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Versatile, Multivalent Nanobody Cocktails Efficiently Neutralize SARS-CoV-2

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Versatile, Multivalent Nanobody Cocktails Efficiently Neutralize SARS-CoV-2

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Nanobodies that neutralize Monoclonal antibodies that bind to the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) show therapeutic promise but must be produced in mammalian cells and need to be delivered intravenously. By contrast, single-domain antibodies called nanobodies can be produced in bacteria or yeast, and their stability may enable aerosol delivery. Two papers now report nanobodies that bind tightly to spike and efficiently neutralize SARS-CoV-2 in cells. Schoof et al. screened a yeast surface display of synthetic nanobodies and Xiang et al. screened anti-spike nanobodies produced by a llama. Both groups identified highly potent nanobodies that lock the spike protein in an inactive conformation. Multivalent constructs of selected nanobodies achieved even more potent neutralization. Science , this issue p. 1473 , p. 1479
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... Collectively, our data demonstrates that intranasal delivery of a neutralizing nanobody IgA-Fc fusion protects animals from infection of SARS-CoV-2 VOC, and the results strongly suggest that the IgA-Fc fused nanobody provides a greater level of protection in the mucosal lining of the nasal passages and lungs, as either an immunoprophylaxis or post-exposure treatment, than the monomeric nanobody. This result is consistent with most recent nanobody studies against SARS-CoV-2, which have shown that multimerization or Fc fusion could significantly increase the efficacy of therapeutic nanobodies (49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60). Since the spike proteins are naturally presented as a trimer on the surface of SARS-CoV-2, one possibility is that the multimerized or Fc fused nanobody could target more than one RBD antigen at the same time, and this multimeric nanobody-antigen structure could be more stable than the monomeric nanobodyantigen complex. ...
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