JP6913209B2 - インターロイキン1α抗体及び有用な方法 - Google Patents
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Description
本出願は、それぞれ、2008年5月30日、2008年12月10日及び2009年5月14日に提出された米国仮特許出願第61/057,586号、第61/121,391号、及び第61/178,350号の優先権を主張する。
[連邦政府がスポンサーとなった研究に関する陳述]
適用なし
本発明は、広くは、免疫学、炎症、癌、血管障害及び医学の分野に関する。より詳細には、本発明は、インターロイキン1α(IL−1α)に特異的に結合する抗体(Ab)、及び、そのような抗体を用いることによってIL−1αの発現異常に関連した疾病を治療、予防又は検出する方法に関する。
可変領域重鎖(V−HC)及び可変領域軽鎖(V−LC)の配列は、米国特許第5,959,085号で提供されているアミノ酸配列情報を用いて合成される遺伝子であった。ATG開始コドンの上流にHindIII/Clal部位を導入し、3’末端にNhel部位を導入して、V−HCをPCR増幅させた。ヒト生殖細胞IgG1定常領域(エキソン及びイントロンを含む)を、最初の2個のアミノ酸Ala−Serをコードする5’トリプレットをNhel部位に組み換えて、3’末端にBamHI部位を導入して、PCR増幅させた。ヒト生殖細胞IgG1定常領域アミノ酸配列は、K171Q及びV261L交換を除いて、Swiss−ProtエントリーP01857に対応していた。V−HC配列と定常IgG1−HC配列とをNhel部位を用いて結合し、HindIII及びBamH1部位を用いてpcDNA3中にクローンした。
MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCTASGFTFSMFGVHWVRQAPGKGLEWVAAVSYDGSNKYYAESVKGRFTISRDNSKNILFLQMDSLRLEDTAVYYCARGRPKVVIPAPLAHWGQGTLVTFSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAQTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIALEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号:1)
atggagttcgggctgagttgggtgttcctggtggctctgctgcggggcgtgcagtgccaggtgcagctggtggagagtgggggtggcgtggtgcagcctggccggtctctgcgcctgtcttgcactgcctccggttttaccttttctatgtttggtgtgcactgggtgcgccaggctcccggcaagggactggaatgggtggccgccgtgagttacgacgggtccaacaaatattacgctgagagcgtgaaaggcagattcaccatcagcagagataattccaagaatattctgttcctgcagatggacagtctgagactggaggacactgctgtgtactactgcgctcgtggacgccctaaggtggtcatccccgcccccctggcacattggggccagggaactctggtgaccttttctagcgctagcaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtccacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtagtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgcccagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccctggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccttaagtccgggaaaataa(配列番号:2)
MDMRVPAQLLGLLLLWFPGSRCDIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYEASNLETGVPSRFSGSGSGSDFTLTISSLQPEDFATYYCQQTSSFLLSFGGGTKVEHRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC[配列番号:3]
