Fig. 5: Epitope mapping of LAG3 antagonist antibodies.
From: Structural basis for mouse LAG3 interactions with the MHC class II molecule I-Ab
a Structural modeling predicts that relatlimab (green) binds an epitope (red spheres) distal to the LAG3-MHC-II interface. The disordered Loop 1 region was derived from an Alphafold25,53 model of hLAG3 D1, and the epitope-bound structure of relatlimab (PDB 7UM3)18 was aligned to the corresponding Loop 1 residues to place relatlimab in the context of LAG3 and MHC-II. b Aligning favezelimab-LAG3 and scLAG3-MHC-II structures predicts that favezelimab binding is incompatible with LAG3-MHC-II interactions due to steric clashes with MHC-II β2 (red). c Mapping the epitopes of 15011 (yellow spheres) and M8-4-6 (orange spheres) onto the structure of scLAG3-MHC-II reveals that the antibodies engage LAG3 residues in or adjacent to the MHC-II binding interface. d Comparison of the MHC-II-binding interface or mLAG3 (top) and the ieramilimab-binding interface of hLAG3 (bottom). The D1-D2 domains of mLAG3 from the scLAG3-MHC-II structure and hLAG3 (PDB: 7TZG) are depicted in surface representation, and the residues bound by MHC-II or ieramilimab. e Residues bound by the mouse LAG3-specific antibody C9B7W (red spheres) are not predicted to disrupt LAG3-MHC-II interactions. To emphasize the position of these residues at the dimer interface, they are shown on scLAG3-MHC-II structures that were modeled as a 2:2 complex. f Model of the D4-specific scFv F7 bound to LAG3-MHC-II. To generate the model, D1 from the human LAG3-F7 complex structure (PDB ID:7TZG) was docked onto D1 from the scLAG3-MHC-II structure. F7 binds a membrane-proximal site in LAG3 D4 and is not predicted to disrupt LAG3-MHC-II interactions.
