JP2013517773A - カリシウイルスウイルス様粒子上の標的化異種抗原提示 - Google Patents
カリシウイルスウイルス様粒子上の標的化異種抗原提示 Download PDFInfo
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Abstract
【選択図】図14
Description
本出願は、2010年1月21日出願の米国仮特許出願第61/297,109号(参照によりその全体が本明細書に組み入れられるものとする)に基づく利益を請求する。
添付の電子申請テキストファイル、すなわち、配列リストのコンピューター可読形式コピー(ファイル名:LIG0_023_01 WO_SeqList_ST25.txt、記録日:2011年1月21日、ファイルサイズ20キロバイト)の内容は、その全体が参照により本明細書に組み入れられるものとする。
本発明は、ウイルス学、分子生物学、およびワクチン開発の分野に関する。特に、本発明は、修飾キャプシドタンパク質から生成されるウイルス様粒子の表面上に異種抗原エピトープを提示できるように、異種抗原エピトープをタンパク質配列中に挿入するように修飾することができるカリシウイルスキャプシドタンパク質に関する。そのような修飾キャプシドタンパク質およびウイルス様粒子は、ワクチン製剤に有用である。
多くの現在のワクチンでは、病原体に対する防御免疫応答を誘導するために弱毒化微生物が利用される。これらのタイプのワクチンは、典型的には、強力な免疫応答を生じるが、病原性微生物に戻る可能性があるので感染の潜在的リスクが存在し、したがって、これらのワクチンは、いくつかの患者集団では禁忌となることもある。組換え抗原を利用した他のワクチンでは、感染のリスクは回避されるが、一般的には、弱毒化生ワクチンよりも弱い免疫応答を生じる。組換え抗原によるそのような弱い免疫応答は、免疫系への抗原提示が効果的でないためと考えられる。したがって、自然感染時に起こる免疫系への抗原提示をより良好に模倣しうるワクチンプラットフォームが必要とされる。
本発明は、一部には、キャプシドタンパク質がVLP形成能を維持するように異種抗原エピトープをカリシウイルスのキャプシドタンパク質中に挿入可能であるという発見に基づく。したがって、本発明は、カリシウイルスキャプシドタンパク質と少なくとも1つの異種抗原またはその断片とを含むキメラタンパク質を提供する。ただし、このキメラタンパク質は、宿主細胞内で発現されたときにVLPを形成可能である。一実施形態では、少なくとも1つの異種抗原またはその断片は、カリシウイルスキャプシドタンパク質のP2ドメイン中に挿入される。他の実施形態では、少なくとも1つの異種抗原またはその断片は、カリシウイルスキャプシドタンパク質のP2ドメインの1つ以上の溶媒露出ループ中に挿入される。カリシウイルスは、たとえば、ノロウイルス、サポウイルス、ラゴウイルス、またはベシウイルスでありうる。
本発明は、キャプシドタンパク質がVLP形成能を維持するように異種ペプチドをカリシウイルスキャプシドタンパク質の特定の溶媒露出(solvent-exposed)領域中に挿入可能であるという発見に基づく。本発明者らは、修飾キャプシドタンパク質から形成されるVLPの表面上に1つ以上の異種抗原が効果的に提示されるようにカリシウイルスキャプシドタンパク質を工学操作する有効な戦略を開発した。したがって、本発明は、カリシウイルスに由来するキャプシドタンパク質と少なくとも1つの異種抗原またはその断片とを含む新規なキメラタンパク質を提供する。ただし、このキメラタンパク質は、宿主細胞内で発現されたときにVLPを形成可能である。
ノロウイルスウイルス様粒子(VLP)のバイオリアクター産生および下流処理は、十分に特徴付けられており、キメラカリシウイルスVLPの生成を実証する初期概念実証試験で使用した。GI.1 Norwalk VP1サブユニットに対して、外来エピトープの挿入に好適な表面露出ループ領域(図1Aを参照)の同定は、高分解能X線結晶構造(PDBコード1IHM)の評価により行った。複合GII.4ノロウイルスキャプシドタンパク質(GII.4コンセンサス)の類似の評価は、プログラムGeno3D2を用いて原子構造モデルを作製した後で行った(図1B参照)。このソフトウェアは、テンプレートとして相同タンパク質(GII.2コンセンサスの場合のG1.I Norwalk)の原子構造を使用して、十分な配列類似性を有しかつ原子構造データの欠失した任意のカリシウイルスキャプシドタンパク質の構造モデルを生成するために同様に使用される戦略を提供する。
