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Refinement of an ovine-based immunoglobulin therapy against SARS-CoV-2, with comparison of whole IgG versus F(ab')₂ fragments.

ABSTRACT: The development of new therapies against SARS-CoV-2 is required to extend the toolkit of intervention strategies to combat the global pandemic. In this study, hyperimmune plasma from sheep immunised with whole spike SARS-CoV-2 recombinant protein has been used to generate candidate products. In addition to purified IgG, we have refined candidate therapies by removing non-specific IgG via affinity binding along with fragmentation to eliminate the Fc region to create F(ab')₂ fragments. These preparations were evaluated for in vitro activity and demonstrated to be strongly neutralising against a range of SARS-CoV-2 strains, including Omicron B2.2. In addition, their protection against disease manifestations and viral loads were assessed using a hamster SARS-CoV-2 infection model. Results demonstrated protective effects of both IgG and F(ab')₂, with the latter requiring sequential dosing to maintain in vivo activity due to rapid clearance from the circulation.

SUBMITTER: Findlay-Wilson S

PROVIDER: S-EPMC10457378 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Refinement of an ovine-based immunoglobulin therapy against SARS-CoV-2, with comparison of whole IgG versus F(ab')<sub>2</sub> fragments.

Findlay-Wilson Stephen S Easterbrook Linda L Smith Sandra S Pope Neville N Aldridge Matthew M Humphries Gareth G Schuhmann Holger H Ngabo Didier D Rayner Emma E Otter Ashley A Coleman Thomas T Hicks Bethany B Halkerston Rachel R Apostolakis Kostis K Taylor Stephen S Fotheringham Susan S Horton Amanda A CanoCejas Irene I Wand Matthew M Tree Julia A JA Sutton Mark M Graham Victoria V Hewson Roger R Dowall Stuart S

Scientific reports 20230825 1

The development of new therapies against SARS-CoV-2 is required to extend the toolkit of intervention strategies to combat the global pandemic. In this study, hyperimmune plasma from sheep immunised with whole spike SARS-CoV-2 recombinant protein has been used to generate candidate products. In addition to purified IgG, we have refined candidate therapies by removing non-specific IgG via affinity binding along with fragmentation to eliminate the Fc region to create F(ab')<sub>2</sub> fragments. ...[more]

PMID: 37626085

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Project description:BackgroundPepsin agglutinators, discovered over 50 years ago, have been recently referred to as anti-hinge antibodies (AHAs) because of their reaction with the IgG hinge epitope. AHAs have different reactivity for each hinge epitope generated by each protease that cleaves the hinge region at different sites. Moreover, AHAs have different reactivity against different hinge epitopes derived from each IgG subclass even when the same protease is used. Since the expression of matrix metalloproteinase-3 (MMP-3) is enhanced in rheumatoid arthritis (RA), AHA production could also be increased. The purpose of this study was to determine whether the levels of AHAs against IgG hinge epitopes produced by MMP-3 are elevated in RA.MethodsThe serum levels of IgG or IgA AHAs against the IgG1/IgG4 F(ab')2 fragments, generated by either MMP-3 or pepsin, were measured using ELISA in 111 patients with RA and 81 healthy controls (HC). Receiver operating characteristic (ROC) analysis was used for obtaining optimal cutoff values and cutoff values indicating high specificity (> 95%) of the AHA. The targeted epitope of a specific AHA was investigated through inhibition ELISA.ResultsSeven AHAs were statistically higher in RA patients than in HC, except IgG AHA against IgG1 F(ab')2, which was generated by MMP-3 proteolytic cleavage. The areas under the ROC curve were 0.66-0.80, although the sensitivities at high specificity were low (5.4-24.3%). The cumulative number of positive AHAs in each individual was statistically higher in RA patients than in HC, suggesting the extreme extent of AHA repertoires in RA. Inhibition studies revealed that IgG AHAs against IgG4 F(ab')2 fragments generated by pepsin cross-reacted with IgG1 F(ab')2 fragments generated by pepsin. Multivariate logistic regression analysis identified the IgG AHA against IgG4 F(ab')2 fragments generated by pepsin as an independent variable for RA diagnosis, even in RA patients who were negative for both RF and ACPA (odds ratio 1.18, 95% CI 1.06-1.32; P = 0.003). Additional experiments using non-RA patients finally strengthened the diagnostic utility.ConclusionIn RA patients, we observed diversification and amplification of AHA repertoires and diagnostic utility of the specific AHA against IgG4 F(ab')2 fragments generated by pepsin but not MMP-3.

Dataset Information

Refinement of an ovine-based immunoglobulin therapy against SARS-CoV-2, with comparison of whole IgG versus F(ab')₂ fragments.

Publications

Refinement of an ovine-based immunoglobulin therapy against SARS-CoV-2, with comparison of whole IgG versus F(ab')<sub>2</sub> fragments.

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Dataset Information

Refinement of an ovine-based immunoglobulin therapy against SARS-CoV-2, with comparison of whole IgG versus F(ab')2 fragments.

Publications

Refinement of an ovine-based immunoglobulin therapy against SARS-CoV-2, with comparison of whole IgG versus F(ab')&lt;sub&gt;2&lt;/sub&gt; fragments.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Refinement of an ovine-based immunoglobulin therapy against SARS-CoV-2, with comparison of whole IgG versus F(ab')₂ fragments.

Refinement of an ovine-based immunoglobulin therapy against SARS-CoV-2, with comparison of whole IgG versus F(ab')<sub>2</sub> fragments.