JP2021048862A - 免疫調節特性が増加した細胞ならびにその使用および製造のための方法 - Google Patents
免疫調節特性が増加した細胞ならびにその使用および製造のための方法 Download PDFInfo
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Abstract
Description
冠詞「1つの(a)」、「1つの(an)」および「この(the)」は、その冠詞の文法上の目的語のうち1つ、または1つよりも多く(例えば、少なくとも1つ)を指すために、本明細書で使用される。例として、「1つの(an)エレメント」とは、1つのエレメントまたは1つよりも多いエレメントを意味する。
本発明は、プログラム死リガンド1(PD−L1)およびインドールアミン2,3−ジオキシゲナーゼ1(IDO−1)の発現レベルが増加した細胞の免疫調節特性を介して免疫系をモジュレートするための組成物および方法を提供する。本発明は一般に、細胞におけるPD−L1および/またはIDO−1発現の増加を達成するために、外因性薬剤で細胞をモジュレートするための方法および組成物に関する。本発明はまた、PD−L1および/またはIDO−1の発現が増加した細胞、ならびに免疫学的障害および炎症の処置を含む治療適用においてかかる細胞を使用する方法に関する。
本発明の一態様は、PD−L1発現増加のために細胞をモジュレートするために使用される薬剤に関する。かかる薬剤には、ポリヌクレオチド、ポリペプチド、小分子、またはそれらの組合せが含まれるがこれらに限定されない。細胞をモジュレートするための小分子には、グルココルチコイドおよび/またはプロスタグランジン経路アゴニスト 抗新生物薬、ドーパミン受容体アゴニストならびに他の薬剤が含まれるがこれらに限定されない。
a.インターフェロン受容体アゴニスト
本発明の一部の態様では、細胞は、ポリ(I:C)を含むポリヌクレオチドでモジュレートされる。ポリイノシン・ポリシチジン酸としても公知のポリ(I:C)は、ポリリボイノシン酸(polyriboinosinic acid)(ポリI)の鎖およびポリリボシチジン酸(polyribocytidylicacid)(ポリC)の鎖からなる合成二本鎖RNAである。ポリ(I:C)は、B細胞、マクロファージおよび樹状細胞の膜において発現されるtoll様受容体3(TLR3)と相互作用することが公知である。本発明での使用のためのポリ(I:C)の商業的供給源には、Invivogen(商標)(CAS番号31852−29−6);Tocris(商標)(CAS番号24939−03−5)、GE Healthcare Life Sciences(商標)(製品コード27−4732−01)、およびSigma−Aldrich(商標)(CAS番号42424−50−0)が含まれるがこれらに限定されない。
本発明の一部の態様では、細胞は、1種または複数種のプロスタグランジン経路アゴニストとの接触によって、PD−L1および/またはIDO−1発現を増加させるためにモジュレートされる。かかるプロスタグランジン経路アゴニストには、cAMPアナログまたはエンハンサー、Gα−sアクチベーター、PGE2 EP2またはPGE2 EP4受容体を選択的に結合する化合物、グルココルチコイド、およびそれらの組合せが含まれるがこれらに限定されない。
本発明の一部の態様では、細胞は、グルココルチコイドおよび/またはグルココルチコイド受容体アゴニストとの接触によって、PD−L1および/またはIDO−1発現増加のためにモジュレートされる。
IDO−1に関し特に興味深い他の薬剤には、抗新生物薬(例えば、ゲムシタビン、レトロゾールおよびフルダラビン)、ドーパミン受容体アンタゴニスト(例えば、フルフェナジン)、ならびにムチン酸イソメテプテン、硫酸ジヒドロストレプトマイシン、プロトリプチリン、テレンゼピン、シクロベンザプリンおよび4−アミノサリチル酸などの種々の他のものが含まれる。
