JP2020525010A - 制御性免疫細胞を産生するための方法及びその使用 - Google Patents
制御性免疫細胞を産生するための方法及びその使用 Download PDFInfo
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Abstract
Description
「UTFCP1312WO.txt」という名前のファイル(Microsoft Windowsで測定)は2 KBであり、2018年6月22日に作成された配列リストは、電子提出により本明細書に提出され、参照により組み込まれる。
本発明は、一般に、医学及び免疫学の分野に関する。より詳細には、本発明が制御性B細胞及び制御性T細胞の産生並びにその使用に関する。
制御性T細胞(Treg)及び制御性B細胞(Breg)は、免疫応答を抑制し、自己免疫疾患に対して重要な役割を果たすことができ、そして移植寛容を提供することができる。末梢血は、これらの抑制性免疫細胞のわずかな割合しか含まないので、エクスビボでの増殖方法を用いて、免疫関連障害のインビボの治療又は予防のために十分な数の抑制性細胞を生成する。現在のTreg増殖に関するプロトコールはTCRライゲーションとIL−2(Heら、2016)を含んでおり、Bregの増殖方法としては、BCRライゲーションとCD40リガンド(Taitanoら、2016)を含んでいる。
本明細書で使用する場合、特定の成分に関して「本質的に含まない」は、本明細書では特定の成分のいずれも組成物に意図的に配合されておらず、かつ/又は汚染物質としてのみ又は微量で存在することを意味するために使用される。従って、組成物の意図しない汚染から生じる特定の成分の総量は0.05%をはるかに下回り、好ましくは0.01%を下回る。最も好ましいのは、標準的な分析方法で特定の成分の量を検出することができない組成物である。
本開示のいくつかの実施形態は、制御性B細胞(Breg)の単離及び増殖に関する。従って、高度に抑制的なBregの集団が本明細書中に開示される。BregはCD4+T細胞などのエフェクターT細胞の増殖を阻害し、エフェクターT細胞による炎症性サイトカイン(例えば、IFNγ及びTNFα)の産生を阻害し、インターロイキン−10(IL−10)を産生する能力によって特徴づけられる。
B細胞の単離された集団は、対象、特にヒト対象から得ることができる。B細胞は、特定の疾患又は状態を有することが疑われる対象、特定の疾患又は状態に対する素因を有することが疑われる対象、又は特定の疾患又は状態に対する治療を受けている対象などの、目的の対象から得ることができる。B細胞は、血液、臍帯血、脾臓、胸腺、リンパ節、及び骨髄を含むがこれらに限定されず、対象に存在する任意の位置から収集することができる。単離されたB細胞は直接分析されてもよいし、又はアッセイが行われるまで(例えば、凍結によって)保存されてもよい。
次いで、B細胞の単離された集団は、細胞の数を増加させるために、及び/又は制御性B細胞の抑制能力を増加させるために、増殖され得る。制御性B細胞集団の増殖は、制御性B細胞の集団を、制御性B細胞の数の増加を引き起こすのに十分な刺激組成物と接触させることによって達成することができる。これは、単離されたCD19+ B細胞を、マイトジェン、サイトカイン、増殖因子、又は、B細胞受容体又はフィーダー細胞に特異的に結合する抗体のような、抗体、と接触させることによって達成され得る。制御性B細胞は、少なくとも2倍、5倍、10倍、例えば少なくとも50倍、100倍、200倍、300倍、500倍、800倍、1000倍、10,000倍、又は100,000倍に増殖させることができる。
特定の実施形態において、単離されたB細胞は、CD40アゴニスト(例えば、可溶性CD40L)単独で、又は他の増殖剤と組み合わせて培養される。「CD40」という用語は、任意の、好ましくは天然に存在するCD40タンパク質を指す。CD40は腫瘍壊死因子α(TNF−α)受容体ファミリーと配列相同性を有する膜貫通糖タンパク質細胞表面受容体であり、当初は、モノクローナル抗体との連結の際にB細胞増殖を誘導するB細胞表面分子として同定されたものである。
