Enhanced Tumor Suppression and Resistance Overcoming with the Bispecific Antibody LY3164530 Targeting MET and EGFR

The epidermal growth factor receptor (EGFR) and the mesenchymal-epithelial transition factor (MET) are both receptor tyrosine kinases that play significant roles in cancer signaling pathways. They are often co-expressed and activated in various tumor types such as non-small cell lung cancer (NSCLC), colorectal, gastric, and head and neck cancers. The interplay between MET and EGFR can lead to resistance to single-agent therapies, as blocking one can result in the up-regulation of the other.

To address this challenge, the bispecific antibody LY3164530 has been developed. This engineered antibody consists of an immunoglobulin G4 (IgG4) linked to a single-chain variable fragment (scFv) that targets both MET and EGFR. It binds with high affinity to the extracellular domains of both receptors, inhibiting their signaling pathways by preventing ligand binding and promoting the internalization and degradation of the receptors.

In tumor cells, LY3164530 effectively binds and co-immunoprecipitates MET and EGFR. It shows increased avidity for MET in cells with higher EGFR levels, leading to improved neutralization of hepatocyte growth factor (HGF). Notably, LY3164530 has demonstrated superior activity in internalizing and degrading both wild type and mutant forms of EGFR compared to combinations of other antibodies.

Furthermore, LY3164530 has shown enhanced efficacy in overcoming HGF-mediated resistance to various EGFR inhibitors in cell-based assays. In vivo studies have revealed dose-dependent antitumor activity in NSCLC and gastric xenografts, with the bispecific antibody demonstrating equivalent or superior antitumor effects compared to the combination of emibetuzumab and cetuximab.

The ongoing Phase 1 study of LY3164530 (NCT02221882) indicates its potential as a novel therapeutic approach for MET- and EGFR-positive cancers, offering a promising strategy to improve patient outcomes and overcome resistance mechanisms associated with single-agent treatments.