JP2023033321A - Cnsにおけるイズロン酸 2-スルファターゼ活性を増加させるための方法および組成物 - Google Patents
Cnsにおけるイズロン酸 2-スルファターゼ活性を増加させるための方法および組成物 Download PDFInfo
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Abstract
Description
本出願は,35U.S.C.§119(e)の下,2009年10月9日に出願された米国仮出願第61/250,378号,および2009年10月29日に出願された米国仮出願第61/256,049号の利益を主張するものであって,両出願はそれらの全体において参照することによって本明細書に援用される。
ムコ多糖症(MPS)II型は,ハンター症候群としても知られており,ムコ多糖を分解する機能を果たす酵素イズロン酸 2-スルファターゼ(IDS)の欠損に起因する遺伝性代謝疾患である。不十分なレベルのIDSは,例えば,心臓,肝臓,および中枢神経系(CNS)において,ヘパラン硫酸およびデルマタン硫酸の病理学的蓄積を引き起こす。神経変性および精神遅滞を含む症状が小児期に現れる;さらに,脳内の臓器障害に起因して,早期死亡が起こりえる。典型的には,治療は組換えIDSによる静脈内酵素補充療法を含む。しかしながら,全身投与された組換えIDSは血液脳関門(BBB)を通過せず,それゆえCNSにおける疾患の作用に対してほとんど影響がない。
本明細書は,イズロン酸 2-スルファターゼ(「IDS」)欠乏症を患っている対象を治療するための方法および組成物を記載している。本明細書で提供する組成物は,血液脳関門(BBB)を通過することができる構造(例えば,抗体,免疫グロブリン)と融合したIDSポリペプチドを含む融合抗体を含む。いくつかの実施態様では,BBBを通過することができる構造は,内在性BBB受容体上でBBBを通過する。いくつかの実施態様では,内在性BBB受容体はインスリン受容体,トランスフェリン受容体,レプチン受容体,リポタンパク質受容体,およびIGF受容体である。いくつかの実施態様では,内在性BBB受容体はインスリン受容体である。いくつかの実施態様では,該方法は,二機能性のヒトインスリン受容体抗体(例えば,HIR Ab)-IDS融合抗体の治療的有効量を全身投与することによって,CNSへのIDSの送達を可能にする。いくつかの実施態様では,HIR Ab-IDS融合抗体はインスリン受容体の細胞外ドメインに結合し,血液脳関門(「BBB」)を越えてCNS内へ輸送され,一方で,イズロン酸 2-スルファターゼ活性を保持している。いくつかの実施態様では,HIR AbはBBB上の内在性インスリン受容体に結合し,分子的トロイの木馬として作用し,IDSを脳内へ運ぶ。全身投与のためのHIR Ab-IDS融合抗体の治療的に有効な全身投与量(systemic dose)は,本明細書に記載されているように,部分的には,末梢血からの融合抗体の特異的CNS取り込み特性に基づいている。
(i)融合抗体が免疫グロブリン重鎖およびIDSのアミノ酸配列を含有する融合タンパク質を含むか,または免疫グロブリン軽鎖およびIDSのアミノ酸配列を含有する融合タンパク質を含み;融合抗体がヒトインスリン受容体の細胞外ドメインに結合し;かつ,融合抗体がデルマタンまたはヘパラン硫酸における結合の加水分解を触媒し;かつ,(ii)IDSのアミノ酸配列が免疫グロブリン重鎖または免疫グロブリン軽鎖のアミノ酸配列のカルボキシ末端と共有結合している,方法を提供する。
本明細書中で言及されている全ての出版物,特許,および特許出願は,個々の出版物,特許,または特許出願が参照することによって援用されることを具体的かつ個々に示されている場合と同一の範囲まで,参照することによって本明細書に援用される。
イントロダクション
