JP7469807B2 - Mage-b2特異性を有するt細胞受容体およびその使用 - Google Patents
Mage-b2特異性を有するt細胞受容体およびその使用 Download PDFInfo
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Description
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
黒色腫関連抗原B2(MAGE-B2)に由来する抗原ペプチドを結合することができる単離されたT細胞受容体(TCR)であって、配列番号3または19の配列に対して少なくとも90%の同一性を有するTCRアルファポリペプチドおよび配列番号5または22の配列に対して少なくとも90%の同一性を有するTCRベータポリペプチドを含むT細胞受容体。
(項目2)
前記抗原ペプチドが、HLA-A2拘束性である、項目1に記載のTCR。
(項目3)
前記抗原ペプチドが、HLA-A*0201拘束性である、項目2に記載のTCR。
(項目4)
前記TCRアルファポリペプチドが、CDR1(配列番号7)、CDR2(配列番号9)、およびCDR3(配列番号11)に対して少なくとも95%の同一性を有する配列を含み、前記TCRベータポリペプチドが、CDR1(配列番号13)、CDR2(配列番号15)、およびCDR3(配列番号17)に対して少なくとも95%の同一性を有する配列を含む、項目1に記載のTCR。
(項目5)
前記TCRアルファポリペプチドが、CDR1(配列番号7)、CDR2(配列番号9)、およびCDR3(配列番号11)に対して少なくとも99%の同一性を有する配列を含み、前記TCRベータポリペプチドが、CDR1(配列番号13)、CDR2(配列番号15)、およびCDR3(配列番号17)に対して少なくとも99%の同一性を有する配列を含む、項目1に記載のTCR。
(項目6)
前記TCRアルファポリペプチドが、CDR1(配列番号7)、CDR2(配列番号9)、およびCDR3(配列番号11)の配列を含み、前記TCRベータポリペプチドが、CDR1(配列番号13)、CDR2(配列番号15)、およびCDR3(配列番号17)の配列を含む、項目1に記載のTCR。
(項目7)
前記ポリペプチドが、配列番号3の配列に対して少なくとも95%の同一性を有し、TCRベータポリペプチドが、配列番号5の配列に対して少なくとも95%の同一性を有する、項目1に記載のTCR。
(項目8)
前記TCRアルファポリペプチドが、配列番号3の配列に対して少なくとも99%の同一性を有し、前記TCRベータポリペプチドが、配列番号5のアミノ酸配列に対して少なくとも99%の同一性を有する、項目1に記載のTCR。
(項目9)
前記TCRアルファポリペプチドが配列番号3の配列を有し、前記TCRベータポリペプチドが配列番号5の配列を有する、項目1に記載のTCR。
(項目10)
前記TCRアルファポリペプチドが、CDR1(配列番号23)、CDR2(配列番号25)、およびCDR3(配列番号27)に対して少なくとも95%の同一性を有する配列を含み、前記TCRベータポリペプチドが、CDR1(配列番号29)、CDR2(配列番号31)、およびCDR3(配列番号33)に対して少なくとも95%の同一性を有する配列を含む、項目1に記載のTCR。
(項目11)
前記TCRアルファポリペプチドが、CDR1(配列番号23)、CDR2(配列番号25)、およびCDR3(配列番号27)に対して少なくとも99%の同一性を有する配列を含み、前記TCRベータポリペプチドが、CDR1(配列番号29)、CDR2(配列番号31)、およびCDR3(配列番号33)に対して少なくとも99%の同一性を有する配列を含む、項目1に記載のTCR。
(項目12)
前記TCRアルファポリペプチドが、CDR1(配列番号23)、CDR2(配列番号25)、およびCDR3(配列番号27)の配列を含み、前記TCRベータポリペプチドが、CDR1(配列番号29)、CDR2(配列番号31)、およびCDR3(配列番号33)の配列を含む、項目1に記載のTCR。
(項目13)
前記ポリペプチドが、配列番号19の配列に対して少なくとも95%の同一性を有し、TCRベータポリペプチドが、配列番号22の配列に対して少なくとも95%の同一性を有する、項目1に記載のTCR。
(項目14)
前記TCRアルファポリペプチドが、配列番号19の配列に対して少なくとも99%の同一性を有し、前記TCRベータポリペプチドが、配列番号22のアミノ酸配列に対して少なくとも99%の同一性を有する、項目1に記載のTCR。
