JP2016520586A - 二重特異性her2およびher3抗原結合性構築物 - Google Patents
二重特異性her2およびher3抗原結合性構築物 Download PDFInfo
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Abstract
Description
本出願は、2013年5月8日に出願された米国仮出願第61/821,197号の恩典を主張し、それはその全体が参照により本明細書に組み入れられる。
本出願は、EFS-Webを経由して提出される配列表を含み、かつそれとともに出願され、その全体が参照により本明細書に組み入れられる。2014年5月8日に作成された前記ASCIIコピーの名称は24689PCT_sequencelisting.txtであり、サイズは137,000バイトである。
本発明の分野は、例えばバイオセラピューティック(biotherapeutic)のために有用な、二重特異性HER2およびHER3抗原結合性構築物である。
ヒト上皮増殖因子受容体(HER、erbB)ファミリーはEGFR(HER1)、HER2(erbB2)、HER3(erbB3)およびHER4(erbB4)を含み、この受容体ファミリーの活性は正常組織の発生および維持を調節している。しかし、この受容体ファミリーの過剰発現および/またはその活性の異常調節はヒト腫瘍細胞の発生および増殖との関連が指摘されており、それ故にこのファミリーのメンバーは癌の治療用の治療用抗体の開発のための標的となってきている。例えば、トラスツズマブ(ハーセプチン(Herceptin)(商標))およびペルツズマブ(パージェタ(Perjeta)(商標))は、ハーセプテスト(Herceptest)(商標)による測定でHER2を高レベルで発現する乳癌(HER2 3+)の治療のために開発された抗HER2抗体であり、一方、トラスツズマブのメイタンシンコンジュゲートであるT-DM1(カドサイラ(Kadcycla)(商標))も、これらの型の乳癌の治療のために開発されている。
以下にさらに詳細に説明するように、本明細書に記載されるのは、二重特異性抗原結合性構築物、例えば二重特異性抗体である。二重特異性抗原結合性構築物は、HER2のECD4と結合する第1の抗原結合性ポリペプチド構築物、およびHER3のECDと特異的に結合する第2の抗原結合性ポリペプチド構築物を含む。抗原結合性構築物の一方はFc型をとり;もう一方はFab型をとる。二重特異性抗原結合性構築物は、二量体化のためのCH3ドメインをそれぞれが有する2つのFcポリペプチドを有するFcを含む。各Fcポリペプチドは、抗原結合性ポリペプチド構築物の1つのC末端と、リンカーを伴ってまたは伴わずに連結されている。単離された二重特異性抗原結合性構築物は、HER2およびHER3を発現する細胞において、2つの第1の抗原結合性ポリペプチド構築物または2つの第2の抗原結合性ポリペプチド構築物を含む参照二価単一特異性抗体と比較して、より大きな最大結合(Bmax)を呈する。
特許請求の範囲および明細書において用いられる用語は、別記しない限り、以下に明記される通りに定義される。
本明細書に開示されるのは、二重特異性抗原結合性構築物、例えば、HER2およびHER3の両方と選択的に結合する抗体である。
本明細書に記載の二重特異性抗原結合性構築物は、Fcを含む。Fcは、二量体化のためのCH3ドメインをそれぞれが有する2つのFcポリペプチドを含む。各FcポリペプチドのN末端は、抗原結合性ポリペプチド構築物の1つのC末端と、リンカーを伴ってまたは伴わずに連結されている。
いくつかの態様においては、二重特異性抗原結合性構築物を、エフェクター機能を改善するために改変することができる。そのような改変は当技術分野において公知であり、アフコシル化、ならびに、ADCCのための活性化受容体、主としてFCGR3aおよびFCGRbに対する抗体のFc部分の親和性、およびCDCのためのC1qに対する親和性の遺伝子操作が含まれる。1つの態様において、エフェクター機能は、CDC、ADCC、ADCP、およびサイトカイン分泌からなる群より選択される1つまたは複数の機能である。1つの特定の態様において、エフェクター機能はADCCである。
いくつかの態様において、二重特異性抗原結合性構築物は、FcγRの選択的結合を促進するための非対称性アミノ酸改変を有する変異型CH2ドメインを含む。いくつかの態様において、変異型CH2ドメインは、本明細書に記載の単離された一価抗体の分離および精製を可能にする。
1つの態様において、Fc領域は、新生児Fc受容体(FcRn)に対する結合親和性を示す。ある態様において、FcRn結合親和性はネイティブなIgG1 Fcのものと実質的に同程度である。いくつかの態様において、FcRnに対する実質的に同程度の結合は、本明細書に記載の構築物のFc領域が、FcRnに対するネイティブなIgG1 Fcドメインの結合親和性の約70%を上回る、またはいくつかの態様においては約80%を上回る、およびいくつかの特定の態様においては約90%を上回るものを示す場合に達成される。
ある態様において、本明細書に記載の構築物のFc領域は、ネイティブなIgG1 Fc領域と比較して、Fc受容体に対する結合親和性の低下、および/またはエフェクター機能の低下を示す。1つのそのような態様において、Fc領域は、ネイティブなIgG1 Fc領域と比較して、50%未満、代替的には20%未満、代替的には10%未満、およびいくつかの態様においては5%未満の、Fc受容体に対する結合親和性、ならびに/またはネイティブなIgG1 Fc領域と比較して、50%未満、代替的には20%未満、代替的には10%未満、およびいくつかの態様においては5%未満のエフェクター機能を示す。
本明細書に記載の二重特異性抗原結合性構築物は、本明細書に記載の2つの抗原結合性ポリペプチド構築物が、本明細書に記載のFcと機能的にカップリングされたものを含む。いくつかの局面において、Fcは、1つまたは複数のリンカーを伴ってまたは伴わずにカップリングされている。いくつかの局面において、Fcは抗原結合性ポリペプチド構築物と直接的にカップリングされている。いくつかの局面(ascpect)において、Fcは、1つまたは複数のリンカーによって抗原結合性ポリペプチド構築物とカップリングされている。
記載された二重特異性抗原結合性構築物は、HER2のECD4と特異的に結合する第1の抗原結合性ポリペプチド構築物、およびHER3のECDと特異的に結合する第2の抗原結合性ポリペプチド構築物を含む。一方の抗原結合性ポリペプチド構築物はFab型をとる;もう一方の抗原結合性ポリペプチド構築物はscFv型をとる。
