High neutralizing potency of swine glyco-humanized polyclonal antibodies against SARS-CoV-2

Heterologous polyclonal antibodies might represent an alternative to the use of convalescent plasma (CP) or monoclonal antibodies (mAbs) in COVID-19 by targeting multiple antigen epitopes. However, heterologous antibodies trigger human natural xenogeneic antibody responses particularly directed against animal-type carbohydrates, mainly the N-glycolyl form of the neuraminic acid (Neu5Gc) and the Gal alpha1,3-galactose (alphaGal), potentially leading to serum sickness or allergy. Here, we immunized cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) and alpha1,3-galactosyl-transferase (GGTA1) double knockout (DKO) pigs with the SARS-CoV-2 spike receptor-binding domain (RBD) to produce glyco-humanized polyclonal neutralizing antibodies (GH-pAb) lacking Neu5Gc and alpha-Gal epitopes. Animals rapidly developed a hyperimmune response with anti-SARS-CoV-2 end-titers binding dilutions over one to a million and end-titers neutralizing dilutions of 1:10,000. The IgG fraction purified and formulated following clinical Good Manufacturing Practices, named XAV-19, neutralized Spike/angiotensin converting enzyme-2 (ACE-2) interaction at a concentration < 1mug/mL and inhibited infection of human cells by SARS-CoV-2 in cytopathic assays. We also found that pig GH-pAb Fc domains fail to interact with human Fc receptors, thereby avoiding macrophage dependent exacerbated inflammatory responses and a possible antibody-dependent enhancement (ADE). These data and the accumulating safety advantages of using GH-pAbs in humans warrant clinical assessment of XAV-19 against COVID-19. This article is protected by copyright. All rights reserved.