JP2014221819A - 多発性硬化症の治療のための組成物 - Google Patents
多発性硬化症の治療のための組成物 Download PDFInfo
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- 239000001632 sodium acetate Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- VIDRYROWYFWGSY-UHFFFAOYSA-N sotalol hydrochloride Chemical compound Cl.CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 VIDRYROWYFWGSY-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
本発明
a)対象者から前駆細胞集団を単離するステップ、
b)IL−10の存在下で前記前駆細胞集団を培養することにより、樹枝状細胞の集団を入手するステップ、
c)多発性硬化症関連抗原の存在下でステップb)の細胞を前記対象者から単離されたCD4+Tリンパ球集団と接触させることで、前記抗原に方向付けられたCD4+T細胞を前記Tr1細胞集団に分化させるステップと、
d)前記Tr1細胞集団をステップc)から回復させるステップ。
a)多発性硬化症関連抗原に方向付けられたCD4+T細胞集団を培養するステップであって、前記CD4+T細胞集団は、適切な量のIFN−αを含む培地において対象者から単離される、ステップ、および
b)前記Tr1細胞集団を回復させるステップ。
a)多発性硬化症関連抗原の存在下においてCD4+T細胞集団をインビトロ活性化させるステップであって、前記多発性硬化症関連抗原は人工抗原提示細胞によって提示される、ステップ、および、
b)少なくとも10%のTr1細胞を含む活性化されたCD4+T細胞を回復させるステップ。好適には、前記人工抗原提示細胞は、HLA II系分子およびヒトLFA−3分子を発現し、副刺激分子B7−1、B7−2、B7−H1、CD40、CD23およびICAM−1を発現しない。
a)多発性硬化症関連抗原および適切な量のIL−10の存在下において、CD4+T細胞集団をインビトロ活性化させるステップ、および
b)前記Tr1細胞集団を回復させるステップ。
a)多発性硬化症関連抗原によって白血球集団または末梢血単核球(PBMC)集団を刺激するステップと、
b)前記刺激された集団から前記抗原特異的Tr1細胞集団を回復させるステップと、
c)任意に前記抗原特異的Tr1細胞集団を拡大(expand)させるステップ。
a)多発性硬化症関連抗原の存在下で白血球集団または末梢血単核球(PBMC)集団を間充織幹細胞と共に培養するステップ、および
b)前記Tr1細胞集団を回復させるステップ。
a)35℃よりも低い温度T1で培地Mfにおいて、支持細胞(例えば、昆虫支持細胞)を培養するステップであって、前記温度T1により、支持細胞の増殖を可能にし、前記支持細胞は、以下の細胞表面タンパク質と相互作用する要素を発現する、ステップ、
−CD3/TCR複合体、
−CD28タンパク質、
−IL−2受容体、
−CD2タンパク質、
−IL−4受容体
b)ステップa)において入手された、除去されたがその培地Mfは除去されていない前記支持細胞と、前記培地Mp中に含まれる前記Tr1細胞集団とを接触させるステップであって、前記培地Mpは、初期にはステップa)において引用された前記要素を含まず、これにより、前記Tr1細胞集団、前記支持細胞および前記培地Mpを含む混合物を入手する、ステップ、
c)ステップb)において入手された、前記混合物を温度T2で培養するステップであって、温度T2は少なくとも35℃であり、前記温度は、前記Tr1細胞集団が増殖しかつ前記支持細胞が増殖しないように選択される、ステップ、および
d)このように拡大した前記Tr1細胞集団を回復させるステップ。
−CD3重鎖の抗CD3細胞質内ドメインが膜貫通領域と交換された変性抗CD3抗体、
−CD80またはCD86タンパク質、
−前記支持細胞によって分泌されるIL−2、
−CD58タンパク質、
−IL−4およびIL−13を含む群から選択されるインターロイキン、
が含まれる。
−インターフェロン(例えば、ヒトインターフェロンベータ−1a(例えば、AVONEX(R)またはRebif(R))、インターフェロンベータ−1b(BETASERON(TM)、位置17において置換されたヒトインターフェロンベータ、Berlex/Chiron))、
−グラチラマー酢酸塩(コポリマー1、Cop−1、COPAXONE(TM)とも呼ばれる、Teva Pharmaceutical Industries,Inc.)および誘導体、
−フマル酸エステル(例えば、フマル酸ジメチル(例えば、Fumaderm(R))、
−リツキサン(R)(リツキシマブ)または別の抗CD20抗体(例えば、リツキシマブと共に重複エピトープと競合するかまたは重複エピトープに結合するもの)、