いくつかの態様において、二重特異性抗原結合性構築物は、単鎖Fab型またはscFabにあるFabを含む。この型の説明は当業者には周知であり、例えば、国際特許公開公報第WO2014/018572号;US2010/0256338号;およびUS20110293613号に記載がある。これらの参考文献によるscFabの設計、発現および使用に関する説明は、参照により組み入れられる。
「解離定数(KD)」という用語は、本明細書で用いる場合、特定の抗原-抗体相互作用の解離速度を指すことを意図している。KDは、「オフ速度(koff)」とも呼ばれる解離の速度と、会合速度、または「オン速度(kon)」との比である。したがって、KDはkoff/konに等しく、モル濃度(M)として表現される。その結果、KDが小さいほど、結合の親和性は強くなる。このため、1mMのKDは、1nMのKDと比較して弱い結合親和性を示している。抗体に関するKD値は、当技術分野において十分に確立した方法を用いて決定することができる。抗体のKDを決定するための1つの方法は、典型的にはBiacore(登録商標)システムなどのバイオセンサーシステムを用いる表面プラズモン共鳴(SPR)を用いることによる。
本明細書に記載の二重特異性抗原結合性構築物は、これらの抗体が以下の有効性因子:a)二重特異性抗原結合性構築物が内部移行される能力、b)二重特異性抗原結合性構築物のBmaxの増大、およびc)二重特異性抗原結合性構築物のアゴニズム/部分的アゴニズムの度合い、の間で示すバランスに応じて、二重特異性溶解性(BSP-L)抗体および二重特異性内部移行性(BSP-I)抗体という2つのサブタイプに分類することができる。
本発明の単離された二重特異性抗原結合性構築物は、HER2およびHER3を発現する細胞において、2つの第1の抗原結合性ポリペプチド構築物(例えば、トラスツズマブ)または2つの第2の抗原結合性ポリペプチド構築物(例えば、H3)を含む参照二価単一特異性抗体と比較して、より大きな最大結合(Bmax)を呈する。いくつかの態様において、二重特異性抗原結合性構築物は、参照二価単一特異性抗体のBmaxの1.1倍、1.2倍、1.3倍、1.4倍、1.5倍、1.6倍、1.7倍、1.8倍、1.9倍または2.0倍であるBmaxを呈する。
本明細書に記載の二重特異性抗原結合性構築物は、少なくとも1つのポリペプチドを含む。本明細書に記載のポリペプチドをコードするポリヌクレオチドも同じく記載される。
また、宿主細胞におけるポリペプチドの発現を介して二重特異性抗原結合性構築物を生産する方法も本明細書に記載される。
ある態様において、記載される構築物は、酵母、細菌などの微生物、またはヒトもしくは動物細胞株からの分泌によって組換え分子として産生される。諸態様において、ポリペプチドは宿主細胞から分泌される。
、およびコンセンサスシグナル配列
が非限定的に含まれる。バキュロウイルス発現系とともに用いうる適したシグナル配列には、gp67シグナル配列(例えば、GenBankアクセッション番号AAA72759のアミノ酸1〜19)がある。
ある態様において、本明細書に記載の二重特異性抗原結合性構築物は、翻訳中または翻訳後に差異を伴って改変される。
ある態様において、二重特異性抗原結合性構築物は、薬物、例えば、毒素、化学療法薬、免疫調節薬、または放射性同位体とコンジュゲートされる。ADC(抗体薬物コンジュゲート)を調製するいくつかの方法が当技術分野において公知であり、例えば、米国特許第8,624,003(ポット法)、第8,163,888号(一段階)および第5,208,020号(二段階法)に記載されている。
ADCは、当業者に公知の有機化学反応、条件および試薬を用いて、いくつかの経路によって調製することができる:(1)抗体の求核基または求電子基と二価リンカー試薬との反応によって、共有結合を介して抗体-リンカー中間体Ab-Lを形成させ、その後に活性化薬物部分Dと反応させること;および(2)薬物部分の求核基または求電子基とリンカー試薬の反応によって、共有結合を介して薬物-リンカー中間体D-Lを形成させ、その後に抗体の求核基または求電子基と反応させること。コンジュゲーション方法(1)および(2)を、種々の抗体、薬物部分およびリンカーとともに使用することにより、本明細書に記載の抗体-薬物コンジュゲートを調製することができる。
薬物はリンカーによって抗体と連結させることができる。mAbに対するリンカーの結びつけは、例えば、表面リジンを通じて、酸化された糖質に対する還元性カップリング、および鎖間ジスルフィド結合を還元することによって自由になったシステイン残基を通じて、といった種々のやり方で実現することができる。ヒドラゾンベースの結合、ジスルフィドベースの結合およびペプチドベースの結合を含む、種々のADC連結システムが当技術分野において公知である。
薬物またはペイロードの例は、DM1(メイタンシン、N2'-デアセチル-N2'-(3-メルカプト-1-オキソプロピル)-またはN2'-デアセチル-N2'-(3-メルカプト-1-オキソプロピル)-メイタンシン)、mc-MMAD(6-マレイミドカプロイル-モノメチルオーリスタチン-DまたはN-メチル-L-バリル-N-[(1S,2R)-2-メトキシ-4-[(2S)-2-[(1R,2R)-1-メトキシ-2-メチル-3-オキソ-3-[[(1S)-2-フェニル-1-(2-チアゾリル)エチル]アミノ]プロピル]-1-ピロリジニル]-1-[(1S)-1-メチルプロピル]-4-オキソブチル]-N-メチル-(9Cl)-L-バリンアミド)、mc-MMAF(マレイミドカプロイル-モノメチルオーリスタチンFまたはN-[6-(2,5-ジヒドロ-2,5-ジオキソ-1H-ピロール-1-イル)-1-オキソヘキシル]-N-メチル-L-バリル-L-バリル-(3R,4S,5S)-3-メトキシ-5-メチル-4-(メチルアミノ)ヘプタノイル-(αR,βR,2S)-β-メトキシ-α-メチル-2-ピロリジンプロパノイル-L-フェニルアラニン)およびmc-Val-Cit-PABA-MMAE(6-マレイミドカプロイル-ValcCit-(p-アミノベンジルオキシカルボニル)-モノメチルオーリスタチンEまたはN-[[[4-[[N-[6-(2,5-ジヒドロ-2,5-ジオキソ-1H-ピロール-1-イル)-1-オキソヘキシル]-L-バリル-N5-(アミノカルボニル)-L-オルニチル]アミノ]フェニル]メトキシ]カルボニル]-N-メチル-L-バリル-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-ヒドロキシ-1-メチル-2-フェニルエチル]アミノ]-1-メトキシ-2-メチル-3-オキソプロピル]-1-ピロリジニル]-2-メトキシ-1-[(1S)-1-メチルプロピル]-4-オキソブチル]-N-メチル-L-バリンアミド)からなる群より選択される。DM1はチューブリン阻害薬メイタンシンの誘導体であり、一方、MMAD、MMAEおよびMMAFはオーリスタチン誘導体である。
