Monoclonal antibody therapies against SARS-CoV-2

Introduction

The first monoclonal antibody (mAb) for clinical use (muromonab-CD3) was approved by the US Food and Drug Administration (FDA) in 1986.¹ Since then, about ten new mAbs have been approved each year (mostly IgG1), with an estimated global yearly sale of US$75 billion in 2021.² Most of these mAbs have been licensed for non-infectious disease indications. However, successful efforts have been made in the COVID-19 pandemic to research and develop mAbs against SARS-CoV-2. At the beginning of the COVID-19 pandemic, IgG mAbs against the spike protein of SARS-CoV-2, either as single agents or mAb cocktails (ie, a combination of two or more mAbs), were announced and advertised by many authorities as the most effective antibody therapeutic solution for COVID-19.³ As of March 4, 2022, the Coronavirus Antibody Database (CoV-AbDab) contains 5210 antibodies and nanobodies against SARS-CoV, MERS-CoV, and SARS-CoV-2.

Many randomised clinical trials of mAb therapy and prophylaxis have been launched, initially for patients being treated in hospital and then for outpatients, all showing overall moderate efficacy and good safety (Table 1, Table 2 ). Many classifications of anti-spike mAbs according to the targeted epitopes have been suggested (table 3 ). In this paper, we review the information available for mAbs against SARS-CoV-2 (panel 1 ) to identify the strengths and weaknesses of this therapeutic strategy, which are apparent from 2 years of clinical experience.

Efficacy in randomised clinical trials

Efficacy of mAbs was measured as reduction of infection rates when mAbs were used in pre-exposure or post-exposure prophylaxis, reduction in hospital admissions when mAbs were administered as treatment for outpatients, or reduction in disease progression or mortality when mAbs were used as treatment for inpatients. Similar to therapies based on neutralising antibodies, such as the cheaper COVID-19 convalescent plasma, therapeutic efficacy was exclusively shown in seronegative and early inpatients. Reductions of the measured variables ranged between 30% and 40%, which was enough to meet statistical significance, but the effect was not sufficiently large for these mAbs to be considered an effective therapy, since a substantial proportion of patients treated with mAbs did not appear to benefit. Better results were observed for prophylactic indications and in outpatients, especially when patients at high risk of disease progression were recruited to increase the cost-effectiveness of the procedure.

Specifically, a randomised clinical trial that led to the authorisation of bamlanivimab (Eli Lilly, Indianapolis, IN, USA) showed that the efficacy of bamlanivimab administered alone was not significant: the proportion of patients who recovered in, or were discharged from, hospital ranged from 82% to 88% for the bamlanivimab group versus 79% to 90% for the placebo group.⁵ REGN-COV2 (a cocktail of two mAbs, casirivimab and imdevimab; Regeneron and Roche, New York, NY, USA) use led to an 84–92% relative risk reduction in developing symptomatic COVID-19 infections, and a significant reduction in mortality in patients treated in hospital at day 28 from baseline.⁷ Sotrovimab (GSK, Brentford, UK) use led to a relative risk reduction of 85% in progression of the infection leading to admission to hospital or death. Regdanvimab (Celltrion, Incheon, South Korea) use reduced the risk of admission to hospital or death by 72% in patients at high risk of progression to severe COVID-19, and only few patients with symptomatic infection required admission to hospital or oxygen therapy, or died.¹³ Bebtelovimab (Eli Lilly, Indianapolis, IN, USA) was approved in patients with mild-to-moderate COVID-19 at high and low risk of disease progression, either administered alone or together with bamlanivimab and etesevimab (Eli Lilly, Indianapolis, IN, USA). In the overall population treated with bebtelovimab alone or the mAb cocktail, a small proportion of patients (1·7–4·0%) required admission to hospital or died.⁵⁶ AZD7442 (a cocktail of tixagevimab and cilgavimab; AstraZeneca, Cambridge, UK) is the only combination approved by the FDA for pre-exposure prophylaxis: among patients who had a negative SARS-CoV-2 PCR test at baseline, tixagevimab and cilgavimab reduced the risk of developing symptomatic COVID-19 by 73–92%, and the risk of disease progression or death ranged from 3·5% to 4·4%.¹¹

