JP7097943B2 - 免疫原性wt-1ペプチドおよびその使用法 - Google Patents
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Description
本願は、アメリカ国立衛生研究所からのグラント(研究助成金)P01 23766によって支援を受けた。アメリカ合衆国政府は、本発明に権利を有する。
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(配列番号51)。
(a)白血球分離等の当技術分野において公知の方法によって、哺乳類供給源から得られる白血球画分を提供するステップと、
(b)向流遠心分離法によって、(a)のステップの白血球画分を4つ以上の細画分に分離するステップと、
(c)(b)のステップから得られた1若しくは複数の画分内の単球の、樹状細胞への転換を、前記細胞をカルシウムイオノホア、GM-CSFおよびIL-13またはGM-CSFおよびIL-4と接触させることで、刺激するステップと、
(d)(c)のステップから得られた、樹状細胞が濃縮された画分を特定するステップと、
(e)(d)のステップの濃縮画分を、好ましくは約4℃で収集するステップとを含む方法によって、DCが単離される。
材料および方法
ペプチドデザイン
3つのコンピュータ支援予測アルゴリズムのBIMAS(http://www-bimas.cit.nih.gov/cgi-bin/molbio/ken_parker_comboform)、SYFPEITHI(http://www.syfpeithi.de/)およびRANKPEP(http://bio.dfci.harvard.edu/Tools/rankpep.html)を用い、健常ドナーにおいて免疫応答を誘導することが可能な天然WT1タンパク質配列から始めることで、CD8T細胞およびCD4T細胞の両方に対するエピトープを選択した。その天然配列よりも高い予測結合性をもたらす、クラスIの天然ペプチドのアンカー残基内の1個のアミノ酸の改変よって、ヘテロクリティックペプチドをデザインした。CD4T細胞およびCD8T細胞の両方を同時に刺激するため、クラスIペプチドに隣接残基を付加することによって、クラスIIペプチドをデザインした。前記アルゴリズムにより多くの配列を予測することができるが、これらのモデルでは、生細胞に対し試験する場合、30%の場合においてMHCに対する結合性は予測されず(Gomez-Nunez et al. Leuk Res. 2006;30(10): 1293-8)、そのためインビトロ試験が必要とされる。さらに、結合性が示された場合でも、細胞傷害性T細胞応答が起こらない場合があり、これにはさらなるインビトロ研究が必要とされる。
全てのペプチドは、ジーンメッド・シンセシス株式会社(Genemed Synthesis, Inc.)(テキサス州サンアントニオ)により合成されたものを購入した。ペプチドは、70%~90%の純度を有して無菌であった。ペプチドをDMSOに溶解し、食塩水で5mg/mLに希釈し、-80℃で保存した。使用される対照ペプチドは、HLA-DR.B1については、JAK-2由来DR.B1結合ペプチドJAK2-DR(GVCVCGDENILVQEF;配列番号59)またはBCR.ABL由来ペプチド(IVHSATGFKQSSKALQRPVASDFEP;配列番号60)であり;HLA-A0201については:ユーイング肉腫由来ペプチドEW(QLQNPSYDK;配列番号61)であり、HLA-A2402については、前立腺特異的膜抗原(PMSA)由来ペプチド624~632(TYSVSFDSL;配列番号62)である。
ヒト白血病細胞株のBA25およびHL-60を、T細胞の細胞毒性を測定するための標的として使用した。ヒト顆粒球マクロファージコロニー刺激因子(GM-CSF)、インターロイキン(IL)-1β、IL-4、IL-6、IL-15、腫瘍壊死因子(TNF)-αおよびプロスタグランジンE2(PGE2)は、R&Dシステムズ社(ミネソタ州ミネアポリス)から購入した。β2-ミクログロブリン(b2-m)は、シグマ社(ミズーリ州セントルイス)から購入した。免疫蛍光法アッセイに用いた抗体、例えば、ヒトCD3、CD4、CD8、HLA-A2(クローンBB7.2)およびアイソタイプ対照に対するmAbは、BDバイオサイエンス社(カリフォルニア州サンディエゴ)から購入した。CD14およびCD3用の細胞単離キットは、ミルテニーバイオテク社(ドイツ、ベルギッシュグラートバハ)から購入した。
T2細胞(TAP-、HLA-A0201+)を、種々の最終濃度(50、10および2μg/ml)のペプチドの非存在下(負の対照)または存在下の、10μg/mlのヒトβ-2m(シグマ社、米国ミズーリ州セントルイス)を添加したFCS非含有RPMI培地中で、1×106細胞/mlで、37℃で一晩インキュベートした。ブレフェルジンA(シグマ社)を5μg/mlで培地に添加し、2時間インキュベーションした。次に、T2細胞を洗浄し、FITC結合型抗HLA-A2.1(BB7.2)mAbを用いて4℃で30分間染色し、その後、染色緩衝液(PBS+1%FBSおよび0.02%アジド)で洗浄した。細胞表面上のHLA-A2の発現を、FACScalibur(ベクトン・ディッキンソン社)によるフローサイトメトリーで測定し、FlowJo9.6.3ソフトウェアで解析した。
HLA型が決定された健常ドナー由来の末梢血単核球(PBMC)をフィコール密度遠心分離によって得た。CD14+単球を、磁気ビーズ結合型ヒトCD14抗mAb(ミルテニーバイオテク社)を用いるポジティブ選択で単離し、T細胞の第一刺激に使用した。PBMCのCD14-分画を、pan T cellアイソレーションキット(ミルテニーバイオテク社)を用いる負の免疫磁気細胞分離(negative immunomagnetic cell separation)による、CD3の単離に用いた。細胞の純度は、常に98%超であった。T細胞を、5%の自己血漿(AP)、20μg/mLの合成ペプチド、1μg/mLのB2-m、および10ng/mLのIL-15を添加したRPMI1640の存在下で7日間刺激した。1%のAP、500ユニット/mLの組換えIL-4、および1,000ユニット/mLのGM-CSFを添加したRPMI1640培地中で細胞を培養することにより、単球由来樹状細胞(DC)をCD14+細胞から得た。インキュベーションの2日目および4日目に、IL-4およびGM-CSFを含有する新鮮な培地を追加、または培地の半分と交換した。5日目に、20μg/mLクラスIIペプチドを、プロセシングのために、未成熟DCに添加した。6日目に、成熟サイトカイン混合物を添加した(Dao et al. Plos One 2009; 4(8):e6730)。7日目または8日目に、T細胞をIL-15を有する成熟DCで再刺激した。ほとんどの場合、T細胞を、DCまたはCD14+細胞を抗原提示細胞(APC)として用いて3回同様に刺激した。最終刺激の1週間後、IFN-g ELISPOTアッセイ(酵素免疫スポットアッセイ)によりペプチド特異的T細胞応答を調べ、細胞毒性を51クロム(Cr)放出アッセイによって試験した。
HA-Multiscreenプレート(ミリポア社)を、100μLのPBS中マウス抗ヒトIFN-g抗体(10Ag/mL;クローン1-D1K;マブテック社(Mabtech))でコートし、4Cで一晩インキュベートし、PBSで洗浄して未結合抗体を除去し、RPMI1640/10%自己血漿(AP)で37℃で2時間ブロッキングした。精製したCD3+T細胞(98%超の純度)を、自己CD14+(E:APC比10:1)または自己DC(E:APC比30:1)と一緒に播種した。種々の試験ペプチドを20μg/mLでウェルに添加した。負の対照のウェルには、ペプチド無しまたは無関係ペプチド有りで、APCおよびT細胞を含ませた。正の対照のウェルには、T細胞およびAPCおよび20μg/mLのフィトヘマグルチニン(PHA、シグマ社)を含ませた。全ての条件を3連で行った。マイクロタイタープレートを37℃で20時間インキュベートし、その後PBS/0.05%トウィーンで十分に洗浄し、100μl/ウェルのビオチン化抗ヒトIFN-g検出抗体(2μg/mL;クローン7-B6~1;マブテック社)を添加した。プレートを37℃でさらに2時間インキュベートし、記述(Dao et al.、前掲)の通りにスポットを発生させた。スポット数を、KS ELISPOT4.0ソフトウェア(カールツァイスビジョン社)を備えたコンピュータ支援ビデオ画像分析機器を用いて自動決定した。
