JP2020506693A - アンジオテンシン変換酵素2(ace2)の活性な低分子量変異体 - Google Patents
アンジオテンシン変換酵素2(ace2)の活性な低分子量変異体 Download PDFInfo
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Abstract
Description
本出願は、その内容は参照により全体が本明細書に組み込まれる、2017年1月24日に出願された米国仮特許出願第62/449,857号に対する35USC§119(e)下での優先権の利益を主張する。
明細書に開示される組成物は、本開示の細菌毒素を含み、それを必要とする対象への投与のために製剤化された医薬組成物を含み得る。そのような組成物は、特定の患者の年齢、性別、体重、及び状態、ならびに投与経路などの要因を考慮して、医学分野の当業者に周知の用量で及び技術により製剤化及び/又は投与することができる。
本発明者らは、非常に高い酵素活性を有するはるかに短い分子量(70kD未満)を有する分子量約110kDの完全長ACE2の新規断片を発見した。ACE2の開示された断片は、治療方法及び医薬組成物で利用され得る。いくつかの実施形態では、それを必要とする対象のAngII(1−8)レベルを低下させるために、開示された方法を実施することができる。また、アンジオテンシンII以外の基質もあり、これらは新規ACE2断片によっても切断される。この方法において、対象は、適切な医薬担体中にアンギオテンシン変換酵素2のポリペプチド断片(ACE2、配列番号1)を含む医薬組成物であり得る。開示された治療方法に適した対象には、糖尿病及び非糖尿病の慢性腎疾患、急性腎不全及びその予防、慢性腎疾患、重度の高血圧、強皮症、皮膚、肺、腎臓及び高血圧の合併症、悪性高血圧、腎動脈狭窄に続発する腎血管性高血圧、特発性肺線維症、大動脈瘤、心線維症及びリモデリング、左心室肥大、及び急性脳卒中を有する及びその発症のリスクがある患者が含まれるが、これらに限定されない。開示された医薬組成物は、静脈内注入及び患者が自宅で自分で注射できる皮下注射を含むがこれらに限定されない任意の適切な方法によって投与されてもよい。開示された医薬組成物は、特発性肺線維症及び他の状態を治療するための使用に非常に実用的であり得る別の投与経路として吸入により投与され得る。
例示的な実施形態以下の実施形態は例示であり、特許請求される主題の範囲を限定するものと解釈されるべきではない。
序論及び目的
レニンアンジオテンシン系(RAS)の活性化は、糖尿病性腎疾患(DKD)の病因及びCKDへのその進行において主要な役割を果たす。糖尿病性腎疾患の全身性強皮症、悪性高血圧症、特発性肺線維症、心肥大のように、RASが全身的又は局所的に、又はその両方で過活性状態になるいくつかの状態がある。アンジオテンシン変換酵素2(ACE2)は、アンジオテンシンII(1−8)(AngII)をアンジオテンシン(1−7)(Ang(1−7))に変換する膜貫通モノカルボキシペプチダーゼである。ACE2によるAngIIレベルの低下は、このペプチドの過剰な有害作用を防止又は軽減するべきである。さらに、AngII切断の結果として形成され、それ自身の受容体に作用するAng(1−7)は、AngIIの組織保護機能と一般的に反対の組織保護機能を持ち、AngIIの低下を補完する。過去の資金提供期間中、我々の研究室は、マウスに与えられたときにヒトACE2の免疫原性を回避する方法として、マウス組換えACE2(mrACE2)を精製及び生産することができた。我々は、mrACE2の毎日の注射又はDNAミニサークル送達により全身投与されたmrACE2の腎臓への影響を調べた。これにより、血漿ACE2活性が持続的かつ大幅に増加し、急性のAngII負荷を代謝する能力が強化された。しかし、ストレプトゾトシン(STZ)ミニサークル遺伝子ACE2デリバリー又はrACE2投与によって誘発されたDKDのマウスでは、尿中ACE2活性を増加させることができず、アルブミン尿、糸球体メサンギウム拡張、糸球体細胞性及び糸球体肥大の改善はなかった。したがって、循環に限定されたACE2の深遠な増大は、糸球体病変及び初期STZ誘発DKDに特徴的な過濾過を改善することができなかった。顕著なACE2増幅で循環RASをターゲットにすることがDKDの改善に効果的でない理由は、全身RASが過剰に活動せず、STZモデルで血圧が上昇しないという事実に起因する(公開のために提出)。対照的に、RASの過活性に対抗するためのrACE2の治療的使用は、全身のAngII過剰のマウスレニントランスジェニックモデルの予備データによってサポートされる。この場合、マウスrACE2はFcタグと融合して作用期間を延長し、血漿AngIIレベルの上昇を著しく低下させ、アルブミン尿及び高血圧を改善する(公開のために提出)。