いくつかの態様において、薬物はメイタンシノイドである。メイタンシン化合物は、マイクロチューブリンタンパク質であるチューブリンの重合阻害によって有糸分裂中の微小管の形成を阻害することによって、細胞増殖を阻害する(Remillard et al (1975) Science 189:1002-1005;米国特許第5,208,020号)。メイタンシンおよびメイタンシノイドは非常に細胞傷害性が強いが、癌治療におけるそれらの臨床用途は、それらの腫瘍選択性の低さに主に起因するそれらの重度の全身副作用によって大いに制限されている。メイタンシンを用いた臨床試験は、中枢神経系および胃腸系に対する重篤な副作用が原因で中止された(Issel et al (1978) Can. Treatment. Rev. 5: 199-207。
いくつかの態様において、薬物はオーリスタチン、例えばオーリスタチンE(当技術分野においてはドラスタチン-10の誘導体としても知られる)またはそれらの誘導体である。オーリスタチンは、例えば、アウリスタチンEとケト酸との間で形成されるエステルであってよい。例えば、アウリスタチンEは、パラアセチル安息香酸またはベンゾイル吉草酸と反応して、それぞれAEBおよびAEVBを生成することができる。他の典型的なアウリスタチンには、AFP、MMAF、およびMMAEが含まれる。例示的なアウリスタチンの合成および構造は、米国特許第6,884,869号、第7,098,308号、第7,256,257号、第7,423,116号、第7,498,298号および第7,745,394号に記載されており、これらはそれぞれその全体があらゆる目的で参照により本明細書に組み入れられる。
いくつかの態様において、二重特異性抗原結合性構築物は化学療法薬とコンジュゲートされる。その例には、シスプラチンおよびラパチニブが非限定的に含まれる。「化学療法薬」とは、癌の治療において有用な化合物のことである。
ある態様において、本明細書に記載の構築物は、本明細書においてさらに詳細に説明する1つまたは複数の生物活性を試験するためのアッセイに用いられる。構築物が特定のアッセイにおいて活性を示す場合、抗原結合性構築物によって構成される抗原結合性構築物は、その生物活性と関連のある疾患に関係している可能性がある。このため、この構築物は、その関連疾患の治療に利用される。
本明細書には、癌を治療するための医薬品の製造のための、本明細書に記載の抗原結合性構築物の使用が提供される。また、免疫系障害に対する医薬品の製造のための、本明細書に記載の抗原結合性構築物も提供される。ある態様においては、腫瘍の増殖を阻害するための医薬品の製造のための、本明細書に記載の抗原結合性構築物の使用がある。ある態様においては、腫瘍を縮小させるための医薬品の製造のための、本明細書に記載の抗原結合性構築物の使用がある。
また、抗原結合性構築物と薬学的に許容される担体とを含む薬学的組成物も含まれる。
本明細書に記載の二重特異性抗原結合性構築物は、対象、例えばヒトに投与することができる。
本明細書に記載の抗原結合性構築物または薬学的組成物は、ヒトに用いる前に、所望の治療的または予防処置的活性に関して、インビトロで、続いてインビボで試験される。例えば、化合物または薬学的組成物の治療的または予防処置的な有用性を実証するためのインビトロアッセイには、細胞株または患者組織試料に対する化合物の効果が含まれる。細胞株および/または組織試料に対する化合物または組成物の効果は、ロゼット形成アッセイおよび細胞溶解アッセイを非限定的に含む、当業者に公知の手法を利用して判定することができる。本発明によれば、特定の化合物の投与が適応となるか否かを判定するために用いうるインビトロアッセイには、患者組織試料を培養下で増殖させ、抗原結合性構築物に曝露させるかまたはそれを別の様式で投与した上で、組織試料に対するそのような抗原結合性構築物の効果を観察する、インビトロ細胞培養アッセイが含まれる。
McDonagh et al Mol Cancer Ther. 2012 Mar;11(3):582-93
Subik et al. (2010) Breast Cancer: Basic Clinical Research:4; 35-41
Anido et al Clin Cancer Res. 2003 Apr;9(4):1274-83
Neve et al Cancer Cell 2006 10:515-527
Dragowska et al BMC Cancer 2011 11:420
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いくつかの例示的な二重特異性抗原結合性構築物、例えば、抗原結合性構築物および対照を、以下に説明する通りに設計した。
実施例1に記載された構築物を、以下の通りにCHO細胞において発現させて精製した。清澄化培養培地をMabSelect SuRe(商標)(GE Healthcare)プロテインAカラムにロードし、10カラム体積のPBS緩衝液、pH 7.2で洗浄した。抗原結合性構築物を10カラム体積のクエン酸緩衝液、pH 3.6で溶出させ、抗体を含有するプール画分をTRIS、pH 11で中和した。図1は、プロテインA精製後の、一価抗体対照変異体878(図1A)および変異体879(図1B)、ならびにbsAb変異体880(図1C)に関するSDS-PAGE分析の結果を示している。この図に示された3つのゲルにおいて、レーン1は発現された全タンパク質を表し、レーン2はフロースルー画分を表し、レーン3は洗浄液、レーン4は精製された画分を表している。これらの結果は、一価対照抗体およびbsAb変異体880がCHO細胞において良好に発現されること、およびプロテインA精製後に約80%の純度に精製されることを示している。
bsAb変異体880の精製および収量を、上記の通りのプロテインA精製およびSEC精製後にLCMSによって試験した。
例示的なbsAbである変異体880の純度を、LCMSを標準的な条件下で用いて決定した。LC-MSへのローディングの前に、PNGasFによって抗体を脱グリコシル化した。液体クロマトグラフィーは、Agilent 1100 Series HPLCにて以下の条件下で実施した。
流速:分離ポストカラムでの1mL/分からMSへの100uL/分まで
溶媒:A=ddH2O中の0.1%ギ酸、B=65%アセトニトリル、25% THF、9.9% ddH2O、0.1%ギ酸
