JPWO2019240218A1 - 免疫チェックポイント阻害療法を促進するための組成物 - Google Patents
免疫チェックポイント阻害療法を促進するための組成物 Download PDFInfo
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- JPWO2019240218A1 JPWO2019240218A1 JP2020525651A JP2020525651A JPWO2019240218A1 JP WO2019240218 A1 JPWO2019240218 A1 JP WO2019240218A1 JP 2020525651 A JP2020525651 A JP 2020525651A JP 2020525651 A JP2020525651 A JP 2020525651A JP WO2019240218 A1 JPWO2019240218 A1 JP WO2019240218A1
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Abstract
Description
[1] 乳酸菌の菌体外多糖を含む、免疫チェックポイント阻害療法を促進するための組成物。
[2] 免疫チェックポイント阻害療法が、CTLA-4(Cytotoxic T-lymphocyte-associated antigen 4)阻害療法、またはPD-1(Programmed Death-1)阻害療法である、1に記載の組成物。
[3] 乳酸菌が、ラクトバチルス属に分類されるものである、1または2に記載の組成物。
[4] 乳酸菌が、ラクトバチルス・デルブルッキー・サブスピーシーズ・ブルガリクスに分類されるものである、1〜3のいずれか1項に記載の組成物。
[5] 発酵乳である、1〜4のいずれか1項に記載の組成物。
[6] 乳酸菌の菌体外多糖を含む、CCR6陽性CD8+T細胞を増加させるための組成物。
[7] 免疫チェックポイント阻害療法を促進するための非医療的方法であって、有効量の乳酸菌の菌体外多糖を含む組成物を対象に摂取させる工程を含む、方法。
[8] 対象におけるCCR6陽性CD8+T細胞を増加させるための非医療的方法であって、有効量の乳酸菌の菌体外多糖を含む組成物を対象に摂取させる工程を含む、方法。
[9] 乳酸菌の菌体外多糖を用いる、CCR6陽性CD8+T細胞を増加させる方法(ヒトに対する医療行為を除く。)。
[10]乳酸菌の菌体外多糖、またはこれを含む組成物を対象に(経口)投与する(摂取させる)工程を含む、対象における免疫チェックポイント阻害療法を促進する方法。
[11]免疫チェックポイント阻害療法を促進するための組成物の製造における、乳酸菌の菌体外多糖の使用。
[12]免疫チェックポイント阻害療法を促進する方法において使用するための、乳酸菌の菌体外多糖、またはそれを含む組成物。
[13]乳酸菌の菌体外多糖、またはそれを含む組成物を対象に(経口)投与する(摂取させる)工程を含む、対象における免疫チェックポイント阻害療法を促進する非治療的方法。
[14]免疫チェックポイント阻害療法を促進するための、乳酸菌の菌体外多糖の使用。
[15]乳酸菌の菌体外多糖、またはこれを含む組成物を対象に(経口)投与する(摂取させる)工程を含む、対象においてCCR6陽性CD8+T細胞を増加させる方法。
[16]CCR6陽性CD8+T細胞を増加させるための組成物の製造における、乳酸菌の菌体外多糖の使用。
[17]CCR6陽性CD8+T細胞の増加方法において使用するための、乳酸菌の菌体外多糖、またはそれを含む組成物。
[18]乳酸菌の菌体外多糖、またはそれを含む組成物を対象に(経口)投与する(摂取させる)工程を含む、対象におけるCCR6陽性CD8+T細胞を増加させる非治療的方法。
[19]CCR6陽性CD8+T細胞を増加させるための、乳酸菌の菌体外多糖の使用。
[20]乳酸菌の菌体外多糖と医薬として許容可能な添加物を配合する工程を含む、免疫チェックポイント阻害療法の促進用、またはCCR6陽性CD8+T細胞の増加用の組成物の製造方法。
本発明は、乳酸菌の産生する菌体外多糖(EPS)を有効成分とする免疫チェックポイント阻害療法を促進するための組成物に関する。
本発明の組成物は、有効成分として乳酸菌のEPSを含む。
本発明の組成物は、免疫チェックポイント阻害療法を促進するために用いることができる。免疫チェックポイント阻害療法を促進するとは、免疫チェックポイント阻害療法と組み合わせて行われた場合に、免疫チェックポイント阻害療法による効果が早く得られるようにすること、免疫チェックポイント阻害療法による効果が高まるようにすること、免疫チェックポイント阻害療法の奏効率を高めること、より低用量の免疫チェックポイント阻害剤の投与で効果が得られるようにすること等をいう。免疫チェックポイント阻害療法による効果には、例えば、がん細胞を殺傷してがんを縮小させる(腫瘍体積を縮小する)、がんの成長を遅らせる(腫瘍体積の増加を抑制する)、がんを治癒させる、がんが転移・再発するのを防ぐ、転移しているかもしれないがん細胞を殺傷することが含まれる。
(食品組成物等)
本発明の組成物は、食品組成物または医薬組成物とすることができる。食品および医薬品は、特に記載した場合を除き、ヒトのためのもののみならず、ヒト以外の動物のためのものを含む。食品は、特に記載した場合を除き、一般食品、機能性食品、栄養組成物を含み、また治療食(治療の目的を果たすもの。医師が食事箋を出し、それに従い栄養士等が作成した献立に基づいて調理されたもの。)、食事療法食、成分調整食、介護食、治療支援用食品を含む。食品は、特に記載した場合を除き、固形物のみならず、液状のもの、例えば飲料、ドリンク剤、流動食、およびスープを含む。機能性食品とは、生体に所定の機能性を付与できる食品をいい、例えば、特定保健用食品(条件付きトクホ[特定保健用食品]を含む)、機能性表示食品、栄養機能食品を含む保健機能食品、特別用途食品、栄養補助食品、健康補助食品、サプリメント(例えば、錠剤、被覆錠、糖衣錠、カプセル、液剤等の各種の剤形のもの)、美容食品(例えば、ダイエット食品)等の、健康食品の全般を包含している。また、本発明において「機能性食品」とは、コーデックス(FAO/WHO合同食品規格委員会)の食品規格に基づく健康強調表示(Health claim)が適用される健康食品を包含している。
本発明の組成物は、免疫チェックポイント阻害療法を行っている対象、免疫チェックポイント阻害療法を行う予定の対象に、摂取させる・投与するのに適している。
本発明の組成物は、それを非経口的に、例えば経管的(胃瘻、腸瘻)に投与してもよいし、経鼻的に投与してもよいし、経口的に投与してもよいが、経口的に投与することが好ましい。
本発明の組成物における、乳酸菌のEPSの含有量は、目的の効果が発揮される量であればよい。組成物は、その被験体の年齢、体重、症状等の種々の要因を考慮して、その投与量または摂取量を適宜設定することができるが、一日量あたりの乳酸菌のEPSの量は、例えば0.1 mg以上とすることができ、0.6 mg以上とすることが好ましく、3 mg以上とすることがより好ましい。一日量あたりのEPSの量の上限値は、下限値がいずれの場合であっても、480 mg以下とすることができ、360 mg以下とすること好ましく、180 mg以下とすることがより好ましく、90 mg以下とすることが特に好ましい。
本発明の組成物は、食品または医薬品として許容可能な他の有効成分や栄養成分を含んでいてもよい。そのような成分の例は、アミノ酸類(例えば、リジン、アルギニン、グリシン、アラニン、グルタミン酸、ロイシン、イソロイシン、バリン)、糖質(グルコース、ショ糖、果糖、麦芽糖、トレハロース、エリスリトール、マルチトール、パラチノース、キシリトール、デキストリン)、電解質(例えば、ナトリウム、カリウム、カルシウム、マグネシウム)、ビタミン(例えば、ビタミンA、ビタミンB1、ビタミンB2、ビタミンB6、ビタミンB12、ビタミンC、ビタミンD、ビタミンE、ビタミンK、ビオチン、葉酸、パントテン酸およびニコチン酸類)、ミネラル(例えば、銅、亜鉛、鉄、コバルト、マンガン)、抗生物質、食物繊維、タンパク質、脂質等である。
本発明の医薬組成物は、経口投与に適した、錠剤、顆粒剤、散剤、丸剤、カプセル剤等の固形製剤、液剤、懸濁剤、シロップ剤等の液体製剤、ジェル剤、エアロゾル剤等の任意の剤形にすることができる。
