Four-in-One Antibodies Have Superior Cancer Inhibitory Activity against EGFR, HER2, HER3, and VEGF through Disruption of HER/MET Crosstalk

Abstract

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. Cancer Res; 75(1); 159-70. Ó2014 AACR.

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

“…Recently, there are a few reports, in which targeting the HER family receptors, rather than any one receptor, in various cancers corroborated with our data. The four-in-one antibody FL518 as potent inhibitors of EGFR, HER2, HER3, and VEGF inhibited their receptor phosphorylation and had superior antitumor activity in colorectal, breast or gastric cancer (43). Pre-clinical data suggested that inhibition of EGFR, HER2, and HER3 by combined treatment with lapatinib, trastuzumab and U3-1287 showed maximum effect in trastuzumab-resistant HER2-overexpressing breast cancer ( Figure 5A).…”

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

“…Another tactic is preventing cross-talk between multiple growth factor receptors (GFRs). For example, two new tetra-specific antibodies recognizing EGFR, HER2, HER3, and VEGF inhibited multiple receptor signaling both in vitro and in vivo [112]. Additionally, cross-talk between HER and MET pathways was disrupted with higher efficacy than bispecific antibodies in multiple tumor models.…”

Design and Validation of a Novel Generic Platform for the Production of Tetravalent IgG1-like Bispecific Antibodies

“…These IgG-like bispecific platforms can be either generic, applicable to any couple of Abs, or nongeneric platforms. The latter requires a two-in-one approach [i.e., selection of the binding sites that recognize two different epitopes with a high affinity (14)(15)(16)], and thus, few of these nongeneric platforms have actually been used. Among generic platforms, some approaches combine the production of recombinant Ab-derived moieties fused to specific interacting domains such as the dock-and-lock technology (17) or the Fab-arm exchange (18).…”