JP2009521707A - 疾患のバイオマーカーとしての脂肪生成アデノウイルス - Google Patents
疾患のバイオマーカーとしての脂肪生成アデノウイルス Download PDFInfo
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Abstract
Description
本願は、2005年12月27日に出願された米国仮特許出願第60/753,402号に関連し、米国仮特許出願第60/753,402号に対する米国特許法第119(e)条の下での利益を主張する。米国仮特許出願第60/753,402号の開示は、本明細書中にその全体が援用される。
この発明は、アデノウイルス−36(Ad−36)のような脂肪生成アデノウイルスによる感染と、肥満になる病因および肥満が関係する癌およびそれ以外の疾患との関係に関する。さらに具体的には、本発明は被験体が乳癌または前立腺を発生する傾向にあるかどうかを予測する手法に関する。また、本発明はAd−36の発現状態について被験体を評価し、Ad−36の発現状態を癌の存在を表すマーカーとして使用して、将来乳癌または前立腺癌のような癌が発生する危険性を予測したり、こうした癌の攻撃性および予後を予測したりすることに関する。
肥満の割合と特定の癌の割合とが同時に劇的に増大している。1980年頃から肥満の世界的流行が劇的に加速した。米国では、成人肥満の割合は、1980年から2000年の20年間で2倍を超えた(15%から31%)が、その20年前の1960年から1980年では、わずかに増大するにとどまった(13.5%から15%)。小児肥満の割合は1970年頃から2000年までに3倍になった。同様に、近年では乳癌、前立腺癌、大腸癌および肝臓癌も罹患率が急速に増大してきた。
本発明の一態様は、被験体が脂肪生成アデノウイルス関連疾患を発生しやすい傾向にあるかどうかを予測する方法に関する。この手法は、被験体から試料を採取し、試料中の脂肪生成アデノウイルスに特異的な抗体の有無をスクリーニングすることにより被験体が脂肪生成アデノウイルスに感染しているかどうかを測定し、試料中の脂肪生成アデノウイルスに特異的な抗体の存在を測定することを含む。抗体は核酸配列配列番号5、配列番号6および配列番号7によりコードされる1つ以上のペプチドに特異的でもよい。そのうえさらに、スクリーニング工程は血清中和法およびELISAからなる群より選択される方法を用いて実施することができる。
本発明は本明細書中に記載された手法、プロトコール、装置、器具、材料および試薬などに限定されず、変更可能であると理解されるものである。また、本明細書で使用される用語は特定の実施形態のみを記載する目的で使用されており、本発明の範囲を限定することを目的としないと理解されるものである。本明細書および添付の請求項で使用されるように、文脈上明確に別の意味が示されない限り、単数表現は複数表現を含むと了解しなければならない。このため、たとえば、「ウイルス粒子」という言及は1つ以上のウイルス粒子および当業者にとって既知な等価物などを指す。
Ad−2はアデノウイルス2型である。
ウィスコンシン州マディソン、フロリダ州ナポリ、ニューヨーク州ニューヨーク市3都市の独立した集団を対象に、502人から採取した血液試料をAd−36感染について測定した。肥満の定義は、BMIが約30kg/m2を超えることとし、集団を肥満の被験体と肥満ではない被験体に分類した。肥満の被験体の血清中Ad−36抗体の保有率は約30%であり、肥満ではない被験体では約11%であった(すなわち、3:1の割合)(図13)。
Ad−36が癌の原因になるきわめて強力な証拠は、ウィスコンシン大学の諸試験から得られた。保管されている乳癌の被験体128例および前立腺癌の被験体37例の血清を入手し、血清中和法を用いてAd−36抗体についてアッセイした。前立腺癌患者の51%および乳癌患者の50%がAd−36抗体陽性であったことが観察された。しかし、試料は匿名であったため、肥満、癌の種類や病期または転移の有無に関するデータはなかった。肥満の個体および肥満ではない個体のAd−36抗体に関するデータから、一般集団の約14%にAd−36抗体が認められると判断した。したがって、乳癌患者および前立腺癌患者のAd−36抗体保有率は概ね4倍になる。
患者18例から前立腺癌組織を採取し、Ad−36繊維タンパク質ゲノムに特有のDNA配列に作成されたプライマーを用いるnestedポリメラーゼ連鎖反応(PCR)によりAd−36DNAについてアッセイした。18例中11例の61%に、癌組織内にAd−36DNAが認められた。図16は、前立腺癌組織にAd−36DNAが存在していることを表わしているPCRゲルを示したものである。上に記載したように、実験動物の複数種の組織でAd−36DNAが確認され、Ad−36繊維タンパク質ゲノムに特有のDNA配列から作成されたプライマーによるnested PCRを用いると、特に脂肪組織で確認された。図17は、Ad−36に感染したサルの脂肪組織から抽出したDNAのPCRゲルを示したものである。対照を除き、感染したサル3例全例にウイルスのDNAが存在した。
この実施例は、Ad−36の臨床検査をマーカーとして用いて癌が発生するおそれがある個体を洗い出すことを示すものである。癌である人の方が癌ではない患者よりもAd−36臨床検査結果が陽性になることがきわめて多い。著者らは乳癌の女性128例および37前立腺癌の男性37例を検査し、その結果を癌ではない患者502例と比較した。癌患者165例のうち83例(50%)がAd−36検査陽性であった(乳癌患者の50%および前立腺癌患者の51%)。米国集団の肥満の割合に基づくと、癌ではない被験体502例のデータは、癌ではない被験体の17%がAd−36検査で陽性であったことを示した。ウィスコンシン州の癌ではない被験体を考慮しさえすれば(癌患者全例がウィスコンシン州出身であったため、これは優れた比較である)、癌ではない被験体の14%がAd−36検査陽性であった。したがって、癌ではない患者のほぼ4倍の癌患者が陽性であった。
