JP5964233B2 - Hpvにより惹起される疾患の治療用組成物 - Google Patents
Hpvにより惹起される疾患の治療用組成物 Download PDFInfo
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Description
i)生殖器疣贅が示される臨床的感染;
ii)病変は目に見えないが、パパニコラウ細胞診などの特別の技法を使用して検出できるウイルス性病変である無症状感染;および、
iii)感染の単独の徴候がHPV DNAの存在である潜伏期。
(i)フィブロネクチンのEDA領域またはそれらの機能的に同等な変異体、および、
(ii)少なくとも1種のHPV E7由来の抗原性ペプチド
を含み、成分(i)と(ii)とが共有結合してなる複合体であって、
抗原性ペプチド(peptide or peptides)に対する細胞傷害性応答を助長する複合体に関する。
(i)本発明の複合体、本発明のポリヌクレオチドまたは遺伝子構築物、本発明のベクター、本発明による宿主細胞、および、
(ii)TLRリガンド、
を一緒にまたは別々に含む第1組成物に関する。
(i)請求項1〜6のいずれか一項に記載の複合体、請求項7に記載のポリヌクレオチドまたは遺伝子構築物、請求項8に記載のベクター、請求項9に記載の宿主細胞、
(ii)TLRリガンドおよび、
(iii)化学療法剤
を一緒にまたは別々に含む第2の組成物に関する。
(i)樹状細胞を、本発明の複合体、本発明のポリヌクレオチド、本発明の遺伝子構築物、本発明のベクター、本発明の細胞、本発明の第1のまたは第2の組成物と、樹状細胞の成熟が起こるのに適した条件で接触させ、かつ
(ii)成熟樹状細胞を回収すること
を含む本発明の方法に関する。
他の態様において、本発明は、医学において使用するための本発明の第2の細胞に関する。
本発明らは、フィブロネクチンのEDA領域とHPV−E7すなわちE7タンパク質の免疫原領域とを含む組替えタンパク質が、インビトロで樹状細胞の成熟を誘発し得ることに加えて、前記タンパク質を発現する腫瘍に対してCD8+T細胞により媒介される強力な抗腫瘍活性を生じ得ることを観察した。したがって、本発明の実施例1で観察されるように、前に言及した融合タンパク質と骨髄由来の樹状細胞との接触により、種々の樹状細胞成熟マーカーの発現レベルの定量から推論されるように、前記細胞の成熟が惹起される。それに加えて、本発明の実施例2で観察されるように、前記融合タンパク質の動物モデルへの投与により、E7タンパク質を発現する腫瘍細胞に対する、細胞傷害性T細胞により媒介される免疫応答を生じさせることができる。
(i)フィブロネクチンのEDA領域または機能的に同等なそれらの変異体、および
(ii)少なくとも1種のHPV E7由来の抗原性ペプチド
を含み、
成分(i)と(ii)とが共有結合してなる複合体であって、抗原性ペプチド(単数または複数)に対する細胞傷害性応答を助長する複合体(以後、本発明の複合体)に関する。
荷によっても規定されるなら、タンパク質に、変性せずにまたは他のタンパク質とそれらとの相互作用を破壊せずに正味の負の電荷を付与するクーマジーブルーを含有する溶液が陰極緩衝剤として使用される。SDS−PAGEゲル中の第2の変性範囲により、スポットを分離して、それに続きコンプレックスを形成するサブユニットの同一性を質量分析法により同定することが可能になる。EDAの機能的と同等な変異体の樹状細胞の成熟を促進する能力を決定するアッセイは、当業者により知られており、例えば、IAb、CD54、CD86およびIL−12などの種々の成熟樹状細胞マーカーの発現レベルを決定することに基づく、本出願の実施例1に記載したアッセイなどがある。
