TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity

Antibodies specific for TNFRSF receptors that bind soluble ligands without getting properly activated generally act as strong agonists upon Fc gamma R binding. Systematic analyses revealed that the Fc gamma R dependency of such antibodies to act as potent agonists is largely independent from isotype, Fc gamma R type, and of the epitope recognized. This suggests that the sole cellular attachment, achieved by Fc domain-Fc gamma R interaction, dominantly determines the agonistic activity of antibodies recognizing TNFRSF receptors poorly responsive to soluble ligands. In accordance with this hypothesis, we demonstrated that antibody fusion proteins harboring domains allowing Fc gamma R-independent cell surface anchoring also act as strong agonist provided they have access to their target. This finding defines a general possibility to generate anti-TNFRSF receptor antibodies with Fc gamma R-independent agonism. Moreover, anti-TNFRSF receptor antibody fusion proteins with an anchoring domain promise superior applicability to conventional systemically active agonists when an anchoring target with localized disease associated expression can be addressed.