SAR256212 (MM-121) HER3 ErbB3 antibody

Targeting ErbB3

ErbB3 is a kinase-dead critical mediator of pro-survival signaling through PI3K/AKT activation and potentially through activation of other pathways involved in proliferation, differentiation, and survival of cancer cells.²⁰ Signaling is mediated by ErbB3 ligands such as heregulin (HRG) and epidermal growth factor receptor (EGFR) ligands like betacellulin (BTC).²¹ Signaling through ErbB3 is a major mechanism by which cancer cells acquire resistance to targeted therapies (including EGFR and HER2 inhibitors); chemotherapies; and, potentially, radiotherapy.<sup>20,21References:
20. Schoeberl et al. Cancer Res. 2010;70:2485-2494; 21. Schoeberlet al. Sci Signal. 2009;2:ra31;</sup>  

 

Clinical development

SAR256212 is being codeveloped with Merrimack Pharmaceuticals Inc. SAR256212 is currently being investigated in a phase I trial in patients with refractory advanced solid tumors; in a phase I/II trial, in combination with erlotinib, in patients with NSCLC; in a phase I trial in combination with the investigational agent SAR245408 in solid tumors; in a phase I trial in combination with cetuximab and irinotecan in solid tumors; and in a phase I trial in combination with multiple chemotherapeutic agents in solid tumors. SAR256212 is also being investigated in a phase II trial in ER/PR+ HER2- breast cancer patients in combination with exemestane. In combination with paclitaxel, SAR256212 is being studied in a phase II trial in ER/PR+ HER2- breast cancer and TNBC, and a phase II trial in platinum-resistant/refractory ovarian cancer.

ER=estrogen receptor; HER2=human epidermal growth factor receptor 2; PR=progesterone receptor; TNBC=triple negative breast cancer.

SAR256212 is an investigational agent and has not been approved by the FDA or any other regulatory agency worldwide for the uses under investigation

ErbB3 is a critical activator of phosphoinositide 3-kinase (PI3K) signaling in epidermal growth factor receptor (EGFR; ErbB1), ErbB2 [human epidermal growth factor receptor 2 (HER2)], and [hepatocyte growth factor receptor (MET)] addicted cancers, and reactivation of ErbB3 is a prominent method for cancers to become resistant to ErbB inhibitors. In this study, we evaluated the in vivo efficacy of a therapeutic anti-ErbB3 antibody, MM-121. We found that MM-121 effectively blocked ligand-dependent activation of ErbB3 induced by either EGFR, HER2, or MET. Assessment of several cancer cell lines revealed that MM-121 reduced basal ErbB3 phosphorylation most effectively in cancers possessing ligand-dependent activation of ErbB3. In those cancers, MM-121 treatment led to decreased ErbB3 phosphorylation and, in some instances, decreased ErbB3 expression. The efficacy of single-agent MM-121 was also examined in xenograft models. A machine learning algorithm found that MM-121 was most effective against xenografts with evidence of ligand-dependent activation of ErbB3. We subsequently investigated whether MM-121 treatment could abrogate resistance to anti-EGFR therapies by preventing reactivation of ErbB3. We observed that an EGFR mutant lung cancer cell line (HCC827), made resistant to gefitinib by exogenous heregulin, was resensitized by MM-121. In addition, we found that a de novo lung cancer mouse model induced by EGFR T790M-L858R rapidly became resistant to cetuximab. Resistance was associated with an increase in heregulin expression and ErbB3 activation. However, concomitant cetuximab treatment with MM-121 blocked reactivation of ErbB3 and resulted in a sustained and durable response. Thus, these results suggest that targeting ErbB3 with MM-121 can be an effective therapeutic strategy for cancers with ligand-dependent activation of ErbB3.

An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation.