Potent LILRB1 D1D2-containing antibodies inhibit RIFIN-mediated immune evasions

The spread of drug-resistant malaria parasites presents a major challenge to global efforts in malaria control, increasing the urgency for new treatments and vaccines. A promising approach involves developing antibodies that can counteract the parasite’s immune evasion mechanisms. In this study, we designed a receptor-containing antibody, targeting the D1D2 domain of the LILRB1 receptor, using a structure-based rational approach. We began with the MDB1 antibody as a scaffold and replaced the LILRB1-D3D4 insertion domain with D1D2.v, a high-affinity variant optimized through yeast surface display. The modified D1D2.v-IgG efficiently blocked the interaction between RIFIN#1 (from PF3D7_1254800) and LILRB1, thereby reversing the inhibition of NK cell activity caused by RIFIN#1. To further enhance this effect, we developed NK-biAb, a bispecific antibody based on D1D2.v-IgG that targets both RIFIN#1 and NKG2D receptors. NK-biAb exhibited superior biological performance compared to D1D2.v-IgG alone. These findings provide a clear framework for designing antibodies that target immune evasion in malaria, potentially guiding the development of more effective treatments and vaccines.