BAADesign enables the immune escaped etesevimab fully-armed against SARS-CoV-2 Omicron subvariants

Monoclonal antibodies (mAbs) are vital for preventing and treating COVID-19 by targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein. However, the rapid emergence of Omicron subvariants, such as BA.2, XBB.1.5, and KP.2, has rendered many mAbs, including etesevimab (CB6), ineffective. To overcome this challenge, George Fu Gao's team introduced BAADesign (broad-spectrum and affinity-mature antibody design), a novel strategy to restore and enhance antibody efficacy.

The BAADesign Approach

1. Negative Effects Classification: Identification of amino acids causing steric hindrance or reduced interactions in antibody-antigen binding.

2. Computational Design: Rosetta-based optimization of structural scaffolds and sequences to improve binding.

3. In vitro Test: To test the binding affinity of the designed mutations using surface plasmon resonance (SPR).

Optimized CB6-IV Antibody

Using BAADesign, CB6 was reengineered into CB6-IV, incorporating seven mutations in the heavy chain and four in the light chain. CB6-IV achieved nanomolar-level binding affinities (0.36–19.07 nM) against Omicron subvariants and demonstrated strong neutralizing effects in cellular assays. Cryo-electron microscopy confirmed improved RBD interactions due to these mutations.

Broader Applications

The study applied BAADesign-derived mutations in the CDR1/2 of CB6-IV to other RBD-1 antibodies (e.g., P2C-1F11, BD-629), to enhance their binding and neutralization capabilities against Omicron subvariants. Further optimization of CDR3 regions of P2C-1F11 and Omi-3 using BAADesign also improved their broad-spectrum activity.

Significance

BAADesign offers a powerful tool for reengineering mAbs to combat emerging SARS-CoV-2 variants, providing a scalable solution for future pandemic preparedness.

See the article:

Enabling the immune escaped etesevimab fully-armed against SARSCoV-2 Omicron subvariants including KP.2

https://doi.org/10.1016/j.hlife.2024.12.006

Funders:

This work was supported by the National Natural Science Foundation of China (82225021).