Journal Article

Potent AMA1-specific human monoclonal antibody against Plasmodium vivax Pre-erythrocytic and Blood Stages

Malachin, Alyssa N., Drago, Chiara L., Tham, Wai-Hong, Roobsoong, Wanlapa, Baldor, Lea, Feufack-Donfack, Lionel Brice, Skomorovska-Prokvolit, Yelenna, Vaughan, Ashley M., Carias, Lenore L., Orban, Agnes, Sattabongkot, Jetsumon, Nielson, Kiersey, Popovici, Jean, Winnicki, Anna C., Bosch, Jürgen, Opi, D. Herbert, Redinger, Karli R., Yeoh, Lee M., McLaine, Olivia S., Zanghi, Gigliola, Kirtley, Payton, King, Christopher L., Rezakhani, Nastaran, Jung, Nicolai C., Aleshnick, Maya, Dietrich, Melanie H., Wilder, Brandon K., Beeson, James G.

2024

Overview

New therapeutics are necessary for preventing Plasmodium vivax malaria due to easy transmissibility and dormancy in the liver that increases the clinical burden due to recurrent relapse. In this manuscript we characterize 12 Pv Apical Membrane Antigen 1 (PvAMA1) specific human monoclonal antibodies from Peripheral Blood Mononuclear Cells of a Pv-exposed individual. PvAMA1 is essential for sporozoite and merozoite invasion, making it a unique therapeutic target. We show that humAb 826827 blocks the invasion of human reticulocytes using Pv clinical isolates and inhibits sporozoite invasion of human hepatocytes in vitro (IC 50 of 0.3 – 3.7 µg/mL). Inoculation of human liver transgenic (FRG-humHep) female mice with humAb 826827 significantly reduces liver infection in vivo. The crystal structure of rPvAMA1 bound to 826827 shows that 826827 partially occupies the highly conserved hydrophobic groove in PvAMA1 that binds its known receptor, RON2. We have isolated a potent humAb that is isolate-transcendent, blocks both pre-erythrocytic and blood stage infection, and could be a potential therapy for Pv. Here the authors isolate monoclonal antibodies specific for Plasmodium vivax apical membrane antigen 1, and characterize the epitope of one antibody that inhibits invasion of reticulocytes and hepatocytes, and reduces liver infection in a mouse model.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/1 / 13 / 13/1 / 13/106 / 13/109 / 38 / 631/250/2152/2153/1291 / 631/250/255/1629 / 631/326/417/2546 / 64/60 / 82/1 / 82/103 / Animals / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - pharmacology / Antibodies, Protozoan - immunology / Antigens / Antigens, Protozoan - immunology / Antigens, Protozoan - metabolism / Apical membrane antigen 1 / Blood / Clinical isolates / Crystal structure / Dormancy / Epitopes / Erythrocytes - immunology / Erythrocytes - parasitology / Female / Grooves / Hepatocytes / Hepatocytes - immunology / Hepatocytes - metabolism / Hepatocytes - parasitology / Humanities and Social Sciences / Humans / Hydrophobicity / Infections / Inoculation / Leukocytes (mononuclear) / Leukocytes, Mononuclear - immunology / Life Sciences / Liver / Liver - parasitology / Malaria / Malaria, Vivax - drug therapy / Malaria, Vivax - immunology / Malaria, Vivax - parasitology / Membrane Proteins - immunology / Membrane Proteins - metabolism / Membranes / Mice / Mice, Transgenic / Microbiology and Parasitology / Monoclonal antibodies / multidisciplinary / Peripheral blood mononuclear cells / Plasmodium vivax / Plasmodium vivax - immunology / Protozoan Proteins - chemistry / Protozoan Proteins - genetics / Protozoan Proteins - immunology / Protozoan Proteins - metabolism / Reticulocytes / Reticulocytes - immunology / Reticulocytes - metabolism / Reticulocytes - parasitology / Science / Science (multidisciplinary) / Sporozoites - immunology / Therapeutic targets / Transgenic mice / Vector-borne diseases