血液脳関門(BBB)は,全身投与されたIDS(例えば,組換えIDS)の中枢神経系への送達に対する深刻な障害である。本開示は,治療的に有意なレベルのIDS活性を,BBBを越えてCNSに送達するための方法および組成物を提供する。いくつかの実施態様では,IDSはBBBを通過することができるように修飾されている。いくつかの実施態様では,全身投与された修飾IDSのCNS内への取り込みの量および速度が提供される。いくつかの実施態様では,IDSは修飾後またはBBB通過後に特定の活性を保持している。本開示は,とりわけ,以下を提供する:(1)BBBを通過することができる免疫グロブリン(重鎖または軽鎖)に(介在配列を介して,または介さずに)融合したIDSを含むIDS融合抗体,ならびに関連する方法および組成物;(2)ヒトインスリン受容体の細胞外ドメインに対する免疫グロブリン(重鎖または軽鎖)に(介在配列を介して,または介さずに)融合したIDSを含むヒトインスリン受容体(HIR)抗体(Ab)-IDS融合抗体,ならびに関連する方法および組成物;(3)IDS欠乏症を治療する方法;ならびに(4)治療的に有効な融合抗体の全身投与量(systemic doses)を,CNSにおけるそれらの取り込みおよびそれらの比活性の特徴付けに基づいて確立する方法。いくつかの実施態様では,本発明は,IDS活性を有し,かつ,受容体媒介BBB輸送系(例えば,ヒトインスリン受容体の細胞外ドメイン)に選択的に結合する二機能性のIDS融合抗体(例えば,HIR Ab-IDS)の治療的有効量を,治療を必要とする対象に全身投与することによって中枢神経系におけるIDS欠乏症を治療する組成物および方法を提供する。
本明細書で用いられている「治療」または「治療すること」は,治療効果および/または予防効果を達成することを含む。治療効果は,治療されている基礎的な障害または状態の根絶または改善を意味する。例えば,ハンター症候群を患っている個体において,治療効果は障害の進行の部分的もしくは完全な停止,または障害の部分的もしくは完全な好転を含む。また,治療効果は,基礎的な状態と関連する生理的または心理的症状の1つ以上の根絶または改善と共に達成されるため,患者が依然として該状態を患っている可能性があるという事実にもかかわらず,患者に改善が観察される。治療の予防効果は,状態の予防,状態の進行の遅延(例えば,リソソーム蓄積症の進行の遅延),または状態の発生の可能性の減少を含む。本明細書で用いられている「治療すること」または「治療」は,予防を含む。
いくつかの実施態様では,本発明は血液脳関門(BBB)を通過することができるIDS融合抗体(例えば,HIR Ab-IDS)を利用する組成物および方法を提供する。該組成物および該方法は,IDSを末梢血から血液脳関門を越えてCNS内へ輸送するのに有用である。本明細書で用いられている「血液脳関門」は,末梢循環と脳および脊髄の間の関門を指し,脳毛細血管内皮血漿膜内の密着結合によって形成され,脳内への分子の輸送を制限する非常に密着した関門を作り出す;BBBは非常に密着しているため,分子量60Daの尿素のような小分子でさえ制限することができる。脳内の血液脳関門,脊髄内の血液脊髄関門,および網膜内の血液網膜関門は,中枢神経系(CNS)内にある近接した毛細血管関門であり,まとめて血液脳関門またはBBBとして言及される。
BBBは,いくつかの巨大分子の血液から脳への輸送を可能にする特異的受容体を有することが示されている;これらの輸送体は,本発明の組成物のための輸送体として適している。本発明に有用な内在性BBB受容体媒介輸送系は,インスリン,トランスフェリン,インスリン様成長因子1および2(IGF1およびIGF2),レプチン,ならびにリポタンパク質を輸送するものを含む。いくつかの実施態様では,本発明は,内在性インスリンBBB受容体媒介輸送系,例えば,ヒト内在性インスリンBBB受容体媒介輸送系を経由してBBBを通過することができる構造(例えば,免疫グロブリン,抗体)を利用する。いくつかの実施態様では,BBBを通過することができる構造(例えば,免疫グロブリン,抗体)は,以下の1つ以上のための受容体に結合することによってBBBを通過する:インスリン,トランスフェリン,インスリン様成長因子1および2(IGF1およびIGF2),レプチン,ならびに/またはリポタンパク質。