特異的CTLの存在を、記述(Dao et al.、前掲)の通りの標準的なクロム放出アッセイにて測定した。簡潔に説明すると、単独の、または50μg/mLの合成ペプチドで37℃で2時間(場合によっては一晩)パルスした標的細胞を、50μCi/106細胞のNa2 51CrO4(NENライフ・サイエンス・プロダクツ社(NEN Life Science Products, Inc.))で標識する。十分に洗浄した後、標的細胞を100:1~10:1の範囲のE:T比のT細胞と一緒にインキュベートする。全ての条件を3連で行った。プレートを37℃、5%CO2で4~5時間インキュベートした。上澄み液を回収し、ガンマカウンタで放射活性を測定した。特異的溶解%を次式から決定した:
[(実験による放出-自発性放出)/(最大放出-自発性放出)]×100%。
最大放出は、放射性標識された標的の1%SDS中の溶解によって決定した。
天然ペプチドおよびその類似ペプチドのHLA-A0201およびHLA-A2402に対する結合
ヒトWT1タンパク質にまたがる15塩基長の重複ペプチドのプールを用いてインビトロでヒトT細胞を感作させることで、配列239~248(NQMNLGATL;配列番号5;本明細書ではNQMと省略、または)が、HLA-A2402との関連において、免疫原性CD8 T細胞エピトープであることが最近特定された(Doubrovina et al., Blood 2012; 123(8):1633-46)。より強い免疫原性を有する類似ペプチドを得るために、3つのオンラインで利用可能なデータベース(BIMAS、RANKPEPおよびSYFPEITHI)を用いて、天然ペプチドおよび2位および9位(クラスIアンカー残基)に種々のアミノ酸置換を有する可能な類似体の予測スコアを選別した。3つデータベース全てから得られた予測結合性スコアは、HLA-A2402分子に対してよりも、HLA-A0201分子に対しての、天然NQMNLGATL(配列番号5)ペプチドのより良好な結合性を示した(表I)。2位のグルタミンがロイシンで置換された場合、3つ全ての予測プログラムによるHLA-A2402に対する結合性スコアは、依然として同様のレベルであった。しかし、HLA-A0201に対して、有意により強い結合性スコアが予測された。一方、2位のグルタミンがチロシンで置換された場合、HLA-A2402に対する結合性スコアは劇的に向上し、約90倍に増加した結合性がBIMAS予測によって示された。RANKPEPアルゴリズムによって3つ全てのペプチドがC末端において切断されていることが予測されたが、これは、ペプチド断片のプロセシングを示唆するものである。9位における種々のアミノ酸との置換により、結合性スコアを調べたが、それらのいずれも、2位における置換と比較して有意に向上された結合性を示さなかった。そのため、2つの類似ペプチド、NLMNLGATL(配列番号6;本明細書では略してNLM、あるいはA24-ヘテロクリティック-1と呼ぶ)およびNYMNLGATL(配列番号7;本明細書では略してNYM、あるいはA24-ヘテロクリティック-2と呼ぶ)をさらなる研究のために選択した。
HLA-A0201分子およびHLA-A2402分子に対するペプチドの結合
MHCクラスI制限ペプチドの免疫原性は、生細胞表面のMHCクラスI分子と結合しそれを安定化させる能力を必要とする。さらに、コンピュータ予測は最大で70%の精度しかなく;そのため、抗原運搬能を欠く(TAP2陰性)HLA-A0201ヒトT2細胞を用いる従来の結合および安定化アッセイを用いた、ペプチドおよびHLA-A0201分子の間の相互作用の強度の、直接的な測定が求められた。T2細胞はTAP機能を欠いているため、クラスI分子に細胞質ゾルで生成された抗原ペプチドを適切に積むことに欠陥がある。外因的に加えられたペプチドと熱不安定性の空のHLA-A0201分子との結合は、それらを安定化することで、BB7.2等の特異的な抗HLA-A0201mAbによって認識される表面HLA-A0201のレベルの上昇をもたらす。
HLA-A0201分子およびA2402分子との関連における、ペプチド特異的CD8 T細胞応答の誘導