カラム:2.1×30mm PorosR2
カラム温度:80℃ ;溶媒も予熱
勾配:20% B(0〜3分)、20〜90% B(3〜6分)、90〜20% B(6〜7分)、20% B(7〜9分)
質量分析法(MS)を、引き続いて、次の条件下でLTQ-Orbitrap XL質量分析計にて実施した:
イオン化法:イオンマックスエレクトロスプレー
較正および調整方法:CsIの2mg/mL溶液を、10μL/分の流速で注入する。Orbitrapを、続いて、Automatic Tune機能を使用してm/z 2211で調整する(観測される全体的なCsIイオン範囲:1690〜2800)。
コーン電圧:40V
チューブレンズ:115V
FT分解能:7,500
スキャン範囲 m/z 400〜4000
スキャン遅延:1.5分
例示的なbsAbである変異体880が、HER2およびHER3という両方の標的と結合する能力を、以下の通りにBIO-RADによるProteOn(商標)XPR36システムを用いるSPR(表面プラズモン共鳴)によって判定した。緩衝液(10mM Hepes pH 6.8)中のHER-2を、アミンカップリングを通じて3000 RUとなるまでCM5チップに固定化した。抗HER2抗体を含有する抗体形式にあるFc変異体を300 RUとなるまでHER-2表面に固定化した。泳動緩衝液および界面活性剤をpH6.8に維持した。精製された分析物Her3をこの泳動緩衝液中に希釈し、20〜30μL/分の流速で2分間注入した後、さらに4分間かけて解離させた。20nMで開始する各抗体の5つの2倍希釈物を三重反復試験にて分析した。センサグラムを1:1 Langmuir結合モデルに全体的に適合させた。すべての実験は室温で行った。
例示的なbsAbである変異体880がHER2/3低発現性細胞株と結合する能力を、細胞株MALME-3Mにおけるフローサイトメトリーによって決定した。FACS分析は下記の通りに実施した。
例示的なbsAbである変異体880がHER2およびHER3受容体をさまざまな細胞密度で発現する細胞株と結合する能力を、細胞株SKOV-ATCCおよびMALME-3Mにおけるフローサイトメトリーによって決定した。表xxは、これらの細胞株におけるHER2およびHER3の相対発現レベルを特定している。FACS分析は、実施例4に記載した通りに行った。
例示的なbsAb変異体880がADCC媒介性細胞死滅を導く能力を、下記の方法に従って、ヒトトリプルネガティブ乳癌細胞株MDA-MB-231において評価した。
MDA-MB-231標的細胞を、800rpmで3分間の遠心処理によって採取した。細胞をアッセイ培地で1回洗浄して遠心処理を行い、ペレットよりも上にある培地を完全に除去した。細胞をアッセイ培地で穏やかに懸濁させて、単細胞溶液を作製した。細胞の数は4倍細胞ストック(50μlのアッセイ培地中に細胞10,000個)に調節した。続いて被験抗体を、上述した所望の濃度まで希釈した。
細胞溶解のパーセンテージを、以下の式に従って計算した。
細胞溶解率(%)=100*(実験データ-(E+T))/(最大放出-最小放出)。
データはGraphpad(v4.0)によって提示し、分析した。
例示的なbsAb変異体880がADCC媒介性細胞死滅を導く能力を、HER2低発現性MCF7細胞株において、実施例6に記載した方法に従って評価した。
いくつかのさらなる抗HER2-HER3二重特異性抗体(bsAb)および対照を設計して調製した。図10は、試験した抗HER2-HER3 bsAbおよび対照のDNA配列組成を列記しており、以下の表2は、被験抗体のエピトープおよび参照文献情報を提示している。
以下の通りに、実施例8に記載された抗HER2-HER3 bsAbおよび対照をクローニングし、50mL培養物において発現させて、精製した。抗体重鎖および軽鎖をコードする遺伝子を、ヒト/哺乳動物での発現のために最適化されたコドンを用いた遺伝子合成を介して構築した。最終的な遺伝子産物を哺乳動物発現ベクターpTT5(NRC-BRI、Canada)中にサブクローニングして、CHO細胞において発現させた(Durocher, Y., Perret, S. & Kamen, A. High-level and high-throughput recombinant protein production by transient transfection of suspension-growing CHO cells. Nucleic acids research 30, E9 (2002))。
例示的なbsAbであるv4248を、生産の拡張性および大規模製造性について評価するために、一過性CHO細胞培養物において最大25Lとして発現させた。抗体の発現および精製は上記の方法を用いて行った。
例示的なbsAbであるv4248を、一段階手順を用いて、抗体-薬物コンジュゲート(ADC)としてコンジュゲートさせた。
抗体変異体の安定性を融解温度に基づいて評価するために、示差走査熱量測定(DSC)を行った。
通常のbsAbおよびアフコシル化bsAbのFcγR結合能力を実証するために、いくつかのヒトFcγRに対する例示的な抗体の結合親和性を、Bio-RadによるProteOn(商標)XPR36システムを用いる表面プラズモン共鳴(SPR)によって測定した。
HER2およびHER3をさまざまなレベルで発現する種々のヒト腫瘍細胞株に対する、例示的なbsAbであるv4248の結合を、フローサイトメトリーによって評価し、親である単一特異性二価抗体対照であるv506と比較した。試験した細胞株であるBT-474、SKOV3、JIMT1、MDA-MB-231およびMCF7の起源および受容体発現レベルは表A1に記載されている。
標的抗原結合に対してコンジュゲーションの影響があるか否かを判定する目的で、bsADC v6362が細胞と結合する能力を評価した。実験は、実施例14に記載された通りに実施した。
下記の通りに、ヒト腫瘍細胞株SK-BR-3、JIMT1、SKOV3およびMDA-MB-231において、bsAb 4248および7186がADCCを媒介する能力を、単一特異性二価抗HER2対照抗体と比較して測定した。対照抗体ハーセプチン(商標)はRocheから購入した。
細胞溶解率(%)=100%×(OD試料-OD非特異)/(ODmax-ODmin)
例示的な抗HER2-HER3 bsAbが、HER2 3+ヒト乳癌細胞株BT-474の増殖を阻害する能力を、以下の通りに評価した。これらのbsAbがヘレグリンの増殖刺激効果を中和する能力を判定するために、外因性ヘレグリンの添加について試験した。
細胞増殖率(%)=100%×(RLU試料)/(RLU非処置)
