JP6851964B2 - 炭水化物が増大している非常に強力な酸性アルファ−グルコシダーゼ - Google Patents
炭水化物が増大している非常に強力な酸性アルファ−グルコシダーゼ Download PDFInfo
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Description
本出願は、2014年9月30日に出願された米国仮特許出願第62/057,842号明細書、2014年9月30日に出願された米国仮特許出願第62/057,847号明細書、2015年2月5日に出願された米国仮特許出願第62/112,463号明細書および2015年3月19日に出願された米国仮特許出願第62/135,345号明細書に対する優先権の利益を主張し、これらはそれぞれ、その全体が参照により援用される。
モノ−マンノース−6−リン酸(M6P)またはビス−M6Pを担持するN−グリカンを含むrhGAAを、Lumizyme(登録商標)(アルグルコシダーゼアルファ;CAS420794−05−0)により例示される従来のrhGAAと比べて多量に含む、CHO細胞に由来するrhGAA組成物。本発明に係る例示的rhGAA組成物は、実施例で説明するATB−200(ATB−200、ATB−200またはCBP−rhGAAと表される場合もある)である。本発明のrhGAA(ATB−200)は、高い親和性(KD約2〜4nM)でCIMPRに結合し、ポンペ線維芽細胞および骨格筋筋芽細胞によって効率的に内在化される(Kuptake約7〜14nM)ことが分かっている。ATB−200がin vivoで特性決定され、現在のrhGAA ERT(t1/2約60分)と比べて見かけ上の血漿中半減期が短い(t1/2約45分)ことが分かった。
既存のMyozyme(登録商標)rhGAA製品およびLumizyme(登録商標)rhGAA製品の限界
ポンペ病用に現在承認されている唯一の処置剤であるMyozyme(登録商標)およびLumizyme(登録商標)におけるrhGAAの能力を評価するために、これらのrhGAA調製物をCIMPRカラム(M6P基を有するrhGAAに結合する)上に注入し、その後に遊離M6勾配で溶出させた。画分を96ウェルプレート中に回収し、4MU−α−グルコース基質でGAA活性をアッセイした。結合したrhGAAおよび結合していないrhGAAの相対量をGAA活性に基づいて決定し、全酵素の割合として報告した。
rh−GAAを発現するDNAでCHO細胞をトランスフェクトした後、rhGAAを産生する形質転換体を選択した。rh−GAAをコードするDNAによるCHO細胞の形質転換用のDNA構築物を図5に示す。rh−GAAを発現するDNAでCHO細胞をトランスフェクトした後、rhGAAを産生する形質転換体を選択した。
CHO細胞株GA−ATB−200を使用して、本発明に係るrhGAAの複数のバッチを振とうフラスコ中でおよび潅流バイオリアクタ中で製造し、CIMPR結合を測定した。様々な製造バッチからの精製されたATB−200 rhGAAに関して、図6Bおよび図7に示すCIMPR受容体結合と同様のCIMPR受容体結合(約70%)を観測し、これは、ATB−200 rhGAAが常に産生され得ることを示す。図6Aおよび図6Bに示すように、Myozyme(登録商標)およびLumizyme(登録商標)のrhGAAは、ATB−200 rhGAAと比べて有意に少ないCIMPR結合を示した。
弱陰イオン交換(「WAX」)液体クロマトグラフィーを使用して、末端リン酸塩に従ってATB−200 rhGAAを分画した。塩の量を増加させてERTを溶出させることにより、溶出プロファイルを作成した。このプロファイルをUV(A280nm)でモニタリングした。ATB−200 rhGAAをCHO細胞から得て精製した。Lumizyme(登録商標)を商業的供給源から得た。Lumizyme(登録商標)は、その溶出プロファイルの左側で高いピークを示した。ATB−200 rhGAAは、Lumizyme(登録商標)の右側に溶出する4つの突出したピークを示した(図8)。このことから、ATB−200 rhGAAがLumizyme(登録商標)と比べて大きい程度までリン酸化されたことが確認される。なぜなら、この評価は、CIMPR親和性ではなく末端電荷によるからである。
