JP2021167325A - 改良された補体結合を有する高次多量体化免疫グロブリンfc組成物を作製するためのヒトタンパク質断片の融合タンパク質 - Google Patents
改良された補体結合を有する高次多量体化免疫グロブリンfc組成物を作製するためのヒトタンパク質断片の融合タンパク質 Download PDFInfo
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Abstract
【解決手段】本発明は、一連の完全組み換え型多量体化形態の免疫グロブリンFcに関し、これにより、免疫細胞受容体に多価免疫グロブリンFcを提示する。融合タンパク質は、ストラドマーと呼ばれる、ホモ二量体画分及び高次多量体画分の両方として存在する。本発明は、多量体化を増加させ、補体に優先的に結合し、かつ疾患の治療及び予防において有用である、ストラドマーに関する。本発明は、1つ以上のヒト免疫グロブリンFcドメインと、1つ以上の多量体化ドメインとを含む生物活性融合タンパク質生物模倣型分子に関し、融合タンパク質のFcドメイン部分は、1つ以上の点変異を含む。
【選択図】なし
Description
本出願は、2015年7月24日に出願された米国仮出願第62/196,478号に対する優先権を主張し、その内容全体が、参照により本明細書に組み込まれる。
本明細書とともに電子的に提出されたテキストファイルの内容全体が、参照により本明細書に組み込まれる:配列表のコンピュータ可読形式のコピー(ファイル名:GLIK_015_01WO_SeqList_ST25.txt、記録日付:2016年7月22日、ファイルサイズ193キロバイト)。
Claims (83)
- (a)1つ以上の点変異を有する少なくとも1つのIgG1 Fcドメインであって、前記1つ以上の点変異が、前記IgG1 Fcドメインの267、268、及び/または324位のうちの少なくとも1つに対応する、IgG1 Fcドメインと、(b)少なくとも1つの多量体化ドメインと、を含む、ストラドマー(stradomer)単位。
- 前記Fcドメインが、267、268、及び324位に点変異を含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異S267E、H268F、及びS324Tを含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、297位に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異S267E、H268F、N297A、及びS324Tを含む、請求項4に記載のストラドマー単位。
- 前記Fcドメインが、234及び235位に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異L234V、L235A、S267E、H268F、及びS324Tを含む、請求項6に記載のストラドマー単位。
- 前記Fcドメインが、234、235、及び297位に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異L234V、L235A、S267E、H268F、N297A、及びS324Tを含む、請求項8に記載のストラドマー単位。
- 前記Fcドメインが、233、234、及び235位に点変異を、ならびに236位にアミノ酸の欠失を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異E233P、L234A、L235A、S267E、H268F、及びS324Tを含む、請求項10に記載のストラドマー単位。
- 前記Fcドメインが、233、234、235、及び297位に点変異を、ならびに236位にアミノ酸の欠失を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異E233P、L234A、L235A、S267E、H268F、N297A、及びS324Tを含む、請求項12に記載のストラドマー単位。
- 前記Fcドメインが、265位に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異D265A、S267E、H268F、及びS324Tを含む、請求項14に記載のストラドマー単位。
- 前記Fcドメインが、238位に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異P238D、S267E、H268F、及びS324Tを含む、請求項16に記載のストラドマー単位。
- 前記Fcドメインが、238及び297位に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異P238D、S267E、H268F、N297A、及びS324Tを含む、請求項18に記載のストラドマー単位。
- 前記Fcドメインが、236位に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異G236R、S267E、H268F、及びS324Tを含む、請求項20に記載のストラドマー単位。
- 前記Fcドメインが、233及び236位に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異E233P、G236R、S267E、H268F、及びS324Tを含む、請求項22に記載のストラドマー単位。
