JP2010222380A - 融合タンパク質の免疫原性の低減 - Google Patents
融合タンパク質の免疫原性の低減 Download PDFInfo
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- JP2010222380A JP2010222380A JP2010151743A JP2010151743A JP2010222380A JP 2010222380 A JP2010222380 A JP 2010222380A JP 2010151743 A JP2010151743 A JP 2010151743A JP 2010151743 A JP2010151743 A JP 2010151743A JP 2010222380 A JP2010222380 A JP 2010222380A
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Abstract
【解決手段】 本発明の方法は、T細胞エピトープを識別し、それがT細胞レセプターと相互作用する能力を低減させるように、融合タンパク質の接合部の1個または複数のアミノ酸をアッセイし、変更し、修飾することを含む。
【選択図】なし
Description
本願は、2001年3月30日に出願された米国仮出願特許出願シリアル番号60/280,625号(その全開示内容は言及によって本願に組込まれる)に基づく優先権およびその利益を主張する。
本発明は概括的に言えば、治療剤として免疫原性が低減されているか免疫原性のない修飾された融合タンパク質を製造および使用するための方法および組成物に関する。より具体的には、本発明は、T−細胞エピトープ候補を識別し、そうしたエピトープを除去するようにアミノ酸配列を修正することにより免疫原性を低減した融合タンパク質に関する。
多くの治療用タンパク質は正常なヒトタンパク質である。例えば、インターロイキン−2、エリスロポエチンおよび成長ホルモンは、すべて、通常これらのタンパク質を既に内成的なレベルで産生しているヒトに与えるヒトタンパク質である。一般に、これらのタンパク質を治療用に用いる場合、完全に正常なヒトタンパク質に対する免疫反応は稀にしか起こらない。
本発明は、治療目的で使用される免疫原性の低減された融合タンパク質を産生するのに有用な方法および組成物を特色とする。例えば、本発明はイムノサイトカイン、イムノフュージン(immunofusins;免疫融合体)、イムノリガンド(immunoligands;免疫リガンド)、他の抗体およびFc融合タンパク質、サイトカイン−サイトカイン融合タンパク質および免疫原性の低減されたアルブミン融合タンパク質を特色とする。
治療用途での使用のために患者に投与される、抗体を含むタンパク質はすべて、レシピエントホストにおいて免疫反応を引き起こす可能性を有する。この免疫反応は、Tリンパ球(T細胞)によって仲介されるが、これは、次いで、Bリンパ細胞(B細胞)を起動して抗体を産生させる。治療剤に対する抗体産生は、治療剤のより多くの迅速な除去に結びつき、アレルギー反応を引き起こすおそれがあるため不利益である。
QKTIDRLAGKPTH(配列番号:8)をQKTADRTAGKPTH(配列番号:9)に変更。
KKLVAASQAALGL(配列番号:13)をKKLVAASQAATTA(配列番号:14)に変更。
HuKS−IL2は、ヒト化されたVHおよびVL領域をヒトのHおよびL鎖定常領域と組み合わせてなる。H鎖は、前に述べたようにそのカルボキシル末端をヒトIL−2の成熟配列に融合した。このH鎖はγ1アイソタイプであり、Fcレセプターに高い親和性がある。この高い親和性のためHuKS−IL2は血液循環からすばやく取り除かれた。特定の理論に拘束されるものではないが、HuKS−IL2の除去は肝臓(クッパー(Kupffer)細胞)および脾臓(抗原提示細胞)中のFcR担持細胞を介して生じると推測される。
(1)Hu14.18−IL2、完全に異なるヒト化されたV領域を備えているが正確に同じC領域およびIL−2との融合接合部を有する分子;
(2)VH1、ヒト残基に張り合わせされた(veneered)、表面露出マウスB細胞エピトープを備えたマウスV領域に由来する、VHおよびVLの領域中にT−細胞エピトープを含まないhuKS−IL2の脱−免疫形;
(3)VH2、ヒト残基に張り合わせされた(veneered)、表面露出マウスB細胞エピトープを備えたマウスV領域に由来する、CDR3中に1個の残存T−細胞エピトープを含むhuKS−IL2の脱−免疫形で、このVHは1個のT−細胞エピトープを含む;
(4)KOLまたはEU Cγ1領域(KSではなく)のいずれかで構築された425−IL2(アロタイプの活性と比較するため);
(5)huKS−mIL2−、マウスC領域およびマウスIL−2に融合したhuKS V領域を備えた分子;
(6)ヒトFc−IL2;
(7)ヒトFcのみ;
(8)ヒトIL−2のみ。
ペプチドスレッディング分析により、強いMHC可能性を有する2個の重複するペプチドセグメントが、イムノサイトカインのFcとIL2部分の間の接合部に識別された。潜在的なT−細胞エピトープのペプチドスレッディングおよび識別は、Carr(WO00/34317)に開示されるように実行した。アミノ酸の変更は、既存の潜在的なMHCクラスII結合エピトープを除去するが、新たな潜在的なMHCクラスIIエピトープを導入しないように行われた。
接合部配列LSLSPGK−AP(配列番号:17)のLNLSPGA−AP(配列番号:19)への修飾(「LSLSからLNLSへ」)(ここで、ハイフンはイムノサイトカインhuKS−IL2接合部である)によっても、接合部由来ペプチド配列はある種のヒトのMHCクラスIIには結合可能である。しかし、KS−IL2タンパク質が哺乳類細胞中で発現され分泌される場合、タンパク質は、NXS/T配列であるため接合部近傍でN−グリコシル化される。
反応性エピトープの修飾による免疫原性の低減を、LSLSをATATに変化させることにより以下のように直接試験する。この配列を模倣する合成ペプチドは、樹状細胞(DC)などの古典的抗原提示細胞の免疫反応を変更する。以下の合成ペプチド:
ヒト血清アルブミン(HSA)は、その著しい半減期の長さのため、生体内で広く分配されるとともに酵素的または免疫学的機能が欠如していることから、治療用のペプチド/タンパク質用の担体として用いられてきた。遺伝子的に操作されたHSA−CD4ハイブリッドは、生体外で可溶性CD4に似た抗ウイルス性を示すとともにCD4+細胞中へのヒト免疫不全ウイルスの侵入を阻むことが示されている(Yehら、PNAS 89:1904−190S、1992年)。したがって、HSAに生体に影響するペプチドを遺伝的に融合することは、分泌される治療用HSA誘導体を設計および回復に有用である。しかし、すべての融合タンパク質と同様に、HSA−CD4は新規な接合部を有し、これは免疫原になり得るとともに、MHCクラスII分子上で提示され得るT−細胞エピトープを含む。実施例1、2、3および4の方法を使用したHSAとCD4との間の接合部の分析はペプチドを、MHCと結合する可能性を識別する。潜在的に免疫原性の配列は、潜在的なTおよびB細胞エピトープを減少または除去させて免疫原性を低減するために修飾される。同様に、免疫原性を低減するために新規なグリコシル化部位を接合領域に導入することができる。
いくつかの例では、X−Fcの向きの融合タンパク質を創出するのが有利である。これらの構成体により、標的タンパク質はN−末端融合タンパク質であり、Fc断片が続く。例えば、グルカゴン様ペプチド(GLP−1)は、その活性のために遊離N−末端が必要であり、したがって、GLP−1−Fc融合体が有用である。
ENBRELまたはエタネルセプト(FDAによって承認されたX−Fc融合タンパク質)は、慢性関節リウマチを治療するために使用される腫瘍壊死因子(TNF)阻害剤である。ENBRELは、ヒトIgG1のFcタンパク質に結合されたTNFレセプターの細胞外のリガンド結合ドメインからなる二量体の融合タンパク質である。TNFR−Fcは、TNFのそのレセプターへの結合を競争的に阻害し、結合したTNFを生物学的に不活性にし、炎症性の活性を顕著に低減させる。GLP−1−Fcについて上述したように、TNFR−Fcは潜在的なT−細胞エピトープを含む新規な接合部を有する。
Fc−IL12−IL2などのFc−X−Yの配置の融合タンパク質は、潜在的に免疫原性である多数の新規な融合接合部を有する。例えば、Fc−IL12は、他のFc−X融合タンパク質またはイムノサイトカイン(実施例1)に類似した融合接合部を有するが、サイトカインIL12の使用のために新規である。融合接合部は免疫原性の結合サイトについて分析され、従って修飾される。第2に、融合タンパク質を構成する2個の異なるサイトカインとともに、実施例5に記載されたそれに匹敵するX−Y融合接合部がある。ペプチドスレッディング分析が融合接合部の各々について使用される。
IL4−Fc−GMCSFなどのX−Fc−Y配置の融合タンパク質は、潜在的なT−細胞エピトープを含む多数の新規な融合接合部を有する。IL4−Fcは、他のX−Fc融合タンパク質(実施例6および7)と類似している接合であるが、サイトカインIL4の使用のために新規である。例えば、ヒンジ領域を使用するFc、CH2およびヒトγ1からのCH3領域を用いる形態が使用される。前述のように、pdCshuFcγl中のγ1ヒンジ配列は、IgG1中の軽鎖とのジスルフィド結合を形成するCys残基を除去するCysのSerへの変異(下線)を含んでもよいし(Loら(1998)Protein Engineering 11:495−500)、これにより、分析のための第3の潜在的に免疫原の融合接合部を生成してもよい。融合接合部は潜在的なT−細胞エピトープについて分析し、実施例1〜4の方法によって修飾した。
抗体またはハイブリッドアイソタイプとの抗体に基づく融合タンパク質を構築し、その結果、異なるアイソタイプの有用な特徴を単一の分子中に組み合わせることは多くの場合有用である。ハイブリッドアイソタイプとの融合タンパク質は免疫原性を低減するために本発明によって修飾してもよい。
Fcエリスロポエチン融合タンパク質を生成するために、次の発現プラスミドを標準的分子生物学技術を使用して構築した。アミノ酸置換His32Gly、Cys33Pro、Trp88CysおよびPro90Alaをもたらす変異を備えた配列をコードするヒトエリスロポエチンの形態を含むXmaI−XhoI DNA断片を、WO01/36489に示されるように、使用した。対応するタンパク質配列は配列番号:56
本発明によれば、融合タンパク質の接合領域のエピトープは、その免疫系との相互作用を調整するためにタンパク質中に変異体を導入する方法を使用して修飾することができる。本発明によれば、本発明によって適用することができる当業者には知られた方法は、先行技術(WO92/10755およびWO96/40792(Novo Nordisk)、EP 0519 596(Merck & Co.)、EP 0699 755(Centro de Immunologia Moelcular)、WO98/52976およびWO98/59244(Biovation Ltd.)に記載されたもの、さらに関連する方法を含む。
(1)予め定義した長さのペプチドセグメントの1次配列を走査し、存在する疎水性脂肪族と芳香族側鎖をすべて識別する。(2)疎水性脂肪族側鎖には芳香族側鎖用のそれより大きな値、好ましくは芳香族側鎖に割り当てる値の約2倍を割り当てる(例えば、疎水性脂肪族側鎖に対しては値2を、芳香族側鎖に対しては値1を割り当てる)。(3)ペプチド内の予め定義した一定の長さの各重複するアミノ酸残基セグメント(ウィンドウ)について存在が決定された値を合計し、特定のセグメント(ウィンドウ)に対する値の合計を、セグメント(ウィンドウ)の中間位置で単一のアミノ酸残基、好ましくは、サンプリングされたセグメント(ウィンドウ)の中間点付近の残基に割り当てる。この手続きを、サンプリングされた各重複するアミノ酸残基セグメント(ウィンドウ)について繰り返す。したがって、ペプチドの各アミノ酸残基は、特定のセグメント(ウィンドウ)内に存在するT細胞エピトープの可能性に関係のある値を割り当てられる。(4)上記ステップ3に記載するように計算し割り当てた値は、評価するアミノ酸残基配列全体のアミノ酸座標に対してプロットすることができる。(5)予め定義した値(例えば値1)のスコアを有する配列のすべての部分は、T細胞エピトープを含むと認められ、必要であれば、修飾することができる。
(ΔGbind)=(ΔGo)+(ΔGhbxNhb)+(ΔGionicxNionic)+(ΔGlipoxNlipo)+(ΔGrot+Nrot)+(EvdW)
式中、Nは特定の項の相互作用を特徴付ける数であり、1つの実施形態では、ΔGo、ΔGhb、ΔGionic、ΔGlipoおよびΔGrotは、それぞれ5.4、−4.7、−4.7、−0.17および1.4の値を与えられる定数である。
Nhb=Σh-bondsf(ΔR,Δα)×f(Nneighb)×fpcs
によって計算される。
f(ΔR,Δ−α)=f1(ΔR)×f2(Δα)
ここで、f1(ΔR)=1(ΔR<=TOLの場合)、
または =1−(ΔR−TOL)/0.4(ΔR<=0.4+TOLの場合)、
または =0(ΔR>0.4+TOLの場合)。
さらに、f2(Δα)=1(Δα<30°の場合)
または =1−(Δα−30)/50(Δα<=80°の場合)
または =0(Δα>80°の場合)。
ΔRはH−O/N水素結合長さの理想的な値(=1.9Å)からの偏差、
Δαは水素結合角度∠N/O-H,O/Nの理想的な値(=180°)からの偏差、
f(Nneighb)は、タンパク質表面の凹面と凸面の部分を識別し、したがってタンパク質表面で見られるものではなくポケットで見られる極性相互作用に大きな重みを割り当てる。この関数は下記方程式4:
f(Nneighb)=(Nneighb/Nneighb,0)α(ここで、α=0.5)
によって計算される。
Nneighb,0=定数25である。
fpcs=β(Apolar/NHB<10Å2の場合)、
またはfpcs=1(Apolar/NHB>10Å2の場合)
Apolarはタンパク質リガンド接触表面の大きさであり、
NHBは水素結合の数であり、
βは定数=1.2である。
Nlipo=ΣILf(rIL)
f(rIL)はすべての脂肪親和性リガンド原子について、1また、すべての脂肪親和性タンパク質原子についてLであり、以下の基準により計算される:
f(rIL)=1(rIL<=R1f(rIL)=(rIL−R1)/(R2−R1)でR2<rIL>R1の場合、
f(rIL)=0(rIL>=R2の場合)。
R2=R1+3.0であり、
r1vdwは、原子1のファンデアワールスの半径であり、
rL vdwは、原子Lのファンデアワールスの半径である。
Evdw=ε1ε2((r1 vdw+r2 vdw)12/r12−(r1 vdw+r2 vdw)6/r6)。
r1 vdw+r2 vdwはファンデアワールスの原子半径であり、
rは1対の原子間の距離である。
本発明は他の具体的なかたちでその精神または基本的な特徴から離れることなく具体化することができる。さらなる具体例として、ここに記載されている発明に限定するというよりは実例として全ての面において、従って考えうる。本発明の範囲内で、従って、先述の明細書によってというよりはさらなる特許請求の範囲によって意図される。さらに、本特許請求の範囲の同等の意味および範囲内に起こる全ての変化は、その中に包括されることを意図している。
ここで上記に意図する、全ての特許、特許明細書および化学文献は、すべてこの明細書の中に組み込まれる。
