JP2022517698A - インテグリンαvβ3に特異的な二環式ペプチドリガンド - Google Patents
インテグリンαvβ3に特異的な二環式ペプチドリガンド Download PDFInfo
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Abstract
Description
本発明は、2以上のペプチドループがスキャフォールドへの取付点の間に内在するように、芳香族分子スキャフォールドに共有結合しているポリペプチドに関する。特に、本発明は、インテグリンαvβ3の高親和性バインダーであるペプチドを記載している。本発明は、1以上のエフェクター及び/又は官能基にコンジュゲートされた、該ペプチドを含む薬物コンジュゲート、該ペプチドリガンド及び薬物コンジュゲートを含む医薬組成物、並びにインテグリンαvβ3によって媒介される疾患又は障害の予防、抑制、又は治療における該ペプチドリガンド及び薬物コンジュゲートの使用も含む。
環状ペプチドは、高い親和性及び標的特異性でタンパク質標的に結合することができ、それゆえ、治療薬の開発のための魅力的な分子クラスである。実際、いくつかの環状ペプチドは、例えば、抗菌ペプチドのバンコマイシン、免疫抑制薬のシクロスポリン、又は抗癌薬のオクトレオチドのように、診療所で使用されるのに既に成功している(Driggersらの文献(2008), Nat Rev Drug Discov 7(7), 608-24)。優れた結合特性は、ペプチドと標的との間で形成される比較的大きな相互作用表面だけでなく、環状構造の立体構造可撓性の低下にも起因する。通常、大環状分子は、環状ペプチドCXCR4アンタゴニストCVX15(400Å2; Wuらの文献(2007), Science 330, 1066-71)、インテグリンαVb3に結合するArg-Gly-Aspモチーフを有する環状ペプチド(355Å2)(Xiongらの文献(2002), Science 296(5565), 151-5)、又はウロキナーゼ型プラスミノゲン活性化因子に結合する環状ペプチド阻害剤ウパイン-1(603Å2; Zhaoらの文献(2007), J Struct Biol 160(1), 1-10)のように、数百平方オングストロームの表面に結合する。
本発明の第一の態様によれば、少なくとも2つのループ配列によって隔てられた少なくとも3つのシステイン残基を含むポリペプチド及び該ポリペプチドのシステイン残基と共有結合を形成する芳香族分子スキャフォールドを含み、その結果、少なくとも2つのポリペプチドループが該分子スキャフォールド上に形成される、インテグリンαvβ3に特異的なペプチドリガンドが提供される。
一実施態様において、該ループ配列は、2、3、4、5、6、又は7つのアミノ酸を含む。
:から選択されるアミノ酸配列、又はその医薬として許容し得る塩を含む。
:から選択されるアミノ酸配列、又はその医薬として許容し得る塩を含む。
A-(配列番号1)-A(本明細書において、BCY2493と称される);
A-(配列番号2)-A(本明細書において、BCY2496と称される);
A-(配列番号3)-A(本明細書において、BCY2497と称される);
A-(配列番号4)-A(本明細書において、BCY2498と称される);
Ac-(配列番号5)-A-Sar10-dK(本明細書において、BCY2615と称される);
Ac-(配列番号5)-A-Sar6-dK(本明細書において、43-06-00-N018 or BCY2558と称される);
A-(配列番号6)-A(本明細書において、BCY2499と称される);
A-(配列番号7)-A(本明細書において、BCY2502と称される);及び
A-(配列番号8)-A(本明細書において、BCY2506と称される)
:から選択されるアミノ酸配列を含む。
Ac-(配列番号4)-A-Sar6-K(本明細書において、BCY2553と称される);
B-Ala-Sar5-A-(配列番号4)(本明細書において、BCY2554と称される);
Ac-(配列番号5)-A-Sar6-K(本明細書において、BCY2555と称される);
B-Ala-Sar5-(配列番号5)(本明細書において、BCY2560と称される);
A-(配列番号9)-A(本明細書において、BCY2494と称される);
A-(配列番号10)-A(本明細書において、BCY2503と称される);及び
B-Ala-Sar5-A-(配列番号11)(本明細書において、BCY2568と称される)
:から選択されるアミノ酸配列を含む。
