Immunomodulatory antibodies represent an exciting new modality for immunotherapy. Whereas checkpoint blockers have translated successfully into the clinic, agonistic antibodies directed to immune receptors have lagged behind and represent an untapped opportunity for immunotherapy. Here, we highlight the salient properties of antibodies required to agonise both activating and inhibitory receptors and discuss the role of affinity, hinge rigidity and geometry. Using examples across the TNFR super-family, (CD40, 4-1BB), the immunoglobulin super-family (CD28) and including inhibitory receptors (PD-1, FcgRIIB), the contribution of each of these aspects will be examined - 1) Affinity, 2) Geometry, 3) Hinge rigidity

Elucidating the mechanisms driving response to CD3 bispecifics, alongside strategies to mitigate toxicity, is critical for expanding and optimizing their efficacy in solid tumor indications.

Targeting oncogenic Ras mutants with small molecules remains highly challenging and has yielded mixed results. We explored a powerful and innovative strategy to target Ras-driven pancreatic cancer by leveraging the natural Ras effector and tumor suppressor Nore1A. We engineered Nore1A into a RasG12D-specific “superbinder” and endowed it with cell-penetrating capabilities. When tested in pancreatic cancer cells harboring the RasG12D mutation, the engineered protein exhibited a dual therapeutic effect, simultaneously suppressing pro-tumorigenic processes while activating anti-cancer pathways.