JP2012504946A - 血小板第4因子変異体1(pf4v1)に対する中和抗体およびそのフラグメント - Google Patents
血小板第4因子変異体1(pf4v1)に対する中和抗体およびそのフラグメント Download PDFInfo
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Abstract
Description
定義
本明細書で使用する「PF4v1」という語は、CXCL4L1、PF4var1、PF4ALTおよびSCYB4V1を包含する(但しこれらに限定されない)全ての同義語の包含を意図している。「PF4v1」という語は、PF4蛋白のヒト天然変異体の天然および組換え型の両者を指す。したがってこの用語は、天然に存在するPF4v1ならびにその変異体および修飾型を包含する。「成熟PF4v1蛋白」という語は、より長いプロペプチドのプロセシングによって得られる、70個のアミノ酸を有する成熟PF4v1蛋白を指す。天然の成熟PF4v1アミノ酸配列の例を配列番号1に開示する(受理番号NP_002611の下にGenPeptデータベースに提供されている蛋白から誘導される成熟蛋白)。PF4v1をコードしている天然ヌクレオチド配列の例は、受理番号NM_002620の下にGenPeptデータベースに提供されている。さらに、「PF4v1」という語はPF4蛋白の霊長類天然変異体をも包含することに留意せねばならない。例えば、霊長類PF4v1蛋白は、GenBank受理番号XM_001102971.1(アカゲザル)およびXP_001156146.1(チンパンジー)の下に提供されている。
本発明は、PF4v1に対する単離された中和抗体またはそのフラグメントを提供する。特に本発明等は、PF4v1、より詳細には、配列番号1に開示する成熟PF4v1のアミノ酸配列の67位にヒスチジン残基を含むエピトープに対する特異性を有するモノクローナル抗体を開発した。
本発明のさらなる局面は、本発明の抗体またはそのフラグメントをコードしている核酸配列に関するものである。
本発明の抗体およびそのフラグメントは、単独での、または組み合わせた、当分野で公知の任意の技術、例えば任意の化学的、生物学的、遺伝学的または酵素的技術(これらに限定されない)によって生産することができる。
本明細書に記載の抗体のアミノ酸配列修飾を企図する。例えば、抗体の結合親和性および/またはその他の生物学的性質を改善することが望ましいかも知れない。非ヒト動物から誘導された抗体のVHおよびVL中のCDRのみをヒト抗体のVHおよびVLのFRに単純に移植することによってヒト化抗体を作製した場合、その抗原結合活性は、非ヒト動物から誘導された元の抗体に比較して低下するということが知られている。非ヒト抗体のVHおよびVLの幾つかのアミノ酸残基は、CDRのみならずFRにおいても、抗原結合活性と直接的または間接的に関連していると考えられる。したがって、これらのアミノ酸残基をヒト抗体のVHおよびVLのFRに由来する異なるアミノ酸残基に置換すると、結合活性が低下するであろう。ヒトCDRで移植された抗体におけるこの問題を解決するためには、ヒト抗体のVHおよびVLのFRのアミノ酸配列の中でも、抗体との結合に直接関連するアミノ酸残基、またはCDRのアミノ酸残基と相互作用するアミノ酸残基、または、抗体の三次元構造を維持し抗原との結合に直接関連しているアミノ酸残基を同定する試みがなされねばならない。低下した抗原結合活性は、その同定されたアミノ酸を、非ヒト動物から誘導された元の抗体のアミノ酸残基に置き換えることにより、増大し得る。
低濃度でヘパリン−セファロースカラムから溶出することに基づき、PF4v1はPF4よりも低い親和性でヘパリンと結合するということが確定された。このような親和性の相違によって初めて天然PF4v1蛋白の精製が可能となった(Struyf et al., 2004)。しかしながら、このような精製方法は、幾つかのクロマトグラフィー工程(即ち、ヘパリン−セファロースアフィニティクロマトグラフィーおよび逆相高速液体クロマトグラフィー)およびさらには質量分析の工程(Struyf et al., 2007)をも含むことから、極めて複雑で時間がかかる。
本発明の抗体またはそのフラグメントは、血管新生の誘導を必要とする任意の病変の処置に有用となり得る。本発明の抗体は、単独で、または任意の適当な物質と組み合わせて使用できる。
本発明の抗体またはそのフラグメントは、薬学的に許容される賦形剤、および場合により持続放出マトリックス、例えば生分解性ポリマーと合して治療用組成物を形成させることができる。
最後に、本発明は本発明の抗体を少なくとも1個含むキットをも提供する。本発明の抗体を含むキットは、生体試料におけるPF4v1発現の検出に用途を見いだせる。本発明のキットは、固体支持体、例えば組織培養プレートまたはビーズ(例えばセファロースビーズ)に結合させた抗体を含むことができる。例えばELISAまたはウェスタンブロットでPF4v1をインビトロ検出および定量するための抗体を含むキットが提供され得る。検出に有用なこのような抗体は、蛍光または放射性標識といった標識と共に提供され得る。