A-(配列番号1)-A(本明細書において、BCY2493と称される);
A-(配列番号2)-A(本明細書において、BCY2496と称される);
A-(配列番号3)-A(本明細書において、BCY2497と称される);
A-(配列番号4)-A(本明細書において、BCY2498と称される);
Ac-(配列番号5)-A-Sar10-dK(本明細書において、BCY2615と称される);
Ac-(配列番号5)-A-Sar6-dK(本明細書において、43-06-00-N018又はBCY2558と称される);
A-(配列番号6)-A(本明細書において、BCY2499と称される);
A-(配列番号7)-A(本明細書において、BCY2502と称される);及び
A-(配列番号8)-A(本明細書において、BCY2506と称される)
:から選択されるアミノ酸配列を含む。
Ac-(配列番号4)-A-Sar6-K(本明細書において、BCY2553と称される);
B-Ala-Sar5-A-(配列番号4)(本明細書において、BCY2554と称される);
Ac-(配列番号5)-A-Sar6-K(本明細書において、BCY2555と称される);
B-Ala-Sar5-(配列番号5)(本明細書において、BCY2560と称される);
A-(配列番号9)-A(本明細書において、BCY2494と称される);
A-(配列番号10)-A(本明細書において、BCY2503と称される);及び
B-Ala-Sar5-A-(配列番号11)(本明細書において、BCY2568と称される)
:から選択されるアミノ酸配列を含む。
A-(配列番号1)-A(本明細書において、BCY2493と称される);
A-(配列番号2)-A(本明細書において、BCY2496と称される);
A-(配列番号4)-A(本明細書において、BCY2498と称される);
Ac-(配列番号5)-A-Sar6-dK(本明細書において、43-06-00-N018又はBCY2558と称される);
A-(配列番号7)-A(本明細書において、BCY2502と称される);及び
A-(配列番号8)-A(本明細書において、BCY2506と称される)
:から選択されるアミノ酸配列を含む。この実施態様のスキャフォールド/ペプチドリガンドは、本明細書中、表1に示されているような優れたインテグリンαvβ3競合結合を示した。
Ac-(配列番号5)-A-Sar6-dK(本明細書において、43-06-00-N018又はBCY2558と称される)
:から選択されるアミノ酸配列を含む。この実施態様のスキャフォールド/ペプチドリガンドは、単独で(本明細書中、表1に示されている)、及び毒素DM-1にコンジュゲートされているとき(本明細書中、表3に示されている)、優れたインテグリンαvβ3競合結合を示した。
A-(配列番号1)-A-Sar6-K-Fl(本明細書において、BCY2572と称される);
Fl-G-Sar5-A-(配列番号1)(本明細書において、BCY2573と称される);
A-(配列番号4)-A-Sar6-K-Fl(本明細書において、BCY2576と称される);
Ac-(配列番号4)-A-Sar6-K-Fl(本明細書において、BCY2577と称される);
Fl-(B-Ala)-Sar5-A-(配列番号4)(本明細書において、BCY2578と称される);
Ac-(配列番号5)-A-Sar6-K-Fl(本明細書において、BCY2579と称される);
Fl-(B-Ala)-Sar5-A-(配列番号5)(本明細書において、BCY2580と称される);
A-(配列番号8)-A-Sar6-K-Fl(本明細書において、BCY2586と称される);
A-(配列番号10)-A-Sar6-K-Fl(本明細書において、BCY2582と称される);
A-(配列番号12)-A-Sar6-K-Fl(本明細書において、BCY2584と称される);
A-(配列番号13)-A-Sar6-K-Fl(本明細書において、BCY2588と称される);
Cy5-(B-Ala)-Sar5-A-(配列番号1)-A(本明細書において、BCY8590と称される);及び
Ac-(配列番号5)-A-Sar6-K-Cy5(本明細書において、BCY8591と称される)
:から選択される。
(付番)
本発明のペプチド内のアミノ酸残基位置に言及する場合、システイン残基(Ci、Cii、及びCiii)は不変であるので、これらは付番から省略され、それゆえ、本発明のペプチド内のアミノ酸残基の付番は、以下のように言及される:
-Ci-L1-D2-H3-M4-E5-Cii-R6-G7-D8-M9-D10-Ciii- (配列番号1)
