JP7454617B2 - 同種異系t細胞を用いた自己免疫疾患の処置方法 - Google Patents
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Description
本出願は、2016年5月25日に出願された米国特許仮出願第62/341,360号、2016年7月7日に出願された米国特許仮出願第62/359,326号、及び2017年4月20日に出願された米国特許仮出願第62/487,814号に対する優先権の利益を主張するものであり、その各々は、全体が参照により本明細書に組み込まれる。
例えば、本明細書に記載される1つ以上のEBVエピトープを認識する同種異系CTLを用いて対象における自己免疫障害(例えば、MS、SAD及び/又はIBD)を処置する方法が本明細書で提供される。一部の実施形態において、本方法はさらに、細胞バンクから同種異系CTLを選択することを含む。一部の実施形態において、本方法はさらに、同種異系CTLを作製することを含む。
便宜上、本明細書、実施例及び添付の特許請求の範囲で使用される特定の用語をここに集める。
一部の実施形態では、クラスI MHC上に提示されるEBVエピトープを含むペプチドに特異的に結合するTCRを発現する同種異系CTLを用いて自己免疫障害(例えばMS、SAD及び/又はIBD)を処置する方法が本明細書において提供される。一部の実施形態では、例えば、CTLを含む試料(すなわち、PBMC試料)を、本明細書に記載されているEBVエピトープの1つ以上を提示する抗原提示細胞(APC)(例えば、クラスI MHC複合体上にEBVエピトープを含む本明細書に記載されているペプチドを提示するAPC)とともにインキュベートすることによって、このような同種異系CTLを生成する方法が本明細書において提供される。
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181 liwmyyhgqr hsdehhhdds lphpqqatdd ssnhsdsnsn egrhhllvsg agdapplcsq
241 nlgapgggpd ngpqdpdntd dngpqdpdnt ddngphdplp qdpdntddng pqdpdntddn
301 gphdplphnp sdsagndggp pnlteevenk ggdrgppsmt dggggdphlp tlllgtsgsg
361 gddddphgpv qlsyyd
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241 rltvcggimf lacvlvlivd avlqlspllg avtvvsmtll llafvlwlss pgglgtlgaa
301 lltlaaalal laslilgtln lttmfllmll wtlvvllics scsscpltki llarlflyal
361 allllasali aggsilqtnf kslsstefip nlfcmllliv agilfilail tewgsgnrty
421 gpvfmclggl ltmvagavwl tvmtntllsa wiltagflif ligfalfgvi rccryccyyc
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121 talaipqcrl tplsrlpfgm apgpgpqpgp lresivcyfm vflqthifae vlkdaikdlv
181 mtkpaptcni kvtvcsfddg vdlppwfppm vegaaaegdd gddgdeggdg degeegqe
クラスI MHC上に提示されるEBVペプチドに特異的に結合するT細胞受容体を発現する同種異系CTLを対象に投与することにより、自己免疫疾患(例えばMS、SAD、IBD)を処置する方法が本明細書において提供される。一部の実施形態では、CTLは、細胞バンクからのものである。一部の実施形態では、MHCはクラスI MHCである。一部の実施形態では、クラスII MHCは、HLA-DMA、HLA-DOA、HLA-DPA、HLA-DQA又はHLA-DRAであるα鎖ポリペプチドを有する。一部の実施形態では、クラスII MHCは、HLA-DMB、HLA-DOB、HLA-DPB、HLA-DQB又はHLA-DRBであるβ鎖ポリペプチドを有する。一部の実施形態では、CTLは、対象に投与される前に細胞ライブラリ又はバンクに保存される。
一部の実施形態では、本明細書において提供される同種異系CTLを対象に投与することによって、対象における自己免疫障害を処置する方法が、本明細書において提供される。一部の実施形態において、同種異系CTLは、細胞バンク(例えば予め生成された第三者ドナー由来のエピトープ特異的CTLのバンク)から選択される。
[実施例1]
エピトープ特異的CTLの第三者ドナー由来のバンクの生成
エピトープ特異的CTLの第三者ドナー由来のバンクを、十分な規模、患者のHLA適合能力の広範さ、及び標的に限定(拘束)された活性のCTL集団を生成するために、ドナーのリンパ球材料の標的化同定法を介して生成する。ドナー材料の同定は、ドナー/材料の遺伝子アノテーション、又は、以下の材料から得られた産生物の品質特性の任意の組合せにより容易になる:
(a)ドナーHLA対立遺伝子 - 特異的HLA対立遺伝子を、標的とした患者集団及び/又は刺激するペプチド配列に含有されるコグネートエピトープを最も広く網羅する能力に基づく、CTL生成用の入力材料として優先し、特に収集し得る。
(b)CTL刺激プロトコールにしたがう効果的な細胞傷害性能力を拡大及び/又は産生する、ドナー材料の試験アリコートの能力。
(c)細胞傷害性試験により、又は脱顆粒、サイトカイン放出、シグナリングアッセイ若しくは標的細胞におけるアポトーシスの他のマーカー及び/若しくはCTLコンパートメントのエピトープ特異的刺激により示される応答の機能的特性解析によって示される、刺激されたドナー材料のエピトープ/HLA拘束性。
(d)共刺激分子の発現、枯渇マーカー、分化マーカー、及び/又は他の得られた産生物の特性に関する試験アリコートにおけるCTL産生物の得られた表現型プロファイル。
エピトープ特異的CTLのバンク由来の第三者ドナーの細胞株からのCTLの選択
バンキングされた産生物に対する患者に特異的な要求を、患者の遺伝的なバックグラウンド又は疾患のバックグラウンドと材料特性を規則正しく優先させて統合することを通じて達成し得る。そのような階層的考察のシーケンスを、これらの入力及び適合するロットの出力を統合するように設計されたアルゴリズムを使用することを通じて達成し得る。このアルゴリズムは、HLA拘束性に基づき得、又は複数のロットが利用できる場合、それぞれを適切に重み付けし、追加のロット並びに/若しくは患者に特異的な特性及びアノテーションを含む一連の追加入力と組み合わせてHLA拘束性により適合させることに基づき得、それにより最も効果的な、患者に特異的なロット、若しくは有害事象の可能性を最も軽減するものを選択する。以下に、そのような要求アルゴリズムに対する代表的な形式を提供する。
(1)細胞株を患者と適合させるために、細胞株及び対象は、高分解能で2つ以上のHLA遺伝子座を共有し、対象の、又は特に、既知の場合、患者のEBV+B細胞のコンパートメントの少なくとも1つのHLA遺伝子座が、所定のCTL細胞株のHLA拘束性に適合する必要がある。
(2)十分な細胞の用量の存在を確認するための、最小Xサイクルで、1用量当たりのY CTL/kg実体重(サイクル(X)当たりのn用量、Xサイクル=nX総用量、したがって利用できる最小用量は少なくともnXY×106CTL/kg実体重の必要がある)で投与する、選択された細胞株からの十分な細胞の存在。最小用量は、患者又は疾患の特性に応じて変化し得る。
(3)ただ1つの細胞株が事前に議論された基準にしたがって同定される場合、その細胞株を使用すべきであり、さらなる選択基準を課すことはない。しかし、いくつかの場合、所定の対象に対して、CTLライブラリーにおいて、HLA適合(1)及び最小用量の要件(2)を満たす1超の細胞株が存在し得る。これらのCTL細胞株の中で、いくつかは、材料ドナーの遺伝子型において拘束性であるか又は限定されているかのいずれかの追加のHLA対立遺伝子の特性を有し得、これは、臨床的に又は間接的なレベルの証拠のいずれかで、有効性が減少する又は有害事象への関連が増すこととして定義される臨床成績の低下に関連し得る。そうである場合、この追加のHLA対立遺伝子の欠如について細胞株を選択する。
(3a)処置された少なくとも4名の患者の中で先の応答率が特定のカットオフ値より大きい細胞株の中で、ライブラリーにおいて利用できる、存在する最大の細胞の用量を選択する。ドナーの出発材料を後続のバッチのために使用し、第一のバッチと同じHLA拘束性が得られた場合、同じHLA拘束性を共有する後続のバッチに対する応答率を、同様に効果的であると仮定することができる。
