JP2019505480A - 酵素の内部移行のための組成物および方法 - Google Patents
酵素の内部移行のための組成物および方法 Download PDFInfo
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Abstract
【選択図】なし
Description
本発明は、記載された特定の実施形態、組成物、方法、および実験条件に限定されるものではないが、それはこうした実施形態、組成物、方法、および条件が異なる場合があるからである。本発明の範囲が添付の特許請求の範囲のみによって限定されるものである以上、本明細書に使用される用語は、特定の実施形態を説明する目的のためだけのものであり、限定することを意図するものではない。
CI−MPR非依存抗体誘導送達系を、酵素をリソソームに送達するように設計した。表3には、分子構築物を列挙し、それらのCHO細胞内発現レベル(図2を参照)、蛍光基質4−メチルウンベリフェリル−α−グルコシドを用いて測定されたおおよそのGAA活性(図3を参照)、ならびにリソソーム標的指向化、内部移行、および活性状態(図4および図5を参照)を示している。
GAA構築物の内部移行を、細胞可溶化物における酵素活性を測定することにより定量した。組換えGAA(配列番号1)の種々の構築物を、HEK293、ヒト骨格筋芽細胞(Lonza、メリーランド州ウォーカーズビル)、または、C2C12マウス筋芽細胞に添加した。酵素構築物の添加の24時間前に、細胞を24ウェルプレートにプレーティングした。酵素構築物を細胞の培地に18時間添加した。続いて、細胞を氷冷PBS中にて十分に洗浄し、氷冷した0.5% NP−40のアッセイ緩衝液(0.2Mの酢酸ナトリウム、0.4Mの塩化カリウム、pH4.3)中で溶解した。溶解物を4℃にて15,000×gで15分間遠心分離し、上清をGAA基質である4−メチルウンベリフェリルアルファ−D−グルコシドと共に、96ウェルプレートでアッセイ緩衝液中にて1時間インキュベートした。グリシン−炭酸緩衝液を用いてpH10.7で反応を停止した。蛍光を、励起波長360nmおよび発光波長450nmにおいてプレートリーダーで読み取った。溶解物のタンパク質濃度を、ビシンコニン酸アッセイキットを用いて定量した。4−メチルウンベリフェロンを基質として用いた。GAA活性を、精製タンパク質1mg当たりに毎時放出される4−メチルウンベリフェロンのnmol数として記録した。Fuller et al.,“Isolation and characterisation of a recombinant,precursor form of lysosomal acid alpha−glucosidase,”234(3)European Journal of Biochemistry 903−909(1995)を参照されたい。
骨格筋芽細胞(ポンペ病における検討対象の組織タイプ)が種々のGAA構築物を取り込む能力を評価した。種々の濃度(すなわち、25nM、50nM、および200nM)の(1)抗CD63−GAA、(2)抗CD63−GAA+5mM M6P、(3)myc−GAA、および(4)myc−GAA+5mM M6Pの存在下、ヒト骨格筋芽細胞を培養した。GAA構築物の内部移行を、4−メチルウンベリフェロンの蓄積によって示される細胞可溶化物で検出したGAA活性レベルから推測し、評価した。200nMのMPR非依存性抗CD63−GAAの取り込み量は、MPR依存性のmyc−GAAの取り込み量よりも5倍超多かった(図5A)。
抗CD63−GAAが3つの異なる種類のポンペ細胞株のリソソームにおいてグリコーゲン蓄積に及ぼす影響を評価した。ポンペ細胞株は、重症の乳児型ポンペ病を発症した患者から得られた線維芽細胞由来であり、GAA遺伝子においてノックアウト変異またはノックダウン変異を含んでいた。使用した細胞株は、GM20089(エクソン18欠失)、GM20090(エクソン14およびエクソン16における複合ヘテロ接合体)、およびGM20090(エクソン2における複合ヘテロ接合体)であった。これらの細胞株をCoriell Institute(ニュージャージー州カムデン)から得た。