NeuroImmunology

Abstract

 we identified a peptide, known as Angiopep-2 (An2), which crosses the blood–brain barrier (BBB) efficiently via receptor-mediated transcytosis, and, when conjugated, endows small molecules and peptides with this property. Extending this strategy to higher molecular weight biologics, we now demonstrate that a conjugate between An2 and an anti-HER2 mAb results in a new chemical entity, ANG4043, which retains in vitro binding affinity for the HER2 receptor and antiproliferative potency against HER2-positive BT-474 breast ductal carcinoma cells. Unlike the native mAb, ANG4043 binds LRP1 clusters and is taken up by LRP1-expressing cells. Measuring brain exposure after intracarotid delivery, we demonstrate that the new An2–mAb conjugate penetrates the BBB with a rate of brain entry (Kin) of 1.6 × 10−3mL/g/s. Finally, in mice with intracranially implanted BT-474 xenografts, systemically administered ANG4043 increases survival. Overall, this study demonstrates that the incorporation of An2 to the anti-HER2 mAb confers properties of increased uptake in brain endothelial cells as well as BBB permeability. These characteristics of ANG4043 result in higher exposure levels in BT-474 brain tumors and prolonged survival following systemic treatment. Moreover, the data further validate the An2–drug conjugation strategy as a way to create brain-penetrant biologics for neuro-oncology and other CNS indications. Mol Cancer Ther; 1–12. ©2014 AACR.

Proven, Versatile, Proprietary Technology

The technology platform has been validated in more than 200 patients in four US clinical trials and in multiple preclinical studies. Strong efficacy and excellent safety have been demonstrated with no evidence of CNS toxicity or immunogenicity, even after repeat dosing up to 22 cycles.

Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocyti...

The blood-brain barrier (“BBB”) consists of a vast network of capillaries that deliver oxygen, nutrients and other necessities to brain cells and carry waste materials away. As in the rest of the body, the walls of the BBB capillaries consist of a single layer of endothelial cells. However, the junctions between the endothelial cells of the BBB capillaries are tightly joined so foreign substances, harmful as well as beneficial, are prevented from passing from the blood, between the cells and into the brain tissue.

 

The endothelial cells that form this formidable barrier allow the transport of desirable molecules between the blood and the brain. Unique physiological mechanisms allow sugars, minerals, proteins, waste materials and other substances to pass through the BBB, maintaining the delicate chemical balance of the brain.

This exchange of substances takes place through channels and receptors found on the surface of the BBB endothelial cells. For instance, melanotransferrin (“MTf”), the protein upon which biOasis’ Transcend is based, attaches itself to receptors on a BBB endothelial cell and is ferried through the cell into the brain where it delivers its normal payload of iron.

 

Making adaptations to an innate transport system, such as MTf, in order to carry therapeutics across the BBB could allow for an effective, safe and non-invasive drug-delivery system, which is what biOasis has done with Transcend.

 

A system that allows the transport of therapeutics across the BBB would address a large unmet medical need in neurological medicine. Due to the BBB, over 98% of small molecule drugs and almost 100% of larger biologic drugs (antibodies, enzymes, etc.) cannot enter the brain at therapeutic concentrations.

The BBB and existing delivery mechanisms of therapeutics to the central nervous system (“CNS”) are the limiting factors in developing treatments for many neurological diseases.