JP2009532477A - 抗炎症特性が増強され、細胞毒性特性が減少したポリペプチドおよび関連する方法 - Google Patents
抗炎症特性が増強され、細胞毒性特性が減少したポリペプチドおよび関連する方法 Download PDFInfo
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Abstract
Description
本出願は、2006年4月5日に出願された米国仮特許出願第60/789,384号に対して優先権を主張するものである。
本発明に至る研究は、一部、国立衛生研究所認可番号AI034662によって支援された。したがって、米国政府が、本発明についてある程度権利を有しうる。
本発明は、炎症性疾患の治療を目的とした、治療用ポリペプチドを設計する新規な方法に関する。
本発明は、そのような方法および分子を提供することによって前述の要求を満たすものである。一実施態様において、本発明は、少なくとも一つのIgG Fc領域を含むポリペプチドを提供するものであり、前記ポリペプチドは、未精製の抗体と比較してより高い抗炎症活性およびより低い細胞毒性を有する。本発明の他の実施形態において、ポリペプチドは、ヒトIgGl、IgG2、IgG3またはIgG4 Fc領域を含み、前記ポリペプチドは、未精製抗体と比較してより高いシアル酸含有量を有する。
図1は、6A6−IgG抗体イソタイプの糖質スペクトルを示す。6A6−IgGl、IgG2aおよびIgG2b由来のN−グリカンは、MALDI−TOP MSによって分析した。シアル酸残基を含むピークは、角括弧で示す。293T細胞の一過性トランスフェクションによって製造される組み換え6A6抗体スイッチ変異体(switch variant)は、Asn−297の位置で付加された糖質中、シアル酸残基の最小限のレベルを含んでいた。
本発明者らは、驚くべきことに、IgG Fcドメインの細胞毒性および抗炎症反応が、Fcに結合したコア多糖のシアル化が異なることに起因することを見出した。IgG抗体の細胞毒性は、シアル化によって減ぜられる;逆に、IVIGの抗炎症活性は増強される。IgG シアル化は、抗原特異的免疫反応の誘導によって制御されることが示され、したがって、抗原投与によって、定常状態の固有の抗炎症分子から、適応的、炎症性種にIgGを転換する新規な方法を提供する。
本明細書および請求項を通じて、免疫グロブリン重鎖における残基のナンバリングは、本明細書に参照として明示的に引用される、Kabat et al.、Sequences of Proteins of Immunological Interest、 5th Ed. Public Health Service、 National Institutes of Health、 Bethesda、 Md. (1991)中のようなEUindexのものである。「Kabat中のようなEUindex」は、ヒトIgGl EU抗体の残基ナンバリングを指す。
本発明のポリペプチドは、N−結合型グリコシル化ができるホスト発現系、すなわち、ホスト細胞において発現させることができる。通常、そのようなホスト発現系としては、菌の、植物の、脊椎動物または無脊椎動物発現系が挙げられる。一実施形態において、ホスト細胞はチャイニーズハムスター卵巣(CHO)細胞株(例えば、CHO−Kl;ATCC CCL−61)、Green Monkey細胞株(COS)(例えばCOS1(ATCC CRL−1650)、COS 7(ATCC CRL−1651))のような哺乳類細胞;マウス細胞(例えばNS/0)、Baby Hamster Kidney(BHK)細胞株(例えば、ATCC CRL−1632またはATCC CCL−10)、またはヒト細胞(例えば、HEK 293(ATCC CRL−1573))、または例えば、American Type Culture Collection、Rockville、Md.Furtherのような公的なバンクから入手可能な他の適切な細胞株である。さらに、鱗翅目細胞株のような昆虫細胞株、例えばSf9、植物細胞株、菌細胞株、例えば、サッカロマイセス・セレヴィシエ、ピキアパストリス(Pichia pastoris)、Hansenula sppのような酵母。当業者には、ヒトIgGのFc領域上で通常見られるように複雑な、二分岐の糖となるためには、ホスト細胞への修飾がN−結合型グリコシル化およびグリカン成熟が確実に起こるために必要とされる場合もあることが理解されるであろう(例えばHamilton、SR、 et al.Science、313、1441(2006);Li、H、et al.、Nature Biotechnology 24、210(2006);Wildt、S and Grengross、TU Nature Reviews Microbiology 3、119(2005)参照)。
少なくとも一つのIgG Fc領域を有するポリペプチドを含む治療製剤は、所望の精製度を有する本発明のポリペプチドと、任意に生理学的に許容されるキャリアー、賦形剤または安定剤とを混合することによって、凍結乾燥製剤または水溶液の形態で、保管のために製造されうる(例えば、Remington’s Pharmaceutical Sciences 16th edition、Osol、A.Ed.(1980)参照)。許容されるキャリアー、賦形剤または安定剤は、用いられる投与量および濃度で患者に毒性がなく、そして、キャリアー、賦形剤または安定剤としては、リン酸塩、クエン酸塩および他の有機酸のようなバッファー;アスコルビン酸およびメチオニンを含む抗酸化剤;(オクタデシルジメチルベンジルアンモニウムクロライド;塩化ヘキサメトニウム;塩化ベンザルコニウム、塩化ベンゼトニウム;フェニル、ブチルまたはベンジルアルコール;メチルまたはプロピルパラベンのようなアルキルパラベン;カテコール;レゾルシノール;シクロヘキサノール;3−ペンタノール;およびm−クレゾールのような)防腐剤;低分子量(約10残基未満)ポリペプチド;血清アルブミン、ゼラチン、または免疫グロブリンのようなタンパク質;ポリビニルピロリドンのような親水性ポリマー;グリシン、グルタミン、アスパラギン、ヒスチジン、アルギニン、またはリシンのようなアミノ酸;単糖、二糖、およびグルコース、マンノース、またはデキストリンを含む他の糖質;EDTAのようなキレート剤;スクロース、マンニトール、トレハロースまたはソルビトールのような糖;ナトリウムのような塩形成対イオン;金属錯体(例えば、Zn−タンパク質錯体);および/またはTWEEN(登録商標)、PLURONICS(登録商標)またはポリエチレングリコール(PEG)のようなノニオン活性剤が挙げられる。
