JP4448282B2 - ヒト癌を処置するのに有用なキメライムノレセプター - Google Patents
ヒト癌を処置するのに有用なキメライムノレセプター Download PDFInfo
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- JP4448282B2 JP4448282B2 JP2002585615A JP2002585615A JP4448282B2 JP 4448282 B2 JP4448282 B2 JP 4448282B2 JP 2002585615 A JP2002585615 A JP 2002585615A JP 2002585615 A JP2002585615 A JP 2002585615A JP 4448282 B2 JP4448282 B2 JP 4448282B2
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Description
[0001]本発明は、癌治療、およびヒト脳腫瘍および他の癌の処置における、キメライムノレセプターを発現する遺伝子修飾されたTリンパ球の使用に関する。
[0002]原発性脳腫瘍は、若年成人の癌関連死亡率の第三の主因であり、小児では第二の主因であり、しかも小児科学的および老年医学的双方の集団において発病率が増加していると考えられる1〜4。神経膠腫は、原発性脳腫瘍の最も一般的なタイプであり、米国では毎年、20,000例が診断され、14,000例の神経膠腫関連死がある5〜8。神経膠腫は、それらの悪性作用に関して不均一(heterogenous)であるが、それらの最も一般的且つ攻撃的な形において、未分化星細胞腫(AA−III度)および多形性神経膠芽細胞腫(GBM−IV度)は、速やかに進行し且つほぼ一様に致死的である9〜10。現在利用可能な治療様式は、これら高度腫瘍に最小限の治癒的可能性しかなく、しばしば、中枢神経系中のそれらの場所に課される既に重症の病的状態を悪化させる。したがって、悪性神経膠腫の患者は、しばしば、生涯の最も生産的な時期に襲われ、頻繁に起こる知的諸能力の低下および高い疾患致命率が、これら腫瘍の特有の個人的および社会的影響の原因となっている。
[0016]本発明は、「ゼータカイン」と称されるキメラ膜貫通イムノレセプターであって、細胞表面に細胞外ドメインを接着すること(tethering)ができる支持体領域に連結した可溶性レセプターリガンドを含む細胞外ドメイン、膜貫通領域および細胞内シグナリングドメインを含んで成るものに関する。ゼータカインは、Tリンパ球の表面上で発現された場合、可溶性レセプターリガンドが特異的であるレセプターを発現するそれら細胞へのT細胞活性を支配する。ゼータカインキメライムノレセプターは、T細胞の抗原特異性を再支配するための抗体に基づくイムノレセプターの新規伸長であり、いろいろな癌の処置に、具体的には、ヒト悪性腫瘍によって利用されるオートクリン/パラクリンサイトカインシステムによって応用される。
[0028]遺伝子操作され再支配されたT細胞での腫瘍標的指向に理想的な細胞表面エピトープは、単に腫瘍細胞上において均一様式でおよび同じ診断の患者集団内の全ての腫瘍上において発現されると考えられる。腫瘍細胞膜からの標的分子のモジュレーションおよび/または流出(shedding)は、再支配されたT細胞認識のための特定の標的エピトープの有用性に影響を与えることもありうる。これまでのところ、「理想的な」腫瘍特異的エピトープは僅かしか定義されていないが、二次エピトープは、臨界的正常組織での発現不足かまたは腫瘍での相対的過剰発現に基づいて標的とされてきている。悪性神経膠腫の場合、この癌の処置のためのT細胞の腔内投与は、CMS外の他の組織による発現においてより小さいストリンジェンシーで、正常CNSではないが腫瘍細胞上で発現されるものへの標的エピトープの増大を可能にする。CMS外の組織の交差反応性による毒性に関する問題は、(a)腔内投与経路に基づくCNSにおける細胞の隔絶(sequestration)、および(b)典型的に全身投与される細胞用量と比較して低い投与細胞数によって軽減される。
[0036]本発明によるイムノレセプターのコーディング配列を、IL13(E13Y)コーディング配列の de novo 合成により、次のプライマーを用いて構築した(イムノレセプターのコーディング配列および発現ベクターの構築を示すフローチャートについては、図8を参照されたい)。
