JP6245622B2 - Il−18と分子標的抗体とを併用する癌治療薬 - Google Patents
Il−18と分子標的抗体とを併用する癌治療薬 Download PDFInfo
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Description
(1)有効成分
本発明に係る癌治療薬は、IL−18と、抗PD−L1抗体、抗PD−1抗体、抗PD−L2抗体、抗CTLA−4抗体、抗CD25抗体、抗CD33抗体および抗CD52抗体からなる群より選ばれる1以上の抗体と、を有効成分として含有する。
本発明に係る癌治療薬は、上記有効成分以外に、必要に応じて、例えば特許文献3に記載されているような、医薬上許容される担体、希釈剤、または賦形剤をさらに含みうる。
本発明に係る癌治療薬は、いずれかの適切な体内経路により患者に投与することができる。
本発明に係る癌治療薬は、上述したように、IL−18と所定の抗体とを有効成分として併用したものである。後述する実施例に示すように、当該併用を行い、本発明に係る癌治療薬を投与することによって、IL−18を単独で用いた場合、および抗体を単独で用いた場合と比較して、腹膜播種を起こす大腸癌細胞を移植したマウスの生存率を相乗的に、著しく向上させることができるという効果が奏された。
(1)マウスおよびセルライン
マウスとしては、日本SLC(浜松市)から購入したBALB/C野生型マウス(6〜8週齢、オス)を用いた。上記マウスを、25℃で、12時間明所、12時間暗所となるサイクルで照明を制御した条件下で、病原体フリーの状態で飼育した。マウスは、水およびペレット状のエサを自由に摂取できる状態にした。
組み換えマウスIL−18(グラクソ・スミスクライン製、品番SB-528775、以下単に「IL−18」と称する)は、グラクソ・スミスクラインplcの厚意により分与されたものを用いた。
(1)In vivoにおける処置
トリプシン‐EDTAを用いて培養容器からサブコンフルエントの状態にあるCT−26細胞を、剥離することによって回収し、PBSを用いて二度洗浄した。生細胞の数はトリパンブルー色素排除試験によって計数し、種々の細胞濃度で生細胞をPBS中に懸濁させ、懸濁液を調製した。上記細胞濃度は、5.0×104個/0.25mlである。
マウスの腹腔滲出細胞(PEC)は、5mlのPBSで3回洗浄することによって腹腔から回収し、ACK溶解バッファー(自家製)によって赤血球を3回除去し、PBSによって3回洗浄した。
養子細胞移入実験用のPECは、CT−26細胞を移植したマウスの腹腔から調製した。マウスには、抗CTLA−4抗体、抗PD−L1抗体、およびIL−18について、種々の組み合わせとした治療薬を、CT−26細胞を移植した日の3日後に腹腔内に注射した。PECは、上記治療薬を腹腔内注射した日の4日後に回収した。回収した細胞のほとんどはリンパ球であった。当該リンパ球を洗浄し、2.5×107cells/mlの細胞密度となるようにPBS中に懸濁させ、細胞懸濁液を調製した。養子細胞移入のために、CT−26細胞を移植したマウスの腹腔内に対し、上記細胞懸濁液0.2ml(約5×106cells/マウス)を、移植した日の3日後,7日後,11日後に注射した。
PECの細胞表面マーカーおよび脾細胞の細胞表面マーカーの解析はフローサイトメトリーを用いて行った。細胞表面マーカーは、FITC標識抗CD4抗体(eBioscience製、クローンGK1.5)、APC標識抗CD8抗体(Biolegend製、クローン54−6.7)、ビオチン標識抗CD8抗体(eBioscience製、クローン53−6.7)、ビオチン標識抗CD11c抗体(Beckton Dickinson製、クローンHL3)、APC標識抗CD45R/B220抗体(Biolegend 製、クローンRA3−6B2)、PE標識抗CD49b抗体(Beckton Dickinson製、クローンDX5)を用いて染色した。フローサイトメトリーによる解析は、FACS Calibur flow cytometer(Beckton Dickinson Biosciences製)を用いて行った。
上記実験方法の(1)に記載したCT−26細胞について、細胞濃度5.0×104個/0.25mlの懸濁液を0.25ml、上記BALB/C野生型マウスの腹腔内に注射し、移植した。
上記〔実験方法〕の(1)に記載したCT−26細胞について、細胞濃度5.0×104個/0.25mlの懸濁液0.25mlを上記BALB/C野生型マウスの腹腔内に注射し、移植した。
実施例1で用いたのと同じ細胞濃度(5.0×104個/0.25ml)を有するCT−26細胞の懸濁液を0.25ml、上記BALB/C野生型マウスの腹腔内に注射し、移植した。
