JP2013532968A - 抗gd2抗体 - Google Patents
抗gd2抗体 Download PDFInfo
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- JP2013532968A JP2013532968A JP2013515579A JP2013515579A JP2013532968A JP 2013532968 A JP2013532968 A JP 2013532968A JP 2013515579 A JP2013515579 A JP 2013515579A JP 2013515579 A JP2013515579 A JP 2013515579A JP 2013532968 A JP2013532968 A JP 2013532968A
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Abstract
【解決手段】 本出願において、キメラ、ヒト化、親和性成熟、安定性増強、および二特異的抗GD2抗体およびその断片が記載される。また、GD2関連病、特に神経芽細胞腫の欠失、予防、および/または治療的処置のための個々の抗体またはその組成物を用いる方法も提供される。
【選択図】 なし
Description
1つの実施形態において、本発明によって提供される抗体は、好ましい実施形態においては、他の種に由来する同族抗GD2抗体のヒト化バージョンであるモノクローナル抗体である。ヒト化抗体は組換えDNA技術によって生産された抗体であり、そこでは、抗原結合で必要とされないヒト免疫グロブリン軽鎖または重鎖(例えば、定常領域および可変ドメインのフレームワーク領域)のアミノ酸のいくつかまたは全てを用いて、同族の非ヒト抗体の軽鎖または重鎖からの対応するアミノ酸に代えて置換する。その例として、所与の抗原に対するネズミ抗体のヒト化バージョンは、その重鎖および軽鎖の双方の上に、(1)ヒト抗体の定常領域;(2)ヒト抗体の可変ドメインからのフレームワーク領域;および(3)ネズミ抗体からのCDRを有する。必要であれば、ヒトフレームワーク領域における1またはそれ以上の残基を、ネズミ抗体における対応する位置での残基に変化させて、抗原に対するヒト化抗体の結合親和性を保持することができる。この変化は、時々、「復帰突然変異」と呼ばれる。同様に、正突然変異を行って、所望の理由、例えば、抗原に対する安定性または親和性のためにネズミ配列に戻してもよい。例えば、hu3F8−H1L1−IgG1復帰突然変異が重鎖配列における19位置、および軽鎖における17位置において、結合のイン・ビトロ親和性を維持するために必要であった。ヒト化抗体は、一般に、キメラヒト抗体と比較して、ヒトにおいて免疫応答をあまり惹起しない。なぜならば、前者はかなり少数の非ヒト成分を含有するからである。
細胞培養およびヒト組織
ヒト神経芽細胞腫細胞系LAN−1はRobert Seeger博士(Los Angelesの小児病院,Los Angeles,CA)によって提供され、およびNB1691はPeter Houghton博士(St.Jude小児研究病院,Memphis,TN)によって提供された。NK−92MIはAmerican Type Culture Collection(ATCC),Manassas,VAから得た。全ての細胞系を37℃にて5%CO2インキュベーターにて、F10[10%胎児ウシ血清(Hyclone,South Logan,UT)、2mMグルタミン、100U/mlペニシリン、および100ug/mlストレプトマイシンを補足したRPMI1640培地]中で成長させた。正常な組織ならびにMemorial Sloan−Kettering Cancer Center(MSKCC)で得られた異なる組織学的タイプの固形腫瘍試料を液体窒素中でスナップ凍結させた。書面による同意の通知は、MSKCCの治験審査委員会のガイドラインに従って患者および/またはそれらの後見人から得た。
ネズミ3F8は、カッパ軽鎖を持つマウスIgG3抗体であった(Cheung et al.,1985,Cancer Res 45,2642−9)。神経芽細胞腫と反応性であるモノクローナル抗体3F8(マウスIgG3、カッパ)、5F11(マウスIgM、カッパ)、および8H9(マウスIgG1、カッパ)は従前に記載されている(Cheung et al.,1985,前掲;Cheung et al.,2004,J Nucl Med 45,867−77;Modak et al.,2001,Cancer Res 61,4048−54)。それらは腹水液として生じ、アフィニティークロマトグラフィー:3F8についてはプロテインA(GE Healthcare,Piscataway,NJ)、8H9ではプロテインG、および5F11についてはClq−セファロース(Pierce,Rockford,IL)によって精製した。これらの抗体はSDS−PAGEによると>90%純粋であった。F(ab’)2断片は、従前に報告されているようにペプシン消化によって調製した(Cheung et al.,1988,J Clin Invest 81,1122−28)。抗GD2ハイブリドーマME361およびTIB114(N.S.7)、IgG3対照抗体を分泌するハイブリドーマはATCCから得た。14.G2aはBD Biosciences,San Jose,CAから購入した。キメラ14.18は、Lexigen Pharmaceuticals,Lexington,MAのStephen Gillies博士によって親切にも提供された。MAB1027(抗−B7−H3 MoAb)はR&D System,Minneapolis,MNから購入した。GD2に対して特異的なマウスIgG3抗体S220−51はNorthstar Bioproducts,Cape Cod,MAから購入した。
m3F8のヒトホモログに基づき、m3F8の重鎖および軽鎖双方のCDR配列をヒトIgG1フレームワークに合体させ、および最適化した。2つの重鎖および2つの軽鎖遺伝子から、hu3F8の4つのバージョンを設計した。これらのhu3F8遺伝子を合成し、およびCHO細胞のために最適化した(Blue Heron Biotechnology,Bothhell,WAまたはGenscript,Piscataway,NY)。bluescriptベクター(Eureka,CA)を用い、hu3F8のこれらの重鎖および軽鎖をDC44細胞にトランスフェクトし、およびG418(InVitrogen,CA)で選択した。Magel.5 CHO細胞(Eurika,CA)にトランスフェクトした場合、特殊なIgG糖型が生じる。同様にマウスVHおよびVL配列をヒトIgG1およびIgG4フレームワークに合体させて、ch3F8−IgG1およびch3F8−IgG4組換え抗体を作成した。
