Biomarker for cardiac disorders

Abstract

The present invention relates generally to assays, methods and kits for the prognosis and/or diagnosis of cardiac disorders. The present invention also provides, for example, binding agents to a novel class of circulating troponin biomarkers for use in predicting or diagnosing a cardiac disorder other than myocardial infarction or unstable angina. In addition, the binding agents of the present invention may be used to enhance the sensitivity and false positive performance of cardiac troponins in the prognosis and diagnosis of myocardial infarction.

1 .- 43 . (canceled) 
     
     
         44 . A method of predicting mortality in a subject who has suffered a cardiac event, the method comprising:
 (i) measuring a level of a Troponin T upstream open reading frame (TnTuORF) peptide in a biological sample from the subject by detecting binding between the TnTuORF peptide and a binding agent that selectively binds to the TnTuORF peptide to determine a level of the TnTuORF peptide in the subject; and   (ii) comparing the level of the TnTuORF peptide measured in (i) against a reference level of the TnTuORF peptide from a suitable control population,   wherein a higher value for the circulating level of the TnTuORF peptide in the subject compared to the reference level of the TnTuORF peptide in the control population is predictive of mortality in the subject,   and wherein the Troponin T upstream open reading frame (TnTuORF) peptide consists of the amino acid sequence set forth in any one of SEQ ID NO:1, SEQ ID NO: 2, SEQ ID NO: 3 or SEQ ID NO: 4.   
     
     
         45 . The method of  claim 44 , wherein step (i) comprises measuring the level of the TnTuORF peptide in a first biological sample taken from the subject at a first point in time to determine a first circulating level of the TnTuORF peptide and measuring the level of the TnTuORF peptide in a second biological sample taken from the subject at a later period in time to determine a second circulating level of the TnTuORF peptide; and comparing the first and second circulating levels of the TnTuORF peptide, wherein an increase in the second circulating level of the TnTuORF peptide relative to the first circulating level is indicative of increased risk to mortality. 
     
     
         46 . The method of  claim 44 , wherein:
 (a) the control population comprises one or more control subjects that are sex and age-matched to the subject and for which no known risk of mortality exists; or   (b) the reference level of the TnTuORF peptide is a mean circulating TnTuORF peptide concentration from the control population; or   (c) the biological sample is a body fluid or a heart tissue sample; or   (d) the body fluid is selected from venous blood, arterial blood, plasma, serum and interstitial fluid.   
     
     
         47 . The method of  claim 44  wherein the binding agent that selectively binds to the TnTuORF peptide is selected from: (i) an antibody or antigen binding fragment thereof; (ii) a polyclonal, monoclonal, chimeric or humanized antibody or antigen binding fragment thereof; (iii) a monoclonal antibody or antigen binding fragment thereof; and (iv) a binding agent or antibody that is immobilized to a solid phase. 
     
     
         48 . An assay method for determining a level of a Troponin T upstream open reading frame (TnTuORF) peptide in a biological sample from a subject who has suffered a cardiac event and who may be at risk from mortality as a result of the cardiac event, the assay method comprising detecting and quantitatively measuring binding between the TnTuORF peptide and a binding agent that selectively binds to the TnTuORF peptide to determine the level of the TnTuORF peptide in the biological sample from the subject, wherein the TnTuORF peptide consists of the amino acid sequence set forth in any one of SEQ ID NO:1, SEQ ID NO: 2, SEQ ID NO: 3 or SEQ ID NO: 4. 
     
     
         49 . The assay method of  claim 48 , wherein one or more of:
 (a) the assay method comprises:
 (i) measuring a level of the Troponin T upstream open reading frame (TnTuORF) peptide in the biological sample from the subject to obtain a measured level of the TnTuORF peptide; and 
 (ii) comparing the measured level of the TnTuORF peptide from (i) to a reference level of the TnTuORF peptide in a biological sample from a suitable control population, 
   wherein an increased level of the TnTuORF peptide measured in (i) relative to the reference level of the TnTuORF peptide in the biological sample from the control population in (ii) is predictive of mortality in the sibject, and further wherein the measuring step comprises detecting binding between the TnTuORF peptide and a binding agent that selectively binds to the TnTuORF peptide; or   (b) the assay method comprises a method that is selected from an immunoassay, an enzyme immunoassay, a radioimmunoassay or a chemiluminescence assay; or   (c) the binding agent that selectively binds to the TnTuORF peptide is an antibody or antigen binding fragment thereof.   
     
     
         50 . A kit for measuring a level of a Troponin T upstream open reading frame (TnTuORF) peptide in a biological sample from a subject who has suffered a cardiac event and who may be at risk of mortality, comprising a binding agent that selectively binds to the TnTuORF peptide and which can be quantitatively measured upon binding to the TnTuORF peptide, wherein the TnTuORF peptide consists of the amino acid sequence set forth in any one of SEQ ID NO:1, SEQ ID NO: 2, SEQ ID NO: 3 or SEQ ID NO: 4. 
     
     
         51 . The kit of  claim 50  in which one or more of:
 (a) the binding agent that selectively binds to the TnTuORF peptide is an antibody or antigen binding fragment thereof, and 
 (b) the kit further comprises instructions for measuring the level of the TnTuORF peptide in the sample.