JP6244350B2 - ヒト化およびキメラ抗因子Bb抗体、ならびにその使用 - Google Patents
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Description
本願は、2012年4月3日出願の米国特許仮出願第61/619,858号の優先権を主張し、その主題が全体として参照により本明細書に援用される。
抗BbIgGlおよびその抗原結合フラグメントのヒト因子Bおよび因子Bbに対する親和性は低pM抗体の範囲内である。Bbに対する抗体結合は、PC3bBb(C3/C5コンベルターゼ)の触媒活性を中和する。抗Bbのヒト因子Bに対する結合は、因子B上の因子D切断部位をブロックする。これらの実験を実施するために、ポリスチレンマイクロタイタープレートを、リン酸緩衝生理食塩水(PBS)中ヒト因子Bおよび因子Bb(ウェルあたり2.0μg/50μl)で一晩4℃にてコーティングした。プロペルジン溶液を吸引した後、1%のウシ血清アルブミン(BSA)(ミズーリ州セントルイス所在のSigma−Aldrich)を含有するPBSで1時間室温にてウェルをブロックした。ペプチドまたはプロペルジンコーティングのないウェルは、バックグラウンド対照としての役割を果たした。ヒト化抗因子BbのアリコートをBおよびBbでコーティングされたウェルに添加し、1時間インキュベートして、結合を起こさせた。室温にて1時間のインキュベーション期間の後、プレートをPBSで5回リンスし、1:2000希釈検出ペルオキシダーゼ複合ヤギ抗ヒトモノクローナル抗体とともにインキュベートした。このインキュベーション後、プレートをリンスし、TMB試薬を用いて結合したペルオキシダーゼを特定した。
先の発明の抗因子B抗体は典型的にはC3bとのB相互作用を阻害した。この新規抗体は因子BのC3bに対する結合を阻害しない。典型的な実験では、ポリスチレンマイクロタイタープレートウェル(96ウェル培地結合プレート、マサチューセッツ州ケンブリッジ所在のCorning Costar)をリン酸緩衝生理食塩水(PBS)pH7.4中C3b(2μg/50μl/ウェル、テキサス州タイラー所在のcomplement technology)で一晩4℃にてコーティングした。C3b溶液を吸引した後、1%のウシ血清アルブミン(BSA;Sigma Chemical)を含有するPBSで1時間室温にてウェルをブロックする。C3bコーティングのないウェルはバックグラウンド対照としての役割を果たす。ヒト化抗Bbのありコートを、一定濃度の因子Bを含有する溶液に添加した。1時間室温にてインキュベーションした後、ウェルをPBSで充分にすすぐ。総結合「B」はポリクローナル抗B抗体で検出された。図4で示されるように、ヒト化抗Bb濃度のいずれも因子BのC3bに対する結合を阻害しなかった。
補体副経路を腸チフス菌(Salmonella Typhosa)由来のリポ多糖により正常ヒト血清中で活性化する。本発明者らは本発明の抗プロペルジン抗体がPC3bBbの形成を阻害するかどうかを示すためにこのパラダイムを利用した。本発明者らは、ヒト化抗Bb抗体の存在下および非存在下でP、C3b、Bb、およびC5b−9の沈着を測定した。沈着したP、C3b、Bb、およびC5b−9は、適切な抗体で検出された。ヒト化抗Bb抗体の存在下で、P、C3b、Bb、およびC5b−9分子のそれぞれの沈着の阻害によって示されるように、C3およびC5コンベルターゼ形成の用量依存的阻害はわかる。
