An ErbB-3 antibody, MP-RM-1, inhibits tumor growth by blocking ligand-dependent and independent activation of ErbB-3/Akt signaling

Abstract

The ErbB receptors, such as ErbB-1 and ErbB-2, have been intensely pursued as targets for cancer therapeutics. Although initially efficacious in a subset of patients, drugs targeting these receptors led invariably to resistance, which is often associated with reactivation of the ErbB-3-PI3K-Akt signaling. This may be overcome by an ErbB-3 ligand that abrogates receptor-mediated signaling. Toward this end, we have generated a mouse monoclonal antibody, MP-RM-1, against the extracellular domain (ECD) of ErbB-3 receptor. Assessment of human tumor cell lines, as well as early passage tumor cells revealed that MP-RM-1 effectively inhibited both NRG-1b-dependent and -independent ErbB-3 activation. The antagonizing effect of MP-RM-1 was of non-competitive type, as binding of [ 125 I]-labeled NRG-1b to ErbB-3 was not influenced by the antibody. MP-RM-1 treatment led, in most instances, to decreased ErbB-3 expression. In addition, MP-RM-1 was able to inhibit the colony formation ability of tumor cells and tumor growth in two human tumor xenograft nude mouse models. Treatment with the antibody was associated with a decreased ErbB-3 and Akt phosphorylation and ErbB-3 expression in the excised tumor tissue. Collectively, these results indicate that MP-RM-1 has the potential to interfere with signaling by ErbB-3 and reinforce the notion that ErbB-3 could be a key target in cancer-drug design.

The anti-HER3 (ErbB3) therapeutic antibody 9F7-F11 induces HER3 ubiquitination and degradation in tumors through JNK1/2- dependent ITCH/AIP4 activation

“…Targeting EGFR or HER2 by antibody-mediated ubiquitination and degradation [24, 25, 27–29, 51] is one attractive way to improve therapeutic benefit in patients. Such mechanism has been also proposed for antibodies against HER3 [15, 50, 52, 53] or IGFR1 [54]. Pre-clinical studies using anti-HER3 antibodies clearly identified receptor degradation as a marker of drug efficacy [55].…”

Targeting of erbB3 receptor to overcome resistance in cancer treatment

“…It also significantly decreases colony formation in pancreatic cancer cells and tumor growth in pancreatic cancer, NSCLC, and colorectal cancer xenograft models [17]. Recently, a new anti-erbB3 Ab (MP-RM-1) and its humanized version (named EV20) both have been shown to exhibit antitumor activity against various cancer types in vitro and in vivo [93,94]. Because this Ab has the ability to inhibit both ligand-dependent and -independent activation of erbB3 [93,94], we speculate that EV20 may have a much broader effect on blocking erbB3 signaling than those Abs (like MM-121) which only prevent ligand-induced activation of erbB3, and thus exert more potent activity to overcome drug resistance in cancer therapy.…”

Carnosine derivatives: new multifunctional drug-like molecules

“…In the context of neurodegenerative disorders, L-Car has been suggested as an inhibitor of Ab toxicity in vitro (Preston et al 1998). Moreover, it has been reported that carnosine has a strong effect in restoring mitochondrial functioning and in counteracting amyloid pathology in triple-transgenic Alzheimer's disease model mice (Corona et al 2011). Very recently, a proteomic approach revealed that L-Car affects tumor cell growth by causing an interference with protein folding/processing and HIF-1a signaling in gliobastomas (Asperger et al 2011).…”