MHC分子に対する親和性はペプチド提示に必要であるが、もう1つ、HLA分子によって提示されたペプチドのT細胞認識も、ペプチド特異的応答を誘発するのに重要な必要条件である。そのため、インビトロ刺激プロトコルを用いて、新規の合成WT1ペプチド類似体を、HLA-A0201ドナーおよびHLA-A2402ドナーの両方においてペプチド特異的T細胞応答を刺激するそれらの能力について評価した。
NQMNLGATL CD8 T細胞エピトープを認識するHLA-DR.B1ペプチドによるT細胞応答の誘導
CD4 T細胞が、CD40/CD40Lシグナル伝達を介してDCを完全に活性化させることによって、およびIL-2およびIFN-gを産生することによって、CD8 CTLを援助し得ることから、CD4エピトープおよびCD8エピトープの両方を併有しているペプチドは、ワクチンデザインに有効な免疫応答を誘起する際に、単一のクラスIエピトープよりも有効であることが示されている。さらに、CD8 T細胞エピトープが組み込まれているより長いペプチドで刺激されたT細胞が短ペプチドを認識できたならば、それによって、CD8 T細胞エピトープのプロセシングが確かめられるだろう。そのため、それぞれNQMNLGATLエピトープおよびNLMNLGATLエピトープにまたがる4つのHLA-DR.B1結合ペプチドをデザインした。
DR-天然-1:cmtwNQMNLGATLkg(配列番号8)
DR-天然-2:wNQMNLGATLkgvaa(配列番号9)
DR-ヘテロクリティック-1:cmtwNLMNLGATLkg(配列番号14)
DR-ヘテロクリティック-2:wNLMNLGATLkgvaa(配列番号17)
NQMNLGATL CD8 T細胞エピトープを認識する他のHLA-DR.B1結合ペプチド
上記のDRペプチドに加え、NQMNLGATLエピトープ、NLMNLGATLエピトープおよびNLMNLGATLエピトープにまたがるさらなるHLA-DR.B1結合ペプチドをデザインし、評価した(表3)。
ヒトHLA-B7クラスIおよびHLA-DrクラスII分子に結合するWT1腫瘍性タンパク質に由来するペプチドの作製
また、HLA-B0702に結合するペプチドをデザインした(表4)。以下のペプチド配列をデザインした:RQRPHPGAL(B7-天然1;配列番号34)、RLRPHPGAL(B7-ヘテロクリティック-1;配列番号37)、RIRPHPGAL(B7-ヘテロクリティック-2;配列番号38)、GALRNPTAC(天然2;配列番号29)、およびGALRNPTAL(B7-ヘテロクリティック-3;配列番号31)。これらおよび他の改変体の予測結合性スコアを表4に示す。これらのペプチドをインビトロで試験し、ヘテロクリティックなT細胞応答を刺激した(図6)。HLA-B0702陽性ドナー由来のCD3 T細胞を、インビトロで、2セットのペプチド(合計5)で5回刺激した。ペプチド特異的応答を、個々のペプチドに対し、IFN-γ ELISPOTアッセイによって測定した。
ヒトHLA-B35、A0101、A0301、A1101クラスIおよびHLA-DRクラスII分子に結合するWT1腫瘍性タンパク質由来ペプチドの作製
ペプチドQFPNHSFKHEDPMGQ(p170~182)(配列番号39)は、HLA-DR.B1 0301および0401との関連においてT細胞応答を誘導する。長ペプチド内に組み込まれている短配列HSFKHEDPMは、B3501との関連においてT細胞応答を誘導する。HLA結合性予測アルゴリズムによる予測に基づいて、ヘテロクリティック-B35-1短ペプチドの伸長物である、1つのヘテロクリティック長ペプチドをデザインした。
ヒトHLA-A1、A3、A11クラスIおよびHLA-DR.B1-0401クラスII分子に結合するWT1腫瘍性タンパク質由来ペプチドの作製
