Background The ability of the heavy chain constant region (CH) to affect antibody affinity and specificity could be at the origin of a stronger or weaker memory response, depending on the isotype. Using as a model the broadly neutralizing human mAb 2F5, directed against the membrane proximal region (MPER) of the HIV-1 envelope transmembrane subunit gp41, we investigated the interplay between 2F5 isotype and functional activity. Methods A 2F5 IgA isotype was constructed from the 2F5 IgG1. Functional monomeric 2F5 IgA and IgG1 were expressed in CHO cells and their immunochemical characteristics and anti-HIV-1 in-vitro activity were evaluated. Results As compared to 2F5 IgG1, 2F5 IgA sharing identical VH and VL domains but in a different CH context: (i) binds with higher affinities gp41 and MPER peptides; (ii) has an increased capacity at inhibiting endocytosis of HIV-1 by dendritic cells; (iii) has an increased HIV-1 neutralizing activity in lymphocytic CD4+ T cells; (iv) blocks more efficiently HIV-1 transcytosis across epithelial monolayers in-vitro and normal human rectal mucosa, but (v) has lower ADCC activity. Epitope mapping with a 7 mer epitope library shows that 2F5 IgA recognizes essentially the same hexapeptide epitope as its IgG counterpart. Discussion These results show that the CH region can fine-tune the specificity of an antibody, by modulating its binding affinity to the antigen and the neutralizing activity of variable- region of otherwise identical antibodies. The determinant role of CH region on affinity and specificity changes our understanding of vaccine responses. In the context of HIV-1, which is mainly transmitted sexually, these results strongly suggest that raising a mucosal humoral IgA based response will be superior to an IgG one in blocking HIV-1 transmission.
CITATION STYLE
Tudor, D., Drillet, A.-S., Schwartz-Cornil, I., Shen, R., Smith, P. D., & Bomsel, M. (2010). The immunoglobulin CH1 constant region modulates antigen binding affinity and functional activities of the broadly neutralizing 2F5 HIV specific antibody. Retrovirology, 7(S1). https://doi.org/10.1186/1742-4690-7-s1-p23
Mendeley helps you to discover research relevant for your work.