JP2023513035A - pH感応性FC変異体 - Google Patents
pH感応性FC変異体 Download PDFInfo
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- JP2023513035A JP2023513035A JP2022546354A JP2022546354A JP2023513035A JP 2023513035 A JP2023513035 A JP 2023513035A JP 2022546354 A JP2022546354 A JP 2022546354A JP 2022546354 A JP2022546354 A JP 2022546354A JP 2023513035 A JP2023513035 A JP 2023513035A
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Images
Classifications
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6843—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a material from animals or humans
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6883—Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
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Abstract
Description
アラニン:A,アルギニン:R,アスパラギン:N,アスパラギン酸:D,システイン:C,グルタミン酸:E,グルタミン:Q,グリシン:G,ヒスチジン:H,イソロイシン:I,ロイシン:L,リシン:K,メチオニン:M,フェニルアラニン:F,プロリン:P,セリン:S,トレオニン:T,トリプトファン:W,チロシン:Y,バリン:V
<1-1>Fc変異体(Q311M/M428L)の生産及び精製
先行研究において半減期延長効果が知られているYTEのM252Y、LSのM428Lに見られるように、FcRn結合力が向上した変異体はMetが他のアミノ酸に置換されていることが確認された(野生型Fcドメインのアミノ酸配列:配列番号1)。これらの理由から、抗体FcのFcRn結合部位におけるMetはFcRnに対するpH依存的な結合力を阻害するアミノ酸であると判断した。PFc29(Q311R及びM428L Fc変異体)に導入するとFcRn結合力を実際に阻害するか否かを確認するために、トラスツズマブ重鎖(配列番号11)にFc変異体(Q311M/M428L)変異体(配列番号2)を導入したトラスツズマブ-MLを作製し、Expi293F動物細胞にトランスフェクションした。具体的には、まず、フリースタイル293発現(Freestyle 293 expression)培養液(Gibco社,12338-018)30mLに、前記Q311にMetを導入したFc変異体(Q311M/M428L)の重鎖遺伝子と軽鎖遺伝子を1:1の割合で混合した。次に、PEI(Polyethylenimine)(ポリサイエンス社,23966):変異体遺伝子=4:1の割合で混合して常温で20分間静置し、1日前に2×106細胞/mLの密度になるように分注して培養したExpi293F細胞株と混合した。振盪培養器にて37℃、125rpm及び8%CO2の条件で7日間培養し、その後遠心分離して上清のみ採取した。その後、25×PBSを用いて平衡(equilibrium)にし、0.2μmフィルター(メルクミリポア社)及びボトルトップフィルター(bottle top filter)を用いて濾過した。濾過した培養液にプロテインAレジン500μLを注入し、4℃で16時間攪拌した。その後、カラムを流してレジンを回収し、5mLのPBSで洗浄して3mLの100mMグリシン(pH2.7)バッファに溶出し、次いで1M Tris-HCl pH8.0を用いて中和させた。バッファを変えるために、遠心濾過器ユニット(centrifugal filter units)3K(メルクミリポア社)を用いた。
