JP5992920B2 - ワクチンとしての使用のためのガス入りの微小胞 - Google Patents
ワクチンとしての使用のためのガス入りの微小胞 Download PDFInfo
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- JP5992920B2 JP5992920B2 JP2013545357A JP2013545357A JP5992920B2 JP 5992920 B2 JP5992920 B2 JP 5992920B2 JP 2013545357 A JP2013545357 A JP 2013545357A JP 2013545357 A JP2013545357 A JP 2013545357A JP 5992920 B2 JP5992920 B2 JP 5992920B2
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Description
好ましい態様によれば、前記免疫調節の治療は、ワクチン接種を含む。
好ましい実施態様では、前記製剤は、前記微小胞を含む水性懸濁液である。
さらに好ましい実施態様によれば、前記抗原は、ワクチン抗原である。
好ましい実施態様によれば、前記安定化膜は、免疫調節アジュバントを含む。
[OVAのチオール化]
OVA(6mg−133nmoles)をPBE(リン酸緩衝液25mM、150mM生理食塩水、1mMEDTA、pH8)中に溶解して、20mg/mLでの溶液を得た。トラウト試薬の溶液(2mg/mL−14.5mM)をPBE中に調製して、この溶液の92μL(10当量)をOVA溶液に加えた。結果として生じた混合物を、室温で1時間、撹拌下でインキュベートした。この溶液を、PBE中で平衡化されたスピンカラム(Zeba spin column 2mL、Pierce、#89890)を用いて回転した。溶液の最終的な量は、約390μLであった。
チオールの酸化の可能性を制限するために、チオール化OVA溶液は、精製の直後に用いた。
DSPE−PEG−マレイミド(6.6mg−2.24μmoles)を、45℃で撹拌(ボルテックス)して、リン酸緩衝液100mM pH6(0.5mL)中に溶解して、透明な溶液を得た。
シクロオクタンへの溶解の前に8.1mgのMPLA(5%モル比)をDSPC/APの混合物中に加えたことを除き、実施例1に従って、マイクロバブルを調製した。
微小胞に共有結合された抗原を内部移行する、マウスCD11c+樹状細胞(DC)の能力を試験するために、Balb/cマウス由来の脾臓を収集して、抗−CD11c mAb/磁性粒子技術(Miltenyi Biotech)を用いた陽性選択に先立ち、単細胞懸濁液に処理した。濃縮されたCD11c+細胞をポリ−L−リジンでコーティングされたマイクロタイタープレートに2時間播き、そしてそれから、微小胞に共有結合された、Cy3色素で蛍光ラベルしたOVA、または抗原を有さない微小胞(実施例1のように調製された)とともに、37℃で3時間インキュベートした。細胞と微小胞の接触を促進するために、DCとのインキュベーション時間の間、マイクロタイタープレートは裏返した。実際に、ガス入りの微小胞は、沈降する代わりに、溶液中で一度、上方へ移動する。それから細胞を収集し、PBSで洗浄して、そしてそれからCy3:OVAに関連する蛍光を消光するために、PBS中で、Trypan blueとともにインキュベートした(DCの細胞表面で吸着され得る)。この方法では、細胞に関係する蛍光シグナルは、DCによって細胞内に取り込まれたOVAのもののみを反映した。それから、細胞を、CD3(PE*Cy7−結合)、MHCII(FITC−結合)およびCD11c(APC−結合)に対するmAbsで標識し、洗浄して、そしてフローサイトメトリーにより分析した。死細胞を除外するためにDAPIを用いた。DAPI−CD3−CD11c+MHCII+Cy3+細胞の割合を計算して、そして、DAPI−CD3−CD11c+MHCII+細胞でのCy3シグナルの平均蛍光強度(MFI)を、LSR II フローサイトメーター(BD Biosciences)を用いて測定した。