本発明のポリペプチドは、未修飾、および/または未精製の抗体と比較してシアル酸の量が増加するように、さらに精製または改変(修飾)することができる。この目的に到達するために多数の方法が存在する。ある一つの方法では、例えば、IVIGが通常精製されるIgGを含む血漿フラクションのような未精製のポリペプチド源を、シアル酸に結合することが知られているレクチンを有するカラムに通過させる。ある実施形態では、レクチンはセウヨウニワトコ(Sambuccus nigra)から分離される。したがって、少なくとも一つのIgG Fc領域を含むポリペプチドのシアル化フラクションは、カラム中に保持されるが、一方、非シアル化(asialylated)フラクションは、通過するであろう。少なくとも一つのIgG Fc領域を含むポリペプチドのシアル化フラクションは、異なるストリンジェンシーな条件のさらなる洗浄によって溶出されうる。このようにして、通常の含有量と比較してシアル酸含有量が増加している本発明のポリペプチドの調製物を得ることができる。さらに、シアル酸転移酵素および例えば米国特許第20060030521号で開示されているようなシアル酸の供与体を用いた酵素反応を用いてもよい。
IgGの特定の糖型が抗体のエフェクター機能を調節することに関与するかどうかを究明するために、あるIgGモノクローナル抗体の細胞毒性の媒介における特定のAsn297に結合した糖質の役割を調べた。Nitnmerjahn et al.、Immunity 23、41(2005)中で以前開示されているように、293細胞中でIgGl、2aまたは2bスイッチ変異体のいずれかとして発現している6A6ハイブリドーマ由来の抗血小板抗体を、これらの具体的な糖質組成および構造を決定するために質量分析によって分析した(図1)。これらの抗体は、最小限のシアル酸残基を含む。セイヨウニワトコレクチンアフィニティークロマトグラフィーによるシアル酸含有種の濃縮は、シアル酸含有量で60〜80倍濃度が高い抗体を産生した(図2Bおよび図3)。シアル化された、および非シアル化6A6−IgGlおよび2b抗体の血小板クリアランスを媒介する能力を比較すると、シアル化とインビボ活性との間で逆相関を示した。6A6 IgG抗体のシアル化により、生物学的活性が40〜80%低下した(図2Cおよび図3)。
マウス
C57BL/6およびNODマウスは、Jackson Laboratory(バーハーバー、メイン州)から購入した。FcyRIIB−/−マウスは、発明者の研究室で作製され、C57BL/バックグラウンドへ12世代戻し交配された。C57BL/6バックグラウンド(K/B)のKRN TCRトランスジェニックマウスは、D.MathisおよびC.Benoist(ハーバードメディカルスクール、ボストン、マサチューセッツ州)から贈与され、K/BxNマウスを作製するためにNODマウスに対して交配させた。8〜10週齢のメスマウスを全ての実験に用い、ロックフェラーユニバーシティ動物施設で飼育した。全ての実験は連邦法および機関ガイドラインにしたがって行われ、ロックフェラーユニバーシティ(ニューヨーク、ニューヨーク州)によって認証された。
6A6抗体スイッチ変異体は、293T細胞の一過性トランスフェクション、次いでNimmerjahn et al.、 Immunity 23、 41 (2005) and Nimmerjahn and Ravetch、 Science 310、1510(2005)に開示されているようにプロテインGを用いて精製することによって作製した。シアル酸リッチ抗体変異体を、Sambucus nigra agglutinin(SNA)アガロース(Vector Laboratories、バーリンゲーム、カリフォルニア州)を用いたレクチンアフィニティークロマトグラフィーによってこれらの抗体調製物から分離した。シアル酸含有量が高いことは、レクチンブロットによって確認した(下記参照)。静脈注射用ヒト免疫グロブリン(IVIG、10%マルトース中5%、クロマトグラフィー精製)は、Octapharma(Hemdon、バージニア州)から購入した。Kaneko Y.et al.、Exp.Med.203、789(2006)に開示されているように、ヒトIVIGの消化を行った。簡単に述べると、IVIGを37℃で1時間0.5mg/mlパパインによって消化し、2.5mg/mlヨードアセトアミドを添加することによって止めた。FabおよびFc結果物フラグメントは、HiPrep 26/60 S−200HRカラム(GE Healthcare、ピスカタウェイ、ニュージャージー州)上で、非消化IVIGから分離し、次いでプロテインGカラム(GE Healthcare)およびプロテインLカラム(Pierce、ロックフォード、イリノイ州)を用いてFcおよびFabフラグメントの精製を行った。フラグメント精製は、抗−ヒトIgG FabまたはFc−特異的抗体(Jackson ImmunoResearch、West Grove、ペンシルバニア州)を用いて免疫ブロット法によって確認した。精製は99%より高いと判別された。F4/80抗体はSerotec(オックスフォード、イギリス)社製である。Ly 17.2抗体は、Caltag(バーリンゲーム、カリフォルニア州)社製である。ヒツジ抗−糸球体基底膜(GBM)抗血清(腎毒性血清(nephrotoxic serum)、NTS)は、M.P.Madaio(ペンシルバニア大学、フィラデルフィア、ペンシルバニア州)から贈与された。C−末端ヘキサヒスチジンタグを含む水溶性Fc レセプターは、293T細胞の一過性トランスフェクションによって作製し、製造元(Qiagen社)によって示されているようにNi−NTAアガロースを用いて細胞培養上清から精製した。
シアル酸含有量が増加したIVIGの調製物
