JP2017500298A - ヒトヘルペスウイルス三量体糖タンパク質B、三量体gBを含むタンパク質複合体、及びワクチンとしてのそれらの使用 - Google Patents
ヒトヘルペスウイルス三量体糖タンパク質B、三量体gBを含むタンパク質複合体、及びワクチンとしてのそれらの使用 Download PDFInfo
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Abstract
Description
本願は、2013年12月11日付で出願された米国仮特許出願第61/914,903号の利益を主張し、その出願日に依拠し、その開示全体が引用することにより本明細書の一部をなす。
本発明は一部、米国軍保健科学大学(USUHS Dean’s Research and Education Endowment)の政府による支援を受けてなされたものである。米国政府は本発明に対して一定の権利を有する。
本願は、ASCIIフォーマットで電子的に提出された配列表を含み、その全体が引用することにより本明細書の一部をなす。2014年12月11日付けで作製された上記ASCIIコピーの名前はHMJ−143−PCT_SL.txtであり、103345バイトのサイズである。
野生型EBV gBをコードする核酸配列は配列番号7に規定される。野生型EBV gBのポリペプチド配列は配列番号8に規定される。HCMV gBと同様に、gBのタンパク質分解プロセシングは、gBサブユニットを形成するジスルフィド結合によって共有結合的に会合したままである2つのセグメントを生じる。
三量体HCMV gBの作製のためのプラスミドの構築。三量体HCMV糖タンパク質Bが、HCMV感染に対する免疫応答を増強する効果的かつ再現可能な手段をもたらすことができるか否かを試験するために、組み換え核酸プラスミド(配列番号3)を配列番号1のアミノ酸23〜750をコードするように設計し、フーリン切断部位のコード配列(配列番号1のアミノ酸457〜461間のRTKRS(配列番号19))を(Gly4Ser)3(配列番号5)リンカーのコード配列に置き換えた。理論に束縛されることを意図するものではないが、(Gly4Ser)3(配列番号5)リンカーの導入は適当なタンパク質フォールディング、ひいてはホモ三量体HCMV糖タンパク質B複合体の形成を可能にすると考えられる。組み換え核酸としては、細胞上清へのタンパク質分泌を指向する5’末端のIgGκリーダー配列をコードする核酸、並びに精製及び免疫組織化学的分析に役立つ3’末端のHis6(配列番号26)配列をコードする核酸も挙げられる。組み換え核酸(配列番号3)をpOptiVECベクター(Life Technologies, Carlsbad, CA)にクローニングし、シークエンシングによって検証した。
精製非三量体組み換えHCMV gBタンパク質。合計2mgのHCMV gBタンパク質をSino Biological, Inc.(Beijing, P.R. China)から購入した。このHCMV gBタンパク質はヒト胎児腎臓(HEK)293細胞系列中で、細胞質ドメイン(配列番号1のアミノ酸777〜907)と連結した細胞外ドメイン(配列番号1のアミノ酸1〜700)をコードし、タンパク質精製に役立つC末端にポリヒスチジンタグが融合したDNA配列を用いて作製された。フーリン切断部位は無傷のままであったが、無効となるように突然変異していた。このHCMV gBタンパク質は818アミノ酸を含み、還元条件下での予測分子質量は93kDaであるが、グリコシル化のために分子質量は130kDa〜140kDaである。このタンパク質の生物活性を、機能ELISAアッセイにおいてビオチン化ヒトCD209−Fcと結合するその能力によって確認した。重要なことには、このHCMV gBタンパク質は、臨床試験に使用される非三量体HCMV gBタンパク質と本質的に同一である(非特許文献2)。
HCMV三量体の糖タンパク質B(gB)は、ウサギにおいて線維芽細胞及び上皮細胞のin vitroHCMV感染を防ぐ高度にブーストされたgB特異的IgG応答を誘導する。12週齢〜15週齢の4匹の雄性ニュージーランドホワイトウサギの群を、水酸化アルミニウム(アラム;1mgのタンパク質当たり0.25ugのアラム)に吸着させた25ugの三量体HCMV gBにより皮下免疫化した。ウサギを0日目、21日目及び42日目に免疫化し、初回免疫化の前及び各免疫化の10日後に血清サンプルを採取した。HCMV gB特異的IgGの血清力価を決定した。三量体HCMV gBによる一次免疫は、二次免疫後に約100倍にブーストされた検出可能なHCMV gB特異的IgGの血清力価を誘発した(図5)。3回目の免疫化は血清力価の更なる増大を示さなかった。
