JP7264329B2 - T細胞療法を向上させるための、哺乳動物t細胞の活性化により誘導可能な合成プロモーター(syn+pro)の作製 - Google Patents
T細胞療法を向上させるための、哺乳動物t細胞の活性化により誘導可能な合成プロモーター(syn+pro)の作製 Download PDFInfo
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Description
本出願は、2017年5月17日に出願された米国仮特許出願第62/507,565号に基づく優先権を主張するものである。この出願に開示された内容は、参照によりその全体が本明細書に明示的に援用される。
本願は電子形式の配列表とともに出願されたものである。この配列表は、SCRI.152WO.TXTのファイル名で2018年5月15日に作成された22kbのファイルとして提供されたものである。この電子形式の配列表に記載の情報は、参照によりその全体が本明細書に援用される。
いくつかの実施形態において、誘導性合成プロモーターライブラリーの作製方法であって、キメラ抗原受容体(CAR)T細胞の活性化により活性化されるプロモーターをスクリーニングして、スクリーニングされたプロモーターを作製する工程;転写因子応答配列をスクリーニングして、スクリーニングされた転写因子応答配列を作製する工程;CAR T細胞による転写因子応答配列の活性化により活性化されるプロモーターを含む誘導性合成プロモーターライブラリーを作製する工程;およびスクリーニングされた転写因子応答配列をコードする第1の配列とスクリーニングされたプロモーターをコードする第2の配列を含むオリゴヌクレオチドを合成する工程を含む方法を提供する。
CAR T細胞療法における遺伝子発現の制御に有用なプロモーターを得るために、合成プロモーターの作製を試みた。図1に示すように、薬剤を使用することにより、導入遺伝子の発現(T細胞におけるCARまたはTCRの発現など)のオンとオフを制御してもよく、あるいは活性化をオンにしてもよい。
ソーティングしたGFP+細胞から得たDNAを次世代シーケンシング(NGS)で分析すると、200,000個を超えるユニークなプロモーターリードが得られる。上位の配列(リード数による順位付け)から約30個のユニークなプロモーターリード配列を選択し、CAR T細胞において試験したところ、これらの大部分は誘導可能なプロモーターであり、6×NFATプロモーターよりも良好に機能した。試験しなかった配列プールには機能性配列がさらに含まれていると予想される。
Syn-iProの配列
配列番号、配列名、配列
配列番号1
S1-17
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAGGAGGAAAAACTCGATGTGACTCATTCGAAGATCAAAGGGTCGAGGAAAGTCCCCTCGACCCTTTGATCTTCGAATGACATCATCTTTCGAGGAAAGTCCCCTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAATGAGTCACATCGATCTCCGCCCCCTCTTCGAGCGCCAAATCGAGGACGTGATCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号2
S1-37
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAGGGGGCGGGGTCGATCTCCGCCCCCTCTTCGAGTTTTTCCTCCTCGAGGGGACTTTCCTCGAATGACATCATCTTTCGACCCTTTGATCTTCGAAGGAAGTTCGATCACGTCCTCGATTTGGCGCTCGAGGGGACTTTCCTCGAAGATCAAAGGGTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号3
S1-4
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGATTTCCAAGAAATCGAGGAAAGTCCCCTCGACCCTTTGATCTTCGAGGAGGAAAAACTCGAATGAGTCACATCGACCCTTTGATCTTCGAAGAGGGGGCGGAGATCGATCTCCGCCCCCTCTTCGAGGAAAGTCCCCTCGACCCTTTGATCTTCGACCCCGCCCCCTCGAGGAAAGTCCCCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号4
S1-1
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGATCTCCGCCCCCTCTTCGAAGATCAAAGGGTCGAGGGGACTTTCCTCGATTTCTTGGAAATCGAATGACATCATCTTTCGATTTGGCGCTCGAATGACATCATCTTTCGACCCTTTGATCTTCGATGTGACTCATTCGAGGGGACTTTCCTCGAAGATCAAAGGGTCGAGGGGACTTTCCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号5
