key: cord-0980045-k32v2wh5
authors: Montefiori, David C.; Acharya, Priyamvada
title: SnapShot: SARS-CoV-2 antibodies
date: 2021-07-14
journal: Cell Host & Microbe
DOI: 10.1016/j.chom.2021.06.005
sha: b8bd0ee6113ae5cbb09afeaafb131280e0250c93
doc_id: 980045
cord_uid: k32v2wh5

nan

Detailed studies of neutralizing monoclonal antibodies (mAbs) from people who recovered from COVID-19 have revealed the antigenic landscape of the viral spike protein and provided opportunities for life-saving therapeutic interventions. The receptor binding domain (RBD) and N-terminal domain (NTD), located in the S1 subunit of the SARS-CoV-2 spike, are the most immunodominant regions targeted by neutralizing antibodies. The receptor binding motif (RBM) spanning residues 437-507 is a variable region within the RBD that contacts the ACE-2 receptor. Some of the most potent SARS-CoV-2 neutralizing antibodies identified to date have epitopes that overlap the RBM. A region centered on a loop spanning residues 140-158 in the NTD is an antigenic supersite that is recognized by neutralizing antibodies isolated from multiple COVID-19-convalescent persons. The S2 subunit plays a critical role in viral entry and is highly conserved, although antibodies targeting this region have shown limited neutralization potency so far.

Many spike-specific mAbs have been isolated from people who recovered from infection with either SARS-CoV-2 or SARS-CoV, and a subset of these mAbs are of therapeutic interest for COVID-19. Most clinical products are developed as either single mAbs or a combination of two non-competing mAbs to mitigate escape. A single mAb and a two-mAb cocktail from Eli Lilly, a two-mAb cocktail from Regeneron Pharmaceuticals, and a single mAb from GSK-VIR have received emergency use authorization for treatment of mild to moderate disease in people who are at high risk for progressing to severe disease. The Regeneron product (REGN-COV2) combines mAbs REGN10933 (Casirivimab) and REGN10987 (Imdevimab). The Lilly mAbs are designated LY-CoV555 (Bamlanivimab) and LY-CoV016 (Etesevimab). The GSK-VIR antibody is derived from S309 and is known as Sotrovimab. All of these mAbs target the RBD. Other RBD mAbs are rapidly progressing through clinical development. Among these are additional 2-mAb cocktails: BRII-196/PC2-1F11 + BRII-198/P2B-1G5-CS (Brii Biologicals); AZD8895/COV2-2196 + AZD1062/COV2-2130 (AstraZeneca); C135 + C144 (Bristol-Myers Squibb); and C6.35 + eCC6.33.1 (International AIDS Vaccine Initiative). Additional single mAbs in clinical development include BI 767551/EX 14870 (Boehringer Ingleheim), CT-P59 (Celltrion), AR-711 (Aridis), and ADG20 (Adagio).

High infection rates and the protracted nature of the pandemic are providing ample opportunities for the virus to acquire immune escape mutations. Variants with mutations in key neutralization epitopes are arising at increasing frequencies at a regional level, and these variants are spreading rapidly among and within other countries. At least five variants of concern (VOC) have demonstrated escape from one or more mAbs of therapeutic interest: 1) B.1.1.7 (also known as 20I/501Y.V1 and Alpha), originating in the United Kingdom, contains spike mutations ΔH69-V70, ΔY144, N501Y, A570D, D614G, P681H, T716I, S982A, and D1118H; 2) B.1.351 (also known as 20H/501Y.V2 and Beta), originating in South Africa, contains spike mutations L18F, D80A, D215G, ΔL242-244, K417N, E484K, N501Y, D614G, and A701V; 3) P.1 (also known as B.1.1.248, 20J/501Y.V3 and Gamma), originating in Brazil, contains spike mutations L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, and T1027I; 4) B.1.429 (also known as CAL.20C, 452R. V1 and Epsilon), first identified in California, contains spike mutations S13I, W152C, L452R, and D614G, and 5) B.1.617, originating in India, comprises two dominant sublineages: B.1.617.1 (also known as Kappa), containing spike mutations G142D, E154K, L452R, E484Q, D614G, P681R, and Q1071H, and B.1.617.2 (also known as Delta), containing spike mutations T19R, G142D, Δ156-157, R158G, L452R, T478K, D614G, P681R, and D950N. As of this writing, B.1.617.2 appears highly contagious and possibly more pathogenic, and it is on track to become the dominant variant in many parts of the world. Notably, all VOCs contain the D614G spike mutation that alone provides a fitness advantage for transmission and that has rapidly replaced the ancestral spike to become globally dominant by mid-May 2020. Acquisition of additional mutations that impart greater transmissibility, such as occurred with B. The ability of SARS-CoV-2 to acquire and tolerate mutations at multiple sites in RBD and NTD, sometimes in combination, forecasts the emergence of additional escape variants that will impact current and future antibody therapeutics. A coordinated effort to identify and characterize newly emerging spike variants in a timely manner is essential, as is the continued development of improved neutralizing mAbs.

Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies