JP2023055722A - 非小細胞肺がんおよびその他のがんに対する免疫療法で使用するためのペプチドおよびペプチド組み合わせ - Google Patents
非小細胞肺がんおよびその他のがんに対する免疫療法で使用するためのペプチドおよびペプチド組み合わせ Download PDFInfo
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Abstract
Description
a)がん精巣抗原:T細胞によって認識され得る、最初に同定されたTAAはこのクラスに属し、元々はがん精巣(CT)抗原と称されたが、それは、そのメンバーが組織学的に異なるヒト腫瘍において発現し、正常組織では精巣の精母細胞/精原細胞のみに存在し、時として胎盤に存在するためであった。精巣の細胞は、クラスIおよびII HLA分子を発現しないので、これらの抗原は正常組織のT細胞によって認識され得ず、したがって免疫学的に腫瘍特異的と見なされる。CT抗原の周知の例は、MAGEファミリーメンバーおよびNY-ESO-1である。
b)分化抗原:これらのTAAは、腫瘍と、それから腫瘍が生じる正常組織との間で共有される。既知の分化抗原のほとんどは、黒色腫および正常メラノサイトに見いだされる。これらのメラノサイト系関連タンパク質の多くは、メラニン生合成に関与し、したがって腫瘍特異的でないが、それでもなおがん免疫療法のために広く利用されている。例としては、黒色腫に対するチロシナーゼとMelan-A/MART-1、または前立腺がんに対するPSAが挙げられるが、これに限定されるものではない。
c)過剰発現TAA:広範に発現されるTAAをエンコードする遺伝子は、組織学的に異なる型の腫瘍において検出され、多数の正常組織においても概してより低い発現レベルで検出されている。正常組織によってプロセスされて潜在的に提示されるエピトープの多くは、T細胞認識の閾値レベル未満であり得る一方で、腫瘍細胞におけるそれらの過剰発現は、以前確立された免疫寛容を破壊することにより、抗がん応答を始動し得る。このクラスのTAAの顕著な例は、Her-2/neu、サバイビン、テロメラーゼまたはWT1である。
d)腫瘍特異的抗原:これらのユニークなTAAは、正常な遺伝子(β-カテニン、CDK4など)の変異から生じる。これらの分子変化のいくつかは、腫瘍性形質転換および/または進行に関連する。腫瘍特異的抗原は、通常、正常組織に対する自己免疫反応のリスクなしに、強力な免疫応答を誘導できる。他方、これらのTAAは、ほとんどの場合、その上でそれらが同定されたまさにその腫瘍のみと関係があり、通常は、多くの個々の腫瘍間で共有されない。腫瘍特異的(関連)イソ型を有するタンパク質では、ペプチドの腫瘍特異性(または関連性)はまた、ペプチドが腫瘍(関連)エクソンに由来する場合に生じてもよい。
e)異常な翻訳後修飾から生じるTAA:このようなTAAは、特異的でなく腫瘍において過剰発現もされないタンパク質から生じてもよいが、それでもなお、腫瘍において主に活性である翻訳後プロセスによって腫瘍関連になる。このクラスの例は、腫瘍にMUC1のような新規エピトープをもたらす改変グリコシル化パターン、または腫瘍特異的であってもなくてもよい分解中のタンパク質スプライシングのような事象から生じる。
f)オンコウイルスタンパク質:これらのTAAはウイルスタンパク質であり、それらは発がん過程において重要な役割を果たしてもよく、外来性である(ヒト由来でない)ため、それらはT細胞応答を誘起し得る。このようなタンパク質の例は、子宮頸がんにおいて発現される、ヒト乳頭腫16型ウイルスタンパク質E6およびE7である。
X1X2LEHVVRX3(配列番号5)
式I
式中、X1はアミノ酸KおよびYから選択され、X2はアミノ酸V、L、およびAから選択され、X3はV、L、A、およびIから選択され、前記ペプチドは、HLAクラスIまたはクラスII分子に結合し、および/またはT細胞と前記ペプチドまたはその薬学的に許容可能な塩との交差反応を誘導する。一態様では、前記ペプチドは、その基礎となる全長ポリペプチドではない。
