JP2020524710A - 免疫応答の抗原特異的リダイレクターとしてのキメラウイルス様粒子およびその使用 - Google Patents
免疫応答の抗原特異的リダイレクターとしてのキメラウイルス様粒子およびその使用 Download PDFInfo
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Abstract
Description
本発明は、パピローマウイルス(PV)L1タンパク質またはL1/L2タンパク質を含み、ヒト病原体(複数可)に由来するCD8+T細胞エピトープ含有ペプチド(複数可)を含むキメラポリペプチドから組み立てられたキメラウイルス様粒子(VLP)、かかるキメラVLPを含む組成物、ならびに癌の処置のための自然免疫および適応免疫の両方の再指向および刺激におけるキメラVLPの治療的使用に関する。
国立がん研究所によれば、総癌死亡率は、減少し続けている:総癌発生率は、男性では減少しており、女性では一定である。すべてではないが、ほとんどの一般的な癌の5年生存率も改善されている。それにもかかわらず、2017年には、米国のみで1,688,780例が新たに癌と診断され、癌死亡者数は600,920人に達すると推定される。
本発明は、パピローマウイルス(PV)L1タンパク質、組換えPVL1タンパク質、またはPVL1タンパク質およびL2タンパク質を含むポリペプチドから組み立てられたキメラウイルス様粒子(VLP)に関する。本発明のキメラVLPはまた、標的ペプチド(複数可)を含む。本明細書中で定義される標的ペプチドは、既存の記憶CD8+T細胞によって認識されるT細胞エピトープを含む。本発明の1つの実施形態では、本発明のキメラVLPは、表面に表示された標的ペプチド(複数可)を含む。いくつかの実施形態では、標的ペプチドは、VLPの表面に付着または抱合されており、いくつかの実施形態では、標的ペプチドは、標的ペプチドが組み立てられたVLPの表面に表示されるように、L1またはL2タンパク質中に組換えによって挿入されている。標的ペプチドは、別のヒト病原体由来のT細胞エピトープを含み、いくつかの実施形態では、標的ペプチドはパピローマウイルスのペプチドではない。いくつかの実施形態では、標的ペプチドは、マウスE7エピトープ(aa49〜57)を含まない。本発明はまた、本発明のキメラVLPを含む組成物、および癌の処置におけるキメラVLPの使用方法に関する。
パピローマウイルスは、小型で二本鎖の環状DNA腫瘍ウイルスである。パピローマウイルスビリオンのシェルは、L1主要キャプシドタンパク質およびL2マイナーキャプシドタンパク質を含む。真核生物または原核生物の発現系におけるL1タンパク質のみまたはL2タンパク質との組み合わせの発現により、キャプソメアおよびVLPが組み立てられることが公知である。本明細書中で使用される場合、用語「キャプソメア」は、パピローマウイルスL1ポリペプチド(全長L1タンパク質およびそのフラグメントを含む)の五量体アセンブリを意味することが意図される。未変性L1キャプシドタンパク質は、分子間ジスルフィド結合を介して自己組み立てされて五量体(キャプソメア)を形成する。
KLWESPQEI(配列番号6)、
YVYDHSGEAVK(配列番号15)、
FLPSDFFPSV(配列番号69)、
FLLTRILTI(配列番号70)、
WLSLLVPFV(配列番号71)、
GLSRYVARL(配列番号72)、
FLLSLGIHL(配列番号73)、
(K)GILGFVFTL(T)(V)(配列番号217)、
KLSTRGVQIASNEN(配列番号125)、
RGLQRRRFVQNALNGNG(配列番号131)、
FMYSDFHFI(配列番号136)、
NLVPMVATV(配列番号151)、
VAIIEVDNEQPTTRAQKL(配列番号152)、
TRAQKLFAMWRITYKDTV(配列番号153)、
GACVAIIEVDNEQPTTRAQKLFAMWRITYKDTVQLRRKL(配列番号154)の任意の9量体配列、
SVRDRLARL(配列番号167)、
LLDRVRFMGV(配列番号217)、
CLGGLLTMV(配列番号196)、または
GLCTLVAML(配列番号143)。
SLPRSRTPI(配列番号218)または
SAPLPSNRV(配列番号219)。
実施例I.VLPの産生