atggacatgcgcgtgcccgcccagctgctggggctgctgctgctgtggttccctggatctaggtgcgacattcagatgacccagtcccccagctcagtgtcagcctccgtgggcgacagagtgacaatcacctgccgcgcctctcagggaatctctagttggctggcctggtaccagcagaagcctggaaaggcccccaagctgctgatctatgaagcctccaacctggagaccggcgtgccctctcgcttcagcggctcaggctcaggcagtgattttactctgaccatcagctccctgcagccagaggatttcgctacttactactgccagcagacctcttccttcctgctgtccttcgggggaggcacaaaggtggagcaccgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagttcaccggtgacaaagagcttcaacaggggagagtgttag[配列番号:4]
NATHMAB−ヒトインターロイキン1α/IgG1重鎖をコードする完全な配列を遺伝子合成した。V−HC配列は、米国特許第5,959,085号に記載されているアミノ酸配列に対応していた。ヒト定常IgG1−HC配列は、Swiss−ProtエントリーP01857に対応していた。このヌクレオチド配列は、CHO細胞における発現に最適化されたコドンであった。Kozac配列(gccacc)を開始ATGの上流に加えた。
MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCTASGFTFSMFGVHWVRQAPGKGLEWVAAVSYDGSNKYYAESVKGRFTISRDNSKNILFLQMDSLRLEDTAVYYCARGRPKVVIPAPLAHWGQGTLVTFSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK[配列番号:5]
gccaccatggagtttggtctgtcctgggtgttcttggtggctctgctgaggggggtgcagtgccaggtccagctggtggagtctggtgggggagtggtgcagcctgggagatctctgcggctgtcttgcactgcctctggtttcactttctctatgtttggtgtgcattgggtcaggcaagcaccaggcaaaggactcgagtgggtcgcagctgtgagctatgacgggtctaacaaatattacgctgagtctgtcaagggtaggtttaccatcagccgggataattccaaaaatatcctgttcctgcaaatggactctctgaggctggaagatactgcagtctactattgtgcaagggggaggccaaaggtggtgatccccgctcccctcgctcactggggacagggaaccctggtgactttcagctctgctagcaccaagggccctagcgtgttcccattggctccttcctccaaatctacttctggaggcaccgccgccctgggatgtctcgtgaaagattattttcctgagcccgtcaccgtgagctggaacagcggcgccctgactagcggcgtgcacacctttcccgcagtgctgcaatctagcgggctgtactccctgagctctgtcgtgaccgtgccctccagcagcctcggaactcagacctacatctgcaatgtcaatcataaaccctctaataccaaagtcgataagaaggtcgaacctaaatcttgcgataaaacccatacctgccccccttgcccagcacccgaactgctgggcggtccctctgtgtttctgttcccccccaaacccaaagataccctgatgatctctaggacccccgaggtcacttgtgtcgtggtggatgtgtcccacgaagatccagaagtcaaattcaactggtatgtggacggggtcgaagtgcacaacgcaaagaccaagcctagggaggaacagtataatagcacatatagggtggtcagcgtcctgaccgtcctgcatcaggactggctgaatggcaaagaatataagtgtaaagtgtccaacaaggccctgccagccccaatcgaaaagacaatctctaaagccaaggggcaaccccgggaacctcaggtctatacactgccaccctctcgggatgaactgaccaagaatcaggtgagcctgacatgtcttgtgaagggtttttatccctccgacattgccgtggagtgggagagcaatggacaaccagaaaataactacaaaaccacaccccctgtgctggactccgatggttccttcttcctctactctaagctgacagtggataagtctaggtggcagcaggggaatgtgttctcctgctctgtgatgcacgaggcactgcacaatcattatacacaaaagtctctgtctctgtctccaggaaagtaa[配列番号:6]