- 前記Fcドメインが、233、236、及び328位に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異E233P、G236R、S267E、H268F、S324T、及びL328Fを含む、請求項24に記載のストラドマー単位。
- 前記Fcドメインが、238及び265位に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異P238D、D265G、S267E、H268F、及びS324Tを含む、請求項26に記載のストラドマー単位。
- 前記Fcドメインが、点変異P238D、D265W、S267E、H268F、及びS324Tを含む、請求項26に記載のストラドマー単位。
- 前記Fcドメインが、328位に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異S267E、H268F、S324T、及びL328Fを含む、請求項29に記載のストラドマー単位。
- 前記Fcドメインが、233、234、235、297、及び328位に点変異を、ならびに236位にアミノ酸の欠失を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異E233P、L234V、L235A、S267E、H268F、N297A、S324T、及びL328Fを含む、請求項31に記載のストラドマー単位。
- 前記Fcドメインが、233、268、及び/または324位に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異E233P、H268F、及び/またはS324Tを含む、請求項33に記載のストラドマー単位。
- 前記Fcドメインが、297位に点変異を更に含む、請求項33または34に記載のストラドマー単位。
- 前記297位の点変異が、N297AまたはN297Q以外の点変異である、請求項35に記載のストラドマー単位。
- 前記Fcドメインが、299位に点変異を更に含み、前記点変異が、T299S及びT299C以外の点変異である、請求項33または34に記載のストラドマー単位。
- 前記Fcドメインが、点変異T299Aを更に含む、請求項33または34に記載のストラドマー単位。
- 前記Fcドメインが、点変異E233P、H268F、S324Tと、点変異S267E以外の267位の点変異と、を含む、請求項33に記載のストラドマー単位。
- 前記Fcドメインが、297位に点変異を更に含む、請求項33または39に記載のストラドマー単位。
- 前記297位の点変異が、N297AまたはN297Q以外の点変異である、請求項40に記載のストラドマー単位。
- 前記Fcドメインが、299位に点変異を更に含み、前記点変異が、T299S及びT299C以外の点変異である、請求項39または40に記載のストラドマー単位。
- 前記Fcドメインが、点変異T299Aを更に含む、請求項39または40に記載のストラドマー単位。
- 前記Fcドメインが、233及び236位に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異E233P、H268F、S324Tと、S267E以外の267位の点変異と、G236R以外の236位の点変異と、を含む、請求項44に記載のストラドマー単位。
- 前記Fcドメインが、297位に点変異を更に含む、請求項44または45に記載のストラドマー単位。
- 前記297位の点変異が、N297AまたはN297Q以外の点変異である、請求項46に記載のストラドマー単位。
- 前記Fcドメインが、299位に点変異を更に含み、前記点変異が、T299S及びT299C以外の点変異である、請求項45または46に記載のストラドマー単位。
- 前記Fcドメインが、点変異T299Aを更に含む、請求項45または46に記載のストラドマー単位。
- 前記Fcドメインが、以下、a.233位、b.235位、c.236位、d.267位、e.268位、f.297位、g.299位、またはh.324位のうちの3つ以上に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、以下、a.233位、b.235位(235Hを除く)、c.236位(236Rを除く)、d.267位(267Eを除く)、e.268位、f.297位(297Aを除く)、もしくは代替的に299位、及び/またはg.324位のうちの3つ以上に点変異を更に含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、IgG1のEEMまたはDEL多型のいずれかを含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、点変異E233P、H268F、及びS324Tを含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、297位にN297AまたはN297Q以外の点変異を更に含む、請求項53に記載のストラドマー単位。
- 前記Fcドメインが、299位に点変異を更に含む、請求項53に記載のストラドマー単位。
- 前記Fcドメインが、点変異S299Aを更に含む、請求項53に記載のストラドマー単位。
- 前記Fcドメインが、点変異E233P、H268F、及びS324Tと、S267Eではない267位の点変異と、を含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、297位にN297AまたはN297Q以外の点変異を更に含む、請求項57に記載のストラドマー単位。