S1-3
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAGGGGACTTTCCTCGAGGGGGCGGGGTCGATTTGGCGCTCGATCTCCGCCCCCTCTTCGAATGAGTCACATCGAGGAAAGTCCCCTCGAGGAGGAAAAACTCGATGTGACTCATTCGATTTCCAAGAAATCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号6
S1-42
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGATTTCCAAGAAATCGATCTCCGCCCCCTCTTCGAATGACATCATCTTTCGAATGACATCATCTTTCGAGGAGGAAAAACTCGACCCCGCCCCCTCGATTTCTTGGAAATCGAGGAAAGTCCCCTCGAGCGCCAAATCGAAGGAAGTTCGAATGACATCATCTTTCGAATGAGTCACATCGAGGAAAGTCCCCTCGAGGAGGAAAAACTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号7
S1-61
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAATGAGTCACATCGATCTCCGCCCCCTCTTCGAGGGGGCGGGGTCGAGGAGGAAAAACTCGAATGAGTCACATCGACCCTTTGATCTTCGAGGGGACTTTCCGGGGTGGAGCAAGCGTGACAAGTCCACGTATGACCCGACCGACGATATCGAAGCCTACGCGCTGAACGCCAGCCCCGATCGACCCCGCCCCCTCGATTTCCAAGAAATCGAATGACATCATCTTTCGAATGACATCATCTTTCGAGGGGACTTTCCTCGAACTTCCTTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGGAGGAAAAACTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号8
S1-62
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGATTTCCAAGAAATCGAGTTTTTCCTCCTCGAGGGGGCGGGGTCGAGGGGACTTTCCTCGACCCTTTGATCTTCGAGGAAAGTCCCCTCGAGCGCCAAATCGATCTCCGCCCCCTCTTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号9
S1-15
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAAGATCAAAGGGTCGATTTCTTGGAAATCGATGTGACTCATTCGATCACGTCCTCGAGGAGGAAAAACTCGAGGAAAGTCCCCTCGAACTTCCTTCGAGGGGGCGGGGTCGAATGAGTCACATCGAGGAAAGTCCCCTCGAGGGGACTTTCCTCGATTTCTTGGAAATCGAAGAGGGGGCGGAGATCGAGTTTTTCCTCCTCGAGGAAAGTCCCCTCGATCGACTCTACATTTTGACACCCCCAT
配列番号10
S1-2
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAATGAGTCACATCGAAGATCAAAGGGTCGACCCTTTGATCTTCGATTTGGCGCTCGATGTGACTCATTCGACCCCGCCCCCTCGAGGAAAGTCCCCTCGAGGAAAGTCCCCTCGAGGAAAGTCCCCTCGAGGAAAGTCCCCTCGAGTTTTTCCTCCTCGAAGAGGGGGCGGAGATCGATTTGGCGCTCGAGGACGTGATCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号11
S1-27
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGATTTCCAAGAAATCGAGTTTTTCCTCCTCGATTTCCAAGAAATCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAATGACATCATCTTTCGATGTGACTCATTCGAAGATCAAAGGGTCGAAGGAAGTTCGAATGAGTCACATCGAATGAGTCACATCGACCCTTGATCTTCGAGGAGGAAAAACTCGATTTGGCGCTCGATTTGGCGCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号12
S1-8
