Main Conference Day 1Wednesday, 27 May 2026 - European Time GMT+1

Bispecific T cell engagers (TcEs) must create an effective immunological synapse, yet how their structural features control potency is poorly defined. We combined solution structural analyses and synapse imaging on supported lipid bilayers to show that both intermembrane distance and complex rigidity critically determine TcE activity. Formats producing close contacts and reduced molecular flexibility enhanced co-stimulatory interactions and cytotoxic responses. These findings provide actionable design principles for next-generation TcE therapeutics.

T cell engagers are highly potent immunotherapeutic modalities. However, their broad application is constrained by on-target, off-tumor toxicity and CRS, resulting in a narrow therapeutic index. We present the development of a conditional, dual-antigen targeting trispecific TCE (TriMab) that integrates a synapse-gated design with affinity-tuned binding arms to achieve AND-gated tumor selectivity. Our work establishes synapse-gated, dual-targeting trispecifics as a next-generation framework for engineering safer and more precise T-cell therapeutics

Our logic-gated CD3 Switch-DARPins are designed to overcome current limitations of T-cell engagers, such as the lack of clean targets and poor therapeutic windows. We developed a MSLNxEpCAM-targeted Switch-DARPin that contains CD2 costimulation and a masked CD3 moiety that is released to activate T cells only when both TAAs are co-expressed on target cells. This format allows for increased tumor specificity via rational selection of tumor target combinations.