)のE7、ヒトHPV血清型95(GenBank:CAF05703)のE7、ヒトHPV血清型43(GenBank:CAF05784)のE7、ヒトHPV血清型5b(GenBank:BAA42818)のE7、ヒトHPV血清型103(GenBank:YP_656493)のE7、ヒトHPV血清型101(GenBank:AAZ39507)のE7、ヒトHPV血清型103(GenBank:AAZ39485)のE7が含まれるが、これらに限定されない。
・HPV E7由来の抗原性ペプチド−フィブロネクチンEDA、
・フィブロネクチンEDA−HPV E7由来の抗原性ペプチド、
・フィブロネクチンEDA−HPV E7由来の抗原性ペプチド−フィブロネクチンEDA、
・HPV E7由来の抗原性ペプチド−フィブロネクチンEDA−HPV35E7由来の抗原性ペプチド、
・最後の2つの反復
である。
この意味で、本発明による好ましい中間アミノ酸配列は、この運動を可能にする構造的延性により特徴づけられる蝶番部であろう。特定の態様において、前記中間アミノ酸配列は柔軟性リンカーである。好ましい態様において、前記柔軟性リンカーは、20アミノ酸以下の長さの柔軟性リンカーペプチドである。
本発明の複合体は、当業者に知られた任意の方法を使用して得ることができる。したがって、EDAペプチドまたは前記タンパク質の変異体を任意の標準的方法により得ることは可能である。例えば、EDAペプチドは、cDNAから、例えば、大腸菌(Escherichia coli)、出芽酵母(Sacharomyces cerevisiae)、メタノール資化性酵母(Pichia pastoris)などの異種生体中における発現により得ることができる。
EDA成分およびHPV E7由来の抗原性ペプチド(単数または複数)が単一のペプチド鎖を形成する特定の事象において、前記複合体をコードするポリヌクレオチドを使用する単一ステップでの複合体の発現は可能である。したがって、他の態様において、本発明は、本発明の複合体をコードするポリヌクレオチドに関する。当業者は、本発明のポリヌクレオチドが、成分(ii)とEDAポリペプチドまたはその機能的に同等な変異体とが単一のペプチド鎖を形成するこれらの複合体だけを、相対的位置関係とは独立に且つ両成分が直接連結しているかまたはスペーサ領域により分離しているかという事実とは独立にコードすることを理解するであろう。
本発明者らは、本発明の複合体とToll様受容体(TLR)アゴニストとの組合せにより、前記成分の各々が別々に投与されたときに得られるよりも大きい免疫応答が生ずることが可能になることを観察した。したがって、実施例3で観察されるように、EDA−HPVE7融合タンパク質およびポリI:Cにより形成した組成物は、融合タンパク質だけが投与されるときには治療可能ではない腫瘍を根絶することができる。
(i)本発明の複合体、本発明のポリヌクレオチドまたは遺伝子構築物、本発明のベクター、本発明による宿主細胞、および
(ii)TLRリガンド
を一緒にまたは別々に含む組成物(本明細書において以後、本発明の組成物1または本発明の第1組成物と称する)に関する。
(i)本発明の複合体、本発明のポリヌクレオチドまたは遺伝子構築物、本発明のベクター、本発明による宿主細胞、
(ii)TLRリガンド、および
(iii)化学療法剤
を含む、本発明の組成物(本明細書において以後、本発明の組成物2または本発明の第2組成物と称する)に関する。
ニン、メトトレキセート、コラスパーゼ(Colaspase)、ラルチトレキセドおよびカペシタビンなどの抗代謝物;(xiii)ナンドロロンなどのタンパク質同化剤;(xiv)酢酸メチルプレドニゾロン、デキサメタゾン、ヒドロコーチゾン、プレドニゾロンおよびプレドニゾンなどの副腎ステロイドホルモン;(xv)カルボプラチン、シスプラチン、オキサリプラチン、エトポシドおよびデカルバジンなどの抗新生物薬、および(xvi)トポテカンおよびイリノテカンなどのトポイソメラーゼ阻害剤が挙げられるが、これらに限定されない。