hu3F8およびch3F8プロデューサー系はOpticho無血清培地(InVitrogen,CA)において培養し、および成熟上清を収穫した。プロテインAアフィニティーカラムを、0.15M NaClを含む25mMクエン酸ナトリウム緩衝液、pH8.2、で予め平衡化させた。結合したHu3F8を、0.1Mクエン酸/クエン酸ナトリウム緩衝液、pH3.9で溶出させ、および25mMクエン酸ナトリウム、pH8.2中でアルカリ化した(1:10 v/v比率)。それをSartobind−Q膜を通過させ、および25mMクエン酸ナトリウム、0.15M NaCl、pH8.2中に5〜10mg/mlまで濃縮した。安定性の実験は、tween80(Sigma)の0.7mg/mlの存在下または不存在下で、25mMクエン酸ナトリウム 0.15M NaCl pH8.2対PBS pH7.4中のhu3F8−IgG1に対して行った。
各2ugの蛋白質を、4〜15%Tris−グリシン Ready Gel System(Bio−Rad,Hercules,CA)を用いて非還元または還元条件下でSDS−PAGEによって分析した。Invitrogen SeeBlue Plus2の予備染色標準を蛋白質の分子量マーカーとして用いた。電気泳動の後、PIERCE’s GleCode Blue Stain Reagentを用いてゲルを染色した。ゲルは、Bio−Rad Fluor−S MultiImager(Bio−Rad)を用いてスキャンし、およびバンドの強度をQuantity Oneソフトウェア(Bio−Rad)で定量した。
マイクロタイタープレートをウェル当たり20ngにてGD2で被覆した。PBS(希釈剤)中の0.5%BSAのウェル当たり150ulを、雰囲気温度にて、少なくとも30分間で各プレートに加えて、過剰な結合部位をブロックし、PBSで少なくとも3回洗浄した。hu3F8−IgG1(ストック濃度1mg/ml)の精製されたバッチを用いて、0.5ug/mlで出発して標準曲線を作成し、続いて、2倍希釈した。100ulの標準および試料(やはり2倍希釈)を各ウェルに加え、および37℃にて2.5時間インキュベートした。プレートをPBSで5回洗浄した後、希釈剤中に1:3500で希釈したヤギ抗ヒト−IgG(H+L)(Jackson Research Laboratory)の100ulを各ウェルに加え、および4℃で1時間インキュベートした。ELISA発色反応を基質過酸化水素と共に色原体OPD(Sigma)で、暗所にて、室温で30分間発色させた。反応物を5N H2SO4で停止し、およびODを490においてELISAプレートリーダーMRX(Dynex)で読み取った。標準曲線に基づき、hu3F8上清の定量を蛋白質のug/mlまたはug/mgで計算した。
CM5センサーチップ(研究グレード)および関連試薬はBiacore USA(Piscataway,NJ)から購入した。ガングリオシドGM1はALEXIS Biochemicals (AXXORA LLC,San Diego,CA)からのものであり、およびGD2はAdvanced ImmunoChemical(Long Beach,CA)からのものであった。GM1を90%エタノール、10%メタノール(v/v)に溶解させ(0.5mg/ml)、およびGD2はエタノールに溶解させた(0.5mg/ml)。ガングリオシドは、疎水性相互作用を介して、CM5センサーチップに直接的に固定化した。参照表面をGM1で固定化した。GM1は100%エタノールで1:1希釈し、次いで、HBS−E緩衝液(10mM HEPES,pH7.4,150mM NaCl,および3mM EDTA)に1/5希釈した。希釈されたGM1(50 μg/ml)を15μl/分の流速にて20分間にわたって注射した(300μl)。広範な洗浄を、安定なベースラインが得られるまで、10mM NaOH(典型的には、5μl/分の流速にて20μlの5回の洗浄)に続いて行った。活性な表面をGD2およびGM1で1:1比率にて固定化した。GD2およびGM1は100%エタノールで1:1希釈し、および1:1比率で混合した。GD2およびGM1の混合物をHBS−E緩衝液(10mM HEPES,pH7.4,150mM NaCl,および3mM EDTA)に1/5希釈した。GD2およびGM1の希釈された混合物(50μg/ml)を20分間にわたって15μl/分の流速で注射した(300μl)。広範な洗浄を、安定なベースラインが得られるまで、10mM NaOH(典型的には、5μl/分の流速にて20μlの5回の洗浄)を続けた。
GD2、GM2、GD1a、GD1b、GT1b、ならびにGD3、GM3、CM1、GD1aを90%エタノール中でウェル当たり20ngでコーティングした。風乾に続いて、ウェルを室温にてウェル当たり150ulでPBS中の0.5%BSAで1時間ブロックし、その後、PBS中で3回洗浄した。抗体を1ug/ml(ウェル当たり100ul)にて三連で0.5%BSAに加えた。バックグラウンド減算のために、(1)抗原無しおよび(2)試料無しでのウェルを用いた。37℃における2時間のインキュベーションおよびPBS5回での洗浄に続いて、マウス抗体(例えば、3F8)についてのHRP−ヤギ抗マウスIgG(Jackson Laboratory,1:1000に希釈)またはヒト化抗体についてのHRP−ヤギ抗ヒトIgG(Jackson Laboratory,1:1000)を用いた。4℃での1時間のさらなるインキュベーションおよびさらなる洗浄に続いて、490においてELISAプレ−トリーダー(MRX(Dynex)を用いてODを読み取り、および交差反応性をGD2に対する%最大結合として表した。
ビオチン(Long Arm)−N−ヒドロキシスクシンイミドエステル(BNHS,Vector Laboratories,Inc.,Burlingame,CA)を50mg/mlの濃度でジメチルスルホキシド(DMSO)に溶解させた。ビオチニル化試薬は試薬の1/10重量比率で抗体に加えた。場合により攪拌しつつ、反応混合物を室温で2時間インキュベートした。ビオチニル化抗体を室温で4時間、または4℃で一晩PBS中で透析した。ビオチニル化抗体の免疫反応性を天然抗体と比較し、およびEC50が相互の20%内にあることを確実とした。
