JP7061068B2 - 癌治療のための併用薬 - Google Patents
癌治療のための併用薬 Download PDFInfo
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- JP7061068B2 JP7061068B2 JP2018531120A JP2018531120A JP7061068B2 JP 7061068 B2 JP7061068 B2 JP 7061068B2 JP 2018531120 A JP2018531120 A JP 2018531120A JP 2018531120 A JP2018531120 A JP 2018531120A JP 7061068 B2 JP7061068 B2 JP 7061068B2
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Description
本出願は、2015年12月18日に出願した米国仮特許出願第62/269,805号、および2016年11月30に出願された米国仮特許出願第62/428,498号の優先権を主張し、その全体が出典の明示により援用される。
N-[5-(3,5-ジフルオロベンジル)-1H-インダゾール-3-イル]-4-(4-メチル-ピペラジン-1-イル)-2-(テトラヒドロ-2H-ピラン-4-イルアミノ)-ベンズアミドおよびベタイン塩酸塩を含む組成物を以下のように調製した。
一または複数の適切用量のN-[5-(3,5-ジフルオロベンジル)-1H-インダゾール-3-イル]-4-(4-メチル-ピペラジン-1-イル)-2-(テトラヒドロ-2H-ピラン-4-イルアミノ)-ベンズアミドと第2薬剤を非小細胞肺癌の治療のために患者に投与する。併用治療による期待される結果は、(1)癌腫瘍の大きさを減少する、(2)癌腫瘍転移を阻害する(すなわち、いくらか転移を遅らせる、好ましくは、停止する)、(3)癌腫瘍増殖をいくらか阻害する(すなわち、増殖をいくらか遅らせる、好ましくは、停止する)、および/または(4)癌に関連する一または複数の症状をいくらか軽減する(または、好ましくは、消滅する)ことを含む。第2薬剤はMEK阻害剤またはERK阻害剤であってもよい。MEK阻害剤の例として、限定されないが、PD0325901、セルメチニブ、コビメチニブ、レファメチニブ、トラメチニブ、ピマセルチブ、ビニメチニブ、AZD8330、RO4987655、RO5126766、WX-554、E-6201、GDC-0623、TAK-733、RG-7304、CKBP-002、RDEA-436、ソラフェニブ、PD-184352、GSK-2091976A、およびAS-703988が挙げられる。ERK阻害剤の例として、限定されないが、TG-02、MK-8353、ウリキセルチニブ、HE-3235、AEZS-134、AEZS-136、およびIDN-5491が挙げられる。
一または複数の適切用量のN-[5-(3,5-ジフルオロベンジル)-1H-インダゾール-3-イル]-4-(4-メチル-ピペラジン-1-イル)-2-(テトラヒドロ-2H-ピラン-4-イルアミノ)-ベンズアミドと第2薬剤を乳頭様甲状腺癌の治療のために患者に投与する。併用治療による期待される結果は、(1)癌腫瘍の大きさを減少する、(2)癌腫瘍転移を阻害する(すなわち、いくらか転移を遅らせる、好ましくは、停止する)、(3)癌腫瘍増殖をいくらか阻害する(すなわち、増殖をいくらか遅らせる、好ましくは、停止する)、および/または(4)癌に関連する一または複数の症状をいくらか軽減する(または、好ましくは、消滅する)ことを含む。第2薬剤はMEK阻害剤またはERK阻害剤であってもよい。MEK阻害剤の例として、限定されないが、PD0325901、セルメチニブ、コビメチニブ、レファメチニブ、トラメチニブ、ピマセルチブ、ビニメチニブ、AZD8330、RO4987655、RO5126766、WX-554、E-6201、GDC-0623、TAK-733、RG-7304、CKBP-002、RDEA-436、ソラフェニブ、PD-184352、GSK-2091976A、およびAS-703988が挙げられる。ERK阻害剤の例として、限定されないが、TG-02、MK-8353、ウリキセルチニブ、HE-3235、AEZS-134、AEZS-136、およびIDN-5491が挙げられる。
一または複数の適切用量のN-[5-(3,5-ジフルオロベンジル)-1H-インダゾール-3-イル]-4-(4-メチル-ピペラジン-1-イル)-2-(テトラヒドロ-2H-ピラン-4-イルアミノ)-ベンズアミドと第2薬剤を神経芽細胞腫の治療のために患者に投与する。併用治療による期待される結果は、(1)癌腫瘍の大きさを減少する、(2)癌腫瘍転移を阻害する(すなわち、いくらか転移を遅らせる、好ましくは、停止する)、(3)癌腫瘍増殖をいくらか阻害する(すなわち、増殖をいくらか遅らせる、好ましくは、停止する)、および/または(4)癌に関連する一または複数の症状をいくらか軽減する(または、好ましくは、消滅する)ことを含む。第2薬剤はMEK阻害剤またはERK阻害剤であってもよい。MEK阻害剤の例として、限定されないが、PD0325901、セルメチニブ、コビメチニブ、レファメチニブ、トラメチニブ、ピマセルチブ、ビニメチニブ、AZD8330、RO4987655、RO5126766、WX-554、E-6201、GDC-0623、TAK-733、RG-7304、CKBP-002、RDEA-436、ソラフェニブ、PD-184352、GSK-2091976A、およびAS-703988が挙げられる。ERK阻害剤の例として、限定されないが、TG-02、MK-8353、ウリキセルチニブ、HE-3235、AEZS-134、AEZS-136、およびIDN-5491が挙げられる。
一または複数の適切用量のN-[5-(3,5-ジフルオロベンジル)-1H-インダゾール-3-イル]-4-(4-メチル-ピペラジン-1-イル)-2-(テトラヒドロ-2H-ピラン-4-イルアミノ)-ベンズアミドと第2薬剤を膵臓癌の治療のために患者に投与する。併用治療による期待される結果は、(1)癌腫瘍の大きさを減少する、(2)癌腫瘍転移を阻害する(すなわち、いくらか転移を遅らせる、好ましくは、停止する)、(3)癌腫瘍増殖をいくらか阻害する(すなわち、増殖をいくらか遅らせる、好ましくは、停止する)、および/または(4)癌に関連する一または複数の症状をいくらか軽減する(または、好ましくは、消滅する)ことを含む。第2薬剤はMEK阻害剤またはERK阻害剤であってもよい。MEK阻害剤の例として、限定されないが、PD0325901、セルメチニブ、コビメチニブ、レファメチニブ、トラメチニブ、ピマセルチブ、ビニメチニブ、AZD8330、RO4987655、RO5126766、WX-554、E-6201、GDC-0623、TAK-733、RG-7304、CKBP-002、RDEA-436、ソラフェニブ、PD-184352、GSK-2091976A、およびAS-703988が挙げられる。ERK阻害剤の例として、限定されないが、TG-02、MK-8353、ウリキセルチニブ、HE-3235、AEZS-134、AEZS-136、およびIDN-5491が挙げられる。
一または複数の適切用量のN-[5-(3,5-ジフルオロベンジル)-1H-インダゾール-3-イル]-4-(4-メチル-ピペラジン-1-イル)-2-(テトラヒドロ-2H-ピラン-4-イルアミノ)-ベンズアミドと第2薬剤をメラノーマの治療のために患者に投与する。併用治療による期待される結果は、(1)癌腫瘍の大きさを減少する、(2)癌腫瘍転移を阻害する(すなわち、いくらか転移を遅らせる、好ましくは、停止する)、(3)癌腫瘍増殖をいくらか阻害する(すなわち、増殖をいくらか遅らせる、好ましくは、停止する)、および/または(4)癌に関連する一または複数の症状をいくらか軽減する(または、好ましくは、消滅する)ことを含む。第2薬剤はMEK阻害剤またはERK阻害剤であってもよい。MEK阻害剤の例として、限定されないが、PD0325901、セルメチニブ、コビメチニブ、レファメチニブ、トラメチニブ、ピマセルチブ、ビニメチニブ、AZD8330、RO4987655、RO5126766、WX-554、E-6201、GDC-0623、TAK-733、RG-7304、CKBP-002、RDEA-436、ソラフェニブ、PD-184352、GSK-2091976A、およびAS-703988が挙げられる。ERK阻害剤の例として、限定されないが、TG-02、MK-8353、ウリキセルチニブ、HE-3235、AEZS-134、AEZS-136、およびIDN-5491が挙げられる。
一または複数の適切用量のN-[5-(3,5-ジフルオロベンジル)-1H-インダゾール-3-イル]-4-(4-メチル-ピペラジン-1-イル)-2-(テトラヒドロ-2H-ピラン-4-イルアミノ)-ベンズアミドと第2薬剤を結腸直腸癌の治療のために患者に投与する。併用治療による期待される結果は、(1)癌腫瘍の大きさを減少する、(2)癌腫瘍転移を阻害する(すなわち、いくらか転移を遅らせる、好ましくは、停止する)、(3)癌腫瘍増殖をいくらか阻害する(すなわち、増殖をいくらか遅らせる、好ましくは、停止する)、および/または(4)癌に関連する一または複数の症状をいくらか軽減する(または、好ましくは、消滅する)ことを含む。第2薬剤はMEK阻害剤またはERK阻害剤であってもよい。MEK阻害剤の例として、限定されないが、PD0325901、セルメチニブ、コビメチニブ、レファメチニブ、トラメチニブ、ピマセルチブ、ビニメチニブ、AZD8330、RO4987655、RO5126766、WX-554、E-6201、GDC-0623、TAK-733、RG-7304、CKBP-002、RDEA-436、ソラフェニブ、PD-184352、GSK-2091976A、およびAS-703988が挙げられる。ERK阻害剤の例として、限定されないが、TG-02、MK-8353、ウリキセルチニブ、HE-3235、AEZS-134、AEZS-136、およびIDN-5491が挙げられる。