これまでの我々の研究は、腎疾患を治療するためにAng II分解を増加させる方法としてACE2増幅を達成することに焦点を合わせてきた3。概念実証として、共同研究者であるケビン・バーンズ博士と彼のグループによって生成された足細胞特異的トランスジェニックマウスを使用して、STZ誘導性DKD 4に対する糸球体ACE2過剰発現の効果を調べた。このポドサイト特異的トランスジェニックマウスでは、糸球体内のACE2発現がわずかに増加(2〜5倍)した。それにもかかわらず、糸球体に制限されたACE2活性のこの比較的小さな増加は、DKD 4のSTZモデルにおけるアルブミン尿及びメサンギウム拡大の減少に基づいて有意な腎保護を付与するのに十分であった4。内因性ACE2を増幅する方法として、小分子化合物(1−[(2−ジメチルアミノ)エチルアミン]−4−(ヒドロキシエチル)−7−[(4−メチルフェニル)スルホニルオキシ]−9H−キサンテン−9−オン)(XNT)を使用した研究を実施した。これは、最初はACE2アクティベーターであると説明されていた。しかし、驚いたことに、XNTはACE2KOマウスのAngII誘発高血圧に効果を発揮し、ACE2とは独立したメカニズムで機能することを示した5。さらに、LC−MS/MSの結果は、XNTが血漿Ang II、Ang(1−7)又はAng(1−5)レベルを変化させなかったのに対し、Ang II分解の増強の結果として、陽性対照として使用されるrACE2は、Ang(1−7)及びAng(1〜5)レベルを著しく増加させた。
レニン−アンジオテンシン系(RAS)は、DKDの病因に広く関与している。循環AngII及び特に局所的に産生されたAngIIは、一連の血行動態及び非血行動態効果を通じて腎疾患を媒介することができる。16−16−2324−26。DKD患者の腎疾患の進行を遅らせ、タンパク尿を減少させるACE阻害剤と他のRASブロッカーの相対的な有効性は、DKDの発生と進行にRASの過剰活動が関与していることのさらなる証拠である。AngII産生を含むグルコースによる腎臓内での局所的なRASの活性化は、培養された足細胞及び尿細管細胞の細胞レベルでよく実証されている24−26。追加の直接的な証拠は、腎臓及びDKDのent歯類モデルからの尿及びDKD の患者からの尿バイオサンプルにおけるRAS成分の増加の発見から得られる22、23、27−31。現在使用されているRASブロッカーは、重要であるが不完全な保護と可変応答率を提供する32−35。したがって、Ang IIの形成又は作用の遮断に基づいて既存のアプローチを拡大及び改善するRASの過剰活動に対抗するための新しいアプローチが必要である。AngIIの散逸には、いくつかの経路が含まれる(図1)。特に興味深いのは、Ang(1−7)の形成をもたらすACE2などの酵素によって駆動されるものである36−43。また、Ang IIからAng(1−7)を形成できるPRCPやPEPなどの他の酵素があるが、一般に、ACE2は最高の効率でAngIIをAng(1−7)に分解すると考えられている6,36,37、42、43。したがって、ACE2のAngIIの低下とAngの増加(1〜7)の二重効果は、治療上非常に効果的であり、過剰なAngIIを処理する自然な経路を複製する。
無傷のACE2は、100〜110kDaの比較的大きなサイズを有しており、我々の実験研究及び理論的考察によれば、糸球体濾過を介した通過による腎臓へのその送達が妨げられる。これは、糸球体の透過性が大きく変化していない場合に、早期にSTZ誘導性のDKDを治療するための潜在的な使用のための無傷のACE2の重要な制限であることを示した。ここでは、糸球体濾過により腎臓に送達可能であるため、局所RAS過活性を直接制御するために管状内腔にアクセスできるACE2の短いフォームを開発及び試験することを提案する。腎臓の近位遠位及び集合尿細管の先端境界に豊富なRASがあり、これはAng IIの腎作用の多くを媒介する71−78。化合物の糸球体濾過には、いくつかの障壁が含まれる:最初に内皮層、糸球体基底膜、最後に有足細胞の足の突起79。最近の研究では、アルブミン尿への定量的寄与における近位尿細管の役割が再検討された80。アルブミンの濾過は、以前に信じられていたよりも大きく、これは、その再吸収によりアルブミン尿を減少させる近位尿細管の役割の増加を決定することが示された80−85。明らかに、分子量66kD(585アミノ酸)のアルブミンは負に帯電しているにもかかわらず、生理学的条件下で糸球体透過性の穏やかな変化でさえもある程度濾過される80−83。
