JP4774368B2 - 改変型il−4ムテイン受容体アンタゴニスト - Google Patents
改変型il−4ムテイン受容体アンタゴニスト Download PDFInfo
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- JP4774368B2 JP4774368B2 JP2006524657A JP2006524657A JP4774368B2 JP 4774368 B2 JP4774368 B2 JP 4774368B2 JP 2006524657 A JP2006524657 A JP 2006524657A JP 2006524657 A JP2006524657 A JP 2006524657A JP 4774368 B2 JP4774368 B2 JP 4774368B2
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- receptor antagonist
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Description
本発明は、ポリエチレングリコールなどの非タンパク質性ポリマーと結合させたIL-4ムテイン受容体アンタゴニストに関する。さらに、治療を目的とする、関連する製剤ならびにそれらの投与量および投与の方法も提供される。これらの改変型IL-4ムテイン受容体アンタゴニスト、ならびに関連する組成物および方法は、重症喘息、慢性閉塞性肺疾患および関連する肺病態に罹患した個体に対する治療的選択肢を提供するのに有用である。
本出願は、2003年8月29日に提出された米国仮特許出願第60/498,906号;2003年12月9日に提出された第60/528,228号;および2003年12月17日に提出された60/530,182号の利益を請求し、これらの開示内容は本明細書に明示的に組み入れられる。
喘息は、さまざまな程度の可逆的な気流閉塞および気道過敏性(AHR)を特徴とし、これには気管支粘膜への活性化Tリンパ球(T細胞)および好酸球の浸潤が伴う。これらの細胞は、常在性気道マスト細胞とともに、この疾患の発生において根本的な役割を果たす種々のサイトカインおよびメディエーターを分泌する。CD4+ Th2細胞は、特定サイトカイン(IL-4、IL-5、IL-9およびIL-13)の放出を通じて、その疾患プロセスを組織化すると考えられている(1,2)。特に、Th2サイトカインであるIL-4およびIL-13は、気道炎症および気道過敏性の発生および維持にとって極めて重要であると考えられている。
本発明は、以前に報告されたムテインよりも半減期の長いIL-4RAムテインを提供する。本発明はまた、IL-4およびIL-13により媒介される免疫応答を抑制する試薬および方法も提供する。本発明の上記およびその他の面は、以下に挙げる態様の1つまたは複数によって提供される。
本発明は、非タンパク質性ポリマーと、好ましくはポリエチレングリコール分子と結合させたIL-4ムテイン受容体を含む、改変型IL-4ムテイン受容体アンタゴニストに関する。
「ポリヌクレオチド」または「核酸配列」または「核酸分子」という用語は、DNA配列またはRNA配列のことを指す。この用語は、4-アセチルシトシン、8-ヒドロキシ-N6-メチルアデノシン、アジリジニル-シトシン、プソイドイソシトシン、5-(カルボキシヒドロキシルメチル)ウラシル、5-フルオロウラシル、5-ブロモウラシル、5-カルボキシメチルアミノメチル-2-チオウラシル、5-カルボキシ-メチルアミノメチルウラシル、ジヒドロウラシル、イノシン、N6-イソ-ペンテニルアデニン、1-メチルアデニン、1-メチルプソイドウラシル、1-メチルグアニン、1-メチルイノシン、2,2-ジメチルグアニン、2-メチルアデニン、2-メチルグアニン、3-メチルシトシン、5-メチルシトシン、N6-メチルアデニン、7-メチルグアニン、5-メチルアミノメチルウラシル、5-メトキシアミノ-メチル-2-チオウラシル、β-D-マンノシルキューオシン、5'-メトキシカルボニル-メチルウラシル、5-メトキシウラシル、2-メチルチオ-N6-イソペンテニルアデニン、ウラシル-5-オキシ酢酸メチルエステル、ウラシル-5-オキシ酢酸、オキシブトキソシン(oxybutoxosine)、プソイドウラシル、キューオシン(queosine)、2-チオシトシン、5-メチル2-チオウラシル、2-チオウラシル、4-チオウラシル、5-メチルウラシル、N-ウラシル-5-オキシ酢酸メチルエステル、ウラシル-5オキシ酢酸、プソイドウラシル、キューオシン、2-チオシトシンおよび2,6-ジアミノプリンといった(ただしこれらには限定されない)、DNAおよびRNAの公知の塩基類似体の任意のものから形成された分子を含む。
アルゴリズム:Needleman et al, 1970, J. Mol. Biol, 48: 443-453;
