JP6411379B2 - レンバチニブ化合物に対する子宮内膜がん対象の応答性を予測及び評価するためのバイオマーカー - Google Patents
レンバチニブ化合物に対する子宮内膜がん対象の応答性を予測及び評価するためのバイオマーカー Download PDFInfo
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- JP6411379B2 JP6411379B2 JP2015555882A JP2015555882A JP6411379B2 JP 6411379 B2 JP6411379 B2 JP 6411379B2 JP 2015555882 A JP2015555882 A JP 2015555882A JP 2015555882 A JP2015555882 A JP 2015555882A JP 6411379 B2 JP6411379 B2 JP 6411379B2
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- Spectroscopy & Molecular Physics (AREA)
Description
「減少した/低減された発現レベル」という用語は、対照における発現レベルより低い発現レベル(量)を意味する。
子宮内膜がんとは、子宮の子宮内膜又は内壁から生じる、数種類の悪性病変を指す。大半の子宮内膜がんは癌腫(一般には腺癌)である。換言すれば子宮内膜がんは、子宮内膜を覆い、子宮筋層腺を形成する1層の上皮細胞に由来する。子宮内膜癌は、以下の2群に分類されることがある:I型は、閉経前及び閉経期の女性に見られるがんを含み、一般に低侵襲である;II型は、より年配の、閉経後の女性で起き、I型よりも予後の悪いがんを含む。まれに見られる子宮内膜間質肉腫は、子宮内膜癌とは対照的に、子宮内膜の非腺部の結合組織に由来するがんである。
レンバチニブ化合物(例えば、レンバチニブメシル酸塩)を含む治療に対する、子宮内膜がんを有する対象の応答性を予測する際に発現レベル(例えば、mRNA又はタンパク質発現レベル)が有用ないくつかの遺伝子が同定されている。遺伝子ID、関連するURL、タンパク質ID及びUniProtKB受託番号により特定されるこれらの遺伝子を表1に列挙する。
上記のように、本発明の方法は、子宮内膜がんを有する、有することが疑われる、又は発症するリスクのある対象由来の生体試料において、1個又は複数の遺伝子(例えば、表1に示す1個又は複数の遺伝子)の発現レベル(例えば、mRNA又はタンパク質濃度)を測定するステップを伴うことがあり、ここで、1個又は複数の前記遺伝子の発現レベルは、それを対照と比べることで、レンバチニブ化合物(例えば、レンバチニブメシル酸塩)を含む治療に対する対象の応答を予測する。ある特定の実施形態では、子宮内膜がんを有する、有することが疑われる、又は発症するリスクのある対象由来の生体試料における、表1のタンパク質の濃度が対照より低い場合、前記対象は、レンバチニブ化合物を含む治療に応答する可能性が高いと認定される。この文脈では「対照」という用語は、レンバチニブ化合物(例えば、レンバチニブメシル酸塩)を含む治療に応答しないと分かっている対象から得られた試料(同一組織由来)を含む。「対照」という用語は、レンバチニブ化合物を含む治療に応答しないと分かっている対象から過去に得られた試料(同一組織由来)であって、治療応答性を予測しようする対象から採られる検査試料と後に比較するための参照として使用される試料も含む。特定の細胞種又は組織での、特定のタンパク質についての「対照」発現レベル/濃度は、レンバチニブ化合物(例えば、レンバチニブメシル酸塩)による治療に応答しなかった1又は複数の(例えば、2、3、4、5、6、7、8、9、10、15、20、25、30、35若しくは40個体、又はそれを超える)同種の対象におけるタンパク質発現解析によって、予め設定しておいてもよい。この予め設定された参照値(治療に応答しなかった複数個体の対象から得た発現レベル/濃度の平均又は中央値であってよい)は次に、タンパク質又は核酸の「対照」濃度/発現レベルとして、検査試料との比較に使用することができる。このような比較では、解析している遺伝子の発現レベルが、予め設定された参照より低い場合、対象は、レンバチニブ化合物(例えば、レンバチニブメシル酸塩)を含む治療に応答すると予測される。
一部の実施形態では、本明細書に記載されている方法は、目的のタンパク質(複数可)の濃度(例えば、表1に列挙した1個又は複数のタンパク質)が所定のカットオフ値を超えるか又は下回るかを決定するステップを含む。
本明細書に記載されている方法に適した生体試料としては、目的の検体生体分子、例えばタンパク質又は核酸(例えば、DNA又はmRNA)などを含むあらゆる体液、細胞、組織又はその画分が挙げられる。生体試料は、例えば、対象(例えば、ヒトなどの哺乳動物)から得られた検体であってもよいし、このような対象に由来していてもよい。試料は、例えば、生検により得られた組織切片、保管腫瘍組織、又は組織培養されている、若しくは組織培養に適合させた細胞であってもよい。生体試料は、血液、血漿、血清若しくは尿などの体液、又はこのような試料を基材(例えば、ガラス、ポリマー、紙)に吸収させたものとすることもできる。生体試料としては、子宮内膜組織試料を挙げることもできる。特定の実施形態では、前記生体試料が、腫瘍又は前がん病変を含むと疑われる対象の領域から得られた腫瘍細胞(複数可)又は腫瘍組織である。例えば、前記生体試料が子宮内膜腫瘍試料であってもよい。必要に応じて、生体試料は、特定の細胞種を含む画分へとさらに分画することができる。血液試料は、例えば、血清へと分画することも、赤血球細胞又は白血球細胞(白血球)などの特定の種類の血球細胞を含む諸画分へと分画することもできる。必要に応じて、試料は、対象由来の諸試料の組合せ、例えば、組織試料及び液体試料の組合せとしてもよい。
遺伝子発現は、標的遺伝子の例えばタンパク質又はRNA発現として検出することができる。つまり、遺伝子の存在又は発現レベル(量)は、その遺伝子のmRNA又はタンパク質発現のレベルを検出及び/又は測定することによって決定できる。一部の実施形態では、遺伝子発現は、ある遺伝子、例えば表1に示す遺伝子にコードされるタンパク質の活性として検出することができる。
本明細書に記載の方法は、子宮内膜がんを有する対象についてのレンバチニブ化合物(例えば、レンバチニブメシル酸塩)治療応答プロファイルを作成するためにも使用され得る。このプロファイルは、例えば、レンバチニブ又はその薬学的に許容される塩での治療の前及び後の1種又は複数の遺伝子(例えば、表1に示されている1種又は複数の遺伝子)の発現レベルを示す情報;並びに/又は任意の子宮内膜腫瘍の組織学的分析を含み得る。本明細書に記載の応答プロファイルは、表1に列挙した少なくとも2種、少なくとも3種、少なくとも4種、少なくとも5種、少なくとも6種、少なくとも7種、少なくとも8種、少なくとも9種又は少なくとも10種の遺伝子の発現又は発現レベルについての情報を含み得る。結果として得られる情報(レンバチニブ治療応答プロファイル)は、子宮内膜がんを有する、有することが疑われる、又は発症するリスクのある対象(例えば、ヒト患者)の、レンバチニブ化合物(例えば、レンバチニブメシル酸塩)を含む治療に対する応答を予測するために使用され得る。
本明細書に開示の方法は、子宮内膜がんを有する、有することが疑われる、又は発症するリスクのある対象が、レンバチニブ化合物(例えば、レンバチニブメシル酸塩)を含む治療に応答する可能性が高いかどうかの評価を可能にする。子宮内膜がんを有する、有することが疑われる、又は発症するリスクのある、レンバチニブ化合物に応答する可能性が高い対象は、レンバチニブ又はその薬学的に許容される塩(例えば、レンバチニブメシル酸塩)を投与され得る。逆に、レンバチニブ化合物に応答する可能性が低い、子宮内膜がんを有する、有することが疑われる、又は発症するリスクのある対象には、子宮内膜がんの治療に好適な別の治療が行われ得る。
本明細書に開示の核酸バイオマーカーを含む核酸アレイは、例えば、遺伝子発現の検出及び/又は遺伝子発現レベルの測定に有用である。このアレイは、例えば、子宮内膜がんを有する対象の、レンバチニブ又はその薬学的に許容される塩(例えば、レンバチニブメシル酸塩)を含む治療に対する応答を予測すること、レンバチニブ又はその薬学的に許容される塩(例えば、レンバチニブメシル酸塩)を含む治療から利益を受け得る、子宮内膜がんを有する対象を認定すること、及びレンバチニブ又はその薬学的に許容される塩(例えば、レンバチニブメシル酸塩)を含む治療から利益を受ける可能性が低い、子宮内膜がんを有する対象を他のがん治療に導くことにも有用である。
本出願は、キットも提供する。ある特定の実施形態では、キットは、表1に列挙したバイオマーカーのうちの1種又は複数又はそれらの濃度若しくは発現レベルの検出に使用可能な1種又は複数の抗体を含んでいてもよい。例えば、キットは、特異的にAng2を結合する抗体を含んでいてもよい。キット中の抗体は、モノクローナル又はポリクローナルであってもよく、検出可能な標識とさらにコンジュゲートされていてもよい。一部の実施形態では、キットは、表1のうちの任意のバイオマーカーの同定又は検出に使用可能なプローブを含む。一部の実施形態では、キットは、本明細書に記載の任意の核酸アレイを含む。一部の実施形態では、キットは、表1のうちの任意のバイオマーカー又はそれらの発現若しくは発現レベルの同定又は検出に使用可能なプローブ及び抗体を含む。キットは、任意選択で、生体試料中の1種又は複数のタンパク質の濃度又はmRNAのレベルを検出及び/又は測定するための説明書を含んでいてもよい。
(i)マイクロプレート(例えば、96ウェルプレート)。このマイクロプレートは、検出可能な標識とコンジュゲートされている抗Ang2抗体でコーティングされていてもよい。抗Ang2抗体は、モノクローナル又はポリクローナルであってもよい。抗体は、例えば、マウス、ウサギ、ラット又はモルモット由来であってもよい。検出可能な標識は、例えば、ワサビペルオキシダーゼ、ビオチン、蛍光部分、放射性部分、ヒスチジンタグ又はペプチドタグであってもよい。マイクロプレートは、カバー及び任意選択で、1種又は複数の接着性ストリップと共に提供されてもよい。
(ii)検出可能な標識とコンジュゲートされている抗Ang2を含んでいるバイアル。検出可能な標識は、例えば、ワサビペルオキシダーゼ、ビオチン、蛍光部分、ヒスチジンタグ、ペプチドタグであってもよい。このバイアルは、保存剤も含んでいてもよい。
(iii)既知の濃度のAng2標準を含んでいるバイアル。Ang2は、組換えヒトAng2であってもよい。
(iv)アッセイ希釈液を含んでいるバイアル。
(v)キャリブレーター希釈液を含んでいるバイアル。
(vi)洗浄緩衝液を含んでいるバイアル。この緩衝液は、濃縮物として提供されてもよい。
(vii)呈色試薬を含んでいる1本又は複数のバイアル
(viii)比色反応を停止するための停止液を含んでいるバイアル。
(b)生存利益:無増悪生存期間(PFS)/全生存期間(OS)。
(a)腫瘍応答:奏効率(ORR);及び
(b)生存利益:全生存期間(OS)。
Evaluating the Safety and Efficacy of Oral E7080 in Medullary and Iodine−131 Refractory,Unresectable Differentiated Thyroid Cancers,Stratified by Histology(ClinicalTrials.gov Identifier:NCT00784303)
Study of E7080 in Patients With Advanced Hepatocellular Carcinoma(HCC)(ClinicalTrials.gov Identifier:NCT00946153)
A Study in Subjects With Recurrent Malignant Glioma(ClinicalTrials.gov Identifier:NCT01137604)
Study of E7080 in Subjects With Advanced Endometrial Cancer and Disease Progression(ClinicalTrials.gov Identifier:NCT01111461)
An Open−Label,2−Cohort,Multicenter,Study of E7080 in Previously Treated Subjects With Unresectable Stage III or Stage IV Melanoma(ClinicalTrials.gov Identifier:NCT01136967)
本発明の特定の実施形態は、以下の通りである:
[1] 子宮内膜がんを治療する方法であって、子宮内膜がんを有するヒト対象に治療有効量のレンバチニブ又はその薬学的に許容される塩を投与するステップを含み、前記ヒト対象が、対照に比べて低いAng2タンパク質発現レベルを有すると認定されている、方法。
[2] 前記ヒト対象が、前記ヒト対象から得られた生体試料において低濃度のAng2タンパク質を有すると認定されている、[1]に記載の方法。
[3] 子宮内膜がんを治療する方法であって、子宮内膜がんを有するヒト対象から得られる生体試料を用意するステップと、前記生体試料において、対照に比べて低いAng2タンパク質発現レベルを測定するステップと、前記ヒト対象に治療有効量のレンバチニブ又はその薬学的に許容される塩を投与するステップとを含む、方法。
[4] 子宮内膜がんを有する、有することが疑われる、又は発症するリスクのあるヒト対象の、レンバチニブ又はその薬学的に許容される塩を含む治療に対する応答を予測する方法であって、前記ヒト対象から得られた生体試料をアッセイし、前記生体試料におけるAng2タンパク質の濃度が、対照に比べて低いことを決定するステップと、前記生体試料において低濃度のAng2タンパク質を有する前記ヒト対象を、レンバチニブ又はその薬学的に許容される塩を含む治療に応答する可能性が高いと認定するステップとを含む、方法。
[5] 子宮内膜がんを有する、有することが疑われる、又は発症するリスクのあるヒト対象の、レンバチニブ又はその薬学的に許容される塩を含む治療に対する応答を予測する方法であって、前記ヒト対象から得られた生体試料をアッセイし、前記生体試料におけるAng2タンパク質の濃度が、対照に比べて高いことを決定するステップと、前記生体試料において高濃度のAng2タンパク質を有する前記ヒト対象を、レンバチニブ又はその薬学的に許容される塩を含む治療に応答する可能性が低いと認定するステップとを含む、方法。
