JP6162167B2 - 胸腺産出の増大およびリンパ球減少症の治療のためのil−15の使用 - Google Patents
胸腺産出の増大およびリンパ球減少症の治療のためのil−15の使用 Download PDFInfo
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Description
本出願は、2009年8月14日出願の米国仮出願第61/234,152号;および2009年8月14日出願の米国仮出願第61/234,155号に恩典を主張する。各出願は参照により、本明細書に組み入れられる。
本発明は、インビトロもしくはインビボにおいてインターロイキン(IL)-15を胸腺組織に接触させることによりT細胞の成熟および胸腺からの例えば末梢リンパおよび非リンパ組織への搬出を促進するための組成物および方法を提供する。
AIDSおよび癌の免疫療法の両方のために、2つの一般的なγ鎖サイトカインであるIL-2およびIL-7が現在認可もしくは検討されている。Sportes, et al., (2008) J Exp Med 205:1701-1714;Levy, Y. (2009) J Clin Invest. 119(4):997-100785;およびRosenberg, et al., (2006) J Immunother 29:313-319を参照。γ鎖サイトカインであるIL-15については、臨床経験は存在しない。Cheever, (2008) Immunological Reviews 222:357-368を参照。
「中枢リンパ組織」もしくは「中枢リンパ器官」という用語は、新しいリンパ球の産生もしくはリンパ球新生が起こる特殊なリンパ組織を指す。例えば、T細胞は胸腺もしくは胸腺組織において発生および成熟する。B細胞およびナチュラルキラー(NK)細胞は骨髄組織において発生する。例えば、Janeway, et al., Immunobiology, 2001, Garland Publishing, New Yorkの第7章を参照。
1) アラニン(A)、グリシン(G);
2) アスパラギン酸(D)、グルタミン酸(E);
3) アスパラギン(N)、グルタミン(Q);
4) アルギニン(R)、リシン(K);
5) イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V);
6) フェニルアラニン(F)、チロシン(Y)、トリプトファン(W);
7) セリン(S)、スレオニン(T);および
8) システイン(C)、メチオニン(M)(例えば、Creighton, Proteins (1984)を参照)。
[本発明1001]
IL-15を胸腺組織に接触させることを含む、胸腺組織におけるT細胞の成熟を促進する方法。
[本発明1002]
胸腺組織がインビボである、本発明1001の方法。
[本発明1003]
IL-15が全身的に投与される、本発明1002の方法。
[本発明1004]
IL-15が局所的に投与される、本発明1002の方法。
[本発明1005]
胸腺組織がインビトロである、本発明1001の方法。
[本発明1006]
IL-15Rαと一緒にヘテロ二量体としてIL-15が送達される、本発明1001の方法。
[本発明1007]
IL-15Rαが膜貫通アンカー部分を欠き、Fc領域と融合している可溶性のIL-15Rαである、本発明1006の方法。
[本発明1008]
IL-15がポリペプチドとして送達される、本発明1001の方法。
[本発明1009]
IL-15をコードするポリヌクレオチドからIL-15が発現される、本発明1001の方法。
[本発明1010]
単一のベクターからIL-15RαをコードするポリヌクレオチドとIL-15が同時に発現される、本発明1009の方法。
[本発明1011]
別々のベクターからIL-15RαをコードするポリヌクレオチドとIL-15が同時に発現される、本発明1009の方法。
[本発明1012]
IL-15が天然のシグナルペプチドを有する、本発明1001の方法。
[本発明1013]
