JP7444781B2 - 細胞免疫療法組成物およびその使用 - Google Patents
細胞免疫療法組成物およびその使用 Download PDFInfo
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Description
本出願に伴う配列リストを、用紙複写物の代わりにテキスト形式において提供し、これによって参照により本明細書に組み込む。配列リストを含有するテキストファイルの名称は、200265_407WO_SEQUENCE_LISTING.txtである。テキストファイルは479KBであり、2019年3月26日に創出され、EFS-Webを介して電子的に提出されている。
本開示の細胞免疫療法組成物の組合せは、細胞免疫療法分子、例えばキメラ貪食受容体(CER)、キメラ抗原受容体およびT細胞受容体(TCR)結合タンパク質をコードする導入遺伝子を含むように改変された免疫細胞からなる。本開示の細胞免疫療法組成物の組合せは、特定の細胞免疫療法分子により改変した、宿主において標的細胞除去のための特徴的な機構、すなわち、細胞溶解および食作用を示す、免疫細胞タイプまたはサブタイプの特定の組合せからなる(図1を参照のこと)。
本開示の組成物は、部分的には、キメラ貪食受容体(CER)をコードする導入遺伝子を含む免疫細胞を含む。キメラ貪食受容体は一般的に、(a)標的抗原に結合する結合ドメインを含む細胞外ドメイン、(b)貪食シグナル伝達ドメイン、および(c)細胞外ドメインと貪食シグナル伝達ドメインとの間に位置し、かつこれらを接続する膜貫通ドメインを含む。ある特定の実施形態においては、本明細書において説明するキメラ貪食受容体の細胞外ドメインは、結合ドメインと膜貫通ドメインとの間に位置し、かつこれらを接続する細胞外スペーサードメインを含んでもよい。
本明細書において説明する通り、CERは、標的抗原に特異的な細胞外ドメインを含む。ある特定の実施形態においては、細胞外ドメインは、標的抗原(例えばホスファチジルセリン)に特異的に結合する結合ドメインを含む。結合ドメインによる標的分子の結合は、標的分子(例えば受容体またはリガンド)と別の分子との間の相互作用を遮断し、かつ例えば、標的分子のある特定の機能(例えばシグナル伝達)を妨害、低減または除去し得る。一部の実施形態においては、標的分子の結合は、除去のために、ある特定の生物学的経路を誘導するか、または標的分子または標的分子を発現する細胞を特定し得る。
CERの貪食シグナル伝達ドメインは、細胞内エフェクタードメインであり、CERの細胞外ドメインの標的分子への結合に応答して、機能的シグナルを細胞に伝達することができる。貪食シグナル伝達ドメインは、十分なシグナル伝達活性を保持する貪食シグナル伝達分子の任意の部分であり得る。一部の実施形態においては、貪食シグナル伝達分子の全長または全長細胞内成分が使用される。一部の実施形態においては、貪食シグナル伝達分子または貪食シグナル伝達分子の細胞内成分の切断部分が使用され、但し、その切断部分は十分なシグナル伝達活性を保持する。さらなる実施形態においては、貪食シグナル伝達ドメインは、貪食シグナル伝達分子の全部分または切断部分の変異型であり、但し、その変異型は十分なシグナル伝達活性を保持する(すなわち、機能的変異型である)。
本開示のCERは、細胞外ドメインと貪食シグナル伝達ドメインとを接続し、かつこれらの間に位置する膜貫通ドメインを含む。膜貫通ドメインは、宿主細胞膜を横断し、かつ宿主細胞膜においてCERを固定する疎水性アルファヘリックスである。膜貫通ドメインは、結合ドメインに、または存在する場合細胞外スペーサードメインに直接的に融合され得る。ある特定の実施形態においては、膜貫通ドメインは、膜内在性タンパク質[例えば受容体、表面抗原分類(CD:cluster of differentiation)分子、酵素、トランスポーター、細胞接着分子その他]に由来する。膜貫通ドメインは、細胞外ドメインまたは貪食シグナル伝達ドメインと同じ分子から選択され得る(例えばTLR4貪食シグナル伝達ドメインおよびTLR4膜貫通ドメインを含むCER、またはTim4結合ドメインおよびTim4膜貫通ドメインを含むCER)。ある特定の実施形態においては、膜貫通ドメインおよび細胞外ドメインは各々、異なる分子から選択される。他の実施形態においては、膜貫通ドメインおよび貪食シグナル伝達ドメインは各々、異なる分子から選択される。また他の実施形態においては、膜貫通ドメイン、細胞外ドメインおよび貪食シグナル伝達ドメインは各々、異なる分子から選択される。
ある特定の実施形態においては、本開示の組成物は、一部には、キメラ抗原受容体(CAR)をコードする導入遺伝子を含む免疫細胞を含む。キメラ抗原受容体は、一般的に:標的抗原に結合する結合ドメインを含む細胞外ドメイン;細胞内シグナル伝達ドメイン;および細胞外ドメインと細胞内シグナル伝達ドメインとの間に位置し、かつこれらを接続する膜貫通ドメインを含む組換え受容体である。キメラ抗原受容体は一般的に、それらが発現される宿主細胞に抗原特異的細胞傷害活性を与える。
