A strain-transcending anti-AMA1 human monoclonal antibody neutralizes malaria parasites independent of direct RON2L receptor blockade.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-03-18 Epub Date: 2025-02-27 DOI:10.1016/j.xcrm.2025.101985

Palak N Patel, Ababacar Diouf, Thayne H Dickey, Wai Kwan Tang, Christine S Hopp, Boubacar Traore, Carole A Long, Kazutoyo Miura, Peter D Crompton, Niraj H Tolia

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Abstract

Plasmodium falciparum apical membrane antigen 1 (AMA1) binds a loop in rhoptry neck protein 2 (RON2L) during red cell invasion and is a target for vaccines and therapeutic antibodies against malaria. Here, we report a panel of AMA1-specific naturally acquired human monoclonal antibodies (hmAbs) derived from individuals living in malaria-endemic regions. Two neutralizing hmAbs engage AMA1 independent of the RON2L-binding site. The hmAb 75B10 demonstrates potent strain-transcending neutralization that is independent of RON2L blockade, emphasizing that epitopes outside the RON2L-binding site elicit broad protection against variant parasite strains. The combination of these hmAbs synergistically enhances parasite neutralization. Vaccination with a structure-based design (SBD1) that mimics the AMA1-RON2L complex elicited antibodies similar to the two neutralizing hmAbs connecting vaccination to naturally acquired immunity in humans. The structural definition of a strain-transcending epitope on AMA1 targeted by naturally acquired hmAb establishes paradigms for developing AMA1-based vaccines and therapeutic antibodies.

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.