Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013:2013:703545.
doi: 10.1155/2013/703545. Epub 2013 Jun 11.

Receptor-mediated endocytosis and brain delivery of therapeutic biologics

Guangqing Xiao  1 , Liang-Shang Gan
Affiliations

Receptor-mediated endocytosis and brain delivery of therapeutic biologics

Guangqing Xiao et al. Int J Cell Biol. 2013.

Abstract

Transport of macromolecules across the blood-brain-barrier (BBB) requires both specific and nonspecific interactions between macromolecules and proteins/receptors expressed on the luminal and/or the abluminal surfaces of the brain capillary endothelial cells. Endocytosis and transcytosis play important roles in the distribution of macromolecules. Due to the tight junction of BBB, brain delivery of traditional therapeutic proteins with large molecular weight is generally not possible. There are multiple pathways through which macromolecules can be taken up into cells through both specific and nonspecific interactions with proteins/receptors on the cell surface. This review is focused on the current knowledge of receptor-mediated endocytosis/transcytosis and brain delivery using the Angiopep-2-conjugated system and the molecular Trojan horses. In addition, the role of neonatal Fc receptor (FcRn) in regulating the efflux of Immunoglobulin G (IgG) from brain to blood, and approaches to improve the pharmacokinetics of therapeutic biologics by generating Fc fusion proteins, and increasing the pH dependent binding affinity between Fc and FcRn, are discussed.

PubMed Disclaimer

Figures

Figure 1
Figure 1
The cTfRMAb-ScFv fusion protein is formed by fusion of the variable region of the heavy chain (VH) of the rat 8D3 MAb against the mouse transferrin receptor (mTfR) (yellow) to the amino terminus of mouse IgG1 constant (C) region (green), and fusion of a single chain Fv (ScFv) antibody against the A amyloid peptide to the carboxyl terminus of the heavy chain C-region. The light chain is composed of the variable region of the light chain (VL) of the rat 8D3 MAb (light blue) and the mouse kappa light chain C-region (CL) (dark red). The heavy chain constant region is composed of 4 domains: CH1, hinge, CH2, and CH3. The CH2-CH3 interface is the binding site for the neonatal Fc receptor (FcRn). The ScFv is composed of the VH (dark blue) and the VL (light red) derived from the anti-AMAb (adapted from Figure 1, [52]).
Figure 2
Figure 2
Ratio of the organ PS product for the HIRMAb-TNFR fusion protein, over the organ PS product for the TNFR:Fc fusion protein, is plotted for each organ. The ratio for brain is the mean of the values for frontal gray matter, frontal white matter, cerebellar gray matter, and cerebellar white matter, which varied between 22 and 37 (adapted and modified from Figure 8, [61]).
Figure 3
Figure 3
(a) Polarized transmigration of FC5 across HCEC monolayers. Transport studies were initiated by adding 10 μg/mL FC5 to either apical (A to B) or basolateral (B to A) compartment and the amount of FC5 in the opposite compartment was determined after 30 min. (b) [14C] Sucrose distribution across the same HCEC monolayers was used as internal control for paracellular transport (adapted and modified from Figure 1, [69]).
Figure 4
Figure 4
Clearance of intravenously injected 125I-labelled mouse IgG1 and chicken IgY antibodies in mice with and without β2-microglobulin. Mouse IgG1, solid line; chicken IgY, broken line; β2-microglobulin +/+, circles; β2-microglobulin +/−, triangles; β2-microglobulin +/−, diamonds; n = 5 for each group (adapted from Figure 1, [90]).
Figure 5
Figure 5
PK profile of OST577-IgG1 WT and mutant Abs following intravenous injection to rhesus monkeys. The concentration of OST577-IgG1 Abs in rhesus serum was measured in a validated ELISA using the mouse anti-OST577 anti-Id mAb for capture and the HRP-conjugated goat anti-human λ L chain Ab for detection (adapted and modified from Figure 2, [99]).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Blumling JP, III, Silva GA. Targeting the brain: advances in drug delivery. Current Pharmaceutical Biotechnology. 2012;13:2417–2426. - PubMed
    1. Gabathuler R. Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases. Neurobiology of Disease. 2010;37(1):48–57. - PubMed
    1. Demeule M, Currie J, Bertrand Y, et al. Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector Angiopep-2. Journal of Neurochemistry. 2008;106(4):1534–1544. - PubMed
    1. Demeule M, Regina A, Ché C, et al. Identification and design of peptides as a new drug delivery system for the brain. Journal of Pharmacology and Experimental Therapeutics. 2008;324(3):1064–1072. - PubMed
    1. Guo J, Gao X, Su L, et al. Aptamer-functionalized PEG-PLGA nanoparticles for enhanced anti-glioma drug delivery. Biomaterials. 2011;32(31):8010–8020. - PubMed