Monoclonal antibody therapies against SARS-CoV-2

Abstract

Monoclonal antibodies (mAbs) targeting the spike protein of SARS-CoV-2 have been widely used in the ongoing COVID-19 pandemic. In this paper, we review the properties of mAbs and their effect as therapeutics in the pandemic, including structural classification, outcomes in clinical trials that led to the authorisation of mAbs, and baseline and treatment-emergent immune escape. We show how the omicron (B.1.1.529) variant of concern has reset treatment strategies so far, discuss future developments that could lead to improved outcomes, and report the intrinsic limitations of using mAbs as therapeutic agents.

Figure

Three-dimensional representation of spike epitopes targeted by mAbs approved to date according to different classifications For each spike glycoprotein epitope classification scheme, structural coordinates of anti-spike mAbs in complex with spike were collected and binned into classes described in each reference. Composite complexes were generated by aligning corresponding RBD monomers in each respective complex. Members of each class are listed in table 3. (A) Structures of anti-spike mAb classes adapted from Finkelstein and colleagues are overlaid in complex with a single spike monomer (PDB 7C2L), with NTD and RBD domains. NTD binding, RBD core clusters I and II, and RBM classes I–III are displayed as mesh space-filling representation. (B) Structures of anti-spike mAb classes adapted from Barnes and colleagues are overlaid in complex with a single RBD domain (PDB 7K8M). Antibody binding classes 1–4 are displayed as mesh space-filling. (C) Structures of anti-spike mAb classes adapted from Yuan and colleagues are overlaid in complex with a single RBD domain (PDB 6XEY). Antibody binding classes RBS-A, RBS-B, RBS-C, CR3022, and S309 are displayed in spheres representation. (D) Classes RBS-A, RBS-B, and RBS-C adapted from Yuan and colleagues are displayed in complex with the full spike trimer in the RBD open configuration (top, PDB 6VYB) and RBD closed configuration (bottom, PDB 6VXX) to show the accessibility of each epitope with respect to spike protein configuration. (E) Summary of anti-spike mAb classes, as described by Finkelstein and colleagues, Barnes and colleagues, and Yuan and colleagues. Each classification was binned into six unifying categories for the purposes of this Review, on the basis of the descriptions and structural alignment of members of each class with available mAb-spike complex coordinates. mAb=monoclonal antibody. NTD=N-terminal domain. RBD=receptor-binding domain. RBM=receptor-binding motif. RBS=receptor-binding site.

Figure

Three-dimensional representation of spike epitopes targeted by mAbs approved to date according to different classifications For each spike glycoprotein epitope classification scheme, structural coordinates of anti-spike mAbs in complex with spike were collected and binned into classes described in each reference. Composite complexes were generated by aligning corresponding RBD monomers in each respective complex. Members of each class are listed in table 3. (A) Structures of anti-spike mAb classes adapted from Finkelstein and colleagues are overlaid in complex with a single spike monomer (PDB 7C2L), with NTD and RBD domains. NTD binding, RBD core clusters I and II, and RBM classes I–III are displayed as mesh space-filling representation. (B) Structures of anti-spike mAb classes adapted from Barnes and colleagues are overlaid in complex with a single RBD domain (PDB 7K8M). Antibody binding classes 1–4 are displayed as mesh space-filling. (C) Structures of anti-spike mAb classes adapted from Yuan and colleagues are overlaid in complex with a single RBD domain (PDB 6XEY). Antibody binding classes RBS-A, RBS-B, RBS-C, CR3022, and S309 are displayed in spheres representation. (D) Classes RBS-A, RBS-B, and RBS-C adapted from Yuan and colleagues are displayed in complex with the full spike trimer in the RBD open configuration (top, PDB 6VYB) and RBD closed configuration (bottom, PDB 6VXX) to show the accessibility of each epitope with respect to spike protein configuration. (E) Summary of anti-spike mAb classes, as described by Finkelstein and colleagues, Barnes and colleagues, and Yuan and colleagues. Each classification was binned into six unifying categories for the purposes of this Review, on the basis of the descriptions and structural alignment of members of each class with available mAb-spike complex coordinates. mAb=monoclonal antibody. NTD=N-terminal domain. RBD=receptor-binding domain. RBM=receptor-binding motif. RBS=receptor-binding site.