JP2018528167A - 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
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)。
数万の供血者からプールされる、プールされたヒトIVIGは、未変性IgG1の可溶性凝集体の天然効果を模倣するIgG1凝集体の非常に少ない可変部分(0.1〜5%)を含有する。IVIGはC1qに結合し、重症筋無力症などの補体媒介疾患において臨床的に有用であることが実証されている。しかしながら、IVIGは、血液産物であることに付随する全てのリスクを有し、組み換え産生されず、不良に制御された量のIgG1凝集体を有し、補体媒介疾患を治療するには不活性の画分で主に構成される。その上、IVIG治療はまた、低親和性Fc受容体への結合によって、多くの場合望まれない炎症促進性応答をもたらす(Andresen et.al.Product equivalence study comparing various human immunoglobulin−G formulations.J Clin Pharmacol2000;40:722−730及びGhielmetti et.al.Gene expression profiling of the effects of intravenous immunoglobulin in human whole blood.Mol Immunol43(2006)939−949)。C1qに強力に結合することによって補体シンクとして作用しながら、同時に低親和性Fc受容体を含む天然リガンドよりも補体成分に優先的に結合することによって望まれない炎症促進性応答を回避する、凝集可溶性IgG1 Fcの天然プロセスを模倣する、新規で一貫性した組み換え産生された療法に対する必要性が存在する。
「Fc断片」は、免疫グロブリンのカルボキシ末端に常に見出されるタンパク質領域またはタンパク質折り畳み構造を説明するために使用される専門用語である。Fc断片は、不完全かつ不十分なプロセスである酵素消化、例えばパパイン消化の使用を通して、モノクローナル抗体のFab断片から単離することができる(Mihaesco C and Seligmann M.Papain Digestion Fragments Of Human IgM Globulins.Journal of Experimental Medicine,Vol127,431−453(1968)を参照されたい)。(抗原結合ドメインを含有する)Fab断片と合わさって、Fc断片は、本明細書において完全な抗体を意味する、ホロ抗体を構成する。Fc断片は、抗体の重鎖のカルボキシ末端部分からなる。Fc断片中の鎖のそれぞれは、約220〜265アミノ酸長であり、鎖は、多くの場合ジスルフィド結合を介して連結される。Fc断片は、多くの場合1つ以上の独立した構造的折り畳みまたは機能的サブドメインを含有する。特に、Fc断片は、本明細書においてFcγ受容体に結合する最小構造として定義されるFcドメインを包含する。単離Fc断片は、二量体化される2つのFc断片の単量体から構成される(例えば、本明細書において更に定義される、抗体の重鎖の2つのカルボキシ末端部分)。2つのFc断片の単量体が会合する場合、結果として得られるFc断片は、補体及び/またはFc受容体結合活性を有する。
「Fc部分断片」とは、抗体の全Fc断片未満を含むが、Fc受容体結合活性及び/または補体結合活性を含む、Fc断片と同一の活性を有するのに十分な構造を保持するドメインである。したがって、Fc部分断片は、Fc部分ドメインが由来する抗体のアイソタイプによって、ヒンジ領域の一部分もしくは全て、CH2ドメインの一部分もしくは全て、CH3ドメインの一部分もしくは全て、及び/またはCH4ドメインの一部分もしくは全てを欠いてもよい。Fc部分断片の別の例としては、IgG1のCH2及びCH3ドメインを含む分子が挙げられる。この例において、Fc部分断片は、IgG1に存在するヒンジドメインを欠く。Fc部分断片は、2つのFc部分断片の単量体から構成される。本明細書において更に定義されるように、2つのそのようなFc部分断片の単量体が会合する場合、結果として得られるFc部分断片は、Fc受容体結合活性及び/または補体結合活性を有する。
