Computational Design of Broad-Spectrum Ebola Antibodies through Framework and Complementarity-Determining Region
Xinhui Zhang1,2, Xiuying Liu1,2, Jingya Zhou1,2
1Key Laboratory of Pathogen Infection Prevention and Control (Ministry of Education), National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Research (Washington, D.C.)
|March 25, 2026
Summary
Computational methods rapidly improved Ebola virus antibodies, enhancing potency and breadth against diverse strains. This pipeline offers a practical way to update therapeutics for emerging viral variants.
Area of Science:
- Immunology and Virology
- Computational Biology and Bioinformatics
- Protein Engineering and Antibody Therapeutics
Background:
- Developing potent and broad-spectrum neutralizing antibodies against highly mutable viruses like Ebola virus (EBOV) remains a significant challenge.
- Existing pan-EBOV antibodies (ADI-15878, ADI-15946) required optimization for enhanced efficacy.
- A computational-experimental pipeline was developed to address these limitations.
Purpose of the Study:
- To enhance the breadth and potency of two pan-EBOV antibodies, ADI-15878 and ADI-15946.
- To utilize a computational-experimental pipeline integrating in silico predictions and wet-lab validation.
- To rapidly generate improved antibody variants for combating diverse or emerging viral variants.
Main Methods:
- Employed computational tools (mCSM-AB, mmCSM-AB, Foldseek, ZDOCK) for in silico prediction of affinity-enhancing mutations in complementarity-determining regions (CDRs) and framework region (FR) modifications.
- Prioritized mutations based on predicted effects on antibody structure and binding affinity.
- Expressed, purified, and evaluated candidate antibody variants using pseudovirus neutralization assays, flow cytometry, and surface plasmon resonance (SPR).
Main Results:
- For ADI-15878, a variant (W32G-LC) showed improved neutralization against EBOV (17-fold), Bundibugyo virus (BDBV) (7-fold), and Sudan virus (SUDV) (2-fold).
- For ADI-15946, multi-site light chain variants demonstrated >40-fold and >100-fold increases in SUDV neutralization, maintaining activity against EBOV/BDBV.
- Enhanced neutralization correlated with increased buried surface area (BSA) and improved SPR-measured affinities.
Conclusions:
- An integrated FR-CDR optimization strategy combined with docking-guided multi-site design rapidly generates antibody variants with superior breadth and potency.
- The developed modular pipeline provides a practical approach for updating therapeutic antibodies against diverse or emerging viral threats.
- This strategy effectively balances antibody potency with broad-spectrum efficacy for mutable pathogens.
