JP2015524390A - Dll4に特異的に結合する新規モノクローナル抗体及びその用途 - Google Patents
Dll4に特異的に結合する新規モノクローナル抗体及びその用途 Download PDFInfo
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Abstract
Description
白血病)の約50%発見された(非特許文献1)。さらに、乳癌の場合、Notch4受容体が、MMTV(マウス乳癌ウイルス)が挿入されたラット(CzechII)で過剰発現されることが発見され、これらのラットの乳腺腫瘍の発生が報告された(非特許文献2)。子宮頚部癌、肺癌、膵臓癌、卵巣癌、乳癌及び前立腺癌などの様々な癌でNotch受容体とリガンド及びNotchシグナル伝達のターゲットが活性化されていることが報告されている(非特許文献3)。Notch1受容体が乳癌患者において 不良な予後と関連されており(非特許文献4)、前立腺癌においては、癌転移と関連している(非特許文献5)。
所のGeneBankを含む公知のデータベースから得ることができ、例えば、Gene bank Accession Number NM_019074.3(Gene ID: 54567)であるDLL4の情報であり得るが、それらに制限されるものではない。
細胞)、PERC.6(ヒト網膜細胞)などの動物細胞など;又は植物細胞を含む。
充填剤、増量剤、結合剤、湿潤剤、崩壊剤、界面活性剤を含む希釈剤又は賦形剤を用いて製形化される。経口投与のための固形製剤には、錠剤、丸剤、散剤、顆粒剤、カプセルなどが含まれる。このような固形製剤は、少なくとも一つ以上の化合物に一つ以上の賦形剤、例えば、デンプン、炭酸カルシウム、スクロース又はラクトース、ゼラチンなどを混ぜて調剤する。単純な賦形剤以外に、ステアリン酸マグネシウム又はタルクなどのような潤滑剤もまた使用され得る。さらに、経口投与のための液状製剤には、懸濁剤、内溶液剤、乳剤、シロップ剤などが含まれる。一般に、単純希釈剤及び流動パラフィンとして使われる水以外に、様々な賦形剤、例えば、湿潤剤、甘味剤、芳香剤、保存剤などが含まれ得る。非経口投与のための製剤には、滅菌された水溶液、非水性溶剤、懸濁剤、乳剤、凍結乾燥製剤、坐剤が含まれる。 プロピレングリコール、ポリエチレングリコール、オリーブ油のような植物性油、オレイン酸エチルのような注射可能なエステルなどが、非水溶液剤及び懸濁剤として使用され得る。坐剤のベースは、ウィテップゾール、マクロゴール、tween 61、カカオ脂、ラウリン脂、グリセロゼラチンなどが使用され得る。
フォスファターゼ、β-D-ガラクトシダーゼ、ホースラディッシュペルオキシダーゼ及びβ-ラクタマーゼを含む。蛍光材料の例は、Eu3+,Eu3+ キレート剤、クリプテートなどを含む。リガンドの例は、ビオチン誘導体などを含み、発光材料の例は、アクリジニウムエステル、イソルミノール誘導体などを含む。さらに、微小粒子の例は、コロイド金、着色されたラテックスなどを含み、放射性同位元素の例は、57Co,3H,125I,and125I- ボルトン・ハンター試薬を含む。
実施例1−1:この実施例で用いられたDLL4の細胞外ドメイン抗体は、R&D Systemから購入されたヒトDLL4タンパク質(Cat: 1506-D4/CF)である。前記DLL4抗原タンパク質は、DLL4のアミノ酸残基27〜522番のアミノ酸を含む。また、そのタンパク質のC-末端がヒスチジンでタグされている。
10μg/mLの組み換えヒトDLL4溶液(R&D System)を免疫試験管に添加して4℃で一晩試験管表面にタンパク質を吸着させた。1%のウシ血清アルブミン(BSA)溶液を試験管に添加してDLL4が付着されない表面を保護した。試験管を空けたあと、1%のBSA溶液に分散された1012CFUの抗体ファージライブラリーを入れ、抗原と結合させた。非特異的に結合したファージを除くため、リン酸緩衝生理食塩水-0.5% Tween 20(PBS-T)溶液で5回洗い、残っている抗原特異的ファージ抗体を100mMトリエチルアミン溶液を利用して回収した。回収したファージを1Mトリスバッファー(pH7.4)で中和させ、次いで 大腸菌ER2537に37℃で1時間感染させた。形質移入された大腸菌をカルベニシリン含有のLuria-Bertani(LB)寒天培地に塗抹し、37℃で一晩培養した。翌日に培養された大腸菌を4mLのスーパーブロス(SB)-カルベニシリン培養液に懸濁して15%グリセロールを添加した。