Malaria is caused by Plasmodium parasites, primarily transmitted through the bites of infected mosquitoes. Of the five species of Plasmodium that cause malaria, Plasmodium falciparum is the deadliest, responsible for the majority of cases and deaths, particularly in Africa, where young children are most vulnerable. The World Health Organization estimated 263 million malaria cases and nearly 600,000 deaths globally during 2023. Advances in antibody drugs have provided a promising avenue for malaria prevention. Monoclonal antibodies (mAbs) have shown potential in neutralizing P. falciparum sporozoites—the parasite’s stage that infects the liver—thereby preventing progression to blood-stage parasites, which cause severe disease and death.
This week, a team of NIH researchers discovered a novel class of anti-malaria antibodies that could lead to the next generation of interventions against malaria. Published in Science, the study highlights a potent monoclonal antibody, MAD21-101, which binds to a previously untargeted region of the P. falciparum sporozoite surface protein, PfCSP. Unlike existing vaccines and mAbs, which target the central repeat region of PfCSP, MAD21-101 binds to a conserved epitope called pGlu-CSP, exposed only after a specific developmental step in the sporozoite. This epitope, widely accessible on the sporozoite surface, is absent from current vaccines, meaning it could be used in combination with existing interventions without diminishing their efficacy. While further studies are needed to assess the activity and effectiveness of MAD21-101 and related antibodies, this discovery represents a crucial step toward reducing the global burden of malaria.
DOI:10.1126/science.adr0510
Meanwhile, a study co-led by scientists from UT Health San Antonio has uncovered a critical weakness in P. falciparum, confirming that individuals in malaria-endemic regions can develop broadly neutralizing antibodies against the parasite. These antibodies target a specific site on the polymorphic erythrocyte membrane protein 1 (PfEMP1), which the parasite relies on to bind to the endothelial protein C receptor (EPCR) of human host cells—an interaction essential for severe malaria to develop. This site, described as the parasite's "Achilles' heel," cannot mutate without compromising its function, making it an ideal target for vaccine development. The findings pave the way for the development of vaccines that mimic the naturally acquired immunity observed in malaria-exposed populations. Further research aims to refine monoclonal antibodies targeting PfEMP1 and optimize computational protein design for future vaccine frameworks.
Another common species of Plasmodium parasites is Plasmodium vivax. Last month, researchers identified and characterized 12 human monoclonal antibodies targeting Pv Apical Membrane Antigen 1 (PvAMA1), a key protein essential for sporozoite and merozoite invasion. Among these, humAb 826827 demonstrated exceptional efficacy by blocking reticulocyte invasion in vitro (IC50: 0.3–3.7 µg/mL) and significantly reducing liver infection in transgenic FRG-humHep mice. With no existing Pv vaccine and limited therapeutic options, humAb 826827 represents a promising candidate for combating Pv malaria, reducing disease burden, and advancing global eradication efforts.
Furthermore, researchers have developed a promising new drug that could help combat the spread of treatment-resistant malaria by targeting PfCLK3, an essential malarial kinase involved in RNA splicing, using a covalent inhibition strategy. By solving the cocrystal structure of PfCLK3 with the reversible inhibitor TCMDC-135051, the team designed chloroacetamide-based covalent inhibitors targeting a unique, poorly conserved cysteine residue (Cys368) in the human kinome. The lead compound, 4, demonstrated nanomolar potency, extended duration of action after a 6-hour washout, and improved selectivity against human kinases and HepG2 cells. Importantly, the compound exhibited a low resistance potential (log MIR > 8.1), addressing a key challenge in antimalarial drug development. This breakthrough represents the first covalent inhibitor targeting a malarial kinase and highlights its potential as a lead compound for a single-dose malaria cure, capable of acting across multiple stages of the parasite lifecycle.