Claims (7)
- 第1のタンパク質がC−末端側のアミノ酸を介して第2のタンパク質のN−末端側のアミノ酸と連結して融合接合部を形成する、第1のタンパク質と第2のタンパク質とを含む融合タンパク質の非自己T細胞エピトープを除去することにより免疫原性を低減する方法であって、該方法は、該融合接合部を取り囲む接合領域の1から15のアミノ酸が変更され、該変更が、以下のステップ:
(i)N−結合グリコシル化部位またはO−結合グリコシル化部位を導入する、
(ii)融合タンパク質中のN−末端融合パートナーの最もC−末端側の8アミノ酸に存在するロイシン、バリン、イソロイシン、メチオニン、フェニルアラニン、チロシンまたはトリプトファンをトレオニン、アラニンまたはプロリンに変更する、
(iii)前記第1のタンパク質がIgG分子またはその断片である場合に、アミノ酸配列Leu−Ser−Leu−SerをAla−Thr−Ala−Thrに変更する、
の1つにより行われる方法。 - 前記ステップ(i)が、前記融合接合部の10、5または2個のアミノ酸内にグリコシル化部位を導入することによって行われる、請求項1に記載の方法。
- 前記ステップ(i)が、Asn−X−Ser/Thrアミノ酸配列(Xは任意のアミノ酸である)を導入することによって行われる、請求項1に記載の方法。
- 前記第1のタンパク質がIg分子またはその断片である、請求項1に記載の方法。
- 前記第1のタンパク質がIg分子またはその断片であり、前記第2のタンパク質がサイトカインである、請求項1に記載の方法。
- 血中半減期を増大するために、さらなる変更がC末端のリジンをアラニンまたはロイシンに変更することにより、融合タンパク質のIgGとサイトカインの部分の間で行われる、請求項5に記載の方法。
- 前記接合領域が1から9個のアミノ酸を含む、請求項1から6のいずれかに記載の方法。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE267215T1 (de) * | 1997-12-08 | 2004-06-15 | Lexigen Pharm Corp | Heterodimäre fusionsproteine zur verwendung für gezielte immuntherapie und allgemeine immunerregung |
US20030105294A1 (en) * | 1998-02-25 | 2003-06-05 | Stephen Gillies | Enhancing the circulating half life of antibody-based fusion proteins |
JP2002511432A (ja) * | 1998-04-15 | 2002-04-16 | レキシジェン ファーマシューティカルズ コーポレイション | 新脈管形成インヒビターの同時投与による抗体−サイトカイン融合タンパク質媒介性免疫応答の増強 |
SK782002A3 (en) | 1999-07-21 | 2003-08-05 | Lexigen Pharm Corp | FC fusion proteins for enhancing the immunogenicity of protein and peptide antigens |
HUP0202442A3 (en) * | 1999-08-09 | 2005-01-28 | Lexigen Pharmaceuticals Corp L | Multiple cytokine-antibody complexes |
US20050202538A1 (en) * | 1999-11-12 | 2005-09-15 | Merck Patent Gmbh | Fc-erythropoietin fusion protein with improved pharmacokinetics |
ATE336514T1 (de) | 2000-02-11 | 2006-09-15 | Merck Patent Gmbh | Steigerung der zirkulierenden halbwertzeit von auf antikörpern basierenden fusionsproteinen |
PT1294401E (pt) * | 2000-06-29 | 2007-11-09 | Merck Patent Gmbh | Aumento das respostas imunológicas mediadas por proteínas de fusão anticorpo-citoquina por tratamento combinado com agentes que aumentam a captação de imunocitoquinas |
KR20090010127A (ko) | 2001-03-07 | 2009-01-28 | 메르크 파텐트 게엠베하 | 하이브리드 이소타입 항체 부분구조를 포함하는 단백질을 위한 발현 기술 |
WO2002079415A2 (en) | 2001-03-30 | 2002-10-10 | Lexigen Pharmaceuticals Corp. | Reducing the immunogenicity of fusion proteins |
US20120148585A1 (en) * | 2001-05-01 | 2012-06-14 | Andrew Saxon | Fusion molecules and methods for treatment of immune diseases |
DK1383785T3 (da) | 2001-05-03 | 2011-05-23 | Merck Patent Gmbh | Rekombinant tumorspecifikt antistof og anvendelse deraf |
DE10122140A1 (de) * | 2001-05-08 | 2002-11-28 | Apotech Res & Dev Ltd | Rekombinante Fusionsproteine und deren Trimere |
ATE542137T1 (de) * | 2001-12-04 | 2012-02-15 | Merck Patent Gmbh | Immunocytokine mit modulierter selektivität |
US7662925B2 (en) | 2002-03-01 | 2010-02-16 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
US20040132101A1 (en) | 2002-09-27 | 2004-07-08 | Xencor | Optimized Fc variants and methods for their generation |
US7317091B2 (en) | 2002-03-01 | 2008-01-08 | Xencor, Inc. | Optimized Fc variants |
US7611700B2 (en) * | 2002-09-09 | 2009-11-03 | Hanall Pharmaceuticals, Co., Ltd. | Protease resistant modified interferon alpha polypeptides |
KR101197500B1 (ko) * | 2002-11-15 | 2012-11-09 | 니프로 가부시키가이샤 | 리포솜 |
WO2004055056A1 (en) | 2002-12-17 | 2004-07-01 | Merck Patent Gmbh | Humanized antibody (h14.18) of the mouse 14.18 antibody binding to gd2 and its fusion with il-2 |
US20090010920A1 (en) | 2003-03-03 | 2009-01-08 | Xencor, Inc. | Fc Variants Having Decreased Affinity for FcyRIIb |
US8388955B2 (en) | 2003-03-03 | 2013-03-05 | Xencor, Inc. | Fc variants |
CA2520254A1 (en) * | 2003-03-26 | 2004-10-07 | Apogenix Gmbh | Treatment of viral infections |
US20070161087A1 (en) * | 2003-05-29 | 2007-07-12 | Wolfgang Glaesner | Glp-1 fusion proteins |
US7452966B2 (en) * | 2003-06-12 | 2008-11-18 | Eli Lilly And Company | GLP-1 analog fusion proteins |
CN1871259A (zh) | 2003-08-22 | 2006-11-29 | 比奥根艾迪克Ma公司 | 具有改变的效应物功能的经改进的抗体和制备它的方法 |
US20050069521A1 (en) * | 2003-08-28 | 2005-03-31 | Emd Lexigen Research Center Corp. | Enhancing the circulating half-life of interleukin-2 proteins |
US8101720B2 (en) | 2004-10-21 | 2012-01-24 | Xencor, Inc. | Immunoglobulin insertions, deletions and substitutions |
US9714282B2 (en) | 2003-09-26 | 2017-07-25 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
CN100453556C (zh) | 2003-10-16 | 2009-01-21 | 麦克罗梅特股份公司 | 多特异性的去免疫化cd3结合物 |
US20050142133A1 (en) * | 2003-12-03 | 2005-06-30 | Xencor, Inc. | Optimized proteins that target the epidermal growth factor receptor |
EP2221315A1 (en) | 2003-12-04 | 2010-08-25 | Xencor, Inc. | Methods of generating variant proteins with increased host string content and compositions thereof |
CN100427599C (zh) * | 2003-12-26 | 2008-10-22 | 吉林大学第一医院 | Albsin/il-18mat杂交细胞因子 |
DE602004013372T2 (de) | 2003-12-30 | 2009-07-02 | Merck Patent Gmbh | Il-7-fusionsproteine mit antikörperportionen, deren herstellung und deren verwendung |
RU2370276C2 (ru) * | 2003-12-31 | 2009-10-20 | Мерк Патент Гмбх | Fc-ЭРИТРОПОЭТИН СЛИТЫЙ БЕЛОК С УЛУЧШЕННОЙ ФАРМАКОКИНЕТИКОЙ |
AU2005203962C1 (en) * | 2004-01-05 | 2012-11-08 | Antisoma Research Limited | Interleukin-12 targeted to oncofoetal fibronectin |
ES2330860T3 (es) | 2004-01-22 | 2009-12-16 | Merck Patent Gmbh | Anticuerpos anticancerosos con fijacion del complemento reducida. |
PL1737961T3 (pl) | 2004-03-19 | 2013-12-31 | Merck Patent Gmbh | Zmodyfikowane białka bouganiny, cytotoksyny i sposoby oraz ich zastosowania |
AU2005227326B2 (en) | 2004-03-24 | 2009-12-03 | Xencor, Inc. | Immunoglobulin variants outside the Fc region |
WO2005097202A2 (en) * | 2004-04-06 | 2005-10-20 | Affibody Ab | Use of serum albumin binding peptides conjugates for the preparation of a medicament |
US7670595B2 (en) * | 2004-06-28 | 2010-03-02 | Merck Patent Gmbh | Fc-interferon-beta fusion proteins |
EP1919950A1 (en) | 2004-07-15 | 2008-05-14 | Xencor, Inc. | Optimized fc variants |
MX2007000921A (es) | 2004-07-22 | 2007-11-09 | Univ Erasmus Medical Ct | Moleculas de union. |
EA014226B1 (ru) | 2004-07-26 | 2010-10-29 | Байоджен Айдек Ма Инк. | Антитела к cd154, их фрагменты и способы применения антител и фрагментов |
CA2581423A1 (en) | 2004-09-23 | 2006-03-30 | Vasgene Therapeutics, Inc. | Polipeptide compounds for inhibiting angiogenesis and tumor growth |
JP4652414B2 (ja) | 2004-11-12 | 2011-03-16 | ゼンコー・インコーポレイテッド | FcRnとの変化した結合を有するFc変異体 |
US8367805B2 (en) | 2004-11-12 | 2013-02-05 | Xencor, Inc. | Fc variants with altered binding to FcRn |
US8802820B2 (en) | 2004-11-12 | 2014-08-12 | Xencor, Inc. | Fc variants with altered binding to FcRn |
CN101072793B (zh) * | 2004-12-09 | 2012-06-20 | 默克专利有限公司 | 具有降低的免疫原性的il-7变体 |
WO2006068910A1 (en) | 2004-12-22 | 2006-06-29 | Eli Lilly And Company | Glp-1 analog fusion protein formulations |
CA2595169A1 (en) * | 2005-01-12 | 2006-07-20 | Xencor, Inc. | Antibodies and fc fusion proteins with altered immunogenicity |
WO2007012188A1 (en) * | 2005-07-27 | 2007-02-01 | Qinghua Wang | GLP/1/EXENDM 4 IgG Fc FUSION CONSTRUCTS FOR TREATMENT OF DIABETES |
US7855279B2 (en) | 2005-09-27 | 2010-12-21 | Amunix Operating, Inc. | Unstructured recombinant polymers and uses thereof |
US20070104689A1 (en) * | 2005-09-27 | 2007-05-10 | Merck Patent Gmbh | Compositions and methods for treating tumors presenting survivin antigens |
EP1931709B1 (en) | 2005-10-03 | 2016-12-07 | Xencor, Inc. | Fc variants with optimized fc receptor binding properties |
ES2856451T3 (es) | 2005-10-11 | 2021-09-27 | Amgen Res Munich Gmbh | Composiciones que comprenden anticuerpos específicos para diferentes especies, y usos de las mismas |
RU2426743C2 (ru) | 2005-12-21 | 2011-08-20 | Микромет Аг | Фармацевтические композиции с устойчивостью к растворимому сеа |
KR101397290B1 (ko) * | 2005-12-30 | 2014-05-21 | 메르크 파텐트 게엠베하 | 감소한 면역원성을 가지는 항-cd19 항체 |
PT1966238E (pt) | 2005-12-30 | 2012-07-31 | Merck Patent Gmbh | Uso de hsp70 como um regulador de atividade enzimática |
WO2007085814A1 (en) * | 2006-01-24 | 2007-08-02 | Domantis Limited | Fusion proteins that contain natural junctions |
US7625564B2 (en) | 2006-01-27 | 2009-12-01 | Novagen Holding Corporation | Recombinant human EPO-Fc fusion proteins with prolonged half-life and enhanced erythropoietic activity in vivo |
EP2038417A2 (en) * | 2006-07-06 | 2009-03-25 | Merck Patent GmbH | Compositions and methods for enhancing the efficacy of il-2 mediated immune responses |
WO2008045380A2 (en) * | 2006-10-04 | 2008-04-17 | Codon Devices, Inc. | Nucleic acid libraries and their design and assembly |
WO2008065372A2 (en) | 2006-11-28 | 2008-06-05 | Nautilus Biotech, S.A. | Modified erythropoietin polypeptides and uses thereof for treatment |
CN103755789B (zh) | 2007-01-30 | 2016-12-07 | 埃皮瓦克斯公司 | 调节性t细胞表位、组合物及其用途 |
MX2009011870A (es) | 2007-05-02 | 2009-11-12 | Ambrx Inc | Polipeptidos de interferon beta modificados y usos de los mismos. |
GB2451928B (en) * | 2007-06-21 | 2011-03-16 | Angelica Therapeutics Inc | Modified Toxins |
US8137979B2 (en) * | 2007-06-25 | 2012-03-20 | Qinetiq Limited | Preconcentrator device |
WO2009012600A1 (en) | 2007-07-26 | 2009-01-29 | Novagen Holding Corporation | Fusion proteins |
CA3128656A1 (en) | 2007-08-22 | 2009-02-26 | The Regents Of The University Of California | Activatable binding polypeptides and methods of identification and use thereof |
PL2808343T3 (pl) | 2007-12-26 | 2019-11-29 | Xencor Inc | Warianty Fc ze zmienionym wiązaniem do FcRn |
WO2009110944A1 (en) * | 2008-02-29 | 2009-09-11 | Angelica Therapeutics, Inc. | Modified toxins |
EP2376105B1 (en) | 2008-12-18 | 2015-07-29 | Dana-Farber Cancer Institute, Inc. | Nkg2d-fc for immunotherapy |
RU2636046C2 (ru) | 2009-01-12 | 2017-11-17 | Сайтомкс Терапьютикс, Инк | Композиции модифицированных антител, способы их получения и применения |
ES2610356T3 (es) | 2009-02-03 | 2017-04-27 | Amunix Operating Inc. | Polipéptidos recombinantes extendidos y composiciones que comprenden los mismos |
EP2398494A4 (en) | 2009-02-23 | 2015-10-28 | Cytomx Therapeutics Inc | Proproteins and their methods of use |
EA201171259A1 (ru) * | 2009-04-22 | 2012-05-30 | Мерк Патент Гмбх | Антительные гибридные белки с модифицированными сайтами связывания fcrn |
MX354555B (es) | 2009-06-08 | 2018-03-09 | Amunix Operating Inc | Polipeptidos de la hormona de crecimiento y metodos de preparacion y su uso. |
PT2440228T (pt) | 2009-06-08 | 2018-12-24 | Amunix Operating Inc | Polipéptidos de regulação da glicose e métodos de preparação e utilização dos mesmos |
JP6166041B2 (ja) | 2009-06-15 | 2017-07-19 | バレリオン セラピューティクス, エルエルシー | ミオチューブラリン1(mtm1)ポリペプチドを含むキメラポリペプチドを使用して筋細管ミオパシーを処置するための方法および組成物 |
WO2011028229A1 (en) | 2009-08-24 | 2011-03-10 | Amunix Operating Inc. | Coagulation factor ix compositions and methods of making and using same |
US9493578B2 (en) | 2009-09-02 | 2016-11-15 | Xencor, Inc. | Compositions and methods for simultaneous bivalent and monovalent co-engagement of antigens |
US8932588B2 (en) | 2009-11-05 | 2015-01-13 | Teva Pharmaceuticals Australia Pty. Ltd. | Treatment of cancer involving mutated KRAS or BRAF genes |
WO2011091078A2 (en) | 2010-01-19 | 2011-07-28 | Xencor, Inc. | Antibody fc variants with enhanced complement activity |
EP2536756B1 (en) | 2010-02-16 | 2018-04-25 | MedImmune, LLC | Hsa-related compositions and methods of use |
WO2012119989A2 (en) | 2011-03-04 | 2012-09-13 | Oryzon Genomics, S.A. | Methods and antibodies for the diagnosis and treatment of cancer |
ES2876421T3 (es) * | 2011-04-13 | 2021-11-12 | Bristol Myers Squibb Co | Proteínas de fusión Fc que comprenden enlazadores o disposiciones nuevos |
JP6430828B2 (ja) * | 2011-05-05 | 2018-11-28 | アルブミディクス リミティド | アルブミン変異体 |
CN102222177A (zh) * | 2011-07-08 | 2011-10-19 | 上海生物信息技术研究中心 | 抗体蛋白的分子改造辅助预测方法 |
WO2013096948A1 (en) | 2011-12-23 | 2013-06-27 | Lydon Nicholas B | Immunoglobulins and variants directed against pathogenic microbes |
US9988439B2 (en) | 2011-12-23 | 2018-06-05 | Nicholas B. Lydon | Immunoglobulins and variants directed against pathogenic microbes |
CA2864904C (en) | 2012-02-15 | 2023-04-25 | Amunix Operating Inc. | Factor viii compositions and methods of making and using same |
EP3549953A1 (en) | 2012-02-15 | 2019-10-09 | Bioverativ Therapeutics Inc. | Recombinant factor viii proteins |
CN107496932A (zh) | 2012-02-27 | 2017-12-22 | 阿穆尼克斯运营公司 | Xten缀合组合物和制造其的方法 |
WO2013184216A1 (en) | 2012-06-05 | 2013-12-12 | Amunix Operating Inc. | Hgh-xten fusion protein and its use in the treatment of growth hormone deficiency |
US9714291B2 (en) * | 2012-10-05 | 2017-07-25 | Kyowa Hakko Kirin Co., Ltd | Heterodimer protein composition |
US10017581B2 (en) | 2013-02-20 | 2018-07-10 | Valerion Therapeutics, Llc | Methods and compositions for treatment of Pompe disease |
WO2014141192A1 (en) | 2013-03-15 | 2014-09-18 | Erasmus University Medical Center | Generation of heavy chain-only antibodies |
JP2016519651A (ja) | 2013-03-15 | 2016-07-07 | アンジェリカ セラピューティックス,インク. | 改質された毒素 |
US10548953B2 (en) | 2013-08-14 | 2020-02-04 | Bioverativ Therapeutics Inc. | Factor VIII-XTEN fusions and uses thereof |
WO2015085311A1 (en) | 2013-12-07 | 2015-06-11 | Case Western Reserve University | Compositions and methods of treating thrombosis |
JP6730926B2 (ja) | 2014-01-08 | 2020-07-29 | プロージット ソウル バイオテクノロジー (ベイジン) カンパニー リミテッド | 融合ポリペプチドおよび使用方法 |
US10221250B2 (en) | 2014-01-13 | 2019-03-05 | Valerion Therapeutics, Llc | Internalizing moieties |
JP6731346B2 (ja) | 2014-02-10 | 2020-07-29 | メルク パテント ゲーエムベーハー | 標的TGFβ阻害 |
GB201403775D0 (en) | 2014-03-04 | 2014-04-16 | Kymab Ltd | Antibodies, uses & methods |
CA2950178A1 (en) * | 2014-06-06 | 2015-12-10 | The California Institute For Biomedical Research | Methods of constructing amino terminal immunoglobulin fusion proteins and compositions thereof |
US10124073B2 (en) | 2014-08-04 | 2018-11-13 | Case Western Reserve University | Targeting peptides and methods of use |
JP2017536091A (ja) | 2014-10-02 | 2017-12-07 | シティ・オブ・ホープCity of Hope | 多価メディトープ、メディトープ結合性抗体およびそれらの使用 |
WO2016087514A1 (en) | 2014-12-02 | 2016-06-09 | Cemm - Forschungszentrum Für Molekulare Medizin Gmbh | Anti-mutant calreticulin antibodies and their use in the diagnosis and therapy of myeloid malignancies |
WO2016149643A2 (en) * | 2015-03-18 | 2016-09-22 | Omnicyte | Fusion proteins comprising modified alpha virus surface glycoproteins and tumor associated antigen and methods thereof |
US11020454B2 (en) | 2015-07-15 | 2021-06-01 | Prosit Sole Biotechnology (Beijing) Co. Ltd | Fusion polypeptides and methods of use |
WO2017024060A1 (en) | 2015-08-03 | 2017-02-09 | Biogen Ma Inc. | Factor ix fusion proteins and methods of making and using same |
CN114853907A (zh) | 2015-11-13 | 2022-08-05 | 达纳-法伯癌症研究所有限公司 | 用于癌症免疫疗法的nkg2d-ig融合蛋白 |
EP4011919A3 (en) | 2015-12-09 | 2022-10-12 | The Scripps Research Institute | Relaxin immunoglobulin fusion proteins and methods of use |
US9567399B1 (en) | 2016-06-20 | 2017-02-14 | Kymab Limited | Antibodies and immunocytokines |
CA3031168A1 (en) | 2016-08-12 | 2018-02-15 | Merck Patent Gmbh | Combination therapy for cancer |
WO2018083248A1 (en) | 2016-11-03 | 2018-05-11 | Kymab Limited | Antibodies, combinations comprising antibodies, biomarkers, uses & methods |
EP3496742A4 (en) | 2016-12-01 | 2020-04-08 | University Of South Florida | PEPTICORPS, COMPOSITIONS THEREOF, AND METHODS FOR TREATING EAR FIBRILLATION |
US11129906B1 (en) | 2016-12-07 | 2021-09-28 | David Gordon Bermudes | Chimeric protein toxins for expression by therapeutic bacteria |
EP3873611A1 (en) | 2018-11-01 | 2021-09-08 | Merck Patent GmbH | Anti-tim-3 antibodies |
EP3873612A2 (en) | 2018-11-01 | 2021-09-08 | Merck Patent GmbH | Methods of administering anti-tim-3 antibodies |
JP2022530216A (ja) * | 2019-04-23 | 2022-06-28 | エルジー・ケム・リミテッド | 免疫グロブリンのFc領域およびGDF15を含む融合ポリペプチド |
JP2022543669A (ja) * | 2019-08-08 | 2022-10-13 | 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 | 新規抗原結合分子フォーマット |
US20230287040A1 (en) | 2019-11-13 | 2023-09-14 | Amunix Pharmaceuticals, Inc. | Barcoded xten polypeptides and compositions thereof, and methods for making and using the same |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000034317A2 (en) * | 1998-12-08 | 2000-06-15 | Biovation Limited | Method for reducing immunogenicity of proteins |
WO2000040615A2 (en) * | 1999-01-07 | 2000-07-13 | Lexigen Pharmaceuticals, Corp. | EXPRESSION AND EXPORT OF ANTI-OBESITY PROTEINS AS Fc FUSION PROTEINS |
WO2000047741A1 (en) * | 1999-02-12 | 2000-08-17 | Amgen Inc. | Glycosylated leptin compositions and related methods |
WO2001010912A1 (en) * | 1999-08-09 | 2001-02-15 | Lexigen Pharmaceuticals Corp. | Multiple cytokine-antibody complexes |
JP2004532620A (ja) * | 2001-02-19 | 2004-10-28 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | 免疫原性の低減された人工タンパク質 |
Family Cites Families (238)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US166877A (en) * | 1875-08-17 | Improvement in electric lights | ||
US193570A (en) * | 1877-07-24 | Improvement in washing-boards | ||
US147311A (en) * | 1874-02-10 | Improvement in electric telegraphs | ||
US44423A (en) * | 1864-09-27 | Improved screw for music-stools | ||
US142374A (en) * | 1873-09-02 | Improvement in stopping mechanisms for doubling and twisting machines | ||
US49227A (en) * | 1865-08-08 | Improvement in construction of railway trains and cars | ||
US12789A (en) * | 1855-05-01 | Office | ||
US166163A (en) * | 1875-07-27 | Improvement in bee-hives | ||
US192222A (en) * | 1877-06-19 | Improvement in watches | ||
US53539A (en) * | 1866-03-27 | Improvement in revolving fire-arms | ||
US105294A (en) * | 1870-07-12 | Erasmus w | ||
US3529A (en) * | 1844-04-10 | yvolfe | ||
US81664A (en) * | 1868-09-01 | Island | ||
US348237A (en) * | 1886-08-31 | richards | ||
US1803686A (en) * | 1923-11-23 | 1931-05-05 | Herman A Brassert | Gas production |
US4196265A (en) * | 1977-06-15 | 1980-04-01 | The Wistar Institute | Method of producing antibodies |
US4522811A (en) * | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US4469797A (en) * | 1982-09-23 | 1984-09-04 | Miles Laboratories, Inc. | Digoxigenin immunogens, antibodies, labeled conjugates, and related derivatives |
US4737462A (en) * | 1982-10-19 | 1988-04-12 | Cetus Corporation | Structural genes, plasmids and transformed cells for producing cysteine depleted muteins of interferon-β |
US4966843A (en) * | 1982-11-01 | 1990-10-30 | Cetus Corporation | Expression of interferon genes in Chinese hamster ovary cells |
US4816567A (en) * | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
KR850004274A (ko) * | 1983-12-13 | 1985-07-11 | 원본미기재 | 에리트로포이에틴의 제조방법 |
US4703008A (en) | 1983-12-13 | 1987-10-27 | Kiren-Amgen, Inc. | DNA sequences encoding erythropoietin |
NZ210501A (en) * | 1983-12-13 | 1991-08-27 | Kirin Amgen Inc | Erythropoietin produced by procaryotic or eucaryotic expression of an exogenous dna sequence |
US5082658A (en) * | 1984-01-16 | 1992-01-21 | Genentech, Inc. | Gamma interferon-interleukin-2 synergism |
EP0158198A1 (en) | 1984-03-29 | 1985-10-16 | Takeda Chemical Industries, Ltd. | DNA and use thereof |
US5807715A (en) | 1984-08-27 | 1998-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin |
GB8422238D0 (en) | 1984-09-03 | 1984-10-10 | Neuberger M S | Chimeric proteins |
US4667016A (en) * | 1985-06-20 | 1987-05-19 | Kirin-Amgen, Inc. | Erythropoietin purification |
US4690915A (en) | 1985-08-08 | 1987-09-01 | The United States Of America As Represented By The Department Of Health And Human Services | Adoptive immunotherapy as a treatment modality in humans |
US5679543A (en) | 1985-08-29 | 1997-10-21 | Genencor International, Inc. | DNA sequences, vectors and fusion polypeptides to increase secretion of desired polypeptides from filamentous fungi |
US5643565A (en) | 1985-09-20 | 1997-07-01 | Chiron Corporation | Human IL-2 as a vaccine adjuvant |
US4676980A (en) * | 1985-09-23 | 1987-06-30 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Target specific cross-linked heteroantibodies |
US4935233A (en) * | 1985-12-02 | 1990-06-19 | G. D. Searle And Company | Covalently linked polypeptide cell modulators |
US5359035A (en) | 1985-12-21 | 1994-10-25 | Hoechst Aktiengesellschaft | Bifunctional proteins including interleukin-2 (IL-2) and granuloctyte macrophage colony stimulating factor (GM-CSF) |
DE3712985A1 (de) | 1987-04-16 | 1988-11-03 | Hoechst Ag | Bifunktionelle proteine |
EP0237019A3 (en) | 1986-03-14 | 1988-03-09 | Toray Industries, Inc. | Interferon conjugate and production thereof using recombinant gene |
