Margetuximab

The HER family of transmembrane receptor tyrosine kinases (RTKs) includes the epidermal growth factor receptor (EGFR/HER1), HER2, HER3, and HER4 proteins; HER family members are generally involved in cell proliferation, angiogenesis, cell motility and invasiveness, and resistance to apoptosis. HER2 is an oncoprotein whose overexpression is observed in breast, gastric, and other cancers. HER2 undergoes both ligand-independent homodimerization and ligand-dependent heterodimerization with other HER family members, followed by RTK phosphorylation and induction of downstream oncogenic signalling pathways. EGFR/HER2 dimerization promotes EGFR recycling and prolonged signalling while HER2/HER3 dimerization potently stimulates the downstream PI3K/AKT pathway; HER2 homodimerization directly activates the RAS/MAPK pathway and indirectly activates the PI3K/AKT pathway.

The prototypical anti-HER2 therapy is trastuzumab, a monoclonal antibody (mAb) that binds the HER2 extracellular domain. Trastuzumab works through several mechanisms: trastuzumab binding induces receptor internalization and c-CBL-mediated HER2 degradation; effector cell binding to the Fc region of trastuzumab through CD16A results in antibody-mediated cell-dependent cytotoxicity (ADCC); finally, trastuzumab binding dampens HER2 activation, phosphorylation, and subsequent downstream oncogenic signalling.

Despite demonstrated clinical efficacy, trastuzumab efficacy is dependent on polymorphisms in CD16A. Effector cells such as natural killer (NK) cells and macrophages bind to mAbs through Fc receptors such as CD16A (FcγRIIIA), CD32A (FcγRIIA), and the inhibitory CD32B (FcγRIIB). CD16A has both high affinity (with valine at position 158; 158V) and low affinity (158F) variants; patients heterozygous or homozygous for the 158F variant have poorer responses to trastuzumab. Margetuximab is derived from the same mouse 4D5 clone as trastuzumab, but with a modified (MGFc0264) Fc region encoding five amino acid substitutions (L235V, F243L, R292P, Y300L, and P396L) to alter Fc receptor binding. Comparatively, margetuximab exhibits increased binding to both the high affinity (KD of 89 nM vs 415 nM) and low affinity (KD of 161 nM vs 1059 nM) CD16A receptors and decreased binding to the inhibitory CD32B receptor (KD of 437 nM vs 52 nM). This, in turn, increases ADCC and anti-tumour effect, especially in cells expressing lower levels of HER2 and in patients with the lower affinity 158F CD16A variant.