[0040]IL13ゼータカインコーディング配列を含有する発現ベクターは、実施例1で得られたIL13ゼータカイン/pSKを、XbaI−NotIで消化し、クレノウ(Klenow)を含むブラント末端を生じ、そして得られたフラグメントをプラスミドpMG^Pac(Invirogen)(SgrAIで開き、クレノウでブラントにし、SAPでの脱リン酸化によって最初に製造される)中に連結して、プラスミドIL13ゼータカイン/pMGを生じることによって生成した。図8を参照されたい。IL13ゼータカイン/pMGのハイグロマイシン耐性領域を、NotI−NheIでの消化によって除去し、そしてプラスミドCE7R/HyTK−pMG(Jensen, City of Hope)からNotI−NheIでの消化によって得られる選択/自殺融合HyTKによって置き換えて、発現ベクターIL13ゼータカイン/HyTK−pMG(6785bp)を生じた。このプラスミドは、Human Elongation Factor−1αプロモーター(hEF1p)を6〜549塩基に、IL13ゼータカインコーディング配列を692〜2185塩基に、シミアンウイルス40後期(Simian Virus 40 Late)ポリアデニル化シグナル(LateSV40pAN)を2232〜2500塩基に、最小の大腸菌(E.coli)複製起点(Ori ColE1)を2501〜3247塩基に、合成ポリAおよび Pause 部位(SpAN)を3248〜3434塩基に、極初期(Immeate-early)CMVエンハンサー/プロモーター(hCMV−1Aprom)を3455〜4077塩基に、ハイグロマイシン耐性チミジンキナーゼコーディング領域融合(HyTK)を4259〜6334塩基に、そしてウシ成長ホルモンポリアデニル化シグナルおよび転写ポーズ(BGh pAn)を6335〜6633塩基に含む。このプラスミドは、PacI線状化部位を3235〜3242塩基に有する。hEF1pおよびIL13ゼータカインエレメントは、IL13ゼータカイン/pMGから得、残りのエレメントは、CE7R/HyTK−pMGから(HyTKエレメントを除いて、最終的には親プラスミドpMG^Pacから)得た。要するに、IL13ゼータカイン/HyTK−pMGは、hEF1プロモーターからIL13ゼータカイン遺伝子、およびCMV−1AプロモーターからHyTK融合を発現する修飾pMG主鎖である。プラスミドIL13ゼータカイン/HyTK−pMGの地図は、図9で明らかである。
[0041]発現されたコンストラクトの統合性の評価を、グリコシル化の阻害剤であるツニカマイシンの存在下または不存在下で培養された Jurkat T細胞安定トランスフェクタント107に由来する全細胞溶解産物の抗ゼータ抗体でプローブされたウェスタンブロットによって最初に表した。図1。Jurkat T細胞安定トランスフェクタント(Jurkat−IL13−pMGバルク系統(bulk line))は、IL13ゼータカイン/HyTK−pMG発現ベクターを Jurkat T細胞にエレクトロポレーション後、陽性トランスフェクタントの選択および増大を行うことによって得た。Jurkat−IL13−pMGバルク系統から2x106個/ウェルの細胞を、24ウェルプレート中に5μg/ml、10μg/mlまたは20μg/mlのツニカマイシンと一緒にまたは不含でプレーティングした。そのプレートを37℃で22時間インキュベートした。細胞を各々のウェルから採取し、各試料をPBSで洗浄し、そして1錠/10ml Complete Protease Inhibitor Cocktail(Boehringer Mannheim, Indianapolis, IN)を含有する50μlのRIPA緩衝液(PBS,1%NP40,0.5%デオキシコール酸ナトリウム,0.1%SDS)中に再懸濁させた。試料を氷上で30分間インキュベート後、21ゲージ針のシリンジでの吸引によって破壊し、次に、氷上で更に30分間インキュベート後、4℃において14,000rpmで20分間遠心分離した。遠心分離された溶解産物上澄み試料を採取し、減圧条件下において等容量の試料用緩衝液中で沸騰させた後、12%アクリルアミドゲル上でSDS−PAGE電気泳動を行った。ニトロセルロースへの転移後、膜を4℃でO/N乾燥させた。翌朝、膜を、T−TBS(トリス緩衝化生理食塩水pH8.0中の0.02%トゥイーン20)中に0.04gm/mlの脱脂粉乳を含有する Blotto 溶液中で1時間ブロックした。次に、膜を、1μg/ml濃度の一次マウス抗ヒトCD3ζモノクローナル抗体(Pharmingen, San Diego, CA)と一緒に2時間インキュベートし、洗浄後、1:3000希釈(Blotto 溶液中)のヤギ抗マウスIgGアルカリ性ホスファターゼ抱合二次抗体(Bio-Rad ImmunoStar Kit, Hercules, CA)と一緒に1時間インキュベートした。展開前に、膜をT−TBS中で更に4回洗浄後、3mlのホスファターゼ基質溶液(Biorad ImmunoStar Kit, Hercules, CA)と一緒に室温で5分間インキュベートした。次に、膜をプラスチックで覆い、x線フィルムに露出させた。野生型ヒトIL−13の既知のグリコシル化パターンと一致して、発現されたIL−13(E13Y)ゼータカインの電気泳動移動度は、ツニカマイシンの存在下で発現された場合に約54kDaのアミノ酸主鎖まで減少する、強くグリコシル化されたタンパク質を示している。