MAGEA4の局在化は、細胞質性として記載されている(Kim et al.,2015)。しかし、MAGEA4染色はまた核内でも検出されており、高分化度がんと低分化型化ガンとの対比では、核と細胞質の間で示差的分布が示された。(Sarcevic et al.,2003)。
進行した食道がん、胃がんまたは肺がんを有する20人の患者に、300μgのタンパク質を含有するMAGEA4ワクチンが、6回の投与で皮下投与された。1回のワクチン接種サイクルを完了した15人の患者のうち4人がMAGEA4特異的体液性応答を示し、これらの患者は抗体応答のない患者よりも全生存期間が長いことが示された。CD4およびCD8T細胞応答がそれぞれ3人の患者および6人の患者で観察され、CD4T細胞ではなくMAGEA4特異的IFNγ産生CD8T細胞の誘導を有する患者は、誘導のない患者より長く生存した(Saito et al.,2014)。
同一性百分率=100[1-(C/R)]
式中、Cは、参照配列と比較される配列との間のアライメント長にわたる、参照配列と比較配列の間の差異の数であり、
(i)比較配列中に対応する整列塩基またはアミノ酸を有しない、参照配列中の各塩基またはアミノ酸、および
(ii)参照配列中の各ギャップ、および
(iii)比較配列中の整列塩基またはアミノ酸と異なる、参照配列中の各整列塩基またはアミノ酸が差異を構成して、
(iv)アライメントは、整合配列の1位から開始しなくてはならず;
Rは、比較配列とのアライメント長にわたる参照配列中の塩基またはアミノ酸の数であり、参照配列中に生じる任意のギャップもまた、塩基またはアミノ酸として数えられる。
アロHLA反応性ペプチド特異的T細胞の生体外生成(Savage et al.2004)
告知に基づく同意を得た後、HLA-A*02陰性の健常ドナー由来のPBMCを使用した。組換えビオチン化HLA-A2クラスIモノマーと、MAG-003を含有するA2蛍光性四量体をMBLI(マサチューセッツ州ウーバン)から得た。リン酸緩衝食塩水(PBS)で希釈した抗CD20SAと共に、PBMCを室温で1時間培養し、洗浄して、ビオチン化A2/MAG-003モノマーと共に室温で30分間培養し、洗浄して、24ウェルプレート内の10%ヒトAB血清添加RPMIに、3×106細胞/ウェルで播種した。インターロイキン7(IL-7;R&D systems、ミネソタ州ミネアポリス)を1日目に10ng/mLで添加し、IL-2(英国ヘアフィールドのChiron)を4日目に10U/mLで添加した。5週間にわたり、細胞を新鮮なPBMCで毎週再刺激し、応答性細胞と1:1の比で混合して、24ウェルプレートに3×106/ウェルで播種した。
ヒト-HCまたはヒトTCRについて遺伝子組換えであるマウスの免疫化
MAG-003を使用して、そのT細胞がマウスTCR欠損を補う多様なヒトTCRレパートリーを発現する、全ヒトTCRαβ遺伝子座(1.1および0.7Mb)について遺伝子組換えであるマウスを免疫化した(Li et al.2010)。高親和性T細胞を得るために、遺伝子組換えマウスから得られたPBMCを四量体フィコエリトリン(PE)と共に培養し、上記のような細胞選別がそれに続いた。次に、当該技術分野で周知の方法を使用して、アミノ酸/DNA配列決定および発現ベクターへのクローニングのために、このようにして得られた高結合活性T細胞を使用してTCRを同定し、単離した。
TCRのクローニング法は、例えば、前記方法に関してその内容全体が参照により本明細書に援用される、米国特許第8,519,100号明細書に記載されるように、当該技術分野で公知である。制限部位NdeIをコードするα鎖可変領域配列特異的オリゴヌクレオチドA1、細菌における発現の効率的な開始のために導入されたメチオニン、および制限部位SalIをコードするα鎖定常領域配列特異的オリゴヌクレオチドA2を使用して、α鎖可変領域を増幅した。β鎖の場合、例えばNdeIなどの制限部位をコードするβ鎖可変領域配列特異的オリゴヌクレオチド、細菌における発現の効率的な開始のために導入されたメチオニン、および例えばAgeIなどの制限部位をコードするβ鎖定常領域配列特異的オリゴヌクレオチドB2を使用して、β鎖可変領域を増幅した。
