JP6352996B2 - 組成物と治療用抗腫瘍ワクチン - Google Patents
組成物と治療用抗腫瘍ワクチン Download PDFInfo
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- JP6352996B2 JP6352996B2 JP2016170936A JP2016170936A JP6352996B2 JP 6352996 B2 JP6352996 B2 JP 6352996B2 JP 2016170936 A JP2016170936 A JP 2016170936A JP 2016170936 A JP2016170936 A JP 2016170936A JP 6352996 B2 JP6352996 B2 JP 6352996B2
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Description
本出願は、米国仮特許出願第60/954,917号(2007年8月9日出願)、およびフランス国特許出願第FR0705767号(2007年8月8日出願)(いずれも参照することにより本明細書に組み込まれる)の優先権を主張する。
赤血球中に封入されているか又はその表面に結合してAPCに送られる抗原を運搬するための担体としての赤血球の使用は、いくつかの文献で企図されている。引き起こされた免疫応答は、インビトロとインビボで研究されている。
本発明において赤血球は、抗原を含有すなわち封入し、これは、抗原が赤血球内にあるか又は基本的にあることを意味する。
− TLR(Toll様受容体)リガンド、特にイミダゾキノロン類、例えば好ましくは、イミダゾキノリン、例えばイミダゾキノリンCL097、イミキモド、レシキモド;CpGオリゴデオキシヌクレオチド;LPS(リポ多糖);ポリ(イノシン酸)−(ポリシチジル酸ポリ(I:C));
− サイトカイン、特にインターフェロンアルファ、IL−2(インターロイキン2)、IFNγ(インターフェロンガンマ)、GM−CSF(顆粒球モノサイト−コロニー刺激因子)、IL−12(インターロイキン12)、TNFα(腫瘍壊死因子アルファ)。
− 細菌成分、特にBCG(バシルスカルメットゲラン)、MDP(ムラミルジペプチド)、TDM(トレハロースジミコレート)、LPS(リポ多糖)、MPL(モノホスホリル脂質A);
− ミネラルアジュバント、特に:水酸化アルミニウム、リン酸アルミニウム、リン酸カリウム、及びリン酸カルシウム;
− 細菌毒素、特に:CT(ビブリオ・コレラ(Vibrio cholera)のコレラ毒素)、CTB(ビブリオ・コレラ(Vibrio cholera)のコレラ毒素)、PT(百日咳菌(Bordetella pertussis)の百日咳毒素)、LT(大腸菌(Escherichia coli)の熱不安定性リンホトキシン);
− KLH(キーホールリンペットヘモシアニン)。
2. 該赤血球ペレットからの赤血球の試料を使用して、浸透圧脆弱性を測定するが、工程1と2は任意の順序で実施可能である(並行して行ってもよい)、
3. 65%又はそれ以上のヘマトクリットレベルの赤血球の懸濁液と、+1〜+8℃に冷却した低張溶解溶液とを、透析カートリッジ中を通過させることを含んでなる、+1〜+8℃で一定温度を維持した同じチャンバー内での腫瘍抗原の溶解とインターナリゼーションプロセス;溶解パラメータは、あらかじめ測定した浸透圧脆弱性に従って調整される;及び
4. 温度は+30〜+40℃で、かつ高張溶液の存在下で、第2のチャンバー中で再封鎖プロセスを行う。
特に透析において、赤血球ペレットは、65%又はそれ以上、好ましくは70%又はそれ以上の高いヘマトクリットレベルで、等張溶液に懸濁され、この懸濁物は+1〜+8℃、好ましくは+2〜6℃、典型的には+4℃の範囲に冷却される。具体例では、ヘマトクリットレベルは65%〜80%、好ましくは70%〜80%である。