本発明の態様は、PD−L1および/またはIDO−1発現増加を達成するためにモジュレートされる細胞に関する。したがって、本発明は、細胞または細胞の組合せにおいてPD−L1発現を増加させることが可能な1種または複数種の薬剤によるモジュレーションに応答する任意の細胞または細胞の組合せを用いて実施され得る。
モジュレートされた細胞は、細胞移植、障害および疾患の処置、ならびに遺伝子治療を含む種々の臨床設定において有用であり得る。したがって、語句「それを必要とする被験体」とは、本明細書で開示される疾患または障害について処置される個体を指す。特定の実施形態では、モジュレートされた細胞は、免疫学的障害または炎症性障害を処置することにおいて用途を見出す。一部の態様では、モジュレートされた細胞は、被験体における免疫応答を阻害することによって、免疫学的障害または炎症性障害を処置する。本明細書で使用する場合、語句「免疫学的障害」には、自己免疫性障害、移植片対宿主病および移植拒絶が含まれるがこれらに限定されない。
ヒト幹細胞および前駆細胞におけるPD−L1(CD274)またはIDO−1の上昇した遺伝子発現レベル
ヒト幹細胞および前駆細胞上のPD−L1(CD274)またはIDO−1表面タンパク質の上昇したレベル
T細胞増殖は、モジュレートされたHSPCの存在下で低減される。
PD−L1発現の時間経過
1000U/mL IFNβ;
5ng/mL IFNγ;
10μg/mLポリ(I:C);
1000U/mL IFNβ+5ng/mL IFNγ;
5ng/mL IFNγ+10μg/mLポリ(I:C);または
1000U/mL IFNβ+5ng/mL IFNγ+10μg/mLポリ(I:C)。
モジュレーション後の貯蔵およびPD−L1発現
一致したおよび一致していないCD34+細胞集団における免疫抑制
PD−L1ポリヌクレオチドによるPD−L1のモジュレーション、および免疫抑制
IDO1ポリヌクレオチドによるIDO−1の遺伝子過剰発現、および免疫抑制
モジュレートされた細胞の接触非依存的効果
グルココルチコイド処理されたCD34+細胞は、1型糖尿病のモデルにおいて、T細胞の増殖およびエフェクター機能を減少させる
これらおよび他の変更が、上に詳述した記載に照らして、これらの実施形態に対してなされ得る。一般に、以下の特許請求の範囲において、使用される用語は、特許請求の範囲を、明細書および特許請求の範囲に開示された具体的実施形態に限定すると解釈すべきではなく、むしろそのような特許請求の範囲が権利付与される均等物の全範囲と共に、全ての可能な実施形態を含むと解釈すべきである。したがって、特許請求の範囲は、本開示によって限定されない。
本発明は、例えば、以下の項目を提供する。
(項目1)
PD−L1および/またはIDO−1発現を増加させることが可能な1種または複数種の外因性薬剤の存在下で細胞の集団をインキュベートして、PD−L1および/またはIDO−1の発現が増加した細胞の集団を得るステップを含む、細胞の集団をモジュレートするための方法。
(項目2)
前記インキュベーションがex vivoである、項目1に記載の方法。
(項目3)
前記インキュベーションが、約5分間〜約72時間の間である、項目1または項目2に記載の方法。
(項目4)
前記インキュベーションが、約4時間〜約48時間の間である、項目1から3のいずれかに記載の方法。
(項目5)
前記インキュベーションが、約4℃〜約37℃の間の温度で実施される、項目1から4のいずれかに記載の方法。
(項目6)
前記インキュベーションが、約37℃の温度で実施される、項目1から5のいずれかに記載の方法。
(項目7)
