JP2017222673A - 抗原特異的t細胞反応を誘導するための免疫原エンハンサーとしての融合タンパク質 - Google Patents
抗原特異的t細胞反応を誘導するための免疫原エンハンサーとしての融合タンパク質 Download PDFInfo
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Abstract
Description
分子生物学は、サブユニットワクチンの生産を可能にした。免疫原は、親タンパク質又は複合体の断片又はサブユニットである。T細胞感作反応を誘導することができ、病原菌の多くの株由来の配列を組み込むのに十分な柔軟性がある安定ワクチンの開発が望まれている。
(a) 上記融合タンパク質のN末端に位置する抗原提示細胞(APC)-結合ドメイン又はCD91受容体-結合ドメインと、
(b) 上記APC-結合ドメイン又はCD91受容体-結合ドメインのC末端に位置する、配列番号:4、2、3又は6と少なくとも90%同一であるアミノ酸配列を含む長さ34-112のアミノ酸残基のトランスロケーションペプチドと、
(c) 上記トランスロケーションペプチドのC末端に位置する病原体の抗原と、
(d) 配列番号:13のアミノ酸配列を含む核外移行シグナルと、
(e) 上記融合タンパク質のC末端に位置する小胞体リテンション配列と、を含む融合タンパク質に関する。
(a) 上記融合タンパク質のN末端に位置する抗原提示細胞(APC)-結合ドメイン又はCD91受容体-結合ドメインと、
(b) 上記APC-結合ドメイン又はCD91受容体-結合ドメインのC末端に位置する配列番号:4、2、3又は6と少なくとも90%同一であるアミノ酸配列を有する長さ34-112のアミノ酸残基のトランスロケーションペプチドと、
(c) 上記トランスロケーションペプチドのC末端に位置する病原体の抗原と、
(d) 配列番号:13のアミノ酸配列を含む核外移行シグナルと、
(e) 上記融合タンパク質のC末端に位置する小胞体リテンション配列、からなる又はから実質的になる。
本発明は、以下の実施例に特に記載されている。多数の変更形態及びバリエーションが当業者にとって明らかであるため、実施例は、説明のためであることを意図している。以下、本発明の様々な実施形態の詳細について説明する。図面に関して、同じ番号は、図全体にわたって、同じ構成要素を示す。本願明細書及び添付の請求項全体に渡る記述において使用している通り、「a」、「an」及び「the」の意味は、文脈において別途明確に示していない限り、複数を含む。また、本願明細書及び添付の請求項全体に渡る記述において使用している通り、「in」の意味は、文脈において別途明確に示していない限り、「in」及び「on」を含む。更に、表題又は副題は、読者の便宜のために明細書において使用されているが、本発明の範囲に対する影響を及ぼすものではない。加えて、この明細書において使用するある種の用語は、下でより詳しくは規定される。
この明細書において使用する用語は、一般的に、本発明の背景内の技術分野、及び、各用語が使用されている特定の文脈における通常の意味を有する。本発明を説明するために用いるある種の用語は、本発明の記述に関して実践者に追加のガイダンスを提供するために、以下、又は、別途明細書中にて説明する。便宜上、ある種の用語は、例えば、イタリック及び/又は引用符を使用して、強調されているだろう。強調表示の使用は、用語の範囲及び意味に対する影響を与えない。用語の範囲及び意味は、それが強調されていようといまいと、同じ文脈において同じである。同じことを複数の方法で述べることができることはいうまでもない。その結果、代替の言葉及び同義語を、本願明細書において述べられる任意の1又は複数の用語のために用いることができるが、本願明細書において詳しく述べている又は議論されているか否かによって与えられる任意の特別は用語はない。ある種の用語の同義語は、提供される。1又は複数の同義語の記載は、他の同義語の使用を排除しない。この明細書における例示(本願明細書に記載の任意の用語の例示を含む)の使用は、解説のためだけにあり、本発明又は任意の例示用語の範囲及び意味を限定するものではない。同様に、本発明は、この明細書が提供する様々な実施形態に限定されない。
発現ベクターの構造
図1Aは、PEが3つのドメイン(I、II及びIII)を含むことを示している。PE407は、PEのa.a.1からa.a.407までの領域である。PE407は、細胞毒性ドメインIIIを含んでいないため、ドメインI及びIIを含む。PE313は、PEのa.a.1からa.a.313までの領域である。従って、PE313は、PEのドメインIa及びドメインIIの部分的なN末端領域だけを含む。
