JP2020532956A - 癌治療のためのt細胞の活性化方法 - Google Patents
癌治療のためのt細胞の活性化方法 Download PDFInfo
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Abstract
Description
本発明のさらに他の実施形態によれば、本発明で提供する抗原提示細胞によって活性化されたT細胞に関する。
1.EBV陽性胃癌細胞抗原ネオエピトープの選別
胃癌細胞で遺伝子変異が蓄積された最も主なシーケンスを予測し、このシーケンスがT細胞のHLAに結合するエピトープを予測するアルゴリズムは、バイオインフォマティクス及びプロテオミクスを利用して開発した。ネオエピトープ予測アルゴリズムとしては、NetMHC及びNetCTLpanを用いた。この時、韓国人にとって最も多く発現しているHLAタイプであるHLA−A*2402、HLA−A*A0201、及びHLA−A*3303を含む様々なHLAタイプで、HLA−A*1101、HLA−A*0206、HLA−A*3101と、HLA−B*5101、HLA−B*4403、HLA−B*5401、HLA−B*5801、HLA−B*3501と結合親和性が高いと予想されるペプチドシーケンスを発掘した。このために、現在存在するEBV+胃癌細胞株のHLAタイピング(typing)により各細胞株のHLAタイプを調べ、EBVウイルスによってEBV+胃癌細胞にのみ存在し、悪性腫瘍を誘発する代表的タンパク質であるLMP−2AとEBNA−1タンパク質に対して、NetMHCプログラムにより各HLAタイプと結合親和性が高いネオエピトープを予測して発掘した。その結果はそれぞれ表1及び2に示した。
健康なヒトの血液から抽出したPBMCをフローサイトメトリーにより単核球(monocyte)と白血球(leukocyte)に分離して、単核球は樹状細胞に分化させるために、GM−CSFとIL−4サイトカインを培養液に入れて、2日間培養した。また、白血球の場合、抗−CD3/CD28抗体とともに3日間培養し、この後、IL−2サイトカインをともに入れた培養液で培養した。樹状細胞に分化した単核球に、前記のように選別したネオエピトープペプチドを電気衝撃遺伝子伝達法(electrophoration)を利用して樹状細胞に伝達する。この後、2日間培養して、樹状細胞の表面で前記ネオエピトープが発現することを確認した後、抗CD3/CD28抗体が含まれた培養液で培養している白血球とともに1:20(樹状細胞:白血球)の比率で共培養する。共培養時、培養液には樹状細胞の抗原提示機能の効能を増加させるサイトカインであるIL−4と、T細胞のメモリ細胞への転換を補助する機能をするサイトカインであるIL−2とIL−7をともに入れたサイトカインカクテルを混ぜて培養した。16時間後、このように活性化されたT細胞のIFN−γの発現程度をELISPOTで測定して、図1〜4に示した。ただし、前記実験に使用された陰性対照群のペプチドは、EBNA−1とLMP−2AでNetMHCを通して抽出されない任意のEBNA−1、LMP−2Aタンパク質のアミノ酸配列9mer(配列:GGSRERARG)を採用した。
これによって、本発明において、前記表1及び2で、各細胞株のHLA−A類型によって選定されたネオエピトープが負荷された樹状細胞によって細胞毒性Tリンパ球(Cytotoxic T lymphocytes、CTLs)を活性化させることができ、このように活性化されたT細胞は、新抗原であるネオエピトープを認知できる抗原特異性を有することが分かった。
前記2.のように、72時間共培養した後、樹状細胞を介して抗原が提示されたメモリーT細胞を選び出すために、IFNrサイトカインを分泌するT細胞を抽出できる磁石を用いた細胞抽出機(MACS)を用いてEBV抗原特異的メモリーT細胞を抽出した。抽出されたメモリーT細胞は、メモリ機能を維持し、細胞の数を増加させるために、IL−2、IL−7、IL−15サイトカインが混合された培養液で培養して、マウスに注入可能な細胞数に到達するまで培養した。
BALB/cヌードマウスの脇腹に、EBV陽性胃癌細胞株であるSNU−719(HLA type:HLA−A*2402)又はEBV感染MKN74(HLA type:HLA−A*3101)を1×107細胞の量でマトリゲルと混合して移植して異種移植動物モデルを作製し、4週経過して癌組織が観察されると、前記2.で活性化されたT細胞を1×107細胞の量で1週に1回ずつ腫瘍内(intratumoral)注入した後、癌組織の大きさを測定して、図13〜16に示した。ただし、前記実験に使用された陰性対照群のペプチドは、EBNA−1とLMP−2AでNetMHCを介して抽出されない任意のEBNA−1、LMP−2Aタンパク質のアミノ酸配列9mer(配列:GGSRERARG)を採用した。
Claims (36)
- 配列番号1〜184のうちのいずれか1つで表される癌特異的ネオエピトープ(neo−epitope)。
- 前記癌特異的ネオエピトープは、HLA−A、HLA−B、HLA−C、HLA−E、HLA−F、HLA−G、β2−ミクログロブリン、HLA−DPA1、HLA−DPB1、HLA−DQA1、HLA−DQB1、HLA−DRA1、HLA−DRB1、HLA−DRB3、HLA−DRB4、HLA−DRB5、HLA−DM、HLA−DOA、及びHLA−DOB遺伝子座のうちの少なくとも1つと結合親和性を示すものである、請求項1に記載の癌特異的ネオエピトープ。
- 前記癌特異的ネオエピトープは、HLA−A*2402、HLA−A*A0201、HLA−A*3303、HLA−A*1101、HLA−A*0206、HLA−A*3101、HLA−B*5101、HLA−B*4403、HLA−B*5401、HLA−B*5801、及びHLA−B*3501のうちの少なくとも1つと結合親和性を示すものである、請求項1に記載の癌特異的ネオエピトープ。
- 前記癌は、エプスタイン−バールウイルス(EBV)陽性癌である、請求項1に記載の癌特異的ネオエピトープ。
- 前記癌は、EBV陽性胃癌、EBV陽性子宮頸癌、EBV陽性バーキットリンパ腫、EBV陽性T細胞リンパ腫、EBV陽性乳癌、EBV陽性平滑筋肉腫(leiomyosarcomas)、EBV陽性平滑筋腫、EBV陽性ホジキンリンパ腫、EBV陽性非咽頭癌、又はEBV陽性移植後リンパ細胞増殖疾患(PTLD)である、請求項4に記載の癌特異的ネオエピトープ。
- 請求項1〜5のいずれか一項に記載の癌特異的ネオエピトープをコードする、核酸分子。
- 請求項6に記載の核酸分子が挿入された、発現ベクター。
- 請求項7に記載の発現ベクターがトランスフェクトされた、宿主細胞。
- 配列番号1〜184のうちのいずれか1つで表される癌特異的ネオエピトープを含む、T細胞の活性化用組成物。
- 前記T細胞は、癌の予防又は治療のためのものである、請求項9に記載のT細胞の活性化用組成物。
- 前記T細胞は、細胞傷害性T細胞、ヘルパーT細胞、ナチュラルキラーT細胞、γδT細胞、制御性T細胞、及びメモリーT細胞からなる群より選択される1種以上を含む、請求項9に記載のT細胞の活性化用組成物。
- 配列番号1〜184のうちのいずれか1つで表される癌特異的ネオエピトープが負荷(loading)された、抗原提示細胞。
- 前記抗原提示細胞は、樹状細胞、B細胞、及びマクロファージのうちの1種以上を含む、請求項12に記載の抗原提示細胞。
- 前記抗原提示細胞は、T細胞の増殖又は分化を促進する、請求項13に記載の抗原提示細胞。
- 配列番号1〜184のうちのいずれか1つで表される癌特異的ネオエピトープ;及び樹状細胞特異的抗体又はその断片を含む、融合タンパク質。
- 前記樹状細胞特異的抗体は、樹状細胞のDCIR、MHCクラスI、MHCクラスII、CD1、CD2、CD3、CD4、CD8、CD11b、CD14、CD15、CD16、CD19、CD20、CD29、CD31、CD40、CD43、CD44、CD45、CD54、CD56、CD57、CD58、CD83、CD86、CMRF−44、CMRF−56、DCIR、DC−ASPGR、CLEC−6、CD40、BDCA−2、MARCO、DEC−205、Clec9A、33D1、マンノース受容体、ランゲリン(Langerin)、DECTIN−1、B7−1、B7−2、IFN−γ受容体、IL−2受容体、ICAM−1、Fcγ受容体、LOX−1、又はASPGRに特異的な抗体である、請求項15に記載の融合タンパク質。
- 配列番号1〜184のうちのいずれか1つで表される癌特異的ネオエピトープが負荷された抗原提示細胞を製造する方法。
