Fig. 1

Potential mechanisms through which truncated PD1 might improve checkpoint blockade. Enhanced affinity: enhancements in either the binding affinity or the functional avidity of truncated PD1 compared to αPD1 antibodies could result in better saturation of PDL1 molecules on the surface of tumors cells. This would provide fewer PDL1 molecules to engage with inhibitory PD1 on the surface of activated T cell resulting in improved blockade efficacy. Blockade of all possible PD1 ligands: αPD1 antibodies might block interactions of PD1 with only a few possible ligands. This would allow for inhibitory signals to be sent to T cells by engagement of PD1 with unblocked ligands. In contrast, truncated PD1 should bind to all potential PD1 ligands, including those which might not be currently appreciated, thus providing a more complete blockade. Enhanced diffusion: αPD1 antibodies are large molecules whose diffusion into the tumor microenvironment from the vasculature is known to be inefficient. In contrast, truncated PD1 is a much smaller protein which might have improved diffusion properties. This could provide a more complete PD1 blockade by saturating a higher percentage of the tumor microenvironment with PD1-blocking reagent