JP2017200933A - 変形性関節症の治療 - Google Patents
変形性関節症の治療 Download PDFInfo
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- JP2017200933A JP2017200933A JP2017114806A JP2017114806A JP2017200933A JP 2017200933 A JP2017200933 A JP 2017200933A JP 2017114806 A JP2017114806 A JP 2017114806A JP 2017114806 A JP2017114806 A JP 2017114806A JP 2017200933 A JP2017200933 A JP 2017200933A
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Abstract
Description
本発明は一般的には、変形性関節症(OA)の治療及び/又は予防に関する。本発明によると、GM−CSFの拮抗薬は変形性関節症の治療に有効となりうる。GM−CSFの拮抗薬は限定しないが、GM−CSF又はGM−CSF受容体に特異的な抗体を含む。本発明は更に、特定の疾患モデルにおいて拮抗薬を試験するのに有用な、GM−CSFノックアウトマウスといった遺伝子導入動物を提供する。
・分配係数logPが−0.4ないし+5.6の範囲にある
・モル屈折率が40ないし130である
・原子の数が20ないし70である
(i)非ヒト源(異種性の免疫系を有する遺伝子導入マウス等)から得られ、その抗体はヒトの生殖細胞系列の配列に基づいているもの;
あるいは
(ii)キメラ型のものであり、可変ドメインが非ヒト起源から得られ、定常ドメインがヒト起源から得られるもの;
あるいは
(iii)CDR移植型であって、可変ドメインのCDRが非ヒト起源由来である一方、可変ドメインの1以上のフレームワークがヒト起源であり、定常ドメインが(ある場合は)ヒト起源であるもの;
と定義される。
及び/又は以下のH−CDR2配列:
及び/又は以下のL−CDR1配列:
及び/又は以下のL−CDR2配列:
及び/又は以下のL−CDR3配列:
を含む。
及び/又は以下のL−CDR2配列:
及び/又は以下のL−CDR3配列:
及び/又は以下のH−CDR1配列:
及び/又は以下のH−CDR2配列:
及び/又は以下のH−CDR3配列:
を含む抗体である。
GM−CSF−/−マウスの産生は「Stanleyら(1994),Proc.Natl.Acad.Sci.USA91:5592」に記載されている。簡潔に言うとキメラマウスは、破壊したGM−CSF遺伝子を有する129/OLA由来のES細胞(H−2b)をC57BL/6(H−2b)の宿主胚盤胞に微量注入することによって産生した。変異型のGM−CSF対立遺伝子の生殖系列の伝達物質は11世代にわたってC57BL/6マウスと交配し、実験で用いられるGM−CSF−/−マウス、GM−CSF+/−マウス、及びGM−CSF+/+マウスを産生するように交配したGM−CSF+/−マウスを提供した。GM−CSF遺伝子型の状態はtail DNAのPCR分析によって決定した。動物は標準的なげっ歯類の固形飼料と水とを適宜給餌され、おがくずを敷いたケージに同一性別の同腹仔とともに収容した。双方の性別のマウスが8ないし15週齢で実験に供された。
GM−CSF−/−マウスは、変形性関節症の実験モデルでC57/BL6マウス(例えば、Millsら,J Immunol 164:6166−6173,2000参照)と比較した。
マウス(群ごとにn=10)は2日前及び0日目に左膝にコラゲナーゼの関節内注射を受けた(Blomら,Arthritis Rheum 56:147−157,2007)。42日目にマウスは屠殺され、膝関節は収集、固定、脱灰され、パラフィンに埋込まれ、ミクロトームで7μmに切断した。スライドはサフラニンO(Safranin−O)/ファストグリーン(Fast Green)、ならびにヘマトキシリン(Haematoxylin)及びエオシン(Eosin)で染色し、関節の病態を実証した。調査した病態は軟骨の損傷、滑膜炎、骨棘形成、及び関節の変形を含む。