ある特定の実施形態においては、本開示の組成物は、一部には、組換えTCR結合タンパク質をコードする導入遺伝子を含む免疫細胞を含む。組換えTCR結合タンパク質には、α鎖ポリペプチドとβ鎖ポリペプチドとのヘテロ二量体(αβ TCR)またはγ鎖ポリペプチドとδ鎖ポリペプチドとのヘテロ二量体(γδ TCR)からなる「伝統的な」TCR;例えば単鎖TCR、単一ドメインTCR、可溶性TCR融合TCRタンパク質およびTCR融合コンストラクト[TRuC(商標)]を含む、その結合性断片および融合タンパク質が含まれる。ある特定の実施形態においては、組換えTCRは、高親和性TCRである。
ある特定の態様においては、本開示は、本明細書において説明する細胞免疫療法分子(例えばCER、CARおよびTCR結合タンパク質)のうちの任意の1つまたは複数をコードする核酸分子を提供する。核酸とは、一本鎖または二本鎖DNA、cDNAまたはRNAを指す場合があり、アンチセンスDNA、cDNAおよびRNAを含む互いに相補する核酸の正の鎖および負の鎖を含み得る。核酸は、DNAまたはRNAの天然形態または合成形態であり得る。所望の受容体をコードする核酸配列は、例えばSambrook et al. (1989 and 2001 editions; Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY)およびAusubel et al. (Current Protocols in Molecular Biology, 2003)において説明される通り、標準技術を使用する当該技術分野において公知の組換え法を使用して、例として所望の配列またはその一部を発現する細胞からのライブラリーをスクリーニングすることによって、所望の配列またはその一部を含むことが公知のベクターからの配列を派生させることによって、または所望の配列またはその一部を含有する細胞または組織から直接的に配列またはその一部を単離することによって、取得または産生することができる。あるいは、目的の配列は、クローニングするのではなく、合成産生することができる。
本開示は、細胞免疫療法組成物の組合せを提供する。細胞免疫療法組成物の組合せは、CERを含む免疫細胞を含む第1の組成物(「組成物1番」とも呼ばれる)と、細胞免疫療法分子、例えばCER、CARまたはTCRを含む免疫細胞を含む第2の組成物(「組成物2番」とも呼ばれる)とを含む。第1の組成物の免疫細胞に存在するCERは、本明細書において説明するCER結合タンパク質のうちの任意の1つまたは複数から選択され得る。第2の組成物の免疫細胞(call)に存在するCER、CARまたはTCRは、本明細書において説明するCER、CARまたはTCR結合タンパク質のうちの任意の1つまたは複数から選択され得る。特定の実施形態においては、第1の組成物中のCERを含む免疫細胞は、本明細書において説明するCER改変宿主細胞であり、第2の組成物の細胞免疫療法分子を含む免疫細胞は、本明細書において説明するCER、CARまたはTCRにより改変した宿主細胞である。宿主免疫細胞と細胞免疫療法分子との組合せの例示的な実施形態を、表2および表3において示す。
一態様においては、本明細書において提供される実施形態のいずれかに記載の細胞免疫療法組成物の組合せは、疾患、障害または望ましくない状態を患う対象を治療する方法において使用され得る。これらの方法の実施形態は、本説明に記載の細胞免疫療法組成物の組合せを含む治療有効量の医薬組成物(複数可)を対象に投与することを含む。
CER、TCR、および改変T細胞の構築
ホスファチジルセリン結合タンパク質Tim4の細胞外ドメインとTim4膜貫通ドメインとを含むポリヌクレオチドを、TLR4の貪食シグナル伝達ドメインに融合して、配列番号94のアミノ酸配列をコードするキメラ貪食受容体「CER5」を創出した。
CD8+T細胞-TCRとCD4+T細胞-CERとの組合せは、抗原特異的細胞溶解活性および食作用活性の向上を示す
標的SCC152細胞のHPV16 E7 TCRおよびCER二重媒介除去を、細胞傷害性アッセイおよび食作用アッセイを使用して検出した(図3を参照のこと)。SCC152細胞は、下咽頭の扁平上皮癌からのHPV16+細胞である。活性化カスパーゼ3/7認識モチーフを、切断に際して蛍光を発する赤色試薬とカップリングさせるカスパーゼ3/7アポトーシス試薬[IncuCyte(登録商標)]を使用して、HPV16 E7特異的TCRを形質導入したCD8+T細胞の細胞傷害活性を検出した。蛍光顕微鏡を使用して蛍光シグナルを測定した。HPV16 E7 TCR形質導入CD8+T細胞および選択したCERを形質導入したCD4+T細胞を、1:1の比において混合し、HPV16 E7+頭頸部扁平上皮癌細胞(SCC152)と1:1の比において共培養し、カスパーゼ3/7アポトーシス試薬を共培養物に添加した。蛍光を測定することによって、細胞傷害活性を経時的に測定した。対照試料は、HPV16 E7 TCR単独を形質導入したCD8+T細胞であった。図4、5および26のグラフ、および図6~18の蛍光顕微鏡写真において示される通り、ほとんどの試験したCERを形質導入したCD4+T細胞の、HPV16 E7 TCRを形質導入したCD8+T細胞への添加により、HPV16 E7 TCRを形質導入したCD8 T細胞による単独治療に優る細胞傷害活性の向上がもたらされた。
