JP2017061541A - 抗腫瘍t細胞応答増強剤 - Google Patents
抗腫瘍t細胞応答増強剤 Download PDFInfo
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Abstract
Description
なお、本出願の発明に関連する先行技術文献情報を以下に示す。
〔1〕インターロイキン6(IL-6)阻害剤、および/または、ゲムシタビン若しくはその塩を含有する、担癌生体の抗腫瘍T細胞応答増強用組成物。
〔2〕IL-6阻害剤、および、ゲムシタビン若しくはその塩を併用して投与することを特徴とする、〔1〕に記載の抗腫瘍T細胞応答増強用組成物。
〔3〕前記IL-6阻害剤がIL-6受容体に結合する物質である、〔1〕または〔2〕に記載の組成物。
〔4〕前記IL-6受容体に結合する物質が抗IL-6受容体抗体である、〔3〕に記載の組成物。
〔5〕前記抗IL-6受容体抗体がキメラ抗体、ヒト化抗体またはヒト抗体である、〔4〕に記載の組成物。
〔6〕前記ゲムシタビン若しくはその塩がゲムシタビン塩酸塩である〔1〕〜〔5〕に記載の組成物。
〔7〕IL-6阻害剤、および/または、ゲムシタビン若しくはその塩を担癌生体に投与する工程を含む、抗腫瘍T細胞応答を増強する方法。
〔8〕前記IL-6阻害剤がIL-6受容体に結合する物質である〔7〕に記載の方法。
〔9〕前記IL-6受容体に結合する物質が抗IL-6受容体抗体である〔8〕に記載の方法。
〔10〕前記抗IL-6受容体抗体がキメラ抗体、ヒト化抗体またはヒト抗体である〔9〕に記載の方法。
〔11〕前記ゲムシタビン若しくはその塩がゲムシタビン塩酸塩である〔7〕〜〔10〕に記載の方法。
〔12〕担癌生体における抗腫瘍T細胞応答の増強に使用するための、IL-6阻害剤。
〔13〕IL-6阻害剤およびゲムシタビン若しくはその塩の併用により抗腫瘍T細胞応答を増強することを特徴とする、〔12〕に記載の阻害剤。
〔14〕前記IL-6阻害剤がIL-6受容体に結合する物質である〔13〕に記載の阻害剤。
〔15〕前記IL-6受容体に結合する物質が抗IL-6受容体抗体である〔14〕に記載の阻害剤。
〔16〕前記抗IL-6受容体抗体がキメラ抗体、ヒト化抗体またはヒト抗体である〔15〕に記載の阻害剤。
〔17〕前記ゲムシタビン若しくはその塩がゲムシタビン塩酸塩である〔13〕〜〔16〕に記載の阻害剤。
なお本明細書において引用された全ての先行技術文献は、参照として本明細書に組み入れられる。
メチルコラントレン誘発偏平上皮癌細胞株 CMC-1 (2x106)をBALB/cマウスに皮内接種し、5日後よりGEM (ジェムザール:塩酸ゲムシタビン)(120 mg/kg)を1週間毎に腹腔内投与した。腫瘍の増殖を2日毎に計測し、GEMによる抗腫瘍効果を評価した。その結果を図1に示した。
CMC-1接種後30日の担癌マウスにGEMを接種し、48時間後、脾臓内の各細胞群の絶対数をフローサイトメトリーにて解析した。その結果を図2に示した。CMC-1接種後30日の担癌マウスにサイクロフォスファミド (CY)(60 mg/kg)、フルオロ-5-ウラシル(5-FU) (120 mg/kg)、GEMを腹腔内投与した。48時間後、脾臓内CD8+細胞を単離し、固層化抗CD3抗体 (2 μg/ml)にて60時間刺激後の増殖能を3H取り込み試験にて評価した。その結果を図3に示した。
これらの結果から、GEMが免疫抑制細胞を排除し、担癌生体のCD8+T細胞に対して優れた増殖促進効果を有することが示された。当該効果は、CYや5-FUでは確認することができなかった。また、腫瘍増殖抑制効果を有することも確認することができた。
CMC-1(2x106)をBALB/cマウスに皮内接種後、5日後よりGEM (120 mg/kg)を1週間毎に腹腔内投与、抗CD8抗体 (250 μg)を3日毎に静脈内投与し、腫瘍径を2日毎に計測した。その結果を図4に示した。
マウス肺癌細胞株 LLCに卵白アルブミン (OVA)遺伝子を導入したLLC-OVA (2x106)をC57BL6マウスに皮内接種し、5日後にGEM (120 mg/kg)を腹腔内投与した。9日後に、所属リンパ節を採取し、OVA特異的CD8+細胞傷害性T細胞の割合をフローサイトメトリーにて評価した。その結果を図5に示した。
これらの結果から、GEMによるCD8+T細胞の活性増加を介して、抗腫瘍効果が認められていることを確認することができた。
メチルコラントレン誘発線維芽肉腫細胞株CMC-G4 (2x106)をBALB/cマウスに皮内接種し、1週間後および2週間後の血清中IL-6濃度をELISAにて測定した。その結果を図6に示した。CMC-G4を皮内接種後、3日毎に抗IL-6受容体抗体(MR16-1:Tamura, T. et al. Proc. Natl. Acad. Sci. USA (1993) 90, 11924-11928) (250 μg)を静脈内投与した。28日後に脾臓細胞を採取し、抗CD3抗体 (2 μg/ml)、あるいはコンカナバリンA (ConA:2.5μg/ml)存在下で36時間培養後の培養上清中IFN-γ濃度をELISAにて測定した。その結果を図7に示した。さらに、腫瘍径を2日毎に測定し、腫瘍増殖抑制効果を評価した。その結果を図8に示した。
