Biodistribution Analysis of an Anti-EGFR Antibody in the Rat Brain: Validation of CSF Microcirculation as a Viable Pathway to Circumvent the Blood-Brain Barrier for Drug Delivery

Abstract

Cerebrospinal fluid (CSF) microcirculation refers to CSF flow through brain or spinal parenchyma. CSF enters the tissue along the perivascular spaces of the penetrating arteries where it mixes with the interstitial fluid circulating through the extracellular space. The potential of harnessing CSF microcirculation for drug delivery to deep areas of the brain remains an area of controversy. This paper sheds additional light on this debate by showing that ABT-806, an EGFR-specific humanized IgG1 monoclonal antibody (mAb), reaches both the cortical and the deep subcortical layers of the rat brain following intra-cisterna magna (ICM) injection. This is significant because the molecular weight of this mAb (150 kDa) is highest among proteins reported to have penetrated deeply into the brain via the CSF route. This finding further confirms the potential of CSF circulation as a drug delivery system for a large subset of molecules offering promise for the treatment of various brain diseases with poor distribution across the blood-brain barrier (BBB). ABT-806 is the parent antibody of ABT-414, an antibody-drug conjugate (ADC) developed to engage EGFR-overexpressing glioblastoma (GBM) tumor cells. To pave the way for future efficacy studies for the treatment of GBM with an intra-CSF administered ADC consisting of a conjugate of ABT-806 (or of one of its close analogs), we verified in vivo the binding of ABT-414 to GBM tumor cells implanted in the cisterna magna and collected toxicity data from both the central nervous system (CNS) and peripheral tissues. The current study supports further exploration of harnessing CSF microcirculation as an alternative to systemic delivery to achieve higher brain tissue exposure, while reducing previously reported ocular toxicity with ABT-414.

Boron Delivery to Brain Cells via Cerebrospinal Fluid (CSF) Circulation in BNCT of Brain-Tumor-Model Rats—Ex Vivo Imaging of BPA Using MALDI Mass Spectrometry Imaging

“…We observed an increased BPA penetration of the tumor tissue after administration for 160 min (Figure 6) compared with 30 min (Figure 5). Our results are generally consistent with those of the literature (Naseri Kouzehgarani G et al) showing that antibody penetration of the brain parenchyma via the periarteriolar spaces starting within 30 min of ABT-806 administration, with additional penetration after 45 and 60 min of administration [20]. We estimated that over 60 min of drug administration is required for penetration throughout the entire brain tissue after infusion (Details were explained in Section 4.1).…”

“…For decades, CSF circulation was thought to be only useful for reaching tissues in the immediate vicinity of the CSF circulatory system [19]. Now, it is recognized that the CSF also flows through the parenchyma via a mechanism referred to as the CSF microcirculation [20]. In recent years, researchers have focused on CSF circulation, instead of blood circulation, for drug delivery to the brain [21][22][23].…”

Brain-Targeted Drug Delivery

“…They show vastly greater and deeper penetration of the monoclonal antibody (mAb) into the brain parenchyma after CSF administration compared to IV administration. The authors demonstrate that circumventing the BBB via CSF microcirculation might be a strategy to improve the delivery of mAbs into the brain, achieving deep penetration of IgG-size biologics [1].…”