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.

Keywords: Fc binding; antibody; biochemical and physicochemical properties; blood–brain barrier; brain shuttle; disposition; molecular Trojan horse; pharmacokinetics; receptor-mediated transcytosis; transferrin.

Figure 1

A schematic depiction of the various engineering optimization strategies for increased transcytosis of antibodies and nanoparticles (NPs) across the BBB. High-affinity monovalent and bivalent anti-TfR antibodies internalize readily into the early endosome (EE) but then direct the antibody–receptor complex toward lysosomal degradation, possibly by crosslinking the TfR and altering its intracellular trafficking. While high-affinity monovalent anti-TfR antibodies can transcytose the BBB, they remain bound to the receptor on the abluminal side, limiting the dose to the brain. In contrast, low-affinity anti-TfR antibodies decrease antibody-TfR sorting to the lysosome and can either be recycled back to the luminal side or are transcytosed to the abluminal side where they dissociate from TfR, leading to increased brain accumulation. Similarly, Tf-coated nanoparticles show a higher transcytosis capability when lowering the Tf coating content, resulting in reduced avidity. Further, pH-sensitive TfR-binding antibodies that can dissociate from TfR in the acidic EE lead to increased transcytosis compared with pH-insensitive antibodies. In the case of the single domain antibody FC5, increased affinity toward the receptor leads to an increase in the amount of transcytosed antibody, highlighting the fact that vectors utilizing different trafficking machinery may require customized optimization. This figure is reproduced from Goulatis and Shusta (2017) with permission of the copyright owner [7].

Figure 2

Lower-affinity anti-TfR^D antibodies (A > D) at therapeutic doses show increased brain uptake. This figure is reproduced from Yu et al. (2013) with permission of the copyright owner [58].

Figure 3

Sagittal PET images obtained at 3 days after administration of the bispecific antibody radiolabeled with I-124 in two transgenic mouse models of AD (ArcSwe and Swe) and wild-type (WT) mice at different ages (12, 18, and 24 months). Quantification of the radiolabeled antibody in brain tissue showed an increasing signal intensity with age (i.e., with increasing Aβ pathology) in the two transgenic AD animal models, while brains of WT mice were devoid of signal regardless of age. This figure is reproduced from Sehlin and Syvänen (2019) with permission of the copyright owner [73].