JP2018538245A - ウイルス抗原特異的t細胞の濃縮および拡大方法 - Google Patents
ウイルス抗原特異的t細胞の濃縮および拡大方法 Download PDFInfo
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- JP2018538245A JP2018538245A JP2018521069A JP2018521069A JP2018538245A JP 2018538245 A JP2018538245 A JP 2018538245A JP 2018521069 A JP2018521069 A JP 2018521069A JP 2018521069 A JP2018521069 A JP 2018521069A JP 2018538245 A JP2018538245 A JP 2018538245A
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Abstract
Description
ヒトの末梢血液からフィコール密度勾配遠心分離法(Ficoll density−gradient centrifugation)で単核球細胞を分離した後、インターフェロンガンマ組換えタンパク質(interferon gamma recombinant protein)1,000U/mLとサイトメガロウイルス(cytomegalovirus;CMV)抗原pp65に対するペプチベータ(peptivator;Miltenyi Biotec,Bergich Gladbach,Germany)を1ug/mL処理した。4日後にインターロイキン−2(interleukin−2;IL−2)組換えタンパク質300U/mLを処理し、21日間培養して、CMV抗原に特異的二重活性T細胞を生産した。IL−2は、2〜3日に一回ずつ300U/mLを追加した。
ヒトの末梢血液からフィコール密度勾配遠心分離法で単核球細胞を分離した後、インターフェロンガンマ組換えタンパク質1,000U/mLを処理した。24時間後に、anti−CD3抗体50ng/mLとインターロイキン−2(IL−2)組換えタンパク質300U/mLを処理し、21日間培養して、一般的なCIK細胞を生産した。IL−2は、2〜3日に一回ずつ300U/mLを追加した。
前記実施例および比較例により誘導された二重活性T細胞およびCIK細胞のT細胞マーカーであるCD3、CD8とNK細胞マーカーであるCD56に対する蛍光−結合抗体を細胞の表面に染色した後、フローサイトメトリーを利用して測定した。CMV抗原に特異的二重活性T細胞を測定するためには、抗原pp65とMHC複合体に結合された蛍光抗体を細胞の表面に染色した後、フローサイトメトリーを利用して測定した。この際、pp65−MHC複合体に結合するT細胞がCMV抗原pp65に特異的二重活性T細胞であると言える。フローサイトメトリーを利用して測定した結果を図2に示し、CMV抗原に特異的T細胞をペンタマー分析を用いて測定した結果を図3に示す。
前記実施例および比較例により生産された二重活性T細胞およびCIK細胞を培養した後、21日目の細胞の表現型を比較した。その結果を図4に示す。
前記実施例および比較例によって生産された細胞を回収して、抗原pp65のペプチベータで刺激した後、これに特異的に分泌されるIFN−gammaを測定した。その結果を図5に示す。
前記実施例1および比較例1によって生産された細胞を回収して、慢性骨髄性白血病由来K562細胞と4時間共培養した後、K562細胞に対する致死効果を測定して、図6に示す。
ヒトの末梢血液からフィコール密度勾配遠心分離法で単核球細胞を分離した後、インターフェロンガンマ組換えタンパク質1,000U/mLとサイトメガロウイルス(CMV)抗原pp65に対するペプチベータ(peptivator;Miltenyi Biotec,Bergich Gladbach,Germany)を1ug/mL処理した。24時間後、anti−CD3抗体50ng/mLとインターロイキン−2(IL−2)組換えタンパク質300U/mLを処理して、21日間CMV抗原に特異的CIK細胞を生産した。IL−2は、2〜3日に一回ずつ300U/mLを追加した。培養過程を簡略に図式化して図1に示す。
前記実施例2および比較例1によって誘導されたCIK細胞のT細胞マーカーであるCD3、CD8とNK細胞マーカーであるCD56に対する蛍光−結合抗体を細胞の表面に染色した後、フローサイトメトリーを利用して測定した。CMV抗原に特異的T細胞を測定するためには、抗原pp65とMHC複合体に結合された蛍光抗体を細胞の表面に染色した後、フローサイトメトリーを利用して測定した。この際、pp65−MHC複合体に結合するT細胞がCMV抗原pp65に特異的T細胞であると言える。フローサイトメトリーを利用して測定した結果を図7に示す。
