Trimeric cell-penetrating peptides for intracellular delivery of macromolecules

• Novel platform technology for intracellular delivery of biological molecules including IgGs, ScFvs, and oligonucleotides
• In vitro proof of concept achieved with IgGs and functional antibodies
• Scaffold core chemistry claimed by composition of matter patent applications

Approximately two-thirds of proteins expressed by the human genome are located intracellularly, rendering most intracellular targets inaccessible by macromolecule-based therapies such as monoclonal antibodies. The ability to intracellularly deliver such cargoes could therefore render previously ‘undruggable’ cytosolic and nuclear proteins viable targets for biologic drugs and enable novel diagnostic methods.  

Various delivery methods have been explored, most notably cell-penetrating peptides (CPPs) utilising the HIV-tat protein. However, these required very high doses to achieve adequate intracellular concentrations and suffered from high toxicity and off-target effects.  

To overcome these challenges, Professor Katherine Vallis and Ole Tietz at University of Oxford and Macquerie University, respectively, have devised an approach utilising a novel chemical scaffold to create trimeric cell-penetrating peptides (tCPP). Compared to previous approaches, these tCPPs are dramatically more efficient, thus decreasing the effective concentrations required to deliver a clinically relevant dose into the cell.

The inventors have optimised the scaffold and peptide orientation to increase intracellular delivery and have demonstrated proof of concept in vitro by delivering functional antibodies to intracellular proteins. They have further demonstrated that systemic dosing of CPPs with tumour-targeting-mAb cargoes leads to the effective accumulation of of these mAbs at tumour sites in vivo.

This platform is available for licensing or collaboration, with the objective of advancing these tCPP platforms for both clinical and research use.