[6] 子宮内膜がんを有する、有することが疑われる、又は発症するリスクのあるヒト対象の、レンバチニブ又はその薬学的に許容される塩を含む治療に対する応答の予測を補助する方法であって、前記ヒト対象から得られた生体試料をアッセイし、前記生体試料におけるAng2タンパク質の濃度が、対照に比べて低いことを決定するステップと、前記生体試料において低濃度のAng2タンパク質を有する前記ヒト対象を、レンバチニブ又はその薬学的に許容される塩を含む治療に応答する可能性が高いと認定するステップとを含む、方法。
[7] 子宮内膜がんを有する、有することが疑われる、又は発症するリスクのあるヒト対象の、レンバチニブ又はその薬学的に許容される塩を含む治療に対する応答の予測を補助する方法であって、前記ヒト対象から得られた生体試料をアッセイし、前記生体試料におけるAng2タンパク質の濃度が、対照に比べて高いことを決定するステップと、前記生体試料において高濃度のAng2タンパク質を有する前記ヒト対象を、レンバチニブ又はその薬学的に許容される塩を含む治療に応答する可能性が低いと認定するステップとを含む、方法。
[8] 前記生体試料が、血液試料、血清試料、血漿試料、子宮内膜保管腫瘍試料、及び子宮内膜生検試料からなる群から選択される、[2]〜[7]のいずれか一項に記載の方法。
[9] 前記生体試料が血漿試料である、[2]〜[7]のいずれか一項に記載の方法。
[10] 前記子宮内膜がんが進行子宮内膜がんである、[1]〜[9]のいずれか一項に記載の方法。
[11] 前記子宮内膜がんが、切除不能なステージIII又はステージIVの子宮内膜がんである、[1]〜[9]のいずれか一項に記載の方法。
[12] 前記子宮内膜がんが再発子宮内膜がんである、[1]〜[9]のいずれか一項に記載の方法。
[13] 前記対照が、予め設定されたカットオフ値である、[1]〜[12]のいずれか一項に記載の方法。
[14] 前記予め設定されたカットオフ値が、カットオフなしに比べてより高い陽性的中率で腫瘍応答を予測する、受信者動作特性解析に基づいて決定されるAng2タンパク質濃度であり、前記予め設定されたカットオフ値以下のAng2タンパク質の濃度が低濃度のAng2であり、前記予め設定されたカットオフ値より高い値が高濃度のAng2である、[13]に記載の方法。
[15] 腫瘍応答が奏効率、臨床的有用率、又は少なくとも30%の最大腫瘍縮小率(%)である、[14]に記載の方法。
[16] 前記予め設定されたカットオフ値が、カットオフで分けられた2群へと分離するシミュレーションモデルを使用して生存期間を予測することに基づいて決定されるAng2タンパク質濃度であり、前記予め設定されたカットオフ値以下のAng2タンパク質の濃度が低濃度のAng2であり、前記予め設定されたカットオフ値より高い値が高濃度のAng2である、[13]に記載の方法。
[17] 生存期間が無増悪生存期間又は全生存期間である、[16]に記載の方法。
[18] 前記予め設定されたカットオフ値が、1866.5〜6024.5pg/mlの範囲内のAng2タンパク質濃度であり、前記予め設定されたカットオフ値以下のAng2タンパク質の濃度が低濃度のAng2であり、前記予め設定されたカットオフ値より高い値が高濃度のAng2である、[13]に記載の方法。
[19] タンパク質の濃度が免疫学的方法で測定される、[1]〜[18]のいずれか一項に記載の方法。
[20] 前記免疫学的方法が、酵素イムノアッセイ、ラジオイムノアッセイ、化学発光イムノアッセイ、電気化学発光イムノアッセイ、ラテックス比濁イムノアッセイ、ラテックス光学イムノアッセイ、イムノクロマトグラフィーアッセイ及びウェスタンブロッティングからなる群から選択される、[19]に記載の方法。
[21] タンパク質濃度が質量分析法によって測定される、[1]〜[18]のいずれか一項に記載の方法。
[22] レンバチニブの薬学的に許容される前記塩がレンバチニブメシル酸塩である、[1]〜[21]のいずれか一項に記載の方法。
[23] ヒト対象における子宮内膜がん治療に使用するためのレンバチニブ又はその薬学的に許容される塩であって、前記ヒト対象が、レンバチニブ又はその薬学的に許容される塩を含む治療に応答する可能性が高い対象として、[4]に記載の方法により認定される、レンバチニブ又はその薬学的に許容される塩。
[24] 子宮内膜がんを有する、有することが疑われる、又は発症するリスクのあるヒト対象の、レンバチニブ又はその薬学的に許容される塩を含む治療に対する応答の予測に使用するためのAng2タンパク質検出剤。
[25] 抗Ang2抗体である、[24]に記載のAng2タンパク質検出剤。
[26] レンバチニブ又はその薬学的に許容される塩を含む、ヒト対象において子宮内膜がんを治療するための医薬組成物であって、前記ヒト対象が、レンバチニブ又はその薬学的に許容される塩を含む治療に応答する可能性が高い対象として、[4]に記載の方法により認定される、医薬組成物。
本発明は、その詳細な説明と併せて記載されているが、上記の記載は、例示することが意図されるものであり、添付の特許請求の範囲の範囲によって規定される、本発明の範囲を制限するものではない。他の態様、利点及び改変形態は、添付の特許請求の範囲の範囲内である。
本出願は、2013年5月14日に出願された米国特許仮出願第61/823034号の利益を主張するものであり、参照によりその開示全体が本明細書に組み込まれている。
Claims (18)
- 子宮内膜がんを有する、有することが疑われる、又は発症するリスクのあるヒト対象の、レンバチニブ又はその薬学的に許容される塩を含む治療に対する応答性の診断を補助する方法であって、
前記ヒト対象から得られた生体試料をアッセイするステップを含み、
前記生体試料におけるAng2タンパク質の濃度が、対照に比べて低いことが、前記ヒト対象がレンバチニブ又はその薬学的に許容される塩を含む治療に応答する可能性が高い指標であることを特徴とする、方法。 - 子宮内膜がんを有する、有することが疑われる、又は発症するリスクのあるヒト対象の、レンバチニブ又はその薬学的に許容される塩を含む治療に対する応答性の診断を補助する方法であって、
前記ヒト対象から得られた生体試料をアッセイするステップを含み、
前記生体試料におけるAng2タンパク質の濃度が、対照に比べて高いことが、前記ヒト対象がレンバチニブ又はその薬学的に許容される塩を含む治療に応答する可能性が低い指標であることを特徴とする、方法。 - 前記生体試料が、血液試料、血清試料、血漿試料、子宮内膜保管腫瘍試料、及び子宮内膜生検試料からなる群から選択される、請求項1又は2に記載の方法。
- 前記生体試料が血漿試料である、請求項1〜3のいずれか一項に記載の方法。
- 前記子宮内膜がんが進行子宮内膜がんである、請求項1〜4のいずれか一項に記載の方法。
- 前記子宮内膜がんが、切除不能なステージIII又はステージIVの子宮内膜がんである、請求項1〜4のいずれか一項に記載の方法。
- 前記子宮内膜がんが再発子宮内膜がんである、請求項1〜4のいずれか一項に記載の方法。
- 前記対照が、予め設定されたカットオフ値である、請求項1〜7のいずれか一項に記載の方法。
- 前記予め設定されたカットオフ値が、カットオフなしに比べてより高い陽性的中率で腫瘍応答を予測する、受信者動作特性解析に基づいて決定されるAng2タンパク質濃度であり、前記予め設定されたカットオフ値以下のAng2タンパク質の濃度が低濃度のAng2であり、予め設定された前記カットオフ値より高い値が高濃度のAng2である、請求項8に記載の方法。
- 腫瘍応答が奏効率、臨床的有用率、又は少なくとも30%の最大腫瘍縮小率(%)である、請求項9に記載の方法。
- 前記予め設定されたカットオフ値が、カットオフで分けられた2群へと分離するシミュレーションモデルを使用して生存期間を予測することに基づいて決定されるAng2タンパク質濃度であり、前記予め設定されたカットオフ値以下のAng2タンパク質の濃度が低濃度のAng2であり、前記予め設定されたカットオフ値より高い値が高濃度のAng2である、請求項8に記載の方法。
- 前記生存期間が無増悪生存期間又は全生存期間である、請求項11に記載の方法。
- 前記予め設定されたカットオフ値が、1866.5〜6024.5pg/mlの範囲内のAng2タンパク質濃度であり、前記予め設定されたカットオフ値以下のAng2タンパク質の濃度が低濃度のAng2であり、前記予め設定されたカットオフ値より高い値が高濃度のAng2である、請求項8に記載の方法。
- タンパク質の濃度が免疫学的方法で測定される、請求項1〜13のいずれか一項に記載の方法。
- 前記免疫学的方法が、酵素イムノアッセイ、ラジオイムノアッセイ、化学発光イムノアッセイ、電気化学発光イムノアッセイ、ラテックス比濁イムノアッセイ、ラテックス光学イムノアッセイ、イムノクロマトグラフィーアッセイ及びウェスタンブロッティングからなる群から選択される、請求項14に記載の方法。
- タンパク質濃度が質量分析法によって測定される、請求項1〜13のいずれか一項に記載の方法。
- レンバチニブの薬学的に許容される前記塩がレンバチニブメシル酸塩である、請求項1〜16のいずれか一項に記載の方法。
- ヒト対象における子宮内膜がん治療に使用するためのレンバチニブ又はその薬学的に許容される塩であって、前記ヒト対象が、レンバチニブ又はその薬学的に許容される塩を含む治療に応答する可能性が高い対象として、請求項1に記載の方法により診断が補助される、レンバチニブ又はその薬学的に許容される塩。
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Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3444363B1 (en) | 2011-06-03 | 2020-11-25 | Eisai R&D Management Co., Ltd. | Biomarkers for prediciting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds |
JP6411379B2 (ja) | 2013-05-14 | 2018-10-24 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | レンバチニブ化合物に対する子宮内膜がん対象の応答性を予測及び評価するためのバイオマーカー |
LT3524595T (lt) | 2014-08-28 | 2022-09-26 | Eisai R&D Management Co., Ltd. | Aukšto grynumo chinolino darinys ir jo gamybos būdas |
WO2016057367A1 (en) * | 2014-10-06 | 2016-04-14 | Dana-Farber Cancer Institute, Inc. | Angiopoietin-2 biomarkers predictive of anti-immune checkpoint response |
RS65049B1 (sr) | 2015-02-25 | 2024-02-29 | Eisai R&D Man Co Ltd | Metoda za suzbijanje gorčine derivata kinolina |
WO2016140717A1 (en) | 2015-03-04 | 2016-09-09 | Merck Sharp & Dohme Corp. | Combination of a pd-1 antagonist and a vegfr/fgfr/ret tyrosine kinase inhibitor for treating cancer |
CA2985596A1 (en) | 2015-05-29 | 2016-12-08 | Eisai R&D Management Co., Ltd. | Biomarkers for a combination therapy comprising lenvatinib and everolimus |
WO2016204193A1 (ja) | 2015-06-16 | 2016-12-22 | 株式会社PRISM Pharma | 抗がん剤 |
KR20190003957A (ko) * | 2016-04-15 | 2019-01-10 | 제넨테크, 인크. | 암 모니터링 및 치료 방법 |
ES2953595T3 (es) | 2017-03-01 | 2023-11-14 | Hoffmann La Roche | Procedimientos diagnósticos y terapéuticos para el cáncer |
WO2020070144A1 (en) * | 2018-10-04 | 2020-04-09 | Synthon B.V. | Crystalline forms and processes of lenvatinib besylate |
EP3861347B1 (en) * | 2018-10-05 | 2022-12-21 | Eisai R&D Management Co., Ltd. | Biomarkers for a combination therapy comprising lenvatinib and everolimus |
WO2021013781A1 (en) * | 2019-07-22 | 2021-01-28 | F. Hoffmann-La Roche Ag | Substance p as blood biomarker for the non-invasive diagnosis of endometriosis |
CN113533544B (zh) * | 2020-04-16 | 2024-08-20 | 海南先声再明医药股份有限公司 | 一种甲磺酸仑伐替尼的有关物质检测方法 |
CN114441764B (zh) * | 2021-12-24 | 2022-09-27 | 广州市妇女儿童医疗中心 | Angiogenin作为先天性巨结肠肠炎早期预测及诊断标志物的应用 |
Family Cites Families (305)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CU22545A1 (es) | 1994-11-18 | 1999-03-31 | Centro Inmunologia Molecular | Obtención de un anticuerpo quimérico y humanizado contra el receptor del factor de crecimiento epidérmico para uso diagnóstico y terapéutico |
