JP6242804B2 - ヒトcsf−1rに対する抗体及びその使用 - Google Patents
ヒトcsf−1rに対する抗体及びその使用 Download PDFInfo
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- JP6242804B2 JP6242804B2 JP2014546487A JP2014546487A JP6242804B2 JP 6242804 B2 JP6242804 B2 JP 6242804B2 JP 2014546487 A JP2014546487 A JP 2014546487A JP 2014546487 A JP2014546487 A JP 2014546487A JP 6242804 B2 JP6242804 B2 JP 6242804B2
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- 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
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
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Description
a)重鎖可変ドメインが、配列番号1のCDR3領域、配列番号2のCDR2領域、及び配列番号3のCDR1領域を含み、ならびに軽鎖可変ドメインが、配列番号4のCDR3領域、配列番号5のCDR2領域、及び配列番号6のCDR1領域を含むこと、もしくは
b)重鎖可変ドメインが、配列番号9のCDR3領域、配列番号10のCDR2領域、及び配列番号11のCDR1領域を含み、ならびに軽鎖可変ドメインが、配列番号12のCDR3領域、配列番号13のCDR2領域、及び配列番号14のCDR1領域を含むこと、又は
c)a)もしくはb)の抗体のCDR移植、ヒト化もしくはT細胞エピトープ枯渇抗体バリアント
を特徴とする。
同じエピトープへの結合は、インビトロ競合的結合阻害アッセイにおいて表面プラズモン共鳴(SPR)により25℃で測定され、
抗体は、以下の特性:
a)NIH3T3−野生型CSF−1R組換え細胞の増殖の、10μg/mlの抗体濃度で90%以上の阻害、及び
b)NIH3T3−変異体CSF−1R L301S Y969F組換え細胞の増殖の、10μg/mlの抗体濃度で60%以上の阻害
を有する。
a)重鎖可変ドメインが、配列番号1のCDR3領域、配列番号2のCDR2領域、及び配列番号3のCDR1領域を含み、ならびに軽鎖可変ドメインが配列番号4のCDR3領域、配列番号5のCDR2領域、及び配列番号6のCDR1領域を含むこと、もしくは
b)重鎖可変ドメインが、配列番号9のCDR3領域、配列番号10のCDR2領域、及び配列番号11のCDR1領域を含み、ならびに軽鎖可変ドメインが、配列番号12のCDR3領域、配列番号13のCDR2領域、及び配列番号14のCDR1領域を含むこと、又は
c)a)もしくはb)の抗体のCDR移植、ヒト化又はT細胞エピトープ枯渇抗体バリアント
を特徴とする。
a)重鎖可変ドメインが、配列番号1のCDR3領域、配列番号2のCDR2領域、及び配列番号3のCDR1領域を含み、ならびに軽鎖可変ドメインが、配列番号4のCDR3領域、配列番号5のCDR2領域、及び配列番号6のCDR1領域を含むこと、もしくは
b)重鎖可変ドメインが、配列番号9のCDR3領域、配列番号10のCDR2領域、及び配列番号11のCDR1領域を含み、ならびに軽鎖可変ドメインが、配列番号12のCDR3領域、配列番号13のCDR2領域、及び配列番号14のCDR1領域を含むこと、又は
c)a)もしくはb)の抗体のCDR移植、ヒト化又はT細胞エピトープ枯渇抗体バリアント
を特徴とする本発明による抗体をコードする核酸である。
a)重鎖可変ドメインが、配列番号1のCDR3領域、配列番号2のCDR2領域、及び配列番号3のCDR1領域を含み、ならびに軽鎖可変ドメインが、配列番号4のCDR3領域、配列番号5のCDR2領域、及び配列番号6のCDR1領域を含むこと、もしくは
b)重鎖可変ドメインが、配列番号9のCDR3領域、配列番号10のCDR2領域、及び配列番号11のCDR1領域を含み、ならびに軽鎖可変ドメインが、配列番号12のCDR3領域、配列番号13のCDR2領域、及び配列番号14のCDR1領域を含むこと、又は
