Central nervous system (CNS) diseases affect as many as 1.5 billion people worldwide,1 accounting for an economic burden of more than $2 trillion in the EU and U.S.2 The market for drug delivery technologies in CNS is expected to grow to $22.5 billion in 2018.3 New CNS drugs are being discovered but with considerably lower success rates than those for non-CNS indications. The main obstacle to effective CNS delivery is the blood-brain barrier.
The blood-brain barrier is made up of specialized capillary endothelial cells that tightly regulate brain homeostasis through multiple transporters, receptors, enzymes, low pinocytotic activity and low paracellular permeability. As it is a highly selective barrier in protecting the brain from harmful substances, the blood-brain barrier also restricts more than 98 percent of small molecule drugs and almost 100 percent of larger biologic drugs (antibodies, enzymes, etc.) cannot enter the brain in therapeutic concentration. It is the key, not only to delivering therapeutics to the CNS, but also to targeting adequate brain cells and correct intracellular compartments in order to elicit therapeutic efficacy.
xB3 is the evolution from the Company’s previous lead BBB technology called Transcend, which Bioasis has been developing and optimizing for drug delivery to the brain. By identifying the key active amino acids from the previous Transcend platform, we have identified a new propriety peptide portion within the platform that is capable of crossing the blood-brain barrier. Preclinical studies conducted in rodent models have shown improved efficiency in brain delivery and target engagement compared to the original platform. Bioasis has also developed a comprehensive suite of linkers that provide the means to link xB3 with a broad spectrum of neurotherapeutics.
Major features of the xB3 platform:
- Small peptide convenient to manufacture, easier to manipulate and lower cost to produce (less than 2% of the size of Transcend)
- xB3 allows for rapid and reproducible synthesis of xB3-based therapeutics
- Therapeutic agents transported more readily across the blood-brain barrier than with Transcend
- Preclinical collaborations demonstrated xB3 does not affect the pharmacokinetics of its therapeutic payload
- xB3 linked to payloads has demonstrated therapeutic efficacy in rodent disease models corresponding to the payload
- xB3 has been demonstrated to be safe in a wide range of doses in rodent models
- The Transcend and xB3 platforms have achieved significant success in studies at over 20 third-party institutions and pharmaceutical companies
- Bioasis has acquired full patent protection for its Transcend and xB3 suite of carriers and linkers
Bioasis is fully committed to advancing CNS drug development in collaboration with academic institutions and pharmaceutical companies, as well as engaging in the commercialization of our platform technologies with licensing opportunities available to the pharmaceutical industry for brain drug delivery.
As Bioasis’ original platform technology, Transcend is based on a naturally occurring human transport protein that is found at low concentrations in the blood. Transcend crosses the blood-brain barrier through a process called receptor-mediated transcytosis where it attaches to receptors on the blood side of the cells that make up the blood-brain barrier and is pulled through those cells and released into the brain.
Our preclinical studies have shown that when Transcend is attached to therapeutics through infusion or injection, the resulting complex attaches to the Transcend receptor on the blood-brain barrier and is transported across the barrier where the therapeutic payload is released to the brain.
Related Research Publications
- Nounou MI, Adkins CE, Rubinchik E, Terrell-Hall T B, Afroz M, Vitalis TZ, Gabathuler R, Tian MM, Lockman PR. (2016) Anti-cancer antibody trastuzumab- melanotransferrin conjugate (BT2111) for the treatment of metastatic HER2+ breast cancer tumors in the brain: an in-vivo study. Pharm Res. Dec;33(12):2930-2942
- Karkan D, Pfeifer C, Vitalis TZ, Arthur G, Ujiie M, Chen QQ, Tsai S, Koliatis G, Gabathuler R, Jefferies WA. (2008) A Unique Carrier for Delivery of Therapeutic Compounds beyond the Blood-Brain Barrier. PLOS ONE 3(6): e2469.
- Creagh LA, Tiong JWC, Tian MM, Haynes CA and Jefferies WA. (2005) Calorimetric studies of melanotransferrin (p97) and its interaction with iron. J. Biol. Chem. Apr 22;280(16) :15735-41.
- Moroo I, Ujiie M, Walker BL, Tiong JWC, Vitalis TZ, Karkan D, Gabathuler R, Moise AR and Jeffries WA. (2003), Identification of a Novel Route of Iron Transcytosis across the Mammalian Blood-Brain Barrier. Microcirculation, 10: 457–462
- Demeule M, Poirier J, Jodoin J, Bertrand Y, Desrosiers RR, Dagenais C, Nguyen T, Lanthier J, Gabathuler R, Kennard M, Jefferies WA, Karkan D, Tsai S, Fenart L, Cecchelli R and Béliveau R. (2002), High transcytosis of melanotransferrin (P97) across the blood–brain barrier. Journal of Neurochemistry, 83: 924–933
- Domínguez A, Álvarez A, Hilario E, et al. (2013) Central nervous system diseases and the role of the blood-brain barrier in their treatment. Neurosci Discov 1:11. doi: 10.7243/2052-6946-1-3
- Ereshefsky L. Venturing Into a New Era of CNS Drug Development
- KK Jain. (2014) Global Drug Delivery in Central Nervous System Diseases – Technologies, Markets, Companies. Basel, Switzerland
- Nounou MI, et al. Anti-cancer Antibody Trastuzumab-Melanotransferrin Conjugate (BT2111) for the Treatment of Metastatic HER2+ Breast Cancer Tumors in the Brain- an In-Vivo Study. Pharm Res. December 2016, 33(12); 2930-2942
- Karkan D, et al. A Unique Carrier for Delivery of Therapeutic Compounds Beyond the Blood-Brain Barrier. PLoS ONE. June 2008, volume 3 (6)