Structural Basis for Enhanced HIV-1 Neutralization by a Dimeric Immunoglobulin G Form of the Glycan-Recognizing Antibody 2G12

The human immunoglobulin G (IgG) 2G12 recognizes high-mannose carbohydrates on the HIV type 1 (HIV-1) envelope glycoprotein gp120. Its two antigen-binding fragments (Fabs) are intramolecularly domain exchanged, resulting in a rigid (Fab)2 unit including a third antigen-binding interface not found in antibodies with flexible Fab arms. We determined crystal structures of dimeric 2G12 IgG created by intermolecular domain exchange, which exhibits increased breadth and >50-fold increased neutralization potency compared with monomeric 2G12. The four Fab and two fragment crystalline (Fc) regions of dimeric 2G12 were localized at low resolution in two independent structures, revealing IgG dimers with two (Fab)2 arms analogous to the Fabs of conventional monomeric IgGs. Structures revealed three conformationally distinct dimers, demonstrating flexibility of the (Fab)2-Fc connections that was confirmed by electron microscopy, small-angle X-ray scattering, and binding studies. We conclude that intermolecular domain exchange, flexibility, and bivalent binding to allow avidity effects are responsible for the increased potency and breadth of dimeric 2G12. [Display omitted] •Structures of a dimeric form of 2G12 IgG, an HIV-1 antibody, are revealed•2G12 IgG dimer is formed by intermolecular domain swapping to create two (Fab)2 arms•Three distinct 2G12 dimer conformations in crystal structures demonstrate flexibility•Increased potency of 2G12 dimer versus monomer is rationalized by greater flexibility 2G12 IgG dimer is a naturally occurring oligomer of a carbohydrate-recognizing antibody against HIV-1 gp120. Here, Bjorkman and colleagues report and characterize three conformationally distinct structures of 2G12 dimer. Their findings suggest that avidity effects via increased flexibility and bivalent binding contribute to the superior efficacy of 2G12 dimer compared with monomer. This provides new insight by presenting a structural description of a multimeric IgG and describes a mechanism by which three-dimensional domain swapping can facilitate broad and potent neutralization of a normally difficult-to-neutralize pathogen.