前記モジュレートされた細胞におけるPD−L1および/またはIDO−1発現の前記増加が、前記外因性薬剤と共にインキュベートされていない細胞と比較して、約3倍〜約80倍である、項目1から6のいずれかに記載の方法。
(項目8)
前記外因性薬剤(複数可)が、ポリヌクレオチド、ポリペプチドおよび小分子から選択される、項目1から7のいずれかに記載の方法。
(項目9)
前記小分子が、グルココルチコイド、プロスタグランジン経路アゴニスト 抗新生物薬、ドーパミン受容体アゴニスト、ムチン酸イソメテプテン、硫酸ジヒドロストレプトマイシン、プロトリプチリン、テレンゼピン、シクロベンザプリンおよび4−アミノサリチル酸を含む、項目8のいずれかに記載の方法。
(項目10)
前記ポリペプチドが、IFN−α、IFN−β、IFN−ε、IFN−κ、IFN−ω、IFN−γ、またはそれらの組合せから選択されるインターフェロン受容体アゴニストである、項目8に記載の方法。
(項目11)
細胞の前記集団が、IFN−βおよびIFN−γでモジュレートされる、項目1から10のいずれかに記載の方法。
(項目12)
前記ポリヌクレオチドが、ポリ(I:C)、PD−L1をコードするポリヌクレオチドおよび/またはIDO−1をコードするポリヌクレオチドから選択される、項目8に記載の方法。
(項目13)
前記プロスタグランジン経路アゴニストが、PGE2、dmPGE2、15(S)−15−メチルPGE2、20−エチルPGE2、8−イソ−16−シクロヘキシル−テトラノルPGE2、16,16−ジメチルPGE2(「dmPGE2」)、p−(p−アセトアミドベンズアミド)フェニルエステル、11−デオキシ−16,16−ジメチルPGE2、9−デオキシ−9−メチレン−16,16−ジメチルPGE2、9−デオキシ−9−メチレンPGE2、9−ケトフルプロステノール、5−トランスPGE2、17−フェニル−オメガ−トリノルPGE2、PGE2セリノールアミド、PGE2メチルエステル、16−フェニルテトラノルPGE2、15(S)−15−メチルPGE2、15(R)−15−メチルPGE2、8−イソ−15−ケトPGE2、8−イソPGE2イソプロピルエステル、8−イソ−16−シクロヘキシル−テトラノルPGE2、20−ヒドロキシPGE2、20−エチルPGE2、11−デオキシPGE1、ノクロプロスト、スルプロストン、ブタプロスト、15−ケトPGE2および19(R)ヒドロキシPGE2から選択される、項目9に記載の方法。
(項目14)
前記グルココルチコイドが、メドリゾン、アルクロメタゾン、ジプロピオン酸アルクロメタゾン、アムシノニド、ベクロメタゾン、ジプロピオン酸ベクロメタゾン、ベタメタゾン、安息香酸ベタメタゾン、吉草酸ベタメタゾン、ブデソニド、シクレソニド、クロベタゾール、酪酸クロベタゾール、プロピオン酸クロベタゾール、クロベタゾン、クロコルトロン、クロプレドノール、コルチゾール、コルチゾン、コルチバゾール、デフラザコート、デソニド、デスオキシメタゾン(desoximetasone)、デスオキシコルトン、デスオキシメタゾン(desoxymethasone)、デキサメタゾン、ジフロラゾン、二酢酸ジフロラゾン、ジフルコルトロン、吉草酸ジフルコルトロン、ジフルオロコルトロン、ジフルプレドナート、フルクロロロン、フルクロロロンアセトニド、フルドロキシコルチド、フルメタゾン(flumetasone)、フルメタゾン(flumethasone)、ピバル酸フルメタゾン、フルニソリド、フルニソリド半水和物、フルオシノロン、フルオシノロンアセトニド、フルオシノニド、フルオコルチン、フルオコルチンブチル、フルオコルトロン、フルオロコルチゾン、フルオロメトロン、フルペロロン、フルプレドニデン、酢酸フルプレドニデン、フルプレドニゾロン、フルチカゾン、プロピオン酸フルチカゾン、ホルモコータル、ハルシノニド、ハロメタゾン、ヒドロコルチゾン、酢酸ヒドロコルチゾン、アセポン酸ヒドロコルチゾン、ヒドロコルチゾンブテプレート、酪酸ヒドロコルチゾン、ロテプレドノール、メプレドニゾン、6a−メチルプレドニゾロン、メチルプレドニゾロン、酢酸メチルプレドニゾロン、アセポン酸メチルプレドニゾロン、モメタゾン、フロ酸モメタゾン、フロ酸モメタゾン一水和物、パラメタゾン、プレドニカルベート、プレドニゾロン、プレドニゾン、プレドニリデン、リメキソロン、チキソコルトール、トリアムシノロン、トリアムシノロンアセトニドおよびウロベタゾール、ならびにそれらの組合せから選択される、項目9に記載の方法。
(項目15)
前記グルココルチコイドが、ベタメタゾン、プロピオン酸クロベタゾール、フルメタゾン、フルオシノロンアセトニド、メドリゾン、ヒドロコルチゾン、トリアムシノロン、アルクロメタゾンおよびデキサメタゾンから選択される、項目14に記載の方法。
(項目16)
前記抗新生物薬が、ゲムシタビン、レトロゾールおよびフルダラビンから選択され、前記ドーパミン受容体アンタゴニストがフルフェナジンである、項目9に記載の方法。
(項目17)
細胞の前記集団が、造血細胞を含む、項目1から16のいずれかに記載の方法。
(項目18)
細胞の前記集団が単離されている、項目1から17のいずれかに記載の方法。
(項目19)
造血細胞の前記集団が、臍帯血、末梢血、骨髄または人工多能性幹細胞(iPSC)に由来する、項目1から18のいずれかに記載の方法。
(項目20)
造血細胞の前記集団が、iPSCから得られる、項目1から19のいずれかに記載の方法。
(項目21)
細胞の前記集団が、造血幹/前駆細胞(HSPC)を含む、項目1から20のいずれかに記載の方法。
(項目22)
細胞の前記集団が、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約85%、少なくとも約90%、少なくとも約95%、少なくとも約98%または少なくとも約99%のHSPCを含む、項目1から21のいずれかに記載の方法。
(項目23)
細胞の前記集団が、HSPCの実質的に純粋な集団を含む、項目22に記載の方法。
(項目24)
細胞の前記集団が、前記外因性薬剤との接触の前に、CD34+HPSCについて富化される、項目1から23のいずれかに記載の方法。
(項目25)
項目1から24のいずれかに記載の方法によって得られた、PD−L1および/またはIDO−1発現が増加した細胞の集団。
(項目26)
項目25に記載の細胞の集団の治療有効量を、それを必要とする患者に投与するステップを含む、免疫学的障害を処置する方法。
(項目27)
細胞の前記集団が、造血細胞を含む、項目26に記載の方法。
(項目28)
造血細胞の前記集団が、臍帯血、末梢血、骨髄またはiPSCに由来する、項目26または項目27に記載の方法。
(項目29)
細胞の前記集団が、HSPCを含む、項目26から28のいずれかに記載の方法。
(項目30)
細胞の前記集団が、少なくとも約50%、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約85%、少なくとも約90%、少なくとも約95%、少なくとも約98%または少なくとも約99%のHSPCを含む、項目26から29のいずれかに記載の方法。
(項目31)
細胞の前記集団が、HSPCの実質的に純粋な集団を含む、項目30に記載の方法。
(項目32)
細胞の前記集団が、前記外因性薬剤との接触の前に、CD34+HPSCについて富化される、項目26から31のいずれかに記載の方法。
(項目33)
細胞の前記集団が、前記患者と同種異系である、項目26から32のいずれかに記載の方法。
(項目34)
細胞の前記集団が、前記患者とHLAが一致している、項目26から33のいずれかに記載の方法。
(項目35)