これらの結果から、抗IL-6受容体抗体が担癌生体におけるIFN−γの産生を促進させる効果を有していることが明らかとなった。当該結果から、抗IL-6受容体抗体もGEM同様に免疫担当細胞に対して優れた活性化促進効果を有することが示された。また、腫瘍増殖抑制効果を有することも確認することができた。
CMC-G4 (2x106)をBALB/cマウスに皮内接種後、6日後からGEM (120 mg/kg)を1週間毎に腹腔内投与、抗IL-6受容体抗体 MR16-1 (200 μg)を3日毎に静脈内投与し、腫瘍径を2日毎に計測した。その結果を図9に示した。
当該結果から、ゲムシタビン(GEM)および抗IL-6受容体抗体(MR16-1)を併用することにより、それぞれ単独で投与したときよりも優れた抗腫瘍効果が得られることが明らかとなった。
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- 本明細書に記載の発明。
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MX2009007830A (es) | 2007-01-23 | 2009-10-07 | Univ Shinshu | Inhibidor de rechazo cronico. |
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PE20091174A1 (es) | 2007-12-27 | 2009-08-03 | Chugai Pharmaceutical Co Ltd | Formulacion liquida con contenido de alta concentracion de anticuerpo |
US10717781B2 (en) * | 2008-06-05 | 2020-07-21 | National Cancer Center | Neuroinvasion inhibitor |
TWI440469B (zh) | 2008-09-26 | 2014-06-11 | Chugai Pharmaceutical Co Ltd | Improved antibody molecules |
AU2010311567B2 (en) | 2009-10-26 | 2015-03-26 | Chugai Seiyaku Kabushiki Kaisha | Method for the production of a glycosylated immunoglobulin |
ES2932398T3 (es) | 2010-05-28 | 2023-01-18 | Chugai Pharmaceutical Co Ltd | Potenciador de la respuesta de las células T antitumorales |
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BR112017014067B1 (pt) | 2015-02-27 | 2021-01-12 | Chugai Seiyaku Kabushiki Kaisha | usos de um anticorpo receptor de il-6 para no tratamento de doenças relacionadas a il-6 |
JP6875683B2 (ja) | 2015-05-19 | 2021-05-26 | 国立研究開発法人国立精神・神経医療研究センター | 多発性硬化症(ms)患者の新規治療適用判断方法 |
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JP7174960B2 (ja) | 2022-11-18 |
HUE060454T2 (hu) | 2023-03-28 |
EP2578231A4 (en) | 2013-10-30 |
JPWO2011149051A1 (ja) | 2013-07-25 |
RS63800B1 (sr) | 2022-12-30 |
JP2022187002A (ja) | 2022-12-15 |
PL2578231T3 (pl) | 2023-01-16 |
US9539322B2 (en) | 2017-01-10 |
ES2932398T3 (es) | 2023-01-18 |
JP2021105067A (ja) | 2021-07-26 |
EP4115906A1 (en) | 2023-01-11 |
JP6952454B2 (ja) | 2021-10-20 |
PT2578231T (pt) | 2022-12-02 |
EP2578231B1 (en) | 2022-10-26 |
SI2578231T1 (sl) | 2023-01-31 |
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WO2011149051A1 (ja) | 2011-12-01 |
DK2578231T3 (da) | 2022-12-12 |
US20130202588A1 (en) | 2013-08-08 |
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