Unfortunately, no randomised clinical trial was done by a pharmaceutical company after vaccine coverage was high, and thus mAbs continued to be administered to individuals with vaccine-induced seropositivity, without any conclusive evidence supporting their efficacy in these settings. Such lack of reappraisal by public investigators is a serious concern for reliability of current evidence on mAbs. However, mAb efficacy in individuals with vaccine-induced seropositivity is likely to be much lower than in individuals who are not vaccinated: novel randomised clinical trials are hence needed to support the assessment of cost versus efficacy of the intervention in this group of individuals, who represent most people nowadays.

Notably, when poor results were observed for patients who were treated in hospital, pharmaceutical research moved to establishing efficacy of, and using, mAbs in outpatients, for whom mAbs were more likely to be effective on the basis of previous experience with antiviral mAbs. These mAb trials had an advantage compared with randomised clinical trials of COVID-19 convalescent plasma because they were sponsored by pharmaceutical companies; trials of COVID-19 convalescent plasma, in which efficacy was likely to be low and there were not as many outpatients, were instead supported by physicians and the medical community to assist patients with advanced disease.⁵⁷

The rapid development of the pandemic highlighted some predictable limitations in the development of mAb therapies: of a very broad pipeline,⁵⁸ only a few candidates were initially approved by regulatory authorities in sufficient time to be used. The initial success of some mAbs, such as casirivimab and imdevimab, discouraged small companies from pursuing other research and development efforts, because of the assumption that the mAbs that had reached the market first would have been adequate and sufficient therapeutics. With the emergence of the delta (B.1.617.2) and omicron (B.1.1.529) variants of SARS-CoV-2, the mAbs that were used early in the pandemic against the wild-type and alpha (B.1.1.7) variants lost their neutralising activity. Therefore, when other mAbs were needed, manufacturing bottlenecks largely hindered large-scale deployment.⁵⁹ However, even if additional mAbs had been widely available, their cost would have probably remained prohibitive even for high-income countries. Notably, when mAbs were ultimately made available, many did not show to be effective against SARS-CoV-2 within a short time after their introduction, because the virus rapidly escaped their narrow specificity with the generation of mAb-resistant variants.⁶⁰

Safety in randomised clinical trials

The safety of mAbs was measured as the number of adverse events and serious adverse events occurring after their administration. Generally, adverse events were non-severe (eg, diarrhoea and nausea) and self-limiting. The most common adverse events were injection-site reactions, headache, chills, and bronchospasm.4, 6, 8, 9, 10, 12, 19 Serious adverse events occurred very rarely,4, 6, 8, 9, 10, 12, 19 and those affecting the respiratory tract (eg, shortness of breath) were probably related to the progression of COVID-19. Death occurred only in few patients, especially those clinically at high risk of disease progression or treated in hospital. More than 95% of patients completed the infusion of mAbs. The incidence of antidrug antibodies was assessed only in the regdanvimab trial,⁶¹ in which they were not detected. Nevertheless, repeated exposure to mAbs, such as in pre-exposure prophylaxis, comes with concerns, such as a growing incidence of treatment-emergent resistance.

Resistance to mAbs

As for any other therapeutic, resistance to mAbs binding the spike protein can be either initial (ie, pre-existing before treatment) or treatment-emergent (ie, positive selection of immune-escape variants after treatment). Both types of resistance can be predicted in vitro, using gene sequencing efforts for initial resistance, or viral serial passage in the presence of the mAb for treatment-emergent resistance. However, the implications of these types of resistance are different. Initial resistance discourages regulatory bodies from introducing a mAb into therapeutic guidelines, when the prevalence of the mutations that confer initial resistance to the mAb in the circulating strains is high. By contrast, a high incidence of treatment-emergent resistance could trigger a mandate follow-up order to promptly detect immune escape and treatment failure. With regard to viral fitness, although widespread circulation of a resistant strain invariably indicates enhanced fitness, typically only a few mutations associated with treatment-emergent resistance are sufficiently fit to spread within communities. This reduced viral fitness is clearly shown by the relative scarcity of SARS-CoV-2 lineages with E406 mutations that are resistant to REGN-COV2 in the Global Initiative on Sharing All Influenza Data (GISAID). In addition to REGN-COV2, the spike E406W mutation abrogates neutralisation mediated by cilgavimab. E406W results in allosteric changes to the ACE2-binding site, thereby reducing receptor recognition by these three mAbs.⁶² On the other hand, sudden emergence of the Q493R mutation in the omicron variant of concern, which is resistant to bamlanivimab, cannot be imputed as immune escape, since the omicron variant emerged many months after the use of bamlanivimab was discontinued worldwide.⁶³

