JP2023083380A - インターロイキン-22の治療用誘導体 - Google Patents
インターロイキン-22の治療用誘導体 Download PDFInfo
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Abstract
Description
HOOC-(CH2)x-CO-*,
(式中、xは、10~18、任意に12~18、14~16または16~18の範囲の整数であり、*は、IL-22タンパク質またはリンカーの結合点を示す)のものであり得る。それは脂肪二酸、例えば、C12、C14、C16、C18またはC20二酸であり得る。有利には、脂肪酸はC16またはC18二酸、最も有利にはそれはC18二酸である。
HOOC-(CH2)x-CO-*,
(式中、xは、10~18、任意に12~18、14~16または16~18の範囲の整数であり、*は、IL-22タンパク質またはリンカーの結合点を示す)のものであり得る。それは脂肪二酸、例えば、C12、C14、C16、C18またはC20二酸であり得る。有利には、脂肪酸はC16またはC18二酸、最も有利にはそれはC18二酸である。
表4は、データセットで表されるIL-22の誘導体及び比較物の概要を提供する。
方法
マウス(n=27)、ラット(n=4~8)及びミニブタ(n=2~5)において選択された誘導体について薬物動態研究を行った。IL-22の誘導体は、比較物としてのhIL-22、hFc-hIL-22及び/またはhIL-22バリアントと並行して試験した。
30匹の8週齢のC57Bl/6雄マウス及び5匹のSprague Dawley雄ラットをTaconic Biosciencesから入手した。マウスを10匹の群で飼育した。動物を実験前の1週間馴化させた。薬物動態計算のために重要である、投薬の前の体重を測定した。動物は、食物及び水へのアクセスができて、実験を通して起きていた。
およそ15kgの体重を有する9ヶ月齢の雌のGottingenミニブタをEllegaard Gottingen Minipigs A/Sから入手した。手術(カテーテルの挿入)前におよそ18日間の馴化期間を設け、その間、ミニブタを社会化し、カテーテルからの皮下投薬及び血液サンプリングのために訓練した。手術の3~5日前にミニブタを一匹で飼育した。投薬の6日前に、すべてのミニブタに2つの中心静脈カテーテル(Cook Medical、C-TPNS-6.5-90-REDO、ケイ素、サイズ6.5フレンチ、106cm長タイプTPN)を挿入し、これにより研究開始(投薬)の少なくとも5日前の手術後に回復時間を設けた。
IL-22の誘導体または比較物の血漿レベルを、先行記載されているインハウスで開発された発光酸素チャネリング(LOCI(登録商標))アッセイを使用して測定した(Poulsen et al.J Biomol Screen,2007,12(2):240-7)。アッセイ中に、濃度依存的ビーズ-分析物-免疫複合体が形成されて光出力が生じ、これをPerkin Elmer Envisionリーダーで測定した。ビーズに対する抗体のカップリング、抗体のビオチン化及びLOCIアッセイ手順は、先行記載されているように実施した(Petersen et al.,J Pharmaceut Biomed,2010,51(1):217-24)。キャリブレータ及び品質管理(QC)サンプルを研究サンプルとして同じマトリックスで生成した。アッセイ精度(%CV)をアッセイし、試験されたサンプルのすべてについて20%未満であることが示された。
表7はマウスで得られたを示しており、表8はラットで得られたを示しており、表9及び10はミニブタで得られた結果を示している。ND=未決定。IV=静脈内投与。SC=皮下投与。
既知の脂肪酸アルキル化GLP-1誘導体であるセマグルチドは、ミニブタにおいて46時間の半減期(Lau et al.,J Med Chem,2015,58(18):7370-80)及びヒトにおいて160時間の半減期を有し、これは2のピーク対トラフ比を有する週1回投薬プロファイルに対応する。Fc-融合GLP-1誘導体であるデュラグルチドの半減期も同様である。
方法
2つのin vitroアッセイを効力を研究するために用いた。
表11は、IL-22受容体媒介STAT3活性化についてのBHK細胞レポーター遺伝子アッセイで測定された重要な誘導体及び比較物のEC50を示している。
