Abstract A144: Therapeutically targeting high-affinity ligand activation of EGFR with MM-151, an oligoclonal therapeutic.
Authors: Werner Shannon L. , Tan Gege , Kearns Jeffrey D. , King Anne M. , Sloss Callum , Gerami-Moayed Nastaran , Bukhalid Raghida , Nielsen Ulrik B. 
Published: June 2012

The Epidermal Growth Factor Receptor (EGFR/ErbB1) is a receptor tyrosine kinase whose activation has been shown to play a key role in tumor growth and development. The EGFR ligand family is comprised of seven transmembrane precursor proteins whose expression and processing is highly regulated. These ligands can be classified based upon their affinity to EGFR; epidermal growth factor (EGF), betacellulin (BTC), heparin-binding epidermal growth factor (HB-EGF), and transforming growth factor alpha (TGFα) are considered high-affinity ligands, whereas amphiregulin (AREG), epiregulin (EREG), and epigen (EPI) are considered low-affinity ligands. EGFR overexpression in tumors is associated with higher risk of recurrence, metastasis, poorer survival and resistance to chemotherapy. Therefore, this pathway is a compelling target for the development of anti-EGFR therapeutics.

Using Merrimack's Network Biology approach, we performed a computational systems analysis to identify an optimal strategy to inhibit the EGFR-ERK signaling network, which is characterized by robust signal amplification from the receptor to downstream effectors. As a result, we developed MM-151, an oligoclonal therapeutic composed of three fully human monoclonal antibodies targeted to distinct EGFR epitopes. MM-151 inhibits EGFR pathway activation by the dual mechanism of EGFR ligand-blocking and enhancement of receptor downregulation.

Our preclinical in vitro studies revealed greater potency for MM-151 versus existing monoclonal antibodies (e.g. cetuximab, panitumumab and nimotuzumab). Importantly, MM-151 was shown to inhibit in vitro ERK signaling and cell proliferation induced by both high- and low-affinity EGFR ligands, unlike existing monoclonal therapeutics, which only block low-affinity ligand-induced signaling and cell proliferation. In in vitro cell proliferation assays, several cell line models that were responsive to anti-EGFR monoclonals in the presence of the low-affinity ligand AREG became increasingly unresponsive to treatment upon titrating in increasing amounts of the high-affinity ligand EGF. Conversely, cells remained responsive to MM-151 even in the presence of high-affinity EGF ligand burden. In preclinical non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) EGFR-wildtype cell line models, overexpression of autocrine AREG is positively correlated with increased sensitivity to the anti-EGFR monoclonal cetuximab or tyrosine kinase inhibitor gefitinib (K. Yonesaka et al., Clin. Cancer Res., 2008, 14: 6963–6973). In the clinic, metastatic colon cancer patients with wild type K-ras tumors highly expressing the low-affinity ligands AREG and EREG are more likely to exhibit disease control on cetuximab treatment (J. B. Baker et al., Br. J. Cancer, 2011, 104: 488–495). Our preclinical data suggest that elevated high-affinity ligand expression would likely correlate with decreased patient response to anti-EGFR monoclonals, and that patients whose tumors are driven by high-affinity EGFR ligands might instead benefit from MM-151 treatment. Together, these data suggest that MM-151, capable of blocking both high and low affinity ligand-driven EGFR signaling, may have the potential to more broadly benefit lung and colon cancer patients as compared to existing EGFR-directed therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A144.