Brain Disposition of Antibody-Based Therapeutics: Dogma, Approaches and Perspectives

Abstract

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.

Drug delivery for neuronopathic lysosomal storage diseases: evolving roles of the blood brain barrier and cerebrospinal fluid

“…Because CSF flow in and out of the brain is highly regulated (Kouhi et al 2021), appropriate distribution of enzymes administered via IT, ICV, or ICM routes needs to be ensured to enable and sustain effective therapeutic concentrations. Indeed, drugs injected into the CSF compartment are known to be rapidly transported out of the brain into the blood, while drug penetration into the brain parenchyma from the CSF is considered minimal (Pardridge 2011).…”

Effect of Monoclonal Antibody Blockade of Long Fragment Neurotensin on Weight Loss, Behavior, and Metabolic Traits After High-Fat Diet Induced Obesity

“…This finding was confirmed by the previous experiments showing that LF NTS mAb induced an increase of weight in mice maintained on chow diet (26), and by the prevention of cachexia induced by cancer by LF NTS mAb (patent PCT/EP2019/073991). Together these observations suggest that LF NTS acts independently of the mature peptide and preferentially in the periphery, since it is admitted that only 0.1% of injected mAb cross the blood-brain barrier (35). As LF NTS mAb was efficient under diverse physiological and pathological circumstances, suggests that LF NTS effects are independent of the obesity process per se.…”

“…It is unlikely that LF NTS polypeptides cross the blood-brain barrier and reach the synaptic cleft involved in the neurotensinergic transmission. It is also reasonable to hypothesize that the antibody does not cross the blood brain barrier either (35). A possible alternative explanation of the observed impact of LF NTS and mAb LF NTS on the behavioral tests might be interference with peripheral neurocrine or hormonal neurotensinergic regulation.…”

Treatment of Neuronopathic Mucopolysaccharidoses with Blood–Brain Barrier-Crossing Enzymes: Clinical Application of Receptor-Mediated Transcytosis

“…This application has become possible thanks to the evolving understanding of intracellular trafficking, receptor binding, and protein engineering [28]. RMT is considered very suitable for application to pharmacotherapy [29] due to the innate physiological mechanism of the BBB that makes abundant receptors available, in addition to which, the very small inter-capillary distances in the brain allow each neuron to be perfused by the blood vessels surrounding it, making it ready to receive the trafficked substance [30]. Moreover, RMT allows highly specific trafficking of the targeted substance to which specific antibodies are fused.…”