JP6875955B2 - ポンペ病の処置のための高濃度α−グルコシダーゼ組成物 - Google Patents
ポンペ病の処置のための高濃度α−グルコシダーゼ組成物 Download PDFInfo
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Description
本願は、各々優先権が主張され、また各々その全体が参照により本明細書に組み込まれる、2012年3月7日出願の米国仮特許出願第61/607,920号明細書、及び2013年1月9日出願の米国仮特許出願第61/750,718号明細書による利益を主張する。
本発明は、ポンペ病を処置し、予防し及び/又は回復させる方法に関する。本発明は、ポンペ病の処置における使用に標識され得る組成物及び薬物にも関する。
ポンペ病(酸マルターゼ欠損)は酵素酸α−グルコシダーゼ(GAA)の欠乏により生じる。GAAは、エネルギーに使用される糖の貯蔵形態であるグリコーゲンをグルコースに代謝する。グリコーゲンの蓄積は、全身に進行性の筋疾患をもたらし、これは様々な身体組織、特に心臓、骨格筋、肝臓及び神経系を冒す。国立神経疾患・脳卒中研究所(National Institute of Neurological Disorders and Stroke)によれば、ポンペ病は40,000人の出生中約1人に発生すると推定されている。
本発明は、ポンペ病(例えば、乳児発症型ポンペ病)の処置のための方法に関し、このような方法は、そのような処置を必要とする個人に、酸α−グルコシダーゼ(GAA)酵素、(例えば、組み換えヒトGAA(rhGAA))を、GAA酵素(例えば、1−デオキシノジリマイシン(DNJ、1−DNJ))のための活性部位特異的シャペロン(ASSC)と組み合わせて投与することによる。
(式中、R1は、H又は1〜12個の炭素原子を含む直鎖若しくは分岐鎖のアルキル、シクロアルキル、アルコキシアルキル若しくはアミノアルキルであり、これらは任意選択で−OH、−COOH、−Cl、−F、−CF3、−OCF3、−O−C(=O)N−(アルキル)2で置換され;R2は、H又は1〜9個の炭素原子を含む直鎖若しくは分岐鎖のアルキル、シクロアルキル若しくはアルコキシルアルキルである)により表され;その薬学的に許容され得る塩、エステル及びプロドラッグを含む。一実施形態において、ASSCは、上記に定義した通りであり、R1はHである。別の実施形態では、ASSCは、上記に定義した通りであり、R2はHである。
により表される1−デオキシノジリマイシン(1−DNJ)、又は1−デオキシノジリマイシンの薬学的に許容され得る塩、エステル若しくはプロドラッグである。一実施形態において、塩は、塩酸塩(即ち、1−デオキシノジリマイシン−HCl)である。
により表されるN−ブチル−デオキシノジリマイシン(NB−DNJ;Zavesca(登録商標)、Actelion Pharmaceuticals Ltd,Switzerland)、又はNB−DNJの薬学的に許容され得る塩、エステル若しくはプロドラッグである。
により表されるC10H19NO4、又はC10H19NO4の薬学的に許容され得る塩、エステル若しくはプロドラッグである。一実施形態において、塩は、塩酸塩である。
本発明は、少なくとも一部は、酸α−グルコシダーゼ(GAA)酵素(例えば、組み換えヒトGAA(rhGAA))をGAA酵素(例えば1−デオキシノジリマイシン)のためのASSCと組み合わせることにより、いずれかの処置単独と比較して、インビボでのGAA活性の驚くほどの増大がもたらされるという発見に基づいている。本発明はまた、少なくとも一部は、GAA酵素(例えばrhGAA)が−インビトロ及びインビボの両方で−GAA酵素のためのASSCの添加後、適切な立体構造を安定化させるという発見に基づいている。本発明はまた、少なくとも一部は、ASSCを高濃度のGAAと組み合わせることにより、高いGAA濃度で通常生じるGAA凝集が低減されるという発見に基づいている。
(i)定義;
(ii)ポンペ病;
(iii)GAA及びASSCの獲得;