本発明の目的はまた、樹状細胞により仲介され、腫瘍細胞又は腫瘍に対する細胞障害性細胞応答を宿主で誘導するための、本発明の組成物の使用である。
本発明の別の目的は、治療用抗腫瘍ワクチンとして使用される本発明の組成物である。
変更態様1:
低張透析法により透析チューブで、オバルブミン(タンパク質45kDa、雌鳥卵のオバルブミン)をマウス赤血球(OF1マウス又はC57Bl/6マウス)に封入した。赤血球懸濁液を数回洗浄後、透析のためにヘマトクリットを70%とする。透析チューブ中で低浸透圧の溶解緩衝液中で、約1時間又は30分間透析を行い、ここで熱処理後に透析が起きる。次に赤血球を、高浸透圧溶液を用いて30分間再封鎖する。数回洗浄後、最終生成物を緩衝液(Sag−マンニトール)に取り、ヘマトクリットを50%にする。
透析カラムで低張透析法により、マウス赤血球中にオバルブミンを封入する。赤血球懸濁液を数回洗浄後、透析のためにヘマトクリットを70%とする。透析カラム中で低浸透圧の溶解緩衝液中で約10分間、透析を行う。赤血球がカラムを出たら、高浸透圧溶液を用いて赤血球を37℃で30分間再封鎖する。数回洗浄後、最終生成物をグルコースSAGマンニトール又は脱補体血漿を含有するNaCl緩衝液に取り、ヘマトクリットを50%に戻す。
実施例1の変更態様1に従って封入を行う時、透析法の前に熱処理を行う。実施例1の変更態様2に従って封入を行う時、透析と再封鎖の後でかつ洗浄工程とNaClグルコース緩衝液の添加前に、熱処理が行われる。
オバルブミンを含有する赤血球の懸濁液を数回洗浄後、インビボ試験用に109細胞/mlに、インビトロ試験用に108細胞/mlにする。これを抗TER119抗体(インビトロ試験用に10μg/ml、インビボ試験用に23μg/ml又は5μg/ml)とともに4℃で30分間インキュベートする。数回洗浄後、注射可能な品質の緩衝液中に最終生成物を取り、ヘマトクリットを50%にする。
オバルブミンを含有する赤血球の懸濁液を数回洗浄後、PBSで1.7×106細胞/μlとし、1容量の2mM BS3(グルコースとリン酸緩衝液を含むBS3溶液、pH7.4)と混合し、1mMのBS3最終濃度を得る。細胞を室温で30分間インキュベートする。1容量の20mMトリス塩酸を加えて、反応をクエンチする。室温で5分間インキュベーション後、混合物を800gで4℃で5分間遠心分離する。次に細胞を、グルコースを含有するPBSで2回洗浄(800gで遠心分離)し、SAG−マンニトールで1回10分間洗浄(1000gで遠心分離)し、次に最終生成物を構成する。
樹状細胞による、実施例1の変更態様1で得られた赤血球の貪食効率に対する種々の処理(熱及び抗体)の効果をインビトロで測定する。赤血球を蛍光標識物であるCFSE(カルボキシフルオレセインスクシニミジルエステル)で、4℃で20分間標識する。CFSEは、細胞膜中を拡散する非蛍光性染料である。いったん細胞内に入ると、この分子は細胞内エステラーゼにより切断されて蛍光性になる。
(A)オバルブミンが装填され、CFSE蛍光色素で標識していない赤血球、
(B)オバルブミンが装填され、CFSEで標識された赤血球、
(C)オバルブミンが装填され、抗TER119抗体で処理し、CFSEで標識した赤血球。
この試験は、オバルブミンを含有するOF1マウス赤血球が同族ではないC57Bl/6マウスに注射されるため、同種異系試験である。
バッチ2:熱処理した(図2、BとE)
バッチ3:抗TER119抗体で処理した(図2、CとF)
OF1マウス赤血球がOF1マウスに注射されるため、この試験は自家試験である。
バッチ2:オバルブミン装填赤血球、熱処理
バッチ3:オバルブミン装填赤血球、抗TER119抗体処理
バッチ4:オバルブミン装填赤血球
バッチ5:NaClグルコース