GI.1 Norwalk VP1サブユニットの好ましい部位への外来エピトープ挿入の包括的スクリーニングのために、2つの異なる戦略、すなわち、1)P2ドメインの溶媒接触ループ中の種々の残基位置での単純挿入、および2)P2ドメインの溶媒接触ループ残基の置換えを利用した。
接着性Sf9昆虫細胞中に導入ベクター(pVL1393−Norwalk VP1)および線状バキュロウイルスDNAを共トランスフェクトし、続いてウイルス増殖を行って高力価ストックを作製することにより、キメラNorwalk VP1サブユニットをコードする組換えバキュロウイルスの産生を行った。キメラVLP産生の初期概念実証スクリーニングとして、インフルエンザ赤血球凝集素抗原に由来するモデルエピトープ(HAエピトープ配列−YPYDVPDYA(配列番号5))をNorwalk VP1残基296、336、362、383、または399の後に直接挿入した。それに加えて、このモデル抗原をNorwalk VP1残基337〜341または残基362〜366と置き換えた構築物で発現実験を行った。図7は、モデル赤血球凝集素エピトープによる直接挿入を含有するかまたはそれにより置き換えられたNorwalk VP1残基を示している。
キメラカリシウイルスVP1サブユニットの適切なタンパク質発現およびVLP形成を確認するために、SDS−PAGE、ウェスタンブロット解析、高分解能質量分析、サイズ排除クロマトグラフィー、および電子顕微鏡法を含むいくつかの分析方法を用いて、産生プロセス全体にわたり特徴付けを行った。実施例3では、SDS−PAGEおよびウェスタンブロット解析の使用に重点を置いた。これらの方法により、キメラNorwalk VLPの適切なサブユニット分子量および外来抗原の存在が示された。ノロウイルスVLPは高分子量(>10MDa)であるので、粗精製出発材料でさえも、サイズ排除クロマトグラフィーにより直接解析可能である。VLP形成を評価するこの方法の有用性は、図11で示される。ここでは、Norwalk VP1−HAキメラ(336挿入)の馴化培地をサイズ排除クロマトグラフィーにより解析した。この試験では、予測保持時間(約8分)を有するピークの存在によりキメラVLPの適切な形成が示された(赤色トレース−220nmでの吸収(Y軸上に示される)、および青色トレース−280nmでの吸収)。
Waveバイオリアクタープラットフォームおよびバイオリアクター槽としての使い捨てのWavebagを用いて、キメラVLPの初期スケールアップバイオリアクター産生を行った。これらの試験では、感染前の細胞密度、感染多重度、および採取前の感染時間を含む基本パラメータの最適化に焦点をあてる。初期最適化はまた、複数の昆虫細胞系/培地の組合せおよび培地補充のスクリーニングを含む。これらの試験は、スケーラブル産生戦略の開発および下流処理への材料供給の両方に役立つ。Waveバイオリアクターシステムおよびさまざまな昆虫細胞/無血清培地の組合せを用いて、ノロウイルスVLPについて、>50mg/Lの範囲内でバイオリアクター産生性を慣例に従って観測した。
実施例1に概説されるように、外来エピトープの好ましい挿入部位は、カリシウイルスVP1原子構造モデルの評価による溶媒接触P2ドメイン表面ループの同定に基づくものであった。エピトープ挿入の最適位置を同定する相補的方法として、以上の構造解析をアミノ酸配列および生化学的データと組み合わせて許容部位の同定に役立てる。構造解析により同定された表面ループ領域に含まれる超可変P2ドメイン残基を同定するために、アミノ酸配列データを多重アライメントで用いる。両方の手段により同定された位置は、外来エピトープ配列の直接挿入に最適であると考えられる。同様に、構造解析により同定された単一表面露出ループに含まれる複数の超可変P2残基を有する位置は、VP1残基の部分的置換えに最適であると考えられ、VP1欠失境界を確立する指針を与えるであろう。カリシウイルスエスケープ突然変異体および/または抗体エピトープのP2ドメイン残基の同定などの生化学的データの使用は、外来エピトープの挿入に好適な位置を際立たせるのに役立つ。