本研究者達は、本発明の複合体が、樹状細胞の成熟を誘発し、ペプチドに対するインビボの抗腫瘍免疫応答の活性化を誘発して、HPVE7タンパク質を発現している十分発育した大きい腫瘍を根絶することができることを観察した(本発明の実施例1から3を参照されたい)。
他の癌療法の取り組みは、免疫教育者としての正常樹状細胞の役割の利点を利用することである。前に言及したように、樹状細胞は数ある中でウイルス抗原を捉えてそれらをT細胞に提示し、初期のT細胞性免疫応答におけるそれらの助勢を募ることである。これは身体に侵入した外来細胞に対してよく機能するが、癌細胞は、しばしば「自己」/「外来」物質検出系を逃れる。研究者達は、樹状細胞を改変することにより、癌細胞に対するT細胞の攻撃を含む特別なタイプの自己免疫応答を活性化することができる。腫瘍作用剤は単独では免疫応答を生じさせるには十分でないという事実に基づき、未成熟樹状細胞と本発明の複合体、本発明のポリヌクレオチド、本発明の細胞、本発明の組成物または本発明の医薬組成物とを接触させることが可能であり、その結果、樹状細胞の活性化、HPV E7由来の抗原(単数または複数)の捕捉、および主要組織適合抗原に関連する表面におけるそれらの提示が生ずる。したがって、これらの活性化した細胞を患者に投与することができ、それで腫瘍抗原が患者の免疫系に提示され、その結果最終的に、T細胞により媒介された、患者の癌細胞に対する免疫応答が生ずる。
(i)樹状細胞と、本発明の複合体、本発明のポリヌクレオチド、本発明の遺伝子構築物、本発明のベクター、本発明の細胞、本発明の組成物または本発明の医薬組成物とを、樹状細胞の成熟が起こるのに適した条件で接触させるステップ、および
(ii)成熟樹状細胞を回収するステップ
を含む方法に関する。
しかしながら、刺激がないと、末梢樹状細胞の抗原提示は効果的でない。外因性シグナルすなわち病原体から来るシグナル(単数または複数)または内因性シグナル(単数または複数)は、樹状細胞を、それらが成熟と称される過程を開始するように誘導し、それにより樹状細胞はAPCおよびTリンパ球活性化因子に形質転換する。
それに加えて、成熟樹状細胞は、上で示した上方発現した膜受容体を提示することができる。
治療は、標準的組織適合試験方法を使用する患者における1種または複数種のHLAアロタイプ同定、およびHLAアロタイプ(単数または複数)が患者と一致するDCによる患者の治療を含むであろう。例えば、HLA−A2およびHLA−A19の患者は、HLA−A2もしくはHLA−A19についてホモ接合体の細胞のいずれかまたは両者の混合物を用いて治療することができる。
マウスおよび細胞ライン
特定の病原体のいない5週齢の雌C57BL/6マウスをHarlan Laboratories(Barcelona、スペイン)から購入し、CIMA動物施設で無菌条件下に水および食物が自由な状態に保った。動物を使用する実験は動物管理のための指示指針にしたがって実施した。
HPV16−E7H2−Db制限エピトープに対応する合成E749−57ペプチド[RAHYNIVTF(配列番号67):アミノ酸に対する一字コード]は、Proirnrnune(Oxford、英国)から購入した。ポリイノシン酸−ポリシチジル酸(PlC、ポリI:C、plCまたはpI:C)はInvivogen(SanDiego、CA)から購入して、注射前にPBS中に希釈した。CpGホスホロチオエートオリゴデオキシヌクレオチドタイプB(CpG1826:5’−TCCATGACGTTCCTGACGTT−3’)はProligo(Paris、France)により合成された。30μgのCpGオリゴデオキシヌクレオチドを、50μLのOptimen培地(Gibco,Grand Island,NY,米国)中に希釈して、60μgのDOTAP(Roche、Mannheim、ドイツ)と混合し、100μLのOptimenで希釈した。シクロホスファミド(CPA)(Sigrna,Steinheim,ドイツ)を注射前にPBSで希釈してワクチン接種の24時間前に投与した。種々の抗原性剤形およびアジュバントを同時に注射した。静脈内投与は眼窩後部注射により200μLの体積で実施した。
