JP5479918B2 - 子宮頸癌の治療のための組成物および方法 - Google Patents
子宮頸癌の治療のための組成物および方法 Download PDFInfo
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- C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
- C07K16/1267—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria
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Description
各実施形態において、子宮頸癌は、後期子宮頸癌(ステージIIIB及びステージIVBを含む)であっても良く、第1のペプチドは、LLOタンパク質のN末端フラグメントであっても良い。
MKKIMLVFITLILVSLPIAQQTEAKDASAFNKENSISSMAPPASPPASPKTPIEKKHADEIDKYIQGLDYNKNNVLVYHGDAVTNVPPRKGYKDGNEYIVVEKKKKSINQNNADIQVVNAISSLTYPGALVKANSELVENQPDVLPVKRDSLTLSIDLPGMTNQDNKIVVKNATKSNVNNAVNTLVERWNEKYAQAYPNVSAKIDYDDEMAYSESQLIAKFGTAFKAVNNSLNVNFGAISEGKMQEEVISFKQIYYNVNVNEPTRPSRFFGKAVTKEQLQALGVNAENPPAYISSVAYGRQVYLKLSTNSHSTKVKAAFDAAVSGKSVSGDVELTNIIKNSSFKAVIYGGSAKDEVQIIDGNLGDLRDILKKGATFNRETPGVPIAYTTNFLKDNELAVIKNNSEYIETTSKAYTDGKINIDHSGGYVAQFNISWDEVNYDPEGNEIVQHKNWSENNKSKLAHFTSSIYLPGNARNINVYAKECTGLAWEWWRTVIDDRNLPLVKNRNISIWGTTLYPKYSNKVDNPIE(ジェンバンクアクセッション番号P13128、配列番号27、核酸配列はジェンバンクアクセッション番号X15127に記載)。この配列に対応する、前駆タンパク質の最初の25アミノ酸は、シグナル配列であり、細菌によって分泌される際、LLOから開裂する。したがって、本実施形態において、全長の活性LLOタンパク質は、504残基長である。別の実施形態において、上記のLLOフラグメントは、本発明のワクチンに組み込まれるLLOフラグメントの源として使用される。それぞれの可能性が、本発明の個別の実施形態を表す。
MKKIMLVFITLILVSLPIAQQTEAKDASAFNKENSISSVAPPASPPASPKTPIEKKHADEIDKYIQGLDYNKNNVLVYHGDAVTNVPPRKGYKDGNEYIVVEKKKKSINQNNADIQVVNAISSLTYPGALVKANSELVENQPDVLPVKRDSLTLSIDLPGMTNQDNKIVVKNATKSNVNNAVNTLVERWNEKYAQAYSNVSAKIDYDDEMAYSESQLIAKFGTAFKAVNNSLNVNFGAISEGKMQEEVISFKQIYYNVNVNEPTRPSRFFGKAVTKEQLQALGVNAENPPAYISSVAYGRQVYLKLSTNSHSTKVKAAFDAAVSGKSVSGDVELTNIIKNSSFKAVIYGGSAKDEVQIIDGNLGDLRDILKKGATFNRETPGVPIAYTTNFLKDNELAVIKNNSEYIETTSKAYTDGKINIDHSGGYVAQFNISWDEVNYD(配列番号25)。
MKKIMLVFITLILVSLPIAQQTEAKDASAFNKENSISSVAPPASPPASPKTPIEKKHADEIDKYIQGLDYNKNNVLVYHGDAVTNVPPRKGYKDGNEYIVVEKKKKSINQNNADIQVVNAISSLTYPGALVKANSELVENQPDVLPVKRDSLTLSIDLPGMTNQDNKIVVKNATKSNVNNAVNTLVERWNEKYAQAYSNVSAKIDYDDEMAYSESQLIAKFGTAFKAVNNSLNVNFGAISEGKMQEEVISFKQIYYNVNVNEPTRPSRFFGKAVTKEQLQALGVNAENPPAYISSVAYGRQVYLKLSTNSHSTKVKAAFDAAVSGKSVSGDVELTNIIKNSSFKAVIYGGSAKDEVQIIDGNLGDLRDILKKGATFNRETPGVPIAYTTNFLKDNELAVIKNNSEYIETTSKAYTD(配列番号26)。
