JP2018104438A - 免疫原性wt1ペプチド及びその使用方法 - Google Patents
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Abstract
Description
本発明は、米国国立衛生研究所の認可番号CA23766、CA59350及びCA08748による支援を受けてなされたものである。米国政府は、本発明において一定の権利を有する。
本発明は、WT1ペプチド、該WT1ペプチドを含む組成物、該WT1ペプチドを含むワクチン、及び、WT1発現癌を治療するか、WT1発現癌の発生率を減少させるかまたはWT1発現癌細胞に対する免疫応答を誘導する方法であって、該WT1ペプチドを投与するステップを含む方法を提供する。
1 SRQRPHPGAL RNPTACPLPH FPPSLPPTHS PTHPPRAGTA AQAPGPRRLL
51 AAILDFLLLQ DPASTCVPEP ASQHTLRSGP GCLQQPEQQG VRDPGGIWAK
101 LGAAEASAER LQGRRSRGAS GSEPQQMGSD VRDLNALLPA VPSLGGGGGC
151 ALPVSGAAQW APVLDFAPPG ASAYGSLGGP APPPAPPPPP PPPPHSFIKQ
201 EPSWGGAEPH EEQCLSAFTV HFSGQFTGTA GACRYGPFGP PPPSQASSGQ
251 ARMFPNAPYL PSCLESQPAI RNQGYSTVTF DGTPSYGHTP SHHAAQFPNH
301 SFKHEDPMGQ QGSLGEQQYS VPPPVYGCHT PTDSCTGSQA LLLRTPYSSD
351 NLYQMTSQLE CMTWNQMNLG ATLKGVAAGS SSSVKWTEGQ SNHSTGYESD
401 NHTTPILCGA QYRIHTHGVF RGIQDVRRVP GVAPTLVRSA SETSEKRPFM
451 CAYPGCNKRY FKLSHLQMHS RKHTGEKPYQ CDFKDCERRF SRSDQLKRHQ
501 RRHTGVKPFQ CKTCQRKFSR SDHLKTHTRT HTGKTSEKPF SCRWPSCQKK
551 FARSDELVRH HNMHQRNMTK LQLAL (SEQ ID NO:194)
WT1タンパク質の上記の配列は、ゲスラーら(Gessler et al.)(37)により公表された配列であり、575個のアミノ酸を含んでおり、かつ、WT116の(エクソン5+,KTS+)アイソフォームでは欠損しているN末端における最初の126個のアミノ酸を含んでいる。
MGSDVRDLNALLPAVPSLGGGGGCALPVSGAAQWAPVLDFAPPGASAYGSLGGPAPPPAPP
PPPPPPPHSFIKQEPSWGGAEPHEEQCLSAFTVHFSGQFTGTAGACRYGPFGPPPPSQASSGQA
RMFPNAPYLPSCLESQPAIRNQGYSTVTFDGTPSYGHTPSHHAAQFPNHSFKHEDPMGQQGS
LGEQQYSVPPPVYGCHTPTDSCTGSQALLLRTPYSSDNLYQMTSQLECMTWNQMNLGATLK
GVAAGSSSSVKWTEGQSNHSTGYESDNHTTPILCGAQYRIHTHGVFRGIQDVRRVPGVAPTL
VRSASETSEKRPFMCAYPGCNKRYFKLSHLQMHSRKHTGEKPYQCDFKDCERRFSRSDQLK
RHQRRHTGVKPFQCKTCQRKFSRSDHLKTHTRTHTGKTSEKPFSCRWPSCQKKFARSDELVR HHNMHQRNMTKLQLAL(GenBankアクセス番号:AY245105;SEQ ID NO:195)。
AAEASAERLQGRRSRGASGSEPQQMGSDVRDLNALLPAVPSLGGGGGCALPVSGAAQWAP
VLDFAPPGASAYGSLGGPAPPPAPPPPPPPPPHSFIKQEPSWGGAEPHEEQCLSAFTVHFSGQF
TGTAGACRYGPFGPPPPSQASSGQARMFPNAPYLPSCLESQPAIRNQGYSTVTFDGTPSYGHT
