JP2017536821A - 抗サイログロブリンt細胞レセプター - Google Patents
抗サイログロブリンt細胞レセプター Download PDFInfo
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Abstract
Description
本願は、2014年11月14日に出願された米国仮特許出願第62/079,713号について優先権を主張し、その全体が本明細書に援用される。
本明細書と同時に提出され、コンピューターで読み取り可能な以下のヌクレオチド/アミノ酸配列リストは、その全体が本明細書に援用される:2015年11月1日付けの「722275_ST25.txt」という名前の68,835バイトのASCII(テキスト)ファイル1件
本発明の一実施形態は、ヒトTGに対する抗原特異性を有する、単離又は精製されたTCRを提供する。本発明のTCR(その機能的部分及びその機能的変異体を含む)は、任意のヒトTGタンパク質、ポリペプチド又はペプチドに対して抗原特異性を有してもよい。本発明の一実施形態では、該TCR(その機能的部分及びその機能的変異体を含む)は配列番号1のアミノ酸配列を含む又はそれからなるヒトTGタンパク質に対して抗原特異性を有する。本発明の一実施形態において、該TCR(その機能的部分及びその機能的変異体を含む)は、NLFGGKFLV(配列番号2)のアミノ酸配列を含む若しくはそれからなるヒトTG470−478ペプチド、又はLVLEIFTLL(配列番号58)のアミノ酸配列を含む若しくはそれからなるヒトTG3−11ペプチドに対して、抗原特異性を有する。本発明の好ましい実施形態では、該TCR(その機能的部分及びその機能的変異体を含む)は、NLFGGKFLV(配列番号2)のアミノ酸配列を含む又はそれからなるヒトTG470−478ペプチドに対する抗原特異性を有する。
10%ウシ胎児血清(FBS;Sigma, St. Louis, MO)、10IU/L甲状腺刺激ホルモン(TSH;Sigma-Aldrich)、インスリン−トランスフェリン−セレン(Life Technologies)を含むダルベッコ改変イーグル培地(DMEM)(Life Technologies, Carlsbad, CA)中で、ヒュルトレがん細胞株XTC(内分泌外科部門、NCI)を維持した。HLA−A2を発現するXTC株(XTC/A2)を、HLA−A*0201を有するレトロウイルスでXTCを形質導入することにより樹立した(手術部門、NCI)。使用した細胞株はTopalian et al., J.Immunol., 142(10): 3714-25(1989)に記載のように、手術部門において切除腫瘍から作製したメラノーマ株624及び938を含んでいた。Cos7、T2及び293GP細胞株を、NCIの手術部門から入手した。線維芽細胞(手術部門、NCI)及び小気道上皮細胞(Lonza, Walkersville, MD)を含む正常なヒト初代培養株を実験の対照として使用し、10%FBSを含むRPMI1640培地(Life Technologies)で維持した。対照として用いたがん細胞株は以下の通り:MDA231(乳腺癌;HLA−A2+)、MDA468(乳腺癌;HLA−A2−)、H2087(肺癌;HLA−A2+)、BE−3(食道下部のバレット食道関連腺癌;HLA−A2+)、SK−BR3(乳腺癌;HLA−A2−)、SK−OV3(卵巣腺癌;HLA−A2−)、BIC(ヒト食道腺癌、HLA−A2+)及び4つの腎細胞癌腫株(HLA−A2+;外科部門、NCI)。
RNAを、外科的に切除した組織から採取するか、又は商業的に購入した(Clonetech, Mountain View, CA)。相補的DNA(cDNA)を、高容量cDNA逆転写キット、又はSUPERSCRIPT III First-Strand cDNA合成システム(Life Technologies)によって合成した。抗原の比較のために、以下のRT-PCR Taqmanプローブを使用した:3'TG(00968047_ml)、TPO(Hs00374163_A1)、IYD(Hs00416923_A1)、FOXE1(Hs00915085_S1)、PAX8(Hs00247586_m1)、及びACTB(Hs03023880_g1)(Life Technologies)。TGについては、正常組織パネルにおけるTGの低発現を評価するために、カスタムデザインのTaqmanプライマー/プローブを用いた。絶対コピー数を、7500FASTリアルタイムPCRシステム(Life Technologies)を用いて、各cDNAをコードするプラスミドを対照として作成した標準曲線に基づいて算出した。