(項目15)
前記TCRアルファポリペプチドが配列番号19の配列を有し、前記TCRベータポリペプチドが配列番号22の配列を有する、項目1に記載のTCR。
(項目16)
膜貫通ドメインを欠く可溶性TCRである、項目1に記載のTCR。
(項目17)
検出可能な標識をさらに含む、項目16に記載のTCR。
(項目18)
治療剤をさらに含む、項目16または項目17に記載のTCR。
(項目19)
項目1から18のいずれかに記載の複数のTCRを含む、多価TCR複合体。
(項目20)
前記多価TCRが、2、3、4またはそれよりも多いTCRを含む、項目19に記載の複合体。
(項目21)
前記多価TCRが、脂質二重層中に存在するか、または粒子に付着している、項目20に記載の複合体。
(項目22)
前記TCRが、リンカー分子を介してコンジュゲートされている、項目20に記載の複合体。
(項目23)
CDR1(配列番号7)、CDR2(配列番号9)、およびCDR3(配列番号11)の配列を含むTCRアルファポリペプチド、ならびに/またはCDR1(配列番号13)、CDR2(配列番号15)、およびCDR3(配列番号17)の配列を含むTCRベータポリペプチドを含む、ポリペプチド。
(項目24)
配列番号3のアミノ酸配列に対して少なくとも90%の同一性を有するTCRアルファポリペプチド、および/または配列番号5のアミノ酸配列に対して少なくとも90%の同一性を有するTCRベータポリペプチドを含む、項目23に記載のポリペプチド。
(項目25)
配列番号3のアミノ酸配列に対して少なくとも95%の同一性を有するTCRアルファポリペプチド、および/または配列番号5のアミノ酸配列に対して少なくとも95%の同一性を有するTCRベータポリペプチドを含む、項目23に記載のポリペプチド。
(項目26)
配列番号3のTCRアルファポリペプチドおよび配列番号5のTCRベータポリペプチドを含む、項目23に記載のポリペプチド。
(項目27)
配列番号3のTCRアルファポリペプチドを含む、項目23に記載のポリペプチド。
(項目28)
配列番号5のTCRベータポリペプチドを含む、項目23に記載のポリペプチド。
(項目29)
CDR1(配列番号23)、CDR2(配列番号25)、およびCDR3(配列番号27)の配列を含むTCRアルファポリペプチド、ならびに/またはCDR1(配列番号29)、CDR2(配列番号31)、およびCDR3(配列番号33)の配列を含むTCRベータポリペプチドを含む、ポリペプチド。
(項目30)
配列番号19のアミノ酸配列に対して少なくとも90%の同一性を有するTCRアルファポリペプチド、および/または配列番号22のアミノ酸配列に対して少なくとも90%の同一性を有するTCRベータポリペプチドを含む、項目23に記載のポリペプチド。
(項目31)
配列番号19のアミノ酸配列に対して少なくとも95%の同一性を有するTCRアルファポリペプチド、および/または配列番号22のアミノ酸配列に対して少なくとも95%の同一性を有するTCRベータポリペプチドを含む、項目23に記載のポリペプチド。
(項目32)
配列番号19のTCRアルファポリペプチドおよび配列番号22のTCRベータポリペプチドを含む、項目23に記載のポリペプチド。
(項目33)
配列番号19のTCRアルファポリペプチドを含む、項目23に記載のポリペプチド。
(項目34)
配列番号22のTCRベータポリペプチドを含む、項目23に記載のポリペプチド。
(項目35)
項目23から34のいずれか一項に記載のポリペプチドをコードするポリヌクレオチド。
(項目36)
項目1から18のいずれかに記載のTCRを含む発現ベクター。
(項目37)
ウイルスベクターである、項目36に記載の発現ベクター。
(項目38)
前記ウイルスベクターが、レトロウイルスベクターまたはレンチウイルスベクターである、項目37に記載の発現ベクター。
(項目39)
リンカードメインをさらに含む、項目36から38のいずれかに記載の発現ベクター。
(項目40)
前記リンカードメインが、前記TCRアルファポリペプチドと前記TCRベータポリペプチドとの間にある、項目39に記載の発現ベクター。
(項目41)
前記リンカードメインが、1つまたは複数の切断部位を含む、項目39または項目40に記載の発現ベクター。
(項目42)
前記1つまたは複数の切断部位が、フューリン切断部位および/またはP2A切断部位である、項目41に記載の発現ベクター。
(項目43)