(iv)ERT及びASSCを用いたポンペ病の処置;
(v)医薬組成物;
(vi)インビトロでの安定性;並びに
(vii)インビボでの安定性。
本明細書で一般的に使用される用語は、本発明の状況、及び各用語が使用される特定の状況において、当技術分野にて通常の意味を有する。所定の用語は、本発明の組成物及び方法、並びにそれらの作製及び使用方法の説明において更なるガイダンスを実践者に提供するために、下記又は本明細書の他の箇所に論じられる。
ポンペ病は、リソソームグリコーゲン代謝を損なう、欠損した酸αグルコシダーゼ(GAA)活性により特徴付けられる、常染色体劣性LSDである。酵素欠損は、リソソームグリコーゲン蓄積に繋がり、進行性の骨格筋脱力、心機能の低下、呼吸不全、及び/又は、疾病の後期におけるCNS障害をもたらす。GAA遺伝子における遺伝子突然変異は、酵素の発現の低下、又は、安定性及び/若しくは生物学的活性が変更された酵素の突然変異体形態の生成をもたらし、最終的に疾病に繋がる(一般に、Hirschhorn R,1995,Glycogen Storage Disease Type II:Acid α−Glucosidase(Acid Maltase)Deficiency,The Metabolic and Molecular Bases of Inherited Disease,Scriver et al.,編,McGraw−Hill,New York,第7版,pp.2443−2464を参照されたい)。ポンペ病の認識された3つの臨床形態(乳児、若年及び成人)は、残留α−グルコシダーゼ活性のレベルと相関する(Reuser A J et al.,1995,Glycogenosis Type II(Acid Maltase Deficiency),Muscle&Nerve Supplement 3,S61−S69)。ASSC(他の箇所で「薬理学的シャペロン」とも称される)は、リソソーム貯蔵疾患(例えばポンペ病)等の遺伝子疾病の処置のための見込みのある新しい治療的アプローチとなる。
GAAは、GAAを内因的に発現する細胞から得ることができ、又はGAAは、本明細書に記載した組み換えヒトGAA(rhGAA)であってもよい。非限定的な一実施形態において、rhGAAは、完全長野生型GAAである。別の非限定的な実施形態では、rhGAAは、野生型GAA内に存在するアミノ酸残基のサブセットを含み、このようなサブセットは、基質結合及び/又は基質還元のための活性部位を形成する、野生型GAAのアミノ酸残基を含む。従って、本発明は、基質結合及び/又は基質還元のための野生型GAA活性部位と、野生型GAA内に存在し得る又はし得ない他のアミノ酸残基とを含む融合タンパク質であるrhGAAを想定する。
本発明によれば、GAA(例えばrhGAA)を、GAAのためのASSCと組み合わせて使用する方法が提供される。本発明の一実施形態は、GAA(例えばhrGAA ERT)及びASSCの組み合わせ療法を提供する。例えば、ASSCシャペロン1−デオキシノジリマイシン−HClは、突然変異体GAAに結合し、GAAが適切な立体構造へと安定化する能力を増大させる。
本発明の化合物及び組成物は、薬学的に許容され得る担体又は賦形剤との混合物により医薬組成物として処方され得る。
GAA製剤の有効期間中にこのような製剤の安定性を確実にすることは、大きな課題である。例えば、Myozyme(登録商標)及びLumizyme(登録商標)の患者説明書は、バイアルが単回使用のみのためであり、また不使用の製品は廃棄する必要があることを注意する。説明書は更に、Myozyme(登録商標)及びLumizyme(登録商標)が医療専門家により再構成され、希釈され、投与される必要があり、また投与は遅延なく行う必要があることを示す。Myozyme(登録商標)及びLumizyme(登録商標)は、2〜8℃で保管する必要があり、また製品はこれらの温度で24時間までのみ安定である。
