REVIEWS Neutralizing monoclonal antibodies for treatment of COVID-19 Peter C. Taylor 1 ✉ , Andrew C. Adams2, Matthew M. Hufford2, Inmaculada de la Torre2, Kevin Winthrop3 and Robert L. Gottlieb 4,5 Abstract | Several neutralizing monoclonal antibodies (mAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and are now under evaluation in clinical trials. With the US Food and Drug Administration recently granting emergency use authorizations for neutralizing mAbs in non-hospitalized patients with mild-to- moderate COVID-19, there is an urgent need to discuss the broader potential of these novel therapies and to develop strategies to deploy them effectively in clinical practice, given limited initial availability. Here, we review the precedent for passive immunization and lessons learned from using antibody therapies for viral infections such as respiratory syncytial virus, Ebola virus and SARS-CoV infections. We then focus on the deployment of convalescent plasma and neutralizing mAbs for treatment of SARS- CoV-2. We review specific clinical questions, including the rationale for stratification of patients, potential biomarkers, known risk factors and temporal considerations for optimal clinical use. To answer these questions, there is a need to understand factors such as the kinetics of viral load and its correlation with clinical outcomes, endogenous antibody responses, pharmacokinetic properties of neutralizing mAbs and the potential benefit of combining antibodies to defend against emerging viral variants. 3–5 Monoclonal antibodies In the midst of the current COVID-19 pandemic, a combination therapy . Therefore, several questions (mAbs). Clonal antibodies variety of prophylactic and therapeutic treatments are need to be addressed about the potential clinical use of recognizing a single epitope on being developed or repurposed to combat COVID-19. neutralizing SARS-CoV-2 mAbs: who should get them; an antigen. Generally used in Monoclonal antibodies (mAbs) that can bind to and ‘neu- what is the best dose and frequency; when in the course reference to recombinant sources. tralize’ the virus in infected patients are a novel class of of the infection will they be most effective; what is the antiviral intervention1,2. Neutralizing mAbs are recom- duration of the protection they provide; and what is their binant proteins that can be derived from the B cells associated benefit- to- risk ratio? In addition, neutraliz- of convalescent patients or humanized mice (FIg. 1). ing mAbs may have a prophylactic role in individuals High- throughput screening of these B cells permits the deemed to be at high risk of severe COVID-19. Indeed, identification of antibodies with the necessary specificity preliminary non- peer- reviewed preprint data suggest and affinity to bind to a virus and block entry of the virus, that mAbs prevent COVID-19 in high- risk individuals 1Botnar Research Centre, University of Oxford, therefore abrogating pathology associated with produc- potentially exposed to SARS- CoV-2 in nursing homes 6,7 Oxford, UK. tive infection. These mAbs are termed ‘neutralizing’ and or within households . 2Eli Lilly and Company, can ultimately be used as a type of passive immunotherapy While vaccines remain the best strategy to prevent Indianapolis, IN, USA. (detailed later) to minimize virulence. In this Review, COVID-19, mAbs could potentially benefit certain 3Oregon Health & Science we highlight the relative value that neutralizing mAbs vulnerable populations before or after exposure to University, Portland, can provide for patients and physicians, and go on to SARS-CoV-2, such as the unvaccinated or recently vacci- OR, USA. examine the role of these agents among the spectrum of nated high- risk patients. The antiviral activity seen with 4Baylor University Medical potential treatments for COVID-19. neutralizing mAb treatment emphasizes the importance Center, Dallas, TX, USA. In the United States, three anti- severe acute res- of early intervention to help counter the devastating 5 Baylor Scott & White piratory syndrome coronavirus 2 (SARS- CoV-2) mAb impact the virus has had in such vulnerable populations Research Institute, Dallas, emergency use authorization TX, USA. therapies have been granted and in other high-risk patients. However, mAbs are com- ✉e- mail: peter.taylor@ (EUA) for treatment of non- hospitalized patients plicated to produce and may be limited in initial supply. kennedy.ox.ac.uk with mild- to- moderate COVID-19 — these are bam- Furthermore, any protection offered would be tempo- https://doi.org/10.1038/ lanivimab as a monotherapy, and bamlanivimab together rary, and the duration of effective protection remains s41577-021-00542- x with etesevimab or casirivimab with imdevimab as a to be