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 tumour-infiltration of a rapidly proliferating progenitor-rich T cell subset.

Alaya.bio has developed a proprietary platform combining the gene transfer efficiency of lentivectors with advanced biodegradable polymer and lipid engineering to improve targeting, specificity, and reduced immunogenicity. Using scalable GMP-compliant bioprocesses, Alaya produces transduction-deficient lentivectors functionalised with shielding polymers and targeting ligands. In NSG mice engrafted with human leukaemia cells, a single intravenous injection controlled tumor burden and prolonged their survival for over 28 days without acute toxicity. CAR-T cells were detected in bone marrow at necropsy. This versatile platform shows strong potential for universal in situ CAR-T therapies and broader cell reprogramming applications beyond immuno-oncology, including genetic disorder treatments.

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.