インビトロでの製剤に関して上述したように、GAAのためのASSCの存在は、外因性GAAの血漿半減期を延長することによって、有効な補充タンパク質レベルをより長期間に亘って維持し、GAAに対する臨床的に罹患した組織の曝露の増大と、ひいては組織中へのタンパク質の取り込みの増大とをもたらす利点を有する。このことは、安心感の向上、投与頻度の低下、及び/又は投与量の低減等の有益な効果を患者に与える。このことはまた、処置費用を低下させるであろう。
100μMのASSC 1−デオキシノジリマイシン塩酸塩(1−DNJ−HCl)を有する及び有しない組み換えヒトGAA(Myozyme(登録商標)、Genzyme Corp.)の安定性を、タンパク質変性を誘導するのに熱を使用する熱安定性アッセイにより決定した。変性は、疎水性アミノ酸(折り畳まれたタンパク質内では曝露されていない)に結合した後、蛍光を発するSYPRO Orange染料を使用して監視される。
残留GAA活性を4つの製剤に関して決定した:
(1)pH7.4でのMyozyme(登録商標)単独;
(2)pH7.4でのMyozyme(登録商標)+50μM 1−DNJ−HCl;
(3)pH5.2でのMyozyme(登録商標)単独;
(4)pH5.2でのMyozyme(登録商標)+50μM 1−DNJ−HCl。
5グループのGAA KOマウスに、以下の製剤の1つを投与した:
(1)未処理対照;
(2)10mg/kgのMyozyme(登録商標)IVを週に1回、3週間迄
(3)(2)と同様のMyozyme(登録商標)注入、+10mg/kgの1−DNJ−HCl;
(4)(2)と同様のMyozyme(登録商標)注入、+100mg/kgの1−DNJ−HCl;
(5)(2)と同様のMyozyme(登録商標)注入、+1000mg/kgの1−DNJ−HCl;
分析用に組織ホモジネートを生成した。酵素活性を4−MUG蛍光発生基質アッセイにより決定した。結果を図3に示す。
概して実施例1に記載した熱安定性実験を、4つの組成物に関して行った:
(1)Myozyme(登録商標)のみの組成物;
(2)Myozyme(登録商標)+1μMの1−DNJ−HCl;
(3)Myozyme(登録商標)+10μMの1−DNJ−HCl;
(4)Myozyme(登録商標)+100μMの1−DNJ−HCl;
図5に示すように、GAAの融解温度が用量依存的に増大することから明かなように、DNJ−HClはGAA熱安定性を増大させる。
4グループのラットに、以下の投与計画の1つを投与した。
(1)生理食塩水+水;
(2)10mg/kgのrhGAA+水;
(3)10mg/kgのrhGAA+3mg/kgの1DNJ−HCl;
(4)10mg/kgのrhGAA+30mg/kgの1DNJ−HCl;
rhGAA又は生理食塩水を1−DNJ−HCl投与の30分後に投与した。概して実施例3に記載したようにGAA活性を決定した。24時間に亘る結果を、図6に示す。1−DNJ−HClは、投与後の酵素活性の損失を抑制し、それによりrhGAAのインビボでの半減期を延長した。rhGAAのインビボ半減期は、1.4±0.2時間(0mg/kgの1−DNJ−HCl)から2.1±0.2時間(3mg/kgの1−DNJ−HCl)及び3.0±0.4時間(30mg/kgの1−DNJ−HCl)に延長した。
3グループのGAA KOマウスに、以下の製剤の1つを投与した:
(1)対照(処置なし);
(2)10mg/kgのrhGAA;
(3)10mg/kgのrhGAAと、rhGAA注入の30分前、及び注入後8時間毎に48時間の100mg/kgの1−DNJ−HCl。
1−DNJ−HClを、全(クエン酸ナトリウム抗凝固)血中にて37℃でrhGAA(例えばMyozyme(登録商標))を安定化させるその能力に関して評価して、数時間の注入中にERTが曝露された環境を模倣した。結果は、図8に示すように、rhGAAが、およそ40%の酵素が4時間迄に、約70%が8時間迄に、及びほぼ100%が24時間迄に不活性化されたように、これらの条件下で不安定であることを示す。(赤い菱形の線のプロット)。これらの結果は、有意な割合のrhGAA用量が、これらの注入が典型的には6時間を超え、場合によっては12時間を超えるため、不活性となる可能性があることを示唆する。