RT Journal Article
SR Electronic
T1 High neutralizing potency of swine glyco-humanized polyclonal antibodies against SARS-CoV-2
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.25.217158
DO 10.1101/2020.07.25.217158
A1 Bernard Vanhove
A1 Odile Duvaux
A1 Juliette Rousse
A1 Pierre-Joseph Royer
A1 Gwénaëlle Evanno
A1 Carine Ciron
A1 Elsa Lheriteau
A1 Laurent Vacher
A1 Nadine Gervois
A1 Romain Oger
A1 Yannick Jacques
A1 Sophie Conchon
A1 Apolline Salama
A1 Roberto Duchi
A1 Irina Lagutina
A1 Andrea Perota
A1 Philippe Delahaut
A1 Matthieu Ledure
A1 Melody Paulus
A1 Ray T. So
A1 Chris Ka-Pun Mok
A1 Roberto Bruzzone
A1 Marc Bouillet
A1 Sophie Brouard
A1 Emanuele Cozzi
A1 Cesare Galli
A1 Dominique Blanchard
A1 Jean-Marie Bach
A1 Jean-Paul Soulillou
YR 2020
UL http://biorxiv.org/content/early/2020/08/07/2020.07.25.217158.abstract
AB 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 α1,3-galactose (α-Gal), ultimately forming immune complexes and potentially leading to serum sickness or allergy. To circumvent these drawbacks, we engineered animals lacking the genes coding for the cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) and α1,3-galactosyltransferase (GGTA1) enzymes to produce glyco-humanized polyclonal antibodies (GH-pAb) lacking Neu5Gc and α-Gal epitopes. We also found that pig 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) to elicit neutralizing antibodies. 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 < 1μg/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.Competing Interest StatementThe authors of this manuscript have conflicts of interest to disclose: JR, PJR, CC, GE, EL, BV are employees of Xenothera, a company developing glycol-humanized polyclonal antibodies as those described in this manuscript and JPS, JMB, CG are cofounders of Xenothera.