A.HPVL1タンパク質のバキュロウイルス発現およびVLPの産生。HPV粒子(VLP)を、当該分野で公知の方法によって産生する。簡潔に述べれば、HPV粒子を、昆虫細胞中で、パピローマウイルス主要キャプシドL1タンパク質を発現する組換えバキュロウイルスから産生する。Trichoplusia ni(High Five(商標))細胞またはSpodoptera frugiperda(SF9細胞)に、無血清条件下のExpress Five培地またはSF900−III培地(無血清培地)中で、高力価組換えバキュロウイルスを感染させる。27℃で96時間のインキュベーション後、細胞を回収し、細胞ペレットを、プロテアーゼインヒビターを含む抽出緩衝液(20mM リン酸緩衝液(pH6.5)、0.5M NaCl、10mM MgCl2)に再懸濁する。凍結融解によって粒子を放出させる。高塩活性ヌクレアーゼの存在下でのインキュベーションによって核酸を消化する。ライセートを、8,000×gで30分間の遠心分離によって清澄化し、Vertrel抽出によって脱脂する。清澄化したライセートを、40%スクロースのクッション上にロードし、SW−28ローター中にて27,000rpm、4℃で90分間遠心分離する。ペレットを、20mMリン酸緩衝液(pH6.5)、1M NaCl、10mM DTT、および0.03%Tween80に再懸濁し、4℃で保存する。ナノ粒子調製物の純度を、SDS−PAGEによって決定し、粒子の形態を、電子顕微鏡法(EM)によって決定する。典型的な調製物の純度は90%超であり、EMによると完全に組み立てられたキャプシド様の50nm粒子のようである。
末端システイン、配列FMYSDFHFI(配列番号136)(インフルエンザ)、またはGILGFVFTL配列番号119(インフルエンザ)、またはKLWESPQEI(配列番号6)(麻疹)、またはFLPSDFFPSV(配列番号69)(HepB)、またはSLPRSRTPI(配列番号218)(水痘ウイルス)またはSAPLPSNRV(配列番号219)(水痘ウイルス)を有するCD8+T細胞エピトープの1つ、およびシステインとT細胞エピトープの間の酵素切断部位(例えば、RRRRまたはRVKR)を含む標的ペプチドを含むキメラVLP(例えば、C−RRRR−エピトープ)を、マレイミド抱合を介する実施例1.AのHPV16(K)−L1 VLPへの標的ペプチドの抱合によって調製する。簡潔に述べれば、L1タンパク質濃度14mMにて50mM NaHCO3(pH8.4)中のHPV VLPを、市販のヘテロ二官能性架橋剤4−(N−マレイミドメチル)−シクロヘキサン−1−カルボキシラート(sSMCC)(Pierce Endogen,Rockfort,IL)と、最終sSMCC/L1タンパク質(mol/mol)比約100まで混合する。反応を2〜8℃で1時間進行させ、次いで、10mMヒスチジン、0.5M NaCl、0.015%ポリソルベート80を含むpH6.2の緩衝液に対する透析によって脱塩して、sSMCC活性化HPV VLPを生成する。マレイミド当量を、DTNBアッセイ(Fan et al.,Vaccine(2004)Vol.22:2993−3003;Ionescu et al.J.Pharmaceutical Sciences,Vol.95(1):70−79(Jan.2006)を参照のこと)によって決定する。標的ペプチドをN2スパージ緩衝液に溶解し、各々をsSMCC活性化HPV VLPとチオ/マレイミド(mom/mol)比約3まで混合する。反応を2〜8℃で約15時間進行させる。次いで、両方の試料を、β−メルカプトエタノールで処理して、任意の過剰なマレイミドをクエンチする。最後に、試料を、0.5M NaClおよび0.015%ポリソルベート80に対して透析する(Dispodialyser MWCO 300000 Spectrum Industries Inc.,Rancho Dominguez,CA)。
標的ペプチドを含む実施例1のキメラHPV VLP(20μg)、または標的ペプチドを含まないHPV VLP(20μg)、またはリン酸緩衝生理食塩水(PBS、20μl)を、骨髄由来樹状細胞(BMDC、106細胞/ウェル)および初代マクロファージのin vitro培養物中に添加する。BMDCおよびマクロファージは、C57BL6マウスから採取される。37℃で24時間の培養後、細胞培養物から上清を採取し、サイトカインプロフィールを、マウス32plex luminex Assayを使用して定量する。
