JP2012511528A - RNA免疫において免疫応答を強化するためのFlt3リガンドの使用 - Google Patents
RNA免疫において免疫応答を強化するためのFlt3リガンドの使用 Download PDFInfo
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Abstract
Description
3’−HO−NNNNNNN−P−−5’
2.負に荷電した残基およびそのアミド:Asn、Asp、Glu、Gln
3.正に荷電した残基:His、Arg、Lys
4.大きな非極性の脂肪族残基:Met、Leu、Ile、Val(Cys)
5.大きな芳香族残基:Phe、Tyr、Trp。
この実施例および以下の実施例で使用した組換えヒトFlt3リガンドは、IgG4との融合タンパク質として調製し、配列番号6の配列を有する。そのために、Flt3L−IgG4融合タンパク質をコードする核酸配列を発現ベクターにクローニングした。作成されたプラスミドをリポフェクションによりHEK293細胞(ATCC Nr. CRL−1573)にトランスフェクトした。上清を集め、プロテインAカラム(GE HiTrap MabSelect SuRe、GE Healthcare社)により製造元の記載に従って精製した。産物をPBSで透析し、等量に分け、使用するまで凍結した。
以下では、様々な公知のアジュバント(アルダラ、モノホスホリルリピッドA、GM−CSF、Poly I:C、IL2)およびFlt3−Lが、リンパ節内投与によるRNA免疫化後に、末梢血でのナイーブT細胞のプライミングおよびその頻度にどのように影響するかを調査した。このために、アジュバントを皮下投与または腹腔内投与し(詳細は図3のキャプションを参照)、3日おきに2度、H−2Kb拘束SIINFEKLエピトープをコードするRNAでマウスを免疫化した。2度目の免疫化から5日後に、エピトープ特異的CD8+T細胞の頻度を、血中のテトラマー測定により定量した。意外なことに、この分析により、Flt3−Lを除くすべてのアジュバントはT細胞プライミングの効率を低下させることが示された(図3)。ネイキッドIVT−RNAの投与の設定におけるアジュバントの使用に関しては、前述の研究のみがこれまで発表されており、その中では、RNA皮内注射後のGM−CSFの投与のみが、RNA注射に先立つ投与とは対照的にRNA単独注射と比べて利点をもたらすことが示された(Carralot, J.P. et al. (2004) Cell Mol. Life Sci. 61、2418〜2424頁(非特許文献52))。このデータは、GM−CSFがRNA免疫化前(−48時間、−24時間)に投与された、我々の実験と一致する。その上、我々のデータによりはじめて、既成のアジュバントは傾向的にT細胞プライミング効率を悪化させるのに対して、Flt3−Lは有意な上昇を誘導することが示される(図3)。最後の免疫化から7日目の末梢血を材料としたさらなるテトラマー分析は、似かよった結果を示す(データは示さない)。
さらなる実験では、ヒトFlt3−Lの投与が、リンパ節内投与によるRNA免疫化後に、別の器官(脾臓)においても抗原特異的機能性T細胞の頻度を有意に上昇させることを証明できた。このために、0日目と3日目に、それぞれ10μgのFlt3−LまたはヒトIgG4をマウスに腹腔内注射した。次いで、7日目と10日目に、SIINFEKLをコードするRNAを用いてリンパ節内免疫化を行なった。15日目に、テトラマー測定および細胞内サイトカイン測定により、エピトープ特異的CD8+T細胞の頻度を定量した(図4)。その際、テトラマー定量化により、Flt3−Lで前処理した群における、エピトープ特異的CD8+T細胞の頻度の有意な上昇が示された(脾臓:8.2%対2.5%)。機能レベルでは、これらの細胞はIFNγを分泌する能力ももつことが示された(図4)。さらなる調査は、2x10μg用量を超えるFlt3−Lの用量上昇が免疫応答の強化を伴わないことを示した(データは示さない)。
Balb/cマウス(n=5)に10μgのCy3蛍光標識されたRNAまたは純粋なCy3リボヌクレオチド(対照)をリンパ節内注入した。5分後および30分後にリンパ節標本を作成し、パラホルムアルデヒド固定後にクリオスタット切片を免疫蛍光顕微鏡で評価した。図5に示す典型的な切片は、対照リンパ節における最小限のバックグラウンド、および細胞のRNAシグナル(赤色)を示し、そのシグナルは5分から30分へと明瞭になる。これは、細胞間に存在するRNAの破壊に起因する。
いくつもの公知のアジュバントについてアジュバント作用の欠如という現象を詳細に調査した。
次に、マクロ飲作用のダウンレギュレーションを伴う、iDCの成熟が、RNAの取り込みをどの程度低下させるかを調査した。結果を図7に示す。
様々なFlt3Lがリンパ節の細胞組成に及ぼす影響