MDMRVPAQLLGLLLLWFPGSRCDIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYEASNLETGVPSRFSGSGSGSDFTLTISSLQPEDFATYYCQQTSSFLLSFGGGTKVEHTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC[配列番号:7]
gccaccatggacatgcgcgttcctgcccagctcctcggactgctgctgctttggttcccaggctcccggtgtgatattcagatgacacagtctccctcctccgtatctgcatccgtgggcgacagggtcacaatcacttgtagggccagccaggggatctctagttggctcgcatggtaccaacaaaagccaggtaaggctccgaaactgctcatttacgaagctagtaacctcgaaacaggcgtgccaagccggtttagcggctccggttccggttctgacttcaccctcactatttcctccctgcaacctgaggattttgccacatattactgtcagcaaacttcttcttttctgctctcctttggtgggggaactaaggtggagcacacagtggccgcccccagcgtctttatcttccccccaagcgatgaacagctgaagtcagggaccgccagcgtggtctgcctgctcaataatttttaccctcgcgaggctaaggtccaatggaaagtggataacgccctccagagcggtaactctcaggagtctgtcacagagcaagacagcaaggatagcacctattccctctccagcaccctgacactgtctaaggccgactacgagaaacacaaagtgtacgcttgtgaggtgactcaccagggactgagtagccctgtgacaaaatctttcaataggggagaatgctga[配列番号:8]
NATHMAB−インターロイキン1αを一時的トランスフェクション方法を用いて発現させ、精製した。細胞培養上澄み又はGタンパク質親和性精製された抗体を、以下に記載されているさらなる分析に供した。ヒト胎児腎臓(HEK)293T細胞を、10%FCSを含むDMEM中で培養し、製造社のプロトコルに従ってjetPEI試剤(Polyplus)を用いて一時的にトランスフェクトした。トランスフェクションの24時間前に10cmのディッシュ上に細胞を撒き(10cmのディッシュ当たりに3×106細胞)、トランスフェクション時に約50%の密度に達するようにした。ディッシュ当たり5μgのpcDNA3−抗ヒトインターロイキン1α−IgG1−Hc及び2倍モル過剰量のpcDNA3−抗ヒトインターロイキン1α−Kappaをトランスフェクションに用いた。回収後に、媒体を、2%FCSを含むDMEM(1ディッシュ当たり10ml)に変更し、5〜6日間抗体を回収した。上澄みを回収し、ろ過し、pH7.5〜8に調整して、さらなる使用まで4℃で保存した。
標準的フィコールパック調製によって軟膜から分離されたヒト末梢血単核細胞(PBMC)を、RPMI−1640CM又は組み換えヒトインターロイキン2(30ナノグラム/ml、ebioscience)を含むRPMI−1640−CMのいずれかにおいて、37℃及び5%CO2中で一晩培養し、作動細胞(E)として用いた。THP1細胞をターゲット(T)として用いた。96ウェルプレートにおいて各ポイントを3回反復して分析を実行した。1×104個のターゲットを様々な濃度のMABp1と共に15分間インキュベートした後に、1×104個のターゲットに25:1及び50:1のET比で作動細胞を加え、さらに4時間培養した。75μlの分析体積を、新しい96ウェルプレートに移し、LDH細胞毒性検出キット(Roche)を用いて製造社のプロトコルに従って細胞毒性を分析した。
%特異的細胞溶解=(平均試験放出−抗体を含まない平均自然放出)×100/(ターゲットからの平均最大放出−ターゲットからの平均自然放出)
A.処理していないPBMCを作動細胞として用いた。
B.組み換えヒトインターロイキン2で処理したPBMCを作動細胞として用いた。
いずれの場合においても、MABp1の濃度(1.25〜20μg/ml)を増加させることは、両方のET比においてターゲット細胞殺傷の増大(約90%まで)をもたらした。
