Neutralizing Antibody Therapeutics for COVID-19

Abstract

The emergence of SARS-CoV-2 and subsequent COVID-19 pandemic has resulted in a significant global public health burden, leading to an urgent need for effective therapeutic strategies. In this article, we review the role of SARS-CoV-2 neutralizing antibodies (nAbs) in the clinical management of COVID-19 and provide an overview of recent randomized controlled trial data evaluating nAbs in the ambulatory, hospitalized and prophylaxis settings. Two nAb cocktails (casirivimab/imdevimab and bamlanivimab/etesevimab) and one nAb monotherapy (bamlanivimab) have been granted Emergency Use Authorization by the US Food and Drug Administration for the treatment of ambulatory patients who have a high risk of progressing to severe disease, and the European Medicines Agency has similarly recommended both cocktails and bamlanivimab monotherapy for use in COVID-19 patients who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19. Efficacy of nAbs in hospitalized patients with COVID-19 has been varied, potentially highlighting the challenges of antiviral treatment in patients who have already progressed to severe disease. However, early data suggest a promising prophylactic role for nAbs in providing effective COVID-19 protection. We also review the risk of treatment-emergent antiviral resistant "escape" mutants and strategies to minimize their occurrence, discuss the susceptibility of newly emerging SARS-COV-2 variants to nAbs, as well as explore administration challenges and ways to improve patient access.

Keywords: COVID-19; SARS-CoV-2; bamlanivimab; casirivimab; etesevimab; imdevimab; neutralizing antibody; resistance.

Figure 1

Localization of SARS-CoV-2 nAbs in late-stage clinical development. The distribution of RBD regions recognized by casirivimab (PDB: 6XDG), CT-P59 (PDB: 7CM4), imdevimab (PDB: 6XDG) and VIR-7831 (S309) (PDB: 6WPS) are compiled and illustrated on the SARS-CoV-2 virus (PDB:6W41). Epitopes are clustered proximal to RBM bound by ACE2, or alternatively at the distal RBD core. SARS-CoV-2 RBD is depicted in gray; the inset shows its location in the context of the entire spike protein (depicted in lavender). Only those nAbs with publicly available structures are shown. RBD, receptor binding domain; RBM, receptor binding motif.

Figure 2

Comparison of the Key Clinical, Virological and Safety Data for Neutralizing Antibodies with EUA for Treatment of Ambulatory Patients with COVID-19. * Based on 112 patients (combination arm) and 156 patients (placebo arm). ^† Interim data from the phase 1/2 portion of the trial reported a time-weighted average change from baseline of −1.74 log₁₀ RNA copies per mL in casirivimab/imdevimab-treated patients (n = 143; combined results from 2400 mg and 8000 mg dose arms) versus a −1.34 log₁₀ RNA copies per mL change from baseline in the placebo arm (n = 78).