Structure-Guided Design of an Anti-dengue Antibody Directed to a Non-immunodominant Epitope (Cell 162:493, 2015)

報告日期: 2015/10/20
報告時間: 4:00/4:50
報告學生: 賴彥仲
講評老師: 王淑鶯
附件下載: 下載[1505-1443054003-1.pdf] 

Structure-Guided Design of an Anti-dengue Antibody

Directed to a Non-immunodominant Epitope

Luke N. Robinson, et al.

Cell. 2015 Jul 30;162(3):493-504. doi: 10.1016

Speaker: Yen-Chung Lai (賴彥仲)                    Time: 16:00 ~17:00, Oct 31, 2015

Commentator: Shu-Ying Wang, Ph.D (王淑鶯) Place: 醫學院 602

Abstract:

Dengue is an important mosquito-borne flavivirus disease, causing 22,000 deaths annually.1 Infection of any of the four serotypes of dengue virus (DENV) can induce life-long protection to the infecting serotype but only transient protection to heterologous serotypes. Nowadays, there are no effective vaccine nor antiviral agent available. Several studies have revealed that passive immunotherapy with monoclonal antibodies (mAb) against DENV E protein reduced viral titers, whereas viral interference may limit the potency which result from a narrow coverage of genetically virus strains.2 The domain III of E protein (EDIII) specific antibodies recently have been shown to contribute to a minor humoral response which can cross-reactive to four-serotypes. To investigate the therapeutic potential of EDIII antibodies, authors employed a structure-guided strategy and validated Epitope-Paratope Connectivity (EPC) network to generate a non-immunodominant, but broadly-neutralizing EDIII-specific antibody (Ab513) from the original antibody 4E11. By introducing six affinity-enhancing mutation and one deletion for engineering, the structured-based affinity-enhancing improved the interaction of Ab513 with EDIII. Treating AG129 mic with Ab513 reduced viral titers of four-serotypes of DENV infection. In addition, the administration of Ab513 mitigated DENV-induced thrombocytopenia, vascular leakage in humanized mice and protected mice in a maternal transfer model of antibody-enhanced disease. The last but not the least, Ab513 improved the survival rate of DENV-infected mice. Taken together, Ab513 exhibits broad neutralization and binding ability against all four DENV serotypes. The results demonstrated a potential immunotherapy of AG129 to control dengue disease.

References:

1. Gubler DJ. Dengue and dengue hemorrhagic fever. Clinical microbiology reviews 1998, 11(3): 480-496.

2. Lai CY, Tsai WY, Lin SR, Kao CL, Hu HP, King CC, et al. Antibodies to envelope glycoprotein of dengue virus during the natural course of infection are predominantly cross-reactive and recognize epitopes containing highly conserved residues at the fusion loop of domain II. Journal of virology 2008, 82(13): 6631-6643.