JPS63267278A (ja) | 1986-03-14 | 1988-11-04 | Toray Ind Inc | インタ−フエロン結合体を暗号化する塩基配列 |
US5225539A (en) * | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
DK173067B1 (da) | 1986-06-27 | 1999-12-13 | Univ Washington | Humant erythropoietin-gen, fremgangsmåde til ekspression deraf i transficerede cellelinier, de transficerede cellelinier sa |
US4954617A (en) | 1986-07-07 | 1990-09-04 | Trustees Of Dartmouth College | Monoclonal antibodies to FC receptors for immunoglobulin G on human mononuclear phagocytes |
US4894227A (en) | 1986-08-01 | 1990-01-16 | Cetus Corporation | Composition of immunotoxins with interleukin-2 |
US4946778A (en) * | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5508031A (en) | 1986-11-21 | 1996-04-16 | Cetus Oncology Corporation | Method for treating biological damage using a free-radial scavenger and interleukin-2 |
US4732683A (en) * | 1986-12-02 | 1988-03-22 | Biospectrum, Inc. | Purification method for alpha interferon |
US5019368A (en) * | 1989-02-23 | 1991-05-28 | Cancer Biologics, Inc. | Detection of necrotic malignant tissue and associated therapy |
JP3101690B2 (ja) * | 1987-03-18 | 2000-10-23 | エス・ビィ・2・インコーポレイテッド | 変性抗体の、または変性抗体に関する改良 |
EP0318554B2 (en) | 1987-05-21 | 2005-01-12 | Micromet AG | Targeted multifunctional proteins |
US5091513A (en) * | 1987-05-21 | 1992-02-25 | Creative Biomolecules, Inc. | Biosynthetic antibody binding sites |
US5258498A (en) | 1987-05-21 | 1993-11-02 | Creative Biomolecules, Inc. | Polypeptide linkers for production of biosynthetic proteins |
DE3853740T2 (de) | 1987-06-10 | 1995-11-09 | Dana Farber Cancer Inst Inc | Bifunktionelle Antikörperkonstruktionen und Verfahren zur selektiven Tötung von Zellbeständen. |
US5064646A (en) | 1988-08-02 | 1991-11-12 | The University Of Maryland | Novel infectious bursal disease virus |
PH26813A (en) | 1987-09-02 | 1992-11-05 | Ciba Geigy Ag | Conjugates of cytokines with immunoglobulins |
PT88641B (pt) | 1987-10-02 | 1993-04-30 | Genentech Inc | Metodo para a preparacao de uma variante de adesao |
PT89121A (pt) | 1987-12-04 | 1989-12-29 | Du Pont | Processo para a preparacao de interleuquina-2 imobilizada e interleuquina-2 contendo uma extensao no terminal-carboxilo com actividade de interleuquina-2 natural |
WO1989006692A1 (en) * | 1988-01-12 | 1989-07-27 | Genentech, Inc. | Method of treating tumor cells by inhibiting growth factor receptor function |
CA1341588C (en) | 1988-01-26 | 2009-01-06 | Michel Revel | Human ifn-beta2/i1-6, its purification and use |
US5120525A (en) * | 1988-03-29 | 1992-06-09 | Immunomedics, Inc. | Radiolabeled antibody cytotoxic therapy of cancer |
DE3812605A1 (de) | 1988-04-15 | 1990-06-07 | Leskovar Peter Dipl Ing Dr Hab | Immunregulative stoffe und stoffgemische zur aktiven beeinflussung des krankheitsverlaufes |
US4975369A (en) | 1988-04-21 | 1990-12-04 | Eli Lilly And Company | Recombinant and chimeric KS1/4 antibodies directed against a human adenocarcinoma antigen |
IE62463B1 (en) | 1988-07-07 | 1995-02-08 | Res Dev Foundation | Immunoconjugates for cancer diagnosis and therapy |
US5601819A (en) * | 1988-08-11 | 1997-02-11 | The General Hospital Corporation | Bispecific antibodies for selective immune regulation and for selective immune cell binding |
IL91933A (en) | 1988-10-11 | 1994-12-29 | Univ Southern California | Their immuno-bracelet and isophiles which are beneficial in increasing vascular permeability or blood supply to tumor or otherwise damaged tissue |
US5457038A (en) | 1988-11-10 | 1995-10-10 | Genetics Institute, Inc. | Natural killer stimulatory factor |
US5242824A (en) | 1988-12-22 | 1993-09-07 | Oncogen | Monoclonal antibody to human carcinomas |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5116964A (en) | 1989-02-23 | 1992-05-26 | Genentech, Inc. | Hybrid immunoglobulins |
US5225538A (en) * | 1989-02-23 | 1993-07-06 | Genentech, Inc. | Lymphocyte homing receptor/immunoglobulin fusion proteins |
US5703055A (en) | 1989-03-21 | 1997-12-30 | Wisconsin Alumni Research Foundation | Generation of antibodies through lipid mediated DNA delivery |
US5166322A (en) | 1989-04-21 | 1992-11-24 | Genetics Institute | Cysteine added variants of interleukin-3 and chemical modifications thereof |
IE63847B1 (en) | 1989-05-05 | 1995-06-14 | Res Dev Foundation | A novel antibody delivery system for biological response modifiers |
US6750329B1 (en) * | 1989-05-05 | 2004-06-15 | Research Development Foundation | Antibody delivery system for biological response modifiers |
US6291158B1 (en) | 1989-05-16 | 2001-09-18 | Scripps Research Institute | Method for tapping the immunological repertoire |
US5399346A (en) * | 1989-06-14 | 1995-03-21 | The United States Of America As Represented By The Department Of Health And Human Services | Gene therapy |
CA2062795A1 (en) | 1989-06-29 | 1990-12-30 | Michael W. Fanger | Bispecific reagents for aids therapy |
ATE123065T1 (de) * | 1989-07-07 | 1995-06-15 | Takeda Chemical Industries Ltd | Proteine und deren herstellung. |
US5073627A (en) | 1989-08-22 | 1991-12-17 | Immunex Corporation | Fusion proteins comprising GM-CSF and IL-3 |
EP0765937B1 (en) | 1989-09-20 | 2002-11-27 | Abbott Laboratories | Method of producing fusion proteins |
US5856298A (en) * | 1989-10-13 | 1999-01-05 | Amgen Inc. | Erythropoietin isoforms |
KR100221066B1 (ko) | 1989-10-13 | 1999-10-01 | 스튜어트 엘.왓트 | 에리트로포이에틴 유사체와 그를 포함하는 제약학적 조성물 |
DK0433827T3 (da) | 1989-12-22 | 1998-09-28 | Hoffmann La Roche | Cytotoksisk lumfocytmodningsfaktor |
US5314995A (en) * | 1990-01-22 | 1994-05-24 | Oncogen | Therapeutic interleukin-2-antibody based fusion proteins |
WO1991013166A1 (en) | 1990-03-02 | 1991-09-05 | Abbott Biotech, Inc. | Antibody constructs with enhanced binding affinity |
ATE158615T1 (de) | 1990-03-20 | 1997-10-15 | Univ Columbia | Chimäre antikörper mit rezeptor-bindenden liganden anstelle ihrer konstanten region |
US5349053A (en) | 1990-06-01 | 1994-09-20 | Protein Design Labs, Inc. | Chimeric ligand/immunoglobulin molecules and their uses |
US7253264B1 (en) | 1990-06-28 | 2007-08-07 | Sanofi-Arentideutschland GmbH | Immunoglobulin fusion proteins, their production and use |
JPH06504262A (ja) | 1990-07-27 | 1994-05-19 | レブリゲン コーポレーション | 脈管形成性の病気の処置用の新規な方法と組成物 |
EP0556328A4 (en) | 1990-11-09 | 1994-06-08 | Abbott Lab | Bridging antibody fusion constructs |
US5650150A (en) | 1990-11-09 | 1997-07-22 | Gillies; Stephen D. | Recombinant antibody cytokine fusion proteins |
JPH09506761A (ja) | 1990-11-09 | 1997-07-08 | ステファン ディー.ギリーズ | サイトカインの免疫複合体 |
KR100237968B1 (ko) | 1990-12-05 | 2000-01-15 | 한센 핀 베네드 | 변화된 에피토프를 지닌 단백질 및 그 제조방법 |
US5709859A (en) * | 1991-01-24 | 1998-01-20 | Bristol-Myers Squibb Company | Mixed specificity fusion proteins |
GB9105245D0 (en) | 1991-03-12 | 1991-04-24 | Lynxvale Ltd | Binding molecules |
US6072039A (en) | 1991-04-19 | 2000-06-06 | Rohm And Haas Company | Hybrid polypeptide comparing a biotinylated avidin binding polypeptide fused to a polypeptide of interest |