(3b)(3a)の基準を満たす細胞株が存在しない場合、(1)及び(2)の要件を満たすCTL細胞株の中で、最も高い応答率及び少なくとも1つの先の応答を有する株を選択する。
(3c)先の応答率を有する細胞株が存在しない場合、そのHLA拘束性が事前に応答を引き出すことが示されている細胞株の中から、HLA拘束性によるとどの細胞株が最も高い先の応答を有する対象(又は対象の疾患)と共有したかを優先して選択する。
(3d)最終的に、先の要件を満たすことができない場合、応答が不十分なことが知られている、又は臨床成績の低下がより優勢である、若しくはそれと潜在的に関連したHLA拘束性を回避している株を選択する。
第三者ドナー由来のCTLを使用するMSの処置
再発寛解型、原発性進行型及び続発性進行型のMSの患者を、EBNA1抗原、LMP1抗原及びLMP2抗原を提示するB細胞及び血漿細胞に対して細胞傷害性を呈する第三者同種異系標的化EBV-CTLで処置する。患者は、2×10^7細胞/m2の用量で、Q2週間隔での(即ち、第1日、第15日、第29日及び第43日に)静脈内投与で、標的化EBV-CTLの投与を4回受ける。再発事象、連続ガドリニウム増強脳MRI、及び連続腰椎穿刺について、患者を評価して、脳脊髄液IgGレベル及びオリゴクローナルバンドの発生率を測定する。総合障害度評価尺度(EDSS)を行って、障害の進行を特徴付ける。併用薬及び有害事象を収集して、処置の安全特性を特徴付ける。以下は、処置の有効性の指標である:
1)同様の患者集団における既存対照と比較する場合、RRMS患者の月に一度の来院時にMRI造影で観察される、新しいガドリニウム増強病変の著しい減少。
2)同様の患者集団における既存対照と比較する場合、月に一度の来院時での臨床再発年率の著しい減少。
3)原発性進行型MS(PPMS)患者、続発性進行型MS(SPMS)患者、及び再発寛解型MS(RRMS)患者におけるベースラインと比較する場合、CSF IgGレベルの著しい低減。
4)原発性進行型、続発性進行型、及び再発寛解型のMS患者の30パーセントで、ベースライン時に存在しているオリゴクローナルバンドが解消される。
5)原発性進行型MS(PPMS)患者、続発性進行型MS(SPMS)患者、及び再発寛解型MS(RRMS)患者における、6か月及び12か月でのEDSSスコアの軽度から中程度の改善。
6)RRMS患者の50%、PPMS患者の30%、及びSPMS患者の25%において、運動強度で起こる著しい改善。
7)RRMS患者の80%は、既存対照の65%が示すのに対して、1年での疾患活動性の証拠を示さない。
第三者ドナー由来のCTL(ATA188)を使用するMSの処置
再発寛解型、原発性進行型及び続発性進行型のMSの患者を、第三者ドナー由来のCTLの養子免疫伝達で処置する。同種異系潜伏-2(latency-2)EBV標的化細胞傷害性Tリンパ球(同種異系L2 EBV CTL)、又はATA188は、潜伏膜タンパク質1(LMP1)、LMP2及びEBNA1を含むEBVタンパク質抗原に特異的な、HLA適合の、インビトロ拡大増殖された抗原特異的T細胞である。健康なEBV血清陽性ドナーの末梢血単核球細胞(PBMC)から、ATA188を産生する。一部のこれらのドナー細胞は、免疫療法用のT細胞となり、一部は、T細胞を刺激するために使用する抗原提示細胞(APC)である。ポリペプチドタンパク質及びトランケートEBNA1タンパク質(AdE1-LMPpoly)を発現する導入遺伝子をコードする、新規の組換え複製欠損アデノウイルスで、APCに形質導入を行う。ポリエピトープタンパク質は、「一連のビーズ」としてのLMP1及びLMP2からの複数のHLAクラスI拘束性CD8+T細胞エピトープを含む。トランケートEBNA1タンパク質は、このタンパク質の翻訳及び内在性のプロセシングを阻害するグリシン-アラニン反復配列を除外し、CD8+及びCD4+T細胞エピトープを維持する。前臨床試験及び臨床試験は、これらのLMP及びEBNA1発現APCが、インターロイキン-2(IL-2)の存在下で、ヒトドナーからの抗原特異的T細胞の急速な拡大増殖を誘導するのに効果が高いことを示している。得られる細胞産生物、ATA188を凍結保存し、細胞傷害性能力を有しHLA拘束性であり且つアデノウイルスの感染性がないことを確認する。
