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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.
Via Krishan Maggon
Last updated December 9, 2014
The LRP-1 Solution: Robust and VersatileThe blood-brain barrier (BBB) does a very good job of preventing most natural molecules and foreign substances from entering the brain via the BBB’s tight junctions of endothelial cells and P-glycoprotein (P-gp) activity.
Essential substances like insulin and growth hormones are able to successfully enter the brain using receptors in the BBB. One of the most important receptors involved in that transport process is lipoprotein receptor-related protein, or LRP-1. By engineering drugs that bind to the LRP-1 receptor, Angiochem has created therapeutics that are able to permeate the BBB while maintaining their activity and efficacy.
Binding Drug Compounds to the Body’s Own LRP-1 ReceptorAngiochem's proprietary, proven, and highly versatile technology platform uses the body’s own receptors, specifically
LRP-1, as therapeutic gateways to the brain.
Angiochem’s drugs bind to the LRP-1 receptor, and cross the BBB through LRP-1 receptor mediated transcytosis, which is the same natural process by which substances like insulin enter the brain.