key: cord-0832370-5gblq4bz
authors: Sajna, Kuttuvan Valappil; Kamat, Siya
title: Antibodies at work in the time of SARS-CoV-2
date: 2020-08-31
journal: Cytotherapy
DOI: 10.1016/j.jcyt.2020.08.009
sha: c587ff335e7a8a133b6dd8341434f0731351e9dc
doc_id: 832370
cord_uid: 5gblq4bz

Even after a decade of continuous emergence of coronaviruses, there aren't any licenced vaccines or therapeutics against the deadly infection. The age-old passive immunization with protective antibodies to neutralize the virus is one of the strategies for emergency prophylaxis and therapy for COVID-19. In this review, we discuss the up-to-date advances in immune-based therapy for COVID-19. The use of convalescent plasma therapy as the first line of defences to treat SARS-CoV-2 infection has been established with encouraging results. Monoclonal antibodies (mAbs) that bind to the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein or blocking the interaction between SARS-CoV-2 RBD and human angiotensin-converting enzyme 2 (hACE2) receptor have been found very promising as the countermeasure to tackle the SARS-CoV-2 infection, though clinical trials are underway. Considering the counterproductive antibody-dependent enhancement of the virus, the mAbs therapy that is safe and efficacious even in people with an underlying condition will be a significant breakthrough. The emerging immunotherapeutic interventions using nanobodies and cellular immunotherapy are also the promising avenues to tackle the COVID-19 pandemic. We also discuss the implication of mAbs against mediators of cytokine storm syndrome to modify the immune response of COVID-19 patients, thus reducing the fatality rate of COVID-19 infection.

The latest 21 st begin with a range of clinical manifestations including fever, cough, and dyspnoea with no or mild pneumonia. Severe cases presented dyspnoea, hypoxia, and >50% pulmonary damage requiring intensive care for respiratory support, while the critical cases were characterized by respiratory and multi-organ failure. SARS-CoV is also known to cause the common complication of acute respiratory distress syndrome (ARDS) in patients, thus requiring mechanical ventilation [2] .

The high morbidity and mortality rates worldwide demonstrate that there seem to be differential responses in COVID-19 patients. The global imperative of the current hour is to rapidly develop immune therapy to prevent COVID-19 [3] . Hence, it is necessary to understand the immunological basis of this infection, the implications of which will offer a better insight into the development of new therapies. Extracorporeal membrane oxygenation (ECMO), is one of the evolving strategies which can be utilized in treating patients with refractory hypoxemia and altered lung properties despite optimal conventional treatment including mechanical ventilation [4] . Combining antiviral and anti-inflammatory treatments is being investigated. Efforts to repurpose drugs for COVID-19 with the challenge of appropriate dosage remains an attractive treatment modality [5] . Many studies have also tried to investigate the function of glucocorticoids to modulate inflammation mediated lung injury, thereby mitigating the progression of respiratory failure and mortality [6] .

The first event in the chronology of SARS-CoV-2 infection is virus binding to a host cell.

The cytopathic virus utilizes its spike glycoprotein (S) located on its surface to bind with the angiotensin-converting enzyme 2 (ACE2) receptor for cell entry. Various research groups have targeted the receptor-binding domain (RBD) of SARS-CoV, SARS-CoV-2, and MERS-CoV with neutralizing antibodies to combat the infection [7] . S protein has two functional subunits-S1 subunit mediates cell attachment and S2 subunit involved in the fusion of viral and cellular membrane [8] . SARS-CoV-2 principally targets airway, alveolar and vascular epithelial cells, and lung macrophages, all of which express the ACE2 entry receptor. SARS-CoV-2 in complex with ACE2 is endocytosed by cells. As a result of the inaccessibility of ACE2 to regulate the renin-angiotensin system (RAS), blood pressure and electrolyte imbalance occur [9] . Furthermore, loss of ACE2 also promotes accumulation of Ang II ( Angiotensin II) which eventually activates ADAM-17 (A disintegrin and metalloproteinase 17) activity, perpetuating membrane shedding of ACE2, RAS overactivation and inflammation [10, 11] . Zhu et al.. investigated the morphogenetic process and cytopathic effect of SARS-CoV-2 infection in the organotropic human airway epithelial cultures [12] . It was observed that the virus infected both ciliated and secretory cells due to which, the authors suggest the possibility of more receptors in addition to ACE2. This is because ACE2 is mainly expressed on ciliated epithelial cells of the human lungs [12] . Viral infection and replication in the upper respiratory tract epithelial cells induce pyroptosis. This inflammatory phenomenon of programmed cell death is commonly observed in SARS-CoV infected cells too [13] . The epidemiology working group for NCIP Epidemic Response, reported the differential fatality rate in males and females where the percentage of death was more in males than in females [14] . This correlates with the immunoregulatory functions of estrogen and testosterone [15] . A cellular serine protease TMPRSS2 is observed to process the S protein and eventually contribute to the host cell entry. Hence, TMPRSS2 is also a potential drug target that has attracted a lot of attention in the field of repurposed drugs against SARS-CoV-2 [14] .