単離されたB細胞の高度に抑制的なBregへの増殖はまた、限定されないが、B細胞を1つ以上のサイトカイン(例えば、限定されないが、IL−4、IL−21、IL−33、IL−2、IL−7、IL−10、IL−21、IL−35、及びBAFF)と接触させる工程を包含し得る。いくつかの態様において、B細胞は、最初にIL−4と接触され、次いで、IL−21の存在下で培養される。サイトカインは、約10〜500IU/mL、例えば約50〜200IU/mL、例えば約75〜150IU/mL、特に約100IU/mLの濃度で存在し得る。いくつかの態様において、IL−4は約1〜5ng/mL、例えば、2ng/mL、2.5ng/mL、3ng/mL、3.5ng/mL、4ng/mL、又は4.5ng/mL、又はその中で誘導可能な任意の範囲など、増殖培養物中に約0.1〜10ng/mLの濃度で存在する。特定の態様において、IL−21は約10〜250ng/mL(例えば、25〜50ng/mL、50〜75ng/mL、75〜125ng/mL、125〜150ng/mL、150〜175ng/mL、175〜225ng/mL、又は225〜250ng/mL)の濃度で増殖培養物中に存在する。
mTOR阻害剤は、ホスファチジルイノシトール−3キナーゼ(PI3K)関連キナーゼ(PIKK)のファミリーに属する、セリン/トレオニン特異的プロテインキナーゼである、mechanistic target of rapamycin(mTOR)を阻害する薬剤のクラスである。現在の方法で使用できる可能性がある典型的なmTOR阻害剤にはラパマイシン、エベロリムス、テムシロリムス、デフォロリムス、BGT226、SF1126、BEZ235、ゲダトリシブ、及びSF1101が含まれるが、これらに限定されない。いくつかの態様では、mTOR阻害剤はPP42(トルキニブとしても知られる)である。mTOR阻害剤は、約50〜500nM、例えば100〜400nm、特に150nM、200nM、250nM、300nM、又は350nMの濃度で存在し得る。
横紋筋肉腫におけるフォークヘッドとしても知られる、フォークヘッドボックスタンパク質O1(FOXO1)は、ヒトではFOXO1遺伝子によってコードされるタンパク質である。FOXO1はインスリンシグナル伝達による糖新生及びグリコーゲン分解の調節において重要な役割を果たす転写因子であり、また、前脂肪細胞が脂肪生成に関与する決定中心である。本発明の方法において使用され得る例示的なFOXO1阻害剤には、AS1842856及びAS1708727が含まれるが、これらに限定されない。FOXO1阻害剤は、約50〜500ng/mL、例えば100〜200ng/mL、200〜300ng/mL、300〜400ng/mL、又は400〜500ng/mLの濃度で存在し得る。
本発明の方法において使用され得るSTAT6阻害剤は、AS1517499及びレフルノミド(ALX−430−095)を含むが、これらに限定されない。STAT6のSH2ドメインを標的とする小分子ペプチド模倣物は、米国特許第6,426,331号及びPCT特許公開第WO2001/083517号に開示されており、両方とも参照により本明細書に組み込まれる。STAT6阻害剤は、約10〜250ng/mL、例えば20〜50ng/mL、50〜75ng/mL、75〜100ng/mL、100〜150ng/mL、150〜200ng/mL、又は200〜250ng/mLの濃度で存在し得る。
特定の実施形態において、B細胞は、CpGヌクレオチドで増殖される。CpGオリゴデオキシヌクレオチド(ODN)は、シトシン三リン酸デオキシヌクレオチドと、それに続く、免疫刺激剤として作用し得るグアニン三リン酸デオキシヌクレオチドとを含有する、短い一本鎖合成DNA分子である。CpGモチーフは、B細胞及び樹状細胞上で発現されるパターン認識受容体(PRR)Toll様受容体9(TLR9)によって認識される病原体関連分子パターン(PAMP)と考えられる。
A.T細胞の開始集団
