Our modelling results showed two distinct features: differences in the peak ELK-1 observed and in the steady state value of ELK-1 (Fig. 1).
Figure 1: Overall effect of scFv-cytokine binding with ELK-1 levels in two regimes: in red, peak, and in green, steady state.
To determine the most effective candidate for scFv targeting, we first analyzed the maximum ELK-1 levels. By identifying the lowest peaks, we can identify which target for our scFv would diminish the effects of a cytokine storm during the most severe circumstances. Thus, the lowest peak ELK-1 values indicate a more effective therapeutic agent for CCS (COVID-19 cytokine storms) patients. As seen in figure 2 below, the lowest peaks corresponded to IFN-γ and IL-1, respectively. On the other end, the tallest peaks corresponded to targeting IL-12 and IL-2 respectively. Thus, we identified IFN-γ and IL-1 as strong candidates for our scFv target.
Figure 2: Maximum ELK-1 levels following scFv-cytokine binding.
Another state we looked into was the steady-state levels of ELK-1. These are significant since our modulatory system should bring the resting cytokine levels to a minimum. By lowering the steady state cytokine levels, our system is able to diminish the cytokine storm further.
However, the body always has cytokines present, such as IL-1 which “ranges from 0.5 to 12 and 0.5 to 5 pg/mL” (O'Neill et al., 2013).
As seen in figure 3 below, the lowest steady state values correspond to targeting IL-1 and IFN-γ, respectively. Though the IL-12 and IL-2 had lower minimums, their average was higher than that of IL-1 and IFN-γ. Targeting IL-12 and IL-2 appeared to cause much larger fluctuations, indicating less control over the system and a weaker negative feedback loop. Thus, we once again identified IFN-γ and IL-1 as strong candidates for our scFv target.
Figure 3: Steady-state ELK-1 levels following scFv-cytokine binding.
While our model does not exactly follow the concentrations detailed in other papers, we found the general behavior and shape of our graph most interesting. From our model, it is apparent that IFN-γ most directly modulates ELK-1. Though IFN-γ may seem like the optimal candidate for sequestration, targeting this cytokine could be dangerous for a cytokine storm patient because IFN-γ takes a critical role in the antiviral immune response (Acharya et al., 2020). Thus, since IL-1 generated the second lowest peak and the lowest steady state value of ELK-1, it appears to be a better scFv target. Although IL-1 is also a key player in the immune response, based on studies that have shown clinical efficacy of IL-1 inhibition (Cavalli et al., 2020), we postulated that IL-1 could still be a critical target for our immunomodulator system.
Acharya, D., Liu, G., & Gack, M. U. (2020). Dysregulation of type I interferon responses in COVID-19. Nat Rev Immunol 20, 397–398 doi:10.1038/s41577-020-0346-x
Cavalli, G., Luca G. D., Campochiaro C., Della-Torre E., Ripa M., Canetti M., … Dagna L. (2020). Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. The Lancet Rheumatology, 2(6), 325-331. doi:10.1016/S2665-9913(20)30127-2
O'Neill, C. M., Lu, C., Corbin, K. L., Sharma, P. R., Dula, S. B., Carter, J. D., Ramadan, J. W., Xin, W., Lee, J. K., & Nunemaker, C. S. (2013). Circulating levels of IL-1B+IL-6 cause ER stress and dysfunction in islets from prediabetic male mice. Endocrinology, 154(9), 3077–3088. https://doi.org/10.1210/en.2012-2138
Yiu, H. H., Graham, A. L., & Stengel, R. F. (2012). Dynamics of a cytokine storm. PloS one, 7(10). doi:10.1371/journal.pone.0045027
This page was written by Sangita Vasikaran, Ethan Levy, Rachel Shen, and Erin Shin