JP6306513B2 - 抗PHF−tau抗体及びその使用 - Google Patents
抗PHF−tau抗体及びその使用 Download PDFInfo
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Description
本発明は、抗PHF−tau抗体及びこのような抗体の使用に関する。このような抗PHF−tau抗体は、PHF−tauのリン酸化エピトープに結合する特性を有していてもよく、PHF−tauの非リン酸化エピトープに結合する特性を有していてもよい。抗PHF−tau抗体は、治療法として、或いは生物学的サンプル、例えば、組織又は細胞においてPHF−tauを検出するための研究又は診断試薬として有用であり得る。
本発明の抗体の抗原結合部位を含むFab、(Fab’)2、scFv断片、又は抗体を含む本発明の抗PHF−tau抗体又はその断片を用いて、AD又は任意の他のタウオパシーに罹患している患者等、脳内にtauの病理学的凝集体を含む神経変性疾患を有する患者における症状を治療、低減、又は予防することができる。任意の特定の理論に束縛されるものではないが、本発明の抗体は、病理学的tau凝集体を低減し、ひいては脳におけるPHF−tauの量を低減することによって有益な効果を発揮し得る。本発明の抗体を用いて任意の分類に属する動物患者を治療することができる。かかる動物の例としては、ヒト、齧歯類、イヌ、ネコ、及び家畜等の哺乳動物が挙げられる。例えば、本発明の抗体は、ADの治療のための薬剤の調製においても有用であり、前記薬剤は、本明細書に定められる投薬量で投与するために調製される。
本発明の抗PHF−tau抗体は、AD又は他のタウオパシー等、tauの病理学的凝集を伴う神経変性疾患を治療又は予防するための治療剤及び予防剤の両方に好適である。無症候性患者では、治療は何歳から開始してもよい(例えば、約10、15、20、25、30歳)。しかし、通常、患者が約40、50、60、又は70歳に達するまで治療を始める必要はない。治療は、典型的に、ある期間にわたる複数回投与を含む。治療は、経時的に治療剤に対する抗体、又は活性化T細胞若しくはB細胞を評価することによってモニタリングしてもよい。反応が低下した場合、追加投与が指示される。
本発明の抗体は、被験体におけるAD又は他のタウオパシーを診断する方法で使用することができる。この方法は、本発明の抗体又はその断片等の診断試薬を用いてPHF−tauの存在を被験体において検出することを含む。
対らせん状細線維−tau(PHF−tau)の精製
Greenberg及びDavies(Greenberg and Davies Proc Natl Acad Sci U S A 87:5827〜31,1990)変法によってPHF−tauを部分的に精製した。簡潔に述べると、組織学的に確認されたアルツハイマー患者から得られた皮質の死後組織を部分的に精製した。典型的に、1000rpmのガラス/テフロンポッター組織ホモジナイザー(IKA Works,Inc;Staufen,Germany)を用いて前頭皮質5mgを10体積の冷バッファBuffer H(10mM Tris、800mM NaCl、1mM EGTA、及び10%スクロース/pH 7.4)中でホモジナイズした。ホモジナイズされた材料をSorvallローターSS34内で20分間264.8N(27000g)で遠心分離した。ペレットを廃棄し、上清を1%(w/v)N−ラウロイルサルコシン及び1%(v/v)2−メルカプトエタノールの最終濃度に調整し、37℃で2時間インキュベートした。次いで、上清を、Beckman 60Tiローター内で20℃にて35分間1059.1N(108000g)で遠心分離した。ペレットを慎重にPBSで洗浄し、PBSに懸濁させた。上記の通り上清を2回目の遠心分離にかけ、最後のペレットを溶解させ、分注し、−80℃で冷凍した。PHF−tau調製物の量を、12% SDS−PAGEと、抗tau抗体AT8及びHT7(ThermoScientific,Rockford,IL)を用いたウエスタンブロットとで評価した。AT8は、S202/T205においてリン酸化されたPHF−tauを検出するが、非リン酸化PHF−tau及び野性型tauには結合しない。HT7は、(配列番号6の)Tauアミノ酸159〜163における非リン酸化エピトープに結合し、tau及びPHF−tauを認識する。優れた品質のPHF−tau調製物は、AT8等の過剰リン酸化PHF−tauと反応する抗体で検出された、ウエスタンブロット上の約60、64、66、及び72kDaの分子量を有する4本のバンドからなる。同等の量及び純度を有する2つの別々のPHF−tau調製物を同じ脳サンプルから作製した。調製物1を免疫に用いた。
PHF−tauに対するモノクローナル抗体の作製
