JP7437705B2 - 抗cd38及び抗cd138キメラ抗原受容体を含むt細胞、及びその用途 - Google Patents
抗cd38及び抗cd138キメラ抗原受容体を含むt細胞、及びその用途 Download PDFInfo
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Description
(1)アラニン(A)、セリン(S)、スレオニン(T)
(2)アスパラギン酸(D)、グルタミン酸(E)
(3)アスパラギン(N)、グルタミン(Q)
(4)アルギニン(R)、リジン(K)
(5)イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V)
(6)フェニルアラニン(F)、チロシン(Y)、トリプトファン(W)
他の実施形態では、保存的置換は、化学的に類似した非天然アミノ酸での置換を網羅する。
(細胞株及び培地)
細胞株(CAG/CAG-ルシフェラーゼ発現ヒト多発性骨髄腫細胞株、及びヒト前立腺癌細胞株PC-3)を、10%ウシ胎児血清(FCS)(Hyクローン)と2mMグルタミンとを補充したRPMI(Biological社製、イスラエル、ベイト・ヘメック)を用いて、5%CO2を含む加湿37℃インキュベーターで培養した。293Tヒト胚細胞(ATCC)とPG13(Gag-Polを発現し、pCL-Amphoウイルスエンベロープタンパク質に感染したマウス細胞株)を、10%FCS、2mMグルタミン、1mMピルビン酸ナトリウムを補充したDMEMで培養した。細胞を、加湿したインキュベーターに入れ、37℃、7.5%CO2でインキュベートした。ヒトリンパ球を、10%FCSと50μM 2-メルカプトエタノールを補充したRPMI-1640で培養し、加湿したインキュベーターに入れ、37℃、5%CO2でインキュベートした。全ての培地に、ペニシリン(100U/ml)、ストレプトマイシン(100μg/ml)、ネオマイシン(10μg/ml)(Bio-Lab社製、イスラエル、エルサレム)を含む混合抗生物質溶液を補充した。PCRを使用して、全ての細胞のマイコプラズマを確認した。細胞を継代数が少ないときに凍結し、解凍後の継代数を記録した。継代数が約12となる4週間以下の期間、細胞を培養した。本研究で使用された初代培養細胞株は、Cell Biologies社に注文し、LonzoはAlmog-Eisenberg Bros社に注文した。データシートに示されているように、初代細胞がそれぞれ増殖した。
精製抗ヒトCD3は、ハイブリドーマOKT3から社内で調製した。精製抗ヒトCD28は、Southern Biotechnology Associates社(バーミンガム、USA)から購入した。ヒトIL-2はNovartis-Pharma(イギリス)から購入した。組換えHis又はヒトFcタグ付きCD38及びCD138タンパク質はSino Biological社から購入した。抗His抗体はAbeamから購入した。抗ヒトFc(γ特異的)抗体はeBioscience社から購入した。抗ヒトCD3APCはBioLegend社から入手した。抗ヒトCD38PE-cy7、抗ヒトCD-138APC、抗ヒトErbB2FITCはeBioscince社から購入した。
次の実施例では、様々なキメラ抗原受容体で形質導入されたヒトT細胞を調製して試験を行った。本実施例の目的は、多発性骨髄腫の治療に臨床的に関連する2つの異なる抗原に特異的に結合する2つの異なるCARでT細胞を形質導入するときの効力を検証することである。当該目的のために、2つの臨床的に関連する抗原としてCD38とCD138を選定し、これらの抗原に特異的に結合することを目的とした2つのCARを生成した。CARの一方は、それぞれ配列番号13及び配列番号14の配列を有するVL及びVHを有する抗CD138特異的モノクローナル抗体に由来するscFvを含む。二番目のCARは、それぞれ配列番号15及び配列番号16の配列を有するVL及びVHを有する抗CD38特異的モノクローナル抗体に由来するscFvを含む。各CARにおけるVL及びVHは、配列GSTSGSGKSSEGKG(配列番号17)を有するアミノ酸14個分のリンカで連結した。
αCDl38-CD28-γ
αCD38-CD28-γ
二重CAR:αCD138-CD28-T2A-αCD38-γ
Switch1(対照群1):N29-CD28-T2A-αCD38-γ
Switch2(対照群2):αCD138-CD28-T2A-N29-γ