試験された本発明の誘導体における脂肪酸共有結合で観察された効力減少は主に、アルブミン結合によって促進され、骨格置換はほとんど寄与しなかった。これは、比較物4及びhIL-22の驚くべき同等効力によって実証された。比較において、前述したように、Genentechは、IL-22のそのFc融合体についてin vitro効力の34分の1の減少を報告している。
この研究は、糖尿病マウスモデルにおける8~16日間の本発明の誘導体の1日1回の投薬の効果を調査するために設計された。研究は、投薬が開始する前に糖尿病病理が発症したことを意味する、処置(予防ではない)様式で行われた。マウスモデルは脂肪肝臓(レプチン受容体ノックアウト)を有するので、それはまた、肝臓疾患の代謝モデルとして機能する。
7~8週齢の雄のC57BKS db/dbマウスをCharles River Laboratoriesから入手し(-10日目)、実験の開始前の少なくとも1週間馴化させた。到着から1週間後(-3日目)、マウスを無作為化し、10匹の群で(または食物摂取研究の場合は単独で)飼育した。-3日目、及び研究の1~16日目の各々で、血中グルコース及び食物摂取を測定した。
研究期間にわたる血中グルコースレベルが図5及び6Aに示されている。
試験された誘導体及びhFc-hIL-22の両方は、db/dbモデルにおいて血中グルコースを正常化し、それによりin vivo治療効果を実証している。重要なことに、そのような効果は、hIL-22の投薬では見られず、長期作用性の誘導体及びFc融合体で得られた慢性曝露が治療効果に必要であることを実証している。抗糖尿病効果のための作用の様式はまだ十分に解明されていないが、肝臓に対するIL-22の効果(肝臓糖新生及び脂質生成)が主要な要因であると考えられる。
この研究は、肝臓傷害マウスモデルにおける本発明の誘導体の投薬の効果を調査するために設計された。研究は、肝臓傷害が投薬が開始された後に初めて誘導されたことを意味する、予防様式で行われた。
10週齢のC57Bl/6Rjマウスを入手し、研究開始前の1週間馴化させた。肝臓傷害をAPAPの単回腹腔内用量(300mg/kg、20ml/kg)で誘導した。IL-22の試験誘導体(誘導体1及び6)をビヒクル対照(n=5~10)と並行して、APAP投薬の2時間前に1.5mg/kgで皮下に投薬した。研究は、APAP投薬から24時間後に終了した。血漿アラニントランスアミナーゼ(ALT)及びアスパラギン酸トランスアミナーゼ(AST)の測定のために最終的出血を確保した。
研究の終了時のALT及びASTの血漿レベルが図9A及び9Bにそれぞれ示されている。ALT及びASTの量は、誘導体1または6で処置されたマウスにおいてビヒクル/APAP対照と比較して肝臓傷害の前に有意に減少することが示された。
ALT及びASTは、肝臓損傷の指標として使用される肝臓酵素である。よって、誘導体1及び6は、APAPによって誘導された傷害に対して肝臓を保護することが示された。
この研究は、肺傷害ラットモデルにおける本発明の誘導体の投薬の効果を調査するために設計された。研究は、投薬が肺傷害が誘導される前に開始され、その後も継続されたことを意味する、予防及び処置様式の両方で行われた。
肺傷害を誘導するために、1日目に単回用量として口腔咽頭吸入によって100μlのブレオマイシンを雄のSprague Dawleyラットの肺に投与した(群2~6)。生理食塩水を陰性対照として投与した(群1)。
顕微鏡的知見の概要が表14に示されており、各群の炎症及び線維症についての平均及び中央値スコアが明らかにされている。
顕微鏡的研究の結果は、本発明の誘導体が、ラットモデルにおいてブレオマイシン誘導性肺炎症及び線維症を予防及び/または減少させることができることを示した。炎症に関して見られた効果は、肺炎症を処置するために知られているコルチコステロイドであるプレドニゾロンで観察されたものと同等であった。しかしながら、本発明の誘導体は、プレドニゾロンでは見られない、線維症に対する独自の作用を有していた。
この研究は、大腸炎マウスモデルにおける本発明の誘導体の投薬の効果を調査するために設計された。研究は、投薬が結腸炎が誘導された日と同じ日に開始され、その後も継続されたことを意味する、予防及び処置様式の両方で行われた。