CER改変CD4 T細胞の特徴付け
また、特定のCERが宿主細胞において広範な低規模食作用応答(例えば90%の細胞における10%の貪食)を与えるか、低頻度であるが強い食作用応答(例えば10%の細胞における90%の貪食)を与えるかを決定するために、様々なCER改変CD4+T細胞を、応答の幅について査定した。CD8+T細胞に、実施例1において説明する通りにHPV16 E7特異的TCRを形質導入した。CD4+T細胞にCER21、CER27、CER104、CER116またはCER117核酸を含むレンチウイルスベクターを形質導入した。模擬形質導入(ベクター単独)CD4+T細胞を対照として使用した。CD4+/CER+およびCD8+/E7 TCR+T細胞をCELLTRACE violetにより染色した。HPV16 E7+頭頸部扁平上皮癌細胞(SCC152)をpHrodo redにより染色した。HPV16 E7 TCR形質導入CD8+T細胞および選択されたCERを形質導入したCD4+T細胞を1:1の比において混合し、SCC152細胞と1:1の比において8時間共培養した。CER形質導入CD4+T細胞による標的SCC152細胞の食作用を、蛍光顕微鏡により分析した。図60Aは、CERの種類による食作用についての規模幅曲線を示す。横軸は、貪食を有するCER形質導入CD4+T細胞の領域%、または標的SCC152細胞により奪われたCER形質導入CD4+T細胞の領域%を表す。この測定は、試験したCERの種類にわたり滅多に40%を超えなかった。縦軸は、食作用性であったCER形質導入CD4+T細胞の割合を表す。CER104について、CER104形質導入CD4+T細胞の約20%が、10%を超える貪食を有する。CER117形質導入CD4+T細胞について、10%未満が10%を超える貪食を有する。図60Bは、CER126形質導入CD4+T細胞によって貪食されたSCC152標的細胞の蛍光顕微鏡写真像を示す。
CER改変T細胞による抗原提示
細胞傷害性CD8+T細胞(CTL)による腫瘍細胞死滅を向上させるための1つの戦略は、MHC I分子において外因性抗原を「交差提示」する独特な能力を有する抗原提示細胞(APC)を利用することである。腫瘍特異的CTL応答を広げることは、腫瘍に対する有効な免疫応答を誘導する可能性を有する。この実施例においては、キメラ貪食受容体(CER)発現細胞の抗原プロセシングおよび提示能力を特徴付けるために、ウイルスHPV E6およびE7腫瘍性タンパク質をモデル抗原として使用した。
CER改変CD4 T細胞のマーカー分析
CD4+T細胞に、CER104、CER116またはCER117核酸を含むレンチウイルスベクターを形質導入した。CER104(配列番号139)は、Tim4結合ドメインと、Tim4膜貫通ドメインと、TLR8シグナル伝達ドメインを含む一次貪食シグナル伝達ドメインおよびDAP12シグナル伝達ドメインを含む二次貪食シグナル伝達ドメインを含む貪食シグナル伝達ドメインとを含む。CER116(配列番号152)は、Tim4結合ドメインと、Tim4膜貫通ドメインと、TRAF6シグナル伝達ドメインを含む一次貪食シグナル伝達ドメインおよびTLR8シグナル伝達ドメインを含む二次貪食シグナル伝達ドメインを含む貪食シグナル伝達ドメインとを含む。CER117(配列番号153)は、Tim4結合ドメインと、Tim4膜貫通ドメインと、TLR8シグナル伝達ドメインを含む一次貪食シグナル伝達ドメインおよびTRAF6シグナル伝達ドメインを含む二次貪食シグナル伝達ドメインを含む貪食シグナル伝達ドメインとを含む。CER形質導入CD4+T細胞を、E7 TCR形質導入CD8+T細胞およびHPV+SCC152標的細胞と共培養し、マスサイトメトリー(CyTOF)によって、viSNEを高次シングルセルデータの可視化のために使用して調査した(図64~66)。インタクトなCERを形質導入したCD4+T細胞を、tSNE1(横)およびtSNE2(縦)軸を示すプロットにおいて示す。viSNE分析のために27個の細胞内マーカーを使用した。各点は、単一の細胞を表す。測定したマーカー(GM-CSF、MIP1b、パーフォリン、TNF、IL-17、グランザイムB、IL-4、IL-2およびIFNγ)のうちのいくつかによってプロットに色を付けると、viSNE「島」にわたり表現型が示される(図64A)。各マーカーについて、赤色は高発現を表し、青色は低発現を表す。全ての27個のマーカーからクラスター化アルゴリズムを使用してCD4+T細胞集団を生成し、viSNEマップ上にオーバーレイした。矢印は、CER104、CER116およびCER117を含有する試料における細胞内マーカーIFNγを発現する島の富化を示す(図64B)。