ヒトインターロイキン1α(MABp1)に対して特異的なもう1つのヒト抗−ヒトインターロイキン1αIgG1/κ軽鎖をコードする完全な配列を合成して上記のように発現させた。重鎖及び軽鎖をコードする核酸中に、開始ATGの上流にKozac配列(gccacc)を加えた。
MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCTASGFTFSMFGVHWVRQAPGKGLEWVAAVSYDGSNKYYAESVKGRFTISRDNSKNILFLQMDSLRLEDTAVYYCARGRPKVVIPAPLAHWGQGTLVTFSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK[配列番号:9]
gccaccatggagtttggtctgtcctgggtgttcttggtggctctgctgaggggggtgcagtgccaggtccagctggtggagtctggtgggggagtggtgcagcctgggagatctctgcggctgtcttgcactgcctctggtttcactttctctatgtttggtgtgcattgggtcaggcaagcaccaggcaaaggactcgagtgggtcgcagctgtgagctatgacgggtctaacaaatattacgctgagtctgtcaagggtaggtttaccatcagccgggataattccaaaaatatcctgttcctgcaaatggactctctgaggctggaagatactgcagtctactattgtgcaagggggaggccaaaggtggtgatccccgctcccctcgctcactggggacagggaaccctggtgactttcagctctgctagcaccaagggccctagcgtgttcccattggctccttcctccaaatctacttctggaggcaccgccgccctgggatgtctcgtgaaagattattttcctgagcccgtcaccgtgagctggaacagcggcgccctgactagcggcgtgcacacctttcccgcagtgctgcaatctagcgggctgtactccctgagctctgtcgtgaccgtgccctccagcagcctcggaactcagacctacatctgcaatgtcaatcataaaccctctaataccaaagtcgataagagggtcgaacctaaatcttgcgataaaacccatacctgccccccttgcccagcacccgaactgctgggcggtccctctgtgtttctgttcccccccaaacccaaagataccctgatgatctctaggacccccgaggtcacttgtgtcgtggtggatgtgtcccacgaagatccagaagtcaaattcaactggtatgtggacggggtcgaagtgcacaacgcaaagaccaagcctagggaggaacagtataatagcacatatagggtggtcagcgtcctgaccgtcctgcatcaggactggctgaatggcaaagaatataagtgtaaagtgtccaacaaggccctgccagccccaatcgaaaagacaatctctaaagccaaggggcaaccccgggaacctcaggtctatacactgccaccctctcgggaggaaatgaccaagaatcaggtgagcctgacatgtcttgtgaagggtttttatccctccgacattgccgtggagtgggagagcaatggacaaccagaaaataactacaaaaccacaccccctgtgctggactccgatggttccttcttcctctactctaagctgacagtggataagtctaggtggcagcaggggaatgtgttctcctgctctgtgatgcacgaggcactgcacaatcattatacacaaaagtctctgtctctgtctccaggaaagtaa[配列番号:10]
MDMRVPAQLLGLLLLWFPGSRCDIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYEASNLETGVPSRFSGSGSGSDFTLTISSLQPEDFATYYCQQTSSFLLSFGGGTKVEHKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC[配列番号:11]
