JP7163189B2 - インターロイキン10の抗炎症効果を亢進するための方法および組成物 - Google Patents
インターロイキン10の抗炎症効果を亢進するための方法および組成物 Download PDFInfo
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Description
別段の定義のない限り、本願明細書中で使用されるすべての技術および科学用語は、本発明が属する分野の当業者により一般に理解されるのと同じ意味を有する。本願明細書中で言及されるすべての刊行物、公開された特許出願および特許は、ここに記述された発明との関係で使用され得る装置、動物モデル、製剤および方法論を記載し、開示する目的のために、その全体として援用される。
本願明細書中で使用される「慢性疼痛」は、特別なタイプの傷害または疾患の過程に関連する自然治癒の時間的経過よりも長く持続する疼痛を指す。
用語「関節」は、骨を互いに接続するじん帯、筋肉を骨に取り付ける腱、関節包、滑液嚢および滑膜を含む、2つの骨が接触する解剖学的構造を指す。本願明細書の方法で処置され得る関節には、固定式、ヒンジ式、ピボット式またはボール・ソケット式関節が含まれる。
「作動可能に連結された」は、そのように記述される構成要素が、それらの通常の機能を発揮するように構成されている、エレメントの配置を指す。よって、コード配列に作動可能に連結された調節配列は、コード配列の発現をもたらすことができる。調節配列は、それらがその発現を導くように機能する限り、コード配列と隣接する必要はない。よって、例えば、転写された非翻訳介在配列が、プロモーター配列とコード配列の間に存在することができ、プロモーター配列はなおコード配列に「作動可能に連結されている」と考えられ得る。
本願明細書中で使用される用語「治療用組成物」または「治療用抗炎症組成物」は、炎症性サイトカインの濃度および/または炎症反応を減少させる能力を有する、IL-10/IL-10R1発現ベクター組成物を指す。本発明の治療用組成物は、公知の動物モデルのいずれかにおいて測定されたときまたはヒトにおいて実行された評価により、例えば、MS、慢性疼痛、関節の炎症、神経炎症および自己免疫疾患を処置することにおいて有用である。
本発明は、インターロイキン10(IL-10)コード配列および1型インターロイキン10受容体(IL-10R1)コード配列を発現するベクターを対象に投与することにより、炎症に関連する疾患および状態を処置するための方法を提供する。好ましい実施形態では、IL-10およびIL-10R1ペプチドは、単一の発現ベクターから発現されるが;代替的実施形態では、IL-10およびIL-10R1のコード配列は、異なる発現ベクターから発現される。一部の実施形態では、IL-10/IL-10R1発現ベクターは、例えば、(例えば、慢性疼痛、神経炎症、MSもしくは自己免疫疾患を処置するために)髄腔内投与を介して、または(関節の炎症を処置するために)関節内注射により対象に投与される。なお他の実施形態では、IL-10/IL-10R1発現ベクターは、細胞治療を介して対象に投与され;すなわち、対象から採取された抗原提示細胞を含む、抗原提示細胞を形質転換または形質導入するために、IL-10/IL-10R1発現ベクターが最初に使用され、次いで、抗原提示細胞が対象に投与される。本発明の方法は、炎症および慢性疼痛、MS、自己免疫疾患、神経炎症および関節の炎症を含むが、それに限定されない任意の疾患または状態に関連する炎症により引き起こされた生理学的損傷を処置するために使用され得る。
本発明の方法の一部の実施形態で使用されるIL-10/IL-10R1発現ベクターは、細菌骨格(プラスミドDNA)またはウイルス骨格;IL-10コード配列;IL-10R1コード配列;任意選択で、IL-10コード配列および/またはIL-10R1コード配列の5’(上流)、3’(下流)もしくはその両方の、少なくとも1つの核ターゲティング配列;内部リボソーム進入部位(IRES)もしくは自己切断型ペプチド;ならびに少なくとも1つのプロモーターおよび1つまたは複数の他のDNA調節配列を含む。IL-10およびIL-10R1ペプチドが単一のベクターから発現される実施形態が好ましく、本願明細書中で詳述される実施形態であるが、IL-10ペプチドおよびIL-10R1ペプチドが別個のベクター上にコードされ、直接対象に、もしくは次いで対象に送達されるレシピエント抗原提示細胞に同時送達され得ることは理解されるべきである。任意選択で、IL-10/IL-10R1発現ベクターは、IL-10/IL-10R1発現ベクターの調製中に、またはレシピエント抗原提示細胞への送達後に形質転換細胞の選択を可能とするために、1つまたは複数のマーカー配列も含む。
