JP2021528433A - EphA2に結合するためのペプチドリガンド - Google Patents
EphA2に結合するためのペプチドリガンド Download PDFInfo
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- JP2021528433A JP2021528433A JP2020571444A JP2020571444A JP2021528433A JP 2021528433 A JP2021528433 A JP 2021528433A JP 2020571444 A JP2020571444 A JP 2020571444A JP 2020571444 A JP2020571444 A JP 2020571444A JP 2021528433 A JP2021528433 A JP 2021528433A
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- peptide
- peptide ligand
- dap
- residues
- cysteine
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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Abstract
Description
A1−X1−A2−X2−A3
(式中、
A1、A2、およびA3は、独立して、システイン、L−2,3−ジアミノプロピオン酸(Dap)、N−ベータ−アルキル−L−2,3−ジアミノプロピオン酸(N−AlkDap)、またはN−ベータ−ハロアルキル−L−2,3−ジアミノプロピオン酸(N−HAlkDap)であり、但し、A1、A2、およびA3のうちの少なくとも1つは、Dap、N−AlkDapまたはN−HAlkDapであることを条件とし、
X1およびX2は、システイン、Dap、N−AlkDapまたはN−HAlkDap残基の間のアミノ酸残基を表し、X1およびX2はそれぞれ、独立して、4、5、6または7個のアミノ酸残基のループ状配列である)
から選択されるアミノ酸配列を含む。
毒素は、任意の適切な細胞毒性剤を指し、
二環は、ループ状ペプチド構造を表し、
nは、1から10から選択される整数を表し、
mは、0から10から選択される整数を表す)
を有する。
− より高い親和性が達成されるように、疎水性効果を活かし、かつより低いオフレートにつながる疎水性部分を組み込むこと、
− 長期にわたるイオン性相互作用を活用する荷電された基を組み込み、より速いオンレートおよびより高い親和性をもたらすこと(例えば、Schreiber et al, Rapid, electrostatically assisted association of proteins (1996), Nature Struct. Biol. 3, 427−31を参照されたい)、ならびに
− このペプチドへ、例えば、エントロピーの損失が標的結合の際に最小であるように、アミノ酸の側鎖を正確に拘束すること、エントロピーの損失が標的結合の際に最小であるように、主鎖の二面角を拘束すること、および同一の理由のために分子中に追加の環化を導入することによって、追加的な拘束を組み込むこと。
(概説については、Gentilucci et al, Curr. Pharmaceutical Design, (2010), 16, 3185−203、およびNestor et al, Curr. Medicinal Chem (2009), 16, 4399−418を参照のこと)。
を有する。
S−R1−N(R3)−R2−P
(式中、
Sは、足場コア、例えば、以下でさらに説明される(ヘテロ)芳香族または(ヘテロ)脂環式環を表し、
R1は、C1からC3アルキレン基、適切にはメチレンまたはエチレン基、最も適切にはメチレン(CH2)であり、
R2は、DapまたはN−AlkDap側鎖のメチレン基であり
R3は、アルキル基のいずれかが、任意選択でハロゲン化されている、H、または分枝状アルキルおよびシクロアルキル、例えばメチルを含むC1〜4アルキルであり、
Pは、ペプチド主鎖を表し、すなわち、上記連結のR2部分は、DapまたはN−AlkDapまたはN−HAlkDap残基のカルボン酸炭素に隣接するペプチド主鎖の炭素原子に連結している)
を有する。
− 種の交差反応性。これは、前臨床の薬力学および薬物動態学的評価のための典型的な要件である。
