JP5677450B2 - 生化学的な血清マーカー - Google Patents
生化学的な血清マーカー Download PDFInfo
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
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Description
a.血清又は血漿からなる生体サンプルを得る工程と、
b.上記生体サンプル中における可溶性BAG3の存在又は濃度を決定する工程と、
c.得られた値を基準値又は生体基準サンプルから得られた値と比較する工程と、
d.任意には、類似の値の更なるグループ分け(場合により、それらの統計的に異なる平均値を持つグループへの更なる分割)を決定する工程と、
e.可溶性BAG3の存在及び/又はレベルを病的状態に結び付ける工程であって、該状態が心臓疾患又は膵臓癌である工程と
を含む方法に関する。
a.血清又は血漿からなる生体サンプルを得る工程
b.かかる生体サンプル中の可溶性BAG3の濃度を決定する工程
c.上記サンプルから得られた結果を、基準値又は基準の血清サンプルから得られた値と比較する工程
d.任意に、統計的に違わない可溶性BAG−3平均値を持つ患者のサブグループ(例えば、21〜43歳の患者のグループと44〜65歳のグループ)を決定する工程
e.可溶性BAG3のレベル又は存在を、心臓疾患又は膵臓癌の中から選択される病的状態と結び付ける工程
例1.親のハイブリドーマからのAC−1、AC−2、AC−3クローンの単離
モノクローナル抗体AC−1、2及び3を親のハイブリドーマ(2002年12月17日にジェノア先進バイオテクノロジーセンターにてNo.PD02009として預けられ、U.S.7,537,760に記載されている)からのサブクローニングにより単離し、培地上でのELISA分析によって選択した。
慢性虚血性心疾患にかかる患者の血清をウエスタン・ブロッティングによって分析した。75kDに対応するバンドをゲル溶出し(図1a参照)、トリプシン消化によって得られた断片を質量スペクトル(MALDI/MS)によって分析し、「MASCOT」ソフトウェアを介して同定した。一部のペプチド配列(図1b)の分析は、BAG3様のタンパク質の同定を可能にした。
およそ220〜250グラムの重さのあるスプラーグ・ドーリー雄ラット(Charles River Laboratories,Italy)を、ペントバルビタール(60mg/kg)の経口での腹腔内注射により麻酔した。前開胸後、心臓を露出させ、下行冠動脈の近位前方管の縫合を受けた。対照動物は、該動脈の結紮を除き、同一の手順を受けた。その手順の翌日、少なくとも35%の左心室を取り込む大きな梗塞の存在についての経胸壁心エコー検査によって全生存者を選択した(IMグループ)。次に、標準的な手順によってラットを犠牲にし、免疫組織化学的手順のため、左心室をホルマリンで処置した。その図は、コントロール及びIMグループを代表するBAG3タンパク質の発現データを示す。
BAG3タンパク質が心臓疾患を患う患者の血液中で検出できるか否かを試験するため、標準物質として以下に記載されるように調製されたBAG3組み換えタンパク質を用いるELISA試験を開発した。
a):
・BAG3タンパク質のaa18〜33の配列(DRDPLPPGYEIKIDPQ)を認識するように設計された第一モノクローナル抗体クローンAC−1;
・免疫原として全組換えタンパク質(RefSeq:NP_004272)を用いることにより開発され、代わりにAC−1抗体によって捕捉されたBAG3タンパク質の検出物質として使用されたTOS−2という名の第二ポリクローナル抗体;
b):
・第一モノクローナル抗体クローンAC−1;
・BAG3タンパク質のaa385〜399の配列(SSPKSVATEERAAPS)を認識するように設計され、検出物資として使用されたAC−2という名の第二モノクローナル抗体;
c):
・第一モノクローナル抗体クローンAC−1;
・BAG3タンパク質のaa533〜547の配列(DKGKKNAGNAEDPHT)を認識するように設計され、検出物質として使用されたAC−3という名の第二モノクローナル抗体;
d):
・第一モノクローナル抗体クローンAC−1;
・検出物質として使用されたAC−2及びAC−3の混合物;
e):
・第一モノクローナル抗体クローンAC−2;
・検出物質としての、AC−1、又はAC−3、又はAC−1及びAC−3抗体の混合物;
f):
・第一モノクローナル抗体クローンAC−3;
・検出物質としての、AC−1、又はAC−2、又はAC−1及びAC−2抗体の混合物;
どんな種類の顕在的な疾患をも患っていない対象におけるBAG3の血清濃度を調べるため、健康なドナーから血清を集めた。ドナーの年齢の範囲は21〜65歳であった。検出したBAG3の濃度は平均で2.38ng/ml±0.32であった。
次いで、心不全を患う患者におけるBAG3タンパク質の検出のためのELISA分析の感度及び特異性の値を明確にするため、得られたデータを統計分析のプログラムを介して分析した。
血清中に放出されたタンパク質の血球上での役割の可能性を決定するため、組み換えBAG3タンパク質をマクロファージ活性化分析に用いた。このため、マウス単球J774細胞株を、陽性コントロールとしてリポ多糖(LPS)等の炎症促進剤を用い、異なる濃度の組み換えBAG3タンパク質によって処置した。J774細胞を集蜜60%にてプレート上に蒔き、濃度が250、500ng/ml及び1mg/mlの組み換えBAG3タンパク質と共に又はそれを濃度が10ng/mlのLPSと組み合わせたものと共に24時間インキュベートした。
1.Bonelli, P., Petrella A., Rosati, A., Romano, M.F., Lerose, R., Pagliuca, M.G., Amelio, T., Festa, M., Martire, G., Venuta, S., Turco, M.C., and Leone, A. (2004). BAG3 protein regulates stress-induced apoptosis in normal and neoplastic leukocytes. Leukemia 18, 358-360.