IL-15が異種のシグナルペプチドを有する、本発明1001の方法。
[本発明1014]
対象にIL-15を投与することを含む、必要としている対象において中枢リンパ組織から1つ以上の末梢組織へのリンパ球の遊走を促進する方法。
[本発明1015]
中枢リンパ組織が胸腺である、本発明1014の方法。
[本発明1016]
リンパ球がT細胞である、本発明1014の方法。
[本発明1017]
末梢組織が末梢リンパ組織である、本発明1014の方法。
[本発明1018]
末梢組織が非リンパ組織である、本発明1014の方法。
[本発明1019]
IL-15が全身的に投与される、本発明1014の方法。
[本発明1020]
IL-15が局所的に投与される、本発明1014の方法。
[本発明1021]
IL-15Rαと一緒にヘテロ二量体としてIL-15が送達される、本発明1014の方法。
[本発明1022]
IL-15Rαが膜貫通アンカー部分を欠き、Fc領域と融合している可溶性のIL-15-Rαである、本発明1014の方法。
[本発明1023]
IL-15がポリペプチドとして送達される、本発明1014の方法。
[本発明1024]
IL-15をコードするポリヌクレオチドからIL-15が発現される、本発明1014の方法。
[本発明1025]
単一のベクターからIL-15RαをコードするポリヌクレオチドとIL-15が同時に発現される、本発明1024の方法。
[本発明1026]
別々のベクターからIL-15RαをコードするポリヌクレオチドとIL-15が同時に発現される、本発明1024の方法。
[本発明1027]
IL-15が天然のシグナルペプチドを有する、本発明1014の方法。
[本発明1028]
IL-15が異種のシグナルペプチドを有する、本発明1014の方法。
[本発明1029]
IL-15を個体に全身的に投与することを含む、必要としている個体において、リンパ球減少症を予防または減少させる方法。
[本発明1030]
IL-15Rαと一緒にヘテロ二量体としてIL-15が送達される、本発明1029の方法。
[本発明1031]
IL-15Rαが膜貫通アンカー部分を欠き、Fc領域と融合している可溶性のIL-15-Rαである、本発明1030の方法。
[本発明1032]
IL-15がポリペプチドとして送達される、本発明1029の方法。
[本発明1033]
IL-15をコードするポリヌクレオチドからIL-15が発現される、本発明1029の方法。
[本発明1034]
単一のベクターからIL-15RαをコードするポリヌクレオチドとIL-15が同時に発現される、本発明1033の方法。
[本発明1035]
別々のベクターからIL-15RαをコードするポリヌクレオチドとIL-15が同時に発現される、本発明1033の方法。
[本発明1036]
IL-15が天然のシグナルペプチドを有する、本発明1029の方法。
[本発明1037]
IL-15が異種のシグナルペプチドを有する、本発明1029の方法。
[本発明1038]
リンパ球減少症が薬物性のリンパ球減少症である、本発明1029の方法。
[本発明1039]
個体がリンパ球減少症を誘導する抗癌薬を受けている、本発明1029の方法。
[本発明1040]
IL-15が抗癌剤と一緒に同時に投与される、本発明1039の方法。
[本発明1041]
IL-15を個体に全身的に投与することを含む、必要としている個体において、末梢組織におけるリンパ球の再増殖を促進する方法。
[本発明1042]
IL-15Rαと一緒にヘテロ二量体としてIL-15が送達される、本発明1041の方法。
[本発明1043]
IL-15がポリペプチドとして送達される、本発明1041の方法。
[本発明1044]
IL-15をコードするポリヌクレオチドからIL-15が発現される、本発明1041の方法。
[本発明1045]
単一のベクターからIL-15RαをコードするポリヌクレオチドとIL-15が同時に発現される、本発明1044の方法。
[本発明1046]
別々のベクターからIL-15RαをコードするポリヌクレオチドとIL-15が同時に発現される、本発明1044の方法。