− プロテアーゼ安定性。二環性ペプチドリガンドは、理想的には、血漿プロテアーゼ、上皮(「膜アンカー型(membrane−anchored)」)プロテアーゼ、胃および腸のプロテアーゼ、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実証するべきである。プロテアーゼ安定性は、二環リード候補が動物モデルで開発可能であり、ヒトに対して高い信頼性で投与可能であるように、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、製剤化および吸収の目的に重要である、荷電および親水性対疎水性残基の割合ならびに分子内/分子間のH結合の関数である。
− 循環中の最適血漿半減期。臨床指標および処置計画に応じて、急性の疾患管理の状況では、短い曝露用の二環性ペプチドを開発するか、または循環中で保持を増強している二環性ペプチドを開発する必要がある場合があり、したがって、より慢性の疾患状態の管理に最適である。望ましい血漿半減期を誘導する他の要因は、薬剤の持続性曝露に起因する、付随する毒物学に対する、最大の治療効率のための持続性曝露の必要性である。
二環は、本明細書に記載される任意の適切なループ状ペプチド構造を表し、
R3およびR4は、独立して、水素またはメチルを表す)
を有する。
毒素は、本明細書で定義される任意の適切な細胞毒性剤を指し、
二環は、本明細書に記載される任意の適切なループ状ペプチド構造を表し、
nは、1から10から選択される整数を表し、
mは、0から10から選択される整数を表す)
によって、二環性ペプチドに連結される。
二環は、本明細書で定義された任意の適切なループ状ペプチド構造を表し、
nは、1から10から選択される整数を表し、
mは、0から10から選択される整数を表す)
を含む。
を有してもよい。
ペプチド合成は、Peptide Instrumentsが製造したSymphonyおよびSymphonyXペプチドシンセサイザーおよびMultiSynTechが製造したSyro IIシンセサイザーを使用する、Fmoc化学に基づいた。適当な側鎖保護基を有する標準のFmoc−アミノ酸(Sigma、Merck)を用いた。ここで、適用可能な標準のカップリング条件を各事例で使用し、続いて、標準の方法を使用して脱保護を行った。HPLCによってペプチドを精製し、単離後に、これらを1,3,5−トリス(ブロモメチル)ベンゼン(TBMB、Sigma)で修飾した。これに対して、直鎖状ペプチドを約35mLまでH2Oで希釈し、アセトニトリル中100mMのTBMB 約500μLを添加し、反応をH2O中1MのNH4HCO3 約5mLで開始した。反応を室温で約30〜60分間進行させ、反応が完了したら(MALDIによって判断した)、1Mのシステイン塩酸塩(Sigma)約500ulでクエンチした。凍結乾燥後、移動相として0.1%のトリフルオロ酢酸を含む水/アセトニトリルを使用してGemini C18カラム(Phenomenex)中で修飾ペプチドを精製した。正しい環化材料を含有する純粋な画分をプールし、凍結乾燥し、保存のために−20℃に保った。
1.蛍光偏光測定
(a)直接結合アッセイ
蛍光タグ(フルオレセイン、SIGMAまたはAlexa Fluor488(商標)、Fisher Scientific)を有するペプチドを0.01%のtween20を含むPBSまたは100mMのNaClおよび0.01%のtweenを含む50mMのHEPES(pH7.4)中で(いずれもアッセイ緩衝液と称される)2.5nMまで希釈した。これを黒色の壁および底を有する低結合低容量の384ウェルプレートにおいて総体積25μL中1nMのペプチドを与えるペプチドとして、同じアッセイ緩衝液中でタンパク質の滴定と組み合わせた(典型的には、5μLのアッセイ緩衝液、10μKのタンパク質(表1)、次いで、10μLの蛍光ペプチド)。2つの連続希釈のうちの1つを使用して、公知の高親和性結合剤での500nMから、低親和性結合剤および選択性アッセイでの10μMまでの範囲の上位濃度を有する12の異なる濃度を得た。485nmで励起し、520nmで平行かつ垂直な放射を検出する「FP 485 520 520」光学モジュールを備えたBMG PHERAstar FSで測定を行った。PHERAstar FSを25℃で、ウェル当たり200フラッシュおよび0.1秒の移動待ち時間に設定し、各ウェルを5から10分の間隔で60分間測定した。分析に使用したゲインを、ウェル中にタンパク質が存在しない60分の終了時に各トレーサーについて決定した。Systat Sigmaplot version 12.0を使用してデータを分析した。mP値をユーザーが定義した二次方程式に当てはめ、Kd値を得た:f = ymin+(ymax−ymin)/Lig*((x+Lig+Kd)/2−sqrt((((x+Lig+Kd)/2)^2)−(Lig*x)))。「Lig」は、使用したトレーサー濃度の規定値であった。