三量体EBV gBの作製のためのプラスミドの構築。ホモ三量体EBV糖タンパク質Bが、EBV感染に対する免疫応答を増強する効果的かつ再現可能な手段をもたらすことができるか否かを試験するために、組み換え核酸プラスミド(配列番号9)を配列番号8のアミノ酸23〜732をコードするように設計し、フーリン切断部位のコード配列(配列番号8のアミノ酸429〜433間のRRRRD(配列番号20))を(Gly4Ser)3(配列番号5)リンカーのコード配列に置き換えた(図8)。理論に束縛されることを意図するものではないが、(Gly4Ser)3リンカーの導入は適当なタンパク質フォールディング、ひいては三量体EBV糖タンパク質B複合体の形成を可能にすると考えられる。EBV gBシグナルペプチド(配列番号8のアミノ酸1〜22)をIgGκリーダー配列(配列番号6)に置き換えた。このため、組み換え核酸として更に、細胞上清へのタンパク質分泌を指向する5’末端のIgGκリーダー配列をコードする核酸、並びに精製及び免疫組織化学的分析に役立つ3’末端のHis6(配列番号26)配列をコードする核酸も挙げられる。組み換え核酸(配列番号9)をpOptiVEC(商標)ベクター(Life Technologies, Carlsbad, CA)にクローニングし、シークエンシングによって検証した。
マウス。雌性BALB/cマウスを米国国立癌研究所(Frederick, MD)から購入し、7週齢〜10週齢で全タンパク質免疫化に用いる。雌性BALB/cマウスをHarlan Laboratories(Indianapolis, IN)から購入し、4週齢〜6週齢で全プラスミドDNAワクチン接種に用いる。これらの研究は、実験動物の管理と使用に関する指針(米国実験動物資源協会、全米研究評議会、1996年改正)に規定される原則に従って行われ、米国軍保健科学大学及びワシントン大学動物実験委員会によって認可される。
HCMV gH/gLヘテロ二量体は、HCMV融合並びに線維芽細胞、上皮細胞、内皮細胞及び樹状細胞への透過に必要とされるヘルペスウイルス科コア融合機構の一部である。組み換えgH/gL単独によるウサギのワクチン接種は、線維芽細胞及び上皮細胞に対する中和抗体を誘発したが、その中和は完全五量体複合体(gH/gL/UL128/130/131A)を使用した場合に上皮細胞に対して幾らか高かった(66)。
線維芽細胞へのHCMVの侵入には、三量体gB、gH及びgLタンパク質のHCMVエンベロープ複合体が必要とされるが、UL128/130/131AからgBと会合したgH/gLへの更なる複合体形成が、内皮細胞、上皮細胞及び樹状細胞並びに白血球への侵入に必要とされる(4、5、6)。
マウス。雌性BALB/cマウスを米国国立癌研究所(Frederick, MD)から購入し、7週齢〜10週齢で全タンパク質免疫化に用いる。雌性BALB/cマウスをHarlan Laboratories(Indianapolis, IN)から購入し、4週齢〜6週齢で全プラスミドDNAワクチン接種に用いる。これらの研究は、実験動物の管理と使用に関する指針(米国実験動物資源協会、全米研究評議会、1996年改正)に規定される原則に従って行われ、米国軍保健科学大学及びワシントン大学動物実験委員会によって認可される。
2.Pass RF, Zhang C, Evans A, Simpson T, Andrews W, Huang ML, Corey L, Hill J, Davis E, Flanigan C, Cloud G. 2009. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med 360: 1191-9
3.Backovic M, Longnecker R, Jardetzky TS. 2009. Structure of a trimeric variant of the Epstein-Barr virus glycoprotein B. Proc Natl Acad Sci U S A 106: 2880-5
4.Hahn G, Revello MG, Patrone M, Percivalle E, Campanini G, Sarasini A, Wagner M, Gallina A, Milanesi G, Koszinowski U, Baldanti F, Gerna G. 2004. Human cytomegalovirus UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. J Virol 78: 10023-33
5.Akter P, Cunningham C, McSharry BP, Dolan A, Addison C, Dargan DJ, Hassan-Walker AF, Emery VC, Griffiths PD, Wilkinson GW, Davison AJ. 2003. Two novel spliced genes in human cytomegalovirus. J Gen Virol 84: 1117-22
