9C7D

Human monoclonal antibody MAD22-38 bound to the N-terminus of cleaved circumsporozoite protein

Summary for 9C7D

• Entry DOI: 10.2210/pdb9c7d/pdb
• Descriptor: Monoclonal antibody MAD22-38 Fab Heavy Chain, Monoclonal antibody MAD22-38 Fab Light Chain, Circumsporozoite protein, ... (5 entities in total)
• Functional Keywords: antibody, malaria, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 50406.76

Authors

Moskovitz, R.,Wilson, I.A. (deposition date: 2024-06-10, release date: 2024-12-25, Last modification date: 2025-01-22)

Primary citation

Dacon, C.,Moskovitz, R.,Swearingen, K.,Da Silva Pereira, L.,Flores-Garcia, Y.,Aleshnick, M.,Kanatani, S.,Flynn, B.,Molina-Cruz, A.,Wollenberg, K.,Traver, M.,Kirtley, P.,Purser, L.,Dillon, M.,Bonilla, B.,Franco, A.,Petros, S.,Kritzberg, J.,Tucker, C.,Paez, G.G.,Gupta, P.,Shears, M.J.,Pazzi, J.,Edgar, J.M.,Teng, A.A.,Belmonte, A.,Oda, K.,Doumbo, S.,Krymskaya, L.,Skinner, J.,Li, S.,Ghosal, S.,Kayentao, K.,Ongoiba, A.,Vaughan, A.,Campo, J.J.,Traore, B.,Barillas-Mury, C.,Wijayalath, W.,Idris, A.,Crompton, P.D.,Sinnis, P.,Wilder, B.K.,Zavala, F.,Seder, R.A.,Wilson, I.A.,Tan, J.
Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein.
Science, 387:eadr0510-eadr0510, 2025

PubMed Abstract: The most advanced monoclonal antibodies (mAbs) and vaccines against malaria target the central repeat region or closely related sequences within the circumsporozoite protein (PfCSP). Here, using an antigen-agnostic strategy to investigate human antibody responses to whole sporozoites, we identified a class of mAbs that target a cryptic PfCSP epitope that is only exposed after cleavage and subsequent pyroglutamylation (pGlu) of the newly formed N terminus. This pGlu-CSP epitope is not targeted by current anti-PfCSP mAbs and is not included in the licensed malaria vaccines. MAD21-101, the most potent mAb in this class, confers sterile protection against infection in a human liver-chimeric mouse model. These findings reveal a site of vulnerability on the sporozoite surface that can be targeted by next-generation antimalarial interventions.

PubMed: 39745947
DOI: 10.1126/science.adr0510

Experimental method

X-RAY DIFFRACTION (1.99 Å)