シアル酸はIVIGの抗炎症活性に必要とされるようであるから、この抗炎症活性に対して高投与量要件基準(1g/kg)は、全IgG調製物中のシアル化IgGの限定濃度でありうる。シアル酸修飾グリカン構造が濃縮されたIgG分子を得るために、IVIGをSNA−レクチンアフィニティカラム上で分画した。
シアル化されうる、軽鎖または重鎖可変領域上のOおよびN結合型グリカンをIVIG中のポリクローナルIgGも含むので、SNA−リッチIgG調製物の抗炎症活性の増加がFc上のN−結合型グリコシル化部位のシアル化が増加した結果であることを我々は確認した。Fc−フラグメントは、分画化されていない、およびSNA分画されたIVIGから作製し、それらのインビボ活性を試験した。インタクトIgGで観察されたように、分画化されていないIVIGから作製したFc−フラグメントと比較した場合、SNA−精製Fc−フラグメントはインビボにおける保護効果を増強した(図4C)。その一方、Fabフラグメントはインビボアッセイにおいて何ら抗炎症活性を示さなかった。したがって、IVIGの抗炎症活性には高投与量が必要であることは、全調製物中に存在するシアル化IgGの寄与がより小さいことに起因している可能性がある。シアル酸結合レクチンクロマトグラフによってこれらのフラクションを濃縮することは、その結果として抗炎症活性を増加した。
グッドパスチャー症候群のマウスモデル
このモデルにおいて、マウスを最初にアジュバントを併用したヒツジIgGで感作し、4日後にヒツジ抗マウス糸球体基底膜調製物を注入した(腎毒性血清、NTS)。簡単に述べると、CFA中ヒツジIgG(Serotec)200μgをマウスに腹腔内に予め免疫し、次いで4日後に体重グラムあたりNTS血清2.5μlを静脈注射した。血液を抗GBM抗血清注入4日後に未処理コントロールマウスから回収し、血清IgGをプロテインG(GE Healthcare、プリンストン、ニュージャージー州)、およびNHS−活性化セファロースカラム(GE Healthcare、プリンストン、ニュージャージー州)上にヒツジIgGを共有カップリングすることによって作製される、セファロース結合ヒツジIgGカラム、アフィニティークロマトグラフィーで精製した。
Claims (22)
- 少なくとも一つのIgGFc領域を含むポリペプチドであり、未精製抗体と比較して、より高い抗炎症活性およびより低い細胞毒性を有する、ポリペプチド。
- 前記ポリペプチドが未精製抗体と比較してシアル酸含有量がより高い、ヒトIgG1、IgG2、IgG3またはIgG4 Fc領域を含む、請求項1に記載のポリペプチド。
- インビトロでの抗炎症性活性が増加している、請求項1または2に記載のポリペプチド。
- インビボでの抗炎症性活性が増加している、請求項1〜3のいずれか1項に記載のポリペプチド。
- 天然に存在する抗体源由来である、請求項1〜4のいずれか1項に記載のポリペプチド。
- 組み換え抗体源由来である、請求項1〜4のいずれか1項に記載のポリペプチド。
- 未修飾抗体と比較してシアル酸含有割合が高く、前記未修飾抗体がIVIGを含む、請求項1〜6のいずれか1項に記載のポリペプチド。
- タンパク質シアル化活性が高い細胞株由来である、請求項1〜7のいずれか1項に記載のポリペプチド。
- シアル酸転移酵素を用いた処理により修飾された、請求項1〜8のいずれか1項に記載の抗体。
- 精製されている、請求項1〜9のいずれか1項に記載の抗体。
- 適切なキャリアーまたは希釈剤と組み合わせて請求項1〜10のいずれか1項に記載の抗体を含む製剤。
- 少なくとも一つのFc領域を含むポリペプチドの製造方法であって、前記ポリペプチドが未精製抗体より高い抗炎症活性および低い細胞毒性を有し、
少なくとも一つのFc領域を含むポリペプチドの未精製源を提供し、ここで、前記少なくとも一つのFc領域を含むポリペプチドの未精製源は、シアル酸を有する少なくとも一つのFc領域を含むポリペプチドの複数およびシアル酸を欠く少なくとも一つのFc領域を有するポリペプチドの複数を含み;そして
シアル酸を欠く少なくとも一つのFc領域を含むポリペプチドの複数に対する、シアル酸を含む少なくとも一つのFc領域を含むポリペプチドの複数の比率を増加させる、
ことを含む、方法。 - 前記少なくとも一つのFc領域を含むポリペプチドの未精製源がヒト未精製IgG抗体を含む、請求項12に記載の方法。
- 前記少なくとも一つのFc領域を含むポリペプチドの未精製源が、発現系で核酸配列を含むベクターを発現させることにより提供され、ここで前記核酸配列がIgG抗体に翻訳される、請求項12または13に記載の方法。
- 前記発現系が、菌の、植物の、脊椎動物のおよび無脊椎動物の発現系、およびこれらの組み合わせからなる群から選択されるN−結合グリコシル化ができる修飾されたホスト発現系を含む、請求項14に記載の方法。
- シアル酸を欠く少なくとも一つのFc領域を含むポリペプチドの複数に対する、シアル酸を含む少なくとも一つのFc領域を含むポリペプチドの複数の比率を増加させる段階が、シアル酸を欠く少なくとも一つのFc領域を含むポリペプチドの除去を通じて達成される、請求項12〜15のいずれか1項に記載の方法。
- 前記除去が物理的または化学的方法により達成される、請求項16の方法。
- 前記除去が、HPLC、レクチンアフィニティクロマトグラフィー、高pHアニオン交換クロマトグラフィー、およびこれらの組み合わせからなる群から選ばれる方法によって達成される、請求項16または17に記載の方法。
- シアル酸を欠く少なくとも一つのFc領域を含むポリペプチドの複数に対する、シアル酸を含む少なくとも一つのFc領域を含むポリペプチドの複数の比率を増加させる段階が、前記少なくとも一つのFc領域を含むポリペプチドの未精製源の濃縮を通じて達成される、請求項12〜18のいずれか1項に記載の方法。
- 前記濃縮が、HPLC、レクチンアフィニティクロマトグラフィー、高pHアニオン交換クロマトグラフィー、およびこれらの組み合わせからなる群から選ばれる方法によって達成される、請求項19に記載の方法。
- 前記シアル化が、少なくとも一つのFc領域を含むポリペプチドに付加された糖質に対して、シアル酸を付加する酵素を用いた化学反応によって達成される、請求項19または20に記載の方法。