比較マトリックス:BLOSUM 62(Henikoff et al., 1992, 前記);
ギャップペナルティー:12
ギャップ長ペナルティ:4
類似性の閾値:0
1)疎水性:ノルロイシン(Nor)、Met、Ala、Val、Leu、Ile;
2)中性親水性:Cys、Ser、Thr、Asn、GIn;
3)酸性:Asp、Glu;
4)塩基性:His、Lys、Arg;
5)鎖の配向に影響を及ぼす残基:Gly、Pro;および
6)芳香族性:Trp、Tyr、Phe。
本明細書で用いる「改変型IL-4ムテイン受容体アンタゴニスト」には、米国特許第6,028,176号および第6,313,272号(それらの全体が参照として組み入れられる)に記載されたIL-4RAムテインにアミノ酸置換が加えられたものであって、前記置換が、ポリプロピレングリコール、ポリオキシアルキレンまたはポリエチレングリコール(PEG)分子などの少なくとも1つの非タンパク質性ポリマーとムテインとの位置特異的結合を可能にするものが含まれる。PEGの位置特異的結合により、例えば、ポリエチレン-グリコシル化(PEG化)分子の利点、すなわち血漿半減期の延長および免疫原性の低下を有する一方で、N末端およびリジン側鎖のPEG化といった非特異的なPEG化戦略を上回る効力を保った、改変ムテインの作製が可能となる。また、発現後の分子の適切なフォールディングを可能にする具体的なアミノ酸置換の部位の選択も、本発明には本来備わっている。改変型IL-4ムテイン受容体アンタゴニストは、IL-4およびIL-13と、IL-4RAのそれに比して10分の1を下回ることのない親和性で結合する。改変型IL-4ムテイン受容体アンタゴニストは、IL-4およびIL-13により媒介される活性を、IL-4RAのそれに比して10分の1を下回ることのない効力で阻害する。加えて、改変型IL-4ムテイン受容体アンタゴニストの血漿半減期は、非改変IL-4RAのそれの少なくとも2〜10倍の長さである。
本発明はまた、改変型IL-4ムテイン受容体アンタゴニストをコードするポリヌクレオチドも提供する。これらのポリヌクレオチドは、例えば、治療用途のためにアンタゴニストを多量に生産するために用いることができる。
アレルギー性喘息の治療における特定のアンタゴニストの有効性を評価するためには、アンタゴニストを、実施例5および6に詳述した細胞増殖アッセイにてインビトロで試験することが可能である。さらに、改変型IL-4ムテイン受容体アンタゴニストの血漿半減期を、実施例6に従った薬物動態試験によってインビボで測定することができる。
上記の改変型IL-4ムテイン受容体アンタゴニストの任意のものを、薬学的に許容される担体を含む薬学的組成物として提供することができる。薬学的に許容される担体は、非発熱性であることが好ましい。組成物は単独で、または安定化化合物などの少なくとも1つの他の作用因子と組み合わせて投与することができ、生理食塩水、緩衝生理食塩水、デキストロースおよび水を非制限的に含む、任意の無菌性で生体適合性のある薬学的担体中にある状態で投与することができる。例えば0.4%食塩水、0.3%グリシンといった、さまざまな水性担体を用いることもできる。これらの溶液は無菌性であり、粒子状物質を一般に含まない。これらの溶液は、従来のよく知られた滅菌手法(例えば、濾過)によって無菌化しうる。
本発明は、IL-4受容体α鎖を結合させて、IL-4およびIL-13により媒介される活性を阻害することにより、障害の症状を改善する方法を提供する。これらの障害には、喘息および他の免疫疾患またはアレルギー性疾患に伴うマスト細胞、好酸球およびリンパ球の動員および活性化を含む、気道過敏性および気道炎症が含まれるが、これらに限定されない。
治療的有効量の決定は当業者の能力の十分な範囲内にある。治療的有効量とは、治療的有効量の非存在下で認められる有効性と比較して喘息を有効に治療するために用いられるアンタゴニストの量のことを指す。
実施例1
IL-4-RAおよびIL-4-REシステインムテインの組換え生産
pET Directional TOPO(登録商標)発現システム(Invitrogen)をIL-4の組換え発現のために選択した。このシステムは、関心対象の遺伝子の大腸菌における高レベルおよびIPTG誘導性発現を目的として平滑末端PCR産物およびT7lacプロモーターの定方向クローニングを行うために、高効率一段階「TOPO(登録商標)Cloning」戦略を用いる。そのほかの特徴には、基礎的な転写を低下させるためのlacI遺伝子、プラスミドの複製および維持のためのpBR322起点、ならびに選択用のアンピシリン耐性遺伝子が含まれる。
組換え発現および精製
