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It is well established that antibodies can efficiently block parasite transmission. In search for naturally acquired antibodies targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed by high-throughput selection of human monoclonal antibodies (mAbs) reactive to sexual stages of\n                    <jats:italic>Pf<\/jats:italic>\n                    in the form of gametes and gametocyte extracts. We isolated mAbs reactive against a range of\n                    <jats:italic>Pf<\/jats:italic>\n                    proteins including well-established targets Pfs48\/45 and Pfs230. One mAb, B1E11K, was cross-reactive to various proteins containing glutamate-rich repetitive elements expressed at different stages of the parasite life cycle. A crystal structure of two B1E11K Fab domains in complex with its main antigen, RESA, expressed on asexual blood stages, showed binding of B1E11K to a repeating epitope motif in a head-to-head conformation engaging in affinity-matured homotypic interactions. Thus, this mode of recognition of\n                    <jats:italic>Pf<\/jats:italic>\n                    proteins, previously described only for Pf circumsporozoite protein (PfCSP), extends to other repeats expressed across various stages. The findings augment our understanding of immune-pathogen interactions to repeating elements of the\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    parasite proteome and underscore the potential of the novel mAb identification method used to provide new insights into the natural humoral immune response against\n                    <jats:italic>Pf<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.7554\/elife.97865","type":"journal-article","created":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T11:25:10Z","timestamp":1716463510000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.97865","source":"Crossref","is-referenced-by-count":1,"title":["Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross-stage recognition of glutamate-rich 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