JP5276017B2 - Egfr変異体仲介性疾患の治療における抗egfr抗体の使用 - Google Patents
Egfr変異体仲介性疾患の治療における抗egfr抗体の使用 Download PDFInfo
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- JP5276017B2 JP5276017B2 JP2009547312A JP2009547312A JP5276017B2 JP 5276017 B2 JP5276017 B2 JP 5276017B2 JP 2009547312 A JP2009547312 A JP 2009547312A JP 2009547312 A JP2009547312 A JP 2009547312A JP 5276017 B2 JP5276017 B2 JP 5276017B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Description
対応表
記号 アミノ酸
1文字 3文字
Y Tyr チロシン
G Gly グリシン
F Phe フェニルアラニン
M Met メチオニン
A Ala アラニン
S Ser セリン
I Ile イソロイシン
L Leu ロイシン
T Thr スレオニン
V Val バリン
P Proプロリン
K Lys リジン
H His ヒスチジン
Q Gln グルタミン
E Glu グルタミン酸
W Trp トリプトファン
R Arg アルギニン
D Asp アスパラギン酸
N Asn アスパラギン
C Cys システイン
フェニルアラニン(PheまたはF) UUUまたはUUC
ロイシン(LeuまたはL) UUAまたはUUGまたはCUUまたはCUCまたはCUAまたはCUG
イソロイシン(IleまたはI) AUUまたはAUCまたはAUA
メチオニン(MetまたはM) AUG
バリン(ValまたはV) GUUまたはGUCまたはGUAまたはGUG
セリン(SerまたはS) UCUまたはUCCまたはUCAまたはUCGまたはAGUまたはAGC
プロリン(ProまたはP) CCUまたはCCCまたはCCAまたはCCGスレオニン(ThrまたはT) ACUまたはACCまたはACAまたはACG
アラニン(AlaまたはA) GCUまたはGCGまたはGCAまたはGCG
チロシン(TyrまたはY) UAUまたはUAC
ヒスチジン(HisまたはH) CAUまたはCAC
グルタミン(GlnまたはQ) CAAまたはCAG
アスパラギン(AsnまたはN) AAUまたはAAC
リジン(LysまたはK) AAAまたはAAG
アスパラギン酸(AspまたはD) GAUまたはGAC
グルタミン酸(GluまたはE) GAAまたはGAG
システイン(CysまたはC) UGUまたはUGC
アルギニン(ArgまたはR) CGUまたはCGCまたは、CGAまたはCGGまたはAGAまたはAGG
グリシン(GlyまたはG) GGUまたはGGCまたはGGAまたはGGG
トリプトファン(TrpまたはW) UGG
終止コドン UAA(オーカー)またはUAG(アンバー)またはUGA(オパール)
活性化表皮増殖因子受容体(EGFR)変異は、ヒト非小細胞肺癌(NSCLC)においては、EGFRvIII変異を有するヒト肺扁平上皮細胞癌の5%およびEGFRキナーゼドメイン変異を有する肺腺癌の10〜30%で起こる。EGFR標的化モノクローナル抗体(mAb806)は、短縮型EGFRvIII変異体と同様に野生型(wt)EGFRのコンフォメーショナルエピトープを認識する。EGFR標的化癌療法のためのこの抗体の抗癌性スペクトルを調査するために、mAb806をEGFRvIII変異またはEGFRキナーゼドメイン変異のいずれかによって引き起こされた肺腫瘍に罹患する遺伝子操作マウスを治療するために使用した。我々の結果は、mAb806がEGFRvIIIシグナリングのブロックおよび腫瘍細胞アポトーシスの誘導に著しく有効であり、したがってEGFRvIIIで引き起こされるマウス肺癌において劇的な腫瘍退縮を結果として生じることをと実証する。他のEGFR標的化抗体(セツキシマブ)は、遺伝的に規定された肺腫瘍において活性を示さなかった。さらに、EGFRvIIIで引き起こされる腫瘍において観察されたものよりも少ない程度とはいえ、EGFRキナーゼドメイン変異によって引き起こされたマウス肺腫瘍のmAb806による治療は、有意な腫瘍退縮を誘導した。総合すれば、これらのデーターは、mAb806がこれらの2つのクラスのEGFR変異を有するNSCLC患者集団の治療において有意な活性を提供できるという仮説を支持する。
導入
結果
セツキシマブではなくmAb806による治療は、EGFRvIII変異による肺腫瘍を持つマウスにおいて腫瘍退縮を誘導する。
mAb806はEGFRvIIIリン酸化を阻害し、Tet−op−EGFRvIII/CCSP−rtTA、Ink4A/Arf−/−マウスにおける腫瘍細胞のアポトーシスを誘導する。
ch806治療はEGFRvIII変異によるマウス肺腫瘍において劇的な腫瘍退縮を導く。
ch806はEGFRのL858R変異を持つマウス肺腫瘍の治療に有効である。
考察
方法
マウスコホート。
mAb806またはch806またはセツキシマブのいずれかをインビボで使用する標的化療法。
肺腫瘍の病理学的評価。
ウエスタンブロット分析。
MRIおよび腫瘍容積測定。
〔文献〕
ヒトEGFR二次変異T790Mを発現するマウスを作製した。mab806を、1マウスあたり1用量あたり0.5mgのI.P.注射を介して肺腫瘍を持つマウスへ4週間毎日送達した。治療したマウスの連続MRIスキャニングを、以下に記載されるような2週間および4週間の治療の終わりで実行した。
Tet−op−hEGFR T790M−L858R/CCSP−rtTAマウスコホートの作製
肺組織におけるEGFR T790M−L858RのRNAレベルでの厳密に調節された発現