実施例1-1で精製したトラスツズマブ-MLのFcRnに対するpH依存的な結合力をELISAにより確認した。具体的には、0.05M Na2CO3(pH9.6)に、4μg/mLに希釈した前記IgG Fc変異体を50μLずつ平底ポリスチレン(Flat Bottom Polystyrene)High Bind 96ウェルマイクロプレート(costar)にて4℃で16時間固定化した。その後、100μLの4%スキムミルク(ゲノムベース;GenomicBase)(in 0.05% PBST pH6.0)にて常温で2時間ブロッキングした。0.05%PBST(pH6.0)180μLで4回ずつ洗浄し、その後1%スキムミルク(in 0.05% PBST,pH6.0)で連続希釈したFcRn 50μLを各ウェルに分注し、常温で1時間反応させた。洗浄過程後に、抗GST-HRPコンジュゲート(GEヘルスケア社)50μLを用いて、常温で1時間抗体反応を行って洗浄した。その後、1-Step Ultra TMB-ELISA基質溶液(Substrate Solution)(サーモフィッシャーサイエンティフィック社)を50μLずつ添加して発色させ、次いで2M H2SO4を50μLずつ注入して反応を終了させ、Epochマイクロプレート分光光度計(Microplate Spectrophotometer)(BioTek社)を用いて分析した。
実施例1-1で選択したQ311M及びM428Lの変異を有するFc変異体より向上したFcRn結合力を有する変異体をさらに見出そうとした。具体的には、L309位にL、G、P、C、Dを除く15種のアミノ酸を導入した変異体15種を実施例1-1と同様に作製し、動物細胞で培養して精製した(図2)。
実施例1-3で精製した変異体のpH6.0におけるFcRnに対する結合力を確認するために、実施例1-2と同様にELISA分析を行った。その結果、pH6.0で最も結合力が高いL309Y、Q311M及びM428L(トラスツズマブ-YML)(図3のYM,以下ではYMLという,配列番号3)変異体が確保された(図3)。よって、選択したYML変異体のFcRnに対するpH依存的な結合力をELISAにより測定した。その結果、従来のPFc29(Q311R及びM428L Fc変異体)及び実施例1-1で選択したML変異体(Q311M及びM428L Fc変異体)よりも、pH6.0におけるFcRnとの結合力が高いことが分かった。また、pH7.4においては同程度の解離を示した(図4a~図4c)。
血中半減期の延長のためにはFcRnに対するFcのpH依存的な結合力が重要であるので(図5参照)、Souders et al 2015を参照して、弱酸性環境における結合瞬間速度(on rate)及び中性環境における解離瞬間速度(off rate)を実施例1-1及び1-4で選択したトラスツズマブ-ML(Q311M及びM428L Fc変異体)及びトラスツズマブ-YML(L309Y、Q311M及びM428L Fc変異体)において確認した。その対照群として、従来のPFc29(Q311R及びM428L Fc変異体)及びPFc41(L309G及びM428L Fc変異体)を用いた。具体的には、NI-NTAバイオセンサ(Pall Fortebio社)に40μg/mLのHisタグ付けしたヒトFcRnを3分間固定化した。その後、pH6.0のPBSバッファを基準(baseline)とし、次いで700nMの各抗体Fc変異体(in PBS pH6.0)を20秒間結合させた。弱酸性環境(pH6.0)でFcRnに抗体Fc変異体が結合した状態において、pH7.4のPBSにバッファを変えて5秒間解離させ、バイオレイヤー干渉法(biolayer interferometry assay)(BLItz,Pall Fortebio社)により測定した。このようにして測定したデータ(sensorgram)において、各pHの線形区間(pH6.0,結合(association):2秒/pH7.4,解離(dissociation):1秒)の傾きにより結合瞬間速度と解離瞬間速度を確認した。その後、Fc変異体の比較のために、各Fc変異体の傾き値を除算して比率を求めた。結合速度比と解離速度比の平均をスコアリング(scoring)し、結合速度と解離速度が最も速いFc変異体を確認した。その結果、半減期延長効果が最も大きくなると期待される抗体Fc変異体(YML,配列番号3)を選択した(図6a~図6c)。
<2-1>Q311M/M428L突然変異を有するトラスツズマブFc変異体の生産及び精製
先行研究によれば、FcRn結合力が向上した変異体はMetが他のアミノ酸に置換されていることが分かる(野生型Fcドメインのアミノ酸配列:配列番号1)。これらの理由から、抗体FcのFcRn結合部位におけるMetはFcRnに対するpH依存的な結合力を阻害するアミノ酸であると判断した。よって、Metを本発明者らが見出したPFc29(Q311R/M428L)に導入するとFcRn結合力を実際に阻害するか否かを確認するために、本実験を行った。
実施例2-1で精製したトラスツズマブ-MLのFcRnに対するpH依存的な結合力を測定するために、ELISAを行った。
前述したように選択したQ311M/M428Lより向上した結合力を有する変異体を見出そうとした。具体的には、FcRnに結合するために重要であることが知られているL309位にL、G、P、C、Dを除く15種のアミノ酸を導入した変異体15種を実施例2-2と同様に動物細胞で培養して精製した(図7)。
前述したように実施例2-3で作製した変異体のpH6.0におけるFcRnに対する結合力を確認するために、ELISAを行った。