[0043]ヒトIgG4Fcによって細胞膜に接着したIL−13(E13Y)(すなわち、IL13(E13Y)ゼータカイン)は、可溶性IL13Rα2−Fc融合タンパク質を用いたフローサイトメトリー分析によって評価されるように、その標的IL13Rα2レセプターに結合することができる。図3。クローン化されたヒトPBMC IL13ゼータカイン−pMGトランスフェクタントは、IL13ゼータカイン/HyTK−pMG発現ベクターをPBMCにエレクトロポレーション後、陽性トランスフェクタント107の選択および増大を行うことによって得た。IL13ゼータカイン+CTLクローン細胞を、細胞表面キメラレセプター発現の分析のために、フルオレセインイソチオシアネート(FITC)抱合マウス抗ヒトFc(ガンマ)フラグメント特異的F(ab’)2(Jackson ImmunoResearch, West Grove, PA)、リコンビナントヒトIL13Rα2/ヒトIgG1キメラ(R&D Systems, Minneapolis, MN)、次に、FITC抱合抗ヒトIgG1モノクローナル抗体(Sigma, St.Louis, MO)およびフィコエリトリン(PE)抱合抗ヒトIL13モノクローナル抗体(Becton Dickinson, San Jose, CA)で染色した。健康ドナーの初代細胞も、FITCに抱合された抗CD4、抗CD8、抗TCRおよびイソタイプ対照モノクローナル抗体(Becton Dickinson, San Jose, CA)で染色して、細胞表面表現型を評価した。各々の染色には、106個の細胞を洗浄し、2%FCS、0.2mg/ml NaN3および5μlの抗体を含有する100μlのPBS中に再懸濁させた。4℃で30分間インキュベーション後、細胞を2回洗浄し、そして二次抗体で染色するかまたは、1%パラホルムアルデヒドを含有するPBS中に再懸濁させ、FACSCaliber サイトメーターで分析した。
[0047]単核細胞を、ヘパリン化全血から、臨床等級 Ficoll(Pharmacia, Uppsula, Sweden)上での遠心分離によって分離する。PBMCを滅菌リン酸緩衝化生理食塩水(Irvine Scientific)中で2回洗浄し、そしてRPMI1640HEPES、10%熱失活FCSおよび4mM L−グルタミンから成る培地中に懸濁させる。患者PBMC中に存在するT細胞を、Orthoclone OKT3の培養物(30ng/ml)への添加によってポリクローナル活性化する。次に、細胞培養物を、研究対象指定インキュベーター中において脱気されたT75組織培養フラスコ中でインキュベートする。培養の開始後24時間に、rhIL−2を25U/mlで加える。
[0054]IL−13RゼータカインキメライムノレセプターおよびHyTKを発現するように実施例5によって遺伝子修飾されたT細胞クローンを、次について選択する。
b.サザンブロットによって示される、染色体に組み込まれたプラスミドベクターDNAの単コピーの存在。
d.4時間クロム放出検定におけるヒトIL−13Rα2+標的の特異的溶解。
f.マイコプラズマ、真菌、細菌の無菌状態および<5EU/mlの内毒素レベル。
g.ガンシクロビルへのクローンの in vitro 感受性。
Claims (3)
- 次の連結エレメント、
(a)IL−13のアミノ酸配列のうち、アミノ酸残基第13番目のグルタミン酸がチロシンに置換された変異体、
(b)IgG4定常領域、
(c)CD4膜貫通ドメイン、および
(d)細胞内T細胞抗原レセプターCD3複合体ゼータ鎖
を規定の順に含む、キメライムノレセプター。 - IL13α2レセプターが過剰発現している神経膠腫に罹患した患者の治療のための、請求項1に記載のキメライムノレセプターを発現する複数の細胞を含む、医薬組成物。
- 請求項1記載のキメライムノレセプターをコードする核酸配列を含む、ベクター。
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CN113164633B (zh) * | 2018-10-09 | 2023-11-21 | 艾比克斯生物科学公司 | 针对细丝蛋白-a的抗体及其治疗用途 |
AR120563A1 (es) | 2019-11-26 | 2022-02-23 | Novartis Ag | Receptores de antígeno quimérico cd19 y cd22 y sus usos |
WO2021244486A1 (zh) * | 2020-06-01 | 2021-12-09 | 上海君赛生物科技有限公司 | 信号转换受体及其用途 |
