JP6769948B2 - 移植拒絶の予防及び自己免疫疾患の治療に使用するための単離されたインターロイキン−34ポリペプチド - Google Patents
移植拒絶の予防及び自己免疫疾患の治療に使用するための単離されたインターロイキン−34ポリペプチド Download PDFInfo
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Description
本発明は、免疫療法の分野にある。より具体的には、本発明は、移植拒絶、自己免疫疾患、遺伝子治療の過程で発現されるタンパク質及び/又は治療用タンパク質に対する望ましくない免疫応答(例えば、第VIII因子、抗体など)並びにアレルギーを予防又は治療するのに使用するための単離されたインターロイキン−34(IL−34)ポリペプチドに関する。
免疫寛容の誘導は、病理学的状態に関与する免疫応答をコントロールするための強力なツールである。サイトカイン、代謝経路をコントロールする酵素、及び寛容を誘導することができる細胞表面分子が記載されている。これらの知見にもかかわらず、同定されていない他の機構の証拠が存在するので、免疫寛容の新たなメディエーターを同定することが重要である。
本発明者らは、IL−34が免疫抑制を誘導し、初代T細胞応答を阻害し、T細胞寛容を誘導することを実証した。自己免疫、アレルギー、移植、治療用タンパク質による処置及び遺伝子治療の分野では、免疫系による自己又は治療分子/組織の分解を避けるために、このアプローチは関心対象である。
本発明は、それを必要とする患者における免疫寛容を誘導及び/又は維持するのに使用するための方法及び組成物(例えば、医薬組成物及びキットオブパーツ組成物)を提供する。
(i)(実施例のセクションに記載されているように)免疫寛容を(ラットでは少なくとも120日間)誘導及び/又は維持する能力;すなわち、混合リンパ球反応(MLR)におけるCD4+及びCD8+T細胞の増殖を阻害する能力;及び/又は
(ii)臓器同種移植モデル(心臓同種移植モデル)における移植拒絶を予防する能力
を意味する。
−改変及び/若しくは異常アミノ酸によるアミノ酸の置換(例えば、Nle、Nva若しくはOrnのような異常アミノ酸によるアミノ酸の置換);並びに/又は
−ペプチドのN末端及び/若しくはC末端の改変(例えば、N末端のアシル化(好ましくは、アセチル化)若しくは脱アミノ化、又はC末端カルボキシル基のアミド若しくはアルコール基への改変);
−2個のアミノ酸間のアミド結合の改変:2個のアミノ酸を連結するアミド結合の窒素原子若しくはアルファ炭素のアシル化(好ましくは、アセチル化)若しくはアルキル化(好ましくは、メチル化);
−2個のアミノ酸を連結するアミド結合のアルファ炭素における改変(例えば、2個のアミノ酸を連結するアミド結合のアルファ炭素のアシル化(好ましくは、アセチル化)又はアルキル化(好ましくは、メチル化));
−キラリティの変化(例えば、1個以上の天然に存在するアミノ酸(Lエナンチオマー)の対応するD−エナンチオマーによる置換);
−(C末端からN末端への)アミノ酸鎖のインバージョンと共に、1個以上の天然に存在するアミノ酸(L−エナンチオマー)が対応するD−エナンチオマーで置換されているレトロインバージョン;
−1個以上のアルファ炭素が窒素原子で置換されているアザペプチド;並びに/又は
−1個以上のアミノ酸のアミノ基がα炭素ではなくβ炭素に結合しているベータペプチド
が挙げられる。
本発明は、単離されたIL−34ポリペプチド又はそれをコードするポリヌクレオチド及び単離されたM−CSFポリペプチド又はそれをコードするポリヌクレオチドを含む医薬組成物に関する。
IL−34ポリペプチド及びM−CSFポリペプチドは、1つの製剤中で混合され、同時に投与され得る。したがって、本発明は、単離されたIL−34ポリペプチド又はそれをコードするポリヌクレオチド及びM−CSFポリペプチド又はそれをコードするポリヌクレオチドを含むキットオブパーツ組成物に関する。
さらなる態様では、本発明は、患者が移植拒絶、自己免疫疾患、治療用タンパク質に対する望ましくない免疫応答又はアレルギーのリスクがあるかを決定するためのin vitro方法であって、前記患者から得られた生物学的サンプルにおけるIL−34の発現レベルを決定する工程を含み、IL−34の存在が、移植拒絶、自己免疫疾患、治療用タンパク質に対する望ましくない免疫応答又はアレルギーのリスクの減少を示すin vitro方法に関する。
IL−34又はM−CSFの発現レベルの決定は、様々な技術によって実施され得る。一般に、決定される発現レベルは、相対的発現レベルである。
本発明はさらに、個別処置計画を開発するための方法を提供する。上記方法によって得られた情報を使用して、移植レシピエントのための個別処置計画を開発し得る。
材料及び方法
健常志願者の血液採取及びPBMCの分離:Etablissement Francais du Sang (Nantes, France)において、インフォームドコンセントを得た後に、健常ドナーから血液を採取した。血液をPBSで2倍希釈してから、Ficoll-Paque density-gradient centrifugation (Eurobio)によって、PBMCを制動せずに2000rpm、室温で30分間単離した。収集したPBMCを、PBS 50mLによって1800rpmで10分間洗浄した。