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGATTTCTTGGAAATCGATTTGGCGCTCGAAGGAAGTTCGAGGGGGCGGGGTCGATTTCCAAGAAATCGAGTTTTTCCTCCTCGAGCGCCAAATCGACCCTTTGATCTTCGATCACGTCCTCGAGCGCCAAATCGAGGACGTGATCGAATGAGTCACATCGAATGAGTCACATCGAATGAGTCACATCGATTTGGCGCTCGATCGGGGGGCGGGGTCGAGGAAAGTCCCCTCGAGGAAAGTCCCCTCGATTTCCAAGAAATCGATTTGGCGCTCGATCTCCGCCCCCTCTTCGATCTCCGCCCCCTCTTCGAGTTTTTCCTCCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号13
S1-30
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAATGACATCATCTTTCGAGGAAAGTCCCCTCGACCCTTTGATCTTCGACCCCGCCCCCTCGAGTTTTTCCTCCTCGAGGAAAGTCCCCTCGACCCTTTGATCTTCGAGGGGACTTTCCTCGAGGGGGCGGGGTCGAGGACGTGATCGAGGAAAGTCCCCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号14
S1-33
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAAGATCAAAGGGTCGAGGAGGAAAAACTCGAGGGGACTTTCCTCGACCCTTTGATCTTCGAATGAGTCACATCGATTTCTTGGAAATCGAAGGAAGTTCGAGGGGACTTTCCTCGAGTTTTTCCTCCTCGAACTTCCTTCGAGGAAAGTCCCCTCGAAGATCAAAGGGTCGAAGGAAGTTCGAAAGATGATGTCATTCGATTTCTTGGAAATCGAAGATCAAAGGGTCGAAGAGGGGGCGGAGATCGATTTCCAAGAAATCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号15
S1-41
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAATGAGTCACATCGAGCGCCAAATCGAGGGGACTTTCCTCGAGGGGGCGGGGTCGAGTTTTTCCTCCTCGATTTCCAAGAAATCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号16
S1-59
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAGTTTTTCCTCCTCGAGGGGACTTTCCTCGAAAGATGATGTCATTCGATCTCCGCCCCCTCTTCGAGGGGACTTTCCTCGAGGAAAGTCCCCTCGAGGAAAGTCCCCTCGAAGATCAAAGGGTCGAATGAGTCACATCGACCCTTTGATCTTCGACCCTTTGATCTTCGATTTCCAAGAAATCGAGGAAAGTCCCCTCGAGGAAAGTCCCCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号17
S1-66
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAGGGGACTTTCCTCGAGGAAAGTCCCCTCGATTTCTTGGAAATCGATTTGGCGCTCGAGGAGGAAAAACTCGATGTGACTCATTCGACCCTTTGATCTTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGCGCCAAATCGAGGAGGAAAAACTCGAGGGGACTTTCCTCGATTTCTTGGAAATCGAAAGATGATGTCATTCGACCCTTTGATCTTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号18
S1-71
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAGGAAAGTCCCCTCGAGGAAAGTCCCCTCGATTTCTTGGAAATCGAATGACATCATCTTTCGATCACGTCCTCGAGGAAAGTCCCCTCGAGTTTTTCCTCCTCGAGGGGACTTTCCTCGATTTCCAAGAAATCGATTTCTTGGAAATCGACCCTTTGATCTTCGAGGAGGAAAAACTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号19
S1-56
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGATGTGACTCATTCGAGGAAAGTCCCCTCGATTTGGCGCTCGATGTGACTCATTCGATTTGGCGCTCGAGGGGACTTTCCTCGATTTCCAAGAAATCGAGGGGACTTTCCTCGAGGAAAGTCCCCTCGAGTTTTTCCTCCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号20