αCD138は抗CD138scFv、αCD38は抗CD38scFv、γはFcRy活性化ドメイン(疫受容体チロシン系活性化モチーフ:ITAM)、CD28はCD28の共刺激要素、T2Aは自己切断ペプチド、N29は抗ErbB2scFvをそれぞれ意味する。
人間の健常ドナーから得た末梢血リンパ球(PBL)を、Lymphoprep勾配(Axis-shield社、ノルウェー、オスロ)で遠心分離をかけて分離し、50μM 2-メルカプトエタノールを補充した完全RPMI-1640 4mLで3×106細胞/ウェルで培養した。1μg/mlの抗CD3抗体とラット抗ヒトCD28抗体(AbD Serotec社、USA)の両方をプレコートした非組織培養処理6ウェルプレート(Falcon)で細胞を2日間刺激した。次に、活性化リンパ球を、PBSでよく洗浄して採取した。遠心分離により細胞をペレット化し、ウイルス上清に2~3×106細胞/mlの密度で再懸濁した。次に、細胞(1.5ml)を、RetroNectin(登録商標)(12μg/ml、4ml/ウェル、宝酒造株式会社、日本、大津)をプレコートした非組織培養処理6ウェルプレート(Falcon)のウェルに加えた。37℃、7.5%CO2で6時間インキュベーションした後、ウイルス上清をゆっくり除去し、IL-2(100IU/ml)を補充したリンパ球培地で置き換え、37℃・5%CO2で一晩中インキュベートした。
まず、異なる抗原を狙う異なるCARで形質導入されたT細胞は、対応抗原を発現する細胞に応答することが分かる。二重CAR、つまりαCD138-CD28-αCD38-γで形質導入されたT細胞の、CD38とCD138の両方を発現するCAG細胞に選択的に応答する能力を比較した。CD38のみを発現するJurkat細胞を対照群として用いた。図2からわかるように、実験条件下で、T細胞におけるαCD38-γCARの存在は、共刺激とは無関係にT細胞に完全な活性化能力を十分与えた。これは、N29-CD28-T2A-αCD38-γ(Switch1)、又はαCD38CARを発現するT細胞が、jurkat細胞とのインキュベーションで高いIFN-γ分泌を記録した結果から容易に結論を導き出せる。
実施例1と同様に実験を構成し、異なる細胞株とのインキュベーション時にCAR-N29、Switch1、Swtich2、又は二重CAR(αCDl38-CD28-T2A-αCD38)で形質導入されたT細胞によるIFN-γの分泌を測定した。細胞株は、対照群細胞株(CD38、ErbB2又はCD138を発現しない)、CAG、PC-3(CD38の発現が低い前立腺癌細胞株)の293株で、標的細胞を含まないリンパ球の培養(培地のみ)も行った。結果を図3Aに示した。
(物質及び方法)
免疫不全マウスのNOD scid-gamma(NSG)における多発性骨髄腫細胞株CAGに基づき、生体内ヒト多発性骨髄腫モデルを較正した。これらのマウスは成熟リンパ球を欠いており、複数のサイトカインシグナリング経路が不足しているため、様々なヒトの細胞や組織を生着できる。研究者らはまず、注入した多発性骨髄腫細胞の最適数、投与経路、CAR-T細胞治療の許容時間を得るためにレシピエントマウスに対して行った試験準備の影響を定めた(データは提示せず)。7日目に106個のCAG多発性骨髄腫細胞をIV注射で投与し、続いて200RADで照射すると、腫瘍の効率的に発生し、望ましい腫瘍モデルが得られることを確認した。
図5によると、CAG多発性骨髄腫細胞の注入後、試験を行った組織全て、つまり肝臓、肺、脾臓、骨から腫瘍病変が観測された。
実施例3と同様の条件で行われた本実験では、CAG腫瘍/腫瘍体積のモニタリングを容易にすべく、イメージングの前にマウスに注入されるルシフェリンに遭遇すると生物発光を放出するCAG-LUC細胞株を使用した。それにより、各マウスの腫瘍強度を比較し、各群における治療の効力を追跡した。結果を図8に示した。
Claims (32)
- 少なくとも2つの別個のキメラ抗原受容体(CAR)を発現する遺伝子改変T細胞であって、
第1のCARはCD138に特異的に結合する抗原結合ドメインを含み、
第2のCARはCD38に特異的に結合する抗原結合ドメインを含み、
前記第1のCARは共刺激ドメインを含むとともに活性化ドメインを欠き、
前記第2のCARは活性化ドメインを含むとともに共刺激ドメインを欠き、
前記CD138に特異的に結合する抗原結合ドメインは、配列番号13のアミノ酸配列を有するV L ドメインおよび配列番号14のアミノ酸配列を有するV H ドメインからなる一本鎖可変断片(抗CD138scFvと表記する)であり、