前記実施例2および比較例1によって生産されたCIK細胞を培養した後、21日目のCIK細胞の表現型を比較した。その結果を図8に示す。
前記実施例2および比較例1によって生産されたCIK細胞を回収して、抗原pp65に特異的T細胞をペンタマー分析を用いて測定した。その結果を図9に示す。
Claims (29)
- 末梢血液単核球の培養時に末梢血液単核球にIFN−γおよびウイルス抗原ペプチド混合物を処理する段階と、前記末梢血液単核球にIL−2を処理する段階とを含む二重活性T細胞(dual−functional T cell)の誘導および増殖方法。
- 前記末梢血液単核球にIFN−γおよびウイルス抗原ペプチド混合物を処理する段階は、培養0日目に行われる、請求項1に記載の二重活性T細胞の誘導および増殖方法。
- 前記末梢血液単核球にIL−2を処理する段階は、培養4日目に行われる、 請求項1に記載の二重活性T細胞の誘導および増殖方法。
- 末梢血液単核球は、正常人または患者から得たものである、請求項1に記載の二重活性T細胞の誘導および増殖方法。
- IFN−γは、500U/mL〜1,000U/mLの濃度で使用される、請求項1に記載の二重活性T細胞の誘導および増殖方法。
- IL−2は、200U/mL〜1,000U/mLの濃度で使用される、請求項1に記載の二重活性T細胞の誘導および増殖方法。
- 二重活性T細胞の誘導および増殖は、合計20日間以上行われる、請求項1に記載の二重活性T細胞の誘導および増殖方法。
- 二重活性T細胞の誘導および増殖は、合計21日間行われる、請求項7に記載の二重活性T細胞の誘導および増殖方法。
- ウイルス抗原は、サイトメガロウイルス(Cytomegalovirus,CMV)、エプスタイン・バール・ウイルス(Epstein barr virus,EBV)、アデノウイルス(Adenovirus,ADV)およびBKウイルス(BK virus,BKV)よりなる群から選択されたものの抗原である、請求項1に記載の二重活性T細胞の誘導および増殖方法。
- 請求項1〜10のいずれか1項に記載の方法によって得られた二重活性T細胞を含むウイルス媒介疾患の予防および治療での使用のための医薬組成物。
- ウイルス媒介疾患は、バーキットリンパ(Burkitt’s lymphoma)、移植後リンパ増殖性疾患(Post−transplant lymphoproliferative disease,PTLD)、ホジキンリンパ腫(Hodgkin’s lymphoma)、NK/T細胞リンパ腫(NK/T cell lymphoma)、びまん性大細胞型B細胞リンパ腫(Diffuse large B−cell lymphoma,DLBCL)、原発性滲出性リンパ腫(Primary effusion lymphoma)、肺炎(Pneumonia)、網膜炎(Retinitis)、腸炎(Enteritis)、骨髄抑制(myelosuppression)、膀胱炎(Cystitis)、肺炎(Pneumonia)、肝炎(Hepatitis)、腎機能障害(Renal dysfunction)および出血性膀胱炎(Hemorrhagic cystitis)よりなる群から選択された一つ以上である、請求項10に記載の医薬組成物。
- 請求項1〜10のいずれか1項に記載の方法によって得られた二重活性T細胞を、これを必要とする対象体に投与することを含むウイルス媒介疾患の治療方法。
- ウイルス媒介疾患は、バーキットリンパ(Burkitt’s lymphoma)、移植後リンパ増殖性疾患(Post−transplant lymphoproliferative disease,PTLD)、ホジキンリンパ腫(Hodgkin’s lymphoma)、NK/T細胞リンパ腫(NK/T cell lymphoma)、びまん性大細胞型B細胞リンパ腫(Diffuse large B−cell lymphoma,DLBCL)、原発性滲出性リンパ腫(Primary effusion lymphoma)、肺炎(Pneumonia)、網膜炎(Retinitis)、腸炎(Enteritis)、骨髄抑制(myelosuppression)、膀胱炎(Cystitis)、肺炎(Pneumonia)、肝炎(Hepatitis)、腎機能障害(Renal dysfunction)および出血性膀胱炎(Hemorrhagic cystitis)よりなる群から選択された一つ以上である、請求項12に記載の治療方法。
- IFN−γ、IL−2およびウイルス抗原のペプチド混合物を含む二重活性T細胞製造用キット。
- 末梢血液単核球の培養時にIFN−γおよびウイルス抗原ペプチド混合物を処理する段階と、anti−CD3およびIL−2を処理する段階とを含むウイルス抗原特異的サイトカイン誘導キラー細胞(cytokine−induced killer cell,CIK cell)の誘導および増殖方法。