- 前記酵素がα−(2,6)シアリルトランスフェラーゼである、請求項21に記載の方法。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017520531A (ja) * | 2014-06-02 | 2017-07-27 | ラボラトワール フランセ デュ フラクショヌマン エ デ ビオテクノロジーLaboratoire Francais du Fractionnement et des Biotechnologies | Fc断片の産生 |
KR20210060359A (ko) * | 2019-11-18 | 2021-05-26 | 건국대학교 산학협력단 | 시알산화된 면역글로불린을 유효성분으로 포함하는 염증성 질환의 치료용 조성물 |
JP2022101682A (ja) * | 2018-07-03 | 2022-07-06 | ギリアード サイエンシーズ, インコーポレイテッド | HIV gp120を標的化する抗体および使用方法 |
Families Citing this family (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8470318B2 (en) | 2005-11-07 | 2013-06-25 | The Rockefeller University | Polypeptides with enhanced anti-inflammatory and decreased cytotoxic properties and relating methods |
US20080206246A1 (en) * | 2006-04-05 | 2008-08-28 | Ravetch Jeffrey V | Polypeptides with enhanced anti-inflammatory and decreased cytotoxic properties and relating methods |
EP3456351A1 (en) * | 2006-04-05 | 2019-03-20 | The Rockefeller University | Polypeptides with enhanced anti-inflammatory and decreased cytotoxic properties and relating methods |
US20090155275A1 (en) | 2007-07-31 | 2009-06-18 | Medimmune, Llc | Multispecific epitope binding proteins and uses thereof |
US20110033378A1 (en) | 2008-01-18 | 2011-02-10 | Medlmmune, Llc. | Cysteine Engineered Antibodies For Site-Specific Conjugation |
US7846744B2 (en) | 2008-04-22 | 2010-12-07 | Ravetch Jeffrey V | Methods of identifying anti-inflammatory compounds |
EP2233499A1 (en) | 2009-03-26 | 2010-09-29 | CSL Behring AG | Antibody composition with altered Fab sialylation |
EP2233502A1 (en) | 2009-03-27 | 2010-09-29 | Deutsches Rheuma-Forschungszentrum Berlin | Sialylated antigen-specific antibodies for treatment or prophylaxis of unwanted inflammatory immune reactions and methods of producing them |
US20120213705A1 (en) | 2009-06-22 | 2012-08-23 | Medimmune, Llc | ENGINEERED Fc REGIONS FOR SITE-SPECIFIC CONJUGATION |
EP2566889A1 (en) | 2010-05-07 | 2013-03-13 | CSL Behring AG | Antibody composition obtained by fractionation of plasma immunoglobulins affinity chromatography on a sambucus nigra affinity column |
CA2799595C (en) | 2010-05-27 | 2022-08-16 | Merck Sharp & Dohme Corp. | Method for preparing antibodies having improved properties |
AR085302A1 (es) | 2011-02-24 | 2013-09-18 | Sanofi Sa | Metodo de produccion de anticuerpos sialilados |
WO2012149197A2 (en) | 2011-04-27 | 2012-11-01 | Abbott Laboratories | Methods for controlling the galactosylation profile of recombinantly-expressed proteins |
SG10202001596VA (en) | 2011-12-19 | 2020-04-29 | Univ Rockefeller | Non-sialylated anti-inflammatory polypeptides |
WO2016141262A1 (en) * | 2015-03-04 | 2016-09-09 | The Rockefeller University | Anti-inflammatory polypeptides |