精製されたATB−200 rhGAAおよびLumizyme(登録商標)のグリカンをMALDI−TOFで評価し、各ERT上で見出される個々のグリカン構造を決定した(図9)。ATB−200サンプルは、Lumizyme(登録商標)と比べて非リン酸化高マンノース型N−グリカンをわずかに低い量で含むことが分かった。ATB−200中のM6Pグリカンの含有量はLumizyme中と比べて高いことから、ATB−200 rhGAAの標的が筋細胞により効率的に設定される。MALDIにより決定したモノ−リン酸化構造およびビス−リン酸化構造の高い割合は、CIMPR受容体へのATB−200の有意に高い結合を示したCIMPRプロファイルと一致する。MALDI−TOF質量分析によるN−グリカン分析から、平均して、各ATB200分子は少なくとも1個の天然ビス−M6P N−グリカン構造を含むことを確認した。ATB−200 rhGAAに関するより高いビス−M6P N−グリカン含有量は、M6P受容体プレート結合アッセイでのCIMPRへの高親和性結合(KD約2〜4nM)(図10A)と直接相関した。
CIMPRに結合することができるrhGAAをより高い割合で有することに加えて、この相互作用の質を理解することが重要である。CIMPRプレート結合アッセイを使用して、Lumizyme(登録商標)およびATB200 rhGAAの受容体結合を測定した。簡潔に言うと、CIMPR被覆プレート使用してGAAを捕捉した。固定した受容体に様々な濃度のrhGAAを塗布し、結合していないrhGGAを洗い落とした。残存するrhGAAの量をGAA活性により測定した。図10Aに示すように、ATB−200 rhGAAは、Lumizymeと比べて有意に多くCIMPRに結合した。
正常な線維芽細胞株およびポンペ線維芽細胞株を使用して、ATB−200およびLumizyme(登録商標)のrhGAAの相対的な細胞取り込みを比較した。比較には、5〜100nMの本発明に係るATB−200 rhGAAと、10〜500nMの従来のrhGAA Lumizyme(登録商標)とを含めた。16時間のインキュベーション後、外部のrhGAAをTRIS塩基で不活性化し、細胞をPBSで3回洗浄した後に回収した。内在化されたGAAを4MU−α−グルコシド加水分解により測定して総細胞タンパク質に対してグラフ化し、結果を図11に示す。
優れたグリコシル化を有するATB−200 rhGAAは、GAA KOマウスの骨格筋におけるグリコーゲンクリアランスに関して、標準的な治療ERTと比べ有意に良好であった
上記で説明したように、組み換えヒトGAA(rhGAA)を使用する酵素補充療法(ERT)は、ポンペ病に利用可能な唯一の承認された処置である。このERTには、細胞取り込みおよびその後の細胞カチオン非依存性M6P受容体(CIMPR)によるリソソームへの送達のために、特殊な炭水化物マンノース6−リン酸(M6P)が必要である。しかしながら、現在のrhGAA ERTが含むM6Pは少量であり、そのため薬剤ターゲティングと疾患関連組織中での有効性とが制限される。本発明者らは、薬物ターゲティングの改善のために、従来のrhGAAと比べて(特に高親和性ビス−M6P N−グリカン構造と比べて)優れたグリコシル化および高いM6P含有量を有するrhGAA(ATB−200 rhGAAと表す)が得られる産生用細胞株および製造方法を開発した。ATB−200 rhGAAは高親和性(KD約2〜4nM)でCI−MPRに結合し、ポンペ線維芽細胞および骨格筋筋芽細胞によりに効率的に内在化された(Kuptake約7〜14nM)。
シャペロンはrhGAA ERTに結合して安定化させ、活性酵素の組織中への取り込みを増加させ、忍容性を改善し、免疫原性を潜在的に軽減する。上記に示すように、CHART(商標)を使用して、好ましくない条件下でのERTのタンパク質安定性を大幅に改善した。CHART:シャペロン改良型補充療法、参照により援用するhttp://_www.amicusrx.com/chaperone.aspx(最終アクセス2015年9月22日)を参照されたい。図13Aおよび図13Bに示すように、AT2221(ミグルスタット、N−ブチル−デオキシノジリマイシン)によりATB−200の安定性が有意に改善した。中性(pH7.4−血漿環境)緩衝液または酸性(pH5.2−リソソーム環境)緩衝液中での熱変性により、rhGAAタンパク質の折り畳みを37℃でモニタリングした。AT2220は、中性pH緩衝液中において24時間を超えてrhGAAタンパク質を安定化させた。
12週齢のGAA KOマウスをLumizyme(登録商標)またはATB200(20mg/kg IVの隔週での4回注射)で処置し、適応がある場合にrhGAAの30分前にミグルスタットを10mg/kgのPOで共投与した。グリコーゲン測定のために、最後の酵素用量の14日後に組織を採取した。図14は、四頭筋および三頭筋の骨格筋中のグリコーゲンの相対的低減を示す。
