JP2015007079A - 関節炎の病態を治療するための組成物 - Google Patents
関節炎の病態を治療するための組成物 Download PDFInfo
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Abstract
Description
―選択された関節関連の抗原に向けられるTr1細胞を取得するステップであって、前記Tr1細胞を前記対象の血液試料から取得する前記ステップと、
―選択された関節関連の抗原に向けられる前記Tr1細胞をクローニングするステップと、
―先のステップで取得したTr1クローンをさらに拡大(expand)するステップと、
―そうして取得したTr1クローンを前記対象に、好ましくは静脈内経路により再注入するステップと、を含む。
本明細書で使用される「Tr1細胞」という用語は、静止状態(at rest)でCD4+CD25−FoxP3−の表現型を有し、活性化されると高レベルのIL−10および有意なレベルのTGF−βを分泌できる細胞を言う。Tr1細胞は、独特なサイトカインプロファイルにより一部特徴付けられる。これらは、高レベルのIL−10、有意なレベルのTGF−β、および中間レベルのIFN−γを産生するが、IL−4またはIL−2はほとんど、もしくは全く産生しない。サイトカイン産生は典型的に、抗CD3+抗CD28抗体またはインターロイキン2、PMA+イオノマイシンのような、Tリンパ球のポリクローナル活性化因子を用いて活性化した後の細胞の培養物において評価される。代替的に、サイトカイン産生は、抗原提示細胞により提示される特異的T細胞抗原を用いて活性化した後の細胞の培養物において評価される。高レベルのIL−10とは、少なくとも約500pg/ml、典型的には約1000、2000、4000、6000、8000、1万、1万2000、1万4000、1万6000、1万8000、もしくは2万pg/ml、またはそれを上回る量に相当する。有意なレベルのTGF−βとは、少なくとも約100pg/ml、典型的には約200、300、400、600、800、もしくは1000pg/ml、またはそれを上回る量に相当する。中間レベルのIFN−γとは、0pg/ml〜少なくとも400pg/mlの間、典型的には約600、800、1000、1200、1400、1600、1800、もしくは2000pg/mlまたはそれを上回る量を含む濃度に相当する。IL−4またはIL−2がほとんど、もしくは全くないとは、約500pg/ml未満、好ましくは約250、100、75、もしくは50pg/mlまたはそれより少ない量に相当する。
本発明は、その必要がある対象における関節炎の病態を治療する方法に関し、関節関連の抗原に向けられるヒトTr1細胞を含有する組成物を前記対象に投与することを含む。
a)対象から前駆細胞集団を単離するステップと、
b)IL−10の存在下で、前記前駆細胞を培養することにより樹状細胞集団を取得するステップと、
c)関節関連の抗原の存在下で、ステップb)の細胞を、前記対象から単離したCD4+Tリンパ球集団と接触させ、前記抗原に向けられるCD4+T細胞の分化によりTr1細胞集団にするステップと、
d)ステップc)のTr1細胞集団を回収するステップと、により取得され得る。
ステップb)では、IL−10は、培地中に50〜250U/ml、好ましくは100U/ml存在する。Tr1細胞を取得するための前記方法は、Wakkachら(Immunity 2003 May;18(5):605−17)に説明されている。
a)対象から単離した関節関連の抗原に向けられるCD4+T細胞集団を、適切な量のIFN−αを用いた培地で培養するステップと、
b)Tr1細胞集団を回収するステップと、により取得され得る。
a)人工抗原提示細胞により提示された関節関連の抗原の存在下で、CD4+T細胞集団をin vitroで活性化させるステップと、
b)少なくとも10%のTr1細胞を含有する活性化させたCD4+T細胞を回収するステップと、により取得され得る。
a)関節関連の抗原および適切な量のIL−10の存在下で、CD4+T細胞集団をin vitroで活性化させるステップと、
b)Tr1細胞集団を回収するステップと、により取得され得る。
a)関節関連の抗原を用いて、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)刺激した集団から、関節関連の抗原−特異的Tr1細胞集団を回収するステップと、
c)前記関節関連の抗原−特異的Tr1細胞集団を随意に拡大するステップと、により取得され得る。
a)白血球集団または末梢血単核球細胞(PBMC)集団を、関節関連の抗原の存在下で間葉系幹細胞を用いて培養するステップと、
b)Tr1細胞集団を回収するステップと、により取得し得る。
a)35℃より下の温度T1、培地Mfにおいて、昆虫フィーダー細胞のようなフィーダー細胞を培養するステップであって、前記温度T1によりフィーダー細胞の増殖が可能となり、前記フィーダー細胞が次の細胞表面タンパク質:
―CD3/TCR複合体、
―CD28タンパク質、
―IL−2受容体、
―CD2タンパク質、および
―IL−4受容体
と相互作用する因子を発現するステップと、
b)ステップa)で取得した、その培地Mfから除去した、またはその培地Mf以外のフィーダー細胞を、培地Mpに包含されたTr1細胞集団と接触させるステップであって、前記培地Mpが、Tr1細胞集団、フィーダー細胞、および培地Mpを包含する混合物を取得するために、ステップa)で記載した因子を最初から包含していない前記ステップと、
c)ステップb)で取得した混合物を、少なくとも35℃の温度T2で培養するステップであって、Tr1細胞集団が増殖し、フィーダー細胞が増殖しないように前記温度を選択する前記ステップと、
d)そのように拡大したTr1細胞集団を回収するステップと、を含む。
―修飾された抗CD3抗体であって、CD3重鎖の抗CD3細胞質内ドメインが膜貫通ドメインと置換された、前記修飾された抗CD3抗体と、
―CD80またはCD86タンパク質と、
―フィーダー細胞から分泌されたIL−2と、
―CD58タンパク質と、
―IL−4およびIL−13を含有する群から選択されるインターロイキンと、を含む。
―前記対象の血液試料を採取するステップと、
―関節関連の抗原に向けられるTr1細胞を取得するステップと、
―関節関連の抗原に向けられる前記Tr1細胞をクローニングするステップと、
―先のステップで取得したTr1クローンをさらに拡大するステップと、
―そうして取得したTr1クローンを前記対象に、好ましくは静脈内注射により注射するステップと、を含む。
a)35℃より下の温度T1、培地Mfで、昆虫フィーダー細胞のようなフィーダー細胞を培養するステップであって、前記温度T1によりフィーダー細胞の増殖が可能となり、前記フィーダー細胞が次の細胞表面タンパク質:
―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
と相互作用する因子を発現するステップと、
b)ステップa)で取得した、その培地Mfから除去した、またはその培地Mf以外のフィーダー細胞を、培地Mpに包含されたTr1細胞集団と接触させるステップであって、前記培地Mpが、Tr1細胞集団、フィーダー細胞、および培地Mpを包含する混合物を取得するために、ステップa)で記載した因子を最初から包含していない前記ステップと、
c)ステップb)で取得した混合物を、少なくとも35℃の温度T2で培養するステップであって、Tr1細胞集団が増殖し、フィーダー細胞が増殖しないように前記温度を選択する前記ステップと、
d)そのように拡大されたTr1細胞集団を回収するステップと、を用いて実行される。
―修飾された抗CD3抗体であって、CD3重鎖の抗CD3細胞質内ドメインが膜貫通ドメインと置換された、前記修飾された抗CD3抗体と、
―CD80またはCD86タンパク質と、
―フィーダー細胞から分泌されたIL−2と、
―CD58タンパク質と、
―IL−4およびIL−13を含有する群から選択されるインターロイキンと、を含む。
―コルチコイド(プレドニゾン)、
―インフリキシマブ、アダリムマブ、エタネルセプトのような抗TNF;
―アナキンラ、AMG108、イグラチモド、アクテムラのような抗インターロイキン
―リツキシマブ、エピラツズマブのような抗Bリンパ球;
―アバタセプト、ベリムマブのような抗−共刺激分子;
―LJP394またはTV−4710のような免疫寛容薬(Bリンパ球表面のDNA受容体に向けられる合成分子);
―エクリズマブのような抗補体タンパク質;
―CP690550のようなT細胞シグナル伝達分子の阻害薬
―ケモカイン受容体の拮抗薬(マラビロク、INCB3284)のような、細胞遊走の阻害薬、
―レフルノミド、
―スルファサラジン、
―ヒドロキシクロロキン、
―アザチオプリン、
―メトトレキサート、
―シクロスポリン、
―ミノサイクリン、
―D―ペニシラミン、
―メトトレキサート+スルファサラジン、メトトレキサート+ヒドロキシクロロキン、メトトレキサート+アザチオプリン、メトトレキサート+インフリキシマブ、メトトレキサート+レフルノミド、メトトレキサート+エタネルセプト、シクロスポリン+ヒドロキシクロロキン、シクロスポリン+メトトレキサート、メトトレキサート+スルファサラジン+ヒドロキシクロロキン、のようなそれらの併用療法。
以下の説明では、詳細なプロトコルが与えられていない全ての実験は、標準的なプロトコルに従って行っている。
Tr1細胞の単離
健常な患者または深刻な関節リウマチの患者から血液試料を採取し、密度勾配遠心分離法により白血球を分離した。次いで、この抗原に向けられるTr1細胞の特異的増殖を誘発するために、II型コラーゲンの存在下で細胞を培養した。培養の13日後、限界希釈法により細胞集団をクローニングした。次いで、II型コラーゲンに対するその特異性、および特徴的なTr1サイトカイン産生プロファイルについてクローンを評価した。