正常Balb/cマウスにおいて標準的なハイブリドーマ技術を用いて抗PHF−tau抗体を作製した(Kohler and Milstein Nature 256:495〜7,1975)。得られたハイブリドーマを96ウェルプレートに播種し、10日後に、下記の通り25ng/ウェルでコーティングされたPHF−tauにおいて直接ELISAでスクリーニングした。陽性細胞を、大腸菌BL21細胞で発現させ、熱処理及び硫酸アンモニウム沈殿で精製したコントロールtau(配列番号6)でコーティングされた10ng/ウェルにおける交差反応性について試験し、直ちにサブクローニングし、陽性クローンを液体窒素で冷凍した。10%ウシ胎仔血清(Hyclone,Europe)、ハイブリドーマフュージョンクローニングサプリメント(2%)(Roche,Brussels,Belgium)2% HT(Sigma,USA)、1mMのピルビン酸ナトリウム、2mMのL−グルタミン及びペニシリン(100U/mL)、並びにストレプトマイシン(50mg/mL)を添加したダルベッコ変法イーグル培地で全てのハイブリドーマを増殖させた。
50μL/ウェルのコーティングバッファ(10mMのトリス、10mMのNaCl、及び10mMのNaN3、pH 8.5)において、25ng/ウェルのPHF−tauを、NUNC Maxisorp(Life Technologies)平底高結合96ウェルマイクロタイタープレートにて4℃で一晩コーティングした。次の日、室温で60分間75μL/ウェルのPBS中0.1%カゼインでプレートをブロッキングした。次に、50μLのハイブリドーマ上清を添加し、37℃で1時間インキュベートした。洗浄後、37℃で1時間、50μL/ウェルのセイヨウワサビペルオキシダーゼと複合体化しているヒツジ抗マウスIgGで検出した(Amersham−Pharmacia Biotech)。両試薬を0.1%カゼイン/PBSで希釈した。プレートを洗浄し、0.42mM 3,5,3’,5’−テトラメチル−ベンジジン、0.003%(v/v)H2O2の100mMクエン酸及び100mMリン酸水素二ナトリウム(pH 4.3)溶液50μLを基質として添加した。室温でプレートシェーカー上に最大15分間反応を進行させ、その後、50μL/ウェルの2 N H2SO4で顕色を停止させ、450nmにてマイクロタイタープレートリーダー(Thermomax,Molecular Devices)でプレートを読み取った。
ハイブリドーマのスクリーニングから得られた選択抗体を、組換え的に発現させたコントロールtau(配列番号6)との交差反応性について試験した。500ngのPHF−tau及び200ngのコントロールtauを、NuPAGE(登録商標)Novex(登録商標)Bis−Tris 4〜12%ゲルにロードし、製造業者の指示に従ってiBlotシステム(Invitrogen)の使用によってニトロセルロースメンブレン上にブロットした。脱脂粉乳(NFDM)(5% w/v;Biorad)を含有するトリス緩衝生理食塩水Tween−20(TBS−T;1M Tris、150mM NaCl、及び0.05% Tween−20、pH 8.5)で1時間メンブレンをブロッキングした。TBS−T含有NFDM(5% w/v)で希釈した一次対照抗体(1μg/mL)HT7、AT8、AT100(ThermoScientific,Rockford,IL)、及びBT2と共に4℃で一晩インキュベートした。ハイブリドーマのスクリーニングから選択されたPT1、PT2、PT3、PT4、及びPT5モノクローナル抗体を、10% FCSを含有する培養上清に添加した。West Dura(登録商標)増強化学発光(Pierce,Thermoscientific)を介してHRPO(TBS−T中1:20000、Amersham Biosciences)と複合体化しているヒツジ抗マウスIgを用いて一次抗体を検出した。Lumi−imagingシステム(Roche Diagnostic)によってシグナルを捕捉した。ウエスタンブロットにおいて、PT1及びPT3は、PHF−tauと反応したが、コントロールtauとは反応しなかった。PT2は、両タンパク質と反応した。HT7及びAT8の結合プロファイルは、上記の通りである。AT100は、リン酸化Ser212/Thr214に結合し、PHF−tauに結合するが、野性型tauには結合しない。BT2は、S199/S202を含む非リン酸化エピトープを認識し、したがって、野性型tauは認識するが、PHF−tauは認識しなかった。
モノクローナル抗体PT1、PT2、PT3、PT4、PT5、AT8(ThermoScientific,Rockford,IL)、AT100(ThermoScientific,Rockford,IL)、及びHT7(MN1000)(Thermo Scientific,Rockford,IL)を、PHF−tau又はリン酸化tauペプチドに対する競合結合について評価した。製造業者の指示に従って、MSD(登録商標)SULF0−TAG NHSエステル(Meso Scale Discovery)を用いて抗体を標識した。
抗PHF−tau抗体は、インビボにおいてPHF−tauの蓄積を減少させる。
5月齢のメスのP301Lマウス(Taconic,cat#002508)を5ヶ月間マウスIgG1、生理食塩水、PT3(500μg/マウス)又はAT8(ハイブリドーマECACCから発現、寄託番号9110086)で週1回処理した。マウスに麻酔をかけ、冷PBSで灌流し、氷上で脳を解剖した。各マウスについて、1つの脳半球を10体積のH−バッファ中でホモジナイズし、次いで、4℃で20分間205.9N(21,000g)で遠心分離した。得られた上清を、60分間205.9N(100,000g)で更に遠心分離した。遠心分離後、ペレット(画分P1)を回収し、Chai等、J Biol Chem 286:34457〜67,2011に記載の通りウエスタン及びELISA分析用にリシスバッファに再懸濁させた。皮質サンプルの場合、画分P1を更に1%(w/v)N−ラウロイルサルコシンで処理し、超遠心して、ペレット中のPHF−tauを更に富化させた。オスのP301Lマウスは、トランスジーンの発現が少ないことが見出され、分析には含まれていなかった。
