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.