Dual Targeting of EGFR and cMet in EGFR-Mutant Lung Cancer: The Role of a Novel Bispecific Antibody with Enhanced Fc Effector Function

3 June 2024
Non-small cell lung cancers (NSCLCs) with specific mutations in the EGFR gene typically respond well to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib. However, resistance to these treatments often develops, with the cMet pathway frequently becoming activated as a compensatory mechanism. This can occur through various means, including MET gene amplification, overexpression of the cMet protein, or an increase in the HGF ligand.

A novel bispecific antibody, JNJ-61186372, has been engineered to target both EGFR and cMet, potentially overcoming resistance mechanisms in NSCLC. This antibody was created using a controlled Fab-arm exchange technique, which allows for the production of bispecific antibodies with a regular IgG1 structure. JNJ-61186372 is capable of binding to both EGFR and cMet and has been shown to inhibit the phosphorylation of these receptors when their ligands bind.

A key feature of JNJ-61186372 is its lower than normal fucose content, which is designed to enhance Fc-dependent effector mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC). In vitro studies have demonstrated the antibody's ADCC activity against a range of NSCLC cell lines, including those with EGFR mutations, KRas mutations, and/or MET gene amplification. The low fucose version of JNJ-61186372 showed superior ADCC activity compared to a version with normal fucose levels.

The bispecific antibody also exhibited increased potency compared to a combination of separate EGFR and cMet antibodies, highlighting the benefits of dual targeting. Additionally, JNJ-61186372 has shown antibody-dependent cell-mediated phagocytosis (ADCP) activity in vitro and has demonstrated in vivo anti-tumor growth activity in a xenograft model with EGFR mutations and cMet activation.

These findings suggest that JNJ-61186372, through its dual targeting of EGFR and cMet, along with its enhanced Fc effector functions, may offer a novel therapeutic approach for treating EGFR mutant NSCLC patients, particularly those with resistance to EGFR TKIs.

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The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

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Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

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By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

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