Neuregulin receptor-mediated gene transfer by human epidermal growth factor receptor 2-targeted antibodies and neuregulin-1

Abstract

The human epidermal growth factor receptors 2, 3, and 4 (HER2, HER3, and HER4, respectively) are frequently overexpressed in many human cancers, and therefore may be potential targets for receptor-mediated gene transfer. To evaluate this possibility, we constructed a series of HER-targeted gene transfer vehicles by covalently linking poly-L-lysine polymers (pLYS) to the epidermal growth factor-like domain of the HER ligand neuregulin-1 (NRG1 177-244 ), a HER2 antibody (Ab), and the Fab fragment of the HER2 Ab. In vitro, pLYS modification of NRG1 177-244 decreased the affinity of the ligand for HER3 or HER4 homodimer receptors by 6-to 7-fold. DNA loading of the pLYS-modified NRG1 177-244 had a minimal additional affect on the affinity of the complex for its receptor. In cell lines engineered to solely express HER2, HER3, or HER4, each vehicle correctly targeted the receptors; the NRG1 177-244 construct transferred a luciferase gene only into cells expressing HER4, whereas the HER2 Ab and Fab constructs transferred the reporter gene only into cells expressing HER2. The most efficient gene transfer occurred using the intact HER2 Ab as a gene transfer vehicle, whereas the Fab fragment of the HER2 Ab was the least efficient, and NRG1 177-244 was intermediate. These studies suggest that the NRG receptor or HER2, a component of the receptor, can be pursued as targets for gene transfer.Key words: Gene transfer; neuregulin-1; human epidermal growth factor receptor 2; human epidermal growth factor receptor 3; human epidermal growth factor receptor 4.

Autocrine activation of ErbB2/ErbB3 receptor complex by NRG-1 in non-small cell lung cancer cell lines

“…In addition, we have previously reported that ErbB2 is over-expressed in human lung cancers [11], that this over-expression is associated with poor prognosis [12,15], and that targeting this receptor may have therapeutic potential [14,17]. Immunohistochemical analyses of fetal lung tissue localized ErbB2 expression and its associated receptor ErbB3 to the pulmonary epithelium [16].…”