PSHHAAQFPNHSFKHEDPMGQQGSLGEQQYSVPPPVYGCHTPTDSCTGSQALLLRTPYSSDN
LYQMTSQLECMTWNQMNLGATLKGHSTGYESDNHTTPILCGAQYRIHTHGVFRGIQDVRRV
PGVAPTLVRSASETSEKRPFMCAYPGCNKRYFKLSHLQMHSRKHTGEKPYQCDFKDCERRF
SRSDQLKRHQRRHTGVKPFQCKTCQRKFSRSDHLKTHTRTHTGEKPFSCRWPSCQKKFARS DELVRHHNMHQRNMTKLQLAL(GenBankアクセス番号:NM_000378;SEQ ID NO:196)。
MQDPASTCVPEPASQHTLRSGPGCLQQPEQQGVRDPGGIWAKLGAAEASAERLQGRRSRGA
SGSEPQQMGSDVRDLNALLPAVPSLGGGGGCALPVSGAAQWAPVLDFAPPGASAYGSLGGP
APPPAPPPPPPPPPHSFIKQEPSWGGAEPHEEQCLSAFTVHFSGQFTGTAGACRYGPFGPPPPSQ
ASSGQARMFPNAPYLPSCLESQPAIRNQGYSTVTFDGTPSYGHTPSHHAAQFPNHSFKHEDP
MGQQGSLGEQQYSVPPPVYGCHTPTDSCTGSQALLLRTPYSSDNLYQMTSQLECMTWNQM
NLGATLKGVAAGSSSSVKWTEGQSNHSTGYESDNHTTPILCGAQYRIHTHGVFRGIQDVRRV
PGVAPTLVRSASETSEKRPFMCAYPGCNKRYFKLSHLQMHSRKHTGEKPYQCDFKDCERRF
SRSDQLKRHQRRHTGVKPFQCKTCQRKFSRSDHLKTHTRTHTGEKPFSCRWPSCQKKFARS DELVRHHNMHQRNMTKLQLAL(GenBankアクセス番号:NP_077742;SEQ ID No:197)。
本発明のペプチド配列(SEQ ID NO:1;図2A)をデザインするために、ゲスラーらの論文(37)に記載のWT1タンパク質の配列を用いた。この配列は、575アミノ酸を含み、N末端における最初の126アミノ酸を欠損しているWT116の(エクソン5+,KTS+)アイソフォームを含む。この配列全体に及ぶ141個のペンタデカペプチドは、各々が次のペプチドに11aaずつ重複(オーバラップ)しており、インビトロゲン社(Invitrogen)(Baltimore, MD)によって、有効な配列、純度95%、無菌性、及び内毒素(エンドトキシン)の非存在からなる仕様に合わせて合成されたものである。これら141個の15−merを等量ずつ混合し、各ペプチドが0.35mcg/mlの濃度で含まれるペプチドのトータルプール(total pool)を作製した。このプールをT細胞感作に用いた。応答を誘発するペプチドを同定するために、12個のペンタデカペプチド(4.17mcg/ml/ペプチド)を含むサブプールを確立して、各ペプチドが2つの互いに重複したサブプールにのみ含まれるようなマッピングマトリックス(mapping matrix)を作成した(図2B)。
A.PBMC単独(バックグラウンドとして)、WT1タンパク質の配列全体に及ぶペンタデカペプチドのトータルプールで一晩共インキュベートしたPBMC(PBMC+WT1プール)、及びWT1ペプチド搭載PBMCで一晩共インキュベートした予め生成しておいたWT1特異的T細胞におけるIFNγの産生;
B.WT1−(自己PHA刺激芽球)標的及びWT1+(WT1ペンタデカペプチドのトータルプールを搭載した自己PHA刺激芽球)標的に対する、WT1トータルプールでの、エフェクタ:スティミュレータ比=50:1での刺激によってインビトロで生成したWT1特異的CTLの細胞傷害性;
C.異なるレスポンダ細胞(キラー細胞)集団(末梢血由来PBMC、自己CAMに搭載されたRMFペプチドでインビトロで感作した予め生成したCTL、及びWT1 15−merのトータルプールで感作した予め生成したCTL)において、非修飾であるかまたは下記のうちの1つ(RMFペプチド、WT1トータルプールで感作したCTLにおいてエピトープマッピング法によって同定したWT1の優性エピトープ、141個のペンタデカペプチドからなるWT1トータルプール)を搭載した自己PBMCで一晩二次刺激後に、FACS染色によって測定されたIFNγ応答;
D.RMF 9−merを搭載した自己CAMまたはWT1 15−merのトータルプールでの感作によってインビトロで生成したWT1特異的T細胞の細胞傷害性。自己WT1陰性標的(PHA活性化芽球)に対して、及び同標的にRMFペプチド、WT1 15−merのトータルプールまたは同T細胞株に関して同定された優性WT1エピトープを搭載したものに対して、T細胞の細胞傷害性を評価した。
A.575アミノ酸からなるWT1タンパク質の配列及び11アミノ酸が重複したペンタデカペプチドの原理を示している。タンパク質全体に及ぶように、全部で141個のペンタデカペプチドが必要である。ゲスラーら論文(37)に記載の575アミノ酸の配列を用いた。この配列は、N末端に追加の126アミノ酸を含む。最長の、最も高頻度で記述されるWT1アイソフォームDとともに用いられるWT1配列内におけるアミノ酸の配列番号をマッチさせるために、最長アイソフォームDにおいて記述される最初の126アミノ酸に負の値を割り振り、次の449アミノ酸に正の値を割り振った;
B.各々が最大で12個のWT1由来ペンタデカペプチドを含む24個のサブプールからなるマッピンググリッド。各ペプチドは、2つの互いに交差するサブプール内に唯一含まれる:例えば、ペプチド75は、サブプール3及び19により唯一共有されている;
C.自己PBMC搭載されたWT1ペンタデカペプチドのサブプールでの一晩の二次刺激に応答してWT1で感作したCTLによるIFNγの産生。1つの共通のペンタデカペプチド#75を含むサブプール#3及び#19に対する優勢応答が観察される;
D.この図の2Cにおいて決定された分析により、最も高い応答を誘発するサブプール内に含まれる1つのペンタデカペプチドでの一晩の二次刺激に反応して、WT1 CTLによりIFNγが産生されることは、ペンタデカペプチド#75内に優性免疫原性配列が含まれていることの立証となる;
E.WT1 CTLドナーによって発現された1つのHLA対立遺伝子にマッチする同種異系CAMまたはPHA芽球のパネルに対するCr51放出アッセイにより同定されたペプチド#75に応答するWT1特異的T細胞のHLA拘束性。これらは、グラフのx軸に沿って示されている。上記アッセイに用いたCAMまたはPHA芽球は、非修飾(灰色の棒グラフ)またはWT1優性エピトープ搭載(黒色の棒グラフ)である。WT1 CTLのWT1に特異的な細胞傷害性は、B3501 HLA対立遺伝子によって拘束される。
**-自己WT1ペプチド搭載APCに対して細胞毒性を示すが白血病細胞に対しては細胞毒性を示さないT細胞
***-一方の対立遺伝子を他方の対立遺伝子なしに受け継いでいる標的がないため、どちらかの対立遺伝子にHLA拘束性を与えることができない。
A.同一優性WT1由来15−mer#41での一晩の二次刺激に応答して、CD8+及びCD4+WT1特異的T細胞によるIFNgの産生;
B.ペプチド#41(LDF−LDFAAPGAS)に特有であるかまたは、互いに隣接しかつ重複する15−mer#40(PVL-PVLDFAPPG、VLD-VLDFAPPGA)及び#42(DFA-DFAPPGASA)内に含まれるかのいずれかである9−merのパネルを搭載した自己PBMCでの一晩の二次刺激の後の、IFNgの産生による、ペンタデカペプチド#41内でのアミノ酸の免疫原性配列の同定。15−mer#41,LDF内で唯一提示される9−merのみがIFNg応答を誘発する;
C.標準的なCr51放出アッセイにてE:T比=25:1で決定された11−mer LDF及び11−mer LDF内に含まれる9−mer LDFの両方に対して、ペプチド#41内に含まれかつ自己PHA刺激芽球に搭載された9−mer及び11−merのパネルに対するWT1 CTLのペプチドに特異的な細胞傷害性が観察される;
D.WT1 CTLの細胞傷害性のHLA拘束性:HLA−A0201拘束性T細胞は、11−merまたは9−merのいずれかが搭載されている標的を溶解させるが、HLA DRB10402拘束性T細胞は、11−merが搭載されている標的のみを溶解させる。
