TNF receptor superfamily members include well-validated cancer and immuno-oncology drug targets, but creating high-potency agonists is made difficult by the molecules' unique mode of ligand binding. Apogenix AG is designing compounds that more closely mimic the natural TNF receptor-ligand interaction than traditional agonist antibodies, using a new technology platform that builds on the company's core fusion protein technology.
According to David Richards, head of immunology at Apogenix, designing a ligand that fits into a TNF receptor's binding pocket isn't enough to properly activate the receptor. "These are more complicated than other ligand-receptor pairs because the receptors, although they exist as single proteins, need to form trimers to initiate good downstream signaling," he said.
In addition, once formed, the receptor trimers need to be clustered together to stimulate a high level of signaling, which creates an extra level of complexity for drug design.
To replicate the natural trimerization and clustering of the TNF receptors, the company created its Hexavalent TNF Superfamily Receptor Agonists (HERA) technology, which produces agonists that each bind and cluster six receptor molecules for any given ligand. To date, Apogenix has