Neutralizing monoclonal antibodies for treatment of COVID-19

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.

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.

Fig. 2. Mechanism of action of monoclonal antibodies for viral infection and antibody-dependent enhancement.

a | Monoclonal antibodies can directly interfere with viral pathogenesis in multiple ways. First, binding of a neutralizing antibody to the virion can prevent target cell binding and/or fusion. Furthermore, antibody binding opsonizes the virions or infected cells for phagocytic uptake. If viral proteins are intercalated into target cell membranes during viral egress, monoclonal antibodies can facilitate target cell death via complement fixation and membrane attack complex (MAC) activation or antibody-dependent cytotoxicity. These mechanisms may result in apoptosis or necrosis of the infected cell. b | In some instances, opsonization of a virion can facilitate viral pathogenesis in a process termed ‘antibody-dependent enhancement’ (ADE). ADE can occur via two distinct mechanisms. First, pathogen-specific antibodies could increase infection via viral uptake and replication in Fcγ receptor (FcγR)-expressing immune cells. Secondly, ADE can be mediated via increased immune activation by Fc-mediated effector functions or immune complex formation. The process of ADE and its potential impact during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is expertly reviewed by Lee et al..

Fig. 3. Inhibition of SARS-CoV-2 target cell engagement by neutralizing monoclonal antibodies.

Neutralizing monoclonal antibodies (mAbs) being developed to combat COVID-19 are generated against the receptor-binding domain (RBD) of the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The anti-RBD mAbs prevent binding of the S protein to its cognate receptor, angiotensin-converting enzyme 2 (ACE2), on target host cells. Three neutralizing mAb regimens have been given emergency use authorization for treatment of COVID-19. (1) Casirivimab and imdevimab bind distinct epitopes on the RBD with dissociation constants K_D of 46 and 47 pM, respectively. Imdevimab binds the S protein RBD from the front or lower-left side, while casirivimab targets the spike-like loop from the top direction (overlapping with the ACE2-binding site^,). (2) Bamlanivimab binds an epitope on the RBD in both its open confirmation and its closed confirmation with dissociation constant K_D = 71pM, covering 7 of the approximately 25 side chains observed to form contact with ACE2 (ref.). (3) Bamlanivimab and etesevimab bind to distinct, but overlapping, epitopes within the RBD of the S protein of SARS-CoV-2. Etesevimab binds the up/active conformation of the RBD with dissociation constant K_D = 6.45 nM (ref.); it contains the LALA mutation in the Fc region, resulting in null effector function.