T細胞の開始集団は、対象、特にヒト対象から単離され得る。T細胞の開始集団は同種異系サンプルのようなドナーサンプルから、又は細胞を受け入れる対象(すなわち、自己)から単離及び増殖され得る。T細胞の開始集団は、特定の疾患又は状態を有することが疑われる対象、特定の疾患又は状態に対する素因を有することが疑われる対象、又は特定の疾患又は状態に対する治療を受けている対象のような、目的の対象から得ることができる。T細胞の開始集団は、血液、臍帯血、脾臓、胸腺、リンパ節、及び骨髄を含むがこれらに限定されない、対象内に存在する任意の部位から収集することができる。T細胞の単離された開始集団は直接使用してもよいし、又は凍結などにより一定期間貯蔵されてもよい。
Tregsの増殖方法は、細胞をT細胞受容体(TCR)活性化因子(例えば、抗CD3抗体)、TCR共刺激因子(例えば、抗CD28抗体)、IL−2、及びmTOR阻害剤(例えば、ラパマイシン)と接触させることを含み得る。TCR活性化因子とTCR共刺激因子との組み合わせは、TCRライゲーションと呼ばれる。増殖培養は約8〜15日間、例えば、約10〜14日間、例えば、10、11、12、13、又は14日間であり得る。
Tregは、遺伝子操作されたTCR及び/又はキメラ抗原受容体(CAR)のような抗原受容体を発現するように遺伝子操作され得る。例えば、宿主細胞(例えば、自己又は同種異系T細胞)は、癌抗原に対して抗原特異性を有するT細胞受容体(TCR)を発現するように改変される。複数のCAR及び/又はTCR(例えば、異なる抗原に対する)が、T細胞に添加され得る。
いくつかの実施形態では、キメラ抗原受容体がa)細胞内シグナル伝達ドメイン、b)膜貫通ドメイン、及びc)抗原結合領域を含む細胞外ドメインを含む。
いくつかの実施形態では、遺伝子操作された抗原受容体が天然に存在するT細胞からクローニングされた組換えT細胞受容体(TCR)及び/又はTCRを含む。「T細胞受容体」又は「TCR」は可変鎖及びβ鎖(それぞれTCRα及びTCRβとしても知られる)又は可変γ及びδ鎖(それぞれTCRγ及びTCRδとしても知られる)を含み、MHC受容体に結合した抗原ペプチドに特異的に結合することができる分子を指す。いくつかの実施形態では、TCRはαβ形態である。
本開示のT細胞のCAR及び/又はTCRは、1つ以上の自殺遺伝子を含み得る。本明細書で使用される「自殺遺伝子」という用語は、殺傷のために細胞を選択的に標的化するために使用され得る遺伝子として定義される。例えば、自殺遺伝子はプロドラッグの投与時に、その宿主細胞を死滅させる化合物への遺伝子産物の移行をもたらし得る。使用され得る自殺遺伝子/プロドラッグの組み合わせの例は、単純ヘルペスウイルス−チミジンキナーゼ(HSV−tk)及びガンシクロビル、アシクロビル、又はFIAU;オキシドレダクターゼ及びシクロヘキシミド;シトシンデアミナーゼ及び5−フルオロシトシン;チミジンキナーゼチミジル酸キナーゼ(Tdk::Tmk)及びAZT;並びにデオキシシチジンキナーゼ及びシトシンアラビノシドである。
いくつかの実施形態において、本開示の細胞はグルココルチコイド受容体、TGFβ受容体(例えば、TGFβ−RII)、及び/又はCISHのような特定の遺伝子の改変された発現を有するように改変される。1つの実施形態において、細胞は、内因性TGFβを枯渇させるためのサイトカインシンクとして機能し得る、ドミナントネガティブTGFβ受容体II(TGFβRIIDN)を発現するように改変され得る。
本開示の特定の実施形態は、炎症性障害又は免疫介在性障害を処置又は予防するための、本明細書中に提供されるBreg集団及び/又はTreg集団の使用のための方法に関する。この方法は治療有効量のBreg及び/又はTregを対象に投与することを含み、それによって、対象における炎症性障害又は免疫介在性障害を処置又は予防する。
