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

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

doi:10.1038/s41467-024-53848-4

ImmunologyNature CommunicationsDec 4, 2024

Peer-reviewed journal article

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

Anna C. Winnicki, Melanie H. Dietrich iD, Lee Ming Yeoh iD, Lenore L. Carias, Wanlapa Roobsoong iD, Chiara L Drago, Alyssa N Malachin, Karli R. Redinger iD, Lionel Brice Feufack-Donfack iD, Léa Baldor iD, Nicolai C Jung iD, Olivia S. McLaine, Yelenna Skomorovska-Prokvolit, Ágnes Orbán iD, D. Herbert Opi iD, Payton Kirtley, Kiersey Nielson iD, Maya Aleshnick iD, Gigliola Zanghì iD, Nastaran Rezakhani iD, Ashley M. Vaughan iD, Brandon Keith Wilder iD, Jetsumon Sattabongkot iD, Wai‐Hong Tham iD, Jean Popovici iD, , Christopher L. King iD

Abstract

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. We isolated 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. HumAb 826827 blocked the invasion of human erythrocytes using Pv clinical isolates and inhibited sporozoite invasion of human hepatocytes in vitro (IC50 of 0.3 - 3.7 {micro}g/mL). It also significantly reduced liver infection of chimeric FRG-humHep mice 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 new therapy for Pv.

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