本実施例は、TPM3-TrkA-G595R融合タンパク質を発現するトランスジェニックBa/F3細胞を生成するために実施した。TPM3-TrkA-G595R融合をコードするcDNAをPCRをベースとした技術によってエントレクチニブ耐性細胞からクローン化し、次に、レンチウイルスベクターpVL-EF1a-MCS-IRES-Puro(BioSettia、San Diego、CA)に挿入した。直接配列決定法によってcDNA挿入物を確認した後、TPM3-TrkA-G595R cDNAを含有する水疱性口内炎ウイルスGP(VSVG)偽型レンチウイルスを、8μg/mLのポリブレン(EMD Millipore)による異なる感染多重度で、マウスIL-3依存性pro-B細胞Ba/F3に形質導入した。形質導入したBa/F3細胞を、10%FBSおよび1μg/mLのピューロマイシンを2週間補充したマウスIL-3含有RPMI培地で選択した。安定した細胞プールを、10%FBSが存在し、マウスIL-3が存在しない状態で4週間補充したRPMI培地(GIBCO(登録商標))でさらに選択した。
TPM3-TrkAまたはTPM3-TrkA-G595Rのいずれかを発現する5~1,000万個のBa/F3細胞を、5%のCO2インキュベータにおいて、異なる濃度のエントレクチニブ(RXDX-101)で2時間インキュベートした。冷たいリン酸緩衝食塩水(PBS)(1倍)で細胞を2回洗浄し、プロテアーゼ阻害剤とホスファターゼ阻害剤のカクテル(EMDMillipore)を有する1倍のRIPAに再懸濁し、得られた混合物を4℃で30分間揺らした。得られた溶解物を4℃で10分間遠心分離(10,000×g)にかけて澄ませた。得られた上清は、ウエスタンブロット分析のために保管した。20~40μgの得られたタンパク質をSDS-PAGE電気泳動で分離し、フッ化ポリビニリデン(PVDF)膜に移動した。得られた膜を、個別のマニュアルに記載の手順に従って、ホスホ-TrkA-Y490、ホスホ-TrkA-Y785、pan-Trk、PLCY1、ホスホ-PLCY1-Y783、MEK1/2、ホスホ-MEK1/2(S217/S221)、β-アクチンから成る抗体(他に断りがない限り細胞シグナル伝達から得た)でブロットした。得られたバンドをECL試薬(Amersham)で展開し、ChemiDoc imager(Bio-Rad)を用いて画像を捕えた。ウエスタンブロット分析の結果を図1に示し、TPM3-TrkA-G595Rを発現するBa/F3細胞対野生型TPM3-TrkAを発現するBa/F3細胞において、p-MEK1/2(Ser217/221)および合計のMEK1/2がアップレギュレーションすることを実証する。
エントレクチニブ(RXDX-101)、トラメチニブ、ならびにエントレクチニブおよびトラメチニブの併用による治療から生じるTPM3-TrkA-G959Rを発現するBa/F3細胞株の増殖の効果を測定した。ウェルあたり約100万のTPM3-TrkA-G959Rを発現するBa/F3細胞を5mLの培地における6ウェルプレートに蒔いた。ウェルに、以下のDMSOの1,000倍のストック:(a)阻害剤なし(対照としてジメチルスルホキシド(DMSO)単独)、(b)濃度が約300nMのエントレクチニブ(RXDX-101)、(c)濃度が約30nMのトラメチニブ、または(d)濃度約300nMのエントレクチニブ(RXDX-101)と濃度約30nMのトラメチニブの併用の1つのを加えた。各個別のウェルの細胞を、トリパンブルー(Invitrogen、Carlsbad、CA)の存在下でCountess(商標)細胞カウンタを用いて3~4日毎に数えた。各ウェルの細胞をカウントした日に少なくとも100万個の生存細胞を含むウェルについては、細胞を含む培地を、それぞれ同濃度のエントレクチニブ、トラメチニブ、またはエントレクチニブとトラメチニブの併用を含む新鮮な増殖培地で1:10に希釈した。各ウェルの細胞をカウントした日にに100万個未満の細胞を含むウェルについては、何も変えなかった。試験結果を図2に示し、エントレクチニブ(300nM)とトラメチニブ(30nM)の併用で処理した細胞は、化合物を含まない(DMSO対照)ウェルの細胞、およびエントレクチニブ(300nM)単独を含むウェルの細胞、およびトラメチニブ(30nM)単独を含むウェルの細胞に比べて、有意な増殖阻害(最大40日)を示すことを実証している。
胸腺欠損のnu/nuマウス(6~7週齢雌)に、2百万個のKM-12 TPM3-NTRK1 G595R細胞/マウスを右側腹部に皮下移植した。平均腫瘍量が約150mm3に達したとき、マウスをランダムに振り分けた。ビヒクル、60mg/kgのエントレクチニブ、1mg/kgのトラメチニブ、およびエントレクチニブ(60mg/kg)+トラメチニブ(1mg/kg)の計10用量をマウスに1日4回(q.d.)経口投与(p.o.)した。全ての治療群に忍容性があった。結果を図3に示し、TPM3-TrkA-G595Rを発現する細胞を移植したマウスの腫瘍増殖が、エントレクチニブ(RXDX-101)(60mg/kg)とトラメチニブ(1mg/kg)の併用薬を投与されたマウスにおいて、対照群(ビヒクル)のマウス、エントレクチニブ単独(60mg/kg)を投与されたマウス、およびトラメチニブ単独(1mg/kg)を投与されたマウスより減少したことを実証している。
腫瘍量(mm3)=[長さ(mm)×幅(mm)×幅(mm)]/2 (1)
%TGI=[(TVvehicle-TVtreatment)/(TVvehicle-TVinitial)]×100
ヒトトロポミオシン受容体キナーゼA(TrkA)
Met Leu Arg Gly Gly Arg Arg Gly Gln Leu Gly Trp His Ser Trp Ala
Ala Gly Pro Gly Ser Leu Leu Ala Trp Leu Ile Leu Ala Ser Ala Gly
Ala Ala Pro Cys Pro Asp Ala Cys Cys Pro His Gly Ser Ser Gly Leu
Arg Cys Thr Arg Asp Gly Ala Leu Asp Ser Leu His His Leu Pro Gly
Ala Glu Asn Leu Thr Glu Leu Tyr Ile Glu Asn Gln Gln His Leu Gln
His Leu Glu Leu Arg Asp Leu Arg Gly Leu Gly Glu Leu Arg Asn Leu
Thr Ile Val Lys Ser Gly Leu Arg Phe Val Ala Pro Asp Ala Phe His
Phe Thr Pro Arg Leu Ser Arg Leu Asn Leu Ser Phe Asn Ala Leu Glu
Ser Leu Ser Trp Lys Thr Val Gln Gly Leu Ser Leu Gln Glu Leu Val
Leu Ser Gly Asn Pro Leu His Cys Ser Cys Ala Leu Arg Trp Leu Gln
Arg Trp Glu Glu Glu Gly Leu Gly Gly Val Pro Glu Gln Lys Leu Gln
Cys His Gly Gln Gly Pro Leu Ala His Met Pro Asn Ala Ser Cys Gly
Val Pro Thr Leu Lys Val Gln Val Pro Asn Ala Ser Val Asp Val Gly
Asp Asp Val Leu Leu Arg Cys Gln Val Glu Gly Arg Gly Leu Glu Gln
Ala Gly Trp Ile Leu Thr Glu Leu Glu Gln Ser Ala Thr Val Met Lys
Ser Gly Gly Leu Pro Ser Leu Gly Leu Thr Leu Ala Asn Val Thr Ser
Asp Leu Asn Arg Lys Asn Val Thr Cys Trp Ala Glu Asn Asp Val Gly
Arg Ala Glu Val Ser Val Gln Val Asn Val Ser Phe Pro Ala Ser Val
Gln Leu His Thr Ala Val Glu Met His His Trp Cys Ile Pro Phe Ser
Val Asp Gly Gln Pro Ala Pro Ser Leu Arg Trp Leu Phe Asn Gly Ser
Val Leu Asn Glu Thr Ser Phe Ile Phe Thr Glu Phe Leu Glu Pro Ala
Ala Asn Glu Thr Val Arg His Gly Cys Leu Arg Leu Asn Gln Pro Thr
His Val Asn Asn Gly Asn Tyr Thr Leu Leu Ala Ala Asn Pro Phe Gly
Gln Ala Ser Ala Ser Ile Met Ala Ala Phe Met Asp Asn Pro Phe Glu
Phe Asn Pro Glu Asp Pro Ile Pro Val Ser Phe Ser Pro Val Asp Thr
Asn Ser Thr Ser Gly Asp Pro Val Glu Lys Lys Asp Glu Thr Pro Phe
Gly Val Ser Val Ala Val Gly Leu Ala Val Phe Ala Cys Leu Phe Leu
Ser Thr Leu Leu Leu Val Leu Asn Lys Cys Gly Arg Arg Asn Lys Phe
Gly Ile Asn Arg Pro Ala Val Leu Ala Pro Glu Asp Gly Leu Ala Met
Ser Leu His Phe Met Thr Leu Gly Gly Ser Ser Leu Ser Pro Thr Glu
Gly Lys Gly Ser Gly Leu Gln Gly His Ile Ile Glu Asn Pro Gln Tyr
Phe Ser Asp Ala Cys Val His His Ile Lys Arg Arg Asp Ile Val Leu
Lys Trp Glu Leu Gly Glu Gly Ala Phe Gly Lys Val Phe Leu Ala Glu
Cys His Asn Leu Leu Pro Glu Gln Asp Lys Met Leu Val Ala Val Lys
Ala Leu Lys Glu Ala Ser Glu Ser Ala Arg Gln Asp Phe Gln Arg Glu