実施例
実施例1:PF4v1に特異的なモノクローナル抗体(MabV1)の特性付け
材料および方法
細胞培養:抗生物質、1%グルタミン、および10%牛胎児血清または10%子牛血清を含有するDMEM(Invitrogen, Cergy Pontoise, France)中でBAE細胞を増殖させ、37℃、10%CO2に維持した。
PF4およびPF4v1の間にはC末端領域に3個のアミノ酸相違があるだけである(図1)。生物活性について試験した場合(牛大動脈内皮細胞による増殖アッセイ)、PF4v1は50倍の活性がある。本発明者等はPF4およびPF4v1について幾つかの突然変異体を作製し、それらを抗体反応性について試験した。
IRdyeによるMabV1の標識化。
CXCL4L1に対するモノクローナル抗体(MabV1)を製造者の指示に従ってIRDye 800CW(Protein Labeling Kit−High MW#928−38040、LI-COR(登録商標)、Lincoln, NE)で標識した。コンジュゲートをリン酸緩衝化生理食塩水に対して広範囲に透析して、過剰の未反応色素を除去した。標識されたMabV1は蛋白1モルあたり2分子の色素と結合し、その初期の活性を失わない。マウスにおける生体内分布、薬物動態学および忍容性の研究に、そしてさらにCXCL4L1を発現する腫瘍へのターゲッティングの研究に、IRdye−MabV1を使用した。
sulfo−NHS−LC−Biotinキット(PIERCE, Rockford, IL)を使用し製造者の指示に従ってMabV1抗体をビオチンで標識した。
抗体のクリアランス速度および起こり得る非特異結合を決定するため、Rag Gammaマウス(n=50)に25μgのIRdye−MabV1を尾静脈へのIV注射で投与した。注射後の様々な時点で、バックグラウンドを上回る検出可能シグナルが無くなるまでMousePOD(登録商標)を備えたオデッセイ・イメージング・システム(LI-COR(登録商標))で動物を画像化した。画像化の後、心臓から血液を採取し、臓器を摘出してオデッセイ・イメージング・システムでスキャンし、ホモジナイズして間接ELISAアッセイによりMabV1濃度を決定した。
被覆溶液で希釈した組換えCXCL4L1蛋白をマイクロプレート上に固定化する。数工程の洗浄および遮断の後、血漿試料および臓器溶解液をこのプレートに加える。ビオチンにコンジュゲートさせたMabV1を含有する試料については、ストレプトアビジン−HRPおよび基質溶液(TMB)の添加直後に、450nmに設定したマイクロプレートリーダーで結果が直接得られる。一方、MabV1を含有する試料では、ビオチニル化抗マウス抗体を使用するさらなる工程が必要である。
Rag Gammaマウスに3.106のBxPC3細胞を皮下注射し、2群に分け、IgG対照抗体50μg(対照群、n=16)または遮断抗体MabV1 50μg(MabV1群、n=16)を投与した。14日目に処置を開始し、抗体を週に2回iv注射した。腫瘍の大きさを毎週測定し、腫瘍体積を式:(4/3)ab2[式中、aおよびbは各々最大半径および最小半径である]を用いて算出した。7週目にマウスを殺し、腫瘍を切除し、測定し、液体窒素中に保存した後免疫組織化学的研究に付した。
皮下にBxPC3腫瘍を有するマウスの尾静脈にIRdye−MabV1抗体を注射した。注射の6日後、動物を安楽死させ、組織を摘出しオデッセイ・イメージング・システムで画像化した。画像化後、直ちに臓器を凍結し、10個に切り分け、各々40μmの切片を免疫組織化学的研究およびオデッセイ画像化に付した。
本発明者等は、本発明の抗体(MabV1)が、インビボでPF4v1の機能を遮断し、インビボで血管新生を誘導できることを示した(図5)。MabV1およびコンジュゲート化MabV1のクリアランスをインビボ解析した(図6〜8)。さらに本発明者等は、MabV1がインビボで腫瘍を標的とすることができることを示した。これは、細胞毒性物質と組み合わせた場合、本発明の抗体が病的血管新生に関連する疾患、例えば癌の処置に有用となり得るということを示すものである。
Claims (14)
- 成熟PF4v1蛋白の67位のヒスチジン残基を認識する、血小板因子変異体1(PF4v1)に対する抗体。
- モノクローナル抗体である、請求項1に記載の抗体。
- マウス抗体である、請求項1または2に記載の抗体。
- 成熟PF4v1蛋白の67位のヒスチジン残基を認識し、PF4v1の抗血管新生活性を遮断する、請求項1〜3のいずれか1項に記載の抗体のフラグメント。
- 請求項1〜3のいずれか1項に記載の抗体または請求項4に記載のそのフラグメントをコードしている配列を含む核酸。
- 請求項5に記載の核酸を含むベクター。
- 請求項5に記載の核酸および/または請求項6に記載のベクターにより形質転換された宿主細胞。
- (i)請求項7に記載の形質転換された宿主細胞を、抗体またはそのフラグメントを発現させるのに適した条件下で培養し、そして(ii)発現された抗体またはそのフラグメントを回収する、ことから成る工程を含む、請求項1〜3のいずれか1項に記載の抗体または請求項4に記載のそのフラグメントを生成する方法。