。
二環コア配列へのN-又はC-末端伸長は、ハイフンによって隔てられた、配列の左側又は右側に付加される。例えば、N-末端βAla-Sar10-Alaテールは:
βAla-Sar10-A-(配列番号X)
と表される。
Nairらの文献(2003) J Immunol 170(3), 1362-1373における開示を考慮して、本明細書に開示されるペプチド配列は、そのレトロ-インベルソ(retro-inverso)形態でも有用性を見出すことが想定される。例えば、配列が逆転し(すなわち、N-末端がC-末端になり、C-末端がN-末端になる)、その立体化学も同様に逆転する(すなわち、D-アミノ酸がL-アミノ酸になり、L-アミノ酸がD-アミノ酸になる)。
本明細書において言及されるペプチドリガンドは、分子スキャフォールドに共有結合したペプチドを指す。典型的には、そのようなペプチドは、スキャフォールドとの共有結合を形成することができる2以上の反応基(すなわち、システイン残基)と、ペプチドがスキャフォールドに結合するときにループを形成するのでループ配列と呼ばれる、該反応基間に内在する配列とを含む。この場合、ペプチドは、少なくとも3つのシステイン残基(本明細書において、Ci、Cii、及びCiiiと呼ばれる)を含み、かつスキャフォールド上に少なくとも2つのループを形成する。
本発明の特定の二環式ペプチドは、それを注射、吸入、経鼻、眼球、経口、又は局所投与のための好適な薬物様分子とみなすことができるいくつかの有利な特性を有する。そのような有利な特性としては、以下のもの挙げられる:
-種交差反応性。これは、前臨床的な薬力学及び薬物動態評価の典型的な必要条件である;
-プロテアーゼ安定性。二環式ペプチドリガンドは、理想的には、血漿プロテアーゼ、上皮(「膜固定型」)プロテアーゼ、胃腸プロテアーゼ、肺表面プロテアーゼ、細胞内プロテアーゼなどに対する安定性を示すべきである。プロテアーゼ安定性は、二環式リード候補を動物モデルで開発するだけでなく、自信を持ってヒトに投与することもできるように、異なる種の間で維持されるべきである;
-望ましい溶解度プロファイル。これは、製剤化及び吸収目的で重要である、荷電残基及び親水性残基と疎水性残基の比率並びに分子内/分子間H-結合の関数である;
-循環中での最適な血漿半減期。臨床的適応及び治療レジメンに応じて、急性疾患管理設定で短期曝露用の二環式ペプチドを開発するか又は循環中での保持が増強された二環式ペプチドを開発する必要があり得るため、より慢性的な疾患状態の管理に最適である。望ましい血漿半減期を推進する他の要因は、最大治療効率のための持続的曝露の要求と薬剤の持続的曝露による随伴毒性である;及び
-選択性。本発明の特定のペプチドリガンドは、他のインテグリン、例えば、αvβ5よりも良好な選択性を示す。特に、二環式ペプチドBCY2493、BCY2503、及びBCY2555は、本明細書中の表2に示されている競合結合アッセイにおいて、αvβ5よりもαvβ3に対する選択性を示した。さらに、二環式ペプチドBCY2572、BCY2576、BCY2579、BCY2580、BCY2582、BCY2584、BCY2586、及びBCY2588は、本明細書中の表4に示されている直接結合アッセイにおいて、αvβ5よりもαvβ3に対する選択性を示した。
塩形態は本発明の範囲内であり、ペプチドリガンドへの言及が該リガンドの塩形態を含むことが理解されるであろう。
本明細書で定義されるペプチドリガンドの修飾誘導体は、本発明の範囲内であることが理解されるであろう。そのような好適な修飾誘導体の例としては、N-末端及び/又はC-末端修飾; 1以上のアミノ酸残基の1以上の非天然アミノ酸残基による置換(例えば、1以上の極性アミノ酸残基の1以上の等配電子又は等電子アミノ酸による置換; 1以上の非極性アミノ酸残基の他の非天然等配電子又は等電子アミノ酸による置換);スペーサー基の付加; 1以上の酸化感受性アミノ酸残基の1以上の酸化抵抗性アミノ酸残基による置換; 1以上のアミノ酸残基のアラニンによる置換、1以上のL-アミノ酸残基の1以上のD-アミノ酸残基による置換;二環式ペプチドリガンド内の1以上のアミド結合のN-アルキル化; 1以上のペプチド結合の代用結合による置換;ペプチド骨格長の修飾; 1以上のアミノ酸残基のα-炭素上の水素の別の化学基による置換、システイン、リジン、グルタミン酸/アスパラギン酸、及びチロシンなどのアミノ酸を官能基化するような、該アミノ酸の好適なアミン、チオール、カルボン酸、及びフェノール反応性試薬による修飾、並びに官能基化に好適である直交反応性を導入するアミノ酸、例えば、それぞれ、アルキン又はアジドを有する部分による官能基化を可能にするアジド又はアルキン基を有するアミノ酸の導入又は置換:から選択される1以上の修飾が挙げられる。