Ala Glu Leu Leu Thr Met Leu Gln His Gln His Ile Val Arg Phe Phe
Gly Val Cys Thr Glu Gly Arg Pro Leu Leu Met Val Phe Glu Tyr Met
Arg His Gly Asp Leu Asn Arg Phe Leu Arg Ser His Gly Pro Asp Ala
Lys Leu Leu Ala Gly Gly Glu Asp Val Ala Pro Gly Pro Leu Gly Leu
Gly Gln Leu Leu Ala Val Ala Ser Gln Val Ala Ala Gly Met Val Tyr
Leu Ala Gly Leu His Phe Val His Arg Asp Leu Ala Thr Arg Asn Cys
Leu Val Gly Gln Gly Leu Val Val Lys Ile Gly Asp Phe Gly Met Ser
Arg Asp Ile Tyr Ser Thr Asp Tyr Tyr Arg Val Gly Gly Arg Thr Met
Leu Pro Ile Arg Trp Met Pro Pro Glu Ser Ile Leu Tyr Arg Lys Phe
Thr Thr Glu Ser Asp Val Trp Ser Phe Gly Val Val Leu Trp Glu Ile
Phe Thr Tyr Gly Lys Gln Pro Trp Tyr Gln Leu Ser Asn Thr Glu Ala
Ile Asp Cys Ile Thr Gln Gly Arg Glu Leu Glu Arg Pro Arg Ala Cys
Pro Pro Glu Val Tyr Ala Ile Met Arg Gly Cys Trp Gln Arg Glu Pro
Gln Gln Arg His Ser Ile Lys Asp Val His Ala Arg Leu Gln Ala Leu
Ala Gln Ala Pro Pro Val Tyr Leu Asp Val Leu Gly(配列番号:1)
Met Ser Ser Trp Ile Arg Trp His Gly Pro Ala Met Ala Arg Leu Trp
Gly Phe Cys Trp Leu Val Val Gly Phe Trp Arg Ala Ala Phe Ala Cys
Pro Thr Ser Cys Lys Cys Ser Ala Ser Arg Ile Trp Cys Ser Asp Pro
Ser Pro Gly Ile Val Ala Phe Pro Arg Leu Glu Pro Asn Ser Val Asp
Pro Glu Asn Ile Thr Glu Ile Phe Ile Ala Asn Gln Lys Arg Leu Glu
Ile Ile Asn Glu Asp Asp Val Glu Ala Tyr Val Gly Leu Arg Asn Leu
Thr Ile Val Asp Ser Gly Leu Lys Phe Val Ala His Lys Ala Phe Leu
Lys Asn Ser Asn Leu Gln His Ile Asn Phe Thr Arg Asn Lys Leu Thr
Ser Leu Ser Arg Lys His Phe Arg His Leu Asp Leu Ser Glu Leu Ile
Leu Val Gly Asn Pro Phe Thr Cys Ser Cys Asp Ile Met Trp Ile Lys
Thr Leu Gln Glu Ala Lys Ser Ser Pro Asp Thr Gln Asp Leu Tyr Cys
Leu Asn Glu Ser Ser Lys Asn Ile Pro Leu Ala Asn Leu Gln Ile Pro
Asn Cys Gly Leu Pro Ser Ala Asn Leu Ala Ala Pro Asn Leu Thr Val
Glu Glu Gly Lys Ser Ile Thr Leu Ser Cys Ser Val Ala Gly Asp Pro
Val Pro Asn Met Tyr Trp Asp Val Gly Asn Leu Val Ser Lys His Met
Asn Glu Thr Ser His Thr Gln Gly Ser Leu Arg Ile Thr Asn Ile Ser
Ser Asp Asp Ser Gly Lys Gln Ile Ser Cys Val Ala Glu Asn Leu Val
Gly Glu Asp Gln Asp Ser Val Asn Leu Thr Val His Phe Ala Pro Thr
Ile Thr Phe Leu Glu Ser Pro Thr Ser Asp His His Trp Cys Ile Pro
Phe Thr Val Lys Gly Asn Pro Lys Pro Ala Leu Gln Trp Phe Tyr Asn
Gly Ala Ile Leu Asn Glu Ser Lys Tyr Ile Cys Thr Lys Ile His Val
Thr Asn His Thr Glu Tyr His Gly Cys Leu Gln Leu Asp Asn Pro Thr
His Met Asn Asn Gly Asp Tyr Thr Leu Ile Ala Lys Asn Glu Tyr Gly
Lys Asp Glu Lys Gln Ile Ser Ala His Phe Met Gly Trp Pro Gly Ile
Asp Asp Gly Ala Asn Pro Asn Tyr Pro Asp Val Ile Tyr Glu Asp Tyr
Gly Thr Ala Ala Asn Asp Ile Gly Asp Thr Thr Asn Arg Ser Asn Glu
Ile Pro Ser Thr Asp Val Thr Asp Lys Thr Gly Arg Glu His Leu Ser
Val Tyr Ala Val Val Val Ile Ala Ser Val Val Gly Phe Cys Leu Leu
Val Met Leu Phe Leu Leu Lys Leu Ala Arg His Ser Lys Phe Gly Met
Lys Asp Phe Ser Trp Phe Gly Phe Gly Lys Val Lys Ser Arg Gln Gly
Val Gly Pro Ala Ser Val Ile Ser Asn Asp Asp Asp Ser Ala Ser Pro
Leu His His Ile Ser Asn Gly Ser Asn Thr Pro Ser Ser Ser Glu Gly
Gly Pro Asp Ala Val Ile Ile Gly Met Thr Lys Ile Pro Val Ile Glu
Asn Pro Gln Tyr Phe Gly Ile Thr Asn Ser Gln Leu Lys Pro Asp Thr
Phe Val Gln His Ile Lys Arg His Asn Ile Val Leu Lys Arg Glu Leu
Gly Glu Gly Ala Phe Gly Lys Val Phe Leu Ala Glu Cys Tyr Asn Leu
Cys Pro Glu Gln Asp Lys Ile Leu Val Ala Val Lys Thr Leu Lys Asp
Ala Ser Asp Asn Ala Arg Lys Asp Phe His Arg Glu Ala Glu Leu Leu
Thr Asn Leu Gln His Glu His Ile Val Lys Phe Tyr Gly Val Cys Val
Glu Gly Asp Pro Leu Ile Met Val Phe Glu Tyr Met Lys His Gly Asp
Leu Asn Lys Phe Leu Arg Ala His Gly Pro Asp Ala Val Leu Met Ala
Glu Gly Asn Pro Pro Thr Glu Leu Thr Gln Ser Gln Met Leu His Ile
Ala Gln Gln Ile Ala Ala Gly Met Val Tyr Leu Ala Ser Gln His Phe
Val His Arg Asp Leu Ala Thr Arg Asn Cys Leu Val Gly Glu Asn Leu
Leu Val Lys Ile Gly Asp Phe Gly Met Ser Arg Asp Val Tyr Ser Thr
Asp Tyr Tyr Arg Val Gly Gly His Thr Met Leu Pro Ile Arg Trp Met
Pro Pro Glu Ser Ile Met Tyr Arg Lys Phe Thr Thr Glu Ser Asp Val
Trp Ser Leu Gly Val Val Leu Trp Glu Ile Phe Thr Tyr Gly Lys Gln
Pro Trp Tyr Gln Leu Ser Asn Asn Glu Val Ile Glu Cys Ile Thr Gln
Gly Arg Val Leu Gln Arg Pro Arg Thr Cys Pro Gln Glu Val Tyr Glu
Leu Met Leu Gly Cys Trp Gln Arg Glu Pro His Met Arg Lys Asn Ile
Lys Gly Ile His Thr Leu Leu Gln Asn Leu Ala Lys Ala Ser Pro Val
Tyr Leu Asp Ile Leu Gly(配列番号:2)
Met Asp Val Ser Leu Cys Pro Ala Lys Cys Ser Phe Trp Arg Ile Phe
Leu Leu Gly Ser Val Trp Leu Asp Tyr Val Gly Ser Val Leu Ala Cys
Pro Ala Asn Cys Val Cys Ser Lys Thr Glu Ile Asn Cys Arg Arg Pro
Asp Asp Gly Asn Leu Phe Pro Leu Leu Glu Gly Gln Asp Ser Gly Asn
Ser Asn Gly Asn Ala Ser Ile Asn Ile Thr Asp Ile Ser Arg Asn Ile
