JP4759010B2 - 結核の免疫治療および診断のための化合物およびそれらの使用方法 - Google Patents
結核の免疫治療および診断のための化合物およびそれらの使用方法 Download PDFInfo
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Description
本発明は、一般に、Mycobacterium tuberculosis感染の検出、処置、および予防に関する。本発明は、より詳細には、Mycobacterium tuberculosis抗原、またはその部分もしくは他の変異体を含むポリペプチド、およびMycobacterium tuberculosis感染に対する診断およびワクチン接種のためのこのようなポリペプチドの使用に関する。
結核は、慢性の、感染性疾患であり、一般にMycobacterium tuberculosisの感染により生じる。結核は発展途上国で主要な疾患であり、そして世界中の先進地域で問題が増大しており、毎年約8百万人が新たに発病し、そして3百万人が死亡する。感染はかなりの期間無症候性であり得るが、この疾患は、最も一般的には、発熱および痰を伴わない咳を生じる肺の急性炎症として発現する。処置しないでおくと、代表的には、重篤な合併症および死をもたらす。
ChanおよびKaufmann、Tuberculosis:Pathogenesis, Protection and Control, Bloom(編)、ASM Press、Washington, DC、1994
簡潔に述べると、本発明は結核を予防および診断するための化合物および方法を提供する。1つの局面において、M.tuberculosis抗原の免疫原性部分またはそのような抗原の変異体(これは、保存的置換および/または改変においてのみ異なる)、配列番号:1、11、12、83、103-108、125、127、129-137、139および140に記載される配列から成る群から選択されるDNA配列、上記配列の相補物、ならびに中程度のストリンジェントな条件下で配列番号:1、11、12、83、103-108、125、127、129-137、139および140に記載される配列またはその相補物にハイブリダイズするDNA配列によってコードされるアミノ酸配列から成る抗原を包含するポリペプチドが提供される。第2の局面において、本発明は、 配列番号:16-33、109、126、138、141、142に提供される配列およびその変異体から成る群から選択されるアミノ酸配列を有する、M.tuberculosis抗原の免疫原性部分を含むポリペプチドを提供する。
(i) 配列番号142に記載のアミノ酸配列;
(ii) 保存的置換および/もしくは改変においてのみ異なる配列番号142の免疫原性変異体であって配列番号142に対して少なくとも90%の同一性を有するアミノ酸配列;または
(iii) 配列番号142に記載のアミノ酸配列の免疫原性部分
を含む、単離されたポリペプチド。
(i) 配列番号142に記載のアミノ酸配列;
(ii) 保存的置換および/もしくは改変においてのみ異なる配列番号142の免疫原性変異体であって配列番号142に対して少なくとも90%の同一性を有するアミノ酸配列;または
(iii) 配列番号142に記載のアミノ酸配列の免疫原性部分
を含むポリペプチドをコードするヌクレオチド配列を含む、単離されたDNA分子。
(a) 上記(1)〜(9)のいずれか1つに記載のポリペプチド;および
(b) 患者の皮膚上で免疫応答を誘導するために、該ポリペプチドを患者の皮膚細胞と接触させるのに十分な器具
を含む、結核の検出のための診断キット。
図1Aおよび1Bは、組換えORF-2およびORF-2に対する合成ペプチドによる、第1のPPD-陽性ドナー(D7と呼ぶ)由来のT細胞における増殖刺激およびインターフェロン−γの産生を、それぞれ、図示する。
上記のように、本発明は、一般に、結核を予防、処置、および診断するための組成物および方法に関する。本発明の組成物は、M.tuberculosis抗原または保存的置換および/または改変でのみ異なるような抗原の変異体の、少なくとも1つの免疫原性部分を含むポリペプチドを含む。本明細書で使用する用語「ポリペプチド」は、全長タンパク質(すなわち、抗原)を含む、任意の長さのアミノ酸鎖を包含し、ここで、アミノ酸残基は共有ペプチド結合によって連結されている。従って、上記の抗原の1つの免疫原性部分を含むポリペプチドは、全体が免疫原性部分からなり得るか、またはさらなる配列を含み得る。さらなる配列は、ネイティブなM.tuberculosis抗原に由来し得るか、または異種のものであり得、そしてこのような配列は、免疫原性であり得る(しかし免疫原性である必要はない)。