次に、細胞懸濁液の一部は、-80℃に保管し、残りの50mLを20mLのSB-カルベニシリ培養液に、2%ブドウ糖溶液を添加して37℃で培養した。培養液の吸光度が600nmで0.6になると、遠心分離して培養液を除去し、残った細胞ペレットは再び20mLのSB-カルベニシリン培養液に懸濁し、1012PFUのVCSM13ヘルパーファージを加えた。細胞培養液は、ゆっくり攪拌し37℃で培養した。翌日、培養液を遠心分離し、培養液のみをポリエチレングリコール8000(PEG8000)を4%、塩化ナトリウム(NaCl)3%を添加して4℃で30分間沈殿させ、次に遠心分離した。上清液を除去し沈殿したファージをPBS1mLに懸濁し、これをライブラリーとして使用し、前記パンニング過程を繰り返すことで、抗原特異的クローンを増幅/濃縮した。
ヒトDLL4タンパク質内のNotch1と結合する部位に結合する抗体を選別するためのに、ヒトDLL4タンパク質とヒトDLL4の特異的領域を示す断片(27番アミノ酸〜251番アミノ酸)を交差して進行し、3回まで進行した。その後、抗体遺伝子を含むLB-寒天培地に塗抹した。培養して単一クローンを得てこれを400μLのSB-カルベニシリン培養液に摂取、培養した後、IPTGで誘導してscFv形態のタンパク質を大腸菌で発現させた。大腸菌をTES溶液(Tris, EDTA, Sucrose)に懸濁した後、4℃で1時間放置した後、遠心分離抽出し、これをELISA法を利用して組み換えヒトDLL4抗原とscFvとの結合を確認・するのに使用した。結合したscFvは、HRP-anti-HA抗体とTMB基質を利用して検出した。これから確認された抗原特異的抗体クローンは、塩基配列分析を通じて分析した。
前記実施例1から分離された抗体をそれぞれMLCK-1、MLCK-2、MLCK-3及びMLCK-4と命名し、それぞれの配列番号1である重鎖可変領域と配列番号15である軽鎖可変領域(MLCK-1)、配列番号5である重鎖可変領域と配列番号19である軽鎖可変領域(MLCK-2)、配列番号8である重鎖可変領域と配列番号23である軽鎖可変領域(MLCK-3)及び配列番号11である重鎖可変領域と配列番号27である軽鎖可変領域(MLCK-4)を含むことを確認した。このような分離された抗体の抗原に対する親和度を下記のように分析した。
ELISA結果と共にFACS分析を通じて抗DLL4抗体がDLL4に結合する能力を測定した。
抗DLL4抗体に対してELISA-溶液競争試験を使用して抗DLL4抗体の中和効果を評価した。
抗DLL4抗体の結合能を調べるために、BIACOREアッセイを実施した。
DLL4に結合する抗体の血管内皮細胞増殖に対する影響を分析するために、対標的な抗−DLL4小唄であるMLCK-2抗体を用いて血管内皮細胞の増殖に及ぼす影響を調査した。
Notchシグナル伝達で、Notch受容体がDLL4と結合すると、Notch受容体の構造的変化をもたらし、Notch受容体が切断され、Notch受容体の細胞内部分(NICD)が核内に移動されNotchシグナル伝達を媒介する。それで、本は発明の抗DLL4抗体がDLL4とNotch受容体間の結合を抑制し、Notchシグナル伝達を防ぐことができるかの有無をNotch受容体の切断抑制の有無を通じて下記のように確認した。
Claims (21)
- ヒトデルタ様リガンド4(DLL4)に特異的に結合し、ヒトデルタ様リガンド4とNotch受容体間の相互作用を阻害するモノクローナル抗体。
- 前記モノクローナル抗体は、配列番号2で記載された重鎖CDR1;配列番号3で記載された重鎖CDR2;及び配列番号4で記載された重鎖CDR3を含む重鎖可変領域と、配列番号16で記載された軽鎖CDR1;配列番号17で記載された軽鎖CDR2;及び配列番号18で記載された軽鎖CDR3を含む軽鎖可変領域を含む請求項1に記載のモノクローナル抗体。
- 前記モノクローナル抗体は、配列番号1で記載された重鎖可変領域のアミノ酸配列及び配列番号15で記載された軽鎖可変領域のアミノ酸配列を含む請求項2に記載のモノクローナル抗体。
- 前記モノクローナル抗体は、配列番号2で記載された重鎖CDR1;配列番号6で記載された重鎖CDR2;及び配列番号7で記載された重鎖CDR3を含む重鎖可変領域と、配列番号20で記載された軽鎖CDR1;配列番号21で記載された軽鎖CDR2;及び配列番号22で記載された軽鎖CDR3を含む軽鎖可変領域を含む請求項1に記載のモノクローナル抗体。