Thr Ser Ile His Ile Glu Asn Trp Arg Ser Leu His Thr Leu Asn Ala
Val Asp Met Glu Leu Tyr Thr Gly Leu Gln Lys Leu Thr Ile Lys Asn
Ser Gly Leu Arg Ser Ile Gln Pro Arg Ala Phe Ala Lys Asn Pro His
Leu Arg Tyr Ile Asn Leu Ser Ser Asn Arg Leu Thr Thr Leu Ser Trp
Gln Leu Phe Gln Thr Leu Ser Leu Arg Glu Leu Gln Leu Glu Gln Asn
Phe Phe Asn Cys Ser Cys Asp Ile Arg Trp Met Gln Leu Trp Gln Glu
Gln Gly Glu Ala Lys Leu Asn Ser Gln Asn Leu Tyr Cys Ile Asn Ala
Asp Gly Ser Gln Leu Pro Leu Phe Arg Met Asn Ile Ser Gln Cys Asp
Leu Pro Glu Ile Ser Val Ser His Val Asn Leu Thr Val Arg Glu Gly
Asp Asn Ala Val Ile Thr Cys Asn Gly Ser Gly Ser Pro Leu Pro Asp
Val Asp Trp Ile Val Thr Gly Leu Gln Ser Ile Asn Thr His Gln Thr
Asn Leu Asn Trp Thr Asn Val His Ala Ile Asn Leu Thr Leu Val Asn
Val Thr Ser Glu Asp Asn Gly Phe Thr Leu Thr Cys Ile Ala Glu Asn
Val Val Gly Met Ser Asn Ala Ser Val Ala Leu Thr Val Tyr Tyr Pro
Pro Arg Val Val Ser Leu Glu Glu Pro Glu Leu Arg Leu Glu His Cys
Ile Glu Phe Val Val Arg Gly Asn Pro Pro Pro Thr Leu His Trp Leu
His Asn Gly Gln Pro Leu Arg Glu Ser Lys Ile Ile His Val Glu Tyr
Tyr Gln Glu Gly Glu Ile Ser Glu Gly Cys Leu Leu Phe Asn Lys Pro
Thr His Tyr Asn Asn Gly Asn Tyr Thr Leu Ile Ala Lys Asn Pro Leu
Gly Thr Ala Asn Gln Thr Ile Asn Gly His Phe Leu Lys Glu Pro Phe
Pro Glu Ser Thr Asp Asn Phe Ile Leu Phe Asp Glu Val Ser Pro Thr
Pro Pro Ile Thr Val Thr His Lys Pro Glu Glu Asp Thr Phe Gly Val
Ser Ile Ala Val Gly Leu Ala Ala Phe Ala Cys Val Leu Leu Val Val
Leu Phe Val Met Ile Asn Lys Tyr Gly Arg Arg Ser Lys Phe Gly Met
Lys Gly Pro Val Ala Val Ile Ser Gly Glu Glu Asp Ser Ala Ser Pro
Leu His His Ile Asn His Gly Ile Thr Thr Pro Ser Ser Leu Asp Ala
Gly Pro Asp Thr Val Val Ile Gly Met Thr Arg Ile Pro Val Ile Glu
Asn Pro Gln Tyr Phe Arg Gln Gly His Asn Cys His Lys Pro Asp Thr
Tyr Val Gln His Ile Lys Arg Arg Asp Ile Val Leu Lys Arg Glu Leu
Gly Glu Gly Ala Phe Gly Lys Val Phe Leu Ala Glu Cys Tyr Asn Leu
Ser Pro Thr Lys Asp Lys Met Leu Val Ala Val Lys Ala Leu Lys Asp
Pro Thr Leu Ala Ala Arg Lys Asp Phe Gln Arg Glu Ala Glu Leu Leu
Thr Asn Leu Gln His Glu His Ile Val Lys Phe Tyr Gly Val Cys Gly
Asp Gly Asp Pro Leu Ile Met Val Phe Glu Tyr Met Lys His Gly Asp
Leu Asn Lys Phe Leu Arg Ala His Gly Pro Asp Ala Met Ile Leu Val
Asp Gly Gln Pro Arg Gln Ala Lys Gly Glu Leu Gly Leu Ser Gln Met
Leu His Ile Ala Ser Gln Ile Ala Ser Gly Met Val Tyr Leu Ala Ser
Gln His Phe Val His Arg Asp Leu Ala Thr Arg Asn Cys Leu Val Gly
Ala Asn Leu Leu Val Lys Ile Gly Asp Phe Gly Met Ser Arg Asp Val
Tyr Ser Thr Asp Tyr Tyr Arg Leu Phe Asn Pro Ser Gly Asn Asp Phe
Cys Ile Trp Cys Glu Val Gly Gly His Thr Met Leu Pro Ile Arg Trp
Met Pro Pro Glu Ser Ile Met Tyr Arg Lys Phe Thr Thr Glu Ser Asp
Val Trp Ser Phe Gly Val Ile Leu Trp Glu Ile Phe Thr Tyr Gly Lys
Gln Pro Trp Phe Gln Leu Ser Asn Thr Glu Val Ile Glu Cys Ile Thr
Gln Gly Arg Val Leu Glu Arg Pro Arg Val Cys Pro Lys Glu Val Tyr
Asp Val Met Leu Gly Cys Trp Gln Arg Glu Pro Gln Gln Arg Leu Asn
Ile Lys Glu Ile Tyr Lys Ile Leu His Ala Leu Gly Lys Ala Thr Pro
Ile Tyr Leu Asp Ile Leu Gly(配列番号:3)
Met Gly Ala Ile Gly Leu Leu Trp Leu Leu Pro Leu Leu Leu Ser Thr
Ala Ala Val Gly Ser Gly Met Gly Thr Gly Gln Arg Ala Gly Ser Pro
Ala Ala Gly Pro Pro Leu Gln Pro Arg Glu Pro Leu Ser Tyr Ser Arg
Leu Gln Arg Lys Ser Leu Ala Val Asp Phe Val Val Pro Ser Leu Phe
Arg Val Tyr Ala Arg Asp Leu Leu Leu Pro Pro Ser Ser Ser Glu Leu
Lys Ala Gly Arg Pro Glu Ala Arg Gly Ser Leu Ala Leu Asp Cys Ala
Pro Leu Leu Arg Leu Leu Gly Pro Ala Pro Gly Val Ser Trp Thr Ala
Gly Ser Pro Ala Pro Ala Glu Ala Arg Thr Leu Ser Arg Val Leu Lys
Gly Gly Ser Val Arg Lys Leu Arg Arg Ala Lys Gln Leu Val Leu Glu
Leu Gly Glu Glu Ala Ile Leu Glu Gly Cys Val Gly Pro Pro Gly Glu
Ala Ala Val Gly Leu Leu Gln Phe Asn Leu Ser Glu Leu Phe Ser Trp
Trp Ile Arg Gln Gly Glu Gly Arg Leu Arg Ile Arg Leu Met Pro Glu
Lys Lys Ala Ser Glu Val Gly Arg Glu Gly Arg Leu Ser Ala Ala Ile
Arg Ala Ser Gln Pro Arg Leu Leu Phe Gln Ile Phe Gly Thr Gly His
Ser Ser Leu Glu Ser Pro Thr Asn Met Pro Ser Pro Ser Pro Asp Tyr
Phe Thr Trp Asn Leu Thr Trp Ile Met Lys Asp Ser Phe Pro Phe Leu
Ser His Arg Ser Arg Tyr Gly Leu Glu Cys Ser Phe Asp Phe Pro Cys
Glu Leu Glu Tyr Ser Pro Pro Leu His Asp Leu Arg Asn Gln Ser Trp
Ser Trp Arg Arg Ile Pro Ser Glu Glu Ala Ser Gln Met Asp Leu Leu
Asp Gly Pro Gly Ala Glu Arg Ser Lys Glu Met Pro Arg Gly Ser Phe
Leu Leu Leu Asn Thr Ser Ala Asp Ser Lys His Thr Ile Leu Ser Pro
Trp Met Arg Ser Ser Ser Glu His Cys Thr Leu Ala Val Ser Val His
Arg His Leu Gln Pro Ser Gly Arg Tyr Ile Ala Gln Leu Leu Pro His
Asn Glu Ala Ala Arg Glu Ile Leu Leu Met Pro Thr Pro Gly Lys His