いくつかの実施形態において、例えば、制御性免疫細胞の産生のための1つ以上の培地及び成分を含み得るキットが提供される。そのような製剤は、B細胞又はT細胞と組み合わせるのに適した形態で、因子のカクテルを含んでもよい。試薬系は、必要に応じて、水性媒体又は凍結乾燥形態のいずれかで包装され得る。キットの容器手段は一般に、少なくとも1つのバイアル、試験管、フラスコ、瓶、注射器又は他の容器を含み、その中に、構成要素が配置され得、そして好ましくは、適切に分注される。キット中に2つ以上の成分が存在する場合、キットはまた、一般に、第2、第3、又は他の追加の容器を含み、その中に追加の成分が別々に配置され得る。しかし、成分のさまざまな組み合わせを1つのバイアル中に含めてもよい。キットの成分は、乾燥粉末として提供することができる。試薬及び/又は成分が乾燥粉末として提供される場合には、粉末を適した溶媒の添加によって再構成することができる。溶媒が別の容器手段で提供されることも想定される。キットはまた、典型的には、商業的販売のためにキット構成要素を密閉して収容するための手段を含む。このような容器は、所望のバイアルが保持される射出成形又はブロー成形プラスチック容器を含み得る。キットはまた、使用説明書(例えば、印刷又は電子フォーマット(例えば、デジタルフォーマット))を含み得る。
以下の実施例は本発明の好ましい具体例を示すために含める。以下の実施例において開示される手法が本発明の実施において十分に機能することが発明者らによって見いだされた技術を代表しており、そのため、本発明の実践において十分に機能することが当業者には理解されるはずである。しかしながら、当業者であれば、本発明の開示を考慮して、開示されかつ同様の結果を得られる特定の実施例において、本発明の精神及び範囲から逸脱することなく、多くの変更が可能であることは理解できるのであろう。
臍帯血又は末梢血から単離した休止期CD4+T細胞においてCD9の発現を評価した。いずれのT細胞集団もCD4+CD9+ T細胞の割合はわずかであった。しかしながら、臍帯血から単離されたT細胞は9.61%であり、末梢血から単離されたT細胞が6.40%であるのと比較して、CD4+CD9+ T細胞の割合が高かった(図1A)。IL−2、CD3/CD28ビーズ、及びラパマイシンでCD4+T細胞を増殖させた後、TregのCD9発現を分析した。臍帯血から増殖させたTregは、末梢血から増殖させたTreg(25.6%)と比較して、CD4+CD9+ T細胞の割合が高い(54.5%)ことが改めて見出された(図1B)。
IFNγ、TNFαのレベル、及びCFSE標識CD4+ T細胞の増殖を測定することにより、種々の方法により増殖させた制御性B細胞の抑制機能を分析した。まず、血液試料からB細胞を単離する。臍帯血又は末梢血を採取し、フィコール分離を行う。次いで、細胞を、CD19、CD5、CD1d、及びaqua live/dead dyeについて染色する。細胞を、暗所、室温で15〜20分間、モノクローナル抗体の各々とともにインキュベートする。次に、2mLの溶解緩衝液(BD Biosciences)を添加し、細胞を室温で3〜5インキュベートする。次いで、T細胞を1500rpmで5分間遠心分離し、上清を廃棄し、2mLのPBSを添加し、細胞を1500rpmで5分間再び遠心分離した後、上清を廃棄する。次に、選別を行い、CD19+又はCD19+CD1dhiCD5+細胞を選択する。増殖はまた、全B細胞から行ってもよい。細胞を計数し、適切な細胞培養プレート又はフラスコを選択する。
以下の参考文献は、本明細書中に記載したものを補足する例示的な手順上又はその他の詳細を提供する範囲で、参照として明確に本明細書に組み入れられる。
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Claims (66)
- CD9+制御性T細胞(Treg)を増殖させるためのインビトロの方法:
(a)CD4+T細胞の集団を得ること;
(b)Treg増殖条件下で前記CD4+ T細胞の集団を培養し、それによって増殖したTregを産生すること;及び
(c)前記増殖したTregからCD9+細胞を選択し、それによってCD9+ Tregの集団を得ること。 - CD4+T細胞が、CD4+CD25+T細胞としてさらに定義される、請求項1記載の方法。
- 前記選択がポジティブ選択としてさらに定義される、請求項1又は2に記載の方法。
- 前記選択が、ネガティブ選択としてさらに定義される、請求項1又は2に記載の方法。