-より高い親和性が達成されるように、疎水性効果を利用し、より低い解離速度をもたらす疎水性部位を組み込むこと;
-長距離イオン相互作用を利用し、より速い会合速度をもたらし、より高い親和性をもたらす荷電基を組み込むこと(例えば、Schreiberらの文献、タンパク質の急速静電アシスト会合(Rapid, electrostatically assisted association of proteins)(1996)、Nature Struct. Biol. 3, 427-31を参照);並びに
-例えば、エントロピーの損失が標的結合時に最小になるように、アミノ酸の側鎖を適切に拘束すること、エントロピーの損失が標的結合時に最小になるように、骨格のねじれ角度を拘束すること、及び同一の理由で分子内にさらなる環化を導入することにより、さらなる拘束性をペプチドに組み込むこと
(総説については、Gentilucciらの文献、Curr. Pharmaceutical Design, (2010), 16, 3185-203、及びNestorらの文献、Curr. Medicinal Chem (2009), 16, 4399-418を参照)。
本発明は、1以上の原子が、同じ原子番号を有するが、天然に通常見られる原子質量又は質量数とは異なる原子質量又は質量数を有する原子によって置き換えられている、本発明の医薬として許容し得る全ての(放射性)同位体標識ペプチドリガンド、並びに関連する(放射性)同位体を保持することができる金属キレート基が取り付けられている本発明のペプチドリガンド(「エフェクター」と呼ばれる)、並びに特定の官能基が関連する(放射性)同位体又は同位体標識された官能基で共有結合的に置き換えられている本発明のペプチドリガンドを含む。
「芳香族分子スキャフォールド」という用語への本明細書における言及は、芳香族炭素環式又はヘテロ環式環系を含有する本明細書で定義される任意の分子スキャフォールドを指す。
本発明のさらなる態様によれば、1以上のエフェクター及び/又は官能基にコンジュゲートされた本明細書で定義されるペプチドリガンドを含む薬物コンジュゲートが提供される。
本発明のペプチドは、標準的な技法によって合成的に製造した後、インビトロで分子スキャフォールドと反応させることができる。これを実施する場合、標準的な化学を使用することができる。これにより、さらなる下流での実験又は検証のための可溶性材料の迅速な大規模調製が可能になる。そのような方法は、Timmermanらの文献(上記)に開示されているもののような従来の化学を用いて達成され得る。
本発明のさらなる態様によれば、本明細書で定義されるペプチドリガンド又は薬物コンジュゲートを1以上の医薬として許容し得る賦形剤との組合せで含む医薬組成物が提供される。
本発明の二環式ペプチドは、インテグリンαvβ3結合剤としての具体的な有用性を有する。
(材料及び方法)
(ペプチド合成)
ペプチド合成は、ペプチド Instrumentsにより製造されたSymphonyペプチド合成装置及びMultiSynTech製のSyro II合成装置を用いるFmoc化学に基づいた。標準的なFmoc-アミノ酸(Sigma, Merck)を適切な側鎖保護基とともに利用し:適用可能な場合、標準的なカップリング条件を各々の場合に使用し、その後、標準的な方法論を用いて、脱保護を行った。HPLCを用いてペプチドを精製し、単離後、これを1,3,5-トリス(ブロモメチル)ベンゼン(TBMB, Sigma)で修飾した。このために、直鎖状ペプチドをH2Oで約35mLまで希釈し、アセトニトリル中の約500μLの100mM TBMBを添加し、H2O中の5mLの1M NH4HCO3で反応を開始させた。反応をRTで約30分から60分間進行させておき、(MALDIにより判断して)反応が終了したら、凍結乾燥させた。凍結乾燥後、修飾されたペプチドを上記のように精製し、一方、Luna C8をGemini C18カラム(Phenomenex)と交換し、酸を0.1%トリフルオロ酢酸に変更した。適切なTBMB修飾材料を含有する純粋な画分をプールし、凍結乾燥させ、保存のために-20℃で保持した。
