Novel receptor trem (triggering receptor expressed on myeloid cells) and uses thereof

• US 20090081199A1
• Filed: 05/09/2008
• Published: 03/26/2009
• Est. Priority Date: 03/20/2001
• Status: Abandoned Application

• Current Assignee: BioXell S.p.A. (Cosmo Pharmaceuticals NV)
• Original Assignee: BioXell S.p.A. (Cosmo Pharmaceuticals NV)
• Inventors: Bouchon, Axel, Colonna, Marco
• Application Number:
  US12/149,930
• Publication Number:
  US 20090081199A1
• Time in Patent Office: Days
• US Class Current: 424/130.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/70503 Immunoglobulin superfamily
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/54 F(ab')2
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/77 Internalization into the cell
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/32 fusions with soluble part of a cell surface receptor, "decoy receptors"
• CPC Class Codes: C07K 2319/43 containing a FLAG-tag
• CPC Class Codes: G01N 2333/70503 Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
• CPC Class Codes: G01N 2500/04 Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 2800/7095 Inflammation

Abstract

Novel activating receptors of the Ig super-family expressed on human myeloid cells, called TREM(s) (triggering receptor expressed on myeloid cells) are provided. Specifically, two (2) members of TREMs, TREM-1 and TREM-2 are disclosed. TREM-1 is a transmembrane glycoprotein expressed selectively on blood neutrophils and a subset of monocytes but not on lymphocytes and other cell types and is upregulated by bacterial and fungal products. Use of TREM-1 in treatment and diagnosis of various inflammatory diseases is also provided. TREM-2 is also a transmembrane glycoprotein expressed selectively on mast cells and peripheral dendritic cells (DCs) but not on granulocytes or monocytes. DC stimulation via TREM-2 leads to DC maturation and resistance to apoptosis, and induces strong upregulation of CCR7 and subsequent chemotaxis toward macrophage inflammatory protein 3-β. TREM-2 has utility in modulating host immune responses in various immune disorders, including autoimmune diseases and allergic disorders.

Claims

1. A fusion protein comprising a TREM-2 polypeptide having the amino acid sequence of SEQ ID NO:

4, or a fragment thereof, and a second polypeptide.

2. The fusion protein according to claim 1, wherein said second polypeptide is an immunoglobulin, or a fragment thereof.

3. The fusion protein according to claim 2, wherein said immunoglobulin is huIgG or huIgM, or a fragment thereof.

4. A pharmaceutical composition, comprising said fusion protein according to claim 1 and a pharmaceutically acceptable carrier.

5. A method for treating a subject having multiple sclerosis, comprising administering to the subject a therapeutically effective amount of a modulator of TREM-2 polypeptide having the amino acid sequence of SEQ ID NO:

4.

6. The method of claim 5, wherein said modulator is administered in combination with at least one other prophylactic or therapeutic agent.

7. The method of claim 5, wherein said modulator is a TREM-2 antagonist.

8. The method of claim 5, wherein said modulator is a anti-TREM-2 antibody.

9. The method of claim 5, wherein said modulator is a TREM-2 agonist.

10. The method of claim 5, wherein said modulator is DNA encoding TREM-2 so that TREM-2 is expressed in vivo.

11. The method of claim 5, wherein said modulator is a fusion protein comprising a TREM-2 polypeptide having the amino acid sequence of SEQ ID NO:

4, or a fragment thereof, and a second polypeptide.

12. The method of claim 11, wherein said second polypeptide is an immunoglobulin, or a fragment thereof.

13. The method of claim 12, wherein said immunoglobulin is huIgG or huIgM, or a fragment thereof.

14. A method for identifying a compound that modulates the activity of TREM-2 polypeptide having the amino acid sequence of SEQ ID NO:

4, which comprises measuring a biological activity of the TREM-2 polypeptide in the presence of a test compound, measuring a biological activity of the TREM-2 polypeptide in the absence of the test compound, comparing the measured biological activity of TREM-2 polypeptide in the presence and absence of the test compound, and identifying a compound which increases or decreases the biological activity of the TREM-2 polypeptide, thereby identifying the compound which modulates the activity of TREM-2 polypeptide.