更に、Myozyme(登録商標)は長い血漿半減期(3時間を超えると報告)を有するため、注入後、かなりの量の酵素が何時間も循環中に残留する高い可能性があり、このような酵素はまた不活性化を受けやすい。一方、rhGAAが同一の実験条件下で50μM 1−DNJ−HClと共にインキュベートされた際、酵素は、試験全体中ずっと完全に活性なままであった(青い正方形の線のプロット)。これらの結果は、1−DNJ−HClがrhGAAを安定化させ、全血中での酵素不活性化を防止したことを示す。重要なことには、これらのデータはまた、血液中に存在する血漿タンパク質がrhGAA酵素活性の損失を防止するのに十分ではない一方、1−DNJ−HClのような薬理学的シャペロンは、酵素不活性化を防止できることを示す。
rhGAAを全血中で様々な濃度の1−DNJ−HCl(0〜100μM)を用いて測定して、rhGAA酵素不活性化を防止する1−DNJ−HClの最低限の濃度を決定した(図9)。予想したように、高い1−DNJ−HCl濃度(50及び100μM)は、rhGAAを安定化させ、酵素不活性化を防止するのに最良であった。しかしながら、低い1−DNJ−HCl濃度(2.5μMもの低さ)も6時間の時間経過に亘って約20%の損失によりrhGAA活性を維持したことは興味深い。これらの結果は、中程度の1−DNJ−HCl濃度(例えば10〜25μM)が、注入中、血液中でrhGAAを安定化させるのに十分であり得ることを示唆する。ヒト血漿PKデータに基づいて、これらの濃度は、診療所内で容易に得ることができる。
12週齢の雄のGAA KOマウスに単一用量のMyozyme(登録商標)(40mg/kg)を、ボーラス尾静脈注射を介して8週間の間1週間置きに投与した。アナフィラキシーを防ぐために、第3及び第4のMyozyme(登録商標)注射前に、Myozyme(登録商標)注射の10分前にジフェンヒドラミン(10mg/kg腹腔内)を投与した。加えて、マウスはMyozyme(登録商標)投与の30分前に、強制経口投与(oral gavage)を介して水又は30mg/kgの1−DNJ−HClのいずれかを受容した。マウスを最終Myozyme(登録商標)投与から14日後に安楽死させた。実験計画を図10に示す。
DNJ及びGAAを含む液体製剤を、DNJを水に溶解して濃度10mM DNJを達成することにより調製した。GAAを1.8mlの水中で再構成し、リン酸緩衝生理食塩水(pH7.4)中で一晩透析した。次いで、GAAの濃度が25mg/mLとなるように、4.4マイクロリットルのDNJ(10mM)を400マイクロリットルのGAAに加えた。
Sprague−Dawleyラットに10mg/kg Myozyme(登録商標)、又は10mg/kg Myozyme(登録商標)と混合した30mg/kg DNJを、尾静脈を介して投与した。GAA活性を血漿及び四頭筋組織内で測定した。GAA又はDNJ及びGAA投与後の測定されたGAAから、四頭筋内のベースラインGAA活性を減算した(約16nMol/mgタンパク質/時間)。
1−DNJ及び異なる賦形剤の存在下でのLumizyme(登録商標)(アルグルコシダーゼα)の溶解度を検査した。
52.5mgタンパク質、210mgマンニトール、0.5mgポリソルベート80、9.9mg Na2HPO4x7H20、及び31.2mg NaH2PO4xH2Oを含むLumizyme(登録商標)のバイアルを、最少容積の水(1mL添加)に溶解して、1.2mLのタンパク質溶液を提供した。5個の240μLアリコート(各々、10.5mgタンパク質を含む)をAmicon Ultra 0.5mL 30kDaカットオフ遠心フィルター装置に移し、エッペンドルフ遠心管内にて14,000xgで10分間遠心分離して、約50μLの残基(retentate)を得た。
1. PEG400(5%w/v)
2. アルギニン(100mM)
3. アルギニン(50mM)+グルタミン酸(50mM)
4. プロリン(250mM)
5. γ−シクロデキストリン(10%)
