ABSTRACT
Dysfunction of the epidermal growth factor receptor (EGFR) family, is the key process in tumorigenesis, and anti-EGFR therapeutic strategies such as cetuximab therapy now are used in the treatment of cancer. However, resistance to cetuximab is commonly reported. Comprehensive blockade of EGFR signaling using different antibodies might be critical to treat cancer effectively and limit drug resistance with potent novel mechanisms. Here, we launch a screen of a phage display library to isolate a novel anti-EGFR antibody, YAH627. YAH627 exhibits superior efficacy in inhibiting EGFR activation, particularly by blocking EGF/HRG-induced EGFR/HER3 heterodimerization and signaling, verifying it as an impressive candidate for clinical translation as a therapeutic antibody. Moreover, we use epitope analysis validates that the epitope of this antibody is within domains II and IV of EGFR and traps EGFR in a silent conformation. Moreover, combining YAH627 with cetuximab produces synergistic antitumor activity in vitro and in vivo. Taken together, our report establishes that YAH627 possesses a novel mechanism of action that, in combination with cetuximab, may achieve clinical efficacy in EGFR-driven cancers.
Subject(s)
Antibodies, Monoclonal/pharmacology , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/immunology , Neoplasms/drug therapy , Neoplasms/enzymology , Receptor, ErbB-3/antagonists & inhibitors , Animals , Antibodies, Monoclonal/immunology , Carcinogenesis , Cell Line, Tumor , Cell Proliferation/physiology , ErbB Receptors/metabolism , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Phosphorylation , Receptor, ErbB-3/metabolism , Signal Transduction/drug effects , Transfection , Xenograft Model Antitumor AssaysABSTRACT
The anti-HER receptor antibodies cetuximab, trastuzumab, and pertuzumab are used widely in clinic to treat metastatic cancer. However, activation of the extensive crosstalk among the HER receptors as well as other RTKs, particularly HER-MET crosstalk, has emerged as a likely source of drug resistance. In this study, we developed two new types of tetra-specific antibodies that recognize EGFR, HER2, HER3, and VEGF. These tetra-specific antibodies, termed FL518 (four-in-one antibody) and CRTB6 (tetra-specific, tetravalent antibody), not only inhibited signaling mediated by these receptors in vitro and in vivo but unexpectedly also disrupted HER-MET crosstalk. When compared with two-in-one antibodies and a series of bispecific antibodies in multiple tumor models, FL518 and CRTB6 were more broadly efficacious. We further showed that tetra-specific antibodies were far more effective than bispecific antibodies in inhibiting the growth of anti-HER-resistant cancer cells, which exhibited elevated levels of MET activation both in vitro and in vivo. Overall, our results establish a new principle to achieve combined HER inhibition and limit drug resistance using a single antibody.