BMDCを、上記の実施例1に記載のように産生させた標的ペプチド(10μg/ml)、HPV16(K)−L1 VLP(10μg/ml)、またはrIFN−γ(1000U/ml)を含むキメラVLPの存在下で、高度に精製した同系T細胞(比1:1)と共に37℃で48時間共培養する。対照として、BMDCを、培地のみで培養するか、T細胞の非存在下での実施例1のキメラVLP(10μg/ml)、HPV16(K)−L1 VLP(10μg/ml)、またはrIFN−γの存在下で培養する。各々の培養条件を、少なくとも2連で実施する。標準的な手順を使用して、各々の培養条件についてのIL−12p70産生を決定する。
A.方法:SHIN−3 DSR卵巣腫瘍を担持するか担持しないマウスに、100μl PBSまたは1%i−カラギーナン(カラギーナンは細胞へのHPV結合を阻害する)を含むPBS中の1×108IUのHPV16−Luc(ルシフェラーゼ)偽ウイルス(psuedovirus)(PsV)(Buck et al.Journal of Virology,(2004),78:751−757またはHung et al.PLoS One(2012);7(7):e40983(本明細書中で参考として援用される)に記載のように調製)を腹腔内注射する。48時間後、ルシフェリン基質を投与し、生物発光を測定する。腹膜腔周囲の目的の領域を抜き取り、平均放射輝度を計算する。全てのデータは、n=5/群の代表値である。
方法:1〜8日目の各々に、標的ペプチドを含むか含まない100μgの実施例1のHPV VLPを、腫瘍担持マウスに投与する。対照として、1〜8日目の各々に、腫瘍担持マウスに100μlのPBSを投与する。
方法:1〜8日目の各々に、HPV VLPおよび各々の実施例1のキメラVLP(100μg)を、腫瘍担持マウス群に投与する。対照として、1〜8日目の各々に、腫瘍担持マウスに100μlのPBSを投与する。
方法:HPV VLPおよび各々の実施例1のキメラVLP(100μg)を、マウスのB16F10黒色腫に直接注射した。腫瘍壊死中心が腫瘍内に迅速に形成し、いくらかの処置マウスは腫瘍を完全に排除する。
方法:ルシフェラーゼを過剰発現するマウスID8卵巣癌細胞株を、オボアルブミンペプチドエピトープSIINFEKL(配列番号220)に特異的なOT−1 CD8+T細胞と共培養するであろう。次いで、SIINFEKL(配列番号220)含有標的ペプチドを含むか含まないVLPを、共培養物に添加するであろう。
HLA−A*0201(AAD)トランスジェニックC57BL/6マウス群に、1/10の用量の実施例1のキメラVLPを1週間間隔で3回皮下注射した。マウスを最後の免疫化の1週間後に安楽死させ、脾臓細胞を回収して、免疫蛍光染色およびインターフェロン−γCD*+T細胞活性化アッセイによりFMYSDFHF(配列番号136)、KLWESPQEI(配列番号6)、またはFLPSDFFPSV(配列番号69)、またはSLPRSRTPI(配列番号218)またはSAPLPSNRV(配列番号219)ペプチドを用いて、HLA−A2拘束性小児期ワクチン抗原特異的応答について分析する。ワクチン接種スケジュールの終了後、脾細胞を、FMYSDFHF(配列番号136)、KLWESPQEI(配列番号6)、またはFLPSDFFPSV(配列番号69)、またはSLPRSRTPI(配列番号218)またはSAPLPSNRV(配列番号219)を含む標的ペプチドを含む実施例1のキメラVLPと共培養し、免疫蛍光染色およびインターフェロン−γCD*+T細胞活性化アッセイを利用してT細胞の再活性化について査定する。裸のVLP(すなわち、標的ペプチドを含まないVLP)を対照として使用する。VLPの結合および抗腫瘍効果を、in vitro細胞傷害性を測定するための発光画像化を介して試験する。いくつかのルシフェラーゼ発現HLA−A2陽性腫瘍株(ID8/A2(卵巣)、B16/A2(黒色腫)、TC−1/A2(子宮頸癌)など)を、キメラVLPをワクチン接種したHLA−A*0201(AAD)トランスジェニックマウス由来の脾細胞と共培養する。これらの腫瘍細胞株は標的ペプチドのCD8+T細胞エピトープと抗原的に関係がないので、腫瘍の死滅は認められない。同様に、裸のVLPの添加は、腫瘍死滅効果を全く持たないか殆ど無い。