MRAMMVVFITANCITINPDIIFAATDSEDSSLNTDEWEEEKTEEQPSEVNTGPRYETAREVSSRDIKELEKSNKVRNTNKADLIAMLKEKAEKGPNINNNNSEQTENAAINEEASGADRPAIQVERRHPGLPSDSAAEIKKRRKAIASSDSELESLTYPDKPTKVNKKKVAKESVADASESDLDSSMQSADESSPQPLKANQQPFFPKVFKKIKDAGKWVRDKIDENPEVKKAIVDKSAGLIDQLLTKKKSEEVNASDFPPPPTDEELRLALPETPMLLGFNAPATSEPSSFEFPPPPTDEELRLALPETPMLLGFNAPATSEPSSFEFPPPPTEDELEIIRETASSLDSSFTRGDLASLRNAINRHSQNFSDFPPIPTEEELNGRGGRP(配列番号23)。別の実施形態において、ActAフラグメントは、配列番号23に記載される配列を含む。別の実施形態において、ActAフラグメントは、当該技術分野で既知の任意の他のActAフラグメントである。別の実施形態において、ActAタンパク質は、配列番号23のホモログである。別の実施形態において、ActAタンパク質は、配列番号23の変異体である。別の実施形態において、ActAタンパク質は、配列番号23のアイソフォームである。別の実施形態において、ActAタンパク質は、配列番号23のフラグメントである。別の実施形態において、ActAタンパク質は、配列番号23のホモログのフラグメントである。別の実施形態において、ActAタンパク質は、配列番号23の変異体のフラグメントである。別の実施形態において、ActAタンパク質は、配列番号23のアイソフォームのフラグメントである。それぞれの可能性が、本発明の個別の実施形態を表す。それぞれの可能性が、本発明の個別の実施形態を表す。
atgcgtgcgatgatggtggttttcattactgccaattgcattacgattaaccccgacataatatttgcagcgacagatagcgaagattctagtctaaacacagatgaatgggaagaagaaaaaacagaagagcaaccaagcgaggtaaatacgggaccaagatacgaaactgcacgtgaagtaagttcacgtgatattaaagaactagaaaaatcgaataaagtgagaaatacgaacaaagcagacctaatagcaatgttgaaagaaaaagcagaaaaaggtccaaatatcaataataacaacagtgaacaaactgagaatgcggctataaatgaagaggcttcaggagccgaccgaccagctatacaagtggagcgtcgtcatccaggattgccatcggatagcgcagcggaaattaaaaaaagaaggaaagccatagcatcatcggatagtgagcttgaaagccttacttatccggataaaccaacaaaagtaaataagaaaaaagtggcgaaagagtcagttgcggatgcttctgaaagtgacttagattctagcatgcagtcagcagatgagtcttcaccacaacctttaaaagcaaaccaacaaccatttttccctaaagtatttaaaaaaataaaagatgcggggaaatgggtacgtgataaaatcgacgaaaatcctgaagtaaagaaagcgattgttgataaaagtgcagggttaattgaccaattattaaccaaaaagaaaagtgaagaggtaaatgcttcggacttcccgccaccacctacggatgaagagttaagacttgctttgccagagacaccaatgcttcttggttttaatgctcctgctacatcagaaccgagctcattcgaatttccaccaccacctacggatgaagagttaagacttgctttgccagagacgccaatgcttcttggttttaatgctcctgctacatcggaaccgagctcgttcgaatttccaccgcctccaacagaagatgaactagaaatcatccgggaaacagcatcctcgctagattctagttttacaagaggggatttagctagtttgagaaatgctattaatcgccatagtcaaaatttctctgatttcccaccaatcccaacagaagaagagttgaacgggagaggcggtagacca(配列番号24)。別の実施形態において、組み換えヌクレオチドは、配列番号24に記載される配列を有する。別の実施形態において、組み換えヌクレオチドは、ActAタンパク質のフラグメントをコード化する任意の他の配列を含む。それぞれの可能性が、本発明の個別の実施形態を表す。
−1M二塩基性リン酸カリウム29μl
−1M一塩基性リン酸カリウム21μl
−l40%ショ糖500(0.45/μmフィルタを通して濾過滅菌)
−水450μl
−リゾチーム60μl(50mg/mL)
1.緩衝液PI、P2およびN3の体積をすべて3倍増量して、増加したバイオマスが完全に溶解されるようにした。
2.P2を添加する前に、再懸濁した細胞に2mg/mLのリゾチームを加えた。次いで、中和する前に、溶解液を37℃で15分間インキュベートした。
3.濃度を増加するために、50μLではなく30μLの溶液にプラスミドDNAを再懸濁した。
1.バルク培地(すなわち、水+表3Aの基本成分)、必須成分、アミノ酸、ビタミンおよび微量元素.