DE69233482T2 (de) | 1991-05-17 | 2006-01-12 | Merck & Co., Inc. | Verfahren zur Verminderung der Immunogenität der variablen Antikörperdomänen |
US5199942A (en) * | 1991-06-07 | 1993-04-06 | Immunex Corporation | Method for improving autologous transplantation |
WO1993003157A1 (en) | 1991-07-29 | 1993-02-18 | Dana Farber Cancer Institute | Plasmids for the rapid preparation of modified proteins |
US20020037558A1 (en) * | 1991-10-23 | 2002-03-28 | Kin-Ming Lo | E.coli produced immunoglobulin constructs |
US5376367A (en) | 1991-11-22 | 1994-12-27 | Immunex Corporation | Fusion proteins comprising MGF and IL-3 |
US6627615B1 (en) | 1991-12-17 | 2003-09-30 | The Regents Of The University Of California | Methods and compositions for in vivo gene therapy |
ATE260971T1 (de) | 1992-04-01 | 2004-03-15 | Univ Rockefeller | Verfahren zur in vitro kultivierung dendritischer vorläuferzellen und deren verwendung zur immunogen herstellung |
WO1993020185A1 (en) | 1992-04-01 | 1993-10-14 | Steinman Ralph M | Method for in vitro proliferation of dendritic cell precursors and their use to produce immunogens |
EP0615451B1 (en) * | 1992-05-26 | 2005-12-07 | Immunex Corporation | Novel cytokine that binds cd30 |
IL105914A0 (en) | 1992-06-04 | 1993-10-20 | Univ California | Methods and compositions for in vivo gene therapy |
US5614184A (en) * | 1992-07-28 | 1997-03-25 | New England Deaconess Hospital | Recombinant human erythropoietin mutants and therapeutic methods employing them |
CA2142007C (en) | 1992-08-11 | 2007-10-30 | Robert Glen Urban | Immunomodulatory peptides |
US5429199A (en) * | 1992-08-26 | 1995-07-04 | Kennametal Inc. | Cutting bit and cutting insert |
DE4228839A1 (de) | 1992-08-29 | 1994-03-03 | Behringwerke Ag | Verfahren zum Nachweis und zur Bestimmung von Mediatoren |
EP0627932B1 (en) | 1992-11-04 | 2002-05-08 | City Of Hope | Antibody construct |
CA2147499C (en) * | 1992-11-05 | 2010-10-19 | Ron S. Israeli | Prostate-specific membrane antigen |
US5738849A (en) * | 1992-11-24 | 1998-04-14 | G. D. Searle & Co. | Interleukin-3 (IL-3) variant fusion proteins, their recombinant production, and therapeutic compositions comprising them |
US5543297A (en) * | 1992-12-22 | 1996-08-06 | Merck Frosst Canada, Inc. | Human cyclooxygenase-2 cDNA and assays for evaluating cyclooxygenase-2 activity |
US6096331A (en) * | 1993-02-22 | 2000-08-01 | Vivorx Pharmaceuticals, Inc. | Methods and compositions useful for administration of chemotherapeutic agents |
AU6816194A (en) * | 1993-04-20 | 1994-11-08 | Robinson, William S. | Methods and materials for treatment of individuals infected with intracellular infectious agents |
WO1994024160A2 (en) | 1993-04-21 | 1994-10-27 | Brigham And Women's Hospital | Erythropoietin muteins with enhanced activity |
US5759551A (en) * | 1993-04-27 | 1998-06-02 | United Biomedical, Inc. | Immunogenic LHRH peptide constructs and synthetic universal immune stimulators for vaccines |
AU6776194A (en) | 1993-04-28 | 1994-11-21 | Hybritech Incorporated | Method for creating optimized regulatory regions affecting protein expression and protein trafficking |
WO1994025055A1 (en) * | 1993-04-29 | 1994-11-10 | Abbott Laboratories | Erythropoietin analog compositions and methods |
US5554512A (en) | 1993-05-24 | 1996-09-10 | Immunex Corporation | Ligands for flt3 receptors |
CA2125763C (en) * | 1993-07-02 | 2007-08-28 | Maurice Kent Gately | P40 homodimer of interleukin-12 |
GB9316989D0 (en) | 1993-08-16 | 1993-09-29 | Lynxvale Ltd | Binding molecules |
ZA946122B (en) | 1993-08-17 | 1995-03-20 | Amgen Inc | Erythropoietin analogs |
AU689214B2 (en) | 1994-02-01 | 1998-03-26 | United States Of America, Represented By The Secretary, Department Of Health And Human Services, The | Fusion proteins that include antibody and nonantibody portions |
WO1995028427A1 (en) | 1994-04-15 | 1995-10-26 | Imclone Systems Incorporated | Chimeric interleukin-3/mutein interleukin-6 lymphokine |
US5837682A (en) | 1996-03-08 | 1998-11-17 | The Children's Medical Center Corporation | Angiostatin fragments and method of use |
US5639725A (en) * | 1994-04-26 | 1997-06-17 | Children's Hospital Medical Center Corp. | Angiostatin protein |
IL113509A (en) * | 1994-04-26 | 2005-12-18 | Childrens Medical Center | Angiostatin protein preparations and methods of use |
DE69522216T2 (de) | 1994-05-13 | 2002-05-02 | Biovation Ltd | Zielzellen-bindende chimäre Peptide |
CU22615A1 (es) | 1994-06-30 | 2000-02-10 | Centro Inmunologia Molecular | Procedimiento de obtención de anticuerpos monoclonales murinos menos inmunogénicos. anticuerpos monoclonales obtenidos |
US6429199B1 (en) | 1994-07-15 | 2002-08-06 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules for activating dendritic cells |
WO1996004388A1 (en) | 1994-07-29 | 1996-02-15 | Smithkline Beecham Plc | Novel compounds |
US5888773A (en) * | 1994-08-17 | 1999-03-30 | The United States Of America As Represented By The Department Of Health And Human Services | Method of producing single-chain Fv molecules |
US6309853B1 (en) | 1994-08-17 | 2001-10-30 | The Rockfeller University | Modulators of body weight, corresponding nucleic acids and proteins, and diagnostic and therapeutic uses thereof |
US5541087A (en) * | 1994-09-14 | 1996-07-30 | Fuji Immunopharmaceuticals Corporation | Expression and export technology of proteins as immunofusins |
EP0706799B1 (en) | 1994-09-16 | 2001-11-14 | MERCK PATENT GmbH | Immunoconjugates II |
WO1996018412A1 (en) | 1994-12-12 | 1996-06-20 | Beth Israel Hospital Association | Chimeric cytokines and uses thereof |
US6086875A (en) * | 1995-01-17 | 2000-07-11 | The Brigham And Women's Hospital, Inc. | Receptor specific transepithelial transport of immunogens |
US6485726B1 (en) | 1995-01-17 | 2002-11-26 | The Brigham And Women's Hospital, Inc. | Receptor specific transepithelial transport of therapeutics |
US5552524A (en) | 1995-01-31 | 1996-09-03 | Eli Lilly And Company | Anti-obesity proteins |
US5691309A (en) | 1995-01-31 | 1997-11-25 | Eli Lilly And Company | Anti-obesity proteins |
US5891680A (en) * | 1995-02-08 | 1999-04-06 | Whitehead Institute For Biomedical Research | Bioactive fusion proteins comprising the p35 and p40 subunits of IL-12 |
AU712585B2 (en) * | 1995-03-10 | 1999-11-11 | Genentech Inc. | Receptor activation by gas6 |
US5719266A (en) * | 1995-03-17 | 1998-02-17 | Eli Lilly And Company | Anti-obesity proteins |
WO1996031526A1 (en) | 1995-04-06 | 1996-10-10 | Amylin Pharmaceuticals, Inc. | Anti-obesity agents |
US6281010B1 (en) * | 1995-06-05 | 2001-08-28 | The Trustees Of The University Of Pennsylvania | Adenovirus gene therapy vehicle and cell line |
AU5893796A (en) | 1995-06-07 | 1996-12-30 | Novo Nordisk A/S | Modification of polypeptides |
WO1997000317A1 (en) | 1995-06-07 | 1997-01-03 | Osteosa Inc. | Osteoclast growth regulatory factor |
GB9511935D0 (en) | 1995-06-13 | 1995-08-09 | Smithkline Beecham Plc | Novel compound |
NL1000614C2 (nl) * | 1995-06-20 | 1996-12-23 | Leer Koninklijke Emballage | Werkwijze voor het vervaardigen van een gelamineerd produkt. |
US5736852A (en) * | 1995-06-21 | 1998-04-07 | Alliedsignal Truck Brake Systems Co. | Circuit and method for conditioning a wheel speed sensor signal |
CN1195293A (zh) * | 1995-06-30 | 1998-10-07 | 伊莱利利公司 | 治疗糖尿病的方法 |
US6406689B1 (en) * | 1995-10-03 | 2002-06-18 | Frank W. Falkenberg | Compositions and methods for treatment of tumors and metastatic diseases |
US5854205A (en) | 1995-10-23 | 1998-12-29 | The Children's Medical Center Corporation | Therapeutic antiangiogenic compositions and methods |
KR19990066981A (ko) | 1995-10-23 | 1999-08-16 | 윌리엄 뉴우 | 치료용 맥관형성억제 조성물 및 방법 |
AU1407997A (en) | 1995-12-01 | 1997-06-19 | Beth Israel Hospital | Il-12 p40 subunit fusion polypeptides and uses thereof |
CZ9802013A3 (cs) | 1995-12-27 | 1998-09-16 | Genentech, Inc. | Deriváty OB proteinu, chimerní OB polypeptidy, prostředky pro léčbu obezity a dalších fyziologických stavů a způsob léčení těmito prostředky, kódující sekvence pro OB protein, expresní vektor nesoucí tuto sekvenci, buňky transformované tímto vektorem a způsob jejich kultivace, a způsob navození růstu buněk s pomocí OB proteinu |
US5723125A (en) * | 1995-12-28 | 1998-03-03 | Tanox Biosystems, Inc. | Hybrid with interferon-alpha and an immunoglobulin Fc linked through a non-immunogenic peptide |
US6080409A (en) * | 1995-12-28 | 2000-06-27 | Dendreon Corporation | Immunostimulatory method |
US7063958B1 (en) | 1996-01-16 | 2006-06-20 | The Rockefeller University | Nucleic acids db, the receptor for leptin |
US6750334B1 (en) | 1996-02-02 | 2004-06-15 | Repligen Corporation | CTLA4-immunoglobulin fusion proteins having modified effector functions and uses therefor |
WO1997030089A1 (en) | 1996-02-13 | 1997-08-21 | Regents Of The University Of California | Novel antibody-cytokine fusion protein, and methods of making and using the same |
US5756541A (en) | 1996-03-11 | 1998-05-26 | Qlt Phototherapeutics Inc | Vision through photodynamic therapy of the eye |
US6046310A (en) | 1996-03-13 | 2000-04-04 | Protein Design Labs., Inc. | FAS ligand fusion proteins and their uses |
WO1997034631A1 (en) | 1996-03-18 | 1997-09-25 | Board Of Regents, The University Of Texas System | Immunoglobin-like domains with increased half lives |
WO1997043316A1 (en) | 1996-05-10 | 1997-11-20 | Beth Israel Deaconess Medical Center, Inc. | Physiologically active molecules with extended half-lives and methods of using same |
CN1136197C (zh) * | 1996-05-30 | 2004-01-28 | 霍夫曼-拉罗奇有限公司 | 新的哒嗪酮衍生物 |
US5922685A (en) * | 1996-06-05 | 1999-07-13 | Powderject Vaccines, Inc. | IL-12 gene therapy of tumors |
JP2002514161A (ja) | 1996-07-02 | 2002-05-14 | バー イラン ユニバーシティー | ガンおよび他の細胞増殖性疾患の治療に有用なレチノイルオキシ(置換)アルキレンブチレート |
AU4075897A (en) | 1996-08-16 | 1998-03-06 | Roger Lallone | A leptin binding protein and its use in methods for diagnosing and treating abnormalities of the endogenous leptin pathway |
EP0826696B1 (de) * | 1996-09-03 | 2002-05-29 | GSF-Forschungszentrum für Umwelt und Gesundheit GmbH | Verwendung bi-und trispezifischer Antikörper zur Induktion einer Tumorimmunität |
US5994104A (en) | 1996-11-08 | 1999-11-30 | Royal Free Hospital School Of Medicine | Interleukin-12 fusion protein |
CA2275183A1 (en) | 1996-12-20 | 1998-07-02 | Amgen Inc. | Ob fusion protein compositions and methods |
US6737057B1 (en) | 1997-01-07 | 2004-05-18 | The University Of Tennessee Research Corporation | Compounds, compositions and methods for the endocytic presentation of immunosuppressive factors |
US6100387A (en) * | 1997-02-28 | 2000-08-08 | Genetics Institute, Inc. | Chimeric polypeptides containing chemokine domains |
US6277375B1 (en) * | 1997-03-03 | 2001-08-21 | Board Of Regents, The University Of Texas System | Immunoglobulin-like domains with increased half-lives |
EP0973550B1 (en) * | 1997-04-11 | 2002-10-09 | G.D. SEARLE & CO. | Antagonistic anti-avb3 integrin antibodies |
JP4086908B2 (ja) | 1997-04-17 | 2008-05-14 | アムジエン・インコーポレーテツド | 安定かつ活性なヒトOBタンパク質と抗体Fc鎖とのコンジュゲートを含む組成物および方法 |
GB2339430A (en) * | 1997-05-21 | 2000-01-26 | Biovation Ltd | Method for the production of non-immunogenic proteins |
GB9712892D0 (en) * | 1997-06-20 | 1997-08-20 | Eclagen Ltd | Identification of mhc binding peptides |
WO1999002709A1 (en) * | 1997-07-10 | 1999-01-21 | Beth Israel Deaconess Medical Center | Recombinant erythropoietin / immunoglobulin fusion proteins |
CA2296770A1 (en) * | 1997-07-14 | 1999-01-28 | Bolder Biotechnology, Inc. | Derivatives of growth hormone and related proteins |
ATE267215T1 (de) * | 1997-12-08 | 2004-06-15 | Lexigen Pharm Corp | Heterodimäre fusionsproteine zur verwendung für gezielte immuntherapie und allgemeine immunerregung |
US20030105294A1 (en) | 1998-02-25 | 2003-06-05 | Stephen Gillies | Enhancing the circulating half life of antibody-based fusion proteins |
WO1999043713A1 (en) | 1998-02-25 | 1999-09-02 | Lexigen Pharmaceuticals Corporation | Enhancing the circulating half-life of antibody-based fusion proteins |
JP2002511432A (ja) | 1998-04-15 | 2002-04-16 | レキシジェン ファーマシューティカルズ コーポレイション | 新脈管形成インヒビターの同時投与による抗体−サイトカイン融合タンパク質媒介性免疫応答の増強 |
RU2217168C2 (ru) * | 1998-04-17 | 2003-11-27 | Лексиген Фармасьютикэлс Корпорейшн | Усиление иммунных ответов, опосредованных белками, слитыми из антитела и цитокина, посредством совместного введения ингибитора простагландина |
AU3655899A (en) | 1998-04-20 | 1999-11-08 | Regents Of The University Of California, The | Modified immunoglobulin molecules and methods for use thereof |
CA2328490A1 (en) | 1998-05-14 | 1999-11-18 | Merck Patent Gesellschaft Mit Beschraenkter Haftung | Fused protein |
DZ2788A1 (fr) | 1998-05-15 | 2003-12-01 | Bayer Ag | Agonistes et antagonistes selectifs à IL-2. |
US6620382B1 (en) * | 1998-05-22 | 2003-09-16 | Biopheresis Technologies, Llc. | Method and compositions for treatment of cancers |
WO1999062944A2 (en) | 1998-06-03 | 1999-12-09 | The Children's Medical Center Corporation | Protein oligomer compositions comprising endostatin protein and methods of using the same |
DE69933216T2 (de) | 1998-06-15 | 2007-09-20 | GTC Biotherapeutics, Inc., Framingham | Erythropoietin-analog-menschliches serum-albumin fusionsprotein |
GB9814383D0 (en) | 1998-07-02 | 1998-09-02 | Cambridge Antibody Tech | Improvements relating to antibodies |
EP1105427A2 (en) | 1998-08-17 | 2001-06-13 | Abgenix, Inc. | Generation of modified molecules with increased serum half-lives |
ATE462725T1 (de) | 1998-08-25 | 2010-04-15 | Merck Patent Gmbh | Expression und export von angiostatin und endostatin als immunofusins |
US6646113B1 (en) | 1998-09-17 | 2003-11-11 | The Trustees Of The University Of Pennsylvania | Nucleic acid molecule encoding human survival of motor neuron-interacting protein 1 (SIP1) deletion mutants |
