The COVID-19 pandemic has led to twin public health and economic crises around the world. Not only has it cost hundreds of thousands of lives but also severely impacted livelihoods and placed enormous strain on community healthcare and welfare services. In this review, we explore the events associated with SARS-CoV-2 pathogenesis and host immunopathological reactivity due to the clinical manifestations of this coronavirus infection. We discuss that the metallopeptidase enzyme ADAM17, also known as tumor necrosis factor-α-converting enzyme, TACE, is responsible for shedding of angiotensin-converting enzyme 2 and membrane-bound interleukin (IL)-6 receptor. This leads to elevated pro-inflammatory responses that result in cytokine storm syndrome. We argue that cytokine balance may be restored by recovering an IL-6 trans-signaling neutralizing buffer system through the mediation of recombinant soluble glycoprotein 130 and recombinant ADAM17/TACE prodomain inhibitor. This cytokine restoration, possibly combined with inhibition of SARS-CoV-2 entry as well as replication and coagulopathy, could be introduced as a novel approach to treat patients with severe COVID-19. In cases of co-morbidity, therapies related to the management of associated disease conditions could ameliorate those clinical manifestations.
Prospects of therapeutic combinations
Many therapeutic strategies against SARS-CoV-2 are already proposed and undergoing testing. Some of these approaches target virus replication while others relate to blockade of cytokines. Unfortunately, none is yet proven to show fully protective effects and thus to promote patient recovery from disease. We believe that there is unlikely to be a ‘magic bullet’ for COVID-19 treatment, at least not anytime soon. Rather, a combinational drug strategy should be advocated as a realistic alternative treatment regimen. Clinical manifestations of disease should be observed from a holistic perspective as viral replication, cytokine storm, coagulation and other events occur simultaneously or in very rapid succession. In addition, at the time they are admitted to critical care facilities the extent of disease progression is specific to each patient, so it becomes extremely challenging for healthcare providers to address the therapeutic needs of the individual. Therefore, based on this complex scenario, in aiming to reduce the severity of disease for as many critical care patients as possible a guideline combinational regimen of treatment with several therapeutics is preferred.
Since patients with comorbidity are likely to experience cytokine imbalance, we consider the first priority to be rescue from cytokine storm. In order to restore the cytokine balance efforts should be taken to switch IL-6 trans-signaling to classical-signaling and to curtail ADAM17-mediated shedding events. In this regard, we propose the use of sgp130 and ADAM17 inhibitor with high specificity, which may show considerably more therapeutic potential than either a global cytokine inhibitor or IL-6R inhibitor. We have already discussed how sgp130 forms a protective neutralizing buffer against IL-6 trans-signaling. Multiple studies have confirmed that sgp130 is highly specific to IL-6 trans-signaling. It inhibits IL-6 trans-signaling by trapping IL-6/sIL-6R without influencing the protective roles of IL-6 classical-signaling. In the event of cytokine storm, it is necessary to neutralize the sIL-6R function without any compromise to broader IL-6 activity. Anti-inflammatory drugs often inhibit global IL-6 function or global immune suppression, whereas it is evident that selective inhibition of IL-6 trans-signaling is greatly superior in this regard to global suppression of IL-6. Immunosuppressive drugs can inadvertently prove fatal to patients with comorbidity by increasing their susceptibility to new infection. A recombinant protein, sgp130Fc, was developed in which the extracellular portion of gp130 is fused to the Fc portion of human IgG1 antibody. Using sgp130Fc, successful inhibition of IL-6 trans-signaling can be achieved both in vitro and in vivo without affecting IL-6 classical-signaling at low concentrations. Moreover, it has been reported that sgp130Fc achieves more effective inhibition (10- to 50-fold) of IL-6 trans-signaling than does sgp130 monomer itself. This protein also showed superior results over the anti-IL-6-R antibody tocilizumab and proved that inhibition of trans-signaling is more desirable to global blockade of IL-6 signaling.
By the time sgp130Fc forms neutralizing buffer to trap excess sIL-6R complex it is also necessary to inhibit ADAM17-mediated IL-6R and ACE2 shedding events. We should bear in mind that the entire IL-6 signaling pathway is concentration-dependent. Under normal circumstances upon activation IL-6 can increase in level many folds higher than sIL-6R whereas sIL-6R increases only modestly. It is worth noting that at steady state the concentration of sIL-6R is not related to ADAM17 shedding but instead depends on differential splicing of IL-6R mRNA. ADAM17-mediated shedding events act to increase sIL-6R concentration continuously. Therefore, we also need to block proteolytic cleavage of IL-6R in order to reduce the sIL-6R molar concentration lower than that of IL-6. If and when the concentration of IL-6 exceeds that of sIL-6R sgp130Fc neutralizes trans-signaling and IL-6 classical-signaling commences.
