Many potent and specific peptides have yet to reach patients due to their inherently short half-lives. Additionally, it is not uncommon that a peptide must be delivered intravenously to see a therapeutic effect. These poor pharmacokinetic properties are mainly due to rapid proteolysis upon injection or removal of the peptide from circulation by the kidney because of the small size of the peptide. Longer-acting versions of peptide-based drugs are clearly needed, and if developed, have the potential to be life-changing therapeutics for patients.
Extend Biosciences has a platform technology that harnesses the biology of vitamin D to prolong the half-life and enhance the absorption and bioavailability of peptides and proteins when delivered subcutaneously. Using our D-VITylation™ technology, Vitamin D is covalently attached to the peptide or protein, and this can be done this site-specifically. When the peptide-vitamin D conjugate is injected subcutaneously, it is recognized by the Vitamin D Binding Protein (VDBP), which naturally waits in the skin for sunlight to activate vitamin D. VDBP then actively transports the conjugate into circulation and carries it around for an extended period of time. This results in an extended half-life and improved absorption and bioavailability of the peptide.
Proof-of-concept studies showed that attachment of this proprietary modification extended the half-life of a peptide from 22 minutes to 8 hours in rats. Our technology also improved the absorption and bioavailability of a small, labile protein 675-fold when administered subcutaneously.
Typically, a large fusion protein or PEG molecule is attached to a protein to extend its half-life. However, with a small peptide, this large modification can significantly reduce the function of the peptide. Improvement in pharmacokinetic properties can also be seen when peptides are modified such that they bind albumin or other albumin-like molecules. However, these conjugates can suffer from reduced efficacy or sub-optimal pharmacokinetic characteristics. Notably, none of these modifications address the low subcutaneous bioavailability of peptides. Extend Biosciences’ modification is small and does not interfere with the activity of the peptide, and improves both half-life and bioavailability.
Use of this technology would reduce the amount of drug needed for injections, as well as the frequency of injections, and would allow for efficient subcutaneous administration. For patients, these attributes translate to an improved quality of life and a more patient-friendly drug that can be self-administered, improving compliance. For pharmaceutical companies, this broadly applicable technology can transform a lead peptide into a viable therapeutic drug.