S1-6
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGATGTGACTCATTCGAGCGCCAAATCGATTTCCAAGAAATCGAATGAGTCACATCGAATGACATCATCTTTCGATGTGACTCATTCGAGGAAAGTCCCCTCGATTTCTTGGAAATCGAGGAAAGTCCCCTCGAGTTTTTCCTCCTCGAAGAGGGGGCGGAGATCGAATGACATCATCTTTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号21
S1-60
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAGGGGACTTTCCTCGATCTCCGCCCCCTCTTCGAGGAAAGTCCCCTCGAAGGAAGTTCGAACTTCCTTCGAGGGGACTTTCCTCGAAGGAAGTTCGAGCGCCAAATCGAATGAGTCACATCGATTTCCAAGAAATCGATCTCCGCCCCCTCTTCGAGGAGGAAAAACTCGAGGGGACTTTCCTCGATTTCCAAGAAATCGAGGGGACTTTCCTCGATCACGTCCTCGAGGACGTGATCGAATGAGTCACATCGATGTGACTCATTCGACCCTTTGATCTTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号22
S1-86
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGATTTCCAAGAAATCGAGGGGGCGGGGTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGGAAAGTCCCCTCGATCTCCGCCCCCTCTTCGAGGAAAGTCCCCTCGAACTTCCTTCGAGGAAAGTCCCCTCGAATGAGTCACATCGATTTGGCGCTCGAGGAAAGTCCCCTCGAGGGGACTTTCCTCGAGGAAAGTCCCCTCGAGGGGGCGGGGTCGAACTTCCTTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号23
S1-32
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAATGAGTCACATCGATCTCCGCCCCCTCTTCGATTTGGCGCTCGAGGGGACTTTCCTCGACCCTTTGATCTTCGAGGGGACTTTCCTCGAGGAAAGTCCCCTCGAGGAAAGTCCCCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号24
S1-10
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGATTTGGCGCTCGATGTGACTCATTCGAGGAAAGTCCCCTCGAGGGGACTTTCCTCGAAGATCAAAGGGTCGAAAGATGATGTCATTCGAGGAAAGTCCCCTCGACCCCGCCCCCTCGATTTCTTGGAAATCGAATGAGTCACATCGATTTCTTGGAAATCGATGTGACTCATTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号25
S1-18
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAGGGGACTTTCCTCGATGTGACTCATTCGATTTCTTGGAAATCGATTTCCAAGAAATCGACCCCGCCCCCTCGAGGAGGAAAAACTCGATTTCCAAGAAATCGAATGACATCATCTTTCGAGGGGACTTTCCTCGAAGATCAAAGGGTCGAAGATCAAAGGGTCGAGGAGGAAAAACTCGATTTCCAAGAAATCGAATGAGTCACATCGAGTTTTTCCTCCTCGATTTCTTGGAAATCGAAGAGGGGGCGGAGATCGATTTGGCGCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号26
S1-14
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAAAGATGATGTCATTCGAATGAGTCACATCGATTTGGCGCTCGAGGGGGCGGGGTCGATTTGGCGCTCGAAAGATGATGTCATTCGAGTTTTTCCTCCTCGACCCTTTGATCTTCGAAGAGGGGGCGGAGATCGAAAGATGATGTCATTCGAATGAGTCACATCGATTTCCAAGAAATCGATTTCCAAGAAATCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号27
