Fifteen Drugs by Blocking. None by Switching On.
The TNF receptor superfamily has produced fifteen approved medicines, and every one of them works by shutting something down. Six receptors have been pushed the other way for twenty years, and not one agonist antibody has been approved.
Adalimumab, etanercept, denosumab and belimumab target different ligands, but they all modulate signalling through the TNF receptor superfamily, and every one works by turning a pathway off. For about twenty years the field has also tried the opposite, activating CD40, OX40, 4-1BB, GITR, TRAIL-R and CD27 with agonist antibodies. That has produced nothing approved, in the United States or Europe. These receptors only signal when several copies are clustered into a particular arrangement, and the clustering has to be supplied by the patient's own FcγRIIB, so potency depends on the tissue as much as on the molecule. Romiplostim shows agonism is not impossible — its receptor just asks for something a two-armed drug can deliver.