JP7341268B2 - 動物モデルにおけるミエロペルオキシダーゼ酸化活性のpic1による阻害 - Google Patents
動物モデルにおけるミエロペルオキシダーゼ酸化活性のpic1による阻害 Download PDFInfo
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Description
本願は、2018年1月9日出願の米国仮出願第62/615,183号、2018年6月6日出願の米国仮出願第62/681,458号、および2018年10月17日出願の米国仮出願第62/746,649号に基づく優先権を主張するものであり、それらの各々の開示は、参照によってその全体が本明細書中に組み入れられる。
本願は、参照によってその全体が本明細書に組み入れられる、ASCIIフォーマットで電子的に提出された配列表を含有している。2019年1月7日に作成された該ASCIIコピーは、Seqlist.txtという名前であり、16,143バイトのサイズである。
NETとは、好中球が、抗微生物分子によって装飾されたDNAの網目状構造物に変化することによって、感染を封じ込める手段である。NETは、全身性エリテマトーデス(SLE)および輸血関連急性肺損傷(TRALI)のような広範囲の炎症性疾患および自己免疫疾患の病原に寄与することが示されている。
[本発明1001]
治療的に有効な量のPIC1を対象へ投与する工程を含む、対象における全身性エリテマトーデス(SLE)を処置する方法。
[本発明1002]
治療的に有効な量のPIC1を対象へ投与する工程を含む、対象における輸血関連急性肺損傷(TRALI)を処置する方法。
[本発明1003]
対象が輸血を投与される前、対象が輸血を投与された後、および/または輸血中に、PIC1が投与される、本発明1002の方法。
[本発明1004]
対象における免疫複合体による補体系の活性化およびNET形成をモジュレートするために有効である、本発明1001~1003のいずれかの方法。
[本発明1005]
対象におけるNETによって媒介される炎症性組織傷害を阻害するために有効である、本発明1001~1004のいずれかの方法。
[本発明1006]
NET形成が、細菌、真菌、寄生虫、またはウイルスのうちの少なくとも一つによって刺激される、本発明1004または本発明1005の方法。
[本発明1007]
PIC1が対象におけるミエロペルオキシダーゼ(MPO)活性を阻害する、本発明1001~1006のいずれかの方法。
[本発明1008]
PIC1が非経口投与される、本発明1001~1007のいずれかの方法。
[本発明1009]
対象がヒトである、本発明1001~1008のいずれかの方法。
[本発明1010]
PIC1が、1個または複数個のPEGモエティを含むペプチドである、本発明1001~1009のいずれかの方法。
[本発明1011]
PIC1がPA-dPEG24である、本発明1010の方法。
[本発明1012]
PA-dPEG24が、
の配列を含む、本発明1011の方法。
の配列を含む。
他に定義されない限り、本明細書中で使用される全ての技術用語および科学用語が、当業者によって一般的に理解されるのと同一の意味を有する。本明細書中に記載されたものに類似しているかまたは等価である方法および材料が、本発明の実施または試行において使用され得るが、適当な方法および材料を以下に記載する。
のポーラーアソータント(polar assortant)(PA)配列を含むペプチドをさし、同一のアミノ酸配列を含むがPEG化のような修飾を含むペプチドもさす。「PIC1バリアント」という用語は、
のPA配列と少なくとも85%同一、または少なくとも90%同一、または少なくとも95%同一、または少なくとも99%同一であるが、100%同一ではない配列を含むペプチドをさす。PIC1バリアントには、PA配列のアミノ酸のうちの少なくとも1個が欠失しているペプチドが含まれ得る。PIC1バリアントには、アミノ酸がPA配列に挿入されているペプチドが含まれ得る。PIC1バリアントには、PA配列のアミノ酸のうちの少なくとも1個が、アラニンのような他のアミノ酸、修飾型アミノ酸、またはサルコシン(Sar)のようなアミノ酸誘導体に置換されているペプチドが含まれ得る。
は、インビトロおよびインビボの両方で、古典経路活性化を阻害し、ラットへ血管内投与された時、30秒までに補体活性化の>90%の全身的な阻害を達成することができることが証明されている。PIC1誘導体は、インビトロで、古典補体経路によって媒介されるABOミスマッチ溶血を阻害することが以前に示されているが、PIC1は、AIHTRのラットモデルにおいて、ミスマッチ赤血球の輸血直前または輸血後に投与された時、抗体によって開始された補体によって媒介される溶血を阻害することができる。さらに、PIC1は、インビトロで、MPOのペルオキシダーゼ活性およびネトーシスを阻害することも示されている。独特のミスマッチ赤血球ベースの「2ヒット」TRALIモデルが開発され、PIC1の予防的投与が、急性肺損傷およびこの呼吸症候群のその他の特徴を軽減することを証明した。