- 前記選択が、CD9+ Tregのためのソーティングを含む、請求項1又は2に記載の方法。
- ソーティングが、抗体ビーズ選択、蛍光関連細胞選別(FACS)、又は磁気活性化細胞選別(MACS)としてさらに定義される、請求項5に記載の方法。
- 前記Treg増殖条件が、TCRライゲーション、IL−2、及びmTOR阻害剤の存在下でCD4+T細胞を培養することを含む、請求項1記載の方法。
- 前記TCRライゲーションが、抗CD3抗体及び抗CD28抗体を含む、請求項7に記載の方法。
- 前記mTOR阻害剤が、ラパマイシンである請求項7に記載の方法。
- 前記Treg増殖条件が、腫瘍壊死因子受容体2(TNFR2)アゴニスト、全トランスレチノイン酸(ATRA)、アデノシン受容体(A2AR)、及び/又はA2ARアゴニストの存在下でCD4+ T細胞を培養することをさらに含む、請求項7〜9のいずれか一項に記載の方法。
- 前記培養が10〜14日間である、請求項1〜9のいずれか一項に記載の方法。
- 前記CD4+T細胞の集団を得ることが、幹細胞、骨髄、末梢血、又は臍帯血からT細胞を単離することを含む、請求項1記載の方法。
- 前記CD4+T細胞の集団を得ることが、プールされた臍帯血からT細胞を単離することを含む、請求項1記載の方法。
- 前記単離が、抗体ビーズ選択又は蛍光関連細胞選別(FACS)を行うことを含む、請求項12又は13に記載の方法。
- 前記CD4+T細胞又はTregが、グルココルチコイド受容体の発現を減少させるか、又は本質的に全く発現しないように操作される、請求項1に記載の方法。
- 前記CD4+T細胞又はTregが、1以上のガイドRNA及びCas9酵素を用いて操作される、請求項15に記載の方法。
- 前記CD4+T細胞又はTregが、キメラ抗原受容体(CAR)及び/又はT細胞受容体(TCR)を発現するように操作される、請求項1記載の方法。
- 前記CD4+T細胞又はTregが、自殺遺伝子を発現するように操作される、請求項1記載の方法。
- 前記自殺遺伝子が、CD20、CD52、EGFRv3、又は誘導性カスパーゼ9である、請求項18に記載の方法。
- 請求項1〜19のいずれか一項に記載の方法によって産生される、CD9+制御性T細胞の集団。
- 請求項20に記載のCD9+制御性T細胞の集団及び薬学的に許容可能な担体を含む、医薬組成物。
- 抑制性制御性B細胞(Breg)を増殖させるインビトロの方法であって、以下を含む:
(a)B細胞の集団を得ること;
(b)IL−4、CpGオリゴデオキシヌクレオチド(ODN)、及びCD40リガンド(CD40L)の存在下で前記B細胞を培養すること;並びに
(c)IL−21、CD40L、並びに、FOXO1阻害剤、mTOR阻害剤、及びSTAT6阻害剤からなる群より選択される少なくとも1つの阻害剤、の存在下で、前記B細胞をさらに増殖させ、それによって抑制性Bregを産生すること。 - 前記工程(b)及び/又は工程(c)が、1つ以上の追加のサイトカインをさらに含む、請求項22に記載の方法。
- 前記追加のサイトカインが、IL−33である、請求項23に記載の方法。
- 前記工程(b)の培養が、FOXO1阻害剤、mTOR阻害剤、及び/又はSTAT6阻害剤の存在をさらに含む、請求項22又は23に記載の方法。
- さらに、前記増殖工程の前に前記B細胞を洗浄することを含む、請求項22に記載の方法。
- CD40Lが可溶性CD40L(sCD40L)である、請求項22に記載の方法。
- 前記FOXO1阻害剤が、AS1842856又はAS1708727である、請求項22に記載の方法。
- 前記FOXO1阻害剤が、AS1842856である、請求項22に記載の方法。
- mTOR阻害剤が、トルキニブ、ラパマイシン、エベロリムス、テムシロリムス、デフォロリムス、BGT226、SF1126、BEZ235、ゲダトリシブ、又はSF1101である、請求項22記載の方法。
- mTOR阻害剤が、トルキニブである、請求項22記載の方法。
- STAT6阻害剤が、AS1517499又はレフルノミドである、請求項22に記載の方法。