ヒトPBMCから生成されたCD4+ T細胞株を用いたM.tuberculosisポリぺプチドの精製および特徴付け
本発明のM.tuberculosis抗原を、M.tuberculosis株H37RvおよびErdmanのcDNAライブラリーの発現クローニングによって、本質的にSandersonら(J.Exp.Med., 1995, 182:1751-1757)によって記載されるように単離し、そしてこれは免疫反応性T細胞株においてPBMC増殖およびIFN-γを誘導することが示された。
M.tuberculosis抗原によるT細胞増殖およびインターフェロン-γ産生の誘導
組換えM.tuberculosis抗原のT細胞増殖およびインターフェロン-γ産生を誘導する能力は、以下のように決定され得る。
マウスM.tuberculosisモデルから生成されたCD4+ T細胞株を使用するM.tuberculosisポリぺプチドの精製および特徴付け
C57BL/6マウスのM.tuberculosisでの感染は、約2〜3週間の進行的な疾患の発症を生じる。次いで、疾患の進行は、強力な防御T細胞媒介免疫応答の出現の結果として終結する。この感染モデルを使用して、防御M.tuberculosis抗原を認識し得るT細胞株を生成した。
合成ポリペプチドの合成
ポリペプチドを、HPTU(O-ベンゾトリアゾール-N,N,N',N'-テトラメチルウロニウムヘキサフルオロホスフェート)活性化と共にFMOC化学を用いて、Millipore 9050ペプチド合成機で合成し得る。Gly-Cys-Gly配列をペプチドのアミノ末端に結合して、ペプチドの結合または標識化の方法を提供し得る。固体支持体からのペプチドの開裂を、以下の開裂混合物を用いて実施し得る:トリフルオロ酢酸:エタンジチオール:チオアニソール:水:フェノール(40:1:2:2:3)。2時間の開裂後、ペプチドを冷メチル-t-ブチル-エーテル中で沈殿させ得る。次いで、ペプチドペレットを、C18逆相HPLCによる精製の前に、0.1%トリフルオロ酢酸(TFA)を含有する水中に溶解し、そして凍結乾燥し得る。水(0.1%TFAを含有する)中の0〜60%アセトニトリル(0.1%TFAを含有する)のグラジエントを用いて、ペプチドを溶出し得る。純画分の凍結乾燥後、ペプチドをエレクトロスプレー質量分析法を用いて、およびアミノ酸分析により特徴付け得る。
Claims (33)
- 以下のアミノ酸配列:
(i) 配列番号142に記載のアミノ酸配列;
(ii) 保存的置換および/もしくは改変においてのみ異なる配列番号142の免疫原性変異体であって配列番号142に対して少なくとも90%の同一性を有するアミノ酸配列;または
(iii) 配列番号142に記載のアミノ酸配列の免疫原性部分
を含むポリペプチドを含んでなる薬学的組成物。 - 前記ポリペプチドが、(i)配列番号142に記載のアミノ酸配列、または(ii)保存的置換および/もしくは改変においてのみ異なる配列番号142の免疫原性変異体であって配列番号142に対して少なくとも90%の同一性を有するアミノ酸配列を含む、請求項1に記載の薬学的組成物。
- 前記変異体が配列番号142に対して少なくとも95%の同一性を有する、請求項2に記載の薬学的組成物。
- 前記ポリペプチドが、(i)配列番号142に記載のアミノ酸配列、または(ii)保存的置換および/もしくは改変においてのみ異なる配列番号142の免疫原性変異体であって配列番号142に対して少なくとも90%の同一性を有するアミノ酸配列からなる、請求項1に記載の薬学的組成物。
- 前記変異体が配列番号142に対して少なくとも95%の同一性を有する、請求項4に記載の薬学的組成物。
- 前記ポリペプチドが、配列番号142に記載のアミノ酸配列、または配列番号142に記載のアミノ酸配列の免疫原性部分を含む、請求項1に記載の薬学的組成物。
- 前記ポリペプチドが、配列番号142に記載のアミノ酸配列、または配列番号142に記載のアミノ酸配列の免疫原性部分からなる、請求項6に記載の薬学的組成物。
- 前記ポリペプチドが、配列番号142に記載のアミノ酸配列を含む、請求項1に記載の薬学的組成物。
- 前記ポリペプチドが、配列番号142に記載のアミノ酸配列からなる、請求項8に記載の薬学的組成物。
- 以下のアミノ酸配列:
(i) 配列番号142に記載のアミノ酸配列;
(ii) 保存的置換および/もしくは改変においてのみ異なる配列番号142の免疫原性変異体であって配列番号142に対して少なくとも90%の同一性を有するアミノ酸配列;または