タンパク質発現
融合タンパク質の発現のためのプラスミド(1) PE313-ORF2-NESK;(2) PE407-ORF2-K3;(3) PE313-E2-NESK;(4) PE407-E2-K3;(5) PE313-VP1-3A-NESK;(6) PE407-VP1-3A-K3;(7) PE313-FHN-NESK;(8) PE407-FHN-K3;(9) PE407-E7-K3;(10) RAP1-PE268-313-E7-NESK及び(11) RAP1-PE268-313-E7-K3を含む大腸菌BL21細胞を、37℃で25ppmのカナマイシンを含有するルーリアベルターニブロスにてそれぞれ培養した。培養が初期対数期(A600=0.1から0.4)に達すると、誘導のためにイソプロピル-1-チオ-β-D-ガラクトピラノシド(IPTG)を、0.5〜2mMの終濃度で加えた。細胞を、誘導の4時間後に回収して、-70℃で直ちに保存した。融合タンパク質を、既に述べられている尿素抽出によって精製し(Liao et al., 1995. Appl. Microbiol. Biotechnol. 43: 498-507)、そして、4℃で一晩、50X体積のTNE緩衝液(50mMのトリス、50mMのNaCl及び1mMのEDTA)において透析方法によってリフォールディングした。リフォールディングタンパク質を、SDS-PAGE分析して、定量分析はブラッドフォードタンパク質アッセイキット(Pierce)を使用して行った。この結果から、ほとんどのリフォールディングタンパク質は還元条件下で単量体であることが示されたことから、融合タンパク質は容易にリフォールディングされ、凝集されなかったことが示された。
PCV2サブユニットワクチン免疫原性アッセイ
マウスは、1週1回を3週間、リン酸アルミニウム(融合タンパク質の徐放のためのタンパク質吸着剤; 10%v/v)及び10μgのサポニン(キラヤサボンソウから抽出されるアジュバント)と共に40μgのPE313-ORF2-NESK又はPE407-ORF2-K3を含む0.1mlのPCV2サブユニットワクチンをs.c.注射を介してワクチン接種を受けた。コントロール群(プラセボ)は、融合タンパク質だけを含まず、アジュバントと共に注射した。全てのマウスは、最後の免疫の14日後に屠殺して、脾臓は回収した。脾細胞を単離して、16時間37℃、1μg/ml GolgiPlug(BD Pharmingen、サンディエゴ、CA)の存在下において組換え型ORF2タンパク質の有り無しで6ウェルプレート(108細胞/2ml/ウェル)で培養した。刺激した脾細胞を、FACScan緩衝液にて洗浄して、フィコエリトリン共役モノクローナルラット抗マウスCD8a及びAF700共役モノクローナルラット抗マウスCD4抗体で染色した。細胞を、製造業者(BD Pharmingen)の指示に従ってCytofix/Cytopermキットを用いて細胞内サイトカインを染色した。細胞内のIFN-γは、AF488共役ラット抗マウスIFN-γで着色して、免疫反応及びサイトカインレベルを測定した。Kaluza分析ソフトウェア(ベックマン・コールター製)を用いたガリオフローサイトメトリーを使用してフローサイトメトリー分析を実施した。
CSFVサブユニットワクチン免疫原性アッセイ
同じ免疫化スケジュール及び用量を用いて、マウスを、PE313-E2-NESK又はPE407-E2-K3を含むCSFVサブユニットワクチンを用いてワクチン接種をして、脾細胞を単離し、培養し、上述したフローサイトメトリー法によってアッセイした。但し、組換え型E2タンパク質を培地中に加えて脾細胞を刺激したことは除いた。
FMDVサブユニットワクチン免疫原性アッセイ
同じ免疫化スケジュール及び用量を用いて、マウスを、PE313-VP1-3A-NESK又はPE407-VP1-3A-K3を含むFMDVサブユニットワクチンを用いてワクチン接種をして、脾細胞を単離し、培養し、(組換え型VP1-3Aタンパク質を培地中に加えて脾細胞を刺激した点以外は、)上述したフローサイトメトリー法によってアッセイした。
NDVサブユニットワクチン免疫原性アッセイ
同じ免疫化スケジュール及び用量を用いて、マウスを、PE313-FHN-NESK又はPE407-FHN-K3を含むFMDVサブユニットワクチンを用いてワクチン接種をして、脾細胞を単離し、培養し、上述したフローサイトメトリー法によってアッセイした。但し、組換え型FHNタンパク質を培地中に加えて脾細胞を刺激したことは除いた。
