Background uptake of monoclonal antibodies in the brain

Abstract

Introduction
Monoclonal antibodies (mAbs) are increasinglyused in neuro-oncology and neurodegenerative disease. Despite their growingclinical relevance, their ability to penetrate the brain remains poorlyunderstood due to the restrictive nature of the blood–brain barrier (BBB).Positron Emission Tomography (PET) imaging with Zirconium-89 (⁸⁹Zr)-labeledmAbs allows quantification of antibody uptake in organs and tumors. This studyquantifies the baseline, non-specific uptake of ⁸⁹Zr-labeled mAbs inbrain tissue and examines the impact of target expression, BBB disruption,lesion viability, and dosing.

Methods
Retrospective Positron EmissionTomography/Computed Tomography (PET/CT) data from three clinical trials with ⁸⁹Zr-labeledmAbs were analyzed. Ki values, representing irreversible tracer uptake, werederived using Patlak analysis from scans ≥1-day post-injection. Brain tissueand metastases were delineated manually, and Ki values were compared acrosscohorts with no target expression, target expression, and brain metastases.Interobserver reliability was assessed, and statistical comparisons wereperformed using Kruskal–Wallis and Wilcoxon tests.

Results
Uptake in normal brain tissue was assessed in18 patients, two of whom had post-treatment brain metastases that were includedin the analysis. Ki in target-negative brain tissue was low but measurable,indicating baseline non-specific uptake. Ki was significantly higher intarget-positive brain tissue, and substantially elevated in post-treatmentbrain metastases. Notably, uptake was particularly high in posttreatmentlesions with viable tumor tissue (n=2), compared to post-treatment lesions withtherapy-related imaging changes. In a subset of five patients with twoinjections with different doses of non-labeled mAb, three showed decreased Kiat higher mass doses.

Conclusion
Irreversible brain uptake of mAbs can be quantified using Patlak-derived Kivalues, even at low levels. This establish a baseline for non-specific brainuptake. Uptake is higher with target expression and even higher in brainmetastases, likely due to BBB disruption. These findings support the use of PETimaging with Patlak analysis as a noninvasive method to evaluate CNS targetengagement and drug delivery in early-phase clinical trials.