JP6211930B2 - ヒト化抗ctla4抗体 - Google Patents
ヒト化抗ctla4抗体 Download PDFInfo
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- JP6211930B2 JP6211930B2 JP2013557119A JP2013557119A JP6211930B2 JP 6211930 B2 JP6211930 B2 JP 6211930B2 JP 2013557119 A JP2013557119 A JP 2013557119A JP 2013557119 A JP2013557119 A JP 2013557119A JP 6211930 B2 JP6211930 B2 JP 6211930B2
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Classifications
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Description
ヒトIgG1定常ドメインに融合されたヒトCTLA4の細胞外ドメインを含む組換えCTLA4融合タンパク質は、R&D Systems(Oxford、UK)から購入した。細胞外CTLA4断片は、CTLA4-Fc融合タンパク質を第Xa因子(Qiagen、Crawley、UK)によるタンパク分解によって切断した後、CTLA4細胞外ドメインのみを残すために、第Xa因子除去樹脂(Qiagen)を使用してプロテアーゼを除去し、プロテインAアガロースを使用して切断されたFc断片を除去することによって調製されたものである。
リードモノクローナル抗体8H5および3B10を産生するサブクローン3B10-4F7、3B10-6E3、8H5-1A1、および8H5-1B1を、可変領域(V領域)配列分析にかけた。全RNAは、RNAqueous-4PCR Kit(Ambion、Warrington、UK)を使用して、3〜10×106ハイブリドーマ細胞から抽出し、cDNAを合成するために使用した。マウス免疫グロブリン重鎖およびカッパ軽鎖V領域断片は、Table 1(表1)において示される縮重マウスリーダー配列プライマー(Sigma)およびユニークな定常ドメインプライマー(Sigma)を使用して、PCRによって増幅した。結果として生じるPCR断片は、pGEM-T Easy I vector system(Promega、Southampton、UK)にサブクローニングし、挿入物は、ベクター特異的プライマー、M13Forward(Sigma)を使用して配列決定した。DNA配列決定はすべて、Geneservice Ltd、Cambridge、UKによって実行された。ユニークなV領域ヌクレオチド配列が、3B10(配列番号1および2)ならびに8H5(配列番号5および6)について得られた。
配列番号9 3B10 CDRH1 DYNMD
配列番号10 3B10 CDRH2 NINPNSESTSYNQKFKG
配列番号11 3B10 CDRH3 DGNRYDAWFAY
配列番号12 3B10 CDRL1 SASSSVTYMH
配列番号13 3B10 CDRL2 STSILAS
配列番号14 3B10 CDRL3 QQRTSYPLT
配列番号15 8H5 CDRH1 SYWIN
配列番号16 8H5 CDRH2 RIAPGSGTTYYNEVFKG
配列番号17 8H5 CDRH3 GDYGSY
配列番号18 8H5 CDRL1 SASSSISYMH
配列番号19 8H5 CDRL2 DTSKLAS
配列番号20 8H5 CDRL3 HQRTSYPLT
リード3B10および8H5モノクローナル抗体の重鎖および軽鎖可変ドメイン配列を、PCR増幅し、pANT抗体発現ベクターにサブクローニングし(図8)、重鎖および軽鎖V領域を、それぞれ、pANT17およびpANT13にクローニングした。重鎖V領域遺伝子は、ヒトγ1重鎖遺伝子(G1m3(G1m(f))アロタイプ)またはヒトγ4重鎖遺伝子と共に、MluIおよびHindIII部位を介してpANT17にインフレームでクローニングし、軽鎖V領域遺伝子は、ヒトカッパ軽鎖定常領域遺伝子(Km3アロタイプ)と共に、BssHIIおよびBamHI部位を介してpANT13にインフレームでクローニングした。重鎖および軽鎖遺伝子の両方の転写は、CMV I/Eプロモーターの制御下とし(US5168062およびUS5385839、University of Iowa)、pANT17プラスミドは、SV40プロモーターの制御下の突然変異dhfrミニ遺伝子(SimonsenおよびLevinson 1983、PNAS 80:2495〜2499頁)および真核細胞における選択のためのpolyA配列を含有した。pANT17およびpANT13の両方は、原核生物の選択のためのβ-ラクタマーゼ(ApR)遺伝子および原核細胞における増殖のためのpMB1複製開始点を含有した。プラスミドはすべて、E. coli XL1-blue(Stratagene Cat. No. 200130)において増殖させた。pANT発現ベクターにクローニングするためのV領域遺伝子を増幅するために使用したプライマーをTable 2(表2)に示す。