[本発明1047]
IL-15が天然のシグナルペプチドを有する、本発明1041の方法。
[本発明1048]
IL-15が異種のシグナルペプチドを有する、本発明1041の方法。
[本発明1049]
末梢組織が末梢リンパ組織である、本発明1041の方法。
[本発明1050]
末梢組織が非リンパ組織である、本発明1041の方法。
1.序論
本発明は、胸腺組織を超生理学的なレベルのIL-15に供することで胸腺においてダブルポジティブCD4+CD8+T細胞からシングルポジティブ(すなわち、CD4+もしくはCD8+)CD3high T細胞へのT細胞の成熟が促進され、アポトーシスの胸腺細胞の発生頻度が減少し、ならびに胸腺からリンパおよび非リンパ末梢組織を含む末梢組織への成熟T細胞の遊走が増大するという驚くべき発見に部分的に基づく。
本発明は、超生理学的なレベルのIL-15を胸腺組織に接触させることにより、胸腺におけるT細胞の成熟を促進し、胸腺におけるT細胞のアポトーシスを減少させ、および胸腺からのT細胞の遊走もしくは産出を促進する方法を提供する。胸腺組織はインビボもしくはインビトロであり得る。
上記に説明したように、一つの局面において、本発明は超生理学的なレベルのIL-15を全身的に投与することでリンパ球の成熟および中枢リンパ組織(例えば、胸腺および骨髄中)からリンパおよび非リンパ末梢組織を含む末梢組織への搬出が促進されるという発見に基づく。
本発明において使用するためのIL-15は、任意の生理学的に活性な(すなわち、機能性の)IL-15であり得る。IL-15はポリペプチドもしくはIL-15をコードするポリヌクレオチドとして送達され得る。IL-15は全長もしくはその生理学的に活性な断片、例えばIL-15Rαおよび/またはIL-15Rβへの結合を保持するIL-15断片、またはT細胞の増殖および/または成熟を促進するIL-15断片であり得る。ある態様において、送達もしくは発現されるIL-15ポリペプチドは、IL-15の生理学的活性を保持したままで、1つ以上のアミノ酸が置換、付加、もしくは欠失している。ある態様において、送達もしくは発現されるIL-15は野生型のIL-15、例えば配列番号:2と少なくとも90%、93%、95%、97%、98%、99%、もしくは100%のアミノ酸配列同一性を共有する。ある態様において、IL-15をコードするポリヌクレオチドは野生型のIL-15コード配列、例えば配列番号:1と少なくとも90%、93%、95%、97%、98%、99%、もしくは100%の核酸配列同一性を共有する。
IL-15の生物学をさらに理解するために、正常もしくはIL-15ノックアウト(KO)マウスのいずれかにおいて、IL-15/IL-15Rα DNAを様々なレベルで全身的および局所的に発現させた。Bergamaschi, et al., (2008) J Biol Chem 283:4189-4199を参照。正常マウスにおける超生理学的なレベルのIL-15/IL-15Rαは、多数の組織において迅速で深遠な効果を有する。脾臓の大きさは迅速かつ可逆的に増大するのに対して、胸腺はより小さくなり、骨髄リンパ球の数は減少する(図2)。我々は以前に、脾臓およびリンパ節の大きさの増大は血漿中のIL-15の量に比例することを示している。Bergamaschi, et al., (2008) J Biol Chem 283:4189-4199を参照。10パラメーターフローサイトメトリー、ならびに細胞の養子移入およびインビボ標識を用いて、多数の組織におけるリンパ球の動態および組成を研究した。我々の結果は、多数の研究者らによっても示唆されるように、リンパ球の発生の全段階におけるIL-15の強い効果を強調する。例えば、Boyman, et al., (2007) Curr Opin Immunol 19:320-326;Sprent, et al., (2008) Immunol Cell Biol 86:312-319;Sprent and Surh, (2003) Immunol Lett 85:145-149;Surh, et al., (2006) Immunol Rev 211:154-163;Surh and Sprent, (2005) Semin Immunol 17:183-191;およびSurh and Sprent, (2008) Immunity 29:848-862に概説されている。