JP7357948B2 - 腎臓障害を治療するための方法 - Google Patents
腎臓障害を治療するための方法 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/775—Apolipopeptides
Description
本出願は、2018年7月13日に出願された米国仮特許出願第62/697,556号の利益を主張し、その全内容は参照により本明細書に完全に組み込まれる。
アポリポタンパク質M(APOM)は、アポリポタンパク質であり、リポカリンタンパク質ファミリーのメンバーである。リポカリンは、配列相同性の限られた領域および共通の三次構造を共有する。それらは、8本鎖の逆平行対称バレルフォールドを有し、これは、本質的に、リガンド結合部位を収容する円筒形に丸められたベータシートである。リポカリンは、免疫応答、フェロモン輸送、生物学的プロスタグランジン合成、レチノイド結合、および癌細胞相互作用など、多くの生物学的プロセスに関連する。APOMは高密度リポタンパク質と関連しており、低密度リポタンパク質およびトリグリセリドに富むリポタンパク質とはそれほど関連していない。APOMは脂質輸送に関与し、スフィンゴシン-1-リン酸、ミリスチン酸、パルミチン酸、ステアリン酸、レチノール、オールトランスレチノイン酸、および9-シスレチノイン酸に結合することができる。APOMは、例えば、Zhangら.,Acta Histochemica,2003;105(1):67-72、Axlerら.,FEBS Lett.2008 Mar 5;582(5):826-8にさらに記載されている。
一態様において、本開示は、アルポート症候群に罹患している腎疾患の治療または予防を必要としている対象において、腎疾患を治療または予防する方法を提供する。したがって、特定の実施形態において、対象は、ヒト組換えアポリポタンパク質Mの投与前にアルポート症候群を有すると診断されている。アルポート症候群の診断は、対象の家族歴、臨床的特徴(タンパク尿、アルブミン尿、血尿、GFR障害、難聴および/または眼の変化を含むがこれらに限定されない)、および組織生検の結果を含むがこれらに限定されないパラメータの評価を通じて達成され得る。腎臓生検は、IV型コラーゲンアルファ-3、アルファ-4、およびアルファ-5鎖の有無について検査することができる。さらに、糸球体の構造変化は、腎臓生検材料の電子顕微鏡検査によって検出することができる。皮膚生検は、IV型コラーゲンアルファ-5鎖の存在について検査することができ、これは通常、皮膚に存在し、X連鎖型のアルポート症候群の男性対象にはほとんど常に存在しない。アルポート症候群の診断には、Col4a3、Col4a4、またはCol4a5遺伝子の1つ以上の変異のスクリーニングが含まれてもよい。
いくつかの実施形態において、ヒトアポリポタンパク質Mの1回以上の投与は、例えば、約1週間~約18ヶ月(例えば、約1ヶ月~約12ヶ月、約1ヶ月~約9ヶ月、または約1ヶ月~約6ヶ月、または約1ヶ月~約3ヶ月)の治療期間にわたって行われる。いくつかの実施形態において、対象は、本明細書に記載のヒトアポリポタンパク質Mの1回以上の用量を、例えば、約1ヶ月~約12ヶ月(52週)(例えば、約2ヶ月、約3ヶ月、約4ヶ月、約5ヶ月、約6ヶ月、約7ヶ月、約8ヶ月、約9ヶ月、約10ヶ月、または約11ヶ月)の治療期間にわたって投与される。
いくつかの実施形態において、ヒトアポリポタンパク質Mは、薬学的に有効な希釈剤、担体、可溶化剤、乳化剤、防腐剤、および/またはアジュバントと共に組成物として製剤化される。医薬組成物には、液体、冷凍、および凍結乾燥組成物が含まれるが、これらに限定されない。