−20℃で30分間、250ulのアセトンで固定されたクライオスタットを用い、5〜7ミクロンの厚い凍結セクションを切断した。PBSでスライドを洗浄した後、スライドを、新たに調製した0.1%過酸化水素に室温で15分間暴露した。洗浄の後、ブロッキングアビジン溶液(VECTOR アビジン−ビオチンブロッキングキット)を加えて、および室温で20分間インキュベートした。洗浄の後、ブロッキングビオチン溶液(VECTOR アビジン−ビオチンブロッキングキット)の滴を加え、室温で20分間インキュベートした。さらなる洗浄の後、>100ulのブロッキング血清(PBS中に新たに希釈した10%ウマ血清)を加え、および室温で1時間インキュベートした。この工程はより長くすることができる。注意:血清を再使用してはならない。ブロッキング血清を各スライドから吸引した後、100ulの1ug/mlビオチニル化MOPC21(陰性対照)または1%ウマ血清に希釈されたビオチニルカ抗体を加え、および室温で1時間インキュベートした。洗浄の後、PBS中の1:100希釈における100ulのアビジン−ビオチン複合体[ABC](Vectastain ABCキット、VECTOR)を加え、および室温で30分間インキュベートした。洗浄の後、200ulの色素(DABペルオキシダーゼ基質キット、ベクター)を各セクションに加え、および(染色の所望の強度が標準における発色に基づいて達成されるまで)2時間の間色を発色させた。セクションを流れる水道水で5分間洗浄し、およびMyerのストックヘマトキシリンで逆染色し、およびさらなる洗浄を流れる水道水中で5分間行った。スライドを、順次、75%、次いで95%、次いで100%エチルアルコール中で脱水した。最終の脱水工程はキシレンまたはキシレン代替物中で行った。新鮮なサイトシール(Cytoseal)の一滴を加え、次いで、セクションをカバーガラスでシールした。
抗体を、腫瘍細胞成長に対するそれらの直接的効果、およびヒト血清またはヒトエフェクター細胞の不存在下における生存についてテストした。腫瘍標的を2mM EDTAまたはトリプシン−EDTAで解離させ、洗浄し、F10における96ウェルの平坦な底のプレートにウェル当たり1.2×103〜3.5×104で平板培養した。37℃および5%CO2のCO2インキュベーター中での24時間のインキュベーションの後、F10における増大させる濃度の抗体を各ウェルに加える。対照ウェルはF10単独を受けた。5%CO2中の37℃での72時間のインキュベーションの後、WST−8試薬を各ウェルに加え、およびCO2インキュベーター中の暗所にて37℃で2〜6時間インキュベートした。ELISAプレートリーダーMRX(Dynex)を用いてODを450nmおよび690nmで読み取った。トリパンブルー(Sigma)またはベックマン・コールター・カウンター(Beckman Coulter,Brea,CA)を用いる直接的細胞カウンティングを用いWSC−8アッセイを検証した。
標的細胞をCa2+Mg2+を含まないPBS中の2mM EDTAで脱着させ、およびRPMI1640(F10)中の10%子ウシ培地(Gibco)中で洗浄した。100μCiの51Crを106の標的細胞と共に250μlの最終容量にてインキュベートし、および15分間隔でペレットの温和な再懸濁と共に37℃で1時間インキュベートした。次いで、細胞を洗浄し、および250ulのF10に再懸濁させ、および37℃にて30分間インキュベートした。洗浄の後、細胞をカウントし、および活力をトリパンブルー(シグマ)で設定し、96ウェルのU底プレートに素早く平板培養した。正常なボランティアからの末梢血液をヘパリン化チューブに集めた。血液を3%デキストラン/PBSと混合し、および室温にて20分間保って、赤血球を沈積させた。次いで、白血球をフィコール処理し、および、各々、PBMC−ADCCおよびPMN−ADCCのために末梢血液単核細胞(PBMC)および顆粒球(PMN)に分離した。細胞をF10中で洗浄し、カウントし、および活力を決定した。PBMC−ADCCを10U/mlのIL−2および2ng/mlのGMCSF中のPMN−ADCCの存在下で行った。ADCCの最終容量は250ul/ウェルであった。抗体をF10中で3倍または5倍希釈において1ug/mlから希釈した。プレートを、室温にて、スナップスピンのために、500rpmで遠心し、次いで、37℃の5%CO2インキュベーター中で4時間インキュベートした。ADCC上清中の放出された51Crをガンマカウンティングのために収集した。合計放出を、10%SDSで決定し、およびバックグラウンドの自然発生放出をエフェクター無しでF10のみで決定した。50:1のE:T比率を一般的に用いた。同様に、ヒトCD16またはヒトCD32 Fc受容体で安定にトランスフェクトされたNK92−MI細胞を用いてADCCアッセイを行った。PBMCまたはPMNとは異なり、アッセイにおいてサイトカインは必要でなかった。E:T比率は一般に20:1に維持した。
抗体のヨウ素化
124Iおよび131Iを用いるヨウ素化はヨードゲン方法を用いて行った(Divgi et al.,2007,Lancet Oncol.8,304−10)。ガラスバイアルを50μgのヨードゲンでコーティングし、および50mMリン酸緩衝液(pH7.4)中の100μgのIgGを1mCiの124I(または131I)と一緒に加えた。ヨウ素124はMSKCCにおけるサイクロトロンによって部位に生じた。0.05M NaOH中の10mCiの124I(0.02〜0.05mL)を1mgのMoAb(〜0.5mL)、0.063mLの1M Tris塩基、および0.4mLの0.2Mリン酸ナトリウムpH7.4と反応バイアル中で混合した。反応を氷上で15分間進行させ、その後、溶液を除去し、およびP6サイズ排除カラムおよびPBS中の1%BSAの溶離剤でのサイズ排除クロマトグラフィーによって精製した。
Lindmoの方法を用いて、免疫反応性を見積もった(Lindmo et al.,1984,J Immunol Methods 72,77−89)。放射性方式MoAbを、50μlが約15,000〜20,000cpm(ほぼ1〜1.5uCi/3ml)が含有するまで1%BSAで希釈した。50μlを、625、375、250、220、190万の腫瘍細胞を含有する500μlの0.5%BSAに加え、および雰囲気温度にて1時間混合した。1500rpmにおける5分間の遠心の後、上清を除去し、および1mlの氷冷0.5%BSAで洗浄した。1500rpmにおける5分間のもう1つの遠心に続いて細胞ペレットをガンマカウンターでカウントした。細胞またはヨウ素化抗体の不存在下におけるバックグラウンドカウントを差し引き、および免疫反応性をLindmo方法によって見積もった(Lindmo et al.,1984,前掲)。
sc LAN1神経芽細胞腫を異種移植した無胸腺ヌードマウスを用いて、薬物動態学/生体内分布および抗腫瘍特性を調べた。腫瘍をキャリパーで測定した。sc腫瘍が〜200mgに到達すると実験を開始した。マウス当たり〜100uCiの放射性ヨウ素化抗体を静脈内注射し、および動物を通常48時間において犠牲にし、およびそれらの器官を摘出し、およびガンマカウンター(Packard Instruments,Perkin Elmer)でカウントした。これらの器官は皮膚、肝臓、脾臓、腎臓、副腎、胃、小腸、大腸、膀胱、大腿骨、筋肉、腫瘍、心臓、肺、脊椎骨、および脳を含んだ。器官に蓄積されたuCiおよび器官の重量に基づき、マウスの%注射用量(ID)/gmを計算した。%ID/gmの正常な組織に対する腫瘍の比率も計算した。
