FcγR binding differentially contributes to protection by two human monoclonal antibodies targeting Plasmodium falciparum circumsporozoite protein

Antibodies mediate protection against a wide range of pathogens through binding and neutralizing the pathogen or through Fc-mediated effector functions. Human monoclonal antibodies (mAbs) CIS43LS and L9LS show high-affinity binding targeting distinct regions on the Plasmodium falciparum circumsporozoite protein (PfCSP) and are highly effective in preventing malaria in humans. However, the role of FcγR binding in protection by these mAbs has not been determined. Here, we assessed several Fc variants of CIS43LS and L9LS for protection against infection with transgenic Plasmodium berghei parasite expressing PfCSP in mice. Limiting binding to FcγRs did not reduce protection compared to the parental mAbs in mice. To determine whether protection could be improved in vivo by Fc modification, we engineered Fc variant mAbs with increased binding to distinct FcγRs. Passive transfer of CIS43LS-DE and CIS43LS-DEAL variants resulted in an approximately two- to threefold reduction in the liver-stage parasite burden in C57BL/6 or human FcγR mice compared with the parental CIS43LS after challenge. CIS43LS-DEAL also enhanced protection of mice after mosquito bite challenge. Systems serology analysis revealed that the CIS43LS-DE and CIS43LS-DEAL variants could enhance human neutrophil and monocyte phagocytosis, as well as NK cell activation, compared with CIS43LS. However, similar Fc modifications incorporated into L9LS did not increase protection compared to the parental mAb. Overall, although FcγR binding by CIS43LS and L9LS is dispensable in mouse models of malaria, enhancing the binding of CIS43LS to FcγR showed a modest increase in the potency of this mAb.