全ての18個のマーカーからクラスター化アルゴリズムを使用してCD4+T細胞集団を生成し、viSNEマップ上にオーバーレイした(図65A)。矢印は、CER104およびCER116形質導入CD4+T細胞を含有する試料におけるT細胞活性化マーカーCD69を発現する島の富化を示す。18個の細胞内マーカー(CD28、CCR7、CD45RA、PD1、CD127、パーフォリン、CD49d、CD85j、CD38、CD27、グランザイムB、CD57、CD25、CD69、CD154、CD56、HLA-DRおよびTCRγδ)による色プロットは、viSNE「島」にわたり表現型を示す(図65B)。各マーカーについて、赤色は高発現を表し、青色は低発現を表す。矢印により強調した領域は、T細胞活性化マーカーCD69を発現する細胞を示す。18個の細胞内マーカー(CD28、CCR7、CD45RA、PD1、CD127、パーフォリン、CD49d、CD85j、CD38、CD27、グランザイムB、CD57、CD25、CD69、CD154、CD56、HLA-DRおよびTCRγδ)からクラスター化アルゴリズムを使用してCD4+T細胞集団を生成し、viSNEマップ上にオーバーレイした。矢印は、対照と比較した、CER104およびCER116試料のうちのCCR7+集団内のナイーブT細胞マーカーCD45RAを発現する島の喪失を示す(図66A)。18個の細胞内マーカーによる色プロットは、viSNE「島」にわたり表現型を示す(図66B)。各マーカーについて、赤色は高発現を表し、青色は低発現を表す。矢印により強調した領域は、ナイーブT細胞マーカーCD45RAを発現する細胞を示す。したがって、このデータは、CER104およびCER116形質導入CD4+T細胞が抗原遭遇後のメモリー形成と関連付けられることを示す。
CD4+CER改変T細胞はインビボで貪食活性の大部分を有し、腫瘍死滅を向上させる
PBMCからCD4+またはCD3+細胞を精製し、活性化し、hCER104核酸を含むレンチウイルスベクターを形質導入した。hCER104は、Tim4結合ドメインと、Tim4膜貫通ドメインと、TLR8貪食シグナル伝達ドメインと、Dap12貪食シグナル伝達ドメインとを含むヒトCER104コンストラクトであり、配列番号176のアミノ酸配列を含む。HCC827細胞はEGFR変異を有し、EGFR阻害剤オシメルチニブによる処理は、細胞表面上のホスファチジルセリンの曝露を誘導する。形質導入したT細胞を拡大増殖させた。CER改変T細胞を、pHrodo-red標識HCC827 NSCLC腺癌細胞と一晩共培養し、pHrodo陽性シグナルについてFACsによって査定して、HCC827標的細胞の食作用を検出した(図67Aを参照のこと、FACsプロット内の囲みは食作用%を示す)。抗体染色を使用して、T細胞サブセットをそれらの食作用能力について分析した。CD4+CER改変T細胞のインビトロ食作用の頻度は、CD8+CER改変T細胞よりかなり高かった(図67Bを参照のこと)。
ファゴリソソームV型ATPアーゼの阻害はCER誘導食作用を消失させる
T細胞に、実施例6において説明するhCER104核酸を含むレンチウイルスベクターを形質導入した。hCER104改変T細胞を、オシメルチニブを伴って、または伴わずに、HCC827腺癌細胞と共培養した。バフィロマイシンは、V型ATPアーゼの阻害剤であり、ファゴソーム酸性化(acificiation)を妨害する。hCER104改変T細胞は、TAMRA-SE蛍光色素標識HCC827細胞の食作用を示した(図73A)。バフィロマイシン(20nM)の共培養物への添加は、hCER104改変T細胞による標識HCC827細胞の取り込みを遮断した(図73A)。hCER104改変T細胞または模擬形質導入対照T細胞におけるインビトロ食作用アッセイからのFACsプロットを図73Bに示す。
hCER104改変CD4+T細胞はインビボでE7特異的TCR改変CD8+T細胞腫瘍死滅を向上させた
HPV+SCC152/ルシフェラーゼ+細胞を、NSGマウスに移植した。腫瘍が確立されると、マウスを、HPV E7特異的TCR(配列番号84)改変CD8+T細胞および模擬形質導入CD4+T細胞により処置するか、HPV E7特異的TCR改変CD8+T細胞およびhCER104(配列番号176)改変CD4+T細胞により処置するか、または処置しなかった(処置群当たりn=5)。HPV E7 CD8+T細胞およびhCER104 CD4+T細胞を、1:1の比において投与した。生物発光画像法によって腫瘍容量を経時的に測定した(図74A~74Bを参照のこと)。HPV E7 CD8+T細胞は、異種移植モデルにおいて非処置対照と比較して抗腫瘍応答を示した。hCER104 CD4+T細胞のHPV E7 CD8+T細胞への添加は、インビボで腫瘍死滅を向上させた。
Claims (40)
- (a)ホスファチジルセリンである第1の標的抗原に結合するTim4結合ドメインを含む細胞外ドメインと、