- 前記モノクローナル抗体は、配列番号5で記載された重鎖可変領域のアミノ酸配列及び配列番号19で記載された軽鎖可変領域のアミノ酸配列を含む請求項4に記載のモノクローナル抗体。
- 前記モノクローナル抗体は、配列番号2で記載された重鎖CDR1;配列番号9で記載された重鎖CDR2;及び配列番号10で記載された重鎖CDR3を含む重鎖可変領域と配列番号24で記載された軽鎖CDR1;配列番号25で記載された軽鎖CDR2;配列番号26で記載された軽鎖CDR3を含む軽鎖可変領域を含む請求項1に記載のモノクローナル抗体。
- 前記モノクローナル抗体は、配列番号8で記載された重鎖可変領域のアミノ酸配列及び配列番号23で記載された軽鎖可変領域のアミノ酸配列を含む請求項6に記載のモノクローナル抗体。
- 前記モノクローナル抗体は、配列番号12で記載された重鎖CDR1;配列番号13で記載された重鎖CDR2;及び配列番号14で記載された重鎖CDR3を含む重鎖可変領域と、配列番号28で記載された軽鎖CDR1;配列番号29で記載された軽鎖CDR2;及び配列番号30で記載された軽鎖CDR3を含む軽鎖可変領域を含む請求項1に記載のモノクローナル抗体。
- 前記モノクローナル抗体は、配列番号11で記載された重鎖可変領域のアミノ酸配列及び配列27で記載された軽鎖可変領域のアミノ酸配列を含む請求項8に記載のモノクローナル抗体。
- 請求項1〜9のいずれかの前記モノクローナル抗体をコードするポリヌクレオチド。
- 請求項10のポリヌクレオチドを含む発現ベクター。
- 請求項11の発現ベクターが導入された形質転換体。
- 請求項11の発現ベクターの発現を含むヒトデルタ様リガンド4(DLL4)に特異的に結合し、ヒトデルタ様リガンド4とNotch受容体間の相互作用を阻害するモノクローナルの製造方法。
- 請求項1〜9のいずれかの前記モノクローナル抗体を含む癌を予防又は治療するための薬学的組成物。
- 前記癌は、食道癌、胃癌、大腸癌、直腸癌、口腔癌、咽頭癌、喉頭癌、肺癌、結腸癌、乳癌、子宮頚部癌、子宮内膜癌、卵巣癌、前立腺癌、精巣腫瘍、膀胱癌、腎癌、肝癌、膵臓癌、骨癌、結合組織癌、皮膚癌、脳癌、甲状腺癌、白血病、ホジキン病、リンパ腫、多発骨髄腫、血液癌からなる群より選択されるものである請求項14に記載の組成物。
- 請求項1〜9のいずれかの前記モノクローナル抗体を癌を有する疑いのある個体に投与することを含む癌の治療方法。
- 請求項1〜9のいずれかの前記モノクローナル抗体を含む癌診断用組成物。
- 請求項1〜9のいずれかの前記モノクローナル抗体を用いて癌を有する疑いのある個体から分離した生物学的試料のデルタ様リガンド4(DLL4)タンパク質を抗原−抗体反応を通じて検出することを含む癌を診断する方法。
- 請求項1〜9のいずれかの前記モノクローナル抗体を含む自己免疫疾患を予防又は治療する薬学的組成物。
- 前記自己免疫疾患は、リウマチ性関節炎、全身性硬化症、全身性紅斑性狼瘡、アトピー皮膚炎、乾癬、円形脱毛症、喘息、クローン病、ベーチェット症候群、シェーグレン症候群、ギラン・バレー症候群、慢性甲状腺炎、多発性硬化症、強直性脊椎炎、脳脊髄炎、線維炎及び結節性多発動脈炎からなる群より選択されるものである請求項19に記載の組成物。
- 請求項1〜9のいずれかの前記モノクローナル抗体を自己免疫疾患を有する疑いのある個体に投与することを含む自己免疫疾患の治療方法。
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JP2021518345A (ja) * | 2018-03-15 | 2021-08-02 | ザ チルドレンズ メディカル センター コーポレーション | 喘息またはアレルギー性疾患を処置するための方法 |
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CN104428319B (zh) | 2018-03-09 |
EP2867259A1 (en) | 2015-05-06 |
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WO2014007513A1 (en) | 2014-01-09 |
EP2867259A4 (en) | 2016-02-24 |
US9598483B2 (en) | 2017-03-21 |
EP2867259B1 (en) | 2020-06-17 |
CN107056940B (zh) | 2020-11-10 |
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