Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/ijms22126442
Keywords
blood-brain barrier; antibody; pharmacokinetics; disposition; biochemical and physicochemical properties; Fc binding; receptor-mediated transcytosis; brain shuttle; molecular Trojan horse; transferrin
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Monoclonal antibodies have high specificity and are being investigated for drug delivery to the CNS for neurological disease treatment, with the main challenge being the presence of the blood-brain barrier limiting drug uptake into the brain. Current research focuses on improving the physicochemical and biochemical properties of antibodies to enhance their uptake in the brain.
Due to their high specificity, monoclonal antibodies have been widely investigated for their application in drug delivery to the central nervous system (CNS) for the treatment of neurological diseases such as stroke, Alzheimer's, and Parkinson's disease. Research in the past few decades has revealed that one of the biggest challenges in the development of antibodies for drug delivery to the CNS is the presence of blood-brain barrier (BBB), which acts to restrict drug delivery and contributes to the limited uptake (0.1-0.2% of injected dose) of circulating antibodies into the brain. This article reviews the various methods currently used for antibody delivery to the CNS at the preclinical stage of development and the underlying mechanisms of BBB penetration. It also describes efforts to improve or modulate the physicochemical and biochemical properties of antibodies (e.g., charge, Fc receptor binding affinity, and target affinity), to adapt their pharmacokinetics (PK), and to influence their distribution and disposition into the brain. Finally, a distinction is made between approaches that seek to modify BBB permeability and those that use a physiological approach or antibody engineering to increase uptake in the CNS. Although there are currently inherent difficulties in developing safe and efficacious antibodies that will cross the BBB, the future prospects of brain-targeted delivery of antibody-based agents are believed to be excellent.
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