JP2021505525A - A群レンサ球菌に対する免疫原性ペプチド - Google Patents
A群レンサ球菌に対する免疫原性ペプチド Download PDFInfo
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- IESDGNYHXIOKRW-LEOABGAYSA-N tuftsin Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-LEOABGAYSA-N 0.000 description 1
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Abstract
Description
配列番号1 LRRDLDASREAKNQVERALE
配列番号2 SREAKNQVERAL
配列番号3 LRRDLDASREAKKQVEKALE
配列番号4 SREAKKQVEKAL
配列番号5 LRRDLDAENEAKKQVEKALE
配列番号6 LRRDLDAEDEAKKQVEKALE
配列番号7 LRRDLDAEREAKNQVEKALE
配列番号8 LRRDLDAEREAKKQVERALE
配列番号9 LRRDLDAEREAKKQVEMALE
配列番号10 LRRDLDAVNEAKKQVEKALE
配列番号11 LRRDLDAVDEAKKQVEKALE
配列番号12 LRRDLDAVREAKNQVEKALE
配列番号13 LRRDLDAVREAKKQVERALE
配列番号14 LRRDLDAVREAKKQVEMALE
配列番号15 LRRDLDASNEAKNQVEKALE
配列番号16 LRRDLDASNEAKKQVERALE
配列番号17 LRRDLDASNEAKKQVEMALE
配列番号18 LRRDLDASDEAKNQVEKALE
配列番号19 LRRDLDASDEAKKQVERALE
配列番号20 LRRDLDASDEAKKQVEMALE
配列番号21 LRRDLDASREAKNQVEMALE
配列番号22 LRRDLDA
配列番号23 NSDNIKENQFEDFDEDWENF
配列番号24 KKKKNSDNIKENQFEDFDEDWENF
配列番号25〜111 それぞれ、ペプチド1〜ペプチド87の下降番号順のTable 3(表3)ペプチドライブラリー
配列番号112 SGSGLRRDLDASREAKKQVEKALE
(i)哺乳動物においてA群レンサ球菌細菌に対する免疫応答を誘発する;
(ii)A群レンサ球菌細菌に対して哺乳動物を免疫化する;及び/又は
(iii)哺乳動物におけるA群レンサ球菌細菌感染症を処置若しくは予防する
ための、配列番号1に記載されるアミノ酸配列を含む単離された免疫原性ペプチド又はそのフラグメント、バリアント若しくは誘導体をコードする1個又は複数の核酸の投与に関する。
小ペプチドエピトープの免疫原性を増強する能力は、一般に、ワクチン開発を促進する。抗体産生のための免疫原性を改善するために取るアプローチは、エピトープのより密接に似ている天然構造を生じる新規フォールディングテクノロジー(例えば、(5))又は抗原提示細胞(例えば、(6、7))又はヘルパーT細胞(8、9)を活性化するペプチドを有するさらなる分子を組み込むストラテジーを中心とする。
ペプチド
ペプチドを、Mimotopes Pty Ltd社(Victoria、Australia)から得た。ペプチドライブラリー(p145を含む87種のペプチド)を、N5末端にカップリングしたビオチンを有する切断したPepSetとして購入し、4個のアミノ酸のリンカー(SGSG)を、ペプチドとビオチンとの間に加えた。ペプチドを、N末端を介してビオチン化して、リガンド結合との干渉を最小にした。p*1-p*18ペプチドを、最小純度>90%を有するカスタムペプチドとして得た。さらなるシステイン残基を、それぞれのペプチドのN末端に加えて、ゲルスピンカラムにカップリングすることを可能にした(以下を参照)。ELISAにおけるコーティングのため使用したp145を、QIMR Berghofer Medical Research Institute、DNA and Peptide Unit又はChina peptidesにて合成した。C末端のシステイン残基を有するp*17ペプチドをChina peptidesにて合成し、他で記載される通り、DTにコンジュゲートさせた(16)。
