Conclusions

Antibody penetration into the lung has been studied for anti-RSV antibodies. There, BALF:serum concentration ratios are reported in the range 0.1-0.2%. While it is tempting to make dose selection evaluations based on systemic exposure alone, solely relying on this information would greatly overestimate target binding in lung BALF. Binding equilibrium is related to concentrations of each species and binding constants, so understanding the concentration of each species at the site of action is crucial.
An important caveat of these simulations is to understand that they are made 1) based on the assumption that the maximal drug concentration instantaneously arrives in the BALF at a pre-defined ratio and 2) equilibrium binding occurs instantaneously and total target concentrations do not change over time. We would expect that unbound TCZ or SIL would constantly cycle into the BALF allowing for more sIL-6R or IL-6, respectively, to be bound. However, TCZ or SIL concentrations would also be falling relative to the maximal concentrations used here. Moreover, these simulations do not account for the synthesis and turn-over rates of sIL-6R and IL-6. If IL-6 is formed and turned over more rapidly, that would tilt the results towards TCZ’s favor. Far more complex, dynamic calculations would be required to understand the push-pull of these effects on binding outcomes. Additionally, variability in TCZ and SIL pharmacokinetics should be considered in more complex simulations.
We are unaware of specific BALF data from COVID-19 subjects and are relying on the translatability of general ARDS cases to the COVID-19 context. Clearly, more specific data from this patient type would be of greater utility and specificity. Moreover, the BALF concentration pattern changes over time, suggesting longitudinal data would provide insight on the timing of treatment.
Care should be taken to not over-interpret these simulations to suggest that SIL should be preferred over TCZ. To the contrary, these simulations suggest that the combined effect of these drugs is better than the monotherapy results. In the context of so much uncertainty around target concentrations, target dynamics and relative importance of each target’s contributions, combination therapy should be considered. Finally, it should be noted that anti-IL-6 therapy, anti-IL-6R therapy, and combination anti-IL-6:IL-6R therapy could have differing efficacies. The nuances of IL-6 signaling must be taken into account when discussing antibodies that target the IL-6 signaling pathway, and we must not treat IL-6 and IL-6R targets or blockers interchangeably.