Comprehensive engineering of a therapeutic neutralizing antibody targeting SARS-CoV-2 spike protein to neutralize escape variants

MAbs. 2022 Jan-Dec;14(1):2040350. doi: 10.1080/19420862.2022.2040350.

Abstract

The emergence of escape variants of SARS-CoV-2 carrying mutations in the spike protein poses a challenge for therapeutic antibodies. Here, we show that through the comprehensive engineering of the variable region of the neutralizing monoclonal antibody 5A6, the engineered antibody, 5A6CCS1, is able to neutralize SARS-CoV-2 variants that escaped neutralization by the original 5A6 antibody. In addition to the improved affinity against variants, 5A6CCS1 was also optimized to achieve high solubility and low viscosity, enabling a high concentration formulation for subcutaneous injection. In cynomolgus monkeys, 5A6CCS1 showed a long plasma half-life and good subcutaneous bioavailability through engineering of the variable and constant region. These data demonstrate that 5A6CCS1 is a promising antibody for development against SARS-CoV-2 and highlight the importance of antibody engineering as a potential method to counteract escape variants.

Keywords: SARS-CoV-2; Therapeutic antibody; antibody engineering; escape variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • COVID-19* / therapy
  • Humans
  • Membrane Glycoproteins
  • Neutralization Tests
  • SARS-CoV-2 / genetics
  • Spike Glycoprotein, Coronavirus* / genetics
  • Viral Envelope Proteins

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Membrane Glycoproteins
  • Spike Glycoprotein, Coronavirus
  • Viral Envelope Proteins
  • spike protein, SARS-CoV-2

Supplementary concepts

  • SARS-CoV-2 variants

Grants and funding

This work was supported by Chugai Pharmaceutical Co. Ltd. This work was also supported by core research grants provided to the Singapore Immunology Network by the Biomedical Research Council (BMRC) and the A*CCLERATE GAP fund (ACCL/19-GAP064-R20H-I) from the Agency of Science, Technology and Research A*CCLERATE GAP fund ACCL/19-GAP064-R20H-I. Funding to pay the Open Access publication charges for this article was provided by Chugai Pharmaceutical Co. Ltd. Singapore Immunology Network (SIgN) at the Agency of Science, Technology and Research (A*STAR) of Singapore (https://www.a-star.edu.sg/sign).