ペプチドスクリーニングのため使用した抗血清は、J8で免疫したB10.BR、J8-DTで免疫したBALB/c、又はp145で免疫したBALB/c、クェッケンブッシュ及びB10.D2マウス由来であった。
GAS株、2031(emm1)は、プラハ委託センターの単離物であり、8830(emm97)は、オーストラリアのNorthern Territoryの臨床単離物である(17)。両方の株を、Menzies School of Health Research(MSHR)から得て、in vivo研究のためマウスに適合させ、ストレプトマイシン抵抗性(200μg/mL)を生じさせた。JRS145は、M-タンパク質陰性変異体である。
ビオチン化ペプチドを用いたELISAを、製造元(Mimotopes社、オーストラリア)が推奨する通り、行った。簡単に言うと、水中の最終濃度5μg/mlのストレプトアビジン(Sigma-Aldrich社、オーストラリア)のアリコート100μlを、Oltrack活性化96ウェルマイクロタイタープレート(Concentrack社、オランダ)に加え、37℃にて一晩インキュベートした。ウェルを、1時間、RTにて、0.05% Tween20及び1%カゼインナトリウムを含有するPBS200μl、pH7.2を用いてブロッキングし、その後、PBS/Tween20を用いて洗浄した。ペプチドを、0.1%アジ化ナトリウムを含むPBS/Tween20において、作用濃度20μg/mlまで希釈し、それぞれ100μlをウェルに加え、1時間、RTにてインキュベートした。完全に洗浄後、マウスp145又はJ8抗血清を加えた。プレートを、1時間、RTにてインキュベートし、洗浄し、HRPコンジュゲートヤギ抗マウスIgG(Bio-Rad社、オーストラリア)(1/3000)を、さらに20分間、RTにて加えた。さらに洗浄後、OPD基質(Sigma-Aldrich社)を加え、OD450にて測定した。力価を、同じ希釈の正常マウス血清を含有する対照ウェルの平均ODより3標準偏差(SD)より大きい光学密度(OD)読み取り値を示す最高希釈として定義した(19)。
全てのプロトコールは、オーストラリアのNational Health and Medical Research (NHMRC)ガイドラインに従い、QIMR Berghofer Medical Research Institute's Animal Ethics Committeeにより承認された。0日目に、クェッケンブッシュマウス(Animal Resources Centre、オーストラリア)(1群当たりn=3匹)に、総体積50μlにおいてフロイント完全アジュバント(CFA)と1:1で乳化した異なるペプチド30μgを尾部基部に皮下(s.c.)接種した。対照マウスは、無菌濾過したCFA中のPBSを受け取った。初回免疫化の3週間後、マウスは、1週間の間隔(21及び28日目)で与えた免疫原(無菌濾過したPBS中それぞれ30μg)の2回の追加免疫化を受けた。1000未満の抗体力価を有するマウスの群は、フロイント不完全アジュバントと1:1で乳化した第3のブーストを受けた。加熱殺菌GAS 2031(emm1)を、既に記載した通り、調製した(18)。皮膚負荷研究のため、BALB/cマウス(n=10匹/群)を、尾部にて、ミョウバンにおいて製剤化したp145-DT又はp*17-DT又は加熱殺菌2031GAS調製物30μgを用いて1回s.c.免疫した。p145用量範囲研究について、0日目でのp145-DT/ミョウバンを用いた初回免疫後、特定のコホートに、21及び28日目に1又は2回のブーストを投与した。対照マウスは、アジュバント単独を受けた。血液を、それぞれのマウスから、ブーストの1日前及び最終免疫化の1週間後に収集した。血液を、4℃にて少なくとも4時間、凝血させて、1000gにて10分間の遠心分離後、血清を収集した。血清を-20℃にて保存した。
