Isolation and characterisation of human monoclonal antibodies that bind the SARS-CoV-2 spike protein.. virus-neutralising_IgM

Pathogen-specific IgM antibodies in blood peak within weeks from infection, and thereafter decline, while IgG levels are maintained. This pattern suggests that IgM offers a rapid advantage, but at some cost. Hypothetical benefits include the postulated avidity gain, and the increase in complement activation, conferred by the pentameric structure of IgM. Possible costs include self-reactivity and complement-mediated immunopathology. To investigate these benefits and costs, we used membrane antigen capture activated cell sorting to isolate spike-protein-specific B cells from donors recently infected with SARS-CoV-2, allowing production of recombinant antibodies. Monoclonal, spike-binding IgM showed no reactivity to human cells, but mediated stronger complement activation on antigen-expressing cells than did other antibody classes. Virus neutralization by IgM was observed at picomolar concentrations, but was lost following artificial switch to IgG. This is consistent with the hypothesis that increased avidity conferred by the multimeric structure of IgM enables pathogen neutralization early in the immune response, by antibodies that have not yet matured to high affinity. This in turn raises the question of how B cells avoid premature class switch.