食餌が与えられた雌のC57Bl/6JRjマウスを体重に基づいて5つの群(1群当たりn=8)に無作為化した。5群のうち4群においてDSSを使用して大腸炎を誘導した。これらのマウスは、研究0日目から6日目までの7日間、それらの飲料水中のDSSを摂取した。5つ目の群では、動物はDSSを有さない水を摂取し、よって、健康な対照として機能した。研究0日目から、DSSマウスをビヒクル、IL-22の試験誘導体(誘導体6;0.35mg/kgまたは1mg/kgで腹腔内に投薬した)または比較物としてのIL-22-Fc融合体(hFc-hIL-22;0.5mg/kgで腹腔内に投薬した)を10日間で1日1回処置した。体重、食物及び水の摂取を毎日モニタリングした。
結腸炎体積は図12に示されている。炎症は、ビヒクル対照(DSSも含有する)と比較して、誘導体6で処置されたマウスにおいて、いずれの用量でも予防されたことが示された。特に、炎症は、健康な対照(DSSを有さないビヒクル)として処置された群について同じ結腸炎体積から明らかなように、誘導体6で処置された群では正常なレベルで維持された。hFc-hIL-22で処置された群についても同じであった。
よって、データは、本発明の誘導体がマウスモデルにおける大腸炎及び粘膜上皮創傷に対する保護において良好な有効性を実証することを示している。このことは、腸の疾患、障害及び病態のための新規かつ改善された処置が見出されたことを示している。特に、その知見は、炎症性腸疾患などの粘膜上皮損傷を特徴とする疾患を処置する潜在性を実証している。
この研究は、第2の肝臓傷害マウスモデル(第1は実施例4で上述されている)における本発明の誘導体の投薬の効果を調査するために設計された。研究は、肝臓傷害が投薬が開始された後に初めて誘導されたことを意味する、予防様式で行われた。
C57Bl6/6j雄マウスを5群(1群当たりn=8)に分けた。ConA処置に対して-26時間及び-2時間で5群のうち2群においてIL-22の試験誘導体(誘導体1)を1mg/kgで腹腔内に投薬した。別の2群は、これらの時点でビヒクルのみを摂取した。ConAを15mg/kgの用量で30秒間にわたって静脈内ボーラスとして4群すべてに与えて肝臓傷害を誘導した。5つ目の群は、健康な対照としてConAを摂取しなかった(上記のようにビヒクルのみ)。
研究の終了時のALT及びASTの血漿レベルが図15A及び15Bにそれぞれ示されている。ALT及びASTの量は、肝臓傷害の前に誘導体1で処置されたマウスでは、ビヒクル/ConA対照と比較して、試験された両方の時点で減少したことが示された。
ALT及びASTは、肝臓損傷の指標として使用される肝臓酵素である。よって、誘導体1は、実施例4においてAPAPによって誘導される傷害に対するものとちょうど同じように、ConAによって誘導される傷害に対して肝臓を保護することが示された。マウスで測定された特定のバイオマーカーは、ヒトに変換できることが知られているので、観察された保護が同様に変換できるであろうということを予測するのは妥当である。
この研究は、肥満及びNASHマウスモデルにおける本発明の誘導体の投薬の効果を調査するために設計された。研究は、投薬が開始する前に肥満及びNASH病理が発症したことを意味する、処置(予防ではない)様式で行われた。
食餌誘導性肥満マウスモデルは、実験前の少なくとも30週間高脂肪食餌が供給された雄のC57BL/6JRjマウスに基づいていた。食餌は、脂肪(40%)、フルクトース(22%)及びコレステロール(2%)が高かった(Research Diets D09100310)。これにより、肥満、NAFLD及び最終的にNASHがもたらされた。
実験の過程にわたる体重が図16に示されている。
研究は、本発明の誘導体(誘導体6)が、陽性対照として使用されたセマグルチド-長期作用型GLP-1受容体アゴニストで見られたものと少なくとも同等のレベルまで、肥満マウスにおいて用量依存的に体重減少を誘導し得ることを実証した。さらに、セマグルチド及び誘導体6の組み合わせを使用して体重減少に対する相加的効果が存在した。体重減少の誘導における誘導体6の有効性は、同様のレベルの標的係合を提供するために選択された用量を用いてhFc-IL-h22で観察されたものよりも高かった。食餌誘導性肥満マウスにおいて誘導体6によって誘導された体重減少は、DSSで処置された痩せたマウスでは見られず、肥満マウスが誘導体6誘導性体重減少に対してより感受性であることを実証している。食餌誘導性肥満マウスにおいて観察された体重減少は、ヒトにおいて使用されるであろうものと同じ読み取り値であるため、観察された体重減少が同様に変換できるであろうということを予測するのは妥当である。
