Fc gamma receptor-binding interface on the SynTac Fc domain (FcγR-binding interface (SynTac))

The Fc gamma receptor-binding interface on the SynTac Fc domain is a structural region of the IgG1 Fc fragment utilized in the Synthetic T-cell Activation (SynTac) platform developed by Cue Biopharma (Cue Biopharma, 2024). In native antibodies, this interface mediates binding to Fc gamma receptors (FcγRs) on effector cells like NK cells and macrophages to trigger antibody-dependent cellular cytotoxicity (ADCC) (Strohl, 2009). However, in SynTac molecules like CUE-101, this interface is engineered with mutations (such as L234A/L235A) to eliminate FcγR binding, rendering the domain "effector-silent" (Quayle et al., 2020). This modification is critical to prevent non-specific immune activation and systemic toxicity, ensuring the molecule's activity is restricted to the targeted T cells (ClinicalTrials.gov, NCT03970382). Despite these mutations, the interface is designed to retain binding to the neonatal Fc receptor (FcRn) to ensure a prolonged therapeutic half-life (Quayle et al., 2020). The SynTac platform uses this engineered Fc domain as a scaffold to present peptide-MHC complexes and co-stimulatory signals to T cells (Cue Biopharma, 2024). By silencing the FcγR interface, the platform avoids the "cytokine storm" risks often associated with systemic T-cell engagers (Quayle et al., 2020). This structural feature is a key differentiator for the SynTac platform in treating cancers and autoimmune diseases (Cue Biopharma, 2024).

Other names

Fc effector interfaceFc gamma receptor binding siteSynTac Fc regionEffector-silent Fc domain

The interface is genetically modified to abolish binding to Fc gamma receptors, thereby preventing off-target immune cell activation and reducing systemic toxicity while preserving the structural integrity and pharmacokinetic profile of the fusion protein (Quayle et al., 2020).