Figure 1

Hypothetical advantage of inhibiting functional subgroups of TGF-β superfamily ligands using selective heterodimeric traps. Human disease states are often characterized by imbalance between mutually antagonistic SMAD2/3 and SMAD1/5/8 signaling pathways. (A) In a hypothetical untreated disease state, excessive SMAD2/3 signaling (black arrow) occurs in combination with diminished SMAD1/5/8 signaling (grey arrow). A successful therapeutic intervention would restore normal balance between these two branches, and in some cases boost SMAD1/5/8 signaling, through selective inhibition of multiple SMAD2/3-activating ligands. (B) A monospecific anti-ligand antibody sequesters one SMAD2/3 ligand, but this partial inhibition might be inadequate to fully restore normal SMAD pathway balance. (C) A homodimeric ligand trap based on receptor ECD-Fc fusion might bind multiple ligands of both SMAD signaling branches, causing deleterious loss of SMAD1/5/8 signal. (D) A selective heterodimeric trap, engineered to target multiple ligands of the SMAD2/3 pathway but not of the SMAD1/5/8 pathway, could normalize SMAD pathway balance through robust inhibition of SMAD2/3 signaling while preserving SMAD1/5/8 signaling and potentially promoting it indirectly through disinhibition (black arrow). I, type I receptor or its ECD; II, type II receptor or its ECD. Ligands and endogenous receptors are depicted as monomeric for clarity.