蛍光タグを有さないペプチドを蛍光タグと公知のKd(表2)を有するペプチドと競合させて試験した。最大5%のDMSOを用いる直接結合アッセイにおいて記載されたように、ペプチドをアッセイ緩衝液中で適当な濃度に希釈し、次いで、2分の1に連続希釈した。希釈したペプチド5μLをプレートに添加し、続いて、使用した蛍光ペプチドに応じた固定濃度のヒトまたはマウスのEphA2(表1)10μL、次いで、10μLの蛍光ペプチドを添加した。直接結合アッセイに関して測定を行ったが、最初の測定の前にゲインを決定した。Systat Sigmaplotバージョン12.0でデータ分析し、mP値をユーザーが定義した三次方程式に当てはめ、Ki値を得た。
f=ymin+(ymax−ymin)/Lig*((Lig*((2*((Klig+Kcomp+Lig+Comp−Prot*c)^2−3*(Kcomp*(Lig−Prot*c)+Klig*(Comp−Prot*c)+Klig*Kcomp))^0.5*COS(ARCCOS((−2*(Klig+Kcomp+Lig+Comp−Prot*c)^3+9*(Klig+Kcomp+Lig+Comp−Prot*c)*(Kcomp*(Lig−Prot*c)+Klig*(Comp−Prot*c)+Klig*Kcomp)−27*(−1*Klig*Kcomp*Prot*c))/(2*((((Klig+Kcomp+Lig+Comp−Prot*c)^2−3*(Kcomp*(Lig−Prot*c)+Klig*(Comp−Prot*c)+Klig*Kcomp))^3)^0.5)))/3))−(Klig+Kcomp+Lig+Comp−Prot*c)))/((3*Klig)+((2*((Klig+Kcomp+Lig+Comp−Prot*c)^2−3*(Kcomp*(Lig−Prot*c)+Klig*(Comp−Prot*c)+Klig*Kcomp))^0.5*COS(ARCCOS((−2*(Klig+Kcomp+Lig+Comp−Prot*c)^3+9*(Klig+Kcomp+Lig+Comp−Prot*c)*(Kcomp*(Lig−Prot*c)+Klig*(Comp−Prot*c)+Klig*Kcomp)−27*(−1*Klig*Kcomp*Prot*c))/(2*((((Klig+Kcomp+Lig+Comp−Prot*c)^2−3*(Kcomp*(Lig−Prot*c)+Klig*(Comp−Prot*c)+Klig*Kcomp))^3)^0.5)))/3))−(Klig+Kcomp+Lig+Comp−Prot*c)))).
アルキルアミノに対するチオエーテルの足場連結の比較のために選択した第1の参照二環性ペプチドを55−03−05−N233と示した。これは、チオエーテル形成ペプチドのトリメチレンベンゼン足場との二環性コンジュゲートである。この二環性誘導体の構造を図2に模式的に示す。コンジュゲーション前の直鎖状ペプチドは配列:
[B−Ala][Sar]10H[dD]VPCPWGPFWCPVNRPGC
を有する。
55−03−05−N314と示した二環性ペプチドを、第1および第2のシステイン残基を、TBMB足場に対してアルキルアミノ連結を形成するDAP残基によって置き換えた、参考例1のペプチドリガンドの二環性領域に対応するものとして作製した。この誘導体の構造を図3に模式的に示す。
[Ac][B−Ala][Sar]10H[dD]VP[Dap]PWGPFW[Dap]PVNRPGC
55−03−05−N316と示した二環性ペプチドを、第2および第3のシステイン残基を、TBMB足場に対してアルキルアミノ連結を形成するDAP残基に置き換えた、参考例1のペプチドリガンドの二環性領域に対応するものとして作製した。この誘導体の構造を図3に模式的に示す。
[Ac][B−Ala][Sar]10H[dD]VPCPWGPFW[Dap]PVNRPG[Dap]
55−03−05−N318と示した二環性ペプチドを、第1および第3のシステイン残基を、TBMB足場に対してアルキルアミノ連結を形成するDAP残基に置き換えた、参考例1のペプチドリガンドの二環性領域に対応するものとして作製した。この誘導体の構造を図4に模式的に示す。
