JP7447014B2 - インターロイキン23受容体に特異的なキメラ抗原受容体 - Google Patents
インターロイキン23受容体に特異的なキメラ抗原受容体 Download PDFInfo
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Classifications
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70517—CD8
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
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- C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
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Description
(i)上記IL-23Rに結合する細胞外結合ドメインと、
(ii)任意選択で、細胞外ヒンジドメインと、
(iii)膜貫通ドメインと、
(iv)細胞内シグナリングドメインと、
(v)任意選択で、タグおよび/またはリーダー配列と、
を含む、キメラ抗原受容体に関する。
配列番号37の配列または配列番号37と少なくとも約70%の同一性を有する配列を有する重鎖可変ドメイン(VH)と、
配列番号38、46、および56、ならびに配列番号38、46、または56と少なくとも約70%の同一性を有する配列を含むかまたはからなる群から選択される配列を有する軽鎖可変ドメイン(VL)と、
任意選択で、VHとVLの間のリンカーと
を含む。
(i)好ましくは配列番号37の配列を有するVHおよび配列番号38の配列を有するVLを含み;(G4S)3リンカー(配列番号3)により結合されている、抗IL-23RscFvと、
(ii)好ましくは配列番号13である、CD8α由来のヒンジドメインと、
(iii)好ましくは配列番号21である、ヒトCD8α膜貫通ドメインと、
(iv)好ましくは配列番号29である、ヒト4-1BBシグナリングドメインと、好ましくは配列番号26である、ヒトCD3ζドメインとを含む細胞内シグナリングドメインと、
(v)任意選択で、タグおよび/またはリーダー配列
を含む。
(i)IL-23Rに結合する、細胞外結合ドメインと、
(ii)任意選択で、細胞外ヒンジドメインと、
(iii)膜貫通ドメインと、
(iv)細胞内シグナリングドメインと、
(v)任意選択で、タグおよび/またはリーダー配列
を含む、
T細胞集団に関する。
(i)IL-23Rに結合する、細胞外結合ドメインと、
(ii)任意選択で、細胞外ヒンジドメインと、
(iii)膜貫通ドメインと、
(iv)細胞内シグナリングドメインと、
(v)任意選択で、タグおよび/またはリーダー配列
を含む、組成物に関する。
(i)上記少なくとも1つのIL-23Rに結合する、細胞外結合ドメインと、
(ii)任意選択で、細胞外ヒンジドメインと、
(iii)膜貫通ドメインと、
(iv)細胞内シグナリングドメインと、
(v)任意選択で、タグおよび/またはリーダー配列
を含み、
上記方法が、IL-23R-CARをコードする核酸による少なくとも1つのT細胞の遺伝子修飾、好ましくは形質導入、および任意選択で形質導入した細胞の増殖ステップを含む、
方法に関する。
(i)上記少なくとも1つのIL-23Rに結合する、細胞外結合ドメインと、
(ii)任意選択で、細胞外ヒンジドメインと、
(iii)膜貫通ドメインと、
(iv)細胞内シグナリングドメインと、
(v)任意選択で、タグおよび/またはリーダー配列と
を含む、方法に関する。
本発明において、以下の用語は以下の意味を有する。
本発明の第1の目的は、少なくとも1つのIL-23受容体(IL-23R)に特異的なキメラ抗原受容体(CAR)であって、
