JP6262715B2 - ヒト化およびキメラ抗c3因子抗体、ならびにその使用 - Google Patents
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Description
本願は、2009年9月23日出願の米国特許出願第12/532,740号の優先権を主張する、2012年4月3日出願の米国特許仮出願第61/619,860号の優先権を主張し、これらの主題は、全体として参照により本明細書に組み入れられる。
本発明の別の態様において、該抗体は、インビボで、急性または慢性の病的傷害に罹患したヒトなどの対象において、副経路を介した補体活性化を阻害するのに用いることができる。本発明は、限定するものではないが、以下の疾患、障害、損傷、および処置と併せて用いることができる。
特段の断りのない限り、試薬は全て、入手可能なハイグレードのものであった。補体タンパク質、古典的副経路および古典的経路の緩衝液、検出抗体、ならびに赤血球は全て、Complement Technologies(テキサス州タイラー所在)またはQuidel Corporation(カリフォルニア州サンディエゴ所在)から得た。フローサイトメトリーの抗体は、カリフォルニア州サンホセ所在のBD Biosciencesから得た。TMB基質は、メリーランド州ゲイザーズバーグ所在のKirkegaard & Perry Limitedから得た。二次抗体は全て、カリフォルニア州サンクレメンテ所在のAmerican Qualexから、BSAおよび他の試薬は、全てミズーリ州セントルイス所在のSigma−Aldrichから得た。
C3bへの抗C3b IgGの親和性は、低pM〜低nMの範囲内である。該抗体およびそのフラグメントは、高親和性でC3bおよびC3cに結合する。 ポリスチレン製マイクロタイタープレートに、リン酸緩衝生理食塩水(PBS)中のヒトC3bを4℃で一晩コーティングさせた。C3b溶液を吸引した後、ウェルをPBS中の1%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)で室温で1時間ブロッキングした。ペプチドまたはC3bコーティングを有さないウェルを、バックグランド対照とした。ブロッキング溶液中のモノクローナル抗C3b抗体IgG、Fab2、およびFabのアリコットを、C3bコーティングウェルに添加し、1時間インキュベートして結合を生じさせた。室温で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回すすぎ、ペルオキシダーゼコンジュゲートヤギ抗マウスモノクローナル抗体と共にインキュベートした。このインキュベートの後、プレートをすすぎ、結合したペルオキシダーゼを、TMB試薬を用いて同定した。
C3bに対する抗C3b IgGの親和性は、低pM〜低nMの範囲内である。該抗体およびそのフラグメントは、高親和性でC3bおよびC3cに結合する。 これらの抗体およびそのフラグメントは、C5へのプロペルジン結合を阻害しない。ポリスチレン製マイクロタイタープレートに、リン酸緩衝生理食塩水(PBS)中のヒトC3bを4℃で一晩コーティングさせた。C3b溶液を吸引した後、ウェルをPBS中の1%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)で室温で1時間ブロッキングした。ペプチドまたはC3bコーティングを有さないウェルを、バックグランド対照とした。2nMビオチン化プロペルジンを含有するブロッキング溶液中のモノクローナル抗C3b抗体IgG、Fab2、およびFabのアリコットを、C3bコーティングウェルに添加し、1時間インキュベートさせて結合を生じさせた。室温で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回すすぎ、ペルオキシダーゼをコンジュゲートされたニュートラビジン(neutavidin)と共にインキュベートした。このインキュベートの後、プレートをすすぎ、結合したペルオキシダーゼを、TMB試薬を用いて同定した。
この赤血球溶解アッセイは、rRBCの表面の末端補体複合体の形成に基づく。結果としてrRBCは、溶解される。900nmでの光散乱の漸減は、赤血球溶解の直接的な指標である。典型的にはrRBCを、5mM MgCl2含有ゼラチンベロナール緩衝液中の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、正常ヒト血清中での副経路の活性化を惹起する。副経路の活性化は、rRBCの表面でのC5b−9複合体形成に誘導する。C5b−9複合体形成を阻害する薬剤は、細胞溶解を阻害すると予測される。抗C3b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、900nmでの読み取りが可能な温度制御されたELISAプレートリーダーで、一定濃度のウサギ赤血球を含む37℃のAP緩衝液中、正常ヒト血清(10%NHS)と共にインキュベートした。光散乱の漸減(インタクト細胞の溶解による)を、時間の関数として900nmで測定した。データは、SpectraMax 190プレートリーダーおよびSoftMaxソフトウエアで記録および分析した。計算では、総阻害を各濃度のIgG、F(ab’)2、およびFabで計算し、結果を非溶解対照の%率として表した。各濃度のデータを、MicroCal Origin Softwareでシグモイドプロットにプロットした。