方法:腫瘍の樹立:HLA−A*0201(AAD)トランスジェニックマウスに、ルシフェラーゼ発現ID8/A2腫瘍細胞を腹腔内(IP)注射する。
VLPを、実施例1に本質的に記載されるように、Trichoplusia ni(High Five(商標))細胞で産生させた。簡潔に述べれば、VLPを、本発明者らのキメラパピローマウイルスL1遺伝子を発現する組換えバキュロウイルスを感染させたTrichoplusia ni(High Five(商標))細胞で産生させた。VLPを、40%スクロース遠心分離、その後の別ラウンドのCsCl段階勾配での精製を使用して精製した。VLP調製物の純度を、SDS−PAGEによって決定し、粒子の形態を、透過型電子顕微鏡法(TEM)によって査定する。典型的な調製物の純度は90%超であり、TEMによると完全に組み立てられたキャプシド様の50nm粒子のようである(図2、左側のパネルのTEM)。標的ペプチド(FMYSDFHFI(配列番号136)(インフルエンザ)、またはGILGFVFTL 配列番号119(インフルエンザ)、またはKLWESPQEI(配列番号6)(麻疹)、またはFLPSDFFPSV(配列番号69)(HepB)、またはSLPRSRTPI(配列番号218)(水痘ウイルス)またはSAPLPSNRV(配列番号219)(水痘ウイルス))を、ポリカチオン性の(N末端マレイミド−Arg4RVKR−エピトープ)17量体ペプチドであるaka MAL−ペプチドとして純度85%超に合成した。抱合のために、空の非抱合VLPを、TCEP(68μM、最終)を含む50mMリン酸ナトリウム(pH6.5)、500mM NaCl、2mM EDTA反応緩衝液と共に還元条件下に供した(TCEP:VLPタンパク質(mol:mol)=10:1)。混合物(体積=625μl)を、15分毎に21℃で1時間穏やかに撹拌した。1時間の還元後、反応緩衝液中のMAL−ペプチド(170μM、625μl)を、TCEP前処理VLP中に、ペプチド:RG−1タンパク質比(mol:mol)=25:1まで添加した。混合物を、約250rpmにて21℃で1時間穏やかに撹拌し、その直後に精製プロセスに進んだ。抱合後、抱合されたVLPを含む組成物を、PBS(pH7)、500mM NaCl中で透析し、その後にダイアフィルトレーション工程を行って過剰なペプチドを除去した。抱合されたVLP(「AIR VLP」)を、TEMによって分析した。複数のAIR VLPバッチのTEMの結果は一貫しており、空の非抱合VLP(50nM)と比較して、わずかに大きなVLP(60〜70nM)を示した。AIR−VLPのSDS−PAGE分析と併せたこの結果は、抱合したVLPへのペプチドの結合量が多いことを示している。この抱合プロセスを異なるVLPに対して実施でき、図3で認められるように、多数の異なる種類の小児期ワクチンエピトープに抱合されたHPV16RG−1 VLPおよび野生型HPV16 VLPを形成するためにこの抱合プロセスを行った。図3は、インフルエンザウイルス、B型肝炎ウイルス、麻疹ウイルス、および水痘ウイルス由来のエピトープに抱合されたHPV16RG−1 VLP(左パネル)または野生型HPV16L1VLP(右パネル)のSDS PAGE分析である。
本明細書中に記載のキメラVLPの広範な腫瘍結合能力を確認するために、マウスの子宮頸癌(TC−1)、卵巣癌(ID8)、乳癌(4T1)、および黒色腫(B16)細胞株をin vitroにて0.3μg/mlのキメラVLPで24時間処置し、細胞を腫瘍結合VLPの存在について染色し、次いで、フローサイトメトリー分析によって染色した細胞を分析した。
抗腫瘍免疫リダイレクターとしての本明細書中に記載の抱合VLPの可能性を評価するために、本発明者らは最初に、モデル抗原OVA(SIINFEKL、配列番号220)を使用した。本発明者らは、フューリン切断部位を有するこのマウスH2−KB拘束OVAエピトープ(SIINFEKL、配列番号220)をHPV16RG−1 VLPに抱合してキメラVLP(AIR−VLP)を生成した。次いで、腫瘍細胞を、種々の量(濃度1.00pM〜0.02nM)のAIR−VLPまたは対照VLP(空のVLP、非抱合VLP、または偽AIR VLP(非抱合VLPおよびVLPに抱合されないペプチドの組成物)など)とin vitroで24時間インキュベートし、次いで、処置した腫瘍細胞を1×105個のOT1特異的CTLとインキュベートした。OT−1特異的CTL活性化を、表面CD8および細胞内IFN−γ染色、その後のフローサイトメトリー分析を介して査定した。有意により多くのCD8+IFN−γ+T細胞がAIR−VLP処置腫瘍細胞とのインキュベーション後に検出され、これはAIR−VLP処置が非OVA発現腫瘍細胞をOVAペプチドで首尾よくコートしたことを示し、その後OT−1特異的CTLによる認識およびその活性化をもたらす(図6を参照のこと)。