- 前記抗原提示細胞は、樹状細胞、B細胞、及びマクロファージのうちの1種以上を含む、請求項17に記載の方法。
- 前記抗原提示細胞は、目的の個体の末梢血液由来の末梢血単核細胞(PBMC)から得られたものである、請求項17に記載の方法。
- 前記負荷は、前記抗原提示細胞を前記癌特異的ネオエピトープと接触させて行われる、請求項17に記載の方法。
- 前記負荷は、前記抗原提示細胞に前記癌特異的ネオエピトープをパルシング(pulsing)して行われる、請求項17に記載の方法。
- 前記負荷は、前記癌特異的ネオエピトープをコードする核酸分子が挿入された発現ベクターを前記抗原提示細胞にヌクレオフェクション(nucleofection)させて行われる、請求項17に記載の方法。
- 前記負荷は、前記癌特異的ネオエピトープ;及び樹状細胞特異的抗体又はその断片を含む融合タンパク質を用いて行われる、請求項17に記載の方法。
- 請求項12〜14のいずれか一項に記載の抗原提示細胞によって活性化されたT細胞。
- 請求項12〜14のいずれか一項に記載の抗原提示細胞によってT細胞を活性化する方法。
- 前記方法は、前記T細胞を前記抗原提示細胞と共培養して行われる、請求項25に記載の方法。
- 前記T細胞は、目的の個体の末梢血単核細胞(PBMC)から得られたものである、請求項25に記載の方法。
- 前記T細胞は、細胞傷害性T細胞、ヘルパーT細胞、ナチュラルキラーT細胞、γδT細胞、制御性T細胞、及びメモリーT細胞からなる群より選択される1種以上を含む、請求項25に記載の方法。
- 前記共培養時、インターロイキン−2(IL−2)、インターロイキン−4(IL−4)、インターロイキン−7(IL−7)、インターロイキン−15(IL−15)、インターロイキン−21(IL−21)、又はこれらの組み合わせを添加して行われる、請求項26に記載の方法。
- 前記共培養時、サイトカイン及び兔疫グロブリン重鎖不変部を含む融合タンパク質を添加して行われる、請求項26に記載の方法。
- 前記サイトカインは、インターフェロン−γ(IFN−γ)、インターロイキン−2(IL−2)、インターロイキン−4(IL−4)、インターロイキン−12(IL−12)、IL−18、腫瘍壊死因子(TNF)、又は顆粒球マクロファージコロニー刺激因子(GMCSF)である、請求項30に記載の方法。
- 前記共培養時、CD27、CXCR3、又はCD62Lのリガンド;及び兔疫グロブリン重鎖不変部を含む融合タンパク質を添加して行われる、請求項26に記載の方法。
- 請求項12〜14のいずれか1項に記載の抗原提示細胞を有効成分として含む、癌の予防又は治療用薬学組成物。
- 前記癌は、エプスタイン−バールウイルス(EBV)陽性癌である、請求項33に記載の薬学組成物。
- 請求項24に記載の活性化されたT細胞を有効成分として含む、癌の予防又は治療用薬学組成物。
- 前記癌は、エプスタイン−バールウイルス(EBV)陽性癌である、請求項35に記載の薬学組成物。
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US20230210896A9 (en) * | 2019-02-08 | 2023-07-06 | Good T Cells, Inc. | Method for t cell activation for cancer treatment |
EP3927361A4 (en) * | 2019-02-21 | 2022-11-30 | Ramot at Tel-Aviv University Ltd. | TREATMENT OF DISEASES WITH MULTIMERIC PEPTIDES |
KR102182555B1 (ko) * | 2019-03-14 | 2020-11-24 | 한국과학기술연구원 | T 세포 면역 반응 활성화를 위한 암 치료용 암항원 발굴 플랫폼 |
KR102322832B1 (ko) * | 2019-04-22 | 2021-11-12 | 한국과학기술연구원 | 인간 백혈구 항원 a24:02 대립유전자에 특이적으로 결합하는 펩타이드 및 이의 용도 |
