(6g) Self-Assembled Protein Hexamers for Intracellular Delivery of Antibodies (INVITED SPEAKER)

Proteins can provide therapeutic functions simply not possible with small molecule drugs, but their large size and folded structure present critical challenges in terms of delivery, stability and activity. We take advantage of protein size, structure and the ability to interact with other proteins, in order to create therapeutic protein materials via self-assembly routes not available for small molecules. The ability to control assembly of therapeutic proteins is essential to manipulating the final physical properties of the material, ensuring retention of protein activity, and directing the interactions between materials and cells. In this presentation, I will describe the development, characterization and performance of Hex nanocarriers, which are self-assembled complexes capable of intracellular protein delivery. The Hex carriers seek to open up the intracellular space for antibodies and antibody variants as an approach to aim at “undruggable” intracellular protein targets. We applied a rational protein design strategy, combining a self-assembling hexamer barrel with six to twelve antibody binding domains that can bind the constant region of any antibody, making it a platform technology. Additionally, we have designed several sequence variations with different properties and features. We have performed extensive molecular characterization to understand the loading, dynamics and stability of our assemblies. We have demonstrated intracellular delivery of both non-specific fluorescent antibodies and specific functional antibodies and have developed insight on the uptake, trafficking and fate of internalized antibodies. The current status of application of these carriers towards therapeutic disease targets will also be shared.