患者は2サイクルの処置を受け、各サイクルは、15日間の処置期間(3回の注入で、それぞれをおよそ7日間あけて、第1日、第8日[±2日]及び第15日[±2日]に)からなる。サイクル1の3回目の注入後、対象は、およそ週に一度の来院による20日間の観察期間に入り、サイクル2の3回目の注入後、対象は、11か月間の月に一度(28±5日毎)の来院による追跡調査期間に入る。同時に、対象を、ATA188の最初の投薬後の少なくとも1年間、観察する。
以下は、処置の有効性の指標である:
1)脳MRIスキャンでのGd増強病変及び新しい又は拡大するT2病変の数のベースラインからの変化。
2)臨床再発年率の減少。
3)原発性進行型MS(PPMS)患者、続発性進行型MS(SPMS)患者、及び再発寛解型MS(RRMS)患者における、EDSSスコアの軽度から中程度の改善。
最近の疾患活動性を有する最大42名のRRMSの対象及び6名のSPMSの対象を、6~10の試験機関に登録する。DLTが試験中に起こらない場合、合計で36名の対象を登録する(RRMSの30名及びSPMSの6名)。
1.以下の基準の1つを満たすMS歴
- MSの診断に対する2010年改訂McDonald基準により定義される、RRMS
又は
- インフォームドコンセントを実施する前の年に再発歴がなく、登録の少なくとも1年前に診断された、SPMS
2.陽性のEBV血清学的値
3.適切な部分HLA適合及び拘束性ATA188の利用可能性
4.年齢が18~45歳の男女
5.3.0~6.5のEDSSスコア
6.文書によるインフォームドコンセントを実施する意図及び能力
1.プロトコール準拠性を限定する、又は許容できないリスクに対象を曝露する、感染などの同時に重篤で制御されていない又は解消されていない健康状態
2.ヒト免疫不全ウイルス(HIV)に対する、陽性の血清学的値及び/又は核酸試験(NAT)
3.活性B型肝炎ウイルス(HBV)感染又はHBVのキャリア状態を示す、血清学的値及び/又はNAT(注:以前のHBV感染を示すがHBV感染が除去されている場合のHBVに対する陽性の血清学的値は除外基準ではない)
4.活性C型肝炎ウイルス(HCV)感染を示す、血清学的値及び/又はNAT
5.梅毒又はヒトT細胞白血病ウイルスI/II(HTLV)に対する、陽性の血清学的値
6.重大な非悪性疾患(例えば、重症な心機能障害又は呼吸機能障害)
7.本試験に参加する能力を損ない得る、制御されていない精神疾患、制御されていないうつ病若しくは自殺危険、物質依存症、又は任意の他の精神学上の状態
8.全血球数、腎機能又は肝機能の臨床的に重大な異常:
a.総ビリルビン(TBILI)>1.5×正常値の上限(ULN、対象が実証されているジルベール疾患を有していない限り)、アスパラギン酸アミノトランスフェラーゼ(AST)又はアラニンアミノトランスフェラーゼ(ALT)>3.0×ULNを含む、肝機能検査値の上昇
b.(Cockcroft-Gaultの式を使用して)クレアチニン>1.5×ULN及びクレアチニンクリアランス推定値<60mL/分の両方である対象
c.ヘモグロビン<10g/dL、血小板<100×109/L、好中球絶対数<1.5×109/L
9.アレルギー、又は、任意の金属片若しくは異物(例えば、動脈瘤クリップ、ペースメーカー、電子インプラント、シャント)を含む、強いパルス勾配静磁場に対して反応する任意の物体など、MRI及び/又はGdの禁忌
10.処置が成功した非黒色腫性皮膚がん又は子宮頚部上皮内癌を除く、12か月以内の再発の可能性が5%以上である過去のがん
11.以下の免疫調節療法(副腎皮質ステロイドの短期コースを除く):
a.B細胞枯渇剤での任意の先の処置
b.アレムツズマブでの任意の先の処置
c.インフォームドコンセントの実施から4週間以内の、酢酸グラチラマー又はIFNβでの処置
d.インフォームドコンセントの実施から4週間以内の、フマル酸ジメチルでの処置
e.インフォームドコンセントの実施から2ヶ月以内の、フィンゴリモドでの処置
f.インフォームドコンセントの実施から6ヶ月以内の、ナタリズマブ、メトトレキセート、アザチオプリン又はシクロスポリンでの処置
g.患者がコレスチラミンでの急速なクリアランスを完了していない限り、インフォームドコンセントの実施から12ヶ月以内の、テリフルノミドでの処置