TLR1シグナル伝達ドメイン、TLR2シグナル伝達ドメイン、TLR3シグナル伝達ドメイン、TLR4シグナル伝達ドメイン、TLR5シグナル伝達ドメイン、TLR6シグナル伝達ドメイン、TLR7シグナル伝達ドメイン、TLR8シグナル伝達ドメイン、TLR9シグナル伝達ドメイン、Traf2シグナル伝達ドメイン、Traf3シグナル伝達ドメイン、Traf6シグナル伝達ドメイン、DAP12シグナル伝達ドメイン、NFAM1シグナル伝達ドメイン、BAFF-Rシグナル伝達ドメイン、CD79bシグナル伝達ドメイン、MERTKシグナル伝達ドメイン、Tyro3シグナル伝達ドメイン、Axlシグナル伝達ドメイン、MyD88シグナル伝達ドメインまたはFcεR1γを含む貪食シグナル伝達ドメインと、
細胞外ドメインと貪食シグナル伝達ドメインとの間に位置し、かつこれらを接続する膜貫通ドメインと
を含むキメラ貪食受容体(CER)を含むCD4+T細胞を含む第1の組成物、および
(b)第2の標的抗原に結合する結合ドメインを含む細胞外ドメインと、
細胞内シグナル伝達ドメインと、
細胞外ドメインと細胞内シグナル伝達ドメインとの間に位置し、かつこれらを接続する膜貫通ドメインと
を含むキメラ抗原受容体(CAR)を含むCD8+T細胞を含む第2の組成物
を含む組合せ細胞免疫療法組成物。 - (a)ホスファチジルセリンである第1の標的抗原に結合するTim4結合ドメインを含む細胞外ドメインと、
TLR1シグナル伝達ドメイン、TLR2シグナル伝達ドメイン、TLR3シグナル伝達ドメイン、TLR4シグナル伝達ドメイン、TLR5シグナル伝達ドメイン、TLR6シグナル伝達ドメイン、TLR7シグナル伝達ドメイン、TLR8シグナル伝達ドメイン、TLR9シグナル伝達ドメイン、Traf2シグナル伝達ドメイン、Traf3シグナル伝達ドメイン、Traf6シグナル伝達ドメイン、DAP12シグナル伝達ドメイン、NFAM1シグナル伝達ドメイン、BAFF-Rシグナル伝達ドメイン、CD79bシグナル伝達ドメイン、MERTKシグナル伝達ドメイン、Tyro3シグナル伝達ドメイン、Axlシグナル伝達ドメイン、MyD88シグナル伝達ドメインまたはFcεR1γを含む貪食シグナル伝達ドメインと、
細胞外ドメインと貪食シグナル伝達ドメインとの間に位置し、かつこれらを接続する膜貫通ドメインと
を含む第1のキメラ貪食受容体(CER)を含むCD4+T細胞を含む第1の組成物、および
(b)第2の標的抗原に結合する組換えT細胞受容体(TCR)を含むCD8+T細胞を含む第2の組成物
を含む組合せ細胞免疫療法組成物。 - (a)CARの結合ドメインが、scFvを含み、および/または
(b)CARの細胞外ドメインが、結合ドメインと膜貫通ドメインの間にスペーサードメインをさらに含む
請求項1に記載の組合せ細胞免疫療法組成物 - CARの細胞外ドメインが、免疫グロブリンヒンジ領域、1型膜タンパク質ヒンジ領域、II型Cレクチンの柄領域、免疫グロブリン定常領域ドメインおよびTLR膜近傍ドメインからなる群より選択される、請求項3に記載の組合せ細胞免疫療法組成物。
- 免疫グロブリンヒンジ領域が、IgG1、IgG2、IgG3、IgG4、IgAおよびIgDヒンジ領域からなる群より選択される、請求項4に記載の細胞免疫療法組成物。
- IgG4ヒンジ領域が、配列番号1に記載のアミノ酸配列を含む、請求項5に記載の細胞免疫療法組成物。
- CARの膜貫通ドメインが、CD28、CD2、CD4、CD8、CD3ε、CD3δ、CD3ζ、CD25、CD27、CD40、CD79A、CD79B、CD80、CD86、CD95(Fas)、CD134(OX40)、CD137(4-1BB)、CD150(SLAMF1)、CD152(CTLA4)、CD200R、CD223(LAG3)、CD270(HVEM)、CD272(BTLA)、CD273(PD-L2)、CD274(PD-L1)、CD278(ICOS)、CD279(PD-1)、CD300、CD357(GITR)、A2aR、DAP10、FcRα、FcRβ、FcRγ、Fyn、GAL9、KIR、Lck、LAT、LRP、NKG2D、NOTCH1、NOTCH2、NOTCH3、NOTCH4、PTCH2、ROR2、Ryk、Slp76、SIRPα、pTα、TCRα、TCRβ、TIM3、TRIM、LPA5およびZap70膜貫通ドメイン、から選択される膜貫通ドメインを含む、請求項1および3~6のいずれか一項に記載の組合せ細胞免疫療法組成物。
- CD28膜貫通ドメインが配列番号49のアミノ酸配列を含む、請求項7に記載の細胞免疫療法組成物。
- CARの細胞内シグナル伝達ドメインが、CD3ζ、CD3γ、CD3δ、CD3ε、CD5、CD22、CD79a、CD278(ICOS)、DAP10、DAP12およびCD66dシグナル伝達ドメインから選択されるITAM含有活性化シグナル伝達ドメインを含む、請求項1および3~8のいずれか一項に記載の組合せ細胞免疫療法組成物。
- CD3ζシグナル伝達ドメインが、配列番号158または159のアミノ酸配列を含む、請求項9に記載の組合せ細胞免疫療法組成物。