前記1つまたは複数の切断部位が、スペーサーによって分離している、項目41または項目39に記載の発現ベクター。
(項目44)
前記スペーサーが、SGSGまたはGSGである、項目43に記載の発現ベクター。
(項目45)
前記TCRアルファポリペプチドおよび前記TCRベータポリペプチドが、IRES配列によって連結している、項目39に記載の発現ベクター。
(項目46)
項目1から18のいずれかに記載のTCRを発現するように操作された宿主細胞。
(項目47)
免疫細胞である、項目46に記載の宿主細胞。
(項目48)
NK細胞、インバリアントNK細胞、NKT細胞、間葉系幹細胞(MSC)、または人工多能性幹(iPS)細胞である、項目46に記載の宿主細胞。
(項目49)
臍帯または血液から単離されている、項目46に記載の宿主細胞。
(項目50)
前記免疫細胞が、T細胞または末梢血リンパ球である、項目46に記載の宿主細胞。
(項目51)
前記T細胞が、CD8 + T細胞、CD4+T細胞、またはγδ T細胞である、項目50に記載の宿主細胞。
(項目52)
同種異系または自家である、項目50に記載の宿主細胞。
(項目53)
項目46から52のいずれかに記載のMAGE-B2 TCR特異的細胞の集団を含む医薬組成物。
(項目54)
MAGE-B2特異的免疫細胞を操作するための方法であって、前記免疫細胞を、項目36から44のいずれかに記載の発現ベクターと接触させることを含む方法。
(項目55)
前記免疫細胞が、T細胞、末梢血リンパ球、NK細胞、インバリアントNK細胞、またはNKT細胞である、項目54に記載の方法。
(項目56)
接触させることが、トランスフェクトすることまたは形質導入することとしてさらに定義される、項目54または項目55に記載の方法。
(項目57)
前記末梢血リンパ球が、OKT3およびIL-2で刺激される、項目55に記載の方法。
(項目58)
前記免疫細胞を選別してTCR操作されたT細胞を単離すること、連続希釈によるT細胞クローニングを実施すること、および急速拡大プロトコールによってT細胞クローンを拡大することをさらに含む、項目54から57のいずれかに記載の方法。
(項目59)
がんの処置のための、項目46から52のいずれか一項に記載の、治療有効量のMAGE-B2 TCR特異的細胞の使用。
(項目60)
前記MAGE-B2 TCR特異的細胞がT細胞である、項目59に記載の使用。
(項目61)
被験体におけるがんの処置のための、項目46から52のいずれか一項に記載の治療有効量のMAGE-B2特異的細胞を含む組成物。
(項目62)
前記MAGE-B2 TCR特異的細胞がT細胞である、項目59に記載の組成物。
(項目63)
被験体におけるがんを処置する方法であって、項目46から52のいずれか一項に記載の治療有効量のMAGE-B2特異的細胞を、前記被験体に投与することを含む方法。
(項目64)
前記MAGE-B2特異的細胞がT細胞である、項目63に記載の方法。
(項目65)
前記被験体が、HLA-A*0201、HLA-A*0202、HLA-A*0203、HLA-A*0204またはHLA-A*0205対立遺伝子を有すると同定される、項目63に記載の方法。
(項目66)
前記治療有効量のMAGE-B2特異的T細胞の投与の前に、前記被験体に対してリンパ球枯渇を実施するステップをさらに含む、項目63に記載の方法。
(項目67)
前記治療有効量のMAGE-B2特異的T細胞が、抗腫瘍活性を有する自家腫瘍浸潤リンパ球(TIL)の試料に由来する、項目64に記載の方法。
(項目68)
前記MAGE-B2特異的細胞が、前記被験体に、静脈内、腹腔内、または腫瘍内投与される、項目63に記載の方法。
(項目69)
前記被験体が、ヒトである、項目63に記載の方法。
(項目70)
少なくとも1つの追加の治療剤を前記被験体に投与するステップをさらに含む、項目63に記載の方法。
(項目71)
前記少なくとも1つの追加の治療剤が、化学療法、放射線療法、および免疫療法からなる群より選択される、項目70に記載の方法。
(項目72)
前記少なくとも1つの追加の治療剤が免疫療法である、項目70に記載の方法。
(項目73)
前記免疫療法が、免疫チェックポイント阻害剤である、項目72に記載の方法。
(項目74)
前記免疫チェックポイント阻害剤が、CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、BTLA、B7H3、B7H4、TIM3、KIR、またはアデノシンA2a受容体(A2aR)からなる群より選択される免疫チェックポイントタンパク質またはそのリガンドを阻害する、項目73に記載の方法。