- 前記Fcドメインが、299位に点変異を更に含む、請求項57に記載のストラドマー単位。
- 前記Fcドメインが、点変異S299Aを更に含む、請求項57に記載のストラドマー単位。
- 前記Fcドメインが、点変異E233P、H268F、及びS324Tと、S267Eではない267位の点変異と、G236Rではない236位の点変異と、を含む、請求項1に記載のストラドマー単位。
- 前記Fcドメインが、297位にN297AまたはN297Q以外の点変異を更に含む、請求項61に記載のストラドマー単位。
- 前記Fcドメインが、299位に点変異を更に含む、請求項61に記載のストラドマー単位。
- 前記Fcドメインが、点変異S299Aを更に含む、請求項61に記載のストラドマー単位。
- 前記多量体化ドメインが、IgG2ヒンジ、イソロイシンジッパー、及びGPPドメインからなる群から選択され、前記ストラドマー単位を多量体化することができる、請求項1に記載のストラドマー単位。
- ストラドマー単位であって、前記多量体化ドメインが、前記ストラドマー単位の多量体を形成する、請求項1に記載のストラドマー単位。
- ストラドマー単位であって、前記ストラドマー単位の前記多量体が、高次多量体である、請求項66に記載のストラドマー単位。
- 前記ストラドマー単位が、FcγRI、FcγRIIa、FcγRIIb、及び/またはFcγRIIIと比較して、補体への優先的結合を呈する、請求項1に記載のストラドマー単位。
- 前記ストラドマー単位が、低親和性Fcγ受容体への低減した結合を呈する、請求項1に記載のストラドマー単位。
- 前記ストラドマー単位が、297、298、または299に変異を含み、C1qに結合し、CDCを阻害し、かつFcγRI、FcγRIIa、FcγRIIb、及び/またはFcγRIIIへの結合を保持する、請求項1に記載のストラドマー単位。
- 前記ストラドマー単位が、267、268、及び/または324位のうちの1つ以上に点変異を含まない同一の構造のストラドマーと比較して、FcγRI、FcγRII、及び/またはFcγRIIIへの低減した結合を呈する、請求項1に記載のストラドマー単位。
- 前記ストラドマーが、アミノからカルボキシ末端にかけて、リーダー配列と、IgG1ヒンジ、IgG1CH2、及びIgG1 CH3を含むFcドメインと、IgG2ヒンジと、を含む、請求項1に記載のストラドマー単位。
- 前記ストラドマーが、配列番号10〜16、18〜63、及び65〜77からなる群から選択されるアミノ酸配列を含む、請求項72に記載のストラドマー単位。
- 前記ストラドマーが、アミノからカルボキシ末端にかけて、リーダー配列と、IgG2ヒンジと、IgG1ヒンジと、IgG1 CH2及びIgG1 CH3を含むFcドメインと、を含む、請求項1に記載のストラドマー単位。
- 前記ストラドマーが、配列番号17及び64からなる群から選択されるアミノ酸配列を含む、請求項74に記載のストラドマー単位。
- 請求項1〜75のいずれか1項に従う2つ以上のストラドマー単位を含む、クラスターストラドマー。
- 補体媒介疾患、抗体媒介疾患、自己免疫疾患、炎症性疾患、アレルギー、または血液障害を治療または予防する方法であって、治療または予防を必要とする対象に請求項1に記載のストラドマーを投与することを含む、方法。
- 前記抗体媒介疾患が、グッドパスチャー病;臓器移植拒絶;視神経脊髄炎;神経性筋強直症;辺縁系脳炎;モルヴァン症候群;重症筋無力症;ランバート・イートン筋無力症症候群;自律神経性ニューロパチー;アルツハイマー病;アテローム動脈硬化症;パーキンソン病;全身硬直症候群または過剰驚愕症;再発性自然流産;ヒューズ症候群;全身性エリテマトーデス;自己免疫性小脳性運動失調症;強皮症、シェーグレン症候群を含む結合組織病;多発性筋炎;リウマチ性関節炎;結節性多発性動脈炎;CREST症候群;心内膜炎;橋本甲状腺炎;混合性結合組織病;チャネル病;小児自己免疫性溶連菌関連性精神神経障害(PANDAS);N−メチル−D−アスパラギン酸受容体、特に、NR1、コンタクチン関連タンパク質2、AMPAR、GluR1/GluR2、グルタミン酸デカルボキシラーゼ、GlyRアルファ1a、アセチルコリン受容体、VGCC P/Q型、VGKC、MuSK、GABA(B)Rに対する抗体に関連する臨床病態;アクアポリン−4;及び天疱瘡からなる群から選択される、請求項77に記載の方法。
- 前記自己免疫疾患が、リウマチ性関節炎である、請求項77に記載の方法。
- 前記自己免疫疾患が、自己免疫関連視力低下または難聴である、請求項77に記載の方法。
- 前記補体媒介疾患が、重症筋無力症;溶血性尿毒症症候群(HUS);非定型溶血性尿毒症症候群(aHUS);発作性夜間ヘモグロビン尿症(PNH);視神経脊髄炎;同種移植片の抗体媒介拒絶;膜性腎症を含む腎症疾患;ならびに膜性増殖性糸球体腎炎(MPGN)及びループス腎炎を含む腎炎疾患からなる群から選択される、請求項77に記載の方法。
- 前記血液障害が、鎌状赤血球症である、請求項77に記載の方法。
- 前記ストラドマーが、静脈内に、皮下に、経口に、腹腔内に、舌下に、頬側に、経皮に、真皮下埋め込みによって、または筋肉内に投与される、請求項77に記載の方法。
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