ヒトパピローマウイルスタイプ16E7タンパク質によって誘導された腫瘍成長の阻害の向上
融合タンパク質PE407-E7-K3、RAP1-PE268-313-E7-K3及びRAP1-PE268-313-E7-NESKは、上記方法と類似の方法を使用して発現させてリフォールディングさせた。s.c.注射を介して2×103のTC-01細胞(HPVタイプ16 E7遺伝子を含むマウス肺上皮細胞)をマウスに投与して、HPV-16タイプ上皮性悪性腫瘍を誘導した。TC-01細胞投与の12日後、1週1回を3週間、アジュバントとしてのAS04C(グラクソスミスクライン)と共に、プラセボ(PBS)、PE407-E7-K3(100mg/投与)、RAP1-PE268-313-E7-K3(100μg/投与)又はRAP1-PE268-313-E7-NESK(100μg/投与)をs.c.にてマウスにワクチン接種した(図6)。AS04Cは、細胞毒性Tリンパ球活性化アジュバントであり、MPL(モノホスホリルリピドA、免疫強化剤)及びリン酸アルミニウム(抗原デリバリーのためのタンパク質吸着剤)を含む。「K3」という用語は、KDELを含むERリテンション配列をいう。例えば、K3は、アミノ酸配列KDELKDELKDEL(配列番号:16)であってもよい。「NESK」という用語は、核外移行シグナル及びERリテンション配列を含む融合ペプチドをいう。本発明の一実施形態において、NESKは、アミノ酸配列LQKKLEELELAKDEL(配列番号:12)である。各群における腫瘍のサイズ及び腫瘍がない動物の数を記録した(図7及び8)。腫瘍成長は、アジュバントとしてのAS04Cを有するワクチンPE407-E7-K3、RAP1-PE268-313-E7-K3及びRAP1-PE268-313-E7-NESKによって著しく抑制された。しかしながら、ワクチンのRAP1-PE268-313-E7-NESKは、腫瘍成長を抑制して、腫瘍がない動物のパーセンテージを増加させることについて、PE407-E7-K3よりも優れており、RAP1-PE268-313-E7-K3よりも良好だった。
以下の融合タンパク質を生成した:PE313-NES-抗原-K、PE1-252-PE268-313-NES-抗原-K、PE1-252-PE280-313-NES-抗原-K。加えて、融合タンパク質PE313-抗原-NESKのPEドメインIa(PE1-252)の断片は、RAP1ドメイン3(配列番号:8)A2Mミニマム(配列番号:9)、HIV-Tatミニマム(配列番号:10)又はHSPミニマム(配列番号:11)によって取り替えて、融合タンパク質RAP1ドメイン3-PE253-313-抗原-NESK、A2M-PE253-313-抗原-NESK、Tat-PE253-313-抗原-NESK及びHSP-PE253-313-抗原-NESK、RAP1ドメイン3-PE268-313-抗原-NESK、A2M-PE268-313-抗原-NESK、Tat-PE268-313-抗原-NESK及びHSP-PE268-313-抗原-NESKワクチン、RAP1ドメイン3-PE280-313-抗原-NESK、A2M-PE280-313-抗原-NESK、Tat-PE280-313-抗原-NESK及びHSP-PE280-313-抗原-NESK、RAP1ドメイン3-PE253-313-NES-抗原-K、A2M-PE253-313-NES-抗原-K、Tat-PE253-313-NES-抗原-K及びHSP-PE253-313-NES-抗原-K、RAP1ドメイン3-PE268-313-NES-抗原-K、A2M-PE268-313-NES-抗原-K、Tat-PE268-313-NES-抗原-K及びHSP-PE268-313-NES-抗原-Kワクチン、RAP1ドメイン3-PE280-313-NES-抗原-K、A2M-PE280-313-NES-抗原-K、Tat-PE280-313-NES-抗原-K及びHSP-PE280-313-NES-抗原-Kを生成する。これらのワクチンによって向上した細胞性免疫反応は、上記方法に類似の方法を使用して検討した。
**:VP1-3Aペプチドは、VP1のa.a.127 - a.a.176及び3Aのa.a.21-a.a.35、即ち、FMDV VP1ペプチド(配列番号: 22)及びFMDV 3Aペプチド(配列番号: 23)の融合で構成される融合抗原である。
***:FHNペプチドは、融合タンパク質のa.a.65-a.a.8及びヘマグルチニン-ノイラミニダーゼのa.a.101-a.a.111、即ち、NDV Fペプチド(配列番号: 25)及びNDV HNペプチド(配列番号: 26)の融合で構成される融合抗原である。
Claims (20)