薬理学的シャペロンとATB−200 rhGAAとの組合せがin vivoでグリコーゲンクリアランスを増強することが分かった。GAA KOマウスに、隔週で20mg/kgにおいてrhGAAを2回IVボーラス投与した。薬理学的シャペロンAT2221を0、1、2および10mg/kgの投与量でrhGAAの30分前に経口投与した。ERTの最後の用量の2週後に組織を摘出し、GAA活性、グリコーゲン含有量、細胞特異的グリコーゲンおよびリソソーム増殖に関して分析した。
<本発明の更なる実施態様>
[実施態様1]
モノ−マンノース−6−リン酸(M6P)またはビス−M6Pを担持するN−グリカンを含むrhGAAを、Lumizyme(登録商標)(アルグルコシダーゼアルファ;CAS420794−05−0)により例示される従来のrhGAAと比べて多量に含む、CHO細胞に由来するrhGAA組成物。
[実施態様2]
前記rhGAAが、配列番号1で表されるアミノ酸配列と少なくとも95%同一であるアミノ酸配列を含む、実施態様1に記載のrhGAA組成物。
[実施態様3]
前記rhGAAの30%以上がカチオン非依存性マノース−6−リン酸受容体(CIMPR)に結合するか、または前記rhGAAの30%以上が、モノ−M6Pもしくはビス−M6Pを担持するN−グリカンを含む、実施態様1に記載のrhGAA組成物。
[実施態様4]
前記rhGAAの50%以上がカチオン非依存性マノース−6−リン酸受容体(CIMPR)に結合するか、または前記rhGAAの50%以上が、モノ−M6Pもしくはビス−M6Pを担持するN−グリカンを含む、実施態様1に記載のrhGAA組成物。
[実施態様5]
前記rhGAAの90%〜100%がカチオン非依存性マノース−6−リン酸受容体(CIMPR)に結合するか、または前記rhGAAの90%〜100%もしくはより多くが、モノ−M6Pもしくはビス−M6Pを担持するN−グリカンを含む、実施態様1に記載のrhGAA組成物。
[実施態様6]
M6Pを担持するN−グリカンの平均含有量が0.5〜7.0mol/mol rhGAAの範囲である、実施態様1に記載のrhGAA組成物。
[実施態様7]
M6Pを担持するN−グリカンの平均含有量が1.0〜4.0mol/mol rhGAAの範囲である、実施態様1に記載のrhGAA組成物。
[実施態様8]
M6Pを担持するN−グリカンの平均含有量が5.0〜6.0mol/mol rhGAAの範囲である、実施態様1に記載のrhGAA組成物。
[実施態様9]
平均して、前記N−グリカンが3mol/mol超のM6Pと4mol/mol超のシアル酸とを含む、実施態様1に記載のrhGAA組成物。
[実施態様10]
平均して、前記rhGAA上の前記N−グリカンの40〜60%が複合型N−グリカンであり、前記rhGAA上のN−グリカンの6.5%以下がハイブリッド型N−グリカンであり、前記rhGAA上の高マンノース型N−グリカンの15%以下が非リン酸化型であり、前記rhGAA上の前記高マンノース型N−グリカンの少なくとも10%がモノ−M6Pリン酸化型であり、および/または前記rhGAA上の前記高マンノース型N−グリカンの少なくとも2%がビス−M6Pリン酸化型である、実施態様1に記載のrhGAA組成物。
[実施態様11]
前記rhGAAが平均して、1molのrhGAA当たり2.0〜8.0個のシアル酸残基を担持する、実施態様1に記載の組成物。
[実施態様12]
前記rhGAAがCHO細胞株ATB200−001−X5−14によりまたはその継代培養物により産生される、実施態様1に記載の組成物。
[実施態様13]
シャペロンを更に含む、実施態様1に記載の組成物。
[実施態様14]
実施態様1に記載の組成物を製造する方法であって、CHO細胞株を培養することと、前記CHO細胞の培養物から前記組成物を回収することとを含む方法。
[実施態様15]
実施態様1に記載の組成物を産生するCHO細胞株。
[実施態様16]
実施態様1に記載の組成物を産生するCHO細胞株GA−ATB−200またはその継代培養物。
[実施態様17]
実施態様15に記載のCHO細胞株を製造する方法であって、rhGAAをコードするDNAでCHO細胞を形質転換させることと、前記rhGAAをコードするDNAを前記CHO細胞の染色体に安定的に組み込み、かつrhGAAを安定的に発現するCHO細胞を選択することと、M6Pまたはビス−M6Pを担持するグリカンの含有量が高いrhGAAを発現するCHO細胞を選択することと、任意選択で、シアル酸含有量が高いN−グリカンを有するおよび/または非リン酸化高マンノース含有量が低いN−グリカンを有するCHO細胞を選択することとを含む方法。
[実施態様18]