プラスミドを含むタンパク質による形質転換を受けたBL21 Star(DE3)One Shot細胞(Invitrogen)を至適発現の特徴に関して調べた上で、0D600が約0.4に達するまで37℃で増殖させ、1mM IPTG(Invitrogen)による誘導処理を37℃で3時間行った。1リットル分の細胞を13,000rpmで10分間遠心してペレット化し、秤量した上で-80℃で保存した。凍結細胞ペレットを、細胞1グラム当たり8mlの細胞破壊用バッファー(0.1Mリン酸緩衝液 pH7.3、0.1% Triton X100、1mM EDTA)中に再懸濁させ、1分間ずつの間をおいて1分間×4回の超音波処理を行った。細胞溶解物を35000g、10分間の遠心処理によって除去した。続いて細胞ペレットを、30mlの細胞破壊用バッファー中に再懸濁させ、1分間の超音波処理の後に遠心処理を行うことを2〜3回繰り返して洗浄した。最終的な細胞ペレットである封入体を-20℃で保存した。封入体を、細胞1グラム当たり5mlの可溶化バッファー(0.2M Tris pH9、7M塩酸グアニジン)中に再懸濁させた。スルホトライシス(Sulphotolysis)試薬(細胞1グラム当たり亜硫酸ナトリウム0.16グラム、テトラチオン酸カリウム0.08グラム)を添加し、封入体を室温で2時間攪拌した。続いて、溶解しなかった成分を35000gでの20分間の遠心によって除去し、可溶化した封入体のみを残した。続いて、タンパク質を単離するために封入体をSuperdex200サイズ排除カラム(Akta)にかけた。カラムをカラム容量(CV)の2倍の6M塩酸グアニジン/PBS pH7により流速1ml/分で平衡化し、タンパク質を1.5 CVに溶出させた。ピーク画分(各1.5ml)を採取し、12%または4〜20%のBis-Tris-SDSゲル電気泳動によりスクリーニングした。タンパク質を含む画分をプールし、タンパク質分子を還元するために最終濃度7.5mMのDTTを添加した。室温での2時間のインキュベーションの後に、この混合物を水で5倍に希釈し、4.5Lの3mM NaH2PO4、7mM Na2HPO4、2mM KCl、120mM NaClに対する透析に供した。透析は、新たな緩衝液に少なくとも3回交換しながら3〜4日間続けた。続いて透析材料を0.2μmフィルターに通して濾過し、酢酸を用いてpHを5に調整した。カラムを10 CVのバッファー1(25mM酢酸アンモニウム pH5)で平衡化し、続いて注入後に20分間の勾配で100%バッファーB(25mM酢酸アンモニウム pH5/1M NaCl)にした。ピーク画分(各0.5ml)を採取し、12%または4〜20%のBis-Tris-SDSゲル電気泳動によりスクリーニングした。産物を含む画分をプールし、バッファーA(0.1% TFA/水)で2倍に希釈した。続いてタンパク質を、C4逆相-HPLC(Beckman system Gold)により、5mlループおよび流速1ml/分を用い、以下のプログラムを用いてクロマトグラフィー処理した:注入期間は10%バッファーA、10分間の勾配で40%バッファーB(0.1% TFA/ACN)に、30分間の勾配で50%バッファーBに、5分間の勾配で100%バッファーBに。ピーク画分(各0.5ml)を採取し、12%または4〜20%のBis-Tris-SDSゲル電気泳動によりスクリーニングした。タンパク質を含む画分を吸引乾燥させ、分析およびアッセイのために0.1M MES pH6.1中に再懸濁させた。
位置特異的システインPEG化および精製
タンパク質のスルフヒドリルと、直鎖状22kDメトキシ-ポリエチレングリコール-マレイミド誘導体(Nektar Therapeutics)のマレイミド基との間の安定的なチオエステル結合を介して、システインを含むIL4 RAムテインをPEG化するためのプロトコールを確立した。2倍モル過剰量のmPEG-MAL 22kD試薬を、反応バッファー(0.1M MES、pH6)中に溶解したタンパク質60□Mに添加した。室温に0.5時間おいた後に、mPEG-MAL 22kDに対して2倍モル過剰量のシステインによって反応を停止させた(図1)。PEG化タンパク質を、反応しなかったmPEG-MAL 22kD(システインにより反応停止させた)および反応しなかったIL4 RAシステインムテインから、陽イオン交換およびサイズ排除クロマトグラフィーによって精製した。粗反応混合物を、0.4mLの0.1M MES、pH6で平衡化したVivapure Mini S陽イオン交換カラム(Vivascience)にかけた。カラムを0.4mLの0.1M MES、pH6で2回洗浄し、各洗浄後に2,000×gで遠心した。0.4mLの0.6M NaCl/0.1M MES、pH6を用いたカラムからの遠心処理によって試料を溶出させた。0.4mLの溶出液を、Beckman HPLC system Goldを用いるTSK-GEL G2000SWXL HPLCサイジングカラム(Tosoh Biosep)にかけた。リン酸緩衝食塩水(Dulbecco's PBS)の移動相を流速1ml/分で30分間用いて試料を分離した。ピーク画分(0.5ml)を採取し、4〜12%のBis-Tris-SDSゲル電気泳動によってPEG化タンパク質に関して評価した。産物を含む画分をプールした上で、分析およびインビトロアッセイのために、Ultrafree Biomax-5装置(Millipore)を製造元のプロトコールに従って用いて濃縮し、約60μM(またはほぼ1mg/ml)とした。PEG化タンパク質の最終濃度はアミノ酸分析によって決定した。最終的な収量は表5に示されている。
