Therapeutic monoclonal antibodies in the central nervous system: Pharmacokinetics, bioanalysis and clinical...

Therapeutic monoclonal antibodies (mAbs) hold major promise as precision diagnostics and disease-modifying agents for central nervous system (CNS) disorders, yet their translation is constrained by limited permeability across the blood brain and blood cerebrospinal fluid barriers. Cerebrospinal fluid (CSF) mAb pharmacokinetics (PK) provides critical insight into barrier penetration, target engagement, and exposure-response relationships. This review integrates current understanding of physiological determinants of CNS mAb distribution with emerging bioanalytical technologies that enable sensitive, reproducible quantitation in low-protein, low-volume matrices such as CSF. Advances including electrochemiluminescence, single-molecule arrays, and hybrid LC-MS/MS now achieve pg/mL detection, supporting PK profiling and characterization of antibody-antigen complexes. We assess physiologically based and target-mediated drug disposition models for interspecies scaling, prediction of CNS penetration under pathological conditions, and optimization of intravenous (IV) versus intrathecal (IT) dosing. Clinical PK data from natalizumab, rituximab, and anti-Aβ antibodies illustrate how CSF measurements inform therapeutic engagement, biomarker-guided dosing, and monitoring of neuroinflammatory risk. Emerging bispecific brain-shuttle platforms and receptor-mediated transcytosis strategies may overcome historical delivery barriers but require rigorous human PK validation. Remaining challenges include mapping regional CNS exposure, quantifying disease-altered barrier function, and standardizing CSF bioanalytics. Progress will depend on integrating barrier physiology, ultrasensitive measurement, mechanistic modeling, and translational pharmacology.