細胞の前記集団が、ハプロタイプ決定済増強HSPCを含む、項目26から34のいずれかに記載の方法。
(項目36)
細胞の前記集団が、前記患者と部分的にHLAが一致しているまたは一致していない、項目26から35のいずれかに記載の方法。
(項目37)
細胞の前記集団の前記治療有効量が、約2×106〜約2×1010のCD34+造血細胞を含む、項目26から36のいずれかに記載の方法。
(項目38)
治療有効量の細胞の、1回よりも多い投与を含む、項目26から37のいずれかに記載の方法。
(項目39)
投与の頻度が、約隔週〜約6カ月毎の範囲である、項目26から38のいずれかに記載の方法。
(項目40)
初回投与が、引き続く投与よりも多い細胞数である、項目26から39のいずれかに記載の方法。
(項目41)
前記免疫学的障害が、急性心筋梗塞、虚血性脳卒中、1型糖尿病、真性糖尿病、多発性硬化症、急性散在性脳脊髄炎、炎症性脱髄疾患、ループス、クローン病、変形性関節症、関節リウマチ、乾癬性関節炎、潰瘍性大腸炎、皮膚炎、過敏性腸症候群、白斑、グレーブス病、橋本病、アジソン病、多発性筋炎、皮膚筋炎、重症筋無力症、自己免疫性肝炎、シェーグレン症候群、自己免疫性胃炎、硬化症、乾癬、喘息またはウェゲナー肉芽腫症から選択される自己免疫性障害である、項目26から40のいずれかに記載の方法。
(項目42)
前記免疫学的障害が、移植片対宿主病または移植拒絶である、項目26から41のいずれかに記載の方法。
(項目43)
前記移植拒絶が、骨髄移植、実質臓器移植または細胞治療(例えば、単離された幹細胞を含む任意の組成物)から生じたものである、項目42に記載の方法。
(項目44)
前記患者が前処置を受けていない、項目26から43のいずれかに記載の方法。
(項目45)
前記患者が、高用量前処置、強度減弱前処置または骨髄非破壊的前処置のうちの少なくとも1つを受けていない、項目26から43のいずれかに記載の方法。
(項目46)
前記患者が、高用量前処置、強度減弱前処置または骨髄非破壊的前処置のうちの少なくとも1つを受けている、項目26から43のいずれかに記載の方法。
(項目47)
前記患者が、細胞移植の候補ではないか、または移植を受けていない、項目26から46のいずれかに記載の方法。
(項目48)
項目25に記載の細胞の集団を含む組成物の治療有効量を、それを必要とする患者に投与するステップを含む、患者において炎症を処置する方法。
(項目49)
細胞の前記集団が、造血細胞を含む、項目48に記載の方法。
(項目50)
造血細胞の前記集団が、臍帯血、末梢血、骨髄またはiPSCに由来する、項目48または項目49に記載の方法。
(項目51)
細胞の前記集団が、HSPCを含む、項目48から50のいずれかに記載の方法。
(項目52)
細胞の前記集団が、少なくとも約50%のHPSC、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約85%、少なくとも約90%、少なくとも約95%、少なくとも約98%または少なくとも約99%のHSPCを含む、項目48から51のいずれかに記載の方法。
(項目53)
細胞の前記集団が、HSPCの実質的に純粋な集団を含む、項目52に記載の方法。
(項目54)
細胞の前記集団が、前記外因性薬剤との接触の前に、CD34+HPSCについて富化される、項目48から53のいずれかに記載の方法。
(項目55)
細胞の前記集団が、前記患者と同種異系である、項目48から54のいずれかに記載の方法。
(項目56)
細胞の前記集団が、前記患者とHLAが一致している、項目48から55のいずれかに記載の方法。
(項目57)
細胞の前記集団が、ハプロタイプ決定済増強HSPCを含む、項目48から56のいずれかに記載の方法。
(項目58)