グレード
0 正常
1 不規則だが無傷
1.5 粗面を有し不規則
2 表面の細線維化
2.5 軟骨層における細胞の減少を伴う表面の細線維化
3 垂直方向の亀裂
3.5 分枝及び/又は水平方向の亀裂、層境界線(tidemark)の破壊
4 層境界線まで延在しない軟骨の損失
4.5 層境界線まで延在する軟骨の損失
5 層境界線を超えるが、骨まで延在しない軟骨の損失
5.5 骨まで延在する軟骨の損失
6 骨の損失/リモデリング/変形
ステージ
1 10%未満の領域の損傷
2 10ないし25%の領域の損傷
3 25ないし50%の領域の損傷
4 50ないし75%の領域の損傷
これらの関節の検査はGM−CSF−/−マウスがコントロールマウスよりも膝関節の病態が小さいことを示し、通常の変形性関節症の病態及び進行におけるGM−CSFの役割を示した。C57/BL6マウスで観察された病態は、軟骨層に対する重篤な損傷、骨棘形成、関節の変形、及び滑膜炎を含む。GM−CSF−/−マウスは骨棘形成又は関節の変形がなく、軟骨の損傷及び滑膜炎がかなり少ないことを示した。
この実験においては、我々はGM−CSFに特異的なモノクローナル抗体を用いて、GM−CSF拮抗薬が変形性関節症を治療するのに有効となりうることを実証した。
0日目及び2日目に、C57BL/6マウスに1ユニットのVII型コラゲナーゼを右膝の関節内に与えて、関節不安定性を誘発した(Blomら(2004)Osteoarthritis Cartilage.12;627−35参照)。
20のマウスを無作為に2の群に分割した(1群につき10のマウス)。
群1(n=10):抗GM−CSF抗体(22E9)
群2(n=10):IgG2aアイソタイプのコントロール抗体
最終注入の6週後に、組織学的診断がマウスの膝関節で行われた。膝関節は収集、固定、脱灰され、パラフィンに埋込まれ、ミクロトームで7μmに切断した。スライドはサフラニンO/ファストグリーン、ならびにヘマトキシリン及びエオシンで染色し、関節の病態を実証した。調査した病態は軟骨の損傷、滑膜炎、骨棘形成、及び関節の変形を含んだ。
0 通常の関節と比較して変化がない
1 滑膜表層の肥厚及び一部の炎症細胞の侵入
2 滑膜表層の肥厚及び中程度の炎症細胞の侵入
3 重度の滑膜表層の肥厚及び最大に観察される炎症細胞の侵入
OAのモデルで用いられる疼痛の指標は、両足圧力差痛覚測定器を用いて測定した特異な重量分布である。この機器は手術した後肢と反対側の手術していない後肢との間の重量分布の変化を測定する。マウスは実験前に3回、機器に環境順応させた。各々の後肢に掛かる重量が5秒間にわたって測定された。マウスごとに各々の時点で取られた3の別個の測定を平均した。測定は実験を通して週に2回行った。結果は(コラゲナーゼを注入した肢/コントロールの肢)×100で表した。
組織学的診断で分析した総ての領域(内側大腿骨を除く)、すなわち外側大腿骨、外側脛骨、及び内側脛骨について、抗GM−CSF抗体で治療したマウスに疾患が少ないという明らかな傾向があった。結果は図5に示す。
実施例3を反復する一方、GM−CSF拮抗薬として、配列番号1に示したような重鎖の可変領域のアミノ酸配列を含むか、あるいは配列番号2に示したような軽鎖の可変領域のアミノ酸配列を含むGM−CSFに特異的な抗体を用いる。マウス以外の別の種属、特にこの実験で用いた抗体が交差反応する種属を用いてもよい。好適にはこの実験で用いた動物種はラットである。
実施例3を反復する。GM−CSF拮抗薬として、配列番号3に示したような重鎖の可変領域のアミノ酸配列を含むか、あるいは配列番号4に示したような軽鎖の可変領域のアミノ酸配列を含むGM−CSFに特異的な抗体を用いる。マウス以外の別の種属、特にこの実験で用いた抗体が交差反応する種属を用いてもよい。好適にはこの実験で用いた動物種はラットである。
実施例3を反復する。GM−CSF拮抗薬として、配列番号5ないし16のうちのいずれか1つから選択されるH−CDR3配列を含むGM−CSFに特異的な抗体を用いる。好適には、前記抗体は更に、配列番号16のH−CDR1配列、及び/又は配列番号17のH−CDR2配列、及び/又は配列番号18のL−CDR1配列、及び/又は配列番号19のL−CDR2配列、及び/又は配列番号20のL−CDR3配列を含む。マウス以外の別の種属、特にこの実験で用いた抗体が交差反応する種属を用いてもよい。好適にはこの実験で用いた動物種はラットである。
