JP2012505179A - 抗ポリマー抗体およびそれと結合するリポソームまたは微小胞を含むターゲッティング構築物 - Google Patents
抗ポリマー抗体およびそれと結合するリポソームまたは微小胞を含むターゲッティング構築物 Download PDFInfo
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- 239000008181 tonicity modifier Substances 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
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Abstract
Description
本発明のある局面は、以下を含む医薬キットに関する:
a)複数のポリマー分子を含む安定化エンベロープを有するリポソームもしくはガス充填微小胞またはその前駆体を含む第1組成物;および
b)ターゲッティングリガンドおよび該ポリマーと選択的に結合することができる抗体を含むターゲッティング構築物を含む第2組成物。
a)(i)該身体部分の分子または組織と選択的に結合するターゲッティングリガンドおよび(ii)ポリマー分子と選択的に結合することができる抗体を含むターゲッティング構築物を含む第1組成物を投与し;
b)複数の該ポリマー分子を含む安定化エンベロープを有する該リポソームまたは該ガス充填微小胞を含む第2組成物を投与する
工程を含む方法に関する。
図面
図1〜3は、本発明のターゲッティング構築物の例を示す。
図4は、本発明のターゲッティング構築物を造影剤/治療薬と共に用いる例を示す。
(定義)
抗ポリマー抗体
ターゲッティングリガンド
[式中、
TLは、リンカーZと反応するかまたはそれを形成することができる部分で機能化されることがある上記ターゲッティングリガンドを表す;
APAは、リンカーZと反応するかまたはそれを形成することができる部分で機能化されることがある上記抗ポリマー抗体を表す;
Zは、共有結合、結合部分、キレーティング部分、結合タンパク質(例えば、アビジンもしくはストレプトアビジン)、または超分子ベクター、例えばミセル、リポソーム、またはナノ粒子から選ばれる2機能性リンカーまたは多機能性リンカーを表す;
nおよびmは、独立して1〜100,000の整数である。]。
ガス充填微小胞
-(O-CH2-CH2)n-O-CH3
[式中、遊離結合は、該ポリマーと微小胞のエンベロープ(またはその成分)との結合を示し、nは、該ポリマーの反復オキシエチレン単位の数を示す整数であり、約10〜約2,000、好ましくは約10〜約200、より好ましくは約40〜160で変化しうる。特に、好ましいポリマーは、メトキシが末端にあるPEG(mPEG)である。
リポソーム
リポソーム/微小胞およびターゲッティング構築物
医薬キット、投与、および画像化
1mgのChromalinkビオチン354S(参考文献# B-1001-110、Solulink、USA)を室温でDMF(100μL)に溶解し、12.3mM溶液を得た。該溶液(10mol当量)を1mg/mLの抗体をリン酸緩衝生理食塩水(pH 7.4)に溶解して調製したラット抗マウスP-セレクチン抗体(クローンRB40.34、参考文献#553741、BD Biosciences、USA)の溶液に加えた。反応混合物を室温で2時間インキュベーションし、次いで、PBSで平衡化したZebaスピンカラム(2min 1,000g、Pierce、USA)でゲル濾過して精製した。得られたビオチン化抗体は、製造業者の推奨に従って光度定量すると2.0ビオチン残基/抗体分子を含んでいた。
実施例1を、抗マウスP-セレクチン抗体をウサギ抗mPEG抗体(クローンPEG-B-47、参考文献2061-1、Epitomics、USA)に置き換えて繰り返した。得られたビオチン化抗体は1.9ビオチン残基/抗体分子を含んでいた。
ビオチン化ラットアイソタイプ抗体(コントロール)の製造
