Abstract 2077A: MM141, a novel bispecific antibody co-inhibitor of IGF-1R and ErbB3, inhibits the proliferation of melanoma cells.

Abstract

Identification of druggable targets along with new therapies in metastatic melanoma is a main concern given the bad prognosis of this disease in the metastatic setting. The development of targeted therapies for cancer has fundamentally changed the ways in which we develop new drugs, select therapy for patients, design and conduct clinical trials and assess treatment outcomes. The problems can be most effectively attacked by an integrated approach that leads from discovery through preclinical and clinical development. Our therapeutic focus is the development of targeted therapeutics and associated predictive biomarkers that can be used to treat melanoma. Here we present data indicating that the IGF-1R and ErbB3 growth factor pathways are co-active in preclinical models of melanoma and propose that MM-141, a novel bispecific antibody co-inhibitor of IGF-1R and ErbB3, has the potential to provide therapeutic benefit to melanoma patients. Our approach is based on a set of 48 melanoma cell lines that have already been extensively characterized both in terms of genetic background and pharmacologic response. We have quantitatively measured basal expression and activation of 40 total and phospho receptor tyrosine kinases expressed by melanoma cell lines. This characterization was placed in the context of the genetic and pharmacologic data that has already been generated in order to develop pathophysiological hypotheses and points of intervention in melanoma. We have also determined anti-proliferative response and mechanism of action for the MM-141 activity in this cell line panel. Proteomic data analyses showed that melanoma cells have lower basal phospho-protein levels relative to other solid tumor cell line panels. The data showed that EGFR and ErbB2 were not overexpressed. ErbB3 and IGF-1R were the most widely expressed RTKs on melanoma cells, and c-MET and FGFR1 were also prevalent. Genomic and proteomic analyses indicated that ErbB3 and IGF-1R mRNA and protein expression were positively correlated. Upon this preliminary analysis of the data we have tested the activity of MM-141 on 48 human melanoma cell lines with well-established genotypes. Taking 15% growth inhibition as a cutoff for response in cell-based assays after 100μg/ml (500nM) MM-141 treatment, 24 out of 48 cell lines resulted in inhibition of cell proliferation 5 days post-treatment. The anti-proliferative response to MM-141 was independent of genotype. We chose 6 cell lines, 3 from the responder population and 3 from the non-responder population to further investigate the mechanism of action of MM-141. No evidence of apoptosis was found after 5 days of MM-141 treatment. All the sensitive cell lines showed a G0/G1 cell cycle arrest in response to MM-141. These combined data provide the rationale for further preclinical and clinical evaluation of MM-141 as a melanoma therapeutic. Citation Format: Erika M. Von Euw, Emily Pace, Karina Covarrubias, Abhi Jairam, Diana Chai, Veerauo Konkankit, Ke-Wei Gong, Bryan Johnson, Birgit Schoeberl, Alexey Lugovskoy, Finn Richard, Dennis Slamon. MM141, a novel bispecific antibody co-inhibitor of IGF-1R and ErbB3, inhibits the proliferation of melanoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2077A. doi:10.1158/1538-7445.AM2013-2077A

Regulation of ERBB3/HER3 signaling in cancer

“…Furthermore, MM-141 has been proven to inhibit pancreatic tumor cell growth and potentiate of effect of gemcitabine in various preclinical models [ 144 ]. In addition, MM-141 has exerted its anti-proliferative activity against melanoma [ 145 ], and this antibody has also attenuated tumor growth and potentiated the activity of mTOR inhibitor everolimus in mouse models of anti-hormone therapy-resistant ER/PR + breast cancer [ 146 ]. Furthermore, previous studies with MM-141 have shown the ablation of HER3 signaling results in the inhibition of PI3K/AKT dependent mammary carcinogenesis and ERK1/2 phosphorylation in pre-neoplastic HER2 overexpressing mammary glands and tumors [ 91 , 147 ].…”