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CANCER CELL MOTILITY AND CANCER CELL INFILTRATION INHIBITOR

Foreign code F110002750
File No. S2008-0392-C0
Posted date Apr 13, 2011
Country WIPO
International application number 2009JP055479
International publication number WO 2009119455
Date of international filing Mar 19, 2009
Date of international publication Oct 1, 2009
Priority data
  • P2008-083588 (Mar 27, 2008) JP
Title CANCER CELL MOTILITY AND CANCER CELL INFILTRATION INHIBITOR
Abstract Provided are an antibody which binds specifically to PAR1 (protease-activated receptor 1) or a fragment of the preceding antibody which sustains similar characteristics thereto; a composition containing the same for inhibiting the motion activity and infiltration activity of cancer cells; and a medicinal composition for treating cancer and the like.
Outline of related art and contending technology BACKGROUND ART
Ability and movement of the cells that have generated as a result of the invasive potential of the disease may typically have a cancer. 1 As one of the most conspicuous threat of cancer and metastasis. Cell motility by metastatic cancer cells can be transferred through a blood vessel from HCCs, after infiltration within the blood vessel, blood flow and metastasize to other tissues. PAR1 (Protease activated receptor 1: protease activated receptor 1) is, capable of being in motion and the invasive potential of cancer cells to activate 7 - transmembrane receptor, a variety of types of cancer (breast cancer, lung cancer, pancreatic cancer and prostate cancer) are involved in the metastasis of the present invention. In particular breast cancer, cancer having a metastatic potential of cultured cell lines and most of the PAR1 is expressed in, cancer-specific protease (MMP1: Matrix Metalloprotease 1: matrix metalloproteinase 1) by, of the PAR1 - terminal extracellular region N (R41 and S42 between) is cut PAR1 is activated has been known. PAR1 Is stimulated, and couples to the intracellular region of a PAR1 g Activation. As a result, intracellular Ca2+ concentration increases locally, this Ca2+ signal and cell invasion by cells capable of being in motion is believed to enhance the ability (see non-patent document 1).
PAR1 Is originally required for the platelets are activated thrombin-dependent receptor (thrombin receptor) were discovered as. Thrombin, PAR1 and MMP1 of the recognition site is formed by cutting the same. In addition, the activation of platelet thrombin receptor as in the case of cancer cells, Ca2+ activating signal. Current, cellular domains of PAR1 monoclonal antibody N powder and has a some embodiments, these antibodies inhibits platelet activation. However, these antibodies to cancer cell motility and invasion but the relation between the report, even in the PAR1 cancer cell motility and invasion-inhibiting antibody, PAR1 antibody or no report that used in the treatment of cancer.
In addition, PAR1 g of the synthesized peptides corresponding to the protein binding sites, which has a membrane permeability this peptide Pepducin made of a material that (see non-patent document 2). G protein a pepducin Covic et al. can be used as an antagonist of inhibiting the activity of PAR1 has succeeded in (the inhibitory effect of the pepducin 3-4μM). On the other hand, practical applications as anti-cancer agents is an antibody, as well as the inhibitory effect of the target molecule activity, immune system cells by antibody dependent cell-mediated cytotoxic activity effect can be expected. The antibody also may be, by genetic engineering is the art of making high affinity antibodies has been established, and ensured safety to the living organism such as an antibody as anti-cancer agents is very favorable to be applied. Therefore, the anti-cancer agent when it is used as PAR1 antibody, anti-cancer agents and more effective pepducin can be considered a lot.
PAR1 Th 56 th Tyr Trp from of the 52 epitope antibody is produced in a phage display library, the antibody, to inhibit the activity of the thrombin cutting PAR1. Wherein the antibody is of PAR1 to inhibit cleavage activity with respect to the (binding to PAR1), in particular 56 epitope Trp is included as the second important (see Patent Document 1) are. The current, the motility of cancer cells to inhibit the invasive and report or PAR1 antibody, PAR1 antibody epitope as effective inhibitory effect of the other peptide sequences is found no report of.
Scope of claims (In Japanese)請求の範囲 [1]
 PAR1(プロテアーゼ活性化受容体1)に特異的に結合してMMP1(マトリックスメタロプロテアーゼ1)による切断を阻害し、がん細胞の運動活性および浸潤活性を阻害する抗体、または該抗体と同様の性質を保持する該抗体のフラグメント。

