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CONDITIONALLY REPLICATING ADENOVIRUS EXPRESSING REIC GENE

Foreign code F160008748
File No. S2014-1019-C0
Posted date May 24, 2016
Country WIPO
International application number 2015JP065004
International publication number WO 2015182574
Date of international filing May 26, 2015
Date of international publication Dec 3, 2015
Priority data
  • P2014-110672 (May 28, 2014) JP
Title CONDITIONALLY REPLICATING ADENOVIRUS EXPRESSING REIC GENE
Abstract The purpose is to provide a conditionally replicating adenovirus having a strong anticancer effect. A conditionally replicating adenovirus growing specifically in cancer cells and expressing an REIC protein or REIC C domain protein, having full-length REIC DNA or REIC C domain DNA inserted into a conditionally replicating adenovirus including an (inverted terminal repeat) ITR sequence of a type 5 adenovirus and having an HRE sequence, hTERT promoter, DNA encoding decorin, and DNA encoding a peptide including an RGD sequence inserted.
Outline of related art and contending technology BACKGROUND ART
So far, proliferation type (cancer cell-specific proliferation of the genetically modified) virus for cancer using a medicament drug in a clinical have been reported (non-patent document 1). These agents in the treatment of cancer is increasing constant result on the other hand, the effect is limited in many cases, a more effective has been desired the development of a drug.
The results of clinical trials to date have been reported using medicaments against cancer proliferation-type virus as a representative example of, adenovirus type 5 Telomelysin backbone (non-patent document 2) and herpes simplex virus type 1 Oncovex old Talimogene laherparepvec(T-VEC, backbone) (non-patent document 3) is.
In recent years, as shown in non-patent document 1, for each virus using medicaments against cancer, anti-cancer immune activation is important to have such a function has been been considered. From this point of view, for (non-patent document 2) Telomelysin, anti-cancer immune activating cytokines such as encoded by the gene is not, the local administration of the adenovirus Telomelysin in the growth of cancer by induction of cell death can be of, systemic potent anti-cancer immune activation effect cannot be expected. This, limiting the therapeutic effect of Telomelysin has been applied to the can.
In addition, for T-VEC, the local administration of a herpesvirus by growing in cancer cell death, and a reduction in the cytokine GM-CSF antigen of cancer cells by expression of anti-cancer immune activation can be expected. However cytokine GM-CSF is, cancer antigen presenting cell to induce the differentiation of dendritic cells that in addition to the action of anti-cancer immune activation (non-patent document 1), at the high dose anti-cancer immune suppressing system induces attenuated immune function, potentially exacerbating the disease condition also reported (non-patent document 4) and, the therapeutic effect of this T-VEC limiting has been applied to the can.
That is, using the existing proliferation-type virus medicaments against cancer taking into account of these problems, the more effective has been desired the development of a drug. In order to solve the above problems and various kinds of proliferation-type adenovirus contains a mutation of proliferation-type adenovirus has been reported (Patent Document 1 and 2 and non-patent document 5-10).
On the other hand, as genes associated with immortalization of cells, REIC gene (REIC/Dkk-3) are known, the expression of this gene in cancer cells reported to be suppressed and, used to treat cancer REIC gene have been reported (patent document 3). The effect of activating REIC anticancer immunity, cancer cells gene expression at the time of the endoplasmic reticulum and having a function for induce cell death. In addition, a portion of the gene of the full-length REIC REIC fragment has the same effect is also reported (patent document 4), adenovirus expressing further REIC/Dkk-3 gene has been reported to have (patent document 5 and non-patent document 11).
Scope of claims (In Japanese)[請求項1]
5型アデノウイルスのゲノムのITR(inverted terminal repeat)配列を含み、HRE配列、hTERTプロモーター、デコリンをコードするDNA及びRGD配列を含むペプチドをコードするDNAが挿入された制限増殖型アデノウイルスに、さらに全長REIC DNA又はREIC CドメインDNAが挿入され、癌細胞で特異的に増殖しREICタンパク質又はREIC Cドメインタンパク質を発現する制限増殖型アデノウイルス。
[請求項2]
プロモーター配列、デコリンをコードするDNA及びpolyA付加配列からなるDNAコンストラクトが5型アデノウイルスのE3領域中に挿入されている、請求項1記載の制限増殖型アデノウイルス。
[請求項3]
(i) hTERTプロモーターがc-Myc結合部位及びSp1結合部位の付加により修飾されたhTERTプロモーターであり、
(ii) hTERTプロモーターの上流に配列番号3で表される塩基配列からなるHRE配列が6つ挿入され、
(iii) E1A領域の一部であって、配列番号4に示す5型アデノウイルスゲノム配列のRb結合領域(Retinoblastoma遺伝子結合領域)を欠失しており、
(iv) E1B領域の一部であって、配列番号4に示す5型アデノウイルスゲノム配列のE1B-19kDaをコードする部分の塩基が欠失しており、
(v) E3領域の一部が欠失しており、
(vi) プロモーター配列、デコリンをコードするDNA及びpolyA付加配列からなるDNAコンストラクトがE3領域中に挿入され、
(vii) RGD配列を含むペプチドをコードするDNAが、E3領域中に挿入され、かつ
(viii) CMVプロモーター配列、REIC DNA又はREIC CドメインDNAをコードするDNA、並びにpolyA付加配列からなるDNAコンストラクトがE1領域中に挿入されている請求項1又は2に記載の制限増殖型アデノウイルス。
[請求項4]
(iii) E1A領域の一部であって、配列番号4に示す5型アデノウイルスゲノム配列の第923~946のRb結合領域(Retinoblastoma遺伝子結合領域)である24個の塩基を欠失しており、
(iv) E1B領域の一部であって、配列番号4に示す5型アデノウイルスゲノム配列の第1722~1986のE1B-19kDaをコードする部分の塩基が欠失しており、
(v) E3領域の一部であって、配列番号4に示す5型アデノウイルスゲノム配列の第28592~30479の塩基が欠失している、
請求項3記載の制限増殖型アデノウイルス。
[請求項5]
REICが全長REICである、請求項1~4のいずれか1項に記載の制限増殖型アデノウイルス。
[請求項6]
REICがREICのCドメインである、請求項1~4のいずれか1項に記載の制限増殖型アデノウイルス。
[請求項7]
請求項1~6のいずれか1項に記載の制限増殖型アデノウイルを有効成分として含む、癌治療剤。
[請求項8]
制限増殖型アデノウイルスが癌細胞中で特異的に増殖し、REICタンパク質を発現し、発現したREICタンパク質が小胞体ストレスにより癌細胞の細胞死を誘導し、さらにREICタンパク質が全身的抗癌免疫活性を誘導する、請求項7記載の癌治療剤。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • NATIONAL UNIVERSITY CORPORATION OKAYAMA UNIVERSITY
  • MOMOTARO-GENE INC.
  • INDUSTRY-UNIVERSITY COOPERATION FOUNDATION HANYANG UNIVERSITY
  • Inventor
  • KUMON Hiromi
  • NASU Yasutomo
  • WATANABE Masami
  • YUN Chae Ok
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JP KE KG KN KP KR KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG

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