JP6895380B2 - 治療免疫細胞の有効性を改良するための方法 - Google Patents
治療免疫細胞の有効性を改良するための方法 Download PDFInfo
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- C12N2510/00—Genetically modified cells
Description
免疫細胞は、強力かつ特異的な「生きた薬剤」であり得る。免疫細胞は、正常な組織を温存しながら腫瘍細胞を標的化する潜在性を有し、いくつかの臨床的観察は、それらが主要な抗癌活性を有し得ることを示している。したがって、同種造血幹細胞移植(HSCT)を受ける患者において、T細胞媒介移植片対宿主病(GvHD)(Weiden,PL et al.,N.Engl.J.Med.1979;300(19):1068−1073;Appelbaum,FR Nature,2001;411(6835):385−389;Porter,DL et al.,N.Engl.J.Med.1994;330(2):100−106;Kolb,HJ et al.Blood.1995;86(5):2041−2050;Slavin,S.et al.,Blood.1996;87(6):2195−2204)、及びドナーナチュラルキラー(NK)細胞アロ反応性(Ruggeri L,et al.Science.2002;295(5562):2097−2100;Giebel S,et al.Blood.2003;102(3):814−819;Cooley S,et al.Blood.2010;116(14):2411−2419)は、白血病再発と逆関係にある。HSCTの文脈に加えて、抑制性シグナルからT細胞を放出する(Sharma P,et al.,Nat Rev Cancer. 2011;11(11):805−812.;Pardoll DM.,Nat Rev Cancer.2012;12(4):252−264)、またはそれらを腫瘍細胞に架橋する(Topp MS,et al.J.Clin.Oncol.2011;29(18):2493−2498)抗体の投与は、固形腫瘍または白血病のいずれかを有する患者において主要な臨床的応答を生成した。最後に、遺伝子改変自家Tリンパ球の注入は、治療抵抗性白血病及びリンパ腫を有する患者において完全かつ持続的な寛解を誘導した(Maude SL,et al.N Engl J Med.2014;371(16):1507−1517)。
方法
Claims (15)
- キメラ抗原受容体(CAR)をコードするヌクレオチド配列を含む第1の核酸と、局在化ドメインに連結した抗体をコードするヌクレオチド配列を含む第2の核酸と、を含む、操作された免疫細胞であって、
前記抗体が:
CD3ε、TCRα、TCRβ、TCRγ、TCRδ、CD3δ、CD3γ、及びCD3ζからなる群から選択される、CD3/T細胞受容体(TCR)複合体中の因子;または
プログラム細胞死タンパク質1(PD−1)、細胞傷害性Tリンパ球関連タンパク質4(CTLA−4)、T細胞免疫グロブリン及びムチンドメイン含有3(Tim3)、キラー免疫グロブリン様受容体(KIR)2DL1、KIR2DL2/DL3、並びにNKG2Aから成る群から選択される、免疫応答を下方制御する前記受容体;
に結合し、前記局在化ドメインに連結した抗体が、前記因子または前記受容体の細胞表面発現を下方制御する、操作された免疫細胞。 - 前記操作された免疫細胞が、操作されたT細胞、操作されたナチュラルキラー(NK)細胞、操作されたNK/T細胞、操作された単球、操作されたマクロファージ、または操作された樹状細胞である、請求項1に記載の操作された免疫細胞。
- 前記CARが、抗CD19−4−1BB−CD3ζCARである、請求項1または2に記載の操作された免疫細胞。
- 前記抗体が、単鎖可変断片(scFv)である、請求項1〜3のいずれか一項に記載の操作された免疫細胞。
- 前記抗体またはscFVが、CD3εに結合し、かつ:
配列番号12のアミノ酸配列とCDR1〜3内の配列が同一であり、配列番号12のアミノ酸配列と少なくとも85%の配列同一性を有する可変重鎖(VH);及び
配列番号13のアミノ酸配列とCDR1〜3内の配列が同一であり、配列番号13のアミノ酸配列と少なくとも85%の配列同一性を有する可変軽鎖(VL);