ペプチドKRPFMCAYPGCNK(320~332)(配列番号44)は、HLA-DR.B1 0401との関連においてT細胞応答を誘導することが示された。長ペプチド内に組み込まれている短配列FMCAYPGCN(配列番号45)は、B35、B7およびA0101との関連においてT細胞応答を誘導する(表6)。予測アルゴリズムを用いて、複数のHLAハプロタイプに対する前記ペプチドの結合性スコアを調べた。ヘテロクリティック-1短ペプチドの伸長物である、1つのヘテロクリティック長ペプチドをデザインした。HLA-A0101、0301および1101により良好に結合する2つの短ヘテロクリティックペプチドをデザインした。前記ペプチドの配列は、クラスIIペプチド:DR.B1-04天然:KRPFMCAYPGCNK(配列番号44)、DR.B1-04ヘテロクリティック:KRPFMCAYPGCYK(配列番号46);クラスIペプチド:1.天然:FMCAYPGCN(配列番号45)、2.DR.B1-04-ヘテロクリティック-1短:FMCAYPGCY(A0101に対する)(配列番号47)、3.DR.B1-04-ヘテロクリティック-2-短:FMCAYPGCK(A0301およびA1101に対する)(配列番号48)である。KRPFMCAYPGCYK(配列番号46)は、DR.B1-04-ヘテロクリティック1短、FMCAYPGCN(配列番号45)の伸長物であり、配列の末端CNがCYになっている。
さらなる交差反応性研究
ELISPOTアッセイを、天然配列(配列番号5)との比較において、ヘテロクリティック24-1(配列番号6)およびヘテロクリティック24-2(配列番号7)A24ペプチドについて、5回刺激後のドナーSAを用いて行った。図7に示すように、ヘテロクリティックペプチドは交差反応を起こす。
Claims (19)
- 医薬組成物であって、
少なくとも2種類の単離ペプチドを含み、
前記少なくとも2種類の単離ペプチドが、
1種類以上の第1のペプチドであって、前記第1のペプチドの各々は、配列番号6(NLMNLGATL)のアミノ酸配列を含むアミノ酸配列からなり、かつ10~30個のアミノ酸からなる長さを有する、該1種類以上の第1のペプチド、
1種類以上の第2のペプチドであって、前記第2のペプチドの各々は、配列番号6(NLMNLGATL)のアミノ酸配列を含むアミノ酸配列からなり、30を超える個数のアミノ酸からなる長さを有し、9~11個のアミノ酸からなる長さにプロセシングされるように適合されている、該1種類以上の第2のペプチド、
配列番号6(NLMNLGATL)のアミノ酸配列からなるペプチド、
配列番号10(CMTWNYMNLGATLKG)のアミノ酸配列を含むアミノ酸配列からなるペプチド、
配列番号19(MTWNYMNLGATLKGV)のアミノ酸配列を含むアミノ酸配列からなるペプチド、
配列番号23(CMTWNYMNLGATLKGVA)のアミノ酸配列を含むアミノ酸配列からなるペプチド、
配列番号11(WNYMNLGATLKGVAA)のアミノ酸配列を含むアミノ酸配列からなるペプチド、および
配列番号20(TWNYMNLGATLKGVA)のアミノ酸配列を含むアミノ酸配列からなるペプチド
からなる群から選択される、医薬組成物。 - 請求項1に記載の医薬組成物であって、
前記少なくとも2種類の単離ペプチドが、前記1種類以上の第1のペプチドを含み、
前記1種類以上の第1のペプチドの少なくとも1つが、
配列番号14(CMTWNLMNLGATLKG)のアミノ酸配列からなるペプチド、
配列番号15(MTWNLMNLGATLKGV)のアミノ酸配列からなるペプチド、
配列番号16(TWNLMNLGATLKGV)のアミノ酸配列からなるペプチド、
配列番号17(WNLMNLGATLKGVAA)のアミノ酸配列からなるペプチド、および
配列番号22(CMTWNLMNLGATLKGVA)のアミノ酸配列からなるペプチド
からなる群から選択される、医薬組成物。 - 請求項1に記載の医薬組成物であって、
前記少なくとも2種類の単離ペプチドが、
配列番号6(NLMNLGATL)のアミノ酸配列からなるペプチド、
配列番号14(CMTWNLMNLGATLKG)のアミノ酸配列からなるペプチド、
配列番号15(MTWNLMNLGATLKGV)のアミノ酸配列からなるペプチド、
配列番号16(TWNLMNLGATLKGV)のアミノ酸配列からなるペプチド、
配列番号17(WNLMNLGATLKGVAA)のアミノ酸配列からなるペプチド、
配列番号22(CMTWNLMNLGATLKGVA)のアミノ酸配列からなるペプチド
配列番号10(CMTWNYMNLGATLKG)のアミノ酸配列を含むアミノ酸配列からなるペプチド、
配列番号19(MTWNYMNLGATLKGV)のアミノ酸配列を含むアミノ酸配列からなるペプチド、