いくつかの実施形態において、本明細書に記載の方法は、腎症などの腎障害、または関連する障害もしくは合併症を予防または治療するための別の薬剤を投与することを含む。このような既知の化合物の例には、ACE阻害薬(例えば、カプトプリル(カポテン(登録商標))、エナラプリル(イノバース(登録商標))、フォシノプリル(スタリル(登録商標))、リシノプリル(ゼストリル(登録商標))、ペリンドプリル(カバーシル(登録商標))、キナプリル(アキュプロ(登録商標))、トランダナロプリル(ゴプテン(登録商標))、ロテンシン、モエキシプリル、ラミプリル);RAS遮断薬;アンジオテンシン受容体遮断薬(ARB)(例えば、オルメサルタン、イルベサルタン、ロサルタン、バルサルタン、カンデサルタン、エプロサルタン、テルミサルタンなど);プロテインキナーゼC(PKC)阻害剤(例えば、ルボキシスタウリン);AGE依存性経路の阻害剤(例えば、アミノグアニジン、ALT-946、ピリドキサミン(ピロドドリン)、OPB-9295、アラゲブリウム);抗炎症剤(例えば、クリクロオキシゲナーゼ(clyclooxigenase)-2阻害剤、ミコフェノール酸モフェチル、ミゾリビン、ペントキシフィリン)、GAG(例えば、スロデキシド(米国特許第5,496,807号));ピリドキサミン(米国特許第7,030,146号);エンドセリン拮抗薬(例えば、SPP 301)、COX-2阻害薬、PPAR-γ拮抗薬、およびアミホスチン(シスプラチン腎症に使用)、カプトプリル(糖尿病性腎症に使用)、シクロホスファミド(特発性膜性腎症に使用)、チオ硫酸ナトリウム(シスプラチン腎症に使用)、トラニラストなど(Williams and Tuttle(2005),Advances in Chronic Kidney Disease,12(2):212-222、Giunti et al.(2006),Minerva Medica,97:241-62)のような他の化合物が含まれるが、これらに限定されない。
ヒト組換えAPOMタンパク質の構築および使用:タンパク質はSino Biological(13495-H02H)から購入した。ヒトAPOMタンパク質(O95445)(Met 1-Asn 188)をコードするDNA配列を、C末端でヒトIgG1のFc領域と融合させた。得られたヒト組換えAPOMタンパク質は、SDS-PAGEで測定される純度が85%を超え、LAL法で測定されるタンパク質1μgあたりのエンドトキシン濃度が1.0EU未満であることが見出された。
驚くべきことに、脂質誘発性腎臓傷害がアルポート症候群に関連して観察された。アルポート症候群(AS)における脂質誘発性腎臓傷害のこの役割は予想外であり、以前は認識されていなかった。Col4a3ノックアウトマウス(アルポート症候群の動物モデル)から単離された糸球体のmRNA(メッセンジャーリボ核酸)レベルを調べると、ABCA1に加えて、ABCG1(ATP結合カセットサブファミリーGメンバー1)およびアポリポタンパク質M(APOM)の発現は、コントロールと比較してASマウスでも減少したことが見出され、このことは、ASの進行において3つのタンパク質すべてが果たし得る役割を示唆している。相乗的に機能する2つのATP結合カセットトランスポータータンパク質であるABCA1とABCG1とは対照的に、APOMは主にHDL粒子に存在するタンパク質であり、高密度リポタンパク質(HDL)代謝において重要な役割を果たすと考えられる。
Claims (4)
- ヒトアポリポタンパク質Mを含む、Col4a3、Col4a4およびCol4a5から選ばれる1以上の遺伝子に変異を有している対象の腎臓疾患の治療または予防剤。
- ヒトアポリポタンパク質Mを含む、アルポート症候群に罹患している対象の腎疾患の治療または予防剤。
- アルブミン尿症またはタンパク尿症に罹患している対象の腎臓疾患の治療用である、請求項1に記載の剤。
- 腎臓疾患の予防用である、請求項1に記載の剤。
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