JP6366507B2 - コラーゲン結合タンパク質による治療剤の送達 - Google Patents
コラーゲン結合タンパク質による治療剤の送達 Download PDFInfo
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Description
本願は、米国仮特許出願第1/570,620号(2011年12月14日出願)及び米国仮特許出願第61/596,869号(2012年2月9日出願)の優先権の利益を主張するものであり、それらは共にその全体が参照により本願に組み込まれる。
本発明は、米国国立衛生研究所(National Institutes of Health)が交付した連邦政府による資金提供(助成金番号NCRR COBRE 8P30GM103450及びINBRE GM103429)を受けて行った。アメリカ合衆国は、本発明に一定の権利を有することができる。
本願には配列表が添付されているが、それらは参照によりその全体が本願に組み込まれる。配列表は、本願と共に2012年12月14日にテキストファイルで提出された。
特定の治療剤が効力を発揮するために必要な、被験者の体内部位への治療剤の送達は発展中の分野である。このようなデリバリーシステムは、一部の治療剤によって引き起こされる毒性を低減すると同時に、治療剤のより有効な使用を可能にする。特定の体内部位に治療剤を標的化するための、抗体などの標的化リポソーム又はポリペプチドの使用は好結果をもたらしているが、さらなる送達剤が求められている。
本明細書において、治療剤での治療を必要とする被験者に、治療剤に結合した細菌性コラーゲン結合ポリペプチドセグメントを含む組成物を投与することによって治療剤を送達する方法が提供される。この実施形態において、治療剤はPTH/PTHrP受容体アゴニスト又はアンタゴニストではなく、bFGF又はEGFポリペプチドでもない。細菌性コラーゲン結合ポリペプチドセグメントは、部分的にねじれていないか又はねじれが不十分なコラーゲン部位に治療剤を送達する。
CBDは、コラーゲンの部分的にねじれていないか又はねじれが不十分な領域を標的とする
クロストリジウム・ヒストリチカムのコラゲナーゼは、結合組織のコラーゲンを広範囲にわたって分解させ、ガス壊疽を引き起こす。これらの酵素のC末端コラーゲン結合ドメイン(CBD)は、コラーゲン細繊維に結合するのに必要な最小限のセグメントである。CBDは、3重らせんコラーゲンの部分的にねじれていないC末端に一方向性に結合する。CBDが、コラーゲン3重らせんの中央部であっても、ねじれが不十分な領域を標的とすることができるかどうかを試験した。部分的にねじれていないコラーゲン性ペプチドは、コラーゲン([(POG)xPOA(POG)y]3(式中x+y=9でありx>3である))にGly→Ala置換を導入することによって合成した。15N標識CBDを用いる1H-15N異核種単一量子コヒーレンス法核磁気共鳴(HSQC NMR)滴定研究によって、ねじれていないミニコラーゲンは、幅10Å、長さ25Åの溝(cleft)に結合することが明らかになった。次いで、それぞれニトロキシドラジカルで標識された6つのねじれていないコラーゲン性ペプチドを15N標識CBDで滴定した。常磁性核スピン緩和効果によって、CBDは、Gly→Ala置換部位又は各ミニコラーゲンのC末端のいずれかに近接して結合することが見出された。X線小角散乱(SAXS)測定によって、CBDは、C末端よりはむしろGly→Ala部位に選択的に結合することが明らかになった。15N標識ミニコラーゲン及びねじれていないミニコラーゲンのHSQC NMRスペクトルは、非標識CBDの滴定によって影響を受けなかった。CBDは部分的に巻き戻されたミニコラーゲンの領域に結合するが、この結果は3重らせんを強くは巻き戻さないことを意味する。
15N標識タンパク質の調製:クロストリジウム・ヒストリチカムクラスIコラゲナーゼ(ColG)由来のs3b(Gly893-Lys1008)ペプチドをグルタチオンS-トランスフェラーゼ(GST)融合タンパク質として発現させた。以前記載したように、GSTタグをトロンビンで切除し、CBDを精製した(Matsushita, et al., (2001) J Biol Chem 276、8761-8770)。40 mM 15NH4Clを含むTanaka最小培地を用いて、均一な15N同位体標識化を行った。マトリックス支援レーザー脱離イオン化−飛行時間型質量分析法(MALDI-TOF-MS)によって、標識効率は99.6%であると算出された。
表1:本明細書に記載のNMR滴定及び実験に用いた種々のミニコラーゲンペプチドの融解温度(Tm)
1H-15N HSQC NMR滴定−ねじれが不十分なコラーゲン部位のCBDによる標的化:N末端から21番目の位置にAlaを有するねじれていないコラーゲン性ペプチド[(POG)6POA(POG)3]3(配列番号36)を合成した。N末端に常磁性スピンラベルを有するために、このペプチドをさらに修飾した。[PROXYL-(POG)6POA(POG)3]3(配列番号36)と15N標識CBDを0.02:1〜1.5:1の比率で用いて1H-15N HSQC NMR滴定を行った。以前明らかにされたように、合計11のコラーゲン結合面上の残基(S928、W956、G971、K995、Y996、L924、T957、Q972、D974、L991及びV993)が、HSQCスペクトルから消失するか、又は滴定の過程において元の位置からの著しい化学シフト摂動を示した。Philominathan,et al. (2009) J Biol Chem 284, 10868-10876。