The destruction of pulmonary cells initiates a local immune response involving macrophages and monocytes which release an array of cytokines. This action also primes the adaptive immunity by T and B cells. The mild cases of COVID-19 are primarily resolved at this stage.

However, severe lung destruction is associated with a dysfunctional immune response.

Pyroptosis of the airway epithelial cells releases IL-1β, a potential trigger for the eventual inflammatory response [16] . This wave of local inflammation is sensed by the alveolar epithelial cells and alveolar macrophages ensuing the secretion of pro-inflammatory cytokines and chemokines like IL-6, IFN-γ, MCP1, and IP-10. This starts the pulmonary recruitment of monocytes and T lymphocytes into the infected site. Thus, the infiltration of lymphocytes into the respiratory airway manifests into T cell lymphopenia, observed in majority of COVID-19 patients [13, 17] .

The escape pathogen SARS-CoV-2 can sabotage the innate response by antagonism of the interferon response like SARS-CoV and disrupt the host protein translation process. This could potentially support viral replication and eventually manifest into pyroptosis associatedaberrant inflammation in the lungs [13, 18] .

In most of the mild cases, the recruited immune cells clear the respiratory airway after which the immune response recedes. But a dysfunctional immune response is observed in severe cases which triggers a massive cytokine storm that mediates extensive lung inflammation.

The cytokine storm involves elevated blood plasma levels of macrophage inflammatory protein 1α (MIP1α) and tumor necrosis factor (TNF), IL-2, IL-7, IL-10, IP-10, MCP1, and granulocyte monocyte colony-stimulating factor (GM-CSF). Also, a high population of CD14 + CD16 + inflammatory monocytes, which also contribute to the cytokine storm, is also observed in severe cases. Lymphocyte counts in the peripheral blood are also observed to remarkably decrease [19] . Other observed consequences of T cell lymphopenia and cytokine storm are hyaluronan formation and pulmonary edema. This contributes to severe breathlessness and vulnerability to secondary infections. The ripple effect of the cytokine storm brings about myocardial damage and multi-organ failure [3] . Transcriptomic analysis of three COVID-19 patients revealed a dynamic early immune response. After reaching a lowest point in the respiratory function, a peak in most of the inflammatory and cytokine signalling gene expression, except expression in IL-1 pathway which preceded the decrease in respiratory function, was observed [20] .

B cell immune response is concomitantly observed 1 week after the onset of symptoms. The antibody response is observed against nucleocapsid and S protein by week 3 of SARS-CoV infection symptoms. However, it is seen that some COVID-19 patients do not develop longlasting antibodies [13, 21] . While a lot of studies represent significant inroads, a clear understanding of the important host immune factors involved in the development of COVID-19 inflammation remains incompletely defined.

