JP5417171B2 - 改善されたsgp130Fc二量体 - Google Patents
改善されたsgp130Fc二量体 Download PDFInfo
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- JP5417171B2 JP5417171B2 JP2009517012A JP2009517012A JP5417171B2 JP 5417171 B2 JP5417171 B2 JP 5417171B2 JP 2009517012 A JP2009517012 A JP 2009517012A JP 2009517012 A JP2009517012 A JP 2009517012A JP 5417171 B2 JP5417171 B2 JP 5417171B2
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- polypeptide dimer
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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Description
イン)が欠失したgp130分子をいう。
、活性成分の生体活性の有効性に干渉せず、投与するホストに対して毒性を示さない任意のキャリアーを含むことを意味する。好適な医薬キャリアーの例は当該分野で知られており、リン酸緩衝液、水、エマルジョン(例えば水中油型エマルジョン)、種々の湿潤剤、無菌溶液などがある。それらのキャリアーは慣例的な方法で調剤し、有効投与量で被験体に投与できる。
寛解をもたらすのに十分な活性成分の量をいう。
,当業者に知られる方法で決定することができる(例えばFinglら, The Pharmocological Basis of Therapeutics, GoodmanおよびGilman編, Macmillan Publishing社, New York, pp. 1-46 (1975)参照)。
(A)材料
Gatewayクローニングシステムの要素(AccuPrime Pfx DNAポリメラーゼ、ドナー・ベクターpDONR221、CMVプロモーターで制御される発現ベクターpcDNA-DEST40、インサートの転移のためのBPおよびLRリコンビナーゼ、およびコンピテントE.coli細胞)は、Invitrogen社(Karlsruhe,ドイツ)から購入した。QuikChange II部位特異的変異導入キットはStratagene社(Amsterdam,オランダ)から得た。PAGE精製した変異導入プライマーはMicrosynth社(Balgach、スイス)から得た。CHO-K1細胞はGerman Collection of Microorganisms and Cell Cultures(Braunschweig、ドイツ)から得た。培養液成分は以下から購入した:Ham's F12培養液、低IgG FBS、およびPBS(PAA Laboratories社; Colbe、ドイツ)、FBS(Biochrom社;Berlin、ドイツ)、トリプシン/EDTA溶液(Invitrogen社)、およびG418溶液(Sigma-Aldrich社; Taufkirchen、ドイツ)。トランスフェクション試薬Lipofectamine 2000はInvitrogen社から得た。免疫沈降のためのProtein A/G Plus AgaroseはSanta Cruz社(Heidelberg、ドイツ)から得た。ウェスタンブロットの免疫沈降および1次検出には、いずれもマウス抗ヒトIgG(Fc)モノクローナル抗体を使用した(CBL102; Chemicon社;Hofheim、ドイツ)。ウェスタンブロットの2次検出は抗マウスIgG HRP-結合抗体、ECL-Plusウェスタンブロッティング基質、およびHyperfilm ECL(全て GE Healthcare社;Munich、ドイツ)を使用して行った。ローラーボトル(2.1L、2,5X surface)はGreiner Bio-One社(Frickenhausen、ドイツ)から購入した。吸引ろ過ユニット用の酢酸セルロース・フィルター(0.45μm)はSartorius社(Gottingen、ドイツ)から購入した。アフィニティー・クロマトグラフィーおよびサイズ排除クロマトグラフィー(SEC)のための物質は全てGE Healthcare社(Munich、ドイツ)から得た;XK16/20カラム中のMabSelect担体(製品コード:17-5199-01)、PD-10脱塩カラム、およびSECのHiLoad 26/60 Superdex 200 pgカラム。Amicon Ultra-15 50 kDa Ultracel-PLメンブレン濃縮ユニットはMillipore社(Eschborn、ドイツ)から購入した。調製済PAGE用アクリルアミド-ビス溶液(19:1、30%)はBio-Rad(Munich、ドイツ)から得た。