(i)上記IL-23Rに結合する、細胞外結合ドメイン(細胞外IL-23R結合ドメインと呼ばれ得る)と、
(ii)任意選択で、細胞外ヒンジドメインと、
(iii)膜貫通ドメインと、
(iv)細胞内シグナリングドメインと、
(v)任意選択で、タグおよび/またはリーダー配列
を含む、キメラ抗原受容体である。
配列番号29の4-1BB細胞内ドメインのアミノ酸配列、または配列番号29と少なくとも約95、好ましくは約96%、97%、98%、もしくは99%の同一性を有するアミノ酸配列、および/または配列番号30のCD27細胞内ドメインのアミノ酸配列、または配列番号30と少なくとも約95、好ましくは約96%、97%、98%、もしくは99%の同一性を有するアミノ酸配列、および/または配列番号31のCD28細胞内ドメインのアミノ酸配列、または配列番号31と少なくとも約95、好ましくは約96%、97%、98%、もしくは99%の同一性を有するアミノ酸配列;ならびに
配列番号25、26、61、もしくは62のCD3ζ細胞内ドメインのアミノ酸配列、または配列番号25、26、61、もしくは62と少なくとも約95、好ましくは約96%、97%、98%、もしくは99%の同一性を有するアミノ酸配列
を含み、
細胞内ドメインに含まれる配列は、同じフレームにおいて単一のポリペプチド鎖として発現される。
配列番号32の4-1BB細胞内ドメインの核酸配列、または配列番号32と少なくとも約95、好ましくは約96%、97%、98%、もしくは99%の同一性を有する核酸配列、および/または配列番号33のCD27細胞内ドメインの核酸配列、または配列番号33と少なくとも約95、好ましくは約96%、97%、98%、もしくは99%の同一性を有する核酸配列、および/または配列番号34のCD28細胞内ドメインの核酸配列、または配列番号34と少なくとも約95、好ましくは約96%、97%、98%、もしくは99%の同一性を有する核酸配列;ならびに
配列番号27もしくは配列番号28のCD3ζ細胞内ドメインの核酸配列、または配列番号27もしくは配列番号28と少なくとも約95、好ましくは約96%、97%、98%、もしくは99%の同一性を有する配列
を含む。
PBMC集団由来のTreg細胞(たとえば白血球アフェレーシスにより回収される)の単離ステップと、
本明細書で上述されるCARをコードする核酸配列がTreg細胞内に導入または伝達される遺伝子修飾ステップと、
任意選択で増殖ステップと、
任意選択で洗浄ステップと、
任意選択で凍結ステップ
を含む。
PBMC集団由来のTreg細胞(たとえば白血球アフェレーシスにより回収される)の単離ステップと、
本明細書で上述されるCARをコードする核酸配列を含むベクターを用いた形質導入またはトランスフェクションのステップと、
任意選択で増殖ステップと、
任意選択で洗浄ステップと、
任意選択で凍結ステップ
を含む。
またはこれら範囲内の全ての整数の値の範囲である。
材料および方法
細胞および試薬
HEK293T細胞(LentiX, Ozyme, France)を、10%のウシ胎仔血清(FBS)を補充したDMEM培地中で培養した。
CD4+CD25+CD127lowTreg細胞を、StemCell製のEasySep(商標)ヒトCD4+CD127lowCD25+Regulatory T Cell Isolation Kitを使用して、バフィーコートからすばやく単離した。単離の後、純度をFoxP3染色により評価した。単離したTreg細胞を、24ウェルプレート(Costar)においてウェルあたり5×105個の細胞で、X-VIVO 15培地(Lonza)中にプレーティングし、抗CD3/抗CD28でコーティングしたマイクロビーズ(Invitrogen, Carlsbad, CA)を用いて、1:1のビーズ:細胞の比率で活性化した。活性化と同時にTreg細胞に、ラパマイシン(100ng/ml)を添加した。2、5、7、および9日目に、IL-2(1000ユニット/ml、Miltenyi)を添加した。
