JP2023051927A - 組換えヒト酸性アルファグリコシダーゼ - Google Patents
組換えヒト酸性アルファグリコシダーゼ Download PDFInfo
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Abstract
Description
本出願は、それぞれの優先権が主張され、それぞれが参照によりその全体が組み込まれる、米国仮特許出願第62/506,561号、2017年5月15日出願、米国仮特許出願第62/506,569号、2017年5月15日出願、米国仮特許出願第62/506,574号、2017年5月15日出願、米国仮特許出願第62/564,083号、2017年9月27日出願、米国仮特許出願第62/567,334号、2017年10月3日出願、米国仮特許出願第62/618,021号、2018年1月16日、米国仮特許出願第62/624,638号、2018年1月31日出願および米国仮特許出願第62/660,758号、2018年4月20日出願の利益を主張する。
本発明は、医薬、遺伝学および組換え糖タンパク質生化学の分野に関与し、具体的には、細胞上のCIMPRを効率的に標的化し、次いでrhGAAを、異常に高いレベルに蓄積したグリコーゲンをそれが分解できるリソソームに送達するマンノース-6-リン酸保有N-グリカンの高い総含有量を有する、組換えヒトα-グルコシダーゼ(rhGAA)組成物に関する。本発明のrhGAAは、従来のrhGAA産生物と比較して優れた筋細胞への取り込み、次いでリソソームへの送達を示し、ポンペ病を有する対象の酵素補充療法のためにそれを特に有効にする他の薬物動態学的特性を示す。
ポンペ病は、酸性αグルコシダーゼ(GAA)活性の欠乏から生じる遺伝性リソソーム貯蔵疾患である。ポンペ病を有する者は、グリコーゲンをグルコース、筋肉のための主なエネルギー源に分解する酵素、酸性αグルコシダーゼ(GAA)を欠いているまたはレベルが低減している。この酵素の欠乏は、通常グリコーゲンおよび他の細胞性デブリまたは老廃物を分解する酵素を含有する細胞内オルガネラであるリソソームにおける過剰なグリコーゲン蓄積を生じる。ポンペ病を有する対象のある特定の組織、特に筋肉におけるグリコーゲン蓄積は、正常に機能する細胞の能力を損なう。ポンペ病では、グリコーゲンは、適切に代謝されず、リソソーム、特に骨格筋細胞中および疾患の乳児発症形態では心筋細胞に進行性で蓄積される。グリコーゲンの蓄積は、筋肉および神経の細胞ならびに罹患した他の組織のものを損傷する。
本明細書において使用される用語は、本発明の内容におけるおよび各用語が使用される具体的な内容における当該技術分野でのそれらの通常の意味を一般に有する。ある特定の用語は、本発明の組成物および方法ならびにそれらをどのように作製および使用するかを記載して、施術者に追加的な指針を提供するために、下に、または本明細書他所で考察される。冠詞「1つの(a)」および「1つの(an)」は、冠詞の文法的目的物の1つまたは1つより多く(すなわち、少なくとも1つ)を指す。用語「または」は、内容が他を明確に示さない限り、用語「および/または」を意味し、互換的に使用される。本出願において単数形の使用は、別に具体的に明記しない限り複数形を含む。さらに用語「含む(including)」ならびに「含む(includes)」および「含んだ(included)」などの他の形態の使用は、限定ではない。本明細書に記載される任意の範囲は、エンドポイントおよびエンドポイント間のすべての値を含むと理解される。語または必要な関連事項を表現するために内容が他を必要とする場合を除いて、本明細書において、語「含む(comprises)」または「含んでいる(comprising)」などの変化形は、包括的意味で使用される、すなわち、本発明の種々の実施形態において述べられる特性の存在を特定するが、さらなる特性の存在または付加を除外しない。
を有する化合物である。
を有する化合物である。
・タンパク質の安定な分子立体構造の形成を増強すること;
・小胞体から別の細胞位置、好ましくは天然での細胞位置へのタンパク質の適切な輸送を増強し、それによりタンパク質の小胞体関連分解を妨げること;
・立体構造的に不安定なまたはミスフォールドしたタンパク質の凝集を妨げること;
・タンパク質の少なくとも部分的な野生型機能、安定性および/もしくは活性を回復および/もしくは増強すること;ならびに/または
・酸性αグルコシダーゼを担持する細胞の表現型もしくは機能を改善すること
の1つまたは複数を有する分子を指すことが意図される。
一部の実施形態では、組換えヒト酸性αグルコシダーゼ(rhGAA)は、配列番号1、配列番号3、配列番号4または配列番号5に記載されるアミノ酸配列を有する酵素である。一部の実施形態では、rhGAAは、配列番号2に記載されるヌクレオチド配列によってコードされる。
単一のrhGAA分子上に7個の潜在的N結合グリコシル化部位がある。これらの潜在的グリコシル化部位は、配列番号5の次の位置:N84、N177、N334、N414、N596、N826およびN869にある。同様に、配列番号1の全長アミノ酸配列について、これらの潜在的グリコシル化部位は、次の位置:N140、N233、N390、N470、N652、N882およびN925にある。rhGAAの他の変異体は、アスパラギン残基の位置に応じて同様のグリコシル化部位を有し得る。一般に、タンパク質中のアミノ酸配列のAsn-X-SerまたはAsn-X-Thrの配列は、XがHisまたはProになりえない例外を有して、潜在的グリコシル化部位を示す。
その全体が参照により本明細書に組み込まれる国際出願第PCT/US2015/053252号に記載のとおり、チャイニーズハムスター卵巣(CHO)細胞などの細胞は、本明細書に記載のrhGAAを産生するために使用され得る。CHO細胞において高M6P rhGAAを発現することは、前者だけがグリカンデグレーション(degration)によって最適なグリコーゲン加水分解を有するrhGAAの形態に転換され得、それにより治療有効性が増強されることから少なくとも部分的に、rhGAAのグリカンプロファイルを翻訳後に修飾することに有利である。
種々の実施形態では、本明細書に記載のrhGAAを単独でまたは他の治療剤および/もしくは薬学的に許容される担体との組合せで含む薬学的組成物は提供される。
A.疾患の処置
本発明の別の態様は、本明細書に記載のrhGAAまたは薬学的組成物を投与することによるグリコーゲン貯蔵調節不全に関する疾患または障害の処置の方法に関する。一部の実施形態では、疾患はポンペ病(酸性マルターゼ欠損症(AMD)およびグリコーゲン貯蔵疾患II型(GSD II)としても周知)である。一部の実施形態では、rhGAAはATB200である。一部の実施形態では、薬学的組成物はATB200を含む。
尿中ヘキソース四糖(Hex4)などの対象の筋線維におけるグリコーゲン蓄積のバイオマーカーは、ポンペ病を有する対象における酵素補充療法の治療効果を評価および比較するために使用され得る。一部の実施形態では、rhGAAまたはrhGAAを含む薬学的組成物のグリコーゲン蓄積への治療効果は、対象におけるHex4のレベルを測定することによって評価される。
薬学的製剤または再構成組成物は、治療的有効量(例えば、一定間隔で投与される場合、疾患に関連する症候を改善する、疾患の発症を予防するもしくは遅らせる、および/または疾患の症候の重症度もしくは頻度を軽減する、などの疾患を処置するために十分である投薬量)で投与される。疾患の処置において治療有効である量は、疾患の影響の性質および程度に応じる場合があり、標準的臨床技術によって決定され得る。加えて、インビトロまたはインビボアッセイは、最適投薬範囲を同定することを補助するために任意選択で使用され得る。少なくとも1つの実施形態では、本明細書に記載のrhGAAまたはrhGAAを含む薬学的組成物は、約5mg/kgから約30mg/kg、典型的には約5mg/kgから約20mg/kgなどの約1mg/kgから約100mg/kgの用量で投与される。少なくとも1つの実施形態では、本明細書に記載のrhGAAまたは薬学的組成物は、約5mg/kg、約10mg/kg、約15mg/kg、約20mg/kg、約25mg/kg、約30mg/kg、約35mg/kg、約40mg/kg、約50mg/kg、約50mg/kg、約60mg/kg、約70mg/kg、約80mg/kg、約90mg/kgまたは約100mg/kgの用量で投与される。一部の実施形態では、rhGAAは、5mg/kg、10mg/kg、20mg/kg、50mg/kg、75mg/kgまたは100mg/kgの用量で投与される。少なくとも1つの実施形態では、rhGAAまたは薬学的組成物は、約20mg/kgの用量で投与される。一部の実施形態では、rhGAAまたは薬学的組成物は、薬理的シャペロンと同時にまたは連続的に投与される。一部の実施形態では、薬理的シャペロンはミグルスタットである。少なくとも1つの実施形態では、ミグルスタットは、約260mgの経口用量として投与される。具体的な個体のための有効用量は、経時的に、個体の必要性に応じて変動(例えば、増加または減少)する場合がある。例えば、身体的疾患もしくはストレスの時期、または抗酸性αグルコシダーゼ抗体が存在するようになるもしくは増加する場合、または病徴が悪化した場合、量は増加されてよい。
1つまたは複数の実施形態では、本明細書に記載のrhGAAまたはrhGAAを含む薬学的組成物は、薬理的シャペロンと同時にまたは連続的に投与される。一部の実施形態では、rhGAAまたは薬学的組成物は、薬理的シャペロンとは異なる経路を介して投与される。例えば薬理的シャペロンは、経口投与される一方でrhGAAまたは薬学的組成物は、静脈内投与される。
本発明の別の態様は、本明細書に記載のrhGAAまたは薬学的組成物を含むキットに関する。1つまたは複数の実施形態では、キットは、rhGAAまたは薬学的組成物(凍結乾燥前または後のいずれか)および再構成、希釈および投与のための説明書を含む容器(例えば、バイアル、チューブ、袋など)を含む。
DG44 CHO(DHFR-)細胞をrhGAAを発現するDNAコンストラクトを用いてトランスフェクトした。DNAコンストラクトを図4に示す。トランスフェクション後、安定に組み込まれたGAA遺伝子を含有するCHO細胞をヒポキサンチン/チミジン欠乏性(-HT)培地)を用いて選択した。これらの細胞でのGAA発現をメトトレキサート処置(MTX、500nM)によって誘導した。
本発明によるrhGAAの複数のバッチをCHO細胞株GA-ATB200を使用して振盪フラスコにおいておよび灌流バイオリアクターにおいて産生し、その産生物を「ATB200」と称する。弱陰イオン交換(「WAX」)液体クロマトグラフィーを末端リン酸塩およびシアル酸によりATB200 rhGAAを分画するために使用した。溶出プロファイルを塩の量を増加させてERTを溶出することによって生成した。プロファイルをUV(A280nm)によってモニターした。同様のCIMPR受容体結合(少なくとも約70%)プロファイルをさまざまな産生バッチ由来の精製ATB200 rhGAAについて観察し(図5)、ATB200 rhGAAが持続的に産生され得ることを示している。
ATB200 rhGAAをさまざまなLC-MS/MS分析技術を使用して部位特異的N-グリカンプロファイルについて分析した。最初の2種のLC-MS/MS法の結果を図6A~6Hに示す。第3のLC-MS/MS法の結果を2-AAグリカンマッピングと共に図32A~32H、図33A~33Bおよび表5に示す。
精製したATB200およびLumizyme(登録商標)N-グリカンを各ERTで見出される個々のN-グリカン構造を決定するためにMALDI-TOFによって評価した。Lumizyme(登録商標)は市販の供給源から得た。図7に示すとおり、ATB200は、Lumizyme(登録商標)の右に溶出される4つの突出したピークを示した。これは、この評価がCIMPR親和性よりも末端電荷によることから、ATB200がLumizyme(登録商標)よりも高い程度でリン酸化されたことを確認している。図8に要約する、Lumizyme(登録商標)よりもATB200試料は、少ない量の非リン酸化高マンノース型N-グリカンを含有することが見出された。
酸性または中性pHバッファー中でのATB200の安定性を、タンパク質が変性すると色素の蛍光が増加するSYPRO Orangeを使用する熱安定性アッセイにおいて評価した。図12に示すとおり、リソソームの酸性環境を模倣する条件pH5.2でのATB200の安定性と比較して、AT2221の添加は、ATB200をpH7.4で濃度依存的様式で安定化した。表6に要約するとおり、AT2221の添加は、ATB200の融解温度(Tm)を10oC近く上昇させた。
ATB200およびAT2221の治療効果をGaa KOマウスにおいて評価および、アルグルコシダーゼアルファに対して比較した。研究のためにオスGaa KO(3から4月齢)および同齢野生型(WT)マウスを使用した。アルグルコシダーゼアルファをボーラス尾静脈静脈内(IV)注射を介して投与した。同時投与レジメンでAT2221を経口経管栄養(PO)を介して、ATB200のIV注射に30分間先行して投与した。処置は、2週間に1回で与えた。処置マウスを最終投与14日後に屠殺し、種々の組織をさらなる分析のために回収した。表7は研究設計を要約している:
図17に示すとおり、ビヒクル処置マウスの大部分が大幅に肥大したリソソーム(緑)(、例えば「B」を参照されたい)、広範なオートファジーのビルドアップ(赤)(例えば「A」を参照されたい)の存在を示した。Myozyme(登録商標)処置マウスは、ビヒクル処置マウスと比較していかなる顕著な差異も示さなかった。対照的に、ATB200を用いて処置したマウスから単離したほとんどの線維は、劇的に減少したリソソームのサイズを示した(例えば「C」を参照されたい)。さらに、オートファジーのビルドアップを有する面積も種々の程度で低減した(例えば「C」を参照されたい)。結果として、ATB200処置マウス由来の分析した筋線維のかなりの部分(36~60%)が、正常または正常に近いと考えられた。下の表8は、図17に示す単一線維分析を要約している。
前臨床研究を、薬物動態(PK)およびグリコーゲン低減の効率を評価するためにATB200酵素補充療法(ERT)およびAT2221シャペロン用量を変動させてGaaノックアウトマウスにおいて実施した。これらのデータをヒトでの相当するAT2221シャペロン用量を推定するために使用した。次に研究ATB200-02(NCT02675465)を非盲検固定連続、漸増投与、ファースト・イン・ヒューマン、第1/2相研究として、ポンペ病を有する患者にAT2221と共投与するATB200の安全性、忍容性、PK、薬力学的(PD)および有効性を評価するために設計した。図19A~19Bは、ATB200-02研究設計を示している。アルグルコシダーゼアルファを用いる酵素補充療法を以前受けた歩行可能患者は、歩行可能ERT-切り替え(もしくはERT-切り替え歩行可能)患者またはコホート1患者と称される。アルグルコシダーゼアルファを用いる酵素補充療法を以前受けた歩行不能患者は、歩行不能ERT-切り替え(もしくはERT-切り替え歩行不能)患者またはコホート2患者と称される。アルグルコシダーゼアルファを用いる酵素補充療法を以前受けていない歩行可能患者は、ERT-未処置(もしくはERT-未処置歩行可能)患者またはコホート3患者と称される。
AT2221についての薬物動態データの概要を図20に示す。ATB200について5mg/kg、10mg/kgおよび20mg/kgでの血漿中の総GAAタンパク質濃度をrhGAA-特異的「シグネチャー」ペプチド(複数可)T09(一次)およびT50(確認)の検証されたLC-MS/MS定量によってステージ1および2を完了した11名のコホート1患者について、ならびにステージ3でPK研究を完了した5名のコホート2患者について決定した。ステージ1について、血漿総GAAタンパク質濃度のための血液試料をATB200点滴の開始に先行してならびに点滴の開始1、2、3、3.5、4、4.5、5、6、8、10、12および24時間後に回収した。ステージ2およびステージ3について、血漿総GAAタンパク質濃度のための血液試料を点滴の開始に先行してならびに点滴開始の1、2、3、3.5、4、4.5、5、6、8、10、12および24時間後に回収した。
図24Aおよび24Bに示すとおり、6MWTは、歩行可能ERT-切り替え患者およびERT-未処置患者を6カ月時点で改善し、観察された利益は12カ月まで継続した。6MWTは、6、9および12カ月でそれぞれ7/10名、8/10名および8/8名のERT-切り替え患者において増加した。6MWTは、6、9および12カ月でそれぞれ5/5名、5/5名および2/2名のERT-未処置患者において増加した。
次の筋肉損傷マーカーを評価した:クレアチンキナーゼ(CK)酵素、アラニンアミノトランスフェラーゼ(ALT)およびアスパラギン酸アミノトランスフェラーゼ(AST)。9カ月間の臨床治験後に入手できる結果を図29A~29Cに報告する(コホート1、2および3についてそれぞれ最大58週間、24週間および36週間から得たデータ;低いn値は、一部のデータが分析できなかったか、またはまだ分析されていないかのいずれかを示している)。これらそれぞれの時点で観察されたベースラインからの平均低減は、およそ、歩行可能ERT-切り替え患者(n=9)について30~35%、歩行不能ERT-切り替え患者(n=4)について5~20%、およびERT-未処置患者(n=5)について40~55%であった。12カ月の臨床治験後に得られたCK酵素についての結果は、図29Dに報告されている(コホート1、2および3について最大12カ月から得たデータ;低いn値は、一部のデータが分析できなかったか、またはまだ分析されていないかのいずれかを示す)。
処置の最も長い継続期間は、20カ月を超えた。有害事象(AE)は、3つすべてのコホートにわたる合計400を超える点滴後に非常に低い率の点滴関連反応(1%未満)を伴って、一般に軽度で一過性であった。これらの発生は、標準的な前投薬によってコントロールされた。
図31に要約のとおり、さまざまなコホートにわたって筋損傷および基質蓄積のマーカー、筋肉機能検査(時限検査および持続時間)、徒手筋力強度の顕著で予想外の平行する改善、ならびに呼吸機能検査での安定化および/または改善を示すATB200-02治験からの中間データに一致がある。筋肉機能は6および9カ月でそれぞれ16/18名および10/10名の患者において改善した。6MWT距離における増加は、ERT-切り替え歩行可能およびERT-未処置患者において12カ月まで一貫し、恒久的であり、ERT-切り替え歩行可能およびERT-未処置患者における他の運動機能検査における改善と同様であった。定性的および定量的測定は、歩行不能ERT-切り替え患者における上肢強度に6および9カ月で増加を示した。FVC、MIPおよびMEPは、ERT-切り替え患者において一般に安定であり、ERT-未処置患者において増加した。疲労スコアにおける改善は、すべてのコホートにおいた観察された。バイオマーカーレベル(例えば、CKおよびHex4のレベル)は、すべてのコホートにおいて減少し、ATB200/AT2221は全般に良好な耐容性を示した。
SEQUENCE LISTING
<110> AMICUS THERAPEUTICS, INC.