CA2859755C (en) | 2011-12-23 | 2021-04-20 | Pfizer Inc. | Engineered antibody constant regions for site-specific conjugation and methods and uses therefor |
WO2013158273A1 (en) | 2012-04-20 | 2013-10-24 | Abbvie Inc. | Methods to modulate c-terminal lysine variant distribution |
US9067990B2 (en) | 2013-03-14 | 2015-06-30 | Abbvie, Inc. | Protein purification using displacement chromatography |
US9334319B2 (en) | 2012-04-20 | 2016-05-10 | Abbvie Inc. | Low acidic species compositions |
US9512214B2 (en) | 2012-09-02 | 2016-12-06 | Abbvie, Inc. | Methods to control protein heterogeneity |
SG11201507230PA (en) | 2013-03-12 | 2015-10-29 | Abbvie Inc | Human antibodies that bind human tnf-alpha and methods of preparing the same |
US9017687B1 (en) | 2013-10-18 | 2015-04-28 | Abbvie, Inc. | Low acidic species compositions and methods for producing and using the same using displacement chromatography |
WO2014151878A2 (en) | 2013-03-14 | 2014-09-25 | Abbvie Inc. | Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosacharides |
US10450361B2 (en) | 2013-03-15 | 2019-10-22 | Momenta Pharmaceuticals, Inc. | Methods related to CTLA4-Fc fusion proteins |
CA2909139C (en) | 2013-04-18 | 2021-07-06 | Institut National De La Sante Et De La Recherche Medicale | Composition with reduced immunogenicity |
US20160108450A1 (en) * | 2013-05-02 | 2016-04-21 | Momenta Pharmaceutcals, Inc. | Sialylated glycoproteins |
EP2996772B1 (en) | 2013-05-13 | 2018-12-19 | Momenta Pharmaceuticals, Inc. | Methods for the treatment of neurodegeneration |
US9598667B2 (en) | 2013-10-04 | 2017-03-21 | Abbvie Inc. | Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins |
EP3058084A4 (en) | 2013-10-16 | 2017-07-05 | Momenta Pharmaceuticals, Inc. | Sialylated glycoproteins |
US9181337B2 (en) | 2013-10-18 | 2015-11-10 | Abbvie, Inc. | Modulated lysine variant species compositions and methods for producing and using the same |
US9085618B2 (en) | 2013-10-18 | 2015-07-21 | Abbvie, Inc. | Low acidic species compositions and methods for producing and using the same |
WO2015073884A2 (en) | 2013-11-15 | 2015-05-21 | Abbvie, Inc. | Glycoengineered binding protein compositions |
EP3207055A1 (en) | 2014-10-15 | 2017-08-23 | Xenothera | Composition with reduced immunogenicity |
US10611842B2 (en) | 2016-08-03 | 2020-04-07 | The Board Of Trustees Of The Leland Stanford Junior University | Disrupting FC receptor engagement on macrophages enhances efficacy of anti-SIRPα antibody therapy |
WO2018052503A1 (en) | 2016-09-14 | 2018-03-22 | Teneobio, Inc. | Cd3 binding antibodies |
SG11202000658PA (en) | 2017-07-26 | 2020-02-27 | Forty Seven Inc | Anti-sirp-alpha antibodies and related methods |
US20200207867A1 (en) | 2017-09-13 | 2020-07-02 | Teneobio, Inc. | Heavy chain antibodies binding to ectoenzymes |