(項目75)
前記免疫チェックポイント阻害剤が、PD-1またはCTLA-4を阻害する、項目74に記載の方法。
本明細書および添付の特許請求の範囲で使用される単数形の用語「a」、「an」および「the」は、文脈上別段の明確な指示がない限り、複数の指示対象を含む。したがって、例えば、「細胞」への言及は、複数のそのような細胞を含み、「ペプチド」への言及は、当業者に公知の1つまたは複数のペプチドおよびその同等物(例えば、ポリペプチド)への言及を含む。
ある特定の実施形態では、本開示は、配列GVYDGEEHSV(配列番号1)を含むMAGE-B2ペプチドエピトープを提供する。MAGE-B2ペプチドエピトープは、T細胞の集団と接触させるか、またはそれを使用してT細胞の集団を刺激して、MAGE-B2ペプチドエピトープを認識または結合するT細胞の増殖を誘発することができる。MAGE-B2ペプチドエピトープを、ヒト患者などの被験体に投与して、がんに対する被験体の免疫応答を増強することができる。MAGE-B2ペプチドエピトープは、能動免疫療法(例えば、がんワクチン)または受動免疫療法(例えば、養子細胞療法)に含まれ得る。能動免疫療法は、精製された腫瘍抗原またはMAGE-B2ペプチドエピトープ(天然または改変)により被験体を免疫化することを含む。あるいは、MAGE-B2ペプチドエピトープでパルスされた(または腫瘍抗原をコードする遺伝子でトランスフェクトされた)抗原提示細胞を被験体に投与することができる。MAGE-B2ペプチドエピトープは、改変されても、または、例えば、置換変異などの1つまたは複数の変異を含んでもよい。養子細胞療法は、細胞を被験体に投与することを伴ってもよく、細胞(例えば、細胞傷害性T細胞)は、in vitroでMAGE-B2ペプチドエピトープに対して感作されている。
一部の態様では、本開示は、MAGE-B2ペプチドエピトープを含む。MAGE-B2ペプチドエピトープは、HLA-A2拘束性MAGE-B2ペプチドGVYDGEEHSV、配列番号1のアミノ酸配列を有し得る。MAGE-B2ペプチドエピトープは、配列番号1のペプチド配列と少なくとも80、85、90、95、96、97、98、99、または100パーセントの配列同一性を有するアミノ酸配列を有し得る。
一部の実施形態では、免疫療法は、リポソームまたは細胞透過性ペプチド(CPP)などの細胞透過性物質に会合している本開示のMAGE-B2ペプチドエピトープを利用し得る。ペプチドでパルスされた抗原提示細胞(樹状細胞など)を使用して、抗腫瘍免疫を増強することができる。一部の実施形態では、免疫療法は、本開示のMAGE-B2ペプチドエピトープをコードする核酸を利用してもよく、核酸は、例えば、ウイルスベクターまたは非ウイルスベクターにおいて送達される。
本開示のMAGE-B2ペプチドエピトープは、HLA-A2などのHLAクラスタンパク質結合領域とのそれぞれの相互作用を変化させないアミノ酸置換、挿入および/または欠失を含有するように改変され得る。非限定的な例として、HLA-A2への検出可能な変化のないペプチド結合によって実証されるように、HLA結合の感知できるほどの損失なしに、本明細書に開示されたMAGE-B2ペプチドにおけるある特定のアミノ酸を他のアミノ酸の代わりに使用することができる。したがって、配列および/または構造が改変されているが、生物学的有用性または活性は変化していない、本明細書に開示されたMAGE-B2ペプチド(またはそのようなペプチドをコードする核酸)は、本明細書に開示された組成物および方法の範囲内にとどまることが企図される。
一部の実施形態では、本開示はMAGE-B2特異的TCRを提供する。TCRは、配列番号6~12のα鎖CDRおよび/または配列番号13~17のβ鎖CDRを含み得る。TCRは、配列番号2~3に対して少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、もしくは100%の同一性もしくは類似性を有するα鎖、および/または配列番号4~5に対して少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、もしくは100%の同一性もしくは類似性を有するβ鎖を含み得る。本明細書で提供されるMAGE-B2 TCRのα鎖および/またはβ鎖をコードするポリペプチドおよびポリヌクレオチドも、本明細書で提供される。本明細書でさらに提供されるのは、本明細書で提供されるMAGE-B2特異的TCRを発現するように操作された、T細胞、NK細胞、インバリアントNK細胞、NKT細胞、MSC、またはiPS細胞などの細胞である。これらの非T細胞エフェクター免疫細胞は、CD3分子またはTCRに連結した他のシグナル伝達ドメインと一緒にTCRを発現することがあり、TCRは、これらの細胞においてシグナル変換を開始する。