フィブロネクチンからのエキストラドメインAを発現するプラスミドpET20b−EDAを、前に記載したようにして調製して(Lasarte,Casares et al.2007)、EDAタンパク質のN端に連結したHPV−E7タンパク質の最初の1〜29アミノ酸およびEDAのC末端に連結したHPV−E7の43〜98アミノ酸を含有する融合タンパク質を発現するための発現プラスミドpET20b−EDA−HPVE7を構築するために使用した。この発現プラスミドは、下記のように2ステップで構築した。TC−1細胞からのRNAは、1×107個の細胞からChomczynskiおよびSacchi(Chomczynski and Sacchi 1987)の方法により、Ultraspec(Biotecx、Houston、TX、米国)をメーカーの指示にしたがって使用して単離した。全RNAを逆転写して、HPV−E7タンパク質をコードする遺伝子を、前に記載したように(Lasarte,Casares et al.2007)上流で最初のUP−1 CATATGCATGGAGATACACCTAC[配列番号68](下線を引いたNdeI制限部位を含む)および下流で最初のDW−1 GCGGCCGCTGGTTTCTGAGAACAGAT[配列番号69](NotI制限部位を含有する)を使用して、PCRにより増幅した。生ずるPCR生成物は、TOPO TAクローニングキット(Invitrogen,Carlsbad,CA,米国)を使用して、pCR2.1−TOPO中にクローニングし、プラスミドpCR2.1−TOPO−HPV−E7に導いた。発現プラスミドpET20b−EDA−HPVE7の構築についての最初のステップについては、プラスミドpCR2.1−TOPOHPV−E7テンプレートとして、プライマーUP−1(配列番号68)およびDW−2(CATATGATTTAATTGCTCATAACA、配列番号70)を使用するPCR反応。生じたフラグメントをpCR2.1−TOPOでサブクローニングするとプラスミドpCR2.1−TOPO−(1〜29)E7が生ずる。このプラスミドをNdeI制限酵素で消化して、生じたフラグメントをNdeIで消化したpET20b−EDAプラスミドでサブクローニングするとプラスミドpET20b−EDA−(1〜29)E7が生ず
る。第2のステップにおいては、プラスミドpCR2.1−TOPO−HPV−E7テンプレートとしてプラスミドUP−2(GCGGCCGCAGGACAAGCAGAACCGGA、配列番号71)およびDW−1(配列番号69)を使用するPCR反応を実施した。生じたPCR生成物をpCR2.1−TOPOでサブクローニングするとプラスミドpCR2.1−TOPO(43〜98)E7が生じ、それをNotIで消化してE7タンパク質のこの部分をコードするフラグメントを精製した。この生成物を前にNotIで消化したプラスミドpET20bEDA−(1〜29)E7でサブクローニングした。この過程の後、本発明者らは、プラスミドpET20b−EDA−HPVE7を得てその配列を決定し、カルボキシ端に6つのヒスチジン残基(6×Hisタグ)を担持する融合タンパク質(1〜29)E7−EDA−(43〜98)E7の正しい発現を確認した。このプラスミドpET20b2−26をBL21(DE3)細胞中に形質移入して、組替えタンパク質を発現し、それを、細胞抽出物の可溶性分画から、FPLCプラットホーム(AKTA、Pharmacia)を使用して親和性クロマトグラフィー(Histrap、Pharmacia)により精製した。溶出したタンパク質を、Hitrap脱塩カラム(Pharmacia)を使用して脱塩し、AmiconのUltra4−5000MWCO遠心濾過デバイス(Millipore Carrighwahill、アイルランド)を使用して濃縮した。この組替えタンパク質を、Endotrapカラム(Profos Ag、Regensburg、ドイツ)を使用することにより、内毒素レベルが、リムルス試験法の定量的発色(Cambrex、Walkersville、MD、米国)により試験して0.2EU/μgタンパク質未満になるまで内毒素を除いて精製した。精製した組替えタンパク質をSDS−PAGEにより分離して、Bio−Safe Coomassie試薬(Bio−Rad、Hercules、CA)を使用し、メーカーの指示にしたがってクーマジーブルーで染色した(図1)。
