JP2010527988A - 移植片対宿主病の治療 - Google Patents
移植片対宿主病の治療 Download PDFInfo
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- JP2010527988A JP2010527988A JP2010508932A JP2010508932A JP2010527988A JP 2010527988 A JP2010527988 A JP 2010527988A JP 2010508932 A JP2010508932 A JP 2010508932A JP 2010508932 A JP2010508932 A JP 2010508932A JP 2010527988 A JP2010527988 A JP 2010527988A
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Abstract
【選択図】図5
Description
本願は、2007年5月25日に出願された米国仮特許出願第60/940,349号明細書(その内容全体が参照により本明細書中に援用される)に対する優先権の利益を主張するものである。
移植片対宿主病の治療に使用される細胞を得るのに好ましい方法は、MSC、MLSC、又はMLSC/PCを単離する任意の特定の方法にとらわれるものではなく、ヒト骨髄等の身体サンプル又は起源から同種性の高いクローン骨髄幹細胞集団又は多分化性幹細胞(MLSC)を単離するために使用される方法である、「亜分画培養法」によるものである。その手順は、米国特許出願公開第2006/0286669号明細書(米国特許出願第11/471,684号明細書、2006年6月19日出願)「多分化性幹細胞の単離(Isolation of Multi-Lineage Stem Cells)」(その内容全体が参照により本明細書中に援用される)に記載されている。
本発明者らは、治療に反応を示さなかった急性又は慢性の移植片対宿主病患者の状態を、米国特許出願公開第2006/0286669号明細書(2006年6月19日出願)「多分化性幹細胞の単離(Isolation of Multi-Lineage Stem Cells)」(その内容全体が参照により本明細書中に援用される)に記載される方法(図1)を用いて分離した間充織幹細胞又は骨髄幹細胞を投与することで改善することができた。
骨髄提供者(治療標的の慢性移植片対宿主病患者の母親)の臀部に局所麻酔を適用した後、注射針を寛骨に挿入して骨髄を抽出した。20%FBS、及び1%ペニシリン/ストレプトマイシン、及び上記の骨髄提供者から抽出した骨髄2mlを含む15mlのDMEM(ダルベッコ変法イーグル培地、GIBCO-BRL, Life-technologies、MD、USA)を100mmの培養容器に入れ、37℃、5%CO2の細胞培養器内で2時間培養した。培養の後、底部に付着した細胞が落ちないように培養容器を少し傾けて、培養容器内の培養液の上層を最大の量で新たな容器に移した。
実施例2.1−フローサイトメトリーを用いた間充織幹細胞又は骨髄幹細胞の特性の分析
上記実施例1の方法を用いて骨髄から分離したcMSC−15細胞が間充織幹細胞又は骨髄幹細胞であるかを検証するために、フローサイトメトリー(BD Biosciences)を使用して、細胞表面抗原が幹細胞特性を有するかを調べた。
本発明者らは、本発明における亜分画培養法を用いて単離した間充織幹細胞の特性についてさらに調べるために、免疫抑制関連サイトカインの発現レベルを分析した。
実施例3.1−間充織幹細胞又は骨髄幹細胞の投与