コラーゲン性ペプチドのN末端のPROXYL基は、滴定の過程において、CBDのNMRシグナルの距離に依存したラインブロードニングを引き起こすことができる。これらの11残基に加えて、さらなる3残基、V973、G975及びS979は、かなりのラインブロードニングを示し、これらの残基は、ついにはCBDの1H-15N HSQCスペクトルから消失した(図5A及び5B)。[PROXYL-(POG)6POA(POG)3]3(配列番号36):CBD複合体がアスコルビン酸で還元された場合、3つの残基は1H-15N HSQCスペクトル中に再び現れた。これら3つの残基の消失は、我々の以前の発表における[PROXYL-G(POG)7]3(配列番号42)(C末端は、N末端PROXYLから22番目の位置である)滴定と矛盾しなかった。これら2つの滴定結果の比較によって、CBDがGly→Ala置換部位を標的としていることは明らかである。もし、CBDが、[PROXYL-(POG)6POA(POG)3]3(配列番号36)のC末端のみに結合していたのであれば(C末端は、N末端PROXYLから30番目の位置である)、公表された[PROXYL-G(POG)7(PRG)]3(配列番号43)の滴定と同様に、精々ただ1つの残基(V973)の消失が観察されることが期待されるであろう。Ca2+結合部位の遠位側に位置する残基(V973、G975及びS979)の消失(図5C)によって、CBDが、ねじれていないコラーゲンにも一方向性に結合することが確定された。CBDにおけるコラーゲン結合表面は、幅10Åm、長さ25Åの溝である。CBDにおける結合溝の幅は3重らせんの直径にマッチし、その長さは[(POG)3]3(配列番号44)を収容することができる。NMR結果は、CBDが、コラーゲンのねじれが不十分な[(POG)2POA]3(配列番号45)領域に結合していることを示唆している。
表2:コラーゲン性ペプチド配列のN末端、C末端又は中央部のいずれかにおけるPROXYLの存在によって消失する残基
表3:種々のCBD:コラーゲン性ペプチド複合体に関して動的光散乱(DLS)及びX線小角散乱(SAXS)から算出した流体力学半径(RH)、見かけの分子量(Mw)、回転半径(Rg)及び最大粒径(Dmax)。
ColH及びColGコラーゲン結合ドメインの構造比較
コラゲナーゼのC末端コラーゲン結合ドメイン(CBD)は、不溶性コラーゲン細繊維への結合とその後のコラーゲン分解に必要である。ColG-CBD(s3b)及びColH-CBD(s3)の高分解能結晶構造において、配列同一性がわずか30%であるにもかかわらず、これらの分子は互いによく似ている(r.m.s.d. Cα = 1.5Å)。Ca2+をキレートする6つの残基のうち、5つが保存されている。s3における二重のCa2+結合部位は、機能的に同等なアスパラギン酸によって完結されている。s3bにおけるコラーゲン相互作用に最も重要な3つの残基は、s3において保存されている。結合ポケットの一般形状は、改変されたループ構造及び側鎖位置によって保持されている。X線小角散乱データによって、s3が、ミニコラーゲンに非対称に結合することもまた明らかにされた。カルシウム結合部位及びコラーゲン結合ポケット以外にも、cis-ペプチド結合の周りの構造的に重要な疎水性残基及び水素結合ネットワークは、メタロペプチダーゼサブファミリーM9Bにおいてよく保存されている。
表5:s3bにおけるトランス-シスペプチド異性化に重要な水素結合とそれらのs3におけるカウンターパート
CBD-PTHアゴニストは発毛を刺激し、CBD-PTHアンタゴニストは発毛を抑制する
CBDが結合したPTH化合物のin vitro解析:各ペプチドのコラーゲン結合は、米国特許公開第2010/0129341号(参照によりその全体が本願に組み込まれる)に記載されているようにして、フロースルーコラーゲン結合アッセイで立証した。コラーゲン結合ドメインに直接的に結合したPTHの最初の33アミノ酸からなるPTH-CBD(配列番号1)は最も強力なアゴニストであり、cAMP集積に関してPTH(1-34)(配列番号7)の効果と同様な効果を示した。Ponnapakkam et al. (2011) Calcif 88:511-520. Epub 2011 Apr 2022。アンタゴニストの中で、PTH(7-33)-CBD(配列番号10)は、発毛研究に用いたものを含め、他のPTHアンタゴニストにおいて見られたものと同様な、低い固有の活性と高い受容体遮断の最良の組み合わせを有していた(図示せず)。Peters, et al. (2001) J Invest Dermatol 117:173-178。
CBD-PTHは、副甲状腺機能亢進症を予防し治療することができる
本実験において、ラットは、3ヶ月齢において外科的に卵巣を切除した。9ヶ月齢において、ラットに、PTH-CBDの単回量(320mcg/kg)又はビヒクル対照のいずれかを注射した。治療6ヶ月後(15ヶ月齢)に動物を屠殺した。PTH-CBDの血清レベルを評価するためにヒトインタクトPTHレベルを測定し、両群において検出されないことが見出された。血清カルシウムを測定したが、両群間に差異はなかった(ビヒクル:13.5+/-1.1、PTH-CBD:14.3+/-1.1mg/dl、NS)。内因性PTH産生を評価するためにラットインタクトPTHレベルを測定した。PTH-CBDは、加齢卵巣切除ラットにおいて通常見られる内因性PTHレベルの増加を抑制した。これらの発見は、PTH-CBDの1回の注射によって、内因性PTH産生の長期抑制を提供することができ、卵巣切除したラットモデルにおいて加齢とともにみられる通常の増加を抑制し、従って副甲状腺機能亢進症の治療として役立つことができることを示している。
Claims (13)