実施例3を反復する。GM−CSF拮抗薬として、配列番号22のL−CDR1配列、及び/又は配列番号23のL−CDR2配列、及び/又は配列番号24のL−CDR3配列、及び/又は配列番号25のH−CDR1配列、及び/又は配列番号26のH−CDR2配列、及び/又は配列番号27のH−CDR3配列を含むGM−CSFに特異的な抗体を用いる。好適には、前記抗体は配列番号22ないし27のCRDを総て含む。マウス以外の別の種属、特にこの実験で用いた抗体が交差反応する種属を用いてもよい。好適にはこの実験で用いた動物種はラットである。
実施例3を反復するが、GM−CSF受容体に特異的なモノクローナル抗体を、GM−CSFに特異的なモノクローナル抗体の代わりに用いることが異なっている。
臨床試験は膝の変形性関節症を罹患した成人患者で行う。プラセボをコントロールとした、無作為の二重盲検臨床試験の目的は:総合的な疼痛軽減における本発明のGM−CSF拮抗薬とプラセボとの間の比較上の差異と;診断された膝の変形性関節症(OA)を有する30名の患者の全検体におけるQOL(quality of life:生活の質)と;を定量することである。別の目的は有害事象、理学的検査、及び生命徴候によって決定されるような本発明のGM−CSF拮抗薬の安全性及び耐容性を決定することである。
40歳以上であり、1箇所以上の膝の変形性関節症と臨床上診断され、かつ、検査前の月に少なくとも15日間膝の疼痛が確認された30名の患者(約15名の成人男性と15名の成人女性)が本研究で登録されている。患者は治療上有効な量のGM−CSF拮抗薬あるいはプラセボを受ける(例えば、約6ヶ月間、2週ごとに1回)。
〈全身の疼痛の変化〉
SF−36v2の全身の疼痛の改善は、本発明のGM−CSF拮抗薬で治療される患者において、プラセボと比較して統計学的に有意である。高い評点の方が、生成物を服用した後の疼痛が低いことを患者が感じていることを表わすため良好である。本発明のGM−CSF拮抗薬を受けた群においては、プラセボ群よりも統計学的に有意な全身の疼痛の改善がある。
プラセボと比較した本発明のGM−CSF拮抗薬の優れた効果は、身体的な健康による機能制限(身体的役割)の点で、8週、12週及び20週で統計学的に有意である。高い評点の方が、身体状態の改善と日常生活動作で受ける制限の低減とを患者が認知していることを表わすため良好である。本発明のGM−CSF拮抗薬を受けた群においては、プラセボ群よりも統計学的に有意な身体的役割の改善がある。
本発明のGM−CSF拮抗薬で治療した群の総合的なWOMAC評点は、プラセボ群の総合的なWOMAC評点よりも統計学的に有意に良好である(低い評点の方が良好である)。
日常生活動作における改善(WOMAC ADLの副評点として測定)は、本発明のGM-CSF拮抗薬で治療した群の方が、プラセボ群よりも顕著である。本発明のGM−CSF拮抗薬を受けた群においては、プラセボ群よりも統計学的に有意なWOMAC ADLの評点の改善があった(低い評点の方が良好である)。
臨床試験は、膝の変形性関節症を有する患者のQOLの改善における本発明のGM−CSF拮抗薬の有効性を示す。臨床試験の結果は更に、重篤な副作用が見出されなかったことから、生成物の安全性及び耐容性を示す。
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Claims (5)
- 対象における変形性関節症の治療のための方法であって、前記対象に有効量のGM−CSFの拮抗薬を投与するステップと具えることを特徴とする方法。
- 請求項1に記載の方法において、前記対象がヒトであることを特徴とする方法。
- 請求項1に記載の方法において、前記対象がマウスであることを特徴とする方法。
- 請求項1に記載の方法において、前記拮抗薬がGM−CSFに特異的な抗体であることを特徴とする方法。
- 請求項1に記載の方法において、前記拮抗薬がGM−CSF受容体に特異的な抗体であることを特徴とする方法。
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