ペプチド特異的血清の精製のため、Microlinkペプチドカップリングキット(Pierce社、米国)を、製造元の指示に従い使用した。簡単に言うと、それぞれのペプチドを、結合バッファー中0.6mg/mlまで希釈し、Ultralink ヨードアセチルゲルスピンカラム(Pierce社、米国)に固定した。カラムを、カップリングバッファーを用いて徹底的に洗浄し、L-システインHCl(10mg/ml)を用いてブロッキングした。その後、カラムを、洗浄バッファー、続いてPBSを用いて洗浄した。親和性精製のため、異なるクェッケンブッシュ血清300μlを、それぞれのカラムに加え、回転しながら、4℃にて一晩インキュベートした。カラムを、PBSを用いて3回洗浄し、抗体を、溶出バッファー100μlを用いて溶出した。その後、カラムを洗浄し、上の通り再度ブロッキングし、さらなる血清を加えた。Nanodrop(Thermo Scientific社、米国)を使用することにより、溶出した免疫グロブリン(Ig)濃度を推定した。濃度5μg/mlの精製したIgG調製物、続いて2倍連続希釈液を、変動する濃度のp145へのそれらの結合についてアセスメントした。
化膿性レンサ球菌へのペプチド抗体の結合を、フローサイトメトリーにより解析した。細菌を、1%ネオペプトンを含むトッド・ヒューウィット培地(THB)において一晩成長させ、PBSにおいて2回洗浄した。その後、細菌(3×107個のコロニー形成単位;cfu)を、Fcブロッカー100μlと、15分間、RTにて事前インキュベートし、続いて、濃度10mg/mlのペプチド抗体を加えた。30分間のRTでのインキュベーション後、細菌を、PBSにおいて2回洗浄し、続いて、FITCコンジュゲート抗マウスIgG(2%BSAを含むPBS中1/50希釈した)とインキュベートし、総体積100μlを、さらに30分間、RTにて加えた。細菌を洗浄し、1%ホルムアルデヒド(PBS中)300μlにて、15分間、RTにてインキュベートし、次に、FACS Calibur フローサイトメーター1(Becton Dickinson社、米国)における読み取りまで、氷上に移した。
化膿性レンサ球菌2031(emm1)、88/30(emm97)及び5448AP(emm1)を、1%ネオペプトン(THBN)を含むTHBにおいて一晩培養し、THBNにおいて2回洗浄し、オリジナルの体積の25%に再懸濁した。接種用量(CFU/ml)を、600nmにおける光学密度及び2%ウマ血液THB寒天上の細菌懸濁液の10倍希釈液を播種することにより、決定した。37℃での一晩のインキュベーション後、コロニーカウントを決定した。最終免疫化の2週間後、免疫化したマウス及び対照マウスに、選択したGAS株を、既に記載した通り(19)、皮膚の感染経路を介して負荷した。
ペプチドp*17及びP145の分子力学(MD)シミュレーションを行い、それらの免疫原性の可能性のある分子バイアスを調べた。結合したC末端のシステインを有するそれらの配列を、PEP-FOLDサーバー(20)に提出して、初期の構造モデルを構築した。これらのモデルを、MDシミュレーションのための開始点として使用し、GROMACS 5において行った(21)。全ての残基を、Amber ff14SB力場を用いてパラメーター表記した(22)。それぞれのペプチドを、溶質とボックスエッジとの間の最短距離1.2nmを有する十二面体のボックスに入れ、続いて、TIP3P水分子を用いて溶媒和させた(23)。次に、塩イオンを、濃度0.15Mまで、システムのバランスイオン電荷に加えた。エネルギー最小化を、急勾配で降下のインテグレーター及び続いてコンジュゲート勾配アルゴリズムを用いて行い、任意の原子上500kJ mol-1nm-1未満の最大力を達成した。Verletカットオフスキーム(24)を使用して、ファンデルワールスと0.8nmで切断した静電気相互作用との両方を用いて、狭い範囲の非結合相互作用を評価した。広範囲の静電気相互作用を、粒子メッシュEwald(PME)方法(25、26)により処理した。結合定数0.1psを用いてサーモスタットの再度スケールを確定した速さを使用して、温度を298Kにて維持し(27)、一方、結合定数1psを用いてBerendsen圧調節器を使用して、圧力を1.0atmにて維持した(28)。
