Antibody-Based therapy
Considered an efficient method for the clinical treatment of different infectious diseases, including MERS-CoV and SARS-CoV-1 (217), antibody-based immunotherapy has been studied as a potentially applicable tool to treat COVID-19. The mechanisms involved with its effects against SARS-CoV-2 are related to preventing the virus from entering the host cells, blocking its replication.
The virus entry block was studied for acting both in the cell receptor ACE2 and directly on the virus (neutralizing antibodies [nAbs]), specifically in the S1 subunit of the S protein (218–220). Regarding the blocking of ACE2 receptors, the application of some mechanisms stand out: the soluble version of ACE2 fused to an immunoglobulin Fc domain (ACE2-Fc), RDB domain attached to Fc (RDB-Fc), and receptor-targeted monoclonal antibodies (mAb) (221).
Viral neutralization by nAbs is also an immunotherapeutic approach and directly recognizes epitopic regions of SARS-CoV-2. This effect can be achieved either directly through mAbs manufactured in laboratories or by using polyclonal antibodies (pAbs) (218). nAbs act directly on the virus, preventing its infectivity by activating several pathways, such as the complement system, cell cytotoxicity, and phagocytic clearance (222–224).
The therapeutic use of mAbs has shown good outcomes, mainly due to its high specificity. Recently, several mAbs against viruses have been developed, including SARS-CoV-1 and MERS-CoV, in which the S protein is the major target described both in vitro and in vivo. According to some studies, the specific nAbs against SARS-CoV-1 RBD in the S protein could effectively block SARS-CoV-2 entry (218, 225). However, Wrapp et al. (226) tested several published SARS-CoV-1 RBD-specific nAbs and found that they do not have substantial binding to the S protein of SARS-CoV-2, suggesting that the cross-reactivity may be limited. Thus, the combination of nAbs with different viral targets and sources could improve treatment efficacy. In addition to experimental studies, to date, more than 10 clinical trials have aimed at testing human mAbs against SARS-Cov-2 (227–235), which could also represent an alternative, effective treatment.
Furthermore, some immunomodulatory mAbs have been tested in the context of COVID-19. It is remarkable that until now most of the data published regarding the use of immunomodulatory mAbs derive from studies using either anti-IL-6 or anti-IL-6R, probably because using IL-6 blockers seems promising at controlling the cytokine storm associated with the development of ARDS in more aggressive patterns of SARS-CoV-2 infection. However, clinical observations remain controversial.
Although some studies found considerable clinical improvements resulting from treatment with IL-6 blockers (236–239), others do not report any significant difference between the clinical features of groups treated with anti-IL6/IL-6R mAbs and their respective controls (without anti-IL-6/IL-6R) (240–243). These controversial results can be explained by the pleiotropic function of IL-6, which also play an important anti-inflammatory role, questioning the use of IL-6 blockade to suppress inflammation-induced tissue damage (244). Additionally, severe side effects have been associated with the use of IL-6 blockers, including enhanced hepatic enzymes, thrombocytopenia, severe bacterial and fungal infections, and sepsis (241, 245). In general, data from analyses on the use of this type of mAbs remain inconclusive (243, 246, 247).
Recent findings are optimistic, but data validation by robust scientific evidence has been hampered by the small sample size in most case reports and studies on the use of mAbs blocking other immune mediators, such as IL-1β, GM-CSF, and complement protein C5 (238, 248–250). However, seeking to verify the effectiveness of using mAbs blocking inflammatory mediators, dozens of clinical trials are currently underway.
Aiming at reducing the hyper inflammation found in the lungs of SARS-CoV-2-infected patients, different clinical studies are currently investigating the activities of mAbs anti-JAK, anti-GM-CSF, anti-GM-CSF receptor, anti-M-CSF receptor, anti-CD14, anti-IFNγ, anti-VEGF, anti-BKT, anti-CCR5, anti-IL-6, anti-IL-6 receptor, anti-TNFα, anti-IL1β, anti-IL1β receptor, and complement C5 inhibitor (220, 251, 252). Similarly, ongoing clinical trials have sought to reverse the hyper-thrombotic state found in critically ill patients by using anti-P-selectin, anti-CTGF, and factor XIIa antagonist mAbs (253, 254). Furthermore, to restore the exhausted T lymphocytes’ and NK cells’ immunity, other clinical studies applied anti-PD1 mAbs under the hypothesis of a stimulus of anti-viral response and prevention of ARDS (255–257).
