JP2019512021A - Cdk4活性のマーカーとしてのp27チロシンリン酸化およびそれを使用するための方法 - Google Patents
Cdk4活性のマーカーとしてのp27チロシンリン酸化およびそれを使用するための方法 Download PDFInfo
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Abstract
Description
本出願は、2016年2月23日に提出された米国仮特許出願第62/298,584号明細書に対する優先権を主張し、その全開示が、本明細書において参照によって完全に組み込まれる。
化合物または医薬組成物の「治療有効量」は、限定を伴うことなく、腫瘍成長もしくはサイズを減少させることまたは投与、すなわち予防的な投与より以前にいかなる腫瘍も形成されていない動物において腫瘍成長が形になるのを妨げることを含め、動物、とりわけヒトにおいて腫瘍成長または転移を調整するのに十分な量を指す。
本発明はまた、少なくとも1つの薬剤を含む医薬組成物をも提供し、少なくとも1つの薬剤は、p27Kip1およびBrkの間の相互作用に干渉する化合物であり、医薬として許容されるキャリヤにおいてp27を「オン」にするリン酸化イベントを阻害する。本発明において使用される好ましい薬剤は、小分子、表2に列挙されるものなどのようなcdk4阻害剤、図1に提供される配列に基づくミメティック、およびsiRNAを含む。そのような医薬組成物は、がん治療を必要とする患者に治療有効量で投与されてもよい。
本発明に従って、ある既知の、化学療法として有効な薬剤と本明細書において記載される薬剤および小分子/ミメティック/siRNAの組み合わせは、腫瘍成長を抑制するよう相乗的に働くこともまた、発見された。したがって、本発明は、医薬として許容されるキャリヤにおいて、特定のチロシン(Y)リン酸化に干渉し、それによってp27を「オフ」の位置に維持する少なくとも1つの薬剤および少なくとも1つの化学療法剤を含む、患者におけるがんの治療のための医薬組成物を提供する。有効量の少なくとも1つのY88リン酸化阻害薬を投与することによって患者におけるがんを治療するための方法もまた、提供される。そのような薬剤は、単独でまたは少なくとも1つの他の抗がん剤と組み合わせて使用することができる。適した薬剤は、パルボシクリブ、アベマシクリブ、リボシクリブ、パクリタキセル(Taxol(登録商標))、シスプラチン、ドセタキセル、カルボプラチン、ビンクリスチン、ビンブラスチン、メトトレキサート、シクロホスファミド、CPT−11、5−フルオロウラシル(5−FU)、ゲムシタビン、エストラムスチン、カルムスチン、アドリアマイシン(ドキソルビシン)、エトポシド、三酸化ヒ素、イリノテカン、およびエポチロン誘導体を含むが、これらに限定されない。そのような薬剤は、同時にまたは連続して投与することができる。
本発明の医薬組成物は、任意の適したルートによって、たとえば注射によって、経口、肺、経鼻、または投与の他の方法によって投与することができる。一般に、本発明の医薬組成物は、中でも、医薬として許容される希釈剤、保存剤、可溶化剤、乳化剤、補助剤、及び/又はキャリヤを含む。ある場合には、キャリヤは、ナノ粒子である。そのような組成物はまた、様々なバッファー内容物(たとえばTris−HCl、酢酸、リン酸)、pH、およびイオン強度の希釈剤;ならびに洗浄剤および可溶化剤(たとえばTween80、ポリソルベート80)、酸化防止剤(たとえばアスコルビン酸、メタ重亜硫酸ナトリウム)、保存剤(たとえばチメロサール、ベンジルアルコール)、ならびに増量剤(たとえばラクトース、マンニトール)などのような添加剤を含むことができる。組成物は、ポリ乳酸、ポリグリコール酸などのような高分子化合物の粒子調製物の中にまたはリポソームの中に組み込むことができる。そのような組成物は、本発明の医薬組成物の構成成分の物理的状態、安定性、インビボにおける放出の速度、およびインビボにおける排除の速度に影響を及ぼしてもよい。たとえば、本明細書において参照によって組み込まれるRemington’s Pharmaceutical Sciences,18th Ed.(1990,Mack Publishing Co.,Easton,PA 18042)pages 1435−1712を参照されたい。本発明の医薬組成物は、たとえば液体の形態で調製することができるまたは乾燥した粉末の形態(たとえば凍結乾燥させた)とすることができる。医薬組成物を投与する特定の方法は、上記に記載される。
前述の産物のいずれも、天然に存在しない検出可能な標識により任意選択で検出可能に標識されているまたは任意選択で固体支持体に付けられているもしくは固定されている、リン酸化および非リン酸化形態をしたY88およびY89に対して免疫特異的な(immunospecific)1つ以上の抗体、Y88およびY89抗原、p27コード核酸による増幅もしくはそれとの特異的なハイブリダイゼーションに適したオリゴヌクレオチド、p27およびAlt−brkの天然に存在しないポリペプチドミメティック、医薬として許容されるキャリヤ、使用のための説明書、容器、投与のための器、アッセイ基質、cdk阻害剤、抗がん剤、またはその任意の組み合わせを含むことができるキットの中に組み込むことができる。
フォワードプライマー 5’−GGCCTCGAGCTAGCTCTCCTGCGCCG−3’(配列番号10)
リバースプライマー 5’GGGGTCTAGAGCCACCATGGACTACAAGGACG
ACGATGACAAGCGCAAGTGGA ATTTCGATTTTC−3’(配列番号11)
であった。
MVSRDQAHLGPKYVGLWDFKSRTDEELSFRAGDVFHVARKEEQWWWATLLDEAGGAVAQG
YVPHNYLAERETVESEPAGHAGCAALQDLAACRGPAAPERGGVLPQPARACELPQGPEPV
PRPAAGRALPEARA(配列番号12)
0=pY染色なし
1=1〜29% pY+細胞、強い染色は0%
2=1〜29% pY+細胞、強い染色は5〜20%だけ
3=30〜100% pY+細胞、強い染色は>20%
0=pY染色なし
1=弱いpY染色
2=中程度のpY染色
3=強いpY染色
試薬:
染色キット:Enzo Lifesciences(ADI−950−100−0001);抗原賦活化溶液:Dako(S1699);PAPペン:Fisher Scientific(XT001−PP);プロテインブロック:Dako(X0909);抗体希釈剤:Dako(S3022);P27抗体:BD Biosciences(610242);マウント溶液:Fisher Scientific(SP15−100)
1日目に、スライドに鉛筆で標識し、30分間、65℃のオーブンで焼き、オーブンからキシレンを含有するコプリンジャーに速やかに移した。スライドを室温でそれぞれ3分間、キシレン4×中ですすぎ、その後、R.T.でそれぞれ3分間、3回の100%−95%−75%エタノールの段階的アルコール洗浄を続けた。次いで、スライドは、3分間、1回、H2O中でのインキュベーションによって水和した。乾燥後、疎水性バリアを、PAPペンを使用して組織のまわりに作った。内因性ペルオキシドを、室温で30分間、ペルオキシドブロックとスライドをインキュベートすることによってブロックした。スライドを、それぞれ3分間、3回、TBS−0.1% Tween 20により洗浄し、その後、3分間、1×PBS中でのインキュベーションを続けた。R.Tでの1時間のプロテインブロックとのインキュベーションの後に、DAKO抗体希釈剤において1:200に希釈したP27 pY88抗体を、4℃での一晩のインキュベーションの間、スライドに追加した。
CDK4阻害剤に対するがん細胞感受性を決定するためのマーカーとしてのPY
この実施例では、pYは、特定の腫瘍がcdk4阻害剤による阻害に適した、適切な範囲のcdk4活性を有するかどうかを決定するためのヒト患者材料におけるマーカーとして使用される。発明者らは、pY p27に対するリン酸化部位特異的抗体を開発し、この抗体が、ホルマリン固定パラフィン包埋長期保存ヒト乳がん材料(ER/PR+/Her2−)においてpYを認識したことを示した。100%の浸透度で、抗体は、ヒト乳房縮小術から得られた良性組織を染色しなかった。分析したER/PR+/Her−2乳がんサンプルの75%は、強度は様々であったが、pYに対してポジティブに染色された。
パルボシクリブおよび他のcdk4選択的阻害剤に対して応答するであろう患者を同定する緊急の必要性がある。患者をパルボシクリブおよびレトロゾールにより治療すると、PFSが有意に改善されたが、全生存率(OS)は、統計的に異ならなかった。この研究では、全くの非レスポンダーをOSデータから排除しなかった。発明者らは、非レスポンダーを同定することができ、治験から取り除いていた場合、よりよい臨床結果であった可能性があると仮定している。パルボシクリブは1年当たり>$100Kのコストがかかるので、応答する可能性のある患者の同定は、目標として望ましい。
pYサブグループ
なし 25.5%
中程度 25.5%
高度 47%
なし:細胞の0%が+pY
中程度:細胞の1〜29%が+pY
高度:細胞の30〜100%が+pY
0=pY染色なし
1=1〜29% pY+細胞、強い染色は0%
2=1〜29% pY+細胞、強い染色は5〜20%だけ
3=30〜100% pY+細胞、強い染色は>20%
