Quantitative Clinical Pharmacology of T‐Cell Engaging Bispecifics: Current Perspectives and Opportunities
- The pharmacological response of TDBs involves complex interactions between T-cells, tumor cells, and TDBs, posing challenges in understanding pharmacokinetics, tissue distribution, target engagement, and exposure-response relationships.
- Dosing strategy is crucial for determining the therapeutic window, aiming to maximize efficacy while managing mechanism-related adverse events like cytokine release syndrome and neurological issues, which are most prominent during initial treatment cycles.
- Kinetic characterization of exposure/target engagement and safety/efficacy outcomes is essential for designing optimal dosing regimens to balance the benefit/risk of TDB agents.
- The review covers clinical pharmacological considerations in TDB drug discovery and development, summarizes current clinical developments, and suggests future opportunities for insights through quantitative clinical pharmacology.
Advancements in antibody engineering and recent clinical successes have led to enthusiasm for the development of bispecific modalities with the unique ability to bind to two distinct antigens or two different epitopes on the same antigen. T‐cell directing/engaging bispecific agents (TDBs), in particular, are rapidly becoming an important class of molecules in oncology drug development. These agents enhance recruitment of effector cells (e.g., cytotoxic T‐cells) to tumor‐associated/specific antigens for targeted cell killing. Like other T‐cell engaging therapies, TDBs engage the host’s T‐cells thereby driving deep and durable clinical response beyond treatment termination. However, unlike chimeric antigen receptor T‐cell therapies, which take weeks from collection of patients’ T‐cells to availability of treatment product, TDBs are available off‐the‐shelf.
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