抗原特異性の判定のため、抗原提示細胞(4.105)の存在下、および特異的抗原(II型コラーゲン)の存在下または非存在下で刺激した、Tr1細胞クローンの48時間後の上清についてサンドイッチELISAを行った。サイトカイン産生プロファイルの決定のため、II型コラーゲンTr1細胞クローンを抗CD3+抗CD28モノクローナル抗体で刺激し、48時間後に上清を収集した。抗IL−4(11B11)、抗IL−10(2A5)、抗IFNγ(XGM1.2)、ビオチン抗IL−4(24G2)、抗IL−10(SXC1)、抗IFNγ(R4−6A2)(Pharmingen Becton Dickinson)を使用してELISAを行った。
抑制研究のため、段階付けた量のII型コラーゲン特異的Tr1クローンを、自己由来CD4陽性Tリンパ球を用いて共培養した。共培養物を、抗CD3+抗CD28モノクローナル抗体を用いて刺激した。別の手段として、II型コラーゲン特異的クローンの上清を、抗CD3+抗CD28モノクローナル抗体で刺激した、CD4陽性Tリンパ球に添加した。3日後、RocheのWST−1増殖キットを使用して細胞増殖の総計を評価した。
図1は、抗原の存在または非存在下で、II型コラーゲンに特異的な2つの別々のTr1細胞集団のIL−10産生を示す。結果は、II型コラーゲンの刺激がIL−10の産生の増加を誘発することを示す。これらの結果は、II型コラーゲンに対する細胞集団の特異性を実証している。
Claims (18)
- 関節関連の抗原に向けられる少なくとも1つのヒトTr1細胞集団を含有する組成物であって、前記関節関連の抗原がHSP、ケラチン、ピルビン酸デヒドロゲナーゼ、トポイソメラーゼI、カルジオリピン、またはIV型コラーゲンではないことを条件とする、組成物。
- 前記ヒトTr1細胞集団がヒトTr1クローン集団である、請求項1に記載の組成物。
- 前記関節関連の抗原が、シトルリンに置換した環状および直鎖状のフィラグリンペプチド、II型コラーゲンペプチド、ヒト軟骨糖タンパク質39(HCgp39)ペプチド、ヘテロ核リボヌクレオタンパク質(hnRNP)A2ペプチド、hnRNP B1、hnRNP D、Ro60/52、BiP、ビメンチン、フィブリノゲン、I、IIIおよびV型コラーゲンのペプチド、アネキシンV、グルコース6リン酸イソメラーゼ(GPI)、アセチル−カルパスタチン、アルドラーゼ、snRNP、PARP、Scl−70、Scl−100、陰イオン性ホスファチジルセリン、中性に荷電したホスファチジルエタノールアミン、およびホスファチジルコリンを含むリン脂質抗原、マトリックスメタロプロテアーゼ、フィブリン、アグリカン、並びにそれらの断片、変異体、および混合物を含む群から選択される、請求項1または請求項2のいずれかに記載の組成物。
- 前記関節関連の抗原が、II型コラーゲン、並びにその断片、変異体、および混合物である、請求項3に記載の組成物。
- 前記関節関連の抗原が、HCgp39、並びにその断片、変異体、および混合物である、請求項3に記載の組成物。
- 関節関連の抗原に向けられる、少なくとも1つのヒトTr1細胞集団を含有する薬剤。
- 1つ以上の薬学的に許容される担体と組み合わせられる、関節関連の抗原に向けられる少なくとも1つのヒトTr1細胞集団を含有する医薬組成物。
- 前記ヒトTr1細胞集団が、ヒトTr1クローン集団である、請求項6に記載の薬剤または請求項7に記載の医薬組成物。
- 前記ヒトTr1細胞集団が、シトルリンに置換した環状および直鎖状のフィラグリンペプチド、II型コラーゲンペプチド、ヒト軟骨糖タンパク質39(HCgp39)ペプチド、HSP、ヘテロ核リボヌクレオタンパク質(hnRNP)A2ペプチド、hnRNP B1、hnRNP D、Ro60/52、BiP、ケラチン、ビメンチン、フィブリノゲン、カルジオリピン、I、III、IVおよびV型コラーゲンのペプチド、アネキシンV、グルコース6リン酸イソメラーゼ(GPI)、アセチル−カルパスタチン、ピルビン酸デヒドロゲナーゼ(PDH)、アルドラーゼ、トポイソメラーゼI、snRNP、PARP、Scl−70、Scl−100、陰イオン性ホスファチジルセリン、中性に荷電したホスファチジルエタノールアミン、およびホスファチジルコリンを含むリン脂質抗原、マトリックスメタロプロテアーゼ、フィブリン、アグリカン、並びにそれらの断片、変異体、および混合物のうちから選択される関節関連の抗原に向けられる、請求項8に記載の薬剤または医薬組成物。
- 前記ヒトTr1細胞集団が、II型コラーゲン、HCgp39、およびHSPのうちから選択される関節関連の抗原に向けられる、請求項8に記載の薬剤または医薬組成物。
- 関節炎の病態を治療するための、請求項6乃至請求項10のいずれか一項に記載の薬剤または医薬組成物。
- 前記関節炎の病態が関節リウマチ、強直性脊椎炎、若年性特発性関節炎、または乾癬性関節炎である、請求項11に記載の薬剤または医薬組成物。