OVA(オバルブミン)特異的CD4 T細胞応答の評価は、OVA特異的CD4 T細胞の割合、これらの細胞の増殖、これらの細胞の活性化レベル、及びIFNg(g=ガンマ)の産生を測定することからなる。
バッチ2:ポリ(I:C)及びオバルブミン装填赤血球
バッチ3:ポリ(I:C)及び遊離オバルブミン
バッチ4:血漿
OVA特異的CD8 T細胞応答の評価は、OVA特異的CD8 T細胞の割合、主要組織適合遺伝子複合体クラスI分子に関連するオバルブミンペプチド257〜264を提示する細胞のインビボでのIFNgの産生と細胞溶解を測定することからなる。OF1マウスからのオバルブミン装填赤血球が同族ではないC57Bl/6マウスに注射されるため、この試験は同種異系試験である。
バッチ2:ポリ(I:C)とオバルブミン装填赤血球
バッチ3:オバルブミンペプチド257〜264に結合したラテックスビーズ
バッチ4:ポリ(I:C)とオバルブミンペプチド257〜264に結合したラテックスビーズ
バッチ5:ポリ(I:C)と遊離オバルブミン
バッチ6:NaClグルコース+血漿
OVA特異的CD8 T細胞応答の維持の評価は、1回注射の34日後のOVA特異的CD8 T細胞の割合と細胞溶解を測定することからなった。
バッチ2:ポリ(I:C)とオバルブミン装填赤血球
バッチ3:オバルブミンペプチド257〜264に結合したラテックスビーズ:BOVAp
バッチ4:ポリ(I:C)とBOVAp
バッチ5:ポリ(I:C)と遊離オバルブミン
バッチ6:NaClグルコース+血漿
OF1マウスのオバルブミンを装填した赤血球が同族ではないC57Bl/6マウスに注射されるため、この試験は同種異系試験である。
バッチ2:ポリ(I:C)と遊離オバルブミン
バッチ3:ポリ(I:C)
バッチ4:グルコース含有NaCl
OF1マウスのオバルブミン装填赤血球が同族ではないC57Bl/6マウスに注射されるため、この試験は同種異系試験である。
バッチ2:抗TER119抗体で処理したオバルブミン装填赤血球
バッチ3:CL097と、オバルブミン装填赤血球
バッチ4:オバルブミン装填赤血球
バッチ5:グルコース含有NaCl
この試験の目的は、ポリ(I:C)と処理又は未処理オバルブミン装填赤血球を1回注射後の、C57Bl/6マウス中のEG.7細胞株の腫瘍増殖の測定することである。EG.7腫瘍細胞はATCCから得た(ATCC−CRL−2113)。EG.7細胞はEL.4細胞株起源であり、これはOVAを構成性に合成し分泌する。
バッチ2:ポリ(I:C)とオバルブミン装填赤血球
バッチ3:非装填赤血球
ブタ赤血球がC57Bl/6マウスに注射されるため、この試験は異種試験である。
バッチ2:グルコース含有NaCl
オバルブミン(実施例1の変更態様2に従って得られる)を装填したか又は装填していないブタ赤血球の2つのバッチを調製した。
バッチ2:OVAを装填していないブタ赤血球
Claims (23)
- 宿主において腫瘍細胞に対する細胞障害性応答を誘導するための組成物を製造する方法であって、該方法は、以下:
(a)腫瘍抗原、及び細胞障害性応答を生成することができるアジュバントを赤血球に封入し、これらの赤血球の懸濁液を調製する工程;又は
(b)腫瘍抗原を第一の赤血球に封入し、細胞障害性応答を生成することができるアジュバントを第二の赤血球に封入し、これらの第一と第二の赤血球の懸濁液又はそれらの別々の懸濁液を調製する工程;又は
(c)腫瘍抗原を赤血球に封入し、これらの赤血球の懸濁液を調製し、細胞障害性応答を生成することができるアジュバントを添加する工程;又は
(d)腫瘍抗原を赤血球に封入し、これらの赤血球の懸濁液を調製し、別々にアジュバント調製物を調製及び提供する工程であって、ここで、該アジュバントは、腫瘍抗原を封入する赤血球の懸濁液とともに投与される患者に投与された場合に、細胞障害性応答を生成することができる上記工程
を含む、上記方法。 - アジュバントはTLR(Toll様受容体)リガンド又はサイトカインである、請求項1に記載の方法。
