Structural highlights
Publication Abstract from PubMedDengue 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. Structure-Guided Design of an Anti-dengue Antibody Directed to a Non-immunodominant Epitope.,Robinson LN, Tharakaraman K, Rowley KJ, Costa VV, Chan KR, Wong YH, Ong LC, Tan HC, Koch T, Cain D, Kirloskar R, Viswanathan K, Liew CW, Tissire H, Ramakrishnan B, Myette JR, Babcock GJ, Sasisekharan V, Alonso S, Chen J, Lescar J, Shriver Z, Ooi EE, Sasisekharan R Cell. 2015 Jul 15. pii: S0092-8674(15)00827-2. doi: 10.1016/j.cell.2015.06.057. PMID:26189681[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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