- CARの細胞内シグナル伝達ドメインが、CD27、CD28、4-1BB、OX40、CD30、CD40、PD-1、ICOS、リンパ球機能関連抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2CおよびB7-H3シグナル伝達ドメインから選択される第1の共刺激性シグナル伝達ドメインを含み、
ここで、任意にはCAR細胞内シグナル伝達ドメインが、CD27、CD28、4-1BB、OX40、CD30、CD40、PD-1、ICOS、リンパ球機能関連抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2CおよびB7-H3シグナル伝達ドメインから選択される第2の共刺激性シグナル伝達ドメインを含む、請求項1および3~10のいずれか一項に記載の組合せ細胞免疫療法組成物。 - 第1の共刺激性シグナル伝達ドメインが、配列番号161または162のアミノ酸配列を含むCD28共刺激性シグナル伝達ドメイン、または配列番号160のアミノ酸配列を含む4-1BB共刺激性シグナル伝達ドメインを含む、請求項11に記載の組合せ細胞免疫療法組成物。
- CARが、第1世代CAR、第2世代CAR、第3世代CARまたはTCR-CARである、請求項1および3~12のいずれか一項に記載の組合せ細胞免疫療法組成物。
- CARの第2の標的抗原が腫瘍抗原であり、
ここで、任意にはCARの第2の標的抗原が、CD138、CD38、CD33、CD123、CD72、CD79a、CD79b、メソテリン、PSMA、BCMA、ROR1、MUC-16、L1CAM、CD22、CD19、CD20、CD23、CD24、CD37、CD30、CA125、CD56、c-Met、EGFR、GD-3、HPV E6、HPV E7、MUC-1、HER2、葉酸受容体α、CD97、CD171、CD179a、CD44v6、WT1、VEGF-α、VEGFR1、IL-13Rα1、IL-13Rα2、IL-11Rα、PSA、FcRH5、NKG2Dリガンド、NY-ESO-1、TAG-72、CEA、エフリンA2、エフリンB2、ルイス式A抗原、ルイス式Y抗原、MAGE、MAGE-A1、RAGE-1、葉酸受容体β、EGFRviii、VEGFR-2、LGR5、SSX2、AKAP-4、FLT3、フコシルGM1、GM3、o-アセチル-GD2およびGD2から選択される腫瘍抗原である、
請求項1および3~13のいずれか一項に記載の組合せ細胞免疫療法組成物。 - 組換えTCRが、αβTCR、γδTCR、高親和性TCR、可溶性TCR、単鎖TCRまたは単一可変ドメインTCRである、請求項2に記載の組合せ細胞免疫療法組成物
- 組換えTCRの第2の標的抗原が、WT-1、メソテリン、MART-1、NY-ESO-1、MAGE-A3、HPV E7、サバイビン、αフェトプロテインまたは腫瘍新生抗原である、請求項2および15のいずれか一項に記載の組合せ細胞免疫療法組成物。
- (a)TCRα鎖が、配列番号89のアミノ酸配列を含む、および/または
(b)TCRβ鎖定常領域が、配列番号87のアミノ酸を含む、請求項2、15および16のいずれか一項に記載の組合せ細胞免疫療法組成物。 - (a)CERの細胞外ドメインが、結合ドメインと膜貫通ドメインの間にスペーサードメインをさらに含む、
請求項1~17のいずれか一項に記載の組合せ細胞免疫療法組成物。 - CERのスペーサードメインが、免疫グロブリンヒンジ領域、1型膜タンパク質ヒンジ領域、II型Cレクチンの柄領域、免疫グロブリン定常領域ドメインおよびTLR膜近傍ドメインからなる群より選択される、請求項18に記載の組合せ細胞免疫療法組成物。
- 免疫グロブリンヒンジ領域が、IgG1、IgG2、IgG3、IgG4、IgAおよびIgDヒンジ領域からなる群より選択される、請求項19に記載の細胞免疫療法組成物。
- IgG4ヒンジ領域が、配列番号1に記載のアミノ酸配列を含む、請求項20に記載の細胞免疫療法組成物。
- CERの膜貫通ドメインが、Tim1、Tim4、Tim3、FcR、CD8、CD28、MERTK、Axl、Tyro3、BAI1、CD4、DAP12、MRC1、FcR、TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8またはTLR9膜貫通ドメインを含む、請求項1~21のいずれか一項に記載の組合せ細胞免疫療法組成物。
- CER膜貫通ドメインが、配列番号37のアミノ酸配列を含むTim1膜貫通ドメイン、配列番号38または39のアミノ酸配列を含むTim4膜貫通ドメイン、配列番号40のアミノ酸配列を含むTim3膜貫通ドメイン、配列番号41のアミノ酸配列を含むFcγR1膜貫通ドメイン、配列番号42のアミノ酸配列を含むFcγR2A膜貫通ドメイン、配列番号43のアミノ酸配列を含むFcγR2B2膜貫通ドメイン、配列番号44のアミノ酸配列を含むFcγR2C膜貫通ドメイン、配列番号45のアミノ酸配列を含むFcγR3A膜貫通ドメイン、配列番号46のアミノ酸配列を含むFcεRIγ膜貫通ドメイン、配列番号47のアミノ酸配列を含むFcαR1膜貫通ドメイン、配列番号48のアミノ酸配列を含むCD8a膜貫通ドメイン、配