患者は急性骨髄性白血病であると診断され、導入療法により寛解に到達した後、同種骨髄移植を受けた18歳の女性であった。6ヶ月間の免疫抑制剤の投与を停止して1ヶ月後、慢性移植片対宿主病が発症し、シクロスポリンA(CsA)、ミコフェノール酸モフェチル(MMF)、及びステロイドを用いて治療したが、継続的な血便、ビリルビン値の上昇、並びに皮膚、口、及び眼の乾燥により患者の状態は悪化し、治療の副作用のためCMVが活性化し、BKウイルスの感染により尿及び血液中でもBKウイルスが見られたため、Cideforvirを用いた治療を開始した。韓国食品医薬品安全庁の応急臨床許可を受けた後、実施例1に記載のように単離した患者の母親の間充織幹細胞又は骨髄幹細胞をGMP施設において培養し、静脈注射を用いて患者に投与した。投与中又は投与後に有害/陰性反応は観察されず、患者の症状は1回目の投与後から徐々に改善され、2回目の投与は1回目と同一の量で3週間後に行なった。その後、患者の症状は大幅に改善され、2回目の投与の34日後に、患者はステロイドの服用を止め、免疫抑制剤としてMMFのみを1.5g/日で服用している状態で退院した。
本発明における亜分画培養法を用いて単離された間充織幹細胞又は骨髄幹細胞が治療に有効であるかを検証するために、本発明者らは、糞便量及び主な指標である血中アルカリホスファターゼの活性を測定した(図4)。血中アルカリホスファターゼの活性化は、市販のキット(Sigma Chemical Company、USA)を用いて行なった。
Claims (31)
- 移植片対宿主病を患っていることが確認された被験者において、ドナー骨髄由来のT細胞の活性を阻害する方法であって、それを必要とする被験者に、治療的に有効な量の同種クローン骨髄幹細胞集団を投与することを含む、方法。
- 前記幹細胞の投与量が、1回の投与につき1×104細胞/kg体重〜1×108細胞/kg体重である、請求項1に記載の方法。
- 前記幹細胞を亜分画培養法を用いて単離する、請求項1に記載の方法。
- 前記幹細胞がCD29細胞表面抗原、CD44細胞表面抗原、及びCD105細胞表面抗原を発現するが、HLA−DR細胞表面抗原は発現しない、請求項1に記載の方法。
- 前記幹細胞がCD29細胞表面抗原、CD44細胞表面抗原、CD73細胞表面抗原、CD90細胞表面抗原、CD105細胞表面抗原、及びCD166細胞表面抗原を発現するが、CD106細胞表面抗原、CD119細胞表面抗原、又はHLA−DR細胞表面抗原は発現しない、請求項1に記載の方法。
- 前記同種クローン骨髄幹細胞が、インターロイキン−10を少なくとも約5ng/mlの濃度で分泌する、請求項1に記載の方法。
- 移植片対宿主病を患っていることが確認された被験者において、移植片対宿主病の症状を治療する方法であって、それを必要とする被験者に、治療的に有効な量の同種クローン骨髄幹細胞集団を投与することを含む、方法。
- 前記移植片対宿主病の症状が、胃腸管症状、皮膚硬化、経口摂取の制限、目の乾燥、肝症状、息切れ、又は腕若しくは脚の緊張である、請求項7に記載の方法。
- 前記胃腸症状が1日糞便量の増加である、請求項8に記載の方法。
- 前記胃腸症状が大腸炎症である、請求項8に記載の方法。
- 前記肝症状が血清中アルカリホスファターゼ値の上昇である、請求項8に記載の方法。
- 移植片対宿主病を患っていることが確認された被験者において、ドナー骨髄由来のT細胞の活性を阻害する方法であって、
(A)骨髄細胞の生体サンプルを操作することであって、
(i)前記細胞サンプルを容器に定着させること、
(ii)上清を前記容器から別の容器に移すこと、及び
(iii)前記サンプルにおいて比較的低い密度を有する細胞を前記上清から単離し、同種クローン骨髄幹細胞集団を得る、単離することを含む、操作すること、並びに
(B)それを必要とする前記被験者に、(A)で得られる同種クローン骨髄幹細胞集団を治療的に有効な量投与することを含む、方法。 - 前記容器をコーティングにより処理する、請求項12に記載の方法。
- 前記コーティングがコラーゲン、ポリリジン、フィブリノーゲン、又はゼラチンである、請求項13に記載の方法。
- 移植片対宿主病を患っていることが確認された被験者において、移植片対宿主病の症状を治療する方法であって、