- 融合タンパク質であって、
(a) 前記融合タンパク質のN末端に位置する抗原提示細胞(APC)-結合ドメイン又はCD91受容体-結合ドメインと、
(b) 前記APC-結合ドメイン又はCD91受容体-結合ドメインのC末端に位置する、配列番号:4、2、3又は6と少なくとも90%同一であるアミノ酸配列を含む長さ34-112のアミノ酸残基のトランスロケーションペプチドと、
(c) 前記トランスロケーションペプチドのC末端に位置する病原体の抗原と、
(d) 配列番号:13のアミノ酸配列を含む核外移行シグナルと、
(e) 前記融合タンパク質のC末端に位置する小胞体リテンション配列と、を含む融合タンパク質。 - 前記APC-結合ドメイン又はCD91受容体-結合ドメインは、配列番号:1及び8-11からなる群より選択される配列と少なくとも90%同一であるアミノ酸配列を含むポリペチドである、請求項1に記載の融合タンパク質。
- 前記核外移行シグナルは、配列番号:14のアミノ酸配列を含む、請求項1に記載の融合タンパク質。
- 前記小胞体リテンション配列は、配列番号:15のアミノ酸配列を含む、請求項1に記載の融合タンパク質。
- 前記核外移行シグナルは、前記トランスロケーションペプチドと前記抗原との間に位置する、請求項1に記載の融合タンパク質。
- 前記核外移行シグナルは、前記抗原と前記小胞体リテンション配列との間に位置する、請求項1に位置する融合タンパク質。
- 前記核外移行シグナル及びERリテンション配列は、配列番号:12と少なくとも90%同一であるアミノ酸配列を含む融合ペプチドを形成する、請求項1に記載の融合タンパク質。
- 前記トランスロケーションペプチドは、長さ34-61のアミノ酸残基を有する、請求項1に記載の融合タンパク質。
- 前記APC-結合ドメイン又はCD91受容体-結合ドメインは、シュードモナスエキソトキシンA(PE)結合ドメインIのアミノ酸配列を有していない、請求項1に記載の融合タンパク質。
- 前記APC-結合ドメイン又はCD91受容体-結合ドメインは、配列番号:8のアミノ酸配列を含む、請求項9に記載の融合タンパク質。
- 前記APC-結合ドメイン又はCD91受容体-結合ドメインのアミノ酸配列は、配列番号:1である、請求項1に記載の融合タンパク質。
- 前記トランスロケーションペプチドは、長さ34-61のアミノ酸残基を有する、請求項11に記載の融合タンパク質。
- 前記核外移行シグナル及びERリテンション配列は、配列番号:12と少なくとも90%同一であるアミノ酸配列を含む融合ペプチドを形成する、請求項12に記載の融合タンパク質。
- 前記トランスロケーションペプチドは、長さ34-46のアミノ酸残基を有する、請求項11に記載の融合タンパク質。
- 前記トランスロケーションペプチドは、長さ34-61のアミノ酸残基を有する、請求項10に記載の融合タンパク質。
- 前記核外移行シグナル及びERリテンション配列は、配列番号:12と少なくとも90%同一であるアミノ酸配列を含む融合ペプチドを形成する、請求項15に記載の融合タンパク質。
- 前記抗原は、病原体由来の2又は3以上の抗原ペプチドの融合抗原である、請求項1に記載の融合タンパク質。
- 請求項1に記載の融合タンパク質であって、
(a) 前記融合タンパク質のN末端に位置する抗原提示細胞(APC)-結合ドメイン又はCD91受容体-結合ドメインと、
(b) 前記APC-結合ドメイン又はCD91受容体-結合ドメインのC末端に位置する配列番号:4、2、3又は6と少なくとも90%同一であるアミノ酸配列を有する長さ34-112のアミノ酸残基のトランスロケーションペプチドと、
(c) 前記トランスロケーションペプチドのC末端に位置する病原体の抗原と、
(d) 配列番号:13のアミノ酸配列を含む核外移行シグナルと、
(e) 前記融合タンパク質のC末端に位置する小胞体リテンション配列、から実質的になる融合タンパク質。 - 請求項1に記載の融合タンパク質とアジュバントを含むワクチン組成物。
- 病原体抗原特異的T細胞反応の向上を誘導するために使用する、請求項1から19のいずれかに記載の融合タンパク質又はワクチン組成物。
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