JP6215234B2 - 鼻咽頭癌の治療方法 - Google Patents
鼻咽頭癌の治療方法 Download PDFInfo
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- JP6215234B2 JP6215234B2 JP2014554798A JP2014554798A JP6215234B2 JP 6215234 B2 JP6215234 B2 JP 6215234B2 JP 2014554798 A JP2014554798 A JP 2014554798A JP 2014554798 A JP2014554798 A JP 2014554798A JP 6215234 B2 JP6215234 B2 JP 6215234B2
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
本出願は、2012年1月24日に出願された米国特許仮出願第61/590,115号に対する優先権を主張する。前述の出願の全内容が、参照により本明細書に組み込まれる。
本出願は、電子的に読み取り可能な形式で、本明細書と一緒に提出される配列表を含む。本電子配列ファイルは、2013年1月22日に作成され、「sequencelisting.txt」と題し、16.8キロバイト(17,249バイト)の大きさを有する。この電子sequencelisting.txtファイルの配列表の全内容が、この参照により本明細書に組み込まれる。
上記に加えて、本発明は以下を提供する:
(項目1)
鼻咽頭癌の治療方法であって、鼻咽頭癌腫瘍試料が核因子カッパ−B(NFκB)p65免疫組織化学(IHC)アッセイによって測定される201〜300のHスコアを有することを特徴とする患者に、治療上有効量の式(I)の化合物:
またはその薬学的に許容される塩もしくは薬学的組成物もしくはボロン酸無水物を投与することを含み、
式中、Z 1 およびZ 2 はそれぞれ独立して、ヒドロキシ、アルコキシ、アリールオキシ、またはアラルコキシであるか、あるいはZ 1 およびZ 2 が一緒になって、ボロン酸錯化剤に由来する部分を形成する、前記方法。
(項目2)
前記NFκB p65 IHCアッセイによって測定される前記Hスコアが、230〜300である、項目1に記載の方法。
(項目3)
前記NFκB p65 IHCアッセイによって測定される前記Hスコアが、250〜300である、項目1に記載の方法。
(項目4)
前記NFκB p65 IHCアッセイが、配列番号1の配列を有するタンパク質に結合する抗体の使用を含む、項目1に記載の方法。
(項目5)
前記NFκB p65 IHCアッセイが、配列番号1、2、3、および4の配列を有するタンパク質の総量を測定する、項目1に記載の方法。
(項目6)
前記NFκB p65 IHCアッセイが、細胞質中に存在する前記NFκB p65の量を測定する、項目1に記載の方法。
(項目7)
前記式(I)の化合物が、静脈内投与される、項目1〜6のいずれかに記載の方法。
(項目8)
前記式(I)の化合物が、経口投与される、項目1〜6のいずれかに記載の方法。
(項目9)
前記式(I)の化合物が、28日周期のうちの1、8、および15日目に投与される、項目1〜6のいずれかに記載の方法。
(項目10)
前記式(I)の化合物が、21日周期のうちの1、4、8、および11日目に投与される、項目1〜6のいずれかに記載の方法。
(項目11)
前記式(I)の化合物が、式(III−A):
(項目12)
前記NFκB p65 IHCアッセイによって測定される前記Hスコアが、230〜300である、項目11に記載の方法。
(項目13)
前記NFκB p65 IHCアッセイによって測定される前記Hスコアが、250〜300である、項目11に記載の方法。
(項目14)
前記NFκB p65 IHCアッセイが、配列番号1の配列を有するタンパク質に結合する抗体の使用を含む、項目11に記載の方法。
(項目15)
前記NFκB p65 IHCアッセイが、配列番号1、2、3、および4の配列を有するタンパク質の総量を測定する、項目11に記載の方法。
