Since the COVID-19 outbreak, an unprecedented challenge for healthcare systems around the world has been placed . According to the World Health Organization, elderly with multiple comorbidities have the highest risk of developing a severe illness . The immune system of elderly is characterized by immunosenescence and inflammaging. These age-related processes are always put forward to explain the susceptibility of older adults to new infections and chronic diseases such as cardiovascular diseases, diabetes and cancer . This report describes by the first time, the effect of an anti-CD6 monoclonal antibody (itolizumab) decreasing circulating IL-6 in critically and severely ill elderly COVID-19 patients.
Cytokine release syndrome (CRS) was found to be the major cause of morbidity in patients infected with SARSCoV and MERS-CoV, previous coronavirus infections producing severe respiratory illness in humans . Similar to these findings, severe COVID-19 has been described in some patients, accompanied by a similar damaging immune reaction. This severe manifestation is characterized by pronounced infiltration of macrophages and monocytes into alveoli and a pro-inflammatory response with increase of inflammatory cytokines mainly IL-6, IL-1, IFNγ and TNFα [22, 23]. Different papers have demonstrated a correlation between high serum IL-6 levels and adverse clinical outcomes in patients with COVID-19 [1, 24]. Similarly, an extremely high concentration of IL-6 is a driving force of cytokine storm, which may cause multiple organ dysfunctions in critically ill patients . The data reported on IL-6 levels during the COVID-19 outbreak show an evident heterogeneity. A systematic review and meta-analysis of seven studies, performed by Aziz and colleagues reported the mean of serum IL-6 in 56.8 pg/mL (41.4-72.3 pg/mL) for severe COVID-19 group , while both our group and Xu et al found higher IL-6 values for severe and critical COVID-19 patients . Different methods, different specimens (serum or plasma) and the different classification of disease severity could explain this heterogeneity. However, the highest concentrations of IL-6 are always in association with severe disease [3, 5, 27, 28], which is in line with our results.
In addition, high values of neutrophils characterized our critically and severely ill patients. Besides, as it has been previously reported [4, 23, 28], a higher number of neutrophils and a lower number of lymphocytes, conducting to the increase of NLR, were found in the critical and severe groups compared to the moderate group of patients.
Modulation of the CRS and the severe inflammatory state in patients with COVID-19, is a very important strategy to limit the severity of COVID-19 pulmonary and systemic complications. This approach could successfully reduce the needs for intensive care support and mechanical ventilation, and eventually decrease mortality . The use of immunosuppressants, specifically the IL-6 inhibitors, in the management of SARS-CoV-2-associated pneumonia is an attractive option to overcome the inflammation and CRS in the lungs. In this sense, the anti-human IL-6 receptor monoclonal antibody tocilizumab, has been used in a limited number of COVID-19 patients with promising results. Predictive biomarkers of clinical succeed using this MAb are currently investigated since some patients are not benefited . In addition, the use of this antibody should be managed with caution because the high risk of bacterial infection reported among its main adverse events .
In our center, we have developed a first- in-class antagonistic MAb that selectively targets the CD6-ALCAM pathway, reducing the activation, proliferation and differentiation of T cells into pathogenic effector T cells and leading to a decrease of pro-inflammatory cytokine production (IL-6, TNF-α and INFg). At the same time, itolizumab preserves the regulatory function of Treg cells and reduces T cell trafficking and infiltration at the inflammation sites . The safety and efficacy of itolizumab in the treatment of patients with rheumatoid arthritis and severe chronic plaque psoriasis have been demonstrated in several clinical studies [30, 31]. According to this, itolizumab become an alternative immunomodulatory intervention that seeks to control the T cell hyperactivated status in order to prevent such CRS. In line with this rationale, an expanded access clinical trial is recruiting patients with critical and severe illness and moderately ill COVID-19 patients with very high risk of developing severe symptoms.
Our patients treated with itolizumab decreased the circulating IL-6 levels 48 hours after the administration, especially in the case of critically and severely ill patients. All the patients with IL-6 baseline levels above 28.3 pg/mL, the cutoff selected by ROC curve to classify the patients with severe disease, significantly decreased the IL-6 concentration.
In the case of moderately ill patients, the baseline serum values didn’t increase 48 hours later. The immunomodulatory therapy was administered shortly after the contagion. In addition to the advance age, all moderately ill patients suffered with comorbidities, which are both risk factors associated with severity and fatal outcome in the course of COVID-19 [32, 33]. Therefore, we suggest that the stabilization of the IL-6 levels over low values was due to the treatment with itolizumab.
Recent studies showed that IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) could be secreted by active pathogenic T cells upon SARS-CoV-2, also CD14+CD16+ inflammatory monocytes activated by GM-CSF could secrete IL-6 and other inflammatory factors [12, 34]. Previous work demonstrated the in vitro capacity of itolizumab inhibiting the induced proliferation of peripheral blood mononuclear cells (PBMC) in the presence of ALCAM and reducing its IFN-γ, IL-6 and TNF-α production . Additionally, a significant decrease in the levels of IL-6, TNF-α and IFN-γ was found in patients with rheumatoid arthritis and psoriasis treated with itolizumab [16, 17]. In this study, the serum TNF-α concentration were undetectable in the majority of the patients, regardless of the severity of illness. Other researchers have found low levels of this cytokine in COVID-19 patients [23, 28]. Interestingly, it has been reported that levels of TNF-α and IL-1β, and some chemotactic cytokines (IL-8 and MCP-1) rise early in COVID-19 hypercytokinemia, facilitating a subsequent sustained increase in IL-6 .
This work has some limitations regarding to the small number of patients, the short follow up of IL-6 levels in serum and the lack of the evaluation of samples from untreated patients as controls. This will be addressed in the forthcoming studies. Nevertheless, it is the first report highlighting the ability of itolizumab reducing circulating IL-6 in severe COVID-19 patients. The effect of itolizumab in the clinical outcome of treated patients remains to be analyzed.