JP5755148B2 - 組換え一価抗体 - Google Patents
組換え一価抗体 Download PDFInfo
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- JP5755148B2 JP5755148B2 JP2011545812A JP2011545812A JP5755148B2 JP 5755148 B2 JP5755148 B2 JP 5755148B2 JP 2011545812 A JP2011545812 A JP 2011545812A JP 2011545812 A JP2011545812 A JP 2011545812A JP 5755148 B2 JP5755148 B2 JP 5755148B2
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- antibody
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- monovalent antibody
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- recombinant
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Classifications
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
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- C07K—PEPTIDES
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- C07K2318/10—Immunoglobulin or domain(s) thereof as scaffolds for inserted non-Ig peptide sequences, e.g. for vaccination purposes
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Description
そのN末端からそのC末端に
イムノグロブリンのVHドメインの構造を有し、前記親抗体の重鎖のCDRを含む領域A及び
ペプチドリンカーとIgGイムノグロブリンのCH2及びCH3ドメインとからなる領域B
から本質的になる第1蛋白質の鎖並びに
そのN末端からそのC末端に
イムノグロブリンのVLドメインの構造を有し、前記親抗体の軽鎖のCDRを含む領域A'及び
第1ポリペプチドの領域Bと同一の領域B
から本質的になる第2蛋白質の鎖とのヘテロ二量体である組換え一価抗体である。
第1及び/又は第2蛋白質の鎖はグリコシル化されていてもよいし、グリコシル化されていなくてもよい。
本発明の発現ベクターの構築及び宿主細胞の形質転換は、分子生物学の慣用の技術によって行われ得る。
本発明の組換え一価抗体は、医薬製品を得るのに用いることができる。これらの医薬製品はまた、本発明の目的の一部である。
ヒトIgG1遺伝子(NCBIアクセッションBC018747)のCH2-CH3ドメインを、NheI/XbaI部位を導入する以下のプライマーを用いて増幅した。
CH2CH3-5':
5'-ATATGCTAGCCCAGCACCTGAACTCCTG-3' (配列番号6);
CH2CH3-3':
5'-ATATTCTAGATTATTTACCCGGAGA-3' (配列番号7)。
得られたフラグメントをpSC-Aベクター(Stratagene, Amsterdam, The Netherlands)に導入し、pSC-A-CH2-CH3ベクターを得た。
VH:
Hc28.3-5':
5'-ATATGCTAGCGGATCCGATATCGTCAAGCTGCAGCAGTCA-3'(配列番号8);
Hc28.3-3':
5'ATATGCTAGCAGATGGTGCAGCCACAGTTGAGGAGACGGTGACCAT3'(配列番号9);
VL:
Lc28.3-5':
5'-ATATGCTAGCGGATCCGATATCGACATCCAGATGACCCAG-3'(配列番号10);
Lc28.3-3':
5'-ATATGCTAGCAGATGGTGCAGCCACAGTCCGTTTTATTTCCAGCTTGG-3'(配列番号11) 。
Cos細胞を、製造業者の取扱説明書に従って、Fugeneリポフェクションキット (Roche Diagnostics, Basel, Switzerland) を用いて、pSec-VH-Fc(CH2-CH3) (VH-Fc)若しくはpSec-VL-Fc(CH2-CH3) (VL-Fc)を用いて別々に形質導入するか、又はpSec-VH-Fc(CH2-CH3)とpSec-VL-Fc(CH2-CH3)とを用いて同時形質導入するか、或いはコントロールとして、無関係の緑色蛍光蛋白質(GFP)をコードするプラスミドで形質導入した。 培養物を3日間 37°Cにて維持し、1/3に分割し、さらに3日間の培養に戻し、その後細胞上清を採集し、10%ポリアクリルアミドゲル中で電気泳動し、ニトロセルロースメンブレンにブロットした。
結果を図2に示す。予想された分子量(還元条件下においてVL-CH2-CH3について42 KDa及びVH-CH2-CH3について44KDa)の免疫反応性蛋白質を細胞上清中で観察できた。非還元条件での併行解析により、ホモ二量体とヘテロ二量体の両方の構成と一致する見かけの分子量を示した。
ホウ酸緩衝液(pH 9.0)中の1μg/mLの組換えヒトCD28(R&D Systems, Abingdon, United Kingdom)を用いて、96ウェルマイクロタイタープレート(Immulon, Chantilly, VA)を一晩4℃にてコートした。これらの固定化されたCD28標的分子は、抗CD28活性を有する免疫反応性分子にのみ結合する。
