Immunotherapeutic approaches to curtail COVID-19

Abstract

COVID-19, the disease induced by the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has imposed an unpredictable burden on the world. Drug repurposing has been employed to rapidly find a cure; but despite great efforts, no drug or vaccine is presently available for treating or prevention of COVID-19. Apart from antivirals, immunotherapeutic strategies are suggested considering the role of the immune response as the host defense against the virus, and the fact that SARS-CoV-2 suppresses interferon induction as an immune evasion strategy. Active immunization through vaccines, interferon administration, passive immunotherapy by convalescent plasma or synthesized monoclonal and polyclonal antibodies, as well as immunomodulatory drugs, are different immunotherapeutic approaches that will be mentioned in this review. The focus would be on passive immunotherapeutic interventions. Interferons might be helpful in some stages. Vaccine development has been followed with unprecedented speed. Some of these vaccines have been advanced to human clinical trials. Convalescent plasma therapy is already practiced in many countries to help save the lives of severely ill patients. Different antibodies that target various steps of SARS-CoV-2 pathogenesis or the associated immune responses are also proposed. For treating the cytokine storm induced at a late stage of the disease in some patients, immune modulation through JAK inhibitors, corticosteroids, and some other cognate classes are evaluated. Given the changing pattern of cytokine induction and immune responses throughout the COVID-19 disease course, different adapted approaches are needed to help patients. Gaining more knowledge about the detailed pathogenesis of SARS-CoV-2, its interplay with the immune system, and viral-mediated responses are crucial to identify efficient preventive and therapeutic approaches. A systemic approach seems essential in this regard.

Keywords: Antibodies; COVID-19; Immunotherapy; Pandemic; Plasma therapy; Severe acute respiratory syndrome coronavirus 2.

Copyright © 2020 Elsevier B.V. All rights reserved.

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Graphical abstract

Fig. 1

Immunization approaches against COVID-19. Active immunization is provided through vaccines, which are still under development for COVID-19. Passive immunization can be performed via natural antibodies using convalescent plasma therapy (CPT) or antibodies that are manufactured. In CPT, neutralizing antibodies derived from a hyperimmune patient would be administered to a COVID-19 patient through plasma transfusion. This approach is already being used and investigated in many countries with acceptable levels of success. On the other hands, different polyclonal or monoclonal antibodies could be produced via using hybridoma cell-lines, animals, or cell-free protein synthesis, which may be administered in patients as a monoclonal antibody or a cocktail of antibodies.

Fig. 2

Potential targets to curtail COVID-19. 26 potential targets for COVID-19 are depicted. 1) receptor binding domain (RBD) located in S1 protein, it is considered as the first and the main target for neutralizing antibodies, 2) S2 protein, consists of HR1 and HR2 domains, SARS-CoV neutralizing antibodies, including CR3022 and S309 potently cross-neutralize SARS-CoV-2 through binding with S2 protein, 3) viroporin, ion channel proteins, hypothesized to be targeted by dewetting monoclonal antibodies, 4) nucleoprotein, target of neutralizing antibodies, 5) envelope, target of neutralizing antibodies, 6) ACE2, angiotensin converting enzyme receptor 2, a receptor found on the cells of respiratory system, gastrointestinal tract, and endothelium, strongly binds with the virus spike, some monoclonal antibodies are designed to compete with the virus in attachment to the ACE2 receptor, 7) TMPRSS2, it is responsible for spike protein cleavage and viral entry, targeted by TMPRSS2 inhibitors including nafamostat and camostat mesylate 8) vimentin, cytoskeleton protein that is important in the formation of SARS-CoV-2-ACE2 complex, 9) viral RNA, 10) cysteine-like protease (3clPro), one of the important viral proteases and targets of antiviral drugs, 11) Papain-like proteases (PLpro), another important viral protease and target of antiviral drugs 12) Bruton tyrosine kinase (BTK), BTK inhibitors, including acalabrutinib, modulate cytokine storm in COVID-19 patients, 13) AP2-associated protein kinase 1 (AAK1), regulates viral endocytosis and is the target of immunomodulators, 14) signal transducer and activator of transcription proteins/Janusassociated kinase (STAT/JAK), modulates viral entry and cytokine storm, JAK inhibitors, including baricitinib are repurposed for SARS-CoV-2 inhibition, 15) dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN), mediates viral entry and is the target of human monoclonal antibody, 16) IL-6, one of the most important cytokines that activates downstream inflammatory process and causes acute respiratory distress syndrome, inhibited by different monoclonal antibodies, including Tocilizumab, 17) granulocyte–macrophage colony-stimulating factor (GM-CSF), causes positive feedback in inflammatory mediators and acute respiratory distress syndrome, target of monoclonal antibodies, 18) TNF, inflammatory mediator and cause of acute respiratory distress syndrome, target of monoclonal antibodies and TNF blockers, including etanercept, 19) IL-17, responsible for aggravation of cytokine storm and pulmonary edema and target of secukinumab, 20) IL-1, responsible for aggravation of cytokine storm and pulmonary edema, target of canakinumab, 21) nicotinamide phosphoribosyltransferase (NAMPT), upregulated by physical stress and causes an increase in the number of TLR4 and lung inflammation, target of monoclonal antibodies, 22) calcineurin, calcineurin inhibitors, including tacrolimus, block T-cell activation, 23) mTOR, mTOR inhibitors including sirolimus, inhibit memory B-cell activation and the antibody-dependent enhancement mechanism, 24) CTLA-4, immune check point and negative regulator of T-cell, target of monoclonal antibodies, 25) PD-1, immune check point and negative regulator of T-cell, target of monoclonal antibodies, 26) intercellular adhesion molecule 3 (ICAM-3), mediates the viral entry.