**-自己WT1ペプチド搭載APCに対して細胞毒性を示すが白血病細胞に対しては細胞毒性を示さないT細胞。
**-白血病サンプルは、不死化白血病細胞株によって、またはWT1+白血病患者から得られた原発性白血病細胞によって提示された。
***-PHA芽球は、WT1+原発性白血病と同じ患者に由来するPBMCから生成された。
A.エピトープマッピングスタディにおいてHLA A0201+ドナーが応答した6−15RDL及び22−31GGCペプチドを含むアミノ酸+2から+31に及ぶ九量体の混合物に対する応答。
B.インビトロでマッピングされた(−75)−(−67)AILDFLLLQエピトープ及びより高い結合親和性を有すると予測されるフランキングペプチド(−78)−(−70)LLAAILDFLに対する応答。
C.インビトロでマッピングされた38−46LDFAPPGASエピトープ及びより高い結合親和性を有すると予測される重複37−45VLDFAPPGAに対する応答。
SEQ ID NO:1.H2N−SRQRP HPGAL RNPTA−COOH
SEQ ID NO:2.H2N−PHPGA LRNPT ACPLP−COOH
SEQ ID NO:3.H2N−ALRNP TACPL PHFPP−COOH
SEQ ID NO:4.H2N−PTACP LPHFP PSLPP−COOH
SEQ ID NO:5.H2N−PLPHF PPSLP PTHSP−COOH
SEQ ID NO:6.H2N−FPPSL PPTHS PTHPP−COOH
SEQ ID NO:7.H2N−LPPTH SPTHP PRAGT−COOH
SEQ ID NO:8.H2N−HSPTH PPRAG TAAQA−COOH
SEQ ID NO:9.H2N−HPPRA GTAAQ APGPR−COOH
SEQ ID NO:10.H2N−AGTAA QAPGP RRLLA−COOH
SEQ ID NO:11.H2N−AQAPG PRRLL AAILD−COOH
SEQ ID NO:12.H2N−GPRRL LAAIL DFLLL−COOH
SEQ ID NO:13.H2N−LLAAI LDFLL LQDPA−COOH
SEQ ID NO:14.H2N−ILDFL LLQDP ASTCV−COOH
SEQ ID NO:15.H2N−LLLQD PASTC VPEPA−COOH
SEQ ID NO:16.H2N−DPAST CVPEP ASQHT−COOH
SEQ ID NO:17.H2N−TCVPE PASQH TLRSG−COOH
SEQ ID NO:18.H2N−EPASQ HTLRS GPGCL−COOH
SEQ ID NO:19.H2N−QHTLR SGPGC LQQPE−COOH
SEQ ID NO:20.H2N−RSGPG CLQQP EQQGV−COOH
SEQ ID NO:21.H2N−GCLQQ PEQQG VRDPG−COOH
SEQ ID NO:22.H2N−QPEQQ GVRDP GGIWA−COOH
SEQ ID NO:23.H2N−QGVRD PGGIW AKLGA−COOH
SEQ ID NO:24.H2N−DPGGI WAKLG AAEAS−COOH
SEQ ID NO:25.H2N−IWAKL GAAEA SAERL−COOH
SEQ ID NO:26.H2N−LGAAE ASAER LQGRR−COOH
SEQ ID NO:27.H2N−EASAE RLQGR RSRGA−COOH
SEQ ID NO:28.H2N−ERLQG RRSRG ASGSE−COOH
SEQ ID NO:29.H2N−GRRSR GASGS EPQQM−COOH
SEQ ID NO:30.H2N−RGASG SEPQQ MGSDV−COOH
SEQ ID NO:31.H2N−GSEPQ QMGSD VRDLN−COOH
SEQ ID NO:32.H2N−QQMGS DVRDL NALLP−COOH
SEQ ID NO:33.H2N−SDVRD LNALL PAVPS−COOH
SEQ ID NO:34.H2N−DLNAL LPAVP SLGGG−COOH
SEQ ID NO:35.H2N−LLPAV PSLGG GGGCA−COOH
SEQ ID NO:36.H2N−VPSLG GGGGC ALPVS−COOH
SEQ ID NO:37.H2N−GGGGG CALPV SGAAQ−COOH
SEQ ID NO:38.H2N−GCALP VSGAA QWAPV−COOH