前記CD38に特異的に結合する抗原結合ドメインは、配列番号15のアミノ酸配列を有するV L ドメインおよび配列番号16のアミノ酸配列を有するV H ドメインからなる一本鎖可変断片(抗CD38scFvと表記する)である、T細胞。 - 前記抗CD138scFv及び抗CD38scFvのV L ドメインおよびV H ドメインは、配列番号17のアミノ酸配列を有するペプチドリンカにより結合される、請求項1に記載のT細胞。
- 前記共刺激ドメインはCD28、4-1BB、OX40、iCOS、CD27、CD80、CD70の共刺激ドメインから選ばれ、前記活性化ドメインはFcRγ及びCD3-ζ活性化ドメインから選ばれる、請求項1または2に記載のT細胞。
- 前記活性化ドメインは配列番号23のアミノ酸配列を含むFcRγ活性化ドメインであり、前記共刺激ドメインは配列番号22のアミノ酸配列を含むCD28の共刺激ドメインである、請求項1~3のいずれか一項に記載のT細胞。
- 前記第1のCARは配列番号24のアミノ酸配列を有し、前記第2のCARは配列番号25のアミノ酸配列を有する、請求項1に記載のT細胞。
- 2つのキメラ抗原受容体(CAR)を発現する設計T細胞であって、
第1のCARは配列番号24のアミノ酸配列を有し、第2のCARは配列番号25のアミノ酸配列を有する、設計T細胞。 - 少なくとも2つの別個のキメラ抗原受容体(CAR)をコードする1つ以上のDNA構築物の少なくとも1つの複製を含み、
前記第1のCARは抗CD138scFvを含み、前記第2のCARは抗CD38scFvを含み、
前記第1のCARは共刺激ドメインを含むとともに活性化ドメインを欠き、
前記第2のCARは活性化ドメインを含むとともに共刺激ドメインを欠く、請求項1に記載のT細胞。 - DNA構築物の少なくとも1つの複製を含み、前記DNA構築物は、
(A)5’位から3’位の方へ、(i)リーダーペプチド、(ii)抗CD138scFv、(iii)膜貫通ドメインI、(iv)共刺激ドメインと、
(B)5’位から3’位の方へ、(v)リーダーペプチド、(vi)抗CD38scFvドメイン、(vii)膜貫通ドメインII、(viii)活性化ドメイン、の両方をコードし、
(A)及び(B)は自己切断ペプチドによって分離される、請求項1のT細胞。 - 前記DNA構築物は、5’位から3’位の方へ、(i)リーダーペプチド、(ii)抗CD138scFv、(iii)膜貫通ドメインI、(iv)共刺激ドメイン、(v)自己切断ペプチド、(vi)リーダーペプチド、(vii)抗CD38scFvドメイン、(viii)膜貫通ドメインII、(ix)活性化ドメインをコードする、請求項8に記載のT細胞。
- 前記DNA構築物は、5’位から3’位の方へ、(i)リーダーペプチド、(ii)抗CD38scFv、(iii)膜貫通ドメインII、(iv)活性化ドメイン、(v)自己切断ペプチド、(vi)リーダーペプチド、(vii)抗CD138scFvドメイン、(viii)膜貫通ドメインI、(ix)共刺激ドメインをコードする、請求項8に記載のT細胞。
- 前記自己切断ペプチドは、配列番号26のアミノ酸配列を有するペプチド、IRESペプチドから選ばれる、請求項8~10のいずれか一項に記載のT細胞。
- 前記自己切断ペプチドは、配列番号27のDNA配列によりコードされる、請求項11記載のT細胞。
- 2つの異なるDNA構築物を含み、
第1のDNA構築物は、5’位から3’位の方へ、(i)リーダーペプチド、(ii)抗CD138scFv、(iii)膜貫通ドメインI、(iv)共刺激ドメインをコードするDNA配列を含み、
第2のDNA構築物は、5’位から3’位の方へ、(i)リーダーペプチド、(ii)抗CD38scFvドメイン、(iii)膜貫通ドメインII、(iv)活性化ドメインをコードするDNA配列を含み、
前記第1のDNA構築物又は前記第2のDNA構築物の一方DNA構造物は活性化ドメインをコードするDNA配列を含むとともに共刺激ドメインをコードするDNA配列を欠き、一方DNA構造物は共刺激ドメインをコードするDNA配列を含むとともに活性化ドメインをコードするDNA配列を欠く、請求項7に記載のT細胞。 - (i)前記リーダーペプチドは配列番号20のアミノ酸配列を有し、及び/又は、
(ii)前記活性化ドメインは配列番号23のアミノ酸配列を有し、及び/又は、
(iii)前記共刺激ドメインは配列番号22のアミノ酸配列を有し、及び/又は、
(iv)前記抗CD138scFvドメインは配列番号18のアミノ酸配列を有し、及び/又は、
(v)前記抗CD38scFvドメインは配列番号19のアミノ酸配列を有する、請求項8~13のいずれか一項に記載のT細胞。 - (i)前記リーダーペプチドは、配列番号39に示されるDNA配列によりコードされ、及び/又は、
