TNF receptor superfamily (TNFRSF) signaling is tightly regulated by their trimeric ligands

TNFSF ligands naturally exist as homo-trimers with three receptor binding sites. The interaction of the trimeric and trivalent TNFSF ligands with their specific cell surface receptors leads to precise alignment of the ectodomains to each other, followed by intracellular signal complex formation and signal transduction. Multiple TNFSF/TNFRSF clusters (a single cluster consists of 3 receptor domains organized by one ligand trimer) are necessary to initiate sufficient signal strength.

Active ectodomain-complexes consist of three receptors aligned around one trimeric ligand in the center. The 4-1BBL/4-1BB co-complex is shown above as an example. Illustrations are based on the structural data deposited in PDB-entry: 6MGP. TNFSF ligand trimerization is the prerequisite for receptor binding as the binding sites are located at the interfaces of the three ligand-subdomains.

Single-chain TNFSF ligands mimic the natural structure and are potent activators of TNFRSF signaling

TriCos Biotherapeutics proprietary single-chain TNFSF ligands are trivalent, but formed by one polypeptide chain only. The three ligand domains are connected with specific linkers. These single-chain ligand modules mimic the endogenous ligand trimer and are capable of inducing the precise physiological 3:3 organization of the receptor/ligand complex. Importantly, the scTNFSF-modules can be used to generate multi-specific biologics.

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TriCos Biotherapeutics trivalent single-chain ligands vs. bivalent antibodies

TNFSF ligand trimerization is the prerequisite for receptor clustering, formation of a signaling complex and efficient signal transduction. Agonistic antibodies are incapable of forming the specific well defined 3:3 receptor:ligand organization resulting in non-efficient signaling.