抗体の単糖およびオリゴ糖分析は、Complex Corbohydrate Research Center,Athens,GAによって行った。単糖分析はHPAECによってアッセイした。N−グリカンプロファイリングはMALDI−MSによって行った。
m3F8の重鎖および軽鎖のCDRを、各々、ヒトフレームワークIGG HV3−33およびIGKV3−15に対するそれらの相同性に基づいて、ヒトIgG1フレームワークに移植した。2つの重鎖および2つの軽鎖設計から、HU3F8の4つのバージョンを遺伝子合成し、DG44細胞に発現させた。キメラ重鎖および軽鎖のアミノ酸配列を、各々、配列番号:1および2に示し、ヒト化重鎖配列huH1−ガンマ1は配列番号:4に示し、huH2−ガンマ1は配列番号:6に示し、および、ヒト化軽鎖配列huL1−カッパは配列番号:5に示しおよびhuL2−カッパは配列番号:7に示す。
GD2をCM5チップ上にコーティングした状態で、抗体結合の動態学(kon、koffおよびKD)を、低いGD2密度にてBIACORE T−100を用いる表面プラズモン共鳴によって比較した(表2)。koffおよびKDは高いGD2密度にて全ての抗体について比例して改良された(データは図示せず)。異なる抗体密度における代表的な抗体のセンサーグラムを、BIACORE CM5チップに関して、双方の低いGD2密度にて(データは図示せず)および高いGD2密度にて(データは図示せず)比較した。
交差反応性実験において、hu3F8−H1L1−IgG1はch3F8−IgG1およびm3F8と同様なプロフィールを有した(表3)。固相GD2上のODに対するELISAによるパーセントODとして表したGD1bとの交差反応性の低いレベルがあった。ウエスタンブロット、またはSPRいずれかによる(データは図示せず)ヒトN−CAM(Patel et al.,1989,Br.J.Cancer 60,861−866)とのm3F8、hu3F8、または14.G2aの交差反応性は無かった。
これらの抗体をイン・ビトロにて神経芽細胞腫細胞に加えると、それらは直接的な細胞の死滅を誘導し、およびイン・ビトロ細胞成長を遅延させた。3日培養系においてWST−8によってアッセイすると、m3F8およびhu3F8は、それらのEC50を比較すると(表4参照)、〜10倍より弱かった14.G2aとは対照的に、同様な能力を有した。
4つのhu3F8 IgG1抗体(H1L1、H1L2、H2L1、H2L2)を、エフェクターとしてボランティアPBMC(データは図示せず)およびボランティアPMN(データは図示せず)を用いてADCCアッセイにおいて比較した。H1L2以外で、全ての3つのhu3F8は匹敵するPBMC−ADCCを有した。しかしながら、最も重要なことには、それらは、全て、>10−100のファクターだけm3F8よりも優れていた。
ヒト補体媒介溶解(CMC)において、異なるhu3F8 IgG1形態(H1L1、H1L2、H2L1、およびH2L2)は有効性において匹敵した(表6)。ch3F8およびhu3F8は40〜60%であり、他方、14G.2aおよびch14.18は、m3F8と同程度にCMCにおいて有効な4〜12%であった(表6)。
hu3F8−IgG1、hu3F8−IgG1n、およびhu3F8−IgG4は、40〜45%程度の匹敵する免疫反応性を持つ131Iで放射性標識した(表7)。48時間内におけるそれらの生体内分布を、sc LAN−1神経芽細胞腫異種移植片を担うマウスにおける131I−m3F8のそれと比較した。%ID/gmによって測定された場合の腫瘍摂取はhu3F8−IgG1(29.6%)とm3F8(28.6%)間で匹敵し、双方は、hu3F8−IgG1nおよびhu3F8−IgG4のそれのほとんど2倍であった(データは図示せず)。通常の組織に対する腫瘍の比率は、NB LAN−1異種移植片に対してこれらの4つの抗体の間で匹敵した。比較において、黒色腫M14に関しては、全ての3つのhu3F8抗体の%ID/gmおよび正常な組織に対する腫瘍の比率の双方はm3F8のそれと同様であった(データは図示せず)。
樹立されたヒト神経芽細胞腫LAN−1(0.5〜1cm直径)で異種移植したマウスを、iv m3F8またはhu3F8−H1L1−IgG1で毎週2回、4週間の間処理した。腫瘍の応答およびマウスの生存をモニターした。腫瘍成長における遅延は、hu3F8−H1L1−IgG1抗体用量(200ug>100ug>20ug、データは図示せず)に依存した。100〜200ugを受けているマウスの生存は、PBS対照またはm3F8を受けているマウスよりも有意に長かった(p=0.003)(データは図示せず)。
抗GD2抗体はGD2陽性神経芽細胞腫についての証明された療法である(Yu et al.,N Engl J Med 363:1324−1334,2010)。ネズミ抗体14.18およびその誘導体(14.G2aおよびch14.18)は、抗GD2療法の将来の改良のための基準を提供した。我々は、14.G2aまたはch14.18と比較して、GD2結合の間におけるその10倍より遅いkoffのため、臨床開発のためにネズミIgG3抗体m3F8を選択した。骨髄における化学抵抗性転移神経芽細胞腫を持つ患者の中では、m3F8+GMCSFは80%完全な寛解を誘導した(Kushner et al.,2001,J Clin Oncol 19,4189−94)。しかしながら、ヒト抗マウス抗体(HAMA)は、その抗原に結合するその能力を中和することによって、抗体の直接的効果をブロックすることによって、および循環からの抗体の除去を加速することによって、ネズミ抗体の効果を減少させることができる。ネズミからヒトIgGフレームワークへ変化させる遺伝子工学はHAMA応答を低下させるはずである。ch14.18およびhu14.18(双方は、14.G2aのVHおよびVLに由来する)は、患者において最小免疫原性を有する。従って、我々は、潜在的次世代の抗GD2抗体としての3F8のキメラおよびヒト化形態をテストした。