(ii)前記抗CD138scFvは、配列番号28に示されるDNA配列によりコードされ、及び/又は、
(iii)前記抗CD38scFvは、配列番号29に示されるDNA配列によりコードされ、及び/又は、
(iv)前記共刺激ドメインは、配列番号30に示されるDNA配列によりコードされ、及び/又は、
(v)前記活性化ドメインは、配列番号31に示されるDNA配列によりコードされる、請求項8~14のいずれか一項に記載のT細胞。 - 前記T細胞は配列番号34のDNA配列を有するDNA構築物の少なくとも1つの複製を含む、請求項8に記載のT細胞。
- 前記T細胞は配列番号32のDNA配列を有するDNA構築物の少なくとも1つの複製及び配列番号33のDNA配列を有するDNA構築物の少なくとも1つの複製を含む、請求項8に記載のT細胞。
- 前記T細胞はCD4+T細胞及びCD8+T細胞から選ばれる、請求項1~17のいずれか一項に記載のT細胞。
- DNA構築物であって、
(A)5’位から3’位の方へ、(i)リーダーペプチド、(ii)抗CD138scFv、(iii)膜貫通ドメインI、(iv)共刺激ドメイン、(v)自己切断ペプチド、(vi)リーダーペプチド、(vii)抗CD38scFvドメイン、(viii)膜貫通ドメインII、及び(ix)活性化ドメインをコードし、
(B)5’位から3’位の方へ、(i)リーダーペプチド、(ii)抗CD38scFvドメイン、(iii)膜貫通ドメインII、(iv)活性化ドメイン、(v)自己切断ペプチド、(vi)リーダーペプチド、(vii)抗CD138scFv、(viii)膜貫通ドメインI、及び(ix)共刺激ドメイン又は活性化ドメインをコードする、DNA構築物。 - (i)前記自己切断ペプチドは配列番号26のアミノ酸配列を有し、及び/又は、
(ii)前記リーダーペプチドは配列番号20のアミノ酸配列を有し、及び/又は、
(iii)前記活性化ドメインは配列番号23のアミノ酸配列を有し、及び/又は、
(iv)前記共刺激ドメインは配列番号22のアミノ酸配列を有し、及び/又は、
(v)前記抗CD138scFvドメインは配列番号18のアミノ酸配列を有し、及び/又は、
(vi)前記抗CD38scFvドメインは配列番号19のアミノ酸配列を有する、請求項19に記載のDNA構築物。 - (i)前記自己切断ペプチドは、配列番号27のDNA配列によりコードされ、及び/又は、
(ii)前記リーダーペプチドは、配列番号39のDNA配列によりコードされ、及び/又は、
(iii)前記活性化ドメインは、配列番号31のDNA配列によりコードされ、及び/又は、
(iv)前記共刺激ドメインは、配列番号30のDNA配列によりコードされ、
(v)前記抗CD138scFvドメインは、配列番号28のDNA配列によりコードされ、及び/又は、
(vi)前記抗CD38scFvドメインは、配列番号29のDNA配列によりコードされる、請求項19~20のいずれか一項に記載のDNA構築物。 - 配列番号32のDNA配列及び配列番号33のDNA配列を含む、請求項21に記載のDNA構築物。
- 配列番号34のDNA配列を含む、請求項21に記載のDNA構築物。
- 前記DNA構築物は、配列番号32のDNA配列及び、配列番号33のDNA配列または配列番号34のDNA配列を含む、請求項21に記載のDNA構築物。
- 請求項19~24のいずれか一項に記載の前記DNA構築物を含む、ベクタ。
- 請求項19~24のいずれか一項に記載のDNA構築物、又は請求項25に記載のベクタを含む、細胞。
- 前記細胞はT細胞である、請求項26に記載の細胞。
- 前記T細胞はCD4+T細胞及びCD8+T細胞から選ばれる、請求項27に記載の細胞。
- 請求項1~18、27又は28のいずれか一項に記載の複数のT細胞、並びに薬学的に許容される担体を含む、医薬組成物。
- 癌の治療を用途とする、請求項29に記載の医薬組成物。
- 前記癌は骨髄腫である、請求項30に記載の用途のための医薬組成物。
- 骨髄腫は多発性骨髄腫である、請求項31に記載の用途のための医薬組成物。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016510597A (ja) | 2013-03-07 | 2016-04-11 | ベイラー カレッジ オブ メディスンBaylor College Of Medicine | がんにおけるcd138の標的化 |