(A)骨髄細胞の生体サンプルを操作することであって、
(i)前記細胞サンプルを容器に定着させること、
(ii)上清を前記容器から別の容器に移すこと、及び
(iii)前記サンプルにおいて比較的低い密度を有する細胞を前記上清から単離し、同種クローン骨髄幹細胞集団を得る、単離することを含む、操作すること、並びに
(B)それを必要とする前記被験者に、(A)で得られる同種クローン骨髄幹細胞集団を治療的に有効な量投与することを含む、方法。 - 前記細胞の投与量が、1×104細胞/kg〜1×108細胞/kgである、請求項15に記載の方法。
- 前記細胞がCD29細胞表面抗原、CD44細胞表面抗原、及びCD105細胞表面抗原を発現するが、HLA−DR細胞表面抗原は発現しない、請求項15に記載の方法。
- 前記細胞がCD29細胞表面抗原、CD44細胞表面抗原、CD73細胞表面抗原、CD90細胞表面抗原、CD105細胞表面抗原、及びCD166細胞表面抗原を発現するが、CD106細胞表面抗原、CD119細胞表面抗原、又はHLA−DR細胞表面抗原は発現しない、請求項15に記載の方法。
- 前記細胞集団が、インターロイキン−10を少なくとも約5ng/mlの濃度で分泌する、請求項15に記載の方法。
- 急性又は慢性の移植片対宿主病を治療するための治療剤であって、活性成分として同種クローン骨髄幹細胞集団を含む、治療剤。
- 前記細胞が、亜分画培養法を用いて単離される、請求項20に記載の治療剤。
- 前記細胞がCD29細胞表面抗原、CD44細胞表面抗原、及びCD105細胞表面抗原を発現するが、HLA−DR細胞表面抗原は発現しない、請求項20に記載の治療剤。
- 前記細胞がCD29細胞表面抗原、CD44細胞表面抗原、CD73細胞表面抗原、CD90細胞表面抗原、CD105細胞表面抗原、及びCD166細胞表面抗原を発現するが、CD106細胞表面抗原、CD119細胞表面抗原、又はHLA−DR細胞表面抗原は発現しない、請求項20に記載の治療剤。
- 前記細胞が少なくとも約5ng/mlのインターロイキン−10(IL−10)を分泌する、請求項20に記載の治療剤。
- 前記細胞が、密度勾配遠心分離法を用いて単離される細胞の少なくとも約5倍のIL−10を分泌する、請求項20に記載の治療剤。
- 密度勾配遠心分離法を用いて単離される細胞の少なくとも約5倍のIL−10を発現する、同種クローン骨髄幹細胞集団。
- 密度勾配遠心分離法を用いて単離される細胞の少なくとも約5倍のIL−10を発現する、同種クローン骨髄幹細胞集団であって、
(i)骨髄細胞のサンプルを容器に定着させること、
(ii)上清を前記容器から別の容器に移すこと、及び
(iii)前記サンプルにおいて比較的低い密度を有する細胞を前記上清から単離することにより得られる、同種クローン骨髄幹細胞集団。 - 前記骨髄細胞を37℃で約1時間〜3時間、次に約2回〜3回繰り返して37℃で約12時間〜36時間、次に37℃で約24時間〜72時間、毎回培養上清の上方を新たな培養容器に移しながらインキュベートする、請求項27に記載の同種クローン骨髄幹細胞集団。
- 前記容器をコーティングにより処理する、請求項27に記載の同種クローン骨髄幹細胞集団。
- 前記コーティングがコラーゲン、ポリリジン、フィブリノーゲン、又はゼラチンである、請求項29に記載の同種クローン骨髄幹細胞集団。
- 前記繰り返しのインキュベーションを約4回〜5回行なう、請求項28に記載の同種クローン骨髄幹細胞集団。
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JP2022513291A (ja) * | 2018-12-17 | 2022-02-07 | エスシーエム ライフサイエンス カンパニー リミテッド | クローナル幹細胞を含む移植片対宿主病の治療用薬学的組成物 |
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