不十分なリソソームrhGAAに関連する状態、障害または疾患を処置する方法であって、実施態様1に記載の組成物を、それを必要とする対象に投与することを含む方法。
[実施態様19]
前記対象がグリコーゲン貯蔵症II型(ポンペ病)を有する、実施態様18に記載の方法。
[実施態様20]
前記組成物を前記対象の心筋に投与することを含む、実施態様18に記載の方法。
[実施態様21]
前記組成物を前記対象の四頭筋、三頭筋またはその他の骨格筋に投与することを含む、実施態様18に記載の方法。
[実施態様22]
前記組成物を前記対象の横隔膜に投与することを含む、実施態様18に記載の方法。
[実施態様23]
前記組成物が薬理学的シャペロンと組み合わされるか、それと共投与されるか、またはそれと共に別々に投与される、実施態様18に記載の方法。
[実施態様24]
前記組成物がAT2220もしくはその塩と組み合わされるか、それと共投与されるか、またはそれと共に別々に投与される、実施態様18に記載の方法。
[実施態様25]
前記組成物がAT2221もしくはその塩と組み合わされるか、それと共投与されるか、またはそれと共に別々に投与される、実施態様18に記載の方法。
[実施態様26]
組織、筋肉、筋繊維、筋細胞、リソソーム、オルガネラ、細胞内コンパートメントまたは細胞質中のグリコーゲンを代謝するか、分解するか、除去するか、またはその他に低減させる方法であって、任意選択でシャペロンまたはrhGAAに対する免疫応答を低減させる薬剤と共に、実施態様1に記載の組成物を対象に投与することを含む方法。
[実施態様27]
細胞中におけるリソソームの増殖、自食作用または開口分泌を調節する方法であって、任意選択でシャペロンとの組合せにおいて、実施態様1に記載の組成物を、それを必要とする対象に投与することを含む方法。
Claims (18)
- 組み換えヒト酸性α−グルコシダーゼ(rhGAA)を含む組成物であって、rhGAAにおけるN−グリカンの40%〜60%が複合型N−グリカンであり、かつrhGAAが、1molのrhGAAあたり3.0〜5.0molのマンノース−6−リン酸(M6P)残基を含む、組成物。
- rhGAAが、1molのrhGAAあたり3.0〜4.0molのM6Pを含む、請求項1に記載の組成物。
- rhGAAが、1molのrhGAAあたり4.0〜5.0molのM6Pを含む、請求項1に記載の組成物。
- rhGAAが、1molのrhGAAあたり少なくとも4molのシアル酸を更に含む、請求項1〜3の何れか一項に記載の組成物。
- rhGAAが、1molのrhGAAあたり2.0〜8.0molのシアル酸を更に含む、請求項1〜3の何れか一項に記載の組成物。
- rhGAAが、rhGAAあたり少なくとも1個のビス−リン酸化N−グリカンを含む、請求項1〜5の何れか一項に記載の組成物。
- rhGAAにおけるN−グリカンの45%〜55%が複合型N−グリカンである、請求項1〜6の何れか一項に記載の組成物。
- rhGAAにおけるN−グリカンの50%が複合型N−グリカンである、請求項1〜7の何れか一項に記載の組成物。
- rhGAAが、1molのrhGAAあたり4molのM6P、1molのrhGAAあたり4.5molのシアル酸、及びrhGAAあたり少なくとも1個のビス−リン酸化N−グリカンを含む、請求項1〜8の何れか一項に記載の組成物。
- 組成物が、薬理学的シャペロンを更に含む、請求項1〜9の何れか一項に記載の組成物。
- 薬理学的シャペロンが、1−デオキシノジリマイシン又は薬理学的に許容されるその塩、及びN−ブチル−デオキシノジリマイシンまたは薬理学的に許容されるその塩からなる群から選択される、請求項10に記載の組成物。
- それを必要とする対象におけるポンペ病の治療における使用のための、請求項1〜11の何れか一項に記載の組成物。
- 対象の心筋に投与される、請求項12に記載の組成物。
- 対象の四頭筋、三頭筋またはその他の骨格筋に投与される、請求項12に記載の組成物。
- 対象の横隔膜に投与される、請求項12に記載の組成物。
- 組成物が薬理学的シャペロンと組み合わされ、かつ組成物と薬理学的シャペロンは単一の薬学的組成物として投与される、または別々に投与される、請求項12〜15の何れか一項に記載の組成物。
- 薬理学的シャペロンが、1−デオキシノジリマイシン、または薬学的に許容されるその塩である、請求項16に記載の組成物。
- 薬理学的シャペロンが、N−ブチル−デオキシノジリマイシン、または薬学的に許容されるその塩である、請求項16に記載の組成物。
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