JP7502320B2 - 効力を判定するための方法 - Google Patents
効力を判定するための方法 Download PDFInfo
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- JP7502320B2 JP7502320B2 JP2021552875A JP2021552875A JP7502320B2 JP 7502320 B2 JP7502320 B2 JP 7502320B2 JP 2021552875 A JP2021552875 A JP 2021552875A JP 2021552875 A JP2021552875 A JP 2021552875A JP 7502320 B2 JP7502320 B2 JP 7502320B2
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Description
の活性物質の高用量投与が、逆の効果を与え、対象におけるpERKの発現を減少させることが分かった。結果として、上記活性物質が多すぎると、身体が癌性細胞や感染細胞を破壊することを助ける、活性T細胞の数を増加させる助けにならない。従って、本明細書に記載されるような治療を受けている対象にとって、対象のpERK発現を上昇させ免疫応答を向上させる(すなわち、T細胞増殖を促進する)レベルで、ナルトレキソンまたはその代謝産物もしくは類似体である活性物を投与されることは、有益である。本発明の方法を用いることで、pERK発現レベルをモニタリングして、上記活性物質が、pERK発現を確実に増加させる所望の低用量且つ有効レベルで投与されているかどうかを判定することができる。
a.治療を受けている対象から得られた試料中のpERKのレベルを測定すること;
b.上記pERKのレベルを標準と比較すること、
を含み、
上記pERKのレベルが上記標準と比較して増加していた場合、上記活性物質は有効レベルで投与されているものとする、
方法が提供される。
量投与が、対象における、バイオマーカーとしてのリン酸化ERK(pERK)の発現を増加させるという発見に基づく。これは、ナルトレキソン化合物によって例示されている。有効な低用量の投与を受けている患者にある特定のレベルのpERK発現が見られるようである。すなわち、ナルトレキソンまたはその代謝産物もしくは類似体による治療を受けながら、対象におけるpERK発現レベルを測定することにより、上記薬剤が所望の低用量且つ有効レベルで投与されているかどうかを、医師がモニタリングすることが可能となる。以上より、本発明者らは、pERKの発現レベルを測定することにより治療をモニタリングし、投与されている活性物質であるナルトレキソンまたはその代謝産物もしくは類似体の量を、効力および安全性が最大となるように変化させるための、インビトロの方法を発明した。
団内の個々の細胞のDNA含量を測定することにより定量することができる。増殖中の細胞集団は、DNA含量レベルが異なる細胞亜集団を含むこととなる。細胞内のDNA含量は、細胞が属している細胞周期の時期に依存することとなる。作用剤により細胞分裂停止が引き起こされた場合、細胞周期の各期に含まれる細胞集団のバランスは異常なものとなる。例えば、細胞分裂停止がS期またはG2期で生じた場合、異常な数の細胞が、体細胞で通常確認されるDNA含量の2倍の含量を含有することとなる。逆に、細胞分裂停止がG0期またはG1期で生じた場合、異常な数の細胞が、体細胞で通常確認されるDNA量を含有することとなる。
ルモン療法」、および「免疫療法」は、当該技術分野における通常の意味を有する。用語「抗がん剤」は、「化学療法剤」と同義的に使用される。併用療法を用いることで、複数の既知の治療法を使用してもよい。
る治療が終わった後、患者に適用され続ける。
5つの治療コホートを用意し、各コホートには8人の健常志願者が含められた。各志願者は、1mg、3mg、4.5mg、6mg、または10mg錠剤としてのナルトレキソンの単回投与による治療を受けた。PBMCを、0時間および48時間の時点でフィコール抽出により回収し、細胞溶解緩衝液中で溶解した。次にそれらの試料に対してウェスタンブロッティングを行い、pERK、tERK、BAX、およびp21を測定した。
図1A、図1C~図1Eに示すように、1mg、4.5mg、6mg、または10mg錠剤を投与した場合、0時間と比較して48時間の時点で、対象におけるpERK発現レベルが減少していた。これは図2のウェスタンブロッティングでも示されており;48時間時点の測定値ブロットA3、C3、D3、およびE3は、0時間時点の対応ブロットA1、C1、D1、およびE1よりも小さかった。図3に示すように、pERK発現と、ナルトレキソンおよび6-β-ナルトレキソールの最高血中濃度との間には逆相関があることが分かり、ナルトレキソンおよび6-β-ナルトレキソールの最高血中濃度が高くなるほど、pERK発現がより大きく低減することになることを示唆している。しかし、図1Bに示すように、3mg錠剤、すなわち所望の低用量を投与した場合、0時間と比較して48時間の時点で、対象におけるpERK発現レベルが減少していた。これは、他の用量を投与された対象と比較して、有利な低用量のナルトレキソンを投与された対象のpERK発現レベルには明確な違いがあることを示している。
Histopaque-1077を用いて、病理学的に健常なドナーから得られた全血から、または全血の白血球除去(leucoreduction)の残留物から、末梢血単核球を単離した。単核画分を回収し、低張塩化アンモニウム溶液中でのインキュベーションにより赤血球混入物を除去した。細胞をリン酸緩衝生理食塩水(PBS)で洗浄し、10分間200gで遠心分離することで血小板混入物を除去し、RPMI-1640培地中1×106個 mlの濃度で再懸濁した。これらの細胞に、ナルトレキソンを、10μMの従来の高用量ナルトレキソン(NTX)または10nMの低用量ナルトレキソン(LDN)のいずれかの濃度で添加し、37℃の空気中、5%CO2を含む加湿雰囲気下で、48時間インキュベートした。末梢血単核球を、洗浄用緩衝液(1%(v/v)FBSおよび0.09%(v/v)NaN3を含有するPBS)で2回洗浄し、関連抗体および標記抗体で4℃で30分間染色し、免疫細胞プロファイルの評価を行った。細胞を洗浄用緩衝液で洗浄し、4%パラホルムアルデヒド中、4℃で20分間固定した。BDバイオサイエンス社製LSR II Flow Cytometerと専用のプロプライエタリソフトウェアを用いて、表面マーカーの発現を解析した。
CD3+細胞の活性化状態はCD69発現によって示され;CD69の発現レベルが高いほど、それに相関して、CD3+の活性化が増大する。CD3+細胞は、細胞傷害性T細胞(CD8+ナイーブT細胞)およびヘルパーT細胞(CD4+ナイーブT細胞)の両方の活性化を助けるT細胞コレセプターである。図5に示されているように、CD3+/CD8+細胞(キラーT細胞)におけるCD69発現は、LDNとの培養後に増加したが、NTXまたは溶媒対照(DMSO)との培養後では、CD69発現は増加しなかった。このように、LDNのプライミングが完了し、pERK発現が増加すると、免疫系は好適にブーストされる。
Claims (20)
- ナルトレキソンまたはその代謝産物もしくは類似体である活性物質による治療法を受けている対象の治療をモニタリングするための方法であって、
前記治療ががん治療またはHIV/エイズ治療であって、
a.治療を受けている対象から得られた試料中のpERKのレベルを測定すること;
b.前記pERKのレベルを標準と比較すること、
を含み、
前記pERKのレベルが前記標準と比較して増加していることが、前記活性物質は有効レベルで投与されていることを示す、方法。 - 前記標準が治療前の前記対象から得られた試料である、請求項1に記載の方法。
- 前記試料が末梢血単核球を含む、請求項1または請求項2に記載の方法。
- 前記ナルトレキソンの代謝産物または類似体が6-β-ナルトレキソール、ナロキソン、またはメチルナルトレキソンである、請求項1~3のいずれか一項に記載の方法。
- 前記対象ががんまたはHIV/エイズの治療中であり、請求項1~4のいずれか一項に記載の方法。
- 前記対象ががんの治療中である、請求項1~5のいずれか一項に記載の方法。
- 前記がんが乳がん、肺がん、メラノーマ、結腸がん、またはグリオーマである、請求項5または6に記載の方法。
- 前記pERKのレベルが前記標準のレベル以下であることが、前記活性物質の量が有効レベルに調整されることを示す、請求項1~7のいずれか一項に記載の方法。
- 前記対象が、前記活性物質が一日あたり4.5mg以下の量のレベルでの治療を受けている、請求項1~8のいずれか一項に記載の方法。
- 前記対象が、前記活性物質が一日あたり3~4.5mgの量のレベルでの治療を受けている、請求項1~9のいずれか一項に記載の方法。
- 前記活性物質がナルトレキソンまたは6-β-ナルトレキソールである、請求項1~10のいずれか一項に記載の方法。
- 前記pERKが前記活性物質の投与の少なくとも24時間後に測定される、請求項1~11のいずれか一項に記載の方法。
- 前記pERKが前記活性物質の投与の少なくとも48時間後に測定される、請求項12に記載の方法。
- 前記pERKレベルがpERK発現レベルを測定することにより求められる、請求項1~13のいずれか一項に記載の方法。
- 前記pERKレベルがウェスタンブロッティングにより求められる、請求項14に記載の方法。
- 前記治療ががん治療である、請求項1~15のいずれか一項に記載の方法。
- 前記がん治療が化学療法、放射線療法、ホルモン療法、または免疫療法である、請求項16に記載の方法。
- 前記がん治療が化学療法である、請求項16に記載の方法。
- 前記治療がHIV/エイズ治療である、請求項1~15のいずれか一項に記載の方法。
- 前記治療が抗レトロウイルス療法である、請求項19に記載の方法。
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