種々の癌細胞株におけるbsAb取り込みのレベルを決定するために、内部移行アッセイを行った。抗体をヒト腫瘍細胞BT-474、JIMT1およびSKOV3とともにインキュベートすることによって誘導される標的受容体のアップレギュレーションまたはダウンレギュレーションと関係する可能性がある、細胞表面結合のレベルの変化についても評価した。
消光効率=QE=1-(Q4/U4)
初期表面受容体レベル=Si=U4
最終表面受容体レベル=Sf=(U37-Q37)/QE
抗体内部移行/蓄積=I=U37-Sf
標的受容体を発現するJIMT1細胞における例示的なbsAbの内部移行を描出し、標的腫瘍細胞内の抗体局在の詳細を明らかにするために、共焦点顕微鏡検査を行った。
bsADC v6362を用いるインビトロ増殖阻害アッセイを、癌細胞株SKOV3、JIMT1およびMDA-MB-231の死滅または増殖阻害におけるその効力および有効性を判定するために行った。実施例17に記載された増殖阻害アッセイに関するものと同じ様式で、細胞を処理し、細胞生存度測定を行った。
外因性増殖因子による刺激下で、ある種のヒト癌細胞はADCによる治療に対してより抵抗性になることがあり、これはインビトロでヘレグリンによって外因性に刺激したBT-474細胞でも同様である(Lewis Phillips et al, Clin Cancer Res 2014 20; 456)。HER2 3+ヒト乳癌細胞BT-474における例示的なbsADCであるv6362の増殖阻害特性を、増殖因子の存在下および非存在下において評価した。
例示的な抗HER2-HER3 bsAbおよびbsADCが、HER2 3+ヒト胃細胞株に対する外因性ヘレグリンによる増殖誘発を中和する能力を、以下の通りに評価した。
臨床的には、トラスツズマブ治療に伴って症例の2〜7%で心機能不全がみられる。心筋症のリスクは、治療を、単独でも心毒性があるドキソルビシンなどのアントラサイクリン化学療法と併用した場合に増大する。このため、同じくHER2を標的とするbsAbによって引き起こされる、より有害な恐れのある毒性作用を同定するために、心筋細胞に対する増殖阻害アッセイを行った。
このインビボ実験は、bsADCの腫瘍増殖阻害有効性を単一特異性抗体対照と比較して判定することを目的とした。トラスツズマブおよび化学療法に抵抗性のT226異種移植モデルを、炎症性表現型を有するHER23+、HER3+、HRG+、EGFR+原発性乳癌から導き出して、例示的な抗HER2-HER3 bsADCの抗腫瘍有効性を評価するために用いた。
このインビボ実験は、抗HER2抵抗性を獲得したモデルにおけるbsADCの腫瘍増殖阻害有効性を判定することを目的とした。トラスツズマブおよび化学療法に抵抗性のT226異種移植モデルを、炎症性表現型を有するHER23+、HER3+、HRG+、EGFR原発性乳癌から導き出して、例示的な抗HER2-HER3 bsADCの抗腫瘍有効性を評価するために用いた。
このインビボ実験は、bsADCの腫瘍増殖阻害有効性を、単一特異性抗体対照と比較して判定することを目的とした。トラスツズマブおよび化学療法に抵抗性のHBCx-13b異種移植モデルを、浸潤性乳管癌のHER23+、HER3+、HRG+転移性病変から導き出して、v6362の抗腫瘍有効性を評価するために用いた。
このインビボ実験は、bsADCの腫瘍増殖阻害有効性を、単一特異性抗体対照と比較して判定することを目的とした。トラスツズマブおよび化学療法に抵抗性のHBCx-5異種移植モデルを、悪液質を伴うHER23+、HER3+乳癌から導き出して、v6362の抗腫瘍有効性を評価するために用いた。
このインビボ実験は、v6246に対する抵抗性を獲得したモデルにおけるbsADCの腫瘍増殖阻害有効性を判定することを目的とした。トラスツズマブおよび化学療法に抵抗性のHBCx-13b異種移植モデルを、浸潤性乳管癌のHER23+、HER3+転移性病変から導き出して、v6362の抗腫瘍有効性を評価するために用いた。
このインビボ実験は、MDA-MB-231皮下腫瘍を保有する動物における血液循環中血小板数に対するv6362の効果を判定することを目的とした。
Claims (60)
- HER2(ヒト上皮増殖因子受容体2)の細胞外ドメイン4(ECD4)と一価でかつ特異的に結合する第1の抗原結合性ポリペプチド構築物;
HER3(ヒト上皮増殖因子受容体3)の細胞外ドメイン(ECD)と一価でかつ特異的に結合する第2の抗原結合性ポリペプチド構築物;
第1のCH3ドメインを含む第1のFcポリペプチドおよび第2のCH3ドメインを含む第2のFcポリペプチドを含み、第1のFcポリペプチドが第1の抗原結合性ポリペプチド構築物のC末端とリンカーを伴ってまたは伴わずに連結されており、第2のFcポリペプチドが第2の抗原結合性ポリペプチド構築物のC末端とリンカーを伴ってまたは伴わずに連結されている、Fc
を含む、単離された二重特異性抗原結合性構築物であって、
第1の抗原結合性ポリペプチド構築物がFab型でありかつ第2の抗原結合性ポリペプチド構築物がscFv型であるか、または第1の抗原結合性ポリペプチド構築物がscFv型でありかつ第2の抗原結合性ポリペプチド構築物がFab型であり、かつ
HER2およびHER3を発現する細胞において、2つの第1の抗原結合性ポリペプチド構築物または2つの第2の抗原結合性ポリペプチド構築物を含む参照二価単一特異性抗体と比較して、より大きな最大結合(Bmax)を呈する、単離された二重特異性抗原結合性構築物。 - v4248からなる、請求項1記載の単離された二重特異性抗原結合性構築物。
- i.第1の抗原結合性ポリペプチド構築物が、v4248のVH1を含む第1のVHおよびv4248のVL1を含む第1のVLを含むFab型であり;
ii.第2の抗原結合性ポリペプチド構築物が、v4248のVH2を含む第2のVHおよびv4248のVL2を含む第2のVLを含むscFv型をとる、請求項1記載の単離された二重特異性抗原結合性構築物。 - 第1の抗原結合性ポリペプチド構築物が、以下:
i.トラスツズマブの3つのVH CDR配列に対して少なくとも95%同一なアミノ酸配列を含む3つのCDR配列を含むポリペプチド構築物;
ii.トラスツズマブの3つのVH CDR配列に対して100%同一なアミノ酸配列を含む3つのCDR配列を含むポリペプチド構築物;
iii.トラスツズマブの3つのVL CDR配列に対して少なくとも95%同一なアミノ酸配列を含む3つのCDR配列を含むポリペプチド構築物;
iv.トラスツズマブの3つのVL CDR配列に対して100%同一なアミノ酸配列を含む3つのCDR配列を含むポリペプチド構築物;