しかしながら、本発明より前には、胸腺におけるIL-15の効果は解明されていなかった。我々の結果は、CD4+CD8+ダブルポジティブ胸腺細胞からCD3highシングルポジティブT細胞への成熟をIL-15が刺激し(図3)、それらの末梢への迅速な遊走を加速することを示している(図4)。胸腺細胞のインサイチュー標識の7日間後に、IL-15/IL-15Rαはそれらの肺への遊走を促進した。IL-15/IL-15Rαの存在下で、肺のリンパ球は高レベルのIL-2/IL-15Rα(CD122、図4、下部を参照)を有しており、それらが活性化されていることを示している。これらの結果は、IL-15が胸腺からの加速された退出だけでなく、これらのリンパ球の末梢組織への遊走および活性化も促進するという概念と一致している。
要約
本実施例は、IL-15の全身的な投与による、正常な幼若マウスにおけるシクロフォスファミド誘導性リンパ球減少症の回復を示す。シクロフォスファミドの2日間後(もしくは2日間および12日間後)に、水圧DNA注入によって高用量のIL-15を1回もしくは2回投与した。その結果は、IL-15を受けなかったシクロフォスファミド誘導性リンパ球減少症の対照マウスと比較して、IL-15投与後はマウスがリンパ球減少症からより速く回復することを示している。IL-15投与後には、末梢組織においてリンパ球がより速く回復した。最初に回復したのはNK細胞であったのに対して、T細胞は約1カ月間のうちに回復した。これらの研究の過程において、我々はIL-15を2回投与することで、IL-15の単回投与よりもT細胞の回復が改善されることを発見した。加えて、低く持続的なレベルのIL-15によって、1回の高用量と比較して、末梢組織へのリンパ球のより効率的な再増殖が提供される。これらの結果により、IL-15がリンパ球減少症を治療および/または予防するのに有用であることが明らかにされる。
シクロフォスファミド投与
6から8週齢の雌Balb/cマウスをチャールズリバー研究所(Frederick, MD)から得た。パイロジェンを含まない生理食塩水にシクロフォスファミド(Sigma)を溶解し、体重の200mg/kgの投与量で腹腔内(i.p.)に注入した。−4日目および−2日目にシクロフォスファミドを用いた2回の処理を実行した。
0日目に、シクロフォスファミド処理マウスに対して、対照ベクターもしくはIL-15およびIL-15Rα発現プラスミドのいずれかの水圧注入を実行した。対照として、シクロフォスファミド未処理マウスに対して空のベクターDNAも投与した。手短に言うと、1.6mlの滅菌0.9% NaCl中の0.2μgから2μgのDNAを、27.5ゲージ針を用いて7秒間以内に尾静脈を通してマウスに注入した。Qiagen EndoFree Gigaキット(Qiagen, Hilden)を用いて、エンドトキシンを含まない高純度のDNAプラスミドを産生した。
DNA注入後の異なる時点(2〜26日目)にマウスを屠殺し、解析のために血清、骨髄、胸腺、脾臓、肝臓、および肺を採取した。
−4日目および−2日目にシクロフォスファミドの2回の注入を行って、リンパ枯渇マウスを生成した。0日目(および、何匹かのマウスについてはさらに10日目)に、IL-15/15Rα DNA発現ベクターを尾静脈に注入し、発表されているように(Bergamaschi, et al., J Biol Chem. (2008) 283(7):4189-99)、全身的な高レベルの生物活性IL-15/15Rαを生成した。シクロフォスファミド処理動物において、陰性対照としての非産生性DNA(ベクターBV)の注入と、IL-15/15Rα DNAの注入後の生物学的効果を比較した。
