JP2008545433A - TNFαを阻害する安定な可溶性抗体 - Google Patents
TNFαを阻害する安定な可溶性抗体 Download PDFInfo
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- JP2008545433A JP2008545433A JP2008515021A JP2008515021A JP2008545433A JP 2008545433 A JP2008545433 A JP 2008545433A JP 2008515021 A JP2008515021 A JP 2008515021A JP 2008515021 A JP2008515021 A JP 2008515021A JP 2008545433 A JP2008545433 A JP 2008545433A
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Abstract
【選択図】なし
Description
炎症、細胞の免疫応答及び多くの疾患の病態においてTNFαが果たす重要な役割により、TNFαのアンタゴニストの探索へと導かれた。
RA及びクローン病の治療における抗TNFα抗体の使用は、Feldmanら(1998) (Transplantation Proceedings 30:4126-4127)、Adoriniら(1997) (Trends in Immunology Today 18:209-211)、及びFeldmannら(1997)(Advanced Immunology 64:283-350)で議論されている。このような治療に使用されるTNFαに対する抗体は、一般的に米国特許公開公報第US5919452号に記載されるようなキメラ抗体である。
米国特許公開公報第US6428787号には、インフリキシマブ(infliximab)、CDP571及びD2E7を含む抗TNF抗体による、神経性のTNFα関連疾患の治療が教示されている。
本発明で引用される全ての刊行物及び参考文献は、その全体が参照により本明細書に含まれる。
配列番号7のVL配列/配列番号2のVH配列
配列番号8のVL配列/配列番号2のVH配列
配列番号1のVL配列/配列番号9のVH配列
配列番号1のVL配列/配列番号25のVH配列
配列番号1のVL配列/配列番号28のVH配列
配列番号1のVL配列/配列番号29のVH配列
配列番号26のVL 配列/配列番号30のVH配列
配列番号27のVL 配列/配列番号30のVH配列
本発明は、本発明のいずれかの抗体又は抗体誘導体をコードするDNA配列、並びに該DNA配列を含むクローニングベクター又は発現ベクターをも提供する。更に、該DNA配列で形質転換された適切な宿主細胞が提供され、これは優先的には、大腸菌、酵母菌又は哺乳動物細胞である。
VPSRFSGSGSGTEFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSG
GGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYSFTHYGMNWVRQAPGQ
GLEWMGWINTYTGEPTYADKFKDRVTLTRDTSIGTVYMELTSLTSDDTAVYYCARER
GDAMDYWGQGTLVTVSS (配列番号3+配列番号10+配列番号4)
配列番号19 = TB-A H_F68V (TB-A H68)
配列番号20 = TB-A H_F70L/L72R (TB-A H70/72)
配列番号21 = TB-A H_A76I/S77G (TB-A H76/77)
配列番号22 = TB-A L_L46R (TB-A L46)
配列番号23 = TB-A L_R65S (TB-A L65)
配列番号24 = TB-A L_Y67S (TB-A L67)
一般的に、開示された任意のVL配列は、開示された任意のVH配列と結合されても良い。
に融合される。本発明の典型的な態様においては、ヒトCκ領域は配列番号14に示される配列を有し、Fab断片の構成に使用されるCH1領域は配列番号15に示される配列を有する。図2は、Fab断片の例を示し、その中では、VL領域がヒトκ定常領域に直接連結して、以下の配列に至り、
(配列番号l+配列番号14)
及び、VH領域が第1の定常領域(CH1)に融合され、以下の配列に至るように、TB-AのVL及びVH領域が使用される。
(配列番号2+配列番号15)
本発明の抗体又は抗体誘導体は、0.8-10000 nMの範囲の解離定数KdでヒトTNFαに対する親和性を有し得る。本発明の好ましい態様においては、Kdは10nM以下である。抗原に対する抗体の親和性は、適切な方法(Berzofskyら. 「抗体-抗原相互作用(Antibody-Antigen Interactions)」, in Fundamental Immunology, Paul, W.E.編集, レイヴン出版(Raven Press): ニューヨーク市, ニューヨーク州(1992); Kuby, J. 「免疫学(Immunology)」, W.H.フリーマン・アンド・カンパニー社(W. H. Freeman and Company): ニューヨーク市, ニューヨーク州) 、及びその中に記載された方法を用いて実験的に測定することができる。