R X R/K R(配列番号209)
フューリン切断部位
Arg Val Lys Arg(配列番号210)
MMP切断ペプチド基質
Glu Pro Cit Gly Hof Tyr Leu(配列番号211)
MMP切断ペプチド基質
Gly Pro Leu Gly Ile Ala Gly Gln(配列番号212)
MMP切断ペプチド基質
Pro Val Gly Leu Ile Gly(配列番号213)
ポリグルタミン酸ドッキング部位
EEEEEEEEC(配列番号214).
ポリグルタミン酸ドッキング部位
CEEEEEEEEC(配列番号215).
EBNA3Cペプチドaa 284〜293はHLA−A2.01を結合する
LLDRVRFMGV(配列番号216)
EBVペプチド
(K)GILGFVFTL(T)(V)(配列番号217)
水痘ウイルス CD8+T細胞エピトープ
SLPRSRTPI(配列番号218)
水痘ウイルス CD8+T細胞エピトープ
SAPLPSNRV(配列番号219)
OVAペプチド
SIINFEKL(配列番号220)
RG−1 VLP配列
QLYKTCKQAG TCPPDIIPKV(配列番号:222)
Claims (44)
- パピローマウイルス(PV)L1タンパク質および表面表示標的ペプチドを含む、キメラウイルス様粒子(VLP)であって、前記標的ペプチドが、ヒト病原体のCD8+T細胞エピトープを含み、前記CD8+T細胞エピトープが、腫瘍関連抗原ではなく、前記標的ペプチドが、VLPに抱合されかつ前記標的ペプチドが、多イオン性システイン配列を介して前記VLPに抱合されない、キメラVLP。
- PVL2タンパク質をさらに含む、請求項1に記載のキメラVLP。
- 前記標的ペプチドが、ジスルフィド結合、マレイミド結合、またはアミド結合を介して前記L1タンパク質のシステイン、リジンまたはアルギニンに抱合される、請求項1に記載のキメラVLP。
- 前記標的ペプチドが、ジスルフィド結合、マレイミド結合、またはアミド結合を介して前記L2タンパク質のシステイン、リジンまたはアルギニンに抱合される、請求項2に記載のキメラVLP。
- 前記標的ペプチドが、パピローマウイルスのペプチドでない、請求項1に記載のキメラVLP。
- 前記CD8+T細胞エピトープが、小児期ワクチンの抗原ポリペプチドに由来する、請求項1に記載のキメラVLP。
- 前記病原体が、ウイルス、細菌、真菌、または寄生虫である、請求項1に記載のキメラVLP。
- 前記ウイルスが、ワクシニアウイルス、水痘帯状疱疹ウイルス、帯状疱疹ウイルス、風疹、肝炎ウイルス、例えば、A型肝炎ウイルスまたはB型肝炎ウイルスまたはC型肝炎ウイルス、A型またはB型インフルエンザウイルス、麻疹ウイルス、ムンプスウイルス、ポリオウイルス、痘瘡(天然痘)ウイルス、狂犬病ウイルス、デングウイルス、エボラウイルス、ウエストナイルウイルス、黄熱病ウイルス、またはジカウイルスである、請求項7に記載のキメラVLP。
- 前記標的ペプチドが、表1に記載のペプチドを含む、請求項1に記載のキメラVLP。
- 前記細菌が、bordatella pertussis、破傷風菌、chlamydia trachomatis、diphtheria、インフルエンザ菌、menigicoccus、例えば、Menigicoccal ACWY、pneumococcus、コレラ菌、結核菌、BCG、typhoid、大腸菌、salmonella、Legionella pneumophila、rickettsias、Treponema pallidum pallidum、streptococcusのA群またはB群、肺炎連鎖球菌、炭疽菌、chostridium botulinum、またはYersinia sp、例えば、yerisnia pestisである、請求項7に記載のキメラVLP。