抗PHF−tau抗体の特性評価
親和性の決定
モノクローナル抗体PT1及びPT3と組換えヒト可溶性tau又はPHF−tauとの相互作用をProteOnによって試験した。ランニング又はシステムバッファとして3mM EDTA及び0.005% Tween−20を添加したPBS(pH 7.4)を用いて25℃で全ての相互作用を試験した。2つの異なる実験フォーマットを用いた。1つは、組換え的に発現させたコントロールtauとの相互作用ののものであり、他方は、PHF−tauとの相互作用のためのものであった。これら実験では、HT7(Pierce、カタログ番号MN1000)、マウス抗tau抗体をポジティブコントロールとして用いた。
** 有意な結合無し
***5実験中4実験で結合無し
Claims (6)
- 配列番号37のVHの抗原結合部位と配列番号38のVLの抗原結合部位とを含む、PHF−tauに結合する単離抗体。
- 配列番号37のVHの抗原結合部位をコードするポリヌクレオチドと、配列番号38のVLの抗原結合部位をコードするポリヌクレオチドとを含む、単離ポリヌクレオチド。
- 請求項2に記載のポリヌクレオチドを含む、ベクター。
- 請求項3に記載のベクターを含む、宿主細胞。
- 請求項4に記載の宿主細胞を培養し、前記宿主細胞によって産生される抗体を回収することを含む、PHF−tauに結合する抗体を製造する方法。
- 請求項1に記載の抗体と薬学的に許容できる担体とを含む、tau凝集体を低減するための医薬組成物。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2018078897A (ja) * | 2011-12-20 | 2018-05-24 | ヤンセン バイオテツク,インコーポレーテツド | 抗PHF−tau抗体及びその使用 |
Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2018132044A (ru) | 2012-07-03 | 2018-10-19 | Вашингтон Юниверсити | Антитела против тау |
BR112015003326A2 (pt) | 2012-08-16 | 2017-07-04 | Ipierian Inc | métodos de tratamento de uma tauopatia |
US8980270B2 (en) | 2013-01-18 | 2015-03-17 | Ipierian, Inc. | Methods of treating a tauopathy |
JP2017512751A (ja) | 2014-02-14 | 2017-05-25 | アイピエリアン,インコーポレイティド | タウペプチド、抗タウ抗体、およびそれらの使用方法 |
EP3486256A3 (en) * | 2014-06-26 | 2019-08-28 | Janssen Vaccines & Prevention B.V. | Antibodies and antigen-binding fragments that specifically bind to microtubule-associated protein tau |
ZA201608812B (en) * | 2014-06-26 | 2019-08-28 | Janssen Vaccines & Prevention Bv | Antibodies and antigen-binding fragments that specifically bind to microtubule-associated protein tau |
TWI734975B (zh) | 2014-06-27 | 2021-08-01 | 美商C2N醫療診斷有限責任公司 | 人類化抗-tau抗體 |
WO2016112078A2 (en) * | 2015-01-08 | 2016-07-14 | Janssen Biotech, Inc. | Anti-phf-tau antibodies and their uses |
TWI669314B (zh) | 2015-02-26 | 2019-08-21 | 美國禮來大藥廠 | 針對tau之抗體及其用途 |
TWI790642B (zh) | 2015-06-05 | 2023-01-21 | 美商建南德克公司 | 抗-tau抗體及使用方法 |
CN107849105B (zh) * | 2015-07-06 | 2021-09-17 | Ucb生物制药有限责任公司 | Tau结合抗体 |
NZ738058A (en) * | 2015-07-06 | 2021-07-30 | UCB Biopharma SRL | Tau-binding antibodies |
US20190224339A1 (en) * | 2016-04-29 | 2019-07-25 | Voyager Therapeutics, Inc. | Compositions for the treatment of disease |