hEGFR変異体の過剰発現が肺腫瘍発生を引き起こすかどうかを決定するために、継続的にドキシサイクリンを投与した両遺伝子を導入したhEGFR T790M−L858R/CCSP−rtTAマウスに連続磁気共鳴画像(MRI)を行い、様々なタイムポイントで肺の組織学的検査のために屠殺した。ドキシサイクリン投与の5〜6週間後にMRIによってのみ腫瘍を観察することができ、腫瘍容積はMRIによって確定されるようにドキシサイクリン処理の延長に続いて増加した。無処理のマウスとは対照的に、初期病変は2〜3週間のドキシサイクリン処理後に肺の実質組織において発生し始めた。4〜5週間後に典型的なBACが現われた。
hEGFR T790M−L858R変異体の発現は実質腺癌および気管支腺癌の両方の腫瘍維持のために必須である
mAb806vsセツキシマブによるEGFR T790M−L858R肺腫瘍の治療の結果を図5に示す。8週間以上の間継続的にドキシサイクリン飼料を与えたマウスにMRIを行ない、全身腫瘍組織量を立証した。mab806を、0.5mgの用量でI.P.注射を介して肺腫瘍を持つマウスへ4週間毎日送達した。セツキシマブを、1用量あたり1mgでI.P.注射によってマウスに対して4週間毎日投与した。マウスは、0、2および4または5週間でMRIにより画像診断し、腫瘍容積の減少を決定した。腫瘍容積は、mAb806による治療によって2週間で減少し(20%以上)、および4週間でより著しく(30%以上)減少した。腫瘍容積はセツキシマブによる治療によって2週間で最初は減少したが、腫瘍容積はセツキシマブによる5週間の治療までに著しく増大した(5週間のセツキシマブ治療で観察された腫瘍容積は、0週間でのもとの容積よりも大きかった)。治療およびMRI画像診断の完了後に、マウスはさらなる組織学的研究および生化学的研究のために屠殺した。同腹仔を対照としてすべての治療研究のために使用した(治療なし)。
Claims (9)
- 哺乳類におけるチロシンキナーゼ阻害剤耐性EGFR仲介性疾患を治療するための医薬組成物であって、該耐性EGFR仲介性疾患が肺癌であり、該耐性EGFR仲介性疾患が変異体EGFRを生じるEGFRにおける二次変異の結果であり、該変異がT790Mであり、変異体EGFRに結合し阻害することが可能な抗EGFR抗体の有効量を含み、該抗体がmAb806抗体またはその活性断片である、医薬組成物。
- 前記mAb806が組換え抗体またはヒト化抗体である、請求項1に記載の医薬組成物。
- 前記肺癌が、肺腺癌、肺扁平上皮癌または非小細胞肺癌である、請求項1に記載の医薬組成物。
- 肺癌患者におけるEGFR仲介性腫瘍増殖を減少させるための医薬組成物であって、該癌患者は予め1以上のチロシンキナーゼ阻害剤により治療されおよびT790Mである二次EGFR変異を発症しており、有効量の抗EGFR抗体を含み、該抗体がmAb806抗体またはその活性断片である、医薬組成物。
- 前記mAb806が組換え抗体またはヒト化抗体である、請求項4に記載の医薬組成物。
- チロシンキナーゼ阻害剤および抗EGFR抗体を含む、哺乳類におけるEGFR仲介性肺癌を治療するための医薬組成物であって、チロシンキナーゼ阻害剤に耐性のある潜在的な二次変異体EGFRを阻害するために、該抗EGFR抗体がセカンドライン療法としてチロシンキナーゼ阻害剤による治療後に投与され、該変異体EGFRがT790Mであり、該抗EGFR抗体がmAb806抗体またはその活性断片である、医薬組成物。
- 前記肺癌が肺腺癌、肺扁平上皮癌または非小細胞肺癌である、請求項6に記載の医薬組成物。
- 前記チロシンキナーゼ阻害剤が可逆的チロシンキナーゼ阻害剤である、請求項6に記載の医薬組成物。
- 該抗体が検出可能な標識または機能的な標識により標識される、請求項1に記載の医薬組成物。
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US89738307P | 2007-01-25 | 2007-01-25 | |
US60/897,383 | 2007-01-25 | ||
PCT/US2008/001024 WO2008091701A2 (en) | 2007-01-25 | 2008-01-24 | Use of anti-egfr antibodies in treatment of egfr mutant mediated disease |
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JP2010516770A JP2010516770A (ja) | 2010-05-20 |
JP2010516770A5 JP2010516770A5 (ja) | 2012-03-08 |
JP5276017B2 true JP5276017B2 (ja) | 2013-08-28 |
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JP2009547312A Active JP5276017B2 (ja) | 2007-01-25 | 2008-01-24 | Egfr変異体仲介性疾患の治療における抗egfr抗体の使用 |
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US (1) | US9090693B2 (ja) |
EP (1) | EP2126127B1 (ja) |
JP (1) | JP5276017B2 (ja) |
CN (4) | CN101711284A (ja) |
CA (1) | CA2676244C (ja) |
ES (1) | ES2609094T3 (ja) |
MX (2) | MX338185B (ja) |
WO (1) | WO2008091701A2 (ja) |
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EP2126127A2 (en) | 2009-12-02 |
MX2009007987A (es) | 2010-03-01 |
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