Discussion
Cytokine signaling through the IL-6 pathway is complex and depends on
multiple factors, including cell type and agonist or antagonist
concentration in the tissue environment.
Though IL-6R is necessary for IL-6 signaling, and is a reasonable target
for IL-6 signaling inhibition, the increase in IL-6 in ARDS is 30-50
times greater than the increase in IL-6R. Near-complete receptor
occupancy of IL-6 by TCZ in the lung could be necessary to achieve a
robust decrease in signal transduction. An ability to achieve this
depends on three factors: the relative concentrations of IL-6 and sIL-6;
the concentrations of antibodies such as SIL and TCZ; and the strength
of the binding in each of their respective complexes (SIL:IL-6,
TCZ:sIL-6R, and sIL-6R:IL-6).
Observational data on IL-6 and sIL-6R induction in ARDS suggests IL-6 is
greatly upregulated, with concentrations reaching 370-fold normal
levels, while sIL-6R is only modestly increased, with concentrations
reaching 4.88-fold normal levels. Maximal achievable serum siltuxumab
concentration exceeds TCZ concentration by approximately two-fold. The
dissocation equilibirum concentration for SIL is two to three
orders-of-magnitude lower than TCZ, meaning that SIL is better at
sequestering IL-6 than TCZ is at sequestering sIL-6. Taking these three
factors into account, results of the simulation greatly favor the use of
SIL over TCZ to inhibit IL-6 signaling. However, these results are
dependent on several key assumptions:
The value for antibody penetration (BALF:serum ratio) of SIL or TCZ has
not been reported. The value used in the simulation (0.2%) represented
the upper-end of reported values for unrelated monoclonal antibodies.
Clearly, having experimentally-obtained penetration values for these
compounds would be ideal, but difficult to source for repurposed drugs
where the lung has not been a studied as a site of action.
The binding model introduced here is complex, yet only captures a
portion of the interactions involved in IL-6 signaling. Specifically,
IL-6 binds to both sIL-6R (via the trans pathway in all cells)
and membrane-bound IL-6R (mIL-6R) (via the classic pathway on certain
cells such as some immune cells). mIL-6R, and therefore classic
signaling, are not included in the model. Similarly, soluble gp130
(sgp130) (an important IL-6 modulator in the trans pathway) was
not included in the model. Signaling complex formation
(IL‑6:sIL‑6R:gp130 and IL-6:mIL-6R:gp130) is not accounted for directly
in the model.
Still, suppression of free IL-6 reduces IL-6:mIL-6R and IL-6:sIL-6R, and
IL-6:sIL-6R is tracked in the model. If anything, the omission of mIL-6R
from the model underscores the relative importance of IL-6 suppression
relative to sIL-6R suppression. While signaling complex formation is not
tracked in the model (for classic or trans signaling), gp130 is
constitutively expressed and is therefore assumed not to be a limiting
factor in IL-6 signaling. Similarly, gp130 transmembrane protein binding
is not included in the model. However, gp130 affinity for IL-6:sIL-6R is
higher than IL-6 for sIL-6R, suggesting that the limiting step is the
binding of IL-6 to sIL-6R.
Finally, a review of the literature revealed a range of binding
constants reported for SIL:IL-6 and TCZ:sIL-6R (Table 2). The selection
of Kd for use in the model was the median reported value (Table 2,
Figure 2). The impact of the true Kds being lower or higher is not
accounted for in this work.
Considerations for Place in
Therapy
A rapid, coordinated innate immune response is the initial line of
defense against viral infections. Hyper-inflammatory responses, however,
can cause immunopathology. Low pathogenic coronaviruses typically infect
the upper airways, while highly pathogenic coronaviruses infect the
lower respiratory tract and can cause severe pneumonia, sometimes
leading to acute lung injury and ARDS. Disease severity of the highly
pathogenic coronaviruses SARS and MERS was influenced by factors such as
initial viral titers in the airways, age, and comorbid conditions
[28].
The clinical course of SARS progressed in three stages. Robust viral
replication dominated the first phase, which lasted a few days. The
second phase was associated with high fever, hypoxemia and progression
to pneumonia despite a decrease in viral load. The third phase is
characterized by strong inflammatory response, in which
~ 20% of patients progressed to ARDS and often death
[29]. MERS progresses more rapidly, and has a higher fatality rate
than SARS. Common clinical manifestations of MERS resemble those of
SARS-CoV-2 and include rapid progression to pneumonia [30, 31]. Like
SARS-CoV-2, the majority of MERS patients with shortness of breath
progressed to severe pneumonia and required admission to the ICU.
Analyses of lungs from patients who died from SARS-CoV showed infection
of both the airway and alveolar epithelial cells, vascular endothelial
cells, macrophages, monocytes and lymphocytes. Neutrophils and
macrophages extensively infiltrated cells [32]. The only tissue
samples available for MERS is the analysis of lung tissue from one
patient, which were consistent with what was seen in SARS [33].
Virus-induced cytopathic effects and viral evasion of host immune
responses are thought to play major roles in disease severity. This
argues for antiviral therapy as early as possible in treatment, with
adjunctive immunotherapy during the time when patients are at risk for
ARDS and in early ARDS. This paradigm would be similar to therapeutic
interventions aimed at MERS viral load reduction, which were somewhat
beneficial when administered early (but not later in) MERS-CoV infection
[30, 34, 35].
IL-6 concentrations skyrocket at the onset of ARDS (i.e. WHO Score ≥ 5
[36]). Immediate treatment with an antibody such as SIL upon
hospital admission for patients with low oxygenation needs (i.e. 200
mmHg < PaO2 to FIO2 ≤300 mmHg with positive end-expiratory
pressure or continuous positive airway pressure ≥5 cmH2O, delivered
invasively or noninvasively; Corresponding to WHO Score of 4 [36])
could drive the immune response out of hyperreactivity. SIL treatment in
early ARDS (i.e. Days 1-3) would be crucial to preventing the IL-6
onslaught that leads to lung damage.
Additionally, treatment with an antibody such as TCZ in patients at risk
of developing ARDS (i.e. WHO Score of 3 [36]) could mediate the IL-6
signaling response synergistically. Preliminary data suggest IL-6R
blockade is most effective in critically ill patients, presumably
because ARDS has progressed and IL-6 concentrations have already
returned to near-normal. For example, Regeneron and Sanofi are amending
their phase 3 trial evaluating sarilumab, an IL-6R antagonist, in
hospitalized patients with “severe” or “critical” illness caused by
COVID-19 to include only “critical” patients, based on preliminary
results that sarilumab provided a clinical benefit to patients requiring
mechanical ventilation or high-flow oxygenation or treatment in an
intensive care unit, but no notable benefit on clinical outcomes in
fpatients who required oxygen supplementation without mechanical or
high-flow oxygenation [37].