US5156840A (en) | 1982-03-09 | 1992-10-20 | Cytogen Corporation | Amine-containing porphyrin derivatives |
US4526988A (en) | 1983-03-10 | 1985-07-02 | Eli Lilly And Company | Difluoro antivirals and intermediate therefor |
ATE85080T1 (de) | 1984-02-17 | 1993-02-15 | Genentech Inc | Menschlicher transformationswachstumsfaktor und vorlaeufer oder fragment hiervon, zellen, dna, vektoren und verfahren zu ihrer herstellung, zusammensetzungen und produkte, die diese enthalten, sowie davon abgeleitete antikoerper und diagnostizierverfahren. |
US4582789A (en) | 1984-03-21 | 1986-04-15 | Cetus Corporation | Process for labeling nucleic acids using psoralen derivatives |
DE8411409U1 (de) | 1984-04-11 | 1984-08-30 | Dr.-Ing. Walter Frohn-Betriebe, 8000 München | Entgasungsventil fuer lager- und/oder transportbehaelter |
JPS6153952A (ja) | 1984-08-25 | 1986-03-18 | 松下電工株式会社 | 融雪システム |
US4563417A (en) | 1984-08-31 | 1986-01-07 | Miles Laboratories, Inc. | Nucleic acid hybridization assay employing antibodies to intercalation complexes |
EP0183858B1 (de) | 1984-11-22 | 1988-09-14 | Holsten-Brauerei AG | Bier und Verfahren zu dessen Herstellung |
ATE92499T1 (de) | 1984-12-04 | 1993-08-15 | Lilly Co Eli | Tumorbehandlung bei saeugetieren. |
JPS61148115A (ja) | 1984-12-21 | 1986-07-05 | Tooa Eiyoo Kk | 難溶性薬物の徐放性製剤及びその製造法 |
GB8524028D0 (en) | 1985-09-30 | 1985-11-06 | Hanger & Co Ltd J E | Leg prosthesis |
JPS62168137A (ja) | 1985-12-20 | 1987-07-24 | Fuji Photo Film Co Ltd | ハロゲン化銀カラ−写真感光材料およびその処理方法 |
CH656535A5 (en) | 1986-01-24 | 1986-07-15 | Spirig Ag | Process for the production of stable pharmaceutical tablets which disintegrate rapidly in water |
US5057313A (en) | 1986-02-25 | 1991-10-15 | The Center For Molecular Medicine And Immunology | Diagnostic and therapeutic antibody conjugates |
JPH07106295B2 (ja) | 1986-07-22 | 1995-11-15 | エーザイ株式会社 | 調湿剤 |
CA1339136C (en) | 1987-07-01 | 1997-07-29 | Sailesh Amilal Varia | Amorphous form of aztreonam |
AU4128089A (en) | 1988-09-15 | 1990-03-22 | Rorer International (Overseas) Inc. | Monoclonal antibodies specific to human epidermal growth factor receptor and therapeutic methods employing same |
US5143854A (en) | 1989-06-07 | 1992-09-01 | Affymax Technologies N.V. | Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof |
US4983615A (en) | 1989-06-28 | 1991-01-08 | Hoechst-Roussel Pharmaceuticals Inc. | Heteroarylamino- and heteroaryloxypyridinamine compounds which are useful in treating skin disorders |
EP0408496A3 (en) | 1989-07-12 | 1992-07-01 | Ciba-Geigy Ag | Solid dosage form for pharmaceutical substances |
US5120548A (en) | 1989-11-07 | 1992-06-09 | Merck & Co., Inc. | Swelling modulated polymeric drug delivery device |
US5180818A (en) | 1990-03-21 | 1993-01-19 | The University Of Colorado Foundation, Inc. | Site specific cleavage of single-stranded dna |
US5210015A (en) | 1990-08-06 | 1993-05-11 | Hoffman-La Roche Inc. | Homogeneous assay system using the nuclease activity of a nucleic acid polymerase |
EP0834575B1 (en) | 1990-12-06 | 2001-11-28 | Affymetrix, Inc. (a Delaware Corporation) | Identification of nucleic acids in samples |
GB9105677D0 (en) | 1991-03-19 | 1991-05-01 | Ici Plc | Heterocyclic compounds |
US5367057A (en) | 1991-04-02 | 1994-11-22 | The Trustees Of Princeton University | Tyrosine kinase receptor flk-2 and fragments thereof |
US5710158A (en) | 1991-05-10 | 1998-01-20 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
CA2102780C (en) | 1991-05-10 | 2007-01-09 | Alfred P. Spada | Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase |
US5721237A (en) | 1991-05-10 | 1998-02-24 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties |
JPH04341454A (ja) | 1991-05-16 | 1992-11-27 | Canon Inc | シート収納装置 |
US5750376A (en) | 1991-07-08 | 1998-05-12 | Neurospheres Holdings Ltd. | In vitro growth and proliferation of genetically modified multipotent neural stem cells and their progeny |
US5211951A (en) | 1991-07-24 | 1993-05-18 | Merck & Co., Inc. | Process for the manufacture of bioerodible poly (orthoester)s and polyacetals |
JPH05194259A (ja) | 1991-08-30 | 1993-08-03 | Mitsubishi Kasei Corp | 抗消化性潰瘍剤 |
US5200194A (en) | 1991-12-18 | 1993-04-06 | Alza Corporation | Oral osmotic device |
WO1993024627A1 (en) | 1992-06-03 | 1993-12-09 | Case Western Reserve University | Bandage for continuous application of biologicals |
GB9221220D0 (en) | 1992-10-09 | 1992-11-25 | Sandoz Ag | Organic componds |
GB9323290D0 (en) | 1992-12-10 | 1994-01-05 | Zeneca Ltd | Quinazoline derivatives |
US6027880A (en) | 1995-08-02 | 2000-02-22 | Affymetrix, Inc. | Arrays of nucleic acid probes and methods of using the same for detecting cystic fibrosis |
US6156501A (en) | 1993-10-26 | 2000-12-05 | Affymetrix, Inc. | Arrays of modified nucleic acid probes and methods of use |
JPH07176103A (ja) | 1993-12-20 | 1995-07-14 | Canon Inc | 光磁気記録再生システムならびにこれに用いる磁気ヘッド及び光磁気記録媒体 |
GB9326136D0 (en) | 1993-12-22 | 1994-02-23 | Erba Carlo Spa | Biologically active 3-substituted oxindole derivatives useful as anti-angiogenic agents |
IL112249A (en) | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
US6811779B2 (en) | 1994-02-10 | 2004-11-02 | Imclone Systems Incorporated | Methods for reducing tumor growth with VEGF receptor antibody combined with radiation and chemotherapy |
JP3660391B2 (ja) | 1994-05-27 | 2005-06-15 | 株式会社東芝 | 半導体装置の製造方法 |
JPH0848078A (ja) | 1994-08-05 | 1996-02-20 | Nippon Paper Ind Co Ltd | 感熱記録体 |
GB9510757D0 (en) | 1994-09-19 | 1995-07-19 | Wellcome Found | Therapeuticaly active compounds |
US5656454A (en) | 1994-10-04 | 1997-08-12 | President And Fellows Of Harvard College | Endothelial cell-specific enhancer |
JP3207058B2 (ja) | 1994-11-07 | 2001-09-10 | 財団法人国際超電導産業技術研究センター | 超電導体薄膜及びその製造方法 |
IL115256A0 (en) | 1994-11-14 | 1995-12-31 | Warner Lambert Co | 6-Aryl pyrido (2,3-d) pyrimidines and naphthyridines and their use |
JPH08176138A (ja) | 1994-12-19 | 1996-07-09 | Mercian Corp | イソクマリン誘導体 |
US5948438A (en) | 1995-01-09 | 1999-09-07 | Edward Mendell Co., Inc. | Pharmaceutical formulations having improved disintegration and/or absorptivity |
US5658374A (en) | 1995-02-28 | 1997-08-19 | Buckman Laboratories International, Inc. | Aqueous lecithin-based release aids and methods of using the same |
US5624937A (en) | 1995-03-02 | 1997-04-29 | Eli Lilly And Company | Chemical compounds as inhibitors of amyloid beta protein production |
US6579314B1 (en) | 1995-03-10 | 2003-06-17 | C.R. Bard, Inc. | Covered stent with encapsulated ends |
DE69522717T2 (de) | 1995-03-30 | 2002-02-14 | Pfizer Inc., New York | Chinazolinderivate |