- 発毛を必要とする被験者において、円形脱毛症を治療するための医薬の調製における、PTH/PTHrP受容体アゴニストに結合した細菌性コラーゲン結合ポリペプチドセグメントの使用であって、
前記PTH/PTHrP受容体アゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメントが、発毛を増進し、
前記PTH/PTHrP受容体アゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメントが、融合タンパク質であり、
前記PTH/PTHrP受容体アゴニストが、配列番号1の残基1‐33、PTH(配列番号7)又は配列番号7の残基1‐34を含み、及び
前記細菌性コラーゲン結合ポリペプチドセグメントが、配列番号13〜34のうちの1つ、配列番号1の残基34‐158及び配列番号1の残基34‐158もしくは配列番号13〜34と少なくとも90%同一であるペプチドからなる群から選択されるM9ペプチダーゼ由来のコラーゲン結合ポリペプチドを含むことを特徴とする使用。 - 前記PTH/PTHrP受容体アゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメントが、配列番号1で特定されるアミノ酸配列を有する融合タンパク質である請求項1に記載の使用。
- 前記PTH/PTHrP受容体アゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメントが、配列番号2で特定されるアミノ酸配列を有する融合タンパク質である請求項1に記載の使用。
- 発毛を遅らせるための医薬の製造における、PTH/PTHrP受容体アンタゴニストに結合した細菌性コラーゲン結合ポリペプチドセグメントの使用であって、
前記PTH/PTHrP受容体アンタゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメントが、発毛を遅らせ、
前記PTH/PTHrP受容体アンタゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメントが、融合タンパク質であり、
前記細菌性コラーゲン結合ポリペプチドセグメントが、配列番号13〜34のうちの1つ、配列番号1の残基34‐158及び配列番号1の残基34‐158もしくは配列番号13〜34と少なくとも90%同一であるペプチドからなる群から選択されるM9ペプチダーゼ由来のコラーゲン結合ポリペプチドを含み、及び
前記PTH/PTHrP受容体アンタゴニストが、配列番号7の残基7‐33を含むことを特徴とする使用。 - 前記PTH/PTHrP受容体アンタゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメントが、配列番号10で特定されるアミノ酸配列を有する融合タンパク質である請求項4に記載の使用。
- 前記PTH/PTHrP受容体アゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメント又は前記PTH/PTHrP受容体アンタゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメントが、局所投与又は限局性部位投与される、請求項1〜5のいずれか1つに記載の使用。
- 前記PTH/PTHrP受容体アゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメント又は前記PTH/PTHrP受容体アンタゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメントが、前記被験者において、単独で投与されたPTH(1‐34)アゴニスト又はPTHアンタゴニストよりも少なくとも50%大きい活性を有する、請求項1〜6のいずれか1つに記載の使用。
- 前記被験者が、ヒトである、請求項1〜7のいずれか1つに記載の使用。
- 前記PTH/PTHrP受容体アゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメント又は前記PTH/PTHrP受容体アンタゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメントが、5.0未満又は6.0を超えるpHの水溶液で投与されるものである、請求項1〜8のいずれか1つに記載の使用。
- 前記細菌性コラーゲン結合ポリペプチドセグメントが、配列番号13〜34のうちの1つ又は配列番号1の残基34‐158を含む、請求項1、4、6、7、8又は9のいずれか1つに記載の使用。
- 前記細菌性コラーゲン結合ポリペプチドセグメントが、配列番号6の残基807‐901を更に含む、請求項1、4又は6〜9のいずれか1つに記載の使用。
- 円形脱毛症を治療するための医薬組成物であって、PTH/PTHrP受容体アゴニストに結合した細菌性コラーゲン結合ポリペプチドセグメントを含み、
前記PTH/PTHrP受容体アゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメントが、配列番号1で特定されるアミノ酸配列を有する融合タンパク質であることを特徴とする医薬組成物。 - 発毛を遅らせるための医薬組成物であって、PTH/PTHrP受容体アンタゴニストに結合した細菌性コラーゲン結合ポリペプチドセグメントを含み、
前記PTH/PTHrP受容体アンタゴニストに結合した前記細菌性コラーゲン結合ポリペプチドセグメントが、配列番号10で特定されるアミノ酸配列を有する融合タンパク質であることを特徴とする医薬組成物。
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