2.バルク培地、必須成分、アミノ酸およびビタミン
3.バルク培地、必須成分およびアミノ酸
4.バルク培地および必須成分
・注射から10分後の注射部位の腫脹、刺激感、免疫応答またはその他の異常の観察
・身体検査所見
・バイタルサイン
・臨床パラメータにおける変化(血液学および血清化学)
・尿中、血液および糞便試料におけるリステリア・モノサイトゲネスの存在
・ECOGパフォーマンス・ステータス
・報告された有害事象
・Lm−LLO−E7は、大半の患者に発熱、悪寒、悪心および嘔吐を含む一連のインフルエンザ様副作用をもたらす。
・これらの副作用は、軽度から中程度であり、1×109および3.3×109群において良好な忍容性を示した。
・薬剤投与と関連する副作用は、主に、短期間の介入可能なインフルエンザ様症候群を含む。
・本治験では肝機能とLM−LLO−E7との関係を決定することはできなかったが、LM−LLO−Eが単独でLFT上昇の近因である可能性は少ないと思われた。
・用量制限性の低血圧が用量1×1010で観察された。
Lm−LLO−E7は、1×109および3.3×109の用量で、末期の子宮頸癌において安全に使用することができる。
Claims (19)
- ヒト対象において後期子宮頸癌を治療するための組成物の調製のための、ヒトパピローマウイルス(HPV)E7抗原に融合された第1のペプチドを含む組み換えポリペプチドを含む、組み換えリステリア株の使用であって、前記第1のペプチドは、LLOタンパク質のN末端フラグメントであり、これによって、前記組み換えリステリア株は、前記E7抗原に対する免疫応答を誘導し、前記組み換えリステリア株は、前記ヒト対象に投与され、前記後期子宮頸癌は、ステージIII又はステージIVである、使用。
- 後期子宮頸癌からヒト対象を保護するための組成物の調製における、ヒトパピローマウイルス(HPV)E7抗原に融合された第1のペプチドを含む組み換えポリペプチドを含む、組み換えリステリア株の使用であって、前記第1のペプチドは、LLOタンパク質のN末端フラグメントであり、これによって、前記組み換えリステリア株は、前記E7抗原に対する免疫応答を誘導し、前記組み換えリステリア株は、前記ヒト対象に投与され、前記後期子宮頸癌は、ステージIII又はステージIVである、使用。
- ヒト対象において後期子宮頸癌に対する免疫応答を誘導するための組成物の調製のための、ヒトパピローマウイルス(HPV)E7抗原に融合された第1のペプチドを含む組み換えポリペプチドを含む、組み換えリステリア株の使用であって、前記第1のペプチドは、LLOタンパク質のN末端フラグメントであり、前記組み換えリステリア株は、前記ヒト対象に投与され、前記後期子宮頸癌は、ステージIII又はステージIVである、使用。
- 後期子宮頸癌のヒト対象において抗E7細胞傷害性T細胞応答を誘導するための組成物の調製のための、ヒトパピローマウイルス(HPV)E7抗原に融合された第1のペプチドを含む組み換えポリペプチドを含む、組み換えリステリア株の使用であって、前記第1のペプチドは、LLOタンパク質のN末端フラグメントであり、前記組み換えリステリア株は、前記ヒト対象に投与され、前記後期子宮頸癌は、ステージIII又はステージIVである、使用。
- 前記LLOタンパク質のN末端フラグメントは配列番号1を含む、請求項1〜4のいずれかに記載の使用。
- 前記組み換えリステリア株は、1×109〜3.31×109の生命体の用量で前記ヒト対象に投与される、請求項1〜4のいずれかに記載の使用。
- 前記組み換えリステリア株は、1×109の生命体の用量で前記ヒト対象に投与される、請求項1〜4及び6のいずれかに記載の使用。
- 前記組み換えリステリア株は、3.31×109の生命体の用量で前記ヒト対象に投与される、請求項1〜4及び6のいずれかに記載の使用。
- 前記組み換えリステリア株は、組み換えリステリア・モノサイトゲネス株である、請求項1〜4のいずれかに記載の使用。
- 前記組み換えリステリア株は、動物宿主で継代されている、請求項1〜4のいずれかに記載の使用。
- 前記組み換えポリペプチドは、前記組み換えリステリア株によって発現される、請求項1〜4のいずれかに記載の使用。
- 前記組み換えリステリア株は、前記組み換えポリペプチドをコード化するプラスミドを含む、請求項1〜4のいずれかに記載の使用。
- 前記プラスミドは、細菌転写因子をコード化する遺伝子を含む、請求項12に記載の使用。
- 前記プラスミドは、代謝酵素をコード化する遺伝子を含む、請求項12に記載の使用。
- 前記E7抗原を含む、または前記E7抗原の発現を誘導する第2の組成物が、前記組み換えリステリア株と併用される、請求項1〜4のいずれかに記載の使用。
- 前記組み換えリステリア株は、凍結または凍結乾燥された細胞バンクに保管されていたものである、請求項1〜4のいずれかに記載の使用。
- 前記組み換えリステリア株は、解凍または再構成時に90%を上回る生存能力を呈する、請求項16のいずれかに記載の使用。
- 前記ステージIIIは、ステージIIIBである、請求項1〜4のいずれかに記載の使用。
- 前記ステージIVは、ステージIVBである、請求項1〜4のいずれかに記載の使用。
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PCT/US2008/003067 WO2008109155A2 (en) | 2007-03-08 | 2008-03-07 | Compositions and methods for treatment of cervical cancer |
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WO2004062597A2 (en) * | 2003-01-09 | 2004-07-29 | The Trustees Of The University Of Pennsylvania | Compositions, methods and kits for enhancing the immunogenicity of a bacterial vaccine vector |
DE102006035617A1 (de) * | 2006-07-31 | 2008-02-21 | Siemens Ag | Automatische Bestimmung von Tumorlast |
WO2008079172A2 (en) * | 2006-08-15 | 2008-07-03 | The Trustees Of The University Of Pennsylvania | Compositions comprising hmw-maa and fragments thereof, and methods of use thereof |
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US8114414B2 (en) | 2012-02-14 |
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US20090081250A1 (en) | 2009-03-26 |
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