この赤血球溶解アッセイは、rRBCの表面上の終末補体複合体の形成に基づく。その結果、rRBCを溶解させる。700nmでの光散乱の段階的減少は、赤血球溶解の直接的尺度である。典型的には、rRBCを、5mMのMgCl2を含有するゼラチンベローナル緩衝液中正常ヒト血清中でインキュベートする。これらの条件下で、rRBCの表面はn正常ヒト血清における副経路の活性化を誘発する。副経路活性化は、rRBCの表面上のC5b−9複合体形成に至る。C5b−9複合体の形成を阻害する薬剤は、細胞溶解を阻害すると予想される。抗プロペルジン抗体およびそのフラグメントの効果を評価するために、様々な濃度のIgG、F(ab’)2、およびFabを、700nmで読み取ることができる恒温ELISAプレートリーダー中一定濃度のウサギ赤血球で、37℃にてAP緩衝液中正常ヒト血清(10%のNHS)とともにインキュベートした。光散乱の段階的減少(インタクト細胞の溶解による)を時間の関数として700nmで測定した。データを記録し、SpectraMax190プレートリーダーおよびSoftMaxソフトウェアを用いて分析した。計算のために、全阻害を各濃度のIgG、F(ab’)2、およびFabで計算し、結果を未溶解対照の%として表した。MicroCal Origin Softwareを用いてシグモイドプロットで各濃度でのデータをプロットした。
本発明のモノクローナル抗体は宿主防御に必要な古典的経路を阻害しない。抗体感作ヒツジ赤血球を、カルシウム(5mMのCaCl2/MgCl2)緩衝液を含有するゼラチンベローナル緩衝液中10%正常ヒト血清とともにインキュベートした。抗体感作ヒツジ細胞は古典的経路を活性化する。その結果、C5b−9が赤血球の表面上に形成され、それによって溶解が起こる。本発明者らは10%の正常ヒト血清を試験した。両条件下で、抗Bbはヒツジ赤血球溶解を阻害しなかった。典型的なアッセイでは、100μlの抗体感作ヒツジ赤血球(テキサス州タイラー所在のComplement Technologies)をCP緩衝液中10%正常ヒト血清中でインキュベートして、補体活性化を起こさせた。CP活性化の結果、赤血球は溶解する。細胞溶解のための光散乱の段階的減少を時間の関数として700nmで測定した。
CDRを有するマウスモノクローナル抗体を配列させ、CDRを様々なhumaフレームワーク領域内にグラフトした。抗体をクローン化し、当該技術分野で開発された方法を用いてCHO細胞で発現させた。図12〜17は抗体CDRおよびフレームワーク領域を示す。
clips技術を用いてBbタンパク質のエピトープマッピングを実施した。複数のオーバーラッピングペプチドを合成し、抗体をペプチドと1μg/mlの濃度で結合させた。最強のシグナルを生じたペプチドを抗体の潜在的なエピトープであると特定した。配列47および48が1つの抗体クローンについて特定された一方で、配列49、50、および51がヒト化抗Bb抗体について特定された。
Claims (18)
- 配列番号14、配列番号16、および配列番号18のアミノ酸配列を有する3つのCDRを含む重鎖可変ドメインと、配列番号21、配列番号23、および配列番号25のアミノ酸配列を有する3つのCDRを含む軽鎖可変ドメインとを含む、単離された抗Bb抗体またはその抗原結合部分。
- ヒト化フレームワーク領域を含み、前記ヒト化フレームワーク領域が配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、および配列番号12のヒト化フレームワーク領域から選択される、請求項1に記載の抗Bb抗体またはその抗原結合部分。
- ヒト化または非天然フレームワーク領域を含み、前記ヒト化または非天然フレームワーク領域が、配列番号13、配列番号15、配列番号17、配列番号19、配列番号20、配列番号22、配列番号24、および配列番号26から選択される、請求項1に記載の抗Bb抗体またはその抗原結合部分。
- ヒト化または非天然フレームワーク領域を含み、前記ヒト化または非天然フレームワーク領域が、配列番号27、配列番号28、配列番号29、配列番号19、配列番号20、配列番号22、配列番号30、および配列番号26から選択される、請求項1に記載の抗Bb抗体またはその抗原結合部分。
- ヒト化または非天然フレームワーク領域を含み、前記ヒト化または非天然フレームワーク領域が、配列番号31、配列番号32、配列番号33、配列番号19、配列番号20、配列番号34、配列番号35、および配列番号26から選択される、請求項1に記載の抗Bb抗体またはその抗原結合部分。