<120> RECOMBINANT HUMAN ACID ALPHA-GLUCOSIDASE
<130> 14322.12-304
<140>
<141>
<150> 62/660,758
<151> 2018-04-20
<150> 62/624,638
<151> 2018-01-31
<150> 62/618,021
<151> 2018-01-16
<150> 62/567,334
<151> 2017-10-03
<150> 62/564,083
<151> 2017-09-27
<150> 62/506,574
<151> 2017-05-15
<150> 62/506,569
<151> 2017-05-15
<150> 62/506,561
<151> 2017-05-15
<160> 5
<170> PatentIn version 3.5
<210> 1
<211> 952
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 1
Met Gly Val Arg His Pro Pro Cys Ser His Arg Leu Leu Ala Val Cys
1 5 10 15
Ala Leu Val Ser Leu Ala Thr Ala Ala Leu Leu Gly His Ile Leu Leu
20 25 30
His Asp Phe Leu Leu Val Pro Arg Glu Leu Ser Gly Ser Ser Pro Val
35 40 45
Leu Glu Glu Thr His Pro Ala His Gln Gln Gly Ala Ser Arg Pro Gly
50 55 60
Pro Arg Asp Ala Gln Ala His Pro Gly Arg Pro Arg Ala Val Pro Thr
65 70 75 80
Gln Cys Asp Val Pro Pro Asn Ser Arg Phe Asp Cys Ala Pro Asp Lys
85 90 95
Ala Ile Thr Gln Glu Gln Cys Glu Ala Arg Gly Cys Cys Tyr Ile Pro
100 105 110
Ala Lys Gln Gly Leu Gln Gly Ala Gln Met Gly Gln Pro Trp Cys Phe
115 120 125
Phe Pro Pro Ser Tyr Pro Ser Tyr Lys Leu Glu Asn Leu Ser Ser Ser
130 135 140
Glu Met Gly Tyr Thr Ala Thr Leu Thr Arg Thr Thr Pro Thr Phe Phe
145 150 155 160
Pro Lys Asp Ile Leu Thr Leu Arg Leu Asp Val Met Met Glu Thr Glu
165 170 175
Asn Arg Leu His Phe Thr Ile Lys Asp Pro Ala Asn Arg Arg Tyr Glu
180 185 190
Val Pro Leu Glu Thr Pro Arg Val His Ser Arg Ala Pro Ser Pro Leu
195 200 205
Tyr Ser Val Glu Phe Ser Glu Glu Pro Phe Gly Val Ile Val His Arg
210 215 220
Gln Leu Asp Gly Arg Val Leu Leu Asn Thr Thr Val Ala Pro Leu Phe
225 230 235 240
Phe Ala Asp Gln Phe Leu Gln Leu Ser Thr Ser Leu Pro Ser Gln Tyr
245 250 255
Ile Thr Gly Leu Ala Glu His Leu Ser Pro Leu Met Leu Ser Thr Ser
260 265 270
Trp Thr Arg Ile Thr Leu Trp Asn Arg Asp Leu Ala Pro Thr Pro Gly
275 280 285
Ala Asn Leu Tyr Gly Ser His Pro Phe Tyr Leu Ala Leu Glu Asp Gly
290 295 300
Gly Ser Ala His Gly Val Phe Leu Leu Asn Ser Asn Ala Met Asp Val
305 310 315 320
Val Leu Gln Pro Ser Pro Ala Leu Ser Trp Arg Ser Thr Gly Gly Ile
325 330 335
Leu Asp Val Tyr Ile Phe Leu Gly Pro Glu Pro Lys Ser Val Val Gln
340 345 350
Gln Tyr Leu Asp Val Val Gly Tyr Pro Phe Met Pro Pro Tyr Trp Gly
355 360 365
Leu Gly Phe His Leu Cys Arg Trp Gly Tyr Ser Ser Thr Ala Ile Thr
370 375 380
Arg Gln Val Val Glu Asn Met Thr Arg Ala His Phe Pro Leu Asp Val
385 390 395 400
Gln Trp Asn Asp Leu Asp Tyr Met Asp Ser Arg Arg Asp Phe Thr Phe
405 410 415
Asn Lys Asp Gly Phe Arg Asp Phe Pro Ala Met Val Gln Glu Leu His
420 425 430
Gln Gly Gly Arg Arg Tyr Met Met Ile Val Asp Pro Ala Ile Ser Ser
435 440 445
Ser Gly Pro Ala Gly Ser Tyr Arg Pro Tyr Asp Glu Gly Leu Arg Arg
450 455 460
Gly Val Phe Ile Thr Asn Glu Thr Gly Gln Pro Leu Ile Gly Lys Val
465 470 475 480
Trp Pro Gly Ser Thr Ala Phe Pro Asp Phe Thr Asn Pro Thr Ala Leu
485 490 495
Ala Trp Trp Glu Asp Met Val Ala Glu Phe His Asp Gln Val Pro Phe
500 505 510
Asp Gly Met Trp Ile Asp Met Asn Glu Pro Ser Asn Phe Ile Arg Gly
515 520 525
Ser Glu Asp Gly Cys Pro Asn Asn Glu Leu Glu Asn Pro Pro Tyr Val
530 535 540
Pro Gly Val Val Gly Gly Thr Leu Gln Ala Ala Thr Ile Cys Ala Ser
545 550 555 560
Ser His Gln Phe Leu Ser Thr His Tyr Asn Leu His Asn Leu Tyr Gly
565 570 575
Leu Thr Glu Ala Ile Ala Ser His Arg Ala Leu Val Lys Ala Arg Gly
580 585 590
Thr Arg Pro Phe Val Ile Ser Arg Ser Thr Phe Ala Gly His Gly Arg
595 600 605
Tyr Ala Gly His Trp Thr Gly Asp Val Trp Ser Ser Trp Glu Gln Leu
610 615 620
Ala Ser Ser Val Pro Glu Ile Leu Gln Phe Asn Leu Leu Gly Val Pro
625 630 635 640
Leu Val Gly Ala Asp Val Cys Gly Phe Leu Gly Asn Thr Ser Glu Glu
645 650 655
Leu Cys Val Arg Trp Thr Gln Leu Gly Ala Phe Tyr Pro Phe Met Arg
660 665 670
Asn His Asn Ser Leu Leu Ser Leu Pro Gln Glu Pro Tyr Ser Phe Ser
675 680 685
Glu Pro Ala Gln Gln Ala Met Arg Lys Ala Leu Thr Leu Arg Tyr Ala
690 695 700
Leu Leu Pro His Leu Tyr Thr Leu Phe His Gln Ala His Val Ala Gly
705 710 715 720
Glu Thr Val Ala Arg Pro Leu Phe Leu Glu Phe Pro Lys Asp Ser Ser
725 730 735
Thr Trp Thr Val Asp His Gln Leu Leu Trp Gly Glu Ala Leu Leu Ile
740 745 750
Thr Pro Val Leu Gln Ala Gly Lys Ala Glu Val Thr Gly Tyr Phe Pro
755 760 765
Leu Gly Thr Trp Tyr Asp Leu Gln Thr Val Pro Ile Glu Ala Leu Gly
770 775 780
Ser Leu Pro Pro Pro Pro Ala Ala Pro Arg Glu Pro Ala Ile His Ser
785 790 795 800
Glu Gly Gln Trp Val Thr Leu Pro Ala Pro Leu Asp Thr Ile Asn Val
805 810 815
His Leu Arg Ala Gly Tyr Ile Ile Pro Leu Gln Gly Pro Gly Leu Thr
820 825 830
Thr Thr Glu Ser Arg Gln Gln Pro Met Ala Leu Ala Val Ala Leu Thr
835 840 845
Lys Gly Gly Glu Ala Arg Gly Glu Leu Phe Trp Asp Asp Gly Glu Ser
850 855 860
Leu Glu Val Leu Glu Arg Gly Ala Tyr Thr Gln Val Ile Phe Leu Ala
865 870 875 880
Arg Asn Asn Thr Ile Val Asn Glu Leu Val Arg Val Thr Ser Glu Gly
885 890 895
Ala Gly Leu Gln Leu Gln Lys Val Thr Val Leu Gly Val Ala Thr Ala
900 905 910
Pro Gln Gln Val Leu Ser Asn Gly Val Pro Val Ser Asn Phe Thr Tyr
915 920 925
Ser Pro Asp Thr Lys Val Leu Asp Ile Cys Val Ser Leu Leu Met Gly
930 935 940
Glu Gln Phe Leu Val Ser Trp Cys
945 950
<210> 2
<211> 3624
<212> DNA
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polynucleotide
<400> 2
cagttgggaa agctgaggtt gtcgccgggg ccgcgggtgg aggtcgggga tgaggcagca 60
ggtaggacag tgacctcggt gacgcgaagg accccggcca cctctaggtt ctcctcgtcc 120
gcccgttgtt cagcgaggga ggctctgggc ctgccgcagc tgacggggaa actgaggcac 180
ggagcgggcc tgtaggagct gtccaggcca tctccaacca tgggagtgag gcacccgccc 240