(GFPをコードするプラスミドを用いて形質導入された)コントロール細胞又はプラスミドpSec-VH-Fc(CH2-CH3)若しくはpSec-VL-Fc(CH2-CH3)の一方のみを用いて形質導入された細胞からの上清は、検出可能なレベルの免疫反応性分子を全く含まなかった。これは、VH-Fc又はVL-Fcホモ二量体がCD28に結合できないことを示す。対照的に、pSec-VH-Fc(CH2-CH3)とpSec-VL-Fc(CH2-CH3)とを用いて同時形質導入された細胞からの上清は、希釈度依存的なレベルの免疫反応性分子を含んでいた。
上清をG蛋白質セファロースカラム(Amersham)に1 ml/分の速度で通過させた。カラムをPBSでリンスし、グリシン緩衝液(pH 2.8)で蛋白質を溶離させ、ポリエチレングリコール(Fluka, Riedel-de Haen, Germany)を用いた浸透的水回収により濃縮し、PBSに対して4℃にて十分に透析した。
これらの結果は、CD28への結合活性の50%に、1.16 nMである100 ng/mlの濃度で達し得ることを示す。
Mono28Fcの結合は、フローサイトメトリーによって、CD28を発現するCD28+ JurkatヒトT細胞又はCD28を発現しないヒトB細胞株であるRaji細胞を用いて確認した。
Jurkat T細胞又はRaji細胞を、精製されたMono28Fc蛋白質と1時間4°Cにて、又は10 mg/mlの CD28.3(VANHOVEら、Blood, 102, 564-70, 2003)のFabフラグメントと30分間インキュベートした。コントロールとして、細胞を、ウサギ抗VH/VH抗体及びFITC標識化ヤギ抗ウサギイムノグロブリンのみと共にインキュベートした。結合したFc融合単量体を、ウサギ抗CD28.3VH/VLとフルオレセインイソチオシアネート(FITC)結合ロバ抗ウサギIg抗体(希釈度1:200; Jackson ImmunoResearch Laboratories)とを用いて30分間4°Cにて検出した。細胞を次いで蛍光活性化セルソーティング(FACS)により解析した。
mono28FcがCD28に結合し、標的T細胞の活性化を誘導しないことを確かめるために、本発明者らは、Mono28Fcの生物学的効果を、スーパーアゴニスト抗体ANC28.1(WAIBLERら、PLoS ONE, 3, e1708, 2008)又はFcドメインを有しない一価抗CD28リガンド であるsc28AT (VANHOVE ら、Blood, 102, 564-70, 2003)のものと比較した。
予想通り、ANC28.1は標的細胞の活発な増殖を誘導した。対照的に、Mono28Fc及びsc28ATは、このアッセイにおいて応答を全く誘導しなかった。
Fcフラグメントと融合された組換え蛋白質及びイムノグロブリンは、内皮及び上皮細胞に存在するFcRn受容体によって認識され、それら分子を血中に戻すリサイクルが可能になるので、インビボで延長された半減期を通常呈する。本発明者らのMono28FC分子も延長された半減期を呈するかどうか決定するために、本発明者らは、マウスにおけるMono28Fcの分布を、一価Fab 28.3抗体フラグメント及び天然型IgG CD28.3抗体と比較して追跡した。
分布半減期 (T1/2a)は、 IgG、Fab及びMono28Fcについて、それぞれ2.5 ± 1.1、5.1 ± 0.3及び5.4 ± 1.2 時間であった。排出半減期(T1/2b)は、IgG、Fab及びMono28Fcについて、それぞれ119 ± 19、39 ± 6及び83 ± 26時間であった(図6)。データは、Fabフラグメントと比較してMono28Fcの排出半減期の有意な増加を明らかにしたが、Mono28Fcを二価IgG と比較したとき、統計的な差異は全く指し示されなかった。
ヒトIgG1 CH1-CH2-CH3 cDNAは、Dr. S. Birkle (Univ. Nantes, France)によって寄贈された。それをpcDNA3.1のHindIII/BamHI 制限部位に挿入し、pcDNA3.1- CH1-CH2-CH3 プラスミドを得た。CD28.3抗体抗ヒトCD28 (NUNESら、Int Immunol, 5, 311-5, 1993) に対応するVH及びVLドメインを上記実施例1に記載されるようにして増幅し、NheI酵素で消化し、pcDNA3.1- CH1-CH2-CH3プラスミドのNheI部位に別々に挿入した。VH- CH1-CH2-CH3及びVL- CH1-CH2-CH3カセットを次いでEcoRV/XbaI消化により切り出し、EcoRVで消化されたpSecTag2B ベクター (Invitrogen)に実施例1に記載されるようにして挿入した。
Claims (13)
- 興味ある抗原を指向する親抗体に由来し、
そのN末端からそのC末端に
イムノグロブリンの重鎖可変ドメインの構造を有し、前記親抗体の重鎖のCDRを含む領域A及び
0〜16アミノ酸のペプチドリンカーとIgGイムノグロブリンのCH2及びCH3ドメインとからなる領域B
からなる第1蛋白質の鎖並びに
そのN末端からそのC末端に
イムノグロブリンの軽鎖可変ドメインの構造を有し、前記親抗体の軽鎖のCDRを含む領域A'及び
第1ポリペプチドの領域Bと同一の領域B
からなる第2蛋白質の鎖とのヘテロ二量体であり、ここで、第1蛋白質の鎖及び第2蛋白質の鎖がいずれもIgGイムノグロブリンのCH1ドメインを含まない組換え一価抗体。 - 前記CH2及びCH3ドメインがIgG1サブクラス又はIgG4サブクラスのイムノグロブリンのものである請求項1に記載の組換え一価抗体。
- 前記領域Aが親抗体の重鎖可変ドメインからなる請求項1又は2に記載の組換え一価抗体。
- 前記領域A'が親抗体の軽鎖可変ドメインからなる請求項1〜3のいずれか1項に記載の組換え一価抗体。
- 前記親抗体がハイブリドーマCNCM I-2582によって産生されるモノクローナルイムノグロブリンCD28.3である請求項1〜4のいずれか1項に記載の組換え一価抗体。
- 前記第1蛋白質の鎖のポリペプチド配列が配列番号2であり、前記第2蛋白質の鎖のポリペプチド配列が配列番号4である請求項1〜5のいずれか1項に記載の組換え一価抗体。
- a)請求項1〜6のいずれか1項に記載の組換え一価抗体の第1蛋白質の鎖をコードする配列、及び
b) 請求項1〜6のいずれか1項に記載の組換え一価抗体の第2蛋白質の鎖をコードする配列