Inhibition of ADAM17 will suppress ACE2 shedding. Through this mechanism Ang II concentration is reduced and M2 macrophage-mediated anti-inflammatory responses are triggered. For this purpose, ADAM17 inhibition may be considered as the preferred and most targeted approach. Therapeutic targeting of ADAM17 inhibitor has necessarily to be highly specific and non-toxic. Several ADAM17-based drug candidates have been tested in the past, of which a number were discontinued due to their lesser efficacy and higher toxicity. Recently, a recombinant ADAM17/TACE prodomain (TPD) was developed, which is reported to be stable, highly specific and auto-inhibitory. This inhibitory prodomain binds to human TACE in a precise manner and successfully inhibits shedding events. Most importantly, this inhibitor is noted not to share any sequence homology with any other related proteins from the ADAM family, to fold correctly and to remain stable in vivo, properties that collectively make it a prime candidate as an ADAM17 prodomain inhibitor. The therapeutic potential of TPD was illustrated by its successful blocking of IL-6 trans-signaling involved in severe disease pathology. A combination of both sgp130Fc and TPD may rescue the balance between cytokines
While protecting ACE2 receptor from shedding will protect from Ang II- and AT1R-mediated ADAM17 activation and pro-inflammatory responses, paradoxically it also offers an opportunity for virus entry by binding of SARS-CoV-2 spike protein to ACE2 receptor. ACE2 receptor is distributed across a wide range of cell surfaces that may provide potential targets for virus spread if replication is not controlled [87], [88], [89]. Hence, use of an antagonist to SARS-CoV-2 entry or replication should additionally be investigated. The mechanisms by which virus entry is inhibited have been explained in detail in current works [90], [91], and therefore are not part of this discussion.
Lastly, the coagulation observed in some COVID-19 cases should not be overlooked [69]. Patients could be admitted to hospital at any stage of disease progression and those with comorbidity who may already have higher sIL-6R are susceptible to developing trans-signaling-associated intravascular coagulation. Therefore, anticoagulant administration may have a beneficial effect if used in combination with TPD, sgp130Fc and a candidate antiviral. Already, use of anticoagulants has shown a degree of therapeutic value.
Future challenges
Recently, an open-label, randomized, phase 2 trial of a triple drug combination was announced. This reported a better outcome by using two antiviral drugs, lopinavir-ritonavir and ribavirin, in combination with immunomodulatory cytokine IFN-β-1b [93]. The findings of this study support our notion to develop a combinatorial therapeutic approach with emphasis on IL-6 signaling modulation. However, we prefer to consider immune-modulation by inhibiting IL-6 trans-signaling specifically rather than by a global means. A complex and interconnected picture of the immunopathogenesis observed in COVID-19 is described herein. Following consideration of these networked events we propose a combinatorial drug-based approach to therapy that includes TPD in order to inhibit shedding of ACE2 and IL-6 that ultimately cascades to cytokine storm, sgp130Fc in order to restore cytokine balance, an antiviral in order to reduce viral load, and an anticoagulant in order to avoid inflammation-associated coagulopathy. Theoretically at least, we consider that this drug combination may well promote enhanced recovery from COVID-19, yet its safety and efficacy first needs to be explored fully by pre-clinical testing and in clinical trials.
To our knowledge, sgp130Fc has passed successfully toxicology tests and phase I clinical trial, although confirmatory data await publication. Based on this premise, multiple phase II trials are ongoing in China, Taiwan and South Korea [94]. Another potential candidate, TPD protein, has not yet undergone clinical trial. A group from The Weizmann Institute of Science in Israel is researching the development of TPD for clinical use [personal communication].
To date, there are still no regulatory approved therapeutic approaches with which to fight this pandemic. However, the US National Institutes of Health have announced a keenly anticipated clinical trial of the anti-inflammatory drug baricitinib plus the antiviral remdesivir co-administered for treatment of COVID-19 patients. From prior experience, we prefer selective inhibition to global suppression of inflammatory cytokines as it is proven to be beneficial in pathophysiological states and to curb disease progression.
Concluding remarks
With a view to developing a promising drug candidate against COVID-19 there is a pressing need right now to bridge existing knowledge gaps and to use the lessons learned from previous trials. In order to address the treatment plan for COVID-19 it should be remembered that the disease manifestations are not caused simply by an imbalance of a single biomolecule. Rather, they reflect an overall dysfunction of the convoluted and intricate immune system due to cytokine imbalance and other associated complex events that are triggered by SARS-CoV-2 infection. Therefore, future development of a therapeutic strategy should recognize the advantages of a combinatorial approach over a reductionist, single drug-based therapy. However, careful evaluation of any clinical trial based on our proposition is recommended to determine the therapeutic potential. Until such drugs are available we should continue to promote best hygiene practices and social distancing measures, to seek early and accurate diagnosis and to explore mechanisms for disease management and prevention that take into consideration as much as possible the economic burden of this pandemic. This is particularly crucial during the ongoing perilous period of undetermined length while an efficacious prophylactic vaccine against SARS-CoV-2 remains in development.
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