本実施例は、ヒト血清における免疫複合体によって媒介される補体活性化のインビトロアッセイ、およびヒト好中球によるNET形成についてのアッセイにおける、補体Clのペプチド阻害剤(PIC1)の試験を記載する。
は、HPLCおよび質量分析によって確認された≧95%の純度で、PolyPeptide Group(San Diego, CA)によって製造された。凍結乾燥PA-dPEG24は、0.01M Na2HP04緩衝剤を含む普通の生理食塩水において37.5mMで可溶化された。精製されたMPOは、Lee Biosolutions(Maryland Heights, MO)から購入された。静脈内免疫グロブリンは、Baxter Healthcare Corporation(Westlake Village, CA)から、卵白アルブミンは、Sigma Aldrich(St Louis, MO)から、抗卵白アルブミン抗体は、Abeam(Cambridge, MA)から購入された。ヤギ抗C1qおよびヒトClは、Complement Technology(Tyler TX)から購入された。PMA(ホルボール12-ミリステート13-アセテート)および過酸化水素は、Fisher Scientific(Hampton, NH)から購入された。
は、C1-抗C1q免疫複合体を含む複数の型の免疫複合体によって開始される補体活性化を用量依存的に阻害して、C5aおよび膜侵襲複合体(sC5b-9)を含む炎症誘発性補体エフェクターの生成を制限することができた。PA-dPEG24は、ホルボール12-ミリステート13-アセテート(PMA)、ミエロペルオキシダーゼ(MPO)、または免疫複合体によって活性化されたヒト血清によって刺激されたヒト好中球によるNET形成も用量依存的に阻害することができた。これらの結果は、PA-dPEG24によるNETの阻害が、NET形成のMPO経路の阻止によって起こることを示唆している。総合すると、これらの結果は、PA-dPEG24が、免疫複合体による補体系の活性化およびNET形成を阻害することができることを証明しており、そのことは、現在の薬理学的処置によって解決されていないSLE病原の二つの重要な局面をモジュレートするための治療アプローチとして、PIC1ペプチドを使用することができることを示唆している。
本実施例においては、ウィスターラットをリポ多糖によって予備刺激し、その後、ラットが既存の抗体を有しているミスマッチ赤血球の30%の輸血を行った。シャム動物および媒体動物が、対照として使用され、動物のサブグループは、輸血の2分前にPIC1を受容した。4時間目に、全血球計算のため、血液を単離した。単離された肺組織を、ヘマトキシロンおよびエオシンによって染色し、肺組織内のミエロペルオキシダーゼ(MPO)活性を、機能アッセイにおいて定量化した。血漿中の遊離DNAを、PicoGreen染色によって検出した。
本実施例は、PIC1の予防的な投与が急性肺損傷を低下させることを示す。ヒトRBCの輸血の直前または後のPIC1のIV投与は、AIHTRモデルにおいて溶血および腎傷害の両方を軽減した。PIC1が新規「2ヒット」モデルにおいてTRALIを減弱させるか否かを確認するため、ラットに、第1ヒットとして2mg/kg LPS IVを投与した。28分後に、ラットは、160mg/kg PIC1または媒体のみのいずれかを受容し、その2分後に、第2ヒットとして、ミスマッチRBCの30%のIV輸血を受容した。AIHTRモデルにおける効力に基づき、160mg/kgというPIC1の用量を利用した。輸血の4時間後に、動物を屠殺し、肺重量を決定し、肺組織を組織学によって評価した。
本実施例は、PIC1が、好中球によって媒介される肺損傷、ミエロペルオキシダーゼ(MPO)活性、および白血球減少症を低下させることを示す。このモデルにおける好中球によって媒介される肺損傷の減弱におけるPIC1の役割を評価するため、媒体によって処理された動物およびPIC1によって処理された動物に由来するH&E切片の好中球浸潤および細胞壁肥厚について盲検的段階分けを実施した。好中球浸潤および細胞壁肥厚を、0のスコアが正常肺を示し、4のスコアが重度の肺損傷を意味する0~4のスケールでスコア化した。肺重量の低下および組織学的分析と一致して、PIC1を受容した動物は、媒体対照動物と比較して有意に改善された肺損傷スコアを有していた(p=0.003)(図12A)。1.5という平均値ならびに25および75の四分位数におけるはるかに狭い分布を有していた、PIC1によって処理された動物と比較して、媒体対照動物は、より高度の傷害を示し、2.0という平均値およびより広い分布を有していた。