IL-10/IL-10R1発現ベクターは、in vivoまたは(ex vivoとも呼ばれる)in vitroのいずれかで対象に導入され得る。in vivoの導入は、IL-10/IL-10R1発現ベクターを対象に直接投与することを含み、in-vitroの導入は、IL-10およびIL-10R1を同時発現するように工学的に操作されている抗原提示細胞を対象に投与することを含む。
本発明の組成物および治療用抗炎症組成物は、IL-10の下方制御を克服して、ロバストなIL-10介在性の炎症抑制を達成するため、したがって、これらは多くの疾患および状態を処置することにおいて有効である。例えば、本発明の方法および治療用抗炎症組成物は、多発性硬化症(MS)により引き起こされた症状および損傷を処置するために使用され得る。MSは、中枢神経系の慢性の、衰弱させることの多い自己免疫疾患である。この疾患は、世界的におよそ250~300万人を苦しめ、米国では約400,000人、毎週200人が診断されている。発症時、約85%の患者が再発寛解型疾患(RRMS)、10%が一次進行型疾患(PPMS)、および5%が進行性再発型疾患(PRMS)を表す。通常、完全な神経学的回復がRRMSの最初のエピソード後に起こるが、これらの患者の約50%は、10年間にわたりその後の再発で持続性の神経障害がだんだん蓄積し、疾患の二次進行期に転換し、だんだんに身体障害性となる。MSの臨床症状は患者それぞれでばらつきが大きい。症状のリストは、認知障害、機能、失明、虚弱、痙縮、協調不全、不均衡、倦怠感、性的、腸および膀胱機能不全、知覚異常および疼痛を含む。臨床的に顕著な疼痛は、65%もの患者においてその疾患の経過にわたって経験され、最も身体障害性のものの一つであり、認識不足であって不適切に処置されることの多い症状である。通常、疼痛は神経障害性であり、関与する損傷されたニューロンに依存して性質が変わる。疼痛が、現行の治療法によって十分に処置されない、顕著なMS症状であることにも注意すべきである。
以下の例は、本発明を作製し、使用する方法の完全な開示および説明を当業者に提供するように提示され、発明者らがその発明であると考えるものの範囲を制限することも意図されず、また以下の実験が実施された実験のすべてであるか唯一のものであるかを表すかまたは暗示するものでもない。広く記載された本発明の精神または範囲から離れることのない特定の実施形態に示されるように、多数の変形および/または改変が本発明に対して行われ得ることが当業者に理解されるであろう。したがって、本実施形態は、すべての点において例示的であり、限定的でないと考えられるべきである。
発現ベクター
XT-250は、ラットIL-10 cDNAを含有する発現プラスミドであり、単にrIL-10がラットIL-10R1受容体と、ヒトIL-10(hIL-10)よりもかなりよく係合するために、これらの研究において使用される。そのhIL-10対応物、XT-150のように、XT-250は、D-マンノース中のDNAの溶液である。種にかかわらず、使用されたIL-10 cDNAのすべては、疼痛モデルにおいて顕著に長い効果の持続時間を生じさせることが見出された(ミリガンら(Milligan et al.)Pain 126(l-3):294-308(2006))アミノ酸変化F129Sを生じさせる点突然変異を含有する。プラスミド骨格は、カナマイシン耐性遺伝子、CMVプロモーター、β-グロビンイントロン、成長ホルモンポリAおよび2つのAAV2 ITRを含有する。このプラスミドは、AAV9ベクターを作製するためにも使用された。
裏付けデータ
IL-10が、種特異性に関していくつかの独自性を表示することは注意されるべきである。例えば、ヒトIL-10はマウスIL-10受容体に結合し、ヒトIL-10はラットIL-10受容体と弱く結合するにもかかわらず、マウスIL-10は、ヒトIL-10受容体と相互作用しない。この理由から、ラットIL-10(rIL-10)は一般にラット実験において使用され、ヒトIL-10(hIL-10)はマウス、イヌおよびウマの研究において使用されてきた。hIL-10が高濃度においてのみ、ラットIL-10受容体を活性化するという事実は、非常に有用な特徴であり、それは、標的ラット組織におけるヒトIL-10R1の同時発現は、ヒトIL-10に対する完全な応答をもたらすからである。送達を単純化するために、rIL-10、hIL-10またはhIL-10R1をコードするアデノ随伴ウイルスが構築された。髄腔内に注射されたときに非常によく分布し、自身がIL-10R1を発現する星状細胞のような抗原提示細胞を含む、広く多様な細胞に形質導入することから、血清型9を選択した。図1に示される通り、AAV9-hIL-10は、神経障害性疼痛のラット慢性絞扼傷害(CCI)モデルにおいて抗アロジニア性であるが、効果は徐々に消えていく。しかしながら、IL-10およびIL-10R1の併せた発現がずっと高い髄腔内投薬を許容して、脊髄および白質路の至る所で炎症の広範な抑制を推進するという仮説と一致して、AAV9-hIL-10およびAAV9-hIL-10R1の1:1混合物は、このモデルにおけるアロジニアの安定した排除を指示する(図2)。白丸=AAV9-hIL-10R1;黒丸=AAV9-hIL-10+XR-101;黒四角=AAV9-hIL-10Ra+AAV9-hIL-10。
運動障害を評価するためのIL-10/IL-10R1発現ベクターによる処置
軽度の再発寛解型MS様病態を誘発するためにMOGを用いて処置されたラットが、尾麻痺のような症状が目に見えるときにこのモデルにおいて有効であることが先に示された(スローンら(Sloane et al.)2009))IL-10プラスミドの用量を髄腔内に注射された。IL-10プラスミドに加えて、ラットの別のコホートが、その中のIL-10 cDNAが、LV02と名付けられたIL-10/IL-10R1カセットで置き換えられている、ほとんど同一のプラスミドの等量を投薬される。この30日間の実験の目標は、より高用量においてLV02がXT-250(IL-10発現のみ)よりもうまく働くかを確証することである。低いプラスミド用量(3μg)では、2つの製剤間でわずかな相違が予想される。しかしながら、XT-250効力の損失が見られる高用量(約100μg)では、LV02の持続した効力が予想される。
脊髄上位病変の低減を評価するためのIL-10/IL-10R1発現ベクターを用いる処置
運動障害に関する有効性が維持されるが、脊髄上位病変が顕著に低減され(H&E)、脱髄が減少される(Luxol Fast Blue)、LV02の投与が達成される、投与量決定実験が行われる。LV02、XT-250またはPBSが、実施例3で実行した実験において有効であることが見出された最高用量でEAEラット(一群あたりN=5)に髄腔内に注射される。この実験の存命期(in-life phase)は、動物が0のスコア(正常)に戻るとき、通常は2週間未満で終わる。CSFの試料が未処置の動物、LV02投与時で灌流/固定の直前の同じ動物から取得される。動物がPBS、続いてPBS/4%パラホルムアルデヒドを用いて灌流される。脊髄および脳が、薄片作製の前に抗凍結剤(PBS中、30%スクロース)に移される。病変およびリンパ球浸潤を識別するために、脊髄(縦方向)および脳(冠状断)の切片(40ミクロン)がヘマトキシリン-エオシン(H&E)を用いて染色される。脱髄域を識別するために、隣接切片が、Luxol Blueを用いて染色される。切片は、ヒトIL-10R1(Millipore #06-1067)、Iba1(ミクログリア)、GFAP(星状細胞)、およびNeuN(ニューロン)についても染色される。MHC-II抗体を用いる同時染色は、抗原提示細胞の活性化を識別する。各レベルの脊髄(腰部、胸部、頸部)において、H&Eにより識別された縦方向切片中の病変がカウントされる。同様に、脳幹、小脳、後頭葉皮質および前頭皮質からの切片が、H&Eにより、病変の存在について点数化される。PBS対照に比較して、脊髄中のXT-250およびLV02両方において有意な(独立t-検定)病変の低減が予想される。脳幹および皮質白質路においてLV02がXT-250よりもうまく機能する場合、切片あたりの病変に有意な相違が検出されるはずである。
体内分布を評価するための、IL-10/IL-10R1発現ベクターを用いる処置
様々な用量のLV02において脳全体のプラスミドDNAの体内分布が評価される。この実験は、プラスミドが白質路および脊髄全体で経時的にどのように分布するかを理解するためにデザインされる。LV02の実行可能な最高用量(300μg)が、未処置マウスのL4/5を介して髄腔内に注射される(1つの時点あたりN=3)。注射の4時間、7および30日後に、脊髄(腰部、胸部、頸部)、脳幹、後頭葉皮質および前頭皮質から組織が単離される。これらの組織からDNAが抽出され、定量的PCRに供される。この実験は、脳全体にLV02がどのように分布するか、およびそれが長期にわたって持続するかを明らかにする。
統計解析
運動障害スコアおよび免疫組織化学的分析データのすべての統計比較が、統計ソフトウエアを用いて計算された。運動障害スコアは、Wilcoxonのノンパラメトリック順位和検定により分析した。反復測定ANOVA統計は、実験全体を通して試験した各時点でグループ効果を調べた。免疫組織化学マーカーが、両側t-検定統計により分析される。
ダウン症候群モデルマウスにおける神経炎症の検出
別の例において(図4)、マウスIL-10F129Sをコードする発現プラスミドの、正常マウスおよびダウン症候群を模倣するように工学的に操作されたマウス(dp16)への注射が、発明者の実験室および公表された知見(例えば、ディングら(Ding,et al.)J Immunol 167(12):6884-6892(2001)を参照されたい)の両方からの他のデータの裏付けとして、IL-10の過剰発現が劇的にIL-10R1mRNAの発現を低減したことを示した。図2は、IL-10(IL-10R1)のシグナル伝達受容体のためのmRNAのレベルを示す。注射なしの対照に比較して、pDNA-IL10処置は、野生型およびダウン症候群マウスの脳の両方において劇的にIL-10R1の遺伝子発現を抑制した。
Claims (34)
- 対象における炎症を処置するための治療用組成物であって、
インターロイキン10(IL-10)ペプチドおよび1型インターロイキン10受容体(IL-10R1)ペプチドのコード配列を含む1つまたは複数の細菌、ウイルス、ファージ、コスミドまたは人工染色体ベクターを含み、
対象における抗原提示細胞中で、前記1つまたは複数のベクターから、インターロイキン10(IL-10)ペプチドおよび1型インターロイキン10受容体(IL-10R1)ペプチドが発現され、
前記1つまたは複数のベクターが、前記IL-10および/またはIL-10R1のコード配列に作動可能に連結された少なくとも1つの構成的プロモーターを含み、
前記少なくとも1つの構成的プロモーターが、前記IL-10およびIL-10R1のコード配列の転写を推進する、組成物。 - 前記組成物が、IL-10シグナル伝達の下方制御を克服する、請求項1に記載の組成物。
- 前記組成物が、抗原提示(IL-10R2陽性)細胞における構成的オートクリンシグナル伝達を達成する、請求項1に記載の組成物。
- 前記ベクターが、
細菌骨格またはウイルス骨格;
任意選択で、IL-10コード配列および/またはIL-10R1コード配列の5’(上流)、3’(下流)もしくはその両方の、少なくとも1つの核ターゲティング配列;
内部リボソーム進入部位(IRES)もしくは自己切断型ペプチド;ならびに
プロモーター配列、ポリアデニル化シグナル、転写終結配列、上流制御ドメイン、複製起点、および内部リボソーム進入部位から選択される1つまたは複数の他の調節配列
を含む、請求項1に記載の組成物。 - 前記ベクターが、プラスミド骨格、カナマイシン耐性遺伝子、CMVプロモーター、β-グロビンイントロン、成長ホルモンポリA、および2つのAAV2 ITRをさらに含む、請求項1に記載の組成物。
- 前記抗原提示細胞中で発現された前記IL-10ペプチドが、前記IL-10ペプチドのヒンジ領域中に突然変異を含む、請求項1および4~5のいずれか一項に記載の組成物。
- 前記IL-10ペプチドが、IL-10野生型配列の129位のフェニルアラニンがセリン、スレオニン、アラニンまたはシステインで置き換えられている突然変異を含む、請求項6に記載の組成物。
- 前記野生型配列の129位のフェニルアラニンがセリンで置き換えられている、請求項7に記載の組成物。
- 前記IL-10およびIL-10R1が単一のベクターから発現される、請求項1に記載の組成物。
- 前記ベクターがウイルスベクターである、請求項9に記載の組成物。
- 前記ウイルスベクターがアデノ随伴ウイルスベクターである、請求項10に記載の組成物。
- 前記ウイルスベクターがレンチウイルスベクターである、請求項10に記載の組成物。
- 前記IL-10およびIL-10R1のコード配列が、単一のmRNAとして転写される、請求項9に記載の組成物。
- 前記ベクターが、前記IL-10および前記IL-10R1のコード配列の間に内部リボソーム進入部位のコード配列をさらに含む、請求項13に記載の組成物。
- 前記ベクターが、前記IL-10およびIL-10R1のコード配列の間に自己切断型2aペプチドのコード配列をさらに含む、請求項13に記載の組成物。
- 前記炎症が神経障害性または慢性疼痛により引き起こされ、前記1つまたは複数のベクターが髄腔内注射により送達される、請求項1に記載の組成物。