6.Gerna G, Percivalle E, Lilleri D, Lozza L, Fornara C, Hahn G, Baldanti F, Revello MG. 2005. Dendritic-cell infection by human cytomegalovirus is restricted to strains carrying functional UL131-128 genes and mediates efficient viral antigen presentation to CD8+ T cells. J Gen Virol 86: 275-84
Claims (40)
- 修飾細胞外ドメイン又はそのフラグメントを含むヒトヘルペスウイルス糖タンパク質B(gB)ポリペプチドであって、該修飾細胞外ドメインがフーリン切断部位に挿入されたペプチドリンカーを含む、ヒトヘルペスウイルスgBポリペプチド。
- 前記ヒトヘルペスウイルスgBがヒトサイトメガロウイルス(HCMV)gB、HSV−1(単純ヘルペスウイルス−1)gB、HSV−2(単純ヘルペスウイルス−2)gB、VZV(水痘帯状疱疹ウイルス)gB、EBV(エプスタインバーウイルス)gB及びHSHV(カポジ肉腫関連ヘルペスウイルス)gBからなる群から選択される、請求項1に記載のヒトヘルペスウイルスgBポリペプチド。
- 前記ヒトヘルペスウイルスgBがHCMV gB又はEBV gBである、請求項2に記載のヒトヘルペスウイルスgBポリペプチド。
- 前記ヒトヘルペスウイルスgBがHCMV gBであり、前記修飾細胞外ドメインが、野生型HCMVアミノ酸配列(配列番号1)のフーリン切断部位に挿入されたペプチドリンカー配列を含む、請求項3に記載のヒトヘルペスウイルスgBポリペプチド。
- 前記ヒトヘルペスウイルスgBポリペプチドが膜貫通ドメイン又は細胞内ドメインを含まない、請求項1〜4のいずれか一項に記載のヒトヘルペスウイルスgBポリペプチド。
- 前記ペプチドリンカーが約6アミノ酸長〜約70アミノ酸長である、請求項1〜5のいずれか一項に記載のヒトヘルペスウイルスgBポリペプチド。
- 前記ペプチドリンカーが約15アミノ酸長である、請求項1〜5のいずれか一項に記載のヒトヘルペスウイルスgBポリペプチド。
- 前記ペプチドリンカーがアミノ酸配列GGGGSGGGGSGGGGS(配列番号5)からなる、請求項1〜7のいずれか一項に記載のヒトヘルペスウイルスgBポリペプチド。
- 前記gBポリペプチドのN末端にリーダー配列を更に含み、該リーダー配列がネイティブgBポリペプチドリーダー配列ではない、請求項1〜8のいずれか一項に記載のヒトヘルペスウイルスgBポリペプチド。
- 前記リーダー配列がアミノ酸配列METDTLLLWVLLLWVPGSTGD(配列番号6)を有する、請求項9に記載のヒトヘルペスウイルスgBポリペプチド。
- 前記ヒトヘルペスウイルスgBポリペプチドのアミノ酸配列が配列番号4を含む、請求項1〜10のいずれか一項に記載のヒトヘルペスウイルスgBポリペプチド。
- 請求項1〜11のいずれか一項に記載のヒトヘルペスウイルスgBポリペプチドを3つ含む、ヘルペスウイルスgBポリペプチドホモ三量体複合体。
- 前記ヘルペスウイルスがHCMVであり、前記ホモ三量体複合体の分子量(MW)が約360kDaである、請求項12に記載のヘルペスウイルスgBポリペプチドホモ三量体複合体。
- 請求項12又は13に記載のヘルペスウイルスgBポリペプチドホモ三量体複合体と、薬学的に許容可能な賦形剤とを含むワクチン組成物。
- 少なくとも1つのヒトヘルペスウイルス抗原を更に含む、請求項14に記載のワクチン組成物。
- 少なくとも1つのヒトヘルペスウイルス抗原が糖タンパク質H(gH)、糖タンパク質L(gL)、糖タンパク質350(gp350)、UL128、UL130、UL131及びそれらの組合せからなる群から選択される、請求項14又は15に記載のワクチン組成物。
- 前記少なくとも1つのヒトヘルペスウイルス抗原が多量体である、請求項15又は16に記載のワクチン組成物。
- アジュバントを更に含む、請求項14〜17のいずれか一項に記載のワクチン組成物。
- 前記ヒトヘルペスウイルスgBポリペプチドの少なくとも70%がホモ三量体である、請求項14〜18のいずれか一項に記載のワクチン組成物。
- ヘルペスウイルスgBポリペプチドホモ三量体複合体と、ヘルペスウイルス糖タンパク質H(gH)と、糖タンパク質L(gL)とを含むタンパク質複合体であって、前記ホモ三量体複合体が3つのヒトヘルペスウイルスgBポリペプチドを含み、各々のヒトヘルペスウイルス糖タンパク質B(gB)ポリペプチドが修飾細胞外ドメイン又はそのフラグメントを含み、該修飾細胞外ドメインがフーリン切断部位に挿入されたペプチドリンカーを含む、タンパク質複合体。
- 前記ヘルペスウイルスgH及び前記ヘルペスウイルスgLがヘルペスウイルスgH/gL融合タンパク質を形成する、請求項20に記載のタンパク質複合体。
- 前記ヒトヘルペスウイルスgBがヒトサイトメガロウイルス(HCMV)gB、HSV−1(単純ヘルペスウイルス−1)gB、HSV−2(単純ヘルペスウイルス−2)gB、VZV(水痘帯状疱疹ウイルス)gB、EBV(エプスタインバーウイルス)gB及びHSHV(カポジ肉腫関連ヘルペスウイルス)gBからなる群から選択される、請求項20又は21に記載のタンパク質複合体。
- 前記ヒトヘルペスウイルスgBがHCMV gB又はEBV gBである、請求項20〜22のいずれか一項に記載のタンパク質複合体。
- 前記ヒトヘルペスウイルスgBがHCMV gBであり、前記修飾細胞外ドメインが、野生型HCMVアミノ酸配列(配列番号1)のフーリン切断部位に挿入されたペプチドリンカー配列を含む、請求項20〜23のいずれか一項に記載のタンパク質複合体。
- 前記ヒトヘルペスウイルスgBポリペプチドが膜貫通ドメイン又は細胞内ドメインを含まない、請求項20〜24のいずれか一項に記載のタンパク質複合体。
- 前記ペプチドリンカーが約6アミノ酸長〜約70アミノ酸長である、請求項20〜25のいずれか一項に記載のタンパク質複合体。
- 前記ペプチドリンカーが約15アミノ酸長である、請求項20〜26のいずれか一項に記載のタンパク質複合体。
- 前記ペプチドリンカーがアミノ酸配列GGGGSGGGGSGGGGS(配列番号5)からなる、請求項20〜27のいずれか一項に記載のタンパク質複合体。
- 前記ヒトヘルペスウイルスgBポリペプチドがN末端にリーダー配列を更に含み、該リーダー配列がネイティブgBポリペプチドリーダー配列ではない、請求項20〜28のいずれか一項に記載のタンパク質複合体。
- 前記リーダー配列がアミノ酸配列METDTLLLWVLLLWVPGSTGD(配列番号6)を有する、請求項29に記載のタンパク質複合体。
- 前記ヘルペスウイルスgH/gL融合タンパク質が配列番号25のアミノ酸配列を含む、請求項21〜30のいずれか一項に記載のタンパク質複合体。
- ヘルペスウイルスUL128、UL130及びUL131ポリペプチドを更に含む、請求項20〜31のいずれか一項に記載のタンパク質複合体。
- 請求項20〜32のいずれか一項に記載のタンパク質複合体と薬学的に許容可能な賦形剤とを含むワクチン組成物。
- アジュバントを更に含む、請求項33に記載のワクチン組成物。
- 患者におけるヘルペスウイルス感染の予防及び/又は治療のための請求項1〜11のいずれか一項に記載のヒトヘルペスウイルスgBポリペプチド、請求項12若しくは13に記載のヘルペスウイルスgBポリペプチドホモ三量体複合体、請求項14〜19若しくは33若しくは34のいずれか一項に記載のワクチン組成物、又は請求項20〜32のいずれか一項に記載のタンパク質複合体の使用。
- 患者におけるヘルペスウイルス感染に対する免疫の誘導のための請求項1〜11のいずれか一項に記載のヒトヘルペスウイルスgBポリペプチド、請求項12若しくは13に記載のヘルペスウイルスgBポリペプチドホモ三量体複合体、請求項14〜19若しくは33若しくは34のいずれか一項に記載のワクチン組成物、又は請求項20〜32のいずれか一項に記載のタンパク質複合体の使用。
- 請求項1〜11のいずれか一項に記載のヒトヘルペスウイルスgBポリペプチドをコードする核酸。
- 請求項37に記載の核酸を含む組み換えベクター。
- 患者におけるヘルペスウイルス感染を予防又は治療する方法であって、該患者に治療有効量の請求項1〜11のいずれか一項に記載のヒトヘルペスウイルスgBポリペプチド、請求項12若しくは13に記載のヘルペスウイルスgBポリペプチドホモ三量体複合体、請求項14〜19若しくは33若しくは34のいずれか一項に記載のワクチン組成物、又は請求項20〜32のいずれか一項に記載のタンパク質複合体を投与することを含む、方法。
- 被験体においてヘルペスウイルス感染に対する免疫を誘導する方法であって、該被験体に請求項1〜11のいずれか一項に記載のヒトヘルペスウイルスgBポリペプチド、請求項12若しくは13に記載のヘルペスウイルスgBポリペプチドホモ三量体複合体、請求項14〜19若しくは33若しくは34のいずれか一項に記載のワクチン組成物、又は請求項20〜32のいずれか一項に記載のタンパク質複合体を投与することを含む、方法。
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