An Anti-EGFR/anti- HER2 Bispecific Antibody with Enhanced Antitumor Activity Against Acquired Gefitinib-Resistant NSCLC Cells
Background: Acquired resistance to epidermal growth factor receptor–tyrosine kinase
inhibitors (EGFR-TKIs) is a recurrent phenomenon during clinical therapy of non-small-cell lung
cancer (NSCLC). Studies have shown that HER2 is a key factor contributing to drug resistance in a
variety of cancers. Furthermore, we have observed that HER2 is overexpressed in PC-9 NSCLC
cells with acquired gefitinib-resistance (PC-9/GR) as compared to that in PC-9 cells.
Objective: We hypothesized that blocking both EGFR and HER2 may serve as a potential strategy
for the treatment of NSCLC with acquired gefitinib-resistance.
Methods: To target both EGFR and HER2 simultaneously, we developed a bispecific antibody
HECrossMAb, which was derived from a humanized Cetuximab and Trastuzumab. The binding affinity
of HECrossMAb for EGFR and HER2 was measured using an enzyme-linked immunosorbent assay.
The MTT assay was used to determine the effect of HECrossMAb on the proliferation of PC-9 and
PC-9/GR cells in vitro. Finally, the effect of HECrossMAb on PI3K/AKT signaling and associated transcription
factors was measured using western blot analysis.
Results: Our results showed that HECrossMAb exerts enhanced cytotoxicity in both PC-9 and PC-9/GR
cells by inhibiting the activation of PI3K/AKT signaling and expression of relevant transcription
factors such as AEG-1, c-Myc, and c-Fos.
Conclusion: Our results suggest that HECrossMAb may function as a potential therapeutic agent for
treating NSCLC overexpressing EGFR and HER2.
Journal Title: Protein & Peptide Letters