Targeting ERBB3 Signaling: The Efficacy of AV-203 in Cancer Therapy

ERBB3, a member of the EGFR receptor tyrosine kinase family, is crucial in the development of various cancers and is associated with poor outcomes. It plays a significant role in HER2-mediated cancers and contributes to tumor progression and resistance to existing treatments. The receptor is found in numerous cancer types and is linked to resistance to therapies like receptor-targeted tyrosine kinase inhibitors. ERBB3 requires interaction with other RTKs for activation, which can be triggered by overexpression, gene amplification, or ligand stimulation such as NRG1 or EGF.

A humanized antibody, AV-203, has been developed to target the ERBB3 RTK. It shows high affinity binding to human ERBB3, with rapid association and slow dissociation. The antibody does not bind to mouse ERBB3, but does to cynomolgus monkey ERBB3, facilitating its toxicological evaluation. AV-203 effectively inhibits ERBB3 activation and the AKT signaling pathway in response to both NRG1 and EGF. It can suppress the steady-state activation of ERBB3/AKT in the presence of overexpressed RTKs like HER2.

The antibody prevents the formation of the ERBB3/HER2 heterodimer and inhibits proliferation in breast cancer cells stimulated by NRG1. It also downregulates the ERBB3 receptor both in vitro and in vivo and has shown to inhibit tumor growth in xenograft models with activated ERBB3 by NRG1 or HER2 overexpression. The first human trial for AV-203 is scheduled for 2012.

The study abstract was presented at the 103rd Annual Meeting of the American Association for Cancer Research and published in Cancer Research journal.