gp130の全細胞外ドメインおよび野生型ヒトIgG1 Fcを含む完全長sgp130FcのcDNA(供与源;ヒトgp130/IL6ST:GenBank配列NM 002184およびsupporting clones;ヒトIgG1/IGHG1の定常領域:例えばGenBank配列AK057754)を、CHO-K1細胞での発現に合わせてコドンを最適化し、Gatewayプライマー、AccuPrime Pfx DNAポリメラーゼ、およびBPリコンビナーゼを用いて、標準的なGatewayクローニング法でpDONR221にサブクローニングした。250-300bp毎の積み重ねられたフォワードおよびリバース・シークエンス用プライマーを用いて、サブクローニングしたインサートの全配列を確認した。QuikChange IIキットによる部位特異的変異導入では、IgG1-Fcの下流ヒンジ領域(EUナンバリングでアミノ酸234、235、および237)を野生型配列の"LLGG"から"AEGA"に変異させた。変異させたクローンは、上記のように全配列シーケンシングによって確認した。次いで、Gateway LR組換えによってインサートを発現ベクターpcDNA-DEST40に転移させた。インサートはFc部分の後に2つの停止コドンをコードするため、pcDNA-DEST40(V5および6xHisエピトープ)にコードされるタグはCR5/18中には存在しない。AlwNI制限酵素消化によってポジティブなクローンを同定し、再び配列を確認した。
CHO-K1細胞を、10% FBS含有Ham's F12培養液中、37℃、5% CO2、水飽和雰囲気中で培養した。3-4日毎に継代培養を行い、20継代までのみ使用した。Invitrogen社のLipofectamine 2000およびCHO-K1の標準的な条件を用いて、発現コンストラクトpcDNA-DEST40_CR5/18を細胞にトランスフェクトした。最初の一過性発現試験では、6-ウェルプレート中でCHO-K1細胞をトランスフェクトし、トランスフェクションの24時間後に細胞および上清の両方を回収した。Protein A/G Plus Agaroseおよび抗ヒトIgG(Fc)抗体を使用し、製造者の取扱説明書に従って、上清からCR5/18を免疫沈降させた。全細胞タンパク質を抽出し、Waetzigら, J. Immunol. 168: 5342 (2002)に記載されるように、抗ヒトIgG(Fc)抗体を用いて細胞溶解物および免疫沈降物のウェスタンブロットを行った。
好適な一過性発現の後、CHO-K1細胞をトランスフェクトし、10cmプレート中、400μg/mlのG418を用いて陽性クローンを選択した。生成物の質および特性を確認するために、予め選択したポリクローナルCHO-K1プールをローラーボトルに移し、低IgG FBSで培養した。コンフルエント細胞の上清を毎週、2-3回回収し、3,500xg、4℃、15分間の遠心分離を2回行って細胞デブリを除去し、直ちに処理するか、または-80℃で凍結した。これと平行して、限界希釈法を用いて予め選択したプールから安定な細胞クローンを選択し、上記のようにウェスタンブロット発現分析による特性決定を行った。最も高度かつ安定に発現したクローンをローラーボトルに移し、恒久的生成に使用した。
P-1蠕動ポンプおよびAKTA Purifier 100 System(いずれもGE Healthcare社; Munich,ドイツ)を用い、ローラーボトル培養液からCR5/18を含有する上清を4℃で精製した。プロトコールはモノクローナル抗体の精製に関する製造者の推奨に基づく。遠心分離後、新鮮なまたは(氷上で)解凍した上清のpHを6.7-7.0に調整した。真空ろ過(0.45nm)を2ラウンド行った後、上清を脱気し、必要に応じて、pH値を6.7-7.0に再調整した。次に、2-4Lの上清を、PBSで平衡化したアフィニティー・クロマトグラフィー・カラム(6-25ml MabSelectをXK16/20カラムに充填)にP-1ポンプを用いて3-10ml/分の流速で負荷した。PBSで洗浄した後、カラムをAKTA Purifierに移し、未結合のタンパク質が定量的に除去された後、A280が安定するまでPBSで洗浄した。溶出後、AKTAシステムに2つの50mMクエン酸ナトリウムバッファー(それぞれpH3.25およびpH5.5。これらを混合して所望のpH条件を得る)を装着した。pH5.1で1回洗浄した後、pH3.7で溶出した。2mlの1M Tris-HCl(pH11)を含有する15mlの試験管に画分10mlを回収した。ピーク画分をプールし、pHを測定し、必要に応じて7.5に調整した。プールのタンパク質濃度をA280で測定し、Amicon Ultra-15 50 kDa Ultracel-PLメンブレン濃縮ユニットを用いてプールを最高1.5mg/mlまで注意深く濃縮した。PBSで平衡化したPD-10脱塩カラムを用いてクエン酸バッファーをPBSで置換した後、再び280nmでタンパク質濃度を測定した。
(A)材料
安定にトランスフェクトされたB細胞前駆細胞系BAF3/gp130およびデザイナー・サイトカイン、ハイパーIL-6を使用した。以下のように培養液成分を購入した:DMEMおよびPBS(PAA Laboratories社;Colbe、ドイツ)、FBS(Biochrom社;Berlin、ドイツ)およびトリプシン/EDTA溶液(Invitrogen社; Karlsruhe、ドイツ)。インターロイキン-6(IL-6)および可溶性インターロイキン-6受容体(sIL-6R)は、それぞれBioSource社(Solingen、ドイツ)およびR&D Systems社(Wiesbaden、ドイツ)から購入した。Cell Titer 96 Aqueous Non-Radioactive Cell Proliferation Assay(MTS)をPromega社(Mannheim、ドイツ)から得た。