定義: 「医薬製剤」という用語は、抗体又は抗体誘導体の生物活性が明確に有効となる形態にあり、該製剤が投与される対象にとって有毒な、追加成分を含まない製剤を指す。「薬剤的に許容される」賦形剤(媒体、添加剤)とは、対象哺乳動物に投与されることで用いられる有効成分の有効量が適度に与えられるようになるものである。
上記のように対象となる抗体又は抗体誘導体の調製を行なった後、これを含む医薬組成物を調製する。処方される抗体は、先に凍結乾燥を行わず、ここで対象となる製剤は水性製剤である。好ましくは、製剤における抗体又は抗体誘導体は、scFvのような抗体断片である。製剤に存在する治療に有効な量の抗原は、例えば、所望の投与量及び投与方法を考慮に入れて決定される。約0.1 mg/mlから約50 mg/ml、好ましくは約0.5 mg/mlから約25 mg/ml、最も好ましくは2 mg/mlから10 mg/mlが製剤内の抗体の例示的な濃度である。
製剤は、抗体による治療を必要とする哺乳動物、好ましくはヒトに、静脈内一括投与若しくは一定期間にわたる継続的点滴、筋肉内、腹腔内、脳脊髄内、皮下、関節内、滑膜内、クモ膜下腔内、経口、局所又は吸入等の経路による公知の方法に従って、投与される。好ましい態様において、製剤は静脈内投与により哺乳動物に投与される。このような目的のため、製剤は例えばシリンジを用いて、又はIVラインを通して注射されてよい。
本発明の別の態様において、製品は、本発明の水性製剤を収容する、容器を含んで提供され、そして任意にその使用説明書が提供される。適切な容器には、例えば、瓶、バイアル及びシリンジが包含される。前記容器は、ガラス又はプラスチックのような種々の材料から形成することができる。例示としての容器は、3-20 ccの使い捨てのガラスバイアルである。また、これに代わり、複数回投与用の製剤については、容器は3-100 ccのガラスバイアルであってよい。前記容器は製剤を収容し、ラベルが張られているか、又は付随しており、容器に使用方法を提示してよい。。製品は更に、他の緩衝剤、希釈剤、フィルター、針、シリンジ、及び使用説明を有する添付文書を含む、商業的及び使用者の視点から所望される他の材料を更に含んでいてもよい。
本発明の抗体又は抗体誘導体は組換え遺伝学の分野におけるルーチン技術を用いて作製することができる。ポリペプチドの配列を知ることにより、それらをコードするcDNAを遺伝子合成によって作成することができる(www.genescript.com)。これらのcDNAは適切なベクタープラスミドにクローニングすることができる。VL及び/又はVH領域をコードするDNAが得られたならば、例えば変異導入プライマーを用いたPCRにより、部位特異的変異導入を行って、種々の誘導体を得ることができる。最適な「開始」配列は、VL及び/又はVH配列内に所望される変異の数に基づいて選択することができる。好ましい配列は、TB-Aの配列であり、そして、その誘導体、例えばscFv配列又はFab融合ペプチド配列等は、PCRによる変異導入及び/又はクローニング用の鋳型として選択される。
慢性及び/又は自己免疫性炎症全般、免疫媒介炎症性障害全般、炎症性CNS疾患、眼、関節、皮膚、粘膜、中枢神経系、胃腸管、尿路又は肺に影響を及ぼす炎症性疾患、ブドウ膜炎全般、網膜炎、HLA-B27+ブドウ膜炎、ベーチェット病、眼乾燥症候群、緑内障、シェーグレン症候群、糖尿病(糖尿病性神経障害を含む)、インスリン抵抗性、関節炎全般、関節リウマチ、変形性関節症、反応性関節炎及びライター症候群、若年性関節炎、強直性脊椎炎、多発性硬化症、ギラン・バレー症候群、重症筋無力症、筋萎縮性側索硬化症、サルコイドーシス、糸球体腎炎、慢性腎臓病、膀胱炎、乾癬(乾癬性関節炎を含む)、化膿性汗腺炎、皮下脂肪組織炎、壊疽性膿皮症、SAPHO症候群(滑膜炎、座瘡、膿疱症、骨化過剰症及び骨炎)、座瘡、スウィート症候群、天疱瘡、クローン病(腸外症状を含む)、潰瘍性大腸炎、気管支喘息、過敏性肺臓炎、アレルギー全般、アレルギー性鼻炎、アレルギー性副鼻腔炎、慢性閉塞性肺疾患(COPD)、肺線維症、ウェゲナー肉芽腫症、川崎病、巨細胞性動脈炎、チャーグ‐ストラウス血管炎(Churg-Strauss vasculitis)、結節性多発性動脈炎、火傷、移植片対宿主病、宿主対移植片反応、器官又は骨髄移植後の拒絶エピソード、全身性及び局所的な血管炎全般、全身性及び円板状エリテマトーデス、多発性筋炎及び皮膚筋炎、強皮症、子癇前症、急性及び慢性膵炎、ウイルス性肝炎、アルコール性肝炎。
術後炎症の予防全般、目の手術(例えば、白内障 の手術(眼内レンズの交換) 又は緑内障の手術)、関節手術 (関節鏡視下手術を含む)、関節関連組織(例えば靭帯)の手術、口腔及び/又は歯科手術、低侵襲心臓血管処置(例えば、PTCA、アテレクトミー、ステント留置術)、腹腔鏡下及び/又は内視鏡下での腹腔内処置並びに婦人科処置、内視鏡下泌尿器処置 (例えば、前立腺手術、子宮鏡検査、膀胱鏡検査、間質性膀胱炎)、術中炎症(予防)全般。
アルツハイマー病、パーキンソン病、ハンチントン病、ベル麻痺、クロイツフェルトヤコブ病。
癌:
癌性骨溶解、癌性炎症、癌性疼痛、癌性悪質液、骨転移。
TNFαの中枢的又は末梢的効果により生じたものかどうかに関係なく、そして、炎症性疼痛、侵害受容性疼痛、又は神経障害性疼痛、坐骨神経痛、腰痛、手根管症候群、複合性局所疼痛症候群(CRPS)、痛風、疱疹後神経痛、線維筋痛症、局所的疼痛状態、転移性腫瘍に起因する慢性疼痛、月経困難として分類されるかどうかに関係ない急性疼痛及び慢性疼痛。
感染:
細菌性敗血症、ウィルス性敗血症、又は真菌性敗血症、結核、エイズ。
心血管疾患:
アテローム性動脈硬化、冠状動脈疾患、高血圧症、異脂肪血症、心不全及び慢性心不全。
配列番号1 TB-AのVL
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKR
配列番号2 TB-AのVH
QVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRFTFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
DIVLTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKRLIYSAFNRYTGVPSRFSGSGSGTEFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKR
QVQLVQSGAEVKKPGASVKVSCTASGYSFTHYGMNWVRQAPGQGLEWMGWINTYTGEPTYADKFKDRVTLTRDTSIGTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
配列番号5 FW2.3のVL
DIVLTQSPSSLSASVGDRVTLTCRASQGIRNELAWYQQRPGKAPKRLIYAGSILQSGVPSRFSGSGSGTEFTLTISSLQPEDVAVYYCQQYYSLPYMFGQGTKLEVKR
配列番号6 FW2.3のVH
QVQLVQSGAEVKKPGASVKVSCTASGYSFTGYFLHWVRQAPGQGLEWMGRINPDSGDTIYAQKFQDRVTLTRDTSIGTVYMELTSLTSDDTAVYYCARVPRGTYLDPWDYFDYWGQGTLVTVSS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYAGSILQSGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKR
配列番号8 TB_L3のVL
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQYYSLPYMFGQGTKLEVKR
QVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGRINPDSGDTIYAQKFQDRFTFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
配列番号10 リンカー
GGGGSGGGGSGGGGSGGGGS
DIVLTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGSGSGTEFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKR
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYSFTHYGMNWVRQAPGQGLEWMGWINTYTGEPTYADKFKDRVTLTRDTSIGTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
DIVLTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKRLIYSAFNRYTGVPSRFSGSGSGTEFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRFTFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
配列番号15 FabのCHl
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFSEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCTS
DIVMTQTPKFLLVSAGDRVTITCTASQSVSNDVVWYQQKPGQSPKMLMYSAFNRYTGVPDRFTGRGYGTDFTFTISSVQAEDLAVYFCQQDYNSPRTFGGGTKLEIKR
配列番号17 TB-wtのVH
QIQLVQSGPELKKPGETVKISCKASGYTFTHYGMNWVKQAPGKGLKWMGWINTYTGEPTYADDFKEHFAFSLETSASTVFLQINNLKNEDTATYFCARERGDAMDYWGQGTSVTVSS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGQGLEWMGWINTYTGEPTYADKFKDRFTFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRVTFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
配列番号20 TB-A H_F70L/L72R、別称TB-A H70/72
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRFTLSRETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRFTFSLETSIGTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
配列番号22 TB-A L_L46R、別称TB-A L46
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKRLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRFTFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGSGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRFTFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGSGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRFTFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
QVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKGRFTFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
配列番号26 V83Fを有するTB-AのVL
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDFAVYYCQQDYNSPRTFGQGTKLEVKR
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDAAVYYCQQDYNSPRTFGQGTKLEVKR
配列番号28 TB-A H43/70/71/73/77のVH
QVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGQGLEWMGWINTYTGEPTYADKFKDRFTLTLDTSAGTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
QVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGQGLEWMGWINTYTGEPTYADKFKDRFTLTLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
QVQLVQSGAEDKKPGGSVKVSCTASGYTFTHYGMNWVRQAPGQGLEWMGWINTYTGEPTYADKFKGRFTLTLDTSAGTVYMELTSLTSDDTATYYCARERGDAMDYWGQGTSVTVSS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWLGWINTYTGEPTYADKFKDRITFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDEAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRFTFSLETSASTAYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGRGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRLTFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGRGLEWMGWINTYTGEPTYADKFKDRITFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRLTFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRATFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRVTLSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRFTLSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
配列番号39 Linker G2R
GRGGSGGGGSGGGGSGGGGS
DIVMTQSPSSLSASVGDRVTLTCTASQSVSNDVVWYQQRPGKAPKLLIYSAFNRYTGVPSRFSGRGYGTDFTLTISSLQPEDVAVYYCQQDYNSPRTFGQGTKLEVKRGGGGSGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCTASGYTFTHYGMNWVRQAPGKGLEWMGWINTYTGEPTYADKFKDRFTFSLETSASTVYMELTSLTSDDTAVYYCARERGDAMDYWGQGTLVTVSS
ヒト化抗ヒトTNFα抗体、又は、一本鎖断片(scFv)又はFab断片のような抗体誘導体を作製するための出発原料は、マウスモノクローナル抗体Di62であった。軽鎖と重鎖の可変領域の配列は、Doringら. (1994, MoI. Immunol. 31:1059-1067)に記載されている。このモノクローナル抗体の特性についても、同刊行物において議論されている。簡潔に言えば、Di62は、ヒトTNFαに対して濃度依存的に特異的に結合する。Di62は、高親和性抗体(Kd= 0.4nM) であり、TNFαのそのレセプターへの結合をブロックすることができる。これに加え、Di62は、ヒトTNFα誘導性の細胞毒性を、マウスL929細胞内において阻害する。
CDRl: L24-L34 (同様のKabat番号付け)
CDR2 : L50-L56 (同様のKabat番号付け)
CDR3: L89-L97 (同様のKabat番号付け)
VH
CDRl: H31-H35 (同様のKabat番号付け)
CDR2: H50-H66 (Kabat番号付け H50-H65)
CDR3: H99-H106 (Kabat番号付け H95-H102)。
TB-A H68 FからVへ 外部ループVH (配列番号19)
TB-A H70/72 FからL、LからRへ 外部ループVH (配列番号20)
TB-A H76/77 AからI、SからGへ 外部ループVH (配列番号21)
TB-A L46 LからRへ 接合部 (配列番号22)
TB-A L65 RからSへ 外部ループVL 配列番号23)
TB-A L67 YからSへ 外部ループVL (配列番号24)
全てのscFv断片を、大腸菌内でのペリプラズム生成用の発現ベクター(Krebberら. (1997), J. Immunol. Methods 201:35-55)にクローニングした。
TB-wt、そのヒト化誘導体、又はFab断片をコードするプラスミドを、ペリプラズム発現用の適切な大腸菌株(例えば、JM83)に導入した。前記scFv変異体を、例えば、BL21大腸菌株内で、封入体としても発現させた。封入体のリフォールディングと、これに続く、例えば、ゲルろ過等の精製により、機能的な一本鎖抗体を得た。
全てのヒト化scFv変異体の組換えヒトTNFαに対する結合特性を、ELISAにて試験した。全変異体の解離定数(Kd)は、0.8から10'000nMを超える範囲内にあった。ヒトのアクセプターフレームワークに対するホモロジーの程度と、個々の結合体の親和性の間には、負の相関関係が存在するように思われる(図4A)。にも関わらず、TB-Bの配列の方に向かう突然変異を含むいくつかのTB-A変異体は、TB-Aと同程度のヒトTNFαに対する親和度を示した。図4Bには、ELISAで比較した場合に、TB-Aと類似する親和性を示す、発現収量が向上された2種類のTB-Aの誘導体(図3Aと比較)が示されている。
インビボでTNFαを中和する抗体又は抗体誘導体の機能は、培養マウスL929繊維芽細胞、又はこれに代わるものとしてヒトKYM-1骨髄肉腫細胞に対するTNFαの細胞毒性の阻害を測定することにより試験することができる(表3)。Di62のヒト化scFv誘導体は、図5Bに示すように、L929アッセイにおいて異なる有効性を示す。いくつかのscFv誘導体は、5ng/mlの範囲のIC50(50%の阻害を達成する抑制濃度)値を示すが、それ以外のものは、L929アッセイにて効果を示さなかった。ELISAのデータとL929アッセイの結果が、必ずしも相関関係を有するわけではない。しかしながら、KYM-1データとL929の結果は、効果を認めるためにより一層高い濃度の組換えヒトTNFと、その結果としてより一層高い濃度のアンタゴニストを必要としたという唯一の違いを有するだけで、良好な相関関係を示した。従って、主としてKYM-1を用いてL929の結果を確認した。テストタンパク質の直接比較のため、力価をTB-Aに対して正規化された相対値(EC50X / EC50TB-A)として表した。しかしながら、一般的に、結合体の配列がヒトアクセプターフレームワーク(FW2.3)に近似するにつれて、IC50値は再度高くなるものである。図5では、TB-Aの異なる誘導体の、マウスL929繊維芽細胞に対するTNFα誘導性細胞毒性をブロックするための力価が比較されている。450nmの吸光度は、細胞の生存と相関している。
5.1. 実験の説明
ESBATech社の抗TNFα抗体誘導体(scFvとFab)が、インビボでの状況においてヒトTNFαの生物活性を機能的に中和する有効性を試験するために、最近発表された急性単関節炎のラットモデルを用いた。このモデルについては、Bolonとその同僚によりその多くが説明されている( Bolonら. (2004), Vet. Pathol. 41:235-243を参照)。簡潔に言うと、この関節炎モデル動物については、オスのLewisラットの膝関節に、ヒトTNFαが関節内注射される。ヒトTNFα注射は、注射された関節において、急性の、自己限定性単関節炎を引き起こす。関節炎は、関節腫脹の測定と組織学的採点法により定量化することができる。従って、個々のTNFαアンタゴニストの生物活性は、TNFα誘導性関節腫脹の減少及び/又は炎症の組織学的パラメターの減少により定量化することができる。
〔実験の設計〕
市販の抗体インフリキシマブ(Infliximab)(レミケード(Remicade)(登録商標))を用いて、上記の系列の代表的なscFv抗体と、代表的なFab抗体の、適切な関節炎動物モデル内でヒトTNFαの生物活性を阻害するそれぞれの能力を試験するように、本実験を設計した。Bolonとその同僚は、先に、10マイクログラムの組換えヒトTNFαをラットの膝関節へ関節内投与することにより、標準的な巨視的及び微視的解析により定量可能な、急性の、自己限定性単関節炎が引き起こされることを示した。従って、この動物モデルは、局所的に投与される抗体誘導体の治療効果を評価する理想的な系として機能した。2種類の実験を連続して完了させた(表4及び5)。1)抗体のヒトTNFα誘導性単関節炎をブロックする全体的な能力を評価する、基本的な効果実験;及び 2)抗体誘導体の相互の相対的効果を評価する用量反応実験。サイトカインと抗体誘導体の両方を、以下に記載するように、別々の注射により一回だけ投与した。使用されたサイトカインの投与量は、Bolonとその同僚による発表に基づくものであったが、抗体誘導体の投与量の範囲は、利用可能な細胞培養データと経験に基づく推測に基づくものであった。一般的な動物保護ガイドラインに沿って実験を行った。
若い成体のオスのLewisラット(6-7週で175-20Og)を無作為に処理群に選定し(n=3/コホート)、そしてBolonら.((2004), Vet. Pathol. 41:235-243)に従って飼育した。
Bolonとその同僚による記載に従って、麻酔とサイトカインの注射を行った。50マイクロリットルの総関節内注射量を超えさせないため、10マイクログラムの組換えヒトTNFαを10マイクロリットルのフィルター滅菌リン酸緩衝食塩水(PBS)中のものとして注射し、各投与量の各抗体を40マイクロリットルのフィルター滅菌リン酸緩衝食塩水中のものとして、サイトカインと抗体誘導体を2つの別々の関節内注射により点滴注射した。関節内投与されたインフリキシマブ(Infliximab)/レミケード(Remicade)(登録商標)で処理された動物に、ヒトTNFαの関節内注射の3時間前に抗体誘導体を腹腔内注射した。関節内投与された抗体で処理された全ての動物体内に、ヒトTNFα注射の5分前に各抗体投与量を注射した。コントロールの動物には、ヒトTNFαを含まないPBSを10マイクロリットル注射した。
組換えヒトTNFαは、ぺプロテックECリミテッド社(PeproTech EC Ltd)から購入した。
それぞれ腹腔内若しくは関節内に投与される抗体誘導体の注射の直前、又は、コントロール動物の場合は、PBS又はTNFαの注射の前に、注射される膝関節の直径を標準的なカリパスにより測定した。TNFα(又はコントロール動物ではPBS)の注射の48時間後、かつ動物を安楽死させる直前に、注射された膝関節の直径を再度測定し、第一の直径測定値から第二の直径測定値を差し引くことにより、関節腫脹を計算した(図6及び9)。
TNFα(又はコントロール動物ではPBS)の注射の48時間後に、動物を安楽死させた。Bolonとその同僚により記載されるように、検死時に注射した膝を足と大腿から分離し、70%エタノールへの浸漬により無傷のまま固定し、標準的なヘマトキシリン・エオジン(HE)染色を進めた。
関節の炎症を測定するための組織学的採点分析を、Bolonとその同僚により記載される通りに行った。関節の炎症を評価するための組織学的採点基準を、Bolonとその同僚に従って適用した(図7、8及び10)。
表4に示すように、第一の一連の実験において、関節内に投与されたESBATech社のscFv抗体、TB-A、及び対応する関節内に投与されたESBATech社のFab抗体の代表例を、それらの関節内と腹腔内に投与されたインフリキシマブ(Infliximab)/レミケード(Remicade)(登録商標)による急性単関節炎の誘発をブロックする能力について比較した:
スコア 1:滑膜表層の軽度の肥厚
スコア 2:滑膜表層の肥厚とサブライニング(sublining)の軽度の炎症
スコア 3:滑膜表層の肥厚とサブライニング(sublining)の中程度の炎症
組織学的炎症スコアに対して、全ての治療で同程度の効果が観察された。
組織学的炎症スコアに対する治療効果に関して得られた結果を図10に示す。
Claims (58)
- TNFαと特異的に結合する、安定な可溶性の抗体又は抗体誘導体であって、配列番号1に示される配列若しくは配列番号1に示される配列から誘導される配列から成る軽鎖可変領域(VL)が、配列番号2に示される配列若しくは配列番号2に示される配列から誘導される配列から成る重鎖可変領域(VH)と結合されたものを含む抗体又は抗体誘導体であり、前記配列が誘導された配列の場合には、該配列は、前記VL領域のフレームワーク中に最大5個の変異を有し及び/又は前記VH領域のフレームワーク中に最大9個の変異を有する、前記抗体又は抗体誘導体。
- 前記VLの変異が、第4番目、第46番目、第65番目、第67番目、第70番目及び/又は第83番目の1箇所以上に存在し、そして前記VHの変異が、第11番目、第16番目、第28番目、第43番目、第68番目、第70番目、第71番目、第72番目、第73番目、第76番目、第77番目、第93番目及び/又は第112番目の1箇所に存在する、請求項1記載の抗体又は抗体誘導体。
- 前記VLの変異が、第4番目、第46番目、第65番目、第67番目、第70番目及び/又は第83番目の1箇所以上に存在し、そして前記VHの変異が、第11番目、第16番目、第28番目、第43番目、第48番目、第68番目、第70番目、第71番目、第72番目、第73番目、第76番目、第77番目、第79番目、第93番目及び/又は第112番目の1箇所以上に存在する、請求項1記載の抗体又は抗体誘導体。
- 少なくとも1の変換により、VLのための配列番号3及び/又はVHのための配列番号4の中に存在するアミノ酸へと至る、請求項1乃至3のいずれか一項に記載の抗体又は抗体誘導体。
- 前記VL領域が、配列番号1に示される配列を含む、請求項1乃至4のいずれか一項に記載の抗体又は抗体誘導体。
- 配列番号2に示される配列から成るVH領域を含む、請求項5記載の抗体又は抗体誘導体。
- 配列番号2に示される配列から誘導されるVH領域であって、ここで、F68がA、L、I、又はVに変異しているVH領域を含む、請求項5記載の抗体又は抗体誘導体。
- 配列番号11の配列から成るVL領域と、配列番号4の配列から成るVH領域を含む、請求項1記載の抗体又は抗体誘導体。
- 少なくとも1のCDRにおいて、少なくとも1のアミノ酸残基が、配列番号5に示されるVL配列、及び/又は配列番号6若しくは配列番号25に示されるVH配列の、対応するCDRに存在する残基へと変換されている、請求項1乃至8のいずれか一項に記載の抗体又は抗体誘導体。
- VL CDR2、VL CDR3、VH CDR2又はVH CDR3から成る群の少なくとも1のCDRが、配列番号5に示されるVL配列及び/又は配列番号25若しくは配列番号6に示されるVH配列の対応するCDRへと変換されている、請求項9記載の抗体又は抗体誘導体。
- 配列番号7又は配列番号8に示されるVL配列、及び配列番号2に示されるVH配列を有する、請求項10記載の抗体又は抗体誘導体。
- 配列番号1に示されるVL配列、及び配列番号4又は配列番号9又は配列番号28又は配列番号29に示されるVH配列を有する、請求項10記載の抗体又は抗体誘導体。
- 配列番号26又は配列番号27に示されるVL配列、及び配列番号30に示されるVH配列を有する、請求項10記載の抗体又は抗体誘導体。
- ヒトTNFαに対する特異性を有する、請求項1乃至13のいずれか一項に記載の抗体又は抗体誘導体。
- 前記VL及びVH領域がリンカーで連結された、scFv抗体である、請求項1乃至14のいずれか一項に記載の抗体誘導体。
- VL-リンカー-VHという配列構成を含む、請求項15記載のscFv抗体。
- 前記リンカーが、配列番号10に示される配列を有するか、又は該配列から誘導されている、請求項15又は16記載のscFv抗体。
- 前記リンカーの少なくとも1のグリシンが、より極性の又は帯電したアミノ酸へと変異している、請求項17記載のscFv抗体。
- 前記リンカーが、配列番号39に示される配列を有する、請求項18記載のscFv抗体。
- 前記VL領域が、ヒトIgκ鎖の定常領域に融合し、前記VH領域が、ヒトIgGのCH1領域に融合し、そして該2本の融合ポリペプチドが、鎖間のジスルフィド架橋により連結しているFab断片である、請求項1乃至14のいずれか一項に記載の抗体誘導体。
- 標識されているか、又は化学的に修飾されている、請求項1乃至20のいずれか一項に記載のscFv抗体又はFab断片。
- 請求項1乃至20のいずれか1項に記載の抗体又は抗体誘導体をコードするDNA配列。
- 請求項22に記載のDNA配列を含むクローニング又は発現ベクター。
- 請求項23記載の発現ベクターで形質転換された適切な宿主細胞。
- 原核細胞又は真核細胞であり、特に、大腸菌、酵母、植物、昆虫又は哺乳動物の細胞である、請求項24記載の宿主細胞。
- 請求項1乃至20のいずれか1項に記載の抗体又は抗体誘導体の分子の生産方法であって、該抗体分子の合成を可能にする条件下で請求項24又は25記載の宿主細胞を培養し、該培養物から前記抗体分子を回収することを含む、前記方法。
- 医薬としての請求項1乃至21のいずれか一項に記載の抗体又は抗体誘導体。
- 請求項1乃至21のいずれか一項に記載の抗体又は抗体誘導体の、TNFα関連疾患、特に、変形性関節症、ブドウ膜炎若しくは炎症性腸疾患の治療用薬物の製造のための使用、又は該疾患の検出のためのインビトロ診断薬としての使用。
- 請求項1乃至21のいずれか一項に記載の抗体を、薬剤的に許容できる担体、希釈剤又は賦形剤と共に含む診断薬又は治療薬組成物。