実施例2-4で精製したトラスツズマブ-YML、トラスツズマブ-EML(配列番号4)の2種の変異体のFcRnに対するpH依存的な結合力を確認するために、ELISAを行った。
<3-1>PFc41(L309G,M428L)のQ311位における17種のアミノ酸置換変異体の作製及び分析
先行研究において半減期が延長されたPFc41(L309G,M428L)及びPFc29(Q311R及びM428L Fc変異体)をベースにL309Gを固定し、Q311位においてQ、C、Rを除く17種のアミノ酸に置換された変異体をバクテリアディスプレイで分析できるように、pMopac12-NlpA-Fc変異体プラスミド(variants plasmid)を作製した。作製したプラスミドに対して、FACSを用いてpH6.0条件におけるヒトFcRnに対する結合力が向上した変異体を選択するために、FACS分析を行った。その結果、先行研究により見出されたPFc29よりpH6.0で結合力が向上し、Q311位においてL、I、V、T、A、Y、H、K、Wに置換された9つの変異体を選択した(M428L、L309G Fc変異体にQ311L、Q311I、Q311V、Q311T、Q311A、Q311Y、Q311H、Q311KまたはQ311W)(図11)。
実施例3-1で選択した9種の変異体の抗体フォーマットにおける特性を確認するために、野生型トラスツズマブ重鎖(heavy chain)(配列番号11)にFc変異体を導入した重鎖発現ベクターと、野生型トラスツズマブ軽鎖(配列番号12)発現ベクターを作製した。その後、Expi293F動物細胞にトランスフェクションした。
野生型トラスツズマブ重鎖(heavy chain)(配列番号11)にFc変異体を導入した重鎖と野生型トラスツズマブ軽鎖(配列番号12)が結合したトラスツズマブ変異体のFcRnに対するpH依存的な結合力を測定するために、ELISA測定を行った。まず、pH6.0条件におけるFcRnに対する結合力を確認するために、0.05M Na2CO3 pH9.6に、4μg/mLに希釈したIgG Fc変異体をそれぞれ50μLずつ平底ポリスチレンhigh bind 96ウェルマイクロプレート(costar)にて4℃で16時間固定化した。その後、100μLの4%脱脂乳(ゲノムベース)(in 0.05% PBST pH6.0)にて常温で2時間ブロッキング(blocking)した。0.05%PBST(pH6.0)180μLで4回ずつ洗浄し、その後1%脱脂乳(in 0.05% PBST pH6.0)で順次希釈(serially dilution)したFcRn 50μLを各ウェルに分注し、常温で1時間反応させた。洗浄後に、抗GST-HRP抗体複合体(GEヘルスケア社)50μLずつを用いて、常温で1時間抗体反応を行って洗浄した。1-Step Ultra TMB-ELISA基質溶液(サーモフィッシャーサイエンティフィック社)を50μLずつ添加して発色させ、その後2M H2SO4を50μLずつ注入して反応を終了させた。その後、Epochマイクロプレート分光光度計(BioTek社)を用いて分析した。その結果、pH6.0条件においてFcRnに対する結合力が向上した上位3つの変異体(L309G/Q311Y/M428L,L309G/Q311H/M428L,L309G/Q311W/M428L)を選択した(図13)。
実施例3-3で選択した3種の変異体(L309G/Q311Y/M428L,L309G/Q311H/M428L,L309G/Q311W/M428L)のうち、先行研究において既に知られているQ311Hを除き、Q311YまたはWを含み、L309位においてF、I、M、V、T、A、Y、H、Q、N、K、E、W、R、Sに置換された15種のトラスツズマブ変異体30種を発現するためのプラスミドを作製した。作製した発現用ベクターを用いて、トラスツズマブ変異体30種を前述した方法と同様に動物細胞で培養し、その後精製し、SDS-PAGEゲルにより確認した(図15)。
実施例3-4の30種のトラスツズマブ変異体のFcRnに対するpH6.0における結合力を測定するために、ELISA測定を行った。まず、FcRnに対するpH依存的な結合力を確認するために、0.05M Na2CO3 pH9.6に、4μg/mLに希釈したIgG Fc変異体をそれぞれ50μLずつ平底ポリスチレンhigh bind 96ウェルマイクロプレート(costar)にて4℃で16時間固定化し、その後100μLの4%脱脂乳(ゲノムベース)(in 0.05% PBST pH6.0)にて常温で2時間ブロッキングした。0.05%PBST(pH6.0)180μLで4回ずつ洗浄し、その後1%脱脂乳(in 0.05% PBST pH6.0)で順次希釈(serially dilution)したFcRn 50μLを各ウェルに分注し、常温で1時間反応させた。洗浄後に、抗GST-HRP抗体複合体(GEヘルスケア社)50μLずつを用いて、常温で1時間抗体反応を行って洗浄した。1-Step Ultra TMB-ELISA基質溶液(サーモフィッシャーサイエンティフィック社)を50μLずつ添加して発色させ、その後2M H2SO4を50μLずつ注入して反応を終了させ、次いでEpochマイクロプレート分光光度計(BioTek社)を用いて分析した。その結果、pH6.0においてPFc29より結合力が向上したL309E/Q311W/M428L(EWL,配列番号8)変異体を見出した(図16)。
