Recent research from Japan describes a neutralising antibody against COVID-19 that the study team says is active against Omicron as well as several other variants.
The scientists explain that SARS-CoV-2 has homotrimeric spike protein antigens on its surface, with each spike monomer comprising the S1 and S2 sub-units. The first of these has a receptor-binding domain (RBD) and an N-terminal domain (NTD).
The RBD mediates host cell attachment by the virus as the first step in the process of infection. The attachment is to the host angiotensin-converting enzyme 2 (ACE2) receptor that is expressed on a variety of human cells. Neutralising antibodies often act by inhibiting the interaction between ACE2 and the RBD, thus preventing SARS-CoV-2 infection.
A number of monoclonal antibodies (mAbs) have been isolated from convalescent serum, with activity against the RBD. The mAb cocktail casirivimab (REGN10933) and imdevimab (REGN10987) have been approved for the treatment of early COVID-19, as has the mAb sotrovimab (VIR-7831).
Newer variants of concern (VOCs) like the Alpha, Beta, Gamma and Delta have been susceptible to these mAbs, though to varying degrees. However, Omicron showed immune escape, resisting neutralisation by casirivimab and imdevimab, presumably due to the mutations at the ACE2-binding site of the RBD, an antigenic supersite. On the other hand, sotrovimab continues to show neutralising activity, though at three-fold lower levels.
The current study shows a novel mAb, UT28K, that has promising broadly-neutralising activity against the virus.
The researchers isolated neutralising mAbs from peripheral blood mononuclear cells from a COVID-19 patient who had recovered from severe illness, on the assumption that strongly neutralising antibodies would be detected. Neutralisation assays showed activity against pseudo-viruses expressing the D614G spike, as well as several other VOC spike variants.
This serum was tested for unique anti-RBD antibodies using the immunospot array assay on a chip (ISAAC). The result was the discovery of UT28K, one of five clones that inhibited spike-ACE2 binding.
UT28K showed picomolar inhibitory concentrations against the VOCs of SARS-CoV-2, but 10-fold lower neutralising activity against Omicron. That is, while the half-maximal inhibitory concentration (IC50) against the earlier VOCs ranged from 40-120 pM, it went up to between 500 and 5 000 pM against Omicron compared to the wild-type virus while still retaining neutralising capability.
In a Syrian hamster model, the intraperitoneal use of UT28K protected against infection by SARS-CoV-2 mutants or pseudo-viruses when the latter was introduced into the trachea. The trachea and lungs were almost completely free of the virus after 24 hours.
The protective dosage was 0.3 mg/kg for Alpha, Gamma, Delta and Kappa, but 10 times higher for Beta and Omicron. This shows a strong protective effect against all variants, though weaker for the latter two.
Novel super-neutralising antibody UT28K is capable of protecting against infection from a wide variety of SARS-CoV-2 variants
Tatsuhiko Ozawa, Hideki Tani, Yuki Anraku, Shunsuke Kita, Emiko Igarashi, Yumiko Saga.
Published in Taylor & Francis Online on 27 April 2022
Many potent neutralising SARS-CoV-2 antibodies have been developed and used for therapies. However, the effectiveness of many antibodies has been reduced against recently emerging SARS-CoV-2 variants, especially the Omicron variant. We identified a highly potent SARS-CoV-2 neutralising antibody, UT28K, in COVID-19 convalescent individuals who recovered from a severe condition. UT28K showed efficacy in neutralising SARS-CoV-2 in an in vitro assay and in vivo prophylactic treatment, and the reactivity to the Omicron strain was reduced. The structural analyses revealed that antibody UT28K Fab and SARS-CoV-2 RBD protein interactions were mainly chain-dominated antigen-antibody interactions. In addition, a mutation analysis suggested that the emergence of a UT28K neutralisation-resistant SARS-CoV-2 variant was unlikely, as this variant would likely lose its competitive advantage over circulating SARS-CoV-2.
Our data suggest that UT28K offers potent protection against SARS-CoV-2, including newly emerging variants.
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