目的1.高い酵素活性を保持し、糸球体濾過を介して腎臓に送達可能な最短のマウス及びヒトACE2タンパク質フラグメントを生成し、アンジオテンシンII分解に対する影響を評価し、慢性的な使用のために、比較的大量に精製及び生産することである。
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Claims (19)
- アンジオテンシン変換酵素2の変異体(ACE2)(配列番号1)の変異体であって、ACE2活性を有し、約70kD未満の分子量を有するACE2の変異体。
- ACE2の変異体が、全長ACE2(配列番号1)と比較して、N末端欠失、C末端欠失、又はその両方を含む、請求項1に記載のACE2の変異体。
- 欠失が完全長ACE2に存在するグリコシル化部位を除去する、請求項2に記載のACE2の変異体。
- ACE2の変異体が約60kD未満の分子量を有する、請求項1に記載のACE2の変異体。
- ACE2の変異体が、AngII(1−8)をAng(1−7)に変換するために、全長ACE2(配列番号1)よりも高いACE2活性を有する、請求項1に記載のACE2の変異体。
- ACE2の変異体が少なくとも1週間の血漿中半減期を有する、請求項1に記載のACE2の変異体。
- 血漿中のACE2の変異体の半減期を増加させる異種アミノ酸配列に融合した請求項1に記載のACE2の変異体を含む融合タンパク質。
- 前記融合タンパク質が、少なくとも1週間の血漿中半減期を有する、請求項7に記載の融合タンパク質。
- 異種アミノ酸配列が、(i)融合ポリペプチドの二量体化を防ぐヒンジ領域を欠損している抗体のFc部分のアミノ酸配列又はその断片;(ii)ヒト血清アルブミンのドメインIIIのアミノ酸配列又はその断片;及び(iii)連鎖球菌プロテインGのC末端アルブミン結合ドメイン3(ABD3)のアミノ酸配列からなる群から選択されるアミノ酸配列を含む、請求項7に記載の融合タンパク質。
- ACE2の変異体と異種アミノ酸配列との間にリンカーアミノ酸配列をさらに含み、リンカー配列がグリシン及びセリンから選択される5〜15個のアミノ酸を含む、請求項7に記載の融合タンパク質。
- N末端又はC末端ヒスチジンタグをさらに含む、請求項7に記載の融合タンパク質。
- ポリエチレングリコールポリマーに結合した請求項1に記載のACE2の変異体を含む結合体。
- ナノ粒子に結合した請求項1に記載のACE2の変異体を含む結合体。
- ポリエチレングリコールポリマー又はナノ粒子に結合した請求項1に記載のACE2の変異体を含む結合体であって、少なくとも1週間の血漿中半減期を有する結合体。
- (i)請求項1に記載のACE2の変異体;及び(ii)適切な医薬用担体を含む医薬組成物。
- 請求項15に記載の医薬組成物を対象に投与することを含む、それを必要とする対象においてAngII(1−8)レベルを減少させる及び/又はAng(1−7)レベルを増加させる方法。
- 前記対象が、糖尿病性腎疾患、急性腎不全、慢性腎疾患、糸球体腎炎、腎動脈狭窄、特発性肺線維症、肝硬変患者などの肝線維症、大動脈瘤、心臓の線維化とリモデリング、左心室肥大、及び急性脳卒中からなる群から選択される状態を有する、請求項16に記載の方法。
- 前記医薬組成物が静脈内投与又は皮下投与により投与される、請求項16に記載の方法。
- 前記医薬組成物が肺投与される、請求項16に記載の方法。
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US11891638B2 (en) | 2024-02-06 |
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