Huie et al.,“Increased occurrence of cleft lip in glycogen storage disease type II(GSDII):exclusion of a contiguous gene syndrome in two patients by presence of intragenic mutations including a novel nonsense mutation Gln58Stop,”85(1)Am.J.Med.Genet.5−8(1999);Huie et al.,“Glycogen storage disease type II:identification of four novel missense mutations(D645N,G648S,R672W,R672Q)and two insertions/deletions in the acid alpha−glucosidase locus of patients of differing phenotype,”244(3)Biochem.Biophys.Res.Commun.921−7(1998)and;Nishiyama et al.,“Akt inactivation induces endoplasmic reticulum stress−independent autophagy in fibroblasts from patients with Pompe disease,”107 Molecular genetics and metabolism 490−5(2012)を参照されたい。新生児ヒト皮膚線維芽(NHDF、Lonza)を対照として用いた。全てのポンペ細胞株は、残留(<0.1%)GAA活性が存在する場合でも、リソソームグリコーゲン蓄積を示した(細胞質内グリコーゲンを低減させるグルコース飢餓の72時間後)(図6、パネルAおよびパネルB)。グリコーゲンをグリコーゲンアッセイキット(Sigma−Aldrich、ミズーリ州セントルイス)を用いて測定した。
GAA(すなわち、交差反応免疫学的物質またはCRIM)に対して起こり得るポンペ患者の免疫応答を回避するために、GAA活性を救済する他のヒトグルコシダーゼを送達することを検討した。GAA(別名は酸性α−グルコシダーゼ)に対して同様のグリコーゲン加水分解活性を有する非リソソーム酵素を調べた。これらの酵素として、スクラーゼ・イソマルターゼ(SI)、マルターゼ・グルコアミラーゼ(MGAM)、グルコシダーゼII(GANAB)、および中性α−グルコシダーゼ(C GNAC)が挙げられる。これらの酵素および種々の組換え実施形態が、Dhital et al.,“Mammalian mucosal α−glucosidases coordinate with α−amylase in the initial starch hydrolysis stage to have a role in starch digestion beyond glucogenesis,”8(4)PLoS One e625462013 Apr 25(2013);Sim et al.,“Human intestinal maltase−glucoamylase:crystal structure of the N−terminal catalytic subunit and basis of inhibition and substrate specificity,”375(3)J.Mol.Biol.782−92(2008);およびQuezada−Calvillo et al.,“Luminal starch substrate “brake”on maltase−glucoamylase activity is located within the glucoamylase subunit,”138(4)J.Nutr.685−92(2008)に記載されている。