列番号49のアミノ酸配列を含むCD28膜貫通ドメイン、配列番号50のアミノ酸配列を含むMERTK膜貫通ドメイン、配列番号51のアミノ酸配列を含むAxl膜貫通ドメイン、配列番号52のアミノ酸配列を含むTyro3膜貫通ドメイン、配列番号53のアミノ酸配列を含むCD4膜貫通ドメイン、配列番号54のアミノ酸配列を含むDAP12膜貫通ドメイン、配列番号55のアミノ酸配列を含むMRC1膜貫通ドメイン、配列番号56のアミノ酸配列を含むTLR1膜貫通ドメイン、配列番号57のアミノ酸配列を含むTLR2膜貫通ドメイン、配列番号58のアミノ酸配列を含むTLR3膜貫通ドメイン、配列番号59のアミノ酸配列を含むTLR4膜貫通ドメイン、配列番号60のアミノ酸配列を含むTLR5膜貫通ドメイン、配列番号61のアミノ酸配列を含むTLR6膜貫通ドメイン、配列番号62のアミノ酸配列を含むTLR7膜貫通ドメイン、配列番号63のアミノ酸配列を含むTLR8膜貫通ドメイン、または配列番号64のアミノ酸配列を含むTLR9膜貫通ドメイン、を含む、請求項22に記載の組合せ細胞免疫療法組成物。
- CERの貪食シグナル伝達ドメインが、配列番号4のアミノ酸配列を含むMERTKシグナル伝達ドメイン、配列番号6のアミノ酸配列を含むTyro3シグナル伝達ドメイン、配列番号7のアミノ酸配列を含むAxlシグナル伝達ドメイン、配列番号9もしくは35のアミノ酸配列を含むTraf6シグナル伝達ドメイン、配列番号11、91もしくは34のアミノ酸配列を含むMyD88シグナル伝達ドメイン、配列番号13のアミノ酸配列を含むFcεRIγシグナル伝達ドメイン、配列番号18のアミノ酸配列を含むBAFF-Rシグナル伝達ドメイン、配列番号19のアミノ酸配列を含むDAP12シグナル伝達ドメイン、配列番号20もしくは36のアミノ酸配列を含むNFAM1シグナル伝達ドメイン、配列番号22もしくは21のアミノ酸配列を含むCD79bシグナル伝達ドメイン、配列番号23のアミノ酸配列を含むTLR1シグナル伝達ドメイン、配列番号24のアミノ酸配列を含むTLR2シグナル伝達ドメイン、配列番号25のアミノ酸配列を含むTLR3シグナル伝達ドメイン、配列番号26のアミノ酸配列を含むTLR4シグナル伝達ドメイン、配列番号27のアミノ酸配列を含むTLR5シグナル伝達ドメイン、配列番号28のアミノ酸配列を含むTLR6シグナル伝達ドメイン、配列番号29のアミノ酸配列を含むTLR7シグナル伝達ドメイン、配列番号30のアミノ酸配列を含むTLR8シグナル伝達ドメイン、配列番号31のアミノ酸配列を含むTLR9シグナル伝達ドメイン、配列番号32のアミノ酸配列を含むTraf2シグナル伝達ドメイン、または配列番号33のアミノ酸配列を含むTraf3シグナル伝達ドメインを含む、請求項1~23のいずれか一項に記載の組合せ細胞免疫療法組成物。
- CERの貪食シグナル伝達ドメインが、一次貪食シグナル伝達ドメインおよび二次貪食シグナル伝達ドメインを含む、ならびにここで、一次貪食シグナル伝達ドメインが、TLR1シグナル伝達ドメイン、TLR2シグナル伝達ドメイン、TLR3シグナル伝達ドメイン、TLR4シグナル伝達ドメイン、TLR5シグナル伝達ドメイン、TLR6シグナル伝達ドメイン、TLR7シグナル伝達ドメイン、TLR8シグナル伝達ドメイン、TLR9シグナル伝達ドメイン、Traf2シグナル伝達ドメイン、Traf3シグナル伝達ドメイン、Traf6シグナル伝達ドメイン、DAP12シグナル伝達ドメイン、NFAM1シグナル伝達ドメイン、BAFF-Rシグナル伝達ドメイン、CD79bシグナル伝達ドメイン、MERTKシグナル伝達ドメイン、Tyro3シグナル伝達ドメイン、Axlシグナル伝達ドメイン、MyD88シグナル伝達ドメイン、またはFcεR1γシグナル伝達ドメインである、請求項1~24のいずれか一項に記載の組合せ細胞免疫療法組成物。
- CERの二次貪食シグナル伝達ドメインが、TLR1シグナル伝達ドメイン、TLR2シグナル伝達ドメイン、TLR3シグナル伝達ドメイン、TLR4シグナル伝達ドメイン、TLR5シグナル伝達ドメイン、TLR6シグナル伝達ドメイン、TLR7シグナル伝達ドメイン、TLR8シグナル伝達ドメイン、TLR9シグナル伝達ドメイン、Traf2シグナル伝達ドメイン、Traf3シグナル伝達ドメイン、Traf6シグナル伝達ドメイン、DAP12シグナル伝達ドメイン、NFAM1シグナル伝達ドメイン、BAFF-Rシグナル伝達ドメイン、CD79bシグナル伝達ドメイン、MERTKシグナル伝達ドメイン、Tyro3シグナル伝達ドメイン、Axlシグナル伝達ドメイン、MyD88シグナル伝達ドメイン、またはFcεR1γシグナル伝達ドメインである、請求項25に記載の組合せ細胞免疫療法組成物。