More recently, the passive administration of pAbs has also been tested in COVID-19 patients (222–224, 258–267), also known as convalescent plasma (CP) or immune plasma, which is already used effectively and safely in the treatment of other severe acute respiratory syndrome infections of viral etiology, such as SARS, MERS, and H1N1, and offers only a short-term but rapid immunity to the susceptible individuals (268).
A strict criterion to select the CP donor states that the individual must show clinical recovery and test negative for the virus presence. Thus, after being confirmed, a high titer of neutralizing antibodies against SARS-CoV-2 must be stored in blood banks (269, 270).
Some reviews related to patients who received transfusion with CP showed a reduction in viral load, improvement in clinical symptoms, better radiological findings, and improved survival (260, 261, 271–273). In addition, after having received CP containing nAbs, COVID-19 patients had significant improvements from the beginning of treatment (until 22 days), presenting lower fever, decreased viral load, and higher nAbs levels. Further, 60% of the patients were discharged one month after the treatment (271). Better outcomes were found in early administration of CP (before SARS-CoV-2 seroconversion), preferably on day 5, for obtaining maximum efficacy (268).
More recently, Li et al. found no statistically significant clinical improvement or mortality reduction in a randomized clinical trial with CP-treated COVID-19 patients (274). However, the authors reported that CP treatment is potentially beneficial to critically ill patients by suggesting a possible antiviral efficiency of high titer of nAbs. Notably, there are clinical controversies, ethical issues, and potential risks associated with convalescent plasma therapy (275), such as the possibility of ADE development, exacerbating the disease severity, and causing a significant illness in future exposure to coronaviruses infection (268, 276, 277) (REF). Divergences between studies may be caused by variations in the composition of CP, which is highly variable and includes a variety of blood-derived components, timing of CP administration, titer of the specific antibody in administered plasma, and presence of blood borne pathogens (268). Nonetheless, understanding the efficacy and safety of CP therapy relies on the completion of the ongoing clinical trials.
Another therapeutic strategy using antibodies is intravenous immunoglobulin (IVIg) that contains polyclonal IgG isolated from healthy donors, which can be further enhanced by using IgG antibodies collected from recovered COVID-19 patients in the same geographical region as the patient. Results have been mostly positive, although many of these therapies have not been formally evaluated through a randomized, double-blind, placebo-controlled clinical trial (278). According to recent studies, IVIg can be used effectively in early stages of SARS-CoV-2 infection (before the initiation of systemic damage), reducing the use of mechanical ventilation, preventing the progression of pulmonary lesions, and promoting early recovery (268). Also, cross-neutralization activity was shown against SARS-CoV-2 in commercial IVIg manufactured prior to the COVID-19 pandemic and are currently under evaluation as potential therapies for COVID-19 (279). Thus, intravenous use of immunoglobulins can prove helpful in therapy against SARS-CoV-2, however, adjustments in the therapeutic regimen are necessary for all IVIg possibilities, as well as a complete understanding of the possible adverse effects, such as the risk of ADE (278, 279), that are being studied in more than 10 ongoing clinical trials.
Some works have shown that therapies focusing on the interaction between SARS-CoV-1 and the ACE2 receptor may be extended for use in SARS-CoV-2 patients as an immunotherapy tool (218). However, other authors refute this idea based on the fact that recent studies showed limited cross-neutralization between SARS-CoV-1 antibodies and SARS-CoV-2 (280, 281). Furthermore, it was shown that SARS-CoV-2 S protein binds ACE2 with a higher affinity than SARS-CoV-1, suggesting that such interaction differs between the two viruses (266).