Targeting intracellular proteins and protein-protein interactions with site-specific lipobodies: a new approach for intracellular antibodies

The RAS family of GTPases is associated with important signalling events responsible for cell growth, proliferation and survival. Mutated RAS are, nevertheless, associated with uncontrolled cell proliferation in 30% of human cancers. Intracellular antibodies targeting oncogenic RAS proteins constitute promising anticancer therapeutics.

Nevertheless, their intrinsic cytosolic instability as well as the lack of methods enabling their proper cellular uptake and localization highly limit their use and further development.

This proposal describes the multicomponent synthesis of lipidic scaffolds (lipo-TAGs) for the permanent or temporal site-selective lipidation of anti-RAS antibody fragments.

Lipidic antibodies (lipobodies) are novel constructs that could share the properties of any lipid-drug conjugate which includes oral bioavailability, enhanced lymphatic/tumour targeting and reduced toxicity.

This project also aims to build amphiphilic lipobodies with the ability to experiment cellular uptake and endosomal escape, thus avoiding lysosomal degradation, and eventually experimenting cytosolic processing to generate the active antibody fragment.

These unique features will be relevant not only at targeting RAS but any other intracellular protein or protein-protein interaction targets.