以下の方法は、43-06-00-N019を産出するための、二環式ペプチド、すなわち、43-06-00-N018(Ac-(配列番号5)-A-Sar6-dK)のジスルフィド活性化と、それに続く、BT43BDC-1を作製するための、DM-1などの細胞毒性剤へのコンジュゲーションを記載している。
LC/MS (ES+) M+3124の計算値;実測値3124。
(インテグリンαvβ3及びαvβ5競合結合アッセイ)
配列:
BCY3844-(ガラクト-RGD)2-AF488(Colomboらの文献(2010) Molecules 15(1), 178-197の方法に従って調製される);
BCY2572-A-(配列番号1)-A-Sar6-K-Fl;
BCY2576-A-(配列番号4)-A-Sar6-K-Fl;及び
BCY10185-FITC-Ahx-(配列番号14)。
Claims (22)
- 少なくとも2つのループ配列によって隔てられた少なくとも3つのシステイン残基を含むポリペプチド及び該ポリペプチドのシステイン残基と共有結合を形成する芳香族分子スキャフォールドを含み、その結果、少なくとも2つのポリペプチドループが該分子スキャフォールド上に形成される、インテグリンαvβ3に特異的なペプチドリガンド。
- 前記ループ配列が、2、3、4、5、6、又は7つのアミノ酸配列を含む、請求項1記載のペプチドリガンド。
- 前記ループ配列が、その両方が5つのアミノ酸からなる2つのループ配列によって隔てられた3つのシステイン残基を含む、請求項1又は請求項2記載のペプチドリガンド。
- 前記ループ配列が、その両方が6つのアミノ酸からなる2つのループ配列によって隔てられた3つのシステイン残基を含む、請求項1又は請求項2記載のペプチドリガンド。
- 前記ループ配列が、その一方が2つのアミノ酸からなり、そのもう一方が7つのアミノ酸からなる2つのループ配列によって隔てられた3つのシステイン残基を含む、請求項1又は請求項2記載のペプチドリガンド。
- 前記ループ配列が、その一方が4つのアミノ酸からなり、そのもう一方が3つのアミノ酸からなる2つのループ配列によって隔てられた3つのシステイン残基を含む、請求項1又は請求項2記載のペプチドリガンド。
- A-(配列番号1)-A(本明細書において、BCY2493と称される);
A-(配列番号2)-A(本明細書において、BCY2496と称される);
A-(配列番号3)-A(本明細書において、BCY2497と称される);
A-(配列番号4)-A(本明細書において、BCY2498と称される);
Ac-(配列番号5)-A-Sar10-dK(本明細書において、BCY2615と称される);
Ac-(配列番号5)-A-Sar6-dK(本明細書において、43-06-00-N018又はBCY2558と称される);
A-(配列番号6)-A(本明細書において、BCY2499と称される);
A-(配列番号7)-A(本明細書において、BCY2502と称される);及び
A-(配列番号8)-A(本明細書において、BCY2506と称される)
:から選択されるアミノ酸配列を含む、請求項1、2、又は7のいずれか一項記載のペプチドリガンド。 - Ac-(配列番号4)-A-Sar6-K(本明細書において、BCY2553と称される);
B-Ala-Sar5-A-(配列番号4)(本明細書において、BCY2554と称される);
Ac-(配列番号5)-A-Sar6-K(本明細書において、BCY2555と称される);
B-Ala-Sar5-(配列番号5)(本明細書において、BCY2560と称される);
A-(配列番号9)-A(本明細書において、BCY2494と称される);
A-(配列番号10)-A(本明細書において、BCY2503と称される);及び
B-Ala-Sar5-A-(配列番号11)(本明細書において、BCY2568と称される)
:から選択されるアミノ酸配列を含む、請求項1、2、又は8のいずれか一項記載のペプチドリガンド。 - 前記分子スキャフォールドが1,3,5-トリス(ブロモメチル)ベンゼン(TBMB)から選択され、前記ペプチドリガンドが、
A-(配列番号1)-A(本明細書において、BCY2493と称される);
A-(配列番号2)-A(本明細書において、BCY2496と称される);
A-(配列番号3)-A(本明細書において、BCY2497と称される);
A-(配列番号4)-A(本明細書において、BCY2498と称される);
Ac-(配列番号5)-A-Sar10-dK(本明細書において、BCY2615と称される);
Ac-(配列番号5)-A-Sar6-dK(本明細書において、43-06-00-N018又はBCY2558と称される);