- アジュバントはポリ(イノシン酸)−(ポリシチジル酸)又はポリ(I:C)である、請求項2に記載の方法。
- アジュバントはイミダゾキノリンである、請求項2に記載の方法。
- イミダゾキノリンはCL097、イミキモド、又はレシキモドである請求項4に記載の方法。
- アジュバントはCpGオリゴデオキシヌクレオチドまたはリポ多糖である、請求項1に記載の方法。
- サイトカインは、インターフェロンアルファ、IL−2(インターロイキン2)、IFNγ(インターフェロンガンマ)、GM−CSF(顆粒球モノサイト−コロニー刺激因子)、IL−12(インターロイキン12)、又はTNFα(腫瘍壊死因子アルファ)よりなる群から選択される、請求項2に記載の方法。
- アジュバントは樹状細胞成熟を活性化することができる、請求項1〜7のいずれか1項に記載の方法。
- アジュバントは赤血球中で、赤血球の表面及び/又はその外に存在する、請求項1〜8のいずれか1項に記載の方法。
- 赤血球の懸濁液とアジュバントは別々であり、同時又は別に投与される、請求項1〜8のいずれか1項に記載の方法。
- 赤血球は、(1)抗原を含有し、かつ(2)樹状細胞による該赤血球の貪食を促進するように、該赤血球の表面のエピトープを認識する免疫グロブリンとの免疫複合体の形である、請求項1〜10のいずれか1項に記載の方法。
- 赤血球は、抗アカゲザル抗体、抗グリコホリンA抗体、又は抗CR1抗体と免疫複合体を形成する、請求項11に記載の方法。
- 赤血球は、抗TER119抗体と免疫複合体を形成する、請求項11に記載の方法。
- 樹状細胞による赤血球の貪食を促進するように、腫瘍抗原を封入した赤血球を、懸濁液を調製する前に熱処理又は化学処理することをさらに含む、請求項1に記載の方法。
- 組成物が、治療される腫瘍に対して免疫応答を誘導するように少なくとも2つの腫瘍抗原を含む、請求項1〜14のいずれか1項に記載の方法。
- 腫瘍抗原は、以下の抗原:アルファ−アクチニン−4;ARTC1;BCR−ABL融合タンパク質(b3a2);B−RAF;CASP−5;CASP−8;ベータ−カテニン;Cdc27;CDK4;CDKN2A;COA−1;dek−can融合タンパク質;EFTUD2;伸長因子2;ETV6−AML1融合タンパク質;FN1;GPNMB;LDLR−フコシルトランスフェラーゼAS融合タンパク質;HLA−A2d;HLA−A11d;hsp70−2;KIAAO205;MART2;ME1;MUM−1f;MUM−2;MUM−3;neo−PAP;ミオシンクラスI;NFYC;OGT;OS−9;pml−RARアルファ−融合タンパク質;PRDX5;PTPRK;K−ras;N−ras;RBAF600;SIRT2;SNRPD1;SYT−SSX1又は−SSX2融合タンパク質;トリオースホスフェートイソメラーゼ;BAGE−1;GAGE−1,2,8;GAGE−3,4,5,6,7;GnTVf;HERV−K−MEL;KK−LC−1;KM−HN−1;LAGE−1;MAGE−A1;MAGE−A2;MAGE−A3;MAGE−A4;MAGE−A6;MAGE−A9;MAGE−A10;MAGE−A12;MAGE−C2;ムチンk;NA−88;NY−ESO−1/LAGE−2;SAGE;Sp17;SSX−2;SSX−4;TRAG−3;TRP2−INT2g;CEA;gp100/Pmel17;カリクレイン4;ママグロビン−A;メラン−A/MART−1;NY−BR−1;OA1;PSA;RAB38/NY−MEL−1;TRP−1/gp75;TRP−2;チロシナーゼ;アジポフィリン;AIM−2;BING−4;CPSF;サイクリンD1;Ep−CAM;EphA3;FGF5;G250/MN/CAIX;HER−2/neu;IL13Ralpha2;小腸カルボキシルエステラーゼ;アルファフェトプロテイン;M−CSF;mdm−2;MMP−2;MUC1;p53;PBF;PRAME;PSMA;RAGE−1;RNF43;RU2AS;セセルニン1;SOX10;STEAP1;スルビビン;テロメラーゼ;WT1;FLT3−ITD;BCLX(L);DKK1;ENAH(hMena);MCSP;RGS5;ガストリン−17;ヒト絨毛性性腺刺激ホルモン、EGFRvIII、HER2、HER2/neu、P501、グアニリルシクラーゼC、PAPよりなる群から選択される、請求項1〜15のいずれか1項に記載の方法。
