Amivantamab 2.24g/14ml solution for injection vials

Mesenchymal-epithelial transition factor (MET) is a receptor with tyrosine kinase activity expressed on epithelial cells that, upon signalling, dimerizes and activates downstream pathways that signal cell division.[A235103][A235128] The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase activity that can further activate downstream pathways that signal cell division, survival, and angiogenesis.[A235103][A235128] Patients with NSCLC with exon 20 insertion mutations in EGFR do not respond to tyrosine kinase inhibitors, and are generally treated with platinum-based therapy.[A235133] Exon 20 insertion mutations in EGFR also lead to conformational changes that activate EGFR.[A235138]

Amivantamab targets both EGFR and MET, preventing ligands from binding to the receptors, blocking signalling, marking the cancerous cells for antibody-dependant cellular cytotoxicity by natural killer cells, and allowing macrophages to perform trogocytosis.[L34193]

Amivantamab's binding to the EGFR H epitope shares some of the same amino acids that [cetuximab] binds to.[A235103]

Amivantamab's binding to the alpha chain of MET stabilizes the Sema domain loop 1 to 2 in a position 6 Angstroms away from the position it would be in under normal binding, preventing its interaction with the hepatocyte growth factor's (HGF) beta chain.[A235103] Another smaller conformational change in the MET Sema domain loop 1 to 3 also contributes to preventing the interaction of the MET Sema domain with HGF's beta chain.[A235103] HGF is no longer able to bind to MET, preventing downstream signalling.[A235103]

Amivantamab's Fc portion contains 90% less fucose than normal antibodies, allowing for increased binding to the FcγRIIIa region.[A235128] Binding of the Fc portion of Amivantamab signals the complement system and innate immune system to target the bound cells for complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis.[A235128] Binding of amivantamab to the Fc receptor also leads to and increase in levels of IFNγ.[A235138]

Amivantamab also significantly downregulates the expression of EGFR and MET on NSCLC cell surfaces, further reducing downstream signalling.[A235138][A235108] EGFR and MET on the cell surface are internalized, and possibly degrading by fusing endosomes with lysosomes.[A235138] Alternatively, EGFR and MET are the subjects of monocyte-dependent trogocytosis.[A235108] Trogocytosis allows monocytes to internalize and break down EGFR and MET from the NSCLC cells without cytotoxicity, downmodulating EGFR and MET receptors.[A235108]