tgctcccacc ggctcctggc cgtctgcgcc ctcgtgtcct tggcaaccgc tgcactcctg 300
gggcacatcc tactccatga tttcctgctg gttccccgag agctgagtgg ctcctcccca 360
gtcctggagg agactcaccc agctcaccag cagggagcca gcagaccagg gccccgggat 420
gcccaggcac accccggccg tcccagagca gtgcccacac agtgcgacgt cccccccaac 480
agccgcttcg attgcgcccc tgacaaggcc atcacccagg aacagtgcga ggcccgcggc 540
tgctgctaca tccctgcaaa gcaggggctg cagggagccc agatggggca gccctggtgc 600
ttcttcccac ccagctaccc cagctacaag ctggagaacc tgagctcctc tgaaatgggc 660
tacacggcca ccctgacccg taccaccccc accttcttcc ccaaggacat cctgaccctg 720
cggctggacg tgatgatgga gactgagaac cgcctccact tcacgatcaa agatccagct 780
aacaggcgct acgaggtgcc cttggagacc ccgcgtgtcc acagccgggc accgtcccca 840
ctctacagcg tggagttctc cgaggagccc ttcggggtga tcgtgcaccg gcagctggac 900
ggccgcgtgc tgctgaacac gacggtggcg cccctgttct ttgcggacca gttccttcag 960
ctgtccacct cgctgccctc gcagtatatc acaggcctcg ccgagcacct cagtcccctg 1020
atgctcagca ccagctggac caggatcacc ctgtggaacc gggaccttgc gcccacgccc 1080
ggtgcgaacc tctacgggtc tcaccctttc tacctggcgc tggaggacgg cgggtcggca 1140
cacggggtgt tcctgctaaa cagcaatgcc atggatgtgg tcctgcagcc gagccctgcc 1200
cttagctgga ggtcgacagg tgggatcctg gatgtctaca tcttcctggg cccagagccc 1260
aagagcgtgg tgcagcagta cctggacgtt gtgggatacc cgttcatgcc gccatactgg 1320
ggcctgggct tccacctgtg ccgctggggc tactcctcca ccgctatcac ccgccaggtg 1380
gtggagaaca tgaccagggc ccacttcccc ctggacgtcc aatggaacga cctggactac 1440
atggactccc ggagggactt cacgttcaac aaggatggct tccgggactt cccggccatg 1500
gtgcaggagc tgcaccaggg cggccggcgc tacatgatga tcgtggatcc tgccatcagc 1560
agctcgggcc ctgccgggag ctacaggccc tacgacgagg gtctgcggag gggggttttc 1620
atcaccaacg agaccggcca gccgctgatt gggaaggtat ggcccgggtc cactgccttc 1680
cccgacttca ccaaccccac agccctggcc tggtgggagg acatggtggc tgagttccat 1740
gaccaggtgc ccttcgacgg catgtggatt gacatgaacg agccttccaa cttcatcaga 1800
ggctctgagg acggctgccc caacaatgag ctggagaacc caccctacgt gcctggggtg 1860
gttgggggga ccctccaggc ggccaccatc tgtgcctcca gccaccagtt tctctccaca 1920
cactacaacc tgcacaacct ctacggcctg accgaagcca tcgcctccca cagggcgctg 1980
gtgaaggctc gggggacacg cccatttgtg atctcccgct cgacctttgc tggccacggc 2040
cgatacgccg gccactggac gggggacgtg tggagctcct gggagcagct cgcctcctcc 2100
gtgccagaaa tcctgcagtt taacctgctg ggggtgcctc tggtcggggc cgacgtctgc 2160
ggcttcctgg gcaacacctc agaggagctg tgtgtgcgct ggacccagct gggggccttc 2220
taccccttca tgcggaacca caacagcctg ctcagtctgc cccaggagcc gtacagcttc 2280
agcgagccgg cccagcaggc catgaggaag gccctcaccc tgcgctacgc actcctcccc 2340
cacctctaca cactgttcca ccaggcccac gtcgcggggg agaccgtggc ccggcccctc 2400
ttcctggagt tccccaagga ctctagcacc tggactgtgg accaccagct cctgtggggg 2460
gaggccctgc tcatcacccc agtgctccag gccgggaagg ccgaagtgac tggctacttc 2520
cccttgggca catggtacga cctgcagacg gtgccaatag aggcccttgg cagcctccca 2580
cccccacctg cagctccccg tgagccagcc atccacagcg aggggcagtg ggtgacgctg 2640
ccggcccccc tggacaccat caacgtccac ctccgggctg ggtacatcat ccccctgcag 2700
ggccctggcc tcacaaccac agagtcccgc cagcagccca tggccctggc tgtggccctg 2760
accaagggtg gagaggcccg aggggagctg ttctgggacg atggagagag cctggaagtg 2820
ctggagcgag gggcctacac acaggtcatc ttcctggcca ggaataacac gatcgtgaat 2880
gagctggtac gtgtgaccag tgagggagct ggcctgcagc tgcagaaggt gactgtcctg 2940
ggcgtggcca cggcgcccca gcaggtcctc tccaacggtg tccctgtctc caacttcacc 3000
tacagccccg acaccaaggt cctggacatc tgtgtctcgc tgttgatggg agagcagttt 3060
ctcgtcagct ggtgttagcc gggcggagtg tgttagtctc tccagaggga ggctggttcc 3120
ccagggaagc agagcctgtg tgcgggcagc agctgtgtgc gggcctgggg gttgcatgtg 3180
tcacctggag ctgggcacta accattccaa gccgccgcat cgcttgtttc cacctcctgg 3240
gccggggctc tggcccccaa cgtgtctagg agagctttct ccctagatcg cactgtgggc 3300
cggggcctgg agggctgctc tgtgttaata agattgtaag gtttgccctc ctcacctgtt 3360
gccggcatgc gggtagtatt agccaccccc ctccatctgt tcccagcacc ggagaagggg 3420
gtgctcaggt ggaggtgtgg ggtatgcacc tgagctcctg cttcgcgcct gctgctctgc 3480
cccaacgcga ccgcttcccg gctgcccaga gggctggatg cctgccggtc cccgagcaag 3540
cctgggaact caggaaaatt cacaggactt gggagattct aaatcttaag tgcaattatt 3600
ttaataaaag gggcatttgg aatc 3624
<210> 3
<211> 952
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 3
Met Gly Val Arg His Pro Pro Cys Ser His Arg Leu Leu Ala Val Cys
1 5 10 15
Ala Leu Val Ser Leu Ala Thr Ala Ala Leu Leu Gly His Ile Leu Leu
20 25 30
His Asp Phe Leu Leu Val Pro Arg Glu Leu Ser Gly Ser Ser Pro Val
35 40 45
Leu Glu Glu Thr His Pro Ala His Gln Gln Gly Ala Ser Arg Pro Gly
50 55 60
Pro Arg Asp Ala Gln Ala His Pro Gly Arg Pro Arg Ala Val Pro Thr
65 70 75 80
Gln Cys Asp Val Pro Pro Asn Ser Arg Phe Asp Cys Ala Pro Asp Lys
85 90 95
Ala Ile Thr Gln Glu Gln Cys Glu Ala Arg Gly Cys Cys Tyr Ile Pro
100 105 110
Ala Lys Gln Gly Leu Gln Gly Ala Gln Met Gly Gln Pro Trp Cys Phe
115 120 125
Phe Pro Pro Ser Tyr Pro Ser Tyr Lys Leu Glu Asn Leu Ser Ser Ser
130 135 140
Glu Met Gly Tyr Thr Ala Thr Leu Thr Arg Thr Thr Pro Thr Phe Phe
145 150 155 160
Pro Lys Asp Ile Leu Thr Leu Arg Leu Asp Val Met Met Glu Thr Glu
165 170 175
Asn Arg Leu His Phe Thr Ile Lys Asp Pro Ala Asn Arg Arg Tyr Glu
180 185 190
Val Pro Leu Glu Thr Pro Arg Val His Ser Arg Ala Pro Ser Pro Leu
195 200 205
Tyr Ser Val Glu Phe Ser Glu Glu Pro Phe Gly Val Ile Val His Arg
210 215 220
Gln Leu Asp Gly Arg Val Leu Leu Asn Thr Thr Val Ala Pro Leu Phe
225 230 235 240
Phe Ala Asp Gln Phe Leu Gln Leu Ser Thr Ser Leu Pro Ser Gln Tyr
245 250 255
Ile Thr Gly Leu Ala Glu His Leu Ser Pro Leu Met Leu Ser Thr Ser
260 265 270
Trp Thr Arg Ile Thr Leu Trp Asn Arg Asp Leu Ala Pro Thr Pro Gly
