JP2006514984A - 癌療法で用いる修飾されたサイトカイン - Google Patents
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Abstract
Description
a)TNFを腫瘍に送達し、局所濃度を増加させることができる融合タンパク質の開発。例えば、TNFおよび腫瘍特異的抗体からなる融合タンパク質が製造されている(4)。
b)抗腫瘍活性を維持し、低下した全身毒性を有するTNF突然変異体の開発。したがって、ただ一つの受容体(p55またはp75)を選択的に認識することができる突然変異体が既に調製されている(5)。
c)その抗腫瘍活性を損なうことなくTNFの幾つかの毒性効果を低下させることができる抗−TNF抗体の使用。そのような抗体は既に文献で記載されている(30)。
d)より長い半減期を有するTNF誘導体の使用(例えば、ポリエチレングリコールとコンジュゲートしたTNF)。
ネズミ組換えTNFおよびCys−Asn−Gly−Arg−Cys−Gly−TNF(NGR−TNF)はE.coliにおける細胞質cDNA発現によって生産された。ネズミMet−TNF1-156(20)をコードするcDNAは、3’および5’プライマーとして、
5’−CTGGATCCTCACAGAGCAATGACTCCAAAG−3’および
5’−TGCCTCACATATGCTCAGATCATCTTCTC−3’
を用い、リポ多糖−刺激ネズミRAW−264.7単球−マクロファージ細胞から単離されたmRNAに対する逆転写酵素ポリメラーゼ連鎖反応(RT−PCR)によって調製した。
TNFおよびNGR−TNFの生物活性は、記載されている(23)L−Nマウス線維芽細胞(ATCC CCL1.2)に基づく標準的な細胞溶解アッセイによって見積もった。RMA−T細胞に対するTNFおよびNGR−TNFの細胞溶解活性は30ng/mlアクチノマイシンDの存在下でテストした。各試料を3つの異なる希釈にて二連で分析した。結果を2〜3の独立したアッセイの平均±SDとして表す。
C57BL/6起源のラウシャーウイルス誘導RMAリンパ腫を、RPMI1640、5%胎児ウシ血清(FBS)、100U/mlペニシリン、100μg/mlストレプトマイシン、0.25μg/mlアンフォテリシンB、2mMグルタミンおよび50μM2−メルカプトエタノール中でインビトロにて維持した。RMA−Tは、Thy1.1対立遺伝子をコード化する構築体でのトランスフェクションによってRMA細胞系から誘導し、記載されているように培養した(14)。
抗−マウスCD13 mAb R3−63は、プロテイン−Gセファロースクロマトグラフィー(Pharmacia−Upjohn,Uppsala,スウェーデン国)によって腹水から精製し、0.9%で塩化ナトリウムに対して透析した。
(CNGRCGのC末端と融合させたヒトTNF1−157からなる)ヒト組換えTNFおよびNGR−TNFは組換えDNA技術によって調製し、実質的には、ネズミTNFおよびNGR−TNFについて記載したように精製した。ヒトNGR−TNFをコードするcDNAは、以下のプライマー:
−NGR−hTNF/1(センス):5’A TAT CAT ATG TGC AAC GGC CGT TGC GGC GTC AGA TCA TCdT TCT CG3’
−NGR−hTNF/2(アンチセンス):5’TCA GGA TCC TCA CAG GGC AAT GAT CCC AAA GTA GAC3’
を用い、hTNFコード配列(33)を含むプラスミドpET11b/hTNFに対するPCRによって調製した。
CNGRCGと融合させた組換えネズミインターフェロン(IFN)γ(NGR−IFNγ)は、実質的にはNGR−TNFについて記載したように組換えDNA技術によって調製した。CNGRCドメインはIFNγのC末端と融合させた。さらに、位置134におけるシステインをセリンで置き換え、メチオニンをE.coli細胞での発現のために位置−1に導入した。NGR−IFNγ cDNAの生産で用いたPCRプライマーは、5’−A TAT CTA CAT ATG CAC GGC ACA GTC ATT GAA AGC C(センス)および5’−TC GGA TCC TCA GCA ACG GCC GTT GCA GCC GGA GCG ACT CCT TTT CCG CTT CCT GAG GCであった。前記cDNAをpET−11b(Nde I/BamHI)にクローン化し、これを用いてBL21(DE3)E.coli細胞(Novagen)を形質転換した。pET11b製造業者の指示に従い、タンパク質の発現はイソプロピル−β−D−チオガラクトシドで誘導した。生成物は、標準的な技術に従い、アガロースに固定化された抗−マウスIFNγ mAb(AN18)を用いる免疫アフィニティークロマトグラフィーによってE.coli抽出物から精製した。最終生成物の還元性および非還元性SDS−PAGEは、16kDaの単一バンドを示した。電子スプレー質量分析は、ネズミMet−IFNγ1−134(C134S)CNGRC(NGR−IFNγ)に対応する16223+3.6Da(予測、1625.5Da)の分子量を示した。
