Fig. 2: Pharmacokinetic model predicts response to local IL-2 therapy.
From: Maximizing response to intratumoral immunotherapy in mice by tuning local retention
Model simulating the disposition of intratumorally injected IL-2 collagen-binding fusion protein over time (t). a During an intratumoral injection, IL-2 fusion protein is instantaneously transferred from the syringe to the tumor compartment (circle) of volume capacity Vholdup and blood compartment (square) of volume Vblood b After injection, diffusion of the injected protein between the tumor and blood compartment occurs based on the rate of intravasation (kintrav) and extravasation (kextrav). Removal of the injected protein from blood occurs at a rate of clearance (kclear). Ø indicates removed protein. The italicized rates depend on the molecular weight of the injected protein. Within the tumor interstitium (inset), the injected protein toggles between target-bound states. The injected protein (free or collagen-bound) binds IL-2 receptor (IL-2R) according to rate of association (kon,IL2R) and dissociation (koff,IL2R) with IL-2R. When bound to IL-2R, the injected-protein-IL-2R complex is internalized and degraded at the rate of IL-2R internalization (kint,IL2R). IL-2 signaling increases the concentration of IL-2R over time. The injected protein (free or IL-2R bound) binds collagen according to the rate of association (kon,col) with collagen and rate of dissociation with collagen (koff,col). Glossary of the model’s variables, initial conditions, and equations are provided in Supplementary Tables 1–3. c Model’s prediction of the intratumoral activity duration of an injected IL-2 fusion protein varying in molecular weight (kD) and collagen affinity (Kd equilibrium dissociation constant in M units) The circles on the heatmap indicate the model’s prediction for the proteins LAIR-LAIR-MSAH464Q-IL2 (red), LAIR-LAIRx-MSAH464Q-IL2 (orange), LAIRx-LAIRx-MSAH464Q-IL2 (yellow), LAIR-IL2 (purple), and LAIRx-IL2 (pink). Each protein’s predicted days of activity is adjacent to color bar. d Percentage of mice from Fig. 1h, i surviving 100 days after treatment (outlined box). On day 100, surviving mice were inoculated with 0.1 M B16F10 on the contralateral left flank. The percentage of mice surviving for another 100 days after tumor rechallenge (filled box). e Correlation between the model’s predicted intratumoral activity in panel c and hazard ratio for treatments from Fig. 1h, i compared to PBS (i.tu.) + TA99 (i.p.) treated control group. Hazard ratio computed by log-rank method. Source data for panel d, e are provided in the Source Data file. Panel a and b created with BioRender.com.