- STAT6阻害剤が、AS1517499である、請求項22に記載の方法。
- さらにBregをanti−miR−155と接触させることを含む、請求項22に記載の方法。
- B細胞の集団を得ることが、血液サンプルからB細胞を単離することを含む、請求項22に記載の方法。
- 前記単離が、抗体ビーズ選択又は蛍光関連細胞選別(FACS)を行うことを含む、請求項35に記載の方法。
- 前記血液サンプルが末梢血又は臍帯血である、請求項35に記載の方法。
- 前記血液サンプルが臍帯血(CB)である、請求項35に記載の方法。
- 前記臍帯血が、2つ以上の個々の臍帯血ユニットからプールされる、請求項38に記載の方法。
- 前記臍帯血が、3、4、又は5個の個々の臍帯血単位からプールされる、請求項38に記載の方法。
- 前記B細胞の集団が、CB単核細胞(CBMC)である、請求項22に記載の方法。
- 前記B細胞の集団が、CD5+CD1dhi B細胞である、請求項22に記載の方法。
- 前記B細胞の集団が、全B細胞である、請求項22に記載の方法。
- 前記Bregが、CD4+T細胞の増殖を抑制する能力を有する、請求項22に記載の方法。
- 前記Bregが、ヒトBregである、請求項22に記載の方法。
- 前記培養が、1〜5日間である、請求項22に記載の方法。
- 前記増殖が、5〜10日間である、請求項22に記載の方法。
- 請求項22〜47のいずれか一項に記載の方法に従って産生された制御性B細胞の集団。
- 請求項48に記載の制御性B細胞の集団及び薬学的に許容可能な担体を含む、医薬組成物。
- 治療有効量の請求項20の抑制性Treg及び/又は請求項48の抑制性Bregを対象に投与することを含む、対象における免疫障害を治療する方法。
- 前記対象がグルココルチコイド治療を受けたか、又は現在受けている、請求項50に記載の方法。
- 前記免疫障害が、炎症、移植片対宿主病、移植片拒絶、又は自己免疫疾患である、請求項50に記載の方法。
- 前記Treg及び/又はBregが、同種異系である、請求項50に記載の方法。
- 前記Treg及び/又はBregが、自己由来である、請求項50に記載の方法。
- 前記免疫障害が、移植片対宿主病(GVHD)である、請求項50に記載の方法。
- 前記GVHDが慢性GVHD(cGVHD)である、請求項55に記載の方法。
- 前記対象が、臍帯血移植(CBT)を以前に投与されている、請求項56に記載の方法。
- 前記Treg及び/又はBregが、前記CBTと同時に投与される、請求項57に記載の方法。
- 前記Treg及び/又はBregが、前記CBTの前又は後に投与される、請求項57に記載の方法。
- 前記免疫障害が移植拒絶であり、移植片が臓器移植片、骨髄又は他の細胞移植片、複合組織移植片、又は皮膚移植片である、請求項50に記載の方法。
- 前記免疫障害が、多発性硬化症、炎症性腸疾患、関節リウマチ、I型糖尿病、全身性エリテマトーデス、接触過敏症、喘息又はシェーグレン症候群である、請求項50に記載の方法。
- 対象がヒトである、請求項50に記載の方法。
- さらに少なくとも第2の治療剤を投与することを含む、請求項50に記載の方法。
- 前記少なくとも第2の治療剤が、治療有効量の免疫調節剤又は免疫抑制剤である、請求項63に記載の方法。
- 前記免疫抑制剤が、カルシニューリン阻害剤、mTOR阻害剤、抗体、化学療法剤照射、ケモカイン、インターロイキン、又はケモカイン若しくはインターロイキンの阻害剤である、請求項64に記載の方法。
- Treg、Breg、及び/又は少なくとも第2の治療剤が、静脈内、腹腔内、気管内、腫瘍内、筋肉内、内視鏡的、病変内、経皮的、皮下、局所的に、又は直接注射もしくは潅流によって投与される、請求項63に記載の方法。
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WO2024071010A1 (ja) * | 2022-09-26 | 2024-04-04 | 国立大学法人京都大学 | T細胞の製造方法 |
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