Nanobodies against Plasmodium adhesins that block receptor engagement and malaria parasite invasion

DSa J; Chen, JZ; Chmielewski, J; Jackson, CJ; Adair, A; Tan, LL; Chan, LJ; Krauss, L; Zeglinski, K; Gouil, Q; Schmidt, CQ; Fleishman, SJ; Pymm, P; Tham, WH

Author(s): DSa J; Chen, JZ; Chmielewski, J; Jackson, CJ; Adair, A; Tan, LL; Chan, LJ; Krauss, L; Zeglinski, K; Gouil, Q; Schmidt, CQ; Fleishman, SJ; Pymm, P; Tham, WH;
Details: Publication Year 2026-08-05,Volume 483,Issue #8,Page 1473-1488
Journal Title: Biochemical Journal
Abstract: Malaria is caused by Plasmodium parasites, and its clinical symptoms are a result of parasite invasion of red blood cells and the subsequent cycles of replication and proliferation. In human populations, Plasmodium vivax is responsible for the most widely distributed recurring malaria infections whereas Plasmodium falciparum inflicts the most mortality and morbidity. One well-characterized family of adhesins involved in red blood cell invasion is the reticulocyte-binding-like protein homolog family, known as the RBL superfamily that includes the PfRh family in P. falciparum and PvRBP family in P. vivax. Here we report a collection of nanobodies against three members of this adhesin family, PfRh5, PfRh4, and PvRBP2b. Nanobodies against these Plasmodium adhesins bind with high affinity across several epitopes and can block receptor engagement and inhibit parasite invasion of red blood cells. Using computational design, we generated stabilized PfRh4 variants that encompass the conserved scaffold present in the PfRh and PvRBP families of adhesins and show that several variants with improved expression retained binding to mouse monoclonal antibodies, nanobodies, and Complement Receptor 1, the human receptor for PfRh4. We also observed that most of the inhibitory nanobodies against the three antigens recognized the conserved structural scaffold that define this family of adhesins. These results demonstrate the potential of nanobodies to block malaria parasite invasion into red blood cells.
Publisher: Portland Press
Keywords: Humans; *Plasmodium falciparum/immunology; *Protozoan Proteins/immunology/antagonists &; inhibitors/metabolism/chemistry/genetics; Erythrocytes/parasitology; Animals; *Single-Domain Antibodies/immunology/pharmacology; *Plasmodium vivax/immunology; Mice; Carrier Proteins; Membrane Proteins; Plasmodium; adhesins; malaria; nanobodies; parasite invasion
Research Division(s): Infection and Global Health; Immunology; Genetics and Gene Regulation
PubMed ID: 42384414
Publisher's Version: https://doi.org/10.1042/BCJ20260354
Open Access at Publisher's Site: https://doi.org/10.1042/BCJ20260354
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-07-09 08:59:09

Last Modified: 2026-07-30 09:26:01