Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

Title: Computationally restoring the potency of a clinical antibody against Omicron

Journal Article · · Nature (London)
ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1];  [1];  [1];  [1];  [2]; ORCiD logo [2]; ORCiD logo [2];  [3]; ORCiD logo [4];  [1]; ORCiD logo [2];  [2]; ORCiD logo [2];  [2];  [1];  [1];  [5];  [1] more »;  [1];  [1];  [1];  [1];  [1]; ORCiD logo [6]; ORCiD logo [3];  [1];  [1];  [1];  [1];  [7];  [8];  [1]; ORCiD logo [3];  [1];  [9];  [9];  [1];  [1];  [1];  [9];  [1];  [1];  [9];  [1];  [10];  [1];  [1];  [1];  [11];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [11];  [11];  [9];  [11];  [9];  [10];  [1];  [10];  [1]; ORCiD logo [9];  [10]; ORCiD logo [12]; ORCiD logo [3]; ORCiD logo [2]; ORCiD logo [2]; ORCiD logo [1] « less
  1. Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
  2. Vanderbilt Univ., Nashville, TN (United States). Medical Center
  3. Washington Univ., St. Louis, MO (United States). School of Medicine
  4. Fred Hutchinson Cancer Center, Seattle, WA (United States)
  5. Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States); Google, Alphabet Inc., Mountain View, CA (United States)
  6. Washington Univ., St. Louis, MO (United States). School of Medicine; Vir Biotechnology, San Francisco, CA (United States)
  7. US Dept. of Defense, Frederick, MD (United States)
  8. Joint Rsearch and Development Inc., Stafford, VA (United States)
  9. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
  10. Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States). Center for Bioengineering
  11. Sandia National Lab. (SNL-CA), Livermore, CA (United States)
  12. Fred Hutchinson Cancer Center, Seattle, WA (United States); Howard Hughes Medical Institute, Seattle, WA (United States)
+ Show Author Affiliations

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs and revealed how quickly viral escape can curtail effective options. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4 and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities.

Research Organization:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Organization:
USDOE National Nuclear Security Administration (NNSA); USDOE Laboratory Directed Research and Development (LDRD) Program
Contributing Organization:
Tri-lab COVID-19 Consortium
Grant/Contract Number:
AC52-07NA27344
OSTI ID:
2406520
Report Number(s):
LLNL--JRNL-839587; 1060519
Journal Information:
Nature (London), Journal Name: Nature (London) Journal Issue: 8013 Vol. 629; ISSN 0028-0836
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

References (29)

Observed Antibody Space: A diverse database of cleaned, annotated, and translated unpaired and paired antibody sequences journal October 2021
Determinants of passive antibody efficacy in SARS-CoV-2 infection: a systematic review and meta-analysis journal November 2023
Boosting with variant-matched or historical mRNA vaccines protects against Omicron infection in mice journal April 2022
Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum journal July 2022
Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants journal January 2023
A pseudovirus system enables deep mutational scanning of the full SARS-CoV-2 spike journal March 2023
Flex ddG: Rosetta Ensemble-Based Estimation of Changes in Protein–Protein Binding Affinity upon Mutation journal January 2018
LigPlot+: Multiple Ligand–Protein Interaction Diagrams for Drug Discovery journal October 2011
Resilience of S309 and AZD7442 monoclonal antibody treatments against infection by SARS-CoV-2 Omicron lineage strains journal July 2022
Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail journal September 2021
Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody journal May 2020
Potently neutralizing and protective human antibodies against SARS-CoV-2 journal July 2020
Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift journal December 2021
Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa journal January 2022
Antibody evasion properties of SARS-CoV-2 Omicron sublineages journal March 2022
Characterization and antiviral susceptibility of SARS-CoV-2 Omicron BA.2 journal May 2022
An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by therapeutic monoclonal antibodies journal January 2022
Large-scale application of free energy perturbation calculations for antibody design journal July 2022
Efficacy of Antibodies and Antiviral Drugs against Omicron BA.2.12.1, BA.4, and BA.5 Subvariants journal August 2022
REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19 journal January 2021
Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19 journal October 2021
Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19 journal June 2022
Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions journal April 2012
The FoldX web server: an online force field journal July 2005
AS2TS system for protein structure modeling and analysis journal July 2005
Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry journal January 2022
SARS-CoV-2 Omicron variant: Antibody evasion and cryo-EM structure of spike protein–ACE2 complex journal February 2022
Antibody-mediated protection against symptomatic COVID-19 can be achieved at low serum neutralizing titers journal March 2023
The Structural Basis of Antibody-Antigen Recognition journal January 2013

Similar Records

Related Subjects

60 APPLIED LIFE SCIENCES
97 MATHEMATICS AND COMPUTING
Antibody therapy
Biological and medical sciences
Computer science
Protein design
SARS-CoV-2