Harnessing the Power of REGN1400: Targeting ERBB3 to Combat Tumor Growth in Preclinical Studies

ERBB3 is a receptor tyrosine kinase that, along with EGFR and HER2, plays a significant role in cancer development. Preclinical research has shown that EGFR and HER2 work in tandem with ERBB3 to trigger the phosphatidylinositol-3 kinase/Akt pathway, which is crucial for tumor cell survival. ERBB3's activation has been linked to resistance against EGFR and HER2 inhibitors in lung and breast cancer cells, respectively. Studies have also shown that anti-ERBB3 monoclonal antibodies can hinder the growth of human tumor xenografts, emphasizing the role of ERBB3 in tumor growth.

REGN1400 is a fully human monoclonal antibody that strongly binds to ERBB3 and inhibits the binding of its ligand, neuregulin 1. It has been demonstrated to reduce the phosphorylation of ERBB3 and Akt in various human tumor cell lines such as A431, MDA-MB-175-VII, and FaDu. REGN1400 has also shown a robust inhibitory effect on the growth of these cell lines in vitro. In vivo studies have confirmed that REGN1400 can significantly suppress the growth of A431 and FaDu tumor xenografts in a dose-dependent manner, with tumor growth inhibition rates of 70% and 97%, respectively.

The antibody's efficacy was further highlighted by its ability to significantly reduce tumor ERBB3 phosphorylation in FaDu tumors, as confirmed by western blot and immunohistochemistry. While REGN1400 as a single agent nearly completely inhibited tumor growth, it did not induce tumor regression. However, when combined with an anti-EGFR antibody, it led to significant tumor regression. Similarly, the combination of REGN1400 with the anti-HER2 antibody trastuzumab showed a more potent inhibitory effect on BT474 breast tumor xenografts than either single agent.

These results suggest that therapies targeting ERBB3 might be more effective when used in combination with treatments that inhibit other members of the ERBB family. Additionally, gene profiling studies on REGN1400-treated tumor cells have identified several genes that could potentially promote resistance to REGN1400, such as ERBB3 and ERBB4. Further investigation into the gene expression changes induced by REGN1400 may lead to the development of effective combination therapies.

In conclusion, REGN1400 has shown significant antitumor activity in preclinical models, indicating its potential to benefit patients with various types of cancer, either as a standalone treatment or in combination with other ERBB-targeting therapies.