BAF3/gp130細胞の増殖および生存能力は、培養液中のIL-6/sIL-6R複合体の存在に依存する。維持のために、BAF3/gp130細胞を10% FBSおよび10ng/mLハイパーIL-6(共有結合したIL-6およびsIL-6Rから成るデザイナー・サイトカイン;Fischerら, 1997, Nat. Biotechnol. 15: 142-145)を含有するDMEM中、5x105細胞/mL未満の密度で培養した。10ng/mLハイパーIL-6は100ng/mLのIL-6および50ng/mLのsIL-6Rで代替できる。細胞は週2回継代した。アッセイのために、ハイパーIL-6 (またはIL-6/sIL-6R)を含有しない培養液で細胞を2回洗浄した後、96ウェルプレートに5,000細胞/ウェルで播種した。CR5/18または親化合物sgp130Fcを20μg/mLから78ng/mLの範囲の種々の濃度で添加した(1:4希釈シリーズ;図3)。次に、細胞を100ng/mL IL-6および50ng/mL sIL-6Rの存在下で3日間インキュベートした。コントロールはCR5/18またはsgp130Fc未含有の、および最大濃度のCR5/18またはsgp130Fc含有の未刺激細胞、および刺激物質IL-6およびsIL-6Rのみと共にインキュベートした細胞を含んでいる(図3)。
細胞培養液中でのCR5/18または野生型sgp130Fcの生体活性を、3日後の生存BAF3/gp130細胞数(MTS基質変換として測定)の低下によって測定した。CR5/18は野生型sgp130Fcより生体活性が高く、約400ng/mLの濃度でそのIC50に達したが、sgp130Fc(IC50=約800ng/mL)は有意な効果を示さなかった(図3)。これは、CR5/18が野生型化合物の約半分の治療濃度で使用できることを示している。
Claims (17)
- アゴニスト複合体IL-6/sIL-6Rの活性を阻害する能力があり、2つの単量体を含むポリペプチド二量体であって、該単量体のそれぞれは、IgG1タンパク質のFcドメインに融合したgp130分子の細胞外部分を含み、少なくともFcドメインのヒンジ領域のアミノ酸残基Leu235が少なくとも1つの親水性アミノ酸残基で置換されており、前記親水性アミノ酸残基がGluまたはAspである、上記ポリペプチド二量体。
- 更にヒンジ領域のアミノ酸残基Leu234がPheまたはAlaで置換されている、請求項1記載のポリペプチド二量体。
- ヒンジ領域のアミノ酸残基Leu234および/またはGly237がアミノ酸残基Alaで置換されている、請求項2記載のポリペプチド二量体。
- ヒンジ領域がLeu234-Leu235-Gly236-Gly237の代わりにAla234-Glu235-Gly236-Ala237のアミノ酸配列モチーフを含有する、請求項1から3のいずれかに記載のポリペプチド二量体。
- ヒンジ領域がアミノ酸配列Asp221-Lys222-Thr223-His224-Thr225-Cys226-Pro227-Pro228-Cys229-Pro230-Ala231-Pro232-Glu233-Ala234-Glu235-Gly236-Ala237-Pro238-Ser239-Val240を含有する、請求項4記載のポリペプチド二量体。
- 可溶性gp130分子が、IgG1タンパク質のFcドメインのヒンジ領域に、直接またはフレキシブルなポリペプチド・リンカーを介して融合している、請求項1から5のいずれかに記載のポリペプチド二量体。
- リンカーがグリシン、セリン、アスパラギン、トレオニン、およびアラニンから成る群から独立して選択される2から50個のアミノ酸残基を含むリンカーである、請求項6記載のポリペプチド二量体。
- 1つまたはそれ以上のN-グリコシル化部位が、可溶性gp130分子とFcドメインとの間に挿入されている、請求項1から7のいずれかに記載のポリペプチド二量体。
- 単量体が、単純な共有結合、フレキシブルなペプチド・リンカー、または1つもしくはそれ以上のジスルフィド架橋を介して互いに結合されている、請求項1から8のいずれかに記載のポリペプチド二量体。
- 該二量体の少なくとも1つの単量体がPEG化されている、請求項1から9のいずれかに記載のポリペプチド二量体。
- 請求項1から9のいずれかに記載のポリペプチド二量体の単量体をコードするポリヌクレオチド。
- 請求項11記載のポリヌクレオチドを含有する発現ベクター。
- 請求項12記載の発現ベクターを含有するホスト細胞。
- 請求項1から9のいずれかに記載のポリペプチド二量体を生成する方法であって、請求項13記載のホスト細胞を培養し、そして該ホスト細胞または培養液からの単量体または二量体を回収することを含む上記方法。
- 請求項1から10のいずれかに記載のポリペプチド二量体を含有する医薬組成物。
- アゴニスト複合体IL-6/sIL-6Rの阻害が有益な効果をもたらす疾患または傷害の治療および/または予防のための医薬組成物を調製するための、請求項1から10のいずれかに記載のポリペプチド二量体の使用。
- 該疾患が、骨吸収、高カルシウム血症、悪液質、腫瘍または他のタイプの癌、自己免疫疾患、炎症性またはアトピー性疾患、感染症、内分泌障害、または代謝性もしくは異化性疾患である、請求項16記載の使用。
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Publication number | Priority date | Publication date | Assignee | Title |
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ATE480568T1 (de) | 2006-06-30 | 2010-09-15 | Conaris Res Inst Ag | Verbesserte sgp 130fc dimere |
CA2690825C (en) | 2007-05-11 | 2019-02-12 | Altor Bioscience Corporation | Fusion molecules and il-15 variants |
EP2050759A1 (en) * | 2007-10-19 | 2009-04-22 | CONARIS research institute AG | Soluble gp 130 muteins with improved binding activity |
KR20140020228A (ko) * | 2010-09-21 | 2014-02-18 | 알토 바이오사이언스 코포레이션 | 다량체성 아이엘 15 용해성 융합 분자 및 그의 제조 및 사용 방법 |
US11053299B2 (en) | 2010-09-21 | 2021-07-06 | Immunity Bio, Inc. | Superkine |
EP3139660B1 (en) * | 2013-09-20 | 2021-01-20 | Intel Corporation | Ap location query |
EP3673915A1 (en) | 2014-06-30 | 2020-07-01 | Altor BioScience Corporation | Il-15-based molecules and methods of use thereof |
US11566082B2 (en) | 2014-11-17 | 2023-01-31 | Cytiva Bioprocess R&D Ab | Mutated immunoglobulin-binding polypeptides |
MA41116A (fr) * | 2014-12-01 | 2017-10-10 | Ferring Bv | Compositions d'inhibiteur de trans-signalisation par l'il-6 sélectif |
DK3226888T3 (da) * | 2014-12-01 | 2021-07-12 | Ferring Bv | Administration af en selektiv inhibitor af il-6-trans-signalering |
US10703774B2 (en) | 2016-09-30 | 2020-07-07 | Ge Healthcare Bioprocess R&D Ab | Separation method |
EP3455241B1 (en) | 2016-05-11 | 2022-02-23 | Cytiva BioProcess R&D AB | Method of cleaning and/or sanitizing a separation matrix |
US10730908B2 (en) | 2016-05-11 | 2020-08-04 | Ge Healthcare Bioprocess R&D Ab | Separation method |
US10654887B2 (en) | 2016-05-11 | 2020-05-19 | Ge Healthcare Bio-Process R&D Ab | Separation matrix |
WO2017194592A1 (en) | 2016-05-11 | 2017-11-16 | Ge Healthcare Bioprocess R&D Ab | Method of storing a separation matrix |
CN109071613A (zh) | 2016-05-11 | 2018-12-21 | 通用电气医疗集团生物工艺研发股份公司 | 分离基质 |
US10889615B2 (en) | 2016-05-11 | 2021-01-12 | Cytiva Bioprocess R&D Ab | Mutated immunoglobulin-binding polypeptides |
EP3529263A4 (en) | 2016-10-21 | 2020-07-08 | Altor BioScience Corporation | MULTIMERIC MOLECULES BASED ON IL-15 |
CN108593912A (zh) * | 2018-04-09 | 2018-09-28 | 北京大学深圳研究生院 | 一种可溶性cd38浓度的检测方法 |
CN108318689A (zh) * | 2018-04-09 | 2018-07-24 | 北京大学深圳研究生院 | 一种多发性骨髓瘤的诊断方法 |
BR112022025166A2 (pt) | 2020-06-10 | 2022-12-27 | Ferring Bv | Composto farmacêutico para o tratamento de doença cardiovascular aterosclerótica |
WO2022139580A1 (en) | 2020-12-22 | 2022-06-30 | Ferring B.V. | Blood gene expression biomarkers to predict response in patients with inflammatory bowel diseases |
CN118043639A (zh) * | 2021-09-01 | 2024-05-14 | 泰利斯制药(创新)有限公司 | 聚集体分离方法 |
WO2024011946A1 (en) * | 2022-07-12 | 2024-01-18 | I-Mab Biopharma (Hangzhou) Co., Ltd | Polypeptide dimers for the treatment of systemic sclerosis |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4751180A (en) | 1985-03-28 | 1988-06-14 | Chiron Corporation | Expression using fused genes providing for protein product |
