Mike Wan
Senior Manager of Clinical Pharmacology Gilead Sciences
Seminars
T-cell engagers have demonstrated remarkable potency in oncology, but in autoimmune diseases they aim to achieve sufficient target-cell killing without triggering cytokine release profiles that are unacceptable in chronic outpatient populations. This technical workshop will explore the molecular architecture, construct design, and developability considerations that underpin next generation autoimmune TCEs by:
- Evaluating CD3 tuning as a molecular design strategy rather than a clinical mitigation tool, examining how affinity modulation, epitope selection, valency, and spatial geometry influence T-cell activation thresholds
- Identifying the structural determinants of efficacy-versus-cytokine separation, to understand construct formats that may uncouple cytotoxic activity from systemic T-cell hyperactivation
- Optimizing engager architecture for autoimmune applications, exploring how binder orientation, domain arrangement, linker design, avidity effects, and target-antigen biology influence immune synapse formation, pharmacology, and safety outcomes
As autoimmune T-cell engagers move beyond first-generation designs, many developers are encountering a common challenge, exhausted and dysfunctional T cells may limit the depth and durability of clinical responses. Co-stimulatory approaches have emerged as a promising strategy to enhance T-cell fitness, persistence, and efficacy, but questions remain around how much co-stimulation is needed and how to balance improved potency with cytokine release and safety risks.
This panel will discuss how co-stimulation could reshape the future of autoimmune therapy by:
- Understanding the biology of T-cell exhaustion and persistence, exploring the mechanisms driving reduced T-cell functionality in autoimmune patients and identifying opportunities to restore effective immune responses
- Evaluating emerging co-stimulatory strategies, comparing approaches leveraging CD28, CD2, 4 1BB, and other pathways to determine how they influence efficacy, durability, immune-cell depletion, and safety profiles
- Defining the optimal balance between potency and safety, discussing how co-stimulation can be integrated into nextgeneration engager designs to maximize clinical benefit while minimizing cytokine release syndrome, off-target activation, and long-term immune suppression
