8DFG

Crystal structure of potently neutralizing human monoclonal antibody 42D6 Fab in complex with MSP1-19

Summary for 8DFG

• Entry DOI: 10.2210/pdb8dfg/pdb
• Descriptor: 42D6 Fab Heavy Chain, 42D6 Fab Light Chain, Merozoite surface protein 1, ... (4 entities in total)
• Functional Keywords: merozoite surface protein 1 (msp1), antigen-antibody complex, plasmodium falciparum, antigenic diversion, structural protein-immune system complex, structural protein/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 123323.28

Authors

Patel, P.N.,Tang, W.K.,Tolia, N.H. (deposition date: 2022-06-22, release date: 2022-10-12, Last modification date: 2024-10-16)

Primary citation

Patel, P.N.,Dickey, T.H.,Hopp, C.S.,Diouf, A.,Tang, W.K.,Long, C.A.,Miura, K.,Crompton, P.D.,Tolia, N.H.
Neutralizing and interfering human antibodies define the structural and mechanistic basis for antigenic diversion.
Nat Commun, 13:5888-5888, 2022

PubMed Abstract: Defining mechanisms of pathogen immune evasion and neutralization are critical to develop potent vaccines and therapies. Merozoite Surface Protein 1 (MSP-1) is a malaria vaccine antigen and antibodies to MSP-1 are associated with protection from disease. However, MSP-1-based vaccines performed poorly in clinical trials in part due to a limited understanding of the protective antibody response to MSP-1 and of immune evasion by antigenic diversion. Antigenic diversion was identified as a mechanism wherein parasite neutralization by a MSP-1-specific rodent antibody was disrupted by MSP-1-specific non-inhibitory blocking/interfering antibodies. Here, we investigated a panel of MSP-1-specific naturally acquired human monoclonal antibodies (hmAbs). Structures of multiple hmAbs with diverse neutralizing potential in complex with MSP-1 revealed the epitope of a potent strain-transcending hmAb. This neutralizing epitope overlaps with the epitopes of high-affinity non-neutralizing hmAbs. Strikingly, the non-neutralizing hmAbs outcompete the neutralizing hmAb enabling parasite survival. These findings demonstrate the structural and mechanistic basis for a generalizable pathogen immune evasion mechanism through neutralizing and interfering human antibodies elicited by antigenic diversion, and provides insights required to develop potent and durable malaria interventions.

PubMed: 36202833
DOI: 10.1038/s41467-022-33336-3

Experimental method

X-RAY DIFFRACTION (2 Å)