[2]
 PAR1(プロテアーゼ活性化受容体1)のMMP1(マトリックスメタロプロテアーゼ1)による切断部位(Arg 41とSer 42の間)を含む領域をエピトープとして特異的に結合し、がん細胞の運動活性および浸潤活性を阻害する請求項1記載の抗体、または該抗体と同様の性質を保持する該抗体のフラグメント。

[3]
 該エピトープのアミノ酸配列が配列番号:1で示されるものである請求項2記載の抗体、または該抗体と同様の性質を保持する該抗体のフラグメント。

[4]
 独立行政法人産業技術総合研究所 特許生物寄託センターから受託番号FERM BP-11105を付与されたハイブリドーマにより産生されるモノクローナル抗体である、請求項3記載の抗体、または該抗体と同様の性質を保持する該抗体のフラグメント。

[5]
 キメラ化またはヒト化されている、請求項1~4のいずれか1項記載の抗体、または該抗体と同様の性質を保持する該抗体のフラグメント。

[6]
 モノクローナル抗体である請求項1~5いずれか1項記載の抗体。

[7]
 ポリクローナル抗体である請求項1~3または5のいずれか1項記載の抗体。

[8]
 請求項1~7のいずれか1項記載の抗体またはフラグメントを含む、がん細胞の運動活性および浸潤活性を阻害するための組成物。

[9]
 請求項1~7のいずれか1項記載の抗体またはフラグメントを含む、がん治療用医薬組成物。

[10]
 請求項1~7のいずれか1項記載の抗体またはフラグメントを含む、医薬組成物の有効量を治療を必要とする対象に投与することを含む、がんの治療方法。

[11]
 がんを治療するための医薬の製造における請求項1~7のいずれか1項記載の抗体またはフラグメントの使用。

[12]
 請求項1~7のいずれか1項記載の抗体またはフラグメントを、対象から得た試料と接触させ、試料中の腫瘍細胞と結合させることを特徴とする、試料中の腫瘍細胞のイメージング方法または腫瘍の検出方法。

[13]
 請求項1~7のいずれか1項記載の抗体またはフラグメントを含む、腫瘍細胞イメージング剤。

[14]
 請求項1~7のいずれか1項記載の抗体または抗体フラグメントを対象に投与して、体内の腫瘍組織と本発明の抗体または抗体フラグメントとの結合を調べることを特徴とする、腫瘍の診断方法。

[15]
 配列番号:1で示されるアミノ酸配列からなるペプチド。

[16]
 配列番号:1で示されるアミノ酸配列からなるペプチドおよびキャリア蛋白からなる抗原性ペプチド。

[17]
 請求項15記載のペプチドまたは請求項16記載の抗原性ペプチドを用いることを特徴とする、PAR1に特異的に結合してMMP1による切断を阻害する抗体、または該抗体と同様の性質を保持する該抗体のフラグメントの作製方法。

[18]
 請求項15記載のペプチドまたは請求項16記載の抗原性ペプチドを用いることを特徴とする、PAR1に特異的に結合してMMP1による切断を阻害する抗体、または該抗体と同様の性質を保持する該抗体のフラグメントの精製方法。

[19]
 請求項15記載のペプチドまたは請求項16記載の抗原性ペプチドを含む、がん細胞の運動活性および浸潤活性を阻害するための組成物。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • TOHOKU UNIVERSITY
  • Inventor
  • GONDA, Kohsuke
  • HIGUCHI, Hideo
  • OHUCHI, Noriaki
  • TAKEDA, Motohiro
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BR BW BY BZ CA CH 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 IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PG PH PL PT RO RS RU SC SD SE SG SK SL SM ST SV SY TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ MD RU TJ TM
EPO: 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 SE SI SK TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG
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