細胞の前記集団が、前記患者と部分的にHLAが一致しているまたは一致していない、項目48から57のいずれかに記載の方法。
(項目59)
細胞の前記集団の前記治療有効量が、約2×106細胞〜約2×1010のCD34+造血細胞を含む、項目48から58のいずれかに記載の方法。
(項目60)
治療有効量の細胞の、1回よりも多い投与を含む、項目48から59のいずれかに記載の方法。
(項目61)
投与の頻度が、約隔週〜約6カ月毎の範囲である、項目48から60のいずれかに記載の方法。
(項目62)
初回投与が、引き続く投与よりも多い細胞数である、項目48から61のいずれかに記載の方法。
(項目63)
炎症性障害が、肺、関節、結合組織、眼、鼻、腸、腎臓、肝臓、皮膚、中枢神経系、内分泌系、心血管系および心臓の炎症から選択される、項目48から62のいずれかに記載の方法。
(項目64)
前記肺の前記炎症が、喘息、成人呼吸促迫症候群、気管支炎、肺炎症、肺線維症および嚢胞性線維症から選択される、項目63に記載の方法。
(項目65)
前記関節の前記炎症が、関節リウマチ、リウマチ性脊椎炎、若年性関節リウマチ、変形性関節症、痛風性関節炎および他の関節炎状態から選択される、項目63に記載の方法。
(項目66)
前記眼の前記炎症が、ブドウ膜炎(虹彩炎を含む)、結膜炎、強膜炎、乾性角結膜炎、ならびに糖尿病性網膜症、未熟児網膜症、網膜色素変性症ならびに萎縮型および滲出型の加齢黄斑変性を含むがこれらに限定されない網膜疾患から選択される、項目63に記載の方法。
(項目67)
前記腸の前記炎症が、クローン病、潰瘍性大腸炎および遠位直腸炎から選択される、項目63に記載の方法。
(項目68)
前記皮膚の前記炎症が、乾癬、湿疹および皮膚炎(例えば、湿疹性皮膚炎、アトピー性皮膚炎および脂漏性皮膚炎、アレルギー性皮膚炎または刺激性接触皮膚炎、亀裂性湿疹、光アレルギー性皮膚炎、光毒性皮膚炎、植物性光線皮膚炎、放射線皮膚炎およびうっ滞性皮膚炎)、強皮症、外傷、熱傷、水疱性障害または皮膚もしくは粘膜の虚血から生じる潰瘍およびびらん、いくつかの形態の魚鱗癬、表皮水疱症、肥厚性瘢痕、ケロイド、自然老化の皮膚変化、光老化、皮膚の機械的剪断によって引き起こされる摩擦水疱形成、コルチコステロイドの外用使用から生じる皮膚萎縮、口唇炎、唇のひび割れ、鼻刺激、粘膜炎ならびに外陰腟炎から選択される、項目63に記載の方法。
(項目69)
前記内分泌系の前記炎症が、自己免疫性甲状腺炎(橋本病)、I型糖尿病、II型糖尿病、ならびに副腎皮質の急性および慢性の炎症から選択される、項目63に記載の方法。
(項目70)
前記心血管系の前記炎症が、冠状動脈梗塞損傷、末梢血管疾患、心筋炎、血管炎、狭窄の血管再生、アテローム動脈硬化症、およびII型糖尿病と関連する血管疾患から選択される、項目63に記載の方法。
(項目71)
前記腎臓の前記炎症が、糸球体腎炎、間質性腎炎、ループス腎炎、ウェゲナー病に対して二次的な腎炎、急性腎炎に対して二次的な急性腎不全、グッドパスチャー症候群、閉塞後症候群および尿細管虚血から選択される、項目63に記載の方法。
(項目72)
前記肝臓の前記炎症が、肝炎(ウイルス感染、自己免疫性応答、薬物処置、毒素、環境因子から生じる、または原発性障害の二次的帰結として生じる)、胆道閉鎖症、原発性胆汁性肝硬変および原発性硬化性胆管炎から選択される、項目63に記載の方法。
(項目73)
前記中枢神経系の前記炎症が、多発性硬化症、およびアルツハイマー病、パーキンソン病、またはHIV感染と関連する認知症などの神経変性疾患から選択される、項目63に記載の方法。
(項目74)
前記投与が全身投与である、項目48から73のいずれかに記載の方法。
(項目75)
前記投与が局所投与である、項目48から73のいずれかに記載の方法。
(項目76)