(項目16)
前記NFκB p65 IHCアッセイが、細胞質中に存在する前記NFκB p65の量を測定する、項目11に記載の方法。
(項目17)
前記式(III−A)の化合物が、静脈内投与される、項目11〜16のいずれかに記載の方法。
(項目18)
前記式(III−A)の化合物が、経口投与される、項目11〜16のいずれかに記載の方法。
(項目19)
前記式(III−A)の化合物が、1つ以上のカプセルで投与される、項目18に記載の方法。
(項目20)
前記式(III−A)の化合物が、28日周期のうちの1、8、および15日目に投与される、項目11〜16のいずれかに記載の方法。
(項目21)
前記式(III−A)の化合物が、21日周期のうちの1、4、8、および11日目に投与される、項目11〜16のいずれかに記載の方法。
(項目22)
前記式(III−A)の化合物の量が、前記式(II)の化合物の量に基づいて約2.3mg〜約5.5mgである、項目11〜16のいずれかに記載の方法。
(項目23)
式(I)の化合物:
またはその薬学的に許容される塩もしくは薬学的組成物もしくはボロン酸無水物を用いて、鼻咽頭癌に罹患している患者を治療するかどうかを決定するための方法であって、
式中、Z 1 およびZ 2 はそれぞれ独立して、ヒドロキシ、アルコキシ、アリールオキシ、またはアラルコキシであるか、あるいはZ 1 およびZ 2 が一緒になって、ボロン酸錯化剤に由来する部分を形成し、
a)前記患者からの鼻咽頭癌腫瘍試料中のNFκB p65のレベルを、NFκB p65 IHCアッセイによって決定されるHスコアとして測定することと、
b)前記鼻咽頭癌腫瘍試料が、NFκB p65 IHCアッセイによって測定される201〜300のHスコアを有することを特徴とする場合、治療上有効量の式(I)の化合物またはその薬学的に許容される塩もしくは薬学的組成物もしくはボロン酸無水物を用いて、前記患者を治療することを決定することと、を含む、前記方法。
(項目24)
前記NFκB p65 IHCアッセイによって測定される前記Hスコアが、230〜300である、項目23に記載の方法。
(項目25)
前記NFκB p65 IHCアッセイによって測定される前記Hスコアが、250〜300である、項目23に記載の方法。
(項目26)
前記NFκB p65 IHCアッセイが、配列番号1の配列を有するタンパク質に結合する抗体の使用を含む、項目23に記載の方法。
(項目27)
前記NFκB p65 IHCアッセイが、配列番号1、2、3、および4の配列を有するタンパク質の総量を測定する、項目23に記載の方法。
(項目28)
前記NFκB p65 IHCアッセイが、細胞質中に存在する前記NFκB p65の量を測定する、項目23に記載の方法。
(項目29)
前記式(I)の化合物が、静脈内投与される、項目23〜28のいずれかに記載の方法。
(項目30)
前記式(I)の化合物が、経口投与される、項目23〜28のいずれかに記載の方法。
(項目31)
前記式(I)の化合物が、28日周期のうちの1、8、および15日目に投与される、項目23〜28のいずれかに記載の方法。
(項目32)
前記式(I)の化合物が、21日周期のうちの1、4、8、および11日目に投与される、項目23〜28のいずれかに記載の方法。
(項目33)
前記式(I)の化合物が、式(III−A):
を特徴とするか、またはその薬学的組成物である、項目23に記載の方法。
(項目34)
前記NFκB p65 IHCアッセイによって測定される前記Hスコアが、230〜300である、項目33に記載の方法。
(項目35)
前記NFκB p65 IHCアッセイによって測定される前記Hスコアが、250〜300である、項目33に記載の方法。
(項目36)
前記NFκB p65 IHCアッセイが、配列番号1の配列を有するタンパク質に結合する抗体の使用を含む、項目33に記載の方法。
(項目37)
前記NFκB p65 IHCアッセイが、配列番号1、2、3、および4の配列を有するタンパク質の総量を測定する、項目33に記載の方法。
