Therapeutic efficacy of antibodies lacking FcgR against lethal dengue virus infection is due to neutralizing potency and blocking of enhancing antibodies

Katherine L. Williams, Soila Sukupolvi-Petty, Martina Beltramello, Syd Johnson, Federica Sallusto, Antonio Lanzavecchia, Michael S. Diamond, Eva Harris

PLoS Pathog. (2013) 9: e1003157.

Speaker: Pei-Wei Chen (陳珮瑋)                                            Time: 15:10~16:00, Feb. 19, 2014

Commentator: Dr. Guey-Chuen Perng (彭貴春 老師)         Place: Room 601

Abstract:

Dengue virus (DENV) is a mosquito-transmitted flavivirus with four serotypes. Infection with DENV may cause life threatening dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). DHF/DSS cases are often associated with secondary heterologous DENV serotype infections which subneutralizing antibodies from primary infection facilitate DENV infection by promoting virus entry via Fcγ receptors (FcγR). This phenomenon is known as antibody-dependent enhancement (ADE). Currently, there is no approved vaccine to prevent dengue infection (1). The authors studied a panel of modified anti-envelope (E) protein monoclonal antibodies (MAbs) which lack the ability to bind FcgR or C1q (2). All of the modified MAbs prevented mortality in virus-only lethal infection. However, only the EDII fusion loop-specific E60 N297Q and EDIII A strand-specific 87.1 LALA MAbs completely protected mice in antibody-enhanced lethal infection model. Further analysis suggested that modified MAbs act therapeutically in antibody-enhanced lethal infection model by competing against enhancing antibodies in polyvalent serum that recognize the same or proximal epitopes. According to the studies, the authors developed an in vitro suppression-of-enhancement assay to predict the therapeutic efficacy of modified MAbs in vivo. Results demostrated that modified MAbs prevent both enhancing polyclonal mouse and human anti-DENV immune serum induced ADE in cell culture, which also correlated with the therapeutic efficacy in antibody-enhanced lethal infection model. In summary, the studies suggest an in vitro assay in which neutralization, avidity, and epitope specificity related to in vivo therapeutic activity of modified MAbs.

References:

1.     Angel RMd, Valle JR-d. (2013) Dengue vaccines: strongly sought but not a reality just yet. PLoS Pathog 9: e1003551.

2.     Balsitis SJ, Williams KL, Lachica R, Flores D, Kyle JL. (2010) Lethal antibody enhancement of dengue disease in mice is prevented by Fc modification. PLoS Pathog 6: e1000790.