抗IL23R CARコンストラクトは、ヒトCD8リーダー配列(aa1-22)(たとえば配列番号39の配列を有する)、ヒトIL23Rに対するscFv(たとえば配列番号55の配列を有する)、CD8ヒンジ(たとえば配列番号13の配列を有する)、およびヒトCD8α由来の膜貫通ドメイン(aa138-206)(たとえば配列番号21の配列を有する)、ヒト4-1BBの活性化ドメイン(aa214-255)(たとえば配列番号29の配列を有する)、およびCD3ζ(aa52-164)(配列番号26の配列を有する)を含む。CARコンストラクトは、P2A-GFPコード配列とフレームが合っている。
CARコンストラクトを、古典的な4-プラスミドレンチウイルス系を使用して産生した。簡潔に述べると、HEK293T細胞を、第3世代のレンチウイルスの移入ベクター(pTX266)、HIV-1 gagpolを発現するプラスミド(pMDLgpRRE)、HIV-1 revを発現するプラスミド(pRSV.Rev)およびVSV-Gを発現するプラスミド(pRSV.Rev)、水疱性口内炎ウイルスのエンベロープ糖タンパク質(pMD2.G)を用いてトランスフェクトした。トランスフェクションから1日後に、ウイルスの上清を回収し、遠心により濃縮し、分割し、長期保存のため-80℃で保存した。mlあたりの形質導入単位(transducing units per milliliter)の数(TU/ml)により表される感染の力価を、ウイルス上清の段階希釈を用いるJurkat T細胞の形質導入の後に入手し、形質導入の効率を、フローサイトメトリーを使用して緑色蛍光タンパク質(GFP)の発現をモニタリングすることにより、3日後に評価した。
Tregを、CD8の配列リーダー、次いでscFv抗IL-23Rから構成されるキメラ受容体によるそれらの活性化から2日後に形質導入した。この細胞外ドメインは、ヒトCD8のヒンジおよび膜貫通領域を介してシグナリング配列に連結される。シグナリング配列は、4-1BBの細胞内ドメイン、次いで細胞内ヒトCD3ζ鎖から構成される。簡潔に述べると、形質導入を、各ウェルに対してmlあたり0.5×107の形質導入単位(TU)をローディングすることにより行った。37℃にて6時間後に、ウイルス粒子を、洗い流しにより除去した。次にプレートを、5%のCO2、37℃でインキュベートした。形質導入の効率(GFP発現により評価)および細胞表面でのキメラ受容体のレベル(プロテインL染色により評価される)を、形質導入から5日後に確認した。
細胞表面CAR発現の定量化を、APCがコンジュゲートされたプロテインLでCARを標識することにより行い、フローサイトメトリーを使用して分析した。簡潔に述べると、洗浄後に、細胞を、氷冷したウォッシュバッファー(PBS 4% BSA)0.2mlに再懸濁し、4℃で20分間、5μgのプロテインLと共にインキュベートした。細胞を、0.2mlの氷冷したウォッシュバッファーで3回洗浄し、次に、0.2mlのウォッシュバッファー中1μlのAPCがコンジュゲートされたストレプトアビジンと共にインキュベートした(暗室で)。免疫蛍光染色を、MacsQuantify software(Miltenyi)を使用してMACQUANT(Miltenyi)で行った。
ヒトのTreg細胞を、CD4+CD127lowCD25+プロファイルに基づきStem Cell製のキットを使用して選別し、ウイルス形質導入を行う前に2日間、抗CD3/抗CD28でコーティングしたビーズおよびIL-2で前刺激した。Tregを、抗-IL-23Rの単鎖可変領域(scFv)から構成されるキメラ抗原受容体(IL-23R-CAR)で形質導入し、ヒトCD8のヒンジおよび膜貫通領域を介してシグナリング配列に連結し、ヒト4-1BBの細胞内部分に連結し、これを次に細胞内ヒトCD3ζ鎖に融合した(図1参照)。