v.トラスツズマブの6つのCDR配列に対して少なくとも95%同一なアミノ酸配列を含む6つのCDR配列を含むポリペプチド構築物;
vi.トラスツズマブの6つのCDR配列に対して100%同一なアミノ酸配列を含む6つのCDR配列を含むポリペプチド構築物;
vii.トラスツズマブのVH配列に対して少なくとも95%同一であるアミノ酸配列を含む第1のポリペプチドおよびトラスツズマブのVL配列に対して少なくとも95%同一であるアミノ酸配列を含む第2のポリペプチドを含むポリペプチド構築物;
viii.トラスツズマブのVH配列に対して100%同一であるアミノ酸配列を含む第1のポリペプチドおよびトラスツズマブのVL配列に対して100%同一であるアミノ酸配列を含む第2のポリペプチドを含むポリペプチド構築物;ならびに
ix.HER2の4D5エピトープと結合するポリペプチド;
x.HER2 ECD4に対するトラスツズマブの結合を50%またはそれを上回って遮断するポリペプチド構築物
から選択される、請求項1記載の単離された二重特異性抗原結合性構築物。 - 第2の抗原結合性ポリペプチド構築物が、以下:
i.H3の3つのVH CDR配列に対して少なくとも95%同一なアミノ酸配列を含む3つのCDR配列を含むポリペプチド構築物;
ii.H3の3つのVH CDR配列に対して100%同一なアミノ酸配列を含む3つのCDR配列を含むポリペプチド構築物;
iii.H3の3つのVL CDR配列に対して少なくとも95%同一なアミノ酸配列を含む3つのCDR配列を含むポリペプチド構築物;
iv.H3の3つのVL CDR配列に対して100%同一なアミノ酸配列を含む3つのCDR配列を含むポリペプチド構築物;
v.H3の6つのCDR配列に対して少なくとも95%同一なアミノ酸配列を含む6つのCDR配列を含むポリペプチド構築物;
vi.H3の6つのCDR配列に対して100%同一なアミノ酸配列を含む6つのCDR配列を含むポリペプチド構築物;
vii.H3のVH配列に対して少なくとも95%同一であるアミノ酸配列を含む第1のポリペプチドおよびH3のVL配列に対して少なくとも95%同一であるアミノ酸配列を含む第2のポリペプチドを含むポリペプチド構築物;
viii.H3のVH配列に対して少なくとも100%同一であるアミノ酸配列を含む第1のポリペプチドおよびH3のVL配列に対して少なくとも100%同一であるアミノ酸配列を含む第2のポリペプチドを含むポリペプチド構築物;
ix.HER3のECDに対する抗HER3 scFv H3の結合を50%またはそれを上回って遮断するポリペプチド構築物;ならびに
x.HER3のECDに対する結合をめぐってヘレグリンと競合するポリペプチド構築物
から選択される、請求項1または請求項4記載の単離された二重特異性抗原結合性構築物。 - 第1の抗原結合性ポリペプチド構築物がFab型をとって第2の抗原結合性ポリペプチド構築物がscFv型をとる、請求項1〜5のいずれか一項記載の単離された二重特異性抗原結合性構築物。
- 第1の抗原結合性ポリペプチド構築物がscFv型をとって第2の抗原結合性ポリペプチド構築物がFab型をとる、請求項1、4または5記載の単離された二重特異性抗原結合性構築物。
- 第1の抗原結合性ポリペプチド構築物がscFv型をとって第2の抗原結合性ポリペプチド構築物がFab型をとり、かつ第2の抗原結合性ポリペプチド構築物がλ定常軽鎖(CL)アミノ酸配列を含む、請求項1、4または5記載の単離された二重特異性抗原結合性構築物。
- 第1の抗原結合性ポリペプチド構築物がscFv型をとって第2の抗原結合性ポリペプチド構築物がFab型をとり、かつ第2の抗原結合性ポリペプチド構築物がκCLアミノ酸配列を含む、請求項1、4または5記載の単離された二重特異性抗原結合性構築物。
- scFv型をとる抗原結合性ポリペプチド構築物が、VH配列とVL配列との間へのジスルフィド結合の追加によって、またはscFvの表面疎水性を低下させることによって安定化されている、請求項1〜9のいずれか一項記載の単離された二重特異性抗原結合性構築物。
- Fcが、IgG1、IgG2、IgG3、IgG4、IgAおよびIgEを含む任意のクラス、またはIgG1、IgG2、IgG3もしくはIgG4を含むIgGサブクラスのいずれか、またはそれらの組み合わせであるFcに由来する、請求項1〜10のいずれか一項記載の単離された二重特異性抗原結合性構築物。
- 少なくとも1つのCH3ドメインが、野生型ホモ二量体Fcと同等の安定性を有するヘテロ二量体Fcの形成を促進する少なくとも1つのアミノ酸改変を含む、請求項1〜11のいずれか一項記載の単離された二重特異性抗原結合性構築物。
- ヘテロ二量体Fcの二量体化したCH3ドメインが、示差走査熱量測定(DSC)による測定で、約68、69、70、71、72、73、74、75、76、77、77.5、78、79、80、81、82、83、84もしくは85℃またはそれよりも高い融解温度(Tm)を有する、請求項12記載の単離された二重特異性抗原結合性構築物。
- 二量体Fcが、産生された場合に約75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98もしくは99%を上回る純度を有するヘテロ二量体形態である;またはFcが、発現された場合もしくは単細胞を介して発現された場合に約75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98もしくは99%を上回る純度を有するヘテロ二量体形態である、請求項12または13のいずれか一項記載の単離された二重特異性抗原結合性構築物。
- i.500nMもしくはそれ未満の解離定数(KD)でHER2と結合する;
ii.500nMもしくはそれ未満のKDでHER3と結合する;
iii.HER3をより低活性のコンフォメーションにする;
iv.活性HER2-HER3ヘテロ二量体シグナル伝達を50〜100%阻害する;
v.EGFR-HER3ヘテロ二量体シグナル伝達を少なくとも50%阻害する;
vi.HER3の、ヘレグリンにより刺激されるシグナル伝達を最大で100%遮断する;
vii.増殖因子の存在下もしくは非存在下における癌細胞の増殖を阻害する;
viii.ヘレグリンの存在下における癌細胞の増殖を阻害する;
ix.HER2および/もしくはHER3を発現する癌細胞による内部移行を受ける;
x.HER2およびHER3を共発現する癌細胞において、参照二価単一特異性抗体と比較して内部移行の増大を示す;
xi.参照抗体と比較して、HER2および/もしくはHER3を発現する癌細胞に対するADCCの増大を媒介する;
xii.HER2および/もしくはHER3を発現する乳癌細胞、卵巣癌細胞および胃癌細胞に対するADCCの増大を媒介する;
