Protection of human ACE2 transgenic Syrian hamsters from SARS CoV-2 variants by human polyclonal IgG from hyper-immunized transchromosomic bovines

Abstract

Pandemic SARS CoV-2 has been undergoing rapid evolution during spread throughout the world resulting in the emergence of many Spike protein variants, some of which appear to either evade antibody neutralization, transmit more efficiently, or potentially exhibit increased virulence. This raises significant concerns regarding the long-term efficacy of protection elicited after primary infection and/or from vaccines derived from single virus Spike (S) genotypes, as well as the efficacy of anti-S monoclonal antibody based therapeutics. Here, we used fully human polyclonal human IgG (SAB-185), derived from hyperimmunization of transchromosomic bovines with DNA plasmids encoding the SARS-CoV-2 Wa-1 strain S protein or purified ectodomain of S protein, to examine the neutralizing capacity of SAB-185 in vitro and the protective efficacy of passive SAB-185 antibody (Ab) transfer in vivo. The Ab preparation was tested for neutralization against five variant SARS-CoV-2 strains: Munich (Spike D614G), UK (B.1.1.7), Brazil (P.1) and SA (B.1.3.5) variants, and a variant isolated from a chronically infected immunocompromised patient (Spike del144-146). For the in vivo studies, we used a new human ACE2 (hACE2) transgenic Syrian hamster model that exhibits lethality after SARS-Cov-2 challenge and the Munich, UK, SA and del144-146 variants. SAB-185 neutralized each of the SARS-CoV-2 strains equivalently on Vero E6 cells, however, a control convalescent human serum sample was less effective at neutralizing the SA variant. In the hamster model, prophylactic SAB-185 treatment protected the hamsters from fatal disease and minimized clinical signs of infection. These results suggest that SAB-185 may be an effective treatment for patients infected with SARS CoV-2 variants.

XAV-19, a Swine Glyco-Humanized Polyclonal Antibody Against SARS-CoV-2 Spike Receptor-Binding Domain, Targets Multiple Epitopes and Broadly Neutralizes Variants

“…In a few studies, however, the viral reduction factor reached 3 or 4 log (33,(42)(43)(44)(45). Interestingly, Gilliland et al (22) reported the absence of viral reduction in the lung of SARS-CoV-2 challenged mice treated with a humanized cow polyclonal antibody, whereas a clear clinical impact was demonstrated. One limitation of our model in which mice airways are transduced with an adenovirus expressing human ACE-2 is the absence of clinical symptoms, as the mice eliminate the virus by themselves within a few days.…”

“…Mutations in the Beta lineage (K417N, E484K, and N501Y in RBD), especially mutations of Spike at E484 but also in the Nterminal domain (NTD; L18F, D80A, D215G, D242-244, and R246I in SA variant (10,11)), reduce neutralization sensitivity or confer neutralization escape from multiple mAbs (4,5,(12)(13)(14)(15)(16)(17)(18)(19)(20). Third, polyclonal antibodies produced in their Fab'2 format from horses (21) or in their IgG format from humanized cows (22) or glyco-humanized pigs (23) have also proven efficacy to neutralize SARS-CoV-2. The safety and tolerability in humans of Fab'2 from horses and of humanized IgG polyclonal antibodies have been confirmed recently in different clinical trials (Lopardo et al, 2021 (21), NCT04453384, NCT04469179, Gaborit et al, 2021 (24)), contrasting with unmodified polyclonal antibodies containing wild-type IgG antibodies that induce serum sickness and allergic reactions (including fever and skin rashes) in 20% to 30% of the patients, excepting for those who concomitantly receive immunosuppression and high doses of steroids (25,26).…”

XAV-19, a swine glyco-humanized polyclonal antibody against SARS-CoV-2 Spike receptor-binding domain, targets multiple epitopes and broadly neutralizes variants

“…In a few studies, however, the viral reduction factor reached 3 or 4 log 33,[42][43][44][45] . Interestingly, Gilliland et al 22 reported absence of viral reduction in the lung of SARS-CoV-2 challenged mice treated with a humanized cow polyclonal antibody, whereas a clear clinical impact was demonstrated. One limitation of our model in which mice airways are transduced with an adenovirus expressing human ACE-2 is the absence of clinical symptoms, as the mice eliminate the virus by themselves within a few days.…”

“…Mutations in the Beta lineage (K417N, E484K, and N501Y in RBD), especially mutations of Spike at E484 but also in the N-terminal Domain (NTD; L18F, D80A, D215G, Δ242-244, and R246I in SA variant 10,11 ) reduce neutralization sensitivity or confer neutralization escape from multiple mAbs 4,5,[12][13][14][15][16][17][18][19][20] . Third, polyclonal antibodies produced in their Fab'2 format from horses 21 or in their IgG format from humanized cows 22 or glyco-humanized pigs 23 have also proven efficacy to neutralize SARS-CoV-2. The safety and tolerability in humans of Fab'2 from horses and of humanized IgG polyclonal antibodies has been confirmed recently in different clinical trials (Lopardo et al, 2021 21 , NCT04453384, NCT04469179, Gaborit et al, 2021 24 ), contrasting with unmodified polyclonal antibodies containing wild-type IgG antibodies that induce serum sickness and allergic reactions (including fever and skin rashes) in 20 to 30% of the patients, excepting for those who concomitantly receive immunosuppression and high doses steroids 25,26 .…”

Is There Any Advantage of Using Polyclonal vs. Monoclonal Antibodies for Passive Enhancement of Immunity in Patients with COVID-19?

“…This affords polyclonal antibodies a distinct advantage over monoclonal antibodies when used as therapeutic agents particularly in patients infected with rapidly mutating SARS-CoV-2 virus. immunoglobulin produced in transchromosomic bovines (Tc-hIgG-SARS-CoV-2) hyperimmunized with two doses of plasmid DNA encoding the SARS-CoV-2 Wuhan strain S gene, followed by repeated immunization with S protein purified from insect cells (6,7). The resulting Tc-hIgG-SARS-CoV-2, termed SAB-185, efficiently neutralizes SARS-CoV-2, and vesicular stomatitis virus (VSV) SARS-CoV-2 chimeras in vitro.…”