The antigens necessary to develop monoclonal antibodies that recognize conformational epitopes must exhibit fully native conformation. This is particularly challenging for proteins with multi-transmembrane domains, such as GPCRs.

For the development of new therapies or preventive strategies, it would be fundamental to have membrane proteins in the purest form but still in native conformation and embedded in a membrane. In contrast to soluble proteins that are quite easy to produce, this is very challenging for integral membrane proteins; indeed, they lay on different mutually incompatible environments, i.e. “aqueous-lipidic-aqueous”. The influence of membrane phospholipids on membrane proteins is especially significant. In absence of such specific environments, membrane proteins do not fold properly and consequently are not functional. In addition, most membrane proteins must acquire specific post-translational modifications for their proper folding and several are active as homo- or hetero-oligomers.

The scientific community is well-aware that these specific constraints can be satisfied for human membrane proteins only by expression in human or animal cells. Therefore, most human membrane proteins produced either synthetically, or in E. coli, or yeast, or insect cells do not present a fully native conformation. In addition, membrane proteins produced in human cells extracted by detergents (even when reinserted in liposomes) lose their native conformations.

Until now, the best source of native membrane proteins for the development of antibodies is whole cells expressing these proteins, or membranes purified from these cells, or VLPs (Viral Like Particles containing HIV or MuLV capsids). Unfortunately, the low concentration of  membrane proteins and the high amount of other proteins (like those of viral capsids) are major drawbacks for developing strong and specific immune responses targeting membrane proteins that are generally poor immunogens.