SEQ ID NO:39.H2N−PVSGA AQWAP VLDFA−COOH
SEQ ID NO:40.H2N−AAQWA PVLDF APPGA−COOH
SEQ ID NO:41.H2N−APVLD FAPPG ASAYG−COOH
SEQ ID NO:42.H2N−DFAPP GASAY GSLGG−COOH
SEQ ID NO:43.H2N−PGASA YGSLG GPAPP−COOH
SEQ ID NO:44.H2N−AYGSL GGPAP PPAPP−COOH
SEQ ID NO:45.H2N−LGGPA PPPAP PPPPP−COOH
SEQ ID NO:46.H2N−APPPA PPPPP PPPPH−COOH
SEQ ID NO:47.H2N−APPPP PPPPP HSFIK−COOH
SEQ ID NO:48.H2N−PPPPP PHSFI KQEPS−COOH
SEQ ID NO:49.H2N−PPHSF IKQEP SWGGA−COOH
SEQ ID NO:50.H2N−FIKQE PSWGG AEPHE−COOH
SEQ ID NO:51.H2N−EPSWG GAEPH EEQCL−COOH
SEQ ID NO:52.H2N−GGAEP HEEQC LSAFT−COOH
SEQ ID NO:53.H2N−PHEEQ CLSAF TVHFS−COOH
SEQ ID NO:54.H2N−QCLSA FTVHF SGQFT−COOH
SEQ ID NO:55.H2N−AFTVH FSGQF TGTAG−COOH
SEQ ID NO:56.H2N−HFSGQ FTGTA GACRY−COOH
SEQ ID NO:57.H2N−QFTGT AGACR YGPFG−COOH
SEQ ID NO:58.H2N−TAGAC RYGPF GPPPP−COOH
SEQ ID NO:59.H2N−CRYGP FGPPP PSQAS−COOH
SEQ ID NO:60.H2N−PFGPP PPSQA SSGQA−COOH
SEQ ID NO:61.H2N−PPPSQ ASSGQ ARMFP−COOH
SEQ ID NO:62.H2N−QASSG QARMF PNAPY−COOH
SEQ ID NO:63.H2N−GQARM FPNAP YLPSC−COOH
SEQ ID NO:64.H2N−MFPNA PYLPS CLESQ−COOH
SEQ ID NO:65.H2N−APYLP SCLES QPAIR−COOH
SEQ ID NO:66.H2N−PSCLE SQPAI RNQGY−COOH
SEQ ID NO:67.H2N−ESQPA IRNQG YSTVT−COOH
SEQ ID NO:68.H2N−AIRNQ GYSTV TFDGT−COOH
SEQ ID NO:69.H2N−QGYST VTFDG TPSYG−COOH
SEQ ID NO:70.H2N−TVTFD GTPSY GHTPS−COOH
SEQ ID NO:71.H2N−DGTPS YGHTP SHHAA−COOH
SEQ ID NO:72.H2N−SYGHT PSHHA AQFPN−COOH
SEQ ID NO:73.H2N−TPSHH AAQFP NHSFK−COOH
SEQ ID NO:74.H2N−HAAQF PNHSF KHEDP−COOH
SEQ ID NO:75.H2N−FPNHS FKHED PMGQQ−COOH
SEQ ID NO:76.H2N−SFKHE DPMGQ QGSLG−COOH
SEQ ID NO:77.H2N−EDPMG QQGSL GEQQY−COOH
SEQ ID NO:78.H2N−GQQGS LGEQQ YSVPP−COOH
SEQ ID NO:79.H2N−SLGEQ QYSVP PPVYG−COOH
SEQ ID NO:80.H2N−QQYSV PPPVY GCHTP−COOH
SEQ ID NO:81.H2N−VPPPV YGCHT PTDSC−COOH
SEQ ID NO:82.H2N−VYGCH TPTDS CTGSQ−COOH
SEQ ID NO:83.H2N−HTPTD SCTGS QALLL−COOH
SEQ ID NO:84.H2N−DSCTG SQALL LRTPY−COOH
SEQ ID NO:85.H2N−GSQAL LLRTP YSSDN−COOH
SEQ ID NO:86.H2N−LLLRT PYSSD NLYQM−COOH
