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2024BIOMED004
Public access from
03/09/2026
Doctoral thesis

Human monoclonal antibodies to the spike subdomain 1 neutralize SARS-CoV-2 and its variants of concern

  • 2024

PhD: Università della Svizzera italiana

SARS-CoV-2
Coronavirus variants
Spike
Subdomain 1
Receptor binding domain
Monoclonal antibodies
Cross-reactive antibodies
B cells
English Progress in the fight against COVID-19 is jeopardized by the emergence of SARS-CoV-2 variants that diminish or abolish the efficacy of vaccines and antiviral monoclonal antibodies. Novel immune therapies are therefore needed, that are broadly effective against present and future coronavirus threats. In principle, this could be achieved by focusing on portions of the virus that are both functionally relevant and averse to change. The subdomain 1 (SD1) of SARS-CoV-2 Spike protein is adjacent to the receptor binding domain (RBD) and its sequence is conserved across SARS-CoV-2 variants, with the exception of one mutation each in the Alpha (A570D) and Omicron BA.1 (T547K) variants and two mutations in the Omicron BA.2.86 (E554K and A570V) variant. To specifically identify and study human antibodies targeting SD1, we designed a flow cytometry-based strategy that combines negative selection of B cells binding to the RBD with positive selection of those binding to an SD1-RBD fusion protein. Among the 25 characterized human monoclonal antibodies, 16 are SD1-specific and 6 of them recognize the SD1-RBDs corresponding to all 12 main variants of concern that were tested. Antibody sd1.040 also neutralizes SARS-CoV-2 pseudovirus variants, including the latest variants Omicron BQ.1.1, EG.5.1, and BA.2.86. Structural studies suggest that this antibody likely locks the Spike trimer in a conformation where the protomers are loosely associated and the fusion peptide is not completely exposed. sd1.040 synergizes with an antibody to the RBD (rbd.042) for neutralization and protects mice when these two antibodies are formulated in a bispecific antibody. Thus, naturally occurring antibodies can neutralize SARS-CoV-2 variants by binding to SD1 and can act synergistically against SARS-CoV-2 in preclinical models. To improve our bispecific antibody, we characterized 37 new RBD antibodies for binding to the 12 main variants of concern. We selected 10 cross-reactive RBD antibodies and tested them in neutralization of ancestral pseudovirus. Three antibodies, rbd.106, rbd.112, and rbd.141, showed broader cross-reactivity and higher neutralizing potency than rbd.042. These antibodies represent promising candidates for the design of a new bispecific antibody.
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  • English
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Medicine
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License undefined
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green
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https://n2t.net/ark:/12658/srd1329216
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