JP2021520834A - Treg細胞の抑制特性を増強するための方法 - Google Patents
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Abstract
Description
(a)細胞集団からTregを単離すること、および
(b)TregにおけるFOXP3発現を増大させること
を含む。
「制御性T細胞」(Treg)という用語は、マーカーCD4、CD25およびFOXP3を発現する(CD4+CD25+FOXP3+)T細胞を意味する。Tregは、細胞表面マーカーCD4およびCD25を使用し、表面タンパク質CD127の低レベル発現の非存在下で、またはこれと組み合わせて同定してもよい(CD4+CD25+CD127−またはCD4+CD25+CD127low)。Tregは、細胞表面に高レベルのCTLA-4(細胞傷害性Tリンパ球関連分子−4)またはGITR(グルココルチコイド誘導性TNF受容体)もまた発現する場合がある。通常のT細胞とは異なり、TregはIL-2を産生せず、またそれ故に、ベースラインではアネルギー性である。
「免疫応答を抑制する能力を増強する」という表現は、免疫応答に対するTreg(またはかかるTregの集団)の抑制効果を、本発明の方法により改変されていない対応Treg(またはかかるTregの集団)の抑制効果と比較して、増大させることを意味する。
「FOXP3」はフォークヘッドボックスP3タンパク質の略称である。FOXP3はFOXタンパク質ファミリーの転写因子のメンバーであり、制御性T細胞の発生および機能における調節経路の主要制御因子として機能する。
「ポリヌクレオチド」および「核酸」という用語は、互いに同義であることを意図する。ポリヌクレオチドは、任意の適切なタイプのヌクレオチド配列、例えば合成RNA/DNA配列、cDNA配列または部分的なゲノムDNA配列であってもよい。
適宜、前記FOXP3ポリペプチドは、ヒトFOXP3のポリペプチド配列、例えばUniProtKBアクセッション番号Q9BZS1、またはその機能性断片、すなわち
を含んでいてもよい。
配列比較は、目測で、またはより一般的には、容易に入手可能な配列比較プログラムを用いて実行することができる。これらの公的かつ商業的に入手可能なコンピュータプログラムにより、2つ以上の配列間の配列同一性を算出することができる。
本発明の幾つかの実施形態では、前記のFOXP3をコードするポリヌクレオチドは、発現ベクターの連続した部分である。
本発明の幾つかの実施形態では、前記のFOXP3をコードするポリヌクレオチドを、ウイルスによる形質導入によって単離Tregに導入する。
幾つかの実施形態では、本発明による方法は、以下(a)および(b)、すなわち
(a)細胞集団からTregを単離すること、および
(b)該TregにおけるFOXP3発現を増大させること
を含む。
また本発明は、本発明の方法により産生される遺伝子操作Tregなどの、遺伝子操作Tregも提供する。
また本発明は、本発明の遺伝子操作Tregを含む医薬組成物も提供する。
また本発明は、疾患の予防および/または治療に使用するための、本発明の遺伝子操作Treg、または本発明の医薬組成物も提供する。
(i)対象からのTregの単離、
(ii)FOXP3ポリペプチドをコードするポリヌクレオチド配列を該Tregに導入する(すなわち、該Tregを遺伝子操作する)こと、および
(iii)遺伝子操作したTregを該対象に投与すること
を含んでいてもよい。
本発明の方法および使用により治療および/または予防される疾患は、病的免疫応答を伴う任意の疾患でありうる。
多発性硬化症(MS)は、欧州および米国の若年成人に最もよく見られる神経障害である。MSは脱髄疾患として特徴付けられており、これは神経接続を妨げて筋力低下、協調運動および発語の喪失ならびに視力障害を引き起こす、脳および/または脊髄の全体にわたり所々にミエリンの段階的な破壊が起こる中枢神経系の慢性変性疾患である。
(実施例)
[実施例1A]
CD4+T細胞は、CD4+陽性選択キットを使用して単離した。細胞をその後、FACS選別の前に、BD ARIAを使用してフローサイトメトリー抗体CD4、CD25およびCD127で染色した。CD4+CD25hiCD127−TregおよびCD4+CD25−CD127+Tconvをポリプロピレンチューブに採集した。細胞選別の純度は、FOXP3 PE抗体の添加により測定した。CD4+CD25+CD127−FOXP3+細胞の純度は通常、>70%であった。
[実施例1B]
0日目に、FACSで選別したTregおよびTconvを、抗-CD3および抗-CD28ビーズと共に1:1で培養することにより、48時間別々に活性化した。2日目に細胞を計数し、完全RPMI(Tconv)またはTexmacs培地(Treg)に1×106/mLで再懸濁した。非組織培養処理24ウェルプレートは、レトロネクチンでコーティングしてからその後PBS中の2%ウシ血清アルブミンでブロックし、さらにPBSで2回洗浄することにより、予め調製した。IL-2の最終濃度は、Tconvについては300μ/mL、およびTregについては1000μ/mLとした。細胞を37℃で一晩インキュベートした後、上清を除去して新鮮な完全培地およびIL-2を補充した。培地は一日置きに取り替えた。