本発明の組成物の製造において、乳酸菌のEPSの配合の段階は、適宜選択することができる。乳酸菌のEPSの特性を著しく損なわない限り配合の段階は特に制限されない。例えば、製造の初期の段階に、原材料に混合して配合することができる。あるいは、本発明の組成物を発酵乳として実施する場合は、EPSを産生する乳酸菌をスターターとして原料乳に添加し、発酵させ、EPSを産生させることで、EPSを含む発酵乳が製造できる。
実施例1においては、脱脂粉乳培地に、乳酸菌スターターとして、Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1およびStreptococcus thermophilusを添加して、脱脂粉乳培地を43℃の温度環境下、2.5時間発酵させて調製したヨーグルトを用いた。実施例2および3においては、10質量%脱脂粉乳培地でLactobacillus delbrueckii subsp. bulgaricus OLL1073R-1を培養した培養物中のEPSを精製した。すなわち、37℃で18時間培養した上記の培養物に対し、終濃度10質量%になるようトリクロロ酢酸を加えて変性タンパク質を除去し、冷エタノールを加えて4℃で2時間静置してEPSを含む沈殿物を得た。これを、透析膜(分画分子量6〜8kDa)を用いてMilliQ水に対して透析し、核酸とタンパク質を酵素分解した後、再度エタノール沈殿を行って沈殿物を得た。これをMilliQ水に溶解し、再度透析を行った後に凍結乾燥を行ってEPSを精製した。
BALB/cマウス、オス、7週齢(日本チャールスリバー)の計32匹を、controlマウス(n=16)とヨーグルト投与マウス(n=16)に群分けした。controlマウスには10%(w/v)脱脂粉乳を、ヨーグルト投与マウスにはヨーグルトを、それぞれ400 μL/匹強制経口投与した。経口投与は解剖前日まで毎日1回実施した。なお、400μLのヨーグルト中のEPS量は、HPLCによりコロナ荷電化粒子検出器で定量したところ28μgであった。
BALB/cマウス、オス、7週齢(日本チャールスリバー)の計24匹をcontrolマウス(n=12)とEPS投与マウス(n=12)に群分けした。controlマウスには蒸留水を、EPS投与マウスにはEPS水溶液(25μg/ml)をそれぞれ自由飲水させ(4-8mL/day程度の摂取をしていると認められた。)、解剖日まで継続した。
培養細胞株TG40(マウスT細胞由来)に、EPS(150ug/ml)を添加し、6時間共培養した。培地はRPMIに10質量パーセント濃度のウシ胎児血清(FBS)を加えて調整し、5×106細胞数/mlでプレートに播種して37℃、5%CO2濃度を保った。
Claims (9)
- 乳酸菌の菌体外多糖を含む、免疫チェックポイント阻害療法を促進するための組成物。
- 免疫チェックポイント阻害療法が、CTLA-4(Cytotoxic T-lymphocyte-associated antigen 4)阻害療法、またはPD-1(Programmed Death-1)阻害療法である、請求項1に記載の組成物。
- 乳酸菌が、ラクトバチルス属に分類されるものである、請求項1または2に記載の組成物。
- 乳酸菌が、ラクトバチルス・デルブルッキー・サブスピーシーズ・ブルガリクスに分類されるものである、請求項1〜3のいずれか1項に記載の組成物。
- 発酵乳である、請求項1〜4のいずれか1項に記載の組成物。
- 乳酸菌の菌体外多糖を含む、CCR6陽性CD8+T細胞を増加させるための組成物。
- 免疫チェックポイント阻害療法を促進するための非医療的方法であって、有効量の乳酸菌の菌体外多糖を含む組成物を対象に摂取させる工程を含む、方法。
- 対象におけるCCR6陽性CD8+T細胞を増加させるための非医療的方法であって、有効量の乳酸菌の菌体外多糖を含む組成物を対象に摂取させる工程を含む、方法。
- 乳酸菌の菌体外多糖を用いる、CCR6陽性CD8+T細胞を増加させる方法(ヒトに対する医療行為を除く。)。
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