配列番号23(CMTWNYMNLGATLKGVA)のアミノ酸配列を含むアミノ酸配列からなるペプチド、
配列番号11(WNYMNLGATLKGVAA)のアミノ酸配列を含むアミノ酸配列からなるペプチド、および
配列番号20(TWNYMNLGATLKGVA)のアミノ酸配列を含むアミノ酸配列からなるペプチド
からなる群から選択される、医薬組成物。 - 請求項1~3のいずれか一項に記載の医薬組成物であって、
前記少なくとも2種類の単離ペプチドが、2種類、3種類、4種類、または4種類以上のペプチドである、医薬組成物。 - 請求項1~4のいずれか一項に記載の医薬組成物であって、
免疫調節性化合物をさらに含む、医薬組成物。 - 請求項5に記載の医薬組成物であって、
前記免疫調節性化合物は、(i)サイトカイン、サイトカイン受容体、ケモカイン、補体成分、インターロイキン1~15のいずれか、インターフェロンα、βもしくはγ、腫瘍壊死因子、顆粒球マクロファージコロニー刺激因子(GM-CSF)、マクロファージコロニー刺激因子(M-CSF)、顆粒球コロニー刺激因子(G-CSF)、好中球活性化タンパク質(NAP)、マクロファージ化学誘引物質および活性化因子(MCAF)、ランテス(RANTES)、またはマクロファージ炎症性ペプチドMIP-1aおよびMIP-1bであるか、若しくは(ii)OX40、OX40L(gp34)、リンホタクチン、CD40、CD40L、B7.1、B7.2、トラップ(TRAP)、ICAM-1、2もしくは3、CD28、CTLA-4、熱安定性抗原(HSA)、またはコンドロイチン硫酸修飾MHC不変鎖(Ii-CS)の発現を刺激または増強する、医薬組成物。 - 医薬組成物であって、
少なくとも2種類のペプチドをコードする少なくとも2種類の核酸または発現ベクターを含み、
前記少なくとも2種類のペプチドは、
1種類以上の第1のペプチドであって、前記第1のペプチドの各々は、配列番号6(NLMNLGATL)のアミノ酸配列を含むアミノ酸配列からなり、かつ10~30個のアミノ酸からなる長さを有する、該1種類以上の第1のペプチド、
1種類以上の第2のペプチドであって、前記第2のペプチドの各々は、配列番号6(NLMNLGATL)のアミノ酸配列を含むアミノ酸配列からなり、30を超える個数のアミノ酸からなる長さを有し、9~11個のアミノ酸からなる長さにプロセシングされるように適合されている、該1種類以上の第2のペプチド、
配列番号6(NLMNLGATL)のアミノ酸配列からなるペプチド、
配列番号10(CMTWNYMNLGATLKG)のアミノ酸配列を含むアミノ酸配列からなるペプチド、
配列番号19(MTWNYMNLGATLKGV)のアミノ酸配列を含むアミノ酸配列からなるペプチド、
配列番号23(CMTWNYMNLGATLKGVA)のアミノ酸配列を含むアミノ酸配列からなるペプチド、
配列番号11(WNYMNLGATLKGVAA)のアミノ酸配列を含むアミノ酸配列からなるペプチド、および
配列番号20(TWNYMNLGATLKGVA)のアミノ酸配列を含むアミノ酸配列からなるペプチド
からなる群から選択される、医薬組成物。 - 請求項7に記載の医薬組成物であって、
前記少なくとも2種類の核酸または発現ベクターがコードする前記少なくとも2種類のペプチドが、前記1種類以上の第1のペプチドを含み、
前記1種類以上の第1のペプチドの少なくとも1つが、
配列番号14(CMTWNLMNLGATLKG)のアミノ酸配列からなるペプチド、
配列番号15(MTWNLMNLGATLKGV)のアミノ酸配列からなるペプチド、
配列番号16(TWNLMNLGATLKGV)のアミノ酸配列からなるペプチド、
配列番号17(WNLMNLGATLKGVAA)のアミノ酸配列からなるペプチド、および
配列番号22(CMTWNLMNLGATLKGVA)のアミノ酸配列からなるペプチド
からなる群から選択される、医薬組成物。 - 請求項7に記載の医薬組成物であって、
前記少なくとも2種類の核酸または発現ベクターがコードする前記少なくとも2種類のペプチドが、
配列番号6(NLMNLGATL)のアミノ酸配列からなるペプチド、
配列番号14(CMTWNLMNLGATLKG)のアミノ酸配列からなるペプチド、
配列番号15(MTWNLMNLGATLKGV)のアミノ酸配列からなるペプチド、