本明細書で使用される場合、「Fcドメイン」は、Fc受容体(FcR)に結合する、またはそれによって結合され得る、(より大きなポリペプチドの文脈における)最小領域または(単離タンパク質の文脈における)最小タンパク質折り畳み構造を説明する。Fc断片及びFc部分断片の両方において、Fcドメインは、分子をFc受容体に結合させる最小結合領域である。Fcドメインは、Fc受容体によって結合される別個のホモ二量体ポリペプチドに限定され得る一方で、Fcドメインが、Fc断片の一部分または全て、ならびにFc部分断片の一部分または全てであり得ることも明らかだろう。本発明において、「Fcドメイン」という用語が使用される場合、2つ以上のFcドメインを意味するものとして当業者に認識されるだろう。Fcドメインは、2つのFcドメインの単量体から構成される。本明細書において更に定義されるように、2つのそのようなFcドメインの単量体が会合する場合、結果として得られるFcドメインは、Fc受容体結合活性及び/または補体結合活性を有する。したがって、Fcドメインは、補体及び/またはFc受容体に結合することができる二量体構造である。本明細書に記載されるストラドマーは、ストラドマーが補体及び/またはFc受容体に結合する能力を改変する1つ以上の変異を含む、Fcドメインを含む。
本明細書で使用される場合、「Fc部分ドメイン」は、Fcドメインの一部分を説明する。Fc部分ドメインとしては、個々の重鎖定常領域ドメイン(例えば、CH1、CH2、CH3、及びCH4ドメイン)、ならびに異なる免疫グロブリンクラス及びサブクラスのヒンジ領域が挙げられる。したがって、本発明のヒトFc部分ドメインとしては、IgG1のCH1ドメイン、IgG1のCH2ドメイン、IgG1のCH3ドメイン、ならびにIgG1及びIgG2のヒンジ領域が挙げられる。他の種における対応するFc部分ドメインは、その種に存在する免疫グロブリン及びその命名に依存するだろう。好ましくは、本発明のFc部分ドメインは、CH1、CH2、ならびにIgG1のヒンジドメイン及びIgG2のヒンジドメインを含む。本発明のFc部分ドメインは、これらのドメイン及びヒンジのうちの2つ以上の組み合わせを更に含んでもよい。しかしながら、本発明の個々のFc部分ドメイン及びその組み合わせは、FcRに結合する能力を欠く。したがって、Fc部分ドメイン及びその組み合わせは、Fcドメイン未満を含む。Fc部分ドメインは、ともに連結されて、補体及び/またはFc受容体結合活性を有するペプチドを形成し、したがって、Fcドメインを形成してもよい。本発明において、Fc部分ドメインは、本明細書に定義される本発明の生物摸倣物を作製するための構成ブロックとして、Fcドメインとともに使用される。各Fc部分ドメインは、2つのFc部分ドメインの単量体から構成される。2つのそのようなFc部分ドメインの単量体が会合する場合、Fc部分ドメインが形成される。
本明細書で使用される場合、「Fc断片の単量体」は、別のFc断片の単量体と会合される場合、Fc断片を含む単鎖タンパク質である。したがって、Fc断片の単量体は、ホロ抗体のFc断片を構成する抗体の重鎖のうちの1つのカルボキシ末端部分である(例えば、IgGのヒンジ領域、CH2ドメイン、及びCH3ドメインを含む重鎖の近接部分)。一実施形態において、Fc断片の単量体は、最小でも、近接して連結してペプチドを形成する、1鎖のヒンジ領域(ヒンジ単量体)、1鎖のCH2ドメイン(CH2ドメイン単量体)、及び1鎖のCH3ドメイン(CH3ドメイン単量体)を含む。一実施形態において、CH2、CH3、及びヒンジドメインは、異なるアイソタイプに由来する。特定の一実施形態において、Fc断片の単量体は、IgG2ヒンジドメイン、ならびにIgG1 CH2及びCH3ドメインを含有する。
本明細書で使用される場合、「Fcドメインの単量体」は、別のFcドメインの単量体と会合される場合、補体に結合することができるFcドメインを含む単鎖タンパク質を説明する。2つのFcドメインの単量体の会合は、1つのFcドメインを作製する。