- 前記炎症が多発性硬化症(MS)により引き起こされ、前記1つまたは複数のベクターが髄腔内注射により送達される、請求項1に記載の組成物。
- 前記炎症が自己免疫疾患により引き起こされ、前記1つまたは複数のベクターが髄腔内注射により送達される、請求項1に記載の組成物。
- 前記炎症が関節内に位置し、前記1つまたは複数のベクターが関節内注射により送達される、請求項1に記載の組成物。
- 前記炎症が神経炎症である、請求項1に記載の組成物。
- 前記抗原提示細胞が、単芽球、単球、星状細胞、オリゴデンドロサイト、ミクログリア、マクロファージ、B細胞、樹状細胞、泡沫細胞、リンパ芽球およびBリンパ球からなる群から選択される、請求項1に記載の組成物。
- 前記抗原提示細胞が、処置される対象から除去され、in vitroで前記1つまたは複数のベクターを用いて形質導入され、前記対象に投与して戻される、請求項1または21に記載の組成物。
- 前記抗原提示細胞が、前記1つまたは複数のベクターを用いて安定に形質転換され、培養中に維持される、請求項1または21に記載の組成物。
- 前記炎症が、多発性硬化症(MS)、神経障害性疼痛、慢性疼痛、関節炎、神経炎症、または自己免疫疾患により引き起こされる、請求項1に記載の組成物。
- インターロイキン10(IL-10)および1型インターロイキン10受容体(IL-10R1)のコード配列と、前記IL-10および/またはIL-10R1のコード配列に作動可能に連結された少なくとも1つの構成的プロモーターとを含み、前記少なくとも1つの構成的プロモーターが、前記IL-10およびIL-10R1のコード配列の転写を推進する、単一のウイルスまたは細菌発現ベクター。
- 前記ベクターが、前記IL-10およびIL-10R1ペプチドの転写を推進する単一の構成的プロモーターを含むウイルスベクターであり、前記IL-10ペプチドのコード配列および前記IL-10R1ペプチドのコード配列の間に置かれた自己切断型2aペプチドをさらに含む、請求項25に記載の単一の発現ベクター。
- 前記ベクターが、
細菌骨格またはウイルス骨格;
任意選択で、IL-10コード配列および/またはIL-10R1コード配列の5’(上流)、3’(下流)もしくはその両方の、少なくとも1つの核ターゲティング配列;
自己切断型ペプチド;ならびに
プロモーター配列、ポリアデニル化シグナル、転写終結配列、上流制御ドメイン、複製起点、および内部リボソーム進入部位から選択される1つまたは複数の他の調節配列
を含む、請求項25または26に記載の単一の発現ベクター。 - 前記ベクターが、プラスミド骨格、カナマイシン耐性遺伝子、CMVプロモーター、β-グロビンイントロン、成長ホルモンポリA、および2つのAAV2 ITRをさらに含む、請求項25または26に記載の単一の発現ベクター。
- 抗原提示細胞中で発現された前記IL-10ペプチドが、前記IL-10ペプチドのヒンジ領域中に突然変異を含む、請求項25~28のいずれか一項に記載の単一の発現ベクター。
- 前記IL-10ペプチドが、IL-10野生型配列の129位のフェニルアラニンがセリン、スレオニン、アラニンまたはシステインで置き換えられている突然変異を含む、請求項25~29のいずれか一項に記載の単一の発現ベクター。
- 前記野生型配列の129位のフェニルアラニンがセリンで置き換えられている、請求項30に記載の単一の発現ベクター。
- 前記構成的プロモーターが、ユビキチンプロモーター、CMVプロモーター、βアクチンプロモーター、ヒストンH4プロモーター、EF-1αプロモーター、PGK遺伝子プロモーター、RNAポリメラーゼIIにより調節されるプロモーター、RNAポリメラーゼIにより調節されるプロモーターエレメント、RNAポリメラーゼIIIにより調節されるプロモーターエレメント、U6プロモーター(U6-1、U6-8、U6-9)、H1プロモーター、7SLプロモーター、ヒトYプロモーター(hY1、hY3、hY4およびhY5)、ヒトMRP-7-2プロモーター、アデノウイルスVA1プロモーター、ヒトtRNAプロモーター、および5sリボソームRNAプロモーターからなる群から選択される、請求項1に記載の組成物または請求項25に記載の単一の発現ベクター。
- 前記構成的プロモーターが、CMVプロモーターである、請求項1に記載の組成物または請求項25に記載の単一の発現ベクター。
- 前記ベクターが、プラスミドである、請求項1に記載の組成物または請求項25に記載の単一の発現ベクター。
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