Epidermal growth factor receptor (EGFR) and Hepatocyte growth factor receptor (HGFR/c-Met) (EGFR/c-Met)

The target of AZD9592 is a dual-antigen complex comprising the Epidermal Growth Factor Receptor (EGFR) and the Hepatocyte Growth Factor Receptor (HGFR, commonly known as c-Met) [4, 6]. Both proteins are members of the receptor tyrosine kinase (RTK) family and are pivotal in regulating cellular processes such as growth, survival, and differentiation through the activation of downstream signaling pathways like MAPK and PI3K/Akt [4, 5]. In various malignancies, including non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), these receptors are frequently overexpressed or mutated, often co-occurring to drive tumor progression and mediate resistance to standard-of-care therapies like EGFR tyrosine kinase inhibitors (TKIs) [1, 5]. AZD9592 is a first-in-class bispecific antibody-drug conjugate (ADC) designed to simultaneously engage both EGFR and c-Met on the tumor cell surface [2, 6]. This bispecific approach facilitates efficient internalization of the ADC and subsequent release of a potent topoisomerase 1 inhibitor (TOP1i) payload, which induces lethal DNA double-strand breaks [4, 7]. Notably, AZD9592 is engineered with a significantly higher affinity for c-Met than for EGFR to enhance tumor specificity and mitigate the dose-limiting toxicities typically associated with systemic EGFR inhibition in healthy tissues [2, 5, 8].

Other names

EGFRc-MetMETHGFRErbB-1HER1Mesenchymal-epithelial transition factorEpidermal growth factor receptorHepatocyte growth factor receptor

AZD9592 is a bispecific antibody-drug conjugate (ADC) that simultaneously binds to the extracellular domains of EGFR and c-Met on the surface of tumor cells [4]. Upon binding, the ADC is internalized via receptor-mediated endocytosis [2]. Once inside the cell, the cleavable linker is processed, releasing a potent topoisomerase 1 inhibitor (TOP1i) payload [6]. This payload stabilizes DNA-topoisomerase I complexes, leading to irreversible DNA double-strand breaks, cell cycle arrest, and apoptosis [4, 7]. The bispecific design, with a higher affinity for c-Met, is intended to enhance tumor specificity and reduce EGFR-mediated toxicities in healthy tissues [5].