Domain exchanged antibodies are a novel antibody structural solution for binding repeating arrays of antigen with high affinity.

High density arrays of carbohydrates present on the surface of pathogens and cancer cells often serve to prevent immune recognition. The nature of these carbohydrate clusters render them hypoimmunogenic and make it especially difficult for the human immune system to elicit a high affinity antibody response. Due to their high epitope density, conventional antibodies do not optimally recognize these antigens because simultaneous binding of both antibody-combining sites may be energetically disfavored. The practical implication of this limitation manifests itself in the form of significantly lower binding affinities of conventional antibody to this class of antigen.

Recently, Calmune’s founders in collaboration with researchers at The Scripps Research Institute have described a novel antibody structure while studying the high affinity binding of the broadly neutralizing HIV antibody 2G12 to oligomannose residues on the surface glycoprotein gp120. In this antibody, framework mutations have resulted in domain exchange of the heavy chain variable regions replacing the usual Y-shape of a conventional antibody with an unusual more linear structure.

In molecular terms, the variable heavy domains of the antibody molecule are exchanged to pair with the "opposite" light chains. Instead of the usual, flexible arrangement found in conventionally structured antibodies with mobile antibody combining sites, this exchange produces an array of antibody combining sites that are fixed and closely spaced – ideal for intercalation with the densely arrayed, repetitive oligomannose residues on the surface of HIV. Consequently, this neutralizing antibody binds with uniquely high affinity to the carbohydrate determinants on the ‘immunologically silent' face of the HIV virion. Structural studies have determined the features of this molecule that are important for achieving domain exchange.