PBMC(末梢血単核細胞)は、抗ヒトCD2、抗ヒトCD3、および抗ヒトCD28抗体(Miltenyi Biotec、Bisley、Surrey)によりコーティングしたビーズを使用して活性化した。5×105個の細胞は、AIM-V培地中96-ウェルプレートのそれぞれのウェルに播種し、細胞当たり1つのビーズの比で細胞にビーズを添加した。試験抗体またはアイソタイプ対照抗体を、AIM-V培地において必要に応じて希釈し、ウェル当たり50μlを細胞に添加し、200μlの最終容量が得られた。培地のみ(抗体なし)の対照も含めた。プレートは、37℃で4日間インキュベートし、細胞は、その後、AIM-V(登録商標)培地において、0.75μCi[3H]-チミジン(Perkin Elmer、Beaconsfield、UK)でパルス標識し、さらに18時間インキュベートした後、TomTec Mach III(Hamden CT、USA)セルハーベスターを使用してフィルターマット(filter mat)(Perkin Elmer)上に収集した。それぞれのウェルについてのカウント毎分(cpm)は、paralux低バックグラウンド計測で、1450 Microbeta Wallac Trilux Liquid Scintillation Counter(Perkin Elmer)で、Meltilex(商標)(Perkin Elmer)シンチレーション計測によって決定した。それぞれの抗体試料についてのカウント毎分は、培地のみの対照に対して標準化した。2つの別の研究において、キメラ抗体は、出発モノクローナル抗体で見られるように、T細胞増殖についてのCTLA4誘発性の阻害を逆転させることが示された(図7)。
ヒト化抗体は、EP1844074(Antitope Ltd)において記載される方法を使用して生成した。マウスV領域の構造モデルは、Swiss PDBを使用して産生し、抗体のCTLA4結合特性にとっておそらく重要であろう、3B10および8H5 V領域由来の重要なアミノ酸(「束縛残基(constraining residue)」)を同定するために分析した。ヒトV領域配列のデータベースは、ヒト化抗体の設計において使用されることとなる束縛残基のそれぞれを含有するヒトV領域配列のセグメントを同定するために使用した。典型的に、2つ以上の代替のV領域配列セグメントを、それぞれの束縛残基を提供するために使用し、8H5および3B10の両方について、ヒト化抗CTLA4 V領域配列の広範囲の可能性のある配列がもたらされた。これらの配列は、その後、Fothergillら(WO9859244、Eclagen Ltd)において記載されるようにインシリコ分析によって非生殖系列MHCクラスIIペプチド結合の予測のために、また、さらに、「The Immune Epitope Database and Analysis Resource」、http://www.immuneepitope.org/を含むデータベースを使用して知られているCD4+T細胞エピトープについて分析した。予測される非生殖系列MHCクラスII結合ペプチドを有するまたはT細胞エピトープデータベースに対して著しくヒットしたV領域配列は除いた。これにより、V領域配列のセットが減少した。V領域配列セグメントの選択された組み合わせは、その後、ヒト化重鎖および軽鎖可変領域アミノ酸配列を産生するために組み合わせた。5つの重鎖および5つの軽鎖配列(それぞれVH1〜VH5およびVK1〜VK5と呼ばれる)を、8H5(それぞれ配列番号41〜45および46〜50)ならびに3B10(それぞれ配列番号31〜35および36〜40)のそれぞれについて選択した。
組換えCTLA4への、HEK由来およびNS0由来8H5および3B10ヒト化変異体の結合は、適切な親キメラ抗体に対する競合ELISAにおいて評価した。親8H5および3B10キメラ抗体は、Biotin Tag(商標) Micro Biotinylation kit(Sigma-Aldrich)を使用してビオチン化した。96ウェルMaxiSorpプレート(Nunc)をDulbecco's PBS中0.5μg/ml組換えヒトCTLA4-Igでコーティングし(100μl最終容量)、4℃で一晩放置した。CTLA4-Igを捨て、プレートは、室温で1時間、Dulbecco's PBS-2%BSAで遮断した。プレートを洗浄バッファー(Dulbecco's-PBS中0.05%Tween20)で3回洗浄した。様々な濃度の試験ヒト化抗体をビオチン化親キメラ抗体とあらかじめ混合し(0.02μg/ml最終濃度)、その後、CTLA4-Igプレートに添加した(100μl最終容量)。試料はすべて二重反復で試験した。プレートを室温で1時間インキュベートし、洗浄バッファーで3回洗浄した。ストレプトアビジンHRP(Sigma-Aldrich)の500倍希釈液100μlを添加し、室温で1時間インキュベートした。プレートを洗浄バッファーで3回洗浄し、SigmaFast OPD基質(Sigma-Aldrich、Cat# P9187)100μlを添加し、暗所、室温で4分間インキュベートした。反応は、50μlの3M HClを添加することによって停止させた。Dynexプレートリーダーを使用してプレートを490nmで読み取った。