xiii.HER2高発現、中発現もしくは低発現細胞、トリプルネガティブ乳癌細胞、エストロゲン受容体陽性乳癌細胞、およびトラスツズマブ抵抗性乳癌細胞から選択される、HER2および/もしくはHER3を発現する乳癌細胞に対するADCCの増大を媒介する;
xiv.癌を引き起こすことが知られている突然変異を含む、HER2および/もしくはHER3を発現する癌細胞に対するADCCの増大を媒介する;ならびに/または
xv.FcγRIIIaF、FcγRIIIaV、FcγRIIaH、FcγRIIaR、FcγRIIbY、FcγRIA、およびC1qのうち1つもしくは複数と結合する、請求項1〜14のいずれか一項記載の単離された二重特異性抗原結合性構築物。 - アフコシル化されている、請求項1〜15のいずれか一項記載の単離された二重特異性抗原結合性構築物。
- 検出可能な標識または薬物とコンジュゲートされている、請求項1〜16のいずれか一項記載の単離された二重特異性抗原結合性構築物。
- 検出可能な標識が放射性化合物、蛍光性化合物、酵素、基質、エピトープタグまたは毒素である、請求項17記載の単離された二重特異性抗原結合性構築物。
- 薬物が毒素、化学療法剤、免疫調節薬、または放射性同位体である、請求項17記載の単離された二重特異性抗原結合性構築物。
- 薬物が、メイタンシン、オーリスタチン、カリケアマイシン、またはそれらの誘導体から選択される、請求項17記載の単離された二重特異性抗原結合性構築物。
- 薬物が、DM1およびDM4から選択されるメイタンシンである、請求項17記載の単離された二重特異性抗原結合性構築物。
- 毒素が、SMCCリンカー(DM1)またはSPDBリンカー(DM4)によって、単離された二重特異性抗原結合性構築物とコンジュゲートされている、請求項21記載の単離された二重特異性抗原結合性構築物。
- 薬物-抗体比(DAR)が1.0〜6.0または3.0〜5.0または3.5〜4.2である、請求項21〜22のいずれか一項記載の単離された二重特異性抗原結合性構築物。
- 請求項1〜23のいずれか一項記載の単離された二重特異性抗原結合性構築物と、薬学的担体とを含む、薬学的組成物。
- 担体が、緩衝剤、抗酸化剤、低分子量分子、薬物、タンパク質、アミノ酸、糖質、脂質、キレート剤、安定化剤、または賦形剤を含む、請求項25記載の薬学的組成物。
- HER2およびHER3を発現する癌細胞の増殖を阻害する方法であって、癌細胞を、請求項1〜23のいずれか一項記載の単離された二重特異性抗原結合性構築物の有効量と、癌細胞の増殖を阻害するのに十分な条件下で接触させる段階を含む、方法。
- 癌細胞が乳癌細胞である、請求項26記載の方法。
- 乳癌細胞が、HER2を3+で発現する乳癌細胞である、請求項27記載の方法。
- 免疫組織化学による測定で乳癌細胞がHER2および/もしくはHER3を高レベルで発現するか、またはHER2および/もしくはHER3の遺伝子が該癌細胞において増幅されている、請求項27記載の方法。
- 癌細胞における抗体依存性細胞性細胞傷害作用(ADCC)を誘導する方法であって、癌細胞を、請求項1〜23のいずれか一項記載の単離された二重特異性抗原結合性構築物の有効量と、癌細胞におけるADCCを誘導するのに十分な条件下で接触させる段階を含む、方法。
- 哺乳動物における、HER2およびHER3を発現する1つまたは複数の腫瘍細胞の増殖(growth)および/または増殖(proliferation)を阻害する方法であって、以下の段階を含む、方法:
請求項1〜23のいずれか一項記載の単離された二重特異性抗原結合性構築物または請求項24もしくは25記載の薬学的組成物の有効量を哺乳動物に投与する段階であって、それによって、哺乳動物における、HER2およびHER3を発現する1つまたは複数の腫瘍細胞の増殖(growth)および/または増殖(proliferation)を阻害する、段階。 - 哺乳動物における、HER2および/またはHER3の過剰発現によって特徴づけられる腫瘍を治療する方法であって、以下の段階を含む、方法:
請求項1〜23のいずれか一項記載の単離された二重特異性抗原結合性構築物または請求項24もしくは25記載の薬学的組成物の有効量を哺乳動物に投与する段階であって、それによって、哺乳動物における、HER2および/またはHER3の過剰発現によって特徴づけられる腫瘍を治療する、段階。 - 哺乳動物における、低レベルのHER2および/またはHER3を発現する腫瘍を治療する方法であって、以下の段階を含む、方法:
請求項1〜23のいずれか一項記載の単離された二重特異性抗原結合性構築物または請求項24もしくは25記載の薬学的組成物の有効量を哺乳動物に投与する段階であって、それによって、哺乳動物における、低レベルのHER2および/またはHER3を発現する腫瘍を治療する、段階。 - 哺乳動物における、HER2およびHER3を共発現する腫瘍を治療する方法であって、以下の段階を含む、方法:
請求項1〜23のいずれか一項記載の単離された二重特異性抗原結合性構築物または請求項24もしくは25記載の薬学的組成物の有効量を哺乳動物に投与する段階であって、それによって、哺乳動物における、HER2およびHER3を共発現する腫瘍を治療する、段階。 - 腫瘍が、乳癌、結腸直腸癌、肝癌、卵巣癌、膵癌、前立腺癌、胃癌、または肺癌腫瘍である、請求項31〜34のいずれか一項記載の方法。
- 腫瘍が乳癌腫瘍である、請求項31〜34のいずれか一項記載の方法。
- 乳癌が、基底細胞様乳癌、HER2リッチ(HER2-enriched)乳癌、ルミナルA乳癌、ルミナルB乳癌、または正常様トリプルネガティブ乳癌から選択されるトリプルネガティブ乳癌である、請求項36記載の方法。
- 腫瘍が、エストロゲン受容体陽性(ER+)BRCA関連乳癌、結腸直腸腺癌、肝臓の肝細胞癌、膵臓腺癌、前立腺腺癌、胃腺癌、または肺腺癌腫瘍である、請求項31〜34のいずれか一項記載の方法。
- 腫瘍が、トラスツズマブ、ペルツズマブ、トラスツズマブエムタンシン(T-DM1)、およびそれらの組み合わせから選択される抗HER2抗体治療に対して不応性または抵抗性である、請求項31〜38のいずれか一項記載の方法。
- 腫瘍が、抗HER3抗体、ラパチニブ、エルロチニブ、ゲフィニチブ、またはerbBファミリーシグナル伝達の他の小分子阻害薬に対して不応性または抵抗性である、請求項31〜38のいずれか一項記載の方法。
- 腫瘍が化学療法に対して不応性である、請求項31〜40のいずれか一項記載の方法。
- 腫瘍がHER2を1+、2+または3+のレベルで発現する、請求項31〜41のいずれか一項記載の方法。