275 280 285
Ala Asn Leu Tyr Gly Ser His Pro Phe Tyr Leu Ala Leu Glu Asp Gly
290 295 300
Gly Ser Ala His Gly Val Phe Leu Leu Asn Ser Asn Ala Met Asp Val
305 310 315 320
Val Leu Gln Pro Ser Pro Ala Leu Ser Trp Arg Ser Thr Gly Gly Ile
325 330 335
Leu Asp Val Tyr Ile Phe Leu Gly Pro Glu Pro Lys Ser Val Val Gln
340 345 350
Gln Tyr Leu Asp Val Val Gly Tyr Pro Phe Met Pro Pro Tyr Trp Gly
355 360 365
Leu Gly Phe His Leu Cys Arg Trp Gly Tyr Ser Ser Thr Ala Ile Thr
370 375 380
Arg Gln Val Val Glu Asn Met Thr Arg Ala His Phe Pro Leu Asp Val
385 390 395 400
Gln Trp Asn Asp Leu Asp Tyr Met Asp Ser Arg Arg Asp Phe Thr Phe
405 410 415
Asn Lys Asp Gly Phe Arg Asp Phe Pro Ala Met Val Gln Glu Leu His
420 425 430
Gln Gly Gly Arg Arg Tyr Met Met Ile Val Asp Pro Ala Ile Ser Ser
435 440 445
Ser Gly Pro Ala Gly Ser Tyr Arg Pro Tyr Asp Glu Gly Leu Arg Arg
450 455 460
Gly Val Phe Ile Thr Asn Glu Thr Gly Gln Pro Leu Ile Gly Lys Val
465 470 475 480
Trp Pro Gly Ser Thr Ala Phe Pro Asp Phe Thr Asn Pro Thr Ala Leu
485 490 495
Ala Trp Trp Glu Asp Met Val Ala Glu Phe His Asp Gln Val Pro Phe
500 505 510
Asp Gly Met Trp Ile Asp Met Asn Glu Pro Ser Asn Phe Ile Arg Gly
515 520 525
Ser Glu Asp Gly Cys Pro Asn Asn Glu Leu Glu Asn Pro Pro Tyr Val
530 535 540
Pro Gly Val Val Gly Gly Thr Leu Gln Ala Ala Thr Ile Cys Ala Ser
545 550 555 560
Ser His Gln Phe Leu Ser Thr His Tyr Asn Leu His Asn Leu Tyr Gly
565 570 575
Leu Thr Glu Ala Ile Ala Ser His Arg Ala Leu Val Lys Ala Arg Gly
580 585 590
Thr Arg Pro Phe Val Ile Ser Arg Ser Thr Phe Ala Gly His Gly Arg
595 600 605
Tyr Ala Gly His Trp Thr Gly Asp Val Trp Ser Ser Trp Glu Gln Leu
610 615 620
Ala Ser Ser Val Pro Glu Ile Leu Gln Phe Asn Leu Leu Gly Val Pro
625 630 635 640
Leu Val Gly Ala Asp Val Cys Gly Phe Leu Gly Asn Thr Ser Glu Glu
645 650 655
Leu Cys Val Arg Trp Thr Gln Leu Gly Ala Phe Tyr Pro Phe Met Arg
660 665 670
Asn His Asn Ser Leu Leu Ser Leu Pro Gln Glu Pro Tyr Ser Phe Ser
675 680 685
Glu Pro Ala Gln Gln Ala Met Arg Lys Ala Leu Thr Leu Arg Tyr Ala
690 695 700
Leu Leu Pro His Leu Tyr Thr Leu Phe His Gln Ala His Val Ala Gly
705 710 715 720
Glu Thr Val Ala Arg Pro Leu Phe Leu Glu Phe Pro Lys Asp Ser Ser
725 730 735
Thr Trp Thr Val Asp His Gln Leu Leu Trp Gly Glu Ala Leu Leu Ile
740 745 750
Thr Pro Val Leu Gln Ala Gly Lys Ala Glu Val Thr Gly Tyr Phe Pro
755 760 765
Leu Gly Thr Trp Tyr Asp Leu Gln Thr Val Pro Ile Glu Ala Leu Gly
770 775 780
Ser Leu Pro Pro Pro Pro Ala Ala Pro Arg Glu Pro Ala Ile His Ser
785 790 795 800
Glu Gly Gln Trp Val Thr Leu Pro Ala Pro Leu Asp Thr Ile Asn Val
805 810 815
His Leu Arg Ala Gly Tyr Ile Ile Pro Leu Gln Gly Pro Gly Leu Thr
820 825 830
Thr Thr Glu Ser Arg Gln Gln Pro Met Ala Leu Ala Val Ala Leu Thr
835 840 845
Lys Gly Gly Glu Ala Arg Gly Glu Leu Phe Trp Asp Asp Gly Glu Ser
850 855 860
Leu Glu Val Leu Glu Arg Gly Ala Tyr Thr Gln Val Ile Phe Leu Ala
865 870 875 880
Arg Asn Asn Thr Ile Val Asn Glu Leu Val Arg Val Thr Ser Glu Gly
885 890 895
Ala Gly Leu Gln Leu Gln Lys Val Thr Val Leu Gly Val Ala Thr Ala
900 905 910
Pro Gln Gln Val Leu Ser Asn Gly Val Pro Val Ser Asn Phe Thr Tyr
915 920 925
Ser Pro Asp Thr Lys Val Leu Asp Ile Cys Val Ser Leu Leu Met Gly
930 935 940
Glu Gln Phe Leu Val Ser Trp Cys
945 950
<210> 4
<211> 952
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 4
Met Gly Val Arg His Pro Pro Cys Ser His Arg Leu Leu Ala Val Cys
1 5 10 15
Ala Leu Val Ser Leu Ala Thr Ala Ala Leu Leu Gly His Ile Leu Leu
20 25 30
His Asp Phe Leu Leu Val Pro Arg Glu Leu Ser Gly Ser Ser Pro Val
35 40 45
Leu Glu Glu Thr His Pro Ala His Gln Gln Gly Ala Ser Arg Pro Gly
50 55 60
Pro Arg Asp Ala Gln Ala His Pro Gly Arg Pro Arg Ala Val Pro Thr
65 70 75 80
Gln Cys Asp Val Pro Pro Asn Ser Arg Phe Asp Cys Ala Pro Asp Lys
85 90 95
Ala Ile Thr Gln Glu Gln Cys Glu Ala Arg Gly Cys Cys Tyr Ile Pro
100 105 110
Ala Lys Gln Gly Leu Gln Gly Ala Gln Met Gly Gln Pro Trp Cys Phe
115 120 125
Phe Pro Pro Ser Tyr Pro Ser Tyr Lys Leu Glu Asn Leu Ser Ser Ser
130 135 140
Glu Met Gly Tyr Thr Ala Thr Leu Thr Arg Thr Thr Pro Thr Phe Phe
145 150 155 160
Pro Lys Asp Ile Leu Thr Leu Arg Leu Asp Val Met Met Glu Thr Glu
165 170 175
Asn Arg Leu His Phe Thr Ile Lys Asp Pro Ala Asn Arg Arg Tyr Glu
180 185 190
Val Pro Leu Glu Thr Pro His Val His Ser Arg Ala Pro Ser Pro Leu
195 200 205
Tyr Ser Val Glu Phe Ser Glu Glu Pro Phe Gly Val Ile Val Arg Arg
210 215 220
Gln Leu Asp Gly Arg Val Leu Leu Asn Thr Thr Val Ala Pro Leu Phe
225 230 235 240
Phe Ala Asp Gln Phe Leu Gln Leu Ser Thr Ser Leu Pro Ser Gln Tyr
245 250 255
Ile Thr Gly Leu Ala Glu His Leu Ser Pro Leu Met Leu Ser Thr Ser
260 265 270
Trp Thr Arg Ile Thr Leu Trp Asn Arg Asp Leu Ala Pro Thr Pro Gly
275 280 285
Ala Asn Leu Tyr Gly Ser His Pro Phe Tyr Leu Ala Leu Glu Asp Gly
290 295 300
Gly Ser Ala His Gly Val Phe Leu Leu Asn Ser Asn Ala Met Asp Val
305 310 315 320
Val Leu Gln Pro Ser Pro Ala Leu Ser Trp Arg Ser Thr Gly Gly Ile
325 330 335
Leu Asp Val Tyr Ile Phe Leu Gly Pro Glu Pro Lys Ser Val Val Gln
340 345 350
Gln Tyr Leu Asp Val Val Gly Tyr Pro Phe Met Pro Pro Tyr Trp Gly
355 360 365
Leu Gly Phe His Leu Cys Arg Trp Gly Tyr Ser Ser Thr Ala Ile Thr
370 375 380
Arg Gln Val Val Glu Asn Met Thr Arg Ala His Phe Pro Leu Asp Val
385 390 395 400
Gln Trp Asn Asp Leu Asp Tyr Met Asp Ser Arg Arg Asp Phe Thr Phe
405 410 415
Asn Lys Asp Gly Phe Arg Asp Phe Pro Ala Met Val Gln Glu Leu His
420 425 430
Gln Gly Gly Arg Arg Tyr Met Met Ile Val Asp Pro Ala Ile Ser Ser