T細胞は、高結合活性TCR(いわゆるTCR療法)、またはMHCI/MAG-003複合体またはMHCII/MAG-003複合体に対する抗原特異性が増強されたタンパク質融合由来キメラ抗原受容体(CAR)を発現するように、遺伝子操作し得る。一態様では、このアプローチは、中枢および末梢寛容に関連するいくつかの制限を克服し、患者における新生T細胞活性化の必要なしに、腫瘍の標的化においてより効率的なT細胞を生じる。
病原体に対する防御の第一線に関与する非従来的なTリンパ球エフェクターであるガンマデルタ(γδ)Τ細胞は、受容体、特に、TCR-γおよびTCR-δ鎖を活性化することで、MHC非依存的様式で腫瘍細胞と相互作用して、腫瘍細胞を根絶し得る。これらのγδT細胞は、活性化に際して、迅速なサイトカイン産生(IFN-γ、TNF-α)および強力な細胞毒性応答細胞傷害性応を可能にする前活性化表現型を示す。これらのT細胞は多くのがんに対して抗腫瘍活性を有し、γδT細胞媒介免疫療法が実行可能であり、客観的な腫瘍応答を誘導し得ることが示唆される。(Braza et al.2013)。
医薬品の製造手順を模倣するプロトコルを用いて、MAG-003の免疫原性を試験した。健常ドナーについて、MAG-003特異的T細胞のプライミングが観察された。生成されたT細胞はペプチド負荷標的細胞を殺滅でき、それらの機能性が実証された。データは、1)MAG-003が免疫原性標的であり、2)MAG-003に対して生成されたT細胞が機能性であることを実証した。
原位置ハイブリダイゼーション(ISH)を用いて、ホルマリン固定または凍結組織切片において直接、mRNA発現を検出する。その高い感度とその空間分解能のために、それは細胞型特異的標的発現およびがん組織切片中の標的発現の分布または頻度を判定するのに適した方法である。
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Claims (41)
- 配列番号1~配列番号24、および配列番号1~配列番号24と少なくとも88%相同的なその変異配列からなる群から選択されるアミノ酸配列を含んでなるペプチド、およびその薬学的に許容可能な塩であって;前記変異型が、主要組織適合性複合体(MHC)分子と結合し、および/またはT細胞を前記変異型ペプチドと交差反応させ;前記ペプチドが完全長ポリペプチドでない、ペプチド。
- MHCクラスIまたはII分子に結合する能力を有し、前記MHCに結合した際に、CD4および/またはCD8T細胞によって認識されることができるようになる、請求項1に記載のペプチド。
- そのアミノ酸配列が、配列番号1~配列番号24のいずれか1つに記載の一続きのアミノ酸を含んでなる、請求項1または2に記載のペプチドまたはその変異型。
- 前記ペプチドまたはその変異型が、8~100、好ましくは8~30、より好ましくは8~16のアミノ酸の全長を有し、最も好ましくは前記ペプチドが、配列番号1~配列番号24のいずれかに記載のアミノ酸配列からなり、またはそれから本質的になる、請求項1~3のいずれか一項に記載のペプチドまたはその変異型。
- 前記ペプチドが、修飾され、および/または非ペプチド結合を含む、請求項1~4のいずれか一項に記載のペプチドまたはその変異型。
- 前記ペプチドが、特にHLA-DR抗原関連不変鎖(Ii)のN末端アミノ酸を含んでなる融合タンパク質の一部である、請求項1~5のいずれか一項に記載のペプチドまたはその変異型。
- 請求項1~6のいずれか一項に記載のペプチドまたはその変異型をエンコードして、任意選択的に異種プロモーター配列に連結する、核酸。
- 請求項7に記載の核酸を発現する能力がある、または発現している、発現ベクター。
- 請求項1~6のいずれか一項に記載のペプチド、請求項7に記載の核酸または請求項8に記載の発現ベクターを含んでなり、好ましくは樹状細胞などの抗原提示細胞である、組換え宿主細胞。
- 請求項1~6に記載のペプチドを提示し、または請求項7に記載の核酸を発現し、または請求項8に記載の発現ベクターを含んでなる請求項9に記載の宿主細胞を培養するステップと、前記ペプチドまたはその変異型を前記宿主細胞またはその培養液から単離するステップとを含んでなる、請求項1~6のいずれか一項に記載のペプチドまたはその変異型を生産する方法。