The most distinctive comorbidities of fatalities or severe cases of COVID-19 have been diabetes, cerebrovascular diseases, hypertension, coronary heart diseases, and cancer. Since cells expressing ACE2 are normally found in the epithelial lining of lungs, intestine, kidney, and blood vessels, it only makes patients with comorbidities susceptible to SARS-CoV-2 [22] . Most therapies routinely prescribed for these comorbidities, favour the gateway of SARS-CoV-2 ( Table 1) . While the efforts to develop targeted immune therapies and vaccines are underway, many health organizations are advocating the practice of yoga, Ayurveda, and maintaining a healthy lifestyle to boost immunity [23, 24] 

While some labs are involved in repurposing old antiviral drugs against the novel virus, some are involved in designing a definite immune therapy. Remedesivir and lopinavir have presented potential antiviral effect and are being clinically investigated for safety and efficacy [34] . The efficacy of corticosteroid treatment for lung inflammation is also being questioned due to complications and delayed clearance of the infection [33] . Clinical trials to validate the efficacy of the anti-malarial drug, hydroxychloroquine which is also used to treat certain autoimmune diseases (lupus and rheumatoid arthritis), anti-cytokine therapies like IL-6 inhibitors, and mesenchymal stromal cell-based therapies in COVID-19 patients are underway [35] . In such a scenario, where the production of an effective vaccine and antiviral medicines are underway, convalescent plasma therapy and nanobodies have become exciting non-vaccine pharmacological tools for prevention [36] .

This is a typical adaptive immunotherapy applied successfully to stem outbreaks of SARS, MERS, H1N1 pandemic of 2009, poliomyelitis, measles, and mumps [37, 38, 39] . However, the application of CP could not treat the Ebola virus disease. Since SARS, MERS, and COVID-19 share some similarities in the immunopathogenesis of their etiological agent, CP is looked upon as a promising option in treating COVID-19 [39, 40] . It has been reported by can be concluded that neutralizing antibodies represented transient humoral immune response, and plasma from newly recovered patients should be more effective. The neutralizing antibody titer of recently recovered COVID-19 patients was above 1:640, which is higher than that of MERS patients [42] .

SARS patients who were given CP before 14 days post-onset of illness (dpoi) demonstrated a better outcome. Similarly, in Duan and co-workers' study, the patients who received CP transfusion before 14 dpoi exhibited a spike in lymphocyte count and reduction in C-reactive protein, which is a marker of inflammation and cytokine storm. Patients who received CP after 14 dpoi showed relatively less improvement, emphasizing the importance of an optimal transfusion time point [42] . The Stony Brook Hospital, New York has initiated trials to test CP therapy for COVID-19 patients (https://clinicaltrials.gov/ct2/show/NCT04344535).

Recently, the US Food and Drug Administration (FDA) approved the access to CP for COVID-19 patients while emphasising on regulatory measures and clinical trials, before routinely administering this therapy [43] . It was reported that worldwide use of this therapy has mushroomed very rapidly due to encouraging results in patients [44] . In a study by Joyner et al., early implications of CP therapy in 500 severe or life-threatening COVID-19

individuals of diverse races in the median age of 62 years were studied [43] . They observed <1% severe adverse events including 0.3% mortality within first four hours of transfusion.

The seven-day mortality rate was 14.9% which could also be due to underlying multi-organ failure, sepsis and other significant comorbidities. The authors discussed the possibility of developing transfusion related acute lung injury (TRALI) and transfusion associated circulatory overload (TACO) as the associated pulmonary complications post therapy which are often difficult to identify. TACO results in circulatory overload followed by pulmonary oedema and hypertension. TRALI is characterized by bilateral pulmonary edema with or without acute respiratory distress syndrome (ARDS) risk factors. In certain cases, it was observed that an underlying lung injury or comorbidities in COVID-19 patients further complicate the diagnosis of TACO and TRALI which could exacerbate transfusion related risks in severe patients [43] . Transmission of pathogen is also a major risk associated with CP therapy [40] . To maintain the activity of the antibodies and inactivate the virus in the donated plasma, Duan et al.., applied methylene blue photochemistry, which is reported to be better than UV-C light [42] . Earlier studies on CP therapy for Ebola have reported transfusion-related acute lung injury. Antibody-dependent infection enhancement can be an uncommon risk which could suppress innate antiviral immunity and thus tolerate intracellular growth of the virus. However, it can be assumed that due to the high titer of neutralizing antibodies, optimal time of infusion and transfusion volume, the risk of antibody-dependent infection can be avoided. Thus, the use of CP therapy can be beneficial for COVID-19

patients [45] .