h.インフォームドコンセントの実施から、又は、研究者により決定されてから12ヶ月以内の、ミトキサントロン、シクロホスファミド、クラドリビン、リツキシマブ、若しくは任意の他の免疫抑制若しくは細胞傷害性療法(ステロイドを除く)での、これらの処置から残留免疫抑制を有するための処置
12.インフォームドコンセントの実施する前の4週間以内の、抗胸腺細胞グロブリン又は同様の抗T細胞抗体療法
13.ATA188での処置を受けている間、及び最後の投与後3か月間、効果が高い避妊方法(即ち、正確かつ一貫して使用する場合、妊娠は年に1%未満という結果となるもの)、例えば、インプラント、注射剤、混合経口避妊剤、いくつかの子宮内避妊デバイス、禁欲、又は精管切除したパートナーを使用することを望まない妊娠可能な女性
又は
ATA188での処置を受けている間、及び最後の投与後3か月間、効果が高い避妊手段を使用することを望まず、及び/又は精液の提供を断つことを望まない、妊娠可能な女性パートナーを有する男性
14.授乳中の女性
15.妊娠
16.試験手順に応じることができないこと
17.EBV T細胞療法での先の処置
解析集団
本試験に登録され、任意の試験産生物を受ける対象全員を、有効性及び安全性の集団に含む。有効性集団は、主要な有効性解析、並びに体内動態、人口統計、及びベースラインの疾患の特性の全ての解析のためのものである。
記述統計を有効性のエンドポイントに対して実施し、さらに、連続する有効性のエンドポイントを、回帰法を使用して解析する。
安全性評価は、全ての関連するAE及び関連のないAEを含む。全てのAEを、医薬品規制用語集を使用してマッピングし、CTCAEバージョン4.03にしたがってグレード決定する。AEが報告された対象の数及び百分率、重篤対軽度、並びに研究者により報告された関連性(関連のない、関連する可能性がある、関連する)によりAEをまとめる。AEの種類及び頻度をまとめるために、記述統計を使用する。
健康なドナーからのCTLによりエフェクター機能が改善することを示す
健康なEBV血清陽性ドナー(NMDPドナー)又はMS患者から、末梢血単核球細胞(PBMC)を得た。これらのドナー細胞の各サンプルの一部を、拡大増殖させたCTLの供給源として使用し、一部を、CTLを刺激するために使用した抗原提示細胞(APC)の供給源として使用した。ポリペプチドタンパク質及びトランケートEBNA1タンパク質(AdE1-LMPpoly)を発現する導入遺伝子をコードする、組換え複製欠損アデノウイルスで、APCに形質導入を行った。ポリエピトープタンパク質は、「一連のビーズ」としてのLMP1及びLMP2からの複数のHLAクラスI拘束性CD8+T細胞エピトープを含んだ。トランケートEBNA1タンパク質は、このタンパク質の翻訳及び内在性のプロセシングを阻害するグリシン-アラニン反復配列を除外したが、CD8+及びCD4+T細胞エピトープを維持した。ドナー細胞のサンプルのCTL部分を、調製したAPCとともに共培養して、EBVエピトープに特異的なサンプルにおいてCTLを拡大増殖させ、刺激した。産生物を含むCTLの刺激及び生成に続き、CTLバッチをFACによりエフェクター機能について試験した。図1から分かるように、健康なドナーから生成されるCTL産生物は、MS患者から生成されるCTL産生物と比較して、インターフェロンγ(IFNg)発現及びCD8+である著しく高い百分率の生存可能なリンパ球であった(マンホイットニーp値0.0002)。これらのデータは、健康なドナーを同種異系移送のためのCTLの供給源として使用する場合、MS患者を自家移送のためのCTLの供給源として使用する場合と比較して、より高い割合のエフェクターCD8 T細胞及び機能性IFNg+CTLを有するより頑強なCTL産生物を生成することを示す。
本発明は、例えば以下の実施形態を包含する:
[実施形態1]対象において自己免疫疾患を処置又は予防する方法であって、クラスI MHC上に提示されるEBVペプチドと特異的に結合するT細胞受容体を発現する同種異系細胞傷害性T細胞(CTL)を対象に投与することを含む方法。
[実施形態2]クラスI MHCが、対象に存在するHLA対立遺伝子によってコードされる、実施形態1に記載の方法。
[実施形態3]自己免疫疾患が多発性硬化症(MS)である、実施形態1又は2に記載の方法。[実施形態4]自己免疫疾患が関節リウマチ(RA)である、実施形態1又は2に記載の方法。[実施形態5]同種異系CTLが細胞バンクから得られる、実施形態1から4のいずれかに記載の方法。