低いkoffを持つが、ADCCまたはCMC活性が枯渇した抗体は、血管周囲の空間を囲う神経繊維上のGD2をブロックするために用いることができようと仮定した。3F8(HM3F8)の熱処理は、そのCD2結合に影響することなくそのADCCおよびCMC活性を枯渇させる(Kushner et al.2011,J Clin Oncol 29,1168−1174)。ラットを熱処理した3F8で予備的に注射すると、天然3F8の5〜10モラー過剰の引き続いての注射に対するそれらの疼痛応答は実質的に低下した。より重要なことには、抗腫瘍効果は危うくなかった。相I臨床試験(IRB−05015、NCT00450307)では、抵抗性神経芽細胞腫(NB)を持つ30の患者は、外来患者設定における3F8+顆粒球−マクロファージコロニー刺激因子1〜2のサイクルを受けた。3F8用量は用量制限性毒性(DLT)の不存在下で、20mg/m2/dで開始し、および20mg/m2/dだけ増加した。プレ投薬は鎮痛剤、抗ヒスタミン剤、および2mg/m2 HM3F8の5分の注入を含むものであった。オピオイドの使用を、20mg/m2/dにおける3F8で処置したが、HM3F8で処置しなかった一次的な対照群と比較した。用量の上昇は、薬物供給限界のため160mg/m2/dで停止させ;この用量レベルを通じてさえ、鎮痛剤の要件は歴史的な対照と同様であり、およびDLTは無かった。80mg/m2/dを通じての3F8用量レベルにおける鎮痛剤の要件は、対照と比較して有意に少なかった。抗NB活性は全ての用量で起こった。この3F8の多数倍用量の上昇は実行可能であって、HM3F8は抗NB活性を平滑とすることなく毒性を修飾することができたことを示唆した。
HM3F8の臨床結果に基づき、我々は、血管周囲の疼痛繊維が、CMCまたはADCC機能を欠如する抗体の小用量によって優先的にブロックすることができると仮定する。m3F8の加熱はそのCMCおよびADCC機能を(結合を保持しつつ)破壊するが、熱修飾されたhu3F8はほとんど十分なCMCおよびADCC機能を保有する。Lan1、NMB7、SKNLP、BE(1)N、およびSHEP1のような異なるNB細胞系においてCMCおよびADCCを活性化するhu3F8−IgG4の無能力(表8、データは図示せず)は、この抗体サブクラスを、HM3F8についての活力のある代替法とする。抗体構造および免疫原性に対する未知の効果を伴う加熱とは異なり、hu3F8−IgG4は作成された蛋白質である。CMCおよびADCC機能の不存在の他に、IgG4のサブクラスはユニークな生化学的特性を有する。慢性抗原刺激によって典型的に誘導され、それらは他の抗体のイソタイプによる免疫複合体形成に干渉することが知られており、それにより、免疫反応を弱らせる(Losen et al.,2008,Ann N Y Acad Sci 1132,174−9)。最も重要なことには、それは、それ自体を一価に還元する天然の能力を有し、それにより、血液中での数時間の期間の後にhu3F8−IgG1と競合するその能力を喪失する(van der Neut Kolfschoten et al.,2007,Science 317,1554−7)。そのような一価は、重鎖および付着した軽鎖(半分子)をもう1つのIgG4分子からの重−軽鎖対と交換することによってFabアームを交換するその既知の特性から由来し、その結果、問題とする特異的抗原に向けての一価がもたらされる(例えば、GD2)。
該ラットモデルを用いて、疼痛副作用をブロックするhu3F8−IgG4の能力をテストした(MSKプロトコル #09−05−010)。m3F8(ラット補体の有効なアクチベーター、Bergman et al.,2000,Cancer Immunol Immunother 49,259−66)およびhu3F8の双方を用いて異痛症を誘導した。hu3F8−IgG4(0.1、0.25、または0.5mg/kg)を、iv m3F8(5mg/kg)、またはhu3F8−IgG1(5mg/kg)、またはch14.18(5mg/kg)に30分間先立って静注として投与した。他の群は熱修飾m3F8(HM3F8)またはhu3F8−IgG4の代わりに対照抗体を受けた。Von Freyフィラメント方法を用いて、MoAb注射に先立って、およびその後に、ベースラインにおける疼痛を見積もった(Chassaing et al.,2006,Br J Clin Pharmacol 61,389−97;Benani et al.,2003,Eur J Neurosci 18,2904−14)。
神経芽細胞腫(LAN−1)の腫瘍を、低い血清IgGを持つ雌NOD/SCID/IL2−gcnull免疫欠乏マウス(群当たりn=10)の群において皮下移植した。マウスに、実験に24時間先立って、1gm/kgのヒトIgGを注射した。hu3F8−IgG4(0.1、0.25、または0.5mg/kg)または対照huIgG4(0.1、0.25、または0.5mg/kg)、またはHM3F8(0.5mg/kg)、または生理食塩水を、131I標識各MoAbで標識されたm3F8、またはhu3F8−IgG1、またはch14.18(5mg/kg)分量に30分間先立って、静注として投与した。血液を1、3、6、12、24、36、48、および96時間において尾から収集した。生体内分布実験において、組織カウントのため、2つの時点(131I−MoAb注射から24時間および48時間後に)マウスを犠牲にした。主な器官を摘出し、および既知の容量の注射でガンマカウンターにてカウントし、およびデータはパーセンテージID/gm組織として表した。薬物動態学分析は、WinNonlinソフトウェアプログラム(Pharsight Corp.,Mountain View,CA)を用い、血清濃度−時間のデータの非区画分析によって行った。実験の別の組において、異種移植マウスを、同様に、しかしながら、131I分量標識無くして処理し、およびそれらのsc腫瘍応答を2カ月間にわたって測定した。
ネズミ抗体をヒト化するプロセスにおいて、構造的に重要な位置にあるフレームワーク残基は、しばしば、ネズミ配列に復帰突然変異させて、抗体安定性および抗原結合の双方を保存する(Honegger,A,2008,Engineering Antibodies for Stability and Efficient Folding,In:Therapeutic Antibodies.Handbook of Experimental Pharmacology,181)。
m3F8可変ドメインの構造モデル
m3F8可変ドメインの相同性モデルを、Discovery Studio (Accerlys,San Diego,CA)においてMODELER(Eswar et al.,2006,Curr Prot Bioinfor,Supplement 15,5.6.1−5.6.30)を用いて作り出した。マラリヤ抗原AMA1抗体Fab(Protein Data Bank code 2Q8A)の結晶構造を、可変軽鎖のための鋳型として選択した(84%同一性)。抗体13G5 Fab(Protein Data Bank code 2GJZ)の結晶構造を、可変重鎖のための鋳型として選択した。