実施例1で用いたのと同じ細胞濃度(5.0×104個/0.25ml)を有するCT−26細胞の懸濁液を0.25ml、上記BALB/C野生型マウスの腹腔内に注射し、移植した。
図5は、CT−26細胞を移植した日から14日後に、抗CTLA−4抗体、抗PD−L1抗体およびIL−18を含有する癌治療薬等を投与した場合の効果を、マウスの生存率として示す図である。横軸および縦軸は図1と同じである。
実施例6では、抗CTLA−4抗体およびIL−18;抗PD−L1抗体およびIL−18;並びに、抗CTLA−4抗体、抗PD−L1抗体およびIL−18が、CT−26細胞を移植したマウスの腹腔滲出細胞(PEC)の数を増加させることができることを示す。
実施例1で用いたのと同じ細胞濃度(5.0×104個/0.25ml)を有するCT−26細胞の懸濁液を0.25ml、上記BALB/C野生型マウスの腹腔内に注射し、移植した。そして、上記〔実験方法〕の(3)に記載したように、CT−26細胞を移植した日の3日後に癌治療薬を腹腔内に注射した。癌治療薬としては、実施例6の図6の(c)について言及した箇所に記載した量のウサギIgG;抗CTLA−4抗体および抗PD−L1抗体;抗CTLA−4抗体、抗PD−L1抗体およびIL−18、を用いた。
本実施例では、実施例6で用いた治療薬のうち、抗PD−L1抗体のみ;IL−18のみ;抗PD−L1抗体およびIL−18;抗CTLA−4抗体および抗PD−L1抗体;抗CTLA−4抗体、抗PD−L1抗体およびIL−18、を実施例6と同様の方法でマウスに腹腔内投与することによって誘導された腹腔内滲出細胞がどのような形質の細胞であるのかを、フローサイトメトリーによって調べた。フローサイトメトリーに供した腹腔内滲出細胞としては、各治療薬あたり5匹のマウスを用い、上記治療薬を投与した日から4日後に回収した細胞を用いた。
本実施例では、抗CTLA−4抗体、抗PD−L1抗体およびIL−18を癌治療薬として投与した場合に、投与から長期間経過後も腹腔内に誘導されたNK細胞を維持できるか否かについて検討した。
本実施例では、本発明に係る癌治療薬を投与したマウスにおけるCD4陽性CD25陽性T細胞の数の変化について検討した。
本実施例では、NK細胞に対する抗体である抗アシアロGM1抗体を用い、本発明に係る癌治療薬の抗腫瘍効果にNK細胞が果たす役割について検討した。
本実施例では、抗アシアロGM1抗体を投与したマウスのPECをフローサイトメトリーによって解析し、NK細胞数の変化について検討した。
本実施例では、抗アシアロGM1抗体を投与したマウスのPECをフローサイトメトリーによって解析し、NK細胞に特異的な細胞表面マーカーの発現の変化について検討した。
本実施例では、抗アシアロGM1抗体を投与したマウスのPECをフローサイトメトリーによって解析し、CD4陽性CD25陽性T細胞の細胞数の変化について検討した。
本実施例では、腫瘍細胞を移植したマウスにおける腹水の貯留に対する、本発明に係る癌治療薬の効果を検討した。
実施例15では、本発明に係る癌治療薬を投与したマウスにおいて、強い自己免疫様の病変は見られず、体重の減少等も確認されなかったため、本発明に係る癌治療薬は副作用が軽減されたものであることが示唆された。そこで本実施例では、本発明に係る癌治療薬の副作用についてより詳細な検討を行った。具体的には、IL−18が上記癌治療薬の有効成分である抗体の副作用を憎悪させる可能性について検討した。
B16黒色腫細胞(メラノーマ)はがんの転移モデルとしてしばしば用いられる。本実施例では、B16黒色腫細胞(2×105個)をマウス(C57BL/6、日本SLC)の尾静脈から移入し、数週間後に肺にできる黒い小結節(ノデュール)の数を数えて転移の多少を測定した。
実施例に示したように、本発明に係る癌治療薬は、抗CTLA−4抗体、抗PD−L1抗体等の分子標的抗体と、IL−18とを併用することにより、癌腹膜播種モデルにおいて非常に優れた抗腫瘍効果を示すことが明らかとなった。この他、肺転移モデルや固形癌モデルにおいても同様に強い抗腫瘍効果を示した。これは、IL−18が分子標的抗体の治療効果を著しく高めることによると考えられる。
Claims (7)
- IL−18と、
抗PD−L1抗体、抗PD−1抗体、抗PD−L2抗体および抗CTLA−4抗体からなる群より選ばれる1以上の抗体と、を有効成分として併用することを特徴とする癌治療薬。 - IL−18と、
抗PD−L1抗体、抗PD−1抗体、抗PD−L2抗体および抗CTLA−4抗体からなる群より選ばれる1以上の抗体と、を有効成分として組み合わせたことを特徴とする癌治療薬。 - 上記癌治療薬は、IL−18と、上記抗体とが混合されておらず、別々に存在することを特徴とする請求項1または2に記載の癌治療薬。
- 上記癌治療薬は、IL−18と、上記抗体とが混合された組成物であることを特徴とする請求項1または2に記載の癌治療薬。
- 上記抗体が、抗PD−L1抗体および/または抗CTLA−4抗体であることを特徴とする請求項1から4のいずれか1項に記載の癌治療薬。
- IL−18の質量と、上記1以上の抗体の質量の合計との比が1:25〜1:200であることを特徴とする請求項1から5のいずれか1項に記載の癌治療薬。
- 上記癌治療薬が、胃癌、大腸癌、卵巣癌、骨肉腫、白血病およびメラノーマからなる群より選ばれる1以上の癌の治療薬であることを特徴とする請求項1から6のいずれか1項に記載の癌治療薬。
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US5680795A (en) | 1995-07-05 | 1997-10-28 | Norco Inc. | Mechanical drive assembly incorporating counter-spring biassed radially-adjustable rollers |
MXPA02001911A (es) | 1999-08-24 | 2003-07-21 | Medarex Inc | Anticuerpos ctla-4 humanos y sus usos. |
CA2412730C (en) | 2000-06-15 | 2011-08-16 | Smithkline Beecham Corporation | Method for preparing a physiologically active il-18 polypeptide |
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CA2602316A1 (en) * | 2005-03-23 | 2006-09-28 | Pfizer Products Inc. | Anti-ctla4 antibody and indolinone combination therapy for treatment of cancer |
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CA2647282A1 (en) | 2006-04-05 | 2007-10-11 | Pfizer Products Inc. | Ctla4 antibody combination therapy |
EP1878440A1 (en) | 2006-07-13 | 2008-01-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for increasing the efficiency of therapeutic antibodies using gamma delta cell activator compounds |
PE20090190A1 (es) | 2007-03-23 | 2009-03-22 | Smithkline Beecham Corp | Combinacion de anticuerpos anti-cd20 y polipeptidos de il-18 |
CN101641116A (zh) * | 2007-03-23 | 2010-02-03 | 史密丝克莱恩比彻姆公司 | 通过施用人il-18组合来治疗癌症的方法 |
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US20110159023A1 (en) | 2008-08-25 | 2011-06-30 | Solomon Langermann | Pd-1 antagonists and methods for treating infectious disease |
RS54233B1 (en) | 2008-08-25 | 2015-12-31 | Amplimmune Inc. | PD-1 ANTAGONIST COMPOSITIONS AND PROCEDURES FOR THEIR APPLICATION |
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PL2560658T3 (pl) | 2010-04-21 | 2017-08-31 | Ventirx Pharmaceuticals, Inc. | Wzmacnianie cytotoksyczności komórkowej zależnej od przeciwciał |
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