THP−1細胞を1×106細胞/ウェルで入れて、培養の安定化のための完全培地中で、37°Cおよび5%CO2で終夜培養した。種々の濃度の指示した抗原を培養液に加えて、15時間のインキュベーション後に、培養上清を収穫した。THP−1細胞ラインにより培地に放出されたヒトTNF−αの濃度を、市販のELISAアッセイ(BD Pharmingen)を使用してメーカーの指示にしたがって定量した。
骨髄(BM)由来の樹状細胞を、マウス大腿骨骨髄細胞の培養により発生させた。赤血球をACK細胞溶解緩衝液で溶解した後、骨髄細胞を洗浄し、続いてCD4(GK1;ATCC、Manassas、VA)、CD8(53.6.72;ATCC)Ly−6G/Gr1(BD−Pharmingen;SanDiego、CA)およびCD45R/B220(BD−Pharmingen)に対する抗体の混合物と続いてウサギ補体とのインキュベーションによりリンパ球をおよび顆粒球完全に除去した。残存する細胞を、12ウェルのプレート中106細胞/mlで、20ng/mlのmGM−CSFおよび20ng/mlのmIL−4(両方ともPeprotech;London、UKから)で補完したCM(10%FCS、2mMグルタミン、100U/mlペニシリン、100μg/mlストレプトマイシンおよび5×10−5Mの2−メルカプトエタノールで補完したRPMI1640)中で増殖させた。2日毎に、培地の3分の2をサイトカインを含有する新鮮培地で置換した。付着しない樹状細胞を第7日に収穫して、種々の刺激剤の存在または不在下に37°Cおよび5%CO2で培養した、24時間の培養後、上清を収穫してIL−12(p70)、TNF−αをELISA(BD−Pharmingen)によりメーカーの指示にしたがって測定した。DC成熟マーカーの発現はフローサイトメトリーにより測定した。細胞をラット抗CD16/32mAb(2.4G2クローン、BD Pharmingen)とともに15分間、前培養して、一次抗体の非特異的結合を阻止した。この初期インキュベーションの後、細胞を一次抗体により4°Cで15分間染色して洗浄し、FACS走査サイトメータ(BD Biosciences、San Diego、CA)で捕捉して、Cell Questソフトウェア(BD Biosciences)を使用して分析した。使用した抗体は:抗IAβb(25−9−17クローン)、抗H−2Kb(AF6−88.5クローン)、抗CD40(3/23クローン)、抗CD54(3E2クローン)、抗CD80(16−10A1クローン)、抗CD86(GL1クローン)、抗CD11c(HL−3クローン)であり、全てBD Pharmingenからのものである。
非線形混合効果モデルで腫瘍成長データを分析するために、Monolixソフトウェア(http://www.monolix.org/)を使用した。経時的な腫瘍の平均直径を、方程式1.1で記述されるモデルを使用して適合させ、治療を尤度比検定を使用して比較した。
EDA−HPVE7融合タンパク質はインビトロで骨髄由来の樹状細胞の成熟を誘発することができる
