Modulators of the function of the core domain of annexins, and uses thereof in autoimmune and/or cancer therapy

Patent metadata

Field	Value
Publication number	US-2018275124-A1
Application number	US-201515541709-A
Country	US
Kind code	A1
Filing date	Nov 19, 2015
Priority date	Jan 15, 2015
Publication date	Sep 27, 2018
Grant date	—

Abstract

The present invention relates to a method for identifying a compound that modulates the interaction of an annexin core domain with a receptor selected from the group of C-type lectin receptors and LRP-1 in a cell, and uses thereof in autoimmune and/or cancer therapy.

First claim

What is claimed is:

1 . A method for identifying a compound that modulates the interaction of an annexin core domain with a receptor selected from the group of C-type lectin receptors and LRP-1 in a cell, comprising the steps of
a) contacting at least one of annexin, a receptor-binding core domain or fragment thereof of annexin, and/or a cell recombinantly expressing a receptor-binding core domain or fragment thereof of annexin with at least one compound that potentially modulates the interaction of said annexin core domain with said receptor in said cell, and b) identifying a modulation of said interaction of said annexin core domain with said receptor in the presence of said at least one compound, compared to the absence of said at least one compound.

2 . The method according to claim 1 , wherein said C-type lectin receptor is selected from Dectin-1 and DC-SIGN.

3 . The method according to claim 1 , wherein said annexin core domain is selected from the group of the annexin 1, 5, and 13 core domain, preferably according a sequence according to SEQ ID NO: 1, 2, 3, 6, 7, or 8, or functional fragments thereof.

4 . The method according to claim 1 , wherein said modulation is selected from a decrease or an increase of (a) an expression of said annexin and/or (b) of binding to said receptor(s) and/or (c) the biological activity of annexin, such as the annexin-mediated immunosuppression or phagocytosis of apoptotic cells.

5 . The method according to claim 1 , wherein said compound is selected from the group consisting of a peptide library, a combinatory library, a cell extract, in particular a plant cell extract, a “small molecular drug”, an antisense oligonucleotide, an siRNA, an mRNA, a peptide binding to a receptor, a soluble fragment of said receptor, and a blocking or activating antibody or fragment thereof specifically interfering with the binding of the annexin core domain to said receptor(s), in particular anti-Dectin-1, anti-DC-SIGN or anti-LRP-1 antibodies or functional fragments thereof.

6 . The method according to claim 1 , wherein said cell is selected from the group of dendritic cells, macrophages, cancer cells, apoptotic cells, and recombinant host cells, such as dendritic cells, macrophages, cancer cells, apoptotic cells, S2 cells, or Mono Mac cells expressing said annexin core domain or fragment thereof, wherein said recombinant host cells optionally express or co-express the receptor(s) or fragment(s) thereof.

7 . A method for manufacturing a pharmaceutical composition for treating or preventing autoimmune diseases, chronic inflammatory diseases, allergies or cancer, comprising the steps of performing a method according to claim 1 , and formulating said compound as identified into a pharmaceutical composition.

8 . An isolated annexin core domain; a complex or fusion of an annexin core domain with at least one antigen or allergenic compound; an activating antibody, optionally coupled to at least one antigen or allergenic compound; or a pharmaceutical composition obtained by the method according to claim 7 for use in the prevention and/or therapy of autoimmune diseases, chronic inflammatory diseases or allergies.

9 . The complex or fusion for use according to claim 8 , wherein said complex or fusion is soluble or bound to a carrier, such as a liposome or latex bead.

10 . An inhibitor of (a) the expression of the annexin core domain and/or (b) of the binding of said core domain to a receptor selected from the group of C-type lectin receptors and LRP-1 and/or (c) of the biological activity of annexin or a pharmaceutical composition comprising said inhibitor for use in the therapy of cancer.

11 . The inhibitor or pharmaceutical composition for use according to claim 10 , wherein said inhibitor is selected from an antisense oligonucleotide, a soluble fragment of said receptor(s), and a blocking antibody or fragment thereof specifically interfering with the binding of said annexin core domain to said receptor(s), in particular anti-Dectin-1, anti-DC-SIGN or anti-LRP-1 antibodies.

12 . A screening tool for screening for a compound that modulates the interaction of an annexin core domain with a receptor selected from the group of C-type lectin receptors and LRP-1 in a cell, comprising an isolated cell expressing a receptor-binding core domain or fragment thereof of annexin, and wherein said cell optionally expresses or co-expresses the receptor(s) or fragment(s) thereof.

13 . The screening tool according to claim 12 , wherein said annexin and/or said receptor(s) and/or the fragments thereof are labeled.

14 . A method for treating or preventing autoimmune diseases, chronic inflammatory diseases or allergies in a patient, comprising administering to said patient an effective amount of a complex or fusion of an annexin core domain with at least one antigen or allergenic compound, an activating antibody or a pharmaceutical composition obtained by the method according to claim 7 .

15 . A method for treating or preventing cancer in a patient, comprising administering to said patient an effective amount of an inhibitor of the expression of the annexin core domain and/or of the binding of said core domain to a receptor selected from the group of C-type lectin receptors and LRP-1 and/or of the biological activity of annexin or a pharmaceutical composition comprising said inhibitor.

Assignees

• Deutsches Krebsforschungszentrum Stiftung Des Oeffentlichen Rechts

Inventors

• Krammer Peter H
• Kurz Alexandra
• Linke Björn
• Weyd Heiko

Classifications

• G01N33/566 Primary

  using specific carrier or receptor proteins as ligand binding reagents {where possible specific carrier or receptor proteins are classified with their target compounds} · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title

• A61K38/00

  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 title

• G01N33/564

  for pre-existing immune complex or autoimmune disease {, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9} · CPC title

• G01N2500/00

  Screening for compounds of potential therapeutic value · CPC title