P329G-mutated Fc region of human IgG1 (P329G Fc)

The P329G-mutated Fc region of human IgG1 is an engineered antibody domain designed to eliminate immunological effector functions while maintaining a long circulatory half-life. This modification involves a proline-to-glycine substitution at position 329 (EU numbering), which disrupts the 'proline sandwich' motif essential for the Fc region's interaction with Fc-gamma receptors (FcγRs) and the complement protein C1q (Schlothauer et al., 2016). By preventing these interactions, the P329G mutation effectively 'silences' the antibody, abolishing activities such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). This is particularly critical for bispecific antibodies and T-cell engagers, where unintended Fc-mediated activation of immune cells could lead to systemic toxicity or cytokine release syndrome (Labrijn et al., 2019). Importantly, the P329G mutation does not significantly impair binding to the neonatal Fc receptor (FcRn), allowing the therapeutic to retain the extended half-life typical of standard IgG1 antibodies (Klein et al., 2016). This technology is a key feature of several approved and investigational therapies, including glofitamab for lymphoma and faricimab for retinal diseases (FDA, 2023).

Other names

P329G mutationEffector-silent FcLALA-PG FcRoche Fc-silencing technologyPG mutation

The P329G mutation disrupts the binding of the IgG1 Fc region to Fc-gamma receptors and C1q, thereby preventing effector-mediated cell lysis and inflammation.