Orthogonal split-antibody-based Interleukin-12 receptors exhibit high affinity for the inert small molecule chelator DOTAM. DOTAM-inducible Interleukin-12 receptors (D12Rs) result in attenuated agonism which is potentiated during concurrent CAR signaling. CAR D12R T cells showed enhanced cytotoxicity under repeated antigen exposure and mediated durable in vivo efficacy in human xenograft models. This effect is mediated by increased tumor-infiltration of a rapidly proliferating progenitor-rich T cell subset.

All approved T-cell engagers engage the TCR complex through CD3ε, but this is not the only therapeutically exploitable site. We developed VHH bispecifics targeting a novel quaternary epitope at the TCRα/β constant region interface, providing pan-αβ T-cell redirection with full TRBC1/TRBC2 allele coverage and inherent human/cynomolgus cross-reactivity. In matched cytotoxicity assays, these anti-TCR bispecifics achieve picomolar potency despite moderate monovalent affinities, raising testable questions about how TCR complex geometry influences T-cell activation.