ウィスコンシン大学病院で、剖検時にヒト9例から脂肪組織を採取し、Ad−36DNAを測定した。9例中7例の脂肪組織にAd−36DNAが認められた。このデータは、Ad−36DNAがヒトおよび動物の脂肪組織から単離されることがあるということ、それよりも重要なのは、組織中のAd−36DNAの存在がAd−36感染後のマーカーになるということを明らかにしている。Ad−36DNAは感染した動物の複数種の組織に現れるため、初回のウイルス血症により、体のほとんどの組織が感染するのは明白であると思われる。このため、以下の具体例6に記載した方法の項に記載したように、癌患者から癌組織または脂肪組織を採取してAd−36DNAの存在を検査することができる。
癌患者および癌ではない患者の乳癌および前立腺の組織試料中のAd−36DNAについて試料を評価し、癌患者の方がAd−36の感染率が高いかどうかを明らかにする。Ad−36の発現状態は癌の存在と相関し、癌の病期、転移の存在および癌犠牲者の予後と相関すると考えられる。抗Ad−36ワクチンは、Ad−36が誘発する癌を予防することができる。
NCI resource banks、the NCI Cooperative Human Tissue Network(CHTN)およびthe NCI Cooperative Breast Cancer Resource(CBCTR)から、匿名の組織試料および完全な医療情報を入手する。以下に記載したnested PCRアッセイにより、試料をAd−36DNAについて評価する。また、DNA試料が入手できなければ、それを注文することができる。DNAが試料から抽出されない場合、下に記載したようなことがある。
外側逆方向プライマー(5=−ATCCAAAATCAAATGTAATAGAGT)(配列番号2)、
内側順方向プライマー(5=−TTAACTGGAAAAGGAATAGGTA)(SEQ ID No.3)、
内側逆方向プライマー(5=−GGTGTTGTTGGTTGGCTTAGGATA)(SEQ ID No.4)。
実施例8
既知の全cDNA配列に対してAd−36ゲノムのcDNA配列をスクリーニングしたところ、25−塩基配列2件および28−塩基配列1件が確認され、いずれもAd−36に特有の繊維をコードする配列中にあった。この3種類の配列は以下のとおりである。
配列番号6 5’−GGTACTGGATCAAGTGCACATGGAG
配列番号7 5’−TTGAAACAGCAAGAGACTCAAAGCTAAC
従来のニワトリ4羽から単離したDNAの核酸プローブハイブリダイゼーションアッセイでは、上の3件の配列をAd−36のプローブに利用したところ、2羽はウイルスに感染して肥満になり、2羽は感染せず、肥満にならなかった。プローブにハイブリダイズしているDNAは、感染した2羽のニワトリのDNAにのみ観察された。アッセイは直接検出を要件とし、検出用レーザー励起蛍光法を用いたキャピラリー電気泳動によるものであった。さらに具体的には、緩衝装置では、電気泳動による分離には置換可能なポリアクリルアミドマトリックスを利用し、検出には5’標識するオリゴおよびチアゾールオレンジ挿入剤を備えた二重装置を利用した。
Claims (24)
- 被験体が脂肪生成アデノウイルス関連疾患を発生しやすい傾向にあるかどうかを予測する方法であって、
該被験体から試料を採取する工程、および
該被験体が該脂肪生成アデノウイルスに感染しているかどうかを測定する工程
を含む、方法。 - 前記被験体が前記脂肪生成アデノウイルスに感染しているかどうかを測定する前記工程は、
前記試料中の該脂肪生成アデノウイルスに特異的な抗体の有無をスクリーニングする工程、および
該試料中の該脂肪生成アデノウイルスに特異的な抗体の存在を測定する工程
を含む、請求項1に記載の方法。 - 前記脂肪生成アデノウイルスは、アデノウイルス5型、アデノウイルス35型およびアデノウイルス37型からなる群より選択される1つ以上の脂肪生成ウイルスである請求項1に記載の方法。
- 前記脂肪生成関連疾患は、癌、前立腺癌、乳癌、膵機能障害、膵疾患、糖尿病、肺疾患、脳および神経系機能不全および副腎機能障害からなる群より選択される疾患である請求項1に記載の方法。
- 前記被験体はヒトである請求項1に記載の方法。
- 前記被験体は動物である請求項1に記載の方法。
- 前記測定する工程における前記抗体は、配列番号5、配列番号6および配列番号7からなる群より選択される核酸配列によりコードされる1つ以上のペプチドに特異的である請求項2に記載の方法。
- 前記スクリーニング工程は血清中和法およびELISAからなる群より選択される方法を用いることにより実施される請求項2に記載の方法。
- 前記試料は生体試料、体液、組織試料、臓器試料、糞便、血液、唾液およびこれらのあらゆる組み合わせからなる群より選択される請求項1に記載の方法。
- 抗脂肪生成アデノウイルスワクチンを被験体に投与することを含む、該被験体の脂肪生成アデノウイルス関連疾患を予防する方法。
- 前記抗脂肪生成アデノウイルスワクチンは、有効投与量の有効成分として、死菌アデノウイルス36型、不活化アデノウイルス36型、アデノウイルス36外被タンパク質またはその断片をコードするタンパク質またはペプチド配列、アデノウイルス36型外被タンパク質またはその断片をコードする核酸配列、アデノウイルス36型E1Aタンパク質、遺伝子組換え非病原性ウイルスおよび非病原性ウイルスからなる群より選択される1つ以上の化合物を含む請求項10に記載の方法。