[Ac][B−Ala][Sar]10H[dD]VP[Dap]PWGPFWCPVNRPG[Dap]
アルキルアミノに対するチオエーテルの足場連結の比較のために選択した第1の参照二環性ペプチドを55−03−05−N238と示した。これは、チオエーテル形成ペプチドのトリメチレンベンゼン足場との二環性コンジュゲートである。コンジュゲーション前の直鎖状ペプチドは配列:
[B−Ala][Sar]10H[dD]VPC[Aib][1Nal]G[Aib]F[1Nal]CP[tBuGly]N[HArg]P[dD]C
を有する。
55−03−05−N315と示した二環性ペプチドを、第1および第2のシステイン残基を、TBMB足場に対してアルキルアミノ連結を形成するDAP残基によって置き換えた、参考例2のペプチドリガンドの二環性領域に対応するものとして作製した。
[B−Ala][Sar]10H[dD]VP[Dap][Aib][1Nal]G[Aib]F[1Nal][Dap]P[tBuGly]N[HArg]P[dD]C
55−03−05−N317と示した二環性ペプチドを、第2および第3のシステイン残基を、TBMB足場に対してアルキルアミノ連結を形成するDAP残基に置き換えた、参考例2のペプチドリガンドの二環性領域に対応するものとして作製した。
[B−Ala][Sar]10H[dD]VPC[Aib][1Nal]G[Aib]F[1Nal][Dap]P[tBuGly]N[HArg]P[dD][Dap]
55−03−05−N319と示した二環性ペプチドを、第2および第3のシステイン残基を、TBMB足場に対してアルキルアミノ連結を形成するDAP残基に置き換えた、参考例2のペプチドリガンドの二環性領域に対応するものとして作製した。
[B−Ala][Sar]10H[dD]VP[Dap][Aib][1Nal]G[Aib]F[1Nal]CP[tBuGly]N[HArg]P[dD][Dap]
2017年12月19日に出願した、本発明者らのより早期の出願であるGB201721265.5に詳細に記載されているように、特定のペプチド配列のシステイン残基に対して3つのチオエーテル連結を有するTBMB足場を有する以下の参照ペプチドリガンドを調製し、EphA2に対する親和性について評価した。
2017年12月19日に出願した本発明者らのより早期の出願であるGB201721259.8に詳細に記載されているように、特定のペプチド配列のシステイン残基に対して3つのチオエーテル連結を有するTATA足場を有する以下の参照ペプチドリガンドを調製し、EphA2に対する親和性について評価した。
Claims (19)
- EphA2に特異的なペプチドリガンドであって、前記ペプチドリガンドが、システイン、L−2,3−ジアミノプロピオン酸(Dap)、N−ベータ−アルキル−L−2,3−ジアミノプロピオン酸(N−AlkDap)およびN−ベータ−ハロアルキル−L−2,3−ジアミノプロピオン酸(N−HAlkDap)から選択される3つの残基を含むポリペプチドを含み、但し、前記3つの残基のうちの少なくとも1つが、Dap、N−AlkDapまたはN−HAlkDapから選択されることを条件とし、前記3つの残基が、少なくとも2つのループ配列及び分子足場によって分離されており、前記ペプチドが、ポリペプチドの前記DapまたはN−AlkDapまたはN−HAlkDap残基との共有結合によるアルキルアミノ連結によって前記足場に連結され、および前記3つの残基がシステインを含む場合には、前記ポリペプチドのシステイン残基とのチオエーテル連結によって前記足場に連結され、2つのポリペプチドループが前記分子足場上に形成されている、ペプチドリガンド。
- 前記ペプチドリガンドが、
A1−X1−A2−X2−A3
(式中、A1、A2、およびA3は、独立して、システイン、L−2,3−ジアミノプロピオン酸(Dap)、N−ベータ−アルキル−L−2,3−ジアミノプロピオン酸(N−AlkDap)、またはN−ベータ−ハロアルキル−L−2,3−ジアミノプロピオン酸(N−HAlkDap)であり、但し、A1、A2、およびA3のうちの少なくとも1つが、Dap、N−AlkDapまたはN−HAlkDapであることを条件とし、
X1およびX2は、システイン、Dap、N−AlkDapまたはN−HAlkDap残基の間のアミノ酸残基を表し、X1およびX2はそれぞれ、独立して、4、5、6または7個のアミノ酸残基を含む)