- その必要がある対象に投与する薬剤または医薬組成物が、前記対象の細胞に自己由来するヒトTr1細胞を含有する、請求項11または12に記載の薬剤または医薬組成物。
- その必要がある対象に、104/kg〜109/kgのTr1細胞を投与する、請求項11乃至請求項13のいずれか一項に記載の薬剤または医薬組成物。
- 有効量の本発明の薬剤または医薬組成物を前記対象に投与することが、関節炎の病態を治療するために使用される1つ以上の治療薬と組み合わせられている、請求項11乃至請求項14のいずれか一項に記載の薬剤または医薬組成物。
- 有効量の本発明の薬剤または医薬組成物を前記対象に投与することが、コルチコイド、抗TNF、抗インターロイキン、抗Bリンパ球、抗−共刺激分子、免疫寛容薬、抗補体タンパク質、T細胞シグナル伝達分子の阻害剤、細胞遊走の阻害薬、メトトレキサート、レフルノミド、スルファサラジン、ヒドロキシクロロキン、アザチオプリン、メトトレキサート、シクロスポリン、ミノサイクリン、D―ペニシラミンの群から選択される1つ以上の治療薬と組み合わせられている、請求項15に記載の薬剤または医薬組成物。
- 前記対象が、コルチコイド、抗TNF、抗インターロイキン、抗Bリンパ球、抗−共刺激分子、免疫寛容薬、抗補体タンパク質、T細胞シグナル伝達分子の阻害剤、細胞遊走の阻害薬、メトトレキサート、レフルノミド、スルファサラジン、ヒドロキシクロロキン、アザチオプリン、メトトレキサート、シクロスポリン、ミノサイクリン、D―ペニシラミンの群における1つ以上の治療薬に十分に反応しないか、または十分に反応しないと見込まれる請求項11乃至請求項14のいずれか一項に記載の薬剤または医薬組成物。
- その必要がある対象における関節炎の病態を治療するための工程であって、
―選択された関節関連の抗原に向けられるTr1細胞を取得するステップであって、前記Tr1細胞を前記対象の血液試料から取得する前記ステップと、
―選択された関節関連の抗原に向けられる前記Tr1細胞をクローニングするステップと、
―先のステップで取得したTr1クローンをさらに拡大するステップと、
―そうして取得したTr1クローンを、好ましくは静脈内経路により前記対象に注射するステップと、を含む工程。
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US20140322188A1 (en) * | 2013-04-26 | 2014-10-30 | Enzo Biochem, Inc. | Tolerizing treatments for autoimmune disease |
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EP2281032B1 (en) | 2016-08-03 |
EP3130666A1 (en) | 2017-02-15 |
JP2011518797A (ja) | 2011-06-30 |
RU2563360C2 (ru) | 2015-09-20 |
CN108159407A (zh) | 2018-06-15 |
AU2009242299A1 (en) | 2009-11-05 |
DK2281032T3 (en) | 2016-10-10 |
EP2113560A1 (en) | 2009-11-04 |
PT2281032T (pt) | 2016-11-11 |
AU2009242299B2 (en) | 2015-05-14 |
SI2281032T1 (sl) | 2017-01-31 |
LT2281032T (lt) | 2016-11-25 |
BRPI0911580A2 (pt) | 2017-05-23 |
CA2722816A1 (en) | 2009-11-05 |
HUE034048T2 (en) | 2018-01-29 |
WO2009132941A1 (en) | 2009-11-05 |
CN102076845A (zh) | 2011-05-25 |
JP6111014B2 (ja) | 2017-04-05 |
EP2281032A1 (en) | 2011-02-09 |
PL2281032T3 (pl) | 2017-01-31 |
CA2722816C (en) | 2018-01-09 |
KR20160093090A (ko) | 2016-08-05 |
US20110038844A1 (en) | 2011-02-17 |
ES2599305T3 (es) | 2017-02-01 |
KR101747902B1 (ko) | 2017-06-16 |
KR20110017373A (ko) | 2011-02-21 |
RU2010148464A (ru) | 2012-06-10 |
US20180250372A1 (en) | 2018-09-06 |
HRP20161221T1 (hr) | 2017-01-13 |
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