[実施例1C]
10日目に、ヒトHLA-DR4およびCD80またはCD86を形質導入したチャイニーズハムスター卵巣(CHO)細胞に、MBP111−129(LSRFSWGAEGQRPGFGYGG)(10μM/mL)を取り込ませた。懸濁液を標準的な組織培養条件で2時間インキュベートした後、放射線を照射し、洗浄してから、適当な濃度で再懸濁した。
[実施例2]
実施例1に記載した実験を、異なるドナーから得たT細胞を使用して繰り返した。
図3は、TCR形質導入T細胞の増殖率を示している。
図4は、共培養実験で採集された上清中のIL-2の濃度を示している。
[実施例3]
偽形質導入TregまたはTCRもしくはTCR+FOXP3を形質導入したTregを、7〜10日目に、Tregマーカー(FOXP3、CD25およびCTLA-4)の発現についてフローサイトメトリーにより解析した。
[実施例4]
実施例1Cに記載した通りに、CD80+CD86+DR4+CHO細胞にペプチドを取り込ませてから放射線を照射した後、0.1×106個の細胞/mLで再懸濁した。形質導入されたレスポンダーT細胞を、温PBS中37℃で3分間、CFSE細胞追跡色素で染色した後、等量の温FBSを添加してさらに3分間インキュベートした。
[実施例6A]
Thy1.1+CD4+CD25+またはCD45.1+CD4+CD25+Tregを、ビーズ選別によりHLA-DRB*0401トランスジェニックマウスのリンパ節および脾細胞から単離した。CD45.1+TregにTCRを形質導入し、またThy1.1+TregにTCR+マウスFOXP3を形質導入した。形質導入の1日後に、TCRまたはTCR+FOXP3形質導入細胞を、4Gy照射による条件付けを行ったHLA-DRB*0401トランスジェニック宿主に1:1の比で注入した。FACSプロットは、注入細胞のCD45.1:Thy1.1の比およびそれらの各FOXP3発現を示している。
[実施例6B]
脾細胞を、無関係なペプチドまたは10uMのMBPをパルスしたCD86+HLA-DR4+CHO細胞と共に4時間培養した。外因性FOXP3を発現するTregは、エフェクターサイトカイン産生の欠如により明示されるように、in vivoで7週間後もTregの機能性を保持していたが、外因性FOXP3を発現しないTregはエフェクターサイトカインを産生する能力を獲得した(図10)。
Claims (27)
- 制御性T細胞(Treg)にFOXP3ポリペプチドをコードするポリヌクレオチドを導入することを含む、該Tregが免疫応答を抑制する能力を増強するための方法。
- 以下(i)あるいは(ii)である、すなわち
(i)前記FOXP3ポリペプチドが、配列番号3もしくは4と少なくとも80%同一であるアミノ酸配列またはその機能性断片を含むか、あるいは
(ii)前記FOXP3ポリペプチドをコードする前記ポリヌクレオチドが、配列番号1もしくは2と少なくとも80%同一であるポリヌクレオチド配列またはその機能性断片を含む、
請求項1記載の方法。 - 前記のFOXP3をコードするポリヌクレオチドが、発現ベクターの連続した部分である、請求項1または2記載の方法。
- 外因性T細胞受容体(TCR)をコードするポリヌクレオチド、またはキメラ抗原受容体(CAR)をコードするポリヌクレオチドを、前記Tregに導入することをさらに含む、請求項1〜3のいずれか1項に記載の方法。
- 前記のFOXP3ポリペプチドをコードするポリヌクレオチド、および前記外因性TCRまたは前記CARをコードする前記ポリヌクレオチドが、単一発現ベクターにより提供される、請求項4記載の方法。
- 前記ベクターが、5’ FOXP3−X−TCR/CARの向きを有する核酸を含み、ここでXは内部自己切断配列である、請求項5記載の方法。
- 前記のFOXP3をコードするポリヌクレオチドをウイルスによる形質導入によって単離Tregに導入し、場合により前記のFOXP3をコードするポリヌクレオチドをレトロウイルスによる形質導入によって単離Tregに導入する、請求項1〜6のいずれか1項に記載の方法。
- 以下(a)および(b)、すなわち
(a)細胞集団からTregを単離すること、および
(b)該TregにおけるFOXP3発現を増大させること
を含む、請求項1〜7のいずれか1項に記載の方法。 - 前記細胞集団が、末梢血単核細胞(PBMC)を含むかまたはPMBCからなる、請求項8記載の方法。
- 前記Tregを単離することが、
CD4+T細胞を単離すること、および
該CD4+T細胞から前記Tregを単離すること
を含む、請求項8または9記載の方法。 - 前記Tregの前記単離が、免疫磁気ビーズまたは蛍光活性化細胞選別(FACS)を利用した選択を含む、請求項8〜10のいずれか1項に記載の方法。
- 前記Tregを、(i)CD4+CD25+CD127−および/またはCD4+CD25+CD127low細胞、(ii)CD4+CD25hiCD127−および/またはCD4+CD25+CD127low細胞について選択することにより単離する、請求項8〜11のいずれか1項に記載の方法。
- 前記TregをFOXP3+細胞について選択することにより単離し、好ましくは前記TregをCD4+CD25+FOXP3+ヘリオス+ニューロピリン1+細胞について選択することにより単離する、請求項8〜12のいずれか1項に記載の方法。
- 請求項1〜13のいずれか1項に記載の方法により取得可能であるかまたは取得する、遺伝子操作Treg。
- FOXP3ポリペプチドをコードする外因性ポリヌクレオチドを含み、かつ対応する非遺伝子操作Tregより高いFOXP3発現を示す、遺伝子操作Treg。
- 前記FOXP3ポリペプチドが、(i)配列番号3もしくは4と少なくとも80%同一であるアミノ酸配列またはその機能性断片を含むか、あるいは(ii)配列番号1もしくは2と少なくとも80%同一であるポリヌクレオチド配列またはその機能性断片によりコードされる、請求項15記載の遺伝子操作Treg。
- 前記のFOXP3をコードする外因性ポリヌクレオチドが、発現ベクターの連続した部分である、請求項16記載の遺伝子操作Treg。
- 外因性T細胞受容体(TCR)をコードするポリヌクレオチド、またはキメラ抗原受容体(CAR)をコードするポリヌクレオチドをさらに含む、請求項14〜17のいずれか1項に記載の遺伝子操作Treg。
- 前記のFOXP3ポリペプチドをコードするポリヌクレオチド、および前記外因性TCRまたは前記CARをコードする前記ポリヌクレオチドが、単一発現により提供される、請求項18記載の遺伝子操作Treg。
- 前記ベクターが、5’ FOXP3−X−TCR/CARの向きを有する核酸を含み、ここでXは内部自己切断配列である、請求項19記載の遺伝子操作Treg。
- 請求項14〜20のいずれか1項に記載の遺伝子操作Tregを含む、医薬組成物。
- 疾患の予防および/または治療に使用するための、請求項14〜20のいずれか1項に記載の遺伝子操作Treg、または請求項21記載の医薬組成物。
- 疾患の予防および/または治療のための薬剤の製造における、請求項14〜20のいずれか1項に記載の遺伝子操作Tregの使用。
- 対象に、請求項14〜21のいずれか1項に記載の遺伝子操作Tregまたは医薬組成物を投与することを含む、疾患の予防および/または治療の方法。
- 前記疾患が自己免疫疾患であり、好ましくは前記疾患が多発性硬化症である、請求項22記載の使用のための遺伝子操作Treg、もしくは使用のための医薬組成物、請求項23記載の遺伝子操作Tregの使用、または請求項24記載の方法。
- 前記疾患が移植片拒絶反応または移植片対宿主病である、疾患の予防および/または治療に使用するための、請求項13〜17のいずれか1項に記載の遺伝子操作Treg。
- 制御性T細胞(Treg)が免疫応答を抑制する能力を増強するための、FOXP3ポリペプチドをコードするポリヌクレオチドの使用。
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WO2019202322A1 (en) | 2019-10-24 |
US20210079425A1 (en) | 2021-03-18 |
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CN112334571B (zh) | 2024-06-25 |
SG11202010154UA (en) | 2020-11-27 |
KR20210003810A (ko) | 2021-01-12 |
JP7391038B2 (ja) | 2023-12-04 |
GB2587988A (en) | 2021-04-14 |
GB202300916D0 (en) | 2023-03-08 |
JP7436383B2 (ja) | 2024-02-21 |
JP2021520831A (ja) | 2021-08-26 |
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CA3098128A1 (en) | 2019-10-24 |
WO2019202323A1 (en) | 2019-10-24 |
US20210145884A1 (en) | 2021-05-20 |
GB202300872D0 (en) | 2023-03-08 |
JP2024026127A (ja) | 2024-02-28 |
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