すでに記載したように、文献WO06134190には、フィブロネクチンからのエキストラドメインA(EDA)、Toll様受容体4(TLR4)の内因性リガンドを包含する組替えタンパク質が、TLR4シグナル伝達経路に結合して活性化することが記載されている。EDAは、DCによるIL−12またはTNF−αなどの炎症誘発性サイトカインの産生も刺激して、インビトロおよびインビボにおけるそれらの成熟を誘発する。それ故、組替えタンパク質EDA−HPV−E7がインビトロでBMDCの成熟も誘発することができるか否かをアッセイした。BMDCを500nMのEDA−HPV−E7とともにインキュベーションすると成熟マーカーIAb、CD54および、程度は低いがCD86分子の発現を上方制御し得ることを見出した(図2)。その上、EDA−HPV−E7は、BMDCによるIL−12サイトカインの産生を強く刺激することができた(図3A)。同様に、組替え融合タンパク質EDA−HPVE7は、TLR4分子を発現するヒト単球細胞ラインTHP−1によるTNF−αサイトカインの産生も誘発することができた(図3B)。これらの結果はEDAとHPVE7タンパク質との融合タンパク質は、EDAの炎症誘発性の性質を保持することを示す。
EDA−HPVE7融合タンパク質は、共アジュバント不在下にインビボでHPVE7特異的CTLを誘発する。
EDA−HOVE7融合タンパク質は共アジュバントの存在下にインビボでHPVE7特異的CTLを誘発する。
EDA−HPVE7融合タンパク質で免疫したマウスが、TLR3リガンドのポリI:C(pI:C)の存在下で、改善されたHPVE7特異的T細胞応答を発生するか否かをアッセイした。マウスは静脈注射によりpI:C(50μg/マウス)の存在下に2nmolEDA−HPVE7またはDTc/E7(49〜57)ペプチドで免疫した。免疫7日後に、マウスを屠殺して脾臓細胞をDTc/E7(49〜57)ペプチドの存在または不在下で培養した。5日培養した後、CTL活性を、DTcペプチドでパルスしたもしくはしない放射性標識EL4細胞(図5A)または放射線照射したTC−1細胞(図5B)を標的細胞として使用して、従来のクロム放出アッセイを使用して測定した(グラフは、ペプチドなしで得られた細胞溶解の値をペプチド存在下で得た値から差し引いて計算した絶対値を示す)。並行して、EDAHPV−E7またはDTc/E7(49〜57)ペプチドで免疫したマウスからの脾臓細胞を、E7(49〜57)ペプチドまたはTC1細胞または放射線照射したEL−4細胞の存在または不在下で24時間インキュベートして、ELISPOTを使用してIFN−γ産生を測定した(図5C)。
ポリI:Cおよびシクロホスファミドと組み合わせたEDA−HPVE7融合タンパク質の治療的有効性。
抗原送達系としておよびワクチンとしてのEDA−HPVE7の効力をさらによく評価するために、この融合タンパク質の治療的有効性とE7(49〜57)ペプチドの治療的有効性とを、両方ともTLRリガンドpI:Cで補完して比較した。それ故、C57BL/6マウスに5×105のTC−1細胞を用いて皮下注射して、25日後に、腫瘍の平均直径が約8mmになったときに治療的に処置した。したがって、静脈注射で以下の組合せのEDAワクチンによりマウスを処置した:(i)50μgのpI:Cを加えた2nmolのEDA−HPVE7;(ii)50μgのpI:Cを加えた2nmolのペプチドE7(49〜57);(iii)2nmolのEDAおよび50μgのpI:Cを加えた2nmolのE7(49〜57)ペプチド;(iv)50μgのpI:Cを加えた2nmolのEDA;(v)50μgのpI:C単独;(vi)2nmolのEDA−HPVE7単独または;(vii)PBS。
Claims (22)
- i)フィブロネクチンのEDA領域またはそれらの機能的に同等な変異体、および
ii)少なくとも1種のHPV E7由来の抗原性ペプチド
を含み、成分(i)と(ii)とが共有結合してなり、前記EDA領域が、2つのHPV E7抗原性ペプチドと並んで配置されている、複合体であって、
前記抗原性ペプチドに対する細胞傷害性応答を助長する、複合体。 - フィブロネクチンのEDA領域がヒト由来である、請求項1に記載の複合体。
