SARS-CoV-2 neutralizing antibodies discovered in a 20-year-old human antibody library

The unprecedented health crisis caused by the Coronavirus 2019 (COVID-19) pandemic has affected more than 247 million people so far. Monoclonal antibodies (mAbs) targeting SARS-CoV-2 have been found to have good equivalent efficacy in treating Ebola, SARS, MERS and MERS infections. In the past as well as in the treatment of COVID-19 as indicated by recent studies.

The viral spike protein was the main target for the development of therapeutic mAbs. Most neutralizing antibodies (NAbs) bind directly to the spike protein receptor binding (RBD) domain, although some NAbs bind to the N-terminal domain. Various sources from which NAbs are derived include SARS patients, memory B cells from convalescent SARS-CoV-2 patients, immunized mice encoding human immunoglobulin repertoires, human single-domain antibodies from existing libraries, alpaca nanobodies, and antibody libraries Anti-bacterial.

SARS-CoV-2 NAbs from a pre-pandemic human combinatorial antibody library

In an article published in the open access journal advanced engineering, a multinational team of researchers has reported the selection and characterization of 3 potent SARS-CoV-2 antibodies – S-E6, S-B8 and S-D4 – from a pre-COVID-19 human fusion antibody library generated 20 years ago. The antibodies bind to the RBD of the spike protein, thus competing with the angiotensin-converting enzyme 2 (hACE2) receptor. Compared with antibodies derived from COVID-19 patients with low somatic hypermutation (SHM), these three antibodies had more than 13–22 SHMs. Several of these mutations were involved in specific interactions with the SARS-CoV-2 spike RBD.

“The fusion antibody library technology allows the same evolutionary process to be performed in vitro because it restores” fossil record “For the individual antibody response in a test tube.”

The results of this study show that a highly diverse combinatorial antibody library can mimic the natural immune selection process and allow detection of unexpected high-affinity antibodies targeting spike protein. It also allows selection of binding molecules with chemicals inaccessible during selection in vivo.

Presence of SARS-CoV-2 NAbs in the pre-pandemic library could indicate previous epidemics involving similar coronaviruses.

Combinatorial antibody libraries can greatly simplify the antibody discovery process and also enable documentation of an individual’s antibody response history. In addition, the COVID-19 pandemic has prompted scientists around the world to use this technology more widely to alleviate the unprecedented public health crisis related to the pandemic.

Selection of scFv antibodies targeting the SARS-CoV-2 spike protein.  a) Workflow of the panning process against S-RBD.  b) Input and output versus the stirring round of the S-RBD-hFc antigen during three rounds of screening.  c) Phage ELISA results for 22 unique antibodies with positive readouts (OD405 S-RBD-hFc/hFc ratio >2).” height=”889″ src=”https://d2jx2rerrg6sh3.cloudfront.net/image-handler/picture/2021/11/Captdure.jpg” srcset=”https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20211103121200/ri/850/picture/2021/11/Captdure.jpg 850w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20211103121200 /ri/650/picture/2021/11/Captdure.jpg 650w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20211103121200/ri/450/picture/2021/11/Captdure.jpg 450w” sizes=”(min-width: 1200px) 673px, (min-width: 1090px) 667px, (min-width: 992px) calc(66.6vw – 60px), (min-width: 890px) 850px, (min-width: 480px) calc (100vw – 40px), calc(100vw – 30px)” title=”Selection of scFv antibodies targeting the SARS-CoV-2 spike protein.  a) Workflow of the panning process against S-RBD.  b) Input and output versus the stirring round of the S-RBD-hFc antigen during three rounds of screening.  c) Phage ELISA results for 22 unique antibodies with positive readouts (OD405 S-RBD-hFc/hFc ratio >2).” width=”850″/></p>
<p><span style=Selection of scFv antibodies targeting the SARS-CoV-2 spike protein. a) Workflow of the panning process against S-RBD. b) Input and output versus the stirring round of the S-RBD-hFc antigen during three rounds of screening. c) Phage ELISA results for 22 unique antibodies with positive readouts (OD405 S-RBD-hFc/hFc ratio >2).

In this study, a human fusion antibody library established in 1999 was used to discover three potent antibodies that can selectively bind to the SARS-CoV-2 protein and neutralize the virus. When combined with antibodies taken from convalescent patients or convalescent plasma, these antibodies derived from synthesis libraries have proven to be an effective therapeutic option and a potential antidote for immune escape through newly emerging variants of SARS-CoV-2.

“A combination of antibodies targeting distinct epitopes can be used to overcome such immune escape. As an individual’s entire antibody repertoire is the primary repository of all possibilities, more about the origins and evolution of the immune response against a viral challenge can also be learned. When it is studied “.

The presence of highly potent NAbs in the pre-pandemic library of donors could indicate “healthy” to prior exposure of donors to similar coronaviruses in the past or to a surface antigen that closely resembles SARS-CoV-2 RBD. According to the authors, it remains to be known whether these antibodies are caused by background immunity. Because there is random association of VH and VL sequences in the original combinatorial antibody library, the isolated antibodies do not fully represent the process of natural selection for the human B-cell repertoire.

The identification of these high-SHM antibodies in the pre-COVID library raises intriguing questions about their origin, evolution, and interaction with SARS-CoV-2. In addition, a better understanding of the immune response regarding the interactions between NAbs and SARS-CoV-2 binding epitopes could provide a blueprint for designing next-generation vaccines.

“We cannot rule out potential implications of such findings from decades-old libraries regarding the origin of currently circulating viruses.”

Journal reference:

  • Qiang, M., Ma, P., Li, Y., Liu, H., Harding, A., Min, C., Wang, F., Liu, L., Yuan, M., Ji, Q., Tao, P., Shi, X., Li, Z., Li, T., Wang, X., Zhang, Y., Wu, N.C., Lee, C.-CD, Zhu, X., Gilbert-Jaramillo, J., Zhang, C., Saxena, A., Huang, X., Wang, H., James, W., Dwek, R. A., Wilson, I. A., Yang, G., Lerner, R. A. Neutralising antibodies to SARS- CoV-2 was selected from a human antibody library created decades ago. case. Sciences. 2021, 2102181. https://doi.org/10.1002/advs.202102181, https://onlinelibrary.wiley.com/doi/10.1002/advs.202102181

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