Poster Session - Abstract # 6

Optimizing the Delivery of Antibody Therapeutics using Blood-Brain Barrier Modulators

Eric Ebert¹, Kelly Schwinghamer¹, Donald W. Miller², and Teruna J. Siahaan¹

¹Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, USA; ²Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, CA

Monoclonal antibody (mAb) therapeutics are an important class of drugs used to treat a wide variety of brain diseases such as Alzheimer’s disease, multiple sclerosis, glioblastoma, and other brain cancers.  However, the brain delivery of mAb therapeutics is challenging due to the presence of the blood-brain barrier (BBB).  The tight junctions of the BBB are formed from protein-protein interactions, including VE-cadherin interactions, that seal the paracellular space. Thus, mAbs cannot cross the BBB into the brain through the paracellular route.  The Siahaan laboratory has developed a novel method of modulating the BBB through the use of cadherin peptides that interfere with the cadherin-cadherin interactions to increase the porosity of the BBB paracellular pathway.  Cadherin peptides (i.e., ADTC5, HAVN1) have been used to deliver a wide variety of molecules into the brain including ¹⁴C-mannitol, gadopentetic acid (a magnetic resonance imaging (MRI) contrast reagent), 13.5 kDa BDNF, 25 kDa polyethylene glycol, 65 kDa albumin and 150 kDa mAbs.  In this project, our goals are to (1) optimize the delivery of mAbs with various physicochemical properties to the brain; (2) evaluate the safety of repeated blood brain barrier opening; and (3) discover new cadherin peptides to improve the delivery mAbs in 3D BBB in vitro system.  Recently, HAVN1 peptide has been shown to increase brain deposition of anti-amyloid β mAb; thus, the effects of HAVN1 to deliver mAbs with various physicochemical properties will be compared.  In the future, the brain deposition mAbs will be evaluated using an mAb tagged with a MRI contrast agent in a mouse model.  Next, multiple administrations of HAVN1 have been shown to cumulatively enhance the brain deposition of an mAb; therefore, the long term safety of multiple injections of the HAVN1 peptide will be investigated in a mouse model.  Finally, a 3D-BBB in vitro system will be used to evaluate activities of new cadherin peptides to enhance mAb delivery across the BBB.