CNSに薬物を送達するための1つの非侵襲的アプローチは,興味のある薬剤を構造,例えばBBB上の受容体と結合する分子と付着することである。次いで,該構造はBBBを越えて薬剤を輸送するためのベクターとして機能する。該構造は,本明細書で「分子的トロイの木馬(MTH)」として言及されている。必ずしもというわけではないが,典型的には,MTHは内在性BBB受容体媒介輸送系でBBBを横切る,内在性BBB受容体媒介輸送系に結合することができる外因性ペプチドまたはペプチド模倣部分(例えば,MAb)である。特定の実施態様では,MTHは輸送系の受容体,例えばインスリン受容体に対する抗体であってよい。いくつかの実施態様では,抗体はモノクローナル抗体(MAb)である。いくつかの実施態様では,MAbはキメラMAbである。それゆえ,Absは通常,脳から排除されるという事実にもかかわらず,それらはBBB上の受容体に対する特異性を有する場合,脳実質内へ分子を送達するための有効なビヒクルとなりうる。
組換えIDS(例えば,エラプラーゼ(Elaprase(登録商標)))の全身投与(例えば,静脈内注射による)は,ハンター症候群を患っている患者のCNSにおけるIDS欠乏症を救出できない。IDSはBBBを通過しないため,BBBを越えた酵素の輸送の不足は,末梢投与後,CNSにおける有意な治療効果を発揮する妨げとなる。しかしながら,本発明のいくつかの実施態様では,IDSがBBBを通過することができる抗体(例えば,HIR Ab)と融合した場合,IDSは,非侵襲性の末梢投与経路,例えば静脈内投与,動脈内投与,筋肉内投与,皮下投与,腹腔内投与,もしくは経口投与,または他の本明細書に記載されている経路での投与後,血液からCNSに入ることができる。IDS融合抗体(例えば,HIR Ab-IDS)の投与は,末梢血から脳内へのIDS活性の送達を可能にする。本明細書に記載されているのは,CNSにおけるIDS欠乏症を治療するための治療的に有効なIDS融合抗体(例えば,HIR Ab-IDS)の全身投与量(systemic dose)の決定である。本明細書に記載されているように,IDS融合抗体(例えば,HIR Ab-IDS)の適切な全身投与量(systemic doses)は,HIR Ab-酵素融合抗体のCNS取り込み特性および酵素活性の定量的決定に基づいて確立される。デルマタン硫酸,ヘパラン硫酸およびヘパリンは可変的に硫酸化されたグリコサミノグリカンであり,二糖単位の反復によって作製される長鎖の非分岐鎖多糖である。L-イズロネート(またはL-イズロン酸)は,デルマタン硫酸およびヘパリンの主成分である。それはヘパラン硫酸にも存在している。本明細書で用いられているIDS(例えば,ジェンバンク受入番号NP_000193で登録されているヒトIDS配列)は,デルマタン硫酸,ヘパラン硫酸およびヘパリンのL-イズロン酸 2-硫酸(L-iduronate 2-sulfate)単位の2-硫酸基の加水分解または除去を触媒することができるいずれかの天然または人工の酵素を指す。
本発明の組成物は:BBBを越えてIDSを輸送する,IDSの治療的有効用量を送達する,および/またはBBBを越えて輸送された時点,もしくは標的抗体と融合した時点でIDSの活性を保持するのに有用であることを含む複数の理由で有用である。本発明の組成物は,融合抗体の中でIDSおよび/またはそれが結合している構造(例えば,免疫グロブリン,抗体)が,独立体(separate entity)としてのその活性と比較してある程度の活性をそれぞれ保持している点においても有用である。
択される必要な他の成分を含有する無菌ビヒクルに組み込むことによって製造される。無菌注射用溶液の製造のための無菌粉末の場合,製造方法は,その前もって無菌濾過した溶液から,有効成分に加えていずれかの付加的な所望の成分の粉末を生じる,真空乾燥および凍結乾燥技術を含む。
よい。そのような治療的に有用な該組成物中の活性化合物の量によって,適切な投薬量が得られるであろう。
本明細書に記載されているのは,本明細書に記載されているようなHIR Ab-IDS融合抗体の治療的有効量を全身投与することによって,BBBを越えてCNSにIDSの有効用量を送達する方法である。本明細書に記載されているように,IDS融合抗体(例えば,HIR MAb)の送達のための適切な全身投与量(systemic doses)は,そのCNS取り込み特性およびIDS比活性に基づく。IDS欠乏症を患っている対象へのIDS融合抗体(例えば,HIR MAb)の全身投与は,CNSへのIDSの非侵襲的送達に対する有効なアプローチである。