標準的なFab調製キット(Pierce Biotechnology,Rockford,IL)を用い、m3F8のFab断片をパパイン消化によって生じさせた。精製されたm3F8を20mM HEPES pH6.5中で12mg/mlまで濃縮し、および0.1M Tris pH8.5、25%w/v PEG3350を含有するHampton Index試薬D9(Hampton Research,Aliso Viejo,CA)を含有する貯蔵器に対して16℃での蒸気拡散によって吊り下げた滴中で結晶化させた。該液滴は、1μlの蛋白質溶液および1μlの貯蔵器溶液を混合することによって液滴を形成した。結晶は、25%グリセロール、0.1M Tris pH8.5、25%w/v PEG3350を含有する低温保護剤によって保護した。データはArgonne Advanced Photon Source beamline 24IDCにおいて収集した。結晶は空間群C2に属し、および1.7Å分解能まで回折する。
ヒト鋳型IgHV3−33−HCおよびIGKV3−15−LCに基づき、m3F8上のフレームワークに導入されるであろう各ヒト化突然変異を、コンピューター化学方法を用いて解析した。m3F8の結晶構造は、CHARMm(Chemistry at Harvard Molecular mechanics)力場(Brooks et al,2009,J.Comp Chem 30,1545−1615)を用いてシミュレートし、および各点突然変異の効果を、突然変異した構造の折り畳み自由エネルギーと野生型蛋白質との間の鎖から計算した。一般化されたBorn近似式を用いて、溶媒の効果を説明し、および全ての静電項をクーロン相互作用および溶媒和エネルギーに対する極性寄与の合計として計算した。ファン・デル・ワールス、静電、エントロピーおよび非極性項の重み付けした和を各点の突然変異につき計算した。全ての計算は、Discovery Studio 3.0(Accelrys,San Diego,CA)を用いて行った。
hu3F8−H1L1重鎖配列では、ヒトIgG重鎖配列IgHV3−33−HCを鋳型として用い、および位置5、9、16、19、20、24、28、29、30、40、48、49、67、71、76、78、81、86、および92において復帰突然変異を行った。hu3F8−H1L1軽鎖では、ヒトIgG軽鎖配列IGKV3−15−LCを鋳型として用い、位置1、7、9、15、19、21、22、43、45、58、60、67、70、73、78、80、および87で復帰突然変異を行った。復帰突然変異はm3F8の相同性モデルに基づいて推測し、および突然変異がCDRループの折り畳みに影響するか、または骨格安定性(GlyおよびProを含む突然変異)に影響するかを決定することを含んだ。
m3F8の結晶構造をコンピューター実験のための鋳型として用いて、抗原認識の分子の詳細を決定した。GD2抗原は、セラミド脂質テイルに連結された五糖頭部から成る。実験的に導かれた3F8:GD2共複合体の不存在下では、コンピュータードッキングはGD2五糖頭部のみで試みられ、ここに、セラミド部位はメチル基によって置き換えた。GD2五糖分子は、コンピュータードッキングにおける場の状態を考えるとドッキング実験のための主な挑戦を表した。最初に、大きな柔軟性リガンドのドッキングは、正確に予測するのは困難である。GD2頭部は30を超える回転可能な結合を有する。そのような高度な柔軟性を持つリガンドについて正確であると報告された、確立されたドッキングプロトコルは無い。第二に、GD2頭部は炭水化物分子であり、力場方法を炭水化物分子に適用した場合に、ドッキング実験の精度に関する少数の報告しか無い。第三に、GD2頭部は炭水化物の特殊なクラスである。というのは、それはそのシアル酸部位で見出された2つの荷電基を含有するからである。そのような大きくて、柔軟であって荷電された炭水化物の結合立体配座を正確に予測することが示された、確立されたドッキング方法は無い。
GLIDEドッキングは、Shrodinger Suite2009(Schrodinger,New York,NY)を用いて行った。OPLS力場を用いて、蛋白質およびリガンドをパラメーター化した。頂部リガンドの姿勢は2.0Åの根平均二乗偏差内でクラスター化し、およびGlideScoreによってスコア取りした。
抗GD2 MoAbは化学抵抗性転移性神経芽細胞腫(NB)に対する証明された療法であり、ch14.18は次世代のMoAbについての基準を提供する。抗GD2 MoAbマウス3F8(m3F8)および顆粒球−マクロファージコロニー刺激因子(GM−CSF)の組合せは、原発性難治性NBを持つ患者の80%において完全な骨髄寛解を一貫して誘導した。第一の完全な/非常に良好な部分的緩解(CR/VGPR)で処置された患者の中では、この組合せは13−シス−表12をプラスする。CDOCKERおよびCHARMmエネルギー最小化レチノイン酸に基づいてGD2と直接的に相互作用する3F8アミノ酸残基は、PFSを51%±7%まで、およびOSを80%±5%まで、過去5年間で改良した。治療効果の分析は、NBおよび他の固形腫瘍のMoAb療法における遺伝子多形に基づくFcR親和性の重要性を反復して示した。抗原に対する、および犠牲にする特異性無しのFcRに対する親和性の改良は、イン・ビトロおよびイン・ビボでのMoAb効力を改良するはずである。
huIgG1サブクラスのキメラ3F8(ch3F8)およびヒト化3F8(hu3F8)は遺伝子工学によって構築し、CHO細胞において発現させ、およびプロテインAアフィニティークロマトグラフィーによって精製した。フコースおよびN−アセチルグルコサミンを欠如するhu3F8のFc糖型(hu3F8nまたはhu3F8−MAGE1.5)を特殊なMAGE1.5 CHO細胞において生じさせた。GD2に対する、およびFcRに対するこれらのMoAb形態の親和性は、BIACORE T−100を用いて比較した。エフェクター機能を、抗体依存性細胞媒介細胞傷害性(ADCC)および補体媒介細胞傷害性(CMC)アッセイを用いてテストし、およびそれらの能力はMoAbのEC50に由来した。これらの戦略を、臨床的潜在能力を持つ他の腫瘍抗原系(B7−H3、HER−2、CSPG4、LI CAM)に対するMoAbに適用した。
ch3F8およびhu3F8はm3F8のそれと同様なKdを維持し、14G.2aまたch14.18と比較した場合、全ては10倍遅いkoffを共有し、その結果、より好都合なKDおよびより長い滞留時間をもたらした。m3F8、ch3F8またはhu3F8はイン・ビトロにてNB細胞系の増殖を阻害し、他方,他の抗GD2抗体は有効でなかった。末梢血液単核細胞(PBMC)−ADCC、顆粒球(PMN)−ADCCまたはCMCにおいて、ch3F8およびhu3F8はch14.18よりも10倍を超えてより強かった。hu3F8nによるPBMC−ADCCはhu3F8よりも10倍効果的であり、およびm3F8よりも>100倍より優れていた。他方、生体内分布実験における131I−hu3F8は、131I−m3F8のそれと匹敵する腫瘍〜通常の組織の比率を示し、hu3F8はNB異種移植片に対して優れた抗腫瘍効果を示した。同様な結論が他の腫瘍抗原系に特異的なキメラおよびヒト化抗体で導くことができたが、腫瘍エピトープ/抗原の性質は腫瘍殺傷の有効性を決定するにおいて臨界的であった。