ヒトGLA(配列番号2)を含む種々の融合タンパク質を構築し、CHO細胞内で発現させた。これらの構築物には、(i)抗CD63重鎖のC末端に融合したGLA(抗CD63−GLA)、(ii)イムノグロブリンFcに融合したGLA(例えば、Fc「ノブ」)、(iii)GLA−抗CD63(すなわち、抗CD63重鎖のN末端に融合したGLA)、および(iv)GLA−myc融合を含めた(図8)。また、GLA部分のない内部移行エフェクター結合タンパク質(IEBP)を、改変かつ発現させた。一例では、IEBPは、CD63に対する結合特異性を持つ一方の半分と、mycに対する結合特異性を持つ他方の半分を備えた二重特異性抗体であった。GLA酵素活性(すなわち、4−メチルウンベリフェリル−β−ガラクトピラノシドの加水分解)を各GLA融合タンパク質に対して評価し、その結果を図9に示す。全構築物は、C末端抗CD63−GLA融合を除外して、α−ガラクトシダーゼ活性を示した(図9)。Fcノブについては、Ridgway et al.,“‘Knobs−into−holes’ engineering of antibody CH3 domains for heavy chain heterodimerization,”9(7)Protein Eng.617−621(1996)に記載されている。
抗CD63抗体または抗APLP2抗体の低pH細胞分画への内部移行を、高M6P含有量を有している、組換えヒトGLA(rhGLA)の低pH分画への内部移行と比較した。GLA、抗CD63、および抗APLP2の各々を、低pH感受性色素pHrodo(登録商標)(Invitrogen、カリフォルニア州カールスバッド)で標識した。HEK細胞、HepG2細胞(肝癌)、およびPC−3細胞(前立腺癌)をpHrodo(登録商標)で標識したタンパク質と接触させ、一晩または約16時間インキュベートした。続いて、細胞をイメージングし、蛍光小胞をカウントした。各タンパク質の標識度合いに応じて蛍光出力を標準化した。HEK細胞、PC−3細胞、およびHepG2細胞は、rhGLAに比べて抗CD63と抗APLP2の取り込み量がより多くなることを示した(図11)。
抗CD63−GAA構築物がリソソーム内でタンパク質分解的にプロセシングされるか否かを、ポンペ細胞可溶化物のウェスタンブロット分析により評価した。GM20089ポンペ細胞を抗CD63−GAAの存在下で培養し、生じた細胞可溶化物を、抗GAA抗体(図12、パネルA)または抗hIgG抗体(図12、パネルB)を用いて還元ウェスタンブロット分析した。
CD63部位でヒト化されたマウス(Valenzuela et al.,“High−throughput engineering of the mouse genome coupled with high−resolution expression analysis,”21 Nature Biotechnology 652 − 659(2003)を参照)に抗CD63−GAAを投与した。組織サンプルを採取し、GAAをウェスタンブロット分析により評価した。GAAは、肝臓、横隔膜、腎臓、心臓、ならびに四頭筋および腓腹筋で検出された(図13)。
筋特異的抗原(抗インテグリンアルファ7、抗CD9、および抗ジストログリカン)に対するビオチン化抗体をGAAノックアウトマウスに投与した。これらの抗体の組織分布をウェスタンブロット分析により測定した。図15には、骨格筋(腓腹筋、四頭筋、および横隔膜)、心筋、肝臓(標準化用のベースラインとして機能する)、腎臓、および脾臓内で見られた抗体レベルのヒストグラムを示す。抗インテグリンアルファ7抗体は、骨格筋および心臓で(肝臓で見られたレベルを上回るレベルで)見られた。抗CD9抗体は骨格筋および心臓で(肝臓で見られたレベルを上回るレベルで)見られ、また腎臓および脾臓でも同様に見られた(図15)。
天然マウスCD63発現を有する2〜3月齢のGAAノックアウト(KO)マウスに、完全長ヒトα−グルコシダーゼ(hGAA)、抗mCD63−GAA(抗マウスCD63)およびその関連軽鎖、または抗hCD63−GAA(抗ヒトCD63)およびその関連軽鎖をコードするプラスミド構築物を流体力学的送達(HDD)した。全ての構築物は、ユビキチンプロモーターとSV40polyAテールとからなる同一のプラスミドバックボーンを用いた。簡単に述べると、各プラスミドの40μg(すなわち、重鎖と軽鎖の40μgまたはhGAAのみの40μg)を滅菌生理食塩水2mL〜3mLで希釈し、GAA KOマウスの尾静脈にすばやく注射した。3日毎の尾出血により、約10日間のhGAA構築物または抗体GAA構築物の血清レベルを明らかにした。マウスをHDDの3週間後に屠殺し、組織を液体窒素で急速凍結した。組織を蒸留水で均質化し、煮沸、遠心沈殿した。蛍光グリコーゲンアッセイキット(MAK016、Sigma Aldrich、ミズーリ州セントルイス)を用いて上清についてグリコーゲンの定量を行った。