実施例6からのヒト化8H5および3B10変異体は、scFvに変換し、pCANTAB5EベクターRPAS Expression Module(Amersham Pharmacia Biotech、Little Chalfont、UK)を使用して、Benhar I.およびReiter Y.、Current Protocols in Immunology, Unit 10.19B、Wiley Online Library、2002年5月(http://www.currentprotocols.com/protocol/im1019b)に記載の通りM13ファージディスプレイベクターにクローニングした。ヒト化VHおよびVK遺伝子は、末端SfiIおよびNotI制限部位、内部Gly4Serリンカー、ならびにC末端his6タグを提供するプライマーを使用して増幅した。scFv構築物は、SfiI-NotI断片としてpCANTAB5Eベクターに挿入し、E.coli HB2151に形質転換することにより、scFvが周辺質および部分的には成長培地に搬出された。scFvは、HIS-Select HF Cartridges(Sigma-Aldrich)を使用して、ニッケル-キレートアフィニティークロマトグラフィーによって成長培地から精製した。精製したscFvは、実施例1において詳述されるように、B7.1-IgおよびB7.2-Ig競合アッセイにおいて試験し、ヒト化scFvはすべてCTLA4への競合的結合を示した。実施例6からのヒト化8H5および3B10変異体はさらに、増幅したヒト化VHおよびVK遺伝子をCH1およびCκ定常領域遺伝子と共にさらに増幅してVH-CH1およびVK-Cκ断片を形成し、これらの断片を上流VH-CH1および下流VK-Cκ遺伝子断片の間で22アミノ酸pelBリーダー配列(Lei S.P.、Lin H.C.、Wang S.S.、Callaway J.、およびWilcox G.、J Bacteriol. 169 (1987) 4379〜4383頁)と接続するためのプライマーでさらに増幅することによりジシストロニックFab遺伝子を得たという点を除いて、scFvについて使用した方法を使用してFabに変換した。ヒト化抗体変異体由来のFabを、scFvについて上記のように生成し、精製し、実施例1において詳述されるようにB7.1-IgおよびB7.2-Ig競合アッセイにおいて試験した。ヒト化Fabはすべて、CTLA4への競合的結合を示した。
PBMCは、UK National Blood Transfusion Service(Addenbrooke's Hospital、Cambridge、UK)から、Addenbrooke's Hospital Local Research Ethics Committeeによって与えられた承認に従って得た健康なコミュニティードナーバフィーコート(24時間以内に採った血液由来)から単離した。PBMCは、Lymphoprep(Axis-shield、Dundee、UK)密度遠心分離によってバフィーコートから単離し、CD8+T細胞は、CD8+ RosetteSep(商標)(StemCell Technologies Inc、London、UK)を使用して除去した。ドナーは、HLA SSP-PCR based tissue-typing kit(Biotest、Solihull、UK)を使用して、HLA-DRハプロタイプを同定することによって特徴づけた。リコール抗原破傷風毒素を含む対照抗原に対するT細胞応答も決定した(KLH Pierce、Cramlingtom、UKならびにインフルエンザA型およびエプスタインバーウイルスに由来するペプチド)。PBMCは、その後、凍結し、必要とされるまで液体窒素中で保存した。
混合リンパ球培養反応アッセイは、ヒトT細胞活性化の尺度としてのIFN-γ分泌に対するCTLA4経路の遮断の効果を測定するために使用した。複数のヒトドナー由来の新鮮な血液(UK National Blood Transfusion Serviceから得た、実施例8)をPBS/2%ヒト血清で1:1に希釈し、900gでの遠心分離のためにLymphoprep溶液(Nycomed)上に重ねた。PBMCを接触面から取り出し、洗浄し、AIM-V培地(Invitrogen)中に再懸濁した。様々なミスマッチドナーペアから生成されたPBMCを、その後、1:1の比で組み合わせ、96ウェルプレートに播種し、試料ウェル当たり合計2.5×105個のPBMCがもたらされた。PHA(フィトヘマグルチニン、Sigma Aldrich)を、T細胞集団の増殖を刺激するために2μg/mlの最終濃度に向けて添加した。リードVH5/VK4抗CTLA4抗体、MDX010抗CTLA4対照抗体(実施例8)、またはアイソタイプ対照IgG1抗体を、150μg/mlの最終濃度まで添加した。