Following the success of immune checkpoint blockade (ICB) therapy against cancer, agonistic antibodies targeting T cell co-stimulatory pathways, are in clinical trials. The tumor necrosis factor superfamily of receptors (TNFRSF) members CD137 and OX40 are co-stimulatory receptors that stimulate T cell proliferation and activation upon interaction with their cognate ligands. Activating CD137 and OX40 with agonistic monoclonal antibodies stimulates the immune system due to their broad expression on CD4+ and CD8+ T cells and NK cells and has antitumor effects in pre-clinical models. Most TNFRSF agonist antibodies require crosslinking via Fcgamma receptors (FcgammaRs), which can limit their clinical activity. FS120 mAb2, a dual agonist bispecific antibody targeting CD137 and OX40, activated both CD4+ and CD8+ T cells in a FcgammaR-independent mechanism, dependent on concurrent binding. A mouse surrogate version of the bispecific antibody displayed antitumor activity in syngeneic tumor models, independent of T regulatory cell (Treg) depletion and of FcgammaR-interaction, but associated with peripheral T cell activation and proliferation. When compared to a crosslink-independent CD137 agonist monoclonal antibody, the FS120 surrogate induced lower liver T cell infiltration. These data support initiation of clinical development of FS120, a first-in-class dual agonist bispecific antibody for the treatment of human cancer.