- 請求項1乃至21のいずれか1項に記載の抗体と、少なくとも1種の第2の化合物とを含む、配合剤。
- 前記第2の化合物が、TNFαに特異的な抗体ではない、請求項30記載の配合剤。
- 薬物として使用するための、請求項30又は31記載の配合剤。
- ヒト及び/又は動物体内での遺伝子治療用途ための医薬としての、請求項23記載のベクター。
- 請求項1乃至21のいずれか1項に記載の抗体又は抗体誘導体を局所的又は局所的に投与する、TNFα関連疾患の治療方法。
- 請求項1乃至21のいずれか1項に記載のVL及び/又はVH配列の発現ベクター中での使用。
- 治療に有効な量の請求項1乃至21のいずれか1項に記載の、先に凍結乾燥されていない抗体又は抗体誘導体と、pHが約4.8から約5.5である酢酸緩衝液と、界面活性剤と、ポリオールとを含み、浸透圧を増大させる量(tonicifying amount)の塩化ナトリウムを含まない、安定な水溶性医薬製剤。
- 等張性である、請求項36記載の製剤。
- 約2-8℃の温度において、少なくとも1年間安定である、請求項36又は37記載の製剤。
- 前記製剤の凍結融解を行った後に安定である、請求項36乃至38のいずれか一項に記載の製剤。
- 約30℃において、少なくとも1ヶ月間安定である、請求項36乃至39のいずれか一項に記載の製剤。
- 前記ポリオールが、非還元性の糖である、請求項36乃至40のいずれか一項に記載の製剤。
- 前記非還元性の糖が、トレハロースである、請求項36乃至41のいずれか一項に記載の製剤。
- 前記非還元性の糖が、スクロースである、請求項36乃至42のいずれか一項に記載の製剤。
- 前記抗体が、抗体断片である、請求項36乃至43のいずれか一項に記載の製剤。
- 前記抗体断片が、scFvである、請求項44記載の製剤。
- 前記抗体が、TNFαに結合する、請求項36乃至45のいずれか一項に記載の製剤。
- 約2-8℃の温度において、少なくとも2年間安定である、請求項36乃至46のいずれか一項に記載の製剤。
- 前記製剤中の前記抗体の濃度が、約0.1 mg/ml乃至約50 mg/mlである、請求項36乃至47のいずれか一項に記載の製剤。
- 前記界面活性剤が、ポリソルベートである、請求項36乃至48のいずれか一項に記載の製剤。
- 前記scFvが、TNFαに結合する、請求項45記載の製剤。
- 前記酢酸が、約5-30 mMの量で存在する、請求項36乃至50のいずれか一項に記載の製剤。
- 前記酢酸が、10-30 mMの量で存在する、請求項51記載の製剤。
- 更に保存剤を含む、請求項50乃至52のいずれか一項に記載の製剤。
- 前記保存剤が、ベンジルアルコールである、請求項53記載の製剤。
- 前記抗体が、約30-50 mg/mlの量で存在する、請求項50乃至54のいずれか一項に記載の製剤。
- 前記緩衝液がpH5の10-30 mMの酢酸ナトリウムであり、前記ポリオールが約2-10% w/vの量のトレハロースであり、前記界面活性剤が約0.01-0.1% v/vの量のポリソルベートであり、更に保存剤としてベンジルアルコールを含み、そして、約2-8℃の温度において、少なくとも2年間安定である、請求項55記載の製剤。
- 治療に有効な量の、先に凍結乾燥されていない抗体と、pHが約4.8から約5.5である酢酸緩衝液と、界面活性剤と、ポリオールとを含み、浸透圧を増大させる量(tonicifying amount)の塩化ナトリウムを含まない、安定な水溶性医薬製剤を収容した容器を含む製品。
- 前記抗体が、請求項1乃至21のいずれか一項に記載の抗体又は抗体誘導体である、請求項57記載の製品。
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2014503202A (ja) * | 2010-12-08 | 2014-02-13 | アッヴィ・インコーポレイテッド | TNF−α結合性タンパク質 |
JP2016508973A (ja) * | 2012-12-21 | 2016-03-24 | グレンマーク ファーマシューティカルズ, エセ.アー. | 抗her2抗体製剤 |
JP2018199720A (ja) * | 2012-12-21 | 2018-12-20 | グレンマーク ファーマシューティカルズ, エセ.アー. | 抗her2抗体製剤 |
JP2017515457A (ja) * | 2014-03-26 | 2017-06-15 | セル メディカ スイッツァランド アーゲー | TNFαに対する結合メンバー |
US10233238B2 (en) | 2014-03-26 | 2019-03-19 | Cell Medica Switzerland Ag | TNF alpha antibody or fragment thereof and methods of use |
US10995138B2 (en) | 2014-03-26 | 2021-05-04 | Cell Medica Inc. | Nucleic acids encoding binding members to TNF alpha |
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