- CERの一次貪食シグナル伝達ドメインおよび二次貪食シグナル伝達ドメインが、互いに独立して、配列番号4のアミノ酸配列を含むMERTKシグナル伝達ドメイン、配列番号6のアミノ酸配列を含むTyro3シグナル伝達ドメイン、配列番号7のアミノ酸配列を含むAxlシグナル伝達ドメイン、配列番号9もしくは35のアミノ酸配列を含むTraf6シグナル伝達ドメイン、配列番号11、91もしくは34のアミノ酸配列を含むMyD88シグナル伝達ドメイン、配列番号13のアミノ酸配列を含むFcεRIγシグナル伝達ドメイン、配列番号18のアミノ酸配列を含むBAFF-Rシグナル伝達ドメイン、配列番号19のアミノ酸配列を含むDAP12シグナル伝達ドメイン、配列番号20もしくは36のアミノ酸配列を含むNFAM1シグナル伝達ドメイン、配列番号22もしくは21のアミノ酸配列を含むCD79bシグナル伝達ドメイン、配列番号23のアミノ酸配列を含むTLR1シグナル伝達ドメイン、配列番号24のアミノ酸配列を含むTLR2シグナル伝達ドメイン、配列番号25のアミノ酸配列を含むTLR3シグナル伝達ドメイン、配列番号26のアミノ酸配列を含むTLR4シグナル伝達ドメイン、配列番号27のアミノ酸配列を含むTLR5シグナル伝達ドメイン、配列番号28のアミノ酸配列を含むTLR6シグナル伝達ドメイン、配列番号29のアミノ酸配列を含むTLR7シグナル伝達ドメイン、配列番号30のアミノ酸配列を含むTLR8シグナル伝達ドメイン、配列番号31のアミノ酸配列を含むTLR9シグナル伝達ドメイン、配列番号32のアミノ酸配列を含むTraf2シグナル伝達ドメイン、および配列番号33のアミノ酸配列を含むTraf3シグナル伝達ドメインから選択される、請求項25または26に記載の組合せ細胞免疫療法組成物。
- CERの一次貪食シグナル伝達ドメインおよび二次貪食シグナル伝達ドメインが、異なる、請求項25~27のいずれか一項に記載の組合せ細胞免疫療法組成物。
- Tim4結合ドメインが配列番号90のアミノ酸配列、または配列番号90のアミノ酸25~314のアミノ酸配列を含む、請求項1~28のいずれか一項に記載の組合せ細胞免疫療法組成物。
- 第1の標的抗原および第2の標的抗原が、同じ標的抗原または異なる標的抗原である、請求項1~29のいずれか一項に記載の組合せ細胞免疫療法組成物。
- CERが、配列番号94~107、110~126、128~157および163~181のいずれか1つである、請求項1~30のいずれか一項に記載の組合せ細胞免疫療法組成物。
- CD4+T細胞が、ナイーブCD4+T細胞、エフェクターメモリーCD4+T細胞またはセントラルメモリーCD4+T細胞である、請求項1~31のいずれか一項に記載の組合せ細胞免疫療法組成物。
- CD8+T細胞が、ナイーブCD8+T細胞、エフェクターメモリーCD8+T細胞またはセントラルメモリーCD8+T細胞である、請求項1~32のいずれか一項に記載の組合せ細胞免疫療法組成物。
- CD4+T細胞、CD8+T細胞またはその両者が、ヒト細胞である、請求項1~33のいずれか一項に記載の組合せ細胞免疫療法組成物。
- 組成物におけるCD4+T細胞のCD8+T細胞に対する比が、約1:1、1:2、1:4、1:8、1:10または1:20である、請求項1~34のいずれか一項に記載の組合せ細胞免疫療法組成物。
- (a)第1の組成物および第2の組成物が各々、薬学的に許容される担体をさらに含み、
および/または
(b)第1の組成物および第2の組成物が、同じ製剤において、または別々の製剤において存在する、
請求項1~35のいずれか一項に記載の組合せ細胞免疫療法組成物。 - 有効量の組成物を対象に投与する事を含む、対象における疾患を治療する方法における使用のための請求項1~36のいずれか一項に記載の組み合わせ細胞免疫療法組成物。
- 疾患ががんであり、ここで、任意にはがんが、固形腫瘍、黒色腫、非小細胞肺がん、腎細胞癌、腎がん、血液がん、前立腺がん、去勢抵抗性前立腺がん、結腸がん、直腸がん、胃がん、食道がん、膀胱がん、頭頸部がん、甲状腺がん、乳がん、三種陰性乳がん、卵巣がん、子宮頸がん、肺がん、尿路上皮がん、膵がん、神経膠芽腫、肝細胞がん、骨髄腫、多発性骨髄腫、白血病、ホジキンリンパ腫、非ホジキンリンパ腫、骨髄異形成症候群、脳がん、CNSがんまたは悪性神経膠腫である、請求項37に記載の使用のための組合せ細胞免疫療法組成物。
- CD4+T細胞が対象にとって自家または同種異系であるか、CD8+T細胞が対象にとって自家または同種異系であるか、またはこれらの任意の組合せである、請求項37または38に記載の使用のための細胞免疫療法組成物。
- 組合せ細胞免疫療法組成物が、追加の治療剤と組み合わせて投与され、
ここで、任意には:
追加の治療剤が、抗体、放射線療法、化学療法剤、免疫チェックポイント分子阻害剤療法、小分子療法、細胞免疫療法、腫瘍溶解性ウイルス、電気パルス療法、UV光療法、高密度焦点式超音波療法、腫瘍溶解性ウイルス、ペプチド、ホルモン、アプタマー、抗炎症剤、抗生物質、抗真菌剤または抗ウイルス剤であり;
および/または、
第1の組成物および第2の組成物が、対象に同時に、または連続して投与され、ここで、さらに任意には第1の組成物が、第2の組成物の約1~7日後に投与される、
請求項37~39のいずれか一項に記載の使用のための細胞免疫療法組成物。
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