さらに、本開示は、HLA-A2陽性がん患者を直接処置するために使用することができる可溶性TCRを提供する。可溶性二重特異性T細胞係合分子(BiTE)は、MAGE-B2 TCRをCD3特異的Fab断片に連結させることによって生成することができる。これらの二重特異性分子は、ペプチド/HLA複合体へのMAGE-B2 TCR結合を介して、腫瘍細胞表面を結合することができ、CD3特異的Fab断片は、標的T細胞などにおいてTCRを架橋する。これにより、細胞の活性化および標的細胞の排除がもたらされる。したがって、これらの可溶性二重特異性TCR構築物は、がん患者を処置するために直接使用することができる。
別の態様では、本明細書で提供されるのは、被験体におけるがんを処置するための方法であって、本明細書で提供される方法のいずれかによって産生されるT細胞、NK細胞、インバリアントNK細胞、NKT細胞、MSC、またはiPS細胞などのMAGE-B2 TCR特異的細胞の集団の治療有効量を、被験体に投与することを含む、方法である。TILがin vitroから培養され得るか、または腫瘍抗原特異的CTLがin vitroから生成され得る細胞を、がんを有する被験体に養子移入することができる。
ある特定の実施形態では、本明細書で提供される方法は、少なくとも1つの追加の治療剤を被験体に投与するステップをさらに含む。本明細書に開示されたすべての追加の治療剤は、任意の潜在的な毒性、起こり得る副作用、および任意の他の関連する要因を考慮に入れて、各特定の組成物または治療法の優良臨床試験基準に従って被験体に投与される。
別の態様では、本明細書で提供されるのは、MAGE-B2 TCR特異的細胞および薬学的に許容される担体を含む医薬組成物および製剤である。
以下の実施例は、本発明の好ましい実施形態を実証するために含まれる。以下の実施例に開示される技術は、本発明の実施において良好に機能するように本発明者らによって発見された技術を表し、したがってその実施のための好ましい様式を構成すると考えることができることが、当業者には認識されるべきである。しかし、当業者であれば、本開示の見地から、本発明の精神および範囲から逸脱することなく、開示された具体的な実施形態において多くの変更がなされ、依然として同様のまたは類似の結果を得ることができることを認識すべきである。
MAGE-B2の発現を、肺がん細胞株および不死化した正常ヒト小気道上皮細胞(HSAEC1-KTおよびHSAEC2-KT)において分析した(図1)。MAGE-B2タンパク質は、ほとんどの肺がん細胞株において強く発現していることが見出され、正常肺(ling)細胞株では発現がほとんど観察されなかった。
T細胞クローンを生成する:完全長MAGE-B2 RNAを、健康なHLA-A2ドナー由来の成熟樹状細胞(DC)にトランスフェクトした。RNAをトランスフェクトしたDCを、IL-21の存在下でDC:T=1:10の比でナイーブT細胞と共培養した。1週間後、RNAをトランスフェクトしたDCを使用して、T細胞を再刺激した。2回の刺激後、CD8および四量体二重陽性T細胞集団を選別し、急速拡大プロトコール(REP)で拡大させた。T細胞クローンは、限界希釈法により生成した。高活性CTLクローンを、がん細胞に対する細胞傷害性アッセイを介してスクリーニングした。
追加のMAGE-B2特異的T細胞産物を、MAGE-B2ペプチド(GVYDGEEHSV;配列番号1)でパルスした樹状細胞を使用して生成し、同じ健康なドナーに由来するPBMCを刺激した(図7)。2回の刺激後、1枚の48ウェルプレートのうちの3つのウェル内でCD8+/四量体+の小集団が観察された。3つの陽性ウェルを、四量体誘導選別技術を使用して別々に選別し、REPにより1回または2回の拡大を行った。最終産物のCD8および四量体染色を、図7に示す。
参考文献
以下の参考文献は、それらが本明細書に記載されたものを補足する例示的な手順または他の詳細を提供する限りにおいて、参照により本明細書に具体的に組み込まれる。
Barnea et al., Eur J Immunol, 32(1):213-22, 2002.
