Zenocutuzumab

Neuregulin 1 (NRG1) is a growth factor characterized by an epidermal growth factor (EGF)-like domain, which facilitates binding with various protein kinases, including receptor tyrosine-protein kinase erbB-2 (ERBB2/HER2) and ERBB3 (HER3). These interactions lead to heterodimerization or oligomerization with other ERBB family members, activating downstream signaling pathways that drive cell growth. Notably, the HER2–HER3 dimer is regarded as the most oncogenic heterodimer within the ERBB family. NRG1 gene fusions act as oncogenic drivers and have been linked to cancers such as non-small-cell lung cancer (NSCLC) and pancreatic cancer. These fusions result in structural DNA alterations and deregulated cell proliferation.

Zenocutuzumab is a bispecific antibody with two different Fab arms that each binds to the extracellular domains of HER2 and HER3 expressed on the surface of cells, including tumour cells. Zenocutuzumab binds to the most abundantly expressed HER2 to inhibit HER2:HER3 dimerization and prevents NRG1 binding to HER3. Zenocutuzumab decreases cell proliferation and signalling through the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway. In addition, zenocutuzumab mediates antibody-dependent cellular cytotoxicity (ADCC).