435 440 445
Ser Gly Pro Ala Gly Ser Tyr Arg Pro Tyr Asp Glu Gly Leu Arg Arg
450 455 460
Gly Val Phe Ile Thr Asn Glu Thr Gly Gln Pro Leu Ile Gly Lys Val
465 470 475 480
Trp Pro Gly Ser Thr Ala Phe Pro Asp Phe Thr Asn Pro Thr Ala Leu
485 490 495
Ala Trp Trp Glu Asp Met Val Ala Glu Phe His Asp Gln Val Pro Phe
500 505 510
Asp Gly Met Trp Ile Asp Met Asn Glu Pro Ser Asn Phe Ile Arg Gly
515 520 525
Ser Glu Asp Gly Cys Pro Asn Asn Glu Leu Glu Asn Pro Pro Tyr Val
530 535 540
Pro Gly Val Val Gly Gly Thr Leu Gln Ala Ala Thr Ile Cys Ala Ser
545 550 555 560
Ser His Gln Phe Leu Ser Thr His Tyr Asn Leu His Asn Leu Tyr Gly
565 570 575
Leu Thr Glu Ala Ile Ala Ser His Arg Ala Leu Val Lys Ala Arg Gly
580 585 590
Thr Arg Pro Phe Val Ile Ser Arg Ser Thr Phe Ala Gly His Gly Arg
595 600 605
Tyr Ala Gly His Trp Thr Gly Asp Val Trp Ser Ser Trp Glu Gln Leu
610 615 620
Ala Ser Ser Val Pro Glu Ile Leu Gln Phe Asn Leu Leu Gly Val Pro
625 630 635 640
Leu Val Gly Ala Asp Val Cys Gly Phe Leu Gly Asn Thr Ser Glu Glu
645 650 655
Leu Cys Val Arg Trp Thr Gln Leu Gly Ala Phe Tyr Pro Phe Met Arg
660 665 670
Asn His Asn Ser Leu Leu Ser Leu Pro Gln Glu Pro Tyr Ser Phe Ser
675 680 685
Glu Pro Ala Gln Gln Ala Met Arg Lys Ala Leu Thr Leu Arg Tyr Ala
690 695 700
Leu Leu Pro His Leu Tyr Thr Leu Phe His Gln Ala His Val Ala Gly
705 710 715 720
Glu Thr Val Ala Arg Pro Leu Phe Leu Glu Phe Pro Lys Asp Ser Ser
725 730 735
Thr Trp Thr Val Asp His Gln Leu Leu Trp Gly Glu Ala Leu Leu Ile
740 745 750
Thr Pro Val Leu Gln Ala Gly Lys Ala Glu Val Thr Gly Tyr Phe Pro
755 760 765
Leu Gly Thr Trp Tyr Asp Leu Gln Thr Val Pro Val Glu Ala Leu Gly
770 775 780
Ser Leu Pro Pro Pro Pro Ala Ala Pro Arg Glu Pro Ala Ile His Ser
785 790 795 800
Glu Gly Gln Trp Val Thr Leu Pro Ala Pro Leu Asp Thr Ile Asn Val
805 810 815
His Leu Arg Ala Gly Tyr Ile Ile Pro Leu Gln Gly Pro Gly Leu Thr
820 825 830
Thr Thr Glu Ser Arg Gln Gln Pro Met Ala Leu Ala Val Ala Leu Thr
835 840 845
Lys Gly Gly Glu Ala Arg Gly Glu Leu Phe Trp Asp Asp Gly Glu Ser
850 855 860
Leu Glu Val Leu Glu Arg Gly Ala Tyr Thr Gln Val Ile Phe Leu Ala
865 870 875 880
Arg Asn Asn Thr Ile Val Asn Glu Leu Val Arg Val Thr Ser Glu Gly
885 890 895
Ala Gly Leu Gln Leu Gln Lys Val Thr Val Leu Gly Val Ala Thr Ala
900 905 910
Pro Gln Gln Val Leu Ser Asn Gly Val Pro Val Ser Asn Phe Thr Tyr
915 920 925
Ser Pro Asp Thr Lys Val Leu Asp Ile Cys Val Ser Leu Leu Met Gly
930 935 940
Glu Gln Phe Leu Val Ser Trp Cys
945 950
<210> 5
<211> 896
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Synthetic
polypeptide
<400> 5
Gln Gln Gly Ala Ser Arg Pro Gly Pro Arg Asp Ala Gln Ala His Pro
1 5 10 15
Gly Arg Pro Arg Ala Val Pro Thr Gln Cys Asp Val Pro Pro Asn Ser
20 25 30
Arg Phe Asp Cys Ala Pro Asp Lys Ala Ile Thr Gln Glu Gln Cys Glu
35 40 45
Ala Arg Gly Cys Cys Tyr Ile Pro Ala Lys Gln Gly Leu Gln Gly Ala
50 55 60
Gln Met Gly Gln Pro Trp Cys Phe Phe Pro Pro Ser Tyr Pro Ser Tyr
65 70 75 80
Lys Leu Glu Asn Leu Ser Ser Ser Glu Met Gly Tyr Thr Ala Thr Leu
85 90 95
Thr Arg Thr Thr Pro Thr Phe Phe Pro Lys Asp Ile Leu Thr Leu Arg
100 105 110
Leu Asp Val Met Met Glu Thr Glu Asn Arg Leu His Phe Thr Ile Lys
115 120 125
Asp Pro Ala Asn Arg Arg Tyr Glu Val Pro Leu Glu Thr Pro Arg Val
130 135 140
His Ser Arg Ala Pro Ser Pro Leu Tyr Ser Val Glu Phe Ser Glu Glu
145 150 155 160
Pro Phe Gly Val Ile Val His Arg Gln Leu Asp Gly Arg Val Leu Leu
165 170 175
Asn Thr Thr Val Ala Pro Leu Phe Phe Ala Asp Gln Phe Leu Gln Leu
180 185 190
Ser Thr Ser Leu Pro Ser Gln Tyr Ile Thr Gly Leu Ala Glu His Leu
195 200 205
Ser Pro Leu Met Leu Ser Thr Ser Trp Thr Arg Ile Thr Leu Trp Asn
210 215 220
Arg Asp Leu Ala Pro Thr Pro Gly Ala Asn Leu Tyr Gly Ser His Pro
225 230 235 240
Phe Tyr Leu Ala Leu Glu Asp Gly Gly Ser Ala His Gly Val Phe Leu
245 250 255
Leu Asn Ser Asn Ala Met Asp Val Val Leu Gln Pro Ser Pro Ala Leu
260 265 270
Ser Trp Arg Ser Thr Gly Gly Ile Leu Asp Val Tyr Ile Phe Leu Gly
275 280 285
Pro Glu Pro Lys Ser Val Val Gln Gln Tyr Leu Asp Val Val Gly Tyr
290 295 300
Pro Phe Met Pro Pro Tyr Trp Gly Leu Gly Phe His Leu Cys Arg Trp
305 310 315 320
Gly Tyr Ser Ser Thr Ala Ile Thr Arg Gln Val Val Glu Asn Met Thr
325 330 335
Arg Ala His Phe Pro Leu Asp Val Gln Trp Asn Asp Leu Asp Tyr Met
340 345 350
Asp Ser Arg Arg Asp Phe Thr Phe Asn Lys Asp Gly Phe Arg Asp Phe
355 360 365
Pro Ala Met Val Gln Glu Leu His Gln Gly Gly Arg Arg Tyr Met Met
370 375 380
Ile Val Asp Pro Ala Ile Ser Ser Ser Gly Pro Ala Gly Ser Tyr Arg
385 390 395 400
Pro Tyr Asp Glu Gly Leu Arg Arg Gly Val Phe Ile Thr Asn Glu Thr
405 410 415
Gly Gln Pro Leu Ile Gly Lys Val Trp Pro Gly Ser Thr Ala Phe Pro
420 425 430
Asp Phe Thr Asn Pro Thr Ala Leu Ala Trp Trp Glu Asp Met Val Ala
435 440 445
Glu Phe His Asp Gln Val Pro Phe Asp Gly Met Trp Ile Asp Met Asn
450 455 460
Glu Pro Ser Asn Phe Ile Arg Gly Ser Glu Asp Gly Cys Pro Asn Asn
465 470 475 480
Glu Leu Glu Asn Pro Pro Tyr Val Pro Gly Val Val Gly Gly Thr Leu
485 490 495
Gln Ala Ala Thr Ile Cys Ala Ser Ser His Gln Phe Leu Ser Thr His
500 505 510
Tyr Asn Leu His Asn Leu Tyr Gly Leu Thr Glu Ala Ile Ala Ser His
515 520 525
Arg Ala Leu Val Lys Ala Arg Gly Thr Arg Pro Phe Val Ile Ser Arg
530 535 540
Ser Thr Phe Ala Gly His Gly Arg Tyr Ala Gly His Trp Thr Gly Asp
545 550 555 560
Val Trp Ser Ser Trp Glu Gln Leu Ala Ser Ser Val Pro Glu Ile Leu
565 570 575
Gln Phe Asn Leu Leu Gly Val Pro Leu Val Gly Ala Asp Val Cys Gly
580 585 590
Phe Leu Gly Asn Thr Ser Glu Glu Leu Cys Val Arg Trp Thr Gln Leu