AU2018388791A1 (en) | 2017-12-19 | 2020-07-16 | The Rockefeller University | Human IgG Fc domain variants with improved effector function |
MX2020006715A (es) | 2017-12-27 | 2020-08-20 | Teneobio Inc | Anticuerpos especificos del heterodimero de cd3-delta/epsilon. |
JP2021534769A (ja) | 2018-08-31 | 2021-12-16 | エーエルエックス オンコロジー インコーポレイテッド | デコイポリペプチド |
US20210355215A1 (en) | 2018-09-21 | 2021-11-18 | Teneobio, Inc. | Methods for purifying heterodimeric, multispecific antibodies |
US20210353752A1 (en) * | 2018-10-11 | 2021-11-18 | Momenta Pharmaceuticals, Inc. | Treatment with highly silylated igg compositions |
KR20210086651A (ko) | 2018-10-26 | 2021-07-08 | 테네오바이오, 인코포레이티드 | Cd38에 결합하는 중쇄 항체 |
CN110297093B (zh) * | 2019-03-18 | 2022-04-22 | 山西瑞豪生物科技有限公司 | 一种检测人免疫球蛋白g4的方法和试剂盒 |
CN115023441A (zh) | 2019-12-18 | 2022-09-06 | 特诺福尔股份有限公司 | 与cd38结合的重链抗体 |
WO2022271987A1 (en) | 2021-06-23 | 2022-12-29 | TeneoFour, Inc. | Anti-cd38 antibodies and epitopes of same |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002030954A1 (fr) * | 2000-10-06 | 2002-04-18 | Kyowa Hakko Kogyo Co., Ltd. | Procede de purification d'un anticorps |
JP2002541854A (ja) * | 1999-04-15 | 2002-12-10 | クルセル ホラント ベスローテン フェンノートシャップ | ヒト細胞における組み換え蛋白質の生産 |
WO2005033135A1 (en) * | 2003-10-09 | 2005-04-14 | Daewoong Co., Ltd. | Process for purifying human thrombopoietin with high content of sialic acid |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
FR2556219B1 (fr) | 1983-12-07 | 1987-06-26 | Merieux Inst | Nouveau medicament immunomodulateur, a base de fragments fc d'igg humaines |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US5047335A (en) * | 1988-12-21 | 1991-09-10 | The Regents Of The University Of Calif. | Process for controlling intracellular glycosylation of proteins |
US5401650A (en) * | 1990-10-24 | 1995-03-28 | The Mount Sinai School Of Medicine Of The City University Of New York | Cloning and expression of biologically active α-galactosidase A |
BR9106995A (pt) | 1990-11-23 | 1993-08-24 | Gen Hospital Corp | Inibicao de interacoes proteina-carboidrato com adesao celular |
US5453272A (en) | 1992-10-02 | 1995-09-26 | Alberta Research Council | Lectin derived carbohydrate binding-peptide |
WO1995023865A1 (en) * | 1994-03-03 | 1995-09-08 | Genentech, Inc. | Anti-il-8 monoclonal antibodies for treatment of inflammatory disorders |
US6656466B1 (en) | 1995-06-06 | 2003-12-02 | Genetech, Inc. | Human tumor necrosis factor—immunoglobulin(TNFR1-IgG1) chimera composition |
US5705364A (en) * | 1995-06-06 | 1998-01-06 | Genentech, Inc. | Mammalian cell culture process |
US20020045207A1 (en) | 1997-10-31 | 2002-04-18 | Lynne A. Krummen | Glycoprotein production process |
US6660843B1 (en) | 1998-10-23 | 2003-12-09 | Amgen Inc. | Modified peptides as therapeutic agents |