5μg/ml CTLA4-Fcもまた、IFN-γ分泌の阻害を実証するために対照として抗体の代わりに使用した。ウェル当たりの合計最終容量を150μlとし、それぞれの抗体を、ドナーの組み合わせ当たり5回試験した。96ウェルプレートを、72時間、通常の培養条件下でインキュベートし、その後、メーカー推奨のプロトコールに従って、ELISA(Thermo scientific、ESS0002)によるIFN-γの測定のために100μl上清を試料採取した。図19におけるデータから、リードVH5/VK4抗体は、すべてのドナーの組み合わせについて、MDX010抗CTLA4対照抗体よりも高度なT細胞活性化を示し、MDX010と比較して、VH5/VK4についてのT細胞活性化において>2倍の平均的な増加があった。
腫瘍動物モデルは、腫瘍成長を阻害する際の抗ヒトCTLA4抗体のインビボにおける分析に使用した。モデルにおいて、MC38マウス結腸腫瘍細胞(Corbettら(1975) Cancer Res 35:2434〜2439頁、OncoImmune, Inc.、Ann Arbor、USAが提供)は、ヒトCTLA4ノックインマウス(OncoImmune, Inc.)において成長させた。
Claims (15)
- (i)配列DYNMD(配列番号9)を含むCDRH1、
(ii)配列NINPNSESTSYNQKFKG(配列番号10)を含むCDRH2、
(iii)配列DGNRYDAWFAY(配列番号11)を含むCDRH3、
(iv)配列SASSSVTYMH(配列番号12)を含むCDRL1、
(v)配列STSILAS(配列番号13)を含むCDRL2、および
(vi)配列QQRTSYPLT(配列番号14)を含むCDRL3、または
(i)配列SYWIN(配列番号15)を含むCDRH1、
(ii)配列RIAPGSGTTYYNEVFKG(配列番号16)を含むCDRH2、
(iii)配列GDYGSY(配列番号17)を含むCDRH3、
(iv)配列SASSSISYMH(配列番号18)を含むCDRL1、
(v)配列DTSKLAS(配列番号19)を含むCDRL2、および
(vi)配列HQRTSYPLT(配列番号20)を含むCDRL3
のCDR配列を有する可変領域を含み、ヒトB7へのCTLA4の結合を阻害する、ヒト化抗CTLA4抗体。 - 軽鎖可変領域についての配列番号36〜40からなる群から選択される配列と組み合わせて、重鎖可変領域についての配列番号31〜35からなる群から選択される可変領域配列を含む、請求項1に記載の抗CTLA4抗体。
- 軽鎖可変領域についての配列番号46〜50からなる群から選択される配列と組み合わせて、重鎖可変領域についての配列番号41〜45からなる群から選択される可変領域配列を含む、請求項1に記載の抗CTLA4抗体。
- 軽鎖可変領域についての配列番号49と組み合わせて、重鎖可変領域についての配列番号45を含む、請求項3に記載の抗CTLA4抗体。
- ヒト集団のHLA-DRアロタイプの分布を有する少なくとも50のヒト血液試料においてCD4+ヘルパーT細胞応答の誘発についてインビトロにおいて試験した場合に、4%以下のT細胞応答を生じる、請求項1から4のいずれか一項に記載の抗CTLA4抗体。
- 可変領域配列が、完全に、ヒト抗体可変領域中の配列に由来する、請求項1から5のいずれか一項に記載の抗体。
- アイソタイプIgG1、IgG2、IgG3、もしくはIgG4のいずれかの重鎖定常領域または突然変異IgG定常領域およびアイソタイプカッパの軽鎖定常領域と共に可変領域から構成され、ヒト定常領域はIgG1およびカッパまたはIgG4およびカッパである、請求項1から6のいずれか一項に記載の抗体。
- scFvまたはFabである、請求項1から6のいずれか一項に記載の抗体。
- 請求項1から8のいずれか一項に記載の1つまたは複数の抗体を含む多特異性抗体。
- 請求項1から9のいずれか一項に記載の抗体をコードするポリヌクレオチド。
- 請求項10に記載のポリヌクレオチドを含むベクター。
- 請求項11に記載のベクターを含む宿主細胞。
- 請求項1から9のいずれか一項に記載の抗CTLA4抗体または請求項10に記載のポリヌクレオチドと、薬学的に許容できる担体とを含む医薬組成物。
- ヒトCTLA4関連性の疾患の診断のための、試料におけるヒトCTLA4抗原の存在をインビトロにおいて検出するための方法における、請求項1から9のいずれか一項に記載の抗体の使用。
- 癌、細胞増殖性疾患、中枢神経系(CNS)の疾患、血液系の疾患、炎症性疾患、感染症、アレルギー、T細胞関連性の疾患、移植片対宿主病、または宿主対移植片病を含む疾患を治療するための、請求項13に記載の医薬組成物。
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EP2683739B1 (en) | 2016-03-09 |
CA2828528A1 (en) | 2012-09-13 |
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