WO2017025323A1 (en) | 2015-08-11 | 2017-02-16 | Cellectis | Cells for immunotherapy engineered for targeting cd38 antigen and for cd38 gene inactivation |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006099875A1 (en) | 2005-03-23 | 2006-09-28 | Genmab A/S | Antibodies against cd38 for treatment of multiple myeloma |
CA2705353C (en) | 2007-11-14 | 2017-07-25 | The Medical Research, Infrastructure, And Health Services Fund Of The Tel Aviv Medical Center | Methods of treating cancer using anti cd24 antibodies |
ES2526433T3 (es) * | 2007-12-26 | 2015-01-12 | Biotest Ag | Inmunoconjugados dirigidos a CD138 y usos de los mismos |
CA2710453C (en) | 2007-12-26 | 2019-07-02 | Biotest Ag | Agents targeting cd138 and uses thereof |
JOP20210044A1 (ar) * | 2010-12-30 | 2017-06-16 | Takeda Pharmaceuticals Co | الأجسام المضادة لـ cd38 |
KR102198058B1 (ko) | 2012-10-02 | 2021-01-06 | 메모리얼 슬로안 케터링 캔서 센터 | 면역치료용 조성물 및 방법 |
WO2014055657A1 (en) | 2012-10-05 | 2014-04-10 | The Trustees Of The University Of Pennsylvania | Use of a trans-signaling approach in chimeric antigen receptors |
KR102466666B1 (ko) * | 2013-03-15 | 2022-11-15 | 메모리얼 슬로안 케터링 캔서 센터 | 면역치료용 조성물 및 방법 |
US10238690B2 (en) * | 2013-03-15 | 2019-03-26 | Celgene Corporation | Modified T lymphocytes comprising an inducible caspase and methods of apoptosis |
US9603927B2 (en) | 2014-02-28 | 2017-03-28 | Janssen Biotech, Inc. | Combination therapies with anti-CD38 antibodies |
EP3593812A3 (en) | 2014-03-15 | 2020-05-27 | Novartis AG | Treatment of cancer using chimeric antigen receptor |
EP3256492A4 (en) * | 2015-02-09 | 2018-07-11 | University of Florida Research Foundation, Inc. | Bi-specific chimeric antigen receptor and uses thereof |
AU2016283102B2 (en) | 2015-06-25 | 2021-03-11 | Icell Gene Therapeutics Llc | Chimeric antigen receptors (CARs), compositions and methods of use thereof |
EP3313874B1 (en) | 2015-06-26 | 2021-03-10 | University of Southern California | Masking chimeric antigen receptor t cells for tumor-specific activation |
