Nucleic acid biomarker and use thereof
Inventors
Schneider, Matthias • BLUM, Sabine • MENDELL-HARARY, Renee Jeanne • Freeman, Daniel J. • BECKMAN, Robert Allen • Jin, Xiaoping
Assignees
Daiichi Sankyo Europe GmbH • Daiichi Sankyo Co Ltd • Amgen Inc
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Publication Number
US-12497666-B2
Publication Date
2025-12-16
Expiration Date
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.
Core Innovation
The invention relates to a method of treating a human subject with locally advanced or metastatic non-small cell lung cancer (NSCLC) characterized as having a high heregulin (HRG) expression at an mRNA level. A tumor sample from the subject is obtained, and the HRG expression at the mRNA level in the tumor sample is determined. The subject is selected for treatment when the tumor sample has high HRG expression at the mRNA level.
An anti-HER3 antibody is administered to the selected subject. HRG is the only gene for which gene expression at the mRNA level is assessed for the purposes of selecting treatment for the subject, and treatment selection is based on whether HRG is high at the mRNA level.
The document further characterizes high HRG expression and refines subject selection. It specifies an approach where HRG mRNA expression can be determined by qRT-PCR using a delta Ct (dCt) threshold to classify high HRG expression, and it includes subject selection refinements based on EGFR status, including wild-type EGFR or lack of mutant EGFR expression.
Claims Coverage
The independent claim covers selection of subjects with locally advanced or metastatic NSCLC based on high HRG mRNA expression, with HRG as the only assessed gene, followed by administration of an anti-HER3 antibody. The dependent claim set adds measurement and threshold specifics, eligibility refinements, named antibody options, and optional co-therapies.
HRG mRNA-based subject selection with anti-HER3 antibody administration
A method of treating a human subject with locally advanced or metastatic NSCLC characterized as having a high heregulin (HRG) expression at an mRNA level by obtaining a tumor sample, determining HRG expression at the mRNA level, selecting the subject for treatment when HRG is high, and administering an anti-HER3 antibody, wherein HRG is the only gene for which gene expression at the mRNA level is assessed for selecting treatment.
High HRG mRNA defined by qRT-PCR dCt threshold
The method determines HRG expression at the mRNA level using qRT-PCR and characterizes high HRG mRNA expression by a delta Ct (dCt) value of 5.0 or less.
Eligibility refined by EGFR status
The method is applied to a subject that expresses a wild-type EGFR or does not express a mutant EGFR.
Selection among specified anti-HER3 antibodies
The method is performed using an anti-HER3 antibody selected from patritumab, duligotumab (MEHD-7945A), seribantumab (MM-121), MM-111, LJM716, RG-7116, a tri-specific anti-EGFR/ERBB3 zybody, and huHER3-8.
Optional co-therapy with additional treatment classes
The method further includes administering one or more additional therapies including a HER inhibitor, chemotherapy, radiation, and/or another targeted agent.
Cetuximab together with cisplatin or carboplatin
The method further includes administering cetuximab together with cisplatin or carboplatin.
Overall, the claim coverage centers on HRG mRNA as the sole gene-expression determinant for selecting NSCLC subjects for anti-HER3 antibody treatment, with dependent claims defining a qRT-PCR dCt threshold, restricting eligibility by EGFR status, enumerating antibody choices, and adding optional co-therapies including a cetuximab plus cisplatin or carboplatin regimen.
Stated Advantages
Documented Applications
Treating a human subject with locally advanced or metastatic NSCLC using HRG mRNA-based selection for anti-HER3 antibody treatment.
Subject selection based on HRG mRNA high/low classification using qRT-PCR dCt determination, with high defined by dCt ≤ 5.0.
Applying the treatment method to subjects having wild-type EGFR expression or not expressing mutant EGFR.
Administering specified anti-HER3 antibodies, including patritumab, duligotumab, seribantumab, MM-111, LJM716, RG-7116, a tri-specific anti-EGFR/ERBB3 zybody, and huHER3-8.
Use in treatment regimens that optionally include additional therapies such as a HER inhibitor, chemotherapy, radiation, and/or another targeted agent.
Use in regimens administering cetuximab together with cisplatin or carboplatin.
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