本実施例は、PIC1が、循環血中の好中球細胞外トラップ(NET)バイオマーカーのレベルを低下させることを示す。TRALIのマウスモデルにおいて、活性化された好中球は、急性肺損傷に寄与するNETを放出することができ、TRALI患者の血中においては、NETバイオマーカーである遊離DNAが上昇している。循環血中の遊離DNAのレベルに対してPIC1が効果を及ぼすか否かを確認するため、PIC1または媒体を受容した動物に由来する血漿中のDNAレベルを、PicoGreenアッセイにおいて定量化した。媒体を受容した動物と比較して、PIC1によって処理された動物から単離された血漿中の遊離DNAのレベルは、有意に低下した(p=0.02)(図14)。総合すると、組織学、肺組織内のMPO活性の低下、白血球減少症の欠如、および循環血中の遊離DNAの低下によって査定されたような、好中球によって媒介される肺損傷の低下は、PIC1が、この新規TRALI動物モデルにおいて、免疫細胞によって媒介される急性肺損傷を低下させることを証明している。
本実施例は、PA-dPEG24が、インビボでMPO活性およびNET形成を阻害することができる程度を試験するための実験を記載する。ラットにおける炎症性腹膜炎モデルを、腹腔内(IP)注射された精製されたMPOを利用して開発した。
に具体的に示され、その全体が本明細書中に示されたのと同一の程度に、参照によって本明細書に組み入れられる。
Claims (16)
- 治療的に有効な量のPIC1ペプチドを含む薬学的組成物であって、
該薬学的組成物が、対象におけるNET形成を阻害するためのものであり、
該PIC1ペプチドが、IALILEPICCQERAA-dPEG24 (SEQ ID NO: 19)の配列を含み、
該PIC1ペプチドが、該対象の体重1 kg当たり5~160 mgの用量で投与され、
該薬学的組成物が、対象における免疫複合体による補体系の活性化をモジュレートするために有効であり、かつ
該NET形成が細菌、真菌、寄生虫、またはウイルスのうちの少なくとも1つによって刺激される、
薬学的組成物。 - 対象における炎症を阻害するために有効である、請求項1記載の薬学的組成物。
- 対象における炎症性組織傷害を阻害するために有効である、請求項1記載の薬学的組成物。
- 対象における正常な肺構造を保つために有効である、請求項1記載の薬学的組成物。
- 対象における肺損傷、肺組織への好中球の浸潤、および肺組織におけるミエロペルオキシダーゼ(MPO)活性のうちの1つまたは複数を阻害するために有効である、請求項1記載の薬学的組成物。
- 前記PIC1ペプチドが、対象の体重1 kg当たり5~100 mgの用量で投与される、請求項1~5のいずれか一項記載の薬学的組成物。
- 静脈内投与される、請求項1~6のいずれか一項記載の薬学的組成物。
- 前記NET形成がウイルスによって刺激される、請求項1記載の薬学的組成物。
- 治療的に有効な量のPIC1ペプチドを含む薬学的組成物であって、
該薬学的組成物が、対象における肺損傷および/または肺組織への好中球浸潤を阻害するためのものであり、
該PIC1ペプチドが、IALILEPICCQERAA-dPEG24 (SEQ ID NO: 19)の配列を含み、
該PIC1ペプチドが、該対象の体重1 kg当たり5~160 mgの用量で投与され、かつ
該肺損傷および/または肺組織への好中球浸潤が、細菌、真菌、寄生虫、またはウイルスのうちの少なくとも1つによって刺激される、
薬学的組成物。 - 対象における炎症を阻害するために有効である、請求項9記載の薬学的組成物。
- 対象における炎症性組織傷害を阻害するために有効である、請求項9記載の薬学的組成物。
- 対象における正常な肺構造を保つために有効である、請求項9記載の薬学的組成物。
- 肺損傷および肺組織への好中球の浸潤を阻害するために有効である、請求項9記載の薬学的組成物。
- 対象における免疫複合体による補体系の活性化をモジュレートするために有効である、請求項9記載の薬学的組成物。
- 前記PIC1ペプチドが、対象の体重1 kg当たり5~100 mgの用量で投与される、請求項9~14のいずれか一項記載の薬学的組成物。
- 静脈内投与される、請求項9~15のいずれか一項記載の薬学的組成物。
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