- 哺乳動物がヒトまたは非ヒト霊長動物である、請求項31〜42のいずれか一項記載の方法。
- 腫瘍に対して細胞分裂抑制性であるかまたは腫瘍に対して細胞傷害性である、請求項31〜43のいずれか一項記載の方法。
- 哺乳動物の全生存期間を増加させる、請求項31〜44のいずれか一項記載の方法。
- 投与する段階が、静脈内注射、腹腔内注射、または皮下注射による、請求項31〜45のいずれか一項記載の方法。
- 投与する段階が、初回負荷量と、その後の間隔を置いたより少量の維持量を含む、請求項31〜46のいずれか一項記載の方法。
- 負荷量が最大で最大耐量(MTD)であり、維持量が最大で10mg/kgであって間隔が7日間程度の短さである(DM1の場合のみ)、請求項47記載の方法。
- 二重特異性抗原結合性構築物または薬学的組成物が他の治療剤と組み合わせて投与される、請求項31〜48のいずれか一項記載の方法。
- 他の治療剤が、ペルツズマブ、セツキシマブ、または有効量の抗エストロゲン薬(例えば、タモキシフェン、レトロゾール)、キナーゼ阻害薬(ラパチニブ、エルロチニブ)、mTOR阻害薬、もしくは化学療法剤(例えば、カペシタビンおよび/もしくはシスプラチン)から選択される、請求項49記載の方法。
- 請求項1〜15のいずれか一項記載の単離された二重特異性抗原結合性構築物を生産する方法であって、以下の段階を含む、方法:
二重特異性抗原結合性構築物を発現するのに適した条件下で宿主細胞を培養する段階であって、宿主細胞が請求項1〜15のいずれか一項記載の単離された二重特異性抗原結合性構築物をコードするポリヌクレオチドを含む、段階、および
二重特異性抗体構築物を精製する段階。 - 請求項1〜15のいずれか一項記載の単離された二重特異性抗原結合性構築物の少なくとも1つのポリペプチドをコードする少なくとも1つの核酸配列を含む、1つの単離されたポリヌクレオチドまたは単離されたポリヌクレオチドのセット。
- 1つのポリヌクレオチドまたはポリヌクレオチドのセットがcDNAである、請求項52記載の単離されたポリヌクレオチド。
- 請求項1〜15のいずれか一項記載の二重特異性抗原結合性構築物をコードする、1つの単離されたポリヌクレオチドまたは単離されたポリヌクレオチドのセット。
- 請求項52〜54のいずれか一項記載の1つのポリヌクレオチドまたはポリヌクレオチドのセットのうち、1つまたは複数を含む、1つのベクターまたはベクターのセット。
- プラスミド、ウイルスベクター、非エピソーム性哺乳動物ベクター、発現ベクターおよび組換え発現ベクターからなる群より選択される、請求項52〜54のいずれか一項記載の1つのポリヌクレオチドまたはポリヌクレオチドのセットのうち、1つまたは複数を含む、1つのベクターまたはベクターのセット。
- 請求項52〜54のいずれか一項記載の1つのポリヌクレオチドもしくはポリヌクレオチドのセット、または請求項55もしくは56記載の1つのベクターもしくはベクターのセットを含む、単離された細胞。
- ハイブリドーマ、チャイニーズハムスター卵巣(CHO)細胞、またはHEK293細胞である、請求項57記載の単離された細胞。
- 1つのポリヌクレオチド、ポリヌクレオチドのセット、1つのベクター、またはベクターのセットによって安定的にトランスフェクトされた、請求項57または58記載の単離された細胞。
- 細胞におけるHER2およびHER3の二量体化を阻害する方法であって、以下の段階を含む、方法:
細胞を請求項1〜23のいずれか一項記載の単離された二重特異性抗原結合性構築物の有効量と接触させる段階であって、それによって、細胞におけるHER2およびHER3の二量体化を阻害する、段階。
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2014
- 2014-05-08 CA CA2910945A patent/CA2910945A1/en not_active Abandoned
- 2014-05-08 WO PCT/US2014/037401 patent/WO2014182970A1/en active Application Filing
- 2014-05-08 JP JP2016513093A patent/JP2016520586A/ja not_active Withdrawn
- 2014-05-08 US US14/888,580 patent/US10239951B2/en not_active Expired - Fee Related
- 2014-05-08 EP EP14794897.0A patent/EP2994164B1/en active Active
- 2014-05-08 AU AU2014262566A patent/AU2014262566A1/en not_active Abandoned
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2021523100A (ja) * | 2018-04-30 | 2021-09-02 | リジェネロン・ファーマシューティカルズ・インコーポレイテッドRegeneron Pharmaceuticals, Inc. | Her2及び/またはaplp2に結合する抗体及び二重特異性抗原結合分子、ならびにそれらのコンジュゲート及び使用 |
JP7328990B2 (ja) | 2018-04-30 | 2023-08-17 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | Her2及び/またはaplp2に結合する抗体及び二重特異性抗原結合分子、ならびにそれらのコンジュゲート及び使用 |
Also Published As
Publication number | Publication date |
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EP2994164A4 (en) | 2017-01-04 |
AU2014262566A1 (en) | 2015-11-12 |
EP2994164A1 (en) | 2016-03-16 |
CA2910945A1 (en) | 2014-11-13 |
US10239951B2 (en) | 2019-03-26 |
WO2014182970A1 (en) | 2014-11-13 |
EP2994164B1 (en) | 2020-08-05 |
US20160083480A1 (en) | 2016-03-24 |
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