EP3496750A2 (en) | 2016-08-09 | 2019-06-19 | Eli Lilly and Company | Combination therapy |
CN110248959B (zh) | 2016-12-07 | 2023-06-30 | 基因泰克公司 | 抗tau抗体和使用方法 |
KR20230146126A (ko) * | 2016-12-07 | 2023-10-18 | 제넨테크, 인크. | 항-타우 항체 및 이의 이용 방법 |
CN110520440A (zh) | 2017-02-17 | 2019-11-29 | 戴纳立制药公司 | 抗τ抗体及其使用方法 |
JOP20180014A1 (ar) | 2017-02-27 | 2019-01-30 | Teijin Pharma Ltd | جسم مضاد متوافق مع البشر لعلاج أو الوقاية من الاضطرابات الإدراكية، وعملية لإنتاجه، وعامل لعلاج أو الوقاية من الاضطرابات الإدراكية باستخدامه |
JOP20180021A1 (ar) * | 2017-03-16 | 2019-01-30 | Janssen Biotech Inc | الأجسام المضادة لتكتلات خيوط بروتين تاو (tau) الحلزونية المزدوجة واستخداماتها |
TW202340244A (zh) | 2017-10-16 | 2023-10-16 | 日商衛材R&D企管股份有限公司 | 抗tau抗體及其用途 |
WO2019171258A1 (en) * | 2018-03-05 | 2019-09-12 | Janssen Pharmaceutica Nv | Assays to detect neurodegeneration |
JOP20200215A1 (ar) * | 2018-03-05 | 2020-09-03 | Janssen Pharmaceutica Nv | الأجسام المضادة لـ PHF-Tau المضاد واستخداماتها |
KR20200144551A (ko) * | 2018-03-28 | 2020-12-29 | 악손 뉴로사이언스 에스이 | 알츠하이머병을 검출하고 치료하는 항체-기반 방법 |
CA3107788A1 (en) | 2018-07-31 | 2020-02-06 | Eli Lilly And Company | Combination of anti-tau antibody and oga inhibitor for treatment of diseases characterized by aberrant tau aggregation |
BR112022020753A2 (pt) | 2020-04-15 | 2022-12-20 | Voyager Therapeutics Inc | Compostos de ligação a tau |
AU2021297873A1 (en) | 2020-06-25 | 2023-02-09 | Merck Sharp & Dohme Llc | High affinity antibodies targeting tau phosphorylated at serine 413 |
WO2022132923A1 (en) | 2020-12-16 | 2022-06-23 | Voyager Therapeutics, Inc. | Tau binding compounds |
CA3214310A1 (en) * | 2021-03-26 | 2022-09-29 | Rupesh Nanjunda | Anti-tau antibodies and uses thereof |
BR112023019205A2 (pt) * | 2021-03-26 | 2023-10-24 | Janssen Biotech Inc | Anticorpos humanizados contra tau de filamento helicoidal pareado e usos dos mesmos |
WO2023250388A1 (en) | 2022-06-22 | 2023-12-28 | Voyager Therapeutics, Inc. | Tau binding compounds |
WO2024059739A1 (en) | 2022-09-15 | 2024-03-21 | Voyager Therapeutics, Inc. | Tau binding compounds |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
JP3909084B2 (ja) * | 1991-10-25 | 2007-04-25 | エヌ・ブイ・インノジェネティクス・ソシエテ・アノニム | 微小管結合タンパク質タウに対するモノクローナル抗体 |