CA2994829A1 (en) | 2015-08-07 | 2017-02-16 | Seattle Children's Hospital (dba Seattle Children's Research Institute) | Bispecific car t-cells for solid tumor targeting |
CA2997551A1 (en) | 2015-09-04 | 2017-03-09 | Memorial Sloan Kettering Cancer Center | Immune cell compositions and methods of use |
GB201518817D0 (en) * | 2015-10-23 | 2015-12-09 | Autolus Ltd | Cell |
CA3016287A1 (en) * | 2016-03-04 | 2017-09-08 | Novartis Ag | Cells expressing multiple chimeric antigen receptor (car) molecules and uses therefore |
CN105820254B (zh) * | 2016-04-12 | 2019-07-02 | 上海优卡迪生物医药科技有限公司 | 抗cd138嵌合抗原受体、编码基因、重组表达载体及其构建方法和应用 |
WO2018144535A1 (en) | 2017-01-31 | 2018-08-09 | Novartis Ag | Treatment of cancer using chimeric t cell receptor proteins having multiple specificities |
CN107326014B (zh) | 2017-07-31 | 2019-09-24 | 时力生物科技(北京)有限公司 | 一种双特异性嵌合抗原受体修饰的t淋巴细胞及其制备方法和应用 |
US20210300986A1 (en) | 2017-12-05 | 2021-09-30 | The Medical Research Infrastrutrure And Health Services Fund Of The Tel Aviv Medecal Center | T-cells comprising two different chimeric antigen receptors and uses thereof |
-
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016510597A (ja) | 2013-03-07 | 2016-04-11 | ベイラー カレッジ オブ メディスンBaylor College Of Medicine | がんにおけるcd138の標的化 |
WO2017025323A1 (en) | 2015-08-11 | 2017-02-16 | Cellectis | Cells for immunotherapy engineered for targeting cd38 antigen and for cd38 gene inactivation |
Non-Patent Citations (4)
Title |
---|
Blood Reviews,2015年03月,Vol.29, No.2,pp.81-91,https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482758/のPDFファイルを参照(上記引用箇所はPDFファイルのページ数を意味する) |
Cancer Immunology Research,2013年07月01日,Vol.1, No.1,pp.43-53,https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881605/のPDFファイルを参照(上記引用箇所はPDFファイルのページ数を意味する) |
Journal of Clinical Immunology,2012年,Vol. 32,pp.1059-1070,https://link.springer.com/article/10.1007/s10875-012-9689-9を参照 |
Molecular Medicine,2006年12月,Vol.12,pp.345-346,https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1829201/を参照 |
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