Dominant Negative Inhibitors
The DN mechanism is illustrated here with DN-TNF. DN protein inhibitors are comprised of monomers of a trimeric cytokine ligand that have been engineered to eliminate affinity for receptor yet retain affinity for other ligand monomers. Upon administration, exchange of DN inhibitors with native endogenous homotrimers depletes the pool of active cytokine, replacing it with heterotrimers that do not bind the cytokine receptor.
A principal advantage of DN inhibitors over existing drugs is the greater control over ligand and target-receptor specificity, enabling improvements in therapeutic profile. For example, XPro®1595 is engineered to inhibit only soluble TNFα, not the membrane-bound TNFα that is critical for immune system function. Additional advantages of DN inhibitors are their small size, low cost, and high stability, potentially allowing formulation for less invasive administration.