Gly Trp Thr Val Leu Gln Gly Arg Ile Gly Arg Pro Asp Asn Pro Phe
Arg Val Ala Leu Glu Tyr Ile Ser Ser Gly Asn Arg Ser Leu Ser Ala
Val Asp Phe Phe Ala Leu Lys Asn Cys Ser Glu Gly Thr Ser Pro Gly
Ser Lys Met Ala Leu Gln Ser Ser Phe Thr Cys Trp Asn Gly Thr Val
Leu Gln Leu Gly Gln Ala Cys Asp Phe His Gln Asp Cys Ala Gln Gly
Glu Asp Glu Ser Gln Met Cys Arg Lys Leu Pro Val Gly Phe Tyr Cys
Asn Phe Glu Asp Gly Phe Cys Gly Trp Thr Gln Gly Thr Leu Ser Pro
His Thr Pro Gln Trp Gln Val Arg Thr Leu Lys Asp Ala Arg Phe Gln
Asp His Gln Asp His Ala Leu Leu Leu Ser Thr Thr Asp Val Pro Ala
Ser Glu Ser Ala Thr Val Thr Ser Ala Thr Phe Pro Ala Pro Ile Lys
Ser Ser Pro Cys Glu Leu Arg Met Ser Trp Leu Ile Arg Gly Val Leu
Arg Gly Asn Val Ser Leu Val Leu Val Glu Asn Lys Thr Gly Lys Glu
Gln Gly Arg Met Val Trp His Val Ala Ala Tyr Glu Gly Leu Ser Leu
Trp Gln Trp Met Val Leu Pro Leu Leu Asp Val Ser Asp Arg Phe Trp
Leu Gln Met Val Ala Trp Trp Gly Gln Gly Ser Arg Ala Ile Val Ala
Phe Asp Asn Ile Ser Ile Ser Leu Asp Cys Tyr Leu Thr Ile Ser Gly
Glu Asp Lys Ile Leu Gln Asn Thr Ala Pro Lys Ser Arg Asn Leu Phe
Glu Arg Asn Pro Asn Lys Glu Leu Lys Pro Gly Glu Asn Ser Pro Arg
Gln Thr Pro Ile Phe Asp Pro Thr Val His Trp Leu Phe Thr Thr Cys
Gly Ala Ser Gly Pro His Gly Pro Thr Gln Ala Gln Cys Asn Asn Ala
Tyr Gln Asn Ser Asn Leu Ser Val Glu Val Gly Ser Glu Gly Pro Leu
Lys Gly Ile Gln Ile Trp Lys Val Pro Ala Thr Asp Thr Tyr Ser Ile
Ser Gly Tyr Gly Ala Ala Gly Gly Lys Gly Gly Lys Asn Thr Met Met
Arg Ser His Gly Val Ser Val Leu Gly Ile Phe Asn Leu Glu Lys Asp
Asp Met Leu Tyr Ile Leu Val Gly Gln Gln Gly Glu Asp Ala Cys Pro
Ser Thr Asn Gln Leu Ile Gln Lys Val Cys Ile Gly Glu Asn Asn Val
Ile Glu Glu Glu Ile Arg Val Asn Arg Ser Val His Glu Trp Ala Gly
Gly Gly Gly Gly Gly Gly Gly Ala Thr Tyr Val Phe Lys Met Lys Asp
Gly Val Pro Val Pro Leu Ile Ile Ala Ala Gly Gly Gly Gly Arg Ala
Tyr Gly Ala Lys Thr Asp Thr Phe His Pro Glu Arg Leu Glu Asn Asn
Ser Ser Val Leu Gly Leu Asn Gly Asn Ser Gly Ala Ala Gly Gly Gly
Gly Gly Trp Asn Asp Asn Thr Ser Leu Leu Trp Ala Gly Lys Ser Leu
Gln Glu Gly Ala Thr Gly Gly His Ser Cys Pro Gln Ala Met Lys Lys
Trp Gly Trp Glu Thr Arg Gly Gly Phe Gly Gly Gly Gly Gly Gly Cys
Ser Ser Gly Gly Gly Gly Gly Gly Tyr Ile Gly Gly Asn Ala Ala Ser
Asn Asn Asp Pro Glu Met Asp Gly Glu Asp Gly Val Ser Phe Ile Ser
Pro Leu Gly Ile Leu Tyr Thr Pro Ala Leu Lys Val Met Glu Gly His
Gly Glu Val Asn Ile Lys His Tyr Leu Asn Cys Ser His Cys Glu Val
Asp Glu Cys His Met Asp Pro Glu Ser His Lys Val Ile Cys Phe Cys
Asp His Gly Thr Val Leu Ala Glu Asp Gly Val Ser Cys Ile Val
Ser Pro Thr Pro Glu Pro His Leu Pro Leu Ser Leu Ile Leu Ser
Val Val Thr Ser Ala Leu Val Ala Ala Leu Val Leu Ala Phe Ser
Gly Ile Met Ile Val Tyr Arg Arg Lys His Gln Glu Leu Gln Ala
Met Gln Met Glu Leu Gln Ser Pro Glu Tyr Lys Leu Ser Lys Leu
Arg Thr Ser Thr Ile Met Thr Asp Tyr Asn Pro Asn Tyr Cys Phe
Ala Gly Lys Thr Ser Ser Ile Ser Asp Leu Lys Glu Val Pro Arg
Lys Asn Ile Thr Leu Ile Arg Gly Leu Gly His Gly Ala Phe Gly
Glu Val Tyr Glu Gly Gln Val Ser Gly Met Pro Asn Asp Pro Ser
Pro Leu Gln Val Ala Val Lys Thr Leu Pro Glu Val Cys Ser Glu
Gln Asp Glu Leu Asp Phe Leu Met Glu Ala Leu Ile Ile Ser Lys
Phe Asn His Gln Asn Ile Val Arg Cys Ile Gly Val Ser Leu Gln
Ser Leu Pro Arg Phe Ile Leu Leu Glu Leu Met Ala Gly Gly Asp
Leu Lys Ser Phe Leu Arg Glu Thr Arg Pro Arg Pro Ser Gln Pro
Ser Ser Leu Ala Met Leu Asp Leu Leu His Val Ala Arg Asp Ile
Ala Cys Gly Cys Gln Tyr Leu Glu Glu Asn His Phe Ile His Arg
Asp Ile Ala Ala Arg Asn Cys Leu Leu Thr Cys Pro Gly Pro Gly
Arg Val Ala Lys Ile Gly Asp Phe Gly Met Ala Arg Asp Ile Tyr
Arg Ala Ser Tyr Tyr Arg Lys Gly Gly Cys Ala Met Leu Pro Val
Lys Trp Met Pro Pro Glu Ala Phe Met Glu Gly Ile Phe Thr Ser
Lys Thr Asp Thr Trp Ser Phe Gly Val Leu Leu Trp Glu Ile Phe
Ser Leu Gly Tyr Met Pro Tyr Pro Ser Lys Ser Asn Gln Glu Val
Leu Glu Phe Val Thr Ser Gly Gly Arg Met Asp Pro Pro Lys Asn
Cys Pro Gly Pro Val Tyr Arg Ile Met Thr Gln Cys Trp Gln His
Gln Pro Glu Asp Arg Pro Asn Phe Ala Ile Ile Leu Glu Arg Ile
Glu Tyr Cys Thr Gln Asp Pro Asp Val Ile Asn Thr Ala Leu Pro
Ile Glu Tyr Gly Pro Leu Val Glu Glu Glu Glu Lys Val Pro Val
Arg Pro Lys Asp Pro Glu Gly Val Pro Pro Leu Leu Val Ser Gln
Gln Ala Lys Arg Glu Glu Glu Arg Ser Pro Ala Ala Pro Pro Pro
Leu Pro Thr Thr Ser Ser Gly Lys Ala Ala Lys Lys Pro Thr Ala
Ala Glu Ile Ser Val Arg Val Pro Arg Gly Pro Ala Val Glu Gly
Gly His Val Asn Met Ala Phe Ser Gln Ser Asn Pro Pro Ser Glu
Leu His Lys Val His Gly Ser Arg Asn Lys Pro Thr Ser Leu Trp
Asn Pro Thr Tyr Gly Ser Trp Phe Thr Glu Lys Pro Thr Lys Lys