正常な甲状腺に由来する全RNAを、RNeasy miniキット(Qiagen, Valencia, CA)を用いて手術標本から精製し、ランダムヘキサマーをプライマーとしたcDNAを、SUPERSCRIPT III First-Strand cDNA合成システム(Life Technologies)により合成した。TG42−8348の5'側に由来する2つの短いcDNA断片(TG42−2186及びTG2172−4292)をPCR増幅し、In−Fusionクローニングキット(Clonetech)を用いてpShuttle2ベクターにクローニングした。配列確認後、pShuttle2/TG42−4292プラスミドをHEK293細胞にトランスフェクションし、ウエスタンブロッティング(抗体:sc-7836, Santa Cruz Biotechnology)を行うことにより、TGタンパク質の産生を調べた。pShuttle2/TG42−4292プラスミドから、制限酵素消化によりサイトメガロウイルス(CMV)プロモーター−TG42−4292断片を得て、pAdeno-Xプラスミドにクローニングした。このプラスミドを、製造者の指示(ADENO-X発現システム1、Clonetech)に従って、組換えアデノウイルスを増幅するために使用した。増幅したウイルスをADENO-X maxi精製キット(Clonetech, Mountain View, CA)で精製し、PD10ゲルろ過カラム(GE Healthcare Life Sciences, Pittsburgh, PA)を用いて緩衝液をPBSと交換した。感染性ウイルスの力価を、ADENO-X rapidタイターキット(Clonetech)を用いて測定した。
Yeti/HLA−A*0201(Yeti/A2)を作製するために、Yetiマウス(Stetson et al., J.Exp.Med., 198(7): 1069-76(2003))を、HLA−A*0201トランスジェニックマウスと交配させた。マウスはまた、IFN−γレポーター遺伝子である黄色蛍光タンパク質(YFP)のトランスジェニックであった。Yetiシステムでは、YFPの発現はIFN−γプロモーターによって駆動される。これらのマウスの細胞がIFN−γを産生する場合、細胞がYFPも発現するのを蛍光顕微鏡で視覚化することができ、又は蛍光活性化細胞スキャン(FACS)によって検出することができる。1億コロニー形成単位(CFU)の組換えアデノウイルス/TG42−4292を用いて、2週間の間隔でYeti/A2を免疫した(半分には尾基部の静脈注射、他方の半分には尾基部への皮下注射を行った)。2回目のアデノウイルスを用いた免疫の2週間後、脾臓細胞を採取し、10%ウシ胎児血清(FBS;Life Technologies)、55μM2−メルカプトエタノール(Life Technologies)、1mMピルビン酸ナトリウム(Life Technologies)、1×MEM非必須アミノ酸(Life Technologies)、10μg/mLゲンタマイシン(Life Technologies)、10U/mLペニシリン、100μg/mLストレプトマイシン(Life Technologies)及び250ng/mLのアンホテリシンB(Life Technologies)を含むRPMI(Life Technologies)に組換えヒト・インターロイキン(IL)−2(30IU/ml)を添加した中で、細胞濃度が100万細胞/ウェルとなるように24ウェルプレート上に播種した。個々のペプチドを、最終濃度で1μMとなるように添加した。1週間での再刺激を、以下に記載するように行った。HLA−A*0201陽性のエプスタイン−バーウイルスで形質転換したBリンパ芽球様T2細胞を100Gyで照射し、1μMの濃度で各ペプチドを室温で2時間パルスした。培地で3回洗浄した後、T2細胞をYeti脾細胞におよそ1:1の細胞数比となるよう加えた。2回目のインビトロ刺激の2日後、蛍光顕微鏡(AX10, Zeiss)及びフローサイトメトリー(FACS; FACSCanto II, BD Biosciences)を用いて黄色蛍光タンパク質(YFP)発現を分析した。YFPを発現した培養細胞を、TG発現標的細胞(TGを発現するようにトランスフェクトしたXTC/A2及びCosA2)との共培養のために選択し、IFN−γ分泌によって反応性を調べた。T細胞受容体遺伝子をクローニングする目的で、RNeasyキットを用いてTG反応性を有する培養細胞からRNAを精製した。