を含むポリヌクレオチド。 - 請求項7のポリヌクレオチドを含む発現ベクター。
- 請求項7に記載のポリヌクレオチドで形質転換され、請求項1〜6のいずれか1項に記載の組換え一価抗体を発現する細胞。
- a) 請求項1〜6のいずれか1項に記載の組換え一価抗体の第1蛋白質の鎖をコードする配列を含むポリヌクレオチド、及び
b) 請求項1〜6のいずれか1項に記載の組換え一価抗体の第2蛋白質の鎖をコードする配列を含むポリヌクレオチド
で形質転換され、請求項1〜6のいずれか1項に記載の組換え一価抗体を発現する細胞。 - 請求項9又は10に記載の形質転換細胞を培養すること及び培養物から組換え一価抗体を回収することを含む請求項1〜6のいずれか1項に記載の組換え一価抗体の製造方法。
- 請求項1〜6のいずれか1項に記載の組換え一価抗体を含む医薬製品。
- 移植拒絶反応、移植片対宿主病、Tリンパ球媒介自己免疫疾患、アレルギー現象及び慢性炎症性疾患からなる群より選択される病的状態を治療するための請求項5又は6に記載の組換え一価抗体。
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EP09290029A EP2210902A1 (en) | 2009-01-14 | 2009-01-14 | Recombinant monovalent antibodies |
EP09290029.9 | 2009-01-14 | ||
PCT/IB2010/000196 WO2010082136A1 (en) | 2009-01-14 | 2010-01-13 | Recombinant monovalent antibodies |
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JP2012514997A JP2012514997A (ja) | 2012-07-05 |
JP2012514997A5 JP2012514997A5 (ja) | 2013-02-28 |
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EP (2) | EP2210902A1 (ja) |
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EP2210902A1 (en) * | 2009-01-14 | 2010-07-28 | TcL Pharma | Recombinant monovalent antibodies |
ES2680570T3 (es) * | 2010-02-18 | 2018-09-10 | Ose Immunotherapeutics | Anticuerpos humanizados anti-CD28 |
EP2905290B1 (en) | 2012-10-05 | 2019-12-04 | Kyowa Kirin Co., Ltd. | Heterodimeric protein composition |
EP3297672B1 (en) | 2015-05-21 | 2021-09-01 | Harpoon Therapeutics, Inc. | Trispecific binding proteins and methods of use |
US11623958B2 (en) | 2016-05-20 | 2023-04-11 | Harpoon Therapeutics, Inc. | Single chain variable fragment CD3 binding proteins |
JP7101621B2 (ja) | 2016-05-20 | 2022-07-15 | ハープーン セラピューティクス,インク. | 単一ドメイン血清アルブミン結合タンパク質 |
AU2017267793B2 (en) | 2016-05-20 | 2024-01-25 | Harpoon Therapeutics, Inc. | Single chain variable fragment CD3 binding proteins |
WO2018037092A1 (en) | 2016-08-26 | 2018-03-01 | Sanofi | Multispecific antibodies facilitating selective light chain pairing |
CN110198955A (zh) | 2016-11-23 | 2019-09-03 | 哈普恩治疗公司 | 前列腺特异性膜抗原结合蛋白质 |
US10844134B2 (en) | 2016-11-23 | 2020-11-24 | Harpoon Therapeutics, Inc. | PSMA targeting trispecific proteins and methods of use |
EP3589662A4 (en) * | 2017-02-28 | 2020-12-30 | Harpoon Therapeutics, Inc. | INDUCTIBLE MONOVALENT ANTIGBINDING PROTEIN |
CA3063362A1 (en) | 2017-05-12 | 2018-11-15 | Harpoon Therapeutics, Inc. | Msln targeting trispecific proteins and methods of use |
AU2018265856B2 (en) | 2017-05-12 | 2023-04-27 | Harpoon Therapeutics, Inc. | Mesothelin binding proteins |
SG11202003341UA (en) | 2017-10-13 | 2020-05-28 | Harpoon Therapeutics Inc | B cell maturation antigen binding proteins |
CR20200196A (es) | 2017-10-13 | 2020-06-05 | Harpoon Therapeutics Inc | Proteínas trispecìficas y mètodos de uso |