- 前記寄生虫が、enamoeba histolytica、トキソプラズマ、trichinella sp.、例えば、旋毛虫、trichomonas sp.、例えば、tricomnas vaginalis、trypanosoma sp.、例えば、ガンビアトリパノソーマ、ローデンシアトリパノソーマ、またはクルーズトリパノソーマ、またはplasmodium、例えば、plamodium falciparium、三日熱マラリア原虫、または四日熱マラリア原虫である、請求項7に記載のキメラVLP。
- 前記L1タンパク質が、BPV1またはHPV1、2、3、4、5、6、8、9、11、15、16、17、18、23、27、38、31、45、33、35、39、51、52、58、66、68、70、76、および92型のL1タンパク質である、請求項1に記載のキメラVLP。
- 前記L2タンパク質が、BPV1またはHPV1、2、3、4、5、6、8、9、11、15、16、17、18、23、27、38、31、45、33、35、39、51、52、58、66、68、70、76、および92型のL2タンパク質である、請求項2に記載のキメラVLP。
- 前記L1タンパク質が、VLPの表面上に提示される3つを超えるシステインを含む、請求項1に記載のキメラVLP。
- 前記L1タンパク質が、HPV16RG−1L1タンパク質(配列番号221)である、請求項14に記載のキメラVLP。
- 前記L1タンパク質が、QLYKTCKQAG TCPPDIIPKV(配列番号222)を含む、請求項15に記載のキメラVLP。
- 前記ペプチドが、前記L1タンパク質のDEループ、HIループまたはヘリックスB4ループの1つまたは複数に抱合される、請求項1に記載のキメラVLP。
- 前記標的ペプチドが、ヒトPV16L1(HPV16L1)のヘリックスB4ループに抱合されるか、ウシPV(BPV)のDEループ、またはPVの等価なアミノ酸136/137に抱合される、請求項1に記載のキメラVLP。
- 癌細胞の成長を阻害するための方法であって、前記細胞を請求項1〜16のいずれか1項に記載のキメラVLPの有効量を含む組成物と接触させることを含む、方法。
- 被験体における腫瘍の成長、進行または転移を阻害するための方法であって、
(a)それを必要とする被験体が病原体に対して免疫化またはワクチン接種されていたかどうかを確認すること、
(b)キメラパピローマウイルス様粒子(VLP)を前記腫瘍の成長、進行または転移の阻害に十分な量で前記被験体に投与すること
を含み、
前記キメラVLPが、パピローマウイルスL1タンパク質および標的ペプチドを含み、前記標的ペプチドが、L1タンパク質のシステイン、リジンまたはアルギニンに抱合され、前記標的ペプチドが、それに対し前記被験体が免疫化されていた病原体のCD8+T細胞エピトープを含みかつ前記標的ペプチドが、キメラVLP上に表面表示される、方法。 - 前記被験体の細胞上に発現されるMHCクラスI分子を決定することおよびキメラVLPを選択することであって前記標的ペプチドが、MHCクラスI分子に結合することが公知である、決定することおよび選択すること、前記キメラVLPを前記被験体に次いで投与することをさらに含む、請求項20に記載の方法。
- 前記病原体が、ウイルス、細菌または寄生虫である、請求項20に記載の方法。
- 前記ウイルスが、ワクシニアウイルス、水痘帯状疱疹ウイルス、帯状疱疹ウイルス、風疹、肝炎ウイルス、例えば、A型肝炎ウイルスまたはB型肝炎ウイルスまたはC型肝炎ウイルス、A型またはB型インフルエンザウイルス、麻疹ウイルス、ムンプスウイルス、ポリオウイルス、痘瘡(天然痘)ウイルス、狂犬病ウイルス、デングウイルス、エボラウイルス、ウエストナイルウイルス、黄熱病ウイルス、またはジカウイルスである、請求項20に記載の方法。
- 前記細菌が、bordatella pertussis、破傷風菌、chlamydia trachomatis、diphtheria、インフルエンザ菌、menigicoccus、例えば、Menigicoccal ACWY、pneumococcus、コレラ菌、結核菌、BCG、typhoid、大腸菌、salmonella、Legionella pneumophila、rickettsias、Treponema pallidum pallidum、streptococcusA群またはB群、肺炎連鎖球菌、炭疽菌、chostridium botulinum、Yersinia sp、例えば、yerisnia pestisである、請求項22に記載の方法。