[実施形態6]対象において自己免疫疾患を処置又は予防する方法であって、
(a)クラスI MHC上に提示されるEBVペプチドと特異的に結合するT細胞受容体を発現する同種異系細胞傷害性T細胞(CTL)を細胞バンクから選択すること、
(b)対象に同種異系CTLを投与すること
を含む方法。
[実施形態7]クラスI MHCが、対象に存在するHLA対立遺伝子によってコードされる、実施形態6に記載の方法。
[実施形態8]自己免疫疾患が多発性硬化症(MS)又は関節リウマチ(RA)である、実施形態6又は7に記載の方法。
[実施形態9]対象において自己免疫疾患を処置又は予防する方法であって、
(a)同種異系細胞傷害性T細胞(CTL)を含むサンプルを、EBVペプチドを提示する抗原提示細胞(APC)とともにインキュベートし、それによりサンプルにおいてペプチド特異的T細胞の増殖を誘導すること、
(b)対象にペプチド特異的同種異系CTLを投与すること
を含む方法。
[実施形態10]クラスI MHCが、対象に存在するHLA対立遺伝子によってコードされる、実施形態9に記載の方法。
[実施形態11]対象において自己免疫疾患を処置又は予防する方法であって、
(a)EBVペプチドをコードする核酸構成物とともに抗原提示細胞(APC)をインキュベートし、それにより、APCがEBVペプチドを提示するように誘導すること
(b)同種異系CTLを含むサンプルを抗原提示細胞(APC)とともにインキュベートし、それにより、CTLが増殖するように誘導することにより、ペプチド特異的CTLの増殖を誘導すること、及び
(c)対象にペプチド特異的同種異系CTLを投与すること
を含む方法。
[実施形態12]クラスI MHCが、対象に存在するHLA対立遺伝子によってコードされる、実施形態11に記載の方法。
[実施形態13]核酸構成物がウイルスベクターである、実施形態11又は12に記載の方法。
[実施形態14]ウイルスベクターがAdE1-LMPpolyである、実施形態13に記載の方法。
[実施形態15]同種異系CTLが、対象に投与する前に細胞バンクに保存される、実施形態9から14のいずれかに記載の方法。
[実施形態16]自己免疫疾患が多発性硬化症(MS)である、実施形態9から15のいずれかに記載の方法。
[実施形態17]自己免疫疾患が関節リウマチ(RA)である、実施形態9から15のいずれかに記載の方法。
[実施形態18]サンプルをステップ(a)において1つ以上のサイトカインとともにインキュベートする、実施形態9から17のいずれかに記載の方法。
[実施形態19]APCがB細胞を含む、実施形態9から18のいずれかに記載の方法。
[実施形態20]APCが抗原提示T細胞を含む、実施形態9から19のいずれかに記載の方法。
[実施形態21]APCが樹状細胞を含む、実施形態9から20のいずれかに記載の方法。
[実施形態22]APCが人工抗原提示細胞を含む、実施形態9から21のいずれかに記載の方法。
[実施形態23]人工抗原提示細胞がaK562細胞である、実施形態22に記載の方法。
[実施形態24]サンプルが末梢血単核球細胞(PBMC)を含む、実施形態9から23のいずれかに記載の方法。
[実施形態25]EBVペプチドがLMP1ペプチド又はその断片を含む、実施形態1から24のいずれかに記載の方法。
[実施形態26]EBVペプチドがLMP2Aペプチド又はその断片を含む、実施形態1から24のいずれかに記載の方法。
[実施形態27]EBVペプチドがEBNA1ペプチド又はその断片を含む、実施形態1から24のいずれかに記載の方法。
<110> THE COUNCIL OF THE QUEENSLAND INSTITUTE OF MEDICAL RESEARCH
<120> METHODS OF TREATING AUTOIMMUNE DISEASE USING ALLOGENEIC T CELLS
<130> PA22-413
<150> US62/341,360
<151> 2016-05-25
<150> US62/359,326
<151> 2016-07-07
<150> US62/487,814
<151> 2017-04-20
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Claims (35)
- 対象における全身性自己免疫疾患の処置又は予防に使用するための、クラスI MHC上に提示されるEBVペプチドと特異的に結合するT細胞受容体を発現する同種異系細胞傷害性T細胞(CTL)を含む医薬組成物。