材料および方法
FoxP3 Tregの単離
CD4+CD25+マウスTreg細胞を、life technologies製のRegulatory T Cell Isolation Kitを使用してC57Bl6マウスの脾臓からすばやく単離した。単離した後に、純度を、FoxP3染色により評価した。単離したTreg細胞を、24ウェルプレートにおいてウェルあたり5×105個の細胞で、RPMI 10% SVF中に置き、抗CD3/抗CD28でコーティングしたマイクロビーズ(Invitrogen)を用いて、2:1のビーズ:細胞の比率で活性化した。活性化と同時および4日目に、Treg細胞にラパマイシン(50ng/ml)を加えた。最後に、0、2、4日目に、IL-2を添加した(1000ユニット/ml)。
この実験で使用される抗マウスIL23R CARコンストラクト(たとえば配列番号77の核酸配列および配列番号78のアミノ酸配列を有する)は、ヒトCD8リーダー配列(CD8)、ヒト/マウスIL23Rに向けられる交差反応性scFv(αIL23R)、マウスCD28由来のヒンジおよび膜貫通ドメイン(mCD28リンカーおよびmCD28 TM)、マウスCD28の活性化ドメイン(mCD28)、ならびにマウスCDζ(mCD3Z)を含む。
CARコンストラクトを、古典的な4-プラスミドレンチウイルス系を使用して産生した。簡潔に述べると、HEK293T細胞を、第3世代のレンチウイルスの移入ベクター、HIV-1 gagpolを発現するプラスミド(pMDLgpRRE)、HIV-1 revを発現するプラスミド(pRSV.Rev)、およびEco-MLVを発現するプラスミド、エコトロピックマウス白血病ウイルスのエンベロープ糖タンパク質(pCMV-Eco)でトランスフェクトした。トランスフェクションしてから1日後に、ウイルスの上清を回収し、遠心により濃縮し、分割し、長期間保存のために-80℃で保存した。TU/mlの数により表される感染の力価を、ウイルス上清の段階希釈を用いるJurkat T細胞の形質導入の後に入手し、形質導入の効率を、フローサイトメトリーを使用して緑色蛍光タンパク質(GFP)の発現をモニタリングすることにより3日後に評価した。
Tregを、CD8の配列リーダー、続いてscFv抗IL-23Rから構成されるキメラ受容体によるそれらの活性化から2日後に形質導入した。この細胞外ドメインは、ヒトCD8のヒンジおよび膜貫通領域を介してシグナリング配列に連結される。シグナリング配列は、4-1BBの細胞内ドメイン、続いて細胞内ヒトCD3ζ鎖に対し構成されている。簡潔に述べると、形質導入を、各ウェルに対して0.5×107TU/mlをローディングすることにより行った。37℃にて6時間後に、ウイルス粒子を、洗い流しにより除去した。次にプレートを、5%のCO2、37℃でインキュベートした。形質導入の効率(GFP発現により評価される)および細胞表面でのキメラ受容体のレベル(プロテインLにより評価される)を、形質導入から5日後に確認した。
活性化アッセイを、培養の7日目に行った。簡潔に述べると、0.05×106個のTregを、200μlの最終容量にて単独でまたは抗CD28/抗CD2でコーティングされたビーズ(2:1のTreg:ビーズの比率)の存在下、またはプレートにコーティングされたマウスIL-23R(1μg/ml)の存在下、または用量が増加するビーズにコーティングされたヒトおよびマウスのIL-23Rの存在下にて、U底96ウェルプレートに播種した。37℃、5%のCO2にて24時間後、細胞を、CD4およびCD69について染色し、次にフローサイトメトリーを使用して分析した。
