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Discovery of potent anti-SARS-CoV-2 antibodies with broad neutralisation potential

SARS-CoV-2 neutralising monoclonal antibodies play a crucial role in the fight against COVID-19 as a post-viral exposure treatment, and as a prophylactic to protect at-risk groups who respond poorly to vaccines. Studies involving X-ray diffraction have resulted in the discovery of potent SARS-CoV-2 neutralising antibodies.

Most antibodies in clinical development target the receptor binding domain (RBD), a key component of the SARS- CoV-2 spike protein. These antibodies were identified primarily by screening a number of antibody-producing B cells from convalescent individuals against the RBD of the SARS-CoV-2 strain first identified in Wuhan, China. Several

of these antibodies have since shown to be affected by mutations found in recent virulent strains.

In this work, using a combination of phage display technology and next generation sequencing, millions of antibody genes were mined from COVID-19 patients in the acute phase of illness to isolate neutralising antibodies and gain insight into the early antibody response. A comprehensive discovery approach involving biochemical, biophysical and functional characterisation resulted in the discovery of potent neutralising antibodies with potential for broad neutralisation coverage of SARS-CoV-2 viral variants. Structural characterisation of one of these antibodies (ION_300) (Figure 144), using X-ray diffraction data collected on beamline ID30A-1, revealed a conserved binding region on RBD (distinct from all previously published anti-SARS-COV-2 antibodies) likely to be unaffected by the mutations in major viral variants.

PRINCIPAL PUBLICATION AND AUTHORS

Cross-Reactive SARS-CoV-2 Neutralizing Antibodies From Deep Mining of Early Patient Responses, G. Bullen (a), J.D. Galson (b), G. Hall (c), P. Villar (a), L. Moreels (a), L. Ledsgaard (a), G. Mattiuzzo (d), E.M. Bentley (d), E.W. Masters (a), D. Tang (e), S. Millett (e), D. Tongue (e), R. Brown (e), I. Diamantopoulos (a), K. Parthiban (a), C. Tebbutt (a), R. Leah (a), K. Chaitanya (a), S. Ergueta-Carballo (a), D. Pazeraitis (a), S.B. Surade (a), O. Ashiru (f), L. Crippa (f), R. Cowan (c), M.W. Bowler (g), J.I. Campbell (g), W-Y.J. Lee (h), M.D. Carr (c), D. Matthews (e), P. Pfeffer (h), S.E. Hufton (d), K. Sawmynaden (e), J. Osbourn (b), J. McCafferty (a), A. Karatt-Vellatt (a), Front. Immunol. 12, 678570 (2021); https:/doi.org/10.3389/fimmu.2021.678570. (a) IONTAS Ltd., Cambridge (UK) (b) Alchemab Therapeutics Ltd., London (UK) (c) Leicester Institute of Structural and Chemical Biology and Department of Molecular and Cell Biology, University of Leicester (UK) (d) National Institute for Biological Standards and Control, Potters Bar (UK) (e) LifeArc, Stevenage (UK) (f) Abcam, Cambridge (UK) (g) EMBL, Grenoble (France) (h) Barts and The London School of Medicine and Dentistry, Queen Mary University of London (UK)

Fig. 144: a) SARS-CoV-2 RBD binding regions of ION_300 (antibody with broad neutralisation potential) and ION_360 (a representative example of majority of antibodies in clinical development). b) Analysis of ION_360 antibody binding residues (shown in sticks) within 5 Å of the RBD shows proximity to several mutations found within major SARS-CoV-2 variants (highlighted in red). c) In contrast, none of these mutations were found within the epitope of ION_300 and the closest mutation (E484K) is at least 15 Å away from its paratope.