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An anti-EGFR/anti- HER2 Bispecific Antibody with Enhanced Antitumor Activity Against Acquired Gefitinib-Resistant NSCLC Cells

Author(s):

Yan Si, Xinxin Pei, Xiangfang Wang, Qianqian Han, Changzhi Xu* and Buchang Zhang  

Abstract:


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 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 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 the treatment of NSCLC overexpressing EGFR and HER2.

Keywords:

NSCLC, EGFR, HER2, bispecific antibody, acquired gefitinib-resistance, HECrossMAb

Affiliation:

Institutes of Physical Science and Information Technology, Anhui University, Hefei, Institutes of Physical Science and Information Technology, Anhui University, Hefei, Institutes of Physical Science and Information Technology, Anhui University, Hefei, Institutes of Physical Science and Information Technology, Anhui University, Hefei, Institutes of Physical Science and Information Technology, Anhui University, Hefei, Institutes of Physical Science and Information Technology, Anhui University, Hefei



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