GB9508538D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
US5654005A (en) | 1995-06-07 | 1997-08-05 | Andrx Pharmaceuticals, Inc. | Controlled release formulation having a preformed passageway |
EP0831829B1 (en) | 1995-06-07 | 2003-08-20 | Pfizer Inc. | Heterocyclic ring-fused pyrimidine derivatives |
US5880141A (en) | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
JPH0923885A (ja) | 1995-07-12 | 1997-01-28 | Dai Ichi Seiyaku Co Ltd | 遺伝子発現ライブラリー及びその製造法 |
GB9514265D0 (en) | 1995-07-13 | 1995-09-13 | Wellcome Found | Hetrocyclic compounds |
GB9520822D0 (en) | 1995-10-11 | 1995-12-13 | Wellcome Found | Therapeutically active compounds |
AR004010A1 (es) | 1995-10-11 | 1998-09-30 | Glaxo Group Ltd | Compuestos heterociclicos |
US6346398B1 (en) | 1995-10-26 | 2002-02-12 | Ribozyme Pharmaceuticals, Inc. | Method and reagent for the treatment of diseases or conditions related to levels of vascular endothelial growth factor receptor |
DE69622183D1 (de) | 1995-11-07 | 2002-08-08 | Kirin Brewery | Chinolinderivate und chinazolinderivate welche die autophosphorylierung des von blutplättchen abstammenden wachstumsfaktorrezeptors inhibiren und sie enthaltende pharmazeutische zusammensetzungen |
US5849759A (en) | 1995-12-08 | 1998-12-15 | Berlex Laboratories, Inc. | Naphthyl-substituted benzimidazole derivatives as anti-coagulants |
GB9604361D0 (en) | 1996-02-29 | 1996-05-01 | Pharmacia Spa | 4-Substituted pyrrolopyrimidine compounds as tyrosine kinase inhibitors |
JPH09234074A (ja) | 1996-03-04 | 1997-09-09 | Sumitomo Electric Ind Ltd | アダプター二本鎖dna及びそれを用いたdna増幅方法 |
IL126610A0 (en) | 1996-04-17 | 1999-08-17 | Du Pont Pharm Co | N-(amidinophenyl)-n'-(subst.)-3h-2,4-benzodiazepin-3- one derivatives as factor xa inhibitors |
WO1997046313A1 (en) | 1996-06-07 | 1997-12-11 | Eos Biotechnology, Inc. | Immobilised linear oligonucleotide arrays |
EP0912175A4 (en) | 1996-06-28 | 1999-09-08 | Merck & Co Inc | FIBRINOGENIC RECEPTOR ANTAGONISTS |
HRP970371A2 (en) | 1996-07-13 | 1998-08-31 | Kathryn Jane Smith | Heterocyclic compounds |
PL331154A1 (en) | 1996-07-13 | 1999-06-21 | Glaxo Group Ltd | Bicyclic heteroaromatic compounds as inhibitors of proteinous tyrosine kinase |
JP4386967B2 (ja) | 1996-07-13 | 2009-12-16 | グラクソ、グループ、リミテッド | プロテインチロシンキナーゼ阻害剤としての縮合複素環式化合物 |
JPH10147524A (ja) | 1996-09-20 | 1998-06-02 | Nippon Kayaku Co Ltd | フォルスコリン誘導体含有経口製剤及び医薬製剤の製法 |
KR100567649B1 (ko) | 1996-09-25 | 2006-04-05 | 아스트라제네카 유케이 리미티드 | 혈관 내피 성장 인자와 같은 성장 인자의 효과를 억제하는 퀴놀린 유도체 |
WO1998014437A1 (fr) | 1996-09-30 | 1998-04-09 | Nihon Nohyaku Co., Ltd. | Derives de 1,2,3-thiadiazole et sels de ces derives, agents en usage dans l'agriculture et l'horticulture pour lutter contre les maladies vegetales, et procede d'utilisation correspondant |
JPH10114655A (ja) | 1996-10-09 | 1998-05-06 | Kyowa Hakko Kogyo Co Ltd | 固形製剤 |
EP0837063A1 (en) | 1996-10-17 | 1998-04-22 | Pfizer Inc. | 4-Aminoquinazoline derivatives |
EP0946554A1 (en) | 1996-11-27 | 1999-10-06 | Pfizer Inc. | Fused bicyclic pyrimidine derivatives |
TW486370B (en) | 1996-12-25 | 2002-05-11 | Yamanouchi Pharma Co Ltd | Rapidly disintegrable pharmaceutical composition |
AU6248798A (en) | 1997-01-29 | 1998-08-18 | Eli Lilly And Company | Treatment for premenstrual dysphoric disorder |
CO4950519A1 (es) | 1997-02-13 | 2000-09-01 | Novartis Ag | Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion |
JP3040486U (ja) | 1997-02-13 | 1997-08-19 | 有限会社ザップ | フィッシングジャケット |
DE69836422T2 (de) | 1997-02-19 | 2007-06-14 | Berlex, Inc., Richmond | N-heterocyclische derivate als nos inhibitoren |
US6090556A (en) | 1997-04-07 | 2000-07-18 | Japan Science & Technology Corporation | Method for quantitatively determining the expression of a gene |
WO1998050346A2 (en) | 1997-04-18 | 1998-11-12 | Smithkline Beecham Plc | Acetamide and urea derivatives, process for their preparation and their use in the treatment of cns disorders |
JPH10316576A (ja) | 1997-05-13 | 1998-12-02 | Nissui Pharm Co Ltd | キトサン含有錠剤 |
DE1019040T1 (de) | 1997-05-23 | 2001-02-08 | Bayer Corp., West Haven | Hemmung von p38 kinase aktivität durch arylharnstoff |
US6093742A (en) | 1997-06-27 | 2000-07-25 | Vertex Pharmaceuticals, Inc. | Inhibitors of p38 |
AU8283898A (en) | 1997-06-30 | 1999-01-25 | University Of Maryland At Baltimore | Heparin binding-epidermal growth factor in the diagnosis of interstitial cystitis |
JP3765918B2 (ja) | 1997-11-10 | 2006-04-12 | パイオニア株式会社 | 発光ディスプレイ及びその駆動方法 |
JP4194678B2 (ja) | 1997-11-28 | 2008-12-10 | キリンファーマ株式会社 | キノリン誘導体およびそれを含む医薬組成物 |
DE1049664T1 (de) | 1997-12-22 | 2001-05-03 | Bayer Corp., Pittsburgh | Hemmung der raf-kinase unter verwendung von symmetrisch und unsymmetrisch substituierten harnstoffen |
JP4403482B2 (ja) | 1997-12-22 | 2010-01-27 | バイエル コーポレイション | 置換複素環尿素合成のための中間体およびその製造方法 |
RU2232015C2 (ru) | 1997-12-22 | 2004-07-10 | Байер Копэрейшн | Способ подавления роста опухолевых клеток, опосредованного киназой raf, гетероциклические производные мочевины (варианты), фармацевтическая композиция (варианты) |
AU762077B2 (en) | 1997-12-22 | 2003-06-19 | Bayer Healthcare Llc | Inhibition of p38 kinase activity using aryl and heteroaryl substituted heterocyclic ureas |
GB9800575D0 (en) | 1998-01-12 | 1998-03-11 | Glaxo Group Ltd | Heterocyclic compounds |
GB9800569D0 (en) | 1998-01-12 | 1998-03-11 | Glaxo Group Ltd | Heterocyclic compounds |
WO1999043654A2 (en) | 1998-02-25 | 1999-09-02 | Genetics Institute, Inc. | Inhibitors of phospholipase enzymes |
CA2322315C (en) | 1998-03-06 | 2008-09-16 | Eurand International S.P.A. | Fast disintegrating tablets |
DE19814257A1 (de) | 1998-03-31 | 1999-10-07 | Asta Medica Ag | Brauseformulierungen |
JPH11322596A (ja) | 1998-05-12 | 1999-11-24 | Shionogi & Co Ltd | 白金錯体および環状リン酸エステルアミドを含有する抗癌剤 |
UA60365C2 (uk) | 1998-06-04 | 2003-10-15 | Пфайзер Продактс Інк. | Похідні ізотіазолу, спосіб їх одержання, фармацевтична композиція та спосіб лікування гіперпроліферативного захворювання у ссавця |
IL141762A0 (en) | 1998-10-01 | 2002-03-10 | Novartis Ag | New oral formulations |
ATE229008T1 (de) | 1998-11-19 | 2002-12-15 | Warner Lambert Co | N- 4-(3-chloro-4-fluoro-phenylamino)-7-(3- morfolin-4-yl-propoxy)-chinazolin-6-yl -akrylamid,ein irreversibler tyrosin-kinasen hemmer |
WO2000042012A1 (en) | 1999-01-13 | 2000-07-20 | Bayer Corporation | φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS |
UA73492C2 (en) | 1999-01-19 | 2005-08-15 | Aromatic heterocyclic compounds as antiinflammatory agents | |