Robbins et al., J. Clin. Oncol, 29(7): 917-24 (2011)に記載されているように、リポフェクタミン2000(Life Technologies)を用いて、抗TG−TCR及びエンベロープタンパク質(RD114)をコードするレトロウイルスベクターで、293GP細胞を共トランスフェクションすることにより、レトロウイルス上清を作製した。リポフェクションの翌日、培地を新しい培地と交換した。上清を48時間後に回収し、抗CD3で刺激した末梢血リンパ球(PBL)を形質導入するために使用した。
全てのPBLは、施設内治験審査委員会が承認した試験に登録された患者からの白血球除去輸血によって収集した。Cohen et al., Cancer Res., 66(17): 8878-86 (2006)に記載のように、5%ヒト血清(Valley Biomedical Inc., Winchester, VA)、及びPBLにとって300IU/mlとなる濃度のIL−2(Prometheus, San Diego, CA)を含有するAIM−V培地(Life Technologies)を用いて、リンパ球を培養した。同種異系ドナーに由来するPBLを、形質導入が行われる前の2日間、可溶性の抗CD3(OKT3、50ng/mL)及びIL−2(300IU/mL)で刺激した。刺激後、レトロネクチン(10μg/mLの濃度で400μLのPBSに溶解されている;宝酒造、日本)で最初にコートした24ウェルプレートに、細胞を加え、続いてウイルス含有培養上清を添加し、遠心分離(2000×g、32℃、2時間)した。ウイルスを添加した後、刺激したPBLを1ウェル当たり5×105細胞の濃度で添加し、プレートを1000×gで10分間遠心分離した。プレートを5%CO2インキュベーター内において、37℃で一晩インキュベートした。翌日、新しいレトロネクチンでコーティングし、ウイルスを添加した24ウェルプレートに細胞を移すことで、2回目の形質導入を行った。細胞を0.5〜1×106細胞/mLの間の細胞密度に維持した。形質導入効率を、形質導入したPBLにおけるマウスTCR−β発現のFACS分析で確認した。
既に、Wang et al., J. Immunol Methods, 366(1-2): 43-51 (2011)に記載のように、形質導入したPBLによるインターフェロン(IFN)−γの放出を決定した。簡潔には、10%FBSを含むRPMI中で37℃、5%CO2条件下で、レトロウイルス形質導入細胞(1×105)を18〜22時間、5×104標的細胞(XTC、XTC/A2、CosA2又はTGでトランスフェクトしたCosA2)又は対照腫瘍細胞株と共に培養した。後日、IFN−γ分泌を、酵素結合免疫吸着アッセイ(ELISA)により決定した。
この実施例は、TGが正常組織、原発性甲状腺癌及びリンパ節転移癌において発現していることを実証する。
この実施例はTG470−478によるYeti/A2脾細胞の刺激を実証する。
この実施例は実施例2のTG470−478で刺激した脾細胞からのネズミ抗TG−TCRの単離を実証する。
この実施例は実施例3のネズミ抗TG−TCRをコードするレトロウイルス組換え発現ベクターの作製を実証する。
この実施例は、ネズミ抗TG−TCRをコードするレトロウイルスベクターによるドナーPBLの形質導入を実証する。
この実施例はHLA−A*0201+/TG+標的に対するネズミ抗TG−TCRの反応性を実証する。
この実施例はHLA−A*0201+/TG+標的に対するネズミ抗TG−TCRの特異性を実証する。
この実施例はヒト抗TG−TCRの単離及びPBLへのヒト抗TG−TCRの形質導入効率を実証する。
この実施例においては実施例8のヒト抗TG−TCRの反応性を示す。
Claims (31)
- ヒト・サイログロブリン(TG)に対する抗原特異性を有し、配列番号3のアミノ酸配列を含むα鎖相補性決定領域(CDR)1と、配列番号4のアミノ酸配列を含むα鎖CDR2と、配列番号5のアミノ酸配列を含むα鎖CDR3と、配列番号6のアミノ酸配列を含むβ鎖CDR1と、配列番号7のアミノ酸配列を含むβ鎖CDR2と、及び配列番号8のアミノ酸配列を含むβ鎖CDR3とを含む、単離又は精製されたT細胞受容体(TCR)。
- 前記TCRが配列番号2のTG470−478アミノ酸配列に対する抗原特異性を有する、請求項1に記載の単離又は精製されたTCR。
- 配列番号9のアミノ酸配列を含むα鎖可変領域、及び配列番号10のアミノ酸配列を含むβ鎖可変領域を含む、請求項1又は2に記載の単離又は精製されたTCR。
- 配列番号13のアミノ酸配列を含むα鎖定常領域、及び配列番号14のアミノ酸配列を含むβ鎖定常領域をさらに含む、請求項1〜3のいずれか一項に記載の単離又は精製されたTCR。
- 配列番号11のアミノ酸配列を含むα鎖、及び配列番号12のアミノ酸配列を含むβ鎖を含む、請求項1〜4のいずれか一項に記載の単離又は精製されたTCR。
