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.

1 . A method of treating a subject having a cell proliferation and/or differentiation disorder comprising administering to said subject an effective amount of an agent capable of binding Siglec-9. 
   
   
       2 . The method of  claim 1 , wherein the cell proliferation and/or differentiation disorder affects cells of the immune system and/or cells of the bone marrow. 
   
   
       3 . The method of  claim 1  or  2 , wherein the cell proliferation and/or differentiation disorder is cancer. 
   
   
       4 . The method of  claim 3 , wherein the cancer is a malignant disorder of the monocytic, macrophage and/or histiocytic lineages and/or acute myeloid leukemia (AML). 
   
   
       5 . The method of  claim 1 , wherein the cell proliferation and/or differentiation disorder is selected from the group consisting of:
 (i) Acute myeloid leukemia (AML) with inv(16)(p13q22);   (ii) Acute myelomonocytic leukemia;   (iii) Acute monoblastic and monocytic leukemia;   (iv) Chronic myelomonocytic leukemia;   v) Juvenile myelomonocytic leukemia;   (vi) Histiocytic sarcoma;   (vii) Langerhans cell histiocytosis; and   (viii) Langerhans cell sarcoma.   
   
   
       6 . The method of any proceeding claim, wherein the Siglec-9 binding agents are selected from the group consisting of:
 (i) small organic molecules;   (ii) peptides;   (iii) carbohydrates; and   (iv) antibodies;   
     or a Siglec-9 binding fragment, analogue or portion thereof. 
   
   
       7 . The method of  claim 7 , wherein the Siglec-9 binding agent is a polyclonal antibody or a monoclonal antibody which specifically binds to Siglec-9. 
   
   
       8 . The method of  claim 7 , wherein the antibody does not induce complement mediated or antibody dependant cellular cytotoxicity (ADCC). 
   
   
       9 . The method of  claim 8 , wherein the antibody is derived from a heterologous species. 
   
   
       10 . The method of  claim 9 , wherein the antibody is a human or humanized antibody. 
   
   
       11 . The method of  claim 6 , wherein the antibody is an antibody fragment selected from the group consisting of:
 (i) F(ab) 2  fragments   (ii) Fab fragments; and   (iii) domain antibodies (nanobodies).   
   
   
       12 . The method of  claim 1 , wherein the Siglec-9 binding agent comprises the natural ligand for Siglec-9, or a Siglec-9 binding fragment, analogue or portion thereof. 
   
   
       13 . The method of  claim 12 , wherein the Siglec-9 binding agent comprises a carbohydrate which further comprises sialic acid. 
   
   
       14 . The method of  claim 1 , wherein the Siglec-9 binding agent modulates the activity of Siglec-9 and/or the proliferative and/or differentiative state of a cell. 
   
   
       15 . The method of  claim 1 , wherein the Siglec-9 binding agent, once bound, is internalized such that the binding agent is delivered to the interior of a cell or to a compartment or vesicle within the cell. 
   
   
       16 . The method of  claim 1 , wherein the Siglec-9 binding agent binds or otherwise associates with Siglec-9 but is not internalized. 
   
   
       17 . The method of  claim 1  wherein the method comprising administering more than one Siglec binding agent. 
   
   
       18 . A Siglec-9 binding agent comprising a binding portion, capable of interacting/binding or otherwise associating with Siglec-9, and an active portion capable of modulating the proliferative and/or differentiative state of a cell for use in treating a cell proliferation and/or differentiation disorder. 
   
   
       19 . The Siglec-9 binding agent of  claim 18 , wherein the active portion of the binding agent is fused, linked, bound, conjugated, joined or otherwise associated with the binding portion. 
   
   
       20 . The Siglec-9 binding agent of  claim 18 , wherein the active portion of the binding agent comprises a heterologous molecule linked to the binding portion of the Siglec-9 binding agent. 
   
   
       21 . The Siglec-9 binding agent of  claim 18 , wherein the binding portion and the active portion of the Siglec-9 binding agent are linked such that upon exposure to certain conditions or agents, the binding portion and the active portion of the Siglec-9 binding agent are separated. 
   
   
       22 . The Siglec-9 binding agent of  claim 21 , wherein the binding portion and the active portion of the Siglec-9 binding agent are linked together by a linking region which comprises a portion which is sensitive to enzymatic cleavage and/or changes in environmental conditions. 
   
   
       23 . The Siglec-9 binding agent of  claim 18 , wherein the active portion of the Siglec-9 binding agent renders an abnormally or aberrantly proliferating and/or differentiating cell, quiescent or dead. 
   
   
       24 . The Siglec-9 binding agent of  claim 23 , wherein the active portion of the Siglec-9 binding agent comprises a toxic or cytotoxic substance or a molecule capable of activating programmed cell death pathways (apoptosis). 
   
   
       25 . The Siglec-9 binding agent of  claim 24 , wherein the active portion of the Siglec-9 binding agent comprises the cytotoxic agent calicheamicin-yl. 
   
   
       26 . The Siglec-9 binding agent of  claim 18  wherein, the Siglec-9 binding agent comprises an antibody which specifically binds to Siglec-9 conjugated to calicheamicin-yl. 
   
   
       27 . A pharmaceutical formulation comprising the Siglec-9 binding agent of  claim 19  in association with a pharmaceutically acceptable carrier or diluent. 
   
   
       28 . The pharmaceutical formulation according to  claim 27  wherein the Siglec-9 binding agent is a Siglec-9 specific antibody or Siglec-9 binding fragment thereof. 
   
   
       29 . A method of screening for agents capable of binding Siglec-9, said method comprising the steps of;
 a) contacting a test agent with a cell expressing Siglec-9; and   b) detecting an interaction between the test agent and Siglec-9.   
   
   
       30 . A method of screening for agents capable of modulating the differentiation and/or proliferation of a cell, said method comprising the steps of:
 a) contacting a test agent with a cell expressing Siglec-9; and   b) comparing the proliferation and/or differentiation of the cell of step (a) with a control cell.   
   
   
       31 . The methods of  claim 29 , wherein the test agent is fused, linked, bound, conjugated, joined or associated to/with a known Siglec-9 binding agent. 
   
   
       32 . A method of detecting a cell proliferation and/or differentiation disorder in a sample obtained from a subject suspected of having a cell proliferation and/or differentiation disorder, said method comprising the steps of;
 a) obtaining a sample from a patient;   b) contacting the sample with an agent capable of binding Siglec-9; and   c) detecting an interaction between the binding agent and Siglec-9,   wherein the presence of Siglec-9 is indicative of a cell proliferation and or differentiation disorder.   
   
   
       33 . The method of  claim 32 , further comprising the step of comparing the level of Siglec-9 detected in the sample derived from the subject, with the level of siglec-9 present in a control sample. 
   
   
       34 . A method of obtaining abnormally or aberrantly proliferating and/or differentiating cells or removing cells expressing siglec-9, from a sample or solution comprising a cell population, said method comprising the steps of;
 a) immobilising a siglec-9 binding agent on to a support substrate; and   (b) contacting said immobilised Siglec-9 binding agent with a cell sample.   
   
   
       35 . The method of  claim 34 , wherein the Siglec-9 binding agent further comprises a means of coupling said Siglec-9 binding agent to the solid support.