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.
How to Use Synapse Database to Search and Analyze Translational Medicine Data?
The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

Click on the image below to go directly to the Translational Medicine search interface.
