Monoclonal antibody exposure in rat and cynomolgus monkey cerebrospinal fluid following systemic administration.

Background: Many studies have focused on the challenges of small molecule uptake across the blood-brain barrier, whereas few in-depth studies have assessed the challenges with the uptake of antibodies into the central nervous system (CNS). In drug development, cerebrospinal fluid (CSF) sampling is routinely used as a surrogate for assessing CNS drug exposure and biomarker levels. In this report, we have studied the kinetic correlation between CSF and serum drug concentration-time profiles for five humanized monoclonal antibodies in rats and cynomolgus monkeys and analyzed factors that affect their CSF exposure.

Results: Upon intravenous (IV) bolus injection, antibodies entered the CNS slowly and reached maximum CSF concentration ( T ) in one to several days in both rats and monkeys. Antibody serum and CSF concentration-time curves converged until they became parallel after T was reached. Antibody half-lives in CSF ( t ) approximated their serum half-lives ( t ). Although the intended targets of these antibodies were different, the steady-state CSF to serum concentration ratios were similar at 0.1-0.2% in both species. Independent of antibody target and serum concentration, CSF-to-serum concentration ratios for individual monkeys ranged by up to tenfold from 0.03 to 0.3%.

Conclusion: Upon systemic administration, average antibodies CSF-to-serum concentration ratios in rats and monkeys were 0.1-0.2%. The t of the antibodies was largely determined by their long systemic t ( t ).