リソソーム酸性リパーゼ(LALまたはLIPA)は、コレステリルエステルおよびトリグリセリドをリソソーム内で分解する酵素である。LIPAにおける欠損(例えば、LAL−Dまたはウォルマン病)は、肝臓、脾臓、および他の器官で脂肪質の蓄積をもたらす。LAL−Dの有病率は、世界で40,000人に1人〜300,000人に1人である。LIPA欠損を持つ乳児は、処置されなければ、多臓器不全のために6か月〜12か月で死亡する。より年長の子供は診断未確定のまま、心臓発作、脳卒中、または肝不全で死亡する可能性がある。
Claims (35)
- エンドサイトーシスを起こす膜タンパク質に結合する抗原結合タンパク質に直接、または単一のリンカーによって連結されているリソソーム酵素を含む、組成物。
- 前記膜タンパク質が、リソソーム膜に局在する、請求項1に記載の組成物。
- 前記リソソーム酵素が、α−ガラクトシダーゼ、β−ガラクトシダーゼ、α−グルコシダーゼ、β−グルコシダーゼ、サポシン−C活性化因子、セラミダーゼ、スフィンゴミエリナーゼ、β−ヘキソサミニダーゼ、GM2活性化因子、GM3シンターゼ、アリールスルファターゼ、スフィンゴ脂質活性化因子、α−イズロニダーゼ、イズロニダーゼ−2−スルファターゼ、ヘパリンN−スルファターゼ、N−アセチル−α−グルコサミニダーゼ、α−グルコサミドN−アセチルトランスフェラーゼ、N−アセチルグルコサミン−6−スルファターゼ、N−アセチルガラクトサミン−6−硫酸スルファターゼ、N−アセチルガラクトサミン−4−スルファターゼ、β−グルクロニダーゼ、およびヒアルロニダーゼからなる群から選択される、請求項1に記載の組成物。
- 前記抗原結合タンパク質が、受容体融合分子、トラップ分子、受容体Fc融合分子、抗体、Fab断片、F(ab’)2断片、Fd断片、Fv断片、一本鎖Fv(scFv)分子、dAb断片、単離相補性決定領域(CDR)、CDR3ペプチド、拘束FR3−CDR3−FR4ペプチド、ドメイン特異的抗体、単一ドメイン抗体、ドメイン欠失抗体、キメラ抗体、CDR移植抗体、ダイアボディ、トリアボディ、テトラボディ、ミニボディ、ナノボディ、一価ナノボディ、二価ナノボディ、小モジュラー免疫薬(SMIP:small modular immunopharmaceutical)、ラクダ抗体(VHH重鎖ホモ二量体抗体)、およびサメ可変IgNARドメインからなる群から選択される、請求項1から請求項3のうちのいずれか1項に記載の組成物。
- 前記膜タンパク質が、CD63、MHC−I、Kremen−1、Kremen−2、LRP5、LRP6、LRP8、トランスフェリン受容体、LDL−受容体、LDL関連タンパク質1受容体、ASGR1、ASGR2、アミロイド前駆体タンパク質様タンパク質−2(APLP2)、アペリン受容体(APLNR)、PRLR(プロラクチン受容体)、MAL(Myelin And Lymphocyteタンパク質、別名VIP17)、IGF2R、液胞型H+ATPアーゼ、ジフテリア毒素受容体、葉酸受容体、グルタミン酸受容体、グルタチオン受容体、レプチン受容体、スカベンジャー受容体、SCARA1−5、SCARB1−3、CD36、CDH16(Cadheri−16)、CLDN16(Claudn−16)、KL(Klotho)、PTH1R(副甲状腺ホルモン受容体)、SLC22A13(溶質輸送体ファミリー22メンバー13)、SLC5A2(ナトリウム/グルコース共輸送体2)、UMOD(ウロモジュリン)、BMPR1A(骨形態形成タンパク質受容体1A)、m−カドヘリン、CD9、MuSK(筋特異的キナーゼ)、LGR4/GPR48(Gタンパク質共役受容体48)、コリン作動性受容体(ニコチン性)アルファ1、CDH15(Cadheri−15)、ITGA7(インテグリンアルファ−7)、CACNG1(L型カルシウムチャネルサブユニットガンマ−1)、CACNAls(L型カルシウムチャネルサブユニットアルファ−15)、CACNG6(L型カルシウムチャネルサブユニットガンマ−6)、SCN1B(ナトリウムチャネルサブユニットベータ−1)、CHRNA1(ACh受容体サブユニットアルファ)、CHRND(ACh受容体サブユニットデルタ)、LRRC14B(ロイシンリッチリピート含有タンパク質14B)、およびPOPDC3(Popeyeドメイン含有タンパク質3)からなる群から選択される、請求項1から請求項4のうちのいずれか1項に記載の組成物。