determined. Answers to these questions will allow 382 | JUNE 2021 | VOLUME 21 www.nature.com/nri 0123456789();: REVIEWS Process Search Sequence and identity Analyse Select Source material Screening for RBD-specific Cloning and expression Validate and characterize single B cells High-confidence Convalescent sequences clustered patient by sequence identity Binding validation Functional validation Multiplexed bead-based assay Stability Live cell-based Humanized mouse assay that received Clonal families Organization target antigen Fluorescence-activated single-cell sorting Affinity Fig. 1 | Neutralizing monoclonal antibodies: identification, selection and production. The neutralizing monoclonal antibodies (mAbs) given emergency use authorization for treatment of COVID-19 were derived from either convalescent patients or humanized mice exposed to severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) antigens. However, mAbs can be generated by multiple methods, including from vaccinated individuals (not depicted here). The pathways of mAb generation depicted here converge in the process of selection and production. RBD, receptor-binding domain. the most efficacious use of these novel and potentially be convenient and adaptable for use in resource- poor life- saving treatments, as we discuss herein. settings14 and can be rapidly deployed to combat novel Passive immunotherapy virus outbreaks. The introduction of monoclonal Passive immunization The antipathogen antibodies from convalescent or polyclonal antibodies More than 125 years ago, the first major success in plasma can mitigate infection by two main mecha- derived from non- human or human blood products to modern immunological intervention was developed: a nisms: namely, antibody effector activity and pathogen provide protection against therapeutic serum from animals actively immunized neutralization. However, in rare cases, pathogen-specific infection or envenomation. against diphtheria toxin8,9. Paul Ehrlich later produced antibodies can augment virulence in a process termed a seminal article tying the curative antiserum to neu- ‘antibody- dependent enhancement’ (ADE) (Fig. 2). Emergency use 10 authorization tralizing antibodies . Today, passive immunization ADE can occur via two distinct mechanisms. First, (EUA). A mechanism to involves infusion of antigen- specific mAbs or polyclonal pathogen- specific antibodies could increase infec- facilitate the availability antibodies derived from non- human or human blood tion by promoting virus uptake and replication in and use of medical products. While polyclonal antibodies collected from Fcγ receptor- expressing immune cells (for example, countermeasures during a immunized animals are the primary source of antisera, as is seen in dengue haemorrhagic virus infection of public health emergency. US Food and Drug Administration there is a risk of ‘serum sickness’, especially after repeated macrophages). With SARS- CoV and SARS- CoV-2 20 issuance of an EUA permits the exposures, as the recipient may generate an immune (REF. ), in vitro evidence amassed to date indicate that use of unapproved medical response against antibodies of non-human origin. These these non- lymphotropic coronaviruses are unable to products or unapproved uses risks are mitigated with the use of convalescent plasma productively replicate within haematopoietic cells21. of approved medical products when no adequate alternatives from human patients. With careful screening (for exam- Alternatively, ADE can be mediated via increased are available. ple, to assess for the presence of infectious agents and immune activation by Fc- mediated effector functions to establish antibody titre and neutralizing capacity), or immune complex formation22. In the case of respira- Convalescent plasma convalescent plasma therapy (CPT) can be effective with tory virus infections, the resulting immune cascade can therapy minimal safety risks. contribute to lung disease. While the hallmarks of severe (CPT). The administration of donated plasma from an Before the current pandemic, CPT was used to treat COVID-19 have features that overlap with this type 11,12 individual who has had an infections with influenza virus , respiratory syncytial of ADE, there is currently no definitive evidence to show illness and recovered from it virus (RSV)13, Ebola virus14 and other coronaviruses12,15–17. ADE occurs with SARS-CoV-2 infection22. (for example, previously CPT appears most efficacious when used early after Nonetheless, steps may be considered to mitigate the infected with severe acute respiratory syndrome the onset of symptoms, rather than during severe or potential risk of ADE. When feasible (as with neutral- 12,15,18 coronavirus 2 (SARS- CoV-2) prolonged infection