There is a long list of “undruggable” targets, protein-protein interactions inside cells that small molecule drugs cannot block. Antibodies, in particular, can be engineered to bind almost any protein and inhibit protein function but have not yet been used against these targets. This is primarily due to the significant, unmet challenge in delivering sufficient amounts of folded, functional antibodies inside cells. We have designed an intracellular antibody carrier using protein self-assembly and demonstrate the cytosolic localization and therapeutic activity of delivered antibodies. By utilizing a coiled-coil protein bundle and generic antibody-binding peptides, nanoscale complexes containing only protein are formed with antibodies. These nanocomplexes deliver significant amounts of IgG into cells and are non-toxic. More importantly, the delivered IgG is able to access the cytosol with its binding function intact. The modular design of the fusion protein enables easy modification to impart additional functionality, including endosomal escape peptides or cell targeting proteins, which can further improve the delivery profile. Characterization of cell and organism interactions with these complexes help explain their function and their application for delivery of intracellular antibody therapeutics to target a wide range of intracellular proteins that are responsible for human disease.

Self-assembled protein nanocomplexes for intracellular antibody delivery

254th National Meeting (2017)

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