野生型トラスツズマブ重鎖(heavy chain)(配列番号11)にEWL Fc変異体(配列番号5)を含む重鎖とトラスツズマブ軽鎖(配列番号12)が結合したトラスツズマブ-EWLのFcRnに対するpH依存的な結合力を測定するために、ELISAを行った。まず、FcRnに対するpH依存的な結合力を確認するために、0.05M Na2CO3 pH9.6に、4μg/mLに希釈したIgG Fc変異体をそれぞれ50μLずつ平底ポリスチレンHigh Bind 96ウェルマイクロプレート(costar)にて4℃で16時間固定化し、その後100μLの4%脱脂乳(ゲノムベース)(in 0.05% PBST pH6.0/pH7.4)にて常温で2時間ブロッキングした。0.05%PBST(pH6.0/pH7.4)180μLで4回ずつ洗浄し、その後1%脱脂乳(in 0.05% PBST pH6.0/pH7.4)で順次希釈(serially dilution)したFcRn 50μLを各ウェルに分注し、常温で1時間反応させた。
Claims (16)
- 野生型免疫グロブリン(immunoglobulin)のFc領域に、カバットナンバリングシステム(Kabat numbering system)によるL309Y、Q311M及びQ311Wからなる群から選択されるアミノ酸残基の改変を含む、Fc変異体。
- 前記Fc変異体は、L309Y及びM428L、L309Y及びQ311M、またはL309Y、Q311M及びM428Lのアミノ酸残基の改変を含む、請求項1に記載のFc変異体。
- 前記Fc変異体は、1)L309Y及びQ311M、2)L309E及びQ311M、3)Q311M及びM428L、4)L309E、Q311M及びM428L、または5)L309Y、Q311M及びM428Lのアミノ酸残基の改変を含む、請求項1に記載のFc変異体。
- 前記Fc変異体は、1)L309E及びQ311W、2)Q311W及びM428L、または3)L309E、Q311W及びM428Lのアミノ酸残基の改変を含む、請求項1に記載のFc変異体。
- 免疫グロブリンがIgA、IgM、IgE、IgD及びIgGからなる群から選択される、請求項1に記載のFc変異体。
- pH7.0~7.8において野生型免疫グロブリンFc領域に比べてFcRnに対す結合親和性が低い、請求項1に記載のFc変異体。
- pH5.6~6.5において野生型免疫グロブリンFc領域に比べてFcRnに対する結合親和性が高い、請求項1に記載のFc変異体。
- 請求項1に記載のFc変異体を含む、ポリペプチド。
- 野生型と比較して生体内半減期(Half-life)が延長された、請求項8に記載のポリペプチド。
- 請求項1に記載のFc変異体を含む、抗体。
- 野生型と比較して生体内半減期が延長された、請求項10に記載の抗体。
- 請求項1に記載のFc変異体、請求項8に記載のポリペプチド、請求項10に記載の抗体をコードする、核酸分子。
- 請求項12に記載の核酸分子を含む、ベクター。
- 請求項13に記載のベクターを含む、宿主細胞。
- 請求項1に記載のFc変異体、非ペプチド性重合体及び生理活性ポリペプチドが共有結合により連結されて生体内半減期が延長された、タンパク質結合体。
- 生理活性ポリペプチドがヒト成長ホルモン、成長ホルモン放出ホルモン、成長ホルモン放出ペプチド、インターフェロン、コロニー刺激因子、インターロイキン、インターロイキン可溶性受容体、TNF可溶性受容体、グルコセレブロシダーゼ、マクロファージ活性化因子、マクロファージペプチド、B細胞因子、T細胞因子、タンパク質A、アレルギー抑制因子、細胞壊死糖タンパク質、免疫毒素、リンホトキシン、腫瘍壊死因子、腫瘍抑制因子、転移成長因子、α1-アンチトリプシン、アルブミン、アポリポタンパク質E、エリスロポエチン、高グリコシル化エリスロポエチン、血液因子VII、血液因子VIII、血液因子IX、プラスミノーゲン活性化因子、ウロキナーゼ、ストレプトキナーゼ、タンパク質C、C反応性タンパク質、レニン阻害剤、コラゲナーゼ阻害剤、スーパーオキシドディスムターゼ、レプチン、血小板由来成長因子、表皮成長因子、骨形成成長因子、骨形成促進タンパク質、カルシトニン、インスリン、インスリン誘導体、グルカゴン、グルカゴン様ペプチド-1(Glucagon Like Peptide-1)、アトリオペプチン、軟骨誘導因子、結合組織活性化因子、卵胞刺激ホルモン、黄体形成ホルモン、卵胞刺激ホルモン放出ホルモン、神経成長因子、副甲状腺ホルモン、リラキシン、セクレチン、ソマトメジン、インスリン様成長因子、副腎皮質ホルモン、コレシストキニン、膵臓ポリペプチド、ガストリン放出ペプチド、コルチコトロピン放出因子、甲状腺刺激ホルモン、受容体類、受容体拮抗物質、細胞表面抗原、モノクローナル抗体、ポリクローナル抗体、抗体フラグメント類及びウイルス由来ワクチン抗原からなる群から選択される、請求項15に記載のタンパク質結合体。