US7297680B2 (en) | 1999-04-15 | 2007-11-20 | Crucell Holland B.V. | Compositions of erythropoietin isoforms comprising Lewis-X structures and high sialic acid content |
DE19927835A1 (de) | 1999-06-18 | 2000-12-21 | Clariant Gmbh | Verwendung von verbesserten Cyanpigmenten in elektrophotographischen Tonern und Entwicklern, Pulverlacken und Ink-Jet-Tinten |
US7064191B2 (en) | 2000-10-06 | 2006-06-20 | Kyowa Hakko Kogyo Co., Ltd. | Process for purifying antibody |
DK2283861T3 (en) | 2000-11-20 | 2016-02-15 | Canadian Blood Services | METHOD OF TREATING TROMBOCYTOPENIA WITH MONOCLONAL IVIG |
US7473680B2 (en) | 2001-11-28 | 2009-01-06 | Neose Technologies, Inc. | Remodeling and glycoconjugation of peptides |
US7427469B2 (en) | 2002-11-05 | 2008-09-23 | Institut Pasteur | Method of treating cytomegalovirus with DC-SIGN blockers |
ES2354610T5 (es) | 2002-12-23 | 2020-09-14 | Bristol Myers Squibb Co | Mejora de la calidad del producto en procedimientos de cultivo de células de mamífero para la producción de proteína |
US20070048740A1 (en) | 2003-02-14 | 2007-03-01 | Research Association For Biotechnology | Full-length cDNA |
DK1613350T3 (da) | 2003-04-09 | 2009-06-22 | Genentech Inc | Behandling af autoimmun sygdom hos en patient med et utilstrækkeligt respons på en TNF-alfa-inhibitor |
RS55723B1 (sr) | 2003-11-05 | 2017-07-31 | Roche Glycart Ag | Molekuli koji se vezuju za antigen sa povećanim afinitetom vezivanja za fc receptor i efektornom funkcijom |
WO2005058244A2 (en) | 2003-12-15 | 2005-06-30 | Alexion Pharmaceuticals, Inc. | Novel anti-dc-sign antibodies |
ES2387028T3 (es) * | 2003-12-31 | 2012-09-12 | Merck Patent Gmbh | Proteína de fusión de Fc-eritropoyetina con farmacocinética mejorada |
PT1896071E (pt) | 2005-06-30 | 2015-07-09 | Janssen Biotech Inc | Métodos e composições com melhorias na atividade terapêutica |
US20070041979A1 (en) | 2005-08-19 | 2007-02-22 | Raju T S | Proteolysis resistant antibody preparations |
US20080206246A1 (en) | 2006-04-05 | 2008-08-28 | Ravetch Jeffrey V | Polypeptides with enhanced anti-inflammatory and decreased cytotoxic properties and relating methods |
US8470318B2 (en) * | 2005-11-07 | 2013-06-25 | The Rockefeller University | Polypeptides with enhanced anti-inflammatory and decreased cytotoxic properties and relating methods |
WO2008057634A2 (en) | 2006-10-26 | 2008-05-15 | The Rockefeller University | Polypeptides with enhanced anti-inflammatory and decreased cytotoxic properties and relating methods |
WO2007055916A2 (en) | 2005-11-07 | 2007-05-18 | The Rockefeller University | Reagents, methods and systems for selecting a cytotoxic antibody or variant thereof |