- 成分(ii)が、配列番号51のアミノ酸の1〜29番を含有する抗原性ペプチド、配列番号52のアミノ酸の43〜98番を含有する抗原性ペプチドまたは両方を含む、請求項1または2に記載の複合体。
- 成分(ii)が成分(i)とともに単一ポリペプチド鎖を形成する、請求項1〜3のいずれか一項に記載の複合体。
- 配列番号53または配列番号72の配列を含む、請求項1〜4のいずれか一項に記載の複合体。
- 請求項4または5に記載の複合体をコードする、ポリヌクレオチドまたは遺伝子構築物。
- 請求項6に記載のポリヌクレオチドまたは遺伝子構築物を含む、ベクター。
- 請求項6に記載のポリヌクレオチドまたは遺伝子構築物、または請求項7に記載のベクターを含む、細胞。
- (i)請求項1〜5のいずれか一項に記載の複合体、請求項6に記載のポリヌクレオチドもしくは遺伝子構築物、請求項7に記載のベクター、請求項8に記載の宿主細胞、および
(ii)TLRリガンド
を一緒にまたは別々に含む、組成物。 - (i)請求項1〜5のいずれか一項に記載の複合体、請求項6に記載のポリヌクレオチドもしくは遺伝子構築物、請求項7に記載のベクター、請求項8に記載の宿主細胞、
(ii)TLRリガンド、および
(iii)化学療法剤
を一緒にまたは別々に含む、組成物。 - TLRリガンドが、TLR3リガンド、TLR9リガンドおよび両者の組合せからなる群から選択される、請求項9または10に記載の組成物。
- TLR3リガンドがポリ(I:C)である、請求項11に記載の組成物。
- TLR9リガンドが、少なくとも1つのCpGモチーフを含むオリゴヌクレオチドである、請求項11に記載の組成物。
- 化学療法剤(iii)がシクロホスファミドである、請求項10〜13のいずれか一項に記載の組成物。
- 請求項1〜5のいずれか一項に記載の複合体、請求項6に記載のポリヌクレオチドもしくは遺伝子構築物、請求項7に記載のベクター、請求項8に記載の細胞、または請求項9〜14のいずれか一項に記載の組成物、および少なくとも1種の薬学的に許容し得る担体もしくはアジュバントを含む、医薬組成物。
- 医薬に使用するための、請求項1〜5のいずれか一項に記載の複合体、請求項6に記載のポリヌクレオチドもしくは遺伝子構築物、請求項7に記載のベクター、請求項8に記載の細胞または請求項9〜15のいずれか一項に記載の組成物。
- ワクチンを製造するための、請求項1〜5のいずれか一項に記載の複合体、請求項6に記載のポリヌクレオチドもしくは遺伝子構築物、請求項7に記載のベクター、請求項8に記載の細胞または請求項9〜15のいずれか一項に記載の組成物の使用。
- ヒトパピローマウイルスにより惹起される感染および/またはHPV感染と関連する子宮頸癌の予防および治療のための医薬を製造するための、請求項1〜5のいずれか一項に記載の複合体、請求項6に記載のポリヌクレオチドもしくは遺伝子構築物、請求項7に記載のベクター、請求項8に記載の細胞または請求項9〜15のいずれか一項に記載の組成物の使用。
- 少なくとも1種のHPV E7抗原を提示する成熟樹状細胞を得るためのインビトロ方法であって、
i)樹状細胞と、請求項1〜5のいずれか一項に記載の複合体、請求項6に記載のポリヌクレオチドもしくは遺伝子構築物、請求項7に記載のベクター、請求項8に記載の細胞または請求項9〜15のいずれか一項に記載の組成物とを、樹状細胞の成熟が起こるために適した条件で接触させ、かつ
ii)成熟樹状細胞を回収すること
を含む、方法。 - 請求項19に記載の方法により得られる、樹状細胞。
- 医薬に使用するための、請求項20に記載の樹状細胞。
- ヒトパピローマウイルスにより惹起される感染および/またはHPV感染と関連する子宮頸癌の予防および治療のための医薬を製造するための、請求項21に記載の細胞の使用。
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