The in-vitro studies that have investigated spike mutations in variants of interest and variants of concern conferring resistance to mAbs are summarised in panel 2 . Caution should be used when drawing conclusions on these complex variants: for example, the delta variant of concern consists of more than 200 sublineages, many of which harbour spike mutations that could affect mAb sensitivity of individual sublineages.⁷⁴ The reduction of mAb neutralising activity by different circulating variants of interest and variants of concern of SARS-CoV-2 is shown in table 4 .

We previously reviewed immune escape to therapeutics based on neutralising antibodies, including mAbs,⁶³ and we provide an update of our previous research as of Feb 15, 2022, in the appendix (pp 1–6).

The omicron hurricane

In November, 2021, omicron emerged, a new variant of concern that led to an unexpected change in the pandemic, due to its high reproduction number and ability to cause breakthrough infections in vaccinated individuals. Because of omicron's high number of spike mutations and deletions compared with previous variants of concern, most clinically approved mAbs suddenly lost their efficacy against SARS-CoV-2 (appendix pp 1–6).¹¹⁴ The FDA was among the first regulatory authority to issue updated guidance documents on mAbs; on Jan 24, 2022, the FDA revised the authorisations for two mAb treatments—REGN-COV2, and a cocktail of bamlanivimab and etesevimab—to limit their use to patients who are likely to have been infected with, or exposed to, a variant that is susceptible to these treatments.¹¹⁵ Attributing infection to a specific variant requires sequencing efforts, which are expensive and poorly scalable, and the long turnaround time is not compatible with early administration of mAbs to seronegative patients. When omicron emerged, only sotrovimab retained in-vitro efficacy; however, because sotrovimab is a single mAb rather than a cocktail, it is susceptible to the emergence of immune-escape variants, such as the E340K mutation, which has been reported in up to 10% of recipients of sotrovimab.116, 117 After new omicron sublineages emerged, resistance of the BA.2 sublineage, which is nowadays dominant, was reported:77, 78, 89, 90, 106, 118 the FDA first restricted the use of sotrovimab on Feb 25, 2022, and withdrew authorisation on April 5, 2022. Despite losses in neutralisation in vitro, S309 (the parent mAb of sotrovimab) or AZD7442 treatments reduced BA.1, BA.1.1, and BA.2 lung infection in susceptible mice that expressed human ACE2 (K18-hACE2);¹¹⁹ however, animal models are clearly not enough.

To improve preparedness, the FDA approved bebtelovimab for outpatients on Feb 11, 2022, on the basis of only a phase 2 clinical trial;¹²⁰ however, similar to sotrovimab, because bebtelovimab is a single mAb, it is susceptible to the emergence of immune-escape variants. Consequently, in the trial, bebtelovimab was co-administered with etesevimab plus bamlanivimab, representing the first cocktail of three mAbs against SARS-CoV-2.

We previously reviewed the limitations of the bamlanivimab plus etesevimab,¹²¹ and the casirivimab plus imdevimab¹²² cocktails, and especially their loss of neutralising activity against the omicron variant of concern, which is currently the dominant variant worldwide.

Fortunately, all the currently available small molecule antivirals—remdesivir, molnupiravir, and nirmatrelvir—have remained effective in vitro against omicron.¹²³ However, these antivirals are expensive, moderately effective in vivo,¹²⁴ and sometimes come with safety concerns, such as the mutagenicity of molnupiravir to host RNA.¹²⁵ Because of the scarcity of antiviral agents, both the FDA¹²⁶ and the International Swaps and Derivatives Association¹²⁷ also reassessed COVID-19 convalescent plasma for outpatients at risk of progression, because its polyclonal nature makes it less susceptible to immune escape by variants.