実施例1を、抗マウスP-セレクチン抗体をラットアイソタイプコントロール抗体(アフィニティ精製ラットIgG1アイソタイプコントロール、eBioscience、ref# 14-4301)で置き換えて繰り返した。得られたビオチン化抗体は1.9ビオチン残基/抗体分子を含んでいた。
実施例1に従って製造したビオチン-抗マウスP-セレクチン抗体10μgおよび実施例2に従って製造したビオチン-抗mPEG抗体10μgを800μLのリン酸緩衝生理食塩水pH 7.4に溶解した。次に、抗体混合物を撹拌下でストレプトアビジン(IBA、参考文献#2-0203-100)を蒸留水に溶解して製造したストレプトアビジン溶液(1 mg/mL)28.3μLに加えた。該溶液を25℃で30分間混合した。
二特異性コントロールストレプトアビジン(コントロール)の製造
実施例4を、ビオチン-抗マウスP-セレクチン抗体を実施例3に従って製造したビオチンラットアイソタイプコントロール抗体に置き換えて繰り返した。
27 mgのDSPCおよび2.2 mgのパルミチン酸を3.9 gのシクロオクタンに60℃で熔解した。得られた溶液を室温に冷却し、5.5 gのPEG4000(Fluka)および19 mgのDPPE-mPEG5000を含む蒸留水50 mLに高速ホモゲナイザー(Polytron T3000)を用いて8000 rpmで1分間分散させた。得られるエマルジョンを撹拌下80℃で1時間加熱し、次いで室温に冷却した。得られるエマルジョンを10%のPEG4000を含む蒸留水で5倍に希釈し、次いでDIN8Rバイアルに充填した(0.75 mL/バイアル)。バイアルを-50℃で2時間凍結し(Christ Epsilon凍結乾燥機)、次いで-20℃、0.5mBarで12時間凍結乾燥し、さらに30℃、0.2mBarで6時間最終乾燥工程を実施した。
a. マウスFc-P-セレクチンでコートしたガラスカバースリップの調製
簡単には、マウスFc P-セレクチンの乾燥粉末(50μg、R&D System、参考文献# 737-PS-050)をグラスバイアル中の100μLのPBS pH 7.4に溶解し、次いで12.4 mLのPBS中に移し、マウスFc P-セレクチンの4μg/mL溶液を得た。マウスFc P-セレクチン溶液(4μg/mLを400μL)を40mmガラスカバースリップ上に置き、4℃で一夜インキュベーションした。次に、過剰のマウスFc P-セレクチン溶液を捨て、室温で2時間、ブロッキング溶液(1%(w/v)BSA含有PBS、500μL)に置換した。カバースリップを洗浄溶液(0.05% Tween含有PBS、3 mL)で洗浄し、次いで-20℃で保存した。使用前に、マウスFc P-セレクチンでコートしたカバースリップを室温で平衡化する。
b.結合試験
二特異性ストレプトアビジン(アイソタイプコントロール抗体および抗mPEG抗体)およびmPEG含有微小胞とのin vitro二段階結合
マウスFc P-セレクチンでコートしたガラスカバースリップを、比較実施例5に従って作製した非結合二特異性ストレプトアビジン400μLと30分間インキュベーションすることにより、実施例7を繰り返した。平均測定値は0.02RMA/minであり、カバースリップの表面への微小胞の結合が実質的に無いことを示す。
精製抗P−セレクチン抗体クローンRB40.34の溶液を、80μLの50mMリン酸緩衝液 150mM NaCl pH 7.4中の20μLの10mMスルホ−LC−SPDP溶液((スルホスクシンイミジル6−[3’−(2−ピリジルジチオ)プロピオンアミド]−ヘキサノエート)、Pierce、#21650)と反応させた。該溶液を、リン酸緩衝液5mM pH7.4中で平衡化した2mLスピンカラムで1000g(Zebaスピンカラム、Pierce、#89889)にてスピンさせた。次に、機能化抗体を1mM TCEP、50mMトリスHCl/5mM EDTA pH6.8にて室温で10分間還元させた。次に、還元抗体を2mLスピンカラムで1000gにてスピンさせ、チオール化抗体のサスペンジョンを得た。
