Widespread brain distribution and activity following i.c.v. infusion of anti‐β‐secretase (BACE1) in nonhuman primates

Abstract

Background and Purpose The potential for therapeutic antibody treatment of neurological diseases is limited by poor penetration across the blood–brain barrier. I.c.v. delivery is a promising route to the brain; however, it is unclear how efficiently antibodies delivered i.c.v. penetrate the cerebrospinal spinal fluid (CSF)‐brain barrier and distribute throughout the brain parenchyma. Experimental Approach We evaluated the pharmacokinetics and pharmacodynamics of an inhibitory monoclonal antibody against β‐secretase 1 (anti‐BACE1) following continuous infusion into the left lateral ventricle of healthy adult cynomolgus monkeys. Key Results Animals infused with anti‐BACE1 i.c.v. showed a robust and sustained reduction (~70%) of CSF amyloid‐β (Aβ) peptides. Antibody distribution was near uniform across the brain parenchyma, ranging from 20 to 40 nM, resulting in a ~50% reduction of Aβ in the cortical parenchyma. In contrast, animals administered anti‐BACE1 i.v. showed no significant change in CSF or cortical Aβ levels and had a low (~0.6 nM) antibody concentration in the brain. Conclusion and Implications I.c.v. administration of anti‐BACE1 resulted in enhanced BACE1 target engagement and inhibition, with a corresponding dramatic reduction in CNS Aβ concentrations, due to enhanced brain exposure to antibody.

Tissue Physiology of Cynomolgus Monkeys: Cross-Species Comparison and Implications for Translational Pharmacology

“…2). The observed 5-10-fold discrepancy is consistent with previous reports of brain antibody concentrations reaching only 0.01-0.02% of steadystate serum concentrations in cynomolgus monkeys [66,67], in contrast with reports of 0.1% in mice [68]. Although it is possible that these interspecies differences in apparent antibody BBB permeability could be due to differences in binding affinity of the antibody Fc region for the neonatal Fc receptor, our results here suggest that more fundamental differences in BBB permeability may exist between species since we used a non-FcRn-binding small molecule probe ( 111 In-DTPA) to measure K p .…”

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

“…Thus, continuous 24/7 ICV infusion for 42 days would enable diffusion alone to cover most of the primate brain. • The distribution of the MAb in the brain was detected with immunocytochemistry, which showed the MAb did not penetrate the white matter of the brain (Yadav et al, 2017). However, perivascular flow in the brain occurs in white matter (Hladky and Barrand, 2014).…”

“…Prediction on the brain/plasma ratio of therapeutic antibodies should be made on the basis of antibody concentrations in brain tissue, not CSF, following IV administration. The concentration of a therapeutic antibody was measured in primate brain tissue after saline clearance of the brain blood volume, and the average brain antibody concentration was 1 nM after an IV infusion of the anti-BACE1 antibody at an ID of 50 mg/kg (Yadav et al, 2017). However, 1 nM is probably an over-estimate of the MAb concentration in brain after IV infusion, and more likely reflects residual MAb still trapped in the plasma volume of the brain.…”

Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development

“…Another important application of bsAbs is to deliver mAbs to areas generally thought to be restricted to antibodies. For example, mAbs exhibit limited distribution to the brain, and mAb concentrations was determined to be 0.1–0.2 % and 0.02 % of the steady‐state circulating mAb concentration in rodents and cynomolgus monkey, respectively . To overcome this limitation, a transferrin receptor (TfR) and β‐secretase 1 (BACE1) bsAbs was generated.…”

“…For example, mAbs exhibit limited distribution to the brain, and mAb concentrations was determined to be 0.1-0.2 % and 0.02 % of the steady-state circulating mAb concentration in rodents and cynomolgus monkey, respectively. 92,93 To overcome this limitation, a transferrin receptor (TfR) and β-secretase 1 (BACE1) bsAbs was generated. By targeting TfR, a transcytosis efficient membrane protein expressed on endothelial cells in brain, these bsAb constructs drastically improved CNS delivery in both rodents and NHPs.…”