JP6861246B2 - 膜stim1を用いた化合物のスクリーニング方法 - Google Patents
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- JP6861246B2 JP6861246B2 JP2019131275A JP2019131275A JP6861246B2 JP 6861246 B2 JP6861246 B2 JP 6861246B2 JP 2019131275 A JP2019131275 A JP 2019131275A JP 2019131275 A JP2019131275 A JP 2019131275A JP 6861246 B2 JP6861246 B2 JP 6861246B2
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Description
全身性エリテマトーデス(systemic lupus erythematosus:SLE)および慢性リンパ性白血病(chronic lymphocytic leukaemia:CLL)は、依然として治療不能である。
細胞のアポトーシス(死)を招く。しかし、これらの治療により、望ましくない影響にさらされる恐れがある。
本発明は、カルシウムチャンネルの活性化および調整に関与するタンパク質であるSTIM1タンパク質の、細胞膜に局在化された画分をSLEおよびCLLの治療標的として使用することによってこれらのニーズに応えることを可能にする。
(1)STIM1タンパク質の発現全体の増加および細胞膜に局在化されたSTIM1
の画分の誘発。これらは、対照群のB細胞では低いままであるか、またはゼロのままでありさえする
(2)安静時に細胞膜に局在化されたSTIM1の画分を有するSLEのB細胞、特に未成熟/遷移段階におけるSLEのB細胞における、Erk1/2キナーゼ(細胞外シグナル制御キナーゼ)のリン酸化を伴うMAPK経路(マイトジェン活性化タンパク質キナーゼ)の活性化
(3)細胞外Ca2+の構成的侵入の増加
(4)細胞の一般的活性化、自己反応性B細胞の生存、およびしたがって自己免疫プロセスを説明し得るSTIM1の発現の増加と細胞外Ca2+の構成的侵入とMAPK ERK1/2経路の活性化の妨害との間の相関関係。
(x1)Bregの不十分な制御活性は、SLEのB細胞におけるSTIM1分子の発現の増加に関係している
(x2)阻止抗体によって特異的に引き起こされるか、またはSLEのB細胞におけるsiRNAを標的とするSTIM1によって非特異的に引き起こされる、細胞膜に局在化されたSTIM1分子の阻止は、(i)SLEのBregによるIL−10の生成、(ii)T細胞の増殖の抑制、および(iii)制御性T細胞の誘発を回復させる。細胞膜に局在化されたSTIM1の阻止は、健常対照群には影響を及ぼさない。
(a)細胞質内カルシウムのベースラインレベルの増加は、CLLのB細胞の生存の増加、MAPK Erk1/2経路の活性化、転写因子NFAT2(活性化T細胞の核因子)およびSTAT3(シグナル伝達性転写因子3)の核転座、ならびにIL−10の合成に関連付けられた([5])
(b)細胞外Ca2+の構成的侵入の増加は、細胞膜に局在化されたSTIM1タンパク質の増加によって調整された
(c)膜にSTIM1タンパク質が存在すること(グループI)またはそれが欠如していること(グループII)は、2つの患者群を区別することを可能にした
(d)細胞膜に存在するSTIM1分子に対して向けられる抗STIM1抗体は、グループIのCLLのB細胞への細胞外Ca2+の構成的侵入を大幅に減少させることができ、グループIIのCLLのB細胞への細胞外Ca2+の構成的侵入をより弱く減少させることができた
(e)細胞膜に局在化されたSTIM1タンパク質の画分を特異的に標的とする抗STIM1抗体と抗CD20抗体(リツキシマブ:RTX)との組み合わせは、グループI患者(細胞膜にSTIM1タンパク質が存在する)のB細胞においてRTXによって誘発されるアポトーシス効果を回復させることができた。抗STIM1抗体の添加は、グループII患者(膜にSTIM1タンパク質が欠如している)の抗CD20のアポトーシス効果には影響を及ぼさない。
制、(ii)このタンパク質の膜アドレッシングの抑制、および(iii)細胞膜に存在するSTIM1タンパク質の生物活性の抑制に関する。
胞外Ca2+の構成的侵入を調節する分子を厳密にスクリーニングするために、無傷である。有利に、本発明のスクリーニング方法において使用される細胞は、細胞膜に局在化されたSTIM1タンパク質の画分との特異な相互作用のために細胞に貫入せずに細胞膜にとどまる分子を選択するために、無傷である。言い換えれば、スクリーニング方法は、非浸透性の分子、すなわち細胞膜を横断しない分子の選択を可能にする。細胞は、分離された細胞であり、試料の形態で本発明のスクリーニング方法に提供され得る。
(a)分離された完全細胞の細胞膜に局在化されたSTIM1タンパク質の画分を細胞の表面で発現させる細胞を含む試料を提供するステップと、
(b)細胞を候補分子と相互作用させることによって候補分子をスクリーニングするステップと、
(c)細胞に貫入することなく、細胞の細胞膜に局在化されたSTIM1タンパク質の画分を結合する候補分子を選択するステップとを備え、
それによって、慢性リンパ性白血病および/または全身性エリテマトーデスの治療に有用な物質を特定する。
さらに、本発明の医薬組成物は、抗CD20抗体、または、タンパク質OraiおよびTRPCなどのSTIM1タンパク質に関連付けられるカルシウムチャンネルを調整するタンパク質複合体に関連付けられるその他の分子であってもよい。この場合、本発明の医薬組成物は、ヒトまたは動物の治療において公知の任意の抗CD20、例えばIDEC−C2B8抗体(ヨーロッパのホフマン・ラ・ロシュ社によって販売されているリツキシマブ)、Drugbank DB00073(BIOD00014、BTD00014)、オファツムマブ(アーゼラ社、グラクソ・スミスクライン社)、トシツモマブ(GSK社、DB00081、BIOD00085、BTD00085)、オビヌツズマブ(Gazyva、ロシュ社、DB08935、GA101)、イブリツモマブ(チウキセタン、I
DECファーマシューティカルズ社、DB00078、BIOD00069、BTD00069)、ウブリツキシマブ(LFB)またはAME−133v(リリー社、LY2469298)、であってもよいが、このリストは限定的なものではない。
Tリンパ球(ノイラミニダーゼで事前処理されたヒツジの赤血球を用いたロゼット技術)および単球(陰性欠失(negative depletion)技術、CD43なしのB細胞キット、ステム・セル・テクノロジーズ社)を除去した後に、で取得された末梢血単核細胞(peripheral blood mononuclear cells:PBMC)から開始して、Bリンパ球を精製した。CD19陽性B細胞の純度をフローサイトメトリによって確認し、95%を上回る純度を示した。
細胞膜に局在化されたSTIM1画分を調節する分子のスクリーニングは、細胞膜においてSTIM1タンパク質を発現させるヒトB細胞株JOKの第1の近似物(approximation)に対して実行される。2種類の細胞、すなわち空ベクタで安定的にトランスフェクトされたJOK細胞(JOK PLP)またはCD5タンパク質を安定的にトランスフェクトされたJOK細胞、が使用される([6])。これらの細胞は、測定可能な構成的カルシウム侵入を示す。スクリーニングは、細胞外カルシウムの構成的侵入に対する細胞の細胞膜に局在化されたSTIM1の画分を標的とする分子の効果を測定することで構成される。蓄えの放出に依存するカルシウム侵入SOCE(容量依存的なカルシウム流入)に対するこれらの分子の効果も、構成的カルシウム侵入に対して作用する分子の流入SOCEに対する分子の効果を判断するために評価される。これらの2つのカルシウム流動の振幅は、蛍光プローブ(Calcium6、モレキュラーデバイス社)を用いて細胞内カルシウム濃度の変化をモニタリングすることによって測定される。細胞は、45分間にわたってウェル当たり100000個の細胞の割合でCellTak(BDバイオサイエンス社)で処理された96個のウェルプレートに付着するようにされる。次いで、細胞は、F
lexstationタイプのマルチウェルプレートリーダ(モレキュラーデバイス社)を用いて細胞内カルシウム濃度の変化を測定する前に、60分間にわたって蛍光プローブ(Calcium6、モレキュラーデバイス社)の存在下で培養によってこのプローブを搭載する。細胞は、細胞に蛍光プローブを搭載させた時に、および細胞内カルシウム濃度の変化の測定の間中ずっと、テスト化合物と接触させられる。
図3A:10μg/mlで使用される抗STIM1抗体(クローンGok/44、BDバイオサイエンス社)は、CLLのB細胞の生存を減少させることができ、mSTIM1+グループ(細胞膜にSTIM1タンパク質が存在する)のCLLでは増加させた。この実験では、48時間にわたって細胞を培養し、次いで生細胞(アネキシンV/ヨウ化プロピジウム標識化(ベックマン・コールター社)なし)のパーセンテージを判断した。
細胞の能力を回復させる。
Claims (4)
- 細胞の細胞膜に局在化されたSTIM1タンパク質の画分と相互作用する物質を含む、慢性リンパ性白血病および/または全身性エリテマトーデスの治療のための医薬組成物であって、前記物質が、配列番号3の配列の前記STIM1タンパク質の断片に対して向けられる抗体である、組成物。
- 前記物質が、前記細胞に侵入しない物質である、請求項1に記載の医薬組成物。
- 抗CD20抗体をさらに含む、請求項1または2に記載の医薬組成物。
- 前記抗CD20抗体が、リツキシマブ抗体である、請求項3に記載の医薬組成物。
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