Asn Asn Pro Ile Ala Lys Lys Glu Pro His Asp Arg Gly Asn Leu
Gly Leu Glu Gly Ser Cys Thr Val Pro Pro Asn Val Ala Thr Gly
Arg Leu Pro Gly Ala Ser Leu Leu Leu Glu Pro Ser Ser Leu Thr
Ala Asn Met Lys Glu Val Pro Leu Phe Arg Leu Arg His Phe Pro
Cys Gly Asn Val Asn Tyr Gly Tyr Gln Gln Gln Gly Leu Pro Leu
Glu Ala Ala Thr Ala Pro Gly Ala Gly His Tyr Glu Asp Thr Ile
Leu Lys Ser Lys Asn Ser Met Asn Gln Pro Gly Pro(配列番号:4)
Met Lys Asn Ile Tyr Cys Leu Ile Pro Lys Leu Val Asn Phe Ala Thr
Leu Gly Cys Leu Trp Ile Ser Val Val Gln Cys Thr Val Leu Asn Ser
Cys Leu Lys Ser Cys Val Thr Asn Leu Gly Gln Gln Leu Asp Leu Gly
Thr Pro His Asn Leu Ser Glu Pro Cys Ile Gln Gly Cys His Phe Trp
Asn Ser Val Asp Gln Lys Asn Cys Ala Leu Lys Cys Arg Glu Ser Cys
Glu Val Gly Cys Ser Ser Ala Glu Gly Ala Tyr Glu Glu Glu Val Leu
Glu Asn Ala Asp Leu Pro Thr Ala Pro Phe Ala Ser Ser Ile Gly Ser
His Asn Met Thr Leu Arg Trp Lys Ser Ala Asn Phe Ser Gly Val Lys
Tyr Ile Ile Gln Trp Lys Tyr Ala Gln Leu Leu Gly Ser Trp Thr Tyr
Thr Lys Thr Val Ser Arg Pro Ser Tyr Val Val Lys Pro Leu His Pro
Phe Thr Glu Tyr Ile Phe Arg Val Val Trp Ile Phe Thr Ala Gln Leu
Gln Leu Tyr Ser Pro Pro Ser Pro Ser Tyr Arg Thr His Pro His Gly
Val Pro Glu Thr Ala Pro Leu Ile Arg Asn Ile Glu Ser Ser Ser Pro
Asp Thr Val Glu Val Ser Trp Asp Pro Pro Gln Phe Pro Gly Gly Pro
Ile Leu Gly Tyr Asn Leu Arg Leu Ile Ser Lys Asn Gln Lys Leu Asp
Ala Gly Thr Gln Arg Thr Ser Phe Gln Phe Tyr Ser Thr Leu Pro Asn
Thr Ile Tyr Arg Phe Ser Ile Ala Ala Val Asn Glu Val Gly Glu Gly
Pro Glu Ala Glu Ser Ser Ile Thr Thr Ser Ser Ser Ala Val Gln Gln
Glu Glu Gln Trp Leu Phe Leu Ser Arg Lys Thr Ser Leu Arg Lys Arg
Ser Leu Lys His Leu Val Asp Glu Ala His Cys Leu Arg Leu Asp Ala
Ile Tyr His Asn Ile Thr Gly Ile Ser Val Asp Val His Gln Gln Ile
Val Tyr Phe Ser Glu Gly Thr Leu Ile Trp Ala Lys Lys Ala Ala Asn
Met Ser Asp Val Ser Asp Leu Arg Ile Phe Tyr Arg Gly Ser Gly Leu
Ile Ser Ser Ile Ser Ile Asp Trp Leu Tyr Gln Arg Met Tyr Phe Ile
Met Asp Glu Leu Val Cys Val Cys Asp Leu Glu Asn Cys Ser Asn Ile
Glu Glu Ile Thr Pro Pro Ser Ile Ser Ala Pro Gln Lys Ile Val Ala
Asp Ser Tyr Asn Gly Tyr Val Phe Tyr Leu Leu Arg Asp Gly Ile Tyr
Arg Ala Asp Leu Pro Val Pro Ser Gly Arg Cys Ala Glu Ala Val Arg
Ile Val Glu Ser Cys Thr Leu Lys Asp Phe Ala Ile Lys Pro Gln Ala
Lys Arg Ile Ile Tyr Phe Asn Asp Thr Ala Gln Val Phe Met Ser Thr
Phe Leu Asp Gly Ser Ala Ser His Leu Ile Leu Pro Arg Ile Pro Phe
Ala Asp Val Lys Ser Phe Ala Cys Glu Asn Asn Asp Phe Leu Val Thr
Asp Gly Lys Val Ile Phe Gln Gln Asp Ala Leu Ser Phe Asn Glu Phe
Ile Val Gly Cys Asp Leu Ser His Ile Glu Glu Phe Gly Phe Gly Asn
Leu Val Ile Phe Gly Ser Ser Ser Gln Leu His Pro Leu Pro Gly Arg
Pro Gln Glu Leu Ser Val Leu Phe Gly Ser His Gln Ala Leu Val Gln
Trp Lys Pro Pro Ala Leu Ala Ile Gly Ala Asn Val Ile Leu Ile Ser
Asp Ile Ile Glu Leu Phe Glu Leu Gly Pro Ser Ala Trp Gln Asn Trp
Thr Tyr Glu Val Lys Val Ser Thr Gln Asp Pro Pro Glu Val Thr His
Ile Phe Leu Asn Ile Ser Gly Thr Met Leu Asn Val Pro Glu Leu Gln
Ser Ala Met Lys Tyr Lys Val Ser Val Arg Ala Ser Ser Pro Lys Arg
Pro Gly Pro Trp Ser Glu Pro Ser Val Gly Thr Thr Leu Val Pro Ala
Ser Glu Pro Pro Phe Ile Met Ala Val Lys Glu Asp Gly Leu Trp Ser
Lys Pro Leu Asn Ser Phe Gly Pro Gly Glu Phe Leu Ser Ser Asp Ile
Gly Asn Val Ser Asp Met Asp Trp Tyr Asn Asn Ser Leu Tyr Tyr Ser
Asp Thr Lys Gly Asp Val Phe Val Trp Leu Leu Asn Gly Thr Asp Ile
Ser Glu Asn Tyr His Leu Pro Ser Ile Ala Gly Ala Gly Ala Leu Ala
Phe Glu Trp Leu Gly His Phe Leu Tyr Trp Ala Gly Lys Thr Tyr Val
Ile Gln Arg Gln Ser Val Leu Thr Gly His Thr Asp Ile Val Thr His
Val Lys Leu Leu Val Asn Asp Met Val Val Asp Ser Val Gly Gly Tyr
Leu Tyr Trp Thr Thr Leu Tyr Ser Val Glu Ser Thr Arg Leu Asn Gly
Glu Ser Ser Leu Val Leu Gln Thr Gln Pro Trp Phe Ser Gly Lys Lys
Val Ile Ala Leu Thr Leu Asp Leu Ser Asp Gly Leu Leu Tyr Trp Leu
Val Gln Asp Ser Gln Cys Ile His Leu Tyr Thr Ala Val Leu Arg Gly
Gln Ser Thr Gly Asp Thr Thr Ile Thr Glu Phe Ala Ala Trp Ser Thr
Ser Glu Ile Ser Gln Asn Ala Leu Met Tyr Tyr Ser Gly Arg Leu Phe
Trp Ile Asn Gly Phe Arg Ile Ile Thr Thr Gln Glu Ile Gly Gln Lys
Thr Ser Val Ser Val Leu Glu Pro Ala Arg Phe Asn Gln Phe Thr Ile
Ile Gln Thr Ser Leu Lys Pro Leu Pro Gly Asn Phe Ser Phe Thr Pro
Lys Val Ile Pro Asp Ser Val Gln Glu Ser Ser Phe Arg Ile Glu Gly
Asn Ala Ser Ser Phe Gln Ile Leu Trp Asn Gly Pro Pro Ala Val Asp
Trp Gly Val Val Phe Tyr Ser Val Glu Phe Ser Ala His Ser Lys Phe
Leu Ala Ser Glu Gln His Ser Leu Pro Val Phe Thr Val Glu Gly Leu
Glu Pro Tyr Ala Leu Phe Asn Leu Ser Val Thr Pro Tyr Thr Tyr
Trp Gly Lys Gly Pro Lys Thr Ser Leu Ser Leu Arg Ala Pro Glu