この実験では、マウスリンパ節の様々な細胞集団に及ぼす影響に関して、市販のFlt3調製物と共に、Flt3リガンド(Flt3−IgG4)を調査した。市販のFlt3調製物としては、細菌内で組換え発現された産物(Peprotech Flt3L、Peprotech社、Hamburg、Germany)、およびヒトHEK293細胞で発現された産物(Humanzyme Flt3L、Humanzyme社、Chicago IL、U.S.A)を使用した。対照としてはヒトIgG4(Sigma−Aldrich社、Deisenhofen、Germany)を使用した。
様々なFlt3LがナイーブT細胞の刺激に及ぼす影響
この実験では、Flt3L−IgG4のアジュバント機能が市販のFlt3L産物とどの程度同等であるかを調査した。このために選ばれたのは、細菌内で組換え発現された産物(Peprotech Flt3L)、およびヒトHEK293細胞で発現された産物(Humanzyme Flt3L)であった。例7を参照のこと。対照としてはヒトIgG4を使用した。
Flt3L−IgG4 の血清半減期の算定
Flt3L−IgG4の血清半減期を算定するために、Balb/cマウス(n=3)の2群に、20μgまたは50μgのFlt3L−IgG4を腹腔内投与した。定められた時点(投与前;3時間、24時間、48時間、3日、5日、7日、9日、14日、21日)にマウスの血清サンプルを保管した。ヒトIgGを定量するために、このサンプルをELISAアッセイで使用した。我々のコンストラクトではヒトIgG4 がFlt3Lに融合されているため、マウス血清中のヒトIgGを定量することでFlt3L濃度を算出することができる。データは、初期最大値に続き、Flt3Lが注入から5日後までマウス血清中に検出可能であることを示す。算出された半減期は、50μgのFlt3L−IgG4の場合40時間であり、20μgの半減期(HWZ)は51時間である。
B16 Ova腫瘍に対する治療上のワクチン接種
Flt3L投与とRNAワクチン接種との併用の相乗作用を調べるために、治療上の腫瘍実験を行なった。この目的で、C57BL/6マウスによる4群(n=10)を形成した。0日目に全マウスにB16 Ova腫瘍細胞(2x105)を皮下注射した(Bellone et al.、J. Immunol.、2000、165、2651〜2656頁(非特許文献54))。このうち一つの対照群はIgG4注射でのみ処理した(10μg;3日目、7日目、14日目、17日目)。第2の対照群にはFlt3L−IgG4注射のみ行なった(15μg;3日目、7日目、14日目、17日目)。最初の治療群は、SIINFEKLをコードするRNAのリンパ節内注入(20μg;11日目、14日目、17日目、24日目)とIgG4投与とを組み合わせて治療し、第2の治療群には、RNA免疫化に加えて、前記のようにFlt3L−IgG4を投与した。
B16 Ova腫瘍に対する治療上のワクチン接種
Flt3LとRNAワクチンの併用投与の相乗効果を証明するために、さらにもう一つの治療上の腫瘍実験を行なった。この目的で、C57BL/6マウスによる4群(n=10)を形成した。0日目に全マウスにB16 Ova腫瘍細胞(2x105)を皮下注射した(Bellone et al.、J. Immunol.、2000、165、2651〜2656頁(非特許文献54))。このうち一つの対照群はIgG4注射でのみ処理した(15μg;3日目、7日目、14日目、18日目)。第2の対照群にはFlt3L−IgG4注射のみ行なった(15μg;3日目、7日目、14日目、18日目)。最初の治療群は、SIINFEKLをコードするRNAのリンパ節内注入(20μg;10日目、14日目、18日目、21日目)とIgG4投与とを組み合わせて治療し、第2の治療群には、RNA免疫化に加えて、前記のようにFlt3L−IgG4(Flt3L)を投与した。腫瘍接種後の以下の日に腫瘍体積を求めた:d7、d10、d13、d16、d19およびd22(d=日)。
Claims (22)
- 少なくとも一つの抗原をコードするRNAとFlt3リガンドとを含む免疫原性調製物。
- RNAがmRNAである、請求項1に記載の免疫原性調製物。
- RNAがin vitro転写によって得られた、請求項1または2に記載の免疫原性調製物。
- 少なくとも一つのRNA安定化因子をさらに含む、請求項1〜3のいずれか一つに記載の免疫原性調製物。
- 請求項1〜4のいずれか一つに記載の免疫原性調製物を含む医薬組成物。
- 薬学的に許容可能な希釈剤および/または薬学的に許容可能な担体をさらに含む医薬組成物。
- ワクチンとしての製剤形態にある、請求項5または6に記載の医薬組成物。
- リンパ節内(intranodale)投与用の製剤形態にある、請求項1〜4のいずれか一つに記載の免疫原性調製物または請求項5〜7のいずれか一つに記載の医薬組成物。
