Biophysical and functional characterization of IgE interactions with a malaria antigen

IgE antibodies are critical mediators of allergic reactions, activating basophils and mast cells via FcεRI receptors. Although their role in anti-parasitic immunity is recognized, their therapeutic potential against parasitic infections, including malaria, remains underexplored. This study investigates interactions between the Plasmodium falciparum circumsporozoite protein (PfCSP) and CIS43ε, an IgE variant of the neutralizing antibody CIS43, to elucidate binding properties and functional implications. Surface plasmon resonance (SPR) analyses revealed biphasic binding of CIS43ε to PfCSP, with higher affinity for a core PfCSP peptide (Peptide 21) than to other known immunogenic NANP repeat motifs, particularly in bivalent interactions. Functional assays using FcεRI-expressing cells showed that multimeric Peptide 21, but not monomers, induced significant degranulation, plateauing at the trimeric state. Full-length PfCSP triggered greater degranulation than tetrameric Peptide 21, underscoring the importance of native antigen structure. These findings highlight the multivalent nature of PfCSP-CIS43ε interactions and their role in effector cell activation, offering insights into the therapeutic potential of IgE antibodies against malaria.