- 腫瘍抗原がペプチド性のものである、請求項1〜16のいずれか1項に記載の方法。
- 組成物が治療用抗腫瘍ワクチンとして使用される、請求項1〜17のいずれか1項に記載の方法。
- 腫瘍抗原を封入する赤血球は、該抗原を封入するために溶解−再封鎖によって調製されている、請求項1〜18のいずれか1項に記載の方法。
- 組成物が40〜70%のヘマトクリットレベルで赤血球を含む、請求項1〜19のいずれか1項に記載の方法。
- 組成物が45〜55%のヘマトクリットレベルで赤血球を含む、請求項20に記載の方法。
- 組成物が50%のヘマトクリットレベルで赤血球を含む、請求項20に記載の方法。
- 組成物が10〜250mlの容量でパッケージされる、請求項1〜22のいずれか1項に記載の方法。
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US20180344822A1 (en) | 2018-12-06 |
CN101873862A (zh) | 2010-10-27 |
IL203714A (en) | 2014-05-28 |
KR101666041B1 (ko) | 2016-10-13 |
HRP20171566T1 (hr) | 2017-11-17 |
FR2919804A1 (fr) | 2009-02-13 |
EP2185164B1 (en) | 2017-08-30 |
AU2008285595B2 (en) | 2012-08-09 |
HUE035983T2 (hu) | 2018-06-28 |
CN101873862B (zh) | 2014-10-01 |
DK2185164T3 (da) | 2017-11-13 |
CA2695478C (en) | 2018-05-08 |
JP2016196517A (ja) | 2016-11-24 |
JP2010535744A (ja) | 2010-11-25 |
NO2185164T3 (ja) | 2018-01-27 |
ES2649761T3 (es) | 2018-01-15 |
KR20100075832A (ko) | 2010-07-05 |
WO2009019317A1 (en) | 2009-02-12 |
FR2919804B1 (fr) | 2010-08-27 |
HK1148688A1 (en) | 2011-09-16 |
US20210077602A1 (en) | 2021-03-18 |
EP2185164A1 (en) | 2010-05-19 |
US9364504B2 (en) | 2016-06-14 |
JP6077195B2 (ja) | 2017-02-08 |
US20120009140A1 (en) | 2012-01-12 |
PT2185164T (pt) | 2017-11-28 |
AU2008285595A1 (en) | 2009-02-12 |
CA2695478A1 (en) | 2009-02-12 |
PL2185164T3 (pl) | 2018-01-31 |
US9950049B2 (en) | 2018-04-24 |
US10780151B2 (en) | 2020-09-22 |
US20160324946A1 (en) | 2016-11-10 |
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