Peptide Drug Conjugates Designed to Cross the Blood-Brain Barrier
Jean Lachowicz
Chief Scientific Officer, Angiochem
The utility of numerous treatments for CNS disorders remains unrealized due to inability to cross the blood-brain barrier (BBB). With tight junctions and efflux proteins, the BBB restricts entry of many pharmaceuticals into the brain while allowing essential molecules, such as glucose, insulin, and growth hormones to penetrate. Overcoming the obstacles posed by the BBB is a critical goal for development of CNS therapeutics, particularly those involving peptides and proteins.
A new family of peptides, termed Angiopeps, derived from proteins that are efficiently transported across the BBB by the low-density lipoprotein receptor related protein (LRP1) has been designed. Binding LRP1, these peptides cross the BBB via receptor-mediated transcytosis. This technology is applicable to both small molecules and biologics and provides a non-invasive and flexible platform for creating new brain-penetrating drugs. A portfolio of new chemical entities including small molecules, peptides and proteins has been built using chemical conjugation or recombinant fusion with Angiopeps. The most advanced is GRN1005 (formerly ANG1005), formed by chemical conjugation of Angiopep-2 to three molecules of paclitaxel. GRN1005 demonstrated safety and efficacy in two phase 1/2 clinical trials for the treatment of primary and secondary brain tumors and is in Phase 2 for brain metastases (licensed to Geron Corporation).
We have created fusion proteins of Angiopep-2 with the anti-obesity hormone leptin and chemical conjugates of the peptides exendin-4 and neurotensin. These peptide drug conjugates have been demonstrated to efficiently cross the BBB in vivo in mice while retaining binding affinity to target proteins. In addition, brain-penetrant monoclonal antibodies and enzymes have been created. Results generated with these novel peptide drug conjugates further validate the utility of Angiopeps in development of new CNS therapeutics.