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Removal promoters and inhibitor for apoptosis cells in vivo achieved

Foreign code F110003487
File No. A131-11EP
Posted date Jun 28, 2011
Country EPO
Application number 02803517
Gazette No. 1459756
Gazette No. 1459756
Date of filing Nov 19, 2002
Gazette Date Sep 22, 2004
Gazette Date Mar 26, 2014
International application number JP2002012053
International publication number WO2003043649
Date of international filing Nov 19, 2002
Date of international publication May 30, 2003
Priority data
  • 2002JP012053 (Nov 19, 2002) WO
  • P2001-354282 (Nov 20, 2001) JP
Title Removal promoters and inhibitor for apoptosis cells in vivo achieved
Abstract The present invention is to provide a removal promoter for apoptotic cells which is capable of immediately removing apoptotic cells in vivo bymacrophages, or a removal inhibitor which inhibits the removal of apoptotic cells in vivo by macrophages.
A removal promoter for apoptotic cells in vivo containing the milk fat globule-EGF factor 8-L (MFG-E8-L), MFG-E8-L mutant having removal promotion action for apoptotic cells in vivo by macrophages, or preferably a recombinant human or mouse MFG-E8-L, or a recombinant human or mouse MFG-E8-L mutant as an active ingredient is prepared.
Such removal promoters specifically bind to apoptotic cells and promote the phagocytosis of apoptotic cells by macrophages by recognizing aminophospholipids such as phosphatidylserine exposed on apoptotic cell surface.
On the other hand, a point mutation (D89E) MFG-E8-L mutant is used as a removal inhibitor.
Scope of claims [claim1]
1. Any one of the following (a) to (f) for use in a treatment of diseases resulting from incomplete phagocytosis of apoptotic cells in vivo by macrophages: (a) MFG-E8-L which has an action to promote phagocytosis by binding to the apoptotic cells; (b) MFG-E8-L mutant which has an action to promote phagocytosis by binding to the apoptotic cells, which is comprised of an amino acid sequence wherein one or more amino acids are deleted, substituted or added in the amino acid sequence comprising MFG-E8-L, and which contains an EGF-2 domain having RGD motif, a proline/threonine-rich domain, and two factor VIII-homologous domains (C1 and C2); (c) the MFG-E8-L of the above (a) or the MFG-E8-L mutant of the above (b), which is enveloped or embedded in liposome; (d) a recombinant vector comprising DNA encoding the MFG-E8-L of the above (a) or the MFG-E8-L mutant of the above (b); (e) a host cell comprising an expression system which can express the MFG-E8-L of the above (a) or the MFG-E8-L mutant of the above (b); or (f) an antibody against the MFG-E8-L of the above (a) or the MFG-E8-L mutant of the above (b).
[claim2]
2. Any one of the following (a) to (f) for use in a treatment of a decline of biodefense mechanism: a) MFG-E8-L which has an action to promote phagocytosis by binding to the apoptotic cells; (b) MFG-E8-L mutant which has an action to promote phagocytosis by binding to the apoptotic cells, which is comprised of an amino acid sequence wherein one or more amino acids are deleted, substituted or added in the amino acid sequence comprising MFG-E8-L, and which contains an EGF-2 domain having RGD motif, a proline/threonine-rich domain, and two factor VIII-homologous domains (C 1 and C2); (c) the MFG-E8-L of the above (a) or the MFG-E8-L mutant of the above (b), which is enveloped or embedded in liposome; (d) a recombinant vector comprising DNA encoding the MFG-E8-L of the above (a) or the MFG-E8-L mutant of the above (b); (e) a host cell comprising an expression system which can express the MFG-E8-L of the above (a) or the MFG-E8-L mutant of the above (b); or (f) an antibody against the MFG-E8-L of the above (a) or the MFG-E8-L mutant of the above (b).
[claim3]
3. The MFG-E8-L or MFG-E8-L mutant for use in a treatment according to claim 1 or 2, which is a recombinant MFG-E8-L or a recombinant MFG-E8-L mutant.
[claim4]
4. The recombinant MFG-E8-L or the recombinant MFG-E8-L mutant for use in a treatment according to claim 3, which is a recombinant human or mouse MFG-E8-L or a recombinant human or mouse MFG-E8-L mutant.
[claim5]
5. The recombinant MFG-E8-L or the recombinant MFG-E8-L mutant for use in a treatment according to claim 3 or 4, which is a translation product in human cells.
[claim6]
6. The recombinant MFG-E8-L for use in a treatment according to any one of claims 3 to 5, which contains an EGF-2 domain having RGD motif, a proline/threonine-rich domain, and two factor VIII-homologous domains (C1 and C2).
[claim7]
7. The antibody for use in a treatment according to claim 1 or 2, which is an anti-MFG-E8-L monoclonal antibody or an anti-MFG-E8-L mutant monoclonal antibody.
[claim8]
8. A detection method for apoptotic cells in vivo wherein a detection agent for apoptotic cells in vivo, which contains a labeled MFG-E8-L or MFG-E8-L mutant having an action to promote phagocytosis of apoptotic cells in vivo by macrophages, or an antibody against them as an active ingredient is used,
wherein the MFG-E8-L mutant is comprised of an amino acid sequence wherein one or more amino acids are deleted, substituted or added in the amino acid sequence comprising MFG-E8-L, and contains an EGF-2 domain having RGD motif, a proline/threonine-rich domain, and two factor VIII-homologous domains (C1 and C2).
[claim9]
9. A screening method for a substance inducing a promotion of phagocytosis or a substance suppressing a promotion of phagocytosis of apoptotic cells in vivo by macrophages wherein MFG-E8-L or a MFG-E8-L mutant having an action to promote phagocytosis of apoptotic cells in vivo by macrophages, or an antibody against them is contacted with a test substance, to evaluate the extent of phagocytosis of apoptotic cells in vivo,
wherein the MFG-E8-L mutant is comprised of an amino acid sequence wherein one or more amino acids are deleted, substituted or added in the amino acid sequence comprising MFG-E8-L, and contains an EGF-2 domain having RGD motif, a proline/threonine-rich domain, and two factor VIII-homologous domains (C 1 and C2).
  • Applicant
  • JAPAN SCIENCE AND TECHNOLOGY AGENCY
  • Inventor
  • NAGATA SHIGEKAZU
IPC(International Patent Classification)
Reference ( R and D project ) CREST Structure and Function of Genomes AREA
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