−ミトキサントロン(NOVANTRONE(R)、Lederle)、
−化学療法薬(例えば、clabribine(LEUSTATIN(R))、アザチオプリン(IMURAN(R))、シクロホスファミド(CYTOXAN(R))、シクロスポリン−A、メトトレキサート、4−アミノピリジン、およびチザニジン)
−コルチコステロイド(例えば、メチルプレドニゾロン(MEDRONE(R)、Pfizer)、プレドニゾン)、
−免疫グロブリン(例えば、リツキサン(R)(リツキシマブ)、CTLA4 Ig、アレムツズマブ(MabCAMPATH(R))またはダクリズマブ(CD25に結合する抗体)、
−スタチン
−免疫グロブリンG静脈内(IgGIV)、
−ナタリズマブ(タイサブリ)抗インテグリンアルファ−4抗体、
−経口CCケモカイン受容体1拮抗薬BX471(ZK811752)、
−FTY720(フィンゴリモド)、
−ヒトサイトカインまたは成長因子の抗体または拮抗薬(例えば、TNF、LT、IL−1、IL−2、IL−6、IL−7、IL−8、IL−12、IL−15、IL−16、IL−17、IL−18、IL−23、EMAP−I1、GM−CSF、FGF、およびPDGF)、
−細胞表面分子に対する抗体(例えば、CD2、CD3、CD4、CD8、CD25、CD28、CD30、CD40、CD45、CD69、CD80、CD86、CD90またはそのリガンド)、
−FK506、ラパマイシン、ミコフェノール酸モフェチル、レフルノミド、非ステロイド性抗炎症薬剤(NSAID)(例えば、ホスホジエステラーゼ阻害剤、アデノシン作動薬、抗血栓剤、補体阻害剤、アドレナリン作動薬、本明細書中に記載のような炎症性サイトカインによるシグナル伝達を阻害する薬剤、IL−1[ベータ]変換酵素阻害剤(例えば、Vx740)、抗P7、PSGL、TACE阻害剤、T細胞シグナル伝達阻害剤(例えば、キナーゼ阻害剤、メタロプロテアーゼ阻害剤、スルファサラジン、アザチオプリン、6−メルカプトプリン、アンジオテンシン変換酵素阻害剤、
−アマンタジン、バクロフェン、パパベリン、メクリジン、ヒドロキシジン、スルファメトキサゾール、シプロフロキサシン、ドキュセート、ペモリン、ダントロレン、デスモプレシン、デキサメタゾン、トルテロジン、フェニトイン、オキシブチニン、ビサコジル、ベンラファクシン、アミトリプチリン、メテナミン、クロナゼパム、イソニアジド、バルデナフィル、ニトロフラントイン、車前子親水性粘漿薬、アルプロスタジル、ガバペンチン、ノルトリプチリン、パロキセチン、臭化プロパンテリン、モダフィニル、フルオキセチン、フェナゾピリジン、メチルプレドニゾロン、カルバマゼピン、イミプラミン、ジアゼパム、シルデナフィル、ブプロピオンおよびセルトラリン。
−グラチラマー酢酸塩およびアルブテロール、
−グラチラマー酢酸塩およびミノサイクリン、
−インターフェロンベータ1aおよびミコフェノール酸モフェチル、
−BHT−3009およびアトルバスタチン
実施例
実験手順
Janvier(Le Genest−St−Isle、フランス)からC57Bl/6マウスを入手した。C57B1/6バックグラウンドのMOG35〜55特異的TCRトランスジェニックマウスをPr.Liblau(InsermU563、Hospital Purpan、Toulouse)の研究所に収容した。全てのマウスは、7〜8週齢のメスであった。
抗体および試薬
T細胞の精製および培養
サイトカインアッセイ
実験的自己免疫脳脊髄炎
結果
抗MOG35〜55Tリンパ球の分化
抗MOG35〜55TRl細胞のインビボ抑制機能
Claims (10)
- ミエリンオリゴデンドロサイトタンパク質(MOG)ペプチド、またはそれらの断片、変異体若しくは混合物に方向付けられた少なくとも1つのTr1細胞集団を、1つ以上の薬学的に許容可能なキャリアと共に含む薬学的組成物であって、前記Tr1細胞集団は、CD4+CD25−FoxP3−の静止状態の表現型を有する、薬学的組成物。
- ミエリンオリゴデンドロサイトタンパク質(MOG)ペプチド、またはそれらの断片、変異体若しくは混合物に方向付けられた少なくとも1つのTr1細胞集団を含む薬剤であって、前記Tr1細胞集団は、CD4+CD25−FoxP3−の静止状態の表現型を有する、薬剤。
- 前記Tr1細胞集団はTr1クローン集団である、請求項1に記載の薬学的組成物または請求項2に記載の薬剤。
- 前記ミエリンオリゴデンドロサイトタンパク質(MOG)ペプチド、またはそれらの断片、変異体若しくは混合物は、MOG35〜55、MOG21〜40、MOG41〜60、MOG71〜90、MOG81〜100、MOG111〜130、MOG63〜37、MOG97〜108、MOG181〜200ペプチドを含む群から選択される、請求項1〜3のいずれか1項に記載の薬学的組成物または薬剤。
- 多発性硬化症の治療のための、請求項1〜4のうちいずれか1項に記載の薬学的組成物または薬剤。
- 必要としている対象者に投与される前記薬剤または薬学的組成物は、前記対象者の細胞に対して自家のTr1細胞を含む、請求項5に記載の多発性硬化症の治療のための薬学的組成物または薬剤。