- 細胞を、少なくとも一つの抗原をコードするRNAおよびFlt3リガンドと接触させることを含む、少なくとも一つの抗原を細胞に供給するための方法。
- 免疫応答を向けさせるべき少なくとも一つの抗原をコードするRNAを投与すること、およびFlt3リガンドを投与することを含む、個体において免疫応答を惹起または強化するための方法。
- 前記免疫応答が、個体に対して保護および/または治療作用を有する、請求項10に記載の方法。
- 前記免疫応答が抗原特異的なT細胞免疫応答を含む、請求項10または11に記載の方法。
- 抗原をコードするRNAを投与すること、およびFlt3リガンドを投与することを含む、個体中において抗原特異的エフェクター細胞の量を上昇させるための方法。
- 前記抗原特異的エフェクター細胞が、CD8+細胞傷害性T細胞、および/またはCD4+ヘルパーT細胞である、請求項13に記載の方法。
- 免疫応答を向けさせるべき腫瘍抗原をコードするRNAを投与すること、およびFlt3リガンドを投与することを含む、個体中でのがんを予防および/または治療するための方法。
- 免疫応答を向けさせるべきウイルス抗原をコードするRNAを投与すること、およびFlt3リガンドを投与することを含む、個体中でのウイルス感染を予防および/または治療するための方法。
- 免疫応答を向けさせるべき細菌性抗原をコードするRNAを投与すること、およびFlt3リガンドを投与することを含む、個体中での細菌感染を予防および/または治療するための方法。
- アレルギーに関連するアレルゲンをコードするRNAを投与すること、およびFlt3リガンドを投与することを含む、個体中でのアレルギーを予防および/または治療するための方法。
- 個体の細胞へのRNAの取り込みを促進するのに適した量でFlt3リガンドが投与される、請求項10〜18のいずれか一つに記載の方法。
- 個体がヒトである、請求項10〜19のいずれか一つに記載の方法。
- RNAとFlt3リガンドが互いに独立に、静脈内、筋内、皮下、経皮、鼻腔内、およびリンパ内投与からなる群から選択される一つの経路で投与される、請求項10〜20のいずれか一つに記載の方法。
- ワクチンRNAの免疫原性を高めるためのFlt3リガンドの使用。
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Application Number | Priority Date | Filing Date | Title |
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DE102008061522.6 | 2008-12-10 | ||
DE102008061522A DE102008061522A1 (de) | 2008-12-10 | 2008-12-10 | Verwendung von Flt3-Ligand zur Verstärkung von Immunreaktionen bei RNA-Immunisierung |
PCT/EP2009/008811 WO2010066418A1 (de) | 2008-12-10 | 2009-12-09 | Verwendung von flt3-ligand zur verstärkung von immunreaktionen bei rna-immunisierung |
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ES2407994T3 (es) | 2013-06-17 |
DE102008061522A1 (de) | 2010-06-17 |
EP2370101A1 (de) | 2011-10-05 |
AU2009326524B2 (en) | 2012-06-07 |
US9486519B2 (en) | 2016-11-08 |
AU2009326524A8 (en) | 2011-09-08 |
US20110311584A1 (en) | 2011-12-22 |
WO2010066418A8 (de) | 2010-08-12 |
EP2370101B1 (de) | 2013-03-27 |
CA2747180C (en) | 2015-02-03 |
EP2370101B8 (de) | 2013-05-01 |
AU2009326524A1 (en) | 2011-07-21 |
DK2370101T3 (da) | 2013-05-13 |
JP2015083585A (ja) | 2015-04-30 |
CA2747180A1 (en) | 2010-06-17 |
JP5931443B2 (ja) | 2016-06-08 |
WO2010066418A1 (de) | 2010-06-17 |
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