特定の実施形態において、本発明の生物模倣型は、ストラドマーを含む。本発明のストラドマーは、補体に結合することができる生物模倣型化合物であり、好ましくは、著しく改善された補体結合を実証する。好ましい一実施形態において、本発明のストラドマーは、増加した補体結合対1つ以上の標準Fc受容体の結合の比率を呈する。ストラドマーは、4つの異なる物理的高次構造、つまり、連続、クラスター、コア、またはFc断片を有し得る。明白であるように、上記に論じられるFc断片、Fc部分断片、Fcドメイン、及びFc部分ドメインは、様々なストラドマー高次構造の構築に使用される。更に、ホモ二量体ストラドマー単位を形成するために最初に産生され、かつその後、多量体化ドメイン(例えば、IgG2ヒンジ)の包含を通して多量体化して、本発明のクラスターストラドマーである多量体構造を形成するのは、これもまた上記に論じられる個々のFcドメインの単量体及びFc部分ドメインの単量体である。具体的なストラドマーは、WO2008/151088及びWO2012/016073に詳細に説明されており、これらの両方の内容全体が、参照により組み込まれる。Fcγ受容体への補体結合及び/またはFcRn結合の比率は、233及び/または234及び/または235及び/または236及び/または238及び/または265及び/または297及び/または299位のうちの1つ以上での追加の変異によって更に改良することができる。
本明細書で使用される場合、「ストラドマー単位単量体」またという用語は、少なくとも第2のストラドマー単位単量体と会合される場合、少なくとも1つのFcドメインを含むホモ二量体ストラドマー単位を形成する、単一の近接ペプチド分子を指す。好ましい実施形態において、ストラドマー単位は、2つの会合したストラドマー単量体から構成される一方で、ストラドマーはまた、3つ以上のストラドマー単量体を含有してもよい。
一実施形態において、本開示に従って使用されるストラドマーは、クラスターストラドマーである。「クラスターストラドマー」は、中央部分である「頭部」及び2つ以上の「脚部」を有する放射状形態を有する生物模倣物であり、各脚部は、少なくとも1つのFcガンマ受容体及び/または補体に結合することができる1つ以上のFcドメインを含む。クラスターストラドマーはまた、ストラドマーの多量体化をもたらす多量体化ドメインの存在のために「多量体化ストラドマー」としても知られている。したがって、1つのストラドマー単量体分子上に複数のFcドメインを含有する連続ストラドマーは、その分子がまた少なくとも1つの多量体化ドメインも含有する限り、依然クラスターストラドマーまたは多量体化ストラドマーとして分類され得る。各クラスターストラドマーは、それぞれが「クラスターストラドマー単位」と呼ばれる2つ以上のホモ二量体タンパク質から構成される。各クラスターストラドマー単位は、少なくとも1つの多量体化する領域、及び少なくとも1つの機能的Fcドメインを含む「脚部」領域から構成される。多量体化領域は、別のクラスターストラドマー単位によって多量体化されると、クラスターストラドマー「頭部」を作製する。脚部領域は、各脚部領域内のFcドメインに存在するだけ多くの補体分子に結合することが可能であり得る。例えば、脚部領域は、各脚部領域内にFcドメインに存在するだけ多くのC1q分子に結合し得る。したがって、クラスターストラドマーは2つ以上のC1q分子に結合し、したがって、下流補体媒介溶解を予防することができる生物模倣型化合物である。本発明の特に強力な生物模倣型は、C1q分子の6つ全ての頭部に結合することができる。
本明細書に記載される補体優先ストラドマーは、増加した補体結合対Fc受容体結合の比率を提供する。したがって、本明細書に提供される補体優先ストラドマーは、いくつかの実施形態において、「補体優先ストラドマー」または「補体結合ストラドマー」と呼ばれる。いくつかの実施形態において、本明細書に提供されるストラドマーは、補体カスケードの1つ以上の成分に結合し、FcγRのそれぞれにも結合する「一般化ストラドマー」である。
本明細書に記載されるストラドマー組成物の投与は、経口的、非経口的、または局所的に、任意の一般的な経路を介したものである。例示的な経路としては、経口、経鼻、頬側、直腸、膣、眼、皮下、筋肉内、腹腔内、静脈内、動脈内、腫瘍内、脊髄内、髄腔内、関節内、動脈内、くも膜下、舌下、口腔粘膜、気管支、リンパ管、子宮内、皮下、腫瘍内、縫合糸などの埋め込み型デバイス上もしくは埋め込み型ポリマーなどの埋め込み型デバイス内への統合、硬膜内、皮質内、または皮膚が挙げられるが、これらに限定されない。そのような組成物は通常、本明細書に記載される薬学的に許容される組成物として投与されるだろう。好ましい一実施形態において、単離されたストラドマーは、静脈内または皮下投与される。