,0.4,0.5,0.75,1.0,1.5,2,または0.125~2.5の間のいずれかのユニットのIDS活性/mgタンパク質を提供する方法を提供する。
下記の特定の実施例は,単に説明の目的で提供されていると解釈されるべきであり,いかなる場合であっても決して本開示の残りの部分を限定するものではない。これ以上詳述しなくても,当業者であれば,本明細書の記載に基づいて,本発明をその最大限の範囲まで利用することができると考えられる。本明細書で引用されている全ての出版物は,それらの全体において参照することによって本明細書に援用される。参照がURLなどの識別名またはアドレスでなされている場合,該識別名は変化してよく,インターネット上の特定の情報は現れたり消えたりしうるが,インターネットを検索することによって等価な情報を見ることができると理解されるべきである。それに対する参照は,該情報が入手可能であり,公に普及していることを証明するものである。
スライ症候群とも呼ばれるMPS-VIIで変異しているリソソーム酵素は, -グルクロニダーゼ(GUSB)である。MPS-VIIは,脳内のグリコサミノグリカンの蓄積をもたらす。GUSB酵素はBBBを通過しないため,MPS-VIIの酵素補充療法(ERT)は,脳の治療に有効ではないようである。BBBを通過するヒトGUSBを再設計する試みにおいて,HIR Ab-GUSB融合タンパク質プロジェクトを開始した。
ハンター症候群とも呼ばれるMPS-IIで変異しているリソソーム酵素は,イズロン酸 2-スルファターゼ(IDS)である。MPS-IIは,脳内のグリコサミノグリカンの蓄積をもたらす。IDS酵素がBBBを通過しないため,MPS-IIの酵素補充療法は脳の治療に有効ではないようである。BBBを通過し,かつ酵素活性を示すことができる二機能性の分子を開発するために,IDSをHIR Abと融合させた。
COS細胞を6ウェルクラスターディッシュに蒔き,pCD-HC-IDS,およびpCD-LCで二重にトランスフェクトしたが,ここでpCD-LCは,HIR Ab-IDS融合タンパク質にも用いられるキメラHIRMAbの軽鎖(LC)をコードしている発現プラスミドである。融合タンパク質の発現を,ヒトIgGに特異的なELISAでスクリーニングした。より大量の融合タンパク質の産生のために,COS細胞を10xT500フラスコ中でトランスフェクトした。3日目および7日目の培地をプールし,2Lの無血清条件培地を接線流濾過(ミリポア社)で400mLまで濃縮し,次いでタンパク質Aアフィニティークロマトグラフィーで精製した。
HIR細胞外ドメイン(ECD)に対する融合タンパク質の親和性は,ELISAで決定した。前にColoma et al. (2000) Pharm Res, 17:266-274に記載されているように,HIR ECDで永続的にトランスフェクトされたCHO細胞を無血清培地(SFM)中で培養し,HIR ECDをコムギ胚芽凝集素アフィニティーカラムで精製した。HIR ECDをNunc-Maxisorb 96ウェルディッシュに蒔き,HIR Ab,またはHIR Ab-IDS融合タンパク質と,HIR ECDの結合を,ビオチン化ヤギ抗ヒトIgG(H+L)二次抗体で検出し,次いでアビジンおよびビオチン化ペルオキシダーゼ(ベクターラボラトリーズ社,バーリンゲーム,カリフォルニア州)で検出した。最大結合の50%を与えるHIR AbまたはHIR Ab-IDS融合タンパク質の濃度を,非線形回帰分析で決定した。図11に示しているように,キメラHIR AbまたはHIR Ab-IDS融合タンパク質はHIR ECDに対して同程度の結合を示し,ED50はそれぞれ0.32±0.05nMおよび0.40±0.05nMであった。
