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Authors: Atyeo et al.

Link to paper: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3612156

Journal/ Pre-Print: Cell Host & Microbe

Tags: Cell Biology; Therapeutics; Vaccines; Antibody Engineering 

Research Highlights 

1. CR3022 Ab is able to bind to conserved RBD and Spike epitopes across different SARS related viruses (SARS1 and SARS2), even in the presence of ACE2 receptor binding. CR3022 has only slight neutralisation capacity for SARS-Cov-2 RBD or S proteins.

2. When CR3022 is reacted against SARS2 Spike protein, it is still able to bind FcgR (2a and 3a), and activates antibody-dependent activities like monocyte phagocytosis, neutrophil phagocytosis, complement deposition and natural killer cell activation, even in the presence of ACE2 up-regulation – even though the effect is somewhat reduced.

Summary 

This paper explored the role of Fc activity in SARS-Cov-2 immunity, focusing on the cross reactive SARS Ab CR3022, that targets conserved RBD, but provides limited neutralisation in SARS2. They found that CR3022 bound to ACE2 is able to bind FcgR 2a and 3a in humans. They then generated 4 Fc variants that either augmented Fc effector functions of CR3022 or abrogated them. They then conducted in vivo profiling using mouse models. Prophylactically, FC-KO CR3022 suppressed viral load whereas neither the enhanced SDIE (Fc enhanced variant resulting in ADCC) nor the WT CR3022 ab suppressed SARS2 viral load in the mice. Therapeutically, the mice treated with FC-KO or SDIE CR3022 had significantly lower viral load in their lungs, compared to the WT CR3022. Whether the FC-KO group is statistically different from SDIE variant is not shown. In both prophylactic and therapeutic conditions, weight loss was higher in the mice receiving SDIE and WT CR3022 treatment. 

Impact for SARS-CoV2/COVID19 research efforts

Understand the immune response to SARS-CoV2/COVID19. Unlike other studies, this paper looks at Fc effector functions surrounding viral cell clearance. 

Study Type

· In vitro study

· In vivo study (mouse)

Strengths and limitations of the paper

Novelty: This paper focuses on studying the Fc effector functions of the Abs generated during SARS infection, in order to understand their contribution to immunity.

Standing in the field: To our knowledge, a lot of the literature are focusing on studying neutralising Ab in SARS2 and dismiss the function of other Ab generated in the same immune response.

Appropriate statistics: The statistics included are correct to our knowledge, however much of the data lacks statistical significance tests.

Viral model used: The paper used SARS2 infection model in mice.

Translatability: There is a great potential for translation in this paper. However, the authors neglect to calculate significant differences in some of their group comparisons and so this attenuates the significance of their findings.

Main limitations: Either there is a typo or figure 2H is missing (line 162).

The labelling for figures 2F and 2G are confusing because of the colour deficits- authors used light blue instead of light purple to denote Fc-KO. So there is lack of consistency.

Although NK activation was measured by MIP1b and IFN-gamma intracellular staining as per the method section, the IFN-gamma data is not represented in the main paper or as supplementary data. It would be useful to see whether the results of the MIP1b staining were mirrored in the IFN-gamma staining.

The authors neglect to demonstrate significant differences in some comparisons where this would be necessary to verify their interpretations, for example the profiling of CD3022 variants (2B-E) and the interpretation of more pronounced reduction in viraemia upon therapeutic intervention with SDIE vs FC-KO CD3022 (line 187-188 and 2G)