Remington: The Science and Practice of Pharmacy, 22nd Edition, Pharmaceutical Press, 2012. Shraibman et al., Mol Cell Proteomics, 15(9):3058-70, 2016.
Claims (14)
- 黒色腫関連抗原B2(MAGE-B2)に由来する抗原ペプチドを結合することができる単離されたT細胞受容体(TCR)であって、配列番号3のTCRアルファポリペプチドおよび配列番号5のTCRベータポリペプチド、または、配列番号19のTCRアルファポリペプチドおよび配列番号21のTCRベータポリペプチドを含むT細胞受容体。
- 前記抗原ペプチドが、HLA-A2拘束性である、請求項1に記載のTCR。
- 前記抗原ペプチドが、HLA-A*0201拘束性である、請求項2に記載のTCR。
- 前記TCRアルファポリペプチドが、CDR1(配列番号7)、CDR2(配列番号9)、およびCDR3(配列番号11)の配列を含み、前記TCRベータポリペプチドが、CDR1(配列番号13)、CDR2(配列番号15)、およびCDR3(配列番号17)の配列を含む、請求項1に記載のTCR。
- 前記TCRアルファポリペプチドが、CDR1(配列番号23)、CDR2(配列番号25)、およびCDR3(配列番号27)の配列を含み、前記TCRベータポリペプチドが、CDR1(配列番号29)、CDR2(配列番号31)、およびCDR3(配列番号33)の配列を含む、請求項1に記載のTCR。
- 膜貫通ドメインを欠く可溶性TCRである、請求項1に記載のTCR。
- 検出可能な標識をさらに含む、請求項6に記載のTCR。
- 治療剤をさらに含む、請求項6または請求項7に記載のTCRを含むTCR複合体。
- 請求項1から7のいずれかに記載のTCRを複数含む、多価TCR複合体。
- CDR1(配列番号7)、CDR2(配列番号9)、およびCDR3(配列番号11)の配列を含むTCRアルファポリペプチド、ならびにCDR1(配列番号13)、CDR2(配列番号15)、およびCDR3(配列番号17)の配列を含むTCRベータポリペプチドを含むポリペプチドであって、MAGE-B2に由来する抗原に結合する、ポリペプチド。
- CDR1(配列番号23)、CDR2(配列番号25)、およびCDR3(配列番号27)の配列を含むTCRアルファポリペプチド、ならびにCDR1(配列番号29)、CDR2(配列番号31)、およびCDR3(配列番号33)の配列を含むTCRベータポリペプチドを含むポリペプチドであって、MAGE-B2に由来する抗原に結合する、ポリペプチド。
- 請求項1から7のいずれかに記載のTCRをコードするポリヌクレオチドを含む発現ベクター。
- MAGE-B2特異的免疫細胞を生産するためのインビトロの方法であって、免疫細胞を、請求項12に記載の発現ベクターと接触させることを含む方法。
- 被験体におけるがんの処置のための、請求項1から7のいずれかに記載のTCRを発現する治療有効量のMAGE-B2特異的免疫細胞を含む組成物。
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