30μgの天然Norwalk VLPまたは実施例3に記載のキメラNorwalk VLP(たとえば、Norwalk VP1の296、336、362、383、もしくは399残基の後に挿入されたHAエピトープまたはHAエピトープによるNorwalk VP1残基337〜341もしくは残基362〜366の置換え)の1つを用いて、約10〜12週齢の雌C57/BL6マウスを腹腔内免疫する。免疫後21日目にマウスから採血し、血清を抗原特異的ELISAで解析して天然およびキメラのNorwalk VLPの抗体価を決定する。結果から、キメラVLPが抗Norwalk抗体および抗HA抗体の両方で有意な力価を生じることが示されると予想される。
より大きい医療適合性外来抗原を含有するキメラノロウイルスVLPを作製するために、呼吸器合胞体ウイルス(RSV)Fタンパク質に由来する29アミノ酸配列(RSV Fエピトープ配列−YMLTNSELLSLINDMPITNDQKKLMSNNV(配列番号7)(これは中和抗体Synagisにより認識される))をNorwalk VP1残基308、338、または363の後に直接挿入した。それに加えて、Norwalk VP1残基307〜311、337〜341、または残基362〜366と置き換えられたRSV Fエピトープを含有する構築物を作製した。組換えバキュロウイルスの作製およびSf9昆虫細胞内でのVLP産生に続いて、キメラVLPを精製し、特徴付けし、免疫原性に関してを調べた。図13は、連続流遠心分離(CFC)によるキメラNorwalk VLP(308挿入)の精製を示している。この際、精製出発材料は、TCF−32ローターを用いた約16時間にわたる100,000×gでの遠心分離により0〜60%の直線スクロース勾配で単離された。この解析では、出発馴化培地(CM)中でのキメラVLPの産生およびウイルス様粒子の予測スクロース密度でバンド形成するキメラVP1サブユニットの顕著なピークが示される。連続流遠心分離により精製された材料でのVLPの形成は、透過型電子顕微鏡法により確認された(図14)。免疫原性を評価するために、20mMヒスチジン(pH−6.5)、150mM NaCl中200μg/mLで、CFC精製キメラVLPを製剤化した。6匹のBalb/cマウスを試験0日目に20μgのキメラVLP(約1μgのRSVエピトープ)で免疫し、試験21日目に追加の20μgのキメラVLPで追加免疫した。試験35日目に血液を採取し、RSV−FおよびNorwalkタンパク質特異的ELISAの両方を用いて全IgG力価を解析した。この試験では、キメラVLPを投与された6匹の動物のうち2匹はまた、抗RSV−F IgGが4倍超の増加を示した(図15)。
多重修飾ループを含有するキメラノロウイルスVLPを作製するために、RSV Fタンパク質の9アミノ酸配列(RSV Fエピトープ配列−LINDMPITN(配列番号6))を同一構築物内の2つのNorwalk VP1表面ループに付加した。これらの試験では、残基338および363への挿入が同時に行われたまたは残基337〜341との置換えと残基363への挿入とが同時に行われたRSV Fエピトープを含有する構築物を作製した。図16に示されるSDS−PAGE解析は、9残基のRSV−F抗原を含有するキメラNorwalk VLPの発現試験の結果を示している(レーン1、分子量標準;レーン2、338および363挿入の遠心分離後の上清;レーン3、338および363挿入の遠心分離ペレット画分;レーン4、338および363挿入の濾液;レーン5、337〜341置換えかつ363挿入の遠心分離後の上清;レーン6、337〜341置換えかつ363挿入の遠心分離ペレット画分;およびレーン7、337〜341置換えかつ363挿入の濾液)。各キメラの遠心分離後上清(レーン2および5)ならびに濾液(レーン4および7)の画分中の予測分子量(約57kDa)の顕著なNorwalk VP1泳動バンドは、天然のNorwalk VP1に類似した発現パターンを呈したことから、この溶媒接触P2ループが外来抗原挿入を効率的に許容する能力が実証される。これらのキメラでは、粒子形成は、SECデータにより示唆され、これらの試験は、実施例6に概説される概念を支持する。