c)a)もしくはb)の抗体のCDR移植、ヒト化もしくはT細胞エピトープ枯渇抗体バリアント
を特徴とする、前記抗体を含む。
a)NIH3T3−野生型CSF−1R組換え細胞の増殖の、10μg/mlの抗体濃度で90%以上の阻害(実施例2参照);
b)NIH3T3−変異体CSF−1R L301S Y969F組換え細胞の増殖の、10μg/mlの抗体濃度で60%以上の阻害((例えば実施例2参照);
c)CSF−1/CSF−1R相互作用の阻害(例えば15ng/ml以下のIC50値で、実施例3参照);
d)野生型NIH3T3‐CSF−1R組換え細胞におけるCSF−1誘導CSF−1Rリン酸化の阻害(例えば80ng/ml以下のIC50値で、実施例4参照);
e)BeWo腫瘍細胞の増殖の阻害(例えば10μg/mlの抗体濃度で80%以上、実施例7参照);
f)マクロファージ分化の阻害(例えば0.8nM以下のIC50値で、実施例8参照)。
a)NIH3T3−野生型CSF−1R組換え細胞の増殖の、10μg/mlの抗体濃度で90%以上の阻害(実施例2参照);
b)NIH3T3−変異体CSF−1R L301S Y969F組換え細胞の増殖の、10μg/mlの抗体濃度で60%以上の阻害((例えば実施例2参照);
c)CSF−1/CSF−1R相互作用の阻害(例えば15ng/ml以下のIC50値で、実施例3参照);
d)野生型NIH3T3−CSF−1R組換え細胞におけるCSF−1誘導CSF−1Rリン酸化の阻害(例えば80ng/ml以下のIC50値で、実施例4参照);
e)BeWo腫瘍細胞の増殖の阻害(例えば10μg/mlの抗体濃度で80%以上、実施例7参照);
f)マクロファージ分化の阻害(例えば0.8nM以下のIC50値で、実施例8参照)。
本発明による好ましいハイブリドーマ細胞株、ハイブリドーマ細胞株<CSF−1R>9D11.2Eは、特許手順上の微生物の寄託の国際的承認に関するブタペスト条約下、アクセッション番号DSM ACC 2920の下、2008年6月10日、Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH(DSMZ)、ドイツに寄託された。
配列番号1 重鎖CDR3、<CSF−1R>9D11.2E8
配列番号2 重鎖CDR2、<CSF−1R>9D11.2E8
配列番号3 重鎖CDR1、<CSF−1R>9D11.2E8
配列番号4 軽鎖CDR3、<CSF−1R>9D11.2E8
配列番号5 軽鎖CDR2、<CSF−1R>9D11.2E8
配列番号6 軽鎖CDR1、<CSF−1R>9D11.2E8
配列番号7 重鎖可変ドメイン、<CSF−1R>9D11.2E8
配列番号8 軽鎖可変ドメイン、<CSF−1R>9D11.2E8
配列番号9 重鎖CDR3、<CSF−1R>10H2.2F12
配列番号10 重鎖CDR2、<CSF−1R>10H2.2F12
配列番号11 重鎖CDR1、<CSF−1R>10H2.2F12
配列番号12 軽鎖CDR3、<CSF−1R>10H2.2F12
配列番号13 軽鎖CDR2、<CSF−1R>10H2.2F12
配列番号14 軽鎖CDR1、<CSF−1R>10H2.2F12
配列番号15 重鎖可変ドメイン、<CSF−1R>10H2.2F12
配列番号16 軽鎖可変ドメイン、<CSF−1R>10H2.2F12
配列番号17 γ1重鎖定常領域
配列番号18 κ軽鎖定常領域
配列番号19 IgG1に由来するヒト重鎖定常領域
配列番号20 L234A及びL235Aで変異したIgG1変異に由来するヒト重鎖定常領域
配列番号21 IgG4に由来するヒト重鎖定常領域
配列番号22 S228Pで変異したIgG4に由来するヒト重鎖定常領域
配列番号23 野生型CSF−1R(wt CSF−1R)
配列番号24 変異体CSF−1R L301S Y969F
以下の例、配列表及び図は、本発明の理解を助けるために提供され、その真の範囲は添付特許請求の範囲に記載されている。変更は、本発明の趣旨から逸脱することなく記載された手順において行われ得ることが理解される。
抗CSF−1R抗体を産生するハイブリドーマ細胞株の生成
NMRIマウスの免疫化手順