IL-15/15Rα投与の効果を評価するために、我々は異なる組織におけるリンパ球の数およびサブセットも解析した。これらの実験は、IL-15/15Rα DNAを(0日目および10日目に)1回もしくは2回投与した後に実行した。
マウスは−4日目および−2日目に処理され、0日目にDNAを注入された。2群のマウスはBV陰性対照DNAもしくはIL-15/IL-15Rα DNAのいずれかを注入された。IL-15/IL-15Rαで処理された動物は、すべての時点について、より高いNK数の傾向を有していた。14日目に、空ベクターを受けている群を2×IL-15/IL-15Rα投与(0日目および10日目にDNA注入)の群と比較したところ、IL-15/15Rαは肺のNK細胞の回復を有意に増大させることが示された(p=0.03)。
NK細胞とは対照的に、肺のT細胞は同じように早くは回復しない。マウスは上記のように処理および解析された。肺のT細胞は、最初のDNA注入後の14日目に数え上げられた。0日目および10日目の2回のIL-15/Rαの投与後の14日目に、Cypで処理された動物と比較して全T細胞が増大することが見出された。図9を参照。
我々は、脾臓において2回のIL-15/15Rαの注入後にT細胞がより速く回復することも見出した(p=0.0357)。肺における結果と同様に、2回のIL-15/15Rα(0日目および10日目)によってCypの後に脾臓のリンパ球を増大させることができた(p=0.03)。図12を参照。
(0日目および10日目に2μgのDNAを2回注入することによって達成された)持続的な高レベルのIL-15によって、最初のDNA注入後の14日目までに骨髄においてT細胞の回復がもたらされた(図13)。IL-15はCD4およびCD8区画の両方に影響を及ぼした。2回のIL-15/15Rαの投与による処理は、Cypで処理された動物と比較して、14日目に高レベルの骨髄のT細胞をもたらした。
様々な形態のIL-15のリンパ球減少症に対する治療効果を解析するために、本実施例でもBlack6マウスを利用した。これらの実験では、2つの異なるマウスの系統であるBALB/cおよびBlack6を使用した。IL-15/IL-15Rαで処理すると、両系統は加速されたリンパ球の再構成を示した。
6〜8週齢の雌のBalb/cもしくはBlack6マウスを、体重の200mg/kgの投与量のシクロフォスファミド(CYP、図14)を用いて腹腔内で処理した。−4日目および−2日目に2回のCYPの注入を実行した。0日目および5日目に、対照DNAもしくはIL-15/IL-15sRα可溶性分子を発現するDNAのいずれかの水圧注入を実行した。対照として、CYP未処理マウスに対照ベクターも送達した。異なる時点においてマウスを屠殺した:CYP誘導性リンパ除去を評価するために−1日目、ならびに外来性IL-15の存在下もしくは非存在下における免疫再構成を追跡するために5、10、17、および24日目。異なる組織(脾臓、胸腺、骨髄、肺、および肝臓)を摘出し、異なるリンパ球サブセットの存在について解析した。細胞を蛍光標識抗体で染色した後にフローサイトメトリーによって解析を実行した。
これらの実施例では、リンパ球減少症を治療するIL-15の治療的送達のために3つの好ましいDNAベクターの組合せが評価される:
1 配列番号:13および配列番号:14等のIL-15および本質的に全長のIL-15Rαを発現する好ましくは最適化された発現プラスミドを用いて、同じ細胞中に同時に送達。
2 配列番号:15等のIL-15および可溶性(s)IL-15Rαを発現する好ましくは最適化された発現プラスミドを用いて、同じ細胞中に同時に送達。
3 配列番号:16および配列番号:19等のIL-15および免疫グロブリン分子の定常領域(Fc)とのIL-15Rα融合物を発現する好ましくは最適化された発現プラスミドを用いて、同じ細胞中に同時に送達。Fc融合タンパク質の構築は、当技術分野において公知である。そのような構築物は、IL-15およびIL15Rα-Fc融合ヘテロ二量体がインビボにおいて活性であることを示すために、マウスのインビボ実験で使用されてきた。