gccaccatggacatgcgcgttcctgcccagctcctcggactgctgctgctttggttcccaggctcccggtgtgatattcagatgacacagtctccctcctccgtatctgcatccgtgggcgacagggtcacaatcacttgtagggccagccaggggatctctagttggctcgcatggtaccaacaaaagccaggtaaggctccgaaactgctcatttacgaagctagtaacctcgaaacaggcgtgccaagccggtttagcggctccggttccggttctgacttcaccctcactatttcctccctgcaacctgaggattttgccacatattactgtcagcaaacttcttcttttctgctctcctttggtggaggaactaaggtggagcacaagcggacagttgctgctcctagcgtctttatcttccctccaagcgatgaacagctgaagtcagggaccgccagcgtggtctgcctgctcaataatttttaccctcgcgaggctaaggtccaatggaaagtggataacgccctccagagcggtaactctcaggagtctgtcacagagcaagacagcaaggatagcacctattccctctccagcaccctgacactgtctaaggccgactacgagaaacacaaagtgtacgcttgtgaggtgactcaccagggactgagtagccctgtgacaaaatctttcaataggggagaatgctga[配列番号:12]
BIAcore2000装置(GE Health Sciences)による表面プラズモン共鳴(SPR)を用いて、精製MABp1の結合親和性を決定した。ヒト抗体捕捉キット及びアミンカップリングキット(GE Health Sciences)を用いて、マウスモノクローナル抗ヒトIgG(Fc)抗体を、CM5センサチップのフローセル上に共有結合で固定化した。典型的には8000−14000RUの固定化レベルが達成されるであろう。マウス抗ヒトIgG(Fc)捕捉抗体の固定化の後に、HBS−EP泳動バッファ(GE Health Sciences)を用いた3回のスタートアップサイクル及びMABp1を用いた2回のスタートアップサイクルを実行して、CM5表面を安定化し、共有結合しないあらゆる抗体を除去した。分析のために、MABp1抗体を、HBS−EP泳動バッファ中で1μg/mlの最終濃度に希釈し、CM5センサチップの1個のフローセル上に700RUまで固定化した。担体を含まないヒトIL−1Aサイトカイン(eBioscience、#34−8019)を、HBS−EP泳動バッファ中によって、100nMから0.05nMの試験範囲にひと続きに希釈した。流速は30μl/分であった。各サイトカイン希釈物の溶出データを15分間記録した。各サイクル後に、3MのMgCl2の単独注射を30μl/分の流速で25秒間行って、CM5表面を再生した。BiaEvaluationソフトウェア及びLangmuir結合モデルを用いてデータを一致させた。MABp1に対するKDは、2.0×10−10M未満であることがわかった。
マトリゲル(BD)、基底膜マトリクスを4℃において一晩解凍し、血清を含まない冷却された細胞培養液で希釈した(5mg/ml〜1mg/ml)。100μlの希釈されたマトリゲルを、24ウェルのトランスウェル(Costar)の上部室に入れ、ゲル化のために37℃で少なくとも4〜5時間培養した。腫瘍細胞(MDA−MB−231及びTHP−1)を、トリプシン/EDTAによって組織培養フラスコから回収し、培養液で洗浄し、1%FBSを含む媒体中に1×106細胞/mlの濃度で再懸濁した。ゲル化したマトリゲルを暖めた無血清培養液で穏やかに洗浄し、各ウェルに100μlの細胞懸濁液を加えた。トランスウェルの下部室を600μlの培養液で満たし、そのプレートを37℃で12〜24時間インキュベートした。マトリゲルに侵入しなかった細胞を各トランスウェル上から綿球で穏やかにこすり落とした。次いで、トランスウェルを24ウェルプレートから取り除き、侵入した細胞を70%エタノール又はメタノールで固定した後に、トランスウェルをクリスタルバイオレットで染色した。侵入した細胞を光学顕微鏡下でカウントした。マトリゲルに侵入する細胞の割合は、MABp1の存在下において有意に阻害された。
低血清増殖サプリメント(Invitrogen)が加えられたM−200溶媒1mL中のヒト臍静脈内皮細胞(HUVEC)(BD Biosciences社)を、1ウェル当たり5×105個で24ウェルプレートに撒いた。細胞を3〜4時間定着させた。溶媒を吸引し、1ウェル当たり1mlのフレッシュなM−200を加えた。MABp1を4.26μg/mlで細胞に直接的に加え、室温で15分間共培養し、次いで、組み換えヒトIL−1α(組み換えヒトインターロイキン1α、eBioscience)を40pg/mlの最終濃度で加えた。ポジティブコントロールウェルにはIL−1αのみを加えた。IL−1α非存在下又はMABp1非存在下のHUVEC細胞をネガティブコントロールとした。