EP0737208B1 (en) * | 1993-12-21 | 2006-08-02 | Innogenetics N.V. | Monoclonal antibodies specific for phf-tau, hybridomas secreting them, antigen recognition by these antibodies and their applications |
JPH10506381A (ja) * | 1994-07-29 | 1998-06-23 | イノジェネティックス・ナムローゼ・フェンノートシャップ | 特定のサブクラスまたは形態のホスホリレーションされたtauのエピトープに特異的なモノクローナル抗体、それらを分泌するハイブリドーマ、これらの抗体の抗原認識およびそれらの応用 |
WO2004006955A1 (en) | 2001-07-12 | 2004-01-22 | Jefferson Foote | Super humanized antibodies |
EP1697741A4 (en) | 2003-12-04 | 2008-02-13 | Xencor Inc | PROCESS FOR PRODUCING PROTEIN VARIANTS WITH INCREASED HOST STRUCTURE CONTENT AND COMPOSITIONS THEREOF |
US20070048785A1 (en) * | 2004-06-09 | 2007-03-01 | Lin Laura L | Anti-IL-13 antibodies and complexes |
EP1790664A1 (en) * | 2005-11-24 | 2007-05-30 | Ganymed Pharmaceuticals AG | Monoclonal antibodies against claudin-18 for treatment of cancer |
US20070280935A1 (en) * | 2006-04-07 | 2007-12-06 | Bernd Bohrmann | Antibody that recognizes phosphorylated peptides |
KR101437188B1 (ko) * | 2006-08-04 | 2014-10-02 | 노바르티스 아게 | Ephb3-특이적 항체 및 이의 용도 |
JP2010235447A (ja) * | 2007-07-30 | 2010-10-21 | Igaku Seibutsugaku Kenkyusho:Kk | 炎症性サイトカインの抑制剤 |
US20100261620A1 (en) | 2008-10-14 | 2010-10-14 | Juan Carlos Almagro | Methods of Humanizing and Affinity-Maturing Antibodies |
US9968574B2 (en) * | 2009-05-15 | 2018-05-15 | The University Of Kentucky Research Foundation | Treatment of MCI and Alzheimer's disease |
CA2765099A1 (en) * | 2009-06-10 | 2010-12-16 | New York University | Phosphorylated tau peptide for use in the treatment of tauopathy |
US8609097B2 (en) * | 2009-06-10 | 2013-12-17 | Hoffmann-La Roche Inc. | Use of an anti-Tau pS422 antibody for the treatment of brain diseases |
US8912355B2 (en) * | 2009-09-29 | 2014-12-16 | University Of Ottawa Heart Institute | Linoleic phospholipids and uses thereof for inhibiting inflammatory and neurodegenerative processes |
WO2011047146A2 (en) | 2009-10-14 | 2011-04-21 | Centocor Ortho Biotech Inc. | Methods of affinity maturing antibodies |
CN103502272B (zh) | 2010-10-07 | 2016-06-15 | Ac免疫有限公司 | 识别Tau的磷酸化特异抗体 |
SI2627672T1 (sl) | 2010-10-11 | 2018-10-30 | Biogen International Neuroscience Gmbh | Človeška protitelesa anti-tau |
MY186066A (en) * | 2011-12-20 | 2021-06-18 | Janssen Biotech Inc | Anti-phf-tau antibodies and their uses |
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