がん、特に乳がんに関連する蔓延および症状を回復させるための試験および治療方法
本発明の別の態様では、試験および治療方法が、開示される。最初に、サンプルを腫瘍から取り、Y88リン酸化レベルをcdk4活性レベルを決定するために評価した。前の実施例で詳細に記載されたように、正常組織で観察されたレベルに比べてY88リン酸化の検出可能なレベルを有しない患者は、cdk4阻害剤療法から恩恵を受けそうにないが、正常組織で観察されたレベルに比べて1、2、または3のレベルのpY88リン酸化を有する患者は、様々な濃度のcdk4阻害剤療法から恩恵を受けるはずである。疾患のサインまたは症状を軽減するためにがんを有する個人を治療するために、表2に開示され、上記の実施例において記載される、cdk2およびcdk4を標的にする適した薬剤を、患者における腫瘍量を低下させるために、単独でまたは組み合わせて、恩恵を受ける可能性が最も高い患者に投与することができる。そのような薬剤は、有効用量で投与されるべきである。総治療用量(2つ以上の標的が調整されることになっている場合)は、単一用量として対象に投与することができまたは分割された治療プロトコールを使用して投与することができ、複数の/別々の用量が、より長期間にわたって、たとえば、一日投薬量の投与を可能にするために一日の期間にわたってまたは所望の期間にわたって用量を投与するためにより長い期間にわたって投与される。
Claims (16)
- 対象におけるがんを治療するための方法であって、
a)対象由来のがん細胞を含む生物学的試料においてp27におけるpY88リン酸化レベルを評価すること及びコントロール組織において観察されるpY88リン酸化レベルと比較して、Y88リン酸化レベルを0、1、2、または3として階層化すること
b)0のレベルをcd4k阻害剤非感受性に、及び1、2、または3のレベルをcdk4阻害に対する感受性に相関させること、ならびに
c)がんによる負担または症状を軽減するために、治療有効量の少なくとも1つのcdk4阻害剤を、工程b)においてcdk4阻害に感受性であると同定された対象に投与することを含む方法。 - 前記Y88リン酸化レベルが1であり、前記対象がcdk4阻害剤療法に応答性である、請求項1に記載の方法。
- 前記Y88リン酸化レベルが2であり、前記対象がcdk4阻害剤療法に応答性である、請求項1に記載の方法。
- 前記Y88リン酸化レベルが3であり、前記対象がcdk4阻害剤療法に応答性である、請求項1に記載の方法。
- 前記がんが、乳房、脳、甲状腺、前立腺、結腸直腸、膵臓、頸部、胃、子宮内膜、肝臓、膀胱、卵巣、精巣、頭部、首、皮膚、中皮内層、白血球、食道、筋肉、結合組織、肺、副腎、甲状腺、腎臓、骨、および胃の少なくとも1つのがんである、請求項1に記載の方法。
- 前記がんが乳がんである、請求項2に記載の方法。
- 前記対象がヒトである、請求項2に記載の方法。
- 前記cdk4阻害剤が、表2に列挙されるcdk4阻害剤から選択される、請求項1に記載の方法。
- cdk2阻害剤の投与をさらに含む、請求項1に記載の方法。
- 抗がん剤の投与をさらに含む、請求項1に記載の方法。
- 前記cdk4阻害剤が、Alt−Brkミメティックである、請求項1に記載の方法。
- 前記阻害剤がパルボシクリブである、請求項1に記載の方法。
- がん細胞を殺すために前記パルボシクリブと相乗的に働くAlt−Brkミメティックの投与をさらに含む、請求項12に記載の方法。
- 前記Alt−brkミメティックが、エクソン2を欠き、BrkのSH3ドメインを含む、請求項13に記載の方法。
- がん治療においてcdk4活性の阻害の効能を評価するための方法であって、1つ以上のcdk阻害剤サンプルを含む抗がん剤による治療の前および後に前記対象由来のがん細胞を含む生物学的サンプルにおけるp27のpY88リン酸化レベルを比較すること、ならびに0または1、2、もしくは≧3としてレベルを階層化することを含み、Y88リン酸化レベルの低下はcdk4阻害およびがん細胞増殖の低下の効能と相関し、Y88の増加はcdk4阻害剤療法の効能の低下または減少と相関する、方法。
- 請求項1に記載の方法を実施するためのキットであって、該キットはp27におけるY88及び/又はY89のリン酸化レベルを決定するのに適した試薬を含み、該試薬はリン酸化および非リン酸化Y88及び/又はY89の検出に免疫学的に特異的な抗体を含み、前記抗体は天然に存在しない検出可能な標識を含みかつ/または固体支持体に任意選択的に付けられており、該キットはリン酸化および非リン酸化Y88及び/又はY89抗原を含む、キット。
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