抑制アッセイを、培養の7日目に行った。OTIIマウス由来の脾細胞(OVAに特異的なTCRのTg)を、マウスのIL-23Rでコーティングされたビーズまたは抗CD3/CD28ビーズを伴うかまたは伴わずに、卵白アルブミン(100μg/ml)の存在下で、形質導入されていないTreg(Poly Treg)またはIL-23RmCAR Tregの存在下で4日間共培養した。4日目に、細胞を回収し、脾細胞由来のCD4の増殖を、dye 450の希釈の決定を介してフローサイトメトリーにより評価した。Tconv増殖の阻害のパーセンテージを、以下のように計算した。
8~10週齢のマウス(C57BL/6)に、連続して7日間、剪毛した背中に市販のIMQ cream(5%)(Aldara;3M Pharmaceuticals)の一日の局所用量の62.5mgを投与した。対照のマウスを、対照のビヒクルクリーム(Vaseline Lanette cream;Fagron)で同様に処置した。2日目に、抗IL-23(100μg)を腹腔内注射し、マウスあたり8×106個のTreg(PolyまたはaIL-23R-CAR)を静脈内注射した。7日目に、全てのマウスを屠殺した。背中の皮膚の炎症の重症度をスコア付けするために、客観的なスコアリングシステムを、臨床的なPASI(Psoriasis Area and Severity Index)に基づき開発した。発赤、スケーリング、および厚さを独立に、0~4:(0、なし;1、わずか;2、中程度;3、顕著;4、著しく顕著)の尺度でスコア付けした。発赤のレベルを、赤い痕跡を伴うスコア付け表を使用してスコア付けした。累積スコア(発赤+スケーリング+厚さ)は、炎症の重症度の測定値として機能した(尺度0~12)。全ての実験は、動物実験に関するフランスの法律によって動物倫理委員会により承認された。
単離の後に、マウスTreg(mTreg)細胞を、ウイルス形質導入を行う前に2日間、抗CD3/抗CD28でコーティングしたビーズおよびIL-2で前刺激した。mTregを、交差反応性hu/ms抗IL-23Rの一本鎖可変フラグメント(scFv)から構成されるキメラ抗原受容体(IL-23R-mCAR)で形質導入し、マウスCD8のヒンジおよび膜貫通領域を介してシグナリング配列に、およびマウスCD28の細胞内部分に連結し、次に、これを細胞内マウスCD3ζ鎖に融合した(図4)。
Claims (19)
- それを必要とする対象におけるIL-23Rを発現する細胞が媒介する疾患または障害の処置において使用するための医薬組成物であって、少なくとも1つのIL-23受容体(IL-23R)に対して特異的なキメラ抗原受容体(CAR)を細胞表面上で発現するように操作されている制御性T細胞集団を含み、
前記CARは、
(i)前記IL-23Rに結合する、細胞外結合ドメインと、
(ii)膜貫通ドメインと、
(iii)細胞内シグナリングドメインと、
を含む、
医薬組成物。 - 前記CARは、細胞外ヒンジドメインおよび/又はタグおよび/又はリーダー配列をさらに含む、請求項1に記載の医薬組成物。
- 前記CARの細胞外結合ドメインが、前記IL-23Rに向けられたscFvフラグメントを含む、請求項1または2に記載の医薬組成物。
- 前記CARの細胞外結合ドメインが、前記IL-23Rに向けられたscFvフラグメントを含み、
前記scFvが、重鎖可変ドメイン(VH)と軽鎖可変ドメイン(VL)とを含み、
前記重鎖可変ドメイン(VH)が、配列番号37の配列を有し、
前記軽鎖可変ドメイン(VL)が、配列番号38、46および56からなる群から選択される配列を有する、
請求項1~3のいずれか1項に記載の医薬組成物。 - 前記CARのscFvフラグメントが、VHとVLの間にリンカーをさらに含む、請求項1~4のいずれか1項に記載の医薬組成物。
- 前記CARの細胞外結合ドメインが、前記IL-23Rに向けられたscFvフラグメントを含み、前記scFvが配列番号55の配列を有する、請求項1~5のいずれか1項に記載の医薬組成物。
- 前記CARのヒンジドメインが、ヒトCD8のヒンジ領域である、請求項1~6のいずれか1項に記載の医薬組成物。
