5AAW

Structure of a redesigned cross-reactive antibody to dengue virus with increased in vivo potency

Replaces:  4UDZ

Summary for 5AAW

• Entry DOI: 10.2210/pdb5aaw/pdb
• Related: 5AAM
• Descriptor: SCFV513, DENGUE SEROTYPE 4 ENVELOPE PROTEIN DOMAIN 3 (3 entities in total)
• Functional Keywords: viral protein, scfv dengue antibody envelope domain iii
• Biological source: MUS MUSCULUS (HOUSE MOUSE); More
• Total number of polymer chains: 12
• Total formula weight: 240720.29

Authors

Wong, Y.,Robinson, L.,Lescar, J.,Sasisekharan, R. (deposition date: 2015-07-30, release date: 2015-09-30, Last modification date: 2024-11-13)

Primary citation

Robinson, L.N.,Tharakaraman, K.,Rowley, K.J.,Costa, V.V.,Chan, K.R.,Wong, Y.H.,Ong, L.C.,Tan, H.C.,Koch, T.,Cain, D.,Kirloskar, R.,Viswanathan, K.,Liew, C.W.,Tissire, H.,Ramakrishnan, B.,Myette, J.R.,Babcock, G.J.,Sasisekharan, V.,Alonso, S.,Chen, J.,Lescar, J.,Shriver, Z.,Ooi, E.E.,Sasisekharan, R.
Structure-Guided Design of an Anti-Dengue Antibody Directed to a Non-Immunodominant Epitope.
Cell(Cambridge,Mass.), 162:493-, 2015

PubMed Abstract: Dengue is the most common vector-borne viral disease, causing nearly 400 million infections yearly. Currently there are no approved therapies. Antibody epitopes that elicit weak humoral responses may not be accessible by conventional B cell panning methods. To demonstrate an alternative strategy to generating a therapeutic antibody, we employed a non-immunodominant, but functionally relevant, epitope in domain III of the E protein, and engineered by structure-guided methods an antibody directed to it. The resulting antibody, Ab513, exhibits high-affinity binding to, and broadly neutralizes, multiple genotypes within all four serotypes. To assess therapeutic relevance of Ab513, activity against important human clinical features of dengue was investigated. Ab513 mitigates thrombocytopenia in a humanized mouse model, resolves vascular leakage, reduces viremia to nearly undetectable levels, and protects mice in a maternal transfer model of lethal antibody-mediated enhancement. The results demonstrate that Ab513 may reduce the public health burden from dengue.

PubMed: 26189681
DOI: 10.1016/J.CELL.2015.06.057

Experimental method

X-RAY DIFFRACTION (3.27 Å)