- 前記寄生虫が、enamoeba histolytica、トキソプラズマ、trichinella sp.、例えば、旋毛虫、trichomonas sp.、例えば、tricomnas vaginalis、trypanosoma sp.、例えば、ガンビアトリパノソーマ、ローデンシアトリパノソーマ、クルーズトリパノソーマ、 plasmodium、例えば、plamodium falciparium、三日熱マラリア原虫、または四日熱マラリア原虫である、請求項22に記載の方法。
- 前記標的ペプチドが、ジスルフィド結合、またはマレイミド結合によって前記L1タンパク質のシステインに抱合される、請求項20に記載の方法。
- 前記標的ペプチドが、前記L1タンパク質のループに抱合される、請求項26に記載の方法。
- 前記標的ペプチドが、L1タンパク質のループに抱合されない、請求項26に記載の方法。
- 前記CD8+T細胞エピトープが、表1に列挙されるエピトープである、請求項20に記載の方法。
- 前記CD8+T細胞エピトープが、表Iに列挙されるMHCクラスI分子に結合する、請求項29に記載の方法。
- 前記MHCクラスI分子が、HLA−A*02:01、HLA−A*03:01/HLA−A*11:01、HLA−A*0201、HLA−A*020101、HLA−A*0203、HLA−A*0206、HLA−A2、HLA−A2.1、またはHLA−A*02である、請求項30に記載の方法。
- 前記CD8+T細胞エピトープが、MHCクラスI分子HLA−A、HLA−BまたはHLA−Cファミリーに結合する、請求項21に記載の方法。
- 前記キメラVLPが、照射療法または化学療法後に投与される、請求項20に記載の方法。
- チェックポイント阻害剤を前記被験体に投与することをさらに含む、請求項20に記載の方法。
- 前記チェックポイント阻害剤が、キメラVLPと順次にまたは本質的に同時に投与される、請求項34に記載の方法。
- 前記チェックポイント阻害剤が、イプリムマブ(Yervoy(登録商標))、ペムブロリズマブ(Keytruda(登録商標))、およびニボルマブ(Opdivo(登録商標))、Atezolizumab(Tecentriq)、Avelumab(Bavencio)、Durvalumab(Imfinzi)である、請求項34に記載の方法。
- 被験体における癌の成長を阻害するための方法であって、
(a)癌を有する被験体として前記被験体を同定すること、
(b)前記被験体に以前に投与されたことのある抗原性因子を含むワクチンを同定すること、
(c)パピローマL1タンパク質および標的ペプチドを含むキメラVLPの有効量を含む組成物を前記被験体に投与することであって、前記標的ペプチドが、L1タンパク質に抱合されかつ前記標的ペプチドが、前記被験体に以前に投与された前記ワクチン中の前記抗原性因子のCD8+T細胞エピトープを含む、投与すること
を含み、
前記キメラVLPが、前記被験体における免疫応答を刺激するのに十分な量で投与され、前記抗原性因子の前記CD8+T細胞エピトープに対し特異的なCD8+T細胞を刺激することかつそれにより前記癌の成長を阻害することを含む、方法。 - 被験体における癌の成長を阻害するための方法であって、
(a)腫瘍を有する被験体として前記被験体を同定すること、
(b)キメラVLPを前記標的ペプチドに対する前記被験体による細胞性免疫応答を誘導するのに十分な量で前記被験体に投与すること
を含み、
前記キメラVLPが、パピローマL1タンパク質もしくはL2タンパク質、またはL1およびL2タンパク質の両方、ならびに標的ペプチドを含み、前記標的ペプチドが、前記L1またはL2タンパク質のシステイン、リジンまたはアルギニンに抱合され、前記標的ペプチドが、前記腫瘍由来の腫瘍関連抗原でないCD8+T細胞エピトープを含み、かつ前記細胞性免疫応答が、前記腫瘍の成長を阻害する、方法。 - パピローマウイルスL1タンパク質、またはL1タンパク質およびL2タンパク質からVLPを組み立てること、前記VLPのキャプシド様正二十面体構造を保持しながら前記VLPを還元するのに十分な還元条件に前記VLPを供すること、および還元されたVLPに前記標的ペプチドを供しそれによりキメラVLPを形成することを含む請求項1に記載のキメラVLPを作製するための方法。
