Inetetamab, a novel anti-HER2 monoclonal antibody, exhibits potent synergistic anticancer effects with cisplatin by inducing pyroptosis in lung adenocarcinoma

Abstract

Cisplatin is a first-line chemotherapy drug for lung adenocarcinoma (LUAD). However, its therapeutic efficacy is limited because of serious side effects and acquired drug resistance. Targeting HER2 has been proven to be a viable therapeutic strategy against LUAD. Moreover, inetetamab, an innovative anti-HER2 monoclonal antibody, has a more potent antibody-dependent cell-mediated cytotoxicity (ADCC)-inducing effect than trastuzumab, which has been shown to be an effective and rational strategy in the clinic when combined with multiple chemotherapeutic agents. Thus, the present study aimed to explore the synergistic effects of cisplatin (DDP) and inetetamab in LUAD cells and investigate the detailed underlying mechanisms. Here, in vitro and in vivo , we found that the combination of inetetamab and cisplatin induced synergistic effects, including induction of pyroptosis, in LUAD. Mechanistic studies revealed that inetetamab combined with cisplatin inhibited HER2/AKT/Nrf2 signaling to increase ROS levels, which triggered NLRP3/caspase-1/GSDMB-mediated pyroptosis to synergistically enhance antitumor efficacy in LUAD cells. In addition, cisplatin enhanced the PBMC-killing ability of inetetamab by inducing GSDMB-mediated pyroptosis, which can be explained by increased secretion of IFN-γ. Our study reveals that the anti-HER2 monoclonal antibody inetetamab may be an attractive candidate for LUAD therapy, which opens new avenues for therapeutic interventions for LUAD.

Phase 1b trial of anti‐HER2 antibody inetetamab and pan‐HER inhibitor pyrotinib in HER2‐positive advanced lung cancer

“…Pyrotinib covalently binds to the ATP binding site of the intracellular kinase domain of HER1, HER2, and HER4 10 . Inetetamab is an anti‐HER2 monoclonal antibody binding to domain IV of HER2 receptor 19 . The addition of inetetamab may exert more potent inhibition of HER2 signaling pathway via dual HER2 blockade.…”

“… 10 Inetetamab is an anti‐HER2 monoclonal antibody binding to domain IV of HER2 receptor. 19 The addition of inetetamab may exert more potent inhibition of HER2 signaling pathway via dual HER2 blockade. Besides, inetetamab, an analog of trastuzumab, was more capable of stimulating antibody‐dependent cell‐mediated cytotoxicity (ADCC) effect with a modified Fc segment.…”

“…Combined with positive findings of studies in breast cancer, dual HER2‐targeted therapy might be a promising strategy to further improve the effect of pyrotinib on lung cancer. Inetetamab, a humanized, recombinant anti‐HER2 monoclonal antibody, binds domain IV of HER2 receptor 19 . Based on the manageable toxicity and antitumor effects shown in clinical trials, inetetamab in combination with vinorelbine has been approved for HER2‐positive metastatic breast cancer by National Medical Products Administration (NMPA) in China 20,21 .…”

“…Inetetamab, a humanized, recombinant anti‐HER2 monoclonal antibody, binds domain IV of HER2 receptor. 19 Based on the manageable toxicity and antitumor effects shown in clinical trials, inetetamab in combination with vinorelbine has been approved for HER2‐positive metastatic breast cancer by National Medical Products Administration (NMPA) in China. 20 , 21 Accumulating studies have investigated the effect of inetetamab combined with pan‐HER TKIs.…”

Promotion of stem cell-like phenotype of lung adenocarcinoma by FAM83A via stabilization of ErbB2

“…Our data indicate that the inhibition of CSC-like phenotypes by FAM83A knockdown is rescued by ErbB2 overexpression. The latest report indicated that patients with ErbB2-amplified LUAD exhibit better immunogenicity and an inflamed time among ErbB2-aberrant tumors [ 40 ]. However, the underlying mechanism of ErbB2 amplification in LUAD remains unclear.…”