Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.25.217158v1?rss=1 Authors: Vanhove, B., Duvaux, O., Rousse, J., Royer, P.-J., Evanno, G., Ciron, C., Lheriteau, E., Vacher, L., Gervois, N., Oger, R., Jacques, Y., Salama, A., Duchi, R., Perota, A., Delahaut, P., Ledure, M., Paulus, M., So, R., Mok, C. K. P., Bruzzone, R., Bouillet, M., Brouard, S., Cozzi, E., Galli, C., Blanchard, D., Bach, J.-M., Soulillou, J.-P. Abstract: Perfusion of convalescent plasma (CP) has demonstrated a potential to improve the pneumonia induced by SARS-CoV-2, but procurement and standardization of CP are barriers to its wide usage. Heterologous polyclonal antibodies of animal origin have been used to fight against infectious agents and are a possible alternative to the use of CP in SARS-CoV-2 disease. However, heterologous polyclonal antibodies trigger human natural xenogeneic antibody responses particularly directed against animal-type carbohydrate epitopes, mainly the N-glycolyl form of the neuraminic acid (Neu5Gc) and the Gal alpha1,3-galactose (a-Gal), ultimately forming immune complexes and potentially leading to serum sickness or allergy. To circumvent these drawbacks, we engineered animals lacking the cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) and alpha1,3-galactosyltransferase (GGTA1) enzymes to produce glyco-humanized polyclonal antibodies (GH-pAb) lacking Neu5Gc and a-Gal epitopes. We also found that these IgG Fc domains fail to interact with human Fc receptors and thereby should confer the safety advantage to avoiding macrophage dependent exacerbated inflammatory responses or elicit antibody-dependent enhancement (ADE), two drawbacks possibly associated with antibody responses against SARS-CoV-2. Therefore, we immunized CMAH/GGTA1 double knockout (DKO) pigs with the SARS-CoV-2 spike receptor binding domain (RBD) domain to elicit neutralizing antibodies. Animals rapidly developed hyperimmune sera with 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/ACE-2 interaction at a concentration < 1microgram/mL and inhibited infection of human cells by SARS-CoV-2 in cytopathic assays. These data and the accumulating safety advantages of using glyco-humanized swine antibodies in humans warrant clinical assessment of XAV-19 to fight against COVID-19. Copy rights belong to original authors. Visit the link for more info