から選択されるアミノ酸配列を含む、請求項1に記載のペプチドリガンド。 - A1、A2およびA3のうちの2つが、Dap、N−AlkDapまたはN−HAlkDapから選択され、3番目のA1、A2およびA3のうちの1つがシステインであり、好ましくはA2がシステインである、請求項1または2に記載のペプチドリガンド。
- A1、A2、およびA3がそれぞれ、N−AlkDapまたはN−HAlkDapである、請求項1から3のいずれか1項に記載のペプチドリガンド。
- 前記分子足場が、芳香族分子足場、例えば、1,3,5−トリス(メチレン)ベンゼンである、請求項1から4のいずれか1項に記載のペプチドリガンド。
- 表3から10の1つもしくは複数に列挙されたペプチドリガンド配列1〜308の1つもしくは複数から選択されるアミノ酸配列、またはその薬学的に許容される塩を含み、但し、前記ペプチドリガンド配列1〜308におけるシステイン残基の1つまたは複数が、Dap、N−AlkDapまたはN−HAlkDapによって置き換えられていることを条件とする、請求項5に記載のペプチドリガンド。
- 前記ペプチドリガンド配列が、
[B−Ala][Sar]10H[dD]VPA1PWGPFWA2PVNRPGA3
または
[B−Ala][Sar]10H[dD]VPA1[Aib][1Nal]G[Aib]F[1Nal]A2P[tBuGly]N[HArg]P[dD]A3
(式中、A1、A2およびA3は、請求項2に定義された通りである)
から選択される、請求項1から6のいずれか1項に記載のペプチドリガンド。 - A2がシステインであり、A1およびA3がDap、N−AlkDapまたはN−HAlkDap、好ましくはDapである、請求項7に記載のペプチドリガンド。
- 前記分子足場が、非芳香族分子足場であり、好ましくは1,1’,1’’−(1,3,5−トリアジナン−1,3,5−トリイル)トリプロパ−2−エン−1−オン(TATA)から選択される、請求項1から4のいずれか1項に記載のペプチドリガンド。
- 表11〜13の化合物1〜98またはその薬学的に許容される塩のうちのいずれか1つから選択され、但し、前記ペプチドリガンド配列1〜98におけるシステイン残基の1つまたは複数が、Dap、N−AlkDapまたはN−HAlkDapで置き換えられている、請求項9に記載のペプチドリガンド。
- 前記EphA2が、ヒトEphA2である、請求項1から10のいずれか1項に記載のペプチドリガンド。
- ヒトEphA2に対して選択的であるが、ヒトEphA1、EphA3またはEphA4と交差反応しない、請求項1から11のいずれか1項に記載のペプチドリガンド。
- 1つまたは複数のエフェクター基および/または官能基にコンジュゲートした、請求項1から12のいずれか1項に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、DM1またはMMAEから選択される、請求項13に記載の薬物コンジュゲート。
- 請求項1から12のいずれか1項に記載のペプチドリガンドまたは請求項13もしくは14のいずれか1項に記載の薬物コンジュゲートを、1つまたは複数の薬学的に許容される賦形剤と組み合わせ得て含む医薬組成物。
- 罹患組織におけるEphA2の過剰発現によって特徴付けられる、疾患または障害を予防する、抑制するまたは処置する際に使用するための、請求項1から12のいずれか1項に記載のペプチドリガンドまたは請求項13もしくは14に記載の薬物コンジュゲート。
- がんを予防する、抑制するまたは処置する際に使用するための、請求項1から12のいずれか1項に記載のペプチドリガンドまたは請求項13もしくは14のいずれか1項に記載の薬物コンジュゲート。
- 肺がんを予防する、抑制するまたは処置する際に使用するための、請求項1から12のいずれか1項に記載のペプチドリガンドまたは請求項13もしくは14のいずれか1項に記載の薬物コンジュゲート。
- 非小細胞肺癌を予防する、抑制するまたは処置する際に使用するための、請求項1から12のいずれか1項に記載のペプチドリガンドまたは請求項13もしくは14のいずれか1項に記載の薬物コンジュゲート。
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PCT/EP2019/065993 WO2019243313A1 (en) | 2018-06-22 | 2019-06-18 | PEPTIDE LIGANDS FOR BINDING TO EphA2 |
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