Nguyen et al.. define hyperimmune globulin as a product that is manufactured from convalescent plasma from thousands of donors with high antibody titers to a specific pathogen. It consists of an immune globulin fraction with well-defined properties [46] .

Plasmapheresis derived plasma from recovered COVID-19 patients, has been proposed to obtain polyclonal hyperimmune globulin. This approach has already been explored for patients with SARS and severe influenza. It has been routinely used to treat hepatitis B and rabies virus infected patients proving its precedence and sound therapeutic plausibility. Díez Another potential source is human trails testing for vaccines since an early immune response to the antigen is enough to release specific neutralizing antibodies with a high binding affinity [51] . S-RBD is an effective candidate as a bait to screen the antibody-producing memory B cells for developing therapeutics and diagnostics for SARS-CoV-2.

The SARS-CoV-2 has a genome sequence that is 79.6% identical to that of SARS-CoV and 96% identical to the bat coronavirus [52] The RBD sequences of SARS-COV-2 share 73.8-74.9% amino acid identity with that of SARS-CoV [53] . Both SARS-CoV and SARS-CoV-2 possess a conserved epitope in RBD, which makes it cross-reactive [54] . S glycoprotein of SARS-CoV-2 has ten times higher affinity to ACE2 than that of SARS-CoV; much of this affinity is attributed to RBD's structural features such as a more compacted ACE2-binding ridge and well-stabilized hotspots [55, 56] . CR3022, a neutralizing antibody obtained from a convalescent SARS-CoV infected patient had cross-reacted with SARS-CoV-2 S, but could not cross-neutralize SARS-CoV-2 in vitro [54] . binding to the RBD of SARS-CoV Se protein [58] . When 80R, m396 and S230 were tested against SARS-CoV-2 RBD, none of them showed significant binding regardless of the high degree of structural homology between SARS-CoV S RBD and SARS-CoV-2 S RBD.

Hence, SARS-CoV-2 S protein would be the ideal probe for the design of therapeutic mAbs against SARS-CoV-2 [55] .Yi et al.., gave some interesting insight into the critical amino acid differences in SARS-CoV and SARS-CoV-2 RBDs, which result in their distinct immunogenicity and limit the cross-neutralizing activity of therapeutic antibodies [59] . which strengthens the species-specific nature of anti-RBD antibodies [59, 63] . A cocktail of mAbs binding to the different epitopes on RBD will be more efficacious in neutralizing of SARS-CoV-2 and preventing immune escape mutants rather than monotherapy with a candidate therapeutic mAb [53, 62] . A major concern that should be addressed before implementation of antibody-based drug induce ADE [81] . Engineering the Fc region of mAbs to abolish its affinity for Fcγ receptor is a feasible solution to mitigate the risk of ADE [80] . To abrogate the risk of ADE of SARS-CoV-2, LALA mutations were introduced to the Fc region of CB6, a potent SARS-CoV-2 neutralizing antibody. CB6 (LALA) effectively reduced viral load and infection-related lung damage associated with SARS-CoV-2 infection in rhesus macaques [68] . Possibility of ADE can also be minimized by maintaining a high concentration of circulating therapeutic antibodies, which is easier to be achieved by improving the half-life of mAbs [83] . Lurie et al.., suggested that rigorous animal testing and preclinical trials should be conducted for the therapeutic candidates against SARS-CoV-2, considering the adverse effects caused by ADE [84] . The current uncertainty about the duration of functional protection by antibodies to SARS-CoV-2 RBD till the second wave of infection must be addressed to enhance the therapeutic efficacy of the monoclonal antibody products [85] .

The ability of a virus to generate escape mutants due to immune pressure is a major challenge for a successful vaccine and a therapeutic antibody development. A pandemic scenario influenced by a highly diverse infected population also facilitates the generation of escape mutants [86] . RNA virus such as SARS-CoV-2 exhibits a high mutation rate, up to a million times higher than its host, which drives viral evolution and adaptability [87, 88] . High viral load of SARS-CoV-2 at the early stage of the disease might also contribute to antiviral resistance [89] . Molecular modelling simulation studies of antigen-antibody complex predict the mutation of antigen that could disrupt the binding of Ab and reduce the efficacy of mAb therapy [90] . It has been reported that escape mutants attenuate SARS-CoV infection

Formulation of more than one therapeutic antibody that binds to non-overlapping epitopes and/or parts of S other than RBD has been proposed to neutralize the resistant variants [91, 92] . A cocktail of mAbs S227.14 and S230.15 had effectively cross-reacted with a broad range of human and zoonotic SARS-CoV isolates including escape mutants [93] . The mAbs combination targeting NTD as well as RBD of SARS-CoV-2 could be effective against viral escape [69] . Single antibody treatment against SARS-CoV-2 induced escape mutants.

Regeneron's mAbs cocktail, REGN10933 and REGN10987, each binds to the distinct epitopes of RBD prevented generation of escape mutants [94] .

An effective passive immune therapy along with stimulation of the endogenous humoral and cellular immune response can provide durable protective immunity. Combining mAbs with immunostimulatory agents or altering antibody effector function through Fc-engineered mAbs, are the possible options to improve the long-lasting protective vaccine-like effects of mAbs [95] . Half-life and effector functions of S309, a mAb with neutralizing activity against SARS-CoV-2 were improved by FC engineering [61] .

The prospect of highly potent super-antibodies that can neutralize multiple viruses of a single-family look quite promising in terms of developing a broadly-active therapeutic agents against the Coronaviridae viruses. Large scale screening for a donor with broadly neutralizing serum and a high throughput B cell isolation are the critical steps involved in the discovery of super-antibodies [96] . Defining the immunodominant regions of the S protein of SARS-CoV-2 is critical as it can reveal potential targets for immune response. Development of mAbs targeting conserved epitopes of RBD and highly similar S2 subdomain is likely to

give cross-protection across betacoronaviruses [71, 97] .

Immunomodulation of cytokine storm syndrome using mAbs therapy: a need of the hour Targeted drug development is a time-consuming process. Repurposed drugs and therapeutic mAbs that modulate the immune response and improve the prognosis of COVID-19 patients should be considered at this critical time until a successful drug is out on the market for viral

clearance. An anti-IL6 mAb, Tocilizumab, routinely used in the treatment of rheumatoid arthritis has been found to mitigate the cytokine storm syndrome and improve the outcome of COVID-19 patients. Apart from the anti-inflammatory action of Tocilizumab, its role in halting the coagulation activation greatly benefits the COVID-19 patients with severe coagulopathy, which make this therapy a very effective treatment than the general antiinflammatory interventions [98] . Tocilizumab has been recommended for critical COVID-19

patients with significantly high levels of IL-6 in China and India [99, 100] . It has also been suggested that mAbs targeting GM-CSF might also give a promising result for the intervention of inflammatory cytokine storm caused by SARS-CoV-2 and a clinical trial is underway (https://clinicaltrials.gov/ct2/show/NCT04341116). Since TNF also is a major player in the inflammatory responses, targeting it with an anti-TNF antibody is also a feasible strategy to reduce the COVID-19 induced lung inflammation and related inflammatory markers [101] . Administration of anti-C5a mAbs is also presumed to have a role in the mitigation of COVID-19 associated lung injury [50] .

Llama based nanobodies have been implicated in designing antiviral therapy against HIV, rotavirus and respiratory syncytial virus [102, 103, 104] . Nanobodies are fully functional single domain antibodies obtained from the Camelid family, comprising of a single variable domain (VHH) instead of two variable domains as in the case of the human antibody. Their small size (≈14 kDa), good solubility and excellent stability along with high antigen specificity make them a superior candidate over the conventional antibodies [105] .

Nanobodies can be easily produced in yeast or bacterial host by recombinant technology [106] . The potency of nanobodies can be enhanced by engineering monovalent VHH into multivalent VHH [102] . 

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The authors declare that they have no competing interests.

Both the authors are equally involved in preparing, editing and finalizing the manuscript.