IL−34は、脾臓CD8+CD45RClowTreg及び寛容同種移植片によって発現された:脾臓由来のCD8+CD40Ig Treg対ナイーブCD8+CD45RClowTregのDNAマイクロアレイ分析により、CD8+CD40Ig Tregによる(最もアップレギュレーションされた遺伝子の中でも)IL−34のアップレギュレーションが強調された(変化倍率4.05)。qPCRによってこのアップレギュレーションを確認したところ、長期脾臓CD8+CD40Ig TregにおけるIL−34 mRNA発現は、ナイーブCD8+CD45RClowTregと比較して11倍超であった(p<0.05、図1A)。
これまで、IL−34の生物学的関連性はほとんどが依然として不明であり、論争中である。IL−34の役割に関する現在の理解は、主に病理学的状況の研究によるものであり、IL−34は、M−CSFなどの炎症機能を発揮することが見出された。様々な研究により、M−CSFの投与は、コラーゲン誘発性RAモデルにおける炎症を増加させること(26)、及びIL−34は、RAモデルにおける滑膜炎、炎症の重症度と相関し(13)、M−CSFと同様にTNFαによって誘導され得る(27)ことが示されている。さらに、IL−34及びM−CSFは両方とも、IL−6、IP10/CXCL10、IL−8/CXCL8、MCP1/CCL2のような炎症促進性サイトカインを誘導する(28)。これらの研究とは対照的に、M−CSF及びより最近ではIL−34は単独で、又は他のサイトカインと組み合わせて、調節性マクロファージを誘導し得ることも示されている(25、29〜32)。移植では、マウスのM−CSF前処理はマクロファージを増殖させ、GVHDを抑制することが実証されている(33)。加えて、M−CSF及びIFNγの組み合わせは、iNOS依存的に心臓同種移植片生存を延長することができる調節性マクロファージの中で単球を識別する(34)。これらの研究は、IL−34の矛盾した役割の基礎となっている。本発明者らの研究では、移植における寛容誘導の複雑な機構を解明するために、本発明者らは、免疫応答及び寛容のマスターレギュレーターとしてのIL−34の予想外の特性の証拠を初めて提供する。本発明者らはまた、IL−34が、寛容同種移植片及びCD8+CD45RClowTregによって発現され得、最も重要なことには、強力な調節性T細胞を誘導し得るという最初の証拠を提供する。
本出願を通して、本発明が関係する現状技術が様々な参考文献に記載されている。これらの参考文献の開示は、参照により本開示に組み込まれる。
Claims (15)
- 患者における免疫寛容を誘導するための、単離されたインターロイキン−34(IL−34)ポリペプチド又はそれをコードするポリヌクレオチドを含む、医薬組成物。
- 患者における移植拒絶を予防又は軽減するための、単離されたIL−34ポリペプチド又はそれをコードするポリヌクレオチドを含む、医薬組成物。
- 移植拒絶が心臓同種移植拒絶である、請求項2に記載の医薬組成物。
- 移植片対宿主病(GvHD)を予防又は軽減するための、単離されたIL−34ポリペプチド又はそれをコードするポリヌクレオチドを含む、医薬組成物。
- 患者における自己免疫疾患、治療用タンパク質に対する望ましくない免疫応答及びアレルギーを予防又は治療するための、単離されたIL−34ポリペプチド又はそれをコードするポリヌクレオチドを含む、医薬組成物。
- IL34ポリペプチドが、配列番号1を含み若しくは配列番号1からなる配列、又は配列番号1の配列と少なくとも90%同一の配列を有する、請求項1〜5のいずれか一項に記載の医薬組成物。
- IL−34ポリペプチドが、異種ポリペプチドに融合されている、請求項1〜6のいずれか一項に記載の医薬組成物。
- 異種ポリペプチドが、免疫グロブリン定常ドメインである、請求項7に記載の医薬組成物。
- 免疫抑制薬をさらに含む、請求項1〜8のいずれか一項に記載の医薬組成物、又は請求項1〜8のいずれか一項に記載の医薬組成物及び免疫抑制薬を含む、キット。
- 免疫抑制薬が、細胞増殖抑制剤;アルキル化剤(シクロホスファミド)及び代謝拮抗剤(アザチオプリン、メルカプトプリン及びメトトレキサート);治療用抗体;カルシニューリン阻害剤(シクロスポリン);グルココルチコイド及びミコフェノール酸モフェチルからなる群より選択される、請求項9に記載の医薬組成物又はキット。
- 免疫抑制薬がラパマイシン(シロリムス)である、請求項10に記載の医薬組成物又はキット。
- 移植拒絶、自己免疫疾患、治療用タンパク質に対する望ましくない免疫応答及びアレルギーを予防又は治療するための、請求項9〜11のいずれか一項に記載の医薬組成物又はキット。
- 患者が移植拒絶、自己免疫疾患、治療用タンパク質に対する望ましくない免疫応答又はアレルギーのリスクがあるかを決定するためのデータを提供するためのin vitro方法であって、前記患者から得られた生物学的サンプルにおけるIL−34の発現レベルを決定する工程を含み、IL−34の存在が、移植拒絶、自己免疫疾患、治療用タンパク質に対する望ましくない免疫応答又はアレルギーのリスクの減少を示す、in vitro方法。
- 前記生物学的サンプルにおけるIL−34の濃度を測定することによって、IL−34の発現レベルを決定する、請求項13に記載の方法。
- 生物学的サンプルが血液サンプル(血清又は血漿サンプル)である、請求項13又は14に記載の方法。
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