接着性マウスDC1940細胞株(25000細胞/ウェル)を、マイクロタイタープレート中に2時間播き、そしてそれから、PBS中に希釈された異なる製剤での、滴定濃度のOVAとともに、37℃で4時間インキュベートした:(a)OVA323−339ペプチド(対照ペプチド:樹状細胞の膜上に発現されたMHCクラスII分子に直接的に結合するOVAのフラグメント;ペプチド:MHCクラスII複合体は、内部移行およびプロセシングを必要とせずに、CD4 T細胞に提示される)、(b)OVA、(c)実施例1により調製されたマイクロバブルに共有結合したOVA、(d)ラテックスビーズに結合したOVA、または(e)両方の構成要素を10分間混合することにより、カチオン性微小胞(20% DSTAP)上に吸着されたOVA。微小胞を用いた場合、細胞と微小胞の接触を促進するために、DC1940細胞とのインキュベーションの期間の間、マイクロタイタープレートは裏返した。コインキュベーション期間後、細胞を収集して、PBSで洗浄して、顕微鏡下でノイバウエル・チャンバー(Neubauer chamber)を用いて計数して、そして、(25000細胞/ウェル)を、CD4 T細胞ハイブリドーマBO97.11(20000細胞/ウェル)とともに24時間、混合した。上清をピペッティングにより回収して、そして、T細胞活性化の指標である、IL−2産生を、酵素結合免疫吸着測定法(ELISA)により定量化した。
本発明の、抗原を含む微小胞の、インビボでのT細胞免疫応答を産生する能力と効率を、微小胞をBalb/cマウスに皮下注射することにより評価した。結果を、同程度の量の抗原分子単独およびアラムと組み合わせた注射と比較した。
実験設定は、実施例3で説明したものと同様であった。
本発明の、抗原を含む微小胞の、インビボの抗体免疫応答を産生する能力および効率を、微小胞をBalb/cマウスに皮下注射することにより評価した。結果を、同程度の量の抗原単独の注射、およびアラムアジュバントと混合した抗原の注射と、比較した。
本発明の、抗原を含む微小胞へのアジュバントの追加を、MPLAを含む微小胞をBalb/cマウスに皮下注射することにより評価した。結果を、MPLAを伴わずに抗原を含む微小胞の、同程度の量の注射と比較した。
8μgの抗原に対応する、OVAを含む製剤100μLを、2週間間隔で3回、マウス(実験グループあたり6)の尾の基部に皮下注射した。
さらに、MPLAを含む、または含まないOVA−微小胞に関する免疫応答のタイプは異なった:MPLAの存在下では、IgG1/IgG2a比が低かった。これは、Th1タイプの免疫応答への移行を示している。
本発明の、抗原を含む微小胞の、インビボでのT細胞とAbの免疫応答を産生する能力を、微小胞をC57BL/6マウスに皮下注射することにより、さらに評価した。結果を、Balb/cマウスでの、同程度の量の微小胞製剤の注射と比較した。
A)PLA2抗原の変性。
PLA2(1mg−54.05nmoles)を、尿素の変性溶液(PBE中で540.54g/L−9M)に溶解して、4mg/mLの溶液を得た。DTTの溶液(8mg/mL−51.86mM)を、尿素9M中に調製して、そして、この溶液の104μL(100当量)を、PLA2尿素溶液に加えた。結果として生じた混合物を、一晩(16時間)、室温で放置した。この溶液を、PBE中で平衡化されたスピンカラム(Zeba spin column 2mL、Pierce、#89890)を用いて回転した。溶液の最終的な量は、約350μLであった。
変性PLA2溶液は、精製の直後に用いた。
PLA2を含む微小胞を、実施例1に記載された方法論により調製した。
本発明の、抗原を含む微小胞の、インビボでのT細胞とAbの免疫応答を産生する能力を、実施例9により調製された微小胞をBalb/cマウスに皮下注射することにより評価した。
本発明の、抗原を含む微小胞の投与により誘導される免疫応答の、OVA発現リステリア菌での感染後の細菌負荷を減少させる能力を、C57BL/6マウスで評価した。
Claims (20)
- 安定化膜を有するガス入りの微小胞を含む医薬製剤であって、
前記微小胞が、前記膜の構成要素に共有結合した抗原を含み、
免疫調節の治療で使用するためのものであり、
前記治療が、超音波照射の不存在下で施されることを特徴とする、
医薬製剤。 - 請求項1に記載の製剤であって、
前記治療が、ワクチン接種を含むことを特徴とする、
製剤。 - 請求項2に記載の製剤であって、
前記抗原が、ワクチン抗原であることを特徴とする、