インフルエンザ赤血球凝集素抗原に由来するモデルエピトープ(HAエピトープ配列−YPYDVPDYA(配列番号5))をVP1上のNorwalk VP1残基アミノ酸338−339間に直接挿入し、本明細書では「HA挿入」と記した。HAエピトープをVP1中のNorwalk VP1残基アミノ酸337〜341と置き換えた追加の構築物を作製し、本明細書では「HA置換え」と記した。免疫前に各構築物の全タンパク質含有量を調べた。「HA挿入」構築物を調べたところ、34μg/mlの全タンパク質を含有し、「HA置換え」構築物を調べたところ、42μg/mlの全タンパク質を含有していた。各チューブから50マイクロリットルを取り出して、0および7日目にマウスの腹腔内に注入した。14日目に血清を採取したが、測定可能な抗原特異的IgGは、ELISAにより検出できなかった。しかしながら、ほぼすべてのマウスで低レベルのHA特異的IgMを検出することができた(図17)。キメラVLPのHA含有量は全タンパク質のわずか1.7%にすぎないので、IgMのみの応答の理由は、低いHA濃度(「HA挿入」では29ngのHAおよび「HA置換え」では36ngのHA)である可能性が高い。アジュバントの存在によりHAに対する免疫応答が増強されるかを調べるために、37日目にAlOH/MPL上に吸着されたキメラVLPをすでに処置されたマウスに投与した。64日目に血清を採取し、HA特異的IgGに関して解析した(図18)。アジュバントの添加により、「HA挿入」で免疫された5匹のマウスのうちの4匹および「HA置換え」で免疫された5匹のマウスのうちの2匹は、検出可能なHA特異的IgG応答を有するようになった。この試験では、マウスはすべて、旧来の値に類似したNorwalk特異的IgGを産生した。結論として、HAエピトープが提示され、免疫系に認識される。この試験で使用される低濃度のHA抗原では、アジュバントを用いて免疫応答を増大させることが可能である。あるいは、HAエピトープの量を増大させれば、免疫応答が増大するであろう。
Claims (38)
- P2ドメインを有するカリシウイルスキャプシドタンパク質と少なくとも1つの異種抗原またはその断片とを含むキメラタンパク質であって、前記少なくとも1つの異種抗原またはその断片が前記キャプシドタンパク質の前記P2ドメイン中に挿入され、かつ前記キメラタンパク質が宿主細胞内で発現されたときにウイルス様粒子を形成可能である、キメラタンパク質。
- 前記少なくとも1つの異種抗原またはその断片が前記P2ドメインの少なくとも1つの溶媒露出ループ中に挿入される、請求項1に記載のキメラタンパク質。
- 前記少なくとも1つの異種抗原またはその断片が前記キャプシドタンパク質の少なくとも1つのアミノ酸と置き換えられる、請求項2に記載のキメラタンパク質。
- 前記少なくとも1つの異種抗原またはその断片が前記キャプシドタンパク質の約2〜約50アミノ酸と置き換えられる、請求項3に記載のキメラタンパク質。
- 前記少なくとも1つの異種抗原またはその断片が前記キャプシドタンパク質の約4〜約20アミノ酸と置き換えられる、請求項4に記載のキメラタンパク質。
- 前記少なくとも1つの異種抗原またはその断片が前記キャプシドタンパク質の約5アミノ酸と置き換えられる、請求項5に記載のキメラタンパク質。
- 前記カリシウイルスがノロウイルスである、請求項1に記載のキメラタンパク質。
- 前記キャプシドタンパク質がVP1である、請求項7に記載のキメラタンパク質。
- 前記キャプシドタンパク質が配列番号1のアミノ酸配列を有する、請求項8に記載のキメラタンパク質。
- 前記少なくとも1つの異種抗原またはその断片が、配列番号1中の295位のアスパラギン残基、296位のグリシン残基、308位のプロリン残基、336位のグリシン残基、338位のセリン残基、362位のアスパラギン残基、363位のグリシン残基、382位のプロリン残基、383位のセリン残基、399位のイソロイシン残基、または402位のアラニン残基の後に直接挿入される、請求項9に記載のキメラタンパク質。
- 前記少なくとも1つの異種抗原またはその断片が、配列番号1中のアミノ酸294〜298、アミノ酸307〜311、アミノ酸337〜341、アミノ酸362〜366、アミノ酸381〜385、またはアミノ酸401〜405と置き換えられる、請求項9に記載のキメラタンパク質。
- 前記キャプシドタンパク質がノロウイルスの2つ以上の流行株に由来する複合キャプシドタンパク質である、請求項7に記載のキメラタンパク質。
- 前記複合キャプシドタンパク質が配列番号2のアミノ酸配列を有する、請求項12に記載のキメラタンパク質。
- 前記ノロウイルスが遺伝子群Iまたは遺伝子群IIのノロウイルスである、請求項7に記載のキメラタンパク質。
- 前記ノロウイルスが遺伝子群I遺伝子型Iのノロウイルスまたは遺伝子群II遺伝子型4のノロウイルスである、請求項14に記載のキメラタンパク質。
