Prognostic, screening and treatment methods and agents for treatment of metstasis and inflammation using t54 oncofoetal glycoprotein

Abstract

Methods and agents are disclosed based on the finding that 5T4 interacts with CXCR4 in the cell membrane to form a complex, and that the 5T4 transmembrane region is involved in the promotion of CXCR4 membrane expression and chemotactic response.

1 . A method for identifying a chemotaxis inhibitor, comprising: providing a 5T4 polypeptide, a CXC chemokine receptor polypeptide and a test agent under conditions in which, in the absence of the test agent, the 5T4 polypeptide and the CXC chemokine receptor polypeptide are able to interact; and
 determining whether the test agent inhibits the interaction between 5T4 polypeptide and the CXC chemokine receptor polypeptide, wherein inhibition of said interaction indicates that the test agent is a chemotaxis inhibitor.   
     
     
         2 .- 17 . (canceled) 
     
     
         18 . An antibody or fragment thereof that binds to:
 a 5T4 polypeptide;   a CXC chemokine receptor polypeptide; and/or   a complex comprising the 5T4 polypeptide and the CXC chemokine receptor polypeptide,   wherein said antibody or fragment thereof inhibits interaction between the 5T4 polypeptide and the CXC chemokine receptor polypeptide or inhibits the activity of said complex.   
     
     
         19 . An antibody or fragment thereof according to  claim 18 , wherein the antibody or fragment thereof inhibits the formation of or inhibits the cell surface expression of a complex comprising the 5T4 polypeptide and the CXC chemokine receptor polypeptide. 
     
     
         20 .- 28 . (canceled) 
     
     
         29 . A method of treating or preventing metastasis of a cancer that has at least one 5T4-positive and CXC chemokine receptor polypeptide-positive cell in a subject, comprising administering a therapeutically effective amount of an antibody or fragment thereof as defined in  claim 18  to the subject. 
     
     
         30 . A method according to  claim 29 , wherein the subject has a primary cancer of breast, ovarian, renal, prostate, gastric, oral, cervix, NSCLC, colorectal, glioma, neuroblastoma or acute lymphoblastic leukaemia origin. 
     
     
         31 . A method of treating or preventing an inflammatory condition in a subject, comprising administering a therapeutically effective amount of an antibody or fragment thereof as defined in  claim 18  to the subject. 
     
     
         32 . A method according to  claim 31 , wherein the inflammatory condition is selected from: rheumatoid arthritis, asthma, atherosclerosis, inflammatory bowel disease and inflamed liver. 
     
     
         33 .- 35 . (canceled) 
     
     
         36 . A method for assessing the prognosis of a subject having acute lymphoblastic leukaemia (ALL), comprising measuring, directly or indirectly, 5T4 expression and/or cell surface expression of a complex comprising a 5T4 polypeptide and a CXC chemokine receptor polypeptide in a bone marrow sample which has been obtained from the subject, wherein elevated 5T4 expression or elevated cell surface expression of said complex in a said sample in comparison with a reference level of 5T4 expression or a reference level of cell surface expression of said complex indicates that said subject has a poor prognosis, and wherein said reference level corresponds to the level of 5T4 expression or cell surface expression of said complex in a bone marrow sample obtained form a subject having low risk ALL which exhibits hyperdiploidy and/or the TEL-AML1 fusion. 
     
     
         37 . A method according to  claim 36 , wherein said poor prognosis comprises: an elevated risk of having or developing extramedullary ALL; an elevated risk of relapse; an elevated risk of therapeutic failure; and/or a lower likelihood of survival. 
     
     
         38 . A method according to  claim 36 , comprising: (a) detecting or determining mRNA levels expressed from the 5T4 gene; (b) determining the presence, amount or cell surface localization of a 5T4 polypeptide; and/or (c) determining the presence, amount or cell surface localization of a complex comprising a 5T4 polypeptide and a CXC chemokine receptor polypeptide. 
     
     
         39 . A kit for assessing the prognosis of a subject having acute lymphoblastic leukaemia, comprising reagents for carrying out the determination of 5T4 expression or cell surface expression of a complex comprising a 5T4 polypeptide and a CXC chemokine receptor polypeptide on a sample and instructions for carrying out the test and, optionally, interpreting the results. 
     
     
         40 . A kit according to  claim 39 , wherein said reagents comprise
 (a) an antibody or fragment thereof capable of recognizing a 5T4 polypeptide;   (b) one or more primers directed to the nucleic acid sequence of the 5T4 gene;   (c) an oligonucleotide probe directed to the nucleic acid sequence of the 5T4 gene; and/or   (d) an antibody or fragment thereof capable of recognizing a complex comprising a 5T4 polypeptide and a CXC chemokine receptor polypeptide.   
     
     
         41 . A method of determining whether a subject having acute lymphocytic leukaemia is suitable for 5T4 polypeptide-targeted and/or CXC chemokine receptor polypeptide-targeted treatment comprising measuring, directly or indirectly:
 5T4 expression in a bone marrow sample which has been obtained from the subject, wherein elevated 5T4 expression in said sample in comparison with a reference level of 5T4 expression indicates that said subject is suitable for said treatment; and/or   cell surface expression of a complex comprising a 5T4 polypeptide and a CXC chemokine receptor polypeptide in a bone marrow sample which has been obtained from the subject, wherein elevated cell surface expression of said complex in comparison with a reference level of cell surface expression of said complex indicates that said subject is suitable for said treatment, and wherein said reference level corresponds to the level in a bone marrow sample obtained from a subject having low risk ALL which exhibits hyperdiploidy and/or the TEL-AML1 fusion.   
     
     
         42 . A method according to  claim 41 , wherein said subject is determined to be suitable for said treatment, the method further comprising administering a therapeutically effective amount of an antibody or fragment thereof as defined in  claim 18  to the subject.