- 前記抗脂肪生成アデノウイルスワクチンを鼻内、経口、静脈内、筋肉内皮下および/または腹腔内に投与する請求項10に記載の方法。
- 前記被験体はヒトである請求項10に記載の方法。
- 前記被験体は動物である請求項10に記載の方法。
- 前記脂肪生成アデノウイルス関連疾患は癌、前立腺癌、乳癌、膵機能障害、膵疾患、糖尿病、肺疾患、脳および神経系機能不全および副腎機能障害からなる群より選択される1つ以上の疾患である請求項10に記載の方法。
- 被験体の癌の攻撃性を予測する方法であって、
該被験体から試料を採取する工程、
該被験体が、脂肪生成アデノウイルスの存在が浸潤癌と相関を成すような脂肪生成アデノウイルスに感染しているかどうかを測定する工程
を含む、方法。 - 前記被験体が前記脂肪生成アデノウイルスに感染しているかどうかを測定する前記工程は、
前記試料中の前記脂肪生成アデノウイルスに特異的な抗体の有無をスクリーニングする工程、および
該試料中の該脂肪生成アデノウイルスに特異的な抗体の存在を測定する工程
を含む、請求項16に記載の方法。 - 前記脂肪生成アデノウイルスはアデノウイルス5型、アデノウイルス35型およびアデノウイルス37型からなる群より選択される1つ以上の脂肪生成ウイルスである請求項16に記載の方法。
- 前記癌は乳癌、前立腺癌、子宮癌、卵巣癌、大腸癌、腎臓癌、膵臓癌および肺癌からなる群より選択される請求項1に記載の方法。
- 前記被験体はヒトである請求項16に記載の方法。
- 前記被験体は動物である請求項16に記載の方法。
- 前記測定する工程の前記抗体は、配列番号5、配列番号6および配列番号7からなる群より選択される核酸配列によりコードされる1つ以上のペプチドに特異的である請求項17に記載の方法。
- 前記スクリーニング工程は血清中和法およびELISAからなる群より選択される方法を用いて実施される請求項17に記載の方法。
- 前記試料は生体試料、体液、組織試料、臓器試料、糞便、血液、唾液およびこれらの任意の組み合わせからなる群より選択される請求項16に記載の方法。
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PCT/US2006/062632 WO2007120362A2 (en) | 2005-12-27 | 2006-12-27 | Adipogenic adenoviruses as a biomarker for disease |
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EP (2) | EP2390372A1 (ja) |
JP (1) | JP2009521707A (ja) |
KR (1) | KR20080114683A (ja) |
CN (1) | CN101389768B (ja) |
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US20120082659A1 (en) * | 2007-10-02 | 2012-04-05 | Hartmut Land | Methods And Compositions Related To Synergistic Responses To Oncogenic Mutations |
JP2009156254A (ja) * | 2007-12-05 | 2009-07-16 | Ibiden Co Ltd | 排気ガス処理体の保持シール部材及び排気ガス処理装置 |
US8466167B2 (en) | 2008-03-03 | 2013-06-18 | Irm Llc | Compounds and compositions as TLR activity modulators |
WO2010011440A2 (en) * | 2008-06-16 | 2010-01-28 | Obetech Llc | Diagnosis and treatment of lipogenic adenovirus infection associated with adipose tissue hypertrophy |
TR201802380T4 (tr) | 2009-06-10 | 2018-03-21 | Glaxosmithkline Biologicals Sa | Benzonaftiridin içeren aşılar. |
AU2010290896B2 (en) | 2009-09-02 | 2014-07-03 | Glaxosmithkline Biologicals S.A. | Immunogenic compositions including TLR activity modulators |
TWI445708B (zh) | 2009-09-02 | 2014-07-21 | Irm Llc | 作為tlr活性調節劑之化合物及組合物 |
WO2011050299A2 (en) * | 2009-10-22 | 2011-04-28 | Obetech Llc | Adenovirus infection in animals |
WO2011057148A1 (en) | 2009-11-05 | 2011-05-12 | Irm Llc | Compounds and compositions as tlr-7 activity modulators |
