Research published in the November 2014 edition of The FASEB Journal, published by the Federation of the American Societies for Experimental Biology, suggests that a very small single domain antibody called FC5 has proven able to cross the blood-brain barrier (BBB). This opens the door to new treatments for a multitude of brain diseases.

Until now, delivering life-saving drugs across the blood-brain barrier and other central nervous system (CNS) targets has been very difficult because the BBB prevents the access of therapeutic antibodies to these sites. However, based the results of a study by researchers at the Human Health Therapeutics Portfolio at the National Research Council of Canada in Ottawa, Ontario, this might become a little easier thanks to a new an antibody, called FC5, one-tenth the size of a traditional antibody – which is able to cross the BBB.

Interestingly, FC5 uses the same pathways as nutrients that the brain needs to survive.  This allows it to smuggle larger antibodies across the barrier.

In in vitro studies the researchers demonstrated that the bivalent fusion of FC5 with Fc increased the rate of transcytosis (Papp) across brain endothelial monolayer by 25% compared with monovalent fusion. After systemic dosing in rats, they observed up to a 30-fold enhanced apparent brain exposure (derived from serum and cerebrospinal fluid pharmacokinetic profiles) of FC5- compared with control domain antibody-Fc fusions.

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Furthermore, the researchers observed improved serum pharmacokinetics of Fc-fused FC5 which contributed to a 60-fold increase in pharmacological potency compared with the single-domain version of FC5. Bivalent and monovalent FC5 fusions with Fc exhibited similar systemic pharmacological potency.

Just like building with Lego
Like a Lego building block, FC5 connects into many types of antibody designs, helping them reach their disease targets in the brain. Based on these results, modular incorporation of FC5 as the so-called BBB-carrier in bispecific antibodies or antibody-drug conjugates could lead the way for the development of new pharmacologically active biotherapeutics to fight a wide range of brain diseases, such as Alzheimer’s, Parkinson’s, cancer, epilepsy, genetic brain diseases, neurodegenerative disease, chronic neuropathic pain, and other conditions.

“Neurological diseases are often devastating for both the affected person and their families. Current treatments are unsatisfactory and have many side effects, and the development of precise, new medicines has so far been unsuccessful because it is difficult or impossible to deliver enough medicine into the brain,” explained Danica B. Stanimirovic, PhD, “With the technology developed in this collaborative work, we hope to open up opportunities for many promising treatments, including antibodies, against neurological diseases to be evaluated in clinical trials and eventually become available to patients.”

Passing a robust “security” system
To make their discovery, Stanimirovic and colleagues attached FC5 to a larger molecule in different configurations and then tested it in cell models and in rats to determine if it was transporting the larger molecules across the BBB. They also incorporated a peptide (a small protein) into the larger molecule being transported by FC5. This peptide was a pain-fighting molecule that cannot enter the brain by itself through the bloodstream. This FC5-peptide combination was injected into the bloodstream and the pain-fighting peptide crossed the BBB to reach the brain.

“The blood-brain barrier is such a robust security system that it should make today’s computer programmers and engineers envious,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “Unfortunately for us, this security system might be a little too good in the sense that it makes it extremely difficult to deliver drugs to the brain. This report may finally offer the key to unlocking a wide range of therapies that could dramatically improve millions of lives.”

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