US6335176B1 (en) * | 1998-10-16 | 2002-01-01 | Pharmacopeia, Inc. | Incorporation of phosphorylation sites |
EP1813624B1 (en) | 1998-10-23 | 2010-08-11 | Amgen Inc. | Methods and compositions for the prevention and treatment of anemia |
DE60041183D1 (de) | 1999-05-06 | 2009-02-05 | Univ Wake Forest | Zusammensetzungen und methoden zur identifikation von antigenen, die eine immunantwort hervorrufen |
JP3660880B2 (ja) | 1999-05-07 | 2005-06-15 | ジェネンテック・インコーポレーテッド | 新規なチンパンジーエリスロポエチン(chepo)ポリペプチドおよびこれをコードする核酸 |
US6348192B1 (en) * | 1999-05-11 | 2002-02-19 | Bayer Corporation | Interleukin-2 mutein expressed from mammalian cells |
BR0010725A (pt) * | 1999-05-19 | 2002-02-19 | Lexigen Pharm Corp | Expressão e exportação de proteìnas de interferon-alfa como proteìnas de fusão de fc |
WO2000078334A1 (en) | 1999-06-17 | 2000-12-28 | University Of Maryland Biotechnology Institute | Chimeric chemokine-antigen polypeptides and uses therefor |
CZ299516B6 (cs) * | 1999-07-02 | 2008-08-20 | F. Hoffmann-La Roche Ag | Konjugát erythropoetinového glykoproteinu, zpusobjeho výroby a použití a farmaceutická kompozice sjeho obsahem |
JO2291B1 (en) * | 1999-07-02 | 2005-09-12 | اف . هوفمان لاروش ايه جي | Erythropoietin derivatives |
US7067110B1 (en) * | 1999-07-21 | 2006-06-27 | Emd Lexigen Research Center Corp. | Fc fusion proteins for enhancing the immunogenicity of protein and peptide antigens |
SK782002A3 (en) | 1999-07-21 | 2003-08-05 | Lexigen Pharm Corp | FC fusion proteins for enhancing the immunogenicity of protein and peptide antigens |
US20050202538A1 (en) | 1999-11-12 | 2005-09-15 | Merck Patent Gmbh | Fc-erythropoietin fusion protein with improved pharmacokinetics |
EP1228214A2 (en) | 1999-11-12 | 2002-08-07 | MERCK PATENT GmbH | Erythropoietin forms with improved properties |
ATE336514T1 (de) * | 2000-02-11 | 2006-09-15 | Merck Patent Gmbh | Steigerung der zirkulierenden halbwertzeit von auf antikörpern basierenden fusionsproteinen |
WO2001062298A2 (en) * | 2000-02-24 | 2001-08-30 | Philogen S.R.L. | Compositions and methods for treatment of angiogenesis in pathological lesions |
US6586398B1 (en) * | 2000-04-07 | 2003-07-01 | Amgen, Inc. | Chemically modified novel erythropoietin stimulating protein compositions and methods |
US6946134B1 (en) * | 2000-04-12 | 2005-09-20 | Human Genome Sciences, Inc. | Albumin fusion proteins |
WO2001088117A2 (en) * | 2000-05-12 | 2001-11-22 | Neose Technologies, Inc. | In vitro fucosylation recombinant glycopeptides |
PT1294401E (pt) * | 2000-06-29 | 2007-11-09 | Merck Patent Gmbh | Aumento das respostas imunológicas mediadas por proteínas de fusão anticorpo-citoquina por tratamento combinado com agentes que aumentam a captação de imunocitoquinas |
HUP0401300A3 (en) * | 2001-01-18 | 2005-06-28 | Merck Patent Gmbh | Bifunctional fusion proteins with glucocerebrosidase activity |
CA2438652A1 (en) | 2001-02-19 | 2002-09-06 | Merck Patent Gesellschaft Mit Beschraenkter Haftung | Method for identification of t-cell epitopes and use for preparing molecules with reeduced immunogenicity |
KR20090010127A (ko) | 2001-03-07 | 2009-01-28 | 메르크 파텐트 게엠베하 | 하이브리드 이소타입 항체 부분구조를 포함하는 단백질을 위한 발현 기술 |
WO2002079415A2 (en) | 2001-03-30 | 2002-10-10 | Lexigen Pharmaceuticals Corp. | Reducing the immunogenicity of fusion proteins |
DK1383785T3 (da) | 2001-05-03 | 2011-05-23 | Merck Patent Gmbh | Rekombinant tumorspecifikt antistof og anvendelse deraf |
US7371371B2 (en) | 2001-08-13 | 2008-05-13 | University Of Southern California | Interleukin-2 mutants with reduced toxicity |
ATE542137T1 (de) * | 2001-12-04 | 2012-02-15 | Merck Patent Gmbh | Immunocytokine mit modulierter selektivität |
AU2002316574B2 (en) | 2002-03-15 | 2008-05-01 | Brandeis University | Central airway administration for systemic delivery of therapeutics |
US6996009B2 (en) * | 2002-06-21 | 2006-02-07 | Micron Technology, Inc. | NOR flash memory cell with high storage density |
WO2004055056A1 (en) * | 2002-12-17 | 2004-07-01 | Merck Patent Gmbh | Humanized antibody (h14.18) of the mouse 14.18 antibody binding to gd2 and its fusion with il-2 |
US20050069521A1 (en) * | 2003-08-28 | 2005-03-31 | Emd Lexigen Research Center Corp. | Enhancing the circulating half-life of interleukin-2 proteins |
DE602004013372T2 (de) * | 2003-12-30 | 2009-07-02 | Merck Patent Gmbh | Il-7-fusionsproteine mit antikörperportionen, deren herstellung und deren verwendung |
RU2370276C2 (ru) | 2003-12-31 | 2009-10-20 | Мерк Патент Гмбх | Fc-ЭРИТРОПОЭТИН СЛИТЫЙ БЕЛОК С УЛУЧШЕННОЙ ФАРМАКОКИНЕТИКОЙ |
ES2330860T3 (es) | 2004-01-22 | 2009-12-16 | Merck Patent Gmbh | Anticuerpos anticancerosos con fijacion del complemento reducida. |
US7670595B2 (en) | 2004-06-28 | 2010-03-02 | Merck Patent Gmbh | Fc-interferon-beta fusion proteins |
CN101072793B (zh) * | 2004-12-09 | 2012-06-20 | 默克专利有限公司 | 具有降低的免疫原性的il-7变体 |
US20070104689A1 (en) * | 2005-09-27 | 2007-05-10 | Merck Patent Gmbh | Compositions and methods for treating tumors presenting survivin antigens |
PT1966238E (pt) * | 2005-12-30 | 2012-07-31 | Merck Patent Gmbh | Uso de hsp70 como um regulador de atividade enzimática |
DK1966244T3 (da) | 2005-12-30 | 2012-04-23 | Merck Patent Gmbh | Anti-il-6-antistoffer der forebygger bindingen af il-6 sammensat af il-6ralfa til gp130 |
KR101397290B1 (ko) | 2005-12-30 | 2014-05-21 | 메르크 파텐트 게엠베하 | 감소한 면역원성을 가지는 항-cd19 항체 |
EP1999154B1 (en) | 2006-03-24 | 2012-10-24 | Merck Patent GmbH | Engineered heterodimeric protein domains |
EP2038417A2 (en) * | 2006-07-06 | 2009-03-25 | Merck Patent GmbH | Compositions and methods for enhancing the efficacy of il-2 mediated immune responses |
-
2002
- 2002-03-29 WO PCT/US2002/009650 patent/WO2002079415A2/en not_active Application Discontinuation
- 2002-03-29 US US10/112,582 patent/US6992174B2/en not_active Expired - Lifetime
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-
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- 2015-01-02 US US14/588,702 patent/US20150141626A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000034317A2 (en) * | 1998-12-08 | 2000-06-15 | Biovation Limited | Method for reducing immunogenicity of proteins |
WO2000040615A2 (en) * | 1999-01-07 | 2000-07-13 | Lexigen Pharmaceuticals, Corp. | EXPRESSION AND EXPORT OF ANTI-OBESITY PROTEINS AS Fc FUSION PROTEINS |
WO2000047741A1 (en) * | 1999-02-12 | 2000-08-17 | Amgen Inc. | Glycosylated leptin compositions and related methods |
WO2001010912A1 (en) * | 1999-08-09 | 2001-02-15 | Lexigen Pharmaceuticals Corp. | Multiple cytokine-antibody complexes |
JP2004532620A (ja) * | 2001-02-19 | 2004-10-28 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | 免疫原性の低減された人工タンパク質 |
Non-Patent Citations (2)
Title |
---|
JPN5003015153; REISFELD: MELANOMA RES. V7 SIPPL.2, 1997, P S99-S106 * |
JPN5003015154; LODE: IMMUNOL. INVEST. V29N2, 2000, P117-120 * |
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