WO2000043366A1 (fr) | 1999-01-22 | 2000-07-27 | Kirin Beer Kabushiki Kaisha | Derives de quinoline et derives de quinazoline |
JP3270834B2 (ja) | 1999-01-27 | 2002-04-02 | ファイザー・プロダクツ・インク | 抗がん剤として有用なヘテロ芳香族二環式誘導体 |
UA71945C2 (en) | 1999-01-27 | 2005-01-17 | Pfizer Prod Inc | Substituted bicyclic derivatives being used as anticancer agents |
CZ303692B6 (cs) | 1999-02-10 | 2013-03-13 | Astrazeneca Ab | Chinazolinové deriváty jako inhibitory angiogeneze |
GB9904103D0 (en) | 1999-02-24 | 1999-04-14 | Zeneca Ltd | Quinoline derivatives |
JP2000328080A (ja) | 1999-03-12 | 2000-11-28 | Shin Etsu Chem Co Ltd | シートベルト用低摩擦化処理剤 |
RS49836B (sr) | 1999-03-31 | 2008-08-07 | Pfizer Products Inc., | Postupci i intermedijeri za dobijanje anti-kancernih jedinjenja |
ATE269357T1 (de) | 1999-04-28 | 2004-07-15 | Univ Texas | Zusammensetzungen und verfahren zur krebsbehandlung durch die selektive hemmung von vegf |
EP1050694A3 (de) | 1999-05-06 | 2002-06-19 | Heidelberger Druckmaschinen Aktiengesellschaft | Vorrichtung zum Lagern eines Schwenkelements |
AU4778500A (en) | 1999-05-20 | 2000-12-12 | Takeda Chemical Industries Ltd. | Composition containing ascorbic acid salt |
JP4304357B2 (ja) | 1999-05-24 | 2009-07-29 | 独立行政法人理化学研究所 | 完全長cDNAライブラリーの作成法 |
PE20010306A1 (es) | 1999-07-02 | 2001-03-29 | Agouron Pharma | Compuestos de indazol y composiciones farmaceuticas que los contienen utiles para la inhibicion de proteina kinasa |
JP2001047890A (ja) | 1999-08-06 | 2001-02-20 | Toyota Motor Corp | 車両用パワープラントの制御装置 |
WO2001012600A1 (en) | 1999-08-12 | 2001-02-22 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
CO5200835A1 (es) | 1999-09-28 | 2002-09-27 | Bayer Corp | Piridinas y piridacinas sustituidas con actividad de inhibicion de angiogenesis |
US6762180B1 (en) | 1999-10-13 | 2004-07-13 | Boehringer Ingelheim Pharma Kg | Substituted indolines which inhibit receptor tyrosine kinases |
UA75054C2 (uk) | 1999-10-13 | 2006-03-15 | Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг | Заміщені в положенні 6 індолінони, їх одержання та їх застосування як лікарського засобу |
JP2001131071A (ja) | 1999-10-29 | 2001-05-15 | Meiji Seika Kaisha Ltd | 非晶質および非晶質を含有する医薬組成物 |
US20080241835A1 (en) | 1999-11-01 | 2008-10-02 | Genentech, Inc. | Differentially expressed genes involved in angiogenesis, the polypeptides encoded thereby, and methods of using the same |
WO2001032926A2 (en) | 1999-11-01 | 2001-05-10 | Curagen Corporation | Differentially expressed genes involved in angiogenesis, the polypeptides encoded thereby, and methods of using the same |
US6492393B1 (en) | 1999-11-16 | 2002-12-10 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as anti-inflammatory agents |
UA75055C2 (uk) | 1999-11-30 | 2006-03-15 | Пфайзер Продактс Інк. | Похідні бензоімідазолу, що використовуються як антипроліферативний засіб, фармацевтична композиція на їх основі |
US20020010203A1 (en) | 1999-12-22 | 2002-01-24 | Ken Lipson | Methods of modulating c-kit tyrosine protein kinase function with indolinone compounds |
DE60018216T2 (de) | 1999-12-24 | 2006-02-16 | Kyowa Hakko Kogyo Co., Ltd. | Kondensierte purinderivate |
US7135466B2 (en) | 1999-12-24 | 2006-11-14 | Kirin Beer Kabushiki Kaisha | Quinoline and quinazoline derivatives and drugs containing the same |
CZ303705B6 (cs) | 2000-02-15 | 2013-03-27 | Sugen, Inc. | Pyrrolem substituovaná 2-indolinonová sloucenina pro pouzití jako inhibitor proteinkináz a farmaceutická kompozice s jejím obsahem |
JP3657203B2 (ja) | 2000-04-21 | 2005-06-08 | エーザイ株式会社 | 銅クロロフィリン塩含有液剤組成物 |
CN1116047C (zh) | 2000-06-05 | 2003-07-30 | 华中科技大学 | 用泥鳅制成的护肝功能食品及其制备方法 |
WO2001096390A2 (en) | 2000-06-09 | 2001-12-20 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of colon cancer |
WO2002016348A1 (en) | 2000-08-09 | 2002-02-28 | Astrazeneca Ab | Antiangiogenic bicyclic derivatives |
DE60137273D1 (de) | 2000-10-20 | 2009-02-12 | Eisai R&D Man Co Ltd | Verfahren zur Herstellung von 4-Phenoxy chinolin Derivaten |
TWI283575B (en) | 2000-10-31 | 2007-07-11 | Eisai Co Ltd | Medicinal compositions for concomitant use as anticancer agent |
US20040034026A1 (en) | 2000-11-22 | 2004-02-19 | Wood Jeannette M | Combination comprising an agent decreasing vegf activity and an agent decreasing egf activity |
AU2002232439A1 (en) | 2000-11-29 | 2002-06-11 | Glaxo Group Limited | Benzimidazole derivatives useful as tie-2 and/or vegfr-2 inhibitors |
US6544552B2 (en) | 2001-01-11 | 2003-04-08 | Particle And Coating Technologies, Inc. | Method of producing porous tablets with improved dissolution properties |
US7101663B2 (en) | 2001-03-02 | 2006-09-05 | University of Pittsburgh—of the Commonwealth System of Higher Education | PCR method |
US6960580B2 (en) | 2001-03-08 | 2005-11-01 | Millennium Pharmaceuticals, Inc. | Nitrogenous heterocyclic substituted quinoline compounds |
KR100862178B1 (ko) | 2001-04-06 | 2008-10-09 | 와이어쓰 | 라파마이신과 겜시타빈 또는 플루오로우라실과의 항신생물제 배합물 |
JP2004536290A (ja) | 2001-04-19 | 2004-12-02 | ゲゼルシャフト フュア バイオテクノロギッシェ フォーシュンク エム ベー ハー(ゲー ベー エフ) | 安定した、再生可能な抗体アレイの作製方法 |
CN1273466C (zh) | 2001-04-27 | 2006-09-06 | 麒麟麦酒株式会社 | 具有唑基的喹啉衍生物和喹唑啉衍生物 |
JP3602513B2 (ja) | 2001-04-27 | 2004-12-15 | 麒麟麦酒株式会社 | アゾリル基を有するキノリン誘導体およびキナゾリン誘導体 |
JP2003026576A (ja) | 2001-05-09 | 2003-01-29 | Eisai Co Ltd | 味覚改善製剤 |
US6812341B1 (en) | 2001-05-11 | 2004-11-02 | Ambion, Inc. | High efficiency mRNA isolation methods and compositions |
EP2253319A1 (en) | 2001-05-16 | 2010-11-24 | Novartis AG | Combination comprising N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2pyrimidine-amine and a chemotherapeutic agent. |
AR036042A1 (es) | 2001-05-30 | 2004-08-04 | Sugen Inc | Derivados aralquilsufonil-3-(pirrol-2-ilmetiliden)-2-indolinona, sus composiciones farmaceuticas y metodo para la modulacion de la actividad catalitica de una proteina quinasa |
EP2088141A3 (en) | 2001-06-22 | 2009-11-18 | Kirin Pharma Kabushiki Kaisha | Quinoline derivatives and quinazoline derivatives capable of inhibiting autophosphorylation of hepatocyte growth factor receptors, and pharmaceutical composition comprising the same |
GB0117144D0 (en) | 2001-07-13 | 2001-09-05 | Glaxo Group Ltd | Process |
US20030013208A1 (en) | 2001-07-13 | 2003-01-16 | Milagen, Inc. | Information enhanced antibody arrays |
JP4827154B2 (ja) | 2001-07-25 | 2011-11-30 | 株式会社オーイズミ | 遊技装置 |
JP3088018U (ja) | 2001-08-02 | 2002-08-30 | ユーエス工業株式会社 | 垂木支持用ブラケットを備えたパイプバンド |
GB0119467D0 (en) | 2001-08-09 | 2001-10-03 | Smithkline Beecham Plc | Novel compound |