MPS II型ハンター症候群の線維芽細胞(Hunter fibroblasts)(GM000298)および健常なヒト線維芽細胞(GM000497)は,コーリエル医学研究所(Coriell Institute for Medical Research)(カムデン,ニュージャージー州)から得,6ウェルクラスターディッシュ内で高密集度になるまで(to confluency)培養した。培地を吸引し,ウェルをリン酸緩衝生理食塩水(PBS)で洗浄し,血清を含まない1mLのダルベッコ変法イーグル培地で,一定濃度範囲のHIRMAb-IDS融合タンパク質と共に,37℃で2時間インキュベートした。培地を吸引し,PBSでウェルを広範囲に洗浄し(1mL/ウェル,5回洗浄),単層を0.3mL/ウェルの溶解緩衝液(5mMギ酸ナトリウム,0.2%トリトンX-100,pH=4.0)中で抽出し,次いで4回の凍結/融解サイクルを行い,4℃で10分間微量遠心した。IDS酵素活性およびビシンコニン酸タンパク質(BCA)アッセイのために,上清を除去した。融合タンパク質の取り込みは,IDS酵素活性/mg細胞タンパク質のnmol/hrとして表した。
HIRAb-IDS融合タンパク質は2つの重鎖(HC)および2つの軽鎖(LC)で構成されるヘテロ四量体タンパク質であり(図6),別々のHCおよびLCタンパク質は別々のHCおよびLC遺伝子から産生される。それゆえ,永続的にトランスフェクトされた宿主細胞による全融合タンパク質の高産生を保証するために,HCおよびLCの両方について宿主細胞内で同様に高い発現を達成することが必要である。さらに,宿主細胞は,導入遺伝子の挿入部位周辺の宿主ゲノムの選択的増幅を可能にするマーカー遺伝子で,永続的にトランスフェクトされていなければならない。例えば,宿主細胞をメトトレキセート(MTX)等の薬物に持続的に曝露すると,標的酵素,すなわちジヒドロ葉酸還元酵素(DHFR)遺伝子を高発現しているクローンを選択することができるであろう。HC融合遺伝子,LC遺伝子,およびDHFR遺伝子の同様に高い発現を保証するために,これら3つの遺伝子をコードしている発現カセットを全て,図15に概略を示しているタンデムベクターと呼ばれる一本鎖のDNA上に配置した。HC融合遺伝子およびLC遺伝子は,5’側にサイトメガロウイルス(CMV)由来プロモーターが隣接し,5’側にウシ成長ホルモン(BGH)遺伝子由来のポリA+配列が隣接している。DHFR遺伝子は5’側にSV40プロモーターが隣接し,3’側に肝炎Bウイルス(HBV)ゲノム由来のポリA配列が隣接していた。TV-HIRMAb-IDSは,neo,すなわちネオマイシン耐性遺伝子をコードしている発現カセットも含み,G418による選別を可能にした(図15)。
チャイニーズハムスター卵巣(CHO)細胞を,1xHTサプリメント(ヒポキサンチンおよびチミジン)を含有する無血清HyQ SFM4CHOユーティリティ培地(ハイクローン社)中で培養した。CHO細胞(5x106個の生細胞)を,5μgのPvuIで直線状にした(linearized)TV-HIRMAb-IDSプラスミドDNAと共にエレクトロポレーションした。次いで,細胞-DNA懸濁液を氷上で10分間インキュベートした。CHO細胞についてのバイオラド・プリセットプロトコール(BioRad pre-set protocol),すなわち,15msecおよび160ボルトのパルスを有する方形波で細胞をエレクトロポレーションした。エレクトロポレーション後,細胞を氷上で10分間インキュベートした。細胞懸濁液を50mL培地に移し,125μl/ウェルで4x96ウェルプレートに蒔いた(10,000細胞/ウェル)。計10回のエレクトロポレーションおよび4,000ウェルを1回の研究で行った。
25個のアミノ酸のシグナルペプチドに続くIDSの最初の8個のアミノ酸はプロペプチドを構成しているが(Flomen et al, Determination of the organization of coding sequences within the iduronate sulphate sulphatase (IDS) gene, Hum. Mol. Genet. 2, 5-10, 1993),これはエンドプロテアーゼによって切断されうる。該切断はHIR AbからのIDSの分離をもたらしうるが,この場合,IDSはHIR Abトロイの木馬によってBBBを越えて輸送され得ない。この場合,IDS cDNAは,表2に記載されている新たなフォワードODN(配列番号19)を用いたPCRによって再増幅されうる。表2に記載されているIDS FWD2 ODNおよびIDS REV ODNによるPCRは,25個のアミノ酸のシグナルペプチド,Met-1~Gly-25を含まず,8個のアミノ酸のプロペプチド,Ser-26~Thr-33を含まず,Thr-34で始まり,Pro-550で終わるヒトIDS配列(NP_000193)であるIDS酵素をコードするIDS cDNAを増幅するであろう。IDS FWD2 ODNは5’末端に「CC」を有し,それによりHIR AbのHCのCH3領域のカルボキシル末端を含むオープンリーディングフレームを維持し,HIR Ab HCのカルボキシル末端とIDSのアミノ末端の間にSer-Serリンカーを配置する。