サンプル2(100mMアルギニン)を除いた全サンプルが、小分子リガンド1−デオキシノジリマイシン塩酸塩(1−DNJ−HCl、AT2220 HCl、2220 HCl)を、リガンドとタンパク質との比1:1(w/w)で含み、サンプル2はリガンドを、低いリガンドとタンパク質との比1:5(w/w)で含んでいた。
表1に示すように、この研究にて試験した賦形剤は、小分子リガンド、1−DNJ−HClの存在下で、タンパク質の溶解度を増大させた。観察された最大値は、アルギニン及びグルタミン酸(242mg/mL)の混合物に関してであり、最小値は、γ−シクロデキストリン(114mg/mL)に関してであった。賦形剤を添加しなかったタンパク質の溶解度は、約80mg/mLと決定された。いずれの理論にも束縛されるものではないが、溶解度の増大は、タンパク質表面の疎水性及び親水性部位とのアミノ酸賦形剤の効率的な相互作用に起因する可能性があり、このような相互作用は、タンパク質−タンパク質会合を競合的に妨害する。
本研究は、GAAノックアウトマウス(GAA KO)がrhGAA、又はrhGAA及び1−DNJの共製剤の反復皮下(SQ)注射に耐えるか否か、rrhGAAの反復SQ注射がGAA KOマウスにおいてrhGAAの組織取り込みを増大させ、グリコーゲンレベルを低下させるか否か、並びに、rhGAA及び1−DNJの共製剤の反復SQ注射が、rhGAA単独のSQ注射と比較して、rhGAAの組織取り込みを増大させ、グリコーゲンレベルを低下させるか否かを検査した。
本研究では、7グループの12週齢の雄のGAA KOマウスを使用した。マウスの各グループに、以下の処置の1つを投与した:
(1)生理食塩水のみ(薬物対照なし);
(2)皮下送達(SQ)したLumizyme(登録商標)単独(20mg/kg);又は
(3)共処方したLumizyme(登録商標)(20mg/kg)及び1−DNJ(30mg/kg)SQ。
組織rhGAA及びグリコーゲン
図15〜25は、3つの処置のうちの1つを受けていた動物から採取した組織サンプルにおける、最終処置用量から3日後のGAA活性、及び最終処置用量から14日後のグリコーゲンレベルを示す。試験した組織の殆どに関して、1−DNJとのrhGAAの共処方は、rhGAA単独の投与と比較して、試験組織内のrhGAA取り込み及び活性を有意に増大させた。加えて、rhGAA、又はrhGAA及び1−DNJの共製剤を用いた処置後、最終処置用量から3日後に、rhGAA活性は腹側皮膚内及び前肢筋内のSQ注射の部位にて高かった。rhGAA活性は、前肢を除いて、試験した全筋肉内よりも肝臓内でより高かった。
共製剤で処置した動物からの血漿サンプル中に存在する1−DNJが、サンプル中のrhGAAを阻害したか否かを決定するために、血漿サンプルからのrhGAAをGAA基質と共に1時間インキュベートし、基質代謝に基づく酵素活性を決定することによってrhGAA活性を決定した。次いで、サンプルを基質と共に3時間インキュベートしてこのようなサンプルを1−DNJを酵素から解離させることによって、1−DNJにより生じた任意の酵素阻害を逆行させて再分析した。2つのアッセイ形式の結果の間に、実質的な変化は見られなかった。
Claims (17)
- 対象におけるポンペ病の治療における使用のための、第一の組成物および第二の組成物であって、第一の組成物は1−デオキシノジリマイシン(DNJ)またはその薬学的に許容され得る塩、およびn−ブチル−デオキシノジリマイシン(NB−DNJ)またはその薬学的に許容され得る塩からなる群より選択される活性部位特異的シャペロンを含み;
第二の組成物は酸α−グルコシダーゼを含み;および
第二の組成物の酸α−グルコシダーゼは、約15〜25mg/mLの量で存在する、使用のための第一の組成物および第二の組成物。 - 第二の組成物の酸α−グルコシダーゼは約25mg/mLの量で存在する、請求項1に記載の、使用のための第一の組成物および第二の組成物。
- 第一の組成物および第二の組成物の少なくとも1は、賦形剤をさらに含む、請求項1または請求項2に記載の、使用のための第一の組成物および第二の組成物。
- 賦形剤は、ポリエチレン グリコール400、アルギニン、グルタミン酸、プロリン、ガンマシクロデキストリンおよびそれらの組合せからなる群より選択される、請求項3に記載の、使用のための第一の組成物および第二の組成物。
