XAV-19, a Swine Glyco-Humanized Polyclonal Antibody Against SARS-CoV-2 Spike Receptor-Binding Domain, Targets Multiple Epitopes and Broadly Neutralizes Variants

Abstract

Amino acid substitutions and deletions in the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can reduce the effectiveness of monoclonal antibodies (mAbs). In contrast, heterologous polyclonal antibodies raised against S protein, through the recognition of multiple target epitopes, have the potential to maintain neutralization capacities. XAV-19 is a swine glyco-humanized polyclonal neutralizing antibody raised against the receptor binding domain (RBD) of the Wuhan-Hu-1 Spike protein of SARS-CoV-2. XAV-19 target epitopes were found distributed all over the RBD and particularly cover the receptor binding motives (RBMs), in direct contact sites with the angiotensin converting enzyme-2 (ACE-2). Therefore, in Spike/ACE-2 interaction assays, XAV-19 showed potent neutralization capacities of the original Wuhan Spike and of the United Kingdom (Alpha/B.1.1.7) and South African (Beta/B.1.351) variants. These results were confirmed by cytopathogenic assays using Vero E6 and live virus variants including the Brazil (Gamma/P.1) and the Indian (Delta/B.1.617.2) variants. In a selective pressure study on Vero E6 cells conducted over 1 month, no mutation was associated with the addition of increasing doses of XAV-19. The potential to reduce viral load in lungs was confirmed in a human ACE-2 transduced mouse model. XAV-19 is currently evaluated in patients hospitalized for COVID-19-induced moderate pneumonia in phase 2a-2b (NCT04453384) where safety was already demonstrated and in an ongoing 2/3 trial (NCT04928430) to evaluate the efficacy and safety of XAV-19 in patients with moderate-to-severe COVID-19. Owing to its polyclonal nature and its glyco-humanization, XAV-19 may provide a novel safe and effective therapeutic tool to mitigate the severity of coronavirus disease 2019 (COVID-19) including the different variants of concern identified so far.

SARS‐CoV‐2 does not infect pigs, but this has to be verified regularly

“…In a subsequent spike/ACE‐2 interaction assay, XAV‐19 showed potent neutralization capacities against the original Wuhan, United Kingdom (Alpha/B.1.1.7) and South African (Beta/B.1.351) variants. These results were confirmed by cytopathogenic assays using Vero E6 cells and live virus variants including the Gamma/P.1 and the Delta/ B.1.617.2 variants 85 …”

“…These results were confirmed by cytopathogenic assays using Vero E6 cells and live virus variants including the Gamma/P.1 and the Delta/ B.1.617.2 variants. 85 …”

A Polyclonal Antibody Dosing Strategy to Reduce the Viral Load of Multiple Coronavirus Mutants in COVID-19 Patients with Pneumonia

“…Since spike protein exhibits high mutation potential, prior monoclonal antibodies are losing their activity against new spike mutants of the virus. For instance, bamlanivimab, an antibody against a spike protein epitope is ineffective against the beta variant of SARS-CoV-2 [3]. On the other hand, XAV-19 has potent activity against the beta variant.…”

“…Thus, XAV-19 will likely be more beneficial in addressing emerging variants. XAV-19 is a humanized antibody raised in knockout pigs and it does not induce adverse allergic reactions that are common with foreign antibodies [3].…”

Seven classes of antiviral agents

“…By contrast to human IgGs, they can neither bind to receptors nor activate complement components in humans; therefore, the exacerbation of viral diseases through antibody-dependent enhancement could be potentially avoided [ 17 , 18 ]. In addition, other animals could be used as production of broadly neutralizing polyclonal antibodies [ 19 ].…”