NMRIマウスは、エレクトロポレーションを利用してhuCSF−1Rの細胞外ドメインをコードする発現ベクターpDisplay(商標)(Invitrogen、USA)を用いて免疫化した。どのマウスも100μg DNAで4回免疫化した。抗huCSF−1Rの血清力価が十分であることがわかった場合、マウスを、融合の4及び3日前に静注で(i.v.)、200μl PBS中50μgの1:1混合物huCSF−1R ECD/huCSF−1R ECDhuFcキメラを用いて1回さらに追加免疫した。
免疫化マウスの血清中抗CSF−1R力価は、抗原特異的ELISAにより決定した。
マウスリンパ球は、単離し、PEGベースの標準的プロトコルを用いてマウス骨髄腫細胞株と融合させてハイブリドーマを生成することができる。得られたハイブリドーマを、次いで抗原特異的抗体の産生についてスクリーニングした。例えば、免疫化マウスからの脾臓由来リンパ球の単一細胞懸濁液を、50%PEGを用いてAg8非分泌マウス骨髄腫細胞P3X63Ag8.653(ATCC、CRL−1580)に融合させる。細胞を平底96ウェルマイクロタイタープレートに約104で播種し、この後選択培地で約2週間インキュベートした。個々のウェルを、次いでヒト抗CSF−1RモノクローナルIgM及びIgG抗体についてELISAによりスクリーニングした。広範なハイブリドーマ増殖が生じたら、抗体分泌ハイブリドーマを再播種し、再度スクリーニングし、及びヒトIgG、抗CSF−1Rモノクローナル抗体に対し依然として陽性であれば、FACSによりサブクローニングすることができる。安定なサブクローンを次いでインビトロで培養して、特徴づけのために組織培地で抗体を産生した。
生成muMAbハイブリドーマを、2mM L−グルタミン(GIBCO−Cat.No.35050−038)、1mMピルビン酸Na(GIBCO−Cat.No.11360−039)、1×NEAA(GIBCO−Cat.No.11140−035)、10%FCS(PAA−Cat.No.A15−649)、1×Pen Strep(Roche−Cat.No.1074440)、1×ニュートリドーマCS(Roche−Cat.No.1363743)、50μMメルカプトエタノール(GIBCO−Cat.No.31350−010)及び50U/ml IL 6マウス(Roche−Cat.No.1444581)を補充したRPMI 1640(PAN−カタログ番号(Cat.No.)PO4−17500)中で、37℃及び5%CO2で培養した。
抗CSF−1Rモノクローナル抗体で処理下の3D培養におけるNIH3T3−CSF−1R(野生型CSF−1R又は変異体CSF−1R L301S Y969F)組換え細胞の増殖阻害による抗体の選択(CellTiterGloアッセイ)
完全長の野生型CSF−1R(配列番号23)又は変異体CSF−1R L301S Y969F(配列番号24)のどちらかの発現ベクターにレトロウイルス感染したNIH3T3細胞(ATCC No.CRL−2795)を、プラスチック表面への接着を防ぐためのポリHEMA(ポリ(2−ヒドロキシエチルメタクリレート))(Polysciences、ウォリントン、PA、USA))被覆皿で、2mM L−グルタミン、2mMピルビン酸ナトリウム、及び非必須アミノ酸、及び10%ウシ胎仔血清(Sigma、タウフキルヘン、ドイツ)を補充したDMEM高グルコース培地(PAA、パシング、オーストリア)中で培養した。細胞は、血清を5ng/ml亜セレン酸ナトリウム、10mg/mlトランスフェリン、400μg/ml BSA及び0.05mM 2−メルカプトエタノールと置換した培地に播種する。100ng/ml huCSF−1(Biomol、ハンブルグ、ドイツ)で処理した場合、wtCSF−1R発現細胞は、足場非依存性と呼ばれる特性である、3次元的に増殖する高密度のスフェロイドを形成する。これらのスフェロイドは、インサイチュで固形腫瘍の3次元構造及び機構に酷似している。
CSF−1/CSF−1R相互作用(ELISA)の阻害
試験はRTで384ウェルマイクロタイタープレート(MicroCoat、DE、Cat.No.464718)で行った。各インキュベーションステップ後、プレートをPBSTで3回洗浄した。
NIH3T3−CSF−1R組換え細胞におけるCSF−1誘導CSF−1Rリン酸化の阻害