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WO2023068710A1 (ko) * | 2021-10-18 | 2023-04-27 | 고려대학교 산학협력단 | PH-의존 FCRN 결합력과 FCγRⅢA 결합 선택성이 향상된 FC 변이체들 |
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JP2011502126A (ja) * | 2007-10-31 | 2011-01-20 | ゼンコア インコーポレイテッド | FcRnへの変異結合を有するFc変異体 |
JP2014509857A (ja) * | 2011-03-16 | 2014-04-24 | アムジエン・インコーポレーテツド | Fc変異体 |
US20140294812A1 (en) * | 2013-03-15 | 2014-10-02 | Xencor, Inc. | Fc variants that improve fcrn binding and/or increase antibody half-life |
WO2018186717A1 (ko) * | 2017-04-07 | 2018-10-11 | 국민대학교 산학협력단 | 혈중 반감기 향상을 위한 항체 Fc 변이체들 |
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TWI667257B (zh) * | 2010-03-30 | 2019-08-01 | 中外製藥股份有限公司 | 促進抗原消失之具有經修飾的FcRn親和力之抗體 |
CN107709364A (zh) * | 2015-04-07 | 2018-02-16 | 豪夫迈·罗氏有限公司 | 具有激动剂活性的抗原结合复合体及使用方法 |
KR101742444B1 (ko) | 2016-11-15 | 2017-05-31 | 한국과학기술원 | 적응형 패턴 인식 기반 고속 디바이스 커플링 방법 및 시스템 |
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- 2021-01-29 JP JP2022546354A patent/JP2023513035A/ja active Pending
- 2021-01-29 EP EP21746991.5A patent/EP4089117A4/en active Pending
- 2021-01-29 WO PCT/KR2021/001237 patent/WO2021154046A1/ko unknown
- 2021-01-29 US US17/759,792 patent/US20230072197A1/en active Pending
- 2021-01-29 CN CN202180011895.7A patent/CN115038721A/zh active Pending
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JP2011502126A (ja) * | 2007-10-31 | 2011-01-20 | ゼンコア インコーポレイテッド | FcRnへの変異結合を有するFc変異体 |
JP2014509857A (ja) * | 2011-03-16 | 2014-04-24 | アムジエン・インコーポレーテツド | Fc変異体 |
US20140294812A1 (en) * | 2013-03-15 | 2014-10-02 | Xencor, Inc. | Fc variants that improve fcrn binding and/or increase antibody half-life |
WO2018186717A1 (ko) * | 2017-04-07 | 2018-10-11 | 국민대학교 산학협력단 | 혈중 반감기 향상을 위한 항체 Fc 변이체들 |
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EP4089117A1 (en) | 2022-11-16 |
EP4089117A4 (en) | 2024-03-27 |
WO2021154046A1 (ko) | 2021-08-05 |
US20230072197A1 (en) | 2023-03-09 |
CN115038721A (zh) | 2022-09-09 |
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