xB3 platform to enhance blood brain barrier crossing
The xB3 platform is derived from melanotransferrin and utilizes the low-density lipoprotein-related protein 1 (LRP1) as a receptor for its action. The LRP1 receptor is specifically expressed on the endothelium of cerebral vessels (Strickland & Muratoglu, Arteriosl Thromb Vasc Biol 2016).
xB3 carries payloads across the BBB via a process of endocytosis and transcytosis. This transport is applicable to a variety of active molecules including antibodies, enzymes and oligo-nucleotides, with a potential for repurposing them in a tailored manner for CNS delivery drugs with proven pharmacological efficacy.
The xB3 technology is exclusively in-licensed from Bioasis Technology Inc, Canada/US, for neuroinflammation.
xB3 outperforms competing blood-brain barrier technologies
The xB3 technology has been shown to allow the delivery to the brain of siRNA, IL1 receptor antagonist and monoclonal antibodies, such as trastuzumab. For example, when coupled to trastuzumab, xB3 allowed its delivery and clinical efficacy against brain metastatic HER2 positive cancer cells. Trastuzumab alone failed to pass the BBB.
In the figures, trastuzumab conjugated to xB3 (here labelled as BT2111) penetrates into the brain and is significantly more efficacious than trastuzumab alone (here BTA) for cancer cell destruction (Nounou et al 2016)
Moreover, xB3 increases penetration and increase CNS exposure to large biological molecules by selective expression of receptors on brain vessels.
xB3 platform for autoimmune neuroinflammatory disorders
Across Pharmaceuticals Inc is developing xB3 combined with other molecules to enhance their penetration into the brain, to optimize their specific anti-neuroinflammatory actions in the brain and to reduce exposure in the general circulation.
The aimed indications are: auto-immune central neuroinflammatory disorders, including multiple sclerosis.
The toxicology and GMP manufacturing have been optimized with xB3. Hence, by combining with approved compounds, preclinical experiments can quickly advance to clinical stage.