PD-1-Cis IL-2R Agonism Determines the Predicted Pharmacological Dose Range for the Immunocytokine Eciskafusp Alfa (PD1-IL2v).

Binding in cis-configuration to the PD-1 receptor (PD-1) and IL-2 $\mathrm{\beta \gamma }$ receptor (IL-2R $\mathrm{\beta \gamma }$ ) has been shown to lead to differentiation of CD8 T cells to better effectors, which is anticipated to drive efficacy of the immune-targeted cytokine eciskafusp alfa, or PD1-IL2v. Here we present a geometrically driven mathematical formulation informed by in vitro and early clinical data which enables prediction of doses at which cis-binding is at its highest, and explains observed differences in concentration-time profiles for patients who had recent exposure to other anti-PD-1 molecules compared with those who had not. Furthermore, binding in cis-configuration is expected to follow a "bell-shaped" relationship with drug concentration such that high concentrations may lead to reduced benefit/risk ratio compared with concentrations around the peak of the bell-shape. Model simulations identify patient cohorts for whom the upper limit of the pharmacological dosing range may be defined by either undesirable off-tumor target engagement or a decrease in on-tumor cis-binding.