製剤。 - 請求項1から3のいずれか一項に記載の製剤であって、
前記治療が、寛容導入の治療を含むことを特徴とする、
製剤。 - 請求項1から3のいずれか一項に記載の製剤であって、
前記治療が、免疫賦活の治療を含むことを特徴とする、
製剤。 - 請求項1に記載の製剤であって、
前記構成要素が、リン脂質であることを特徴とする、
製剤。 - 請求項6に記載の製剤であって、
前記リン脂質が、ペグ化リン脂質であることを特徴とする、
製剤。 - 請求項1〜7のいずれか一項に記載の製剤であって、
前記抗原が、前記膜中に0.1%〜20%のモル量で存在することを特徴とする、
製剤。 - 請求項1〜8のいずれか一項に記載の製剤であって、
前記微小胞中に含まれる前記ガスが、フッ素化ガスを含むことを特徴とする、
製剤。 - 請求項9に記載の製剤であって、
前記ガスが、空気または窒素との混合物であることを特徴とする、
製剤。 - 請求項1〜10のいずれか一項に記載の製剤であって、
前記安定化膜が、少なくとも50重量%のリン脂質を含むことを特徴とする、
製剤。 - 請求項1〜11のいずれか一項に記載の製剤であって、
前記膜が、さらに免疫調節アジュバントを含むことを特徴とする、
製剤。 - 請求項12に記載の製剤であって、
前記アジュバントが、前記膜の0.1モル%〜50モル%に相当することを特徴とする、
製剤。 - 請求項1〜13のいずれか一項に記載の製剤であって、
前記抗原が、アレルギー性抗原、ウイルス性抗原、細菌性抗原、真菌性抗原、毒素由来抗原、寄生性抗原、自己抗原、腫瘍抗原またはそれらの混合であることを特徴とする、
製剤。 - 前記ガス入りの微小胞を含む水性懸濁液の形態にある、請求項1〜14のいずれか一項に記載の製剤。
- 生理的に許容できる水性担体中で再構成可能な乾燥粉末物質の形態にある、請求項1〜14のいずれか一項に記載の製剤。
- 免疫調節の治療で使用するための医薬の製造における、安定化膜を有するガス入りの微小胞の、水性懸濁液の使用であって、
前記微小胞が、前記膜の構成要素に共有結合した抗原を含み、
前記治療が、超音波照射の不存在下で施されることを特徴とする、
使用。 - 請求項17に記載の使用であって、
前記微小胞が、抗原提示細胞による効果的な取り込みをもたらすことを特徴とする、
使用。 - 免疫調節の治療においてそれぞれの抗原提示細胞による抗原の取り込みを増加させるための医薬の製造における抗原の使用であって、
前記抗原は、ガス入りの微小胞に共有結合しており、
前記治療が、超音波照射の不存在下で施されることを特徴とする、
使用。 - 請求項19に記載の使用であって、
前記抗原提示細胞が樹状細胞であることを特徴とする、
使用。
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WO2018225785A1 (ja) * | 2017-06-06 | 2018-12-13 | 株式会社Atomis | ワクチン組成物 |
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US5556610A (en) | 1992-01-24 | 1996-09-17 | Bracco Research S.A. | Gas mixtures useful as ultrasound contrast media, contrast agents containing the media and method |
US5445813A (en) | 1992-11-02 | 1995-08-29 | Bracco International B.V. | Stable microbubble suspensions as enhancement agents for ultrasound echography |
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CN103269717B (zh) | 2016-08-03 |
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EP2654788A1 (en) | 2013-10-30 |
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