Human C. difficile-specific memory B cells encode protective IgG1 despite predominance of non-neutralizing antibodies

Clostridioides difficile remains a common source of nosocomial infection resulting in a wide range of clinical outcomes and for which there is no vaccine and limited therapeutic options. C. difficile Toxin B (TcdB)-specific IgG is the best correlate of protection against severe and recurrent disease. However, there are very few therapeutic IgG fully human monoclonal antibodies (hmAbs) that have shown efficacy thus far. We therefore hypothesized that the memory B cell (Bmem) compartment of individuals who have recovered from infection may be dominated by non-protective IgG molecules but encode some antibodies that are protective. We therefore produced hmAbs from a library of Bmem-encoded IgG1 sequences. Most TcdB-specific hmAbs displayed low affinity binding and poor neutralization of TcdB in vitro while a few hmAbs had high affinity binding and good TcdB neutralization. The results correlated with in vivo studies in which high affinity, TcdB-neutralizing hmAbs provided moderate protection of C57Bl/6 mice against C. difficile disease. Similar protection was observed in Tg32 mice expressing the human FcRn transgene, indicating that gut delivery of hmAb did not account for limited efficacy. Although non-protective antibody sequences dominate the repertoire, human Bmem cells may be a good source of therapeutic hmAbs for C. difficile treatment.