(iii) 配列番号142に記載のアミノ酸配列の免疫原性部分
を含むポリペプチドをコードするヌクレオチド配列を含むDNA分子を含んでなる薬学的組成物。 - 前記DNA分子が、(i)配列番号142に記載のアミノ酸配列、または(ii)保存的置換および/もしくは改変においてのみ異なる配列番号142の免疫原性変異体であって配列番号142に対して少なくとも90%の同一性を有するアミノ酸配列を含むポリペプチドをコードするヌクレオチド配列を含む、請求項10に記載の薬学的組成物。
- 前記DNA分子が、配列番号142に記載のアミノ酸配列、または配列番号142に記載のアミノ酸配列の免疫原性部分を含むポリペプチドをコードするヌクレオチド配列を含む、請求項10に記載の薬学的組成物。
- 前記DNA分子が、配列番号142に記載のアミノ酸配列を含むポリペプチドをコードするヌクレオチド配列を含む、請求項10に記載の薬学的組成物。
- 前記DNA分子が、配列番号140に記載のヌクレオチド配列を含む、請求項10に記載の薬学的組成物。
- 前記DNA分子が、(i)配列番号142に記載のアミノ酸配列、または(ii)保存的置換および/もしくは改変においてのみ異なる配列番号142の免疫原性変異体であって配列番号142に対して少なくとも90%の同一性を有するアミノ酸配列からなるポリペプチドをコードするヌクレオチド配列を含む、請求項11に記載の薬学的組成物。
- 前記DNA分子が、(i)配列番号142に記載のアミノ酸配列、または(ii)配列番号142に記載のアミノ酸配列の免疫原性部分からなるポリペプチドをコードするヌクレオチド配列を含む、請求項12に記載の薬学的組成物。
- 前記DNA分子が、配列番号142に記載のアミノ酸配列からなるポリペプチドをコードするヌクレオチド配列を含む、請求項13に記載の薬学的組成物。
- 前記DNA分子が、配列番号140に記載のヌクレオチド配列からなる、請求項14に記載の薬学的組成物。
- 請求項1〜9のいずれか1項に記載の少なくとも1つのポリペプチドおよび生理学的に許容される担体を含む、M. tuberculosis(結核菌)に対する防御免疫を誘導するための、薬学的組成物。
- 請求項10〜18のいずれか1項に記載の少なくとも1つのDNA分子および生理学的に許容される担体を含む、M. tuberculosisに対する防御免疫を誘導するための、薬学的組成物。
- 請求項1〜9のいずれか1項に記載の少なくとも1つのポリペプチドおよび非特異的な免疫応答エンハンサーを含む、防御免疫を誘導するためのワクチン。
- 前記非特異的な免疫応答エンハンサーがアジュバントである、請求項21に記載の防御免疫を誘導するためのワクチン。
- 請求項10〜18のいずれか1項に記載の少なくとも1つのDNA分子および非特異的な免疫応答エンハンサーを含む、防御免疫を誘導するためのワクチン。
- 前記非特異的な免疫応答エンハンサーがアジュバントである、請求項23に記載の防御免疫を誘導するためのワクチン。
- 請求項1〜9のいずれか1項に記載のポリペプチドと第2のM. tuberculosis抗原とを含む融合タンパク質を含んでなる薬学的組成物。
- 請求項25に記載の融合タンパク質をコードするヌクレオチド配列を含むDNA分子を含んでなる薬学的組成物。
- 請求項25に記載の少なくとも1つの融合タンパク質および生理学的に許容される担体を含む、M. tuberculosisに対する防御免疫を誘導するための、薬学的組成物。
- 請求項26に記載の少なくとも1つのDNA分子および生理学的に許容される担体を含む、M. tuberculosisに対する防御免疫を誘導するための、薬学的組成物。
- 請求項25に記載の融合タンパク質および非特異的な免疫応答エンハンサーを含む、防御免疫を誘導するためのワクチン。
- 請求項26に記載の少なくとも1つのDNA分子および非特異的な免疫応答エンハンサーを含む、防御免疫を誘導するためのワクチン。
- 前記非特異的な免疫応答エンハンサーがアジュバントである、請求項29または30に記載の防御免疫を誘導するためのワクチン。
- 以下のもの:
(a) 請求項1〜9のいずれか1項に記載のポリペプチド;および
(b) 患者の皮膚上で免疫応答を誘導するために、該ポリペプチドを患者の皮膚細胞と接触させるのに十分な器具
を含む、結核の検出のための診断キット。 - 免疫応答が硬結である、請求項32に記載の診断キット。
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