SEQ ID NO:87.H2N−TPYSS DNLYQ MTSQL−COOH
SEQ ID NO:88.H2N−SDNLY QMTSQ LECMT−COOH
SEQ ID NO:89.H2N−YQMTS QLECM TWNQM−COOH
SEQ ID NO:90.H2N−SQLEC MTWNQ MNLGA−COOH
SEQ ID NO:91.H2N−CMTWN QMNLG ATLKG−COOH
SEQ ID NO:92.H2N−NQMNL GATLK GVAAG−COOH
SEQ ID NO:93.H2N−LGATL KGVAA GSSSS−COOH
SEQ ID NO:94.H2N−LKGVA AGSSS SVKWT−COOH
SEQ ID NO:95.H2N−AAGSS SSVKW TEGQS−COOH
SEQ ID NO:96.H2N−SSSVK WTEGQ SNHST−COOH
SEQ ID NO:97.H2N−KWTEG QSNHS TGYES−COOH
SEQ ID NO:98.H2N−GQSNH STGYE SDNHT−COOH
SEQ ID NO:99.H2N−HSTGY ESDNH TTPIL−COOH
SEQ ID NO:100.H2N−YESDN HTTPI LCGAQ−COOH
SEQ ID NO:101.H2N−NHTTP ILCGA QYRIH−COOH
SEQ ID NO:102.H2N−PILCG AQYRI HTHGV−COOH
SEQ ID NO:103.H2N−GAQYR IHTHG VFRGI−COOH
SEQ ID NO:104.H2N−RIHTH GVFRG IQDVR−COOH
SEQ ID NO:105.H2N−HGVFR GIQDV RRVPG−COOH
SEQ ID NO:106.H2N−RGIQD VRRVP GVAPT−COOH
SEQ ID NO:107.H2N−DVRRV PGVAP TLVRS−COOH
SEQ ID NO:108.H2N−VPGVA PTLVR SASET−COOH
SEQ ID NO:109.H2N−APTLV RSASE TSEKR−COOH
SEQ ID NO:110.H2N−VRSAS ETSEK RPFMC−COOH
SEQ ID NO:111.H2N−SETSE KRPFM CAYPG−COOH
SEQ ID NO:112.H2N−EKRPF MCAYP GCNKR−COOH
SEQ ID NO:113.H2N−FMCAY PGCNK RYFKL−COOH
SEQ ID NO:114.H2N−YPGCN KRYFK LSHLQ−COOH
SEQ ID NO:115.H2N−NKRYF KLSHL QMHSR−COOH
SEQ ID NO:116.H2N−FKLSH LQMHS RKHTG−COOH
SEQ ID NO:117.H2N−HLQMH SRKHT GEKPY−COOH
SEQ ID NO:118.H2N−HSRKH TGEKP YQCDF−COOH
SEQ ID NO:119.H2N−HTGEK PYQCD FKDCE−COOH
SEQ ID NO:120.H2N−KPYQC DFKDC ERRFS−COOH
SEQ ID NO:121.H2N−CDFKD CERRF SRSDQ−COOH
SEQ ID NO:122.H2N−DCERR FSRSD QLKRH−COOH
SEQ ID NO:123.H2N−RFSRS DQLKR HQRRH−COOH
SEQ ID NO:124.H2N−SDQLK RHQRR HTGVK−COOH
SEQ ID NO:125.H2N−KRHQR RHTGV KPFQC−COOH
SEQ ID NO:126.H2N−RRHTG VKPFQ CKTCQ−COOH
SEQ ID NO:127.H2N−GVKPF QCKTC QRKFS−COOH
SEQ ID NO:128.H2N−FQCKT CQRKF SRSDH−COOH
SEQ ID NO:129.H2N−TCQRK FSRSD HLKTH−COOH
SEQ ID NO:130.H2N−KFSRS DHLKT HTRTH−COOH
SEQ ID NO:131.H2N−SDHLK THTRT HTGKT−COOH
SEQ ID NO:132.H2N−KTHTR THTGK TSEKP−COOH