- 前記リソソーム酵素が、前記抗原結合タンパク質に直接連結している、請求項1から請求項5のうちのいずれか1項に記載の組成物。
- 前記抗原結合タンパク質が抗体を含み、前記酵素が前記抗体の重鎖のC末端に共有結合している、請求項6に記載の組成物。
- 前記リソソーム酵素が、単一のリンカーによって前記抗原結合タンパク質に連結している、請求項1から請求項5のうちのいずれか1項に記載の組成物。
- 前記抗原結合タンパク質が半抗体を含み、前記リソソーム酵素がイムノグロブリンのFcドメインに共有結合し、前記酵素に共有結合した前記Fcドメインが、前記抗原結合タンパク質のFcドメインと結合している、請求項8に記載の組成物。
- 前記リンカーが開裂可能なリンカーである、請求項8に記載の組成物。
- 前記リソソーム酵素がGAAであるか、またはGAA活性を含み、前記膜タンパク質が、CD63、APLP2、およびPRLRからなる群から選択される、請求項1から請求項10のうちのいずれか1項に記載の組成物。
- 前記リソソーム酵素がGAAであるか、またはGAA活性を含み、前記膜タンパク質がCD63である、請求項1から請求項11のうちのいずれか1項に記載の組成物。
- 前記リソソーム酵素が配列番号1のアミノ酸配列を含む、請求項1から請求項12のうちのいずれか1項に記載の組成物。
- 前記リソソーム酵素がGLAであるか、またはGLA活性を含み、前記膜タンパク質が、CD63、APLP2、およびPRLRからなる群から選択される、請求項1から請求項10のうちのいずれか1項に記載の組成物。
- 前記酵素がGLAであるか、またはGLA活性を含み、前記膜タンパク質がCD63である、請求項1から請求項10および請求項14のうちのいずれか1項に記載の組成物。
- 前記リソソーム酵素が配列番号2のアミノ酸配列を含む、請求項1から請求項10、請求項14、および請求項15のうちのいずれか1項に記載の組成物。
- リソソーム蓄積症(LSD)に罹患している対象を治療する方法であって、
前記対象に(a)酵素と(b)エンドサイトーシスを起こす膜タンパク質に結合する抗原結合タンパク質とを含む生物学的治療用複合体を投与することを含み、
前記生物学的治療用複合体が、前記対象の細胞のリソソームに入って、前記リソソームに前記酵素を送達し、それが前記LSDに関連する酵素活性(「内因性酵素」)を補充する、前記方法。 - 前記LSDが、スフィンゴリピドーシス、ムコ多糖症、およびグリコーゲン蓄積症からなる群から選択される、請求項17に記載の方法。
- 前記LSDが、ファブリー病、ゴーシェ病I型、ゴーシェ病II型、ゴーシェ病III型、ニーマン・ピック病A型、ニーマン・ピック病B型、GM1−ガングリオシドーシス、サンドホフ病、テイ・サックス病、GM2−活性化因子欠損、GM3−ガングリオシドーシス、異染性白質ジストロフィー、スフィンゴ脂質活性化因子欠損、シャイエ病、ハーラー・シャイエ病、ハーラー病、ハンター病、サンフィリポA、サンフィリポB、サンフィリポC、サンフィリポD、モルキオ症候群A、モルキオ症候群B、マロトー・ラミー病、スライ病、MPS IX、およびポンペ病からなる群から選択される、請求項17または請求項18に記載の方法。
- 前記LSDがファブリー病またはポンペ病である、請求項17から請求項19のうちのいずれか1項に記載の方法。
- 前記酵素が、α−ガラクトシダーゼ、β−ガラクトシダーゼ、α−グルコシダーゼ、β−グルコシダーゼ、サポシン−C活性化因子、セラミダーゼ、スフィンゴミエリナーゼ、β−ヘキソサミニダーゼ、GM2活性化因子、GM3シンターゼ、アリールスルファターゼ、スフィンゴ脂質活性化因子、α−イズロニダーゼ、イズロニダーゼ−2−スルファターゼ、ヘパリンN−スルファターゼ、N−アセチル−α−グルコサミニダーゼ、α−グルコサミドN−アセチルトランスフェラーゼ、N−アセチルグルコサミン−6−スルファターゼ、N−アセチルガラクトサミン−6−硫酸スルファターゼ、N−アセチルガラクトサミン−4−スルファターゼ、β−グルクロニダーゼ、およびヒアルロニダーゼからなる群から選択される、請求項17に記載の方法。
