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 .- 53 . (canceled) 
     
     
         54 . A method of treating a human subject harboring a locally advanced or metastatic non-small cell lung cancer (NSCLC) tumor comprising administering a treatment comprising an anti-HER3 antibody to a human subject diagnosed with a locally advanced or metastatic NSCLC 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 a locally advanced or metastatic NSCLC. 
     
     
         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 tumor 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 locally advanced or metastatic NSCLC, 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 (MEHD-7945A), seribantumab (MM-121), MM-111, LIM716, RG-7116, tri-specific anti-EGFR/ER13133 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-fluoniracil, paclitaxel, docetaxel, and capecitabine. 
     
     
         67 . The method of  claim 54 , wherein the HRG gene expression is assessed using an FDA-approved test. 
     
     
         68 . A method of treating a human subject harboring a locally advanced or metastatic non-small cell lung cancer (NSCLC) tumor comprising withholding a treatment comprising an anti-HER3 antibody to a human subject diagnosed with a locally advanced or metastatic NSCLC whose HRG gene expression at an mRNA level is assessed as low. 
     
     
         69 . The method of  claim 68  in which the HRG gene expression at an mRNA level is assessed as low if a delta Ct (dCt) value is observed, which is at or above a predetermined threshold, from a biological sample taken from the subject diagnosed with a locally advanced or metastatic NSCLC. 
     
     
         70 . The method of  claim 69  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. 
     
     
         71 . The method of  claim 70  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. 
     
     
         72 . The method of  claim 68 , wherein the subject harbors wild-type EGFR. 
     
     
         73 . The method of  claim 68 , wherein the tumor has progressed on at least one prior systemic therapy. 
     
     
         74 . The method of  claim 69  in which the biological sample comprises a tumor sample. 
     
     
         75 . The method of  claim 68  in which the treatment withheld comprises 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. 
     
     
         76 . A method of receiving or undergoing a treatment for a locally advanced or metastatic non-small cell lung cancer (NSCLC) tumor or abstaining therefrom comprising:
 providing an autologous tissue sample or consenting to a taking of same to facilitate an assessment of HRG gene expression at an mRNA level in a human subject diagnosed with a locally advanced or metastatic NSCLC; and   receiving or undergoing a treatment comprising an anti-HERS antibody if the HRG gene expression at an mRNA level is assessed as high, or   abstaining from a treatment comprising an anti-HERS antibody if the HRG gene expression at an mRNA level is assessed as low.   
     
     
         77 . The method of  claim 76  in which (i) the HRG gene expression at an mRNA level is assessed as high if a delta et (dCt) value is observed, which is below a predetermined threshold, from a biological sample taken from the subject diagnosed with a locally advanced or metastatic NSCLC or (ii) the HRG gene expression at an mRNA level is assessed as low if a dCt value is observed, which is at or above the predetermined threshold, from the biological sample taken from the subject diagnosed with the locally advanced or metastatic NSCLC. 
     
     
         78 . The method of  claim 77  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. 
     
     
         79 . The method of  claim 78  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. 
     
     
         80 . A method of electing a treatment for a locally advanced or metastatic non-small cell lung cancer (NSCLC) tumor comprising:
 receiving or undergoing an assessment of HRG gene expression at an mRNA level in a human subject diagnosed with a locally advanced or metastatic NSCLC; and   electing to withhold or abstain from a treatment comprising an anti-HERS antibody if the HRG gene expression at an mRNA level is assessed as low, or   electing to receive or undergo a treatment comprising an anti-HER3 antibody if the HRG gene expression at an mRNA level is assessed as high.   
     
     
         81 . The method of  claim 80  in which (i) 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 a locally advanced or metastatic NSCLC or (ii) the HRG gene expression at an mRNA level is assessed as low if a dCt value is observed, which is at or above the predetermined threshold, from the biological sample taken from the subject diagnosed with the locally advanced or metastatic NSCLC. 
     
     
         82 . The method of  claim 81  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. 
     
     
         83 . The method of  claim 82  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.