Nucleic acid biomarker and use thereof

Abstract

The present invention is directed to methods of identifying and treating a human subject harboring a tumor or other disease comprising assessing HRG gene expression at an mRNA level in the human subject and administering a treatment comprising an anti-HER3 antibody to the human subject whose HRG gene expression at an mRNA level is assessed as high. The present invention is also directed to methods of identifying a human subject harboring a tumor or other disease comprising assessing HRG gene expression at an mRNA level in the human subject and withholding a treatment comprising an anti-HER3 antibody to the human subject whose HRG gene expression at an mRNA level is assessed as low.

1 . A method of treating a human subject harboring a locally advanced or metastatic non-small cell lung cancer (NSCLC) tumor comprising:
 assessing HRG gene expression at an mRNA level in a human subject diagnosed with a locally advanced or metastatic NSCLC; and   administering a treatment comprising an anti-HER3 antibody to a human subject whose HRG gene expression at an mRNA level is assessed as high.   
     
     
         2 .- 12 . (canceled) 
     
     
         13 . A method of treating a human subject harboring a locally advanced or metastatic non-small cell lung cancer (NSCLC) tumor comprising:
 assessing HRG gene expression at an mRNA level in a human subject diagnosed with a locally advanced or metastatic NSCLC; and   withholding a treatment comprising an anti-HER3 antibody to a human subject whose HRG gene expression at an mRNA level is assessed as low.   
     
     
         14 .- 41 . (canceled) 
     
     
         42 . A method of identifying a human patient diagnosed with a locally advanced or metastatic non-small cell lung cancer (NSCLC) tumor who is likely to benefit from a treatment comprising an anti-HER3 antibody comprising:
 receiving a biological sample from a human patient diagnosed with a locally advanced or metastatic NSCLC;   using the sample, determining a value for gene expression at an mRNA level in the human subject; and   optionally, recording the value determined.   
     
     
         43 .- 53 . (canceled) 
     
     
         54 . A method of treating a human subject harboring head and neck cancer comprising administering a treatment comprising an anti-HER3 antibody to a human subject diagnosed with head and neck cancer whose HRG gene expression at an mRNA level is assessed as high. 
     
     
         55 . The method of  claim 54  in which the HRG gene expression at an mRNA level is assessed as high if a delta Ct (dCt) value is observed, which is below a predetermined threshold, from a biological sample taken from the subject diagnosed with head and neck cancer. 
     
     
         56 . The method of  claim 55  in which the predetermined threshold is statistically determined, refined, adjusted and/or confirmed through, on, or based on randomized clinical data and optionally non-clinical data. 
     
     
         57 . The method of  claim 56  in which the predetermined threshold dCt value is selected from the group consisting of 5.0, 4.9. 4.8. 4.7, 4.6. 4.5, 4.4, 4.3, 4.2, 4.1, 4.0. 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3,2, 3.1, 3.0, 2.9, 2.8. 2.7, 2.6. 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0. 0.9, 0.8. 0.7, 0.6, 0.5, 0.4, 0.3. 0.2, 0,1, 0, −0.1, −0.2, −0.3, −0.4, −0.5, −0.6, −0.7, −0.8, −0.9, −1.0, −1.1, −1.2, −1.3, −1.4, −1.5, −1.6, −1.7, −1.8, −1.9, −2.0, −2.1, −2.2, −2,3, −2.4, −2.5, −2.6, −2.7, −2.8, −2.9. −3.0, −3.1, −3.2, −3.3, −3.4, −3.5, −3.6, −3.7, −3.8, −3.9, −4.0, −4.1, −4.2, −4.3, −4.4, −4.5, −4.6, −4.7, −4.8, −4.9, −5.0, −5.1, −5.2, −5.3, −5.4, −5.5, −5.6, −5.7, −5,8, −5.9, −6.0, −6.1, −6.2, −6.3, −6.4, −6.5, −6.6, −6.7, −6.8, −6.9, −7.0, −7.1, −7.2 and −7.3. 
     
     
         58 . The method of  claim 56 , wherein the predetermined threshold dCt value is in a range of from about 2.7 to about 4.1. 
     
     
         59 . The method of  claim 54 , wherein the subject harbors wild-type EGFR. 
     
     
         60 . The method of  claim 54 , wherein the head and neck cancer has progressed on at least one prior systemic therapy. 
     
     
         61 . The method of  claim 54 , further comprising assessing gene expression at an mRNA level, in the human subject diagnosed with the head and neck cancer, wherein the HRG gene expression at an mRNA level is assessed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), RNA sequencing or ISH. 
     
     
         62 . The method of  claim 55  in which the biological sample comprises a tumor sample. 
     
     
         63 . The method of  claim 54  in which the anti-HER3 antibody is selected from the group consisting of patritumab, duligotumab (MEND-7945A), seribantumab (MM-121), MM-111, LJM716, RG-7116, tri-specific anti-EGFR/ERBB3 zybody, huHER3-8, and a derivative or fragment of any of these. 
     
     
         64 . The method of  claim 54  in which the treatment comprises administering an anti-HER3 antibody in combination with one or more of (i) a HER inhibitor, (ii) a chemotherapy, (iii) radiation, and (iv) an other targeted agent. 
     
     
         65 . The method of  claim 64 , wherein the HER inhibitor is selected from the group consisting of trastuzumab, T-DM1, lapatinib, pertuzumab, cetuximab, panitumumab gefitinib, afatinib, dacomitinib, KD-019 and erlotinib. 
     
     
         66 . The method of  claim 64 , wherein the chemotherapy is selected from the group consisting of cisplatin, carboplatin, gemcitabine, pemetrexed, irinotecan, 5-fluoruracil, paclitaxel, docetaxel, and capecitabine. 
     
     
         67 . The method of  claim 64 , wherein the anti-HER3 antibody is administered in combination with (i) cetuximab and (ii) cisplatin or carboplatin. 
     
     
         68 . The method of  claim 67 , wherein the anti-HER3 antibody is patritumab. 
     
     
         69 . The method of  claim 62 , in which a tumor tissue or fragment thereof for or with which the HRG gene expression is assessed has been removed from the subject prior to any therapy. 
     
     
         70 . The method of  claim 55 , in which the predetermined threshold dCt value is in a range of from about −7.3 to about 5.0. 
     
     
         71 . The method of  claim 54 , wherein the HRG gene expression is assessed using an FDA-approved test.