JP6216371B2 - YersiniapestisF1−V融合タンパク質を発現するSalmonellaTyphiTy21aおよびその使用 - Google Patents
YersiniapestisF1−V融合タンパク質を発現するSalmonellaTyphiTy21aおよびその使用 Download PDFInfo
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- JP6216371B2 JP6216371B2 JP2015514155A JP2015514155A JP6216371B2 JP 6216371 B2 JP6216371 B2 JP 6216371B2 JP 2015514155 A JP2015514155 A JP 2015514155A JP 2015514155 A JP2015514155 A JP 2015514155A JP 6216371 B2 JP6216371 B2 JP 6216371B2
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
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- A61K39/00—Medicinal preparations containing antigens or antibodies
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- A61K39/025—Enterobacteriales, e.g. Enterobacter
- A61K39/0291—Yersinia
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- C07K2319/00—Fusion polypeptide
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- C07K2319/036—Fusion polypeptide containing a localisation/targetting motif targeting to the medium outside of the cell, e.g. type III secretion
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Description
本願は、2012年5月23日に出願された米国仮出願第61/650,676号の利益を主張する。米国仮出願第61/650,676号は、その全体が本明細書に参考として援用される。
本開示は、ペストの病原体であるYersinia pestisに対する防御のための免疫原性組成物の開発に関する。この開示はさらに、F1−V融合タンパク質発現構築物を含有するSalmonella Typhi Ty21a株およびこれらの使用法にも関する。
Yersinia pestisは、ペストの病原体である。歴史上、少なくとも3度のペストの世界的大流行が記録されており、これによりほぼ2億人が死亡した。ペストは、通常感染したノミにかまれることによって伝染する人獣共通感染症である。Y.pestisの天然の保有宿主としては、げっ歯類、リスおよびプレーリードッグが挙げられる。Y.pestisの大規模保有宿主は、現在オーストラリアを除く全主要居住大陸に存在する(Sunら、J Infect Dev Ctries 5(9):614−627,2011)。ペストは、アフリカ、中国、インド、南米の一部および米国南西部を含む、世界の多くの地域に特有である(Yangら、J Immunol 178:1059−1067,2007;Learyら、Microb Pathog 23:167−179,1997)。最近の疫学的研究は、世界中で年間およそ4,000人のペストの症例が存在することを示している(Sunら、J Infect Dev Ctries 5(9):614−627,2011)。したがって、ペストは、依然として深刻な公衆衛生上の懸念である。
特定の実施形態では、例えば以下が提供される:
(項目1)
大腸菌(Escherichia coli)htrAプロモーター配列に作動可能に連結されたYersinia pestisF1−V融合タンパク質コード配列を含む組換え核酸分子であって、前記核酸分子が配列番号1のヌクレオチド1−1558と少なくとも95%同一の配列を含む、組換え核酸分子。
(項目2)
前記核酸分子が配列番号1のヌクレオチド1−1558の配列を含む、項目1に記載の組換え核酸分子。
(項目3)
前記F1−V融合タンパク質コード配列にインフレームで融合された分泌シグナルペプチドコード配列をさらに含む、項目1または項目2に記載の組換え核酸分子。
(項目4)
前記分泌シグナルペプチドが大腸菌HlyA分泌シグナルペプチドである、項目3に記載の組換え核酸分子。
(項目5)
前記核酸分子の配列が、配列番号1と少なくとも95%同一である、項目3または項目4に記載の組換え核酸分子。
(項目6)
前記核酸分子の配列が配列番号1を含む、項目5に記載の組換え核酸分子。
(項目7)
大腸菌htrAプロモーター配列に作動可能に連結されたY.pestis F1−V融合タンパク質コード配列を含み、前記F1−V融合タンパク質コード配列にインフレームで融合された大腸菌HlyA分泌シグナルペプチド分泌シグナルペプチドコード配列をさらに含む組換え核酸分子であって、前記核酸分子の配列が配列番号1を含む、組換え核酸分子。
(項目8)