- 前記酵素が、前記対象において免疫反応を誘導しない、請求項17から請求項21のうちのいずれか1項に記載の方法。
- 前記酵素がアイソザイムである、請求項17から請求項22のうちのいずれか1項に記載の方法。
- 前記LSDがポンペ病であり、前記内因性酵素がα−グルコシダーゼ(GAA)であり、前記アイソザイムが、酸性α−グルコシダーゼ、スクラーゼ・イソマルターゼ(SI)、マルターゼ・グルコアミラーゼ(MGAM)、グルコシダーゼII(GANAB)、および中性α−グルコシダーゼ(C GNAC)からなる群から選択される、請求項23に記載の方法。
- 前記LSDがファブリー病であり、前記内因性酵素がα−ガラクトシダーゼA(GLA)であり、前記アイソザイムがGLA活性を得るように操作されたα−N−アセチルガラクトサミニダーゼである、請求項23に記載の方法。
- 前記膜タンパク質が、CD63、MHC−I、Kremen−1、Kremen−2、LRP5、LRP6、LRP8、トランスフェリン受容体、LDL−受容体、LDL関連タンパク質1受容体、ASGR1、ASGR2、アミロイド前駆体タンパク質様タンパク質−2(APLP2)、アペリン受容体(APLNR)、PRLR(プロラクチン受容体)、MAL(Myelin And Lymphocyteタンパク質、別名VIP17)、IGF2R、液胞型H+ATPアーゼ、ジフテリア毒素受容体、葉酸受容体、グルタミン酸受容体、グルタチオン受容体、レプチン受容体、スカベンジャー受容体、SCARA1−5、SCARB1−3、CD36、CDH16(Cadheri−16)、CLDN16(Claudn−16)、KL(Klotho)、PTH1R(副甲状腺ホルモン受容体)、SLC22A13(溶質輸送体ファミリー22メンバー13)、SLC5A2(ナトリウム/グルコース共輸送体2)、UMOD(ウロモジュリン)、BMPR1A(骨形態形成タンパク質受容体1A)、m−カドヘリン、CD9、MuSK(筋特異的キナーゼ)、LGR4/GPR48(Gタンパク質共役受容体48)、コリン作動性受容体(ニコチン性)アルファ1、CDH15(Cadheri−15)、ITGA7(インテグリンアルファ−7)、CACNG1(L型カルシウムチャネルサブユニットガンマ−1)、CACNAls(L型カルシウムチャネルサブユニットアルファ−15)、CACNG6(L型カルシウムチャネルサブユニットガンマ−6)、SCN1B(ナトリウムチャネルサブユニットベータ−1)、CHRNA1(ACh受容体サブユニットアルファ)、CHRND(ACh受容体サブユニットデルタ)、LRRC14B(ロイシンリッチリピート含有タンパク質14B)、およびPOPDC3(Popeyeドメイン含有タンパク質3)からなる群から選択される、請求項17から請求項25のうちのいずれか1項に記載の方法。
- 前記膜タンパク質がCD63である、請求項17から請求項26のうちのいずれか1項に記載の方法。
- 前記膜タンパク質がAPLP2である、請求項17から請求項26のうちのいずれか1項に記載の方法。
- 前記抗原結合タンパク質が、抗体、抗体断片、または他の抗原結合タンパク質である、請求項17から請求項28のうちのいずれか1項に記載の方法。
- 前記抗原結合タンパク質が、前記酵素と前記膜タンパク質とに結合する二重特異性抗体である、請求項29に記載の方法。
- 前記酵素がイムノグロブリンのFcドメインに連結しており、前記抗原結合タンパク質が半抗体を含む、請求項17から請求項29のうちのいずれか1項に記載の方法。
- 前記酵素が、抗膜タンパク質抗体の前記重鎖のC末端に共有結合している、請求項17から請求項29のうちのいずれか1項に記載の方法。
- 前記酵素が、抗膜タンパク質抗体の前記重鎖のN末端に共有結合している、請求項17から請求項29のうちのいずれか1項に記載の方法。
- 前記酵素がGLAを含み、前記膜タンパク質がCD63であり、および前記LSDがファブリー病である、請求項30に記載の方法。
- 前記酵素がGAAを含み、前記膜タンパク質がCD63であり、および前記LSDがポンペ病である、請求項30に記載の方法。
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