Delivery of Biologics Across the Blood–Brain Barrier with Molecular Trojan Horse Technology

@article{Pardridge2017DeliveryOB,
  title={Delivery of Biologics Across the Blood–Brain Barrier with Molecular Trojan Horse Technology},
  author={William M. Pardridge},
  journal={BioDrugs},
  year={2017},
  volume={31},
  pages={503-519}
}
Biologics are potential new therapeutics for many diseases of the central nervous system. Biologics include recombinant lysosomal enzymes, neurotrophins, decoy receptors, and therapeutic antibodies. These are large molecule drugs that do not cross the blood–brain barrier (BBB). All classes of biologics have been tested, without success, in clinical trials of brain disease over the last 25 years. In none of these past clinical trials was the biologic re-engineered to enable transport across the… 

Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain

TLDR
Future drug or gene development for the brain will be accelerated by future advances in BBB delivery technology in parallel with new drug discovery.

Emerging Technologies for Delivery of Biotherapeutics and Gene Therapy Across the Blood–Brain Barrier

TLDR
Emergence and refinement of core technologies of genetic engineering and editing as well as biomanufacturing of viral vectors and cell-derived products have de-risked the path to the development of systemic gene therapy approaches for the CNS.

Highly Specific Blood-Brain Barrier Transmigrating Single-Domain Antibodies Selected by an In Vivo Phage Display Screening

TLDR
In vivo screening approach allowed the selection of highly specific nano-antibody scaffolds with promising properties for brain targeting and drug delivery, and validated the brain drug delivery proof-of-concept.

Transport Mechanisms at the Blood–Brain Barrier and in Cellular Compartments of the Neurovascular Unit: Focus on CNS Delivery of Small Molecule Drugs

TLDR
The current knowledge on specific BBB transporters that either limit drug uptake into the brain or can be targeted for optimized drug delivery is reviewed, with an emphasis on transport mechanisms in these cell types that can influence drug distribution within the brain.

Brain drug delivery: overcoming the blood-brain barrier to treat tauopathies.

TLDR
This review is concentrated on summarizing the available methods and approaches for effective therapeutics delivery through BBB to treat neurodegenerative disorders with a focus on tauopathies, describing the traditional approaches but also new nanotechnology strategies emerging with new advanced medical techniques.

Novel Blood–Brain Barrier Shuttle Peptides Discovered through the Phage Display Method

TLDR
The results indicate that the peptides identified by the in vitro phage display technology could serve as transporters for the administration of biopharmaceuticals into the brain.

Brain Delivery of IGF1R5, a Single-Domain Antibody Targeting Insulin-like Growth Factor-1 Receptor

The ability of drugs and therapeutic antibodies to reach central nervous system (CNS) targets is greatly diminished by the blood–brain barrier (BBB). Receptor-mediated transcytosis (RMT), which is
...

References

SHOWING 1-10 OF 151 REFERENCES

Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier.

Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates

TLDR
It is shown that bispecific antibodies with optimized binding to the transferrin receptor (TfR) that target β-secretase (BACE1) can cross the BBB and reduce brain amyloid-β (Aβ) in mice.

Targeted delivery of protein and gene medicines through the blood–brain barrier

  • W. Pardridge
  • Biology
    Clinical pharmacology and therapeutics
  • 2015
TLDR
Certain peptidomimetic monoclonal antibodies that target endogenous receptors on the BBB, such as the insulin or transferrin receptor, enable the re‐engineering of biologic drugs that cross theBBB.

Engineering and expression of a chimeric transferrin receptor monoclonal antibody for blood–brain barrier delivery in the mouse

TLDR
The genetic engineering, expression, and validation of a chimeric TfRMAb with high activity for the mouse TfR is described, which can be used in future engineering of therapeutic fusion proteins for BBB drug delivery in the mouse.

Drug Targeting of Erythropoietin Across the Primate Blood-Brain Barrier with an IgG Molecular Trojan Horse

TLDR
A novel IgG-EPO fusion protein has been engineered, expressed, and shown to be bifunctional with retention of high-affinity binding to both the insulin and EPO receptors.

Addressing Safety Liabilities of TfR Bispecific Antibodies That Cross the Blood-Brain Barrier

TLDR
It is reported that when mice were dosed with therapeutic TfR antibodies, the animals showed acute clinical reactions and a reduction in immature red blood cells, known as reticulocytes, which suggest that the blood-brain barrier is not the only obstacle to surmount on the way to the brain, at least when using TFR as a molecular lift.
...