項目1から7のいずれか一項に記載の組換え核酸分子を含むプラスミド。
(項目9)
前記プラスミドが低コピー数プラスミドである、項目8に記載のプラスミド。
(項目10)
選択可能なマーカーをさらに含む、項目8または項目9に記載のプラスミド。
(項目11)
前記選択可能なマーカーが抗生物質耐性遺伝子である、項目10に記載のプラスミド。
(項目12)
大腸菌HlyBおよびHlyDタンパク質コード配列をさらに含む、項目8から11のいずれか一項に記載のプラスミド。
(項目13)
項目7に記載の組換え核酸分子、複製起点、選択可能なマーカーおよび前記大腸菌HlyBおよびHlyDタンパク質コード配列を含むプラスミド。
(項目14)
項目1から7のいずれか一項に記載の組換え核酸分子または項目8から13のいずれか一項に記載のプラスミドを含む、Salmonella Typhi Ty21a細菌。
(項目15)
項目14に記載のSalmonella Typhi Ty21a細菌および薬学的に許容され得るキャリアを含む免疫原性組成物。
(項目16)
前記組成物が経口投与用に製剤化される、項目15に記載の免疫原性組成物。
(項目17)
項目14に記載のSalmonella Typhi Ty21a細菌を被験体に投与するか、または項目15もしくは項目16に記載の免疫原性組成物を投与することを含む、前記被験体においてYersinia pestisに対する免疫応答を誘発する方法。
(項目18)
前記免疫応答が防御免疫応答である、項目17に記載の方法。
(項目19)
項目14に記載のSalmonella Typhi Ty21aを被験体に投与するか、または項目15もしくは項目16に記載の免疫原性組成物を投与することを含む、前記被験体においてペストを予防する、ペストの発症の危険性を低減する、またはペストを処置する方法。
添付の配列表に列挙される核酸配列およびアミノ酸配列は、米国特許施行規則1.822に規定されているように、ヌクレオチド塩基に対する標準的な文字の省略形、およびアミノ酸に対する3文字コードを用いて示される。各核酸配列の片方の鎖だけが示されるが、相補鎖は、表示される鎖に対する任意の参照によって含められると理解される。配列表は、2013年5月9日に作成された13.8KBのASCIIテキストファイルとして提出されており、それは、本明細書中に参考として援用される。添付の配列表において、以下のとおりである:
配列番号1は、プラスミドpHtrF1-V-HlyにクローニングされたF1-V融合DNA挿入物のヌクレオチド配列である。配列番号1は以下のエレメントを含む:
ヌクレオチド1〜112=htrAプロモーター配列
ヌクレオチド113〜562=F1抗原コード配列
ヌクレオチド563〜580=リンカー配列
ヌクレオチド581〜1558=V抗原コード配列
ヌクレオチド1559〜1747=HlyA分泌シグナル配列。
I.省略形
CFU コロニー形成単位
ELISA 酵素結合免疫吸着測定法
F1 分画1抗原
IFN インターフェロン
IL インターロイキン
i.p. 腹腔内
ORI 複製起点
PA 防御抗原
SDS−PAGE ドデシル硫酸ナトリウム−ポリアクリルアミドゲル電気泳動
TNF 腫瘍壊死因子
V 毒性抗原
II.用語および方法
別段述べられない限り、専門用語は、慣例的用法に従って使用される。分子生物学における一般的な用語の定義は、Benjamin Lewin,Genes V,Oxford University Pressによる出版,1994(ISBN0−19−854287−9);Kendrewら(eds.),The Encyclopedia of Molecular Biology,Blackwell Science Ltd.による出版,1994(ISBN0−632−02182−9);およびRobert A.Meyers(ed.),Molecular Biology and Biotechnology:a Comprehensive Desk Reference,VCH Publishers,Inc.による出版,1995(ISBN1−56081−569−8)に見られ得る。
アジュバント:抗原に対する免疫応答を非特異的に強化する物質またはビヒクル。アジュバントは、抗原が吸着される無機物の懸濁液、(ミョウバン、水酸化アルミニウムまたは燐酸アルミニウム);または抗原溶液が鉱油中で乳化された油中水エマルジョン(例えば、不完全フロイントアジュバント)、時として、さらに抗原性を強化するために殺されたマイコバクテリアを含む場合(完全フロイントアジュバント)を含むことができる。免疫賦活性オリゴヌクレオチド(例えば、CpGモチーフを含む免疫賦活性オリゴヌクレオチド)もまた、アジュバントとして使用可能である(例えば、米国特許第6,194,388号;第6,207,646;第6,214,806号;第6,218,371号;第6,239,116号;第6,339,068号;第6,406,705号;および第6,429,199号を参照されたい)。アジュバントは、生体分子、例えば、補助刺激分子もまた含む。例示的生物学的アジュバントとしては、IL−2、RANTES、GM−CSF、TNF−α、IFN−γ、G−CSF、LFA−3、CD72、B7−1、B7−2、OX−40Lおよび41BBLが挙げられる。
本明細書において、Yersinia pestis F1−V融合タンパク質の発現のためのプラスミド構築物の開発を開示する。また、例えば、ペストに対する経口ワクチンとして使用するための、F1−V融合タンパク質発現プラスミドを含有するSalmonella enterica血液型亜型Typhi Ty21a株(本明細書において「Salmonella Typhi Ty21a」または「Ty21a」とも称される)も開示する。
本明細書に開示の組換え核酸分子、プラスミドおよび免疫原性組成物は、単位剤形で便利に提示でき、従来の薬学的技術を使用して調製できる。このような技術は、活性成分と、薬学的キャリア(複数可)または賦形剤(複数可)とを組み合わせるステップを含む。一般に、製剤は、活性成分と液体キャリアとを均一および密に組み合わせることにより調製される。製剤は、単位用量または複数用量の容器、例えば密閉されたアンプルおよびバイアルで提示でき、使用直前に滅菌液体キャリア、例えば注射用水の添加だけが必要とされる、フリーズドライ(凍結乾燥)状態で保存できる。即時注射の溶液および懸濁液は、当業者により一般に使用される滅菌の散剤、顆粒および錠剤から調製可能である。
プラスミドの構築ならびにF1−Vの発現および分泌の分析
この実施例は、Salmonella Typhi Ty21aワクチン株中のYersinia pestis莢膜タンパク質画分1(F1)/毒性抗原融合タンパク質前駆体(LcrV)融合タンパク質(F1−V融合タンパク質と称される)の発現のための、遺伝学的に安定なプラスミド系の作製を記載する。
マウスにおけるワクチン構築物の免疫原性
この実施例は、血清IgG力価および刺激された脾臓細胞のサイトカイン発現により測定した、F1−V融合発現構築物を保有するSalmonella Typhi Ty21aの免疫原性を記載する。
(実施例3)
Y.pestisによる感染症を予防または阻害する方法
この実施例は、Y.pestisによる感染症を予防または阻害し、それによって危険性のある被験体においてペストの発症を予防または阻害するために使用可能な例示的方法を記載する。
Claims (10)
- 組換え核酸分子を含むプラスミドを含む、Salmonella Typhi Ty21a細菌であって、前記組換え核酸分子は、
大腸菌(Escherichia coli)htrAプロモーター配列に作動可能に連結されたYersinia pestis F1−V融合タンパク質コード配列;および
前記F1−V融合タンパク質コード配列にインフレームで融合された大腸菌HlyA分泌シグナルペプチドコード配列
を含み、前記核酸分子の配列が、配列番号1と少なくとも95%同一な配列を含む、Salmonella Typhi Ty21a細菌。 - 前記プラスミドが低コピー数プラスミドである、請求項1に記載のSalmonella Typhi Ty21a細菌。
- 前記プラスミドが選択可能なマーカーをさらに含む、請求項1に記載のSalmonella Typhi Ty21a細菌。
- 前記選択可能なマーカーが抗生物質耐性遺伝子である、請求項3に記載のSalmonella Typhi Ty21a細菌。
- 前記プラスミドが大腸菌HlyBおよびHlyDタンパク質コード配列をさらに含む、請求項1に記載のSalmonella Typhi Ty21a細菌。
- 請求項1〜5のいずれか一項に記載のSalmonella Typhi Ty21a細菌および薬学的に許容され得るキャリアを含む免疫原性組成物。
- 前記組成物が経口投与用に製剤化される、請求項6に記載の免疫原性組成物。
- 請求項1に記載のSalmonella Typhi Ty21a細菌、または請求項6もしくは請求項7に記載の免疫原性組成物を含む、被験体においてYersinia pestisに対する免疫応答を誘発するための組成物。
- 前記免疫応答が防御免疫応答である、請求項8に記載の組成物。
- 請求項1に記載のSalmonella Typhi Ty21aまたは請求項6もしくは請求項7に記載の免疫原性組成物を含む、被験体においてペストを予防する、ペストの発症の危険性を低減する、またはペストを処置するための組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261650676P | 2012-05-23 | 2012-05-23 | |
US61/650,676 | 2012-05-23 | ||
PCT/US2013/042240 WO2013177291A1 (en) | 2012-05-23 | 2013-05-22 | Salmonella typhi ty21a expressing yersinia pestis f1-v fusion protein and uses thereof |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2015519061A JP2015519061A (ja) | 2015-07-09 |
JP2015519061A5 JP2015519061A5 (ja) | 2016-06-09 |
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JP (1) | JP6216371B2 (ja) |
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US3856935A (en) | 1971-04-29 | 1974-12-24 | Schweiz Serum & Impfinst | Oral typhoid vaccine and method of preparing the same |
GB9326425D0 (en) | 1993-12-24 | 1994-02-23 | Secr Defence | Vaccine compositions |
ATE420171T1 (de) | 1994-07-15 | 2009-01-15 | Univ Iowa Res Found | Immunomodulatorische oligonukleotide |
US6429199B1 (en) | 1994-07-15 | 2002-08-06 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules for activating dendritic cells |
US6239116B1 (en) | 1994-07-15 | 2001-05-29 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US6207646B1 (en) | 1994-07-15 | 2001-03-27 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
DK0815235T3 (da) | 1995-03-13 | 2003-04-22 | Secr Defence | Vacciner mod pest |
WO1998037919A1 (en) | 1997-02-28 | 1998-09-03 | University Of Iowa Research Foundation | USE OF NUCLEIC ACIDS CONTAINING UNMETHYLATED CpG DINUCLEOTIDE IN THE TREATMENT OF LPS-ASSOCIATED DISORDERS |
US6406705B1 (en) | 1997-03-10 | 2002-06-18 | University Of Iowa Research Foundation | Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant |
EP1003531B1 (en) | 1997-05-20 | 2007-08-22 | Ottawa Health Research Institute | Processes for preparing nucleic acid constructs |
AU760549B2 (en) | 1998-04-03 | 2003-05-15 | University Of Iowa Research Foundation, The | Methods and products for stimulating the immune system using immunotherapeutic oligonucleotides and cytokines |
DK1108034T3 (da) * | 1998-09-04 | 2008-11-10 | Emergent Product Dev Uk Ltd | Svækkede salmonella SPI2-mutanter som antigenbærere |
GB9921275D0 (en) * | 1999-09-10 | 1999-11-10 | Secr Defence | Recombinant microorganisms |
WO2005026203A2 (en) | 2003-09-18 | 2005-03-24 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Dna promoters and anthrax vaccines |
CA2547425A1 (en) * | 2003-12-09 | 2005-06-23 | Avant Immunotherapeutics, Inc. | Orally-administered live bacterial vaccines for plague |
US20080124355A1 (en) * | 2006-09-22 | 2008-05-29 | David Gordon Bermudes | Live bacterial vaccines for viral infection prophylaxis or treatment |
EP1921149A1 (en) * | 2006-11-13 | 2008-05-14 | AEterna Zentaris GmbH | Microorganisms as carriers of nucleotide sequences coding for antigens and protein toxins, process of manufacturing and uses thereof |
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EP2852405B1 (en) | 2019-03-13 |
US9409956B2 (en) | 2016-08-09 |
CN104470537B (zh) | 2017-04-26 |
JP2015519061A (ja) | 2015-07-09 |
EP2852405A1 (en) | 2015-04-01 |
CN104470537A (zh) | 2015-03-25 |
IN2014DN09618A (ja) | 2015-07-31 |
IL235615A0 (en) | 2015-01-29 |
WO2013177291A8 (en) | 2014-12-24 |
WO2013177291A1 (en) | 2013-11-28 |
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