SEQ ID NO:133.H2N−RTHTG KTSEK PFSCR−COOH
SEQ ID NO:134.H2N−GKTSE KPFSC RWPSC−COOH
SEQ ID NO:135.H2N−EKPFS CRWPS CQKKF−COOH
SEQ ID NO:136.H2N−SCRWP SCQKK FARSD−COOH
SEQ ID NO:137.H2N−PSCQK KFARS DELVR−COOH
SEQ ID NO:138.H2N−KKFAR SDELV RHHNM−COOH
SEQ ID NO:139.H2N−RSDEL VRHHN MHQRN−COOH
SEQ ID NO:140.H2N−LVRHH NMHQR NMTKL−COOH
SEQ ID NO:141.H2N−HNMHQ RNMTK LQLAL−COOH
Claims (19)
- 単離されたWT1ペプチドであって、
前記WT1ペプチドは、WT1タンパク質のエクソン1より上流側の最初の126個のアミノ酸からなる配列内のペプチドであり、前記最初の126個のアミノ酸からなる配列は、SEQ ID NO:194の1番目から126番目までのアミノ酸からなる配列であり、前記WT1ペプチドは、SEQ ID NO:194の1番目から60番目までのアミノ酸からなる配列内か、またはSEQ ID NO:194の80番目から90番目までのアミノ酸からなる配列内に位置し、
前記WT1ペプチドは、
AILDFLLLQ(SEQ ID NO:147)、RQRPHPGAL(SEQ ID NO:142)、GALRNPTAC(SEQ ID NO:143)、THSPTHPPR(SEQ ID NO:146)、PGCLQQPEQQG(SEQ ID NO:149)、PLPHFPPSL(SEQ ID NO:144)、HFPPSLPPT(SEQ ID NO:145)、LLAAILDFL(SEQ ID NO:184)、及びALRNPTACPL(SEQ ID NO:191)からなる群より選択されるアミノ酸配列からなることを特徴とするペプチド。 - 医薬組成物であって、
請求項1に記載の単離されたWT1ペプチドと、
薬学的に許容される担体、媒体または賦形剤とを含むことを特徴とする医薬組成物。 - ワクチンであって、
(a)請求項1に記載の1以上の単離されたWT1ペプチドと、
(b)アジュバントまたは担体とを含むことを特徴とするワクチン。 - 請求項3に記載のワクチンであって、
前記アジュバントが、QS21、フロインド不完全アジュバント、リン酸アルミニウム、水酸化アルミニウム、BCG、ミョウバン、成長因子、サイトカイン、ケモカイン、インターロイキン、Montanide、またはGM−SFであることを特徴とするワクチン。 - ワクチンであって、
(a)請求項1に記載の単離されたWT1ペプチドと、
(b)抗原提示細胞とを含むことを特徴とするワクチン。 - 請求項5に記載のワクチンであって、
前記抗原提示細胞が、樹枝状細胞、単球、マクロファージ、サイトカインにより活性化された単球、またはEBV形質転換Bリンパ芽球様細胞(EBV−BLCL)であることを特徴とするワクチン。 - 請求項6に記載のワクチンであって、
前記抗原提示細胞が、細胞株に由来する前記樹枝状細胞であることを特徴とするワクチン。 - 請求項3〜6のいずれかに記載のワクチンであって、
リンパ球、単球、マクロファージ、樹枝状細胞、内皮細胞、幹細胞、またはそれらの組み合わせを含む細胞集団を更に含み、
前記細胞集団は、自己細胞、同系細胞、または同種異系細胞であることを特徴とするワクチン。 - 請求項8に記載のワクチンであって、
前記細胞集団は、末梢血、白血球血液製剤、アフェレーシス血液製剤、末梢リンパ節、腸管関連リンパ系組織、脾臓、胸腺、臍帯血、腸間膜リンパ節、肝臓、免疫傷害部位、膵臓、脳脊髄液、腫瘍標本、または肉芽腫組織から得られたものであること特徴とするワクチン。 - インビトロまたはエクスビボでWT1に特異的な細胞障害性Tリンパ球(CTL)、WT1に特異的なCD8+リンパ球、WT1に特異的なCD4+リンパ球、またはそれらの組み合わせの形成及び増殖を誘導する方法であって、
1以上のペプチドでリンパ球細胞集団を刺激するステップを含み、
それによって、WT1に特異的なリンパ球の形成及び増殖を誘導するようにしたことを特徴とし、