KR102335916B1 (ko) * | 2019-04-22 | 2021-12-08 | 한국과학기술연구원 | 인간 백혈구 항원 a02:01 대립유전자에 특이적으로 결합하는 펩타이드 및 이의 용도 |
WO2021061736A1 (en) * | 2019-09-23 | 2021-04-01 | Dana-Farber Cancer Institute, Inc. | Methods of high-throughput identification of t cell epitopes by capturing cytokines on the surface of antigen-presenting cells |
KR20210102091A (ko) | 2020-02-11 | 2021-08-19 | 주식회사 리스큐어바이오사이언시스 | 미성숙 수지상 세포의 성숙화 유도를 이용한 암의 예방 또는 치료용 조성물 |
KR20220118225A (ko) | 2021-02-18 | 2022-08-25 | 주식회사 리스큐어바이오사이언시스 | 미성숙 수지상 세포의 성숙화 유도를 이용한 암의 예방 또는 치료용 조성물 |
KR20220131170A (ko) | 2021-03-19 | 2022-09-27 | 주식회사 리스큐어바이오사이언시스 | 미성숙 수지상 세포의 성숙화 유도를 이용한 암의 예방 또는 치료용 조성물 |
CN113321724B (zh) * | 2021-03-24 | 2022-02-01 | 深圳市新靶向生物科技有限公司 | 一种与食道癌驱动基因突变相关的抗原肽及其应用 |
WO2023227085A1 (zh) * | 2022-05-26 | 2023-11-30 | 苏州尔生生物医药有限公司 | 用于预防或治疗癌症的特异性t细胞及其制备方法 |
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US20200289630A1 (en) | 2020-09-17 |
EP3666887A4 (en) | 2021-09-01 |
KR20200102402A (ko) | 2020-08-31 |
US20240156927A1 (en) | 2024-05-16 |
CN111433355B (zh) | 2024-03-29 |
CN110997903A (zh) | 2020-04-10 |
KR20220136957A (ko) | 2022-10-11 |
BR112020002816A2 (pt) | 2020-08-04 |
CN111433355A (zh) | 2020-07-17 |
EP3666887A2 (en) | 2020-06-17 |
JP2020532957A (ja) | 2020-11-19 |
US20210009952A1 (en) | 2021-01-14 |
KR102148866B1 (ko) | 2020-10-14 |
WO2019031938A2 (ko) | 2019-02-14 |
JP2023113855A (ja) | 2023-08-16 |
CN110997903B (zh) | 2024-03-29 |
WO2019031938A3 (ko) | 2019-07-04 |
KR20200141424A (ko) | 2020-12-18 |
JP7364237B2 (ja) | 2023-10-18 |
KR102190890B1 (ko) | 2020-12-15 |
WO2019031939A3 (ko) | 2019-07-18 |
KR20190017702A (ko) | 2019-02-20 |
WO2019031939A2 (ko) | 2019-02-14 |
US11969463B2 (en) | 2024-04-30 |
US11918634B2 (en) | 2024-03-05 |
EP3666888A2 (en) | 2020-06-17 |
KR20190017705A (ko) | 2019-02-20 |
EP3666888A4 (en) | 2021-09-01 |
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