Immunoglobulin G1 Fc region (P329G mutation) (P329G Fc)

The P329G mutated Fc region is an engineered variant of the human IgG1 constant domain designed to eliminate immune effector functions. In native IgG1, the proline residue at position 329 is critical for forming a 'proline sandwich' that facilitates binding to Fc-gamma receptors (FcγRs) and the complement protein C1q (Schlothauer et al., 2016). By substituting this proline with glycine, the binding affinity to all FcγRs and C1q is significantly reduced or abolished, preventing induction of ADCC, ADCP, and CDC (Lo et al., 2017). This modification is frequently employed in the development of bispecific antibodies and agonist antibodies where target cell killing is undesirable or where systemic cytokine release must be minimized. For example, in T-cell engaging bispecifics like glofitamab, an effector-silent Fc region prevents the non-specific cross-linking of T-cells and FcγR-expressing cells (Roche, 2023). While the mutation silences effector functions, it is designed to maintain structural stability and neonatal Fc receptor (FcRn) binding to preserve a standard monoclonal antibody half-life.

Other names

P329G mutationEffector-silent FcLALA-PGPG mutationFc-gamma receptor binding-deficient Fc

The P329G mutation disrupts the 'proline sandwich' motif in the CH2 domain of the IgG1 Fc region, which is essential for binding to Fc-gamma receptors and the C1q component of the complement system, thereby eliminating immune effector functions.