- 104/kg〜109/kgのTr1細胞が前記必要としている対象者に投与される、請求項5または6に記載の多発性硬化症の治療のための薬学的組成物または薬剤。
- 有効量の本発明の薬剤または薬学的組成物の前記対象者への前記投与は、多発性硬化症の治療に用いられる1つ以上の治療薬と組み合わせて行われる、請求項5〜7のうちのいずれか1項に記載の多発性硬化症の治療のための薬学的組成物または薬剤。
- 有効量の本発明の薬剤または薬学的組成物の前記対象者への前記投与は、インターフェロンベータ、グラチラマー酢酸塩、ミトキサントロン、シクロホスファミド、メトトレキサート、アジアトロピンまたはナタリズマブの群中の1つ以上の治療薬と組み合わせて行われる、請求項8に記載の多発性硬化症の治療のための薬学的組成物または薬剤。
- 前記対象者は、インターフェロンベータ、グラチラマー酢酸塩、ミトキサントロン、シクロホスファミド、メトトレキサート、アジアトロピンまたはナタリズマブの群中の1つ以上の治療薬に対して適切に応答しないかまたは適切に応答しない可能性がある、請求項5〜7のうちのいずれか1項に記載の多発性硬化症の治療のための薬学的組成物または薬剤。
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EP2710122B1 (en) * | 2011-05-19 | 2021-03-31 | TiGenix, S.A.U. | Cell populations having immunoregulatory activity, methods for the preparation and uses thereof |
GB201300684D0 (en) | 2013-01-15 | 2013-02-27 | Apitope Int Nv | Peptide |
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RU2600160C1 (ru) * | 2015-08-07 | 2016-10-20 | Юрий Леонидович Шевченко | Способ лечения рассеянного склероза и других системных аутоиммунных заболеваний |
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WO2018078112A1 (en) * | 2016-10-27 | 2018-05-03 | Aarhus Universitet | Glp-1 agonist (eg liraglutide) for use in the treatment of multiple sclerosis |
US11733232B2 (en) | 2017-03-01 | 2023-08-22 | National University Corporation Hokkaido University | Method for producing disease modeling non-human animal, disease modeling non-human animal, and method for screening drug and method for determining risk of disease using the same |
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CN101842478A (zh) | 2010-09-22 |
US9517253B2 (en) | 2016-12-13 |
WO2009050283A1 (en) | 2009-04-23 |
DK2205720T3 (en) | 2017-03-20 |
AU2008313694B2 (en) | 2015-03-26 |
ES2618583T3 (es) | 2017-06-21 |
EP2050814A1 (en) | 2009-04-22 |
US20170042992A1 (en) | 2017-02-16 |
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CA2702634C (en) | 2017-06-13 |
US20100221219A1 (en) | 2010-09-02 |
HRP20170353T1 (hr) | 2017-05-05 |
RU2010119505A (ru) | 2011-11-27 |
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CA2702634A1 (en) | 2009-04-23 |
HUE032066T2 (en) | 2017-09-28 |
SI2205720T1 (sl) | 2017-04-26 |
EP2205720B1 (en) | 2016-12-14 |
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