Claims (15)
- リンカーによってIL-22タンパク質に共有結合した脂肪酸を含むIL-22の誘導体であって、
(i)脂肪酸はC18二酸であり、
(ii)前記IL-22タンパク質は、ネイティブ成熟ヒトIL-22(hIL-22;配列番号1)のバリアントであり、前記バリアントは、
(a)hIL-22の位置1でCys置換を含み;
(b)N末端G-P-Gを含み;および
(c)hIL-22と少なくとも10%の配列同一性を有し、
(iii)前記リンカーは、γGlu-OEG-OEG-C2DA-Acを含み、hIL-22の位置1で置換されたCys残基に結合されている、
誘導体。 - 前記バリアントは、hIL-22と少なくとも20%、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%、少なくとも80%、少なくとも90%、または少なくとも95%の配列同一性を有する、請求項1に記載の誘導体。
- 前記バリアントは、hIL-22内に1又は2以上のバリエーションを含む、請求項1または2に記載の誘導体。
- 前記バリアントは、hIL-22の位置1、35、および64で置換されている、請求項3に記載の誘導体。
- 前記バリアントは、N35QおよびN64QのhIL-22の置換を含む、請求項4に記載の誘導体。
- 前記バリアントは、配列番号16又は配列番号18に示される配列を有する、請求項1~5のいずれか一項に記載の誘導体。
- 配列番号16に示される配列を有し、リンカーγGlu-OEG-OEG-C2DA-Acに結合したC18脂肪二酸を含むIL-22タンパク質である、誘導体1であって、
前記リンカーは、配列番号16の位置4のCys残基に共有結合している、誘導体1。 - 配列番号18に示される配列を有し、リンカーγGlu-OEG-OEG-C2DA-Acに結合したC18脂肪二酸を含むIL-22タンパク質である、誘導体6であって、
前記リンカーは、配列番号18の位置4のCys残基に共有結合している、誘導体6。 - 請求項1~8のいずれか一項に記載の誘導体を調製するためのプロセスであって、前記脂肪酸をリンカーによってバリアント中の置換されたCys残基に共有結合させることを含む、プロセス。
- 請求項1~8のいずれかに記載の誘導体及び薬学的に許容可能なビヒクルを含む薬学的組成物であって、吸入による投与、注射による投与、局所的投与、または眼投与に適している、薬学的組成物。
- 注射が、腹腔内注射、皮下注射、または静脈内注射である、請求項10に記載の薬学的組成物。
- 誘導体が、請求項6~8のいずれか一項に記載の誘導体である、請求項10または11に記載の薬学的組成物。
- 療法において使用するための、請求項1~8のいずれか一項に記載の誘導体または請求項10~12のいずれか一項に記載の薬学的組成物。
- 代謝、肝臓、肺、腸、腎臓または皮膚の疾患、障害または状態の治療において使用するための、請求項1~8のいずれか一項に記載の誘導体または請求項10~12のいずれか一項に記載の薬学的組成物。
- (i)前記代謝の疾患、障害または状態は、肥満、1型糖尿病、2型糖尿病、脂質異常症、高血糖または高インスリン血症である;
(ii)前記肝臓の疾患、障害または状態は、非アルコール性脂肪肝疾患(NAFLD)、非アルコール性脂肪性肝炎(NASH)、肝硬変、アルコール性肝炎、急性肝不全、慢性肝不全、慢性肝不全急性増悪(ACLF)、アセトアミノフェン誘導性肝臓毒性、急性肝臓傷害、硬化性胆管炎、胆汁性肝硬変または手術もしくは移植によって引き起こされる病理学的状態である;
(iii)前記肺の疾患、障害または状態は、慢性閉塞性肺疾患(COPD)、嚢胞性線維症、気管支拡張症、特発性肺線維症、急性窮迫症候群、化学的傷害、ウイルス感染症、細菌感染症または真菌感染症である;
(iv)前記腸の疾患、障害または状態は、炎症性腸疾患(IBD)、潰瘍性結腸炎、クローン病、移植片対宿主病(GvHD)、化学的傷害、ウイルス感染症または細菌感染症である;
(v)前記腎臓の疾患、障害または状態は、急性腎臓疾患または慢性腎臓疾患である;
(vi)前記皮膚の疾患、障害または状態は、創傷、炎症性疾患またはGvHDである
請求項14に記載の誘導体または薬学的組成物。
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