Cell avidity as a novel biomarker for candidate selection of cell-based immunotherapies
Jens Eberlein, Justin Moser, Keith Bailey, Song-My Hoang, Zhou Zhong, Gulpreet Kaur, Andrea Candelli, Rogier M Reijmers, Will Singleterry
LUMICKS, Paalbergweg 3, 1105 AG Amsterdam, Netherlands and LUMICKS, 800 South Street, Suite 100, Waltham, MA, 02453, USA
Cellular immunotherapies are increasingly complex in design. Affinity readouts, i.e., the measurement of the strength of single receptor-ligand interactions, are frequently used to characterize binding of chimeric antigen receptors (CARs) or T cell receptors (TCRs) to their ligand. However, affinity is a poor predictor of effector function of the engineered downstream product and therefore new tools are needed to evaluate the binding strength of CAR and TCR-transgenic cells to their cognate target in a more biologically relevant context.
Recent studies demonstrated the utility of measuring cell avidity as a novel biomarker for identifying and developing potent and safe immunotherapies. Unlike affinity, cell avidity is driven by the overall strength of dynamic surface interactions between effector cells and their targets by integrating receptor density, the sum of individual affinities, and engagement of the multitude of co-receptors within the immunological synapse.
Here, we show that increased specific avidity, i.e., TCRs with the strongest antigen binding and the lowest background, correlated with improved effector function both in vitro and in vivo. For CAR-T, higher avidity was significantly correlated with improved tumor control in in vivo murine models, but also associated with toxicities in patients, suggesting tuning of cell therapies to the desired avidity for ideal function is needed.
