title: 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-1β-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-1β 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.
authors.affiliation: MediaPharma s.r.l., Chieti, Italy. g.sala@unich.it
authors.forename: G
authors.initials: G
authors.lastname: Sala
authors.forename: S
authors.initials: S
authors.lastname: Traini
authors.forename: M
authors.initials: M
authors.lastname: D'Egidio
authors.forename: G
authors.initials: G
authors.lastname: Vianale
authors.forename: C
authors.initials: C
authors.lastname: Rossi
authors.forename: E
authors.initials: E
authors.lastname: Piccolo
authors.forename: R
authors.initials: R
authors.lastname: Lattanzio
authors.forename: M
authors.initials: M
authors.lastname: Piantelli
authors.forename: N
authors.initials: N
authors.lastname: Tinari
authors.forename: P G
authors.initials: PG
authors.lastname: Natali
authors.forename: R
authors.initials: R
authors.lastname: Muraro
authors.forename: S
authors.initials: S
authors.lastname: Iacobelli
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D055503:Protein Multimerization; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D008024:Ligands; D020893:Receptor, ErbB-3; D051057:Proto-Oncogene Proteins c-akt