本発明のモノクローナル抗体は、宿主防御に必要とされる古典的経路を阻害しない。抗体感作したヒツジ赤血球を、カルシウム(5mM CaCl2/MgCl2)緩衝液を含有するゼラチンベロナール緩衝液中で1%または10%正常ヒト血清と共にインキュベートした。抗体感作したヒツジ細胞は、古典的経路を活性化する。結果としてC5b−9が、溶解を起こした赤血球(erythrocyte acused lysis)の表面に形成される。本発明者らは、1%および10%正常ヒト血清を試験した。両条件下で、抗C3bは、赤血球溶解を阻害した。典型的なアッセイにおいて、赤血球をCP緩衝液中の1%/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る。CP活性化の結果、C5b−9が、細胞溶解を起こした赤血球の表面に形成される。細胞溶解による光散乱の漸減を、時間の関数として700nmで測定する。
副補体経路は、正常ヒト血清中で、腸チフス菌由来のリポ多糖により活性化される。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否かを実証するためにこのパラダイムを利用した。本発明者らは、抗プロペルジン抗体およびそのフラグメントの存在下および非存在下で、P、C3b、Bb、およびC5b−9の付着を測定した。C3およびC5コンバターゼの形成を、適切な抗体で検出した。抗プロペルジン抗体の存在下では、用量依存的なC3およびC5コンバターゼ形成阻害が、認められた。典型的なアッセイにおいて、ポリスチレン製マイクロタイタープレートウェルを、PBS中の2μg/50μlのLPS(腸チフス菌由来リポ多糖)でコーティングした。ウェルをPBS中の1%BSAと共にインキュベートして、ウェル中の非占有部位をブロッキングした。室温での2時間のブロッキングおよびPBSでのすすぎに続いて、AP緩衝液中の正常ヒト血清(10%)を、様々な濃度の抗体およびフラグメントと混合した。混合物をLPSコーティングのウェルに入れてインキュベートした。プレートを37℃で2時間インキュベートして、補体AP活性化を起こさせた。インキュベーションに続いて、プレートをPBSで徹底的に洗浄して、C3コンバターゼの成分を、適切な抗体で検出した。本発明者らは、ブロッキング溶液中の1:2000のウサギ抗ヒトC3cと、ブロッキング溶液中の1:2000のヤギ抗ヒトPと、ブロッキング溶液中の1:500のヤギ抗ヒトBb因子と、ブロッキング溶液中の1:2000のHRPOコンジュゲート抗ヒト(anti−huma)C5b−9とでC3bを検出した。プレートを各抗体と共に室温で1時間インキュベートした。インキュベーションに続いて、プレートをPBSですすいで、結合した抗体を、C3b検出については1:2000のペルオキシダーゼ標識ヤギ抗ウサギで、P検出についてはブロッキング溶液中の1:2000のペルオキシダーゼ標識ウサギ抗ヤギで検出した。プレートは全て、PBSでの徹底的な洗浄に続いてTMBで発色させた。青色を1Mオルトリン酸でクエンチした。図9は、P付着の用量依存的阻害を示す。
抗C3抗体は、対象における心肺バイパス(CPB)および/または透析処置などの体外循環処置において用いることができる。これらの処置において、循環血を対象の血管から導管を通して再度、対象の血管に戻すことができる。導管は、対象の血液中で補体活性化、血小板活性化、白血球活性化、または血小板−白血球接着のうちの少なくとも1つを誘発し得る材料を含む内腔表面を有することができる。抗C3b抗体を、補体活性化、血小板活性化、白血球活性化、または血小板−白血球接着のうちの少なくとも1つを減少させるのに有効な量で対象の血流に導入して、循環血を導管に通過させることができる。対象の血液は、抗C3抗体またはそのフラグメントの段階的導入の前および/または導入中および/または導入後に導管を通過させることができる。好ましくは、抗プロペルジン抗体は、補体成分C3から補体成分C3aおよびC3bへの副経路依存的変換、ならびに/またはC5b−9の副経路依存的形成、ならびに/または副経路依存的白血球活性化を減少させる。
活性化された単球は、炎症媒介物質であるTNF−αを放出する。単球は、C3aにより活性化される。抗C3b処理された体外循環中の血液試料は、TNF−αの用量依存的阻害を示す。
マウスモノクローナル抗体の産生は、当業者により記載されており、一般的方法となっている。典型的には抗原、この場合C3bタンパク質を、モノクローナル抗体を産生する手法でマウスに投与した。ヒト化およびキメラ抗体が、CDRグラフティングにより、一般的な定常領域を利用して産生された。C3bに特異的なマウスモノクローナル抗体を、副経路阻害アッセイに基づいて選択した。C3bは、古典的経路の一部でもあり、意外にもこの抗C3b抗体は、古典的経路を阻害せず、副経路のみを阻害する。マウス抗体は、キメラおよびヒト化抗体に変換された。
キメラ抗C3b抗体Fabは、基質結合C3bに結合する。ポリスチレン製マイクロタイタープレートウェル(96ウェル培地は結合プレート、Corning Costar、マサチューセッツ州ケンブリッジ所在)に、リン酸緩衝生理食塩水(PBS、pH7.4)中のC3b(2μg/50μl/ウェル、Complement Technology、テキサス州タイラー所在)を4℃で一晩コーティングした。C3b溶液を吸引した後、ウェルを1%ウシ血清アルブミン(BSA;Sigma Chemical)を含有するPBSで1時間、室温でブロッキングした。C3bコーティングを有さないウェルを、バックグランド対照とした。ブロッキング溶液中のキメラ抗体のアリコットを、C3bコーティングELISAウェルに添加した。結合したキメラ抗体の量を、ペルオキシダーゼコンジュゲート抗ヒトIgG軽鎖抗体で検出した。
キメラ抗C3b抗体Fabは、C3bに結合し、副経路に依存的な赤血球溶解を阻害する。アッセイは、実施例3に記載されたものと同様である。
様々な濃度の抗C3b抗体を、一定濃度の正常ヒト血清に添加した。血清−抗体混合物を、実施例3に示したように、ウサギ赤血球に添加して溶血アッセイに供した。抗体は、高濃度では赤血球溶血を阻害し、変曲点はほぼ1000nMの抗体濃度であった。存在する総C3は、3200nMの範囲内である。これらのデータから、抗体:C3の比が0.33:1となる化学量論比が示唆される。
マウスCDRを様々なフレームワークにグラフティングして、図17および18に示されたヒト化抗体を生成した。フレームワークおよびCDRは両者とも、図19に含まれ、フレームワークは、図20、21、および22に含まれる。
Claims (16)
- 配列番号12、配列番号14および配列番号16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19、配列番号21および配列番号23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、を含む抗C3bヒト化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、および配列番号10から選択されるヒト化フレームワーク領域を含む、請求項1に記載の抗C3bヒト化抗体またはその抗原結合部分。
- 配列番号11、配列番号13、配列番号15、配列番号17、配列番号18、配列番号20、配列番号22、および配列番号24から選択されるヒト化フレームワーク領域または非天然フレームワーク領域を含む、請求項1に記載の抗C3bヒト化抗体またはその抗原結合部分。
- 配列番号25、配列番号26、配列番号27、配列番号28、配列番号29、配列番号30、配列番号31、および配列番号32から選択されるヒト化フレームワーク領域または非天然フレームワーク領域を含む、請求項1に記載の抗C3bヒト化抗体またはその抗原結合部分。
- 配列番号41、配列番号42、配列番号43、配列番号44、配列番号45、配列番号46、配列番号47、および配列番号48から選択されるヒト化フレームワーク領域または非天然フレームワーク領域を含む、請求項1に記載の抗C3bヒト化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、新たに産生されるPC3bBbの形成を阻害する、請求項1〜5のいずれか1項に記載の抗C3bヒト化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、新たに産生されるC3a、C5a、SC5b−9の形成を阻害する、請求項1〜5のいずれか1項に記載の抗C3bヒト化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1〜5のいずれか1項に記載の抗C3bヒト化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1〜5のいずれか1項に記載の抗C3bヒト化抗体またはその抗原結合部分。
- 治療有効量の請求項1〜5のいずれか1項に記載の抗C3bヒト化抗体またはその抗原結合部分を含む医薬組成物。
- 請求項1〜5のいずれか1項に記載の抗C3bヒト化抗体またはその抗原結合部分を含む、炎症性障害の処置に使用するための医薬組成物であって、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において見出される、医薬組成物。
- 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、全身エリテマトーデス、多発性硬化症、または、身体の免疫系が調整を受ける他の自己免疫疾患である、請求項11に記載の医薬組成物。
- 請求項1〜5のいずれか1項に記載の抗C3bヒト化抗体またはその抗原結合部分を含む、眼疾患の処置に使用するための医薬組成物であって、補体活性化が疾病病状に関与する、医薬組成物。
- 前記眼疾患が、湿性および乾性加齢性黄斑変性、脈絡膜新生血管、ブドウ膜炎、糖尿病性網膜症、糖尿病黄斑浮腫、病的近視、フォン・ヒッペル・リンドウ病、糖尿病性網膜症、目のヒストプラスマ症、糖尿病性網膜症、脈絡膜新生血管(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)、ならびに網膜血管新生を含む群から選択される、請求項13に記載の医薬組成物。
- 請求項1〜5のいずれか1項に記載の抗C3bヒト化抗体またはその抗原結合部分を含む、補体関連障害の処置に使用するための医薬組成物であって、前記障害が、喘息性または気道の炎症、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(allergic bronchitis bronchiecstasis)、嚢胞性線維症、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、好酸球増加症候群、鼻炎、副鼻腔炎、運動誘発性喘息、公害による喘息、咳喘息、肺寄生虫症、呼吸系発疹ウイルス(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、医薬組成物。
- 副経路が、疾患病理に寄与するか、または状態もしくは疾患により引き起こされる少なくとも1つの症状を増悪させる、前記状態もしくは疾患に罹患しているか、またはそれを発症するリスクがある、哺乳類における副経路活性化の阻害に使用するための医薬組成物であって、請求項1〜5のいずれか1項に記載の抗C3bヒト化抗体またはその抗原結合部分を含む医薬組成物。
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