JP2018508564A - 骨関節炎処置を治療目的としたColl2−1ペプチド及びそのニトロ化形態 - Google Patents
骨関節炎処置を治療目的としたColl2−1ペプチド及びそのニトロ化形態 Download PDFInfo
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Abstract
Description
国際公開第2003/076947号は、2つの抗血清、D3及びD37がそれぞれ、Coll2−1及びColl2−1NO2に対して特異性が高いことが同定されたことを記載している。抗血清D3は、ヒト固有のI型コラーゲン及びII型コラーゲン、ヒト熱変性I型コラーゲン及びII型コラーゲン、並びにBSAを認識しなかった。これは、抗血清D3が、Coll2−1の線形形態に特異的であることを示唆した。親和性が同じD3はまた、Coll2−1のニトロ化形態を認識した。抗血清D37は、Coll2−1NO2に対する高い親和性を示した。ゆえに、抗血清D37との、非ニトロ化ペプチド(Coll2−1)及びヒトニトロ化II型コラーゲンの交差反応性はそれぞれ、0.02%及び0.08%未満と算出された。さらに、抗血清D37は、ヒトニトロ化I型コラーゲン、固有のヒトI型コラーゲン及びII型コラーゲン、ニトロ化BSA、BSA、並びに3−ニトロ−L−チロシン残基を認識しなかった。Coll2−1NO2/D37結合を置換するのに必要な、Coll2−1及びニトロ化コラーゲンII型の濃度が非常に高いことは、D37がColl2−1NO2に特異的であることを示唆した。
以下の記載は、本発明の1つ又は複数の活性剤を含有し得る医薬組成物を指す。
本発明は特に、Coll2−1ペプチド又はColl2−1NO2ペプチドに向けられる抗体を指し、当該抗体は、当該ペプチドの活性を部分的に、又は完全に引き下げることとなる。本発明はさらに、Coll2−1ペプチド又はColl2−1NO2ペプチドに特異的に結合する抗体を含む組成物を提供する。抗体が特異的に結合するペプチドは、配列番号1のアミノ酸配列を有する。抗体は、ポリクローナル抗体、モノクローナル抗体、ヒト化抗体、Fcフラグメント、Fabフラグメント、単鎖抗体(scFv)、キメラ抗体、又は他の抗原特異的抗体フラグメントであってよい。特に、前記抗体は、一般的な抗体(2つのタンパク質重鎖及び2つの軽鎖で構成される)、一般的な抗体のFabフラグメント、単鎖可変フラグメント、又は単ドメイン抗体(sdAb)であってよい。抗体は、医薬的に許容可能なキャリアで製剤化さてよい。好ましい実施形態において、抗体は、配列番号1のアミノ酸配列を有するColl2−1又はColl2−1NO2を特異的に認識して、これに結合する。さらに、好ましい抗体は、エピトープ(配列番号1に示されるアミノ酸配列内の5つ以上の連続アミノ酸残基のストレッチ)を特異的に認識する。
本発明はまた、投与に適した抗体の調製物及び抗体組成物、例えば抗体及び医薬的に許容可能なキャリアを含む組成物を指す。抗体組成物は、当該技術分野において知られている方法によって、静脈内投与経路、筋肉内投与経路、皮下投与経路、及び経皮投与経路が挙げられるあらゆる投与経路用に製剤化され得る。一実施形態において、抗体組成物は、治療的に有効な量、すなわち、治療的に有益な効果を達成するのに十分な量の抗体を提供する。
本発明はまた、骨関節炎並びに他のリウマチ疾患及び筋骨格疾患(RMD)を処置する方法であって、それを必要とする対象に、先に記載される抗体又は抗体組成物を投与することによって処置する方法を指す。骨関節炎の処置の標的患者集団として、骨関節炎を患う哺乳類、例えばヒトが挙げられる。
1.1 患者。膝の骨関節炎(OA)の10人の患者(8人の女性、2人の男性;平均年齢70+/−6歳)から、総膝関節置換手術時に、滑膜組織サンプルを得た。全対象が、インフォームドコンセントを提示した。
蛍光プローブを用いて、酸化ストレスに及ぼすColl2−1ペプチド及びColl2−1NO2ペプチドの影響を調査した。これを行うために、いくつかのパラメータを研究した。第1の結果は、滑膜線維芽細胞によるH2O2の細胞内産生であった。図1A及び図1Bに示すように、Coll2−1ペプチド(0.45nmol及び4.5nmol)及びColl2−1NO2ペプチド(4pmol及び40pmol)の双方によるH2O2の細胞内産生は、4.5nmolの濃度(*P<0.05)のColl2−1によって、そして4pmol(**P<0.01)及び40pmol(**P<0.01)の濃度のColl2−1NO2によって、有意に増大した。
リアルタイムPCR技術を用いて、血管形成因子の発現に及ぼすColl2−1ペプチド及びColl2−1NO2ペプチドの影響を調査した。Coll2−1ペプチド(0.45nmol及び4.5nmol)若しくはColl2−1NO2ペプチド(4pmol及び40pmol)の濃度を増大させずに、又は増大させて、滑膜線維芽細胞を24時間インキュベートした。TSP1(トロンボスポンジン(TSP)−1;抗血管形成因子)遺伝子及びVEGF(血管内皮増殖因子;血管形成誘発性因子)遺伝子の発現を分析した。図4に示されるように、Coll2−1ペプチド及びColl2−1NO2ペプチドは双方とも、TSP1発現を引き下げた。この影響は、40pmolの濃度のColl2−1NO2で有意であった(**P<0.01;図4B)。対照的に、VEGF発現は、図5に示すように、濃度が増大するColl2−1ペプチド及びColl2−1NO2ペプチドの存在下で、増大する傾向があった。興味深いことに、これらの2つの遺伝子の差別的発現は、血管形成プロセスに有利になる血管形成誘発性因子と抗血管形成因子との間のアンバランスを明らかにした。
さらに、炎症プロセスに及ぼすColl2−1ペプチド及びColl2−1NO2ペプチドの影響も調査した。OA生理病理学プロセスに関係する2つの遺伝子、IL(インターロイキン)−8遺伝子及びIL−6遺伝子の発現を分析した。図6に示すように、Coll2−1ペプチド及びColl2−1NO2ペプチドの濃度の増大は、OA滑膜線維芽細胞による双方のサイトカインの発現を増大させた。特に、0.45nmol(**P<0.01)及び4.5nmol(*P<0.05)でのColl2−1は、用量依存的に、IL8遺伝子発現を増大させた。これらのデータは、Coll2−1ペプチドの炎症誘発性を強調する。
II型コラーゲンペプチドを中和する抗体又は他の剤を、関節炎を処置する生物療法として用いることができるという仮説を実証するために、Coll2−1ペプチドに向けられる特異的ポリクローナル抗体を試験した。実施例1の項1.8に記載するように、Coll2−1ペプチド(108HRGYPGLDG116)でウサギを免疫化した。ポリクローナル抗体を得て、Protein A Columns(Pierce,Gent、ベルギー)で精製して、血清IgGのみを保持した。精製したIgGの吸光度は、280nmにて測定して、1.974であった。濃度は、2.6649mg/ml(1.974Xモル吸光係数(IgG=1.35))であった。ポリクローナル抗体を、AS0619と名付けた。
Claims (11)
- 骨関節炎の予防及び/又は処置に用いられる、Coll2−1ペプチド活性の阻害剤及び/又はColl2−1NO2ペプチド活性の阻害剤を活性成分として含む医薬。
- リウマチ疾患及び筋骨格疾患(RMD)の予防及び/又は処置に用いられる、Coll2−1ペプチド活性の阻害剤及び/又はColl2−1NO2ペプチド活性の阻害剤を活性成分として含む医薬。
- Coll2−1ペプチド活性及び/又はColl2−1NO2ペプチド活性の阻害剤は、それぞれ、Coll2−1ペプチド及びColl2−1NO2ペプチドに起因し、又は、それぞれ、Coll2−1ペプチド及びColl2−1NO2ペプチドを含むペプチドに起因する、請求項1に記載の医薬。
- Coll2−1ペプチド活性又はColl2−1NO2ペプチド活性の前記阻害剤は、関節炎の滑膜線維芽細胞中での、H2O2の産生、血管形成因子の発現、IL−6及びIL−8の発現のいずれか1つ若しくはそれ以上、又は全てに及ぼすColl2−1ペプチド活性又はColl2−1NO2ペプチド活性の増強作用を阻害し、又は引き下げる、請求項1〜3のいずれか一項に記載の医薬。
- Coll2−1ペプチド活性又はColl2−1NO2ペプチド活性の前記阻害剤は、アミノ酸配列HRGYPGLDG(配列番号1)内に含まれるエピトープと免疫反応性である免疫学的結合パートナーである、請求項1〜4のいずれか一項に記載の医薬。
- 前記免疫学的結合パートナーは、ポリクローナル抗体、モノクローナル抗体、ヒト化抗体、Fcフラグメント、Fabフラグメント、単鎖抗体(scFv)、キメラ抗体、バイオベター、又はColl2−1ペプチド若しくはColl2−1NO2ペプチドに特異的に結合する他の抗原特異的抗体フラグメントからなる群から選択される、請求項5に記載の医薬。
- 前記免疫学的結合パートナーは、Coll2−1ペプチド又はColl2−1NO2ペプチドに特異的に結合するモノクローナル抗体又はポリクローナル抗体である、請求項5に記載の医薬。
- 前記医薬は、Coll2−1ペプチドに特異的に結合する免疫学的結合パートナー、及びColl2−1NO2ペプチドに特異的に結合する免疫学的結合パートナーの混合物を含む、請求項5に記載の医薬。
- 骨関節炎の予防方法及び/又は処置方法であって、それを必要とする対象への、有効用量のColl2−1ペプチド活性の阻害剤及び/又はColl2−1NO2ペプチド活性の阻害剤の投与を含む方法。
- リウマチ疾患及び筋骨格疾患(RMD)の予防方法及び/又は処置方法であって、それを必要とする対象への、有効用量のColl2−1ペプチド活性の阻害剤及び/又はColl2−1NO2ペプチド活性の阻害剤の投与を含む方法。
- 活性成分は、アミノ酸配列HRGYPGLDG(配列番号1)内に含まれるエピトープと免疫反応性である免疫学的結合パートナーである、請求項9又は10に記載の方法。
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