完全長CSF−1R(配列番号23)の発現ベクターにレトロウイルス感染した4.5×103NIH 3T3細胞を、DMEM(PAA Cat.No.E15−011)、2mM L−グルタミン(Sigma、Cat.No.G7513、2mMピルビン酸ナトリウム、1×非必須アミノ酸、10%FKS(PAA、Cat.No.A15−649)及び100μg/ml PenStrep(Sigma、Cat.No.P4333[10mg/ml])中でコンフルエンシーに達するまで培養した。その後、細胞を、亜セレン酸ナトリウム[5ng/ml](Sigma、Cat.No.S9133)、トランスフェリン[10μg/ml](Sigma、Cat.No.T8158)、BSA[400μg/ml](Roche Diagnostics GmbH、Cat.No.10735078)、4mM L−グルタミン(Sigma、Cat.No.G7513)、2mMピルビン酸ナトリウム(Gibco、Cat.No.11360)、1×非必須アミノ酸(Gibco、Cat:11140−035)、2−メルカプトエタノール[0.05mM](Merck、Cat.No.M7522)、100μg/ml及びPenStrep(Sigma、Cat.No.P4333)を補充した無血清DMEM培地(PAA Cat.No.E15−011)で洗浄し、30μlの同じ培地で16時間インキュベートして受容体アップレギュレーションを可能にした。10μlの希釈抗CSR−1R抗体を細胞に1.5h添加した。次いで細胞を、10μlの100ng/ml huM−CSF−1(Biomol Cat.No.60530)で5分間刺激した。インキュベーション後、上清を除去し、細胞を80μlの氷冷PBSで2回洗浄し、50μlの新しく調製した氷冷溶解緩衝液(150mM NaCl/20mM Tris pH7.5/1mM EDTA/1mM EGTA/1%Triton X−100/10ml緩衝液当たり1プロテアーゼ阻害剤タブレット(Roche Diagnostics GmbH Cat.No.1836170)/10μl/mlホスファターゼ阻害剤カクテル1(Sigma Cat.No.P−2850、100×Stock)/10μl/mlプロテアーゼ阻害剤1(Sigma Cat.No.P−5726、100×Stock)/10μl/ml 1M NaF)を添加した。氷上で30分後、プレートをプレート振盪器で3分間強く振盪し、次いで2200rpmで10分間遠心分離した(Heraeus Megafuge 10)。
CSF−1Rに対する抗CSF−1R抗体の親和性の決定
機器: BIACORE(登録商標)A100
チップ: CM5(Biacore BR−1006−68)
カップリング: アミンカップリング
緩衝液: PBS(Biacore BR−1006−72)、pH7.4、35℃
親和性測定に関して、36μg/ml抗マウスFcγ抗体(ヤギ由来、Jackson Immuno Research JIR115−005−071)を、CSF−1Rに対する抗体を捕捉するためにチップ表面にカップリングした。CSF−1R ECD(R&D−Systems 329−MR又は実験室内サブクローン化pCMV−presS−HisAvitag−hCSF−1R−ECDを、様々な濃度で溶液に添加した。結合は35℃で1.5分間、CSF−1R−注射により測定し、解離は35℃で10分間、チップ表面を緩衝液で洗浄して測定した。リガンド−受容体相互作用を阻害する抗CSF−IR SC−02、クローン2−4A5(Santa Cruz Biotechnology、US;Sherr,C.J.ら、Cell 41(1985)665−676頁も参照)を参照対照として使用した。
SPRの利用による交差競合に基づく抗CSF−1Rモノクローナル抗体のエピトープマッピング
機器: BIACORE(登録商標)A100
チップ: CM5(Biacore BR−1006−68)
カップリング: アミンカップリング
緩衝液: PBS(Biacore BR−1006−72)、pH7.4、25℃
交差競合によるエピトープマッピングアッセイに関して、36μg/ml抗マウスFcγ抗体又は抗ラットFcγ抗体(ヤギ由来、Jackson Immuno Research Cat.No.115−005−071及びCat.No.112−005−071)を、CSF−1Rに対する抗体の提示のためにセンサーチップ表面にカップリングした。5μg/ml抗CSF−1Rモノクローナル抗体からの捕捉後、捕捉抗体の遊離結合能力を250μg/mlマウス又はラット免疫グロブリン(Pierce Cat.No.31202及びPierce Cat.No.31233)でブロックし、その後12.5μg/ml CSF−1R(R&D−Systems Cat.No.329−MR)を2分間注射した。