IL-15を提供する代わりの方法として、精製タンパク質の送達を使用できる。IL-15/IL-15Rα複合体を過剰産生する細胞株からのタンパク質の精製が達成されている。DNAと同様に、適当な効果を得るために、異なる形態のヘテロ二量体を単独もしくは組み合わせて使用できる:
1 配列番号:10および配列番号:12等の、精製されたIL-15/可溶性(s)IL-15Rαの送達。
2 精製されたIL-15/IL-15RαFc融合タンパク質の送達(配列番号:17および配列番号:20等の、免疫グロブリン分子の定常領域との融合物)。
Claims (18)
- ヒト対象の末梢組織におけるリンパ球の枯渇の予防、減少もしくは阻害、および/または枯渇したリンパ球の再増殖の促進に使用するための、可溶型のIL-15Rαに結合したIL-15を含むIL-15/可溶性IL-15Rαヘテロ二量体を含む、薬学的組成物であって、IL-15Rα-Fc融合タンパク質に結合したIL-15を含むIL-15/IL-15Rα-Fcヘテロ二量体を含む第二の薬学的組成物と組み合わせて用いられる、薬学的組成物。
- 前記薬学的組成物が、第二の薬学的組成物の投与と同時にまたは連続して、対象に投与されるものである、請求項1記載の薬学的組成物。
- IL-15Rα-Fc融合タンパク質が、配列番号:20のアミノ酸31から431を含む、請求項1または2記載の薬学的組成物。
- 可溶型のIL-15Rαが、天然のIL-15Rαのアミノ酸31〜205または31〜185を含む、請求項1〜3のいずれか一項記載の薬学的組成物。
- IL-15/可溶性IL-15Rαヘテロ二量体およびIL-15/IL-15Rα-Fcヘテロ二量体が、ポリペプチドとして送達される、請求項1〜4のいずれか一項記載の薬学的組成物。
- IL-15/可溶性IL-15Rαヘテロ二量体およびIL-15/IL-15Rα-Fcヘテロ二量体が、ポリヌクレオチドとして送達される、請求項1〜4のいずれか一項記載の薬学的組成物。
- IL-15/可溶性IL-15Rαヘテロ二量体のIL-15および可溶性IL-15Rαが、単一のベクターから同時に発現される、請求項6記載の薬学的組成物。
- 可溶性IL-15Rαをコードするポリヌクレオチドが、配列番号:11の核酸配列を含む、請求項7記載の薬学的組成物。
- 単一のベクターが、配列番号:13、配列番号:14または配列番号:15の核酸配列を含む、請求項7記載の薬学的組成物。
- IL-15/IL-15Rα-Fcヘテロ二量体のIL-15およびIL-15Rα-Fc融合タンパク質が、単一のベクターから同時に発現される、請求項6から9のいずれか一項記載の薬学的組成物。
- 単一のベクターが、配列番号:16または配列番号:19の核酸配列を含む、請求項10記載の薬学的組成物。
- IL-15/可溶性IL-15Rαヘテロ二量体のIL-15および可溶性IL-15Rαが、別々のベクターから同時に発現される、請求項6記載の薬学的組成物。
- IL-15/IL-15Rα-Fcヘテロ二量体のIL-15およびIL-15Rα-Fc融合タンパク質が、別々のベクターから同時に発現される、請求項6または12記載の薬学的組成物。
- IL-15/可溶性IL-15Rαヘテロ二量体のIL-15をコードする核酸および/またはIL-15/IL-15Rα-Fcヘテロ二量体のIL-15をコードする核酸が、異種のタンパク質からのシグナルペプチドをコードする、請求項6記載の薬学的組成物。
- 異種のタンパク質が、組織プラスミノーゲン活性化因子(tPA)、成長ホルモン、顆粒球マクロファージコロニー刺激因子(GM-CSF)、または免疫グロブリンである、請求項14記載の薬学的組成物。
- IL-15をコードする核酸が、配列番号:18のポリペプチドをコードする核酸配列を含む、請求項15記載の薬学的組成物。
- 対象が癌を患っている、請求項1から16のいずれか一項記載の薬学的組成物。
- 対象がリンパ球減少症を有している、請求項1から17のいずれか一項記載の薬学的組成物。
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |