Anti-erbB-2 (Her-2/neu) (Margetuximab) (IVMB0478)

erbB-2 encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases¹. erbB-2 enhances kinase-mediated activation of downstream signaling pathways by forming a heterodimer with other ligand-bound EGF receptor family members. Dysregulation of erbB-2 contributes to tumorigenesis in breast, ovarian, gastric, and other cancers.

Margetuximab is a human/mouse chimeric anti-erbB-2 monoclonal IgG1 antibody derived from mouse clone 4D5, the precursor of trastuzumab². Margetuximab has an Fc domain (MGFc0264) engineered for increased binding to both alleles of human activating Fcγ receptor IIIA (CD16A) and for reduced binding to CD32B. Compared with WT Fc domain, the optimized MGFc0264 domain demonstrates increased affinity for both alleles of human CD16A as well as human C1q but decreased binding to human CD32B (inhibitory FcγR) and the 131R allele of CD32A (human activating FcγR). Binding to the 131H allele is not substantially modified. The optimized Fc domain also confers improved antibody-dependent cell cytotoxicity against erbB-2-positive tumor cells, including low ERBB2 expressors, independent of the FcγR variant for the effector cells.

The MGFc0264 Fc domain was generated by mutating five sites: L235V, F243L, R292P, Y300L, and P396L². The L235V mutation was inserted to reduce CD32B binding. The Fc domain modifications do not influence antigen recognition or anti-proliferative activity in the absence of effector cells.

In clinical trials, Margetuximab binds to erbB-2 with high affinity and produces direct growth suppression of erbB-2-expressing tumor cell lines³. Positive data from clinical trials led to US Food and Drug Administration approval for Margetuximab in the treatment of metastatic HER2-positive breast cancer in 2020⁴.