2.Bruno, A.P., Festa, M., Dal Piaz, F., Rosati, A., Turco, M.C., Giuditta, A., Marzullo, L. (2008). Identification of a synaptosome-associated form of BAG3 protein. Cell Cycle 7(19), 3104-3105.
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5.Chen, L., Wu, W., Dentchev, T., Zeng, Y., Wang, J., Tsui, I., Tobias, J.W., Bennett, J., Baldwin, D., Dunaief, J.L. (2004). Light damage induced changes in mouse retinal gene expression. Exp Eye Res 79(2), 239-247.
6.Chiappetta, G., Ammirante, M., Basile, A., Rosati, A., Festa, M., Monaco, M., Vuttariello, E., Pasquinelli, R., Arra, C., Zerilli, M., Todaro, M., Stassi, G., Pezzullo, L., Gentilella, A., Tosco, A., Pascale, M., Marzullo, L., Belisario, M.A., Turco, M.C. and Leone, A. (2007). The antiapoptotic protein BAG3 is expressed in thyroid carcinomas and modulates apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand. J Clin Endocrinol Metab 92(3), 1159-1163.
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Claims (14)
- 未知の生体サンプル中における可溶性BAG3タンパク質の存在及び/又は濃度を検出する方法であって、
b.予め得られた血清又は血漿からなる生体サンプル中における可溶性BAG3の存在又は濃度値を決定する工程と、
c.前記サンプルから得られた値を基準値又は生体基準サンプルから得られた値と比較する工程と、
e.可溶性BAG3の存在及び/又はレベルを、心臓疾患又は膵臓癌の病状からなる群から選択される病的状態と結び付ける工程と
を含む方法。 - d.類似の値の更なるグループ分け又は統計的に異なる平均値を持つグループへの分割を決定する工程を更に含む、請求項1に記載の方法。
- 決定工程b)が、可溶性BAG3に対して特異的なリガンドを用いて行われる、請求項1又は2に記載の方法。
- 前記生体サンプルがヒト由来のものである、請求項1〜3のいずれかに記載の方法。
- 抗凝固物質を前記生体サンプルに加える、請求項1〜4のいずれかに記載の方法。
- 前記特異的なリガンドが抗体である、請求項3に記載の方法。
- 決定工程b)が、モノクローナル、ポリクローナル若しくは組み換えの抗BAG3抗体又はそれらの断片(scFv、二重特異性抗体、ミニ抗体)を用いて行われる、請求項6に記載の方法。
- 前記抗体が、モノクローナルであり、BAG3一次配列のアミノ酸配列18〜33、385〜399若しくは533〜547からなる群から選択される少なくとも1種のBAG3エピトープを認識するか、又はヒト化された若しくは組み換えにより修飾されたその組み換え誘導体である、請求項7に記載の方法。
- 前記抗体又はリガンドが、フルオロフォア、発色団又は基質を発色団に変換できる酵素で標識されている、請求項3及び6〜8のいずれかに記載の方法。
- 決定工程b)が、BAG3捕獲リガンド及び検出リガンドによるサンドイッチELISAを用いて行われ、ここで、一番目及び二番目がモノクローナル抗体であり、第二抗体が、使用した捕獲抗体によって認識されるものと異なるエピトープを認識するか又は複数のモノクローナル抗体の混合物である、請求項3〜9のいずれかに記載の方法。
- 前記病的状態が心臓疾患である、請求項6〜10のいずれかに記載の方法。
- 前記心臓疾患(工程(e))が、狭心症、梗塞前狭心症、心筋梗塞、心不全、急性冠動脈疾患、急性心不全、慢性心不全又は医原性心臓疾患からなる群から選択される、請求項1〜11のいずれかに記載の方法。
- 酸化ストレスと関連した病的状態の血清マーカーとしての、ヒト可溶性BAG3タンパク質の使用であって、前記病的状態が心臓疾患又は膵臓癌である使用。
- 前記心臓疾患が、狭心症、梗塞前狭心症、心筋梗塞、心不全、急性冠動脈疾患、急性心不全、慢性心不全及び医原性心臓疾患からなる群から選択される、請求項13に記載の使用。
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ITUB20155097A1 (it) | 2015-11-05 | 2017-05-05 | Biouniversa Srl | Anticorpi umanizzati anti-BAG3 |
IT201600069391A1 (it) * | 2016-07-04 | 2016-10-04 | Univ Degli Studi Di Salerno | Uso della proteina bag3 e suoi frammenti peptidici per il controllo dell’omeostasi vascolare |
IT201600111877A1 (it) | 2016-11-07 | 2018-05-07 | Biouniversa Srl | Anti-BAG3 antibodies in combination with inhibitors of immune check-point for therapeutic use |
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CA3107625A1 (en) | 2017-07-28 | 2019-01-31 | Biouniversa S.R.L. | Anti-bag3 antibodies as therapeutic reagent in cardiovascular diseases |
IT201700113648A1 (it) * | 2017-10-10 | 2019-04-10 | Biouniversa Srl | Anti-BAG3 antibodies as therapeutic reagent in cardiovascular diseases |
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