を用いた調和位置抑制を、非溶媒分子の全ての重原子に適用した。平衡後、抑制なしのそれぞれのシステムについて100ns間、産生MDシミュレーションを行った。3回の複製MD実行を初期の速さの生成のための乱数シードを変動させることにより、それぞれのシステムについて実行した。平衡を可能にするためのそれぞれの100-nsの実行の最終40nsにてGROMACS 5の本来のプログラムにより、MD軌跡の解析を行った。
標準公式を使用して、平均及び標準誤差を計算した。マン・ホイットニーの検定を使用して、2群間の抗体力価を比較した。別段指定しない限り、複数の比較のためのボンフェローニ方法を使用して、P値を訂正した。テューキー事後検定法を用いたANOVAを使用して、それぞれの時点における試験した全てと対照コホートとの間の有意性を決定した。
本発明者らの目標は、p145内の最小の12個のアミノ酸エピトープ内の変異配列の反復ラウンドの選択を使用して、p145と比較して、GASに対する優れたペプチド免疫原を設計することであった(Table1(表1))。当初、本発明者らは、変異ペプチドライブラリー(L1)を設計して、p145の抗原性が単一の変異と共に増大し得るかどうかを問うた。本発明者らは、抗原性を増強するが、公知のヒトタンパク質に似ている配列を生じることなく、変異を同定することを考えた。
ペプチドワクチンの開発は、ペプチドの免疫原性を増大させる技術により非常に促進されるであろう。選択的アミノ酸置換を使用して免疫原性を改変する研究は非常に希であり、試験する場合はこれらは、CD8+T細胞の刺激を増強するためのエピトープ改変に焦点を当てており、その結果は様々であった。ここで、本発明者らは、化膿性レンサ球菌由来の複合体12個のアミノ酸らせん合成ペプチドの免疫原性を有意に増強する戦略を記載する。いくつかの二重に改変したペプチドは、免疫化ペプチド及び親ペプチドに対する抗体を誘導することに関して、有意に増強した免疫原性を実証し、幾つかの抗血清はまた、レンサ球菌の表面への増強した結合を示した。親ペプチドと生物(抗p*17)の両方に最も強く結合した抗血清を含むペプチドを、ワクチンとして試験して、レンサ球菌感染症を予防し、ここで、本発明者らは、単回の免疫化が、皮膚及び浸潤性疾患からの有意に増強した保護を生じることを観察した(皮膚レンサ球菌の生物負荷における100倍より多い低減及び血液細菌負荷に対する>10,000分の1の低減)。
Claims (26)
- 哺乳動物においてA群レンサ球菌細菌に対する免疫応答を誘発する方法であって、配列番号3の残基13及び17のアミノ酸置換を含む改変されたp145ペプチドアミノ酸配列を含む単離されたタンパク質;単離されたタンパク質又はそのフラグメント若しくはバリアントに結合するか、又はそれに対して生じる抗体若しくは抗体フラグメント;或いは単離されたタンパク質又はそのフラグメント若しくはバリアントをコードする単離された核酸を哺乳動物に投与することにより、免疫応答を誘発する工程を含む方法。
- 哺乳動物においてA群レンサ球菌細菌の感染症に対する免疫を誘導する方法であって、配列番号3の残基13及び17のアミノ酸置換を含む改変されたp145ペプチドアミノ酸配列を含む単離されたタンパク質;単離されたタンパク質又はそのフラグメント若しくはバリアントに結合するか、又はそれに対して生じる抗体若しくは抗体フラグメント;或いは単離されたタンパク質又はそのフラグメント若しくはバリアントをコードする単離された核酸を、哺乳動物に投与することにより、哺乳動物においてA群レンサ球菌細菌の感染症に対する免疫を誘導する工程を含む方法。
- 哺乳動物においてA群レンサ球菌細菌の感染症を処置又は予防する方法であって、配列番号3の残基13及び17のアミノ酸置換を含む改変されたp145ペプチドアミノ酸配列を含む単離されたタンパク質;単離されたタンパク質又はそのフラグメント若しくはバリアントに結合するか、又はそれに対して生じる抗体若しくは抗体フラグメント;或いは単離されたタンパク質又はそのフラグメント若しくはバリアントをコードする単離された核酸を、哺乳動物に投与することにより、哺乳動物においてA群レンサ球菌細菌の感染症を予防又は処置する工程を含む方法。