- 前記CARのヒンジドメインが、配列番号13の配列を有するヒトCD8のヒンジ領域である、請求項1~7のいずれか1項に記載の医薬組成物。
- 前記CARの膜貫通ドメインが、ヒトCD8α由来の膜貫通ドメインである、請求項1~8のいずれか1項に記載の医薬組成物。
- 前記CARの膜貫通ドメインが、配列番号21の配列を有するヒトCD8α由来の膜貫通ドメインである、請求項1~9のいずれか1項に記載の医薬組成物。
- 前記CARの細胞内シグナリングドメインが、4-1BB、ICOS、CD27、OX40、CD28、CTLA4およびPD-1からなる群から選択される分子の共刺激シグナリングドメインとT細胞プライマリーシグナリングヒトCD3ζとを含む、請求項1~10のいずれか1項に記載の医薬組成物。
- 前記CARの細胞内シグナリングドメインが、
配列番号29の配列を有するヒト4-1BBの共刺激シグナリングドメインと、配列番号26の配列を有するT細胞プライマリーシグナリングヒトCD3ζと、を含むか、または
配列番号31の配列を有するCD28の共刺激シグナリングドメインと、配列番号26の配列を有するT細胞プライマリーシグナリングヒトCD3ζと、を含む、
請求項1~11のいずれか1項に記載の医薬組成物。 - 前記CARは、
(i)VHが配列番号37の配列を有し、VLが配列番号38の配列を有し、(G4S)3リンカー(配列番号3)により連結されている、VHとVLを含む抗IL-23RscFvと、
(ii)CD8α由来のヒンジドメインと、
(iii)ヒトCD8α膜貫通ドメインと、
(iv)4-1BB、ICOS、CD27、OX40、CD28、CTLA4およびPD-1からなる群から選択される分子の共刺激シグナリングドメインとヒトCD3ζドメインとを含む、細胞内シグナリングドメインと、
(v)タグおよび/またはリーダー配列と、
を含む、請求項1~12のいずれか1項に記載の医薬組成物。 - 前記CARは、
(i)VHが配列番号37の配列を有し、VLが配列番号38の配列を有し、(G4S)3リンカー(配列番号3)により連結されている、VHとVLを含む抗IL-23RscFvと、
(ii)配列番号13の配列を有するCD8α由来のヒンジドメインと、
(iii)配列番号21の配列を有するヒトCD8α膜貫通ドメインと、
(iv)配列番号29の配列を有するヒト4-1BBシグナリングドメインまたは配列番号31の配列を有するCD28シグナリングドメインと配列番号26の配列を有するヒトCD3ζドメインとを含む、細胞内シグナリングドメインと、
(v)タグおよび/またはリーダー配列と、
を含む、請求項1~13のいずれか1項に記載の医薬組成物。 - 前記制御性T細胞集団が、CD4+CD25+Foxp3+Treg、Tr1細胞、TGF-β分泌Th3細胞、制御性NKT細胞、制御性γδT細胞、制御性CD8+T細胞、およびダブルネガティブ制御性T細胞からなる群から選択される、請求項1~14のいずれか1項に記載の医薬組成物。
- 少なくとも1つの薬学的に許容される賦形剤または担体をさらに含む、請求項1~15のいずれか1項に記載の医薬組成物。
- 前記IL-23Rを発現する細胞が媒介する疾患または障害が、自己免疫性および/または炎症性疾患および/または障害である、請求項1~16のいずれか1項に記載の医薬組成物。
- 前記自己免疫性および/または炎症性疾患および/または障害が、炎症性腸疾患、全身性エリテマトーデス、関節リウマチ、若年性特発性関節炎、シェーグレン症候群、全身性硬化症、強直性脊椎炎、1型糖尿病、自己免疫性甲状腺障害、多発性硬化症、重症筋無力症、乾癬、乾癬性関節炎およびぶどう膜炎からなる群から選択される、請求項17に記載の医薬組成物。
- 前記自己免疫性および/または炎症性疾患および/または障害が、クローン病または潰瘍性大腸炎である、請求項17に記載の医薬組成物。
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