前記1以上のペプチドは、WT1タンパク質のエクソン1より上流側の最初の126個のアミノ酸からなる配列内のWT1ペプチドから選択され、前記最初の126個のアミノ酸からなる配列は、SEQ ID NO:194の1番目から126番目までのアミノ酸からなる配列であり、前記WT1ペプチドは、SEQ ID NO:194の1番目から60番目までのアミノ酸からなる配列内か、またはSEQ ID NO:194の80番目から90番目までのアミノ酸からなる配列内に位置し、
前記WT1ペプチドは、SEQ ID NO:147、142、143、144、145、146、149、184、及び191から選択されたアミノ酸配列からなることを特徴とする方法。 - 請求項10に記載の方法であって、
前記刺激するステップが、
前記1以上のペプチドと、アジュバント、担体、または抗原提示細胞を組み合わせてリンパ球細胞集団を刺激するステップを含むことを特徴とする方法。 - 請求項8または9に記載のワクチンであって、
前記細胞集団が、ヒトまたはドナーから得られたものであることを特徴とするワクチン。 - 請求項10または11に記載の方法であって、
前記細胞集団が、ヒトまたはドナーから得られたものであることを特徴とする方法。 - 請求項3〜9及び12のいずれかに記載のワクチンであって、
WT1発現癌を有する対象を治療するために使用されるか、または前記対象におけるWT1発現癌の発生率若しくは再発率を減少させるために使用されることを特徴とするワクチン。 - WT1発現癌を有する対象を治療するための医薬、または前記対象におけるWT1発現癌の発生率若しくは再発率を減少させるための医薬を製造するための、請求項10または11に記載の方法によって得られるWT1に特異的な細胞障害性Tリンパ球(CTL)、WT1に特異的なCD8+リンパ球、またはWT1に特異的なCD4+リンパ球の使用。
- 請求項14に記載のワクチンであって、
前記WT1発現癌が、白血病、線維形成性小円形細胞腫瘍、胃癌、結腸癌、肺癌、乳癌、胚細胞腫瘍、卵巣癌、子宮癌、甲状腺癌、肝臓癌、腎臓癌、カポジ肉腫、肉腫、肝細胞癌、ウィルムス腫瘍、急性骨髄性白血病(AML)、骨髄異形成症候群(MDS)、非小細胞肺癌(NSCLC)、または中皮腫であることを特徴とするワクチン。 - 請求項15に記載のリンパ球の使用であって、
前記WT1発現癌が、白血病、線維形成性小円形細胞腫瘍、胃癌、結腸癌、肺癌、乳癌、胚細胞腫瘍、卵巣癌、子宮癌、甲状腺癌、肝臓癌、腎臓癌、カポジ肉腫、肉腫、肝細胞癌、ウィルムス腫瘍、急性骨髄性白血病(AML)、骨髄異形成症候群(MDS)、非小細胞肺癌(NSCLC)、または中皮腫であることを特徴とする使用。 - 請求項11に記載の方法であって、
前記アジュバントが用いられ、
前記アジュバントが、QS21、フロインド不完全アジュバント、リン酸アルミニウム、水酸化アルミニウム、BCG、ミョウバン、成長因子、サイトカイン、ケモカイン、インターロイキン、Montanide、またはGM−SFであることを特徴とする方法。 - 請求項11に記載の方法であって、
前記抗原提示細胞が用いられ、
前記抗原提示細胞が、樹枝状細胞、単球、マクロファージ、サイトカインにより活性化された単球、またはEBV形質転換Bリンパ芽球様細胞(EBV−BLCL)であることを特徴とする方法。
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EP3520810A3 (en) | 2019-11-06 |
US20150104413A1 (en) | 2015-04-16 |
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US10815274B2 (en) | 2020-10-27 |
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US10100087B2 (en) | 2018-10-16 |
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US20170334951A1 (en) | 2017-11-23 |
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