- 前記少なくとも1つの異種抗原またはその断片が約5〜約70アミノ酸長である、請求項1に記載のキメラタンパク質。
- 前記少なくとも1つの異種抗原またはその断片が抗原エピトープを含む、請求項16に記載のキメラタンパク質。
- 前記少なくとも1つの異種抗原またはその断片が、ウイルス、細菌、真核病原体、腫瘍関連抗原、またはアレルゲンに由来する、請求項1に記載のキメラタンパク質。
- 前記少なくとも1つの異種抗原またはその断片が、ロタウイルス、呼吸器合胞体ウイルス、パラインフルエンザウイルス、およびメタニューモウイルスよりなる群から選択されるウイルスに由来する、請求項18に記載のキメラタンパク質。
- 請求項1に記載のキメラタンパク質を含むウイルス様粒子。
- 請求項20に記載のウイルス様粒子を含むワクチン製剤。
- アジュバントをさらに含む、請求項21に記載のワクチン製剤。
- 請求項1に記載のキメラタンパク質をコードする単離された核酸。
- 請求項23に記載の単離された核酸を含むベクター。
- 請求項24に記載のベクターを含む宿主細胞。
- 前記宿主細胞が、細菌細胞、昆虫細胞、酵母細胞、または哺乳動物細胞である、請求項25に記載の宿主細胞。
- 請求項1に記載のキメラタンパク質を宿主細胞内で発現することと、
ウイルス様粒子が形成される条件で前記宿主細胞を増殖させることと、
を含む、キメラウイルス様粒子の作製方法。 - 前記少なくとも1つの異種抗原またはその断片が前記P2ドメインの少なくとも1つの溶媒露出ループに融合される、請求項27に記載の方法。
- 前記少なくとも1つの異種抗原またはその断片が前記キャプシドタンパク質の少なくとも1つのアミノ酸と置き換えられる、請求項28に記載の方法。
- 前記少なくとも1つの異種抗原またはその断片が前記キャプシドタンパク質の1〜約50アミノ酸と置き換えられる、請求項29に記載の方法。
- 前記少なくとも1つの異種抗原またはその断片が前記キャプシドタンパク質の約4〜約20アミノ酸と置き換えられる、請求項30に記載の方法。
- 前記少なくとも1つの異種抗原またはその断片が前記キャプシドタンパク質の約5アミノ酸と置き換えられる、請求項31に記載の方法。
- 前記少なくとも1つの異種抗原またはその断片が約5〜約70アミノ酸長である、請求項27に記載の方法。
- 前記少なくとも1つの異種抗原またはその断片が抗原エピトープを含む、請求項33に記載の方法。
- 前記カリシウイルスがノロウイルスである、請求項27に記載の方法。
- 前記ノロウイルスが遺伝子群Iまたは遺伝子群IIのノロウイルスである、請求項35に記載の方法。
- 前記ノロウイルスが遺伝子群I遺伝子型Iのノロウイルスまたは遺伝子群II遺伝子型4のノロウイルスである、請求項36に記載の方法。
- 請求項21に記載のワクチン製剤を被験者に投与することを含む、外来因子に対する免疫応答を誘導する方法であって、前記少なくとも1つの異種抗原またはその断片が前記外来因子由来のタンパク質に由来する、方法。
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AU2011207355B2 (en) | 2015-04-02 |
CN102791286B (zh) | 2017-08-08 |
CA2787666A1 (en) | 2011-07-28 |
WO2011091279A2 (en) | 2011-07-28 |
US8980275B2 (en) | 2015-03-17 |
SG182636A1 (en) | 2012-08-30 |
CN102791286A (zh) | 2012-11-21 |
WO2011091279A3 (en) | 2012-02-02 |
EP2525816A2 (en) | 2012-11-28 |
AU2011207355A1 (en) | 2012-08-09 |
EP2525816A4 (en) | 2013-10-02 |
US20130052216A1 (en) | 2013-02-28 |
US20150252082A1 (en) | 2015-09-10 |
JP2016106101A (ja) | 2016-06-16 |
KR20120125627A (ko) | 2012-11-16 |
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