前記投与が、静脈内、動脈内、筋内、髄腔内、嚢内、眼窩内、心臓内、真皮内、腹腔内、経気管、皮下(真皮下)、表皮下、関節内、嚢下、くも膜下、脊髄内、胸骨内注射である、または注入による、項目48から75のいずれかに記載の方法。
(項目77)
組合せ治療の一部である、項目48から76のいずれかに記載の方法。
(項目78)
モジュレートされていない造血細胞の集団におけるPD−L1および/またはIDO−1発現のレベルと比較して約3倍〜約80倍であるPD−L1および/またはIDO−1発現の増加したレベルを発現するモジュレートされた造血細胞の集団を含む医薬組成物。
(項目79)
薬学的に許容されるキャリアをさらに含む、項目78に記載の医薬組成物。
(項目80)
造血細胞の前記集団が、臍帯血、末梢血、骨髄またはiPSCに由来する、項目78または項目79に記載の医薬組成物。
(項目81)
造血細胞の前記集団が、分化したiPSCに由来する、項目78から80のいずれかに記載の医薬組成物。
(項目82)
造血細胞の前記集団が、HSPCを含む、項目78から81のいずれかに記載の医薬組成物。
(項目83)
造血細胞の前記集団が、少なくとも約50%のHPSC、少なくとも約50%、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約85%、少なくとも約90%、少なくとも約95%、少なくとも約98%または少なくとも約99%のHSPCを含む、項目78から82のいずれかに記載の医薬組成物。
(項目84)
造血細胞の前記集団が、HSPCの実質的に純粋な集団を含む、項目83に記載の方法。
(項目85)
造血細胞の前記集団が、CD34+HPSCについて富化されている、項目78から84のいずれかに記載の医薬組成物。
(項目86)
静脈内投与、動脈内投与、筋内投与、髄腔内投与、嚢内投与、眼窩内投与、心臓内投与、真皮内投与、腹腔内投与、経気管投与、皮下(真皮下)投与、表皮下投与、関節内投与、嚢下投与、くも膜下投与、脊髄内投与、胸骨内投与および注入のために製剤化されている、項目78から85のいずれかに記載の医薬組成物。
(項目87)
局所投与または非静脈内投与のために製剤化されている、項目78から86のいずれかに記載の医薬組成物。
(項目88)
造血細胞の前記集団が、約2×106〜約2×1010のCD34+造血細胞を含む、項目78から87のいずれかに記載の医薬組成物。
(項目89)
項目78から89のいずれかに記載の医薬組成物と、組合せ治療における使用のための第2の活性薬剤とを含むキット。
Claims (3)
- PD−L1をコードするポリヌクレオチドの外因性コピーを含むように改変された、改変された造血幹細胞(HSC)の集団。
- (a)請求項1に記載の改変されたHSCの集団、および、(b)薬学的に許容されるキャリアを含む、医薬組成物。
- 免疫学的障害を有する患者に請求項2に記載の医薬組成物を投与するステップを含む、免疫学的障害を処置する方法であって、前記改変されたHSCの集団が、改変されていないHSCの集団よりも高いレベルでPD−L1を発現する、方法。
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JP2021050220A (ja) | 2021-04-01 |
AU2016211688A1 (en) | 2017-08-10 |
WO2016123117A1 (en) | 2016-08-04 |
AU2021202391B2 (en) | 2023-10-12 |
EP3770252A1 (en) | 2021-01-27 |
CN107429232B (zh) | 2023-01-03 |
US20200102540A1 (en) | 2020-04-02 |
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