配列番号16(TWNLMNLGATLKGV)のアミノ酸配列からなるペプチド、
配列番号17(WNLMNLGATLKGVAA)のアミノ酸配列からなるペプチド、
配列番号22(CMTWNLMNLGATLKGVA)のアミノ酸配列からなるペプチド
配列番号10(CMTWNYMNLGATLKG)のアミノ酸配列を含むアミノ酸配列からなるペプチド、
配列番号19(MTWNYMNLGATLKGV)のアミノ酸配列を含むアミノ酸配列からなるペプチド、
配列番号23(CMTWNYMNLGATLKGVA)のアミノ酸配列を含むアミノ酸配列からなるペプチド、
配列番号11(WNYMNLGATLKGVAA)のアミノ酸配列を含むアミノ酸配列からなるペプチド、および
配列番号20(TWNYMNLGATLKGVA)のアミノ酸配列を含むアミノ酸配列からなるペプチド
からなる群から選択される、医薬組成物。 - 請求項7~9のいずれか一項に記載の医薬組成物であって、
前記少なくとも2種類のペプチドが、2種類、3種類、4種類、または4種類以上のペプチドである、医薬組成物。 - 請求項7~10のいずれか一項に記載の医薬組成物であって、
免疫調節性化合物をさらに含む、医薬組成物。 - 請求項11に記載の医薬組成物であって、
前記免疫調節性化合物は、(i)サイトカイン、サイトカイン受容体、ケモカイン、補体成分、インターロイキン1~15のいずれか、インターフェロンα、βもしくはγ、腫瘍壊死因子、顆粒球マクロファージコロニー刺激因子(GM-CSF)、マクロファージコロニー刺激因子(M-CSF)、顆粒球コロニー刺激因子(G-CSF)、好中球活性化タンパク質(NAP)、マクロファージ化学誘引物質および活性化因子(MCAF)、ランテス(RANTES)、またはマクロファージ炎症性ペプチドMIP-1aおよびMIP-1bであるか、若しくは(ii)OX40、OX40L(gp34)、リンホタクチン、CD40、CD40L、B7.1、B7.2、トラップ(TRAP)、ICAM-1、2もしくは3、CD28、CTLA-4、熱安定性抗原(HSA)、またはコンドロイチン硫酸修飾MHC不変鎖(Ii-CS)の発現を刺激または増強する、医薬組成物。 - 請求項1~12のいずれか一項に記載の医薬組成物であって、
薬剤的に許容できる担体、ビヒクル、賦形剤、抗原提示細胞、アジュバント、または担体をさらに含む、
医薬組成物。 - 請求項13に記載の医薬組成物であって、
前記アジュバントを含み、
前記アジュバントが、QS21、フロイント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、増殖因子、サイトカイン、ケモカイン、インターロイキン、モンタナイドISA51、またはGM-CSFである、医薬組成物。 - 請求項1~14のいずれか一項に記載の医薬組成物であって、
前記医薬組成物が、ワクチンとして使用される、医薬組成物。 - WT1を発現するがんを有する対象を治療するか、もしくはWT1を発現するがんの発生率または再発率を減少させる医薬を製造するための、請求項1~15のいずれか一項に記載の医薬組成物の使用。
- 請求項16に記載の使用であって、
前記WT1を発現するがんが、白血病、線維形成性小円形細胞腫瘍、胃がん、結腸がん、肺がん、乳がん、胚細胞性腫瘍、卵巣がん、子宮がん、甲状腺がん、肝臓がん、腎がん、カポジ肉腫、肉腫、肝細胞がん、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)、中皮腫、または非小細胞肺がん(NSCLC)である、使用。 - WT1を発現するがんの細胞に特異的なCTLの形成および増殖を誘導する医薬を製造するための、請求項1~15のいずれか一項に記載の医薬組成物の使用。
- 請求項18に記載の使用であって、
前記WT1を発現するがんが、白血病、線維形成性小円形細胞腫瘍、胃がん、結腸がん、肺がん、乳がん、胚細胞性腫瘍、卵巣がん、子宮がん、甲状腺がん、肝臓がん、腎がん、カポジ肉腫、肉腫、肝細胞がん、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)、中皮腫、または非小細胞肺がん(NSCLC)である、使用。
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