37℃及び5%CO2での17〜20時間のインキューベーションの後に、細胞を、CellStripper試剤(Cellgro Mediatech)を用いた20分間の非酵素的処理によってプレートから離し、次いで、標準的流動細胞計測法プロトコルを用いてCD54(ICAM−1)発現について直ちに分析した。染色バッファは、2%の熱不活性化されたウシ胎児血清が加えられたダルベッコPBSで構成されていた。PE結合マウス抗ヒトCD54(ICAM−1)モノクローナル抗体(eBioscience、クローンHA58)又はPE結合マウスIgG1kアイソタイプコントロール(eBiocience、#12−4714)を製造社の説明書に従って用いて、100マイクロリットルの染色体積で、暗闇において室温で20分間HUVEC細胞を染色した。続いて、染色バッファ中における2回の洗浄を行い、次に、FACSCaliburフローサイトメーター(BD Biosciences)でサンプルを得た。いくつかの独立した試験(n=5)において、HUVEC細胞表面の組み換えヒトインターロイキン1αによって誘導されるICAM−1接着分子のアップレギュレーションは、MABp1によって促進されていないHUVEC細胞によって示されたベースラインレベルまで中和された。
ICAM−1誘導に対するその効果と同様に、HUVEC細胞に対するCD62E(E−セレクチン)の誘導のMABp1によって媒介される中和も観察された。HUVEC細胞が、可溶性組み換えヒトインターロイキン1αによってではなく、DG44CHO細胞(GPI−IL1A細胞)の表面にグリコシル−ホスファチジルイノシトールによって固定された膜性IL−1aによって促進される場合、この効果が最も顕著であった。この試験において、6ウェルプレート中のHUVEC細胞のコンフルエント培養液を、単独で、10μg/mlのMABp1の存在下で、又は、10μg/mlのD5アイソタイプコントロール抗体の存在下で、M−200媒体中の5×106個のGPI−IL1A DG44細胞と共に一晩共培養した。17〜20時間後に、HUVEC単層を、ダルベッコPBSで広く洗浄し、次に、CellStripper試剤(Cellgro Mediatech)を用いた20分間の非酵素的処理によって離し、、次いで、標準的流動細胞計測法プロトコルを用いてCD62E(E−セレクチン)発現について直ちに分析した。染色バッファは、2%熱不活性化ウシ胎児血清が加えられたダルベッコPBSで構成されていた。PE結合マウス抗ヒトCD62Eモノクローナル抗体(eBioscience、クローンP2H3)又はPE結合マウスIgG1kアイソタイプコントロール(eBiocience、クローンP3)を製造社の説明書に従って用いて、100マイクロリットルの染色体積で、暗闇において室温で20分間HUVEC細胞を染色した。続いて、染色バッファ中で2回の洗濯を行い、次に、FACSCaliburフローサイトメーター(BD Biosciences)でサンプルを得た。膜性GPI−IL−1aによって誘導されるHUVEC細胞表面においてアップレギュレートされるE−セレクチン発現は、MABp1によって、促進されていないHUVEC細胞によって示されるベースラインレベルまで中和された。
ATCCコレクション(CCL−171)から胎児ヒト肺繊維芽細胞に由来するMRC−5細胞株を得た。MRC−5細胞からのIL−1Aによって誘導されるIL−6の放出を測定することによって、MABp1のIL−1中和能力を分析した。MRC−5細胞を、100マイクロリットルのDMEM完全培地中に1ウェル当たり5×103で96ウェルプレートに撒いた。加湿した5%CO2インキュベータ内において37℃で細胞を一晩培養した。続いて、コンフルエントのMRC−5細胞を、単独で又は増大させた濃度のMABp1の存在下で、20pg/mlの組み換えヒトIL−1A(組み換えヒトインターロイキン1A、eBioscience)と共にさらに24時間培養した。ネガティブコントロール細胞は、組み換えヒトインターロイキン1Aによって刺激されなかった。24時間後に上澄みを回収し、eBioscienceのIL−6ELISAキットを用いてIL−6放出について分析した。IC50、又は、最大のIL−6放出の50%を阻害するのに必要なMABp1の濃度は、0.001〜0.01μg/mLの範囲内であった。
