US2014309263A1PendingUtilityA1

Biomarkers of therapeutic responsiveness

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Assignee: MESO SCALE TECHNOLOGIES LLCPriority: Feb 1, 2013Filed: Jan 31, 2014Published: Oct 16, 2014
Est. expiryFeb 1, 2033(~6.5 yrs left)· nominal 20-yr term from priority
Inventors:Simone BarberoEli N. GlezerAnu MathewMingyue Wang
G01N 33/5751G01N 33/57525A61K 31/404C12Q 1/485A61K 31/44G01N 2800/60G01N 33/5743G01N 33/57438G01N 2033/57461G01N 2033/57457
59
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Claims

Abstract

The present invention relates to methods of diagnosing a kidney disorder in a patient, as well as methods of monitoring the progression of a kidney disorder and/or methods of monitoring a treatment protocol of a therapeutic agent or a therapeutic regimen. The invention also relates to assay methods used in connection with the diagnostic methods described herein.

Claims

exact text as granted — not AI-modified
1 . A method for evaluating the efficacy of a treatment regimen in a patient diagnosed with renal cell carcinoma (RCC) or metastatic melanoma, said method comprising
 (a) obtaining a test sample from a patient undergoing said treatment regimen for RCC;   (b) measuring a level of a biomarker in said test sample, wherein said biomarker comprises total, phosphorylated, and dephosphorylated isoforms of c-Met, beta-catenin, SFRP-1, Akt, Wnt3A, Rb, VEGF, E-cadherin, GSK3beta, and combinations thereof;   (c) comparing said level to a normal control level of said biomarker; and   (d) evaluating from said comparing step (c) whether said patient is responsive to said treatment regimen.   
     
     
         2 . A method for evaluating the efficacy of a treatment regimen in a patient diagnosed with renal cell carcinoma (RCC) or metastatic melanoma, said method comprising
 (a) ordering a test comprising a measurement of a level of a biomarker in a test sample obtained from a patient undergoing said treatment regimen for RCC, wherein said biomarker comprises total, phosphorylated, and dephosphorylated isoforms of c-Met, beta-catenin, SFRP-1, Akt, Wnt3A, Rb, VEGF, E-cadherin, GSK3beta, and combinations thereof;   (b) comparing said level to a normal control level of said biomarker; and   (c) evaluating from said comparing step (b) whether said patient is responsive to said treatment regimen.   
     
     
         3 . A method of administering a treatment regimen to a patient in need thereof for treating renal cell carcinoma (RCC) or metastatic melanoma, comprising:
 (a) obtaining a test sample from a patient undergoing said treatment regimen for RCC;   (b) measuring a level of a biomarker in said test sample, wherein said biomarker comprises total, phosphorylated, and dephosphorylated isoforms of c-Met, beta-catenin, SFRP-1, Akt, Wnt3A, Rb, VEGF, E-cadherin, GSK3beta, and combinations thereof;   (c) comparing said level to a normal control level of said biomarker;   (d) evaluating from said comparing step (c) whether said patient is responsive to said treatment regimen; and   (e) adjusting said treatment regimen based on said evaluating step (d).   
     
     
         4 . A method of administering a treatment regimen to a patient in need thereof for treating renal cell carcinoma (RCC) or metastatic melanoma, comprising:
 (a) obtaining a test sample from a patient prior to the commencement of said treatment regimen for RCC;   (b) measuring a level of a biomarker in said test sample, wherein said biomarker comprises total, phosphorylated, and dephosphorylated isoforms of c-Met, beta-catenin, SFRP-1, Akt, Wnt3A, Rb, VEGF, E-cadherin, GSK3beta, and combinations thereof;   (c) comparing said level to a normal control level of said biomarker;   (d) evaluating from said comparing step (c) whether said patient will be responsive to said treatment regimen; and   (e) administering said treatment regimen based on said evaluating step (d).   
     
     
         5 . A method of administering a treatment regimen to a patient in need thereof for treating renal cell carcinoma (RCC) or metastatic melanoma, comprising:
 (a) evaluating a level of a biomarker in a test sample obtained from a patient undergoing said treatment regimen for RCC or metastatic melanoma relative to a normal control level of said biomarker, wherein said biomarker comprises total, phosphorylated, and dephosphorylated isoforms of c-Met, beta-catenin, SFRP-1, Akt, Wnt3A, Rb, VEGF, E-cadherin, GSK3beta, and combinations thereof; and   (b) adjusting said treatment regimen based on said evaluating step (a).   
     
     
         6 . A method of administering a treatment regimen to a patient in need thereof for treating renal cell carcinoma (RCC) or metastatic melanoma, comprising:
 (a) evaluating a level of a biomarker in a test sample obtained from a patient prior to the commencement of said treatment regimen for RCC or metastatic melanoma relative to a normal control level of said biomarker, wherein said biomarker comprises total, phosphorylated, and dephosphorylated isoforms of c-Met, beta-catenin, SFRP-1, Akt, Wnt3A, Rb, VEGF, E-cadherin, GSK3beta, and combinations thereof; and   (b) administering said treatment regimen based on said evaluating step (a).   
     
     
         7 . A method of treating renal cell carcinoma (RCC) or metastatic melanoma, comprising administering a VEGF-inhibitor to a patient whose levels of a biomarker for RCC or metastatic melanoma were determined to be at least 1.5-fold greater/less than those values in a normal control, wherein said biomarker of RCC or metastatic melanoma is selected from total, phosphorylated, and dephosphorylated isoforms of c-Met, beta-catenin, SFRP-1, Akt, Wnt3A, Rb, VEGF, E-cadherin, and GSK3beta. 
     
     
         8 . The method according to  claim 1  wherein said measuring step comprises conducting a multiplexed assay measurement of a plurality of said biomarkers in said test sample, wherein said multiplexed assay measurement is conducted using one reaction volume comprising said test sample. 
     
     
         9 . The method of  claim 1  wherein said method comprises measuring levels of two or more biomarkers. 
     
     
         10 . The method of  claim 9  wherein said measuring step comprises measuring levels of a first biomarker and an additional biomarker, wherein said first biomarker is a total form of a biomarker and said additional biomarker is a phosphorylated form of said biomarker. 
     
     
         11 . The method of  claim 1  wherein said biomarker comprises c-Met, beta-catenin, SFRP-1, Akt, Wnt3A, Rb, VEGF, E-cadherin, GSK3beta, and combinations thereof. 
     
     
         12 . The method of  claim 1  wherein said treatment regimen comprises administering an agonist of a VEGF-signaling pathway. 
     
     
         13 . The method of  claim 1  wherein said treatment regimen comprises administering an antagonist of a VEGF-signaling pathway. 
     
     
         14 . The method of  claim 12  wherein said treatment regimen comprises administering a multi-kinase inhibitor. 
     
     
         15 . The method of  claim 14  wherein said treatment regimen comprises administration of a therapeutic agent comprising sorafenib, sunitinib, cediranib, and combinations thereof. 
     
     
         16 . The method of  claim 15  wherein said patient is diagnosed with metastic melanoma. 
     
     
         17 . The method of  claim 16  wherein said patient is diagnosed with RCC. 
     
     
         18 . The method of  claim 1  further comprising one or more additional measuring steps including:
 (x) measuring a baseline level(s) of said biomarker before said treatment regimen is initiated, and said evaluating step further comprises comparing said level and said baseline level; and 
 (y) measuring an interim level of said biomarker during said treatment regimen and said evaluating step further comprises comparing said level, said interim level and said baseline level. 
 
     
     
         19 . The method of  claim 1 , wherein said evaluating step comprises comparing said level of said biomarker to a detection cut-off level, wherein said level above said detection cut-off level is indicative of RCC or metastatic melanoma. 
     
     
         20 . The method of  claim 1 , wherein said evaluating step comprises comparing said level of said biomarker to a detection cut-off level, wherein said level below said detection cut-off level is indicative of RCC or metastatic melanoma. 
     
     
         21 . The method of  claim 1  further comprising determining from said level of said biomarker the disease progression of RCC or metastatic melanoma. 
     
