggcc 300 ctgtggggag actttggcat ggatgtgtgg ggcaagggca ctctggtgac agtgagcagt 360 ggagggggcg gcagcggtgg cggtggaagt ggcggaggag gcagtgacat ccagatgacc 420 cagagcccct ccacactgtc tgcttccatc ggggacagag tcaccatcac ctgccgcgcc 480 agcgagggca tctaccactg gctggcctgg taccagcaga aaccaggaaa agcccccaag 540 ctgctgattt acaaggcctc ctccctggct tcaggcgccc caagccgctt cagcggctcc 600 ggctctggaa cagacttcac cctgacaatc agcagcctgc agccagatga ttttgccacc 660 tattactgcc agcagtactc caactacccc ctgaccttcg gcgggggcac caagttggag 720 atcaaggaac aaaaactcat ctcagaagag gatctggtga agctgagcaa agaggccaag 780 cagagactac agcagctctt caaggggagc cagtttgcca ttcgctgggg ctttatccct 840 cttgtgattt acctgggatt taagaggggt gcagatcccg gaatgcctga accaactgtt 900 ttgagcctac tttggggata a 921 <![CDATA[<210> 102]]> <![CDATA[<211> 306]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> scFvMSLN-myc-TOM7之胺基酸序列]]> <![CDATA[<400> 102]]> Met Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Arg Pro Gly 1 5 10 15 Ala Ser Val Gln Val Ser Cys Arg Ala Ser Gly Tyr Ser Ile Asn Thr 20 25 30 Tyr Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Ala Gly Leu Glu Trp 35 40 45 Met Gly Val Ile Asn Pro Ser Gly Val Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Leu Thr Asn Asp Thr Ser Thr Asn Thr Val Tyr 65 70 75 80 Met Gln Leu Asn Ser Leu Thr Ser Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Ala Leu Trp Gly Asp Phe Gly Met Asp Val Trp Gly Lys 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 130 135 140 Thr Leu Ser Ala Ser Ile Gly Asp Arg Val Thr Ile Thr Cys Arg Ala 145 150 155 160 Ser Glu Gly Ile Tyr His Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly 165 170 175 Lys Ala Pro Lys Leu Leu Ile Tyr Lys Ala Ser Ser Leu Ala Ser Gly 180 185 190 Ala Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln 210 215 220 Gln Tyr Ser Asn Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu 225 230 235 240 Ile Lys Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Val Lys Leu Ser 245 250 255 Lys Glu Ala Lys Gln Arg Leu Gln Gln Leu Phe Lys Gly Ser Gln Phe 260 265 270 Ala Ile Arg Trp Gly Phe Ile Pro Leu Val Ile Tyr Leu Gly Phe Lys 275 280 285 Arg Gly Ala Asp Pro Gly Met Pro Glu Pro Thr Val Leu Ser Leu Leu 290 295 300 Trp Gly 305
(無)
Claims (14)
- 一種經修飾粒線體,其包含一抗癌劑。
- 如請求項1之經修飾粒線體,其中該抗癌劑係結合了三苯基鏻(TPP)或其一衍生物之抗癌劑。
- 如請求項1之經修飾粒線體,其中該抗癌劑係選自由以下組成之群:一化學抗癌劑、一靶向抗癌劑及一驅蟲劑。
- 如請求項3之經修飾粒線體,其中該化學抗癌劑係選自由以下組成之群中之任一種:一烷化劑、一微管抑制劑、一抗代謝物及一拓樸異構酶抑制劑。
- 如請求項3之經修飾粒線體,其中該靶向抗癌劑係選自由以下組成之群中之任一種:靶向BTK、Bcr-abl、EGFR、PDGFR/VEGFR/FGFR家族、MEK/RAF、HER2/Neu、CDK、泛蛋白、JAK、MAP2K、ALK、PARP、TGFβRI、蛋白酶體、Bcl-2 Braf、C-Met、VR1、VR2、VR3、c-kit、AXL及RET之化合物。
- 如請求項3之經修飾粒線體,其中該驅蟲劑係選自由以下組成之群中之任一種:一OXPHOS (氧化磷酸化)抑制劑、一醣解抑制劑、一醣解相關間接抑制劑、一PPP(戊醣磷酸途徑)抑制劑及一自噬抑制劑。
- 如請求項1之經修飾粒線體,其中該粒線體係該經修飾粒線體,其中特異性結合至一腫瘤相關抗原的一抗體係存在於一細胞中。
- 如請求項1之經修飾粒線體,其中該腫瘤相關抗原係選自由以下組成之群中之任一種:CD19、CD20、黑色素瘤抗原E (MAGE)、NY-ESO-1、癌胚抗原(CEA)、黏蛋白1細胞表面相關蛋白(MUC-1)、前列腺酸性磷酸酶(PAP)、前列腺特異性抗原(PSA)、存活素、酪胺酸相關蛋白1 (tyrp1)、酪胺酸相關蛋白2 (tyrp2)、短尾蛋白(Brachyury)、間皮素、表皮生長因子受體(EGFR)、人類表皮生長因子受體2 (HER-2)、ERBB2、威爾姆斯腫瘤蛋白(Wilms tumor protein,WT1)、FAP、EpCAM、PD-L1、ACPP、CPT1A、IFNG、CD274、FOLR1、EPCAM、ICAM2、NCAM1、LRRC4、UNC5H2、LILRB2、CEACAM、連接蛋白-3 (Nectin-3)及其等之一組合。
- 如請求項1之經修飾粒線體,其中該癌症係選自由以下組成之群中之任一種:乳癌、肺癌、胰臟癌、神經膠質母細胞瘤、胃癌、肝癌、結腸直腸癌、前列腺癌、卵巢癌、子宮頸癌、甲狀腺癌、喉癌、急性骨髓性白血病、腦瘤、神經母細胞瘤、視網膜母細胞瘤、頭頸癌、唾液腺癌及淋巴瘤。
- 一種用於預防或治療癌症之醫藥組成物,其包含如請求項1之經修飾粒線體作為一活性成分。
- 一種如請求項1之經修飾粒線體在製備用於治療癌症之醫藥組成物中之用途。
- 一種治療癌症之方法,其包含將如請求項1之經修飾粒線體投予一個體。
- 一種製備包含一抗癌劑之粒線體之方法,其包含: 將該抗癌劑及經分離之粒線體混合。
- 一種經修飾抗癌劑,其中TPP或其一衍生物結合至一抗癌劑。
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US20230372529A1 (en) | 2023-11-23 |
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