成熟ヒトIDSは,HIR AbのHCのカルボキシル末端と,2個のアミノ酸のリンカー,Ser-Ser(図5で下線を引いている)で融合している。多数のリンカーのバリエーションがSer-Serリンカーの代わりに用いられる。2個のアミノ酸のリンカーは保持されてよいが,アミノ酸配列は代替のアミノ酸,例えばGly-Gly,Ser-Gly,もしくはAla-Ser,または20個の天然アミノ酸の多数の組み合わせに変化してよい。または,リンカーは1個のアミノ酸,または0個のアミノ酸に減少している。0個のアミノ酸のリンカーの場合,IDSのアミノ末端はHIR AbのHCのカルボキシル末端と直接融合している。あるいは,リンカーの長さは3,4,5,6,7,8,9,10,11,12,13,14,15個のアミノ酸まで伸長してよい。融合タンパク質の設計における最適なアミノ酸リンカーを決定するための複数の公に入手可能なプログラムがあるため,該リンカーは当該技術分野で周知である。頻繁に用いられるリンカーは,反復配列におけるGlyおよびSerの様々な組み合わせ,例えば(Gly4Ser)3,または他のバリエーションを含む。
ムコ多糖症(MPS)II型(MPS-II),またはハンター症候群は,リソソーム酵素,イズロン酸-2-スルファターゼ(IDS)をコードしている遺伝子の欠損に起因するリソソーム蓄積症である。MPS-IIは酵素補充療法(ERT)において組換えヒトIDSで治療される[Muenzer, et al, A phase II/III clinical study of enzyme replacement therapy with idurosulfase in mucopolysaccharidosis II (Hunter syndrome). Genet. Med. 8 (2006) 465-473]。しかしながら,MPS-IIの多くの症例は中枢神経系に影響する[Al Sawaf, et al, Neurological findings in Hunter disease: pathology and possible therapeutic effects reviewed. J Inherit Metab Dis 31 (2008) 473-480]。IDSはBBBを通過しないためERTは脳に有効ではなく,脳に影響するMPS-II症例において,ERTの使用は任意であると考えられている[Wraith, et al, Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr 167 (2008) 267-77]。MPS-IIを患う対象の脳を治療することは現在不可能であり,MPS-IIと関連する容赦ない神経機能の低下および死を防ぐための新たな治療が必要とされている。
Claims (9)
- 融合抗体の治療的有効量および医薬的に許容される賦形剤を含む、ハンター症候群の治療のための静脈内注射用の医薬組成物であって、
該融合蛋白質が、(a)免疫グロブリン重鎖およびイズロン酸-2-スルファターゼのアミノ酸配列を含む融合タンパク質であって、イズロン酸-2-スルファターゼのアミノ酸配列が免疫グロブリン重鎖のアミノ酸配列のカルボキシ末端に共有結合している融合タンパク質、ならびに(b)免疫グロブリン軽鎖を含み、且つ、内在性の血液脳関門(BBB)受容体媒介輸送系を経由して、血液脳関門(BBB)を通過し、かつ、デルマタン硫酸、ヘパラン硫酸またはヘパリンのL-イズロン酸 2-硫酸単位の2-硫酸基の加水分解を触媒するものである、
医薬組成物。 - 該融合抗体がスルファターゼ修飾因子1(SUMF1)によって翻訳後修飾されている、請求項1に記載の医薬組成物。
- 該融合抗体がホルミルグリシンを含む、請求項1に記載の医薬組成物。