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US5015628A (en) * | 1986-06-12 | 1991-05-14 | The University Of Melbourne | Anticariogenic phosphopeptides |
US5041138A (en) * | 1986-11-20 | 1991-08-20 | Massachusetts Institute Of Technology | Neomorphogenesis of cartilage in vivo from cell culture |
ATE145428T1 (de) * | 1990-12-14 | 1996-12-15 | Cell Genesys Inc | Chimärische ketten zur transduktion von rezeptorverbundenen signalwegen |
DE4120325A1 (de) * | 1991-06-20 | 1992-12-24 | Merck Patent Gmbh | Implantatwerkstoff |
US5514378A (en) * | 1993-02-01 | 1996-05-07 | Massachusetts Institute Of Technology | Biocompatible polymer membranes and methods of preparation of three dimensional membrane structures |
US5522895A (en) * | 1993-07-23 | 1996-06-04 | Rice University | Biodegradable bone templates |
US5626861A (en) * | 1994-04-01 | 1997-05-06 | Massachusetts Institute Of Technology | Polymeric-hydroxyapatite bone composite |
US6065476A (en) * | 1994-12-21 | 2000-05-23 | Board Of Regents, University Of Texas System | Method of enhancing surface porosity of biodegradable implants |
JP2653423B2 (ja) * | 1995-03-29 | 1997-09-17 | 工業技術院長 | リン酸カルシウム化合物−セルロース繊維複合材料及びその製造法 |
JP2862509B2 (ja) * | 1996-05-28 | 1999-03-03 | 東洋電化工業株式会社 | リパーゼ固定化用担体及び固定化リパーゼ |
US5837674A (en) * | 1996-07-03 | 1998-11-17 | Big Bear Bio, Inc. | Phosphopeptides and methods of treating bone diseases |
US6281257B1 (en) * | 1998-04-27 | 2001-08-28 | The Regents Of The University Of Michigan | Porous composite materials |
AU2472400A (en) * | 1998-10-20 | 2000-05-08 | City Of Hope | CD20-specific redirected T cells and their use in cellular immunotherapy of CD20+ malignancies |
US6165486A (en) * | 1998-11-19 | 2000-12-26 | Carnegie Mellon University | Biocompatible compositions and methods of using same |
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EP1392818A4 (en) | 2005-01-05 |
WO2002088334A9 (en) | 2003-08-07 |
AU2002256390B2 (en) | 2007-08-30 |
US20030171546A1 (en) | 2003-09-11 |
JP2010047591A (ja) | 2010-03-04 |
CA2445746A1 (en) | 2002-11-07 |
CA2445746C (en) | 2012-09-18 |
AU2002256390B9 (en) | 2002-11-11 |
EP1392818A1 (en) | 2004-03-03 |
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