Structural delineation and computational design of SARS-CoV-2-neutralizing antibodies against Omicron subvariants

Abstract

SARS-CoV-2 Omicron subvariants have evolved to evade receptor-binding site (RBS) antibodies that exist in diverse individuals as public antibody clones. We rationally selected RBS antibodies resilient to mutations in emerging Omicron subvariants. Y489 was identified as a site of virus vulnerability and a common footprint of broadly neutralizing antibodies against the subvariants. Multiple Y489-binding antibodies were encoded by public clonotypes and additionally recognized F486, potentially accounting for the emergence of Omicron subvariants harboring the F486V mutation. However, a subclass of antibodies broadly neutralized BA.4/BA.5 variants via hydrophobic binding sites of rare clonotypes along with high mutation-resilience under escape mutation screening. A computationally designed antibody based on one of the Y489-binding antibodies, NIV-10/FD03, was able to bind XBB with any 486 mutation and neutralized XBB.1.5. The structural basis for the mutation-resilience of this Y489-binding antibody group may provide important insights into the design of therapeutics resistant to viral escape.

Distinct evolution of SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 lineages combining increased fitness and antibody evasion

“…This novel lineage carries numerous mutations known to allow mAb evasion (Wang et al ., 2023a), including the K356T substitution conferring resistance to Sotrovimab (Addetia et al ., 2023) (Ragonnet-Cronin et al ., 2023). Novel mAbs are under pre-clinical and clinical development (Cao et al ., 2022a; Moriyama et al, 2023; Park et al, 2022a). It will be worth carefully scrutinizing their antiviral activity against BA.2.86 and other emerging subvariants.…”

“…This novel lineage carries numerous mutations known to allow mAb evasion 28 , including the K356T substitution conferring resistance to Sotrovimab 51 52 . Novel mAbs are under pre-clinical and clinical development 11,60,61 . It will be worth scrutinizing their antiviral activity against BA.2.86.1/JN.1 and other emerging subvariants.…”

Overcoming antibody-resistant SARS-CoV-2 variants with bispecific antibodies constructed using non-neutralizing antibodies

“…Consequently, the clinical application of anti-RBD antibodies has led to reduced neutralization and inhibitory activities. 22 , 26 , 30 , 31 , 58 Although efforts to develop broadly neutralizing antibodies that target pan-coronavirus conserved epitopes are actively underway, 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 the possibility of emerging immune-evading mutant variants remains, posing a recurrent challenge to monoclonal antibody therapy. Therefore, the exploration of alternative approaches is attractive.…”

From De Novo Design to Redesign: Harnessing Computational Protein Design for Understanding SARS-CoV-2 Molecular Mechanisms and Developing Therapeutics

“…Moriyama et al reported the design of antibody NIV-10/FD03 using computational techniques, leveraging the Y489 residue in the receptor-binding site of SARS-CoV-2 RBD. 114 This antibody effectively binds to Omicron XBB variants, even in the presence of mutations at position 486, and successfully neutralizes XBB.1.5. This achievement provided a foundation for developing therapeutics that can resist viral escape.…”

“…These methodologies empower researchers to foresee and tackle the hurdles posed by viral variants, providing them with the flexibility to adjust their strategies as required. Moriyama et al reported the design of antibody NIV-10/FD03 using computational techniques, leveraging the Y489 residue in the receptor-binding site of SARS-CoV-2 RBD . This antibody effectively binds to Omicron XBB variants, even in the presence of mutations at position 486, and successfully neutralizes XBB.1.5.…”