Computational epitope discovery and in silico design of a bispecific antibody model (COMED hook) to block Plasmodium invasion into erythrocytes.

Malaria remains a major global health threat, with Plasmodium species, especially P. falciparum, increasingly resistant to drugs and vaccines. Novel strategies are needed to address antigenic diversity and the parasite's intracellular immune evasion. This study aimed to identify conserved and immunogenic B-cell epitopes in P. falciparum and human erythrocytes to design a bispecific antibody model, COMED hook, capable of blocking erythrocyte invasion. Surface and secretory proteins of P. falciparum and erythrocytes were retrieved from public databases. B-cell epitopes were predicted and filtered based on antigenicity, allergenicity, and toxicity. Conservancy was assessed via BLAST. Selected epitopes were structurally modeled, docked to B-cell receptors, and used for antibody design via DiffAb. A total of 123 antigenic P. falciparum B-cell epitopes were identified, with 58 conserved across species. Additionally, 92 non-conserved human erythrocyte B-cell epitopes were discovered, of which 12 were selected as host-targeting domains. Two highly conserved Plasmodium epitopes (KHVETWTQRVQNM, LHSNFYIKRF) were predicted to have favorable Fab binding. Designed antibodies likewise exhibited computationally suggested sequence and docking profiles compatible with COMED hook construction. Overall, this study presents an in silico computational design framework for a bispecific antibody model targeting both Plasmodium and host erythrocytes, generating testable predictions for future work. The predicted interactions and the proposed COMED hook concept will require experimental validation to assess biological feasibility.