(項目38)
前記NFκB p65 IHCアッセイが、細胞質中に存在する前記NFκB p65の量を測定する、項目33に記載の方法。
(項目39)
前記式(III−A)の化合物が、静脈内投与される、項目33〜38のいずれかに記載の方法。
(項目40)
前記式(III−A)の化合物が、経口投与される、項目33〜38のいずれかに記載の方法。
(項目41)
前記式(III−A)の化合物が、1つ以上のカプセルで投与される、項目40に記載の方法。
(項目42)
前記式(III−A)の化合物が、28日周期のうちの1、8、および15日目に投与される、項目33〜38のいずれかに記載の方法。
(項目43)
前記式(III−A)の化合物が、21日周期のうちの1、4、8、および11日目に投与される、項目33〜38のいずれかに記載の方法。
(項目44)
前記式(III−A)の化合物の量が、前記式(II)の化合物の量に基づいて約2.3mg〜約5.5mgである、項目33〜38のいずれかに記載の方法。
式中、Z1およびZ2はそれぞれ独立して、ヒドロキシ、アルコキシ、アリールオキシ、またはアラルコキシであるか、あるいはZ1およびZ2が一緒になって、ボロン酸錯化剤に由来する部分を形成する。
式中、Z1およびZ2はそれぞれ独立して、ヒドロキシ、アルコキシ、アリールオキシ、またはアラルコキシであるか、あるいはZ1およびZ2が一緒になって、ボロン酸錯化剤に由来する部分を形成する。
式中、Z1およびZ2はそれぞれ独立して、ヒドロキシ、アルコキシ、アリールオキシ、またはアラルコキシであるか、あるいはZ1およびZ2が一緒になって、ボロン酸錯化剤に由来する部分を形成する。
式中、Z1およびZ2はそれぞれ独立して、ヒドロキシ、アルコキシ、アリールオキシ、またはアラルコキシであるか、あるいはZ1およびZ2が一緒になって、ボロン酸錯化剤に由来する部分を形成し、
本方法は、
a)この患者からの鼻咽頭癌腫瘍試料中のNFκB p65のレベルを、NFκB p65 IHCアッセイによって決定されるHスコアとして測定することと、
b)この鼻咽頭癌腫瘍試料が、NFκB p65 IHCアッセイによって測定される201〜300のHスコアを有することを特徴とする場合、治療上有効量の式(I)の化合物またはその薬学的に許容される塩もしくは薬学的組成物もしくはボロン酸無水物を用いて、この患者を治療することを決定することと、を含む。
式(I)の化合物の薬学的に許容される塩が、これらの組成物に使用される場合、その塩は、好ましくは、無機または有機酸または塩基に由来する。好適な塩の検証については、例えば、Berge et al,J.Pharm.Sci.66:1−19(1977)、およびRemington:The Science and Practice of Pharmacy,20th Ed.,ed.A.Gennaro,Lippincott Williams & Wilkins,2000を参照のこと。
式(II)の化合物[(1R)−1−({[(2,5−ジクロロベンゾイル)アミノ]アセチル}アミノ)−3−メチルブチル]ボロン酸は、OlhavaおよびDancaの米国特許第7,442,830号(参照によりその全体が本明細書に組み込まれる)に開示される方法によって調製される。式(III−A)の化合物2,2’−{2−[(1R)−1−({[(2,5−ジクロロベンゾイル)アミノ]アセチル}アミノ)−3−メチルブチル]−5−オキソ−1,3,2−ジオキサボロラン−4,4−ジイル}二酢酸は、Elliottらの国際公開第WO09/154737号(参照によりその全体が本明細書に組み込まれる)に開示される方法によって調製される。式(III−A)の化合物の経口カプセル製剤は、Elliottらの国際公開第WO09/154737号(参照によりその全体が本明細書に組み込まれる)に開示される方法によって調製される。式(III−A)の化合物のIV製剤は、Elliottらの国際公開第WO09/154737号(参照によりその全体が本明細書に組み込まれる)に開示される方法によって調製される。IV製剤に再構成するのに好適な式(III−A)の化合物の凍結乾燥製剤は、Elliottらの国際公開第WO09/154737号(参照によりその全体が本明細書に組み込まれる)に開示される方法によって調製される。
事前に調製されたホルマリン固定パラフィン包埋(FFPE)免疫組織化学(IHC)のスライドを、Sakura DRSスライド着色剤上でキシレンおよび段階的アルコールを使用して脱パラフィン化し、次いで、3% H2O2中で5分間インキュベートする。このスライドを、pH6で、クエン酸塩緩衝剤中で、蒸気を用いて30分間処理する。次いで、スライドを、湿潤チャンバー内で、NFκB p65抗原ウサギモノクローナル抗体[Cell Signaling Technologies、クローン(C22B4) #4764]の1:50の溶液で一晩処理する。一晩インキュベートした後、スライドを洗浄し、Dako Autostainer上に置き、二次抗体(Ultravision,Thermo Fisher)およびDAB+基質(Dako)で現像させる。現像後、スライドを脱イオン水で洗浄し、Meyerのヘマトキシリンを使用して対比染色し、脱水し、カバースリップした。
(1)原発性鼻咽頭癌の組織マイクロアレイ(US Biomax,Inc.から得られる)(n=35)
(2)転移性鼻咽頭癌の組織マイクロアレイ(US Biomax,Inc.から得られる)(n=15)
(3)頭頸部癌の他の組織構造の組織マイクロアレイ(US Biomax,Inc.から得られる)(n=68)
(4)頭頸部扁平上皮癌に罹患している患者のアーカイブ原発腫瘍の生検試料(n=14)。すべての試料は、適切なインフォームドコンセント下で得られた。患者は、週に2回のスケジュール(21日周期のうちの1、4、8、および11日目)で、IV注入として、式(III−A)の化合物を投与された。
事前に調製されたFFPE IHCのスライドを、Sakura DRSスライド着色剤上でキシレンおよび段階的アルコールを使用して脱パラフィン化し、次いで、3% H2O2中で5分間インキュベートする。このスライドを、pH6で、クエン酸塩緩衝剤中で、蒸気を用いて30分間処理する。次いで、スライドを、Dako Autostainer上で、NFκB p65抗原ヤギポリクローナル抗体[Santa Cruz, sc−372−G]の1:200の溶液で1時間処理する。1時間のインキュベーション後、このスライドを、二次抗体(Bio−goat Elite(Vector)およびDAB+基質(Dako)で現像させる。現像後、スライドを脱イオン水で洗浄し、Meyerのヘマトキシリンを使用して対比染色し、脱水し、カバースリップした。
事前に調製されたFFPE IHCのスライドを、Sakura DRSスライド着色剤上でキシレンおよび段階的アルコールを使用して脱パラフィン化し、次いで、3% H2O2中で5分間インキュベートする。スライドを、pH6で、クエン酸塩緩衝剤中、マイクロ波圧力鍋内で8分間処理する。次いで、スライドを、Dako Autostainer上で、NFκB p65抗原ウサギポリクローナル抗体[Invitrogen、51−0500]の1:200の溶液で1時間処理する。1時間のインキュベーション後、このスライドを、二次抗体(Ultravision、Thermo Fisher)およびDAB+基質(Dako)で現像させる。現像後、スライドを脱イオン水で洗浄し、Meyerのヘマトキシリンを使用して対比染色し、脱水し、カバースリップした。
組織マイクロアレイ切片および商業的供給源からの全鼻咽頭腫瘍切片は、実施例2に記載される方法によってアッセイされた。200を上回るHスコアを有した試料の罹患率は、組織マイクロアレイ試料(n=20)については、35%であり、全組織切片(n=35)については、31%であった。
商業的供給源からの全鼻咽頭腫瘍切片は、実施例2に記載される方法によってアッセイされた。
Claims (20)
- 鼻咽頭癌の治療のための組成物であって、式(III−A)の化合物:
前記組成物が、鼻咽頭癌腫瘍試料が核因子カッパ−B(NFκB)p65免疫組織化学(IHC)アッセイによって測定される300のHスコアを有することを特徴とする患者に投与される、前記組成物。 - 前記NFκB p65 IHCアッセイが、配列番号1の配列を有するタンパク質に結合する抗体の使用を含む、請求項1に記載の組成物。
- 前記NFκB p65 IHCアッセイが、配列番号1、2、3、および4の配列を有するタンパク質の総量を測定する、請求項1に記載の組成物。
- 前記NFκB p65 IHCアッセイが、細胞質中に存在する前記NFκB p65の量を測定する、請求項1に記載の組成物。
- 前記組成物が、静脈内投与されることを特徴とする、請求項1〜4のいずれかに記載の組成物。
- 前記組成物が、経口投与されることを特徴とする、請求項1〜4のいずれかに記載の組成物。
- 前記組成物が、28日周期のうちの1、8、および15日目に投与されることを特徴とする、請求項1〜4のいずれかに記載の組成物。
- 前記組成物が、21日周期のうちの1、4、8、および11日目に投与されることを特徴とする、請求項1〜4のいずれかに記載の組成物。
- 前記組成物が、1つ以上のカプセルで投与されることを特徴とする、請求項1〜8のいずれかに記載の組成物。
- 前記式(III−A)の化合物の量が、式(II)の化合物
- 鼻咽頭癌腫瘍試料においてNFκB p65 IHCアッセイによって決定されるHスコアを、
式(III−A)の化合物:
前記方法は、前記患者からの前記鼻咽頭癌腫瘍試料中のNFκB p65のレベルを、前記Hスコアとして測定することを含み、
前記鼻咽頭癌腫瘍試料が、前記NFκB p65 IHCアッセイによって測定される300の前記Hスコアを有することを特徴とする場合、前記式(III−A)の化合物またはその前記薬学的に許容される塩を含む医薬を用いて、前記患者を治療すべきとすることを特徴とする、前記方法。 - 前記NFκB p65 IHCアッセイが、配列番号1の配列を有するタンパク質に結合する抗体の使用を含む、請求項11に記載の方法。
- 前記NFκB p65 IHCアッセイが、配列番号1、2、3、および4の配列を有するタンパク質の総量を測定する、請求項11に記載の方法。
- 前記NFκB p65 IHCアッセイが、細胞質中に存在する前記NFκB p65の量を測定する、請求項11に記載の方法。
- 前記式(III−A)の化合物を含む前記医薬が、静脈内投与のために製剤化される、請求項11〜14のいずれかに記載の方法。
- 前記式(III−A)の化合物を含む前記医薬が、経口投与のために製剤化される、請求項11〜14のいずれかに記載の方法。
- 前記式(III−A)の化合物を含む前記医薬が、28日周期のうちの1、8、および15日目の投与のために製剤化される、請求項11〜14のいずれかに記載の方法。
- 前記式(III−A)の化合物を含む前記医薬が、21日周期のうちの1、4、8、および11日目の投与のために製剤化される、請求項11〜14のいずれかに記載の方法。
- 前記式(III−A)の化合物を含む前記医薬が、1つ以上のカプセルでの投与のために製剤化される、請求項11〜18のいずれかに記載の方法。
- 前記式(III−A)の化合物の量が、式(II)の化合物
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EP2812338A4 (en) | 2015-09-23 |
EP2812338A1 (en) | 2014-12-17 |
CN104271583B (zh) | 2017-10-24 |
US20140357596A1 (en) | 2014-12-04 |
CN104271583A (zh) | 2015-01-07 |
JP2015508058A (ja) | 2015-03-16 |
US20170157155A1 (en) | 2017-06-08 |
CA2862320A1 (en) | 2013-08-01 |
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