- T細胞を、適切な抗原提示細胞の表面に、または抗原提示細胞を模倣する人工コンストラクトの表面に発現される抗原負荷ヒトクラスIまたはII MHC分子に、前記T細胞を抗原特異的様式で活性化させるのに十分な時間にわたり、生体外で接触させるステップを含んでなり、前記抗原が、請求項1~4のいずれか一項に記載のペプチドである、活性化Tリンパ球を生産するインビトロ法。
- 請求項1~4のいずれか一項に記載のアミノ酸配列を含んでなるポリペプチドを提示する細胞を選択的に認識する、請求項11に記載の方法によって生産される活性化Tリンパ球。
- 請求項12で定義される活性T細胞の有効数を患者に投与するステップを含んでなる、その標的細胞が、請求項1~4のいずれか一項に記載のアミノ酸配列を含んでなるポリペプチドを提示する患者において、標的細胞を死滅させる方法。
- MHC分子と結合した際に、好ましくは請求項1~5のいずれか一項に記載のペプチドまたはその変異型である、請求項1~5のいずれか一項に記載のペプチドまたはその変異型を特異的に認識する、特に可溶性または膜結合抗体である、抗体。
- 医療で使用される、請求項1~6のいずれか一項に記載のペプチドまたはその変異型、請求項7に記載の核酸、請求項8に記載の発現ベクター、請求項9に記載の宿主細胞、請求項12に記載の活性化Tリンパ球または請求項14に記載の抗体。
- がんの診断および/または治療で使用される、またはがんに対する薬剤の製造で使用される、請求項1~6のいずれか一項に記載のペプチドまたはその変異型、請求項7に記載の核酸、請求項8に記載の発現ベクター、請求項9に記載の宿主細胞、請求項12に記載の活性化Tリンパ球または請求項14に記載の抗体。
- 前記がんが、配列番号1~配列番号24のペプチドがそれに由来するタンパク質の過剰発現を示す、非小細胞肺がん、小細胞肺がん、腎細胞、脳がん、胃がん、結腸直腸がん、肝細胞がん、膵臓がん、前立腺がん、白血病、乳がん、メルケル細胞がん、黒色腫、卵巣がん、膀胱がん、子宮がん、胆嚢および胆管がん、および食道がん、およびその他の腫瘍の群から選択され、前記がんが、群から選択される(wherein said cancer is selected from the group of wherein said cancer is selected from the group of)、請求項16に従って使用される、請求項1~6のいずれか一項に記載のペプチドまたはその変異型、請求項7に記載の核酸、請求項8に記載の発現ベクター、請求項9に記載の宿主細胞、請求項12に記載の活性化Tリンパ球または請求項14に記載の抗体。
- (a)請求項1~6のいずれか一項に記載のペプチド若しくはその変異型、請求項7に記載の核酸、請求項8に記載の発現ベクター、請求項9に記載の細胞、請求項12に記載の活性化Tリンパ球、または請求項14に記載の抗体を含有する医薬組成物を溶液または凍結乾燥形態で含んでなる容器;
(b)任意選択的に、前記凍結乾燥製剤のための希釈剤または再構成溶液を含有する第2の容器;
(c)任意選択的に、配列番号1~配列番号24からなる群から選択される少なくとももう1つのペプチド、および
(d)任意選択的に、(i)前記溶液の使用、または(ii)前記凍結乾燥製剤の再構成および/または使用のための取扱説明書
を含んでなるキット。 - (iii)緩衝液、(iv)希釈剤、(v)フィルター、(vi)針、または(v)シリンジの1つまたは複数をさらに含んでなる、請求項18に記載のキット。
- 前記ペプチドが、配列番号1~配列番号24からなる群から選択される、請求項18または19に記載のキット。
- HLAリガンドと反応する、好ましくは可溶性または膜結合性TCRまたはその機能性断片である、T細胞受容体(TCR)であって、前記リガンドが、配列番号1~配列番号24からなる群から選択されるアミノ酸配列と少なくとも85%の同一性を有する、または前記アミノ酸配列が配列番号1~配列番号24からなる、T細胞受容体(TCR)。