- 前記標的ペプチドが、前記VLPのL1またはL2タンパク質のシステイン(cystiene)および/またはリジンに抱合される、請求項39に記載の方法。
- 前記標的ペプチドが、ジスルフィド結合マレイミド結合、またはアミド結合を介して前記VLPのL1またはL2タンパク質に抱合される、請求項39に記載の方法。
- 前記VLPの表面システインの少なくとも30%が、標的ペプチドを含む、請求項40に記載の方法。
- 前記VLPの表面システインの少なくとも約30%が、標的ペプチドを含む、請求項39に記載の方法。
- キメラVLP集団を含む組成物であって、各々のVLPが、パピローマウイルスL1タンパク質および標的ペプチドを含み、前記VLPの前記システインの少なくとも30%または前記リジンの30%または前記システインおよび前記リジンの両方の30%が、ジスルフィド結合、マレイミド結合を介して標的ペプチドに抱合される、組成物。
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US11813329B2 (en) * | 2014-10-24 | 2023-11-14 | Hpvvax, Llc | Method and composition for treating cancer or skin lesion using a vaccine |
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US11560408B2 (en) | 2018-12-27 | 2023-01-24 | Verimmune Inc. | Conjugated virus-like particles and uses thereof as anti-tumor immune redirectors |
CN111655734A (zh) * | 2019-04-28 | 2020-09-11 | 广州市雷德生物科技有限公司 | 一种促进蛋白二聚体形成的拉链扣结构及其应用 |
JP2023552040A (ja) | 2020-10-19 | 2023-12-14 | ヴェリミューン インコーポレイテッド | ウイルスにインスパイアされた組成物及びがんの治療のために同じものを使用して、既存の免疫応答をリダイレクトする方法 |
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EP3641809A2 (en) | 2020-04-29 |
CA3068012A1 (en) | 2018-12-27 |
BR112019027488A2 (pt) | 2020-07-07 |
AU2018289540B2 (en) | 2024-06-13 |
US20220226460A1 (en) | 2022-07-21 |
MY202196A (en) | 2024-04-16 |
IL271461B1 (en) | 2023-05-01 |
US11944677B2 (en) | 2024-04-02 |
CN110891602A (zh) | 2020-03-17 |
EP3641809A4 (en) | 2021-04-21 |
IL271461A (en) | 2020-01-30 |
AU2018289540A1 (en) | 2020-01-16 |
SG11201912480SA (en) | 2020-01-30 |
US11285203B2 (en) | 2022-03-29 |
WO2018237115A3 (en) | 2019-01-31 |
IL271461B2 (en) | 2023-09-01 |
MX2019015769A (es) | 2020-08-03 |
KR20200027956A (ko) | 2020-03-13 |
US20200113996A1 (en) | 2020-04-16 |
WO2018237115A2 (en) | 2018-12-27 |
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