EP3456351A1 (en) | 2006-04-05 | 2019-03-20 | The Rockefeller University | Polypeptides with enhanced anti-inflammatory and decreased cytotoxic properties and relating methods |
AU2008345558B2 (en) | 2007-12-27 | 2014-08-21 | Baxalta GmbH | Methods for differentiating plasma-derived protein from recombinant protein in a sample |
-
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- 2009-04-22 HK HK09103730.0A patent/HK1124074A1/xx active IP Right Maintenance
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- 2013-05-16 US US13/896,070 patent/US20130273040A1/en not_active Abandoned
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- 2018-03-20 JP JP2018053298A patent/JP6686058B2/ja active Active
- 2018-09-28 US US16/145,688 patent/US20190031737A1/en not_active Abandoned
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-
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- 2019-01-10 US US16/245,053 patent/US20190127446A1/en not_active Abandoned
- 2019-12-20 US US16/724,137 patent/US20200385443A1/en not_active Abandoned
-
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- 2020-04-01 JP JP2020065891A patent/JP6989979B2/ja active Active
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-
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-
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- 2022-12-20 US US18/085,190 patent/US20230121427A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002541854A (ja) * | 1999-04-15 | 2002-12-10 | クルセル ホラント ベスローテン フェンノートシャップ | ヒト細胞における組み換え蛋白質の生産 |
WO2002030954A1 (fr) * | 2000-10-06 | 2002-04-18 | Kyowa Hakko Kogyo Co., Ltd. | Procede de purification d'un anticorps |
WO2005033135A1 (en) * | 2003-10-09 | 2005-04-14 | Daewoong Co., Ltd. | Process for purifying human thrombopoietin with high content of sialic acid |
Non-Patent Citations (4)
Title |
---|
JPN6012037052; Biochem Biophys Res Commun. Vol.286, No.2, 20010817, p.243-249 * |
JPN6013012204; Anal Chem. Vol.77, No.9, 20050501, p.2802-2809 * |
JPN6013012205; Mol Immunol. Vol.44, No.7, 20061011, p.1524-1534 * |
JPN6014018092; Annu Rev Biophys Biomol Struct. Vol.24, 1995, p.551-577 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017520531A (ja) * | 2014-06-02 | 2017-07-27 | ラボラトワール フランセ デュ フラクショヌマン エ デ ビオテクノロジーLaboratoire Francais du Fractionnement et des Biotechnologies | Fc断片の産生 |
JP2022101682A (ja) * | 2018-07-03 | 2022-07-06 | ギリアード サイエンシーズ, インコーポレイテッド | HIV gp120を標的化する抗体および使用方法 |
JP7455156B2 (ja) | 2018-07-03 | 2024-03-25 | ギリアード サイエンシーズ, インコーポレイテッド | HIV gp120を標的化する抗体および使用方法 |
KR20210060359A (ko) * | 2019-11-18 | 2021-05-26 | 건국대학교 산학협력단 | 시알산화된 면역글로불린을 유효성분으로 포함하는 염증성 질환의 치료용 조성물 |
KR102549282B1 (ko) * | 2019-11-18 | 2023-06-30 | 건국대학교 산학협력단 | 시알산화된 면역글로불린을 유효성분으로 포함하는 염증성 질환의 치료용 조성물 |
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