» Articles » PMID: 33576494

High Neutralizing Potency of Swine Glyco-humanized Polyclonal Antibodies Against SARS-CoV-2

Abstract

Heterologous polyclonal antibodies might represent an alternative to the use of convalescent plasma or monoclonal antibodies (mAbs) in coronavirus disease (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 α1,3-galactose, potentially leading to serum sickness or allergy. Here, we immunized cytidine monophosphate-N-acetylneuraminic acid hydroxylase and α1,3-galactosyl-transferase (GGTA1) double KO pigs with the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor binding domain to produce glyco-humanized polyclonal neutralizing antibodies lacking Neu5Gc and α1,3-galactose 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 interaction at a concentration <1 μg/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. These data and the accumulating safety advantages of using GH-pAbs in humans warrant clinical assessment of XAV-19 against COVID-19.

Citing Articles

Antibody-dependent enhancement of coronaviruses.

Tao T, Tian L, Ke J, Zhang C, Li M, Xu X Int J Biol Sci. 2025; 21(4):1686-1704.

PMID: 39990674 PMC: 11844293. DOI: 10.7150/ijbs.96112.


Current development of severe acute respiratory syndrome coronavirus 2 neutralizing antibodies (Review).

Zhang T, Yang D, Tang L, Hu Y Mol Med Rep. 2024; 30(2).

PMID: 38940338 PMC: 11228696. DOI: 10.3892/mmr.2024.13272.


Anti-SARS-CoV-2 glyco-humanized polyclonal antibody XAV-19: phase II/III randomized placebo-controlled trial shows acceleration to recovery for mild to moderate patients with COVID-19.

Poulakou G, Royer P, Evgeniev N, Evanno G, Shneiker F, Marcelin A Front Immunol. 2024; 15:1330178.

PMID: 38694503 PMC: 11061480. DOI: 10.3389/fimmu.2024.1330178.


Polyclonal antibodies selectively inhibit tumor growth and invasion and synergize with immune checkpoint inhibitors.

Ciron C, Morice P, Rousse J, Roy P, Royer P, Gauthier O JCI Insight. 2023; 9(3).

PMID: 38085594 PMC: 10967460. DOI: 10.1172/jci.insight.166231.


Effect of Swine Glyco-humanized Polyclonal Neutralizing Antibody on Survival and Respiratory Failure in Patients Hospitalized With Severe COVID-19: A Randomized, Placebo-Controlled Trial.

Gaborit B, Vanhove B, Lacombe K, Guimard T, Hocqueloux L, Perrier L Open Forum Infect Dis. 2023; 10(11):ofad525.

PMID: 37942459 PMC: 10629360. DOI: 10.1093/ofid/ofad525.


References
1.
Taylor A, Foo S, Bruzzone R, Dinh L, King N, Mahalingam S . Fc receptors in antibody-dependent enhancement of viral infections. Immunol Rev. 2015; 268(1):340-64. PMC: 7165974. DOI: 10.1111/imr.12367. View

2.
Reynard O, Jacquot F, Evanno G, Mai H, Salama A, Martinet B . Anti-EBOV GP IgGs Lacking α1-3-Galactose and Neu5Gc Prolong Survival and Decrease Blood Viral Load in EBOV-Infected Guinea Pigs. PLoS One. 2016; 11(6):e0156775. PMC: 4900587. DOI: 10.1371/journal.pone.0156775. View

3.
Coish J, MacNeil A . Out of the frying pan and into the fire? Due diligence warranted for ADE in COVID-19. Microbes Infect. 2020; 22(9):405-406. PMC: 7311339. DOI: 10.1016/j.micinf.2020.06.006. View

4.
Salama A, Mosser M, Leveque X, Perota A, Judor J, Danna C . Neu5Gc and α1-3 GAL Xenoantigen Knockout Does Not Affect Glycemia Homeostasis and Insulin Secretion in Pigs. Diabetes. 2017; 66(4):987-993. DOI: 10.2337/db16-1060. View

5.
Liu L, Wei Q, Lin Q, Fang J, Wang H, Kwok H . Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight. 2019; 4(4). PMC: 6478436. DOI: 10.1172/jci.insight.123158. View