JPH04218000A (ja) | 1990-02-13 | 1992-08-07 | Kirin Amgen Inc | 修飾ポリペプチド |
WO1994012520A1 (en) | 1992-11-20 | 1994-06-09 | Enzon, Inc. | Linker for linked fusion polypeptides |
US5457035A (en) * | 1993-07-23 | 1995-10-10 | Immunex Corporation | Cytokine which is a ligand for OX40 |
US5783672A (en) | 1994-05-26 | 1998-07-21 | Immunex Corporation | Receptor for oncostatin M |
PL199659B1 (pl) * | 1998-02-25 | 2008-10-31 | Merck Patent Gmbh | Białko fuzyjne przeciwciała hu-KS IL2, cząsteczka DNA kodująca białko fuzyjne przeciwciała hu-KS IL2 i sposób wytwarzania białka fuzyjnego przeciwciała hu-KS IL2 |
US6472179B2 (en) | 1998-09-25 | 2002-10-29 | Regeneron Pharmaceuticals, Inc. | Receptor based antagonists and methods of making and using |
DE19941897B4 (de) | 1999-09-02 | 2006-06-14 | GSF - Forschungszentrum für Umwelt und Gesundheit GmbH | IL-6 Rezeptor-Protein, Beta-Kette (gp130) des IL-6 Rezeptor-Proteins, für diese Proteine kodierende DNA, davon abgeleitete RNA, Peptid mit den Aminosäuren 771-811 dieser Beta-Kette oder Teilen davon und deren Verwendungen |
ES2269366T3 (es) * | 2000-02-11 | 2007-04-01 | Merck Patent Gmbh | Mejoramiento de la vida media en circulacion de proteinas de fusion basadas en anticuerpos. |
DE60037648T2 (de) * | 2000-04-21 | 2010-06-17 | Conaris Research Institute Ag | Fusionsproteine, die zwei lösliche gp130 Moleküle enthalten |
KR20030097876A (ko) | 2001-05-21 | 2003-12-31 | 넥타르 테라퓨틱스 | 화학적으로 개질된 인슐린의 폐 투여 |
US7507412B2 (en) * | 2001-07-18 | 2009-03-24 | Merck Patent Gmbh | Glycoprotein VI fusion proteins |
AU2002356511A1 (en) * | 2001-07-30 | 2003-04-01 | Immunex Corporation | T. reesei phytase enyzmes, polynucleides encoding the enzymes, vectors and host cells thereof, and methods of using |
CA2526169A1 (en) * | 2003-06-12 | 2004-12-23 | Eli Lilly And Company | Fusion proteins |
EP1491554A1 (en) | 2003-06-23 | 2004-12-29 | CONARIS research institute AG | PEGylated soluble gp130-dimers useful as a medicament |
KR20060124656A (ko) * | 2003-12-31 | 2006-12-05 | 메르크 파텐트 게엠베하 | 개선된 약물동태를 가지는 Fc-에리스로포이에틴 융합단백질 |
PT1630232E (pt) | 2004-08-27 | 2008-10-02 | Conaris Res Inst Ag | Sequências de nucleótidos optimizadas que codificam sgp130 |
EP1801121A1 (en) | 2005-12-23 | 2007-06-27 | CONARIS research institute AG | Soluble gp130 molecule variants useful as a medicament |
ATE480568T1 (de) | 2006-06-30 | 2010-09-15 | Conaris Res Inst Ag | Verbesserte sgp 130fc dimere |
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