Thr Val Pro Ser Ala Pro Glu Asn Pro Arg Ile Phe Ile Leu Pro
Ser Gly Lys Cys Cys Asn Lys Asn Glu Val Val Val Glu Phe Arg
Trp Asn Lys Pro Lys His Glu Asn Gly Val Leu Thr Lys Phe Glu
Ile Phe Tyr Asn Ile Ser Asn Gln Ser Ile Thr Asn Lys Thr Cys
Glu Asp Trp Ile Ala Val Asn Val Thr Pro Ser Val Met Ser Phe
Gln Leu Glu Gly Met Ser Pro Arg Cys Phe Ile Ala Phe Gln Val
Arg Ala Phe Thr Ser Lys Gly Pro Gly Pro Tyr Ala Asp Val Val
Lys Ser Thr Thr Ser Glu Ile Asn Pro Phe Pro His Leu Ile Thr
Leu Leu Gly Asn Lys Ile Val Phe Leu Asp Met Asp Gln Asn Gln
Val Val Trp Thr Phe Ser Ala Glu Arg Val Ile Ser Ala Val Cys
Tyr Thr Ala Asp Asn Glu Met Gly Tyr Tyr Ala Glu Gly Asp Ser
Leu Phe Leu Leu His Leu His Asn Arg Ser Ser Ser Glu Leu Phe
Gln Asp Ser Leu Val Phe Asp Ile Thr Val Ile Thr Ile Asp Trp
Ile Ser Arg His Leu Tyr Phe Ala Leu Lys Glu Ser Gln Asn Gly
Met Gln Val Phe Asp Val Asp Leu Glu His Lys Val Lys Tyr Pro
Arg Glu Val Lys Ile His Asn Arg Asn Ser Thr Ile Ile Ser Phe
Ser Val Tyr Pro Leu Leu Ser Arg Leu Tyr Trp Thr Glu Val Ser
Asn Phe Gly Tyr Gln Met Phe Tyr Tyr Ser Ile Ile Ser His Thr
Leu His Arg Ile Leu Gln Pro Thr Ala Thr Asn Gln Gln Asn Lys
Arg Asn Gln Cys Ser Cys Asn Val Thr Glu Phe Glu Leu Ser Gly
Ala Met Ala Ile Asp Thr Ser Asn Leu Glu Lys Pro Leu Ile Tyr
Phe Ala Lys Ala Gln Glu Ile Trp Ala Met Asp Leu Glu Gly Cys
Gln Cys Trp Arg Val Ile Thr Val Pro Ala Met Leu Ala Gly Lys
Thr Leu Val Ser Leu Thr Val Asp Gly Asp Leu Ile Tyr Trp Ile
Ile Thr Ala Lys Asp Ser Thr Gln Ile Tyr Gln Ala Lys Lys Gly
Asn Gly Ala Ile Val Ser Gln Val Lys Ala Leu Arg Ser Arg His
Ile Leu Ala Tyr Ser Ser Val Met Gln Pro Phe Pro Asp Lys Ala
Phe Leu Ser Leu Ala Ser Asp Thr Val Glu Pro Thr Ile Leu Asn
Ala Thr Asn Thr Ser Leu Thr Ile Arg Leu Pro Leu Ala Lys Thr
Asn Leu Thr Trp Tyr Gly Ile Thr Ser Pro Thr Pro Thr Tyr Leu
Val Tyr Tyr Ala Glu Val Asn Asp Arg Lys Asn Ser Ser Asp Leu
Lys Tyr Arg Ile Leu Glu Phe Gln Asp Ser Ile Ala Leu Ile Glu
Asp Leu Gln Pro Phe Ser Thr Tyr Met Ile Gln Ile Ala Val Lys
Asn Tyr Tyr Ser Asp Pro Leu Glu His Leu Pro Pro Gly Lys Glu
Ile Trp Gly Lys Thr Lys Asn Gly Val Pro Glu Ala Val Gln Leu
Ile Asn Thr Thr Val Arg Ser Asp Thr Ser Leu Ile Ile Ser Trp
Arg Glu Ser His Lys Pro Asn Gly Pro Lys Glu Ser Val Arg Tyr
Gln Leu Ala Ile Ser His Leu Ala Leu Ile Pro Glu Thr Pro Leu
Arg Gln Ser Glu Phe Pro Asn Gly Arg Leu Thr Leu Leu Val Thr
Arg Leu Ser Gly Gly Asn Ile Tyr Val Leu Lys Val Leu Ala Cys
His Ser Glu Glu Met Trp Cys Thr Glu Ser His Pro Val Thr Val
Glu Met Phe Asn Thr Pro Glu Lys Pro Tyr Ser Leu Val Pro Glu
Asn Thr Ser Leu Gln Phe Asn Trp Lys Ala Pro Leu Asn Val Asn
Leu Ile Arg Phe Trp Val Glu Leu Gln Lys Trp Lys Tyr Asn Glu
Phe Tyr His Val Lys Thr Ser Cys Ser Gln Gly Pro Ala Tyr Val
Cys Asn Ile Thr Asn Leu Gln Pro Tyr Thr Ser Tyr Asn Val Arg
Val Val Val Val Tyr Lys Thr Gly Glu Asn Ser Thr Ser Leu Pro
Glu Ser Phe Lys Thr Lys Ala Gly Val Pro Asn Lys Pro Gly Ile
Pro Lys Leu Leu Glu Gly Ser Lys Asn Ser Ile Gln Trp Glu Lys
Ala Glu Asp Asn Gly Cys Arg Ile Thr Tyr Tyr Ile Leu Glu Ile
Arg Lys Ser Thr Ser Asn Asn Leu Gln Asn Gln Asn Leu Arg Trp
Lys Met Thr Phe Asn Gly Ser Cys Ser Ser Val Cys Thr Trp Lys
Ser Lys Asn Leu Lys Gly Ile Phe Gln Phe Arg Val Val Ala Ala
Asn Asn Leu Gly Phe Gly Glu Tyr Ser Gly Ile Ser Glu Asn Ile
Ile Leu Val Gly Asp Asp Phe Trp Ile Pro Glu Thr Ser Phe Ile
Leu Thr Ile Ile Val Gly Ile Phe Leu Val Val Thr Ile Pro Leu
Thr Phe Val Trp His Arg Arg Leu Lys Asn Gln Lys Ser Ala Lys
Glu Gly Val Thr Val Leu Ile Asn Glu Asp Lys Glu Leu Ala Glu
Leu Arg Gly Leu Ala Ala Gly Val Gly Leu Ala Asn Ala Cys Tyr
Ala Ile His Thr Leu Pro Thr Gln Glu Glu Ile Glu Asn Leu Pro
Ala Phe Pro Arg Glu Lys Leu Thr Leu Arg Leu Leu Leu Gly Ser
Gly Ala Phe Gly Glu Val Tyr Glu Gly Thr Ala Val Asp Ile Leu
Gly Val Gly Ser Gly Glu Ile Lys Val Ala Val Lys Thr Leu Lys
Lys Gly Ser Thr Asp Gln Glu Lys Ile Glu Phe Leu Lys Glu Ala
His Leu Met Ser Lys Phe Asn His Pro Asn Ile Leu Lys Gln Leu
Gly Val Cys Leu Leu Asn Glu Pro Gln Tyr Ile Ile Leu Glu Leu
Met Glu Gly Gly Asp Leu Leu Thr Tyr Leu Arg Lys Ala Arg Met
Ala Thr Phe Tyr Gly Pro Leu Leu Thr Leu Val Asp Leu Val Asp
Leu Cys Val Asp Ile Ser Lys Gly Cys Val Tyr Leu Glu Arg Met
His Phe Ile His Arg Asp Leu Ala Ala Arg Asn Cys Leu Val Ser
Val Lys Asp Tyr Thr Ser Pro Arg Ile Val Lys Ile Gly Asp Phe
Gly Leu Ala Arg Asp Ile Tyr Lys Asn Asp Tyr Tyr Arg Lys Arg
Gly Glu Gly Leu Leu Pro Val Arg Trp Met Ala Pro Glu Ser Leu
Met Asp Gly Ile Phe Thr Thr Gln Ser Asp Val Trp Ser Phe Gly
Ile Leu Ile Trp Glu Ile Leu Thr Leu Gly His Gln Pro Tyr Pro
Ala His Ser Asn Leu Asp Val Leu Asn Tyr Val Gln Thr Gly Gly
Arg Leu Glu Pro Pro Arg Asn Cys Pro Asp Asp Leu Trp Asn Leu