以下の実施例は、腫瘍ホーミング抗体およびペプチドCNGRCの組合せに基づく、TNFの「デュアル」標的化の可能性を示す。
マウスB16F1メラノーマ細胞を従前に記載されているように培養した(Curnis et al.,2000;Moro et al.,1997)。
TおよびNK細胞は免疫適格性マウスにおけるIFNの一次源である。NGR−TNF/ドキソルビシン組合せ療法におけるIFNの源としてのT−細胞の重要性を調べるために、我々は、T−細胞を欠くB16F1腫瘍担持nu/nuマウスにおいてこれらの薬物の効果を調べた。このモデルにおいて、NGR−TNF/ドキソルビシンの相乗的活性は失われた(図7A〜C)。しかしながら、これらの薬物をIFNと組み合わせて投与した場合、相乗効果が再度観察された(図7D)。これらの動物における内因性IFNの量は、NGR−TNF/ドキソルビシン共同作用を活性化するのに十分ではなく、他方、内因性IFNの投与は共同投与を回復したようである。
我々は、既に、NGR−TNF/ドキソルビシン共同作用に対する重要なメカニズムはNGR−TNFによる内皮バリアー機能の改変および腫瘍におけるドキソルビシンの増大した侵入に関連することを示した。従って、我々は、IFNがこの効果に対して臨界的であるか否かを調べた。この目的で、我々は、TS/A腫瘍におけるドキソルビシンの侵入に対する内因性IFNの効果を測定した(図10)。この実験は、ドキソルビシンが蛍光化合物である、処理後に動物から回収された腫瘍細胞の蛍光強度が、腫瘍に侵入したドキソルビシンの量の指標であるという事実を利用する。実験は、内因性IFNの効果を低下させるためにnu/nuマウスで行った。腫瘍担持マウスをNGR−TNFで処理し、2時間後に、ドキソルビシンで処理すると、未処理対照と比較して、ドキソルビシンの有意な増加は腫瘍細胞では見出されなかった。しかしながら、NGR−TNFと組み合わせたIFNの投与は腫瘍におけるドキソルビシンの侵入を増加させた。これは、IFNが化学療法薬物のTNF誘導侵入に対して重要であることを示唆する。
Claims (15)
- 有効量のTNFおよびCD13受容体のリガンドまたはそれにつきコード化するポリヌクレオチドのコンジュゲーション生成物、および有効量のIFNγまたはそれにつきコード化するポリヌクレオチドを含む医薬組成物。
- 医薬上許容される担体および賦形剤を含む請求項1に記載の組成物。
- 前記TNFがTNFαまたはTNFβである請求項1または2に記載の組成物。
- 前記CD13受容体のリガンドが抗体またはその活性断片、ペプチドまたはペプチド類似体からなる群より選択される請求項1〜3のいずれかに記載の組成物。
- 前記リガンドがNGRモチーフを含有するペプチドである請求項4に記載の組成物。
- 前記ペプチドがCNGRCVSGCAGRC、NGRAHA、GNGRG、シクロCVLNGRMEC、線状CNGRC、および環状CNGRCからなる群より選択される請求項5に記載の組成物。
- 前記TNFがポリエチレングリコールまたはアシル残基で誘導体化された請求項1〜6のいずれかに記載の組成物。
- 前記TNFが抗体、抗体断片およびビオチンからなる群より選択される化合物でさらにコンジュゲートされており、前記抗体またはその断片は腫瘍抗原、腫瘍脈管形成マーカーまたは細胞外マトリックスの成分からからなる群より選択される化合物に対して作られる前記請求項のいずれかに記載の組成物。
- 前記TNFが、CD13リガンド、および抗体、および抗体断片、およびビオチンからなる群より選択される化合物の双方にコンジュゲートされている請求項8に記載の組成物。
- 注射溶液または懸濁液または注入用の液体の形態である請求項1〜9のいずれかに記載の組成物。
- リポソームの形態である請求項1〜9のいずれかに記載の組成物。
- さらに、もう一つの抗腫瘍剤または診断腫瘍イメージング化合物を含む前記請求項のいずれかに記載の組成物。
- もう一つの抗腫瘍剤がドキソルビシンである請求項12に記載の組成物。
- 請求項1〜13のいずれかの医薬組成物を投与することを含む癌患者の治療または診断方法。
- 他の抗腫瘍剤または診断腫瘍イメージング化合物をさらに投与することを含む請求項14に記載の方法。
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US10/287,811 | 2002-11-05 | ||
US10/287,811 US7309694B2 (en) | 2000-02-15 | 2002-11-05 | Modified cytokines for use in cancer therapy |
US10/426,019 US7109303B2 (en) | 2000-02-15 | 2003-04-30 | Modified cytokines for use in cancer therapy |
