A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Non-small cell lung cancer (NSCLC) often develops resistance to EGFR tyrosine kinase inhibitors (TKIs) through mechanisms like EGFR T790M mutations or cMet pathway activation.
• Targeting both EGFR and cMet pathways simultaneously is a potential strategy to overcome this resistance.

Purpose of the Study:

• To engineer and evaluate a bispecific antibody (JNJ-61186372) targeting both EGFR and cMet for the treatment of NSCLC.
• To assess the efficacy and safety of JNJ-61186372 in preclinical NSCLC models.

Main Methods:

• Engineering of a bispecific antibody (JNJ-61186372) with dual EGFR and cMet inhibitory functions.
• In vitro assessment of JNJ-61186372's ability to block ligand-induced phosphorylation and inhibit downstream signaling pathways (ERK, AKT).
• In vivo evaluation of JNJ-61186372 efficacy in NSCLC tumor models, including combination therapy with a third-generation EGFR TKI, and safety assessment in cynomolgus monkeys.

Main Results:

• JNJ-61186372 potently inhibited EGFR and cMet phosphorylation and downstream signaling (p-ERK, p-AKT) compared to single-target antibodies.
• Treatment with JNJ-61186372 led to tumor regression in NSCLC models via signaling inhibition, receptor downregulation, and Fc-mediated effector functions.
• Combination therapy of JNJ-61186372 and a third-generation EGFR TKI achieved complete and durable regression of human lung xenograft tumors.
• JNJ-61186372 exhibited a favorable safety profile in cynomolgus monkeys, notably lacking the skin rash associated with other EGFR inhibitors.

Conclusions:

• JNJ-61186372 is a promising bispecific antibody that effectively inhibits key resistance mechanisms in NSCLC.
• The dual targeting of EGFR and cMet, combined with Fc-mediated functions, offers a potent anti-tumor effect.
• JNJ-61186372 demonstrates potential as a differentiated therapeutic agent for overcoming EGFR TKI resistance in NSCLC, with a favorable safety profile.