Singlec-9 binding agents

Abstract

The present invention relates to agents capable of binding sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) and their use in the treatment of cell proliferation and differentiation disorders. Furthermore, the present invention provides associated pharmaceutical formulations and methods.

Description

FIELD OF THE INVENTION[0001]The present invention relates to agents which bind the cell surface marker Siglec-9 and their use in the treatment of cell proliferation disorders and assays.BACKGROUND[0002]Sialic acid-binding immunoglobulin-like lectins (Siglec(s)) are I-type lectins that are expressed by a number of cells including cells of the haematopoietic system. The Siglecs comprise a number of families of molecules, each characterised by the presence of a N-terminal V-set Ig-like domain, which mediates sialic acid binding, followed by varying numbers of C2-set Ig-like domains4.[0003]CD33 and the CD33 related siglecs encompass eight of the 11 human siglecs. These molecules share a high degree of sequence similarity and show significant differences in composition amongst mammalian species. The genes encoding these receptors are clustered on chromosome 19q13.3-13.4 and appear to be predominantly expressed in the haematopoietic and immune systems and exhibit differential expression p...

AI Technical Summary

Benefits of technology

[0016]Antibodies of the present invention may be derived from any species especially mammals, for example a horse, a human or a rodent, for example a rabbit, rat or mouse. Advantageously the antibodies may be modified so as to be “humanised”. The techniques used to humanise antibodies derived from species other than a human are well known in the art. In addition, the nucleic acid encoding a specific antibody may be isolated and further manipulated so as to, for example, improve the binding specificity, “humanise” or adjust the size and / or structure of the molecule. It may be possible, to isolate the nucleic acid encoding the Siglec-9 binding agent, for example an anti-Siglec-9 antibody, by removing specific regions of the nucleic acid encoding the binding agent, to reduce the molecule to comprising specific domains such as, for example, the variable region of an antibody. In addition, it may be possible to alter certain residues comprising the molecule to modulate the structure and / or binding specificity.

[0030]It is particularly advantageous to use Siglec-9 as a target molecule for binding agents of the present invention, as the levels of cell-free Siglec-9 are considerably lower than for other related Siglecs. It should be noted that “cell-free Siglec” refers to Siglec molecules which are not associated with a cell and which are detectable in the plasma fraction of whole blood. Accordingly “cell-free” Siglec-9 may also be referred to as or “soluble” or “plasma” Siglec-9. By way of example, the level of Siglec-5 and CD-33 detectable in plasma is significantly higher than the level of Siglec-9 and as such, binding agents with specificity for Siglec-9 are less likely to be neutralised or absorbed by soluble ligand. Thus, Siglec-9 binding agents may be more efficacious than binding agents specific for other siglec molecules.

[0031]It has been observed that Siglec-9 is expressed on subsets of AML cells associated with severe disease. As such, the use of Siglec-9 as a target molecule for agents of the present invention may facilitate the identification and / or diagnosis of patients with severe disease (M4 and M5 FAB classification) and / or may provide an effective drug target for severe disease.

Problems solved by technology

The loss of red blood cells may lead to complications such as anaemia, infection and bleeding.

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