US10/426,019 | 2003-04-30 | ||
PCT/IB2003/005657 WO2004041297A2 (en) | 2002-11-05 | 2003-11-05 | Modified cytokines for use in cancer therapy |
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EP (1) | EP1562620B1 (ja) |
JP (1) | JP4761963B2 (ja) |
CN (1) | CN100393356C (ja) |
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AU (1) | AU2003283699B2 (ja) |
CA (1) | CA2504963C (ja) |
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JP2014520510A (ja) * | 2011-07-06 | 2014-08-25 | 常州▲ば▼標生物医薬研究所有限公司 | 腫瘍ターゲティング腫瘍壊死因子関連アポトーシス誘導リガンド変異体及びその応用 |
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US7612194B2 (en) * | 2001-07-24 | 2009-11-03 | Monsanto Technology Llc | Nucleic acid sequences from Diabrotica virgifera virgifera LeConte and uses thereof |
GB0209896D0 (en) | 2002-04-30 | 2002-06-05 | Molmed Spa | Conjugate |
GB0209893D0 (en) * | 2002-04-30 | 2002-06-05 | Molmed Spa | Conjugate |
GB0312309D0 (en) * | 2003-05-29 | 2003-07-02 | Gaslini Children S Hospital G | Targeted liposome |
EP2364995A1 (en) * | 2004-12-23 | 2011-09-14 | Molmed SpA | Conjugation product |
GB0803076D0 (en) * | 2008-02-20 | 2008-03-26 | Univ Ghent | Mucosal Membrane Receptor and uses thereof |
CA2723823C (en) * | 2008-05-13 | 2012-10-16 | Molmed S.P.A. | Conjugates for the treatment of mesothelioma |
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JP2014520510A (ja) * | 2011-07-06 | 2014-08-25 | 常州▲ば▼標生物医薬研究所有限公司 | 腫瘍ターゲティング腫瘍壊死因子関連アポトーシス誘導リガンド変異体及びその応用 |
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CN1732016A (zh) | 2006-02-08 |
ES2326530T3 (es) | 2009-10-14 |
WO2004041297A2 (en) | 2004-05-21 |
AU2003283699B2 (en) | 2009-11-19 |
US20060115451A1 (en) | 2006-06-01 |
US20040018171A1 (en) | 2004-01-29 |
JP4761963B2 (ja) | 2011-08-31 |
CA2504963C (en) | 2013-09-03 |
ATE431742T1 (de) | 2009-06-15 |
CA2504963A1 (en) | 2004-05-21 |
AU2003283699A1 (en) | 2004-06-07 |
EP1562620B1 (en) | 2009-05-20 |
US7109303B2 (en) | 2006-09-19 |
US7622105B2 (en) | 2009-11-24 |
DE60327710D1 (de) | 2009-07-02 |
WO2004041297A3 (en) | 2004-07-29 |
EP1562620A2 (en) | 2005-08-17 |
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