- ヒト化または非天然フレームワーク領域を含み、前記ヒト化または非天然フレームワーク領域が、配列番号43、配列番号44、配列番号45、配列番号19、配列番号46、配列番号40、配列番号41、および配列番号42から選択される、請求項1に記載の抗Bb抗体またはその抗原結合部分。
- 前記抗Bb抗体またはその抗原結合部分が、配列番号47、配列番号48、配列番号49、配列番号50、および配列番号51からなる群から選択されるアミノ酸配列を有する因子Bb上に位置するペプチド領域に結合する、請求項1〜6のいずれか1項に記載の抗Bb抗体またはその抗原結合部分。
- 前記抗体またはその抗原結合部分抗体が、PC3bBb複合体の形成の阻害によりC3bの形成を阻害する、請求項1〜7のいずれか1項に記載の抗Bb抗体またはその抗原結合部分。
- 前記抗体またはその抗原結合部分抗体が、新たに産生されるC3a、C5a、SC5b−9の形成を阻害する、請求項1〜7のいずれか1項に記載の抗Bb抗体またはその抗原結合部分。
- 前記抗体またはその抗原結合部分が、好中球、単球、および血小板の活性化を阻害する、請求項1〜7のいずれか1項に記載の抗Bb抗体またはその抗原結合部分。
- 前記抗体またはその抗原結合部分が赤血球の溶解を阻害する、請求項1〜7のいずれか1項に記載の抗Bb抗体またはその抗原結合部分。
- 処置有効量の請求項1〜11のいずれか1項に記載の抗Bb抗体またはその抗原結合部分を含む医薬組成物。
- 炎症性障害の処置のための請求項1〜11のいずれか1項に記載の抗Bb抗体またはその抗原結合部分であって、C3a、C5a、またはC5b−9を含む炎症媒介物質の異常なレベルが前記障害で見出される、抗Bb抗体またはその抗原結合部分。
- 前記炎症性障害が、自己免疫疾患、関節リウマチ、若年性関節炎、全身性エリテマトーデス、多発性硬化症、および身体の免疫系が調整を受ける他の自己免疫疾患を含む群から選択される自己免疫疾患である、請求項13に記載の抗Bb抗体またはその抗原結合部分。
- 補体活性化が疾病病状に関与する、眼障害の処置における請求項1〜11のいずれか1項に記載の抗Bb抗体またはその抗原結合部分。
- 前記眼疾患が、湿潤型および乾燥型加齢黄斑変性症、脈絡膜血管新生、ブドウ膜炎、糖尿病性網膜症、糖尿病性黄斑浮腫、病的近視、フォン・ヒッペル・リンドウ病、糖尿病性網膜症、眼のヒストプラスマ症、糖尿病性網膜症、脈絡膜新血管形成(CNV)、網膜中心静脈閉塞症(CRVO)、角膜血管新生、地図状萎縮、結晶腔疾患(drusen disease)、および網膜血管新生を含む群から選択される、請求項15に記載の抗Bb抗体またはその抗原結合部分。
- 補体関連障害の処置のための請求項1〜11のいずれか1項に記載の抗Bb抗体またはその抗原結合部分であって、前記障害が、喘息性または気道炎症、喘息、慢性閉塞性肺疾患(COPD)、アレルギー性気管支肺アスペルギルス症、過敏性肺炎、好酸球性肺炎、気腫、気管支炎、アレルギー性気管支炎気管支拡張症(bronchiecstasis)、嚢胞性線維症(cyctic fibrosis)、結核、過敏性肺炎、職業性喘息、サルコイド、反応性気道疾患症候群、間質性肺疾患、好酸球増多症候群、鼻炎、副鼻腔炎、運動誘発喘息、公害誘発喘息、咳喘息、寄生虫性肺疾患、呼吸器合胞体ウイルス(RSV)感染、パラインフルエンザウイルス(PIV)感染、ライノウイルス(RV)感染、およびアデノウイルス感染を含む群から選択される気道炎症を含む群から選択される、抗Bb抗体またはその抗原結合部分。
- 副経路が疾病病状に関与しているか、あるいは副経路が状態もしくは疾患の原因となる少なくとも1つの症状を悪化させているような状態もしくは疾患に罹患しているか、または前記状態もしくは疾患を発症するリスクのある哺乳類での副経路活性化の阻害において使用するための、請求項1〜11のいずれか1項に記載の抗Bb抗体またはその抗原結合部分。
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