EP1436620B1 (en) | 2001-09-10 | 2014-04-23 | Meso Scale Technologies, LLC | Methods and apparatus for conducting multiple measurements on a sample |
CA2460845A1 (en) | 2001-09-20 | 2003-03-27 | Ab Science | Use of potent, selective and non toxic c-kit inhibitors for treating interstitial cystitis |
JP4130179B2 (ja) | 2001-09-27 | 2008-08-06 | ノバルティス アクチエンゲゼルシャフト | 骨髄腫を処置するためのc−kit阻害剤の使用 |
CA2461812C (en) | 2001-09-27 | 2011-09-20 | Allergan, Inc. | 3-(arylamino)methylene-1,3-dihydro-2h-indol-2-ones as kinase inhibitors |
EP1435959A2 (en) | 2001-10-09 | 2004-07-14 | University of Cincinnati | Inhibitors of the egf receptor for the treatment of thyroid cancer |
US7521053B2 (en) | 2001-10-11 | 2009-04-21 | Amgen Inc. | Angiopoietin-2 specific binding agents |
US7658924B2 (en) | 2001-10-11 | 2010-02-09 | Amgen Inc. | Angiopoietin-2 specific binding agents |
WO2003033472A1 (fr) | 2001-10-17 | 2003-04-24 | Kirin Beer Kabushiki Kaisha | Derives de quinoline ou de quinazoline inhibant l'autophosphorylation de recepteurs du facteur de croissance des fibroblastes |
ATE370123T1 (de) | 2001-11-27 | 2007-09-15 | Wyeth Corp | 3-cyanochinoline als inhibitoren von egf-r- und her2-kinasen |
GB0201508D0 (en) | 2002-01-23 | 2002-03-13 | Novartis Ag | Organic compounds |
US7498414B2 (en) | 2002-03-04 | 2009-03-03 | Imclone Systems Incorporated | Human antibodies specific to KDR and uses thereof |
JP2003252737A (ja) | 2002-03-04 | 2003-09-10 | Shin Etsu Chem Co Ltd | 口腔用組成物 |
WO2003074045A1 (fr) | 2002-03-05 | 2003-09-12 | Eisai Co., Ltd. | Agent antitumoral comprenant une combinaison d'un compose heterocyclique contenant un sulfamide et d'un inhibiteur d'angiogenese |
AU2003226676A1 (en) | 2002-03-20 | 2003-09-29 | Dana-Farber Cancer Institute Inc. | Methods and compositions for the identification, assessment, and therapy of small cell lung cancer |
US6790852B2 (en) | 2002-04-18 | 2004-09-14 | Hoffmann-La Roche Inc. | 2-(2,6-dichlorophenyl)-diarylimidazoles |
JPWO2003093238A1 (ja) | 2002-05-01 | 2005-09-08 | 麒麟麦酒株式会社 | マクロファージコロニー刺激因子受容体自己リン酸化を阻害するキノリン誘導体およびキナゾリン誘導体 |
TW200406374A (en) | 2002-05-29 | 2004-05-01 | Novartis Ag | Diaryl urea derivatives useful for the treatment of protein kinase dependent diseases |
UA77303C2 (en) | 2002-06-14 | 2006-11-15 | Pfizer | Derivatives of thienopyridines substituted by benzocondensed heteroarylamide useful as therapeutic agents, pharmaceutical compositions and methods for their use |
AU2003251968A1 (en) | 2002-07-16 | 2004-02-02 | Children's Medical Center Corporation | A method for the modulation of angiogenesis |
EP1523512B1 (en) | 2002-07-22 | 2019-12-25 | Aspen Aerogels Inc. | Polyimide aerogels, carbon aerogels, and metal carbide aerogels and methods of making same |
US7169936B2 (en) | 2002-07-23 | 2007-01-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Indolinone derivatives substituted in the 6-position, their preparation and their use as medicaments |
US7252976B2 (en) | 2002-08-28 | 2007-08-07 | Board Of Regents The University Of Texas System | Quantitative RT-PCR to AC133 to diagnose cancer and monitor angiogenic activity in a cell sample |
NZ538617A (en) | 2002-08-30 | 2005-12-23 | Eisai Co Ltd | Azaarene derivatives |
MXPA05003706A (es) | 2002-10-09 | 2005-07-01 | Kosan Biosciences Inc | Epo d+5-fu/gemcitabina. |
GB0223380D0 (en) | 2002-10-09 | 2002-11-13 | Astrazeneca Ab | Combination therapy |
ES2534713T3 (es) | 2002-10-16 | 2015-04-27 | Takeda Pharmaceutical Company Limited | Preparaciones sólidas estables |
JP4749660B2 (ja) | 2002-10-16 | 2011-08-17 | 武田薬品工業株式会社 | 安定な固形製剤 |
ATE327977T1 (de) | 2002-10-21 | 2006-06-15 | Warner Lambert Co | Tetrahydrochinolin-derivate als crth2 antagonisten |
JPWO2004039782A1 (ja) | 2002-10-29 | 2006-03-02 | 麒麟麦酒株式会社 | Flt3自己リン酸化を阻害するキノリン誘導体およびキナゾリン誘導体並びにそれらを含有する医薬組成物 |
DE10250711A1 (de) | 2002-10-31 | 2004-05-19 | Degussa Ag | Pharmazeutische und kosmetische Zubereitungen |
BR0316004A (pt) | 2002-11-06 | 2005-09-13 | Cyclacel Ltd | Composição farmacêutica compreendendo um inibidor de cdk e gemcitabina |
GB0226434D0 (en) | 2002-11-13 | 2002-12-18 | Astrazeneca Ab | Combination product |
ITSV20020056A1 (it) | 2002-11-14 | 2004-05-15 | Alstom Transp Spa | Dispositivo e metodo di verifica di motori software logici di comando di impianti ferroviari, in particolare di impianti di stazione |
AR042042A1 (es) | 2002-11-15 | 2005-06-08 | Sugen Inc | Administracion combinada de una indolinona con un agente quimioterapeutico para trastornos de proliferacion celular |
AU2004206860B2 (en) | 2003-01-14 | 2010-03-18 | Cytokinetics, Inc. | Compounds, compositions and methods |
JP3581361B1 (ja) | 2003-02-17 | 2004-10-27 | 株式会社脳機能研究所 | 脳活動測定装置 |
WO2004073632A2 (en) | 2003-02-19 | 2004-09-02 | Biovail Laboratories Inc. | Rapid absorption selective 5-ht agonist formulations |
RS53118B (en) | 2003-02-26 | 2014-06-30 | Sugen Inc. | AMINOHETEROARYL UNITS AS PROTEIN KINASE INHIBITORS |
EP1603864A4 (en) | 2003-03-05 | 2007-04-11 | Celgene Corp | DIPHENYLETHYLENE COMPOUNDS AND THEIR USE |
EP1604665B1 (en) | 2003-03-10 | 2011-05-11 | Eisai R&D Management Co., Ltd. | C-kit kinase inhibitor |
US7435590B2 (en) | 2003-03-14 | 2008-10-14 | Taisho Pharmaceutical Co., Ltd. | Monoclonal antibody and hybridoma producing the same |
EP1604981A4 (en) | 2003-03-14 | 2008-12-24 | Ono Pharmaceutical Co | NITROGENIC HETEROCYCLIC DERIVATIVES AND MEDICAMENTS CONTAINING THEM AS AN ACTIVE SUBSTANCE |
US20050014753A1 (en) | 2003-04-04 | 2005-01-20 | Irm Llc | Novel compounds and compositions as protein kinase inhibitors |
US20070117842A1 (en) | 2003-04-22 | 2007-05-24 | Itaru Arimoto | Polymorph of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide and a process for the preparation of the same |
EP1473043A1 (en) | 2003-04-29 | 2004-11-03 | Boehringer Ingelheim Pharma GmbH & Co.KG | Pharmaceutical combination for the treatment of diseases involving cell proliferation, migration or apotosis of myeloma cells, or angiogenesis |
JP2005008534A (ja) | 2003-06-17 | 2005-01-13 | Soc De Conseils De Recherches & D'applications Scientifiques (Scras) | 抗癌剤及び癌の治療方法 |
MXPA06000114A (es) | 2003-07-10 | 2006-04-27 | Astrazeneca Ab | Uso del derivado de quinazolina zd6474 combinado con compuestos de platino y, opcionalmente, con radiacion ionizante, en el tratamiento de enfermedades asociadas con la angiogenesis y/o la permeabilidad vascular incrementada. |
JP2007502809A (ja) | 2003-08-15 | 2007-02-15 | アブ サイエンス | II型糖尿病を治療するためのc−kit阻害剤の使用方法 |
WO2005021531A1 (en) | 2003-08-21 | 2005-03-10 | Osi Pharmaceuticals, Inc. | N-substituted benzimidazolyl c-kit inhibitors |