- 前記T細胞受容体が、可溶性分子として提供され、任意選択的に抗体断片、免疫刺激ドメインおよび/または毒素などのさらなるエフェクター機能を保有する、請求項21に記載のT細胞受容体。
- 前記TCRが、αおよびβ鎖定常ドメイン配列を含んでなるα/βヘテロ二量体TCRであり、前記定常ドメイン配列が、例えば、どちらかのTRACのエクソン2のCys4と、TRBC1またはTRBC2のエクソン2のCys2との間で、天然ジスルフィド結合によって連結する、請求項21または22に記載のT細胞受容体。
- 前記TCRが、検出可能標識、治療薬、PK修飾部分またはそれらの任意の組み合わせと結合する、請求項21~23のいずれか一項に記載のT細胞受容体。
- 前記治療薬が、前記TCRのα鎖またはβ鎖のC末端またはN末端に共有結合する抗CD3抗体である、請求項24に記載のT細胞受容体。
- 請求項21~25のいずれか一項に記載のT細胞受容体をコードする核酸であって、任意選択的に、異種プロモーター配列、または前記核酸を発現できる発現ベクターに連結する、核酸。
- 請求項26に記載の核酸、または請求項14に記載の抗体をコードする核酸、または請求項26に記載の発現ベクターを含んでなる、好ましくはT細胞またはNK細胞である、宿主細胞。
- 請求項27に記載の宿主細胞を培養するステップと、前記T細胞受容体を前記宿主細胞および/またはその培養液から単離するステップとを含んでなる、請求項21~24のいずれか一項に記載のT細胞受容体を生産する方法。
- a)前記個々の患者からの腫瘍サンプルによって提示される腫瘍関連ペプチド(TUMAP)を同定するステップと;
b)a)で同定された前記ペプチドを、正常組織との比較で腫瘍における免疫原性および/または過剰提示について予備選別されたペプチド貯蔵庫と比較するステップと;
c)少なくとも1つのペプチドを、前記患者において同定されたTUMAPと一致する前記貯蔵庫から選択するステップと;
d)ステップc)に基づいて、前記個別化ワクチンまたは化合物ベースのまたは細胞療法を作成および/または処方するステップとを含んでなる、個々の患者のための化合物ベースのおよび/または細胞療法のための個別化抗がんワクチンを生産する方法。 - 前記TUMAPが、
a1)前記腫瘍サンプルからの発現データを前記腫瘍サンプルの組織型に対応する正常組織サンプルからの発現データと比較して、前記腫瘍サンプルにおいて過剰発現されまたは異常に発現されるタンパク質を同定するステップと;
a2)前記発現データを、前記腫瘍サンプル中のMHCクラスI/またはクラスII分子と結合しているMHCリガンドの配列と相関させて、前記腫瘍によって過剰発現されまたは異常に発現されるタンパク質に由来するMHCリガンドを同定するステップと
によって同定される、請求項29に記載の方法。 - 結合ペプチドを前記腫瘍サンプルから単離されたMHC分子から溶出させて、前記溶出したリガンドを配列決定することで、MHCリガンドの配列が同定される、請求項29または30に記載の方法。
- 前記腫瘍サンプルの組織型に対応する前記正常組織が、前記同一患者から得られる、請求項29~31のいずれか一項に記載の方法。
- 前記貯蔵庫に包含される前記ペプチドが、
aa.正常組織または組織群と比較して悪性組織で過剰発現される遺伝子を同定するステップを含んでなる、マイクロアレイまたは配列決定ベース発現プロファイリングなどの高度並列法によって、ゲノム規模メッセンジャーリボ核酸(mRNA)発現解析を実施するステップと;
ab.ステップaaで検出された、選択的に発現されまたは過剰発現される遺伝子によってコードされる、ペプチドを選択するステップと;
ac.健常ドナーまたは前記患者からのヒトT細胞を使用した生体外免疫原性アッセイを含んでなる、前記選択されたペプチドによる生体内T細胞応答の誘導を判定するステップ;
ba.HLAリガンドを前記腫瘍サンプルから質量分析を使用して同定するステップと;
bb.正常組織または組織群と比較して悪性組織で過剰発現される遺伝子を同定するステップを含んでなる、マイクロアレイまたは配列決定ベース発現プロファイリングなどの高度並列法によって、ゲノム規模メッセンジャーリボ核酸(mRNA)発現解析を実施するステップと;