第2抗CSF−1R抗体の結合を2分間の注射により分析し、解離は緩衝液で5分間洗浄して測定した。アッセイ及び測定は25℃で行った。第2抗CSF−1R抗体の特異的結合を、同じチップ設定であるがCSF−1Rの注射のみをしないスポットに対して参照した。交差競合データは、第2抗CSF−1R抗体の予測結合応答のパーセンテージ(%)で計算した。第2抗体の結合に関する項目「予測結合応答のパーセンテージ(%)」は、「100*相対的Response(general_stability_early)/rMax」(rMaxは、Biacoreエピトープマッピング指示書(BIACORE(登録商標)A100機器の)に記載されている通り、「相対的Response(general_stability_late)*抗体分子量/抗原分子量」により計算される)により計算した。
抗CSF−1Rモノクローナル抗体で処理下の3D培養におけるBeWo腫瘍細胞の増殖阻害(CellTiterGlo−アッセイ)
BeWo絨毛腫細胞(ATCC CCL−98)を、10%FBS(Sigma)及び2mM L−グルタミンを補充したF12K培地(Sigma、シュタインハイム、ドイツ)中で培養した。5×104細胞/ウェルを、0.5%FBS及び5%BSAを補充したF12K培地を含有する96ウェルポリHEMA(ポリ(2−ヒドロキシエチルメタクリレート))被覆プレートに播種した。同時に、200ng/ml huCSF−1及び10μg/mlの異なる抗CSF−1Rモノクローナル抗体を添加し、6日間インキュベートした。CellTiterGloアッセイを用いて、相対発光量(RLU)での細胞のATP含量を測定して細胞の生存を検出した。BeWoスフェロイド培養物を、異なる抗CSF−1R抗体(10μg/ml)で処理した場合、CSF−1誘導増殖の阻害が観察された。抗体媒介阻害を計算するために、非刺激BeWo細胞の平均RLU値を全ての試料から減算した。CSF−1刺激細胞の平均RLU値は、100%に任意に設定した。CSF−1で刺激し、抗CSF−1R抗体で処理した細胞の平均RLU値は、CSF−1刺激RLUの%で計算した。表6は計算データを示し、図1は平均RLU値を示す。各平均値は3通りから得た。
抗CSF−1Rモノクローナル抗体で処理下のマクロファージ分化の阻害(CellTiterGlo−アッセイ)
単球は、RosetteSep(商標)Human Monocyte Enrichment Cocktail(StemCell Tech.−Cat.No.15028)を用いて末梢血から単離した。濃縮単球集団を、10 FCS(GIBCO−Cat.No.011−090014M)、4mM L−グルタミン(GIBCO−Cat.No.25030)及び1×PenStrep(Roche Cat.No.1074440)を補充した100μl RPMI 1640(Gibco−Cat.No.31870)中で、96ウェルマイクロタイタープレート(2.5×104細胞/ウェル)に37℃及び5%CO2で播種した。150ng/ml huCSF−1を該培地に添加した場合、接着マクロファージへの明らかな分化を観察することができた。この分化は、抗CSF−1R抗体の添加により阻害することができた。さらに、単球生存が影響され、CellTiterGlo(CTG)分析により分析することができた。抗体処理による単球の生存の濃度依存的阻害から、IC50を計算した(表7参照)。
Claims (16)
- CSF−1リガンド依存性及び/又はCSF−1リガンド非依存性CSF−1R発現細胞における細胞増殖の阻害のための薬剤であって、ヒトCSF−1Rに結合する抗体を含み、
a)重鎖可変ドメインが、配列番号1のCDR3領域、配列番号2のCDR2領域、及び配列番号3のCDR1領域を含み、ならびに軽鎖可変ドメインが、配列番号4のCDR3領域、配列番号5のCDR2領域、及び配列番号6のCDR1領域を含むこと、もしくは
b)重鎖可変ドメインが、配列番号9のCDR3領域、配列番号10のCDR2領域、及び配列番号11のCDR1領域を含み、ならびに軽鎖可変ドメインが、配列番号12のCDR3領域、配列番号13のCDR2領域、及び配列番号14のCDR1領域を含むこと、又は
c)a)もしくはb)の前記抗体のCDR移植、ヒト化又はT細胞エピトープ欠失抗体バリアント
を特徴とし、
該抗体が、以下の特性:
a)NIH3T3−野生型CSF−1R組換え細胞の増殖の、10μg/mlの抗体濃度で90%以上の阻害、及び
b)NIH3T3−変異体CSF−1R L301S Y969F組換え細胞の増殖の、10μg/mlの抗体濃度で60%以上の阻害
を有する、薬剤。 - CSF−1R発現細胞が癌細胞である、請求項1に記載の薬剤。
- ヒトCSF−1Rに結合する抗体であって、
a)重鎖可変ドメインが、配列番号1のCDR3領域、配列番号2のCDR2領域、及び配列番号3のCDR1領域を含み、ならびに軽鎖可変ドメインが、配列番号4のCDR3領域、配列番号5のCDR2領域、及び配列番号6のCDR1領域を含むこと、もしくは
b)重鎖可変ドメインが、配列番号9のCDR3領域、配列番号10のCDR2領域、及び配列番号11のCDR1領域を含み、ならびに軽鎖可変ドメインが、配列番号12のCDR3領域、配列番号13のCDR2領域、及び配列番号14のCDR1領域を含むこと、又は
c)a)もしくはb)の前記抗体のCDR移植、ヒト化又はT細胞エピトープ欠失抗体バリアント
を特徴とし、
該抗体が、以下の特性:
a)NIH3T3−野生型CSF−1R組換え細胞の増殖の、10μg/mlの抗体濃度で90%以上の阻害、及び
b)NIH3T3−変異体CSF−1R L301S Y969F組換え細胞の増殖の、10μg/mlの抗体濃度で60%以上の阻害
を有する、抗体。 - 前記抗体が、ヒトIgG4サブクラスである、又はヒトIgG1サブクラスであることを特徴とする、請求項3に記載の抗体。
- 請求項3又は4に記載の抗体又はその抗原結合性断片を含むことを特徴とする、薬学的組成物。
- 癌の治療のための医薬であって、請求項3又は4に記載の抗体を含む、医薬。
- 骨量減少の治療のための医薬であって、請求項3又は4に記載の抗体を含む、医薬。
- 癌の転移の予防又は治療のための医薬であって、請求項3又は4に記載の抗体を含む、医薬。
- 炎症性疾患の治療のための医薬であって、請求項3又は4に記載の抗体を含む、医薬。
- 前記抗体が、請求項3に記載の重鎖及び軽鎖可変ドメインを含むことを特徴とする、CSF−1Rに結合する抗体の重鎖及び軽鎖をコードする、核酸。
- 原核又は真核宿主細胞においてCSF−1Rに結合する抗体を発現させるための、請求項10に記載の核酸を含むことを特徴とする、発現ベクター。
- 請求項11に記載のベクターを含む、原核又は真核宿主細胞。
- 請求項3又は4に記載の組換え抗体の作製方法であって、原核又は真核宿主細胞において請求項10に記載の核酸を発現させること、及び前記細胞又は細胞培養上清から前記抗体を回収することを特徴とする、作製方法。
- 癌の治療のための医薬を製造するための、請求項3又は4に記載の抗体の使用。
- 骨量減少の治療のための医薬を製造するための、請求項3又は4に記載の抗体の使用。
- 癌の転移の予防又は治療のための医薬を製造するための、請求項3又は4に記載の抗体の使用。
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RU2658603C2 (ru) | 2018-06-21 |
US20140336363A1 (en) | 2014-11-13 |
EP2791174B1 (en) | 2018-02-28 |
WO2013087699A1 (en) | 2013-06-20 |
CN104159921A (zh) | 2014-11-19 |
CN104159921B (zh) | 2018-05-04 |
JP2015501823A (ja) | 2015-01-19 |
HK1201282A1 (en) | 2015-08-28 |
US10023643B2 (en) | 2018-07-17 |
BR112014012624A2 (pt) | 2018-10-09 |
CA2853889A1 (en) | 2013-06-20 |
RU2014127438A (ru) | 2016-02-10 |
US10336830B2 (en) | 2019-07-02 |
EP2791174A1 (en) | 2014-10-22 |
US20180346582A1 (en) | 2018-12-06 |
MX356337B (es) | 2018-05-23 |
KR20140113683A (ko) | 2014-09-24 |
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