Considerations for the development of monoclonal antibodies to address new viral variants in COVID-19

ABSTRACT

Introduction

Monoclonal antibody (mAb) therapies proved safe and effective in preventing progression of COVID-19 to hospitalization, but most were eventually defeated by continued viral evolution. mAb combinations and those mAbs that were deliberatively selected to target conserved regions of the SARS-CoV-2 spike protein proved more resilient to viral escape variants as evident by longer clinical useful lives.

Areas covered

We searched PubMed for literature covering the need, development and use of mAb therapies for COVID-19. As much of humanity now has immunity to SARS-CoV-2, the population at most risk is that of immunocompromised individuals. Hence, there continues to be a need for mAb therapies for immunocompromised patients. However, mAb use in this population carries the risk for selecting mAb-resistant variants, which could pose a public health concern if they disseminate to the general population.

Expert opinion

Going forward, structural knowledge of the interactions of Spike with its cellular receptor has identified several regions that may be good targets for future mAb therapeutics. A focus on designing variant-resistant mAbs together with cocktails that target several epitopes and the use of other variant mitigating strategies such as the concomitant use of small molecule antivirals and polyclonal preparations could extend the clinical usefulness of future preparations.

KEYWORDS:

• Monoclonal antibodies
• Spike
• COVID-19
• SARS-CoV-2

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Abbreviations

ADE, antibody dependent enhancement; CCP, COVID-19 convalescent plasma; Fc receptor (FcR); mAb, monoclonal antibodies.

Article highlights

• mAb therapies developed and deployed during the COVID-19 pandemic proved safe and effective, but epitope drift caused by continuous SARS-CoV-2 evolution facilitated viral escape

• A wealth of structural and functional information from the first generation of neutralizing mAbs can be leveraged to generate mAbs that are resilient to epitope drift by prioritizing conserved epitopes or to create mAb cocktails with diverse specificities.

• Currently, with most of the general population having immunity to SARS-CoV-2, the major need for mAb therapies is in immunosuppressed individuals.

• In immunosuppressed individuals, prolonged infection and high viral burden lead to in-host viral selection of resistant variants which can pose a public health concern if these enter the general population.

• Despite the need for new mAb therapies for COVID-19 and the existence of strategies that reduce the vulnerability of antibodies to viral escape, the future of this strategy is uncertain because of continue viral evolution and the financial considerations involved in developing costly reagents for a relatively small market.

Declaration of interest

A Casadevall serves on the scientific advisory board of SAB Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

A Casadevall wrote the first draft; S McConnell provided manuscript text and created figure 1; D Focosi provided intellectual input and revised the manuscript.

Additional information

Funding

This paper was not funded.