- 自己切断型ウイルスリンカーペプチドを含む、請求項1〜5のいずれか一項に記載の単離又は精製されたTCR。
- 請求項1〜6のいずれか一項に記載のTCRの機能的部分を含む単離又は精製されたポリペプチドであって、前記機能的部分が(a)配列番号3〜5、(b)配列番号6〜8、又は(c)配列番号3〜8のアミノ酸配列を含む、ポリペプチド。
- 請求項1〜6のいずれか一項に記載のTCRの機能的部分を含む単離又は精製されたポリペプチドであって、前記機能的部分が(a)配列番号9、(b)配列番号10、又は(c)配列番号9及び10の両方のアミノ酸配列を含む、ポリペプチド。
- 請求項1〜6のいずれか一項に記載のTCRの機能的部分を含む単離又は精製されたポリペプチドであって、前記機能的部分が(a)配列番号11、(b)配列番号12、又は(c)配列番号11及び12の両方のアミノ酸配列を含む、ポリペプチド。
- 自己切断型ウイルスリンカーペプチドを含む、請求項7〜9のいずれか一項に記載の単離又は精製されたポリペプチド。
- 少なくとも1つの請求項7〜10のいずれか一項に記載のポリペプチドを含む、単離又は精製されたタンパク質。
- 配列番号3〜5のアミノ酸配列を含む第1ポリペプチド鎖、及び配列番号6〜8のアミノ酸配列を含む第2ポリペプチド鎖を含む、請求項11に記載の単離又は精製されたタンパク質。
- 配列番号9のアミノ酸配列を含む第1ポリペプチド鎖、及び配列番号10のアミノ酸配列を含む第2ポリペプチド鎖を含む、請求項11又は12に記載の単離又は精製されたタンパク質。
- 配列番号11のアミノ酸配列を含む第1ポリペプチド鎖、及び配列番号12のアミノ酸配列を含む第2ポリペプチド鎖を含む、請求項11〜13のいずれか一項に記載の単離又は精製されたタンパク質。
- 前記タンパク質が融合タンパク質である、請求項11〜14のいずれか一項に記載の単離又は精製されたタンパク質。
- 前記タンパク質が組換え抗体である、請求項11〜15のいずれか一項に記載の単離又は精製されたタンパク質。
- 自己切断型ウイルスリンカーペプチドを含む、請求項11〜16のいずれか一項に記載の単離又は精製されたタンパク質。
- 請求項1〜6のいずれか一項に記載のTCR、請求項7〜10のいずれか一項に記載のポリペプチド、又は請求項11〜17のいずれか一項に記載のタンパク質をコードするヌクレオチド配列を含む、単離又は精製された核酸。
- 配列番号22〜27のヌクレオチド配列を含む、請求項18に記載の核酸。
- 配列番号15及び16のヌクレオチド配列を含む、請求項18又は19に記載の核酸。
- 配列番号19及び20のヌクレオチド配列をさらに含む、請求項18〜20のいずれか一項に記載の核酸。
- 配列番号17及び18のヌクレオチド配列を含む、請求項18〜21のいずれか一項に記載の核酸。
- 請求項18〜22のいずれか一項に記載の核酸を含む、組換え発現ベクター。
- 配列番号21のヌクレオチド配列を含む、請求項23に記載の組換え発現ベクター。
- 請求項23又は24に記載の組換え発現ベクターを含む、単離された宿主細胞。
- 前記細胞がヒトである、請求項25に記載の宿主細胞。
- 請求項25又は26に記載の少なくとも1つの宿主細胞を含む、細胞集団。
- 請求項1〜6のいずれか一項に記載のTCRの機能的部分に特異的に結合する抗体又はその抗原結合部分であって、前記機能的部分が、配列番号3〜8のアミノ酸配列を含む、抗体又はその抗原結合部分。
- 請求項1〜6のいずれか一項に記載のTCRと、請求項7〜10のいずれか一項に記載のポリペプチドと、請求項11〜17のいずれか一項に記載のタンパク質と、請求項18〜22に記載の核酸と、請求項23又は24に記載の組換え発現ベクターと、請求項25又は26に記載の宿主細胞と、請求項27に記載の細胞集団と、請求項28に記載の抗体又はその抗原結合部分と、医薬的に許容される担体とを含む、医薬組成物。
- 哺乳動物におけるがんの検出、治療又は予防に用いるための、請求項1〜6のいずれか一項に記載のTCR、請求項7〜10のいずれか一項に記載のポリペプチド、請求項11〜17のいずれか一項に記載のタンパク質、請求項18〜22に記載の核酸、請求項23若しくは24に記載の組換え発現ベクター、請求項25又は26に記載の宿主細胞、請求項27に記載の細胞集団、請求項28に記載の抗体若しくはその抗原結合部分、又は請求項29に記載の医薬組成物。
- 前記がんが甲状腺癌又は神経芽細胞腫である、請求項30に記載のTCR、ポリペプチド、タンパク質、核酸、組換え発現ベクター、宿主細胞、細胞集団、抗体若しくはその抗原結合部分、又は医薬組成物。
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