US10815311B2 (en) | 2018-09-25 | 2020-10-27 | Harpoon Therapeutics, Inc. | DLL3 binding proteins and methods of use |
JP2023527609A (ja) | 2020-02-21 | 2023-06-30 | ハープーン セラピューティクス,インク. | Flt3結合タンパク質および使用方法 |
AU2021329378A1 (en) | 2020-08-19 | 2023-03-23 | Xencor, Inc. | Anti-CD28 compositions |
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US7408041B2 (en) * | 2000-12-08 | 2008-08-05 | Alexion Pharmaceuticals, Inc. | Polypeptides and antibodies derived from chronic lymphocytic leukemia cells and uses thereof |
US7723482B2 (en) * | 2000-12-26 | 2010-05-25 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Anti-CD28 antibody |
US7053202B2 (en) * | 2001-10-19 | 2006-05-30 | Millennium Pharmaceuticals, Inc. | Immunoglobulin DNA cassette molecules, monobody constructs, methods of production, and methods of use therefor |
GB0230203D0 (en) * | 2002-12-27 | 2003-02-05 | Domantis Ltd | Fc fusion |
PL1718677T3 (pl) * | 2003-12-19 | 2012-09-28 | Genentech Inc | Jednowartościowe fragmenty przeciwciała stosowane jako środki lecznicze |
US7563443B2 (en) * | 2004-09-17 | 2009-07-21 | Domantis Limited | Monovalent anti-CD40L antibody polypeptides and compositions thereof |
WO2006050346A2 (en) * | 2004-11-01 | 2006-05-11 | Medimmune, Inc. | Ultra high throughput capture lift screening methods |
US7612181B2 (en) * | 2005-08-19 | 2009-11-03 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
TW200732350A (en) | 2005-10-21 | 2007-09-01 | Amgen Inc | Methods for generating monovalent IgG |
KR20090039666A (ko) * | 2006-02-01 | 2009-04-22 | 아라나 테라퓨틱스 리미티드 | 도메인 항체 구조체 |
WO2008145138A1 (en) * | 2007-05-31 | 2008-12-04 | Genmab A/S | Recombinant fucose modified monovalent half-antibodies obtained by molecular engineering |
US20110097339A1 (en) * | 2008-07-18 | 2011-04-28 | Domantis Limited | Compositions monovalent for CD28 binding and methods of use |
EP2210902A1 (en) * | 2009-01-14 | 2010-07-28 | TcL Pharma | Recombinant monovalent antibodies |
ES2680570T3 (es) * | 2010-02-18 | 2018-09-10 | Ose Immunotherapeutics | Anticuerpos humanizados anti-CD28 |
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Also Published As
Publication number | Publication date |
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EP2387587A1 (en) | 2011-11-23 |
US20110313135A1 (en) | 2011-12-22 |
JP2012514997A (ja) | 2012-07-05 |
CA3037902C (en) | 2021-08-31 |
US9587023B2 (en) | 2017-03-07 |
CA2749627C (en) | 2019-05-14 |
US20170166643A1 (en) | 2017-06-15 |
EP2210902A1 (en) | 2010-07-28 |
US10689444B2 (en) | 2020-06-23 |
CA2749627A1 (en) | 2010-07-22 |
WO2010082136A1 (en) | 2010-07-22 |
CA3037902A1 (en) | 2010-07-22 |
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