Structures of a pan-specific antagonist antibody complexed to different isoforms of TGFβ reveal structural plasticity of antibody-antigen interactions

Various important biological pathways are modulated by TGF isoforms; as such they are potential targets for therapeutic intervention. Fresolimumab, also known as GC1008, is a pan-TGF neutralizing antibody that has been tested clinically for several indications including an ongoing trial for focal segmental glomerulosclerosis. The structure of the antigen-binding fragment of fresolimumab (GC1008 Fab) in complex with TGF3 has been reported previously, but the structural capacity of fresolimumab to accommodate tight interactions with TGF1 and TGF2 was insufficiently understood. We report the crystal structure of the single-chain variable fragment of fresolimumab (GC1008 scFv) in complex with target TGF1 to a resolution of 3.00 angstrom and the crystal structure of GC1008 Fab in complex with TGF2 to 2.83 angstrom. The structures provide further insight into the details of TGF recognition by fresolimumab, give a clear indication of the determinants of fresolimumab pan-specificity and provide potential starting points for the development of isoform-specific antibodies using a fresolimumab scaffold. ;