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

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.

doi:10.1101/2020.07.25.217158

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bioRxiv · 10.1101/2020.07.25.217158

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

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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. Many monoclonal antibodies (mAbs) have been developed but appear insufficient to neutralize SARS-CoV-2 unless two or three of them are being combined. Therefore, heterologous polyclonal antibodies of animal origin, that have been used for decades to fight against infectious agents might represent a highly efficient alternative to the use of CP or mAbs in COVID-19 by targeting multiple antigen epitopes. However, conventional 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 1,3-galactose (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 1,3-galactosyl-transferase (GGTA1) enzymes to produce glyco-humanized polyclonal antibodies (GH-pAb) lacking Neu5Gc and -Gal epitopes. We 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, a drawback possibly associated with antibody responses against SARS-CoV-2 or to avoiding a possible antibody-dependent enhancement (ADE). 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 < 1g/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 warranted clinical assessment of XAV-19 to fight against COVID-19.

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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.. 2020-07-25. High neutralizing potency of swine glyco-humanized polyclonal antibodies against SARS-CoV-2. https://doi.org/10.1101/2020.07.25.217158

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