     
         22 . A method for detecting abnormal GSK3beta activity in a patient diagnosed with renal cell carcinoma (RCC) or metastatic melanoma, said method comprising
 (a) obtaining a test sample from said patient;   (b) measuring a level of a biomarker in said test sample, wherein said biomarker comprises total, phosphorylated, and dephosphorylated isoforms of c-Met, beta-catenin, SFRP-1, Akt, Wnt3A, Rb, VEGF, E-cadherin, GSK3beta, and combinations thereof;   (c) comparing said level to a normal control level of said biomarker; and   (d) evaluating from said comparing step (c) whether said GSK3beta activity is abnormal relative to said normal control level of said biomarker.   
     
     
         23 . A method for detecting an alteration in GSK3beta activity in a patient diagnosed with renal cell carcinoma (RCC) or metastatic melanoma, said method comprising
 (a) obtaining a baseline test sample from said patient at t 0 ;   (b) measuring a baseline level of a biomarker in said baseline test sample, wherein said biomarker comprises total, phosphorylated, and dephosphorylated isoforms of c-Met, beta-catenin, SFRP-1, Akt, Wnt3A, Rb, VEGF, E-cadherin, GSK3beta, and combinations thereof;   (c) obtaining an additional test sample from said patient at time t (0+n) , wherein n is >1 hour from t 0 ;   (d) measuring an additional level of said biomarker in said additional test sample;   (e) comparing said additional level to said baseline level of said biomarker; and   (f) evaluating from said comparing step (e) whether said GSK3beta activity is altered relative to said baseline level of said biomarker.   
     
     
         24 . The method of  claim 22  wherein said measuring step comprises conducting a multiplexed assay measurement of a plurality of said biomarkers in said test sample, wherein said multiplexed assay measurement is conducted using one reaction volume comprising said test sample. 
     
     
         25 . The method of  claim 22  wherein said method comprises measuring levels of two or more biomarkers. 
     
     
         26 . The method of  claim 25  wherein said measuring step comprises measuring levels of a first biomarker and an additional biomarker, wherein said first biomarker is a total form of a biomarker and said additional biomarker is a phosphorylated form of said biomarker. 
     
     
         27 . A method of  claim 22  wherein said biomarker comprises c-Met, beta-catenin, SFRP-1, Akt, Wnt3A, Rb, VEGF, E-cadherin, GSK3beta, and combinations thereof. 
     
     
         28 . The method of  claim 22 , wherein said evaluating step comprises comparing said level of said biomarker to a detection cut-off level, wherein said level above said detection cut-off level is indicative of RCC or metastatic melanoma. 
     
     
         29 . The method of  claim 22 , wherein said evaluating step comprises comparing said level of said biomarker to a detection cut-off level, wherein said level below said detection cut-off level is indicative of RCC or metastatic melanoma. 
     
     
         30 . The method of  claim 22  further comprising determining from said level of said biomarker the disease progression of RCC or metastatic melanoma. 
     
     
         31 . The method of  claim 22  wherein said measuring step(s) are conducted on a single sample. 
     
     
         32 . The method of  claim 22  wherein said measuring step(s) are conducted in a single assay chamber. 
     
     
         33 . A kit for the analysis of a kidney disease panel comprising
 (a) a multi-well assay plate comprising a plurality of wells, each well comprising at least four discrete binding domains to which capture antibodies to the following human analytes are bound: c-Met, beta-catenin, SFRP-1, Akt, Wnt3A, Rb, VEGF, E-cadherin, GSK3beta, and combinations thereof;   (b) in one or more vials, containers, or compartments, a set of labeled detection antibodies specific for said human analytes; and   (c) in one or more vials, containers, or compartments, a set of calibrator proteins.   
     
     
         34 . The kit of  claim 33  wherein said kit further comprises one or more diluents. 
     
     
         35 . The kit of  claim 33  wherein said detection antibodies are labeled with an electrochemiluminescent (ECL) label. 
     
     
         36 . The kit of  claim 35  wherein said kit further comprises an ECL read buffer. 
     
     
         37 . The kit of  claim 33  wherein said discrete binding domains are positioned on an electrode within said well. 
     
     
         38 . The kit of  claim 33  wherein said set of calibrator proteins comprise a lyophilized blend of proteins. 
     
     
         39 . The kit of  claim 33  wherein said set of calibrator proteins comprise a liquid formulation of calibrator proteins.

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