Human immunoglobulin G1 Fc region (P329G mutant) (IgG1 Fc (P329G))

The P329G-mutated Fc region of human IgG1 is an engineered antibody domain designed to eliminate effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) [Schlothauer et al., 2016, Protein Engineering, Design and Selection]. This mutation involves the substitution of proline with glycine at position 329 (EU numbering) within the CH2 domain, which disrupts the 'proline sandwich' required for binding to Fc gamma receptors (FcγRs) and the C1q complement protein [Lo et al., 2017, JBC]. By abolishing these interactions, the P329G mutation prevents the unintended activation of immune cells like natural killer cells and macrophages, which is critical for bispecific antibodies and T-cell engagers where non-specific immune activation could lead to cytokine release syndrome [Labrijn et al., 2019, Nature Reviews Drug Discovery]. Despite the loss of FcγR binding, the P329G mutation preserves binding to the neonatal Fc receptor (FcRn), maintaining the long serum half-life characteristic of IgG antibodies [Schlothauer et al., 2016]. This technology is utilized in several approved therapeutics, including Glofitamab and Mosunetuzumab, to enhance safety and target specificity in oncology and other therapeutic areas [FDA Label: Columvi; FDA Label: Lunsumio]. It is often combined with other mutations, such as L234A and L235A (LALA-PG), to ensure a completely effector-silent profile.

Other names

P329G FcLALA-PG FcEffector-silent Fc regionP329G-mutated human IgG1 FcRoche P329G technology

Abolition of Fc-mediated effector functions (ADCC, ADCP, CDC) by disrupting the binding interface with Fc gamma receptors and C1q through the substitution of proline 329 with glycine.