US7485658B2 (en) | 2003-08-21 | 2009-02-03 | Osi Pharmaceuticals, Inc. | N-substituted pyrazolyl-amidyl-benzimidazolyl c-Kit inhibitors |
BRPI0413785A (pt) | 2003-08-21 | 2006-11-07 | Osi Pharm Inc | composto, composição, e, método de tratamento de distúrbio hiperproliferativo |
CA2537991A1 (en) | 2003-09-23 | 2005-03-31 | Novartis Ag | Combination of a vegf receptor inhibitor with a chemotherapeutic agent |
ES2651730T3 (es) | 2003-09-26 | 2018-01-29 | Exelixis, Inc. | Moduladores c-Met y métodos de uso |
JP2005124034A (ja) | 2003-10-20 | 2005-05-12 | Nippon Telegr & Teleph Corp <Ntt> | 発信者の特定及び発信者への呼び返しを可能とする回線設定方法 |
US7683172B2 (en) | 2003-11-11 | 2010-03-23 | Eisai R&D Management Co., Ltd. | Urea derivative and process for preparing the same |
RU2006122853A (ru) | 2003-11-28 | 2008-01-10 | Новартис АГ (CH) | Производные диарилмочевины для лечения заболеваний, зависимых от протеинкиназы |
RU2402567C2 (ru) | 2003-12-05 | 2010-10-27 | Бристоль-Майерз Сквибб Компани | Ингибиторы рецепторов фактора роста эндотелия сосудов типа 2 |
US7612208B2 (en) | 2003-12-25 | 2009-11-03 | Eisai R&D Management Co., Ltd. | Crystalline form of the salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide or the solvate of the salt and a process for preparing the same |
CA2553423C (en) | 2004-01-23 | 2012-03-20 | Amgen Inc. | Heterocyclic compounds for use in the treatment of cancer and the inhibition of angiogenesis |
US20070270421A1 (en) | 2004-02-27 | 2007-11-22 | Tomohiro Matsushima | Novel pyridine Derivative and Pyrimidine Derivative (1) |
KR20050091462A (ko) | 2004-03-12 | 2005-09-15 | 한국과학기술연구원 | 푸로피리미딘 화합물 및 이를 포함하는 ddr2 티로신키나아제 활성 저해제 |
JP4341454B2 (ja) | 2004-04-08 | 2009-10-07 | トヨタ自動車株式会社 | 固体電解質型燃料電池の製造方法 |
US7459562B2 (en) | 2004-04-23 | 2008-12-02 | Bristol-Myers Squibb Company | Monocyclic heterocycles as kinase inhibitors |
JP2005312393A (ja) | 2004-04-30 | 2005-11-10 | Niigata Prefecture | バクテリオシンの生産方法,バクテリオシン含有物及び清酒製造方法 |
JP2008501652A (ja) | 2004-06-03 | 2008-01-24 | エフ.ホフマン−ラ ロシュ アーゲー | ゲムシタビン及びegfrインヒビターによる治療 |
US7173031B2 (en) | 2004-06-28 | 2007-02-06 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
US20050288521A1 (en) | 2004-06-29 | 2005-12-29 | Phytogen Life Sciences Inc. | Semi-synthetic conversion of paclitaxel to docetaxel |
JP5368701B2 (ja) | 2004-07-02 | 2013-12-18 | エクセリクシス、インコーポレイテッド | c−Metモジュレーター及び使用方法 |
US8772269B2 (en) | 2004-09-13 | 2014-07-08 | Eisai R&D Management Co., Ltd. | Use of sulfonamide-including compounds in combination with angiogenesis inhibitors |
EP2364699A1 (en) | 2004-09-13 | 2011-09-14 | Eisai R&D Management Co., Ltd. | Joint use of sulfonamide based compound with angiogenesis inhibitor |
CA2579810C (en) | 2004-09-17 | 2012-01-24 | Eisai R&D Management Co., Ltd. | Stable pharmaceutical compositions of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide |
US20060079494A1 (en) | 2004-09-27 | 2006-04-13 | Santi Daniel V | Specific kinase inhibitors |
US20070298111A1 (en) | 2004-10-01 | 2007-12-27 | Eisai R&D Management Co., Ltd. | Fine Particle-Containing Composition and Manufacturing Method Therefor |
BRPI0518209A (pt) * | 2004-10-19 | 2008-11-04 | Amgen Inc | agentes de ligação especìficos à angiopoietina-2 |
JP2008520746A (ja) | 2004-11-22 | 2008-06-19 | キング・ファーマシューティカルズ・リサーチ・アンド・デベロプメント・インコーポレイティッド | アデノシンa3受容体アンタゴニストを用いる癌及びhif−1が介在する疾患の促進的治療 |
EP1827434B1 (en) | 2004-11-30 | 2014-01-15 | Amgen Inc. | Quinolines and quinazoline analogs and their use as medicaments for treating cancer |
CN100341504C (zh) | 2004-12-01 | 2007-10-10 | 鲁南制药集团股份有限公司 | 佐米曲普坦速释制剂 |
EP1824843A2 (en) | 2004-12-07 | 2007-08-29 | Locus Pharmaceuticals, Inc. | Inhibitors of protein kinases |
CA2595610C (en) * | 2004-12-21 | 2013-03-05 | Astrazeneca Ab | Antibodies directed to angiopoietin-2 and uses thereof |
JP2006230816A (ja) | 2005-02-25 | 2006-09-07 | H & A Investment:Kk | サンダル用ホルダー |
US20080286282A1 (en) | 2005-02-28 | 2008-11-20 | Eisai R & D Management Co., Ltd. | Novel Use of Sulfonamide Compound in Combination with Angiogenesis Inhibitor |
CA2599115A1 (en) | 2005-02-28 | 2006-08-31 | Eisai R & D Management Co., Ltd. | Novel combinational use of sulfonamide compound |
JP5106098B2 (ja) | 2005-02-28 | 2012-12-26 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | スルホンアミド化合物の抗癌剤との新規併用 |
BRPI0610066A2 (pt) | 2005-05-17 | 2010-05-25 | Plexxikon Inc | compostos que modulam atividade de c-kit e c-fms e usos para estes |
MX2007016463A (es) | 2005-06-22 | 2008-03-04 | Plexxikon Inc | Derivados de pirrolo [2,3-b] piridina como inhibidores de proteina cinasa. |
US7550483B2 (en) | 2005-06-23 | 2009-06-23 | Eisai R&D Management Co., Ltd. | Amorphous salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and process for preparing the same |
WO2006137474A1 (ja) | 2005-06-23 | 2006-12-28 | Eisai R & D Management Co., Ltd. | 4-(3-クロロ-4-(シクロプロピルアミノカルボニル)アミノフェノキシ)-7-メトキシ-6-キノリンカルボキサミドの塩のアモルファスおよびその製造方法 |
JP2008546821A (ja) | 2005-06-29 | 2008-12-25 | ロゼリ、 パトリツィア | Vegf受容体を制御する化合物、およびその使用 |
MX2008000573A (es) | 2005-07-18 | 2008-03-14 | Univ Pennsylvania | Implantes que contienen farmacos y metodos de uso de los mismos. |
US8101799B2 (en) | 2005-07-21 | 2012-01-24 | Ardea Biosciences | Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK |
US20080219977A1 (en) | 2005-07-27 | 2008-09-11 | Isaiah Josh Fidler | Combinations Comprising Gemcitabine and Tyrosine Kinase Inhibitors for the Treatment of Pancreatic Cancer |
US20100105031A1 (en) | 2005-08-01 | 2010-04-29 | Esai R & D Management Co., Ltd. | Method for prediction of the efficacy of vascularization inhibitor |
US9006240B2 (en) | 2005-08-02 | 2015-04-14 | Eisai R&D Management Co., Ltd. | Method for assay on the effect of vascularization inhibitor |
AU2006282456C1 (en) | 2005-08-24 | 2012-10-04 | Eisai R & D Management Co., Ltd. | Novel pyridine derivative and pyrimidine derivative (3) |
JP5209966B2 (ja) | 2005-09-01 | 2013-06-12 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 崩壊性の改善された医薬組成物の製造方法 |
CN1308012C (zh) | 2005-11-02 | 2007-04-04 | 广州中医药大学第二附属医院 | 一种治疗脑出血的中药组合物及其制备方法 |
WO2007052849A1 (ja) | 2005-11-07 | 2007-05-10 | Eisai R & D Management Co., Ltd. | 血管新生阻害物質とc-kitキナーゼ阻害物質との併用 |
WO2007061130A1 (ja) | 2005-11-22 | 2007-05-31 | Eisai R & D Management Co., Ltd. | 多発性骨髄腫に対する抗腫瘍剤 |
WO2007066187A2 (en) | 2005-12-05 | 2007-06-14 | Pfizer Products Inc. | Method of treating abnormal cell growth |
AR059066A1 (es) | 2006-01-27 | 2008-03-12 | Amgen Inc | Combinaciones del inhibidor de la angiopoyetina -2 (ang2) y el inhibidor del factor de crecimiento endotelial vascular (vegf) |