- 配列番号1のアミノ酸配列を含む単離されたタンパク質又はそのフラグメント若しくはバリアント;単離されたタンパク質又はそのフラグメント若しくはバリアントに結合するか、又はそれに対して生じる抗体若しくは抗体フラグメント;或いは単離されたタンパク質又はそのフラグメント若しくはバリアントをコードする単離された核酸を投与する工程が、哺乳動物に筋肉内に投与される、請求項1から3のいずれか一項に記載の方法。
- 免疫応答が、粘膜の免疫応答である、請求項1から4のいずれか一項に記載の方法。
- 粘膜の免疫応答が、粘膜IgGの産生により特徴付けられる、請求項5に記載の方法。
- 粘膜の免疫応答が、粘膜IgAが実質的に存在しないこと、又はIgAの産生が少なくとも低減されることにより特徴付けられる、請求項5又は6に記載の方法。
- 改変されたp145ペプチドアミノ酸配列が、残基13のアスパラギン(N)アミノ酸及び残基17のアルギニン(R)アミノ酸を含む、請求項1から7のいずれか一項に記載の方法。
- 改変されたp145ペプチドアミノ酸配列が、配列番号1に記載される、請求項8に記載の方法。
- フラグメントが、配列番号2に記載されるアミノ酸配列を含む、請求項8に記載の方法。
- 改変されたp145ペプチド、バリアント又はフラグメントが、担体タンパク質にコンジュゲート、カップリング、又はそうでなければ結合している、請求項1から10のいずれか一項に記載の方法。
- 担体タンパク質が、ジフテリア毒素、CRMタンパク質又はそのフラグメントである、請求項11に記載の方法。
- SpyCEPタンパク質の免疫原性フラグメントを投与する工程をさらに含む、請求項1から12のいずれか一項に記載の方法。
- SpyCEPのフラグメントが、S2ペプチド(配列番号23)若しくはそのバリアントであるか、又はそれを含む、請求項13に記載の方法。
- バリアントが、K4S2ペプチド(配列番号24)である、請求項14に記載の方法。
- 配列番号3の残基13及び17のアミノ酸置換を含む改変されたp145ペプチドアミノ酸配列を含む単離されたタンパク質、そのフラグメント若しくはバリアント、単離されたタンパク質又はそのフラグメント若しくはバリアントに結合するか、又はそれに対して生じる抗体又は抗体フラグメント、或いは単離されたタンパク質又はそのフラグメント若しくはバリアントをコードする単離された核酸;並びにSpyCEPタンパク質の免疫原性フラグメント又はそのバリアント、SpyCEP免疫原性フラグメント若しくはそのバリアントに結合するか、又はそれに対して生じる抗体又は抗体フラグメント、或いはSpyCEP免疫原性フラグメント若しくはそのバリアントをコードする単離された核酸、を含む単離されたタンパク質を含む、組成物。
- 改変されたp145ペプチドアミノ酸配列が、残基13のアスパラギン(N)アミノ酸及び残基17のアルギニン(R)アミノ酸を含む、請求項16に記載の組成物。
- 改変されたp145ペプチドアミノ酸配列が、配列番号1に記載される、請求項17に記載の組成物。
- 改変されたp145ペプチドのフラグメントが、配列番号2に記載されるアミノ酸配列を含む、請求項18に記載の組成物。
- 改変されたp145ペプチド、バリアント又はフラグメントが、担体タンパク質にコンジュゲート、カップリング、又はそうでなければ結合している、請求項16から19のいずれか一項に記載の組成物。
- 担体タンパク質が、ジフテリア毒素、CRMタンパク質又はそのフラグメントである、請求項20に記載の組成。
- SpyCEPのフラグメントが、S2ペプチド(配列番号23)若しくはそのバリアントであるか、又はそれを含む、請求項16から21のいずれか一項に記載の組成物。
- バリアントが、K4S2ペプチド(配列番号24)である、請求項22に記載の組成物。
- アジュバントをさらに含む、請求項16から23のいずれか一項に記載の組成物。
- 筋肉内投与に適当である、請求項16から24のいずれか一項に記載の組成物。
- 請求項1から15のいずれか一項に記載の方法による使用のための、請求項16から25のいずれか一項に記載の組成物。
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