Passive Immunotherapy Against SARS-CoV-2: From Plasma-Based Therapy to Single Potent Antibodies in the Race to Stay Ahead of the Variants

Abstract

The COVID-19 pandemic is now approaching 2 years old, with more than 440 million people infected and nearly six million dead worldwide, making it the most significant pandemic since the 1918 influenza pandemic. The severity and significance of SARS-CoV-2 was recognized immediately upon discovery, leading to innumerable companies and institutes designing and generating vaccines and therapeutic antibodies literally as soon as recombinant SARS-CoV-2 spike protein sequence was available. Within months of the pandemic start, several antibodies had been generated, tested, and moved into clinical trials, including Eli Lilly’s bamlanivimab and etesevimab, Regeneron’s mixture of imdevimab and casirivimab, Vir’s sotrovimab, Celltrion’s regdanvimab, and Lilly’s bebtelovimab. These antibodies all have now received at least Emergency Use Authorizations (EUAs) and some have received full approval in select countries. To date, more than three dozen antibodies or antibody combinations have been forwarded into clinical trials. These antibodies to SARS-CoV-2 all target the receptor-binding domain (RBD), with some blocking the ability of the RBD to bind human ACE2, while others bind core regions of the RBD to modulate spike stability or ability to fuse to host cell membranes. While these antibodies were being discovered and developed, new variants of SARS-CoV-2 have cropped up in real time, altering the antibody landscape on a moving basis. Over the past year, the search has widened to find antibodies capable of neutralizing the wide array of variants that have arisen, including Alpha, Beta, Gamma, Delta, and Omicron. The recent rise and dominance of the Omicron family of variants, including the rather disparate BA.1 and BA.2 variants, demonstrate the need to continue to find new approaches to neutralize the rapidly evolving SARS-CoV-2 virus. This review highlights both convalescent plasma- and polyclonal antibody-based approaches as well as the top approximately 50 antibodies to SARS-CoV-2, their epitopes, their ability to bind to SARS-CoV-2 variants, and how they are delivered. New approaches to antibody constructs, including single domain antibodies, bispecific antibodies, IgA- and IgM-based antibodies, and modified ACE2-Fc fusion proteins, are also described. Finally, antibodies being developed for palliative care of COVID-19 disease, including the ramifications of cytokine release syndrome (CRS) and acute respiratory distress syndrome (ARDS), are described. Supplementary Information The online version contains supplementary material available at 10.1007/s40259-022-00529-7.

Probing the biophysical constraints of SARS-CoV-2 spike N-terminal domain using deep mutational scanning

“…As the major antigen of SARS-CoV-2, spike (S) glycoprotein plays a critical role in facilitating virus entry ( 3 , 4 ). Therefore, antibodies to SARS-CoV-2 S are often neutralizing ( 5 , 6 ). SARS-CoV-2 S protein consists of an N-terminal S1 subunit, which is responsible for engaging the host receptor angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD), as well as a C-terminal S2 subunit, which mediates virus-host membrane fusion ( 4 , 7 , 8 ).…”

Evaluation of Antibody-Dependent Fc-Mediated Viral Entry, as Compared With Neutralization, in SARS-CoV-2 Infection

“…A single antibody can have multifunctional capacity ( 66 ) by mediating both neutralization and ADCC, and similarly could mediate both ADCC and FVE, depending on environmental conditions. Passive immunotherapies have been developed for treatment and protection against emerging SARS-CoV-2 variants, recently reviewed in detail ( 67 ). Among those treatments, convalescent plasma therapies have been evaluated with mixed outcome, but are generally determined to be safe.…”

Probing the biophysical constraints of SARS-CoV-2 spike N-terminal domain using deep mutational scanning

“…Landing pad cells were maintained using complete growth medium consisting of Dulbecco’s Modified Eagle’s Medium (DMEM) (Corning), 10% v/v FBS (VWR), Pen-Strep (Gibco), non-essential amino acid (Gibco), and 2 μg/mL doxycycline. 1.2 μg of plasmid was transfected into 6 × 10 5 landing pad cells. For the deep mutational scanning experiment, eight transfection reactions were carried out in parallel to minimize loss of mutant diversity at the transfection step.…”

“…As the major antigen of SARS-CoV-2, spike (S) glycoprotein plays a critical role in facilitating virus entry 3, 4 . Therefore, antibodies to SARS-CoV-2 S are often neutralizing 5, 6 . SARS-CoV-2 S protein consists of an N-terminal S1 subunit, which is responsible for engaging the host receptor angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD), as well as a C-terminal S2 subunit, which mediates virus-host membrane fusion 4, 7, 8 .…”