一実施形態において、補体媒介疾患もしくは病態などの疾患もしくは病態の治療または予防方法であって、IgG1 Fcドメイン及び多量体化ドメインを含むストラドマーを、それを必要とする対象に投与することを含み、ストラドマーが、増加した補体結合対Fc受容体結合の割合を呈する、方法が提供される。更なる一実施形態において、ストラドマーは、FcγRへの結合の低減もしくは欠如、及び/またはFcRn結合への結合の低減もしくは欠如を呈し、かつ補体への改良された結合または優先的結合を呈する。更なる一実施形態において、ストラドマーは、C1qへの改良された結合または優先的結合を呈する。
補体優先結合ストラドマーを生成するために、様々なアプローチを取った。Fcドメインに少なくとも1つの点変異が導入されたストラドマーを生成し、この変異は補体結合を改良した。具体的には、WO2012/016073に記載されるGL−2045ストラドマーのFcドメインの267、268、及び324位に以下の変異、つまり、S267E、H268F、及びS324Tを行った。いくつかのストラドマーにおいて、追加の変異を行って、FcγR結合及び/またはFcRn結合を改変することによって補体結合対標準FcγR結合の比率を更に増加させた。例示的なストラドマーのアミノ酸配列を、上記の表1及び表2に示す。
親GL−2045またはFc陰性対照G001と比較した、ストラドマーG994、G996、G997、及びG998間のC1q結合の比較を、図31に提供する。図31Aは、増加濃度の示されるストラドマーの吸光度を示し、図31Bは、試験したストラドマーのそれぞれの、対数変換データ及びEC50値を示す。Ec50値は、μg/mLで示す。合わせると、データは、ストラドマーG997、G998、G996、及びG994が、G001(IgG1 Fc対照)と比較して優れたC1q結合を呈し、親ストラドマーGL−2045と比較して優れたClq結合を呈することを実証する。
C3への補体優先ストラドマーの結合を評価するための研究を実行した。
C3b、C4、及びC5への補体優先ストラドマーの結合を評価するための研究を実行した。
Thy−1腎炎モデル(抗Thy−1誘導性メサンギウム増殖性糸球体腎炎)において、補体優先ストラドマーを評価した。このモデルにおいて、胸腺細胞(ATS)に対する抗体は、ラットメサンギウム細胞上に存在する表面Thy−1抗原に反応性である(Yamamoto1987及びJefferson1999)。ATSの投与は、補体依存性メサンギウム融解、その後、注射後5日以内にピークになり、経時的に消散する急速なメサンギウム増殖性糸球体腎炎を誘導する。
抗Fx1a血清(Probetexカタログ番号PTX−002S)を注射することによって、0日目にラットにおいて疾患を誘導した。0日目の抗血清注射の2時間前(0日目用量)、または抗血清注射の1日後である1日目(1日目用量)に、G998を60mg/kgで投薬し、投薬を1週間に2回、3週間にわたって継続した。ビヒクル対照マウスは、抗Fx1a血清のみを受けた。投薬前ならびに抗血清注射の1、2、及び3週間後に尿を収集し、タンパク尿について評価した。
単回用量後のラットにおける補体優先ストラドマーG994、G998、及びG1033の半減期を測定するための研究を行った。異なる時点で取得した血液試料中の補体活性を評価することによって、機能的半減期を測定した。血液試料を、薬物標的である補体因子c1qのレベルについて、及び薬物のどの画分及びC1qが結合されているかを評価するためにも測定した。
補体優先化合物の単回用量後のカニクイザルにおける、G994、G998、またはG1033の半減期を測定するための研究を行った。
C3、C3b、C4、及びC5への補体優先ストラドマーの結合を評価するための追加の研究を実行した。96ウェルプレートを、1ウェル当たりPBS100μl中の補体成分(C3ではQuidel番号A401、1μg/ml;C3bではGenWay Biotech番号GWB−8BA994、1μg/ml;C4ではQuidel番号A402、1μg/ml;及びC5ではQuidel A403、1μg/ml)で、4Cで一晩コーティングし、その後、3回洗浄した(300μlのPBS1× 0.1%のTween20)。プレートをブロッキング緩衝液(PBS1× +2%のBSA+0.05%のTween20)中で、室温で2時間ブロッキングし、その後、3回洗浄した(300μlのPBS1× 0.1%のTween20)。化合物を、ブロッキング緩衝液中、100μg/mlで開始して、1:1で希釈して、補体成分に室温で2時間反応させ、その後、3回洗浄した(300μlのPBS1× 0.1%のTween20)。ブロッキング緩衝液100μl中、ビオチン化マウス抗ヒトIgG1(BD番号555 869)+ストレプトアビジン−HRP(カタログ番号:7100−05、Southern Biotech)それぞれ1/5000によって結合した化合物を室温で1時間検出した。TMB基質試薬を用いて室温で20分間発色させ、50μlのH2SO4(1M)で反応を停止させ、吸光度の読み取りは450/650nmであった。
