The immunoglobulin CH1 constant region modulates antigen binding affinity and functional activities of the broadly neutralizing 2F5 HIV specific antibody

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.

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.

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.

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.

Affiliations

1. Institut Cochin, Paris, France

   • Daniela Tudor
   • , Anne-Sophie Drillet
   •  & Morgane Bomsel

2. INRA, Jouy-en-Josas, France

   • Isabelle Schwartz-Cornil

3. University of Birmingham, Alabama, USA

   • Ruizhong Shen
   •  & Phillip D Smith

Corresponding author

Correspondence to Daniela Tudor.

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