A-(配列番号6)-A(本明細書において、BCY2499と称される);
A-(配列番号7)-A(本明細書において、BCY2502と称される);及び
A-(配列番号8)-A(本明細書において、BCY2506と称される)
:から選択されるアミノ酸配列を含む、請求項9記載のペプチドリガンド。 - 前記分子スキャフォールドが1,3,5-トリス(ブロモメチル)ベンゼン(TBMB)から選択され、前記ペプチドリガンドが、
Ac-(配列番号4)-A-Sar6-K(本明細書において、BCY2553と称される);
B-Ala-Sar5-A-(配列番号4)(本明細書において、BCY2554と称される);
Ac-(配列番号5)-A-Sar6-K(本明細書において、BCY2555と称される);
B-Ala-Sar5-(配列番号5)(本明細書において、BCY2560と称される);
A-(配列番号9)-A(本明細書において、BCY2494と称される);
A-(配列番号10)-A(本明細書において、BCY2503と称される);及び
B-Ala-Sar5-A-(配列番号11)(本明細書において、BCY2568と称される)
:から選択されるアミノ酸配列を含む、請求項10記載のペプチドリガンド。 - 前記分子スキャフォールドが1,3,5-トリス(ブロモメチル)ベンゼン(TBMB)から選択され、前記ペプチドリガンドが、
Ac-(配列番号5)-A-Sar6-dK(本明細書において、43-06-00-N018又はBCY2558と称される)
:から選択されるアミノ酸配列を含む、請求項9又は請求項11記載のペプチドリガンド。 - フルオレセイン(Fl)又はシアニン5(Cy5)などの蛍光部分をさらに含み、かつ
A-(配列番号1)-A-Sar6-K-Fl(本明細書において、BCY2572と称される);
Fl-G-Sar5-A-(配列番号1)(本明細書において、BCY2573と称される);
A-(配列番号4)-A-Sar6-K-Fl(本明細書において、BCY2576と称される);
Ac-(配列番号4)-A-Sar6-K-Fl(本明細書において、BCY2577と称される);
Fl-(B-Ala)-Sar5-A-(配列番号4)(本明細書において、BCY2578と称される);
Ac-(配列番号5)-A-Sar6-K-Fl(本明細書において、BCY2579と称される);
Fl-(B-Ala)-Sar5-A-(配列番号5)(本明細書において、BCY2580と称される);
A-(配列番号8)-A-Sar6-K-Fl(本明細書において、BCY2586と称される);
A-(配列番号10)-A-Sar6-K-Fl(本明細書において、BCY2582と称される);
A-(配列番号12)-A-Sar6-K-Fl(本明細書において、BCY2584と称される);
A-(配列番号13)-A-Sar6-K-Fl(本明細書において、BCY2588と称される);
Cy5-(B-Ala)-Sar5-A-(配列番号1)-A(本明細書において、BCY8590と称される);及び
Ac-(配列番号5)-A-Sar6-K-Cy5(本明細書において、BCY8591と称される)
:から選択される、請求項1又は請求項2記載のペプチドリガンド。 - 医薬として許容し得る塩が、遊離酸又はナトリウム、カリウム、カルシウム、アンモニウム塩から選択される、請求項1~14のいずれか一項記載のペプチドリガンド。
- 前記インテグリンαvβ3がヒトインテグリンαvβ3である、請求項1~15のいずれか一項記載のペプチドリガンド。
- 1以上のエフェクター及び/又は官能基にコンジュゲートされた、請求項1~13及び15~16のいずれか一項記載のペプチドリガンドを含む薬物コンジュゲート。
- 1以上の細胞毒性剤にコンジュゲートされた、請求項1~13及び15~16のいずれか一項記載のペプチドリガンドを含む薬物コンジュゲート。
- 前記細胞毒性剤がDM-1から選択される、請求項18記載の薬物コンジュゲート。
- 請求項1~13もしくは15~16のいずれか一項記載のペプチドリガンド又は請求項17~20のいずれか一項記載の薬物コンジュゲートを1以上の医薬として許容し得る賦形剤との組合せで含む、医薬組成物。
- インテグリンαvβ3によって媒介される疾患又は障害の予防、抑制、又は治療において使用するための、請求項1~13もしくは15~16のいずれか一項記載のペプチドリガンド又は請求項17~20のいずれか一項記載の薬物コンジュゲート。
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