単離末梢血単核球(PMBC)から、G994及びG1033のサイトカイン誘導を評価するための追加の研究を実行した。100mLのヒト血液を、ヘパリンコーティングした収集管内に収集した。10mLのアリコートの血液を50mLの円錐管に移し、10mLのPBSで希釈し、その後、穏やかに混合した。20mLの希釈した血液試料を、50mLの円錐管内、15mLのFicoll−Paque PLUS上に層状にし、400×g、18〜20℃で30〜40分間遠心分離する。遠心分離後、パスツールピペットを使用して上層を除去し、リンパ球層を未撹乱のまま界面に残した。リンパ球層を清潔な50mLの円錐管に移し、30mLのPBSを添加した。希釈したリンパ球層を、60〜100×g、18〜20℃で10分間遠心分離した。遠心分離後、上清を除去し、30mLのPBS中で細胞を洗浄し、再度遠心分離した。細胞ペレットを、10%のウシ胎仔血清(FBS)で補助した1〜2mLのRPMI培地中に再懸濁した。細胞を計数し、5×106個の細胞/管で管内にアリコートし、試験材料(G019、G994、またはG1033)とともに4または24時間インキュベートした。市販のELISAキットによって、4時間目及び20時間目のサイトカインレベルを決定した。
雌のルイスラットにおいて、確立されたII型コラーゲン関節炎において生じる腫れを阻害する上での、G994、G998、及びG1033の有効性を決定するために、コラーゲン誘導性関節炎(CIA)研究を実行した。ラットに、ブタII型コラーゲンを皮内/皮下(ID/SC)注射して、関節炎を誘導した。その後、11、13、及び14日目に、ラットにリン酸緩衝食塩水(PBS対照)、G994(40mg/ラット)、G998(40mg/ラット)、またはG1033(40mg/ラット)を静脈内(IV)投薬した。11〜16日目に、陽性対照を経口(PO)経路によって基準化合物デキサメタゾン(Dex、0.075mg/kg)で毎日(QD)治療した。治療は、研究完了後まで盲検であった。有効性評価は、足首ノギス測定に基づいた(図57)。
G994の配列を塩基配列として使用して追加のストラドマーを生成して、追加の補体優先ストラドマーを特定し、試験するだけでなく、特定の残基での変異の機能も評価した。G994(配列番号10または11)は、G045c背景及び233、236、267、268、及び324位に点変異を有するストラドマーである。具体的には、G994は、以下の変異、E223P、G236R、S267E、H268F、及びS324Tを有する。
S267E/H268F/S324T三重変異を含む追加の化合物を生成して、追加の補体優先変異体を生成した。
Turhan et all(2004)Blood103:2397及びChang et al(2008)Blood111:915に詳細に記載される鎌状赤血球症のマウスモデルにおいて、補体優先ストラドマーG994、G998、G1033、G1022、G1032、G1023、G1006、G1027、及びG996を評価する。簡潔には、生後12〜16週間の雄のSCDマウス(Townes SSマウス、ホモ接合型Hbatm1(HBA)Tow及びホモ接合型Hbbtm2(HBG1,HBB*)Tow(M21遺伝子型)をランダムに群に割り当て、外科的準備の20分前に、生理食塩水、IVIG(400mg/kg)、hIgG1(400mg/kg)、アルブミン(400mg/kg)、またはストラドマー(G045c、G994、G998、G1003、及びG1033、60mg/kg)のいずれかとともに(静脈内)投薬する。精巣挙筋細静脈中の好中球接着、ローリング、及び血小板好中球凝集を分析する。末端血液を引き出した後、血漿を収集して、sE−セレクテイン(selectein)、sP−セレクチング(selecting)、sVCAM−1、及びsICAM−1を含むマーカーを分析する。
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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