- 第一の組成物および第二の組成物の少なくとも1は、緩衝液をさらに含む、請求項1から4のいずれか一項に記載の、使用のための第一の組成物および第二の組成物。
- 緩衝液は、クエン酸緩衝液、酢酸緩衝液、重炭酸緩衝液、リン酸緩衝液、およびそれらの組合せからなる群より選択される請求項5に記載の、使用のための第一の組成物および第二の組成物。
- 第一の組成物の活性部位特異的シャペロンは、NB−DNJまたはその薬学的に許容され得る塩である、請求項1から6のいずれか一項に記載の、使用のための第一の組成物および第二の組成物。
- 第一の組成物のNB−DNJまたは薬学的に許容され得る塩は、約0.5mMから約20mMの量で存在する、請求項7に記載の、使用のための第一の組成物および第二の組成物。
- 第一の組成物のNB−DNJまたは薬学的に許容され得る塩は、約10mg/mLから約200mg/mLの量で存在する、請求項7に記載の、使用のための第一の組成物および第二の組成物。
- 第一の組成物の活性部位特異的シャペロンは、DNJまたはその薬学的に許容され得る塩である、請求項1から6のいずれか一項に記載の、使用のための第一の組成物および第二の組成物。
- 第一の組成物のDNJまたは薬学的に許容され得る塩は、約0.5mMから約20mMの量で存在する、請求項10に記載の、使用のための第一の組成物および第二の組成物。
- 第一の組成物のDNJまたは薬学的に許容され得る塩は、約10mg/mLから約200mg/mLの量で存在する、請求項10に記載の、使用のための第一の組成物および第二の組成物。
- 第一の組成物および第二の組成物の少なくとも1は、液体製剤である、請求項1から12のいずれか一項に記載の、使用のための第一の組成物および第二の組成物。
- 第一の組成物および第二の組成物の少なくとも1は、皮下注射に適している、請求項1から13のいずれか一項に記載の、使用のための第一の組成物および第二の組成物。
- 第一の組成物および第二の組成物の少なくとも1は、1、2、3、4、5、6、7、8、9または10ミリリットルの単一皮下注射に適している、請求項14に記載の、使用のための第一の組成物および第二の組成物。
- 第一の組成物および第二の組成物の少なくとも1は、静脈内投与に適している、請求項1から13のいずれか一項に記載の、使用のための第一の組成物および第二の組成物。
- 第一の組成物は、経口投与に適しており、第二の組成物は、静脈内投与に適している、請求項16に記載の、使用のための第一の組成物および第二の組成物。
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US20200188494A1 (en) | 2020-06-18 |
MX2014010669A (es) | 2014-10-17 |
KR20230066482A (ko) | 2023-05-15 |
US20220347272A1 (en) | 2022-11-03 |
MX349992B (es) | 2017-08-22 |
WO2013134530A1 (en) | 2013-09-12 |
US20140193390A1 (en) | 2014-07-10 |
KR20210062731A (ko) | 2021-05-31 |
EP2823043A4 (en) | 2016-09-07 |
US20150044194A1 (en) | 2015-02-12 |
US9303249B2 (en) | 2016-04-05 |
US10046033B2 (en) | 2018-08-14 |
KR20140135222A (ko) | 2014-11-25 |
CA2866683A1 (en) | 2013-09-12 |
US10512677B2 (en) | 2019-12-24 |
US20170056483A1 (en) | 2017-03-02 |
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