- 前記IFN−γおよびウイルス抗原ペプチド混合物を処理する段階は、培養0日目に行われる、請求項15に記載のウイルス抗原特異的サイトカイン誘導キラー細胞の誘導および増殖方法。
- 前記anti−CD3およびIL−2を処理する段階は、培養1日目に行われる、請求項15に記載のウイルス抗原特異的サイトカイン誘導キラー細胞の誘導および増殖方法。
- 末梢血液単核球は、正常人または患者から得たものである、請求項15に記載のウイルス抗原特異的サイトカイン誘導キラー細胞の誘導および増殖方法。
- IFN−γは、500U/mL〜1,000U/mLの濃度で使用される、請求項15に記載のウイルス抗原特異的サイトカイン誘導キラー細胞の誘導および増殖方法。
- Anti−CD3は、30ng/mL〜150ng/mLの濃度で使用される、請求項15に記載のウイルス抗原特異的サイトカイン誘導キラー細胞の誘導および増殖方法。
- IL−2は、200U/mL〜1,000U/mLの濃度で使用される、請求項15に記載のウイルス抗原特異的サイトカイン誘導キラー細胞の誘導および増殖方法。
- サイトカイン誘導キラー細胞の誘導および増殖は、合計20日間以上行われる、請求項15に記載のウイルス抗原特異的サイトカイン誘導キラー細胞の誘導および増殖方法。
- サイトカイン誘導キラー細胞の誘導および増殖は、合計21日間行われる、請求項22に記載のウイルス抗原特異的サイトカイン誘導キラー細胞の誘導および増殖方法。
- ウイルス抗原は、サイトメガロウイルス(Cytomegalovirus,CMV)、エプスタイン・バール・ウイルス(Epstein barr virus,EBV)、アデノウイルス(Adenovirus,ADV)およびBKウイルス(BK virus,BKV)よりなる群から選択されたものの抗原である、請求項15に記載のウイルス抗原特異的サイトカイン誘導キラー細胞の誘導および増殖方法。
- 請求項15〜24のいずれか1項に記載の方法によって得られたサイトカイン誘導キラー細胞を含むウイルス媒介疾患の予防および治療での使用のための医薬組成物。
- ウイルス媒介疾患は、バーキットリンパ(Burkitt’s lymphoma)、移植後リンパ増殖性疾患(Post−transplant lymphoproliferative disease,PTLD)、ホジキンリンパ腫(Hodgkin’s lymphoma)、NK/T細胞リンパ腫(NK/T cell lymphoma)、びまん性大細胞型B細胞リンパ腫(Diffuse large B−cell lymphoma,DLBCL)、原発性滲出性リンパ腫(Primary effusion lymphoma)、肺炎(Pneumonia)、網膜炎(Retinitis)、腸炎(Enteritis)、骨髄抑制(myelosuppression)、膀胱炎(Cystitis)、肺炎(Pneumonia)、肝炎(Hepatitis)、腎機能障害(Renal dysfunction)および出血性膀胱炎(Hemorrhagic cystitis)よりなる群から選択された一つ以上である、請求項25に記載の医薬組成物。
- 請求項15〜24のいずれか1項に記載の方法によって得られた二重活性T細胞を、これを必要とする対象体に投与することを含むウイルス媒介疾患の治療方法。
- ウイルス媒介疾患は、バーキットリンパ(Burkitt’s lymphoma)、移植後リンパ増殖性疾患(Post−transplant lymphoproliferative disease,PTLD)、ホジキンリンパ腫(Hodgkin’s lymphoma)、NK/T細胞リンパ腫(NK/T cell lymphoma)、びまん性大細胞型B細胞リンパ腫(Diffuse large B−cell lymphoma,DLBCL)、原発性滲出性リンパ腫(Primary effusion lymphoma)、肺炎(Pneumonia)、網膜炎(Retinitis)、腸炎(Enteritis)、骨髄抑制(myelosuppression)、膀胱炎(Cystitis)、肺炎(Pneumonia)、肝炎(Hepatitis)、腎機能障害(Renal dysfunction)および出血性膀胱炎(Hemorrhagic cystitis)よりなる群から選択された一つ以上である、請求項27に記載の治療方法。
- IFN−γ、anti−CD3、IL−2およびウイルス抗原のペプチド混合物を含むウイルス抗原特異的サイトカイン誘導キラー細胞製造用キット。
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BLOOD, vol. 118, no. 12, JPN6019007423, 2011, pages 3301 - 3310 * |
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