抗原またはFcRについてのkoff(またはKD)はエフェクターの機能を個々に改良し、一緒にそれらの効果は、抗GD2 MoAb 3F8について増殖性に見えた。双方の親和性の改良に向けられた将来の戦略は、さらに、これまでに観察されたMoAbの臨床的有効性を拡大するはずである。
重鎖における三重突然変異DEL(S239D/A330L/I332E)を持つhu3F8−IgG1−DEL(Lazar et al.,2006,PNAS USA 103,4005−10)は、FcR3AおよびFcR2Aに対する、のみならずFcR2Bに対する親和性の実質的な増加を伴って作成された(表14中のBIACOREデータ参照)。しかしながら、hu3F8−IgGnに対する活性化対阻害性シグナルについてのA/I比率は、臨床的な利点(Nimmerjahn and Ravetch,Immunol Rev,236:265−275,2010)を有することが仮定されている、hu3F8−IgG1−DELに対する30と比較して、CD16−158Vに対して196である。
NK92−CD16エフェクター細胞を、4時間の51Cr放出アッセイにおいて異なる抗体濃度での5:1のエフェクター:標識比率でLAN1神経芽細胞腫の腫瘍標的に加えた。
ヒト補体を、4時間の51Cr放出アッセイにおいて、増大させる抗体濃度にて、1:100の最終の血清補体希釈で神経芽細胞腫LAN−1腫瘍標的に加えた。補体媒介溶解(CMC、データは図示せず)において、hu3F8−IgG1−DELはhu3F8−IgG1またはhu3F8−IgG1nよりも悪くはなかった。IgG重鎖における三重突然変異をhu3F8−IgG1nと組み合わせると、ADCCにおいてさらなる改良はなかった。
T細胞またはTリンパ球は、細胞−媒介免疫において立役者であるWBCである。それらはT細胞受容体(TCR)と呼ばれるそれらの細胞表面での特殊な受容体の存在によってB細胞およびナチュラルキラー(NK)細胞のような他のリンパ球タイプから区別することができる、また、それらは、CD3と呼ばれるユニークな表面マーカーを運ぶ。Tは、T細胞の成熟を担う主たる器官である胸腺を表す。T細胞の数個のサブセットが存在し、各々が区別される機能を備えている。Tヘルパー細胞(TH細胞)は、抗体を分泌するためのB細胞の成熟、および細胞傷害性T細胞およびマクロファージの活性化を含めた、免疫学的プロセスにおいて他のWBCを援助する。それらはCD4+T細胞と呼ばれるようになった。なぜならば、それらはCD4蛋白質を運ぶからである。活性化された場合、ヘルパーT細胞は、迅速に分裂し、およびサイトカインを分泌して、免疫応答を調節し、または援助する。これらの細胞は、異なるサイトカインを分泌して、免疫応答を変調する数個のサブタイプ(例えば、TH1、TH2、TH3、TH17、またはTFH)に分化することができる。いくつかの腫瘍モデルにおいて、CD4+T細胞もまた、癌の成長を抑制するにおいて十分である。規則的な活性化シグナルは抗原提示細胞(APC)から来るが、それらの表面CD3が抗体によって架橋された場合に、CD4+T細胞は活性化されたようになることができる。細胞傷害性T細胞(CTL)はウイルスに感染した細胞および腫瘍細胞を破壊し、また、移植または移植片拒絶の原因でもある。それらはCD8+T細胞と呼ばれる。なぜならば、それらは表面CD8糖蛋白質を発現するからである。それらは、多くのヒト腫瘍では存在しないか、または少ない、主要組織適合性複合体(MHC)クラスI分子に関連する抗原を認識することによって標的を係合させる。記憶T細胞は、ウイルスまたは腫瘍細胞が殺傷された後、長時間執拗に存在する抗原特異的T細胞である。それらは、腫瘍抗原で攻撃された場合に素早く多数に拡大でき、かくして、免疫系に癌に対する「記憶」を与える。ナチュラルキラーT細胞(NKT細胞)は、二次免疫系と先天性免疫系とを橋渡しするT細胞の特殊な種類である。MHC上のペプチド抗原を認識する慣用的なT細胞とは異なり、NKT細胞はCD1dと呼ばれる分子によって提示された糖脂質抗原を認識する。一旦活性化されると、これらの細胞はThおよびTc細胞双方と同様な機能(例えば、サイトカインの生産および細胞溶解性/細胞殺傷性分子の放出)を行うことができる。それらは腫瘍細胞を認識し、排除することが知られている。γδT細胞(ガンマデルタT細胞)は、それらの表面にTCRを運ぶT細胞の小さなサブセットを表す。T細胞の大部分は、α−およびβ−TCR鎖と呼ばれる2つの糖蛋白質鎖から成るTCRを有する。しかしながら、γδT細胞においては、TCRは1つのγ−鎖および1つのδ−鎖から成る。それらは合計T細胞の5%のみを表すが、腸粘膜で最も豊富であり(上皮内リンパ球、IELと命名される)。γδT細胞を活性化する抗原は知られておらす;しかしながら、γδT細胞がMHC制限されておらず、恐らくは、MHC上のペプチドよりはむしろ全蛋白質を認識する。
Claims (36)
- GD2に結合することができるヒト化またはキメラ抗体またはその断片であって、ネズミ抗体m3F8可変軽鎖のCDR1、CDR2、およびCDR3のアミノ酸配列の少なくとも1つと/またはネズミ抗体m3F8可変重鎖のCDR1、CDR2、およびCDR3のアミノ酸配列の少なくとも1つとを有するGD2に結合することができるヒト化またはキメラ抗体またはその断片。
- 請求項1記載のキメラ抗体またはその断片において、前記抗体は配列番号:1の可変重鎖ドメインおよび配列番号:2の可変軽鎖ドメインを有するものである、キメラ抗体またはその断片。
- 請求項1記載のキメラ抗体またはその断片において、前記抗体は配列番号:3の可変重鎖ドメインおよび配列番号:2の可変軽鎖ドメインを有するものである、キメラ抗体またはその断片。
- 請求項1記載のヒト化抗体またはその断片において、前記抗体は配列番号:4の可変重鎖ドメインおよび配列番号:5の可変軽鎖ドメインを有するものである、ヒト化抗体またはその断片。
- 請求項1記載のヒト化抗体またはその断片において、前記抗体は配列番号:6の可変重鎖ドメインおよび配列番号:7の可変軽鎖ドメインを有するものである、ヒト化抗体またはその断片。
- 請求項1記載のヒト化抗体またはその断片において、前記抗体は配列番号:8の可変重鎖ドメインおよび配列番号:5の可変軽鎖ドメインを有するものである、ヒト化抗体またはその断片。
- 請求項1記載のヒト化抗体またはその断片において、前記抗体は配列番号:9の可変重鎖ドメインおよび配列番号:10の可変軽鎖ドメインを有するものである、ヒト化抗体またはその断片。