BiaCore IL-4受容体結合アッセイ
IL-4受容体を、BIAcore CM5研究用グレードセンサーチップ上にアミン結合によって固定化した。センサー表面をEDC/NHSパルスにより活性化させた。IL-4受容体を10mM酢酸緩衝液(pH 5.0)中に溶解させてフローセル2に注入し、その後に表面を失活させるために1.0Mエタノールアミン-HCLのパルスを与えた。受容体の固定化レベルはほぼ300RUであった。フローセル1はリガンドを用いずに活性化させ、ブランクとして用いた。動態分析の実施にはBiacore Wizardを用いた。IL-4REアンタゴニストの候補をHBS-EP(泳動バッファー)中に希釈し、30μl/分の流速で3分間注入し、解離時間は15分間とした。チップの再生処理は、一連の濃度における次の注入の前にベースラインに対する10mMグリシン pH2.5(流速100μl/分)の30秒間の2回の注入によって行った。解離定数(KD)値を、直接結合による反応速度論に基づいて各候補について算出した(表5)。その結果、構築物IL4-RE-A104C、IL4-RE-N105CおよびIL4-RE-Q106Cのすべてで0.6nM未満の解離定数が得られたことが示された。
TF-1細胞増殖アッセイ
IL-4(0.5ng/ml、0.033nM)またはIL-13(5ng/ml、0.416nM)に対するTF-1細胞の増殖応答を用いて、IL-4RE分子の機能的拮抗活性を評価した。このアッセイでは、96ウェルプレート(1×104個/ウェル、容積100μl)において、10%血清を加えたRPMI中で、IL-4またはIL-13およびIL-4RE分子の存在下または非存在下でTF-1細胞を2〜4日間培養した。GM-CSF処理を陽性対照として用いた。最終的な読み取りの24時間前に、10μlのAlamarBlue(容積比10%)を各ウェルに添加した。530/590nmでの蛍光を、WALLAC Victor 2を用いて測定した。増殖阻害濃度50%(IC50)はIL-4RE分子候補の用量漸増法によって決定した。IL-4およびIL-13の阻害に関するTF-1バイオアッセイの結果の要約が表6に示されている。これらの結果は、構築物IL4-RE-K37C、IL4-RE-N38CおよびIL4-RE-Al04Cが、IL-4またはIL-13の存在下でIL-4-RAのそれと同程度のIC50値を示したことを示している。
初代細胞増殖アッセイ
IL-4に対するヒト初代細胞(T細胞およびB細胞)の増殖応答もIL-4RE分子の前処理後に評価した。末梢血単核細胞(PBMC)を末梢血から単離し、T細胞芽球化を誘導するためにその一部をPHAで4日間処理した。B細胞活性を活性化するためにPBMCを抗CD40でも処理し、直ちに用いた。細胞を96ウェルプレート(1ウェル当たり細胞105個)に播いた。PHA T細胞芽球およびB細胞調製物を、種々の濃度のIL-4RE分子の存在下で、IL-4(10ng/ml、0.667nM)により3日間刺激した。インキュベーションの最後の20時間におけるトリチウム標識チミジンの取り込みを増殖の指標として用いた。これらのアッセイの結果は表7に示されている。これらの結果は、どちらの初代細胞アッセイに関しても、すべてのPEG化構築物がIL-4RAの5倍未満のIC50を示したことを示している。
ラット薬物動態試験
体重250〜300グラムの成体雄性Sprague-Dawleyラットを用いた。血液試料の採取のために、ラットに頸静脈カテーテルを挿管した。さらに、静脈内(IV)投与群のラットには、薬剤投与のために大腿静脈カテーテルも挿管した。
Claims (23)
- a)SEQ ID NO:4、SEQ ID NO:5、もしくはSEQ ID NO:6に示されたヌクレオチド配列;または
b)SEQ ID NO:12、SEQ ID NO:13、もしくはSEQ ID NO:14に示されたアミノ酸配列を有するポリペプチドをコードするヌクレオチド配列
を含む、精製されたポリヌクレオチド。 - 請求項1記載のポリヌクレオチドを含む発現ベクター。
- 請求項2記載の発現ベクターを含む宿主細胞。
- 改変型IL-4ムテイン受容体アンタゴニストを作製する方法であって、
a)請求項3記載の宿主細胞をアンタゴニストが発現される条件下で培養する段階;および
b)宿主細胞培養物からアンタゴニストを精製する段階
を含む方法。 - 活性型の改変型IL-4ムテイン受容体アンタゴニストを作製する方法であって、
a)請求項3記載の宿主細胞をアンタゴニストが発現される条件下で培養する段階;
b)アンタゴニストをジチオトレイトールの存在下でリフォールディングさせる段階;および
c)宿主細胞培養物からアンタゴニストを精製する段階
を含む方法。 - d)アンタゴニストを非タンパク質性ポリマーと結合させる段階;および
e)非タンパク質性ポリマーと結合させたアンタゴニストを精製する段階
をさらに含む、請求項5記載の方法。 - IL-4およびIL-13により媒介される活性を阻害する、請求項4から6のいずれか一項記載の方法によって生産される改変型IL-4ムテイン受容体アンタゴニスト。
- SEQ ID NO:12、SEQ ID NO:13、またはSEQ ID NO:14に示されたアミノ酸配列を含む、請求項7記載の改変型IL-4ムテイン受容体アンタゴニスト。
- ポリエチレングリコール、ポリプロピレングリコールおよびポリオキシアルキレンからなる群より選択される非タンパク質性ポリマーと結合している、請求項7または8記載の改変型IL-4ムテイン受容体アンタゴニスト。
- 野生型IL-4に従って番号付けされた37、38、または104位にあるアミノ酸残基で個々に、非タンパク質性ポリマーと結合している、請求項7〜9のいずれか一項記載の改変型IL-4ムテイン受容体アンタゴニスト。
- SEQ ID NO:12、SEQ ID NO:13、もしくはSEQ ID NO:14に示されたアミノ酸配列を有するポリペプチドを含む改変型IL-4ムテイン受容体アンタゴニストであって、該改変型IL-4ムテイン受容体アンタゴニストは、野生型IL-4に従って番号付けされた37、38、または104位にあるアミノ酸残基で個々に、非タンパク質性ポリマーと結合しており、かつ非タンパク質性ポリマーがポリエチレングリコール、ポリプロピレングリコールまたはポリオキシアルキレンである、改変型IL-4ムテイン受容体アンタゴニスト。
- 0.1nM〜10μMのKdでIL-4受容体α鎖と結合する、請求項7〜11のいずれか一項記載の改変型IL-4ムテイン受容体アンタゴニスト。
- 0.5nM〜1μMのK d でIL-4受容体α鎖と結合する、請求項12記載の改変型IL-4ムテイン受容体アンタゴニスト。
- 1.0nM〜100nMのK d でIL-4受容体α鎖と結合する、請求項13記載の改変型IL-4ムテイン受容体アンタゴニスト。
- IL-4もしくはIL-13に対するTF-1細胞の増殖応答、またはIL-4に対するヒトB細胞もしくはヒトT細胞の増殖応答を、0.1nM〜10μMのIC50で阻害する、請求項7〜11のいずれか一項記載の改変型IL-4ムテイン受容体アンタゴニスト。
- IC 50 が0.5nM〜1μMである、請求項15記載の改変型IL-4ムテイン受容体アンタゴニスト。
- IC 50 が1.0nM〜100nMである、請求項16記載の改変型IL-4ムテイン受容体アンタゴニスト。
- 血漿半減期が、非改変IL-4受容体アンタゴニストの少なくとも2〜10倍の長さである、請求項9〜11のいずれか一項記載の改変型IL-4ムテイン受容体アンタゴニスト。
- a)請求項7〜18のいずれか一項記載の改変型IL-4ムテイン受容体アンタゴニスト;および
b)薬学的に許容される担体
を含む薬学的組成物。 - IL-4およびIL-13の活性の増加に関連するヒト障害を治療するための、請求項7〜18のいずれか一項記載の改変型IL-4ムテイン受容体アンタゴニスト。
- IL-4およびIL-13の活性の増加に関連するヒト障害を治療するための、請求項19記載の薬学的組成物。
- 障害が喘息、慢性閉塞性肺疾患または関連する肺病態である、請求項20記載の改変型IL-4ムテイン受容体アンタゴニストまたは請求項21記載の薬学的組成物。
- 慢性閉塞性肺疾患が肺気腫または慢性気管支炎である、請求項22記載の改変型IL-4ムテイン受容体アンタゴニストまたは薬学的組成物。
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US49890603P | 2003-08-29 | 2003-08-29 | |
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US52822803P | 2003-12-09 | 2003-12-09 | |
US60/528,228 | 2003-12-09 | ||
US53018203P | 2003-12-17 | 2003-12-17 | |
US60/530,182 | 2003-12-17 | ||
US10/820,559 US7404957B2 (en) | 2003-08-29 | 2004-04-08 | Modified IL-4 mutein receptor antagonists |
US10/820,559 | 2004-04-08 | ||
PCT/US2004/023310 WO2005023860A2 (en) | 2003-08-29 | 2004-07-20 | Modified il-4 mutein receptor antagonists |
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US7785580B2 (en) * | 2003-08-29 | 2010-08-31 | Aerovance, Inc. | Modified IL-4 mutein receptor antagonists |
MX2007002903A (es) * | 2004-09-10 | 2007-07-11 | Pharmaorigin Aps | Metodos para el tratamiento de hemoptisis o hemorragias traqueales, bronquiales o alveolares, locales. |
US20070009479A1 (en) * | 2005-06-17 | 2007-01-11 | Aerovance, Inc. | Methods for treating dermatitis using mutant human IL-4 compositions |
NZ599176A (en) * | 2005-08-03 | 2014-04-30 | Immunogen Inc | Immunoconjugate formulations |
MX2008008968A (es) * | 2006-01-11 | 2008-09-10 | Aerovance Inc | Metodos y composiciones para tratar asma en primates humanos y no humanos. |
EP2049147A2 (en) * | 2006-07-06 | 2009-04-22 | Apogenix GmbH | Human il-4 muteins in combination with chemotherapeutics or pro-apoptotic agents in cancer therapy |
EA201070129A1 (ru) * | 2007-07-11 | 2010-10-29 | Аэрованс, Инк. | Фармацевтический сухой порошкообразный аэрозольный состав, включающий полипептид, и способ его приготовления |
JP2012520326A (ja) * | 2009-03-13 | 2012-09-06 | アエロヴァンス インコーポレイティッド | 組換えタンパク質の再生法 |
SI2580236T1 (sl) | 2010-06-08 | 2019-08-30 | Pieris Pharmaceuticals Gmbh | Muteini lipokalina solz, ki vežejo IL-4 R alfa |
WO2015000585A1 (en) | 2013-07-02 | 2015-01-08 | Walter Sebald | Muteins of cytokines of the gamma-chain receptor family conjugated to a non-protein group |
RU2758092C1 (ru) * | 2018-02-01 | 2021-10-26 | Бэйцзин Кавин Текнолоджи Шеа-Холдинг Ко., Лтд. | АНТИТЕЛО К IL-4Rα И ЕГО ПРИМЕНЕНИЕ |
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US5986059A (en) | 1996-06-14 | 1999-11-16 | Bayer Corporation | T-cell selective interleukin-4 agonists |
US6028176A (en) | 1996-07-19 | 2000-02-22 | Bayer Corporation | High-affinity interleukin-4 muteins |
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IS8315A (is) | 2006-02-20 |
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US7404957B2 (en) | 2008-07-29 |
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US20050059590A1 (en) | 2005-03-17 |
AU2004270638A1 (en) | 2005-03-17 |
JP2007526757A (ja) | 2007-09-20 |
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