- 前記CTLが、クラスI MHC上に提示されるEBVペプチドと特異的に結合するT細胞受容体を発現する同種異系CTLを細胞バンクから選択することにより得られる、請求項1に記載の医薬組成物。
- 対象における全身性自己免疫疾患の処置又は予防に使用するための、ペプチド特異的同種異系CTLを含む医薬組成物であって、該CTLが、同種異系CTLを含むサンプルを、クラスI MHCにEBVペプチドを提示する抗原提示細胞(APC)とともにインキュベートし、それによりクラスI MHC上に提示されるEBVペプチドと特異的に結合するT細胞受容体を発現するペプチド特異的CTLの増殖を誘導することにより得られる、医薬組成物。
- 対象における全身性自己免疫疾患の処置又は予防に使用するための、EBVペプチドと特異的に結合するT細胞受容体を発現するペプチド特異的同種異系CTLを含む医薬組成物であって、該CTLが、
(a)EBVペプチドをコードする核酸構成物とともにAPCをインキュベートし、それにより、APCがクラスI MHC上にEBVペプチドを提示するように誘導すること、及び
(b)同種異系CTLを含むサンプルをEBVペプチド提示APCとともにインキュベートし、それにより、EBVペプチドと特異的に結合するT細胞受容体を発現するCTLの増殖を誘導することにより、ペプチド特異的CTLの増殖を誘導すること
により得られる、医薬組成物。 - クラスI MHCが、対象に存在するHLA対立遺伝子によってコードされる、請求項1から4のいずれか1項に記載の医薬組成物。
- 核酸構成物がウイルスベクターである、請求項4又は5に記載の医薬組成物。
- ウイルスベクターがAdE1-LMPpolyである、請求項6に記載の医薬組成物。
- 同種異系CTLが、対象に投与する前に細胞バンクに保存される、請求項1から7のいずれか1項に記載の医薬組成物。
- 全身性自己免疫疾患が、関節リウマチ(RA)、全身性エリテマトーデス及びシェーグレン症候群から選択される、請求項1から8のいずれか1項に記載の医薬組成物。
- 全身性自己免疫疾患が関節リウマチ(RA)である、請求項1から8のいずれか1項に記載の医薬組成物。
- 同種異系CTLを含むサンプルを1つ以上のサイトカインとともにインキュベートする、請求項3から10のいずれか1項に記載の医薬組成物。
- APCがB細胞を含む、請求項3から11のいずれか1項に記載の医薬組成物。
- APCが抗原提示T細胞を含む、請求項3から12のいずれか1項に記載の医薬組成物。
- APCが樹状細胞を含む、請求項3から13のいずれか1項に記載の医薬組成物。
- APCが人工抗原提示細胞を含む、請求項3から14のいずれか1項に記載の医薬組成物。
- 人工抗原提示細胞がaK562細胞である、請求項15に記載の医薬組成物。
- サンプルが末梢血単核球細胞(PBMC)を含む、請求項3から16のいずれか1項に記載の医薬組成物。
- EBVペプチドがLMP1ペプチド又はその断片を含む、請求項1から17のいずれか1項に記載の医薬組成物。
- EBVペプチドがLMP2Aペプチド又はその断片を含む、請求項1から17のいずれか1項に記載の医薬組成物。
- EBVペプチドがEBNA1ペプチド又はその断片を含む、請求項1から17のいずれか1項に記載の医薬組成物。
- 対象における全身性自己免疫疾患の処置又は予防に使用するための医薬の製造における、クラスI MHC上に提示されるEBVペプチドと特異的に結合するT細胞受容体を発現する同種異系CTLの使用。
- 前記CTLが、クラスI MHC上に提示されるEBVペプチドと特異的に結合するT細胞受容体を発現する同種異系CTLを細胞バンクから選択することにより得られる、請求項21に記載の使用。
- 対象における全身性自己免疫疾患の処置又は予防に使用するための医薬の製造における、ペプチド特異的同種異系CTLの使用であって、該CTLが、同種異系CTLを含むサンプルを、クラスI MHCにEBVペプチドを提示する抗原提示細胞(APC)とともにインキュベートし、それによりクラスI MHC上に提示されるEBVペプチドと特異的に結合するT細胞受容体を発現するペプチド特異的CTLの増殖を誘導することにより得られる、使用。
- 対象における全身性自己免疫疾患の処置又は予防に使用するための医薬の製造における、EBVペプチドと特異的に結合するT細胞受容体を発現するペプチド特異的同種異系CTLの使用であって、該CTLが、