KR100728926B1 (ko) | 2006-03-20 | 2007-06-15 | 삼성전자주식회사 | 3축 힌지 구조를 갖는 휴대용 전자기기 |
RU2448708C3 (ru) | 2006-05-18 | 2017-09-28 | Эйсай Ар Энд Ди Менеджмент Ко., Лтд. | Противоопухолевое средство против рака щитовидной железы |
ES2375284T3 (es) | 2006-08-23 | 2012-02-28 | Eisai R&D Management Co., Ltd. | Sal de un derivado de fenoxipiridina, o cristal de la misma, y procedimiento de producción de la misma. |
US8865737B2 (en) | 2006-08-28 | 2014-10-21 | Eisai R&D Management Co., Ltd. | Antitumor agent for undifferentiated gastric cancer |
US7790885B2 (en) | 2006-08-31 | 2010-09-07 | Eisai R&D Management Co., Ltd. | Process for preparing phenoxypyridine derivatives |
WO2008029123A1 (en) | 2006-09-07 | 2008-03-13 | Astrazeneca Ab | Method for evaluating patients for treatment with drugs targeting ret receptor tyrosine kinase |
JP2009184925A (ja) | 2006-11-02 | 2009-08-20 | Dai Ichi Seiyaku Co Ltd | 5−(1h−1,2,3−トリアゾール−4−イル)−1h−ピラゾール誘導体 |
BRPI0806898A2 (pt) | 2007-01-19 | 2015-07-14 | Ardea Biosciences Inc | Inibidores de mek |
KR20090108086A (ko) | 2007-01-19 | 2009-10-14 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 췌장암 치료용 조성물 |
US8962655B2 (en) | 2007-01-29 | 2015-02-24 | Eisai R&D Management Co., Ltd. | Composition for treatment of undifferentiated gastric cancer |
WO2008102870A1 (ja) | 2007-02-23 | 2008-08-28 | Eisai R & D Management Co., Ltd. | Hgfr遺伝子増幅細胞株に優れた細胞増殖阻害効果および抗腫瘍効果を示すピリジン誘導体またはピリミジン誘導体 |
TW200901975A (en) | 2007-03-05 | 2009-01-16 | Kyowa Hakko Kogyo Kk | Pharmaceutical composition |
CA2680161A1 (en) | 2007-03-05 | 2008-09-12 | Kyowa Hakko Kirin Co., Ltd. | Pharmaceutical composition |
US7807172B2 (en) | 2007-06-13 | 2010-10-05 | University Of Washington | Methods and compositions for detecting thyroglobulin in a biological sample |
PE20090368A1 (es) | 2007-06-19 | 2009-04-28 | Boehringer Ingelheim Int | Anticuerpos anti-igf |
JP5479337B2 (ja) | 2007-07-30 | 2014-04-23 | アルディア バイオサイエンス,インク. | Mek阻害剤およびrafキナーゼ阻害剤の組み合わせ、ならびにその使用 |
JP5638244B2 (ja) | 2007-11-09 | 2014-12-10 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 血管新生阻害物質と抗腫瘍性白金錯体との併用 |
JP2009132660A (ja) | 2007-11-30 | 2009-06-18 | Eisai R & D Management Co Ltd | 食道癌治療用組成物 |
JP5399926B2 (ja) | 2008-01-29 | 2014-01-29 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 血管阻害物質とタキサンとの併用 |
GB2456907A (en) | 2008-01-30 | 2009-08-05 | Astrazeneca Ab | Method for determining subsequent VEGFR2 inhibitor therapy comprising measuring baseline VEGF level. |
WO2009111648A1 (en) | 2008-03-05 | 2009-09-11 | Vicus Therapeutics, Llc | Compositions and methods for mucositis and oncology therapies |
US8044240B2 (en) | 2008-03-06 | 2011-10-25 | Ardea Biosciences Inc. | Polymorphic form of N-(S)-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide and uses thereof |
EA201001639A1 (ru) | 2008-04-14 | 2011-06-30 | Арди Байосайенсиз, Инк. | Композиции и способы их получения и применения |
US8637554B2 (en) | 2008-05-07 | 2014-01-28 | The Trustees Of The University Of Pennsylvania | Methods for treating thyroid cancer |
WO2009140549A1 (en) | 2008-05-14 | 2009-11-19 | Amgen Inc. | Combinations vegf(r) inhibitors and hepatocyte growth factor (c-met) inhibitors for the treatment of cancer |
WO2009150256A1 (en) | 2008-06-13 | 2009-12-17 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Markers for predicting response and survival in anti-egfr treated patients |
CA2729914A1 (en) | 2008-07-11 | 2010-01-14 | Novartis Ag | Combination of (a) a phosphoinositide 3-kinase inhibitor and (b) a modulator of ras/raf/mek pathway |
US20110257035A1 (en) * | 2008-10-21 | 2011-10-20 | Bayer Healthcare Llc | Identification of signature genes associated with hepatocellular carcinoma |
EP2461835A4 (en) | 2009-08-07 | 2013-05-15 | Wistar Inst | COMPOSITIONS WITH JARID1B INHIBITORS AND METHOD FOR THE TREATMENT OF CANCER |
EP2468281B1 (en) | 2009-08-19 | 2016-01-27 | Eisai R&D Management Co., Ltd. | Quinoline derivative-containing pharmaceutical composition |
CA2771606A1 (en) | 2009-08-21 | 2011-02-24 | Mount Sinai School Of Medicine Of New York University | Methods of using cd44 fusion proteins to treat cancer |
EP2293071A1 (en) * | 2009-09-07 | 2011-03-09 | Universität Zu Köln | Biomarker for colorectal cancer |
AU2011270165B2 (en) | 2010-06-25 | 2015-12-24 | Eisai R&D Management Co., Ltd. | Antitumor agent using compounds having kinase inhibitory effect in combination |
US20120077837A1 (en) | 2010-09-24 | 2012-03-29 | Eisai R&D Management Co., Ltd. | Anti-tumor agent |
US9133162B2 (en) | 2011-02-28 | 2015-09-15 | Sunshine Lake Pharma Co., Ltd. | Substituted quinoline compounds and methods of use |
WO2012119095A1 (en) | 2011-03-02 | 2012-09-07 | Board Of Regents, The University Of Texas System | Fus1/tusc2 therapies |
CN103476943A (zh) | 2011-03-10 | 2013-12-25 | 普罗维克图斯药品公司 | 用于增强治疗癌症的局部和全身性免疫调节疗法的组合 |
CN102221615A (zh) * | 2011-03-31 | 2011-10-19 | 广州华灿医药科技有限公司 | 一种基于Angiogenin检测的双抗夹心ELISA方法 |
WO2012154935A1 (en) * | 2011-05-12 | 2012-11-15 | Eisai R&D Management Co., Ltd. | Biomarkers that are predictive of responsiveness or non-responsiveness to treatment with lenvatinib or a pharmaceutically acceptable salt thereof |
WO2012157672A1 (ja) | 2011-05-17 | 2012-11-22 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 血管新生阻害剤の効果を予測する方法 |
EP3444363B1 (en) | 2011-06-03 | 2020-11-25 | Eisai R&D Management Co., Ltd. | Biomarkers for prediciting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds |
WO2014113729A2 (en) | 2013-01-18 | 2014-07-24 | Foundation Mecicine, Inc. | Methods of treating cholangiocarcinoma |
CA2901168C (en) | 2013-02-28 | 2020-09-22 | Eisai R&D Management Co., Ltd. | Tetrahydroimidazo[1,5-d][1,4]oxazepine derivative |
JP6411379B2 (ja) | 2013-05-14 | 2018-10-24 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | レンバチニブ化合物に対する子宮内膜がん対象の応答性を予測及び評価するためのバイオマーカー |
JP6287148B2 (ja) | 2013-12-10 | 2018-03-07 | いすゞ自動車株式会社 | エンジンの過給システム |
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US20160089366A1 (en) | 2016-03-31 |
MX2015015605A (es) | 2016-07-07 |
MX368099B (es) | 2019-09-19 |
CN105264380A (zh) | 2016-01-20 |
KR20160009551A (ko) | 2016-01-26 |
AU2014266223B2 (en) | 2020-06-25 |
WO2014185540A1 (en) | 2014-11-20 |
CA2912219A1 (en) | 2014-11-20 |
AU2014266223A1 (en) | 2015-11-26 |
CA2912219C (en) | 2021-11-16 |
RU2658601C2 (ru) | 2018-06-21 |
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EP2997377A1 (en) | 2016-03-23 |
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