595 600 605
Gly Ala Phe Tyr Pro Phe Met Arg Asn His Asn Ser Leu Leu Ser Leu
610 615 620
Pro Gln Glu Pro Tyr Ser Phe Ser Glu Pro Ala Gln Gln Ala Met Arg
625 630 635 640
Lys Ala Leu Thr Leu Arg Tyr Ala Leu Leu Pro His Leu Tyr Thr Leu
645 650 655
Phe His Gln Ala His Val Ala Gly Glu Thr Val Ala Arg Pro Leu Phe
660 665 670
Leu Glu Phe Pro Lys Asp Ser Ser Thr Trp Thr Val Asp His Gln Leu
675 680 685
Leu Trp Gly Glu Ala Leu Leu Ile Thr Pro Val Leu Gln Ala Gly Lys
690 695 700
Ala Glu Val Thr Gly Tyr Phe Pro Leu Gly Thr Trp Tyr Asp Leu Gln
705 710 715 720
Thr Val Pro Ile Glu Ala Leu Gly Ser Leu Pro Pro Pro Pro Ala Ala
725 730 735
Pro Arg Glu Pro Ala Ile His Ser Glu Gly Gln Trp Val Thr Leu Pro
740 745 750
Ala Pro Leu Asp Thr Ile Asn Val His Leu Arg Ala Gly Tyr Ile Ile
755 760 765
Pro Leu Gln Gly Pro Gly Leu Thr Thr Thr Glu Ser Arg Gln Gln Pro
770 775 780
Met Ala Leu Ala Val Ala Leu Thr Lys Gly Gly Glu Ala Arg Gly Glu
785 790 795 800
Leu Phe Trp Asp Asp Gly Glu Ser Leu Glu Val Leu Glu Arg Gly Ala
805 810 815
Tyr Thr Gln Val Ile Phe Leu Ala Arg Asn Asn Thr Ile Val Asn Glu
820 825 830
Leu Val Arg Val Thr Ser Glu Gly Ala Gly Leu Gln Leu Gln Lys Val
835 840 845
Thr Val Leu Gly Val Ala Thr Ala Pro Gln Gln Val Leu Ser Asn Gly
850 855 860
Val Pro Val Ser Asn Phe Thr Tyr Ser Pro Asp Thr Lys Val Leu Asp
865 870 875 880
Ile Cys Val Ser Leu Leu Met Gly Glu Gln Phe Leu Val Ser Trp Cys
885 890 895
Claims (77)
- チャイニーズハムスター卵巣(CHO)細胞由来の組換えヒト酸性αグルコシダーゼ(rhGAA)分子の集団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けるポンペ病を処置する方法であって、
rhGAA分子が、7個の潜在的N-グリコシル化部位を含み;
rhGAA分子が、平均で3~4個のマンノース-6-リン酸(M6P)残基を含み;
rhGAA分子が、液体クロマトグラフィー-タンデム質量分析(LC-MS/MS)を使用して決定されたrhGAA 1molあたり平均で少なくとも約0.5molのビス-マンノース-6-リン酸(ビス-M6P)を第1の潜在的N-グリコシル化部位に含み;
rhGAAの集団が、対象において疾患進行を逆転させることができる投薬量で投与される、方法。 - 疾患進行を逆転させることが、対象の筋肉中のリソソームのサイズを低減することを含む、請求項1に記載の方法。
- 疾患進行を逆転させることが、対象の筋肉中のオートファジーのビルドアップを消滅させることを含む、請求項1または2に記載の方法。
- 対象において分析された筋線維の65%未満が、処置後にオートファジーのビルドアップを有する、請求項3に記載の方法。
- 対象がERT-切り替え患者である、請求項1から4のいずれか一項に記載の方法。
- ERT-切り替え患者が、少なくとも2年間、アルグルコシダーゼアルファを用いて以前処置されたことがある、請求項5に記載の方法。
- 対象において分析された筋線維の少なくとも36%が、処置後に正常または正常に近い所見を有する、請求項1から6のいずれか一項に記載の方法。
- チャイニーズハムスター卵巣(CHO)細胞由来の組換えヒト酸性αグルコシダーゼ(rhGAA)分子の集団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けるポンペ病を処置する方法であって、
rhGAA分子が、7個の潜在的N-グリコシル化部位を含み;
rhGAA分子が、平均で3~4個のマンノース-6-リン酸(M6P)残基を含み;
rhGAA分子が、LC-MS/MSを使用して決定されたrhGAA 1molあたり平均で少なくとも約0.5molのビス-マンノース-6-リン酸(ビス-M6P)を第1の潜在的N-グリコシル化部位に含み;
処置後の対象の筋肉中のグリコーゲン含有量が、アルグルコシダーゼアルファが同じ投薬量で投与された場合よりも速く低減される、方法。 - 処置後の対象の筋肉中のグリコーゲン含有量が、アルグルコシダーゼアルファが同じ投薬量で投与された場合の速度より少なくとも約1.25、1.5、1.75、2.0または3.0倍速い速度で低減される、請求項8に記載の方法。
- 1、2、3、4、5または6回投与後に評価した場合に、処置後の対象の筋肉中のグリコーゲン含有量が、アルグルコシダーゼアルファが同じ投薬量で投与された場合よりもさらに有効に低減される、請求項8または9に記載の方法。
- 処置後の対象の筋肉中のグリコーゲン含有量が、アルグルコシダーゼアルファが同じ投薬量で投与された場合よりも、少なくとも約10%、20%、30%、50%、75%または90%さらに有効に低減される、請求項10に記載の方法。
- グリコーゲン含有量が6回投与後に評価される、請求項10または11に記載の方法。
- 対象が処置後に尿中ヘキソース四糖のレベルの低減を示す、請求項8から12のいずれか一項に記載の方法。
- 処置後6カ月の尿中ヘキソース四糖のレベルが、ベースラインと比較して少なくとも30%低減される、請求項13に記載の方法。
- 対象が歩行可能ERT-切り替え患者または歩行不能ERT-切り替え患者であり、処置後6カ月の対象の尿中ヘキソース四糖のレベルが、ベースラインと比較して少なくとも35%低減される、請求項13に記載の方法。
- 対象が、歩行可能ERT-未処置患者であり、処置後6カ月の対象の尿中ヘキソース四糖のレベルが、ベースラインと比較して少なくとも45%低減される、請求項13に記載の方法。
- チャイニーズハムスター卵巣(CHO)細胞由来の組換えヒト酸性αグルコシダーゼ(rhGAA)分子の集団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けるポンペ病を処置する方法であって、
rhGAA分子が、7個の潜在的N-グリコシル化部位を含み;
rhGAA分子が、平均で3~4個のマンノース-6-リン酸(M6P)残基を含み;
rhGAA分子が、LC-MS/MSを使用して決定されたrhGAA 1molあたり平均で少なくとも約0.5molのビス-マンノース-6-リン酸(ビス-M6P)を第1の潜在的N-グリコシル化部位に含み;
rhGAAの集団が、対象において運動機能を改善できる投薬量で投与される、方法。 - 対象における運動機能の改善が、6分間歩行検査(6MWT)、タイムドアップアンドゴー検査、4段上り検査、10メートル歩行検査、ガワーズ検査、歩行-段-ガワー-椅子(GSGC)検査およびこれらの組合せからなる群から選択される少なくとも1つの運動機能検査によって測定される、請求項17に記載の方法。
- ベースラインと比較して、処置後6カ月の対象の6MWT距離が、少なくとも20メートル増加する、処置後6カ月の対象のタイムドアップアンドゴー検査時間が少なくとも1秒間減少する、処置後6カ月の対象の4段上り検査時間が少なくとも0.6秒間減少する、処置後6カ月の対象の10メートル歩行検査時間が少なくとも0.7秒間減少する、処置後6カ月の対象のガワーズ検査時間が少なくとも1秒間減少する、または処置後6カ月の対象のGSGCスコアが少なくとも1減少する、請求項18に記載の方法。
- 対象が、歩行可能ERT-切り替え患者であり、ベースラインと比較して、処置後6カ月の対象の6MWT距離が、少なくとも20メートル増加する、処置後6カ月の対象のタイムドアップアンドゴー検査時間が少なくとも1.5秒間減少する、処置後6カ月の対象の4段上り検査時間が少なくとも0.6秒間減少する、または処置後6カ月の対象のガワーズ検査時間が少なくとも1秒間減少する、請求項18に記載の方法。
- 対象が、歩行可能ERT未処置患者であり、ベースラインと比較して、処置後6カ月の対象の6MWT距離が、少なくとも40メートル増加する、処置後6カ月の対象のタイムドアップアンドゴー検査時間が少なくとも1秒間減少する、処置後6カ月の対象の4段上り検査時間が少なくとも0.6秒間減少する、処置後6カ月の対象の10メートル歩行検査時間が少なくとも0.7秒間減少する、または処置後6カ月の対象のGSGCスコアが少なくとも1減少する、請求項18に記載の方法。
- 対象が、以前アルグルコシダーゼアルファ酵素補充療法を受けており、以前のアルグルコシダーゼアルファ酵素補充療法後の対象の運動機能検査結果と比較して、rhGAAの集団を用いた処置後に、対象が、少なくとも1つの運動機能検査において改善を示す、請求項18に記載の方法。
- チャイニーズハムスター卵巣(CHO)細胞由来の組換えヒト酸性αグルコシダーゼ(rhGAA)分子の集団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けるポンペ病を処置する方法であって、
rhGAA分子が、7個の潜在的N-グリコシル化部位を含み;
rhGAA分子が、平均で3~4個のマンノース-6-リン酸(M6P)残基を含み;
rhGAA分子が、LC-MS/MSを使用して決定されたrhGAA 1molあたり平均で少なくとも約0.5molのビス-マンノース-6-リン酸(ビス-M6P)を第1の潜在的N-グリコシル化部位に含み;
rhGAAの集団が、対象において上半身強度を改善できる投薬量で投与される、方法。 - 対象における上半身強度の改善が、徒手筋力スコアによって測定される、請求項23に記載の方法。
- 対象が、歩行可能ERT-切り替え患者であり、処置後6カ月にベースラインと比較して上半身徒手筋力スコアにおいて少なくとも1の改善を示す、請求項24に記載の方法。
- 対象が、歩行不能ERT-切り替え患者であり、処置後6カ月にベースラインと比較して上半身徒手筋力スコアにおいて少なくとも5.5の改善を示す、請求項24に記載の方法。
- 対象における上半身強度の改善が、上肢強度の改善であり、上肢強度が、肩内転、肩外転、肘屈曲および肘伸展からなる群から選択される少なくとも1つの上肢筋群の定量的筋力検査または徒手筋力検査によって測定される、請求項23に記載の方法。
- 対象が、歩行不能ERT-切り替え患者であり、ベースラインと比較して処置後6カ月の対象の肩内転が少なくとも8ポンド力改善される、処置後6カ月の対象の肩外転が少なくとも1ポンド力改善される、処置後6カ月の対象の肘屈曲が少なくとも2ポンド力改善される、または処置後6カ月の対象の肘伸展が少なくとも5ポンド力改善される、請求項27に記載の方法。
- 対象が、歩行可能であり、処置後に下半身強度および/または全身強度の改善をさらに示す、請求項23に記載の方法。
- 対象が、以前アルグルコシダーゼアルファ酵素補充療法を受けており、以前のアルグルコシダーゼアルファ酵素補充療法後の対象の上半身強度と比較して、rhGAAの集団を用いた処置後に、対象が、上半身強度において改善を示す、請求項23に記載の方法。