実施例9を、抗マウスモノクローナル抗体を抗mPEGウサギモノクローナル抗体(Epitomics #2061-1)に置き換えて繰り返し、抗mPEG抗体を得た。
2mg(0.69μmol)のDSPE-PEG2000-マレイミドを40℃でエタノールに溶解した。該溶媒をN2下、40℃で除去して脂質フィルムを得た。該脂質フィルムを真空(0.2mBar)下、25℃で一夜乾燥させた。乾燥フィルムを60℃で0.5 mLのリン酸緩衝液(50mM pH=6.5)で水和し、DSPE-PEG2000-マレイミドミセルの透明なサスペンジョンを得た。
実施例9に従って製造したチオール化抗P-セレクチン抗体クローンRB40.34、325μLおよび実施例10に従って製造したチオール化抗mPEG抗体のサスペンジョン325μLを混合し、実施例11に従って製造したミセルサスペンジョン250μLに加えた。混合物を25℃で3時間混合する。次に、残存するマレイミド基をブロックするため、該溶液にシステイン(0.69μmol)を加える。
ウサギモノクローナルIgG抗mPEG(クローンPEG-B-47、Epitomix、USA)および抗P-セレクチン抗体クローンRB40.34を、修飾緩衝液(100mMリン酸塩、150 mM塩化ナトリウム、pH 7.2 - BupH(登録商標)PBS、Pierce、Switzerland)で1.5 mg/mL(すなわち、10μM)に希釈する。
30.2mgのコレステロール、73.2mgのDSPC、23.0mgのDPPG.Na、および3.6mgのDIOを65℃で20mLのクロロホルムに溶解し、次いで31μLの3Hコレステリルヘキサデシルエーテルを加えた。溶媒を蒸発させ、成分の混合物を真空下で2時間乾燥した。残渣を10 mg/mLの濃度まで蒸留水に再懸濁し、リポソームのサスペンジョンを得た。次に、該サスペンジョンを1 um、0.6 um、および0.4 umのフィルターを用いて押し出し、リポソームのサイズを減少させた。リポソームサスペンジョンをリン酸緩衝グルコース溶液に対して透析した。次に、10.5mgのDSPE-PEG2000-マレイミドを0.5 mLのリン酸緩衝グルコース溶液に溶解した。この溶液をリポソームサスペンジョンに加えた。該サスペンジョンを65℃で1時間維持し、リポソームの構造へのマレイミド誘導体の挿入を可能にする。次に、472μLのストレプトアビジンの10 mg/mL溶液を実施例9に記載の手順に従って処理し、対応するチオール化ストレプトアビジンを得た。チオール化ストレプトアビジンをリポソームサスペンジョンに加え、室温で2.5時間反応させた。リポソームサスペンジョンを遠心分離(30000gで30分間)して精製し、次いでトリス緩衝グルコース溶液に再懸濁した。
リポソームサスペンジョンを、ウサギ抗PEG抗体をビオチン化ウサギ非特異的IgGで置き換えた以外は、実施例14に記載のごとく製造した。
リポソームサスペンジョンを、抗P-セレクチン抗体クローンRB40.34をラット非特異的IgG1で置き換えた以外は実施例14に記載のごとく製造した。
Thermanox(登録商標)ディスクを実施例7に記載の方法論に従ってマウス-Fc-P-セレクチンでコートした。コートしたディスクを24ウェルプレートのウェルに置いた。
30.2mgのコレステロール、73.2mgのDSPC、23.0mgのDPPG.Na、および3.6mgのDIOを65℃で20 mLのクロロホルムに溶解し、次いで31μLの放射性マーカー3Hコレステリルヘキサデシルエーテルを加えた。溶媒を蒸発させ、成分の混合物を真空下で2時間乾燥した。残渣を蒸留水に濃度10 mg/mLまで再懸濁し、リポソームのサスペンジョンを得た。次に、該サスペンジョンを1 um、0.6 um、および0.4 umのフィルターで押し出した。リポソームサスペンジョンをリン酸緩衝グルコース溶液に対して透析した。次に、10.5mgのDSPE-mPEG2000を0.5 mLのリン酸緩衝グルコース溶液に溶解した。この溶液をリポソームサスペンジョンに加えた。該サスペンジョンを65℃で1時間維持し、リポソームの構造中にマレイミド誘導体の挿入を可能にした。リポソームサスペンジョンを遠心分離(30000gで30分間)して精製し、次いでトリス緩衝グルコース溶液に再懸濁した。
