cytokine-neutralizing antibody as a structural mimetic of 2 receptor interactions

TGF-β isoforms are key modulators of a broad range of biological pathways and increasingly are exploited as therapeutic targets. Here, we describe the crystal structures of a pan-TGF-β neutralizing antibody, GC-1008, alone and in complex with TGF-β3. The antibody is currently in clinical evaluation for idiopathic pulmonary fibrosis, melanoma, and renal cell cancer. GC-1008 recognizes an asymmetric binding interface across the TGF-β homodimer with high affinity. Whereas both cognate receptors, TGF-β-receptor types I and II, are required to recognize all 3 TGF-β isoforms, GC-1008 has been engineered to bind with high affinity to TGF-β1, 2, and 3 via a single interaction surface. Comparison with existing structures and models of TGF-β interaction with its receptors suggests that the antibody binds to a similar epitope to the 2 receptors together and is therefore a structurally different but functionally identical mimic of the binding mode of both receptors.