- 請求項4記載の抗体において、前記抗体は末端マンノース、N−アセチルグルコース、またはグルコースでグリコシル化されているが、フコースではグリコシル化されていないものである、抗体。
- 請求項4〜8記載の抗体において、前記抗体は前記抗体の前記重鎖ドメイン配列において以下のアミノ酸置換のうちの少なくとも1つを有し、前記置換はS239D、A330L、I332E、およびG54Iから成るものである、抗体。
- 請求項4〜9記載の抗体において、前記抗体は前記抗体の前記軽鎖におけるアミノ酸置換を有し、前記置換はA43Sである、抗体。
- 請求項2〜10記載の抗体において、前記抗体は、前記抗体をコードする核酸を有する組換えベクターによって生産されるものである、抗体。
- 配列番号:1〜10のいずれか1記載のコーディング配列を有する単離された核酸分子。
- 請求項12記載の核酸分子を有する組換えベクター。
- 請求項13記載の組換えベクターを有する宿主細胞。
- 請求項1〜10のいずれか1記載の抗体またはその断片を生産する方法であって、抗体またはその断片の発現を可能とする条件下で培養基において請求項14記載の宿主細胞を培養する工程、および前記培養基から前記抗体またはその断片を分離する工程を有する方法。
- 請求項1〜10いずれか記載の抗体またはその断片を有する組成物。
- 請求項16記載の組成物において、前記抗体は細胞傷害性剤にコンジュゲートされたものである、組成物。
- 請求項16または17記載の組成物の抗体または断片を有し、さらに医薬上許容される担体または希釈剤を有する医薬組成物。
- 対象において医学的疾患を治療または予防する方法であって、前記医学的疾患はGD2発現によって特徴付けられ、治療上有効量の請求項1〜10いずれか1記載の抗体またはその断片を前記対象に投与する工程を有する方法。
- 請求項19記載の対象において医学的疾患を治療または予防する方法であって、前記医学的疾患は神経芽細胞腫、黒色腫、肉腫、脳腫瘍、または癌腫である、方法。
- 請求項20記載の方法において、前記病気は骨肉腫、脂肪肉腫、線維肉腫、悪性線維性組織球腫、平滑筋肉腫、紡錘細胞肉腫、脳腫瘍、小細胞肺癌、網膜芽細胞腫、HTLV−1感染T細胞白血病、および他のGD2陽性腫瘍から成る群から選択されるものである、方法。
- ヒト化3F8抗体に由来する第一の抗原結合部位と、第二の抗原結合部位とを有する二特異的抗体。
- 請求項22に記載の二特異的分子において、前記第一の抗体は軽鎖および重鎖を有する免疫ブログリン分子であり、前記第二の抗体はscFv、scFab、Fab、またはFvから成る群から選択されるものである、二特異的分子。
- 請求項22記載の二特異的抗体において、前記第二の抗原結合部位は、Tリンパ球NK細胞、Bリンパ球、樹状細胞、単球、マクロファージ、好中球、間葉幹細胞、神経幹細胞から成る群から選択される免疫学的細胞と会合するものである、二特異的抗体。
- 請求項22記載の二特異的抗体において、前記第二の抗原結合部位はCD3に対して特異的である、二特異的抗体。
- 請求項25記載の二特異的抗体において、前記抗体は配列番号:23を有するものである、二特異的抗体。
- 請求項23記載の二特異的抗体において、前記第二の抗体はDOTA(金属)に対して特異的であり、前記二特異的抗体は配列番号:24を有するものである、二特異的抗体。
- 請求項22〜27記載の二特異的抗体をコードする配列を有する核酸。
- 請求項28記載の核酸配列を有する発現ベクター。
- 請求項29記載のベクターを有する宿主細胞。
- 請求項22〜27記載の二特異的抗体を有する医薬組成物。
- hu3F8抗体の抗原結合ドメインを有するキメラ抗原受容体。
- 請求項32記載のキメラ抗原受容体において、前記抗原結合ドメインはsvFvである、キメラ抗原受容体。
- 請求項33記載のキメラ抗原受容体において、前記キメラ抗原受容体は免疫エフェクター細胞によって発現されたものである、キメラ抗原受容体。
- GD2発現に関連する疾患の治療または検出のための、請求項32〜34記載のキメラ抗原受容体の使用。
- モノクローナル抗体を係合させる二特異的T細胞であって、hu3F8モノクローナル抗体からのscFvを有するものである、二特異的T細胞。
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CN103347894A (zh) | 2013-10-09 |
EP3323830B1 (en) | 2023-08-23 |
US10287365B2 (en) | 2019-05-14 |
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JP6029581B2 (ja) | 2016-11-24 |
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WO2011160119A3 (en) | 2012-05-10 |
AU2011268110A1 (en) | 2012-12-06 |
KR20130115210A (ko) | 2013-10-21 |
KR101834026B1 (ko) | 2018-03-02 |
EP3323830A1 (en) | 2018-05-23 |
US9315585B2 (en) | 2016-04-19 |
EP4269563A2 (en) | 2023-11-01 |
CN103347894B (zh) | 2017-05-10 |
CA2801210C (en) | 2020-07-21 |
EP2582722A2 (en) | 2013-04-24 |
JP2017019812A (ja) | 2017-01-26 |
EP2582722A4 (en) | 2013-12-18 |
WO2011160119A8 (en) | 2013-02-21 |
US20130216528A1 (en) | 2013-08-22 |
NZ603581A (en) | 2015-05-29 |
WO2011160119A2 (en) | 2011-12-22 |
ES2961381T3 (es) | 2024-03-11 |
CA2801210A1 (en) | 2011-12-22 |
US20170253660A1 (en) | 2017-09-07 |
NZ702680A (en) | 2016-07-29 |
AU2011268110B2 (en) | 2016-05-19 |
US20160176981A1 (en) | 2016-06-23 |
EP4269563A3 (en) | 2024-01-10 |
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