Met Thr Gln Cys Trp Ala Gln Glu Pro Asp Gln Arg Pro Thr Phe
His Arg Ile Gln Asp Gln Leu Gln Leu Phe Arg Asn Phe Phe Leu
Asn Ser Ile Tyr Lys Ser Arg Asp Glu Ala Asn Asn Ser Gly Val
Ile Asn Glu Ser Phe Glu Gly Glu Asp Gly Asp Val Ile Cys Leu
Asn Ser Asp Asp Ile Met Pro Val Ala Leu Met Glu Thr Lys Asn
Arg Glu Gly Leu Asn Tyr Met Val Leu Ala Thr Glu Cys Gly Gln
Gly Glu Glu Lys Ser Glu Gly Pro Leu Gly Ser Gln Glu Ser Glu
Ser Cys Gly Leu Arg Lys Glu Glu Lys Glu Pro His Ala Asp Lys
Asp Phe Cys Gln Glu Lys Gln Val Ala Tyr Cys Pro Ser Gly Lys
Pro Glu Gly Leu Asn Tyr Ala Cys Leu Thr His Ser Gly Tyr Gly
Asp Gly Ser Asp(配列番号:5)
Claims (22)
- 治療を必要とする患者に投与するための癌治療のための、治療有効量の第1薬剤および治療有効量の第2薬剤を含む併用薬であって、前記第1薬剤がN-[5-(3,5-ジフルオロベンジル)-1H-インダゾール-3-イル]-4-(4-メチル-ピペラジン-1-イル)-2-(テトラヒドロ-2H-ピラン-4-イルアミノ)-ベンズアミド、またはその薬学的に許容される塩であり、
前記第2薬剤が、トラメチニブであり、
前記患者が配列番号:4に記載のALKポリペプチドのアミノ酸残基G1202またはG1269に対応する位置から選択されるALK受容体チロシンキナーゼポリペプチドに少なくとも1つの変異を有する、併用薬。 - ALK受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異が配列番号:4に記載の前記ALKポリペプチドのアミノ酸残基G1202に対応する位置にある、請求項1に記載の併用薬。
- ALK受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異が配列番号:4に記載の前記ALKポリペプチドのアミノ酸残基G1269に対応する位置にある、請求項1に記載の併用薬。
- 治療を必要とする患者に投与するための癌治療のための、治療有効量の第1薬剤および治療有効量の第2薬剤を含む併用薬であって、前記第1薬剤がN-[5-(3,5-ジフルオロベンジル)-1H-インダゾール-3-イル]-4-(4-メチル-ピペラジン-1-イル)-2-(テトラヒドロ-2H-ピラン-4-イルアミノ)-ベンズアミド、またはその薬学的に許容される塩であり、
前記第2薬剤が、トラメチニブであり、
前記患者が配列番号:5に記載のROS1ポリペプチドのアミノ酸残基G2032またはG2101に対応する位置から選択されるROS1受容体チロシンキナーゼポリペプチドに少なくとも1つの変異を有する、併用薬。 - ROS1受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異が配列番号:5に記載の前記ROS1ポリペプチドのアミノ酸残基G2032に対応する位置にある、請求項4に記載の併用薬。
- ROS1受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異が配列番号:5に記載の前記ROS1ポリペプチドのアミノ酸残基G2101に対応する位置にある、請求項4に記載の併用薬。
- 治療を必要とする患者に投与するための癌治療のための、治療有効量の第1薬剤および治療有効量の第2薬剤を含む併用薬であって、前記第1薬剤がN-[5-(3,5-ジフルオロベンジル)-1H-インダゾール-3-イル]-4-(4-メチル-ピペラジン-1-イル)-2-(テトラヒドロ-2H-ピラン-4-イルアミノ)-ベンズアミド、またはその薬学的に許容される塩であり、
前記第2薬剤が、トラメチニブであり、
前記患者が配列番号:1に記載のTrkAポリペプチドのアミノ酸残基G595またはG667に対応する位置から選択されるTrkA受容体チロシンキナーゼポリペプチドに少なくとも1つの変異を有する、併用薬。 - TrkA受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異が配列番号:1に記載の前記TrkAポリペプチドのアミノ酸残基G595に対応する位置にある、請求項7に記載の併用薬。
- TrkA受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異がGlu-to-Arg置換(G595R)である、請求項8に記載の併用薬。
- TrkA受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異が配列番号:1に記載の前記TrkAポリペプチドのアミノ酸残基G667に対応する位置にある、請求項7に記載の併用薬。
- TrkA受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異がGlu-to-Cys置換(G667C)である、請求項10に記載の併用薬。
- 治療を必要とする患者に投与するための癌治療のための、治療有効量の第1薬剤および治療有効量の第2薬剤を含む併用薬であって、前記第1薬剤がN-[5-(3,5-ジフルオロベンジル)-1H-インダゾール-3-イル]-4-(4-メチル-ピペラジン-1-イル)-2-(テトラヒドロ-2H-ピラン-4-イルアミノ)-ベンズアミド、またはその薬学的に許容される塩であり、
前記第2薬剤が、トラメチニブであり、
前記患者が配列番号:2に記載のTrkBポリペプチドのアミノ酸残基G639またはG709に対応する位置から選択されるTrkB受容体チロシンキナーゼポリペプチドに少なくとも1つの変異を有する、併用薬。 - TrkB受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異が配列番号:2に記載の前記TrkBポリペプチドのアミノ酸残基G639に対応する位置にある、請求項12に記載の併用薬。
- TrkB受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異がGlu-to-Arg置換(G639R)である、請求項13に記載の併用薬。
- TrkB受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異が配列番号:2に記載の前記TrkBポリペプチドのアミノ酸残基G709に対応する位置にある、請求項12に記載の併用薬。
- TrkB受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異がGlu-to-Cys置換(G709C)である、請求項15に記載の併用薬。
- 治療を必要とする患者に投与するための癌治療のための、治療有効量の第1薬剤および治療有効量の第2薬剤を含む併用薬であって、前記第1薬剤がN-[5-(3,5-ジフルオロベンジル)-1H-インダゾール-3-イル]-4-(4-メチル-ピペラジン-1-イル)-2-(テトラヒドロ-2H-ピラン-4-イルアミノ)-ベンズアミド、またはその薬学的に許容される塩であり、
前記第2薬剤が、トラメチニブであり、
前記患者が配列番号:3に記載のTrkCポリペプチドのアミノ酸残基G623またはG696に対応する位置から選択されるTrkC受容体チロシンキナーゼポリペプチドに少なくとも1つの変異を有する、併用薬。 - TrkC受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異が配列番号:3に記載の前記TrkCポリペプチドのアミノ酸残基G623に対応する位置にある、請求項17に記載の併用薬。
- TrkC受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異がGlu-to-Arg置換(G623R)である、請求項18に記載の併用薬。
- TrkC受容体チロシンキナーゼポリペプチドのz先期少なくとも1つの変異が配列番号:3に記載の前記TrkCポリペプチドのアミノ酸残基G696に対応する位置にある、請求項17に記載の併用薬。
- TrkC受容体チロシンキナーゼポリペプチドの前記少なくとも1つの変異がGlu-to-Cys置換(G696C)である、請求項20に記載の併用薬。
- 前記癌が、非小細胞肺癌、乳頭様甲状腺癌、神経芽細胞腫、膵臓癌、メラノーマ、及び結腸直腸癌より成る群から選択される少なくとも1つの癌である、請求項1~21のいずれか1項に記載の併用薬。
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AU2016370846B2 (en) | 2022-08-25 |
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US20190000840A1 (en) | 2019-01-03 |
JP2019502683A (ja) | 2019-01-31 |
IL259996A (en) | 2018-07-31 |
MX2018007266A (es) | 2018-11-09 |
US20210113555A1 (en) | 2021-04-22 |
BR112018012255A2 (pt) | 2018-12-04 |
EP3389645A4 (en) | 2019-12-18 |
EP3389645A1 (en) | 2018-10-24 |
US10869864B2 (en) | 2020-12-22 |
CN108697661A (zh) | 2018-10-23 |
CA3008663A1 (en) | 2017-06-22 |
WO2017106492A1 (en) | 2017-06-22 |
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