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

ABSTRACT Binding in cis‐configuration to the PD‐1 receptor (PD‐1) and IL‐2 receptor (IL‐2R) 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.