- 該融合タンパク質が、イズロン酸-2-スルファターゼのアミノ酸配列と免疫グロブリン重鎖のアミノ酸配列のカルボキシ末端の間のリンカーをさらに含む、請求項1に記載の医薬組成物。
- 該融合抗体のイズロン酸-2-スルファターゼの比活性が少なくとも約10,000ユニット/mgである、請求項1に記載の医薬組成物。
- 該融合抗体のイズロン酸-2-スルファターゼの比活性が、独立体(separate entity)としてのその活性と比較して、その活性の少なくとも20%を保持している、請求項1に記載の医薬組成物。
- 該融合抗体のイズロン酸-2-スルファターゼおよび免疫グロブリンが、独立体(separate entity)としてのその活性と比較して、その活性の少なくとも20%をそれぞれ保持している、請求項1に記載の医薬組成物。
- 該免疫グロブリン重鎖がIgGの免疫グロブリン重鎖である、請求項1に記載の医薬組成物。
- 該融合抗体がインスリン受容体、トランスフェリン受容体、レプチン受容体、リポタンパク質受容体、およびIGF受容体からなる群から選択される内在性BBB受容体を経由してBBBを通過する、請求項1に記載の医薬組成物。
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- 2010-10-08 HU HUE10822810 patent/HUE044865T2/hu unknown
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2014
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2016
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2018
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SI2485761T1 (sl) | 2019-05-31 |
WO2011044542A1 (en) | 2011-04-14 |
US11028156B2 (en) | 2021-06-08 |
EP2485761A1 (en) | 2012-08-15 |
JP2018154629A (ja) | 2018-10-04 |
EP4273164A3 (en) | 2024-01-24 |
US20190185551A2 (en) | 2019-06-20 |
EP3533467A2 (en) | 2019-09-04 |
DK2485761T3 (da) | 2019-05-06 |
EP2485761B1 (en) | 2019-02-27 |
US20180251535A1 (en) | 2018-09-06 |
HUE044865T2 (hu) | 2019-11-28 |
US8834874B2 (en) | 2014-09-16 |
HRP20190690T1 (hr) | 2019-06-28 |
EP3533467B1 (en) | 2023-07-26 |
JP2013507131A (ja) | 2013-03-04 |
US20110110935A1 (en) | 2011-05-12 |
PT2485761T (pt) | 2019-05-30 |
EP2485761A4 (en) | 2013-04-03 |
JP2016155805A (ja) | 2016-09-01 |
EP3533467A3 (en) | 2020-01-15 |
US10011651B2 (en) | 2018-07-03 |
US20150004160A1 (en) | 2015-01-01 |
US20210253681A1 (en) | 2021-08-19 |
PL2485761T3 (pl) | 2019-10-31 |
EP4273164A2 (en) | 2023-11-08 |
ES2725200T3 (es) | 2019-09-20 |
JP2021008488A (ja) | 2021-01-28 |
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