US8585588B2 (en) | 2009-11-18 | 2013-11-19 | Nohands, Llc | Method and system for preventing virus-related obesity and obesity related diseases |
JP5814933B2 (ja) | 2009-12-15 | 2015-11-17 | ノバルティス アーゲー | 免疫増強化合物の均質な懸濁物およびその使用 |
EP2549990A1 (en) | 2010-03-23 | 2013-01-30 | Irm Llc | Compounds (cystein based lipopeptides) and compositions as tlr2 agonists used for treating infections, inflammations, respiratory diseases etc. |
WO2011119915A2 (en) * | 2010-03-25 | 2011-09-29 | Obetech Llc | Method for detecting lipogenic adenovirus |
US9192661B2 (en) | 2010-07-06 | 2015-11-24 | Novartis Ag | Delivery of self-replicating RNA using biodegradable polymer particles |
WO2012006512A1 (en) * | 2010-07-08 | 2012-01-12 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Adenovirus ad36 e4orf1 protein for prevention and treatment of non-alcoholic fatty liver disease |
WO2012006550A2 (en) * | 2010-07-09 | 2012-01-12 | Obetech Llc | Methods and compositions for treatment of lipogenic virus related conditions |
WO2012083302A2 (en) | 2010-12-17 | 2012-06-21 | Globeimmune, Inc. | Compositions and methods for the treatment or prevention of human adenovirus-36 infection |
CN105188747A (zh) | 2013-02-01 | 2015-12-23 | 葛兰素史密斯克莱生物公司 | 包含toll样受体激动剂的免疫组合物的皮内递送 |
CA2966754A1 (en) | 2014-11-05 | 2016-05-12 | The United States Of America As Represented By The Secretary Of The Navy | Synthetic antigen constructs against campylobacter jejuni |
KR20200123436A (ko) | 2018-02-12 | 2020-10-29 | 이니뮨 코퍼레이션 | 톨-유사 수용체 리간드 |
IL302449A (en) | 2020-11-04 | 2023-06-01 | Eligo Bioscience | CUTIBACTERIUM ACNES PHAGES RECOMBINANT, the production method and their uses |
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BRPI0620755A2 (pt) | 2011-11-22 |
US20090087833A1 (en) | 2009-04-02 |
CA2635269A1 (en) | 2007-10-25 |
US20130323273A1 (en) | 2013-12-05 |
KR20080114683A (ko) | 2008-12-31 |
US7442511B2 (en) | 2008-10-28 |
RU2008130893A (ru) | 2010-02-10 |
AU2006342053A1 (en) | 2007-10-25 |
CN101389768A (zh) | 2009-03-18 |
EP1977009A2 (en) | 2008-10-08 |
US20090087455A1 (en) | 2009-04-02 |
WO2007120362A2 (en) | 2007-10-25 |
WO2007120362A3 (en) | 2008-08-14 |
EP2390372A1 (en) | 2011-11-30 |
US7910310B2 (en) | 2011-03-22 |
US7745110B2 (en) | 2010-06-29 |
US20110189235A1 (en) | 2011-08-04 |
EP1977009A4 (en) | 2009-06-03 |
MX2008008453A (es) | 2008-11-28 |
US20070218081A1 (en) | 2007-09-20 |
CN101389768B (zh) | 2015-11-25 |
EP1977009B1 (en) | 2016-08-17 |
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