100マイクロリットルのナトリウムヘパリン抗凝結全血をポリスチレンFACSチューブに等分した。サンプルを、2mlの熱不活性化ウシ胎児血清を加えた1mgのヒトIgG(精製されたプロテインA)と共に室温において15分間インキュベートすることによって、Fc受容体をブロックした。その後、サンプル:アレクサ−488でラベルされた1mgのMABp1、FITCでラベルされた1mgのモノクローナル抗膜ヒトIL1A抗体(FAB200F、R&D Systems)、又は、1mgのマウスアイソタイプコントロール(IC002F、R&D Systems)のいずれかに一次抗体を加えた。一次抗体を、暗闇の室温において30分間サンプルと共にインキュベートした。その後、サンプル赤血球を室温において15分間溶解させ(BD Biosciences PharmLyse溶液)、300×gで5分間遠心分離して吸引した。サンプルペレットを、2%熱不活性化胎児血清を含む1mlのハンクス液(HBSS)で3回洗浄した。サンプルを0.3mlのHBSS+2%FBS中に再懸濁し、データをFACSCaliburフローサイトメーターで得て、CellQuestソフトウェアを用いて分析した。MABp1を用いたヒトPBMCのフローサイトメトリー分析は、PBMCの0.2%のみがインターロイキン1αに対してポジティブであることを示した。
MABp1を用いたヒトPBMCの(実施例11のような)フローサイトメトリー分析は、IL−1α+に対してポジティブなPBMCのパーセントが、通常のコントロールと比較して、無症状感染を有する対象において3.6倍に増加したことを示した。同様に、炎症を起こした親知らずを有する対象において、IL−1α+に対してポジティブなPBMCのパーセントが増加した。IL−1α+PBMCの数における実質的減少は、親知らずの除去の14日後から45日後までみられた。
ヒト対象の血漿中には一般に非常に低いレベルのIL−1αが存在する。多くの場合においてこれらのレベルは従来的免疫分析の検出閾を外れているので、改善された感度を有するELISAが開発された。このELISAにおいては、抗体がサンプル中のインターロイキン1αに結合することを許容する条件下で、試験される生体サンプル(例えばヒト血漿)に外因性の抗インターロイキン1α抗体(例えばMABp1)を加えることができる。ヒト血漿サンプル中のインターロイキン1αのほとんどすべてが内因性抗インターロイキン1α抗体に既に結合して存在することがわかっているので、多くの場合においては後のステップを省略することができる。その後、ヒトインターロイキン1α抗体複合体を含むサンプルを、約100kDaの分子量遮断装置を有するフィルター(Amicon遠心装置)に適用することによって、サンプル中の分子量遮断未満の分子からヒトインターロイキン1α抗体複合体を分離した。ある試験においてはこれによって濃度が50倍になった。その後、処理されたサンプル(及びその希釈物)を、抗ヒトIgG捕捉抗体(2μg/mlのマウス抗ヒトIgG、Fc特異的、Southern Biotech 製品コード#9042−01)でコーティングされたマイクロタイタープレートのウェル中に加えた。サンプル中のヒトインターロイキン1α抗体複合体に結合するための時間を与えた後に、ウェルを洗浄して結合しない成分を除去した。その後、ラベルされた抗ヒトインターロイキン1α二次抗体(0.2μg/mlのビオチン結合モノクローナルマウス抗ヒトIL−1A抗体、クローンCRM6、eBioscienceカタログ#13−7017)をそのウェルに加えた。ウェル中のインターロイキン1αに結合するための時間を与えた後に、プレートを洗浄し、試験したサンプル中のインターロイキン1αの濃度の指標として、各ウェル中のラベルされた抗ヒトインターロイキン1αの量を定量した。
本発明はその詳細な説明と共に記載されているが、前記説明は例示的なものであり、本発明の範囲を限定するように意図されておらず、本発明の範囲が添付の特許請求の範囲によって定められることは理解されるであろう。その他の態様、長所及び変更は、添付の特許請求の範囲に含まれる。
Claims (7)
- ヒトIL−1αに特異的に結合するヒトIgG1モノクローナル抗体であって、前記モノクローナル抗体が、軽鎖に共有結合した重鎖を含み、前記重鎖が配列番号9の20乃至471位のアミノ酸配列を含み、前記軽鎖が配列番号11の23−236位のアミノ酸配列を含むことを特徴とするヒトIgG1モノクローナル抗体。
- 請求項1に記載のヒトIgG1モノクローナル抗体の重鎖をコードする第1の核酸配列、および、請求項1に記載のヒトIgG1モノクローナル抗体の軽鎖をコードする第2の核酸配列を含む核酸のセット。
- 請求項2に記載の核酸のセットにおいて、前記核酸のセットが、少なくとも1つの発現ベクター中に含まれていることを特徴とする核酸のセット。
- 請求項2または3に記載の核酸のセットを含む宿主細胞。
- 請求項4に記載の宿主細胞において、前記宿主細胞が、哺乳類宿主細胞であることを特徴とする宿主細胞。
- 療法に使用するための医薬組成物であって、前記医薬組成物が、薬学的に許容できる担体および請求項1に記載のヒトIgG1モノクローナル抗体を含むことを特徴とする医薬組成物。
- 医薬の製造における、薬学的に許容できる担体および請求項1に記載のヒトIgG1モノクローナル抗体を含む医薬組成物の使用。
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