(a)EBVペプチドをコードする核酸構成物とともにAPCをインキュベートし、それにより、APCがクラスI MHC上にEBVペプチドを提示するように誘導すること、及び
(b)同種異系CTLを含むサンプルをEBVペプチド提示APCとともにインキュベートし、それにより、EBVペプチドと特異的に結合するT細胞受容体を発現するCTLの増殖を誘導することにより、ペプチド特異的CTLの増殖を誘導すること
により得られる、使用。 - クラスI MHCが、対象に存在するHLA対立遺伝子によってコードされる、請求項21から24のいずれか1項に記載の使用。
- 核酸構成物がウイルスベクターである、請求項24又は25に記載の使用。
- ウイルスベクターがAdE1-LMPpolyである、請求項26に記載の使用。
- 同種異系CTLが、対象に投与する前に細胞バンクに保存される、請求項21から27のいずれか1項に記載の使用。
- 全身性自己免疫疾患が、関節リウマチ(RA)、全身性エリテマトーデス及びシェーグレン症候群から選択される、請求項21から28のいずれか1項に記載の使用。
- 同種異系CTLを含むサンプルを1つ以上のサイトカインとともにインキュベートする、請求項23から29のいずれか1項に記載の使用。
- APCが、B細胞、抗原提示T細胞、樹状細胞又は人工抗原提示細胞を含む、請求項23から30のいずれか1項に記載の使用。
- APCが抗原提示T細胞を含む、請求項23から31のいずれか1項に記載の使用。
- 人工抗原提示細胞がaK562細胞である、請求項31に記載の使用。
- サンプルが末梢血単核球細胞(PBMC)を含む、請求項23から33のいずれか1項に記載の使用。
- EBVペプチドが、LMP1ペプチド、LMP2Aペプチド、EBNA1ペプチド、又はそれらの断片を含む、請求項23から31のいずれか1項に記載の使用。
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US20030147865A1 (en) * | 2002-02-07 | 2003-08-07 | Benoit Salomon | Cell therapy using immunoregulatory T-cells |
US20090324630A1 (en) * | 2008-04-21 | 2009-12-31 | Jensen Michael C | Fusion multiviral chimeric antigen |
RU2013157923A (ru) * | 2011-05-26 | 2015-07-10 | ДЖИНЕИУС БАЙОТЕКНОЛОДЖИ ИНВЕСТМЕНТС, ЭлЭлСи | Терапия на основе модулирования иммунодоминантности |
CN104491857B (zh) * | 2014-12-24 | 2018-08-31 | 深圳市中美康士生物科技有限公司 | 一种用于免疫治疗ebv相关疾病的抗原组合物、生物制剂及其制备方法 |
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CA3024277A1 (en) | 2017-11-30 |
JP7136701B2 (ja) | 2022-09-13 |
EP3463399A4 (en) | 2020-03-18 |
CN109475578A (zh) | 2019-03-15 |
BR112018073136A2 (pt) | 2019-03-12 |
AU2024204831A1 (en) | 2024-08-01 |
KR20190030661A (ko) | 2019-03-22 |
CL2018003284A1 (es) | 2019-06-14 |
US20220409662A1 (en) | 2022-12-29 |
AU2017271134A1 (en) | 2019-01-03 |
RU2018145500A (ru) | 2020-06-25 |
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EP3463399A1 (en) | 2019-04-10 |
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