Perspectives

Despite the widespread use of mAbs in medicine, relatively few have been developed against viral diseases: among them, palivizumab (AstraZeneca, Cambridge, UK) has been approved for pre-exposure prophylaxis of respiratory syncytial virus in infants at high risk,¹²⁸ RAB-1 (Serum Institute of India, Pune, India) for post-exposure prophylaxis of rabies, and the REGN-EB3 cocktail (Regeneron, New York, NY, USA), which is a combination of atoltivimab, maftivimab, and odesivimab, for the treatment of Ebola virus disease.

In contrast to the respiratory viruses that cause systemic infections, such as measles, rubella, varicella, and smallpox (which was declared eradicated by WHO in 1980), the endemic coronaviruses, influenza viruses, respiratory syncytial viruses, parainfluenza viruses, and SARS-CoV-2 primarily infect epithelial cells on mucosal surfaces and generate a reduced systemic immune response, at least initially and in patients who have mild disease. Furthermore, because replication of these viruses occurs in the nostrils, systemic humoral immunity is low such that antibodies specific for viral antigens are not able to always prevent infection. These antibodies thus elicit incomplete and transient protective immunity leading to reinfections. Additionally, systemically administered vaccines elicit systemic responses that are effective at moderating the severity of disease but do not prevent infection.

The coronaviruses pose major challenges because they combine high infectivity and genomic variability that translates into frequent protein changes, resulting in high antigenic variation. Consequently, coronaviruses are hard to eradicate; yet, pandemic preparedness plans include the development of universal vaccines¹²⁹ and mAbs targeting shared epitopes among coronaviruses. Furthermore, modern recombinant mAb technology introduces several modifications to the primary sequence to improve or ablate effector functions and increase circulation half-life.¹³⁰

Conclusions

The rapid deployment of multiple mAb therapies during the pandemic has been a remarkable human accomplishment. mAb therapies have undoubtedly saved thousands of lives by preventing progression of early disease to life-threatening conditions that would have otherwise required treatment in hospital. However, the experience of the past 2 years has also shown limitations of this approach, which could have been foreseen from what was known about antibody action and the antigenic variability of SARS-CoV-2. Although a few regulatory authorities promptly issued recommendations to avoid the inappropriate use of mAbs against resistant variants of concern as soon as they became locally dominant (NCT04501978),¹¹⁵ the use of ineffective and costly treatments has often continued for months, thus wasting economical resources and increasing the incidence of unnecessary side-effects.¹⁶⁶ Such unjustified use of therapeutics is unacceptable in modern, evidence-based medicine, and can have serious consequences during a pandemic.

The clinical efficacy of mAbs has remained limited to patients with early and mild disease stages, as would be expected for a therapy that works primarily as an antiviral agent. Their high cost means that they are unlikely to become prominent treatment options in low-income and middle-income countries that cannot afford them. Scaling up of manufacturing is also a bottleneck for high-income economies, which often have had difficulties at procurement. Several lessons were learnt from the pandemic, such as the need for combining different (ideally non-overlapping) mAbs to minimise immune escape. Recombinant technology has been deployed to increase half-life and minimise off-target toxicity.

Overall, mAbs remain an important achievement of modern science, but their feasibility and economical sustainability against pathogens are likely to be maximal in small outbreaks and localised epidemics, rather than under pandemic settings. During a pandemic, an enormous number of affordable doses would be needed to have a positive impact on a global scale. In such instance, alternatives that are more robust and scalable than mAbs are preferred, such as convalescent plasma, or oral or intravenous small-chemical antivirals;¹⁶⁷ however, small-chemical antivirals are expensive and often associated with pharmacokinetic contraindications.

Search strategy and selection criteria

Declaration of interests

AC is the Chair of the US National COVID-19 Convalescent Plasma Project and reports being part of the scientific advisory board of SAB Therapeutics, a company developing cow polyclonal antibodies. All other authors declare no competing interests.

Supplementary Material