- 請求項1〜3のいずれか1項に記載の抗体、および/または請求項4に記載のそのフラグメント、または請求項5に記載の核酸、および/または請求項6に記載のベクター、および/または請求項7に記載の宿主細胞を、薬学的に許容される担体と共に含む医薬組成物。
- 検出可能な分子または物質で標識されている、請求項1〜3のいずれか1項に記載の抗体、または請求項4に記載のそのフラグメント。
- 生体試料を、請求項1〜3のいずれか1項に記載の抗体、または請求項4に記載のそのフラグメント、または請求項10に記載の標識された抗体もしくはそのフラグメントと接触させる工程を含む、生体試料中のPF4v1を検出する方法。
- アテローム性動脈硬化症、例えば冠動脈性心疾患および末梢動脈疾患;創傷治癒障害;虚血;高血圧および糖尿病より成る群から選ばれる血管新生の誘導を必要とする病変の処置のための、請求項1〜3のいずれか1項に記載の抗体、または請求項4に記載のそのフラグメント。
- 血小板減少症、ヘパリン起因性血小板減少症(HIT)、血小板増加症および骨髄異形成症候群といった血液疾患を処置するための、請求項1〜3のいずれか1項に記載の抗体、または請求項4に記載のそのフラグメント。
- 抗体またはそのフラグメントを細胞毒性物質と組み合わせた、癌、加齢黄斑変性症(AMD)およびその他の過剰増殖性眼疾患ならびに慢性炎症性疾患より成る群から選ばれる病的血管新生に関連する疾患の処置のための、請求項1〜3のいずれか1項に記載の抗体または請求項4に記載のそのフラグメント。
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PCT/EP2009/063005 WO2010040766A1 (en) | 2008-10-07 | 2009-10-07 | Neutralizing antibodies and fragments thereof directed against platelet factor-4 variant 1 (pf4v1) |
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EP (1) | EP2355847A1 (ja) |
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WO2010060920A1 (en) * | 2008-11-27 | 2010-06-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Cxcl4l1 as a biomarker of pancreatic cancer |
WO2012072595A1 (en) * | 2010-11-30 | 2012-06-07 | Universiteit Gent | Platelet factor 4 variant for the prognosis of cardiovascular outcome in patients having heart disease |
WO2012101125A1 (en) * | 2011-01-24 | 2012-08-02 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Specific antibodies against human cxcl4 and uses thereof |
WO2014177662A1 (en) * | 2013-04-30 | 2014-11-06 | INSERM (Institut National de la Santé et de la Recherche Médicale) | In vitro method for determining if a subject suffering from cancer is responsive to a treatment comprising administering an effective amount of cxcl4l1 or an inhibitor of cxcl4l1 |
US20220175886A1 (en) * | 2018-09-13 | 2022-06-09 | The Children's Hospital Of Philadelphia | Net stabilization as a therapy for sepsis |
CN114430683A (zh) * | 2019-03-25 | 2022-05-03 | 新南创新私人有限公司 | 使用抗原结合片段治疗免疫性血小板病症 |
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EP2355847A1 (en) | 2011-08-17 |
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