Thermanox(登録商標)ディスクを実施例7に記載の方法論に従ってマウス-Fc-P-セレクチンでコートした。コートしたディスクを24ウェルプレートのウェルに置いた。次に、実施例4に従って作製した二特異性ストレプトアビジン溶液を、Thermanoxディスク上で1時間インキュベーションした(各ウェル中400μL)。
70.3mgのDSPC、22.1mgのDPPG.Na、および29.1mgのコレステロールを20 mLのクロロホルムに溶解した。該溶液を丸底フラスコ中で60℃に加熱し、クロロホルムを減圧下で蒸発させ、次いで、残存する溶媒を、真空オーブン中最大真空下で3時間完全に除去した。次に、該脂質を、775m/mLgのイオメプロールを含有するイオメプロール(Bracco Imaging)溶液で再水和し、イオメプロールをロードしたリポソームを形成した。次に、リポソームのサスペンジョンを、選択したポアサイズのフィルターを通して押しだし、0.2μmに減少させた。次に、得られた較正リポソームを5%グルコース溶液に対して透析した。DSPE-PEG2000の溶液をpH7.4のTween 20mMに溶解し、1mLのこの溶液を、10mLのリポソームサスペンジョンに加えた。この混合物を撹拌し、65℃で1時間インキュベーションした。X線造影剤としてさらに使用可能な、イオメプロールをロードしたペグ化リポソームを得た。
実施例1を、抗P-セレクチン抗体クローンRB40.34をビオチン-マウス抗ヒトフィブリン抗体で置き換えて繰り返した。10μgのフィブリン抗体および10μgのビオチン-抗mPEG抗体(実施例2に従って製造した)を800μLのリン酸緩衝生理食塩水pH 7.4に溶解する。次に、該抗体混合物を、撹拌下で28.3μLのストレプトアビジンの溶液(1 mg/mL)に加え、ストレプトアビジン(IBA、参考文献#2-0203-100)を蒸留水に溶解し、次いで該溶液を25℃で30分間混合した。
ヒトの血餅をラットの左頸動脈に挿入する。次に、実施例21に従って製造した二特異性構築物をラットに静脈内注射する。2時間後、実施例21に従って製造したイオメプロール含有リポソームをイオメプロール用量0.5mg/kgでラットに静脈内注射する。次に、造影された血栓の画像をラットのコンピュータ断層撮影により得る。イオメプロール溶液の注射後に得られた画像に比較して、血栓のコントラストが増強する。
a. 二特異性ストレプトアビジン構築物(抗マウスP-セレクチン抗体および抗PEG抗体E11)の製造
実施例4を、ビオチン化抗mPEG抗体をビオチン化抗PEG抗体E11で置き換えて実施した(参考文献30参照)。
b. コポリマーPEG-ポリリジンでコートしたガス微小気泡の製造
c. フローチャンバー中のP-セレクチンコートしたカバースリップに対するin vitro結合
a. 二特異性ターゲッティング構築物の製造
実施例4を、ビオチン化IgG 抗P-セレクチンを、LNCaP細胞上に過剰発現したヘプシンレセプターと特異的に結合するファージディスプレースクリーニングにより選択したビオチン-ペプチド配列(IPLVVPLGGSC-ビオチン)に置き換えて繰り返す(参考文献56参照)。
b. in vitro遺伝子送達実験
a. 抗PEGターゲッティング構築物の製造
実施例4を、ビオチン化IgG 抗P-セレクチンを、腫瘍の新生血管の内皮細胞に過剰発現したKDRのレセプターに特異的に結合するビオチン-ペプチド配列で置き換えて繰り返す(例えば、参考文献39参照)。
b. in vivo超音波画像診断試験
a. 二特異性ターゲッティング構築物(抗PEG B-47およびペプチドHVGGSSV)の製造
抗PEGターゲッティング構築物を、Cy7標識ストレプトアビジン、ビオチン化抗mPEG B-47(実施例2)、およびビオチン化ペプチド配列 HVGGSSV(1:1:2)を用いて製造する。このペプチドを、ファージディスプレイ(T7ファージベースのランダムペプチドライブラリー)により選択し、該ペプチドは放射線療法で治療される腫瘍に対する特異的結合を示す(参考文献57参照)。
b. 反応する腫瘍と反応しない腫瘍を区別するためのin vivo画像診断
a. 二特異性抗体(抗マウスVEGFR2および抗mPEG)の製造
実施例13を、IgG抗P-セレクチンを抗VEGFR2(CD101、参考文献56参照)に置き換えて繰り返す。
b. in vivo投与
a. 二特異性ターゲッティング構築物の製造
実施例4を、ビオチン化IgG 抗P-セレクチンを、LNCaP細胞上に過剰発現したヘプシンレセプターと特異的に結合するファージディスプレースクリーニングにより選択したビオチン-ペプチド配列(IPLVVPLGGSC-ビオチン)に置き換えて繰り返す(参考文献57参照)。
b. in vitro遺伝子送達実験
a. 抗PEG ターゲッティング構築物の製造
実施例4を、ビオチン化IgG 抗P-セレクチンを、腫瘍の新生血管の内皮細胞に過剰発現したKDRのレセプターに特異的に結合するビオチン-ペプチド配列で置き換えて繰り返す(例えば、参考文献39参照)。
b. in vivo超音波画像診断試験
a. 二特異性ターゲッティング構築物(抗PEG B-47およびペプチドHVGGSSV)の製造
抗PEGターゲッティング構築物を、Cy7標識ストレプトアビジン、ビオチン化抗mPEG B-47(実施例2)、およびビオチン化ペプチド配列 HVGGSSV(1:1:2)を用いて製造する。このペプチドを、ファージディスプレイ(T7ファージベースのランダムペプチドライブラリー)により選択し、該ペプチドは放射線療法で治療される腫瘍に対する特異的結合を示す(参考文献58参照)。
b. 反応する腫瘍と反応しない腫瘍を区別するためのin vivo造影
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Claims (15)
- a)複数のポリマー分子を含む安定化エンベロープを有するリポソームもしくはガス充填微小胞またはその前駆体を含む第1組成物、および
b)ターゲッティングリガンドおよび該ポリマーと選択的に結合することができる抗体を含むターゲッティング構築物を含む第2組成物
を含む医薬キット。 - 該ポリマーが親水性ポリマーである請求項1記載の医薬キット。
- 該ポリマーが反復オキシエチレン単位を含む請求項1記載の医薬キット。
- 該ポリマーがメトキシ基で終わる請求項3記載の医薬キット。
- 該ポリマーがポリエチレングリコールである請求項3記載の医薬キット。
- 該抗体が、該反復オキシエチレン単位の配列と選択的に結合する請求項3記載の医薬キット。
- 該抗体が、メトキシ基で終わる反復オキシエチレン単位の配列と選択的に結合する請求項4記載の医薬キット。
- 該ポリマーが、該安定化エンベロープの成分の総量に対して少なくとも0.05%のモル量で存在する、先の請求項のいずれかに記載の医薬キット。
- 該モル量が少なくとも0.2%である請求項8記載の医薬キット。
- 該モル量が少なくとも1%である請求項8記載の医薬キット。
- 該ガス充填微小胞が50モル%以上のリン脂質を含む先の請求項のいずれかに記載の医薬キット。
- 該リポソームが治療剤または造影剤を含む先の請求項のいずれかに記載の医薬キット。
- 該ターゲッティングリガンドが該抗体と非共有結合して該ターゲッティング構築物を形成する先の請求項のいずれかに記載の医薬キット。
- 該ターゲッティング構築物がミセルまたはリポソームの形である請求項13記載の医薬キット。
- a)親水性ポリマー、b)該親水性ポリマーと結合した抗体、およびc)該抗体と結合したターゲッティングリガンドを含む、リポソームもしくはガス充填微小胞、またはその前駆体。
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