Tocilizumab (Actemra®) in COVID-19 Treatment
What is Tocilizumab?
Tocilizumab, also called atlizumab, is an immunosuppressive humanised monoclonal antibody which targets the IL-6 receptor. IL-6 is a cytokine which is involved in many important immune responses—discussed below— but which can also contribute to the pathogenesis of certain diseases, specifically autoimmune diseases and certain types of cancers. Most notably, IL-6 is implicated in cytokine release syndrome and thus targeting it or its receptor is thought to be a promising therapeutic intervention.
History and Development
Tocilizumab is sold under the trade names of Actemra© and RoActemra©, and was developed by Roche and their Japanese subsidiary Chugai Pharmaceuticals. It was approved by the FDA under the trade name Actemra for rheumatoid arthritis in 2010. In 2017, the FDA approved tocilizumab usage for cytokine release syndrome (CRS).
Current Uses of Actemra©
Tocilizumab has primarily been employed in the treatment of rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis, a rare form of aggressive autoimmune arthritis in children. It is usually administered as an intravenous infusion or subcutaneous injection (Source).
IL-6 has been implicated in CRS, where a sustained increase in IL-6 followed the acute response cytokine release in patients with infection-mediated sepsis (Source). Chimeric antigen receptor T-cell therapy (CAR-T therapy) can cause CRS and induce the massive and coordinated release of pro-inflammatory cytokines. This unintended side effect of cancer cell therapy can be treated with tocilizumab in patients over the age of two with severe CRS.
Tocilizumab is a humanised murine monoclonal antibody which targets the IL-6 receptor.
Humanised antibodies are not synonymous in name or structure with chimeric antibodies. While chimeric (represented with the inclusion of ‘-xi-’ within the non-proprietary name) and humanised (bearing ‘-zu-’ in their generic names) both contain mouse and human protein sequences, chimeric antibodies have significantly more non-human protein segments. In contrast, humanised antibodies are nearly identical to their human equivalents despite having key antigen binding domains originate in mice.
In the case of tocilizumab, the complementarity determining regions (CDR) of anti human IL-6 receptor antibodies generated in mice were fused to human IgG1. This combination creates an antibody that recognises and binds the human IL-6 receptor, but which also bears a human constant region. Having an antibody which closely mimics the structure of human-generated antibodies reduces the chance of a drug being immunogenic. When the immune system of a patient recognises a therapeutic antibody as foreign, neutralising antibodies are produced and the efficacy of the drug is generally reduced (Source).
Mechanism of Action: Tocilizumab & IL-6 Receptors
Tocilizumab binds to both soluble and membrane-bound IL-6 receptors. This interaction blocks IL-6 from exerting the downstream pro-inflammatory effects it is able to produce when left unchecked. The competitive inhibition of IL-6 /IL-6 receptor binding occurs as tocilizumab recognises binding sites on both receptor forms.
IL-6 production is up-regulated in response to acute inflammatory mediators such as TNF alpha and IL-1. It has a crucial role in maintaining chronic inflammation. The shift from acute to chronic inflammation is thought to be at least partially dependent on IL-6 binding to its soluble receptor. This ‘trans-signalling’ (a transduction mechanism unique to IL-6 ) facilitates a perpetual IL-6-induced inflammatory response, and activates other mediators of sustained inflammation (Source).
IL-6 signal transduction of the bound receptor relies on receptor/ligand binding and successful interaction with the glycoprotein gp130, found on the surface of target cells. gp130 helps to facilitate the downstream signalling into the cytosol by activating the JAK/STAT pathway. Ultimately, this leads to the transcription of anti-apoptotic and cytokine-associated genes (Source).
Thus, inhibiting this interaction and pathway can reduce chronic inflammation in certain contexts.
Fig 1. IL-6 transduction via the transmembrane IL-6 receptor. (Source: Sinead Kinsella, PhD)
Actemra© Therapeutic Action in COVID-19
Tocilizumab has been added to China’s COVID-19 treatment guidelines.This therapeutic intervention targets the damaging, uncontrolled immune response associated with some cases of the disease rather than attacking the virus directly. Tocilizumab can now be officially used to treat severe cases of the disease with lung damage and high levels of IL-6 detected. Elevated levels of IL-6 are reported to be an indicator of the disease progressing and the prognosis worsening. (Source)
SARS-CoV-2, the causative viral agent of COVID-19, can cause pneumonia in some patients. This pneumonia can induce acute respiratory distress syndrome (ARDS), which is respiratory failure mediated by rapid, widespread inflammation in the lungs. Symptoms of ARDS include rapid breathing, shortness of breath, and the onset of a bluish skin tone. Usually, treatment includes the use of a mechanical ventilator to increase the amount of oxygen available to a patient. Despite intervention, ARDS is a fatal condition in more than 30% of cases (Source).
Controlling the inflammatory response at this critical stage could help reduce mortality. As phase III human trials are launched, the world will wait with bated breath to see if tocilizumab has a measurable effect on the outcome of COVID-19.
More information about ongoing and upcoming COVID-19/Tocilizumab trials is available here.