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Results for “Bi-specific targeting”

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PubMed2025

Efficacy of amivantamab, a bi-specific antibody targeting EGFR and MET, in ALK-rearranged non-small-cell lung cancer cell lines.

BACKGROUND: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are highly effective in treating ALK-rearranged non-small-cell lung cancer (NSCLC). However, at least 40% of patients develop acquired resistance during treatment. Adaptive or acquired resistance to ALK TKIs could be mediated through epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling. Sixteen percent of acquired resistance cases are linked to bypass signaling. METHODS: In this study, we evaluated the effects of amivantamab, a bi-specific antibody targeting both EGFR and MET, on ALK-rearranged NSCLC cells. We investigated the effect of amivantamab on the ALK-rearranged NSCLC cell lines H3122, ABC-19, and ABC-11. RESULTS: Combining alectinib with amivantamab resulted in greater inhibition of cell growth inhibition in H3122 and ABC-19 cells compared to alectinib alone, but not in ABC-11 cells. EGFR TKI erlotinib showed similar efficacy in H3122 and ABC-19 cells, whereas MET TKI tepotinib was ineffective in both, suggesting that the efficacy of amivantamab is through EGFR inhibition. Unlike H3122 and ABC-19 cells, ABC-11 cells were resistant to EGFR/MET signaling inhibition. Interestingly, amivantamab enhanced alectinib efficacy against ABC-11 cells in the presence of peripheral blood mononuclear cells (PBMCs), despite showing no effect alone without PBMCs, suggesting action through non-signal inhibitory mechanisms. Finally, we treated alectinib-resistant cellswith alectinib, with or without amivantamab, and found that amivantamab restored the sensitivity of these cells to alectinib. CONCLUSION: The bi-specific antibody amivantamab, which targets EGFR and MET, enhanced the efficacy of alectinib through both signal and non-signal inhibitory mechanisms in ALK-rearranged NSCLC cells.

Humans↗

PubMed2026

Integrated molecular and immune profiling identifies FOXA1 as a complementary co-target to MUC1 for bispecific immunotherapy in breast cancer.

In breast cancer immunotherapy, Mucin 1 (MUC1) is a well-established target with promising preclinical results; however, single targeting of MUC1 has demonstrated limited efficacy in clinical trials, largely due to tumor heterogeneity, diverse glycosylation patterns, and an immunosuppressive TME. Identification of complementary co-targets enables bi-specific or dual-target immunotherapy, limiting antigen escape, improving specificity, and reducing relapse. Here, we employed a comprehensive multi-layered analytical approach to evaluate MUC1 expression, clinical relevance, and methylation status, followed by systematic screening of MUC1-correlated genes. Antigenicity prediction and protein-protein interaction analyses identified Forkhead Box A1 (FOXA1) as a potential functional partner. Expression analysis revealed concordant patterns of MUC1 and FOXA1 across breast cancer samples, while network mapping demonstrated shared interactions with adhesion-associated proteins, including CTNNB1, CTNND1, and CDH1, suggesting roles in epithelial organization and tumor progression. Further validation using gene expression datasets from Indian breast cancer cohorts confirmed consistent expression and correlation patterns, supporting reproducibility across populations. Immune profiling revealed an inverse association between MUC1-FOXA1 co-expression and immune-related gene signatures, with high co-expression linked to reduced infiltration of dendritic cells, CD4⁺ and CD8⁺ T cells, macrophages, and natural killer cells, indicative of an immunosuppressive microenvironment. Negative correlations with MHC Class I genes further suggested impaired antigen presentation. Epitope prediction identified high-affinity peptides from both targets with strong MHC Class I binding potential. Collectively, these findings support the associated role of MUC1 and FOXA1 as dual immunotherapeutic targets in breast cancer.

Hepatocyte Nuclear Factor 3-alpha↗