bc.前記同定されたHLAリガンドを前記遺伝子発現データと比較するステップと;
bd.ステップbcで検出された、選択的に発現されまたは過剰発現される遺伝子によってコードされる、ペプチドを選択するステップと;
be.ステップbdから選択されたTUMAPを腫瘍組織上で再検出し、健常組織上の検出欠如または希な検出が、mRNAレベルにおける過剰発現の関連性を裏付けるステップと;
bf.健常ドナーまたは前記患者からのヒトT細胞を使用した生体外免疫原性アッセイを含んでなる、前記選択されたペプチドによる生体内T細胞応答の誘導を判定するステップと
に基づいて同定される、請求項29~32のいずれか一項に記載の方法。 - 前記貯蔵庫に包含される前記ペプチドの免疫原性が、生体外免疫原性アッセイ、個々のHLA結合についての患者免疫モニタリング、MHC多量体染色、ELISPOTアッセイおよび/または細胞内サイトカイン染色を含んでなる方法によって判定される、請求項29~33のいずれか一項に記載の方法。
- 前記貯蔵庫が、配列番号1~配列番号24からなる群から選択される複数のペプチドを含んでなる、請求項29~34のいずれか一項に記載の方法。
- 前記個々の患者からの正常な対応する組織と比較して前記腫瘍サンプルに特有の少なくとも1つの変異を同定するステップと、前記ワクチンに包含するために、または細胞療法を作成するために、前記変異に関連があるペプチドを選択するステップとをさらに含んでなる、請求項29~35のいずれか一項に記載の方法。
- 前記少なくとも1つの変異が、全ゲノム配列決定によって同定される、請求項36に記載の方法。
- a)配列番号1~配列番号24からなる群から選択されるペプチド;
b)a)に記載のペプチドおよび/または前記ペプチドMHC複合体と反応性のT細胞受容体;
c)a)に記載のペプチドと、前記HLA-DR抗原関連不変鎖(Ii)のN末端のアミノ酸1~80とを含んでなる融合タンパク質;
d)a)~c)のいずれかをコードする核酸、または前記核酸を含んでなる発現ベクター;
e)d)の発現ベクターを含んでなる宿主細胞;
f)T細胞を、抗原特異的様式で前記T細胞を活性化するのに十分な時間にわたり、適切な抗原提示細胞の表面に発現されるa)に記載のペプチドと生体外で接触させるステップを含んでなる方法、ならびにこれらの活性化T細胞を自己または他の患者に移入する方法によって得られる、活性化Tリンパ球;
g)a)に記載のペプチドおよび/または前記ペプチド-MHC複合体および/またはa)に記載のペプチドを提示する細胞と反応性であり、例えば、免疫活性化ドメインまたは毒素との融合によって潜在的に修飾される、抗体、または可溶性T細胞受容体;
h)配列番号1~配列番号24からなる群から選択されるペプチドを認識し、および/または配列番号1~配列番号24からなる群から選択されるペプチドとMHC分子との複合体を認識する、アプタマー;
i)a)~h)のいずれかに記載のコンジュゲートされまたは標識されたペプチドまたはスキャフォールド
からなる群から選択される、少なくとも1つの活性成分と、薬学的に許容できる担体、および任意選択的に、薬学的に許容可能な賦形剤および/または安定剤とを含んでなる医薬組成物。 - 請求項1~5のいずれか一項に記載のペプチドまたはその変異型、好ましくはMHC分子と結合している請求項1~5のいずれか一項に記載のペプチドまたはその変異型を特異的に認識する、アプタマー。
- 請求項38に記載の医薬品組成物をそれを必要とする対象に投与するステップを含んでなる、非小細胞肺がん、小細胞肺がん、腎細胞、脳がん、胃がん、結腸直腸がん、肝細胞がん、膵臓がん、前立腺がん、白血病、乳がん、メルケル細胞がん、黒色腫、卵巣がん、膀胱がん、子宮がん、胆嚢および胆管がん、食道がん、またはそれらの組み合わせである、がんを治療する方法。
- 前記がんが非小細胞肺がんである、請求41項に記載の方法。
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