EV20, a Novel Anti-ErbB-3 Humanized Antibody, Promotes ErbB-3 Down-Regulation and Inhibits Tumor Growth In Vivo

Abstract

ErbB-3 (HER-3) receptor is involved in tumor progression and resistance to therapy. Development of specific inhibitors impairing the activity of ErbB-3 is an attractive tool for cancer therapeutics. MP-RM-1, a murine monoclonal antibody targeting human ErbB-3, has shown anticancer activity in preclinical models. With the aim to provide novel candidates for clinical use, we have successfully generated a humanized version of MP-RM-1. The humanized antibody, named EV20, abrogates both ligand-dependent and ligand-independent receptor signaling of several tumor cell types, strongly promotes ErbB-3 down-regulation, and efficiently and rapidly internalizes into tumor cells. Furthermore, treatment with EV20 significantly inhibits growth of xenografts originating from prostatic, ovarian, and pancreatic cancers as well as melanoma in nude mice. In conclusion, we provide a novel candidate for ErbB-3-targeted cancer therapy.

Dual targeting of ErbB-2/ErbB-3 results in enhanced antitumor activity in preclinical models of pancreatic cancer

“…Instead, the growth of HPAF-II and SW1990 xenografts was only reduced in animals treated with the combination of the two monoclonal antibodies. The results obtained with BxPC-3 xenograft are in accordance with previous reports, where single treatment with EV20 23 or trastuzumab 5 caused a significant restrain of tumor growth. Here, we show for the first time that dual targeting of ErbB-2 and ErbB-3 significantly delays tumor growth of xenografts originating from K-Ras-mutated HPAF-II and SW1990 cells.…”

“…Indeed, exposure of these cells to EV20 lead to receptor downregulation and inhibition of ligand-dependent and -independent ErbB-3/Akt phosphorylation. 23 Here, we show that EV20 in combination with trastuzumab produces a complete suppression of the NRG-1β-driven Akt induction and a marked inhibition of cell growth in vitro , (Figure 3). …”

“…We previously showed that EV20 markedly reduced the growth of several tumor xenografts, including those originating from pancreatic BxPC-3 cells. 23 Thus, we wondered whether the dual inhibition of ErbB-2/ErbB-3 by EV20 and trastuzumab combination could result in a potentiation of therapeutic activity in vivo . To this end, animals bearing xenografts originating from BxPC-3, HPAF-II and SW1990 cells were treated either with EV20, trastuzumab or their combination.…”

“…For ErbB-3 inhibition, we utilized EV20, a humanized antibody recently developed in our laboratory that proved to have an antitumor activity in different cancer models, including PC cells, by ligand-dependent and -independent ErbB-3/Akt inhibition. 22,23 To target ErbB-2, we used trastuzumab, a monoclonal antibody currently used for treatment of breast and gastric cancer. 24,25 …”

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

“…Notably, the antibody cannot displace HER3-bound NRG, yet able to decrease tumor growth in several animal models. 130,131 REGN1400 is a fully human IgG molecule directed to HER3 and able to inhibit NRG binding. 132 In combination with anti-EGFR antibodies, REGN1400 can synergistically promote regression of HNSCC (FaDu) and colorectal cancer (LIM1215) models in animals.…”