S1-16
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAGGAGGAAAAACTCGATTTCTTGGAAATCGAGGGGACTTTCCTCGAAAGATGATGTCATTCGAAGATCAAAGGGTCGATGTGACTCATTCGAGGGGACTTTCCTCGAGGGGGCGGGGTCGAATGACATCATCTTTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAATGACATCATCTTTCGATTTCTTGGAAATCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号28
S1-19
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGATCTCCGCCCCCTCTTCGAGTTTTTCCTCCTCGATTTCTTGGAAATCGAAGATCAAAGGGTCGATTTCTTGGAAATCGAGGGGACTTTCCTCGAGGAAAGTCCCCTCGAGGGGACTTTCCTCGAGGAGGAAAAACTCGATTTGGCGCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号29
S1-26
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAAAGATGATGTCATTCGAGTTTTTCCTCCTCGAAGGAAGTTCGAGGACGTGATCGAAGAGGGGGCGGAGATCGAATGAGTCACATCGAAGGAAGTTCGAGGAAAGTCCCCTCGAGGAAAGTCCCCTCGAAGATCAAAGGGTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号30
S1-65
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGACCCCGCCCCCTCGAGCGCCAAATCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号31
S2-n1
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAGGGGGCGGGGTCGAATGACATCATCTTTCGAGGAAAGTCCCCTCGAGGAAAGTCCCCTCGAGGAAAGTCCCCTCGATTTCCAAGAAATCGACCCTTTGATCTTCGAAGATCAAAGGGTCGATGTGACTCATTCGAAGATCAAAGGGTCGATTTGGCGCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号32
S4-n1
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGAGGAAAGTCCCCTCGAGTTTTTCCTCCTCGAAGAGGGGGCGGAGATCGATTTCCAAAAAACTCGAATGACATCATCTTTCGAAGATCAAGGGGTCGAAGATCAAAGGGTCGATTTCCAAGAAATCGATTTCTTGGAAATCGAGGAAAGTCCCCTCGACCCTTTGATCTTCGATCTCCGCCCCCTCTTCGAAGATCAAAGGGTCGAAGAGGGGGCGGAGATCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号33
S6-n1
CTGCTTAGGGTTAGGCGTTTTGCGCTGCTTCGCGATCGATTTCCAAGAAATCGATTTCTTGGAAATCGAATGACATCATCTTTCGAGTTTTTCCTCCTCGAAGAGGGGGCGGAGATCGAGGAAAGTCCCCTCGATTTCCAAGAAATCGAACTTCCTTCGAAGGAAGTTCGAGGAGGAAAAACTCGAGGGGGCGGGGTCGAGTTTTTCCTCCTCGAGGGGACTTTCCTCGACCCCGCCCCCTCGACCCTTTGATCTTCGATTTCCAAGAAATCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCAT
配列番号34
S1-325
TCGAAGATCAAAGGGTCGATTTCCAAGAAATCGATGTGACTCATTCGATTTGGCGCTCGACCCCGCCCCCTCGAAGAGGGGGCGGAGATCGAATGAGTCACATCGAGGAAAGTCCCCTCGATTTCTTGGAAATCGAGGAAAGTCCCCTCGAGGGGACTTTCCTCGAGGAGGAAAAACTCGAATGACATCATCTTTCGAATGAGTCACATCGATTTCTTGGAAATCGAGGGGACTTTCCTCGACCCCGCCCCCTCGAGGTGACTTTCCTCGAGGGGACTTTCCTCGATGTGACTCATTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGACCCTTTGATCTTCGATTTGGCGCTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCA
配列番号35
S1-60
TCGAATGAGTCACATCGATCTCCGCCCCCTCTTCGAGGGGGCGGGGTCGAGGAGGAAAAACTCGAATGAGTCACATCGACCCTTTGATCTTCGAGGGGACTTTCCGGGGTGGAGCAAGCGTGACAAGTCCACGTATGACCCGACCGACGATATCGAAGCCTACGCGCTGAACGCCAGCCCCGATCGACCCCGCCCCCTCGATTTCCAAGAAATCGAATGACATCATCTTTCGAATGACATCATCTTTCGAGGGGACTTTCCTCGAACTTCCTTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGGAGGAAAAACTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCA
配列番号36
S2-274
TCGAATGAGTCACATCGATCTCCGCCCCCTCTTCGAGGGGGCGGGGTCGAGGAGGAAAAACTCGAATGAGTCACATCGACCCTTTGATCTTCGAGGGGACTTTCCGGGGTGGAGCAAGCGTGACAAGTCCACGTATGACCCGACCGACGATATCGAAGCCTACGCGCTGAACGCCAGCCCCGATCGACCCCGCCCCCTCGATTTCCAAGAAATCGAATGACATCATCTTTCGAATGACATCATCTTTCGAGGGGACTTTCCTCGAACTTCCTTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGGAGGAAAAACTCGAAAGATGATGTCATTCGAGTTTTTCCTCCTCGAGGAGGAAAAACTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCA
配列番号37
S2-310
TCGAATGAGTCACATCGATCTCCGCCCCCTCTTCGAGGGGGCGGGGTCGAGGAGGAAAAACTCGAATGAGTCACATCGACCCTTTGATCTTCGAGGGGACTTTCCGGGGTGGAGCAAGCGTGACAAGTCCACGTATGACCCGACCGACGATATCGAAGCCTACGCGCTGAACGCCAGCCCCGATCGACCCCGCCCCCTCGATTTCCAAGAAATCGAATGACATCATCTTTCGAATGACATCATCTTTCGAGGGGACTTTCCTCGAACTTCCTTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGGAGGAAAAACTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCA
配列番号38
S1-367
TCGATTTCCAAGAAATCGACCCCGCCCCCTCGAACTTCCTTCGATTTCTTGGAAATCGAGGAAAGTCCCCTCGATTTCTTGGAAATCGATTTCTTGGAAATCGAATGACATCATCTTTCGATTTCTTGGAAATCGACCCTTTGATCTTCGAGGAGGAAAAACTCGAATGACATCATCTTTCGATCACGTCCTCGAAGATCAAAGGGTCGAGTTTTTCCTCCTCGAGGAAAGTCCCCTCGATGTGACTCATTCGATTTCTTGGAAATCGAGGGGACTTTCCTCGAGGGGACTTTCCTCGAGTTTTTCCTCCTCGAGGAGGAAAAACTCGATTTCCAAGAAATCGAGGGGACTTTCCTCGACCCTTTGATCTTCGAGCGCCAAATCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCA
配列番号39
S1-7
TCGATTTCTTGGAAATCGATTTGGCGCTCGAAGGAAGTTCGAGGGGGCGGGGTCGATTTCCAAGAAATCGAGTTTTTCCTCCTCGAGCGCCAAATCGACCCTTTGATCTTCGATCACGTCCTCGAGCGCCAAATCGAGGACGTGATCGAATGAGTCACATCGAATGAGTCACATCGAATGAGTCACATCGATTTGGCGCTCGATCGGGGGGCGGGGTCGAGGAAAGTCCCCTCGAGGAAAGTCCCCTCGATTTCCAAGAAATCGATTTGGCGCTCGATCTCCGCCCCCTCTTCGATCTCCGCCCCCTCTTCGAGTTTTTCCTCCTCGAGTAGAGTCTAGACTCTACATTTTGACACCCCCA
Claims (27)
- 誘導性合成プロモーターの作製方法であって、
(a)CD8+ T細胞の活性化によりアップレギュレートされた遺伝子の転写因子結合部位を含む、複数の転写因子応答配列を選択する工程;
(b)前記転写因子応答配列を含み、互いに異なる複数のオリゴヌクレオチドを合成する工程;
