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Feb 1, 2009 (Vol. 29, No. 3)

Strategies to Overcome Blood-Brain Barrier

Complex Biology of CNS Diseases Continues to Hamper Development of Effective Drugs

  • Receptor-Mediated Transport

    The other major system that is used in normal mammalian physiology to enable needed molecules to cross the BBB is receptor-mediated transport (RMT). The brain uses RMT to transport proteins, peptides, and lipoproteins that are needed for brain function across the BBB. Examples of biomolecules that are transported into the brain via RMT include insulin, insulin-like growth factor (IGF), leptin, transferrin, and low-density lipoprotein (LDL).

    In RMT, molecules in the circulation may bind to specific receptors on the luminal surface of brain capillaries (i.e., the surface that interfaces with the bloodstream). Upon binding, the receptor-ligand complex is internalized into the endothelial cell by a process called receptor-mediated endocytosis. The ligand may then be transported across the abluminal membrane of the endothelial cell (i.e., the membrane that interfaces with brain tissue) into the brain. This whole process is called receptor-mediated transcytosis.

    William Pardridge, M.D., professor of medicine at  UCLA, has been exploiting RMT to develop large molecule CNS drugs that can cross the BBB. Such large molecule drugs may include peptides, recombinant proteins, monoclonal antibodies (mAbs), and small interfering RNAs (siRNAs).

    In designing such large molecule drugs, researchers use what are called molecular Trojan horses (MTHs). MTHs are either peptide or protein ligands that target RMT systems (e.g., receptor-binding sequences of insulin) or MAbs that are specific for target receptors. In designing protein drugs that can transit the BBB, researchers typically construct fusion proteins between the desired therapeutic protein and the MTH. BBB receptors that are typically targeted with MTHs include the receptors for insulin, transferrin, IGF, leptin, and LDL.

    ArmaGen has an  MTH technology that utilizes RMT to cross the BBB. The company is a spin-off of Dr. Pardridge’s laboratory. ArmaGen and the Pardridge laboratory have developed fusion proteins between mAbs to the transferrin and insulin receptors with various therapeutic proteins that cannot themselves cross the BBB. They have demonstrated that these MTH-based agents cross the BBB in animal models, including nonhuman primates.

    ArmaGen’s lead product, AGT-120, is a fusion protein between a human transferrin receptor mAb and brain-derived neurotrophic factor. It is in the pre-IND stage and is intended for treatment of stoke and neurodegenerative diseases.

    AGT-181, a fusion protein between a human insulin receptor (HIR) mAb and the enzyme alpha-L-iduronidase (IDUA), is an enzyme-replacement therapeutic for treatment of the lysosomal storage disease Hurler’s syndrome (Mucopolysaccaridosis Type 1).

    ArmaGen is also developing a product for treatment of Alzheimer’s disease. This is a trifunctional fusion antibody, which consists of moieties that bind to HIR, Abeta peptide (which makes up amyloid plaques that researchers believe causes Alzheimer’s disease), and the neonatal Fc receptor. The anti-HIR moiety serves as an MTH to enable the agent to cross the BBB, the anti-Abeta peptide moiety binds to anyloid plaque and disaggregates it, and the anti-neonatal Fc receptor moiety enables the Abeta-bound agent to exit the brain via the BBB.

    The Pardridge laboratory and ArmaGen have also developed a delivery system to enable siRNAs to cross the BBB. This agent consists of an mAb to the transferrin receptor, linked to streptavidin. This carrier is designed to bind biotinylated siRNAs (via streptavidin-biotin binding), and transfer them across the BBB.

    Another company that has been developing MTH technology is to-BBB, a spin-off of the Blood-Brain Barrier Research group of Leiden University. to-BBB’s technology platform, 2B-Trans, is based on the use of the nontoxic diphtheria toxin mimetic CRM197. CTRM197 binds to a receptor on capillaries of the BBB, which is a membrane-bound precursor of heparin-binding epidermal growth factor. This receptor is also known as the diphtheria toxin receptor (DTR). DTR is constitutively expressed on brain capillaries and in neurons and glial cells of the brain.

    to-BBB’s lead product, 2B3-101, is a liposome-encapsulated ribavirin conjugated to CRM197. It is intended as a therapeutic against Japanese encephalitis virus (JEV). 

    The Immune Disease Institute at Harvard Medical School has been developing a MTH for delivery of siRNAs to the brain. This MTH, called the CORVUS peptide, is a fusion peptide between a 29-amino acid peptide from the rabies virus glycoprotein (RVG) and a 9-amino acid peptide made up entirely of D-arginine units.

    The CORVUS peptide is designed to bind the negatively charged si-RNAs via its nona-D-arginine moiety, and to bind the receptor for the virus, the nicotinic acetylcholine receptor (nAChR). nAChR is expressed on capillaries of the BBB and on neurons of the brain. CORVUS thus serves to transport the siRNAs across the BBB and into neurons. The CORVUS MTH is in the research stage. The researchers showed that intravenously injected CORVUS complexed with an siRNA specific for the JEV envelope gene gave mice 80% protection from JEV infection.

  • Outlook

    Click Image To Enlarge +
    Figure 2

    CNS drug researchers generally agree that design and discovery of drugs that can readily cross the BBB is a major bottleneck for the development of new CNS drugs, especially those that address major unmet needs. Academic and corporate researchers have been developing technologies that enable the design of small and large molecule drugs that are actively transported across the BBB, and have demonstrated the feasibility of these technologies in animal studies.

    Nevertheless, the majority of companies developing CNS drugs continue to rely on traditional medicinal chemistry-based methods for design of small molecule drugs that cross the BBB via passive diffusion (and which are poor substrates for P-gp), or they have no specific programs on crossing the BBB at all.

    This is seen in the results of a survey carried out by Cambridge Healthtech Institute in conjunction with our recent BBB report. Despite the traditional orientation of most companies’ BBB research programs, many of them are focusing on CNS indications such as neurodegenerative diseases that are underserved by current CNS drugs, and for which drugs that cross the BBB via passive diffusion have so far been poorly applicable.

    However, the survey indicates that a substantial minority of companies are working on development of large-molecule (protein, peptide, or nucleic acid) drugs that can cross the BBB via use of MTH technology. Others are using another early-stage technology, naonparticle carriers, to enable their large molecule drugs to cross the BBB (Figure 2).

    Thus, although most companies developing CNS drugs are not applying novel technologies that enable active transport of drugs across the BBB, these technologies have begun to penetrate the industry. As these early-stage technologies prove themselves in the clinic, we expect that there will be a great interest in utilizing them, including partnering between large pharmaceutical and biotechnology companies and BBB specialty companies, and commercialization of academic research in this area. We expect that, as this occurs, those companies that are already utilizing these technologies will have an advantage over others.

    Researchers cite the BBB as a major challenge to developing novel CNS drugs, and some see the BBB as the major bottleneck in this area. However, understanding the complex biology of CNS diseases is an equally important challenge. Thus, although development of clinically proven BBB transport technologies will represent a major breakthrough, the biology of CNS diseases will still challenge CNS drug developers.


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