を含む、請求項1または4に記載の操作された免疫細胞。 - 前記抗体またはscFVが、NKG2Aに結合し、かつ:
配列番号32のアミノ酸配列とCDR1〜3内の配列が同一であり、配列番号32のアミノ酸配列と少なくとも85%の配列同一性を有する可変重鎖(VH);及び
配列番号33のアミノ酸配列とCDR1〜3内の配列が同一であり、配列番号33のアミノ酸配列と少なくとも85%の配列同一性を有する可変軽鎖(VL);
を含む、請求項1または4に記載の操作された免疫細胞。 - 前記抗体またはscFVが、KIR2DL1及びKIR2DL2/DL3に結合し、かつ:
配列番号36のアミノ酸配列とCDR1〜3内の配列が同一であり、配列番号36のアミノ酸配列と少なくとも85%の配列同一性を有する可変重鎖(VH);及び
配列番号37のアミノ酸配列とCDR1〜3内の配列が同一であり、配列番号37のアミノ酸配列と少なくとも85%の配列同一性を有する可変軽鎖(VL);
を含む、請求項1または4に記載の操作された免疫細胞。 - 前記局在化ドメインが、小胞体(ER)またはゴルジ保持配列;プロテオソーム局在化配列;あるいはCD8α、CD8β、4−1BB、CD28、CD34、CD4、FcεRIγ、CD16、OX40、CD3ζ、CD3ε、CD3γ、CD3δ、TCRα、CD32、CD64、VEGFR2、FAS、またはFGFR2Bに由来する膜貫通ドメイン配列を含む、請求項1〜7のいずれか一項に記載の操作された免疫細胞。
- 前記ERまたはゴルジ保持配列が、アミノ酸配列KDEL(配列番号4)、KKXX(配列番号9)、KXD/E(配列番号10)、またはYQRL(配列番号11)を含み、ここで、Xは、任意のアミノ酸であるか、あるいは前記プロテオソーム局在化配列が、PESTモチーフを含む、請求項8に記載の操作された免疫細胞。
- 対象における癌を治療するための、請求項1〜9のいずれか一項に記載の操作された免疫細胞を含む医薬組成物。
- 静脈内注入、動脈内注入、腫瘍への直接注射及び/または手術後の腫瘍母地の灌流、人工スキャフォールドにおける腫瘍部位での移植、髄腔内投与、または眼内投与によって前記対象に投与するのに適している、請求項10に記載の医薬組成物。
- 前記癌が、固形腫瘍または血液学的悪性腫瘍である、請求項10または11に記載の医薬組成物。
- 請求項1〜9のいずれか一項に記載の操作された免疫細胞を生成するためのインビトロの方法であって、
免疫細胞に、キメラ抗原受容体をコードするヌクレオチド配列を含む核酸と、局在化ドメインに連結した抗体をコードするヌクレオチド配列を含む核酸とを導入する工程であって、それによって操作された免疫細胞を生成する、工程、を含み、
前記抗体が:
CD3ε、TCRα、TCRβ、TCRγ、TCRδ、CD3δ、CD3γ、及びCD3ζからなる群から選択される、CD3/T細胞受容体(TCR)複合体中の因子;または
プログラム細胞死タンパク質1(PD−1)、細胞傷害性Tリンパ球関連タンパク質4(CTLA−4)、T細胞免疫グロブリン及びムチンドメイン含有3(Tim3)、キラー免疫グロブリン様受容体(KIR)2DL1、KIR2DL2/DL3、並びにNKG2Aから成る群から選択される、免疫応答を下方制御する前記受容体;
に結合し、前記局在化ドメインに連結した抗体が、前記因子または前記受容体の細胞表面発現を下方制御する、方法。 - 前記操作された免疫細胞が、同種細胞から生成される、請求項13に記載の方法。
- 前記操作された免疫細胞が、自家細胞から生成される、請求項13に記載の方法。
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US11679132B2 (en) | 2015-02-06 | 2023-06-20 | National University Of Singapore | Methods for enhancing efficacy of therapeutic immune cells |
JP7320560B2 (ja) | 2015-02-06 | 2023-08-03 | ナショナル ユニバーシティ オブ シンガポール | 治療免疫細胞の有効性を改良するための方法 |
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