(c)複数の試験用合成プロモーターを得るために、前記複数のオリゴヌクレオチドを互いにランダムにライゲーションする工程;および
(d)(i)CD8+ T細胞の活性化によって誘導可能であり、かつ(ii)CD8+ T細胞の活性化がない場合に静止される誘導性合成プロモーターを、前記試験用合成プロモーターからスクリーニングする工程
を含み、
任意で、前記誘導性合成プロモーターが、配列番号1~33のいずれか1つと少なくとも95%の配列同一性を有するヌクレオチド配列を含む方法。 - 前記(d)工程が、(i)試験用合成プロモーターおよびレポーター遺伝子を含む第1のポリヌクレオチドならびに(ii)リガンドに結合可能なキメラ抗原受容体(CAR)をコードする第2のポリヌクレオチドをT細胞に導入することを含む、請求項1に記載の方法。
- さらに前記T細胞を活性化することを含む、請求項2に記載の方法。
- 前記活性化することが、前記T細胞に、(i)抗CD3抗体もしくはその抗原結合断片、および/または抗CD28抗体もしくはその抗原結合断片、(ii)ホルボール12-ミリスタート13-アセテート(PMA)、(iii)ロノマイシン、または(iv)前記リガンドを接触させることを含む、請求項3に記載の方法。
- 前記誘導性合成プロモーターが、配列番号1~33のいずれか1つと少なくとも95%の配列同一性を有するヌクレオチド配列を含み、任意で配列番号7、9、18および27のいずれか1つのヌクレオチド配列を含んでもよい、請求項1~4のいずれか1項に記載の方法。
- 請求項1~5のいずれか1項に記載の方法により作製された誘導性合成プロモーターであって、
配列番号1~33のいずれか1つと少なくとも95%の配列同一性を有するヌクレオチド配列を含む第1の配列;および
最小プロモーターをコードする第2の配列を含み、
(i)CD8+ T細胞の活性化によって誘導可能であり、かつ(ii)CD8+ T細胞の活性化がない場合に静止される、誘導性合成プロモーター。 - 前記第1の配列が、配列番号7、9、18および27のいずれか1つのヌクレオチド配列を含む、請求項6に記載の誘導性合成プロモーター。
- 前記第1の配列が、配列番号7または9のヌクレオチド配列を含む、請求項7に記載の誘導性合成プロモーター。
- CARがリガンドに結合することによって誘導可能である、請求項6~8のいずれか1項に記載の誘導性合成プロモーター。
- 抗CD3抗体、抗CD3抗体の抗原結合断片、抗CD28抗体または抗CD28抗体の抗原結合断片によって誘導可能である、請求項6~8のいずれか1項に記載の誘導性合成プロモーター。
- PMAまたはロノマイシンによって誘導可能である、請求項6~8のいずれか1項に記載の誘導性合成プロモーター。
- 前記最小プロモーターが最小IL-2プロモーターを含む、請求項6~11のいずれか1項に記載の誘導性合成プロモーター。
- 請求項6~12のいずれか1項に記載の誘導性合成プロモーターを含むベクター。
- レンチウイルスベクター、トランスポゼースを用いたミニサークル、またはナノプラスミドである、請求項13に記載のベクター。
- 分子発現用細胞であって、
前記分子をコードするポリヌクレオチドと作動可能に連結されている、請求項6~12のいずれか1項に記載の誘導性合成プロモーターを含む核酸;および
キメラ抗原受容体(CAR)をコードする配列
を含む細胞。 - 造血幹細胞である、請求項15に記載の細胞。
- CD8+ T細胞またはCD4+ T細胞である、請求項15に記載の細胞。
- 前記CARが抗CD19 CARである、請求項15~17のいずれか1項に記載の細胞。
- 前記CARが、4-1BBドメインおよびCD3ζドメインを含む細胞内シグナル伝達ドメインを含む、請求項15~18のいずれか1項に記載の細胞。
- 前記分子がタンパク質である、請求項15~19のいずれか1項に記載の細胞。
- 前記分子が、CD122、CD127およびCD360から選択されるキメラサイトカイン受容体(CCR);PD1:CD28およびdnSHP1/2から選択されるPD1キメラ;miRNA155;またはCASTAT5である、請求項15~19のいずれか1項に記載の細胞。
- 対象におけるがんの緩和、抑制または治療に使用される、請求項15~21のいずれか1項に記載の細胞であって、前記がんがリガンドを含み、前記CARが前記リガンドに特異的に結合可能な細胞。
- 前記対象から得られたものである、請求項22に記載の細胞。
- 前記分子の発現を誘導する薬剤と組み合わせて使用される、請求項22または23に記載の細胞。
- 前記薬剤が、PMAおよびロノマイシンから選択される、請求項24に記載の細胞。
- 前記対象に前記細胞を投与する前に前記分子の発現が誘導されており、任意で、前記誘導が、前記細胞に、抗CD3抗体、抗CD3抗体の抗原結合断片、抗CD28抗体または抗CD28抗体の抗原結合断片を接触させてもよい、請求項22~25のいずれか1項に記載の細胞。
- 前記がんが、白血病、乳癌、胃癌、食道癌、脳腫瘍、子宮癌、前立腺癌、骨癌、肝臓癌、膵臓癌、卵巣癌、肺癌、大腸癌、腎臓癌、膀胱癌および甲状腺癌から選択される、請求項22~26のいずれか1項に記載の細胞。
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