- チャイニーズハムスター卵巣(CHO)細胞由来の組換えヒト酸性αグルコシダーゼ(rhGAA)分子の集団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けるポンペ病を処置する方法であって、
rhGAA分子が、7個の潜在的N-グリコシル化部位を含み;
rhGAA分子が、平均で3~4個のマンノース-6-リン酸(M6P)残基を含み;
rhGAA分子が、LC-MS/MSを使用して決定されたrhGAA 1molあたり平均で少なくとも約0.5molのビス-マンノース-6-リン酸(ビス-M6P)を第1の潜在的N-グリコシル化部位に含み;
rhGAAの集団が、対象において肺機能を改善できる投薬量で投与される、方法。 - 対象における肺機能の改善が、直立位努力肺活量(FVC)検査、最大呼気圧(MEP)検査、最大吸気圧(MIP)検査およびこれらの組合せからなる群から選択される少なくとも1つの肺機能検査によって測定される、請求項31に記載の方法。
- ベースラインと比較して、処置後6カ月の対象のFVCが少なくとも4%改善する、処置後6カ月の対象のMEPが少なくとも16cmH2O改善する、または処置後6カ月の対象のMIPが少なくとも0.3cmH2O改善する、請求項32に記載の方法。
- 対象が、歩行可能ERT-切り替え患者であり、ベースラインと比較して、処置後6カ月の対象のMEPが少なくとも16cmH2O改善する、請求項32に記載の方法。
- 対象が、歩行可能ERT-未処置患者であり、ベースラインと比較して、処置後6カ月の対象のFVCが少なくとも4%改善する、または処置後6カ月の対象のMIPが少なくとも11cmH2O改善する、請求項32に記載の方法。
- 対象が、以前アルグルコシダーゼアルファ酵素補充療法を受けており、以前のアルグルコシダーゼアルファ酵素補充療法後の対象の肺機能検査結果と比較して、rhGAAの集団を用いた処置後に、対象が、少なくとも1つの肺機能検査において改善を示す、請求項32に記載の方法。
- チャイニーズハムスター卵巣(CHO)細胞由来の組換えヒト酸性αグルコシダーゼ(rhGAA)分子の集団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けるポンペ病を処置する方法であって、
rhGAA分子が、7個の潜在的N-グリコシル化部位を含み;
rhGAA分子が、平均で3~4個のマンノース-6-リン酸(M6P)残基を含み;
rhGAA分子が、LC-MS/MSを使用して決定されたrhGAA 1molあたり平均で少なくとも約0.5molのビス-マンノース-6-リン酸(ビス-M6P)を第1の潜在的N-グリコシル化部位に含み;
rhGAAの集団が、疲労重症度スケール(FSS)スコアによって測定される対象における疲労を低減できる投薬量で投与される、方法。 - 処置後6カ月の対象のFSSスコアが、ベースラインと比較して少なくとも3.5減少する、請求項37に記載の方法。
- 対象が歩行不能ERT-切り替え患者である、請求項38に記載の方法。
- 対象が、歩行可能ERT-切り替え患者であり、処置後6カ月の対象のFSSスコアが、ベースラインと比較して少なくとも8減少する、請求項37または38に記載の方法。
- 対象が、歩行可能ERT-未処置患者であり、処置後6カ月の対象のFSSスコアが、ベースラインと比較して少なくとも5減少する、請求項37または38に記載の方法。
- 対象が、以前アルグルコシダーゼアルファ酵素補充療法を受けており、以前のアルグルコシダーゼアルファ酵素補充療法後の対象のFSSスコアと比較して、rhGAAの集団を用いた処置後に、対象のFSSスコアが低下する、請求項37に記載の方法。
- チャイニーズハムスター卵巣(CHO)細胞由来の組換えヒト酸性αグルコシダーゼ(rhGAA)分子の集団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けるポンペ病を処置する方法であって、
rhGAA分子が、7個の潜在的N-グリコシル化部位を含み;
rhGAA分子が、平均で3~4個のマンノース-6-リン酸(M6P)残基を含み;
rhGAA分子が、LC-MS/MSを使用して決定されたrhGAA 1molあたり平均で少なくとも約0.5molのビス-マンノース-6-リン酸(ビス-M6P)を第1の潜在的N-グリコシル化部位に含み;
rhGAAの集団が、クレアチンキナーゼ、アラニンアミノトランスフェラーゼ(ALT)、アスパラギン酸アミノトランスフェラーゼ(AST)およびこれらの組合せからなる群から選択される少なくとも1つの筋損傷バイオマーカーのレベルを低減できる投薬量で投与される、方法。 - 少なくとも1つの筋損傷バイオマーカーがクレアチンキナーゼである、請求項43に記載の方法。
- ベースラインと比較して、処置後6カ月の対象のクレアチンキナーゼレベルが少なくとも15%低減する、処置後6カ月の対象のALTレベルが少なくとも5%低減するまたは処置後6カ月の対象のASTレベルが少なくとも5%低減する、請求項43に記載の方法。
- 対象が、歩行可能ERT-切り替え患者であり、ベースラインと比較して、処置後6カ月の対象のクレアチンキナーゼレベルが少なくとも15%低減する、処置後6カ月の対象のALTレベルが少なくとも15%低減する、または処置後6カ月の対象のASTレベルが少なくとも10%低減する、請求項43に記載の方法。
- 対象が、歩行不能ERT-切り替え患者であり、ベースラインと比較して、処置後6カ月の対象のクレアチンキナーゼレベルが少なくとも20%低減する、処置後6カ月の対象のALTレベルが少なくとも5%低減する、または処置後6カ月の対象のASTレベルが少なくとも5%低減する、請求項43に記載の方法。
- 対象が、歩行可能ERT-未処置患者であり、ベースラインと比較して、処置後6カ月の対象のクレアチンキナーゼレベルが少なくとも35%低減する、処置後6カ月の対象のALTレベルが少なくとも35%低減する、または処置後6カ月の対象のASTレベルが少なくとも30%低減する、請求項43に記載の方法。
- rhGAA分子の集団が、約1mg/kgから約100mg/kgの用量で投与される、請求項1から48のいずれか一項に記載の方法。
- rhGAA分子の集団が、約20mg/kgの用量で投与される、請求項1から49のいずれか一項に記載の方法。
- rhGAA分子の集団が、2カ月に1回、1カ月に1回、2週間に1回、1週間に1回、1週間に2回または毎日投与される、請求項1から50のいずれか一項に記載の方法。
- rhGAA分子の集団が、2週間に1回投与される、請求項51に記載の方法。
- rhGAA分子の集団が、静脈内投与される、請求項1から52のいずれか一項に記載の方法。
- rhGAA分子の集団が、薬理的シャペロンと同時にまたは連続的に投与される、請求項1から53のいずれか一項に記載の方法。
- 薬理的シャペロンが、ミグルスタットまたは薬学的に許容されるその塩である、請求項54に記載の方法。
- ミグルスタットまたは薬学的に許容されるその塩が、経口投与される、請求項55に記載の方法。
- ミグルスタットまたは薬学的に許容されるその塩が、約200mgから約600mgの用量で投与される、請求項55または56に記載の方法。
- ミグルスタットまたは薬学的に許容されるその塩が、約260mgの用量で投与される、請求項57に記載の方法。
- rhGAA分子の集団が、約5mg/kgから約20mg/kgの用量で静脈内投与され、ミグルスタットまたは薬学的に許容されるその塩が、約233mgから約500mgの用量で経口投与される、請求項57に記載の方法。
- ミグルスタットまたは薬学的に許容されるその塩が、約50mgから約200mgの用量で経口投与される、請求項56に記載の方法。
- rhGAA分子の集団が、約20mg/kgの用量で静脈内投与され、ミグルスタットまたは薬学的に許容されるその塩が、約260mgの用量で経口投与される、請求項56に記載の方法。
- ミグルスタットまたは薬学的に許容されるその塩が、rhGAAの投与に先行して投与される、請求項55から61のいずれか一項に記載の方法。
- ミグルスタットまたは薬学的に許容されるその塩が、rhGAAの投与に約1時間先行して投与される、請求項62に記載の方法。
- 対象が、ミグルスタットまたは薬学的に許容されるその塩の投与前少なくとも2時間および投与後少なくとも2時間絶食する、請求項62または63に記載の方法。
- rhGAA分子が、配列番号1または配列番号5に少なくとも95%同一のアミノ酸配列を含む、請求項1~64のいずれか一項に記載の方法。
- rhGAA分子が、配列番号1または配列番号5に同一のアミノ酸配列を含む、請求項1から65のいずれか一項に記載の方法。
- 少なくとも30%のrhGAA分子が、LC-MS/MSを使用して決定される、1つのマンノース-6-リン酸残基(モノ-M6P)またはビス-M6Pを保有する1つまたは複数のN-グリカン単位を含む、請求項1から66のいずれか一項に記載の方法。
- rhGAA分子が、LC-MS/MSを使用して決定される、1molのrhGAAあたり平均で約0.5molから約7.0molのモノ-M6Pまたはビス-M6Pを含む、請求項1から67のいずれか一項に記載の方法。
- rhGAA分子が、LC-MS/MSを使用して決定される、1molのrhGAAあたり平均で少なくとも2.5molのM6Pおよび1molのrhGAAあたり少なくとも4molのシアル酸を含む、請求項1から68のいずれか一項に記載の方法。
- rhGAA分子が、1molのrhGAAあたり平均で:
(a)第2の潜在的N-グリコシル化部位に約0.4から約0.6molのモノ-M6P;
(b)第4の潜在的N-グリコシル化部位に約0.4から約0.6molのビス-M6P;および
(c)第4の潜在的N-グリコシル化部位に約0.3から約0.4molのモノ-M6P;
を含み、
(a)~(c)がLC-MS/MSを使用して決定される、請求項1から69のいずれか一項に記載の方法。 - rhGAA分子が、1molのrhGAAあたり約4molから約7.3molのシアル酸をさらに含み;
rhGAA分子が、1molのrhGAAあたり平均で:
(a)第3の潜在的N-グリコシル化部位に約0.9から約1.2molのシアル酸;
(b)第5の潜在的N-グリコシル化部位に約0.8から約0.9molのシアル酸;および
(c)第6の潜在的N-グリコシル化部位に約1.5から約4.2molのシアル酸
を含み、
(a)~(c)がLC-MS/MSを使用して決定される、請求項70に記載の方法。 - rhGAA分子の集団が、薬学的組成物に製剤化される、請求項1から71のいずれか一項に記載の方法。
- 薬学的組成物が、クエン酸塩、リン酸塩およびこれらの組合せからなる群から選択される少なくとも1つのバッファー、ならびにマンニトール、ポリソルベート80およびこれらの組合せからなる群から選択される少なくとも1つの賦形剤をさらに含み、薬学的組成物が約5.0から約7.0のpHを有する、請求項72に記載の方法。
- 薬学的組成物が約5.0から約6.0のpHを有する、請求項73に記載の方法。
- 薬学的組成物が、水、酸性化剤、アルカリ化剤またはこれらの組合せをさらに含む、請求項73または74に記載の方法。
- 薬学的組成物中の、rhGAA分子の集団が、約5~50mg/mLの濃度で存在し、少なくとも1つのバッファーが、約10~100mMの濃度で存在するクエン酸ナトリウムバッファーであり、少なくとも1つの賦形剤が、約10~50mg/mLの濃度で存在するマンニトールおよび約0.1~1mg/mLの濃度で存在するポリソルベート80であり、薬学的組成物が、水をさらに含み、任意選択で酸性化剤および/またはアルカリ化剤を含み;薬学的組成物が、約6.0のpHを有する、請求項73に記載の方法。
- 薬学的組成物中の、rhGAA分子の集団が、約15mg/mLの濃度で存在し、クエン酸ナトリウムバッファーが、約25mMの濃度で存在し、マンニトールが、約20mg/mLの濃度で存在し、ポリソルベート80が、約0.5mg/mLの濃度で存在する、請求項76に記載の方法。
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